PMID- 30303569 TI - Accuracy of grading pancreatic neuroendocrine neoplasms with Ki-67 index in fine needle aspiration cellblock material. AB - OBJECTIVE: The aim of this study was to assess the preoperative tumour grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki-67 index in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) material and to correlate the preoperative tumour grade with the postoperative tumour grade in surgical specimens. METHODS: We performed a retrospective review of the institutional pathology database over a 10-year period (2007-2017) to identify all cases of panNENs with corresponding preoperative EUS-FNA cytological material and surgical specimens. Fifteen cases with adequate EUS-FNA material (more than 400 tumour cells on cellblock) were identified. The cytological and histological samples were graded based on the mitotic rate and the Ki-67 index in accordance with the 2017 World Health Organisation grading system for panNENs. The tumour grades determined on EUS-FNA cellblock material were compared with the histological tumour grades. RESULTS: Mean age at diagnosis was 64.8 +/- 12.7 years (range, 38-85 years). The grading scores assigned to the cytological and histological samples were concordant in all 15 (100%) cases. Of those, two (13%) cases were scored as grade 1, nine (60%) cases as grade 2 and four (27%) cases as grade 3 tumours. CONCLUSION: Our study shows that tumour grade in patients with PanNENs can be reliably determined by assessing the Ki-67 index in EUS-FNA specimens based on the 2017 World Health Organisation classification and grading system. PMID- 30303570 TI - Bioelectrical Impedance Phase Angle and Morbidity and Mortality in Critically Ill Children. AB - BACKGROUND: Nutrition markers may be useful for diagnosis and monitoring and, also, as additional indicators of estimating death risk. We tested the association of body composition indicators (mid-upper arm circumference and phase angle) with pediatric intensive care unit (PICU) length of stay and mortality in critically ill pediatric patients. METHODS: Data from children aged 2 months-18 years were collected, and bioelectrical impedance was performed to obtain phase angle. Severity was evaluated by scoring the Pediatric Index of Mortality. Descriptive statistics were reported for nominal variables. Receiver operating characteristic curve was used to analyze the association of phase angle with 30 day mortality and to find the best cutoff. Survival probabilities and PICU length of stay were estimated using the Kaplan-Meier method. RESULTS: We evaluated 247 children with a median age of 4.8 years whose main cause of admission was sepsis. Survival curves showed higher survival in patients with phase angle >2.8 degrees compared with patients with phase angle <=2.8 degrees (P < .0001). Kaplan-Meier time-to-event analysis showed that children with lower phase angle values were more likely to remain in the PICU (hazard ratio, 1.84; P = .003). Lower survival was also observed in patients who presented mid-upper arm circumference values <=5th percentile (P < .03). CONCLUSIONS: Mid-upper arm circumference and phase angle were associated with mortality and morbidity in critically ill children, suggesting that these parameters may be useful not only for nutrition diagnosis and monitoring, but also as an additional indicator in estimating prognosis. PMID- 30303571 TI - Interfacial Solar Steam Generation Enables Fast-Responsive, Energy-Efficient, and Low-Cost Off-Grid Sterilization. AB - Steam sterilization is widely used as one of the most reliable sterilization methods for public health. However, traditional steam sterilization mainly relies on electricity, a constrained resource for many developing countries and areas. The lack of available and affordable sterilization techniques in these areas is exposing human beings to a high risk of various epidemic diseases, and calls for the development of off-grid sterilization solutions. For the first time, the kinetic advantages of interfacial solar steam generation is fundamentally revealed and it is demonstrated that interfacial solar steam generation can enable fast-responsive (as short as 8.4 min for a full sterilization cycle) and energy-efficient (100 J mL-1 for steam reaching 121 degrees C) sterilization, superior to those of the conventional sterilization techniques. The key solar absorber is made of low cost and widely available biochar. A proof-of-concept sterilization system with a 10.5 L solar autoclave is built with very low cost of whole life-cycle and operates with minimum carbon footprint. Effective sterilization (~99.999999% inactivation of pathogen), exceeding the requirements of Food and Drug Administration is demonstrated, making the sterilization strategy a promising and complementary personalized sterilization solution, particularly beneficial for off-grid areas. PMID- 30303572 TI - Unravelling the Twin and Tunability of the Crystal Domain Sizes in the Medium Pore Zeolite ZSM-57 by Electron Crystallography. AB - Tailoring the morphology of the specific crystalline material through distinct crystal growth mechanisms (classical and nonclassical) is challenging. Herein, we report two unique morphologies of a medium pore (10 * 8-ring) zeolite ZSM-57 by employing the identical organic structure-directing agent (OSDA) and different inorganic cations such as Na+ and K+, denoted as ZSM-57-Na (pentagonal nano plate) and ZSM-57-K (pentagonal nano-prism), respectively. The tunable twin domain size and twin boundaries in both samples are unravelled at the atomic level by electron crystallography. It is of significance to note that the 10-ring pore openings run perpendicular to pentagonal nano-plate and nanoprism. Moreover, the distinct crystal growth mechanisms, resulting in the different unique morphologies and tunable twin domains, are further determined by electron crystallography combined with other techniques. Nonclassical growth involving the aggregation of amorphous aluminosilicate nanoparticles to the smooth ZSM-57-Na crystal surface dominates the ZSM-57-Na crystallization process. For the ZSM-57-K sample, the classical layer by layer growth via the addition of silica molecules to advancing steps on the crystal surface dominates the ZSM-57-K crystallization process. The different morphologies of both samples result in the distinct catalytic lifespan of the methanol conversion and selectivity of lower olefins. PMID- 30303573 TI - The change in position of the axillary nerve with rotation of the arm. AB - The axillary nerve is the most commonly injured nerve around the arm. In the deltopectoral approach, classical teaching states that lateral rotation of the humerus increases the distance between the subscapularis and the axillary nerve. This is the first anatomical study to quantify the distance change between the axillary nerve and subscapularis produced by arm rotation. Eight arms were placed in the supine position and a classical deltopectoral approach was performed. With digital calipers, measurements were made from the closest identifiable margin of the nerve to the inferior extent of the tenotomy. All measurements were made with the arm in 0 degrees abduction and elbow in 90 degrees of flexion, and repeated with the arm in 45 degrees of medial rotation, 0 degrees lateral rotation and 45 degrees of lateral rotation. The mean d Axillary Nerve to subscapularis was recorded as 30.9 mm (95% CI:25.3-36.3), 39.4 mm(95% CI:34.1-44.8), and 46.1 mm (95% CI:41.1-51.2) for 45 degrees MR, 0 degrees , and 45 degrees LR, respectively. Using paired-samples T-testing, the mean change in distance when moving from 45 degrees MR to 0 degrees was +8.5 mm (P < 0.0001), and from 0 degrees to LR 45 degrees , +6.7 mm (P < 0.0001). There is a significant difference in the distance between the subscapularis tenotomy and the axillary nerve with medial and lateral rotation. Laterally rotating the arm increased the distance by 6.7 mm, reaffirming that positioning the glenohumeral joint in a position of LR during subscapular tenotomy is protective against iatrogenic injury of the axillary nerve. Clin. Anat., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30303575 TI - B-B Coupling and B-B Catenation: Computational Study of the Structure and Reactions of Metal-Bis(borylene) Complexes. AB - A detailed molecular orbital analysis of the metal-bis(borylene) complex [Fe(CO)3 {B(Dur)B(N(SiMe3 )2 )}] (Dur=2,3,5,6-tetramethylphenyl) (1 a) serves as a focal point of recent developments in this area of chemistry, such as B-B coupling and B-B catenation reactions. There is strong a pi delocalization between the Fe(CO)3 and (B-Dur)(B-N(SiMe3 )2 ) units; the short B-B distance in 1 a is due to this pi delocalization. The pi-donor ligand N(SiMe3 )2 on the boron provides a decisive stability to the complex 1 a. The LUMO of 1 a has B-B sigma-bonding character. Hence B-B coupling is facilitated by filling the LUMO. Strong sigma-donating ligands, such as PMe3 or PCy3 , induce B-B coupling. Expulsion of one CO from 1 a followed by dimerization leads to [Fe(CO)2 {B(Dur)B(N(SiMe3 )2 )}]2 (3 a) with a short Fe-Fe distance of 2.355 A. A detailed mechanism for the reaction of 3 a with CO to give the B-B catenation product 2 f is presented. The bonding of all intermediates is compared to their isolobal main-group analogues. PMID- 30303576 TI - A tetratricopeptide repeat domain protein has profound effects on assembly of periplasmic flagella, morphology and motility of the lyme disease spirochete Borrelia burgdorferi. AB - Spirochetes possess a unique periplasmic flagellar motor component called the collar. However, little is known about the composition or function of the flagellar collar proteins. To identify a collar protein, we have inactivated almost all genes annotated as motility-related in the Borrelia burgdorferi genome and identified only FlbB, which comprises the base of the collar. Since the major components of the collar complex remained unidentified, we took advantage of a protein-protein interaction map developed in another spirochete, Treponema pallidum to identify proteins of unknown function that could be collar proteins. Subsequently, using various comprehensive approaches, we identified a tetratricopeptide repeat protein BB0236 as a potential candidate for the collar. Biochemical assays indicated that FlbB interacts with BB0236. Furthermore, ?bb0236 mutant analyses indicated that BB0236 is crucial for collar structure assembly, cellular morphology, motility, orientation of periplasmic flagella and assembly of other flagellar structures. Moreover, using comparative motor analyses, we propose how the collar structure is assembled in B. burgdorferi. Together, our studies provide new insights into the organization and the complex assembly inherent to the unique spirochetal collar structure. PMID- 30303577 TI - Sequential Templating Approach: A Groundbreaking Strategy to Create Hollow Multishelled Structures. AB - Thanks to their distinguished properties such as optimized specific surface area, low density, high loading capacity, and sequential matter transfer and storage, hollow multishelled structures (HoMSs) have attracted great interest from scientists in broad fields, including catalysis, drug delivery, solar cells, supercapacitors, lithium-ion batteries, electromagnetic wave absorption, and sensors. However, traditional synthesis methods such as soft-templating and hierarchical self-assembly methods can hardly realize the controllable synthesis of HoMSs, thus limiting their development and application. Here, the development process of HoMSs is first succinctly reviewed and the shortcomings of the traditional synthesis method are concluded. Subsequently, the sequential templating approach, which shows great generality for the synthesis of HoMSs with controllable composition and geometry configuration and exhibits remarkable effect on the scientific research field, is introduced. The basic material science and chemical reaction mechanism involved in the synthesis and manipulation of HoMSs using the sequential templating approach are then explained in detail. In addition, the effect of the geometric characteristics of HoMSs on their application properties is highlighted. Finally, the current challenges and future research directions of HoMSs are also suggested. PMID- 30303578 TI - Epithelial-mesenchymal transition and cancer stem cells: at the crossroads of differentiation and dedifferentiation. AB - In this review, we explore the connections between epithelial-mesenchymal transition (EMT) and differentiation status. EMTs in development have been described as differentiation events, while in most cases EMTs in cancer have been depicted as dedifferentiation events. We will briefly summarize both embryo development and cancer progression with regard to the involvement of EMT and cell differentiation status. We further present the studies that provide evidence that EMT results in both differentiation and dedifferentiation. Finally, we present our resolution to this dilemma by suggesting that EMT brings about dedifferentiation that enables subsequent differentiation. In normal development, EMT events may cause a partial reversal of differentiation to overcome differentiation barriers. When EMT is aberrantly activated in cancer, cells gain attributes of stem cells that contribute to self-renewal capabilities, and are able to differentiate to all cell types represented in the tumor. The resulting cancer stem cells attain hallmarks of cancer including replicative immortality, resistance to cell death, and invasiveness. This article is protected by copyright. All rights reserved. PMID- 30303579 TI - Lysine propionylation modulates the transcriptional activity of phosphate regulator PhoP in Saccharopolyspora erythraea. AB - Phosphate concentration extensively modulates the central physiological processes mediated by the two-component system PhoR-PhoP in actinobacteria. The system serves a role beyond phosphate metabolism, mediating crucial functions in nitrogen and carbon metabolism, and secondary metabolism in response to the nutritional states. Here, we found that the phosphate-sensing regulator PhoP was propionylated, and thus lost its DNA-binding activity in vivo and in vitro in Saccharopolyspora erythraea. Two key conserved lysine residues 198 and 203 (K198 and K203) in winged HTH motif at the C-terminal domain of PhoP are propionylated by protein acyltransferase AcuA (encoding by sace_5148). Single amino acid mutation of these two lysine residues resulted in severely impaired binding of PhoP to PHO box. The addition of propionate (to supply precursors for erythromycin biosynthesis) increases the intracellular propionylation level of PhoP, resulting in the loss of response to phosphate availability. Furthermore, simultaneous mutation of K198 and K203 of PhoP to arginine, mimicking the non propionylated form, promotes the expression of the PhoP regulon under the condition of propionate addition. Together, these findings present a common regulatory mechanism of genes' expression mediated by posttranslational regulation of OmpR family transcriptional regulator PhoP and provide new insights into the multifaceted regulation of metabolism in response to nutritional signals. PMID- 30303580 TI - Prevalence and social and health determinants of pre-diabetes and diabetes among adults in Laos: a cross-sectional national population-based survey, 2013. AB - OBJECTIVE: Diabetes is a major and fast-growing public health problem in Southeast Asia. We determined the prevalence of pre-diabetes and diabetes and assessed the levels of awareness, treatment and control in Lao People's Democratic Republic (PDR). METHODS: A national cross-sectional study based on a stratified cluster random sampling was conducted in 2013. The sample comprised 2492 individuals aged 18-64 years (59.3% females; mean age 38.7 years, SD = 12.8) from Lao PDR. We followed the WHO STEPS method: step 1, questionnaire interview; step 2, anthropometric and Blood Pressure (BP) measurements; and step 3, biochemistry tests. Multinominal logistic regression was used to investigate the determinants of pre-diabetes and diabetes (fasting plasma glucose levels >= 7.0 mmol/L; or using insulin or oral hypoglycaemic drugs; or having a history of diagnosis of diabetes). RESULTS: 5.7% of the population had diabetes, 4.7% of men and 6.4% of women, and 2.3% had pre-diabetes, 1.8% of men and 2.6% of women. Only 14.1% of the population sample indicated that they had ever their blood glucose measured by a health-care worker. This was higher in urban (20.9%) than rural (10.9%) dwellers (P < 0.001), and among female (16.6%) than male (10.5%) participants (P < 0.001). Among those with diabetes, 58.1% were aware of their diabetes status, 40.3% were taking treatment and 10.9% had controlled diabetes. The factor independently associated with impaired fasting glycaemia (IFG) or pre diabetes was central obesity (Adjusted Relative Risk Ratio-ARRR: 3.92, Confidence Interval-CI: 1.89, 8.14) but none of the other health (general body weight, fruit and vegetable consumption, physical activity, substance use, hypertension and cholesterol) and sociodemographic (age, sex, education, employment status, marital status, ethno-linguistic group and residence status) variables. Factors independently associated with diabetes were older age (ARRR: 5.12, CI: 1.55, 10.20), central obesity (ARRR: 2.15, CI: 1.16, 4.00), low or moderate physical activity (ARRR: 0.75, CI: 0.60, 0.93), having hypertension (ARRR: 1.68, CI: 1.01, 2.83), and dyslipidaemia (ARRR: 1.75, CI: 1.08, 2.81). CONCLUSION: A public health response is needed in the form of integrated and comprehensive action targeting major non-communicable diseases in the country. PMID- 30303581 TI - CEComparison of allogeneic and autogenous bone grafts for augmentation of alveolar ridge defects-A 12-month retrospective radiographic evaluation. AB - OBJECTIVES: The aim of this study was to compare three-dimensional alterations following the use of autogenous versus allogeneic onlay grafts for augmentation at single tooth defects. MATERIALS AND METHODS: Alveolar bone width at specific implant sites were assessed using sagittal and cross-sectional CBCT images prior grafting and at three subsequent time points. Twenty-one patients received autogenous bone blocks harvested from the retromolar region and another 21 patients received freeze-dried cancellous allogeneic bone blocks. RESULTS: The vertical and horizontal dimensions did not significantly differ between autogenous and allogeneic bone grafts at any time point. In addition, there were no statistically significant differences in graft remodeling rates between autogenous (mean shrinkage rate after 12 months: 12.5% +/- 7.8%) and allogeneic onlay grafts (mean shrinkage rate after 12 months: 14.4% +/- 9.8%). CONCLUSIONS: Freeze-dried cancellous allogeneic bone blocks showed equivalent volumetric shrinkage rates as autogenous bone blocks when used for treating circumscribed bone defects classified as Type-II to Type-IV according to the ITI-treatment guide categories. Therefore, it is not necessary to over-contour the alveolar ridge when using allogeneic blocks for treating single tooth defects, but to apply the same procedure as when using autogenous blocks. PMID- 30303582 TI - Effect of additional polishing methods on the physical surface properties of different nanocomposites: SEM and AFM study. AB - This evaluated the arrangement of filler particles in depth of nanocomposites, and surface roughness, wettability, microtopography, and micromorphology following additional polishing step. Forty samples of each composite tested [Filtek Z350XT (FZ), IPS Empress Direct (IP)] were fabricated and finished/polished/additionally polished using one of the following methods (n = 10/group): no finishing/polishing (NFP), Sof-Lex Pop-On + no additional polishing (SP), Sof-Lex Pop-On + Astropol rubber polisher (SP+A), and Sof-Lex Pop-On + felt disc with polishing paste (SP+FP). Surface roughness (Ra) and contact angles were measured using a profilometer and goniometer, respectively. Microtopography and micromorphology were evaluated using atomic force microscopy and scanning electron microscopy, respectively. Ra and contact angle data were examined by two way analysis of variance and Tukey's test (p < .05). Organic matrix, lower and larger filler particles were disposed in depth. Mean Ra values were lowest and contact angles were smallest in the NFP group for both composite resins. SP+A and SP+FP decreased mean Ra in comparison with SP for FZ, whereas only SP+FP decreased mean Ra in comparison with SP for IP. Only SP+FP increased contact angles in comparison with SP for FZ, whereas contact angles in the SP+A, SP+FP, and SP groups were similar for FZ. Both composites presented more uniform topography and smother surfaces following SP+A and SP+FP in comparison with SP. Therefore, additional polishing improved surface smoothness and decreased wettability of the composite resins studied. SP+FP produced smoother and less wettable surfaces for FZ and IP. PMID- 30303583 TI - From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability. PMID- 30303584 TI - Deep Brain Stimulation for Chronic Cluster Headache: A Review. AB - OBJECTIVES: Cluster headaches are a set of episodic and chronic pain syndromes that are sources of significant morbidity for patients. The standard of care for cluster headaches remains medication therapy, however a minority of patients will remain refractory to treatment despite changes to dosage and therapeutic combinations. In these patients, functional neuromodulation using Deep Brain Stimulation (DBS) presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain. MATERIAL AND METHODS: We review the literature on chronic cluster headache, including the growing number of DBS case reports and series that describe the alleviation of pain in a majority of patients through conventional or endoventricular targeting of the posterior hypothalamus and ventral tegmental area, with a minimal side effect profile. RESULTS: In this review, the history and outcomes of DBS use for medication-refractory cluster headaches are examined, with discussion on future directions for improving this novel treatment modality and providing efficacious, longer-lasting pain relief in headache patients. CONCLUSION: In patients with chronic cluster headache, functional neuromodulation using DBS presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain. PMID- 30303585 TI - Identification of green energy ranunculaceous flora of district Chitral, Northern Pakistan using pollen features through scanning electron microscopy. AB - Pollen micro-morphological features have proven to be helpful for the plant taxonomists in the identification and classification of plants. The utilization of this plantmayhelpfulin the areas of lignocellulosic conversion to biofuels and diversify application toward biomass. The current study was planned with the aim to evaluate the pollen features of complex Ranunculaceous flora of District Chitral, Northern Pakistan using both scanning electron microscopy (SEM) and Light Microscope (LM) for their taxonomic importance. Pollens of 18 Ranunculaceous species belonging to 6 genera were collected from different localities of the research area. SEM and LM were used to examine both qualitative and quantitative micro-morphological features. Sculptring of the sexine include; Scabrate, psilate, echinate, verrucate, perforate gemmate, and reticulate and so forth. Shape of the pollens was sub-spheroidal, spheroidal, prolate, subprolate and oblate and so forth. Type of pollen was ranged from mono to tricolpate and tricolporate. Quantitative characters include length/width of the pollen, colpus, exine thickness, and P/E ratio. Based on these micro-morphological features a taxonomic key was prepared for the fast and correct identification. RESEARCH HIGHLIGHT: Study of the pollen micro-morphological features of Ranunculaceous species by SEM and LM. Analysing both qualitative and quantitative characters of the pollens. Preparation of taxonomic key based on micro-morphological features for the correct and fast identification. PMID- 30303586 TI - Trends, patterns and causes of respiratory disease mortality among inpatients in Tanzania, 2006-2015. AB - OBJECTIVE: To determine the causes, patterns and trends of respiratory diseases related deaths in hospitals of Tanzania 2006-2015. METHODS: Retrospective study involving 39 hospitals. Medical records of patients who died in hospital were retrieved, reviewed and analysed. Sources of data were hospital admission registers, death registers and International Classification of Diseases report forms. Information on demographic characteristics, date of death, the immediate underlying cause of death and co-morbid conditions was collected. RESULTS: Of the 247 976 deaths reported during the 10-year period, respiratory diseases accounted for 12.92% (n = 32 042). The majority of the respiratory mortality was reported among males (55.9%). Overall median age at death was 31 years with an interquartile range (IQR) of 1-47. Median age at death was significantly higher among males (35 years) than females (28 years) (P < 0.0001). Most deaths (37.8%) occurred in eastern Tanzania. About one-third (31.3%) of all respiratory mortality was reported among under-five children, being among girls than boys (34.3% vs. 28.9%, chi2 = 10.3, P < 0.0001). Adolescent and young adult females (15-29 years) had higher age-standardised mortality rates per 100 000 due respiratory diseases than males. Pneumonia (n = 16 639; 51.9%) and pulmonary tuberculosis (n = 9687; 30.2%) accounted for the majority of deaths due to respiratory diseases. Significantly more females (n = 7665; 54.5%) than males died from pneumonia (n = 8878; 49.8%; chi2 = 8.5, P < 0.0001). By contrast, significantly more males (n = 6024; 34%) than females (n = 3596; 26%; chi2 = 15.5, P < 0.0001) died of tuberculosis. The proportion of death due to tuberculosis declined from 32.8% in 2006-2010 to 7.9% in 2011-2015. However, there was a significant increase in the proportion of death due to pneumonia from 49.6% in 2006-2010 to 53.4% in 2011-2015. Co-morbid conditions contributed to 9.1% (2871/31 628) of all deaths due to respiratory diseases. The most common co morbid condition was HIV which accounted for 1735 (60.4%) deaths and was more common among males (60.8%; n = 957) than among females (59.7%; n = 764). CONCLUSIONS: Respiratory diseases account for a substantial proportion of all causes of hospital death in Tanzania. Pneumonia and tuberculosis contribute to more than three quarters of all deaths due to respiratory diseases. Since most major respiratory illnesses are avoidable, it is important to strengthen the capacity of the health delivery system in managing cases of respiratory diseases. PMID- 30303587 TI - Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. AB - Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders. PMID- 30303588 TI - Transoral surgery using the Flex Robotic System: Initial experience in the United States. AB - BACKGROUND: This multicenter, retrospective review documents the initial experience using the Flex system for transoral surgery in 2 United States academic centers. METHODS: All patients who underwent transoral robotic surgery using the Medrobotics Flex Robotic System (Raynham, MA) between September 2015 and May 2017 were reviewed. Rates of successful surgery and complications were evaluated. RESULTS: Thirty-six men and 32 women were enrolled in the study. The average age was 55.6 years (range 17-82 years). The Flex system was used successfully in surgery of the tongue base, the palatine tonsils, the supraglottis, the glottis, the hypopharynx, the oral tongue, and the soft palate. Only 6 cases (7.6%) required readmission after discharge. There were no intraoperative or immediate postoperative complications, with no cases of intraoperative hemorrhage. CONCLUSION: To the best of our knowledge, this is the first study in the United States evaluating the use of the Flex system to safely resect lesions in the oral cavity, larynx, and pharynx. PMID- 30303589 TI - The anatomy of urination: What every physician should know. AB - Normal voiding needs a coordinated, sustained bladder contraction of adequate size and duration. It requires a decrease in resistance of the bladder neck and urethra and no obstruction. Voiding problems can arise from abnormal storage of urine or problems with urinary control. The aim of this article was to review the functional anatomy and physiology of urinary control and micturition and the pathophysiology of urinary control problems. The Medline (PubMed) database, Cochrane Library, and Science Citation Index were searched electronically to identify original published studies on bladder anatomy, function and urinary control. References were searched from relevant chapters in specialized texts and all were included. Voiding problems are the most common presenting urological symptoms in general medical practice. Urinary incontinence occurs when the normal process of storing and passing urine is disrupted. A history of coexisting fecal incontinence suggests a neuropathic etiology. A better understanding of the physiology of urinary control could lead to preventive measures for postoperative urinary retention and incontinence such as fluid restriction and to appropriate anesthesia/analgesia, autonomic nerve preservation, total mesorectal excision (TME) for rectal cancer, and biofeedback exercises. It could also suggest appropriate therapeutic measures for established urinary incontinence. Clin. Anat., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30303590 TI - Overexpression of cysteine-glutamate transporter and CD44 for prediction of recurrence and survival in patients with oral cavity squamous cell carcinoma. AB - BACKGROUND: This study analyzed the expression of CD44 and cystine-glutamate transporter SLC7A11 (xCT) in primary oral cavity squamous cell carcinoma (SCC) and the relationships of expression to tumor recurrence and patient survival. METHODS: Associations between CD44 and xCT expression and clinicopathologic results were analyzed in 231 patients with oral cavity SCC. Cox proportional hazard analyses were used to identify factors associated with recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: Overexpression of CD44 and/or xCT was associated with advanced T classification, perineural invasion, and lymphovascular invasion (P < .05 each). High expression of xCT was also associated with nodal metastasis and depth of invasion (P < .01 each). Multivariate analysis indicated that high expression of xCT and both xCT and CD44 were independent predictors of poor RFS, DSS, and OS (P < .05 each). CONCLUSION: Overexpression of xCT or xCT plus CD44 may predict posttreatment recurrence and survival in patients with oral cavity SCC. PMID- 30303591 TI - Usefulness of OLGA and OLGIM system not only for intestinal type but also for diffuse type of gastric cancer, and no interaction among the gastric cancer risk factors. AB - BACKGROUND: The operative link on gastric atrophy (OLGA) and operative link on gastric intestinal metaplasia (OLGIM) stages have been suggested for risk estimation of gastric cancer (GC). However, usefulness of OLGA/OLGIM systems in diffuse type of GC was not investigated so far. The aims of this study were to evaluate the OLGA/OLGIM systems in estimating the GC risk according to Lauren's classification and to investigate the interaction among the risk factors. MATERIALS AND METHODS: The OLGA/OLGIM stages were evaluated in 1398 (765 control and 633 GC patients) who were prospectively enrolled in the Seoul National University Bundang Hospital. Synergistic interaction among the risk factors for GC was calculated using an additive model. RESULTS: Among 387 intestinal-type GC patients, 71 (18.3%) were high-risk OLGA stages (III, IV) and 113 (29.2%) were high-risk OLGIM stages (III, IV). Of the 246 patients with diffuse-type GC, 36 (14.6%) were high-risk OLGA stages and 39 (15.9%) were high-risk OLGIM stages. Multivariable analysis revealed family history of GC, Helicobacter pylori infection, high-risk OLGA stages, and high-risk OLGIM stages as independent risk factors for GC regardless of histologic type (odds ratios [ORs] 1.78, 1.94, 2.63, and 3.18, respectively). There was no significant risk modification among the H. pylori infection, family history of GC, and high-risk OLGA/OLGIM stages. CONCLUSION: High-risk OLGA/OLGIM stages are important prediction markers for GC regardless of H. pylori infection or family history of GC not only for the intestinal type but also for diffuse-type GC. PMID- 30303592 TI - Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence. AB - Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-kappaB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2 O2 . OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 uM, but not 50 uM, of H2 O2 increased expression of TLR4, IL-1beta and COX-2. We found that NF-kappaB signaling was activated only upon stimulation with 100 uM H2 O2 leading to upregulation of TLR4 signaling and IL-1beta. The NF-kappaB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-kappaB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once. PMID- 30303593 TI - Transcriptome analysis provides insights into differentially expressed genes and long noncoding RNAs involved in sex-related differences in Amur sturgeon (Acipenser schrenckii). AB - In the present study, the next-generation sequencing technology was used to develop a transcriptome database of gonad and liver from 3-year-old male and female Amur sturgeons (Acipenser schrenckii). A total of 139,406 unigenes were generated after the Illumina Hiseq. 2500 sequence and assembled by Trinity. The differential expression analysis between male and female obtained 5,199 differentially expressed genes (DEGs) in gonad and 457 DEGs in liver. Gene Ontology enrich analysis showed that the specific DEGs of gonad play a dominant role in reproductive processes. Although the specific DEGs of liver indicated their primary responsibility for energy metabolism, the DEGs of liver and gonad co-own enriched in terms associated with reproduction suggested that liver also plays a role in sex-related differences in Amur sturgeon. Furthermore, genes related to sex-related differences were selected to validate among the four different tissues by real-time quantitative polymerase chain reaction (qRT-PCR). In addition, by trans-acting analysis, a total of 5,206 putative long noncoding RNAs (lncRNAs) and 3,490 target genes of lncRNAs were predicted from gonad and liver. Moreover, several lncRNAs targeting Mea1, Piwil1, Tdrd1, Nanos2, Ankrd49, and ZP3 may have potential regulatory effect related to gametogenesis and gonadal differentiation were identified and validated by qRT-PCR. These results suggested for the first time that lncRNAs might be one of the effect factors in regulating the differential expression of messenger RNAs associated with sex-related differences in Amur sturgeon. PMID- 30303594 TI - Remodeling of the Photosynthetic Chain Promotes Direct CO2 Conversion into Valuable Aromatic Compounds. AB - Directing CO2 conversion using photosynthetic microorganisms offers a promising route to couple CO2 sequestration with petrochemical replacement. However, the low-flux shikimate pathway remains largely unexploited for the synthesis of valuable aromatics. In addition, it is unclear how an enhanced low-flux pathway would influence the photosynthetic chain. We created a powerful metabolic sink by introducing the 2-phenylethanol pathway and an artificial feedback-inhibition resistant cassette to Synechococcus elongatus. More than 30 % of the fixed carbon was redirected to the shikimate pathway for aromatic synthesis, and carbon fixation and O2 evolution increased significantly. A "self-remodeling" mechanism of the photosynthetic chain was discovered, which accelerates electron transport and reduces energy waste. This study represents a significant step toward the industrial viability of CO2 conversion into aromatic compounds and provides design guidance for improving photosynthetic efficiency. PMID- 30303595 TI - Characterizing the Somatosensory Profile of Patients With Failed Back Surgery Syndrome With Unilateral Lumbar Radiculopathy Undergoing Spinal Cord Stimulation: A Single Center Prospective Pilot Study. AB - OBJECTIVES: Currently little objective evidence exists regarding the phenotype or somato-sensory profile of patients with Failed Back Surgery Syndrome (FBSS). The aim of this study is to characterize the somato-sensory profile of the patients with FBSS undergoing spinal cord stimulation (SCS). METHODS: A combined quantitative sensory test and questionnaire approach was used to characterize the somatosensory profiles of patients undergoing SCS. RESULTS: Baseline somatosensory profiles were obtained from 23 patients and full three-month data was obtained from 19 patients. At baseline, there was a high prevalence (>50% prevalence of moderate to severe sensation) of burning, tingling, electric shock, numbness, and pressure pain sensitivity. None of the sensory symptoms were present at significant levels at three months following SCS. At baseline, 65% of patients had an inefficient conditioned pain modulation (CPM). Three months post SCS, 95% of patients had an efficient CPM. All the patients who had an inefficient CPM at baseline had a successful implant at three months and their CPM became efficient in all but one patient. Only 50% of the patients with an efficient CPM at baseline, had a successful implant at three months post-SCS. CONCLUSION: Although very low numbers, we could demonstrate the somatosensory profiles of patients with FBSS undergoing SCS. Early indication may associate an efficient CPM profile having a higher chance of an unsuccessful implant at three months. PMID- 30303596 TI - Effect of collagenase ointment versus moist exposed burn ointment on healing of full-thickness burns in mice by removing of necrotic tissue. AB - The presence of necrotic tissue is one of the major problems that affect healing of burn wounds. The present study was designed to find the effectiveness of collagenase versus moist exposed burn ointment (MEBO) on removal of necrotic tissue of burns. Twenty mice randomly assigned and divided into four groups. For Group 1, burn wounds were treated with collagenase ointment only, Group 2 burn wounds were treated with MEBO, Group 3 burn wounds were treated with white vaseline alone, and Group 4 burn wounds were considered as control and left without treatment. In each group, the time of treatment was considered. The results indicated that the removal time of necrotic tissue and healing process was better in the case of using collagenase than using MEBO for treatment of burns. PMID- 30303597 TI - Long-term cost comparison between surgical and medical therapy for benign prostatic hyperplasia: a study using hospital billing data. AB - OBJECTIVES: To analyse actual long-term medical treatment of benign prostatic hyperplasia (BPH) and compare the incurred cost with that of patients with BPH who underwent early surgery. PATIENTS AND METHODS: Patients who were first diagnosed with BPH from 1 January 2008 to 31 December 2010 were identified using the Clinical Data Warehouse. Hospital billing data generated by the electronic hospital management system were collected until December 2015. For outpatient care, only procedures, materials and drugs directly related to the management of BPH were selected for the analysis. For inpatient care, all procedures, materials and drugs ordered on dates with continuity with BPH surgery date were included. The primary endpoint of the study was the total treatment-related direct costs of patients undergoing a long-term curative medical therapy for BPH (Group 1), which was arbitrarily defined as any medical therapy including a 5alpha-reductase inhibitor with a minimum medication possession ratio of 0.5 during >=5 consecutive years, or >=1 year until BPH surgery due to medical therapy failure. In all, 70 patients who underwent BPH surgery at <1 year of initial visit served as controls (Group 2). RESULTS: Amongst 137 patients in the Group 1, four patients underwent BPH surgery at a median of 57.8 months after the initial visit (2.9%). At a median follow-up of 76 months, the mean total treatment cost was significantly higher in Group 1 than in Group 2 ($3987 vs $3036 [USA dollars], P < 0.001). Similarly, the mean 'out-of-pocket' cost was significantly higher in Group 1 than in Group 2 ($1742 vs $1436, P = 0.005). When a linear increment of annual BPH treatment cost is assumed for Group 1 and all costs are assumed to be produced within the first year for Group 2, the total and out-of-pocket costs became equal at the end of the fifth year of medical treatment. For both total and out-of-pocket costs, medication-related costs occupied the largest proportion, exceeding half of the costs. CONCLUSIONS: We suggest patient counselling at the beginning of BPH treatment should include the likelihood that the cumulative out-of-pocket cost at 5 years of continuous medication will exceed that of early surgery. Our cost study using hospital billing data extractable from the electronic hospital management system may be a good model for cost studies that could provide valuable information to health providers and payers. PMID- 30303598 TI - Cherenkov Radiation-Mediated In Situ Excitation of Discrete Luminescent Lanthanide Complexes. AB - Lanthanide luminescence, while ideal for in vivo applications owing to sharp emission bands within the optical window, requires high-intensity, short wavelength excitation of small organic "antenna" chromophores in the vicinity of the lanthanide complex to access excited f-orbital states through intersystem crossing. Herein, we explored Cherenkov radiation of the radioisotopes 18 F and 89 Zr as an in situ source of antenna excitation. The effective inter- and intramolecular excitation of the terbium(III) complexes of a macrocylic polyaminocarboxylate ligand (hydration number (q)=0, quantum yield (phi)=47 %) as well as its analogue functionalized to append an intramolecular Cherenkov excitation source (q=0.07, phi=63 %) was achieved. Using conventional small animal fluorescence imaging equipment, we have determined a detection limit of 2.5 nmol of Tb(III) complex in presence of 10 MUCi of 18 F or 89 Zr. Our system is the first demonstration of the optical imaging of discrete luminescent lanthanide complexes without external short-wave excitation. PMID- 30303599 TI - Prostate cancer in 432 men aged <50 years in the prostate-specific antigen era: a new outlook. AB - OBJECTIVE: To evaluate the clinical presentation and treatment outcomes of prostate cancer (PCa) in 432 consecutive patients aged < 50 years in the prostate specific antigen (PSA) era. METHODS: Retrospective analysis was performed on all patients with PCa (14 570) from the years 1994 to 2017. A total of 432 consecutive patients aged < 50 years were identified. The patients were stratified by D'Amico risk groups, and their clinical presentation and treatment outcomes were analysed. The rates of biochemical recurrence after surgery were compared with the D'Amico prediction model as well as with older propensity-score matched patients. The surgical pathology results in patients undergoing active surveillance (AS) were compared with those of low-risk patients who underwent immediate surgery. RESULTS: A total of 44%, 42% and 13% of patients harboured low risk, intermediate-risk and high-risk PCa, respectively. Their median age was 47 years and a positive family history of PCa was reported in 39.1%. Clinical stage was T1 in 65.5% and T2 in 30.0% of patients, and 2.0% of patients had metastatic disease at presentation. Radical prostatectomy (RP) was performed in 78.4% of patients (n = 339) and the biochemical recurrence rates were 7.8% (low-risk), 15.3% (intermediate-risk) and 23.3% (high-risk) at 5 years post-surgery. These rates were lower than expected according to the D'Amico prediction model or when compared with older matched patients. A total of 74 patients with low-risk PCa underwent AS and only 17.6% (n = 13) required radical treatment after a median follow-up of 46 months. The surgical pathology results in patients undergoing ASdid not differ significantly from patients with low-risk PCa who underwent immediate surgery (positive surgical margins [P = 0.145], tumour volume [P = 0.257] or seminal vesicle involvement [P = 0.100]). Of the present cohort, only 0.4% died from PCa during a median follow-up of 65 months. CONCLUSIONS: The clinical presentation and prognosis of young patients has changed dramatically during the PSA era. Patients nowadays present with lower-risk disease that can be treated adequately, with reassuring biochemical recurrence rates at 5 years post surgery. AS appears to be safe in patients with low-risk. PCa. PMID- 30303600 TI - Unveiling the Sulfur-Sulfur Bridge: Accurate Structural and Energetic Characterization of a Homochalcogen Intermolecular Bond. AB - By combining rotational spectroscopy in supersonic expansion with the capability of state-of-the-art quantum-chemical computations in accurately determining structural and energetic properties, the genuine nature of a sulfur-sulfur chalcogen bond between dimethyl sulfide and sulfur dioxide has been unveiled in a gas-jet environment free from collision, solvent and matrix perturbations. A SAPT analysis pointed out that electrostatic S???S interactions play the dominant role in determining the stability of the complex, largely overcoming dispersion and C H???O hydrogen-bond contributions. Indeed, in agreement with the analysis of the quadrupole-coupling constants and of the methyl internal rotation barrier, the NBO and NOCV/CD approaches show a marked charge transfer between the sulfur atoms. Based on the assignment of the rotational spectra for 7 isotopologues, an accurate semi-experimental equilibrium structure for the heavy-atom backbone of the molecular complex has been determined, which is characterized by a S???S distance (2.947(3) A) well below the sum of van der Waals radii. PMID- 30303601 TI - Selective Nitrogen-Atom Transfer Driven by a Highly Efficient Intersystem Crossing in the [CeON]+ /CH4 System. AB - The thermal gas-phase reactions of [CeON]+ with methane have been explored by FT ICR mass spectrometry and high-level quantum-chemical calculations. Nitrogen-atom transfer from the cluster ion to methane was observed as the only reaction channel. Based on computational work, the neutral molecule formed corresponds to either CH2 NH2 or CH3 NH. In addition to a rather weak OCe+ -N bond, this reaction benefits from a highly efficient intersystem crossing. Mechanistic aspects and the associated electronic origins are discussed, and a detailed comparison of [CeON]+ , [CeO]+ , [CeN]+ , [CeO2 ]+ , and atomic N in their reactions with CH4 is given. PMID- 30303602 TI - Chromatographic separation, determination and identification of ecdysteroids: Focus on Maral root (Rhaponticum carthamoides, Leuzea carthamoides). AB - The review presents general principles for choosing optimal conditions for ecdysteroid separation, identification, and isolation using HPLC/TLC techniques in RP, NP-HILIC or NP modes. Analytics of ecdyteroids pose a still insufficiently resolved problem. Plant-derived ecdysteroids are a point of interest of pharmaceutical industry and sport medicine due to their postulated adaptogenic and anabolic properties. In insects, ecdysteroids regulate larval transformation. Maral root (Rhaponticum carthamoides, Leuzea carthamoides), traditional Siberian folk-medicine plant used as stimulant to boost overall health and fitness, is a particularly rich source of a wide variety of phytoecdysteroids. The similarity of molecular structures of ecdysteroids present in its extracts together with high content of unrelated compounds of similar chromatographic characteristics makes optimization of separation, identification and isolation of ecdysteroids a difficult analytical task. In that respect, two-dimensional separations, two dimensional separations, 2D HPLC or 2D TLC, could be of use. For identification, the hyphenated techniques are particularly important. Thus, comprehensive overview of MS spectral parameters of ecdysteroids is provided. Described principles could easily be applied for separation of ecdysteroids in extracts from other sources. They are also useful for development of separation procedures for isolation of ecysteroids in preparative-scale applications. PMID- 30303603 TI - Current opinions in organ allocation. AB - Existing methods of academic publication provide limited opportunity to obtain stakeholder input on issues of broad interest. This article reports the results of an experiment to produce a collaborative, crowdsourced article examining a current controversial issue in transplant medicine (hereby referred to as the "C4 Article"). The editorial team as a whole selected the topic of organ allocation, then divided into six sections, each supported by an individual editorial team. Widely promoted by the American Journal of Transplantation, the C4 Article was open for public comment for 1 month. The nonblinded editorial teams reviewed the contributions daily and interacted with contributors in near-real time to clarify and expand on the content received. Draft summaries of each section were posted and subsequently revised as new contributions were received. One hundred ninety four individuals viewed the manuscript, and 107 individuals contributed to the manuscript during the submission period. The article engaged the international transplant community in producing a contemporary delineation of issues of agreement and controversy related to organ allocation and identified opportunities for new policy development. This initial experience successfully demonstrated the potential of a crowdsourced academic manuscript to advance a broad-based understanding of a complex issue. PMID- 30303604 TI - Use of chitosan membranes after nerve-sparing radical prostatectomy improves early recovery of sexual potency: results of a comparative study. AB - OBJECTIVES: To evaluate the 1-year efficacy of chitosan membrane (ChiMe) application on the neurovascular bundles (NVBs) after nerve-sparing (NS) robot assisted radical prostatectomy (RARP) in potency recovery rate. To compare the results with those of a contemporary cohort of patients who did not benefit from chitosan use. PATIENTS AND METHODS: Patients in the ChiMe group were enrolled at our institution from July 2015 to September 2016 in a preliminary phase II study. All of them underwent NS-RARP with ChiMe applied on the NVBs and were followed over time to complete a 1-year follow-up. The control group was composed of patients who underwent NS-RARP at our institution without the application of ChiMe from January 2015. The patients were further classified into two groups based on the amount of nerves spared: Group A, comprised patients who underwent a monolateral or bilateral full NS; Group B, comprised patients in which a full NS was not performed. The demographics, peri- and postoperative data, and complications were recorded and compared. Potency recovery was recorded for Group A vs Group B in both the ChiMe and the control groups. RESULTS: In all, 136 patients were enrolled in the ChiMe group and 334 patients in the control group. There were no differences between groups in terms of baseline variables. Based on the amount of nerves preserved, 183 patients were included in Group A and 287 in Group B. Odds ratios at different time points showed that the only two factors influencing potency recovery were the amount of nerves preserved (Group A vs Group B) and the application or not of ChiMe on the NVBs spared. Comparing the ChiMe vs control groups at different time points, we found a statistically significant improvement in the potency recovery rate in the ChiMe group at 1 month (36.76% vs 25.88%; P = 0.02) and 2 months (52.2% vs 39.22%; P = 0.01) after surgery, showing a favourable trend at every time point of the entire follow-up period, even if not significant after the second postoperative month. In Group A, the log-rank test showed a statistically significant difference between the ChiMe vs control groups (P = 0.02), in particular at 1 and 2 months after surgery (P = 0.02 and P = 0.01, respectively). CONCLUSION: The application of ChiMe on the NVBs resulted in a higher potency recovery rate at 1 and 2 months after a bilateral or monolateral full NS-RARP. A trend of a higher and shorter potency recovery rate showed it to be favourable to use ChiMe, even in the cohort of patients who did not undergo a full NS procedure. PMID- 30303605 TI - Defined High Molar Mass Poly(2-Oxazoline)s. AB - Poly(2-alkyl-2-oxazoline)s (PAOx) are regaining interest for biomedical applications. However, their full potential is hampered by the inability to synthesise uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain end tautomerisation and derived improved polymerization conditions to suppress chain transfer, allowing the synthesis of highly defined poly(2-ethyl-2 oxazoline)s up to ca. 50 kDa (dispersity (D) <1.05) and defined polymers up to at least 300 kDa (D<1.2). The determination of the chain transfer constants for the polymerisations hinted towards the tautomerisation of the oxazolinium chain end as most plausible cause for chain transfer. Finally, the method was applied for the preparation of up to 60 kDa molar mass copolymers of 2-ethyl-2-oxazoline and 2-methoxycarbonylethyl-2-oxazoline. PMID- 30303606 TI - Enhanced Light-Matter Interactions in Self-Assembled Plasmonic Nanoparticles on 2D Semiconductors. AB - Two-dimensional (2D) transition-metal dichalcogenide (TMD) monolayers of versatile material library are spotlighted for numerous unexplored research fields. While monolayer TMDs exhibit an efficient excitonic emission, the weak light absorption arising from their low dimensionality limits potential applications. To enhance the light-matter interactions of TMDs, while various plasmonic hybridization methods have been intensively studied, controlling plasmonic nanostructures via self-assembly processes remains challenging. Herein, strong light-matter interactions are reported in plasmonic Ag nanoparticles (NPs) hybridized on TMDs via an aging-based self-assembly process at room temperature. This hybridization is implemented by transferring MoS2 monolayers grown via chemical vapor deposition onto thin-spacer-covered Ag films. After a few weeks of aging in a vacuum desiccator, the Ag atoms in the heterolayered film diffuse to the MoS2 layers through a SiO2 spacer and self-cluster onto MoS2 point defects, resulting in the formation of Ag-NPs with an estimated diameter of ~50 nm. The photoluminescence intensities for the Ag-NP/MoS2 hybrids are enhanced up to 35 fold compared with bare MoS2 owing to the local field enhancement near the plasmonic Ag-NPs. The localized surface plasmon resonances modes of this hybrid are systematically investigated via numerical simulations and dark-field scattering microscopy. PMID- 30303607 TI - Efficient Ternary Organic Solar Cells with Two Compatible Non-Fullerene Materials as One Alloyed Acceptor. AB - Efficient ternary organic solar cells (OSCs) are fabricated by employing a polymer PBT1-C as the donor and two non-fullerene materials, MeIC and MeIC2, as one alloyed acceptor. The optimized ternary OSCs with 30 wt% MeIC2 in acceptors achieve a power conversion efficiency (PCE) of 12.55%, which is much higher than that of 11.47% for MeIC-based binary OSCs and 11.41% for MeIC2-based binary OSCs. The >9.4% improvement in PCE is mainly attributed to the optimized photon harvesting and morphology of ternary active layers, resulting in the simultaneously improved short-circuit current and fill factor. Furthermore, good compatibility and similar lowest unoccupied molecular orbital energy levels of MeIC and MeIC2 are beneficial to form one alloyed acceptor for efficient electron transport in the ternary active layers. This work may provide new insight when selecting the third component for preparing efficient ternary OSCs. PMID- 30303609 TI - C4: An experiment in academic dialogue. PMID- 30303610 TI - Safety of D-dimer testing as a stand-alone test for the exclusion of deep vein thrombosis as compared with other strategies. AB - Essentials The aim of deep vein thrombosis (DVT) diagnostic work-up is to maximize both safety and efficiency. We explored whether D-dimer is safe and efficient as a stand-alone test to exclude DVT. Our findings suggest it is a safe, efficient and simplified diagnostic strategy. The safety of age-adjusted D dimer as a stand-alone test requires further investigation. SUMMARY: Background Several strategies for safely excluding deep vein thrombosis (DVT) while limiting the number of imaging tests have been explored. Objectives To determine whether D dimer testing could safely and efficiently exclude DVT as a stand-alone test, and evaluate its performance as compared with strategies that incorporate the Wells score and age-adjusted D-dimer. Patients/Methods We included consecutive outpatients referred with suspected DVT to the Emergency Department at Ostfold Hospital, Norway. STA-Liatest D-Di PLUS D-dimer was analyzed for all patients. Patients with a D-dimer level of >= 0.5 MUg mL-1 were referred for compression ultrasonography (CUS). In patients with a D-dimer level of < 0.5 MUg mL-1 , no further testing was performed and anticoagulation was withheld. Patients were followed for 3 months for venous thromboembolism (VTE). Results Of the 913 included patients, 298 (33%) had a negative D-dimer result. One hundred and seventy-three patients (18.9%) were diagnosed with DVT at baseline. One of 298 patients had DVT despite having a negative D-dimer result, resulting in a failure rate of 0.3% (95% confidence interval [CI] 0.1-1.9%). Adding the modified Wells score would have yielded a failure rate of 0.0% (95% CI 0.0-1.8%) while necessitating 87 more CUS examinations. Age-adjusted D-dimer as a stand-alone test would have necessitated 80 fewer CUS examinations than fixed D-dimer as a stand-alone test, at the cost of a failure rate of 1.6% (95% CI 0.7-3.4%). Conclusions This outcome study shows that a negative high-sensitivity D-dimer result safely excludes DVT in an outpatient population, and necessitates fewer CUS than if used in combination with Wells score. The safety of stand-alone age adjusted D-dimer needs further assessment in prospective outcome studies. PMID- 30303608 TI - Ex vivo induction of regulatory T cells from conventional CD4+ T cells is sensitive to substrate rigidity. AB - The immune system maintains a balance between protection and tolerance. Regulatory T cells (Tregs) function as a vital tolerance mechanism in the immune system to suppress effector immune cells. Additionally, Tregs can be utilized as a form of immunotherapy for autoimmune disorders. As T cells have previously been shown to exhibit sensitivity to the rigidity of an activating substrate upon activation via IL-2 secretion, we herein explore the previously unknown effect of substrate rigidity on the induction of Tregs from conventional naive mouse CD4+ T cells. Substrates with modulatable rigidities ranging from a hundred kilopascals to a few megapascals were fabricated via poly(dimethylsiloxane). We found that there was a significant increase in Treg induction at lower substrate rigidities (i.e., E ~ 100 kPa) compared to higher rigidity levels (i.e., E ~ 3 MPa). To confirm that this significant difference in induction rate was truly related to T cell mechanosensing, we administered compound Y-27632 to inhibit myosin contractility. In the presence of Y-27632, the myosin-based contractility was disrupted and, as a result, the difference in Treg induction caused by the substrate rigidity was abrogated. This study demonstrates that mechanosensing is involved in Treg induction and raises questions about the underlying molecular mechanisms involved in this process. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3001-3008, 2018. PMID- 30303611 TI - Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. AB - AIMS: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics. METHODS AND RESULTS: All patients randomized in the remede System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by 6.8 +/- 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system. CONCLUSIONS: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life. PMID- 30303612 TI - Effect on morphine requirement of early administration of oral acetaminophen versus acetaminophen/tramadol combination in acute pain. AB - OBJECTIVES: To evaluate the effect of pain treatment starting at triage on opioid requirement, and satisfaction in emergency department(ED) patients with acute pain. METHODS: This is a single-blind, randomized, prospective study conducted in ED. The included patients were randomly assigned to single oral dosed of placebo, acetaminophen or tramadol/acetaminophen combination. Protocol treatment was given at the triage.The primary outcome is the need for rescue morphine during EDstay. Secondary outcome included patient satisfaction,ED length of stay, and percentage of patients discharged from the ED with Visual Analogue Scale(VAS)<30. RESULTS: We included 1485 patients,496 patients in placebo group,497 in acetaminophen group and 492 in tramadol/acetaminophen combination group. The groups were similar regarding demographic and clinical characteristics and baseline VAS pain scores. Rescue morphine was significantly decreased in tramadol/acetaminophen combination group compared to placebo and acetaminophen groups(11.5%,23.2%,and 18.9%respectively;p=0.03). Patient satisfaction was higher in tramadol/acetaminophen combination group(77% vs69% in acetaminophen group and 68% in placebo group). VAS<30 was observed in84% of patients in group placebo,83% in group acetaminophen and 87%in group tramadol/acetaminophen combination,p=0.01 between acetaminophen group and tramadol/acetaminophen combination group. ED length of stay was 60min for acetaminophen and tramadol/acetaminophen combination groups and 71min for the placebo group(p=0.04). CONCLUSION: Oral tramadol/acetaminophen combination administered early in the triage was associated with a decrease in intravenous morphine requirement and increase on satisfaction in ED patients with acute pain when compared with patients taking acetaminophen. No significant increase in side effects was found. This intervention may be considered in EDs with an aim of similar benefits. This article is protected by copyright. All rights reserved. PMID- 30303613 TI - Programmed Hierarchical Hybrid Nanostructures from Fullerene-Dendrons and Pyrene Dendrons. AB - The construction of fullerene (C60 ) hierarchical nanostructures with the help of amphiphilic molecules remains a challenging task in nanoscience and nanotechnology. Utilizing the host-guest complex concept, sub-10 nm layered superstructures are constructed from a monofunctionalized C60 dendron (C60 D, guest) and tweezer-like pyrene dendron (PD, host). Since C60 D and PD are asymmetric shape amphiphiles having liquid crystal (LC) dendrons, both C60 D and PD construct head-to-head bilayer superstructures by themselves. From fluorescence titration experiments, it is realized that the host-guest complex shows 1:1 stoichiometric binding with a binding constant (Ksv = 2.45 * 105 m-1 ). Based on the morphological observations and scattering analyses, it is found that buckle-like asymmetric building blocks (C60 D.PD) are self-assembled by the host guest complex and construct multilayer hybrid nanostructures. The hierarchical hybrid nanostructures consist of the self-assembled C60 D.PD bilayer with a 2D C60 .P nanoarray sandwiched between LC dendrons. This advanced strategy is expected to be a practicable and rational guideline for the fabrication of programmed hierarchical hybrid nanostructures. PMID- 30303614 TI - Five-year follow up of a low glycaemic index dietary randomised controlled trial in pregnancy-no long-term maternal effects of a dietary intervention. AB - OBJECTIVE: To determine whether a dietary intervention in pregnancy had a lasting effect on maternal outcomes of diet, HbA1c and weight retention 5 years post intervention; and to establish whether modifiable maternal behaviours were associated with these outcomes. DESIGN: Randomised control trial of low glycaemic index (GI) diet in pregnancy with longitudinal follow up to 5 years post intervention. SETTING: Dublin, Ireland (2007-2016). POPULATION: In all, 403 women of 759 (53.1%) were followed up at 5 years. A total of 370 (intervention n = 188; control n = 182) were included in this analysis. METHODS: Fasting glucose was measured at 13 and 28 weeks' gestation and HbA1c (mmol/mol) at 5-year follow up. Weight retention (kg) from early pregnancy to 5 years post-intervention was calculated. Dietary intakes, anthropometry, and lifestyle factors were measured in pregnancy and 5 years post-intervention. Multiple linear regression models, controlling for confounders, were used for analysis. OUTCOME: Maternal diet, HbA1c, and weight retention at 5 years post-intervention. RESULTS: There was no difference between the intervention and control at 5 years post-intervention for any long-term maternal outcomes measured. HbA1c at 5 years post-intervention was associated with early-pregnancy fasting glucose (B 1.70, 95% CI 0.36-3.04) and parity >=3 (B 1.04, 95% CI 0.09-1.99). Weight retention was associated with change in well-being from pregnancy to 5 years (B -0.06, 95% CI -0.11 to -0.02), gestational weight gain (B 0.19, 95% CI 0.00-0.38), and GI (B 0.26, 95% CI 0.06 0.46) at 5 years. CONCLUSIONS: The ROLO low-GI dietary intervention in pregnancy had no impact on maternal dietary intakes, HbA1c or body composition 5 years post intervention. Maternal factors and lifestyle behaviours in pregnancy have long term effects on glucose metabolism and weight retention up to 5 years later. TWEETABLE ABSTRACT: Pregnancy factors are associated with maternal glucose metabolism and weight retention 5 years later-findings from the ROLO Study. PMID- 30303615 TI - Conductive Molybdenum Sulfide for Efficient Electrocatalytic Hydrogen Evolution. AB - Molybdenum sulfide (MoS2 ) is a layered material with high activity for electrocatalytic hydrogen evolution reaction (HER). In conventional MoS2 , the high electrical resistance between the layers hampers the bulk charge transfer and therefore greatly limits its performance in electrolysis. Herein, ultrathin MoS2 nanosheets with bent layers on reduced graphene oxide (RGO) are reported. In sharp contrast to the bulk MoS2 , the resulting MoS2 has mostly 1 or 2 layers, and the layer distance is significantly expanded to ~1 nm. From computational studies, the prepared MoS2 with limited layer numbers and expanded layer distances has similar physical and chemical features with single-layer MoS2 . Importantly, the bent single layer is electrically conductive and is intrinsically more active than a normal flat single layer. In addition, the unusual features of confined sizes and distorted lattices in the prepared MoS2 can bring about plentiful active sites and are beneficial for mass diffusion during electrocatalysis. The hybrid material exhibits high activity for electrocatalytic HER, affording a current density of 10 mA cm-2 at a low overpotential of 66 mV. PMID- 30303616 TI - A pilot study documenting increased thrombin generation following abrupt withdrawal of heparin therapy in healthy dogs. AB - OBJECTIVE: To document if a transient hypercoagulable state occurs in healthy dogs following abrupt cessation of unfractionated heparin (UFH) therapy. DESIGN: Prospective experimental pilot study. SETTING: University research facility. ANIMALS: Seven adult random-source male dogs. INTERVENTION: Thromboelastography (TEG) and thrombin-antithrombin (TAT) complex formation were used to assess coagulation status in healthy dogs. Seven adult research dogs received 200-300 IU/kg subcutaneous UFH every 8 hours for 4 days. A final IV bolus of 100 IU/kg was given on day 4 and the peak measured heparin concentration 1 hour later is defined as the start of heparin withdrawal (time 0). Citrated whole blood samples were collected at baseline (prior to heparin administration) and 3, 6, 12, 30, and 48 hours after UFH withdrawal. At all time points, a kaolin-activated TEG was performed and citrated plasma for measurement of TAT concentration was collected for batch analysis. Fibrinogen concentration, PCV, total plasma proteins, and platelet count were measured at baseline and 48 hours after heparin withdrawal. MEASUREMENTS AND MAIN RESULTS: Compared to baseline, TAT was increased 12 hours after heparin withdrawal and returned to baseline by 30 hours. TEG clot formation time (K) was decreased 30 and 48 hours after heparin withdrawal. CONCLUSION: TAT results suggest that a transient increase in thrombin generation developed 12 hours after withdrawal of UFH therapy. Though clot kinetics were rapid compared to baseline beginning 30 hours after heparin withdrawal, a return to baseline was not documented. Future studies are warranted to determine the clinical relevance of these results and to evaluate the effect of UFH withdrawal in critically ill animals. PMID- 30303617 TI - Nitrogen-Doped Biomass-Derived Carbon Formed by Mechanochemical Synthesis for Lithium-Sulfur Batteries. AB - Nitrogen-doped carbons were synthesized by a solvent-free mechanochemically induced one-pot synthesis by using renewable biomass waste. Three solid materials are used: sawdust as a carbon source, urea and/or melamine as a nitrogen source, and potassium carbonate as an activation agent. The resulting nitrogen-doped porous carbons offer a very high specific surface area of up to 3000 m2 g-1 and a large pore volume up to 2 cm3 g-1 . Also, a high nitrogen content of 4 wt % (urea only) up to 12 wt % (melamine only) is generated, depending on the nitrogen and carbon sources. The mechanochemical reaction and the impact of different wood components on the porosity and surface functionalities are investigated by nitrogen physisorption and high-resolution X-ray photoelectron spectroscopy (XPS). These N-doped carbons are highly suitable as cathode materials for Li-S batteries, showing high initial discharge capacities of up to 1300 mAh gsulfur -1 (95 % coulombic efficiency) and >75 % capacity retention within the first 50 cycles at low electrolyte volume. PMID- 30303618 TI - Flexible Transient Phototransistors by Use of Wafer-Compatible Transferred Silicon Nanomembranes. AB - Flexible transient photodetectors, a form of optoelectronic sensors that can be physically self-destroyed in a controllable manner, could be one of the important components for future transient electronic systems. In this work, a scalable, device-first, and bottom-up thinning process enables the fabrication of a flexible transient phototransistor on a wafer-compatible transferred silicon nanomembrane. A gate modulation significantly restrains the dark current to 10-12 A. With full exposure of the light-sensitive channel, such a device yields an ultrahigh photo-to-dark current ratio of 107 with a responsivity of 1.34 A W-1 (lambda = 405 nm). The use of a high-temperature degradable polymer transient interlayer realizes on-demand self-destruction of the fabricated phototransistors, which offers a solution to the technical security issue of advanced flexible electronics. Such demonstration paves a new way for designing transient optoelectronic devices with a wafer-compatible process. PMID- 30303619 TI - Methods to Measure MDSC Immune Suppressive Activity In Vitro and In Vivo. AB - This unit presents methods to assess the immunosuppressive properties of immunoregulatory cells of myeloid origin, such as myeloid-derived suppressor cells (MDSCs), both in vitro and in vivo in mice, as well as in biological samples from cancer patients. These methods could be adapted to test the impact of different suppressive populations on T cell activation, proliferation, and cytotoxic activity; moreover, they could be useful to assess the influence exerted by genetic modifications, chemical inhibitors, and drugs on immune suppressive pathways (c) 2018 by John Wiley & Sons, Inc. PMID- 30303620 TI - Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics-Based Combination Antitumor Therapy. AB - Different strategies of chemotherapeutics-based combination cancer therapy have presented enhanced antitumor efficiency and are widely used in clinical cancer treatments. However, several drawbacks of the systems for systemic administration, including low drug accumulation at tumor sites and significant systemic side effects limit their efficacy and application in the clinic. Local drug co-delivery systems based on injectable hydrogels may have considerable advantages, such as a facile drug-delivery procedure, targeted delivery of antitumor agents to tumor sites in a sustained manner, and markedly reduced systemic toxicities. Thus, in recent years, these systems have received increasing attention and consequently various injectable hydrogels have been tested as platforms for local chemotherapeutics-based combination antitumor therapy. In this review, the focus is on recent advances in injectable hydrogel based drug co-delivery systems for local combination antitumor therapy, including multiple chemotherapeutics combination therapy, chemo-immunotherapy, chemo radiotherapy, and hyperthermia-chemotherapy. Moreover, the rationale and preparation of local co-delivery systems are summarized and discussed. PMID- 30303621 TI - A Core-Shell Nanoplatform for Synergistic Enhanced Sonodynamic Therapy of Hypoxic Tumor via Cascaded Strategy. AB - Sonodynamic therapy (SDT) always causes tumor hypoxia aggravation which can induce malignant cell proliferation and drug resistance. To overcome these disadvantages, a cascaded drug delivery system (Lipo/HMME/ACF@MnO2 -AS1411) is constructed for synergistic enhanced sonodynamic therapy. First, hematoporphyrin monomethyl ether (HMME) and acriflavine (ACF) are encapsulated in the lipid layers and the inner aqueous cores of the liposomes, respectively. Then the ultrathin manganese dioxide (MnO2 ) nanosheets are coated on the surface of the liposomes by using KMnO4 and polyethylene glycol through "one step reduction and modification" method. Furthermore, the nanoparticles are decorated with tumor targeting AS1411 aptamer through the phosphate groups on the DNA strand which can bind to Mn sites to obtain Lipo/HMME/ACF@MnO2 -AS1411 delivery system. Herein, HMME can act as a sonosensitizer, and ACF is used to prevent the formation of HIF 1alpha/HIF-1beta dimerization to overcome the negative effects after SDT. The Lipo/HMME/ACF@MnO2 -AS1411 delivery system has multiple functions, including codelivery of HMME and ACF, pH/glutathione/ultrasound triple responses, synergistic cascaded enhancement of SDT, precise tumor-targeting, and magnetic resonance imaging. The in vitro and in vivo results suggest that the Lipo/HMME/ACF@MnO2 -AS1411 delivery system is a promising core-shell nanoplatform for synergistic enhancement of sonodynamic therapy, which can provide a new approach in the related research fields. PMID- 30303622 TI - October 2018 at a glance: from demographic variables to genotype-phenotype interactions. PMID- 30303623 TI - Corrigendum to 'Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology' [Eur J Heart Fail 2018;20:3-15]. PMID- 30303624 TI - Stable Surface Modification of Mesenchymal Stem Cells Using the Avidin-Biotin Complex Technique. AB - Mesenchymal stem cells (MSCs) hold promise in cell-based therapies because of their strong tissue repair ability and immunosuppressive effects; however, the therapeutic efficacy of transplanted MSCs is limited due to low survival rates and short-term functioning after transplantation. While the functionalization of MSCs is an ideal way to solve these problems, conventional cell functionalization methods have disadvantages such as cell damage, changes in cellular characteristics, and short-term modification. This unit describes a technique for MSC functionalization by surface modification via the avidin-biotin complex (ABC). This technique provides long-term modification MSC surfaces with biotinylated compounds. This easy method of MSC functionalization will support effective MSC-based therapy. (c) 2018 by John Wiley & Sons, Inc. PMID- 30303625 TI - Analysis of Mitochondrial Dimensions and Cristae Structure in Pluripotent Stem Cells Using Transmission Electron Microscopy. AB - Dynamic alterations to mitochondrial structure and function regulate cell fate decisions and underlie multiple age-related and genetic diseases that are modeled using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Transmission electron microscopy (TEM) can be used to obtain high-resolution micrographs of mitochondria, but mitochondrial ultrastructure is easily distorted during specimen processing. This unit describes a method that preserves mitochondrial membrane structure from adherent ESC cultures for TEM sample preparation. This procedure is useful for assessing ultrastructural changes to mitochondria during differentiation, reprogramming, or experimental manipulation of ESC metabolism. We provide comprehensive protocols for: (1) preparation of ESC cultures for TEM; (2) retrieval of thin sections from individual ESCs; and (3) contrast staining and morphometric analysis of mitochondria and cristae. This unit also describes an alternative procedure for samples with low cell numbers and a supporting protocol for morphometric image analysis. Collectively, these protocols allow for the observation and quantitative analysis of mitochondria in ESCs. (c) 2018 by John Wiley & Sons, Inc. PMID- 30303626 TI - Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects. AB - The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single-center, double-blind, randomized, placebo-controlled, parallel, single- and repeat-ascending-dose study. Thirty-six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single dose session (session 1), a repeat-dose session (session 2), a 10-day washout period between the sessions, and then a follow-up visit 10 +/- 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [Cmax ] and area under the concentration-time curve [AUC]) increased with dose in an approximately proportional manner. Plasma Tmax was achieved rapidly at approximately 0.08 hours, and the terminal elimination half-life (T1/2 ) was approximately 40 hours. Tmax and T1/2 did not change between days or doses in the single- and repeat-dose sessions. Following 10 daily doses of 200, 500, and 700 MUg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC0-24 ) and R(Cmax ) were 2.4-3.0 and 1.5-1.7, respectively. Steady state was achieved by 6-7 days, based on trough observed plasma drug concentration (Ctrough ) values. PMID- 30303627 TI - Nerves and Proliferation of Progenitor Cells in Limb Regeneration. AB - Nerves, in conjunction with the apical epidermal cap (AEC), play an important role in the proliferation of the mesenchymal progenitor cells comprising the blastema of regenerating urodele amphibian limbs. Reinnervation after amputation requires factors supplied by the forming blastema, and neurotrophic factors must be present at or above a quantitative threshold for mitosis of the blastema cells. The AEC forms independently of nerves, but requires nerves to be maintained. Urodele limb buds are independent of nerves for regeneration, but innervation imposes a regenerative requirement for nerve factors on their cells as they differentiate. There are three main ideas on the functional relationship between nerves, AEC, and blastema cells: (1) nerves and AEC produce factors with different roles in maintaining progenitor status and mitosis; (2) the AEC produces the factors that promote blastema cell mitosis, but requires nerves to express them; (3) blastema cells, nerves, and AEC all produce the same factor(s) that additively attain the required threshold for mitosis. PMID- 30303628 TI - A Randomized, Open-Label, Crossover Phase 1 Study to Evaluate the Effects of Food on the Pharmacokinetics of a Single Oral Dose of a 15-mg Tylerdipine Tablet in Healthy Chinese Male Volunteers. AB - Tylerdipine hydrochloride is a novel L-type and T-type dual calcium channel antagonist that has the potential effects of expanding blood vessels and lowering blood pressure. It is expected to reduce the side effect of ankle edema observed with other drugs in the same class. A randomized, open-label, crossover phase 1 study was performed to evaluate the effect of food on the bioavailability of tylerdipine. Fourteen healthy male volunteers were enrolled. The administration of tylerdipine after a high-fat meal increased the bioavailability of tylerdipine. In the fed state there was a 130% increase in the mean total systemic exposure (AUCinf ) and a 73% increase in the mean peak plasma concentration (Cmax ) compared with that in the fasting state. The geometric mean ratios (90% confidence interval) of Cmax and AUCinf were 2.54 (1.94, 3.33) and 1.75 (1.50, 2.04) for tylerdipine. The exposures of the 2 main metabolites M2 and M4 were increased by approximately 10% after a high-fat meal. The median time to peak plasma concentration of tylerdipine showed no difference between fasting and fed states. PMID- 30303629 TI - Co9 S8 -Catalyzed Growth of Thin-Walled Graphite Microtubes for Robust, Efficient Overall Water Splitting. AB - Co9 S8 crystals can catalyze the growth of thin-walled graphite microtubes (GMTs) through a catalytic chemical vapor deposition (CCVD) process using thiourea as the precursor. The growth of GMTs follows a tip-growth mechanism with tube diameters up to a few micrometer. The hollow interiors of the GMTs are filled with carbon nanotubes and wrinkled graphene layers, which form a unique nanotube/graphene-in-microtube structure. As-formed GMTs are N,S-codoped with lots of Co9 S8 nanoparticles encapsulated in their inner walls. These GMTs are room-temperature ferromagnets and can be loaded on Ni foams to work as binder free electrocatalysts with low overpotential (310 mV at 50 mA cm-2 for the oxygen evolution reaction (OER) and 284 mV at 50 mA cm-2 for the hydrogen evolution reaction (HER)) and long-term durability (continuous work for 120 h without loss in performance). Our research proves that metal sulfides can catalyze the growth of graphite microtubes and as-formed GMTs may potentially be used as functional building blocks to construct new kinds of electrochemical devices for various energy-related applications. PMID- 30303630 TI - Factors related to exclusive breastfeeding in Thai adolescent mothers: Concept mapping approach. AB - The advantages of exclusive breastfeeding for the first 6 months are well-known. Unfortunately, adolescent mothers have lower rates of breastfeeding exclusivity and shorter duration of breastfeeding. There is limited evidence regarding exclusive breastfeeding determinants in adolescent mothers. The purpose of this study was to obtain adolescent mother-generated factors related to exclusive breastfeeding at 6 months. A mixed-methods design was conducted through concept mapping. Thirty adolescent mothers aged 15-19 years who had wide range of exclusive breastfeeding experiences brainstormed about specific factors. They then sorted and rated the statements into key clusters. Finally, half of the participants were involved in the interpretation of the mapping results and the creation of pathway diagrams. Data were analysed by multivariate statistics in the Concept System Global MAX program. The results showed that the adolescent mothers brainstormed about 104 statements on the factors related to exclusive breastfeeding at 6 months. These factors can be categorized into the following six key clusters: (a) breastfeeding advantages; (b) facilitating factors and necessary skills; (c) promotion and support needed; (d) community and social influence; (e) internal and external barriers; and (f) key problems in families. The pattern matching provided understanding of how key clusters are important to successful breastfeeding through comparing three groups of exclusive breastfeeding durations. Finally, the relationships of the stated factors were drawn in pathway diagrams. Exclusive breastfeeding experiences among Thai adolescent mothers showed complexity involving multilevel influences of social systems. The promotion of optimal breastfeeding should recognize the influences of both personal and environmental factors. PMID- 30303631 TI - Dynamic Hydrogels from Host-Guest Supramolecular Interactions. AB - Hydrogel biomaterials are pervasive in biomedical use. Applications of these soft materials range from contact lenses to drug depots to scaffolds for transplanted cells. A subset of hydrogels is prepared from physical cross-linking mediated by host-guest interactions. Host macrocycles, the most recognizable supramolecular motif, facilitate complex formation with an array of guests by inclusion in their portal. Commonly, an appended macrocycle forms a complex with appended guests on another polymer chain. The formation of poly(pseudo)rotaxanes is also demonstrated, wherein macrocycles are threaded by a polymer chain to give rise to physical cross-linking by secondary non-covalent interactions or polymer jamming. Host-guest supramolecular hydrogels lend themselves to a variety of applications resulting from their dynamic properties that arise from non-covalent supramolecular interactions, as well as engineered responsiveness to external stimuli. These are thus an exciting new class of materials. PMID- 30303633 TI - Staffing: It's Getting Scary Again. PMID- 30303632 TI - Ultra-small Albumin Templated Gd/Ru Composite Nanodots for In Vivo Dual modal MR/Thermal Imaging Guided Photothermal Therapy. AB - Multifunctional theranostic nanoagents which realize precise diagnosis and treatment of tumors are attracting increasing interests in recent years. However, efficient and controlled synthesis of ultra-small noble metal nanoagents remains a challenge. Here, monodisperse Gd/Ru@BSA nanodots (GRBNDs) are successfully fabricated via a totally "green", "one-pot" protocol for in situ reduction of Ru(III) and biomineralization of Gd(III) in the presence of albumin. The as prepared nanoagent possesses the features of being ultra small in size (~6.7 nm), having strong colloidal stability, and thermal stability as well as high photothermal conversion efficiency (eta = 50.7%). As expected, the GRBNDs achieve a significant efficacy of anticancer therapy under LASER activation both in vitro and in vivo. It also exhibits superior T1 -weighted magnetic resonance (MR) imaging ability due to its high longitudinal relaxivity value (r1 = 10.98 * 10-3 m-1 s-1 ). Moreover, it is demonstrated to be renal clearable with negligible systemic toxicity. This work highlights a straightforward and repeatable approach for synthesizing highly effective and multifunctional noble metal nanoagent of great clinical promising for cancer theranostics. PMID- 30303634 TI - A Wonderful Year - A Bright Tomorrow. PMID- 30303635 TI - The Winds of Change Are Upon Us. PMID- 30303636 TI - The Health and Safety of Nephrology Nurses and the Environments in Which They Work: Important for Nurses, Patients, and Organizations. AB - Nurse health and safety and the environments in which nurses work impact nurses, patient safety and quality of care, and organizational outcomes. In January 2018, we conducted a comprehensive national assessment of the overall health and safety of nephrology nurses and their work environments as a follow-up study to the 2014 study on Patient Safety Culture in Nephrology Nurse Settings conducted by American Nephrology Nurses Association. This article presents initial broad findings of this national study. Results identified a number of opportunities for improvement in nephrology nurse work environments, especially in the areas of staffing, optimizing the knowledge and skills of registered nurses, and mental and physical health. PMID- 30303637 TI - Water Treatment for Hemodialysis: What You Must Know to Keep Patients Safe. AB - It is critical for all staff members to work together to keep patients safe. Nephrology nurses with responsibility for hemodialysis (HD) need to know and understand the clinical ramifications of water treatment and dialysate preparation. Although some HD programs may have full-time technical staff who operate and test the water treatment and dialysate preparation systems, many programs rely on nursing staff members for the dayto- day operation and testing of these systems. This article details the reasons safe water and dialysate are critical for patients on HD; and reviews components of water treatment systems, dialysate concentrate preparation, and the monitoring and testing necessary to assure that both water and dialysate are safe for patient use. Integrated HD systems (i.e., those that combine water treatment and dialysate preparation and delivery in an individual machine "package") are also described. PMID- 30303638 TI - Improvement of Immunosuppressive Medication Adherence Using a SystemCHANGE Intervention: Case Study of an Older Adult Kidney Transplant Recipient. AB - This article reports a case study of an older adult kidney transplant recipient with poor medication adherence enrolled in an innovative six-month SystemCHANGE intervention that seeks to systematically improve medication adherence by identifying and shaping routines, involving others in routines, and using medication-taking feedback through small, patient-led experiments. Medication adherence increased immediately and was sustained throughout the intervention and maintenance phases. This is the first case study to demonstrate effectiveness of the SystemCHANGE intervention for promoting medication adherence in a kidney transplant recipient. The intervention improved the timing of doses by linking them to a regularly occurring behavior and providing feedback. The SystemCHANGE intervention represents a systems-thinking approach for both provider and patients, and gives healthcare providers the tools needed to assist patients in using habits and routines, and feedback to improve medication taking and timing. PMID- 30303639 TI - Exercise Benefits and Barriers: The Perceptions of People Receiving Hemodialysis. AB - Negative perceptions of people receiving hemodialysis towards exercise have been proposed as barriers to exercise. The aims of this study were to explore perceptions of patients on hemodialysis concerning exercise and to investigate whether exposure to an exercise program was associated with patients' perceptions. Participants (n=274) from 10 hemodialysis clinics completed an adapted English-language version of the Dialysis Patient-Perceived Exercise Benefits and Barriers Scale. Most patients agreed that exercise was positive towards preventing muscular wasting, bone disease, keeping body weight at a steady level, improving mood and quality of life, and enhancing their selfcare activities. Reported barriers to exercise were treatment side effects, fear of falling, family burden, exercise knowledge, and vascular access. The majority perceived exercise as positive for them and for people receiving hemodialysis. Patients who had witnessed or participated in an exercise program were more positive towards exercise than those who had not. PMID- 30303640 TI - Focusing on the Fundamentals: A Simplistic Differentiation Between Qualitative and Quantitative Research. AB - This article describes qualitative, quantitative, and mixed methods research. Various classifications of each research design, including specific categories within each research method, are explored. Attributes and differentiating characteristics, such as formulating research questions and identifying a research problem, are examined, and various research method designs and reasons to select one method over another for a research project are discussed. PMID- 30303641 TI - Listening. PMID- 30303642 TI - The Value of Certification. PMID- 30303643 TI - Reaching Consensus on Outcomes for Successful Cannulation of an Arteriovenous Fistula: Patient and Healthcare Provider Perspectives. AB - There is a lack of consensus on what constitutes successful arteriovenous fistula (AVF) cannulation. The purpose of this study was to describe outcomes of successful cannulation of the AVF from both patient and healthcare provider perspectives. This was a mixed method study. Results reflecting the patient's description of success through interviews were reported previously. A sample of nursing and physician experts in vascular access completed a one-time survey. Results from healthcare providers suggest they consider cannulator ability to assess the AVF, knowledge of AVF anatomy, and patient-centered care as most important to cannulation success. Patient comfort, patient-centered care, and available support staff (i.e., expert cannulators) were perceived by both patients and healthcare provider groups as contributing to success. Strategies that promote patient comfort, patient-centered care, and having access to cannulation experts have the potential to improve cannulation outcomes. PMID- 30303644 TI - Symptoms, Coping, and Quality of Life of People with Chronic Kidney Disease. AB - The purpose of this study was to explore how symptoms affect quality of life (QOL) for people living with chronic kidney disease (CKD) and kidney transplants, and to determine the relationship among various coping styles, symptoms, and QOL. An online survey was conducted; 42 people with CKD or a kidney transplant completed all parts of the survey. We found strong significant relationships between symptoms and QOL ratings. Problem-focused coping strategies were the most frequently employed, but there were few significant relationships between symptoms and coping, or between problem focused coping strategies and QOL. Future research should explore whether interventions to address emotion-focused coping strategies impact QOL as well as symptom burden. PMID- 30303645 TI - The Patient Experience of Waiting on the Deceased Donor Kidney Transplant List While Receiving Dialysis. AB - End stage renal disease (ESRD) is a global health problem, and the gold standard treatment is kidney transplantation. However, due to the global shortage of organs, many patients with ESRD rely on dialysis for survival while waiting several years for a kidney transplant. An integrative review of qualitative studies was conducted on the experience of patients with ESRD who require either peritoneal dialysis or hemodialysis while waiting for a deceased donor kidney transplant. Eight international studies were selected for review. Six themes were identified: 1) living in hope, 2) uncertainty, 3) mixed emotions, 4) coping with waiting, 5) restrictions on freedom, and 6) support network. Patients on dialysis and waiting for a kidney transplant have emotional, educational, and informational needs that need to be better understood and addressed by nurses and physicians. PMID- 30303646 TI - Exploring Subjective Frames of Patients on Hemodialysis on Acquiring Resilience: A Q Methodology Study. AB - This study explored subjectivity frames of reference of resilience of patients on hemodialysis by using Q methodology. Participants included 35 patients on hemodialysis. Data were obtained from October to December 2016 and were analyzed by the PQ method. Five factors were identified: 1) finding the value of life by focusing on the meaning of a new life through hemodialysis, 2) compromising actively with the situation of hemodialysis, 3) internalizing sadness and emphasizing the meaning of life itself, 4) finding a support system to help overcome hemodialysis, and 5) building the will to live by getting strength from family. The common theme of the five factors was overcoming hemodialysis and moving forward with their lives. This study can help nurses understand the resilience of patients on hemodialysis and presents strategies that can be used to develop an intervention program to improve the resilience of patients on hemodialysis. PMID- 30303647 TI - Positive Coping and Self-Assessed Levels of Health and Burden in Unpaid Caregivers of Patients with End Stage Renal Disease Receiving Hemodialysis Therapy. AB - Caregiver burden has negative consequences on the perceived health and quality of life of caregivers. There is limited research on the positive aspects of caregiving. A descriptive convenience sample of 89 caregivers of patients on hemodialysis responded to an online survey distributed on the National Kidney Foundation's email list. Participants completed the Self-Assessed Health Measure (SAH), Positive Aspects of Caregiving (PAC), and the Caregiving Stress Appraisal (CAS) survey instruments. Caregivers with higher self-assessed levels of health, who view their caregiver role positively, experienced lesser degrees of burden (Pearson r=-0.537, p=0.000; and r=-0.335, p=<0.001, respectfully). Healthcare providers must take into consideration the health, wellness, and needs of unpaid caregivers. PMID- 30303648 TI - Focusing on the Fundamentals: Reading Qualitative Research with a Critical Eye. PMID- 30303649 TI - Hand Washing Adherence - Is That Really Our Goal? PMID- 30303650 TI - [EVALUATION OF CARDIOVASCULAR RISKS WITH THE USE OF MORPHOGENETIC KLOTHO PROTEIN IN PATIENTS WITH CHRONIC RENAL DISEASE]. AB - The aim: of the study was to explore the Klotho protein significance in patients with different stages of chronic kidney disease (CKD) and to assess the influence of antihypertensive therapy on Klotho protein serum levels. Materials and methods: 130 patients with stage 5 CKD1 were included in the study. Serum PTH, calcium and phosphorus were measured. ELISA was used to determine serum soluble alpha Klotho. Blood pressure including brachial and central (aortic) pressure was measured in all patients together with pulse wave velocity (using a "Sfigmokor" device); in addition, echocardiography (EchoCG), and X-ray examination of the abdominal aorta by Kauppila method were performed. Results: The dynamic study of serum Klotho level showed that it changes with decreasing glomerular filtration rate faster than a rise in phosphate and PTH levels starting from stage 3A of CKD. The two later variables increased at stages 4-5.According to the ROC analysis, the values of serum Klotho below 387 pg /ml suggested enhanced risk of myocardial calcification with 80% sensitivity and 76% specificity. In addition, the highest Klotho serum levels were observed in patients whose target BP values were achieved with angiotensin receptor blockers (ARB) compared to those who used other drugs [r<0,01] or failed to reached target BP levels [p=0,008]. Conclusion: The study showed the possibility of practical use of Klotho protein as an early diagnostic marker of cardiovascular risk. Reduced serum Klotho was less pronounced in patients who used ARB for correction of high blood pressure. Normal Klotho protein levels in serum have been associated with a lower frequency of heart and vessels calcification in CKD patients. PMID- 30303651 TI - [PEMPHIGUS ACANTHOLYTICUS PARANEOPLASTIC: LITERATURE REVIEW AND CASE REPORT]. AB - The article describes the clinical observation of a rare severe dermatosis, paraneoplastic acantholyticus pemphigus, associated with colon cancer with reference to pathogenesis, clinical variations and difficulties of diagnostics of this condition. PMID- 30303652 TI - [MODERN APPROACH TO THERAPY OF PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS]. AB - A case of the treatment of a patients with idiopathic pulmonary fibrosis with pirfenidone and nintedanib is reported with reference to the role of these medications in therapy of his condition in the context of modern theory of its pathogenesis. PMID- 30303653 TI - [INFLAMMATION AND HEMOCOAGULATION]. AB - Problems of inflammation are extensively studied all over the world. Its mechanisms are known to involve hundreds of factors. The blood coagulation system is a major component of each living organism. This article was designed to analyze the relationship between inflammation and hemocoagulation and discuss definition of the term "low-grade inflammation" with reference to the blood coagulation system. PMID- 30303654 TI - [ACUTE HEPATIC LESION ASSOCIATED WITH MYOCARDIAL INFARCTION: CLINICAL SIGNIFICANCE AND MODERN DIAGNOSTICS]. AB - This review of the literature is devoted to the problem of acute kidney injury (AKI) in patients with acute myocardial infarction (MI). We discuss the occurrence of AKI in patients with MI, mechanisms of its development and modern diagnostic methods. The article examines biomarkers of kidney injury that may be useful for early diagnostics of AKI. PMID- 30303655 TI - Barriers and facilitators to improving health care for adults with intellectual and developmental disabilities: what do staff tell us? AB - INTRODUCTION: Adults with intellectual and developmental disabilities (IDD) have high rates of morbidity and are less likely to receive preventive care. Emergency departments and primary care clinics are important entry points into the health care system. Improving care in these settings can lead to increased prevention activities, early disease identification, and ongoing management. We studied barriers and facilitators to improving the care of patients with IDD in three primary and three emergency care sites in Ontario. METHODS: Data sources included structured implementation logs at each site, focus groups (n = 5) and interviews (n = 8). Barriers and facilitators were coded deductively based on the Consolidated Framework for Implementation Research (CFIR). Synthesis to higher level themes was achieved through review and discussion by the research team. Focus was given to differences between higher and lower implementing sites. RESULTS: All sites were challenged to prioritize care improvement for a small, complex population and varied levels of implementation were achieved. Having national guidelines, using local data to demonstrate need and sharing evidence on value were important engagement strategies. Factors present at higher implementing sites included strong champions, alignment with site mandate, and use of electronic prompts/reminders. Lower implementing sites showed more passive endorsement of the innovation and had lower capacity to implement. CONCLUSION: Providing effective care for small, complex groups, such as adults with IDD, is critical to improving long-term health outcomes but is challenging to achieve. At a systemic level, funding incentives, access to expertise and improved electronic record systems may enhance capacity. PMID- 30303656 TI - Breast cancer detection method, diagnostic interval and use of specialized diagnostic assessment units across Ontario, Canada. AB - INTRODUCTION: Breast cancer is detected through screening or through signs and symptoms. In Canada, mammograms for breast cancer screening are offered in organized programs or independently (opportunistic screening). Province of Ontario breast Diagnostic Assessment Units (DAUs) are facility-based programs that provide coordinated breast cancer diagnostic services, as opposed to usual care, in which the primary care provider arranges the tests and consultations. This study describes breast cancer detection method, diagnostic interval and DAU use across Ontario. METHODS: The study cohort consisted of 6898 women with invasive breast cancer diagnosed in 2011. We used the Ontario Cancer Registry linked to administrative health care databases. We determined the detection method using the Ontario Breast Screening Program (OBSP) data and physician claims. The diagnostic interval was the time between the initial screen, specialist referral or first diagnostic test and the cancer diagnosis. The diagnostic route (whether through DAU or usual care) was determined based on the OBSP records and biopsy or surgery location. We mapped the diagnostic interval and DAU coverage geographically by women's residence. RESULTS: In 2011, 36% of Ontario breast cancer patients were screen-detected, with a 48% rate among those aged 50 to 69. The provincial median diagnostic interval was 32 days, with county medians ranging from 15 to 65 days. Provincially, 48.4% were diagnosed at a DAU, and this ranged from zero to 100% across counties. CONCLUSION: The screening detection rate in age-eligible breast cancer patients was lower than published population-wide screening rates. Geographic mapping of the diagnostic interval and DAU use reveals regional variations in cancer diagnostic care that need to be addressed. PMID- 30303657 TI - The association of school connectedness and bullying involvement with multiple screen-time behaviours among youth in two Canadian provinces: a COMPASS study. AB - INTRODUCTION: Screen time, a proxy for sedentary behaviours, has emerged as a critical health determinant among youth in contemporary societies, where most aspects of youth life involve access to screen-time devices. An understudied approach to reducing screen time among youth is bullying reduction. This study aims to understand the association between bullying perpetration, victimization, youth perception of the school environment and multiple screen-time behaviours. METHODS: A total of 44,861 youth aged between 13 and 18 years in two Canadian provinces completed a validated questionnaire that collected student data on health behaviours and outcomes, including multiple screen-time behaviours, bullying perpetration and victimization, and school connectedness. The outcome variables were total screen time, time spent watching television, playing video games, internet surfing, and communication- based screen-time behaviours. Using a random intercept, the final models were built using PROC MIXED in SAS 9.4. These models were adjusted for age, ethnicity, weekly disposable income, daylight hours, and weather variables. RESULTS: Compared to youth who reported non involvement in bullying, youth who were bullies, victims, or both bullies and victims spent on average more minutes per day in front of screens across all screen time categories. Youth who felt happy and safe at school, and who perceived their teachers as being fair, reported lower levels of multiple screen time behaviours. CONCLUSION: With non-involvement in bullying showing a strong negative association with multiple screen-time behaviours, school policies to address bullying and screen time through school connectedness could offer a novel approach in minimizing these harmful behaviours. PMID- 30303658 TI - At-a-glance - Bringing equity into the fold: a review of interventions to improve mental health. AB - In Canada, it is challenging to find examples of positive population mental health interventions that meet scientific standards of evidence. It is even more difficult to identify effective interventions that address health equity. The discrepancy between standards of evidence in the health sciences, and the evidence that can be gleaned from social experiments, is not new. Efforts to reconcile these differences show a general tendency toward controlled interventions in public health. However, it is possible to extract findings from quasi-experimental interventions that meet scientific standards while also showing promise of positive impacts on mental health equity. This article describes work undertaken in 2015 to begin to address this evidence gap. PMID- 30303659 TI - At-a-glance - How Healthy are Canadians? A brief update. PMID- 30303660 TI - Release notice - The Canadian Paediatric Surveillance Program 2017 Results. PMID- 30303661 TI - [ZIKA FEVER: CLINICAL, EPIDEMIOLOGICAL, LABORATORY, AND DIAGNOSTIC ASPECTS]. AB - The authors overview data on the prevalence of Zika fever with reference to biological properties of the causative agent, epidemiological process, pathogenesis, and clinical symptoms of the disease. Special attention is given to the identification of the virus in pregnant women, microcephaly in the babies born by Zika-infected women, algorithm of laboratory diagnostics, and measures needed to prevent and control mosquitoes that spread viruses. PMID- 30303662 TI - [SUBCLINICAL HYPOTHYROIDISM]. AB - Subclinical hypothyroidism is a rather common disorder of the thyroid gland. Despite the fact that subclinical hypothyroidism has no clear-cut clinical picture, this condition is associated with changes in various organs and systems, moreover, it is a risk factor of cardiovascular diseases. The article summarizes the available data on subclinical hypothyroidism, principles of its diagnostics and treatment. PMID- 30303663 TI - [INTESTINAL MICROBIOTA: ITS ROLE IN PATHOGENESIS OF ARTERIAL HYPERTENSION]. AB - The review presents data on the relationship of intestinal microbiota and the development of arterial hypertension. Mechanisms through which intestinal dysbiosis may contribute to the development of this disease are reviewed. Results of studies on modulation of intestinal microbiota in patients with arterial hypertension with the use of probiotics and antibiotics are presented. It is concluded that the development of innovative dietary strategies ensuring restoration of the balance in the intestinal microbiota will allow to effectively control and treat arterial hypertension. PMID- 30303664 TI - [THE INFLUENCE OF DEFICIT OF ENDOGENOUS NEUROPEPTIDES ON THE CLINICAL COURSE OF CORONARY HEART DISEASE]. AB - The study is aimed at elucidating the relationship between the blood b-endorphin level in patients with coronary heart disease (CHD) with metabolic syndrome (MS) and cardiovascular risk factors and evaluating the possibility to correct them by dalargin therapy. The study included 123 patients (61 men and 62 women) at the mean age 57.6+/-5,2 years randomized into 2 groups. The patients of group 1 (n=63) were given the standard treatment, those of group 2 (n=60) additionally received 2 mg/day of dalargin for 10 days (3 courses during 3 months). The group of comparison (n=84) contained 84 CHD patients without MS. Biochemical and immunological characteristics were measured by immuno enzyme and immunochemiluminescent assays before and 3 months after treatment. The study revealed inverse correlation between b-endorphin levels and those of leptin, insulin, cortisol, TNF-a, IL-6, oxidized LDLP, triglycerides (TG), and HDLP cholesterol. Standard therapy resulted in a 6.5% reduction of insulin level, 9,4% , 6,1%, and 17,4% reduction of TNF-a , IL-6, TG levels respectively; it increased the HDLP cholesterol level by 10,3% (p<0,05 for all values) but did not change other parameters of interest. Dalargin therapy caused a 32,6% and 17,4%, rise in the b-endorphin and HDLP cholesterol levels but decreased leptin, insulin, cortisol, TNF-a, IL-6, LDLP, and tG levels by 36,1%, 22,4%, 23,9%, 55%, 56,3%, 14% and 27,2% respectively (p<0,001). It is concluded that the decrease of the blood b-endorphin level in the patients with coronary heart disease and metabolic syndrome is associated with enhanced blood atherogenicity, hyperinsulinemia, hypercortisolemia, activation of pro-inflammatory cytokines and lipid peroxidation. Supplementation of conventional therapy with dalargin results in the increased b-endorphin level, enhanced anti-atherogenic effect, reduced activity of pro-inflammatory cytokines and lipid peroxidation, reduction of leptin, insulin and cortisol levels. PMID- 30303665 TI - [DIFFERENTIAL APPROACH TO THE EVALUATION OF RIGHT VENTRICULAR SYSTOLIC FUNCTION BY PULSED WAVE DOPPLER ULTRASOUND]. AB - A method for diagnostics of systolic function of the right ventricle of the heart in patients with cardiovascular disease is proposed. Its application expands possibilities for detecting disorders of the discharge RV function using a conventional pulsed wave Doppler ultrasonography. PMID- 30303666 TI - [MELATONIN: THE POSSIBILITY TO ANALYSE THE MARKER OF AGE-RELATED PATHOLOGY IN THE BUCCAL EPITHELIUM AND URINE]. AB - Extrapineal and pineal melatonin is the marker of the aging rate of organism making it possible to characterize functional condition of the neuro-immuno endocrine system. In this article we have used the new method for non-invasive diagnostics of melatonin expression in buccal epithelium and determination of the main melatonin metabolite 6-hydroxymelatonin sulfate (6-HMS) in urine of elderly people. Normal, impaired and enhanced melatonin expression was documented in 20.5%, 43.2% and 36.30% of the patients respectively. Such comprehensive melatonin and 6-COMT studies can be recommended for elderly patients with oncological, neurodegenerative, cardiovascular diseases, and ageing macular dystrophy. Moreover, melatonin expression analysis in buccal cells can be used for integral investigation of biorhythms in elderly people. PMID- 30303671 TI - [MODERN CLINICAL EPIDEMIOLOGICAL CHARACTERISTIC OF LUPUS ERYTHEMATOSUS BASED ON THE DATA OF REGIONAL REGISTRY]. AB - Systemic lupus erythematosus (SLE) is a severe rheumatic disease characterized by polysymptomatic clinical picture. At the present stage, there are no updated epidemiological data due to the low prevalence of the disease. The aim of the study was to examine the current clinical and epidemiological characteristics of patients with systemic lupus erythematosus based on the information contained in the territorial register, analysis of occurrence and symptoms at the early stage of the disease. This study demonstrated the epidemiological and clinical characteristics of SLE from the analysis of 107 cases during the period from 2011 to 2013 and retrospective analysis of the cases for 1980-2013. The epidemiological situation was evaluated based on extensive and intensive indicators using statistical software license. The current SLE prevalence was estimated at 5,59 per 100 000 population in 2013, the incidence between 1994 and 2003 at 0,29 per 100 000 population and between 2004 and 2013 at 0,49, with the peak in 2010 up to 1,35 per 100 000 population. The average absolute growth and growth rate of SLE in the first decade was 0,05% and 0,24%, in the second decade 0,001% and 0,006% respectively, with the female to male ratio being 9:1, mean age of the patients 37,62+/-11,65 years), and ethnic composition of 87 Slavs and 15 Crimean Tatars. The most common symptoms at the early (polyarthritis, fever, dermatitis) and advanced (polyarthritis, Raynaud's syndrome, carditis, myalgia) stages differed from those specified by American College of Rheumatology (1997). The difference between early and late symptoms of SLE was documented . Based on the data obtained, the division of the disease into clinical subtypes (phenotypes) is proposed. PMID- 30303672 TI - [EVALUATION OF BODY MASS INDICES AND ARTERIAL PRESSURE AS CARDIOVASCULAR RISK FACTORS IN THE ADULT POPULATION OF THE CITY OF VORONEZH]. AB - Aim: To determine body mass index (BMI) and blood pressure (BP) of the Voronezh city adult population. Materials and methods: 1108 residents of Voronezh city at the age from 20 to 75 years were examined in 2015 including measurement of their height, body mass, arterial pressure, and BMI calculation. Medical histories were analyzed to reveal arterial hypertension in the preceding period in the following age groups: 20-29, 30-39, 40-49, 50-59, 60-75 yr and the entire study group (20 75 yr). Results: The mean BMI of the residents of Voronezh was 28.5 (23.8; 33.1) kg/m. The highest values were found between 40 and 59 years. BMI in women under 40 was lower than in men of the same age. The education level affected the prevalence of obesity in that people with secondary vocational education were more likely to be obese than those given higher education. At the age of 40, the incidence of hypertension among women was lower than among men of the same age, it more frequently occurred at the age of 60-75 years. Both age and BMI were related to the level of blood pressure: higher BMI and blood pressure were recorded at an older age. The prevalence of hypertension also increased with age. Conclusion: Obesity was detected in 29.7% of the Voronezh population recruited to the study. The prevalence of obesity among young adults (20-29 years) iproved lower than in the middle and old age groups. 30.9% of the residents suffered from AH. PMID- 30303673 TI - To the Readers of the Annals of Medicine. PMID- 30303674 TI - A physiologist observing and reporting supra-pharmacologic dobutamine stress testing: can we trust them, and can we trust the results? AB - In a study, published in this issue of Echo Research and Practice, Ntoskas et al. retrospectively analyzed the safety of a cardiac physiologist performing, and interpreting, Dobutamine stress echocardiography (DSE) in of 300 patients undergoing DSE for the detection of inducible reversible ischemia, myocardial viability and valvular heart disease. While safety during the tests themselves did not appear to be compromised with this unsupervised approach, the interpretation of these DSEs causes concerns regarding broad patient safety relative to misread results.Dobutamine stress echocardiography (DSE) has been utilized extensively in the detection of coronary artery disease (CAD) and prediction of patient outcome (1, 2, 3, 4). Its safety has also been thoroughly investigated in the contemporary era of contrast utilization (4). The test, though, does require giving supra-pharmacologic doses (up to 40 ug/kg/min) of an inotrope to patients with potentially significant CAD. The addition of atropine (up to 2 mg) is associated with other risks associated with anticholinergic side effects. Despite all these potential complications, the administration of these agents to thousands of patients has been shown to be safe, with a low likelihood of myocardial infarction or life-threatening arrhythmias (5). With this degree of safety, the question has been raised as to whether the test could safely be performed in the absence of a physician. In a study, published in this issue of Echo Research and Practice, Ntoskas et al. retrospectively analyzed the safety of a cardiac physiologist performing, and interpreting, the DSEs of 300 patients undergoing DSE for the detection of inducible reversible ischemia, myocardial viability, and valvular heart disease (6). Although the expected complications of arrhythmias and hypotension were observed, the team of cardiac physiologists managed these conditions appropriately, and safety did not appear to be compromised with this unsupervised approach (6).The COCATS 4 Training Guidelines in the United States have given specific instructions for who can perform and supervise stress echocardiograms (7). This requires the minimum performance of 150 echocardiograms and the interpretation of 300 echocardiograms before one can be expected to achieve reasonable competency in the area of regional wall motion analysis. In addition to this, one must also perform 100 stress echocardiograms in the presence of an experienced level III echocardiographer who has experience in running a stress echocardiography laboratory. The main concerning aspect of the study is that interpretation of the study was also done by the cardiac physiologist. Although median duration of follow-up was not reported, case notes for hospital follow-up (but not overall follow-up) were reviewed at 18-24 months. The majority of the referrals were for CAD assessment. Most of the studies appeared to be in patients with low to intermediate pretest probability. Although abnormal studies had high positive predictive value for detecting angiographically relevant CAD, there were seven patients in whom the study was read as negative who returned with significant complications due to multivessel CAD. Although we cannot determine the true false-negative rate in this study population, the results of this small pilot retrospective study tell us that there is a danger with the entire process of a physiologist-run program, if the interpretation of the studies is left in their hands. The authors of this study do not give us the specific training background of the cardiac physiologists in this study, and as imaging cardiologists, we are all aware of the difficulties inherent in interpreting wall motion. Although supra-pharmacologic doses of dobutamine have some potentially dangerous consequences, the pilot study by Ntoskas et al. reminds us that the biggest danger associated with DSE is in misinterpreting the data obtained from the study. PMID- 30303675 TI - Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography AB - Pulmonary hypertension is defined as a mean arterial pressure of >=25 mmHg as confirmed on right heart catheterisation. Traditionally, the pulmonary arterial systolic pressure has been estimated on echo by utilising the simplified Bernoulli equation from the peak tricuspid regurgitant velocity and adding this to an estimate of right atrial pressure. Previous studies have demonstrated a correlation between this estimate of pulmonary arterial systolic pressure and that obtained from invasive measurement across a cohort of patients. However, for an individual patient significant overestimation and underestimation can occur and the levels of agreement between the two is poor. Recent guidance has suggested that echocardiographic assessment of pulmonary hypertension should be limited to determining the probability of pulmonary hypertension being present rather than estimating the pulmonary artery pressure. In those patients in whom the presence of pulmonary hypertension requires confirmation, this should be done with right heart catheterisation when indicated. This guideline protocol from the British Society of Echocardiography aims to outline a practical approach to assessing the probability of pulmonary hypertension using echocardiography and should be used in conjunction with the previously published minimum dataset for a standard transthoracic echocardiogram. PMID- 30303676 TI - EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: Prenatal diagnosis of congenital heart disease AB - This review article will guide the reader through the background of prenatal screening for congenital heart disease. The reader will be given insight into the normal screening views, common abnormalities, risk stratification of lesions and also recent advances in prenatal cardiology. PMID- 30303677 TI - Evaluation of the quality of transesophageal echocardiography images and verification of proficiency AB - Various metrics have been used in curriculum-based transesophageal echocardiography (TEE) training programs to evaluate acquisition of proficiency. However, the quality of task completion, that is the final image quality, was subjectively evaluated in these studies. Ideally, the endpoint metric should be an objective comparison of the trainee-acquired image with a reference ideal image. Therefore, we developed a simulator-based methodology of preclinical verification of proficiency (VOP) in trainees by tracking objective evaluation of the final acquired images. We utilized geometric data from the simulator probes to compare image acquisition of anesthesia residents who participated in our structured longitudinal simulator-based TEE educational program vs ideal image planes determined from a panel of experts. Thirty-three participants completed the study (15 experts, 7 postgraduate year (PGY)-1 and 11 PGY-4). The results of our study demonstrated a significant difference in image capture success rates between learners and experts (chi2 = 14.716, df = 2, P < 0.001) with the difference between learners (PGY-1 and PGY-4) not being statistically significant (chi2 = 0, df = 1, P = 1.000). Therefore, our results suggest that novices (i.e. PGY-1 residents) are capable of attaining a level of proficiency comparable to those with modest training (i.e. PGY-4 residents) after completion of a simulation-based training curriculum. However, professionals with years of clinical training (i.e. attending physicians) exhibit a superior mastery of such skills. It is hence feasible to develop a simulator-based VOP program in performance of TEE for junior anesthesia residents. PMID- 30303678 TI - Left ventricular diastolic dysfunction: identifying presence by left atrial function AB - Objective: The left atrium (LA) is exposed to left ventricular pressure during diastole. Applying the 2016 American Society of Echocardiography left ventricular diastolic function (LVDF) guidelines, this study aims to investigate whether left atrial ejection fraction (LAEF) and left atrial active emptying fraction (LAAEF) are markers of diastolic dysfunction (LVDD). Methods: Retrospective cohort of consecutive patients (n = 124) who underwent transthoracic echocardiography were studied. Doppler peak velocities of passive (MV E) and active filling (MV A) were measured and ratio E/A calculated. Tissue Doppler imaging parameters of peak early (e') of the septal and lateral mitral annulus were measured, and average E/e' ratio (E/e') was calculated. Tricuspid regurgitation velocity, left atrial maximum volume, left atrial minimum volume and LA volume pre-contraction were measured, allowing calculation of LAEF and LAAEF. Subjects were assigned LVDF categories. Results: Binomial logistic regression model (X2(2) = 48.924, P < 0.01) determined that LAEF and LAAEF predicted diastolic dysfunction with sensitivity 85.5% and specificity 78%. ROC curves determined good diagnostic accuracy for LAEF and LAAEF to predict LVDD, AUC 0.826 and 0.861 respectively. Logistic regression model (X2(2) = 39.525, P < 0.01) predicted those patients with E/e' >=14 using LAEF and LAAEF with sensitivity 51.6% and specificity 92.4%. Moderate correlations were found between E/e' and log derivatives of LAEF and LAAEF. Conclusions: A decline in LAAEF and LAEF is associated with worsening LVDD. PMID- 30303679 TI - Safety and efficacy of physiologist-led dobutamine stress echocardiography: experience from a tertiary cardiac centre AB - Background: Dobutamine stress echocardiography (DSE) services have traditionally been medically led. In some UK institutions, DSE lists are led by physiologists with medical support. In our tertiary cardiac centre at New Cross Hospital (NCH), the DSE service was established by a consultant echocardiographer. Following intensive training and assessment, the Trust approved drug administration by named senior cardiac physiologists. We believe this is the first report of a cardiac physiologist-managed DSE service, including physiologist drug administration. We have assessed the feasibility, safety and validity of this physiologist-led DSE service. Methods: Retrospective analysis of 333 patients undergoing stress echocardiogram for inducible reversible ischaemia, myocardial viability and valvular heart disease over 6 months. Patients' case notes review after 18-24 months. Results: Overall, 92% of all cases (306) were performed by physiologists. In 300 studies, dobutamine was administered. The majority of the referrals were for coronary artery disease (CAD) assessment (281). In 235 cases, the study was uncomplicated. Sixty-seven patients developed dobutamine-related side effects. In 16 cases, complications led to early termination of the study. In two cases, urgent medical review was needed. Of the 281 studies for CAD assessment, 239 were negative for ischaemia, 28 were positive and 14 inconclusive. In 5 out of 28 cases with echocardiogram, evidence of inducible ischaemia, coronary angiography revealed unobstructed coronary arteries. Conclusion: This study demonstrates the safety and effectiveness of this practice and provides potential for the expansion of the physiologists' role and physiologist-led DSE services in other hospitals. PMID- 30303680 TI - Clinical and echocardiographic follow-up of patients following surgical heart valve repair or replacement: a tertiary centre experience AB - International best practice guidelines recommend lifelong follow-up of patients that have undergone valve repair or replacement surgery and provide recommendations on the utilization of echocardiography during follow-up. However, such follow-up regimes can vary significantly between different centres and sometimes within the same centre. We undertook this study to determine the patterns of clinical follow-up and use of transthoracic echocardiography (TTE) amongst cardiologists in a large UK tertiary centre. In this retrospective study, we identified patients that underwent heart valve repair or replacement surgery in 2008. We used local postal codes to identify patients within our hospital's follow-up catchment area. We determined the frequency of clinical follow-up and use of transthoracic echocardiography (TTE) during the 9-year follow-up period (2009-2016 inclusive). Of 552 patients that underwent heart valve surgery, 93 (17%) were eligible for local follow-up. Of these, the majority (61/93, 66%) were discharged after their 6-week post-operative check-up with no further follow-up. Of the remaining 32 patients, there was remarkable heterogeneity in follow-up regimes and use of TTE. This variation did not correlate with the prosthesis type. In summary, the frequency of clinical follow-up and use of echocardiography is highly variable in contemporary practice. Many patients are inappropriately discharged back to their family doctor with no plans for hospital follow-up. These data further support the creation of dedicated specialist heart valve clinics to optimize patient care, ensure rational use of TTE and optimize adherence with best practice guidelines. PMID- 30303681 TI - A male with multiple cardiac masses AB - Summary: Thirty-seven-year-old male presented with cough, dyspnea, significant weight loss (20 kg) and subacute fever for the past 2 months. Physical examination revealed inspiratory and expiratory wheezing bilaterally. A normal S1, S2 and a 3/6 systolic ejection murmur at the left upper parasternal border with respiratory variation were found during cardiac auscultation. Kidney and bone marrow biopsy reported a high-grade B-cell lymphoma. Echocardiography and cardiac CT findings consisted of multiple intracardiac masses affecting the right ventricular (RV) outflow track, RV apex, medial portion of the right atrium and posterior left atrium, as well as mild impairment of the RV systolic function. The masses in the RV outflow track caused partial obstruction (pulmonary valve peak velocity 2.3 m/s) with a RV systolic pressure of 43 mmHg. The infiltrative mass in the interatrial septum extended into both the right and left atrial cavities. The right superior pulmonary vein was occluded. This patient was treated with aggressive chemotherapy and had a good clinical response that resulted in mass size reduction after the first course of chemotherapy. Multimodality imaging techniques such as echocardiography, cardiac CT and PET scan can provide complementary information to better evaluate, stage and manage these patients. Learning Points: Lymphoma can be found as a primary tumor in cardiac tissue, but secondary cardiac lymphoma is far more common.Appropriate investigation, histopathology, immunophenotype, staging and risk assessment are required for definite diagnosis and treatment.Cardiac lymphoma frequently manifests as an ill-defined, infiltrative mass. Typical location is in the atrium (right atrium is the most common site). Pericardial thickening or effusion is also common.Echocardiography is a quick, bedside, non-invasive assessment of anatomical involvement and hemodynamics affected by cardiac lymphoma. Echocardiographic findings of cardiac lymphoma include a hypoechoic, ill-defined infiltrative masses in the myocardium, nodular protrusion into cardiac chambers and pericardial effusion. Obstruction of inflow/outflow track can also be found.If a diagnosis of cardiac lymphoma is made, the most effective treatment is chemotherapy. Surgical treatment may have a role when hemodynamic compromise does not respond to chemotherapy and radiotherapy. PMID- 30303682 TI - [Development of Lyophilization Procedure Ensuring Survival of Bifidobacteria and Preservation of Their Probiotic Potential upon Long-Term Storage]. AB - Survival of bifidobacteria and preservation of their morphological characteristics after 12-month storage of lyophilized cells was studied for the strains of Bifidobacterium bifidum and B. animalis isolated and maintained in the microbial collection of the Department of Microbiology, Moscow State University. A combined approach to pre-lyophilization treatment of microorganisms and subsequent storage was developed in order to improve cell survival. Compared to the standard cryoprotector concentrations, sucrose and glucose (5% and higher) in skim milk, as well as freezing at -70 degrees C with subsequent storage at the same temperature resulted in improved survival of bifidobacteria. Under such conditions, the number of viable cells (CFU) after 12 months of storage was two to three orders of magnitude higher than in the case of the standard lyophilization procedure. Investigation of dynamics of resistance of reactivated clones to such gastrointestinal stress factors as gastric juice and bile acids revealed preservation of these properties at all storage modes. However, since the number of surviving cells decreased during storage according to the standard procedure, the number of stress-affected cells was correspondingly lower. Reactivated cultures exhibited high resistance to oxygen, with survival decreasing to 35% of the initial level. PMID- 30303683 TI - Catastrophic stroke in a patient with left ventricular non-compaction AB - Summary: We present the case of a 32-year-old man who presented with a remote history of chest pain and was diagnosed with non-compaction cardiomyopathy on echocardiography. On presentation, he was relatively asymptomatic with normal cardiac function. Unfortunately, he presented 1 year later with a catastrophic embolic stroke. Learning points: Left ventricular non-compaction (LVNC) is a myocardial disorder characterised by prominent left ventricular (LV) trabeculae, a thin compacted layer and deep intertrabecular recesses.Two-dimensional echocardiography with colour Doppler is the study of choice for diagnosis and follow-up of LVNC. CMR serves an important role where adequate echocardiographic imaging cannot be obtained.LVNC is associated with high rates of mortality and morbidity in adults, including heart failure, thromboembolic events and tachyarrhythmias. PMID- 30303684 TI - Sub-acute leaflet thrombosis: a reversible cause of aortic stenosis AB - A 77-year-old male underwent elective bioprosthetic aortic valve replacement (23 mm Carpentier-Edwards Perimount MagnaEase) for severe aortic stenosis. His pre discharge transthoracic echocardiogram (TTE) was normal. He presented 9 days after surgery with dyspnea and fever. He was in sinus rhythm. Blood cultures were taken and he was commenced on empirical antibiotics for possible infective endocarditis (subsequently all negative). Repeat TTE showed a well-seated prosthesis without regurgitation but elevated gradients (peak/mean gradients 69/48mmHg respectively). Transoesophageal echocardiography (TOE) revealed marked thickening of the leaflets, without obvious vegetations (Fig. 1 and Videos 1, 2). The patient was diagnosed with subacute prosthetic valve thrombosis and was anticoagulated with apixaban. He underwent repeat TOE 3 months later, which demonstrated thin, mobile valve leaflets with normalized transprosthetic gradients (Figs 2, 3 and Videos 3, 4). Thrombosis of a bioprosthetic valve is usually diagnosed in the early postoperative period, when endothelialisation of the suture zone is incomplete (1). Although previously considered rare (2), a recent observational study using cardiac CT imaging found an incidence of 4% (5/138) and 13% (101/752) in patients with surgical and transcatheter valves respectively (3). We have had another two cases of sub-acute bioprosthetic valve leaflet thrombosis in our centre this year, highlighting that this condition is not as rare as previously thought. Anticoagulation therapy - and not anti platelet drugs - was associated with successful prevention and treatment of subclinical leaflet thrombosis (3). Indeed, American guidelines on valvular heart disease give a Class IIb recommendation for a period (3-6 months) of formal anticoagulation after bioprosthetic AVR (4). Patients with established risk factors, including atrial fibrillation and a history of thromboembolic event, may have most to benefit from a brief period of routine post-operative anticoagulation (5). PMID- 30303685 TI - Safety and efficacy of physiologist-led dobutamine stress echocardiography AB - Dr Porter in his editorial comment (1) on a physiologist-led stress echo service (2) acknowledges that the service was safe in terms of adverse effects but is concerned that 'the interpretation of the study was also done by the cardiac physiologist'. He reminds us 'that the biggest danger associated with dobutamine stress echocardiography is in misinterpreting the data obtained...'. PMID- 30303686 TI - Transoesophageal echocardiography (TOE): contra-indications, complications and safety of perioperative TOE AB - Transoesophageal echocardiography (TOE) has, in certain clinical situations, become an almost universal monitor and diagnostic tool. In the perioperative environment, TOE is frequently used to guide anaesthetic management and assist with surgical decision making for, but not limited to, cardiothoracic, major vascular and transplant operations. The use of TOE is not limited to the theatre environment being frequently used in outpatient clinics, emergency departments and intensive care settings. Two case reports, one of oesophageal perforation and another of TOE utilization in a patient having previously undergone an oesophagectomy, introduce the need for care while using TOE and highlight the need for vigilance. The safe use of TOE, the potential complications and the suggested contra-indications are then considered together with suggestions for improving the safety of TOE in adult and paediatric patients. PMID- 30303687 TI - Impact of 3D echocardiography on grading of mitral stenosis and prediction of clinical events AB - Background: The mitral valve orifice area (MVOA) is difficult to assess accurately by 2D echocardiography because of geometric assumptions; therefore, 3D planimetry may offer advantages. We studied the differences in MVOA measurements between the most frequently used methods, to determine if 3D planimetry would result in the re-grading of severity in any cases, and whether it was a more accurate predictor of clinical outcomes. Methods: This was a head-to-head comparison of the three most commonly used techniques to grade mitral stenosis (MS) by orifice area and to assess their impact on clinical outcomes. 2D measurements (pressure half-time (PHT), planimetry) and 3D planimetry were performed retrospectively on patients with at least mild MS. The clinical primary endpoint was defined as a composite of MV balloon valvotomy, mitral valve repair or replacement (MVR) and/or acute heart failure (HF) admissions. Results: Forty one consecutive patients were included; the majority were female (35; 85.4%), average age 55 (17) years. Mean and peak MV gradients were 9.4 (4) mmHg and 19 (6) mmHg, respectively. 2D and 3D measures of MVOA differed significantly; mean 2D planimetry MVOA was 1.28 (0.40) cm2, mean 3D planimetry MVOA 1.15 (0.29) cm2 (P = 0.003). Mean PHT MVOA was 1.43 (0.44) cm2 (P = 0.046 and P < 0.001 in comparison to 2D and 3D planimetry methods, respectively). 3D planimetry reclassified 7 (17%) patients from mild-to-moderate MS, and 1 (2.4%) from moderate to severe. Overall, differences between the two methods were significant (X2, P < 0.001). Only cases graded as severe by 3D predicted the primary outcome measure compared with mild or moderate cases (odds ratio 5.7). Conclusion: 3D planimetry in MS returns significantly smaller measurements, which in some cases results in the reclassification of severity. Routine use of 3D may significantly influence the management of MS, with a degree of prediction of clinical outcomes. PMID- 30303688 TI - A retrospective study of 251 patients admitted to a multidisciplinary, neurorehabilitation unit with intensive care unit capabilities. AB - INTRODUCTION: In Denmark, specialised neurorehabilitation is centralised in two centres; one is Hammel Neurocentre. The neurointensive stepdown unit at Silkeborg Regional Hospital offers intensive care in addition to specialised neurorehabilitation of patients transferring to Hammel. Knowledge on patient's characteristics and course of rehabilitation in this kind of setting is sparse. OBJECTIVE: To characterise the patients, their change in function and to identify variables associated with referral time to Hammel. METHODS: Functional scores and available covariates were extracted from hospital records on 251 patients admitted from 01 November 2011 to 31 July 2016. Statistical methods included logistic regression and paired tests. RESULTS: Mean (standard deviation) time from injury to admission at the neurointensive stepdown unit was 30 (22) d, medians (interquartile range) of Functional Independence Measure and Early Functional Abilities increased significantly from 18 (18, 19) to 24 (18, 44) and 37 (30, 46) to 52 (43, 70), respectively, during admission (p < 0.01). Spontaneous ventilation and Early Functional Abilities score on admission were positively associated with early referral. Obesity and anoxic brain injury were negatively associated with early referral. CONCLUSIONS: This study demonstrated functional improvement in patients in a neurointensive stepdown unit and identified variables associated with early referral. The study indicated higher sensitivity of the Early Functional Abilities score as compared to the Functional Independence Measure. Implications for rehabilitation Patients requiring prolonged intensive care services after severe acquired brain injury may require the fusion of neurorehabilitation and intensive care services to benefit maximally. There is a need for a consensus on which functional scores to use when documenting functional level and functional changes in patients with severe acquired brain injury and very low functional levels. The Early Functional Abilities score is an example of a valuable tool when assessing functional levels of patients with severe acquired brain injury and very low functional levels. PMID- 30303689 TI - Comments on "A Survey of Fellowship-Trained Upper Extremity Surgeons on Treatment of Lateral Epicondylitis". PMID- 30303690 TI - Oxidative stress, autophagy and airway ion transport. AB - Mucociliary clearance is critically important in protecting the airways from infection and from the harmful effects of smoke and various inspired substances known to induce oxidative stress and persistent inflammation. An essential feature of the clearance mechanism involves regulation of the periciliary liquid layer (PCL) on the surface of the airway epithelium, which is necessary for normal ciliary beating and for maintaining mucus hydration. The underlying ion transport processes associated with airway surface hydration include ENaC dependent Na+ absorption occurring in parallel with CFTR and Ca2+-activated Cl- channel-dependent anion secretion, which are coordinately regulated to control the depth of the PCL layer. Oxidative stress is known to cause both acute and chronic effects on airway ion transport function and an increasing number of studies within the past few years have identified an important role for autophagy as part of the physiological response to the damaging effects of oxidation. In this review recent studies addressing the influence of oxidative stress and autophagy on airway ion transport pathways are presented along with results showing the potential of autophagy modulators in restoring the function of ion channels involved in transepithelial electrolyte transport necessary for effective mucociliary clearance. PMID- 30303691 TI - Intersex, Hermaphroditism, and Gonadal Plasticity in Vertebrates: Evolution of the Mullerian Duct and Amh/Amhr2 Signaling. AB - In vertebrates, sex organs are generally specialized to perform a male or female reproductive role. Acquisition of the Mullerian duct, which gives rise to the oviduct, together with emergence of the Amh/Amhr2 system favored evolution of viviparity in jawed vertebrates. Species with high sexspecific reproductive adaptations have less potential to sex reverse, making intersex a nonfunctional condition. Teleosts, the only vertebrate group in which hermaphroditism evolved as a natural reproductive strategy, lost the Mullerian duct during evolution. They developed for gamete release complete independence from the urinary system, creating optimal anatomic and developmental preconditions for physiological sex change. The common and probably ancestral role of Amh is related to survival and proliferation of germ cells in early and adult gonads of both sexes rather than induction of Mullerian duct regression. The relationship between germ cell maintenance and sex differentiation is most evident in species in which Amh became the master male sex-determining gene. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30303692 TI - The incidence of atrial fibrillation and the added value of thumb ECG for detecting new cases. AB - OBJECTIVES: To evaluate the incidence of atrial fibrillation (AF) as well as the value of thumb electrocardiography (ECG) for identification of paroxysmal AF in a Swedish cohort of middle-aged men from the general population. DESIGN: A population based random cohort of 798 men underwent screening at the age of 50 and re-examined at the age of 60 and 71 years. At the last examination, a thumb ECG recording was conducted for 2 weeks twice a day in 479 men from the original cohort. Registered hospital AF diagnoses were retrieved from the Swedish Patient Registry from 1993 to 2014. RESULTS: During a 21-year follow-up, 77 men (9.6%) were diagnosed with AF; of these men, 49.4% (38 of 77) had permanent AF. Fifteen of 479 (3.1%) patients had paroxysmal AF. Of those, seven had been previously diagnosed with paroxysmal AF through Patient Registry. The incidence of AF increased from 2.2 per 1000 years at risk at the age of 50-54 years to 9.3 per 1000 years at risk at the age 65-70 years. The prevalence of AF at the age of 71 years was increased from 7.1% to 9.9% using thumb ECG. CONCLUSIONS: In addition to medical history, patient register and 12-lead -ECG, the use of thumb ECG increased the number of detected paroxysmal AF by 21%. PMID- 30303693 TI - The impact of lipid accumulation product (LAP) and visceral adiposity index (VAI) on clinical, hormonal and metabolic parameters in lean women with polycystic ovary syndrome. AB - This study was performed to assess the impact of lipid accumulation product (LAP) and visceral adiposity index (VAI) on clinical, hormonal, and metabolic parameters in lean women with PCOS. Retrospective analysis of 120 consecutive lean PCOS subjects was performed. Subjects were divided into two groups according to HOMA-IR, as IR + and IR-. A HOMA-IR value above 2.5 was used to indicate IR. Clinical, hormonal and metabolic parameters were compared between the two groups. Correlations between LAP and VAI and clinical, hormonal, metabolic features in women PCOS were analyzed. One hundred twenty lean PCOS subjects were enrolled, of which 39 were insulin resistant. Comparison of group means showed significantly higher values for TG levels, FAI, FGS, TG/HDL-c, TyG, LAP, and VAI indexes and lower values for glucose/insulin ratio and QUICKI in the IR + group. LAP and VAI were both found to be positively correlated with each other and with WC, FAI, FGS, TG, TC levels, lipid ratios, TyG index, and HOMA-IR and negatively correlated with Glucose/Insulin ratio, QUICKI, and HDL-c in lean women with PCOS. LAP and VAI may be promising in early identification of IR and cardiometabolic risk and may be useful for the assessment of hyperandrogenism in lean women with PCOS. PMID- 30303694 TI - Benign lesion evaluation: Factors causing the "stiff rim" sign in breast tissues using shear-wave elastography. AB - OBJECTIVE:: To investigate the factors causing the "stiff rim" sign in breast lesions using shear-wave elastography. METHODS:: A total of 907 patients with 907 lesions were included retrospectively in this study. Traditional ultrasound and shear-wave elastography imaging were both performed. Patients age, maximum diameter, depth, distance, echogenicity, shape, boundary, margin, internal components, CDFI, calcification, echogenicity attenuation and longitudinal growth of lesions were observed and calculated by both univariate and multivariate analyses. RESULTS:: Univariate analyses indicated that the age, depth, shape, margin, internal components, CDFI, calcification and pathology showed significant difference between the benign lesions with and without a "stiff rim", whereas there was no correlation of "stiff rim" with maximum diameter, distance, boundary, echogenicity, echo attenuation and longitudinal growth of the lesions. Multivariate analysis expressed that CDFI, margin, internal components, depth and age were significantly associated with the "stiff rim" sign in breast benign lesions, whereas there was no correlation with the pathology, shape or calcification of the lesions. CONCLUSIONS:: The "stiff rim" sign can be helpful for differentiation between benign and malignant lesions. Older patients with a "stiff rim" sign whose benign masses are deep, poorly defined, heterogeneous and have a positive CDFI should be examined more closely to avoid unnecessary false positives. ADVANCES IN KNOWLEDGE:: The "stiff rim" sign can be helpful for differentiation between benign and malignant lesions. Positive CDFI, poorly defined margin, heterogeneous internal components, deep depth and older age were significantly associated with the "stiff rim" sign in benign breast lesions. PMID- 30303696 TI - Fighting Parkinson's ... and Winning: A memoir of my recovery from Parkinson's Disease. PMID- 30303695 TI - Elevation of the adiponectin/leptin ratio in women with gestational diabetes mellitus after supplementation with alpha-lipoic acid. AB - Alpha-lipoic acid (ALA) is a short chain fatty acid and is known as a universal antioxidant. The aim of the current clinical trial study was to explore the effects of ALA supplementation on maternal circulating values of adiponectin (A), leptin (L); and A/L, L/A, adiponectin/homeostatic model assessment for insulin resistance (A/H), and malondialdehyde/total antioxidant capacity (MDA/TAC) ratios in pregnant women with gestational diabetes mellitus (GDM). Sixty women diagnosed as GDM during 24 and 28 weeks of pregnancy were randomly divided into drug (n = 30) and placebo (n = 30) groups. They consumed ALA (100 mg) and cellulose acetate (100 mg) respectively for 8 weeks, per day. The biochemical variables were evaluated before and after the trial. Maternal fasting serum values of glucose (p < .001), HOMA-IR (p < .001), MDA/TAC (p < .001), and L/A (p = .008) were decreased while values of adiponectin (p = .011), A/L (p = .001), and A/H (p < .001) were increased in the drug group after the intervention. In summary, current study had shown that after daily supplementation with 100 mg of ALA for 8 weeks in women with GDM, maternal circulating values of adiponectin, A/L, and A/H were increased while values of L/A and MDA/TAC were decreased. PMID- 30303697 TI - Comment on: LectureKeepr: A novel approach to studying in the adaptive curriculum. PMID- 30303698 TI - Value of Computed Tomography-Based Three-Dimensional Pre-operative Planning in Cup Placement in Total Hip Arthroplasty With Dysplastic Acetabulum. AB - OBJECTS: To investigate the value of CT-based 3D templating software for pre operative planning in patients with acetabular dysplasia undergoing total hip arthroplasty (THA) with a minimum follow-up of 2 years. METHODS: We performed a retrospective review of a single surgeon's cohort of patients with Crowe I to III developmental dysplastic hip (49 hips in 41 patients) who underwent cementless primary THA and were available for follow-up at a mean of 2.7 years after THA. We analyzed the accuracy of cup size prediction, the reliability of pre- and post operative cup orientation and position of reconstructed rotation center using CT based 3D templating software. Post-operative Harris Hip Score and lower limb discrepancy was obtained at the last follow-up. RESULTS: The sizes of 71% of the cup components (35/49) were estimated exactly, and 100% of the cup size estimates were accurate to within one-cup size. There was good reproducibility of pre- and post-operative position of reconstructed rotation center (correlation coefficient r = 0.396 for vertical position, p = 0.005; r = 0.326 for horizontal position, p = 0.024). There was no substantial agreement between the planned acetabular orientation and that measured post-operatively (correlation coefficient -0.174 for inclination and 0.045 for anteversion). There were 44 (90%) excellent or good results according to HHS. Seven patients (14%) reported lower limb discrepancy. CONCLUSIONS: Pre-operative CT-based 3D templating made it possible to predict accurate cup size and achieve reproducible cup position in patients with dysplastic acetabulum. The reproducibility of cup orientation could not be demonstrated in this study. PMID- 30303699 TI - Does the empty follicle syndrome occur in cases of low number of maturing follicles in assisted reproduction? AB - The pathophysiology of the genuine empty follicle syndrome (EFS) is still debated. Ovarian aging has been contested as a cause of this condition. Our aim was to investigate the occurrence of the genuine EFS in cases of a low number of mature follicles in a prospective manner. Ninety-five infertile women were recruited and evaluated following conventional controlled ovarian stimulation (COS) with <= six follicles of >=14 mm diameter on the day of hCG administration. Enrolled women were 37.5 +/- 5.2 years of age with basal FSH level of 9.1 +/- 3.7 mIU/L, antral follicle count (AFC) of 6.9 +/- 4.6, and number of >=14 mm follicles (on the day of hCG) of 3.4 +/- 1.5. Among the 95 women, four were complicated by the genuine EFS (4.2%) with features of the depleted ovarian reserve. Comparison between these four cases and the 91 controls revealed significant differences between age, AFC, number of >=14 mm follicles, and serum E2 level corresponding to 41.8 +/- 1.7 versus 37.4 +/- 5.2 years, 1.7 +/- 0.6 versus 7.1 +/- 4.5, 2.0 +/- 0.8 versus 3.4 +/- 1.5 follicles, and 356 +/- 200 versus 975 +/- 557 pg/mL, respectively. Post hoc analysis revealed that 56 among the 95 women fulfilled the Bologna criteria for poor ovarian response and all four cases matched the definition of the genuine EFS raising its incidence to 7.1% in this group. A logistic regression analysis showed that AFC was a significant factor in the development of the genuine EFS. We conclude that the genuine EFS complicates infertile women characterized by a low number of mature follicles. Our findings suggest that the mechanism behind this occurrence is associated with a more exhausted ovarian reserve. PMID- 30303700 TI - Does oral contraceptives pretreatment affect the pregnancy outcome in polycystic ovary syndrome women undergoing ART with GnRH agonist protocol? AB - This study aims to investigate whether oral contraceptive pills (OCP) pretreatment impairs pregnancy outcomes in polycystic ovary syndrome (PCOS) women undergoing GnRH agonist protocol. A total of 1025 couples underwent their first cycle of in vitro fertilization. Patients were divided into GnRH agonist protocol group (LP group) and OCP dual suppression GnRH agonist protocol group (OC-LP group). Logistic regressions were performed to estimate the risk factors affecting live birth following fresh embryo transfer between groups. Frozen thawed embryos from the first oocyte retrieval cycle were replaced into uterus for women did not get live birth. Cumulative live birth rates between groups were compared by Kaplan-Meier survival analysis. Serum luteinizing hormone level, endometrial thickness, and live birth rate were significantly reduced in the OC LP group in fresh cycle. Thinner endometrium, higher progesterone, and poorer embryo quality were independent risk factors for failure in getting live birth following fresh embryo transfer. However, cumulative live birth rate, medium embryo transfer attempts required to achieve live birth were comparable between groups. OCP pretreatment in GnRH agonist protocol does not seem to impair the pregnancy outcome when calculated by cumulative live birth rate in PCOS women. PMID- 30303702 TI - Comment on: How much basic science content do second-year medical students remember from their first year? PMID- 30303701 TI - Single fresh blastocyst transfer or single cryopreserved-thawed blastocyst transfer: which is preferable for infertile patients in IVF/ICSI cycles? A meta analysis. AB - PURPOSES: Nowadays, an increasing number of studies have proposed single embryo transfer (SET), especially single blastocyst transfer (SBT). To compare the clinical outcomes of single fresh blastocyst transfer (BT) and single cryopreserved-thawed BT in patients undergoing in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) cycles. METHODS: The PubMed, Embase, and Cochrane Library databases were searched from the start dates until February 2018. The primary outcomes were clinical pregnancy rate (CPR) and embryo implantation rate (IR). The secondary outcomes were multiple pregnancy rate (MPR), live birth rate (LBR), and miscarriage rate (MR). Using the Mantel Haenszel random effects model to analyze summary risk ratio (RR) with 95% confidence intervals (CIs). Statistical heterogeneity scores were assessed with the standard Cochrane's Q test and I2 statistic. RESULTS: In total, eight studies (two prospective studies, six retrospective studies) were included in our analysis. There was no statistically significant difference regarding clinical pregnancy (RR = 1.18, 95% CI = 0.91-1.55) and embryo implantation (RR = 1.04, 95% CI = 0.77-1.41). Regarding secondary outcomes, there was no significant difference regarding miscarriage (RR = 0.79, 95% CI = 0.60-1.03) and multiple pregnancy (RR = 1.23, 95% CI = 0.75-2.04). However, single fresh BT is associated with an increased live birth (RR = 1.28, 95% CI = 1.05-1.57) compared with single cryopreserved-thawed BT. CONCLUSIONS: In summary, this meta-analysis supports the hypothesis that single cryopreserved BT might not be the best choice compared with single fresh BT in patients undergoing IVF/ICSI cycles. PMID- 30303703 TI - Preoperative Colorectal-Cancer Detection: Do We Need Anything Else? An Invited Brief Commentary on Is CT Scan More Accurate than Endoscopy in Identifying Distance from the Anal Verge for Left-sided Colon Cancer? A Comparative Cohort Analysis. PMID- 30303704 TI - The Role of Insulin in Hepatic Regeneration: A New Frontier in Liver Function. An Invited Brief Commentary on "Insulin Metabolism and Assessment of Hepatic Insulin Extraction During Liver Regeneration. A Study in a Rat Model". PMID- 30303705 TI - The serotonin transporter (SERT) and non-selective transporters are involved in peripheral serotonin uptake in the Gulf toadfish, Opsanus beta. AB - In mammals, circulating serotonin (5-hydroxytryptamine; 5-HT) is sequestered by platelets via the 5-HT transporter (SERT) to prevent unintended signaling by this potent signaling molecule. Teleost fish appear to lack a similar circulating storage pool, although the diverse effects of 5-HT in teleosts likely necessitate an alternative method of tight regulation, such as uptake by peripheral tissues. Here, a 5-HT radiotracer was used to explore the 5-HT uptake capacity of peripheral tissues in the Gulf toadfish, Opsanus beta, and to elucidate the primary excretion routes of 5-HT and its metabolites. Pharmacological inhibition of SERT and other transporters enabled assessment of the SERT dependence of peripheral 5-HT uptake and excretion. The results indicated rapid and substantial uptake of 5-HT by the heart atrium, heart ventricle, and gill that was at least partly SERT dependent. The results also supported the presence of a partial blood brain barrier that prevented rapid changes in brain 5-HT content despite fluctuating plasma 5-HT concentrations. The renal pathway appeared to be the dominant excretory route for 5-HT and its metabolites over shorter time frames (up to ~30 min), but hepatic excretion was substantial over several hours. SERT inhibition ultimately reduced the excretion of 5-HT and its metabolites by urinary, biliary, and/or intestinal pathways. In addition, branchial excretion of 5-HT and its metabolites could not be ruled out. In summary, this study reveals that the toadfish heart and gill play active roles in regulating circulating 5-HT and yields important insights into the control of peripheral 5-HT in this teleost fish. PMID- 30303706 TI - Elevated Resting Blood Pressure Augments Autonomic Imbalance in Posttraumatic Stress Disorder (PTSD). AB - Posttraumatic stress disorder (PTSD) is characterized by increased sympathetic nervous system (SNS) activity, blunted parasympathetic nervous system (PNS) activity, and impaired baroreflex sensitivity (BRS) that contribute to accelerated cardiovascular disease (CVD). PTSD patients also have chronic stress related elevations in resting blood pressure (BP), often in the prehypertensive range; yet, it is unclear if elevated resting blood pressure (ERBP) augments these autonomic derangements in PTSD. We hypothesized that compared to normotensive PTSD (N-PTSD), those with ERBP (E-PTSD) have further increased SNS, decreased PNS activity and impaired BRS at rest, and exaggerated SNS reactivity, PNS withdrawal, and pressor responses during stress. In 16 E-PTSD and 17 matched N-PTSD, we measured continuous BP, ECG, muscle sympathetic nerve activity (MSNA), and heart rate variability (HRV) markers reflecting cardiac PNS activity (standard deviation of R-R intervals (SDNN), root mean square of differences in successive R-R intervals (RMSSD), and high frequency power (HF)) during five minutes of rest and three minutes of mental arithmetic. Resting MSNA (p=0.943), sympathetic BRS (p=0.189) and cardiovagal BRS (p=0.332) were similar between groups. However, baseline SDNN (56+/-6 vs 78+/-8ms, p=0.019), RMSSD (39+/-6 vs 63+/-9 ms, p=0.018), and HF (378+/-103 vs 693+/-92 ms2, p=0.015) were lower in E PTSD vs. N-PTSD. During mental stress, the systolic blood pressure response (p=0.011) was augmented in E-PTSD. While MSNA reactivity was not different (p>0.05), the E-PTSD group had an exaggerated reduction in HRV during mental stress (p<0.05). PTSD with ERBP have attenuated resting cardiac PNS activity, coupled with exaggerated BP reactivity and PNS withdrawal during stress. PMID- 30303707 TI - Short-term low-carbohydrate high-fat diet with or without post-meal walks on glycemic control and inflammation in type 2 diabetes: A randomized trial. AB - Lowering carbohydrate consumption effectively lowers glucose but impacts on inflammation are unclear. The objectives of this study were to: 1) Determine whether reducing hyperglycemia by following a low-carbohydrate high-fat (LCHF) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D); and 2) Examine if the combination of a LCHF diet with strategically-timed post-meal walking was superior to a LCHF diet alone. Participants with T2D (N=11) completed a randomized crossover study involving three 4-day diet interventions: i) Low-fat low-glycemic index control (CON); ii) LC, and iii) LC with 15-min post meal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex as compared to LC (-5%, P ? 0.05) while both LC+Ex (-16%, P ? 0.001) and LC (-12%, P ? 0.001) conditions were lower than CON. A significant main effect of time was observed for phosphorylated c-Jun N-terminal kinase (p-JNK; P < 0.001), with decreases in all three conditions (CON; -32%, LC; -45%, LC+Ex; -44%). A significant condition by time interaction was observed for monocyte microparticles (P = 0.040) with a significant decrease in CON (-76%, P = 0.035) and a tendency for a reduction in LC (-70%, P = 0.064) whereas there was no significant change in LC+Ex (+0.5%, P = 0.990). Both LC (-27%, P = 0.001) and LC+Ex (-35%, P = 0.005) also led to significant reductions in circulating proinsulin. A LCHF diet, with or without daily post-meal walks, improved 4-day glycemic control and fasting proinsulin levels when compared to CON. PMID- 30303708 TI - A direct effect of the autonomic nervous system on somatic stem cell proliferation? AB - Regulation of somatic stem cell proliferation is critical for the maintenance of tissue and organ function throughout the body. Modulators of this process include nutrients and peptides, but the role of a neural influence on stem cell proliferation has been neglected. This article describes the literature in support of autonomic nervous system (ANS) influence on somatic stem cells, with emphasis on intestinal epithelial stem cells (IESCs) as a representative somatic stem cell. Based on the current available data, models for the direct influence of both branches of the ANS, the sympathetic and parasympathetic nervous systems, on intestinal epithelial stem cells (IESCs) are outlined. Finally, the prospect of treatments derived from ANS influence on somatic stem cells is explored. PMID- 30303709 TI - Reduced Uterine Perfusion Pressure Causes Loss of Pancreatic Beta Cell Area but Normal Function in Fetal Rat Offspring. AB - Maternal hypertension during pregnancy is a major risk factor for intrauterine growth restriction (IUGR), which increases susceptibility to cardiovascular and metabolic disease in adulthood through unclear mechanisms. The aim of this study was to characterize pancreatic beta cell area and function in the fetal rat offspring of reduced uterine perfusion pressure (RUPP) model of gestational hypertension. At embryonic day 19.5, RUPP dams exhibited lower body weight, elevated mean blood pressure, reduced litter size, and higher blood glucose compared to sham-operated controls. In RUPP placental lysates, non-significant change in mTOR activity markers, phosphorylated S6 at serine 240 and phosphorylated AKT (at S473) was observed. RUPP offspring showed significantly reduced beta cell to pancreas area and increased beta cell death, but normal insulin levels in serum. Isolated islets had normal insulin content and secretory function in response to glucose and palmitate. Fetal pancreatic lysates showed a tendency for reduced insulin levels, with a significant reduction in total mTOR protein with RUPP surgery. In addition, its downstream complex 2 targets phosphorylation of AKT at S473 and pAKT at Thr308 tended to be reduced in the fetal RUPP pancreas. Altogether, these data show that RUPP offspring demonstrated increased beta cell death, reduced beta cell area and altered nutrient-sensor mTOR protein level in pancreas. This could represent a mechanistic foundation in IUGR offspring's risk for enhanced susceptibility to type 2 diabetes and other metabolic vulnerabilities seen in adulthood. PMID- 30303710 TI - Serum and Urinary SOD3 in Patients with Type 2 Diabetes: Comparison with Early Chronic Kidney Disease and Association with Development of Diabetic Nephropathy. AB - Extracellular superoxide dismutase (SOD3), one member of the antioxidant defense system and a superoxide scavenger, has been noted to be downregulated in the kidneys of diabetic mice and is characterized by a heparin-binding domain that can anchor the protein to the endothelium and extracellular matrix. The association of the serum and urinary SOD3 levels with diabetic nephropathy in different stages has never been evaluated. It remains unclear how urinary SOD3 changes in different renal diseases. We recruited 98 Taiwanese patients with type 2 diabetes and 10 patients with early chronic kidney disease (CKD) into this study. Biochemical analyses were performed, including evaluation of the serum SOD3, urinary SOD3, urinary albumin, urinary vascular endothelial growth factor (VEGF) and urinary angiotensinogen (ANG). The Kruskal-Wallis rank sum test was used to compare various parameters among the three groups of patients, early CKD, diabetes alone and diabetes with CKD. Results showed that lower serum and urinary SOD3 levels were observed in the group of patients with diabetes alone. Higher serum and urinary SOD3 levels were observed in the group of diabetes with CKD patients, which has higher albuminuria and serum creatinine levels. The serum SOD3 level was significantly positively correlated with the renal function according to the serum creatinine level. The urinary levels of SOD3 were significantly correlated with the other urinary biomarkers, such as urinary ANG and VEGF. Furthermore, albuminuria can positively predict the serum SOD3 level for urinary albumin/urinary creatinine ratio (ACR)>1190.769 mg/gm and the urinary SOD3 level for ACR>=300 mg/gm. PMID- 30303711 TI - Aerobic interval exercise improves renal functionality and affects mineral metabolism in obese Zucker rats. AB - Obesity, metabolic syndrome and renal injury are considered risk factors for type 2 diabetes, as well as kidney disease. Functional and structural changes in the kidney as consequence of obesity and metabolic syndrome may lead to impaired mineral metabolism in what is known as chronic kidney disease-mineral and bone disorder. Lifestyle interventions such as physical activity are good strategies to manage these pathologies and, therefore, prevent the loss of kidney functionality and related complications in mineral metabolism. In this study, we have used forty male Zucker rats that were randomly allocated into four different experimental groups, two of them (an obese and a lean one) performed an aerobic interval training protocol, and the other two groups were sedentary. At the end of the experimental period (8 weeks), urine, plasma and femur were collected for biochemical and mineral composition analysis, whereas the kidney was processed for histological studies. The obese rats exhibited albuminuria, glomerulosclerosis and hypertrophy in glomeruli and renal tubule in some areas, together with alterations in mineral content of plasma but not of femur. The training protocol prevented the generation of albuminuria and glomerulosclerosis, showing a significant action on plasma and bone mineral levels. Therefore, the specific training protocol used in this study was able to prevent the development of diabetic nephropathy, and affected the metabolism of certain minerals. PMID- 30303712 TI - A conditionally immortalized Gli1-positive kidney mesenchymal cell line models myofibroblast transition. AB - Gli1-positive resident mesenchymal stem cell-like cells are the predominant source of kidney myofibroblasts in fibrosis but investigating Gli1-positive myofibroblast progenitor activation is hampered by the difficulty of isolating and propagating primary cultures of these cells. Using a genetic strategy with positive and negative selection, we isolated Kidney-Gli1 (KG1) cells that maintain expression of appropriate mesenchymal stem cell-like cell markers, respond to hedgehog pathway activation and display robust myofibroblast differentiation upon treatment with TGFb. Co-culture of KG1 cells with endothelium stabilizes capillary formation. Single cell RNA-sequencing (scRNA seq) analysis during differentiation identified autocrine ligand-receptor pair upregulation and a strong focal adhesion pathway signal. This led us to test the serum response factor inhibitor CCG-203971 which potently inhibited TGFb-induced pericyte to myofibroblast transition. scRNA-seq also identified the unexpected upregulation of nerve growth factor (NGF) which we confirmed in two mouse kidney fibrosis models. The Ngf receptor Ntrk1 is expressed in tubular epithelium in vivo, suggesting a novel interstitial to tubule paracrine signaling axis. Thus KG1 cells accurately model myofibroblast activation in vitro, and the development of this cell line provides a new tool to study resident mesenchymal stem cell like progenitors in health and disease. PMID- 30303713 TI - Role of connecting tubule glomerular feedback in obesity related renal damage. AB - Zucker obese rats (ZOR) have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response, in addition it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases PGC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (PSF), which is an indirect measurement of PGC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 +/- 0.60 mm Hg) in comparison to the ZLR (8.54 +/- 0.73 mm Hg, P < 0.05), and CTGF was elevated in ZOR (5.34 +/- 0.87 mm Hg) compared to ZLR (1.12 +/- 1.28 mm Hg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum PSF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 +/- 1.07 mm Hg vs. ZLR, 9.5 +/- 1.53 mm Hg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage. PMID- 30303714 TI - Renal cold storage followed by transplantation impairs proteasome function and subsequently mitochondrial protein homeostasis. AB - Identification of renal cold storage (CS)-related pathways that lead to renal damage after transplantation (Tx) will help us design new pathway-specific therapies to improve graft outcome. Our recent report showed that mitochondrial function was compromised after CS alone, and this was exacerbated when CS was combined with Tx (CS/Tx). The goal of this study was to determine whether proteasome pathways are involved with exacerbation of mitochondrial dysfunction after CS/Tx. Kidneys of male rats and NRK cells were exposed to CS/Tx or rewarming (CS/RW), respectively. To compare CS-induced effects, kidney Tx without CS exposure (ATx) was also used. Our study provides the first evidence that chymotrypsin-like (ChT-L) peptidase activity of the proteasome declined only after CS/Tx or CS/RW, but not after CS or ATx. Interestingly, key mitochondrial respiratory proteins (SDHA and ATP5B) were detected in the detergent-insoluble fraction after CS/Tx or CS/RW. Pharmacologic inhibition of ChT-L activity in NRK cells also resulted in increased levels of SDHA and ATP5B in the insoluble fraction, as well as reduced activities of complexes I and II. On the other hand, antimycin A inhibition of mitochondrial respiration in NRK cells resulted in compromised ChT-L function and increased amounts of SDHA and ATP5B in the insoluble fraction. Our results suggest that mitochondrial respiratory dysfunction during CS precedes compromised ChT-L function after CS/Tx, and proteasome dysfunction further leads to altered mitochondrial protein homeostasis and reduced respiration in kidneys after CS/Tx. Therefore, therapeutics that could preserve mitochondrial and proteasome function during CS may provide beneficial outcomes following transplantation. PMID- 30303715 TI - Reflections on the Void: The Art of Micturition Analysis. PMID- 30303716 TI - Improper Disposal of Prescription Opioids Among Young Adults. PMID- 30303717 TI - Delivering Equitable Care to Underserved Communities. PMID- 30303718 TI - Multilevel Thinking and Life Course Perspectives Inform Public Health Practice: A Public Health of Consequence, November 2018. PMID- 30303719 TI - Lead Poisoning in the 21st Century: The Silent Epidemic Continues. PMID- 30303720 TI - Using Credit Scores to Understand Predictors and Consequences of Disease. PMID- 30303721 TI - AJPH Global News. PMID- 30303723 TI - Implications of the Australian Experience With Firearm Regulation for US Gun Policy. PMID- 30303725 TI - HIV-1 Genetic and Contact Networks Among Men Who Have Sex With Men May Inform Public Health Efforts. PMID- 30303726 TI - Balancing Freedom of Conscience and Equitable Access. PMID- 30303727 TI - What Do Clinical Environments Say to Our Patients? A Replicable Model for Creative Advocacy. PMID- 30303728 TI - Defining Appropriate Roles for Corporations in Public Health Research and Practice. PMID- 30303729 TI - Shining a Light on Industry Research Funding. PMID- 30303730 TI - Tractor Rollovers Are Preventable. PMID- 30303732 TI - News From The Nation's Health. PMID- 30303731 TI - Human Rights: The Violence Against Women Act Reauthorization Is Due. PMID- 30303733 TI - The 1918 Influenza Pandemic: Lessons Learned and Not-Introduction to the Special Section. PMID- 30303734 TI - Cleveland Versus the Clinic: The 1960s Riots and Community Health Reform. AB - During the 1960s, cities across the United States erupted with rioting. Subsequent inquiries into its sources revealed long-simmering discontent with systemic deprivation and exploitation in the country's most racially segregated and resource-scarce neighborhoods. Urban medical centers were not exempt from this anger. They were standing symbols of maldistribution, cordoned off to those without sufficient economic means of access. In this article, I examine the travails of the world-famous and prestigious Cleveland Clinic after the 1966 riot in the Hough neighborhood on the East Side of Cleveland, Ohio. After years of unbridled expansion, fueled by federal urban renewal efforts, the riots caught the Clinic's leadership off guard, forcing it to rethink the long-standing insularity between itself and its neighbors. The riots were central to the Clinic's programmatic reorientation, but the concessions only went so far, especially as the political foment from the riots dissipated in the years afterward. The Cleveland experience is part of a larger-and still ongoing-debate on social obligations of medical centers, "town-gown" relations between research institutions and their neighbors, and the role of protest in catalyzing community health reform. PMID- 30303735 TI - Alert: Public Health Implications of Electronic Cigarette Waste. PMID- 30303736 TI - Neuropathology of vitamin B12 deficiency in the Cd320-/- mouse. AB - In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320-/-) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320-/- mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320-/- mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320-/- mouse. PMID- 30303737 TI - Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. AB - Mutations in the a disintegrin and metalloproteinase with thrombospondin motif like 2 ( ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF-beta signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF-beta binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network. Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. PMID- 30303738 TI - Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1. AB - Microcephalin-1 (MCPH1) exists as 2 isoforms that regulate cyclin-dependent kinase-1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin-dependent kinase-1-dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase-promoting complex/cyclosome-CDH1 E3 ligase complex. Anaphase-promoting complex/cyclosome-CDH1 target proteins generally have D-Box or KEN-Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D-Box dependent, whereas the short isoform was KEN-Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.-Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1. PMID- 30303739 TI - Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ-free mice. AB - Remodeling of the gut microbiota is implicated in various metabolic and inflammatory diseases of the gastrointestinal tract. We hypothesized that the gut microbiota affects the DNA methylation profile of intestinal epithelial cells (IECs) which could, in turn, alter intestinal function. In this study, we used mass spectrometry and methylated DNA capture to respectively investigate global and genome-wide DNA methylation of intestinal epithelial cells from germ-free (GF) and conventionally raised mice. In colonic IECs from GF mice, DNA was markedly hypermethylated. This was associated with a dramatic loss of ten-eleven translocation activity, a lower DNA methyltransferase activity and lower circulating levels of the 1-carbon metabolite, folate. At the gene level, we found an enrichment for differentially methylated regions proximal to genes regulating the cytotoxicity of NK cells (false-discovery rate < 8.9E-6), notably genes regulating the cross-talk between NK cells and target cells, such as members of the NK group 2 member D ligand superfamily Raet. This distinct epigenetic signature was associated with a marked decrease in Raet1 expression and a loss of CD56+/CD45+ cells in the intestine of GF mice. Thus, our results indicate that altered activity of methylation-modifying enzymes in GF mice influences the IEC epigenome and modulates the crosstalk between IECs and NK cells. Epigenetic reprogramming of IECs may modulate intestinal function in diseases associated with altered gut microbiota.-Poupeau, A., Garde, C., Sulek, K., Citirikkaya, K., Treebak, J. T., Arumugam, M., Simar, D., Olofsson, L. E., Backhed, F., Barres, R. Genes controlling the activation of natural killer lymphocytes are epigenetically remodeled in intestinal cells from germ-free mice. PMID- 30303740 TI - Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet. AB - The dietary R-3-hydroxybutyrate- R-1,3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1,3-butanediol diacetoacetate (BD-AcAc2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high fat diet (HFD)-induced obesity. Thirty-five-week-old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups ( n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+30% energy from BD-AcAc2. Mean energy intake throughout the study was ~26% lower in the KE compared to the Con group (8.2 +/- 0.5 vs. 11.2 +/- 0.7 kcal/d; P < 0.05). Final body weight (26.8 +/- 3.6 vs. 34.9 +/- 4.8 g; P < 0.001) and fat mass (5.2 +/- 1.2 vs. 11.3 +/- 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat-mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein-1, deiodinase-2, and peroxisome proliferator-activated receptor gamma coactivator-1alpha) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD-AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD-induced obesity.-Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet. PMID- 30303741 TI - Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion. AB - Adaptor protein p66Shc is overexpressed in smooth muscle cells of renal resistance vessels of hypertensive salt-sensitive rats and is involved in the regulation of renal vascular tone. We applied 2-photon laser scanning fluorescence microscopy to analyze spontaneous dynamic fluctuations in intracellular calcium concentrations ([Ca2+]i) in smooth muscle cells embedded in the walls of freshly isolated renal resistance arteries. The amplitude, number of events, and frequency of spontaneous [Ca2+]i oscillations triggered by endogenously released endothelin-1 were recorded in smooth muscle cells of the renal arteries. Endothelin receptor A antagonist BQ123 dramatically reduced the amplitude and frequency of spontaneous Ca2+ events, producing marked inhibition of renal vessels spontaneous motion. Spontaneous Ca2+ fluctuations in smooth muscle cells of p66Shc knockout (p66ShcKO) rats had significantly higher amplitude than in control rats. The frequency of spontaneous [Ca2+]i oscillations did not change in p66ShcKO rats, suggesting that p66Shc expression did not affect endothelin-1 release from resident endothelial cells. Acute application of endothelin-1 revealed significantly elevated production of the total [Ca2+]i in p66ShcKO rats. Spontaneous cytosolic Ca2+ oscillations in smooth muscle cells of renal vessels mediate their spontaneous motion via the endothelin-1/endothelin receptor A pathway. p66Shc decreases the amplitude of individual changes in [Ca2+]i, which mitigates the spontaneous motion of renal vessels.-Palygin, O., Miller, B. S., Nishijima, Y., Zhang, D. X., Staruschenko, A., Sorokin, A. Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion. PMID- 30303742 TI - Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition. AB - Preterm premature rupture of fetal membranes precedes 30-40% of preterm births. Activation of matrix metalloproteases (MMPs) is the one of the major causes of extracellular matrix (ECM) degradation in membrane rupture. Increased cortisol, regenerated by 11beta-hydroxysteroid dehydrogenase 1 in the amnion at parturition, is known to participate in a number of parturition-pertinent events. However, whether cortisol has a role in the regulation of MMPs in the membranes is not known. Here, we addressed this issue using human amnion tissue, the most tensile layer of the membranes. RNA-sequencing revealed that cortisol induced MMP7 expression dramatically in amnion fibroblasts, which was confirmed by real time quantitative RT-PCR and Western blotting analysis in cortisol-treated amnion explants and fibroblasts. Measurement of collagen IV alpha5 chain (COL4A5), a substrate for MMP-7, showed that cortisol reduced its extracellular abundance, which was blocked by an antibody against MMP-7. Moreover, increased MMP-7 but decreased COL4A5 abundance was observed in the amnion tissue following labor initiated spontaneous rupture of membranes. Mechanistic studies showed that cortisol increased the phosphorylation of c-Jun and the expression of c-Fos, the 2 major components of activated protein 1 (AP-1), respectively. The knocking down of c-Fos or c-Jun significantly attenuated the induction of MMP7 expression by cortisol. Chromatin immunoprecipitation assays showed that cortisol stimulated the enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter. The data suggest that induction of MMP7 by cortisol via AP-1 may be a contributing factor to ECM degradation in membrane rupture at parturition.-Wang, L.-Y., Wang, W.-S., Wang, Y.-W., Lu, J.-W., Lu, Y., Zhang, C.-Y., Li, W.-J., Sun, K., Ying, H. Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition. PMID- 30303743 TI - HuR stabilizes a polyadenylated form of replication-dependent histone mRNAs under stress conditions. AB - All metazoan mRNAs have a poly(A) tail at the 3' end with the exception of replication-dependent histone (RDH) mRNAs, which end in a highly conserved stem loop (SL) structure. However, a subset of RDH mRNAs are reported to be polyadenylated under physiologic conditions. The molecular details of the biogenesis of polyadenylated RDH [poly(A)+ RDH] mRNAs remain unknown. In this study, our genome-wide analyses reveal that puromycin treatment or UVC irradiation stabilizes poly(A)+ RDH mRNAs, relative to canonical RDH mRNAs, which end in an SL structure. We demonstrate that the stabilization of poly(A)+ RDH mRNAs occurs in a translation-independent manner and is regulated via human antigen R (HuR) binding to the extended 3' UTR under stress conditions. Our data suggest that HuR regulates the expression of poly(A)+ RDH mRNAs.-Ryu, I., Park, Y., Seo, J.-W., Park, O. H., Ha, H., Nam, J.-W., Kim, Y. K. HuR stabilizes a polyadenylated form of replication-dependent histone mRNAs under stress conditions. PMID- 30303744 TI - Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complications and mortality, suggesting that treatment of NASH might benefit from combined approaches that target the liver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G protein-coupled bile acid-activated receptor 1 (GPBAR1) agonism reverses liver and vascular damage in mouse models of NASH. NASH is associated with accelerated vascular inflammation representing an independent risk factor for development of cardiovascular diseases and cardiovascular-related mortality. GPBAR1, also known as TGR5, is a G protein-coupled receptor for secondary bile acids that reduces inflammation and promotes energy expenditure. Using genetic and pharmacologic approaches, we investigated whether GPBAR1 agonism by 6beta ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501) reverses liver and vascular damage induced by exposure to a diet enriched in fat and fructose (HFD-F). Treating HFD F mice with BAR501 reversed liver injury and promoted the browning of white adipose tissue in a Gpbar1-dependent manner. Feeding HFD-F resulted in vascular damage, as shown by the increased aorta intima-media thickness and increased expression of inflammatory genes (IL-6,TNF-alpha, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule-1, and endothelial selectin) in the aorta, while reducing the expression of genes involved in NO and hydrogen sulfide generation, severely altering vasomotor activities of aortic rings in an ex vivo assay. BAR501 reversed this pattern in a Gpbar1-dependent manner, highlighting a potential role for GPBAR1 agonism in treating the liver and vascular component of NASH.-Carino, A., Marchiano, S., Biagioli, M., Bucci, M., Vellecco, V., Brancaleone, V., Fiorucci, C., Zampella, A., Monti, M. C., Distrutti, E., Fiorucci, S. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. PMID- 30303745 TI - Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. AB - Preeclampsia leads to adverse outcomes for pregnant women. Bisphenol A (BPA) is an environmental endocrine disruptor and has been shown to be positively associated with increased risk of preeclampsia in human studies. We investigated whether BPA exposure causes preeclampsia-like features in pregnant mice and the associated underlying mechanisms. Experiments were performed in animal models and cell cultures. In pregnant mice, BPA-exposed mice exhibited preeclampsia-like features including hypertension, disruption of the circulation, and the placental angiogenesis biomarkers fms-related tyrosine kinase 1 and placenta growth factor, and glomerular atrophy; urinary protein was not affected. These preeclampsia-like features correlated with increased retention of smooth muscle cells and reduced vessel areas at the junctional zone of the placenta. In addition, there were disrupted expression of invasion-related genes including increased tissue inhibitors of metalloproteinases, decreased metalloproteinases, and Wnt family member WNT2/beta-catenin, which correlated with increased DNA methylation in its promoter region and upregulation of DNA methyltransferase (Dnmt)1. BPA exposure impeded the interaction between the human cytotrophoblast cell line, HTR-8/SVneo, and endothelium cells. BPA exposure down-regulated WNT2 expression, and elevated the DNA methylation of WNT2; these results were consistent with in vivo observations. Inhibition of DNMT in HTR-8/SVneo cells resulted in reduced DNA methylation and increased expression of WNT2. Taken together, these data demonstrate that BPA exposure alters trophoblast cell invasion and causes abnormal placental vessel remodeling, both of which lead to the development of preeclampsia-like features in pregnant mice. Our results suggest that this phenomenon involves the epigenetic reprogramming and down-regulation of WNT2 mediated by DNMT1.-Ye, Y., Tang, Y., Xiong, Y., Feng, L., Li, X. Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. PMID- 30303746 TI - Efficacy and Tolerability of Ketotifen in the Treatment Of Seasonal Allergic Conjunctivitis: Comparison between Ketotifen 0.025% and 0.05% Eye Drops. AB - PURPOSE: To study the tolerability and efficacy of two formulations of topical ketotifen ophthalmic solutions for the treatment of seasonal allergic conjunctivitis (SAC). METHODS: 81 active SAC patients were treated with either ketotifen 0.025% or 0.05% eye drops for 3 weeks. Allergic signs and symptoms were evaluated at baseline (V0), after 7 (V1) and 21 days (V2). Drugs tolerability and ratings of global efficacy were recorded. RESULTS: Both concentrations of ketotifen were highly effective. The total signs and symptoms scores (TSSS) were significantly better reduced by ketotifen 0.025% compared to 0.05% at both V1 and V2 (p < 0.001). Ketotifen 0.025% was better tolerated than 0.05% at the first instillation and at days 2, 4, and 6 (p < 0.0001), and had a better responder rate (p < 0.001) according to the patient's and investigator's assessments. CONCLUSIONS: Ketotifen 0.025% was more effective and better tolerated than 0.05% in SAC. PMID- 30303747 TI - An Unusual Case with Unilateral Epithelial Basement Membrane Detachment. AB - PURPOSE: To present a case with unusual epithelial basement membrane detachment. METHODS: A 29-year-old female presented with blurred-vision and pain in left-eye for 2 months. Slit-lamp showed almost total bullous epithelial detachment with subepithelial fluid, and intraocular pressure rise. Recurrences were observed, despite repeated epithelial debridement and topical medication. RESULTS: Decrease in corneal endothelial cell density and changes resembling cytomegalovirus (CMV) keratitis were noted on specular microscopy. PCR for CMV came negative; however, we had success with topical gancyclovir and steroids, in addition to topical antiglaucomatous agents and artificial tears. During the following 12 months, no recurrence was observed. CONCLUSION: According to her clinic and response to medication, we believe that this case represents an atypical form of CMV endotheliitis. PMID- 30303748 TI - On the Representational Nature of Value-Driven Spatial Attentional Biases. AB - Reward learning biases attention towards both reward-associated objects and reward-associated regions of space. The relationship between objects and space in the value-based control of attention, as well as the contextual specificity of space-reward pairings, remains unclear. In the present study, using a free viewing task, we provide evidence of overt attentional biases towards previously rewarded regions of texture scenes that lack objects. When scrutinizing a texture scene, participants look more frequently towards, and spend a longer amount of time looking at, regions that they have repeatedly oriented to in the past as a result of performance feedback. These biases were scene-specific, such that different spatial contexts produced different patterns of habitual spatial orienting. Our findings indicate that reinforcement learning can modify looking behavior via a representation that is purely spatial in nature, in a context specific manner. PMID- 30303749 TI - Excitatory and inhibitory crossed reflex pathways in mice. AB - Sensory information from one leg has been known to elicit reflex responses in the contralateral leg, known as "crossed reflexes", have been investigated extensively in cats and humans. Furthermore, experiments with mice have shown commissural pathways in detail by using in vitro and in vivo physiological approaches combined with genetics. However, the relationship between these commissural pathways discovered in mice and crossed reflex pathways described in cats and humans is not known. Here, we analyzed the crossed reflex in mice by using in vivo EMG recording techniques combined with peripheral nerve stimulation protocols to provide a detailed description of the crossed reflex pathways. We show that excitatory crossed reflexes are mediated by both proprioceptive and cutaneous afferent activation. In addition, we provide evidence for a short latency inhibitory crossed reflex pathway likely mediated by cutaneous feedback. Furthermore, the short-latency crossed inhibition is down-regulated in the knee extensor muscle and the ankle flexor muscle during locomotion. In conclusion, this paper provides an analysis of excitatory and inhibitory crossed reflex pathways during resting and locomotion mice in vivo. The data presented here paves the way for future research aimed at understanding crossed reflexes using genetics in mice. PMID- 30303750 TI - A new biomimetic assay reveals the temporal role of matrix stiffening in cancer cell invasion. AB - Tumor initiation and growth is associated with significant changes in the surrounding tissue. During carcinoma progression, a global stiffening of the extracellular matrix is observed and is interpreted as a signature of aggressive invasive tumors. However, it is still unknown whether this increase in matrix rigidity promotes invasion and whether this effect is constant along the course of invasion. Here we have developed a biomimetic in vitro assay that enabled us to address the question of the importance of tissue rigidity in the chronology of tumor invasion. Using low concentrations of the sugar threose, we can effectively stiffen reconstituted collagen I matrices and control the stiffening in time with no direct effect on residing cells. Our findings demonstrate that, depending on the timing of its stiffening, the extracellular matrix could either inhibit or promote cancer cell invasion and subsequent metastasis: while matrix stiffening after the onset of invasion promotes cancer cell migration and tumor spreading, stiff matrices encapsulate the tumor at an early stage and prevent cancer cell invasion. Our study suggests that adding a temporal dimension in in vitro models to analyze biological processes in four dimensions is necessary to fully capture their complexity. PMID- 30303751 TI - Uroplakins play conserved roles in egg fertilization and acquired additional urothelial functions during mammalian divergence. AB - Uroplakin (UP) tetraspanins and their associated proteins are major mammalian urothelial differentiation products that form unique 2D-crystals of 16-nm particles ("urothelial plaques") covering the apical urothelial surface. Although uroplakins are highly expressed only in mouse urothelium and are often referred to as being urothelium-specific, they are also expressed in several nonurothelial cell types in stomach, kidney, prostate, epididymis, testis/sperms and ovary/oocytes. In oocytes, uroplakins co-localize with CD9 on cell surface and multivesicular body-derived exosomes, and the cytoplasmic tail of UPIIIa undergoes a conserved fertilization-dependent, Fyn-mediated tyrosine phosphorylation that also occurs in Xenopus laevis eggs. Uroplakin knockout and antibody blocking reduce mouse eggs' fertilization rate in in vitro fertilization assays, and UPII/IIIa double-knockout mice have a smaller litter size. Phylogenetic analyses showed that uroplakin sequences underwent significant mammal-specific changes. These results suggest that, by mediating signal transduction and modulating membrane stability that do not require 2D-crystal formation, uroplakins can perform conserved and more ancestral fertilization functions in mouse and frog eggs. Uroplakins acquired the ability to form 2D- crystalline plaques during mammalian divergence enabling them to perform additional functions, including umbrella cell enlargement and the formation of permeability and mechanical barriers, in order to protect/modify the apical surface of the modern-day mammalian urothelium. PMID- 30303752 TI - Higher-Order, Multi-Featural Object Encoding by the Oculomotor System. AB - Previous behavioral and physiological research has demonstrated that as the behavioral relevance of potential saccade goals increases, they elicit more competition during target selection processing as evidenced by increased saccade curvature and neural activity. However, these effects have only been demonstrated for lower-order feature singletons and it remains unclear whether more complicated featural differences between higher-order objects also elicit vector modulation. Therefore, we measured human saccades curvature elicited by distractors bilaterally flanking a target during a visual search saccade task and systematically varied subsets of features shared between the two distractors and the target, referred to as objective similarity (OS). Our results demonstrate that saccades deviated away from the distractor highest in OS to the target and that there was a linear relationship between the magnitude of saccade deviation and the number of feature differences between the most similar distractor and the target. Furthermore, an analysis of curvature over the time-course of the saccade demonstrated that curvature only occurred in the first 20-30 ms of the movement. Given the multi-featural complexity of the novel stimuli, these results suggest that saccadic target selection processing involves dynamically reweighting vector representations for movement planning to several possible targets based on their behavioural relevance. PMID- 30303753 TI - Input-specific maturation of NMDAR-mediated transmission onto parvalbumin expressing interneurons in layers 2/3 of the visual cortex. AB - Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit dynamics. In terms of the excitation driving PV interneuron activity, the NMDA receptor (NMDAR)-mediated component onto PV interneurons tends to be smaller than that onto pyramidal neurons, but makes a significant contribution to their physiology and development. In the visual cortex, PV interneurons mature during the critical period. We hypothesize that during the critical period the NMDAR mediated signaling and functional properties of glutamatergic synapses onto PV interneurons are developmentally regulated. We therefore compared the AMPAR- and NMDAR-mediated synaptic responses before (P15-P20), during (P25-P40), and after (P50-P60) the visual critical period. AMPAR miniature EPSCs (mEPSCs) showed a developmental decrease in frequency, while NMDAR mEPSCs were absent or showed extremely low frequencies throughout development. For evoked responses, we consistently saw a NMDAR-mediated component, suggesting pre- or postsynaptic differences between evoked and spontaneous neurotransmission. Evoked responses showed input-specific developmental changes. For intralaminar inputs, the NMDAR mediated component significantly decreased with development. This resulted in adult intralaminar inputs almost exclusively mediated by AMPARs, suited for the computation of synaptic inputs with precise timing, and likely having NMDAR independent forms of plasticity. In contrast, interlaminar inputs maintained a stable NMDAR-mediated component throughout development but had a shift in the AMPAR paired pulse ratio (PPR) from depression to facilitation. Adult interlaminar inputs with facilitating AMPAR responses and a substantial NMDAR component would favor temporal integration of synaptic responses and could be modulated by NMDAR-dependent forms of plasticity. PMID- 30303754 TI - Immunohistochemistry by anti-cleaved-Lamin A: an improved approach to tackle the misuse of glucocorticoids in cattle. AB - The illegal use of glucocorticoids (GCs) as growth-promoters (GPs) is prohibited in farm animals in the European Union because the strong pharmacological activity of most synthetic GCs produces residues that are dangerous for human consumption. Among the alternative methods proposed to increase the efficacy of official controls, histology was the technique of choice in Italy on account of its high performance level. The aim of this study was to evaluate the reliability of immunohistochemistry (IHC) using anti-cleaved-Lamin A antibody to enhance the performance of the histological test applied to GC-related microscopic changes in the thymus. Veal calves (VC) and beef cattle (BC) were raised and both underwent different growth-promoting protocols or were left untreated. The morphology of the thymus parenchyma was evaluated for cortical atrophy with concurrent adipose tissue infiltration, and a score of 1 to 3 was attributed. A semi-quantitative IHC analysis was also performed by counting the number of positive thymocytes in 5 randomly selected high-power fields (HPFs). The distribution of the thymus atrophy scores was significantly different among the subgroups in both BC and VC. The IHC values were higher in untreated than in treated animals, for both BC and VC. The association between thymus atrophy score and IHC positivity showed higher median values in control than in treated animals (independently of the treatment protocol), for both BC and VC. Our data shows that IHC against anti-cleaved-Lamin A antibody is a reliable marker to detect illegal GC treatments, administered either alone or in association with other growth promoters, in both BC and VC. Combining IHC with the thymus atrophy score improves the accuracy of the histological method in correctly identifying treated animals and could represent a valuable, reproducible method to be applied to large-scale screening programmes. PMID- 30303755 TI - Trauma-Informed Care - Reflections of a Primary Care Doctor in the Week of the Kavanaugh Hearing. PMID- 30303756 TI - Production of bacterial cellulose from Komagataeibacter saccharivorans strain BC1 isolated from rotten green grapes. AB - Bacterial cellulose (BC) is one of the prominent biopolymers that has been acquiring attention currently due to its distinctive properties and applications in various fields. The current work presents the isolation of Komagataeibacter saccharivorans strain BC1 isolated from rotten green grapes, followed by biochemical and genotypic characterization, which confirmed that the strain is capable of synthesizing cellulose. Further, production media was designed and certain variables such as carbon, nitrogen sources, pH, and temperature were optimized in order to obtain the maximum concentration of cellulose production. We found mannitol to be the ideal carbon source and yeast extract as the ideal nitrogen source with a highest BC dry yield of 1.81 +/- 0.25 g/100 mL at pH 5.76 for a week at 30 degrees C.The charcterization of pellicles by FTIR spectrum depicted similar functional groups present in synthesized BC as that of the commercial cellulose. X-ray diffraction revealed that BC showed 82% crystallinity. Surface morphology of the dried pellicle was studied by SEM image which showed that the BC surface was tightly packed with thin fibers with less porosity. Hence the study demonstrates that the isolates of K.saccharivorans could be used to produce a biopolymer in a short period of time using a modified production medium. PMID- 30303757 TI - Rapid classification of virgin and recycled EPS containers by Fourier transform infrared spectroscopy and chemometrics. AB - A rapid and sensitive method for classification of virgin and recycled expanded polystyrene (EPS) food containers was developed using Fourier transform infrared spectroscopy (FTIR) and chemometrics. This method includes preparing a transparent film by dissolution, examining by FTIR and developing classification models. The degradation of EPS containers occurring during the recycling process was reflected by the carbonyl region of the infrared spectrum which was used as variables for multivariate data analysis. PCA was used to reduce the data dimension and view the sample similarities. Soft independent modelling of class analogy (SIMCA), partial least squares-discrimination analysis (PLS-DA) and linear discrimination analysis (LDA) were applied to construct three classification models. The best discrimination results were obtained by an LDA model, with all samples correctly classified. PLS-DA and SIMCA could not classify the recycled EPS samples with low levels of adulteration. When applying this method to commercially available EPS containers, about 45% of samples were shown to contain recycled polystyrene resins. It is concluded that the carbonyl region of the infrared spectra coupled with chemometrics could be a powerful tool for the classification of virgin and recycled EPS food containers. PMID- 30303758 TI - Hippocampal replays under the scrutiny of reinforcement learning models. AB - Multiple in vivo measures have shown that place cells from the hippocampus replay previously experienced trajectories. These replays have been thought to support memory consolidation for a long time. Some data, however, have highlighted a functional link between replays and reinforcement learning (RL). This theory, extensively used in machine learning, has introduced efficient algorithms and can explain various behavioral and physiological measures from different brain regions. RL algorithms provide a raison d'etre for replays enabling to reduce the number of iterations required to explore the environment in either model-based, model-free or hybrid model types. We review here the main findings concerning the different hippocampal replays' types and the possible associated RL models. We conclude by tying these frameworks together. We illustrate the link between data and RL through a series of model simulations. This review, at the frontier between informatics and biology, paves the way for further work on replays. PMID- 30303759 TI - Investigating the Association Between Advanced Practice Providers and Chemotherapy-Related Adverse Events in Women With Breast Cancer: A Nested Case Control Study. AB - PURPOSE:: The effect of advanced practice provider (APP) involvement in oncology care on cancer-specific outcomes is unknown. We examined the association between team-based APP-physician care during chemotherapy and chemotherapy-related adverse events (AEs) among women with breast cancer. METHODS:: We performed separate nested case-control analyses in two national cohorts of women who received chemotherapy for incident breast cancer. Cohorts were identified from Medicare (>= 65 years of age) and MarketScan (18 to 64 years of age) data. Cases experienced a chemotherapy-related AE (emergency room visit and/or hospitalization). Controls were matched 1:1 on the basis of each patient's age, comorbidities, census region, state's APP scope of practice regulations, and observation period from chemotherapy initiation to first AE. APP exposure (any outpatient claim billed by an APP during the observation period) was assessed for each matched pair member. RESULTS:: Among the 1,948 cases in the Medicare cohort, 225 (12%) had APP exposure before the first chemotherapy-related AE, compared with 213 controls (11%; P = .54). Among the 725 cases in the MarketScan cohort, 52 (7%) had APP exposure compared with 65 controls (9%; P = .21). In the matched case-control analysis, there was no association between outpatient APP exposure during chemotherapy and AEs in either cohort (Medicare: OR, 1.06 [95% CI, 0.87 to 1.30]; MarketScan: OR, 0.76 [95% CI, 0.50 to 1.14]). CONCLUSION:: Our results suggest that team-based APP-physician care that includes an APP who is billing independently, at least for certain patients receiving chemotherapy, may be a viable strategy to safely leverage the scarce oncology workforce to increase access and delivery of cancer care. PMID- 30303760 TI - Pellagra Secondary to GI Malignancy and Fluorouracil-Based Chemotherapy. PMID- 30303761 TI - Use of Ultrasound for Joint Dislocation Reduction in an Austere Wilderness Setting: A Case Report. AB - Point-of-care ultrasound has been shown to have a demonstrable impact in the austere/out-of-hospital environment. As ultrasounds become more affordable and portable, a myriad of uses in austere environments are becoming recognized. We present a case of a stranded hiker with an ultrasound-confirmed glenohumeral joint dislocation who underwent ultrasound-guided intra-articular lidocaine injection and ultrasound-confirmed reduction. This procedure allowed the patient to hike out under his own power, avoiding the potential dangers of extrication to both patient and rescuers. We believe this case demonstrates the feasibility and utility of ultrasound in the out-of-hospital environment both procedurally and diagnostically. PMID- 30303762 TI - Cross-modal phonetic encoding facilitates the McGurk illusion and phonemic restoration. AB - In spoken language, audiovisual (AV) perception occurs when the visual modality influences encoding of acoustic features (e.g., phonetic representations) at the auditory cortex. We examined how visual speech (lip-movements) transforms phonetic representations, indexed by changes to the N1 auditory evoked potential (AEP). EEG was acquired while human subjects watched and listened to videos of a speaker uttering consonant vowel (CV) syllables, /ba/ and /wa/, presented in auditory-only, AV congruent or incongruent contexts, or in a context in which the consonants were replaced by white noise (noise-replaced). Subjects reported whether they heard 'ba' or 'wa'. We hypothesized that the auditory N1 amplitude during illusory perception (caused by incongruent AV input, like in the McGurk illusion, or white noise-replaced consonants in CV utterances) should shift to reflect the auditory N1 characteristics of the phonemes conveyed visually (by mouth movements) as opposed to acoustically. Indeed, the N1 AEP became larger and occurred earlier when listeners experienced illusory 'ba' (video /ba/, audio /wa/, heard as 'ba') and vice versa when they experienced illusory 'wa' (video /wa/, audio /ba/, heard as 'wa'), mirroring the N1 AEP characteristics for /ba/ and /wa/ observed in natural acoustic situations (e.g., auditory-only setting). This visually-mediated N1 behavior was also observed for noise-replaced CVs. Taken together, the findings suggest that information relayed by the visual modality modifies phonetic representations at the auditory cortex and that similar neural mechanisms support the McGurk illusion and phonemic restoration. PMID- 30303763 TI - Solid state fermentation of Bacillus gottheilii M2S2 in laboratory-scale packed bed reactor for tannase production. AB - Production of tannase was performed in packed bed reactor filled with an inert support polyurethane foam (PUF) using Bacillus gottheilii M2S2. The influence of process parameters such as fermentation time (24-72 h), tannic acid concentration (0.5-2.5% w/v), inoculum size (7-12% v/v), and aeration rate (0-0.2 L/min) on tannase production with PUF were analyzed using one variable at a time (OVAT) approach. The outcome of OVAT was optimized by central composite design. Based on the statistical investigation, the proposed mathematical model recommends 1% (w/v) of tannic acid, 10% (v/v) of inoculum size and 0.13 L/min of aeration rate for maximum production (76.57 +/- 1.25 U/L). The crude enzyme was purified using ammonium sulfate salt precipitation method followed by dialysis. The biochemical properties of partially purified tannase were analyzed and found the optimum pH (4.0), temperature (40 degrees C) for activity, and Km (1.077 mM) and Vmax (1.11 uM/min) with methyl gallate as a substrate. Based on the SDS-PAGE analysis, tannase exhibited two bands with molecular weights of 57.5 and 42.3 kDa. Briefly, the partially purified tannase showed 4.2 fold increase (63 +/- 1.60 U/L) in comparison to the submerged fermentation and the production of tannase was validated by using NMR spectrometer. PMID- 30303764 TI - Analytical determination of bisphenol A (BPA) and bisphenol analogues in paper products by LC-MS/MS. AB - In this study a sensitive analytical method based on liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous analysis of bisphenol A (BPA), bisphenol AF (BPAF), bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF) and bisphenol S in different paper and board products, including virgin fibre samples and recycled samples. Analytes were extracted from the paper matrix using a simple solvent extraction and chromatographic separation was performed on a C18 core-shell (100 mm x 2.1 mm i.d.; 1.7 um particle size) column. The developed method showed good linearity (R2 > 0.9921) for all analytes. Absolute recoveries ranged from 71 to 115% and precision in terms of reproducibility and repeatability (intra- and inter-day) yielded in relative standard deviations (RSDs) of less than 15.0% and 17.4%, respectively. The limit of detection (LOD) and limit of quantification (LOQ) for the different analytes ranged from 0.29 to 0.40 ug kg-1 paper and from 1.09 to 1.32 ug kg-1 paper, being in the same range for all analytes. Quantitation of the analytes was performed using the internal standard procedure, with concentrations of < LOQ to 9599 ug kg-1 for the different analytes. Furthermore, a calculation of the maximum migration, assuming the 'worst case' scenario of 100% migration was performed. PMID- 30303765 TI - Rpp1 Encodes a ULP1-NBS-LRR Protein That Controls Immunity to Phakopsora pachyrhizi in Soybean. AB - Phakopsora pachyrhizi is the causal agent of Asian soybean rust. Susceptible soybean plants infected by virulent isolates of P. pachyrhizi are characterized by tan-colored lesions and erumpent uredinia on the leaf surface. Germplasm screening and genetic analyses have led to the identification of seven loci, Rpp1 to Rpp7, that provide varying degrees of resistance to P. pachyrhizi (Rpp). Two genes, Rpp1 and Rpp1b, map to the same region on soybean chromosome 18. Rpp1 is unique among the Rpp genes in that it confers an immune response (IR) to avirulent P. pachyrhizi isolates. The IR is characterized by a lack of visible symptoms, whereas resistance provided by Rpp1b to Rpp7 results in red-brown foliar lesions. Rpp1 maps to a region spanning approximately 150 kb on chromosome 18 between markers Sct_187 and Sat_064 in L85-2378 (Rpp1), an isoline developed from Williams 82 and PI 200492 (Rpp1). To identify Rpp1, we constructed a bacterial artificial chromosome library from soybean accession PI 200492. Sequencing of the Rpp1 locus identified three homologous nucleotide binding site leucine rich repeat (NBS-LRR) candidate resistance genes between Sct_187 and Sat_064. Each candidate gene is also predicted to encode an N-terminal ubiquitin like protease 1 (ULP1) domain. Cosilencing of the Rpp1 candidates abrogated the immune response in the Rpp1 resistant soybean accession PI 200492, indicating that Rpp1 is a ULP1-NBS-LRR protein and plays a key role in the IR. PMID- 30303766 TI - Selection of marker peptides from casein phosphopeptide and application for quantification in infant formula. AB - Casein phosphopeptides (CPPs) have been used worldwide as a nutritional supplement. However, the peptide components have been unknown; as a consequence, few quantification methods of CPP in infant formula were reported. This study introduced a quantification method based on peptide marker and corresponding peptide selection strategy using a simplified model with four commercial types of CPP. The peptides from four commercial CPPs were first identified. Due to the great variety of CPPs, two marker selection strategies were adopted: on one hand, universal marker peptide VLPVPQK can be used for the quantification of all four commercial CPPs, if the CPP can be obtained as a standard. On the other hand, the specific marker peptide LYQEPVLGPV can be used for identification and quantification of commercial CPP type K content in infant formula with a fixed calculation factor. In the simplified model, the combination use of the two markers can meet most of the requirements of CPP analysis in infant formula. The method validation revealed that this was suitable for the routine analysis laboratories without proteomics backgrounds. This selection strategy was suggested for the large-scale marker peptide selection with all commercial CPPs, which can give a comprehensive solution of CPP quantification in infant formula. Abbreviations: CPP: Casein phosphopeptides; LC: Liquid chromatography; TQMS: Triple quadrupole mass spectrometry; MRM: Multiple reaction monitoring; RSD: Relative standard deviation; L*: [13C6, 15N]-leucine; SSSEE: Peptides sequence of serine-serine-serine-glutamic acid-glutamic acid. PMID- 30303767 TI - Prevention of Cell Growth by Suppression of Villin Expression in Lithocholic Acid stimulated HepG2 Cells. AB - Cholestasis is a condition wherein bile flow is interrupted and lithocholic acid is known to play a key role in causing severe liver injury. In this study, we performed in-depth analysis of the morphological changes in bile canaliculi and the biological role of villin in cholestasis using lithocholic acid-stimulated HepG2 human hepatocarcinoma cells. We confirmed disruption of the bile canaliculi in liver sections from a liver allograft patient with cholestasis. Lithocholic acid caused strong cytotoxicity in HepG2 cells, which was associated with abnormal morphology. Lithocholic acid reduced villin expression, which recovered in the presence of nuclear receptor agonists. Furthermore, villin mRNA expression increased following small interfering RNA (siRNA)-mediated knockdown of the nuclear farnesoid X receptor and pregnane X receptor. Villin knockdown using siRNA caused cell growth arrest in HepG2 cells. The effect of villin-knockdown on whole-genome expression in HepG2 cells was analyzed by DNA microarray. Our data suggest that lithocholic acid caused cell growth arrest by suppressing villin expression via farnesoid X receptor and pregnane X receptor in HepG2 cells. PMID- 30303768 TI - A novel bagging ensemble approach for predicting summer time ground level ozone concentration. PMID- 30303769 TI - Prophage Diversity of "Candidatus Liberibacter asiaticus" Strains in California. AB - Huanglongbing (HLB) is a highly destructive citrus disease and is associated with a non-culturable bacterium, "Candidatus Liberibacter asiaticus" (CLas). CLas in the U.S. was first found in Florida in 2005 and is now endemic there. In California, CLas was first detected in Hacienda Heights in Los Angeles County in 2012 and has now been detected in multiple urban locations in southern California. Knowledge of CLas strain diversity in California is important for HLB management. In this study, genomic diversity among ten CLas strains from six California locations were analyzed using next generation sequencing (Illumina MiSeq and HiSeq) approach. Draft genome sequences of CLas strains were assembled. Sequences of 16S rRNA gene and nrdB confirmed CLas identity. Prophages were detected in all CLas strains. The California CLas strains formed four prophage typing groups (PTGs): PTG1 with Type 1 prophage only (strains from Anaheim, San Gabriel, and Riverside); PTG2 with Type 2 prophage only (strains from Hacienda Heights); PTG1-3 with both Type 1 and 3 prophages (a strain from Cerritos); and PTG1-2 with both Type 1 and Type 2 prophages (a strain from La Habra). Analyses of terL sequence showed that all California CLas strains were not introduced from Florida but likely locations in Asia. Miniature inverted-repeat transposable elements (MITEs) were found in all CLas strains, yet, a jumping-out event was detected in the CLas strain from Cerritos. Altogether, this study demonstrated NGS approach focusing on prophage variation was sensitive and effective in revealing diversity of CLas strains in California. PMID- 30303770 TI - Characterization of antagonistic Bacillus methylotrophicus isolated from rhizosphere and its biocontrol effects on maize stalk rot. AB - Stalk rot is one of the most serious and widespread diseases in maize, and effective control measures are currently lacking. Therefore, this study aimed to develop a new biological agent to manage this disease. An antagonistic bacterial strain, TA-1, was isolated from rhizosphere soil and identified as Bacillus methylotrophicus based on morphological and biochemical characterization and 16S rRNA and gyrB gene sequence analyses. TA-1 exhibited a strong antifungal effect on the growth of Fusarium graminearum mycelium, with 86.3% inhibition at a concentration of 108 colony forming units (CFU) per mL. Transmission electron microscopy (TEM) showed that TA-1 could disrupt the cellular structure of the fungus, induce necrosis, and degrade the cell wall. Greenhouse and field trials were performed to evaluate the biocontrol efficacy of TA-1 on maize stalk rot, and the results of greenhouse experiment revealed that the bacterium significantly reduced disease incidence and disease index. Seeds treated with a 108 CFU mL-1 cell suspension had the highest disease suppression at 86.8%. Results of field trials show that seed bacterization with TA-1 could not only reduce maize stalk rot incidence but also increase maize height, stem diameter and grain yield. The lipopeptide antibiotics were isolated from the culture supernatants of TA-1 and identified as surfactins and iturins. Consequently, B. methylotrophicus TA-1 is a potential biocontrol agent against maize stalk rot. PMID- 30303771 TI - Promise and pitfalls of endemic resistance for cultural resources threatened by Phytophthora ramorum. AB - Invasive forest pathogens can harm cultural, economic, and ecological resources. Here we demonstrate the potential of endemic tree pathogen resistance in forest disease management using Phytophthora ramorum, cause of sudden oak death, in the context of management of tanoak (Notholithocarpus densiflorus), an ecologically unique and highly valued tree within Native American communities of Northern California and Southern Oregon, USA. We surveyed resistance to P. ramorum on the Hoopa Valley Indian Reservation and Yurok Indian Reservation in a set of study sites with variable management intensities. Variation in resistance was found at all sites with similar mean and variation across stands, tended to have a random spatial distribution within stands, but was not associated with previous stand management (thinning, prescribed fire) or structural characteristics such as tree density, basal area, or pairwise relatedness among study trees. These results did not suggest host, genetic, management, and/or environment interactions that could be easily leveraged into treatments to increase the prevalence of resistant trees. We applied epidemiological models to assess the potential application of endemic resistance in this system and to examine our assumption that in planta differences in lesion size - our measure of resistance - reflect linkages between mortality and transmission (resistance) vs reduced mortality with no change in transmission (tolerance). This assumption strongly influenced infection dynamics, but changes in host populations - our conservation focus - was dependent on community-level variation in transmission. For P. ramorum slowing mortality rates (whether by resistance or tolerance) conserves host resources when a second source of inoculum is present; these results are likely generalizable to pathogens with a broader host. However, when the focal host is the sole source of inoculum, increasing tolerant individuals led to the greatest stand-level pathogen accumulation in our model. When seeking to use variation in mortality rates to affect conservation strategies, it is important to understand how these traits are linked with transmission because tolerance will be more useful for management in mixed-host stands that are already invaded, compared to single-host stands with low or no pathogen presence where resistance will have the greatest conservation benefits. PMID- 30303772 TI - Pluripotent Stem Cell-Derived Pancreatic Progenitors and beta-Like Cells for Type 1 Diabetes Treatment. AB - In this review, we focus on the processes guiding human pancreas development and provide an update on methods to efficiently generate pancreatic progenitors (PPs) and beta-like cells in vitro from human pluripotent stem cells (hPSCs). Furthermore, we assess the strengths and weaknesses of using PPs and beta-like cell for cell replacement therapy for the treatment of Type 1 diabetes with respect to cell manufacturing, engrafting, functionality, and safety. Finally, we discuss the identification and use of specific cell surface markers to generate safer populations of PPs for clinical translation and to study the development of PPs in vivo and in vitro. PMID- 30303773 TI - The Difference delta-Cells Make in Glucose Control. AB - The role of beta and alpha-cells to glucose control are established, but the physiological role of delta-cells is poorly understood. Delta-cells are ideally positioned within pancreatic islets to modulate insulin and glucagon secretion at their source. We review the evidence for a negative feedback loop between delta and beta-cells that determines the blood glucose set point and suggest that local delta-cell-mediated feedback stabilizes glycemic control. PMID- 30303774 TI - Physiology in Perspective: Understanding the Aging Process. PMID- 30303775 TI - Conflict and Compromise: Using Reversible Remodeling to Manage Competing Physiological Demands at the Fish Gill. AB - The structural features of the fish gill necessary for oxygen uptake also favor undesirable, passive movements of ions and water. Reversible gill remodeling is one solution to this conflict. Cell masses that limit functional surface area are lost when oxygen availability decreases in hypoxia or oxygen demand increases with exercise or high temperature. However, much remains to be learned about how widespread reversible gill remodeling is among fish species, and how and why it occurs. PMID- 30303776 TI - Energy Constraint as a Novel Mechanism Linking Exercise and Health. AB - Humans and other species adapt dynamically to changes in daily physical activity, maintaining total energy expenditure within a narrow range. Chronic exercise thus suppresses other physiological activity, including immunity, reproduction, and stress response. This exercise-induced downregulation improves health at moderate levels of physical activity but can be detrimental at extreme workloads. PMID- 30303777 TI - APS: Moving Forward to Aid Our Membership. PMID- 30303778 TI - Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging. AB - Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered. PMID- 30303779 TI - Engaging Patients: Models for Patient- and Family-centered Care in Radiology. AB - This article examines how radiologists can meet the objectives of patient- and family-centered care set forth by the National Committee for Quality Assurance (NCQA) program for primary care providers. The breadth of initiatives in radiology that can be mapped to the NCQA objectives is impressive and invites the idea of creating a similar program in radiology. (c)RSNA, 2018. PMID- 30303780 TI - Optimizing Performance by Preventing Disruptive Behavior in Radiology. AB - Disruptive behaviors impede delivery of high-value health care by negatively impacting patient outcomes and increasing costs. Health care is brimming with potential triggers of disruptive behavior. Given omnipresent environmental and cultural factors such as constrained resources, stressful environments, commercialization, fatigue, unrealistic expectation of perfectionism, and burdensome documentation, a burnout epidemic is raging, and medical providers are understandably at tremendous risk to succumb and manifest these unprofessional behaviors. Each medical specialty has its own unique challenges. Radiology is not exempt; these issues do not respect specialty or professional boundaries. Unfortunately, preventive measures are too frequently overlooked, provider support programs rarely exist, and often organizations either tolerate or ineffectively manage the downstream disruptive behaviors. This review summarizes the background, key definitions, contributing factors, impact, prevention, and management of disruptive behavior. Every member of the health care team can gain from an improved understanding and awareness of the contributing factors and preventive measures. Application of these principles can foster a just culture of understanding, trust, support, respect, and teamwork balanced with accountability. The authors discuss these general topics along with specific issues for radiologists in the current medical environment. Patients, providers, health care organizations, and society all stand to benefit from better prevention of these behaviors. There is a strong moral, ethical, and business case to address this issue head-on. (c)RSNA, 2018. PMID- 30303781 TI - Never Events in Radiology and Strategies to Reduce Preventable Serious Adverse Events. AB - The term never event in medicine was originally coined by Kenneth W. Kizer, MD, MPH, former chief executive officer of the National Quality Forum, to describe particularly shocking medical errors that should never occur, such as wrong-site surgery or death associated with introduction of a metallic object into the MRI area. With time, the National Quality Forum's list of never events, or "serious reportable events," has been expanded to include adverse events that are unambiguous, serious, and usually preventable. In this article, the never event framework has been used to describe (a) the errors that may occur in an imaging department that are serious and usually preventable with a review of the causative factors and (b) strategies to eliminate and reduce the adverse effects of these avoidable errors. These errors are often rooted in communication breakdowns and can only be eliminated with a true shift to a culture of open reporting and patient safety. (c)RSNA, 2018. PMID- 30303782 TI - Establishing and Running a Three-dimensional and Advanced Imaging Laboratory. AB - Multidetector CT technology has advanced during the past 2 decades from single digit numbers of sections to 320-section CT scanners. The ability to perform three-dimensional (3D) postprocessing of acquired data has accompanied this technical progress. Multiple considerations are involved in developing and deploying a 3D and advanced imaging laboratory to provide postprocessing for both CT and MRI examinations. Establishing and running a 3D laboratory requires administrators to buy into the process and also requires regular input from radiologists and other stakeholders. Technologists with prior 3D experience are rare, and extensive immersive training is typically required. Laboratory space and equipment must be maintained and updated regularly to continue to meet stakeholders' needs. Postprocessing protocols must be established and reviewed periodically. Quality control is also necessary to ensure that postprocessing outputs adhere to the protocols. Laboratory technologists can also provide postprocessing support for research examinations and can lend their technical expertise to research projects. Regular review of laboratory productivity is essential to ensure longevity and availability of necessary resources (human, environmental, and technical). As the technologies for the imaging equipment, the picture archiving and communication system, and postprocessing continue to advance, the role of the 3D laboratory will also evolve to include other services. This evolution will affect ongoing training of technologists, as well as the requirements when new technologists are hired. The 3D laboratory is often positioned to take on novel technology and augment radiologists' workflow as new modalities and techniques enter the clinical workflow. (c)RSNA, 2018. PMID- 30303783 TI - The Late-Career Radiologist: Options and Opportunities. AB - More than 25% of the present radiology workforce, or nearly 8300 radiologists, are actively practicing late-career radiologists. While these individuals could decide to retire from active practice, their continued presence in the workforce helps to maintain adequate and appropriate patient imaging services. To ensure their continued participation, issues important to all late-career radiologists need to be appreciated, discussed, and addressed. These issues include call-duty requirements, compensation, physical and cognitive health, and organized phase out programs. The gamut of these issues is addressed in this review article. (c)RSNA, 2018. PMID- 30303784 TI - Informatics Solutions for Driving an Effective and Efficient Radiology Practice. AB - Radiologists are facing increasing workplace pressures that can lead to decreased job satisfaction and burnout. The increasing complexity and volumes of cases and increasing numbers of noninterpretive tasks, compounded by decreasing reimbursements and visibility in this digital age, have created a critical need to develop innovations that optimize workflow, increase radiologist engagement, and enhance patient care. During their workday, radiologists often must navigate through multiple software programs, including picture archiving and communication systems, electronic health records, and dictation software. Furthermore, additional noninterpretive duties can interrupt image review. Fragmented data and frequent task switching can create frustration and potentially affect patient care. Despite the current successful technological advancements across industries, radiology software systems often remain nonintegrated and not leveraged to their full potential. Each step of the imaging process can be enhanced with use of information technology (IT). Successful implementation of IT innovations requires a collaborative team of radiologists, IT professionals, and software programmers to develop customized solutions. This article includes a discussion of how IT tools are used to improve many steps of the imaging process, including examination protocoling, image interpretation, reporting, communication, and radiologist feedback. (c)RSNA, 2018. PMID- 30303785 TI - Running a Radiology Residency Program: Strategies for Success. AB - Running a successful radiology residency program requires departments to navigate the evolving educational landscape at the departmental, institutional, and national levels. To attract the best applicants, departments must invest time and money to support the leadership of the program and its faculty to provide innovative educational opportunities in a positive learning environment while simultaneously complying with all of the requirements of the Accreditation Council for Graduate Medical Education. The key administrative requirements of a successful radiology residency program are described and can be grouped into (a) essential administrative components, (b) the clinical learning environment review and self-study process, and (c) resident recruitment. Ten specific strategies for running a successful residency program are also presented. The goal is for this article to serve as a guide for not only existing diagnostic and interventional radiology residency programs but also newly formed programs that are in the process of seeking accreditation. (c)RSNA, 2018. PMID- 30303786 TI - Creating a Radiology Quality and Safety Program: Principles and Pitfalls. AB - All radiology departments are now expected to create organized and comprehensive quality and safety (QS) programs. No matter the department size, there are fundamental principles that should be at the core of each program. "Just culture" and culture of safety are essential principles in establishing effective programs. Physician leaders of QS programs must involve stakeholders, define program goals, and develop an effective program structure. QS programs should establish reliable quality assurance and patient safety systems. Integrating continuous quality improvement and learning into the department and prioritizing patient and referring clinician experiences will enhance outcomes. Physician QS leaders will face common obstacles in program development and management. Heightened awareness of these obstacles and understanding potential solutions will help programs succeed. Leveraging resources offered by professional societies and engaging in radiology QS community networks will provide ongoing support for program leaders. (c)RSNA, 2018. PMID- 30303787 TI - Invited Commentary on "Navigating Generational Differences in Radiology". PMID- 30303788 TI - Contemporary Risk Management for Radiologists. AB - Although radiologists want to avoid being sued for malpractice, their primary objective is to treat patients in the best way possible. Good risk management safeguards both patients and radiologists. The main objective is not to wait until an untoward event occurs and then manage it retrospectively, but rather to anticipate what may go wrong or cause an injury, so that it can be avoided. Thus, good risk management is characterized by two words: anticipate and avoid. Although avoiding lawsuits is the apparent objective of risk management, the real objective is to optimize the care and treatment of patients. Potential causes of error and injury must be identified to prevent such problems from occurring so that the conduct of radiologists allows patients to benefit from their knowledge and technology. If radiologic diagnoses and treatment are beyond reproach, then malpractice suits are less likely. The most common and potentially injurious risks that should be anticipated and avoided are closely entwined with radiologic diagnosis, incidental findings, communication of findings to referring physicians, "curbstone consultations," disclosure of and apology for errors, breast density laws, American College of Radiology parameters, radiation exposure, the Health Insurance Portability and Accountability Act, electronic health records, and imaging traumatic brain injury with functional MRI. Peer review and the current status of the medical malpractice environment are also relevant. (c)RSNA, 2018. PMID- 30303789 TI - Essential Role of a Medical Physicist in the Radiology Department. AB - The medical physicist plays a number of essential roles in the radiology department. These roles can be examined under the tripartite mission of a radiology department: patient care, teaching, and research. Under patient care, the role of a medical physicist involves quality and safety activities, which include performing acceptance testing, conducting periodic evaluation of imaging modalities for regulatory and accreditation compliance, and providing patient dose estimations. Regulation and accreditation requirements that paved the way for the medical physicist's role are discussed. As for teaching, medical physicists are typically involved in teaching radiology residents and radiation technologists and also providing in-service education to staff and others. A number of emerging roles are propelling the medical physicist to be the "go-to person" with regard to not only regulatory compliance but also the safety and quality of imaging. (c)RSNA, 2018. PMID- 30303791 TI - Radiology Report Value Equation. AB - Value in medicine is defined as the ratio of quality and service and health care outcomes to the costs and inefficiencies of providing care. Creating patient centered value in radiology reporting requires radiologists to provide accurate diagnostic interpretations in an accessible format with useful advice on further imaging, as well as report-embedded reference materials desired by the referring provider. The value- and service-centered radiologist provides urgent communications when appropriate and is readily available for report consultations. Indirect costs or inefficiencies embedded in report style can erode value. Value is preserved when radiologists strive for concise, clear, and timely reporting. (c)RSNA, 2018. PMID- 30303790 TI - Improving Imaging Care for Diverse, Marginalized, and Vulnerable Patient Populations. AB - Although much attention has been paid to the reduction of disparities in health care within the United States, these issues continue to exist. Such efforts include increased focus on patient centeredness and cultural responsivity. These concepts are based on the recognition that diverse, marginalized, and vulnerable patients may possess different physical, psychologic, or social characteristics that contribute to their diversity and susceptibility. Such patients may face numerous obstacles and barriers when seeking medical care, including financial constraints, difficulties with communication, a limited understanding of how to navigate the health care system, and not feeling welcomed, respected, or safe. It is essential that the radiologist and members of the radiology care team understand and embrace patients' unique characteristics to provide effective and appropriate care to all patients. This article illustrates the spectrum of knowledge that benefits radiologists and members of the radiology care team when interacting with and providing care for the growing pool of diverse, marginalized, and vulnerable patients. (c)RSNA, 2018. PMID- 30303792 TI - Acing the Joint Commission Regulatory Visit: Running an Effective and Compliant Safety Program. AB - Ensuring the safety of patients and staff is a core effort of all health care organizations. Many regulatory agencies, from The Joint Commission to the Occupational Safety and Health Administration, provide policies and guidelines, with relevant metrics to be achieved. Data on safety can be obtained through a variety of mechanisms, including gemba walks, team discussion during safety huddles, audits, and individual employee entries in safety reporting systems. Data can be organized on a scorecard that provides an at-a-glance view of progress and early warning signs of practice drift. In this article, relevant policies are outlined, and instruction on how to achieve compliance with national patient safety goals and regulations that ensure staff safety and Joint Commission ever-readiness are described. Additional critical components of a safety program, such as department commitment, a just culture, and human factors engineering, are discussed. (c)RSNA, 2018. PMID- 30303793 TI - Navigating Generational Differences in Radiology. AB - Generations are cohorts of individuals born in a particular time period who share similar values or value systems owing to historic events that occurred at crucial times during their development. Generations are defined to study how views and values change over time and to assess the differential impact that formative experiences have on groups. Understanding and navigating generational differences will be a critical skill for radiology leaders in the coming decade, as four distinct generations are working side by side for the first time in history. The four generations currently in the workforce are categorized as traditionalists, baby boomers, Generation Xers, and millennials. Beginning in 2016, millennials became the largest generation in the U.S. workforce, surpassing the number of Generation Xers. This major demographic shift will have a profound impact on workplace culture, recruitment efforts, and trainee education. While each generation has similar basic needs, meeting those needs and motivating individuals of different generations are best accomplished using different approaches. Radiology leaders must encourage and support these varied generations to work harmoniously to foster high-performance organizations. (c)RSNA, 2018. PMID- 30303795 TI - Rules and Regulations Relating to Roles of Nonphysician Providers in Radiology Practices. AB - Nonphysician providers (NPPs) in radiology practices include nurse practitioners, physician assistants, and radiologist assistants. The number of NPPs has been increasing both within and outside of radiology departments. In order for leaders in radiology departments to incorporate NPPs effectively into their practice, they require nuanced knowledge of appropriate coding and billing for services these professionals render. Furthermore, the existing body of literature suggests that with a defined and appropriate scope of practice and proper supervision, NPPs can provide care that is at least equivalent to that provided by attending physicians for narrowly defined tasks. A broader understanding of the rapidly evolving NPP workforce both within radiology practices and throughout other health care specialties will inform practice leaders who are adapting to a health care system that is moving rapidly toward value-based incentive payment models. (c)RSNA, 2018. PMID- 30303794 TI - The Road to Wellness: Engagement Strategies to Help Radiologists Achieve Joy at Work. AB - Physician wellness is recognized as a critical component of enhancing the quality of health care. An epidemic of symptoms related to stress and burnout among medical professionals, including radiologists, in the workplace is threatening not only health care providers at a personal level but also the entire health care system. In this review, the authors highlight recognized stressors in the contemporary radiology workplace and offer practical suggestions for mitigating burnout, improving professional engagement, and promoting wellness. Thematic goals to focus on include fostering an integrated and harmonious community at work, diminishing workplace detractors, creating opportunities to cultivate positive attitudes and intellect, and implementing effective leadership practices. (c)RSNA, 2018. PMID- 30303796 TI - Social Media Tools for Department and Practice Communication and Branding in the Digital Age. AB - With nearly 70% of adults in the United States using at least one social media platform, a social media presence is increasingly important for departments and practices. Patients, prospective faculty and trainees, and referring physicians look to social media to find information about our organizations. The authors present a stepwise process for planning, executing, and evaluating an organizational social media strategy. This process begins with alignment with a strategic plan to set goals, identification of the target audience(s), selection of appropriate social media channels, tracking effectiveness, and resource allocation. The article concludes with a discussion of advantages and disadvantages of social media through a review of current literature. (c)RSNA, 2018. PMID- 30303797 TI - Customer Service in Radiology: Satisfying Your Patients and Referrers. AB - Radiology has long been a service-oriented specialty. Although physicians in other specialties have direct interactions with patients, radiologists' interactions with patients are often indirect, most often occurring as a direct result of another provider's order. As such, radiology practices have had to focus on two distinct groups, patients and ordering providers, to grow their businesses and retain their patients. One could argue that during the past 2 decades, many of the most visible customer service initiatives in radiology practices have been directed toward the ordering provider. These initiatives have included implementing picture archiving and communication systems to improve image distribution and availability, voice dictation systems to decrease report turnaround time, computerized order entry to ease the ordering process, and structured reporting to improve the readability of the radiology report. As the practice of radiology is evolving to become more patient oriented, it is clear that the specialty needs to pivot and implement more initiatives that directly benefit patients. In this article, the concepts of customer service and a radiology department's primary customer are defined and discussed, and the concept of service quality is introduced. In addition, the author highlights the five dimensions of service quality: reliability, assurance, tangibles, empathy, and responsiveness. Each dimension is described in detail, first by using an archetypal business example and then by using an example of a project that has been successfully implemented in the author's radiology department. (c)RSNA, 2018. PMID- 30303799 TI - The 2018 RadioGraphics Monograph Issue: Radiology Practice Management Editor's Page. PMID- 30303798 TI - Building and Implementing an Operational Plan. AB - Radiology practices engage in planning processes with varying frequency. Organizational planning can occur on three levels. Strategic planning is an infrequent event occurring every 5-7 years. It is aspirational and is guided by the mission and the vision of the organization. Operational planning is a yearly process in which businesses articulate their goals for the year. Creating a yearly operational plan provides departmental employees with a road map for the upcoming year and helps to tie their daily activities to the larger strategic plan of the organization. Finally, a project plan provides details describing how a specific goal will be met. The differences among these three types of plans (strategic plan, operational plan, and project plan) are described. The article then focuses on operational planning, providing a rationale for building an operational plan and then a description of the method used in the authors' division to build an operational plan. (c)RSNA, 2018. PMID- 30303800 TI - Lessons on Leadership. AB - Leadership is increasingly recognized as a distinct set of trainable skills that are different from the skills of management. Dedicated attention to these skills by future leaders and the people who hire them is necessary to stem the tide of failed leadership that continues to remain all too common. Effective leaders prioritize others over self and are skilled communicators. They integrate information from disparate parties, encourage collaborative engagement, create a sense of urgency, and set the organizational vision. Never complacent, effective leaders look for disruptive influences and confront them without fear. Effective leaders are change agents. If you wish to be a leader but believe that you first need a title, think again. The most effective leaders do not need one. Practice, train, and emphasize your colleagues and organization above yourself, and the rest will take care of itself. (c)RSNA, 2018. PMID- 30303801 TI - Fundamentals of Diagnostic Error in Imaging. AB - Imaging plays a pivotal role in the diagnostic process for many patients. With estimates of average diagnostic error rates ranging from 3% to 5%, there are approximately 40 million diagnostic errors involving imaging annually worldwide. The potential to improve diagnostic performance and reduce patient harm by identifying and learning from these errors is substantial. Yet these relatively high diagnostic error rates have persisted in our field despite decades of research and interventions. It may often seem as if diagnostic errors in radiology occur in a haphazard fashion. However, diagnostic problem solving in radiology is not a mysterious black box, and diagnostic errors are not random occurrences. Rather, diagnostic errors are predictable events with readily identifiable contributing factors, many of which are driven by how we think or related to the external environment. These contributing factors lead to both perceptual and interpretive errors. Identifying contributing factors is one of the keys to developing interventions that reduce or mitigate diagnostic errors. Developing a comprehensive process to identify diagnostic errors, analyze them to discover contributing factors and biases, and develop interventions based on the contributing factors is fundamental to learning from diagnostic error. Coupled with effective peer learning practices, supportive leadership, and a culture of quality, this process can unquestionably result in fewer diagnostic errors, improved patient outcomes, and increased satisfaction for all stakeholders. This article provides the foundational elements for implementing this type of process at a radiology practice, with examples to help radiologists and practice leaders achieve meaningful practice improvement. (c)RSNA, 2018. PMID- 30303802 TI - Addressing Needs of Women Radiologists: Opportunities for Practice Leaders to Facilitate Change. AB - Women are, and have always been, underrepresented in radiology. This gender disparity must be addressed. Women bring a different perspective to the workplace; and their collaborative, empathetic, and compassionate approach to patient care and education is an asset that the radiology community should embrace and leverage. Radiologic organizations should focus on removing barriers to the entry of women physicians into radiology as a specialty and to their career advancement. Organizations should address bias, promote physician well being, and cultivate a safe and positive work environment. Radiology leaders committed to increasing gender diversity and fostering an inclusive workplace have the opportunity to strengthen their organizations. This article outlines the key steps that practice leaders can take to address the needs of women in radiology: (a) marketing radiology to talented women medical students, (b) addressing recruitment and bias, (c) understanding and accommodating the provisions of the Family and Medical Leave Act of 1993 and the Fair Labor Standards Act for both trainees and radiologists in practice, (d) preventing burnout and promoting well-being, (e) offering flexible work opportunities, (f) providing mentorship and career advancement opportunities, and (g) ensuring equity. (c)RSNA, 2018. PMID- 30303803 TI - Invited Commentary on "Addressing Needs of Women Radiologists". PMID- 30303804 TI - Strategies for Implementing a Standardized Structured Radiology Reporting Program. AB - Radiology practices are increasingly implementing standardized report templates to overcome the drawbacks of individual templates. However, implementing a standardized structured reporting program is not necessarily straightforward. This article provides practical guidance for radiologists who wish to implement standardized structured reporting in their practice. Challenges that radiology groups encounter tend to fall into two categories: technical and organizational. Defining and carrying out technical work can be tedious but tends to be relatively straightforward, whereas overcoming organizational challenges often requires changes in individuals' strongly held values, beliefs, roles, and relationships. Established organizational change models can help frame the organizational strategy to implement a standardized structured reporting program. Once leadership support is secured, a standardized structured reporting committee can be convened to establish report priorities, standards, design principles, and guidelines. Report standards help to establish the common framework upon which all report templates are constructed, helping to ensure report consistency. By using these standards, committee members can create reports relevant to their subspecialties, which can then be edited for formatting and content. Once report templates have been developed, edited, and published, an abbreviated form of the same process can be used to maintain the reports, which can be accomplished with much less effort than that initially required to create the templates. After standardized structured report templates are implemented and become embedded in practice, most radiologists eventually appreciate the merits of the program. (c)RSNA, 2018. PMID- 30303805 TI - Migrating to the Modern PACS: Challenges and Opportunities. AB - With progressive advancements in picture archiving and communication system (PACS) technology, radiology practices frequently look toward system upgrades and replacements to further improve efficiency and capabilities. The transition between PACS has the potential to derail the operations of a radiology department. Careful planning and attention to detail from radiology informatics leaders are imperative to ensure a smooth transition. This article is a review of the architecture of a modern PACS, highlighting areas of recent innovation. Key considerations for planning a PACS migration and important issues to consider in data migration, change management, and business continuity are discussed. Beyond the technical aspects of a PACS migration, the human factors to consider when managing the cultural change that accompanies a new informatics tool and the keys to success when managing technical failures are explored. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 30303806 TI - Costs of Quality and Safety in Radiology. AB - With the movement toward at-risk population health management-related payment models, a core factor for the success and survival of health care organizations has become understanding and decreasing costs. In medical specialties such as radiology, understanding models for procedure-based costing will become increasingly important. Using bottom-up models for procedure-based costing, such as time-driven activity-based costing, is more advantageous than using the inaccurate ratio of costs to charges approach; however, these approaches are more resource intensive when compared to top-down approaches. Understanding the costs of quality is also important for creating an accounting and budgeting process that reflects the total cost of quality. The costs of quality are divided into two main categories: the cost of control (also referred to as the costs of conformance) and the costs of failure of control (also referred to as the costs of nonconformance). The costs of control are the expenditures that occur to ensure quality. The costs of noncontrol are the expenses that arise from the lack of quality and safety. The cost of control has two subcategories: prevention costs and appraisal costs. The cost of noncontrol also has two subcategories: internal failure costs and external failure costs. Adopting a mind-set that takes into account the costs of control, or the costs to ensure high-quality care, and the costs of noncontrol, or the hidden costs of poor-quality care, will be essential for successful health care organizations in the future. (c)RSNA, 2018. PMID- 30303807 TI - Ongoing Professional Practice Evaluation of Radiologists: Strategies and Tools for Simplifying a Complex Process. AB - The Joint Commission, our major accreditation organization, requires that all physicians who have been granted privileges at an organization must undergo evaluation of and collect data relating to their performance, to make the decisions of privileging more objective and continuous by that organization. For radiologists, this so-called ongoing professional practice evaluation (OPPE) can be assessed by using the six general core competencies. These competencies were initially developed for graduate medical education and defined by the Accreditation Council for Graduate Medical Education and have now been expanded to provide a general framework for defining categories of data to be collected in assessing the performance of practicing radiologists. Within each core competency, various radiology-relevant metrics exist that can be measured to fulfill the OPPE requirements. Each radiology department can determine the specific type of data to be collected, including determining what items are defined as acceptable performance metrics, what data or outcomes require further monitoring, and what specific data or data trends would trigger the need for an additional focused and more thorough professional practice evaluation, also known as a focused professional practice evaluation (FPPE). (c)RSNA, 2018. PMID- 30303808 TI - Evaluation of a score for the prehospital distinction between cerebrovascular disease and stroke mimic patients. AB - Background Patients with a sudden onset of focal neurological deficits consistent with stroke, who turn out to have alternative conditions, have been labeled stroke mimics. Aims We assessed a recently validated telemedicine-based stroke mimic score (TeleStroke mimic score; TM-score) and individual patient characteristics with regard to its discriminative value between cerebrovascular disease and stroke mimic patients in the in-person, pre-hospital setting. Methods We evaluated patients cared for in a mobile stroke unit in Berlin, Germany. We investigated whether the TM-score (comprising six parameters), Face Arm Speech Time test, and individual patient characteristics were able to differentiate cerebrovascular disease from stroke mimic patients. Results We included 423 patients (299 (70.7%) cerebrovascular disease and 124 (29.3%) stroke mimic) in the final analysis. A TM-score > 30 indicated a high probability of a cerebrovascular disease and a score <=15 of a stroke mimic. The TM-score performed well to identify stroke mimics (area under the curve of 0.74 under receiver-operating characteristic curve analysis). The cerebrovascular disease patients were older (74.8 vs. 69.8 years, p = 0.001), had more often severe strokes (NIHSS > 14 25.8% vs. 11.3%, p = 0.001), presented more often with weakness of the face (70.9% vs. 42.7%, p = 0.001) or arm (60.9% vs. 33.9%, p = 0.001), dysarthria (59.5% vs. 40.3%, p < 0.001), history of atrial fibrillation (38.1% vs. 21.0%, p = 0.001), arterial hypertension (78.9% vs. 53.2%, p < 0.001), and less often with seizure (0.7% vs. 21.0%, p < 0.001). Conclusions The TM-score and certain patient characteristics can help paramedics and emergency physicians in the field to identify stroke mimic patients and select the most appropriate hospital destination. PMID- 30303809 TI - Glial fibrillary acidic protein for the early diagnosis of intracerebral hemorrhage: Systematic review and meta-analysis of diagnostic test accuracy. AB - Background and aims Glial fibrillary acidic protein (GFAP) has shown promise in several studies for its ability to diagnose intracerebral hemorrhage (ICH). We evaluated the diagnostic accuracy of blood GFAP level to differentiate (ICH) from acute ischemic stroke (AIS) and stroke mimics, both overall, and in the first three hours after symptom onset. Methods We searched multiple databases, without language restriction, from inception until December 2017. Hierarchical summary receiver operating characteristic (HSROC) modeling was used to meta-analyze results. We conducted subgroup analyses restricted to blood samples collected within 0-60, 60-120, and 120-180 min time groups after symptom onset, to evaluate diagnostic accuracy in the early pre-hospital phase. Between and within study heterogeneity was explored using meta-regression. Results The search identified 199 potentially relevant citations from which 11 studies involving 1297 participants (350 ICH, 947 AIS, or mimic) were included. The pooled sensitivity, specificity, and area under the HSROC curve were 0.756 (95% CI 0.630-0.849), 0.945 (95% CI 0.858-0.980), and 0.904 (95% CI 0.878-0.931), respectively. Differences in assays used, but not the other covariates, partially explained between-study heterogeneity ( p = 0.034). The summary estimates for the 0-60, 60 120, and 120-180 min subgroups were comparable to the primary analysis and there was no statistically significant difference in diagnostic accuracy between subgroups. Conclusions GFAP is a promising diagnostic biomarker for ICH diagnosis in the early pre-hospital phase. Test accuracy is affected by assay subtype, but there are still unexplained sources of heterogeneity. High quality, international multi-center trials are warranted to develop and validate a point-of-care GFAP assay for the rapid triage and evaluation of acute stroke in the pre-hospital setting. PMID- 30303810 TI - A core outcome set for aphasia treatment research: The ROMA consensus statement. AB - Background A core outcome set (COS; an agreed, minimum set of outcomes) was needed to address the heterogeneous measurement of outcomes in aphasia treatment research and to facilitate the production of transparent, meaningful, and efficient outcome data. Objective The Research Outcome Measurement in Aphasia (ROMA) consensus statement provides evidence-based recommendations for the measurement of outcomes for adults with post-stroke aphasia within phases I-IV aphasia treatment studies. Methods This statement was informed by a four-year program of research, which comprised investigation of stakeholder-important outcomes using consensus processes, a scoping review of aphasia outcome measurement instruments, and an international consensus meeting. This paper provides an overview of this process and presents the results and recommendations arising from the international consensus meeting. Results Five essential outcome constructs were identified: Language, communication, patient-reported satisfaction with treatment and impact of treatment, emotional wellbeing, and quality of life. Consensus was reached for the following measurement instruments: Language: The Western Aphasia Battery Revised (WAB-R) (74% consensus); emotional wellbeing: General Health Questionnaire (GHQ)-12 (83% consensus); quality of life: Stroke and Aphasia Quality of Life Scale (SAQOL-39) (96% consensus). Consensus was unable to be reached for measures of communication (where multiple measures exist) or patient-reported satisfaction with treatment or impact of treatment (where no measures exist). Discussion Harmonization of the ROMA COS with other core outcome initiatives in stroke rehabilitation is discussed. Ongoing research and consensus processes are outlined. Conclusion The WAB-R, GHQ 12, and SAQOL-39 are recommended to be routinely included within phases I-IV aphasia treatment studies. This consensus statement has been endorsed by the Collaboration of Aphasia Trialists, the British Aphasiology Society, the German Society for Aphasia Research and Therapy, and the Royal College of Speech Language Therapists. PMID- 30303811 TI - Systematic review of organizational models for intra-arterial treatment of acute ischemic stroke. AB - Background Intra-arterial treatment of acute ischemic stroke requires changes to acute stroke services since most hospitals do not have on-site intra-arterial treatment facilities. Aim To identify models for delivery of intra-arterial treatment and to compare process performance and clinical and radiological outcomes of the different models. Methods We systematically searched the literature and contacted experts in the field. We performed a qualitative synthesis to identify models, and a quantitative review and meta-analysis of clinical and radiological outcomes under different organizational models. Summary of review The searches retrieved 148 publications, of which 27 were used for the identification and description of models, and 9 for the comparison of the different models. We identified four main models: the mother-ship, drip-and ship, mobile interventionist, and mobile stroke unit models. There were no randomized controlled trials of the different models, but non-randomized comparisons were possible using data from 8 observational studies and 1 randomized-controlled trial of intra-arterial therapy, of a total of 4127 patients. Comparison between the mother-ship and drip-and-ship models showed no difference in survival (OR 0.81; 95% CI 0.63-1.03), favorable functional outcome (OR 0.96; 95% CI 0.73 1.25), or arterial patency (OR 0.89; 95% CI 0.73-1.08). Conclusions Different organizational models exist for intra-arterial treatment of acute ischemic stroke, but there is insufficient evidence to recommend a particular, universal model. Until one model can be shown to be superior, the choice of model should depend on local factors and patient characteristics. PMID- 30303812 TI - A prospective study of patients' pain intensity after cardiac surgery and a qualitative review: effects of examiners' gender on patient reporting. AB - : Background and aims As indicated by experimental studies, reports of pain intensity may depend on the examiner's gender. Until now, it is unclear whether this is relevant in clinical routine. This study investigated prospectively whether the gender of assessor plays a role in patients' pain reports and whether this role differs in male and female patients. Methods 165 patients (66.4 years+/ 0.63; 118 males) scheduled for heart surgery were allocated consecutively to one examiner out of four students of both genders: two females and two males (aged 24.3 years+/-1.7). Therefore, the following study groups were defined: Group 1: female assessors-female patients, 2: female-male; 3: male-female, 4: male-male. Using a standardized analgesic scheme, patients were asked to rank their pain intensity on a numeric rating scale (NRS: 0-10), postoperatively. STATISTICS: Kruskal-Wallis, Mann-Whitney; p<0.05. Additionally, a qualitative literature review of the databases Medline and CENTRAL was performed focusing on experimental and clinical studies on experimenter gender bias. Due to the review, this prospective clinical study was designed to investigate whether patients after surgery report lower pain intensities when assessed by a female compared to a male assessor. Results Summarizing all patients, pain intensity on POD_1 was rated 4.0+/-2.4 on NRS and decreased on POD_2 to 3.0+/-2.1 [H(3)=37.941, p=0.000]. On average, pain intensity did not differ between males and females (NRS: 3.5 vs. 3.6). Only on the second postoperative day, more intense pain was reported in front of female assessors and less intense pain in front of male assessors (NRS: 3.4 vs. 2.4; p=0.000). A main effect for the four groups was seen (p=0.003): male patients reported higher pain scores to female assessors (NRS: 3.5 vs. 2.3; p=0.000). Conclusions Together, contrary to the expectations, patients after cardiac surgery reported a higher pain intensity in front of a female and a lower pain intensity in front of a male assessor. In particular, female caregivers may heighten the reported pain intensity up to 1.2 NRS-points; this bias seems to be more relevant for male patients. Implications Therefore, despite some methodological weakness, our data suggest that attention should be paid to a rather small, but somehow significant and consistent examiner gender bias after cardiac surgery especially in male patients. Further clinical studies are needed to show the true extent of clinical relevance and exact mechanisms underlying these gender reporting bias. PMID- 30303813 TI - Incontinence-Associated Dermatitis: State of the Science and Knowledge Translation. AB - This review of the literature updates and considers the evidence on incontinence associated dermatitis (IAD). Best practice strategies for the management of skin damage from IAD (both prevention and treatment) are provided. A mnemonic to help clinicians translate IAD evidence into practice is introduced. Workplace experiences supplement this evidence synthesis. Approaches to assist in translation of this knowledge and evidence into practice are also provided. PMID- 30303814 TI - The Role and Value of Public Members in Health Care Regulatory Governance. AB - American medicine has progressively embraced transparency and accountability in professional self-regulation. While public members serving on health care regulatory boards involved with the accreditation, assessment, certification, education, and licensing of physicians provide formal opportunities for voicing public interests, their presence has not been deeply explored. Using 2016 survey and interview data from health care organizations and public members, the authors explore the value and challenges of public members. Public members were often defined as individuals who did not have a background in health care and provided a patient perspective, but in some instances prior health care experience did not automatically exclude these individuals from serving as public members. Public members served on the majority of national health care regulatory boards and constituted an average 9%-15% of board composition, depending on how rigidly the organizations defined "public member." Public members were valued for their commitment to the priorities and interests of the public, ability to help boards maintain that public focus, and various professional skills they offer to boards. A main challenge that public members faced was their lack of familiarity with and knowledge of the health care field. The authors suggest several considerations for improved public member integration into health care regulatory organizations: clearly defined roles of public members, including evaluating whether or not previous health care experience either contributes or hinders their role within the organization; greater visibility of opportunities for the public to serve on these boards; and potentially a more intensive orientation for public members. PMID- 30303815 TI - Socially Accountable Academic Health Centers: Pursuing a Quadripartite Mission. AB - Academic health centers (AHCs) in the United States have had a leading role in educating the medical workforce, generating new biomedical knowledge, and providing tertiary and quaternary clinical care. Yet the health status of the U.S. population lags behind that of almost every other developed world economy. One reason is that the health care system is not organized optimally to address the major driver of health status, the social determinants of health (SDOH). The United States' overall poor health status is a reflection of dramatic disparities in health that exist between communities and population groups, and these are associated with variations in the underlying SDOH. Improving health status in the United States thus requires a fundamental reengineering of the health delivery system to address SDOH more explicitly and systematically. The AHC's tripartite mission, which has served so well in the past, is no longer sufficient to position AHCs to lead and resolve the intractable drivers of poor health status, such as unfair and unjust health disparities, health inequities, or the population's SDOH.AHCs enjoy broad public support and have an opportunity-and an obligation-to lead in improving the nation's health. This Perspective proposes a new framework for AHCs to expand upon their traditional tripartite mission of education, research, and clinical care to include explicitly a fourth mission of social accountability. Through this fourth mission, comprehensive community engagement can be undertaken, addressing SDOH and measuring the health impact of interventions by using a deliberate structure and process yielding defined outcomes. PMID- 30303816 TI - Developing an Inclusive and Welcoming LGBTQ Clinic. AB - People who identify as lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) are underserved and face barriers to knowledgeable health care. Most health systems are ill prepared to provide care that addresses the needs of the LGBTQ community. Basic steps to developing an LGBTQ welcoming health care program are presented. It can be adapted to diverse health care models, from obstetrics and gynecology and other primary care services whether public or private and to hospitals and specialty clinics. This LGBTQ inclusive health care model was developed in collaboration with the LGBTQ community, a multidisciplinary team of health care providers, and professionals of Law and Information Technology. PMID- 30303817 TI - Nighttime Sleep and Daytime Sleepiness Improved With Pimavanserin During Treatment of Parkinson's Disease Psychosis. AB - INTRODUCTION: Impaired nocturnal sleep and excessive daytime sleepiness are common problems for patients with Parkinson's disease, and patients with Parkinson's disease with sleep dysfunction are 5 times more likely to experience psychotic symptoms. Pimavanserin, a 5-HT2A inverse agonist approved to treat Parkinson's disease psychosis, may improve sleep quality in patients with Parkinson's disease experiencing sleep disturbances. METHODS: Scales for Outcomes in Parkinson's Disease nighttime sleep (SCOPA-NS) and SCOPA-daytime sleepiness (DS) data obtained during 2 double-blind placebo-controlled studies of pimavanserin in persons with Parkinson's disease psychosis were evaluated. Data from the placebo and pimavanserin 34 mg groups in the 2 studies were pooled to provide further information on the effect of pimavanserin 34 mg on sleep. Additional analyses on the pooled study data were performed on participants with significantly impaired nighttime sleep and daytime sleepiness, defined as SCOPA NS >=7 and SCOPA-DS >=5, respectively. RESULTS: In the pooled analysis, treatment effects, expressed as least squares mean reductions in SCOPA-NS at week 6, were 1.4 for pimavanserin 34 mg and -0.5 for placebo. At week 6, the decrease from baseline in SCOPA-DS for the pimavanserin 34 mg group was -1.7 and -1.2 for the placebo group (P = 0.108). When evaluating participants with impaired nighttime sleep and daytime sleepiness at baseline, the SCOPA-NS score change was -4.4 for the pimavanserin 34 mg group and -2.3 for the placebo group (P = 0.002), whereas the SCOPA-DS change was -2.9 and -1.9 for the pimavanserin 34 mg and placebo groups (P = 0.120), respectively. CONCLUSION: The data from the trials suggest that nighttime sleep improved with administration of pimavanserin, a novel 5-HT2A receptor inverse agonist/antagonist. PMID- 30303818 TI - Recurrent Genomic Alterations in Soft Tissue Perineuriomas. AB - Perineuriomas are rare nerve sheath tumors, divided into intraneural and extraneural (soft tissue) types. Intraneural perineuriomas frequently contain TRAF7 mutations, and rarely, chr22q12 deletions. While chr22q losses can occur in soft tissue perineuriomas, comprehensive high-resolution molecular profiling has not been reported in these tumors and TRAF7 status is unknown. We used whole exome sequencing and OncoScan single nucleotide polymorphism (SNP) array to evaluate 14 soft tissue perineuriomas. Thirteen cases showed 2 or more chromosomal abnormalities, composed primarily of large deletions. Recurrent chr22q deletions, containing the NF2 locus (n=6) and the previously unreported finding of chr17q deletions, with the NF1 locus (n=4) were frequent events and were mutually exclusive in all but1 case. In addition, 5 cases had varying chr2 deletions; and 4 cases had chr6 deletions. A chr10 deletion (previously reported in the sclerosing variant of soft tissue perineurioma) was observed in one case and another case had chr7 chromothripsis as the sole chromosomal abnormality. No TRAF7 mutations or alterations were identified in any case and no other evaluated gene (MAF<0.0001) had recurrent, deleterious mutations in >2 cases. The molecular genetic profiles showed no association with patient sex, age, tumoral histology or anatomic site. OncoScan SNP array analysis was performed on 10 cases and showed high concordance with the whole exome data, validating the large-scale deletions, duplications, and chr7 chromothripsis findings. In soft tissue perineuriomas, recurrent 22q12 deletions (with NF2) and 17q11 deletions (with NF1) appear to be mutually exclusive events, and alterations in NF1 or NF2 likely contribute to perineurioma pathogenesis, similar to other nerve sheath tumors. Moreover, the lack of TRAF7 mutations in soft tissue perineuriomas indicates divergent pathogenetic mechanisms from those of intraneural perineuriomas. PMID- 30303819 TI - Somatic Mutations of TSC2 or MTOR Characterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm. AB - The differential diagnosis of renal cell neoplasms with solid or nested architecture and eosinophilic cytoplasm has become increasingly complex. Despite recent advances in classifying a number of entities exhibiting this morphology, some tumors remain in the unclassified category. Here we describe a morphologically distinct group of sporadic renal cell carcinoma (RCC) with predominantly nested architecture, eosinophilic, and remarkably vacuolated cytoplasm retrospectively identified from a cohort of previously unclassified tumors. We examined the clinicopathologic and immunohistochemical features of these tumors and investigated their mutational and copy number alterations using a targeted next-generation sequencing platform. The study included 7 patients with a mean age of 54 years (range: 40 to 68 y) and a male to female ratio of 3:4. All patients presented with a solitary renal mass and had no prior medical or family history raising concern for syndromic conditions. Tumors were well circumscribed, unencapsulated, and comprised of nests of eosinophilic cells in a hypocellular and often edematous stroma. Tumor cells had round nuclei with prominent nucleoli and granular cytoplasm with striking vacuolization. Thick walled vessels and calcifications were also frequently present, whereas increased mitotic activity, necrosis, foamy histiocytes or lymphocytic infiltrates were not identified. All cases were positive for PAX8, had retained expression of SDHB and FH, and exhibited a CK7-/CK20- phenotype. While cathepsin-K was positive in 5 cases, none exhibited immunoreactivity to HMB45 or Melan A, or TFE3 immunostaining. Next-generation sequencing identified somatic inactivating mutations of TSC2 (3/5 tumors tested) or activating mutations of MTOR (2/5) as the primary molecular alterations, consistent with hyperactive mTOR complex 1 signaling which was further demonstrated by phospho-S6 and phospho-4E-BP1 immunostaining. Copy number analysis revealed a loss of chromosome 1 in both cases with MTOR mutation. These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1-TSC2 complex or the mTOR complex 1 pathway. Recognition of their characteristic morphologic and immunophenotypic features will allow them to be readily identified and separated from the unclassified RCC category. PMID- 30303820 TI - Novel pathogenic variants in GBE1 causing fetal akinesia deformation sequence and severe neuromuscular form of glycogen storage disease type IV. AB - Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144 1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM_000158). Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum. PMID- 30303821 TI - Utilization of Time-driven Activity-based Costing to Determine the True Cost of a Single or 2-level Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: This is a prospective case series. OBJECTIVE: To determine the actual cost of performing 1- or 2-level anterior cervical discectomy and fusion (ACDF) using actual patient data and the time-driven activity-based cost methodology. SUMMARY OF BACKGROUND DATA: As health care shifts to use value-based reimbursement, it is imperative to determine the true cost of surgical procedures. Time-driven activity-based costing determines the cost of care by determining the actual resources used in each step of the care cycle. MATERIALS AND METHODS: In total, 30 patients who underwent a 1- or 2-level ACDF by 3 surgeons at a specialty hospital were prospectively enrolled. To build an accurate process map, a research assistant accompanied the patient to every step in the care cycle including the preoperative visit, the preadmission testing, the surgery, and the postoperative visits for the first 90 days. All resources utilized and the time spent with every member of the care team was recorded. RESULTS: In total, 27 patients were analyzed. Eleven patients underwent a single level ACDF and 16 underwent a 2-level fusion. The total cost for the episode of care was $29,299+/-$5048. The overwhelming cost driver was the hospital disposable costs ($13,920+/-$6325) which includes every item used during the hospital stay. Intraoperative personnel costs including fees for the surgeon, resident/fellow, anesthesia, nursing, surgical technician, neuromonitoring, radiology technician and orderlies, accounted for the second largest cost at $6066+/-$1540. The total cost excluding hospital overhead and disposables was $9071+/-$1939. CONCLUSIONS: Reimbursement for a bundle of care surrounding a 1- or 2-level ACDF should be no less than $29,299 to cover the true costs of the care for the entire care cycle. However, this cost may not include the true cost of all capital expenditures, and therefore may underestimate the cost. PMID- 30303823 TI - Commentary on Patients' Body Image Improves After Mohs Micrographic Surgery for Nonmelanoma Head and Neck Skin Cancer. PMID- 30303822 TI - Fecal calprotectin is not superior to serum C-reactive protein or the Harvey Bradshaw index in predicting postoperative endoscopic recurrence in Crohn's disease. AB - BACKGROUND: Fecal calprotectin (FC) is a widely used noninvasive marker of gut inflammation that is associated with endoscopic severity in Crohn's disease (CD). However, FC has been inconsistent in predicting postoperative recurrence of CD, and its utility in the postoperative setting remains unclear. MATERIALS AND METHODS: Blood and fecal samples were collected in consecutively recruited patients with CD who had undergone ileocolonic resection and required a colonoscopy to assess postoperative recurrence, as defined by the Rutgeerts score (RS). RESULTS: A total of 86 patients were prospectively recruited at five centers. Overall, 49 (57%) had CD recurrence (RS>=i2). FC concentrations trended to increase with RS severity; FC median (interquartile range) was significantly higher in patients with endoscopic recurrence than those in endoscopic remission [172.5 (75-375) vs. 75 (36.5-180.5) MUg/g, respectively]. The same occurred for C reactive protein (CRP) [0.5 (0.1-0.95) vs. 0.1 (0.02-0.27)] mg/dl and the Harvey Bradshaw index (HBI) [4 (2-7) vs. 1 (0-3.5)]. The three variables significantly correlated. The area under the curve to discriminate between patients in endoscopic remission and recurrence was 0.698 for FC, with 62 MUg/g being the optimal cut-off point. This indicated FC would have 85.7% sensitivity and 45.9% specificity in detecting any recurrence, having positive predictive value and negative predictive value of 67.7 and 70.8%, respectively. Area under the curve for CRP and HBI were both 0.710. The combination of CRP and HBI provided a positive predictive value 95.7 and a diagnostic odds ratio of 30.8. CONCLUSION: FC is not better than CRP combined with HBI to predict endoscopic postoperative recurrence of CD. PMID- 30303824 TI - Hooked on Hooks? A Study in the Utilization of Skin Hooks. AB - BACKGROUND: The skin hook is a valuable instrument used in the practice of dermatologic surgery. However, because of numerous factors, the degree of its use varies extensively. OBJECTIVE: The purpose of this study was to examine practice trends among dermatologic surgeons regarding the use of skin hooks, as well as analyze factors influencing their use. METHODS: A survey comprising 14 questions was distributed to members of the American College of Mohs Surgery and the American Society for Dermatologic Surgery. Results were recorded, and statistical analysis was conducted using the 2-sample z-test to compare 2 population proportions. RESULTS: Five hundred seventy-one responses were received, with comments. 85.1% of respondents reported using skin hooks. Their use was further characterized as minimal (20.7%), moderate (29.0%), and extensive (35.4%). The utilization of skin hooks was additionally categorized based on age, gender, fellowship training, number of years in practice, practice setting, and history of experience/observance of a sharps exposure. Only the presence or absence of fellowship training demonstrated a statistically significant difference in the use of skin hooks. CONCLUSION: Skin hooks are highly used tools among dermatologic surgeons. Their use requires appropriate training and experience, and care must be taken to minimize risk of exposure. PMID- 30303825 TI - Detection of Lipid Mediators of Inflammation in the Human Tear Film. AB - PURPOSE: Lipid mediators of inflammation are a group of signaling molecules produced by various cells under physiological conditions and modulate the inflammatory process during various pathologic conditions. Although eicosanoids and F2-isoprostanes are recognized lipid mediators of inflammation, there is no consensus yet on the extraction and mass spectrometry (MS) method for their analysis in individual human tear samples. Thus, the aim of this study was to develop an optimal method for extraction of lipid mediators of inflammation in the tear film and evaluate MS techniques for their analysis. METHODS: Basal tears were collected from each eye of 19 subjects using glass microcapillaries. Lipid extraction was performed using either varying concentrations of acidified methanol, a modified Folch method, or solid-phase extraction. Initially, an untargeted analysis of the extracts was performed using SCIEX TripleTOF 5600 mass spectrometer to identify any lipid mediators of inflammation (eicosanoids) and later a targeted analysis was performed using the SCIEX 6500 Qtrap to identify and quantify prostaglandins and isoprostanes. Mass spectra and chromatograms were analyzed using Peakview, XCMS, and Multiquant software. RESULTS: Prostaglandins and isoprostanes were observed and quantified using the Qtrap mass spectrometer under multiple reaction monitoring (MRM) mode after solid-phase extraction. Extraction with acidified methanol along with the Folch method produced cleaner spectra during MS with the Triple time of flight (TOF) mass spectrometer. Lipid mediators of inflammation were not observed in any of the tear samples using the Triple TOF mass spectrometer. CONCLUSIONS: Solid-phase extraction may be the method of choice for extraction of prostaglandins and isoprostanes in low volumes of tears. The SCIEX Qtrap 6500 in MRM mode may be suitable to identify and quantify similar lipid mediators of inflammation. PMID- 30303826 TI - Hypotension and Transient ST Elevation After Reversal of Heparin With Protamine. PMID- 30303827 TI - Predictors of Referral to a Pediatric Outpatient Chronic Pain Clinic. AB - OBJECTIVES: To retrospectively characterize the rate of referrals to an outpatient chronic pain clinic among adolescents with chronic pain, and to identify factors associated with referral. METHODS: Adolescents 13-18 years of age seen in 2010-2015 at outpatient clinics associated with Nationwide Children's Hospital (NCH) and diagnosed with chronic pain were included if they lived near NCH and had not been previously referred to the NCH outpatient chronic pain clinic. Subsequent referrals to the pain clinic were tracked through December 2017 using a quality improvement database. Factors predicting referral were assessed at the initial encounter in another outpatient clinic, and analyzed using multivariable logistic regression. RESULTS: The analysis included 778 patients (569 female; median age 15?y), of whom 96 (12%) were subsequently referred to the chronic pain clinic, after a median period of 3 months. Generalized chronic pain (adjusted odds ratio [aOR]=1.8; 95% confidence interval [CI]: 1.1, 3.1; P=0.023) and regional pain syndromes (aOR=3.1; 95% CI: 1.5, 6.7; P=0.003) were associated with increased likelihood of referral. Referral was also more likely among female patients and among patients with a mental health comorbidity or recent surgery or hospitalization. DISCUSSION: Referrals to our chronic pain clinic were more likely for adolescents with generalized chronic pain, regional pain syndromes, and patients with mental health comorbidities. Recent hospitalization or surgery, but not recent emergency department visits, were associated with pain clinic referral. Multivariable analysis did not find disparities in referral by race or socioeconomic status. PMID- 30303828 TI - Post-traumatic stress disorder in combat veterans. PMID- 30303829 TI - Post-traumatic stress disorder in veterans: Treatments and risk factors for nonadherence. AB - Post-traumatic stress disorder (PTSD) affects about 20% of US military veterans and is a major cause of mortality in these men and women. The incidence of PTSD has persisted over the last decade with the Iraq and Afghanistan wars, yet treatment and adherence remain inadequate in part due to clinician lack of knowledge about cognitive processing therapy and prolonged exposure, the proven gold standards in treatment. This article reviews the most current and successful PTSD treatment options and identifies risk factors for patient nonadherence in hopes of reducing the rate of veteran suicide related to PTSD. PMID- 30303830 TI - Preventing sudden infant death syndrome and other sleep-related infant deaths. AB - Sudden infant death syndrome, a type of sleep-related sudden unexpected infant death (SUID) is the leading cause of postneonatal mortality in the United States and the third leading cause of infant death overall. Despite the evidence-based risk-reduction strategies and the highly publicized campaigns for a safe sleep environment, some infants continue to sleep in unsafe sleep conditions. Clinicians need to know the current best practices to reduce the incidence of sleep-related SUID and be knowledgeable to counsel caregivers who may resist adhering to these recommendations. This article describes the different types of SUID, associated risk factors, and highlights recommendations to help parents and caregivers ensure safe sleep environments for infants. PMID- 30303831 TI - Limping on split-belt treadmills implies opposite kinematic and dynamic lower limb asymmetries. AB - Walking on a split-belt treadmill (each of the two belts running at a different speed) has been proposed as an experimental paradigm to investigate the flexibility of the neural control of gait and as a form of therapeutic exercise. However, the scarcity of dynamic investigations challenges the validity of the available findings. The aim of the present study was to investigate the dynamic asymmetries of lower limbs of healthy adults during adaptation to gait on a split belt treadmill. Ten healthy adults walked on a split-belt treadmill mounted on force sensors, with belts running either at the same speed ('tied' condition) or at different speeds ('split' condition, 0.4 vs. 0.8 or 0.8 vs. 1.2 m/s). The sagittal power and work provided by ankle, knee and hip joints, joint rotations, muscle lengthening, and surface electromyography were recorded simultaneously. Various tied/split walking sequences were requested. In the split condition a marked asymmetry between the parameters recorded from each of the two lower limbs, in particular from the ankle joint, was recorded. The work provided by the ankle (the main engine of body propulsion) was 4.8 and 2.2 times higher (in the 0.4 vs. 0.8, and 0.8 vs. 1.2 m/s conditions, respectively) compared with the slower side, and 1.2 and 1.1 times higher compared with the same speed in the tied condition. Compared with overground gait in hemiplegia, split gait entails an opposite spatial and dynamic asymmetry. The faster leg mimics the paretic limb temporally, but the unimpaired limb from the spatial and dynamic point of view. These differences challenge the proposed protocols of split gait as forms of therapeutic exercise. PMID- 30303832 TI - Effectiveness of antibiotics versus ibuprofen in relieving symptoms of nosocomial urinary tract infection: A comparative study. AB - BACKGROUND AND PURPOSE: Antibiotic therapy has been the mainstay of treatment in the management of hospitalized patients with nosocomial urinary tract infection (UTI); however, its use is associated with an increase in resistance and high cost. Ibuprofen showed effectiveness in relieving symptoms of UTI, but its superiority is questionable. The goal of this study was to compare the effectiveness of antibiotics against ibuprofen in relieving symptoms of UTI and to identify factors that affect symptom relief. METHODS: This study was conducted in three public hospitals in Jordan. Patients with nosocomial UTI were assigned to either antibiotics or ibuprofen. Symptoms of UTI were assessed at the time of initiation of treatment and 5 days later. CONCLUSIONS: Antibiotics were more effective in relieving symptoms of UTI than Ibuprofen. Comorbidity and length of hospitalization affected symptom relief during the treatment of UTI. IMPLICATION FOR PRACTICE: Nurse practitioners in the clinical settings can take an active role in helping patients with UTI to achieve relief of symptoms by supporting the use of antibiotics over ibuprofen in symptom resolution. PMID- 30303833 TI - The perceptions and experiences of national regulatory nurse leaders in advancing the advanced practice registered nurse compact policy agenda. AB - BACKGROUND AND PURPOSE: The Advanced Practice Registered Nurse (APRN) Compact was approved at the National Council of State Boards of Nursing Delegate Assembly in May 2015. Since that date, only three states have been successful in the legislative adoption of the compact. Thus, the purpose of this study was to explore the experiences and perceptions of nursing regulatory leaders involved with the individual state adoption of the APRN Compact. METHODS: This qualitative study followed a phenomenological-hermeneutic methodology approach. CONCLUSIONS: Four themes emerged from within the data: legislative political environment; professional organizational barriers; strategies to push past barriers; and moving forward. An overarching theme of consistent communication was evident. IMPLICATIONS FOR PRACTICE: This study identifies barriers experienced in the legislative state adoption process and successful strategies to overcome these barriers to move the APRN compact forward. PMID- 30303834 TI - Advance Care Planning and Parent-Reported End-of-Life Outcomes in Children, Adolescents, and Young Adults With Complex Chronic Conditions. AB - OBJECTIVES: For children, adolescents, and young adults with complex chronic conditions advance care planning may be a vital component of optimal care. Advance care planning outcomes research has previously focused on seriously ill adults and adolescents with cancer where it is correlated with high-quality end of-life care. The impact of advance care planning on end-of-life outcomes for children, adolescents, and young adults with complex chronic conditions is unknown, thus we sought to evaluate parental preferences for advance care planning and to determine whether advance care planning and assessment of specific family considerations during advance care planning were associated with differences in parent-reported end-of-life outcomes. DESIGN: Cross-sectional survey. SETTING: Large, tertiary care children's hospital. SUBJECTS: Bereaved parents of children, adolescents, and young adults with complex chronic conditions who died between 2006 and 2015. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: One-hundred fourteen parents were enrolled (54% response rate) and all parents reported that advance care planning was important, with a majority (70%) endorsing that discussions should occur early in the illness course. Parents who reported advance care planning (65%) were more likely to be prepared for their child's last days of life (adjusted odds ratio, 3.78; 95% CI, 1.33 10.77), to have the ability to plan their child's location of death (adjusted odds ratio, 2.93; 95% CI, 1.06-8.07), and to rate their child's quality of life during end-of-life as good to excellent (adjusted odds ratio, 3.59; 95% CI, 1.23 10.37). Notably, advance care planning which included specific assessment of family goals was associated with a decrease in reported child suffering at end-of life (adjusted odds ratio, 0.23; 95% CI, 0.06-0.86) and parental decisional regret (adjusted odds ratio, 0.42; 95% CI, 0.02-0.87). CONCLUSIONS: Parents of children, adolescents, and young adults with complex chronic conditions highly value advance care planning, early in the illness course. Importantly, advance care planning is associated with improved parent-reported end-of-life outcomes for this population including superior quality of life. Further studies should evaluate strategies to ensure high-quality advance care planning including specific assessment of family goals. PMID- 30303835 TI - Risk of Sepsis and Mortality Among Patients With Chronic Obstructive Pulmonary Disease Treated With Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. AB - OBJECTIVES: This study aimed to compare the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk and outcomes of sepsis in patients with chronic obstructive pulmonary disease. DESIGN: A retrospective study. SETTING: Taiwan's National Health Insurance Research Database. PATIENTS: All patients with chronic obstructive pulmonary disease who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for more than 90 days between 2000 and 2005 were recruited for this study. Pairwise matching (1:1) of the angiotensin-converting enzyme inhibitor and angiotensin receptor blocker groups resulted in two similar subgroups with 5,959 patients in each. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was sepsis, and the secondary outcome was death. The occurrence rate of sepsis was 3.67 per 100 person-years for the patients receiving angiotensin converting enzyme inhibitors and 2.87 per 100 person-years for those receiving angiotensin receptor blockers. In addition, the patients receiving angiotensin converting enzyme inhibitors had a higher risk of septic shock (adjusted hazard ratio, 1.45; 95% CI, 1.26-1.67) and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.22-1.40) than those receiving angiotensin receptor blockers. No matter whether the patients had prior severe exacerbation before the index date, those receiving angiotensin-converting enzyme inhibitors had a higher risk of sepsis, septic shock, and mortality than those receiving angiotensin receptor blockers (all p < 0.001). CONCLUSIONS: Angiotensin receptor blockers were associated with lower rates of sepsis and mortality than angiotensin-converting enzyme inhibitors in the patients with chronic obstructive pulmonary disease. The similar findings were also noted in subgroup analysis. PMID- 30303836 TI - Association Between Elevated Mean Arterial Blood Pressure and Neurologic Outcome After Resuscitation From Cardiac Arrest: Results From a Multicenter Prospective Cohort Study. AB - OBJECTIVES: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. DESIGN: Preplanned analysis of a prospective cohort study. SETTING: Six academic hospitals in the United States. PATIENTS: Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. INTERVENTIONS: Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. MEASURES AND MAIN RESULTS: We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70-90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76). CONCLUSIONS: Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest. PMID- 30303837 TI - Combination of High-Calorie Delivery and Organ Failure Increases Mortality Among Patients With Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Among critically ill patients, the benefits of nutrition support may vary depending on severity of organ dysfunction. The objective of the current article was to explore the relationship between organ failure and calories exposure with hospital mortality during the first week of acute respiratory distress syndrome. DESIGN: Retrospective observational study. SETTING: Single center ICU. PATIENTS: Adults admitted to the ICU with a diagnosis of acute respiratory distress syndrome. INTERVENTIONS: Calorie delivery from enteral nutrition, parenteral nutrition, propofol, and dextrose containing fluids were collected for 7 days following intubation. Sequential Organ Failure Assessment score was calculated at ICU admit and for the same 7 days to describe organ dysfunction; four different Sequential Organ Failure Assessment variables were created 1) Sequential Organ Failure Assessment at ICU admit, 2) average Sequential Organ Failure Assessment for the first 7 days following intubation, 3) the highest Sequential Organ Failure Assessment for the first 7 days following intubation, and 4) change in Sequential Organ Failure Assessment from intubation to 7 days later. MEASUREMENTS AND MAIN RESULTS: A total of 298 patients were included. Sequential Organ Failure Assessment at ICU admit, average Sequential Organ Failure Assessment for the first 7 days following intubation, highest Sequential Organ Failure Assessment for the first 7 days following intubation, change in Sequential Organ Failure Assessment from intubation to 7 days later, and calorie delivery the first 7 days following intubation were all associated with increased likelihood of mortality. Compared with patients with low organ failure and low-calorie delivery, those with high-calorie delivery and low organ failure, low-calorie delivery and high organ failure, and the combination of both high organ failure with high-calorie delivery were associated with an incremental increase in the likelihood or mortality. CONCLUSIONS: Organ failure appears to modify the relationship between calorie exposure and ICU outcome. Additional research is needed to identify appropriate thresholds for safe calorie exposure with increased organ failure. PMID- 30303838 TI - Late Awakening in Survivors of Postanoxic Coma: Early Neurophysiologic Predictors and Association With ICU and Long-Term Neurologic Recovery. AB - OBJECTIVES: To examine neurophysiologic predictors and outcomes of patients with late awakening following cardiac arrest. DESIGN: Observational cohort study. SETTING: Academic ICU. PATIENTS: Adult comatose cardiac arrest patients treated with targeted temperature management and sedation. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Time to awakening was calculated starting from initial sedation stop following targeted temperature management and rewarming (median 34 hr from ICU admission). Two-hundred twenty-eight of 402 patients (57%) awoke: late awakening (> 48 hr from sedation stop; median time to awakening 5 days [range, 3-23 d]) was observed in 78 subjects (34%). When considering single neurophysiologic tests, late awakening was associated with a higher proportion of discontinuous electroencephalography (21% vs 6% of early awakeners), absent motor and brainstem responses (38% vs 11%; 23 vs 4%, respectively), and serum neuron specific enolase greater than 33 ng/mL (23% vs 8%; all p < 0.01): no patient had greater than 2 unfavorable tests. By multivariable analysis-adjusting for cardiac arrest duration, Sequential Organ Failure Assessment score, and type of sedation discontinuous electroencephalography and absent neurologic responses were independently associated with late awakening. Late awakening was more frequent with midazolam (58% vs 45%) and was associated with higher rates of delirium (62% vs 39%) and unfavorable 3-months outcome (27% vs 12%; all p = 0.005). CONCLUSIONS: Late awakening is frequent after cardiac arrest, despite early unfavorable neurophysiologic signs and is associated with greater neurologic complications. Limiting benzodiazepines during targeted temperature management may accelerate awakening. Postcardiac arrest patients with late awakening had a high rate of favorable outcome, thereby supporting prognostication strategies relying on multiple rather than single tests and that allow sufficient time for outcome prediction. PMID- 30303839 TI - Estimating ICU Benefit: A Randomized Study of Physicians. AB - OBJECTIVES: The distinction between overuse and appropriate use of the ICU hinges on whether a patient would benefit from ICU care. We sought to test 1) whether physicians agree about which types of patients benefit from ICU care and 2) whether estimates of ICU benefit are influenced by factors unrelated to severity of illness. DESIGN: Randomized study. SETTING: Online vignettes. SUBJECTS: U.S. critical care physicians. INTERVENTIONS: Physicians were provided with eight vignettes of hypothetical patients. Each vignette had a single patient or hospital factor randomized across participants (four factors related and four unrelated to severity of illness). MEASUREMENTS AND MAIN RESULTS: The primary outcome was the estimate of ICU benefit, assessed with a 4-point Likert-type scale. In total, 1,223 of 8,792 physicians volunteered to participate (14% recruitment rate). Physician agreement of ICU benefit was poor (mean intraclass correlation coefficient for each vignette: 0.06; range: 0-0.18). There were no vignettes in which more than two thirds of physicians agreed about the extent to which a patient would benefit from ICU care. Increasing severity of illness resulted in greater estimated benefit of ICU care. Among factors unrelated to severity of illness, physicians felt ICU care was more beneficial when told one ICU bed was available than if ICU bed availability was unmentioned. Physicians felt ICU care was less beneficial when family was present than when family presence was unmentioned. The patient's age, but not race/ethnicity, also impacted estimates of ICU benefit. CONCLUSIONS: Estimates of ICU benefit are widely dissimilar and influenced by factors unrelated to severity of illness, potentially resulting in inconsistent allocation of ICU care. PMID- 30303840 TI - Above the GRADE: Evaluation of Guidelines in Critical Care Medicine. AB - OBJECTIVES: We examined recommendations within critical care guidelines to describe the pairing patterns for strength of recommendation and quality of evidence. We further identified recommendations where the reported strength of recommendation was strong while the reported quality of evidence was not high/moderate and then assessed whether such pairings were within five paradigmatic situations offered by Grading of Recommendations Assessment, Development and Evaluation methodology to justify such pairings. DATA SOURCES AND EXTRACTION: We identified all clinical critical care guidelines published online from 2011 to 2017 by the Society of Critical Care Medicine along with individual guidelines published by Surviving Sepsis Campaign, Kidney Disease Improving Global Outcomes, American Society for Parenteral and Enteral Nutrition, and the Infectious Disease Society of America/American Thoracic Society. DATA SYNTHESIS: In all, 15 documents specifying 681 eligible recommendations demonstrated variation in strength of recommendation (strong n = 215 [31.6%], weak n = 345 [50.7%], none n = 121 [17.8%]) and in quality of evidence (high n = 41 [6.0%], moderate n = 151 [22.2%], low/very low n = 298 [43.8%], and Expert Consensus/none n = 191 [28.1%]). Strength of recommendation and quality of evidence were positively correlated (rho = 0.66; p < 0.0001). Of 215 strong recommendations, 69 (32.1%) were discordantly paired with evidence other than high/moderate. Twenty two of 69 (31.9%) involved Strong/Expert Consensus recommendations, a category discouraged by Grading of Recommendations Assessment, Development and Evaluation methodology. Forty-seven of 69 recommendations (68.1%) were comprised of Strong/Low or Strong/Very Low variation requiring justification within five paradigmatic scenarios. Among distribution in the five paradigmatic scenarios of Strong/Low and Strong/Very Low recommendations, the most common paradigmatic scenario was life threatening situation (n = 20/47; 42.6%). Four Strong/Low or Strong/Very Low recommendations (4/47; 8.5%) were outside Grading of Recommendations Assessment, Development and Evaluation methodology. CONCLUSIONS: Among a large, diverse assembly of critical care guideline recommendations using Grading of Recommendations Assessment, Development and Evaluation methodology, the strength of evidence of a recommendation was generally associated with the quality of evidence. However, strong recommendations were not infrequently made in the absence of high/moderate quality of evidence. To improve clarity and uptake, future guideline statements may specify why such pairings were made, avoid such pairings when outside of Grading of Recommendations Assessment, Development and Evaluation criteria, and consider separate language for Expert Consensus recommendations (good practice statements). PMID- 30303841 TI - Immunotherapy With Antiprogrammed Cell Death 1 Antibody Improves Outcome in a Mouse Model of Spinal Cord Injury Followed by Staphylococcus aureus Pneumonia. AB - OBJECTIVES: In patients with spinal cord injury, spinal cord injury-immune depression syndrome induces pneumonia. We aimed to develop a new spinal cord injury-immune depression syndrome mouse model and to test antiprogrammed cell death 1 therapy. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: RjOrl: SWISS and BALB/cJ mice. INTERVENTIONS: Mouse model of spinal cord injury-immune depression syndrome followed by a methicillin-susceptible Staphylococcus aureus pneumonia. Lung injuries were assessed by histologic analysis. Membrane markers and intracytoplasmic cytokines were assessed by flow cytometry. Cytokine production was assessed by quantitative polymerase chain reaction (messenger RNA) and enzyme-linked immunosorbent assay (protein). Animals were treated with blocking antiprogrammed cell death 1 antibodies (intraperitoneal injection). MEASUREMENTS AND MAIN RESULTS: Spinal cord injury mice were more susceptible to methicillin-susceptible S. aureus pneumonia (increased mortality rate). An early inflammatory response was observed in spinal cord injury mice characterized in lungs by a decreased percentage of aerated tissue, an increased production of proinflammatory cytokines (tumor necrosis factor-alpha). In spleen, an increased expression of major histocompatibility complex class II molecules on dendritic cells, and an increased production of proinflammatory cytokines (interleukin-12, interferon-gamma) was observed. Following this pulmonary and systemic inflammation, spinal cord injury-immune depression syndrome was observed in spleens as acknowledged by a decrease of spleen's weight, a lymphopenia, a decrease of major histocompatibility complex class II expression on dendritic cells. An increase of interleukin-10 production and the increase of a cell exhaustion marker expression, programmed cell death 1 receptor on T-cell were also observed. Blockade of programmed cell death 1 molecules, improved survival of spinal cord injury infected mice and enhanced interferon-gamma production by natural killer T cells as well as number of viable CD4 T cells. CONCLUSIONS: This model of spinal cord injury in mice mimics a clinical scenario rendering animals prone to a secondary pneumonia. We show for the first time an acute T-cell exhaustion-like phenomenon following an initial inflammatory response. Finally, inhibition of exhaustion pathway should be considered as a new therapeutic option to overcome spinal cord injury-immune depression syndrome and to decrease the rate of nosocomial pneumonia. PMID- 30303842 TI - Renal Outcomes of Vasopressin and Its Analogs in Distributive Shock: A Systematic Review and Meta-Analysis of Randomized Trials. AB - OBJECTIVES: To systematically review the literature and synthesize evidence concerning the effects of vasopressin and its analogs compared with other vasopressors in distributive shock, focusing on renal outcomes. DATA SOURCES: We performed a systematic review in MEDLINE, Embase, Cochrane Central, and Clinicaltrials.gov databases. STUDY SELECTION: Randomized clinical trials that compared vasopressin and its analogs with other vasopressors and reported renal outcomes in adult patients with distributive shock. DATA EXTRACTION: Paired reviewers independently screened citations, conducted data extraction and assessed risk of bias. Three prespecified subgroup analyses were conducted. Three main outcomes related to acute renal failure were analyzed: the need for renal replacement therapy, acute kidney injury incidence, and acute kidney injury-free days. I test was used to evaluate heterogeneity between studies. Substantial heterogeneity was defined as I greater than 50%. A random-effects model with Mantel-Haenszel weighting was used for all analyses. Heterogeneity was explored using subgroup analysis. The quality of evidence for intervention effects was summarized using Grading of Recommendations Assessment, Development, and Evaluation methodology. This study was registered in the PROSPERO database (CRD42017054324). DATA SYNTHESIS: Three-thousand twenty-six potentially relevant studies were identified, and 30 articles were reviewed in full. Seventeen studies met the inclusion criteria, including a total of 2,833 individuals. Of these, 11 studies (2,691 individuals) were suitable for quantitative meta-analysis. Overall, the evidence was of low to moderate quality. Patients who received vasopressin and its analogs had a reduced need for renal replacement therapy (odds ratio, 0.59 [0.37-0.92]; p = 0.02; I = 49%) and a lower acute kidney injury incidence (odds ratio, 0.58 [0.37-0.92]; p = 0.02; I = 63%). These results should be interpreted with caution, due to excessive heterogeneity. Acute kidney injury free data was not pooled, since the small number of studies and extreme heterogeneity. CONCLUSIONS: In patients with distributive shock, vasopressin and its analogs use is associated with a reduced need for renal replacement therapy and lower acute kidney injury incidence. These results are supported by high risk of bias evidence. PMID- 30303843 TI - Female Physician Leadership During Cardiopulmonary Resuscitation Is Associated With Improved Patient Outcomes. AB - OBJECTIVES: A recently published simulation study suggested that women are inferior leaders of cardiopulmonary resuscitation efforts. The aim of this study was to compare female and male code leaders in regard to cardiopulmonary resuscitation outcomes in a real-world clinical setting. DESIGN: Retrospective cohort review. SETTING: Two academic, urban hospitals in San Diego, California. SUBJECTS: One-thousand eighty-two adult inpatients who suffered cardiac arrest and underwent cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed whether physician code leader gender was independently associated with sustained return of spontaneous circulation and survival to discharge and with markers of quality cardiopulmonary resuscitation. Of all arrests, 327 (30.1%) were run by female physician code leaders with 251 (76.8%) obtaining return of spontaneous circulation, and 122 (37.3%) surviving to discharge. Male physicians ran 757 codes obtaining return of spontaneous circulation in 543 (71.7%) with 226 (29.9%) surviving to discharge. When adjusting for variables, female physician code leader gender was independently associated with a higher likelihood of return of spontaneous circulation (odds ratio, 1.36; 95% CI, 1.01-1.85; p = 0.049) and survival to discharge (odds ratio, 1.53; 95% CI, 1.15-2.02; p < 0.01). Additionally, the odds ratio for survival to discharge was 1.62 (95% CI, 1.13-2.34; p < 0.01) for female physicians with a female code nurse when compared with male physician code leaders paired with a female code nurse. Gender of code leader was not associated with cardiopulmonary resuscitation quality. CONCLUSIONS: In contrast to data derived from a simulated setting with medical students, real life female physician leadership of cardiopulmonary resuscitation is not associated with inferior outcomes. Appropriately, trained physicians can lead high-quality cardiopulmonary resuscitation irrespective of gender. PMID- 30303844 TI - Quality Measures in Total Hip and Total Knee Arthroplasty. AB - INTRODUCTION: Total joint arthroplasty represents the largest expense for a single condition among Medicare beneficiaries. Payment models exist, such as bundled payments, where physicians and hospitals are reimbursed based on providing cost-efficient, high-quality care. There is a need to explicitly define "quality" relevant to hip and knee arthroplasty. Based on prior quality measure research, we hypothesized that less than 20% of developed quality measures are outcome measures. METHODS: This study systematically reviewed current and candidate quality measures relevant to total hip and knee arthroplasty using several quality measure databases and an Internet library search. RESULTS: We found a total of 35 quality measures and 81 candidate measures, most of which were process measures (N = 21, 60%), and represented the National Quality Strategy priorities of patient- and caregiver-centered experience and outcomes (31%), effective clinical care (28%), or patient safety (19%). CONCLUSION: Various stakeholders have developed quality measures in total joint arthroplasty, with increasing focus on developing outcome measures. The results of this review inform orthopaedic surgeons on quality measures that payers could use value-based payment models like the Merit-based Incentive Payment System and Comprehensive Care for Joint Replacement. LEVEL OF EVIDENCE: Level I, systematic review of level I evidence. PMID- 30303845 TI - Greater Arc Perilunate Injury Through a Lunotriquetral Carpal Coalition: A Case Report. AB - CASE: A 31-year-old Caucasian man presented with a greater arc perilunate variant injury after falling from a friend's shoulders onto an outstretched hand. Imaging revealed a minimally displaced scaphoid waist fracture and a nondisplaced transverse fracture through a previously unrecognized lunotriquetral coalition. A volar intercalated segmental instability (VISI) deformity was present. Open reduction with osseous fixation (a headless compression screw for the scaphoid waist fracture and 3 Kirschner wires across the midcarpal joint) and repair of the torn volar ligaments partially restored the carpal alignment. At 1 year postoperatively, the patient had regained approximately 90% of grip and pinch strength, 70% of wrist flexion, and 80% of wrist extension when compared with the contralateral, uninjured side. Despite persistent VISI alignment, he was satisfied with the outcome and had returned to his preoperative employment and recreational activities. CONCLUSION: A high index of suspicion for a perilunate injury should be maintained for all scaphoid fractures, particularly when abnormal anatomy is present. PMID- 30303846 TI - Osteosarcoma in an Adolescent with Kniest Dysplasia: A Case Report. AB - CASE: A 19-year-old adolescent with Kniest dysplasia was incidentally found to have osteosarcoma of the proximal aspect of the humerus after having a chest radiograph for evaluation of an upper respiratory infection. He underwent chemotherapy and resection of the tumor, and there was no evidence of metastasis at the 16-month follow-up. CONCLUSION: Patients with osteochondrodysplasias often have multiple orthopaedic symptoms. Changes in chronic pain symptoms should be investigated to rule out insidious secondary causes of musculoskeletal pain, such as osteosarcoma. PMID- 30303847 TI - Congenital Aplasia of the Patella and the Distal Third of the Quadriceps Mechanism: A Case Report. AB - CASE: Congenital aplasia or hypoplasia of the patella by itself is a rare condition; to our knowledge, it has been associated with aplasia of the quadriceps mechanism only 3 times in the literature. We describe a 5-year-old boy who had bilateral fixed flexion deformity of the knee as well as bilateral hypoplasia of the patella and quadriceps mechanism; he never had been able to stand upright and walk. We present the clinical and radiographic features, the surgical details, and the successful outcome after treatment. CONCLUSION: Corrective femoral osteotomies with soft-tissue reconstruction to provide active knee extension provided a satisfactory outcome. At the last follow-up, the child was walking without support and had good active knee extension. PMID- 30303848 TI - Failure of a Unidirectional Barbed-Suture Device at the Arthrotomy Repair Site Following Total and Unicondylar Knee Arthroplasty: A Case Report. AB - CASE: We report the failure of a routine arthrotomy repair following knee arthroplasty. Five additional cases of arthrotomy failure occurred within a 14 month period during which a specific unidirectional knotless barbed suture device had been used for arthrotomy closure. CONCLUSION: Additional study on larger cohorts may be useful to understand the effectiveness of barbed suture for arthrotomy closure in knee arthroplasty. PMID- 30303849 TI - Competitive Running After Total Hip Arthroplasty: The World's Fastest Total Hip: A Case Report. AB - CASE: We report the case of a young man who underwent total hip arthroplasty (THA) for osteonecrosis at the age of 20 years, and subsequently competed in collegiate long-distance running. The pinnacle of his career was setting the school record time of 3:47.64 (min:sec) in the 1,500-m "metric mile" run (equivalent to 4:05.09 for the "English" mile). This is the fastest known time for any patient who has undergone THA. Excellent clinical and radiographic outcomes had been maintained at 6 years postoperatively. CONCLUSION: Patients who undergo arthroplasty procedures may be capable of remarkable physical accomplishments, but pursuing such feats is not advised. PMID- 30303851 TI - Ischemic stroke in young adults. AB - PURPOSE OF REVIEW: Although the clinical approach to the young adult stroke patient is similar to that of an older adult, several important differences exist. The purpose of this article is to concisely review the epidemiology, pathophysiology, risk factors, clinical manifestations, diagnostic methods and current treatment options for the young adult ischemic stroke patient. RECENT FINDINGS: Evidence clearly indicates that the incidence ischemic stroke in young adults is on the rise. A variety of factors are implicated, including an increased burden of classic and emerging vascular risk factors, and improved stroke detection, among other causes. Improved awareness, prevention and successful treatment of the young adult stroke patient is of great importance, particularly given the major long-term socioeconomic impact strokes have on the patient, their family and society at large. SUMMARY: In this review, we focus on the latest epidemiologic, diagnostic and treatment paradigms to improve physician awareness and optimize outcomes in young adult ischemic stroke patients. An overview of the clinical presentations of various stroke syndromes is described, emphasizing key causes physicians should consider, as well as providing recommendations regarding evaluation and treatment. Important causes including dissection and inflammatory and noninflammatory vasculopathies are emphasized. The diagnoses of cerebral venous thromboses, cardioembolic stroke and paradoxical emboli are also discussed. The effects of established and emerging risk factors on large and small vessel disease, as well as genetic contributions, are also highlighted. PMID- 30303852 TI - Perioperative use of the intra-aortic balloon pump: where do we stand in 2018? AB - PURPOSE OF REVIEW: Intraaortic balloon pump (IABP) has been the most widely used device to help patients recover from circulatory disorder mainly because of cardiogenic shock; however, no evidence-based clinical benefit derived from IABP support has been reported in recent clinical trials. This review provides an overview of the current outcomes and challenges in perioperative IABP use for cardiogenic shock patients. RECENT FINDINGS: Although IABP support yielded no significant difference in mortality for myocardial infarction complicated by cardiogenic shock, perioperative IABP use generated beneficial clinical outcomes for high-risk patients undergoing coronary revascularization. The latest technology such as optical fiber sensor incorporated into the devices provides some beneficial effects on hemodynamics and reduces device-related complications. SUMMARY: Perioperative IABP use is reasonable for cardiogenic shock patients as a bridge to further surgical intervention, to wean from cardiopulmonary bypass, and to postoperative recovery. Over the next years, a revolutionary technology will overcome the currently limited IABP therapy. Larger and longer term clinical investigations are also required to identify ideal patients for IABP use and to establish the position of IABP therapy. PMID- 30303853 TI - Perioperative safety in coronary artery bypass grafting: the role of the anesthesiologist. AB - PURPOSE OF REVIEW: As our population ages and cardiovascular disease increases in prevalence, a growing number of patients will be candidates for coronary artery bypass grafting (CABG). Outcomes from this common surgery can be improved by a coordinated team approach involving physicians, nurses, and healthcare professionals from multiple specialties. This review will discuss the role cardiovascular anesthesiologists play in the perioperative care of these complex patients. RECENT FINDINGS: Cardiovascular anesthesiologists may play a variety of important roles throughout the entire perioperative period of patients undergoing CABG. This may include identification and optimization of preoperative comorbidities, employment of enhanced recovery pathways, perioperative echocardiographic assessment of complex cardiovascular states, management of patients on cardiopulmonary bypass, and others. There is growing evidence that each of these areas contributes to better care and improved outcomes. SUMMARY: Care of the patient undergoing CABG requires a team approach. Optimal team dynamics translate into better care for patients and improved outcomes. The cardiovascular anesthesiologist is an integral member of this team whose role is central in the coordination of all aspects of perioperative care. Preoperative optimization begins the process, which continues throughout surgery, cardiopulmonary bypass, and into the postoperative period. PMID- 30303854 TI - Role of local coronary blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and coronary plaque. AB - PURPOSE OF REVIEW: The natural history of coronary atherosclerosis is complex and atherosclerotic plaques exhibit large morphologic and functional variability within the same individual as well as over time. The purpose of this article is to review the role of blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and atherosclerosis progression. RECENT FINDINGS: Recent breakthroughs in cardiovascular imaging have facilitated in-vivo characterization of the anatomic and functional characteristics of atherosclerotic plaques and have highlighted the role of endothelial shear stress and epicardial and microvascular endothelial dysfunction in the natural history of coronary atherosclerosis. SUMMARY: There is an important need to identify individual lesions which may progress to vulnerable plaque in order to provide early therapeutic management. Evaluation of endothelial shear stress, local blood flow patterns, epicardial and microvascular endothelial dysfunction, as well as their complex associations might indicate those patients who have microvascular endothelial dysfunction and increased risk for upstream epicardial endothelial dysfunction and plaque progression. Such high risk patients could potentially be targeted for more intensive therapeutic strategies to prevent the progression of both microvascular and epicardial atherosclerotic manifestations. PMID- 30303856 TI - Advances in the treatment of gastric cancer. AB - PURPOSE OF REVIEW: To review the recent literature regarding treatment of gastric cancer. RECENT FINDINGS: Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan. In a Japanese adjuvant chemotherapy trial, addition of docetaxel to standard S-1 chemotherapy improved disease-free survival; this regimen will become their new standard for adjuvant therapy. Microsatellite instability (MSI) high status is emerging as a favorable prognostic marker in resected gastric cancer and may indicate a group of patients who do not gain additional benefit from treatment with adjuvant chemotherapy. In metastatic gastric cancer, the addition of ramucirumab, an antivascular endothelial growth factor receptor 2-targeted antibody, to first-line chemotherapy did not improve survival over chemotherapy alone. Trifluridine/tipiracil treatment in chemotherapy-refractory gastric cancer improved survival compared to placebo and will emerge as a late-line therapy option. Phase II and III trials indicate activity for the immune checkpoint inhibitors pembrolizumab and nivolumab in chemotherapy-refractory gastric cancer and have led to US regulatory approval for pembrolizumab in chemotherapy-refractory programmed death ligand 1-positive or MSI-high gastric cancer, and approval in Japan for nivolumab in chemotherapy refractory gastric cancer. However, a phase III trial in advanced gastric cancer failed to show a survival benefit for pembrolizumab over conventional paclitaxel. The poly ADP ribose polymerase inhibitor, olaparib, added to second-line paclitaxel in advanced gastric cancer failed to improve overall survival compared with paclitaxel alone. SUMMARY: Perioperative or postoperative adjuvant chemotherapy without radiation therapy remains the standard of care in gastric cancer. Addition of docetaxel to adjuvant S-1 will likely emerge as a new care standard. Pembrolizumab and nivolumab improve survival and now are treatment options in chemotherapy-refractory gastric cancer, especially for programmed death ligand 1-positive or MSI-high cancers. PMID- 30303857 TI - Mitochondrial biogenesis mediated by melatonin in an APPswe/PS1dE9 transgenic mice model. AB - Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease, but the pathogenesis is unclear. Damaged mitochondrial biogenesis has been observed in AD. Increasing evidence suggests that mitochondrial biogenesis is involved in the pathogenesis of AD, but the exact mechanism is unclear. In this study, we used the amyloid precursor protein Swedish mutations K594N/M595L (APPswe)/presenilin 1 with the exon-9 deletion (PS1dE9) transgenic mouse model of AD, which was successfully established by the expression of amyloid beta precursor protein and presenilin 1 (PS1). Then, we compared APPswe/PS1dE9 transgenic mice with and without melatonin (MT) in drinking water for 4 months (estimated 0.5 mg/day) and control C57BL/6J mice without MT for expression of mitochondrial biogenesis factors (mitochondrial transcription factor A, nuclear respiratory factor 1 and 2, peroxisome proliferator-activated receptor gamma coactivator 1-alpha), mitochondrial structure, mitochondrial DNA to nuclear DNA ratio, behavioral changes, and amyloid beta (Abeta) deposition and soluble Abeta levels in the cerebral cortex and hippocampus. Compared with controls, APPswe/PS1dE9 mice with long-term MT intake showed increased levels of mitochondrial biogenesis factors, alleviated mitochondrial impairment, enhanced mitochondrial DNA copy number, improved spatial learning and memory deficits, and reduced Abeta deposition and soluble Abeta levels. Defective mitochondrial biogenesis may contribute toward the damaged mitochondrial structure and function in AD. MT may alleviate AD by promoting mitochondrial biogenesis. PMID- 30303858 TI - Effect of social distance on outcome evaluation in self-other decision-making: evidence from event-related potentials. AB - Previous studies have shown that social distance influences one's judgment at the decision-making stage, although its impact in the outcome evaluation stage, which is a vital stage in the decision-making process, is ignored. Using event-related potentials, we examined the influence of social distance on outcome feedback by requiring participants to make decisions for themselves, their friends, or strangers. Increased social distance reduced the feedback-related negativity amplitude in the early stage of outcome evaluation and reduced the P300 amplitude in the late stage of outcome evaluation. These results provide evidence for the power of social distance in decreasing motivation, emotional arousal, and cognitive investment in the outcome evaluation stage. PMID- 30303859 TI - Diagnostic Value of Elastography and Endobronchial Ultrasound in the Study of Hilar and Mediastinal Lymph Nodes. AB - BACKGROUND: The aim of this study was to explore elastography features and its ability to distinguish between benign and malignant lymph nodes by comparing the results with an anatomopathologic examination used as gold standard. METHODS: Patients were randomized in 2 groups [endobronchial ultrasound (EBUS) and EBUS elastography]. Echographic characteristics of the lymph nodes were collected in both categories. In the EBUS-elastography group, elastographic data were also determined. RESULTS: A total of 100 lymph nodes were evaluated. Group 1 (EBUS) consisted of 57 lymph nodes. Group 2 (EBUS-elastography) included 43 lymph nodes. In group 2, lymph nodes with predominantly blue pattern were associated with a pathologic determination of malignancy, and the probability of presenting malignant infiltration with this color pattern was 86.7% (P=0.00004). Malignant lymph nodes presented less color dispersion (48.8 vs. 94.8, P=0.00013), higher ratio of blue pixels (66% vs. 32.5%, P=0.016), and higher strain ratio (7.1 vs. 2.48, P=0.005). The cut-off points to distinguish between benign and malignant lymph nodes were 4 for strain ratio, 61 for frequency histograms, and 52 for blue pixel ratio. The area under the curve of the ROC curves were 0.75, 0.83, and 0.87, respectively. Group 2 presented a lower number of nondiagnostic samples (2.3% vs. 21%, P=0.001) and a higher rate of malignant results (42% vs. 16%, P=0.005). CONCLUSION: EBUS-elastography is feasible during EBUS and may be helpful in predicting malignant lymph node infiltration. It could improve anatomopathologic sample collection and increase diagnostic efficiency. PMID- 30303860 TI - PET imaging in glioma: techniques and current evidence. AB - PET holds potential to provide additional information about tumour metabolic processes, which could aid brain tumour differential diagnosis, grading, molecular subtyping and/or the distinction of therapy effects from disease recurrence. This review discusses PET techniques currently in use for untreated and treated glioma characterization and aims to critically assess the evidence for different tracers ([F]Fluorodeoxyglucose, choline and amino acid tracers) in this context. PMID- 30303861 TI - Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions. AB - BACKGROUND: For a number of mental health disorders, including posttraumatic stress disorders (PTSD), there are not many available treatment options. Recently, there has been renewed interest in the potential of methylenedioxymethamphetamine (MDMA) to restore function for patients with these disorders. The primary hypothesis is that MDMA, via prosocial effects, increases the ability of patients to address the underlying psychopathology of the disorder. However, the use of MDMA poses potential problems of neurotoxicity, in addition to its own potential for misuse. METHODS: In this article, the proposed potential of MDMA as an adjunct to psychotherapy for PTSD is evaluated. The rationale for the use of MDMA and the positive results of studies that have administered MDMA in the treatment of PTSD are provided (pros). A description of potential adverse effects of treatment is also presented (cons). An overview of MDMA pharmacology and pharmacokinetics and a description of potential adverse effects of treatments are also presented. Methylenedioxymethamphetamine-produced oxytocin release and decreased expression of fear conditioning as well as one of the MDMA enantiomers (the n R- entaniomer) are suggested as potential mechanisms for the beneficial effects of MDMA in PTSD (suggestions). RESULTS: There is some evidence that MDMA facilitates recovery of PTSD. However, the significant adverse effects of MDMA raise concern for its adoption as a pharmacotherapy. Alternative potential treatments with less adverse effects and that are based on the ubiquitous pharmacology of MDMA are presented. CONCLUSIONS: We suggest that additional research investigating the basis for the putative beneficial effects of MDMA might reveal an effective treatment with fewer adverse effects. Suggestions of alternative treatments based on the behavioral pharmacology and toxicology of MDMA and its enantiomers are presented. PMID- 30303862 TI - Is There Always a Right or Wrong?: Comments on the FDA Warnings About Triptans and the Serotonin Syndrome. PMID- 30303863 TI - Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems. AB - BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues. PMID- 30303864 TI - Dexamethasone Is Superior to Dexmedetomidine as a Perineural Adjunct for Supraclavicular Brachial Plexus Block: Systematic Review and Indirect Meta analysis. AB - BACKGROUND: Both dexamethasone and dexmedetomidine are effective peripheral nerve block (PNB) perineural adjuncts that prolong block duration. However, each is associated with side effects. With paucity of head-to-head comparisons of these adjuncts, the question of the best adjunct to mix with local anesthetics (LA) for PNB is unanswered. This meta-analysis aims to inform current practice and future research by identifying the superior adjunct by comparing dexamethasone and dexmedetomidine. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, trials comparing the combination of perineural dexamethasone or dexmedetomidine with LA to LA alone for PNB were sought. The Cochrane Risk of Bias Tool was used to assess the methodological quality of trials, and indirect or network meta-analyses using random-effects modeling were planned. We designated duration of analgesia as a primary outcome. Secondary outcomes included sensory and motor block durations, sensory and motor block onset times, and the risks of hypotension, sedation, and neurological symptoms. RESULTS: Fifty trials were identified, including only 1 direct comparison, precluding a network meta-analysis. Indirect meta-analysis of 49 trials (3019 patients) was performed. Compared to dexmedetomidine, dexamethasone prolonged the duration of analgesia by a mean difference (95% confidence interval [CI]) of 148 minutes (37-259 minutes) (P = .003), without prolonging sensory/motor blockade. Dexmedetomidine increased rates of hypotension (risk ratio [95% CI], 6.3 [1.5-27.5]; P = .01) and sedation (risk ratio [95% CI], 15.8 [3.9-64.6]; P = .0001). Overall risk of bias was moderate, and publication bias was noted, resulting in downgrading evidence strength. CONCLUSIONS: There is low quality evidence that both adjuncts similarly prolong sensory/motor blockade. However, dexamethasone may be a superior adjunct; it improves the duration of analgesia by a statistically significant increase, albeit clinically modest, equivalent to 2.5 hours more than dexmedetomidine, without the risks of hypotension or sedation. Future direct comparisons are encouraged. PMID- 30303865 TI - Airway Management and Clinical Outcomes in External Laryngeal Trauma: A Case Series. AB - External laryngeal trauma is a rare but potentially fatal event that presents several management challenges. This retrospective observational case series conducted at a level-1 trauma center over a 12-year period consists of 62 cases of acute external laryngeal trauma. Patient demographics, mode and mechanisms of injury, presenting signs and symptoms, initial imaging results, airway management, time to surgical management, and 6-month outcomes including airway status, deglutition status, and voice quality were investigated. No difference was found in mortality or 6-month outcomes between patients requiring surgical repair and/or tracheostomy versus patients with less severe injuries managed conservatively. PMID- 30303866 TI - Labor Pain's Relationship With Depression: From Whence, and What Shall be Done? PMID- 30303867 TI - Propofol Regulates Neural Stem Cell Proliferation and Differentiation via Calmodulin-Dependent Protein Kinase II/AMPK/ATF5 Signaling Axis. AB - BACKGROUND: Propofol can cause degeneration of developing brain cells and subsequent long-term learning or memory impairment. However, at the early stage of embryonic development, the molecular mechanism of propofol-induced inhibition in neural stem cells (NSCs) neurogenesis is still unclear. The aim of this study was to determine the role of propofol in NSCs neurogenesis and, more importantly, to explore the underlying mechanism. METHODS: First, a single intraperitoneal injection of propofol was performed in pregnant mice, and 6 hours after administration of propofol, the hippocampus RNA and the protein of the embryos' brains was extracted to analyze the expression of neuron-specific markers. Second, the primary NSCs were isolated from the hippocampus of mouse embryonic brain and then treated with propofol for cell viability, immunostaining, and transwell assays; more importantly, we performed RNA sequencing (RNA-seq) and q reverse transcription polymerase chain reaction assays to identify genes regulated by propofol; the Western blot, small interfering RNA (SiRNA), and luciferase reporter assays were used to study the effects of propofol on calmodulin-dependent protein kinase (CaMk) II/5' adenosine monophosphate activated protein kinase (AMPK)/activating transcription factor 5 (ATF5) signaling pathway. RESULTS: Our results indicated that propofol treatment could inhibit the proliferation, migration, and differentiation of NSCs. The results of RNA-seq assays showed that propofol treatment resulted in downregulation of a group of Ca-dependent genes. The following mechanism studies showed that propofol regulates the proliferation, differentiation, and migration of NSCs through the CaMkII/phosphorylation of serine at amino acid position 485 (pS485)/AMPK/ATF5 signaling pathway. CONCLUSIONS: The results from study demonstrated that propofol inhibits the proliferation, differentiation, and migration of NSCs, and these effects are partially mediated by CaMkII/pS485/AMPK/ATF5 signaling pathway. PMID- 30303868 TI - Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group. AB - As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed. PMID- 30303869 TI - Osteosarcoma in a Child Below 2 Years of Age: Case Report and Review of the Literature. AB - BACKGROUND: Osteosarcoma in children below the age of 5 is extremely rare. OBSERVATION: We report on a previously well 14-month-old male infant, who presented with a reluctance to weight-bear on his right leg and had an associated limp. Plain imaging and a magnetic resonance imaging scan demonstrated a lytic lesion in the right distal femur. An open surgical biopsy confirmed the diagnosis of osteosarcoma. There was no significant family history of cancer and genetic screening for Li-Fraumeni syndrome was negative. CONCLUSIONS: This case highlights the importance of timely consideration of osteosarcoma in an infant, when the clinical presentation and medical imaging are consistent with that diagnosis. PMID- 30303870 TI - Acute Megakaryoblastic Leukemia With Diffuse Periosteal Reaction of Bilateral Lower Extremities. AB - We report the case of a 3-year-old girl diagnosed with acute megakaryoblastic leukemia, who presented after >1 year of bilateral leg pain. At times the pain was severe enough to prevent ambulation, prompting visits to her primary care provider. However, it was not until acute respiratory failure occurred with subsequent hospitalization in the pediatric intensive care unit that severe anemia and thrombocytopenia were discovered and the diagnosis of acute myeloid leukemia was made. Bilateral lower extremity swelling was noted on admission and radiographs showed diffusely abnormal appearance of the long bones of her lower extremities with periosteal reaction and echogenic debris in the subperiosteal space, thought to represent leukemic cells. This case highlights the importance of recognizing atypical signs and symptoms of myelodysplastic syndrome progressing to acute leukemia in the context of abnormal bone pain and radiographic changes. PMID- 30303871 TI - Choosing Stones, Moving Mountains: Performance Excellence, Primary Prevention, and Culture Change in a State Health Department. PMID- 30303872 TI - In the Next Issue. PMID- 30303873 TI - Single-incision Laparoscopy Versus Multiport Laparoscopy for Colonic Surgery: A Multicenter, Double-blinded, Randomized Controlled Trial. AB - OBJECTIVE: To compare outcome of single-port laparoscopy (SPL) and multiport laparoscopy (MPL) laparoscopy for colonic surgery. SUMMARY OF BACKGROUND DATA: Benefits of SPL over MPL are yet to be demonstrated in large randomized trials. METHODS: In this prospective, double-blinded, superiority trial, patients undergoing laparoscopic colonic resection for benign or malignant disease were randomly assigned to SPL or MPL (NCT01959087). Primary outcome was length of theoretical hospital stay (LHS). RESULTS: One hundred twenty-eight patients were randomized and 125 analyzed: 62 SPL and 63 MPL, including 91 right (SPL: n = 44, 71%; MPL: n = 47, 75%) and 34 left (SPL: n = 18, 29%; MPL: n = 16, 25%) colectomies, performed for Crohn disease (n = 53, 42%), cancer (n = 36, 29%), diverticulitis (n = 21, 17%), or benign neoplasia (n = 15, 12%). Additional port insertion was required in 5 (8%) SPL patients and conversion to laparotomy occurred in 7 patients (SPL: n = 3, 5%; MPL: n = 4, 7%; P = 1.000). Total length of skin incision was significantly shorter in the SPL group [SPL: 56 +/- 41 (range, 30-300) mm; MPL: 87 +/- 40 (50-250) mm; P < 0.001]. Procedure duration, intraoperative complication rate, postoperative 30-day morbidity, postoperative pain, and time to first bowel movement were similar between the groups, leading to similar theoretical LHS (SPL: 6 +/- 3 days; MPL: 6 +/- 2; P = 0.298). At 6 months, quality of life was similar between groups, but patients from the SPL group were significantly more satisfied with their scar aspect than patients from the MPL group (P = 0.003). CONCLUSION: SPL colectomy does not confer any additional benefit other than cosmetic result, as compared to MPL. PMID- 30303874 TI - Preoperative Biliary Stenting and Major Morbidity After Pancreatoduodenectomy: Does Elapsed Time Matter?: The FRAGERITA Study Group. AB - OBJECTIVE: To analyze possible associations between the duration of stent placement before surgery and the occurrence and severity of postoperative complications after pancreatoduodenectomy (PD). BACKGROUND: The effect of preoperative stent duration on postoperative outcomes after PD has not been investigated. METHODS: From 2013 to 2016, patients who underwent PD for any reasons after biliary stent placement at 5 European academic centers were analyzed from prospectively maintained databases. The primary aim was to investigate the association between the duration of preoperative biliary stenting and postoperative morbidity. Patients were stratified by stent duration into 3 groups: short (<4 weeks), intermediate (4-8 weeks), and long (>=8 weeks). RESULTS: In all, 312 patients were analyzed. The median time from stent placement to surgery was 37 days (2-559 days), and most operations were performed for pancreatic cancer (67.6%). Morbidity and mortality rates were 56.0% and 2.6%, respectively. Patients in the short group (n = 106) experienced a higher rate of major morbidity (43.4% vs 20.0% vs 24.2%; P < 0.001), biliary fistulae (13.2% vs 4.3% vs 5.5%; P = 0.031), and length of hospital stay [16 (10-52) days vs 12 (8 35) days vs 12 (8-43) days; P = 0.025]. A multivariate adjusted model identified the short stent duration as an independent risk factor for major complications (odds ratio 2.64, 95% confidence interval 1.23-5.67, P = 0.013). CONCLUSIONS: When jaundice treatment cannot be avoided, delaying surgery up to 1 month after biliary stenting may reduce major morbidity, procedure-related complications, and length of hospital stay. PMID- 30303875 TI - Clinical Validation of the Comprehensive Complication Index as a Measure of Postoperative Morbidity at a Surgical Department: A Prospective Study. AB - OBJECTIVE: Using clinical outcomes, to validate the comprehensive complication index (CCI) as a measure of postoperative morbidity in all patients undergoing surgery at a general surgery department. BACKGROUND: The Clavien-Dindo classification (CDC) is the most widely used system to assess postoperative morbidity. The CCI is a numerical scale based on the CDC. Once validated, it could be used universally to establish and compare the real postoperative complications of each surgical procedure. METHODS: Observational prospective cohort study. All patients who underwent surgery during the 1-year study period were included. All the complications graded with the CDC and related to the initial admission, or until discharge if the patient was readmitted within 90 days of surgery, were included. Surgical procedures were classified according to the operative severity score (OSS) as minor, moderate, major, or major+. The clinical validation of the CCI was performed by assessing its correlation with 4 different clinical outcomes. RESULTS: A total of 1850 patients were included: 513 (27.7%) presented complications and 101 (5.46%) were readmitted. In the multivariate analysis, the CCI and CDC were associated with postoperative stay, prolongation of postoperative stay, readmission, and disability in all OSS groups (P < 0.001). The CCI was superior to the CDC in all models except for prolongation of stay for OSS moderate and major+. CONCLUSIONS: The CCI can be applied in all the procedures carried out at general surgery departments. It is able to determine the morbidity and allows the comparison of the outcomes at different services. PMID- 30303876 TI - Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin. AB - BACKGROUND: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. METHODS: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. RESULTS: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. CONCLUSION: RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection. PMID- 30303877 TI - Diversity, Transgender, Vulnerable, Fetus, Entitlement, Evidence-Based, and Science-Based. PMID- 30303878 TI - What Is the Risk of Revision Surgery in Hydroxyapatite-coated Femoral Hip Stems? Findings From a Large National Registry. AB - BACKGROUND: Despite wide adoption of hydroxyapatite (HA)-coated femoral stems in THA, no studies have found differences in the risk of revision surgery with its use or investigated the interaction of different prosthesis designs with stem coating. QUESTIONS/PURPOSES: The purpose of this study was to evaluate the risk of revision in THAs with HA-coated stems compared with non-HA-coated. To achieve this purpose, we asked: (1) What is the difference in risk of revision of THAs with HA-coated femoral stems compared with non-HA-coated using an aggregate analysis? (2) What is the difference in risk of revision of THAs with HA-coated femoral stems compared with non-HA-coated for five prosthesis types that used the same femoral and acetabular component combination but where the femoral stem had both a HA and non-HA coating option? METHODS: The Australian Orthopaedic Association National Joint Replacement Registry analyzed cementless primary THA registered between September 1, 1999, and December 31, 2014. Of the 147,645 cases that fit our selection criteria, 81.1% (N = 119,673) had HA-coated stems. Overall (that is, all procedures with any prostheses in the registry) and five prosthesis designs where both an HA-coated stem and non-HA-coated stem exist (Zimmer's VerSys(r)/Trilogy(r) [N = 3924], Biomet's Mallory-Head(r)/Mallory-Head [N = 2538], Smith & Nephew's SL-Plus/EP Fit-Plus [N = 2028], Biomet's Taperloc(r)/Exceed [N = 1668], and Biomet's Taperloc/Mallory-Head [N = 1240]) were evaluated. Revision surgery was the outcome of interest. Survival analyses were conducted and hazard ratios (HRs) were adjusted for age, sex, bearing surface, femoral head size, and acetabular component HA coating. RESULTS: In the overall cohort, HA stems had a lower any-cause revision risk after 6 months (HR, 0.83; 95% confidence interval [CI], 0.72-0.95; p = 0.007). However, the risk of revision varied when we evaluated the effect of HA on revision for specific prothesis combinations that had both HA and non-HA options for the femoral stem. VerSys/Trilogy, Mallory-Head/Mallory-Head, Taperloc/Exceed, and Taperloc/Mallory Head did not have a lower risk of any-cause revision with HA-coated stems compared with non-HA-coated. Only the SL-Plus/EP Fit-Plus subgroup showed a lower risk of revision for loosening (HR, 0.17; 95% CI, 0.06-0.44 between 0 and 7 years; p < 0.001) with HA- compared with non-HA-coated stems, but this was observed after an early (< 6 months) higher risk of revision for any reason (HR, 2.88; 95% CI, 1.15-7.21; p = 0.024). CONCLUSIONS: Overall, HA coating of femoral stems was found to be associated with a 17% lower risk of revision for any reason. However, the lower risk of revision associated with HA was not consistent for all prosthesis designs where both HA- and non-HA-coated femoral stem versions were available. Some HA-coated stems have higher revision rates compared with their non-HA-coated versions. Our findings suggest that the effect of HA coating on revision risk varies depending on prosthesis design. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 30303879 TI - Eligibility Criteria for Lower Extremity Joint Replacement May Worsen Racial and Socioeconomic Disparities. AB - BACKGROUND: Cost-containment strategies may discourage hospitals from performing surgery for patients with preexisting risk factors such as those with high body mass index (BMI), those with high hemoglobin A1c (HbA1c), or those who smoke cigarettes. Because these risk factors may not appear in equal proportions across the population, using these risk factors as inflexible eligibility criteria for lower extremity joint arthroplasty may exacerbate existing racial-ethnic, gender, and socioeconomic disparities pertaining to access to an operation that can improve health and quality of life. However, any effects on such disparities have not yet been quantified nor have the groups been identified that may be most affected by inflexible eligibility criteria. QUESTIONS/PURPOSES: Does the use of inflexible eligibility criteria related to (1) BMI; (2) HbA1c level; and (3) smoking status potentially decrease the odds of lower extremity joint arthroplasty eligibility for members of racial-ethnic minority groups, women, and those of lower socioeconomic status more than it does for non-Hispanic whites, men, and those of higher socioeconomic status? METHODS: We pooled data from 21,294 adults aged >= 50 years from the 1999-2014 National Health and Nutrition Examination Survey (NHANES). NHANES is a nationally administered series of surveys that assess the health and nutritional status of the US population and collect information on many risk factors for diseases. NHANES is uniquely suited to examine our study questions because it includes data from physical examinations and laboratory assessments as well as comprehensive questionnaires, and it is nationally representative. We determined the odds of lower extremity arthroplasty eligibility by running separate multivariable logistic regressions for each criterion (that is, for each dependent variable): (1) BMI < 35 kg/m; (2) BMI < 40 kg/m; (3) HbA1c < 8%; and (4) current nonsmoker status. Independent variables of interest were race-ethnicity, gender, educational level, and annual household income. Each model included all independent variables of interest, age, and survey year. RESULTS: The BMI < 35-kg/m criterion resulted in lower arthroplasty eligibility for non-Hispanic blacks compared with non-Hispanic whites (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.55-0.70; p < 0.001), women versus men (OR, 0.61; 95% CI, 0.55-0.69; p < 0.001), individuals of lower socioeconomic status versus those of higher socioeconomic status (annual household income < USD 45,000 versus >= USD 45,000 [OR, 0.81; 95% CI, 0.71-0.93; p = 0.002], and those with a high school degree or less versus those with a degree beyond a high school degree (OR, 0.66; 95% CI, 0.57-0.77; p < 0.001). The HbA1c < 8% criterion resulted in lower arthroplasty eligibility for non-Hispanic blacks (OR, 0.44; 95% CI, 0.37-0.53; p < 0.001) and Hispanics (OR, 0.41; 95% CI, 0.33-0.51; p < 0.001) versus non-Hispanic whites, for individuals of lower socioeconomic status versus those of higher socioeconomic status (OR, 0.73; 95% CI, 0.56-0.94; p = 0.015), and for those with a high school degree or less versus those with a degree beyond a high school degree (OR, 0.58; 95% CI, 0.44-0.77; p < 0.001). Excluding smokers resulted in lower arthroplasty eligibility for non Hispanic blacks versus non-Hispanic whites (OR, 0.84; 95% CI, 0.73-0.97; p = 0.019), for individuals of lower socioeconomic status versus those of higher socioeconomic status (OR, 0.53; 95% CI, 0.47-0.61; p < 0.001), and for those with a high school degree or less versus those with a degree beyond a high school degree (OR, 0.29; 95% CI, 0.24-0.35; p < 0.001). CONCLUSIONS: Payment structures and clinical decision-making algorithms that set inflexible cutoffs with respect to BMI, HbA1c, and smoking status disproportionately discourage performing lower extremity arthroplasty for non-Hispanic blacks and individuals of lower socioeconomic status. We do not advocate performing elective surgery for patients with multiple, uncontrolled medical comorbidities. However, ample evidence suggests that many patients whose BMI values are > 35 kg/m (or even > 40 kg/m) may be reasonable candidates for arthroplasty surgery, and BMI is not an easily modifiable risk factor for many patients. We discourage across-the-board cutoff parameters in these domains because such cutoffs will worsen current racial ethnic, gender-based, and socioeconomic disparities and limit access to an operation that can improve quality of life. LEVEL OF EVIDENCE: Level III, economic and decision analysis. PMID- 30303880 TI - Not the Last Word: Agonizing Appropriately Over the Residency Match Rank List. PMID- 30303881 TI - Reply to the Letter to the Editor: Medicolegal Sidebar: Who Should Obtain Informed Consent? PMID- 30303882 TI - Portable Infrared Pupillometer in Patients With Subarachnoid Hemorrhage: Prognostic Value and Circadian Rhythm of the Neurological Pupil Index (NPi). AB - BACKGROUND: Portable automated infrared pupillometry is becoming increasingly popular. To generate an objective reference base, the Neurological Pupil index (NPi) which combines different values of the pupillary light reflex is being introduced into clinical practice. In this explorative study, we examined different aspects of the NPi in relation to clinical severity and outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). MATERIALS AND METHODS: Patients with serial assessment of the NPi (NeurOptics pupillometer NPi-200, Irvine, CA) starting no later than day 2 after aSAH onset were included in the study. Relative numbers of pathologic NPi's, absolute NPi values, and their variances were compared according to aSAH clinical severity grade, functional outcome, and case fatality. The correlation between NPi and intracranial pressure, and NPi periodicity, were also examined. RESULTS: In total, 18 patients with 4456 NPi values were eligible for inclusion in the analysis. The general trend of the NPi over time reflected the course of the neurological illness. Mean NPi tended to be lower in patients with clinically severe compared with nonsevere aSAH (3.75+/-0.40 vs. 4.56+/-0.06; P=0.171), and in patients with unfavorable compared with favorable outcomes (3.64+/-0.48 vs. 4.50+/-0.08; P=0.198). The mean variance of the NPi was higher in patients with severe compared with nonsevere aSAH (0.49+/-0.17 vs. 0.06+/-0.02; P=0.025). Pathologic NPi values were recorded more frequently in patients with severe compared with nonsevere aSAH (16.3%+/ 8.8% vs. 0.0%+/-0.0%; P=0.002), and in those with unfavorable compared with favorable outcomes (19.2%+/-10.6% vs. 0.7%+/-0.6%; P=0.017). NPi was inversely correlated with intracranial pressure (Spearman r=-0.551, P<0.001). We observed a circadian pattern of NPi's which was seemingly disrupted in patients with fatal outcome. CONCLUSIONS: On the basis of this preliminary study, the assessment of NPi by pupillometry is feasible and might complement multimodal neuromonitoring in patients with aSAH. PMID- 30303883 TI - Development of a Multistep Hypertension Quality Improvement Program in an Academic General Medicine Practice. AB - Hypertension is a common problem and a major risk factor for cardiovascular disease. It is unclear whether efforts to control blood pressure (BP) known to be effective in integrated healthcare systems can be successfully implemented in an academic setting. We describe our experience implementing a multistep quality improvement program within an academic general medicine practice aimed at improving BP among patients with uncontrolled hypertension. Ensuring medical assistants were correctly measuring BP provided the basis for accurate data entry into the electronic medical record (EMR); our EMR-based registry data allowed us to feedback primary care provider (PCP) level data on BP control for panel management, which resulted in improvements in BP for a substantial proportion of patients, particularly for those with more practice visits. However, due to PCP, patient, and system barriers, our initial attempt to integrate a pharmacist into our team for hypertension management was only successful for a small number of patients who engaged in pharmacist in-person visits. Future improvement efforts will focus on addressing the barriers to more intensive BP management, integrating lessons from this experience. As chronic disease management shifts to a population-based model, team change will be a necessary component for achieving clinical improvement. PMID- 30303884 TI - What Is the Risk of Anal Carcinoma in Patients With Anal Intraepithelial Neoplasia III? AB - BACKGROUND: The risk of anal carcinoma after previous diagnosis of anal intraepithelial neoplasia III is unclear. OBJECTIVE: The purpose of this study was to estimate the risk of anal carcinoma in patients with anal intraepithelial neoplasia III and to identify predictors for subsequent malignancy. DESIGN: This was a retrospective review using the Surveillance, Epidemiology, and End Results registry (1973-2014). SETTING: The study was composed of population-based cancer registries from the United States. PATIENTS: Patients who were diagnosed with anal intraepithelial neoplasia III were included. MAIN OUTCOME MEASURES: The primary outcome was rate of subsequent anal squamous cell carcinoma. Predictors for anal cancer were identified using logistic regression and Cox proportional hazard models. RESULTS: A total of 2074 patients with anal intraepithelial neoplasia III were identified and followed for a median time of 4.0 years (interquartile range, 1.8-6.7 y). Of the cohort, 171 patients (8.2%) subsequently developed anal cancer. Median time from anal intraepithelial neoplasia III diagnosis to anal cancer diagnosis was 2.7 years (interquartile range, 1.1-4.5 y). Fifty-two patients (30.4%) who developed anal carcinoma were staged T2 or higher. Ablative therapies for initial anal intraepithelial neoplasia III were associated with a reduction in the risk of anal cancer (OR = 0.3 (95% CI, 0.1 0.7); p = 0.004). Time-to-event analysis revealed that the 5-year incidence of anal carcinoma after anal intraepithelial neoplasia III was 9.5% or ~1.9% per year. LIMITATIONS: The registry did not record HIV status, surveillance schedule, use of high-resolution anoscopy, or provider specialty. CONCLUSIONS: In the largest published cohort of patients with anal intraepithelial neoplasia III, ~10% of patients were projected to develop anal cancer within 5 years. Nearly one third of anal cancers were diagnosed at stage T2 or higher despite a previous diagnosis of anal intraepithelial neoplasia III. Ablative procedures were associated with a decreased risk of cancer. This study highlights the considerable rate of malignancy in patients with anal intraepithelial neoplasia III and the need for effective therapies and surveillance. See Video Abstract at http://links.lww.com/DCR/A764. PMID- 30303885 TI - Intra-abdominal Sepsis After Ileocolic Resection in Crohn's Disease: The Role of Combination Immunosuppression. AB - BACKGROUND: Intra-abdominal sepsis complicates <10% of ileocolic resections for Crohn's disease, but the impact of combination immunosuppression and repeat resection on its development remains unknown. OBJECTIVE: The purpose of this study was to determine risk factors for intra-abdominal sepsis after ileocolic resection, specifically examining the role of combination immunosuppression and repeat intestinal resection. DESIGN: This was a retrospective review of patient records from 2007 to 2017. SETTINGS: The study was conducted at a single institution IBD tertiary referral center. PATIENTS: Patients with a diagnosis of Crohn's disease who were undergoing ileocolic resection with primary anastomosis were included. Diverted patients were excluded. MAIN OUTCOME MEASURES: Preoperative and intraoperative variables, including preoperative immunosuppressive regimens and previous intestinal resection, were evaluated as potential risk factors for intra-abdominal sepsis. RESULTS: A total of 621 patients (55% women) underwent ileocolic resection for Crohn's disease; 393 (63%) were first-time resections. The rate of 30-day intra-abdominal sepsis was 8% (n = 50). On univariate analysis, triple immunosuppression (combination of a corticosteroid, immunomodulator, and biological) and previous intestinal resection were significantly associated with intra-abdominal sepsis. Both risk factors remained significant on multivariable analysis (OR for triple immunosuppression (vs none) = 3.53 (95% CI, 1.27-9.84); previous intestinal resection OR = 2.27 (95% CI, 1.25-4.13)). A significant trend was seen between an increasing number of these risk factors (triple immunosuppression and previous intestinal resection) and rate of intra-abdominal sepsis (5%, 12%, and 22% for 0, 1, and 2 risk factors; p < 0.01). A trend was observed between increasing number of previous intestinal resections and the rate of intra-abdominal sepsis (p < 0.01). LIMITATIONS: This study is limited by its single-institution tertiary referral center scope. CONCLUSIONS: Combination immunosuppression and previous intestinal resection were both associated with the development of intra-abdominal sepsis. In light of these results, surgeons should consider the effects of combination immunosuppression and a history of previous intestinal resection, in addition to other risk factors, when deciding which patients warrant temporary intestinal diversion. See Video Abstract at http://links.lww.com/DCR/A664. PMID- 30303886 TI - Predicting the Risk of Readmission From Dehydration After Ileostomy Formation: The Dehydration Readmission After Ileostomy Prediction Score. AB - BACKGROUND: All-cause readmission rates in patients undergoing ileostomy formation are as high as 20% to 30%. Dehydration is a leading cause. No predictive model for dehydration readmission has been described. OBJECTIVE: The purpose of this study was to develop and validate the Dehydration Readmission After Ileostomy Prediction scoring system to predict the risk of readmission for dehydration after ileostomy formation. DESIGN: Patients who underwent ileostomy formation were identified using the American College of Surgeons National Surgical Quality Improvement Program data set (2012-2015). Predictors for dehydration were identified using multivariable logistic regression analysis and translated into a point scoring system based on corresponding beta-coefficients using 2012-2014 data (derivation). Model discrimination was assessed with receiver operating characteristic curves using 2015 data (validation). SETTINGS: This study used the American College of Surgeons National Surgical Quality Improvement Program. PATIENTS: A total of 8064 (derivation) and 3467 patients (validation) were included from the American College of Surgeons National Surgical Quality Improvement Program. MAIN OUTCOME MEASURES: Dehydration readmission within 30 days of operation was measured. RESULTS: A total of 8064 patients were in the derivation sample, with 2.9% (20.1% overall) readmitted for dehydration. Twenty-five variables were queried, and 7 predictors were identified with points assigned: ASA class III (4 points), female sex (5 points), IPAA (4 points), age >=65 years (5 points), shortened length of stay (5 points), ASA class I to II with IBD (7 points), and hypertension (9 points). A 39-point, 5 tier risk category scoring system was developed. The model performed well in derivation (area under curve = 0.71) and validation samples (area under curve = 0.74) and passed the Hosmer-Lemeshow goodness-of-fit test. LIMITATIONS: Limitations of this study pertained to those of the American College of Surgeons National Surgical Quality Improvement Program, including a lack of generalizability, lack of ileostomy-specific variables, and inability to capture multiple readmission International Classification of Diseases, 9/10 edition, codes. CONCLUSIONS: The Dehydration Readmission After Ileostomy Prediction score is a validated scoring system that identifies patients at risk for dehydration readmission after ileostomy formation. It is a specific approach to optimize patient factors, implement interventions, and prevent readmissions. See Video Abstract at http://links.lww.com/DCR/A746. PMID- 30303889 TI - Commentary on "Evaluating the Validity of DSM-5 Alcohol Use Disorder Diagnostic Criteria in a Sample of Treatment Seeking Native Americans". PMID- 30303888 TI - Evaluating the Validity of the DSM-5 Alcohol Use Disorder Diagnostic Criteria in a Sample of Treatment-seeking Native Americans. AB - OBJECTIVE: Despite high rates of alcohol use disorder (AUD) and alcohol-induced deaths among Native Americans, there has been limited study of the construct validity of the AUD diagnostic criteria. The purpose of the current study was to examine the validity of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) AUD criteria in a treatment-seeking group of Native Americans. METHODS: As part of a larger study, 79 Native Americans concerned about their alcohol or drug use were recruited from a substance use treatment agency located on a reservation in the southwestern United States. Participants were administered the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID for DSM-IV-TR) reworded to assess 11 DSM-5 criteria for AUD. Confirmatory factor analysis (CFA) was used to test the validity of the AUD diagnostic criteria, and item response theory (IRT) was used to examine the item characteristics of the AUD diagnostic criteria in this Native American sample. RESULTS: CFA indicated that a 1-factor model of the 11 items provided a good fit of the data. IRT parameter estimates suggested that "withdrawal," "social/interpersonal problems," and "activities given up to use" had the highest magnitude of discrimination. "Much time spent using" and "activities given up to use" were associated with the greatest severity. CONCLUSIONS: The current study provided support for the validity of the AUD DSM-5 criteria and a unidimensional latent construct of AUD in this sample of treatment-seeking Native Americans. IRT analyses replicate findings from previous studies. To our knowledge, this is the first study to examine the validity of the DSM-5 AUD criteria in a treatment seeking sample of Native Americans. Continued research in other Native American samples is needed. PMID- 30303890 TI - Characteristics of Patients With Opioid Use Disorder Associated With Performing Overdose Reversals in the Community: An Opioid Treatment Program Analysis. AB - OBJECTIVE: The primary outcome of this study is to identify characteristics of study participants in a large opioid treatment program (OTP) for opioid use disorder (OUD) who used take-home naloxone to perform 1 or more opioid overdose (OD) reversal(s) in the community. METHODS: This 6-month prospective cohort study provided take-home naloxone and opioid OD education for 287 study participants with OUD. Characteristics associated with use of the take-home naloxone were determined from among 16 variables using multivariable logistic regression. RESULTS: The study participants who had greater odds of using the take-home naloxone to perform OD reversals, compared to those who did not use the take-home naloxone, (a) received emergency room care themselves for OD (OR = 4.89, 95% CI 1.54-15.52, P = 0.007), (b) previously witnessed someone else OD (OR = 5.67, 95% CI 1.24-25.87, P = 0.025), (c) tested positive for 2 or more illicit substances at their 6-month urine analysis (OR = 5.26, 95% CI 1.58-17.54, P = 0.007) or were missing their 6-month urine analysis (OR = 3.46, 95% CI 1.42-8.43, P = 0.006). In addition, they had greater odds of being (d) less than 30 years old (OR = 2.80, 95% CI 1.02-7.66, P = 0.045), and (e) Hispanic (OR = 3.98, 95% CI 1.41-11.21, P = 0.009). CONCLUSIONS: This study prospectively identified several characteristics of patients enrolled in an OTP with increased odds of using take-home naloxone in their social networks. Future harm reduction efforts may benefit by using targeted characteristics to identify those most likely to use naloxone in their communities.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30303891 TI - Symptom Perception, Evaluation, Response to Symptom, and Delayed Care Seeking in Patients With Acute Heart Failure: An Observational Study. AB - BACKGROUND: Exacerbation of heart failure (HF) requires early intervention to prevent hospital admission and to reduce mortality. Early care seeking requires that patients perceive symptoms, accurately evaluate perceived symptoms, and respond appropriately. How perception, evaluation, and response to symptoms are associated with delay in seeking care for worsening symptoms has rarely been studied. OBJECTIVE: The aims of this study were to investigate the associations of perception of symptoms, evaluation of symptoms, and response to symptoms with delayed care seeking in patients with HF and to identify factors associated with delayed care seeking. METHODS: Patients admitted for acute exacerbation of HF were enrolled in this cross-sectional observational study. We used structured interviews, questionnaires, and medical record review to collect data. Factors related to delayed care seeking were identified using nonlinear regression. RESULTS: Analysis was performed in 109 patients with HF. The median delay time was 124 hours. Delayed care seeking was associated with younger age and perception of fatigue, whereas evaluation of and response to symptoms were not associated with delay. CONCLUSIONS: Few characteristics of the symptom experience are associated with delayed care seeking among patients with HF who experience an exacerbation of symptoms. Further research is needed to determine why early care seeking is difficult among patients with HF. PMID- 30303892 TI - Relationship Between Types of Social Support, Coping Strategies, and Psychological Distress in Individuals Living With Congenital Heart Disease. AB - BACKGROUND: Many people with congenital heart disease (CHD) experience psychological distress related to medical complications and psychosocial issues related to the disease. Although studies show that social support and coping strategies are closely associated with psychological distress in people struggling with different chronic health challenges, very little is known about whether the same factors hold true for the psychological distress of people living with CHD. OBJECTIVE: The purpose of this study was to examine the relationships between types of social support, coping strategies, and psychological distress for individuals living with CHD. DESIGN: A cross-sectional survey design with self-report questionnaires was used. METHOD: A convenience sample of 272 participants was obtained from the Adult Congenital Heart Disease program at a tertiary care hospital in Western Canada. Structural equation modeling was conducted to examine hypothesized relationships among study variables. RESULTS: Perceived social support was directly related to both anxiety and depression. Received social support influenced anxiety and depression, but its effect was through perceived social support. Wishful-thinking coping strategies mediated the relationships between perceived social support and both anxiety and depression. CONCLUSION: Individuals with CHD who have low perceived and received social support are vulnerable to experiences of psychological distress. Assessments of social support and facilitation of positive coping strategies are integral to nursing care for adults with CHD. PMID- 30303893 TI - Correlates of Endothelial Function in Older Adults With Untreated Obstructive Sleep Apnea and Cardiovascular Disease. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent and consequential sleep disorder in older adults. Untreated moderate to severe OSA substantially increases the risk for hypertension and cardiovascular disease (CVD), which can be attributed to the accelerated progression of atherosclerosis and endothelial dysfunction. OBJECTIVE: The aim of this study was to identify factors that can function as correlates of endothelial function in older adults with untreated, moderate to severe OSA and CVD or CVD risk factors. METHODS: A subsample (N = 126) of adults aged 65 years and older from the HeartBEAT study were included in the analyses. Univariate analyses and multiple linear regression models were conducted to establish which demographic and CVD risk factors were the best correlates of endothelial function. RESULTS: In the univariate analyses, sex, employment status, body mass index, waist circumference, hip-to-waist ratio, neck circumference, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, total cholesterol to high-density lipoprotein cholesterol ratio, plasminogen activator inhibitor-1, calcium channel blocker use, and beta-blocker use were associated with endothelial function at a level of P < .10. In the most parsimonious model, male sex (b = -0.305, P < .001), calcium channel blocker use (b = -0.148, P < .019), and body mass index (b = -.014, P < .037) were negatively associated with endothelial function after adjusting for the other covariates. CONCLUSIONS: The authors identified correlates of endothelial function in older adults with untreated OSA and CVD or CVD risk factors, which are different than the correlates in middle-aged adults with the same conditions. PMID- 30303894 TI - Psychometric Testing of the Revised Self-Care of Heart Failure Index. AB - BACKGROUND: Self-care is essential in people with chronic heart failure (HF). The process of self-care was refined in the revised situation specific theory of HF self-care, so we updated the instrument measuring self-care to match the updated theory. The aim of this study was to test the psychometric properties of the revised 29-item Self-Care of Heart Failure Index (SCHFI). METHODS: A cross sectional design was used in the primary psychometric analysis using data collected at 5 sites in the United States. A longitudinal design was used at the site collecting test-retest data. We tested SCHFI validity with confirmatory factor analysis and predictive validity in relation to health-related quality of life. We tested SCHFI reliability with Cronbach alpha, global reliability index, and test-retest reliability. RESULTS: Participants included 631 adults with HF (mean age, 65 +/- 14.3 years; 63% male). A series of confirmatory factor analyses supported the factorial structure of the SCHFI with 3 scales: Self-Care Maintenance (with consulting behavior and dietary behavior dimensions), Symptom Perception (with monitoring behavior and symptom recognition dimensions), and Self-Care Management (with recommended behavior and problem-solving behavior dimensions). Reliability estimates were 0.70 or greater for all scales. Predictive validity was supportive with significant correlations between SCHFI scores and health-related quality-of-life scores. CONCLUSIONS: Our analysis supports validity and reliability of the SCHFI v7.2. It is freely available to users on the website: www.self-care-measures.com. PMID- 30303896 TI - PCNA News. PMID- 30303897 TI - Introducing Our New Associate Editors. PMID- 30303895 TI - Individualized Family-Centered Developmental Care: An Essential Model to Address the Unique Needs of Infants With Congenital Heart Disease. AB - BACKGROUND: Infants born with critical congenital heart disease (cCHD) who require surgical intervention in the newborn period are often hospitalized in a cardiac intensive care unit (CICU). Cardiac surgery and the CICU environment are traumatic to infants and their families. Infants are exposed to overwhelming stress, which can result in increased pain, physiologic instability, behavioral disorganization, disrupted attachment, and altered brain development. Individualized Family-centered Developmental Care (IFDC) is a model that can address the unique needs and developmental challenges of infants with cCHD. PURPOSE: The purpose of this article is to (1) clearly describe the uniqueness of the infant with cCHD, including the medical, neurological, and parental challenges, and (2) propose methods to apply IFDC to support recovery of infants with cCHD in the CICU. CONCLUSIONS: The experiences in the CICU shape the developing brain and alter recovery and healing, thus adversely impacting development. Individualized Family-centered Developmental Care is a promising model of care that nurses can integrate into the CICU to promote neuroprotection and development. Nurses can effectively integrate IFDC into the CICU by understanding the unique characteristics of infants with cCHD and applying IFDC interventions that include both maturity and recovery perspectives. CLINICAL IMPLICATIONS: The incorporation of IFDC interventions is essential for the infant with cCHD and should be a standard of care. Applying IFDC with a recovery perspective in all aspects of caregiving will provide opportunities for individualization of care and parent engagement, allowing infants in the CICU to recover from surgery while supporting both short- and long-term neurodevelopment. PMID- 30303899 TI - Do Depressed Elderly Heart Failure Patients Benefit From Yoga? A Future Direction for Research: Erratum. PMID- 30303898 TI - Eliminating Cardiovascular Health Disparities: There Has Been Progress, but There Is More to Do! PMID- 30303900 TI - Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147158. PMID- 30303901 TI - Management of Anesthesia and Delivery in Women With Chiari I Malformations. AB - OBJECTIVE: To estimate whether vaginal delivery or neuraxial anesthesia poses a risk of neurologic deterioration in women with uncorrected Chiari I malformation. METHODS: To assemble this case series, electronic record databases were used to identify women with Chiari I malformation who delivered on two busy tertiary care obstetric services over a 5-year period from January 2010 through December 2015. Women who had undergone surgical decompression were not included in the study. The size of the Chiari malformation, neurologic symptoms before delivery, mode of delivery, anesthetic method used, and neurologic complications were recorded. RESULTS: Ninety-five deliveries in 63 patients were identified. The size of the Chiari malformation was 9.3+/-4.3 mm (mean+/-SD). In 58 pregnancies, women reported no headaches; in 36 they did. There was no association between the size of the Chiari malformation and the incidence of headache. Forty-four neonates were delivered by cesarean delivery and 51 were delivered vaginally. No neurologic deterioration occurred in either group. Neuraxial anesthesia was administered before 62 deliveries. No neurologic complications occurred. None of the women who delivered vaginally or received neuraxial anesthesia had signs of increased intracranial pressure. The upper limit of the 95% CI for the risk of neurologic complications from our study of 95 deliveries was 3.1%. CONCLUSION: This case series support that in patients with Chiari I malformation who have no signs of increased intracranial pressure, the mode of delivery should be based on obstetric rather than neurologic considerations. The absence of complications in patients who received epidural or spinal anesthesia suggests that these procedures should be made available to women with Chiari I malformation. PMID- 30303902 TI - Incidence of Venous Thromboembolism After Different Modes of Gynecologic Surgery. AB - OBJECTIVE: To evaluate the incidence of postoperative venous thromboembolism after gynecologic surgery by mode of incision. METHODS: We conducted a retrospective cohort study of all patients who underwent gynecologic surgery from May 2006 to June 2015 at two tertiary care academic hospitals in Massachusetts. Billing and diagnosis codes were used to identify surgeries and cases of venous thromboembolism. RESULTS: A total of 43,751 surgical encounters among 37,485 individual patients were noted during the study. The overall incidence of venous thromboembolism is 0.2% for all gynecologic surgeries, 0.7% for hysterectomy, and 0.2% for myomectomy. Compared with patients undergoing laparotomy, patients who underwent minimally invasive gynecologic surgery were less likely to develop venous thromboembolism (laparoscopy risk ratio 0.22, 95% CI 0.13-0.37; vaginal surgery risk ratio 0.07, 95% CI 0.04-0.12). This effect persisted when data were adjusted for other known venous thromboembolism risk factors such as age, race, cancer, medical comorbidities, use of pharmacologic thromboprophylaxis, admission status, and surgical time. CONCLUSION: Minimally invasive surgery is associated with a decreased risk of venous thromboembolism in patients undergoing gynecologic surgery, including hysterectomy and myomectomy. Although society guidelines and risk assessment tools do not currently account for mode of surgery when assessing venous thromboembolism risk and recommendations for prevention, there is a small but growing body of evidence in both general and gynecologic surgery literature that surgical approach affects a patient's risk of postoperative venous thromboembolism. Mode of surgery should be considered when assessing venous thromboembolism risk and planning venous thromboembolism prophylaxis for patients undergoing gynecologic surgery. PMID- 30303903 TI - A Comprehensive Evaluation of Obstetrics and Gynecology Residencies' Global Health Training Programs. AB - OBJECTIVE: To compile a comprehensive summary of obstetrics and gynecology global health training programs and to describe program type, global distribution of work, effect, and reciprocity within programs. METHODS: This cross-sectional observational study identified all U.S. obstetrics and gynecology residencies with global health training programs, described residency and program characteristics, and evaluated the publications resulting from them. Eligible articles included those published in 2011-2016 about work done in a global health training location by global health training faculty. All eligible articles were evaluated for academic effect. The inclusion of host country authors on articles served as a proxy for reciprocity. Article content was assessed to evaluate whether programs addressed Millennium Development Goals. RESULTS: Among 245 obstetrics and gynecology residencies, 196 (80%) had global health training programs. Location and faculty members were identified for 67 (34%) programs, of which 26 (39%) had global health training faculty who had published articles meeting inclusion criteria. Of 698 articles reviewed, 78% addressed at least one Millennium Development Goal, including 39% that addressed improving maternal health (Millennium Development Goal 5). Approximately half (48%) of authors were from host countries. CONCLUSION: Most obstetrics and gynecology residencies are offering global health training. The majority of programmatic work addresses Millennium Development Goals and thus is aligned with global health priorities. The effect and reciprocity of global health training programs varies across institutions. Residencies could benefit from internal analysis of their global health training programs to evaluate whether knowledge gained is being disseminated and to ensure equitable partnerships and the creation of sustainable, influential initiatives. PMID- 30303904 TI - Nitrous Oxide Compared With Intravenous Sedation for Second-Trimester Abortion: A Randomized Controlled Trial. AB - OBJECTIVE: To assess whether inhaled nitrous oxide is noninferior to intravenous (IV) sedation for pain control during outpatient surgical abortion between 12 and 16 weeks of gestation. METHODS: We enrolled women undergoing surgical abortion at 12-16 weeks of gestation into a multisite, double-blind clinical trial. Participants were randomized to sedation with nitrous oxide (70% nitrous/30% oxygen) or IV fentanyl (100 micrograms) and midazolam (2 mg). Paracervical block was administered to both groups. The primary outcome measure was immediate postabortion recall of maximum pain on a 100-mm visual analog scale. RESULTS: Between August 2016 and March 2017, we assessed 170 women for eligibility and enrolled 39, 19 in the nitrous group and 20 in the IV sedation group. Seven participants in the nitrous group (36.8%) required conversion to IV sedation for inadequate pain control. No participants in the IV sedation group required additional medication. The proportion of women requiring additional pain control in the nitrous group exceeded our predefined stopping rule. Intention-to-treat analysis demonstrated that immediate postabortion visual analog scale pain scores were lower by 20.1 mm (95% CI 1.6-38.6) in women randomized to IV sedation than in women randomized to nitrous. CONCLUSION: Intravenous sedation is a better choice than inhaled nitrous oxide for pain control in second-trimester abortion. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02755090. PMID- 30303905 TI - Torsemide for Prevention of Persistent Postpartum Hypertension in Women With Preeclampsia: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether torsemide reduces the rate of persistent postpartum hypertension in women with preeclampsia. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of women with preeclampsia at a tertiary center from August 2016 to September 2017. Those with gestational hypertension or renal or cardiopulmonary failure were excluded. Within 24 hours of delivery, women were randomized one to one to oral torsemide, 20 mg/d, or placebo, for 5 days. Our primary outcome was blood pressure greater than or equal to 150 mm Hg systolic or 100 mm Hg diastolic (or both) on two occasions at least 4 hours apart by postpartum day 5 or by the time of hospital discharge. Assuming a 50% rate of persistent hypertension in women with preeclampsia, 118 participants were required to detect a 50% rate reduction. Analyses were by intention to treat. RESULTS: From August 2016 to September 2017, 118 women were randomized: 59 were allocated to torsemide and 59 to placebo. Overall, 43 (73%) women in the torsemide and 45 (76%) in the placebo group had either preeclampsia with severe features or preeclampsia superimposed on chronic hypertension. The rate of persistent postpartum hypertension was 44% in the torsemide and 58% in the placebo group (relative risk 0.76, 95% CI 0.5-1.1). No differences were seen in rate of hypertension 7-10 days or 6 weeks postpartum, severe hypertension, length of postpartum hospital stay, readmission for hypertension, or adverse events. There were no cases of severe composite morbidity or deaths. CONCLUSION: In this trial of women with preeclampsia, a 5-day course of postpartum torsemide did not have a significant effect on the rate of postpartum hypertension. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02813551. PMID- 30303906 TI - Characterization of Risk Factors and Timing of Venous Thromboembolism in Patients With Uterine Serous Carcinoma. AB - OBJECTIVE: To characterize risk factors and timing of venous thromboembolism in women with uterine serous carcinoma. METHODS: A retrospective cohort study was performed including all women diagnosed with uterine serous carcinoma from 1999 to 2016 at our institution. Clinicopathologic data and information regarding timing of venous thromboembolism were abstracted from the medical record. Logistic regression and Cox proportional hazards modeling were used to examine the association between covariates and risk and timing of venous thromboembolism. RESULTS: Seventy of the 413 included patients (17%) developed venous thromboembolism, with a median time from presentation to venous thromboembolism of 7.2 months (interquartile range 1.0-24.8) and from surgery to venous thromboembolism of 13.2 months (interquartile range 3.5-33.6). Fifty-nine of the 70 patients (84%) who developed venous thromboembolism were diagnosed either before surgery or greater than 6 weeks postoperatively. Twenty-two of the 70 patients (31%) who developed clots were on chemotherapy at the time of diagnosis. Venous thromboembolism was highly associated with cancer stage and presence of hypertension (P<.01). Cox proportional hazards modeling revealed that only cancer stages III and IV (hazard ratio [HR] 3.20, 95% CI 1.54-6.64 and HR 8.68, 95% CI 4.50-16.73, respectively) and hypertensive or cardiovascular diseases (HR 2.29, 95% CI 1.08-4.85 and HR 1.82, 95% CI 1.05-3.13) were associated with time to venous thromboembolism. CONCLUSION: Patients with uterine serous carcinoma are at high risk of developing venous thromboembolism even many months after their cancer diagnosis. This study generates the hypothesis that venous thromboembolism prophylaxis may be beneficial in patients with uterine serous carcinoma during other time points along the continuum of disease rather than only in the postoperative period, especially for those with advanced cancer. PMID- 30303907 TI - Hereditary Cancer Risk Assessment and Genetic Testing in the Community-Practice Setting. AB - OBJECTIVE: To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor. METHODS: This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up. Outcomes related to hereditary cancer assessment and testing were measured during an 8-week postintervention period. Patients and health care providers were surveyed about satisfaction with the process. Data also were collected during the 8 weeks before the intervention to assess the effects of screening process improvements. RESULTS: A total of 4,107 patients were seen during the postintervention period, and 92.8% (3,811) were assessed for hereditary cancer risk. Among those assessed, 906 of 3,811 (23.8%) women met National Comprehensive Cancer Network guidelines for genetic testing, and 813 of 906 (89.7%) eligible patients were offered genetic testing. A total of 165 of 4,107 (4.0%) women completed genetic testing and received a final test result. This represents a fourfold increase over genetic testing immediately before the intervention (1.1%) and an eightfold increase over the previous year (0.5%). Testing identified pathogenic variants in 9 of 165 (5.5%) tested women. All health care providers (15/15) reported that they will continue to use the established hereditary cancer risk assessment process. In addition, 98.8% (167/169) of patients who submitted a sample for genetic testing and completed a patient satisfaction survey stated that they were able to understand the information provided, and 97.6% (165/169) expressed satisfaction with the overall process. CONCLUSION: It is feasible to incorporate hereditary cancer risk assessment, education, and testing into community obstetrics and gynecology practices. As a result, multigene panel testing identified significant cancer risks that otherwise would not have been recognized. PMID- 30303908 TI - External Use of an Oxidized Regenerated Cellulose Agent in the Treatment of Labial Agglutination in Postmenopausal Women. AB - BACKGROUND: Vulvovaginal diseases affect women of all ages. Vaginal atrophy and vulvar lichen sclerosus are common etiologies for chronic vulvovaginal pruritus and labial agglutination in both prepubertal and postmenopausal women. CASES: We present two cases of a novel approach in management of symptomatic labial agglutination in postmenopausal women. At the time of surgical intervention, an oxidized regenerated cellulose gauze was sutured in place within the operative field of separation of the labia minora and clitoral hood adhesions. At more than 18-months' follow-up, no recurrence of agglutination has been noted. CONCLUSION: The use of an oxidized regenerated cellulose agent may create an effective barrier to recurrence of labial agglutination in postmenopausal women. PMID- 30303909 TI - A Decision Analysis Model of 1-Year Effectiveness of Intended Postplacental Compared With Intended Delayed Postpartum Intrauterine Device Insertion. AB - OBJECTIVE: To compare, using decision analysis methodology, the 1-year probability of pregnancy after intended postplacental intrauterine device (IUD) insertion with intended delayed insertion at an outpatient postpartum visit (delayed postpartum placement). METHODS: We developed an evidence-based decision model with the primary outcome of 1-year probability of pregnancy. We compared 1 year probability of pregnancy after intended postplacental or intended delayed postpartum IUD placement. We obtained estimates from the literature for the proportions of the following: mode of delivery, successful IUD placement, IUD type, postpartum visit attendance, IUD expulsion, IUD discontinuation, and contraceptive use, choice, and efficacy after IUD discontinuation. We performed sensitivity analyses and a Monte Carlo simulation to account for variations in proportion estimates. RESULTS: One-year probabilities of pregnancy among a theoretical cohort of 2,500,000 women intending to receive a postplacental IUD after vaginal birth and 1,250,000 women intending to receive a postplacental IUD after cesarean birth were 17.3% and 11.2%, respectively; the 1-year probability of pregnancy among a theoretical cohort of 2,500,000 women intending to receive a delayed postpartum IUD was 24.6%. For delayed postpartum IUD placement to have effectiveness equal to postplacental placement, 91.4% of women delivering vaginally and 99.7% of women delivering by cesarean would need to attend postpartum care. Once placed, the effectiveness of postplacental IUDs was lower than that of delayed postpartum IUDs: 1-year probabilities of pregnancy after IUD placement at a vaginal birth, cesarean birth, and an outpatient postpartum visit were 15.4%, 6.6%, and 3.9%, respectively. CONCLUSION: After accounting for factors that affect successful IUD placement and retention, this decision model indicates that intended postplacental IUD insertion results in a lower 1-year probability of pregnancy as compared with intended delayed postpartum IUD insertion. PMID- 30303910 TI - Prospective Validation of a Standardized Ultrasonography-Based Ovarian Cancer Risk Assessment System. AB - OBJECTIVE: To evaluate the performance of a system that standardizes ovarian cancer risk assessment and reporting on ultrasonography. METHODS: We conducted a prospective community-based cohort study of average-risk women undergoing ultrasonography in 2016 using a reporting system that requires adnexal masses to be categorized as 1, 2, 3, or X based on standardized ultrasound criteria including size, presence of solid components, and vascularity assessed by Doppler. With a median follow-up of 18 months, the risk of ovarian cancer or borderline tumor diagnosis for each category was determined. RESULTS: Among 43,606 women undergoing ultrasonography, 6,838 (16%) had an abnormal adnexal mass reported: 70% were category 1, 21% category 2, 3.7% category 3, and 5.4% category X. Among these women, 89 (1.3%) were subsequently diagnosed with ovarian cancer and 59 (0.9%) with borderline tumors. The risks of ovarian cancer diagnosis associated with masses reported as categories 1, 2, 3, and X were 0.2% (95% CI 0.05-0.3%), 1.3% (95% CI 0.7-1.9%), 6.0% (95% CI 3.0-8.9%), and 13.0% (95% CI 9.5 16.4%), respectively; risks of either ovarian cancer or borderline tumor were 0.4% (95% CI 0.2-0.6%), 2.3% (95% CI 1.6-3.1%), 10.4% (95% CI 6.6-14.1%), and 18.9% (95% CI 14.9-23.0%) respectively. Among 36,768 (84%) women with normal or benign adnexal findings reported, 38 women were diagnosed with ovarian cancer, for a risk of 0.1% (95% CI 0.07-0.14%). CONCLUSION: In a community-based setting with low ovarian cancer prevalence, our standardized reporting system differentiated adnexal masses into four categories with distinct levels of risk with 9-10% of women having higher risk masses and 70% of women having masses associated with a risk of cancer similar to that of normal ultrasound findings. The system supports risk-based management by providing clinicians a more consistent assessment of risk based on ultrasound characteristics. PMID- 30303911 TI - Cesarean Scar Pregnancy, Incidence, and Recurrence: Five-Year Experience at a Single Tertiary Care Referral Center. AB - OBJECTIVE: To describe the treatment and subsequent pregnancy outcomes in patients with cesarean scar pregnancies at a single institution over 5 years. METHODS: This is a case series of all cesarean scar pregnancies diagnosed from May 2013 to March 2018 at Yale-New Haven Hospital. Data were collected on each patient using electronic medical record review and included patient demographics; medical, surgical, and obstetric history; pregnancy characteristics; treatment modalities used; response to therapy; complications; and subsequent pregnancy outcomes. RESULTS: Thirty cases of cesarean scar pregnancies were diagnosed in 26 patients, including one recurrence in one patient and three recurrences in another. Forty-six percent of cesarean scar pregnancies were in Hispanic women. The median number of prior cesarean deliveries was two. Mean gestational age at the time of diagnosis was 46 days (SD+/-10). Fetal cardiac activity was detected in 18 cases. Three patients initially were erroneously diagnosed with a viable intrauterine pregnancy and failed medical termination. Others opted for termination through systemic methotrexate alone (n=4), systemic and local methotrexate (n=12), systemic and local methotrexate with potassium chloride injected into the gestational sac (n=3), potassium chloride injection with laparotomy and wedge resection (n=1), methotrexate with bilateral uterine artery embolization (n=2), or intrauterine balloon (n=4). Five patients who underwent expectant management or methotrexate therapy had retained products of conception and required hysteroscopy and curettage. One patient opted for hysterectomy after failed curettage. After complete resolution of cesarean scar pregnancies, there were 10 subsequent spontaneous conceptions in eight patients, including four recurrent cesarean scar pregnancies, four term pregnancies, and one spontaneous abortion. One viable normally located pregnancy is ongoing. CONCLUSION: There is a wide array of treatment modalities available for cesarean scar pregnancies. Women with a cesarean scar pregnancy are at risk for its recurrence in the future, although normal pregnancy after a cesarean scar pregnancy is also possible. Safe outcomes depend on timely diagnosis and multidisciplinary care by skilled clinicians. PMID- 30303912 TI - Racial and Ethnic Disparities in the Incidence of Severe Maternal Morbidity in the United States, 2012-2015. AB - OBJECTIVE: To describe racial and ethnic disparities in the incidence of severe maternal morbidity during delivery hospitalizations in the United States. METHODS: We conducted a pooled, cross-sectional analysis of 2012-2015 data from the National Inpatient Sample to define the prevalence of chronic conditions and incidence of severe maternal morbidity among deliveries to non-Hispanic white, non-Hispanic black, Hispanic, Asian or Pacific Islander, and Native American or Alaska Native women. We used weighted multivariable logistic regression and predictive margins to generate prevalence and incidence estimates. Adjusted rate ratios and differences were calculated to quantify disparities across racial and ethnic categories. Subgroup analyses were performed to examine the incidence of severe maternal morbidity among deliveries to women with comorbid physical health conditions, behavioral health conditions, and multiple chronic conditions within each racial and ethnic category. RESULTS: The incidence of severe maternal morbidity was significantly higher among deliveries to women in every racial and ethnic minority category compared with deliveries among non-Hispanic white women. Severe maternal morbidity occurred in 231.1 (95% CI 223.6-238.5) and 139.2 (95% CI 136.4-142.0) per 10,000 delivery hospitalizations among non-Hispanic black and non-Hispanic white women, respectively (P<.001). When excluding cases in which blood transfusion was the only indicator of severe maternal morbidity, only deliveries to non-Hispanic black women had a higher incidence of severe maternal morbidity compared with deliveries among non-Hispanic white women: 50.2 (95% CI 47.6-52.9) and 40.9 (95% CI 39.6-42.3) per 10,000 delivery hospitalizations, respectively (risk ratio 1.2 [95% CI 1.2-1.3], risk difference 9.3 [95% CI 6.5 12.2] per 10,000 delivery hospitalizations; P<.001 for each comparison). Among deliveries to women with comorbid physical and behavioral health conditions, significant differences in severe maternal morbidity were identified among racial and ethnic minority compared with non-Hispanic white women and the largest disparities were identified among women with multiple chronic conditions. CONCLUSION: Programs for reducing racial and ethnic disparities in severe maternal morbidity may have the greatest effect focusing on women at highest risk for blood transfusion and maternity care management for women with comorbid chronic conditions, particularly multiple chronic conditions. PMID- 30303913 TI - What Is New in Bladder Pain?: Best Articles From the Past Year. AB - This month we focus on current research in bladder pain. Dr. Whiteside discusses four recent publications, which are concluded with a "bottom-line" that is the take-home message. A complete reference for each can be found in Box 1 on this page along with direct links to abstracts. PMID- 30303914 TI - Connect the Dots-November 2018. PMID- 30303915 TI - Ultrasound Screening for Ovarian Cancer: Are We There Yet? PMID- 30303916 TI - Survival of Women With Type I and II Epithelial Ovarian Cancer Detected by Ultrasound Screening. AB - OBJECTIVE: To estimate the effect of ultrasound screening on stage at detection and long-term disease-specific survival of at-risk women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women 50 years of age or older and women 25 years of age or older with a documented family history of ovarian cancer. From 1987 to 2017, 46,101 women received annual ultrasound screening in a prospective cohort trial. Women with a persisting abnormal screen underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Seventy-one invasive epithelial ovarian cancers and 17 epithelial ovarian tumors of low malignant potential were detected. No women with a low malignant potential tumor experienced recurrent disease. Stage distribution for screen-detected invasive epithelial ovarian cancers was stage I-30 (42%), stage II-15 (21%), stage III-26 (37%), and stage IV-0 (0%). Follow-up varied from 9.2 months to 27 years (mean 7.9 years). Disease-specific survival at 5, 10, and 20 years for women with invasive epithelial ovarian cancer detected by screening was 86+/-4%, 68+/-7%, and 65+/-7%, respectively, vs 45+/-2%, 31+/-2%, and 19+/-3%, respectively, for unscreened women with clinically detected ovarian cancer from the same geographic area who were treated at the same institution by the same treatment protocols (P<.001). Twenty-seven percent of screen-detected malignancies were type I and 73% were type II. The disease-specific survival of women with type I and type II screen-detected tumors was significantly higher than that of women with clinically detected type I and type II tumors and was related directly to earlier stage at detection. CONCLUSION: Annual ultrasound screening of at-risk asymptomatic women was associated with lower stage at detection and increased 5-, 10-, and 20-year disease-specific survival of women with both type I and type II epithelial ovarian cancer. CLINICAL TRIAL REGISTRATION: OnCore Clinical Trials Management System, NCI-2013-01954. PMID- 30303917 TI - The Sign of Leser-Trelat and Malignant Acanthosis Nigricans Associated With Fallopian Tube Carcinoma. AB - BACKGROUND: The sign of Leser-Trelat is controversial and rarely reported in gynecologic malignancies. It is characterized by rapid development of new or enlarging seborrheic keratoses. CASE: A 78-year-old woman presented with unintentional weight loss and new-onset erythematous patches and plaques with thickened, rugated skin and stuck-on brown waxy papules on the chest and back. Her symptoms were concerning for a paraneoplastic eruption; workup revealed an elevated CA 125 level and an ovarian mass on abdominal computed tomography scan. Exploratory laparotomy revealed a stage IIIC serous fallopian tube carcinoma and a synchronous low-grade endometrioid adenocarcinoma of the endometrium. CONCLUSION: The sign of Leser-Trelat can be associated with fallopian tube carcinoma. When recognized, paraneoplastic dermatoses can prompt clinicians to initiate a workup for occult malignancy. PMID- 30303918 TI - Starting Health Disparities Education During Resident Orientation: Our Patients, Our Community. AB - Disparities in women's reproductive health outcomes are persistent and prevalent. Cultural competency education of trainees is central to reducing patient-, system , and practitioner-level factors that promote disparate health outcomes. Such issues include health literacy, access to health care, and unconscious bias. We suggest that recognizing and reducing health disparities should be a longitudinal theme in resident education, first introduced during intern orientation and continued with dedicated didactics, experiential learning opportunities, grand rounds, and journal clubs built into the residency curricula. In this commentary, we present various methods of introducing health disparities education and commencing a larger conversation about inequity and race in medicine. We hope to encourage other training programs to incorporate this important topic earlier into their educational curriculum. PMID- 30303919 TI - Novel Approach to Reduction of an Incarcerated Uterus. AB - BACKGROUND: Incarceration of the pregnant uterus is a rare condition and can lead to bladder obstruction, renal failure, or uterine rupture. We present a novel, noninvasive technique to reduce an incarcerated uterus. METHOD: With conscious sedation, the patient was placed in all-fours position. The physician's hands were placed on the patient's abdomen and pressure applied until the uterine fundus was palpated. Gentle, steady fundal pressure on both sides was directed toward the maternal chest (bilateral mediocephalad pressure) elevating the uterus out of the pelvis. This approach successfully reduced the gravid incarcerated uterus and was well tolerated by the patient and fetus. EXPERIENCE: The author's experience with this method is limited to this case. Prior experience with reduction of the incarcerated uterus has been with methods previously described in the literature. CONCLUSION: In conjunction with conscious sedation and all fours positioning, transabdominal manipulation of the uterine fundus with bilateral mediocephalad pressure may facilitate reduction of an incarcerated uterus. This method may obviate the need for more invasive procedures. PMID- 30303920 TI - Implementation of the "Pregnancy Reasonably Excluded Guide" for Pregnancy Assessment: A Quality Initiative in Outpatient Gynecologic Surgery. AB - OBJECTIVE: Preoperative evaluation for pregnancy at our institution lacked standardization among individual health care providers and surgical services. This pilot project aimed to improve assessment for pregnancy before scheduled outpatient gynecologic surgical procedures. The Pregnancy Reasonably Excluded Guide incorporates historic, evidence-based criteria to facilitate identification of patients with a higher chance of pregnancy. METHODS: We retrospectively reviewed documentation for women undergoing gynecologic surgery at an outpatient surgical center from March through September 2016, before and after implementation of the pregnancy assessment protocol. After implementation, all eligible women (aged 18-50 years, not undergoing an emergent or pregnancy-related procedure) were assessed using the Pregnancy Reasonably Excluded Guide on arrival to the preoperative area. The Pregnancy Reasonably Excluded Guide checklist uses traditional and World Health Organization criteria for reasonable exclusion of pregnancy. Nursing staff reviewed responses with patients and pregnancy tests were completed as indicated by patient responses. Women who were unable to read, understand, or freely respond to the checklist received pregnancy testing. Pregnancy assessment, testing, results, and delays were recorded. This project was deemed exempt by the institutional review board. RESULTS: Two hundred thirteen eligible patients underwent outpatient gynecologic procedures during the study period (excluding a 2-week washout period at implementation). In the preimplementation period, 93 of 136 patients (68%) had pregnancy risk documented; 73 of 77 (95%) had documentation in the postimplementation period (P<=.01). Pregnancy tests were completed in 45 preimplementation patients (33%) and 16 postimplementation patients (21%) (P=.06). No pregnancy test results were positive. No procedural delays were associated with pregnancy assessment. CONCLUSION: Patient-centered assessment using the Pregnancy Reasonably Excluded Guide at presentation for outpatient gynecologic surgery significantly improved evaluation and documentation of pregnancy status before scheduled procedures without increasing the number of pregnancy tests or causing procedural delays. PMID- 30303921 TI - Effect of Minimum-Volume Standards on Patient Outcomes and Surgical Practice Patterns for Hysterectomy. AB - OBJECTIVE: To model the effect of implementing minimum-volume standards for women who underwent hysterectomy on patient outcomes and surgeon practice patterns. METHODS: We conducted a retrospective cohort study using the New York Statewide Planning and Research Cooperative System to capture data for all women who underwent hysterectomy from 2010 to 2014. We estimated the number of hysterectomies performed by each patient's physician during the prior year. Multivariable models were used to estimate the ratio of observed to expected complications based on each surgeon's volume during the prior year. The mean observed/expected ratio of surgeons was then plotted by volume. The number of patients and surgeons who would be eliminated and the reduction in complications if minimum-volume standards (lowest fifth and 10th percentiles) were implemented were analyzed. Separate analyses were performed for each route of hysterectomy. RESULTS: We identified a total of 127,202 patients. For abdominal hysterectomy, increasing surgeon volume was associated with a decreasing rate of complications (P<.001). Overall, 17.5% of surgeons (n=1,260) had a prior year volume of one abdominal hysterectomy. The mean observed/expected ratio of surgeons with a prior year abdominal hysterectomy volume of one was 1.47 (SD 2.71). Within this group of surgeons, 31.4% had an observed/expected ratio of 1 or greater, indicating a higher than expected complication rate, and 68.7% of the surgeons had a observed/expected ratio of less than 1, suggesting a lower complication rate than expected based on case mix. Selection of a prior year volume standard of one would restrict 12.5% of surgeons performing robotic-assisted, 16.8% of those performing laparoscopic, and 27.6% of surgeons performing vaginal hysterectomy. CONCLUSION: Implementing minimum-volume standards for hysterectomy, for even the lowest volume physicians, would restrict a significant number of gynecologic surgeons, including many with outcomes that are better than predicted. PMID- 30303922 TI - Complication Rates and Outcomes After Hysterectomy in Transgender Men. AB - OBJECTIVE: To describe the rate and 30-day outcomes after gender affirmation surgery in transgender men. METHODS: We conducted a cross-sectional population based study. Patients with male gender who underwent hysterectomy for benign indications between 2013 and 2016 in the American College of Surgeons' National Surgical Quality Improvement database were identified. Propensity score matching was performed to ameliorate selection bias. Student t test and Mann-Whitney tests were used to compare continuous variables between two groups where appropriate. The chi and Fisher exact tests were used where appropriate to compare categorical variables across groups. Logistic regression models were used to evaluate factors associated with any postoperative adverse event. RESULTS: Of 159,736 hysterectomies performed during the study period, 521 (0.3%) were performed in transgender men. The mean age was 23.9+/-13.8 years, and the median body mass index was 29.0 (range 24.8-34.2). The majority of patients were white (64.5%). The most common specified diagnosis associated with hysterectomy was gender identity disorder (20.9%). Laparoscopy was the most common route (57.2%) followed by laparoscopic-assisted vaginal hysterectomy (20.0%) and abdominal hysterectomy (15.2%). After propensity matching was performed, the composite rate of postoperative complications was similar between the transgender male and control groups (3.4% vs 3.3%, P=.92). On multivariate logistic regression controlling for age, presence of a major medical comorbidity, and primary mode of surgery, transgender male status and presence of a major medical comorbidity were not significantly associated with complications (adjusted odds ratio [OR] 1.11, 95% CI 0.56-2.10 and adjusted OR 1.16, 95% CI 0.58-2.27, respectively). Age remained weakly associated with postoperative complications (adjusted OR 1.04, 95% CI 1.01 1.06), whereas minimally invasive approaches to hysterectomy were significantly associated with lower incidences of complications (vaginal, adjusted OR 0.04, 95% CI 0.002-0.17; laparoscopic adjusted OR 0.09, 95% CI 0.04-0.18; and laparoscopic assisted vaginal hysterectomy, adjusted OR 0.07, 95% CI 0.02-0.20). CONCLUSION: Less than 1% of hysterectomies performed annually are for transgender male patients. Postoperative complications after hysterectomy in this patient population are similar to the complication rates found in cisgender women. PMID- 30303923 TI - Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean+/-SD age of 43+/-5 years (cohort 2, 42+/-5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37. PMID- 30303924 TI - Topical Estrogen Prescription Fill Rates for Women With a History of Breast Cancer Who Are Taking Hormone Therapy. AB - OBJECTIVE: To evaluate how often women with a history of breast cancer who are taking hormone therapy (HT) filled prescriptions for topical estrogens and whether this frequency varied over time and by type of HT used. METHODS: We performed a retrospective cohort study using medical and outpatient drug claims from a large commercial claims database for the years 2010-2015. Women younger than age 65 years taking HT for breast cancer were classified as users of 1) tamoxifen only, 2) aromatase inhibitor(s) only, or 3) any other or multiple HTs. Our outcome variable was filling a prescription for topical estrogen in a given year. We used multivariable logistic regression models estimated with generalized estimating equations to determine whether the fill rate varied over time and by HT category adjusting for age, receipt of surgical or radiation treatment, types of outpatient health care provider visits, and comorbidities. RESULTS: We identified 352,118 records from 176,012 unique patients (mean age 54.3 years, range 18-64 years) who met eligibility criteria. Aromatase inhibitors were used more commonly (56.0% of patient-years) than tamoxifen (38.8%). Overall, 3.0% (range 2.9-3.1%) of women filled any topical estrogen prescription in a given calendar year. More than half of filled topical estrogen prescriptions were for tablets (57.0%) with the remainder for creams (25.8%) and rings (17.3%). In adjusted analyses, the fill rate for women taking tamoxifen was significantly less (2.4%; 95% CI 2.3-2.5%) than for women taking aromatase inhibitors (3.3%; 95% CI 3.2-3.4%). There was a small but statistically significant increase in fill rates across years (odds ratio 1.03, 95% CI 1.02-1.04). CONCLUSION: A small proportion of women with a history of breast cancer who were taking HT filled a topical estrogen prescription, with significant differences by type of HT. More evidence is needed to inform national guidelines regarding safety and appropriate use of topical estrogens in this patient population. PMID- 30303925 TI - Vulvar Cancer as a Result of GATA2 Deficiency, a Rare Genetic Immunodeficiency Syndrome. AB - BACKGROUND: Vulvar cancer has become more prevalent, and its causes include chronic dermatoses and human papillomavirus (HPV)-mediated disease. Younger immunocompromised women can also be affected. We describe a case of vulvar carcinoma as a result of GATA2 deficiency. CASE: A 19-year-old woman presented to our gynecologic oncology clinic for management of a large vulvar mass. She was diagnosed with stage IB vulvar carcinoma after vulvectomy. GATA2 deficiency was the contributing factor causing vulvar carcinoma. CONCLUSION: GATA2 deficiency causes immunodeficiency in young women, and patients with early-onset HPV-related disease, a family or personal history of leukemia, recurrent infection, or immune irregularities should be screened. Health care providers for these women are often obstetrician-gynecologists, who can provide diagnosis, treatment, referral, and prevention of HPV-related diseases. PMID- 30303926 TI - The Masseter Muscle and Its Role in Facial Contouring, Aging, and Quality of Life: A Literature Review. AB - BACKGROUND: Masseter muscle hypertrophy manifests itself as enlargement of masseter muscle. It can be associated with square shaped lower face, pain, dental attrition, maxillary and mandibular bone resorption, and accelerated aging process of the lower face. OBJECTIVE: Is to assess efficacy and safety of botulinum toxin type A in contouring the masseter and its impact on quality of life, the aging process of the lower face, and it's role in full face rejuvenation. METHODS: A PubMed search was conducted for articles on masseter treatment with botulinum toxin type A, masseter muscle hypertrophy, and aging process of the lower face. Key studies are reviewed and findings are summarized. RESULTS: Botulinum toxin type A can be injected in the lower posterior aspect of the masseter muscle. Treatment decreases muscle bulk and reshapes the lower face. Furthermore, patient quality of life measures, including pain and symptoms of grinding and clenching are improved. Treatment can decrease shear stress on maxillary and mandibular bones and can possibly prevent tooth loss and progressive bone resorption of the lower face. Adverse effects are minimal and short lasting. CONCLUSION: Botulinum toxin type A is a safe and effective treatment of masseter hypertrophy. The treatment results in improvement of functionality, cosmesis and restoring facial harmony. PMID- 30303927 TI - Tissue Expander Complications Do Not Preclude A Second Successful Implant Based Breast Reconstruction. AB - BACKGROUND: Implant based breast reconstruction is the most common method of breast reconstruction in the United States but the outcomes of subsequent implant based reconstruction after a tissue expander (TE) complication are rarely studied. The purpose of this study is to determine the long term incidence of implant loss in patents with a previous TE complication. METHODS: This is a retrospective review of the long term outcomes of all patients with TE complications at a large academic medical center from 2003-2013. Patients with subsequent TE or implant complications were compared to those with no further complications to assess risk factors for additional complications, or reconstructive failure. RESULTS: One hundred sixty-two women were included in this study. The mean follow up was 8.3 +/- 3.1 years. Forty-eight women (30%) went on to have a second TE or implant placed. They did not differ from women who went on to autologous reconstruction or no further reconstruction. Of these, 34 women (71%) had no further complications, and 38 women (79%) had a successful implant based reconstruction at final follow-up. There were no patient or surgical factors significantly associated with a second complication or implant loss. CONCLUSIONS: Following TE complications, it is reasonable to offer women a second attempt at tissue expansion and implant placement. This study demonstrates that long term success rates are high and there are no definitive patient or surgical factors that preclude a second attempt at implant based breast reconstruction. PMID- 30303928 TI - Effect of the endogenous vascular endothelial growth factor on flap surgical delay in a rat flap model. AB - BACKGROUND: Experimental evidence suggests that endogenous vascular endothelial growth factor (VEGF) may play a major role in the surgical delay phenomenon. The purpose of this study was to investigate the effect of the endogenous vascular endothelial growth factor on flap surgical delay. METHODS: A total of 82 adult male Sprague-Dawley rats with an average weight of 330g were used for these experiments. These experiments were then conducted in two parts. In part 1, thirty-two rats were used to assess the effectiveness of VEGF inhibitor through western blot assay and ELISA. In part 2, fifty rats were used to investigate the effect of VEGF on flap surgical delay via arteriography, histology analysis, and flap viability. RESULTS: The VEGF protein inhibition ratio reached the maximum (approximately 91.6%) on the 5 to 7 days. The number of transverse arteries and the number of vessels > 0.1mm in diameter on the 3-day delay duration and the 6 day delay duration were significantly greater than those of the normal group. The number of transverse arteries and the number of vessels > 0.1mm in diameter on the 6-day inhibition duration were not significantly changed compared with the normal group. Microvascular density on the 6-day delay duration obviously increased whereas the 6-day inhibition duration was not significantly changed in comparison to the normal group. CONCLUSIONS: Endogenous VEGF is an initiating factor of the surgical delay effect by controlling choke vessel dilation and neovascularization within the choke zones. PMID- 30303929 TI - Evaluation of prepectoral implant placement and complete coverage with TiLoop(r) Bra mesh for breast reconstruction: a prospective study on long-term and patient reported BREAST-Q outcomes. AB - BACKGROUND: Breast reconstruction is rapidly evolving, owing to the changing face of cancer surgery and the growing acceptance of acellular dermal matrices (ADM) and synthetic meshes. Although some early reports showed encouraging results after prepectoral breast reconstruction, there is a paucity of data on long term outcomes. METHODS: Between January 2012 and March 2015, 179 patients undergoing mastectomy were enrolled at our institution. Patients underwent mastectomy and immediate prepectoral breast reconstruction with the definitive implant entirely wrapped in a titanium-coated polypropylene mesh (TiLoop(r)). BREAST-Q questionnaire was administered prior to surgery and after 2 years. Capsular contracture was evaluated by Baker scale. Oncological, surgical and aesthetic outcomes along with the changes in BREAST-Q score were analyzed over time. RESULTS: Patients were followed up for an average of 38.5 months. A total of 250 mastectomies were performed. Locoregional recurrence rate was 2.1 %. Complications requiring a reoperation were recorded in 6 patients (2.4%) and implant removal was necessary in 3 cases (1.2%), followed by reconstruction with submuscular expanders. Grade IV capsular contracture was detected in 5 breasts (2%), while 212 breasts were evaluated as grade I (84.8%), 28 breasts as grade II (11.2%) and 5 breast as grade III (2%). Patients reported significant high rates in the BREAST-Q overall satisfaction with outcome (73.8), overall satisfaction with breasts (72.5), psychosocial well-being (77.7) and sexual well-being (57.9), scoring a significant increase in these domains from the preoperative to the postoperative period (p<0.05). CONCLUSIONS: In this study we report encouraging results of a prepectoral direct-to-impant reconstruction technique using a synthetic mesh, supporting the evaluation of the muscle-sparing subcutaneous approach as a valid alternative to traditional subcmuscular reconstruction. PMID- 30303930 TI - "Three-Dimensional Topography of the Emerging Point of the Ophthalmic Artery." AB - BACKGROUND: During periorbital noninvasive and surgical procedures there is the risk of iatrogenic injury to the emerging point of the ophthalmic artery. This study aimed to determine the three-dimensional location of the emerging point of the ophthalmic artery and to provide clinicians with anatomic information that would help them to avoid associated complications. METHODS: Seventeen hemifaces of the emerging point of the ophthalmic artery from 10 Korean and 7 Thai cadavers were dissected and scanned by a three-dimensional scanner. The emerging points of the ophthalmic artery of 30 healthy Korean volunteers were also detected using an ultrasound imaging system. RESULTS: The transverse distance from the medial canthus to the emerging of the ophthalmic artery was 3.8+/-1.0 mm medially, while the vertical distance was 14.0+/-2.9 mm superiorly. The transverse distance from the midline was 16.5+/-1.7 mm to the emerging point of the ophthalmic artery and 20.0+/-2.0 mm to the medial canthus. The measured depth from the skin surface to the emerging point of the ophthalmic artery was 4.8+/-1.7 mm in three-dimensional scanning and 4.5+/-1.1 mm in ultrasound detection. The vertical distance from the inferior margin of the superior orbital rim to the emerging point of the ophthalmic artery was 5.3+/-1.4 mm. CONCLUSIONS: These data inform clinicians about the anatomic three-dimensional location of the emerging point of the ophthalmic artery, which will help them to avoid iatrogenic injury when they are performing periorbital clinical procedures. PMID- 30303931 TI - The First AAPS Cannon Student Scholarship Experience. PMID- 30303932 TI - Preparing for the Plastic Surgery In-Service Examination: Evidence-Based Essentials for the Plastic Surgery Resident. PMID- 30303933 TI - Walking Pace Is Associated with Lower Risk of All-Cause and Cause-Specific Mortality. AB - PURPOSE: Walking pace is associated with all-cause and cardiovascular disease (CVD) mortality. Whether this association extends to other health outcomes and whether it is independent of total amount of time walked are currently unknown. Therefore, the aim of this study was to investigate whether usual walking pace is associated with a range of health outcomes. METHODS: 318,185 UK Biobank participants (54% women) aged 40-69 years were included. Walking pace and total walking time were self-reported. The outcomes comprised: all-cause mortality as well as incidence and mortality from cardiovascular disease (CVD), respiratory disease and cancer. The associations were investigated using Cox proportional hazard models. RESULTS: Over a mean of 5.0 years [ranging from 3.3 to 7.8], 5,890 participants died, 18,568 developed CVD, 5,430 respiratory disease and 19,234 cancer. In a fully adjusted model, compared to slow pace walkers, men and women, respectively, with a brisk pace having lower risk of mortality from all-causes (HR0.79 [95% CI: 0.69; 0.90] and 0.73 [95% CI: 0.62; 0.85]), CVD (HR 0.62 [0.50; 0.76] and 0.80 [0.73; 0.88]), respiratory disease (HR 0.58 [95% CI 0.43; 0.78] and 0.66 [0.57; 0.77]), COPD (HR 0.26 [95% 0.12; 0.56] and 0.28 [0.16; 0.49]). No associations were found for all-cause cancer, colorectal, breast cancer. However, brisk walking was associated with a higher risk of prostate cancer. CONCLUSIONS: Walking pace is associated with lower risk of a wide range of important health conditions, independently of overall time spent walking. PMID- 30303934 TI - Two-Year Agility Maintenance Training Slows the Progression of Parkinsonian Symptoms. AB - INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative condition and it is unclear if long-term non-pharmaceutical interventions can slow the progression of motor and non-motor symptoms and lower drug dose. METHODS: In a randomized trial, after an initial 3-week-long, 15-session supervised high-intensity sensorimotor agility exercise (E) program designed to improve postural instability, the Exercise+Maintenance (E+M, n=19) group continued to exercise three times per week for 2 years, while E (n=16) and the no exercise and no maintenance control (C, n=20) continued habitual living. Eight outcomes were measured before and after the 3-week initial exercise program and then at 3, 6, 9, 12, 18, and 24 months in all patients. RESULTS: The Group by Time interactions (all p<0.005) revealed robust and favorable effects of the initial 3-week agility program on all 6 non-motor (e.g., primary outcome MDS UPDRS-M-EDL: ~7 points; EuroQoL: ~9 points) and on each of the 2 motor outcomes (timed up and go test: ~6 s; posturography: up to 7 mm improvements in center of pressure path). E+M maintained but did not further improve the benefits produced by the initial 3-week program. In E, the favorable effects of the 3-week agility program lasted for 3 to 12 months. In C, patients declined steadily in all outcomes over 2 years. By year 2, Leva-dopa equivalents increased by 99.4 mg/day (Time main effect, p = 0.008). CONCLUSION: A high-intensity sensorimotor agility program with but not without a 2-year maintenance program slowed the progression of parkinsonian symptoms. PMID- 30303935 TI - Accelerometer Data Processing and Energy Expenditure Estimation in Preschoolers. AB - PURPOSE: To assess the capacity of different acceleration metrics from wrist accelerations to estimate total and activity energy expenditure (TEE, AEE) using doubly labelled water (DLW) in preschool children. METHODS: Thirty-nine preschoolers (5.5+/-0.1 years) were included. TEE was measured using DLW during 14 days and AEE was then calculated using a predicted basal metabolic rate. Participants wore a wGT3X-BT accelerometer on their non-dominant wrist for >=5 days. We derived the following metrics from raw accelerations: raw ActiGraph activity counts using the normal filter (NFCounts) and the low-frequency extension (LFECounts); and alternate summary metrics such as the Euclidian norm minus 1 g (ENMO), Euclidian norm of the high-pass filtered accelerations (HFEN), the band-pass filtered accelerations (BFEN), the HFEN plus Euclidean norm of low pass filtered accelerations minus 1 g (HFEN+) and the mean amplitude deviation (MAD). RESULTS: Alternate summary metrics explained a larger proportion of the variance in TEE and AEE than ActiGraph's activity counts (counts: 7-8 and 25% of TEE and AEE; alternate summary metrics: 13-16% and 35-39% of TEE and AEE). Adjustments for body weight and height resulted in an explanation of 51% of AEE by ENMO. All of the metrics adjusted for fat mass (FM) and fat-free mass (FFM) explained up to 84% and 67% of TEE and AEE, respectively. CONCLUSIONS: ENMO and the other alternate summary metrics explained more of the variance in TEE and AEE than the ActiGraph's activity counts in five-year-old children, suggesting further exploration of these variables in studies on physical activity and energy expenditure in preschoolers. Our results need confirmation in other populations with wider age groups and varying body compositions. PMID- 30303936 TI - Twenty-Year Trajectories of Physical Activity Types from Midlife to Old Age. AB - PURPOSE: Correlates of physical activity (PA) vary according to type. However, predictors of long-term patterns of PA types into old age are unknown. This study aimed to identify 20-year trajectories of PA types into old age and their predictors. METHODS: 7735 men (aged 40-59 years) recruited from UK towns in 1978 80 were followed up after 12, 16 and 20 years. Men reported participation in sport/exercise, recreational activity and walking, health status, lifestyle behaviours and socio-demographic characteristics. Group-based trajectory modelling (GBTM) identified the trajectories of PA types and associations with time-stable and time-varying covariates. RESULTS: Men with >=3 measures of sport/exercise (n=5116), recreational activity (n=5085) and walking (n=5106) respectively were included in analyses. Three trajectory groups were identified for sport/exercise, four for recreational activity and three for walking. Poor health, obesity and smoking were associated with reduced odds of following a more favourable trajectory for all PA types. A range of socioeconomic, regional and lifestyle factors were also associated with PA trajectories but the magnitude and direction were specific to PA type. For example, men with manual occupations were less likely to follow a favourable sport/exercise trajectory but more likely to follow an increasing walking trajectory compared to men with non-manual occupations. Retirement was associated with increased PA but this was largely due to increased sport/exercise participation. CONCLUSION: PA trajectories from middle to old age vary by activity type. The predictors of these trajectories and effects of major life events, such as retirement, are also specific to the type of PA.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30303937 TI - Rate of Spiral Ganglion Cell Loss in Idiopathic Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: To calculate the spiral ganglion neural decay rate among patients diagnosed with idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective. SETTING: Temporal bone histopathology bank. PATIENTS: Subjects diagnosed during life with unrecovered unilateral ISSNHL. INTERVENTION(S): Spiral ganglion cell count in the bilateral reconstructed Rosenthal canal. MAIN OUTCOME MEASURE(S): Decay rate of spiral ganglion cells. RESULTS: Nine patients were enrolled. The average age of ISSNHL diagnosis and death was 52 and 63 years, respectively. The total and segmental SGCC decay shows a temporal dependency. The time lag between the ISSNHL event and death was linearly proportional to the SGCC decay. Subjects who died less than 5 years from diagnosis of ISSNHL had no more than 13% loss of their total SGCC, and no more than 14% of SGCC per Rosenthal canal segment. When a longer period passed from ISSNHL diagnosis to death (19-20 yr), a loss of 16% and 13 to 18% of total and segmental SGCC occurred, respectively. CONCLUSIONS: SGCC decline from ISSNHL diagnosis through life. PMID- 30303938 TI - Surgical Management for Dysplastic or Congenitally Absent Oval Window. AB - OBJECTIVE: To evaluate surgical findings and hearing results for patient's undergoing the described surgical approach for congenitally absent or dysplastic oval window (OW). STUDY DESIGN: The Institutional Review Board approved retrospective review of patients with conductive hearing loss (CHL) operated on from 1992 to 2016. SETTING: Academic tertiary center. PATIENTS: Patients with CHL, an intact tympanic membrane (TM), and without history of chronic infection underwent middle ear exploration. Eleven patients and 13 ears underwent an oval window drill-out (OWD) procedure. INTERVENTION: Eleven patients presented, all with dysplastic or congenitally absent oval window (CAOW). CHL was identified using audiometry and tuning forks, many patients also had preoperative computed tomography temporal bones. A transcanal approach was used and an OWD was performed with a variety of prostheses placed. MAIN OUTCOME MEASURE: Audiometric studies before and after intervention were compared with 12 month and long-term follow-up (1-22 yr). RESULTS: Preoperative air-bone gaps ranged from 40 to 60 dB and averaged 55.1 dB. Postoperative air-bone gaps ranged from 0 to 60 dB and averaged 24.1 dB. The preoperative pure-tone average (PTA) ranged from 55 to 99 dB and averaged 71.3 dB. Postoperative PTA ranged from 21 to 108 dB and averaged 49.6 dB. CONCLUSION: Dysplastic and CAOW are uncommon congenital major ear anomalies. OWD is a viable treatment option, though careful counseling is critical, as significant complications are possible, especially with facial nerve (FN) abnormalities. This series demonstrates successful closure of the air-bone gap for many patients with this technique. PMID- 30303939 TI - Superiority of Second Stage Ossiculoplasty. AB - OBJECTIVE: To compare hearing results of single stage ossiculoplasty with second stage ossiculoplasty, and to provide a proper indication of operation options (single stage or second stage ossiculoplasty) according to patients' clinical conditions. STUDY DESIGN: Retrospective case review study. SETTING: Tertiary referral center. PATIENTS: A total of 175 patients with chronic otitis media. INTERVENTIONS: Tympanoplasty or mastoidectomy with tympanoplasty (M&T) as well as ossiculoplasty of either single or second stage between January 2009 and March 2016 by one surgeon (S.N.P.). MAIN OUTCOME MEASURES: Hearing outcomes evaluated by mean postoperative air-bone gap (ABG) and success rates in various subgroups of middle ear surgeries and different types of ossiculoplasty were analyzed. RESULTS: Among 175 patients, 120 underwent single stage ossiculoplasty, and 55 underwent second stage ossiculoplasty. The benefit of second stage ossiculoplasty in hearing results both at 3 months visit (p < 0.001) and 2 years visit (p = 0.003) were observed. The superiority of second stage ossiculoplasty was found in 20 dBHL cut off value with a statistical significance. The subgroups of canal wall down mastoidectomy and the first, non-revision middle ear surgery showed statistically significant benefits with second stage ossiculoplasty. CONCLUSION: Second stage ossiculoplasty has overall advantage in hearing results compared with single stage ossiculoplasty and could be more advantageous to the patient who needs canal wall down mastoidectomy or whose operation is the first middle ear surgery. PMID- 30303940 TI - Focal Degeneration of Vestibular Neuroepithelium in the Cristae Ampullares of Three Human Subjects. AB - BACKGROUND: We report a unique pattern of focal degeneration of the neuroepithelium of cristae ampullares, thick subepithelial extracellular deposits, and neural degeneration in three humans. OBJECTIVE: To characterize the pattern of vestibular degeneration and measure the thickness of subepithelial deposits in these three cases and controls. METHODS: The subepithelial deposits of vestibular end organs in three subject cases and controls were studied using hematoxylin and eosin, periotic acid-Schiff, Gomori trichrome staining, and immunostaining for antineurofilament, antimyosin VIIa, and anticollagen 4a1. The thickness of deposit as measured by light microscopy was compared with that of control groups (age-matched controls, patients with unilateral Meniere's disease, vestibular neuritis, cupulolithiasis, severe nonfocal degeneration of the vestibular neuroepithelium, and Alport syndrome). The correlation of thickness of deposits with age from 0 to 100 years was also investigated. RESULTS: Focal loss of hair cells in the neuroepithelium, thick subepithelial deposits, and degeneration of subepithelial dendrites and Scarpa's ganglion were found in all three cristae of three subject cases. Immunostaining demonstrated a decrease of afferent neural fibers in the cristae and focal fragmentation of the basement membrane adjacent to the deposits. The thickness of the subepithelial deposits in three cristae of three subject cases was significantly greater than that of all controls. In the three cristae of normal controls, the thickness of deposits demonstrated a positive correlation with age. CONCLUSION: Although both age and degeneration of the vestibular neuroepithelium may be associated with the thickness of the subepithelial deposits, in this unique pattern of degeneration, the thickness of the subepithelial deposits was significantly greater than that in all controls. PMID- 30303941 TI - Can a Chronic BPPV With a History of Trauma be the Trigger of Symptoms in Vestibular Migraine, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Whiplash Associated Disorders (WAD)? A Retrospective Cohort Study. AB - BACKGROUND: In patients with chronic benign paroxysmal positional vertigo (BPPV), i.e., chronic vestibular multicanalicular canalithiasis (CVMCC), abnormal signals are transmitted from diseased labyrinths via the healthy vestibular nuclei complex to their end organs. The vestibulo-thalamo-cortical reflex as proposed in vestibular migraine is just one of these reflexes. In a group of patients diagnosed with CVMCC otolith repositioning maneuvers specific for each semicircular canal (SCC) ameliorated pain and other symptoms in 90%. Increased awareness of CVMCC may reduce suffering and continuous medication. OBJECTIVE: To evaluate if CVMCC can be the trigger of symptoms in vestibular migraine, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and whiplash associated disorders (WAD). STUDY DESIGN: Retrospective consecutive observational cohort study. SETTING: Ambulatory at a private Otoneurology Centre. PATIENTS: One hundred sixty-three patients with CVMCC and a history of trauma. INTERVENTION: Based on the symptoms (structured symptom questionnaire), the patients are post hoc sub grouped according to the criteria of the different diagnoses. MAIN OUTCOME MEASURE: Frequency of patients with CVMCC who fulfill the criteria of the different diagnoses. RESULTS: 98% of all patients with CVMCC fulfill the Barany Society criteria of a probable vestibular migraine; 17% fulfill the International Classification of Headache Disorders defined vestibular migraine criteria; 63% fulfill the Fukuda criteria of ME/CFS; 100% of the patients with WAD suffer from CVMCC. CONCLUSION: This survey supports the hypothesis that CVMCC can be the trigger of symptoms in vestibular migraine, ME/CFS, and WAD. The actual diagnosis the patient receives is often in accordance with the patient's dominant symptom. PMID- 30303942 TI - A Systematic Review on Factors Associated With Percutaneous Bone Anchored Hearing Implants Loss. AB - OBJECTIVE: To investigate factors associated with percutaneous bone anchored hearing implant (BAHI) loss. DATA SOURCES: Africa-Wide, Biosis, Cochrane, Embase, Global Health, LILACs, Medline, Pubmed, and Web of Science electronic databases. STUDY SELECTION: All studies reporting on adult and/or pediatric patients with a BAHI loss were identified. Retrieved articles were screened using predefined inclusion criteria. Eligible studies underwent critical appraisal for directness of evidence and risk of bias. Studies that successfully passed critical appraisal were included for data extraction. DATA EXTRACTION: Extracted data included study characteristics (study design, number of total implants and implant losses, follow-up), patient characteristics (sex, age, comorbidities, previous therapies), and information regarding BAHI loss (etiology of loss, timing of occurrence). DATA SYNTHESIS: From the 5,151 articles identified at the initial search, 847 remained after title and abstract screening. After full text review, 96 articles were eligible. Fifty-one articles passed quality assessment, however, due to overlapping study population, 48 articles reporting on 34 separate populations were chosen for data extraction. Three hundred one implant losses occurred out of 4,116 implants placed, resulting in an overall implant loss occurrence rate of 7.3%. Failed osseointegration was responsible for most implant losses (74.2%), followed by fixture trauma (25.7%). Most losses due to failed osseointegration occurred within 6 months of the implantation. BAHI implant loss occurred more frequently in pediatric patients (p < 0.005). CONCLUSION: The current systematic review identified factors associated with BAHI loss. These factors should be considered when assessing patients' candidacy and when investigating reasons for impeded implant stability and loss. PMID- 30303943 TI - Serum Fibrinogen as a Prognostic Factor in Sudden Sensorineural Hearing Loss: A Meta-analysis. AB - OBJECTIVE: High blood viscosity has been proposed as a mechanism for sudden sensorineural hearing loss (SSNHL); however, the relationship between blood markers of fibrinolysis or coagulation and severity or prognosis of SSNHL is still unclear. The aim of this study is to investigate the relationship between serum fibrinogen and SSNHL. DATA SOURCES: PubMed and Scopus were searched for English language articles using the following keywords: SSNHL, sudden hearing loss, sudden deafness, idiopathic hearing loss or idiopathic sensorineural hearing loss, and fibrinogen. STUDY SELECTION: The articles in the study related to SSNHL and provided data about the serum fibrinogen level. DATA EXTRACTION: The data included patient profiles, fibrinogen level, recovery, and treatment modality. DATA SYNTHESIS: Nineteen articles were selected. The aggregated data were analyzed using the random effect model. Two articles that included the fibrinogen level with recovery rates were analyzed for the relationship between the fibrinogen level and recovery. CONCLUSIONS: The average fibrinogen level was 318 +/- 8.5 mg/dl (mean +/- standard error, within normal range). There was no difference in the fibrinogen level between SSNHL patients and the control group. The fibrinogen level of the recovery group was lower than that of the no recovery group. This showed that a high fibrinogen level was associated with poor prognosis, and it could be related to the severity of the pathological change rather than being the cause of the SSNHL. SSNHL includes various pathologies; therefore, the appropriate therapy should be selected based on each condition. PMID- 30303944 TI - Significance of Endolymphatic Hydrops Herniation Into the Semicircular Canals Detected on MRI. AB - OBJECTIVE: The objective of this study was to investigate the relationship between endolymphatic hydrops (EH) and hearing level or vestibular symptoms by focusing on EH herniation into the semicircular canal (SCC). STUDY DESIGN: Retrospective study. SETTING: University hospital. METHODS: The study included 1,548 ears of 775 patients who underwent magnetic resonance imaging (MRI) examination in our university hospital to investigate possible EH. MRI was performed 4 hours after intravenous injection of a standard dose of gadodiamide hydrate and/or 24 hours after intratympanic injection of gadopentetate dimeglumine diluted eightfold. The hearing threshold and vestibular symptoms were compared between ears with unilateral and bilateral EH herniation into the SCC and between ears having vestibular EH adjacent to the stapes footplate with or without EH herniation. RESULTS: Forty-four ears (19 men and 25 women, mean age 53.6 yr) showed EH herniation into the SCC. The average hearing thresholds at 500 to 4000 Hz and presence of vestibular EH adjacent to the stapes footplate were significantly higher in ears with unilateral herniation than in those with bilateral herniation. The average hearing thresholds at 500 and 1000 Hz were significantly higher in the group of ears having adjacency with herniation than in those without herniation. Vestibular symptoms did not differ significantly between groups. CONCLUSION: Unilateral herniation occurs with EH progression. Bilateral herniation may occur regardless of EH progression and might be influenced by other factors that alter the membranous labyrinth. PMID- 30303945 TI - Assessment of Vestibulo-ocular Reflex Gain and Catch-up Saccades During Vestibular Rehabilitation. AB - OBJECTIVE: To assess, in patients referred to vestibular rehabilitation (VR) for persistence of disability after acute unilateral vestibulopathy (AUV), whether the video head impulse test (vHIT) can be a useful technique to define the efficacy of the treatment. STUDY DESIGN: Prospective clinical study. SETTING: Tertiary academic referral hospitals. PATIENTS: Thirty patients with residual symptoms after AUV were included. INTERVENTION: Patients underwent a 10-week VR program. MAIN OUTCOME MEASURES: Evaluation of dizziness handicap inventory score, high-velocity vestibulo-ocular reflex gain, asymmetry index, and catch-up saccade parameters before and after VR. RESULTS: All patients reported a clear clinical improvement after VR, also demonstrated by better dizziness handicap inventory scores (p < 0.001). A consistent increased gain and decreased asymmetry index were also observed (p < 0.001 for both). Patients did not show any change in covert catch-up saccades, while a statistically significant reduction of the number and amplitude of the overt catch-up saccades was interestingly detected (p = 0.009 and p = 0.030, respectively). CONCLUSION: VR is a valid approach for patients with residual disability after AUV. A reduction in number and amplitude of overt catch-up saccades seems useful to evaluate the efficacy of VR and to be related to clinical improvement. PMID- 30303946 TI - The Effect of a Distributed Virtual Reality Simulation Training Program on Dissection Mastoidectomy Performance. AB - OBJECTIVE: To investigate the effect on final-product performance of a distributed, virtual reality (VR) simulation training program on cadaveric dissection performance and learning curves compared with standard VR simulation training during a temporal bone course. STUDY DESIGN: Educational interventional cohort study. SETTING: The national Danish temporal bone courses of 2016 and 2017. SUBJECTS: Postgraduate year 2 to 5 residents in otorhinolaryngology. INTERVENTION: Nine participants volunteered for additional VR simulation training (intervention) before the temporal bone course, with training blocks distributed (i.e., separated). The remaining 28 participants received standard VR simulation training during the temporal bone course (control). MAIN OUTCOME MEASURE: VR simulation and cadaveric dissection final-product performances were analyzed by blinded raters using a 26-item modified Welling Scale. RESULTS: Distributed VR simulation training before the temporal bone course (intervention) significantly increased dissection final-product performance by 25% compared with standard VR simulation training during the course (control) (mean scores 12.8 points versus 10.3 points, p < 0.01). Distributed and repeated VR simulation practice markedly decreased drilling time. Guidance by the simulator-integrated tutor-function significantly increased final-product performance by 2.3 points compared with nontutored procedures but at the cost of increased drilling time. CONCLUSION: Skills acquired in a VR simulation environment translate to cadaveric dissection skills and repeated and distributed VR simulation can be used to further increase performance compared with standard VR simulation training during a temporal bone course. Further dissemination of inexpensive VR simulators would allow all future temporal bone course participants to train locally before attending future centralized courses. PMID- 30303947 TI - Cochlear Implant Insertion Depth Prediction: A Temporal Bone Accuracy Study. AB - HYPOTHESIS: The aim of this study was to present and validate the accuracy of a method to predict the required cochlear implant (CI) electrode array length for a specific angular insertion depth (AID). BACKGROUND: The human cochlea exhibits remarkable interindividual morphological differences. The prediction of the required array length for a specific AID can help to improve the outcome of cochlear implant surgery. METHODS: We estimated the linear insertion depth required for an angular insertion of 540 degrees using computed tomography images of 16 temporal bone specimens (eight Thiel fixed, eight formalin fixed). Free fitting electrode arrays were marked accordingly and inserted through a custom made insertion guide tube. The achieved AIDs were assessed using postoperative micro-computed tomography scans. RESULTS: In the Thiel specimens, the difference between the aimed depth of 540 degrees and achieved insertion depth was small (average 529 degrees, p = 0.076), with a mean prediction error of -11 degrees (maximum 30 degrees), indicating a small underestimation. By contrast, we observed early resistance during the insertions in the formalin specimens (average 409 degrees, p < 0.0001), resulting in a mean error of -131 degrees and bending of the electrode array in the cochlear basal turn in four of eight specimens. CONCLUSION: The equation presented in this study for calculating linear insertion depths can be helpful for the selection of adequate electrode array lengths in a clinical setting. The Thiel conservation is a highly suitable model for cadaveric electrode insertion studies. A free online calculator is available at http://www.hno.insel.ch/de/forschung/ci_estimator/. PMID- 30303948 TI - Human Immunodeficiency Virus Serodiscordance and Dual Contraceptive Method Use Among Human Immunodeficiency Virus-infected Men and Women in Lilongwe, Malawi. AB - BACKGROUND: Some human immunodeficiency virus (HIV) serodiscordant couples are faced with the dual challenge of preventing HIV transmission to the uninfected partner and avoiding unintended pregnancy. Therefore, we hypothesized that serodiscordance is associated with dual method use at last sex. METHODS: We analyzed data from a cross-sectional survey of HIV-infected men and women attending 2 ante-retroviral therapy clinics in Lilongwe, Malawi. We used Fisher exact test and Wilcoxon rank sum to assess for associations between serodiscordance, covariates, and dual method use. Multivariable logistic regression was used to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) of dual method use at last sex, comparing serodiscordant to seroconcordant relationships. Separate analyses were conducted for men and women. RESULTS: We surveyed 253 HIV-infected men, of which 44 (17.4%) were in a known serodiscordant relationship and 63 (24.9%) were using dual methods at last sex. Likewise, among 302 HIV-infected women surveyed, 57 (18.9%) were in a known serodiscordant relationship, and 80 (26.5%) were using dual method at last sex. Serodiscordance was not significantly associated with dual method use at last sex for among HIV-infected men (aOR, 0.62; 95% CI, 0.27-1.44) or women (aOR, 1.21; 95% CI, 0.59-2.47). CONCLUSION: Dual method use was low among all HIV-infected individuals, irrespective of their partner's HIV status. Given these findings, we recommend greater efforts to encourage HIV providers to counsel their patients about the importance of dual method use to prevent both unintended pregnancy and sexually transmitted infections. PMID- 30303949 TI - Sexual Behaviors of Human Immunodeficiency Virus-Infected Pregnant Women and Factors Associated With Sexually Transmitted Infection in South Africa. AB - BACKGROUND: Sexual behaviors in human immunodeficiency virus (HIV)-infected pregnant women in South Africa are not well understood. METHODS: Human immunodeficiency virus-infected pregnant women were recruited into a prospective cohort at first antenatal care visit. Sociodemographic information and self collected vulvovaginal swab samples were collected from participants. Vulvovaginal swab samples were tested for Chlamydia trachomatis, Neisseria gonorrhoea, and Trichomonas vaginalis using GeneXpert. We investigated sexual behaviors, alcohol use, factors associated with condomless sex during pregnancy, and prevalent sexually transmitted infection (STI) among our cohort. We report descriptive, univariate and multivariable logistic regression results of sexual behaviors and alcohol use, factors associated with condomless sex at last sex, and having any STI during pregnancy adjusting for a priori confounders. RESULTS: We recruited and enrolled 430 HIV-infected pregnant women. Median age was 30 years; median gestational age was 20 weeks. Eighty-nine percent of women reported sex during pregnancy. At last sex, 68% reported condomless sex; 18% reported having more than 1 sex partner in the past 12 months. Adjusting for age, income and relationship status, condom use at last sex was associated with prior knowledge of HIV status (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.54-3.92) and being in a concordant HIV-positive (aOR, 3.17; 95% CI, 1.84 5.50), or serodiscordant relationship (aOR, 6.50; 95% CI, 3.59-11.80). The prevalence of any STI was 41% (95% CI, 36%-45%). Adjusting for mothers' age and employment, odds of having an STI increased if the woman reported alcohol use during pregnancy (aOR, 1.96; 95% CI, 1.06-3.64) or if the father of the child was a non-cohabiting or casual partner (aOR, 1.42; 95% CI, 0.97-2.03). CONCLUSIONS: Almost all HIV-infected pregnant women were sexually active during pregnancy and most women reported condomless sex at last sex. Condom use was associated with knowledge of serostatus and/or partner's serostatus before first antenatal care visit. Factors associated with having STIs included: alcohol use during pregnancy and father of child being a non-cohabiting partner. PMID- 30303950 TI - Ultrasound-Guided versus Thoracoscopic Pleural Biopsy for Diagnosing Tuberculous Pleurisy Following Inconclusive Thoracentesis: A Randomized, Controlled Trial. AB - BACKGROUND Traditional diagnostic methods for tuberculosis (TB) cannot be reliably applied to tuberculous pleurisy. Therefore, this prospective, randomized, controlled trial was performed to compare the diagnostic sensitivity and safety of ultrasound-guided cutting-needle pleural biopsy versus thoracoscopic pleural biopsy in patients suspected of tuberculous pleurisy following inconclusive thoracentesis. MATERIAL AND METHODS A total of 196 adult patients with acid-fast bacillus (AFB)-negative exudative pleural effusions clinically suspected of tuberculous pleurisy were recruited. Enrollees were randomized into 2 cohorts: ultrasound-guided cutting-needle pleural biopsy (n=96) or thoracoscopic pleural biopsy (n=96). The overall diagnostic yields, diagnostic sensitivities for tuberculous pleurisy, and post-procedural complications for both cohorts were statistically compared. RESULTS Ultrasound-guided pleural biopsy displayed an overall diagnostic yield of 83%, while thorascopic pleural biopsy displayed a similar overall diagnostic yield of 86% (chi2=1.88, df=1, p=0.17). There were 127 patients conclusively diagnosed with tuberculous pleurisy, resulting in a tuberculous pleurisy prevalence of 65% in this patient population (66% in the ultrasound cohort vs. 63% in the thoracoscopy cohort; p>0.05). Ultrasound-guided pleural biopsy displayed a sensitivity of 82% in detecting tuberculous pleurisy, while thorascopic pleural biopsy displayed a similar sensitivity of 90% (chi2=1.05, df=1, p=0.30). The sensitivities of these 2 modalities did not significantly differ based on the degree of pleural thickening (p>0.05). Post-procedural complications were minor. CONCLUSIONS Ultrasound-guided and thoracoscopic pleural biopsy both display strong (>80%) but statistically similar overall diagnostic yields for diagnosing pleural effusions following inconclusive thoracentesis. Both modalities also display strong (>80%) but statistically similar sensitivities in detecting tuberculous pleurisy. PMID- 30303951 TI - Rotation of sex combs in Drosophila melanogaster requires precise and coordinated spatio-temporal dynamics from forces generated by epithelial cells. AB - The morphogenesis of sex combs (SCs), a male trait in many species of fruit flies, is an excellent system in which to study the cell biology, genetics and evolution of a trait. In Drosophila melanogaster, where the incipient SC rotates from horizontal to a vertical position, three signal comb properties have been documented: length, final angle and shape (linearity). During SC rotation, in which many cellular processes are occurring both spatially and temporally, it is difficult to distinguish which processes are crucial for which attributes of the comb. We have used a novel approach combining simulations and experiments to uncover the spatio-temporal dynamics underlying SC rotation. Our results indicate that 1) the final SC shape is primarily controlled by the inhomogeneity of initial cell size in cells close to the immature comb, 2) the final angle is primarily controlled by later cell expansion and 3) a temporal sequence of cell expansion mitigates the malformations generally associated with longer rotated SCs. Overall, our work has linked together the morphological diversity of SCs and the cellular dynamics behind such diversity, thus providing important insights on how evolution may affect SC development via the behaviours of surrounding epithelial cells. PMID- 30303952 TI - Modeling effects of voltage dependent properties of the cardiac muscarinic receptor on human sinus node function. AB - The cardiac muscarinic receptor (M2R) regulates heart rate, in part, by modulating the acetylcholine (ACh) activated K+ current IK,ACh through dissociation of G-proteins, that in turn activate KACh channels. Recently, M2Rs were noted to exhibit intrinsic voltage sensitivity, i.e. their affinity for ligands varies in a voltage dependent manner. The voltage sensitivity of M2R implies that the affinity for ACh (and thus the ACh effect) varies throughout the time course of a cardiac electrical cycle. The aim of this study was to investigate the contribution of M2R voltage sensitivity to the rate and shape of the human sinus node action potentials in physiological and pathophysiological conditions. We developed a Markovian model of the IK,ACh modulation by voltage and integrated it into a computational model of human sinus node. We performed simulations with the integrated model varying ACh concentration and voltage sensitivity. Low ACh exerted a larger effect on IK,ACh at hyperpolarized versus depolarized membrane voltages. This led to a slowing of the pacemaker rate due to an attenuated slope of phase 4 depolarization with only marginal effect on action potential duration and amplitude. We also simulated the theoretical effects of genetic variants that alter the voltage sensitivity of M2R. Modest negative shifts in voltage sensitivity, predicted to increase the affinity of the receptor for ACh, slowed the rate of phase 4 depolarization and slowed heart rate, while modest positive shifts increased heart rate. These simulations support our hypothesis that altered M2R voltage sensitivity contributes to disease and provide a novel mechanistic foundation to study clinical disorders such as atrial fibrillation and inappropriate sinus tachycardia. PMID- 30303953 TI - Rice transcription factor OsMADS25 modulates root growth and confers salinity tolerance via the ABA-mediated regulatory pathway and ROS scavenging. AB - Plant roots are constantly exposed to a variety of abiotic stresses, and high salinity is one of the major limiting conditions that impose constraints on plant growth. In this study, we describe that OsMADS25 is required for the root growth as well as salinity tolerance, via maintaining ROS homeostasis in rice (Oryza sativa). Overexpression of OsMADS25 remarkably enhanced the primary root (PR) length and lateral root (LR) density, whereas RNAi silence of this gene reduced PR elongation significantly, with altered ROS accumulation in the root tip. Transcriptional activation assays indicated that OsMADS25 activates OsGST4 (glutathione S-transferase) expression directly by binding to its promoter. Meanwhile, osgst4 mutant exhibited repressed growth and high sensitivity to salinity and oxidative stress, and recombinant OsGST4 protein was found to have ROS-scavenging activity in vitro. Expectedly, overexpression of OsMADS25 significantly enhanced the tolerance to salinity and oxidative stress in rice plants, with the elevated activity of antioxidant enzymes, increased accumulation of osmoprotective solute proline and reduced frequency of open stoma. Furthermore, OsMADS25 specifically activated the transcription of OsP5CR, a key component of proline biosynthesis, by binding to its promoter. Interestingly, overexpression of OsMADS25 raised the root sensitivity to exogenous ABA, and the expression of ABA-dependent stress-responsive genes was elevated greatly in overexpression plants under salinity stress. In addition, OsMADS25 seemed to promote auxin signaling by activating OsYUC4 transcription. Taken together, our findings reveal that OsMADS25 might be an important transcriptional regulator that regulates the root growth and confers salinity tolerance in rice via the ABA mediated regulatory pathway and ROS scavenging. PMID- 30303954 TI - Interaction of the Warsaw breakage syndrome DNA helicase DDX11 with the replication fork-protection factor Timeless promotes sister chromatid cohesion. AB - Establishment of sister chromatid cohesion is coupled to DNA replication, but the underlying molecular mechanisms are incompletely understood. DDX11 (also named ChlR1) is a super-family 2 Fe-S cluster-containing DNA helicase implicated in Warsaw breakage syndrome (WABS). Herein, we examined the role of DDX11 in cohesion establishment in human cells. We demonstrated that DDX11 interacts with Timeless, a component of the replication fork-protection complex, through a conserved peptide motif. The DDX11-Timeless interaction is critical for sister chromatid cohesion in interphase and mitosis. Immunofluorescence studies further revealed that cohesin association with chromatin requires DDX11. Finally, we demonstrated that DDX11 localises at nascent DNA by SIRF analysis. Moreover, we found that DDX11 promotes cohesin binding to the DNA replication forks in concert with Timeless and that recombinant purified cohesin interacts with DDX11 in vitro. Collectively, our results establish a critical role for the DDX11-Timeless interaction in coordinating DNA replication with sister chromatid cohesion, and have important implications for understanding the molecular basis of WABS. PMID- 30303955 TI - Transcriptomic and functional analyses of the piRNA pathway in the Chagas disease vector Rhodnius prolixus. AB - The piRNA pathway is a surveillance system that guarantees oogenesis and adult fertility in a range of animal species. The pathway is centered on PIWI clade Argonaute proteins and the associated small non-coding RNAs termed piRNAs. In this study, we set to investigate the evolutionary conservation of the piRNA pathway in the hemimetabolous insect Rhodnius prolixus. Our transcriptome profiling reveals that core components of the pathway are expressed during previtellogenic stages of oogenesis. Rhodnius' genome harbors four putative piwi orthologs. We show that Rp-piwi2, Rp-piwi3 and Rp-ago3, but not Rp-piwi1 transcripts are produced in the germline tissues and maternally deposited in the mature eggs. Consistent with a role in Rhodnius oogenesis, parental RNAi against the Rp-piwi2, Rp-piwi3 and Rp-ago3 results in severe egg laying and female adult fertility defects. Furthermore, we show that the reduction of the Rp-piwi2 levels by parental RNAi disrupts oogenesis by causing a dramatic loss of trophocytes, egg chamber degeneration and oogenesis arrest. Intriguingly, the putative Rp Piwi2 protein features a polyglutamine tract at its N-terminal region, which is conserved in PIWI proteins encoded in the genome of other Triatomine species. Together with R. prolixus, these hematophagous insects are primary vectors of the Chagas disease. Thus, our data shed more light on the evolution of the piRNA pathway and provide a framework for the development of new control strategies for Chagas disease insect vectors. PMID- 30303956 TI - Trauma exposure and IPV experienced by Afghan women: Analysis of the baseline of a randomised controlled trial. AB - BACKGROUND: Four decades of conflict has indelibly impacted the lives of Afghans, exposing many to different forms of trauma. The aim of this paper investigate a hypothesis that (mostly war related) trauma is a key driver of partner violence in Afghanistan. METHODS: 1,463 women aged 18-48 were recruited into a randomised controlled trial (RCT) to evaluate a women empowerment intervention in 8 villages of Kabul and Nangarhar provinces. The women were interviewed at baseline. The analysis uses multivariable logistic regression and structural equation modelling (SEM) to describe relationships between measures. RESULTS: 57.4% of women reported exposure to one of four types of trauma: 23.3% an armed attack, 39.4% had felt close to death, 10.6% witnessed a friend or family member being killed and 21.4% witnessed the death of a stranger or someone unknown. Trauma exposure was associated with being older, Pashtan, madrassa educated, and food insecure. Women who were trauma exposed were more likely to have ever experienced IPV, have hit their children in the last 4 weeks, and be hit by a sibling or relative of their husband or their mother-in-law in the last year. They held less patriarchal personal gender attitudes and perceived the community to be more patriarchal. The SEM showed that all pathways between trauma exposure and IPV were ultimately mediated by either (mostly mental) ill-health or quarrelling, but not both of these. There were multiple paths through which trauma exposure impacted women's past year experience of physical IPV. One was mediated by childhood trauma exposure and a latent variable for ill health. Other paths were mediated by women's education and personal gender attitudes and ill-health, or else by quarrelling. Trauma exposure was related to lower educational levels. Another path was mediated by less patriarchal personal gender attitudes and ill health. Community gender attitudes was a mediating variable on a path which was also mediated by ill health and another mediated by quarrelling. It was also a mediator on a path which included personal gender attitudes and ill-health. Food insecurity mediated another path with ill health. It was also connected to childhood trauma, community gender attitudes and educational level. CONCLUSION: Trauma exposure due to conflict will persist until the conflict ends but the impact on women can be ameliorated. This analysis suggests interventions to reduce women's exposure to IPV should focus on reducing poverty, changing social norms on gender, providing relationship skills to help reduce quarrelling and supporting women's mental health. PMID- 30303957 TI - Robust cell particle detection to dense regions and subjective training samples based on prediction of particle center using convolutional neural network. AB - In recent years, finding the cause of pathogenesis is expected by observing the cell images. In this paper, we propose a cell particle detection method in cell images. However, there are mainly two kinds of problems in particle detection in cell image. The first is the different properties between cell images and standard images used in computer vision researches. Edges of cell particles are ambiguous, and overlaps between cell particles are often occurred in dense regions. It is difficult to detect cell particles by simple detection method using a binary classifier. The second is the ground truth made by cell biologists. The number of training samples for training a classifier is limited, and incorrect samples are included by the subjectivity of observers. From the background, we propose a cell particle detection method to address those problems. In our proposed method, we predict the center of a cell particle from the peripheral regions by convolutional neural network, and the prediction results are voted. By using the obvious peripheral edges, we can robustly detect overlapped cell particles because all edges of overlapping cell particles are not ambiguous. In addition, voting from peripheral views enables reliable detection. Moreover, our method is useful in practical applications because we can prepare many training samples from a cell particle. In experiments, we evaluate our detection methods on two kinds of cell detection datasets. One is challenging dataset for synthetic cells, and our method achieved the state-of-the-art performance. The other is real dataset of lipid droplets, and our method outperformed the conventional detector using CNN with binary outputs for particles and non-particles classification. PMID- 30303958 TI - Novel RNA aptamers targeting gastrointestinal cancer biomarkers CEA, CA50 and CA72-4 with superior affinity and specificity. AB - Gastric cancer is the third most common cause of death from cancer in the world and it remains difficult to cure in Western countries, primarily because most patients present with advanced disease. Currently, CEA, CA50 and CA72-4 are commonly used as tumor markers for gastric cancer by immunoassays. However, the drawback and conundrum of immunoassay are the unceasing problem in standardization of quality of antibodies and time/effort for the intensive production. Therefore, there is an urgent need for the development of a standardized assay to detect gastric cancer at the early stage. Aptamers are DNA or RNA oligonucleotides with structural domain which recognize ligands such as proteins with superior affinity and specificity when compared to antibodies. In this study, SELEX (Systematic Evolution of Ligands by Exponential enrichment) technique was adopted to screen a random 30mer RNA library for aptamers targeting CEA, CA50 and CA72-4 respectively. Combined with high-throughput sequencing, we identified 6 aptamers which specifically target for these three biomarkers of gastrointestinal cancer. Intriguingly, the predicted secondary structures of RNA aptamers from each antigen showed significant structural similarity, suggesting the structural recognition between the aptamers and the antigens. Moreover, we determined the dissociation constants of all the aptamers to their corresponding antigens by fluorescence spectroscopy, which further demonstrated high affinities between the aptamers and the antigens. In addition, immunostaining of gastric adenocarcinoma cell line AGS using CEA Aptamer probe showed positive fluorescent signal which proves the potential of the aptamer as a detection tool for gastric cancer. Furthermore, substantially decreased cell viability and growth were observed when human colorectal cell line LS-174T was transfected with each individual aptamers. Taking together, these novel RNA aptamers targeting gastrointestinal cancer biomarker CEA, CA50 and CA72-4 will aid further development and standardization of clinical diagnostic method with better sensitivity and specificity, and potentially future therapeutics development of gastric cancer. PMID- 30303959 TI - An EST-SSR based genetic linkage map and identification of QTLs for anthracnose disease resistance in water yam (Dioscorea alata L.). AB - Water yam (Dioscorea alata L.) is one of the most important food yams with wide geographical distribution in the tropics. One of the major constraints to water yam production is anthracnose disease caused by a fungus, Colletotrichum gloeosporioides (Penz.). There are no economically feasible solutions as chemical sprays or cultural practices, such as crop rotation are seldom convenient for smallholder farmers for sustainable control of the disease. Breeding for development of durable genetic resistant varieties is known to offer lasting solution to control endemic disease threats to crop production. However, breeding for resistance to anthracnose has been slow considering the biological constraints related to the heterozygous and vegetative propagation of the crop. The development of saturated linkage maps with high marker density, such as SSRs, followed by identification of QTLs can accelerate the speed and precision of resistance breeding in water yam. In a previous study, a total of 1,152 EST-SSRs were developed from >40,000 EST-sequences generated from two D. alata genotypes. A set of 380 EST-SSRs were validated as polymorphic when tested on two diverse parents targeted for anthracnose disease and were used to generate a saturated linkage map. Majority of the SSRs (60.2%) showed Mendelian segregation pattern and had no effect on the construction of linkage map. All 380 EST-SSRs were mapped into 20 linkage groups, and covered a total length of 3229.5 cM. Majority of the markers were mapped on linkage group 1 (LG 1) comprising of 97 EST-SSRs. This is the first genetic linkage map of water yam constructed using EST-SSRs. QTL localization was based on phenotypic data collected over a 3-year period of inoculating the mapping population with the most virulent strain of C. gloeosporioides from West Africa. Based on threshold LOD scores, one QTL was consistently observed on LG 14 in all the three years and average score data. This QTL was found at position interval of 71.1-84.8 cM explaining 68.5% of the total phenotypic variation in the average score data. The high marker density allowed identification of QTLs and association for anthracnose disease, which could be validated in other mapping populations and used in marker-assisted breeding in D. alata improvement programmes. PMID- 30303961 TI - CASS: A distributed network clustering algorithm based on structure similarity for large-scale network. AB - As the size of networks increases, it is becoming important to analyze large scale network data. A network clustering algorithm is useful for analysis of network data. Conventional network clustering algorithms in a single machine environment rather than a parallel machine environment are actively being researched. However, these algorithms cannot analyze large-scale network data because of memory size issues. As a solution, we propose a network clustering algorithm for large-scale network data analysis using Apache Spark by changing the paradigm of the conventional clustering algorithm to improve its efficiency in the Apache Spark environment. We also apply optimization approaches such as Bloom filter and shuffle selection to reduce memory usage and execution time. By evaluating our proposed algorithm based on an average normalized cut, we confirmed that the algorithm can analyze diverse large-scale network datasets such as biological, co-authorship, internet topology and social networks. Experimental results show that the proposed algorithm can develop more accurate clusters than comparative algorithms with less memory usage. Furthermore, we confirm the proposed optimization approaches and the scalability of the proposed algorithm. In addition, we validate that clusters found from the proposed algorithm can represent biologically meaningful functions. PMID- 30303960 TI - Adults who stutter lack the specialised pre-speech facilitation found in non stutterers. AB - OBJECTIVES: Persistent developmental stuttering is a speech fluency disorder defined by its symptoms, where the underlying neurophysiological causes remain uncertain. This study examined the underlying neurophysiological mechanisms of the speech planning process, using facilitation in the motor cortex during speech preparation as an analogue. METHODS: transcranial magnetic stimulation (TMS) pulses induced motor evoked potentials (MEPs), which were recorded from the tongue. Eighteen adults who stutter (AWS) and 17 adults who do not stutter (ANS) completed three experiments, which involved reading a German prefix+verb utterance from a screen. Each experiment involved 120 trials with three distinct levels of speech production: immediate speech, delayed speech without pacing and delayed speech with predefined pacing. TMS was applied shortly before speech onset. Trial MEPs were normalised to average non-speech MEPs. MEP amplitude, MEP facilitation ratio (amplitude: pre-speech offset) and group difference were the outcomes of interest analysed by multiple regression, as well as speech reaction time analysed by correlation. RESULTS: MEP values were 11.1%-23.4% lower in AWS than ANS (by standardised Beta), across all three experiments. MEP facilitation ratio slopes were also 4.9%-18.3% flatter in AWS than ANS across all three experiments. Reaction times for AWS were only significantly slower than for ANS in immediate speech and predefined pacing experiments. No stuttering was detected during the trials. The group difference in immediate speech was 100% and 101% greater than the other two experiments respectively. DISCUSSION: While performance of both ANS and AWS worsens under disturbed speech conditions, greater disturbance conditions affected controls worse than AWS. Future research and therapy in stuttering should focus on non-disturbed speech. PMID- 30303962 TI - CFSH: Factorizing sequential and historical purchase data for basket recommendation. AB - To predict what products customers will buy in next transaction is an important task. Existing work in next-basket prediction can be summarized into two paradigms. One is the item-centric paradigm, where sequential patterns are mined from customers' transactional data and leveraged for prediction. However, these approaches usually suffer from the data sparseness problem. The other is the user centric paradigm, where collaborative filtering techniques have been applied on customers' historical data. However, these methods ignore the sequential behaviors of customers which is often crucial for next-basket prediction. In this paper, we introduce a hybrid method, namely the Co-Factorization model over Sequential and Historical purchase data (CFSH for short) for next-basket recommendation. Compared with existing methods, our approach conveys the following merits: 1) By mining global sequential patterns, we can avoid the sparseness problem in traditional item-centric methods; 2) By factorizing product product and customer-product matrices simultaneously, we can fully exploit both sequential and historical behaviors to learn customer and product representations better; 3) By using a hybrid recommendation method, we can achieve better performance in next-basket prediction. Experimental results on three real-world purchase datasets demonstrated the effectiveness of our approach as compared with the state-of-the-art methods. PMID- 30303963 TI - Re-evaluating the occupation history of Koh Ker, Cambodia, during the Angkor period: A palaeo-ecological approach. AB - Throughout the Angkor period (9th to 15th centuries CE), the Khmer kingdom maintained a series of interconnected cities and smaller settlements across its territory on mainland Southeast Asia. One such city was Koh Ker, which for a brief period in the 10th century CE even served as a royal capital. The complexity of the political landscape meant the Khmer kings and the elite were particularly mobile through the Angkor period, and rupture in royal houses was common. However, while the historical record chronicles the 10th century migration of the royal seat from Koh Ker back to Angkor, the fate of Koh Ker's domestic population has remained unknown. In this article, we reconstruct the settlement history of Koh Ker, using palaeoecological and geoarchaeological techniques, and show that human activity and land use persisted in the city for several centuries beyond the city's abandonment by the royal court. These results highlight the utility of multi-proxy environmental reconstructions of Khmer urban settlements for re-evaluating prevailing assumptions regarding the use and occupation of Angkor-period cities. PMID- 30303964 TI - The modular network structure of the mutational landscape of Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways. PMID- 30303965 TI - Atomic force microscopy reveals new biophysical markers for monitoring subcellular changes in oxidative injury: Neuroprotective effects of quercetin at the nanoscale. AB - Oxidative stress has been recognised as an important pathological mechanism underlying the development of neurodegenerative diseases. The biomarkers for assessing the degree of oxidative stress have been attracting much interest because of their potential clinical relevance in understanding the cellular effects of free radicals and evaluation of the efficacy of drug treatment. Here, an interdisciplinary approach using atomic force microscopy (AFM) and cellular and biological molecular methods were used to investigate oxidative damage in P19 neurons and to reveal the underlying mechanism of protective action of quercetin. Biological methods demonstrated the oxidative damage of P19 neurons and showed that quercetin improved neuronal survival by preventing H2O2-induced p53 and Bcl 2 down-regulation and modulated Akt and ERK1/2 signalling pathways. For the first time, AFM was employed to evaluate morphologically (roughness, height, Feret dimension) and nanomechanical (elasticity) properties in H2O2-induced neuronal damage. The AFM analysis revealed that quercetin suppressed H2O2-provoked changes in cell membrane elasticity and morphological properties, thus confirming its neuroprotective activity. The obtained results indicate the potential of AFM measured parameters as a biophysical markers of oxidative stress-induced neurodegeneration. In general, our study suggests that AFM can be used as a highly valuable tool in other biomedical applications aimed at screening and monitoring of drug-induced effects at cellular level. PMID- 30303966 TI - Efficacy of behavioral classroom programs in primary school. A meta-analysis focusing on randomized controlled trials. AB - OBJECTIVE: This meta-analysis evaluated the efficacy of behavioral classroom programs on symptoms of Attention-deficit Hyperactivity Disorder or Oppositional Defiant and/or Conduct Disorder in primary school children. METHOD: Online database searches (in PubMed, Embase, Psycinfo, and Eric) yielded nineteen randomized controlled trials (N = 18,094), comparing behavioral classroom programs (including multimodal programs involving a classroom program) to no treatment/treatment as usual. Random-effects meta-analyses were conducted for teacher-rated and classroom-observed disruptive classroom behavior and for classroom-observed on-task behavior. Post-hoc analyses investigated whether effects depended on type and severity of problem behavior. Meta-regressions studied the moderating effects of age, gender, and intervention duration. RESULTS: Small positive effects were found on teacher-rated disruptive behavior (d = -0.20) and classroom-observed on-task behavior (d = 0.39). Program effects on teacher-rated disruptive behavior were unrelated to age, gender, type and severity, but negatively associated with intervention duration (R2 = 0.43). CONCLUSION: Behavioral classroom programs have small beneficial effects on disruptive behavior and on-task behavior. Results advocate universal programs for entire classrooms to prevent and reduce disruptive classroom behavior. PMID- 30303967 TI - Complete genome sequences of two strains of Treponema pallidum subsp. pertenue from Indonesia: Modular structure of several treponemal genes. AB - BACKGROUND: Treponema pallidum subsp. pertenue (TPE) is the causative agent of yaws, a multistage disease endemic in tropical regions in Africa, Asia, Oceania, and South America. To date, seven TPE strains have been completely sequenced and analyzed including five TPE strains of human origin (CDC-2, CDC 2575, Gauthier, Ghana-051, and Samoa D) and two TPE strains isolated from the baboons (Fribourg Blanc and LMNP-1). This study revealed the complete genome sequences of two TPE strains, Kampung Dalan K363 and Sei Geringging K403, isolated in 1990 from villages in the Pariaman region of Sumatra, Indonesia and compared these genome sequences with other known TPE genomes. METHODOLOGY/PRINCIPAL FINDINGS: The genomes were determined using the pooled segment genome sequencing method combined with the Illumina sequencing platform resulting in an average coverage depth of 1,021x and 644x for the TPE Kampung Dalan K363 and TPE Sei Geringging K403 genomes, respectively. Both Indonesian TPE strains were genetically related to each other and were more distantly related to other, previously characterized TPE strains. The modular character of several genes, including TP0136 and TP0858 gene orthologs, was identified by analysis of the corresponding sequences. To systematically detect genes potentially having a modular genetic structure, we performed a whole genome analysis-of-occurrence of direct or inverted repeats of 17 or more nucleotides in length. Besides in tpr genes, a frequent presence of repeats was found in the genetic regions spanning TP0126-TP0136, TP0856-TP0858, and TP0896 genes. CONCLUSIONS/SIGNIFICANCE: Comparisons of genome sequences of TPE Kampung Dalan K363 and Sei Geringging K403 with other TPE strains revealed a modular structure of several genomic loci including the TP0136, TP0856, and TP0858 genes. Diversification of TPE genomes appears to be facilitated by intra strain genome recombination events. PMID- 30303969 TI - Highly efficient degradation of pharmaceutical sludge by catalytic wet oxidation using CuO-CeO2/gamma-Al2O3 as a catalyst. AB - Pharmaceutical sludge is considered as a hazardous material with high treatment and disposal costs. In the present study, the catalytic wet oxidation (CWO) of pharmaceutical sludge by CuO-CeO2/gamma-Al2O3 as the catalyst was investigated. The catalyst was prepared by traditional wet impregnation. The catalyst was characterized using X-ray Powder Diffraction (XRD) and Scanning Electron Microscopy (SEM). CWO was performed in an experimental batch reactor. Several parameters that could affect the catalytic degradation efficiency, including catalyst dose, temperature, time, oxygen pressure and pH, were investigated. Under optimum conditions, the highest removal rate of volatile suspended solids (VSS) was 87.3% and was achieved at 260 degrees C for 60 min with an oxygen pressure of 1.0 MPa and 10 g/L of catalyst. At the same time, the chemical oxygen demand (COD) removal rate reached as high as 72.6%. This work implies that catalytic wet oxidation is a promising method for the highly efficient degradation of pharmaceutical sludge. PMID- 30303970 TI - Home range size, vegetation density, and season influences prey use by coyotes (Canis latrans). AB - To ensure reproductive success, Canis species establish contiguous mosaics of territories in suitable habitats to partition space and defend limiting resources. Consequently, Canis species can exert strong effects on prey populations locally because of their year-round maintenance of territories. We assessed prey use by coyotes (Canis latrans) by sampling scats from within known territories in southeastern Alabama and the Savannah River area of Georgia and South Carolina. We accounted for the size and habitat composition of coyote home ranges to investigate the influence of space use, vegetation density, and habitat type on coyote diets. Coyote use of prey was influenced by a combination of mean monthly temperature, home range size, vegetation density, and hardwood forests. For example, coyote use of adult white-tailed deer (Odocoileus virginianus) was associated with cooler months and smaller home ranges, whereas use of rabbits (Sylvilagus spp.) was associated with cooler months, larger home ranges, and less vegetation density. Coyotes in our study relied primarily on nutritionally superior mammalian prey and supplemented their diet with fruit when available, as their use of mammalian prey did not appreciably decrease with increasing use of fruit. We suggest that differential use of prey by coyotes is influenced by habitat heterogeneity within their home ranges, and prey-switching behaviors may stabilize local interactions between coyotes and their food resources to permit stable year-round territories. Given that habitat composition affects coyote prey use, future studies should also incorporate effects of habitat composition on coyote distribution and abundance to further identify coyote influences on prey communities. PMID- 30303971 TI - Nature as a living presence: Drawings by Tupinamba and New York Children. AB - Child-nature interaction has undergone drastic changes in modern history, from a free outdoor childhood to a confined daily life connected to electronic devices, with negative consequences to development and well-being. Any resulting lack of connection to the natural environment can hamper involvement in solving environmental problems. This research attempted to assess children's perceptions of nature, as well as their feelings and values. Six- to 14-year-old children from the Tupinamba group (n = 91), an indigenous society in Brazil, and from New York (n = 54) drew pictures of nature and answered five questions about their drawings, feelings, and values in regard to natural environments. Quantitative (descriptive) and qualitative (content) analyses of the drawings were carried out, and their liveness and animism were estimated. The answers given by children to the questions about nature were organized into emerging categories from the data. The Tupinamba children's drawings were generally livelier than those of the New York children. However, the difference failed to reach statistical significance among the younger children, and the difference only approached significance among the older children. The drawings of the Tupinamba contained more animism, depicting non-humans and non-animals with facial expressions, than those of the New Yorkers. Compared with the New Yorkers, the Tupinamba children more often included human constructions such as roads and houses in their drawings. The indigenous children more often saw human and non-human elements as integrated compared with the nonindigenous children. The study reinforces theoretical tendencies about the environmental perception of children in relation to the natural environment and highlights peculiarities of the participating groups, indicating relevant questions for future investigations. PMID- 30303968 TI - Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. AB - BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63 0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D. PMID- 30303972 TI - Brain gray and white matter abnormalities in preterm-born adolescents: A meta analysis of voxel-based morphometry studies. AB - INTRODUCTION: Studies using voxel-based morphometry report variable and inconsistent abnormalities of gray matter volume (GMV) and white matter volume (WMV) in brains of preterm-born adolescents (PBA). In such circumstances a meta analysis can help identify the most prominent and consistent abnormalities. METHOD: We identified 9 eligible studies by systematic search of the literature up to October 2017. We used Seed-based d Mapping to analyze GMV and WMV alterations between PBA and healthy controls. RESULTS: In the GMV meta-analysis, PBA compared to healthy controls showed: increased GMV in left cuneus cortex, left superior frontal gyrus, and right anterior cingulate cortex; decreased GMV in bilateral inferior temporal gyrus (ITG), left superior frontal gyrus, and right caudate nucleus. In the WMV meta-analysis, PBA showed: increased WMV in right fusiform gyrus and precuneus; decreased WMV in bilateral ITG, and right inferior frontal gyrus. In meta-regression analysis, the percentage of male PBA negatively correlated with decreased GMV of bilateral ITG. INTERPRETATION: PBA show widespread GMV and WMV alterations in the default mode network, visual recognition network, and salience network. These changes may be causally relevant to socialization difficulties and cognitive impairments. The meta-regression results perhaps reveal the structural underpinning of the cognition-related sex differences in PBA. PMID- 30303973 TI - Effects of ten weeks dynamic or isometric core training on climbing performance among highly trained climbers. AB - This is the first study to compare the effects of isometric vs. dynamic core training and characterize core-training adaptations using climbing-specific performance and core strength tests in elite climbers. The aim of the study was to compare the effects of attending a progressive core-training program on climbing performance. 19 advanced and elite climbers (7.3+/-5.6 years climbing experience, red point skill grade 19 IRCRA) were randomized into a dynamic (DCT) or isometric (ICT) core training group and trained twice weekly for ten weeks. The climbers were tested using two climbing-specific core tests (body lock-off and body-lift) and four non-specific core strength tests-one dynamic (superman) and three isometric (trunk flexion and trunk rotation left and right). Between group comparisons showed no differences between the groups at post-test (p = 0.328-0.824) and neither group demonstrated greater improvement compared with the other (p = 0.300-0.926). The ICT group demonstrated 10.8% and 29.6% improvement in trunk flexion and body-lift (p = 0.029-0.037 with no improvement in body lock off and rotation (p = 0.101-0.343). The DCT group demonstrated 5.0-14.9% improvement in the core strength tests (p = 0.012-0.043), a non-significant 33.8% improvement in body-lift (p = 0.100) and no improvement in body lock-off (p = 0.943). In conclusion, none of the training groups demonstrated greater improvement than the other and both dynamic and isometric core training improved climbing-specific test performance. Dynamic training was slightly more favorable although not significantly superior to isometric core training in improving core strength. PMID- 30303974 TI - Mixed partisan households and electoral participation in the United States. AB - Research suggests that partisans are increasingly avoiding members of the other party-in their choice of neighborhood, social network, even their spouse. Leveraging a national database of voter registration records, we analyze 18 million households in the U.S. We find that three in ten married couples have mismatched party affiliations. We observe the relationship between inter-party marriage and gender, age, and geography. We discuss how the findings bear on key questions of political behavior in the US. Then, we test whether mixed-partisan couples participate less actively in politics. We find that voter turnout is correlated with the party of one's spouse. A partisan who is married to a co partisan is more likely to vote. This phenomenon is especially pronounced for partisans in closed primaries, elections in which non-partisan registered spouses are ineligible to participate. PMID- 30303975 TI - Nest boxes increase reproductive output for Tree Swallows in a forest grassland matrix in central British Columbia. AB - Secondary cavity-nesting birds depend on tree cavities for nesting and roosting, but many studies of these birds are conducted using nest boxes. Implementation of effective conservation strategies for cavity-nesting species such as nest-site supplementation requires careful comparisons of fecundity and other vital rates for birds using both natural and artificial nest site types. We compared breeding phenology, clutch and brood sizes, and fledging success of Tree Swallows (Tachycineta bicolor) nesting in tree cavities and nest boxes during 2001-2003 in British Columbia, Canada. Swallows using nest boxes initiated egg-laying and hatched young at approximately the same time as those in tree cavities (2 June, 23 June, respectively). Female Tree Swallows in boxes laid larger clutches (5.9 +/- 0.9 eggs, N = 76) than those in tree cavities (4.2 +/- 1.6 eggs, N = 67). The mean number of nestlings hatched was greater in nest boxes (5.2 +/- 1.1 nestlings, N = 67) than in tree cavities (2.6 +/- 2.0 nestlings, N = 58). Pairs in boxes were over twice as successful in producing fledglings (93.4%; 57 of 61 pairs fledged > 1 young) than those in tree cavities (35.8%; 19 of 53 pairs). Of those successful nests, pairs nesting in boxes fledged 5.1 +/- 1.1 young (N = 57), whereas those in tree cavities fledged 3.5 +/- 1.2 young (N = 18). Because cavities in nest boxes averaged 60% larger in volume and 1.8 cm wider internally than tree cavities, we suggest that increased reproductive output was correlated with boxes enabling a larger clutch size. In previous research, we found that Tree Swallows were a poor competitor with other cavity-nesting passerines for tree cavities. The addition of nest boxes may serve as an effective way to supplement local reproduction for secondary cavity-nesting bird populations by reducing competition for limited nest sites. This is especially true in regions where the availability of natural nesting sites is highly variable, and where species compete with many other cavity-nesting passerines using a similar ecological niche and nesting cavities. PMID- 30303976 TI - Dynasore protects the ocular surface against damaging oxidative stress. AB - Water soluble "vital" dyes are commonly used clinically to evaluate health of the ocular surface; however, staining mechanisms remain poorly understood. Recent evidence suggests that sublethal damage stimulates vital dye uptake by individual living cells. Since cell damage can also stimulate reparative plasma membrane remodeling, we hypothesized that dye uptake occurs via endocytic vesicles. In support of this idea, we show here that application of oxidative stress to relatively undifferentiated monolayer cultures of human corneal epithelial cells stimulates both dye uptake and endocytosis, and that dye uptake is blocked by co treatment with three different endocytosis inhibitors. Stress application to stratified and differentiated corneal epithelial cell cultures, which are a better model of the ocular surface, also stimulated dye uptake; however, endocytosis was not stimulated, and two of the endocytosis inhibitors did not block dye uptake. The exception was Dynasore and its more potent analogue Dyngo 4a, both small molecules developed to target dynamin family GTPases, but also having off-target effects on the plasma membrane. Significantly, while Dynasore blocked stress-stimulated dye uptake at the ocular surface of ex vivo mouse eyes when treatment was performed at the same time as eyes were stressed, it had no effect when used after stress was applied and the ocular surface was already damaged. Thus, Dynasore could not be working by inhibiting endocytosis. Employing cytotoxicity and western blotting assays, we went on to demonstrate an alternative mechanism. We show that Dynasore is remarkably protective of cells and their surface glycocalyx, preventing damage due to stress, and thus precluding dye entry. These unexpected and novel findings provide greater insight into the mechanisms of vital dye uptake and point the direction for future study. Significantly, they also suggest that Dynasore and its analogues might be used therapeutically to protect the ocular surface and to treat ocular surface disease. PMID- 30303977 TI - Identification of hospital cost drivers using sparse group lasso. AB - Public hospital spending consumes a large share of government expenditure in many countries. The large cost variability observed between hospitals and also between patients in the same hospital has fueled the belief that consumption of a significant portion of this funding may result in no clinical benefit to patients, thus representing waste. Accurate identification of the main hospital cost drivers and relating them quantitatively to the observed cost variability is a necessary step towards identifying and reducing waste. This study identifies prime cost drivers in a typical, mid-sized Australian hospital and classifies them as sources of cost variability that are either warranted or not warranted and therefore contributing to waste. An essential step is dimension reduction using Principal Component Analysis to pre-process the data by separating out the low value 'noise' from otherwise valuable information. Crucially, the study then adjusts for possible co-linearity of different cost drivers by the use of the sparse group lasso technique. This ensures reliability of the findings and represents a novel and powerful approach to analysing hospital costs. Our statistical model included 32 potential cost predictors with a sample size of over 50,000 hospital admissions. The proportion of cost variability potentially not clinically warranted was estimated at 33.7%. Given the financial footprint involved, once the findings are extrapolated nationwide, this estimation has far reaching significance for health funding policy. PMID- 30303978 TI - Transcriptomics reveal potential vaccine antigens and a drastic increase of upregulated genes during Theileria parva development from arthropod to bovine infective stages. AB - Theileria parva is a protozoan parasite transmitted by the brown ear tick Rhipicephalus appendiculatus that causes East Coast fever (ECF) in cattle, resulting in substantial economic losses in the regions of southern, eastern and central Africa. The schizont form of the parasite transforms the bovine host lymphocytes into actively proliferating cancer-like cells. However, how T. parva causes bovine host cells to proliferate and maintain a cancerous phenotype following infection is still poorly understood. On the other hand, current efforts to develop improved vaccines have identified only a few candidate antigens. In the present paper, we report the first comparative transcriptomic analysis throughout the course of T. parva infection. We observed that the development of sporoblast into sporozoite and then the establishment in the host cells as schizont is accompanied by a drastic increase of upregulated genes in the schizont stage of the parasite. In contrast, the ten highest gene expression values occurred in the arthropod vector stages. A comparative analysis showed that 2845 genes were upregulated in both sporozoite and schizont stages compared to the sporoblast. In addition, 647 were upregulated only in the sporozoite whereas 310 were only upregulated in the schizont. We detected low p67 expression in the schizont stage, an unexpected finding considering that p67 has been reported as a sporozoite stage-specific gene. In contrast, we found that transcription of p67 was 20 times higher in the sporoblast than in the sporozoite. Using the expression profiles of recently identified candidate vaccine antigens as a benchmark for selection for novel potential vaccine candidates, we identified three genes with expression similar to p67 and several other genes similar to Tp1-Tp10 schizont vaccine antigens. We propose that the antigenicity or chemotherapeutic potential of this panel of new candidate antigens be further investigated. Structural comparisons of the transcripts generated here with the existing gene models for the respective loci revealed indels. Our findings can be used to improve the structural annotation of the T. parva genome, and the identification of alternatively spliced transcripts. PMID- 30303979 TI - Two subspecies of bent-winged bats (Miniopterus orianae bassanii and oceanensis) in southern Australia have diverse fungal skin flora but not Pseudogymnoascus destructans. AB - Fungi are increasingly being documented as causing disease in a wide range of faunal species, including Pseudogymnoascus destructans, the fungus responsible for white nose syndrome which is having a devastating impact on bats in North America. The population size of the Australian southern bent-winged bat (Miniopterus orianae bassanii), a critically endangered subspecies, has declined over the past 50 years. As part of a larger study to determine whether disease could be a contributing factor to this decline, southern bent-winged bats were tested for the presence of a range of potentially pathogenic fungi: P. destructans, dermatophytes and Histoplasma capsulatum (a potential human pathogen commonly associated with caves inhabited by bats). Results were compared with those obtained for the more common eastern bent-winged bat (M. orianae oceanensis). All bats and their environment were negative for P. destructans. A large number of fungi were found on the skin and fur of bats, most of which were environmental or plant associated, and none of which were likely to be of significant pathogenicity for bats. A 0-19% prevalence of H. capsulatum was detected in the bat populations sampled, but not in the environment, indicative of a low zoonotic risk. Based on the results of this study, fungi are unlikely to be contributing significantly to the population decline of the southern bent winged bat. PMID- 30303980 TI - A randomized trial of serological and cellular responses to hepatitis B vaccination in chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of hepatitis B infection and impaired seroconversion to hepatitis B vaccine (HBV). Studies examining augmented vaccine schedules to enhance seroconversion have so far been inconclusive. Furthermore, the defects responsible for impaired vaccine immunity in CKD have not yet been identified. METHODS: We studied serological and cellular responses to HBV in CKD to identify a defect in vaccine-induced cellular responses that could account for impaired seroconversion in CKD and clarify the effects of an augmented vaccine dose schedule. We compared these results with responses to seasonal influenza vaccination (Fluvax). RESULTS: We found a clear benefit in rates and magnitude of seroconversion after an augmented 40mcg HBV dose schedule in CKD. This permitted comparison of responders and non-responders. Serological non-responders with CKD exhibited reduction in CXCR3+CCR6- CXCR5+ memory T cells at baseline. Unlike Fluvax, HBV elicited a poor plasmablast (PB) response. Both vaccinations induced activation of the CXCR3+CCR6- CCR7- subset of circulating T follicular helper cells (cTFH), although this response was impaired in CKD after HBV. CONCLUSIONS: CKD confers a specific T cell defect that contributes to the impaired seroconversion to HBV. PMID- 30303981 TI - Characterization of gene expression changes over healthy term pregnancies. AB - During pregnancy, women experience numerous physiological changes but, to date, there is limited published data that characterize accompanying changes in gene expression over pregnancy. This study sought to characterize the complexity of the transcriptome over the course of pregnancy among women with healthy pregnancies. Subjects provided a venous blood sample during early (6-15 weeks) and late (22-33 weeks) pregnancy, which was used to isolate peripheral blood mononuclear cells prior to RNA extraction. Gene expression was examined for 63 women with uncomplicated, term deliveries. We evaluated the association between weeks gestation at sample collection and expression of each transcript. Of the 16,311 transcripts evaluated, 439 changed over pregnancy after a Bonferroni correction to account for multiple comparisons. Genes whose expression increased over pregnancy were associated with oxygen transport, the immune system, and host response to bacteria. Characterization of changes in the transcriptome over the course of healthy term pregnancies may enable the identification of genes whose expression predicts complications or adverse outcomes of pregnancy. PMID- 30303982 TI - Body inversion effect in monkeys. AB - Humans visually process human body images depending on the configuration of the parts. However, little is known about whether this function is evolutionarily shared with nonhuman animals. In this study, we examined the body posture discrimination performance of capuchin monkeys, a highly social platyrrhine primate, in comparison to humans. We demonstrate that, like humans, monkeys exhibit a body inversion effect: body posture discrimination is impaired by inversion, which disrupts the configural relationships of body parts. The inversion effect in monkeys was observed when human body images were used, but not when the body parts were replaced with cubic and cylindrical figures, the positions of the parts were scrambled, or only part of a body was presented. Results in human participants showed similar patterns, though they also showed the inversion effect when the cubic/cylindrical body images were used. These results provide the first evidence for configural processing of body forms in monkeys and suggest that the visual attunement to social signals mediated by body postures is conserved through the evolution of primate vision. PMID- 30303983 TI - Sequential codend improves quality of trawl-caught cod. AB - Trawl-caught fish are frequently associated with deteriorated catch quality. This study presents a new dual sequential codend concept with the aim of improving the quality of trawl-caught fish by minimizing the frequency and severity of catch damage. During towing, the fish are retained in an anterior codend segment with the legislated mesh size. A quality improving codend segment, is attached to the aft part of the first codend segment. Its entrance is closed during the towing phase and opened at a predefined depth during haul-back. Comparing the quality of cod (Gadus morhua L.) retained in the sequential codend with cod caught in a conventional codend, demonstrated a significant improvement in the catch quality, i.e. reduction in catch damages. Cod caught in a conventional codend had only a 3.6% probability of being without visually detectable catch damage. The probability for catching cod without catch damage was five times higher when using the dual sequential codend. Furthermore, cod caught in the sequential codend had a significantly reduced probability of incurring specific catch damage, such as gear marks, poor exsanguination, ecchymosis, and skin abrasions. PMID- 30303985 TI - May furtive predation provide enemy free space in ant-tended aphid colonies? AB - In furtive predation, a predator is able to exploit its prey without generating significant defensive behaviors from them. However, in aphidophagous guild, if furtive predator can benefit from dilution effects generated by the aphids, they also suffer from intraguild predation from more mobile and active-searching predators. In this context ant-tended aphid colonies might not only represent an important food source but also potentially an enemy-free space for furtive predators if they remain unharmed by ants while other active predators are being repelled. Here we use the furtive predator Aphidoletes aphidimyza and two distinct instars of an active-searching predator, the Asian ladybeetle Harmonia axyridis, to test hypotheses related to predator persistence within aphid colonies in presence of ants. Our results show that persistence rate over time of the furtive predator was not affected by ant presence while it was strongly reduced for both instars of the active-searching predator. Furthermore, when ran in paired trials within ant-tended aphid colonies, furtive predator persistence rate was significantly higher than for active-searching predators, with these latter always leaving the plants quicker. Finally, we tested the importance of predator mobility in detection susceptibility and aggressive responses in ants using mobile and immobile active-searching predators. While the number of antennal palpations was similar for both treatments indicating similar detection rate, the number of ant attacks was significantly higher on mobile individuals highlighting the importance of movement in triggering aggressive responses in ants. Overall our results indicate that furtive predation represents an efficient strategy to limit ant aggressions, while the exclusion of active-searching predators might create an enemy-free space for furtive predators within ant tended aphid colonies. PMID- 30303984 TI - Apolipoprotein E is a pancreatic extracellular factor that maintains mature beta cell gene expression. AB - The in vivo microenvironment of tissues provides myriad unique signals to cells. Thus, following isolation, many cell types change in culture, often preserving some but not all of their in vivo characteristics in culture. At least some of the in vivo microenvironment may be mimicked by providing specific cues to cultured cells. Here, we show that after isolation and during maintenance in culture, adherent rat islets reduce expression of key beta-cell transcription factors necessary for beta-cell function and that soluble pancreatic decellularized matrix (DCM) can enhance beta-cell gene expression. Following chromatographic fractionation of pancreatic DCM, we performed proteomics to identify soluble factors that can maintain beta-cell stability and function. We identified Apolipoprotein E (ApoE) as an extracellular protein that significantly increased the expression of key beta-cell genes. The ApoE effect on beta cells was mediated at least in part through the JAK/STAT signaling pathway. Together, these results reveal a role for ApoE as an extracellular factor that can maintain the mature beta-cell gene expression profile. PMID- 30303986 TI - Elevated circulating tumor cells and squamous cell carcinoma antigen levels predict poor survival for patients with locally advanced cervical cancer treated with radiotherapy. AB - OBJECTIVE: To evaluate the prognostic effects of combining serum circulating tumor cells (CTCs) and squamous cell carcinoma antigen (SCC-Ag) levels on patients with locally advanced cervical cancer treated with radiotherapy. METHODS: Ninety-nine patients with locally advanced cervical cancer ([FIGO] stage IIB-IVA) undergoing radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) were identified. The association between serum CTC level and clinicopathological parameters was examined. Univariate and multivariate survival analyses were performed by using Cox's proportional hazards regression model. RESULTS: Elevated CTC and SCC-Ag levels were significantly associated with poor disease-free survival (DFS). Multivariate analysis suggest that serum CTC level, FIGO stage and serum SCC-Ag level were independent prognostic factors for two-year DFS. When CTC and SCC-Ag levels were combined into a new risk model to predict disease progression of cervical cancer patients, it performed a significantly better predictive efficiency compared with either biomarker alone. CONCLUSION: Serum CTC and SCC-Ag levels are potentially useful biomarkers for prediction of prognosis in locally advanced cervical cancer patients and their combination significantly improves predictive ability for survival in locally advanced cervical cancer patients. PMID- 30303987 TI - Ethnicity and wealth: The dynamics of dual segregation. AB - Creating inclusive cities requires meaningful responses to inequality and segregation. We build an agent-based model of interactions between wealth and ethnicity of agents to investigate 'dual' segregations-due to ethnicity and due to wealth. As agents are initially allowed to move into neighbourhoods they cannot afford, we find a regime where there is marginal increase in both wealth segregation and ethnic segregation. However, as more agents are progressively allowed entry into unaffordable neighbourhoods, we find that both wealth and ethnic segregations undergo sharp, non-linear transformations, but in opposite directions-wealth segregation shows a dramatic decline, while ethnic segregation an equally sharp upsurge. We argue that the decrease in wealth segregation does not merely accompany, but actually drives the increase in ethnic segregation. Essentially, as agents are progressively allowed into neighbourhoods in contravention of affordability, they create wealth configurations that enable a sharp decline in wealth segregation, which at the same time allow co-ethnics to spatially congregate despite differences in wealth, resulting in the abrupt worsening of ethnic segregation. PMID- 30303988 TI - Distribution of low-molecular lipophilic extractives beneath the surface of air- and kiln-dried Scots pine sapwood boards. AB - During industrial wood drying, extractives migrate towards the wood surfaces and make the material more susceptible to photo/biodegradation. The present work provides information about the distribution, quantity and nature of lipophilic substances beneath the surface in air- and kiln-dried Scots pine (Pinus sylvestris L.) sapwood boards. Samples were taken from knot-free sapwood surfaces and the composition of lipophilic extractives, phenols and low-molecular fatty/resin acids layers at different nominal depths below the surface was studied gravimetrically, by UV-spectrometry and by gas chromatography-mass spectrometry (GC-MS). The concentration of total extractives was significantly higher in kiln-dried than in air-dried samples and was higher close to the surface than in the layers beneath. The scatter in the values for the lipophilic extractives was high in both drying types, being highest for linoleic acid and slightly lower for palmitic, oleic and stearic acids. The amount of fatty acids was low in kiln-dried boards, probably due to a stronger degradation due to the high temperature employed. The most abundant resin acid was dehydroabietic acid followed by pimaric, isopimaric, and abietic acids in both drying types. It is concluded that during kiln-drying a migration front is created at a depth of 0.25 mm with a thickness of about 0.5 mm. PMID- 30303989 TI - New evidence of megafaunal bone damage indicates late colonization of Madagascar. AB - The estimated period in which human colonization of Madagascar began has expanded recently to 5000-1000 y B.P., six times its range in 1990, prompting revised thinking about early migration sources, routes, maritime capability and environmental changes. Cited evidence of colonization age includes anthropogenic palaeoecological data 2500-2000 y B.P., megafaunal butchery marks 4200-1900 y B.P. and OSL dating to 4400 y B.P. of the Lakaton'i Anja occupation site. Using large samples of newly-excavated bone from sites in which megafaunal butchery was earlier dated >2000 y B.P. we find no butchery marks until ~1200 y B.P., with associated sedimentary and palynological data of initial human impact about the same time. Close analysis of the Lakaton'i Anja chronology suggests the site dates <1500 y B.P. Diverse evidence from bone damage, palaeoecology, genomic and linguistic history, archaeology, introduced biota and seafaring capability indicate initial human colonization of Madagascar 1350-1100 y B.P. PMID- 30303990 TI - Inducing rapid seed germination of native cool season grasses with solid matrix priming and seed extrusion technology. AB - There is a need to develop effective techniques for establishing native vegetation in dryland ecosystems. We developed a novel treatment that primes (hydrates) seeds in a matrix of absorbent materials and bio-stimulants and then forms the mixture into pods for planting. In the development process, we determined optimal conditions for priming seeds and then compared seedling emergence from non-treated seeds, non-primed-seed pods, and primed-seed pods. Emergence trials were conducted on soils collected from a hillslope and ridgetop location on the Kaibab Plateau, Arizona, USA. Poa fendleriana and Pseudoroegneria spicata were used as test species. Seeds were primed from -0.5 to -2.5 MPa for up to 12 d. Seeds primed under drier conditions (-1.5 to -2.5 MPa) tended to have quicker germination. Days to 50% emergence for primed-seed pods was between 66.2 to 82.4% faster (5.2 to 14.5 d fewer) than non-treated seeds. Seedling emergence from primed-seed pods for P. fendleriana was 3.8-fold higher than non-treated seeds on the ridgetop soil, but no difference was found on the other soil. Final density of P. spicata primed-seed pods were 2.9 to 3.8-fold higher than non treated seeds. Overall, primed-seed pods show promise for enhancing germination and seedling emergence, which could aid in native plant establishment. PMID- 30303991 TI - Fluorescent peptide dH3w: A sensor for environmental monitoring of mercury (II). AB - Heavy metals are hazardous environmental contaminants, often highly toxic even at extremely low concentrations. Monitoring their presence in environmental samples is an important but complex task that has attracted the attention of many research groups. We have previously developed a fluorescent peptidyl sensor, dH3w, for monitoring Zn2+ in living cells. This probe, designed on the base on the internal repeats of the human histidine rich glycoprotein, shows a turn on response to Zn2+ and a turn off response to Cu2+. Other heavy metals (Mn2+, Fe2+, Ni2+, Co2+, Pb2+ and Cd2+) do not interfere with the detection of Zn2+ and Cu2+. Here we report that dH3w has an affinity for Hg2+ considerably higher than that for Zn2+ or Cu2+, therefore the strong fluorescence of the Zn2+/dH3w complex is quenched when it is exposed to aqueous solutions of Hg2+, allowing the detection of sub-micromolar levels of Hg2+. Fluorescence of the Zn2+/dH3w complex is also quenched by Cu2+ whereas other heavy metals (Mn2+, Fe2+, Ni2+, Co2+, Cd2+, Pb2+, Sn2+ and Cr3+) have no effect. The high affinity and selectivity suggest that dH3w and the Zn2+/dH3w complex are suited as fluorescent sensor for the detection of Hg2+ and Cu2+ in environmental as well as biological samples. PMID- 30303992 TI - The MIS5 Pietersburg at '28' Bushman Rock Shelter, Limpopo Province, South Africa. AB - In the past few decades, a diverse array of research has emphasized the precocity of technically advanced and symbolic practices occurring during the southern African Middle Stone Age. However, uncertainties regarding the regional chrono cultural framework constrain models and identification of the cultural and ecological mechanisms triggering the development of such early innovative behaviours. Here, we present new results and a refined chronology for the Pietersburg, a techno-complex initially defined in the late 1920's, which has disappeared from the literature since the 1980's. We base our revision of this techno-complex on ongoing excavations at Bushman Rock Shelter (BRS) in Limpopo Province, South Africa, where two Pietersburg phases (an upper phase called '21' and a lower phase called '28') are recognized. Our analysis focuses on the '28' phase, characterized by a knapping strategy based on Levallois and semi-prismatic laminar reduction systems and typified by the presence of end-scrapers. Luminescence chronology provides two sets of ages for the upper and lower Pietersburg of BRS, dated respectively to 73+/-6ka and 75+/-6ka on quartz and to 91+/-10ka and 97+/-10ka on feldspar, firmly positioning this industry within MIS5. Comparisons with other published lithic assemblages show technological differences between the Pietersburg from BRS and other southern African MIS5 traditions, especially those from the Western and Eastern Cape. We argue that, at least for part of MIS5, human populations in South Africa were regionally differentiated, a process that most likely impacted the way groups were territorially and socially organized. Nonetheless, comparisons between MIS5 assemblages also indicate some typological similarities, suggesting some degree of connection between human groups, which shared similar innovations but manipulated them in different ways. We pay particular attention to the end scrapers from BRS, which represent thus far the earliest documented wide adoption of such tool-type and provide further evidence for the innovative processes characterizing southern Africa from the MIS5 onwards. PMID- 30303993 TI - A study of the car-to-train assignment problem for rail express cargos in the scheduled and unscheduled train services network. AB - A freight train service network generally involves two categories of trains: unscheduled trains, whose operating frequencies fluctuate with the freight demand, and scheduled trains, which are operated based on regular timetables similar to passenger trains. The timetables for scheduled trains are released to the public once determined, and they are not influenced by the freight demand. Typically, the total capacity of scheduled trains can satisfy the predicted average demand of express cargos. However, in practice, the demand always changes. Therefore, a method to assign the shipments to scheduled and unscheduled train services has become an important issue faced in railway transportation. This paper focuses on the coordinated optimization of rail express cargo assignment in a hybrid train services network. On the premise of fully utilizing the capacity of scheduled train services, we propose a car-to-train assignment model to reasonably assign rail express cargos to scheduled and unscheduled trains. The objective aims to maximize the profit of transporting the rail express cargos. The constraints include the capacity restriction on the service arcs, flow balance constraints, transportation due date constraints and logical relationship constraints among the decision variables. Furthermore, we discuss a linearization technique to convert the nonlinear transportation due date constraint into a linear constraint, making it possible to solve by a standard optimization solver. Finally, an illustrative case study based on the Beijing Guangzhou Railway Line is carried out to demonstrate the effectiveness and efficiency of the proposed solution approach. PMID- 30303994 TI - In vitro electrochemical assessment of electrodes for neurostimulation in roach biobots. AB - Biobotics investigates the use of live insects as biological robots whose locomotion can be controlled by neurostimulation through implanted electrodes. Inactivity in the biobots (biological robots) can sometimes be noticed following extended neurostimulation, partly owing to incompatibility of implanted electrodes with the biobotic application or gradual degradation of the tissue electrode interface. Implanted electrodes need to sufficiently exhibit consistent, reliable, and stable performance during stimulation experiments, have low tissue-electrode impedance, facilitate good charge injection capacity, and be compact in size or shape. Towards the goal of finding such electrodes suitable for biobotic applications, we compare electrochemical performances of five different types of electrodes in vitro with a saline based electrolytic medium. These include stainless steel wire electrodes, microfabricated flexible gold electrodes coated with PEDOT:PSS conductive polymer, eutectic gallium indium (EGaIn) in a tube, and "hybrid" stainless steel electrodes coated with EGaIn. We also performed accelerated aging of the electrodes to help estimate their longitudinal performance. Based on our experimentation, microfabricated electrodes with PEDOT:PSS and stainless steel electrodes coated with EGaIn performed remarkably well. This is the first time conductive polymer and liquid metal electrodes were studied comparatively for neurostimulation applications. These in vitro comparison results will be used in the future to provide a benchmark for subsequent in vivo tests with implanted electrodes in cockroach biobots. PMID- 30303995 TI - Knowledge translation of clinical practice guidelines among neurologists: A mixed methods study. AB - OBJECTIVES: Clinical practice guidelines have the potential to improve care, but are often not optimally implemented. Improving guideline use in clinical practice may improve care. The objective of this study was to identify the barriers and facilitators (determinants) of guidelines use among neurologists and to propose a strategy to improve guideline implementation. METHODS: This was a mixed-methods study design. A quantitative, population-based, cross-sectional survey of Canadian neurologists was conducted. Associations between guidelines use and determinants of guidelines use were examined. Focus groups and interviews were conducted using purposeful sampling of the population. Determinants of guideline use were mapped to interventions to establish a strategy for guideline implementation among neurologists. RESULTS: 38.7% (n = 311) of neurologists responded to the survey. Typically, respondents had been practicing for 16.6 years and worked in an academic institution in an urban setting. Being male and having an academic affiliation was associated with guideline use. Determinants of guideline use differed between guideline users and non-users; non-users consistently rating determinants lower than users, especially applicability. Two focus groups and one interview (n = 11) identified six main themes of determinants of guideline use: Credibility, knowledge, applicability, resources, motivation, and target audience; which was congruent with the quantitative data. The proposed knowledge translation strategy contains three pillars: guidelines development, dissemination, and interventions. CONCLUSIONS: Several determinants of guideline use not commonly discussed in the literature were identified (applicability, target audience, credibility). The proposed implementation strategy is a valuable resource for guideline developers and policy/decision makers to improve knowledge translation of guidelines among neurologists. PMID- 30303996 TI - Intersectoral collaboration for the prevention and control of vector borne diseases to support the implementation of a global strategy: A systematic review. AB - INTRODUCTION: Vector Borne Diseases (VBDs) have a major impact on public health and socio-economic development. Inter-sectoral collaboration was recommended as one of the key elements of Integrated Vector Management (IVM), however limited evidence measures the effect and contribution of intersectoral approaches including but not only IVM. This systematic review aims to assess the existing evidence on all forms of inter-sectoral collaboration in VBD control and prevention, identify any gaps and develop a framework from a global perspective. METHODS: Articles were identified through a search of PUBMED, Science of Direct, Web of Knowledge, Google Scholar and WHO archives using key words and excluded duplications (n = 2,034). The exclusion of non-VBDs control and prevention interventions resulted in 194 eligible titles/abstract/keywords for full text assessment. Further exclusion of non-peer reviewed articles, non-declaration of ethical clearance, reviews and expert opinion articles resulted in 50 articles finally being included for analysis with the extraction of data on outcome, factor/s influencing the effectiveness, indicators of collaboration and sustainability. RESULTS: Of the 50 articles included in the analysis, 19 articles were categorized as of moderate-strong quality. All articles compared pre- and post-intervention outcomes against disease or vector variables. Three papers included outcome variables on intersectoral collaboration and participation indicator. However, no paper undertook component analysis by different sectors or different activities. Only one paper compared cost data for community intersectoral intervention for IRS and traditional "vertical" IRS. Six factors were identified as influencing the effectiveness of inter-sectoral collaboration. Five of six factors are the main ones, namely the approach (37/47), resources (34/47), relationships (33/47), management (29/47) and shared vision (20/47) factors. A conceptual framework has been developed based on this review. CONCLUSION: This review shows the importance of inter-sectoral collaboration to reduce VBDs or vector densities. However, very few studies measured how much inter-sectoral collaboration contributes to the impact. Further high-quality studies using inter-sectoral collaboration indicators are recommended to be undertaken. PMID- 30303997 TI - Monomeric Camelus dromedarius GSTM1 at low pH is structurally more thermostable than its native dimeric form. AB - Glutathione S-transferases (GSTs) are multifunctional enzymes that play an important role in detoxification, cellular signalling, and the stress response. Camelus dromedarius is well-adapted to survive in extreme desert climate and it has GSTs, for which limited information is available. This study investigated the structure-function and thermodynamic properties of a mu-class camel GST (CdGSTM1) at different pH. Recombinant CdGSTM1 (25.7 kDa) was expressed in E. coli and purified to homogeneity. Dimeric CdGSTM1 dissociated into stable but inactive monomeric subunits at low pH. Conformational and thermodynamic changes during the thermal unfolding pathway of dimeric and monomeric CdGSTM1 were characterised via a thermal shift assay and dynamic multimode spectroscopy (DMS). The thermal shift assay based on intrinsic tryptophan fluorescence revealed that CdGSTM1 underwent a two-state unfolding pathway at pH 1.0-10.0. Its Tm value varied with varying pH. Another orthogonal technique based on far-UV CD also exhibited two-state unfolding in the dimeric and monomeric states. Generally, proteins tend to lose structural integrity and stability at low pH; however, monomeric CdGSTM1 at pH 2.0 was thermally more stable and unfolded with lower van't Hoff enthalpy. The present findings provide essential information regarding the structural, functional, and thermodynamic properties of CdGSTM1 at pH 1.0-10.0. PMID- 30303998 TI - The impact of skeletal muscle mass on survival outcome in biliary tract cancer patients. AB - Low skeletal muscle mass is frequently observed in cancer patients and is known to be a poor prognostic factor for survival outcomes. The purposes of our study were to determine the prevalence of sarcopenia and its relation to mortality in biliary tract cancer. Body composition measurements (skeletal muscle index, total fat mass, bone mineral content) were evaluated by using dual-energy x-ray absorptiometry in 75 biliary tract cancer patients before chemotherapy. Muscle strength was measured by handgrip strength and gait speed. Overall survival and its associated factors were determined. The mean appendicular muscle mass was 17.8+/-2.7 kg in men and 14.0+/-2.1 kg in women (p < 0.05). Sarcopenia was diagnosed in 46 patients (61.3%) and higher proportion of men was classified as sarcopenia than women (69.0% vs 35.3%, p < 0.05). Multivariable analysis adjusted for chemotherapy regimen and age revealed that high appendicular muscle mass independently predicted better survival outcomes (HR 0.40; 95% CI, 0.18 to 0.88; p = 0.023). Sarcopenia is common in biliary tract cancer patients and low appendicular muscle mass was associated with poor survival outcome. PMID- 30304000 TI - Antimicrobial nano-zinc oxide-2S albumin protein formulation significantly inhibits growth of "Candidatus Liberibacter asiaticus" in planta. AB - Huanglongbing (HLB, also known as citrus greening) is considered to be the most devastating disease that has significantly damaged the citrus industry globally. HLB is caused by the Candidatus Liberibacter asiaticus (CLas), the fastidious phloem-restricted gram-negative bacterium, vectored by the asian citrus psyllid. To date, there is no effective control available against CLas. To alleviate the effects of HLB on the industry and protect citrus farmers, there is an urgent need to identify or develop inhibitor molecules to suppress or eradicate CLas from infected citrus plant. In this paper, we demonstrate for the first time an in planta efficacy of two antimicrobial compounds against CLas viz. 2S albumin (a plant based protein; ~12.5 kDa), Nano-Zinc Oxide (Nano-ZnO; ~ 4.0 nm diameter) and their combinations. Aqueous formulations of these compounds were trunk injected to HLB affected Mosambi plants (Citrus sinensis) grafted on 3-year old rough lemon (C. jambhiri) rootstock with known CLas titer maintained inside an insect-free screen house. The effective concentration of 2S albumin (330 ppm) coupled with the Nano-ZnO (330 ppm) at 1:1 ratio was used. The dynamics of CLas pathogen load of treated Mosambi plants was assessed using TaqMan-qPCR assay every 30 days after treatment (DAT) and monitored till 120 days. We observed that 2S albumin-Nano-ZnO formulation performed the best among all the treatments decreasing CLas population by 96.2%, 97.6%, 95.6%, and 97% of the initial bacterial load (per 12.5 ng of genomic DNA) at 30, 60, 90, and 120 DAT, respectively. Our studies demonstrated the potency of 2S albumin-Nano-ZnO formulation as an antimicrobial treatment for suppressing CLas in planta and could potentially be developed as a novel anti CLas therapeutics to mitigate the HLB severity affecting the citrus industry worldwide. PMID- 30303999 TI - Proteome analysis of Phytomonas serpens, a phytoparasite of medical interest. AB - The protozoan Phytomonas serpens (class Kinetoplastea) is an important phytoparasite that has gained medical importance due to its similarities to Trypanosoma cruzi, the etiological agent of Chagas disease. The present work describes the first proteome analysis of P. serpens. The parasite was separated into cytosolic and high density organelle fractions, which, together with total cell extract, were subjected to LC-MS/MS analyses. Protein identification was conducted using a comprehensive database composed of genome sequences of other related kinetoplastids. A total of 1,540 protein groups were identified among the three sample fractions. Sequences from Phytomonas sp. in the database allowed the highest number of identifications, with T. cruzi and T. brucei the human pathogens providing the greatest contribution to the identifications. Based on the proteomics data obtained, we proposed a central metabolic map of P. serpens, which includes all enzymes of the citric acid cycle. Data also revealed a new range of proteins possibly responsible for immunological cross-reactivity between P. serpens and T. cruzi. PMID- 30304001 TI - Inhibition of autophagy and chemokine induction by sphingosine 1-phosphate receptor 1 through NF-kappaB signaling in human pulmonary endothelial cells infected with influenza A viruses. AB - Endothelial cells have been considered the central regulators of cytokine storm in the respiratory system during influenza virus infection. Studies have found that elevated autophagy could be an essential component of viral pathogenesis in influenza infection. However, few studies have been performed to examine whether autophagy occurs in human pulmonary endothelial cells (HPMECs). In addition, specific mechanisms about how inflammatory responses are regulated in the endothelial cells remain unclear. We hypothesized that infection of influenza A viruses subtypes H1N1 and H9N2 triggered autophagy, which played an important role in the induction of proinflammatory cytokines, both in human lung epithelial A549 cells and in HPMECs. In this report, we showed our evidence that blockage of autophagy significantly inhibited influenza virus-induced proinflammatory responses and suppressed viral replication. Our data indicated that the inhibition of the cytokine response and viral replication was affected by increasing the expression of endothelial sphingosine 1-phosphate receptor 1 (S1PR1), which might be through the regulation of NF-kappaB signaling. Overexpression of S1PR1 decreased p65 phosphorylation and translocation into the nucleus. Furthermore, we demonstrated that S1PR1 stimulation inhibited Akt-mTOR signaling, which might contribute to activation of autophagy in HPMECs. Thus, our study provides knowledge crucial to better understanding novel mechanisms underlying the S1PR1-mediated attenuation of cytokine amplification in the pulmonary system during influenza virus infection. PMID- 30304004 TI - Carbon price volatility: The case of China. AB - Based on carbon spot prices selected from seven carbon pilots, we assess the financial performances related to carbon volatility in China on the overall perspective. According to the results, the Chinese carbon market fluctuated severely at the beginning of carbon trading, but has stabilised in general, despite several dramatic changes related to 'yearly compliance events'. Long-term memory exists in the volatility series. Moreover, asymmetry exists in the Chinese carbon market, and volatility reacts more severely to good news than to bad news. Finally, we discuss our empirical results, and make certain suggestions regarding firms' awareness, international cooperation and individual investors not only for policy makers in China but also for other developing countries who are contemplating either commencing carbon trading or improving the current market. PMID- 30304002 TI - Investigating behavioral drivers of seasonal Shiga-Toxigenic Escherichia Coli (STEC) patterns in grazing cattle using an agent-based model. AB - The causes of seasonal variability in pathogen transmission are not well understood, and have not been comprehensively investigated. In an example for enteric pathogens, incidence of Escherichia coli O157 (STEC) colonization in cattle is consistently higher during warmer months compared to cooler months in various cattle production systems. However, actual mechanisms for this seasonality remain elusive. In addition, the influence of host (cattle) behavior on this pattern has not been thoroughly considered. To that end, we constructed a spatially explicit agent-based model that accounted for the effect of temperature fluctuations on cattle behavior (direct contact among cattle and indirect between cattle and environment), as well as its effect on pathogen survival in the environment. We then simulated the model in a factorial approach to evaluate the hypothesis that temperature fluctuations can lead to seasonal STEC transmission dynamics by influencing cattle aggregation, grazing, and drinking behaviors. Simulation results showed that higher temperatures increased the frequency at which cattle aggregated under shade in pasture, resulting in increased direct contact and transmission of STEC between individual cattle, and hence higher incidence over model simulations in the warm season. In contrast, increased drinking behavior during warm season was not an important transmission pathway. Although sensitivity analyses suggested that the relative importance of direct vs. indirect (environmental) pathways depend to upon model parameterization, model simulations indicated that factors influencing cattle aggregation, such as temperature, were likely strong drivers of transmission dynamics of enteric pathogens. PMID- 30304003 TI - Protein restricted diet during gestation and/or lactation in mice affects 15N natural isotopic abundance of organs in the offspring: Effect of diet 15N content and growth. AB - OBJECTIVES AND STUDY: This study aimed at measuring the effect in normal to restricted protein diets with specific 15N natural isotopic abundance (NIA) given during gestation and/or lactation on the 15N NIA of fur, liver and muscle in dams and their offspring from birth to adulthood. The secondary aim was to study the effect of growth on the same parameters. METHODS: Female Balb/c mice were fed normal protein diet containing 22% protein or isocaloric low protein diet containing 10% protein throughout gestation. Dam's diets were either maintained or switched to the other diet until weaning at 30 days. All animals were fed standard chow thereafter. Offspring were sacrificed at 1, 11, 30, 60, 480 days and a group of dams at d1. Growth was modeled as an exponential function on the group followed up until 480 days. Fur, liver and muscle were sampled at sacrifice and analyzed for bulk 15N NIA. Fixed effects and interactions between fixed effects and random elements were tested by three-way ANOVA. RESULTS: Higher 15N NIA in the diet resulted in higher organ 15N NIA. Switching from one diet to another changed 15N NIA in each organ. Although dam and offspring shared the same isotopic environment during gestation, 15N NIA at day 1 was higher in dams. Growth rate did not differ between groups after 10 days and decreased between 1 and 5 months. 15N NIA differed between organs and was affected by growth and gestation/lactation. CONCLUSION: Dietary 15N NIA is a major determinant of the 15N NIA of organs. 15N NIA depended on organ and age (i.e. growth) suggesting an effect of metabolism and/or dilution space. Post-natal normal-protein diet of lactating dams could reverse the effect of a protein-restricted diet during gestation on the offspring growth. Measuring 15N NIA in various matrices may open a field of application particularly useful in studying the pre- and post-natal origins of health and disease. PMID- 30304005 TI - Influence of the use of complete denture adhesives on microbial adhesion and biofilm formation by single- and mixed-species. AB - OBJECTIVES: To verify whether the Ultra Corega Cream and Corega Strip Denture Adhesive adhesives interfere in the microbial adhesion and biofilm formation by Candida albicans and Lactobacillus casei in single- and mixed-species settings, and observe whether synergistic or antagonistic relationships between these species occur. METHODS: Specimens made from heat-polymerized acrylic resin (Lucitone 550) were fabricated (n = 144) with a circular shape and standardized roughness (3.0 MUm +/-0.3 Ra) and were divided into three groups: Without Adhesive (WA), with Ultra Corega Cream adhesive (CA) and Corega Strips adhesive (SA). These groups were divided into three subgroups each: C. albicans single species, L. casei single-species and C. albicans with L. casei (mixed-species). Microbial adhesion and biofilm formation assays were performed in duplicate at four distinct experimental times (n = 8 per experimental condition). The amount of each microorganism on the surfaces of the specimens was observed by counting of the Colony Forming Units (CFU) per substrate. Additional specimens were characterized by Scanning Electron Microscopy (SEM), with 18 specimens being used in this analysis (n = 18), 2 per experimental condition (n = 2). Two-way ANOVA and Tukey's test for multiple comparisons were employed, using alpha<=0.05. RESULTS: L. casei (mixed-species) adhered more on the WA substrate than the CA, while C. albicans (single- and mixed-species) adhered more on the SA. C. albicans, both single- and mixed-species adhered more than the L. casei (single- and mixed-species), regardless of the substrate. L. casei (single-species) formed more biofilm on the WA, but in its mixed cultivation, it had no difference of growth among the tested situations. C. albicans (single- and mixed-species) formed more biofilm on the SA than the CA, and the fungus formed more biofilm when compared to L. casei. In general, whenever a species was compared in its single- and mixed-species situation, no statistically significant difference was observed. SEM of biofilm formation assays demonstrated that L. casei single species WA formed more biofilm than when the adhesives tested were used, and C. albicans (both single- and mixed-species) formed more biofilm on the SA than on the CA. CONCLUSIONS: (1) The two denture adhesives tested increased the adhesion of C. albicans but not of L. casei; (2) biofilm formation by C. albicans (single- and mixed-species) was increased on the SA; (3) Relations of synergism or antagonism was not observed between the two microorganisms studied. PMID- 30304006 TI - Costs of multiple sclerosis in Panama from societal, patient perspectives and health-related quality of life. AB - The purpose of this work is to estimate the costs associated with managing patients with MS in Panama and evaluating the impact of the disease on their health-related quality of life (HRQoL). Multicentric observational, retrospective, cross-sectional study. The costs were estimated from societal and patient perspectives and expressed in USD, 2015. The focus of the study is based on prevalence and on a "bottom-up" approach. To estimate the total cost per patient, annual reported use for each resource was multiplied by its unit cost. To evaluate HRQoL, patients completed the EQ-5D-3L questionnaire. 108 patients took part in the study. 82.41% were women with 44.78 (SD: 12.27) years. 61.11% presented mild (EDSS = 0-3.5), 25.93% moderate (EDSS = 3.5-6) and 12.96%, severe disability (EDSS>=6.5). The mean annual cost from the patient's perspective was estimated at 777.99 USD (SD: 1,741.45) per patient. The mean cost from a societal perspective was estimated at 23,803.21 USD (SD: 13,331.83) per patient. Disease modifying therapies (DMT) accounted for the main component of the cost. A deterioration in HRQoL was observed as the disease advances and as disability increases, with mobility and usual activities being the areas most affected by its progression. From both perspective, the cost per MS patient in Panama is high. In addition to the high economic impact, MS also exerts a negative impact on patient HRQoL, which increases as the disease advances. PMID- 30304008 TI - Where am I in virtual reality? AB - It is currently not well understood whether people experience themselves to be located in one or more specific part(s) of their body. Virtual reality (VR) is increasingly used as a tool to study aspects of bodily perception and self consciousness, due to its strong experimental control and ease in manipulating multi-sensory aspects of bodily experience. To investigate where people self locate in their body within virtual reality, we asked participants to point directly at themselves with a virtual pointer, in a VR headset. In previous work employing a physical pointer, participants mainly located themselves in the upper face and upper torso. In this study, using a VR headset, participants mainly located themselves in the upper face. In an additional body template task where participants pointed at themselves on a picture of a simple body outline, participants pointed most often to the upper torso, followed by the (upper) face. These results raise the question as to whether head-mounted virtual reality might alter where people locate themselves making them more "head-centred". PMID- 30304007 TI - Characterizing postural oscillation in children and adolescents with hereditary sensorimotor neuropathy. AB - Charcot Marie Tooth disease (CMT) has negative functional impact on postural control of children; however, it has not been widely studied. Stabilometry can provide insights about postural control and guide preventive interventions in immature perceptual and musculoskeletal systems as those seen in children with CMT. This cross-sectional study aimed to identify and interpret stabilometric variables that reflect the postural control of children with CMT. 53 subjects (age 6-17) were assigned to one of the two groups: CMT (15 males and 14 females with CMT) or Control (13 males and 11 females healthy). Quiet standing was tested in different conditions: with open and closed eyes on regular surface (open regular, closed-regular) and foam surface (open-foam, closed-foam) using a force platform. The minimum of 2 and maximum of 3 trials of 30 seconds for each test condition provided the classical stabilometric variables and Romberg Quotient (RQv). CMT group showed increase of confidence ellipse area, mean velocity, mediolateral and anteroposterior velocities associated with decreased mean body oscillation frequency, as the complexity of tasks increased. CMT postural deficit was identified by greater and faster sway associated with these lower frequencies, when compared to Control. PMID- 30304009 TI - First findings of brown hare (Lepus europaeus) reintroduction in relation to seasonal impact. AB - In Europe, brown hare (Lepus europaeus) populations have been declining steadily since the 1970s. Gamekeepers can help to support brown hare wild populations by releasing cage-reared hares into the wild. Survival rates of cage-reared hares has been investigated in previous studies, however, survival times in relation to seasonality, which likely plays a crucial role for the efficacy of this management strategy, has not been evaluated. Here we examine the survival duration and daytime home ranges of 22 hares released and radio-tracked during different periods of the year in East Bohemia, Czech Republic. The majority of hares (82%) died within the first six months after release, and 41% individuals died within the first 10 days. Significant differences were found in the duration of survival with respect to the release date. Hares released in the summer months (July and August) survived the longest (on average 103.2 days, SD +/- 23.8) and hares released throughout all other months of the year survived for significantly shorter periods of time (on average 20.4 days, SD +/- 11.5). The most likely cause of death was red fox predation (38.9%) followed by disease (coccidiosis and other health problems) (27.8%). Three hares (16.6%) were killed by automobile traffic. After six months of radiotracking, we found the average survival time of all hares released was 58 (SD +/- 70.9) days. Hares in this study preferred to remain in the vicinity of the release area and the average distance from release point to the center of the home range was 471 m. PMID- 30304010 TI - Two distance memories in desert ants-Modes of interaction. AB - Navigation plays an essential role for many animals leading a mobile mode of life, and for central place foragers in particular. One important prerequisite for navigation is the ability to estimate distances covered during locomotion. It has been shown that Cataglyphis desert ants, well-established model organisms in insect navigation, use two odometer mechanisms, namely, stride and optic flow integration. Although both mechanisms are well established, their mode of interaction to build one odometer output remains enigmatic. We tackle this problem by selectively covering the ventral eye parts in Cataglyphis fortis foragers, the eye regions responsible for optic flow input in odometry. Exclusion of optic flow cues was implemented during different sections of outbound and inbound travel. This demonstrated that the two odometers have separate distance memories that interact in determining homing distance. Possible interpretations posit that the two odometer memories (i) take on different relative weights according to context or (ii) compete in a winner-take-all mode. Explanatory values and implications of such interpretations are discussed. We are able to provide a rough quantitative assessment of odometer cue interaction. An understanding of the interaction of different odometer mechanisms appears valuable not only for animal navigation research but may inform discussions on sensor fusion in both behavioural contexts and potential technical applications. PMID- 30304011 TI - Dietary starch to lipid ratios influence growth performance, nutrient utilisation and carcass traits in broiler chickens offered diets with different energy densities. AB - Twelve experimental diets with three levels of energy densities (11.25, 12.38 and 13.50 MJ/kg) and fours levels of starch to lipid ratios (14:1, 12:1, 7:1, 4:1) were offered to 288 male Ross 308 broiler chickens. All the diets were formulated to contain consistent digestible lysine to metabolisable energy ratios (0.87 g digestible lysine/MJ AMEn) and ideal amino acid ratios. Growth performance was monitored from 7 to 27 days post-hatch and parameters of nutrient utilisation (AME, AMEn, AME:GE ratios, N retention) were determined from 24 to 26 days post hatch. Apparent protein (N) and starch digestibility coefficients, carcass yield and composition were determined at 27 days post-hatch. There were no interactions between energy densities and starch to lipid ratios on growth performance and carcass weights (P > 0.05). Feed intake was reduced with increased energy densities (P < 0.001). Weight gain and FCR were improved with increased dietary energy densities (P < 0.0001). Starch to lipid ratios linearly increased weight gain (r = 0.448, P = 0.001) and feed intake (r = 0.509, P < 0.001) without influencing FCR (P > 0.75). Both nutrient densities and starch to lipid ratios significantly impacted on carcass weight and yield. Heavier carcass weights and higher yields were observed in broiler chickens offered diets with high nutrient density (P <= 0.001). Carcass weight (r = 0.441, P < 0.005) was positively correlated with starch to lipid ratios and this tended to be the case for carcass yield (r = 0.277, P = 0.057) too. However, there were interactions on lipid concentrations in carcass (P < 0.001) as broiler chickens offered diet containing the lowest nutrient density and the highest starch to lipid ratio had the highest lipid carcass concentration of 12.94%. In conclusion, protein and energy need to be considered in tandem in practical diet formulation, especially in diets containing high crystalline amino acid inclusions. The impact of lipid on feed intake and starch on carcass lipid concentrations should also be taken into consideration. PMID- 30304012 TI - Optimizing long chain-polyunsaturated fatty acid synthesis in salmonids by balancing dietary inputs. AB - The increasing use of terrestrial plant lipids to replace of fish oil in commercial aquafeeds requires understanding synthesis and storage of long chain polyunsaturated fatty acids (LC-PUFA) in farmed fish. Manipulation of dietary fatty acids may maximize tissue storage of LC-PUFA, through increased production and selective utilization. A data synthesis study was conducted to estimate optimal levels of fatty acids that may maximize the production and storage of LC PUFA in the edible portion of salmonids. Data were compiled from four studies with Atlantic salmon, rainbow trout, and steelhead trout (total n = 180) which were fed diets containing different terrestrial-based oils to replace fish oil. LC-PUFA (%) were linearly correlated between diet and muscle tissue (p < 0.001; r2 > 44%), indicating proportional storage after consumption. The slope, or retention rate, was highest for docosahexaenoic acid (DHA) at 1.23, indicating that an additional 23% of DHA was stored in the muscle. Dietary saturated fatty acids were positively related to DHA stored in the muscle (p < 0.001; r2 = 22%), which may involve membrane structural requirements, as well as selective catabolism. DHA was found to be optimally stored with a dietary n-3: n-6 ratio of 1.03: 1. These new results provide a baseline of optimal dietary ratios that can be tested experimentally to determine the efficacy of balancing dietary fatty acids for maximum LC-PUFA storage. PMID- 30304013 TI - Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers. AB - INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients >=18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit >=24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation. PMID- 30304015 TI - Low coverage of influenza vaccination among Chinese children aged 12-23 months: Prevalence and associated factors. AB - This study aimed to investigate prevalence and associated factors of influenza vaccination (IV) among children aged 12-23 months. Our cross-sectional survey interviewed 489 parents of children aged 12-23 months anonymously at twelve maternal and child health centers in Hong Kong. Results showed that only 11.5% of the children had ever received IV (64.3% being subsidized). Adjusted for the child's age, significant factors of the children's IV included parental knowledge about governmental policy/recommendation (Adjusted odds ratio [AOR] = 2.64, 95%CI = 1.09,6.40), knowledge about annual IV requirement (AOR = 2.30, 95%CI = 1.21,4.38), perceived safety-related barrier (AOR>=0.14, 95%CI = 0.06,0.33), cue to action (AOR = 7.79, 95%CI = 3.45,17.58), and subjective norm (AOR = 4.59, 95%CI = 2.34,9.00). IV prevalence of children aged 12-23 months remained low despite a subsidization scheme. The higher IV prevalence of older children reported by other studies suggested that parents postponed action. Promotion campaigns should shift emphases from cost reduction and mass media approaches to dissemination of knowledge about IV policy and safety, enhancement of health professionals' advice, and creation of supportive subjective norm. PMID- 30304014 TI - Human umbilical cord blood plasma as an alternative to animal sera for mesenchymal stromal cells in vitro expansion - A multicomponent metabolomic analysis. AB - Mesenchymal Stromal cells (MSCs) have a potential role in cell-based therapies. Foetal bovine serum (FBS) is used to supplement the basal cell culture medium but presents several disadvantages and risks. Other alternatives have been studied, including human umbilical cord blood plasma (hUCBP), aiming at the development of xeno-free culturing protocols. A comparative characterization of multicomponent metabolic composition of hUCBP and commercial FBS based on Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate statistical analysis was performed. The analysis of 1H-NMR spectra revealed both similarities and differences between the two proposed supplements. Similar metabolites (amino acids, glucose, lipids and nucleotides) were found in the hUCBP and FBS NMR spectra. The results show that the major difference between the metabolic profiles of the two proposed supplements are due to the significantly higher levels of glucose and lower levels of lactate, glutamate, alanine and branched chain amino acids in hUCBP. Similar or slightly different levels of important proteinogenic amino acids, as well as of nucleotides, lipids were found in the hUCBP and FBS. In order to validate it's suitability for cell culture, umbilical cord-MSCs (UC-MSCs) and dental pulp stem cells (DPSCs) were expanded using hUCBP. In both hMSCs, in vitro culture with hUCBP supplementation presented similar to improved metabolic performances when compared to FBS. The two cell types tested expressed different optimum hUCBP percentage content. For DPSCs, the optimum hUCBP content was 6% and for UC-MSCs, 4%. Cultured hMSCs displayed no changes in senescence indicators, as well as maintained characteristic surface marker's expression. FBS substitution was associated with an increase in early apoptosis events, in a dose dependent manner, as well as to slight up- and down-regulation of targeted gene's expression. Tri-lineage differentiation capacity was also influenced by the substitution of FBS by hUCBP. PMID- 30304016 TI - Ovarian stromal cells as a source of cancer-associated fibroblasts in human epithelial ovarian cancer: A histopathological study. AB - Fibroblasts are a major component of cancer tissue and known to contribute to cancer progression. However, it remains unknown whether they are derived from local fibroblasts or of other origin. This study was designed to identify the contribution of local stromal cells to cancer stroma in human epithelial ovarian cancer. Seventy-six cases of surgically resected primary ovarian carcinoma (48 cases confined to the ovaries and 28 cases with distant metastases) and 17 cases of secondary ovarian tumor (e.g. colon cancer metastasized to the ovary) were enrolled in this study. The tissues were immunostained for forkhead box protein L2 (FOXL2), a transcription factor crucial for ovarian development and function, and markers for cancer-associated fibroblasts (CAFs) and inflammatory cells. Under normal condition, FOXL2 expression was restricted to ovarian stromal cells and some other types of cells in female genital tracts and never found in other sites of the body. FOXL2-positive cells were found in all primary and secondary tumors in the ovary, and were the dominant stromal cells in most cases. In contrast, only a few FOXL2-positive cells were found in peritoneal seeding sites of four serous carcinoma cases, and all the other tumors at extraovarian sites had no FOXL2-positive cells. FOXL2-positive cells in the ovarian lesion variably expressed CAFs markers, such as alpha-smooth muscle actin and fibroblast activating protein, as determined by double immunostaining. Background inflammation, but not histological subtype or origin of the neoplasm seemed to correlate with the proportion of FOXL2-positive cells. These results suggest that ovarian stromal cells are the main source of cancer stroma in the ovary but do not seem to move to distant sites via circulation together with tumor cells. Our results also support the hypothesis that cancer-associated fibroblasts may originate locally, which was previously demonstrated using animal models. PMID- 30304017 TI - Educational outcomes of a new curriculum on interproximal oral prophylaxis for dental students. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of a preclinical oral prophylaxis education program by examining the effectiveness of the teaching module on changes to the students' attitudes towards their individual hygiene behaviors with interdental brushes (IDBs). METHODS: As being part of a new didactic program on oral interproximal prophylaxis, all preclinical third-year students (n = 96) enrolled in the 2014/15 academic year received theoretical, preclinical, and clinical lessons on interproximal prophylaxis. The evaluation of educational outcomes was linked to observed changes in students' hygiene behaviors using interdental brushes. Knowledge, skills, attitudes, satisfaction, competence and performance were also explored. The evaluation interviews were recorded at each recall, i.e., 1 week, 1 month, 3 months and 1 year after baseline. RESULTS: Motivation to use IDBs is clearly related to the perception of the effectiveness of the brushes and the perception of bleeding reduction. At one week, 89.6% of subjects reported using IDBs. Individual use decreased significantly from one week to one month (-26%, p = 0.006) while a non significant upward trend occurred between one month and three months. Among students reporting usage of IDBs at 1 year (20.8%), only 2.0% used IDBs daily. Most students would recommend IDBs to other people at the beginning (69.8%). However, this share dropped to 50% at 3 months. IDB-users prescribed more than non-users. DISCUSSION AND PUBLIC HEALTH IMPLICATIONS: The implementation of a module on interdental hygiene practices in the oral health program is strongly recommended. However, corrective measures should be considered regarding the organization and frequency of recall periods in order to improve the performance of the curriculum. PMID- 30304018 TI - The excessive length of first ray as a risk factor for hallux valgus recurrence. AB - BACKGROUND: It is still unknown whether the excessive length of the first ray is a risk factor for hallux valgus recurrence. The purpose of this study is to clarify the relationship between the excessive length of the first ray and the recurrence of hallux valgus. METHODS: Between 2008 and 2011, a total of 186 feet (left 105, right 81) who underwent chevron osteotomy combined with distal soft tissue procedure in our foot and ankle center were retrospectively reviewed. A postoperative hallux valgus angle(HVA) >=20 degrees was defined as recurrence. Patients were divided into two groups: recurrence and non-recurrence group. Weight-bearing radiographs were evaluated preoperatively and at the time of last follow-up for both groups. Radiographic parameters including the length of the great toe(P1), the length of the second toe(P2), the length distance between the first and second metatarsal(D), the hallux valgus angle(HVA) were obtained. The excessive length of the first ray(EL) was calculated using the equation of EL = P1-P2-D. RESULTS: A total of 45 patients (24.2%) had hallux valgus recurrence at the time of last follow-up with a mean follow-up of 83.7 +/-12.1 months (range, 66-110). The mean postoperative P1 was 5.06+/-0.39cm for recurrence group and 4.84+/-0.34cm for no recurrence group(p<0.001). The mean post operative EL was 5.71+/-5.01mm for recurrence group and 1.61+/-4.09mm for no recurrence group(p<0.001). The predictive cutoff value of postoperative P1 and postoperative EL for hallux valgus recurrence was 4.9cm [odds ratio (OR) = 8.67, p = 0.03] and 0.4cm (OR = 6.79, p = 0.001) respectively. CONCLUSIONS: Significant relationships between postoperative P1, postoperative EL and hallux valgus recurrence were identified according to our radiographic results. A postoperative P1>4.9cm and postoperative EL>0.4cm can be risk factors for hallux valgus recurrence. The appreciation of the excessive length of the first ray prior to surgery may help to improve the surgical outcome. PMID- 30304019 TI - Punishing liars-How monitoring affects honesty and trust. AB - Previous experiments have shown that the possibility to punish liars does not per se increase honesty in principal-agent relationships. In this study, we first establish a punishment mechanism that substantially enhances honest behavior and trust in a sender-receiver game: the possibility to impose severe sanctions that are cost-free for enforcers. Adopting this effective mechanism, we investigate how variations in the probability of detecting lies affect sender and receiver. We find that high honesty levels persist under such punishment mechanism even when the detection probability is significantly reduced. Furthermore, the relationship between monitoring and honesty does not follow a linear trend, as a moderate monitoring level proves to be less effective in enhancing honesty than high or very low levels. The punishment mechanism has an even more robust effect on receivers, showing similarly high levels of trust independently of the detection probability. Our analysis of subjects' beliefs provides further insights into the mechanics behind these behavioral patterns. PMID- 30304020 TI - Grain number and grain yield distribution along the spike remain stable despite breeding for high yield in winter wheat. AB - Two winter wheat (Triticum aestivum L.) populations, i.e. 180 genetic resources and 210 elite varieties, were compared in a field trial to analyse how grain number and grain yield distribution along the spike changed during the breeding process and how this associates to yield-related traits. Elites showed in average 38% more yield compared to resources. This breeding improvement mainly derived from an increase in grains and yield per spike in addition to grains and yield per spikelet. These increments corresponded to 19, 23, 21 and 25%, respectively. Not much gain in thousand grain weight (4%) was observed in elites as compared to resources. The number of spikelets per spike was not, or even negatively, correlated with most traits, except of grains per spike, which suggests that this trait was not favoured during breeding. The grain number and grain yield distributions along the spike (GDAS and GYDAS) were measured and compared by using a novel mathematical tool. GDAS and GYDAS measure the deviation of a spike of interest from the architecture of a model spike with even grain and yield distribution along all spikelets, respectively. Both traits were positively correlated. Elites showed in average only a 1% improvement in GDAS and GYDAS values compared to resources. This comparison revealed that breeding increased grain number and yield uniformly along the spike without changing relative yield input of individual spikelets, thereby, maintaining the general spike architecture. PMID- 30304021 TI - Correction: The effects of increasing longevity and changing incidence on lifetime risk differentials: A decomposition approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0195307.]. PMID- 30304022 TI - CaSTLe - Classification of single cells by transfer learning: Harnessing the power of publicly available single cell RNA sequencing experiments to annotate new experiments. AB - Single-cell RNA sequencing (scRNA-seq) is an emerging technology for profiling the gene expression of thousands of cells at the single cell resolution. Currently, the labeling of cells in an scRNA-seq dataset is performed by manually characterizing clusters of cells or by fluorescence-activated cell sorting (FACS). Both methods have inherent drawbacks: The first depends on the clustering algorithm used and the knowledge and arbitrary decisions of the annotator, and the second involves an experimental step in addition to the sequencing and cannot be incorporated into the higher throughput scRNA-seq methods. We therefore suggest a different approach for cell labeling, namely, classifying cells from scRNA-seq datasets by using a model transferred from different (previously labeled) datasets. This approach can complement existing methods, and-in some cases-even replace them. Such a transfer-learning framework requires selecting informative features and training a classifier. The specific implementation for the framework that we propose, designated ''CaSTLe-classification of single cells by transfer learning,'' is based on a robust feature engineering workflow and an XGBoost classification model built on these features. Evaluation of CaSTLe against two benchmark feature-selection and classification methods showed that it outperformed the benchmark methods in most cases and yielded satisfactory classification accuracy in a consistent manner. CaSTLe has the additional advantage of being parallelizable and well suited to large datasets. We showed that it was possible to classify cell types using transfer learning, even when the databases contained a very small number of genes, and our study thus indicates the potential applicability of this approach for analysis of scRNA-seq datasets. PMID- 30304023 TI - Modification of cellular membranes conveys cryoprotection to cells during rapid, non-equilibrium cryopreservation. AB - Rapid cooling and re-warming has been shown promising to cryopreserve living cells, which cannot be preserved by conventional slow freezing methods. However, success is limited by the cytotoxicity of highly concentrated cryoprotective agents. Recent results have shown that cryoprotective agents do not need to suppress intracellular ice crystals completely to allow for survival after cryopreservation. Cryoprotective agents like DMSO or ethylene glycol can also lead to a tolerance of cells towards intracellular ice. It is however unclear by which mechanism this tolerance is achieved. These substances are also known to modulate properties of cellular membranes. It is shown here that cryoprotective DMSO and ethylene glycol have a clear influence on the mobility of lipids in the plasma membrane of HeLa cells. To isolate changes of the properties of plasma membranes from effects on ice formation, the membrane properties were modulated in absence of cryoprotective agents. This was achieved by changing their sterol content. In cells with elevated sterol content, an immobile lipid fraction was present, similar to cells treated with DMSO and ethylene glycol. These cells showed also significantly increased plasma membrane integrity after rapid freezing and thawing in the absence of classical cryoprotective agents. However, their intracellular lysosomes, which cannot be enriched with sterols, still got ruptured. These results clearly indicate that a modulation of membrane properties can convey cryoprotection. Upon slow cooling, elevated sterol content had actually an adverse effect on the plasma membranes, which shows that this effect is specific for rapid, non-equilibrium cooling processes. Unraveling this alternative mode of action of cryoprotection should help in the directed design of novel cryoprotective agents, which might be less cytotoxic than classical, empirically-found cryoprotective agents. PMID- 30304024 TI - Impaired myogenic development, differentiation and function in hESC-derived SMA myoblasts and myotubes. AB - Spinal muscular atrophy (SMA) is a severe genetic disorder that manifests in progressive neuromuscular degeneration. SMA originates from loss-of-function mutations of the SMN1 (Survival of Motor Neuron 1) gene. Recent evidence has implicated peripheral deficits, especially in skeletal muscle, as key contributors to disease progression in SMA. In this study we generated myogenic cells from two SMA-affected human embryonic stem cell (hESC) lines with deletion of SMN1 bearing two copies of the SMN2 gene and recapitulating the molecular phenotype of Type 1 SMA. We characterized myoblasts and myotubes by comparing them to two unaffected, control hESC lines and demonstrate that SMA myoblasts and myotubes showed altered expression of various myogenic markers, which translated into an impaired in vitro myogenic maturation and development process. Additionally, we provide evidence that these SMN1 deficient cells display functional deficits in cholinergic calcium signaling response, glycolysis and oxidative phosphorylation. Our data describe a novel human myogenic SMA model that might be used for interrogating the effect of SMN depletion during skeletal muscle development, and as model to investigate biological mechanisms targeting myogenic differentiation, mitochondrial respiration and calcium signaling processes in SMA muscle cells. PMID- 30304025 TI - Thrombin-antithrombin complex measurement using a point-of-care testing device for diagnosis of disseminated intravascular coagulation in dogs. AB - Reference interval for thrombin-antithrombin complex (TAT) level was determined using an in-house TAT measurement device, and its validity for diagnosis of disseminated intravascular coagulation (DIC) was evaluated in dogs. One hundred and two clinically healthy dogs and 247 diseased dogs with conditions that potentially caused DIC were recruited in the study. Six diagnostic testing for DIC were evaluated in diseased dogs and the diseased dogs were categorized into five groups depending on abnormal findings. TAT was measured in all study animals and between-group differences were evaluated. TAT level was positively associated with severity of DIC. There were no significant differences in TAT levels among clinically healthy dogs, diseased dogs without any abnormal finding and diseased dogs with one abnormal finding in the DIC diagnostic testing. TAT levels in groups with two or more abnormal findings were significantly higher than clinically healthy dogs. Reference interval of TAT level for clinically healthy dogs was <= 0.25 ng/ml. Validity of using TAT for early detection of DIC was evaluated. In-house TAT measurement was suggested to be a clinically relevant and useful tool for early detection of canine DIC. PMID- 30304027 TI - Correction: Human DNA Helicase B Functions in Cellular Homologous Recombination and Stimulates Rad51-Mediated 5'-3' Heteroduplex Extension In Vitro. AB - [This corrects the article DOI: 10.1371/journal.pone.0116852.]. PMID- 30304026 TI - To be thin but not healthy - The body-image dilemma may affect health among female university students in China. AB - An increasing number of young girls have attached great importance to their body image in China. Body-image dissatisfaction has resulted in increased weight loss behavior. The aim of this study was to investigate the factors that were associated with underweight body-image in female college students. Self administered questionnaires were completed by 2,023 young female participants from eight Chinese universities. In addition, 160 participants were involved in a qualitative study. The ideal body-image and the factors that influence weight were determined using descriptive and analytical statistics. We found that 1,484 out of 2,023 participants (73.36%) had taken action to lose weight in the past six months. Among these participants, 618 (30.55%, out of 2023) participants were already underweight, and 1,161 (57.39%, out of 2023) would like to be much thinner, which would lead to more underweight individuals. Moreover, non scientific physical activity and diets were found to lead participants to the underweight subgroup. The participants' Body Mass Index (BMI), peer advice and western culture influenced the problematic thin-ideal (ideal BMI < 18.5 was considered as the problematic thin-ideal) (P<0.05). Together, western influences leading to the "problematic thin-ideal" and "unhealthy weight-control behavior" have brought about an increased prevalence of desired underweight body-image among female college students in China, which might be harmful for their health. PMID- 30304028 TI - Human intestinal parasites in Mahajanga, Madagascar: The kingdom of the protozoa. AB - INTRODUCTION: Intestinal parasitic infections are a major public health problem in inter-tropical areas. The aim of our study was to describe the situation in Mahajanga, Madagascar with a particular focus on two protozoa, Dientamoeba fragilis and Blastocystis sp. METHODS: This was a prospective study from February to June 2015. Stool samples from symptomatic hospitalized patients and asymptomatic volunteers were submitted to microscopy and molecular assays in order to detect parasites. RESULTS: A wide panel of intestinal parasites were identified among the 265 included subjects, protozoa being the most prevalent with 72.8% whereas the prevalence of helminths and microsporidia was of 7.9% and 4.5%, respectively. Blastocystis sp. was the most prevalent protozoa (64.5% of the entire cohort) followed by various amoebas (35.5%) and flagellates (27,5%). We only detected subtypes 1, 2 and 3 of Blastocystis sp. Among the patients positive for D. fragilis (9.4%), 23 carried genotype 1 and 1 genotype 2. For the first time, we detected in 4 human stools the DNA of a recently described protozoon, Simplicimonas similis. Interestingly, subjects living in urban areas harbored significantly more different parasitic species than subjects living in rural areas with a correlation between sanitary level of neighborhood and protozoan infection. However, there was no difference in prevalence of digestive symptoms between parasite-free and parasite-infected subjects, except for Giardia intestinalis which had more symptomatic carriers. DISCUSSION: Our study reveals a high overall parasite prevalence, similar to what had been found in 2003 in the same city and to other prevalence studies conducted in Africa. The poor access of the population to sanitary infrastructures may explain this result. Data from our study provide valuable key for sanitation programs and prevention of fecal related infectious diseases. PMID- 30304029 TI - Body temperature elevation during exercise is essential for activating the Akt signaling pathway in the skeletal muscle of type 2 diabetic rats. AB - This study examined the effect of changes in body temperature during exercise on signal transduction-related glucose uptake in the skeletal muscle of type 2 diabetic rats. Otsuka Long-Evans Tokushima Fatty rats (25 weeks of age), which have type 2 diabetes, were divided into the following four weight-matched groups; control (CON, n = 6), exercised under warm temperature (WEx, n = 8), exercised under cold temperature (CEx, n = 8), and heat treatment (HT, n = 6). WEx and CEx animals were subjected to running on a treadmill at 20 m/min for 30 min under warm (25 degrees C) or cold (4 degrees C) temperature. HT animals were exposed to single heat treatment (40-41 degrees C for 30 min) in a heat chamber. Rectal and muscle temperatures were measured immediately after exercise and heat treatment, and the gastrocnemius muscle was sampled under anesthesia. Rectal and muscle temperatures increased significantly in rats in the WEx and HT, but not the CEx, groups. The phosphorylation levels of Akt, AS160, and TBC1D1 (Thr590) were significantly higher in the WEx and HT groups than the CON group (p < 0.05). In contrast, the phosphorylation levels of AMP-activated protein kinase, ACC, and TBC1D1 (Ser660) were significantly higher in rats in the WEx and CEx groups than the CON group (p < 0.05) but did not differ significantly between rats in the WEx and CEx groups. Body temperature elevation by heat treatment did not activate the AMPK signaling. Our data suggest that body temperature elevation during exercise is essential for activating the Akt signaling pathway in the skeletal muscle of rats with type 2 diabetic rats. PMID- 30304031 TI - Retraction: MicroRNA-143 Targets Syndecan-1 to Repress Cell Growth in Melanoma. PMID- 30304030 TI - Quadriceps neuromuscular function in women with patellofemoral pain: Influences of the type of the task and the level of pain. AB - The present study aimed at investigating whether the neuromuscular system behaves differently (in terms of force and muscle activity generation) as a function of the task being performed (i.e. maximal voluntary efforts vs stair negotiation) and the presence of patellofemoral pain (PFP) and possible influences of pain intensity. Thirty-eight women with (n = 19) and without PFP (n = 19) had their knee strength (extension joint torque) measured during maximal voluntary isometric contractions (MVIC) and electromyography (EMG) data recorded during both MVIC and stair ascent tasks, which were performed before and after a loading protocol designed to exacerbate pain symptoms. Women with PFP displayed lower levels of vastus medialis (p = 0.002) and vastus lateralis (p = 0.032) EMG activation during MVIC assessments. Conversely, the PFP group showed higher levels of vastus medialis muscle activity during stair climbing (p = 0.007), which happened exclusively after the loading protocol. Similarly, women with PFP displayed lower knee extensor torque only during the MVIC tests performed after the loading protocol, which was moderately correlated with the increase in self reported pain (p = 0.041, r = 0.37), whereas the changes in EMG activity during stair ascent were not correlated with changes in pain intensity (p = 0.215, r = 0.12). These results suggest that, in comparison to pain-free controls, women with PFP display lower levels of quadriceps EMG activation during maximal contractions, but higher activation during dynamic tasks (stair ascent). In addition, the moderate association between the decrease in knee extensor torque and increase in self-reported pain indicates that care should be taken by clinicians during quadriceps strength evaluation in women with PFP, as misleading outcomes may emerge if the intensity of knee pain is not considered during screening. Additionally, rehabilitation strategies should focus on both restoring neuromuscular control and increasing muscle strength. PMID- 30304032 TI - Compromised knee internal rotation in total knee arthroplasty patients during stair climbing. AB - Due to the significant role of rotational properties for normal knee function, this study aimed to investigate transverse plane kinematics and kinetics in total knee arthroplasty and unicondylar knee arthroplasty patients during activities of daily living compared to a healthy control group, including stair ascent and descent. The study participants consisted of a total knee arthroplasty group including posterior cruciate retaining and posterior stabilized designs as well as a unicondylar knee arthroplasty group and a healthy control group. Three dimensional kinematics and kinetics were captured using a Vicon system and two Kistler force plates embedded in the floor and another two in a staircase. Inverse dynamics of the lower limbs was computed in AnybodyTM Modeling System. Transverse plane joint angles and joint moments were analyzed utilizing the statistical non-parametric mapping approach, considering the entire curve shape for statistical analysis. The patients with total knee arthroplasty exhibited significantly reduced knee internal rotation of the operated knee compared to the control group and the patients' unimpaired limb, especially during the stair climbing tasks. Both unicondylar and total knee arthroplasty patients were found to have similar reduced internal rotation motion time series in stair descent. In conclusion, potential kinematic and kinetic benefits of unicondylar knee arthroplasty over total knee arthroplasty could not be proven in the current study. Aside from the usually mentioned reasons inducing constrained knee internal rotation in total knee arthroplasty patients, future studies should investigate to what extent co-contraction may contribute to this functional impairment in patients after knee arthroplasty surgery. PMID- 30304034 TI - Hippo signaling pathway is altered in Duchenne muscular dystrophy. AB - Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment. PMID- 30304035 TI - Anatomy and systematics of the sauropodomorph Sarahsaurus aurifontanalis from the Early Jurassic Kayenta Formation. AB - Sarahsaurus aurifontanalis, from the Kayenta Formation of Arizona, is one of only three sauropodomorph dinosaurs known from the Early Jurassic of North America. It joins Anchisaurus polyzelus, from the older Portland Formation of the Hartford Basin, and Seitaad reussi, from the younger Navajo Sandstone of Utah, in representing the oldest North American sauropodomorphs. If it is true that sauropodomorphs were absent from North America during the Late Triassic, the relationship among these three dinosaurs offers a test of the mechanisms that drove recovery in North American biodiversity following the end-Triassic extinction event. Here we provide the first thorough description of Sarahsaurus aurifontanalis based on completed preparation and computed tomographic imaging of the holotype and referred specimens. With new anatomical data, our phylogenetic analysis supports the conclusion that Sarahsaurus aurifontanalis is nested within the primarily Gondwanan clade Massospondylidae, while agreeing with previous analyses that the three North American sauropodomorphs do not themselves form an exclusive clade. A revised diagnosis and more thorough understanding of the anatomy of Sarahsaurus aurifontanalis support the view that independent dispersal events were at least partly responsible for the recovery in North American vertebrate diversity following a major extinction event. PMID- 30304033 TI - A systematic review on the effects of resistance and plyometric training on physical fitness in youth- What do comparative studies tell us? AB - INTRODUCTION: To date, several meta-analyses clearly demonstrated that resistance and plyometric training are effective to improve physical fitness in children and adolescents. However, a methodological limitation of meta-analyses is that they synthesize results from different studies and hence ignore important differences across studies (i.e., mixing apples and oranges). Therefore, we aimed at examining comparative intervention studies that assessed the effects of age, sex, maturation, and resistance or plyometric training descriptors (e.g., training intensity, volume etc.) on measures of physical fitness while holding other variables constant. METHODS: To identify relevant studies, we systematically searched multiple electronic databases (e.g., PubMed) from inception to March 2018. We included resistance and plyometric training studies in healthy young athletes and non-athletes aged 6 to 18 years that investigated the effects of moderator variables (e.g., age, maturity, sex, etc.) on components of physical fitness (i.e., muscle strength and power). RESULTS: Our systematic literature search revealed a total of 75 eligible resistance and plyometric training studies, including 5,138 participants. Mean duration of resistance and plyometric training programs amounted to 8.9 +/- 3.6 weeks and 7.1+/-1.4 weeks, respectively. Our findings showed that maturation affects plyometric and resistance training outcomes differently, with the former eliciting greater adaptations pre-peak height velocity (PHV) and the latter around- and post-PHV. Sex has no major impact on resistance training related outcomes (e.g., maximal strength, 10 repetition maximum). In terms of plyometric training, around-PHV boys appear to respond with larger performance improvements (e.g., jump height, jump distance) compared with girls. Different types of resistance training (e.g., body weight, free weights) are effective in improving measures of muscle strength (e.g., maximum voluntary contraction) in untrained children and adolescents. Effects of plyometric training in untrained youth primarily follow the principle of training specificity. Despite the fact that only 6 out of 75 comparative studies investigated resistance or plyometric training in trained individuals, positive effects were reported in all 6 studies (e.g., maximum strength and vertical jump height, respectively). CONCLUSIONS: The present review article identified research gaps (e.g., training descriptors, modern alternative training modalities) that should be addressed in future comparative studies. PMID- 30304036 TI - Postnatal changes in the development of rat submandibular glands in offspring of diabetic mothers: Biochemical, histological and ultrastructural study. AB - Development and maturation of submandibular salivary glands are influenced by intrauterine diabetic environment. Several studies investigated the effects of diabetes on the salivary glands. However, the effects of maternal diabetes on the submandibular glands of the offspring was not properly examined. Therefore, the present study was designed to describe the changes in the development of the submandibular glands of the offspring of diabetic mothers. The submandibular glands of the offspring of Streptozotocin (STZ)-induced diabetic female rats were examined at two and four weeks after birth. Detection of mRNA demonstrated that maternal diabetes affects the level of different indicators. The reduction of expression of epidermal growth factor (EGF); a protein mitogen, cytokeratin 5 (CK5); an epithelial cell progenitor, CK7 and aquaporin 5 (AQP5); differentiation markers and B cell lymphoma 2 (Bcl2); an antiapoptotic marker were found. Increase in Bcl2-associated X protein (Bax); an apoptotic marker was detected. These changes indicate their effects on saliva secretion, glands tumorigenesis, growth of normal oral flora and oral microbes, with decreased protein synthesis and production of xerostomia and dental caries. Loss of normal glandular architecture, significant increase in fibrosis, by the detection of collagen fibers, and stagnation of secretory granules were found with atrophic changes in the acinar cells. Marked defect of polysaccharides in the acinar cells, denoting functional changes, was manifested by significant reduction of the intensity of periodic acid-Schiff (PAS) reaction. The positive immunoreactivity of caspase-3, denoting cellular apoptosis, and minimal reaction of alpha-smooth muscle actin (alpha SMA) and proliferating cell nuclear antigen (PCNA) were evident in the offspring of diabetic mothers. We conclude that maternal diabetes produces degenerative effects in the structure and function of the submandibular salivary glands of the offspring, reflecting possible influences on their secretory activity affecting oral and digestive health. PMID- 30304037 TI - Strength exercise weakens aerobic exercise-induced cognitive improvements in rats. AB - Aerobic exercise improves cognitive function and adult hippocampal neurogenesis. However, the effects of aerobic exercise combined with strength exercise on cognitive function and adult hippocampal neurogenesis are still unknown. In this study, we established exercise paradigms in rats to mimic aerobic exercise combined with low- and high-intensity strength exercise. We found that aerobic exercise improved spatial learning and memory as well as adult hippocampal neurogenesis, whereas strength exercise suppressed aerobic exercise-induced cognitive improvements and adult hippocampal neurogenesis in an intensity dependent manner. Furthermore, the levels of beta-hydroxybutyrate (beta-HB) and its downstream effector brain-derived neurotrophic factor (BDNF) were increased in the aerobic exercise group, and strength exercise impaired the aerobic exercise-induced increases in beta-HB and BDNF mRNA levels. Taken together, these results demonstrated that strength exercise weakened aerobic exercise-induced cognitive improvements and adult hippocampal neurogenesis in rats. PMID- 30304038 TI - Managers, modelers, and measuring the impact of species distribution model uncertainty on marine zoning decisions. AB - Marine managers routinely use spatial data to make decisions about their marine environment. Uncertainty associated with this spatial data can have profound impacts on these management decisions and their projected outcomes. Recent advances in modeling techniques, including species distribution models (SDMs), make it easier to generate continuous maps showing the uncertainty associated with spatial predictions and maps. However, SDM predictions and maps can be complex and nuanced. This complexity makes their use challenging for non technical managers, preventing them from having the best available information to make decisions. To help bridge these communication and information gaps, we developed maps to illustrate how SDMs and associated uncertainty can be translated into readily usable products for managers. We also explicitly described the potential impacts of uncertainty on marine zoning decisions. This approach was applied to a case study in Saipan Lagoon, Commonwealth of the Northern Mariana Islands (CNMI). Managers in Saipan are interested in minimizing the potential impacts of personal watercraft (e.g., jet skis) on staghorn Acropora (i.e., Acropora aspera, A. formosa, and A. pulchra), which is an important coral assemblage in the lagoon. We used a recently completed SDM for staghorn Acropora to develop maps showing the sensitivity of zoning options to three different prediction and three different uncertainty thresholds (nine combinations total). Our analysis showed that the amount of area and geographic location of predicted staghorn Acropora presence changed based on these nine combinations. These dramatically different spatial patterns would have significant zoning implications when considering where to exclude and/or allow jet skis operations inside the lagoon. They also show that different uncertainty thresholds may lead managers to markedly different conclusions and courses of action. Defining acceptable levels of uncertainty upfront is critical for ensuring that managers can make more informed decisions, meet their marine resource goals and generate favorable outcomes for their stakeholders. PMID- 30304039 TI - Time resolved 3D live-cell imaging on implants. AB - It is estimated that two million new dental implants are inserted worldwide each year. Innovative implant materials are developed in order to minimize the risk of peri-implant inflammations. The broad range of material testing is conducted using standard 2D, terminal, and invasive methods. The methods that have been applied are not sufficient to monitor the whole implant surface and temporal progress. Therefore, we built a 3D peri-implant model using a cylindrical implant colonized by human gingival fibroblasts. In order to monitor the cell response over time, a non-toxic LIVE/DEAD staining was established and applied to the new 3D model. Our LIVE/DEAD staining method in combination with the time resolved 3D visualization using Scanning Laser Optical Tomography (SLOT), allowed us to monitor the cell death path along the implant in the 3D peri-implant model. The differentiation of living and dead gingival fibroblasts in response to toxicity was effectively supported by the LIVE/DEAD staining. Furthermore, it was possible to visualize the whole cell-colonized implant in 3D and up to 63 hours. This new methodology offers the opportunity to record the long-term cell response on external stress factors, along the dental implant and thus to evaluate the performance of novel materials/surfaces. PMID- 30304040 TI - Spatial variation in leopard (Panthera pardus) site use across a gradient of anthropogenic pressure in Tanzania's Ruaha landscape. AB - Understanding large carnivore occurrence patterns in anthropogenic landscapes adjacent to protected areas is central to developing actions for species conservation in an increasingly human-dominated world. Among large carnivores, leopards (Panthera pardus) are the most widely distributed felid. Leopards occupying anthropogenic landscapes frequently come into conflict with humans, which often results in leopard mortality. Leopards' use of anthropogenic landscapes, and their frequent involvement with conflict, make them an insightful species for understanding the determinants of carnivore occurrence across human dominated habitats. We evaluated the spatial variation in leopard site use across a multiple-use landscape in Tanzania's Ruaha landscape. Our study region encompassed i) Ruaha National Park, where human activities were restricted and sport hunting was prohibited; ii) the Pawaga-Idodi Wildlife Management Area, where wildlife sport hunting, wildlife poaching, and illegal pastoralism all occurred at relatively low levels; and iii) surrounding village lands where carnivores and other wildlife were frequently exposed to human-carnivore conflict related-killings and agricultural habitat conversion and development. We investigated leopard occurrence across the study region via an extensive camera trapping network. We estimated site use as a function of environmental (i.e. habitat and anthropogenic) variables using occupancy models within a Bayesian framework. We observed a steady decline in leopard site use with downgrading protected area status from the national park to the Wildlife Management Area and village lands. Our findings suggest that human-related activities such as increased livestock presence and proximity to human households exerted stronger influence than prey availability on leopard site use, and were the major limiting factors of leopard distribution across the gradient of human pressure, especially in the village lands outside Ruaha National Park. Overall, our study provides valuable information about the determinants of spatial distribution of leopards in human-dominated landscapes that can help inform conservation strategies in the borderlands adjacent to protected areas. PMID- 30304041 TI - Four types of vibration behaviors in a mole cricket. AB - Vibrational communication is known in some subterranean insects. Except for their use in sexual signaling, vibration behavior has rarely been reported. We report here four distinct types of substrate-based vibration behaviors in the mole cricket, Gryllotalpa orientalis, which are not associated with sexual signaling because of the occurrence of these behaviors in nymphs: (1) scraping with the forelegs; (2) foreleg taps (tapping with the forelegs); (3) palpal taps (tapping with the maxillary palpi); and (4) tremulation (back-and-forth movement of the whole body). Scraping is hypothesized to be used for the inspection of borrows. Foreleg taps are possibly informing nearby individuals of their presence, because it is never observed in solitary conditions. Palpal taps are rarely observed and its function is unknown. Tremulation is possibly related to avoidance of conspecific individual approaching and touching. The combination of the four vibration behaviors in the mole cricket may be unique among insects. PMID- 30304042 TI - Does Calypogeia azurea (Calypogeiaceae, Marchantiophyta) occur outside Europe? Molecular and morphological evidence. AB - Oil bodies are the unique feature of most liverworts. Their shape, color and distribution pattern in leaf and underleaf cells are important taxonomic features of the genus Calypogeia. Most species of the genus Calypogeia have pellucid and colorless oil bodies, whereas colored, including gray to pale brown, purple-brown or blue oil bodies, are rare. To date, C. azurea was the only species with blue oil bodies to have been considered as a species of the Holarctic range. This species has been noted in various parts of the northern hemisphere-from North America, through Europe to the Far East. The aim of this study was to determine the genetic diversity of C. azurea from different parts of its distribution range and to ascertain whether blue oil bodies appeared once or several times in the evolution of the genus Calypogeia. The phylogenetic analyses based on four plastid regions (rbcL, trnG, trnL, trnH-psbA) and one nuclear region (ITS2) revealed that C. azurea is presently a paraphyletic taxon, with other Calypogeia species nested among C. azurea accessions that were clustered into four different clades. Based on the level of genetic divergence (1.03-2.17%) and the observed morphological, ecological and geographical differences, the evaluated clades could be regarded as previously unrecognized species. Four species were identified: C. azurea Stotler & Crotz (a European species corresponding to the holotype), two new species from Pacific Asia-C. orientalis Buczkowska & Bakalin and C. sinensis Bakalin & Buczkowska, and a North American species which, due to the lack of identifiable morphological features, must be regarded as the cryptic species of C. azurea with a provisional name of C. azurea species NA. PMID- 30304043 TI - Field evaluation of SD BIOLINE HIV/Syphilis Duo assay among pregnant women attending routine antenatal care in Juba, South Sudan. AB - The SD BIOLINE HIV/Syphilis Duo assay is the first World Health Organization prequalified dual rapid diagnostic test for simultaneous detection of HIV and Treponema pallidum antibodies in human blood. Prior to introducing the test into antenatal clinics across South Sudan, a field evaluation of its clinical performance in diagnosing both HIV and syphilis in pregnant women was conducted. SD Bioline test performance on venous blood samples was compared with (i) Vironostika HIV1/2 Uniform II Ag/Ab reference standard and Alere Determine HIV 1/2 non-reference standard for HIV diagnosis, and (ii) Treponema pallidum hemagglutination reference standard and Rapid plasma reagin non-reference standard for syphilis. Sensitivity, specificity, positive predictive value (PPN), negative predictive value (NPV) and kappa (kappa) value were calculated for each component against the reference standards within 95% confidence intervals (CIs); agreements between Determine HIV 1/2 and SD Bioline HIV tests were also calculated. Of 442 pregnant women recruited, eight (1.8%) were HIV positive, 22 (5.0%) had evidence of syphilis exposure; 14 (3.2%) had active infection. For HIV diagnosis, the sensitivity, specificity, PPV and NPV were 100% (95% CI: 63.1 100), 100% (95% CI: 99.2-100), 100% (95% CI: 63.1-100) and 100% (95% CI: 99.2 100) respectively with kappa value of 1 (95% CI: 0.992-1.000). Overall agreement of the Duo HIV component and Determine test was 99.1% (95% CI: 0.977-0.998) with 66.7% (95% CI: 34.9-90.1) positive and 100% (95% CI: 0.992-1.000) negative percent agreements. For syphilis, the Duo assay sensitivity was 86.4% (95% CI: 65.1-97.1) and specificity 100% (95% CI: 99.1-100) with PPV 100% (95% CI: 82.4 100), NPV 99.2% (95% CI: 97.9-99.9) and kappa value 0.92 (95% CI: 0.980-0.999). Our findings suggest the SD Bioline HIV/Syphilis Duo Assay could be suitable for HIV and syphilis testing in women attending antenatal services across South Sudan. Women with positive syphilis results should receive treatment immediately, whereas HIV positive women should undergo confirmatory testing following national HIV testing guidelines. PMID- 30304044 TI - Dynamics of collective performance in collaboration networks. AB - Today, many complex tasks are assigned to teams, rather than individuals. One reason for teaming up is expansion of the skill coverage of each individual to the joint team skill set. However, numerous empirical studies of human groups suggest that the performance of equally skilled teams can widely differ. Two natural question arise: What are the factors defining team performance? and How can we best predict the performance of a given team on a specific task? While the team members' task-related capabilities constrain the potential for the team's success, the key to understanding team performance is in the analysis of the team process, encompassing the behaviors of the team members during task completion. In this study, we extend the existing body of research on team process and prediction models of team performance. Specifically, we analyze the dynamics of historical team performance over a series of tasks as well as the fine-grained patterns of collaboration between team members, and formally connect these dynamics to the team performance in the predictive models. Our major qualitative finding is that higher performing teams have well-connected collaboration networks-as indicated by the topological and spectral properties of the latter which are more robust to perturbations, and where network processes spread more efficiently. Our major quantitative finding is that our predictive models deliver accurate team performance predictions-with a prediction error of 15-25%-on a variety of simple tasks, outperforming baseline models that do not capture the micro-level dynamics of team member behaviors. We also show how to use our models in an application, for optimal online planning of workload distribution in an organization. Our findings emphasize the importance of studying the dynamics of team collaboration as the major driver of high performance in teams. PMID- 30304045 TI - Hepatobiliary scintigraphy allows the evaluation of short-term functional toxicity of liver stereotactic body radiotherapy: Results of a pilot study. AB - PURPOSE: To study the potential of (99m)Tc-Mebrofenin hepatobiliary scintigraphy (HBS) in identifying the short-term variations of liver function after stereotactic body radiotherapy (SBRT) for liver cancers. MATERIAL AND METHODS: We treated with SBRT 3 patients (pts) affected by a cholangiocarcinoma and 3 patient presenting liver metastases (3x15 Gy, 4 pts; 5x8 Gy, 1 pt; 6x5 Gy, 1 pt). All patients received HBS before and 3 months after SBRT, which were co-registered with the simulation CT-scan. Structures corresponding to isodoses from 10-90 Gy were created, with intervals of 10 Gy. Finally, the variations of the mean activity (MBq) in each isodose structure have been calculated. Then, a linear regression analysis was performed. RESULTS: We showed a linear reduction of the activity, significantly related to the delivered dose (p<0.01), and a reduction of the perfusion of 0.78% for each delivered Gy. The linear equation has predictive value of the loss of the function of 96% (R2 = 0.9605). CONCLUSIONS: HBS could improve treatment plans for liver SBRT, by allowing the identification of the liver function variations after SBRT and, potentially, the prediction of remnant liver function after SBRT. These preliminary results should be confirmed on long-term prospective data and larger population. PMID- 30304046 TI - Neutrophilia as prognostic biomarker in locally advanced stage III lung cancer. AB - OBJECTIVE: To study the prognostic value of baseline leukocytosis or neutrophiliain two retrospective cohorts of stage III Non-Small Cell Lung Cancer (NSCLC) patients. MATERIALS AND METHODS: Clinical records of consecutive previously untreated NSCLC patients in our Institution between June 2001 and September 2016 for stage III NSCLC were collected. The prognostic value of pretreatment leucocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophil count exceeding 10 and 7 G/L, respectively. RESULTS: We identified 238 patients, displaying baseline leukocytosis or neutrophilia in 39% and 40% respectively. Most were diagnosed with adenocarcinoma (48%), and stage IIIB NSCLC (58%). 3-year actuarial overall survival (OS) and progression-free survival (PFS) were 35% and 27% respectively. Local relapses were reported in 100 patients (42%), and distant metastases in 132 patients (55%). In multivariate analysis, leukocytosis, neutrophilia, and induction chemotherapy regimen based on carboplatin/paclitaxel were associated with worse OS and PFS (p<0.05). Neutrophilia independently decreased Locoregional Control (LRC) (HR = 2.5, p<0.001) and Distant Metastasis Control (DMC) (HR = 2.1, p<0.001). Neutrophilia was significantly associated with worse brain metastasis control (p = 0.004), mostly in adenocarcinoma patients (p<0.001). CONCLUSION: In stage III NSCLC patients, treated with concurrent cisplatin-based chemoradiation, baseline leukocytosis and neutrophilia were associated with worse OS, PFS, LRC, and DMC. In addition with previously available markers, this independent cost-effective biomarker could help to stratify stage III NSCLC population with more accuracy. PMID- 30304047 TI - Unilateral electrical stimulation of the heart 7 acupuncture point to prevent emergence agitation in children: A prospective, double-blinded, randomized clinical trial. AB - BACKGROUND: Emergence agitation (EA) is a frequent phenomenon in children recovering from general anaesthesia and increases the risk of self-injury. Previously, our group reported that stimulating the heart 7 (HT7) acupuncture point bilaterally using two neuromuscular transmission monitoring devices (NTMs) decreased the incidence of EA. However, bilateral stimulation is a barrier to clinical use because two NTMs are needed for one patient. OBJECTIVE: The objective of this study was to examine the efficacy of unilateral electrical stimulation of HT7 using an NTM to prevent EA in children. DESIGN: Prospective, double-blinded, randomized clinical trial. SETTING: Kanagawa Children's Medical Centre, Yokohama, Japan. PATIENTS: One hundred children (ages 18-96 months) with ASA-PS I or II, who were scheduled to undergo inguinal hernia repair or orchiopexy under sevoflurane anaesthesia. INTERVENTION: Patients were randomly assigned to one of the following two groups: (1) HT7 group: unilateral (right side) stimulation of the HT7 acupuncture point using a single-twitch electrical stimulus (1 Hz, 50 mA) throughout the surgery, and (2) control group: electrodes alone were attached to the HT7 point on the right side; an electrical stimulus was not applied. MAIN OUTCOME MEASURES: The primary outcome was the incidence of EA evaluated using the pediatric anaesthesia emergence delirium (PAED) scale. The secondary outcomes were the incidence of EA evaluated using Aono's scale, the severity of EA, PACU stay duration, and postoperative pain. RESULTS: There was no statistical difference between the incidence of EA in the HT7 and the control group (28.0% and 24.0%, respectively; P > 0.99). The risk ratio was 1.17 (95% confidence interval: 0.60-2.27). CONCLUSIONS: We observed that there was no effect of unilateral single-twitch electrical stimulation to the HT7 on the incidence of EA, contrary to the findings with bilateral HT7 stimulation. PMID- 30304048 TI - A longitudinal study of infants' early speech production and later letter identification. AB - Letter identification is an early metric of reading ability that can be reliability tested before a child can decode words. We test the hypothesis that early speech production will be associated with children's later letter identification. We examined longitudinal growth in early speech production in 9 typically developing children across eight occasions, every 3 months from 9 months to 30 months. At each occasion, participants and their caregivers engaged in a speech sample in a research lab. This speech sample was transcribed for a variety of vocalizations, which were then transformed to calculate consonant vowel ratio. Consonant-vowel ratio is a measure of phonetic complexity in speech production. At the age of 72 months, children's letter knowledge was measured. A multilevel model including fixed quadratic age change and a random intercept was estimated using letter identification as a predictor of the growth in early speech production from 9-30 months, measured by the outcome of consonant-vowel ratio. Results revealed that the relation between early speech production and letter identification differed over time. For each additional letter that a child identified, their consonant-vowel ratio at the age of 9 months increased. As such, these results confirmed our hypothesis: more robust early speech production is associated with more accurate letter identification. PMID- 30304049 TI - Post-mortem serum concentrations of GFAP correlate with agony time but do not indicate a primary cerebral cause of death. AB - BACKGROUND AND PURPOSE: The astroglial protein GFAP is a blood biomarker indicative of intracerebral hemorrhage in patients with acute stroke. Due to its brain specificity and the necessity of brain damage for its detectability in blood, we hypothesized that GFAP could be an interesting marker in cases with primary cerebral cause of death, e.g., traumatic brain injury. METHODS: All corpses scheduled for an autopsy in the Frankfurt Department of Forensic medicine within a 15-month period were included in the study. Cases with a known history of brain disease in the 3 months before death were excluded. During autopsy, blood was collected and GFAP serum levels were determined using a commercially available ELISA. The autopsy protocols were reviewed for the presence of a primary cerebral or a primary non-cerebral cause of death. Agony time was also determined. RESULTS: A total of 129 autopsy cases were included. GFAP concentrations did not differ between cerebral (median 0.96 MUg/l, IQR 5.03) and non-cerebral causes of death (1.21 MUg/l, 3.58). GFAP levels were found to be unaffected by hemolysis or post-mortem interval. GFAP levels were found to be increased in cases with prolonged agony times (median 1.76 MUg/l [IQR 4.70]) compared to short (0.58 MUg/l [0.58]; p<0.001) and ultra-short agony times (0.21 MUg/l [0.12]; p = 0.002). CONCLUSION: Post-mortem GFAP serum concentrations correlate with agony time and might therefore be useful for the evaluation of the severity of brain damage in prolonged death. Elevated GFAP serum levels do not indicate a primary cerebral cause of death. PMID- 30304050 TI - Detection of adulterated drugs in traditional Chinese medicine and dietary supplements using hydrogen as a carrier gas. AB - Helium, a minor component of natural gas and radioactive minerals, is most commonly used as a carrier in gas chromatography-mass spectrometry (GC-MS). Its scarcity leads to limited availability and higher costs. In this experiment, hydrogen from a safe source of a hydrogen generator was tested as a substitutive carrier gas for the detection of adulterant in traditional Chinese medicine (TCM) and food supplements by GC-MS analysis. We found that the limits of detection (LODs) of using hydrogen were from 10 to 1000 MUg/g. The levels of LODs tested among 170 drugs remain the same whether hydrogen or helium was used as a carrier gas with the exception of 7 drugs-benzbromarone, estradiol benzoate, bezafibrate, mefenamic acid, oxymetholone, piperidenafil and cetilistat. The real sample analysis results using hydrogen were as satisfactory as those using helium. In addition, the retention time was shortened after the chromatographic performance was optimized. In summary, it is worth considering hydrogen as a carrier gas due to its affordable costs, energy efficiency, carbon reduction and chromatographic advantages to detect adulterated drugs in TCM and dietary supplement using GC-MS. PMID- 30304051 TI - Molecular imaging of MMP activity discriminates unstable from stable plaque phenotypes in shear-stress induced murine atherosclerosis. AB - PURPOSE: As atherosclerotic plaque ruptures are the primary cause of ischaemic events, their preventive identification by imaging remains a clinical challenge. Matrix metalloproteinases (MMP) are involved in plaque progression and destabilisation and are therefore promising targets to characterize rupture-prone unstable plaques. This study aims at evaluating MMP imaging to discriminate unstable from stable plaque phenotypes. METHODS: ApoE deficient mice (ApoE-/-) on a high cholesterol diet underwent implantation of a tapered cuff around the right common carotid artery (CCA) inducing a highly inflamed atherosclerotic plaque upstream (US) and a more stable plaque phenotype downstream (DS) of the cuff. 8 weeks after surgery, the MMP inhibitor-based photoprobe Cy5.5-AF443 was administered i.v. 3h prior to in situ and ex vivo fluorescence reflectance imaging of the CCAs. Thereafter, CCAs were analysed regarding plaque size, presence of macrophages, and MMP-2 and MMP-9 concentrations by immunohistochemistry and ELISA. RESULTS: We found a significantly higher uptake of Cy5.5-AF443 in US as compared to DS plaques in situ (1.29 vs. 1.06 plaque-to background ratio; p<0.001), which was confirmed by ex vivo measurements. Immunohistochemistry revealed a higher presence of macrophages, MMP-2 and MMP-9 in US compared to DS plaques. Accordingly, MMP-2 concentrations were significantly higher in US plaques (47.2+/-7.6 vs. 29.6+/-4.6 ng/mg; p<0.05). CONCLUSIONS: In the ApoE-/- cuff model MMP-2 and MMP-9 activities are significantly higher in upstream low shear stress-induced unstable atherosclerotic plaques as compared to downstream more stable plaque phenotypes. MMP inhibitor-based fluorescence molecular imaging allows visualization of these differences in shear stress-induced atherosclerosis. PMID- 30304053 TI - Enhancing organic and inorganic carbon sequestration in calcareous soil by the combination of wheat straw and wood ash and/or lime. AB - Increasing organic carbon sequestration in agricultural soils is important for improving soil fertility and mitigating climate change. Wood ash is generally applied as a potassium fertilizer, but the effects of simultaneous incorporation of wood ash and crop straw on the turnover of soil organic carbon (SOC) and inorganic carbon (SIC) are not well understood. In this study, a 118-day lab incubation experiment was conducted using a calcareous soil (with 10 years of continuous maize cropping history) to study the effects of adding wheat straw, wood ash and lime. Our study showed that straw addition led to an increase in both SOC (19%) and SIC (3%). Wood ash and lime addition decreased CO2 emission by 182 and 1210 mg kg-1 and increased SIC by 125 and 1001 mg kg-1 during the incubation, respectively, which was due to supply of CaO from wood ash and lime. The increase of SOC content was 2.4% due to the addition of lime. In addition to straw addition enhanced straw-derived OC content, the addition of lime also increased straw-derived OC content by 34.5%. This study demonstrated that lime was more effective in reducing CO2 emission and and enhancing SOC than wood ash. In conclusion, adding lime to calcareous soil might be an effective method of enhancing carbon sequestration and slowing climate change. PMID- 30304052 TI - Patient support for tuberculosis patients in low-incidence countries: A systematic review. AB - BACKGROUND: Patient support during tuberculosis treatment is expected to be more often available and more customized in low tuberculosis incidence, high-resource settings than in lower-resource settings. The aim of this systematic review is to provide an overview of tuberculosis patient support interventions implemented in low-incidence countries and an evaluation of their effects on treatment-related outcomes as well as their acceptability by patients and providers. METHODS: PubMed, Social Science Citation Index and Cumulative Index to Nursing and Allied Health and Literature were searched for the period 01.2006-05.2016 on publications describing tuberculosis patient support interventions in low incidence countries (<20 patients per 100,000 population). RESULTS: Through our search strategy, 1875 unique publications were identified. Forty publications were included: 17 evaluated patient support quantitatively, 9 qualitatively and 14 only described the patient support. Nineteen publications assessed treatment supervision options only, 21 assessed (combinations of) treatment supervision, socio-economic, psycho-emotional, health-educational and other support. Of eight studies quantitatively evaluating the effects of support with a control group, four showed positive effects: two out of three that used combinations of patient support and two out of five that compared treatment supervision options. Heterogeneity of interventions precluded pooling of results. Qualitative and descriptive studies showed that patients appreciated individualized support including treatment supervision, psycho-emotional and socio-economic support; and digital health interventions. CONCLUSION: Our review shows that a variety of patient support interventions is implemented in low-incidence countries. Although only a few interventions were evaluated quantitatively, we identified potential best practices. The scarcity of evidence on effectiveness, however, indicates the need for further research to evaluate potential best practices. PMID- 30304055 TI - Multi-resolution speech analysis for automatic speech recognition using deep neural networks: Experiments on TIMIT. AB - Speech Analysis for Automatic Speech Recognition (ASR) systems typically starts with a Short-Time Fourier Transform (STFT) that implies selecting a fixed point in the time-frequency resolution trade-off. This approach, combined with a Mel frequency scaled filterbank and a Discrete Cosine Transform give rise to the Mel Frequency Cepstral Coefficients (MFCC), which have been the most common speech features in speech processing for the last decades. These features were particularly well suited for the previous Hidden Markov Models/Gaussian Mixture Models (HMM/GMM) state of the art in ASR. In particular they produced highly uncorrelated features of small dimensionality (typically 13 coefficients plus deltas and double deltas), which was very convenient for diagonal covariance GMMs, for dealing with the curse of dimensionality and for the limited computing resources of a decade ago. Currently most ASR systems use Deep Neural Networks (DNN) instead of the GMMs for modeling the acoustic features, which provides more flexibility regarding the definition of the features. In particular, acoustic features can be highly correlated and can be much larger in size because the DNNs are very powerful at processing high-dimensionality inputs. Also, the computing hardware has reached a level of evolution that makes computational cost in speech processing a less relevant issue. In this context we have decided to revisit the problem of the time-frequency resolution in speech analysis, and in particular to check if multi-resolution speech analysis (both in time and frequency) can be helpful in improving acoustic modeling using DNNs. Our experiments start with several Kaldi baseline system for the well known TIMIT corpus and modify them by adding multi-resolution speech representations by concatenating different spectra computed using different time-frequency resolutions and different post-processed and speaker-adapted features using different time-frequency resolutions. Our experiments show that using a multi-resolution speech representation tends to improve over results using the baseline single resolution speech representation, which seems to confirm our main hypothesis. However, results combining multi resolution with the highly post-processed and speaker-adapted features, which provide the best results in Kaldi for TIMIT, yield only very modest improvements. PMID- 30304054 TI - Peanut-specific T cell responses in patients with different clinical reactivity. AB - Whole extract or allergen-specific IgE testing has become increasingly popular in the diagnosis of peanut allergy. However, much less is known about T cell responses in peanut allergy and how it relates to different clinical phenotypes. CD4+ T cells play a major role in the pathophysiology of peanut allergy as well as tolerance induction during oral desensitization regimens. We set out to characterize and phenotype the T cell responses and their targets in peanut sensitized patients. Using PBMC from peanut-allergic and non-allergic patients, we mapped T cell epitopes for three major peanut allergens, Ara h 1, 2 and 3 (27 from Ara h 1, 4 from Ara h 2 and 43 from Ara h 3) associated with release of IFNgamma (representative Th1 cytokine) and IL5 (representative Th2 cytokine). A pool containing 19 immunodominant peptides, selected to account for 60% of the total Ara h 1-3-specific T cell response in allergics, but only 20% in non allergics, was shown to discriminate T cell responses in peanut-sensitized, symptomatic vs non-symptomatic individuals more effectively than peanut extract. This pool elicited positive T cell responses above a defined threshold in 12/15 sensitized, symptomatic patients, whereas in the sensitized but non-symptomatic cohort only, 4/14 reacted. The reactivity against this peptide pool in symptomatic patients was dominated by IL-10, IL-17 and to a lesser extend IL-5. For four distinct epitopes, HLA class II restrictions were determined, enabling production of tetrameric reagents. Tetramer staining in four donors (2 symptomatic, 2 non-symptomatic) revealed a trend for increased numbers of peanut epitope-specific T cells in symptomatic patients compared to non-symptomatic patients, which was associated with elevated CRTh2 expression whereas cells from non-symptomatic patients exhibited higher levels of Integrin beta7 expression. Our results demonstrate differences in T cell response magnitude, epitope specificity and phenotype between symptomatic and non-symptomatic peanut sensitized patients. In addition to IgE reactivity, analysis of peanut-specific T cells may be useful to improve our understanding of different clinical manifestations in peanut allergy. PMID- 30304056 TI - Effectiveness of PCR primers for the detection of occult hepatitis B virus infection in Mexican patients. AB - BACKGROUND: Occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HVB) DNA in the liver of HBsAg negative individuals with or without detectable viral DNA in serum. OBI is a diagnostic challenge as it is characterized by a very low viral load, intermittently detectable through time. Individuals with OBI can develop chronic hepatic disease, including liver cirrhosis and hepatocellular carcinoma. The aim of this work was to produce tools to improve OBI detection of the HVB genotypes prevalent in Mexico. METHODS: We designed and tested primers to detect OBI in serum samples by nested and real time PCR. Conserved sites in the viral genome were determined by alignment of the most frequent HBV genotypes in Mexico (H, G/H, F and D) and primers spanning the entire viral genome were designed for first round and nested PCR. Primers were tested in serum samples of 45 patients not co-infected with hepatitis C virus or with HIV, out of a group of 116 HBsAg (-)/anti-HBc (+) individuals. Primers were also tested in a control group with chronic HBV. Nested PCR products obtained from HBsAg (-)/anti-HBc (+) were sequenced and used to design primers for real time PCR (SYBR Green). RESULTS: The most effective primer pairs to detect HBV products by nested PCR targeted ORF regions: PreS2/P, S/P, X/PreC, and C; while by real-time PCR they targeted ORF regions PreS2/P, S/P, X, and C. Out of the 45 HBsAg (-)/anti-HBc (+) patients tested, the viral genome was detected in 28 (62.2%) and 34 (75.5%), with nPCR and real-time PCR respectively. CONCLUSION: Primers designed for real-time PCR detected up to 75.5% of suspected OBI Mexican patients, with or without liver disease, which represents an improvement from previous PCR strategies. PMID- 30304057 TI - Vibrissa growth rate in California sea lions based on environmental and isotopic oscillations. AB - Pinniped vibrissae provide information on changes in diet at seasonal and annual scales; however, species-specific growth patterns must first be determined in order to interpret these data. In this study, a simple linear model was used to estimate the growth rate of vibrissae from adult female California sea lions (Zalophus californianus) from San Esteban Island in the Gulf of California, Mexico. The delta15N and delta13C values do not display a marked oscillatory pattern that would permit direct determination of the time period contained in each vibrissa; thus, time (age) was calculated in two ways: 1) based on the correlation between the observed number of peaks (Fourier series) in the delta15N profile and the length of each vibrissa, and 2) through direct comparison with the observed number of peaks in the delta15N profile. Cross-correlation confirmed that the two peaks in the delta15N profile reflected the two peaks in the chlorophyll-a concentration recorded annually around the island. The mean growth rate obtained from the correlation was 0.08 +/- 0.01 mm d-1, while that calculated based on the observed number of peaks was 0.10 +/- 0.05 mm d-1. Both are consistent with the rates reported for adult females of other otariid species (0.07 to 0.11 mm d-1). Vibrissa growth rates vary by individual, age, sex, and species; moreover, small differences in the growth rate can result in significant differences over the time periods represented by the isotopic signal. Thus, it is important to assess this parameter on a species-by-species basis. PMID- 30304058 TI - Comparison of endothelial cell attachment on surfaces of biodegradable polymer coated magnesium alloys in a microfluidic environment. AB - Polymeric coatings can provide temporary stability to bioresorbable metallic stents at the initial stage of deployment by alleviating rapid degradation and providing better interaction with surrounding vasculature. To understand this interfacing biocompatibility, this study explored the endothelial cytocompatibility of polymer-coated magnesium (Mg) alloys under static and dynamic conditions compared to that of non-coated Mg alloy surfaces. Poly (carbonate urethane) urea (PCUU) and poly (lactic-co-glycolic acid) (PLGA) were coated on Mg alloys (WE43, AZ31, ZWEKL, ZWEKC) and 316L stainless steel (316L SS, control sample), which were embedded into a microfluidic device to simulate a vascular environment with dynamic flow. The results from attachment and viability tests showed that more cells were attached on the polymer-coated Mg alloys than on non-coated Mg alloys in both static and dynamic conditions. In particular, the attachment and viability on PCUU-coated surfaces were significantly higher than that of PLGA-coated surfaces of WE43 and ZWEKC in both static and dynamic conditions, and of AZ31 in dynamic conditions (P<0.05). The elementary distribution map showed that there were relatively higher Carbon weight percentages and lower Mg weight percentages on PCUU-coated alloys than PLGA coated alloys. Various levels of pittings were observed underneath the polymer coatings, and the pittings were more severe on the surface of Mg alloys that corroded rapidly. Polymer coatings are recommended to be applied on Mg alloys with relatively low corrosion rates, or after pre-stabilizing the substrate. PCUU coating has more selective potential to enhance the biocompatibility and mitigate the endothelium damage of Mg alloy stenting. PMID- 30304059 TI - Small intra-individual variability of the pre-ejection period justifies the use of pulse transit time as approximation of the vascular transit. AB - BACKGROUND: Vascular transit time (VTT) is the propagation time of a pulse wave through an artery; it is a measure for arterial stiffness. Because reliable non invasive VTT measurements are difficult, as an alternative we measure pulse transit time (PTT). PTT is defined as the time between the R-wave on electrocardiogram and arrival of the resulting pulse wave in a distal location measured with photoplethysmography (PPG). The time between electrical activation of the ventricles and the resulting pulse wave after opening of the aortic valve is called the pre-ejection period (PEP), a component of PTT. The aim of this study was to estimate the variability of PEP at rest, to establish how accurate PTT is as approximation of VTT. METHODS: PTT was measured and PEP was assessed with echocardiography (gold standard) in three groups of 20 volunteers: 1) a control group without cardiovascular disease aged <50 years and 2) aged >50 years, and 3) a group with cardiovascular risk factors, defined as arterial hypertension, dyslipidemia, kidney failure and diabetes mellitus. RESULTS: Per group, the mean PEP was: 1) 58.5 +/- 13.0 ms, 2) 52.4 +/- 11.9 ms, and 3) 57.6 +/ 11.6 ms. However, per individual the standard deviation was much smaller, i.e. 1) 2.0-5.9 ms, 2) 2.8-5.1 ms, and 3) 1.6-12.0 ms, respectively. There was no significant difference in the mean PEP of the 3 groups (p = 0.236). CONCLUSION: In conclusion, the intra-individual variability of PEP is small. A change in PTT in a person at rest is most probably the result of a change in VTT rather than of PEP. Thus, PTT at rest is an easy, non-invasive and accurate approximation of VTT for monitoring arterial stiffness. PMID- 30304060 TI - Commercialization of obstetric and neonatal care in the Democratic Republic of the Congo: A study of the variability in user fees in Lubumbashi, 2014. AB - OBJECTIVE: In the Democratic Republic of the Congo, insufficient state financing of the health system produced weak progress toward targets of Millennium Development Goals 4 and 5. In Lubumbashi, almost all women pay out-of-pocket for obstetric and neonatal care. As no standard pricing system has been implemented, there is great variation in payments related to childbirth between health facilities and even within the same facility. This work investigates the determinants of this variation. METHODS: We conducted a cross-sectional study including women from admission through discharge at 92 maternity wards in Lubumbashi in March 2014. The women's payments were collected and validated by triangulating interviews of new mothers and nurses with document review. We studied payments related to delivery from the perspective of women delivering. The total was the sum of the payments linked to seeking and accessing care and transport of the woman and companion. The determinants were assessed by multilevel regression. RESULTS: Median payments for delivery varied by type: for an uncomplicated vaginal delivery, US$45 (range, US$17-260); for a complicated vaginal delivery US$60 (US$16-304); and for a Cesarean section, US$338 (US$163 782). Vaginal delivery was more expensive at health centers than in general referral hospitals or polyclinics. Cesarean sections done in corporate polyclinics and hospitals were more expensive than those done in the general referral hospitals. Referral of delivering women, use of more highly trained personnel, and a longer stay in the maternity unit contributed to higher expenses. A vaginal delivery in the private sector was more cost-effective than in the public sector. CONCLUSION: To guarantee universal coverage of high-quality care, we suggest that the government and funders in DRC support health insurance and risk pool initiatives, and introduce and institutionalize free mother and infant care. PMID- 30304061 TI - HIV-genetic diversity and drug resistance transmission clusters in Gondar, Northern Ethiopia, 2003-2013. AB - BACKGROUND: The HIV-1 epidemic in Ethiopia has been shown to be dominated by two phylogenetically distinct subtype C clades, the Ethiopian (C'-ET) and East African (C-EA) clades, however, little is known about the temporal dynamics of the HIV epidemic with respect to subtypes and distinct clades. Moreover, there is only limited information concerning transmission of HIV-1 drug resistance (TDR) in the country. METHODS: A cross-sectional survey was conducted among young antiretroviral therapy (ART)-naive individuals recently diagnosed with HIV infection, in Gondar, Ethiopia, 2011-2013 using the WHO recommended threshold survey. A total of 84 study participants with a median age of 22 years were enrolled. HIV-1 genotyping was performed and investigated for drug resistance in 67 individuals. Phylogenetic analyses were performed on all available HIV sequences obtained from Gondar (n = 301) which were used to define subtype C clades, temporal trends and local transmission clusters. Dating of transmission clusters was performed using BEAST. RESULT: Four of 67 individuals (6.0%) carried a HIV drug resistance mutation strain, all associated with non-nucleoside reverse transcriptase inhibitors (NNRTI). Strains of the C-EA clade were most prevalent as we found no evidence of temporal changes during this time period. However, strains of the C-SA clade, prevalent in Southern Africa, have been introduced in Ethiopia, and became more abundant during the study period. The oldest Gondar transmission clusters dated back to 1980 (C-EA), 1983 (C-SA) and 1990 (C'-ET) indicating the presence of strains of different subtype C clades at about the same time point in Gondar. Moreover, some of the larger clusters dated back to the 1980s but transmissions within clusters have been ongoing up till end of the study period. Besides being associated with more sequences and larger clusters, the C-EA clade sequences were also associated with clustering of HIVDR sequences. One cluster was associated with the G190A mutation and showed onward transmissions at high rate. CONCLUSION: TDR was detected in 6.0% of the sequenced samples and confirmed pervious reports that the two subtype C clades, C-EA and C' ET, are common in Ethiopia. Moreover, the findings indicated an increased diversity in the epidemic as well as differences in transmission clusters sizes of the different clades and association with resistance mutations. These findings provide epidemiological insights not directly available using standard surveillance and may inform the adjustment of public health strategies in HIV prevention in Ethiopia. PMID- 30304062 TI - KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment. AB - INTRODUCTION: The therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins. AIM: The aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin. MATERIALS AND METHODS: This was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment. RESULTS: The c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008). CONCLUSION: Being a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant. PMID- 30304063 TI - IFN-gamma immune priming of macrophages in vivo induces prolonged STAT1 binding and protection against Cryptococcus neoformans. AB - Development of vaccines against opportunistic infections is difficult as patients most at risk of developing disease are deficient in aspects of the adaptive immune system. Here, we utilized an experimental immunization strategy to induce innate memory in macrophages in vivo. Unlike current trained immunity models, we present an innate memory-like phenotype in macrophages that is maintained for at least 70 days post-immunization and results in complete protection against secondary challenge in the absence of adaptive immune cells. RNA-seq analysis of in vivo IFN-gamma primed macrophages revealed a rapid up-regulation of IFN-gamma and STAT1 signaling pathways following secondary challenge. The enhanced cytokine recall responses appeared to be pathogen-specific, dependent on changes in histone methylation and acetylation, and correlated with increased STAT1 binding to promoter regions of genes associated with protective anti-fungal immunity. Thus, we demonstrate an alternative mechanism to induce macrophage innate memory in vivo that facilitates pathogen-specific vaccine-mediated immune responses. PMID- 30304065 TI - Human DREF/ZBED1 is a nuclear protein widely expressed in multiple cell types derived from all three primary germ layers. AB - Drosophila DNA replication-related element binding factor (DREF) is a transcription regulatory factor that binds the promoters of many genes involved in replication and cell proliferation and is required for normal cell cycle progression. Human DREF/zinc finger BED domain-containing protein 1 (ZBED1), an orthologue of Drosophila DREF, also has DNA binding activity, but its cellular functions remain largely uncharacterized. Herein, we show that ZBED1 is a chromatin-associated nuclear protein with a wide expression profile in human tissues from all three primary germ layers. For instance, ZBED1 was expressed in mesodermal-derived epithelial cells of the reproductive system and urinary tract, in endodermal-derived epithelial cells throughout the gastrointestinal tract, and in epidermal epithelium from the ectoderm. ZBED1 was also expressed in connective tissue and smooth muscle cells of multiple organs. To investigate whether ZBED1 is implicated in cell proliferation, similar to Drosophila DREF, we compared the tissue distribution of ZBED1 to that of the proliferation marker Ki-67. ZBED1 and Ki-67 were co-expressed in many epithelial tissues, but ZBED1 expression extended widely beyond that of Ki-67-positive cells. In other tissues, ZBED1 expression was more restricted than Ki-67 expression. These results suggest that ZBED1 is not a cell proliferation-associated factor such as Drosophila DREF, and our study adds to the cumulative understanding of the functions of ZBED1 in human cells and tissues. PMID- 30304064 TI - N-dodecanoyl-homoserine lactone influences the levels of thiol and proteins related to oxidation-reduction process in Salmonella. AB - Quorum sensing is a cell-cell communication mechanism mediated by chemical signals that leads to differential gene expression in response to high population density. Salmonella is unable to synthesize the autoinducer-1 (AI-1), N-acyl homoserine lactone (AHL), but is able to recognize AHLs produced by other microorganisms through SdiA protein. This study aimed to evaluate the fatty acid and protein profiles of Salmonella enterica serovar Enteritidis PT4 578 throughout time of cultivation in the presence of AHL. The presence of N dodecanoyl-homoserine lactone (C12-HSL) altered the fatty acid and protein profiles of Salmonella cultivated during 4, 6, 7, 12 and 36 h in anaerobic condition. The profiles of Salmonella Enteritidis at logarithmic phase of growth (4 h of cultivation), in the presence of C12-HSL, were similar to those of cells at late stationary phase (36 h). In addition, there was less variation in both protein and fatty acid profiles along growth, suggesting that this quorum sensing signal anticipated a stationary phase response. The presence of C12-HSL increased the abundance of thiol related proteins such as Tpx, Q7CR42, Q8ZP25, YfgD, AhpC, NfsB, YdhD and TrxA, as well as the levels of free cellular thiol after 6 h of cultivation, suggesting that these cells have greater potential to resist oxidative stress. Additionally, the LuxS protein which synthesizes the AI-2 signaling molecule was differentially abundant in the presence of C12-HSL. The NfsB protein had its abundance increased in the presence of C12-HSL at all evaluated times, which is a suggestion that the cells may be susceptible to the action of nitrofurans or that AHLs present some toxicity. Overall, the presence of C12-HSL altered important pathways related to oxidative stress and stationary phase response in Salmonella. PMID- 30304067 TI - Root Resection and Hemisection Revisited. Part II: A Retrospective Analysis of 195 Treated Patients with Up to 40 Years of Follow-up. AB - Root resection and hemisection is a well-documented treatment option for extending the life span of furcated molars. The aim of the present study was to retrospectively evaluate the long-term results of root resection and hemisection of 195 patients with up to 40 years of follow-up. Records of 195 patients who had undergone root resection or hemisection were reviewed. A minimum follow-up of 5 years was needed. A molar was recorded as a survival if it was still present and functional without any signs of discomfort, pain, or pathology from restorative, endodontic, and periodontal points of view. Ninety-eight patients were excluded for not accomplishing the minimum 5-year observation period. Of the 97 remaining patients, 5 teeth were lost during the first 5 years of treatment and 92 teeth survived the follow-up period, ranging from 5 to 40 years. The overall survival rate was 94.8%. When up to 40 years of follow-up data were analyzed, it was found that high survival rates can be obtained with root resection and hemisection. The results are satisfying when a proper case selection, endodontic treatment, restorative design, and good maintenance program are given. This treatment option should always be considered before every extraction and implant placement. PMID- 30304066 TI - Extracellular polymeric substance (EPS)-degrading enzymes reduce staphylococcal surface attachment and biocide resistance on pig skin in vivo. AB - Staphylococcal extracellular polymeric substances (EPS) such as extracellular DNA (eDNA) and poly-N-acetylglucosamine surface polysaccharide (PNAG) mediate numerous virulence traits including host colonization and antimicrobial resistance. Previous studies showed that EPS-degrading enzymes increase staphylococcal biocide susceptibility in vitro and in vivo, and decrease virulence in animal models. In the present study we tested the effect of EPS degrading enzymes on staphylococcal skin colonization and povidone iodine susceptibility using a novel in vivo pig model that enabled us to colonize and treat 96 isolated areas of skin on a single animal in vivo. To quantitate skin colonization, punch biopsies of colonized areas were homogenized, diluted, and plated on agar for colony forming unit enumeration. Skin was colonized with either Staphylococcus epidermidis or Staphylococcus aureus. Two EPS-degrading enzymes, DNase I and the PNAG-degrading enzyme dispersin B, were employed. Enzymes were tested for their ability to inhibit skin colonization and detach preattached bacteria. The effect of enzymes on the susceptibility of preattached S. aureus to killing by povidone iodine was also measured. We found that dispersin B significantly inhibited skin colonization by S. epidermidis and detached preattached S. epidermidis cells from skin. A cocktail of dispersin B and DNase I detached preattached S. aureus cells from skin and increased their susceptibility to killing by povidone iodine. These findings suggest that staphylococcal EPS components such as eDNA and PNAG contribute to skin colonization and biocide resistance in vivo. EPS-degrading enzymes may be a useful adjunct to conventional skin antisepsis procedures in order to further reduce skin bioburden. PMID- 30304068 TI - The "Scalloped Guide": A Proof-of-Concept Technique for a Digitally Streamlined, Pink-Free Full-Arch Implant Protocol. AB - Inadequate restorative space can result in mechanical, biologic, and esthetic complications with full-arch fixed implant-supported prosthetics. As such, clinicians often reduce bone to create clearance. The aim of this paper was to present a protocol using stacking computer-aided design/computer-assisted manufacturing (CAD/CAM) guides to minimize and accurately obtain the desired bone reduction, immediately place prosthetically guided implants, and load a provisional that replicates predetermined tissue contour. This protocol can help clinicians minimize bone reduction and place the implants in an ideal position that allows them to emerge from the soft tissue interface with a natural, pink free zirconia fixed dental prostheses. PMID- 30304069 TI - Temporary Single Palatal Implant for Denture Stabilization During Augmentation and Implant Procedure: A Case Report. AB - This case report introduces a temporary denture with reduced extension stabilized in the edentulous maxilla as a possible treatment method for patients with a severe gag reflex, allowing them to test the function, esthetics, and tolerance of the denture prior to hard tissue augmentation and implant placement. A 4-mm implant was placed in the central anterior palate and allowed to heal for 3 months. During the complete treatment period, a denture with reduced extension can be delivered on a fixed Locator abutment. This method was successfully applied in three patients, and the palatal implant remained stable until the final removable prosthesis could be delivered. PMID- 30304071 TI - A Case Series of Vertical Ridge Augmentation Using a Nonresorbable Membrane: A Multicenter Study. AB - Vertical ridge augmentation (VRA) using titanium-reinforced dense polytetrafluorethylene (d-PTFE) membranes has been associated with promising clinical outcomes. This retrospective multicenter case series was prepared for the purpose of identifying the elements that contribute to the predictability of this surgical technique. VRA procedures were carried out in 35 patients (13 male and 22 female) with an age range of 43 to 76 years. The average bone gain was 5.44 mm. In the Kaplan-Meier estimates of cumulative survival calculated at 15 months, membrane exposure (P = .045) was a predictor for VRA. PMID- 30304070 TI - Periodontal Regeneration and Orthodontic Treatment of Severely Periodontally Compromised Teeth: 10-Year Results of a Prospective Study. AB - The aim of this study was to investigate the long-term clinical conditions of periodontally compromised teeth treated by means of orthodontics after periodontal regeneration (GTR). Forty-eight patients affected by severe periodontitis who presented at least one nonmolar, malpositioned tooth with a pocket depth (PD) >= 7 mm, were consecutively enrolled in a private specialist practice. The treatment consisted of the following steps: infection control, provisional splinting, GTR, orthodontic treatment, final splinting, and supportive periodontal therapy (SPT). Thirty-six patients completed the 10-year study, as 12 were lost to follow-up. The total number of sites with PD >= 7 mm decreased from 25.4 +/- 16.7 to 1.8 +/- 2.1. PD of the teeth involved in the orthoperio treatment significantly decreased from 6.3 +/- 1.5 mm to 3.1 +/- 0.6 mm. One test tooth had to be extracted before the final examination due to root fracture, while two teeth lost vitality and received a root canal treatment. Eight episodes of recurrence, which required additional treatment, occurred during the 10 years of follow-up. The results of this study suggest that if a periodontal infection is under control, the orthodontic treatment does not reduce the long-term benefits of periodontal regeneration, even where the disease has caused massive tissue destruction. PMID- 30304072 TI - Thirty-Two-Year Success of Dental Implants in Periodontally Compromised Dentition. AB - Osseointegrated dental implants have become an integral factor in the replacement of missing teeth. These implants have demonstrated long-term success for periodontally compromised patients, who require a high level of success to maintain a sense of optimism. This case report offers 32-year results of implant treatment in the maxilla and 25-year results in the mandible. Some maxillary implants suffered a few threads of bone loss, but all seven mandibular implants met Albrektsson's definition of success after 25 years. The purpose of this case report is to provide evidence that further supports the findings of osseointegrated implant treatment's longevity and success, as reported in other studies. PMID- 30304073 TI - Interproximal Tunneling with a Customized Connective Tissue Graft: A Microsurgical Technique for Interdental Papilla Reconstruction. AB - Interdental papilla reconstruction is one of the most challenging clinical procedures in periodontal plastic surgery. Several surgical approaches have been proposed but have varying degrees of success. It has long been acknowledged that the narrowness of the interdental papilla and the limited blood supply are major impediments to achieving predictable outcomes. Advances in microsurgery could offer an opportunity to overcome these anatomic and biologic barriers. The authors propose an original microsurgical technique based on interproximal tunneling combined with utilization of a customized tissue graft for interdental papilla reconstruction. PMID- 30304074 TI - Classification of Soft Tissue Grafting Materials Based on Biologic Principles. AB - Since periodontal plastic surgery's recent emergence and continuous, extensive development, various treatment modalities and materials have been developed alongside it to help clinicians pursue optimal esthetics and long-term stability around natural teeth and dental implants. To achieve satisfying and predictable long-term outcomes, promote more predictable results, and reduce complications following periodontal plastic surgery procedures, the authors reviewed articles published in peer-reviewed journals to better understand the biologic principles and potential of the soft tissue grafting materials and techniques being applied. That information was used to support a new classification system. This system aims to give clinicians guidance when selecting the most appropriate grafting materials and techniques for periodontal plastic surgery, using the graft materials' two most important features to guide the consideration/decision process: the source of blood supply and whether the grafts contain vital cells. PMID- 30304075 TI - Comparison of Periodontal Inflammatory Parameters and Whole Salivary Cytokine Profile Among Saudi Patients with Different Obesity Levels. AB - The aim of the present study was to compare clinical periodontal parameters and salivary interleukin (IL)-1beta and IL-6 levels in patients with different obesity levels. A total of 419 individuals with class I, II, and III obesity and nonobese with chronic periodontitis were included. Clinical periodontal parameters were recorded, and whole salivary IL-1beta and IL-6 were quantified using enzyme-linked immunosorbent assay. Clinical parameters and salivary cytokine concentrations were analyzed using one-way analysis of variance. For multiple comparisons, Bonferroni post hoc adjustment test was used. Clinical periodontal parameters and salivary IL-1beta and IL-6 levels were statistically significant in class II and class III obese as compared to class I obese patients (P < .01) but were comparable between class II and class III obese individuals. These findings should be interpreted with caution due to the inclusion of hyperglycemic patients. PMID- 30304076 TI - A Powdering Technique for Veneering Zirconia and Its Effect on the Flexural Strength of Ceramic Bilayers. AB - The aim of this study was to assess the powdering technique and its effects on the flexural strength of bilayered zirconia. Bars made of zirconia partially stabilized by yttrium (Y-TZP) received porcelain by the following techniques (n = 10 per group): (1) L: VM9 application; (2) P: powdering technique + VM9 application; (3) C: Y-TZP coloring before sintering + Y-TZP sintering + VM9 application; or (4) CP: Y-TZP coloring before sintering + Y-TZP sintering + powdering technique + VM9 application. The powdering technique consisted of the application of VM9 margin powder followed by sintering. The samples were subjected to a 4-point flexural strength test and contact angle. Data were analyzed by one-way ANOVA and Tukey test (alpha = 5%). Surface treatments did not affect the flexural strength of bilayered specimens (P = .1264), but contact angle was affected by surface treatments (P < .0001), wherein the association of coloring and powdering (CP) reached higher values of wettability. Powdering did not affect the flexural strength of bilayered specimens, but did increase the Y TZP wettability. PMID- 30304077 TI - Minimizing Patient Morbidity Following Palatal Gingival Harvesting: A Randomized Controlled Clinical Study. AB - This clinical study was conducted to evaluate the impact of different hemostatic treatments following palatal gingival harvesting on patient discomfort. Fifty patients who needed a mucogingival surgery requiring gingival graft harvesting were enrolled and randomly assigned to one of five groups: (1) a control group in which only sutures were applied; (2) a cyanoacrylate group; (3) a periodontal dressing material group; (4) a hemostatic gelatin sponge group; and (5) a group in which the gelatin sponge and cyanoacrylate were combined. In the 2 weeks following the procedures, perception of pain, healing, consumption of drugs, and willingness to repeat the procedure were recorded through visual analog scale (VAS) by patients. Over the 2 weeks, lower pain (VAS) was found in all test groups compared to the control group (P < .01, value for time-group interaction). Notably, the gelatin sponge combined with cyanoacrylate group had very low pain (VAS <= 0.5 points) throughout the 14 days. The lowest healing scores at day 10 were associated with the control group (6.8 VAS points) in contrast to the four test groups (8.2 to 9.0 VAS points, P = .0001). Pain was inversely correlated with age (P < .05). Pain also depended on the apicocoronal dimension of the graft: the higher the graft, the more pain was experienced by the participants (0.4 VAS points per 1 mm, P < .05). Within the limitations of this study, palatal coverage appears to result in better outcomes when compared to suture alone. In particular, a double-layered protection of the palatal wound with a gelatin sponge combined with cyanoacrylate appeared to be the best option in reducing pain and postoperative discomfort. PMID- 30304078 TI - The Influence of Initial Hard and Soft Tissue Dimensions on Initial Crestal Bone Loss of Immediately Loaded Dental Implants. AB - The aim of this case-control study was to evaluate the influence of soft tissue thickness at implant placement (thin [< 3 mm] vs thick [>= 3 mm]) and bone volume (abundant vs limited) on initial crestal bone remodeling of immediate postextraction and delayed (healed site) implants in immediate loading situations. A total of 67 patients with 133 implants could be evaluated, of which 77 were placed immediately after extraction and 56 in healed ridges. If sufficient bone volume is present and primary stability is achieved, immediate loading of the implant yields good clinical and radiographic outcomes, yet implants placed in healed ridges with thin soft tissues are more prone to initial crestal bone loss. PMID- 30304079 TI - Acute Dental Pain and Salivary Biomarkers for Stress and Inflammation in Patients with Pulpal or Periapical Inflammation. AB - AIMS: To investigate whether acute dental pain due to pulpal or periapical inflammation is associated with increased expression of cortisol and inflammatory markers and mediators in the saliva, as well as changes in salivary flow rate. METHODS: Patients experiencing pain (n = 42) were recruited when seeking emergency dental treatment. A 0 to 10 numeric rating scale (NRS) was used as a measure of the severity of pain, and the number of days with pain sensation was also recorded. Unstimulated saliva was collected for 3 minutes (salivary flow measured in mL/minute) and stored at -80 degrees C. Saliva was analyzed for the biomarkers cortisol, C-reactive protein (CRP), and cytokines interleukin-1beta (IL-1beta) and interleukin-6. In addition, the participants completed a simple questionnaire about stress-inducing factors such as insomnia, dental anxiety, or home/workplace stress. Patients received a dental examination and diagnosis (eg, symptomatic pulpitis/apical periodontitis or acute apical abscess), which was confirmed during dental treatment. The control group (n = 39) consisted of participants without any pain and no known medical or dental problems. RESULTS: Patients experiencing acute pain due to pulpal or periapical inflammation had a mean NRS score of 7.0 +/- 2.59. The mean duration of pain was 6.5 +/- 7.9 days. There was no significant difference in pain level between male and female subjects, tooth type affected, or diagnosis. Higher levels of cortisol, IL-1beta, and IL-6 and increased salivary flow were detected in patients with pain when compared to controls (P < .05). CRP was higher in patients with acute pain compared to control participants without pain, but this difference was not statistically significant. Stress at home or the workplace was reported by 79% of patients experiencing pain and by 28% of control participants. CONCLUSION: Acute dental pain due to pulpal or periapical inflammation was associated with an increase in salivary cortisol, IL-1beta, and IL-6 levels and in salivary flow rate. Stress arising from home or the workplace may aggravate a symptom-free pulpal or periapical inflammation to an acute phase. Inflammation in the pulp and periapical region can have effects in regions remote from the disease site. PMID- 30304080 TI - Pain Duration and Intensity Are Related to Coexisting Pain and Comorbidities Present in Temporomandibular Disorder Pain Patients. AB - AIMS: To investigate the relationships between three pain parameters (duration, intensity, and frequency), the number of pain sites and comorbidities, and the risk of having coexisting pain and/or comorbidities in patients with temporomandibular disorder (TMD) pain. METHODS: The sample consisted of 198 outpatients attending the Dental Hospital of Chulalongkorn University. TMD pain was determined using the Diagnostic Criteria for TMD. Pain lasting 3 months or longer was defined as chronic pain. Pain intensity was reflected using a 0- to 10 point numeric rating scale, and pain frequency was assessed with the percentage of pain days over a 2-week period. The number of pain sites was evaluated using the Widespread Pain Index. The presence of comorbidities was assessed with a validated diagnostic questionnaire. The associations were analyzed using Spearman rho test, multiple linear regression, and logistic regression, with a significance level of P <= .05. Age and gender were analyzed as confounders. RESULTS: The number of pain sites was related to pain duration, pain intensity, and age. The number of comorbidities was associated with pain duration. Neither pain frequency nor gender were related to the number of pain sites or comorbidities. When the pain duration reached 1 month, patients had a 1.045-times higher probability of pain beyond the orofacial area (odds ratio [OR] = 1.045; 95% confidence interval [CI] = 1.024 to 1.066; P = .001) and a 1.028-times higher probability of comorbidities (OR = 1.028; 95% CI = 1.005 to 1.05; P = .008). For an increase of 1 score on the numeric rating scale, patients had a 1.206-times higher probability of pain presence beyond the orofacial area (OR = 1.206; 95% CI = 1.068 to 1.344; P = .026). CONCLUSION: High pain intensity and long pain duration increase the probability of having coexisting pain and comorbidities in TMD pain patients. PMID- 30304081 TI - Orofacial Pain During Rest and Chewing in Dementia Patients Admitted to Acute Hospital Wards: Validity Testing of the Orofacial Pain Scale for Non-Verbal Individuals. AB - AIMS: To assess the validity of the resting and chewing components of the recently developed observational diagnostic tool, the Orofacial Pain Scale for Non-Verbal Individuals (OPS-NVI). METHODS: This cross-sectional observational study was carried out in two UK hospitals. A total of 56 participants with dementia who were admitted to the acute hospital were observed for 3 minutes during rest and during chewing, and the OPS-NVI was used to identify orofacial pain. Afterwards, the participants were asked about the presence of orofacial pain using self-report pain scales. The sensitivity, specificity, and area under the receiver operating curve (AUROC) of the OPS-NVI were calculated for each activity. Spearman coefficient was calculated to assess the correlation between the number of positively scored behavior items of the OPS-NVI and the presence of orofacial pain according to self-report. RESULTS: According to the OPS-NVI, orofacial pain was present in 5.4% of participants during rest and in 9.1% during chewing. According to self-report, the prevalence of orofacial pain was 5.4% during rest and 10.7% during chewing. The specificity of the OPS-NVI was 98.1% to 100%, the sensitivity was 66.7% to 83.3%, and the AUROC was 0.824 to 0.917. The predictive validity showed a strong correlation (0.633 to 0.930, P < .001) between the number of positive behavior items and the self-reported presence of orofacial pain. CONCLUSION: The resting and chewing components of the OPS-NVI showed promising concurrent and predictive validity. Nevertheless, further validation is required and highly recommended. PMID- 30304082 TI - Erratum. AB - [This corrects the article doi: 10.1590/1518-8345.2249.3003]. PMID- 30304083 TI - Risk factors for extubation failure in the intensive care unit. AB - OBJECTIVE: To determine the risk factors for extubation failure in the intensive care unit. METHODS: The present case-control study was conducted in an intensive care unit. Failed extubations were used as cases, while successful extubations were used as controls. Extubation failure was defined as reintubation being required within the first 48 hours of extubation. RESULTS: Out of a total of 956 patients who were admitted to the intensive care unit, 826 were subjected to mechanical ventilation (86%). There were 30 failed extubations and 120 successful extubations. The proportion of failed extubations was 5.32%. The risk factors found for failed extubations were a prolonged length of mechanical ventilation of greater than 7 days (OR = 3.84, 95%CI = 1.01 - 14.56, p = 0.04), time in the intensive care unit (OR = 1.04, 95%CI = 1.00 - 1.09, p = 0.03) and the use of sedatives for longer than 5 days (OR = 4.81, 95%CI = 1.28 - 18.02; p = 0.02). CONCLUSION: Pediatric patients on mechanical ventilation were at greater risk of failed extubation if they spent more time in the intensive care unit and if they were subjected to prolonged mechanical ventilation (longer than 7 days) or greater amounts of sedative use. PMID- 30304084 TI - Use of topical glutamine as an adjuvant for the treatment of oral ulcers. PMID- 30304085 TI - Characteristics and outcome of burned children admitted to a pediatric intensive care unit. AB - OBJECTIVE: To analyze the characteristics and outcomes of children hospitalized for burns in a pediatric trauma intensive care unit for burn patients. METHODS: An observational study was conducted through the retrospective analysis of children (< 16 years) admitted to the pediatric trauma intensive care unit for burn victims between January 2013 and December 2015. Sociodemographic and clinical variables were analyzed including the causal agent, burned body surface, presence of inhalation injury, length of hospital stay and mortality. RESULTS: The study analyzed a sum of 140 patients; 61.8% were male, with a median age of 24 months and an overall mortality of 5%. The main cause of burns was scalding (51.4%), followed by accidents involving fire (38.6%) and electric shock (6.4%). Mechanical ventilation was used in 20.7% of the cases. Associated inhalation injury presented a relative risk of 6.1 (3.5 - 10.7) of needing ventilatory support and a relative risk of mortality of 14.1 (2.9 - 68.3) compared to patients without this associated injury. A significant connection was found between burned body surface and mortality (p < 0.002), reaching 80% in patients with a burned area greater than 50%. Patients who died had a significantly higher Tobiasen Abbreviated Burn Severity Index than survivors (9.6 +/- 2.2 versus 4.4 +/- 1.1; p < 0.001). A Tobiasen Abbreviated Burn Severity Index >= 7 represented a relative risk of death of 68.4 (95%CI 9.1 - 513.5). CONCLUSION: Scalding burns are quite frequent and are associated with high morbidity. Mortality is associated with the amount of burned body surface and the presence of inhalation injury. Special emphasis should be given to accidents involving fire, reinforcing proper diagnosis and treatment of inhalation injury. PMID- 30304086 TI - Reply to: The Epimed Monitor ICU Database(r): a cloud-based national registry for adult intensive care unit patients in Brazil. PMID- 30304088 TI - Effects of combined oral doxycycline and topical cyclosporine treatment on ocular signs, symptoms, and tear film parameters in rosacea patients. AB - PURPOSE: This study reports the effects of combined use of oral doxycycline and topical cyclosporine on ocular signs, symptoms, and tear film parameters in rosacea patients. METHODS: Fifty-four right eyes of 54 patients were included in this study. All patients underwent full ophthalmologic examination-including best corrected visual acuity measurement, slit-lamp anterior segment and fundus examination, tear film break-up time, and Schirmer test-before treatment and six months post-treatment. Patients were divided into two treatment groups. The first group was treated with oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. The second group received topical 0.05% cyclosporine emulsion drops twice daily for six months in addition to the oral doxycycline treatment regimen. All patients received preservati ve-free artificial tear drops, warm compress, eyelash cleaning, and topical corticosteroid drops three times daily for one month. RESULTS: A significant improvement in ocular signs and symptoms was recorded for all patients in groups 1 and 2 after treatment. There was not a significant difference in terms of itching, burning, meibomian gland inspissation, corneal neovascularization, and conjunctival hyperemia score changes between groups 1 and 2. The increases in Schirmer test and break-up time scores were significantly higher in group 2 than in group 1. CONCLUSIONS: Our results support the finding that topical cyclosporine in addition to the standard regimen improves tear function, as shown by Schirmer test and break-up time scores, in ocular rosacea patients. PMID- 30304087 TI - Ultrastructural viewpoints on the interaction events of Scedosporium apiospermum conidia with lung and macrophage cells. AB - BACKGROUND: Scedosporium apiospermum is a ubiquitous, emerging and multidrug resistant fungal pathogen with still rather unknown virulence mechanisms. OBJECTIVES/METHODS: The cellular basis of the in vitro interaction between fungi and host cells/tissues is the determinant factor for the development of a successful in vivo infection. Herein, we evaluated the interaction of S. apiospermum conidia with lung epithelial (A549), lung fibroblast (MRC-5) and RAW 264.7 macrophages by light and scanning/transmission electron microscopy. FINDINGS: After 4 h of fungi-host cell contact, the percentage of infected mammalian cells and the number of fungi per infected cell was measured by light microscopy, and the following association indexes were calculated for A549, MRC-5 and macrophage cells: 73.2 +/- 25.9, 69.7 +/- 22.5 and 59.7 +/- 11.1, respectively. Both conidia and germinated conidia were regularly observed interacting with the evaluated cells, with a higher prevalence of non-germinated conidia. Interestingly, nests of germinated conidia were evidenced at the surface of lung cells by scanning electron microscopy. Some germination projections and hyphae were seen penetrating/evading the mammalian cells. Furthermore, internalised conidia were seen within vacuoles as visualised by transmission electron microscopy. MAIN CONCLUSIONS: The present study contributes to a better understanding of S. apiospermum pathogenesis by demonstrating the first steps of the infection process of this opportunistic fungus. PMID- 30304089 TI - Effect of superior blepharoplasty on tear film: objective evaluation with the Keratograph 5M - a pilot study. AB - PURPOSE: To evaluate the effect of superior blepharoplasty on the tear film using the corneal topographer Keratograph 5M. METHODS: A prospective study was performed of 27 eyes of 14 patients with superior dermatochalasis who underwent superior blepharoplasty between May and June 2016. Conservative upper eyelid blepharoplasty was performed by an en bloc resection of anterior lamellar tissue that included skin, subcutaneous tissue, and the orbicularis oculi muscle. All the eyes were imaged using the noninvasive tear breakup time tools of the Keratograph 5M. The following parameters were recorded in each patient before and 6 weeks after surgery: first noninvasive Keratograph 5M tear breakup time (the time at which the first breakup of tears occurs) and average noninvasive Keratograph 5M tear breakup time (the average time of all breakup incidents). The exclusion criteria were ophthalmological pathology, previous eyelid surgery, use of eye drops, systemic pathology, and medication that interferes with lacrimal tears. RESULTS: The mean age of the patients was 65.1 years (range, 51-84); 86% were female. Student's t-test was used to compare the values of first and average noninvasive Keratograph 5M tear breakup times before and after surgery. The values for first noninvasive Keratograph 5M tear breakup time evaluated before and after surgery were not significantly different (9.04 and 8.71, respectively; p=0.926). The values for average noninvasive Keratograph 5M tear breakup time evaluated before and after surgery were also not significantly different (13.01 seconds and 13.14 seconds, respectively; p=0.835). CONCLUSIONS: The results of this pilot study suggest that upper blepharoplasty does not affect tear breakup time according to the objective evaluation of breakup time with the Keratograph 5M. PMID- 30304090 TI - The relationship between topical anti-glaucoma medications and the development of lacrimal drainage system obstruction. AB - PURPOSE: To evaluate whether any topical anti-glaucoma medications increase the risk of lacrimal drainage system obstruction or whether the presence of preservatives alone is sufficient to generate obstruction. METHODS: This nested case-control study compared a group of patients with lacrimal duct obstruction who received topical anti-glaucoma medications to a control group of patients without obstruction. RESULTS: The medical records of 255 patients with glaucoma who consulted the Oculoplastic Section with complaints of watery eyes were reviewed. Among these patients, 59 exhibited lacrimal drainage obstruction. Ninety-four percent of patients with lacrimal drainage obstruction used beta blockers, and 41% used prostaglandin analogs. A logistic regression model was used to adjust for age, sex, and the use of other medications. No significant differences were observed regarding the topical anti-glaucoma medications used between groups. CONCLUSION: No single topical anti-glaucoma medication demonstrated a stronger association with the development of lacrimal duct obstruction. PMID- 30304091 TI - Trends in corneal transplantation from 2001 to 2016 in Brazil. AB - A retrospective and analytical study was conducted by using data from the National Transplantation System on 184,575 corneal transplantations performed between January 2001 and December 2016 in order to analyze thetrends in corneal transplantation from 2001 to 2016 in Brazil. The Cochran-Armitage test, analysis of variance, and Duncan's multiple comparisons were used to verify the existence of trends, compare the mean values between regions, and verify the mean differences, respectively. A significance level of 5% was used for all tests. The analysis showed that there was a 2.4-fold increase in the number of corneal transplantations (from 6,193 [35.2 per million people (pmp)] to 14,641 [71 pmp]; p<0.001), a 50.7% increase in the efficacy of meeting the population's demand for corneal transplantation (from 35.3% to 53.2%; p<0.001), an 11-fold increase in the number of corneal transplantation centers (from 32 to 356), and a 2.5-fold increase in the number of corneal transplantation teams (from 276 to 688) in Brazil during the period studied. The waiting list for corneal transplantation decreased by 45.4% (from 23,549 [123 pmp] to 12,865 [62.4 pmp]; p<0.001), and the corneal transplantation teams performed about 19 corneal transplantations per year. The best indices were observed in the southern, midwestern, and southeastern regions, and the worst indices were in the northern and northeastern regions. Brazil has been improving its capacity to perform corneal transplantation in the past 16 years, although this improvement varies across regions. However, the population's demand for corneal transplantation is yet to be satisfactorily met, primarily due to the low number of corneal donations. PMID- 30304092 TI - The outcomes of 326 external dacryocystorhinostomy operations in children with dacryostenosis - 30-year experience of an oculoplastic surgeon. AB - PURPOSE: To report demographic features and surgical outcomes of 320 children undergoing external dacryocystorhinostomy for dacryostenosis. METHODS: We performed a retrospective evaluation of the records of patients aged <16 years who underwent external dacryocystorhinostomy. Patient demographic features and success rates of the operations were analyzed from the data records. Children with <12-month follow-up were not enrolled in the study. RESULTS: We identified 326 operative records of 320 children (162 [50.6%] girls and 158 [49.4%] boys) who underwent external dacryocystorhinostomy with a mean follow-up of 26.03 +/- 11.11 months. Overall, we evaluated 116 (35.6%) cases of congenital nasolacrimal duct obstruction. Our series demonstrated a 99.4% success rate for external dacryocystorhinostomy. CONCLUSIONS: External dacryocystorhinostomy in children has a high success rate if performed by an experienced oculoplastic surgeon. PMID- 30304093 TI - T-cell lymphoma with rhabdomyolysis: case report and literature review. AB - Rhabdomyolysis refers to the destruction or disintegration of striated muscles. This syndrome is characterized by muscle breakdown and necrosis, resulting in the leakage of intracellular muscle constituents into the circulation and extracellular fluid. We report a rare case of rhabdomyolysis complicating multi organ failure caused by T-cell lymphoma in a 32-year-old woman. The final diagnosis was rhabdomyolysis caused by peripheral T-cell lymphoma based on bone marrow aspirate and biopsy. PMID- 30304094 TI - Ventilation-induced changes correlate to pulmonary vascular response and VEGF, VEGFR-1/2, and eNOS expression in the rat model of postnatal hypoxia. AB - Neonatal asphyxia occurs due to reduction in oxygen supply to vital organs in the newborn. Rapid restoration of oxygen to the lungs after a long period of asphyxia can cause lung injury and decline of respiratory function, which result from the activity of molecules that induce vascular changes in the lung such as nitric oxide (NO) and vascular endothelial growth factors (VEGF). In this study, we evaluated the pulmonary and vascular morphometry of rats submitted to the model of neonatal asphyxia and mechanical ventilation, their expression of pulmonary VEGF, VEGF receptors (VEGFR-1/VEGFR-2), and endothelial NO synthase (eNOS). Neonate Sprague-Dawley rats (CEUA #043/2011) were divided into four groups (n=8 each): control (C), control submitted to ventilation (CV), hypoxia (H), and hypoxia submitted to ventilation (HV). The fetuses were harvested at 21.5 days of gestation. The morphometric variables measured were body weight (BW), total lung weight (TLW), left lung weight (LLW), and TLW/BW ratio. Pulmonary vascular measurements, VEGFR-1, VEGFR-2, VEGF, and eNOS immunohistochemistry were performed. The morphometric analysis showed decreased TLW and TLW/BW ratio in HV compared to C and H (P<0.005). Immunohistochemistry showed increased VEGFR-2/VEGF and decreased VEGFR-1 expression in H (P<0.05) and lower eNOS expression in H and HV. Median wall thickness was increased in H, and the expression of VEGFR-1, VEGFR-2, VEGF, and eNOS was altered, especially in neonates undergoing H and HV. These data suggested the occurrence of arteriolar wall changes mediated by NO and VEGF signaling in neonatal hypoxia. PMID- 30304095 TI - Importance of the putative furin recognition site 742RNRR745 for antiangiogenic Sema3C activity in vitro. AB - Angiogenesis is one of the key processes in the growth and development of tumors. Class-3 semaphorins (Sema3) are characterized as axon guidance factors involved in tumor angiogenesis by interacting with the vascular endothelial growth factor signaling pathway. Sema3 proteins convey their regulatory signals by binding to neuropilins and plexins receptors, which are located on the effector cell. These processes are regulated by furin endoproteinases that cleave RXRR motifs within the Sema, plexin-semaphorins-integrin, and C-terminal basic domains of Sema3 protein. Several studies have shown that the furin-mediated processing of the basic domain of Sema3F and Sema3A is critical for association with receptors. It is unclear, however, if this mechanism can also be applied to other Sema3 proteins, including the main subject of this study, Sema3C. To address this question, we generated a variant of the full-length human Sema3C carrying point mutation R745A at the basic domain at the hypothetical furin recognition site 742RNRR745, which would disable the processing of Sema3C at this specific location. The effects produced by this mutation were tested in an in vitro angiogenesis assay together with the wild-type Sema3C, Sema3A, and Sema3F proteins. Our results showed that the inhibitory effect of Sema3C on microcapillary formation by human umbilical vein endothelial cells could be abrogated upon mutation at the Sema3C basic domain within putative furin cleavage site 742RNRR745, indicating that this site was essential for the Sema3 biological activity. PMID- 30304097 TI - Vascular trauma in the Amazon: updating the challenge. AB - OBJECTIVE: to evaluate the epidemiological data of patients operated on due to vascular trauma at a referral hospital in Para state, to determine the variables that increase the risk of death, and to make a comparative analysis with the results previously published by the same institution. METHODS: an analytical retrospective study was performed through data collection from patients operated due to vascular injuries, between March 2013 and March 2017. Demographic and epidemiological data, such as the mechanism and topography of the lesion, distance between the trauma site and the hospital, and type of treatment and complications, were analyzed. Multivariate analysis and logistic regression studies were performed, to evaluate significant dependence between some variables and death occurrence. RESULTS: two hundred and eighty eight patients with 430 lesions were studied; 92.7% were male, 49.7% were between 25 and 49 years old; 47.2% of all injuries were caused by firearm projectiles; 47.2% of the lesions were located in the upper limbs, 42.7% in the lower limbs, 8% in the cervical region, 3.1% in the thoracic region, and 0.7% in the abdominal region; 52.8% of the patients were hospitalized for seven days or less. Amputation was required in 6.9% of patients and there was mortality in 7.93% of the cases. CONCLUSION: distances greater than 200km were associated with prolonged hospitalization and greater probability of limb amputation. Significant correlation between death occurrence and arterial injury, vascular injury in the cervical region, and vascular injury in the thoracic region was found. PMID- 30304096 TI - A pilot study on the identification of human papillomavirus genotypes in tongue cancer samples from a single institution in Ecuador. AB - The relationship between human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma has been established. However, data from Ecuador is limited. The objective of this study was to characterize HPV infection in Ecuadorian patients with tongue cancer. Fifty-three patients with tongue cancer treated at the tertiary referral center Sociedad de Lucha Contra el Cancer (SOLCA), Guayaquil, between 2006 and 2011 were identified. Linear Array(r) HPV genotyping was used to identify the presence and types of HPV on formalin-fixed paraffin-embedded biopsy samples from these patients with tongue cancer. HPV was identified in 42% (n=22) and high-risk (HR) HPV in 17% (n=9), with 18 different HPV types identified. The most common types were the HR HPV 33 (14%) and low-risk HPV 67 (14%), followed by the HR HPV 58. More than one HPV type was identified in 27.3% of cases. HPV 33 was frequently associated with other HPV types. No statistically significant differences in gender (P=0.58) and age (P=0.12) were observed between HPV positive and HPV-negative cases. HPV was identified in almost half of the tongue cancer samples, with subtypes 33 and 67 being the most common. This suggested that HPV played an important role in this disease in the population studied. Given these results, current HPV vaccines may not be as effective in reducing tongue cancer rates in this population. PMID- 30304098 TI - Fatal cardiac trauma in the city of Manaus, Amazonas state, Brazil. AB - OBJECTIVE: to determine the frequency of fatal cardiac trauma in the city of Manaus, Brazil, between November 2015 and October 2016, and to clarify the mechanisms of trauma and death, previous hospital treatment, as well as the injuries associated with cardiac trauma. METHODS: retrospective, observational, and cross-sectional study, which reviewed the necropsy reports of individuals whose cause of death was cardiac injury. RESULTS: the cardiac trauma rate was of 5.98% (138 cases) out of 2,306 necropsies performed in the study period by Instituto Medico Legal (IML) de Manaus (IML is a Brazilian institute responsible for necropsies and cadaveric reports). Males accounted for 92% of the cases. The median age was 27 years (14-83). Gunshot wounds (GSW) was the trauma mechanism in 62.3% and stab wound (SW) in 29.7%. Exsanguination was responsible for most of the deaths and cardiac tamponade was present in second place. On-site death occurred in 86.2% of the cases. The ventricles were the most common site of cardiac injury. Hemothorax was identified in 90.6% of the individuals. Only 23 patients (16.7%) were taken to the hospital (Emergency Room), but six (26.2%) were submitted only to chest drainage, not to thoracotomy. The lung was unilaterally affected in 57% of the cases and bilaterally in 43%. CONCLUSION: fatal cardiac trauma represented an index of 5.98% in the city of Manaus. Most patients die at the scene of the trauma, usually due to exsanguination caused by gunshot wound. About a quarter of patients who reached the hospital and died were not diagnosed with cardiac trauma in time. PMID- 30304099 TI - Elderly who refuse to use hearing aids: an analysis of the causes. AB - PURPOSE: The present research sought to describe the elements that interfere with the use of hearing aids in the elderly beneficiaries of a hearing aid delivery from Chile in a Family Health Center. METHODS: A descriptive, cross-sectional study was conducted with 24 beneficiary users, with application of a closed question questionnaire prepared by the researchers. RESULTS: A 75% adherence to the use of hearing aids is reported. There was a difference of 3.8 h in the use between adherents and non-adherents and in the frequency of use. The main reasons for not using the hearing aids are discomfort due to mold and noise. CONCLUSION: It is necessary to provide quality education during the implementation process, as well as to address the technical difficulties related to atrial adjustment and calibration of the hearing aid in order to increase adherence. PMID- 30304101 TI - Region-specific reference intervals for TSH in pregnancy: time for changes in Brazil. PMID- 30304100 TI - Impact of levodopa treatment in the voice pattern of Parkinson's disease patients: a systematic review and meta-analysis. AB - PURPOSE: Investigate the association between levodopa therapy and vocal characteristics in Parkinson's disease patients. SEARCH STRATEGY: Studies published at MEDLINE, LILACS, and SciELO, from 1960 to December 2016. A systematic review and meta-analysis was performed using the following keywords: Parkinson's disease; levodopa; L-dopa; voice; speech disorders; dysphonia; dysarthria. After analyzing titles and abstracts, two independent reviewers selected all clinical trials that met the eligibility criteria and selected the articles and the data recorded in a previously standardized table. SELECTION CRITERIA: Trials published in English between 1960 and December 2016 individuals with clinical diagnosis of Parkinson's disease; use of levodopa therapy in stable doses; acoustic analysis combined or not with auditory-perceptual analysis to evaluate the vocal parameters under investigation. DATA ANALYSIS: The following vocal parameters were analyzed: fundamental frequency (F 0), jitter, and vocal intensity. Standardized mean differences (SMD) were calculated using the Comprehensive Meta-analysis V2 software. RESULTS: Nine articles met the eligibility criteria and were selected, with a total of 119 individuals. From these, six articles with 83 individuals were included in the meta-analysis. During the levodopa therapy "on" state, modifications in F 0 (SMD=0.39; 95% CI - 0.21-0.57) and jitter (SMD=0.23; 95% CI - 0.02-0.45) were observed. Vocal intensity was not affected (SMD=0.09; 95% CI - 0.22-0.39) by levodopa ingestion. Data of the included studies were controversial in the auditory-perceptual analysis of voice. CONCLUSION: Levodopa therapy modifies F0 and jitter. No changes in vocal intensity were observed in either the "on" or "off" states of levodopa therapy. PMID- 30304102 TI - Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro. AB - OBJECTIVES: American Thyroid Association (ATA)'s new guidelines recommend use of population-based trimester-specific reference range (RR) for thyrotropin (TSH) in pregnancy. The aim of this study was to determine first trimester TSH RR for a population of pregnant women in Rio de Janeiro State. SUBJECTS AND METHODS: Two hundred and seventy pregnant women without thyroid illness, defined by National Academy of Clinical Biochemistry, and normal iodine status were included in this sectional study. This reference group (RG) had normal median urinary iodine concentration (UIC = 219 MUg/L) and negative anti-thyroperoxidase antibodies (TPOAb). Twin pregnancy, trophoblastic disease and use of drugs or supplements that influence thyroid function were excluded. In a second step, we defined a more selective reference group (SRG, n = 170) by excluding patients with thyroiditis pattern on thyroid ultrasound and positive anti-thyroglobulin antibodies. This group also had normal median UIC. At a final step, a more selective reference group (MSRG, n = 130) was defined by excluding any pregnant women with UIC < 150 MUg/L. RESULTS: In the RG, median, 2.5th and 97.5th percentiles of TSH were 1.3, 0.1, and 4.4 mIU/L, respectively. The mean age was 270 +/- 5.0 and the mean body mass index was 25.6 +/- 5.2 kg/m2. In the SRG and MSRG, 2.5th and 975th percentiles were 0.06 and 4.0 (SRG) and 0.1 and 3.6 mIU/L (MSRG), respectively. CONCLUSIONS: In the population studied,TSH upper limit in the first trimester of pregnancy was above 2.5 mIU/L. The value of 3.6 mIU/L, found when iodine deficiency and thyroiditis (defined by antibodies and ultrasound characteristics) were excluded, matches recent ATA guidelines. PMID- 30304103 TI - The effect of levothyroxine treatment on left ventricular function in subclinical hypothyroidism. AB - OBJECTIVE: Treatment of subclinical hypothyroidism (ScH), especially the mild form of ScH, is controversial because thyroid hormones influence cardiac function. We investigate left ventricular systolic and diastolic function in ScH and evaluate the effect of 5-month levothyroxine treatment. SUBJECTS AND METHODS: Fifty-four patients with newly diagnosed mild ScH (4.2 = 50% stenosis being indicative of obstructive CAD, and patients were divided into groups according to main epicardial coronary arteries with plaques (0, 1, 2, 3). Lipid profiles and a homeostasis model assessment (HOMA-IR) were determined. RESULTS: Serum median (25% and 75% percentile) TSH levels in patients with group 2 and 3 (2.25; 1.66-3.12 mU/L and 4.99; 4.38-23.60 mU/L, respectively) had significantly higher TSH concentrations (p < 0.0001) than the group 0 (1.82; 1.35 2.51 mU/L). Furthermore, patients of group 3 had higher TSH concentration (p < 0.0001) than those of group 1 (1.60; 0.89-2.68 mU/L). Group 3 were older (64 +/- 8.5 vs. 59 +/- 9.5, p = 0.001), had more patients with dyslipidemia (84% versus 58%, p < 0.001), male (54% versus 44%, p = 0.01), hypertension (100% versus 86%, p < 0.001), and smoking (61% versus 33%, p < 0.001) than group 0. Multivariate stepwise logistic analysis showed TSH, age, HbA1c, and HOMA-IR were the CAD associated variables. CONCLUSIONS: In this cohort, elevated TSH levels in the high normal range or above are associated with the presence and severity of CAD besides may represent a weak CAD risk factor. PMID- 30304105 TI - Waist circumference measurement sites and their association with visceral and subcutaneous fat and cardiometabolic abnormalities. AB - OBJECTIVES: To estimate the degree of variability of the waist circumference (WC) when obtained in different anatomical sites and compare the performance of the measurement sites as predictors of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and cardiometabolic abnormalities. SUBJECTS AND METHODS: Cross-sectional study involving 119 individuals with overweight (50.3 +/- 12.2 years), in which six WC measurement sites were evaluated (minimal waist, immediately below the lowest rib, midpoint between the lowest rib and the iliac crest, 2 cm above the umbilicus, immediately above the iliac crest, umbilicus level), in addition to the VAT and SAT (quantified by computed tomography) and cardiometabolic parameters. RESULTS: The differences between the measurements ranged from 0.2 +/- 2.7 cm to 6.9 +/- 6.7 cm for men, and from 0.1 +/- 3.7 cm to 10.1 +/- 4.3 cm for women. The minimum waist showed significant correlation with VAT (r = 0.70) and with a higher number of cardiometabolic parameters among men. Regarding women, the WC measurement showed high correlation with SAT and moderate correlation with VAT, not being found superiority of one measurement protocol in relation to the others when assessed the correlation with VAT and with cardiometabolic parameters. CONCLUSIONS: Greater variability between the measuring sites was observed among women. With respect to men, the minimum waist performed better as a predictor of VAT and cardiometabolic alterations. PMID- 30304106 TI - Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. AB - OBJECTIVE: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. MATERIALS AND METHODS: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. RESULTS: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: -0.32% [-0.54, -0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, -0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, 1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, -1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction >= 0.5%, weight loss >= 2 kg, SBP reduction >= 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. CONCLUSION: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies. PMID- 30304107 TI - Lean mass as a determinant of bone mineral density of proximal femur in postmenopausal women. AB - OBJECTIVE: To verify which component of body composition (BC) has greater influence on postmenopausal women bone mineral density (BMD). SUBJECTS AND METHODS: Four hundred and thirty women undergoing treatment for osteoporosis and 513 untreated women, except for calcium and vitamin D. Multiple linear regression analysis was performed in order to correlated BMD at lumbar spine (LS), total femur (FT), femoral neck (FN) with body mass (BM), total lean mass (LM) and total fat mass (FM), all determined by DXA. RESULTS: BM significantly correlated with all bone sites in untreated and treated women (r = 0.420 vs 0.277 at LS; r = 0.490 vs 0.418 at FN, r = 0.496 vs 0.414 at FT, respectively). In untreated women, the LM correlated better than FM with all sites, explaining 179% of LS; 32.3% of FN and 30.2% of FT; whereas FM explained 13.2% of LS; 277% of FN, 23.4% of FT In treated women, correlations with BC were less relevant, with the LM explaining 6.7% of BMD at LS; 15.2% of FN, 16% of FT, whereas the FM explained 8.1% of LS; 179% of FN and 176% of FT. CONCLUSION: LM in untreated women was better predictor of BMD than FM, especialy for distal femur, where it explained more than 30% of the BMD, suggesting that maintaining a healthy muscle mass may contribute to decrease osteoporosis risk. Treatment with anti-osteoporotic drugs seems to mask these relationships. Arch Endocrinol Metab. 2018;62(4):431-7. PMID- 30304108 TI - Combination therapy of curcumin and alendronate modulates bone turnover markers and enhances bone mineral density in postmenopausal women with osteoporosis. AB - OBJECTIVE: This study evaluated the effects of combination therapy of curcumin and alendronate on BMD and bone turnover markers in postmenopausal women with osteoporosis. SUBJECTS AND METHODS: In a randomized, double-blind trial study, 60 postmenopausal women were divided into three groups: control, alendronate, and alendronate + curcumin. Each group included 20 patients. Total body, total hip, lumbar spine and femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of therapy. Bone turnover markers such as bone-specific alkaline phosphatase (BALP), osteocalcin and C terminal cross-linking telopeptide of type I collagen (CTx) were measured at the outset and 6 months later. RESULTS: Patients in the control group suffered a significant decrease in BMD and increased bone turnover markers at the end of study. The group treated with only alendronate showed significantly decreased levels of BALP and CTx and increased levels of osteocalcin compared to the control group. The alendronate group also showed significant increases in the total body, total hip, lumbar spine and femoral neck BMDs at the end of study compared to the control group. In the curcumin + alendronate group, BALP and CTx levels decreased and osteocalcin levels increased significantly at the end of study compared to the control and alendronate groups. BMD indexes also increased in four areas significantly at the end of study compared to the control and alendronate groups. CONCLUSION: The combination of curcumin and alendronate has beneficial effects on BMD and bone turnover markers among postmenopausal women with osteoporosis. Arch Endocrinol Metab. 2018;62(4):438-45. PMID- 30304109 TI - Association between undercarboxylated osteocalcin, bone mineral density, and metabolic parameters in postmenopausal women. AB - OBJECTIVE: Osteocalcin has been associated with several effects on energy and glucose metabolism. However, the physiological role of undercarboxylated osteocalcin (U-osc; the hormonally active isoform of osteocalcin) is still controversial. To correlate the serum levels of U-osc with bone mineral density (BMD) values and metabolic parameters in postmenopausal women. SUBJECTS AND METHODS: Cross-sectional study including 105 postmenopausal women (age 56.5 +/- 6.1 years, body mass index [BMI] 28.2 +/- 4.9 kg/m2) grouped based on the presence of three or less, four, or five criteria of metabolic syndrome according to the International Diabetes Federation (IDF). The subjects underwent dualenergy x-ray absorptiometry (DXA) for the assessment of body composition and BMD and blood tests for the measurement of U-osc and bone-specific alkaline phosphatase (BSAP) levels. RESULTS: The mean U-osc level was 3.1 +/- 3.4 ng/mL (median 2.3 ng/mL, range 0.0-18.4 ng/mL) and the mean BSAP level was 12.9 +/- 4.0 ng/mL (median 12.1 ng/mL, range 73-24.4 ng/mL). There were no associations between U osc and BSAP levels with serum metabolic parameters. Lower fasting glucose levels were observed in participants with increased values of U-osc/femoral BMD ratio (3.61 +/- 4 ng/mL versus 10.2 +/- 1.6 ng/mL, p = 0.036). When the participants were stratified into tertiles according to the U-osc/ femoral BMD and U osc/lumbar BMD ratios, lower fasting glucose levels correlated with increased ratios (p = 0.029 and p = 0.042, respectively). CONCLUSION: Based on the ratio of U-osc to BMD, our study demonstrated an association between U-osc and glucose metabolism. However, no association was observed between U-osc and metabolic parameters.The U-osc/BMD ratio is an innovative way to correct the U-osc value for bone mass. PMID- 30304110 TI - Low serum 25-hydroxy vitamin D levels are associated with aggressive breast cancer variants and poor prognostic factors in patients with breast carcinoma. AB - OBJECTIVE: This study was conducted to assess the serum 25-hydroxy (OH) vitamin D levels in patients with breast cancer compared to healthy controls and to identify its association with aggressive breast cancer phenotypes. MATERIALS AND METHODS: Serum 25-OH vitamin D levels of 78 breast cancer patients and 78 matched healthy controls were estimated using ELISA. The cases and controls were matched with respect to age, menopausal status, parity, weight, height and co morbidities. Prognostic factors like grade of tumour, hormone receptor status, HER2 neu status and lymphovascular invasion were compared with 25-OH vitamin D levels. RESULTS: The mean serum 25-OH vitamin D levels of cases were significantly lower compared to the controls (22.33 +/- 8.19 vs. 37.41 +/- 12.9 ng/mL; p = 0.0001). Patients with higher grades of tumour, non-luminal types of breast cancer and breast cancers with estrogen receptor negativity had significantly lower serum 25-OH vitamin D levels than their opposing groups. Patients with excellent and good Nottingham's prognostic Index (NPI) had significantly higher serum 25-OH vitamin D levels than the moderate and poor NPI groups. CONCLUSION: Newly diagnosed breast cancer patients have significantly lower serum 25-OH vitamin D levels than healthy controls. Lower level of serum 25 OH vitamin D correlates with aggressive breast cancer phenotypes. PMID- 30304111 TI - Hounsfield unit value has null effect on thyroid nodules at 18F-FDG PET/CT scans. AB - OBJECTIVES: Detection rate of thyroid nodules is increasing with the use of new imaging modalities, especially in screening for malignancies. Positron emission tomography/computed tomography (PET/ CT)-positive thyroid nodules should be differentiated for malignancy to avoid unnecessary operations and further follow up. Most trials evaluate the role of SUVmax, but there is no definitive information about the utility of Hounsfield unit (HU) values for prediction of malignancy. This study aimed to evaluate the HU values beside SUVmax for detecting malignancy risk of PET/CT-positive thyroid nodules. SUBJECTS AND METHODS: Results of 98 cancer patients who had fine needle aspiration biopsy (FNAB) for thyroid nodules detected on PET/CT between January 2011 and December 2015 were assessed. The FNABs and surgical pathological results were recorded. RESULTS: FNABs revealed benign results in 32 patients (32.7%), malignant in 18 (18.4%), non-diagnostic in 20 (20.4%), and indeterminate in 28 (28.5%). Twenty four patients underwent thyroidectomy. The mean HU values were not significantly different in benign and malignant nodules (p = 0.73). However, the mean SUVmax was significantly higher (p < 0.001) in malignant ones. Area under curve (AUC) was 0.824 for SUVmax; the cut-off value was over 5.55 (p < 0.001), with 80% sensitivity, 84.5% specificity. CONCLUSIONS: Our current study demonstrated that HU value does not add any additional valuable information for discriminating between malignant and benign thyroid nodules. We also defined a SUV cut-off value of 5.55 for malignant potential of thyroid nodules detected on PET/CT Arch Endocrinol Metab. 2018;62(4):460-5. PMID- 30304112 TI - Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis. AB - OBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses. PMID- 30304113 TI - A brief review about melatonin, a pineal hormone. AB - Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues, besides being a hormone that is centrally produced in the pineal gland of vertebrates, particularly in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the organism's physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin presents specific mechanisms and ways of action devoted to its role as a time-giving agent, being widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its synthesis and/or function disruptions. PMID- 30304114 TI - The low-density lipoprotein receptor-related protein 5 (LRP5) 4037C>T polymorphism: candidate for susceptibility to type 1 diabetes mellitus. AB - OBJECTIVE: The present study has investigated the association between low-density lipoprotein receptor-related protein 5 (LRP5) 4037C>T polymorphism and type 1 diabetes mellitus (T1DM) susceptibility in a Brazilian population. SUBJECTS AND METHODS: A total number of 134 T1DM patients and 180 normoglycemic individuals (NG) aged 6-20 years were studied. Glycated hemoglobin and glucose levels were determined. Genotyping of LRP5 4037C>T (rs3736228) was performed. RESULTS: T1DM patients showed poor glycemic control. Genotypes in the codominant (CT: OR = 2.99 [CI 95%: 1.71-5.24], p < 0.001; TT: OR = 5.34 [CI 95%: 1.05-2702], p < 0.001), dominant (CT + TT: OR = 3.16 [CI 95%: 1.84-5.43], p < 0.001) and log-additive (OR = 2.78 [CI 95%: 1.70-4.52], p < 0.001) models, and LRP5 4037T allele (OR = 2.88, [CI 95%: 1.78-4.77], p < 0.001) were associated with an increased risk of developing T1DM. LRP5 4037CT and CT+TT carriers in T1DM group showed higher concentrations of serum glucose and glycated hemoglobin when compared with CC carriers. CONCLUSION: The LRP5 4037C>T may represent a candidate for T1DM susceptibility, as well as poor glycemic control. PMID- 30304115 TI - Type 1 diabetes mellitus: can coaching improve health outcomes? AB - OBJECTIVE: To evaluate the introduction of coaching in the interdisciplinary care of individuals with type 1 diabetes mellitus in the public health care system. SUBJECTS AND METHODS: Ten patients routinely attending a public health care service and with a glycated hemoglobin (HbA1c) level above 75% participated in eight coaching sessions. This study evaluated the patients' self-management of the disease and personal behavior. The participants were assessed at the beginning of the program and on two occasions after the intervention, with evaluation of biochemical and anthropometric data, and frequency of self monitoring of blood glucose (SMBG). Questionnaires were applied during these evaluations to analyze emotional burden (B-PAID), medication adherence (Morisky Adherence Scale), and self-efficacy (IMDSES). RESULTS: HbA1c had a median level of 8.0% (range 76-10.3%) at the beginning of the study and reduced significantly 3 months after initiation of the intervention (7.78% [6.5-10%], p = 0.028), with no significant increase at 6 months (8.3% [713-9.27%], p = 0.386). SMBG improved significantly from the beginning to the end of the study, with the median number of glucose tests per week varying from 16.5 (range 0-42) at baseline to 29.0 (7 42) at 3 months and 27.5 (10-48) at 6 months (p = 0.047). No significant differences were observed in anthropometric parameters or in the scores of the instruments between the three measurements. CONCLUSION: A coaching intervention focused on patients' values and sense of purpose may provide added benefit to traditional diabetes education programs and could be an auxiliary method to help individuals with type 1 diabetes achieve their treatment goals. PMID- 30304116 TI - Community health services and risk of readmission in public psychiatric hospitals of Belo Horizonte, Brazil, 2005-2011. AB - INTRODUCTION: The readmission phenomenon in psychiatry not only reflects the severity and chronicity of the underlying disorders, but also indicates the quality of mental healthcare. In the context of the Brazilian mental healthcare reform, no study has included the availability of outpatient care among the potential determinants for psychiatric readmission. OBJECTIVE: To correlate the availability of community healthcare resources at the place of residence with the risk of psychiatric readmission. METHODS: All admission records from 2005 to 2011 in the two public psychiatric hospitals of Belo Horizonte were included (n=19,723). Variables related to patients and characteristics of hospitalization were collected, and indicators of community healthcare coverage were calculated for each place of residence yearly. The outcome of interest was early (<7 days), medium-term (8-30 days) and late (31-365 days) readmissions. The analysis was based on Cox regressions. RESULTS: The coverage of basic health units and of psychiatrists was associated with lower readmission risks. Coverage of specialized centers for psychosocial attention (Centros de Atencao Psicossocial [CAPS]) and psychologists did not show any protective effects. Young, male patients and those residing outside the capital had greater risk of early readmission. Compared to other psychotic disorders, mood disorders and neurotic disorders were seen as protective factors for readmission. CONCLUSION: Regionalized attention offered by the CAPS did not result in reduced readmission risks. PMID- 30304117 TI - The relationship between insight and affective temperament in bipolar disorder: an exploratory study. AB - INTRODUCTION: In recent years, the association between temperament and clinical characteristics of mood disorders has been studied. Most bipolar patients show deficits in their awareness of signs and symptoms. The relationship between affective temperament and insight in bipolar patients has not been carried out in the literature so far. OBJECTIVE: To evaluate the relationship between affective temperament and insight in bipolar disorder. METHOD: A group of 65 bipolar patients were followed during a year. Patients underwent a clinical assessment and were diagnosed using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Insight was evaluated through the Insight Scale for Affective Disorders (ISAD), and affective temperament, through the TEMPS-Rio de Janeiro. The relationship between affective temperament and insight was explored with Spearman rho correlations between scores on each item of the ISAD and on the TEMPS-Rio de Janeiro subscales. RESULTS: In euthymic phases, bipolars with depressive temperament were associated with a higher level of insight about the consequences of the disorder; when in mania, patients showed better insight about having an affective disorder, presenting psychomotor alterations, and suffering from guilt or grandiosity. Similarly, bipolar patients with higher scores of anxious temperament, when in mania, had better insight on alterations in attention. Bipolar patients with higher scores of hyperthymic temperament, when in mania, showed the worst insight about thought disorder. CONCLUSION: In addition to being determined by the phase of the disease and several varying symptoms, the level of insight in bipolar patients is also influenced by affective temperament. PMID- 30304118 TI - Impact of resilience on the improvement of depressive symptoms after cognitive therapies for depression in a sample of young adults. AB - INTRODUCTION: Few studies have evaluated positive measures for therapeutic response. Thus, the objective of this study was to assess the effects of resilience on severity of depressive and anxious symptoms after brief cognitive psychotherapy for depression. METHODS: This was a clinical follow-up study nested in a randomized clinical trial of cognitive therapies. The Resilience Scale was applied at baseline. The Hamilton Anxiety Rating Scale (HARS) and the Hamilton Depression Rating Scale (HDRS) were used at baseline, post-intervention, and at six-month follow-up. RESULTS: Sixty-one patients were assessed at baseline, post intervention and at six-month follow-up. Resilience scores were significantly different between baseline and post-intervention assessments (p<0.001), as well as at baseline and at six-month follow-up (p<0.001). We observed a weak negative correlation between baseline resilience scores and HDRS scores at post intervention (r=-0.295, p=0.015) and at six-month follow-up (r=-0.354, p=0.005). Furthermore, we observed a weak negative correlation between resilience scores and HARS scores at post-intervention (r=-0.292, p=0.016). CONCLUSION: Subjects with higher resilience scores at baseline showed a lower severity of symptoms at post-intervention and at six-month follow-up. PMID- 30304119 TI - Coping strategies among caregivers of people with Alzheimer disease: a systematic review. AB - INTRODUCTION: Caregivers of people with Alzheimer disease (PwAD) report significant stress, burden and depression compared to caregivers of people with other dementias, especially when neuropsychiatric symptoms are prominent. Adequate coping strategies can modify the impact of stressful situations and increase the caregivers' quality of life. OBJECTIVE: To systematically review the different coping strategies used by caregivers of PwAD to manage neuropsychiatric symptoms. METHOD: We carried out electronic searches using MEDLINE (PubMed), SciELO, Web of Knowledge Cross Search (Thomson Scientific/ISI Web Services) and PsycINFO databases to select studies on coping in PwAD caregivers published from January 2005 to July 2017. The search terms were coping, caregivers, strategy, onset, adaptation, family, behavior, dementia and Alzheimer. The studies were organized in three categories: problem-focused, emotion-focused and dysfunctional coping strategies. RESULTS: We found 2,277 articles. After application of exclusion criteria and exclusion of redundant references, 24 articles were analyzed. Emotion-focused coping was the most commonly used strategy among PwAD caregivers. The use of this strategy associated with religion and spirituality may help reduce symptoms of depression and anxiety. Problem-focused coping strategies were mostly used with active coping interventions. Problem-solving coping may have buffered the impact of acute psychological stressors on procoagulant activity. Dysfunctional coping strategies were associated with increase of caregiver burden. CONCLUSION: The evaluated studies showed that the use and development of coping strategies may have ameliorated the depressive symptoms, anxiety and burden of caregivers. However, longitudinal studies are still needed that clearly describe the type of coping strategy used in relation to the presented results. PMID- 30304120 TI - One-year prospective clinical study comparing patient satisfaction and masticatory performance of mandibular overdentures supported by one versus two implants. AB - OBJECTIVE: There is a lack of clinical evidence on mandibular overdentures (MOD) supported by a single implant. To compare patient satisfaction and masticatory performance in MOD supported by one versus two implants in a two-group parallel randomized clinical trial. MATERIAL AND METHODS: Twenty-one patients wearing new maxillary and mandibular complete dentures (CDs) were randomly divided to receive one (GI, n = 11) or two (GII, n = 10) implants in the mandibular arch. Four months after implant placement, o-ring abutments were installed in the implants, and matrix attachments were placed in the lower complete dentures. Patient satisfaction with their dentures and masticatory performance were compared at baseline, 3, 6, and 12 months after the procedure. Data on patient satisfaction were analyzed using the Friedman test and the Mann-Whitney U test. Data on masticatory performance were analyzed using one-way repeated measures analysis of variance (ANOVA) and Student's t test (alpha=0.05). RESULTS: Both groups exhibited a significant increase in overall patient satisfaction in all periods evaluated (p<0.05), except for GI after 12 months, which had values similar to baseline (p=0.74). Satisfaction levels of GI and GII were similar at baseline, 3 and 6 months, but GII showed higher satisfaction levels (p=0.01) than GI at 12 months. GI and GII exhibited a significant increase (p<0.05) in masticatory performance for all periods relative to baseline. However, GII had higher masticatory performance with dentures than GI, regardless of the period (p<0.05). CONCLUSION: MOD supported by two implants demonstrated better patient satisfaction in the follow-up at 12 months and better masticatory performance than MOD supported by one implant. PMID- 30304121 TI - Volumetric reconstruction and determination of minimum crosssectional area of the pharynx in patients with cleft lip and palate: comparison between two different softwares. AB - OBJECTIVE: The aim of this study was to assess the accuracy of volumetric reconstruction of the pharynx by comparing the volume and minimum crosssectional area (mCSA) determined with open-source applications (ITK-Snap, www.itksnap.org ; SlicerCMF) and commercial software (Dolphin3D, 11.8, Dolphin Imaging & Management Solutions, Chatsworth, CA, USA) previously validated in the literature. MATERIAL AND METHODS: The sample comprised of 35 cone-beam computed tomography (CBCT) scans of patients with unilateral cleft lip and palate, with mean age of 29+/-15. Three-dimensional volumetric models of the pharynx were reconstructed using semi automatic segmentation using the applications ITK-Snap (G1) and Dolphin3D (G2). Volumes and minimum cross-sectional areas were determined. Inter- and intra observer error were calculated using ICC test. Comparison between applications was calculated using the Wilcoxon test. RESULTS: Volumes and minimum crosssectional area were statistically similar between applications. ITK-Snap showed higher pharynx volumes, but lower mCSA. Visual assessment showed that 62.86% matched the region of mCSA in Dolphin3D and SPHARM-PDM. CONCLUSION: Measurements of volume and mCSA are statistically similar between applications. Therefore, open-source applications may be a viable option to assess upper airway dimensions using CBCT exams. PMID- 30304122 TI - IFN-gammaR2 is strongly expressed on endothelial cells of gingival tissues from patients with chronic periodontitis. AB - OBJECTIVE: Chronic periodontitis (CP) is characterized by gingival inflammation and bone destruction. It has been reported that interferon-gamma (IFN-gamma) levels are high in CP patients; however, the IFN-gamma receptor (IFN-gammaR) has not been studied in gingival tissue from these patients. To evaluate IFN-gamma levels and IFN-gammaR expression in gingival tissue biopsies from chronic periodontitis patients compared with healthy subjects (HS). MATERIAL AND METHODS: Gingival tissues were obtained from all study subjects, CP (n = 18) and healthy subjects (HS) (n = 12). A tissue section of each study subject was embedded in paraffin blocks to determine the expression of IFN-gamma R (IFN-gammaR1 and IFN gammaR2) through immunohistochemistry. Another section of the tissue was homogenized and IFN-gamma was measured by the ELISA technique. RESULTS: No significant differences were found in the IFN-gammaR1 expression within the cell layers of the gingival tissue of the study groups. When analyzing the IFN-gammaR2 expression it was found that IFN-gammaR2 is strongly expressed in the endothelial cells of CP patients when compared to HS (p<0.05). IFN-gamma concentrations in the gingival tissue were significantly higher in CP patients than in HS. No significant correlation between IFN-gamma levels and the expression of IFN gammaR1 and IFN-gammaR2 was found. However, a positive correlation between IFN gamma levels and clinical parameters [probing depth (PD) and clinical attachment level (CAL)] was found. CONCLUSION: The study of IFN-gammaR expression in gingival tissue samples from patients with CP showed an increase only in the IFN gammaR2 chain in endothelial cells when compared to HS. PMID- 30304123 TI - Quorum sensing LuxS/autoinducer-2 inhibits Enterococcus faecalis biofilm formation ability. AB - OBJECTIVE: To investigate the relation between biofilm formation ability and quorum sensing gene LuxS/AI-2. MATERIALS AND METHODS: Enterococcus faecalis (E. faecalis) standard strain ATCC 29212 was used in the study. Long flanking homology polymerase chain reaction method was used to build the LuxS gene knockout strain. Sequential culture turbidity measurement and CFU counting were used to assess the proliferation ability of E. faecalis after the depletion of LuxS. 96-well plate assay was used to quantify the biofilm formation ability; CLSM was used to observe the attached bacteria areas, while scanning electron microscopy (SEM) was performed to observe biofilm microstructure conditions. RESULTS: LuxS gene knockout strains were successfully constructed and identified. The results showed that proliferation ability of E. faecalis was not affected by the depletion of the luxS gene, and the biofilm formation ability of DeltaLuxS 29212 significantly decreased (P<0.05). CONCLUSIONS: Collectively, our studies provide the LuxS gene's key role in controlling biofilm formation of E. faecalis, which presented a negative regulation, and furthermore, providing us a possible way to conquer the persistent apical periodontitis. PMID- 30304125 TI - Pulp analysis of teeth submitted to different types of forces: a histological study in rats. AB - OBJECTIVE: The purpose of this study was to histologically evaluate pulp and dentin under induced tooth movement (ITM) with different types of forces. MATERIAL AND METHODS: The maxillary right first molars of rats were submitted to movement with continuous (CF), continuous interrupted (CIF) and intermittent (IF) forces during 5, 7 and 9 days with nickel-titanium (NiTi) closed-coil springs exerting 50cN force magnitude. The groups were histologically evaluated as for cellularity pattern, presence of dystrophic, hemodynamic alterations in the pulp as well dentin alterations. The main observed alterations were related to hemodynamic pulp characteristics, such as presence of thrombosis, vascular congestion and hemorrhages. The hemodynamic alterations were statistically evaluated by Shapiro-Wilk normality test and analysis of variance by the Kruskall Wallis test. RESULTS: There was no significant differences observed between groups in the different types of applied forces and duration of ITM (vascular congestion, p=1.000; hemorrhage, p=0.305; thrombosis, p=1.000). CONCLUSIONS: Pulp tissue alterations resulting from ITM were limited to hemodynamic events, without progressing to irreversible degeneration, regardless of the type of force applied. PMID- 30304124 TI - Effects of experimental bleaching agents on the mineral content of sound and demineralized enamels. AB - OBJECTIVE: High concentrations of hydrogen peroxide can cause adverse effects on composition and structure of teeth. However, the addition of calcium and fluoride in bleaching agents may reduce enamel demineralization. To evaluate chemical changes of sound and demineralized enamels submitted to high concentrations of hydrogen peroxide containing fluoride (F) or calcium (Ca). MATERIAL AND METHODS: Enamel blocks of bovine incisors with standard dimensions were obtained and half of them were submitted to pH-cycling to promote initial enamel caries lesions. Sound and demineralized enamel samples were divided into (n=10): (C) Control (no whitening treatment); (HP) 35% hydrogen peroxide; and two experimental groups: (HPF) 35% HP+0.2% F and (HPC) 35% HP+0.2% Ca. Experimental groups were submitted to two in-office bleaching sessions and agents were applied 3 times for 15 min to each session. The control group was kept in remineralizing solution at 37 degrees C during the bleaching treatment. The surface mineral content of sound and demineralized enamels was determined through Fourier Transform Raman spectroscopy (FT-Raman), Energy dispersive Micro X-ray fluorescence spectroscopy (MU-EDXRF); and the subsurface, through cross-sectional microhardness (CSMH). In addition, polarized light microscopy (PLM) images of enamel subsurface were observed. RESULTS: According to three-way (FT-Raman and MU-EDXRF analyses) or two-way analysis of variance (ANOVA) (CSMH) and Tukey test (alpha=5%), the calcium or fluoride added to high-concentrated bleaching agents increased phosphate and carbonate concentrations on sound and demineralized enamels (p<0.05). However, HPC and HPF were unable to completely reverse the subsurface mineral loss promoted by bleaching on sound and demineralized enamels. The calcium/ phosphate (Ca/P) ratio of sound enamel decreased after HP treatment (p<0.001). CONCLUSION: Even though experimental bleaching agents with Ca or F reduced mineral loss for both sound and demineralized enamel surfaces, these agents were unable to reverse the enamel subsurface demineralization. PMID- 30304126 TI - The role of potassium channels in the endothelial dysfunction induced by periodontitis. AB - OBJECTIVE: Periodontitis is associated with endothelial dysfunction, which is clinically characterized by a reduction in endothelium-dependent relaxation. However, we have previously shown that impairment in endothelium-dependent relaxation is transient. Therefore, we evaluated which mediators are involved in endothelium-dependent relaxation recovery. MATERIAL AND METHODS: Rats were subjected to ligature-induced experimental periodontitis. Twenty-one days after the procedure, the animals were prepared for blood pressure recording, and the responses to acetylcholine or sodium nitroprusside were obtained before and 30 minutes after injection of a nitric oxide synthase inhibitor (L-NAME), cyclooxygenase inhibitor (Indomethacin, SC-550 and NS- 398), or calcium-dependent potassium channel blockers (apamin plus TRAM- 34). The maxilla and mandible were removed for bone loss analysis. Blood and gingivae were obtained for C-reactive protein (CRP) and myeloperoxidase (MPO) measurement, respectively. RESULTS: Experimental periodontitis induces bone loss and an increase in the gingival MPO and plasmatic CRP. Periodontitis also reduced endothelium-dependent vasodilation, a hallmark of endothelial dysfunction, 14 days after the procedure. However, the response was restored at day 21. We found that endothelium-dependent vasodilation at day 21 in ligature animals was mediated, at least in part, by the activation of endothelial calcium-activated potassium channels. CONCLUSIONS: Periodontitis induces impairment in endothelial-dependent relaxation; this impairment recovers, even in the presence of periodontitis. The recovery is mediated by the activation of endothelial calcium-activated potassium channels in ligature animals. Although important for maintenance of vascular homeostasis, this effect could mask the lack of NO, which has other beneficial properties. PMID- 30304127 TI - Clinical wear of approximal glass ionomer restorations protected with a nanofilled self-adhesive light-cured protective coating. AB - OBJECTIVE: High viscous glass ionomer cement (GIC) has gained popularity as a restorative material; however, high wear is pointed as one of the major drawbacks of this material. Protective surface coatings were developed to protect GIC from water contamination with the additional advantage of occluding any surface cracks or porosities commonly found in this material, possibly resulting in an increased wear resistance of the restorations. The objective of this study was to investigate the clinical wear of GIC approximal restorations in primary molars protected either with a nanofilled self-adhesive light-cured protective coating (NPC) or with petroleum jelly. MATERIAL AND METHODS: Approximal caries lesions in primary molars from 32 schoolchildren previously enrolled in another clinical trial were included in this investigation. GIC restorations were performed according to the Atraumatic Restorative Treatment approach and protected with either petroleum jelly or a NPC. Impressions of the restored hemiarch were done after 1 day and 6, 12, 24 and 36 months. The impressions were scanned in a 3-D appliance and the obtained images were superimposed using an appropriate computer software. Two-way ANOVA for repeated measures and Tukey's post-hoc test were used to analyze the wear of restorations (alpha=5%). RESULTS: A significant difference was found between the two groups, with a wear protection offered by the application of a NPC. Conclusion: These results suggest that the application of a NPC has a protective effect on the clinical wear of approximal GIC restorations in primary teeth. PMID- 30304128 TI - Acoustic and aerodynamic measures in singers: a comparison between genders. AB - PURPOSE: Compare acoustic and aerodynamic voice measures between male and female singers. METHODS: A cross-sectional, observational, comparative study conducted with a convenience sample. Study participants were 30 male and 30 female singers. Acoustic (vocal intensity and fundamental frequency) and aerodynamic (expiration time, air pressure, expiratory and voice airflow, expiratory volume, aerodynamic power and resistance, acoustic impedance, and aerodynamic efficiency) measures were assessed during emission of the syllable /pa/, at usual frequency and intensity, for seven consecutive times. These emissions enable extraction of air pressure measures (obtained by the plosive consonant /p/, which estimates glottic pressure), as well as of airflow and acoustic voice measures (obtained by the vowel /a/ and the syllable /pa/). RESULTS: Women presented higher values of fundamental frequency compared with those of men. No differences were identified in the evaluation of aerodynamic measures between the groups. CONCLUSION: Values of aerodynamic measures do not differ between male and female singers. PMID- 30304129 TI - Influence of the age, level of schooling and gender on the occurrence of the DSI test pauses. AB - PURPOSE: To evaluate the influence of variables age, educational status and sex in the occurrence of pauses after the standard time in the dichotic sentence identification test. METHODS: This investigation included 200 right-handed subjects divided into four groups according to age: group I - from 13 to 19 years old, group II - from 20 to 29 years old, group III - from 30 to 39 years old and group IV - from 40 to 49 years old. Each group contained 50 subjects (25 men and 25 women) matched by educational level. The following eligibility criteria was adopted: Brazilian Portuguese mother language, listeners, and fluent readers independent of the educational level. It was applied the dichotic sentence identification test in the steps of binaural integration, directed listening, and it was noted the need for pauses in the test after the standard time. The descriptive and inferential statistics were performed. RESULTS: For the binaural integration stages there was a positive association between age and pause occurrence. The educational variable presented a negative association with the occurrence of pauses in all stages of the DSI test. The gender variable showed no association with the occurrence of pause in any of the test steps. CONCLUSION: With increasing age, there is an increase in the incidence of pauses in the binaural integration stages of the test. The more years of study the less chance that the individual will need breaks to perform the test at all stages of presentation. The variable gender did not influence the occurrence of pauses. PMID- 30304130 TI - Essential oil of Pterodon polygalaeflorus Benth attenuates nociception in mice. AB - Essential oils (EO) are volatile liquids responsible for the aroma of plants. Pterodon polygalaeflorus seeds have received widespread use in folk medicine for the treatment of inflammatory diseases. For this reason and because Pterodon polygalaeflorus seeds have great EO content, which is frequently pharmacologically active, the present study aimed to evaluate the antinociceptive effect of EO from Pterodon polygalaeflorus (EOPPgfl) and its acute toxic effects. The EEOPPgfl sample, which was extracted by steam distillation of the seeds, had a yield of 2.4% of the seeds weight and had, as major constituents, beta-elemene (48.19%), trans-caryophyllene (19.51%), and epi-bicyclosesquiphellandrene (12.24%). The EOPPgfl sample showed mild acute toxicity and its calculated median lethal dose (LD50) was 3.38 g/kg. EOPPgfl (20-60 mg/kg) showed antinociceptive activity as evidenced by several tests and inhibited writhing induced by acetic acid. The maximum effect was obtained with the 30 mg/kg dose and at 60 min after its administration. EOPPgfl also decreased formalin-induced nociception, as verified by the inhibition of the first and second phase of the formalin test. At 30 mg/kg, EOPPgfl also decreased thermally stimulated nociception. Nociception may be related to inflammatory and antiedematogenic activity and at doses ranging 10-100 mg/kg, EOPPgfl blocked dextran- and carrageenan-induced edema. The results demonstrated that EOPPgfl presented, at doses approximately 100 times smaller than LD50, an antinociceptive effect that probably was due to anti-inflammatory activities. PMID- 30304131 TI - Acute exercise inhibits gastric emptying of liquids in rats: influence of the NO cGMP pathway. AB - We previously found that acute exercise inhibited the gastric emptying of liquid in awake rats by causing an acid-base imbalance. In the present study, we investigated the involvement of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, vasoactive intestinal peptide (VIP), and corticotropin releasing factor (CRF) peptide in this phenomenon. Male rats were divided into exercise or sedentary group and were subjected to a 15-min swim session against a load (2.5 or 5% b.w.). The rate of gastric emptying was evaluated after 5, 10, or 20 min postprandially. Separate groups of rats were treated with vehicle (0.9% NaCl, 0.1 mL/100 g, ip) or one of the following agents: atropine (1.0 mg/kg, ip), the NO non-selective inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10.0 mg/kg, ip), or the selective cGMP inhibitor 1H (1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip), the i-NOS non specific inhibitor (aminoguanidine; 10.0 mg/kg, ip), the corticotropin-releasing factor receptor antagonist (astressin; 100 ug/kg, ip), or the vasoactive intestinal peptide (VIP) receptor antagonist Lys1, Pro2,5, Arg3,4, Tyr6 (100 ug/kg, ip). Compared to sedentary rats, both the 2.5 and 5% exercise groups exhibited higher (P<0.05) values of blood lactate and fractional gastric dye recovery. Corticosterone and NO levels increased (P<0.05) in the 5% exercised rats. Pretreatment with astressin, VIP antagonist, atropine, L-NAME, and ODQ prevented the increase in gastric retention caused by exercise in rats. Acute exercise increased gastric retention, a phenomenon that appears to be mediated by the NO-cGMP pathway, CRF, and VIP receptors. PMID- 30304132 TI - Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder. AB - This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes. PMID- 30304133 TI - Lactate-upregulation of lactate oxidation complex-related genes is blunted in left ventricle of myocardial infarcted rats. AB - Lactate modulates the expression of lactate oxidation complex (LOC)-related genes and cardiac blood flow under physiological conditions, but its modulatory role remains to be elucidated regarding pathological cardiac stress. The present study evaluated the effect of lactate on LOC-related genes expression and hemodynamics of hearts submitted to myocardial infarction (MI). Four weeks after MI or sham operation, isolated hearts of male Wistar rats were perfused for 60 min with Na+ lactate (20 mM). As expected, MI reduced cardiac contractility and relaxation with no changes in perfusion. The impaired cardiac hemodynamics were associated with increased reactive oxygen species (ROS) levels (Sham: 19.3+/-0.5 vs MI: 23.8+/-0.3 uM), NADPH oxidase (NOX) activity (Sham: 42.2+/-1.3 vs MI: 60.5+/-1.5 nmol.h-1.mg-1) and monocarboxylate transporter 1 (mct1) mRNA levels (Sham: 1.0+/ 0.06 vs MI: 1.7+/-0.2 a.u.), but no changes in superoxide dismutase (SOD), catalase, NADH oxidase (NADox), and xanthine oxidase activities. Lactate perfusion in MI hearts had no additional effect on ROS levels, NADox, and NOX activity, however, it partially reduced mct1 mRNA expression (MI-Lactate 1.3+/ 0.08 a.u.). Interestingly, lactate significantly decreased SOD (MI-Lactate: 54.5+/-4.2 umol.mg-1.min-1) and catalase (MI: 1.1+/-0.1 nmol.mg-1.min-1) activities in MI. Collectively, our data suggest that under pathological stress, lactate lacks its ability to modulate the expression of cardiac LOC-related genes and the perfused pressure in hearts submitted to chronic MI. Together, these data contribute to elucidate the mechanisms involved in the pathogenesis of heart failure induced by MI. PMID- 30304134 TI - Cryotherapy: biochemical alterations involved in reduction of damage induced by exhaustive exercise. AB - When exercises are done in intense or exhaustive modes, several acute biochemical mechanisms are triggered. The use of cryotherapy as cold-water immersion is largely used to accelerate the process of muscular recovery based on its anti inflammatory and analgesic properties. The present study aimed to study the biochemical effects of cold-water immersion treatment in mice submitted to exercise-induced exhaustion. Swiss albino mice were divided into 4 treatment groups: control, cold-water immersion (CWI), swimming exhaustive protocol (SEP), and SEP+CWI. Treatment groups were subdivided into times of analysis: 0, 1, 3, and 5 days. Exhaustion groups were submitted to one SEP session, and the CWI groups submitted to one immersion session (12 min at 12 degrees C) every 24 h. Reactive species production, inflammatory, cell viability, and antioxidant status were assessed. The SEP+CWI group showed a decrease in inflammatory damage biomarkers, and reactive species production, and presented increased cell viability compared to the SEP group. Furthermore, CWI increased acetylcholinesterase activity in the first two sessions. The present study showed that CWI was an effective treatment after exercise-induced muscle damage. It enhanced anti-inflammatory response, decreased reactive species production, increased cell viability, and promoted redox balance, which could decrease the time for the recovery process. PMID- 30304135 TI - Opiophobia and opiophilia: the war continues. PMID- 30304136 TI - Lumbar herniated disc - endoscopic discectomy treatment. AB - The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient. PMID- 30304137 TI - Tuberculous peritonitis following intestinal perforation in malignancy. AB - Tuberculous peritonitis is one of the most common causes of exudative ascites, especially in the young, and is an important cause of extra-pulmonary disease. However, tuberculous peritonitis is challenging to diagnose because there are no pathognomonic clinical features or imaging findings. Therefore, it is commonly misdiagnosed as another type of peritoneal disease, especially so in elderly patients with malignant disease. In this report, we described two cases of tuberculous peritonitis that were observed after intestinal perforation in elderly patients with malignancies. These diagnoses were established by laparoscopic peritoneal biopsy or AFB cultures of the ascitic fluid. Both patients were treated with anti-TB medications. PMID- 30304138 TI - Osteoma of the cochlear promontory. PMID- 30304139 TI - Hand-foot syndrome due to hepatitis C therapy. AB - INTRODUCTION: Direct-acting antivirals are new drugs for chronic hepatitis C treatment. They are usually safe and well tolerated, but can sometimes cause serious adverse effects and there is no consensus on how to treat or prevent them. We described a case of hand-foot syndrome due to hepatitis C virus interferon-free therapy. METHODS: We report the case of a 49-year-old man with compensated liver cirrhosis due to chronic hepatitis C genotype 1, treatment naive, who started viral treatment with sofosbuvir, simeprevir and ribavirin for 12 weeks. RESULTS: At the sixth week of treatment he had anemia, requiring a lower dose of ribavirin. At the tenth week, he had erythematous, pruritic, scaly and flaky lesions on hands and feet, which showed a partial response to oral antihistamines and topical corticosteroids. It was not necessary to discontinue antiviral treatment, but in the first week after the end of treatment, there was worsening of injuries, including signs of secondary infection, that required hospitalization, antibiotics and oral corticosteroid, with progressive improvement. Biopsy of the lesions was consistent with pharmacodermia. The patient had sustained a virological response, despite the side effect. He had a history of pharmacodermia one year ago attributed to the use of topiramate, responsive to oral corticosteroid. CONCLUSION: Interferon-free therapies can rarely lead to severe adverse reactions, such as skin lesions. Patients receiving ribavirin combinations and those who had a history of pharmacodermia or skin disease may be more susceptible. There is no consensus on how to prevent skin reactions in these patients. PMID- 30304140 TI - Functionality, comorbidity, complication & surgery of hip fracture in older adults by age distribution. AB - BACKGROUND: Hip fractures may be the greatest complication secondary to osteoporotic disorder. The objective of this study was to determine the influence of age distribution in the functionality, comorbidity, complications and surgical features of older adults with hip fractures. METHODS: A prospective cohort study was carried out from 2013 to 2014. A sample of 557 adults over 75 years old with osteoporotic hip fractures was recruited from the Orthogeriatric Unit of the Leon University Hospital (Spain). Age distributions of 75-84, 85-90 and >90 years old were considered. Firstly, sociodemographic data, fracture type and hospital staying days were collected. Secondly, baseline functionality (Barthel index), ambulation, cognitive impairment and comorbidities were described. Thirdly, surgical intervention, urgency, type, American Association of Anesthesiologists (ASA) scores, non-surgical cause, and baseline pharmacologic treatments were determined. Finally, complications and features at hospital discharge were observed. RESULTS: The age ranges did not show any statistically-significant differences (P<.05; R2=.000-.005) for gender, fracture type, or number of hospital staying days. Statistically-significant differences (P<.05; R2=.011 .247) between age groups were observed for Barthel index, cognitive impairment, dementia, osteoporosis, Parkinson's disease, aortic stenosis, surgery type, ASA score, non-surgical cause, benzodiazepines, antidementia, anti-osteoporosis, insulin, pharmacologic treatments, renal function alteration, heart failure, destination and ambulation features. All other measurements did not show statistically-significant differences (P>.05; R2=.000-.010). CONCLUSION: Age distributions greater than 75 years old may determine the functionality, comorbidities, surgical features, baseline pharmacologic treatments, complications and features at hospital discharge for older adults who suffer a hip fracture. PMID- 30304141 TI - Mecobalamin and early functional outcomes of ischemic stroke patients with H-type hypertension. AB - OBJECTIVE: To analyze the effect of mecobalamin on the early-functional outcomes of patients with ischemic stroke and H-type hypertension. METHODS: From October of 2014 to October of 2016, 224 cases of ischemic stroke and H-type hypertension were selected. The patients were randomly divided into treatment control groups, with 112 patients in each group. The control group was treated with the conventional therapy. The observation group was treated with 500 ug of mecobalamin three times a day in addition to the conventional therapy. We compared serum homocysteine (Hcy), hs-CRP levels, carotid plaques, and NIHSS scores between the two groups on the 2nd day and at 4 weeks, 8 weeks, 3 months, and 6 months. RESULTS: After 4 weeks, 8 weeks, 3 months and 6 months, the difference of serum Hcy level between the two groups was statistically significant (t = 4.049, 3.896, 6.052, 6.159, respectively. All P <0.05). After the treatment, at 4 weeks, 8 weeks, 3 months and 6 months, the levels of hs-CRP in the treatment group were significantly lower than those in the control group (t = 37.249, 28.376, 26.454, 20.522, respectively. All P <0.01). After 3 months and 6 months, the carotid artery plaques were significantly reduced in the treatment group compared to those in the control group (t = 2.309 and 2.434. All P <0.05). After 3 months and 6 months, the NIHSS score was significantly higher in the treatment group compared to those in the control group (t = 2.455 and 2.193. All P <0.05). CONCLUSION: Mecobalamin can reduce the level of plasma homocysteine, then lead to reductions of levels of plasma inflammatory factors and volume of carotid artery plaques, resulting in more significant functional recovery. PMID- 30304142 TI - Evaluation of plaque characteristics in coronary artery patients with impaired glucose tolerance through optical coherence tomography. AB - OBJECTIVE: With the adoption of optical coherence tomography (OCT), this study targets the impacts on plaque characteristics brought about by impaired glucose tolerance (IGT) in patients with coronary artery disease. METHODS: For this study, 150 patients with coronary artery disease were recruited. Regarding glycosylated hemoglobin (HbAlc), the patients were sectioned into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) groups. Coronary angiography (CAG) and OCT were conducted for 150 patients. RESULTS: There were 186 plaques discovered in 150 patients (37, 40, 44, and 65 in the NGT, IFG, IGT, and DM groups, respectively). Compared to the NGT group, the lipid core size, which is presented as the average angle of the lipid arc, was markedly larger in the IFG,IGT and DM groups ( 135.7 +/- 32.7 E, 161.2 +/- 55.7 E, 162.5 +/- 55.8 E, and 170.2 +/- 59.7 E, respectively, all P values< 0.05). Meanwhile, the fibrous cap over the lipid core in the NGT group was remarkably thicker than that in the IFG, IGT, and DM groups (115.7 +/- 47.7 MUm vs. 77.7 +/- 23.5 MUm, 75.1 +/- 23.2 um, 71.2 +/- 22.1 um, all P values<0.05). CONCLUSION: Coronary plaques in coronary artery patients with NDT are more stable than in those with IGT and DM. PMID- 30304143 TI - The serum homocysteine level in patients with acute ischemic stroke (AIS) after thrombolysis and its relationship with clinical outcomes. AB - OBJECTIVE: The present study aims to investigate whether hyperhomocysteinemia (HHcy) affects the outcomes of the thrombolytic treatment for patients with AIS. METHODS: A sample of 120 AIS patients were recruited and grouped according to their serum homocysteine (Hcy) levels. The National Institute of Health Stroke Scale (NIHSS) was obtained before treatment and 7 days after it to evaluate neurological outcomes; modified Rankin Scale (mRS) was obtained 12 weeks later to assess functional outcomes. Receiver operating characteristic curve (ROC) was used to demonstrate the relationship between serum Hcy level and the outcomes after tPA treatment. RESULTS: The serum Hcy level of 120 patients was of 27.57+/ 20.17MUmol/L. The NIHSS scores of the patients in the low Hcy level group were remarkably lower compared to those in the high-level group (p<0.05), after 7 days of treatment. In addition, the mRS scores of the patients in the low Hcy level group, after 12 weeks, were remarkably lower compared to those in the high-level group (p<0.01). ROC demonstrated that the serum Hcy level is related to the clinical outcomes of thrombolytic treatment with moderate specificity (80.3%) and sensitivity (58.2%). CONCLUSION: In conclusion, higher serum Hcy levels can indicate poorer clinical outcomes of thrombolytic treatment in patients with AIS. PMID- 30304144 TI - Success of promotion strategies for a stroke rehabilitation protocol. AB - OBJECTIVE: To prospectively evaluate the success of promotion strategies for a protocol of motor rehabilitation strategies for patients with stroke at Albert Einstein Hospital. METHODS: In a clinical trial of neuromodulation and rehabilitation for patients with stroke, conventional methods of dissemination and publications about the research protocol in social networks or on the hospital's website were performed. Frequencies of types of advertisements that reached potentially eligible subjects were calculated. RESULTS: Data from 80 potentially eligible patients were analyzed. The types of ads that motivated contacts more frequently were social media (38.8%) and information provided to physicians from other hospitals (23.8%) (p=0,288). The frequencies of contacts motivated by publications on the internet (53%) and conventional strategies (47%) were similar. Facebook was the digital strategy associated with the higher number of contacts, followed by the hospital's website. CONCLUSION: Social networks and websites can be as effective as traditional methods of advertisement, in order to reach patients for stroke rehabilitation protocols. These results may have an impact on the planning of clinical trials, including studies that evaluate effects of rehabilitation interventions in patients with stroke. PMID- 30304145 TI - The cardiac profile and electrocardiographic standard of at-height workers. AB - BACKGROUND: The Medical Control Program for Occupational Health establishes the required supplementary exams, according to the activity exercised by the worker and its inherent risks. The Regulatory Norm No. 35, recently deployed, stipulates that at-height workers must undergo electrocardiogram exams as an additional routine examination. OBJECTIVE: To evaluate the electrocardiographic standard in at-height. METHODOLOGY: A cross-sectional study, developed from May 2014 to January 2015 with male at-height workers. Anthropometric and clinical data were collected after the electrocardiogram (ECG). The workers included in the program were evaluated by an occupational medicine service of Serra Gaucha, responsible for medical assessment and occupational tests. All workers were assessed by the researcher. RESULTS: A total of 561 at-height workers participated in the study. The average age was 35.9 +/- 12.2 years. A total of 176 (31%) presented electrocardiographic changes in the analysis of the resting ECG. Regarding the amendments in the resting ECG, 15.7% were attributed to changes in ventricular repolarization, 8% as blocks conductions, and 5.8% as left ventricular overload. Demographic variables were not associated with changes in the electrocardiographic tracing. CONCLUSION: This study demonstrated the electrocardiographic alterations and the profile of at-height workers. These findings can help determine prevention strategies and provide warnings of possible future harms to the health of these workers. PMID- 30304146 TI - Analysis of influencing factors of severity in acute pancreatitis using big data mining. AB - OBJECTIVES: To evaluate the epidemiological characteristics of acute pancreatitis (AP) and explore potential relationships between these factors and severity. METHODOLOGY: Data-sets of 5,659 patients with AP from health statistics and the Information Center of Jiangsu province, between 2014 and 2016, were analyzed. A self-organizing map (SOM) neural network was used for data clustering. RESULTS: Biliary acute pancreatitis (BAP) (86.7%) was the most frequent etiological factor. A total of 804 (14.2%) patients had severe acute pancreatitis (SAP). The mean age of patients was 53.7 + 17.3 (range 12~94y). Most of the AP patients were married (75.4%); 6% of mild /moderately severe AP (MAP/MASP) patients were unmarried, which was less than SAP patients (P=0.016). AP patients with blood type AB in the general population (8.8%) was significantly lower than that of AP cases (13.9%) (P=0.019) and SAP cases(18.7%) (P=0.007). The number of AP patients in southern Jiangsu was much higher than that in northern Jiangsu province, especially in Nanjing (1229, 21.7%). The proportion of acute alcoholic pancreatitis (AAP) in the north of Jiangsu (Xuzhou 18.4%) was much higher than that in southern Jiangsu (Suzhou 2.6%). The whole sample was divided into five classes by SOM neural network. If BAP patients were male, old, divorced, and blood type AB or B, they were more likely to develop SAP. Middle-age, unmarried or divorced male patients with blood type B/AB who suffered from HAP or AAP were also more likely to develop SAP. CONCLUSIONS: The number of unmarried patients with MAP/MASP was smaller than that of SAP. Blood types AB and B were more frequent in AP, especially in SAP. The differences between southern Jiangsu and northern Jiangsu, in number of AP patients and the proportion of AAP, were significant. In class I and class IV, the ratio of SAP was much higher than in other classes and the whole sample. PMID- 30304147 TI - The use of drugs and medical students: a literature review. AB - INTRODUCTION: The consumption and abuse of alcohol and other drugs are increasingly present in the lives of university students and may already be considered a public health problem because of the direct impacts on the physical and mental health of these individuals. The requirements of the medical program play a vital role in the increasing rate of drug users. OBJECTIVES: To carry out a systematic review of the literature on the use of drugs, licit or not, in Brazilian medical students. METHODS: A descriptive-exploratory study, in which the SciELO and MEDLINE databases were used. A total of 99 articles were found, of which 16 were selected for this review. RESULTS: Alcohol and tobacco were the most frequently used licit drugs among medical students. The most consumed illicit drugs were marijuana, solvents, "lanca-perfume" (ether spray), and anxiolytics. The male genre presented a tendency of consuming more significant amounts of all kinds of drugs, with the exception of tranquilizers. It was found an increasing prevalence of drug consumption in medical students, as the program progressed, which may result from the intrinsic stress from medical school activities. Students who do not use psychoactive drugs are more likely to live with their parents, to disapprove drugs consumption, to practice religious beliefs and to be employed. CONCLUSION: The prevalence of licit and illicit drug use among medical students is high, even though they understand the injuries it may cause. PMID- 30304148 TI - Are women living with HIV prone to osteoporosis in postmenopause? A systematic review. AB - BACKGROUND: Some researchers have suggested that HIV infections can increase the cytokines, which might interfere with the bone metabolism and increase the risk of bone mass loss. However, this issue has yet to be consolidated in postmenopausal women. OBJECTIVE: To analyze studies that evaluated the loss of bone mass through DEXA in women living with HIV. MATERIALS AND METHODS: A systematic review was conducted following the PRISMA guideline. The MEDLINE, EMBASE and Cochrane databases were consulted from January 1987 to March 2017. Studies assessing bone mineral density (BMD) in postmenopausal women living with HIV were included. The secondary outcome was to evaluate the impact of antiretroviral on BMD. RESULTS: Sixty percent of the manuscripts suggested that women living with HIV had more bone loss than women in the control group, mainly in the lumbar spine. Forty percent did not observe any difference between groups. One study reported the influence of antiretroviral drugs on bone mass but did not find any difference between groups. CONCLUSION: Our data suggest that HIV infections may have a negative influence on bone mass loss in women. Further studies on the mechanism of this HIV consequence are necessary to clarify the connection as well as the impact of the antiretroviral action on BMD in postmenopausal women. PMID- 30304149 TI - Traditional and ultrasound physical examinations: a hybrid approach to improve clinical care. AB - Point-of-care ultrasonography, which is performed at the bedside by physicians who are not specialists in imaging, has become possible thanks to recent technological advances that have allowed for a device with greater portability while maintaining image quality. The increasing use of point-of-care ultrasonography in different specialties has made it possible to expand physical examinations, make timely decisions about the patients and allows the performance of safer medical procedures. In this review, three cases from our experience are presented that highlight the use of point-of-care ultrasonography by clinicians. Bedside ultrasonography is a convenient modality used in a clinical setting to aid in early diagnosis of several common conditions. It is suggested that a hybrid approach of physical examination and point-of-care ultrasonography in the everyday clinical practice is an inevitable change of paradigm that is improving quality of care in a variety of clinical settings. PMID- 30304150 TI - With professional overexposure, how to protect yourself from litigation? PMID- 30304151 TI - An interview with Simonas Grybauskas. PMID- 30304152 TI - There is no pulp necrosis or calcific metamorphosis of pulp induced by orthodontic treatment: biological basis. AB - To biologically explain why the orthodontic treatment does not induce pulp necrosis and calcific metamorphosis of the pulp, this paper presents explanations based on pulp physiology, microscopy and pathology, and especially the cell and tissue phenomena that characterize the induced tooth movement. The final reflections are as follows: 1) the orthodontic movement does not induce pulp necrosis or calcific metamorphosis of the pulp; 2) there is no literature or experimental and clinical models to demonstrate or minimally evidence pulp alterations induced by orthodontic movement; 3) when pulp necrosis or calcific metamorphosis of the pulp is diagnosed during orthodontic treatment or soon after removal of orthodontic appliances, its etiology should be assigned to concussion dental trauma, rather than to orthodontic treatment; 4) the two pulp disorders that cause tooth discoloration in apparently healthy teeth are the aseptic pulp necrosis and calcific metamorphosis of the pulp, both only induced by dental trauma; 5) the concussion dental trauma still requires many clinical and laboratory studies with pertinent experimental models, to increasingly explain its effects on the periodontal and pulp tissues. PMID- 30304153 TI - Side effects of mandibular advancement splints for the treatment of snoring and obstructive sleep apnea: a systematic review. AB - INTRODUCTION: Occlusal side effects or development of pain and/or functional impairment of the temporomandibular complex are potential reasons for poor compliance or abandonment of mandibular advancement splints treatment for snoring and obstructive sleep apnea. OBJECTIVE: This study aimed at providing a comprehensive review evaluating the craniofacial side effects of oral appliance therapy for snoring and obstructive sleep apnea. METHODS: An electronic search was systematically conducted in PubMed and Virtual Health Library from their inception until October 2016. Only Randomized Controlled Trials whose primary aim was to measure objectively identified side effects on craniofacial complex of a custom-made oral appliance for treating primary snoring or obstructive sleep apnea were included. Studied patients should be aged 20 or older. The risk of bias in the trials was assessed in accordance with the recommendations of The Cochrane Risk of Bias criteria. RESULTS: A total of 62 full-text articles were assessed for eligibility. After the review process, only 6 met all the inclusion criteria. All studies were rated as having a high risk of bias. The most uniformly reported mandibular advancement splint side effects were predominantly of dental nature and included a decrease in overjet and overbite. The risk of developing pain and function impairment of the temporomandibular complex appeared limited with long-term mandibular advancement splint use. CONCLUSION: The limited available evidence suggests that mandibular advancement splint therapy for snoring and obstructive sleep apnea results in changes in craniofacial morphology that are predominantly dental in nature, specially on a long-term basis. Considering the chronic nature of obstructive sleep apnea and that oral appliance use might be a lifelong treatment, a thorough customized follow-up should therefore be undertaken to detect possible side effects on craniofacial complex. It is also important to provide adequate information to the patients regarding these possible changes, especially to those in whom larger occlusal changes are to be expected or in whom they are unfavorable. Long-term assessments of adverse effects of oral appliance therapy, with larger study samples and recruitment of homogenous patient population are still required. PMID- 30304154 TI - Canine transposition as an alternative to trauma of the maxillary incisors: case report. AB - OBJECTIVE: The present article aims at reporting the clinical case of a patient who suffered trauma at two years of age, causing almost complete apical displacement of the deciduous maxillary left central incisor and of the permanent incisor. METHODS: Ectopia secondary to intrusion was minimized by surgical removal of the ectopic tooth, and the left permanent canine was submitted to orthodontic traction to replace the extracted tooth. RESULTS: The treatment period lasted 36 months, resulting in correct occlusion and a good aesthetic outcome. CONCLUSIONS: Dental transposition carried out by means of orthopedic traction is a good alternative in cases of a very unfavorable ectopic tooth position. PMID- 30304155 TI - Evidence in Orthodontics related to qualitative research. AB - INTRODUCTION: Research in Orthodontics has historically followed the positivist model based on the direct relationship of cause and effect between diseases and their specific etiological factors. Despite the objectivity and the great potential of statistical procedures, quantitative methods have progressively been sharing space with other models that can encompass the multiplicity of factors that affect the health-disease process, which until such time was reduced to its biological dimension. OBJECTIVES: This study aims, through an integrative review, to identify orthodontics articles published over a 10-year period that have used, exclusively or not, some method of qualitative research, and analyze the main aspects of their content. METHODS: A survey was performed on Pubmed, Medline, Scopus, and Lilacs databases from 2007 to 2016 with a focus on the applicability of the qualitative methodology in orthodontic research. RESULTS: The 27 articles selected showed a trend to increase in publications, with the most recent four years concentrating almost 60% of them. Most studies were from Europe, particularly the UK, and the more frequent study objectives were related to the perception of people about the reasons for orthodontic treatment, about the aesthetic and psychosocial impact of malocclusion or orthodontic treatment, and the implications of these factors for their quality of life. CONCLUSIONS: Because of its potential to explore behaviours and socio-cultural attitudes sustained in subjectivity, qualitative research offers new possibilities for orthodontic studies and can be used in an exclusive or complementary way in relation to quantitative methods. PMID- 30304156 TI - Evaluation of tongue/mandible volume ratio in children with obstructive sleep apnea. AB - OBJECTIVE: The present study was an attempt to investigate tongue/mandible volume ratio in children, using volumetric magnetic resonance imaging (MRI) for early screening and to aid in treatment planning. METHODS: Volumetric evaluation of tongue volume/mandible volume ratio (TV/MV ratio) in children with obstructive sleep apnea (OSA) using MRI was carried out retrospectively on available DICOM MR images of children in the age group of 10-14 years. MRI image records of patients diagnosed with OSA were obtained from interventional radiology department records, at Sharad Pawar Dental College and Hospital (Datta Meghe Institute of Medical Sciences, Nagpur/India). The age, gender, height and weight of the subjects were retrieved from patient database and registered. For the control group, available MRI images of healthy subjects without OSA were retrieved. Body mass index (BMI) was also calculated using the height and the weight present in the records. Measurements from MR images were made using DICOM image processing software. Soft tissue and bony structure segmentation was performed by manual tracing. The tongue volume and mandible volume were directly computed using the software. The tongue volume/mandible volume ratio (TV/MV) was generated using the above values and expressed as a percentage for both groups. RESULTS: The difference between OSA group and control group with respect to TV/MV ratio was found to be highly significant at 0.05 level of significance. There was no significant correlation between BMI and TV/MV ratio in OSA group (p= 0.451) as well as in control group (p= 0.094). CONCLUSION: TV/MV ratio may be an appropriate variable to evaluate the risk of OSA, representing the balance between skeletal morphology and soft tissue morphology in craniofacial complex. PMID- 30304157 TI - Hypodontia of mandibular incisors: considerations on the orthodontic treatment. AB - Hypodontia is the most prevalent craniofacial malformation in mankind. It may present a wide variety of manifestations and, depending on the number and location of missing teeth, it may affect the esthetics, mastication, speech and occlusal balance. This paper discusses the therapeutic approaches to solve this condition, describing a case report with hypodontia of one mandibular lateral incisor, which treatment option included space closure at the region of hypodontia associated with composite resin restorations in the mandibular central incisors. The three-year follow-up after treatment revealed occlusal stability, adequate intercuspation in Class I relationship and excellent micro and macroesthetics. PMID- 30304158 TI - Plain access to justice and the orthodontist's activity in Brazil: vulnerability in the professional practice in the face of risks of malpractice lawsuits. AB - OBJECTIVE: the present study aimed at evaluating the risks and vulnerability of orthodontists to legal compensation actions and verifying the hypothesis of these health care professionals having little knowledge concerning their rights and obligations as service providers. METHODS: Three groups were formed to participate in a semi-structured interview. The first group had thirteen law professionals, the second group was composed of eleven orthodontists and the third group was made up of nine randomly selected orthodontic patients. RESULTS: Relevant aspects related to the exercise of the professional activity of orthodontists that influence on the vulnerability of orthodontists in lawsuits were identified. After transcription, reading, and comparing the answers of the interviews, items capable of influencing judicial decisions, from the standpoint of Brazilian Justice Courts, were evaluated. CONCLUSION: It was verified that Brazilian orthodontists do not have adequate formation concerning the legal consequences of the exercise of their professional activity. Orthodontists also failed to establish proper contractual relationship, organize orthodontic records, and, most importantly, failed in communicating the risks and the therapeutic processes to patients during all phases of treatment. PMID- 30304159 TI - Shear bond strength and adhesive remnant index of orthodontic brackets bonded to enamel using adhesive systems mixed with TiO2 nanoparticles. AB - INTRODUCTION: It is recently suggested that titanium dioxide (TiO2) nanoparticles can be added to bracket luting agents in order to reduce bacterial activity and protect the enamel. However, it is not known if this addition can affect the shear bond strength (SBS) below clinically acceptable levels. Therefore, this study examined this matter within a comprehensive setup. METHODS: This in vitro experimental study was conducted on 120 extracted human premolars randomly divided into four groups (n=30): in groups 1 and 2, Transbond XT light-cured composite with or without TiO2 was applied on bracket base; in groups 3 and 4, Resilience light-cured composite with or without TiO2 was used. Brackets were bonded to teeth. Specimens in each group (n=30) were divided into three subgroups of 10 each; then incubated at 37 degrees C for one day, one month, or three months. The SBS and adhesive remnant index (ARI) were calculated and compared statistically within groups. RESULTS: The SBS was not significantly different at one day, one month or three months (p>0.05) but composites without TiO2 had a significantly higher mean SBS than composites containing TiO2 (p<0.001). The SBS of Transbond XT was significantly higher than that of Resilience (p<0.001). No significant differences were noted in ARI scores based on the type of composite or addition of TiO2 (p>0.05). CONCLUSIONS: Addition of TiO2 nanoparticles to Transbond XT decreased its SBS to the level of SBS of Resilience without TiO2; thus, TiO2 nanoparticles may be added to Transbond XT composite for use in the clinical setting. PMID- 30304160 TI - Assessment of skeletal maturity using the calcification stages of permanent mandibular teeth. AB - INTRODUCTION: Knowledge of the growth status of patients is essential to formulate and initiate a precise treatment plan. This study aimed at determining the role of calcification of permanent mandibular teeth for the assessment of skeletal maturity. METHODS: A cross-sectional study was conducted using lateral cephalograms and dental panoramic radiographs of 360 patients (ages 7-18 years) equally divided into six groups according to cervical vertebral maturation stages. Skeletal age was determined using Baccetti et al. method and dental age was calculated using Nolla and Demirjian methods. RESULTS: Mean chronological stage at CS5 revealed a significant difference between male and female subjects (p= 0.003), which showed that the latter achieved skeletal maturity one year earlier than the former. A significant difference (p= 0.007) was found for dental age using Nolla's stages at CS3, which showed females demonstrated a dental age of 1.4 years less than males. Mandibular canine showed the highest correlation with Demirjian index (DI) in males (rho = 0.818) and females (rho = 0.833). Mandibular second premolar showed the highest correlation with Nolla's stages in males (rho = 0.654) and females (rho = 0.664). CONCLUSION: Comparisons between sexes revealed that females are skeletally and dentally advanced. The DI indicated stage F and Nolla's stages identified stages 9, 10 to be indicative of CS2-3 for the mandibular canine and stages F and G and 9-10 for CS2-3 for the first premolars, second premolars and second molars, respectively. PMID- 30304161 TI - Nursing Perspectives and the "Nursing Now" Campaign. PMID- 30304162 TI - Classification tree to screen for the nursing diagnosis Ineffective airway clearance. AB - OBJECTIVE: to identify the defining characteristics of Ineffective airway clearance with better predictive power using classification trees. METHOD: the predictive power of the defining characteristics of Ineffective airway clearance was evaluated based on classification trees generated from the data of 249 children with acute respiratory infection. RESULTS: Ineffective cough and adventitious breath sounds were identified as the main defining characteristics when screening for Ineffective airway clearance in accordance with trees based on three different computational algorithms. CONCLUSION: Ineffective coughing and adventitious breath sounds had better predictive capacity for Ineffective airway clearance in the sample. PMID- 30304163 TI - Referral and counter-referral: repercussions of coronary artery bypass graft in the perspective of Primary Care. AB - OBJECTIVE: to understand how repercussions of the referral and counter-referral of patients with indication/submitted to Coronary Artery Bypass Graft Surgery in the context of Primary Health Care. METHOD: qualitative research with a theoretical-methodological contribution anchored in the Grounded Theory. Theoretical sampling was performed with 41 participants, divided into three sample groups (patients, health professionals and managers) in the Metropolitan Region and Western Region of Santa Catarina State. RESULTS: the need for improvement in the process of recording clinical data in the regulation system emerged to strengthen patient referral; and the absence of a formal process of counter-referral and adaptation of lifestyle with repercussion in the counter referral. FINAL CONSIDERATIONS: the repercussions of the referral and counter referral of patients with indication/submitted to the CABGS in the context of Primary Care are experienced through professional guidance and, in particular, by family support. PMID- 30304164 TI - Health-Care Waste: Knowledge of Primary Care nurses. AB - OBJECTIVE: to describe the knowledge of nurses on Health-Care Waste Management (HCW) in Family Health Units (FHU) of Sao Carlos city, Sao Paulo State. METHOD: exploratory, descriptive and quantitative approach. The research was carried out with nurses of 16 FHU of the municipality of Sao Carlos-SP. Data were collected through an interview using a tool validated and analyzed using descriptive statistics. RESULTS: it is noteworthy that 68.7% (11) of the nurses did not know how to describe how chemical waste was sorted. In addition, regarding the treatment of HCW, 50.0% (8) of the nurses did not know if the general waste were subjected to some type of treatment. CONCLUSION: the HCW management can be considered a challenge in the nurses' agenda inserted in the Primary Care services, which refers to the need to implement periodic training on the management of this waste. PMID- 30304165 TI - Bowel rehabilitation of individuals with spinal cord injury: video production. AB - OBJECTIVE: produce and validate an educational video about bowel emptying maneuvers for training of individuals with neurogenic bowel in bowel rehabilitation process. METHOD: this is a methodological study developed in four stages: script/storyboard production, validation, educational video production and pilot study, which was conducted from January 2013 to July 2015. Instruments for validation, which was performed from December 2014 to February 2015 by a group of experts. A value equal to or greater than 70% was considered for validation of agreement and relevance of the script and storyboard, using descriptive statistics for data analysis. RESULTS: the script and storyboard were validated by 94% of the experts in the subject and 100% of the technicians. After validation and video recording, the pilot study was conducted with six individuals with neurogenic bowel - 100% of them evaluated the video positively. CONCLUSION: the video may contribute to the education of individuals with neurogenic bowel. PMID- 30304166 TI - Adaptation of the Nursing Activities Score for oncologic care. AB - OBJECTIVE: To adapt the contents of the Nursing Activities Score (NAS) tool to assist patients with cancer. METHOD: Methodological research that according to the Delphi Technique is a method aiming at the validation of content through agreement of experts. RESULTS: It took two rounds of opinion of experts, which added content contributions without modifying the structure and score of the original tool. The level of agreement ranged from 71 to 86%, and biological factors and assistance were more suggested: Monitoring and controls; Laboratory investigations; Support and care for family members and patients; Intravenous replacement; Renal support; Management activities. CONCLUSION: A high level of complexity of patients with cancer, and the demand for care and biopsychosocial spiritual care was diagnosed. This tool will enable the measurement of the workload of the Oncology Nursing team, which can contribute to the staffing dimensioning. PMID- 30304167 TI - Being-patient-waiting-for-cardiac-surgery: the preoperative period under the Heideggerian perspective. AB - OBJECTIVE: to investigate the patients' experience in the cardiac surgery preoperative period under the Heideggerian perspective. METHOD: exploratory qualitative research. Twelve patients were interviewed, from March to April, 2016, while they waited for myocardial revascularization surgery or valve replacement surgery. RESULTS: the analysis of the speeches allowed finding two dimensions of the being-there-patient-waiting-for-cardiac surgery, two meanings of the beingness: being-there-in-a-reduced-world and being-there-in-a-unknown world. CONCLUSION: the experiences were related to alterations and limitations coming from the surgery, potential generators of anxiety, depression and existential conflicts in the cardiac surgery preoperative period. Reinforcing the care as being-with-the-other is suggested, considering the dimensions referred to and the patient's integrality. PMID- 30304168 TI - Nursing consultation software for hypertensive users of the Family Health Strategy. AB - OBJECTIVE: To report the development of a nursing consultation software for hypertensive users of the Family Health Strategy. METHOD: Applied methodological research based on Roger Pressman's Software Engineering, developed in three cycles: planning, composed of the definition of the database prototyping and modelling; development of the navigation interface; and development of functional expressions and programming. RESULT: The software consists of administrative and nursing consultation screens. In the history, there is the option of undertaking the first and next consultation; nursing diagnoses are suggested by the system after entering information and can be selected by nurses. Interventions for diagnoses are suggested and can be chosen by nurses after structuring the medical plan. CONCLUSION: It is believed that the introduction of computer technology for nursing consultation brings several contributions, such as standardization, integration with different information systems, and continuous update. PMID- 30304169 TI - Comparison of tools for assessing fatigue in patients with heart failure. AB - OBJECTIVE: To compare the distributions of measurements of the Dutch Fatigue Scale (DUFS), Dutch Exertion Fatigue Scale (DEFS), and Fatigue Pictogram tools, according to the New York Heart Association (NYHA) Functional Classification and left ventricular ejection fraction (LVEF). METHOD: Methodological, cross sectional study with 118 patients with heart failure. Variance analysis, Pearson's correlation, and Fisher's exact tests were carried out, with a significance level of 0.05. RESULTS: There was an increase in the DUFS and DEFS means with worsening of the NYHA-FC (p<0.001, for both tools). Correlations among the LVEF resulted in positive and weak magnitude for the DEFS (r=0.18; p=0.05) and for the DUFS (r=0.16; p=0.08). Just the item A on the Fatigue Pictogram had an association with the NYHA-FC (p<0.001) and the LVEF (p=0.03). CONCLUSION: Three tools detected worsening in fatigue levels according to the illness severity assessed by the NYHA-FC. PMID- 30304170 TI - Promoting the autonomy of rural older adults in active aging. AB - OBJECTIVE: to understand how the rural older adults promote their autonomy in active aging. METHOD: qualitative research through the Paulo Freire's research itinerary, consisting of three steps: area of research; encoding and decoding; and critical unveiling. Seventeen older adults living in the rural area of a municipality in Southern Brazil participated in the research. Six culture circles were conducted from July to December 2016. RESULTS: the investigation revealed two generating themes: joint pain and participation in groups. The understanding of autonomy promotion for the active aging of older adults is focused on the physical capacity and independence of activities of daily living. FINAL CONSIDERATIONS: the culture circles have promoted reflection moments for the participants, especially about the advantages and difficulties related to the practice of autonomy in the exercise of citizenship for active aging in the rural area. PMID- 30304171 TI - Self-care of men with priapism and sickle cell disease. AB - OBJECTIVE: To identify self-care demands of men with sickle cell disease and priapism and describe self-care measures in light of Orem's Self-Care Theory. METHOD: This is a descriptive exploratory study with qualitative approach conducted with nine men with a history of sickle cell disease and priapism. Data were analyzed using Orem's Self-Care Theory. RESULTS: Some demands were identified: from universal self-care - difficulty in social interaction and solitude, changes in self-image, self-esteem and sexual activity; from development - the experience with priapism and little knowledge about the pathophysiology of the disease; regarding health deviations - pain crises. CONCLUSION: Orem's theory allowed to identify self-care demands, which are essential for the nursing care provided for men with priapism. Nursing has an essential role in the measures for the different demands presented. PMID- 30304172 TI - Software for systematization of nursing care in medical units. AB - OBJECTIVE: To describe the development of a software prototype to apply the nursing process in clinical units of a general hospital, and assess its usefulness. METHOD: Applied methodological research of technological production of a program based on prototyping software engineering developed in three stages: specification, development, and validation. RESULTS: Produced under the name of INFOSAE, the system represents a set of stages (history, diagnosis, expected outcomes, and nursing intervention) providing guidance to nurses to direct and guarantee the necessary care to patients, also allowing an assessment of this care. CONCLUSION: The INFOSAE software prototype, an easy-to-use computerized technology, obtained a favorable assessment by the user nurses that participated in the whole development process, from the specification to the validation of the system. PMID- 30304173 TI - Pedagogical preparation of nursing professors for professional secondary technical education. AB - OBJECTIVE: To understand how the nursing professor pedagogically prepares for teaching in professional secondary technical education in the light of the Pedagogical Content Knowledge of Lee S. Shulman. METHOD: This is a qualitative and descriptive study. Two pedagogical workshops were held to collect data, with the participation of six professors from two technical schools. RESULTS: The categories Pedagogical preparation for the teaching exercise and Knowledge Base for Teaching have emerged. The results revealed the difference between the real and the ideal in the perception of the participants, when their preparation for the teaching exercise is situated between the learning with colleagues and the mastery over the Content Knowledge. FINAL CONSIDERATIONS: Professor training is necessary and is an alternative to qualify teaching in professional secondary technical education. PMID- 30304174 TI - Polypharmacy and potentially inappropriate medications for elder people in gerontological nursing. AB - OBJECTIVE: To identify polypharmacy and potentially inappropriate medications (PIM) for elder people with chronic health situations and its implications for gerontological nursing. METHOD: Descriptive and transversal study, conducted from March to September 2016 by pharmaceutical residents in the clinic of Endocrinology of a hospital in Mid-West region of Brazil. RESULTS: 44 elder people with an average age of 69.5 (+/- 6.79) years old had their assessed prescriptions. We identified 65 medications prescribed 253 times, in which 10 PIM (15.4%) were prescribed 51 times. 33 seniors (72.7%) had at least one PIM, of those, 66.7% were polymedicated. Of the total, 22 elder people (50%) were subjected to polypharmacy and made use of at least one PIM. CONCLUSION: The results showed high incidence of PIM and polypharmacy, as well as their physiological impacts to the elder population. The study provokes discussions about that the trained nurse in human aging has skills and competencies able to enhance interventions related to pharmacotherapy. PMID- 30304175 TI - The teaching approach on communicative skills in different teaching methodologies. AB - OBJECTIVE: to understand, from the perspective of professors, which are the facilities and difficulties in the development of communication skills in nursing undergraduates who experiment different teaching-learning methodologies. METHOD: qualitative research performed with 30 nursing professors from two public education institutions. The data was collected by semi-structured individual interview with guiding questions. We used Bardin's content analysis for the data processing and analysis. RESULTS: the development of communication skills is influenced by factors such as the experience of practical activities, students' individual characteristics, use of active methodologies, access to the mass media, relationship of proximity between student and professor, and knowledge of theoretical concepts of communication and nursing. FINAL CONSIDERATIONS: there is similarity between the influential factors, however, the use of active methodologies seems to favor the development of communication skills. PMID- 30304176 TI - Brazilian and North-American nursing in the HOPE Project (1972): approximations and gaps. AB - OBJECTIVE: Understand the structuring and operation of the Nursing Service on the hospital ship HOPE and the relations between Nursing from North America and from Rio Grande do Norte. METHOD: Qualitative, sociohistorical research, developed by consulting documentary and oral sources. RESULTS: The analysis revealed the categories: The HOPE Project: impressions of its nurses and Nursing on the hospital ship SS HOPE: Brazilian impressions. These categories revealed a Nursing Service similar to that of a general hospital, ordered by scales and which functioned uninterruptedly in the three shifts. FINAL CONSIDERATIONS: The Nursing Service consisted exclusively of nurses; followed a hierarchical system; with accumulation of administrative and care functions; strict, precise and technical execution of the work. The language and cultural barriers do not seem to have compromised the Exchange and the work system in counterparts. PMID- 30304177 TI - Elderly caring for the elderly: spirituality as tensions relief. AB - OBJECTIVE: To investigate the forms of coping used to relieve tensions by elderly caregivers of elderly relatives and to know the type of support they receive from the Primary Health Care service at home. METHOD: A qualitative study with a theoretical-methodological contribution of Grounded Theory, carried out with 10 elderly caregivers interviewed between August 2014 and January 2015. RESULTS: Participants use primarily religious coping to deal with adverse situations that arise in their lives; they attribute to the sacred the strength to continue to age and care for another elderly person at home. Religiousness was the main coping strategy used by the participants, but little recognized by the health service. FINAL CONSIDERATIONS: It is recommended that the Primary Health Care service provide greater support to these caregivers and be attentive to the spiritual dimension as an auxiliary element in the process of comprehensive and inclusive health care of these elderly caregivers. PMID- 30304178 TI - Application of Merleau-Pontyan perspective on the physical and psychological implications of venous ulcers. AB - OBJECTIVE: to verify the application of the Merleau-Pontyan perspective on the physical and psychological implications of chronic venous ulcers in the existence of people who experience the disease. METHOD: a qualitative study, of the descriptive phenomenological type, developed with 36 patients. The field of investigation was the Outpatient Clinic of Wound Repair of the Hospital Universitario Antonio Pedro. The collection occurred from June to December 2016, through a phenomenological interview. RESULTS: the experiences inherent in people who have venous ulcers pass through the world and "return" to the body itself, reflecting on the biopsychosocial aspects and the sensitivity left on the being. CONCLUSION: the biological characteristics of the subject affected by the venous ulcer have repercussions on their physical aspect, promoting influences along with the emotional and social changes originating from the clinical picture on the social aspects and consequently reverberating on the quality of life of this individual. PMID- 30304179 TI - Hypertension as a risk factor for female sexual dysfunction: cross-sectional study. AB - OBJECTIVE: to evaluate the sexual dysfunction in hypertensive patients compared to normotensive patients. METHOD: this was a cross-sectional study. Samples were composed of 54 hypertensive patients and 54 normotensive patients. The female sexual dysfunction was evaluated by the Female Sexual Function Index (FSFI). RESULTS: the average FSFI score differed highly between hypertensive and normotensive patients (22.4+/- 7.4 versus 26.8 +/-5.4, p< 0.001). Among hypertensive patients, 63% showed sexual dysfunction in opposition to 39% of normotensive patients (p=0.02). Hypertensive women had 1.67 more chances of showing the dysfunction than women with normal blood pressure. CONCLUSION: the sexual dysfunction prevalence is higher in hypertensive than in normotensive women hence, hypertension is a potentiator factor for female sexual dysfunction. PMID- 30304180 TI - Case study: using participatory photographic methods for the prevention of medication errors. AB - OBJECTIVE: To describe the experience of using participatory photographic research methods to engage nurses and researchers in a collaborative study to improve medication safety conditions, particularly in patients with feeding tubes in a nursing home for the elderly (NHE). METHOD: This qualitative study was conducted in Brazil and proceeded in iterative phases of visual and textual data collection and analysis. Interviews, subsequent nurse-led photo-narrated walkabouts, and photo elicitation were used with nurses. RESULTS: The need to transform the work design and the workplace to improve medication safety and improving medication processes through effective communication was identified. Unsafe workforce is a challenge in achieving safe medication administration practices; and lack of a patient safety culture is a barrier for adaptive learning and growth. CONCLUSION: Our findings demonstrated the effectiveness of a restorative research approach for supporting nurses to study and act on medication safety. PMID- 30304181 TI - Brazilian nursing journals: strengths, weaknesses and challenges. AB - OBJECTIVE: To evaluate, qualitatively, the Brazilian nursing journals and identify their strengths and weaknesses when compared to international journals in the area. METHODS: A historic approach regarding the period from 2012 to 2016. We included national nursing journals indexed in the SciELO Database and international journals with an impact factor above 1.0 and below 1.8 indexed in the WoS and Scopus databases. RESULTS: The national journals met SciELO requirements for internationalization and obtained visibility when they were included in international indexing bases. Their citations were mostly national, with the following mean values: 86% in Portuguese; 12% in Spanish and 2% in English. CONCLUSION: The excellence requirements of the national journals are being accomplished. The publication of articles in Spanish can impact on the increase of bibliometric indicators. PMID- 30304182 TI - Profile and quality of life of women in pelvic floor rehabilitation. AB - OBJECTIVE: Describe the sociodemographic, clinical, and sexual profile, identify profile variables that affect the Health-Related Quality of Life (HRQoL), and evaluate the correlation between two HRQoL questionnaires used in a pelvic floor rehabilitation program. METHOD: This is an observational, analytical, and cross sectional study, based on patient records and two questionnaires for HRQoL evaluation. RESULTS: Women presented a mean age of 55.4 years; were married; white; had stress, urge, or mixed urinary incontinence (UI) of moderate to large urine release; and daily or diurnal UI. Only 50.5% had an active sex life and most had sexual complaints. The change in sexual activity and some types of UI affected the HRQoL. The two questionnaires presented a correlation. CONCLUSION: The profile and correlation between the questionnaires are consistent with the literature. The type of UI and changes in sexual activity affect the HRQoL. PMID- 30304183 TI - Health diagnosis: a responsibility of community health nursing in Angola. AB - OBJECTIVE: To characterize the health situation of the population in the Imbondeiro neighborhood, sector C (Luanda). METHOD: This is a descriptive, cross sectional and quantitative study. Families living in the sector were included, included in the sample by "door to door" contact. They accepted to participate through a free and consented form. RESULTS: Health diagnosis of 341 family households was conducted, involving 1,312 people. A total of 46.02% are male and 54.08% are female; from these, 42.62% are children, 15.14% adolescents and 42.24% adults. CONCLUSION: The results obtained and presented are in accordance with the data from the National Institute of Statistics of Angola (INE), revealing that it is necessary to intervene and to promote healthy lifestyle habits, regarding issues such as domestic violence, alcohol consumption, inappropriate eating habits, sexually communicable diseases, among others. PMID- 30304184 TI - Out-of-pocket payments in hospital bills: a challenge to management. AB - OBJETIVE: To analyse out-of-pocket payments (OOP) by health insurance company in hospital bills. METHOD: Cross-sectional study with quantitative approach. The information was obtained in the database of a health insurance company in the north of Parana State and categorised into administrative and technical OOP. We analysed reports regarding OOP made in eight hospitals of the accredited network company, from 2013 to 2015. RESULTS: The analysed data totalled 36 thousand items paid out-of-pocket. The highest OOP rates occurred in hospital 1 (67.6%); emergency room service (50.1%); time of hospitalization, <= 1 day (70.8%) and medical-hospital materials (59.2%). The year with the highest rates of administrative (54.51%) and technical (48.05%) OOP was 2013. CONCLUSION: We concluded that OOP are indicators for the institutions to check the critical topics to be improved and that managers must work on originator aspects of OOP, to prevent greater loss. PMID- 30304185 TI - Epidemiological investigation of perinatal deaths in Recife-Pernambuco: a quality assessment. AB - OBJECTIVE: to evaluate the completeness of perinatal death investigation sheets, stratified by age components. METHOD: descriptive study carried out in Recife, PE, in 2014. Among 308 perinatal deaths, 46 were excluded from this study due to association with congenital malformations, and 7 due to missing investigation sheets. Analysis included 255 deaths (160 fetal deaths, and 95 preterm neonatal deaths). The degree of completeness of 98 variables was calculated. They were aggregated into six blocks: identification, prenatal care, birth care, family characteristics, occurrence of death and conclusions and recommendations. RESULTS: the median rate of completeness for perinatal death investigation sheets was 85.7% (82.8% for records of fetal deaths and 89.5% for records of preterm neonatal deaths). The best-filled information block was "identification" (96.1%), as well as its components: fetal (94.7%) and preterm neonatal (97.9%). The worst was "prenatal care" (69.8%), along with its components: fetal (73.8%) and preterm neonatal (67.4%). CONCLUSION: investigation sheets had good completeness; there were differences between variables and components of perinatal death. PMID- 30304186 TI - Early neonatal mortality and risk factors: a case-control study in Parana State. AB - OBJECTIVE: to analyze the Early Neonatal Mortality risk factors according to the risk stratification criteria of the Guideline of the Rede Mae Paranaense Program. METHOD: a case-control epidemiological study with secondary data from the Mortality and Live Birth Information System in 2014. The crude analysis was performed by the Odds Ratio association measure, followed by the adjusted analysis, considering risk factors as independent variables, and early neonatal death as dependent variable. RESULTS: were considered as maternal risk factors: absence of partner and miscarriages; neonatal: male, low birth weight, prematurity, Apgar less than seven in the fifth minute, presence of congenital anomaly; and care: up to six prenatal appointments. CONCLUSION: an innovative study of risk factors for early neonatal death from the Guideline's perspective, a technological management tool for maternal and child health, in search of its qualification and greater sensitivity. PMID- 30304187 TI - People living with AIDS: Association between nursing diagnoses and sociodemographic/clinical characteristics. AB - OBJECTIVE: To analyze the association between nursing diagnoses and sociodemographic and clinical characteristics in people living with AIDS. METHOD: Cross-sectional study with 100 people living with AIDS in a University Hospital. Data collection took place between January and July 2015, using an interview script and physical examination. The association occurred through Pearson's Chi-Square Test and Fisher's Exact Test. RESULTS: The most prevalent nursing diagnoses were: ineffective protection, poor knowledge, lack of adherence and sexual dysfunction. Significant associations were observed among nursing diagnoses with the following sociodemographic and clinical characteristics: marital status, place of residence, level of schooling, family income, modes of transmission of acquired immunodeficiency virus, current opportunistic infection, abandonment of treatment, difficulty of access to health services and use of alcohol and illicit drugs. CONCLUSION: The diagnoses presented significant associations with sociodemographic and clinical aspects. PMID- 30304188 TI - Detection of tuberculosis: respiratory symptoms flow and results achieved. AB - OBJECTIVE: to analyze the flow of care to the person with symptoms of tuberculosis and the results achieved in the detection of cases in Primary Health Care units of two municipalities of Rio Grande do Sul. METHOD: descriptive of mixed methods, developed between 2013 and 2016. We used secondary data of 69 units and semi-structured interviews with 10 professionals. Descriptive statistical analysis and content analysis were used. RESULTS: it was observed that the fragmented flow of attention to the respiratory symptoms in Pelotas resulted in low detection of cases by Primary Care, 8.8% of the diagnoses of the municipality. The Sapucaia do Sul flow presents continuity of care, and Primary Care performed 50% of the diagnoses of the municipality. CONCLUSION: the organization of flows by municipal management was instrumental in promoting or limiting the commitment of Primary Health Care teams in coordinating care and consequently in achieving the goals of disease control. PMID- 30304189 TI - Odor evaluation scales for odor in neoplastic wounds: an integrative review. AB - OBJECTIVE: Checking for the existence of assessment instruments for odor in neoplastic wounds. METHOD: Integrative review performed in the databases Lilacs, SCiELO, Ibecs and MedLine, including national and international publications. RESULTS: 15 articles were analyzed, in its majority performed by nurses and being of the revision type. Nine scales were found, of which the majority assesses only the odor intensity. The scale most used to evaluate products and/or bandage covers for neoplastic injuries was the Odor Evaluation Guideline, of qualitative quantitative nature, that establishes the symptom within four levels; only one of which being validated (Teler scale). CONCLUSION: The results of this study showed that, currently, there is only one scale that is validated for assessing odor in neoplastic wounds, pointing towards the need to develop new instruments that incorporate validated and reliable instruments in clinical practice. PMID- 30304190 TI - Cardiovascular adverse events associated with oral antineoplastic therapy. AB - OBJECTIVE: To identify in the literature the cardiovascular adverse events resulting from oral antineoplastic therapy. METHOD: Integrative review of the literature through the SCOPUS, Scientific Electronic Library Online (SciELO), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Literature Analysis and Retrieval System Online (MEDLINE) databases. The antineoplastic, cardiotoxicity, cardiovascular system and adverse reaction descriptors were used in Portuguese, English and Spanish. We selected 23 articles published between 1985 and 2015. RESULTS: Twenty studies were related to cardiac events and eleven to peripheral vascular events. The most frequent adverse cardiac events were reduced left ventricular ejection fraction, myocardial infarction, changes in the electrocardiogram, heart failure and angina, whereas peripheral vascular events were hypertension and thromboembolism. CONCLUSION: Oral antineoplastic therapy is associated with different adverse events, including cardiac and peripheral vascular events. PMID- 30304191 TI - Mobile technologies in the Nursing area. AB - OBJECTIVE: To identify in the literature studies on mobile technologies in Nursing. METHOD: Integrative literature review in which was used the Population, Interest and Context (PICo) strategy, the tool of the National Library of Medicine for formulation of the research question, and search without a determined period of time in the following bibliographic databases: Medical Literature and Retrieval System onLine/PubMed(r)), Cumulative Index to Nursing & Allied Health Literature (CINAHL), SCOPUS (Elsevier), Latin American and Caribbean Literature in Health Sciences (LILACS) and Nursing Database (BDENF). Data collection period was from January to March 2017. RESULTS: Fifteen articles were selected, in which were addressed mobile technologies in Nursing for nurses, undergraduate students and patients. CONCLUSION: Mobile technologies in Nursing are a recent theme and enable care data sharing, experience acquisition by undergraduate students and patient empowerment. PMID- 30304192 TI - Keeping the light on - Nursing history center in Ceara - NUDIHMEn. AB - OBJECTIVE: To share the implementation of the Center for Documentation, Information, History and Memory of Nursing in Ceara - NUDIHMEn and its achievements in caring for, producing and preserving the history and the memory of Nursing in Ceara. METHOD: It is an experience report regarding the work carried out in NUDIHMEN from 2009 to 2017. RESULTS: The NUDIHMEn holds a database of 1,454 newspaper articles, mapped data of 35 manuscript volumes of the Ecclesiastical History of Ceara about Nursing precursors, in addition to 23 minutes books from the Fortaleza Santa Casa (1879 to 1970), documentation belonging to the Sao Vicente de Paulo Nursing School, 8 scanned minutes books from the UECE Nursing Course, among other research resources. CONCLUSION: The NUDIHMEn provides records on Nursing history in Ceara for knowledge, socialization and scientific production of the community concerned. PMID- 30304193 TI - A paradigmatic visionary perspective: professional master's in nursing. AB - OBJECTIVE: To reflect on the key concepts of the book The Structure of Scientific Revolutions and its applicability in professional master's in nursing. METHOD: This is a theoretical-reflective study that uses the philosophical and epistemological conceptions of the philosopher Thomas Samuel Kuhn to consider its applicability on the paradigm shift of stricto sensu graduate courses in nursing. The main concepts of Kuhn were used as support: paradigm, anomaly, scientific community and scientific revolution. RESULTS: The propositions of this philosopher are applied to and support the theoretical reflection on professional master's programs, contributing to clarify what would be a paradigmatic visionary perspective in stricto sensu master's models in nursing. CONCLUSION: From Kuhn's propositions it was possible to conclude that professional master's programs in nursing can break away from the dominant paradigm, strengthening a scientific revolution within the academia. PMID- 30304194 TI - A physical resilience conceptual model - contributions to gerontological nursing. AB - OBJECTIVES: To analyze and reflect on the potential applicability of the contribution of the physical resilience conceptual model of Whitson et al. in the care for older adults. METHOD: The present article of reflection was structured based on the consultation of articles and definition of inherent concepts, with analysis and reason of the potentialities of its application in geriatric nursing care. RESULTS: Physical resilience is influenced by diverse stimuli. The identification of stressors and early intervention enable the delay of the functional capacity decline. In practice, the planning of interventions that depend on the innate capacity of older adults is of utmost importance. CONCLUSION: The trajectory outlined over a debilitating event is relevant to understand the factors that contribute to the development of frailty or pre frailty conditions. This knowledge allows nurses to adjust their practice and contribute to the effectiveness of interventions and a better prevention of the frailty syndrome. PMID- 30304195 TI - Rebirth of childbirth: reflections on medicalization of the Brazilian obstetric care. AB - OBJECTIVE: to reflect on the medicalization process of childbirth and birth and its consequences based on a Brazilian audiovisual media artifact. METHOD: reflective and interpretive analysis of the documentary O Renascimento do Parto (The Rebirth of Childbirth) based on Critical Discourse Analysis. RESULTS: c section emerges as an alternative to adverse conditions of pregnancy. However, it has become a routine and abusive practice of a medicalized obstetric care, thus becoming a social problem. In order to the incidence of c-sections decrease, women's protagonism must be restored, in addition to considering psychological, affective, emotional, spiritual, cultural, and contextual aspects in childbirth. CONCLUSION: childbirth is established as a material element and a mental phenomenon of social practices. We must interrupt the predominant model, allowing the body to express itself through the release of oxytocin, and decrease the segregation that c-section causes, thus enabling affective bonds. PMID- 30304196 TI - Violence in health care settings: rethinking actions. AB - OBJECTIVE: To present a reflection on the forms of violence in health care settings and on preventive actions. METHOD: This is a theoretical reflection about the phenomenon of violence and its possible coping actions. RESULTS: Nurses and other professionals working in health care environments may experience situations of aggression and disrespect through institutional or managerial violence, horizontal violence and patient violence. FINAL CONSIDERATIONS: Violent practices are not applicable in any workplace, especially in care settings. Actions or measures of control should be taken in pursuit of healthier environments and in harmony with the culture of peace. PMID- 30304197 TI - Incidents reporting: barriers and strategies to promote safety culture. AB - OBJECTIVE: The purpose was to identify the barriers of underreporting, the factors that promote motivation of health professionals to report, and strategies to enhance incidents reporting. METHOD: Group conversations were carried out within a hospital multidisciplinary team. A mediator stimulated reflection among the subjects about the theme. Sixty-five health professionals were enrolled. RESULTS: Complacency and ambition were barriers exceeded. Lack of responsibility about culture of reporting was the new barrier observed. There is a belief only nurses should report incidents. The strategies related to motivation reported were: feedback; educational intervention with hospital staff; and simplified tools for reporting (electronic or manual), which allow filling critical information and traceability of management risk team to improve the quality of report. CONCLUSION: Ordinary and practical strategies should be developed to optimize incidents reporting, to make people aware about their responsibilities about the culture of reporting and to improve the risk communication and the quality of healthcare and patient safety. PMID- 30304198 TI - The use of IRAMUTEQ software for data analysis in qualitative research. AB - OBJECTIVE: To describe the use of IRAMUTEQ software in qualitative data analysis. METHOD: A description for using a software program as a tool to support data processing in qualitative research, carried out in 2015. Data collection was done through interviews using a semi-structured script. RESULTS: Twenty-one (21) companions participated in the study. The five classes resulting from data processing by the software allowed for analysis and interpretation of the nursing performance with the parturient as an active participant in the process of labor and delivery, and in the role of companion in this period. CONCLUSION: The use of IRAMUTEQ software as a tool for processing qualitative data through the Descending Hierarchical Classification emerged classes and a connection between them, which further allowed for secure and credible data analysis. It is necessary to explore the other possibilities of using this tool in greater depth. PMID- 30304199 TI - Knowledge and practices of primary care providers on skin cancer and skin self examination. AB - OBJECTIVE: To determine the knowledge and practices related to skin cancer and skin self-examination of primary care providers. METHOD: This cross-sectional descriptive study was conducted in Turkey. The study was carried out in primary health centers such as family health centers, community health centers, early cancer detection centers and family planning centers in 2016-2017. Participants' socio-demographic characteristics, their knowledge and practices related to skin cancer, skin cancer risk factors and skin self-examination were determined. RESULTS: The study population included 94 primary care providers. The symptoms of which the participants were most aware were changes in the color of moles or skin spots (95.71%), and of which participants were the least aware was the itching of a mole (71.43%). Among participants, the most recognized risk factor was having fair skin (97.14%), whereas the least known was the presence of birthmarks (24.29%). The mean scores the participants obtained from the questionnaire were as follows: 5.39+/-1.61 for skin cancer risk factors and 10.47+/-2.73 for skin cancer symptoms. Of the participants, 14.29% received training on skin self examination, 38.57% knew how to perform skin self-examination, and 67.14% did not perform skin self-examination. Of the participants, 61.7% did not perform skin self-examination because they did not know what to look for. Of the participants, 85.71% did not have continuing education/workshop about skin self-examination after graduation. CONCLUSION: Although the primary care providers' knowledge of skin cancer symptoms was adequate, their knowledge of skin cancer risk factors was not sufficient. Primary care providers' knowledge of skin self-examination was good, but they did not perform skin self-examination adequately. PMID- 30304200 TI - Incidence of infiltration/extravasation in newborns using peripheral venous catheter and affecting factors. AB - OBJECTIVE: The objective of this study was to identify the incidence of infiltration and extravasation in newborns using peripheral venous catheter, and affecting factors. METHOD: This observational study examined catheters inserted into newborns who received inpatient care in the neonatal intensive care unit of a state hospital located in the west of Turkey. A total of 452 peripheral venous catheters inserted into 152 newborns were observed. The forms were completed by the researchers based on their observations at each shift. RESULTS: The infiltration/extravasation occurred in 45.6% of peripheral venous catheters inserted into newborns; 19.7% were stage I and 11.7% were stage IV. A statistically significant relationship was found between the gestation week as well as the birth weight of newborns and the occurrence of infiltration/extravasation complication. In addition, there were statistically significant relationships between the administration of single or multiple antibiotics, total parenteral nutrition and the incidence of infiltration/extravasation complication. CONCLUSION: It is recommended to use an appropriate scale for the assessment of infiltration/extravasation as well as to implement measures for preventing the occurrence of infiltration/extravasation. PMID- 30304201 TI - Stroke prevention within primary care: management of atrial fibrillation using oral anticoagulation. PMID- 30304202 TI - Validity and reproducibility of retinal arteriole and venule diameter measurements: ELSA-Brasil study. A cross-sectional study. AB - BACKGROUND: Investigation of alterations to retinal microvasculature may contribute towards understanding the role of such changes in the pathophysiology of several chronic non-communicable diseases. The objective here was to evaluate the validity and reproducibility of retinal arteriole and venule diameter measurements made by Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) graders. DESIGN AND SETTING: Cross-sectional study at six teaching and research institutions. METHODS: To evaluate validity, each of 25 retinal images from the University of Wisconsin (gold standard) was measured by five ELSA-Brasil graders. To evaluate reproducibility, 105 images across the spectrum of vessel diameters were selected from 12,257 retinal images that had been obtained between 2010 and 2012, and each image was reexamined by the same grader and by an independent grader. All measurements were made using the Interactive Vessel Analysis (IVAN) software. Bland-Altman plots, paired t tests and intraclass correlation coefficients (ICCs) were analyzed. RESULTS: Mean differences between ELSA-Brasil and gold-standard readings were 0.16 um (95% CI -0.17-0.50; P = 0.31) for central retinal artery equivalent (CRAE), -0.21 um (95% CI -0.56-0.14; P = 0.22) for central retinal vein equivalent (CRVE) and 0.0005 (95% CI -0.008-0.009; P = 0.55) for arteriole/venule ratio (AVR). Intragrader ICCs were 0.77 (95% CI 0.67-0.86) for CRAE, 0.90 (95% CI 0.780.96) for CRVE and 0.70 (0.55-0.83) for AVR. Intergrader ICCs were 0.75 (95% CI 0.64-0.85) for CRAE, 0.90 (95% CI 0.79-0.96) for CRVE and 0.68 (95% CI 0.55-0.82) for AVR. CONCLUSIONS: Retinal microvascular diameter measurements are valid and present moderate to high intra and intergrader reproducibility in ELSA-Brasil. PMID- 30304203 TI - Pediatric Wilson's disease: findings in different presentations. A cross sectional study. AB - BACKGROUND: Wilson's disease (WD) may present with different manifestations: from an asymptomatic state to liver cirrhosis. Here, we aimed to evaluate clinical presentations and laboratory findings and prognoses among WD cases. DESIGN AND SETTING: Cross-sectional study based on patients' records from the university hospital, Inonu University, Malatya, Turkey. METHODS: The medical records of 64 children with WD were evaluated focusing on the clinical, laboratory and liver biopsy findings in different clinical presentations. RESULTS: The mean age at diagnosis was 8.6 +/- 3.26 years (range 3.5-17) and mean length of follow-up was 2.49 years (range 0-9). There were 18 cases (28.1%), 12 (18.8%), 9 (14.1%) and 6 (9.4%) of chronic liver disease, fulminant liver failure, neurological WD and acute hepatitis, respectively. Nineteen (29.7%) were asymptomatic. The most common sign and laboratory finding were jaundice (45.3%) and hypertransaminasemia (85.9%), respectively. The lowest serum zinc level was found in the fulminant liver failure group (P = 0.035). Hepatosteatosis was detected in 35% of the 20 patients who underwent liver biopsy. Among those with hepatosteatosis, 57.1% were asymptomatic. While 35% had copper staining, 25% presented iron accumulation in liver biopsies. Nine cases underwent liver transplantation and seven of these presented fulminant liver failure (77.8%). CONCLUSION: The presentation, symptoms and signs of our cases were similar to those in previously reported series, except for the high proportion of fulminant WD cases. Further studies are needed to clarify the relationship between zinc levels and development of a fulminant course and between iron status and WD. PMID- 30304204 TI - Self-reported smoking status and urinary cotinine levels in patients with asthma. AB - OBJECTIVE: To determine the frequency of active smoking among patients with asthma and individuals without asthma by self-report and urinary cotinine measurement. METHODS: This was a cross-sectional study conducted in the city of Salvador, Brazil, and involving 1,341 individuals: 498 patients with severe asthma, 417 patients with mild-to-moderate asthma, and 426 individuals without asthma. Smoking status was determined by self-report (with the use of standardized questionnaires) and urinary cotinine measurement. The study variables were compared with the chi-square test and the Kruskal-Wallis test. RESULTS: Of the sample as a whole, 55 (4.1%) reported being current smokers. Of those, 5 had severe asthma, 17 had mild-to-moderate asthma, and 33 had no asthma diagnosis. Of the 55 smokers, 32 (58.2%) were daily smokers and 23 (41.8%) were occasional smokers. Urinary cotinine levels were found to be high in self reported nonsmokers and former smokers, especially among severe asthma patients, a finding that suggests patient nondisclosure of smoking status. Among smokers, a longer smoking history was found in patients with severe asthma when compared with those with mild-to-moderate asthma. In addition, the proportion of former smokers was higher among patients with severe asthma than among those with mild to-moderate asthma. CONCLUSIONS: Former smoking is associated with severe asthma. Current smoking is observed in patients with severe asthma, and patient nondisclosure of smoking status occurs in some cases. Patients with severe asthma should be thoroughly screened for smoking, and findings should be complemented by objective testing. PMID- 30304205 TI - Noncompliance with the law prohibiting the sale of cigarettes to minors in Brazil: an inconvenient truth. AB - OBJECTIVE: To draw up an up-to-date scenario of compliance with the law prohibiting the sale of cigarettes to minors. METHODS: We used data about youth access to cigarette purchase that were obtained through a nationwide survey conducted in 2015 among students aged 13-17 years. We estimated simple proportions of attempts to buy cigarettes, success of attempts, purchase of cigarettes on a regular basis, and purchase of cigarettes on a regular basis in a store or bar. All estimates were stratified by gender, age group, and Brazilian macro-region. Crude absolute difference and adjusted absolute difference in the proportion of smokers in each category by variable of interest were analyzed by a generalized linear model with binomial distribution and identity link function. RESULTS: Approximately 7 in every 10 adolescent smokers attempted to buy cigarettes at least once in the 30 days prior to the survey. Of those, approximately 9 in every 10 were successful, and individuals aged 16-17 years (vs. those aged 13-15 years) were less often prevented from buying cigarettes (adjusted absolute difference, 8.1%; p <= 0.05). Approximately 45% of all smokers aged 13-17 years in Brazil reported buying their own cigarettes on a regular basis without being prevented from doing so, and, of those, 80% reported buying them in a store or bar (vs. from a street vendor). CONCLUSIONS: Our findings raise an important public health concern and may contribute to supporting educational and surveillance measures to enforce compliance with existing anti tobacco laws in Brazil, which have been disregarded. PMID- 30304206 TI - Global TB Network: working together to eliminate tuberculosis. PMID- 30304207 TI - The Exponentiated Power Generalized Weibull: Properties and Applications. AB - We propose a new lifetime model called the exponentiated power generalized Weibull (EPGW) distribution, which is obtained from the exponentiated family applied to the power generalized Weibull (PGW) distribution. It can also be derived from a power transform on an exponentiated Nadarajah-Haghighi random variable. Since several structural properties of the PGW distribution have not been studied, they can be obtained from those of the EPGW distribution. The model is very flexible for modeling all common types of hazard rate functions. It is a very competitive model to the well-known Weibull, exponentiated exponential and exponentiated Weibull distributions, among others. We also give a physical motivation for the new distribution if the power parameter is an integer. Some of its mathematical properties are investigated. We discuss estimation of the model parameters by maximum likelihood and provide two applications to real data. A simulation study is performed in order to examine the accuracy of the maximum likelihood estimators of the model parameters. PMID- 30304208 TI - The Lindley Weibull Distribution: properties and applications. AB - We introduce a new three-parameter lifetime model called the Lindley Weibull distribution, which accommodates unimodal and bathtub, and a broad variety of monotone failure rates. We provide a comprehensive account of some of its mathematical properties including ordinary and incomplete moments, quantile and generating functions and order statistics. The new density function can be expressed as a linear combination of exponentiated Weibull densities. The maximum likelihood method is used to estimate the model parameters. We present simulation results to assess the performance of the maximum likelihood estimation. We prove empirically the importance and flexibility of the new distribution in modeling two data sets. PMID- 30304209 TI - The phase portrait of the Hamiltonian system associated to a Pinchuk map. AB - In this paper we describe the global phase portrait of the Hamiltonian system associated to a Pinchuk map in the Poincare disc. In particular, we prove that this phase portrait has 15 separatrices, five of them singular points, and 7 canonical regions, six of them of type strip and one annular. PMID- 30304210 TI - A weighted negative binomial Lindley distribution with applications to dispersed data. AB - A new discrete distribution is introduced. The distribution involves the negative binomial and size biased negative binomial distributions as sub-models among others and it is a weighted version of the two parameter discrete Lindley distribution. The distribution has various interesting properties, such as bathtub shape hazard function along with increasing/decreasing hazard rate, positive skewness, symmetric behavior, and over- and under-dispersion. Moreover, it is self decomposable and infinitely divisible, which makes the proposed distribution well suited for count data modeling. Other properties are investigated, including probability generating function, ordinary moments, factorial moments, negative moments and characterization. Estimation of the model parameters is investigated by the methods of moments and maximum likelihood, and a performance of the estimators is assessed by a simulation study. The credibility of the proposed distribution over the negative binomial, Poisson and generalized Poisson distributions is discussed based on some test statistics and four real data sets. PMID- 30304211 TI - Objective and subjective prior distributions for the Gompertz distribution. AB - This paper takes into account the estimation for the unknown parameters of the Gompertz distribution from the frequentist and Bayesian view points by using both objective and subjective prior distributions. We first derive non-informative priors using formal rules, such as Jefreys prior and maximal data information prior (MDIP), based on Fisher information and entropy, respectively. We also propose a prior distribution that incorporate the expert's knowledge about the issue under study. In this regard, we assume two independent gamma distributions for the parameters of the Gompertz distribution and it is employed for an elicitation process based on the predictive prior distribution by using Laplace approximation for integrals. We suppose that an expert can summarize his/her knowledge about the reliability of an item through statements of percentiles. We also present a set of priors proposed by Singpurwala assuming a truncated normal prior distribution for the median of distribution and a gamma prior for the scale parameter. Next, we investigate the effects of these priors in the posterior estimates of the parameters of the Gompertz distribution. The Bayes estimates are computed using Markov Chain Monte Carlo (MCMC) algorithm. An extensive numerical simulation is carried out to evaluate the performance of the maximum likelihood estimates and Bayes estimates based on bias, mean-squared error and coverage probabilities. Finally, a real data set have been analyzed for illustrative purposes. PMID- 30304212 TI - A new characterization of the Euclidean sphere. AB - In this paper, we obtain a new characterization of the Euclidean sphere as a compact Riemannian manifold with constant scalar curvature carrying a nontrivial conformal vector field which is also conformal Ricci vector field. PMID- 30304213 TI - Chemical composition and evaluation of antileishmanial and cytotoxic activities of the essential oil from leaves of Cryptocarya aschersoniana Mez. (Lauraceae Juss.). AB - Leishmaniasis is an endemic disease caused by protozoa of the genus Leishmania, which affects around two million people worldwide. One major drawback in the treatment of leishmaniasis is the emergence of resistance to current chemotherapeutics. Medicinal and aromatic plants constitute a major source of natural organic compounds. In this study, the leaf essential oil of Cryptocarya aschersoniana was obtained by hydrodistillation in a Clevenger-type apparatus, and the chemical composition was analyzed by GC-MS and GC-FID. The essential oil of these species was predominantly constituted by monoterpene hydrocarbons (48.8%). Limonene (42.3%), linalool (9.7%) and nerolidol (8.6%) were the main constituents in the oil of C. aschersoniana. The in vitro activity of the oil was evaluated against the promastigote forms of Leishmania amazonensis, the causative agent of cutaneous leishmaniasis in humans. The essential oil of C. aschersoniana showed high activity against L. amazonensis promastigote forms (IC50 = 4.46 ug/mL), however, it also demonstrated a relatively high cytotoxicity on mouse peritoneal macrophages (CC50 = 7.71 ug/mL). This is the first report of the chemical composition and the leishmanicidal and cytotoxic activities of the leaf essential oil of C. aschersoniana. PMID- 30304214 TI - Essential oils from Piper aduncum inflorescences and leaves: chemical composition and antifungal activity against Sclerotinia sclerotiorum. AB - Even though essential oils from Piper aduncum (Piperaceae) have different biological activities, little is known about their application to agricultural areas. White mold is a plant disease caused by the phytopathogen Sclerotinia sclerotiorum, which needs to be controlled by alternative measures. This study aimed at evaluating the effect of essential oils from P. aduncum leaves (PL-EO) and inflorescences (PI-EO) on the mycelial growth of S. sclerotiorum. Essential oils from P. aduncum were obtained by hydrodistillation by a Clevenger-type apparatus while their chemical composition was analyzed by GC-MS and GC-FID. Piperitone (23.4 %), myristicin (12.4 %), terpinen-4-ol (12.3 %), beta caryophyllene (7.2 %), alpha-humulene (6.9 %), germacrene-D (6.9 %) and dillapiol (6.3 %) were the main constituents found in oils from P. aduncum. The in vitro antifungal activity showed that PI-EO dose above 30 uL inhibited mycelial growth in 100 %, whereas PL-EO at 50 uL inhibited it in 98.74 %. This is the first report of the chemical composition of PI-EO and results suggest that the essential oils under evaluation have high potential to control the phytopathogenic fungus S. sclerotiorum. PMID- 30304215 TI - Seasonal variations, metal distribution and water quality in the Todos os Santos River, Southeastern Brazil: a multivariate analysis. AB - In aquatic habitats, metal contamination from natural and anthropogenic sources continues to pose a concern for human and environmental health. Thus, it is important to complete monitoring studies to assess patterns and the extent of metal contamination in these ecosystems. The purpose of this work was to determine the concentrations of 31 chemical elements and water quality parameters of the Todos os Santos River located in the Mucuri Valley, Minas Gerais, Brazil. A multivariate statistical analysis was used to determine any seasonal and spatial patterns from the data. Results demonstrated that metals including Al, Fe, and Ni exceeded Brazilian and international guidelines nutrients as P also exceed water quality standards. Principal components analysis indicated distinct geographical and seasonal patterns for multiple elements with hierarchical cluster analysis confirming the observed spatial patterns of contamination in the Todos os Santos River. PMID- 30304216 TI - Environmental diagnosis of metals in streams near sugarcane cultivation areas: current and historical analysis in the central region of the State of Sao Paulo. AB - In Brazil, innumerable regions of native landcover have been removed and replaced by agricultural cultivation, especially of sugarcane. In this culture, the application of fertilizers containing metals has caused impacts on the water resources causing contamination of stream sediments and occasioning bioaccumulation of metals in aquatic invertebrates. In the year of 2006, an environmental diagnosis of metals in sediments of streams located near sugarcane cultivation areas and in streams located in preserved areas, was published. That study pointed to high concentrations of metals in stream sediments in agricultural areas. These streams have been monitored over the last 10 years conducting analyses of metals and monitoring possible changes in land use. In the present paper, a historical comparison of metals contamination in the sediments of the same streams is conducted, aiming to present a status of 10 years later, analyzing 5 metals (Zn, Cd, Mn, Cr and Fe) found in the sediments of 8 streams, five located in areas of sugarcane cultivation and three located in preserved areas. This study also shows that there is higher concentration of metals in the sediments of streams near sugarcane cultivation than in preserved areas. The temporal historical evaluation showed high concentrations of Cd in 2016 when compared to the year 2006 for streams near sugarcane cultivation. PMID- 30304217 TI - Monitoring vegetation coverage in Tongren from 2000 to 2016 based on Landsat7 ETM+ and Landsat8. AB - Vegetation coverage is an important indicator in regional ecological environment monitoring and plays a key role in its quality assessment. We consider Landsat7 ETM+ in 2000 and Landsat8 in 2016 as data sources using a different time phase partial image substitution method to eliminate cloud effects and an NDVI dimidiate pixel model to invert the vegetation coverage of the two time phases. We further classify them into five grades, provide statistics and analyse the areas of different grades at different time periods, while monitoring the spatial evolution of vegetation coverage over the past 16 years in Tongren. Experimental results showed that: (1) the different time phase partial image substitution method could reduce the influence of clouds on vegetation extraction; (2) in Tongren, the vegetation coverage area was decreased from 17,300.1 km2 to 17,224.8 km2 (i.e. decreased by 75.3 km2); (3) the areas of grade I and V increased by 0.42% and 15.08%, respectively, whereas the areas of grade II, III and IV decreased by 3.15%, 6.98% and 5.37%, respectively, which indicates that most of the area containing lower amount of vegetation gradually altered into an area containing a higher coverage of vegetation, whereas a few areas became bare land; and (4) the vegetation areas decreased due to expansion of cities and construction of dams, while vegetation increased due to the cultivation of crops and trees. Research shows that the overall evolution of vegetation coverage in Tongren is considerably good. However, while undertaking future development in the mountainous Karst region, one should be aware of the land's intensive use and environmental protection. PMID- 30304218 TI - Biochemical characterization of the nuclease StoNurA from the hyperthermophilic archaeon Sulfolobus tokodaii. AB - The DNA nuclease gene ST2109 has been cloned from the hyperthermophilic archaeon Sulfolobus tokodaii and expressed in Escherichia coli. The recombinant protein StoNurA has been purified to homogeneity by affinity chromatography and gel filtration chromatography. Biochemical analyses demonstrated that StoNurA exhibited DNA binding and 5'-3' exonuclease activities towards ssDNA and dsDNA. The temperature and pH optima of StoNurA were determined to be 65 degrees C and 8.0, respectively. The activity of StoNurA was found to be dependent of Mn2+, and its half-life of heat inactivation at 100 degrees C was 5 min. Gel filtration chromatography revealed that StoNurA could form dimers in solution. Pull-down assays also showed that StoNurA physically interacted with a DNA helicase (StoHerA). Our data suggest that NurA may play a key functional role in the processing of DNA recombinational repair. PMID- 30304219 TI - Simulation of a surface spill of different diesel/biodiesel mixtures in an ultisol, using natural attenuation and bioaugmentation/biostimulation. AB - Accidents caused by leaks and/or spills on soils need to be addressed. Natural attenuation, biostimulation and bioaugmentation can be useful bioremediation strategies for decontamination processes in soils of diesel/biodiesel mixtures. The purpose of this study was to evaluate the degradation rate of the different fuels (B0, B20 and B100) in an ultisol under natural attenuation and biostimulation/bioaugmentation during 60 days of incubation in a controlled microcosm simulating a surface spill over soil. The degradation of different diesel/biodiesel mixtures was monitored for up to 60 days by dehydrogenase activity, respirometry by CO2 release, the most probable number of heterotrophic and degrading microorganism and gas chromatography. The bacterial inoculum employed for biostimulation/bioaugmentation strategy consisted of Bacillus megaterium, Bacillus pumilus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The two bioremediation strategies have showed great degradation rates. The natural attenuation was effective for B0 and B20 treatments. The addition of the bacterial consortium and macronutrients contributed to the increased degradation of pure biodiesel in relation to natural attenuation, with higher rates for CO2 release, enzymatic and degrading activity. It is suggested that the bacterial consortium has proven effective for presenting significant values for such parameters until the end of the 60-day incubation period. PMID- 30304220 TI - Wollastonite to hinder growth of Aspergillus niger fungus on cotton textile. AB - Effects of Aspergillus niger was investigated on the strength of cotton textile specimens impregnated with nano-wollastonite, and then compared with normal specimens. Cotton strips were cut and prepared in warp and wept directions according to the standard specifications ASTM D-5035. Results showed that incubation of A. niger on specimens for three months resulted in a significant decrease in tensile stress as well as weight mass change in both directions. Impregnating specimens with NW ameliorated the negative effects of fungal attack on tensile stress to a considerable extent. Moreover, weight change was significantly decreased. It is concluded that NW positively protect cotton textile against A. nigra; the ultimate NW-content should be studied in complimentary studies. PMID- 30304221 TI - Mutations in the melanocortin-1 receptor (MC1R) gene have no influence on the distinct patterns of melanic plumage found in the manakins of the genus Antilophia (Aves: Pipridae). AB - The melanocortin-1 receptor gene is the most widely-used marker for the investigation of the genetic determination of melanic plumage patterns. Studies of a number of wild bird species have shown an association between non-synonymous mutations of the MC1R gene and the presence of melanic variants. The genus Antilophia (Pipridae) includes only two manakin species (A. galeata and A. bokermanni), which are distinguished primarily by the differences in the pattern of melanic coloration of the plumage of the mantle in the adult males. In A. galeata, this plumage is black, while in A. bokermanni, it is predominantly white. This study investigates the possible association between mutations of the MC1R marker and the variation in plumage coloration observed in the two species. The MC1R sequences of the two species was analyzed, and the observed nucleotide variation was compared. Six polymorphic sites were identified, representing seven distinct genotypes. Five of these polymorphic mutations were non-synonymous, but were not related to the different phenotypes. Neutral evolution and the absence of any systematic association between the variants of the MC1R and plumage coloration in the Antilophia species indicate that alternative mechanisms regulate the expression of the coloration of the plumage in the adult males. PMID- 30304222 TI - Hypoglycemic property of triterpenoid saponin PFS isolated from Polyscias fruticosa leaves. AB - This paper evaluated the inhibitory effect of 3-O-[beta-d-glucopyranosyl-(1->4) beta-d-glucuronopyranosyl] oleanolic acid 28-O-beta-d-glucopyranosyl ester (PFS), a major saponin isolated from Polyscias fruticosa leaves, on alpha-amylase and alpha-glucosidase, and its potential for reducing the postprandial blood glucose level in mice. In enzyme inhibition assays, PFS strongly inhibited porcine pancreas alpha-amylase and yeast alpha-glucosidase. Using the Lineweaver-Burk equation, we found that PFS inhibited porcine pancreas alpha-amylase in a mixed noncompetitive mode, and yeast alpha-glucosidase via noncompetitive inhibition. In the sucrose tolerance test, PFS at 100 mg/kg body weight significantly decreased the postprandial blood glucose level in mice fed a high-sucrose diet. These findings suggest that P. fruticosa leaves and their major saponin PFS can be used to prevent and treat diabetes and its complications. PMID- 30304223 TI - Structural characterization of vegetative organs of the endangered Brazilian native species Hesperozygis ringens (Benth.) Epling. AB - The aim of this study was to describe the structural characterization of Hesperozygis ringens (Benth.) Epling vegetative organs. For this purpose, leaves, stems and roots of the endangered Lamiaceae were collected from a population located in Santo Antao, Santa Maria municipality, Rio Grande do Sul, Brazil. Results demonstrated that the H. ringens leaf blade presents glandular and non glandular trichomes as well as two morphs of diallelocytic stomata, which are usually found above the epidermis level. The petiole is concave on ventral face and convex on its dorsal face, containing glandular and non-glandular trichomes as well as stomata in the epidermis. These types of trichomes were also detected in the stem. In addition, the presence of intercellular spaces within the organ is highlighted. Stomata above epidermis level also occurred in the stem. Phenolic idioblasts were found in the cortical region of plant root and deposit of lipophilic substance was observed in phloem cells. Great amount of apparently two different crystals were detected in all organs. Information obtained in this study provides knowledge about the characterizationof H. ringens, which may be used to distinguish characters of taxa and can help understand the species survival in its occurrence sites. PMID- 30304225 TI - Brazilian fruit processing, wastes as a source of lipase and other biotechnological products: a review. AB - The global food loss and waste is the most urgent research area in food science to attend the current demand for more sustainable and profitable processes. Along the productive chain about 1/3 of the food is lost or wasted, this number reaches 1/2 for fruit and vegetable production in developing countries. Brazil has been investing in researches aiming to turn its wastes into byproducts, as biomolecules of high value such as lipases. These enzymes are found in a high diversity of plant sources and their researches are covered by promising market growth expectations due to the current demand for biofuels and bio-transformed food. Thus, the aim of the present study is to discuss the potential of wastes generated by the Brazilian fruit processing to become a source of lipases, by the analysis of the most recent studies on fruit lipases, as well as the inclusion of this process in the biorefinery concept. According to this concept, different products can be obtained from the same raw material. Considering the confirmation of the presence of lipases on fruit wastes, the annual fruit production and the percentage of residues, the assessed data showed that wastes from the processing of orange, mango, papaya and palmare promising for lipase obtainment. PMID- 30304224 TI - Occurrence and characterization of entomogenic galls in an area of Cerrado sensu stricto and Gallery forest of the state of Bahia, Brazil. AB - We surveyed insect galls in an area of Cerrado sensu stricto and Gallery forest in the municipality of Caetite (BA) to contribute to current knowledge of the local flora and its associated gall-inducing insects. Monthly collections were made between February/2015 and January/2016, totaling 12 field campaigns (involving two or three people and lasting four hours) that followed an established path through the countryside. A total of 63 gall morphotypes were identified on 47 host plant species belonging to 22 families; 17 morphotypes were found in the Gallery forest and 46 in Cerrado vegetation. The plant families showing the greatest gall richness were Leguminosae (n=15), Myrtaceae (n=9), and Asteraceae (n=7). The species with the greatest number of galls was Mimosa gemmulata Barneby (Leguminosae) (n=3). Most galls were observed on leaves (66%) and stems (24%); they were mostly green (49.3%) or brown (26%), with globoid shapes (39.7%) or marginal roll (17.4%), and were unilocular (87%), glabrous (62%) and isolated (89%). Cecidomyiidae (Diptera) were the principal gall inducing insects. The associated fauna was principally composed of Hymenoptera. Eight plant taxa were recorded for the first time as hosts of galling fauna. PMID- 30304226 TI - Light environment influences the flood tolerance in Cordia americana (L.) Gottschling & J.S.Mill. AB - The subtropical riverine forests present a variation in soil water availability throughout the year, following precipitation seasonality. The objective of this work was to evaluate the responses of Cordia americana to different light intensities combined with soil flooding. Seedlings were acclimated to light treatments, with full sun and shade conditions. Sun and shade plants were subjected to soil flooding during periods of 10 (short) and 30 (longer) days. After 10 days, flooded plants had a higher root dry mass accumulation and soluble sugars content, regardless of the light condition. Shade plants presented higher shoot soluble sugars content in relation to the sun plants. After 30 days, a higher shoot soluble sugar content was observed in sun and shade flooded plants. In addition, a higher root soluble sugar content was also observed in sun plants under flood. Periods of short flooding, characterized in subtropical forests as from 5 to 15 days, favor the growth of shade plants and the roots sugar accumulation, fact that can explain the species distribution. However, long periods of flooding may be associated with light environment plasticity, suggesting that the sun plants present a higher flooding tolerance, directly associated with the ability to maintain the sugar content. PMID- 30304227 TI - Production of lipolytic enzymes by bacteria isolated from biological effluent treatment systems. AB - This work aimed to evaluate the production of lipolytic complexes, produced by microorganisms isolated from a biological treatment system of effluents from a hotel. To select the best lipolytic microorganism for use in biotechnological processes, we tested 45 bacterial isolates recovered from the raw effluent of the hotel's restaurant waste tank. Lipase production was assayed in culture medium supplemented with olive oil and rhodamine B, incubated at 25 degrees C and 30 degrees C for 24 h - 48 h. Results showed 22 isolates lipase producers. All isolates were inoculated on medium without yeast extract to select the ones with highest enzyme yields. Out of these, nine isolates showed high lipase activity. The strain with the larger halo was assayed in submerged culture using an orbital shaker and a bioreactor, with three different substrates (olive oil, grape seed oil, and canola oil). Isolate G40 identified as Acinetobacter baylyi was selected to run the production assays because it showed the best result in the solid medium. In the bioreactor, maximum lipase production was obtained after 12 h of culture with the three substrates evaluated: 0,358 U/mL.min-1 in olive oil, 0,352 U/mL.min-1 with grapeseed oil, and 0,348 U/mL.min-1 with canola oil. PMID- 30304228 TI - A new species of Microtetrameres (Nematoda, Tetrameridae) parasitizing Buteogallus urubitinga (Aves, Accipitridae) from northeastern Argentina. AB - A new tetramerid nematode, Microtetrameres urubitinga n. sp., is described from specimens recovered from the proventriculus of the great black-hawk, Buteogallus urubitinga (Aves: Accipitridae), from Formosa Province, Argentina. The males of the new species are characterized by having spicules unequal (length ratio of spicules 1:3.8-5.9) and dissimilar in shape (right spicule with a simple tip, left spicule with a symmetrical bifurcated tip), caudal papillae arranged asymmetrically (two pairs precloacal and two pairs postcloacal) and cloacal lips highly protruded forming a tube. The gravid females are permanently coiled clockwise or counterclockwise in a spiral and having a tail tapering gradually to a sharp point, with a cuticular fold. This is the first nominal species of Microtetrameres (Travassos, 1915) described parasitizing birds from Argentina. The relationship between the diet of B. urubitinga and the low prevalence of M. urubitinga n. sp. is discussed. PMID- 30304229 TI - Immunophenotyping lymphocyte and acute phase proteins in canine X-linked muscular dystrophy. AB - Duchenne Muscular Dystrophy (DMD) is the most common X-linked muscular disease affecting humans. The Golden Retriever Muscular Dystrophy model (GRMD) is considerthe most suitable for several studies. This assay aims to quantify lymphocyte subpopulations CD4, CD5, and CD8, and standardize, the serum electrophoretic profile, to understand their contribution to the pathologic process in normal Golden Retriever dogs (GR group) and dystrophic's (GRMD group), through the umbilical cord blood, in dogs aged from 2 to 3 months (GR II and GRMD II), and in dogs over 1 year of age (GR III and GRMD III). No significant differences were observed between the CD8+ lymphocyte subpopulations of the groups studied. The CD4+ and CD5+ lymphocyte subpopulations were significantly higher in the GRMD III group compared to the GR III group. Twenty-two different proteins in the gel were identified. The serum concentrations of the proteins belonging to the GR I and GRMD I groups were significantly lower than those of the other groups. We show that expression of acute phase proteins are worst during the aging of the dogs. We hope to expand knowledge to better understand the GRMD model and the translational data. PMID- 30304230 TI - Tracking atmospheric dispersion of metals in Rio de Janeiro Metropolitan region (Brazil) with epiphytes as bioindicators. AB - The atmospheric dispersion atmospheric plume of the metropolitan region and neighborhoods of the city of Rio de Janeiro was investigated through elemental analyzes (Na, K, Al, Mn, Pb, Ni, Cr) and stable lead isotopes in two epiphytes; the lichen Parmotrema crinitum (Ach.) and the bromeliad Tillandsia usneoides (L.). All the elements had lower concentrations in epiphytes than in rocks of the local geological basement, with the exception of K, which was similar to rocks. This behavior was attributed to the nutritional essentiality and abundance of this element in the environment. The concentrations of Na, Pb and the 206Pb/207Pb and 208Pb/206Pb ratios indicated the presence of spatial gradients in the path (a) sea shore -> continent, and (b) urban center -> farmlands. These patterns were associated with the mesoscale atmospheric circulation regime, in which, during the arrival of cold fronts, air masses from the metropolitan region of Rio de Janeiro are transported towards the mountainous region of Teresopolis, which acts as a barrier to the dispersion of pollutants. The bromeliad Tillandsia usneoides and the lichen Parmotrema crinitum were linked to Na and Pb atmospheric levels, respectively. PMID- 30304231 TI - Ongoing quiescence in the Borborema Plateau Plague focus (Paraiba, Brazil). AB - Plague is a zoonosis caused by Yersinia pestis, whose cycle is based on a reservoir system composed of mammals and their fleas. Its transmission cycle presents long enzootic periods with undetected cases, sometimes misleading that the cycle is extinct. While surveillance activities in Brazil are being carried out only in some focal areas, the serologic results confirm the persistence of Y. pestis in all monitored areas. We studied the small mammal assembly and Y. pestis presencein the Borborema Plateau Focus within the state of Paraiba, which staged the last Brazilian plague outbreak (1986-1987), through aninventory and Y. pestis detection survey of small mammals in peridomestic and sylvatic areas from two municipalities in the state of Paraiba.The field sampling captured 45 specimens (27 marsupials, 18 rodents), of 10 species. Only two species (one marsupial, one rodent) were captured in both peridomestic and sylvatic ecotopes. The sylvatic ecotope had higher richness and abundance. No evidence of circulation of the pathogen was detected, however, this result does not discard the necessity of continuous epidemiological surveillance due to the risk of rekindling the foci after long dormant periods, especially given the current epidemiological transition occurring on a Global scale. PMID- 30304232 TI - Description of the final instar larva of Argia serva Hagen in Selys, 1865 (Odonata Coenagrionidae). AB - The American genus Argia, with more than 100 species described, is the most speciose genus of Odonata in the world. In this contribution, the final stadium larva of Argia serva, the southernmost distributed species of Argia, is described and diagnosed based on reared material from Martin Garcia island, Buenos Aires, Argentina. The larva of this species can be easily separated from the other Argentinean Argia by the following combination of characters: sternum of S8 covered with spines (bare in A. translata); antennal segment 3 longer than 1+2 (equal to or shorter than 1+2 in A. joergenseni and A. jujuya); palpal setae absent (present in A. croceipennis). A key to the known larvae of Argia of the Southern Cone is provided. PMID- 30304233 TI - New records of the rare Troschel's Pampas Snake, Phimophis guianensis (Serpentes: Dipsadidae) in Brazil. AB - The Troschel's Pampas Snake, Phimophis guianensis (Troschel, 1848), is widely distributed in Amazonian Savannas at northern South America and a small portion of southern Central America, being recorded to Brazil based on three historical records, that ranged from 1997 to 2002, in Amapa and Para states. In this study, we revise all known records of P. guianensis, providing an updated distribution map, and the first record to Roraima state. PMID- 30304234 TI - The family Phoxocephalopsidae (Crustacea: Amphipoda) from Brazilian coastal waters with description of four new species. AB - Phoxocephalopsids are fossorial amphipods endemic to the Southern Hemisphere and currently encompass five genera and 15 species, including the four new species herein described. Previous records of the family along the Brazilian coast are limited to Phoxocephalopsis zimmeri Schellenberg, 1931. Based on material from the Crustacean Collection of Museu Nacional/UFRJ four new species of Phoxocephalopsidae areherein described: Phoxocephalopsis ruffoi sp. nov. from Rio de Janeiro, Sao Paulo, Parana and Rio Grande do Sul (23o-30oS); Puelche irenae sp. nov. from Espirito Santo and Rio de Janeiro (19o-23oS); Puelche longidactylus sp. nov. from Bahia, Espirito Santo and Rio de Janeiro (12o-23oS) and Puelche mourae sp. nov. found only at Rio de Janeiro. High diversity was recorded from the Campos Basin region, which extends from the north of Rio de Janeiro to south of Espirito Santo (21o-23oS), with the presence of all four phoxocephalid species. A key to Phoxocephalopsidae species from Brazil, including P. orensanzi Barnard and Clark, 1982 is provided. PMID- 30304236 TI - Glucocorticoid susceptibility and in vivo ABCB1 activity differ in murine B cell subsets. AB - Glucocorticoids are produced and released by the adrenal gland and become elevated in response to stress. Although glucocorticoids are well known for their immunosuppressive effects, less is known about their effects on B cells. ABCB1 is an efflux pump expressed in both cancer and normal cells, modulating the gradient of various metabolites, including hydrocortisone. Our goal was to evaluate the effect of this glucocorticoid on murine B cell differentiation and whether sensitivity to hydrocortisone could be related to ABCB1 activity in vivo. C57BL/6 mice received one or three consecutive i.p. injections of hydrocortisone (70, 140 and 200 mg/kg/day). ABCB1 activity was evaluated via the rhodamine-123 transport and inhibited by cyclosporin A in hydrocortisone-treated and control mice. Cells from bone marrow, spleen and blood were counted, incubated with antibodies and analyzed by flow cytometry. A single hydrocortisone injection did not alter the number of bone marrow subsets. Conversely, three daily injections were able to reduce the cell number of most bone marrow subsets, excepting c-kit-sca-1+ and mature B cells. This treatment reduced marginal zone, follicular and transitional B cells, though splenic subsets were more resistant than bone marrow B cells. Recirculating follicular B cells in the blood were resistant to hydrocortisone. With the exception of follicular B cells, all subpopulations exhibited ABCB1 activity. However, hydrocortisone treatment did not affect ABCB1 activity in most subsets analyzed. Results suggest that hydrocortisone is able to regulate B cell lymphopoiesis although ABCB1 activity is not related to the susceptibility to that glucocorticoid in B cell subsets. PMID- 30304235 TI - New technique of intragastric sleeve: viability and survival in a pig model. AB - Developing a less invasive, practical and cost-effective operative technique for obesity treatment represents a pressing need for our society. In this way, intragastric single port sleeve by endoplication was tested in six pigs during 18 weeks. Celiotomy was performed with animal placed in dorsal decubitus position. Single port gastrostomy was performed and double tobacco pouch sutures were made in fundic region, making a gastric sleeve. At the end, stomach layers and skin were closed in a conventional manner. Means and the standard deviations of surgical time were calculated. The procedure was simple and all animals survived; there were no significant blood loss and no intra and postoperative complications. The procedure was fast (67.4 minutes). The technique has the advantage of not requiring the use of mechanical sutures, making it less costly. The innovation of this procedure was the use of a single port gastrostomy device to perform an intraluminal sleeve. What made this technique less invasive were the use of a single port, nonmanipulation of the stomach intra-abdominally, ease of execution and no need of pneumoperitoneum. The new technique is acceptable and has reproducible viability, had a short procedure time without intra and postoperative complications. PMID- 30304237 TI - L-carnitine supplementation in the recovery of plasma L-carnitine in patients with heart failure submitted to coronary artery bypass grafting. AB - Coronary artery bypass grafting reduces plasma L-carnitine and may impair the production of myocardial energy. L-carnitine supplementation may elevate plasma L carnitine and increase cardiac mechanical efficiency. The objective of this study was to verify the recovery of preoperative plasma LC in patients with heart failure undergoing coronary artery bypass grafting supplemented with a daily oral dose of 50 mg / kg. Volunteers with ischemic heart failure who underwent surgery were randomized into a supplemented group (A-received 50 mg / kg L-carnitine) or placebo group (B) for 60 days. Supplementation was started on the third postoperative day. The spectrophotometric enzymatic method was used to quantify plasma L-carnitine. In the preoperative period, both groups had plasma L carnitine adequate to the reference range (18.9-71.1 MUM). On the second postoperative day, there was a reduction in plasma L-carnitine in groups A (17.4%) and B (14.4%). In the comparison between the groups, plasma L-carnitine was higher in group A than B in 10o (p = 0.024), 30o (p = 0.001), and 60o postoperative day (p = 0.008). Supplementation of L-carnitine at a daily oral dose of 50 mg / kg in patients with heart failure undergoing coronary artery bypass grafting may recover preoperative plasma L-carnitine within 10 days. PMID- 30304238 TI - Methodological description and preliminary results of a cohort study on the influence of the first 1,000 days of life on the children's future health. AB - The aim of this report is to describe general and methodological characteristics of a cohort study in southern Brazil (Coorte Brasil Sul), aimed at understanding the impact of the first 1,000 days of life on children's health. It is a cohort study involving all children born in 2009 and their families living in the municipality of Palhoca, State of Santa Catarina, Brazil. Face-to-face interviews with parents at home using a structured questionnaire and children's physical and clinical examinations at schools have been carried out. Cross-sectional analyzes, longitudinal comparisons and hierarquical regression analysis will allow understanding if the first 1,000 days of life can influence on 6-year-old children's health. The Coorte Brasil Sul is in its retrospective phase together with the children's physical data collection. Preliminary data (n=1270) related to nutritional status point to a high prevalence of overweight (16.4%) and obesity (15.5%). With the continuity of the study, it is expected to evaluate if the first phases of life can influence health during adolescence and in adult life, mainly in relation to chronic diseases. PMID- 30304239 TI - Spray-dried porcine plasma added to diets contaminated with aflatoxins and fumonisins shows beneficial effects to piglet health. AB - This study was aimed to analyze the effects of spray-dried porcine plasma (SDPP) on the health of post weaning piglets challenged with diets contaminated with aflatoxins and fumonisins. Fifty-six male piglets (7.15 +/- 0.61 kg) were allocated in four groups: CTL group received a regular diet; SDPP group received a regular diet and 6% SDPP; MYC group received a diet containing 300 ug/kg aflatoxins and 8,000 ug/kg fumonisins; group MYC+SDPP received 300 ug/kg aflatoxins, 8,000 ug/kg fumonisins and 6% SDPP. The animals that received the experimental diet containing mycotoxins (MYC group) had lower weight gain at the end of the experiment compared to the other treatments. Animals receiving SDPP showed decreased urea levels throughout the experiment (P<0.05). Animals from MYC group presented an increased on reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels and decreased catalase activity (P<0.05). In contrast, SDPP prevented the increase of ROS and TBARS and stimulated superoxide dismutase activity (P<0.05). In conclusion, diet contaminated with mycotoxins (group MYC) caused subclinical intoxication in the piglets, as observed by the increase on free radical's production and lipid peroxidation. Conversely, SDPP presented a protective effect, minimizing the effects of oxidative stress caused by aflatoxins and fumonisins ingestion. PMID- 30304240 TI - Cohort study of cardiovascular risk in asymptomatic young adults: subclinical atherosclerosis and coronary calcium score. AB - Coronary artery calcification is an early marker of subclinical atherosclerosis, but little research has been done in asymptomatic individuals under 45 years. In this cohort study with 17 years of follow-up, 155 participants were assessed in 2016 with a coronary calcium score for the association with cardiovascular risk factors. During follow-up, there was a significant increase in anthropometric measurements, cholesterol and fractions, and diastolic pressure. Participants who gained 1 cm in waist circumference had a mean reduction of 0.36 mg/dL in HDL cholesterol and those who gained 1 kg/m2 in body mass index had a reduction of 0.72 mg/dL in HDL-cholesterol. Married participants had a 4.78 mg/dL reduction in HDL-cholesterol levels compared to singles. There was an increase of 2.09 mg/dL in HDL-cholesterol at each higher level of self-perceived health. One single case, a 32-year-old male, smoker, sedentary individual with a family history of cardiovascular disease, presented coronary calcification (0.6%). His HDL cholesterol was reduced by 43.4%, with levels of less than 25 mg/dL at the time of coronary calcium scoring. Our findings may prompt broader studies of populations under 35 years with HDL-C levels below 25 mg/dL and family histories of cardiovascular disease, associated with obesity, sedentary lifestyle and smoking. PMID- 30304242 TI - Establishment of an environmental microbiological monitoring program in a mice barrier facility. AB - Rodents used in biomedical research are maintained behind barriers to exclude microbial contaminants. Several check points have to be monitored to eliminate the potential of introducing adventitious agents into the facility. Microbiological monitoring of a mouse facility environment enables to evaluate the efficiency of sanitization and cleaning procedures, air quality, and technician good practices. At our SPF mouse facility, we implemented an environmental microbiological monitoring program based in sedimentation and swabbing, inexpensive and easy to use methods. The aim of this work was to evaluate the results and the efficiency of the monitoring program after seven years. The median for bacteria and fungi counts in the SPF sampled areas was <=2 CFU/2 h for settle plates and <1 CFU per swabbing plate, satisfying the requirements for grade C of the EU-GMP, with some modifications. The environmental monitoring program was useful to detect early warning of problems and enabled us to define a safe range of microbiological counts. In addition, SPF status defined for our mice was maintained throughout this study, confirmed by our HM program. This work could encourage directors and technicians of other mouse facilities in Latin America and rest of the world to implement this kind of program. PMID- 30304241 TI - Dextran Sulphate of Sodium-induced colitis in mice: antihyperalgesic effects of ethanolic extract of Citrus reticulata and potential damage to the central nervous system. AB - Citrus species are widely related to antihyperalgesic and anti-inflammatory effects. The aim of this study was to investigate if treatment with ethanolic extract from peels of mature Citrus reticulata Blanco causes antihyperalgesic effects on the referred mechanical hyperalgesia in a model of dextran sulphate of sodium (DSS)-induced colitis in mice, as well as the possible oxidative damage in different regions of the brain induced by its inflammatory reaction. Antihyperalgesia (30 to 300 mg/kg) was investigated by behavioral response (frequency of response to von Frey filament stimulation) in Swiss mice, while damage to central nervous system was investigated through techniques that evaluated oxidative stress using male black C57 BL6 mice (n=8). Treatment of the animals with the extract (100 mg/kg) from days 3 to 5 after colitis induction reduced referred the mechanical hyperalgesia (32.6 +/- 5.1) in relation to the control group (57.4 +/- 2.0). Levels of lipid peroxidation or carbonyl proteins were augmented in colitis-induced animals in relation to the disease group. These results indicated an antihyperalgesic effect of the studied extract and a potential impairment of the central nervous system functioning caused by inflammation during colitis, which could be related to mental disorders observed in patients suffering of this pathology. PMID- 30304243 TI - Hibiscus acetosella extract protects against alkylating agent-induced DNA damage in mice. AB - Hibiscus acetosella was shown to exert beneficial effects in humans and animal models however, the effects of this plant on DNA are unknown. The aim of this study was to determine the antigenotoxic and antimutagenic effects of H. acetosella extracts on alkylating agent methyl methanesulfonate (MMS) in vivo in mice. Initially, we performed analysis of phenolic compounds in extracts of H. acetosella by high-performance liquid chromatography (HPLC). Next, mice were divided into 8 groups and treated with distilled water or plant extract (0.1 ml/10 g) by gavage for 15 days, followed by intraperitoneal (ip) administration of saline solution or MMS (40 mg/Kg b.w) on day 16. Caffeic acid, following by gallic acid, gallocatechin, coumaric acid, and 3,4-dihydroxybenzoic acid were found to be present in extracts of H. acetosella leaves. In peripheral blood analysis of groups receiving pretreatment with H. acetosella at doses of 50 or 100 mg/kg plus MMS decreased DNA damage as evidenced by comet assay and Micronucleus assays relative to MMS alone. These results suggested that H. acetosella extracts exerted protective effects dose dependent against genotoxicity and mutagenicity induced by alkylating agents. PMID- 30304244 TI - Satellite Telemetry and Image Reception with Software Defined Radio Applied to Space Outreach Projects in Brazil. AB - Software Defined Radio (SDR) uses a processor, a special receiver and software that play the main parts of the receiver (mixer, filters, amplifiers, modulators, demodulators, etc.) and it is quite advantageous for its flexibility and compact size as it reduces the amount of hardware components while adapting for different needs. This work briefly presents the SDR concept and approach for obtaining satellite telemetries and imagery in the context of different modulation schemes, link budget requirements and different satellites types. Two case studies are presented for supporting affordable ground segment and promoting satellites projects in Brazil. Reception from the 1st Brazilian picosatellite, Tancredo-1, with specific software developed, UbaTM is presented for obtaining satellite raw telemetries, convert them to engineering value and friendly present on user screen. A series of support software packages are then introduced so that one can pipeline various operations and automate tasks in the ground station. Finally, a second study case was performed in order to receive NOAA class satellites imagery over VHF band and decoded by specific software freely available. Using the proposed SDR approach, it can adapt to projects mainly those with a limited budget and outreach for major inclusion on space topics in Brazil. PMID- 30304245 TI - Study of barium sulfate dissolution by scale dissolver based on solutions of DTPA. AB - In offshore oil wells it is very common to perform seawater injection through injection wells for hydrocarbon recovery. When seawater, rich in sulfate ion, mixes with formation water, whose composition can contain divalent cations such as barium and calcium, it often leads to sulfate salts formation due to their chemical incompatibility. These salts can cause serious damage in production wells. The barium sulfate (BaSO4) is the most problematic scale and may cause many complications. In order to solve this issue, polycarboxylic acids, such as diethylene triamine pentaacetic acid, are used. Thus, the primary focus of this work was to develop an experimental procedure to study the BaSO4 dissolution. Initially, through static tests to understand the relationship between dissolver concentration, temperature and dissolution time, and then through dynamic tests in sandstone reservoirs. Based on the results obtained, in the static tests the best condition for barite to dissolve was at high temperatures (80 oC) and contact time of 48 hours, since from 50 degrees C there is an increase in dissolution rate, associated with a long contact time between dissolver and barite. In the dynamic tests, after scale formation, barite could be removed, but the high DTPA concentration should be avoided. PMID- 30304246 TI - Expanded perlite/cork fillers applied to aerospace insulation materials. AB - Insulations for rocket motors such as Flexible Thermal Protections (FTPs) and Rigid Thermal Protection (RTPs) act as thermal barriers against the hyperthermal environment from the solid propellant combustion. FTPs present dual function: to extend RTPs performance, and to attenuate the propellant contraction. FTPs used in the Brazilian Space Program have asbestos in their composition since the 70's; however, they are hazardous for human health. In this context, a mixture of Expanded Perlite (PExp) and Cork Powder (CP) was investigated as a replacement for asbestos. Results showed reduction about 21 % in density and an increase of 13 % in the ablative properties. The low mechanical properties not interfere in this type of FTP due to your function of attenuate the propellant contraction. PMID- 30304247 TI - The positive moderating effect of absorptive capacity on R&D investment: the case of Argentina's ict firms. AB - The model analyzes the positive moderating role of absorptive capacity (ACAP) in the innovative outcomes of the firms. It focuses on ACAP as a moderating variable of the innovative efforts that firms develop or have the chance of incorporating from outside and not just as an antecedent of the innovation results. The empirical evidence collected comes from a study conducted on 189 SMEs working in IT services in Argentina and the results prove the main hypothesis of how ACAP is a positive moderating factor of the innovative effort of firms, even in the case of the connections created by their the participation in international networks not having a high correlation. Some suggestions for policymaker managers and future lines of research are provided. PMID- 30304248 TI - Erratum. AB - [This corrects the article doi: 10.1590/0001-3765201720160903]. PMID- 30304249 TI - Erratum. AB - [This corrects the article doi: 10.1590/0001-3765201820180460]. PMID- 30304250 TI - Methods of aril removal and lightness conditions on seeds physiological quality of sour passion fruits. AB - Passion fruits species presents a larger economic importance for in natura consumption and industry. The main way to propagate these species is by seeds; however, the aril presence and environmental conditions may inhibit the seeds germination. In this sense, the objective of this study was to evaluate the effect of aril removal methods and light conditions on P. edulis var. flavicarpa seeds quality and germination. There were used five methods to remove the seeds aril: (1) friction on steel mesh sieve for 5 minutes; (2) friction with coarse sand on steel mesh sieve for 5 minutes; (3) immersion in lime solution at 10% (w/v), for 30 minutes; (4) fermentation in sugar solution at 10% (w/v), during 48 hours; and (5) natural pulp fermentation, during five days. The seeds were submitted to germination test at darkness and lightness, as well as, to length seedlings and emergence test. Regardless the aril removal method, the germination percentage was lower at lightness than darkness highlighting the natural pulp fermentation treatment, which presented 86% of seeds germinated. On the other hand, the aril removal methods did not affect the seedlings emergence, with emergence percentages ranged from 88 to 94%. PMID- 30304251 TI - Yeasts and filamentous fungi in psittacidae and birds of prey droppings in midwest region of Brazil: a potential hazard to human health. AB - Birds of prey and from Psittacidae family are host to fungal microbiota and play an important role in the epidemiology of zoonoses. Few studies in the literature have characterized mycelial and yeast fungi in the droppings of these birds and correlated the isolates with the zoonotic potential of the microorganisms. Droppings from 149 birds were evaluated and divided into two groups: captive: Rhea americana araneipes, Primolius maracana, Ara ararauna, Ara chloropterus, Anodorhynchus hyacinthinus, Amazona aestiva, Ara macao macao, Ramphastos toco, Sarcoramphus papa, Busarellus nigricollis, Bubo virginianus nacurutu, Buteogallus coronatus, Buteogallus urubitinga urubitinga, Spizaetus melanoleucus, Spizaetus ornatus ornatus, Buteo albonotatus, Geranoaetus albicaudatus albicaudatus, Rupornis magnirostris magnirostris and Harpia harpyja, and quarantined birds: Amazona aestiva and Eupsitulla aurea. The fungal isolates were identified according to macroscopic (gross colony appearance), micromorphological and biochemical characteristics. Among birds displayed in enclosures, Aspergillus niger (41.1%) and Candida kefyr (63.8%) were the fungi most frequently isolated in Harpia harpyja and Ramphastos toco, respectively. For quarantined birds, the following percentages were observed in Eupsittula aurea , (76.6%) C. krusei, (84.4%) C. kefyr and (15.2%) C. famata, while in Amazona aestiva, (76.2%) C. krusei was observed. These findings indicate potentially pathogenic species in the bird droppings assessed, which constitute a risk of exposure for keepers and individuals who visit the zoo. Birds of the Cerrado and Pantanal of Mato Grosso (Central Western region of Brazil) could act in the epidemiological chain of important zoonoses. PMID- 30304252 TI - Xiphidiocercariae from naturally infected Lymnaea columella (Mollusca, Gastropoda) in urban area: morphology and ultrastructure of the larvae and histological changes in the mollusc host. AB - Urban agriculture is very common in the cities, as Rio de Janeiro and adjacencies, being important as economic activity. However, this practice can create appropriate conditions for establishment and maintenance of life cycle of many parasites. Lymneid snails can act as intermediate hosts of many trematodes species, including those that infect humans and wild and domestic. In the present study, the snail Lymnaea columella was collected from an urban watercress plantations and the morphology of cercariae released by them was analyzed by light and scanning electron microscopy. The specimens were identified as xiphidiocercariae, belonging to the Cercariae Ornatae group, of the order Plagiorchiiformes. Histological examination of the digestive gland of the infected snails revealed the presence of developing sporocysts, with hemocitary infiltration and metaplasia in the epithelial tissue. PMID- 30304253 TI - Frequency of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) in non-clinical Enterococcus faecalis and Enterococcus faecium strains. AB - The fidelity of the genomes is defended by mechanism known as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) systems. Three Type II CRISPR systems (CRISPR1- cas, CRISPR2 and CRISPR3-cas) have been identified in enterococci isolates from clinical and environmental samples. The aim of this study was to observe the distribution of CRISPR1-cas, CRISPR2 and CRISPR3-cas in non-clinical strains of Enterococcus faecalis and Enterococcus faecium isolates from food and fecal samples, including wild marine animals. The presence of CRISPRs was evaluated by PCR in 120 enterococci strains, 67 E. faecalis and 53 E. faecium. It is the first report of the presence of the CRISPRs system in E. faecalis and E. faecium strains isolated from wild marine animal fecal samples. The results showed that in non-clinical strains, the CRISPRs were more frequently detected in E. faecalis than in E. faecium. And the frequencies of CRISPR1-cas and CRISPR2 were higher (60%) in E. faecalis strains isolated from animal feces, compared to food samples. Both strains showed low frequencies of CRISPR3-cas (8.95% and 1.88%). In conclusion, the differences in the habitats of enterococcal species may be related with the results observe in distribution of CRISPRs systems. PMID- 30304254 TI - Environmental impacts of a reduced flow stretch on hydropower plants. AB - In Brazil, given its privileged hydrology, the unexplored economic use of water resources has many dimensions, such as hydroelectric power. This energy will face increasingly rigorous social and environmental impact assessments (40% of potential is located in the Amazon region). Hydropower inventory studies conducted over decades, with solutions such as ecological river flows, that flood smaller areas and reduce natural river flows modifications, are being reviewed. The river extension from dam to the point where the waters are returned after the powerhouse is known as the Reduced Flow Stretch (RFS). Even mega-projects, such as the 11.3 GW Belo Monte dam, are designed with deviating flows reaching an astounding 13,000 m 3/s (excavated material higher than Panama Canal). RFS requires to be carefully studied to achieve appropriate ecological flows, since RFS flows increased reduces the plant's electricity production to the same installed capacity. Balancing RFS requirements and hydroelectric power remains a challenge and, clearly, there is no consensus. Here, we performed an analysis of the main environmental impacts caused by RFS requirements, considering the multiple water use specific for each dam site. The natural variability of river flows provides diversity of habitats and maintains the richness and complexity of biological communities. Therefore, the present study has great ecological, social and economic relevance, since proper evaluation of the RFS requirements avoids potential destabilization of biological communities and even loss of biodiversity. This type of arrangement was more common in dams located in headwaters of rivers, as in the slopes of the Andes mountain range, and in regions like the Alps. There are many hydroelectric plants in South America and Europe that have this type of arrangement of engineering works. But the times are different and the environmental impacts have to be better evaluated. A final aspect also involves the maintenance of ecological flows downstream of dams. Regularization reservoirs need to keep downstream, even if they do not have a TVR, adequate flows that represent minimally the seasonality of the river, with floods and droughts, that propitiate the maintenance of the ecosystems downstream. There are cases such as the Sobradinho Plant in the Sao Francisco River that has been much questioned in this regard, especially when the climate is changing in the basin, with long periods of drought, and with increasing water use. So this is a very important and increasingly current issue. PMID- 30304255 TI - Phytosociological contrast of ferns and lycophytes from forest fragments with different surroundings matrices in southern Brazil. AB - Forest edges typically exhibit higher luminosity and lower humidity than the forest interior, resulting in an abiotic gradient. However, the degree of abiotic difference can be affected from the type of the matrix, influencing the selection of species. We compared the floristic and phytosociological structure of understory communities of ferns and lycophytes of the edge and interior of three forest sites influenced by different types of surrounding matrices (natural field, Pinus plantation, and cultivation of crops). In the region of Araucaria Forest, in Rio Grande do Sul, Brazil, twelve 10 * 10 m plots were selected at the edge and interior of each site, totaling 72 plots and to evaluate the phytosociological contrast, using as a parameter coverage and species richness per plot to evaluate this contrast. We recorded a total of 38 species in the studied areas, distributed in 15 families. The results show that the edge effect acts at different intensities in the analyzed sites. In the site with unnatural matrix, the composition was more homogeneous both in the edges and in the interiors and presented lower richness, showing a more pronounced and deep impact. Already in the site with natural matrix surroundings, although the border also presents low richness, the interior was about 3x richer. Based on our results, we concluded that fern conservation efforts should focus on fragments of Araucaria Forest inserted in the natural field, because the conversion of natural field into Pinus planting and cultivation of crops decreases ferns species both in the edges and forest interiors of the studied fragments, besides altering the phytosociological structure leading the communities to simplification. PMID- 30304256 TI - Rubus sellowii Cham. & Schlitdl. (Rosaceae) fruit nutritional potential characterization. AB - The aim of this study was to know the physical, chemical and nutritional characteristics of Rubus sellowii (Rosaceae) fruits, known as blackberry, native plant mainly to Rio Grande do Sul State (RS), Brazil. For this, three different populations of this plant were selected and the fruits were analyzed through moisture, ash, titratable acidity, pH, lipids, fibers, carbohydrates, proteins, carotenoids, lycopene, ascorbic acid, aminogram and in vitro digestibility. Fruits showed high acidity (3.28 percent), ash and protein (1.02 and 0.93 percent) and higher ascorbic acid (38.43 mg per 100 g) if compared to Rubus cultivars. Due to Rubus sellowii nutritional properties, they provide benefits to human health. PMID- 30304257 TI - Ciliated microeukaryotes (Alveolata: Ciliophora) of a lotic urban system located in Minas Gerais - Brazil. PMID- 30304258 TI - First record of Nais schubarti Marcus, 1944 (Oligochaeta: Naididae) in the State of Sao Paulo. PMID- 30304259 TI - Electrocardiogram in Chagas disease: can anything be learned from an old tool? PMID- 30304260 TI - Electrocardiogram in Chagas disease. AB - Since the initial descriptions of Chagas cardiomyopathy (ChCM), the electrocardiography has played a key role in patient evaluations. The diagnostic criterion of chronic ChCM is the presence of characteristic electrocardiographic (ECG) abnormalities in seropositive individuals, regardless of the presence of symptoms. However, these ECG abnormalities are rarely specific to ChCM and, particularly among the elderly, can be caused by other simultaneous cardiomyopathies. ECG abnormalities can predict the occurrence of heart failure, stroke, and even death. Nevertheless, most prognostic studies have included Chagas disease (ChD) populations and, not exclusively, ChCM. Thus, more studies are required to evaluate the efficacy of ECG in predicting reliable prognoses in established chronic ChCM. This review exclusively discusses the role of the 12 lead ECG in the clinical evaluation of chronic ChD. PMID- 30304261 TI - Hepatitis B and asymptomatic malaria coinfection in Sub-Saharan African immigrants: epidemiological and clinical features of HBV infection. AB - INTRODUCTION: Here, we conducted an epidemiological study of hepatitis B virus (HBV) mono-infected and asymptomatic malaria/HBV coinfected immigrants and further discussed the possibility of malaria disease modifying the clinical presentation of HBV infection. METHODS: A total of 195 African immigrants were examined for HBV infection or coinfection with HBV and asymptomatic malaria. HBV infection was diagnosed using serological tests and confirmed by PCR; furthermore, we performed a pan-Plasmodium-specific-nucleic-acid-sequence-based amplification (NASBA) assay to detect asymptomatic malaria infection. The stage/grade of the liver disease was determined using echotomography and elastometry. RESULTS: PCR-NASBA results confirmed that 62 of 195 subjects (31.8%) were positive for Plasmodium infection, whereas 41 of 195 subjects (21%) tested positive for HBV chronic hepatitis (HBV-DNA positive). Among the HBV-positive subjects, 26 (63.4%) of them were mono-infected patients (Group A), whereas 15 (36.6%) patients had HBV chronic hepatitis and asymptomatic malaria coinfections (Group B). The HBV-DNA median levels were 1.4*105IU/mL in HBV-mono-infected patients and 2.0*105IU/mL in coinfected patients. Echotomography and hepatic elastometry presented similar findings for both groups of patients. CONCLUSIONS: Coinfected patients seem to present with the same clinical symptoms of the liver disease as HBV mono-infected patients. PMID- 30304262 TI - Prostaglandin A1 triggers Mayaro virus inhibition and heat shock protein 70 expression in an epithelial cell model. AB - INTRODUCTION: The Mayaro virus (MAYV), which is an arbovirus closely related to the Chikungunya virus, causes a dengue-like acute illness that is endemic to Central and South America. We investigated the anti-MAYV activity of prostaglandin A1 (PGA1), a hormone which exhibits antiviral activity against both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) viruses. Further, we examined the effects of inducting the stress protein HSP70 following PGA1 treatment. METHODS: Hep-2 cells infected with MAYV were treated with PGA1 (0.1 6MUg/ml) 12h before infection and for different periods post-infection. Inhibition of viral replication inhibition was analyzed via viral titer determination, whereas the effect of PGA1 on viral morphogenesis was examined via transmission electron microscopy (TEM). Autoradiography (with 35S methionine labeling) and western blotting were used to assess the effect of PGA1 treatment on viral and cellular protein synthesis, and on HSP70 induction, respectively. RESULTS: PGA1 strongly reduced viral replication in Hep-2 cells, particularly when added during the early stages of viral replication. Although PGA1 treatment inhibited viral replication by 95% at 24 hours post-infection (hpi), viral structural protein synthesis was inhibited only by 15%. TEM analysis suggested that PGA1 inhibited replication before viral morphogenesis. Western blot and densitometry analyses showed that PGA1 treatment increased HSP70 protein levels, although this was not detectable via autoradiography. CONCLUSIONS: PGA1 inhibits MAYV replication in Hep-2 cells at early stages of viral replication, prior to production of viral structural proteins, possibly via HSP70 induction. PMID- 30304263 TI - Diagnostic significance of immunoglobulin G avidity in symptomatic and asymptomatic West Nile virus infection. AB - INTRODUCTION: West Nile virus (WNV) immunoglobulin M (IgM) antibodies have been shown to persist for up to 500 days in certain patients. To evaluate the usefulness of immunoglobulin G (IgG) avidity assessment in the diagnosis of WNV infection, we analyzed 54 WNV IgM- and/or IgG-positive serum samples from 39 patients with neuroinvasive disease and 15 asymptomatic cases tested during a seroprevalence investigation. METHODS: Serological tests (WNV IgM/IgG antibody detection, IgG avidity) were performed using commercially available enzyme-linked immunosorbent assays. RESULTS: WNV IgM antibodies were detected in 47 (87%) samples. Acute/recent WNV infection was confirmed based on low/borderline avidity index (AI) in 44 IgM-positive samples (93.6%). In three IgM-positive samples (6.4%), high IgG AIs were detected, thus indicating persisting IgM antibodies from previous infections. All IgM-negative samples showed high AIs. Patients with WNV neuroinvasive disease tested within 30 days showed low AIs. In six patients tested 34-50 days after disease onset, AI was borderline (42%-60%), suggesting earlier WNV IgG maturation. Samples with the highest IgM values were associated with the lowest AIs (Spearman's rho coefficient -0.767, p < 0.001). CONCLUSIONS: Our results indicate that IgG avidity differentiates current/recent WNV infection from persistent IgM seropositivity from the previous WNV transmission season both in patients with WNV neuroinvasive disease and in asymptomatic persons. A strong negative correlation between IgM antibody levels and AI indicates that in cases with very high IgM levels, determination of IgG avidity may not be necessary. As many patients showed rapid avidity maturation, low IgG avidity is indicative of WNV infection within the previous month. PMID- 30304264 TI - Prevalence of low bone mass and changes in vitamin D levels in human immunodeficiency virus-infected adults unexposed to antiretrovirals. AB - INTRODUCTION: The prevalence of low bone mass is 3 times higher in people living with human immunodeficiency virus (PLWH) and using antiretrovirals than in the HIV-unaffected population. Changes in vitamin D levels is one of the factors associated with decreased bone mass. The objective of this study is to evaluate the low bone mass and altered vitamin D levels in PLWH who have not been exposed to antiretrovirals. METHODS: A cross-sectional study was carried out with HIV infected individuals between the ages of 18 and 55 years immediately prior to the start of antiretroviral therapy in a specialized reference center focusing on infectious and parasitic diseases. Results of clinical examination (patient's weight, height, blood pressure, and clinical history), laboratory tests, and X ray absorptiometry, were collected. RESULTS: Sixty patients were included, with a mean age of 34 years. Nine (16.7%) patients presented with low bone mass and 4 (7.1%) patients showed low total femur BMD. Analysis revealed that 23.3% and 36.7% of the patients had deficient and insufficient levels of 25-hydroxyvitamin D3, respectively. CONCLUSIONS: Our study population presented with compromised bone health and with low bone mineral density and 25-(OH)-vitamin D levels. PMID- 30304265 TI - Molecular analysis, biofilm formation, and susceptibility of methicillin resistant Staphylococcus aureus strains causing community- and health care associated infections in central venous catheters. AB - INTRODUCTION: The behavior of methicillin-resistant Staphylococcus aureus (MRSA) isolated from central venous catheter-related infection was evaluated to determine its biofilm potential, antimicrobial resistance, and adhesion genes. METHODS: A total of 1,156 central venous catheters (CVC) were evaluated to screen for pathogens. Antimicrobial sensitivity, biofilm formation potential, and molecular analysis of MRSA were examined following standard guidelines. RESULTS: Of the 1,156 samples, 882 (76%) were colonized by bacteria or candida. Among the infected patients, 69% were male and 36% were female with median age of 32 years. Staphylococcus aureus infected 39% (344/882) of CVCs in patients. Of the 59% (208/344) of patients with MRSA, 57% had community acquired MRSA and 43% had hospital acquired MRSA. Linezolid and vancomycin killed 100% of MRSA; resistance levels to fusidic acid, doxycycline, clindamycin, azithromycin, amikacin, trimethoprim-sulfamethoxazole, gentamycin, tobramycin, and ofloxacin were 21%, 42%, 66%, 68%, 72%, 85%, 95%, 97%, and 98% respectively. Strong biofilm was produced by 23% of samples, moderate by 27%, and weak by 50% of MRSA. The presence of adhesion genes, sdrC and sdrD (90%), eno (87%), fnbA (80%), clfA and sdrE (67%), fnbB, sdrD (61%), and cna (51%), in most MRSA samples suggested that the adhesion genes are associated with biofilm synthesis. CONCLUSIONS: The superbug MRSA is a major cause of CVC-related infection. Antibiotic resistance to major classes of antibiotics and biofilm formation potential enhanced superbug MRSA virulence, leading to complicated infection. MRSA causes infection in hospitals, communities, and livestock. PMID- 30304266 TI - Phenotypic and molecular detection of metallo-beta-lactamase-producing Pseudomonas aeruginosa isolates from patients with burns in Tehran, Iran. AB - INTRODUCTION: Health care-associated infections caused by metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa are a significant growing concern in patients with burns worldwide. The aims of this study were to determine the antibiotic susceptibility of and detect the presence of MBLs among P. aeruginosa isolates and assess their clonal relationship using enterobacterial repetitive intergenic consensus (ERIC)-PCR. METHODS: Non-duplicated clinical isolates (160) of P. aeruginosa were collected from patients with burns at the Motahari Hospital in Tehran, Iran. All isolates were identified using standard laboratory methods and further characterized for antimicrobial susceptibility. Any carbapenem resistant isolates were then examined for MBL production by the E-test and MBL encoding genes were detected by PCR. The clonal relatedness of MBL-producing isolates was assessed by ERIC-PCR. RESULTS: For multidrug-resistant isolates, the highest rates of susceptibility were observed for colistin 160 (100%), polymyxin B 160 (100%), and ceftazidime 32 (20%). In total, 69 (43.7%) isolates were identified as MBL producers. Twenty-eight (17.5%) isolates were positive for the bla VIM-1 gene followed by the bla IMP-1 (15.6%) and bla SPM-1 (5.6%) genes. ERIC PCR revealed three separate genotypes, where type A (76.8%) was the most prevalent, followed by B (20.3%), and then C (2.9%). CONCLUSIONS: Our present study found that the bla IMP-1 and bla VIM-1 genes were present at a significant frequency and also detected the bla SPM-1 gene in P. aeruginosa isolates for the first time, highlighting the need for establishing suitable infection control measures to successfully treat patients and prevent further spread of these resistant organisms among patients with burns. PMID- 30304267 TI - Trypanosoma cruzi seroprevalence among solid organ donors in Ceara State, Brazil. AB - INTRODUCTION: The transmission of Chagas disease (CD) through blood transfusion, organ transplantation, and oral transmission has gained greater visibility as a result of intensified vector control activities in endemic regions and to control CD in non-endemic regions. In Brazil, Ceara is one of the states that perform the most organ transplants. Therefore, the objective of this study was to assess the prevalence of Trypanosoma cruzi infection in organ donor candidates. METHODS: A retrospective analysis was performed on data from potential organ donors at the Center of Transplantation of the State of Ceara from 2010 - 2015. RESULTS: Data from a total of 2,822 potential donors were obtained, of which 1,038 were effective donors and 1,784 were excluded, likely due to lack of family authorization or medical contraindication. The prevalence of T. cruzi infection among these potential donors was 1.3% (n = 29). The majority of infected donors were males aged 41 - 60 years, residing in the interior of the state. Interestingly, 72.4% (n = 21) had positive or inconclusive serology for additional infections, such as cytomegalovirus, hepatitis B and C, and toxoplasmosis. Probability analysis revealed that stroke was the most common cause of death among potential donors with CD. CONCLUSIONS: There was a high prevalence of CD and other coinfections among potential solid organ donors in Ceara, and statistical tests have shown that these individuals are at increased risk of stroke when compared to potential non-reactive donors. This work highlights the importance of screening DC infection in potential donors. PMID- 30304268 TI - Demographic and clinical characterization of human visceral leishmaniasis in the State of Pernambuco, Brazil between 2006 and 2015. AB - INTRODUCTION: Human visceral leishmaniasis (HVL) primarily occurs in regions that present socioeconomic, health, and environmental vulnerability. In Pernambuco, Brazil, this neglected zoonosis has expanded in magnitude as well as geographically, and efforts to manage HVL have been insufficient to contain its spread. The objective of this study was to describe the epidemiological profile of human illness due to HVL during 2006 to 2015 in Pernambuco State. METHODS: This study was conducted using secondary data collected from the Health Information System. RESULTS: During the study period, Pernambuco accounted for 2.4% of HVL cases in Brazil, with 49.6% of these concentrated in the macroregions of Sao Francisco Valley and Araripe. The percentage of municipalities that reported cases at the beginning of the study period increased from 21.1% (n = 39) to 43.8% (n = 81) by the end of the period. Cases were found predominantly among males, brown-skinned individuals, children aged 1-4 years, and individuals with incomplete 1st to 4th grade education. Coinfection with HIV was present in 5.6% of cases. Incidence was 9.7 cases per 100,000 inhabitants, and lethality was 12.3%. CONCLUSIONS: HVL has shown worrying expansion and evolution, in addition to high lethality, in Pernambuco. The only study of its kind in the past decade, it was evident from this study that despite efforts to contain this disease, HVL in Pernambuco exhibits patterns similar to those described in previous studies. Based on our results, we suggest reassessing the current prevention and control measures in the state. PMID- 30304269 TI - Clinical impact and cost analysis of the use of either the Xpert MTB Rif test or sputum smear microscopy in the diagnosis of pulmonary tuberculosis in Rio de Janeiro, Brazil. AB - INTRODUCTION: The molecular test Xpert MTB/RIF (Xpert) has been recommended for use in the diagnosis of pulmonary tuberculosis (PTB); however, data on the cost of incorporating it under routine conditions in high-burden countries are scarce. The clinical impact and costs incurred in adopting the Xpert test in routine PTB diagnosis was evaluated in a prospective study conducted from November 2012 to November of 2013, in the City of Rio de Janeiro, Brazil. METHODS: The diagnostic and therapeutic cascade for TB treatment was evaluated using Xpert in the first stage (S1), and sputum smear microscopy (SSM) in the second stage (S2). The mean costs associated with each diagnostic test were calculated including equipment, human resources, supplies, and infrastructure. RESULTS: We included 232 subjects with probable TB (S1 = 87; S2 = 145). The sensitivities of Xpert and SSM were 91.7% (22/24) and 79.1% (34/43), respectively. The median time between triage and TB treatment initiation in S1 (n = 24) was 14.5 days (IQR 8-28.0) and in S2 (n = 43) it was 8 days [interquartile range (IQR) 6-12.0]. The estimated mean costs per examination in S1 and S2 were US$24.61 and US$6.98, respectively. CONCLUSIONS: Compared with SSM, Xpert test showed a greater sensitivity, but it also had a time delay with respect to treatment initiation and a higher mean cost per examination. PMID- 30304270 TI - Social determinants of tuberculosis via a zero-inflated model in small areas of a city in Southeastern Brazil. AB - INTRODUCTION: This study aimed to analyze social factors involved in the spatial distribution and under-reporting of tuberculosis (TB) in the city of Vitoria, Espirito Santo State, Brazil. METHODS: This was an ecological study of the reported cases of TB between 2009 and 2011, according to census tracts. The outcome was TB incidence for the study period and the variables of exposure were proportions of literacy, inhabitants with an income of up to half the minimum monthly wage (MMW), and inhabitants associated with sewer mains or with access to safe drinking water. We used a zero-inflated process, zero-inflated negative binomial regression (ZINB), and selected an explanatory model based on the Akaike Information Criterion (AIC). RESULTS: A total of 588 cases of tuberculosis were reported in Vitoria during the study period, distributed among 223 census tracts (38.6%), with 354 (61.4%) tracts presenting zero cases. In the ZINB model, the mean value of p i was 0.93, indicating that there is a 93% chance that an observed false zero could be due to sub-notification. CONCLUSIONS: It is important to prioritize areas exhibiting determinants that influence the occurrence of TB in the municipality of Vitoria. The zero-inflated model can be useful to the public health sector since it identifies the percentage of false zeros, generating an estimate of the real epidemiological condition of TB in Vitoria. PMID- 30304271 TI - Distribution of clinical isolates of Candida spp. and antifungal susceptibility of high biofilm-forming Candida isolates. AB - INTRODUCTION: The increase in the incidence of fungal infections, especially those caused by Candida albicans and other Candida species, necessitates the understanding and treatment of Candida-associated infections. In this study, we aimed to investigate the identification, distribution, and biofilm formation ability of different clinical Candida isolates and evaluate the distribution and antifungal susceptibilities of high biofilm-forming (HBF) Candida isolates. METHODS: For identification, carbohydrate fermentation, carbohydrate assimilation, and ChromAgar tests were used. Biofilm formation was assessed using crystal violet binding assay, while the susceptibility to antifungal agents was determined using ATBTM Fungus 3 test kits. RESULTS: The majority of Candida species were C. parapsilosis (31.3%; 31/99) and C. tropicalis (30.3%; 30/99). C. tropicalis was found to be the most frequently isolated species among all HBF Candida species. HBF Candida isolates were more frequently isolated from vaginal swab (35.7%; 10/28), tracheal aspirate (17.9%; 5/28), and urine (17.9%; 5/28). The majority of tested isolates were resistant to itraconazole and voriconazole, whereas no isolate was deemed resistant to 5-flucytosine. CONCLUSIONS: C. tropicalis displays the highest biofilm formation ability among all the Candida species evaluated, and HBF Candida isolates were more frequently seen in vaginal swab, tracheal aspirate, and urine samples. Our findings revealed that 5 flucytosine is the most efficient antifungal agent against HBF Candida isolates. PMID- 30304272 TI - Delayed healthcare and secondary infections following freshwater stingray injuries: risk factors for a poorly understood health issue in the Amazon. AB - INTRODUCTION: This study aimed to describe the profile of freshwater stingray injuries in the State of Amazonas, Brazilian Amazon, and to identify the associated risk factors for secondary infections. METHODS: This cross-sectional study used surveillance data from 2007 to 2014 to identify factors associated with secondary infections from stingray injuries. RESULTS: A total of 476 freshwater stingray injuries were recorded, with an incidence rate of 1.7 cases/100,000 person/year. The majority of injuries were reported from rural areas (73.8%) and 26.1% were related to work activities. A total of 74.5% of patients received medical assistance within the first 3 hours of injury. Secondary infections and necrosis were observed in 8.9% and 3.8%, respectively. Work-related injuries [odds ratio (OR) 4.1, confidence interval (CI); 1.87-9.13] and >24 hours from a sting until receiving medical care (OR; 15.5, CI; 6.77 35.40) were independently associated with the risk of secondary bacterial infection. CONCLUSIONS: In this study, work-related injuries and >24 hours from being stung until receiving medical care were independently and significantly associated with the risk of secondary infection. The frequency of infection following sting injuries was 9%. The major factor associated with the risk of secondary bacterial infection was a time period of >24 hours from being stung until receiving medical care. PMID- 30304274 TI - Effect of chaotropes in Chagas disease and leishmaniasis cross-reacting serology assays for epidemiological surveys. AB - INTRODUCTION: Serological cross-reactivity between leishmaniasis and Chagas disease, especially at low titers, leads to difficulties of the seroepidemiological interpretation. METHODS: We have studied the ability of urea as a chaotrope to select high-avidity antibodies in IgG ELISA, thus reducing low avidity IgG cross-reactivity in serologically positive samples in both assays. RESULTS: Using 0.5M urea for diluting the sample efficiently defined leishmaniasis or double infections in high-avidity IgG ELISA and eliminated false positive results. CONCLUSIONS: The use of a chaotropic diluting agent is useful for improving the specificity of Chagas disease and leishmaniasis immunoassays. PMID- 30304273 TI - Clinical and epidemiological characteristics of Chagas disease in an endemic area of Sergipe State, Brazil. AB - INTRODUCTION: We evaluated clinical and epidemiological characteristics of Trypanosoma cruzi infection in Sergipe. METHODS: In this cross-sectional study, we collected serum samples to identify serological markers of Chagas disease. A questionnaire was used, and electrocardiogram, echocardiogram, chest radiography, and contrast radiography of esophagus and colon were performed. RESULTS: T. cruzi infection seroprevalence was 12.1%, mean age of subjects was 55 years, 90% had an elementary school education, 78.6% were agriculture workers, and 60.5% had electrocardiographic abnormalities. CONCLUSIONS: A high prevalence of T. cruzi infection was observed in mostly elderly individuals. PMID- 30304275 TI - The burden of hepatitis C infection in a Southern Brazilian State. AB - INTRODUCTION: The study aimed to estimate the burden of hepatitis C in Santa Catarina, Brazil. METHODS: An ecologic study was carried out to estimate the disability-adjusted life years (DALY) by summing the number of years of life lost and the number of years lived with disability. RESULTS: A rate of 1,075.9 DALY/100,000 population was estimated, and was similar by sex. The highest burden was between the ages of 45 to 59 years and in the Grande Oeste region. CONCLUSIONS: The burden of hepatitis C was high and concentrated in adult age groups with variations among regions. PMID- 30304276 TI - In vitro resistance of Enterobacter cloacae isolated from fresh seafood to colistin. AB - INTRODUCTION: Enterobacter cloacae is a clinically important bacterium from the Enterobacteriaceae family. This study evaluated resistance of E. cloacae strains from fish (n=14) and shrimp (n=9) to colistin. METHODS: Biochemical identification and antimicrobial susceptibility tests were carried out in an automated Vitek(r)2 instrument. RESULTS: Colistin resistance was observed in 21.4% and 66.7% of the strains from fish and shrimp, respectively. We observed minimum inhibitory concentrations of >=16 mg/L and <=5 mg/L in 8 and 15 of all strains, respectively. CONCLUSIONS: Fish and shrimp can carry drug-resistant enterobacteria, which can be of clinical interest. PMID- 30304277 TI - Increased antimicrobial resistance in Klebsiella pneumoniae from a University Hospital in Rio Grande do Sul, Brazil. AB - INTRODUCTION: The spread of multidrug-resistant Gram-negative bacilli is a health threat, limiting therapeutic options and increasing morbimortality rates. METHODS: This study aimed to evaluate the antimicrobial susceptibility profile of 1805 Klebsiella pneumoniae isolates collected from Hospital Universitario de Santa Maria between January 2015 and December 2016. RESULTS: Resistance to colistin (239.3%), meropenem (74.2%), ciprofloxacin (68%), gentamicin (35.1%), tigecycline (33.9%), imipenem (29.7%), ertapenem (26.8%), and amikacin (21.4%) was found increased. CONCLUSIONS: Infection control measures in the hospitals are necessary for reducing the spread of multidrug-resistant microorganisms and preventing efficacy loss of these drugs. PMID- 30304278 TI - Seroprevalence and spatial distribution of canine leishmaniasis in an endemic region in Brazil: how has the situation changed after 10 years? AB - INTRODUCTION: Herein, we assessed the seroprevalence and spatial distribution of Leishmania infantum in dogs in Garanhuns, Northeastern Brazil. METHODS: Sera samples (n = 242) were analyzed using an enzyme-linked immunosorbent assay (ELISA). The spatial distribution of dogs seropositive for anti-Leishmania infantum antibodies was evaluated using kernel density estimation. RESULTS: A total of 2.4% (6/242) of the animals were seropositive for anti-Leishmania infantum antibodies. The kernel map showed their distribution to be heterogeneous over the city, with a hotspot in the northeastern region. CONCLUSIONS: The reported data illustrate the circulation of parasites of the genus Leishmania in a canine population. PMID- 30304280 TI - Snail transmitters of schistosomiasis and other mollusks of medical and economic importance at the Simplicio Queda Unica Hydroelectric Plant, Southeast Brazil. AB - INTRODUCTION: This paper presents the results of an extensive survey of freshwater mollusks in the Simplicio Queda Unica Hydroelectric Development area, Southeast Brazil. METHODS: Mollusks were collected between 2008 and 2013. All specimens were examined for the presence of larval trematodes. RESULTS: In total, 12,507 specimens classified into 16 genera were obtained. Known snail vectors of schistosomiasis and fascioliasis and exotic species were identified, and new records are reported. CONCLUSIONS: No specimens parasitized by larval trematodes of medical interest were detected. However, the results reinforce the importance of surveillance in study areas vulnerable to the occurrence of schistosomiasis transmission. PMID- 30304279 TI - Seroprevalence and risk factors associated with canine visceral leishmaniasis in the State of Paraiba, Brazil. AB - INTRODUCTION: The aim of this study was to determine the seroprevalence and risk factors associated with canine visceral leishmaniasis in Paraiba State. METHODS: Blood samples were collected from 411 dogs in four municipalities of Paraiba State. The seroprevalence was assessed by using ELISA. RESULTS: The seroprevalence ranged from 7.2% to 20%. The risk factors that were associated with the disease were the presence of ticks and contact with other animals. CONCLUSIONS: The seroprevalence of canine visceral leishmaniasis is high in Paraiba, indicating the need for health authorities to resume visceral leishmaniasis control activities. The ruralization of suburban areas in the region tends to homogenize the risk factors between suburban and rural areas. PMID- 30304281 TI - Acute kidney injury due to systemic Loxoscelism: a cross-sectional study in Northeast Brazil. AB - INTRODUCTION: Loxoscelism is a clinical condition involving spiders of the genus Loxosceles. One of the most severe complications is acute kidney injury (AKI). This study aimed to investigate AKI and other complications associated with loxoscelism. METHODS: We analyzed cases diagnosed with loxoscelism in an area where most accidents were caused by Loxosceles amazonica from January 2010 to December 2015. AKI was defined according to the KDIGO criteria. RESULTS: Forty five patients were recorded: 95.6% presented characteristic necrotic skin lesions and 13.3% AKI. CONCLUSIONS: Loxoscelism could cause kidney involvement which is uncommon and could lead to the death of these patients. PMID- 30304282 TI - Injuries caused by fish in a community of Pantanal fishermen: detection, treatment, and prevention of envenomations and trauma. AB - INTRODUCTION: Injuries caused by fish are common in the Pantanal, a flooded area in Midwestern Brazil. METHODS: A survey was conducted to identify venomous and trauma-inducing fish and the incidence of such injuries in a local fishing community. RESULTS: The injuries were caused by catfish, freshwater stingrays, and piranhas. All fishermen had suffered injuries, and nearly 30% had recent injuries. CONCLUSIONS: A leaflet and discussions decreased the injuries (only two were recorded in the next year). The campaign educated fishermen about prevention of and first aid for injuries. Similar campaigns will be performed in other communities of the Pantanal. PMID- 30304283 TI - Sudden bilateral sensorineural hearing loss in a patient immunocompromised by the human immunodeficiency virus. AB - It is known that in less than a third of patients presenting sudden hearing loss, the disorder can be attributed to viral infection, trauma, neoplasms, and vascular and autoimmune diseases. However, the role of the HIV in the onset of this disease has not yet been well described. A 46-year-old female, in an immunosuppression state induced by HIV infection, presented with sudden bilateral hearing loss, with no improvement despite treatment. Several mechanisms were reported by which the virus could induce damage to the auditory pathway. However, little is known regarding the prevention and treatment of this morbidity. PMID- 30304284 TI - Ralstonia mannitolilytica bacteremia in a neonatal intensive care unit. AB - Ralstonia mannitolilytica, a Gram-negative bacterium, is rarely isolated in clinical laboratories. It has been associated with outbreaks due to its ability to survive in liquid media and hospital devices. We describe three cases of bacteremia caused by R. mannitolilytica in a neonatal intensive care unit in Curitiba, Southern Brazil. All isolates presented the same PFGE profile. The common source of infection was undetected in surveillance cultures for the outbreak survey. All patients received antimicrobial treatment and were discharged from the maternity. Due to the characteristics of the microorganism, clinicians and microbiologists should pay attention to the emergence of Ralstonia spp. infections. PMID- 30304286 TI - The first Acanthamoeba keratitis case in the Midwest region of Brazil: diagnosis, genotyping of the parasite and disease outcome. AB - We report an Acanthamoeba keratitis case associated with the use of contact lens in a 28-year-old female from Brasilia, Brazil. Samples from corneal scraping and contact lens case were used for culture establishment, PCR amplification, and partial sequencing (fragments of ~400kb) of small subunit rDNA; both culture and PCR were positive. The sequence analyses of the cornea and of isolates from the contact lens case showed similarity with the T4 genotype. To the best of our knowledge, this is the first report of T4 Acanthamoeba keratitis case from the Midwest region of Brazil. PMID- 30304287 TI - A human immunodeficiency virus-positive woman with toxic epidermal necrolysis treated with human intravenous immunoglobulin. PMID- 30304285 TI - First autochthonous case of canine visceral leishmaniasis in Rondonia, Brazil, a region with no history of visceral leishmaniasis. AB - This report describes the first autochthonous case of canine visceral leishmaniasis in Rondonia, northern Brazil. A canine resident of the municipality of Cacoal, with clinical signs and symptoms of visceral leishmaniasis, was treated by a veterinarian. Samples were analyzed by a reference laboratory. Dual path platform (DPP) assay, indirect immunofluorescence technique (IIT), enzyme linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), isolation in a culture medium, and direct parasitological analysis were performed. DPP assay, IIT, and ELISA revealed positive results for Leishmania; PCR identified the species as Leishmania infantum. Based on the clinical presentation and test results, canine visceral leishmaniasis was diagnosed. PMID- 30304288 TI - Central nervous system histoplasmosis mimicking tentorium meningioma. PMID- 30304289 TI - Yellow fever vaccination and neurological complications. PMID- 30304290 TI - PROLONGED GASTROESOPHAGEAL REFLUX MONITORING BY IMPEDANCE-PHMETRY: A REVIEW OF THE SUBJECT PONDERED WITH OUR EXPERIENCE WITH 1,200 CASES. AB - BACKGROUND: Prolonged monitoring increased our knowledge on gastroesophageal reflux (GER), and the disease became known as gastroesophageal reflux disease (GERD). Prolonged reflux monitoring permits the diagnosis of GERD when endoscopic findings are not enough to characterize it. OBJECTIVE: The objective of this paper is to review the current knowledge on impedance-pH monitoring, taking into account the published literature and the authors experience with 1,200 exams. METHODS: The different types of prolonged reflux monitoring, namely: conventional pHmetry, catheter-free pHmetry and impedance-pHmetry will be briefly described. The new possibilities of evaluation with impedance-pHmetry are emphasized, namely: the study of symptomatic patients in use of proton pump inhibitors (PPIs); evaluation of patients with symptoms suggestive of GERD although with normal endoscopy and normal pHmetry, diagnostic elucidation of patients with atypical symptoms or supra-esophageal symptoms, mainly chronic cough, study of patients complaining of belch, differentiating gastric and supra-gastric belching, and the proper work-up before anti-reflux surgery. RESULTS: When impedance was associated to pH monitoring, an impressive technological evolution became apparent, when compared to pH monitoring alone. The main advantages of impedance-pHmetry are: the ability to detect all types of reflux: acid, non-acid, liquid, gaseous. In addition, other important measurements can be made: the ability of the esophagus in transporting the bolus, the measurement of basal mucosal impedance and the evaluation of primary peristalsis post reflux. CONCLUSION: Impedance-pHmetry is a promising method, with great advantages over conventional pHmetry. The choice between these two types of monitoring should be very judicious. The authors suggest the importance of careful evaluation of each reflux episode by the physician responsible for the examination, necessary for the correct interpretation of the tracings. PMID- 30304291 TI - ARE THE PERSISTENT SYMPTOMS TO PROTON PUMP INHIBITOR THERAPY DUE TO REFRACTORY GASTROESOPHAGEAL REFLUX DISEASE OR TO OTHER DISORDERS? AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is a clinical condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Transient lower esophageal sphincter relaxation is the main pathophysiological mechanism of GERD. Symptoms and complications can be related to the reflux of gastric contents into the esophagus, oral cavity, larynx and/or the lung. Symptoms and other possible manifestations of GERD are heartburn, regurgitation, dysphagia, non-cardiac chest pain, chronic cough, chronic laryngitis, asthma and dental erosions. The proton pump inhibitor (PPI) is the first-choice drug and the most commonly medication used for the treatment of GERD. The most widespread definition of Refractory GERD is the clinical condition that presents symptoms with partial or absent response to twice-daily PPI therapy. Persistence of symptoms occurs in 25% to 42% of patients who use PPI once-daily and in 10% to 20% who use PPI twice-daily. OBJECTIVE: The objective is to describe a review of the current literature, highlighting the causes, diagnostic aspects and therapeutic approach of the cases with suspected reflux symptoms and unresponsive to PPI. CONCLUSION: Initially, the management of PPI refractoriness consists in correcting low adherence to PPI therapy, adjusting the PPI dosage and emphasizing the recommendations on lifestyle modification change, avoiding food and activities that trigger symptoms. PPI decreases the number of episodes of acid reflux; however, the number of "non-acid" reflux increases and the patient continues to have reflux despite PPI. In this way, it is possible to greatly reduce greatly the occurrence of symptoms, especially those dependent on the acidity of the refluxed material. Response to PPI therapy can be evaluated through clinical, endoscopic, and reflux monitoring parameters. In the persistence of the symptoms and/or complications, other causes of Refractory GERD should be suspected. Then, diagnostic investigation must be initiated, which is supported by clinical parameters and complementary exams such as upper digestive endoscopy, esophageal manometry and ambulatory reflux monitoring (esophageal pH monitoring or esophageal impedance-pH monitoring). Causes of refractoriness to PPI therapy may be due to the true Refractory GERD, or even to other non-reflux diseases, which can generate symptoms similar to GERD. There are several causes contributing to PPI refractoriness, such as inappropriate use of the drug (lack of patient adherence to PPI therapy, inadequate dosage of PPI), residual acid reflux due to inadequate acid suppression, nocturnal acid escape, "non-acid" reflux, rapid metabolism of PPI, slow gastric emptying, and misdiagnosis of GERD. This is a common cause of failure of the clinical treatment and, in this case, the problem is not the treatment but the diagnosis. Causes of misdiagnosis of GERD are functional heartburn, achalasia, megaesophagus, eosinophilic esophagitis, other types of esophagitis, and other causes. The diagnosis and treatment are specific to each of these causes of refractoriness to clinical therapy with PPI. PMID- 30304292 TI - FUNCTIONAL AND ANATOMICAL ANALYSIS OF THE ANORECTUM OF FEMALE SCLERODERMA PATIENTS AT A CENTER FOR PELVIC FLOOR DISORDERS. AB - BACKGROUND: Scleroderma or progressive systemic sclerosis is characterized by a chronic inflammatory process with proliferation of fibrous connective tissue and excessive deposition of collagen and extracellular matrix in the skin, smooth muscle, and viscera. The smooth muscle most involved in scleroderma is that of the esophagus, and dysphagia is the most commonly reported symptom. However, the internal anal sphincter may also be impaired by degeneration and fibrosis, leading to concomitant anal incontinence in scleroderma patients. These patients may neglect to complain about it, except when actively questioned. OBJECTIVE: To assess anorectal function and anatomy of female scleroderma patients with symptoms of anal incontinence through Cleveland Clinic Florida Fecal Incontinence Score (CCFIS), anorectal manometry and endoanal ultrasound at the outpatient clinic of colorectal and anal physiology, Clinics Hospital, University of Sao Paulo Medical School (HC-FMUSP). METHODS: Female scleroderma patients were prospectively assessed and questioned as to symptoms of anal incontinence. The anorectal manometry and endoanal ultrasound results were correlated with clinical data and symptoms. RESULTS: In total, 13 women were evaluated. Their mean age was 55.77 years (+/-16.14; 27-72 years) and their mean disease duration was 10.23 years (+/-6.23; 2-23 years). All had symptoms of fecal incontinence ranging from 1 to 15. Seven (53.8%) patients had fecal incontinence score no higher than 7; three (23.1%) between 8 and 13; and three (23.1%) 14 or higher, corresponding to mild, moderate, and severe incontinence, respectively. Ten (76.92%) patients had hypotonia of the internal anal sphincter. Three-dimensional endoanal ultrasound showed tapering associated with muscle atrophy of the internal sphincter in six cases and previous muscle defects in three cases. CONCLUSION: A functional and anatomical impairment of the sphincter is an important factor to assess in patients with progressive systemic sclerosis and it should not be underestimated. PMID- 30304293 TI - Biotic potential and reproductive parameters of Spodoptera cosmioides (Walker) (Lepidoptera: Noctuidae) in the laboratory. AB - In this study we evaluate the biotic potential and reproductive parameters of Spodoptera cosmioides (Walker, 1858) under controlled conditions (25 +/- 1 degrees C, 70 +/- 10% RH and 14 hour photophase). Females, on average, (14.433 days) did not live significantly longer than their male counterparts (13.100 days). The mean durations of the pre-oviposition, oviposition and post oviposition periods were 2.767, 10.600 and 1.067 days, respectively. The mean fecundity of females was 5,073.533 eggs and the mean fertility was 5,021.027 larvae. On average, females copulated 1.167 times. Fecundity was positively correlated with the number of copulations (r = 0.583, P <0.001). The number of copulations, however, was negatively correlated whit the duration of the pre oviposition (r = -0.560, P = 0.007) and oviposition (r = -0.479, P = 0.048) periods, and overall longevity (r = -0.512, P = 0.031). The biotic potential was estimated at 6.547 x 1021 individuals/female/year. The net reproductive rate (Ro) was 2,193.722 times per generation and the mean generation time (T) was 46.407 days. The intrinsic rate of increase (rm) was 0.166, with a finite rate of increase (lambda) of 1.180, per week. PMID- 30304294 TI - Does intensive feeding frequency affect growth performance of common snook Centropomus undecimalis (Bloch, 1792)? AB - Salt water recirculation systems using automatic feeders are a new frontier for marine aquaculture. It is possible to decrease the vulnerability of the traditional fish farming in open systems and reduce wasteful feeding and discharge of effluents, as well as increase the economic returns. An experiment with common snook fingerings (4.31 +/- 1.42 g and 8.4 +/- 1.0 cm) was performed. Three feeding treatments were evaluated: six, twelve and eighteen feeding times per day. Each treatment had three replications. Among the three tested frequencies (fed 6, 12 and 18 times a day), the feeding frequency of 12 times per day (every two hours) showed the best values of the parameters evaluated for production performance. The final weight values, condition factor, specific growth rate and daily weight gain of the treatment 12 feeding times per day were all significantly higher than the lower and higher frequencies. Our results demonstrate that high feeding frequency is not synonymous of higher performance, but is extremely necessary to find out the best range for the target species. Besides, this relationship between feeding frequency and growth performance might change over weight range. Therefore, future studies should address higher weight ranges for comparison to our results. PMID- 30304295 TI - Use of eugenol for anesthesia of lesser guitarfish Zapteryx brevirostris (Rhinobatidae). AB - Anesthesia can be utilized as a non-lethal procedure to allow easy handling of teleosts and elasmobranchs in captivity or in the wild. For this, anesthetic protocols need to be established according to the species. The aim of this study was to determine the ideal concentration of eugenol for anesthesia of Zapteryx brevirostris. Four concentrations were tested: 21.25, 42.50, 85.00 and 170.00 mg L-1 (ratio of 1:5 with absolute ethanol). The perfect concentration of eugenol for this species was 85.0 mg L-1 , which enabled up to 300 seconds of work on the fish, without any response to handling. PMID- 30304296 TI - An ovotestis event in the gonochoric sea urchin Loxechinus albus (Echinodermata: Echinoidea). PMID- 30304297 TI - Impaired baroreflex sensitivity and increased systolic blood pressure variability in chronic post-ischemic stroke. AB - OBJECTIVES: Acute post-stroke patients present cardiovascular autonomic dysfunction, which manifests as lower heart rate variability and impaired baroreflex sensitivity. However, few studies performed to date have evaluated cardiovascular autonomic function in chronic post-stroke patients. The aim of this study was to evaluate cardiovascular autonomic modulation in chronic post ischemic stroke patients. METHODS: The seventeen enrolled subjects were divided into a stroke group (SG, n=10, 5+/-1 years after stroke) and a control group (CG, n=7). Non-invasive curves for blood pressure were continuously recorded (Finometer(r)) for 15 minutes while the subject was in a supine position. Heart rate variability and blood pressure variability were analyzed in the time and frequency domains. RESULTS: No differences were observed in systolic and diastolic pressure and heart rate between post-stroke patients and healthy individuals. The SG group had lower indexes for heart rate variability in the time domain (standard deviation of normal to normal R-R intervals, SDNN; variance of normal to normal R-R intervals, VarNN; and root mean square differences of successive R-R intervals, RMSSD) and a lower high-frequency band for heart rate variability than was observed in the CG. Systolic blood pressure variability and the low-frequency band for systolic pressure were higher in post-stroke patients, while the alpha index was lower in the SG than in the CG. CONCLUSION: After ischemic stroke, affected patients present chronically reduced heart rate variability, impaired cardiac vagal modulation, increased systolic blood pressure variability and higher sympathetic vascular modulation along with impaired baroreflex sensitivity, which can increase the risk of cardiovascular events, despite adequate blood pressure control. PMID- 30304298 TI - Underwater endoscopic mucosal resection of serrated adenomas. AB - OBJECTIVES: Serrated polyps, which are considered to be precursors of colorectal carcinoma, include hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. With the exception of hyperplastic polyps, all of these lesions must be removed. This study sought to examine whether underwater endoscopic mucosal resection is a safe and effective technique for treating serrated polyps. METHODS: Cases in which patients were submitted for underwater endoscopic mucosal resection and histologically diagnosed with sessile serrated adenoma were prospectively registered. RESULTS: The median patient age was 54.5 years (range, 48 to 72 years), and the patients included 4 men (28.5%) and 10 women (71.5%). One lesion (6.2%), 10 lesions (62.5%), 1 lesion (6.2%), 3 lesions (18.8%) and 1 lesion (6.2%) were found in the cecum, the ascending colon, the hepatic flexure, the transverse colon and the descending colon, respectively. The median lesion size was 20 mm (range, 10 to 35 mm). Eight lesions (50%) were removed en bloc, and the remaining eight lesions (50%) were removed using a piecemeal technique. None of the cases were complicated by perforation or delayed bleeding. CONCLUSION: Underwater resection could be a feasible, safe and effective alternative for the resection of sessile serrated adenomas. PMID- 30304299 TI - Age and mini-mental state examination score can predict poor-quality spirometry in the elderly: a cross-sectional study. AB - OBJECTIVES: The goal was to identify predictors of poor-quality spirometry in community-dwelling older adults and their respective cutoffs. METHODS: This was a cross-sectional population-based study involving 245 elderly subjects (age>=60 years). The spirometric data were categorized as good or poor quality, and cognitive status was assessed using an adapted version (scaled to have a maximum of 19 points) of the Mini-Mental State Examination. Multivariate analysis was used to assess the association between poor-quality spirometry and sociodemographic, behavioral and health characteristics. The best cutoff points for predicting poor-quality spirometry were evaluated by the receiver operating characteristic curve. RESULTS: In this population, 61 (24.9%) subjects with poor quality spirometry were identified. After multiple logistic regression analysis, only age and Mini-Mental State Examination score were still associated with poor quality spirometry (p<=0.05). The cutoff for the Mini-Mental State Examination score was 15 points, with an area under the receiver operating characteristic curve of 0.628 (p=0.0017), sensitivity of 74.5% and specificity of 49.5%; for age, the cutoff was 78 years, with an area under the receiver operating characteristic curve of 0.718 (p=0.0001), sensitivity of 57.4% and specificity of 79.9%. CONCLUSION: Age and Mini-Mental State Examination score together are good predictors of poor-quality spirometry and can contribute to the screening of community-dwelling older adults unable to meet the minimum quality criteria for a spirometric test. PMID- 30304301 TI - Breaking Paradigms: Students in Perspective. PMID- 30304300 TI - Quality of life after stroke: impact of clinical and sociodemographic factors. AB - OBJECTIVES: The aim of the study was to analyze the impact of ischemic stroke on health-related quality of life (QoL) and associate this event with individuals' clinical and sociodemographic characteristics. METHODS: We investigated the clinical and demographic aspects of stroke patients. The Modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS) and the Stroke Specific Quality of Life Scale (SS-QoL) were used for correlation analysis. RESULTS: Among 131 patients with ischemic stroke, 53.4% of patients presented with moderate to severe disability on the Rankin Scale. According to the SS-QoL, several QoL domains were compromised. QoL was significantly negatively correlated with the values of the Rankin and NIHSS scales, indicating lower QoL among people with worse functional status and greater clinical severity of stroke (p<0.001). The use of orthosis and total anterior circulation infarct subtype of stroke led to a more marked reduction in QoL. CONCLUSION: The present study described an inversely proportional relationship between the severity of stroke, disability and QoL. The use of orthosis also had a negative impact on QoL. Early identification of these factors could promote better interventions for individuals with ischemic stroke, minimizing disabilities and improving QoL. PMID- 30304302 TI - Effect of ductus deferens lavage on the time to achieve azoospermia in patients undergoing vasectomy. AB - OBJECTIVE: To evaluate the effect of normal saline lavage of the distal vas deferens ampulla in patients undergoing vasectomy on the time to achieve azoospermia. METHODS: A prospective randomized study of 60 men divided into two groups, group lavage (GL, n=30) in which distal vas deferens ampulla lavage was performed with 10 ml of normal saline during the vasectomy, and group without lavage (GWL, n=30) in which control patients received only a vasectomy. The patients provided sperm for semen analysis at the 5th, 10th, 15th, 20th and 25th ejaculations. RESULTS: Fifteen participants in GL and 16 in GWL, for a total of 31 patients, were excluded due to not completing the control spermiogram. The tests carried out at the five ejaculations showed immobile spermatozoa in 40 and 85.71%, 66.67 and 78.57%, 93.33 and 85.71%, 86.67 and 71.43%, and 93.33 and 85.71% of participants in GL and GWL, respectively. CONCLUSION: Vas deferens duct lavage with 10 ml of normal saline during vasectomy did not decrease the time required to achieve postoperative azoospermia. PMID- 30304303 TI - The brazilian FRAX model: an introduction. PMID- 30304304 TI - Spinal muscular atrophy 5Q - Treatment with nusinersen. AB - The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient. PMID- 30304305 TI - Erysipelatoid Carcinoma. AB - Erysipelatoid Carcinoma (EC), also known as Inflammatory Metastatic Carcinoma, is a rare form of cutaneous metastasis, secondary to an internal malignancy, more often related to breast cancer. Clinically, the lesion has a well-marked, bound erythematous appearance, much like an infectious process, such as erysipelas and cellulitis, these being the most common differential diagnoses. It is characterized by an acute or subacute appearance with an erythematous plaque, sometimes hot and painful, being more often situated in the primary tumor vicinity, especially in the thorax wall in the region of a mastectomy due to breast cancer. Here we present the case of a 75-year-old patient with ductal infiltrated carcinoma for 3 years, who presented an acute erythematous and infiltrated plaque in the region of a previous mastectomy, with a final diagnosis of EC. PMID- 30304306 TI - Cutaneous lesions caused by the yellow fever vaccine - have you ever seen them? AB - The Yellow Fever virus was isolated in 1927 and the disease is considered endemic and epidemic in tropical regions of South America and Africa, with thousands of new cases reported annually. Several side effects of the vaccine have already been reported. Although reports of skin rash secondary to the vaccine range from 0 to 15%, no image or detailed description of the lesions were found in the literature. Here we describe a rash on a toddler vaccinated to travel. PMID- 30304307 TI - Repair of soft tissue defects of the fingers with medial plantar venous flap. AB - OBJECTIVE: To report the surgical procedures and efficacy of using medial plantar venous flap for the repair of soft tissue defects of the fingers. METHODS: From March 2010 to April 2012, medial plantar venous flaps were harvested to repair the wounds of 31 fingers in 29 cases. Among them, there were 13 middle fingers with defects at the tips in 11 cases, 7 fingers with defects in the dorsal part in 7 cases, and 11 fingers with defects in the finger pulp in 11 cases. The size of the defects ranged from 1.2cm*1.5 cm to 2.5cm * 3.5cm. Medial plantar venous flaps of 1.5cm * 2cm - 3*4 cm were harvested. Full-thickness skin grafts were adopted for the donor areas. RESULTS: All 31 flaps survived, except for 1 flap with arterial crisis and 2 cases with venous crisis. These conditions were timely corrected by secondary anastomosis of artery and vein and the flaps survived. The wounds and the donor areas achieved healing by the first intention. All grafted skins survived. Postoperative follow-up was conducted for 26 fingers in 24 cases for 4-12 months, excluding 5 cases with lost follow-up. The dorsal part of the damaged fingers had normal morphology, and the skin color and texture were similar to those of the normal skin. After the repair of defects in the fingertip and pulp, fingerprints appeared, and the protective sensation was restored. CONCLUSION: The soft tissue defects of the fingers can be satisfactorily repaired with medial plantar venous flap, and little damage is caused to the donor area. This method is proven effective for the repair of soft tissue defects of the fingers. PMID- 30304308 TI - Acute kidney injury and other factors associated with mortality in hiv-infected patients. AB - OBJECTIVE: HIV-related mortality is still high, especially in developed countries. The aim of this study is to investigate factors associated to death in HIV-infected patients. METHODS: This is a cross-sectional study with all HIV adult patients admitted to a tertiary infectious diseases hospital in Fortaleza, Northeast Brazil, from January 2013 to December 2014. Patients were divided into two groups: survivors and non-survivors. Demo-graphical, clinical and laboratory data were compared and a logistic regression was performed in order to investigate risk factors for death. P values <=0.05 were considered statistically significant. RESULTS: A total of 200 patients with mean age of 39 years were including in the study, 69.5% males. Fifteen patients (7.5%) died. Non-survivors presented a higher percentage of males (93.3 vs. 67.3%, p = 0.037). Non-survivors presented AKI (73.3 vs. 10.3%, p < 0.001), liver dysfunction (33.3 vs. 11.5, p = 0.031), dyspnea (73.3 vs. 33.0%, p = 0.002) and disorientation (33.3 vs. 12.4%, p = 0.025) more frequently. Non-survivors also had higher levels of urea (73.8 +/- 52.7vs. 36.1 +/- 29.1 mg/dL, p < 0.001), creatinine (1.98 +/- 1.65 vs. 1.05 +/- 1.07 mg/dL, p < 0.001), aspartate aminotransferase (130.8 vs. 84.8 U/L, p = 0.03), alanine aminotransferase (115.6 vs. 85.4 U/L, p = 0.045) and lactate dehydrogenase (LDH) (1208 vs. 608 U/L, p = 0.012), as well as lower levels of bicarbonate (18.0 +/- 4.7 vs. 21.6 +/- 4.6 mEq/L, p = 0.016) and PCO2 (27.8 +/- 7.7 vs. 33.0 +/- 9.3 mmHg, p = 0.05). In multivariate analysis, disorientation (p = 0.035, OR = 5.523, 95%CI = 1.130 - 26.998), dyspnoea (p = 0.046, OR = 4.064, 95%CI = 1.028 - 16.073), AKI (p < 0.001, OR = 18.045, 95%CI = 4.308 - 75.596) and disseminated histoplasmosis (p = 0.016, OR = 12.696, 95%CI = 1.618 - 99.646) and LDH > 1000 U/L (p = 0.038, OR = 4.854, 95%CI = 1.093 - 21.739) were risk factors for death.]CONCLUSION: AKI and disseminated histoplasmosis (DH) were the main risk factors for death in the studied population. Neurologic and respiratory impairment as well as higher levels of LDH also increased mortality in HIV infected patients. PMID- 30304309 TI - Percutaneous endoscopic debridement and irrigation for thoracic infections. AB - OBJECTIVE: To investigate the safety and efficacy of percutaneous endoscopic debridement and irrigation for thoracic infections and to make an appropriate choice according to the patient's condition. METHODS.: Thirty patients with thoracic infections who received surgical treatment from August 2014 to December2016 were retrospectively analyzed. There were 16 males and 14 females, aged from 41 to 90 years, with an average of 64.4 years. A total of 9 cases were treated with percutaneous endoscopic debridement and irrigation (minimal group), and 21 cases were treated with open debridement in combination with pedicle screw fixation (conventional group). Patients underwent follow-up for 1 month. General condition, operative index, laboratory results, and imaging features were recorded. RESULTS.: Compared with the conventional group, there were more comorbidities in patients in the minimal group (8 cases in the minimal group, 10 cases in the conventional group, P=0.049), shorter hospital stay (10.1 + 2.26 days in the minimal group, 16.1 + 6.81 days in the conventional group, P=0.016), less bleeding volume (383.3 + 229.86ml in the minimal group, 90 + 11.18ml in the conventional group, P=0.000), lower VAS score at discharge (2.9 + 0.93 in the minimal group, 3.9 + 0.91 in the conventional group, P=0.013). There was no spinal instability case in the minimal group, 10 cases in the conventional group, P=0.013. There were significant differences. The C reaction protein prior to operation in the minimal group was 28.4+/-7.50mg/L. Compared with 45.1 + 15.78mg/L in the conventional group, P=0.005, it was lower. CONCLUSIONS.: Percutaneous endoscopic debridement and irrigation are an effective surgery for treatment of thoracic infections, especially suitable for patients with comorbidities and poor general condition. However, for severe infection and spinal instability, we tend to choose open surgery in combination with fixation. PMID- 30304310 TI - Ki-67 expression in mature B-cell neoplasms: a flow cytometry study. AB - OBJECTIVE: Ki-67 is a nuclear protein associated with cellular proliferation in normal or leukemic conditions that can help identify more aggressive diseases and is usually evaluated with immunohistochemistry. The aim of this was to assess Ki 67 expression on mature B-cell neoplasms samples with flow cytometry immunophenotyping. METHOD: After surface staining with CD19 and CD45, intracellular staining for Ki-67 was performed in leukemic mature B-cells. Ki-67 expression was evaluated with flow cytometry. RESULTS: Ki-67 expression was higher in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cases. It was also associated with CD38 mean fluorescence intensity. CONCLUSIONS: Ki-67 expression evaluated by flow cytometry can be a useful tool in the diagnosis of mature B-cell neoplasms. More studies are needed to validate Ki 67 assessment with flow cytometry immunophenotyping. PMID- 30304311 TI - Evaluation of body image, quality of life, tactile sensitivity and pain in women with breast cancer submitted to surgical intervention. AB - OBJECTIVE: Breast cancer is one of the most common types of tumor in the world and the most common among women. There are several treatments for breast cancer; however, the condition often can be accompanied by severe complications in a woman's life. To evaluate and compare body image perception, quality of life, tenderness, and pain in women with breast cancer during preoperative and postoperative periods of 30, 60 and 90 days. MATERIALS AND METHODS: We conducted a prospective longitudinal study. The patients answered the questionnaire "How I relate to my own body", EORTC QLQ-C30 and EORTC QLQ-BR23. We assessed upper limb and breast sensitivity with an esthesiometer. Patients were questioned about the presence and level of pain on a scale of 0 to 10. RESULTS: For body image, it was possible to observe a significant difference between pre and postoperative at 30 days. There were changes in some areas of the EORTC QLQ C30 and EORTC QLQ BR23 questionnaires, such as arm and breast symptoms, social function, constipation, sexual function and satisfaction, among others. For evaluation of breast and axilla sensitivity and assessment of pain, all postoperative periods showed significant differences when compared to the preoperative period. The sensitivity of the inner region of the arm presented no significant change. CONCLUSION: The difference found in the study shows that evaluations on all scales should be done in several periods, using a proper treatment for the changes and individuality of each patient. PMID- 30304312 TI - Religiousness is associated with lower levels of anxiety, but not depression, in medical and nursing students. AB - OBJECTIVES: To evaluate the association between religious and spiritual beliefs, anxiety and depression in medical and nursing students. METHODS: A cross sectional study was carried out with medical and nursing students from a Brazilian university. Students were randomly selected and filled out a questionnaire that contained sociodemographic, religious (Duke Religion Index), spirituality (Self-spirituality rating scale) and mental health - depression and anxiety (Hospital Anxiety and Depression Scale) data. Linear regression models were used to evaluate the association of R/E with mental health, with adjustments for sociodemographic variables. RESULTS: A total of 187 students (90.7%) were included in the study, 56.1% female, an average of 23 years old, and 69% were enrolled in the medical program. Of the students, 29.4% attended religious services once a week or more often, 10.7% had private religious activities once a day or more often, and the indexes of intrinsic religiosity and spirituality were moderate. In the linear regression, adjusted for sociodemographic variables, the religious attendance was the only factor associated with lower levels of anxiety (Beta: -0.178, p=0.026). The other dimensions of religiousness or spirituality were not associated with levels of anxiety and depression. CONCLUSIONS: The present study showed that only the religious attendance was associated with the mental health of the medical and nursing students. These results demonstrate that some students use religious support in an attempt to minimize the negative effects of their university life. This support seems to be more effective when it involves participation in religious social activities in relation to private activities. PMID- 30304313 TI - Benign versus life-threatening causes of pneumatosis intestinalis: differentiating CT features. AB - OBJECTIVE: To assess the diagnostic performance of CT findings in differentiating causes of pneumatosis intestinalis (PI), including benign and life-threatening causes. METHODS: All CT reports containing the word "pneumatosis" were queried from June 1st, 2006 to May 31st, 2015. A total of 42 patients with PI were enrolled (mean age, 63.4 years; 23 males and 19 females) and divided into two groups on based on electronic medical records: a benign group (n=24) and a life threatening group (n=18). Two radiologists reviewed CT images and evaluated CT findings including bowel distension, the pattern of bowel wall enhancement, bowel wall defect, portal venous gas (PVG), mesenteric venous gas (MVG), extraluminal free air, and ascites. RESULTS: CT findings including bowel distension, decreased bowel wall enhancement, PVG, and ascites were more commonly identified in the life-threatening group (all p<0.05). All cases with PVG were included in the life threatening group (8/18 patients, 44.4%). Bowel wall defect, extraluminal free air, and mesenteric venous gas showed no statistical significance between both groups. CONCLUSION: PI and concurrent PVG, bowel distension, decreased bowel wall enhancement, or ascites were significantly associated with life-threatening causes and unfavorable prognosis. Thus, evaluating ancillary CT features when we encountered PI would help us characterize the causes of PI and determine the appropriate treatment option. PMID- 30304314 TI - Relationship of the skin and subcutaneous tissue thickness in the tensiomyography response: a novel ultrasound observational study. AB - BACKGROUND: The aim of the study was to describe and correlate the skin, subcutaneous tissue, and superficial fascia thickness assessed by ultrasonography (US) with the lumbar erector spinae muscles contractile properties evaluated by tensiomyography (TMG). METHODS: A cross-sectional descriptive study with 50 healthy participants was performed. The point of maximum lordosis in the lumbar region of the right erector spinae was evaluated by US and TMG. First, the skin, subcutaneous tissue, and superficial fascia thicknesses (cm) were assessed by US. Second, the five contractile TMG parameters were analyzed from the right erector spinae muscles belly displacement-time curves: maximal radial displacement (Dm), contraction time (Tc), sustain time (Ts), delay time (Td), and half-relaxation time (Tr). Finally, correlation analyses using Pearson (r for parametric data) and Spearman (rs for non-parametric data) coefficients were performed. RESULTS: A strong negative correlation was shown between Dm and subcutaneous tissue thickness (rs=-0.668; P<.001). Furthermore, moderate negative correlations were observed between Dm and skin thickness (r=-0.329; P=0.020) as well as Tr and subcutaneous tissue thickness (rs=-0.369; P=0.008). The rest of the parameters did not show statistically significant correlations (P >.05). CONCLUSION: Therefore, the lumbar erector spinae contractile properties during TMG assessments, especially Dm and Tr, may be widely correlated by the skin and subcutaneous tissue thickness. PMID- 30304315 TI - Platelets volume indexes and cardiovascular risk factors. AB - Obesity, diabetes and hypertension are risk factors for cardiovascular diseases (CVD) because they promote a state of hypercoagulability. It is known that platelets play an important role in the development of atherosclerosis. Recent studies have evaluated platelet volume indexes (PVIs) in individuals with risk factors for CVD to better understand the platelet mechanisms involved in their development. The IVPs indirectly estimate platelet function and are easily obtained from automated hematology analyzers, which provide platelet counts, mean platelet volume (MPV), platelet distribution width (PDW) and the platelet-large cell ratio (P-LCR). The present study aims to review literature studies that investigated the association between PVIs and obesity, diabetes, and arterial hypertension, in order to evaluate its use as a potential subclinical marker of CVD. Studies have shown promising results for MPV, an index that allows for early detection of platelet activation and may be useful in identifying patients before the onset of CVD development so that preventive strategies can be implemented. The PDW, although evaluated by a smaller number of studies, also showed promising results. However, there is still a long way to go in order for the MPV and PDW to be used in clinical practice, since there is still a need for more epidemiological evidence, establishing reference values, and standardizing the way results are presented. PMID- 30304317 TI - Autoimmune Thyroiditis and Depression-Reply. PMID- 30304316 TI - Isoflavones in gynecology. PMID- 30304318 TI - Compressive Lateral Femoral Cutaneous Neuropathy Secondary to Sartorius Muscle Fibrosis. PMID- 30304319 TI - Blistering Distal Dactylitis. PMID- 30304320 TI - Hearing Loss Treatment in Older Adults With Cognitive Impairment: A Systematic Review. AB - Purpose: The purpose of this systematic review was to assess studies of treating hearing loss in older adults with cognitive impairment. Of interest to this review is identifying clinical adaptations that may be used to tailor hearing loss treatment to older adults with cognitive impairment in order to better serve this vulnerable population. Method: A systematic search with controlled vocabulary and key word terms was applied to PubMed, the Cochrane Library, Embase, CINAHL, and PsycINFO. Search concepts included terms related to hearing loss and cognitive impairment. The overall search resulted in 4,945 unique references, 50 of which were eligible for full-text review and 13 of which were included in the final review. Included manuscripts were categorized according to the American Speech-Language-Hearing Association's levels of evidence and the National Institutes of Health Quality Assessment Tools. Results: Only 1 study implemented a randomized controlled trial design to assess cognitive function and behavioral symptoms after treatment with hearing aids. Other quasiexperimental studies evaluated dementia-related symptoms and/or auditory function after treating hearing loss in pre/post research designs. Finally, evidence from case studies suggested that hearing loss treatment is feasible, reduces stressful communication for caregivers, and improves dementia-related behavior problems. Conclusion: Based on the systematic review, evidence suggests that treating hearing loss in persons with cognitive impairment can have benefits to communication and quality of life. Because of the quasi- and nonexperimental nature of most of the evidence found in this review, further studies are necessary to understand the effect of treatment in the context of a variable and progressive disease. PMID- 30304321 TI - Ensuring Optimal Adjustment for Determinations of Institutional Quality. PMID- 30304322 TI - Minding Our Metaphors. PMID- 30304323 TI - Survival-associated alternative splicing signatures in esophageal carcinoma. AB - Alternative splicing (AS), a major mechanism for the enhancement of transcriptome and proteome diversity, has been widely demonstrated to be involved in the full spectrum of oncogenic processes. High-throughput sequencing technology and the rapid accumulation of clinical data sets have provided an opportunity to systemically analyze the association between messenger RNA AS variants and patient clinical outcomes. Here, we compared differentially spliced AS transcripts between esophageal carcinoma (ESCA) and non-tumor tissues, profiled genome-wide survival-associated AS events in 87 patients with esophageal adenocarcinoma (EAC) and 79 patients with esophageal squamous cell carcinoma (ESCC) using The Cancer Genome Atlas (TCGA) RNA-seq data set, and constructed predictive models as well as splicing regulation networks by integrated bioinformatic analysis. A total of 2326 AS events in 1738 genes and 1812 AS events in 1360 genes were determined to be significantly associated with overall survival (OS) of patients in the EAC and ESCC cohorts, respectively, including some essential participants in the oncogenic process. The predictive model of each splice type performed reasonably well in distinguishing good and poor outcomes of patients with esophageal cancer, and values for the area under curve reached 0.942 and 0.815 in the EAC exon skip predictive model and the ESCC alternate acceptor site predictive model, respectively. The splicing regulation networks revealed an interesting correlation between survival-associated splicing factors and prognostic AS genes. In summary, we created prognostic models for patients with esophageal cancer based on AS signatures and constructed novel splicing correlation networks. PMID- 30304324 TI - Financial Burden of Employer-Sponsored High-Deductible Health Plans for Low Income Adults With Chronic Health Conditions. PMID- 30304325 TI - Ensuring Optimal Adjustment for Determinations of Institutional Quality-Reply. PMID- 30304326 TI - Efficacy of a Discharge Educational Strategy vs Standard Discharge Care on Reduction of Vascular Risk in Patients With Stroke and Transient Ischemic Attack: The DESERVE Randomized Clinical Trial. AB - Importance: Despite secondary prevention strategies with proven efficacy, recurrent stroke rates remain high, particularly in racial/ethnic minority populations who are disproportionately affected by stroke. Objective: To determine the efficacy of a culturally tailored skills-based educational intervention with telephone follow-up compared with standard discharge care on systolic blood pressure reduction in a multiethnic cohort of patients with mild/moderate stroke/transient ischemic attack. Design, Setting, and Participants: Randomized clinical trial with 1-year follow-up. Participants were white, black, and Hispanic patients with mild/moderate stroke/transient ischemic attack prospectively enrolled from 4 New York City, New York, medical centers during hospitalization or emergency department visit between August 2012 and May 2016. Through screening of stroke admissions and emergency department notifications, 1083 eligible patients were identified, of whom 256 declined to participate and 275 were excluded for other reasons. Analyses were intention to treat. Interventions: The Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) intervention is a skills-based, culturally tailored discharge program with follow-up calls delivered by a community health coordinator. This intervention was developed using a community engagement approach. Main Outcomes and Measures: The primary outcome was systolic blood pressure reduction at 12 months postdischarge. Results: A total of 552 participants were randomized to receive intervention or usual care (281 women [51%]; mean [SD] age, 64.61 [2.9] years; 180 Hispanic [33%], 151 non-Hispanic white [27%], and 183 non-Hispanic black [33%]). At 1-year follow-up, no significant difference in systolic blood pressure reduction was observed between intervention and usual care groups (beta = 2.5 mm Hg; 95% CI, -1.9 to 6.9). Although not powered for subgroup analysis, we found that among Hispanic individuals, the intervention arm had a clinically and statically significant 9.9 mm Hg-greater mean systolic blood pressure reduction compared with usual care (95% CI, 1.8-18.0). There were no significant differences between arms among non Hispanic white (beta = 3.3; 95% CI, -4.1 to 10.7) and non-Hispanic black participants (beta = -1.6; 95% CI, -10.1 to 6.8). Conclusions and Relevance: Few behavioral intervention studies in individuals who have had stroke have reported clinically meaningful reductions in blood pressure at 12 months, and fewer have focused on a skills-based approach. Results of secondary analyses suggest that culturally tailored, skills-based strategies may be an important alternative to knowledge-focused approaches in achieving sustained vascular risk reduction and addressing racial/ethnic stroke disparities; however, these findings should be tested in future studies. Trial Registration: ClinicalTrials.gov identifier: NCT01836354. PMID- 30304327 TI - Association Between Psoriasis and Sexual and Erectile Dysfunction in Epidemiologic Studies: A Systematic Review. AB - Importance: Sexual health is a major aspect of life. Increasing scientific evidence shows a potential association between psoriasis and sexual dysfunction (SD) and erectile dysfunction (ED). Objective: To evaluate the available scientific evidence regarding epidemiologic associations and treatment outcomes between psoriasis and SD and ED. Evidence Review: Information sources were MEDLINE and Embase databases, using the Scopus search engine. The search was performed on August 25, 2017. Search terms were psoriasis and sexual or sexual dysfunction, and the search was limited to epidemiologic studies published in English answering any of the 4 research questions. Quality was assessed according to the Centre for Evidence-Based Medicine. Findings: Twenty-eight studies representing 52 520 cases of psoriasis and 1 806 022 controls were included for review. Of the 28 studies, 19 were cross-sectional, 3 were clinical trials, 3 were quasi-experimental, 2 were population-based cohort, and 1 was population based case-control. Prevalence of SD and ED ranged from 40.0% to 55.6% and 34.2% to 81.1%, respectively. Two of 2 studies observed an association between psoriasis and SD after adjusting for physical and psychological comorbidities. Five of 8 studies observed an independent association between ED and psoriasis. Among patients with psoriasis, the features that showed the strongest association with SD were anxiety and depression (5 of 5 studies), psoriatic arthritis (3 of 4 studies), and genital psoriasis (5 of 7 studies). Regarding ED, anxiety and depression (2 of 2 studies) and increasing age (3 of 3 studies) showed the strongest association. All 3 clinical trials using biologic drugs showed an improvement in SD compared with placebo. Conclusions and Relevance: Patients with psoriasis have physical and psychological comorbidities that have been associated with a higher risk of SD. In addition, psoriasis may play a role in its development. The presence of anxiety, depression, psoriatic arthritis, genital lesions, and increasing age should raise the awareness of SD. Biologic drugs have demonstrated the improvement of SD in patients with psoriasis. PMID- 30304328 TI - Autoimmune Thyroiditis and Depression. PMID- 30304329 TI - Association of Chronic Kidney Disease With Allopurinol Use in Gout Treatment. AB - Importance: Clinicians are often cautious about use of allopurinol in patients with gout when renal function declines. Objective: To assess the association of allopurinol use in gout with the risk of developing chronic kidney disease stage 3 or higher. Design, Setting, and Participants: A time-stratified propensity score-matched, population-based, prospective cohort study of individuals with newly diagnosed gout who initiated allopurinol (>=300 mg/d) compared with those who did not initiate allopurinol, using the Health Improvement Network (THIN), a United Kingdom general practitioner electronic health records database, was carried out. The data were analyzed using Cox proportional hazards regression. Among adults aged 18 to 89 years with newly diagnosed gout, we propensity score matched 4760 initiators of allopurinol (>=300 mg/d) to the same number of noninitiators of allopurinol, excluding those with chronic kidney disease stage 3 or higher or urate-lowering therapy use before their gout diagnosis. Exposures: Allopurinol initiation at a dose of 300 mg or more per day. Main Outcomes and Measures: Development of chronic kidney disease stage 3 or higher. Results: Of the 4760 allopurinol initiators (3975 men, 785 women) and same number of noninitiators (3971 men, 789 women), 579 and 623, respectively, developed chronic kidney disease stage 3 or higher, with a mean follow-up time of 5 and 4 years, mean age of 57 years, and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 for both groups. Use of allopurinol of at least 300 mg/d was associated with lower risk of developing chronic kidney disease stage 3 or higher compared with nonusers, with a hazard ratio (HR) of 0.87 (95% CI, 0.77-0.97). Allopurinol initiation at less than 300 mg/d was not associated with renal function decline (HR, 1.00; 95% CI, 0.91-1.09). Conclusions and Relevance: In this large cohort, allopurinol initiation of at least 300 mg/d was associated with a lower risk of renal function deterioration. Because allopurinol does not appear to be associated with renal function decline, clinicians should consider evaluating other potential causes when patients with gout experience renal function decline. PMID- 30304330 TI - Long-term Follow-up of Autologous Fat Transfer vs Conventional Breast Reconstruction and Association With Cancer Relapse in Patients With Breast Cancer. AB - Importance: Autologous fat transfer (AFT or fat grafting) has become an invaluable tool for the correction of disfiguring deformities after breast cancer surgery. However, clinical and animal studies have shown conflicting results regarding its oncologic safety. Objective: To determine whether exposure to AFT vs conventional breast reconstruction is associated with increased rates of cancer relapse in patients with breast cancer. Design, Setting, and Participants: This matched cohort study involved retrospective medical record review to identify all patients in a local patient database receiving AFT between 2006 and 2014. Each AFT case was matched with a nonexposed control patient with similar baseline characteristics. The mean (SD) follow-up of patients receiving AFT was 9.3 (4.9) years including 5.0 (1.7) years following AFT. Control patients were followed up for a mean (SD) of 8.6 (1.8) years from the primary surgery. Patients were identified through the local patient database of the Tergooi Hospital in Hilversum, the Netherlands. A total of 287 patients with breast cancer (300 affected breasts) who received AFT for breast reconstruction after cancer were included in the intervention group. Each AFT case was matched with a respective control patient based on age, type of oncologic surgery, tumor invasiveness, and disease stage. In addition, individual AFT-control pairs were selected to have the same locoregional recurrence-free interval at baseline. Data were analyzed between 2016 and 2017. Exposures: Reconstruction with AFT vs conventional breast reconstruction or none. Main Outcomes and Measures: Primary end points were the cumulative incidences of oncologic events in AFT and control patients and their respective hazard ratios. Results: Of the 587 total patients, all were women and the mean age was 48.1 years for the patients undergoing AFT and 49.4 years for the control patients. Eight locoregional recurrences were observed in the treatment group (287 patients) and 11 among the control group (300 patients), leading to an unadjusted hazard ratio of 0.63 (95% CI, 0.25-1.60; P = .33). No increased locoregional recurrence rates were seen in relevant subgroups based on the type of oncological surgery, tumor invasiveness, or pathological stage. In addition, no increased risks with AFT were detected with respect to distant recurrences or breast cancer-specific mortality. Conclusions and Relevance: No significant differences in the locoregional recurrence rates between the AFT and control groups were observed after 5 years of follow-up. These findings confirm the results of previous studies; therefore, clinical evidence suggesting that AFT is associated with increased risk for cancer relapse is still lacking. PMID- 30304331 TI - Using Brain-Based Phenotyping to Improve Discovery in Psychiatry. PMID- 30304333 TI - Analysis of Diagnostic Test Ordering Habits Among Internal Medicine Residents. PMID- 30304332 TI - Impact of carbohydrate substrate complexity on the diversity of the human colonic microbiota. AB - The diversity of the colonic microbial community has been linked with health in adults and diet composition is one possible determinant of diversity. We used carefully controlled conditions in vitro to determine how the complexity and multiplicity of growth substrates influence species diversity of the human colonic microbiota. In each experiment, five parallel anaerobic fermenters that received identical faecal inocula were supplied continuously with single carbohydrates (either arabinoxylan-oligosaccharides (AXOS), pectin or inulin) or with a '3-mix' of all three carbohydrates, or with a '6-mix' that additionally contained resistant starch, beta-glucan and galactomannan as energy sources. Inulin supported less microbial diversity over the first 6 d than the other two single substrates or the 3- and 6-mixes, showing that substrate complexity is key to influencing microbiota diversity. The communities enriched in these fermenters did not differ greatly at the phylum and family level, but were markedly different at the species level. Certain species were promoted by single substrates, whilst others (such as Bacteroides ovatus, LEfSe P = 0.001) showed significantly greater success with the mixed substrate. The complex polysaccharides such as pectin and arabinoxylan-oligosaccharides promoted greater diversity than simple homopolymers, such as inulin. These findings suggest that dietary strategies intended to achieve health benefits by increasing gut microbiota diversity should employ complex non-digestible substrates and substrate mixtures. PMID- 30304334 TI - San Francisco Voters End the Sale of Flavored Tobacco Products Despite Strong Industry Opposition. PMID- 30304335 TI - TIVAN: Tissue-specific cis-eQTL single nucleotide variant annotation and prediction. AB - Summary: Predicting genetic regulatory variants, most of which locate in noncoding genomic regions, still remains a challenge in genetic research. Among all non-coding regulatory variants, cis-eQTL single nucleotide variants (SNVs) are of particular interest for their crucial role in regulating gene expression. Since different gene expression patterns are believed to contribute to the etiologies of different phenotypes, it is desirable to characterize the impact of cis-eQTL SNVs in a context-specific manner. Though computational methods for predicting the potential of variants being pathogenic or deleterious are wellestablished, methods for annotating and predicting cis-eQTL SNVs are underdeveloped. Here, we present TIVAN (TIssue-specific Variant ANnotation and prediction), an ensemble method of decision trees, to predict tissue-specific ciseQTL SNVs. TIVAN is trained based on a comprehensive collection of features including genome-wide genomic and epigenomic profiling data. As a result, TIVAN has been shown to accurately discriminate cis-eQTL SNVs from noneQTL SNVs and perform favorably to other methods by obtaining higher fivefold cross-validation AUC values (CV-AUC) and Leave-One-Chromosome-Out predicted AUC values (LOCO-AUC) across 44 different tissues belonging to 27 different tissue classes. Finally, TIVAN consistently maintains top performance on an independent testing dataset, which includes 7 tissues in 11 studies. Availability and Implementation: TIVAN software is available at https://github.com/lichen-lab/TIVAN. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30304336 TI - Autoimmune Thyroiditis and Depression. PMID- 30304337 TI - Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models. AB - Importance: Schizophrenia and bipolar disorder are severe and complex brain disorders characterized by substantial clinical and biological heterogeneity. However, case-control studies often ignore such heterogeneity through their focus on the average patient, which may be the core reason for a lack of robust biomarkers indicative of an individual's treatment response and outcome. Objectives: To investigate the degree to which case-control analyses disguise interindividual differences in brain structure among patients with schizophrenia and bipolar disorder and to map the brain alterations linked to these disorders at the level of individual patients. Design, Setting, and Participants: This study used cross-sectional, T1-weighted magnetic resonance imaging data from participants recruited for the Thematically Organized Psychosis study from October 27, 2004, to October 17, 2012. Data were reanalyzed in 2017 and 2018. Patients were recruited from inpatient and outpatient clinics in the Oslo area of Norway, and healthy individuals from the same catchment area were drawn from the national population registry. Main Outcomes and Measures: Interindividual differences in brain structure among patients with schizophrenia and bipolar disorder. Voxel-based morphometry maps were computed, which were used for normative modeling to map the range of interindividual differences in brain structure. Results: This study included 218 patients with schizophrenia spectrum disorders (mean [SD] age, 30 [9.3] years; 126 [57.8%] male), of whom 163 had schizophrenia (mean [SD] age, 31 [8.7] years; 105 [64.4%] male) and 190 had bipolar disorder (mean [SD] age, 34 [11.3] years; 79 [41.6%] male), and 256 healthy individuals (mean [SD] age, 34 [9.5] years; 140 [54.7%] male). At the level of the individual, deviations from the normative model were frequent in both disorders but highly heterogeneous. Overlap of more than 2% among patients was observed in only a few loci, primarily in frontal, temporal, and cerebellar regions. The proportion of alterations was associated with diagnosis and cognitive and clinical characteristics within clinical groups. Patients with schizophrenia, on average, had significantly reduced gray matter in frontal regions, cerebellum, and temporal cortex. In patients with bipolar disorder, mean deviations were primarily present in cerebellar regions. Conclusions and Relevance: This study found that group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient. This study presents a workable route toward precision medicine in psychiatry. PMID- 30304338 TI - Long-term Oncological and Functional Outcomes of Chemoradiotherapy Followed by Organ-Sparing Transanal Endoscopic Microsurgery for Distal Rectal Cancer: The CARTS Study. AB - Importance: Treatment of rectal cancer is shifting toward organ preservation aiming to reduce surgery-related morbidity. Short-term outcomes of organ preserving strategies are promising, but long-term outcomes are scarce in the literature. Objective: To explore long-term oncological outcomes and health related quality of life (HRQL) in patients with cT1-3N0M0 rectal cancer who underwent neoadjuvant chemoradiotherapy (CRT) followed by transanal endoscopic microsurgery (TEM). Design, Setting, and Participants: In this multicenter phase II feasibility study, patients with cT1-3N0M0 rectal cancer admitted to referral centers for rectal cancer throughout the Netherlands between February 2011 and September 2012 were prospectively included. These patients were to be treated with neoadjuvant CRT followed by TEM in case of good response. An intensive follow-up scheme was used to detect local recurrences and/or distant metastases. Data from validated HRQL questionnaires and low anterior resection syndrome questionnaires were collected. Data were analyzed from February 2011 to April 2017. Main Outcomes and Measures: The primary study outcome of the study was the number of ypT0-1 specimens by performing TEM. Secondary outcome parameters were locoregional recurrences and HRQL. Results: Of the 55 included patients, 30 (55%) were male, and the mean (SD) age was 64 (39-82) years. Patients were followed up for a median (interquartile range) period of 53 (39-57) months. Two patients (4%) died during CRT, 1 (2%) stopped CRT, and 1 (2%) was lost to follow-up. Following CRT, 47 patients (85%) underwent TEM, of whom 35 (74%) were successfully treated with local excision alone. Total mesorectal excision was performed in 16 patients (4 with inadequate responses, 8 with completion after TEM, and 4 with salvage for local recurrence). The actuarial 5-year local recurrence rate was 7.7%, with 5 year disease-free and overall survival rates of 81.6% and 82.8%, respectively. Health-related quality of life during follow-up was equal to baseline, with improved emotional well-being in patients treated with local excision (mean score at baseline, 72.0; 95% CI, 67.1-80.1; mean score at follow-up, 86.9; 95% CI, 79.2 94.7; P = .001). Major, minor, and no low anterior resection syndrome was experienced in 50%, 28%, and 22%, respectively, of patients with successful organ preservation. Conclusions and Relevance: In early-stage rectal cancer (cT1 3N0M0), CRT enables organ preservation with additional TEM surgery in approximately two-thirds of patients with good long-term oncological outcome and HRQL. This multimodality treatment triggers a certain degree of bowel dysfunction, and one-third of patients still undergo radical surgery and are overtreated by CRT. PMID- 30304339 TI - Osteopathic Evaluation of Urinary Retention Caused by Atypical Presentation of Invasive Cervical Cancer Mimicking Primary Urothelial Tumor. AB - Cancer of the uterine cervix is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers in the United States. Cervical cancer is frequently asymptomatic until it reaches a locally advanced stage. The authors present a case of urinary retention caused by an atypical presentation of invasive cervical cancer mimicking primary urothelial tumor. The patient was evaluated by a multidisciplinary team, with osteopathic structural examination, intraoperative examination, surgical resection, and histopathologic analysis. PMID- 30304340 TI - Purple Urine Bag Syndrome. PMID- 30304341 TI - Treatment of Severe Hailey-Hailey Disease With Apremilast. AB - Importance: Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure. Objective: To determine whether the novel phosphodiesterase-4 inhibitor apremilast is effective in the treatment of HHD. Design, Setting, and Participants: Clinical case series of 4 patients with severe, treatment-resistant HHD at an outpatient clinic in the Department of Dermatology of Nice University Hospital, Nice, France. The patients were treated with apremilast; after the initial titration, the dose was 30 mg, twice daily. Main Outcomes and Measures: Objective clinical response was assessed by the treating dermatologist using the physician global assessment score; recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. Results: Three women and 1 man, with a mean age of 56 years, were treated and followed up for 6 to 10 months. Family history of the disease was noted in 3 (75%) of the cases. The lesions affected the axillary regions (75%), submammary regions (75%), inguinal regions (100%), and back and neck areas (50%). An improvement in the symptoms was reported by all of the patients after a treatment period of 1 month. After 6 months, the improvement of HHD lesions was reported as moderate to almost cleared among the patients. However, 2 patients developed some flares after 6 to 10 months of treatment and stopped apremilast therapy. One of the patients developed uncontrolled diffuse lesions and apremilast was reintroduced, resulting in partial control of her disease. Conclusions and Relevance: Apremilast appears to offer a low-risk therapeutic alternative or adjunct in resistant and severe forms of HHD. A prospective controlled trial with long-term follow-up is required to confirm these preliminary observations. PMID- 30304342 TI - Concatenation of the Moving Window Technique for Auditory-Perceptual Analysis of Voice Quality. AB - Purpose: The purpose of this study is to develop a program to concatenate acoustic vowel segments that were selected with the moving window technique, a previously developed technique used to segment and select the least perturbed segment from a sustained vowel segment. The concatenated acoustic segments were compared with the nonconcatenated, short, individual acoustic segments for their ability to differentiate normal and pathological voices. The concatenation process sometimes created a clicking noise or beat, which was also analyzed to determine any confounding effects. Method: A program was developed to concatenate the moving window segments. Listeners with no previous rating experience were trained and, then, rated 20 normal and 20 pathological voice segments, both concatenated (2 s) and short (0.2 s) for a total of 80 segments. Listeners evaluated these segments on both the Grade, Roughness, Breathiness, Asthenia, and Strain scale (GRBAS; 8 listeners) and the Consensus Auditory-Perceptual Evaluation of Voice (Kempster, Gerratt, Abbott, Barkmeier-Kraemer, & Hillman, 2009) scale (7 listeners). The sensitivity and specificity of these ratings were analyzed using a receiver-operating characteristic curve. To evaluate if there were increases in particular criteria due to the beat, differences between beat and nonbeat ratings were compared using a 2-tailed analysis of variance. Results: Concatenated segments had a higher sensitivity and specificity for distinguishing pathological and normal voices than short segments. Compared with nonbeat segments, the beat had statistically similar increases for all criteria across Consensus Auditory-Perceptual Evaluation of Voice and GRBAS scales, except pitch and loudness. Conclusions: The concatenated moving window method showed improved sensitivity and specificity for detecting voice disorders using auditory perceptual analysis, compared with the short moving window segment. It is a helpful tool for perceptual analytic protocols, allowing for voice evaluation using standardized and automated voice-segmenting procedures. Supplemental Material: https://doi.org/10.23641/asha.7100951. PMID- 30304343 TI - E-Cigarette Use by Young Adult Nonsmokers: Next-Generation Nicotine Dependence? PMID- 30304344 TI - Association Between Unintentional Child Injury in the Home and Parental Implementation of Modifications for Safety. PMID- 30304345 TI - Chiari Type I Malformation Associated With Verbal Fluency Impairment. AB - Purpose: Chiari malformation (CM) Type I is a rare disorder that implies an anomaly in the craniocervical junction, where one or both cerebellar tonsils are displaced below the foramen magnum into the cervical spinal channel. Research carried out regarding cognitive symptoms such as verbal fluency is scarce. The aim of this study was to investigate whether verbal fluency is impaired in a CM clinical group compared to a group of healthy control individuals while controlling for depression and anxiety symptomatology. Method: For this purpose, 101 individuals were enrolled to take part in the study (51 CM, 50 healthy controls). The Controlled Oral Word Association Test (Benton, de Hamsher, & Sivan, 1983) and the Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983) were administered. Results: Results showed significantly lower scores for the CM group in verbal fluency compared to the control group (p < .005). After performing an analysis of covariance to eliminate depression and anxiety symptomatology tendencies, it was observed that verbal fluency could not be predicted by this variable (p > .005). Conclusions: From the results of this study, it can be concluded that people suffering from CM exhibit less verbal fluency than healthy control individuals and that this difference is not caused by depression or anxiety. PMID- 30304347 TI - Omitted Dates of Ethical Approval and Timing of Patient Recruitment. PMID- 30304346 TI - Defining the Value of Treatments of Rare Pediatric Conditions. PMID- 30304348 TI - Risk of Subsequent Cutaneous Melanoma in Moderately Dysplastic Nevi Excisionally Biopsied but With Positive Histologic Margins. AB - Importance: Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins). Objective: To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more. Design, Setting, and Participants: A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The chi2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018. Main Outcomes and Measures: Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins. Results: A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23 5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up. Conclusions and Relevance: This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site. PMID- 30304350 TI - Estimating the Risk of Attempted Suicide Among Sexual Minority Youths: A Systematic Review and Meta-analysis. AB - Importance: Suicide is the second-leading cause of death among adolescents. Sexual minority individuals are at a higher risk of suicide and attempted suicide, but a precise and systematic evaluation of this risk among sexual minority youths has not been documented to our knowledge. Objective: To examine the risk of attempted suicide among sexual minority adolescents, differentiating for each sexual minority group. Data Sources: Electronic databases (PubMed, Embase, and PsycINFO) were searched for articles published through April 30, 2017, with the following search terms: heterosexual, homosexual, bisexual, transgender, adolescents, teens, and attempted suicide. Study Selection: Studies that reported attempted suicide in sexual minority adolescents compared with heterosexual peers were included. Thirty-five studies satisfied criteria for inclusion of 764 records identified. Data Extraction and Synthesis: Pooled analyses were based on odds ratios (ORs), with relevant 95% CIs, weighting each study with inverse variance models with random effects. Risk of publication bias and analysis of heterogeneity through univariable and multivariable meta regressions were also rated. Main Outcomes and Measures: The evaluation of increased odds of attempted suicide among sexual minority youths compared with heterosexual peers. Results: Thirty-five studies reported in 22 articles that involved a total of 2 378 987 heterosexual and 113 468 sexual minority adolescents (age range, 12-20 years) were included in the analysis. Sexual minority youths were generally at higher risk of attempted suicide (OR, 3.50; 95% CI, 2.98-4.12; c2 = 3074.01; P < .001; I2 = 99%). If estimated in each sexual minority group, the OR was 3.71 in the homosexual group (95% CI, 3.15-4.37; c2 = 825.20; P < .001; I2 = 97%) and 4.87 in the bisexual group (95% CI, 4.76-4.98; c2 = 980.02; P < .001; I2 = 98%); transgender youths were described as an individual group in only 1 study, which reported an OR of 5.87 (95% CI, 3.51-9.82). Meta regressions weighted for the study weight highlighted that the presence of young participants (12 years old) was associated with heterogeneity in the bisexual group, whereas the year of sampling was associated with heterogeneity in the whole group when combined with other covariates. Conclusions and Relevance: Our findings suggest that youths with nonheterosexual identity have a significantly higher risk of life-threatening behavior compared with their heterosexual peers. Public awareness is important, and a careful evaluation of supportive strategies (eg, support programs, counseling, and destigmatizing efforts) should be part of education and public health planning. PMID- 30304349 TI - CircRNA_001569 promotes cell proliferation through absorbing miR-145 in gastric cancer. AB - Gastric cancer severely threatens human life, while its pathogenesis is still unclear. The present study was to explore the potential pathogenic mechanism underlying gastric cancer. Real-time PCR was performed to detect the expression of circRNA_001569 and miR-145; western blot was performed to detect the expression of NR4A2. Cell cycle and apoptosis was determined using flow cytometry, and cell viability was determined using Cell counting kit-8 (CCK-8) assay. Luciferase reporter assay was carried out to validate the relationship between miR-145 and NR4A2. Both circRNA_001569 and NR4A2 were overexpressed in tissues and cells of gastric cancer, while miR-145 was down-regulated. Overexpressed circRNA_001569 significantly increased cell viability, and decreased cell apoptosis, while down-regulated circRNA_001569 dramatically decreased cell viability and promoted cell apoptosis. CircRNA_001569 regulated the expression of miR-145, the effect of pcDNA-circRNA_001569 was abolished by miR-145 mimic, and the effect of si-circRNA_001569 was abolished by miR-145 inhibitor. MiR-145 targets NR4A2 to regulate its expression. Overexpressed miR 145 suppressed cell viability and promoted cell apoptosis. Taken together, the present study indicated that overexpressed circRNA_001569 promoted cell viability of gastric cancer through suppressing the expression of miR-145, which was mediated by NR4A2. The research will provide great theoretical basis for further clinical diagnosis and therapy. PMID- 30304351 TI - Observation of Moderately Dysplastic Nevi With Positive Margins: Are We There Yet? PMID- 30304352 TI - Hyperpigmented Macule on the Palm and Diminished Sensation. PMID- 30304354 TI - A Promising Skills-Based Intervention to Reduce Blood Pressure in Individuals With Stroke and Transient Ischemic Attack. PMID- 30304353 TI - Receipt of Overlapping Opioid and Benzodiazepine Prescriptions Among Veterans Dually Enrolled in Medicare Part D and the Department of Veterans Affairs: A Cross-sectional Study. AB - Background: Overlapping use of opioids and benzodiazepines is associated with increased risk for overdose. Veterans receiving medications concurrently from the U.S. Department of Veterans Affairs (VA) and Medicare may be at higher risk for such overlap. Objective: To assess the association between dual use of VA and Medicare drug benefits and receipt of overlapping opioid and benzodiazepine prescriptions. Design: Cross-sectional. Setting: VA and Medicare. Participants: All veterans enrolled in VA and Medicare Part D who filled at least 2 opioid prescriptions in 2013 (n = 368 891). Measurements: Outcomes were the proportion of patients with a Pharmacy Quality Alliance (PQA) measure of opioid benzodiazepine overlap (>=2 filled prescriptions for benzodiazepines with >=30 days of overlap with opioids) and the proportion of patients with high-dose opioid-benzodiazepine overlap (>=30 days of overlap with a daily opioid dose >120 morphine milligram equivalents). Augmented inverse probability weighting regression was used to compare these measures by prescription drug source: VA only, Medicare only, or VA and Medicare (dual use). Results: Of 368 891 eligible veterans, 18.3% received prescriptions from the VA only, 30.3% from Medicare only, and 51.4% from both VA and Medicare. The proportion with PQA opioid benzodiazepine overlap was larger for the dual-use group than the VA-only group (23.1% vs. 17.3%; adjusted risk ratio [aRR], 1.27 [95% CI, 1.24 to 1.30]) and Medicare-only group (23.1% vs. 16.5%; aRR, 1.12 [CI, 1.10 to 1.14]). The proportion with high-dose overlap was also larger for the dual-use group than the VA-only group (4.7% vs. 2.3%; aRR, 2.23 [CI, 2.10 to 2.36]) and Medicare-only group (4.7% vs. 2.9%; aRR, 1.06 [CI, 1.02 to 1.11]). Limitation: Data are from 2013 and cannot capture medications purchased without insurance; unmeasured confounding may remain in this cross-sectional study. Conclusion: Among a national cohort of veterans dually enrolled in VA and Medicare, receiving prescriptions from both sources was associated with greater risk for receiving potentially unsafe overlapping prescriptions for opioids and benzodiazepines. Primary Funding Source: U.S. Department of Veterans Affairs. PMID- 30304355 TI - LION LBD: a Literature-Based Discovery System for Cancer Biology. AB - Motivation: The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-Based Discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD. Results: We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections. Availability: The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page http://lbd.lionproject.net. Supplementary information: Supplementary information is available at Bioinformatics online. PMID- 30304356 TI - Google Trends as a Tool for Evaluating Public Interest in Facial Cosmetic Procedures. AB - Background: The utility of Google Trends (GT) in analyzing worldwide and regional patient interest for plastic surgery procedures is becoming invaluable to plastic surgery practices. GT data may offer practical information to plastic surgeons pertaining to seasonal and geographic trends in interest in facial cosmetic procedures. Objective: The authors sought to analyze geographic and temporal trends between GT search volumes and US surgery volumes using univariate analysis. Methods: The "related queries" feature of GT generated potential search terms. GT data were compiled for cheek implants, mentoplasty, otoplasty, blepharoplasty, rhytidectomy, forehead lift, hair transplantation, lip augmentation, lip reduction, platysmaplasty, and rhinoplasty from January 2004 to December 2017. Annual volumes for respective procedures were obtained from annual statistics reports of the American Society of Plastic Surgeons (ASPS) from 2006 to 2017 and American Society of Aesthetic Plastic Surgery (ASAPS) from 2004 to 2017. Results: Geographical and temporal variations in search volume were detected during the study. Search volume trends that correlated significantly with both ASPS and ASAPS surgery volume trends were: "eyelid plastic surgery" (ASPS R2 = 0.336, P = 0.048; ASAPS R2 = 0.661, P = 0.001); "facelift" (ASPS R2 = 0.767, P <= 0.001; ASAPS R2 = 0.767, P = 0.001); "lip injections" (ASPS R2 = 0.539, P = 0.007; ASAPS R2 = 0.461, P = 0.044); and "rhinoplasty surgery" (ASPS R2 = 0.797, P <= 0.001; ASAPS R2 = 0.441, P = 0.01). Several search terms demonstrated no significant relationships or were significant with only one database. Conclusions: GT may provide a high utility for informing plastic surgeons about the interest expressed by our patient population regarding certain cosmetic search terms and procedures. GT may represent a convenient tool for optimizing marketing and advertising decisions. PMID- 30304357 TI - Risk score model for predicting complications in patients undergoing ventricular tachycardia ablation: insights from the National Inpatient Sample database. AB - Aims: Outcome data on ventricular tachycardia (VT) ablation has been limited to few experienced centres. We sought to identify complication rates, predictors, and create a risk score model for predicting complications in patients from real world data. Methods and results: A total of 25 451 patients undergoing VT ablation from year 2006 to 2013 were identified from the National Inpatient Sample (NIS) database. The whole cohort was randomly divided into derivation cohort to derive the model and validation cohort to validate the model. Multivariate predictors of any complication were identified using regression model. Each predictor was assigned a risk score and each patient was assigned to one of the four groups (risk score in parenthesis) based on total combined risk score: Group 0 (0), Group 1 (1-5), Group 2 (6-10), and Group 3 (>11). The rate of 'any complication' and 'in-hospital mortality' in whole cohort was 14.7% and 2.8%, respectively. The predictors of any complication include chronic kidney disease, coagulopathy, chronic liver disease, stroke (cerebrovascular accident), emergency procedure, age >= 65 years, coronary artery disease, peripheral vascular disease, and female gender. There was a significant increase in complication rate in a linear fashion as the risk score increased. The incidence of any complications increased from 2.7% in Group 0 to 31% in Group 3. The risk score model performed well in predicting complications associated with VT ablation. Conclusion: Patients with higher risk scores have significant increase in any complication and in-hospital mortality from VT ablation. The simple risk score model can help to risk stratify patients prior to VT ablation. PMID- 30304358 TI - Using Quality Improvement to Promote Clinical Trials of Emergency Trauma Therapies. PMID- 30304359 TI - Minding Our Metaphors-Reply. PMID- 30304360 TI - Why Should Young Aesthetic Plastic Surgeons Care About Aesthetic Medicine? AB - Young aesthetic surgeons may wonder, "why care about aesthetic medicine?" The answered is based on the "Five Principles" of aesthetic medicine: patient acquisition, patient retention, patient optimization, patient education, and patient conversion. The explosion in new nonsurgical technologies and treatments combined with patients' demands behoove young plastic surgeons to look at incorporating aesthetic medicine into their practice to help them grow and deliver the best results possible. Beyond injectables, nonsurgical treatments like fat reduction and skin care can help acquire new patients when a growing surgical practice offers diverse services with a range of price points. PMID- 30304364 TI - Dynamic Assessment of Narratives Among Navajo Preschoolers. AB - Purpose: This study examined whether the Predictive Early Assessment of Reading and Language (PEARL), a dynamic assessment of narratives that measures language comprehension and production, accurately classifies Navajo preschoolers with typically developing (TD) language or with language impairment (LI). Method: Ninety 4- and 5-year-old Navajo preschoolers were identified as having LI or are TD (n = 45 each) via a 5-measure battery: parent report, teacher report, English narrative, independent educational plan, and the Clinical Evaluation of Language Fundamental Preschool-Second Edition (Wiig, Secord, & Semel, 2004). Children completed a PEARL pretest, a narrative mediation phase providing principles of narrative structure, and a PEARL posttest. A modifiability score reflected responsiveness to mediation. Results: The PEARL pretest and posttest each distinguished children with LI versus TD children with 89% accuracy; modifiability scores identified children with 100% accuracy. The PEARL story grammar subtest at pretest and posttest best distinguished LI versus TD. A revised cutoff score on the PEARL pretest decreased the diagnosis of TD children as having LI; the standard PEARL posttest cutoff was retained. Conclusion: The PEARL is a promising assessment for accurately differentiating Navajo preschool children with LI from those with TD language, particularly with a revised pretest cutoff score. PMID- 30304363 TI - Inappropriate Statistical Analysis and Reporting in Medical Research: Perverse Incentives and Institutional Solutions. PMID- 30304365 TI - Researcher Requests for Inappropriate Analysis and Reporting: A U.S. Survey of Consulting Biostatisticians. AB - Background: Inappropriate analysis and reporting of biomedical research remain a problem despite advances in statistical methods and efforts to educate researchers. Objective: To determine the frequency and severity of requests biostatisticians receive from researchers for inappropriate analysis and reporting of data during statistical consultations. Design: Online survey. Setting: United States. Participants: A randomly drawn sample of 522 American Statistical Association members self-identifying as consulting biostatisticians. Measurements: The Bioethical Issues in Biostatistical Consulting Questionnaire soliciting reports about the frequency and perceived severity of specific requests for inappropriate analysis and reporting. Results: Of 522 consulting biostatisticians contacted, 390 provided sufficient responses: a completion rate of 74.7%. The 4 most frequently reported inappropriate requests rated as "most severe" by at least 20% of the respondents were, in order of frequency, removing or altering some data records to better support the research hypothesis; interpreting the statistical findings on the basis of expectation, not actual results; not reporting the presence of key missing data that might bias the results; and ignoring violations of assumptions that would change results from positive to negative. These requests were reported most often by younger biostatisticians. Limitations: The survey provides information on the reported frequency of inappropriate requests but not on how such requests were handled or whether the requests reflected researchers' maleficence or inadequate knowledge about statistical and research methods. In addition, other inappropriate requests may have been made that were not prespecified in the survey. Conclusion: This survey suggests that researchers frequently make inappropriate requests of their biostatistical consultants regarding the analysis and reporting of their data. Understanding the reasons for these requests and how they are handled requires further study. Primary Funding Source: U.S. Department of Health and Human Services. PMID- 30304366 TI - Smoking Trends and Lung Cancer Mortality: The Good, the Bad, and the Ugly. PMID- 30304367 TI - MetaOmics: Analysis Pipeline and Browser-based Software Suite for Transcriptomic Meta-Analysis. AB - Summary: The rapid advances of omics technologies have generated abundant genomic data in public repositories and effective analytical approaches are critical to fully decipher biological knowledge inside these data. Meta-analysis combines multiple studies of a related hypothesis to improve statistical power, accuracy and reproducibility beyond individual study analysis. To date, many transcriptomic meta-analysis methods have been developed, yet few thoughtful guidelines exist. Here, we introduce a comprehensive analytical pipeline and browser-based software suite, called MetaOmics, to meta-analyze multiple transcriptomic studies for various biological purposes, including quality control, differential expression analysis, pathway enrichment analysis, differential co-expression network analysis, prediction, clustering and dimension reduction. The pipeline includes many public as well as > 10 in-house transcriptomic meta-analytic methods with data-driven and biological-aim-driven strategies, hands-on protocols, an intuitive user interface and step-by-step instructions. Key words: gene expression, meta-analysis, omics data integration, Graphical User Interface (GUI), R Shiny. Availability: MetaOmics is freely available at https://github.com/metaOmics/metaOmics. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304369 TI - RiboProP: A Probabilistic Ribosome Positioning Algorithm for Ribosome Profiling. AB - Motivation: Ribosome profiling has been widely used to study translation in a genome-wide fashion. It requires deep sequencing of ribosome protected mRNA fragments followed by mapping of fragments to the reference genome. For applications such as identification of ribosome pausing sites, it is not enough to map a fragment to a given gene, but the exact position of the ribosome represented by the fragment must be identified for each mRNA fragment. The assignment of the correct ribosome position is complicated by the broad length distribution of the ribosome protected fragments caused by the known sequence bias of micrococcal nuclease (MNase), the most widely used nuclease for digesting mRNAs in bacteria. Available mapping algorithms suffer from either MNase bias or low accuracy in characterizing the ribosome pausing kinetics. Results: In this paper, we introduce a new computational method for mapping the ribosome protected fragments to ribosome locations. We first develop a mathematical model of the interplay between MNase digestion and ribosome protection of the mRNAs. We then use the model to reconstruct the ribosome occupancy profile on a per gene level. We demonstrate that our method has the capability of mitigating the sequence bias introduced by MNase and accurately locating ribosome pausing sites at codon resolution. We believe that our method can be broadly applied to ribosome profiling studies on bacteria where codon resolution is necessary. Availability: Source code implementing our approach can be downloaded under GPL3 license at http://bioserv.mps.ohio-state.edu/RiboProP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304368 TI - Statins and Multiple Noncardiovascular Outcomes: Umbrella Review of Meta-analyses of Observational Studies and Randomized Controlled Trials. AB - Background: Many effects of statins on non-cardiovascular disease (non-CVD) outcomes have been reported. Purpose: To evaluate the quantity, validity, and credibility of evidence regarding associations between statins and non-CVD outcomes and the effects of statins on these outcomes. Data Sources: MEDLINE and EMBASE (English terms only, inception to 28 May 2018). Study Selection: Meta analyses (published in English) of observational studies and of randomized controlled trials (RCTs) that examined non-CVD outcomes of statin intake. Data Extraction: Two investigators extracted data from meta-analyses and individual studies. Credibility assessments based on summary effect sizes from a random effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance, and credibility ceilings were devised to classify evidence. Data Synthesis: This review explored 278 unique non-CVD outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of RCTs. For observational studies, no convincing (class I) evidence, 2 highly suggestive (class II) associations (decreased cancer mortality in patients with cancer and decreased exacerbation in patients with chronic obstructive pulmonary disease), 21 suggestive (class III) associations, and 42 weak (class IV) associations were identified. One outcome from the RCTs (decreased all-cause mortality in patients with chronic kidney disease) attained a sufficient amount of evidence with no hints of bias. For adverse events, observational studies showed suggestive evidence that statins increase the risk for diabetes and myopathy. Among the RCTs, no statistically significant effects were found on myopathy, myalgia, or rhabdomyolysis. Limitations: Studies with relevant data and outcomes not included in the meta-analyses may have been missed. Credibility assessments relied on several assumptions and arbitrary thresholds. Conclusion: The absence of convincing evidence of an association between statins and non-CVD outcomes supports leaving the current recommendations unchanged. Primary Funding Source: None. PMID- 30304370 TI - Pisces: An Accurate and Versatile Variant Caller for Somatic and Germline Next Generation Sequencing Data. AB - Motivation: Next-Generation Sequencing (NGS) technology is transitioning quickly from research labs to clinical settings. The diagnosis and treatment selection for many acquired and autosomal conditions necessitate a method for accurately detecting somatic and germline variants. Results: We have developed Pisces, a rapid, versatile and accurate small variant calling suite designed for somatic and germline amplicon sequencing applications. Accuracy is achieved by four distinct modules, each incorporating a number of novel algorithmic strategies. Availability: Pisces is distributed under an open source license and can be downloaded from https://github.com/Illumina/Pisces. Pisces is available on the BaseSpaceTM SequenceHub. It is distributed on Illumina sequencing platforms such as the MiSeqTM and is included in the PraxisTM Extended RAS Panel test which was recently approved by the FDA. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30304371 TI - The association of Inflammatory Bowel diseases with autoimmune disorders: a population-based report from the epi-IIRN. AB - Introduction: There are conflicting data on the association between inflammatory bowel diseases (IBD) and autoimmunity disorders. The aim of this study was to explore this association including the effect of medications on this association. Methods: We utilized health administrative data collected by 3 of 4 Israel's Health Maintenance Organizations (HMO) covering 52% of the population of Israel. We explored the prevalence of the following autoimmune disorders: Insulin Dependent Diabetes Mellitus (IDDM), psoriasis, Sjogren syndrome, celiac, systemic lupus erythematosus (SLE), primary sclerosis cholangitis (PSC) and autoimmune thyroiditis, among all IBD patients versus non-IBD controls. Case ascertainment was determined according to validated computerized algorithms. Results: 12,625 IBD patients were compared to 12,625 controls. A total of 1,395 (11.1%) IBD patients had at least one autoimmune disease compared with 740 (5.9%) of non-IBD controls (OR 95%CI=1.99 (1.81-2.19); P<0.05); all autoimmune diseases, except for thyroiditis, were more prevalent among IBD patients. Adjusted for confounding variables, anti-TNF medications were associated with a higher prevalence of psoriasis (54 (5.7%) in IBD vs 177 (4.1%) in controls; OR 95%CI=1.50 (1.07-2.08); P<0.05) but lower prevalence of Sjogren (1 (0.1%) vs. 39 (0.9%); OR 95%CI=0.13 (0.02-0.94); P<0.05) and celiac disease (11 (1.2%) vs. 68 (1.6%); OR 95%CI=0.51 (0.27-0.99); P<0.05). Thiopurines and 5ASA were not associated with any autoimmune disorder. Conclusion: IBD is associated with all autoimmune diseases explored here except for thyroiditis. Anti-TNF users have a higher prevalence of psoriasis, and lower prevalence of Sjogren and celiac disease. PMID- 30304373 TI - TEPIC 2 - An extended framework for transcription factor binding prediction and integrative epigenomic analysis. AB - Summary: Prediction of transcription factor (TF) binding from epigenetics data and integrative analysis thereof are challenging. Here we present TEPIC 2 a framework allowing for fast, accurate and versatile prediction and analysis of TF binding from epigenetics data: it supports 30 species with binding motifs, computes TF gene scores up to two orders of magnitude faster than before due to improved implementation, and offers easy-to-use machine learning pipelines for integrated analysis of TF binding predictions with gene expression data allowing the identification of important TFs. Availability and Implementation: TEPIC is implemented in C++, R, and Python. It is freely available at https://github.com/SchulzLab/TEPIC and can be used on Linux based systems. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304372 TI - Mitochondrial biology and prostate cancer ethnic disparity. AB - Prostate cancer remains the second most prevalent cancer in men. Its incidence, progression and mortality profiles vary significantly by race and ethnicity, with African-American men having the highest incidence rate and mortality rate in the world. Although these disparities can be partially explained by socioeconomic factors, the underlying molecular causes are complex and require careful research. A considerable amount of literature exists, supporting the association between mitochondrial health and the incidence, aggression and risk of prostate cancer. Genetic alterations in mitochondrial DNA are frequent in prostate cancer; therefore, the resulting mitochondrial dysfunction and metabolic dysregulation may contribute to or indicate oncogenesis. Many of the prominent features of cancer cells are also closely related to mitochondrial functions, such as resistance to apoptosis, excess reactive oxygen species production and altered oxidative phosphorylation. In addition, prostate cancer ethnic disparity is influenced by environmental and lifestyle factors, which involves differences in mitochondrial metabolism and retrograde signaling events. PMID- 30304374 TI - Atrial Fibrillation and Mortality Risk: Seeing the Big Picture. PMID- 30304375 TI - Changing Nonstuttering Preschool Children's Stuttering Attitudes. AB - Purpose: Negative or uninformed stuttering attitudes proliferate among the general public, and bourgeoning research has shown that such attitudes might emerge as early as the preschool years. Much remains unknown about young children's stuttering attitudes, and conclusive recommendations to improve attitudes toward stuttering have yet to be advanced. This study sought to determine the effect of a new educational program on improving stuttering attitudes among preschool children using objective measures. Method: Thirty-seven preschool children learned about stuttering and sensitive peer interactions by participating in the newly developed Attitude Change and Tolerance program. The program teaches children about human differences with an emphasis on stuttering and how to interact with people who stutter. Children's stuttering attitudes were measured using the Public Opinion Survey of Human Attributes-Stuttering/Child (Weidner & St. Louis, 2014) before and after the program. Results: Pre-post comparisons showed statistically significant improvements in children's overall stuttering attitudes. In particular, children demonstrated gains relative to their perceptions of and reactions toward people who stutter. Conclusion: This study provides empirical evidence that young children's stuttering attitudes can be improved using the Attitude Change and Tolerance program. In addition, it supports previous research that negative stuttering attitudes emerge as early as preschool. PMID- 30304376 TI - Chemoradiotherapy and Local Excision for Organ Preservation in Early Rectal Cancer-The End of the Beginning? PMID- 30304377 TI - Discrimination of Odors Associated With Conspecific and Heterospecific Frass by Sibling Species Dendroctonus frontalis (Coleoptera: Curculionidae: Scolytinae) and Dendroctonus mesoamericanus (Coleoptera: Curculionidae: Scolytinae). AB - In the Central American region, the aggressive, sibling bark beetles Dendroctonus frontalis Zimmermann (Coleoptera: Curculionidae: Scolytinae) and Dendroctonus mesoamericanus Armendariz-Toledano & Sullivan (Coleoptera: Curculionidae: Scolytinae) commonly colonize pines concurrently, and in nature they avoid heterospecific pairing, although it can be produced in the lab. We performed walking arrestment bioassays in the lab to examine the capacity of both sexes of both species to discriminate odors from frass expelled from gallery entrances of either solitary females or conspecific pairs of either species. Males of both species strongly preferred odors of frass from solitary, conspecific females over those of heterospecific females or pairs of either species. Female D. frontalis did not discriminate among these frass categories, whereas female D. mesoamericanus preferred frass of conspecific females. In gas chromatography electroantennographic detection and gas chromatography-mass spectrometry analyses, we determined that males of both species could sense a nearly identical spectrum of approximately 16 host- and beetle-produced compounds present in frass of females of one or both species. Only two of these compounds, endo-brevicomin and ipsdienol, which were present in frass of female D. mesoamericanus and pairs of either species but absent in frass of solitary D. frontalis females, qualitatively distinguished these categories. Several known attractants and synergists for either species declined in concentration postpairing. Our results complement earlier research and indicate how semiochemical composition and concentration in frass might mediate male discrimination of attack sites of conspecific, unpaired females. Furthermore, our data indicate that semiochemical responses for walking females differ from those of males and between species. PMID- 30304378 TI - A novel approach for drug response prediction in cancer cell lines via network representation learning. AB - Motivation: Prediction of cancer patient's response to therapeutic agent is important for personalized treatment. Because experimental verification of reactions between large cohort of patients and drugs is time-intensive, expensive, and impractical, preclinical prediction model based on large-scale pharmacogenomic of cancer cell line is highly expected. However, most of the existing computational studies are primarily based on genomic profiles of cancer cell lines while ignoring relationships among genes and failing to capture functional similarity of cell lines. Results: In this study, we present a novel approach named NRL2DRP, which integrates protein-protein interactions and captures similarity of cell lines' functional contexts, to predict drug responses. Through integrating genomic aberrations and drug responses information with protein-protein interactions, we construct a large response related network, where the neighborhood structure of cell line provides a functional context to its therapeutic responses. Representation vectors of cell lines are extracted through network representation learning method, which could preserve vertices' neighborhood similarity and serve as features to build predictor for drug responses. The predictive performance of NRL2DRP is verified by cross-validation on GDSC dataset and methods comparison, where NRL2DRP achieves AUC > 79% for half drugs and outperforms previous methods. The validity of NRL2DRP is also supported by its effectiveness on uncovering accurate novel relationships between cell lines and drugs. Lots of newly predicted drug responses are confirmed by reported experimental evidences. Availability: The code and documentation are available on https://github.com/USTC-HIlab/NRL2DRP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304380 TI - Editor's Note. PMID- 30304379 TI - PrecursorFinder: a customized biosynthetic precursor explorer. AB - Summary: Synthetic biology has a great potential to produce high value pharmaceuticals, commodities or bulk chemicals. However, many biosynthetic target molecules have no defined or predicted biosynthetic pathways. Biosynthetic precursors are crucial to create biosynthetic pathways. Thus computer-assisted tools for precursor identification are urgently needed to develop novel metabolic pathways. To this end, we present PrecursorFinder, a computational tool that explores biosynthetic precursors for the query target molecules using chemical structure, similarity as well as MCS (maximum common substructure). This platform comprises more than 60,000 compounds biosynthesized for being promising precursors, which are extracted from >500,000 scientific literatures and manually curated by more than 100 people over the past 8 years. The PrecursorFinder could speed up the process of biosynthesis research and make synthetic biology or metabolic engineering more efficient. Availability: PrecursorFinder is available at: http://www.rxnfinder.org/precursorfinder/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304381 TI - Autoimmune Thyroiditis and Depression. PMID- 30304383 TI - Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. AB - Aims: Long noncoding RNAs (lncRNAs) are involved in the regulation of vascular smooth muscle cells and cardiovascular pathology. However, the contribution of lncRNAs to pulmonary hypertension (PH) remains largely unknown. The over proliferation of pulmonary artery smooth muscle cells (PASMCs) causes pulmonary arterial smooth muscle hypertrophy and stenosis of the pulmonary vascular lumen, resulting in PH. Here, we investigated the biological role of a novel lncRNA, Hoxa cluster antisense RNA 3 (Hoxaas3), in the regulation of cell proliferation in PH. Methods and results: Hoxaas3 was upregulated in the lung vasculature of hypoxic mice and in PASMCs under hypoxic conditions. Histone H3 Lysine 9 acetylation of Hoxaas3 promoted gene expression. Moreover, high expression of Hoxaas3 was associated with cell proliferation and modulated cell cycle distribution by upregulating Homeobox a3 at the mRNA and protein levels. Conclusions: The present study defined the role and mechanism of action of Hoxaas3 in the regulation of cell proliferation in PH, which should facilitate the development of new therapeutic strategies for the treatment of this disease. PMID- 30304384 TI - Unrecognized Myocardial Infarction and Unrecognized Cardiovascular Risk. PMID- 30304382 TI - Weight Bias Internalization and Long-Term Weight Loss in Patients With Obesity. AB - Background: The relationship between weight bias internalization (WBI) and long term weight loss is largely unknown. Purpose: To determine the effects of weight loss on WBI and assess whether WBI impairs long-term weight loss. Methods: One hundred thirty-three adults with obesity completed the Weight Bias Internalization Scale (WBIS) at baseline, after a 14-week lifestyle intervention in which they lost >=5 per cent of initial weight, and at weeks 24 and 52 of a subsequent randomized controlled trial (RCT) for weight-loss maintenance (66 weeks total). Linear mixed models were used to examine the effects of weight loss on WBIS scores and the effects of baseline WBIS scores on weight change over time. Logistic regression was used to determine the effects of baseline WBIS scores on achieving >=5 and >=10 per cent weight loss. Results: Changes in weight did not predict changes in WBIS scores. Baseline WBIS scores predicted reduced odds of achieving >=5 and >=10 per cent weight loss at week 24 of the RCT (p values < .05). At week 52, the interaction between participant race and WBIS scores predicted weight loss (p = .046) such that nonblack (but not black) participants with higher baseline WBIS scores had lower odds of achieving >=10 per cent weight loss (OR = 0.38, p = .01). Baseline WBIS scores did not significantly predict rate of weight change over time. Conclusions: Among participants in a weight loss maintenance trial, WBI did not change in relation to changes in weight. More research is needed to clarify the effects of WBI on long-term weight loss and maintenance across race/ethnicity. Clinical trials registration: ClinicalTrials.gov identifier NCT02388568. PMID- 30304385 TI - CDK4/6 inhibitors as neoadjuvant treatment in breast cancer - what can we learn? PMID- 30304386 TI - Behavior Change Techniques and Their Mechanisms of Action: A Synthesis of Links Described in Published Intervention Literature. AB - Background: Despite advances in behavioral science, there is no widely shared understanding of the "mechanisms of action" (MoAs) through which individual behavior change techniques (BCTs) have their effects. Cumulative progress in the development, evaluation, and synthesis of behavioral interventions could be improved by identifying the MoAs through which BCTs are believed to bring about change. Purpose: This study aimed to identify the links between BCTs and MoAs described by authors of a corpus of published literature. Methods: Hypothesized links between BCTs and MoAs were extracted by two coders from 277 behavior change intervention articles. Binomial tests were conducted to provide an indication of the relative frequency of each link. Results: Of 77 BCTs coded, 70 were linked to at least one MoA. Of 26 MoAs, all but one were linked to at least one BCT. We identified 2,636 BCT-MoA links in total (mean number of links per article = 9.56, SD = 13.80). The most frequently linked MoAs were "Beliefs about Capabilities" and "Intention." Binomial test results identified up to five MoAs linked to each of the BCTs (M = 1.71, range: 1-5) and up to eight BCTs for each of the MoAs (M = 3.63, range: 1-8). Conclusions: The BCT-MoA links described by intervention authors and identified in this extensive review present intervention developers and reviewers with a first level of systematically collated evidence. These findings provide a resource for the development of theory-based interventions, and for theoretical understanding of intervention evaluations. The extent to which these links are empirically supported requires systematic investigation. PMID- 30304387 TI - Community dynamics in a nitrate-reducing microbial consortium cultivated with p alkylated vs. non-p-alkylated aromatic compounds. AB - In this study, we established the nitrate-reducing, aromatic compound-degrading enrichment culture pMB18. Its community structure was controlled by the aromatic substrate applied. In the presence of a p-alkylated substrate, microorganisms related to Sulfuritalea, Ignavibacterium and Comamonadaceae were abundant. Non-p alkylated structural analogues promoted the enrichment of Azoarcus, which was probably favored by the excretion of nitrite. The analysis of the bamA gene, which is a functional marker for anaerobic aromatic compound degradation, as well as a differential abundance analysis suggested the involvement of Sulfuritalea and Comamonadaceae in the degradation of p-alkylated substrates. Members of the genus Azoarcus were assumed to be the key players for the degradation of the non p-alkylated substrates. A gene cluster encoding a putative 4-methylbenzoyl-CoA reductase, which is supposed to be specific for the dearomatization of p alkylated benzoyl-CoA intermediates, was detected in culture pMB18 dominated by Sulfuritalea, Ignavibacterium and Comamonadaceae, but not in an Azoarcus dominated culture. This study allowed insight into a microbial community, whose composition was guided by the aromatic substrate applied. PMID- 30304388 TI - Serpina3n, Dominantly Expressed in Female Osteoblasts, Suppresses the Phenotypes of Differentiated Osteoblasts in Mice. AB - It is well known that sex differences exist concerning the severity of osteoporosis and bone metabolism, suggesting that factors other than sex hormones might be responsible for sex differences of bone metabolism. We therefore examined sex differences of osteoblast phenotypes of mouse osteoblasts and then performed comparative gene expression analyses using a comprehensive DNA microarray between female and male osteoblasts. Alkaline phosphatase (ALP) activity, mineralization, and the expression of Osterix, ALP, and bone sialoprotein were significantly lower in mouse female osteoblasts compared with male osteoblasts. We identified Serpina3n, a novel serine protease inhibitor, as the gene whose expression has the highest ratio of females to males. A reduction in endogenous levels of Serpina3n by small interfering RNA significantly enhanced the mRNA levels of Runx2, ALP, osteocalcin, and type I collagen (Col1a1) in both male and female osteoblasts. Moreover, Serpina3n overexpression significantly suppressed the mRNA levels of Osterix, ALP, osteocalcin, and Col1a1 in MC3T3-E1 cells. Serpina3n overexpression did not affect Osterix, ALP, and osteocalcin mRNA levels enhanced by bone morphogenetic protein (BMP)-2 in ST2 cells, adipogenic differentiation in ST2 and 3T3-L1 cells, and receptor activator of nuclear factor kappaB ligand-induced osteoclast formation in RAW264.7 cells, although it significantly suppressed mineralization in ST2 cells differentiated into osteoblasts by BMP-2. In conclusion, we found Serpina3n as the most female osteoblast-dominant gene. Serpina3n exerts a suppression of the osteoblast phenotypes such as Col1a1 expression and ALP activity in differentiated osteoblasts, which might partly explain sex differences of the osteoblast phenotypes in mice. PMID- 30304391 TI - Integration of Circadian and Metabolic Control of Reproductive Function. AB - Optimal fertility in humans and animals relies on the availability of sufficient metabolic fuels, information about which is communicated to the brain via levels of the hormones leptin and insulin. The circadian clock system is also critical; this input is especially evident in the precise timing of the female-specific surge of GnRH and LH secretion that triggers ovulation the next day. Chronodisruption and metabolic imbalance can both impair reproductive activity, and these two disruptions exacerbate each other, such that they often occur simultaneously. Kisspeptin neurons located in the anteroventral periventricular nucleus of the hypothalamus are able to integrate both circadian and metabolic afferent inputs and use this information to modulate the timing and magnitude of the preovulatory GnRH/LH surge. In an environment in which exposure to high caloric diets and chronodisruptors such as artificial night lighting, shift work, and transmeridian travel have become the norm, the implications of these factors for couples struggling to conceive deserve closer attention and more public education. PMID- 30304393 TI - Inappropriate Use of Medical Conditions as Metaphors. PMID- 30304394 TI - Rapid expansion of a highly germline-expressed mariner element acquired by horizontal transfer in the fire ant genome. AB - Transposable elements (TEs) are present in almost all organisms and affect the host in various ways. TE activity can increase genomic variation and thereby affect host evolution. Currently active TEs are particularly interesting because they are likely generating new genomic diversity. These active TEs have been poorly studied outside of model organisms. In this study, we aimed to identify currently active TEs of a notorious invasive species, the red imported fire ant Solenopsis invicta. Using RNA profiling of male and female germline tissues, we found that the majority of TE-containing transcripts in the fire ant germline belong to the IS630-Tc1-Mariner superfamily. Subsequent genomic characterization of fire ant mariner content, molecular evolution analysis, and population comparisons revealed a highly expressed and highly polymorphic mariner element that is rapidly expanding in the fire ant genome. Additionally, using comparative genomics of multiple insect species we showed that this mariner has undergone several recent horizontal transfer events (<5.1 My). Our results document a rare case of a currently active TE originating from horizontal transfer. PMID- 30304392 TI - A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling and miRNA dysregulation. AB - Aims: Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. Methods and Results: We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harboring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number and reduction of the Wnt/beta-catenin signaling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Conclusions: Downregulation of the canonical Wnt/beta-catenin signaling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most upregulated and miR-499-5p the most downregulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/beta-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease. PMID- 30304395 TI - Effect of impaired cardiac conduction after alcohol septal ablation on clinical outcomes: Insights from the Euro-ASA registry. AB - Aims: We analysed the impact of bundle branch block (BBB) and pacemaker (PM) implantation on symptoms and survival after alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM). Methods and Results: Among 1416 HCM patients from the Euro-ASA registry 58 (4%) patients had a PM and 64 (5%) patients had an implantable cardioverter defibrillator (ICD) before ASA. At latest follow-up (5.0+/-4.0 years) after ASA, 118 (8%) patients had an ICD and 229 (16%) patients had a PM. In patients without an implantable device prior to ASA 13% had a PM and 5% had an ICD implanted following ASA. New onset BBB was present in 44% (right BBB in 31%) of patients without previous BBB. At latest follow-up, we found no associations between BBB and New York Heart Association (NYHA) class 3-4 (OR 0.98, CI 0.63-1.51, p = 0.91) or Canadian Cardiovascular Society (CCS) class 3-4 (OR 1.5, CI 0.32-6.7, p = 0.62), respectively, and no associations between PM and NYHA class 3-4 (OR 1.2, CI 0.70-2.0, p = 0.52) or CCS 3-4 (OR 1.3, CI 0.24-6.6, p = 0.79), respectively. The survival after ASA was not reduced in patients with BBB (HR 0.73, CI 0.53-1.01, p = 0.06) or PM (HR 0.78, CI 0.52-1.17, p = 0.24). Conclusions: Development of BBB or need for a PM after ASA in patients with obstructive HCM was not associated with inferior symptomatic outcome or reduced survival, thus concerns for the negative impact of impaired cardiac conduction on the clinical outcome after ASA were not confirmed. PMID- 30304396 TI - Perspective and practice of surgical atrial fibrillation ablation: an international survey of cardiac surgeons. AB - Aims: Despite recommendations stating that surgical atrial fibrillation (AF) ablation is reasonable for patients with AF undergoing cardiac surgery for other indications, the clinical impact of this procedure remains unclear. We aimed to describe surgeons' practices and perceptions of this procedure. Methods and results: We built a self-administered survey in collaboration with content and methodology experts. We surveyed 268 cardiac surgeons from 80 centres in 18 countries. The response rate was 76% (n = 204/276), 49% from North America, 39% Europe, and 12% other regions. Respondents performed a median 10 [interquartile range (IQR) 4-30] AF ablation procedures/year, with marked variation in proportions of patients with AF considered for ablation (median 25%, IQR 10-61). 94% and 80% of surgeons respectively, thought symptomatic and asymptomatic patients benefit from ablation. Surgeons estimated the added major complication rate of concomitant AF ablation at 16% [median (IQR) 7-25]. Of participating surgeons, 61% believed that evidence supported surgical AF ablation reducing the incidence of thrombo-embolic complications, and 46% modified anticoagulation decision-making based on whether they performed AF ablation. During coronary artery bypass grafting, isolated pulmonary vein isolation was the most commonly performed lesion set (70%), whereas complete left atrial ablation (46%) and biatrial ablation (44%) were favoured with valve surgery. Conclusion: In a multinational group of academic surgeons, surgical AF ablation utilization appears variable, and average case volumes are low. Despite no evidence to that effect, the majority believe that ablation reduces AF-related thrombo-embolic risk of patients. Reported practice patterns suggest clinical equipoise; a definitive trial appears feasible based on respondent willingness to participate. PMID- 30304398 TI - Mitophagy activation repairs Leber's Hereditary Optic Neuropathy associated mitochondrial dysfunction and improves cell survival. AB - Leber's Hereditary Optic Neuropathy (LHON) is a classical mitochondrial disease caused by mutations in the mitochondrial DNA encoding complex I subunits. Oxidative stress associated with complex I defect has been implicated in developing LHON phenotype such as retinal ganglionic cell (RGC) death and loss of vision. However the mechanism of LHON pathogenesis is still not very clear and thus no effective therapies are available till date. Using cybrid models for LHON, we show that autophagy is significantly compromised in cells carrying LHON specific mtDNA mutations, which results in reduced clearance of dysfunctional mitochondria contributing to cell death. We further show that pharmacological activation of autophagy selectively clears the damaged mitochondria and thus repairs mitochondrial defects and improves overall cell survival in LHON cell models. Our results suggest that compromised autophagy is the missing link from oxidative stress to LHON pathogenesis. Activation of mitophagy ameliorates mitochondrial defects and exerts a protective role by improving cell survival in cells carrying LHON mutations that could be utilized as a potential therapeutic target for LHON treatment. PMID- 30304399 TI - Reply to Burnham, Kakol, Vazquez-Guillamet. PMID- 30304400 TI - The Persistent Problem of Overuse of Diagnostic Testing Among House Staff-Time to Move Forward. PMID- 30304397 TI - Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers. AB - Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-beta42, tau, ptau181, tau/amyloid beta42, ptau181/amyloid-beta42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean +/- standard deviation = 71.4 +/- 9.2) were followed for up to 16.9 years (mean +/- standard deviation = 6.2 +/- 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE E4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE E2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ~70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE E in modulating amyloid accumulation in CDR > 0 with APOE E4 being deleterious and APOE E2 protective. PMID- 30304401 TI - Optical Approaches for Interrogating Neural Circuits Controlling Hormone Secretion. AB - Developments in optical imaging and optogenetics are transforming the functional investigation of neuronal networks throughout the brain. Recent studies in the neuroendocrine field have used genetic mouse models combined with a variety of light-activated optical tools as well as GCaMP calcium imaging to interrogate the neural circuitry controlling hormone secretion. The present review highlights the benefits and caveats of these approaches for undertaking both acute brain slice and functional studies in vivo. We focus on the use of channelrhodopsin and the inhibitory optogenetic tools, archaerhodopsin and halorhodopsin, in addition to GCaMP imaging of individual cells in vitro and neural populations in vivo using fiber photometry. We also address issues around the use of genetic vs viral delivery of encoded proteins to specific Cre-expressing cell populations, their quantification, and the use of conscious vs anesthetized animal models. To date, optogenetics and GCaMP imaging have proven useful in dissecting functional circuitry within the brain and are likely to become essential investigative tools for deciphering the different neural networks controlling hormone secretion. PMID- 30304402 TI - In situ responses of the sponge microbiome to ocean acidification. AB - Climate change is causing rapid changes in reef structure, biodiversity, and function, though most sponges are predicted to tolerate conditions projected for 2100. Sponges maintain intimate relationships with microbial symbionts, with previous studies suggesting that microbial flexibility may be pivotal to success under ocean acidification (OA). We performed a reciprocal transplantation of the coral reef sponges Coelocarteria singaporensis and Stylissa cf. flabelliformis between a control reef site and an adjacent CO2 vent site in Papua New Guinea to explore how the sponge microbiome responds to OA. Microbial communities of C. singaporensis, which differed initially between sites, did not shift towards characteristic control or vent microbiomes, even though relative abundances of Chloroflexi and Cyanobacteria increased and that of Thaumarchaeota decreased 7 months after transplantation to the control site. Microbial communities of S. cf. flabelliformis, which were initially stable between sites, did not respond specifically to transplantation but collectively exhibited a significant change over time, with a relative increase in Thaumarchaeota and decrease in Proteobacteria in all treatment groups. The lack of a community shift upon transplantation to the vent site suggests that microbial flexibility, at least in the adult life-history stage, does not necessarily underpin host survival under OA . PMID- 30304403 TI - Hair Regrowth in a Patient With Long-standing Alopecia Totalis and Atopic Dermatitis Treated With Dupilumab. PMID- 30304404 TI - Viral Insulin/IGF-1-Like Peptides: Novel Regulators of Physiology and Pathophysiology? PMID- 30304405 TI - Embryonic myosin is a regeneration marker to monitor utrophin based therapies for DMD. AB - Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. Constitutive utrophin expression, a structural and functional paralogue of dystrophin, can successfully prevent the dystrophic pathology in the dystrophin-deficient mdx mouse model. In dystrophic muscles, utrophin is increased as part of the repair process and localised at the sarcolemma of regenerating myofibers. The presence of developmental myosin such as embryonic myosin (MyHC-emb) and neonatal (MyHC-neo) represents a useful marker of muscle regeneration and a meaningful indicator of muscle damage which correlates with the clinical severity of milder Becker Muscular dystrophy (BMD) and DMD patients. In the present study, we demonstrate that MyHC-emb is a robust marker of regeneration at different ages and in different skeletal muscles. We also evaluate the correlation between utrophin, dystrophin and MyHC-emb in wild-type and regenerating dystrophic muscles. Restoration of dystrophin significantly reduced MyHC-emb levels. Similarly, overexpression of utrophin in the transgenic mdx-Fiona mice reduced the number of MyHC-emb positive fibres to wild-type level, prevented the regenerative process and rescued the muscle function. In contrast, the absence of utrophin in the dystrophin deficient double knock out (dko) mice resulted in a higher MyHC-emb content and in a more severe dystrophic pathophysiology than in mdx mice. These data illustrate the importance of monitoring utrophin and MyHC-emb levels in the pre-clinical evaluation of therapies and provide translational support for the use of developmental myosin as a disease biomarker in DMD clinical trials. PMID- 30304406 TI - Should I Participate in a Cardiac Rehabilitation Program? PMID- 30304407 TI - Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia. AB - Importance: Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration. Objective: To estimate the long-term survival and value of tisagenlecleucel for children and young adults with B-cell acute lymphoblastic leukemia. Design, Setting, and Participants: In this cost-effectiveness analysis, a decision analytic model was designed to extrapolate trial evidence to a patient lifetime horizon. The survival evidence for the model was extracted from 3 studies: B2202 (enrolled patients from April 8, 2015, to November 23, 2016), B2205J (enrolled patients from August 14, 2014, to February 1, 2016), and B2101J (enrolled patients from March 15, 2012, to November 30, 2015). Long-term survival and outcomes of patients younger than 25 years with B-cell acute lymphoblastic leukemia that is refractory or in second or later relapse were derived using flexible parametric modeling from the direct extrapolation of event-free survival and overall survival curves. The published Kaplan-Meier curves were digitized from November 1, 2017, to November 30, 2017, using an algorithm to impute patient level time-to-event data. Sensitivity and scenario analyses assessed uncertainty in the evidence and model assumptions to further bound the range of cost effectiveness. Data were analyzed from December 1, 2017, to March 31, 2018. Interventions: The primary intervention of interest was tisagenlecleucel. The comparator of interest was the chemoimmunotherapeutic agent clofarabine. Main Outcomes and Measures: Model outcomes included life-years gained, quality adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. Results: Forty percent of patients initiating treatment with tisagenlecleucel are expected to be long-term survivors, or alive and responding to treatment after 5 years. Tisagenlecleucel had a total discounted cost of $667 000, with discounted life-years gained of 10.34 years and 9.28 QALYs gained. The clofarabine comparator had a total discounted cost of approximately $337 000, with discounted life-years gained of 2.43 years and 2.10 QALYs gained. This difference resulted in an incremental cost-effectiveness ratio of approximately $42 000 per life-year gained and approximately $46 000 per QALY gained for tisagenlecleucel vs clofarabine. These results were robust to probabilistic sensitivity analyses. Across scenario analyses that included more conservative assumptions regarding long-term relapse and survival, the incremental cost effectiveness ratio ranged from $37 000 to $78 000 per QALY gained. Conclusions and Relevance: Tisagenlecleucel likely provides gains in survival and seems to be priced in alignment with these benefits. This study suggests that payers and innovators should develop novel payment models that reduce the risk and uncertainty around long-term value and provide safeguards to ensure high-value care. PMID- 30304408 TI - Mass drug administration to control and eliminate malaria in Africa: how do we best utilize the tools at hand? PMID- 30304409 TI - Inbreeding depression in line 1 Hereford cattle population using pedigree and genomic information1. AB - This study aimed at assessing inbreeding and its effect on growth and fertility traits using the longtime closed line 1 Hereford cattle population. Inbreeding was estimated based on pedigree (FPED) and genomic information. For the latter, three estimates were derived based on the diagonal elements of the genomic relationship matrix using estimated (FGRM) or fixed (FGRM0.5) minor allele frequencies or runs of homozygosity (ROH) (FROH). A pedigree containing 10,186 animals was used to calculate FPED. Genomic inbreeding was evaluated using 785 animals genotyped for 30,810 SNP. Traits analyzed were birth weight (BWT), weaning weight (WWT), yearling weight (YWT), ADG, and age at first calving (AFC). The number of ROH per animal ranged between 6 and 119 segments with an average of 83. The shortest and longest segments were 1.36 and 64.86 Mb long, respectively, reflecting both ancient and recent inbreeding occurring in the last 30 to 40 generations. The average inbreeding was 29.2%, 16.1%, 30.2%, and 22.9% for FPED, FGRM, FGRM0.5, and FROH, respectively. FROH provided the highest correlations with FPED (r = 0.66). Across paternal half-sib families, with minimal variation in FPED, there were substantial variations in their genomic inbreeding. Inbreeding depression analyses showed that a 1% increase in an animal's FPED resulted in a decrease of 1.20 kg, 2.03 kg, and 0.004 kg/d in WWT, YWT, and ADG, respectively. Maternal inbreeding showed significantly negative effects on progeny growth performance. AFC increased by 1.4 and 0.8 d for each 1% increase in FPED of the cow and her dam, respectively. Using genomic inbreeding, similar impact on growth traits was observed although the magnitude of the effect varied between methods. Across all genomic measures, WWT, YWT, and ADG decreased by 0.21 to 0.53 kg, 0.46 to 1.13 kg, and 0.002 to 0.006 kg/d for each 1% increase in genomic inbreeding, respectively. Four chromosomes (9, 12, 17, and 27) were identified to have a significant association between their homozygosity (FROH CHR) and growth traits. Variability in genomic inbreeding could be useful when deciding between full and half-sib selection candidates. Despite the high level of inbreeding in this study, its negative impact on growth performance was not as severe as expected, which may be attributed to the purging of the deleterious alleles due to natural or artificial selection over time. PMID- 30304410 TI - MRSA Nasal Screening Adds Limited Value to the Choice of Empiric Antibiotics in Community Acquired Pneumonia. PMID- 30304411 TI - In Memoriam-Honoring the Victims of Opioid Addiction. PMID- 30304412 TI - In-home Robots Improve Social Skills in Children With Autism. PMID- 30304413 TI - Researchers Test New Techniques to Rule Out and Predict Heart Attacks. PMID- 30304414 TI - Immediate vs Delayed Pushing During the Second Stage of Labor. PMID- 30304415 TI - The Evolving Epidemiology and Management of Spontaneous Pneumothorax. PMID- 30304417 TI - The Surprising Resiliency of the Affordable Care Act. PMID- 30304418 TI - Adequate Supply of Physicians Makes Lower Educational Standards Unnecessary. PMID- 30304419 TI - Using Big Data to Determine Reference Values for Laboratory Tests. PMID- 30304420 TI - Biological, Legal, and Moral Definitions of Brain Death. PMID- 30304421 TI - Meta-analysis of LDL-C Lowering and Mortality. PMID- 30304422 TI - Using Big Data to Determine Reference Values for Laboratory Tests-Reply. PMID- 30304423 TI - Biological, Legal, and Moral Definitions of Brain Death-Reply. PMID- 30304424 TI - Meta-analysis of LDL-C Lowering and Mortality-Reply. PMID- 30304425 TI - Effect of Immediate vs Delayed Pushing on Rates of Spontaneous Vaginal Delivery Among Nulliparous Women Receiving Neuraxial Analgesia: A Randomized Clinical Trial. AB - Importance: It is unclear whether the timing of second stage pushing efforts affects spontaneous vaginal delivery rates and reduces morbidities. Objective: To evaluate whether immediate or delayed pushing results in higher rates of spontaneous vaginal delivery and lower rates of maternal and neonatal morbidities. Design, Setting, and Participants: Pragmatic randomized clinical trial of nulliparous women at or beyond 37 weeks' gestation admitted for spontaneous or induced labor with neuraxial analgesia between May 2014 and December 2017 at 6 US medical centers. The interim analysis suggested futility for the primary outcome and recruitment was terminated with 2414 of 3184 planned participants. Follow-up ended January 4, 2018. Interventions: Randomization occurred when participants reached complete cervical dilation. Immediate group participants (n = 1200) began pushing immediately. Delayed group participants (n = 1204) were instructed to wait 60 minutes. Main Outcomes and Measures: The primary outcome was spontaneous vaginal delivery. Secondary outcomes included total duration of the second stage, duration of active pushing, operative vaginal delivery, cesarean delivery, postpartum hemorrhage, chorioamnionitis, endometritis, perineal lacerations (>=second degree), and a composite outcome of neonatal morbidity that included neonatal death and 9 other adverse outcomes. Results: Among 2414 women randomized (mean age, 26.5 years), 2404 (99.6%) completed the trial. The rate of spontaneous vaginal delivery was 85.9% in the immediate group vs 86.5% in the delayed group, and was not significantly different (absolute difference, -0.6% [95% CI, -3.4% to 2.1%]; relative risk, 0.99 [95% CI, 0.96 to 1.03]). There was no significant difference in 5 of the 9 prespecified secondary outcomes reported, including the composite outcome of neonatal morbidity (7.3% for the immediate group vs 8.9% for the delayed group; between-group difference, -1.6% [95% CI, -3.8% to 0.5%]) and perineal lacerations (45.9% vs 46.4%, respectively; between-group difference, -0.4% [95% CI, -4.4% to 3.6%]). The immediate group had significantly shorter mean duration of the second stage compared with the delayed group (102.4 vs 134.2 minutes, respectively; mean difference, -31.8 minutes [95% CI, -36.7 to -26.9], P < .001), despite a significantly longer mean duration of active pushing (83.7 vs 74.5 minutes; mean difference, 9.2 minutes [95% CI, 5.8 to 12.6], P < .001), lower rates of chorioamnionitis (6.7% vs 9.1%; between-group difference, -2.5% [95% CI, -4.6% to -0.3%], P = .005), and fewer postpartum hemorrhages (2.3% vs 4.0%; between-group difference, -1.7% [95% CI, -3.1% to -0.4%], P = .03). Conclusions and Relevance: Among nulliparous women receiving neuraxial anesthesia, the timing of second stage pushing efforts did not affect the rate of spontaneous vaginal delivery. These findings may help inform decisions about the preferred timing of second stage pushing efforts, when considered with other maternal and neonatal outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02137200. PMID- 30304426 TI - Association Between Third-Trimester Tdap Immunization and Neonatal Pertussis Antibody Concentration. AB - Importance: Immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended in the United States during weeks 27 through 36 of pregnancy to prevent life-threatening infant pertussis. The optimal gestation for immunization to maximize concentrations of neonatal pertussis toxin antibodies is unknown. Objective: To determine pertussis toxin antibody concentrations in cord blood from neonates born to women immunized and unimmunized with Tdap vaccine in pregnancy and optimal gestational age for immunization to maximize concentrations of neonatal antibodies. Design, Setting, and Participants: Prospective, observational, cohort study of term neonates in Houston, Texas (December 2013 March 2014). Exposures: Tdap immunization during weeks 27 through 36 of pregnancy or no Tdap immunization. Main Outcomes and Measures: Primary outcome was geometric mean concentrations (GMCs) of pertussis toxin antibodies in cord blood of Tdap-exposed and Tdap-unexposed neonates and proportions of Tdap-exposed and Tdap-unexposed neonates with pertussis toxin antibody concentrations of 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher, cutoffs representing quantifiable antibodies or levels that may be protective until the infant immunization series begins. Secondary outcome was the optimal gestation for immunization to achieve maximum pertussis toxin antibodies. Results: Six hundred twenty-six pregnancies (mean maternal age, 29.7 years; 41% white, 27% Hispanic, 26% black, 5% Asian, 1% other; mean gestation, 39.4 weeks) were included. Three hundred twelve women received Tdap vaccine at a mean gestation of 31.2 weeks (range, 27.3-36.4); 314 were unimmunized. GMC of neonatal cord pertussis toxin antibodies from the Tdap-exposed group was 47.3 IU/mL (95% CI, 42.1-53.2) compared with 12.9 IU/mL (95% CI, 11.7-14.3) in the Tdap-unexposed group, for a GMC ratio of 3.6 (95% CI, 3.1-4.2; P < .001). More Tdap-exposed than Tdap unexposed neonates had pertussis toxin antibody concentrations of 15 IU/mL or higher (86% vs 37%; difference, 49% [95% CI, 42%-55%]), 30 IU/mL or higher (72% vs 17%; difference, 55% [95% CI, 49%-61%]), and 40 IU/mL or higher (59% vs 12%; difference, 47% [95% CI, 41%-54%]); P < .001 for each analysis. GMCs of pertussis toxin antibodies were highest when Tdap vaccine was administered during weeks 27 through 30 and declined thereafter, reaching a peak at week 30 (57.3 IU/mL [95% CI, 44.0-74.6]). Conclusions and Relevance: Immunization with Tdap vaccine during the third trimester of pregnancy, compared with no immunization, was associated with higher neonatal concentrations of pertussis toxin antibodies. Immunization early in the third trimester was associated with the highest concentrations. PMID- 30304427 TI - Trends in the Incidence and Recurrence of Inpatient-Treated Spontaneous Pneumothorax, 1968-2016. AB - Importance: Spontaneous pneumothorax is a common disease known to have an unusual epidemiological profile, but there are limited contemporary population-based data. Objective: To estimate the incidence of hospital admissions for spontaneous pneumothorax, its recurrence and trends over time using large, longstanding hospitalization data sets in England. Design, Setting, and Participants: A population-based epidemiological study was conducted using an English national data set and an English regional data set, each spanning 1968 to 2016, and including 170 929 hospital admission records of patients 15 years and older. Final date of the study period was December 31, 2016. Exposures: Calendar year (for incidence) and readmission to hospital for spontaneous pneumothorax (for recurrence). Main Outcomes and Measures: Primary outcomes were rates of hospital admissions for spontaneous pneumothorax and recurrence, defined as a subsequent hospital readmission with spontaneous pneumothorax. Record-linkage was used to identify multiple admissions per person and comorbidity. Risk factors for recurrence over 5 years of follow-up were assessed using cumulative time-to failure analysis and Cox proportional hazards regression. Results: From 1968 to 2016, there were 170 929 hospital admissions for spontaneous pneumothorax (median age, 44 years [IQR, 26-88]; 73.0% male). In 2016, there were 14.1 spontaneous pneumothorax admissions per 100 000 population 15 years and older (95% CI, 13.7 14.4), a significant increase compared with earlier years, up from 9.1 (95% CI, 8.1-10.1) in 1968. The population-based rate per 100 000 population 15 years and older was higher for males (20.8 [95% CI, 20.2-21.4]) than for females (7.6 [95% CI, 7.2-7.9]). Of patients with spontaneous pneumothorax, 60.8% (95% CI, 59.5% 62.0%) had chronic lung disease. Record-linkage analysis demonstrated that the overall increase in admissions over time could be due in part to an increase in repeat admissions, but there were also significant increases in the annual rate of first-known spontaneous pneumothorax admissions in some population subgroups, for example in women 65 years and older (annual percentage change from 1968 to 2016, 4.08 [95% CI, 3.33-4.82], P < .001). The probability of recurrence within 5 years was similar by sex (25.5% [95% CI, 25.1%-25.9%] for males vs 26.0% [95% CI, 25.3%-26.7%] for females), but there was variation by age group and presence of chronic lung disease. For example, the probability of readmission within 5 years among males aged 15 to 34 years with chronic lung disease was 39.2% (95% CI, 37.7%-40.7%) compared with 19.6% (95% CI, 18.2%-21.1%) in men 65 years and older without chronic lung disease. Conclusions and Relevance: This study provides contemporary information regarding the trends in incidence and recurrence of inpatient-treated spontaneous pneumothorax. PMID- 30304429 TI - Choledocholithiasis. PMID- 30304428 TI - Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial. AB - Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669. PMID- 30304433 TI - More Youth Vaccinated for HPV. PMID- 30304431 TI - The Giving Body. PMID- 30304434 TI - Breastfeeding Report Card. PMID- 30304435 TI - Studying Drug Safety in the Real World. PMID- 30304436 TI - On the Gender Identity of Breast Patients. PMID- 30304437 TI - Fallopian tube perfusion in ex-vivo and in-vivo laparoscopic hysterectomy specimens: potential application for uterine transplantation. AB - STUDY QUESTION: Is there perfusion to the fallopian tubes in ex-vivo and in-vivo uteri at the time of total laparoscopic hysterectomy (TLH), as observed using laser angiography with indocyanine green (ICG)? SUMMARY ANSWER: The fallopian tubes may have perfusion from the utero-ovarian vasculature alone. WHAT IS KNOWN ALREADY: The fallopian tubes are perfused by the uterine and utero-ovarian vessels. Perfusion can be measured using laser angiography with ICG. STUDY DESIGN, SIZE, DURATION: This prospective pilot cohort study included 15 women, ages 32-59 years old, who underwent TLH with bilateral salpingectomy for benign indications. PARTICIPANTS/MATERIALS, SETTING, METHODS: In five participants, TLH was performed and the utero-ovarian artery was cannulated ex vivo and injected with ICG. The other 10 participants underwent the in-vivo protocol. The mesosalpinx and uterine vessels were transected in the partial protocol. Colpotomy was also performed in the complete protocol. All fallopian tubes were imaged using laser angiography with ICG. The relative fluorescence and the fluorescence intensity ratio (length of fluorescent fallopian tube/total length of fallopian tube) of the fallopian tubes were measured in the ex-vivo and in vivo protocols, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Ex vivo, the fimbria of the ipsilateral fallopian tube had 47% median relative fluorescence as compared to the contralateral fallopian tube, which had 2.4% median relative fluorescence. In vivo, the post-ICG fluorescence intensity ratios were 0.61 +/- 0.40 for the partial protocol, and 0.78 +/- 0.30 for the complete protocol, with mean differences of 0.37 (95% CI: 0.23-0.50, P < .0001) and 0.22 (95% CI: 0.12 0.31, P < 0.0001), respectively, between the pre-procedure and the post-ICG fluorescence intensity ratios. Greater than 0.75 fluorescence intensity ratios (i.e. >75% tubal length fluorescence) was seen in 60% of fallopian tubes. LIMITATIONS, REASONS FOR CAUTION: This is a pilot study with a small sample size and pathologic uteri, which would not be appropriate for uterine transplantation. No conclusions can be made regarding the functionality of the fallopian tubes. WIDER IMPLICATIONS OF THE FINDINGS: The fallopian tubes may have perfusion with the utero-ovarian vasculature alone, potentially allowing for future animal studies regarding tubal viability in recipients of uterine-tubal transplants. If successful, human uterine-tubal transplantation may allow for spontaneous conception rather than IVF. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. S.F., P.F.P., K.A.S. and R.F. have no conflicts of interest to report. M.L.S. is an educational consultant for Medtronic (Dublin, Republic of Ireland) and Applied Medical (Rancho Santa Margarita, CA, USA), as well as a stockholder for SynDaver Labs (Tampa, FL, USA). S.E.Z. is an educational consultant for Applied Medical (Rancho Santa Margarita, CA, USA) and is on the advisory board for AbbVie Inc. (Chicago, IL, USA). TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30304438 TI - Respiratory Infections as Predictors of Hospital Admission for Myocardial Infarction and Stroke: Pathophysiologic and Therapeutic Considerations. PMID- 30304439 TI - CANDI: an R package and Shiny app for annotating radiographs and evaluating Computer-Aided Diagnosis. AB - Motivation: Radiologists have used algorithms for Computer-Aided Diagnosis (CAD) for decades. These algorithms use machine learning with engineered features, and there have been mixed findings on whether they improve radiologists' interpretations. Deep learning offers superior performance, but requires more training data and has not been evaluated in joint algorithm-radiologist decision systems. Results: We developed the Computer-Aided Note and Diagnosis Interface (CANDI) for collaboratively annotating radiographs and evaluating how algorithms alter human interpretation. The annotation app collects classification, segmentation, and image captioning training data, and the evaluation app randomizes the availability of CAD tools to facilitate clinical trials on radiologist enhancement. Availability: Demonstrations and source code are hosted at {{https://candi.nextgenhealthcare.org}}, and {{https://github.com/mbadge/candi}}, respectively, under GPL-3 license. Supplementary information: We demonstrate CANDI with chest x-ray datasets and deep learning models for cardiopulmonary diseases. In the online Supplement we describe these datasets, data security, and model training and performance evaluation. PMID- 30304440 TI - Species Composition of Alate Aphids (Hemiptera: Aphididae) Harboring Potato Virus Y and the Harbored Virus Strains in Hokkaido, Northern Japan. AB - Many studies have evaluated transmission abilities of laboratory-reared aphids for potato virus Y (PVY), but few have focused on PVY-harboring species of field collected aphids and the strains of PVY harbored by aphids. In the present study, we collected alate aphids in yellow pan traps in potato fields with Japanese commercial cultivars in Hokkaido, northern Japan in single 24-h periods during the tuber bulking stage and examined whether individual whole aphids harbored PVY by nested RT-PCR. PVY-positive individuals were identified to species using the gene sequence for cytochrome c oxidase subunit I and, when needed, morphological data and distribution records. In addition, individual strains of PVY harbored were determined using partial sequences of coat protein. Among 1,857 aphids trapped, 195 aphids had PVY and comprised 19 species; 17 species were identified to species-group taxa. Most of the aphid species detected as PVY positive colonize weeds that are common around potato fields in Hokkaido. Five species group taxa had not been reported previously as a vector aphid of PVY and might be new PVY-vector species. PVYNTN was most frequently detected from PVY-positive aphids as found recently in PVY-infected potatoes in commercial fields in Hokkaido. Two or three PVY strains were rarely detected from a single aphid, and no obvious difference was found in the proportion of the harbored PVY strains among positive aphid species. The first documentation of the species composition of PVY-harboring aphids and the strains of PVY harbored in East Asia should aid understanding of the epidemiology of PVY in Japan. PMID- 30304441 TI - Cucumber Metal Tolerance Protein 6 (CsMTP6) affects the mitochondrial Fe2+ and Mn2+ homeostasis. AB - Members of the cation diffusion facilitator family have been identified in all kingdoms of life. They have been divided into three subgroups - Zn-CDF, Fe/Zn-CDF and Mn-CDF - based on their putative specificity to transported metal ions. The plant metal tolerance protein 6 (MTP6) proteins fall into the Fe/Zn-CDF subgroup, however their function in iron/zinc transport has not been confirmed yet. Here we characterize the MTP6 protein from cucumber. When expressed in yeast and protoplasts isolated from A. thaliana cells, CsMTP6 localized in mitochondria and contributed to the efflux of iron and manganese from the mitochondria. The immunolocalization of CsMTP6 in cucumber membranes confirmed that CsMTP6 is associated with mitochondria. The root expression and protein level of CsMTP6 were significantly up-regulated in conditions of iron deficiency and iron excess but were not affected by Mn availability. These results indicate that plant MTP6 proteins contribute to the distribution of iron and manganese between the cytosol and mitochondria of plant cells and are regulated by Fe to maintain the mitochondrial and cytosolic iron homeostasis under various Fe availability. PMID- 30304442 TI - Association of Pre-onset Subthreshold Psychotic Symptoms With Longitudinal Outcomes During Treatment of a First Episode of Psychosis. AB - Importance: The clinical high-risk state in psychosis is most often characterized by subthreshold psychotic symptoms (STPS) and represents a target for psychosis prevention. However, evidence suggests that between 30% and 50% of patients with a first episode of psychosis (FEP) report no prior history of STPS, indicating that not all patients with FEP experience a previous clinical high-risk phase. As with other early characteristics of illness onset, this diversity in the early course of symptoms may offer prognostic value for subsequent clinical trajectories. Objective: To determine whether a history of pre-onset STPS is associated with differential 1-year treatment outcomes in an early intervention service for FEP. Design, Setting, and Participants: Data on 195 patients 15 to 35 years of age who were recruited between January 17, 2003, and October 17, 2013, were collected from a catchment-based specialized early intervention service for FEP. Patients who reported experiencing at least 1 STPS prior to the onset of FEP were identified as STPS present (STPSp; n = 135); those who reported no such history were identified as STPS absent (STPSa; n = 60). Statistical analysis was conducted from December 15, 2016, to February 15, 2018. Main Outcomes and Measures: Summary scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia, Hamilton Anxiety Rating Scale, Global Assessment of Functioning scores, and Social and Occupational Functioning Assessment Scale scores at baseline and after 1 year of treatment were analyzed to evaluate 1-year outcomes. Results: Individuals in the STPSp group (39 female and 96 male participants; mean [SD] age, 23.4 [4.2] years) and the STPSa group (20 female and 40 male participants; mean [SD] age, 23.9 [5.1] years) did not differ in symptom severity or functioning at baseline. Although both groups improved by 1 year of treatment, mixed analyses of covariance (controlling for duration of untreated psychosis) revealed group-by-time interactions for scores on the Scale for the Assessment of Negative Symptoms (F1,192 = 6.17; P = .01), the Global Assessment of Functioning (F1,188 = 7.54; P = .006), and the Social and Occupational Functioning Assessment Scale (F1,192 = 3.79; P = .05). Mixed analyses of covariance also revealed a group effect for scores on the Scale for the Assessment of Positive Symptoms (F1,192 = 5.31; P = .02). After controlling for multiple comparisons, all significant results indicate poorer 1-year outcomes for patients with STPSp compared with patients with STPSa. Conclusions and Relevance: A history of pre onset STPS consistent with a prior clinical high-risk state is associated with poorer outcomes in psychotic symptoms and global functioning for patients after 1 year of treatment for FEP. The presence or absence of pre-onset STPS therefore has prognostic value for treatment outcomes, even during a later stage of psychotic illness. PMID- 30304443 TI - Genetic mechanisms underlying spermatic and testicular traits within and among cattle breeds: systematic review and prioritization of GWAS results. AB - Reduced bull fertility imposes economic losses in bovine herds. Specifically, testicular and spermatic traits are important indicators of reproductive efficiency. Several genome-wide association studies (GWAS) have identified genomic regions associated with these fertility traits. The aims of this study were as follows: 1) to perform a systematic review of GWAS results for spermatic and testicular traits in cattle and 2) to identify key functional candidate genes for these traits. The identification of functional candidate genes was performed using a systems biology approach, where genes shared between traits and studies were evaluated by a guilt by association gene prioritization (GUILDify and ToppGene software) in order to identify the best functional candidates. These candidate genes were integrated and analyzed in order to identify overlapping patterns among traits and breeds. Results showed that GWAS for testicular-related traits have been developed for beef breeds only, whereas the majority of GWAS for spermatic-related traits were conducted using dairy breeds. When comparing traits measured within the same study, the highest number of genes shared between different traits was observed, indicating a high impact of the population genetic structure and environmental effects. Several chromosomal regions were enriched for functional candidate genes associated with fertility traits. Moreover, multiple functional candidate genes were enriched for markers in a species specific basis, taurine (Bos taurus) or indicine (Bos indicus). For the different candidate regions identified in the GWAS in the literature, functional candidate genes were detected as follows: B. Taurus chromosome X (BTX) (TEX11, IRAK, CDK16, ATP7A, ATRX, HDAC6, FMR1, L1CAM, MECP2, etc.), BTA17 (TRPV4 and DYNLL1), and BTA14 (MOS, FABP5, ZFPM2). These genes are responsible for regulating important metabolic pathways or biological processes associated with fertility, such as progression of spermatogenesis, control of ciliary activity, development of Sertoli cells, DNA integrity in spermatozoa, and homeostasis of testicular cells. This study represents the first systematic review on male fertility traits in cattle using a system biology approach to identify key candidate genes for these traits. PMID- 30304444 TI - Thrombotic and Infectious Risks of Parenteral Nutrition in Hospitalized Pediatric Inflammatory Bowel Disease. AB - Background: Malnutrition is common in inflammatory bowel disease (IBD), requiring timely and sufficient nutritional supplementation. In patients hospitalized for active disease, symptoms and/or altered intestinal function hinder enteral nutrition feasibility. In this scenario, parenteral nutrition (PN) is used. We aimed (1) to assess the frequency of PN use between 1997 and 2012 among hospitalized pediatric patients with IBD, (2) to determine the risk of in hospital thrombus and infection associated with PN, and (3) to identify predictors of thrombus and infection in pediatric IBD hospitalizations utilizing PN. Methods: We performed a cross-sectional analysis of pediatric patients hospitalized between 1997 and 2012. We used the Kids' Inpatient Database (KID) to identify pediatric patients (<=18 years of age) with Crohn's disease (CD) or ulcerative colitis (UC), PN exposure, and primary outcomes including thrombus and infection. We used multivariable regression to identify risk factors for outcomes of interest. Results: Parenteral nutrition was utilized in 3732 (12%) of 30,914 IBD hospitalizations. Three percent of PN patients experienced a thrombotic complication, and 5.5% experienced an infectious complication. Multivariate analysis showed PN as an independent risk factor for thrombus (odds ratio [OR], 4.3; 95% confidence interval [CI], 3.2-5.6) and infection (OR, 3.8; 95% CI, 3.1 4.6). Surgery was an independent risk factor for thrombus (OR, 2.0; 95% CI, 1.4 2.7) and infection (OR, 2.5; 95% CI, 2.0-3.1) in hospitalizations exposed to PN. Conclusions: Hospitalized pediatric IBD patients, particularly surgical, receiving PN are at increased risk for thrombosis and infection. Clinicians must balance these risks with the benefits of PN. PMID- 30304445 TI - The ER exit sites are specialized ER zones for the transport of cargo proteins from the ER to the Golgi apparatus. AB - The endoplasmic reticulum (ER) is a multifunctional organelle, including secretory protein biogenesis, lipid synthesis, drug metabolism, Ca2+ signaling, and so on. Since the ER is a single continuous membrane structure, it includes distinct zones responsible for its different functions. The export of newly synthesized proteins from the ER is facilitated via coat protein complex II (COPII)-coated vesicles, which form in specialized zones within the ER, called the ER exit sites (ERES) or transitional ER. In this review, we highlight recent advances in our understanding of the structural organization of ERES, the correlation between the ERES and Golgi organization, and the faithful cargo transport mechanism from the ERES to the Golgi. PMID- 30304446 TI - CAV1 regulates primordial follicle formation via the Notch2 signalling pathway and is associated with premature ovarian insufficiency in humans. AB - STUDY QUESTION: What is the function of CAV1 in folliculogenesis and female reproduction? SUMMARY ANSWER: CAV1 regulates germline cyst breakdown and primordial follicle (PF) formation in mice, and CAV1 mutation may be related to premature ovarian insufficiency (POI). WHAT IS KNOWN ALREADY: Pre-granulosa cells are essential for the establishment of the PF pool, which determines female fertility and reproductive lifespan. Cav1 participates in vascularization in fetal mouse ovaries. However, the role of CAV1 in early folliculogenesis and POI pathogenesis remains unclear. STUDY DESIGN, SIZE, DURATION: Cav1 function was investigated in mice and Human Embryonic Kidney 293 cells. Ovaries (six per group) were randomly assigned to Cav1-vivo-morpholino, control and control morpholino groups, and all experiments were repeated at least three times. To investigate CAV1 mutations in women, 200 Chinese women with POI and 200 control individuals with regular menstrual cycles and normal endocrine profiles were recruited from the Center for Reproductive Medicine of Shandong University between September 2012 and December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Wild-type CD1 mice, Lgr5-EGFP-ires-CreERT2 (Lgr5-KI) reporter mice and Human Embryonic Kidney 293 cells were used for these experiments. Protein expression was detected by Western blot, and quantitative RT-PCR was used to detect gene expression. The expression pattern of CAV1 in mouse ovaries and the phenotype of Cav1 deficiency in mice were detected by immunofluorescence. Pre granulosa cell proliferation in ovaries was detected by bromodeoxyuridine (BrdU) assay and immunofluorescence. The coding region of the CAV1 gene was sequenced in 200 women with POI and 200 controls. The functional effect of the novel mutation c.142 G > C (p.Glu48Gln) was investigated by Cell Counting Kit-8 (CCK8) assays and Western blot. MAIN RESULTS AND THE ROLE OF CHANCE: We confirmed that Cav1 deficiency in mouse ovary induced by CAV1-vivo-morpholino resulted in more multi oocyte follicles than in the control and control-morpholino groups (P < 0.01). Suppression of Cav1 decreased Leucine rich repeat containing G protein coupled receptor 5 (Lgr5)-positive cell proliferation (P < 0.01) and reduced the number of Lgr5 and Forkhead box L2 (Foxl2) double-positive cells (P < 0.01). Furthermore, suppression of Cav1 inhibited ovarian epithelial Lgr5-positive cell proliferation and differentiation through the Notch2 signalling pathway. Two of the POI women carried novel CAV1 mutations (c.45 C > G synonymous and c.142 G > C [Glu48Gln]). The deleterious effect of p.Glu48Gln was corroborated by showing that it adversely affected the function of CAV1 in cell proliferation and NOTCH2 expression in HEK293FT cells. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The novel Glu48Gln mutation was only detected in one of 200 POI patients and we were unable to investigate its effects in the ovary. WIDER IMPLICATIONS OF THE FINDINGS: The identification of CAV1 as a potentially causative gene for POI provides a theoretical basis to devise treatments for POI in women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Basic Research Program of China (973 Programs: 2012CB944700; 2013CB945501; 2013CB911400; 2014CB943202), the National Key Research and Development Program of China (2016YFC1000604, 2017YFC1001301), the State Key Program of National Natural Science Foundation of China (81430029), and the National Natural Science Foundation of China (31571540, 81522018, 81471509, 81601245, 81701406, 81571406). The authors declare no competing financial interests. PMID- 30304447 TI - Metabolic events in HIV-infected patients using abacavir are associated with erythrocyte inosine triphosphatase activity. AB - Objectives: Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients. Methods: ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs. Results: In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype. Conclusions: This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism. PMID- 30304448 TI - Case-Fatality Ratio of Blood Culture-Confirmed Typhoid Fever in Dhaka, Bangladesh. AB - With impending rollout of new conjugate typhoid vaccines, better estimates of typhoid case-fatality ratio are needed for countries to set priorities for public health programs. We enrolled 1425 patients of all ages with blood culture confirmed Salmonella Typhi from laboratory networks serving inpatients and outpatients in Dhaka, Bangladesh. Participants were asked about symptoms and complications including death experienced over a median 3-month period following blood culture diagnosis. Four fatal cases were identified (case-fatality ratio of 0.3% [95% confidence interval, .05%-.55%]). Applying this case-fatality ratio to global typhoid burden estimates would reduce deaths by 70%. PMID- 30304449 TI - A microsimulation model projecting the health care costs for resistance to antibacterial drugs in Sweden. AB - Background: Previous studies have shown that increasing antibacterial resistance (ABR) globally will cause extensive morbidity, deaths and escalated health care costs. Methods: To project economic consequences of resistance to antibacterial drugs for the Swedish health care sector, we used an individual-based microsimulation model, SESIM. Health care consumption was represented as increased numbers of hospital days, outpatient visits and contact tracing for individuals getting clinical infections or becoming asymptomatic carriers. The risk of contracting a resistant bacterium was calculated using the incidence of mandatorily notifiable ABR in Sweden. Results: We estimate accumulated additional health care costs attributable to notifiable ABR from 2018 until 2030 to EUR 406 million and EUR 1, 503 million until 2050. Until 2030 the largest proportion, more than EUR 247 million (EUR 958 million until 2050), was due to ESBL, followed by methicillin resistant Staphylococcus aureus, carbapenemase-producing Enterobacteriaceae, vancomycin-resistant Enterococci and penicillin non susceptible Pneumococci which incurred costs of EUR 128 million (EUR 453 million, 2050), EUR 15 million (EUR 58 million, 2050), EUR 13 million (EUR 28 million, 2050) and EUR 2 million (EUR 6 million, 2050), respectively. Conclusions: Projections concerning the future costs of ABR can be used to guide priorities and distribution of limited health care resources. Our estimates imply that costs in Sweden will have doubled by 2030 and increased more than 4-fold by 2050 if present trends continue and infection control practices remain unchanged. Still, indirect societal costs and costs for non-notifiable resistance remain to be added. PMID- 30304450 TI - What's new in heart failure therapy 2018? AB - Even though significant progress has been made over the past 3 decades, heart failure remains one of the leading causes of mortality and morbidity in developed countries and contributes significantly to the economic burden of modern health care systems. Especially in patients with preserved ejection fraction, valid therapeutic options are missing due to a lack of evidence. In face of a very heterogeneous condition with an ongoing debate over aetiology and pathophysiology, clinicians face a challenge in providing optimal care for these patients. Recent data suggest that the optimal treatment of the underlying conditions as well as comorbidities that are associated with heart failure might play an ever increasing role in improving outcomes. This focused review summarizes and reviews current data for the treatment of heart failure with both preserved and reduced ejection fractions based on the latest recommendations covering medical therapy and interventional strategies. PMID- 30304451 TI - Anaerobic aromatic compound degradation in Sulfuritalea hydrogenivorans sk43H. AB - Sulfuritalea hydrogenivorans sk43H is well recognized as a chemolithoautotrophic microorganism that oxidizes thiosulfate, sulfur or hydrogen. In this study, pathways for aromatic compound degradation were identified in the respective genome and proved for functionality by cultivation. S. hydrogenivorans sk43H harbors gene clusters encoding pathways for the anaerobic degradation of benzoate and phenylacetate via benzoyl-CoA as well as a partial pathway for anaerobic cinnamate degradation. Aerobic hybrid pathways were identified for the degradation of benzoate and 2-aminobenzoate. An aerobic pathway involving mono- and dioxygenases was found for 4-hydroxybenzoate. The organization of the gene clusters for anaerobic aromatic compound degradation in S. hydrogenivorans sk43H was found to be similar to that of the corresponding gene clusters in 'Aromatoleum aromaticum' strain EbN1. Cultivation experiments revealed that S. hydrogenivorans sk43H degrades benzoate, 4-hydroxybenzoate, phenylacetate and 4 hydroxyphenylacetate under nitrate-reducing conditions. The results imply a so far overlooked role of this microorganism in anaerobic aromatic compound degradation. Due to the frequent detection of Sulfuritalea-related microorganisms at hydrocarbon-contaminated sites, an involvement of this genus in the degradation of aromatic pollutants should be considered. PMID- 30304452 TI - Aging in Tunisia. AB - Owing in part to its diversity of citizenship, Tunisia has a rich history of economic and social changes-including some of the same age-based demographic changes witnessed globally. Faced with an increasing older population and fewer young adults available to provide support, the government of Tunisia has implemented policies for the older population. These new governmental policies are intended to provide limited funds for older adults to supplement financial assistance provided by their families. Yet, even with a demographic transition occurring, recent published research on the aging Tunisian adult is limited at best. Policy change and research that improve the well-being of Tunisia's aging population must be based on adequate data. Thus, understanding the state of aging in Tunisia provides policymakers and researchers more complete information to use in decision making. Further studies should address more aspects of the Tunisian aging experience and add data that are more contemporary. PMID- 30304453 TI - Corrigendum. PMID- 30304454 TI - Association of Unrecognized Myocardial Infarction With Long-term Outcomes in Community-Dwelling Older Adults: The ICELAND MI Study. AB - Importance: Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known. Objective: To determine the long term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI). Design, Setting, and Participants: Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67-93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure). Results: Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%). At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P < .001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27 2.04), MACE (HR, 1.56; 95% CI, 1.26-1.93), MI (HR, 2.09; 95% CI, 1.45-3.03), and heart failure (HR, 1.52; 95% CI, 1.09-2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71-1.38) and MACE (HR, 1.23; 95% CI, 0.91-1.66) vs RMI. Conclusions and Relevance: In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing. PMID- 30304455 TI - The Need to Integrate Climate Science Into Public Health Preparedness for Hurricanes and Tropical Cyclones. PMID- 30304456 TI - Frequency and Associations of Prescription Nonsteroidal Anti-inflammatory Drug Use Among Patients With a Musculoskeletal Disorder and Hypertension, Heart Failure, or Chronic Kidney Disease. AB - Importance: International nephrology societies advise against nonsteroidal anti inflammatory drug (NSAID) use in patients with hypertension, heart failure, or chronic kidney disease (CKD); however, recent studies have not investigated the frequency or associations of use in these patients. Objectives: To estimate the frequency of and variation in prescription NSAID use among high-risk patients, to identify characteristics associated with prescription NSAID use, and to investigate whether use is associated with short-term, safety-related outcomes. Design, Setting, and Participants: In this retrospective cohort study, administrative claims databases were linked to create a cohort of primary care visits for a musculoskeletal disorder involving patients 65 years and older with a history of hypertension, heart failure, or CKD between April 1, 2012, and March 31, 2016, in Ontario, Canada. Exposure: Prescription NSAID use was defined as at least 1 patient-level Ontario Drug Benefit claim for a prescription NSAID dispensing within 7 days after a visit. Main Outcomes and Measures: Multiple cardiovascular and renal safety-related outcomes were observed between 8 and 37 days after each visit, including cardiac complications (any emergency department visit or hospitalization for cardiovascular disease), renal complications (any hospitalization for hyperkalemia, acute kidney injury, or dialysis), and death. Results: The study identified 2 415 291 musculoskeletal-related primary care visits by 814 049 older adults (mean [SD] age, 75.3 [4.0] years; 61.1% female) with hypertension, heart failure, or CKD, of which 224 825 (9.3%) were followed by prescription NSAID use. The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%-16.7%) among 7365 primary care physicians. Within a sample of 35 552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, 0.001 to 0.002; P = .74). Conclusions and Relevance: While prescription NSAID use in primary care was frequent among high-risk patients, with widespread physician level variation, use was not associated with increased risk of short-term, safety related outcomes. PMID- 30304457 TI - Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. AB - STUDY QUESTION: Is oral dydrogesterone 30 mg daily non-inferior to 8% micronized vaginal progesterone (MVP) gel 90 mg daily for luteal phase support in IVF? SUMMARY ANSWER: Oral dydrogesterone demonstrated non-inferiority to MVP gel for the presence of fetal heartbeats at 12 weeks of gestation (non-inferiority margin 10%). WHAT IS KNOWN ALREADY: The standard of care for luteal phase support in IVF is the use of MVP; however, it is associated with vaginal irritation, discharge and poor patient compliance. Oral dydrogesterone may replace MVP as the standard of care if it is found to be efficacious with an acceptable safety profile. STUDY DESIGN, SIZE, DURATION: Lotus II was a randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide, from August 2015 until May 2017. In total, 1034 premenopausal women (>18 to <42 years of age) undergoing IVF were randomized 1:1 (stratified by country and age group), using an Interactive Web Response System, to receive oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects received either oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation. The primary outcome measure was the presence of fetal heartbeats at 12 weeks of gestation, as determined by transvaginal ultrasound. MAIN RESULTS AND THE ROLE OF CHANCE: Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates in the full analysis sample (FAS) at 12 weeks of gestation of 38.7% (191/494) and 35.0% (171/489) in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). Live birth rates in the FAS of 34.4% (170/494) and 32.5% (159/489) were obtained for the oral dydrogesterone and MVP gel groups, respectively (adjusted difference 1.9%; 95% CI: -4.0 to 7.8). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP gel. LIMITATIONS, REASONS FOR CAUTION: The analysis of the results was powered to consider the ongoing pregnancy rate, but a primary objective of greater clinical interest may have been the live birth rate. This study was open-label as it was not technically feasible to make a placebo applicator for MVP gel, which may have increased the risk of bias for the subjective endpoints reported in this study. While the use of oral dydrogesterone in fresh-cycle IVF was investigated in this study, further research is needed to investigate its efficacy in programmed frozen-thawed cycles where corpora lutea do not exist. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates that oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF. STUDY FUNDING/COMPETING INTERESTS(S): This study was sponsored and supported by Abbott. G.G. has received investigator fees from Abbott during the conduct of the study. Outside of this submitted work, G.G. has received non-financial support from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope and Gedeon Richter, as well as personal fees from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope, VitroLife, NMC Healthcare, ReprodWissen, Biosilu, Gedeon Richter and ZIVA. C.B. is the President of the Belgian Society of Reproductive Medicine (unpaid) and Section Editor of Reproductive BioMedicine Online. C.B. has received grants from Ferring Pharmaceuticals, participated in an MSD sponsored trial, and has received payment from Ferring, MSD, Biomerieux, Abbott and Merck for lectures. G.S. has no conflicts of interest to be declared. A.P. is the General Secretary of the Indian Society of Assisted Reproduction (2017-2018). B.D. is President of Pune Obstetric and Gynecological Society (2017-2018). D.-Z.Y. has no conflicts of interest to be declared. Z.-J.C. has no conflicts of interest to be declared. E.K. is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott. C.P.-F. is an employee of Abbott GmbH & Co. KG, Wiesbaden, Germany and owns shares in Abbott. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Origio, Besins, Ferring and Mithra (now Allergan); and H.T. has received consultancy fees from Finox-Gedeon Richter, Merck, Ferring, Abbott and ObsEva. TRIAL REGISTRATION NUMBER: NCT02491437 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 08 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 17 August 2015. PMID- 30304458 TI - Radial and Circumferential Collagen Fibers Are a Feature of the Peripapillary Sclera of Human, Monkey, Pig, Cow, Goat, and Sheep. AB - Purpose: To test the hypothesis that human, monkey, pig, sheep, cow, and goat eyes exhibit circumferential, radial, and interweaving collagen architecture in the posterior sclera. Methods: We analyzed 1,327 cryosections from the posterior poles of 4 human, 4 monkey, 5 pig, 8 sheep, 1 goat, and 2 cow eyes. Images were acquired using polarized light microscopy and processed to obtain polar fiber orientations relative to the center of the canal. Circumferential, radial, and interweaving regions were identified and analyzed for mean fiber orientation and anisotropy and region width and thickness. Results: Every eye exhibited circumferential, radial, and interweaving fibers in consistent locations. Radial fibers extended out from near the canal into the peripapillary and peripheral sclera in the innermost sclera. Circumferential fibers were directly adjacent to the canal and most prevalent in the outermost, posterior sclera. Interweaving fibers were found throughout the sclera thickness. Across all species, median anisotropy in the radial, circumferential, and interweaving regions were 0.95, 0.96, and 0.28, respectively. Conclusions: Regions of radial, circumferential, and interweaving fibers occur in the posterior pole sclera of human, monkey, pig, sheep, cow, and goat eyes. The consistency across species in scleral architecture suggests that they are primary organizational components whose functions should be better understood. PMID- 30304459 TI - A Novel Dichoptic Optokinetic Nystagmus Paradigm to Quantify Interocular Suppression in Monocular Amblyopia. AB - Purpose: To develop a novel dichoptic optokinetic nystagmus (OKN) paradigm and investigate its effectiveness in objectively quantifying the interocular suppression in subjects with monocular amblyopia. Methods: Centripetal moving gratings with different contrast ratios and constant velocity were dichoptically presented to eight monocular anisometropic amblyopes and eight normal subjects. We analyzed the OKN records with an eye tracker (EyeLink; SR-Research, Ontario, Canada) to obtain the relationship between ocular-dominance of OKN and the interocular contrast ratio by fitting power curves, and examined the correlation between the effective contrast ratio for a balanced OKN and the visual acuity of the amblyopic eye in amblyopes. Results: In normal subjects, the OKN pursuit times were roughly balanced for opposite directions when stimulated with centripetal gratings of same contrast; however, in amblyopes, the OKN pursuit times of the dominant eye exceeded that of the amblyopic eye. Increasing the contrast of one eye's grating led to an increase in its OKN dominance. The OKN directional ratio (y) could be well fitted by a power function of the interocular contrast ratio (x): y = axb. Moreover, in amblyopes, the effective contrast ratio (xb) for a balanced OKN correlated significantly positively with the visual acuity of the amblyopic eye (Spearman's correlation coefficient, 0.9698). Conclusions: The OKN induced by dichoptic gratings moving centripetally could be used as a reliable measure to objectively quantify the interocular suppression. This paradigm, avoiding the need for subjective report from patients, offers a promising alternative index for research on the mechanisms of amblyopia and in clinical practice. PMID- 30304460 TI - Accessibility to and Quality of Human Eye Tissue for Research: A Cross-Sectional Survey of ARVO Members - EBAA Commentary. PMID- 30304461 TI - A New Online Portal Will Match Eye Banks With Researchers Seeking Human Ocular Tissues. PMID- 30304462 TI - Accessibility to and Quality of Human Eye Tissue for Research: A Cross-Sectional Survey of ARVO Members. AB - Purpose: To assess experiences of vision scientists concerning the availability, quality, and documentation of human eye tissue for research, and to elicit researcher feedback about the establishment of an online portal that pairs eye bank capabilities with researcher needs. Methods: An online survey was designed by a working group of vision scientists and eye bank personnel and sent to members of ARVO. Results: A total of 407 responses were received from across ARVO scientific sections and career stages. Most respondents report typically obtaining human eye tissue from their local eye bank (57%). Almost half (43%) find it "difficult" or "very difficult" to get an adequate quantity of human eye tissue for their research, and 88% report that they would use more human eye tissue if it were more accessible. Regarding tissue quality, 43% of respondents regularly limit the scope of their work due to difficulty obtaining tissue that meets their needs, and almost half (43%) indicate that they question their findings due to tissue quality at least sometimes. Respondents uniformly desire more documentation about ocular tissue than they typically receive. Most (62%) would "definitely" or "very likely" use a proposed online resource to facilitate connections between eye banks and researchers. Conclusions: Vision scientists report difficulty in obtaining human eye tissue with the quality and clinical documentation required for their research. An online portal may better help pair researcher needs and eye bank capabilities. PMID- 30304463 TI - The Third Postmastectomy Reconstruction Option-Autologous Fat Transfer. PMID- 30304464 TI - Facilitating early treatment of influenza in hospitals: empiric antivirals or empiric diagnostics? PMID- 30304465 TI - The progression of tricuspid regurgitation: it seems capricious, or are we just too ignorant to understand it? PMID- 30304466 TI - E-Cigarette Use Without a History of Combustible Cigarette Smoking Among U.S. Adults: Behavioral Risk Factor Surveillance System, 2016. PMID- 30304467 TI - Level of Reconciliation Payments by Safety-Net Hospital Status Under the First Year of the Comprehensive Care for Joint Replacement Program. PMID- 30304469 TI - The C-terminal D/E-rich domain of MBD3 is a putative Z-DNA mimic that competes for Zalpha DNA-binding activity. AB - The Z-DNA binding domain (Zalpha), derived from the human RNA editing enzyme ADAR1, can induce and stabilize the Z-DNA conformation. However, the biological function of Zalpha/Z-DNA remains elusive. Herein, we sought to identify proteins associated with Zalpha to gain insight into the functional network of Zalpha/Z DNA. By pull-down, biophysical and biochemical analyses, we identified a novel Zalpha-interacting protein, MBD3, and revealed that Zalpha interacted with its C terminal acidic region, an aspartate (D)/glutamate (E)-rich domain, with high affinity. The D/E-rich domain of MBD3 may act as a DNA mimic to compete with Z DNA for binding to Zalpha. Dimerization of MBD3 via intermolecular interaction of the D/E-rich domain and its N-terminal DNA binding domain, a methyl-CpG-binding domain (MBD), attenuated the high affinity interaction of Zalpha and the D/E-rich domain. By monitoring the conformation transition of DNA, we found that Zalpha could compete with the MBD domain for binding to the Z-DNA forming sequence, but not vice versa. Furthermore, co-immunoprecipitation experiments confirmed the interaction of MBD3 and ADAR1 in vivo. Our findings suggest that the interplay of Zalpha and MBD3 may regulate the transition of the DNA conformation between B- and Z-DNA and thereby modulate chromatin accessibility, resulting in alterations in gene expression. PMID- 30304468 TI - Indexation of Tobacco Excise and Customs Duty and Smoking Prevalence Among Australian Adults, 2001-2010: A Serial Cross-sectional Study. AB - Introduction: Australia's excise and customs duty on tobacco has been automatically increased biannually since 1984. Increases in duty on par with inflation ensured that tobacco stayed at least as costly as other goods. This would be expected to maintain, rather than drive down, smoking prevalence. We examined the association between smoking prevalence and duty over a 10-year period. Methods: Using monthly data from five Australian capital cities, collected from March 2001 to March 2010 among Australians aged at least 18 years, multiple linear regression modeled associations between smoking prevalence and the two components (duty and non-duty) of the recommended retail price of an average packet of cigarettes, adjusting for policy covariates. Results : revalence declined from 23.6% in March 2001 to 17.0% in March 2010 [absolute difference 6.6%; 95% confidence interval (CI) = 6.5% to 6.8%]. Duty increased from $0.2026 to $0.2622 per cigarette over the same period. In the adjusted model, a 1-cent increase in the duty component of price was not associated with changes in prevalence (0.019; 95% CI = -0.035% to 0.028%). Increased non-duty component of price was associated with a decline in prevalence (-0.027; 95% CI = 0.052% to -0.002%). This effect was stronger when changes in income were controlled for. Conclusions: In line with expectations, inflation-adjusted duty was not associated with changes in smoking prevalence, but it may have prevented upward pressure on prevalence that increasing affordability could have exerted. Frequent increases in duty greater than the growth in both wages and goods would more effectively reduce smoking than regular indexation. Implications : ew countries inflation-adjusted excise duty to ensure that tobacco products do not become more affordable; however, Australia experienced a decade of inflation adjustment alone, enabling the impact of this policy to be studied. This study shows that inflation-adjusted duty likely did prevent tobacco becoming more affordable and that indexation was associated with declines in smoking when tobacco companies over-shifted the duty rises (ie, increased price over and above duty rises).The study also suggests that frequent increases in taxation that exceed both wage growth and increases in costliness of other goods are needed to prompt increased rates of quitting. PMID- 30304470 TI - Inter-rater Agreement Between Exposure Assessment Using Automatic Algorithms and Using Experts. AB - Objectives: To estimate the inter-rater agreement between exposure assessment to asthmagens in current jobs by algorithms based on task-based questionnaires (OccIDEAS) and by experts. Methods: Participants in a cross-sectional national survey of exposure to asthmagens (AWES-Asthma) were randomly split into two subcohorts of equal size. Subcohort 1 was used to determine the most common asthmagen groups and occupational groups. From subcohort 2, a random sample of 200 participants was drawn and current occupational exposure (yes/no) was assessed in these by OccIDEAS and by two experts independently and then as a consensus. Inter-rater agreement was estimated using Cohen's Kappa coefficient. The null hypothesis was set at 0.4, because both the experts and the automatic algorithm assessed the exposure using the same task-based questionnaires and therefore an agreement better than by chance would be expected. Results: The Kappa coefficients for the agreement between the experts and the algorithm-based assessments ranged from 0.37 to 1, while the agreement between the two experts ranged from 0.29 to 0.94, depending on the agent being assessed. After discussion by both experts the Kappa coefficients for the consensus decision and OccIDEAS were significantly larger than 0.4 for 7 of the 10 asthmagen groups, while overall the inter-rater agreement was greater than by chance (P < 0.0001). Conclusions: The web-based application OccIDEAS is an appropriate tool for automated assessment of current exposure to asthmagens (yes/no), and requires less time-consuming work by highly-qualified research personnel than the traditional expert-based method. Further, it can learn and reuse expert determinations in future studies. PMID- 30304471 TI - Host Plant Use for Oviposition by the Insidious Flower Bug (Hemiptera: Anthocoridae). AB - The availability of oviposition sites for the predators of arthropod pests is crucial for the success of biological control. The resources for oviposition and offspring survival offered to the predators by crops and the surrounding natural vegetation are relevant in the context of conservation biological control. The endophytic oviposition of Orius insidiosus (Say) depends on the characteristics of the plant tissues. We thus examined, by single- and multiple-choice tests, 1) the oviposition of O. insidiosus in strawberry, analyzing the tissue characteristics of the different plant structures, and 2) the preference for oviposition among strawberry, tomato, bell pepper, eggplant, and the wild South American poppy Bidens pilosa L. (Asterales: Asteraceae). The calyx and flower petiole received more eggs than the other structures. The thickness of the external tissues did not affect oviposition. All structures of the different plants tested offer sufficient space to house eggs, except for the leaflet lamina. Bidens pilosa was preferred by ovipositing O. insidiosus over the other plants tested. The cultivation of this plant in proximity to strawberry and other horticultural crops could constitute a promising strategy for augmenting the resources for oviposition for this predator. PMID- 30304472 TI - Detection of epigenetic field defects using a weighted epigenetic distance-based method. AB - Identifying epigenetic field defects, notably early DNA methylation alterations, is important for early cancer detection. Research has suggested these early methylation alterations are infrequent across samples and identifiable as outlier samples. Here we developed a weighted epigenetic distance-based method characterizing (dis)similarity in methylation measures at multiple CpGs in a gene or a genetic region between pairwise samples, with weights to up-weight signal CpGs and down-weight noise CpGs. Using distance-based approaches, weak signals that might be filtered out in a CpG site-level analysis could be accumulated and therefore boost the overall study power. In constructing epigenetic distances, we considered both differential methylation (DM) and differential variability (DV) signals. We demonstrated the superior performance of the proposed weighted epigenetic distance-based method over non-weighted versions and site-level EWAS (epigenome-wide association studies) methods in simulation studies. Application to breast cancer methylation data from Gene Expression Omnibus (GEO) comparing normal-adjacent tissue to tumor of breast cancer patients and normal tissue of independent age-matched cancer-free women identified novel epigenetic field defects that were missed by EWAS methods, when majority were previously reported to be associated with breast cancer and were confirmed the progression to breast cancer. We further replicated some of the identified epigenetic field defects. PMID- 30304474 TI - Genenames.org: the HGNC and VGNC resources in 2019. AB - The HUGO Gene Nomenclature Committee (HGNC) based at EMBL's European Bioinformatics Institute (EMBL-EBI) assigns unique symbols and names to human genes. There are over 40 000 approved gene symbols in our current database of which over 19 000 are for protein-coding genes. The Vertebrate Gene Nomenclature Committee (VGNC) was established in 2016 to assign standardized nomenclature in line with human for vertebrate species that lack their own nomenclature committees. The VGNC initially assigned nomenclature for over 15000 protein coding genes in chimpanzee. We have extended this process to other vertebrate species, naming over 14000 protein-coding genes in cow and dog and over 13 000 in horse to date. Our HGNC website https://www.genenames.org has undergone a major design update, simplifying the homepage to provide easy access to our search tools and making the site more mobile friendly. Our gene families pages are now known as 'gene groups' and have increased in number to over 1200, with nearly half of all named genes currently assigned to at least one gene group. This article provides an overview of our online data and resources, focusing on our work over the last two years. PMID- 30304475 TI - The U.S. Food and Drug Administration's Dilemma: How Tightly to Regulate Electronic Cigarettes? PMID- 30304473 TI - Bre1-dependent H2B ubiquitination promotes homologous recombination by stimulating histone eviction at DNA breaks. AB - Repair of DNA double-strand breaks (DSBs) requires eviction of the histones around DNA breaks to allow the loading of numerous repair and checkpoint proteins. However, the mechanism and regulation of this process remain poorly understood. Here, we show that histone H2B ubiquitination (uH2B) promotes histone eviction at DSBs independent of resection or ATP-dependent chromatin remodelers. Cells lacking uH2B or its E3 ubiquitin ligase Bre1 exhibit hyper-resection due to the loss of H3K79 methylation that recruits Rad9, a known negative regulator of resection. Unexpectedly, despite excessive single-strand DNA being produced, bre1Delta cells show defective RPA and Rad51 recruitment and impaired repair by homologous recombination and response to DNA damage. The HR defect in bre1Delta cells correlates with impaired histone loss at DSBs and can be largely rescued by depletion of CAF-1, a histone chaperone depositing histones H3-H4. Overexpression of Rad51 stimulates histone eviction and partially suppresses the recombination defects of bre1Delta mutant. Thus, we propose that Bre1 mediated-uH2B promotes DSB repair through facilitating histone eviction and subsequent loading of repair proteins. PMID- 30304476 TI - E-cigarette Usage Is Associated With Increased Past-12-Month Quit Attempts and Successful Smoking Cessation in Two US Population-Based Surveys. AB - Introduction: We examined past-12-month quit attempts and smoking cessation from 2006 to 2016 while accounting for demographic shifts in the US population. In addition, we sought to understand whether the current use of electronic cigarettes was associated with a change in past-12-month quit attempts and successful smoking cessation at the population level. Methods: We analyzed data from 25- to 44-year-olds from the National Health Interview Survey (NHIS) from 2006 to 2016 (N = 26,354) and the Tobacco Use Supplement to the Current Population Survey (TUS-CPS) in 2006-2007, 2010-2011, and 2014-2015 (N = 33,627). Data on e-cigarette use were available in the 2014-2016 NHIS and 2014-2015 TUS CPS surveys. Results: Past-12-month quit attempts and smoking cessation increased in recent years compared with 2006. Current e-cigarette use was associated with higher quit attempts (adjusted odds ratio [aOR] = 2.29, 95% confidence interval [CI] = 1.87 to 2.81, p < .001) and greater smoking cessation (aOR = 1.64, 95% CI = 1.21 to 2.21, p = .001) in the NHIS. Multivariable logistic regression of the TUS-CPS data showed that current e-cigarette use was similarly significantly associated with increased past-12-month quit attempts and smoking cessation. Significant interactions were found for smoking frequency (everyday and some-day smoking) and current e-cigarette use for both outcomes (p < .0001) with the strongest positive effects seen in everyday smokers. Conclusions: Compared with 2006, past-12-month quit attempts and smoking cessation increased among adults aged 25-44 in recent years. Current e-cigarette use was associated with increased past-12-month quit attempts and successful smoking cessation among established smokers. These findings are relevant to future tobacco policy decisions. Implications: E-cigarettes were introduced into the US market over the past decade. During this period, past-12-month quit attempts and smoking cessation have increased among US adults aged 25-44. These trends are inconsistent with the hypothesis that e-cigarette use is delaying quit attempts and leading to decreased smoking cessation. In contrast, current e-cigarette use was associated with significantly higher past-12-month quit attempts and past-12-month cessation. These findings suggest that e-cigarette use contributes to a reduction in combustible cigarette use among established smokers. PMID- 30304477 TI - Translating an Evidence-based Multicomponent Intervention for Older Adults With Dementia and Caregivers. AB - Background and Objectives: Effective community-based programs to maintain health and well-being of adults with dementia are needed. This article describes the translation, implementation, and effectiveness of a multicomponent exercise plus behavioral/psychosocial intervention (Reducing Disability in Alzheimer's Disease NorthWest [RDAD-NW]) conducted by staff in regional Area Agencies on Aging (AAAs). Research Design and Methods : Staggered multiple baseline design was used; 10 AAAs, 20 case managers, and 255 community-residing persons with dementia (PWDs), and family caregivers were enrolled. RDAD-NW was conducted in-home over 6 weeks with aerobic/endurance, strength, and balance/flexibility exercises, dementia education, training to increase pleasant events, and activator-behavior consequence problem-solving approach. Outcomes included case manager treatment fidelity, and caregiver/PWD physical activity, restricted activity days, physical functioning, quality of life, and affect. Results: RDAD-NW was successfully translated and implemented by AAA agency staff through their usual service provision mechanisms. Staff responded positively and delivered the program with a high degree of fidelity. Caregiver/PWD dyads also responded favorably engaging in both exercise and behavioral/psychosocial portions of the program. A total of 207 dyads (81%) completed the intervention and 140 (55%) completed the 13-month follow-up. PWD physical activity increased significantly pre- to posttreatment (p < .001, ES = .54), and 13 months (p < .01, ES = .21). Quality of life of PWD increased significantly pre- to posttreatment (p < .001, ES = .29); caregiver depression improved pre- to posttreatment (p = .01, ES = -.18). Discussion and Implications: RDAD-NW was successfully translated and implemented by AAA case managers and resulted in increased physical activity and improved behavioral and emotional outcomes of caregiver/PWDs. Results support continued dissemination and implementation of RDAD-NW. Clinical Trials Registration: NCT01708304. PMID- 30304479 TI - Non-steroidal anti-inflammatory drugs, acetaminophen and ibuprofen, induce phenotypic antibiotic resistance in Escherichia coli: roles of marA and acrB. AB - The factors contributing to antibiotic resistance in bacteria are an important area of study. Sodium salicylate (NaSal), a non-steroidal anti-inflammatory drug (NSAID), increases antibiotic resistance by inducing the expression of MarA, a transcription factor, which increases the AcrAB-TolC efflux pump. MarA is a substrate of Lon protease and the Deltalon strain displays a high degree of antibiotic resistance. This study was initiated to identify commonly used NSAIDs that may induce antibiotic resistance and to compare their efficacies with NaSal and acetyl salicylic acid (ASA). Quantitative real-time expression analysis revealed induction of marA and acrB by NaSal, ASA, acetaminophen (APAP) and ibuprofen. Further, dose studies demonstrated that NaSal and ASA induce resistance at ~2 mM while APAP and ibuprofen induce resistance at ~5-10 mM. To dissect the roles of key molecules, atomic force microscopy and functional studies were performed using WT, Deltalon, DeltamarA, DeltaacrB, DeltalonDeltamarA and DeltalonDeltaacrB strains. The induction of antibiotic resistance by NaSal, ASA and APAP is relatively higher and is partly dependent on marA, whereas ibuprofen which induces lower antibiotic resistance shows complete marA dependence. Notably, NaSal, ASA, APAP and ibuprofen induce antibiotic resistance in an acrB-dependent manner. The possible significance of some NSAIDs in inducing antibiotic resistance is discussed. PMID- 30304478 TI - MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. AB - Nucleotides in the free pool are more susceptible to nonenzymatic methylation than those protected in the DNA double helix. Methylated nucleotides like O6 methyl-dGTP can be mutagenic and toxic if incorporated into DNA. Removal of methylated nucleotides from the nucleotide pool may therefore be important to maintain genome integrity. We show that MutT homologue 1 (MTH1) efficiently catalyzes the hydrolysis of O6-methyl-dGTP with a catalytic efficiency similar to that for 8-oxo-dGTP. O6-methyl-dGTP activity is exclusive to MTH1 among human NUDIX proteins and conserved through evolution but not found in bacterial MutT. We present a high resolution crystal structure of human and zebrafish MTH1 in complex with O6-methyl-dGMP. By microinjecting fertilized zebrafish eggs with O6 methyl-dGTP and inhibiting MTH1 we demonstrate that survival is dependent on active MTH1 in vivo. O6-methyl-dG levels are higher in DNA extracted from zebrafish embryos microinjected with O6-methyl-dGTP and inhibition of O6 methylguanine-DNA methyl transferase (MGMT) increases the toxicity of O6-methyl dGTP demonstrating that O6-methyl-dGTP is incorporated into DNA. MTH1 deficiency sensitizes human cells to the alkylating agent Temozolomide, a sensitization that is more pronounced upon MGMT inhibition. These results expand the cellular MTH1 function and suggests MTH1 also is important for removal of methylated nucleotides from the nucleotide pool. PMID- 30304481 TI - PlateDesigner: a web-based application for the design of microplate experiments. AB - Availability and implementation: PlateDesigner is written in R/Shiny and is hosted online by the Center of Biostatistics at the Icahn School of Medicine at Mount Sinai. This application is freely available at platedesigner.net. PMID- 30304480 TI - Regulation of muscle atrophy-related genes by the opposing transcriptional activities of ZEB1/CtBP and FOXO3. AB - Multiple physiopathological and clinical conditions trigger skeletal muscle atrophy through the induction of a group of proteins (atrogenes) that includes components of the ubiquitin-proteasome and autophagy-lysosomal systems. Atrogenes are induced by FOXO transcription factors, but their regulation is still not fully understood. Here, we showed that the transcription factor ZEB1, best known for promoting tumor progression, inhibits muscle atrophy and atrogene expression by antagonizing FOXO3-mediated induction of atrogenes. Compared to wild-type counterparts, hindlimb immobilization in Zeb1-deficient mice resulted in enhanced muscle atrophy and higher expression of a number of atrogenes, including Atrogin 1/Fbxo32, MuRF1/Trim63, Ctsl, 4ebp1, Gabarapl1, Psma1 and Nrf2. Likewise, in the C2C12 myogenic cell model, ZEB1 knockdown augmented both myotube diameter reduction and atrogene upregulation in response to nutrient deprivation. Mechanistically, ZEB1 directly represses in vitro and in vivo Fbxo32 and Trim63 promoter transcription in a stage-dependent manner and in a reverse pattern with MYOD1. ZEB1 bound to the Fbxo32 promoter in undifferentiated myoblasts and atrophic myotubes, but not in non-atrophic myotubes, where it is displaced by MYOD1. ZEB1 repressed both promoters through CtBP-mediated inhibition of FOXO3 transcriptional activity. These results set ZEB1 as a new target in therapeutic approaches to clinical conditions causing muscle mass loss. PMID- 30304482 TI - Genome-wide mapping reveals conserved and diverged R-loop activities in the unusual genetic landscape of the African trypanosome genome. AB - R-loops are stable RNA-DNA hybrids that have been implicated in transcription initiation and termination, as well as in telomere maintenance, chromatin formation, and genome replication and instability. RNA Polymerase (Pol) II transcription in the protozoan parasite Trypanosoma brucei is highly unusual: virtually all genes are co-transcribed from multigene transcription units, with mRNAs generated by linked trans-splicing and polyadenylation, and transcription initiation sites display no conserved promoter motifs. Here, we describe the genome-wide distribution of R-loops in wild type mammal-infective T. brucei and in mutants lacking RNase H1, revealing both conserved and diverged functions. Conserved localization was found at centromeres, rRNA genes and retrotransposon associated genes. RNA Pol II transcription initiation sites also displayed R loops, suggesting a broadly conserved role despite the lack of promoter conservation or transcription initiation regulation. However, the most abundant sites of R-loop enrichment were within the regions between coding sequences of the multigene transcription units, where the hybrids coincide with sites of polyadenylation and nucleosome-depletion. Thus, instead of functioning in transcription termination the most widespread localization of R-loops in T. brucei suggests a novel correlation with pre-mRNA processing. Finally, we find little evidence for correlation between R-loop localization and mapped sites of DNA replication initiation. PMID- 30304483 TI - Towards region-specific propagation of protein functions. AB - Motivation: Due to the nature of experimental annotation, most protein function prediction methods operate at the protein-level, where functions are assigned to full-length proteins based on overall similarities. However, most proteins function by interacting with other proteins or molecules, and many functional associations should be limited to specific regions rather than the entire protein length. Most domain-centric function prediction methods depend on accurate domain family assignments to infer relationships between domains and functions, with regions that are unassigned to a known domain-family left out of functional evaluation. Given the abundance of residue-level annotations currently available, we present a function prediction methodology that automatically infers function labels of specific protein regions using protein-level annotations and multiple types of region-specific features. Results: We apply this method to local features obtained from InterPro, UniProtKB and amino acid sequences and show that this method improves both the accuracy and region-specificity of protein function transfer and prediction. We compare region-level predictive performance of our method against that of a whole-protein baseline method using proteins with structurally-verified binding sites and also compare protein-level temporal holdout predictive performances to expand the variety and specificity of GO terms we could evaluate. Our results can also serve as a starting point to categorize GO terms into region-specific and whole-protein terms and select prediction methods for different classes of GO terms. Availability: The code and features are freely available at: https://github.com/ek1203/rsfp. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30304484 TI - Pancreas cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 30304485 TI - City Living and Psychotic Disorders-Implications of Global Heterogeneity for Theory Development. PMID- 30304487 TI - Early oseltamivir after hospital admission is associated with shortened hospitalization: A five-year analysis of oseltamivir timing and clinical outcomes. AB - Background: Neuraminidase inhibitors (NAIs) are currently the only effective therapy for influenza infections, but few studies have assessed the impact of early NAI therapy in hospitalized patients on clinical outcomes or the patient level factors that determine early NAI delivery. Methods: We conducted a retrospective cohort study of all adults hospitalized in a metropolitan tertiary care hospital with confirmed influenza from April 2009 to March 2014. We performed logistic regression to determine patient-level factors that were associated with early NAI therapy. We analyzed the association of early NAI therapy with hospital length of stay (LOS) and in-hospital mortality using linear and logistic regression, respectively. Results: 699 patients were admitted with influenza during the 5 influenza seasons. 582 (83.4%) received NAI therapy, however, only 26.0% received the first dose within 6 hours of hospitalization (early NAI). Patients with diabetes mellitus or pregnancy were more like to receive early NAI (p=0.01, p<0.001) as were those reporting fever or myalgias at presentation (p=0.002, p=0.005). Immunosuppressed patients were less likely to receive early NAI (p=0.04). Early NAI was associated with shorter hospital LOS (p<0.001). No patients died in the early NAI group compared to 18 deaths in the 399 patients receiving NAI after 6 hours (4.5%) and 4 deaths in the 116 patients not receiving NAI (3.4%). Conclusions: Over multiple influenza seasons, early NAI therapy was associated with shorter LOS in patients admitted with influenza. This suggests that efforts should focus on facilitating earlier therapy in patients with suspected influenza. PMID- 30304488 TI - Estimating conductive sapwood area in diffuse and ring porous trees with electronic resistance tomography. AB - Accurately estimating sapwood area is essential for modelling whole-tree or stand scale transpiration from point-flow sap-flux observations. In this study, we tested the validity of electrical resistance tomography (ERT) to locate the sapwood-heartwood (SW/HW) interface for two ring porous (Quercus nigra L. and Quercus virginiana Mill.) and one diffuse porous (Acer rubrum L.) species. Estimates derived from the ERT analyses were compared with the SW/HW interface measured following dye perfusion testing. The ERT results revealed spatial variation in electrical resistance, with higher resistivity in the inner part of the cross sections. Regression analyses showed that ERT was able to accurately account for 97% and 80% of the variation in sapwood area (calculated as R2) for Q. virginiana (n = 19) and Q. nigra (n = 7), respectively, and 56% of the variation in the diffuse porous species (n = 8). Root mean square error (RMSE) values for sapwood areas of the ring porous species were 11.12 cm2 (19%) and 25.98 cm2 (33%) for Q. virginiana and Q. nigra, respectively. Sapwood area estimates for diffuse wood carried greater error (RMSE = 33.52 cm2 (131%)). Model bias for all sapwood area estimates was negative, suggesting that ERT had a tendency to overestimate sapwood areas. Electrical resistance tomography proved to be a significant predictor of sapwood area in the three investigated species, although it was more reliable for ring porous wood. In addition to the results, a comprehensive code sequence for use with R statistical software is provided, so that other investigators may follow the same method. PMID- 30304489 TI - The association of under-weight and obesity with mortality after hip arthroplasty. AB - Background: although many studies have demonstrated the association between body mass index (BMI) and many diseases, there is little evidence of postoperative mortality after hip arthroplasty. The aim of this study was to evaluate the association between BMI and mortality after hip arthroplasty in the older population. Methods: a total of 3,627 older patients who underwent hip arthroplasty from 2010 to 2013 were included. We used Cox regression analysis to evaluate the association between BMI and mortality after hip arthroplasty. The hazard ratios (HRs) was calculated from 30 days, 31-365 days, and from the first day of surgery to the day of death during the study. Results: under-weight (BMI under 18.5 kg/m2) is significantly associated with increased mortality (HR:1.423; 95% Confidence Interval (CI): 1.023-1.981) after hip arthroplasty compared to the normal range. However, in the short-term mortality within 30 days after surgery, both under-weight (HR: 2.368; 95%CI: 1.130-4.960) and obesity (25-29.9 kg/m2, HR: 2.023; 95%CI: 1.008-4.059) are associated with increased mortality. Conclusion: our study suggested that under-weight is associated with increased risk of mortality after hip arthroplasty. Further, in a short-term outcome, obesity appear to be associated with increased mortality after hip arthroplasty within 30 days. PMID- 30304486 TI - Viroid research and its significance for RNA technology and basic biochemistry. AB - Viroids were described 47 years ago as the smallest RNA molecules capable of infecting plants and autonomously self-replicating without an encoded protein. Work on viroids initiated the development of a number of innovative methods. Novel chromatographic and gelelectrophoretic methods were developed for the purification and characterization of viroids; these methods were later used in molecular biology, gene technology and in prion research. Theoretical and experimental studies of RNA folding demonstrated the general biological importance of metastable structures, and nuclear magnetic resonance spectroscopy of viroid RNA showed the partially covalent nature of hydrogen bonds in biological macromolecules. RNA biochemistry and molecular biology profited from viroid research, such as in the detection of RNA as template of DNA-dependent polymerases and in mechanisms of gene silencing. Viroids, the first circular RNA detected in nature, are important for studies on the much wider spectrum of circular RNAs and other non-coding RNAs. PMID- 30304491 TI - Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections. AB - Background: Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% fT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients. Objectives: To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage. Methods: A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients. Results: A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR >=90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion. Conclusions: Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem susceptible life-threatening infections. PMID- 30304492 TI - The EVcouplings Python framework for coevolutionary sequence analysis. AB - Summary: Coevolutionary sequence analysis has become a commonly used technique for de novo prediction of the structure and function of proteins, RNA, and protein complexes. We present the EVcouplings framework, a fully integrated open source application and Python package for coevolutionary analysis. The framework enables generation of sequence alignments, calculation and evaluation of evolutionary couplings (ECs), and de novo prediction of structure and mutation effects. The combination of an easy to use, flexible command line interface and an underlying modular Python package makes the full power of coevolutionary analyses available to entry-level and advanced users. Availability: https://github.com/debbiemarkslab/evcouplings. PMID- 30304493 TI - PHO15 genes of Candida albicans and Candida parapsilosis encode HAD-type phosphatases dephosphorylating 2-phosphoglycolate. AB - Most of the phosphatases of human fungal pathogens Candida albicans and C. parapsilosis have never been experimentally characterised, although dephosphorylation reactions are central to many biological processes. PHO15 genes of these yeasts have been annotated as the sequences encoding 4-nitrophenyl phosphatase, on the basis of homology to PHO13 gene from the bakers' yeast Saccharomyces cerevisiae. To examine the real function of these potential phosphatases from Candida spp., CaPho15p and CpPho15p were prepared using expression in Escherichia coli and characterised. They share the hallmark motifs of the haloacid dehalogenase superfamily, readily hydrolyse 4-nitrophenyl phosphate at pH 8-8.3 and require divalent cations (Mg2+, Mn2+ or Co2+) as cofactors. CaPho15p and CpPho15p did not dephosphorylate phosphopeptides, but rather hydrolysed molecules related to carbohydrate metabolism. The preferred substrate for the both phosphatases was 2-phosphoglycolate. Among the other molecules tested, CaPho15 showed preference for glyceraldehyde phosphate and beta glycerol phosphate, while CpPho15 dephosphorylated mainly 1,3-dihydroxyacetone phosphate. This type of substrate specificity indicates that CaPho15 and CpPho15 may be a part of metabolic repair system of C. albicans and C. parapsilosis. PMID- 30304494 TI - Multimodal Network Diffusion Predicts Future Disease-Gene-Chemical Associations. AB - Motivation: Precision medicine is an emerging field with hopes to improve patient treatment and reduce morbidity and mortality. To these ends, computational approaches have predicted associations among genes, chemicals and diseases. Such efforts, however, were often limited to using just some available association types. This lowers prediction coverage and, since prior evidence shows that integrating heterogeneous data is likely beneficial, it may limit accuracy. Therefore, we systematically tested whether using more association types improves prediction. Results: We study multimodal networks linking diseases, genes, and chemicals (drugs) by applying three diffusion algorithms and varying information content. Ten-fold cross-validation shows that these networks are internally consistent, both within and across association types. Also, diffusion methods recovered missing edges, even if all the edges from an entire mode of association were removed. This suggests that information is transferable between these association types. As a realistic validation, time-stamped experiments simulated the predictions of future associations based solely on information known prior to a given date. The results show that many future published results are predictable from current associations. Moreover, in most cases, using more association types increases prediction coverage without significantly decreasing sensitivity and specificity. In case studies, literature-supported validation shows that these predictions mimic human-formulated hypotheses. Overall, this study suggests that diffusion over a more comprehensive multimodal network will generate more useful hypotheses of associations among diseases, genes, and chemicals, which may guide the development of precision therapies. Availability: Code and data are available at https://github.com/ChihHsuLin/multimodal-network-diffusion. Supplementary information: See Bioinformatics online. PMID- 30304495 TI - Author's reply to comments from the International Sweeteners Association (ISA) in response to "Revisiting the safety of aspartame" by Arbind Kumar Choudhary and Etheresia Pretorius Nutrition Reviews 2017;75:718-730. PMID- 30304496 TI - Corrigendum for "Revisiting the safety of aspartame" by Arbind Kumar Choudhary and Etheresia Pretorius Nutrition Reviews 2017;75:718-730. PMID- 30304497 TI - Comments from the International Sweeteners Association (ISA) in response to "Revisiting the safety of aspartame" by Arbind Kumar Choudhary and Etheresia Pretorius Nutrition Reviews 2017;75:718-730. PMID- 30304499 TI - It's Time to Make the Time to Viral Suppression After HIV Diagnosis a Metric of HIV Care Success. PMID- 30304498 TI - Deficiencies in health-related quality of life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016. AB - Background: Quality of life (QoL) is a relevant endpoint and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an endpoint in cancer phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of underreporting and delay of publication. Methods: All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about endpoints was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. Results: 446 publications were eligible. In 210 (47.1%), QoL was not included among endpoints. QoL was not an endpoint in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory endpoint, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as endpoint or with missing QoL results was relevant in all tumour types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. Conclusions: QoL is not included among endpoints in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant underreporting and delay in publication. PMID- 30304500 TI - Machine learning based automated dynamic quantification of left heart chamber volumes. AB - Aims: Studies have demonstrated the ability of a new automated algorithm for volumetric analysis of 3D echocardiographic (3DE) datasets to provide accurate and reproducible measurements of left ventricular and left atrial (LV, LA) volumes at end-systole and end-diastole. Recently, this methodology was expanded using a machine learning (ML) approach to automatically measure chamber volumes throughout the cardiac cycle, resulting in LV and LA volume-time curves. We aimed to validate ejection and filling parameters obtained from these curves by comparing them to independent well-validated reference techniques. Methods and results: We studied 20 patients referred for cardiac magnetic resonance (CMR) examinations, who underwent 3DE imaging the same day. Volume-time curves were obtained for both LV and LA chambers using the ML algorithm (Philips HeartModel), and independently conventional 3DE volumetric analysis (TomTec), and CMR images (slice-by-slice, frame-by-frame manual tracing). Automatically derived LV and LA volumes and ejection/filling parameters were compared against both reference techniques. Minor manual correction of the automatically detected LV and LA borders was needed in 4/20 and 5/20 cases, respectively. Time required to generate volume-time curves was 35 +/- 17 s using ML algorithm, 3.6 +/- 0.9 min using conventional 3DE analysis, and 96 +/- 14 min using CMR. Volume-time curves obtained by all three techniques were similar in shape and magnitude. In both comparisons, ejection/filling parameters showed no significant inter-technique differences. Bland-Altman analysis confirmed small biases, despite wide limits of agreement. Conclusion: The automated ML algorithm can quickly measure dynamic LV and LA volumes and accurately analyse ejection/filling parameters. Incorporation of this algorithm into the clinical workflow may increase the utilization of 3DE imaging. PMID- 30304501 TI - Layer-specific strain in acute coronary syndrome: back to the future! PMID- 30304502 TI - Are mechanisms of inflammation joint-specific in osteoarthritis? PMID- 30304503 TI - Attraction of Culex pipiens pallens (Diptera: Culicidae) to Floret Volatiles and Synthetic Blends of Its Nectar Host Plant Abelia chinensis (Rubiales: Caprifoliaceae). AB - Abelia chinensis R. Br. (Dipsacales: Caprifoliaceae) is one of the preferred nectar host plants for Culex pipiens pallens Coquillett (Diptera: Culicidae). However, the volatile compounds of its flowers that might be involved in directing mosquitoes' orientation to its nectaries remain unknown. In the present study, the volatile compounds released by A. chinensis florets were collected by solid phase microextraction fiber and analyzed by gas chromatography-mass spectrometry system. Based on the major component species in the volatile profile, a synthetic phytochemical blend (Blend B, composed of six compounds at their most attractive concentrations) was formulated, and its attractiveness was tested against the pentane extract of A. chinensis florets at most attractive concentration (Blend A) and a formerly developed synthetic phytochemical blend (Blend C) in the olfactometer, respectively. The results revealed that the volatile profile of A. chinensis florets was mainly composed of aromatic compounds, most of which had been reported to be attractive to other mosquito species. The synthetic Blend B was as attractive as Blend A (10-1-fold of the crude pentane extract) in the olfactometer bioassays, but they were not as attractive as the formerly developed Blend C. The present study indicated that quantitative and qualitative differences in the constituents of phytochemical blends could significantly affect their attractiveness to Cx. pipiens pallens, and the capture efficiency of phytochemical attractants deserves further research before being applied in the field. PMID- 30304504 TI - Smoking and Lung Cancer Mortality in the United States From 2015 to 2065: A Comparative Modeling Approach. AB - Background: Tobacco control efforts implemented in the United States since the 1960s have led to considerable reductions in smoking and smoking-related diseases, including lung cancer. Objective: To project reductions in tobacco use and lung cancer mortality from 2015 to 2065 due to existing tobacco control efforts. Design: Comparative modeling approach using 4 simulation models of the natural history of lung cancer that explicitly relate temporal smoking patterns to lung cancer rates. Setting: U.S. population, 1964 to 2065. Participants: Adults aged 30 to 84 years. Measurements: Models were developed using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010). Each model projected lung cancer mortality by smoking status under the assumption that current decreases in smoking would continue into the future (status quo trends). Sensitivity analyses examined optimistic and pessimistic scenarios. Results: Under the assumption of continued decreases in smoking, age-adjusted lung cancer mortality was projected to decrease by 79% between 2015 and 2065. Concomitantly, and despite the expected growth, aging, and longer life expectancy of the U.S. population, the annual number of lung cancer deaths was projected to decrease from 135 000 to 50 000 (63% reduction). However, 4.4 million deaths from lung cancer are still projected to occur in the United States from 2015 to 2065, with about 20 million adults aged 30 to 84 years continuing to smoke in 2065. Limitation: Projections assumed no changes to tobacco control efforts in the future and did not explicitly consider the potential effect of lung cancer screening. Conclusion: Tobacco control efforts implemented since the 1960s will continue to reduce lung cancer rates well into the next half-century. Additional prevention and cessation efforts will be required to sustain and expand these gains to further reduce the lung cancer burden in the United States. Primary Funding Source: National Cancer Institute. PMID- 30304506 TI - Host and microbial factors in kidney transplant recipients with Escherichia coli acute pyelonephritis or asymptomatic bacteriuria: a prospective study using whole genome sequencing. AB - Background: Urinary tract infection is the most common infection among kidney transplant recipients (KTRs). Many transplant physicians fear that host compromise will allow low-virulence strains to cause pyelonephritis in KTRs, so they often treat asymptomatic bacteriuria with antibiotics. Identification of the host/microbe factors that determine the clinical presentation (i.e. pyelonephritis versus asymptomatic bacteriuria) once an Escherichia coli strain enters a KTRs bladder could inform management decisions. Methods: We prospectively collected all E. coli isolates causing either pyelonephritis or asymptomatic bacteriuria in KTRs at our institution (December 2012-June 2015). Whole-genome sequencing was used to assess bacterial characteristics (carriage of 48 virulence genes and phylogenetic and clonal background). Host parameters were also collected. Results: We analysed 72 bacteriuria episodes in 54 KTRs (53 pyelonephritis, 19 asymptomatic bacteriuria). The pyelonephritis and asymptomatic bacteriuria isolates exhibited a similar total virulence gene count per isolate [median 18 (range 5-33) and 18 (5-30), respectively; P = 0.57] and for individual virulence genes differed significantly only for the prevalence of the pap operon (pyelonephritis 39%,versus asymptomatic bacteriuria 0%; P = 0.002). No other significant between-group differences were apparent for 86 other bacterial and host variables. Conclusions: Our findings suggest that bacterial adherence plays a role in the pathogenesis of pyelonephritis in KTRs despite significantly altered host urinary tract anatomy and weakened immunity. Whether KTRs might benefit from targeted therapies (e.g. vaccination or inhibitors of fimbrial adhesion) has yet to be studied. PMID- 30304505 TI - Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP): An Overview and Lessons Learned. AB - Objective: The objective of Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP), a multiphase surveillance study characterizing the burden of disease in South Asia, was to inform data collection for prospective surveillance and to capture clinical aspects of disease. Methods: Through a retrospective record review conducted at hospitals in Bangladesh, India, Nepal, and Pakistan, we examined laboratory and clinical records to assess the culture positivity rate for Salmonella Typhi and Salmonella Paratyphi, age and sex distribution, and antimicrobial susceptability in each country. Results: Of all blood cultures performed in Bangladesh, India, Nepal, and Pakistan, 1.5%, 0.43%, 2%, and 1.49%, respectively, were positive for S. Typhi and 0.24%, 0.1%, 0.5%, and 0.67%, respectively, were positive for S. Paratyphi. A higher proportion of laboratory confirmed infections in Bangladesh and Pakistan were aged <=5 years, while India and Nepal had a higher proportion of participants aged 15-25 years. In all countries, the sex of the majority of participants was male. The majority of isolates in all countries were resistant to fluoroquinolones, with a high proportion also resistant to ampicillin, chloramphenicol, and trimethoprim sulfamethoxazole. Discussion: Enteric fever remains endemic in South Asia. Data generated by this study can help inform strategies for implementation and evaluation of prevention and control measures. PMID- 30304507 TI - Modulation of quorum sensing-controlled virulence factors in Chromobacterium violaceum by selective amino acids. AB - Bacterial pathogenesis regulation requires N-acyl homoserine lactone (AHL)-based quorum sensing (QS). The main objective of this study was to assess the anti-QS and anti-biofilm potential of five different amino acids, namely serine, aspartic acid, lysine, leucine and tryptophan. The selected amino acids were assessed for their ability to inhibit QS activity via such mechanisms as exopolysaccharide (EPS) production, biofilm formation, pigment production in Chromobacterium violaceum and swarming motility. At 0.684 mM concentration, lysine inhibited the biofilm formation by 16% at 24 h, chitinolytic activity by 88.3% at 24 h and EPS production by 12.5% at 24 h. It also exhibited inhibition of swarming motility in C. violaceum. Confocal laser scanning microscopy revealed a decrease in the average thickness of the biofilms when treated with lysine. Modulation in the expression of cvi I and cvi A was observed when treated with all the amino acids, with the greatest reduction observed with lysine. Our results conclude that the amino acid lysine showed anti-QS and significant anti-biofilm activities; it could be further exploited as a main constituent in the synthesis of peptide/protein, and testing the same for treatment of bacterial infections, eventually reducing the utilization of conventional antibiotics. PMID- 30304508 TI - Structure of the Ambrosia Beetle (Coleoptera: Curculionidae) Mycangia Revealed Through Micro-Computed Tomography. AB - Ambrosia beetles (Coleoptera: Curculionidae: Scolytinae and Platypodinae) rely on a symbiosis with fungi for their nutrition. Symbiotic fungi are preserved and transported in specialized storage structures called mycangia. Although pivotal in the symbiosis, mycangia have been notoriously difficult to study, given their minute size and membranous structure. We compared the application of novel visualization methods for the study of mycangia, namely micro-computed tomography (micro-CT) and laser ablation tomography (LATscan) with traditional paraffin sectioning. Micro-CT scanning has shown the greatest promise in new organ discovery, while sectioning remains the only method with sufficient resolution for cellular visualization. All three common types of mycangia (oral, mesonotal, and pronotal) were successfully visualized and presented for different species of ambrosia beetles: Ambrosiodmus minor (Stebbing) 1909, Euplatypus compositus (Say) 1823, Premnobius cavipennis Eichhoff 1878, Scolytoplatypus raja Blandford 1893, Xylosandrus crassiusculus (Motschulsky) 1866 and X. amputatus (Blandford) 1894. A reconstruction of the mycangium and the surrounding musculature in X. amputatus is also presented. The advantages of micro-CT compared to the previously commonly used microtome sectioning include the easy visualization and recording of three dimensional structures, their position in reference to other internal structures, the ability to distinguish natural aberrations from technical artifacts, and the unprecedented visualizations of the anatomic context of mycangia enabled by the integrated software. PMID- 30304509 TI - Guidelines for enhanced recovery after lung surgery: recommendations of the Enhanced Recovery After Surgery (ERAS(r)) Society and the European Society of Thoracic Surgeons (ESTS). AB - Enhanced recovery after surgery is well established in specialties such as colorectal surgery. It is achieved through the introduction of multiple evidence based perioperative measures that aim to diminish postoperative organ dysfunction while facilitating recovery. This review aims to present consensus recommendations for the optimal perioperative management of patients undergoing thoracic surgery (principally lung resection). A systematic review of meta analyses, randomized controlled trials, large non-randomized studies and reviews was conducted for each protocol element. Smaller prospective and retrospective cohort studies were considered only when higher-level evidence was unavailable. The quality of the evidence base was graded by the authors and used to form consensus recommendations for each topic. Development of these recommendations was endorsed by the Enhanced Recovery after Surgery Society and the European Society for Thoracic Surgery. Recommendations were developed for a total of 45 enhanced recovery items covering topics related to preadmission, admission, intraoperative care and postoperative care. Most are based on good-quality studies. In some instances, good-quality data were not available, and subsequent recommendations are generic or based on data extrapolated from other specialties. In other cases, no recommendation can currently be made because either equipoise exists or there is a lack of available evidence. Recommendations are based not only on the quality of the evidence but also on the balance between desirable and undesirable effects. Key recommendations include preoperative counselling, nutritional screening, smoking cessation, prehabilitation for high-risk patients, avoidance of fasting, carbohydrate loading, avoidance of preoperative sedatives, venous thromboembolism prophylaxis, prevention of hypothermia, short-acting anaesthetics to facilitate early emergence, regional anaesthesia, nausea and vomiting control, opioid-sparing analgesia, euvolemic fluid management, minimally invasive surgery, early chest drain removal, avoidance of urinary catheters and early mobilization after surgery. These guidelines outline recommendations for the perioperative management of patients undergoing lung surgery based on the best available evidence. As the recommendation grade for most of the elements is strong, the use of a systematic perioperative care pathway has the potential to improve outcomes after surgery. PMID- 30304510 TI - Fast and global detection of periodic sequence repeats in large genomic resources. AB - Periodically repeating DNA and protein elements are involved in various important biological events including genomic evolution, gene regulation, protein complex formation, and immunity. Notably, the currently used genome editing tools such as ZFNs, TALENs, and CRISPRs are also all associated with periodically repeating biomolecules of natural organisms. Despite the biological importance of periodically repeating sequences and the expectation that new genome editing modules could be discovered from such periodical repeats, no software that globally detects such structured elements in large genomic resources in a high throughput and unsupervised manner has been developed. We developed new software, SPADE (Search for Patterned DNA Elements), that exhaustively explores periodic DNA and protein repeats from large-scale genomic datasets based on k-mer periodicity evaluation. With a simple constraint, sequence periodicity, SPADE captured reported genome-editing-associated sequences and other protein families involving repeating domains such as tetratricopeptide, ankyrin and WD40 repeats with better performance than the other software designed for limited sets of repetitive biomolecular sequences, suggesting the high potential of this software to contribute to the discovery of new biological events and new genome editing modules. PMID- 30304511 TI - Mass drug administration with dihydroartemisinin-piperaquine and malaria transmission dynamics in The Gambia - a prospective cohort study. AB - Background: Mass drug administration (MDA) may further reduce malaria transmission in low transmission areas. The impact of MDA on dynamics of malaria transmission was determined in a prospective cohort study. Methods: Annual rounds of MDA with dihydroartemisinin-piperaquine (DP) were implemented over two years (2014 and 2015) in six village pairs before the malaria transmission season. Monthly blood samples were collected from all residents between July and December for microscopy and nested PCR. The incidence and prevalence of infection and clinical disease, and the risk of malaria re-infection post-MDA were determined. Results: Coverage of three DP doses was 68.2% (2014) and 65.6% (2015), compliance was greater than 80%. Incidence of infection was significantly lower in 2014 (IR=0.2 PPY) than in 2013 (IR=1.1 PPY) (P<0.01); monthly infection prevalence declined in the first three months post-MDA. Clinical malaria incidence was significantly lower in 2014 (IR=0.1 PPY) and 2015 (IR=0.2 PPY) than in 2013 (IR=0.4 PPY) (P<0.01) but remained higher in eastern Gambia. Individuals infected before MDA had a 2-fold higher odds of re-infection post-MDA (AOR=2.5, 95% CI: 1.5-4.3, P<0.01). Conclusions: MDA reduced malaria infection and clinical disease during the first months of each transmission season. The reduction was maintained in low transmission areas, but not in eastern Gambia. One MDA round could be followed by focal MDA targeting individuals found infected during the dry season. Repeated MDA rounds, some of them during the dry season over a much larger geographical area, may result in a more marked and sustained decrease of malaria transmission. PMID- 30304512 TI - Low levels of NMNAT2 compromise axon development and survival. AB - NMNAT2 is an endogenous axon maintenance factor that preserves axon health by blocking Wallerian-like axon degeneration. Mice lacking NMNAT2 die at birth with severe axon defects in both the PNS and CNS so a complete absence of NMNAT2 in humans is likely to be similarly harmful, but probably rare. However, there is evidence of widespread natural variation in human NMNAT2 mRNA expression so it is important to establish whether reduced levels of NMNAT2 have consequences that impact health. Whilst mice that express reduced levels of NMNAT2, either those heterozygous for a silenced Nmnat2 allele, or compound heterozygous for one silenced and one partially silenced Nmnat2 allele, remain overtly normal into old age, we now report that Nmnat2 compound heterozygote mice present with early and age-dependent peripheral nerve axon defects. Compound heterozygote mice already have reduced numbers of myelinated sensory axons at 1.5 months and lose more axons, likely motor axons, between 18 and 24 months and, crucially, these changes correlate with early temperature insensitivity and a later-onset decline in motor performance. Slower neurite outgrowth and increased sensitivity to axonal stress are also evident in primary cultures of Nmnat2 compound heterozygote superior cervical ganglion neurons. These data reveal that reducing NMNAT2 levels below a particular threshold compromises the development of peripheral axons and increases their vulnerability to stresses. We discuss the implications for human neurological phenotypes where axons are longer and have to be maintained over a much longer lifespan. PMID- 30304513 TI - Temporal Trends in Adoption and Outcomes of Transcatheter Aortic Valve Implantation: A Swisstavi Registry Analysis. AB - Aims: To describe temporal trends in adoption and performance of transcatheter aortic valve implantation (TAVI) in Switzerland over a period of 5 years. Methods and Results: Between 2011 and 2015, a total of 3'493 patients were consecutively included in the SwissTAVI Registry (NCT01368250) and analyzed for the purpose of this study. The primary outcome measure was all-cause mortality at 1-year after TAVI. Over the five-year period, a six-fold increase in the number of procedures was observed, whereas the baseline surgical risk estimated by the Society of Thoracic Surgeon (STS) score declined (from 6.8 +/- 4.4% to 4.6 +/- 3.6, p < 0.001). Overall, 1-year mortality amounted to 12.8%; mortality was highest in the first annual cohorts (14.6%, 14.8% and 15.9% in 2011, 2012 and 2013, respectively) and decreased to 13.4% in 2014 and 9.7% in 2015, with a significant temporal trend. While rates of cerebrovascular events, peri-procedural myocardial infarction, moderate/severe paravalvular regurgitation and stage 3 acute kidney injury did not significantly change over time, a significant reduction in life threatening or major bleeding was noted during the latest compared with earlier years of recruitment. Conclusions: This long-term recruitment analysis of a national TAVI registry showed rapid adoption paralleled by a progressive decrease of patients' baseline risk profile. Early and late survival significantly improved over time as did the rate of life threatening or major bleeding. PMID- 30304514 TI - Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. AB - LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, which are often seen in mitochondrial DNA (mtDNA) diseases and other muscle disorders. However, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation Complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1alpha subunit of PDH, which inhibits enzyme activity. Blocking E1alpha phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild type LonP1 in siblings' fibroblasts down-regulated phosphoE1alpha. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1alpha, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which may promote severe neurologic impairment and neurodegeneration. PMID- 30304516 TI - Multiplication of the SNCA locus exacerbates neuronal nuclear aging. AB - Human induced Pluripotent Stem Cell (hiPSC)-derived models have advanced the study of neurodegenerative diseases, including Parkinson's (PD). While age is the strongest risk factor for these disorders, hiPSC-derived models represent rejuvenated neurons. We developed hiPSC-derived Aged dopaminergic and cholinergic neurons to model PD and related synucleinopathies. Our new method induces aging through a 'semi-natural' process, by passaging multiple times at the Neural Precursor Cell stage, prior to final differentiation. Characterization of isogenic hiPSC-derived neurons using heterochromatin and nuclear envelope markers, as well as DNA damage and global DNA methylation validated our age inducing method. Next, we compared neurons derived from a patient with SNCA triplication (SNCA-Tri) and a Control. The SNCA-Tri neurons displayed exacerbated nuclear aging, showing advanced-aging signatures already at the Juvenile stage. Noteworthy, the Aged SNCA-Tri neurons showed more alpha-synuclein aggregates per cell versus the Juvenile. We suggest a link between the effects of aging and SNCA overexpression on neuronal nuclear architecture. PMID- 30304515 TI - Protective Efficacy and Long-Term Immunogenicity in Cynomolgus Macaques by Ebola Virus Glycoprotein Synthetic DNA Vaccines. AB - Background: There remains an important need for prophylactic anti-Ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines. Methods: We designed novel synthetic anti-Ebola virus glycoprotein (EBOV-GP) DNA vaccines as a strategy to expand protective breadth against diverse EBOV strains and evaluated the impact of vaccine dosing and route of administration on protection against lethal EBOV-Makona challenge in cynomolgus macaques. Long-term immunogenicity was monitored in nonhuman primates for >1 year, followed by a 12-month boost. Results: Multiple-injection regimens of the EBOV-GP DNA vaccine, delivered by intramuscular administration followed by electroporation, were 100% protective against lethal EBOV-Makona challenge. Impressively, 2 injections of a simple, more tolerable, and dose-sparing intradermal administration followed by electroporation generated strong immunogenicity and was 100% protective against lethal challenge. In parallel, we observed that EBOV-GP DNA vaccination induced long-term immune responses in macaques that were detectable for at least 1 year after final vaccination and generated a strong recall response after the final boost. Conclusions: These data support that this simple intradermal-administered, serology-independent approach is likely important for additional study towards the goal of induction of anti EBOV immunity in multiple at-risk populations. PMID- 30304517 TI - Characterization of Cell Fusion in an Experimental Mouse Model of Endometriosis. AB - Cell fusion is involved in the development of some adult organs, is implicated in the pathogenesis of specific types of cancer, and is known to participate in repair/regeneration processes mediated by bone-marrow derived cells (BMDCs). Endometriosis is a disease characterized by growth of functional endometrial tissue outside of the uterine cavity. Endometriosis shares some molecular properties with cancer and BMDCs home to endometriosis lesions in a mouse model. Our objective was to determine if cell fusion can occur in endometriosis and establish whether bone marrow derived cells participate in cell fusion events in lesions. We employed a Cre-Lox system to identify cell fusion events in a mouse model of endometriosis. Fused cells were detected in endometriotic lesions, albeit at a low frequency (~1 in 400 cells), localized to the stromal compartment, and displayed restricted proliferation. Using 5-fluorouracil-based non-gonadotoxic bone marrow transplantation model, we demonstrate that bone marrow cells represent a principal cell source for fusion events in lesions. Cell fusion progeny uniformly lacked expression of selected markers of hematopoietic, endothelial, and epithelial markers, though they expressed the mesenchymal/stromal markers Sca-1 and CD29. This study is first to describe the phenomenon of cell fusion in endometriosis and points to a mesenchymal population derived from cell fusion events with limited proliferative activity, properties previously attributed to endometrial stem cells. Their putative role in the pathogenesis of the disease remains to be elucidated. PMID- 30304518 TI - Transcranial Direct Current Stimulation Improves Semantic Speech-Gesture Matching in Patients With Schizophrenia Spectrum Disorder. AB - Background: Patients with schizophrenia spectrum disorders (SSD) have severe deficits in speech and gesture processing that contribute considerably to the burden of this disorder. Brain imaging shows left inferior frontal gyrus involvement for impaired processing of co-verbal gestures in patients with schizophrenia. Recently, transcranial direct current stimulation (tDCS) of the left frontal lobe has been shown to modulate processing of co-verbal gestures in healthy subjects. Although tDCS has been used to reduce symptoms of patients with SSD, the effects of tDCS on gesture processing deficits remain hitherto unexplored. Objective: Here we tested the hypothesis that inhibitory cathodal tDCS of the left frontal lobe decreases pathological dysfunction and improves semantic processing of co-verbal gestures in patients with SSD. Methods: We measured ratings and reaction times in a speech-gesture semantic relatedness assessment task during application of frontal, frontoparietal, parietal, and sham tDCS to 20 patients with SSD and 29 healthy controls. Results: We found a specific effect of tDCS on speech-gesture relatedness ratings of patients. Frontal compared to parietal and sham stimulation significantly improved the differentiation between related and unrelated gestures. Placement of the second electrode (right frontal vs parietal) did not affect the effect of left frontal stimulation, which reduced the preexisting difference between patients and healthy controls. Conclusion: Here we show that left frontal tDCS can improve semantic co-verbal gesture processing in patients with SSD. tDCS could be a viable tool to normalize processing in the left frontal lobe and facilitate direct social communicative functioning in patients with SSD. PMID- 30304519 TI - Spontaneous tumor lysis syndrome ocurring in untreated gastric adenocarcinma. AB - Tumor lysis syndrome (TLS) is an oncologic emergency. It's characterized by laboratory findings of hyperkaliemia, hyperuricemia, hyperphosphatemia, and hypocalcemia. Disruption is caused by massive tumor cell lysis in which the contents os the lysed tumor cells are released into bloodstream. TLS is a complication that occurs more frequently in hematological tumors or with a large tumor burden, but what is exceptional its appearance spontaneously (STLS). In this article, we report a case of STLS in a patient with gastric adenocarcinoma. Only three cases of spontaneous SLT had been described previously in literature. PMID- 30304520 TI - Proposing a New Indicator for the National Human Immunodeficiency Virus/AIDS Strategy: Percentage of Newly Diagnosed Persons Achieving Viral Suppression Within 3 Months of Diagnosis. AB - We propose an outcome indicator, the percentage of newly diagnosed persons achieving viral suppression within 3 months of diagnosis, to be included in the US National HIV/AIDS Strategy to monitor the progress in human immunodeficiency virus (HIV) care among persons newly diagnosed with HIV. Using HIV registry data, we reported that the percentage in New York City increased from 9% in 2007 to 37% in 2016. We recommend that the Centers for Disease Control and Prevention and local health agencies use this new indicator to monitor the progress in HIV care among persons newly diagnosed with HIV in the United States. PMID- 30304521 TI - Development and Validation of Social Motivation Questionnaire. AB - Background and Objectives: Information-seeking (IS) and emotion-regulatory (ER) motivation play meaningful roles in age-related changes in social interaction across adulthood. This study aimed to develop and validate the Social Motivation Questionnaire (SMQ) to assess these two types of motivation. Research Design and Methods: Ten items were selected from a pool as the candidate items of SMQ and were administered to 480 German adults (20-91 years old) for validation. These items were also administered to 150 U.S. (18-40 years old) and 131 Hong Kong younger adults (18 to 26 years old) for cultural-invariance examination. Results: Exploratory and confirmatory factor analyses showed that a two-factor, eight-item structure fits the German adults' data well with satisfactory reliability. Multigroup comparisons showed cross-age invariance among younger, middle-aged, and older German adults, as well as cross-cultural invariance among German, U.S., and Hong Kong younger adults. Discussion and Implications: A new questionnaire, SMQ, was developed and validated to measure IS and ER social motivation across adulthood and across cultures. PMID- 30304522 TI - Update on the Management of Calciphylaxis. AB - Calciphylaxis is a disease of significant morbidity and mortality, predominantly affecting dialysis patients. The term 'calciphylaxis' was coined by Seyle et al in 1961 to describe calcium deposition in the skin and subcutaneous soft tissue of uremic rats in response to 'triggers' (e.g. trauma, metallic salts) after exposure to 'sensitizing agents' (e.g. vitamin D and parathyroid hormone). In humans, calciphylaxis, however, is not a disorder of induced hypersensitivity. Instead, it is a disorder of cutaneous microvascular occlusion caused by thrombosis and calcification. Progressive, excruciatingly painful, non-healing wounds develop in these patients, predisposing them to high risk of sepsis and death. Calciphylaxis has no approved therapies. Increased awareness and research in this field have facilitated identification of risk factors and causation pathways. Development of therapeutic options and wound care management, however, are still at a nascent stage. Certain therapies have shown a promise that needs evaluation in prospective clinical trials. It is hoped that ongoing research will help us better understand the pathogenesis of this complex disease and develop efficacious treatment options. In this review, we outline the components involved in calciphylaxis diagnosis and treatment. PMID- 30304523 TI - Expression Analysis of Long Non-Coding RNA HAR1A and HAR1B in HBV-Induced Hepatocullular Carcinoma in Chinese Patients. AB - Objective: To determine the clinical relevance of long noncoding RNA (lncRNA) HAR1A and HAR1B expression in hepatocellular carcinoma (HCC). Methods: In this study, we enrolled 50 cases of chronic hepatitis B (CHB) without cirrhosis, 50 cases of CHB and liver cirrhosis (LC), and 100 cases of HBV and HCC. The expression profiles of lncRNA HAR1A and HAR1B were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: The expression levels of HAR1A and HAR1B were significantly lower in the HCC group, compared with the CHB and LC groups (P <.01). HAR1A and HAR1B were negatively associated with histologic grade and TNM (tumor/nodes/metastasis) stage (all P <.05). Univariable multivariable analysis showed that decreased HAR1A (HR = 0.753, P = .02) and HAR1B (HR = 0.551, P = .01) levels were independent predictors for shorter overall survival (OS) in HCC. Conclusion: Decreased HAR1A and HAR1B expression in HCC indicates poor prognosis. PMID- 30304524 TI - Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease. AB - Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly-conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections, and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients. PMID- 30304525 TI - Taking preventative health messages into the wider caring professions: the views of housing staff and tenants. AB - Background: In order to harness the potential impact of the wider public health workforce, innovative services are providing opportunities for social housing staff to extend their public health role. This study explored the views of housing professionals and social housing residents on the delivery of preventative health messages by housing staff in the context of the evaluation of the roll-out of a new service. Methods: We conducted semi structured interviews with 21 neighbourhood housing officers, 4 managers and 30 social housing tenants to understand their views on the widening role and the potential impact on the preventative healthcare messages being delivered. Results: Neighbourhood officers were willing to discuss existing health conditions with tenants; but they often did not feel comfortable discussing their lifestyle choices. Most tenants also reported that they would feel discussions around lifestyle behaviours to be intrusive and outside the remit of housing staff. Conclusions: Resistance to discussions of lifestyle topics during home visits was found among both housing staff and tenants. Appropriate staff training and the development of strong and trusting relationships between officers and tenants is needed, if similar programmes to extend the role of housing staff are to succeed in terms of health impact. PMID- 30304526 TI - Serum chemerin levels are negatively associated with male fertility and reproductive hormones. AB - STUDY QUESTION: Are chemerin levels different in subfertile men compared to men from the general population, and how does chemerin relate to reproductive hormonal status? SUMMARY ANSWER: Chemerin is negatively associated to LH, SHBG and estradiol and lower levels of chemerin are detected among subfertile men compared to controls. WHAT IS KNOWN ALREADY: Adipokines have pleiotropic effects on tissue homeostasis and have been shown to affect both sex steroid production and action. Among adipokines the newly characterized chemokine chemerin is suggested to influence testosterone production in males, but whether serum levels associate with testosterone or male subfertility has not yet been reported. STUDY DESIGN, SIZE, DURATION: Case control study comprising a consecutive group of men from infertile couples referred to Reproductive Medicine Centre at Skane University Hospital from 2006 through 2012, and age-matched controls. Participants were enrolled in years 2011-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Males from infertile couples (n = 180) aged 18-50 years with sperm concentration <20 * 106/ml and age-matched controls (n = 139) from the general population were enrolled. Serum concentrations of total testosterone (TT), calculated free testosterone (cFT), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2) and sex-hormone binding globuline (SHBG) as well as the adipokines chemerin, adiponectin and leptin were measured. Anthropometrics and biochemical parameters of glucose and lipid metabolism were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Chemerin levels were lower in subfertile men compared to controls (mean diff. 7.1 ng/ml; 95% CI, 3.7; 11 ng/ml; P < 0.001) even after adjustment for BMI. After adjustment for age, BMI, smoking, leptin and adiponectin, chemerin associated negatively with LH (beta = -4.2; P = 0.02), E2 (beta = -10; P = 0.004) and SHBG (beta = -7.4, P = 0.003). Men with elevated LH levels had lower chemerin levels compared to those with LH levels within the normal range (mean diff. 4.8 ng/ml; 95% CI, 0.16; 9.4 ng/ml; P = 0.04). LIMITATIONS, REASONS FOR CAUTION: Single sample blood test with immunoassays for determination of hormone levels. Heterogeneous group of subfertile subjects. WIDER IMPLICATIONS OF THE FINDINGS: Even though chemerin has been positively associated with BMI, inverse association with subfertility suggests that it is independently linked to reproductive function, a hypothesis that warrants further assessment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from EU Interreg V (ReproUnion) program as well as Swedish Governmental Fund for Clinical Research. The authors have no conflicts of interest. PMID- 30304527 TI - Education Differentially Buffers Cognitive Performance in Black and White Older Adults. AB - Objectives: Given that black American older adults are more likely to have lower educational attainment and perform worse on cognitive tests than white Americans, we examined whether increased education would confer greater cognitive advantage to black Americans on measures of global and specific domains of cognitive function. Methods: The sample included 522 community-dwelling older adults from a larger study. An analysis of covariance was conducted with race and education as between-participant factors and global cognition as the dependent variable. A multivariate analysis of covariance was conducted with five cognitive domains (immediate memory, visuospatial/constructional ability, language, attention, and delayed memory) as the dependent variables. Results: Significant main effects indicated that black Americans, F(1,516) = 29.18, p < .001, and individuals with less education, F(1,516) = 44.93, p < .001, evidenced lower cognitive functioning, controlling for age and overall health status, and the interaction term reached statistical significance, F(1,516) = 7.95, p = .005. The impact of education on global cognitive function for black participants was more than twice as large (Cohen's d = 1.30) than for white participants (Cohen's d = .52). There was a significant race * education interaction for the cognitive domain of attention (p < .001) and a composite measure of non-memory domains (i.e., language, visuospatial/constructional, and attention; p < .001). Discussion: Our findings suggest that educational attainment is particularly important for black Americans with respect to global cognitive function, attention, and non-memory domains. PMID- 30304528 TI - Ultraviolet radiation exposure time and intensity modulate tomato resistance against herbivory through activation of the jasmonic acid signaling. AB - Ultraviolet (UV) radiation modulates plant defenses against herbivorous arthropods. We investigated how different UV exposure times and irradiance intensities affected tomato (Solanum lycopersicum) resistance against thrips (Frankliniella occidentalis). We assessed UV effects on thrips-associated damage and host-selection, selected metabolites and phytohormone content, expression of defense-related genes, and trichome density and chemistry, the latter having a dual role in defense and UV protection. Short UV daily exposure times increased thrips resistance in the tomato cultivar 'Moneymaker'. This UV-mediated induction of tomato defenses against thrips was not explained by changes in the content of selected leaf polyphenols or terpenes, nor trichome-associated defenses. UV irradiance intensity also affected tomato resistance against thrips. Further analysis using the tomato mutants def-1, impaired in jasmonic acid (JA) biosynthesis, od-2, defective in the production of functional type-VI trichomes, and their wild-type 'Castlemart' showed that UV enhanced thrips resistance in Moneymaker and od-2, but not in def-1 and Castlemart. UV increased salicylic acid (SA) and JA-Isoleucine concentrations, and expression of SA- and JA-associated genes in Moneymaker, while inducing expression of JA-defensive genes in od-2. Our results demonstrate that UV-mediated enhancement of tomato resistance to thrips is likely associated with the activation of JA-associated signaling, but not with plant secondary metabolism or trichome-related traits. PMID- 30304529 TI - Diversity of Rickettsiae in Feeding and Questing Ticks Collected From a Malaysian Forest Reserve Area. AB - High seropositivity to Rickettsia conorii and Rickettsia felis has been reported in Malaysian indigenous community living in settlements adjacent to forest areas. The current study was conducted to determine the type and distribution of rickettsiae in feeding and questing ticks that were collected from a forest reserve area at Kuala Lompat in Pahang, Malaysia. Using PCR assays targeting citrate synthase (gltA), outer membrane protein A (ompA) and B (ompB) genes, rickettsiae were detected from approximately one-third of 98 ticks (mainly Dermacentor and Haemaphysalis spp.) collected from the forest reserve. BLAST analysis reveals the predominance of Rickettsia sp. RF2125 in both feeding and questing ticks and Rickettsia sp. TCM1 in the questing ticks. Sequences exhibiting close genetic relationship with Rickettsia raoultii, Rickettsia tamurae, Rickettsia heilongjiangensis, and Rickettsia asiatica were also detected from the ticks. This study highlights the diversity of rickettsial species and potential tick vectors which may contribute to the high seropositivity observed among the local communities. PMID- 30304530 TI - Oxygen and Arsenite Synergize Phosphine Toxicity by Distinct Mechanisms. AB - Phosphine is the only fumigant approved globally for general use to control insect pests in stored grain. Due to the emergence of resistance among insect pests and the lack of suitable alternative fumigants, we are investigating ways to synergistically enhance phosphine toxicity, by studying the mechanism of action of known synergists, such as oxygen, temperature, and arsenite. Under normoxia, exposure of the model organism C. elegans for 24 hours at 20 degrees C to 70 ppm phosphine resulted in 10% mortality, but nearly 100% mortality if the oxygen concentration was increased to 80%. In wild type C. elegans, toxicity of phosphine was negatively affected by a decrease in temperature to 15 degrees C and positively affected by an increase in temperature to 25 degrees C. The dld 1(wr4) strain of C. elegans is resistant to phosphine due to a mutation in the dihydrolipoamide dehydrogenase gene. It also exhibits increased mortality that is dependent on hyperoxia, when exposed to 70 ppm phosphine at 20 degrees C. As with the wild type strain, mortality decreased when exposure was carried out at 15 degrees C. At 25 degrees C, however, the strain was completely resistant to the phosphine exposure at all oxygen concentrations. Arsenite is also a synergist of phosphine toxicity, but only in the dld-1(wr4) mutant strain. Thus, exposure to 4 mM arsenite resulted in 50% mortality, which increased to 89% mortality when 70 ppm phosphine and 4 mM arsenite were combined. In stark contrast, 70 ppm phosphine rendered 4 mM arsenite non-toxic to wild type C. elegans. These results reveal two synergists with distinct modes of action, one of which targets individuals that carry a phosphine resistance allele in the dihydrolipoamide dehydrogenase gene. PMID- 30304533 TI - An Outbreak of Human Parvovirus B19 Hidden by Dengue Fever. AB - Background: Seasonal outbreaks of dengue often result in hundreds of dengue suspected cases where a clinical diagnosis cannot be confirmed. Usually, during large outbreaks of dengue and other pathogens that can cause acute febrile illnesses, the search for secondary pathogens with similar disease outcomes is rare. Methods: Using total RNA sequencing and targeted diagnostic assays, we discovered an outbreak of parvovirus B19 in dengue-suspected patients that occurred from November 2013 to February 2014. Results: Of the 182 cases investigated, 63% were viremic for the B19 virus. Moreover, we found that >43% of infected patients had no serological evidence of prior infection. Parvovirus B19 is a typical childhood infection, yet we observed that 82% of the infected patients were adults. Additionally, we perceived that infected adults had significantly higher presentations of myalgia than in children. We also obtained viral protein (VP) 1/VP2 gene nucleotide sequences from 43 patients. Conclusions: Our results support the utility of next-generation sequencing for symptomatic patients with unknown etiologies during seasonal outbreaks of dengue and other arborviruses. Our findings could improve the vigilance of hospitals and laboratories by raising awareness of co-circulating pathogens such as parvovirus B19 that may be hidden in plain sight. PMID- 30304532 TI - Streptococcus suis contains multiple phase-variable methyltransferases that show a discrete lineage distribution. AB - Streptococcus suis is a major pathogen of swine, responsible for a number of chronic and acute infections, and is also emerging as a major zoonotic pathogen, particularly in South-East Asia. Our study of a diverse population of S. suis shows that this organism contains both Type I and Type III phase-variable methyltransferases. In all previous examples, phase-variation of methyltransferases results in genome wide methylation differences, and results in differential regulation of multiple genes, a system known as the phasevarion (phase-variable regulon). We hypothesized that each variant in the Type I and Type III systems encoded a methyltransferase with a unique specificity, and could therefore control a distinct phasevarion, either by recombination-driven shuffling between different specificities (Type I) or by biphasic on-off switching via simple sequence repeats (Type III). Here, we present the identification of the target specificities for each Type III allelic variant from S. suis using single-molecule, real-time methylome analysis. We demonstrate phase variation is occurring in both Type I and Type III methyltransferases, and show a distinct association between methyltransferase type and presence, and population clades. In addition, we show that the phase-variable Type I methyltransferase was likely acquired at the origin of a highly virulent zoonotic sub-population. PMID- 30304531 TI - New Insight into Parrots' Mitogenomes Indicates That Their Ancestor Contained a Duplicated Region. AB - Mitochondrial genomes of vertebrates are generally thought to evolve under strong selection for size reduction and gene order conservation. Therefore, a growing number of mitogenomes with duplicated regions changes our view on the genome evolution. Among Aves, order Psittaciformes (parrots) is especially noteworthy because of its large morphological, ecological, and taxonomical diversity, which offers an opportunity to study genome evolution in various aspects. Former analyses showed that tandem duplications comprising the control region with adjacent genes are restricted to several lineages in which the duplication occurred independently. However, using an appropriate polymerase chain reaction strategy, we demonstrate that early diverged parrot groups contain mitogenomes with the duplicated region. These findings together with mapping duplication data from other mitogenomes onto parrot phylogeny indicate that the duplication was an ancestral state for Psittaciformes. The state was inherited by main parrot groups and was lost several times in some lineages. The duplicated regions were subjected to concerted evolution with a frequency higher than the rate of speciation. The duplicated control regions may provide a selective advantage due to a more efficient initiation of replication or transcription and a larger number of replicating genomes per organelle, which may lead to a more effective energy production by mitochondria. The mitogenomic duplications were associated with phenotypic features and parrots with the duplicated region can live longer, show larger body mass as well as predispositions to a more active flight. The results have wider implications on the presence of duplications and their evolution in mitogenomes of other avian groups. PMID- 30304534 TI - Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species. AB - Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type voltage-gated calcium channels (VGCCs), has been strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. How genetic variation in CACNA1C contributes to risk for these disorders is however not fully known. Both schizophrenia and bipolar disorder are associated with impairments in reversal learning (RL), which may contribute to symptoms seen in these conditions. We used a translational RL paradigm to investigate whether genetic variation in CACNA1C affects RL in both humans and transgenic rats. Associated changes in gene expression were explored using in situ hybridization and quantitative PCR in rats and the BRAINEAC online human database. Risk-associated genetic variation in CACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion of Cacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found that Cacna1c +/- rats show decreased expression of Bdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation in CACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation in CACNA1C may contribute to risk for schizophrenia and bipolar disorder by impacting behavioral flexibility, potentially through altered regulation of BDNF expression in the prefrontal cortex. Tests of RL may be useful for translational studies and in the development of therapies targeting VGCCs. PMID- 30304535 TI - p53 deletion rescues lethal microcephaly in a mouse model with neural stem cell abscission defects. AB - Building a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early or undergo apoptosis but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1 or KRMP1) have small cortices that show elevated apoptosis and defects in maturation of NSC MBs, which mediate cytokinetic abscission. Here we test the contribution of intrinsic NSC apoptosis to brain size reduction in this lethal microcephaly model. By making double mutants with the pro-apoptotic genes Bax and Trp53 (p53), we find that p53-dependent apoptosis of cortical NSCs accounts for most of the microcephaly, but that there is a significant apoptosis independent contribution as well. Remarkably, heterozygous p53 deletion is sufficient to fully rescue survival of the Kif20b mutant into adulthood. In addition, the NSC midbody (MB) maturation defects are not rescued by p53 deletion, showing that they are either upstream of p53 activation, or in a parallel pathway. Accumulation of p53 in the nucleus of mutant NSCs at MB stage suggests the possibility of a novel MB-mediated pathway for p53 activation. This work elucidates both NSC apoptosis and abscission mechanisms that could underlie human microcephaly or other brain malformations. PMID- 30304536 TI - Sand Fly Fauna Associated With Dwellings and Forest Habitats Along the BR-319 Highway, Amazonas, Brazil. AB - Roads and highways can affect the spread of insect-borne diseases by limiting or amplifying the spatiotemporal distribution of vectors, pathogens, and hosts, which can, in turn, lead to the creation of a nidus of infection. The aim of this study was to compare the diversity (richness and abundance) of phlebotomine sand flies in household and forest edge environments found along two different segments of an Amazonian highway. Sampling was conducted along the northern and southern portions of highway BR-319, in Amazonas State, Brazil. At each sampling point, Hoover Pugedo traps were set in indoor and outdoor habitats, and at forests edges, and captures were made between 06:00 pm and 06:00 am. A total of 1,189 sand flies were captured and 48 species were identified. As expected, a greater number of species and individuals were captured in forest edge environments. Permutational Multivariate Analyses of Variance (PERMANOVA) and Permutational Analyses of Multivariate Dispersions (PERMDISP) analyses showed that sand fly fauna differed significantly among habitats, but no variance in species composition was observed between the two road segments. Some of the captured species were species that have been implicated as vectors of Leishmania spp. Ross, 1903 (Kinetoplastida: Trypanosomatidae). PMID- 30304537 TI - Mouse Gambling Task reveals differential effects of acute sleep debt on decision making and associated neurochemical changes. AB - Sleep loss is associated with sleepiness, sustained attention, and memory deficits. However, vulnerability of higher cognitive processes (i.e. decision making) to sleep debt is less understood. Therefore, a major challenge is to understand why and how higher cognitive processes are affected by sleep debt. We had established in mice correlations between individual decision-making strategies, prefrontal activity, and regional monoaminergic levels. Now, we show that acute sleep debt (ASD) disturbs decision-making processes and provokes brain regional modifications of serotonin and dopamine that could explain why ASD promotes inflexible and more risk-prone behaviors. Finally, we highlight, for the first time, that in a large group of healthy inbred mice some of them are more sensitive to ASD by showing inflexible behavior and decision-making deficits. We were also able to predict mice that would be the most vulnerable to ASD depending of their behavior before ASD exposure. PMID- 30304538 TI - A systematic review of pocket-sized imaging devices: small and mighty? AB - Introduction: Hand-held imaging devices are widely used in clinical practice and are a useful tool. There is no published review examining the diagnostic parameters achieved with these devices in clinical practice. Methods: We searched three online medical literature databases (PubMed, EMBASE and MEDLINE) for all literature published up until January 2018. We selected studies that (1) were conducted in the adult population; (2) used a truly hand-held device; (3) featured sensitivities and/or specificities on the use of the hand-held scanner. We extracted and summarised the diagnostic metrics from the literature. Results: Twenty-seven articles were excluded from the initial 56 relevant articles, as the device featured was not truly hand-held. Ultimately a total of 25 studies were analysed. Sixteen studies were carried out by experienced users, seven by users with little previous experience and two studies by nurses. High diagnostic parameters were achieved by all three groups when scanning cardiac pathology and intra-abdominal structures. Training of non-expert users varied, taking a mean of 21.6 h. These hand-held devices can change diagnoses at the bedside and be used as gate-keepers to formal echocardiography. Individual studies show them to be cost-effective. Conclusion: Hand-held echocardiography is a useful tool in the hands of experts and novices alike. Studies conducted are highly heterogeneous making it difficult to pool data for the diagnostic metrics. Further studies with rigorous methodology are needed to evaluate the true diagnostic potential in the hands of non-experts and in the community as well as to validate training protocols. PMID- 30304539 TI - Rapid Communication: The relationship of enterocyte proliferation with intestinal morphology and nutrient digestibility in weaning piglets. AB - Understanding the regulatory mechanisms of intestinal morphology and function is essential for improving postweaning growth in pigs. The objective of this study was to identify the relationships of enterocyte proliferation with intestinal villus height, crypt depth, and nutrient digestibility in piglets. Sixty-four 21 d-old weaned piglets were used. Gastrointestinal cell proliferation was evaluated via Ki-67 immunohistochemistry. Villus height and crypt depth were measured using hematoxylin and eosin (H&E)-stained sections. The apparent total tract digestibility (ATTD) of CP and GE was determined by chemical analysis. The activities of lactase and sucrase were determined with commercial kits. Western blot was carried out to assess the expression of nutrient transporters. The number of Ki-67 positive cells was associated with villus height (r = 0.548, P < 0.001) and crypt depth (r = 0.759, P < 0.001) in the jejunum. The number of Ki-67 positive cells was also associated with the ATTD of CP (r = 0.715, P = 0.001). Furthermore, a positive relationship between Ki-67 positive cell populations and lactase activity (r = 0.559, P < 0.001) was observed. Additionally, the number of Ki-67 positive cells was associated with the protein expression levels of nutrient transporters PEPT1 (r = 0.511, P = 0.030) and SGLT1 (r = 0.601, P = 0.014). Weak relationships were found between Ki-67 positive cell numbers and the ATTD of GE (r = 0.401, P = 0.099) and the activity of sucrase (r = 0.313, P = 0.087). In conclusion, enterocyte proliferation was positively associated with intestinal villus height, crypt depth, and nutrient digestibility in weaning piglets. Our findings suggested that intestinal morphology and function can be improved by regulating epithelial cell proliferation in piglets. PMID- 30304541 TI - Stomatin-like protein-2 relieve myocardial ischemia/reperfusion injury by adenosine 5'-monophosphate-activated protein kinase signal pathway. AB - Previous studies have shown that stomatin-like protein-2 (SLP-2) could regulate mitochondrial biogenesis and function. The study was designed to explore the contribution of SLP-2 to the myocardial ischemia and reperfusion (I/R) injury. Anesthetized rats were treated with SLP-2 and subjected to ischemia for 30 minutes before 3 hours of reperfusion. An oxygen-glucose deprivation/reoxygenation model of I/R was established in H9C2 cells. In vivo, SLP-2 significantly improved cardiac function recovery of myocardial I/R injury rats by increasing fractional shortening and ejection fraction. SLP-2 pretreatment alleviated infarct area and myocardial apoptosis, which was paralleled by decreasing the level of cleaved caspase-3 and the ratio of Bax/Bcl 2, increasing the content of superoxide dismutase and reducing oxidative stress damage in serum. In addition, SLP-2 increased the level of ATP and stabilized mitochondrial potential (Psim). The present in vitro study revealed that overexpression with SLP-2 reduced H9C2 cells apoptosis, accompanied by an increased level of ATP, the ratio of mitochondrial DNA/nuclear DNA, activities of complex II and V, and decreased the production of mitochondrial reactive oxygen species. Simultaneously, SLP-2 activated the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway in myocardial I/R injury rats and H9C2 cells. This study revealed that SLP-2 mediates the cardioprotective effect against I/R injury by regulating AMPK signaling pathway. PMID- 30304543 TI - MiR-101a ameliorates AngII-mediated hypertensive nephropathy by blockade of TGFbeta/Smad3 and NF-kappaB signalling in a mouse model of hypertension. AB - Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR-101a in relieving angiotensin II (Ang II)-mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28-day AngII infusion. Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated. Dual luciferase reporter assay was used to explore the target of miR-101a. mRNA levels of miR-101a, TGFbetaRI, fibrotic markers (Collagen I and alpha-SMA) and pro-inflammatory cytokines (IL-1beta and TNF-alpha) were determined by real-time PCR. Protein levels of TGFbetaRI, Collagen I, alpha-SMA, IL-1beta, TNF-alpha, t-p65, P-p65, t-Smad3, P-Smad3, t IkappaBalpha and P-IkappaBalpha were detected by western blot. MiR-101a mimics significantly improved GFR and inhibited AngII-induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR-101a mimics partially abolished AngII-induced increase in the mRNA and protein level of fibrotic markers by targeting TGFbetaRI and inhibiting TGFbeta/Smad3 pathway. Moreover, TGFbetaRI inhibitor galunisertib inhibited AngII-mediated renal injury in mice with hypertensive nephropathy. Additionally, miR-101a overexpression blocked AngII induced up-regulation of pro-inflammatory markers via suppressing NF-kappaB pathway. MiR-101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFbeta/Smad3 and NF-kappaB signalling pathways. PMID- 30304542 TI - Computational insights into pH-dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants. AB - The mycobacterial enzyme pyrazinamidase (PZase) is the target of key tuberculosis drug, pyrazinamide. Mutations in PZase cause drug resistance. Herein, three point mutations, W68G, L85P, and V155G, were investigated through over 8 us of molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions. The 51-71 flap region exhibited drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Accessibility of solvent to the active site of the mutant enzymes was also reduced. The protonation of key surface residues at low pH results in more contribution of these residues to structural stability and integrity of the enzyme and reduced interactions with solvent molecules, which acts as a cage, keeping the enzyme together. The observed results suggest a pattern of structural alterations due to point mutations in PZase, which is consistent with other experimental and theoretical investigations and, can be harnessed for drug design purposes. PMID- 30304544 TI - Angiotensin-converting enzyme insertion/deletion (rs106180) and angiotensin type 1 receptor A1166 C (rs106165) genotypes and psoriasis: Correlation with cellular immunity, lipid profile, and oxidative stress markers. AB - Psoriasis is a chronic inflammatory skin condition and angiotensin-converting enzyme (ACE) is a key circulating enzyme converting angiotensin (Ang) I to the vasoactive peptide Ang II. The exact role of ACE insertion (I)/deletion (D) polymorphism (rs106180) in psoriasis is not clear. We aimed to examine whether the ACE I/D and Ang II type 1 receptor (AT1R) A1166 C-polymorphisms (rs106165), lipid profile, and stress oxidative are associated with susceptibility to psoriasis. One hundred patients with psoriasis and 100 sex- and age-matched unrelated healthy controls were recruited for this case-control study. ACE I/D and AT1R A1166 C polymorphisms were identified by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively, malondialdehyde (MDA) was detected by the high-performance liquid chromatography, serum arylesterase (ARE) activity of paraoxonase and catalase activities were detected by the spectrophotometry, superoxide dismutase (SOD) activity and vascular adhesion protein (VAP)-1 were measured by ELISA. The presence of C allele of AT1R A1166 C and I allele of ACE considerably increased the risk of psoriasis by 6.42-fold (P < 0.001). The distribution of II-genotype of ACE was significantly higher in psoriasis patients than in control group and increased the risk of disease by 3.11-times (P = 0.023). The higher levels of MDA in patients and the higher activity of SOD, ARE, and CAT was observed in healthy controls with I/D+I/I-genotype of ACE I/D. This study for the first time demonstrated that the ACE I/D and AT1R A 1166 C genes polymorphisms robustly increases the risk of developing psoriasis in population from west of Iran. In addition, these individuals had significantly higher VAP-1 and MDA concentration and lower enzymatic and nonenzymatic antioxidant-status, suggesting that psoriatic patients carrying C allele of AT1R1166 polymorphism may be more susceptible to cardiovascular disease and myocardial infarction compared with A allele. PMID- 30304540 TI - Applying the new intensive blood pressure categories to a nondialysis chronic kidney disease population: the Prevalence, Awareness and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China survey. AB - Background: The 2017 high blood pressure (BP) clinical practice guideline reported by the American College of Cardiology/American Heart Association put forward new categories of BP. This study aimed to assess the applicability of the new guideline in a nondialysis chronic kidney disease (CKD) population. Methods: This is a nationwide, multicenter, cross-sectional study with a large sample. A total of 8927 nondialysis CKD patients in 61 tertiary hospitals in all 31 provinces, municipalities and autonomous regions of China (except Hong Kong, Macao and Taiwan) were analyzed. The categories of BP were defined as normal BP (<120/80 mmHg), elevated BP [systolic BP (SBP) 120-130 and diastolic BP (DBP) <80 mmHg], and Stage 1 (SBP 130-139 or DBP 80-89 mmHg) and Stage 2 (SBP >=140 or DBP >=90 mmHg) hypertension. The prevalence and control of hypertension were estimated using a new definition, and the association between the main target organs' injury and new categories of BP was analyzed. Results: The prevalence, awareness and treatment of hypertension in nondialysis CKD patients were 79.8, 72.4 and 68.3%, respectively. Approximately 11.9% had BP <130/80 mmHg and 6.6% had BP <120/80 mmHg. Subgroups by categories of BP had significant differences in age, sex, body mass index category, primary cause and CKD stage (P < 0.001). After multivariable adjustment, only Stage 2 hypertension was associated with decreased renal function [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.9 3.0, P < 0.001], cardiovascular disease (OR 2.0, 95% CI 1.3-3.1, P = 0.001) and cerebrovascular disease (OR 2.7, 95% CI 1.2-5.8, P = 0.015). Conclusions: Using the new definition of hypertension, the higher prevalence and lower control of hypertension were shown in nondialysis CKD participants. More studies are necessary to confirm the applicability of new categories of BP in CKD population because only Stage 2 hypertension showed statistical association with the main target organs' injury. PMID- 30304545 TI - Dysregulation of FTX/miR-545 signaling pathway downregulates Tim-3 and is responsible for the abnormal activation of macrophage in cirrhosis. AB - BACKGROUND: Accumulating evidence has suggested the involvement of miR-545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR 545 and lncRNA FTX in hepatitis B virus (HBV)-related cirrhosis. METHOD: The level of Tim-3, TLR-4, and endotoxin was detected in CD14+ , CD14 + CD16 + , and CD14 + CD16 - monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), IL-1beta, and Nuclear factor kB (NF-kB). In-silico analysis, luciferase assay, real-time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR-545 and Tim-3. RESULTS: The levels of Tim-3, Tim-3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim-3 was also decreased in the CD14 + CD16 - monocytes isolated from patients with cirrhosis, whereas the level of Tim-3 in CD14 + CD16 + monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR-4 was highly expressed in CD14 + CD16 + monocytes isolated from patients with cirrhosis, whereas Tim-3 was negatively regulated by endotoxin and the correlation coefficient was -0.5287. After the LPS stimulation, although the level of TNF-a, IL-6, IL-1beta, and NF-kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim-3, but a higher level of miR-545. Moreover, miR-545 directly bound to the 3'untranslated region (3'UTR) of Tim-3 and inhibited the luciferase activity of cells cotransfected with miR-545 mimics and wild-type 3'UTR of Tim-3. Furthermore, FTX downregulated the expression of miR-545, TNF-a, IL-6, IL-1beta, and NF-kB, but upregulated the expression of Tim-3. CONCLUSION: The results of this study confirmed the effect of FTX, miR-545, and Tim-3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV-related cirrhosis. PMID- 30304546 TI - ERBB2 and KRAS Alterations Mediate Response to EGFR Inhibitors in Early Stage Gallbladder Cancer. AB - The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n=25) and recurrent mutations in 14% tumors (n=44); along with co-occurring KRAS mutation in 7% tumors (n=44). We demonstrate that ERBB2 heterodimerize with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatninb inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti EGFR treatment in colorectal cancer. This article is protected by copyright. All rights reserved. PMID- 30304547 TI - Tamoxifen ameliorates obstructive nephropathy through Src and the PI3K/Akt/mTOR pathway. AB - BACKGROUND INFORMATION: Tubulointerstitial fibrosis is the end-point of chronic kidney diseases. Tamoxifen, a selective oestrogen receptor (ER) modulator, attenuates renal fibrosis, by regulating the transforming growth factor (TGF) beta/Smad signalling. Src and phosphoinositide 3-kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, the activation of the non-canonical TGF-beta signalling in renal fibrosis after treatment with tamoxifen remains unclear. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. Tamoxifen was orally administered after UUO. Additionally, HK-2 cells were treated with tamoxifen in the presence or absence of TGF-beta1. The selective ER down-regulator ICI and ER-alpha silencing were used to confirm the involvement of ER-alpha on the effect of tamoxifen on TGF beta1-stimulated fibrosis in HK-2 cells. RESULTS: Tamoxifen treatment ameliorated UUO-induced renal fibrosis as shown by decreased expression of alpha-smooth muscle actin (SMA), fibronectin and connective tissue growth factor (CTGF). The phosphorylation of Src, PI3K, Akt, mammalian target of rapamycin (mTOR) and p70S6K significantly decreased in UUO kidneys from tamoxifen-treated animals. Tamoxifen dose-dependently suppressed the TGF-beta1-induced expression of alpha SMA and CTGF, and phosphorylation of Src, PI3K, Akt, mTOR and p70S6K in HK-2 cells. These anti-fibrotic effects were reversed by treatment with ICI and silencing of ER-alpha. Moreover, inhibition of the PI3K/Akt and mTOR/p70S6K pathways was observed in HK-2 cells co-treated with PP1 (a Src kinase inhibitor) and tamoxifen. CONCLUSIONS: The anti-fibrotic effects of tamoxifen are associated with the suppression of Src kinase function via ER-alpha, followed by inhibition of the PI3K/Akt and mTOR/p70S6K signalling pathways. SIGNIFICANCE: Our findings suggest that tamoxifen is a novel therapeutic option for the prevention and treatment of renal fibrosis. PMID- 30304548 TI - Acutely induced cell mortality in the unicellular green alga Chlamydomonas reinhardtii (Chlorophyceae) following exposure to acrylic resin nanoparticles. AB - Nanoparticles have unique properties that make them attractive for use in industrial and medical technology industries but can also be harmful to living organisms, making an understanding of their molecular mechanisms of action essential. We examined the effect of three different sized poly(isobutyl cyanoacrylate) nanoparticles (iBCA-NPs) on the unicellular green alga Chlamydomonas reinhardtii. We found that exposure to iBCA-NPs immediately caused C. reinhardtii to display abnormal swimming behaviors. Furthermore, after one hour, most of the cells had stopped swimming and 10%-30% of cells were stained with trypan blue, suggesting that these cells had severely impaired plasma membranes. Observation of the cyto-ultrastructure showed that the cell walls had been severely damaged and that many iBCA-NPs were located in the space between the cell wall and plasma membrane, as well as inside the cytosol in some cases. A comparison of three strains of C. reinhardtii with different cell wall conditions further showed that the cell mortality ratio increased more rapidly in the absence of a cell wall. Interestingly, cell mortality over time was essentially identical regardless of iBCA-NP size if the total surface area was the same. Furthermore, direct observation of the trails of iBCA-NPs indicated that the first trigger was their contact with the cell wall, which is most likely accompanied by the inactivation or removal of adsorbed proteins from the cell wall surface. Cell mortality was accompanied by the overproduction of reactive oxygen species, which was detected more readily in cells grown under constant light rather than in the dark. PMID- 30304549 TI - Comprehensive analysis of microRNA-messenger RNA regulatory network in gemcitabine-resistant bladder cancer cells. AB - Chemotherapy is still a standard treatment of unresectable bladder cancer or distant metastases. The chemotherapy resistance always occurs after a period of treatment indicating poor prognosis. The current study aimed to explore the molecular mechanism of chemoresistance in bladder cancer cells. The gene expression profiles of GSE77883, including three untreated T24 cells samples and three gemcitabine-resistant T24 cells samples, was downloaded from Gene Expression Omnibus database. The screening of differentially expressed genes (DEGs), gene function analysis, and interaction prediction between microRNAs (miRNAs) and DEGs were performed by R software. The protein-protein interaction (PPI) and miRNA-DEGs networks were constructed and visualized by Cytoscape software. Then, the small molecules, with potential synergistic or antagonistic effects to gemcitabine resistance, were identified using the Connectivity Map database. Finally, gemcitabine-resistant T24 cell line was established and key genes were validated by quantitative real-time polymerase chain reaction (qRT PCR). In total, 536 upregulated and 513 downregulated genes were screened and mainly enriched in oxidative stress response and signaling pathways related to extracellular matrix-receptor interaction and focal adhesion. PPI network showed interleukin 6, tumor necrosis factor, kinesin family member 11, and BUB1 mitotic checkpoint serine/threonine kinase B were key genes. The miRNA-DEGs regulatory networks included 18 miRNAs and 185 DEGs, including miR-182-5p, miR-590-3p, miR 320a and serum- and glucocorticoid-regulated kinase 1 (SGK1). Then, the related key genes and miRNAs were confirmed by qRT-PCR. Furthermore, 81 small molecules with antagonistic or synergistic effect to GEM were screened. We have investigated the molecular mechanisms driving GEM-resistance in bladder cancer cells that would contribute to the development of chemotherapy for advanced bladder cancer. PMID- 30304551 TI - TrkC-miR2 regulates TGFbeta signaling pathway through targeting of SMAD3 transcript. AB - TrkC, neurotrophin receptor, functions inside and outside of the nervous system and has a crucial effect on the regulation of cardiovascular formation. Recently, we introduced TrkC-miR2 as a novel microRNA located in TrkC gene, which is a regulator of the Wnt signaling pathway. Here, we presented a lot of evidence showing that TrkC-miR2 also regulates the transforming growth factor-beta (TGFbeta) signaling pathway. Bioinformatics studies predicted SMAD3 as one of the bona fide TrkC-miR2 target genes. Quantitative reverse transcription PCR (RT qPCR), Western blot analysis, and dual luciferase assay analysis confirmed that SMAD3 is targeted by TrkC-miR2. On the other hand, overexpression of TrkC-miR2 in cardiosphere-derived cells (CDCs) rendered downregulation of TGFbetaR1, TGFbetaR2, and SMAD7 detected by RT-qPCR. Consistently, an inverse correlation of expression between TrkC-miR2 and SMAD3 genes was detected during the course of CDC differentiation, and also during the course of human embryonic stem cells differentiation to cardiomyocytes. Overall, we conclude that TrkC-miR2 downregulates the expression of SMAD3 and potentially regulates the TGFbeta signaling pathway. Knowing its approved effect on Wnt signaling, TrkC-miR2 here is introduced as a common regulator of both the Wnt and TGFbeta signaling pathways. Therefore, it may be a potential key element in controlling both of these signaling pathways in cell processes like colorectal cancer and cardiogenesis. PMID- 30304550 TI - Detection of exosomal tyrosine receptor kinase B as a potential biomarker in ovarian cancer. AB - Ovarian cancer (OC) is a lethal disease diagnosed at advanced stages due to the lack of specific biomarkers. Tyrosine receptor kinase B (TrkB), which has recently been found to be related to OC progression, represents a promising potential biomarker for OC diagnosis and prognosis. The discovery of circulating exosomes as biomarkers for various diseases led us to explore exosomal TrkB in OC. Our previous study proved that the expression of TrkB was elevated in OC tissues. In this study, we focused on the detection of exosomal TrkB in OC. Exosomes were first gathered from three different OC cell lines' conditioned medium, serum samples of patients with OC as well as xenograft mice serum by serial centrifugation method. Then, we identified exosomes by transmission electron microscopy, NanoSight analysis, and expression of typical exosomal protein markers. The existence of TrkB in exosomes was measured by Western blot analysis, and the expression was detected by enzyme-linked immunosorbent assay. In this study, we demonstrated that exosomes could derive from OC cell lines, serum from OC xenograft nude mice, and clinical patients. Our study shows that serum exosomal TrkB may be considered a minimally invasive biomarker for OC. PMID- 30304552 TI - Total flavonoids from Smilax glabra Roxb blocks epithelial-mesenchymal transition and inhibits renal interstitial fibrosis by targeting miR-21/PTEN signaling. AB - BACKGROUND: Smilax glabra Roxb, a traditional Chinese herb, has been widely used in folk medicine. The current study was performed to investigate the protective effect of S. glabra Roxb extract, pure total flavonoids from Smilax glabra Roxb (PTFS), on renal interstitial fibrosis (RIF) and its underlying mechanism. METHODS: First, a surgical model of unilateral ureteral obstruction was established in rats to induce RIF. Then, rats were grouped and treated with PTFS at different concentration. Second, HK-2 cells underwent an epithelial mesenchymal transition (EMT) by the addition of transforming growth factor-beta1 (TGF-beta1). Additionally, HK-2 cells after inducing for EMT were transfected with microRNA-21 (miR-21) mimic or inhibitor. These HK-2 cells were grouped and treated with PTFS at different concentration. Finally, real-time polymerase chain reaction and Western blot analysis were performed to detect the expression of possible signaling factor involved in RIF in renal tissues or HK-2 cells after PTFS treatment. RESULTS: In vivo and in vitro experiments indicated that PTFS treatment could decrease the expression of alpha-smooth muscle actin (alpha-SMA; mesenchymal marker) and increase the expression of E-cadherin (epithelial marker) in both messenger RNA and protein level. Moreover, PTFS also attenuated the expression of TGF-beta1/Smad signaling in both renal tissues and HK-2 cells that underwent EMT. Overexpression or inhibition of miR-21 in HK-2 cells activated or blocked the PI3K/Akt signaling via targeting phosphatase and tension homolog (PTEN), and then promoted or suppressed the progress of TGF-beta1-induced EMT by regulating the expression of alpha-SMA and E-cadherin. Furthermore, PTFS treatment inhibited TGF-beta1-induced EMT progress by blocking miR 21/PTEN/PI3K/Akt signaling. CONCLUSION: PTFS has strong anti-EMT and antifibrosis effects both in vitro and in vivo. The mechanism underlying these effects may be related to inhibition of TGF-beta1/Smad, and their downstream miR-21/PTEN signaling, leading to blocks of EMT process during RIF. PMID- 30304553 TI - A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells. AB - Doxorubicin (Dox) is a well-known chemotherapeutic agent used in the treatment of various cancers. However, Dox-induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin-conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox-induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox-induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4-phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA-MB-231 cells, BAA significantly enhanced Dox-induced cytotoxicity through upregulating Dox induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation. PMID- 30304554 TI - Effects of microRNA-494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c-myc through the p38 MAPK signaling pathway. AB - Medulloblastoma (MB) is the most prevalent brain tumor that occurs during childhood and originates from cerebellar granule cell precursors. Based on recent studies, the differential expression of several microRNAs is involved in MB, while the role of microRNA-494 (miR-494) in MB remains unclear. Therefore, we conducted this study to investigate the regulative role of miR-494 in MB cells via the p38 mitogen-activated protein kinase (MAPK) signaling pathway by mediating c-myc. In the current study, MB cells were collected and transfected with miR-494 mimic, miR-494 inhibitor, siRNA- c-myc, and miR-494 inhibitor + siRNA-c-myc. The expressions of miR-494, c-myc, p38 MAPK, B-cell lymphoma-2 (Bcl 2), Bcl-2-associated X protein (Bax), interleukin-6 (IL-6), metadherin (MTDH), phosphatase and tensin homolog (PTEN) and survivin were determined. Cell proliferation, cell-cycle distribution, apoptosis, migration, and invasion were evaluated. The results revealed that there was a poor expression of miR-494 and high expression of c-myc in MB tissues. C-myc was determined as the target gene of miR-494. In response to miR-494 mimic, MB cells were found to have increased Bax and PTEN expressions, as well as cell number in G1 phase and cell apoptosis and decreased c-myc, p38 MAPK, Bcl-2, MTDH, IL-6, and survivin expression and cell number count in the S phase, cell proliferation, migration, and invasion. In conclusion, the results demonstrated that the upregulation of miR-494 results in the suppression of cell proliferation, migration, and invasion, while it promotes apoptosis of MB cells through the negative mediation of c-myc, which in turn inactivates the p38 MAPK pathway. PMID- 30304555 TI - Serum exosomal miR-210 as a potential biomarker for clear cell renal cell carcinoma. AB - Exosomal microRNAs (miRNAs) are suggested to reflect molecular changes occurring in their cells of origin and are potential indicators in the early detection of cancers. This study aimed to determine whether certain exosomal miRNAs from tumor tissue can be used as noninvasive biomarkers for clear cell renal cell carcinoma (ccRCC). Based on ccRCC miRNA expression profiles and the literature, we selected six miRNAs (miR-210, miR-224, miR-452, miR-155, miR-21, and miR-34a) and analyzed their expression in tissues, sera, and serum exosomes through quantitative real time polymerase chain reaction in hypoxia-induced (with CoCl2 ) renal cell lines. miR-210, miR-224, miR-452, miR-155, and miR-21 were upregulated in tumor tissues compared with normal tissues. Serum miR-210 and miR-155 levels were higher in patients with ccRCC than in healthy controls (HCs). Furthermore, only exosomal miR-210 was significantly upregulated in patients with ccRCC than in HCs. Moreover, receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve of 0.8779 (95% confidence interval, 0.7987-0.9571) and a sensitivity and specificity of 82.5% and 80.0%, respectively. Moreover, exosomal miR-210 was upregulated at an advanced stage, and Fuhrman grade and metastasis decreased significantly one month after surgery. Acute hypoxia exposure activates miR-210 and release of exosomes with upregulated miR-210 in both normal and tumor RCC cell lines and interferes with vacuole membrane protein 1 mRNA expression, especially in the metastatic ccRCC cell line. In conclusion, Serum exosomal miR 210 originating from tumor tissue has potential as a novel noninvasive biomarker for the detection and prognosis of ccRCC. PMID- 30304556 TI - Glaucocalyxin B protects against oxygen-glucose-deprivation/reperfusion-induced neuronal injury in PC-12 cells. AB - Oxidative stress has been implicated in the development of cerebral ischemia/reperfusion (I/R) injury. Glaucocalyxin B (GLB), one of five ent kauranoid diterpenoids, was reported to possess neuroprotective activity. However, the effect of GLB on oxygen-glucose-deprivation/reperfusion (OGD/R) induced cell injury in PC-12 cells has not been explored. PC-12 cells was treated with various concentrations of GLB (0, 2.5, 5 and 10 MUM), and cell viability was detected using the MTT assay. PC-12 cells were pretreated with the indicated concentration of GLB (2.5-10 MUM, 2 hours pretreatment), and were maintained under OGD for 3 hours, followed by 24 hours of reoxygenation. Cell viability was assessed using the MTT assay. The levels of superoxide dismutase, malondialdehyde, and glutathione peroxidase were detected using commercially available ELISA Kits. Intracellular reactive oxygen species level was measured using the fluorescent probe 2',7'-dichlorofluorescein diacetate. The levels of Bcl-2, Bax, p-Akt, Akt, p-mTOR, mTOR were detected using Western blot. Our results revealed that GLB significantly protected PC12 cells against OGD/R induced cell injury. In addition, GLB efficiently inhibited oxidative stress and cell apoptosis in OGD/R-stimulated PC-12 cells. Mechanistic studies revealed that pretreatment with GLB could induce the activation of Akt/mTOR signaling pathway resulting in protection of OGD-treated PC12 cells. In conclusion, our data indicate for the first time that GLB protects against OGD/R-induced neuronal injury in PC-12 cells. The mechanism of the protective effect of GLB is partially associated with activation of the Akt/mTOR signaling pathway. Thus, GLB may be a potential agent for protection against cerebral I/R injury. PMID- 30304557 TI - Long noncoding RNA PVT1 promotes laryngeal squamous cell carcinoma development by acting as a molecular sponge to regulate miR-519d-3p. AB - OBJECTIVE: This study was designed to investigate the effects and mechanism of long noncoding RNA (lncRNA) PVT1 on cell migration, proliferation, and apoptosis of laryngeal squamous cell carcinoma (LSCC). METHODS: We screened lncRNAs expression profiles in four pair LSCC and matched noncancerous tissues by microarray assay. The messenger RNA levels of PVT1 in tissues and cells were evaluated by quantitative real-time polymerase chain reaction analysis. StarBase website was used to predict the target miRNAs for PVT1. And the interaction between PVT1 and target miRNA-519d-3p in LSCC cells was analyzed using dual luciferase reporter assay. MTT assay was used to investigate the cell viability. Cell counting assay was used to explore the cell proliferation. Annexin-V propidium iodide flow cytometry was used to examine the cell apoptosis, and transwell assay was used to investigate the effects of lncRNA PVT1 on cell migration. RESULTS: PVT1 was significantly overexpressed in human LSCC tissues and several LSCC cell lines. Upregulation of lncRNA PVT1 markedly facilitated proliferation suppressed apoptosis and promoted cell migration in LSCC cells. We further demonstrated that silencing PVT1 strikingly suppressed proliferation, promoted apoptosis, and reduced migration in LSCC cells. Further bioinformatic analysis and dual-luciferase reporter assay revealed that PVT1 could function as an oncogenic transcript partly through sponging miR-519d-3p. Besides, mechanistic investigations indicated that PVT1 could promote cell and migration through interacting with miR-519d-3p. CONCLUSION: LncRNA PVT1 is consistently overexpressed in human LSCC, and overexpression of lncRNA PVT1 contributes to the proliferation and migration of LSCC through inhibiting miR-519d-3p expression. PMID- 30304558 TI - Identification of surrogate prognostic biomarkers for allergic asthma in nasal epithelial brushing samples by WGCNA. AB - BACKGROUND: Allergic asthma is a lower respiratory tract disease of Th2 inflammation with multiple molecular mechanisms. The upper and lower airways can be unified by the concept of a united airway and, as such, gene expression studies of upper epithelial cells may provide effective surrogate biomarkers for the prognostic study of allergic asthma. OBJECTIVE: To identify surrogate biomarkers in upper airway epithelial cells for the prognostic study of allergic asthma. METHODS: Nasal epithelial cell gene expression in 40 asthmatic and 17 healthy control subjects were analyzed by weighted gene coexpression network analysis (WGCNA) to identify gene network modules and profiles in allergic asthma. Functional enrichment analysis was performed on the coexpression genes in certain highlighted modules. RESULTS: A total of 13 coexpression modules were constructed by WGCNA from 2804 genes in nasal epithelial brushing samples of the 40 asthmatic and 17 healthy subjects. The number of genes in these modules ranged from 1086 (Turquoise module) to 45 (Salmon). Eight coexpression modules were found to be significantly correlated (P < 0.05) with two clinic traits, namely disease status, and severity. Four modules were positively correlated ( P < 0.05) with the traits and these, therefore, contained genes that are mostly overexpressed in asthma. Contrastingly, the four other modules were found to be negatively correlated with the clinic traits. Functional enrichment analysis of the positively correlated modules showed that one (Magenta) was mainly enriched in mast cell activation and degranulation; another (Pink) was largely involved in immune cell response; the third (Yellow) was predominantly enriched in transmembrane signal pathways; and the last (Blue) was mainly enriched in substructure components of the cells. The hub genes in the modules were KIT, KITLG, GATA2, CD44, PTPRC, and CFTR, and these were confirmed as having significantly higher expression in the nasal epithelial cells. Combining the six hub genes enabled a relatively high capacity for discrimination between asthmatics and healthy subjects with an area under the receiver operating characteristic (ROC) curve of 0.924. CONCLUSIONS: Our findings provide a framework of coexpression gene modules from nasal epithelial brushing samples that could be used for the prognostic study of allergic asthma. PMID- 30304559 TI - LINC00152 promotes the proliferation of gastric cancer cells by regulating B-cell lymphoma-2. AB - LINC00152 has been considered to be associated with the tumorigenesis and the occurrence of gastric cancer; however, the mechanism of LINC00152 has yet to be fully elucidated. In the present study, the expression levels of LINC00152 in tissues, serum, and peripheral blood mononuclear cells (PBMCs) of patients with gastric cancer were determined using real-time polymerase chain reaction. The functions of LINC00152 with respect to the proliferation, apoptosis, migration, and invasive abilities of the gastric cancer cells were evaluated by cell proliferation analysis, flow cytometry, cell scratch wound assay, and transwell migration experiments. A mouse xenotransplant model of gastric tumors was established to detect the role of LINC00152 in vivo, and the expression levels of B-cell lymphoma-2 (Bcl-2) family proteins were investigated by Western blot analysis. The results revealed that LINC00152 was overexpressed in tissues, serum, and PBMCs of patients with gastric cancer. Moreover, LINC00152 could promote the migration and invasive abilities and suppress the apoptosis, of gastric cancer cells through regulating the Bcl-2 protein family. LINC00152 could bind with Bcl-2 directly to induce the activation of cell cycle signaling, and this may be a potential target for the therapy of gastric cancer in the future. PMID- 30304560 TI - Gas exchange characteristics of giant cacti species varying in stem morphology and life history strategy. AB - PREMISE OF THE STUDY: Giant cacti species possess long cylindrical stems that store massive amounts of water and other resources to draw on for photosynthesis, growth, and reproduction during hot and dry conditions. Across all giant cacti taxa, stem photosynthetic surface area to volume ratio (S:V) varies by several fold. This broad morphological diversity leads to the hypothesis that giant cacti function along a predictable resource use continuum from a "safe" strategy reflected in low S:V, low relative growth rates (RGR), and low net assimilation rates (Anet ) to a high-risk strategy that is reflected in high S:V, RGR, and Anet . METHODS: To test this hypothesis, whole-plant gas exchange, chlorophyll fluorescence, and whole-spine-tissue carbon isotope ratios (delta13 C) were measured in four giant cacti species varying in stem morphology and RGR. Measurements were conducted on five well-watered, potted plants per species. KEY RESULTS: Under conditions of mild diel temperatures and low atmospheric vapor pressure deficit, Anet , transpiration (E), and stomatal conductance (Gs ) were significantly higher, and water-use efficiency (Anet : Gs ) was lower in fast growing, multi-stemmed species compared to the slower growing, single-stemmed species. However, under warmer, less optimal conditions, gas exchange converged between stem types, and neither delta13 C nor chlorophyll fluorescence varied among species. CONCLUSIONS: The results add to a growing body of evidence that succulent-stemmed plants function along a similar economic spectrum as leaf bearing plants such that functional traits including stem RGR, longevity, morphology, and gas exchange are correlated across species with varying life history strategies. PMID- 30304561 TI - MicroRNA-193a-5p exerts a tumor suppressor role in glioblastoma via modulating NOVA1. AB - BACKGROUND AND OBJECTIVES: Glioblastoma (GBM) is the most common and lethal of intracranial tumors, which is characterized by extensive proliferation and the diffused invasion of tumor cells. MicroRNA-193a-5p (miR-193a-5p) have been demonstrated previously as a functional suppressor in the development and progression of various cancers. The current study aimed to investigate whether miR-193a-5p influences cell proliferation and migration through the mitogen activated protein kinase/extracellular signal-regulated kinase signaling pathway by targeting neuro-oncological ventral antigen 1 (NOVA1) in glioblastoma. MATERIALS AND METHODS: The miR-193a-5p expression was detected by quantitative real-time polymerase chain reaction assay in GBM tissues and cell lines. Cell Counting Kit-8 assay, colony formation analysis, wound-healing, and transwell invasion assays were performed to evaluate cell proliferation, colony formation, migration, and invasion, respectively. Western blot analysis and luciferase reporter gene assay were performed to verify the downstream target gene of miR 193a-5p. RESULTS: The expression of miR-193a-5p was significantly downregulated in GBM tissues and cell lines. Kaplan-Meier analysis showed that patients with low miR-193a-5p expression had a shorter disease-free survival (P < 0.05). Functionally, miR-193a-5p overexpression dramatically suppressed the proliferation, colony formation, migration, and invasion in glioma cells. Bioinformatics prediction and a luciferase assay confirmed that NOVA1 was a direct functional target of miR-193a-5p. Moreover, ectopic expression of NOVA1 could partially reverse the inhibitory effects of miR-193a-5p on glioma cell proliferation, colony formation, migration, and invasion. NOVA1 overexpression abrogated the inhibitory effect of miR-193a-5p on the PTEN/PI3k/AKT pathway. CONCLUSION: Taken together, our findings suggested that miR-193a-5p functions as a tumor suppressor in glioma cells by directly targeting NOVA1. PMID- 30304562 TI - The prospects for constraining productivity through time with the whole-plant physiology of fossils. AB - Anatomically preserved fossils allow estimation of hydraulic parameters, potentially providing constraints on interpreting whole-plant physiology. However, different organ systems have typically been considered in isolation - a problem given common mismatches of high and low conductance components coupled in the hydraulic path of the same plant. A recent paper addressed the issue of how to handle resistance mismatches in fossil plant hydraulics, focusing on Carboniferous medullosan seed plants and arborescent lycopsids. Among other problems, however, a fundamental error was made: the transpiration stream consists of resistances in series (where resistances are additive and the component with the largest resistance can dominate the behavior of the system), but emphasis was instead placed on the lowest resistance, effectively treating the system as resistances in parallel (where the component with the smallest resistance will dominate the behavior). Instead of possessing high assimilation capacities to match high specific stem conductances, it is argued here that individual high conductance components in these Paleozoic plants are nonetheless associated with low whole-plant productivity, just as can be commonly seen in living plants. Resolution of how to handle these issues may have broad implications for the Earth system including geobiological feedbacks to rock weathering, atmospheric composition, and climate. PMID- 30304563 TI - Exploring the effect of N308D mutation on protein tyrosine phosphatase-2 cause gain-of-function activity by a molecular dynamics study. AB - One of the most common protein tyrosine phosphatase-2 (SHP2) mutations in Noonan syndrome is the N308D mutation, and it increases the activity of the protein. However, the molecular basis of the activation of N308D mutation on SHP2 conformations is poorly understood. Here, molecular dynamic simulations were performed on SHP2 and SHP2-N308D to explore the effect of N308D mutation on SHP2 cause gain of function activity, respectively. The principal component analysis, dynamic cross-correlation map, secondary structure analysis, residue interaction networks, and solvent accessible surface area analysis suggested that the N308D mutation distorted the residues interactions network between the allosteric site (residue Gly244-Gly246) and C-SH2 domain, including the hydrogen bond formation and the binding energy. Meanwhile, the activity of catalytic site (residue Gly503 Val505) located in the Q-loop in mutant increased due to this region's high fluctuations. Therefore, the substrate had more chances to access to the catalytic activity site of the precision time protocol domain of SHP2-N308D, which was easy to be exposed. In addition, we had speculated that the Lys244 located in the allosteric site was the key residue which lead to the protein conformation changes. Consequently, overall calculations presented in this study ultimately provide a useful understanding of the increased activity of SHP2 caused by the N308D mutation. PMID- 30304564 TI - Renalase rs10887800 polymorphism is associated with severe pre-eclampsia in southeast Iranian women. AB - Evidence has shown that pre-eclampsia (PE) is associated with an increased level of catecholamines. Renalase is a catecholamine-metabolizing enzyme, which contributes to the occurrence of hypertension. In the current study, we aimed to assess the relation between two renalase gene ( RNLS) polymorphisms, including rs2576178 at the 5'-flanking region and rs10887800 at intron 6, near the exon/intron border and PE susceptibility. In this case-control study, 179 women with PE and 202 normotensive pregnant women were genotyped for RNLS rs2576178 and rs10887800 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism method. There was no association between RNLS rs10887800 and rs2576178 polymorphisms and PE, neither in the dominant nor in the recessive model. Although there was no association between RNLS rs10887800 polymorphism and mild PE, this polymorphism was associated with 2.2-fold higher risk of severe PE in the recessive model (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2 4.4; P = 0.01) but not in the dominant model. The RNLS rs2576178 and rs10887800 polymorphisms were not associated with PE severity. The RNLS rs10887800 and rs2576178 GG/GG combined genotypes were associated with 8.4- and 16.7-fold higher risk of PE and severe PE, respectively (OR, 8.4; 95% CI, 1-71.1; P = 0.048 and OR, 16.7; 95% CI, 1.6-167; P = 0.018). Also, the G-G haplotype was associated with 1.7-fold risk of PE and mild PE (OR, 1.7; 95% CI, 1.1-2.4; P = 0.009 and OR, 1.7; 95% CI, 1.1-2.5; P = 0.02). The RNLS rs10887800 polymorphism was associated with severe PE. The RNLS rs10887800 and rs2576178 GG/GG combined genotypes and G G haplotype were associated with higher risk of PE. PMID- 30304565 TI - SIRT1-ZEB1-positive feedback promotes epithelial-mesenchymal transition process and metastasis of osteosarcoma. AB - Osteosarcoma is the most common malignant bone cancer that mainly affects children and young adults. Recently, the NAD+ -dependent deacetylase, sirtuin 1 (SIRT1), has been reported to play a key role in the development of malignant tumors. The study aimed to investigate the role of SIRT1 in osteosarcoma and explore its underlying oncogenic mechanisms. The prognostic value of SIRT1 in osteosarcoma was assessed through detection of SIRT1 expression based on osteosarcoma biopsy tissue. Then, to further investigate the effect of SIRT1 in osteosarcoma, osteosarcoma cells were treated with small interfering RNA SIRT1 and overexpressed SIRT1 to detect the cell migration, invasion, and epithelial mesenchymal transition (EMT). The levels of SIRT1 expression were significantly higher in osteosarcoma tissues than those in adjacent normal tissues, and the SIRT1 protein level may be coupled with metastatic and poor prognosis risk in patients with osteosarcoma. Moreover, SIRT1 silencing inhibited the migration as well as invasion ability of osteosarcoma cells in vitro, and SIRT1 upregulation reversed those effects. Finally, we found that SIRT1-ZEB1-positive feedback enhanced the EMT process and metastasis of osteosarcoma. Altogether, the results of the current study revealed that high levels of SIRT1 might be a biomarker for a high metastatic rate in patients with osteosarcoma, which suggested that inhibition of SIRT1 might be promising for the therapeutics of osteosarcoma. PMID- 30304566 TI - Role of RKIP in human hepatic stellate cell proliferation, invasion, and metastasis. AB - The purpose of this study was to investigate the effect of Raf kinase inhibitor protein (RKIP) on the growth, apoptosis, invasion, and metastasis of human hepatic stellate cell line (LX-2). A recombinant plasmid (pcDNA3.1-RKIP) or RKIP targeting small interfering RNA (siRNA) vector (siRNA-RKIP) was transfected into LX-2 cells to interfere with the RKIP expression. The results demonstrated that increased RKIP expression significantly reduced cell viability, clonogenic growth, and invasion. Further, it promoted cell apoptosis and induced cell cycle arrest in the G1 phase. Overexpression of RKIP led to inactivation of LX-2 cells, as evidenced by the decrease in the expression levels of collagen I and alpha smooth muscle actin (alpha-SMA). In addition, increased RKIP expression significantly reduced the phosphorylation of Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), the transcriptional activity of nuclear factor-kappaB (NF-kappaB), and the levels of matrix metalloproteinases-1 and -2. In conclusion, these findings clearly demonstrate that RKIP inhibits LX-2 cell growth, metastasis, and activation, primarily by downregulating the ERK/MAPK and NF-kappaB signaling pathways. PMID- 30304567 TI - Chemical inhibition of HSP90 inhibits TNF-alpha mediated proliferation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. AB - Rheumatoid arthritis fibroblast-like synoviocytes (RAFLS) proliferate abnormally and resist apoptosis. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents that inhibited cancer cell growth. In this study, we explored the effects of HSP90 inhibitor, GA, on tumor necrosis factor (TNF) alpha-induced proliferation and apoptosis of RAFLS, and the underlying mechanism. Human RAFLS was isolated from the knee joints of patients with RA and subjected to TNF-alpha treatment in combination of various concentration of GA. We found that GA dose-dependently inhibited TNF-alpha-induced RAFLS proliferation as measured, but promoted RAFLS apoptosis. Further mechanistic study identified that GA dose-dependently attenuated TNF-alpha-mediated activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) pathways, both of which are involved in TNF-alpha-mediated RAFLS proliferation. Moreover, GA induced apoptosis and mitochondrial damage of RAFLS, as evidenced by increased Bax/Bcl-2 ratio and mitochondrial cytochrome c release, and enhanced cleavages of caspase-3, caspase-9, and poly-(ADP-ribose) polymerase. Collectively, our results revealed that chemical inhibition of HSP90 by GA suppressed TNF-alpha-induced proliferation of RAFLSs through the MAPK and NF-kappaB signaling pathways and induces RAFLS apoptosis via mitochondria-dependent pathway. These findings demonstrated for the first time that HSP90 inhibition in RAFLS could be therapeutic beneficial for RA. PMID- 30304568 TI - Molecular Sieving of Ethane from Ethylene through the Molecular Cross-Section Size Differentiation in Gallate-based Metal-Organic Frameworks. AB - Purification of C2 H4 from an C2 H4 /C2 H6 mixture, one of the most important while challenging industrial separation processes, is mainly through energy intensive cryogenic distillation. Now a family of gallate-based metal-organic framework (MOF) materials is presented, M-gallate (M=Ni, Mg, Co), featuring 3D interconnected zigzag channels, the aperture sizes of which (3.47-3.69 A) are ideally suitable for molecular sieving of ethylene (3.28*4.18*4.84 A3 ) and ethane (3.81*4.08*4.82 A3 ) through molecular cross-section size differentiation. Co-gallate shows an unprecedented IAST selectivity of 52 for C2 H4 over C2 H6 with a C2 H4 uptake of 3.37 mmol g-1 at 298 K and 1 bar, outperforming the state of-the-art MOF material NOTT-300. Direct breakthrough experiments with equimolar C2 H4 /C2 H6 mixtures confirmed that M-gallate is highly selective for ethylene. The adsorption structure and mechanism of ethylene in the M-gallate was further studied through neutron diffraction experiments. PMID- 30304569 TI - UCK2 upregulation might serve as an indicator of unfavorable prognosis of hepatocellular carcinoma. AB - Uridine-cytidine kinases (encoded by UCK1, UCKL1, and UCK2) catalyze the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP). In this study, using data from the Cancer Genome Atlas (TCGA), we analyzed the expression profile of uridine-cytidine kinase genes in hepatocellular carcinoma (HCC), their prognostic value, and the epigenetic alterations associated with their dysregulation. Results showed that UCKL1 and UCK2, but not UCK1 were significantly upregulated in HCC tissues than in adjacent normal tissues. Only UCK2 was significantly upregulated in the deceased group and the recurrence group, compared to the control groups. Multivariate analysis confirmed that increased UCK2 expression was an independent prognostic indicator of shorter overall survival (OS) (HR: 1.760, 95% CI: 1.398-2.216, P < 0.001) and recurrence-free survival (RFS) (HR: 1.543, 95% CI: 1.232-1.933, P < 0.001). Two CpG sites (cg09277749 and cg21143899) were significantly hypomethylated in HCC tissues than in adjacent normal tissues and were negatively correlated with UCK2 expression. However, survival analysis showed that only high methylation of cg0927774 was associated with better OS and RFS of HCC patients. Based on the findings above, we infer that UCK2 upregulation might be a valuable prognostic marker in HCC. The methylation of status cg0927774 might play a critical role in its expression. (c) 2018 IUBMB Life, 2018. PMID- 30304570 TI - Application of Human-Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders. AB - Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human-induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC-derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease related synaptopathy. PMID- 30304571 TI - Biochar amendment suppresses N2 O emissions but has no impact on 15 N site preference in an anaerobic soil. AB - RATIONALE: Biochar amendments often decrease N2 O gas production from soil, but the mechanisms and magnitudes are still not well characterized since N2 O can be produced via several different microbial pathways. We evaluated the influence of biochar amendment on N2 O emissions and N2 O isotopic composition, including 15 N site preference (SP) under the anaerobic conditions. METHOD: An agricultural soil was incubated with differing levels of biochar. Incubations were conducted under anaerobic conditions for 10 days with and without acetylene, which inhibits N2 O reduction to N2 . The N2 O concentrations were measured every 2 days, the SPs were determined after 5 days of incubation, and the inorganic nitrogen concentrations were measured after the incubation. RESULTS: The SP values with acetylene were consistent with N2 O production by bacterial denitrification and those without acetylene were consistent with bacterial denitrification that included N2 O reduction to N2 . There was no effect of biochar on N2 O production in the presence of acetylene between Day 3 and Day 10. However, in the absence of acetylene, soils incubated with 4% biochar produced less N2 O than soils with no biochar addition. Different amounts of biochar amendment did not change the SP values. CONCLUSIONS: Our study used N2 O emission rates and SP values to understand biochar amendment mechanisms and demonstrated that biochar amendment reduces N2 O emissions by stimulating the last step of denitrification. It also suggested a possible shift in N2 O-reducing microbial taxa in 4% biochar samples. PMID- 30304572 TI - Electrochemical Reduction of N2 to NH3 at Low Potential by a Molecular Aluminum Complex. AB - Electrochemical generation of ammonia (NH3 ) from nitrogen (N2 ) using renewable electricity is a desirable alternative to current NH3 production methods, which consume roughly 1 % of the world's total energy use. The use of catalysts to manipulate the required electron and proton transfer reactions with low energy input is also a chemical challenge that requires development of fundamental reaction pathways. This work presents an approach to the electrochemical reduction of N2 into NH3 using a coordination complex of aluminum(III), which facilitates NH3 production at -1.16 V vs. SCE. Reactions performed under 15 N2 liberate 15 NH3 . Electron paramagnetic resonance spectroscopic characterization of a reduced intermediate and investigations of product inhibition, which limit the reaction to sub-stoichiometric, are also presented. PMID- 30304573 TI - Physicians' views on patient participation in choice of oral anticoagulants in atrial fibrillation-a qualitative study. AB - Direct oral anticoagulants provide an alternative to vitamin K antagonists for the anticoagulation therapy in atrial fibrillation (AF). The availability of several treatment options with different attributes makes shared decision-making appropriate for the choice of anticoagulation therapy. The aim of this study was to understand how physicians choose an oral anticoagulant (OAC) for patients with AF and how physicians view patients' participation in this decision. Semi structured interviews with 17 Finnish physicians (eight general practitioners and nine specialists) working in the public sector were conducted. An interview guide on experience, prescribing and opinions about oral anticoagulants was developed based on previous literature. The data were thematically analysed using deductive and inductive approaches. Based on the interviews, patient's opinion was the most influential factor in decision-making when there were no clinical factors limiting the choice between OACs. Of patient's preferences, the most important was the attitude towards co-payments of OACs. Patients' opinions on monitoring of treatment, dosing and antidote availability were also mentioned by the interviewees. The choice of an OAC in AF was patient-centred as all interviewees expressed that patient's opinion affects the choice. PMID- 30304574 TI - Metabotropic glutamate receptor 1-mediated calcium mobilization in the neonatal hippocampal marginal zone. AB - The hippocampal marginal zone contains Cajal-Retzius (C-R) cells and participates in the regulation of cortical development. Two subtypes of group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, are found in the central nervous system and are considered to regulate neuronal excitability. The release of Ca2+ from intracellular stores is thought to be a main consequence of activation of these receptor subtypes. In hippocampal C-R cells, the expression of mGluR1 has been showed using immunohistochemical techniques, but its function has not been elucidated. In this study, Ca2+ mobilization through mGluR1 activation was demonstrated in the neonatal rat hippocampus. In marginal zone C-R cells, intracellular Ca2+ elevation was detected by fluorescence imaging after the application of a group I mGluR-specific agonist. This response was prevented by application of an mGluR1 antagonist but was not changed by application of an mGluR5 antagonist. The intracellular Ca2+ elevation induced by mGluR1 activation was still observed in Ca2+ -free perfusate, indicating the release of Ca2+ from intracellular stores. gamma-Aminobutyric acid and ionotropic glutamate receptor mediated intracellular Ca2+ elevation was also detected in mGluR1-possessing neurons, although the former was much smaller than that mediated by mGluR1. These results indicate that mGluR1 is functionally expressed in C-R cells in the neonatal marginal zone and regulates cell function through the elevation of intracellular Ca2+ . PMID- 30304575 TI - Compositional and beam size dependent effects on pressure baseline (PBL) in clumped isotope mass spectrometry. AB - RATIONALE: The analysis of carbonate samples for the application of clumped isotopes to paleoclimate reconstruction necessitates smaller beam intensities. However, there is a relationship between beam intensity and pressure-dependent baseline (PBL), and therefore between beam intensity and the correction for PBL. Here we explain the relationship between PBL and beam intensity to develop a better correction protocol and an improved understanding of clumped isotope mass spectrometry. METHODS: We describe a beam size experiment on our Isoprime isotope ratio mass spectrometer in which samples of the reference carbonate standard IAEA C1 were analyzed at 30, 50, and 70 nA to establish an optimal protocol and a new method to correct for PBL using the theoretical constraint of invariable Delta47 over a range of delta47 (bulk isotope composition) values. We also explore the effects of both over-and under-correction of PBL on equilibrated and heated gas samples to understand the effect of mis-correction of PBL on the absolute reference frame. RESULTS: The results of our beam size experiments showed that a direct measurement either at a set point or at a peak scan-determined point of the baseline consistently introduced variability to measurements of the Delta47 of heated gases, equilibrated gases, and carbonate standards. These results necessitated a new protocol to account for PBL in our system. Our new approach flattens the reference frame line slope to 0 and, importantly, reduces the variability of data points about the heated gas line. We also describe, for the first time, an empirically-derived description of the compositional effect of PBL. CONCLUSIONS: A seemingly small change in our isotope ratio mass spectrometer resulted in a better understanding of PBL, for which we have developed an empirically based correction protocol to apply. Our new protocol has the potential to reduce analytical time for laboratories measuring PBL, and supports the need for carbonate mineral-based clumped isotope standards. PMID- 30304576 TI - Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus. AB - As more genes conferring risks to neurodevelopmental disorders are identified, translating these genetic risk factors into biological mechanisms that impact the trajectory of the developing brain is a critical next step. Here, we report that disrupted signaling mediated MET receptor tyrosine kinase (RTK), an established risk factor for autism spectrum disorders, in the developing hippocampus glutamatergic circuit leads to profound deficits in neural development, synaptic transmission, and plasticity. In cultured hippocampus slices prepared from neonatal mice, pharmacological inhibition of MET kinase activity suppresses dendritic arborization and disrupts normal dendritic spine development. In addition, single-neuron knockdown (RNAi) or overexpression of Met in the developing hippocampal CA1 neurons leads to alterations, opposite in nature, in basal synaptic transmission and long-term plasticity. In forebrain-specific Met conditional knockout mice (Metfx/fx ;emx1cre ), an enhanced long-term potentiation (LTP) and long-term depression (LTD) were observed at early developmental stages (P12-14) at the Schaffer collateral to CA1 synapses compared with wild-type littermates. In contrast, LTP and LTD were markedly reduced at young adult stage (P56-70) during which wild-type mice show robust LTP and LTD. The altered trajectory of synaptic plasticity revealed by this study indicate that temporally regulated MET signaling as an intrinsic, cell autonomous, and pleiotropic mechanism not only critical for neuronal growth and functional maturation, but also for the timing of synaptic plasticity during forebrain glutamatergic circuits development. PMID- 30304577 TI - Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology. AB - Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. The results have demonstrated for the first time that NOTCH2 mutations contribute to POI etiology. We therefore recommend sequencing NOTCH2's open reading frame in large panels of POI patients to establish an accurate genotype-phenotype correlation. We cannot rule out the fact that patients affected by Alagille syndrome carrying NOTCH2 mutations may suffer ovarian dysfunction. PMID- 30304578 TI - Perfection of eccentricity: Mitochondrial genomes of diplonemids. AB - Mitochondria are the sandbox of evolution as exemplified most particularly by the diplonemids, a group of marine microeukaryotes. These protists are uniquely characterized by their highly multipartite mitochondrial genome and systematically fragmented genes whose pieces are spread out over several dozens of chromosomes. The type species Diplonema papillatum was the first member of this group in which the expression of fragmented mitochondrial genes was investigated experimentally. We now know that gene expression involves separate transcription of gene pieces (modules), RNA editing of module transcripts, and module joining to mature mRNAs and rRNAs. The mechanism of cognate module recognition and ligation is distinct from known intron splicing and remains to be uncovered. Here, we review the current status of research on mitochondrial genome architecture, as well as gene complement, structure, and expression modes in diplonemids. Further, we discuss the potential molecular mechanisms of posttranscriptional processing, and finally reflect on the evolutionary trajectories and trends of mtDNA evolution as seen in this protist group. (c) 2018 IUBMB Life, 70(12):1197-1206, 2018. PMID- 30304579 TI - Higher parental education was associated with better asthma control. AB - AIM: Inhaled corticosteroids have resulted in the improved control of asthma and a reduced need for hospitalisation. This study aimed to examine the prevalence of uncontrolled asthma and factors that affect asthma control. METHODS: The data came from a longitudinal cohort study of children. The parents answered questionnaires from age 6 months to 12 years. The response rate at age 12 years was 76% (3637/4777) and doctor-diagnosed asthma was reported in 6.4% (n = 233). Asthma control was examined with the Asthma Control Test (ACT), where scores below 20 denote uncontrolled asthma. RESULTS: Of the children with asthma at age 12 years, 15% had an ACT value below 20, that is uncontrolled asthma. Independent risk factors for uncontrolled asthma were wheeze triggered by exercise (adjusted OR, aOR 5.6; 1.9-16.6), cat at home (aOR 3.5; 1.2-10.0) and current doctor diagnosed rhinitis (aOR 2.8; 95% CI 1.1-7.0). A higher education in the parents reduced the risk of uncontrolled asthma (aOR 0.3; 95% CI 0.1-0.8). Only six children (i.e. 2.6%) reported hospitalisation due to asthma during the last year. CONCLUSION: Of the children with asthma, 15% had uncontrolled asthma. Higher education in the parents was associated with better asthma control in the children. PMID- 30304580 TI - Ring-Opening Polymerisation of Low-Strain Nickelocenophanes: Synthesis and Magnetic Properties of Polynickelocenes with Carbon and Silicon Main Chain Spacers. AB - Polymetallocenes based on ferrocene, and to a lesser extent cobaltocene, have been well-studied, whereas analogous systems based on nickelocene are virtually unexplored. It has been previously shown that poly(nickelocenylpropylene) [Ni(eta5 -C5 H4 )2 (CH2 )3 ]n is formed as a mixture of cyclic (6x ) and linear (7) components by the reversible ring-opening polymerisation (ROP) of tricarba[3]nickelocenophane [Ni(eta5 -C5 H4 )2 (CH2 )3 ] (5). Herein the generality of this approach to main-chain polynickelocenes is demonstrated and the ROP of tetracarba[4]nickelocenophane [Ni(eta5 -C5 H4 )2 (CH2 )4 ] (8), and disila[2]nickelocenophane [Ni(eta5 -C5 H4 )2 (SiMe2 )2 ] (12) is described, to yield predominantly insoluble homopolymers poly(nickelocenylbutylene) [Ni(eta5 C5 H4 )2 (CH2 )4 ]n (13) and poly(tetramethyldisilylnickelocene) [Ni(eta5 -C5 H4 )2 (SiMe2 )2 ]n (14), respectively. The ROP of 8 and 12 was also found to be reversible at elevated temperature. To access soluble high molar mass materials, copolymerisations of 5, 8, and 12 were performed. Superconducting quantum interference device (SQUID) magnetometry measurements of 13 and 14 indicated that these homopolymers behave as simple paramagnets at temperatures greater than 50 K, with significant antiferromagnetic coupling that is notably larger in carbon bridged 6x /7 and 13 compared to the disilyl-bridged 14. However, the behaviour of these polynickelocenes deviates substantially from the Curie-Weiss law at low temperatures due to considerable zero-field splitting. PMID- 30304581 TI - Novel extremophilic proteases from Pseudomonas aeruginosa M211 and their application in the hydrolysis of dried distiller's grain with solubles. AB - Proteases are the most important group of industrial enzymes and they can be used in several fields including biorefineries for the valorization of industrial byproducts. In this study, we purified and characterized novel extremophilic proteases produced by a Pseudomonas aeruginosa strain isolated from Mauritia flexuosa palm swamps soil samples in Peruvian Amazon. In addition, we tested their ability to hydrolyze distillers dried grains with solubles (DDGS) protein. Three alkaline and thermophilic serine proteases named EI, EII, and EIII with molecular weight of 35, 40, and 55 kDa, respectively, were purified. EI and EIII were strongly inhibited by EDTA and Pefabloc being classified as serine metalloproteases, while EII was completely inhibited only by Pefabloc being classified as a serine protease. In addition, EI and EII exhibited highest enzymatic activity at pH 8, while EIII at pH 11 maintaining almost 100% of it at pH 12. All the enzymes demonstrated optimum activity at 60 degrees C. Enzymatic activity of EI was strongly stimulated in presence of Mn2+ (6.9-fold), EII was stimulated by Mn2+ (3.7-fold), while EIII was slightly stimulated by Zn2+ , Ca2+ , and Mg2+ . DDGS protein hydrolysis using purified Pseudomonas aeruginosa M211 proteases demonstrated that, based on glycine released, EIII presented the highest proteolytic activity toward DDGS. This enzyme enabled the release 63% of the total glycine content in wheat DDGS protein, 2.2-fold higher that when using the commercial Pronase(r). Overall, our results indicate that this novel extremopreoteases have a great potential to be applied in DDGS hydrolysis. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30304582 TI - Acid digestion of carbonates using break seal method for clumped isotope analysis. AB - RATIONALE: Acid digestion of carbonates to release CO2 is a crucial and sensitive step in sample preparation for clumped isotope analysis. In addition to data reduction and instrumental artefacts, many other uncertainties in the clumped isotope analysis of carbonates arise from the method used for the preparation of CO2 . We describe here an in-house designed reaction vessel that circumvents degassing and contamination problems commonly associated with the McCrea type digestion protocols. METHODS: We designed a leak-free break seal reaction vessel (made of PyrexTM ) suitable for prolonged acid digestion at 25 degrees C. Using this new vessel, several carbonate reference materials widely used in the clumped isotope community and other in-house laboratory standards were acid-digested and analysed for their delta13 C, delta18 O and Delta47 values in a dual inlet MAT 253 isotope ratio mass spectrometer following standard GC purification and data evaluation protocols. RESULTS: Long term reproducibility in Delta47 determination was established using international references and in-house working standards as enumerated below (mean and SE): Carrara-1 (0.395 +/- 0.002 0/00, n=43), Carrara-2 (0.441 +/- 0.003 0/00, n=22), OMC (0.587 +/- 0.004 0/00, n=16), NBS 19 (0.393 +/- 0.005 0/00, n=10), NBS 18 (0.473 +/- 0.003 0/00, n=5), ETH 1 (0.271 +/- 0.005 0/00, n=7), ETH 3 (0.698 +/- 0.005 0/00 , n=3), MZ (0.715 +/- 0.002 0/00, n=3) and several others. CONCLUSION: A new method using a break seal tube was found to be efficient for the clumped isotope analysis of carbonates that require longer reaction time at 25 degrees C. This method yields good precision in Delta47 analysis and was found to be suitable for acid digestions at any desired temperature. PMID- 30304583 TI - Spatiotemporal-Controlled Reporter for Cell-Surface Proteolytic Enzyme Activity Visualization. AB - Live-cell imaging of cell-surface-associated proteolytic enzymes is crucial to understand their biological roles and functions in both physiological and pathological processes. However, the complexity of the cell membrane environment increases difficulties in specifically investigating targeted proteolytic activities within the microenvironment. Towards this end, a unique, photoremovable, furin-responsive peptide probe that can undergo spatiotemporal control through UV-light illumination has been designed and synthesized to aid in visualizing the activity of a cell-surface-associated protease enzyme, furin, in live cells. Prior to light irradiation, the photolabile moiety, 4,5-dimethoxy-2 nitrobenzyl, in the peptide sequence of the reporter will block furin-like enzymatic hydrolysis, and thus, no fluorescence will be observed. Upon simple light illumination, photolysis will occur, thereby revealing the uncaged peptide probe, which can undergo enzyme hydrolysis and lead to an increase in fluorescence signal; this allows the real-time imaging of endogenous cell-surface associated furin-like enzyme function in living cells through precise spatial and temporal resolution. PMID- 30304584 TI - Corrigendum to "On the integrity of functional brain networks in schizophrenia, Parkinson's disease, and advanced age: Evidence from connectivity-based single subject classification." PMID- 30304585 TI - Emotional Competence: Demonstrated Performance. AB - Component behaviors of emotional competence and nurse develop- ment of an action plan to demonstrate performance of these behaviors are examined. The critical impact of emotional compe- tence on professional role satisfaction and on success of an organi- zation is explored. PMID- 30304586 TI - Blood Transfusion Vital Sign Frequency: What Does the Evidence Say?. AB - Blood transfusion vital sign protocols do not have sufficient evi- dence to mandate surveillance frequency. The purpose of this study was to examine the relationship of vital sign changes to reaction times in an effort to determine best practice for monitoring patients receiving blood products. PMID- 30304587 TI - Nurse Residency Program Designed for a Large Cohort of New Graduate Nurses: Implementation and Outcomes. AB - A nurse residency program was designed to train a large group of new graduate nurses hired into multiple specialty areas. The program included a generalist 1 month 5 day/week clinical orientation followed by specialty clinical orientation with ongoing generalist education. Retention rate after 1 year was 91%. PMID- 30304588 TI - A Novel Approach to Reducing RN Distraction During Medication Access. AB - Use of a noise-reducing headset to decrease distractions at medication stations was evaluated. Observational data demonstrated a statistically significant decrease in the frequency with, which RNs were visibly distracted when using the headset. PMID- 30304589 TI - Enhanced Recovery in Orthopedics: A Prospective Audit of an Enhanced Recovery Program for Patients Undergoing Hip or Knee Arthroplasty. AB - Hip and knee arthroplasty are common 'surgical procedures. Enhanced recovery programs help reduce length of stay with good patient outcomes and satisfaction. An audit is described showing improved pain management, reduced nausea and vomiting, and quicker recovery through an interprofessional approach. PMID- 30304590 TI - Felty's Syndrome: A Qualitative Case Study. AB - Felty's syndrome is a triad of rheumatoid arthritis, splenomegaly, and neutropenia. This rare disorder is difficult to diagnose and produces many complications. The purpose of this descriptive qualitative case study was to provide a comprehensive, context-bound understanding of one patient's struggle with the condition. PMID- 30304591 TI - Tranexamic Acid in Total Hip Arthoplasty: Management of Complications and Use. AB - Use of tranexamic acid for management of blood loss in total hip arthroplasty is growing. It is important for healthcare providers to be aware of the pharmacology, efficacy, management, complica- tions, and side effects of this medication. PMID- 30304592 TI - Assessment of Airway Defenses in the Neurologically Impaired Patient. AB - Impairment of cough and swallow is a potential consequence of neurological dysfunction that places affected patients at increased risk for respiratory compromise and death. Nurses are critical to early identification and frequent screening of airway defense mechanisms to reduce aspiration risk and improve clinical outcomes in patients with neurological impairment. PMID- 30304593 TI - Stroke Transitions of Care. AB - This quality improvement project focused on improving patient education and patient satisfaction, and reducing all-cause 30-day readmissions. A 72-hour discharge follow-up telephone call was completed in patients discharged home with diagnosis of stroke. PMID- 30304594 TI - The Use of Intravenous Ibuprofen and Intravenous Acetaminophen in Surgical Patients and the Effect on Opioid Reduction. AB - Healthcare providers typically use opioids to treat postoperative pain. Use of intravenous ibuprofen and acetaminophen as adjuncts to opioids is evaluated for potential to reduce opioid use and improve postoperative pain management. PMID- 30304595 TI - The Patient's Experience in Total Knee Arthroplasty: Past-Now-Future. AB - Total knee arthroplasty (TKA) affects patients' lives in many ways. In this descriptive qualitative study, effects of knee problems were identified as influential on patients' decisions during the preopera- tive period. Patients also stated they experienced difficulties postop- eratively that were unique to TKA. PMID- 30304596 TI - Care of LGBTQ Patients. AB - The Medical-Surgical Nursing Certification Board (MSNCB) is a professional organization whose mission is to validate excellence in medical-surgical nursing. MSNCB administers the Certified Medical-Surgical Registered Nurse (CMSRN[R]) and Certified in Care Coordination and Transition Management (CCCTM) certification programs because certification is the recognized path for registered nurses to build and demonstrate commitment, confidence, and credibility. Certification provides an added credential beyond licensure. It demonstrates, by examination, that the registered nurse adheres to specialized nursing standards and has acquired a core body of specialized knowledge in their practice or specialty. The topic of this article is part of the comprehensive examination given by MSNCB. The following scenario and questions offer an example that potential certificants may use to test their knowledge. PMID- 30304597 TI - Immunizations for the Adult Patient. PMID- 30304598 TI - When Compassion is Lost. PMID- 30304599 TI - Thyroid Storm. PMID- 30304600 TI - Peer Review. PMID- 30304601 TI - When Visitors Become Violent: What is the Ethical Response? PMID- 30304602 TI - Discharge by 11:00 a.m.: The Significance of Discharge Planning. AB - An interprofessional program was introduced to streamline the dis- charge process to occur earlier in the day, and to reduce the disruption in patient flow caused by overcrowding in departments dependent on the availability of medical-surgical beds. PMID- 30304603 TI - Comparison of Outcomes: Nurse-Driven vs. Physician-Driven Weight-Based Intravenous Heparin Protocol. AB - The transition from a physician-driven heparin protocol to a nurse- driven heparin protocol at one institution resulted in shorter times to therapeutic activated partial thromboplastin time (aPTT), increased time within goal aPTT range, and an increased percent- age of patients who ultimately achieved a therapeutic aPTT. PMID- 30304605 TI - Characteristics and Predictors of Readmission to a Medical Short-Stay Unit. AB - Short-stay units are medical units with anticipated lengths of stay of 24-72 hours. The purpose of this study was to identify characteristics and predictors of 30-day readmission among patients admitted to a short-stay unit during two separate time periods. Findings suggest the presence of previous Emergency Department visits or hospitalizations should be considered when aligning discharge needs, as these may impact subsequent patient readmissions. PMID- 30304604 TI - Hyperglycemia in the Hospital Setting. AB - Nurses who understand contributing factors to insulin action and uncontrolled glucose and insulin action can assist in promoting optimal care. Common barriers to glucose control and current best practices in the acute care setting are reviewed. PMID- 30304607 TI - Untangling Polypharmacy in Older Adults. AB - Polypharmacy, the use of five or more medications at one time, is increasingly prevalent in older adults. The nurse's role in education, care coordination, communication, and regular medication recon- ciliation is vital to improve outcomes. PMID- 30304606 TI - Reducing 30-Day Readmissions for Chronic Obstructive Pulmonary Disease. AB - A quality improvement project to reduce 30-day readmissions for chronic obstructive pulmonary disease (COPD) is described. A telephone assessment using the Medical Research Council Scale was completed within the first 5 days after discharge in patients with a diagnosis of COPD to evaluate dyspnea level. PMID- 30304608 TI - Preparing New Nurses to Address Bullying: The Effect of an Online Educational Module on Learner Self-Efficacy. AB - Newly licensed nurses who start their careers in supportive, nurtur- ing environments are more likely to overcome challenges and successfully transition into professional practice (Spiva et al., 2013). Introduction of content about bullying in the workplace via an online educational module can be an effective strategy for the academic preparation of pre-licensure nursing students. PMID- 30304609 TI - 'What Do I Do Next?' Nurses' Confusion and Uncertainty with ECG Monitoring. AB - The prevalence of telemetry monitoring is increasing on medical- surgical units, but no evidence-based guidelines standardize nursing education. Research indicates nurses feel uncertain and report a lack of knowledge when caring for patients with telemetry monitoring. PMID- 30304610 TI - Care of the veteran. AB - The Medical-Surgical Nursing Certification Board (MSNCB) is a professional organization whose mission is to validate excellence in medical-surgical nursing. MSNCB administers the Certified Medical- Surgical Registered Nurse (CMSRN[R]) and Certified in Care Coordination and Transition Management (CCCTM) certification programs because certification is the recognized path for registered nurses to build and demonstrate commitment, confidence, and credibility. Certification provides an added credential beyond licensure. It demonstrates, by examination, that the registered nurse adheres to specialized nursing standards and has acquired a core body of specialized knowledge in his or her practice or specialty. The topic of this article is part of the comprehensive examination given by MSNCB. The following scenario and questions offer an example that potential certificants may use to test their knowledge. PMID- 30304611 TI - Negative Pressure Wound Therapy. PMID- 30304612 TI - Ethical Concerns in Medical-Surgical Nursing. PMID- 30304613 TI - Valuing our Senior Nurses. PMID- 30304614 TI - Trustworthiness in Qualitative Research. PMID- 30304616 TI - Healthy Nurse, Healthy NationTM. PMID- 30304615 TI - Nurse Fatigue: Dangerous for Nurses and Patients. PMID- 30304617 TI - Using Post-Discharge Telephone Follow-Up by Nephrology Nurses to Reduce 30-Day Readmissions and Post-Discharge Complications for Adult Patients on Hemodialysis. AB - Hospital readmissions are responsible for considerable health care costs. About 35% of patients with end stage renal disease (ESRD) who are hospitalized are readmitted within 30 days of discharge (United States Renal Data System, 2017). Studies point to the considerable percentage of readmissions that are preventable through effective discharge planning and patient follow-up after discharge (Mistiaen & Poot, 2006). Telephone follow up is a high-quality, low-cost method of providing discharge follow up. This project examined the effectiveness of an evidence-based quality improvement process in providing post-discharge telephone follow up to adult patients on hemodialysis by experienced nephrology nurses through standardized unit workflow and leveraging of the electronic medical record (EMR). Results indicated a lower percentage of admissions from the emergency department (59.9% pre- vs. 55.4% post-intervention) and a lower percentage of 30-day readmissions (28.4% pre- vs. 24.6% post-intervention). PMID- 30304618 TI - Identification of Potential Mediators Between Depression and Fluid Adherence in Older Adults Undergoing Hemodialysis Treatment. AB - Controlled fluid intake is an important aspect of living with end stage renal disease (ESRD), and is complicated by depression, the most common mental health issue affecting individuals with ESRD. Factors that mitigate the deleterious effects of depression are underexplored. This study sought to identify potential mediators between depression and fluid adherence in 107 individuals with ESRD aged 50 years and older by comparing four logistic regression models. Age was associated with an increase in fluid adherence (adjusted odds ratio [AOR]=1.08, 95% confidence interval [CI]=1.02-1.14), whereas depression was associated with a decrease in fluid adherence (AOR=0.82, 95% CI=0.67-0.99), but when self-efficacy was entered into the model, the association between depression and fluid adherence weakened. Findings suggest that self-efficacy and age are important factors in fluid adherence, and self-efficacy can potentially mediate the negative effects of depression in older adults with ESRD. PMID- 30304619 TI - Association of Infections with the Use of a Temporary Double-Lumen Catheter for Hemodialysis. AB - The goal of this study was to identify the occurrence of secondary infection due to the use of temporary double-lumen catheters for hemodialysis in 96 patients with acute kidney injury or acute chronic kidney disease. For each patient, we collected a swab from the skin localized in the insertion of catheter before antisepsis; blood cultures from the catheter lumen, peripheral vein, and central venous access in withdrawing catheter; and cultures of catheter tips. Catheters were implanted into a femoral vein in 56.2% of patients. In 67.7% of patients, the catheter remained in place for 1 to 10 days, microbiological colonization was found in 51% of the catheters, 14.3% of patients had a bloodstream infection related to catheter, and 10.4% had an infection at the catheter insertion site. This study pointed out many health concerns related to the use of a catheter. PMID- 30304620 TI - Improving Communication Skills within the Nephrology Unit. AB - Effective communication skills are critical in nephrology units for patients, staff members, and the organization to decrease errors, work together as an interdisciplinary team, and have smoothly running unit operations. The desire and willingness to communicate are important for maintaining safety in healthcare settings, and the lack of effective communication is the most common patient complaint. Skills needed for successful communication include verbal dialogue, active listening, interpretation of body language, empathy, confidence, charisma, and cooperativeness. Miscommunication can occur due to language barriers, misinterpretation, and poor listening skills. Effective communication skills are an essential competence for all members of the interdisciplinary team. PMID- 30304621 TI - Impact of Population Differences: Post-Kidney Transplant Readmissions. AB - Early hospital readmissions after kidney transplantation are common and considered an indicator of healthcare quality. The purpose of this study was to identify and describe the risk factors for and causes of 30-day readmission post kidney transplant for adults in a predominantly Hispanic Southern Texas population in comparison to the United States kidney transplant population and published research. A single-center, descriptive, retrospective study of adult kidney transplant recipients readmitted to a hospital in southern Texas was conducted. Results indicated that this population had lower education levels, a greater percentage of Spanish-speaking patients, and a high number of patients with either or both diabetes mellitus and hypertension, necessitating the development of additional methods of increasing understanding and adherence to restrictions, requirements, and medication regimes. PMID- 30304622 TI - Focusing on the Fundamentals: Reading Quantitative Research with a Critical Eye. AB - Nephrology nurses must be able to critically analyze research to improve their practice. This article defines the components of a quantitative research article, reviews principles that nephrology nurses can use when reading and interpreting a quantitative research article, and provides a methodical way of approaching a quantitative research article to determine its merits and limitations. PMID- 30304623 TI - Safety: Are We Better Now? PMID- 30304624 TI - Speaking Up for Nurses and Patients. PMID- 30304625 TI - Workplace Violence - Are You Prepared? PMID- 30304626 TI - Make Your Wishes About You (MY WAY): Using Motivational Interviewing to Foster Advance Care Planning for Patients with Chronic Kidney Disease. AB - Advance care planning for persons with chronic kidney disease is under-utilized despite evidence it can improve care at the end of life. Motivational interviewing and Stages of Change Theory can help healthcare professionals elicit behavior change. This article outlines an approach to advance care planning using motivational interviewing with a healthcare coach to assist patients in expressing their unique values and wishes regarding care at the end of life. This Make Your Wishes About You (MY WAY) approach to advance care planning for patients with chronic kidney disease includes patient education material and a coach training curriculum freely available from the Coalition for Supportive Care of Kidney Patients. PMID- 30304627 TI - Use of Ultrasound Guidance During Cannulation of Arteriovenous Fistulas. AB - Individuals who require renal replacement therapy overwhelmingly choose outpatient hemodialysis. Appropriate cannulation techniques are an essential element in access preservation and in the prevention of access-related complications. Missed cannulations can result in damage of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs). Ultrasound-guided cannulation is an effective technique for the placement of peripheral intravenous (IV) catheters and central venous catheters (CVCs) for hemodialysis. The purposes of this project were to determine if ultrasound-guided cannulation of AVFs decreased the number of missed cannulations, to determine staff and patient perceptions regarding cannulation, and to implement a quality incentive program (QIP) to implement an evidence-based ultrasound-guided policy and procedure, training program, and competency evaluation at a hospital-based dialysis facility. PMID- 30304628 TI - A Window into the World of Nephrology Nursing: Nephrology Nurses' Views of the Health and Safety of Their Work Environments, the Impact on Patient Care, and Opportunities for Improvement. AB - In January 2018, the American Nephrology Nurses Association and Nephrology News and Issues conducted a national study, The Health and Safety of Nephrology Nurses and the Environments in Which They Work. This article presents initial qualitative results from that study - in the words of nephrology nurses. Based on responses of participants, themes and subthemes were identified: staffing, nursing practice (time to provide nursing care, nursing work hours, level of practice, nurses responsibility for the practice of others), work environment conditions (physical environments, psychological environments, civility/ incivility, environmental health, and work spaces), respect, recognition, interprofessional collaboration and support, and career and job satisfaction. Results of the study provide insight into what it is like to work on the frontlines of nephrology nursing. PMID- 30304629 TI - Care Coordination Between the Nephrology Nurse and the Payor: Working Together to Bridge the Gaps in Care for Patients with Kidney Disease. AB - Integrated care management is a key buzz phrase in health care. Most providers, nurse practitioners, nurses, and payors believe their area of expertise, such as direct patient care or insurance companies, has integrated nursing plans and forgotten about opportunities to collaborate outside of their immediate area. However, collaboration between nurses in dialysis clinics, physicians, nurse practitioners, and case managers from payors, such as insurance companies, is often missing. This collaboration can result in better patient outcomes and in meeting goals for the patient, the provider, and the payor, including maximizing value-based purchasing opportunities. PMID- 30304630 TI - Effects of Application of Elastic Compression Stockings on Blood Pressure, Pulse Rate, and Hypotensive Symptoms in Patients with Intradialytic Hypotension. AB - This study was conducted to identify the effect of elastic compression stockings on hypotension in patients with intradialytic hypotension. Subjects of this study were 59 patients (29 in the experimental group, 30 in the control group). Elastic compression stockings were applied to patients in the experimental group during hemodialysis. To evaluate effects of treatment, systolic blood pressure, diastolic blood pressure, pulse rate, and hypotension symptom scores were measured. Results indicated the decrease in systolic blood pressure in the experimental group was less than that in the control group. Hypotension symptom scores were significantly decreased in the experimental group. Considering these results, the application of elastic compression stockings can be regarded as an effective nursing intervention to help prevent intradialytic hypotension in patients undergoing hemodialysis. PMID- 30304631 TI - Using Creative Activities to Improve Treatment Perceptions of Patients on Hemodialysis. AB - Hemodialysis (HD) has a significant impact on health-related quality of life (HRQoL). We performed an observational study to assess the mental and physical status of 41 patients on chronic HD treatment. We planned and launched a program of recreational and therapeutic intradialysis activities to reduce patients' boredom due to inactivity. Patients' mental and physical status was reassessed at 12 months. Our initial attempt to introduce these recreational activities as intradialysis therapy has been rated positively by all patients. After one year, anxiety decreased (without statistical significance) and willingness to participate in activities increased from 50.00% to 85.71% (p=0.019). No improvement was observed on the remaining studied variables. This preliminary initiative is promising. We plan to maintain these successful therapies and include others to help consolidate this program. PMID- 30304632 TI - Kidney Transplantation in Older Adult Recipients. PMID- 30304633 TI - The Interdisciplinary Team and the Patient: Working Together to Achieve Buy-In for a UF Rate Less Than 13 mL/Kg/Hr. AB - The Centers for Medicare & Medicaid Services (CMS) metric for reporting ultrafiltration (UF) recommends limiting UF at a range of 10 to 13 mL/Kg/Hr to avoid organ stunning. All organ stunning has an impact on patient quality of life (QoL). As this new standard of UF is implemented, the interdisciplinary team (IDT) and the patient must work together toward achieving a less than 13 mL/Kg/Hr UF buy-in. Understanding the CMS goals and target date of January 1, 2018, for data collection purposes was key to early initiation of staff and patient education. Dialysis treatment centers must rise to implement mandated fluid removal objectives. Education and knowledge are the best facilitators of success when implementing change. The IDT must work together to continually reinforce the standards set by CMS. PMID- 30304634 TI - The use of Apixaban for the treatment of an LV thrombus AB - Summary: A 42-year-old male was admitted with shortness of breath secondary to suspected heart failure and chest infection. An echocardiogram revealed a dilated and impaired left ventricle; ejection fraction 29%, with a large, mobile thrombus within the left ventricular apex. Due to the presence of liver dysfunction, vitamin K antagonists were deemed inappropriate; thus, the decision was taken to use the novel anticoagulation agent Apixaban. After 6 days of receiving Apixaban, a cardiac magnetic resonance scan was preformed, which showed complete resolution of the LV apical thrombus. Learning points: Patients with a dilated and impaired LV are at an increased risk of developing LV thrombus.A large and mobile LV thrombus is associated with an increased risk of embolic events.Vitamin K antagonists (VKAs) are often the first-line therapy for LV thrombus; however, these may be inappropriate in some patients.NOACs are advantageous in comparison to VKAs and are used to treat: non-valvular atrial fibrillation, pulmonary embolisms and used in the prevention of recurrent deep vein thrombosis in adults.To date, NOACs are not licensed for the treatment of an LV thrombus; however, there are growing evidence whereby there use has shown promise in reducing the risk of embolic events and demonstrate rapid reduction in size/full resolution of an LV thrombus.Large, randomised research trials comparing NOACs and VKAs in the treatment of LV thrombus are needed, which may lead to a change in standard clinical practice that could benefit patients. PMID- 30304635 TI - Concomitant acute stroke, pulmonary and myocardial infarction due to in-transient thrombus across a patent foramen ovale AB - Non-atherosclerotic myocardial infarction (MI) is an important but often misdiagnosed cause of acute MI. Furthermore, non-atherosclerotic MI with concomitant acute stroke and pulmonary embolism due to in-transit thrombus across a patent foramen ovale (PFO) is a rare but potentially fatal combination (1, 2, 3). Early detection of this clinical entity can facilitate delivery of targeted therapies and avoid poor outcome (1, 2). Here, we describe a 68-year-old female with hypertension, tobacco abuse and chronic obstructive pulmonary disease presenting with facial droop, right arm weakness and aphasia. Head computed tomography (CT) without contrast was unremarkable. ECG showed an acute inferolateral ST-elevation MI (Fig. 1, Panel A). As patient presented with both an acute neurological deficit and MI, clinical suspicion of non-atherosclerotic MI was raised and the patient underwent concurrent emergency coronary angiography (CAG) and transesophageal echocardiogram (TEE). TEE revealed highly mobile masses in the left and right atrium (Fig. 1, Panel B and Video 1). The large mass (thrombus or cast of a deep venous thrombus) was caught in a PFO (Fig. 1, Panel C, D, E and Videos 2, 3). A second smaller mass/thrombus was seen on the Eustachian valve near the right atrial/inferior vena cava junction (Fig. 1, Panel F and Video 4). CAG confirmed a 100% occluded distal right posterolateral artery suggestive of an embolic phenomenon. The patient underwent successful thrombectomy, retrieving a large thrombus burden (Fig. 1, Panel G and Videos 5, 6, 7). CT angiography showed occluded internal carotid artery (Fig. 1, Panel H). Pathology from thrombectomy confirmed fibrin-rich thrombus. The patient had bilateral lower extremity deep vein thrombosis and bilateral diffuse pulmonary embolisms. PMID- 30304636 TI - Biventricular mural vegetations without valvular involvement: an unusual presentation of Staphylococcus aureus endocarditis AB - A 42-year-old intravenous drug user presented with seizures and septicaemia. CT and MRI were suggestive of multiple brain and systemic emboli, and blood and CSF cultures were positive for Staphylococcus aureus. Initial transthoracic echocardiogram did not show any abnormalities but subsequent transoesophageal echocardiography showed two masses in the left and the right ventricle. The LV mass was large, irregular, non-mobile and attached to the basal anterolateral LV segment abutting but not involving the mitral valve. (Fig. 1). The RV mass was smaller and mobile and appeared attached to the primary chordae of anterior tricuspid valve leaflet, not encroaching the valve or affecting its function (Fig. 2). Once commenced on antibiotic treatment the patient's condition improved, and there were no further embolic events. There was no valvular damage and sequential echo studies showed significant reduction in vegetation size. Although the formal echocardiographic definition of vegetation includes non oscillating masses on any endocardial surface (1), primary mural endocarditis without valvular involvement is considered extremely rare (2). The diagnosis is supported by the septic and embolic clinical picture but requires awareness of this uncommon presentation. The present case is even more unusual in view of the biventricular mural localisation of the vegetations, a pattern that has been mentioned in only very few case reports (3, 4). PMID- 30304637 TI - Imaging Advances in Chronic Obstructive Pulmonary Disease: Insights from COPDGene. AB - The Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, which began in 2007, is an ongoing multicenter observational cohort study of >10,000 current and former smokers, aimed at understanding the etiology, progression, and heterogeneity of COPD. In addition to genetic analysis, the participants have been extensively characterized by clinical questionnaires, spirometry, volumetric inspiratory and expiratory CT, and longitudinal follow-up, including follow-up CT at five years after enrollment. The purpose of this review is to summarize the major advances in our understanding of COPD resulting from the imaging findings in the COPDGene study. Imaging features that are associated with adverse clinical outcomes include early interstitial lung abnormalities, visual presence and pattern of emphysema, the ratio of pulmonary artery to ascending aortic diameter, quantitative evaluation of emphysema, airway wall thickness, and expiratory gas trapping. COPD is characterized by the early involvement of the small conducting airways, and the addition of expiratory scans has enabled measurement of small airways disease. Computational advances have enabled indirect measurement of non-emphysematous gas trapping. These metrics have provided insights into the pathogenesis and prognosis of COPD and have aided early identification of disease. Important quantifiable extrapulmonary findings include coronary arterial calcification, cardiac morphology, intrathoracic and extrathoracic fat, and osteoporosis. Current active research includes identification of novel quantitative measures for emphysema and airway disease, evaluation of dose reduction techniques, and use of deep learning for phenotyping COPD. PMID- 30304638 TI - Aerobic training reduces immune cell recruitment and cytokine levels in adipose tissue in obese mice. AB - Obesity is associated with an energy imbalance that results from excessive energy intake, low diet quality and a sedentary lifestyle. In this regard, the increased consumption of a high-refined carbohydrate diet (HC) is strongly related to higher adiposity and low-grade inflammation. Aerobic training is a well-known non pharmacological intervention to treat obesity and metabolic disturbances. However, the mechanisms through which aerobic training ameliorates the low-grade inflammation induced by the HC diet need to be further investigated. Herein, our hypothesis was that aerobic training would decrease the recruitment of leukocytes in the adipose tissue thereby reducing the levels of cytokines and improving metabolism in mice fed the HC diet. Male Balb/c were assigned to the following groups: control non-trained (C-NT), control trained (C-T), HC-NT and HC-T. Mice were submitted to moderate-intensity training sessions that consisted of running 60 min/day for 8 weeks. The intravital microscopy technique was performed in vivo in anesthetized mice to visualize the microvasculature of the adipose tissue. The HC diet induced obesity and increased the influx of immune cells into the adipose tissue. In contrast, HC-T mice presented a lower adiposity and adipocyte area. Furthermore, HC-T mice showed an increased resting energy expenditure, a decreased recruitment of immune cells in the adipose tissue, reduced cytokine levels, and ameliorated hyperglycemia and fatty liver deposition relative to HC NT mice. Collectively, our data enhance the understanding about the anti inflammatory effect of aerobic training and shed light on the adipose tissue mediated mechanisms by which training promotes a healthier metabolic profile. PMID- 30304639 TI - Human Sexuality: Making Informed Decisions - Fifth Edition. PMID- 30304640 TI - A Neuroeconomic Framework for Creative Cognition. AB - Neuroeconomics is the study of the neurobiological bases of subjective preferences and choices. We present a novel framework that synthesizes findings from the literatures on neuroeconomics and creativity to provide a neurobiological description of creative cognition. We propose that value-based decision-making processes and activity in the locus ceruleus-norepinephrine (LC NE) neuromodulatory system underlie creative cognition, as well as the large scale brain network dynamics shown to be associated with creativity. This reconceptualization leads to several falsifiable hypotheses that can further understanding of creativity, decision making, and brain network dynamics. PMID- 30304641 TI - The value of European immigration for high-level UK research and clinical care: cross-sectional study. AB - Objective The UK's impending departure ('Brexit') from the European Union may lead to restrictions on the immigration of scientists and medical personnel to the UK. We examined how many senior scientists and clinicians were from other countries, particularly from Europe, in two time periods. Design Cross-sectional study. Setting United Kingdom. Participants Individuals who had been elected as Fellows of the Royal Society or of the Academy of Medical Sciences, and UK medical doctors currently practising and listed in the Medical Register for 2015. Main outcome measures Percentages of Fellows of the Royal Society, Fellows of the Academy of Medical Sciences and UK medical doctors by nationality (UK and Irish: UKI, European: EUR and rest of world: RoW) over time. Fellows of the Royal Society and the Academy of Medical Sciences proportions were assessed for two time periods, and doctors over decades of qualification (<1960s to 2010s). Results Percentages of European Fellows of the Royal Society increased from 0.8% (1952-1992) (the year the UK signed the Maastricht treaty) to 4.3% (1993-2015). For Fellows of the Academy of Medical Sciences, percentages increased from 2.6% (pre-1992) to 8.9% (post-1992) (for both, p < 0.001). In the 1970s, only 6% of doctors were trained in the EU; the proportion increased to 11% in the last two decades (also p < 0.001). Europeans replaced South Asians as the main immigrant group. Among these, doctors from the Czech Republic, Greece, Poland and Romania made the largest contribution. Conclusions Any post-Brexit restriction on the ability of the UK to attract European researchers and medical doctors may have serious implications for the UK's science leadership globally and healthcare provision locally. PMID- 30304642 TI - Mechanical Ventilation in Mice: Does Longer Equal Better? PMID- 30304643 TI - Development of a Bacterial Macroarray for the Rapid Screening of Targeted Antibody-Secreted Hybridomas. AB - Hybridoma screening is a key step for the successful generation of high-affinity analyte-specific monoclonal antibodies (MAbs). This work presents an innovative screening method, known as a bacterial macroarray, generated by contact printing of hybridoma cell supernatant samples on a nitrocellulose (NC) membrane initially coated with fluorescein isothiocyanate (FITC)-labeled bacteria. Given that bacterial fixation will be influenced by complex bacterial surface structures, we selected both gram-positive bacteria ( Staphylococcus aureus and Listeria monocytogenes) and gram-negative bacteria ( Escherichia coli O157:H7 and Cronobacter sakazakii) to optimize the fixation conditions for binding to the NC membrane, such as the aperture of the NC membrane, the concentration of bacteria, the dosage of glycerin in the spotting buffer, and the fixation time and temperature. As a result, we found that a better bacterial macroarray could be developed when the spotting buffer, containing 1011 CFU mL-1 of FITC-labeled bacteria and 15% (V/V) glycerol, was spotted onto a 0.45 um NC membrane with an incubation of 2 h at 37 degrees C. Finally, we verified the stability and specificity of the prepared bacterial macroarray by detecting cell cultures with the addition of two MAbs ( Escherichia coli O157:H7 MAb E7 and Cronobacter sakazakii MAb 1E9) to simulate the screening experiments. Here, we describe a bacterial macroarray to efficiently screen the targeted antibody-secreted hybridomas. PMID- 30304644 TI - The effects and costs of home-based rehabilitation for heart failure with reduced ejection fraction: The REACH-HF multicentre randomized controlled trial. AB - Background Cardiac rehabilitation improves health-related quality of life (HRQoL) and reduces hospitalizations in patients with heart failure, but international uptake of cardiac rehabilitation for heart failure remains low. Design and methods The aim of this multicentre randomized trial was to compare the REACH-HF (Rehabilitation EnAblement in CHronicHeart Failure) intervention, a facilitated self-care and home-based cardiac rehabilitation programme to usual care for adults with heart failure with reduced ejection fraction (HFrEF). The study primary hypothesis was that the addition of the REACH-HF intervention to usual care would improve disease-specific HRQoL (Minnesota Living with Heart Failure questionnaire (MLHFQ)) at 12 months compared with usual care alone. Results The study recruited 216 participants, predominantly men (78%), with an average age of 70 years and mean left ventricular ejection fraction of 34%. Overall, 185 (86%) participants provided data for the primary outcome. At 12 months, there was a significant and clinically meaningful between-group difference in the MLHFQ score of -5.7 points (95% confidence interval -10.6 to -0.7) in favour of the REACH-HF intervention group ( p = 0.025). With the exception of patient self-care ( p < 0.001) there was no significant difference in other secondary outcomes, including clinical events ( p > 0.05) at follow-up compared with usual care. The mean cost of the REACH-HF intervention was L418 per participant. Conclusions The novel REACH-HF home-based facilitated intervention for HFrEF was clinically superior in disease-specific HRQoL at 12 months and offers an affordable alternative to traditional centre-based programmes to address current low cardiac rehabilitation uptake rates for heart failure. PMID- 30304645 TI - Managing urinary incontinence in women - a review of new and emerging pharmacotherapy. AB - INTRODUCTION: The pharmacological treatment of urinary incontinence and overactive bladder (OAB) has been, for a longer time, based on antimuscarinic agents. In recent years, two other pharmacological principles have been introduced for the treatment of OAB and urgency urinary incontinence: the beta3 adrenergic agent mirabegron and botulinum neurotoxin. Meanwhile, there is lack of effective drugs for the treatment of stress incontinence. Areas covered: This literature review presents synthetic compounds aimed to treat female urinary incontinence that are in phase II-III clinical development. Expert opinion: Antimuscarinic agents will continue to represent the current gold standard for the first-line pharmacological management of OAB and urgency urinary incontinence. The class of beta3-agonists will certainly expand with the discovery and clinical development of novel agents. Combination therapy of antimuscarinic agents and beta3-agonists could offer an alternative treatment in these patients, including those with symptoms refractory to first-line monotherapy. A huge number of preclinical studies are underway in this field exploring the therapeutic potential of many novel compounds while some have advanced to clinical phases of development. PMID- 30304646 TI - Disease Intervention Specialist Education for the Future: An Analysis of Public Health Curricula. AB - OBJECTIVES:: The objectives of this study were to (1) determine the degree of alignment between an existing public health curricula and disease intervention specialist (DIS) workforce training needs, (2) assess the appropriateness of public health education for DISs, and (3) identify existing curriculum gaps to inform future DIS training efforts. METHODS:: Using the iterative comparison analysis process of crosswalking, we compared DIS job tasks and knowledge competencies across a standard Council on Education for Public Health (CEPH) accredited bachelor of science in public health (BSPH) and master of public health (MPH) program core curricula offered by the Georgia Southern University Jiann-Ping Hsu College of Public Health. Four researchers independently coded each DIS task and competency as addressed or not in the curriculum and then discussed all matches and non-matches between coders. Researchers consulted course instructors when necessary, and discussion between researchers continued until agreement was reached on coding. RESULTS:: The BSPH curriculum aligned with 75% of the DIS job tasks and 42% of the DIS knowledge competencies. The MPH core curriculum aligned with 55% of the job tasks and 40% of the DIS knowledge competencies. Seven job tasks and 9 knowledge competencies were considered unique to a DIS and would require on-the-job training. CONCLUSIONS:: Findings suggest that an accredited public health academic program, grounded in CEPH competencies, could address multiple components of DIS educational preparation. Similar analyses should be conducted at other CEPH-accredited schools and programs of public health to account for variations in curriculum. PMID- 30304648 TI - Classification, Ontology, and Precision Medicine. PMID- 30304649 TI - Radial Fracture Due to Parathyroid Carcinoma. PMID- 30304650 TI - Informed Consent and the Role of the Treating Physician. PMID- 30304651 TI - A Seat at the Table. PMID- 30304647 TI - Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. AB - BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.). PMID- 30304653 TI - Subclinical Hyperthyroidism. PMID- 30304652 TI - Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy. AB - JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .). PMID- 30304654 TI - Real-Time Patient-Provider Video Telemedicine Integrated with Clinical Care. PMID- 30304655 TI - Classification and Personalized Prognosis in Myeloproliferative Neoplasms. AB - BACKGROUND: Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. METHODS: We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort. RESULTS: A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy. CONCLUSIONS: Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients' outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.). PMID- 30304657 TI - Bilateral Vestibular Schwannomas in Neurofibromatosis Type 2. PMID- 30304658 TI - Endovenous Ablation in Venous Ulceration. PMID- 30304659 TI - Venetoclax in a Patient with a Blastic Plasmacytoid Dendritic-Cell Neoplasm. PMID- 30304660 TI - Neuroblastoma and Histone Demethylation. PMID- 30304661 TI - Case 31-2018: A 37-Year-Old Man with a Self-Inflicted Gunshot Wound. PMID- 30304662 TI - Safety Trials of Long-Acting beta2-Agonists. PMID- 30304663 TI - Understanding the role of the public transport network in the greater Sydney area in providing access to dental care. AB - Objective The aim of this study was to examine the spatial accessibility of the aged and older adult population of the greater Sydney region to the bus public transport network, and the proximity of this transportation route to public and private dental services.Methods This study used geographic information systems (GIS) to examine, at a population level, the spatial accessibility of the public transport network and dental provider locations. The prime focus of the present study was on the aging population residing within 50 km of the General Post Office of metropolitan Sydney. Retirees (aged >=65 years) and older adults (aged >=85 years) were the two subsets of the aging population.Results Sydney's bus network is currently supplying bus transport to both older and disadvantaged groups, facilitating the needs of more than half a million older people. Regardless of socioeconomic status, 12% of the entire population, 11.5% of retirees and 10.8% of older adults resided 500 m away from accessible medium frequency bus stops. Approximately 40% of the overall population consisted of people of lower socioeconomic status living within 500 m of a medium-frequency bus stop, whereas 60% of the population were of a high socioeconomic status and lived within 500 m of a medium-frequency bus stop.Conclusion Metropolitan Sydney has a transport system that is substantial and robust, and appears to offer relatively similar spatial accessibility for all socioeconomic groups. This system is an example of great urban planning, where the distribution of bus stops is evenly positioned in both high-density areas and areas of low socioeconomic status.What is known about the topic? Older adults and disadvantaged people suffer from higher levels of dental disease compared with the rest of the population. Older adults and disadvantaged people are more likely to rely on public transport to access healthcare services, including dental care. The Australian population is aging rapidly.What does this paper add? Although a previous study examined the accessibility to services via the train network, this is the first analysis of the spatial accessibility to dental services via the bus network in Sydney. Most older adults and disadvantaged people in Sydney enjoy acceptable spatial access to the public transport network, and thereby to dental practices. Urban planning, in terms of determining healthcare service locations and the public transport network, needs to consider the distribution of older adults and disadvantaged populations.What are the implications for practitioners? Practitioners are more likely to attract older adult patients to their practices or clinics if these are located within easy access to the public transport network. PMID- 30304664 TI - Tissue plasminogen activator (tPA) of paternal origin is necessary for the success of invitro but not of invivo fertilisation in the mouse. AB - Besides its fibrinolytic function, the plasminogen-plasmin (PLG-PLA) system is also involved in fertilisation, where plasminogen activators bind to plasminogen to produce plasmin, which modulates sperm binding to the zona pellucida. However, controversy exists, depending on the species, concerning the role of the different components of the system. This study focused its attention on the role of the PLG-PLA system on fertilisation in the mouse with special attention to tissue plasminogen activator (tPA). The presence of exogenous plasminogen reduced in vitro fertilisation (IVF) rates and this decline was attenuated by the presence of plasmin inhibitors in combination with plasminogen. The incubation of spermatozoa with either oocytes or cumulus cells together with plasminogen did not change the acrosome reaction but reduced the number of spermatozoa attached. When spermatozoa from tPA-/- mice were used, the IVF rate decreased drastically, although the addition of exogenous tPA during gamete co-incubation under in vitro conditions increased fertilisation success. Moreover, fertility could not be restored after in vivo insemination of tPA-/- spermatozoa in the female ampulla, although tPA-/- males were able to fertilise in vivo. This study suggests a regulatory role of the PLG-PLA system during fertilisation in the mouse with possible implications in human reproduction clinics, such as failures in tPA production, which could be partially resolved by the addition of exogenous tPA during IVF treatment. PMID- 30304656 TI - Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. AB - BACKGROUND: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial. METHODS: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or >=4 mg per deciliter with a rapid increase of >=0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days. RESULTS: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients). CONCLUSIONS: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .). PMID- 30304665 TI - Comparison of Postoperative Analgesia in Patients Undergoing Ileostomy Closure with and Without Dual Transversus Abdominis Plane (TAP) Block: A Randomized Controlled Trial. AB - BACKGROUND AND AIMS: Multimodal analgesia comprising opioid, paracetamol, and non steroidal anti-inflammatory drugs is used for managing postoperative surgical pain after ileostomy closure (IC). We investigated the efficacy of unilateral dual transversus abdominis plane (TAP) block to reduce morphine consumption in the first 24 hours along with a reduction in visual analogue score for pain and in postoperative nausea/vomiting. METHODS: This was a single-center, investigator initiated, prospective, parallel-group, placebo-controlled randomized study involving patients undergoing IC under general anesthesia. We recruited 55 patients in two groups: 28 in a TAP group and 27 in a placebo group. The TAP group patients received 30 mL of 0.375% bupivacaine: 15 mL by a posterior TAP approach and 15 mL by a subcostal approach using ultrasonography. Patients in the placebo group received 30 mL normal saline (placebo) using the same approaches. Blocks were administered at the end of surgery before extubation. To monitor for the primary outcome-24-hour morphine consumption for both groups-patients were transferred to a high-dependency unit. The secondary outcome was to compare postoperative nausea/vomiting in both groups. RESULTS: The demographic data, gender distribution, ASA physical status, duration of surgery, and time of first morphine dose was comparable in both groups. The 24-hour morphine consumption was 3.29+/-2.78 mg and 9.23+/-2.94 mg for the TAP and placebo groups, respectively, which was statistically significant (P=0.001). CONCLUSION: Dual TAP block reduces opioid consumption in the first 24 hours after an IC and can facilitate early recovery with less adverse effects seen than with opioids and NSAIDs. PMID- 30304666 TI - Epigenetic alterations caused by aflatoxin b1: a public health risk in the induction of hepatocellular carcinoma. AB - Aflatoxin B1 (AFB1) is currently the most commonly studied mycotoxin due to its great toxicity, its distribution in a wide variety of foods such as grains and cereals and its involvement in the development of + (hepatocellular carcinoma; HCC). HCC is one of the main types of liver cancer, and has become a serious public health problem, due to its high incidence mainly in Southeast Asia and Africa. Studies show that AFB1 acts in synergy with other risk factors such as hepatitis B and C virus leading to the development of HCC through genetic and epigenetic modifications. The genetic modifications begin in the liver through the biomorphic AFB1, the AFB1-exo-8.9-Epoxy active, which interacts with DNA to form adducts of AFB1-DNA. These adducts induce mutation in codon 249, mediated by a transversion of G-T in the p53 tumor suppressor gene, causing HCC. Thus, this review provides an overview of the evidence for AFB1-induced epigenetic alterations and the potential mechanisms involved in the development of HCC, focusing on a critical analysis of the importance of severe legislation in the detection of aflatoxins. PMID- 30304667 TI - Liver X Receptors Protect Dorsal Root Ganglia from Obesity-Induced Endoplasmic Reticulum Stress and Mechanical Allodynia. AB - Obesity is associated with many complications, including type 2 diabetes and painful neuropathy. There is no cure or prevention for obesity-induced pain, and the neurobiology underlying the onset of the disease is still obscure. In this study, we observe that western diet (WD)-fed mice developed early allodynia with an increase of ER stress markers in the sensory neurons of the dorsal root ganglia (DRG). Using cell-specific approaches, we demonstrate that neuronal liver X receptor (LXR) activation delays ER stress and allodynia in WD-fed mice. Our findings suggest that lipid-binding nuclear receptors expressed in the sensory neurons of the DRG play a role in the onset of obesity-induced hypersensitivity. The LXR and lipid-sensor pathways represent a research avenue to identify targets to prevent debilitating complications affecting the peripheral nerve system in obesity. PMID- 30304669 TI - Social Isolation Induces Rac1-Dependent Forgetting of Social Memory. AB - Social isolation (SI) has detrimental effects on human and animal cognitive functions. In particular, acute isolation in adult mice impairs social recognition memory (SRM). Previous accounts of this impairment have focused primarily on memory consolidation. However, the current study suggests that impaired SRM results from enhanced forgetting. SI accelerates SRM decay without affecting memory formation. The impairment is caused by elevated Rac1 activity in the hippocampus. Using adeno-associated-virus-based genetic manipulation, we found that inhibition of Rac1 activity blocked forgetting of SRM in isolated adult mice, whereas activation of Rac1 accelerated forgetting in group-housed mice. Moreover, resocialization reversed the accelerated forgetting following isolation in correlation with suppression of Rac1 activity. In addition, accelerated long-term potentiation (LTP) decay in isolated mice brain slices was rescued by inhibition of Rac1 activity. Taken together, the findings lead us to conclude that social memory deficits in isolated mice are mediated by enhanced Rac1-dependent forgetting. PMID- 30304668 TI - Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons. AB - Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes. PMID- 30304670 TI - Theta Phase-Coordinated Memory Reactivation Reoccurs in a Slow-Oscillatory Rhythm during NREM Sleep. AB - It has been proposed that sleep's contribution to memory consolidation is to reactivate prior encoded information. To elucidate the neural mechanisms carrying reactivation-related mnemonic information, we investigated whether content specific memory signatures associated with memory reactivation during wakefulness reoccur during subsequent sleep. We show that theta oscillations orchestrate the reactivation of memories during both wakefulness and sleep. Reactivation patterns during sleep autonomously re-emerged at a rate of ~1 Hz, indicating a coordination by slow oscillatory activity. PMID- 30304671 TI - Agrobacterium Delivers Anchorage Protein VirE3 for Companion VirE2 to Aggregate at Host Entry Sites for T-DNA Protection. AB - Agrobacterium tumefaciens transfers oncogenic DNA (T-DNA) and effector proteins into various host plants. T-DNA is generated inside the bacteria and subsequently delivered into plant cells along with the companion effectors VirD2, VirE2, and VirE3. However, it is not clear how the T-complex consisting of VirD2 and VirE2 is assembled inside plant cells. Here, we report that the effector protein VirE3 localized to plant plasma membranes as an anchorage through a conserved alpha helical-bundle domain. VirE3 interacted with itself and enabled VirE2 accumulation at host entry sites through direct interactions. VirE3 was critical for VirE2 function in T-DNA protection. Our data indicate that VirE3 functions as a previously unrecognized anchorage protein consisting of membrane-binding, self interacting, and VirE2-interacting domains. Both VirE2 and VirE3 are conserved among Agrobacterium and rhizobia species but not other organisms, suggesting that a group of anchorage proteins have been generated through evolution to facilitate the nucleoprotein assembly at plant membranes. PMID- 30304672 TI - Entry, Replication, Immune Evasion, and Neurotoxicity of Synthetically Engineered Bat-Borne Mumps Virus. AB - Bats harbor a plethora of viruses with an unknown zoonotic potential. In-depth functional characterization of such viruses is often hampered by a lack of virus isolates. The genome of a virus closely related to human mumps viruses (hMuV) was detected in African fruit bats, batMuV. Efforts to characterize batMuV were based on directed expression of the batMuV glycoproteins or use of recombinant chimeric hMuVs harboring batMuV glycoprotein. Although these studies provided initial insights into the functionality of batMuV glycoproteins, the host range, replication competence, immunomodulatory functions, virulence, and zoonotic potential of batMuV remained elusive. Here, we report the successful rescue of recombinant batMuV. BatMuV infects human cells, is largely resistant to the host interferon response, blocks interferon induction and TNF-alpha activation, and is neurotoxic in rats. Anti-hMuV antibodies efficiently neutralize batMuV. The striking similarities between hMuV and batMuV point at the putative zoonotic potential of batMuV. PMID- 30304673 TI - B Cell Competition for Restricted T Cell Help Suppresses Rare-Epitope Responses. AB - The immune system responds preferentially to particular antigenic-epitopes contained within complex immunogens, such as proteins or microbes. This poorly understood phenomenon, termed "immunodominance," remains an obstacle to achieving polyvalent immune responses against multiple antigenic-epitopes through vaccination. We observed profound suppression in the hapten-specific antibody response in mice immunized with hapten-protein conjugate, mixed with an excess of protein, relative to that in mice immunized with hapten-protein alone. The suppression was robust (100-fold and 10-fold with a 10- or 2-fold excess of protein, respectively), stable over a 6-log range in antigen dose, observed within 10 days of vaccination, and resistant to boosting and adjuvants. Furthermore, there were reduced frequencies of antigen-specific germinal-center B cells and long-lived bone-marrow plasma cells. The mechanism of this "antigen competition" was mediated largely by early access to T-helper cells. These results offer mechanistic insights into B cell competition during an immune response and suggest vaccination strategies against HIV, influenza, and dengue. PMID- 30304674 TI - Microtubule-Actomyosin Mechanical Cooperation during Contact Guidance Sensing. AB - Cancer cell migration through and away from tumors is driven in part by migration along aligned extracellular matrix, a process known as contact guidance (CG). To concurrently study the influence of architectural and mechanical regulators of CG sensing, we developed a set of CG platforms. Using flat and nanotextured substrates with variable architectures and stiffness, we show that CG sensing is regulated by substrate stiffness and define a mechanical role for microtubules and actomyosin-microtubule interactions during CG sensing. Furthermore, we show that Arp2/3-dependent lamellipodia dynamics can compete with aligned protrusions to diminish the CG response and define Arp2/3- and Formins-dependent actin architectures that regulate microtubule-dependent protrusions, which promote the CG response. Thus, our work represents a comprehensive examination of the physical mechanisms influencing CG sensing. PMID- 30304675 TI - A RECK-WNT7 Receptor-Ligand Interaction Enables Isoform-Specific Regulation of Wnt Bioavailability. AB - WNT7A and WNT7B control CNS angiogenesis and blood-brain barrier formation by activating endothelial Wnt/beta-catenin signaling. The GPI-anchored protein RECK and adhesion G protein-coupled receptor GPR124 critically regulate WNT7-specific signaling in concert with FZD and LRP co-receptors. Here, we demonstrate that primarily the GPR124 ectodomain, but not its transmembrane and intracellular domains, mediates RECK/WNT7-induced canonical Wnt signaling. Moreover, RECK is the predominant binding partner of GPR124 in rat brain blood vessels in situ. WNT7A and WNT7B, but not WNT3A, directly bind to purified recombinant soluble RECK, full-length cell surface RECK, and the GPR124:RECK complex. Chemical cross linking indicates that RECK and WNT7A associate with 1:1 stoichiometry, which stabilizes short-lived, active, monomeric, hydrophobic WNT7A. In contrast, free WNT7A rapidly converts into inactive, hydrophilic aggregates. Overall, RECK is a selective WNT7 receptor that mediates GPR124/FZD/LRP-dependent canonical Wnt/beta catenin signaling by stabilizing active cell surface WNT7, suggesting isoform specific regulation of Wnt bioavailability. PMID- 30304676 TI - Relationship between PIWIL4-Mediated H3K4me2 Demethylation and piRNA-Dependent DNA Methylation. AB - Retrotransposon genes are silenced by DNA methylation because of potential harm due to insertional mutagenesis. DNA methylation of retrotransposon genes is erased and re-established during male germ cell development. Both piRNA-dependent and piRNA-independent mechanisms are active during the re-establishment process, with the piRNA-independent mechanism occurring first. In this study, we analyzed the role of PIWIL4/MIWI2 in the modification of histone H3 and subsequent piRNA dependent DNA methylation. Dimethylation at H3K4 is highly enriched at piRNA dependent methylated regions and anti-correlated with de novo DNA methylation during the phase of piRNA-independent DNA methylation. In addition, PIWIL4, which binds the H3K4 demethylases KDM1A and KDM5B, is required for removing H3K4me2 marks. These data show that PIWIL4 plays important roles in histone modification and piRNA-dependent DNA methylation. PMID- 30304678 TI - Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype. AB - Most genes mutated in microcephaly patients are expressed ubiquitously, and yet the brain is the only major organ compromised in most patients. Why the phenotype remains brain specific is poorly understood. In this study, we used in vitro differentiation of human embryonic stem cells to monitor the effect of a point mutation in kinetochore null protein 1 (KNL1; CASC5), identified in microcephaly patients, during in vitro brain development. We found that neural progenitors bearing a patient mutation showed reduced KNL1 levels, aneuploidy, and an abrogated spindle assembly checkpoint. By contrast, no reduction of KNL1 levels or abnormalities was observed in fibroblasts and neural crest cells. We established that the KNL1 patient mutation generates an exonic splicing silencer site, which mainly affects neural progenitors because of their higher levels of splicing proteins. Our results provide insight into the brain-specific phenomenon, consistent with microcephaly being the only major phenotype of patients bearing KNL1 mutation. PMID- 30304677 TI - Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors. AB - Despite a prevalence exceeding 1%, mechanisms underlying autism spectrum disorders (ASDs) are poorly understood, and targeted therapies and guiding parameters are urgently needed. We recently demonstrated that cerebellar dysfunction is sufficient to generate autistic-like behaviors in a mouse model of tuberous sclerosis complex (TSC). Here, using the mechanistic target of rapamycin (mTOR)-specific inhibitor rapamycin, we define distinct sensitive periods for treatment of autistic-like behaviors with sensitive periods extending into adulthood for social behaviors. We identify cellular and electrophysiological parameters that may contribute to behavioral rescue, with rescue of Purkinje cell survival and excitability corresponding to social behavioral rescue. In addition, using anatomic and diffusion-based MRI, we identify structural changes in cerebellar domains implicated in ASD that correlate with sensitive periods of specific autism-like behaviors. These findings thus not only define treatment parameters into adulthood, but also support a mechanistic basis for the targeted rescue of autism-related behaviors. PMID- 30304679 TI - Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity. AB - Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC) expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFDeltaPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity. PMID- 30304680 TI - Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair. AB - Colorectal cancer (CRC) onset is profoundly affected by Western diet. Here, we report that high-fat (HF) diet-induced, organ-specific colonic lysine homocysteinylation (K-Hcy) increase might promote CRC onset by impeding DNA damage repair. HF chow induced elevated methionyl-tRNA synthetase (MARS) expression and K-Hcy levels and DNA damage accumulation in the mouse and rat colon, resulting in a phenotype identical to that of CRC tissues. Moreover, the increased copy number of MARS, whose protein product promotes K-Hcy, correlated with increased CRC risk in humans. Mechanistically, MARS preferentially bound to and modified ataxia-telangiectasia and Rad3-related protein (ATR), inhibited ATR and its downstream effectors checkpoint kinase-1 and p53, and relieved cell-cycle arrest and decreased DNA damage-induced apoptosis by disrupting the binding of ATR-interacting protein to ATR. Inhibiting K-Hcy by targeting MARS reversed these effects and suppressed oncogenic CRC cell growth. Our study reveals a mechanism of Western-diet-associated CRC and highlights an intervention approach for reversing diet-induced oncogenic effects. PMID- 30304683 TI - Tankyrase Mediates K63-Linked Ubiquitination of JNK to Confer Stress Tolerance and Influence Lifespan in Drosophila. AB - Tankyrase (Tnks) transfers poly(ADP-ribose) on substrates. Whereas studies have highlighted the pivotal roles of Tnks in cancer, cherubism, systemic sclerosis, and viral infection, the requirement for Tnks under physiological contexts remains unclear. Here, we report that the loss of Tnks or its muscle-specific knockdown impairs lifespan, stress tolerance, and energy homeostasis in adult Drosophila. We find that Tnks is a positive regulator in the JNK signaling pathway, and modest alterations in the activity of JNK signaling can strengthen or suppress the Tnks mutant phenotypes. We further identify JNK as a direct substrate of Tnks. Although Tnks-dependent poly-ADP-ribosylation is tightly coupled to proteolysis in the proteasome, we demonstrate that Tnks initiates degradation-independent ubiquitination on two lysine residues of JNK to promote its kinase activity and in vivo functions. Our study uncovers a type of posttranslational modification of Tnks substrates and provides insights into Tnks mediated physiological roles. PMID- 30304681 TI - Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress. AB - Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in females. PMID- 30304682 TI - Critical Role for a Subset of Intestinal Macrophages in Shaping Gut Microbiota in Adult Zebrafish. AB - The gut microbiota is strongly influenced by environmental factors, although host contribution is far less understood. We leveraged macrophage-deficient interferon regulatory factor irf8 zebrafish mutants to investigate the role of macrophages in this process. In conventionally raised adult irf8-deficient mutants, we found a significant loss of intestinal macrophages associated with a strikingly altered gut microbiota when compared to co-housed siblings. The destabilization of the gut commensal microbiota was associated with a severe reduction in complement C1q genes and outgrowth of a rare bacterial species. Consistent with a critical function of irf8 in adult intestinal macrophages, irf8 is abundantly expressed in these cells normally, and restoring macrophage irf8 expression in irf8 mutants was sufficient to recover commensal microbes and C1q genes expression. This study reports an important subpopulation of intestinal macrophages that requires irf8 to establish in the gut, ensure normal colonization of gut microbes, and prevent immune dysregulation. PMID- 30304685 TI - Polyploid Superficial Cells that Maintain the Urothelial Barrier Are Produced via Incomplete Cytokinesis and Endoreplication. AB - The urothelium is an epithelia barrier lined by a luminal layer of binucleated, octoploid, superficial cells. Superficial cells are critical for production and transport of uroplakins, a family of proteins that assemble into a waterproof crystalline plaque that helps protect against infection and toxic substances. Adult urothelium is nearly quiescent, but rapidly regenerates in response to injury. Yet the mechanism by which binucleated, polyploid, superficial cells are produced remains unclear. Here, we show that superficial cells are likely to be derived from a population of binucleated intermediate cells, which are produced from mononucleated intermediate cells via incomplete cytokinesis. We show that binucleated intermediate and superficial cells increase DNA content via endoreplication, passing through S phase without entering mitosis. The urothelium can be permanently damaged by repetitive or chronic injury or disease. Identification of the mechanism by which superficial cells are produced may be important for developing strategies for urothelial repair. PMID- 30304684 TI - A Dimerization Function in the Intrinsically Disordered N-Terminal Region of Src. AB - The mode of regulation of Src kinases has been elucidated by crystallographic studies identifying conserved structured protein modules involved in an orderly set of intramolecular associations and ligand interactions. Despite these detailed insights, much of the complex behavior and diversity in the Src family remains unexplained. A key missing piece is the function of the unstructured N terminal region. We report here the function of the N-terminal region in binding within a hydrophobic pocket in the kinase domain of a dimerization partner. Dimerization substantially enhances autophosphorylation and phosphorylation of selected substrates, and interfering with dimerization is disruptive to these functions. Dimerization and Y419 phosphorylation are codependent events creating a bistable switch. Given the versatility inherent in this intrinsically disordered region, its multisite phosphorylations, and its divergence within the family, the unique domain likely functions as a central signaling hub overseeing much of the activities and unique functions of Src family kinases. PMID- 30304686 TI - Growth of Cyanobacteria Is Constrained by the Abundance of Light and Carbon Assimilation Proteins. AB - Cyanobacteria must balance separate demands for energy generation, carbon assimilation, and biomass synthesis. We used shotgun proteomics to investigate proteome allocation strategies in the model cyanobacterium Synechocystis sp. PCC 6803 as it adapted to light and inorganic carbon (Ci) limitation. When partitioning the proteome into seven functional sectors, we find that sector sizes change linearly with growth rate. The sector encompassing ribosomes is significantly smaller than in E. coli, which may explain the lower maximum growth rate in Synechocystis. Limitation of light dramatically affects multiple proteome sectors, whereas the effect of Ci limitation is weak. Carbon assimilation proteins respond more strongly to changes in light intensity than to Ci. A coarse grained cell economy model generally explains proteome trends. However, deviations from model predictions suggest that the large proteome sectors for carbon and light assimilation are not optimally utilized under some growth conditions and may constrain the proteome space available to ribosomes. PMID- 30304687 TI - Light Control of the Tet Gene Expression System in Mammalian Cells. AB - Gene expression and its network structure are dynamically altered in multicellular systems during morphological, functional, and pathological changes. To precisely analyze the functional roles of dynamic gene expression changes, tools that manipulate gene expression at fine spatiotemporal resolution are needed. The tetracycline (Tet)-controlled gene expression system is a reliable drug-inducible method, and it is used widely in many mammalian cultured cells and model organisms. Here, we develop a photoactivatable (PA)-Tet-OFF/ON system for precise temporal control of gene expression at single-cell resolution. By integrating the cryptochrome 2-cryptochrome-interacting basic helix-loop-helix 1 (Cry2-CIB1) light-inducible binding switch, expression of the gene of interest is tightly regulated under the control of light illumination and drug application in our PA-Tet-OFF/ON system. This system has a large dynamic range of downstream gene expression and rapid activation/deactivation kinetics. We also demonstrate the optogenetic regulation of exogenous gene expression in vivo, such as in developing and adult mouse brains. PMID- 30304688 TI - Real-Time Imaging of Mitochondrial ATP Dynamics Reveals the Metabolic Setting of Single Cells. AB - Reprogramming of metabolic pathways determines cell functions and fate. In our work, we have used organelle-targeted ATP biosensors to evaluate cellular metabolic settings with high resolution in real time. Our data indicate that mitochondria dynamically supply ATP for glucose phosphorylation in a variety of cancer cell types. This hexokinase-dependent process seems to be reversed upon the removal of glucose or other hexose sugars. Our data further verify that mitochondria in cancer cells have increased ATP consumption. Similar subcellular ATP fluxes occurred in young mouse embryonic fibroblasts (MEFs). However, pancreatic beta cells, senescent MEFs, and MEFs lacking mitofusin 2 displayed completely different mitochondrial ATP dynamics, indicative of increased oxidative phosphorylation. Our findings add perspective to the variability of the cellular bioenergetics and demonstrate that live cell imaging of mitochondrial ATP dynamics is a powerful tool to evaluate metabolic flexibility and heterogeneity at a single-cell level. PMID- 30304690 TI - Accurate Drug Repositioning through Non-tissue-Specific Core Signatures from Cancer Transcriptomes. AB - Experimental large-scale screens for drug repositioning are limited by restriction to in vitro conditions and lack of applicability to real human conditions. Here, we developed an in silico screen in human in vivo conditions using a reference of single gene mutations' non-tissue-specific "core transcriptome signatures" (CSs) of 8,476 genes generated from the TCGA database. We developed the core-signature drug-to-gene (csD2G) software to scan 3,546 drug treatment profiles against the reference signatures. csD2G significantly outperformed conventional cell line-based gene perturbation signatures and existing drug-repositioning methods in both coverage and specificity. We highlight this with 3 demonstrated applications: (1) repositioned category of psychiatric drugs to inhibit the TGF-beta pathway; (2) antihypertensive calcium channel blockers predicted to activate AMPK and inhibit AKT pathways, and validated by clinical electronic medical records; and (3) 7 drugs predicted and validated to selectively target the AKT-FOXO and AMPK pathways and thus regulate worm lifespan. PMID- 30304689 TI - The 10,000 Immunomes Project: Building a Resource for Human Immunology. AB - There is increasing appreciation that the immune system plays critical roles not only in the traditional domains of infection and inflammation but also in many areas of biology, including tumorigenesis, metabolism, and even neurobiology. However, one of the major barriers for understanding human immunological mechanisms is that immune assays have not been reproducibly characterized for a sufficiently large and diverse healthy human cohort. Here, we present the 10,000 Immunomes Project (10KIP), a framework for growing a diverse human immunology reference, from ImmPort, a publicly available resource of subject-level immunology data. Although some measurement types are sparse in the presently deposited ImmPort database, the extant data allow for a diversity of robust comparisons. Using 10KIP, we describe variations in serum cytokines and leukocytes by age, race, and sex; define a baseline cell-cytokine network; and describe immunologic changes in pregnancy. All data in the resource are available for visualization and download at http://10kimmunomes.org/. PMID- 30304691 TI - Green synthesis of labeled CeO2 nanoparticles with 99mTc and its biodistribution evaluation in mice. AB - AIMS: The in vivo targeted diagnostic applications of biosynthetic Cerium oxide nanoparticles (CeO2-NPs), prepared by applying chitosan as a stabilizer, was explored by evaluating the cytotoxicity through MTT assay on WEHI 164 cell line, the Hemolytic activity of CeO2-NPs and biodistribution in rats. MAIN METHODS: The CeO2-NPs were characterized through the use of TGA/DTG, PXRD, FESEM, FTIR, and UV Vis spectroscopy. The biodistribution of CeO2-NPs were determined by directly labeled nanoparticles with Technetium-99 m (99mTc) radioisotope (99mTc-CeO2-NPs). The labeling efficiency and stability of 99mTc-CeO2-NPs were also measured with Instant Thin Layer Chromatography (ITLC) method. The saturation study was investigated by 1 mCi of 99mTc-CeO2-NPs using different concentrations of WEHI 164 cells after 4 h of incubation. In vivo biodistribution study was performed by intravenous injection of 600 MUCi/200 MUL 99mTc-CeO2-NPs through rat's tail. KEY FINDINGS: CeO2-NPs seemed to have a low cytotoxic effect on WEHI 164 cell line and did not result in hemolysis. The biodistribution of CeO2-NPs has shown that a huge amount of 99mTc-CeO2-NPs was amassed in the living human organs, including liver, lung, spleen, stomach, and thyroid which shows the in vivo stability of the labeled conjugate. Herein, we have developed a facile, economical, and greener synthetic procedure applying Chitosan template. This green approach is comparable to conventional methods that utilize hazardous materials which are would be a suitable alternative to circumvent synthetic issues related to these materials. SIGNIFICANCE: The bio-applications of nano-sized CeO2-NPs were explored to find new horizon to use nanotechnology as the diagnostic tool. PMID- 30304692 TI - Early intervention of swimming exercises attenuate articular cartilage destruction in a rat model of anterior cruciate ligament and meniscus knee injuries. AB - AIM: The anterior cruciate ligament (ACL) and meniscus injuries often cause post traumatic knee osteoarthritis (PTOA), which can place great limitations on patients. But to date there is no effective therapy to delay the progression of cartilage destruction in PTOA. This study aimed to compare the effects of early versus delayed swimming exercise on the chondroprotective effects in a rat PTOA model with ACL and meniscus injuries. MAIN METHODS: Thirty-two adult male Sprague Dawley rats received unilateral ACL transection and medial meniscectomy (ACLMT). These were randomly allocated to four groups: early swimming (eSW), delayed swimming (dSW), sham-operated early swimming (sham-eSW) and sham-operated delayed swimming (sham-dSW). Swimming (30 min per session) continuing for 28 days was started three days and three months after ACLMT surgery as a protocol for eSW and dSW intervention. Cartilage quality was assessed by Mankin HHGS examination (H&E, Safranin-O stain) and collagen type II (CoII) and matrix metalloproteases-13 (MMP13) immunohistochemistry. KEY FINDINGS: ACLMT induced the PTOA histopathological changes, inhibited CoII and enhanced MMP13 expressions in cartilage for both sham-eSW and sham-dSW groups. eSW intervention significantly enhanced CoII expression and suppressed MMP13 overexpression in superficial and transitional zones of cartilage, as well as better Mankin scores, corresponding to sham-swimming controls (P < 0.05). dSW intervention provided less enhancement of CoII expression and improvement of histopathological scoring, but significantly reduced MMP13 overexpression compared to animals in eSW (P < 0.05). SIGNIFICANCE: Early intervention by swimming at very early stages of cartilage damage provides greater benefits than delayed intervention when PTOA has already developed. PMID- 30304693 TI - Association study between inwardly rectifying potassium channels 2.1 and 4.1 and autism spectrum disorders. AB - Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders involving structural and functional impairment of the brain. Inwardly rectifying potassium (Kir) channels may contribute to the etiology of ASD by altering brain function. This study investigated the associations between genetic variants of KCNJ2 and KCNJ10 genes (encoding Kir2.1 and Kir4.1, respectively) and ASD risk in patients, and Kir channel expression in ASD model rats. This case-control study involved a cohort of 269 Chinese children with ASD and 243 unrelated healthy controls. Twelve tag single nucleotide polymorphisms (SNPs) from the KCNJ2 and KCNJ10 genes were genotyped by Sequenom Mass Array, while a valproic acid (VPA) induced rat model of ASD was used to evaluate Kir channel expression in the hippocampus. Among the 12 examined SNPs, only KCNJ10 rs1186689 was significantly associated with disease susceptibility; the variant T allele conferred a lower risk of developing ASD [odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.47-0.80, p false discovery rate (FDR) = 0.012, and OR = 0.63, 95% CI = 0.48 0.84, pFDR = 0.014 at the allelic and genotypic levels, respectively]. Additionally, hippocampal Kir2.1 and Kir4.1 levels were decreased in VPA as compared to control rats. These results demonstrated that KCNJ10 (rs1186689) polymorphisms was correlated with ASD susceptibility in Chinese Han children, and the abnormal expression of Kir2.1 and Kir4.1 in ASD model rats suggested a mechanism by which Kir channels may play a role in ASD. PMID- 30304694 TI - Potential role of alpha-lipoic acid and Ginkgo biloba against silver nanoparticles-induced neuronal apoptosis and blood-brain barrier impairments in rats. AB - AIMS: This study explored whether silver nanoparticles (AgNPs) can disrupt tight junctions integrity resulted in blood-brain barrier dysfunction along with oxidative stress, pro-inflammation, and apoptosis induction. Additionally, neuroprotective activities of alpha-lipoic acid (LA) and Ginkgo biloba (GB) were investigated. MAIN METHODS: Forty adults rats were enrolled into; Control, AgNPs (50 mg/kg), LA (100 mg/kg) + AgNPs, and GB (120 mg/kg) + AgNPs. After 30 days, neuronal changes were assessed biochemically and histopathologically. Brain tissues oxidative indices, mRNA expression of proinflammatory cytokines and tight junction proteins and pro-apoptotic biomarker, caspase-3 were investigated. KEY FINDINGS: AgNPs exposure enhanced lipid peroxidation (+195%) along with declines in glutathione (-43%), glutathione peroxidase (-34%), glutathione S-transferase ( 31%), catalase (-43%), and superoxide dismutase (-38%) activities in brain tissues. The apparent brain oxidative damage was associated with obvious neuronal dysfunction that was ascertained by neuropathological lesions. AgNPs lowered serum acetylcholine esterase, iron and copper levels, and increased creatine phosphokinase and creatine phosphokinase-brain type activities. Following AgNPs exposure, brain silver and iron contents were increased, but the copper level was decreased. AgNPs up-regulated TNF-alpha (6.5-fold) and IL-1beta (8.9-fold) transcript levels, and simultaneously over-expressed the caspase-3 protein in cerebrum and cerebellum inducing cell apoptosis. Moreover, AgNPs down-regulated the transcript levels of tight-junction proteins; JP-1 (0.65-fold) and JAM-3(0.81 fold). SIGNIFICANCE: LA and relatively GB improved the serious effects of AgNPs on the blood-brain barrier function and tight-junction proteins through their antioxidants, anti-inflammatory, and anti-apoptotic efficacies. Co-treatment with LA or GB may be favorable in ameliorating the neurotoxic side effects of AgNPs. PMID- 30304695 TI - Women in Stem Cell Science: Part II. AB - Part II of this series continues a focus on top female researchers in the stem cell field, with personal stories and reflections on career paths. Women play key roles as leaders in the field and with the International Society for Stem Cell Research. Part I was published in the September 2018 issue of Stem Cell Reports. PMID- 30304696 TI - Quick Access to Human Astrocytic Software that Drives Neuronal Hardware. AB - Astrocytes have important functions in the brain and their deregulation may cause disease. Current ways to derive astrocytes from pluripotent stem cells are labor, time, and resource intensive, but in this issue of Stem Cell Reports, Li et al. present a faster method to produce functional astrocytes using transcription factors. PMID- 30304697 TI - Regenerative Medicine: Taming the Chimaera. AB - In this issue of Stem Cell Reports, Hamanaka et al. (2018) describe the generation of chimeric mice with all vascular endothelial cells derived from pluripotent stem cells. This approach is desirable to prevent immune rejection when human stem cells are combined with animal embryos to grow human organs in animals. PMID- 30304698 TI - Protective effect of lodoxamide on hepatic steatosis through GPR35. AB - Although GPR35 is an orphan G protein-coupled receptor, synthetic agonists and antagonists have been developed. Recently, cromolyn, a mast cell stabilizer, was reported as an agonist of GPR35 and was shown to exhibit antifibrotic effects through its actions on hepatocytes and stellate cells. In this study, the role of GPR35 in hepatic steatosis was investigated using an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis and an in vivo model of high fat diet-induced liver steatosis. GPR35 was expressed in Hep3B human hepatoma cells and mouse primary hepatocytes. A specific LXR activator, T0901317, induced lipid accumulation in Hep3B cells. Lodoxamide, the most potent agonist of GPR35, inhibited lipid accumulation in a concentration-dependent manner. The protective effect of lodoxamide was inhibited by a specific GPR35 antagonist, CID2745687, and by siRNA-mediated knockdown of GPR35. The expression of SREBP-1c, a key transcription factor for lipid synthesis, was induced by T0901317 and the induction was inhibited by lodoxamide. Through the use of specific inhibitors of cellular signaling components, the lodoxamide-induced inhibition of lipid accumulation was found to be mediated through p38 MAPKs and JNK, but not through Gi/o proteins and ERKs. Furthermore, the protective effect of lodoxamide was confirmed in mouse primary hepatocytes. Lodoxamide suppressed high fat diet induced fatty liver development, which suggested the protective function of GPR35 in liver steatosis. Therefore, the present data suggest that GPR35 may function to protect against fatty liver development. PMID- 30304699 TI - Serum miRNA-371b-5p and miRNA-5100 act as biomarkers for systemic lupus erythematosus. AB - MicroRNAs (miRNAs) play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Here, we investigated the serum miRNAs expression profiles in the serum of SLE and healthy controls, and identified the potential serum biomarkers for SLE. We screened and identified the differentially expressed miRNAs such as miR-371b-5p, miR-5100, miR-146a-5p among active SLE, inactive SLE and healthy controls based on the miRNAs expression array. Furthermore, the results of RT-qPCR confirmed that miR-371b-5p and miR-5100 expression was different among active SLE, inactive SLE and healthy controls. Moreover, we performed in a large cohort which we validated that expression of miR-371b-5p and miR-5100 was increased significantly in the serum of SLE compared with healthy controls and rheumatoid arthritis (RA), and was also higher in active SLE than that in inactive SLE. In addition, we found the associations between the expression levels of miR-371b-5p and miR-5100 and these clinical parameters of SLE. These results suggested that miR-371b-5p and miR-5100 may act as serum biomarkers for SLE. PMID- 30304700 TI - Interaction of gentamicin sulfate with alginate and consequences on the physico chemical properties of alginate-containing biofilms. AB - BACKGROUND: Alginate is one of the main extracellular polymeric substances (EPS) in biofilms of Cystic Fibrosis (CF) patients suffering from pulmonary infections. Gentamicin sulfate (GS) can strongly bind to alginate resulting in loss of pharmacological activity; however neither the mechanism nor its repercussion is fully understood. In this study, we investigated how GS modifies the alginate macromolecular network and its microenvironment. MATERIAL AND METHODS: Alginate gels of two different compositions (either enriched in guluronate units (G) or enriched in mannuronate units (M)) were crosslinked with Ca2+ and exposed to GS at varying times and concentrations. The complexes formed were characterized via turbidimetry, mechanical tests, swelling assay, calorimetry techniques, nuclear magnetic resonance, Ca2+ displacement, macromolecular probe diffusion and pH alteration. RESULTS: In presence of GS, the alginate network and its environment undergo a tremendous reorganization in terms of gel density, stiffness, diffusion property, presence and state of the water molecules. We noted that the intensity of those alterations is directly dependent on the polysaccharide motif composition (ratio M/G). CONCLUSION: Our results underline the importance of alginate as biofilm component, its pernicious role during antibiotherapy and could represent a potential macromolecular target to improve anti-infectious therapies. PMID- 30304701 TI - Squalene-PEG: Pyropheophorbide-a nanoconstructs for tumor theranostics. AB - Novel nanoscale drug delivery biomaterials are of great importance for the diagnosis and treatment of different cancers. We have developed a new pegylated squalene (SQ-PEG) derivative with self-assembly properties. Supramolecular assembly with a lipophilic photosensitizer pyropheophorbide-a (Ppa) by nanoprecipitation gave nanoconstructs SQ-PEG:Ppa with an average size of 200 nm in diameter and a drug loading of 18% (w/w). The composite material demonstrates nanoscale optical properties by tight packing of Ppa within Sq-PEG:Ppa resulting in 99.99% fluorescence self-quenching. The biocompatibility of the nanomaterial and cell phototoxicity under light irradiation were investigated on PC3 prostate tumor cells in vitro. SQ-PEG:Ppa showed excellent phototoxic effect at low light dose of 5.0 J/cm2 as a consequence of efficient cell internalization of Ppa by the nanodelivery system. The diagnostic potential of SQ-PEG:Ppa nanoconstructs to deliver Ppa to tumors in vivo was demonstrated in chick embryo model implanted with U87MG glioblastoma micro tumors. PMID- 30304702 TI - Do the rat anterior thalamic nuclei contribute to behavioural flexibility? AB - The rodent anterior thalamic nuclei (ATN) are vital for spatial memory. A consideration of their extensive frontal connections suggests that these nuclei may also subserve non-spatial functions. The current experiments explored the importance of the ATN for different aspects of behavioural flexibility, including their contribution to tasks typically associated with frontal cortex. In Experiment 1, rats with ATN lesions were tested on a series of response and visual discriminations in an operant box and, subsequently, in a water tank. The tasks included assessments of reversal learning as well switches between each discrimination dimension. Results revealed a mild and transient deficit on the operant task that was not specific to any stage of the procedure. In the water tank, the lesion animals were impaired on the reversal of a spatial discrimination but did not differ from controls on any other measure. Experiment 2 examined the impact of ATN damage on a rodent analogue of the 'Stroop', which assesses response choice during stimulus conflict. The lesion animals successfully acquired this task and were able to use contextual information to disambiguate conflicting cue information. However, responding during the initial presentation of conflicting cue information was affected by the lesion. Taken together, these results suggest that the ATN are not required for aspects of behavioural flexibility (discrimination learning, reversals or high-order switches) typically associated with the rat medial prefrontal cortex. The results from Experiment 2 suggest that the non-spatial functions of the ATN may be more aligned with those of the anterior cingulate cortex. PMID- 30304703 TI - Origin and roles of a novel copper-zinc superoxide dismutase (CuZnSOD) gene from the harmful dinoflagellate Prorocentrum minimum. AB - Superoxide dismutase (SOD) acts as the first line of defence against reactive oxygen species (ROS) within cells. In this study, we characterized a novel SOD gene (PmCuZnSOD) from the dinoflagellate Prorocentrum minimum, and examined its structural features, putative origin and gene expression. The SOD cDNA is 895 bp in length, containing dinoflagellate splice-leader (dinoSL) sequence, 714-bp ORF (237 aa), and poly (A) tail. In addition, PmCuZnSOD is coded on the dinoflagellate nuclear genome without introns and in a non-tandem repeat manner; however, the encoded protein is probably localized in chloroplasts. Phylogenetic analysis indicated that it might be acquired from cyanobacteria via horizontal gene transfer (HGT) and then the gene possibly relocated from the chloroplast to the nuclear genome. Excess copper dramatically increased the PmCuZnSOD transcripts and SOD activity in cells, caused by ROS generation and decrease of photosynthetic efficiency in the treated cells. These suggest that CuZnSOD may function to defend against oxidative stress for the survival of the dinoflagellate. PMID- 30304704 TI - Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms. AB - Radiation therapy leads to increased risk of late-onset fragility and bone fracture due to the loss of bone mass. On the other hand, iron overloading causes osteoporosis by enhancing bone resorption. It has been shown that total body irradiation increases iron level, but whether the systemic bone loss is related to the changes in iron level and hepcidin regulation following bone irradiation remains unknown. To investigate the potential link between them, we first created an animal model of radiation-induced systemic bone loss by targeting the mid shaft femur with a single 2 Gy dose of X-rays. We found that mid-shaft femur focal irradiation led to structural deterioration in the distal region of the trabecular bone with increased osteoclasts surface and expressions of bone resorption markers in both irradiated and contralateral femurs relative to non irradiated controls. Following irradiation, reduced hepcidin activity of the liver contributed to elevated iron levels in the serum and liver. By injecting hepcidin or deferoxamine (an iron chelator) to reduce iron level, deterioration of trabecular bone microarchitecture in irradiated mice was abrogated. The ability of iron chelation to inhibit radiation-induced osteoclast differentiation was observed in vitro as well. We further showed that ionizing radiation (IR) directly stimulated osteoclast differentiation and bone resorption in bone marrow cells isolated not from contralateral femurs but from directly irradiated femurs. These results suggest that increased iron levels after focal radiation is at least one of the main reasons for systemic bone loss. Furthermore, bone loss in directly irradiated bones is not only due to the elevated iron level, but also from increased osteoclast differentiation. In contrast, the bone loss in the contralateral femurs is mainly due to the elevated iron level induced by IR alone. These novel findings provide proof-of-principle evidence for the use of iron chelation or hepcidin as therapeutic treatments for IR-induced osteoporosis. PMID- 30304706 TI - Phytochemical and biological evaluation of metabolites produced by alginate immobilized Bionts isolated from the lichen Cladonia substellata vain. AB - In this work, new biotechnological procedures have been optimized on the basis of immobilization in alginate of bionts isolated from the lichen C. substellata. From these immobilizates, soluble and biologically active phenolics can be obtained. During bionts-immobilization, stictic, norstictic and usnic acids were secreted to the medium. The amount produced of each of them differed depending on the immobilization time, the precursor supplied and the type of biont used. Greater amounts of stictic acid were detected and maintained over time in all bioreactors. The opposite occurs in non-immobilized thallus. Virtually, all lichen phenols exhibit antioxidant activity to a greater or lesser degree, so that the antioxidant capacity of stictic acid (82.13% oxidation inhibition) was tested. The soluble extract of immobilized algae co-incubated in sodium acetate with fungal hyphae contained carbohydrates and exhibited a potent antioxidant capacity after 13 days of immobilization (94.87%). Therefore, attempts have been made to relate both parameters. On the other hand, the growth of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae was inhibited by phenolic compounds produced by immobilizates, although the organic extract of the whole lichen showed the highest activity due to a possible synergy with other indeterminate compounds. Thus, C. substellata immobilized bionts are a potential source of different natural antioxidant and antimicrobial compounds. PMID- 30304705 TI - Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy. AB - Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures. PMID- 30304707 TI - JM-20, a novel hybrid molecule, protects against rotenone-induced neurotoxicity in experimental model of Parkinson's disease. AB - Oxidative stress and mitochondrial dysfunction are two pathophysiological factors often associated with the neurodegenerative process involved in Parkinson's disease (PD). The aim of this study was to investigate the effects of a novel hybrid molecule, named JM-20, in different in vitro and in vivo models of PD induced by rotenone. To perform in vitro studies, SHSY-5Y cells were exposed to rotenone and/or treated with JM-20. To perform in vivo studies male Wistar rats were intoxicated with rotenone (2.5 mg/kg) via intraperitoneal injection and/or treated with JM-20 (40 mg/kg) administered via oral (for 25 days, both treatment). Rats were evaluated for global motor activity by measurement of locomotor activity. In addition, the effects on mortality, general behavior and redox parameters were also investigated. JM-20 protected SHSY-5Y cells against rotenone-induced cytotoxicity, evidenced by a significant diminution of cell death. In in vivo studies, JM-20 prevented rotenone-induced vertical exploration and locomotion frequency reductions, moreover prevented body weight loss and mortality induced by rotenone. It also improved the redox state of rotenone exposured animals by increasing superoxide dismutase and catalase activities, total tissue-SH levels and decreasing malondialdehyde concentrations. Finally, JM 20 inhibited spontaneous mitochondrial swelling and membrane potential dissipation in isolated rats brain mitochondria. These results demonstrate that JM-20 is a potential neuroprotective agent against rotenone-induced damage in both in vitro and in vivo models, resulting in reduced neuronal oxidative injury and protection of mitochondria from impairment. PMID- 30304708 TI - Genomic analysis of RNA-Seq and sRNA-Seq data identifies potential regulatory sRNAs and their functional roles in Staphylococcus aureus. AB - sRNAs are important post-transcriptional regulators in bacteria. The current study exploits potential of next-generation technology with computational analyses to develop a whole-genome sRNA-gene network for drug-resistant S. aureus by subjecting public expression-profiles to a novel analysis pipeline. Clustering and examination of the resultant global-interactome indicated a coordinated regulation of numerous processes by various sRNAs with 9 sRNAs and 10 genes as potential hubs. 10 major sRNA-modules were annotated with various functions, among which a major module including of Rsa sRNAs was predicted to be a central regulatory unit. In addition, sRNA95, a hub molecule associated with this unit was predicted to be a vulnerable target. Finally, novel associations between transcriptional-regulators and sRNAs have been mined resulting in some insights into the association between RNAIII and RsaA. To our knowledge, this is the first study in S. aureus throwing insights into global sRNA-gene interactions and identify potential sRNAs to explore sRNA-based applications for therapeutics. PMID- 30304709 TI - Sodium butyrate improves memory and modulates the activity of histone deacetylases in aged rats after the administration of d-galactose. AB - Aging is a complex biological process. Epigenetic alterations have been related to both aging and memory decline. Included amongst these alterations is histone acetylation, which may play a crucial role in aging. Thus, the aims of the present study were to standardize the animal model of d-galactose (d-gal), and to evaluate the effects caused by sodium butyrate (SB), which is a histone deacetylase inhibitor on memory, the modulation of histone deacetylases (HDACs), and also DNA damage in 2, 6 or 16-month-old Wistar rats which were subjected to administrations of d-gal. To help choose the best dose of d-gal for the induction of the aging model, we performed a dose-response curve (100, 200 or 300 mg/kg). d Gal was administered orally to the 2-month-old rats for a period of 30 days. After this, d-gal (200 mg/kg) or water were administered to the 2, 6 or 16-month old rats for a period of 30 days. On the 24th day, treatment was started with SB (600 mg/kg) intraperitoneally, for a period of 7 days. SB was able to reverse the damage to habituation memory caused by d-gal in the 2 and 6-month-old rats, but was unable to reverse the damage in the 16 month-old animals. In addition, SB was able to reverse the damage caused by natural aging in the 16-month-old animals. In the inhibitory avoidance task, SB improved the damage caused by d-gal in the 2, 6 and 16-month-old animals and had the same result against the effects of natural aging in the 16-month-old rats. Moreover, d-gal caused an increase in the level of HDACs activity in the 16-month-old animals, and SB was able to reverse this effect in the frontal cortex and hippocampus. The 16-month-old animals showed an increase in the frequency of DNA damage in peripheral blood, and SB was able to reduce this damage. Moreover, d-gal caused an increase in the index and frequency of DNA damage in the 2 and 6-month-old animals, and treatment with SB was able to prevent this damage. Thus, the present study showed the protective effects of SB on the memory of naturally aged and d-gal induced aging in rats. Therefore, the present study shows new findings for the use of SB in aging. PMID- 30304710 TI - Nucleus-translocated matrix metalloprotease 1 regulates innate immune response in Pacific abalone (Haliotis discus hannai). AB - As an important economical shellfish in coastal area of China, abalone is susceptible to bacterial infection, especially Vibiro parahemolyticus (V. parahemolyticus). Matrix metalloproteinases (MMPs) have been extensively investigated in the immune response of mammals. However, little is known about the involvement of MMP in abalone innate immune system against pathogen infection. In this study, the role of MMP-1 in the immune response of Pacific abalone (Haliotis discus hannai) was explored. The results showed that V. parahemolyticus infection induced significantly elevated expression of MMP-1 as well as immune related genes including allograft inflammatory factor 1 (AIF-1), macrophage expressed gene 1 (MPEG-1) and TPA-inducible sequence 11 family protein (Tis11FP). Notably, silencing of MMP-1 reduced the expression of these genes, suggesting that MMP-1 was an upstream regulatory factor in V. parahemolyticus infection. Further analysis showed that MMP-1 was engaged in the regulation of cellular (phagocytosis, apoptosis) and humoral [superoxide dismutase (SOD), alkaline phosphatase (ALP), acid phosphatase (ACP)] immunity. Interestingly, the extracellularly distributed MMP-1 could be translocated to the nuclei of hemocytes, thereby functioning as a transcriptional regulator or by selectively activating or inactivating other components through proteolysis. Hence, our study established an important role of MMP-1 in abalone innate immunity against V. parahemolyticus infection and it represented the first report on the investigation of MMP in abalone. PMID- 30304711 TI - Congenital human toxoplasmosis caused by non-clonal Toxoplasma gondii genotypes in Argentina. AB - Toxoplasmosis, a worldwide distributed zoonosis, can be transmitted congenitally affecting fetuses and developing variable clinical signs. Different Toxoplasma gondii genotypes and infective dose are related factors with different clinical manifestations. Several studies indicate that atypical strains could produce more severe clinical manifestations compared to typical strains. Umbilical cord blood (n = 37) and placenta (n = 19) were collected at birth from women with acute T. gondii infection and processed for isolation by mice bioassay. Six isolates were obtained and identified as TgHm14-4Arg, TgHm15-02Arg, TgHm16-01Arg, TgHm16-02Arg, TgHm17-01Arg and TgHm17-02Arg. Three genotypes described previously on Toxo-DB were identified: #138 identified in chickens from Brazil, #182 isolated from eared doves from Brazil, #14 from wallaby kangaroos and chickens from Argentina, chickens from Brazil, Colombia, Chile and Venezuela, cats and dogs from Brazil and Colombia and also coyotes from USA indicating worldwide distribution of these genotypes. Two new allele combinations were obtained showing high genotypes diversity in Argentina. Four of the isolates (TgHm14-4Arg, TgHm15-02Arg, TgHm16 01Arg, TgHm16-02Arg) and two of them (TgHm17-01Arg, TgHm17-02Arg) produced chronic and acute infections in mice, respectively. Until now, seven T. gondii isolates have been obtained from humans in Argentina, and all were atypical or non-clonal genotypes. The identification of atypical strains causing congenital toxoplasmosis and circulating in our region, make important to perform the serological screenings according Argentine Consensus of Toxoplasmosis and to apply and monitoring treatments earlier in pregnancy. To achieve this aim, it is necessary to inform general population about T. gondii infection, diagnostics and control measures. These results should serve to generate awareness about congenital toxoplasmosis in South America. PMID- 30304712 TI - Intimate relationships and patterns of drug and sexual risk behaviors among people who inject drugs in Kazakhstan: A latent class analysis. AB - BACKGROUND: Multiple drug and sexual risk behaviors among people who inject drugs (PWID) in intimate relationships increase the risk of HIV and HCV transmission. Using data on PWID in intimate partnerships in Almaty, Kazakhstan, this study performed latent class analysis (LCA) on drug and sexual risk behaviors and estimated associations between dyadic relationship factors and membership in latent classes. METHODS: LCA was performed on a sample of 510 PWID (181 females/FWID, 321-males/MWID) to identify levels of drug and sexual risk behaviors. Generalized structural equation modeling with multinomial regressions estimated associations between relationship factors (length risk reduction communication, risk reduction self-efficacy) and class membership after adjusting for substance use severity, overdose, depression, binge drinking, intimate partner violence, structural factors, and sociodemographic characteristics. Models were sex-stratified to include FWID and PWID. RESULTS: A 3-class model best fit the data and consisted of low, medium, and high-risk classes. GSEM found that greater injection self-efficacy was associated with a lower likelihood of membership in the high-risk class for PWID and FWID. For MWID, greater length of the relationship was associated with a lower likelihood of membership in the medium-risk class. Greater relationship communication was associated with increased risk of membership in the high-risk latent class for MWID. CONCLUSIONS: Future research must investigate if increasing risk reduction and safe sex self efficacy could reduce drug and sexual risk behaviors and HIV transmission among PWID and their intimate partners. Interventions are needed that reduce power inequities within relationships as a method of increasing self-efficacy, particularly among women. PMID- 30304713 TI - Key Cell Functions are Modulated by Compression in an Animal Model of Hypertrophic Scar. AB - INTRODUCTION: The value of compression studies and applications in hypertrophic scar (HTS) treatment is often undermined due to the lack of ideal controls, patient compliance, and clear action mechanisms. OBJECTIVE: This study assesses the genome-wide compression effects on scars under well-controlled conditions. MATERIALS AND METHODS: An automated pressure delivery system (APDS) applied controlled doses of pressure to scars in a red Duroc swine HTS model. Full thickness wounds were created by a skin grafting instrument on each animal's bilateral flanks and were observed through reepithelialization and scar development. On day 70, the APDSs were mounted on the developed scars; right flank scars received a pressure of 30 mm Hg, while left flank scars received APDSs with no pressure (sham) for 2 weeks. A genome-wide assessment of compression effect on transcription in scar specimens before (early), shortly after (mid), and long after (late) compression initiation were performed. RESULTS: Analysis of early-phase biopsies showed similar transcriptome profiles, which diverged thereafter in gene numbers and functions between compression- and sham-treated scars in the mid phase. The majority of these changes persisted in the late-phase scar samples. Canonical pathway analysis of differentially regulated genes resulted in an almost identical list of pathways during the early phase prior to compression. In the mid and late phases after compression, many of the identified pathways shifted in significance, and new pathways such as calcium signaling and cholesterol synthesis emerged. CONCLUSIONS: Compression modulates transcription and affects multiple biological functions associated with an improved scar appearance. PMID- 30304715 TI - Elevated Serum Exosomal miR-125b Level as a Potential Marker for Poor Prognosis in Intermediate-Risk Acute Myeloid Leukemia. AB - BACKGROUND: The prognostic significance of miR-125b in intermediate-risk acute myeloid leukemia has not been well investigated. The aim of the study was to reveal the relationship between the elevated exosomal miR-125b level and the poor prognosis in adult patients with this disease. METHODS: A total of 154 consecutive patients with intermediate-risk acute myeloid leukemia were enrolled. Exosomes were isolated from blood specimens. The exosomal miR-125b level was determined using quantitative real-time polymerase chain reaction. Patients received standardized therapy and were followed up for 1-24 months. Details about relapse and overall death were recorded. RESULTS: Patients were divided into the high miR-125b level group (n = 77) and the low miR-125b level group (n = 77). In the multivariate Cox proportional hazard regression model, the high miR-125b level group was separately associated with increased risks of relapse and overall death in 2 years (hazard ratio [HR] 2.84, 95% CI 1.81-4.33 and HR 2.69, 95% CI 1.87-4.52). Kaplan-Meier analysis also revealed that a high miR-125b level was related to a higher cumulative relapse and overall death rates (p < 0.001 and p < 0.001, respectively). CONCLUSION: Circulating exosomal miR-125b concentration might be an independent prognostic indicator in intermediate-risk acute myeloid leukemia patients. An elevated miR-125b level indicated higher risks of relapse and overall death. PMID- 30304716 TI - Introduction to Extracorporeal Multiple Organ Support. PMID- 30304714 TI - Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data. AB - BACKGROUND: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. METHODS: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 ug/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 ug/L and/or TSAT >=40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 ug/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. RESULTS: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. CONCLUSIONS: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. TRIAL REGISTRATION: EudraCT number: 2013-002267-25. PMID- 30304717 TI - Pregnancy Outcomes of Patients Exposed to Adalimumab in Japan. AB - BACKGROUND: This is the first retrospective report of pregnancy outcomes after exposure to adalimumab treatment in Japan. METHODS: Using the AbbVie safety database, we analyzed pregnancy outcome data from patients who received adalimumab treatment from April 16, 2008, to May 15, 2017. RESULTS: Data were extracted retrospectively for 74 pregnancies in 73 patients. More than half of the patients included in the study received adalimumab for the treatment of Crohn's disease (37.8%) or ulcerative colitis (20.3%), while 9.5% received adalimumab for rheumatoid arthritis. Of the 53 pregnancies with available outcome data, 45 newborns (45/53 [84.9%]) were delivered. Of these births, 30 were full term, 2 were preterm, and 13 were unknown. Apgar scores were available for 11 of the 16 newborns whose mothers were exposed to adalimumab in the third trimester; all scores were within the normal range. Low birth weight was observed in 5 infants out of the 30 full-term deliveries. There were also 5 miscarriages (5/53 [9.4%]), 2 induced abortions (2/53 [3.8%]), and 1 stillbirth (1/53 [1.9%]). Eight maternal adverse events were observed in 5 pregnancies; no serious adverse events occurred. CONCLUSION: Although safety concerns were inconclusive, these data do not report additional risk to pregnancy outcomes with adalimumab exposure. PMID- 30304718 TI - Pharmacokinetics of Ceftolozane-Tazobactam during Prolonged Intermittent Renal Replacement Therapy. AB - BACKGROUND: Prolonged intermittent renal replacement therapy (PIRRT) eliminates many drugs, and without dosing data, for new antibiotics like ceftolozane/tazobactam, suboptimal concentrations and treatment failure are likely. OBJECTIVES: Herein, we describe the effect of PIRRT on the plasma pharmacokinetics of ceftolozane/tazobactam ad-ministered in a critically ill 55 year-old patient with a polymicrobial sternal wound osteomyelitis, including a multiresistant Pseudomonas aeruginosa. METHOD: Blood samples were taken over 4 days where the patient received a 7.5-h PIRRT treatment. One- and 2-compartment models were tested for ceftolozane and tazobactam separately, and the log likelihood ratio and goodness-of-fit plots were used to select the final model. RESULTS: Two-compartment models were developed for ceftolozane and tazobactam separately and described significant differences in clearance of ceftolozane and tazobactam with and without PIRRT (8.273 vs. 0.393 and 8.020 vs. 0.767 L/h, respectively). CONCLUSIONS: A ceftolozane/tazobactam dose of 500 mg/250 mg appears to be sufficient to attain pharmacokinetic/pharmacodynamic targets during PIRRT while the manufacturer's recommended dosing of 100 mg/50 mg every 8 h was sufficient during non-PIRRT periods. PMID- 30304719 TI - Changes in Profiles of Kawasaki Disease Noted over Time in Suzhou, China. AB - OBJECTIVES: The purpose of the present study was to explore the changes in epidemiological, clinical and laboratory characteristics of Kawasaki disease (KD) over a 12-year period in this area. METHODS: The medical records of KD patients hospitalized in the Children's Hospital of Soochow University from January 2006 to December 2017 were retrospectively reviewed and analyzed. To elucidate the changes more clearly in these years, we divided all patients into three groups according to the time of admission, 5-year time intervals apart. RESULTS: We found the number of KD had increased in recent years, although the age compositions had some variances. The male-to-female ratio peaked in patients aged 6-11 months and then decreased with ages. Incidence rates of clinical characteristics were almost the same except for cervical lymphadenopathy. Significant differences were noted in percentage of neutrophils, albumin, C reactive protein, erythrocyte sedimentation rate (ESR) and platelets. However, only ESR and platelets were significantly different after adjusting the days of disease onset. A trend showing a shorter fever duration before intravenous immunoglobulin treatment was also noted. CONCLUSIONS: The number of KD was increasing annually. Our results were indicative of a possibly changed etiology of the disease. However, further large-scale long-term surveillance is warranted. PMID- 30304720 TI - The Utility of Flow Rate Compared with Left Ventricular Stroke Volume Index in the Hemodynamic Classification of Severe Aortic Stenosis with Preserved Ejection Fraction. AB - OBJECTIVES: To substitute the stroke volume index (SVi) with flow rate (FR) in the hemodynamic classification of severe aortic stenosis (AS) with preserved ejection fraction (EF), in order to evaluate its prognostic value. METHODS: A total of 529 patients (78.8 +/- 9.8 years old, 44.1% males) with isolated severe AS (aortic valve area, AVA < 1 cm2), EF >=50%, in sinus rhythm, who underwent transthoracic echocardiography, were stratified by FR (>=/< 200 mL/s) and mean pressure gradient (MG) (>=/< 40 mm Hg): FRnormal/MGhigh, FRlow/MGhigh, FRnormal/MGlow, and FRlow/MGlow. RESULTS: Aortic valve replacement was more frequently performed in the FRnormal/MGhigh than in the FRlow/MGlow group (69.3 vs. 47%, respectively, p < 0.0001), yielding a similar survival benefit across all four groups. Over a median follow-up of 51 +/- 29 months, there were 249 deaths. In highly adjusted models, the FRlow/MGlow group had a higher all-cause mortality (HR = 1.7, 95% CI: 1.1-2.6, p = 0.02) than patients with FRnormal/MGhigh. FR had a stronger association with AVA than SVi (r = 0.51 vs. 0.41, respectively, p = 0.0002), and a similar predictive value for death (AUC = 0.57 and 0.58, respectively, p = 0.88). CONCLUSIONS: The FRlow/MGlow subset of AS is associated with the worst prognosis, and FR is not superior to SVi in the hemodynamic classification of severe AS. PMID- 30304721 TI - Matrix Gla Protein, Plaque Stability, and Cardiovascular Events in Patients with Severe Atherosclerotic Disease. AB - OBJECTIVE: This study aims to investigate whether plasma matrix Gla protein (MGP) species, desphospho-uncarboxylated (dp-uc) MGP, and total uncarboxylated (t-uc) MGP are associated with plaque levels of uncarboxylated (uc) MGP, markers of plaque stability, and cardiovascular disease (CVD) risk. METHODS: From the Athero Express biobank, we selected carotid plaque samples of 100 patients who underwent carotid endarterectomy. The level of agreement between plasma MGP species and plaque ucMGP levels was assessed using weighted kappa (kappa). We analyzed histological characteristics of plaque composition (plaque hemorrhage, lipid and calcification content). Logistic regression analyses were used to assess the association between plasma MGP and plaque characteristics. Furthermore, CVD endpoints (n = 20) were collected over a mean follow-up of 2.6 years. RESULTS: Weighted kappa statistics of plasma dp-ucMGP and t-ucMGP and plaque ucMGP were 0.10 (95% CI -0.31 to 0.52) and 0.14 (95% CI -0.20 to 0.48). Higher dp-ucMGP levels tended to be associated with less plaque hemorrhage (ORper 500 nM 0.96; 95% CI 0.92-1.00). No association was found for lipid and calcification content. Cox proportional hazards models showed no association between dp-ucMGP (HRper 200 pM 0.92; 95% CI 0.75-1.11) and an inverse association between t-ucMGP (HRper 500 nM 0.79; 95% CI 0.62-0.99) and cardiovascular events. CONCLUSIONS: Plasma dp ucMGP and t-ucMGP concentrations do not reflect plaque ucMGP levels. Elevated dp ucMGP levels may be associated with less plaque hemorrhage, suggestive of more stable plaques. T-ucMGP was not related with markers of plaque stability; however, elevated plasma t-ucMGP levels were associated with a reduced CVD risk. PMID- 30304722 TI - Comparison between Hyper-CVAD and PETHEMA ALL-93 in Adult Acute Lymphoblastic Leukemia: A Single-Center Study. AB - BACKGROUND: Although cure rates in pediatric acute lymphoblastic leukemia (ALL) are quite high with combined chemotherapy regimens, complete response (CR) and long-term survival rates in adults are 80-90 and 30-40%, respectively. Currently, combined chemotherapy regimens, such as Hyper-CVAD and PETHEMA, are used in patients with adult ALL. However, there has been no study comparing the results of Hyper-CVAD and PETHEMA ALL-93. METHODS: In this retrospective single-center study, we evaluated the results of Hyper-CVAD and PETHEMA ALL-93 in 51 ALL patients treated between September 2008 and March 2017 at the Department of Hematology, Faculty of Medicine, Karadeniz Technical University. RESULTS: Thirty eight patients were treated with Hyper-CVAD and 13 with PETHEMA ALL-93. CR was obtained in 90 and 100% of patients, respectively. Survival estimates were comparable between Hyper-CVAD and PE-THEMA ALL-93, with a median overall survival (OS) and a median disease-free survival (DFS) of 17.5 and 12.1 months, respectively, for Hyper-CVAD and of 18.6 and 12.9 months, respectively, for PETHEMA ALL-93. The 2-year OS rates for Hyper-CVAD and PETHEMA ALL-93 were 30 and 40%, respectively, and the 2-year DFS rates were 28 and 44%, respectively. PETHEMA ALL-93 resulted in more hepatotoxicity, hypofibrinogenemia, aspergillus infection, and skin rash than Hyper-CVAD. CONCLUSIONS: Although Hyper-CVAD and PE THEMA ALL-93 showed similar effects, Hyper-CVAD was tolerated better. Age and comorbidities should be taken into account before a chemotherapy regimen is determined for patients with ALL. PMID- 30304723 TI - Whole Blood Gene Expression Reveals Specific Transcriptome Changes in Neonatal Encephalopathy. AB - BACKGROUND: Variable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies; hence better disease stratification may facilitate the development of individualized neuroprotective therapies. OBJECTIVES: We examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. MATERIAL AND METHODS: We performed next-generation sequencing on whole blood RNA from 12 babies with neonatal encephalopathy and 6 time-matched healthy term babies. Genes significantly differentially expressed between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. RESULTS: We identified 950 statistically significant genes discriminating perfectly between healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p = 0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 signaling and production in macrophages (p = 0.003), and hypoxia inducible factor 1alpha signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. CONCLUSION: Babies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profiles may be useful for disease stratification and for developing personalized neuroprotective therapies. PMID- 30304724 TI - The Effects of Gusher-Related Intracochlear Pressure Changes on Hearing Preservation in Cochlear Implantation: A Comparative Series. AB - AIM: To investigate and compare residual hearing preservation between patients based on the presence of intraoperative gusher. METHODOLOGY: We retrospectively compared 2 cohorts of cochlear implant recipients significantly distinguished by whether or not they experienced gusher intraoperatively. Patients underwent cochlear implantation using 24-mm lateral wall electrode arrays as well pharmacologic steroid protection. All patients were assessed by a hearing implant MDT. Hearing preservation rates and speech perception outcomes were assessed at 1, 6, 12, 24, 36, 48, and 60 months. RESULTS: The patients with no gusher demonstrated complete hearing preservation. The patients with gusher demonstrated significant postoperative reduction of hearing thresholds, which declined at a significantly higher pace during follow-up. All patients demonstrated significantly better speech performance after cochlear implantation. CONCLUSION: The present study suggests that intraoperative gusher is associated with a significant drop in residual hearing, both immediately and over time, which may be related to the large change in intracochlear pressure intraoperatively. PMID- 30304725 TI - Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats. AB - This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and alpha2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and alpha2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective alpha2 adrenoceptor (yohimbine), alpha-2A (BRL 44408), alpha-2B (ARC 239), and alpha-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (? p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (? p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and alpha2A, alpha2B, and alpha2C-adrenoceptors contributed to the antiallodynic effects of areca nut. PMID- 30304726 TI - Colonoscopy Should Be Performed After an Episode of Uncomplicated Diverticulitis. PMID- 30304727 TI - Occult Hiatal Hernia in Achalasia Patients: Its Incidence and Treatment Options. AB - BACKGROUND: Achalasia patients occasionally coexist with esophageal hiatal hernias. The purpose of this study was to clarify the incidence and clinical features of achalasia cases concomitant with hiatal hernia, and to investigate whether our surgical technique was appropriate. METHODS: Consecutive achalasia patients who underwent laparoscopic Heller myotomy with Dor fundoplication (LHD) were extracted from the prospectively compiled surgical database, and the perioperative outcomes and the presence rate of hiatal hernia were obtained. RESULTS: We enrolled 58 patients with LHD from 2005 to 2016. Hiatal hernia was seen in 12 patients (20.7%) without preoperative diagnosis. There was no significant difference in preoperative symptoms between patients with and without hiatal hernia. In 6 patients with trivial hiatal hernia, we did not perform hernia repair. In 6 cases with large hiatal hernia, cruroplasty was added. No serious postoperative complications were observed in either of the groups and no patient required reoperation. Symptoms were improved in all patients postoperatively. Residual symptoms were successfully treated with medication, and no patient experienced severe reflux esophagitis or required hiatal hernia repair after surgery. CONCLUSION: Hiatal hernia was found in 20.7% of patients who received surgical treatment for achalasia, but no cases were diagnosed prior to surgery. PMID- 30304728 TI - Nintedanib for Advanced Epithelial Ovarian Cancer: A Change of Perspective? Summary of Evidence from a Systematic Review. AB - BACKGROUND/AIMS: Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women. Results with available therapies are far from being satisfactory and, therefore, current research is focusing on new anticancer drugs to improve the clinical response of these patients. Nintedanib is an oral multiple tyrosine kinases inhibitor, which targets angiogenesis. Considering the current scenario, the aim of this systematic review is to highlight the prevailing knowledge about pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC. METHODS: We performed a systematic review of the literature, screening all available articles about the treatment of advanced EOC with Nintedanib, including phase I, II, and III trials. RESULTS: Although in early phase clinical trials, Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel. In the phase III trial AGO-OVAR 12, it obtained a modest improvement in progression-free survival (PFS) as first-line combination therapy for patients with advanced EOC. Interestingly, a PFS increase was observed in patients with non-high progression risk or low tumor burden. CONCLUSION: Despite the promising results, further studies are needed to evaluate Nintedanib efficacy in women affected by EOC. PMID- 30304729 TI - Effect of Leaking Foveal Microaneurysms on the Treatment of Center-Involving Diabetic Macular Edema: A Pilot Study. AB - PURPOSE: Evaluate the effect of foveal leaking microaneurysms (MAs) on the required number of intravitreal ranibiz-umab (IVR) injections in the treatment of center-involving diabetic macular edema (DME) when treated with focal/grid laser. DESIGN: A pilot study of prospective, nonrandomized, multicenter clinical trial. METHODS: This study enrolled 21 eyes with DME for which pro re nata IVR injections were combined with short-pulse focal/grid laser. At 12 months, best corrected visual acuity (BCVA), central subfield macular thickness (CMT), and the required number of IVRs to maintain CMT < 300 um were compared between eyes with or without foveal leaking MAs, termed the MA(+) and MA(-) groups, respectively. RESULTS: Significant CMT improvements (p < 0.0001) and increased BCVA of 4.0 +/- 8.5 letters were observed at 12 months. The MA(-) group required significantly fewer IVRs than did the MA(+) group (mean: 4.9 +/- 3.0 vs. 8.6 +/- 3.0; p = 0.0306). In the latter 6 months of the 1-year follow-up, 50% (4/8) of MA(-) eyes did not require any IVR administration to sustain CMT < 300 um. CONCLUSIONS: A combination therapy of short-pulse focal/grid laser and reduced IVR injections appeared noninferior to previous reports of IVR monotherapy. Further large-scale investigations are warranted. PMID- 30304730 TI - Extension of the Clinical Significance of the "Cog". AB - OBJECTIVE: To study the clinical anatomy of the epitympanum, the attic, and its medial wall, to try to discover a new clinical operation-related anatomical landmark, and to investigate the adjacent anatomical relationship with this landmark. MATERIALS AND METHODS: Eight donor temporal bone specimens were dissected endoscopically. For 29 healthy persons (17 males and 12 females), CT images of the temporal bone (57 ears) were taken, 3-dimensional (3-D) reconstruction and multidimensional plane reconstruction were performed, and identification and assessment of 3-D spatial relationships between any 2 of these complex structures were done. RESULTS: 3-D images of the temporal bone structures including the facial nerve, the cochlea, the semicircular canal, and the brain plate were reconstructed and shown in detail. We discovered a new clinical surgery-related anatomical landmark (the "cog" tangent and the trailing edge of the cog). Based on the tangent and the trailing edge of the cog, we quantified the anatomical relationship between it and its neighboring important structures. CONCLUSION: Based on endoscopic anatomy and the temporal bone spiral CT 3-D structure reconstruction of the epitympanum, the attic, and the adjacent structures, we found an extension of the clinical significance the cog. Quantification of the adjacent anatomical relationship of this landmark is very important for otology microsurgical operation. PMID- 30304731 TI - First-Trimester Placental Growth Factor for the Prediction of Preeclampsia in Nulliparous Women: The Great Obstetrical Syndromes Cohort Study. AB - BACKGROUND: First-trimester maternal serum markers have been associated with preeclampsia (PE). We aimed to evaluate the performance of first-trimester placental growth factor (PlGF) for the prediction of PE in nulliparous women. SUBJECTS AND METHODS: We conducted a prospective cohort study of nulliparous women with singleton pregnancy at 11-13 weeks. Maternal serum PlGF concentration was measured using B.R.A.H.M.S PlGFplus KRYPTOR automated assays and reported in multiple of the median adjusted for gestational age. We used proportional hazard models, along with receiver operating characteristic curves and areas under the curve (AUC). RESULTS: Out of 4,652 participants, we observed 232 (4.9%) cases of PE including 202 (4.3%) term and 30 (0.6%) preterm PE. PlGF was associated with the risk of term (AUC = 0.61, 95% confidence interval [CI] 0.57-0.65) and preterm PE (AUC = 0.73, 95% CI 0.64-0.83). The models were improved with the addition of maternal characteristics (AUC for term PE 0.66, 95% CI 0.62-0.71; AUC for preterm PE 0.81, 95% CI 0.72-0.91; p < 0.01). At a false-positive rate of 10%, PlGF combined with maternal characteristics could have predicted 26% of term and 55% of preterm PE. The addition of pregnancy-associated plasma protein A did not significantly improve the prediction models. CONCLUSION: First-trimester PlGF combined with maternal characteristics is useful to predict preterm PE in nulliparous women. PMID- 30304732 TI - Peripheral Neuroimmunoendocrine Interactions: Contribution of TNFRp55 to the Circadian Synchronization of Progesterone and Cytokine Production in Joints of Mice in Late Pregnancy. AB - OBJECTIVE: Circadian rhythms are generated by the suprachiasmatic nucleus of the hypothalamus and involve rhythmic expression of clock genes and proteins. This rhythmicity is transferred to peripheral tissues by neural and hormonal signals. Late pregnancy is considered a state of inflammation which impacts on peripheral tissues such as joints. Tumor necrosis factor (TNF) mediates inflammatory and circadian responses through its p55 receptor (TNFRp55). Neuroimmunoendocrine interactions in joints have not been studied completely. The purpose of this study was to analyze these interactions, investigating the circadian rhythms of progesterone (Pg) and pro- and anti-inflammatory cytokines in the joints at the end of pregnancy (gestational day 18). Moreover, the impact of TNFRp55 deficiency on these temporal oscillations was explored. METHODS: Wild-type and TNFRp55 deficient (KO) C57BL/6 mice were kept under constant darkness in order to study their endogenous circadian rhythms. The expression of the clock genes Bmal1 and Per1 at circadian time 7 was studied by reverse transcription polymerase chain reaction in the ankle joints of nonpregnant and pregnant (gestational day 18) mice. In late pregnancy, Pg and the cytokines interleukin 17 (IL-17), IL-6, and IL-10 were measured in the joints throughout a 24-h period by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: A significant increase in Bmal1 and Per1 mRNA expression was detected in the joints of pregnant KO mice. Furthermore, KO mice displayed a desynchronization of articular Pg and cytokine production. CONCLUSIONS: Our results show that TNF, via TNFRp55 signaling, modulates articular Pg and cytokine circadian rhythms in late pregnancy. These findings suggest a temporal neuroimmunoendocrine association in peripheral tissues in late pregnancy. PMID- 30304733 TI - Challenging Diagnosis of a Solitary Retroperitoneal Mass: A Case Report of Castleman's Disease and Review of the Literature. AB - Castleman's disease (CD) is an uncommon type of lymphoproliferative disorder. Its etiology and prevalence are unclear. The retroperitoneum is a very rare site for presentation of the unicentric variant, where it mimics malignant tumors. A 59 year-old man is referred to the urology outpatient clinic for the study of microhematuria found in a routine analysis. CT scan of the abdomen identified a solid, circumscribed mass, measuring 28 * 30 * 31 mm in the left para-aortic zone, with homogeneous contrast enhancement. Excisional surgery and regional lymphadenectomy were performed via laparoscopy. Postoperative course concurred without incidences. Histological diagnosis confirmed unicentric CD, hyaline vascular type. CD is a rare entity, and the unicentric type presents as an asymptomatic mass. Retroperitoneum is a rare localization, where initial imaging diagnosis is unclear and surgical resection is the preferred treatment. PMID- 30304734 TI - Lhermitte-Duclos Disease in a Six-Year Old Child: A Rare Presentation. AB - Lhermitte-Duclos disease (LDD) is a rare, slow-growing, benign lesion of the cerebellum. It is often seen in the second and fourth decades. This disease is extremely rare in childhood. A 6-year-old girl presented with loss of balance. A mass lesion in the right cerebellum was detected by magnetic resonance imaging. The patient underwent surgical removal of the lesion, and the histological diagnosis was dysplastic gangliocytoma (LDD). The patient was discharged without complication, and her balance improved in the follow-up period. In this report, we present this rare occurrence in childhood and discuss the clinical course and management. LDD is very rare in early childhood and should be considered in the differential diagnosis of posterior fossa lesions. PMID- 30304735 TI - Localisation of DBS Electrodes Post-Implantation, to CT or MRI? Which Is the Best Option? PMID- 30304736 TI - Lung Ultrasound for the Differential Diagnosis of Respiratory Distress in Neonates. AB - BACKGROUND: Respiratory distress (RD) is the most common neonatal illness. Lung ultrasound (LUS) is a technique previously tested in neonatal studies on RD, but literature regarding its routine clinical applicability is still lacking. OBJECTIVE: To assess the concordance between LUS performed by neonatologists with different training levels and chest X-ray (CXR) for the diagnosis of RD in newborns during the first 24 h of life. METHODS: We enrolled newborns with RD during the first 24 h of life. Patients underwent LUS and CXR. LUS and CXR diagnosis were compared to evaluate concordance. Twenty percent of patients received two LUS (one from an experienced and one from a novice sonographer) to calculate the interobserver agreement. The difference in time needed to reach a diagnosis with LUS and CXR, and from novice and expert operators, was measured. RESULTS: We studied 124 patients; 134 diagnoses were reported. The concordance between LUS and CXR diagnosis was 91% (95% CI 86-96%) with a kappa statistic of 0.88 (95% CI 0.81-0.94). The median time to diagnosis was shorter for LUS (9.5 min, IQR 5-15) than for CXR (50 min, IQR 33-64) (p < 0.0001). In 25/124 patients, LUS was performed by both novice and experienced sonographers with complete concordance. The median time to diagnosis was shorter for expert (9 min, IQR 5 15) than novice operators (15 min, IQR 10-20) (p < 0.0002). CONCLUSION: LUS and CXR have a high concordance in the differential diagnosis of neonatal RD in the first 24 h of life. LUS has a shorter operation time than CXR. PMID- 30304737 TI - Onset of Retinal Pigment Epithelium Atrophy Subsequent to Anti-VEGF Therapy in Patients with Neovascular Age-Related Macular Degeneration. AB - PURPOSE: The aim of this study was to evaluate risk factors for the development of retinal pigment epithelium (RPE) atrophy in patients with neovascular age related macular degeneration (nAMD). PROCEDURES: This post hoc analysis of the prospective RESPONSE study includes 52 therapy-naive nAMD patients without baseline RPE atrophy, who were treated with >=9 anti-vascular endothelial growth factor (VEGF) injections for >=3 years. RPE atrophy was assessed via multimodal imaging. Baseline aqueous VEGF and serum complement levels (C3d/C3) were measured. Risk factors for atrophy development were evaluated via logistic regression analysis. RESULTS: Atrophy onset was significantly associated with the duration of nAMD (mean 5.34 years; odds ratio = 1.83, p = 0.012). Anti-VEGF injection number, age, C3d/C3 ratio, baseline intraocular VEGF, or delay to the first treatment had no influence on RPE atrophy. CONCLUSIONS: The duration of treatment-requiring nAMD was identified as primary risk factor for the onset of concomitant RPE atrophy after commencing therapy. Targeting concomitant atrophy in nAMD patients might improve the long-term prognosis of the disease. PMID- 30304738 TI - Benzodiazepine Use and Long-Term Mortality in Real-Life Chronic Heart Failure Outpatients: A Cohort Analysis. PMID- 30304739 TI - Regulation of epithelial migration by epithelial cell adhesion molecule requires its Claudin-7 interaction domain. AB - Epithelial cell adhesion molecule (EpCAM) is a glycoprotein on the surface of epithelial cells that is essential for intestinal epithelial integrity and expressed at high levels in many epithelial derived cancers and circulating tumor cells. Here we show the effect of EpCAM levels on migration of Madin-Darby-Canine Kidney (MDCK) epithelial cells. MDCK cells depleted of EpCAM show increased activation of extracellular signal-regulated kinase (ERK) and of myosin, and increased cell spreading and epithelial sheet migration into a gap. In contrast, over-expression of EpCAM inhibits ERK and myosin activation, and slows epithelial sheet migration. Loss of EpCAM is rescued by EpCAM-YFP mutated in the extracellular domain required for cis-dimerization whereas EpCAM-YFP with a mutation that inhibits Claudin-7 interaction cannot rescue increased ERK, myosin activation, and increased migration in EpCAM-depleted cells. In summary, these results indicate that interaction of EpCAM and Claudin-7 at the cell surface negatively regulates epithelial migration by inhibiting ERK and actomyosin contractility. PMID- 30304740 TI - Symptom patterns in childhood arterial ischemic stroke: Analysis of a population based study in Germany. AB - HINTERGRUND: Die zeitliche Verzogerung zwischen Symptombeginn und Diagnose ist eine Herausforderung in der Behandlung von Kindern mit arteriell ischamischem Schlaganfall. Fruhere Studien zur klinischen Prasentation beschaftigten sich v. a. mit kumulativen Symptomen. ZIELSETZUNG: Ziel dieser Studie ist es, mogliche Symptommuster aufzuzeigen. METHODEN: In einer aktiven Beobachtungsstudie zwischen 01/2015 und 12/2016 (ESPED-Studie) wurden Kinder mit Erstdiagnose eines arteriell ischamischen Schlaganfalls eingeschlossen. Isoliert auftretende Erstsymptome wurden verschiedenen Symptomkombinationen gegenubergestellt. Zudem wurde untersucht, inwieweit ein als "akut" oder "progredient" klassifiziertes Auftreten der Symptome Ruckschlusse auf die zugrundeliegende Atiologie erlaubt. ERGEBNISSE: Es wurden 99 Kinder in die Studie eingeschlossen. Unabhangig vom Alter traten uberwiegend fokale Symptome auf (86%). Krampfanfalle als Initialsymptom wurden insbesondere bei Sauglingen beschrieben (67%), wohin-gegen diffuse, unspezifische Symptome vor allem bei Vorschulkindern (38%) und alteren Kindern (59%) auftraten. Isoliert traten fokale Symptome bei 37 Kindern auf, 48 Kinder zeigten zusatzlich unspezifische Symptome, darunter auch 9 Kinder mit Krampfanfallen. Isolierte unspezifische Symptome zeigten sich lediglich bei 7 Kindern, 2 Kinder wurden nur mit Krampfanfallen symptomatisch. Die Akuitat des Symptombeginns wurde bei 53/78 als "akut" und bei "25/78 Fallen als "progredient" klassifiziert, lieferte jedoch keinen Hinweis auf die zugrundeliegende Atiologie. SCHLUSSFOLGERUNG: Jedes neue fokal neurologische Defizit sollte unabhangig vom Auftreten (isoliert oder kombiniert, akut oder progredient) an einen kindlichen Schlaganfall denken lassen. BACKGROUND: Time delay between onset of clinical symptoms and diagnosis is a challenge in childhood arterial ischemic stroke. Most previous studies reported cumulative symptoms. OBJECTIVE: We attempted to identify typical symptom patterns and assessed their emergence in childhood stroke. METHODS: Prospective active surveillance in ESPED, a hospital based Pediatric Surveillance Unit for rare diseases in Germany, between January 2015 and December 2016. Case definition: first diagnosis of a radiologically confirmed arterial ischemic stroke. Symptom patterns were identified as occurring in isolation or in combination. We distinguished acute vs. progressive onset. We ascertained risk factors to identify the possible etiology. RESULTS: 99 children with childhood arterial ischemic stroke were reported. Focal symptoms were the predominant presenting feature (86%), independent of age. Seizures were more often seen in infants < 1 year (67%), whereas diffuse symptoms were more present in pre-school children (38%) and older children (59%). 37 children had focal features alone and 48 additional non-specific features, including 9 with seizures. Isolated non-specific features accounted for 7 cases, and 2 children had (focal) seizures as the only symptom. In 77% of all cases at least one risk factor was identified. The emergence of symptoms was acute in 53/78 cases and progressive in 25/78 cases. The pattern of emergence was unrelated to the underlying etiology. CONCLUSIONS: Any new focal neurological deficit in isolation, or associated with seizures or further non-specific symptoms should alert to childhood stroke. PMID- 30304741 TI - Juvenile Canavan Disease: A Leukodystrophy without White Matter Changes. PMID- 30304742 TI - Vestibular Migraine with Visual Aura and Olfactory Hallucination in Children: Two Case Reports. AB - BACKGROUND: Approximately 3.9% children with migraine have olfactory hallucination which was defined as a perception of a smell without the substantial existence of any physical odor. CASE: We described the first two cases of children with vestibular migraine, presenting visual aura and olfactory hallucination. We reported two children with vertigo, visual aura, and olfactory hallucination before the headache who were responsive to topiramate. CONCLUSION: The clinical description of olfactory hallucination presented some characteristics of migraine aura. Olfactory hallucinations could be inserted as a migraine aura in International Classification of Headache Disorders. PMID- 30304744 TI - ? PMID- 30304743 TI - Clinical Assessment of Dysarthria in Children with Cerebellar Syndrome Associated with PMM2-CDG. AB - Phosphomannomutase deficiency (PMM2-CDG) causes a cerebellar syndrome that has been evaluated using the International Cooperative Ataxia Rating Scale (ICARS). However, no particular dysarthria tests have been used. Speech ICARS subscore subjectively assesses fluency and clarity of speech with two items. Repetition of syllables, traditionally used for characterization of ataxic speech, was validated in early-onset ataxia conditions. We assess the validity of the PATA test (SCA Functional Index [SCAFI]) in PMM2-CDG patients.PATA rates from 20 patients were compared with a control population were and correlated with ICARS and neuroimaging.There was a difference between the PATA rate in patients and controls. PATA rate increased with age in controls. In patients, the improvement of PATA rate with age was not significant. In patients, the PATA rate was negatively correlated with the total ICARS score and the Speech ICARS subscore. Regarding neuroimaging, midsaggital vermis relative diameter was positively correlated with PATA results. These last differences were also significant when the results are corrected by age.PATA rate provides an easy measure for a quantitative assessment of dysarthria that may help clinicians to monitor patients' evolution in a regular consultation. It could also be used in PMM2-CDG clinical trials implementing ICARS speech subscore information. PMID- 30304745 TI - Factors Influencing Sustained Engagement with ECG Self-Monitoring: Perspectives from Patients and Health Care Providers. AB - BACKGROUND: Patient-generated health data (PGHD) collected digitally with mobile health (mHealth) technology has garnered recent excitement for its potential to improve precision management of chronic conditions such as atrial fibrillation (AF), a common cardiac arrhythmia. However, sustained engagement is a major barrier to collection of PGHD. Little is known about barriers to sustained engagement or strategies to intervene upon engagement through application design. OBJECTIVE: This article investigates individual patient differences in sustained engagement among individuals with a history of AF who are self-monitoring using mHealth technology. METHODS: This qualitative study involved patients, health care providers, and research coordinators previously involved in a randomized, controlled trial involving electrocardiogram (ECG) self-monitoring of AF. Patients were adults with a history of AF randomized to the intervention arm of this trial who self-monitored using ECG mHealth technology for 6 months. Semistructured interviews and focus groups were conducted separately with health care providers and research coordinators, engaged patients, and unengaged patients. A validated model of sustained engagement, an adapted unified theory of acceptance and use of technology (UTAUT), guided data collection, and analysis through directed content analysis. RESULTS: We interviewed 13 patients (7 engaged, 6 unengaged), 6 providers, and 2 research coordinators. In addition to finding differences between engaged and unengaged patients within each predictor in the adapted UTAUT model (perceived ease of use, perceived usefulness, facilitating conditions), four additional factors were identified as being related to sustained engagement in this population. These are: (1) internal motivation to manage health, (2) relationship with health care provider, (3) supportive environments, and (4) feedback and guidance. CONCLUSION: Although it required some modification, the adapted UTAUT model was useful in understanding of the parameters of sustained engagement. The findings of this study provide initial requirement specifications for the design of applications that engage patients in this unique population of adults with AF. PMID- 30304746 TI - [Correction: Multiresistant Pathogens in Oncological and Cardiological Rehabilitation - Results of a Surveillance Study in Brandenburg]. PMID- 30304747 TI - Antiphospholipid Antibodies in a General Obstetric Population: Clinical Impact on Pregnancy Outcome and Relationship with the M2 Haplotype in the Annexin A5 (ANXA5) Gene. AB - Antiphospholipid (aPL) antibodies are recognised risk factors for adverse obstetric outcomes. Recently, carriers of the M2 haplotype in the Annexin A5 gene have been shown to have a higher susceptibility to develop aPL antibodies. In a general obstetric population, we prospectively evaluated the possible relationship between: (1) aPL antibodies and M2 haplotype; and (2) aPL antibodies and/or M2 haplotype and obstetric outcomes. From a cohort of 3,097 consecutive pregnant women, 1,286 samples were analysed for the presence of both anti cardiolipin and anti-human beta2-glycoprotein I antibodies; samples with available DNA (n = 606) were also investigated for the M2 haplotype. Overall, 41/1,286 (3.2%) women showed the presence of aPL antibodies. Among them, 2 (4.8%) experienced a pregnancy loss and 38 (92.7%) gave birth to live-born babies (p value = non-significant vs. those without aPL antibodies). M2 haplotype was identified in 140 (23.1%) out of 606 women with DNA available: 3/140 (2.1%) M2 carriers and 17/466 (3.6%) non-carriers tested positive for aPL antibodies, respectively (p-value = non-significant). In total, 15/150 (10%) M2 and/or aPL antibody carriers, and 38/445 (8.5%) non-aPL antibody and/or M2 carriers suffered from obstetric complications, respectively (p-value = non-significant). No relationship between aPL antibodies and M2 haplotype was found. Furthermore, neither aPL antibodies nor the M2 haplotype is associated with obstetric complications. PMID- 30304749 TI - [Comparison of a commercially available, formula-based nutritional therapy enriched with oats fiber with a non-formula isocaloric therapy to treat non alcoholic fatty liver disease (NAFLD) - a randomized, controlled intervention trial]. AB - Non-alcoholic fatty liver disease (NAFLD) is mainly treated with caloric restriction and consecutive weight reduction. Protein, in exchange for starch and sugar as well as monounsaturated and long chain omega-3-fatty acids and prebiotic beta-glucan, are thought to be supportive.In a randomized controlled intervention study, two different dietary concepts were tested regarding effects on intrahepatic lipid content as well as on biochemical parameters in patients with a body-mass-index (BMI) > 30 kg/m2 and signs of fatty liver disease. The intervention group (IG, n = 17) received a commercially available formula diet supplemented with oats fibers. The control group (CG, n = 19) received a comparably restricted diet (approx. 1000 kcal/d) according to the "low glycemic and insulinemic diet" method.After twelve weeks, both interventions resulted into a reduction of BMI (IG: 33.8 +/- 2.9 to 29.3 +/- 2.5 kg/m2, CG: 33.7 +/- 2.8 to 30.1 +/- 3.2 kg/m2, both p < 0.001), as well as an improvement of liver and other metabolic functions. The hepatorenal index decreased in both groups, however, this reduction was more pronounced in the IG than in the CG (end of the study: 1.1 +/- 0.2 vs. 1.9 +/- 0.3, p < 0.05). A reduction of blood pressure only occurred in the IG (systolic from 136 +/- 15 mmHg to 122 +/- 11 mmHg, diastolic from 89 +/- 9 mmHg to 79 +/- 11 mmHg, both p < 0.01).In conclusion, we found that both dietetic interventions were similarly effective regarding weight reduction, but the formula diet with oats fibers was more effective regarding the reduction of intrahepatic lipid content and blood pressure than the control diet. PMID- 30304748 TI - [Neuroendocrine Neoplasia within the German NET Registry]. AB - Neuroendocrine neoplasias (NEN) comprise a rare tumor entity with heterogeneous biology, prognosis and therapeutic options. Together with the recent publication of the first German guidelines on diagnostics and therapy of NEN, an analysis of the German NET-registry cohort of the German Society of Endocrinology (DGE) was performed. For this purpose, 2686 cases were extracted and their patient characteristics (e. g., age, sex, histopathological characterization, grading and staging) were displayed and outcomes were calculated. Additionally, the systemic treatment reality in the two largest subgroups, small intestinal and pancreatic NEN, was analyzed within metastatic patients.Distribution of primary tumor localization, histopathological classification, disease stage and overall survival was comparable with results from international registry studies. In concordance with current guidelines, somatostatin analogues (SSA) and peptide receptor-radionuclide-therapy (PRRT) were the most common therapeutic modalities in small intestinal NEN. In pancreatic NEN, chemotherapy was used in first line as often as SSA. In second line, chemotherapy was used as often as PRRT. WHO classification of 2010 and TNM staging proved to be of prognostic relevance.The current analysis of the German NET-registry characterizes a multicentric, interdisciplinary cohort of NEN patients throughout Germany and it describes the applied systemic treatment modalities and overall outcome as well as the prognostic value of the WHO classification of 2010 and TNM staging. PMID- 30304750 TI - [The acid pocket - a novel target for the treatment of gastro-esophageal reflux disease]. AB - Increased acid reflux after meals is a key feature of gastro-esophageal reflux disease (GERD) and is the most important cause for patient symptoms, particularly heartburn and acid regurgitation. Chronic acid exposure also predisposes to associated pathologies including reflux esophagitis, esophageal stricture, Barrett's esophagus, and Barrett's carcinoma (esophageal adenocarcinoma). The severity of esophageal symptoms and mucosal damage is related to two key factors, (i) the acidity of the refluxate, which depends primarily on the gastric secretory output and its distribution within the stomach, and (ii) the frequency and duration of reflux events which depends on the efficacy of the reflux barrier at the gastro-esophageal junction and the esophageal clearance function. The concept of the acid pocket is an attempt to bring these two factors into a unified patho-mechanism.The acid pocket describes an area of unbuffered, highly acidic, gastric secretion in the proximal stomach adjacent to the esophago gastric junction (GEJ) which forms in the postprandial period and is the source of acid refluxate into the esophagus. It is observed both in healthy individuals as well as in reflux patients. However, the presence of a hiatus hernia and/or a weak lower esophageal sphincter in patients allows the acid pocket to encroach on the gastro-esophageal junction. This results in very high acid exposure of the squamous epithelium of the distal esophagus, leading to mucosal damage and symptoms. Recently, the acid pocket has been proposed as a target for pharmacological and surgical therapies of GERD. Proton pump inhibitors and related medications reduce its acidity; whereas, alginate preparations, prokinetics, and fundoplication displace it away from the gastro-esophageal junction. PMID- 30304751 TI - [Elastography characteristics of liver lesions - a new diagnostic tool?] PMID- 30304752 TI - [Persons with Severe Mental Illness in Germany - Having (not) a "Good Life"]. PMID- 30304753 TI - [The Impact of Non-Pharmacologic Lifestyle Interventions in People with Severe Mental Illness - A Systematic Review]. AB - BACKGROUND: In recent years public and research interests focused more and more in lifestyle as a key factor for health. Particularly lifestyle of people with severe mental illness in combination with modifiable risk factors and adverse effects of the antipsychotic medication is especially critical. The present paper investigated the effect of multimodal healthy lifestyle interventions concerning weight and BMI reduction. METHODS: We systematically searched electronic databases (Medline, EMBASE, PsycINFO, Cochrane Library) for reviews and RCTs. RESULTS: Six systematic reviews and three single RCTs met inclusion criteria. Analyzed lifestyle interventions, mostly combined approaches of nutrition and sports, showed short and medium term effects in weight and BMI reduction compared with controls. CONCLUSION: Lifestyle interventions appear effective for treating overweight among people with serious mental illness. Further research is needed for evaluating long-term effects of the lifestyle interventions as well as focusing special components of the interventions with especially high user benefit. PMID- 30304755 TI - [Exercise Testing in Respiratory Medicine - DGP Recommendations]. AB - This document replaces the DGP recommendations published in 1998 and 2013. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method and its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for blood gas analysis and right heart catheterization during exercise, walk tests, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, obesity, monitoring of rehabilitation or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine. PMID- 30304756 TI - Resilience for health-an emergent property of the "health systems as a whole". AB - Resilience has become a popular term, and its meaning varies widely depending on the context of its use. Its Latin origin, resilire, means "bouncing back"-should bouncing back be understood literally or rather metaphorically in the context of health, illness, dis-ease, and disease? This essay examines ecological, physiological, personal, and health system perspectives inherent in the concept of resilience. It emerges that regardless of the level of aggregation, resilience is a systems property-it is as much a property of each of the subsystems of network physiology, the person, and the health care delivery system as it is a property of the health system as a whole. Given the interdependencies between people, their internal and external environments, and the health service system, strengthening resilience, ie, the ability to positively adapt to challenges and changing circumstances, will require a broad-based public discourse: "How can we strengthen resilience and health for the benefit of people and society at large". PMID- 30304757 TI - Allergic contact dermatitis caused by vinylpyrrolidone/eicosene copolymer in a sunscreen. PMID- 30304758 TI - Allergic contact dermatitis caused by Dermabond in a paediatric patient undergoing skin surgery. PMID- 30304759 TI - Needs of families of children with cerebral palsy in Bangladesh: A qualitative study. AB - PURPOSE: Families of children with disabilities often have needs related to the care of their child with a disability. Although there has been extensive exploration of family needs in high-income contexts, there is little known about this issue in low and middle-income countries like Bangladesh. In this study, we explored the needs of families of children with cerebral palsy in Bangladesh. Such understanding is important as it will help to improve services for children with disabilities and their families. METHODS: We used a qualitative approach and interviewed 20 family members of children with cerebral palsy who visited the Centre for the Rehabilitation of the Paralysed, Bangladesh. We thematically analyzed data from semistructured interviews. RESULTS: Five different themes were found on needs of families with children with disabilities: (a) financial needs, (b) needs for disability-related services, (c) needs for family and community cohesion, (d) informational needs, and (e) emotional needs. Participants overwhelmingly reported that financial needs were their highest priority. CONCLUSION: Needs of families of children with disabilities must be considered in rehabilitation services to improve children's outcomes. Further studies are required to explore needs of families of children with disabilities who do not have access to rehabilitation services. PMID- 30304760 TI - Detection of bacterial contamination in platelet concentrates from Brazilian donors by molecular amplification of the ribosomal 16S gene. AB - OBJECTIVE: The aim of our work was to establish a semi-automated high-throughput DNA amplification method for the universal screening of bacteria in platelet concentrates (PCs). BACKGROUND: Among cases of transfusion transmission of infectious agents, bacterial contamination ranks first in the number of events, morbidity and mortality. Transmission occurs mainly by transfused PCs. Automated culture is adopted by some blood banks for screening of bacterial contamination, but this procedure is expensive and has a relatively long turnaround time. METHODS: PCs were spiked with suspensions of five different bacterial species in a final concentration of 1 and 10 colony-forming units (CFU) per millilitre. After incubation, the presence of bacteria was investigated by real-time polymerase chain reaction (PCR) and by the Enhanced Bacterial Detection System (eBDS, Pall) assay as a reference method. Real-time PCR amplification was performed with a set of universal primers and probes targeting the 16S rRNA gene. Co-amplification of human mitochondrial DNA served as an internal control. RESULTS: Using the real-time PCR method, it was possible to detect the presence of all bacterial species tested with an initial concentration of 10 CFU mL-1 24 h after contamination, except for Staphylococcus hominis. The PCR assay also detected, at 24 h, the presence of Serratia marcescens and Enterobacter cloacae with an initial concentration of 1 CFU mL-1 . CONCLUSIONS: The real-time PCR assay may be a reliable alternative to conventional culture methods in the screening of bacterial contamination of PCs, enabling bacterial detection even with a low initial concentration of microorganisms. PMID- 30304761 TI - Evaluation of an interprofessional continuing professional development course on comprehensive diabetes care: A mixed-methods approach. AB - RATIONALE: Since there are only 33 endocrinologists within the Department of Defence and over 150 000 beneficiaries with diabetes, most patients with diabetes will be treated by primary care providers (PCPs). Comprehensive diabetes care visits are extensive and the clinical practice guidelines (CPGs) routinely change; thus, providing current evidence-based care is difficult. Most professional development courses aim to update PCPs on CPGs but are often inadequate as they focus on only the PCPs (not the interdisciplinary team) without a plan to implement changes into practice. OBJECTIVE: To evaluate the biannual (twice yearly), 3-day, interprofessional Diabetes Champion Course (DCC) developed by the US Air Force Diabetes Center of Excellence on comprehensive diabetes care. METHODS: A mixed-methods approach was used to evaluate three iterations of the DCC course (Sept 2014-Sept 2015). Quantitatively, pre-course and post-course surveys were used to obtain impact on knowledge, skills, and intention to change clinical practice. Qualitatively, semi-structured phone interviews were conducted with participants to obtain benefits to their clinic related to attending the DCC and barriers to implementation of the CPG process improvement project. RESULTS: Twelve of 19 responding clinics (63%) reported implementing all or part of their original CPG project developed at the DCC, and 17 of 19 clinics (89%) reported improvements associated with attending the DCC. Post-course surveys, from on location participants, revealed significant improvements in knowledge (P < 0.01). Likewise, foot exam skills and ability to demonstrate glucose meters to patients improved. Even with high pre-course confidence, 97% of providers reported acquiring new knowledge about prescribing and titrating insulin. CONCLUSION: The DCC is innovative as it employs a team based, interprofessional, didactic, and interactive approach that is effective in improving knowledge, skills, and intention to change clinical practice, which should translate to better care for patients with diabetes. PMID- 30304762 TI - Are the Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio Prognostic Factors for Patients with Locally Advanced Pancreatic Cancer Treated with Chemoradiotherapy? PMID- 30304763 TI - Mesoporous Titanium Dioxide: Synthesis and Applications in Photocatalysis, Energy and Biology. AB - Mesoporous materials are materials with high surface area and intrinsic porosity, and therefore have attracted great research interest due to these unique structures. Mesoporous titanium dioxide (TiO2) is one of the most widely studied mesoporous materials given its special characters and enormous applications. In this article, we highlight the significant work on mesoporous TiO2 including syntheses and applications, particularly in the field of photocatalysis, energy and biology. Different synthesis methods of mesoporous TiO2-including sol-gel, hydrothermal, solvothermal method, and other template methods-are covered and compared. The applications in photocatalysis, new energy batteries and in biological fields are demonstrated. New research directions and significant challenges of mesoporous TiO2 are also discussed. PMID- 30304764 TI - Association between Work and Chronic Obstructive Pulmonary Disease (COPD). AB - To support occupational physicians in their assessment and notification of occupational diseases, diagnostic registration guidelines are developed with information about associations between work-related risk factors and diseases. The objective of this review of systematic reviews is to examine whether work related risk factors are associated with chronic pulmonary obstructive disease (COPD). We searched the electronic database of Medline for systematic reviews published between 1 January 2009 and 20 June 2017. Reviews were included when COPD was assessed by data on lung function and when work-related exposures to vapors, dusts, gases, or fumes (VDGF) were described. One author selected studies and extracted data; two authors assessed study quality using A MeaSurement Tool to Assess systematic Reviews (AMSTAR). In all eight systematic reviews included, various exposures to vapors, dusts, gases, and fumes (VGDF) at work are associated with COPD. Two-thirds of the included studies are cross-sectional and show a high heterogeneity in population, setting, and mostly self-reported exposures. Two high-quality reviews (AMSTAR score >= 9) including meta-analyses show associations and excess risk of COPD for work-related general exposure to VDGF with a summary odds ratio of 1.4 (95% confidence interval (CI) 1.19-1.73) and to inorganic dust with a mean difference in predicted forced expiratory volume in one second (FEV1) of -5.7% (95% CI: -8.62% to -2.71%). Exposure to VGDF at work is associated with a small but increased risk of COPD. More detailed workplace measurements of specific VGDF are warranted to gain an insight into dose-response relationships. PMID- 30304767 TI - Policies to Reduce Lead Exposure: Lessons from Buffalo and Rochester. AB - Lead exposure remains a major issue in cities, such as Buffalo and Rochester, with concentrated, segregated poverty and old, deteriorated housing stock. Exploring and comparing local policies and programs in these two cities, the author suggests that increasing the number of proactive housing inspections in high-risk areas and forming a single-purpose non-profit group dedicated to lead education and advocacy are two valuable interventions. He recommends additional policy steps, such as more stringent inspection standards; state adoption of the Environmental Protection Agency's Renovation and Repair Program; the lowering of state elevated blood level thresholds; a focus on in-person, interactive education by community health workers; and more vigorous enforcement of testing requirements among physicians. PMID- 30304766 TI - A Qualitative Evaluation of the eaTracker(r) Mobile App. AB - BACKGROUND: eaTracker(r) is Dietitians of Canada's online nutrition/activity self monitoring tool accessible via website and mobile app. The purpose of this research was to evaluate the eaTracker(r) mobile app based on user perspectives. METHODS: One-on-one semi-structured interviews were conducted with adult eaTracker(r) mobile app users who had used the app for >= 1 week within the past 90 days. Participants (n = 26; 89% female, 73% 18-50 years) were recruited via email. Interview transcripts were coded using first level coding and pattern coding, where first level codes were grouped according to common themes. RESULTS: Participants mentioned several positive aspects of the mobile app which included: (a) Dashboard displays; (b) backed by dietitians; (c) convenience and ease of use; (d) portion size entry; (e) inclusion of food and physical activity recording; and (f) ability to access more comprehensive information via the eaTracker(r) website. Challenges with the mobile app included: (a) Search feature; (b) limited food database; (c) differences in mobile app versus website; and (d) inability to customize dashboard displayed information. Suggestions were provided to enhance the app. CONCLUSION: This evaluation provides useful information to improve the eaTracker(r) mobile app and also for those looking to develop apps to facilitate positive nutrition/physical activity behavior change. PMID- 30304765 TI - Sleep Quality in Patients with Rheumatoid Arthritis and Associations with Pain, Disability, Disease Duration, and Activity. AB - We aimed to assess the subjective sleep quality in patients with rheumatoid arthritis (RA) and its correlation with disease activity, pain, inflammatory parameters, and functional disability. In a cross-sectional study, patients with confirmed RA diagnosis responded to a questionnaire (consisting of socio demographic data, the Health Assessment Questionnaire Disability Index, and the Medical Outcome Study Sleep Scale). Disease activity was assessed with the Clinical Disease Activity Index, and pain levels using the visual analogue scale. In addition, inflammatory markers (C-reactive protein, interleukin-6, and tumor necrosis factor alpha) were analyzed. Ninety-five patients were analyzed, predominantly female, with an average age of 50.59 (9.61) years. Fifty-seven percent reported non-optimal sleep duration, where functional disability (92.7% vs. 69.8%; p = 0.006) and higher median pain levels (3.75 (2.3-6.0) vs. 2.5 (2.0 3.5); p = 0.003) were also more prevalent. No differences in sociodemographic variables, disease duration or activity, inflammatory parameters, or use of biological and corticosteroid therapy were observed. The multivariate regression analysis showed that more intense pain was associated with a lower likelihood of optimal sleep (odds ratio (OR) = 0.68, 95% confidence interval (CI) 0.47-0.98, p = 0.038). Patients with RA report a high prevalence of non-optimal sleep, which is linked to pain level. Clinicians need to be aware of this issue and the potential effects on health and functional status. PMID- 30304768 TI - SmartFall: A Smartwatch-Based Fall Detection System Using Deep Learning. AB - This paper presents SmartFall, an Android app that uses accelerometer data collected from a commodity-based smartwatch Internet of Things (IoT) device to detect falls. The smartwatch is paired with a smartphone that runs the SmartFall application, which performs the computation necessary for the prediction of falls in real time without incurring latency in communicating with a cloud server, while also preserving data privacy. We experimented with both traditional (Support Vector Machine and Naive Bayes) and non-traditional (Deep Learning) machine learning algorithms for the creation of fall detection models using three different fall datasets (Smartwatch, Notch, Farseeing). Our results show that a Deep Learning model for fall detection generally outperforms more traditional models across the three datasets. This is attributed to the Deep Learning model's ability to automatically learn subtle features from the raw accelerometer data that are not available to Naive Bayes and Support Vector Machine, which are restricted to learning from a small set of extracted features manually specified. Furthermore, the Deep Learning model exhibits a better ability to generalize to new users when predicting falls, an important quality of any model that is to be successful in the real world. We also present a three-layer open IoT system architecture used in SmartFall, which can be easily adapted for the collection and analysis of other sensor data modalities (e.g., heart rate, skin temperature, walking patterns) that enables remote monitoring of a subject's wellbeing. PMID- 30304770 TI - Optimization of Growth and Carotenoid Production by Haloferax mediterranei Using Response Surface Methodology. AB - Haloferax mediterranei produces C50 carotenoids that have strong antioxidant properties. The response surface methodology (RSM) tool helps to accurately analyze the most suitable conditions to maximize C50 carotenoids production by haloarchaea. The effects of temperature (15-50 degrees C), pH (4-10), and salinity (5-28% NaCl (w/v)) on the growth and carotenoid content of H. mediterranei were analyzed using the RSM approach. Growth was determined by measuring the turbidity at 600 nm. To determine the carotenoid content, harvested cells were lysed by freeze/thawing, then re-suspended in acetone and the total carotenoid content determined by measuring the absorbance at 494 nm. The analysis of carotenoids was performed by an HPLC system coupled with mass spectrometry. The results indicated the theoretical optimal conditions of 36.51 or 36.81 degrees C, pH of 8.20 or 8.96, and 15.01% or 12.03% (w/v) salinity for the growth of haloarchaea (OD600 = 12.5 +/- 0.64) and production of total carotenoids (3.34 +/- 0.29 mg/L), respectively. These conditions were validated experimentally for growth (OD600 = 13.72 +/- 0.98) and carotenoid production (3.74 +/- 0.20 mg/L). The carotenoid profile showed four isomers of bacterioruberin (89.13%). Our findings suggest that the RSM approach is highly useful for determining optimal conditions for large-scale production of bacterioruberin by haloarchaea. PMID- 30304769 TI - A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia. AB - MYC-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC-translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis. The University of Padua T-cell acute lymphoblastic leukemia 13 (UP ALL13) cell line has all the main features of the above described MYC translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H DNMT3A mutation typically found in myeloid leukemia. Chromatin immunoprecipitation coupled with high-throughput sequencing for histone H3 lysine 27 (H3K27) acetylation revealed numerous putative super-enhancers near key transcription factors, including MYC, MYB, and LEF1. Marked cytotoxicity was found following bromodomain-containing protein 4 (BRD4) inhibition with AZD5153, suggesting a strict dependency of this particular subtype of T-ALL on the activity of super-enhancers. Altogether, this cell line may be a useful model system for dissecting the signaling pathways implicated in NOTCH1-independent T ALL and for the screening of targeted anti-leukemia agents specific for this T ALL subgroup. PMID- 30304771 TI - "Cutting Down on Sugar" by Non-Dieting Young Women: An Impact on Diet Quality on Weekdays and the Weekend. AB - Restricted sugar intake is an important part of a healthy lifestyle and may contribute to the prevention of diet-related diseases. The aim of the study was to investigate whether declared sugar restriction is reflected in actual sucrose intake and diet quality of young non-dieting women, with differentiation between the weekend and weekdays. A convenient sample of 192 non-dieting women aged 20-30 years old was recruited. The sample was divided into two groups based on each woman's declaration: "restricting sugar" (RS, n = 76) and "not restricting sugar" (nRS, n = 116). Comparisons between groups were made separately for seven days of the week, five weekdays and two weekend days without and with an adjustment for 2000 kcal of energy. Relative differences (RD, in %) in mean diet nutritional values between groups were calculated, where RD (%) = (RS - nRS) * 100/nRS, and were verified with a two-tailed t-test. In the seven-day diet of the RS group, in comparison to the nRS group, a lower daily intake of sucrose (by 22%) and MUFA (by 8%) and a higher content of most nutrients (by 7-38%) was found. No significant differences were observed in energy intake between RS and nRS women over the course of seven days, including weekdays and the weekend. Daily intake for the weekend, in comparison to weekdays, in RC and nRC women was higher with respect to energy (by 530 and 512 kcal, i.e., 37% and 34%, respectively), sucrose (44% and 23%, respectively), and most nutrients (by 17-98% and 16-42%, respectively). However, after the adjustment for 2000 kcal of energy, the daily intake of most nutrients in the weekend was lower (by 6-30% and 3-27%, in RS and nRS groups, respectively), than during weekdays. The intention to restrict sucrose has improved diet quality by decreasing sucrose intake and increasing the content of most nutrients, but had no effect on energy intake throughout the week. The quality of the women's diet during the weekend was compromised, regardless of restricting or not restricting sugar. Encouragement to restrict sugar intake throughout the week and control the food intake during the weekend may be an effective strategy for young women to maintain a healthy diet. PMID- 30304772 TI - Teicoplanin-Induced Anaphylactic Reaction in Children: A Case Report. AB - Teicoplanin is now increasingly used as a first-line prophylactic therapy for major surgical procedures, treatment of methicillin-resistant Staphylococcus aureus infections and for those with reported penicillin allergy. Teicoplanin is rarely associated with anaphylaxis and there is limited information on the prevalence of teicoplanin-induced perioperative anaphylaxis. Here, we describe a case of a 12-year-old child with teicoplanin-induced anaphylaxis peri operatively. PMID- 30304774 TI - Regulatory Efficacy of the Polyunsaturated Fatty Acids from Microalgae Spirulina platensis on Lipid Metabolism and Gut Microbiota in High-Fat Diet Rats. AB - Ultra-high performance liquid chromatography coupled with photo-diode array detector and electrospray ionization-mass spectrometry was employed to analyze the major fatty acids in Spirulina platensis 95% ethanol extract (SPL95). The effects of SPL95 on hepatoprotection were evaluated, including liver tissue histopathology, liver, and serum biochemical analysis. The active principle of SPL95 revealed a hypolipidemic effect, as indicated by down-regulating the mRNA and protein levels of sterol regulatory element-binding transcription factor-1c, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, acetyl CoA carboxylase pathway, and upregulating adenosine 5'-monophosphate-activated protein kinase-alpha in liver. SPL95 enriched the beneficial bacteria, including Prevotella, Alloprevotella, Porphyromonadaceae, Barnesiella, and Paraprevotella. Treatment with SPL95 led to a decrease in microbes, such as Turicibacter, Romboutsia, Phascolarctobacterium, Olsenella, and Clostridium XVIII, which were positively correlated with serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, but negatively correlated with the serum high density-lipoprotein cholesterol levels. These results provide evidence that the fatty acid from SPL95 may be used as a novel adjuvant therapy and functional food to regulate gut microbiota in obese and diabetic individuals. PMID- 30304773 TI - AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications. AB - Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation. PMID- 30304776 TI - Forming Quality Analysis on the Cold Roll Forming C-channel Steel. AB - Cold roll forming, as a metal plastic forming process, is still mainly used in industrial production by the trial-and-error method, which wastes a lot of time and materials. In this paper, the C-channel steel is taken as the research object. First, the empirical equations of forming passes are verified and analyzed, then the cold roll forming model of C-channel steel is established, the forming quality of each pass and the stress-strain distribution of the whole sheet metal are analyzed, and the validity of the model is verified by experiments. The residual stresses of the web zone and flange of the finished product were measured. The results show that the empirical formulas are still not universal and the forming quality of the bite zone is poor. It needs to be adjusted by improving the distribution of deformation. The external surface of the C-channel steel is undertensile stress, while the internal surface is undercompressive stress, and the residual stresses of the flange are far greater than those of the web zone. The research provides a reference for the design of the bite zone and the number of forming passes. PMID- 30304775 TI - Effects of Streptozotocin-Induced Diabetes on the Pineal Gland in the Domestic Pig. AB - Several observations from experiments in rodents and human patients suggest that diabetes affects pineal gland function, including melatonin secretion; however, the accumulated data are not consistent. The aim of the present study was to determine the effects of streptozotocin-induced diabetes on the pineal gland in the domestic pig, a species widely used as a model in various biomedical studies. The study was performed on 10 juvenile pigs, which were divided into two groups: control and diabetic. Diabetes was evoked by administration of streptozotocin (150 mg/kg of body weight). After six weeks, the animals were euthanized between 12.00 and 14.00, and the pineal glands were removed and divided into two equal parts, which were used for biochemical analyses and for preparation of explants for the superfusion culture. The pineal contents (per 100 MUg protein) of serotonin, 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid, 5-methoxytryptophol, and 5-methoxytryptamine were significantly lower in diabetic pigs than in control pigs. In contrast, the level of N acetylserotonin was significantly higher in diabetic animals. No significant differences were found in the level of melatonin between control and experimental pigs. The amounts of 3,4-dihydroxyphenylalanine, dopamine, norepinephrine, and 3,4-dihydroxyphenylacetic acid were significantly lower in the pineal glands of diabetic animals. The level of vanillylmandelic acid was higher in diabetic pigs. No differences were observed in the level of basal and NE-stimulated release of N acetylserotonin or melatonin between the pineal explants prepared from control and experimental animals. In vitro treatment with insulin was ineffective. In conclusion, streptozotocin-induced diabetes affects both indole metabolism and adrenergic neurotransmission in the pig pineal gland. PMID- 30304777 TI - The Content of Biogenic Amines in Croatian Wines of Different Geographical Origins. AB - Samples of white and red wines produced in two different wine-growing regions, coastal (Dalmatia) and continental (Hrvatsko zagorje) of Croatia, were analysed for biogenic amines content. Biogenic amines content was determined, and its concentration levels were associated with the geographical origin of the wine. Due to its high sensitivity, HPLC method with ultraviolet detector was used, including the derivatisation step with dansyl chloride. The method was applied to detect and quantify 11 biogenic amines in 48 red and white wines. It was found that both Dalmatian red and white wines are characterised by tryptamine (0.23 1.22 mg L-1), putrescine (0.41-7.5 mg L-1) and ethanolamine (2.87-24.32 mg L-1). White wines from the Hrvatsko zagorje region are characterised by content of isopentylamine (0.31-1.47 mg L-1), putrescine (0.27-1.49 mg L-1) and ethanolamine (3.80-17.96 mg L-1). In contrast to white wines from the Hrvatsko zagorje region, in the red wines, all biogenic amines except ethylamine, were found and equally presented. PMID- 30304779 TI - Organotin(IV) Dithiocarbamate Complexes: Chemistry and Biological Activity. AB - Significant attention has been given to organotin(IV) dithiocabamate compounds in recent times. This is due to their ability to stabilize specific stereochemistry in their complexes, and their diverse application in agriculture, biology, catalysis and as single source precursors for tin sulfide nanoparticles. These complexes have good coordination chemistry, stability and diverse molecular structures which, thus, prompt their wide range of biological activities. Their unique stereo-electronic properties underline their relevance in the area of medicinal chemistry. Organotin(IV) dithiocabamate compounds owe their functionalities and usefulness to the individual properties of the organotin(IV) and the dithiocarbamate moieties present within the molecule. These individual properties create a synergy of action in the hybrid complex, prompting an enhanced biological activity. In this review, we discuss the chemistry of organotin(IV) dithiocarbamate complexes that accounts for their relevance in biology and medicine. PMID- 30304781 TI - An Ultrasonication-Assisted Cobalt Hydroxide Composite with Enhanced Electrocatalytic Activity toward Oxygen Evolution Reaction. AB - A catalyst toward oxygen evolution reaction (OER) was synthesized by depositing cobalt hydroxide on carbon black. Ultrasonication was applied during precipitation to improve the performance of the catalyst. The ultrasonic-assisted process resulted in the refinement of the cobalt hydroxide particles from 400 nm to 50 nm, and the thorough incorporation of these particles with carbon black substrate. The resulting product exhibited enhanced OER catalytic activity with an onset potential of 1.54 V (vs. reversible hydrogen electrode), a Tafel slope of 18.18 mV/dec, and a stable OER potential at a current density of 10 mA cm-2, because of the reduced resistance of the catalyst and the electron transfer resistance. PMID- 30304780 TI - Recombinant GII.P16/GII.4 Sydney 2012 Was the Dominant Norovirus Identified in Australia and New Zealand in 2017. AB - For the past two decades, norovirus pandemic variants have emerged every 3-5 years, and dominate until they are replaced by alternate strains. However, this scenario changed in 2016 with the co-circulation of six prevalent viruses, three of which possessed the pandemic GII.4 Sydney 2012 capsid. An increased number of institutional gastroenteritis outbreaks were reported within the Oceania region in mid-2017. This study identified emerging noroviruses circulating in Australia and New Zealand in 2017 to assess the changing dynamics of the virus infection. RT-PCR-based methods, next generation sequencing, and phylogenetic analyses were used to genotype noroviruses from both clinical and wastewater samples. Antigenic changes were observed between the capsid of pandemic Sydney 2012 variant and the two new Sydney recombinant viruses. The combination of these antigenic changes and the acquisition of a new ORF1 through recombination could both facilitate their ongoing persistence in the population. Overall, an increased prevalence of GII.P16/GII.4 Sydney 2012 viruses was observed in 2017, replacing the GII.P16/GII.2 recombinant that dominated in the region at the end of 2016. This shift in strain dominance was also observed in wastewater samples, demonstrating the reliability of wastewater as a molecular surveillance tool. PMID- 30304782 TI - 2'-O-Methyl-8-methylguanosine as a Z-Form RNA Stabilizer for Structural and Functional Study of Z-RNA. AB - In contrast to Z-DNA that was stabilized and well-studied for its structure by chemical approaches, the stabilization and structural study of Z-RNA remains a challenge. In this study, we developed a Z-form RNA stabilizer m8Gm, and demonstrated that incorporation of m8Gm into RNA can markedly stabilize the Z-RNA at low salt conditions. Using the m8Gm-contained Z-RNA, we determined the structure of Z-RNA and investigated the interaction of protein and Z-RNA. PMID- 30304778 TI - Whole-Body 12C Irradiation Transiently Decreases Mouse Hippocampal Dentate Gyrus Proliferation and Immature Neuron Number, but Does Not Change New Neuron Survival Rate. AB - High-charge and -energy (HZE) particles comprise space radiation and they pose a challenge to astronauts on deep space missions. While exposure to most HZE particles decreases neurogenesis in the hippocampus-a brain structure important in memory-prior work suggests that 12C does not. However, much about 12C's influence on neurogenesis remains unknown, including the time course of its impact on neurogenesis. To address this knowledge gap, male mice (9-11 weeks of age) were exposed to whole-body 12C irradiation 100 cGy (IRR; 1000 MeV/n; 8 kEV/um) or Sham treatment. To birthdate dividing cells, mice received BrdU i.p. 22 h post-irradiation and brains were harvested 2 h (Short-Term) or three months (Long-Term) later for stereological analysis indices of dentate gyrus neurogenesis. For the Short-Term time point, IRR mice had fewer Ki67, BrdU, and doublecortin (DCX) immunoreactive (+) cells versus Sham mice, indicating decreased proliferation (Ki67, BrdU) and immature neurons (DCX). For the Long Term time point, IRR and Sham mice had similar Ki67+ and DCX+ cell numbers, suggesting restoration of proliferation and immature neurons 3 months post-12C irradiation. IRR mice had fewer surviving BrdU+ cells versus Sham mice, suggesting decreased cell survival, but there was no difference in BrdU+ cell survival rate when compared within treatment and across time point. These data underscore the ability of neurogenesis in the mouse brain to recover from the detrimental effect of 12C exposure. PMID- 30304783 TI - Nanostructured Dihydroartemisinin Plus Epirubicin Liposomes Enhance Treatment Efficacy of Breast Cancer by Inducing Autophagy and Apoptosis. AB - The heterogeneity of breast cancer and the development of drug resistance are the relapse reasons of disease after chemotherapy. To address this issue, a combined therapeutic strategy was developed by building the nanostructured dihydroartemisinin plus epirubicin liposomes. Investigations were performed on human breast cancer cells in vitro and xenografts in nude mice. The results indicated that dihydroartemisinin could significantly enhance the efficacy of epirubicin in killing different breast cancer cells in vitro and in vivo. We found that the combined use of dihydroartemisinin with epirubicin could efficiently inhibit the activity of Bcl-2, facilitate release of Beclin 1, and further activate Bax. Besides, Bax activated apoptosis which led to the type I programmed death of breast cancer cells while Beclin 1 initiated the excessive autophagy that resulted in the type II programmed death of breast cancer cells. In addition, the nanostructured dihydroartemisinin plus epirubicin liposomes prolonged circulation of drugs, and were beneficial for simultaneously delivering drugs into breast cancer tissues. Hence, the nanostructured dihydroartemisinin plus epirubicin liposomes could provide a new therapeutic strategy for treatment of breast cancer. PMID- 30304784 TI - SiO2 Stabilized Magnetic Nanoparticles as a Highly Effective Catalyst for the Degradation of Basic Fuchsin in Industrial Dye Wastewaters. AB - Catalytic degradation of organic pollutants by nanomaterials is an effective way for environmental remediation. The Fenton reaction involving H2O2 oxidation catalysed by Fe3+ is an advisable way for wastewater degradation. Herein, Fe3O4/SiO2 core-shell nanoparticles were prepared as catalyst by coprecipitation and sol-gel methods, and this catalyst is used for degradation of fuchsin in wastewater by H2O2. The Fenton reaction between H2O2 and Fe3O4 is proposed to explain the catalytic performance. The coating of SiO2 on Fe3O4 nanoparticles could dramatically stabilize the Fe3O4 in aqueous solution and prevent their oxidation. More importantly, the magnetic property of Fe3O4 nanoparticles endows them with good recyclability. Thus, due to the outstanding catalytic results, almost 100% removal degradation was achieved within 5 min over a wide pH value range at room temperature, which is better than that without catalysts. Temperature is a positive factor for improving the degradation rate, but room temperature is selected as the best temperature for economic and energy savings reasons, because more than 98% of fuchsins can still be degraded at room temperature. Moreover, these Fe3O4/SiO2 core-shell nanoparticles exhibit excellent magnetic recyclability and stable properties after repeated utilization. Therefore, these as-presented Fe3O4/SiO2 core-shell nanoparticles with low-cost and high performance are expected to be applied in practical industry wastewater degradation. PMID- 30304786 TI - Molecular Dynamics Study on the Reverse Osmosis Using Multilayer Porous Graphene Membranes. AB - In this study, the reverse osmosis (RO) of a salt solution was investigated using a molecular dynamics method to explore the performance of a multilayer porous graphene membrane. The effects of the salt solution concentration, pressure, layer separation and pore offset on the RO performance of the membrane were investigated and the influences of the number of layers and the gradient structure were determined. The results show that as the salt solution concentration increases, the energy barrier of the water molecules passing through the bilayer porous graphene membranes changes slightly, indicating that the effect of the water flux on the membrane can be ignored. The salt rejection performance of the membrane improves with an increase in the concentration of the salt solution. When the pressure is increased, the energy barrier decreases, the water flux increases and the salt rejection decreases. When the layer separation of the bilayer porous graphene membrane is the same as the equilibrium spacing of the graphene membrane, the energy barrier is the lowest and the membrane water flux is the largest. The energy barrier of the bilayer porous graphene membrane increases with increasing layer separation, resulting in a decrease in the water flux of the membrane. The salt rejection increases with increasing layer separation. The water flux of the membrane decreases as the energy barrier increases with increasing pore offset and the salt rejection increases. The energy barrier effect is more pronounced for a larger number of graphene layers and the water flux of the membrane decreases because it is more difficult for the water molecules to pass through the porous graphene membrane. However, the salt rejection performance improves with the increase in the number of layers. The gradient pore structure enhances the energy barrier effect of the water molecules permeating through the membrane and the water flux of the membrane decreases. The salt rejection performance is improved by the gradient pore structure. The research results provide theoretical guidance for research on the RO performance of porous graphene membranes and the design of porous graphene membranes. PMID- 30304788 TI - Interference-Aware Adaptive Beam Alignment for Hyper-Dense IEEE 802.11ax Internet of-Things Networks. AB - The increasing use of Internet of Things (IoT) devices in specific areas results in an interference among them and the quality of communications can be severely degraded. To deal with this interference issue, the IEEE 802.11ax standard has been established in hyper-dense wireless networking systems. The 802.11ax adopts a new candidate technology that is called multiple network allocation vector in order to mitigate the interference problem. In this paper, we point out a potential problem in multiple network allocation vector which can cause delays to communication among IoT devices in hyper-dense wireless networks. Furthermore, this paper introduces an adaptive beam alignment algorithm for interference resolution, and analyzes the potential delays of communications among IoT devices under interference conditions. Finally, we simulate our proposed algorithm in densely deployed environments and show that the interference can be mitigated and the IEEE 802.11ax-based IoT devices can utilize air interface more fairly compared to conventional IEEE 802.11 distributed coordination function. PMID- 30304787 TI - Effect of Low-Fat Diet in Obese Mice Lacking Toll-like Receptors. AB - Background: This study aimed at assessing the effect of a low-fat diet (LFD) in obese mice lacking toll-like receptors (Tlr) and understanding the expression and regulation of microRNAs during weight reduction. Methods: C57BL/6, Tlr5-/-, Tlr2 /- and Tlr4-/- mice were used in this study. A group of mice were fed with a high fat diet (HFD) (58% kcal) for 12 weeks to induce obesity (diet-induced obesity, DIO). Another group that had been fed with HFD for eight weeks (obese mice) were switched to a low-fat diet (LFD) (10.5% kcal) for the next four weeks to reduce their body weight. The control mice were fed with a standard AIN-76A diet for the entire 12 weeks. The body weight of the mice was measured weekly. At the end of the experiment, epididymal fat weight and adipocyte size were measured. The differentially expressed miRNAs in the fat tissue was determined by next generation sequencing with real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Target prediction and functional annotation of miRNAs were performed using miRSystem database. Results: Switching to LFD significantly reduced the body weight and epididymal fat mass in the HFD-fed C57BL/6 and Tlr5-/- mice but not in Tlr2-/- and Tlr4-/- mice. Weight reduction significantly decreased the size of adipocytes in C57BL/6 but not in the Tlr knockout mice. In Tlr2-/- and Tlr4-/- mice, feeding with HFD and the subsequent weight reduction resulted in an aberrant miRNA expression in the epididymal fat tissue unlike in C57BL/6 and Tlr5-/-. However, target prediction and functional annotation by miRSystem database revealed that all the top 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathways of the dysregulated miRNAs during weight reduction in the C57BL/6 mice were also found in the regulated pathways of Tlr5-/-, Tlr2-/-, and Tlr4-/- strains. However, among these pathways, gene sets involved in arginine and proline metabolism and glutathione metabolism were mainly involved in the Tlr knockout mice but not in the C57BL/6 mice. Conclusions: In this study, we demonstrated that feeding of LFD leads to significant body weight reduction in C57BL/6 and Tlr5-/- mice, but not in Tlr2-/- and Tlr4-/- mice. Significant reduction in the size of adipocytes of epididymal fat was only found in C57BL/6, but not in Tlr5-/-, Tlr2-/-, and Tlr4-/- mice. The dysregulated miRNAs in Tlr2-/- and Tlr4-/- mice were different from those in C57BL/6 and Tlr5-/- strains. Among those miRNA-regulated pathways, arginine and proline metabolism as well as glutathione metabolism may have important roles in the Tlr knockout mice rather than in C57BL/6 mice. PMID- 30304789 TI - Ebola Virus Maintenance: If Not (Only) Bats, What Else? AB - The maintenance mechanisms of ebolaviruses in African forest ecosystems are still unknown, but indirect evidences point at the involvement of some bat species. Despite intense research, the main bat-maintenance hypothesis has not been confirmed yet. The alternative hypotheses of a non-bat maintenance host or a maintenance community including, or not, several bat and other species, deserves more investigation. However, African forest ecosystems host a large biodiversity and abound in potential maintenance hosts. How does one puzzle out? Since recent studies have revealed that several bat species have been exposed to ebolaviruses, the common denominator to these hypotheses is that within the epidemiological cycle, some bats species must be exposed to the viruses and infected by these potential alternative hosts. Under this constraint, and given the peculiar ecology of bats (roosting behaviour, habitat utilisation, and flight mode), we review the hosts and transmission pathways that can lead to bat exposure and infection to ebolaviruses. In contrast to the capacity of bats to transmit ebolaviruses and other pathogens to many hosts, our results indicate that only a limited number of hosts and pathways can lead to the transmission of ebolaviruses to bats, and that the alternative maintenance host, if it exists, must be amongst them. A list of these pathways is provided, along with protocols to prioritise and investigate these alternative hypotheses. In conclusion, taking into account the ecology of bats and their known involvement in ebolaviruses ecology drastically reduces the list of potential alternative maintenance hosts for ebolaviruses. Understanding the natural history of ebolaviruses is a health priority, and investigating these alternative hypotheses could complete the current effort focused on the role of bats. PMID- 30304790 TI - Enhanced Adsorption of Zn(II) onto Graphene Oxides Investigated Using Batch and Modeling Techniques. AB - Graphene oxide (GO) was synthesized and employed as an adsorbent for Zn(II) removal from an aqueous solution. The adsorption isotherms showed that Zn(II) adsorption can be better described using the Freundlich model than the Langmuir model. The maximum adsorption capacity of Zn(II) on GO determined using the Langmuir model at pH 7.0 and 293 K was 208.33 mg/g. The calculation of thermodynamic parameters revealed that the process of Zn(II) adsorption on GO was chemisorptions, endothermic, and spontaneous. Kinetic studies indicated that the pseudo-second-order kinetic model showed a better simulation of Zn(II) adsorption than the pseudo-first-order kinetic model. On the basis of surface complexation modeling, the double layer model provided a satisfactory prediction of Zn(II) by inner-sphere surface complexes (for example, SOZn+ and SOZnOH species), indicating that the interaction mechanism between Zn(II) and GO was mainly inner sphere complexation. In terms of reusability, GO could maintain 92.23% of its initial capability after six cycles. These findings indicated that GO was a promising candidate for the immobilization and preconcentration of Zn(II) from aqueous solutions. PMID- 30304785 TI - Strengthening the Brain-Is Resistance Training with Blood Flow Restriction an Effective Strategy for Cognitive Improvement? AB - Aging is accompanied by a decrease in physical capabilities (e.g., strength loss) and cognitive decline. The observed bidirectional relationship between physical activity and brain health suggests that physical activities could be beneficial to maintain and improve brain functioning (e.g., cognitive performance). However, the exercise type (e.g., resistance training, endurance training) and their exercise variables (e.g., load, duration, frequency) for an effective physical activity that optimally enhance cognitive performance are still unknown. There is growing evidence that resistance training induces substantial brain changes which contribute to improved cognitive functions. A relative new method in the field of resistance training is blood flow restriction training (BFR). While resistance training with BFR is widely studied in the context of muscular performance, this training strategy also induces an activation of signaling pathways associated with neuroplasticity and cognitive functions. Based on this, it seems reasonable to hypothesize that resistance training with BFR is a promising new strategy to boost the effectiveness of resistance training interventions regarding cognitive performance. To support our hypothesis, we provide rationales of possible adaptation processes induced by resistance training with BFR. Furthermore, we outline recommendations for future studies planning to investigate the effects of resistance training with BFR on cognition. PMID- 30304792 TI - In Situ Generation of Fluorescent Copper Nanoclusters Embedded in Monolithic Eggshell Membrane: Properties and Applications. AB - Luminescent metal nanoclusters have attracted considerable research attention in recent years due to their unique properties and extensive usage in many fields. Three different synthetic routes were developed to in situ generate orange and red emitting copper nanoclusters embedded in monolithic eggshell membrane (Cu NCs@ESM) using different reducing reagents including N2H4.H2O, NH2OH.HCl and Vitamin C at room temperature for the first time. The routes are extremely facile, low-cost and versatile. The obtained Cu NCs@ESM nanocomposites exhibit excellent photostability and chemical stability, laying the foundation for various practical applications. Fluorescent surface patterning was demonstrated based on the proposed strategy easily. Significantly, the Cu NCs@ESM shows selective fluorescence quenching response to Hg2+ ions and good catalytic activity for methylene blue (MB) reduction degradation making it ideal as portable sensing strip and recyclable catalyst. The work provides a general strategy for the fabrication of other various monolithic nanomaterials with potential applications. PMID- 30304791 TI - Improved Application of Carbon Nanotube Atomic Force Microscopy Probes Using PeakForce Tapping Mode. AB - In this work PeakForce tapping (PFT) imaging was demonstrated with carbon nanotube atomic force microscopy (CNT-AFM) probes; this imaging mode shows great promise for providing simple, stable imaging with CNT-AFM probes, which can be difficult to apply. The PFT mode is used with CNT-AFM probes to demonstrate high resolution imaging on samples with features in the nanometre range, including a Nioprobe calibration sample and gold nanoparticles on silicon, in order to demonstrate the modes imaging effectiveness, and to also aid in determining the diameter of very thin CNT-AFM probes. In addition to stable operation, the PFT mode is shown to eliminate "ringing" artefacts that often affect CNT-AFM probes in tapping mode near steep vertical step edges. This will allow for the characterization of high aspect ratio structures using CNT-AFM probes, an exercise which has previously been challenging with the standard tapping mode. PMID- 30304793 TI - Exposure to Adverse Social Behavior in the Workplace and Sickness Presenteeism among Korean Workers: The Mediating Effects of Musculoskeletal Disorders. AB - Adverse social behavior (ASB) by colleagues or superiors in the workplace is considered highly stressful for workers in South Korea. The authors investigate the mechanism by which ASB reduces productivity (measured in terms of sickness presenteeism (SP)), by examining the potential mediating role of musculoskeletal disorders (MSDs). All data are derived from the fourth Korean Working Conditions Survey, which investigated a representative sample of the working population. The authors analyze their general characteristics (age, gender, income, and education), work-related factors (job type, occupational ergonomic risk, job resource, employment contract, work schedule, working hour, and job demand), and health-related factors (self-rated health and MSDs). The authors use a two-step regression analysis to estimate the direct effect of ASB on SP and the indirect effect of SP via MSDs. The authors find that MSDs mediate 16.7% of the total effect of ASB on SP. When employment type and job conditions are considered, the role of the mediating variable in the group with a permanent contract, no shift or night work, and high working time is greater than the counterpart of each variable. Various strategies are needed to address MSDs according to the working environment, which might help limit the negative impact of ASB on SP. PMID- 30304794 TI - Horizontal Plasmonic Ruler Based on the Scattering Far-Field Pattern. AB - A novel method is proposed to detect the horizontal shift of a specific nanoblock relative to a reference nanoblock using surface plasmon modes at nanometer resolution. To accomplish this task, two orthogonal localized surface plasmon resonances were excited within the air gap region between the silver nanoblocks at the respective wavelengths, 890 nm, and 1100 nm. This technique utilized the scattering far-field intensities of the two block nanostructures at the two specific wavelengths at two specific directional spots. The ratio of the scattering intensities at the two spots changed according to the horizontal shift of the block that moved. Correspondingly, this ratio can be used to provide the precise location of the block. This method can be applied to many fields, including label-free bio-sensing, bio-analysis and alignment during nano fabrication, owing to the high resolution and simplicity of the process. PMID- 30304795 TI - 66Ga: A Novelty or a Valuable Preclinical Screening Tool for the Design of Targeted Radiopharmaceuticals? AB - Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, 66Ga (t1/2 = 9.5 h, beta+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of 66Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. 66Ga was produced by irradiation of a natZn target. 66Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 +/- 2.8% recovery of 66Ga3+. Three ligands were radiolabeled in 46.4 +/- 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 +/- 380 MBq/umol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by uPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [68Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of 66Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h. PMID- 30304796 TI - Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings. AB - Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons-Smith reaction was followed to build up further three membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry. PMID- 30304797 TI - Safe Synthesis of 4,7-Dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine and Its SNAr Reactions. AB - A safe and efficient synthesis of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine from the commercial diaminomaleonitrile is reported. Conditions for selective aromatic nucleophilic substitution of one or two bromine atoms by oxygen and nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Buchwald-Hartwig or Ullmann techniques are successful for incorporation of a weak nitrogen base, such as carbazole, into the [1,2,5]thiadiazolo[3,4-d]pyridazine core. The formation of rather stable S...eta2-(N=N) bound chains in 4,7 bis(alkylthio)-[1,2,5]thiadiazolo[3,4-d]pyridines makes these compounds promising for the design of liquid crystals. PMID- 30304798 TI - Preparation of Parabolic Superhydrophobic Material for Oil-Water Separation. AB - In order to prepare parabolic superhydrophobic materials, copper meshes were used as the substrate and ultrasonic etching and oxidative corrosion were carried out with FeCl3 solution and H2O2 solution, respectively, and then the surface was modified with stearic acid (SA). The topological structure and surface wettability of the prepared mesh were characterized by fluorescence microscope, scanning electron microscopy and contact angle measurement. Finally, the as prepared copper meshes were applied to oil-water separation. The results showed that the micro-nano-mastoid structure on the surface of the copper mesh was flaky bulges, forming a rough structure similar to a paraboloid. When the oxidative corrosion time of H2O2 was 1 min, it is more beneficial to increase the hydrophobicity of the surface of the copper mesh and increase the contact angle of water droplets on the surface of the membrane. Additionally, based on superhydrophobic materials of the parabolic copper mesh, the static contact angles of the water droplets, engine oil and carbon tetrachloride with the surface were approximately 153.6 degrees , 5 degrees and 0.1 degrees , respectively and the sliding angle of the water droplets with the surface were approximately 4.9 degrees . The parabolic membrane was applied to discuss the separation efficiency of different oils with deionized water and the separation efficiency was obtained as benzene > carbon tetrachloride > oil > machine oil. Therefore, based on the research, the parabolic superhydrophobic material has good efficiency of oil-water separation. PMID- 30304799 TI - Extension of the Advanced REACH Tool (ART) to Include Welding Fume Exposure. AB - The Advanced REACH Tool (ART) is a mechanistic higher tier model to estimate inhalation exposure to chemicals using a Bayesian approach. Currently the ART model does not include exposure to welding fumes within its applicability domain; it has only been calibrated for vapours, mists, and dusts. To extend the scope to metal fumes it is necessary to review the model structure to ensure that it is appropriate, and to calibrate the updated model using available welding fume exposure measurements. This paper provides a discussion of the key modifying factors (MFs) that should be considered to extend the ART model to include welding fume exposure. Based on our literature review, welding process type, input power level, shield gas, and welding electrodes have important impact on fume formation rates (FFRs). In addition, the convective dispersion of the fume away from the weld and the interaction of the welder with the fume plume should be incorporated into the ART model. Other aspects of the ART, such as the local ventilation, do not require modification to accommodate welding fume exposure. The ART does not include the impact of wearing personal protective equipment and so this is not included in our evaluation. Proposals are made for extending the scope of the ART to include welding processes. PMID- 30304800 TI - Exploring the Remote Ties between Helitron Transposases and Other Rolling-Circle Replication Proteins. AB - Rolling-circle replication (RCR) elements constitute a diverse group that includes viruses, plasmids, and transposons, present in hosts from all domains of life. Eukaryotic RCR transposons, also known as Helitrons, are found in species from all eukaryotic kingdoms, sometimes representing a large portion of their genomes. Despite the impact of Helitrons on their hosts, knowledge about their relationship with other RCR elements is still elusive. Here, we compared the endonuclease domain sequence of Helitron transposases with the corresponding region from RCR proteins found in a wide variety of mobile genetic elements. To do that, we used a stepwise alignment approach followed by phylogenetic and multidimensional scaling analyses. Although it has been suggested that Helitrons might have originated from prokaryotic transposons or eukaryotic viruses, our results indicate that Helitron transposases share more similarities with proteins from prokaryotic viruses and plasmids instead. We also provide evidence for the division of RCR endonucleases into three groups (Y1, Y2, and Yx), covering the whole diversity of this protein family. Together, these results point to prokaryotic elements as the likely closest ancestors of eukaryotic RCR transposons, and further demonstrate the fluidity that characterizes the boundaries separating viruses, plasmids, and transposons. PMID- 30304801 TI - Fractionation of Glycomacropeptide from Whey Using Positively Charged Ultrafiltration Membranes. AB - Fractionation of the bovine glycomacropeptide (GMP) from the other proteins in cheese whey was examined using ultrafiltration membranes surface modified to contain positively charged polymer brushes made of polyhexamethylene biguanide. By placing a strong positive charge on a 1000 kDa ultrafiltration membrane and adjusting the pH of whey close to the isoelectric point of GMP, a 14-fold increase in selectivity was observed compared to unmodified membranes. A one stage membrane system gave 90% pure GMP and a three-stage rectification system gave 97% pure GMP. The charged membrane was salt-tolerant up to 40 mS cm-1 conductivity, allowing fractionation of GMP directly from cheese whey without first lowering the whey conductivity by water dilution. Thus, similarly sized proteins that differed somewhat in isoelectric points and were 50-100 fold smaller than the membrane molecular weight cut-off (MWCO), were cleanly fractionated using charged ultrafiltration membranes without water addition. This is the first study to report on the use of salt-tolerant charged ultrafiltration membranes to produce chromatographically pure protein fractions from whey, making ultrafiltration an attractive alternative to chromatography for dairy protein fractionation. PMID- 30304803 TI - New Fe2O3-Clay@C Nanocomposite Anodes for Li-Ion Batteries Obtained by Facile Hydrothermal Processes. AB - New iron-oxide-based anodes are prepared by an environmentally-friendly and low cost route. The analysis of the composition, structure, and microstructure of the samples reveals the presence of a major hematite phase, which is accompanied by a certain concentration of an oxyhydroxide phase, which can act as a "lithium reservoir". By using sodium alginate as a binder, the synthesized anodes display superior electrochemical response, i.e., high specific capacity values and high stability, not only versus Li but also versus a high voltage cathode in a full cell. From these bare materials, clay-supported anodes are further obtained using sepiolite and bentonite natural silicates. The electrochemical performance of such composites is improved, especially for the sepiolite-containing one treated at 400 degrees C. The thermal treatment at this temperature provides the optimal conditions for a synergic nano-architecture to develop between the clay and the hematite nanoparticles. High capacity values of ~2500 mA h g-1 after 30 cycles at 1 A g-1 and retentions close to 92% are obtained. Moreover, after 450 cycles at 2 A g-1 current rate, this composite electrode displays values as high as ~700 mA h g-1. These results are interpreted taking into account the interactions between the iron oxide nanoparticles and the sepiolite surface through hydrogen bonds. The electrochemical performance is not only dependent on the oxidation state and particle morphology, but the composition is revealed as a key feature. PMID- 30304804 TI - A Novel Method for the Micro-Clearance Measurement of a Precision Spherical Joint Based on a Spherical Differential Capacitive Sensor. AB - A spherical joint is a commonly used mechanical hinge with the advantages of compact structure and good flexibility, and it becomes a key component in many types of equipment, such as parallel mechanisms, industrial robots, and automobiles. Real-time detection of a precision spherical joint clearance is of great significance in analyzing the motion errors of mechanical systems and improving the transmission accuracy. This paper presents a novel method for the micro-clearance measurement with a spherical differential capacitive sensor (SDCS). First, the structure and layout of the spherical capacitive plates were designed according to the measuring principle of capacitive sensors with spacing variation. Then, the mathematical model for the spatial eccentric displacements of the ball and the differential capacitance was established. In addition, equipotential guard rings were used to attenuate the fringe effect on the measurement accuracy. Finally, a simulation with Ansoft Maxwell software was carried out to calculate the capacitance values of the spherical capacitors at different eccentric displacements. Simulation results indicated that the proposed method based on SDCS was feasible and effective for the micro-clearance measurement of the precision spherical joints with small eccentricity. PMID- 30304802 TI - The CHA2DS2-VASc Score Predicts Major Bleeding in Non-Valvular Atrial Fibrillation Patients Who Take Oral Anticoagulants. AB - BACKGROUND: Patients with atrial fibrillation (AF) are at a substantial risk of ischemic stroke. The CHA2DS2-VASc score predicts the risk of thromboembolism, but its role in predicting major bleeding in patients taking oral anticoagulants is unclear. METHODS: We used the National Health Insurance Research Database (NHIRD) of Taiwan to identify patients with AF from 2010 to 2016. They were divided into four groups according to the oral anticoagulants. The outcomes were ischemic stroke/systemic thromboembolism, and major bleeding. RESULTS: A total of 279,776 patients were identified. Ischemic stroke or systemic embolism events were observed in 1.73%, 3.62%, 4.36%, and 5.02% of the patients in the apixaban, rivaroxaban, dabigatran, and warfarin groups, respectively. Major bleeding was recorded in 1.18%, 2.66%, 3.23%, and 4.70% of the patients in the apixaban, rivaroxaban, dabigatran, and warfarin groups, respectively. The highest rates for both ischemic stroke and bleeding events occurred in the patients with a CHA2DS2 VASc score of five or more. CONCLUSION: Non-valvular AF patients with high CHA2DS2-VASc scores are susceptible to both systemic thromboembolism and major bleeding. The trend was consistently observed in patients who took non-vitamin K oral anticoagulants (NOACs) or warfarin. NOACs might be potentially more effective in reducing overall events. PMID- 30304805 TI - Strain-Dependent Consequences of Zika Virus Infection and Differential Impact on Neural Development. AB - Maternal infection with Zika virus (ZIKV) during pregnancy can result in neonatal abnormalities, including neurological dysfunction and microcephaly. Experimental models of congenital Zika syndrome identified neural progenitor cells as a target of viral infection. Neural progenitor cells are responsible for populating the developing central nervous system with neurons and glia. Neural progenitor dysfunction can lead to severe birth defects, namely, lissencephaly, microcephaly, and cognitive deficits. For this study, the consequences of ZIKV infection in human pluripotent stem cell-derived neural progenitor (hNP) cells and neurons were evaluated. ZIKV isolates from Asian and African lineages displayed lineage-specific replication kinetics, cytopathic effects, and impacts on hNP function and neuronal differentiation. The currently circulating ZIKV isolates exhibit a unique profile of virulence, cytopathic effect, and impaired cellular functions that likely contribute to the pathological mechanism of congenital Zika syndrome. The authors found that infection with Asian-lineage ZIKV isolates impaired the proliferation and migration of hNP cells, and neuron maturation. In contrast, the African-lineage infections resulted in abrupt and extensive cell death. This work furthers the understanding of ZIKV-induced brain pathology. PMID- 30304807 TI - Alignment of Supermarket Own Brand Foods' Front-of-Pack Nutrition Labelling with Measures of Nutritional Quality: An Australian Perspective. AB - Two voluntary front-of-pack nutrition labels (FOPNL) are present in Australia: the government-led Health Star Ratings (HSR) and food industry-led Daily Intake Guide (DIG). Australia's two largest supermarkets are key supporters of HSR, pledging uptake on all supermarket own brand foods (SOBF). This study aimed to examine prevalence of FOPNL on SOBF, and alignment with patterns of nutritional quality. Photographic audits of all SOBF present in three large supermarkets were conducted in Perth, Western Australia, in 2017. Foods were classified as nutritious or nutrient-poor based on the Australian Guide to Healthy Eating (AGTHE), NOVA level of food processing, and HSR score. Most (81.5%) SOBF featured FOPNL, with only 55.1% displaying HSR. HSR was present on 69.2% of Coles, 54.0% of Woolworths, and none of IGA SOBF. Half (51.3%) of SOBF were classified as nutritious using the AGTHE, but using NOVA, 56.9% were ultra-processed foods. Nutrient-poor and ultra-processed SOBF were more likely than nutritious foods to include HSR, yet many of these foods achieved HSR scores of 2.5 stars or above, implying they were a healthy choice. Supermarkets have a powerful position in the Australian food system, and they could do more to support healthy food selection through responsible FOPNL. PMID- 30304808 TI - Chemical Constituents from Scindapsus officinalis (Roxb.) Schott. and Their Anti Inflammatory Activities. AB - One new monoterpene glycoside (1), one new phenyl glycoside (2), one new caffeoyl derivative (3), were isolated from Scindapsus officinalis (Roxb.) Schott., along with four known compounds (4-7). Structures of the isolated compounds were elucidated by extensive analysis of spectroscopic data, especially 2D NMR data and comparison with literatures. All isolates were evaluated for anti inflammatory activity against nitric oxide (NO) production in vitro. Compounds 3 and 7 exhibited moderate inhibitory effects on NO production with IC50 values of 12.2 +/- 0.8 and 18.9 +/- 0.3 MUM, respectively. PMID- 30304806 TI - Controversial Impact of Sirtuins in Chronic Non-Transmissible Diseases and Rehabilitation Medicine. AB - A large body of evidence reports about the positive effects of physical activity in pathophysiological conditions associated with aging. Physical exercise, alone or in combination with other medical therapies, unquestionably causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting outcome however, remain largely obscure. Epigenetics, exploring at the interface between environmental signals and the remodeling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of sirtuins (Sirts) a class III histone deacetylases (HDACs), which function has been frequently associated, often with a controversial role, to the pathogenesis of aging-associated pathophysiological conditions, including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking mitochondrial function, DNA structure remodeling and gene expression regulation to designed medical therapies leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. In spite of this controversial effect, it is doubtless that studying sirtuins in chronic diseases might lead to an unprecedented improvement of life quality in the elderly. PMID- 30304809 TI - The Role of Rayleigh-Wood Anomalies and Surface Plasmons in Optical Enhancement for Nano-Gratings. AB - We propose and report on the design of a 1-D metallo-dielectric nano-grating on a GaAs substrate. We numerically study the impact of grating period, slit and wire widths, and irradiating angle of incidence on the optical response. The optimal wire width, w = 160 nm, was chosen based on previous results from investigations into the influence of wire width and nano-slit dimensions on optical and electrical enhancements in metal-semiconductor-metal photodetectors. In this present project, resonant absorption and reflection modes were observed while varying the wire and nano-slit widths to study the unique optical modes generated by Rayleigh-Wood anomalies and surface plasmon polaritons. We observed sharp and diffuse changes in optical response to these anomalies, which may potentially be useful in applications such as photo-sensing and photodetectors. Additionally, we found that varying the slit width produced sharper, more intense anomalies in the optical spectrum than varying the wire width. PMID- 30304810 TI - GSK461364A, a Polo-Like Kinase-1 Inhibitor Encapsulated in Polymeric Nanoparticles for the Treatment of Glioblastoma Multiforme (GBM). AB - Glioblastoma Multiforme (GBM) is a common primary brain cancer with a poor prognosis and a median survival of less than 14 months. Current modes of treatment are associated with deleterious side effects that reduce the life span of the patients. Nanomedicine enables site-specific delivery of active pharmaceutical ingredients and facilitates entrapment inside the tumor. Polo-like kinase 1 (PLK-1) inhibitors have shown promising results in tumor cells. GSK461364A (GSK) is one such targeted inhibitor with reported toxicity issues in phase 1 clinical trials. We have demonstrated in our study that the action of GSK is time dependent across all concentrations. There is a distinct 15-20% decrease in cell viability via apoptosis in U87-MG cells dosed with GSK at low concentrations (within the nanomolar and lower micromolar range) compared to higher concentrations of the drug. Additionally, we have confirmed that PLGA-PEG nanoparticles (NPs) containing GSK have shown significant reduction in cell viability of tumor cells compared to their free equivalents. Thus, this polymeric nanoconstruct encapsulating GSK can be effective even at low concentrations and could improve the effectiveness of the drug while reducing side effects at the lower effective dose. This is the first study to report a PLK-1 inhibitor (GSK) encapsulated in a nanocarrier for cancer applications. PMID- 30304811 TI - Cytotoxicity and Toxicity Evaluation of Xanthone Crude Extract on Hypoxic Human Hepatocellular Carcinoma and Zebrafish (Danio rerio) Embryos. AB - Xanthone is an organic compound mostly found in mangosteen pericarp and widely known for its anti-proliferating effect on cancer cells. In this study, we evaluated the effects of xanthone crude extract (XCE) and alpha-mangostin (alpha MG) on normoxic and hypoxic human hepatocellular carcinoma (HepG2) cells and their toxicity towards zebrafish embryos. XCE was isolated using a mixture of acetone and water (80:20) and verified via high performance liquid chromatography (HPLC). Both XCE and alpha-MG showed higher anti-proliferation effects on normoxic HepG2 cells compared to the control drug, 5-fluorouracil (IC50 = 50.23 +/- 1.38, 8.39 +/- 0.14, and 143.75 +/- 15.31 MUg/mL, respectively). In hypoxic conditions, HepG2 cells were two times less sensitive towards XCE compared to normoxic HepG2 cells (IC50 = 109.38 +/- 1.80 MUg/mL) and three times less sensitive when treated with >500 MUg/mL 5-fluorouracil (5-FU). A similar trend was seen with the alpha-MG treatment on hypoxic HepG2 cells (IC50 = 10.11 +/- 0.05 MUg/mL) compared to normoxic HepG2 cells. However, at a concentration of 12.5 MUg/mL, the alpha-MG treatment caused tail-bend deformities in surviving zebrafish embryos, while no malformation was observed when embryos were exposed to XCE and 5-FU treatments. Our study suggests that both XCE and alpha-MG are capable of inhibiting HepG2 cell proliferation during normoxic and hypoxic conditions, more effectively than 5-FU. However, XCE is the preferred option as no malformation was observed in surviving zebrafish embryos and it is more cost efficient than alpha-MG. PMID- 30304812 TI - The Effect of Training in the Preparatory and Competitive Periods on Trunk Rotational Power in Canoeists, Ice-Hockey Players, and Tennis Players. AB - This study evaluates changes in trunk rotational power at different weights and velocities after the preparatory and competitive periods in ice-hockey players, tennis players, and canoeists. The subjects performed trunk rotations to each side with a barbell of different weights placed on the shoulders (6, 10, 12, 16, 20, 22, and 26 kg) prior to and after 6 weeks of the preparatory period and 6 weeks of the competitive period. The results showed that mean power produced in the acceleration phase of trunk rotations increased significantly at weights from 10 to 26 kg or 6 to 26 kg after the preparatory and competitive periods in tennis players. The values obtained during trunk rotations with weights >=12 kg also increased significantly after the preparatory period in ice-hockey players, whereas there were no significant changes after the competitive period. Similarly, the mean power during trunk rotations with weights >=10 kg increased significantly only after the preparatory period in canoeists. Similar changes were observed for the peak power. These findings demonstrate that changes in trunk rotational power reflect the specificity of their training programs. This information may provide a basis for designing exercises focused on improvements of power produced during trunk rotations under loading conditions. PMID- 30304814 TI - The Pertinence of Microwave Irradiated Coconut Shell Bio-Sorbent for Wastewater Decolourization: Structural Morphology and Adsorption Optimization Using the Response Surface Method (RSM). AB - Palm oil mill effluent contains carcinogenic coloured compounds that are difficult to separate due to their aromatic structure. Though colour treatment using adsorption processes at lower pH (<4) have been reported effectual, due to its acidity the remediated effluent poses an environmental hazard as a result. Thus, the current study focused on achieving decolourization at neutral pH by enhancing the morphology of the coconut shell activated carbon (CSAC) using N2 as activating-agent with microwave irradiation heating. The microwave pretreated and non-pretreated CSAC were characterized using scanned electron microscopy (SEM), energy dispersive X-ray (EDX) and Brunauer-Emmett-Teller (BET) analysis. A significant modification in the porous structure with a 66.62% increase in the specific surface area was achieved after the pretreatment. The adsorption experimental matrix was developed using the central composite design to investigate the colour adsorption performance under varied pH (6-7), dosage (2-6 g) and contact time (10-100 min). At optimum conditions of neutral pH (7), 3.208 g dosage and contact time of 35 min, the percentage of colour removal was 96.29% with negligible differences compared with the predicted value, 95.855%. The adsorption equilibrium capacity of 1430.1 ADMI * mL/g was attained at the initial colour concentration of 2025 ADMI at 27 degrees C. The experimental data fitted better with the Freundlich isotherm model with R2 0.9851. PMID- 30304815 TI - Glycosylation of Methoxylated Flavonoids in the Cultures of Isaria fumosorosea KCH J2. AB - Flavonoids are widely described plant secondary metabolites with high and diverse pro-health properties. In nature, they occur mostly in the form of glycosides. Our research showed that an excellent way to obtain the sugar derivatives of flavonoids is through biotransformations with the use of entomopathogenic filamentous fungi as biocatalysts. In the current paper, we described the biotransformations of five methoxylated flavonoid compounds (2'-methoxyflavanone, 3'-methoxyflavanone, 4'-methoxyflavanone, 6-methoxyflavanone, and 6 methoxyflavone) in cultures of Isaria fumosorosea KCH J2. As a result, we obtained twelve new flavonoid 4-O-methylglucopyranosides. The products were purified with methods that enabled the reduction of the consumption of organic solvents (preparative TLC and flash chromatography). The structures of the products were confirmed with spectroscopic methods (NMR: 1H, 13C, HSQC, HMBC, COSY). The compounds obtained by us expand the library of available flavonoid derivatives and can be used in biological research. PMID- 30304816 TI - Risk Management of Hazardous Materials in Manufacturing Processes: Links and Transitional Spaces between Occupational Accidents and Major Accidents. AB - Manufacturing processes involving chemical agents are evolving at great speed. In this context, managing chemical risk is especially important towards preventing both occupational accidents and major accidents. Directive 89/391/EEC and Directive 2012/18/EU, respectively, are enforced in the European Union (EU) to this end. These directives may be further complemented by the recent ISO 45001:2018 standard regarding occupational health and safety management systems. These three management systems are closely related. However, scientific literature tackles the researching of these accidents independently. Thus, the main objective of this work is to identify and analyse the links and transitional spaces between the risk management of both types of accident. Among the results obtained, three transitional spaces can be pointed out which result from the intersection of the three systems mentioned. Similarly, the intersection of these spaces gives shape to a specific transitional space defined by the individual directives linked to Directive 89/391/EEC. These results are limited from a regulatory and technical perspective. Thus, the results are a starting point towards developing models that integrate the management systems studied. PMID- 30304817 TI - Multivariate-Time-Series-Driven Real-time Anomaly Detection Based on Bayesian Network. AB - Anomaly detection is an important research direction, which takes the real-time information system from different sensors and conditional information sources into consideration. Based on this, we can detect possible anomalies expected of the devices and components. One of the challenges is anomaly detection in multivariate-sensing time-series in this paper. Based on this situation, we propose RADM, a real-time anomaly detection algorithm based on Hierarchical Temporal Memory (HTM) and Bayesian Network (BN). First of all, we use HTM model to evaluate the real-time anomalies of each univariate-sensing time-series. Secondly, a model of anomalous state detection in multivariate-sensing time series based on Naive Bayesian is designed to analyze the validity of the above time-series. Lastly, considering the real-time monitoring cases of the system states of terminal nodes in Cloud Platform, the effectiveness of the methodology is demonstrated using a simulated example. Extensive simulation results show that using RADM in multivariate-sensing time-series is able to detect more abnormal, and thus can remarkably improve the performance of real-time anomaly detection. PMID- 30304813 TI - Selenium Analysis and Speciation in Dietary Supplements Based on Next-Generation Selenium Ingredients. AB - Selenium is essential for humans and the deficit of Se requires supplementation. In addition to traditional forms such as Se salts, amino acids, or selenium enriched yeast supplements, next-generation selenium supplements, with lower risk for excess supplementation, are emerging. These are based on selenium forms with lower toxicity, higher bioavailability, and controlled release, such as zerovalent selenium nanoparticles (SeNPs) and selenized polysaccharides (SPs). This article aims to focus on the existing analytical systems for the next generation Se dietary supplement, providing, at the same time, an overview of the analytical methods available for the traditional forms. The next-generation dietary supplements are evaluated in comparison with the conventional/traditional ones, as well as the analysis and speciation methods that are suitable to reveal which Se forms and species are present in a dietary supplement. Knowledge gaps and further research potential in this field are highlighted. The review indicates that the methods of analysis of next-generation selenium supplements should include a step related to chemical species separation. Such a step would allow a proper characterization of the selenium forms/species, including molecular mass/dimension, and substantiates the marketing claims related to the main advantages of these new selenium ingredients. PMID- 30304818 TI - Genetic Characterization and Pathogenicity of a Novel Recombined Porcine Reproductive and Respiratory Syndrome Virus 2 among Nadc30-Like, Jxa1-Like, and Mlv-Like Strains. AB - Recombination among porcine reproductive and respiratory syndrome viruses (PRRSVs), coupled with point mutations, insertions, and deletions occurring in the genome, is considered to contribute to the emergence of new variants. Here, we report the complete genome sequences of a PRRSV field strain, designated SCN17, isolated from a RespPRRS MLV-vaccinated piglet in China in 2017. Sequence alignment revealed that SCN17 had discontinuous 131-amino acid (111 + 1 + 19-aa) deletion in the NSP2-coding region identical to that of NADC30 when compared to VR-2332. Notably, the strain, SCN17, contained an additional 1-aa deletion in NSP2, a 1-aa deletion in ORF5, and a unique 3-nt deletion in the 3'-UTR. Phylogenetic analysis showed that SCN17 clustered into NADC30-like lineage based on ORF5 genotyping, whereas it belonged to an inter-lineage between the NADC30 like and VR-2332-like lineages as established based on the full-length genome. Importantly, the SCN17 was identified as a novel virus recombined between a NADC30-like (moderately pathogenic), a JXA1-like (highly pathogenic), and an attenuated vaccine strain, RespPRRS MLV (parental strain VR-2332). Furthermore, we tested its pathogenicity in piglets. SCN17 infection caused a persistent fever, moderate interstitial pneumonia, and increased the viremia and antibody levels in the inoculated piglets. Of note, all SCN17-infected piglets survived throughout the study. The new virus was showed to be a moderately virulent isolate and have lower pathogenicity than HP-PRRSV strain, SCwhn09CD. Our results provide evidence for the continuing evolution of PRRSV field strain by genetic recombination and mutation leading to outbreaks in the vaccinated pig populations in China. PMID- 30304820 TI - An Electrochemical Cholesterol Biosensor Based on A CdTe/CdSe/ZnSe Quantum Dots Poly (Propylene Imine) Dendrimer Nanocomposite Immobilisation Layer. AB - We report the preparation of poly (propylene imine) dendrimer (PPI) and CdTe/CdSe/ZnSe quantum dots (QDs) as a suitable platform for the development of an enzyme-based electrochemical cholesterol biosensor with enhanced analytical performance. The mercaptopropionic acid (MPA)-capped CdTe/CdSe/ZnSe QDs was synthesized in an aqueous phase and characterized using photoluminescence (PL) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, transmission electron microscopy (TEM), X-ray power diffraction (XRD), energy dispersive X-ray (EDX) spectroscopy. The absorption and emission maxima of the QDs red shifted as the reaction time and shell growth increased, indicating the formation of CdTe/CdSe/ZnSe QDs. PPI was electrodeposited on a glassy carbon electrode followed by the deposition (by deep coating) attachment of the QDs onto the PPI dendrimer modified electrode using 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), and N-hydroxysuccinimide (NHS) as a coupling agent. The biosensor was prepared by incubating the PPI/QDs modified electrode into a solution of cholesterol oxidase (ChOx) for 6 h. The modified electrodes were characterized by voltammetry and impedance spectroscopy. Since efficient electron transfer process between the enzyme cholesterol oxidase (ChOx) and the PPI/QDs modified electrode was achieved, the cholesterol biosensor (GCE/PPI/QDs/ChOx) was able to detect cholesterol in the range 0.1-10 mM with a detection limit (LOD) of 0.075 mM and sensitivity of 111.16 MUA mM-1 cm-2. The biosensor was stable for over a month and had greater selectivity towards the cholesterol molecule. PMID- 30304821 TI - Quercetagetin and Patuletin: Antiproliferative, Necrotic and Apoptotic Activity in Tumor Cell Lines. AB - Quercetagetin and patuletin were extracted by the same method from two different Tagetes species that have multiple uses in folk medicine in Mexico and around the globe, one of which is as an anticancer agent. Their biological activity (IC50 and necrotic, apoptotic and selective activities of these flavonols) was evaluated and compared to that of quercetin, examining specifically the effects of C6 substitution among quercetin, quercetagetin and patuletin. We find that the presence of a methoxyl group in C6 enhances their potency. PMID- 30304819 TI - Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases. AB - The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer's disease, Parkinson's disease, and prion diseases. It is believed that misfolded and abnormal beta-sheets forms of wild type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrPC) is a glycosyl phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc, the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlights the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer's disease and Tauopathy, as well as other neurodegenerative disorders. Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER (Endoplasmic Reticulum) quality control of GPI-anchored proteins and describe the "prion-like" properties of amyloid-beta and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interaction with protein and lipid membrane components and their implications in both prion and Alzheimer's diseases. PMID- 30304822 TI - Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development. AB - Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disorder that affects synovial joints, both small and large joints, in a symmetric pattern. This disorder usually does not directly cause death but significantly reduces the quality of life and life expectancy of patients if left untreated. There is no cure for RA but, patients are usually on long-term disease modifying anti-rheumatic drugs (DMARDs) to suppress the joint inflammation, to minimize joint damage, to preserve joint function, and to keep the disease in remission. RA is strongly associated with various immune cells and each of the cell type contributes differently to the disease pathogenesis. Several types of immunomodulatory molecules mainly cytokines secreted from immune cells mediate pathogenesis of RA, hence complicating the disease treatment and management. There are various treatments for RA depending on the severity of the disease and more importantly, the patient's response towards the given drugs. Early diagnosis of RA and treatment with (DMARDs) are known to significantly improve the treatment outcome of patients. Sensitive biomarkers are crucial in early detection of disease as well as to monitor the disease activity and progress. This review aims to discuss the pathogenic role of various immune cells and immunological molecules in RA. This review also highlights the importance of understanding the immune cells in treating RA and in exploring novel biomarkers. PMID- 30304823 TI - Surface Modification of Magnetic Iron Oxide Nanoparticles. AB - Functionalized iron oxide nanoparticles (IONPs) are of great interest due to wide range applications, especially in nanomedicine. However, they face challenges preventing their further applications such as rapid agglomeration, oxidation, etc. Appropriate surface modification of IONPs can conquer these barriers with improved physicochemical properties. This review summarizes recent advances in the surface modification of IONPs with small organic molecules, polymers and inorganic materials. The preparation methods, mechanisms and applications of surface-modified IONPs with different materials are discussed. Finally, the technical barriers of IONPs and their limitations in practical applications are pointed out, and the development trends and prospects are discussed. PMID- 30304825 TI - Chitosan-Based In Situ Gels for Ocular Delivery of Therapeutics: A State-of-the Art Review. AB - Ocular in situ gels are a promising alternative to overcome drawbacks of conventional eye drops because they associate the advantages of solutions such as accuracy and reproducibility of dosing, or ease of administration with prolonged contact time of ointments. Chitosan is a natural polymer suitable for use in ophthalmic formulations due to its biocompatibility, biodegradability, mucoadhesive character, antibacterial and antifungal properties, permeation enhancement and corneal wound healing effects. The combination of chitosan, pH sensitive polymer, with other stimuli-responsive polymers leads to increased mechanical strength of formulations and an improved therapeutic effect due to prolonged ocular contact time. This review describes in situ gelling systems resulting from the association of chitosan with various stimuli-responsive polymers with emphasis on the mechanism of gel formation and application in ophthalmology. It also comprises the main techniques for evaluation of chitosan in situ gels, along with requirements of safety and ocular tolerability. PMID- 30304826 TI - Comprehensive Analysis of MicroRNA-Messenger RNA from White Yak Testis Reveals the Differentially Expressed Molecules Involved in Development and Reproduction. AB - Testis development is a vital and tightly regulated process in mammals. Understanding the biological mechanisms underlying testis development will benefit the animal reproduction industry. Expression changes in microRNA and messenger RNA in response to dynamic regulation effects have been associated with this process. However, very little is known about the roles of these molecules in yak development. Using whole-genome small RNA and messenger RNA sequencing, we performed a comprehensive analysis of the microRNA-messenger RNA interaction network expression in the testicles of Tianzhu white yaks during three developmental stages. Using Short Time-series Expression Miner analysis we identified 589 differentially expressed microRNAs (DERs) and 3383 differentially expressed messenger RNAs (DEGs) in the three age groups. A total of 93 unique DEGs are primarily involved in reproduction and testis development. Subsequently, four integration networks were constructed according to the DEGs and DERs in three biological processes. Nineteen DEGs were potentially regulated by 60 DERs, of which miR-574 and target gene AURKA played a crucial role in yak testis development and reproduction. The results of this study provide a basis for further exploration of the microRNA-messenger RNA interactions in testis development and reproduction and aid in uncovering the molecular mechanisms of spermatogenesis in male mammals. PMID- 30304824 TI - Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases. AB - Neuronal cell death in the central nervous system has always been a challenging process to decipher. In normal physiological conditions, neuronal cell death is restricted in the adult brain, even in aged individuals. However, in the pathological conditions of various neurodegenerative diseases, cell death and shrinkage in a specific region of the brain represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe evidence for cell death in the context of individual common neurodegenerative diseases, discussing our current understanding of cell death by connecting with renowned pathogenic proteins, including Tau, amyloid-beta, alpha-synuclein, huntingtin and TDP-43. PMID- 30304828 TI - Ultrasensitive Electrochemical Sensor Based on Polyelectrolyte Composite Film Decorated Glassy Carbon Electrode for Detection of Nitrite in Curing Food at Sub Micromolar Level. AB - To ensure food quality and safety, developing cost-effective, rapid and precision analytical techniques for quantitative detection of nitrite is highly desirable. Herein, a novel electrochemical sensor based on the sodium cellulose sulfate/poly (dimethyl diallyl ammonium chloride) (NaCS/PDMDAAC) composite film modified glass carbon electrode (NaCS/PDMDAAC/GCE) was proposed toward the detection of nitrite at sub-micromolar level, aiming to make full use of the inherent properties of individual component (biocompatible, low cost, good electrical conductivity for PDMDAAC; non-toxic, abundant raw materials, good film forming ability for NaCS) and synergistic enhancement effect. The NaCS/PDMDAAC/GCE was fabricated by a simple drop-casting method. Electrochemical behaviors of nitrite at NaCS/PDMDAAC/GCE were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Under optimum conditions, the NaCS/PDMDAAC/GCE exhibits a wide linear response region of 4.0 * 10-8 mol.L-1~1.5 * 10-4 mol.L-1 and a low detection 1imit of 43 nmol.L-1. The NaCS/PDMDAAC shows a synergetic enhancement effect toward the oxidation of nitrite, and the sensing performance is much better than the previous reports. Moreover, the NaCS/PDMDAAC also shows good stability and reproducibility. The NaCS/PDMDAAC/GCE was successfully applied to the determination of nitrite in ham sausage with satisfactory results. PMID- 30304827 TI - Cigarette Smoke During Breastfeeding in Rats Changes Glucocorticoid and Vitamin D Status in Obese Adult Offspring. AB - Maternal smoking increases obesogenesis in the progeny. Obesity is associated with several hormonal dysfunctions. In a rat model of postnatal tobacco smoke exposure, we previously reported increased central fat depot and disruption of some hormonal systems in the adult offspring. As both glucocorticoids and vitamin D alter lipogenesis and adipogenesis, here we evaluated the metabolism of these two hormones in visceral adipose tissue (VAT) and liver by Western blotting, and possible associations with lipogenesis biomarkers in adult rats that were exposed to tobacco smoke during their suckling period. At postnatal day (PN) 3, dams and offspring of both sexes were exposed (S group) or not (C group) to tobacco smoke, 4 * 1 h/day. At PN180, corticosteronemia was lower in S male and higher in S female offspring, without alterations in peripheral glucocorticoid metabolism and receptor. Adrenal ACTH receptor (MC2R) was higher in both sexes of S group. Despite unchanged serum vitamin D, liver 25-hydroxylase was higher in both sexes of S group. Male S offspring had higher 1alpha-hydroxylase, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) in VAT. Both sexes showed increased ACC protein content and reduced sirtuin mRNA in liver. Male S offspring had lower liver peroxisome proliferator-activated receptor-alpha. Tobacco exposure during lactation induced abdominal obesity in both sexes via distinct mechanisms. Males and females seem to develop HPA-axis dysfunction instead of changes in glucocorticoid metabolism and action. Lipogenesis in VAT and liver, as well as vitamin D status, are more influenced by postnatal smoke exposure in male than in female adult rat offspring. PMID- 30304830 TI - Adaptive Compressive Sensing and Data Recovery for Periodical Monitoring Wireless Sensor Networks. AB - The development of compressive sensing (CS) technology has inspired data gathering in wireless sensor networks to move from traditional raw data gathering towards compression based gathering using data correlations. While extensive efforts have been made to improve the data gathering efficiency, little has been done for data that is gathered and recovered data with unknown and dynamic sparsity. In this work, we present an adaptive compressive sensing data gathering scheme to capture the dynamic nature of signal sparsity. By only re-sampling a few measurements, the current sparsity as well as the new sampling rate can be accurately determined, thus guaranteeing recovery performance and saving energy. In order to recover a signal with unknown sparsity, we further propose an adaptive step size variation integrated with a sparsity adaptive matching pursuit algorithm to improve the recovery performance and convergence speed. Our simulation results show that the proposed algorithm can capture the variation in the sparsities of the original signal and obtain a much longer network lifetime than traditional raw data gathering algorithms. PMID- 30304829 TI - Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells. AB - Zearalenone (ZEN), a nonsteroidal estrogen mycotoxin, is widely found in feed and foodstuffs. Intestinal cells may become the primary target of toxin attack after ingesting food containing ZEN. Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 ug/mL) or pretreated with (81, 162, and 324 ug/mL) N acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (DeltaPsim), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent. PMID- 30304832 TI - Environmental Drivers of Bacillus-Positive Blood Cultures in a Cancer Hospital, Sapporo, Japan. AB - The Bacillus species is a well-documented causative pathogen of nosocomial bloodstream infection. The present study aimed to identify climatological variables that are associated with Bacillus-positive blood culture in Sapporo, Japan. All cases with Bacillus-positive blood cultures from January 2011 to December 2016 were retrospectively analysed. Climatological data from 2011 to 2016, including daily mean temperature and absolute humidity, were retrieved from the Japan Meteorological Agency. Employing a hazard-based statistical model to describe the non-homogeneous counting process in which temperature and absolute humidity act as explanatory variables, we computed all possible models with variable lengths of time lag. Akaike Information Criterion was computed to identify the best fitted model. High wavelet power at 12 months was identified for the period from 2013 onwards, which coincided with the time period in which sampling multiple sets of blood culture has been recommended. The temperature only model with a lag of six days yielded a high sensitivity value (72.1%) and appeared to be the optimal model to predict Bacillus-positive blood culture with the highest area under the receiver operating characteristic curve value. Temperature was identified as a climatological driver of Bacillus-positive blood culture. Our statistical modelling exercise offers an important message for infection control practices to improve awareness among healthcare workers of the identified association and mechanically controlled in-room temperature. PMID- 30304831 TI - Meroterpenoid-Rich Fraction of the Ethanolic Extract from Sargassum serratifolium Suppressed Oxidative Stress Induced by Tert-Butyl Hydroperoxide in HepG2 Cells. AB - Sargassum species have been reported to be a source of phytochemicals, with a wide range of biological activities. In this study, we evaluated the hepatoprotective effect of a meroterpenoid-rich fraction of the ethanolic extract from Sargassum serratifolium (MES) against tert-butyl hydroperoxide (t-BHP) treated HepG2 cells. Treatment with MES recovered the cell viability from the t BHP-induced oxidative damage in a dose-dependent manner. It suppressed the reactive oxygen species production, lipid peroxidation, and glutathione depletion in the t-BHP-treated HepG2 cells. The activity of the antioxidants induced by t BHP, including superoxide dismutase (SOD) and catalase, was reduced by the MES treatment. Moreover, it increased the nuclear translocation of nuclear factor erythroid 2-related factor 2, leading to the enhanced activity of glutathione S transferase, and the increased production of heme oxygenase-1 and NAD(P)H:quinine oxidoreductase 1 in t-BHP-treated HepG2 cells. These results demonstrate that the antioxidant activity of MES substituted the activity of the SOD and catalase, and induced the production of detoxifying enzymes, indicating that MES might be used as a hepatoprotectant against t-BHP-induced oxidative stress. PMID- 30304833 TI - Fluorescence Studies of the Interplay between Metal-Enhanced Fluorescence and Graphene-Induced Quenching. AB - Fluorescence microscopy and spectroscopy were applied for studying the optical properties of a hybrid nanostructure, in which we combine plasmon-induced metal enhanced fluorescence with energy transfer to epitaxial graphene. Covering the layer of silver islands with a monolayer graphene, while turning on the efficient energy transfer from emitters, only moderately affects the enhancement of fluorescence attributed to the plasmon resonance in metallic nanostructures-as evidenced by the analysis of fluorescence decays. The results show that it is feasible to combine the properties of graphene with metal-enhanced fluorescence. The importance of the layer thickness of the emitters is also pointed out. PMID- 30304834 TI - Migration Energy Barriers for the Surface and Bulk of Self-Assembly ZnO Nanorods. AB - Post-annealing treatment is a necessary process to create/eliminate/repair defects in self-assembly (SA) metal oxide by providing enough thermal energy to the O atoms to overcome the migration energy barrier in ZnO. The height of migration energy barrier is dependent on the depth from the surface, which is hard to be estimated by theoretical calculations, as well as the optical analyses. SA ZnO nanorods (ZNRs) have high surface-to-volume ratio to provide complete picture between the optical and surface properties obtained by photoluminescence (PL) and ultraviolet/X-ray photoemission spectroscopy (UPS/XPS), which is used to investigate the evolution of structure and chemical states of the surface layers to reveal mutual agreement on all observations in PL, XPS, and UPS. We demonstrate variation of the surface structure of SA-ZNRs by scanning over a range of annealing temperatures and time to regulate the structure variation of SA-ZNRs, and their optical analyses agrees well with PL, XPS and UPS, which indicates the dependence of migration energy barriers on the depth from the surface of ZNR. The results reveal the well ZNRs formed at 570 degrees C and the further oxidation process and the formation of hydroperoxide on the Zn-rich surface of ZNRs at 640 degrees C. PMID- 30304835 TI - Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2. AB - The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients. PMID- 30304836 TI - Specific Targeting of Plant and Apicomplexa Parasite Tubulin through Differential Screening Using In Silico and Assay-Based Approaches. AB - Dinitroanilines are chemical compounds with high selectivity for plant cell alpha tubulin in which they promote microtubule depolymerization. They target alpha tubulin regions that have diverged over evolution and show no effect on non photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as Toxoplasma gondii and Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on Arabidopsis thaliana and mammal tubulin structural models together with cell based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards T. gondii and P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs. PMID- 30304838 TI - Application of Differential Entropy in Characterizing the Deformation Inhomogeneity and Life Prediction of Low-Cycle Fatigue of Metals. AB - The relation between deformation inhomogeneity and low-cycle-fatigue failure of T2 pure copper and the nickel-based superalloy GH4169 under symmetric tension compression cyclic strain loading is investigated by using a polycrystal representative volume element (RVE) as the material model. The anisotropic behavior of grains and the strain fields are calculated by crystal plasticity, taking the Bauschinger effect into account to track the process of strain cycles of metals, and the Shannon's differential entropies of both distributions of the strain in the loading direction and the first principal strain are employed at the tension peak of the cycles as measuring parameters of strain inhomogeneity. Both parameters are found to increase in value with increments in the number of cycles and they have critical values for predicting the material's fatigue failure. Compared to the fatigue test data, it is verified that both parameters measured by Shannon's differential entropies can be used as fatigue indicating parameters (FIPs) to predict the low cycle fatigue life of metal. PMID- 30304837 TI - New Cytokines in the Pathogenesis of Atopic Dermatitis-New Therapeutic Targets. AB - Atopic dermatitis (AD) is a recurrent, chronic, and inflammatory skin disease, which processes with severe itchiness. It often coexists with different atopic diseases. The number of people suffering from AD is relatively high. Epidemiological research demonstrates that 15-30% of children and 2-10% adults suffer from AD. The disease has significant negative social and economic impacts, substantially decreasing the quality of life of the patients and their families. Thanks to enormous progress in science and technology, it becomes possible to recognise complex genetic, immunological, and environmental factors and epidermal barrier defects that play a role in the pathogenesis of AD. We hope that the new insight on cytokines in AD will lead to new, individualised therapy and will open different therapeutic possibilities. In this article, we will focus on the cytokines, interleukin (IL)-17, IL-19, IL-33, and TSLP (thymic stromal lymphopoietin), which play a significant role in AD pathogenesis and may become the targets for future biologic therapies in AD. It is believed that the new era of biological drugs in AD will give a chance for patients to receive more successful treatment. PMID- 30304839 TI - The Use of Selective Laser Melting to Increase the Performance of AlSi9Cu3Fe Alloy. AB - For the first time, the comprehensive characterization of the additively manufactured AlSi9Cu3Fe alloy is reported in this paper. Conventionally, the AlSi9Cu3(Fe) alloy is prepared by high-pressure die casting (HPDC), but this technology largely does not offer such opportunities as additive manufacturing (AM) does, especially in the design of new lightweight parts. In the present paper, testing samples were prepared by selective laser melting (SLM), one of the AM technologies, and characterized in terms of their microstructure (by means of light microscopy, scanning electron microscopy and transmission electron microscopy in combination with analytical techniques for evaluation of chemical and phase composition) and mechanical properties (static tension, compression, and hardness). All the characteristics were compared with the HPDC reference material. Our study showed an excellent improvement both in strength (374 +/- 11 MPa compared to 257 +/- 17 MPa) and plasticity (1.9 +/- 0.2% compared to 1.2 +/- 0.5%) of the material thanks to its very fine and distinctive microstructure. PMID- 30304840 TI - Chitosan-Based Polyelectrolyte Complexes for Doxorubicin and Zoledronic Acid Combined Therapy to Overcome Multidrug Resistance. AB - This study aimed to develop nanovectors co-encapsulating doxorubicin (Doxo) and zoledronic acid (Zol) for a combined therapy against Doxo-resistant tumors. Chitosan (CHI)-based polyelectrolyte complexes (PECs) prepared by ionotropic gelation technique were proposed. The influence of some experimental parameters was evaluated in order to optimize the PECs in terms of size and polydispersity index (PI). PEC stability was studied by monitoring size and zeta potential over time. In vitro studies were carried out on wild-type and Doxo-resistant cell lines, to assess both the synergism between Doxo and Zol, as well as the restoring of Doxo sensitivity. Polymer concentration, incubation time, and use of a surfactant were found to be crucial to achieving small size and monodisperse PECs. Doxo and Zol, only when encapsulated in PECs, showed a synergistic antiproliferative effect in all the tested cell lines. Importantly, the incubation of Doxo-resistant cell lines with Doxo/Zol co-encapsulating PECs resulted in the restoration of Doxo sensitivity. PMID- 30304841 TI - You Are Not My Handler! Impact of Changing Handlers on Dogs' Behaviours and Detection Performance. AB - Dog-handler relationships can directly impact team success. Changing a dog's handler may therefore compromise detection performance. However, there are currently few studies which support this. This research explored the performance and behavioural impact of changing a dog's handler. Nine dogs trained at scent detection were accuracy tested with a familiar and unfamiliar handler. Both handlers were female with similar dog handling experience. The dogs were tested along brick lines containing target, non-target, and control samples. Testing was separated into four sessions, with each session having 36 samples. The dogs' accuracy scores were then calculated and testing footage behaviour coded. The dogs had significantly higher sensitivity (p = 0.045) and negative predictive value (NPV) (p = 0.041) scores when handled by the familiar handler. With the unfamiliar handler the dogs performed more stress-related behaviours, and were distracted for a higher proportion of time (p = 0.012). Time spent distracted was negatively correlated to detection performance (correlation = -0.923, p < 0.001). With the unfamiliar handler the dogs' performance did not improve throughout testing (p = 0.553). This research demonstrates how these dogs' detection performances were impacted by changing handlers. Future research is required to determine if professional dog-handler teams are impacted similarly. PMID- 30304842 TI - Sugar-Sweetened Beverage Consumption in Relation to Obesity and Metabolic Syndrome among Korean Adults: A Cross-Sectional Study from the 2012-2016 Korean National Health and Nutrition Examination Survey (KNHANES). AB - It is well known that the consumption of sugar-sweetened beverages (SSBs) increases the risk of developing obesity and metabolic syndrome (MetS). However, there are not many studies investigating the link between SSBs and increased incidences of diseases in the Asian population, and in particular, in Korea. We explored the association of SSB consumption with the risk of developing obesity and MetS among Korean adults (12,112 participants from the 2012-2016 Korean National Health and Nutrition Examination Survey). We calculated the total SSB consumption frequency by counting each beverage item, including soda beverages, fruit juices, and sweetened rice drinks. Obesity was defined as a body mass index >=25 kg/m2, and MetS was defined using the National Cholesterol Education Program, Adult Treatment Panel III. A survey logistic regression analyses was conducted to examine the association of SSB consumption with obesity and MetS, adjusting for related confounders such as age, energy intake, household income, education, alcohol drinking, smoking status, and physical activity. The SSB consumption was positively associated with an increased risk of the prevalence for obesity (Odd ratio (OR): 1.60; 95% confidence interval (CI): 1.23-2.09; p for trend = 0.0009) and MetS (OR: 1.61; 95% CI: 1.20-2.16; p for trend = 0.0003) among women. In men, SSB consumption only contributed to a higher prevalence of obesity (OR: 1.38; 95% CI: 1.11-1.72; p for trend = 0.0041). In conclusion, increased consumption of SSBs was closely linked with a higher prevalence of obesity and MetS in the Korean population. PMID- 30304843 TI - Toward High Throughput Core-CBCM CMOS Capacitive Sensors for Life Science Applications: A Novel Current-Mode for High Dynamic Range Circuitry. AB - This paper proposes a novel charge-based Complementary Metal Oxide Semiconductor (CMOS) capacitive sensor for life science applications. Charge-based capacitance measurement (CBCM) has significantly attracted the attention of researchers for the design and implementation of high-precision CMOS capacitive biosensors. A conventional core-CBCM capacitive sensor consists of a capacitance-to-voltage converter (CVC), followed by a voltage-to-digital converter. In spite of their high accuracy and low complexity, their input dynamic range (IDR) limits the advantages of core-CBCM capacitive sensors for most biological applications, including cellular monitoring. In this paper, after a brief review of core-CBCM capacitive sensors, we address this challenge by proposing a new current-mode core-CBCM design. In this design, we combine CBCM and current-controlled oscillator (CCO) structures to improve the IDR of the capacitive readout circuit. Using a 0.18 MUm CMOS process, we demonstrate and discuss the Cadence simulation results to demonstrate the high performance of the proposed circuitry. Based on these results, the proposed circuit offers an IDR ranging from 873 aF to 70 fF with a resolution of about 10 aF. This CMOS capacitive sensor with such a wide IDR can be employed for monitoring cellular and molecular activities that are suitable for biological research and clinical purposes. PMID- 30304844 TI - Relationship between Molarity and Color in the Crystal ('Dramada') Produced by Scytalidium cuboideum, in Two Solvents. AB - Pigments from wood-decay fungi (specifically spalting fungi) have a long history of use in wood art, and have become relevant in modern science due to their longevity and colorfastness. They are presently under investigation as colorants for wood, bamboo, oils, paints and textiles. Major hurdles to their commercialization have been color repeatability (in that the same strain of the same species of fungus may produce different colors over time), and the binding of the pigments to glass storage containers. This is persistent as they do not naturally exist in a loose form. Due to these issues, the 'standard' color for each was historically determined not by the amount of pigment, but by the color in a solution of dichloromethane (DCM), using the CIE L*a*b colorspace. This method of standardization severely limited the use of these pigments in industrial applications, as without a dry form, standard methodologies for repeatable color processing into other materials could not be easily implemented. Recent studies have developed a method to crystalize the red pigment from Scytalidium cuboideum (Sacc. & Ellis) Sigler & Kang, producing a highly pure (99%) solid crystal named 'Dramada'. Herein a method is detailed to compare the molarity of this crystallized pigment to variations in the color, to determine a color saturation curve (by weight) for the pigment from S. cuboideum in DCM and acetone. The molarities for this experiment ranged from 0.024 mM to 19 mM. Each molarity was color read and assigned a CIEL*a*b* value. The results showed that there was a correlation between the molarity and color difference, with the maximum red color occurring between 0.73 mM and 7.3 mM in DCM and between 0.97 mM to 0.73 mM in acetone. Extremely low molarities of pigment produced strong coloration in the solvent, and changes in molarity significantly affected the color of the solution. Having a saturation and color curve for the crystal 'Dramada' from S. cuboideum will allow for the reliable production of distinct colors from a known quantity (by weight) of pigment, erasing the final hurdle towards commercial development of the crystallized pigment from S. cuboideum as an industrial dyestuff. PMID- 30304845 TI - Comparison of Two Methods for the Determination of Selected Pesticides in Honey and Honeybee Samples. AB - Developed and validated analytical methods for the determination of a wide spectrum of pesticide residues in honey and honeybee samples after the modification of QuEChERS extraction in combination with gas chromatography-tandem quadrupole mass spectrometry (GC-MS/MS) and liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS) were discussed and compared. The developed methods were evaluated regarding the utilized equipment and reagents using Eco-Scale and compared in terms of extraction time, accuracy, precision, sensitivity and versatility, with similar procedures. The results proved that the QuEChERS protocol in combination with LC and GC techniques fulfills the requirements of green analytical chemistry, so it can be used as a tool in environmental monitoring. The recovery was 85-116% for honey and 85.5-103.5% for honeybee samples. The developed methods were successfully applied in monitoring real samples collected from three districts of Pomerania in Poland. Analysis of real samples revealed the presence of the following pesticides: bifenthrin, fenpyroximate, methidathione, spinosad, thiamethoxam, triazophos, metconazole and cypermethrin at levels higher than the MRLs established by the EU. PMID- 30304847 TI - Analytical Micromechanics Models for Elastoplastic Behavior of Long Fibrous Composites: A Critical Review and Comparative Study. AB - Elasto-plastic models for composites can be classified into three categories in terms of a length scale, i.e., macro scale, meso scale, and micro scale (micromechanics) models. In general, a so-called multi-scale model is a combination of those at various length scales with a micromechanics one as the foundation. In this paper, a critical review is made for the elastoplastic models at the micro scale, and a comparative study is carried out on most popular analytical micromechanics models for the elastoplastic behavior of long fibrous composites subjected to a static load, meaning that creep and dynamic response are not concerned. Each model has been developed essentially following three steps, i.e., an elastic homogenization, a rule to define the yielding of a constituent phase, and a linearization for the elastoplastic response. The comparison is made for all of the three aspects. Effects of other issues, such as the stress field fluctuation induced by a high contrast heterogeneity, the stress concentration factors in the matrix, and the different approaches to a plastic Eshelby tensor, are addressed as well. Correlation of the predictions by different models with available experimental data is shown. PMID- 30304846 TI - Low PD-L1 Expression Strongly Correlates with Local Recurrence in Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma after Radiation-Based Therapy. AB - The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV) positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080; HR = 1.88; 95% CI = 1.18-3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022; HR = 0.46; 95% CI = 0.24-0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials. PMID- 30304848 TI - Probabilistic Damage Detection of a Steel Truss Bridge Model by Optimally Designed Bayesian Neural Network. AB - Excellent pattern matching capability makes artificial neural networks (ANNs) a very promising approach for vibration-based structural health monitoring (SHM). The proper design of the network architecture with the suitable complexity is vital to the ANN-based structural damage detection. In addition to the number of hidden neurons, the type of transfer function used in the hidden layer cannot be neglected for the ANN design. Neural network learning can be further presented in the framework of Bayesian statistics, but the issues of selection for the hidden layer transfer function with respect to the Bayesian neural network has not yet been reported in the literature. In addition, most of the research works in the literature for addressing the predictive distribution of neural network output is only for a single target variable, while multiple target variables are rarely involved. In the present paper, for the purpose of probabilistic structural damage detection, Bayesian neural networks with multiple target variables are optimally designed, and the selection of the number of neurons, and the transfer function in the hidden layer, are carried out simultaneously to achieve a neural network architecture with suitable complexity. Furthermore, the nonlinear network function can be approximately linear by assuming the posterior distribution of network parameters is a sufficiently narrow Gaussian, and then the input dependent covariance matrix of the predictive distribution of network output can be obtained with the Gaussian assumption for the situation of multiple target variables. Structural damage detection is conducted for a steel truss bridge model to verify the proposed method through a set of numerical case studies. PMID- 30304849 TI - Digital Images Authentication Technique Based on DWT, DCT and Local Binary Patterns. AB - In the last few years, the world has witnessed a ground-breaking growth in the use of digital images and their applications in the modern society. In addition, image editing applications have downplayed the modification of digital photos and this compromises the authenticity and veracity of a digital image. These applications allow for tampering the content of the image without leaving visible traces. In addition to this, the easiness of distributing information through the Internet has caused society to accept everything it sees as true without questioning its integrity. This paper proposes a digital image authentication technique that combines the analysis of local texture patterns with the discrete wavelet transform and the discrete cosine transform to extract features from each of the blocks of an image. Subsequently, it uses a vector support machine to create a model that allows verification of the authenticity of the image. Experiments were performed with falsified images from public databases widely used in the literature that demonstrate the efficiency of the proposed method. PMID- 30304851 TI - Protective Immune Responses Generated in a Murine Model Following Immunization with Recombinant Schistosoma japonicum Insulin Receptor. AB - There is a pressing need to develop vaccines for schistosomiasis given the current heavy dependency on praziquantel as the only available drug for treatment. We previously showed the ligand domain of the Schistosoma japonicum insulin receptor 1 and 2 (rSjLD1 and 2) fusion proteins conferred solid protection in mice against challenge infection with S. japonicum. To improve vaccine efficacy, we compared the immunogenicity and protective efficacy of rSjLD1 on its own and in combination with S. japonicum triose-phosphate isomerase (SjTPI), formulated with either of two adjuvants (QuilA and montanide ISA 720VG) in murine vaccine trials against S. japonicum challenge. The level of protection was higher in mice vaccinated only with rSjLD1 formulated with either adjuvant; rSjTPI or the rSjTPI-rSjLD1 combination resulted in a lower level of protection. Mirroring our previous results, there were significant reductions in the number of female worms (30-44%), faecal eggs (61-68%), liver eggs (44-56%), intestinal eggs (46-48%) and mature intestinal eggs (58-63%) in the rSjLD1-vaccinated mice compared with the adjuvant only groups. At 6-weeks post-cercarial challenge, a significantly increased production of interferon gamma (IFNgamma) in rSjLD1 stimulated splenic CD4+ T cells was observed in the rSjLD1-vaccinated mice suggesting a Th1-type response is associated with the generated level of protective efficacy. PMID- 30304850 TI - Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis. AB - Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is known to be an inhibitor of NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase activity and is highly effective in suppressing the production of superoxide. The neuroprotective effects of apocynin have been investigated in numerous brain injury settings, such as stroke, traumatic brain injury (TBI), and epilepsy. Our lab has demonstrated that TBI or seizure-induced oxidative injury and neuronal death were reduced by apocynin treatment. Several studies have also demonstrated that neuroblast production is transiently increased in the hippocampus after seizures. Here, we provide evidence confirming the hypothesis that long-term treatment with apocynin may enhance newly generated hippocampal neuronal survival by reduction of superoxide production after seizures. A seizure was induced by pilocarpine [(25 mg/kg intraperitoneal (i.p.)] injection. Apocynin was continuously injected for 4 weeks after seizures (once per day) into the intraperitoneal space. We evaluated neuronal nuclear antigen (NeuN), bromodeoxyuridine (BrdU), and doublecortin (DCX) immunostaining to determine whether treatment with apocynin increased neuronal survival and neurogenesis in the hippocampus after seizures. The present study indicates that long-term treatment of apocynin increased the number of NeuN+ and DCX+ cells in the hippocampus after seizures. Therefore, this study suggests that apocynin treatment increased neuronal survival and neuroblast production by reduction of hippocampal oxidative injury after seizures. PMID- 30304852 TI - ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis. AB - Interleukin 17 (IL-17) and its cognate receptor A (IL-17RA) play a crucial role in Th17 cells-mediated pro-inflammatory pathway and pathogenesis of several autoimmune disorders including psoriasis. IL-17 is mainly produced by activated Th-17 helper cells upon stimulation by IL-23 and, via binding to its receptors, mediates IL-17-driven cell signaling in keratinocytes. Hyper-proliferation of keratinocytes belongs to major clinical manifestations in psoriasis. To modulate IL-17-mediated inflammatory cascade, we generated a unique collection of IL-17RA targeting protein binders that prevent from binding of human IL-17A cytokine to its cell-surface receptor. To this goal, we used a highly complex combinatorial library derived from scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived high-affinity ligands of human IL-17RA, called ARS binders. From 67 analyzed ABD variants, 7 different sequence families were identified. Representatives of these groups competed with human IL-17A for binding to recombinant IL-17RA receptor as well as to IL-17RA-Immunoglobulin G chimera, as tested in enzyme-linked immunosorbent assay (ELISA). Five ARS variants bound to IL-17RA-expressing THP-1 cells and blocked binding of human IL-17 cytokine to the cell surface, as tested by flow cytometry. Three variants exhibited high-affinity binding with a nanomolar Kd value to human keratinocyte HaCaT cells, as measured using Ligand Tracer Green Line. Upon IL-17-stimulated activation, ARS variants inhibited secretion of Gro-alpha (CXCL1) by normal human skin fibroblasts in vitro. Thus, we identified a novel class of inhibitory ligands that might serve as immunosuppressive IL-17RA-targeted non-IgG protein antagonists. PMID- 30304854 TI - Fatigue Damage Evaluation Using Nonlinear Lamb Waves with Quasi Phase-Velocity Matching at Low Frequency. AB - Due to the dispersive and multimode natures, only nonlinear Lamb waves with exact phase-velocity matching were generally used in previous studies to evaluate the evenly distributed microstructural evolution in the incipient stage of material degradation, because of the cumulative generation of second harmonics, which was also found within a significant propagation distance for mode pair S0-s0 with quasi phase-velocity matching at low frequency. To explore the feasibility of fatigue damage evaluation by using this mode pair and fully utilize its unique merits, the cumulative second harmonic analysis was performed on aluminum alloy specimens with various material damage produced by the continuous low cycle fatigue tests. Similar to mode pair S1-s2 with exact phase-velocity matching, a mountain shape curve between the normalized acoustic nonlinearity parameter and the fatigue life was also achieved with the peak point at about 0.65 fatigue life for mode pair S0-s0, even though a relatively higher sensitivity to fatigue damage was observed for mode pair S1-s2. The excited frequency selection was further analyzed in a certain frequency range, where the quasi phase-velocity matching condition was satisfied for mode pair S0-s0 owing to the less dispersive property. Results show that the fatigue damage can be effectively detected using the mode pair S0-s0, and a relatively lower excited frequency was preferred due to its higher sensitivity to microstructural evolution. PMID- 30304856 TI - Antizyme Inhibitors in Polyamine Metabolism and Beyond: Physiopathological Implications. AB - The intracellular levels of polyamines, cationic molecules involved in a myriad of cellular functions ranging from cellular growth, differentiation and apoptosis, is precisely regulated by antizymes and antizyme inhibitors via the modulation of the polyamine biosynthetic and transport systems. Antizymes, which are mainly activated upon high polyamine levels, inhibit ornithine decarboxylase (ODC), the key enzyme of the polyamine biosynthetic route, and exert a negative control of polyamine intake. Antizyme inhibitors (AZINs), which are proteins highly homologous to ODC, selectively interact with antizymes, preventing their action on ODC and the polyamine transport system. In this review, we will update the recent advances on the structural, cellular and physiological functions of AZINs, with particular emphasis on the action of these proteins in the regulation of polyamine metabolism. In addition, we will describe emerging evidence that suggests that AZINs may also have polyamine-independent effects on cells. Finally, we will discuss how the dysregulation of AZIN activity has been implicated in certain human pathologies such as cancer, fibrosis or neurodegenerative diseases. PMID- 30304853 TI - The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor. AB - Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer's disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin. PMID- 30304857 TI - Quantitative Study of Using Piloti for Passive Climate Adaptability in a Hot Summer and Cold-Winter City in China. AB - There has been an insufficient study of passive climate adaptability that considers both the summer and winter season for the outdoor thermal environment of hot-summer and cold-winter cities. In this study, we performed a quantitative simulation to research the passive climate adaptability of a residential area, considering piloti as the main method for climate adaptation in a hot-summer and cold-winter city in China. Numerical simulations were performed with a coupled simulation method of convection, radiation, and conduction. A cubic non-linear k epsilon model proposed by Craft et al. was selected as the turbulence model and three-dimensional multi-reflections of shortwave and longwave radiations were considered in the radiation simulation. Through the simulation, we found that setting the piloti at the two ends of the building was the optimal piloti arrangement for climate adaptation. Then the relationship between the piloti ratio (0%, 20%, 40%, 60%, and 80%) and the outdoor thermal environment was studied. It could be concluded that with the increasing piloti ratio, the wind velocity increased, the mean radiant temperature (MRT) decreased slightly, and the average standard effective temperature (SET*) decreased to 3.6 degrees C in summer, while in winter, with the increasing piloti ratio, the wind velocity, MRT, and SET* changed slightly. The wind environment significantly affected the SET* value, and the piloti ratio should be between 12% and 38% to avoid wind induced discomfort. PMID- 30304855 TI - "Out of the Can": A Draft Genome Assembly, Liver Transcriptome, and Nutrigenomics of the European Sardine, Sardina pilchardus. AB - Clupeiformes, such as sardines and herrings, represent an important share of worldwide fisheries. Among those, the European sardine (Sardina pilchardus, Walbaum 1792) exhibits significant commercial relevance. While the last decade showed a steady and sharp decline in capture levels, recent advances in culture husbandry represent promising research avenues. Yet, the complete absence of genomic resources from sardine imposes a severe bottleneck to understand its physiological and ecological requirements. We generated 69 Gbp of paired-end reads using Illumina HiSeq X Ten and assembled a draft genome assembly with an N50 scaffold length of 25,579 bp and BUSCO completeness of 82.1% (Actinopterygii). The estimated size of the genome ranges between 655 and 850 Mb. Additionally, we generated a relatively high-level liver transcriptome. To deliver a proof of principle of the value of this dataset, we established the presence and function of enzymes (Elovl2, Elovl5, and Fads2) that have pivotal roles in the biosynthesis of long chain polyunsaturated fatty acids, essential nutrients particularly abundant in oily fish such as sardines. Our study provides the first omics dataset from a valuable economic marine teleost species, the European sardine, representing an essential resource for their effective conservation, management, and sustainable exploitation. PMID- 30304858 TI - Gradient Projection with Approximate L0 Norm Minimization for Sparse Reconstruction in Compressed Sensing. AB - In the reconstruction of sparse signals in compressed sensing, the reconstruction algorithm is required to reconstruct the sparsest form of signal. In order to minimize the objective function, minimal norm algorithm and greedy pursuit algorithm are most commonly used. The minimum L1 norm algorithm has very high reconstruction accuracy, but this convex optimization algorithm cannot get the sparsest signal like the minimum L0 norm algorithm. However, because the L0 norm method is a non-convex problem, it is difficult to get the global optimal solution and the amount of calculation required is huge. In this paper, a new algorithm is proposed to approximate the smooth L0 norm from the approximate L2 norm. First we set up an approximation function model of the sparse term, then the minimum value of the objective function is solved by the gradient projection, and the weight of the function model of the sparse term in the objective function is adjusted adaptively by the reconstruction error value to reconstruct the sparse signal more accurately. Compared with the pseudo inverse of L2 norm and the L1 norm algorithm, this new algorithm has a lower reconstruction error in one dimensional sparse signal reconstruction. In simulation experiments of two dimensional image signal reconstruction, the new algorithm has shorter image reconstruction time and higher image reconstruction accuracy compared with the usually used greedy algorithm and the minimum norm algorithm. PMID- 30304859 TI - Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors. AB - Myeloid hematological malignancies are clonal bone marrow neoplasms, comprising of acute myeloid leukemia (AML), the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), the myeloproliferative neoplasms (MPN) and systemic mastocytosis (SM). The field of epigenetic regulation of normal and malignant hematopoiesis is rapidly growing. In recent years, heterozygous somatic mutations in genes encoding epigenetic regulators have been found in all subtypes of myeloid malignancies, supporting the rationale for treatment with epigenetic modifiers. Histone deacetylase inhibitors (HDACi) are epigenetic modifiers that, in vitro, have been shown to induce growth arrest, apoptotic or autophagic cell death, and terminal differentiation of myeloid tumor cells. These effects were observed both at the bulk tumor level and in the most immature CD34+38- cell compartments containing the leukemic stem cells. Thus, there is a strong rationale supporting HDACi therapy in myeloid malignancies. However, despite initial promising results in phase I trials, HDACi in monotherapy as well as in combination with other drugs, have failed to improve responses or survival. This review provides an overview of the rationale for HDACi in myeloid malignancies, clinical results and speculations on why clinical trials have thus far not met the expectations, and how this may be improved in the future. PMID- 30304861 TI - Targeted Theranostic Nanoparticles for Brain Tumor Treatment. AB - The poor prognosis and rapid recurrence of glioblastoma (GB) are associated to its fast-growing process and invasive nature, which make difficult the complete removal of the cancer infiltrated tissues. Additionally, GB heterogeneity within and between patients demands a patient-focused method of treatment. Thus, the implementation of nanotechnology is an attractive approach considering all anatomic issues of GB, since it will potentially improve brain drug distribution, due to the interaction between the blood-brain barrier and nanoparticles (NPs). In recent years, theranostic techniques have also been proposed and regarded as promising. NPs are advantageous for this application, due to their respective size, easy surface modification and versatility to integrate multiple functional components in one system. The design of nanoparticles focused on therapeutic and diagnostic applications has increased exponentially for the treatment of cancer. This dual approach helps to understand the location of the tumor tissue, the biodistribution of nanoparticles, the progress and efficacy of the treatment, and is highly useful for personalized medicine-based therapeutic interventions. To improve theranostic approaches, different active strategies can be used to modulate the surface of the nanotheranostic particle, including surface markers, proteins, drugs or genes, and take advantage of the characteristics of the microenvironment using stimuli responsive triggers. This review focuses on the different strategies to improve the GB treatment, describing some cell surface markers and their ligands, and reports some strategies, and their efficacy, used in the current research. PMID- 30304862 TI - High Potency of Melaleuca alternifolia Essential Oil against Multi-Drug Resistant Gram-Negative Bacteria and Methicillin-Resistant Staphylococcus aureus. AB - PURPOSE: Herein, an extended investigation of Tea tree oil (TTO) against a number of multi-drug resistant (MDR) microorganisms in liquid and vapor phases is reported. METHODS: The activity of TTO was tested against methicillin-sensitive Staphylococcus aureus (MSSA), Escherichia coli, and clinical strains of methicillin-resistant S. aureus (MRSA), extended-spectrum beta lactamases producer carbapenem-sensitive Klebsiella pneumoniae (ESBL-CS-Kp), carbapenem resistant K. pneumoniae (CR-Kp), Acinetobacter baumannii (CR-Ab), and Pseudomonas aeruginosa (CR-Pa). Minimal inhibitory/bactericidal concentrations (MIC/MBCs) and synergistic activity between TTO and different antimicrobials were determined. In the vapor assay (VP), TTO-impregnated discs were placed on the lid of a petri dish and incubated for 24 h at 37 degrees C. RESULTS: TTO showed a potent bactericidal activity against all the tested microorganisms. TTO in combination with each reference antimicrobial showed a high level of synergism at sub inhibitory concentrations, particularly with oxacillin (OXA) against MRSA. The VP assay showed high activity of TTO against CR-Ab. CONCLUSION: Evaluation of in vitro activity clearly indicated TTO as a potential effective antimicrobial treatment either alone or in association with known drugs against MDR. Therefore, TTO could represent the basis for a possible role in non-conventional regimens against S. aureus and Gram-negative MDR. TTO in VP might represent a promising option for local therapy of pneumonia caused by CR-Ab. PMID- 30304863 TI - De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data. AB - The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole genome sequencing data. PMID- 30304864 TI - Scabiosa Genus: A Rich Source of Bioactive Metabolites. AB - The genus Scabiosa (family Caprifoliaceae) is considered large (618 scientific plant names of species) although only 62 have accepted Latin binominal names. The majority of the Scabiosa species are widely distributed in the Mediterranean region and some Scabiosa species are used in traditional medicine systems. For instance, Scabiosa columbaria L. is used traditionally against diphtheria while S. comosa Fisch. Ex Roem. and Schult. is used in Mongolian and Tibetan traditional medical settings to treat liver diseases. The richness of Scabiosa species in secondary metabolites such as iridoids, flavonoids and pentacyclic triterpenoids may contribute to its use in folk medicine. Details on the most recent and relevant pharmacological in vivo studies on the bioactive secondary metabolites isolated from Scabiosa species will be summarized and thoroughly discussed. PMID- 30304860 TI - The Various Roles of Fatty Acids. AB - Lipids comprise a large group of chemically heterogeneous compounds. The majority have fatty acids (FA) as part of their structure, making these compounds suitable tools to examine processes raging from cellular to macroscopic levels of organization. Among the multiple roles of FA, they have structural functions as constituents of phospholipids which are the "building blocks" of cell membranes; as part of neutral lipids FA serve as storage materials in cells; and FA derivatives are involved in cell signalling. Studies on FA and their metabolism are important in numerous research fields, including biology, bacteriology, ecology, human nutrition and health. Specific FA and their ratios in cellular membranes may be used as biomarkers to enable the identification of organisms, to study adaptation of bacterial cells to toxic compounds and environmental conditions and to disclose food web connections. In this review, we discuss the various roles of FA in prokaryotes and eukaryotes and highlight the application of FA analysis to elucidate ecological mechanisms. We briefly describe FA synthesis; analyse the role of FA as modulators of cell membrane properties and FA ability to store and supply energy to cells; and inspect the role of polyunsaturated FA (PUFA) and the suitability of using FA as biomarkers of organisms. PMID- 30304865 TI - Increasing Environmental Health Literacy through Contextual Learning in Communities at Risk. AB - Environmental health literacy (EHL) has recently been defined as the continuum of environmental health knowledge and awareness, skills and self-efficacy, and community action. In this study, an interdisciplinary team of university scientists, partnering with local organizations, developed and facilitated EHL trainings with special focus on rainwater harvesting and water contamination, in four communities with known environmental health stressors in Arizona, USA. These participatory trainings incorporated participants' prior environmental health risk knowledge and personal experiences to co-create training content. Mixed methods evaluation was conducted via pre-post participant surveys in all four trainings (n = 53). Participants who did not demonstrate baseline environmental science knowledge pre-training demonstrated significant knowledge increase post training, and participants who demonstrated low self-efficacy (SE) pre-training demonstrated a significant increase in SE post-training. Participants overall demonstrated a significant increase in specific environmental health skills described post-training. The interdisciplinary facilitator-scientist team also reported multiple benefits, including learning local knowledge that informed further research, and building trust relationships with community members for future collaboration. We propose contextual EHL education as a valuable strategy for increasing EHL in environmental health risk communities, and for building academia-community partnerships for environmental health research and action. PMID- 30304867 TI - A Hybrid Finite Volume and Extended Finite Element Method for Hydraulic Fracturing with Cohesive Crack Propagation in Quasi-Brittle Materials. AB - High-pressure hydraulic fractures are often reported in real engineering applications, which occur due to the existence of discontinuities such as cracks, faults, or shear bands. In this paper, a hybrid finite volume and extended finite element method (FVM-XFEM) is developed for simulating hydro-fracture propagation in quasi-brittle materials, in which the coupling between fluids and deformation is considered. Flow within the fracture is modelled using lubrication theory for a one-dimensional laminar flow that obeys the cubic law. The solid deformation is governed by the linear momentum balance equation under quasi-static conditions. The cohesive crack model is used to analyze the non-linear fracture process zone ahead of the crack tip. The discretization of the pressure field is implemented by employing the FVM, while the discretization of the displacement field is accomplished through the use of the XFEM. The final governing equations of a fully coupled hydro-mechanical problem is solved using the Picard iteration method. Finally, the validity of the proposed method is demonstrated through three examples. Moreover, the fluid pressure distribution along the fracture, the fracture mouth width, and the pattern of the fracture are investigated. It is shown that the numerical results correlated well with the theoretical solutions and experimental results. PMID- 30304866 TI - Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation. AB - Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1beta biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism. PMID- 30304869 TI - Temperature Dependence of Mechanical, Electrical Properties and Crystal Structure of Polyethylene Blends for Cable Insulation. AB - There is a long-standing puzzle concerning whether polyethylene blends are a suitable substitution for cable-insulation-used crosslinking polyethylene (XLPE) especially at elevated temperatures. In this paper, we investigate temperature dependence of mechanical, electrical properties of blends with 70 wt % linear low density polyethylene (LLDPE) and 30 wt % high density polyethylene (HDPE) (abbreviated as 70 L-30 H). Our results show that the dielectric loss of 70 L-30 H is about an order of magnitude lower than XLPE, and the AC breakdown strength is 22% higher than XLPE at 90 degrees C. Moreover, the dynamic mechanical thermal analysis (DMA) measurement and hot set tests suggest that the blends shows optimal mechanical properties especially at high temperature with considerable temperature stability. Further scanning electron microscope (SEM) observation and X-ray diffraction (XRD) analysis uncover the reason for the excellent high temperature performance and temperature stability, which can be ascribed to the uniform fine-spherulite structure in 70 L-30 H blends with high crystallinity sustaining at high temperature. Therefore, our findings may enable the potential application of the blends as cable insulation material with higher thermal-endurance ability. PMID- 30304870 TI - A Novel MIMO-SAR Solution Based on Azimuth Phase Coding Waveforms and Digital Beamforming. AB - In multiple-input multiple-output synthetic aperture radar (MIMO-SAR) signal processing, a reliable separation of multiple transmitted waveforms is one of the most important and challenging issues, for the unseparated signal will degrade the performance of most MIMO-SAR applications. As a solution to this problem, a novel APC-MIMO-SAR system is proposed based on the azimuth phase coding (APC) technique to transmit multiple waveforms simultaneously. Although the echo aliasing occurs in the time domain and Doppler domain, the echoes can be separated well without performance degradation by implementing the azimuth digital beamforming (DBF) technique, comparing to the performance of the orthogonal waveforms. The proposed MIMO-SAR solution based on the APC waveforms indicates the feasibility and the spatial diversity of the MIMO-SAR system. It forms a longer baseline in elevation, which gives the potential to expand the application of MIMO-SAR in elevation, such as improving the performance of multibaseline InSAR and three-dimensional SAR imaging. Simulated results on both a point target and distributed targets validate the effectiveness of the echo separation and reconstruction method with the azimuth DBF. The feasibility and advantage of the proposed MIMO-SAR solution based on the APC waveforms are demonstrated by comparing with the imaging result of the up- and down-chirp waveforms. PMID- 30304868 TI - B Chromosomes in Populations of Mammals Revisited. AB - The study of B chromosomes (Bs) started more than a century ago, while their presence in mammals dates since 1965. As the past two decades have seen huge progress in application of molecular techniques, we decided to throw a glance on new data on Bs in mammals and to review them. We listed 85 mammals with Bs that make 1.94% of karyotypically studied species. Contrary to general view, a typical B chromosome in mammals appears both as sub- or metacentric that is the same size as small chromosomes of standard complement. Both karyotypically stable and unstable species possess Bs. The presence of Bs in certain species influences the cell division, the degree of recombination, the development, a number of quantitative characteristics, the host-parasite interactions and their behaviour. There is at least some data on molecular structure of Bs recorded in nearly a quarter of species. Nevertheless, a more detailed molecular composition of Bs presently known for six mammalian species, confirms the presence of protein coding genes, and the transcriptional activity for some of them. Therefore, the idea that Bs are inert is outdated, but the role of Bs is yet to be determined. The maintenance of Bs is obviously not the same for all species, so the current models must be adapted while bearing in mind that Bs are not inactive as it was once thought. PMID- 30304872 TI - Comparative Rice Bran Metabolomics across Diverse Cultivars and Functional Rice Gene-Bran Metabolite Relationships. AB - Rice (Oryza sativa L.) processing yields ~60 million metric tons of bran annually. Rice genes producing bran metabolites of nutritional and human health importance were assessed across 17 diverse cultivars from seven countries using non-targeted metabolomics, and resulted in 378-430 metabolites. Gambiaka cultivar had the highest number and Njavara had the lowest number of metabolites. The 71 rice bran compounds of significant variation by cultivar included 21 amino acids, seven carbohydrates, two metabolites from cofactors and vitamins, 33 lipids, six nucleotides, and two secondary metabolites. Tryptophan, alpha-ketoglutarate, gamma-tocopherol/beta-tocopherol, and gamma-tocotrienol are examples of bran metabolites with extensive cultivar variation and genetic information. Thirty four rice bran components that varied between cultivars linked to 535 putative biosynthetic genes using to the OryzaCyc 4.0, Plant Metabolic Network database. Rice genes responsible for bran composition with animal and human health importance is available for rice breeding programs to utilize in crop improvement. PMID- 30304873 TI - Presomal morphology and development of Prosthorhynchus formosus, Prosthenorchis elegans, and Moniliformis dubius (Acanthocephala). AB - Larvae removed at one-day intervals from laboratory infected intermediate hosts provided material for a comparative study of presomal development in Prosthorhynchus formosus (Van Cleave, '18) Travassos, '26, Prosthenorchis elegans (Diesing, 1851) Travassos, '15, and Moniliformis dubius Meyer, '33. Acanthellae begin development soon after entering intermediate hosts' hemocoels, and by the 18th day all three species possess three nuclear masses representing primordia of the proboscis, proboscis receptacle and ganglion, and trunk musculature and genitalia. Presomal development of P. formosus and P. elegans results in structures concurring with morphology of other adult palaeacanthocephalans and archiacanthocephalans. Development of M. dubius, however, differs from that of other archiacanthocephalans in that the muscular receptacle wall lines the entire surface of the nonmuscular sheath, failing to form a ventral cleft characteristic of other archiacanthocephalans. Unlike receptacle protrusor muscles of other archiacanthocephalan species, those of M. dubius spiral around the receptacle as they extend posteriad to attach individually to a pouchlike, muscular thickening at the receptacle's base. These protrusor muscles are distinct from the receptacle wall, as attested by their development alongside neck retractor muscles, not from the receptacle primordium, and the manner in which they are left to trail behind the receptacle when it is drawn anteriorly into the proboscis during larval development. The proboscis receptacle of M. dubius should not be thought of as being double-walled, as envisioned by previous workers. PMID- 30304874 TI - Slit sense organs on the scorpion leg (Androctonus australis L., Buthidae). AB - As in other arthropods the exoskeleton of arachnids is subjected to loads generated by external stimuli and behavioral activities. Far from being mere by products of various activities such loads act as signals for mechanoreceptors capable of detecting minute displacements caused by them in the cuticle. In arachnids the slit sense organs serve in this capacity. Spiders have the most elaborate system of slit sense organs. Our previous studies clearly pointed to a functional significance of their specific location and orientation, as well as degree and type of aggregation (isolated, grouped, compound or lyriform) on respective body parts. The present study extends our work to the slit sense organs of scorpions. It gives a detailed account of the topography of the organs on the walking legs. In general slits are less orderly arranged on the legs of scorpions than on those of spiders. In the scorpion they never aggregate to form lyriform organs. Instead there are groups at comparable locations forming much more irregular, but still specific patterns. Isolated slits are more numerous on the scorpion leg, but are also less regularly distrubuted there. A common feature of the majority of slits on both the spider and the scorpion leg is their position on the lateral surfaces and their orientation roughly parallel to the long axis of the leg. PMID- 30304875 TI - Fine structure of the intersegmental membrane glands of the sixth abdominal sternum of female Nomia melanderi (Hymenoptera, Apoidea). AB - The fine structure of the intersegmental glands of the sixth abdominal sternum in 1-week old females of Nomia melanderi is presented. The plasma membrane of the secretory cell is unfolded in many places and is covered by a basement membrane. The microvillous surface is invaginated to form a rather long sinuous cavity. The endoplasm is almost entirely filled by secretory granules. Many secretory granules are located close to the inner surface of the invaginated plasma membrane. The invagination contains a porous ductule, apparently of cuticulin origin, that is connected directly with the inner layer of the transport duct of the duct-forming cell. This type of arrangement allows the direct flow of the secretory substance to the outside in a continuous way. The cylindrical duct forming cell, besides having typical cell organelles, contains a cuticular transport duct. This duct is composed of a thin cuticulin layer surrounded by a rather thick epicuticular one. The results suggest that the secretory cell has two secretory cycles. The first occurs while the gland is differentiating (at the pupal stage) and is involved in secretion of the cuticulin that forms the porous ductule. The second cycle, which starts by the beginning of nesting, is involved in the secretion of a substance that is carried to the outside via the transport duct of the duct-forming cell. PMID- 30304876 TI - Functional morphology of the neck organ in Artemia salina nauplii. AB - Fine structure of the ion transporting epithelium of the neck organ in the brine shrimp (Artemia salina) nauplius is described. The neck organ is a dome-like gland situated atop the cephalothorax of the larva and is composed of 50 to 60 cuboidal epithelial cells. These cells possess many of the characteristics of salt-secretory cells from other tissues. They contain many mitochondria and exhibit a high degree of plasma membrane elaboration. This membrane amplification takes two forms; the apical plasmalemma is infolded into irregular loops, while the basal and lateral membranes penetrate the cytoplasm in the form of branching sinusoids. The labyrinth of tubular reticulum thus formed fills most of the cell volume. Mitochondria in the labyrinth are often in intimate contact with these tubular membranes and regular arrays of parallel mitochondria with constricted intervening sinusoids are often observed. Other organelles including Golgi complexes, multivesicular bodies, and rough endoplasmic reticulum are also numerous, particularly in the narrow rim of cytoplasm which lies between the apical infolds and the labyrinth. Yolk platelets and glycogen fields are conspicuous in the basal perinuclear regions of the cells. PMID- 30304877 TI - Sensilla on the antennal flagellum of the sawyer beetles Monochamus notatus (Drury) and Monochamus scutellatus (Say) (Coleoptera: Cerambycidae). AB - The antennae of the sawyer beetles Monochamus notatus and M. scutellatus were examined with the light and scanning electron microscopes to determine the types, number, distribution and innervation of the sense organs. Nine types of sensilla are described. Both short, thin-walled pegs (sensilla basiconica) and reversely curved thick-walled hairs (sensilla trichodea) are chemoreceptors. There are three types of long, thick-walled hairs (sensilla chaetica) which may be mechanoreceptors. One of these is modified in males to form unique snail-shaped pegs. A few dome-shaped organs, probably campaniform sensilla, were found. In addition to sense organs, many glands occur in association with the sensilla, and the antennae are well supplied with dermal glands connected by canals to small pores on the surface. PMID- 30304871 TI - Roles of TGF beta and FGF Signals in the Lens: Tropomyosin Regulation for Posterior Capsule Opacity. AB - Transforming growth factor (TGF) beta and fibroblast growth factor (FGF) 2 are related to the development of posterior capsule opacification (PCO) after lens extraction surgery and other processes of epithelial-mesenchymal transition (EMT). Oxidative stress seems to activate TGF beta1 largely through reactive oxygen species (ROS) production, which in turn alters the transcription of several survival genes, including lens epithelium-cell derived growth factor (LEDGF). Higher ROS levels attenuate LEDGF function, leading to down-regulation of peroxiredoxin 6 (Prdx6). TGF beta is regulated by ROS in Prdx6 knock-out lens epithelial cells (LECs) and induces the up-regulation of tropomyosins (Tpms) 1/2, and EMT of LECs. Mouse and rat PCO are accompanied by elevated expression of Tpm2. Further, the expression of Tpm1/2 is induced by TGF beta2 in LECs. Importantly, we previously showed that TGF beta2 and FGF2 play regulatory roles in LECs in a contrasting manner. An injury-induced EMT of a mouse lens as a PCO model was attenuated in the absence of Tpm2. In this review, we present findings regarding the roles of TGF beta and FGF2 in the differential regulation of EMT in the lens. Tpms may be associated with TGF beta2- and FGF2-related EMT and PCO development. PMID- 30304878 TI - Post embryonic development of the central nervous system of the spider Argiope aurantia (Lucas). AB - Volumetric and histological changes of the central nervous system were studied during post embryonic development of a spider, Argiope aurantia. The neural mass of Argiope grows allometrically with respect to volume of the cephalothorax and body weight. In the first instar 46% of the cephalothoracic volume constitutes the neural mass and this is reduced to 4% in the female (9th stage) and 12% in the male (7th stage) spider. Growth curves for the cephalic ganglion, measured at all stages, represent a straight line. The neural mass of females is two and a half times larger than that of the males. The ganglion increased 24 fold in female and 10 fold in male spiders. Addition of neural mass occurs in all stages. The brain volume is greater than that of the subesophageal ganglion in the first two instars. In subsequent stadia, the subesophageal ganglion grows faster, and in females it is finally three times and in males two times larger than the brain. Growth of cortex and neuropile depict exponential curves. Comparison of growth patterns of these shows an inverse relationship during development. While the volume of the cortex is higher in the first two or three stages, the volume of the neuropile is higher in the remaining stadia. The causes for this growth pattern are discussed. Counts of cell numbers show that there is a constant population of neurons throughout the post-embryonic development. The number of nerve cells in females is higher than in males, 11% in the subesophageal ganglion and 58% in the brain. The growth of the cortex is partly accomplished by an increase in cell volume. In male and female spiders the increase in Type-B cells is 20 and 50 fold, while that of large motor neurons is 200 and 600 fold respectively. The motor neurons of 20 MU and above number 63 in male and 916 in female adult spiders. The growth of neuropile occurs through an increase of dendritic arborization and axonal branching. The largest axons measure 1 MU in the first and 16 MU in adult stages. An increase of incoming sensory fibers is also noticed during development. Invasion of neural lamella into cortex and neuropile increases during development. Neural lamella which are 1-2 MU in the first stage grow to 40-100 MU thickness in adult female spiders, near the origin of the main nerves. One type of astral cells, counted in neuropile, increases 10 fold. The appearance of a central body and the beginning of web construction coincide during the second instar. The relationship between these two is discussed. PMID- 30304879 TI - Functional anatomy and sexual dimorphism of the cephalic clasper in the pacific ratfish (Chimaera collei). AB - The cephalic clasper of the male Chimaera collei is a cartilaginous rod equipped with denticles and presumably used to grasp the female during copulation. It is attached to the skull by ligaments but there is no joint cavity or articular surface. It has no intrinsic muscles, its movements being provided by attachments to muscles of the lower jaw and labial cartilages. The cephalic clasper is apparently elevated by a branch of the preorbitalis muscle, whose main function is to elevate the lower jaw. It appears to be forcefully depressed during copulation by M. levator anguli oris, whose primary function is to move the labial cartilages. When not in use, the cephalic clasper is held passively depressed by an elastic tendon from M. preorbitalis. In the female the cephalic clasper is represented by an apparently functionless rudiment. PMID- 30304880 TI - Structure development and evolution of the male pheromone system in some noctuidae (Lepidoptera). AB - Pheromone systems from seven species of noctuid are examined. Much of the structure of scales from the wings and/or the abdomen is interpreted as a modification for secretion or release of a pheromone. Scales with an extremely complex surface provide a large evaporation surface, while those connected to secretory cells show less superficial folding than body-covering scales. The development of the secretory gland and diseminatory scales in Mamestra configurata is followed from the exuvial pharate adult stage to emergence. Both components are paired and develop from epidermal cells lining a pair of large lateral invaginations. They may have resulted through division of a group of less specialized cells that originally combined the function of pheromone production and release. PMID- 30304881 TI - Structure and function of the head in flabelligerid polychaetes. AB - The functional anatomy of the head of Flabelliderma commensalis is described and compared to other flabelligerid polychaetes. Prostomial parts include the dorsal lip, the palps, two pairs of nuchal organs, four eyes and the prostomial lobe and ridge. The eyes are inverse pigment cup types with the medial portions of the sensory cells expanded to form a clear lens-like body. Peristomial parts include the median and ventral lips, the branchial membrane and the branchiae. The derivation of the nephridiopore is unknown. The spiraled branchiae of Coppingeria and the gill books of Diplocirrus are newly described variations in branchial structure. The head is retractable in some species and the anterior setigers are modified to form a protective setal cage. Two methods are employed for feeding: one for host fecal pellets and the other for detrital materials. Chemoreception, respiration, feeding and cleaning rely on a complex pattern of ciliary currents. PMID- 30304882 TI - Scanning electron microscopy of the air bladder in the spotted gar, Lepisosteus occulatus. AB - The surface of the gar respiratory epithelium was examined by scanning electron microscopy. Nonciliated and ciliated cells constitute the epithelium. Puffs appear to be an unusual feature of the ciliated cells as well as nonciliated cells. There appears to be a transition from nonciliated to puff ciliated cells through a puff stage. The role of the cell types as related to oxygen available in the air bladder is discussed. PMID- 30304883 TI - 9TH International Conference on Early Psychosis - To the New Horizon, 17 November 2014, Tokyo Japan. PMID- 30304884 TI - Histological classification of canine ovarian cyst types with reference to medical history. AB - Ovaries of 21 bitches presented with gynecopathies were surgically removed and histologically examined. Standard histological, as well as immunohistochemical, classification of 193 cystic structures resulted in the classification of 72 cysts of subsurface epithelial structures (SES), 61 follicular cysts (FCs), 38 cystic rete ovarii (CRO), 13 lutein cysts (LCs), and 9 non-classifiable cysts (NCCs). In addition to the histological classification, results were interpreted according to subject medical history, clinical examination outcome, and macroscopic observations during ovariohysterectomy. Dogs with ovarian cysts (OCs) and associated reproductive perturbations were mostly nulliparous, of large breed, and had an average of 9.5 +/- 3 years. Prolonged or shortened inter-estrus intervals of past heats, however, seemed to be relatively low-risk factors for the development of OCs in dogs. Furthermore, we provide histological observations of a rarely seen canine LC including a degenerated oocyte in the central cavity. PMID- 30304885 TI - Freemartinism in replacement ewe-lambs of the Ripollesa sheep breed. AB - The freemartinism syndrome affects almost all female calves born as co-twins to male calves, whereas little is known about this phenomenon in female sheep. Within this context, 1,185 ewe-lambs from the Ripollesa sheep breed were genotyped for the presence of oY1 polymorphism (a non-autosomal region of the Y chromosome). Neither ewe-lambs from single births (856) nor ewe-lambs from all female multiple births (170) were revealed as freemartins, whereas five of 159 ewe-lambs from multiple births with male co-twins were freemartins (3.15 +/- 1.38%). All freemartin ewe-lambs were confirmed by physical examination of external genitalia. The results confirm a low incidence of freemartinism from heterosexual twin pregnancies in Ripollesa sheep. PMID- 30304886 TI - Genomic analysis of Sheldrake origin goose hemorrhagic polyomavirus, China. AB - Goose hemorrhagic polyomavirus (GHPV) is not a naturally occurring infection in geese in China; however, GHPV infection has been identified in Pekin ducks, a domestic duck species. Herein, we investigated the prevalence of GHPV in five domestic duck species (Liancheng white ducks, Putian black ducks, Shan Sheldrake, Shaoxing duck, and Jinyun Sheldrake) in China. We determined that the Jinyun Sheldrake duck species could be infected by GHPV with no clinical signs, whereas no infection was identified in the other four duck species. We sequenced the complete genome of the Jinyun Sheldrake origin GHPV. Genomic data comparison suggested that GHPVs share a conserved genomic structure, regardless of the host (duck or geese) or region (Asia or Europe). Jinyun Sheldrake origin GHPV genomic characterization and epidemiological studies will increase our understanding of potential heterologous reservoirs of GHPV. PMID- 30304887 TI - WITHDRAWN: Detection of digital and interdigital dermatitis in Holstein Frisian dairy cows by means of infrared thermography. AB - Ahead of Print article withdrawn by publisher. PMID- 30304888 TI - Dapsone modulates lipopolysaccharide-activated bone marrow cells by inducing cell death and down-regulating tumor necrosis factor-alpha production. AB - Dapsone, an antibiotic, has been used to cure leprosy. It has been reported that dapsone has anti-inflammatory activity in hosts; however, the anti-inflammatory mechanism of dapsone has not been fully elucidated. The present study investigated the anti-inflammatory effects of dapsone on bone marrow cells (BMs), especially upon exposure to lipopolysaccharide (LPS). We treated BMs with LPS and dapsone, and the treated cells underwent cellular activity assay, flow cytometry analysis, cytokine production assessment, and reactive oxygen species assay. LPS distinctly activated BMs with several characteristics including high cellular activity, granulocyte changes, and tumor necrosis factor alpha (TNF-alpha) production increases. Interestingly, dapsone modulated the inflammatory cells, including granulocytes in LPS-treated BMs, by inducing cell death. While the percentage of Gr-1 positive cells was 57% in control cells, LPS increased that to 75%, and LPS plus dapsone decreased it to 64%. Furthermore, dapsone decreased the mitochondrial membrane potential of LPS-treated BMs. At a low concentration (25 MUg/mL), dapsone significantly decreased the production of TNF-alpha in LPS treated BMs by 54%. This study confirmed that dapsone has anti-inflammatory effects on LPS-mediated inflammation via modulation of the number and function of inflammatory cells, providing new and useful information for clinicians and researchers. PMID- 30304889 TI - Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease. AB - In many countries, vaccines are used for the prevention of foot-and-mouth disease (FMD). However, because there is no protection against FMD immediately after vaccination, research and development on antiviral agents is being conducted to induce protection until immunological competence is produced. This study tested whether well-known chemicals used as RNA virus treatment agents had inhibitory effects on FMD viruses (FMDVs) and demonstrated that ribavirin showed antiviral effects against FMDV in vitro/in vivo. In addition, it was observed that combining the administration of the antiviral agents orally and complementary therapy with vaccines synergistically enhanced antiviral activity and preserved the survival rate and body weight in the experimental animals. Antiviral agents mixed with an adjuvant were inoculated intramuscularly along with the vaccines, thereby inhibiting virus replication after injection and verifying that it was possible to induce early protection against viral infection prior to immunity being achieved through the vaccine. Finally, pigs treated with antiviral agents and vaccines showed no clinical signs and had low virus excretion. Based on these results, it is expected that this combined approach could be a therapeutic and preventive treatment for early protection against FMD. PMID- 30304890 TI - Combination of berberine and ciprofloxacin reduces multi-resistant Salmonella strain biofilm formation by depressing mRNA expressions of luxS, rpoE, and ompR. AB - Bacterial biofilms have been demonstrated to be closely related to clinical infections and contribute to drug resistance. Berberine, which is the main component of Coptis chinensis, has been reported to have efficient antibacterial activity. This study aimed to investigate the potential effect of a combination of berberine with ciprofloxacin (CIP) to inhibit Salmonella biofilm formation and its effect on expressions of related genes (rpoE, luxS, and ompR). The fractional inhibitory concentration (FIC) index of the combination of berberine with CIP is 0.75 showing a synergistic antibacterial effect. The biofilm's adhesion rate and growth curve showed that the multi-resistant Salmonella strain had the potential to form a biofilm relative to that of strain CVCC528, and the antibiofilm effects were in a dose-dependent manner. Biofilm microstructures were rarely observed at 1/2 * MIC/FIC concentrations (MIC, minimal inhibition concentration), and the combination had a stronger antibiofilm effect than each of the antimicrobial agents used alone at 1/4 * FIC concentration. LuxS, rpoE, and ompR mRNA expressions were significantly repressed (p < 0.01) at 1/2 * MIC/FIC concentrations, and the berberine and CIP combination repressed mRNA expressions more strongly at the 1/4 * FIC concentration. The results indicate that the combination of berberine and CIP has a synergistic effect and is effective in inhibiting Salmonella biofilm formation via repression of luxS, rpoE, and ompR mRNA expressions. PMID- 30304891 TI - Benefits of procyanidins on gut microbiota in Bama minipigs and implications in replacing antibiotics. AB - Several studies have reported the effect of absorption of procyanidins and their contribution to the small intestine. However, differences between dietary interventions of procyanidins and interventions via antibiotic feeding in pigs are rarely reported. Following 16S rRNA gene Illumina MiSeq sequencing, we observed that both procyanidin administration for 2 months (procyanidin-1 group) and continuous antibiotic feeding for 1 month followed by procyanidin for 1 month (procyanidin-2 group) increased the number of operational taxonomic units, as well as the Chao 1 and ACE indices, compared to those in pigs undergoing antibiotic administration for 2 months (antibiotic group). The genera Fibrobacter and Spirochaete were more abundant in the antibiotic group than in the procyanidin-1 and procyanidin-2 groups. Principal component analysis revealed clear separations among the three groups. Additionally, using the online Molecular Ecological Network Analyses pipeline, three co-occurrence networks were constructed; Lactobacillus was in a co-occurrence relationship with Trichococcus and Desulfovibrio and a co-exclusion relationship with Bacillus and Spharerochaeta. Furthermore, metabolic function analysis by phylogenetic investigation of communities by reconstruction of unobserved states demonstrated modulation of pathways involved in the metabolism of carbohydrates, amino acids, energy, and nucleotides. These data suggest that procyanidin influences the gut microbiota and the intestinal metabolic function to produce beneficial effects on metabolic homeostasis. PMID- 30304893 TI - Ovarian teratoma removed by laparoscopic ovariectomy in a dog. AB - An elective laparoscopic ovariectomy on a healthy dog revealed a cystic structure in the left ovary. The surgical procedure was successful. Histopathological examination showed the presence of a teratoma adjacent to the ovary. To the best of the authors' knowledge, this is the first reported case of an ovarian teratoma removed by laparoscopic ovariectomy in a dog by using a multiport laparoscopic ovariectomy technique. PMID- 30304892 TI - First detection and genetic characterization of porcine parvovirus 7 from Korean domestic pig farms. AB - Porcine parvovirus 7 (PPV7) was first detected in Korean pig farms in 2017. The detection rate of PPV7 DNA was 24.0% (30/125) in aborted pig fetuses and 74.9% (262/350) in finishing pigs, suggesting that PPV7 has circulated among Korean domestic pig farms. Phylogenetic analysis based on capsid protein amino acid sequences demonstrated that the nine isolated Korean strains (PPV-KA1-3 and PPV KF1-6) were closely related to the previously reported USA and Chinese PPV7 strains. In addition, the Korean strains exhibit genetic diversity with both insertion and deletion mutations. This study contributes to the understanding of the molecular epidemiology of PPV7 in Korea. PMID- 30304894 TI - DIAGNOSTIC VALUE OF EOSINOPENIA AND NEUTROPHIL TO LYMPHOCYTE RATIO ON EARLY ONSET NEONATAL SEPSIS. AB - Purpose: To determine the diagnostic value of eosinopenia and neutrophil to lymphocyte ratio (NLR) for diagnosing Early Onset Neonatal Sepsis (EONS). Methods: This is a cross sectional study that conducted in Neonatology Subdivision of Child Health Department of R.D. Kandou General Hospital Manado from July to October 2017. Samples were obtained from all neonates that were met the inclusion criteria as having EONS. Datas were encoded using logistic regression analysis, biserial point correlation, chi square, and ROC curve with p value <0.05 considered as significant. Results: Of 120 neonates who met the inclusion criteria, 73 (60.8%) were males and 47 (39.2%) were females. Ninety (75%) subjects were included in sepsis group and 30 (25%) were in non sepsis group. Mean eosinophil count in EONS and non-EONS group were 169.8 +/- 197.1 cells/mm3 and 405.7 +/- 288.9 cells/mm3, respectively, considered as significant (p<0.001). Result from diagnostic test of eosinopenia from the EONS group (cut off point 140 cells/mm3) obtained 60.0% sensitivity and 90.0% specificity. Mean NLR in EONS and non-EONS group were 2.82 +/- 2.29 and 0.82 +/- 0.32, respectively, also considered as significant (p<0.001). Result for diagnostic test of NLR in EONS group (cut-off point 1.24) obtained 83.3% sensitivity and 93.3% specificity. Conclusion: Eosinopenia has a high specificity value as a diagnostic marker of EONS and an increased in NLR has a high sensitivity and specificity value as a marker to diagnose EONS. PMID- 30304896 TI - Rapidly growing pediatric trampoline-related injuries in Korea: a 10-year single center retrospective study. AB - Purpose: Several published policy statements have warned for risk of trampoline and have recommended safety guideline. However, few studies have focused on trampoline-related injuries in Korea. The aim of this study was to assess the incidence and characteristics of pediatric trampoline-related injuries presenting to our hospital. Methods: We retrospectively reviewed the medical record of children <16 years old with trampoline-related injuries who visited our emergency department from 2008 to 2017. Results: Over the 10-year period investigated, 178 trampoline-related injuries occurred, which represented a significant increase (p=0.004). The majority (87.6%) of injuries occurred during the last 5 study years and a rapid increase was observed in injuries in children < 6 years old. Lower extremity injuries (62.4%) were most common, followed by upper extremity injuries, head and face, and trunk injuries, including injuries to the neck and spine. Sixty-seven children (37.6%) had fractures, and the most common fractures were proximal tibia fractures. Fractures were significantly more common in younger children (<6 years old) than other ages (p = 0.026). Conclusion: In Korea, the mechanism of trampoline injury is similar to that in indoor trampoline parks but is characterized by a smaller space and multi-users. The use of trampolines and injuries in children < 6 years old are increasing rapidly. Prohibiting the use of trampolines by children <6 years old, restricting simultaneous use by multiple children, and ensuring adult supervision should be strictly emphasized. Public awareness and policy guideline development are needed to reduce trampoline-related injuries. PMID- 30304895 TI - Understanding of type 1 diabetes mellitus: what we know and where we go. AB - The incidence of type 1 diabetes mellitus (T1DM) in children and adolescents is increasing worldwide. Combined effects of genetic and environmental factors cause T1DM, which make it difficult to predict whether an individual will inherit the disease. Due to the level of self-care necessary in T1DM maintenance, it is crucial for pediatric settings to support achieving optimal glucose control, especially when adolescents are beginning to take more responsibility for their own health. Innovative insulin delivery systems, such as continuous subcutaneous insulin infusion (CSII), and noninvasive glucose monitoring systems, such as continuous glucose monitoring (CGM), allow patients with T1DM to achieve a normal and flexible lifestyle. However, there are still challenges in achieving optimal glucose control despite advanced technology in T1DM administration. In this article, disease prediction and current management of T1DM are reviewed with special emphasis on biomarkers of pancreatic beta-cell stress, CSII, glucose monitoring, and several other adjunctive therapies. PMID- 30304897 TI - Changes in the Thyroid Hormone Profiles in Children with Nephrotic Syndrome. AB - Purpose: We compared thyroid hormone profiles in children with nephrotic syndrome (NS) at nephrotic phase and after remission. Methods: This study included thirty one pediatric NS patients. Thyroid hormone profiles consist of serum T3, T4, TSH and free T4. Results: Of the 31 patients, 16 (51.6%) showed abnormal findings in their thyroid hormone profiles: six, overt hypothyroidism; eight, subclinical hypothyroidism, and two, low T3 syndrome. The mean serum T3, T4, and free T4 levels were 82.37+/-23.64 ng/dL and 117.88+/-29.49 ng/dl, 5.47+/-1.14 ug/dl and 7.91+/-1.56 ug/dl, and 1.02+/-0.26 ng/dl and 1.38+/-0.23 ng/dl at NS nephrotic phase and remission, respectively, and were significantly lower at NS nephrotic phase (P=0.0007, <0.0001, and 0.0002). The mean serum TSH level at NS nephrotic phase and remission was 8.05+/-3.53 uIU/mL and 4.08+/-2.05 uIU/mL, respectively, and was significantly higher at NS nephrotic phase (P=0.0005). The urinary protein/creatinine ratio at NS nephrotic phase was significantly correlated with serum T3, T4, and free T4 levels (r=-0.5995, P=0.0032; r=-0.5797, P=0.0047; r= 0.5513, P=0.0078) as well as with TSH levels (r=0.5022, P=0.0172). A significant correlation was found between serum albumin levels and serum T3 levels at NS nephrotic phase (r=0.5385, P=0.0018) but not between serum albumin and T4, TSH, or free T4 levels. These significant correlations were all disappeared after remission. Conclusion: Thyroid hormone profile abnormal findings were observed in 51.6% of pediatric patients with NS. Thyroid hormone levels normalized after remission, regardless of levothyroxine therapy. PMID- 30304898 TI - Lymphocyte-monocyte ratio at day 14 of first cisplatin-doxorubicin chemotherapy is associated with treatment outcome of pediatric patients with localized osteosarcoma. AB - Purpose: We aimed to determine the prognostic significance of lymphocyte counts and lymphocyte-monocyte ratio (LMR) in pediatric patients with osteosarcoma. Methods: We retrospectively reviewed the medical records of 27 pediatric patients with localized extremity osteosarcoma treated at Korea Cancer Center Hospital between May 2002 and March 2016. Pretreatment and day 14 of first cisplatin doxorubicin chemotherapy leukocyte counts and LMR (LMR14) were evaluated. Patients were dichotomized according to the median value of these parameters, and survival rates were compared. Results: The median age of the 27 patients was 9.9 years (range, 3.2-14.1 years) and tumor sites were; distal femur (n=14), proximal humerus (n=7), proximal tibia (n=2), proximal fibula (n=2), and elsewhere (n=2). Patients were followed for a median of 76.4 months (range, 4.5-174.7 months), and 5-year overall (OS) and event-free survival (EFS) rates were 66.0+/-9.8% and 60.9+/-9.7%, respectively. Patients with a higher pretreatment lymphocyte count (>= 2,320/uL) had better OS (90.9% vs. 46.2%, P=0.04) and EFS (83.9% vs. 38.5%, P=0.02). However, day 14 lymphocyte count was not associated with survival. While no survival difference was observed between patients grouped according to pretreatment LMR (median value 6.3), patients with a higher LMR14 (>= 5) fared better than those with lower LMR14 (5-year OS, 83.3% vs. 46.3%, P=0.04). Conclusion: In addition to pretreatment lymphocyte count, LMR during chemotherapy had prognostic significance in pediatric osteosarcoma patients. Further studies involving larger cohorts are necessary to validate our findings. PMID- 30304899 TI - Dorsal midline cutaneous stigmata associated with occult spinal dysraphism in pediatric patients. AB - Purpose: To investigate the prevalence of occult spinal dysraphism (OSD) and subsequent neurosurgery in pediatric patients with isolated or combined dorsal midline cutaneous stigmata with or without other congenital malformations. Methods: We undertook a retrospective review of patients who had undergone sonography or magnetic resonance imaging (MRI) evaluation for OSD because of suspicious dorsal midline cutaneous stigmata (defined as presumed markers for OSD) between January 2012 and June 2017. Information about patient's characteristics, physical examination findings, spinal ultrasound and MRI results, neurosurgical notes, and other accompanying congenital anomalies was collected. Results: A total of 250 patients (249 ultrasound and one MRI screening) were enrolled for analysis. Eleven patients underwent secondary MRI examinations. The prevalence of OSD confirmed on MRI was 2.4% (six patients including one MRI screening). Five patients (2%) had tethered cord and underwent prophylactic neurosurgery, three of whom had a sacrococcygeal dimple and a fibrofatty mass. The prevalence of tethered cord elevated with increasing number of additional markers to a sacrococcygeal dimple (0.5% of the isolated marker group, 8.1% of the two-marker group, and 50% of the three-marker group). The incidence of OSD with surgical detethering in 17 other congenital anomaly patients was 11.8%, which was higher than the 1.3% in 233 patients without other congenital anomalies. Conclusion: Our results suggest that adding other dorsal midline cutaneous stigmata, particularly fibrofatty masses, to a sacrococcygeal dimple is associated with OSD or cord tethering requiring surgery. Concurrent presence of other congenital anomalies should be considered a predictable condition for OSD. PMID- 30304900 TI - Clinical features and prognostic factors of early-onset sepsis : a 7.5-year experience in one neonatal intensive care unit. AB - Purpose: This study was undertaken to investigate the clinical features and prognostic factors of early-onset sepsis (EOS) in neonatal intensive care unit (NICU) patients. Methods: A retrospective analysis of the medical records was conducted in a NICU of a university hospital over a 7.5-year period (Jan 2010-Jun 2017). Results: During the study period, there were 45 (1.2%) episodes of EOS in 3,862 infants. The most common pathogen responsible for EOS was Streptococcus group B (GBS) in 10 cases (22.2%), followed by E. coli in 9 cases (20%). The frequency of Gram-positive sepsis was higher in term than in preterm infants, while the rate of Gram-negative infection was higher in preterm than in term infants (P<0.05). The overall mortality was 37.8% (17 of 45), and 47% of deaths occurred within the first 3 days of infection. There was a significant difference in terms of gestational age (26.8 weeks vs. 35.1 weeks) and birth weight (957 g vs. 2,520 g) between the death and survival groups. In a comparison after adjusting for the difference in gestational age and birth weight between the two groups, Gram-negative pathogens (OR: 42, 95% CI: 1.4~1281.8) and some clinical findings, such as neutropenia (OR: 46, 95% CI: 1.3~1628.7) and decreased activity (OR: 34, 95% CI: 1.8~633.4), were associated with fatality. Conclusion: The common pathogens responsible for EOS in NICU patients are GBS and E. coli. Infection caused by Gram-negative bacteria, decreased activity in the early phase of infection, and neutropenia were associated with poor outcomes. PMID- 30304901 TI - Genotype-Phenotype Correlations in Pediatric Patients with Myotonic Dystrophy Type 1. AB - Purpose: Myotonic dystrophy (also known as dystrophia myotonica; DM) is an autosomal dominant disorder with two genetically distinct forms. DM Type 1 (DM1) is the more common form, and is caused by abnormal expansion of CTG repeat in the DM protein kinase (DMPK) gene. Our study aimed to determine whether age of onset is correlated with CTG-repeat length in a pediatric patient population having DM1. Methods: We retrospectively identified 30 pediatric patients with DM1 that underwent DMPK testing, 17 of which had sufficient clinical data. The cohort was divided into two subgroups based on clinical phenotype (congenital-onset versus late-onset) and number of CTG repeats (< 1,000 versus >= 1,000). Results: We found no significant difference between age of onset and CTG-repeat length in our pediatric patient population. Based on clinical subgrouping, we found that the congenital-onset subgroup was statistically different in several variables including prematurity, rate of admission to neonatal intensive care unit, need for respiratory support at birth, hypotonia, dysphagia, ventilator dependence, and functional status at last visit, compared to the late-onset subgroup. Based on genetic subgrouping, we found a single variable (poor feeding in neonate) that was significantly different in the large-CTG subgroup than in the small-CTG subgroup. Conclusions: Clinical variables exhibiting statistically significant differences between the subgroups should be the focus for prognosis and preparation of tailored management approaches for patients, and our findings will contribute to achieve this important goal for patients with DM1. PMID- 30304902 TI - Current use of safety restraint systems and front seats in Korean children based on the 2008-2015 Korea National Health and Nutrition Examination Survey. AB - Purpose: The use of proper safety restraint systems by children is vital for the reduction of traffic accident-related injury and death. This study evaluated the rates of use of safety restraint systems and front seats by Korean children. Methods: Based on data from the National Health and Nutrition Examination Survey from 2008 to 2015, I investigated the frequencies of safety restraint systems and front seat use by children under six and 12 years of age, respectively. Results: The percentage of respondents who said they always use safety restraint systems increased from 17.7% in 2008 to 45.0% in 2015. The rate of children who did not use the front seats at all was 47.3% in 2008 compared to 33.4% in 2015. Multivariate logistic regression analysis showed a decrease in safety-restraint system use as age increased (odds ratio 0.63, 95% confidence interval [CI] 0.51 0.77). The use rate of front-passenger seat belts by the mother is significantly correlated with the safety-restraint-system use rate by children (odds ratio 2.14, 95% CI 1.12-4.06). Conclusion: Although the rate of safety-restraint-system use for children is increasing annually, it remains low. Additionally, the use rate of front passenger seats for children is high. To reduce the rates of injury and death of children from traffic accidents, it is necessary to educate on the appropriate use of safety restraint systems according to age and body size and to develop stronger regulations. PMID- 30304903 TI - Outcomes of transcatheter closure of ductus arteriosus in infants less than six months of age - A single-center experience. AB - Purpose: Transcatheter device closure of patent ductus arteriosus (PDA) is challenging in early infancy. We evaluated PDA closure in infants less than 6 months old. Methods: We performed a retrospective review of infants less than 6 months of age who underwent attempted transcatheter device closure in our institution since 2004. To compare clinical outcomes between age groups, infants aged 6-12 months in the same study period were reviewed. Results: A total of 22 patients underwent transcatheter PDA closure during the study period. Patient mean age was 3.3 +/- 1.5 months, and weight was 5.7 +/- 1.3 kg. The duct diameter at the narrowest point was 3.0 +/- 0.8 mm as measured by angiography. The most common duct type was C in the Krichenko classification. Procedural success was achieved in 19 patients (86.3%). Major complications occurred in 5 patients (22.7%), including device embolization (N=1), acquired aortic coarctation (N=2), access-related vascular injury requiring surgery (N=1), and acute deterioration requiring intubation during the procedure (N=1). Two patients had minor complications (9.1%). Twenty-four infants aged 6-12 months received transcatheter device closure. The procedural success rate was 100%, and there were no major complications. The major complication rate was significantly higher in the group less than 6 months of age (P=0.045). There was a trend toward increased major complication and procedural failure rates in the younger age group (P<0.01). Conclusion: A relatively higher incidence of major complications was observed in infants less than 6 months of age. The decision regarding treatment modality should be individualized. PMID- 30304904 TI - A long-term subacute sclerosing panencephalitis survivor treated with intraventricular interferon-alpha for 13 years. AB - Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, and fatal central nervous system disorder resulting from persistent measles virus infection. Long-term data are scarce, with a maximum follow-up period of 10 years. Interferon-alpha (IFN-alpha) is a protein that exerts its antiviral activity via enhancement of cellular immune response and is reported to be an effective drug for the treatment of SSPE. However, there is currently no consensus regarding the optimal duration of IFN-alpha therapy. Here, we present a case report of a patient with SSPE treated with long-term intraventricular IFN alpha therapy, which facilitated clinical improvement and neurological stabilization without causing serious adverse effects. To the best of our knowledge, this is one of the longest follow-up studies investigating a patient with SSPE receiving intraventricular INF-alpha treatment. Further studies are necessary to validate the benefits and safety of long-term intraventricular IFN alpha treatment in patients with SSPE. PMID- 30304905 TI - Non-alcoholic fatty liver disease in obese and non-obese pediatric patients. AB - Purpose: Obesity is risk factor for nonalcoholic fatty liver disease (NAFLD). However, non-obese patients are also increasingly susceptible to NAFLD. The aim of this study was to compare the clinical characteristics of obese and non-obese pediatric patients with NAFLD. Methods: We retrospectively studied 68 NAFLD patients between January 2010 and October 2016 who diagnosed at 10-18 years of age. Other diseases were excluded in all patients. Body mass index (BMI) >=95th percentile for age and sex was defined as obesity. Abdominal ultrasonography and Laboratory, anthropometrics measurements were evaluated. Results: Among the 68, 26 (38.2%) were non-obese patients. The ratio of male-to female was 5.8:1, and the median age at diagnosis was 13 years (range, 10-17 years). Significant higher triglyceride (223.0 vs. 145.9 mg/dL, p = 0.047) and total cholesterol levels (211.6 vs. 173.2 mg/dL, p = 0.011) were shown in non-obese than obese patients. High-density lipoprotein cholesterol level < 40mg/dL (HR: 6.5, 95% CI = 2.13 7.10, p = 0.048), total cholesterol level >200 mg/dL (HR: 5.6, 95% CI = 1.23 15.31, p = 0.038) and abdominal obesity (HR: 2.53, 95% CI = 1.22-4.68, p = 0.013) were significant risk factors for NAFLD in non-obese patients. Conclusions: Non obese patients present a substantial proportion of pediatric NAFLD cases. Significant abnormal lipid concentrations were found in non-obese and abdominal obesity was important risk factor for non-obese NAFLD. PMID- 30304906 TI - The clinical characteristics and prognosis of subgaleal hemorrhage in newborn. AB - Purpose: Subgaleal hemorrhage (SGH) is a rare but potentially fatal condition in newborns; however, few studies have reported on this condition. We aimed to identify the clinical characteristics and prognostic factors of SGH. Methods: We retrospectively reviewed the medical records of 20 neonates diagnosed with SGH between January 2000 and June 2017. Enrolled neonates were clinically diagnosed when they had tender fluctuant scalp swelling that crossed the suture lines. Results: Among 20 neonates with SGH, 12 were boys and 7 were girls; median hospitalization duration was 9.7+/-6.9 days. Fourteen neonates (70%) were born via vacuum-assisted vaginal delivery, and 4 via vacuum-assisted cesarean section. Of the neonates enrolled, half of them initially showed unstable vital signs, including apnea, desaturation, and cyanosis. Ten neonates had acidosis and 3 had asphyxia (pH <7.0). Intracranial lesions associated with SGH were observed in 15 neonates (75%), including subdural hemorrhage (50%), subarachnoid hemorrhage (15%), intraventricular hemorrhage (5%), cerebral infarct (15%), skull fracture (30%), and cephalohematoma (20%). Twelve neonates (60%) required transfusion, 5 (25%) had seizures, and 3 (15%) died. Eight neonates (40%) had hyperbilirubinemia (mean total bilirubin = 13.1+/-7.4). The mean follow-up period was 8.4+/-7.5 months. At follow-up, 10 neonates (58.8%) were healthy with normal development, whereas 7 (41.2%) had neurological deficits. Conclusion: The morbidity rate was 41.2% due to severe metabolic acidosis. Anemia, hyperbilirubinemia, low Apgar scores, and subdural hemorrhage did not affect the prognosis. The long-term outcomes of neonates with SGH are generally good. Only arterial blood pH was significantly associated with death. PMID- 30304907 TI - Clinical manifestations of headache in children younger than 7 years. AB - PURPOSE: Headache is a common symptom during childhood. It is usually persistent and requires special care. This study aimed to identify the characteristics of headache in children <7 years of age. METHODS: We reviewed 3 years of clinical files on children <7 years of age with a chief complaint of headache. RESULTS: This study included 146 children (66 males, 80 females; mean age, 5.5+/-1.0 years). Mean symptom duration was 5.8+/-7.9 months. Attack durations were longer than 2 hours in 31 patients, shorter than 2 hours in 70 patients, and unchecked in 45 patients. Attack frequency was 15.1+/-10.6 times per month. Pain locations and characteristics were also variable. Mean pain severity score was 5.1+/-2.2 on the visual analog scale. Of 38 patients who underwent electroencephalography, 9 showed positive findings. Of 41 who underwent brain magnetic resonance imaging, 20 showed positive findings. The diagnoses were migraine (including probable migraine) in 34, tension-type headache in 5, and congenital malformations in 3. Medications were used in 29 patients: acetaminophen in 17, ibuprofen in 8, naproxen sodium in 1, and topiramate or amitriptyline in 3. CONCLUSION: In children aged <7 years, headache has a relatively benign course, but detailed history taking is needed for more accurate diagnosis. PMID- 30304908 TI - Common features of atopic dermatitis with hypoproteinemia. AB - PURPOSE: The purpose of this study was to identify the causes, symptoms, and complications of hypoproteinemia to prevent hypoproteinemia and provide appropriate treatment to children with atopic dermatitis. METHODS: Children diagnosed with atopic dermatitis with hypoproteinemia and/or hypoalbuminemia were retrospectively reviewed. The patients' medical records, including family history, weight, symptoms, treatment, complications, and laboratory test results for allergies and skin cultures, were examined. RESULTS: Twenty-six patients (24 boys) were enrolled. Seven cases had growth retardation; 7, keratoconjunctivitis; 6, aural discharges; 5, eczema herpeticum; 4, gastrointestinal tract symptoms; and 2, developmental delays. In 21 cases, topical steroids were not used. According to the blood test results, the median values of each parameter were elevated: total IgE, 1,864 U/mL; egg white-specific IgE, 76.5 kUA/L; milk IgE, 20.5 kUA/L; peanut IgE, 30 kUA/L; eosinophil count, 5,810/MUL; eosinophil cationic protein, 93.45 MUg/L; and platelet count, 666.5*103/MUL. Serum albumin and total protein levels decreased to 2.7 g/dL and 4.25 g/dL, respectively. Regarding electrolyte abnormality, 10 patients had hyponatremia, and 12, hyperkalemia. Systemic antibiotics were used to treat all cases, and an antiviral agent was used in 12 patients. Electrolyte correction was performed in 8 patients. CONCLUSION: Hypoproteinemia accompanying atopic dermatitis is common in infants younger than 1 year and may occur because of topical steroid treatment continuously being declined or because of eczema herpeticum. It may be accompanied by growth retardation, keratoconjunctivitis, aural discharge, and eczema herpeticum and can be managed through skin care and topical steroid application without intravenous albumin infusion. PMID- 30304909 TI - Transient intubation for surfactant administration in the treatment of respiratory distress syndrome in extremely premature infants. AB - PURPOSE: To investigate the effectiveness of transient intubation for surfactant administration and extubated to nasal continuous positive pressure (INSURE) for treatment of respiratory distress syndrome (RDS) and to identify the factors associated with INSURE failure in extremely premature infants. METHODS: Eighty four infants with gestational age less than 28 weeks treated with surfactant administration for RDS for 8 years were included. Perinatal and neonatal characteristics were retrospectively reviewed, and major pulmonary outcomes such as duration of mechanical ventilation (MV) and bronchopulmonary dysplasia (BPD) plus death at 36-week postmenstrual age (PMA) were compared between INSURE (n=48) and prolonged MV groups (n=36). The factors associated with INSURE failure were determined. RESULTS: Duration of MV and the occurrence of BPD at 36-week PMA were significantly lower in INSURE group than in prolonged MV group (P<0.05), but BPD plus death at 36-week PMA was not significantly different between the 2 groups. In a multivariate analysis, a reduced duration of MV was only significantly associated with INSURE (P=0.001). During the study period, duration of MV significantly decreased over time with an increasing rate of INSURE application (P<0.05), and BPD plus death at 36-week PMA also tended to decrease over time. A low arterial-alveolar oxygen tension ratio (a/APO2 ratio) was a significant predictor for INSURE failure (P=0.001). CONCLUSION: INSURE was the noninvasive ventilation strategy in the treatment of RDS to reduce MV duration in extremely premature infants with gestational age less than 28 weeks. PMID- 30304910 TI - The first Korean case with Floating-Harbor syndrome with a novel SRCAP mutation diagnosed by targeted exome sequencing. AB - Floating-Harbor syndrome is a rare autosomal dominant genetic disorder associated with SRCAP mutation. To date, approximately 50 cases of Floating-Harbor syndrome have been reported, but none have been reported in Korea yet. Floating-Harbor syndrome is characterized by delayed bony maturation, unique facial features, and language impairment. Here, we present a six-year-old boy with a triangular face, deep-set protruding eyes, low-set ears, wide nose with narrow nasal bridge, short philtrum, long thin lips, clinodactyly, and developmental delay that was transferred to our pediatric clinic for genetic evaluation. He showed progressive delay in the area of language and cognition-adaption as he grew. He had previously undergone chromosomal analysis at another hospital due to his language delay, but his karyotype was normal. We performed targeted exome sequencing, considering several syndromes with similar phenotypes. Library preparation was performed with the TruSight One sequencing panel (Illumina, USA), which enriches the sample for about 4800 genes of clinical relevance. Massively parallel sequencing was conducted with NextSeq (Illumina, USA). An identified variant was confirmed by Sanger sequencing of the patient and his parents. Finally, the patient was confirmed as the first Korean case of Floating-Harbor syndrome with a novel SRCAP (Snf2 related CREBBP activator protein) mutation (c.7732dupT, p.Ser2578Phefs*6), resulting in early termination of the protein; it was not found in either of his healthy parents or a control population. To our knowledge, this is the first study to describe a boy with Floating-Harbor syndrome with a novel SRCAP mutation diagnosed by targeted exome sequencing in Korea. PMID- 30304911 TI - Evaluation of prolonged pain in preterm infants with pneumothorax using heart rate variability analysis and EDIN (Echelle Douleur Inconfort Nouveau-Ne, neonatal pain and discomfort scale) scores. AB - PURPOSE: The EDIN scale (Echelle Douleur Inconfort Nouveau-Ne, neonatal pain and discomfort scale) and heart rate variability has been used for the evaluation of prolonged pain. The aim of our study was to assess the value of the newborn infant parasympathetic evaluation (NIPE) index and EDIN scale for the evaluation of prolonged pain in preterm infants with chest tube placement due to pneumothorax. METHODS: This prospective observational study assessed prolonged pain in preterm infants with a gestational age between 33 and 35 weeks undergoing installation of chest tubes. Prolonged pain was assessed using the EDIN scale and NIPE index. RESULTS: There was a significant correlation between the EDIN scale and NIPE index (r=-0.590, P=0.003). Prolonged pain is significantly more severe in the first 6 hours following chest tube installation (NIPE index: 60 [50-86] vs. 68 [45-89], P<0.002; EDIN score: 8 [7-11] vs. 6 [4-8], P<0.001). CONCLUSION: Prolonged pain can be accurately assessed with the EDIN scale and NIPE index. However, evaluation with the EDIN scale is time-consuming. The NIPE index can provide instantaneous assessment of prolonged and continuous pain. PMID- 30304912 TI - Renal involvement in children and adolescents with inflammatory bowel disease. AB - PURPOSE: The incidence of inflammatory bowel disease (IBD) is rapidly increasing, and several reports have described the renal complications of IBD. We sought to evaluate the clinical manifestations of renal complications in children with IBD in order to enable early detection and prompt treatment of the complications. METHODS: We retrospectively reviewed the medical records of 456 children and adolescents aged <20 years who had been diagnosed with IBD since 2000. We analyzed patient age, sex, medication use, IBD disease activity, and clinical manifestations of renal symptoms. RESULTS: Our study comprising 456 children with IBD included 299 boys (65.6%) and 157 girls (34.4%). The study included 346 children with Crohn disease and 110 children with ulcerative colitis. The incidence of kidney-related symptoms was 14.7%, which was significantly higher than that in normal children. We observed 26 children (38.8%) with isolated hematuria, 30 children (44.8%) with isolated proteinuria, and 11 children (16.4%) with hematuria and concomitant proteinuria. A renal biopsy was performed in 7 children. Histopathological examination revealed immunoglobulin A nephropathy in 5 children (71.4%). All children presented with mild disease and well-controlled disease activity of IBD. CONCLUSION: Children with IBD are more likely to show kidney-related symptoms than healthy children and adolescents are. Therefore, regular screening of urine and evaluation of renal function in such children are necessary for early detection of renal complications. PMID- 30304914 TI - Nitrogen Sources Inhibit Biofilm Formation of Xanthomonas oryzae pv. oryzae. AB - Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight, which results in a severe economic damage to rice farms. Xoo produces biofilms for pathogenesis and survival both inside and outside the host. Biofilms, which are important virulence factors, play a key role in causing the symptoms of Xoo infection. In the present study, we investigated nutritional conditions for the biofilm formation of Xoo. Although the biofilm formation of Xoo may be initiated by their interactions with the host, there is no mature biofilm formation without the support of favorable nutritional conditions. Nitrogen sources inhibited biofilm formation by overwhelming the positive effect of cell growth on biofilm formation. Limited nutrients with low amino acid concentration supported the biofilm formation of Xoo in the xylem sap rather than in the phloem sap of rice. PMID- 30304913 TI - Comparison of conservative therapy and steroid therapy for Bell's palsy in children. AB - PURPOSE: Bell's palsy is characterized by sudden onset of unilateral facial weakness. The use of corticosteroids for childhood Bell's palsy is controversial. This study aimed to identify clinical characteristics, etiology, and laboratory findings in childhood Bell's palsy, and to evaluate the efficacy of corticosteroid treatment. METHODS: We conducted a retrospective analysis of children under 19 years of age treated for Bell's palsy between January 2009 and June 2017, and followed up for over 1 month. Clinical characteristics, neuroimaging data, laboratory findings, treatments, and outcomes were reviewed. Patients with Bell's palsy were divided into groups with (group 1) and without (group 2) corticosteroid treatment. Differences in onset age, sex, laterality, infection and vaccination history, degree of facial nerve palsy, and prognosis after treatment between the groups were analyzed. RESULTS: One hundred patients were included. Mean age at presentation was 7.4+/-5.62 years. A total of 73 patients (73%) received corticosteroids with or without intravenous antiviral agents, and 27 (27%) received only supportive treatment. There was no significant difference in the severity, laboratory findings, or neuroimaging findings between the groups. Significant improvement was observed in 68 (93.2%) and 26 patients (96.3%) in groups 1 and 2, respectively; this rate was not significantly different between the groups (P=0.48). CONCLUSION: Childhood Bell's palsy showed good prognosis with or without corticosteroid treatment; there was no difference in prognosis between treated and untreated groups. Steroid therapy in childhood Bell's palsy may not significantly improve outcomes. PMID- 30304915 TI - Hepatitis E Virus Papain-like Cysteine Protease Inhibits Type I Interferon Induction by Down-regulating Melanoma Differentiation-Associated Gene 5. AB - Upon viral infection, the host cell recognizes the invasion through a number of pattern recognition receptors. MDA5 and RIG-I recognizes RNA molecules derived from invading viruses, activating down-stream signaling cascades, culminating in the induction of the type I interferon. On the other hand, viruses have evolved to evade type I interferon-mediated inhibition. Hepatitis E virus has been shown to encode a few antagonists of type I interferon and it is not surprising a virus encodes multiple mechanisms of viral evasion. In the present study, we demonstrated that HEV PCP strongly down-regulates melanoma differentiation associated gene 5 (MDA5)-mediated activation of interferon b induction in a dose dependent manner. Interestingly, MDA5 protein expression was almost completely abolished. In addition, polyinosinic polycytidylic acid (poly(A:C))- and Sendai virus-mediated activation of type I interferon responses were similarly abrogated in the presence of HEV PCP. Furthermore, HEV PCP down-regulates several molecules which play critical roles in the induction of type I IFN expression. Taken together, these data collectively suggest that HEV-encoded PCP is a strong antagonist of type I interferon. PMID- 30304916 TI - Zinc Ions Affect Siderophore Production by Fungi Isolated from the Panax ginseng Rhizosphere. AB - Although siderophore compounds are mainly biosynthesized as a response to iron deficiency in the environment, they also bind with other metals. A few studies demonstrated prompting impact of heavy metals on the siderophore-mediated iron uptake by microbiome. Here, we investigated siderophore production by a variety of rhizosphere fungi under different concentrations of Zn2+ ion. These strains were specifically isolated from the rhizosphere of Panax ginseng (Korean ginseng). The siderophore production of isolated fungi was investigated with chrome azurol S (CAS) assay liquid media amended with different concentrations of Zn2+ (50 to 250 MUg mL-1). The percentage of siderophore units was quantified using the ultra-violet (UV) irradiation method. The results indicated that high concentrations of Zn2+ ion increase the production of siderophore in iron-limited cultures. Maximum siderophore production by the fungal strains was detected at Zn2+ ion concentration of 150 MUg mL-1 except for Mortierella sp., which had the highest siderophore production at 200 MUg mL-1. One potent siderophore-producing strain (Penicillium sp. JJHO)was strongly influenced by the presence of Zn2+ ions and showed high identity to P. commune (100% using 18S-rRNA sequencing). The purified siderophore of the Penicillium sp. JJHO strain was chemically identified using UV, Fourier-transform infrared spectroscopy (FTIR), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS)spectra. PMID- 30304917 TI - Effect of the pat, fk, stpk gene knock-out and mdh gene knock-in on mannitol production in Leuconostoc mesenteroides. AB - Leuconostoc mesenteroides can be used to produce mannitol by fermentation, but the mannitol productivity is not high. Therefore, this study modify the chromosome of Leuconostoc mesenteroides by genetic methods to obtain high-yield strains of mannitol. In this study, gene knock-out strains and gene knock-in strains were constructed by a two-step homologous recombination method. The mannitol productivity of the pat gene (which encoding phosphate acetyltransferase) deleteon strain (Deltapat::amy), fk gene (which encoding fructokinase) deleteon strain (Deltafk::amy) and stpk gene (which encoding serine threonine protein kinase) deleteon strain (Deltastpk::amy) were all increased compared to the wild type, and the productivity of mannitol were 84.8 %, 83.5 % and 84.1% respectively. The mannitol productivity of mdh gene (which encoding mannitol dehydrogenase) knock-in strain Deltapat::mdh, Deltafk::mdh and Deltastpk::mdh was increased than the single gene deletion strains, and the productivity of mannitol was 96.5 %, 88 % and 93.2 % respectively. The multi mutant strain DeltadtsDeltaldhDeltapat::mdhDeltastpk::mdhDeltafk::mdh with a mannitol productivity of 97.3 %. This work shows that multi-gene knock-out and gene knock-in strains have the greatest impact on mannitol production, with a mannitol productivity of 97.3% and an increase of 24.7 % over wild type. This study used the methods of gene knock-out and gene knock-in to genetically modify the chromosome of Leuconostoc mesenteroides. It is of great significance to increase the synthesis ability of mannitol and has broad development prospects. PMID- 30304918 TI - Enhanced 2,5-furandicarboxylic acid (FDCA) production in Raoultella ornithinolytica BF60 by manipulation of the key genes in FDCA biosynthesis pathway. AB - The compound 2,5-furandicarboxylic acid (FDCA), an important bio-based monomer for the production of various polymers, can be obtained from 5 hydroxymethylfurfural (HMF). However, efficient production of FDCA from HMF via biocatalysis has not been well studied. In this study, we report the identification of key genes that are involved in FDCA synthesis and then the engineering of Raoultella ornithinolytica BF60 for biocatalytic oxidation of HMF to FDCA using its resting cells. Specifically, previously unknown candidate genes, adhP3 and alkR, which were responsible for the reduction of HMF to the undesired product 2,5-bis(hydroxymethyl) furan (HMF alcohol), were identified by transcriptomic analysis. Combinatorial deletion of these two genes resulted in 85.7% reduction in HMF alcohol formation and 23.7% improvement in FDCA production (242.0 mM). Subsequently, an aldehyde dehydrogenase, AldH, which was responsible for the oxidation of the intermediate 5-formyl-2-furoic acid (FFA) to FDCA, was identified and characterized. Finally, FDCA production was further improved by overexpressing AldH, resulting in a 96.2% yield of 264.7 mM FDCA. Importantly, the identification of these key genes not only contributes to our understanding of the FDCA synthesis pathway in R. ornithinolytica BF60 but also allows for improved FDCA production efficiency. Moreover, this work is likely to provide a valuable reference for producing other furanic chemicals. PMID- 30304919 TI - Can we distinguish three maintenance processes in working memory? AB - We describe three mechanisms-consolidation, refreshing, and removal-as processes that may serve to strengthen new memories. We detail their explicit and implied differences and similarities, and highlight points upon which theorists disagree about their supposed characteristics. We consider the challenges remaining in refining definitions of these processes and with situating them within working memory theories, and consider how these process definitions and theories should restrict each other. PMID- 30304921 TI - Editor's Introduction to This Issue (G&I 16:2, 2018). PMID- 30304920 TI - EZH2-Mediated microRNA-139-5p Regulates Epithelial-Mesenchymal Transition and Lymph Node Metastasis of Pancreatic Cancer. AB - Pancreatic cancer (PC) is one of the most aggressive cancers presenting with high rates of invasion and metastasis, and unfavorable prognoses. The current study aims to investigate whether EZH2/miR-139-5p axis affects epithelial-mesenchymal transition (EMT) and lymph node metastasis (LNM) in PC, and the mechanism how EZH2 regulates miR-139-5p. Human PC and adjacent normal tissues were collected to determine expression of EZH2 and miR-139-5p, and their relationship with clinicopathological features of PC. Human PC cell line was selected, and treated with miR-139-5p mimics/inhibitors, EZH2 vector or shEZH2 in order to validate the regulation of EZH2-mediated miR-139-5p in PC cells. Dual-luciferase report gene assay and chromatin immunoprecipitation assay were employed to identify the relationship between miR-139-5p and EZH2. RT-qPCR and Western blot analysis were conducted to determine the expression of miR-139-5p, EZH2 and EMT-related markers and ZEB1/2. Tumor formation ability and in vitro cell activity were also analyzed. Highly-expressed EZH2 and poorly-expressed miR-139-5p were detected in PC tissues, and miR-139-5p and EZH2 expressions were associated with patients at Stage III/IV, with LNM and highly-differentiated tumors. EZH2 suppressed the expression of miR-139-5p through up-regulating Histone 3 Lysine 27 Trimethylation (H3K27me3). EMT, cell proliferation, migration and invasion were impeded, and tumor formation and LNM were reduced in PC cells transfected with miR-139-5p mimics and shEZH2. MiR-139-5p transcription is inhibited by EZH2 through up regulating H3K27me3, thereby down-regulation of EZH2 and up-regulation of miR-139 5p impede EMT and LNM in PC. In addition, the EZH2/miR-139-5p axis presents as a promising therapeutic strategy for the treatment of PC. PMID- 30304922 TI - Mutation Analysis of Synthetic DNA Barcodes in a Fission Yeast Gene Deletion Library by Sanger Sequencing. AB - Incorporation of unique barcodes into fission yeast gene deletion collections has enabled the identification of gene functions by growth fitness analysis. For fine tuning, it is important to examine barcode sequences, because mutations arise during strain construction. Out of 8,708 barcodes (4,354 strains) covering 88.5% of all 4,919 open reading frames, 7,734 barcodes (88.8%) were validated as high fidelity to be inserted at the correct positions by Sanger sequencing. Sequence examination of the 7,734 high-fidelity barcodes revealed that 1,039 barcodes (13.4%) deviated from the original design. In total, 1,284 mutations (mutation rate of 16.6%) exist within the 1,039 mutated barcodes, which is comparable to budding yeast (18%). When the type of mutation was considered, substitutions accounted for 845 mutations (10.9%), deletions accounted for 319 mutations (4.1%), and insertions accounted for 121 mutations (1.6%). Peculiarly, the frequency of substitutions (67.6%) was unexpectedly higher than in budding yeast (~28%) and well above the predicted error of Sanger sequencing (~2%), which might have arisen during the solid-phase oligonucleotide synthesis and PCR amplification of the barcodes during strain construction. When the mutation rate was analyzed by position within 20-mer barcodes using the 1,284 mutations from the 7,734 sequenced barcodes, there was no significant difference between up-tags and down-tags at a given position. The mutation frequency at a given position was similar at most positions, ranging from 0.4% (32/7,734) to 1.1% (82/7,734), except at position 1, which was highest (3.1%), as in budding yeast. Together, well-defined barcode sequences, combined with the next-generation sequencing platform, promise to make the fission yeast gene deletion library a powerful tool for understanding gene function. PMID- 30304923 TI - Comparison of the Genetic Alterations between Primary Colorectal Cancers and Their Corresponding Patient-Derived Xenograft Tissues. AB - Patient-derived xenograft (PDX) models are useful tools for tumor biology research and testing the efficacy of candidate anticancer drugs targeting the druggable mutations identified in tumor tissue. However, it is still unknown how much of the genetic alterations identified in primary tumors are consistently detected in tumor tissues in the PDX model. In this study, we analyzed the genetic alterations of three primary colorectal cancers (CRCs) and matched xenograft tissues in PDX models using a next-generation sequencing cancer panel. Of the 17 somatic mutations identified from the three CRCs, 14 (82.4%) were consistently identified in both primary and xenograft tumors. The other three mutations identified in the primary tumor were not detected in the xenograft tumor tissue. There was no newly identified mutation in the xenograft tumor tissues. In addition to the somatic mutations, the copy number alteration profiles were also largely consistent between the primary tumor and xenograft tissue. All of these data suggest that the PDX tumor model preserves the majority of the key mutations detected in the primary tumor site. This study provides evidence that the PDX model is useful for testing targeted therapies in the clinical field and research on precision medicine. PMID- 30304925 TI - Transfer Dysphagia Due to Focal Dystonia. AB - OBJECTIVE: The inability to propel a bolus of food successfully from the posterior part of the oral cavity to the oropharynx is defined as transfer dysphagia. The present case series describes the varied presentation of transfer dysphagia due to focal dystonia and highlights the importance of early detection by following up on strong suspicions. METHODS: We describe seven cases of transfer dysphagia due to focal dystonia. Transfer dysphagia as a form of focal dystonia may appear as the sole presenting complaint or may present with other forms of focal dystonia. RESULTS: Four out of seven patients had pure transfer dysphagia and had previously been treated for functional dysphagia. A high index of suspicion, barium swallow including videofluoroscopy, associated dystonia in other parts of the body and response to drug therapy with trihexyphenidyl/tetrabenazine helped to confirm the diagnosis. CONCLUSION: Awareness of these clinical presentations among neurologists and non-neurologists can facilitate an early diagnosis and prevent unnecessary investigations. PMID- 30304924 TI - Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age. AB - Kawasaki disease (KD) is an acute febrile vasculitis predominately affecting infants and children. The dominant incidence age of KD is from 6 months to 5 years of age, and the incidence is unusual in those younger than 6 months and older than 5 years of age. We tried to identify genetic variants specifically associated with KD in patients younger than 6 months or older than 5 years of age. We performed an age-stratified genome-wide association study using the Illumina HumanOmni1-Quad BeadChip data (296 cases vs. 1,000 controls) and a replication study (1,360 cases vs. 3,553 controls) in the Korean population. Among 26 candidate single nucleotide polymorphisms (SNPs) tested in replication study, only a rare nonsynonymous SNP (rs4365796: c.1106C>T, p.Thr369Met) in the lymphoid enhancer binding factor 1 (LEF1) gene was very significantly associated with KD in patients younger than 6 months of age (odds ratio [OR], 3.07; pcombined = 1.10 * 10-5), whereas no association of the same SNP was observed in any other age group of KD patients. The same SNP (rs4365796) in the LEF1 gene showed the same direction of risk effect in Japanese KD patients younger than 6 months of age, although the effect was not statistically significant (OR, 1.42; p = 0.397). This result indicates that the LEF1 gene may play an important role as a susceptibility gene specifically affecting KD patients younger than 6 months of age. PMID- 30304926 TI - Musculoskeletal Problems Affect the Quality of Life of Patients with Parkinson's Disease. AB - OBJECTIVE: Musculoskeletal problems are more common in patients with Parkinson's disease (PD) than in normal elderly, but the impact of musculoskeletal problems on health-related quality of life (HRQoL) in patients with PD is unknown. METHODS: Four hundred consecutive patients with PD were enrolled for the evaluation of musculoskeletal problems and HRQoL. HRQoL was assessed by the 36 Item Short Form Health Survey, which comprised physical health and mental health. RESULTS: Of the total patients, 265 patients had musculoskeletal problems, and 135 patients did not have musculoskeletal problems. Patients with musculoskeletal problems reported lower levels of HRQoL in terms of physical health than did patients without musculoskeletal problems (p < 0.05). In women, all components of physical health were lower in patients with musculoskeletal problems than in patients without musculoskeletal problems (p < 0.05). Meanwhile, in men, only the bodily pain score of physical health was lower in patients with musculoskeletal problems than in patients without musculoskeletal problems. Mental health and physical health were negatively correlated with depression, Unified Parkinson's Disease Rating Scale I & II scores, and pain severity from musculoskeletal problems, in that order (p < 0.01 for all). CONCLUSION: These results suggest that musculoskeletal problems in patients with PD affect HRQoL significantly, mainly in terms of physical health rather than mental health and especially in women rather than men. Musculoskeletal problems should not be overlooked in the care of patients with PD. PMID- 30304927 TI - Cognition, Olfaction and Uric Acid in Early de novo Parkinson's Disease. AB - OBJECTIVE: Cognitive impairment is one of the nonmotor symptoms in Parkinson's disease (PD), and olfactory dysfunction is used as a marker to detect premotor stages of PD. Serum uric acid (sUA) levels have been found to be a risk factor for PD. Our objective in this study was to examine whether sUA levels are associated with cognitive changes and olfactory dysfunction in early de novo PD patients. METHODS: The study participants included 196 de novo PD patients. We assessed cognitive function by the Korean versions of the Mini-Mental State Examination and the Montreal Cognitive Assessment and assessed olfactory function by the Korean version of the Sniffin' Sticks test. RESULTS: The mean sUA level was 4.7 mg/dL and was significantly lower in women than in men. Cognitive scores were lower in women, suggesting that sUA levels were related to cognitive function. The olfactory functions were not related to sUA level but were clearly associated with cognitive scores. Olfactory threshold, odor discrimination, and odor identification were all significantly related to cognitive scores. CONCLUSION: We conclude that lower sUA levels were associated with cognitive impairment, not olfactory dysfunction, in de novo PD patients. This finding suggests that UA is neuroprotective as an antioxidant in the cognitive function of PD patients. PMID- 30304928 TI - A Patient with Myotonic Dystrophy Type 1 Presenting as Parkinsonism. AB - The current body of literature contains 5 reports of myotonic dystrophy (DM) with parkinsonism: 4 reports of DM type 2 and 1 report of clinically suspected DM type 1. To date, there have been no genetically proven cases of DM type 1 with parkinsonism. Here, we report the first case of genetically proven DM type 1 and parkinsonism that developed ahead of muscle symptoms with bilateral putaminal, presynaptic dopaminergic deficits on imaging. A 54-year-old female patient presented with bradykinesia, axial and bilateral limb rigidity, stooped posture, and hypomimia, which did not respond to levodopa. At age 56, she developed neck flexion weakness. Examination showed bilateral facial weakness, percussion and grip myotonia, and electromyography confirmed myotonic discharges. A genetic study of DM type 1 showed a DMPK mutation. At age 58, gait freezing, postural instability, and frequent falling developed and did not respond to increasing doses of levodopa. At age 59, the patient died from asphyxia. PMID- 30304929 TI - Postoperative Outcomes of Stoma Takedown: Results of Long-term Follow-up. AB - PURPOSE: Stoma takedown is a frequently performed procedure with considerable postoperative morbidities. Various skin closure techniques have been introduced to reduce surgical site infections. The aim of this study was to assess postoperative outcomes after stoma takedown during a long-term follow-up period. METHODS: Between October 2006 and December 2015, 84 consecutive patients underwent a colostomy or ileostomy takedown at our institution. Baseline characteristics and perioperative outcomes were analyzed through retrospective reviews of medical records. RESULTS: The proportion of male patients was 60.7%, and the mean age of the patients was 59.0 years. The overall complication rate was 28.6%, with the most common complication being prolonged ileus, followed by incisional hernia, anastomotic leakage, surgical site infection, anastomotic stenosis, and entero-cutaneous fistula. The mean follow-up period was 64.3 months. The univariate analysis revealed no risk factors related to overall complications or prolonged ileus. CONCLUSION: The postoperative clinical course and long-term outcomes following stoma takedown were acceptable. Stoma takedown is a procedure that can be performed safely. PMID- 30304930 TI - The Impact of the Outcome of Treating a High Anal Fistula by Using a Cutting Seton and Staged Fistulotomy on Saudi Arabian Patients. AB - PURPOSE: A cutting seton is used after a partial distal fistulotomy to treat patients with a high exrasphincteric fistula in ano to avoid fecal incontinence and recurrence. In Saudi Arabia, religious practices necessitate complete cleanness, which makes conditions affecting anal continence a major concern to patients affected by an anal fistula. Therefore, we aimed to evaluate the efficiency of the cutting seton in treating a high anal fistula among Saudi Arabians. METHODS: Between January 2005 and December 2014, a prospective study was done for 372 Saudi Arabian patients diagnosed as having a high anal fistula and treated with a cutting seton at Al-Ansar General Hospital, Medina, Saudi Arabia. 0-silk sutures were used. All patients underwent the same preoperative assessment, operative technique, and postoperative follow-up. Weekly, the seton was tightened in outpatient clinics. RESULTS: Two hundred ninety-eight patients (80.1%) were males and 74 (19.9%) females. The duration of symptoms varied from 3 21 months. The fistula healed completely in 363 patients (97.6%); 58 patients (15.6%) reported some degree of incontinence to flatus, but none to feces. In 9 patients (2.4%) the fistula recurred. CONCLUSION: The utilization of the cutting seton method in the treatment of patients with a high anal fistula is highly efficient as it simultaneously drains the abscess, cuts the fistulous tract, and causes fibrosis along the tract. Treatment of a high anal fistula by using a staged fistulotomy with a cutting seton was very rewarding to Saudi Arabian patients who feared anal incontinence for religious reasons and was associated with low postoperative complication and recurrence rates. PMID- 30304931 TI - Abdominosacral Resection in the Management of Large-Size Retrorectal Tumors: A Report of 2 Rare Cases. AB - Management of large-size retrorectal gastrointestinal stromal tumors (GISTs) is complex and challenging from diagnosis to treatment. This may create technical difficulties in surgical access and complete resection of the tumor. The abdominosacral resection has the benefit of improved visualization via the anterior incision, with enhanced exposure of the midrectal area, which makes resecting the tumor completely via the posterior approach easier. We report 2 cases of patients with a retrorectal GIST and neurofibromatosis type 1, one in a 27-year-old woman with a defecation complaint and the other in a 58-year-old woman with a defecation and urination complaint. Based on the anatomical pathology, both patients were diagnosed with a GIST. The tumors were excised via an abdominosacral resection. Retrorectal GISTs are rare, and abdominosacral resection allows complete resection of a large-size retrorectal GIST with low morbidity and an absence of functional impairment. The abdominosacral resection should be considered in certain situations. PMID- 30304932 TI - Transposons and the PIWI pathway: genome defense in gametes and embryos AB - Hiding in plain sight within the genome of virtually every eukaryotic organism are large numbers of sequences known as transposable elements (TEs). These sequences often comprise 50% or more of the DNA in many mammals and are transcriptionally constrained by DNA methylation and repressive chromatin marks. Individual TEs, when relieved of these epigenetic constraints, can readily move from one genomic location to another, either directly or through RNA intermediates. Demethylation and removal of repressive histone marks during epigenetic reprogramming stages of gametogenesis and embryogenesis render the genome particularly susceptible to increased TE mobilization, which has significant implications for the fidelity of genome replication and subsequent viability of the progeny. Importantly, however, TEs have functionally integrated themselves into developmental events to the extent that complete suppression precludes normal gamete and embryo development. Consequently, multiple mechanisms have evolved to limit the extent of TE expression and mobilization during reprogramming without completely suppressing it. One of the most important TE repression mechanisms is the PIWI/piRNA pathway, in which 25-32 nucleotide RNA molecules known as piRNAs associate with Argonaute proteins from the PIWI clade to form piRISC complexes. These complexes target and silence TEs post transcriptionally and through the induction of epigenetic changes at the loci from which they are expressed. This review will briefly discuss the intricate molecular detente between TE expression and its suppression by the PIWI pathway, with particular emphasis on mammalian species including human, bovine and murine. PMID- 30304933 TI - Programming of the reproductive axis by hormonal and genetic manipulation in mice AB - In mammals, the reproductive function is controlled by the hypothalamic-pituitary gonadal axis. During development, mechanisms mediated by gonadal steroids exert an imprinting at the hypothalamic-pituitary level, by establishing sexual differences in the circuits that control male and female reproduction. In rodents, the testicular production of androgens increases drastically during the fetal/neonatal stage. This process is essential for the masculinization of the reproductive tract, genitals and brain. The conversion of androgens to estrogens in the brain is crucial for the male sexual differentiation and behavior. Conversely, feminization of the brain occurs in the absence of high levels of gonadal steroids during the perinatal period in females. Potential genetic contribution to the differentiation of brain cells through direct effects of genes located on sex chromosomes is also relevant. In this review, we will focus on the phenotypic alterations that occur on the hypothalamic-pituitary-gonadal axis of transgenic mice with persistently elevated expression of the human chorionic gonadotropin hormone (hCG). Excess of endogenously synthesized gonadal steroids due to a constant hCG stimulation is able to disrupt the developmental programming of the hypothalamic-pituitary axis in both transgenic males and females. Locally produced estrogens by the hypothalamic aromatase might play a key role in the phenotype of these mice. The 'four core genotypes' mouse model demonstrated a potential influence of sex chromosome genes in brain masculinization before critical periods of sex differentiation. Thus, hormonal and genetic factors interact to regulate the local production of the neurosteroids necessary for the programming of the male and female reproductive function. PMID- 30304934 TI - Contractility of the epididymal duct: function, regulation and potential drug effects AB - During their transit through the epididymis, spermatozoa mature and acquire motility and fertilizing capacity. The smooth muscle cells (SMCs) of the epididymal duct are thought to be responsible for the adequate transport of spermatozoa. Thus, precise regulation of SMC function also represents a prerequisite for sperm maturation thereby contributing to male fertility. In this review, we would like to highlight various aspects of epididymal SMC function and discuss several angles with respect to regulation of contraction and relaxation. Different to the vas deferens, where disturbed SMC pathways resulting in male infertility could be defined, comparable information is missing in the epididymis. We therefore include some vas deferens data which could also be useful for a better understanding of epididymal SMC function. Furthermore, we would like to draw attention to drugs used in clinical practice and their potential (side) effects on contractions in the epididymis. PMID- 30304935 TI - Osimertinib and Low-Dose Itraconazole Combination: Vigilance in Elderly Patients. PMID- 30304936 TI - A randomized controlled study of intervention to improve continuity care engagement among HIV-infected persons after release from jails. AB - Short-term stay, multiple jail admissions and social and financial difficulties are significant obstacles for continuity care engagement (CCE) after release among HIV-infected jail detainees. However, data existing on interventions or strategies to increase post-release CCE among this population are limited. We conducted a randomized controlled study among HIV-infected detainees at Cook County Jail during 2011-2014. The intervention group received telephone contact within 2-4 days of release by a continuity clinic coordinator, who scheduled and informed the ex-detainees of their appointment date within 6 weeks post-release plus standard of care, while the control group received standard of care. The standard of care included comprehensive discharge planning, offering substance abuse treatment and provision of information on how to self-schedule an appointment with the chosen clinics. Of the 166 detainees enrolled, 56 were excluded due to being sent to prison or re-incarcerated within 6 weeks. The final cohort included 55 detainees in each of the groups. The rate of CCE within 6 weeks after release was significantly higher in the intervention group compared to the control group (58% vs. 33%; P = .007). In multivariable logistic regression analysis, being in the control group was the only factor associated with no CCE within 6 weeks (adjusted odds ratio 2.66; 95% confidence interval 1.18-6.00; P = .02). The study findings suggest that the simple telephone contact intervention significantly improved CCE among HIV-infected jail detainees. PMID- 30304937 TI - Reply: Incidence and Risk Factors for Development of Thrombocytopenia in Patients Treated With Linezolid for 7 Days or Greater. PMID- 30304938 TI - Development and Preliminary Evaluation of a Pain Management Manual for Hospice Providers to Support and Educate Family Caregivers. AB - BACKGROUND: Family caregivers encounter many barriers to managing patients' pain in the home hospice setting. However, there are limited clinically applicable resources for hospice providers to help family caregivers identify and address these barriers. AIM: To develop a pain management manual for hospice providers to support family caregivers and conduct a preliminary providers' evaluation of the manual. DESIGN AND PARTICIPANTS: A pain management manual was developed and structured into 3 parts: (1) 5 common pain management case scenarios based on a secondary data analysis of a hospice clinical trial; (2) a list of suggested assessment questions and strategies for each case scenario was developed based on a caregiver framework; and (3) pain educational material was included from established clinical guidelines. The manual was vetted by 5 experts and then was evaluated by interviewing 25 hospice providers. Interview data were analyzed using thematic analysis. RESULTS: The hospice providers found that the manual could potentially serve as a reference in their practice and be a source for their continuing education. They suggested enhancing the clarity of the case scenarios and adding additional strategies to the manual. Moreover, they suggested expanding the paper-based version and developing a web-based platform to deliver the content would maximize its utility. CONCLUSIONS: The manual has the potential to be integrated into routine hospice care to improve the quality of pain management. PMID- 30304939 TI - The Association Between HIV Infection and the Use of Palliative Care in Patients Hospitalized With Heart Failure. AB - BACKGROUND: The number of adults with heart failure (HF) and HIV infection is increasing. These patients may benefit from palliative care (PC). OBJECTIVES: Determine the association between HIV infection, other HIV characteristics, and PC among hospitalized patients with HF in the Veterans Health Administration (VHA). DESIGN: Nested case-control study of patients with HF hospitalized from 2003 to 2015 and enrolled in the Veterans Aging Cohort Study. SETTING/PATIENTS: Two hundred and ten hospitalized patients with HF who received PC matched to 1042 patients with HF who did not receive PC, by age, discharge date, and left ventricular ejection fraction. MEASUREMENTS: Palliative care use was the primary outcome. Independent variables included HIV infection identified by International Classification of Diseases Ninth Revision code and further characterized as the primary diagnosis for hospitalization, unsuppressed HIV-1 RNA, CD4 counts <200 cells/mm3, and other covariates. We examined associations between independent variables and PC using conditional logistic regression. RESULTS: The sample was 99% male, mean age was 64 years (standard deviation +/-10), 54% of cases and 59% of controls were black, and 30% of cases and 31% of controls were HIV-infected. In adjusted models, HIV as the primary diagnosis for hospitalization (odds ratio [OR]: 3.69, 95% confidence interval [CI]: 1.30-10.52), unsuppressed HIV-1 RNA (OR: 2.62, 95% CI: 1.31-5.24), and CD4 counts <200 cells/mm3 (OR: 3.47; 1.78 6.77), but not HIV infection (OR: 0.79, 95% CI: 0.55-1.13), were associated with PC. CONCLUSIONS: HIV characteristics indicative of severe disease are associated with PC for hospitalized VHA patients with HF. Increasing access to PC for patients with HF and HIV is warranted. PMID- 30304940 TI - The use of social marketing campaigns to increase HIV testing uptake: a systematic review. AB - Social marketing campaigns have been increasingly used in HIV prevention efforts to address barriers to HIV testing. The purpose of this review is to evaluate the social marketing campaigns in the past ten years (2008-2017) that have targeted HIV testing or intent to test as an outcome, and synthesize the results to determine which campaigns work or do not work. The search was conducted using PubMed, Scopus, PsycINFO, EMBASE, and ABI/Inform. The quality assessment tool for quantitative studies developed by the Effective Public Health Practice Project was used to assess study quality. The search generated 373 articles, of which 13 articles met the inclusion criteria. These articles were from 13 distinct campaigns carried out in 9 countries, twelve of which were in high income countries. Sixty-nine percent (n = 9) of the campaigns targeted MSM, gay men, or MSMW, 23% (n = 3) targeted the general population, while 8% (n = 1) focused on African-American women. The study designs for evaluating the campaigns were predominantly cross-sectional, with 4 of the articles combining two or three study designs to evaluate their campaign. Overall, 38% (n = 5) of the campaigns had an increase in HIV testing outcomes, 23% (n = 3) reported no change in HIV testing outcomes, and the remaining 38% (n = 5) of the studies reported mixed outcomes. The results of the quality rating showed that 69% (n = 9) of the papers had weak global ratings, while 31% (n = 4) had moderate rating. None of the articles had a strong rating. This review displayed that social marketing campaigns intended to increase HIV testing uptake were effective in some context. Social marketing practitioners will need to come up with a standardized way of communicating the results of campaign exposure and impact so as to enhance comparison among the multitude of campaigns. PMID- 30304941 TI - Theophylline and Caffeine as Alternatives During an Aminophylline Shortage. AB - The latest aminophylline shortage has prompted a need for alternative reversal agents for pharmacological stress testing. Cardiac stress testing is common for diagnosis and prognosis in patients with coronary heart disease. Options for pharmacological stress test agents include adenosine, regadenoson, dipyridamole, and dobutamine, whereas aminophylline is the recommended reversal agent. Adenosine and dobutamine can be used as alternatives to regadenoson and dipyridamole to decrease or eliminate the use of aminophylline. Alternatives to aminophylline include theophylline and caffeine. It is important to efficiently identify alternatives during a drug shortage to maintain optimal patient outcomes. PMID- 30304942 TI - Barriers to preexposure prophylaxis use among individuals with recently acquired HIV infection in Northern California. AB - Barriers to HIV preexposure prophylaxis (PrEP) use have not been well characterized in people who became HIV-infected, all of whom could have benefited from PrEP. We invited Kaiser Permanente Northern California members diagnosed with HIV during 2014-2016, following a negative HIV test in the prior year, to complete a survey assessing barriers to PrEP use before HIV diagnosis. Of 268 patients surveyed, 122 (46%) responded. Median age was 36, most (84%) were men who have sex with men, and 64% were of minority racial/ethnic background. Thirty six (30%) had discussed PrEP with a provider, of whom 10 were diagnosed with HIV at PrEP intake. Overall, only 5 (4.1%) had used PrEP, and all 5 discontinued before diagnosis. Among all respondents, the most common barrier to PrEP use was lack of PrEP awareness (51%). Among those aware of PrEP, the most common barriers were cost/insurance concerns (36%) and perceived low risk for HIV (24%). Lack of PrEP awareness ranged from 39% among those aged 25-34 to 88% among those aged <25 (P = 0.011), and from 33% among Hispanics to 69% among Blacks (P = 0.055). Increasing awareness and affordability of PrEP, and facilitating accurate assessment of HIV risk, are critical to reducing missed opportunities for PrEP. PMID- 30304943 TI - Role of Exercise Activity in Alleviating Neuropathic Pain in Diabetes via Inhibition of the Pro-Inflammatory Signal Pathway. AB - Hyperalgesia and allodynia are commonly observed in patients with diabetic neuropathy. The treatment and management of painful peripheral neuropathy is important in these patients. The purpose of this study was to examine the role of exercise in modulating neuropathic pain induced by diabetes. Diabetes was induced in rats by an intraperitoneal injection of streptozotocin (STZ). Control rats received saline injections. Groups included control rats without exercise (NT control, n = 12), control rats with exercise (EX-control, n = 16), STZ rats without exercise (NT-STZ, n = 18), and STZ rats with exercise (EX-STZ, n = 22). Rats in EX groups ran on a treadmill 4 days/week for 5 weeks beginning from the week of STZ administration. Mechanical hypersensitivity (mechanical paw withdrawal thresholds [PWTs]) and glucose levels were tested weekly. Then, enzyme linked immunoassay and Western blot analysis were used to determine the levels of pro-inflammatory cytokines (PICs) and their receptors in sensory nerves. PWTs were significantly increased after 4-5 weeks of exercise in STZ rats ( p < .05 vs. NT-STZ rats). Inhibition of neuropathic pain by exercise in STZ rats was accompanied by decreases in interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha levels and downregulated expression of their receptors. Furthermore, blocking individual PIC receptors elevated PWTs to a greater degree in STZ rats ( p < .05 vs. control rats). Overall, our data suggest that exercise can play a role in improving neuropathic pain induced by STZ and that PIC signaling is a part of the mechanism involved in this effect. PMID- 30304944 TI - Simple Techniques That Can Facilitate Radial Artery Access. PMID- 30304946 TI - Transverse Maxillary Development in Complete Cleft Patients: Comparison of 2 Treatment Strategies by Longitudinal and Cross-Sectional Model Analysis. AB - OBJECTIVE: This study aimed to compare differences in the maxillary transverse dimension following cleft repair using 2 protocols involving a 2-staged palatal closure with similar timing but different techniques. DESIGN: Retrospective study. Two matched study samples, each containing 10 patients. SETTING: Cleft center A is a university hospital. Cleft Center B is a general teaching hospital. PATIENTS: Patients with cleft lip alveolus and palate (CLAP) were matched by cleft type, gender, age, and palatal morphology at the age of 1 month. Differences in the transverse dimension were measured at 4 ages in 2 matched groups (A and B from center A and B), each including 5 patients with unilateral CLAP (UCLAP) and 5 patients with bilateral CLAP (BCLAP). INTERVENTIONS: Orthodontic/orthopedic expansion treatment began at 8 and 5 years of age at centers A and B, respectively. RESULTS: The mean intercanine distance decreased by 8 mm (standard deviation [SD] = 1.6; P = .030) in group A patients with UCLAP between 1 and 5 years (SD = 1.6; P = .030) and by 6.3 mm (SD = 3.2; P = .016) in group B patients with BCLAP. The mean intermolar distance increased by 4 mm (SD = 3.4; P = .076) in patients with BCLAP. A trend toward improved canine positioning was observed in patients with BCLAP by 12 years of age, with improvement occurring between 4 and 12 years. CONCLUSION: The type of palatal closure (inducing scar tissue at the bony level) and the late installment of orthodontic/orthopedic expansion probably reduced the intercanine width in bilateral complete clefts. PMID- 30304945 TI - Preoperative CT of cardiac veins for planning left ventricular lead placement in cardiac resynchronization therapy. AB - Background Successful cardiac resynchronization therapy (CRT) requires appropriate left ventricular (LV) lead placement on a suitable segment of the free LV wall. Current guidelines suggest targeted lead placement, but the individual anatomy of the cardiac veins is often a limiting factor. Purpose To map cardiac veins with multidetector computed tomography (MDCT) and plot the veins in cardiac segments to facilitate successful CRT implantation. Material and Methods Ninety-nine patients were included (mean age = 68 +/- 9 years; 26% women; 46% ischemic cardiomyopathy). Contrast-enhanced, ECG-gated, dose-modulated MDCT was used to depict the coronary veins. CT data were reformatted into short-axis view. Veins with diameter >=1.5 mm and traversing the free LV wall were manually transferred into a 17-segment bulls-eye plot model. Results In 98 patients, a CT scan with acceptable image quality was obtained. Median radiation dose as dose length protocol was 231 mGy/cm (interquartile range = 276 mGy/cm). Mean contrast dose, expressed as total iodine load, was 38 +/- 8 g. A median of three suitable veins (range = 1-7) covered a mean of 4.4 +/- 1.5 relevant LV segments. There was no difference between patients with dilated or ischemic cardiomyopathy in number of veins (2.5 vs. 2.7, P = 0.45) or in number of cardiac segments traversed by suitable veins (4.4 vs. 4.5, P = 0.74). Conclusion In CRT patients, MDCT can be used for preoperative mapping of the cardiac veins to assess availability of suitable veins in potential target segments for pacemaker-lead placement. Using the 17-segment plot of the left ventricle may improve the clinical usefulness of the data. PMID- 30304947 TI - Mental health in South African adolescents living with HIV. AB - We examined the prevalence of mental health conditions, social support, and associated factors among adolescents living with HIV. We conducted a cross sectional analysis with adolescents (ages 9-19) attending a primary care clinic in Johannesburg, South Africa. We analyzed the results of four self-report tools: Children's Depression Inventory-Short, Revised Manifest Anxiety Scale, Child Post Traumatic Stress Disorder (PTSD) Checklist, and a modified version of the Medical Outcomes Study Social Support Scale. We used robust Poisson regression to quantify the association between social support and mental health. Among 278 adolescents, the majority were perinatally infected with HIV (92%), and had at least one deceased parent (59%). Depression symptom threshold scores were found among 8% of adolescents, and 7% screened positive for symptoms of anxiety. Few (1%) met the criteria for PTSD. Overall, 12% of adolescents screened positive for symptoms of depression, anxiety or PTSD. Older adolescents reported less social support than younger adolescents. Adolescents were less likely to have mental health symptoms if they had higher measures of social support (adjusted Prevalence Ratio 0.38, 95% CI 0.20-0.73). Attention should be paid to social support for adolescents living with HIV as this may play an important role in their mental health. PMID- 30304948 TI - Targeting the mitochondrial apoptosis pathway by a newly synthesized COX-2 inhibitor in pediatric ALL lymphocytes. AB - AIM: Acute lymphoblastic leukemia (ALL) is known as a barely curable malignancy. Particular mutations involved in apoptosis may have a main role in the onset of ALL in the pediatric patients. It has been proven that cycloxygenase-2 is capable of impairing the apoptosis pathway through mitochondria in tumor cells. METHODOLOGY: In this study, we investigated selective toxicity of a newly synthesized chalconeferrocenyl derivative as a selective cycloxygenase-2 inhibitor in ALL and healthy B-lymphocytes, and also isolated mitochondria obtained from them. For this purpose, we evaluated the cellar parameters like viability, apoptosis/necrosis, caspase-3 activation and ATP content, and also mitochondrial parameters like mitochondrial membrane potential decline, reactive oxygen species formation, cytochrome C release and mitochondrial swelling. CONCLUSION: Our results implied that this compound can selectively induce cellular and mitochondrial toxicity in cancerous ALL B-lymphocytes and obtained mitochondria from them without any detrimental effects on healthy subjects. PMID- 30304949 TI - What We Do: Povidone-Iodine Solution to Delineate the Cutaneous Roll. AB - BACKGROUND: Establishing continuity of the cutaneous roll is critical to cleft lip repair. Unfortunately, this landmark can be difficult to appreciate depending on the patient's skin tone, surgical lighting, or preexisting scar. SOLUTION: When applied to the lip, dilute povidone-iodine solution beads off the cutaneous roll and dry vermilion, clearly defining these structures. What We Do: We use dilute povidone-iodine solution not only to prep the lip but to delineate landmarks critical to cleft lip repair. PMID- 30304950 TI - National Scientific Misconduct Policies in Argentina: Two Definitions of Research Misconduct. AB - In "An International Study of Research Misconduct Policies", Resnik et al. count Argentina in the list of countries without national research misconduct policies. In this paper, we clarify that Argentina has national policies of research misconduct and present the research misconduct definitions of two official science organisms: the National Scientific and Technical Research Council (CONICET) and the Ethics Committee of the Argentine Ministry of Science (MINCyT). PMID- 30304951 TI - Novel Bluetooth-Enabled Tubeless Insulin Pump: A User Experience Design Approach for a Connected Digital Diabetes Management Platform. AB - BACKGROUND:: Medical device technology is evolving at a rapid pace, with increasing patient expectations to use modern technologies for diabetes management. With the significant expansion of the use of wireless technology and complex, securely connected digital platforms in medical devices, end user needs and behaviors have become essential areas of focus. METHODS:: This article provides a detailed description of the user-centered design approach implemented in developing the Omnipod DASHTM Insulin Management System (Insulet Corp., Billerica, MA) Bluetooth(r)-enabled locked-down Android device handheld controller (Personal Diabetes Manager, PDM). Key methodologies used in the PDM design are described, including how the science of user experience (UX) was integrated into new agile product development. UX methods employed included heuristic evaluations of insulin pumps, iterative formative usability testing, information architecture studies, in-home ethnographic visits, participatory design activities, and interviews. RESULTS:: Over 343 users participated in UX research and testing. Key design choices informed by UX research included updating the layout of critical data on the PDM home page, providing access to requested contextual information while a bolus is in progress, and creating an easy-to-understand visual of a 24-hour basal program. Task completion rates for comprehending information on the PDM home page were 87% or greater. The System Usability Scale result for the design prior to limited market release was 84.4 +/ 13.4 (out of 100; n = 37). CONCLUSIONS:: The UX process described in this article can serve as a blueprint for medical device manufacturers seeking to enhance product development. Adopting UX research methodologies will help ensure that new diabetes devices are safe, easy-to-use, and meet the needs of users. PMID- 30304952 TI - HTX-019: polysorbate 80- and synthetic surfactant-free neurokinin 1 receptor antagonist for chemotherapy-induced nausea and vomiting prophylaxis. AB - Chemotherapy-induced nausea and vomiting (CINV) may occur during the acute (0-24 h) or delayed (25-120 h) phase following chemotherapy administration. The addition of a neurokinin 1 receptor antagonist to antiemetic regimens containing a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone has resulted in improved CINV prophylaxis. Due to numerous adverse events and hypersensitivity reactions associated with fosaprepitant, a commonly used neurokinin 1 receptor antagonist, there remains an unmet need for better-tolerated formulations. HTX 019, the US FDA-approved polysorbate 80- and synthetic surfactant-free aprepitant injectable emulsion, is bioequivalent to and better tolerated (fewer treatment emergent adverse events) than fosaprepitant. HTX-019 represents a valuable alternative to fosaprepitant for CINV prophylaxis. PMID- 30304953 TI - Does Economic Abuse Affect the Health Outcomes of Women in Ghana? AB - Although academically underexplored, economic abuse is common in most societies. Using data collected from 2,289 ever-married Ghanaian women, this study employed regression techniques to examine dimensions of economic abuse (employment sabotage, economic exploitation, and economic deprivation) on the cardiovascular, psychosocial, and overall general health of respondents. Results showed respondents with experiences of economic sabotage had poor psychosocial health. Meanwhile, compared with those with no such experiences, respondents with experiences of economic exploitation not only reported poor psychosocial health but were also more likely to live with cardiovascular diseases. Women with experiences of economic deprivation reported poor psychosocial health, were more likely to live with cardiovascular diseases, and more likely to report poor or good than very good health. Our findings suggest the need to screen for economic abuse as a correlate of poor health among women in Ghana. PMID- 30304954 TI - New Biomarkers for Prediction of Disseminated Intravascular Coagulation in Patients With Sepsis. AB - Complication of disseminated intravascular coagulation (DIC) is a determinant of the prognosis for patients with sepsis. The purpose of this study was to find DIC related peptides in blood for prediction and early diagnosis of DIC in patients with sepsis. The participants were 20 patients with sepsis (age: 68.9 +/- 11.4 years) and they were divided into 2 groups with (n = 8) and without (n = 12) a complication of DIC. Peptides in the serum of the patients were inclusively analyzed by a new method for peptidome analysis using a target plate, BLOTCHIP. By differential analysis of peptides in the blood from patients in the groups with and without DIC, we selected 13 mass spectrometry (MS) peaks as candidate marker peptides for prediction of DIC. By subsequent MS/MS structural analysis, 8 peptides were successfully identified as marker peptides for DIC in patients with sepsis. The peptides were fragments of serum amyloid A-2 protein, alpha2-HS glycoprotein, fibrinogen alpha chain, fibrinogen beta chain, serum albumin, collagen alpha1 (I) chain, collagen alpha1 (III) chain, and coagulation factor XIII A chain. In receiver-operating characteristic analysis for the relationships between the marker peptides and DIC, the area under the curve for each of these peptides was 0.594 to 0.760. We identified 8 blood marker peptides for prediction of DIC complication in patients with sepsis. Further studies by direct measurements of the serum peptide levels in larger numbers of patients with sepsis-induced DIC are needed to confirm the findings of this study. PMID- 30304955 TI - Real-world efficacy: intravenous palonosetron three-drug regimen for chemotherapy induced nausea and vomiting with highly emetogenic chemotherapy. AB - AIM: Real-world palonosetron effectiveness was evaluated in an antiemetic regimen with highly emetogenic chemotherapy (HEC). PATIENTS & METHODS: In this Phase IV, prospective, multicenter observational study, HEC-treated cancer patients received palonosetron, a neurokinin 1 receptor antagonist, and dexamethasone. Primary objective was to assess complete response (CR) for acute (<=24 h), delayed and overall (<=120 h) chemotherapy-induced nausea and vomiting. RESULTS: Of 159 patients, 65.4% had breast cancer, 64.8% received anthracycline (doxorubicin)-plus-cyclophosphamide-containing chemotherapy; 155 completed one HEC cycle. CR was 60.0% acute, 39.4% delayed and 34.8% overall, and then increased (all phases) in 69 patients completing four HEC cycles. Anthracycline (doxorubicin) plus cyclophosphamide-receiving patients had especially low CR. CONCLUSION: Even within a recommended three-drug antiemetic regimen, palonosetron may provide suboptimal chemotherapy-induced nausea and vomiting control with HEC in real-world settings. PMID- 30304956 TI - Factors Associated with Recent HIV Testing among Men Who Have Sex with Men in Philadelphia: a Cross-Sectional Analysis of the National Behavioral Surveillance System Survey. AB - The main objective of this study was to determine the demographic, geographic and socioeconomic characteristics of men who have sex with men (MSM) in Philadelphia that were associated with having a recent HIV test. We used data from the National HIV Behavioral Surveillance System (NHBS) surveys from 2011 and 2014 among MSM in Philadelphia, with the outcome of interest of having received an HIV test in the past twelve months. Of 1043 HIV-negative MSM, 70.2% had an HIV test. Multivariable analysis showed that seeing a medical provider (aOR: 1.73; p = .0039) or having heard of PrEP (aOR: 2.24; p < .0001) was associated with recent HIV testing. Those participants forty-five years of age or older (aOR 0.40, p = .0001) and those with Medicaid had lower rates of HIV testing (aOR 0.48, p = .002). Although over 80% of participants had seen a medical provider in the past year, only 50% had been offered an HIV test by a provider. Optimizing HIV testing through the expansion and increased awareness of PrEP, especially among older MSM, is critical. Further research is needed to delineate barriers that prevent MSM from utilizing medical providers for HIV testing and for those with Medicaid from receiving HIV testing. PMID- 30304957 TI - Enabling cultural safety in Indigenous primary healthcare. AB - The Aboriginal Health Access Centre (AHAC) and Aboriginal Community Health Centre Model of Wholistic Health and Wellbeing is critical to addressing inequities and barriers that limit access to comprehensive primary healthcare for Indigenous people. Even with this model in place, there are multiple points of intersection with mainstream healthcare service providers across health sectors. Further, there is considerable cultural diversity among Indigenous healthcare staff and professional groups. These factors place Indigenous people at risk of culturally unsafe experiences causing harm. Given this, it is essential that leaders focus on cultural safety education to address both intercultural frictions within the Indigenous centres and systemic and structural racism widespread within the broader healthcare system. This article explores how one AHAC has undertaken to examine these complex challenges, while offering some direction on leadership within the sector. PMID- 30304958 TI - A structured exercise programme combined with proprioceptive neuromuscular facilitation stretching or static stretching in posttraumatic stiffness of the elbow: a randomized controlled trial. AB - OBJECTIVES: To compare the different stretching techniques, proprioceptive neuromuscular facilitation (PNF) stretching and static stretching, in patients with elbow stiffness after a treated elbow fracture. DESIGN: Randomized controlled, single-blind study. SETTING: Department of physiotherapy and rehabilitation. SUBJECTS: Forty patients with posttraumatic elbow stiffness (24 women; mean age, 41.34 +/- 7.57 years). INTERVENTION: PNF stretching group ( n = 20), hold-relax PNF stretching combined with a structured exercise programme (two days per week for six weeks); static stretching group ( n = 20), static stretching combined with a structured exercise programme (two days per week for six weeks). MAIN MEASURES: The primary outcome is the Disabilities of the Arm, Shoulder and Hand (DASH). The secondary outcomes are active range of motion (AROM), visual analogue scale (VAS), Tampa Scale for Kinesiophobia, Short Form-12 and Global Rating of Change. Participants were assessed at baseline, after a six week intervention period and one-month later (follow-up). RESULTS: After treatment, improvement in the mean DASH score was slightly better in the PNF stretching group (8.66 +/- 6.15) compared with the static stretching group (19.25 +/- 10.30) ( p = 0.03). The overall group-by-time interaction for the 2 * 3 mixed model analysis of covariance (ANCOVA) was also significant for elbow flexion AROM (mean change for PNF stretching group; static stretching group; 41.10, 34.42, p = 0.04), VAS-rest (-1.31, -1.08, p = 0.03) and VAS-activity (-3.78, -3.47, p = 0.01) in favour of PNF stretching group. The other outcomes did not differ significantly between the two groups. CONCLUSION: The study demonstrated that the structured exercise programme combined with PNF stretching might be effective in patients with posttraumatic elbow stiffness with regard to improving function, elbow flexion AROM, pain at rest and during activity. PMID- 30304959 TI - Obligatory Nasal Turbulence as a Trigger for the Development of Posterior Nasal Fricatives in a Child With Repaired Cleft Palate. AB - Posterior nasal fricatives (PNFs) are unusual articulations that occur in some children with and without cleft palate. The etiology of PNFs is unclear. A young girl with repaired cleft palate is described who exhibited inconsistent obligatory nasal turbulence during production of stops at 2 years of age. At 3 years of age, she exhibited various phonological processes and used PNFs to replace sibilants and affricates. Pressure-flow testing showed a relatively small velopharyngeal area during production of stops. These observations are consistent with obligatory nasal turbulence triggering the development of PNFs as an unusual phonological process, perhaps facilitated by reduced hearing. PMID- 30304960 TI - Isolation and structural characterization of a non-diketopiperazine phytotoxin from a potato pathogenic Streptomyces strain. AB - Two Streptomyces spp. strains responsible for potato common scab infections in Uruguay which do not produce diketopiperazines were identified through whole genome sequencing, and the virulence factor produced by one of them was isolated and characterized. Phylogenetic analysis showed that both pathogenic strains can be identified as S. niveiscabiei, and the structure of the phytotoxin was elucidated as that of the polyketide desmethylmensacarcin using MS and NMR methods. The metabolite is produced in yields of ~200 mg/L of culture media, induces deep necrotic lesions on potato tubers, stuns root and shoot growth in radish seedlings, and is comparatively more aggressive than thaxtomin A. This is the first time that desmethylmensacarcin, a member of a class of compounds known for their antitumor and antibiotic activity, is associated with phytotoxicity. More importantly, it represents the discovery of a new virulence factor related to potato common scab, an economically-important disease affecting potato production worldwide. PMID- 30304961 TI - Prevalence of Osteochondral Lesions in Rotational Type Ankle Fractures With Syndesmotic Injury. AB - BACKGROUND: The aim of this study was to report the incidence of associated osteochondral lesions (OCLs) on postop CTs, which may benefit from arthroscopic treatment, in patients with rotational type ankle fractures with syndesmotic injury. The diagnosis and treatment of associated OCLs may be an additional benefit of the use of arthroscopy in the management of rotational type ankle fractures with syndesmotic injury. METHODS: We retrospectively reviewed data of a prospective cohort study of patients who underwent open reduction and surgical fixation of an ankle fracture with syndesmotic injury. These patients underwent routine bilateral postoperative CT assessment. Two independent observers classified ankle fractures according to Weber and OCLs according to the classification system by Berndt and Harty. Fifty-nine patients were included. There were 19 (32%) Weber B type ankle fractures and 39 (66%) Weber C type fractures. One patient (2%) had fixation for a medial malleolus fracture and syndesmotic rupture without fibula fracture. RESULTS: Talar OCLs were present in 8 patients (14%). In one patient, 2 OCLs were found, which resulted in a total of 9 lesions. Two lesions were found on the medial side, both anterior. The other 7 were located laterally, of which 1 was anterior, 3 central, and 3 posterior on the talus. According to the Berndt and Harty classification, 1 was classified as stage I, 4 as stage III, and 4 as stage IV. CONCLUSION: The prevalence of OCLs in ankle fractures with syndesmotic instability was 14%. We believe that lesions were arthroscopically accessible in 6 patients (10%). Moreover, most lesions were located on the lateral dome, and thus also potentially approachable through an anterolateral arthrotomy during open reduction and internal fixation. The majority of OCLs found in this series were Berndt and Harty type III or IV, and so likely would preferably have been addressed during the index procedure. LEVEL OF EVIDENCE: Level III, diagnostic cohort study. PMID- 30304962 TI - Neurovascular and Clinical Outcomes of the Percutaneous Endoscopically Assisted Calcaneal Osteotomy (PECO) Technique to Correct Hindfoot Malalignment. AB - BACKGROUND: Standard open calcaneal osteotomies to correct hindfoot malalignment have been associated with high complication rates, including nerve damage and wound infection. This has resulted in the development of minimally invasive techniques such as the percutaneous endoscopically assisted calcaneal osteotomy (PECO), which in cadaver studies has been shown to be potentially safer than open surgeries. The aim of this study was to demonstrate the safety and effectiveness of PECO in a clinical setting, with regard to neurovascular injury rates, infection, and short-term radiographic and functional outcomes. METHODS: Forty one (41) patients with planovalgus or cavovarus foot deformities underwent treatment using PECO. Outcomes were analyzed at 6 months and primarily included neurovascular outcomes and wound infection rates. Secondarily, radiographic and functional (visual analog scale for pain [VAS], 36-Item Short Form Medical Outcomes Survey [SF-36], and Foot Function Index [FFI] scores) outcomes were also assessed. RESULTS: There were no reported cases of superficial wound infections, lateral calcaneal or sural nerve dysesthesia. Minor complications occurred in 6/41 feet. The mean postoperative hindfoot correction was 8.3 +/- 2.2 mm (range: 6-15mm) compared to preoperative status. Compared to preoperative status, significant improvements ( P = .001 for all) were seen in the VAS, SF-36, and FFI at 6 months postoperatively. CONCLUSIONS: PECO resulted in minimal complications with no lateral calcaneal or sural nerve dysesthesias and no wound complications. It also resulted in significant improvements in postoperative radiographic and functional outcomes from baseline to 6-months postoperatively, demonstrating its use as a safe and effective means of treating hindfoot malalignment. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 30304963 TI - Nivolumab for the treatment of hepatocellular carcinoma. AB - INTRODUCTION: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD 1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing. PMID- 30304964 TI - Investigation of the link between PROP taste perception and vegetables consumption using FAOSTAT data. AB - In this work we investigated, in populations located in Central Asia, the relationship between PROP taste perception and vegetables liking and consumption using FAOSTAT dataset. Collected data were analysed using distance matrices, Mantel test and Pearson correlation. Populations showing similar ability in tasting PROP bitterness are more similar as respect to vegetable consumption (r = 0.63, p-value = .05). Moreover, a significant negative correlation was found between the percentage of Non Taster (NT) in different countries and the percentage of vegetable consumption (r = -0.87, p-value = .02), while a significant positive correlation emerged between the percentage of Super Taster (ST) and the percentage of vegetable liking (r = 0.87, p-value = .02). In our work we showed that differences in bitter perception among populations contributes to differences in vegetable liking and vegetable consumption. More in detail, populations with higher percentage of ST consume more vegetables than population where the majority of individuals are NT. PMID- 30304965 TI - Role of Th17-cell related cytokines in geriatric asthma. AB - Objective This study aimed to investigate the pathogenesis of geriatric asthma through immunoglobulin E (IgE), interleukin-17A (IL-17A), IL-17F, and glucocorticoid receptor-beta (GR-beta) expression. Methods We studied 51 geriatric male patients with asthma and 50 young male patients with asthma. We also included 21 normal geriatric males and 21 normal young males. All geriatric and young patients were divided into groups according to pulmonary function. Levels of cytokines, such as IgE, IL-17A, IL-17F, and GR-beta, were measured. Pulmonary function was assessed. The results from patients were compared with those from the 42 healthy subjects. Results Serum IgE, IL-17A, IL-17F, and GR beta levels in geriatric patients with moderate or severe asthma were significantly higher than those in young patients with moderate asthma and in the normal population. Geriatric patients with asthma had higher asthma control test scores than did young patients with asthma. Conclusion Hormone resistance in geriatric male patients with asthma is more serious than that in young male patients with asthma. Airway inflammation and airway remodeling in geriatric male patients with asthma may be more serious than those in young male patients with asthma, even when there is similar pulmonary function. PMID- 30304966 TI - Choledocholithiasis in elderly patients with gallbladder in situ - is ERCP sufficient? AB - INTRODUCTION: Along with increased life expectancy, the proportion of elderly patients with choledocholithiasis will increase and with this, the need for endoscopic cholangiopancreatography (ERCP). Current recommendations suggest laparoscopic cholecystectomy in all patients with choledocholithiasis to prevent biliary events. However, adherence to these recommendations is low, especially in older patients. METHODS: Retrospective study that included non-cholecystectomized patients aged > =75 years who underwent ERCP for choledocholithiasis from 2013 2016 (n = 131). A new biliary event was defined as the need for a new ERCP, cholecystitis, cholangitis or gallstone pancreatitis. AIM: The aim of this study was to compare the outcomes of new biliary events and mortality in cholecystectomized vs non-cholecystectomized patients after ERCP. RESULTS: Cholecystectomy was performed in 22% of the patients (92% laparoscopic). The post cholecystectomy complication rate was 13% and the mortality rate was 7%. During the follow-up period (669 +/- 487 days) a new biliary event occurred in 20% of patients - 10% new ERCP, 9% cholecystitis, 9% cholangitis and 2% pancreatitis. Cholecystectomized patients had fewer events (7% vs 24%, p = .048) and longer time to event (p = .016). There was no statistically significant difference in all-cause mortality (14% vs 27%, p = .13), mortality related to lithiasis (0% vs 9%, p = .11) or time to mortality from all causes (p = .07) and related to biliary events (p = .07). CONCLUSIONS: In this group of elderly patients, cholecystectomy after ERCP prevented the occurrence of new biliary events but resulted in a non-statistically significant difference in mortality. PMID- 30304967 TI - Liquorice flavonoid oil suppresses hyperglycaemia accompanied by skeletal muscle myocellular GLUT4 recruitment to the plasma membrane in KK-Ay mice. AB - For over 4000 years, liquorice has been one of the most frequently employed botanicals as a traditional herbal medicine. Although previous reports have found that liquorice flavonoids possess various health beneficial effects, the underlying mechanism responsible for the anti-diabetic effect of liquorice flavonoids remains unclear. The present study demonstrates that liquorice flavonoid oil (LFO) improves type 2 diabetes mellitus through GLUT4 translocation to the plasma membrane by activating both the adenosine monophosphate-activated protein kinase (AMPK) pathway and Akt pathway in muscle of KK-Ay mice. Furthermore, LFO lowered postprandial hyperglycaemia in a human study. These results indicate that LFO may exert a therapeutic effect on metabolic disorders, such as diabetes and hyperglycaemia, by modulating glucose metabolism through AMPK- and insulin-dependent pathways in skeletal muscle. PMID- 30304968 TI - Cerebellar volume in early-onset schizophrenia and its association with severity of symptoms. AB - Objectives This study aimed to investigate whether early-onset schizophrenia (EOS) cases differ from controls regarding volumes of the total cerebellum and the right and left cerebellar hemispheres, and volumetric asymmetry. Correlations of cerebellar volumes and asymmetry indices with severity of symptoms and general functioning in cases of EOS were also assessed. Methods Adolescents with EOS (n = 23) were compared with controls (n = 23). Sociodemographic and clinical data, and magnetic resonance imaging scans that were acquired for routine clinical purposes were collected retrospectively. Cerebellar volumes were evaluated using the stereological method. Asymmetry indices were subsequently calculated. Scores of the Positive and Negative Syndrome Scale and the Children's Global Assessment Scale were used to assess the severity of symptoms and general functionality. Results There were no significant differences in any of the cerebellar volumes and asymmetry indices between the two groups. Neither cerebellar volumes nor asymmetry indices were correlated with the severity of symptoms and general functionality in EOS. Conclusions Our findings suggest that the early-onset form of schizophrenia does not show apparent volumetric changes of the cerebellum. Additionally, the neural circuits involved in formation of symptomatology may not reflect any correlation with cerebellar volumes at mid-adolescence. PMID- 30304969 TI - Relationship of fibroblast growth factor 21, sirtuin 1, visfatin, and regulators in children with short stature. AB - Fibroblast growth factor 21 (FGF21) is mainly secreted by the liver. It is a factor that is not fully understood in relation to growth. Sirtuin 1 (SIRT1) is a deacetylase protein. It is thought that may have an effect on the release and function of GH and IGF-1. Visfatin is synthesized from adipose tissue as primary. It may be prognostic marker associated with growth factors. As a result of our work, FGF21 is not associated with short stature but levels of SIRT1 and visfatin are associated with short stature. The decrease in visfatin value in the short stature group is thought to be due to an insufficient amount of adipose tissue, which is important for growth and development. SIRT1 might decrease GH effect by increasing STAT5 deacetylation in the liver and we think that the result of this reduction of SIRT1 would negatively impact IGF-1 and IGFBP-3 production. PMID- 30304970 TI - Risk factors for nicotine dependence in Chinese patients with lung cancer. AB - Objective Smoking is a poor prognostic factor for lung cancer. Nicotine dependence remains the major cause of failure of smoking cessation. We investigated the risk factors for nicotine dependence in patients with lung cancer. Methods Eligible patients were identified from November 2014 to February 2015. Age, marital status, educational level, annual household income, occupation, histology of lung cancer, tumor stage, smoking status, neuron specific enolase (NSE) level, drive gene mutations, sleep quality, and patient personality were assessed. Physical nicotine dependence was assessed by the Fagerstrom Test for Nicotine Dependence (FTND). Results In total, 202 smokers were included in this study. Univariate analysis showed that marital status and pain were significantly correlated with nicotine dependence. Pearson's correlation analysis showed that age at the initiation of smoking, attempts to quit, NSE level, and sleep quality were significantly correlated with FTND scores. Conclusions Pain, more attempts to quit, and poorer sleep quality were significantly associated with nicotine dependence. These risk factors could help to prevent smoking in Chinese patients with lung cancer. PMID- 30304971 TI - A systematic review and meta-analysis of prevalence of vitamin D deficiency among adolescent girls in selected Indian states. AB - BACKGROUND: Vitamin D deficiency among adolescents is an emerging public health priority as adolescence marks a period of rapid growth and the onset of the reproductive phase. However, lack of national prevalence data and intervention strategies is of public health concern. OBJECTIVE: The objective of this study was to determine the pooled prevalence of vitamin D deficiency among adolescent girls in selected Indian states. METHODS: A systematic literature review was performed using three different search engines. The searches yielded nine eligible articles. Study quality was assessed for 10 different criteria. Meta analysis was performed to estimate pooled prevalence of vitamin D deficiency among adolescent girls and to assess the heterogeneity among selected studies. RESULTS: A sample of n=1352 was used to study prevalence among adolescent girls. The random effects combined estimate for overall prevalence was 25.70% (95% CI 3.89-2137.9). High heterogeneity (tau2=1.71, I2=100%) was observed and seven out of nine studies showed low to moderate risk and two showed high risk of bias. The test for overall effect was observed to be Z=0.77 ( p=0.44). CONCLUSIONS: High prevalence of vitamin D deficiency among adolescent girls identifies the need to introduce screening of adolescents and introduce proven public-health interventions such as fortification of foods to address deficiency. PMID- 30304972 TI - Methionine restriction for improving progeria: another autophagy-inducing anti aging strategy? AB - Methionine restriction, i.e., a partial depletion of the essential sulfur amino acid methionine from nutrition, extends lifespan in model organisms including yeast, nematodes, mice and rats. Recent results indicate that this strategy also prolongs health span and longevity in 2 short-lived strains of mice (with the LmnaG609G/G609G or zmpste24-/- genotypes) that represent animal models of Hutchinson-Gilford progeria syndrome (HGPS). The beneficial effects of methionine restriction on HGPS could be linked to reduced inflammation, and improved DNA stability, as well as the normalization of lipid and bile acid metabolism. Previous work has established that behavioral, nutritional, pharmacological and genetic manipulations that extend longevity in model organisms are only efficient if they induce increased autophagic flux. Methionine restriction extends lifespan in Saccharomyces cerevisiae in an Atg5- and Atg7-dependent fashion, supporting the notion that methionine restriction may indeed mediate its antiaging effects through the induction of macroautophagy/autophagy as well. Based on these findings, we speculate that autophagy might constitute an actionable therapeutic target to treat progeroid syndromes. PMID- 30304974 TI - Validity of Garmin Vivofit 1 and Garmin Vivofit 3 for School-Based Physical Activity Monitoring. AB - PURPOSE: Activity trackers are useful tools for physical activity promotion in adolescents, but robust validity evaluations have not been done under free-living conditions. This study evaluated the validity of the Garmin Vivofit 1 (G1) and Garmin Vivofit 3 (G3) in different settings and contexts. METHODS: The participants (girls: 52%, age: 15.9 [1.9] y) wore the G1 and G3 on their nondominant wrist and the Yamax pedometer on their right hip for a period of 1 week. Validity was examined in 4 discrete segments (before school, in school, after school, and whole day). The criterion method was the Yamax pedometer. RESULTS: Both the G1 and G3 could be considered equivalent to the Yamax pedometer regarding the before school, in school, and whole day segments. The G1 showed wider limits of agreement than G3. CONCLUSIONS: The G1 and G3 trackers exhibited acceptable validity for 3 of the 4 segments (before school, in school, and whole day measurements). The results were less accurate during the after-school segment. The evidence that the validity of the monitors varied depending on the setting and context is an important consideration for research on adolescent activity patterns. PMID- 30304973 TI - Arterial Switch Operation With Neoaortic Valve Replacement in a 13-Year Old Patient With Transposition of Great Arteries With Ventricular Septal Defect and Left Ventricular Outflow Tract Obstruction-A Case Report. AB - The surgical management of d-transposition of great arteries (d-TGAs) with ventricular septal defect (VSD) and left ventricular outflow tract obstruction (LVOTO) is ever evolving and still remains a challenge because of wide anatomic variability, age of presentation, surgical options available, and their variable long-term results in different series. We describe a patient with d-TGA, VSD, and LVOTO who presented to us at 13 years of age and underwent an arterial switch operation along with neoaortic valve replacement with a mechanical prosthesis. The postoperative course was uneventful, and at hospital discharge, the echocardiogram was satisfactory. We present the pros and cons of this hitherto undescribed treatment option. PMID- 30304975 TI - Serum levels of IL-6, IL-8, and IL-10 are indicators of prognosis in pancreatic cancer. AB - Objective Early detection and prognosis prediction are critical to improve patient survival in pancreatic cancer. This study aimed to investigate whether interleukins could serve as indicators of prognosis in pancreatic cancer. Methods Sixty-eight patients with pancreatic cancer were enrolled in the study during the period between 2012 and 2014. The serum levels of a broad spectrum of interleukins in these patients were determined, including IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-13, IL-15, and IL-23. Results IL-6, IL-8, and IL-10 showed significant positive correlations with each other. Moreover, high levels of serum IL-6, IL-8, and IL-10 were independently strongly associated with poor survival of patients with pancreatic cancer. Conclusions Our results suggest that serum levels of IL-6, IL-8, and IL-10 could be useful markers for prediction of prognosis in patients with pancreatic cancer. PMID- 30304976 TI - Extracardiac Fontan With Direct Inferior Vena Cava to Main Pulmonary Artery Connection Without Cardiopulmonary Bypass. AB - We report the case of a six-year-old patient who underwent an extracardiac Fontan operation including bilateral bidirectional superior cavopulmonary anastomosis and direct inferior vena cava to main pulmonary artery connection that was performed without cardiopulmonary bypass. PMID- 30304977 TI - Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia. AB - Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagy-lysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/calcineurin. At the later stages of ischemia, a gradual decrease in the level of nuclear TFEB was coupled with a progressive decline in lysosomal activity, accumulation of autophagosomes and autophagy substrates, and exacerbation of the ischemic injury. Notably, neuron-specific overexpression of TFEB significantly enhanced ALP function and rescued the ischemic damage, starting as early as 6 h and even lasting to 48 h after ischemia. Furthermore, neuron-specific knockdown of TFEB markedly reversed the activation of ALP and further aggravated the neurological deficits and ischemic outcome at the early stage of pMCAO. These results highlight neuronal-targeted TFEB as one of the key players in the pMCAO-mediated dysfunction of ALP and ischemic injury, and identify TFEB as a promising target for therapies aimed at neuroprotection in cerebral ischemia. Abbreviations: AAV, adeno-associated virus; AIF1/IBA1, allograft inflammatory factor 1; ALP, autophagy-lysosomal pathway; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; CsA, cyclosporin A; GFAP, glial fibrillary acidic protein; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated protein 1 light chain 3; MAP2, microtubule-associated protein 2; mNSS, modified Neurological Severity Score; MTOR, mechanistic target of rapamycin kinase; OGD, oxygen and glucose deprivation; pMCAO, permanent middle cerebral artery occlusion; RBFOX3/NeuN, RNA binding fox-1 homolog 3; SQSTM1, sequestosome1; TFEB, transcription factor EB; TTC, 2,3,5-triphenyltetrazolium chloride. PMID- 30304978 TI - Stationary Exercise in Overweight and Normal Weight Children. AB - PURPOSE: This study examined differences in lower extremity kinematics and muscle activation patterns between normal weight (NW) and overweight (OW) children during stationary exercises (running in place, frontal kick, and butt kick) at submaximal intensity. METHODS: Healthy children (aged 10-13 y) were stratified into OW (n = 10; body fat percentage: 34.97 [8.60]) and NW (n = 15; body fat percentage: 18.33 [4.87]). Electromyography was recorded for rectus femoris, vastus lateralis, biceps femoris, gastrocnemius, and tibialis anterior. In addition, the ratings of perceived exertion and range of motion of hip, knee, and ankle joints were collected during stationary exercises. Repeated-measures analysis of variance compared muscle activation, range of motion, and ratings of perceived exertion between groups and exercises. Friedman test examined sequencing of muscles recruitment. RESULTS: Compared with NW, OW experienced significantly greater ratings of perceived exertion (13.7 [0.8] vs 11.7 [0.7]; P < .001) and electromyography amplitude in all muscles apart from vastus lateralis during stationary exercises. In addition, NW children used more consistent muscles' recruitment pattern in comparison with OW children. The range of motion was similar between groups at all joints. CONCLUSION: OW children may adopt a more active neuromuscular strategy to provide greater stability and propulsion during stationary exercises. Stationary exercise can be prescribed to strengthen lower extremity muscles in OW children, but mode and intensity must be considered. PMID- 30304979 TI - Coronary tortuosity is negatively correlated with coronary atherosclerosis. AB - Objective The impact of coronary tortuosity on coronary atherosclerosis remains unclear. This study was performed to determine to the relationship between coronary tortuosity and the presence of coronary atherosclerosis. Methods Tortuosity and the presence of coronary atherosclerosis in the main coronary arteries were evaluated. The coronary artery was divided into non-tortuous and tortuous segments. The incidence of coronary atherosclerosis between the two segments was compared. Results The prevalence of coronary atherosclerotic stenosis was significantly lower in the tortuous than non-tortuous segment. Conclusion The prevalence of coronary atherosclerotic stenosis is lower in the coronary tortuous than non-tortuous segment, indicating that coronary tortuosity might be considered a protective factor for atherosclerosis. PMID- 30304980 TI - Comparison of articular manifestations of mixed connective tissue disease and systemic lupus erythematosus on clinical examination and musculoskeletal ultrasound. AB - BACKGROUND: Polyarthritis is common to both mixed connective tissue disease (MCTD) and systemic lupus erythematosus (SLE). Apart from being erosive and deforming in the former, we speculated that it was more common and the extent of joints involved would be higher in MCTD. METHODS: This was a cross-sectional study that included patients with MCTD aged 18-75 years fulfilling the Kasukawa criteria. An equal number of patients with SLE matched for disease duration and gender were included. Clinical manifestations were compared between patients with MCTD and with SLE. Examination of joints was done for the presence of tenderness or swelling and deformity. Musculoskeletal ultrasound was done on the non dominant hand for detection of synovitis and tenosynovitis and radiographs of the hands were obtained. The use of methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) for arthritis was noted. Statistical tests used were non parametric. RESULTS: Forty patients with MCTD and forty patients with SLE were included in this study, with patients being slightly older in MCTD than SLE (36 +/- 10.2, 31.8 +/- 13.3 years, p = 0.01). There were no significant differences in disease duration (4.7 +/- 3.1, 3.7 +/- 2.3, p = 0.1) or gender (females = 38, 38). Nearly one-half of patients with MCTD had at least one swollen joint compared with only 15% of patients with SLE. Median (95% confidence interval) tender joint count (5 (4.8-10.4), 0 (1.3-7.2), p = 0.01) and swollen joint count (0 (0.9-2.6), 0 (0-1.2), p = 0.002) was significantly higher in patients with MCTD compared with SLE. More patients with MCTD than SLE had tender or swollen proximal interphalangeal joints (12, 4, p = 0.025). More patients with MCTD than SLE had received methotrexate (8,2, p = 0.04) and NSAIDs (39, 32, p = 0.03) for arthritis. There was no difference in the number of patients with MCTD or SLE who had evidence of synovitis or tenosynovitis on ultrasound. There was no difference in erosive disease on hand radiographs, but acro-osteolysis was higher among MCTD patients. CONCLUSIONS: A higher proportion of patients with MCTD had at least one swollen and tender joint as compared with patients with SLE, as well as higher use of methotrexate and NSAIDs. However, there was no difference in ultrasound detected synovitis or tenosynovitis. PMID- 30304982 TI - Moving Forward With Accelerometer-Assessed Physical Activity: Two Strategies to Ensure Meaningful, Interpretable, and Comparable Measures. AB - Significant advances have been made in the measurement of physical activity in youth over the past decade. Monitors and protocols promote very high compliance, both night and day, and raw measures are available rather than "black box" counts. Consequently, many surveys and studies worldwide now assess children's physical behaviors (physical activity, sedentary behavior, and sleep) objectively 24 hours a day, 7 days a week using accelerometers. The availability of raw acceleration data in many of these studies is both an opportunity and a challenge. The richness of the data lends itself to the continued development of innovative metrics, whereas the removal of proprietary outcomes offers considerable potential for comparability between data sets and harmonizing data. Using comparable physical activity outcomes could lead to improved precision and generalizability of recommendations for children's present and future health. The author will discuss 2 strategies that he believes may help ensure comparability between studies and maximize the potential for data harmonization, thereby helping to capitalize on the growing body of accelerometer data describing children's physical behaviors. PMID- 30304981 TI - Physical confinement alters sarcoma cell cycle progression and division. AB - Tumor cells experience physical confinement on one or multiple axes, both in the primary tumor and at multiple stages during metastasis. Recent work has shown that confinement in a 3D spheroid alters nucleus geometry and delays cell division, and that vertical confinement impairs mitotic spindle rounding, resulting in abnormal division events. Meanwhile, the effects of bi-axial confinement on cell cycle progression has received little attention. Given the critical role of nuclear shape and mechanics in cell division, we hypothesized that bi-axial physical confinement of the cell body and nucleus would alter cell cycle progression. We used sarcoma cells stably expressing the fluorescence ubiquitination cell cycle indicator (FUCCI), along with fibronectin-coated microchannel devices, and explored the impact of bi-axial physical confinement on cell cycle progression. Our results demonstrate that bi-axial physical confinement reduces the frequency of cell division, which we found to be attributed to an arrest in the S/G2/M phase of the cell cycle, and increases the frequency of abnormal division events. Cell and nuclear morphology were both altered in confinement, with the most confining channels preventing cells from undergoing the normal increase in size from G1 to S/G2/M during cell cycle progression. Finally, our results suggest that confinement induces a mechanical memory to the cells, given our observation of lasting effects on cell division and morphology, even after cells exited confinement. Together, our results provide new insights into the possible impact of mechanical forces on primary and secondary tumor formation and growth. PMID- 30304983 TI - Relationships Between Outdoor Time, Physical Activity, Sedentary Time, and Body Mass Index in Children: A 12-Country Study. AB - PURPOSE: This study investigated the relationship between outdoor time and physical activity (PA), sedentary time (SED), and body mass index z scores among children from 12 lower-middle-income, upper-middle-income, and high-income countries. METHODS: In total, 6478 children (54.4% girls) aged 9-11 years participated. Outdoor time was self-reported, PA and SED were assessed with ActiGraph GT3X+ accelerometers, and height and weight were measured. Data on parental education, neighborhood collective efficacy, and accessibility to neighborhood recreation facilities were collected from parent questionnaires. Country latitude and climate statistics were collected through national weather data sources. Gender-stratified multilevel models with parental education, climate, and neighborhood variables as covariates were used to examine the relationship between outdoor time, accelerometry measures, and body mass index z scores. RESULTS: Each additional hour per day spent outdoors was associated with higher moderate- to vigorous-intensity PA (boys: +2.8 min/d; girls: +1.4 min/d), higher light-intensity PA (boys: +2.0 min/d; girls: +2.3 min/d), and lower SED (boys: -6.3 min/d; girls: -5.1 min/d). Effect sizes were generally weaker in lower-middle-income countries. Outdoor time was not associated with body mass index z scores. CONCLUSIONS: Outdoor time was associated with higher PA and lower SED independent of climate, parental education, and neighborhood variables, but effect sizes were small. However, more research is needed in low- and middle income countries. PMID- 30304984 TI - Pharmacokinetics of cisplatin in an esophageal cancer patient on hemodialysis who was treated with a full-dose cisplatin-fluorouracil regimen: A case report. AB - Introduction Cancer patients undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remain unknown and out of concern related to the potential development of severe adverse effects. However, patients with chemosensitive cancer, such as esophageal cancer, should receive chemotherapy at a dose that is sufficient to attain a favorable therapeutic effect. We herein present an interesting case involving an esophageal cancer patient who was successfully treated with subtotal thoracic esophagectomy, and adjuvant full-dose chemotherapy with cisplatin and 5-fluorouracil while concomitantly undergoing hemodialysis. We carried out a pharmacokinetics analysis of cisplatin, and also conducted a systematic review on the dose and pharmacokinetics. Case report A 57-year-old male patient with esophageal cancer who was undergoing hemodialysis was referred to our hospital. He underwent subtotal thoracic esophagectomy. The pathological diagnosis was T1b, N2 (5/26), M0, ly2, v2, stage IIIA (Union for International Cancer Control, 8th edition). Because of the high degree of lymph node metastasis, adjuvant chemotherapy with cisplatin was recommended. Cisplatin (80 mg/m2) was infused intravenously within 30 min on day 1, and 5-fluorouracil (800 mg/m2) was infused continuously on days 1-5 of a 28-day cycle. Thrombocytopenia (grade 3) occurred on day 16, leucopenia (grade 3) occurred on day 23, and anemia (grade 3) occurred on day 30. The onset of hematologic toxicities was prolonged in comparison to patients with a normal renal function. PMID- 30304985 TI - Updates and novel treatments in urothelial carcinoma. AB - Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease. Novel treatment approaches for UC have significantly impacted the management of patients. In 2016-2017, five immune checkpoint inhibitors marked a new paradigm in the treatment of UC for patients with advanced or metastatic disease or who are unable to tolerate platinum-based chemotherapy. Most recently, the U.S. Food and Drug Administration set restrictions on two commonly utilized checkpoint inhibitors, atezolizumab and pembrolizumab, in the first-line setting in patients with UC due to decreased survival associated with low expression of the protein programmed death ligand 1. Furthermore, Breakthrough Therapy Designations have been granted for enfortumab vedotin and erdafitinib for patients following platinum-based chemotherapy and those with fibroblast growth factor receptor mutated UC, respectively. Additional updates include dose-dense gemcitabine and cisplatin for muscle-invasive bladder cancer and preoperative checkpoint blockade. This article will review the available data on updates in the treatment of UC and future direction of therapies. PMID- 30304987 TI - An integrated framework for identification of effective and synergistic anti cancer drug combinations. AB - Combination drug therapy is considered a better treatment option for various diseases, such as cancer, HIV, hypertension, and infections as compared to targeted drug therapies. Combination or synergism helps to overcome drug resistance, reduction in drug toxicity and dosage. Considering the complexity and heterogeneity among cancer types, drug combination provides promising treatment strategy. Increase in drug combination data raises a challenge for developing a computational approach that can effectively predict drugs synergism. There is a need to model the combination drug screening data to predict new synergistic drug combinations for successful cancer treatment. In such a scenario, machine learning approaches can be used to alleviate the process of drugs synergy prediction. Experimental data from a single-agent or multi-agent drug screens provides feature data for model training. On the contrary, identification of effective drug combination using clinical trials is a time consuming and resource intensive task. This paper attempts to address the aforementioned challenges by developing a computational approach to effectively predict drug synergy. Single drug efficacy is used for predicting drug synergism. Our approach obviates the need to understand the underlying drug mechanism to predict drug combination synergy. For this purpose, nine machine learning algorithms are trained. It is observed that the Random forest models, in comparison to other models, have shown significant performance. The [Formula: see text]-fold cross-validation is performed to evaluate the robustness of the best predictive model. The proposed approach is applied to mutant-BRAF melanoma and further validated using melanoma cell-lines from AstraZeneca-Sanger Drug Combination Prediction DREAM Challenge dataset. PMID- 30304986 TI - A neuropathologic diagnosis of Alzheimer's disease in an older adult with HIV associated neurocognitive disorder. AB - We discuss the challenges associated with diagnosing neurodegenerative disorders in older adults living with HIV, illustrated through a case report where neurologic co-diagnosis of Alzheimer's disease (AD) and HIV-associated Neurocognitive Disorder (HAND) are considered. The patient was followed and evaluated for over 4 years and underwent post-mortem neuropathologic evaluation. Further work is needed to identify diagnostic tests that can adequately distinguish HAND from early stage neurodegenerative disorders among older adults living with HIV and cognitive changes. PMID- 30304988 TI - WBFQC: A new approach for compressing next-generation sequencing data splitting into homogeneous streams. AB - Genomic data nowadays is playing a vital role in number of fields such as personalized medicine, forensic, drug discovery, sequence alignment and agriculture, etc. With the advancements and reduction in the cost of next generation sequencing (NGS) technology, these data are growing exponentially. NGS data are being generated more rapidly than they could be significantly analyzed. Thus, there is much scope for developing novel data compression algorithms to facilitate data analysis along with data transfer and storage directly. An innovative compression technique is proposed here to address the problem of transmission and storage of large NGS data. This paper presents a lossless non reference-based FastQ file compression approach, segregating the data into three different streams and then applying appropriate and efficient compression algorithms on each. Experiments show that the proposed approach (WBFQC) outperforms other state-of-the-art approaches for compressing NGS data in terms of compression ratio (CR), and compression and decompression time. It also has random access capability over compressed genomic data. An open source FastQ compression tool is also provided here ( http://www.algorithm skg.com/wbfqc/home.html ). PMID- 30304989 TI - Attachment security and cortical responses to fearful faces in infants. AB - The present study measured event-related potentials (ERPs) to investigate whether cortical responses to facial expressions of fear are associated with the development of secure and insecure patterns of infant-mother attachment during the first year. Based on previous findings showing reduced attentional biases to fearful faces in infants with insecure and disorganized attachment, we hypothesized that insecure and disorganized attachment would be associated with reduced ERP differentiation of fearful from non-fearful faces. ERPs to facial expressions were measured at 7 months of age and attachment was assessed at 14 months of age with the Strange Situation Procedure (n = 61). Occipitotemporal face-sensitive ERP responses particularly in the time range of the N290 component were related to attachment security at 14 months. Only securely attached infants showed age-typical cortical discrimination of fearful from non-fearful faces at 7 months, whereas a similar pattern of ERP responses was not observed in infants with insecure and disorganized attachment. These results add to previous findings by suggesting that patterns of secure and insecure infant attachment are related to early-emerging differences in the perceptual processing of facial emotions, which could have implications for the development of social competence. PMID- 30304990 TI - Tensions Living Out Professional Values for Physical Therapists Treating Injured Workers. AB - Health care services provided by workers' compensation systems aim to facilitate recovery for injured workers. However, some features of these systems pose barriers to high quality care and challenge health care professionals in their everyday work. We used interpretive description methodology to explore ethical tensions experienced by physical therapists caring for patients with musculoskeletal injuries compensated by Workers' Compensation Boards. We conducted in-depth interviews with 40 physical therapists and leaders in the physical therapy and workers' compensation fields from three Canadian provinces and analyzed transcripts using concurrent and constant comparative techniques. Through our analysis, we developed inductive themes reflecting significant challenges experienced by participants in upholding three core professional values: equity, competence, and autonomy. These challenges illustrate multiple facets of physical therapists' struggles to uphold moral commitments and preserve their sense of professional integrity while providing care to injured workers within a complex health service system. PMID- 30304991 TI - Silencing of cyt-c4 led to decrease of biofilm formation in Aeromonas hydrophila. AB - : Aquaculture suffers from a number of diseases caused by Aeromonas hydrophila. Biofilm can protect bacteria from antibiotic therapy. To identify the genes those play crucial roles in A. hydrophila biofilm formation, a library of mini-Tn10 transposon insertion mutants of A. hydrophila B11 has been constructed, and 10 mutants were subjected to biofilm formation assay. The biofilm formation ability of mutant (B188) was significantly decreased compared with B11. The DNA sequence flanking the mini-Tn10 transposon inserted showed that an ORF of approximately 576 bp of the mutant strain B188 was inserted. This ORF putatively displays the highest identity (92%) with the cytochrome c4 gene (cyt-c4) of A. hydrophila subsp. hydrophila ATCC 7966. Silencing cyt-c4 led to deficiencies in biofilm formation, adhesion, drug resistance and pathogenicity of A. hydrophila, which suggests that cyt-c4 plays crucial role in the biofilm formation and virulence mechanisms of A. hydrophila. ABBREVIATIONS: GEN: gentamycin; SDZ: sulfadiazine; AK: amikacin; P: penicillin; CFP: cefoperazone; LEV: levofloxacin; MH: minocycline; FFC: florfenicol; TE: tetracycline; AMP: ampicillin; KAN: kanamycin; STR: streptomycin; SXT: sulfamethoxazole/trimethoprim; DO: doxycycline; OT: Oxytetracycline. PMID- 30304992 TI - Reduced Stroop interference under stress: Decreased cue utilisation, not increased executive control. AB - Since the 1960s, researchers have been reporting that stress reduces Stroop interference. This is puzzling, as stress and anxiety typically have deleterious effects on cognitive control and performance. The traditional explanation is that stress reduces "cue utilisation": It withdraws attentional resources from less relevant stimuli (including the distracter word), meaning that the target colour is left with a stronger influence over response selection. However, it could also be that stress somehow boosts distracter inhibition, or some other aspect of executive control. To test these two accounts, 59 students completed a Stroop task featuring occasional startlingly loud sounds (high stress) or the same sounds at a lower, comfortable volume (low stress). Alongside standard Stroop interference, two measures of executive control-negative priming and conflict adaptation-were calculated from the Stroop data. Stress produced a clear reduction of Stroop interference, but it did not influence negative priming, and no conflict adaptation effects were detected at all. These findings support the cue utilisation account. Furthermore, for the first time, stress was shown to reduce Stroop interference in a task with no congruent trials, showing that the effect does not result from stress's modulating any strategy changes participants might make in response to congruent trials. PMID- 30304993 TI - Developing a Culturally Informed Survey Instrument to Assess Biomedical Research Participation Among Latinos on the U.S.-Mexico Border. AB - Racial/ethnic minorities, rural populations, and those with low socioeconomic status income are underrepresented in research in the United States (U.S.). Assessing preferences for recruitment, participation, and the role of beliefs about biomedical research in specific and unique underserved communities represents a potentially critical step in reducing barriers to biomedical research participation. We developed a culturally informed survey to measure factors related to participation, knowledge, expectations, and barriers to biomedical research participation among Latinos living in a U.S. border community. We employed a multidisciplinary team approach to a sequential, three phase qualitative study that included interviews ( n = 35), focus groups ( n =24), and "think-aloud" cognitive interviews ( n = 5). Our study demonstrates the value of applying multiple qualitative approaches to inform a culturally relevant quantitative survey incorporating words and constructs relevant to the population of interest. The study contributes to qualitative method research paradigms by developing a research protocol that integrates the expertise and perspectives of researchers and community members from multiple disciplines and institutions. PMID- 30304994 TI - Sharing a mental number line across individuals? The role of body position and empathy in joint numerical cognition. AB - A growing body of research shows that the human brain acts differently when performing a task together with another person than when performing the same task alone. In this study, we investigated the influence of a co-actor on numerical cognition using a joint random number generation (RNG) task. We found that participants generated relatively smaller numbers when they were located to the left (vs. right) of a co-actor (Experiment 1), as if the two individuals shared a mental number line and predominantly selected numbers corresponding to their relative body position. Moreover, the mere presence of another person on the left or right side or the processing of numbers from loudspeaker on the left or right side had no influence on the magnitude of generated numbers (Experiment 2), suggesting that a bias in RNG only emerged during interpersonal interactions. Interestingly, the effect of relative body position on RNG was driven by participants with high trait empathic concern towards others, pointing towards a mediating role of feelings of sympathy for joint compatibility effects. Finally, the spatial bias emerged only after the co-actors swapped their spatial position, suggesting that joint spatial representations are constructed only after the spatial reference frame became salient. In contrast to previous studies, our findings cannot be explained by action co-representation because the consecutive production of numbers does not involve conflict at the motor response level. Our results therefore suggest that spatial reference coding, rather than motor mirroring, can determine joint compatibility effects. Our results demonstrate how physical properties of interpersonal situations, such as the relative body position, shape seemingly abstract cognition. PMID- 30304995 TI - Oxidative Stress Impairs Fatty Acid Oxidation and Mitochondrial Function in the Term Placenta. AB - Placental fatty acid oxidation (FAO) is impaired and lipid storage is increased in pregnancy states associated with chronic oxidative stress. The effect of acute oxidative stress, as seen in pregnancies complicated with asthma, on placental lipid metabolism is unknown. We hypothesized that induction of acute oxidative stress would decrease FAO and increase esterification. We assessed [3H]-palmitate oxidation and esterification in term placental explants from lean women after exposure to hydrogen peroxide (H2O2) for 4 hours. Fatty acid oxidation decreased 16% and 24% in placental explants exposed to 200 ( P = .02) and 400 uM H2O2 ( P = .01), respectively. Esterification was not altered with H2O2 exposure. Neither messenger RNA nor protein expression of key genes involved in FAO (eg, peroxisome proliferator-activated receptor alpha, carnitine palmitoyl transferase 1b) were altered. Adenosine triphosphate (ATP) levels decreased with induction of oxidative stress, without increasing cytotoxicity. Acute oxidative stress decreased FAO and ATP production in the term placenta without altering fatty acid esterification. As decreases in placental FAO and ATP production are associated with impaired fetal growth, pregnancies exposed to acute oxidative stress may be at risk for fetal growth restriction. PMID- 30304996 TI - MiR-1204 promotes ovarian squamous cell carcinoma growth by increasing glucose uptake. AB - MiR-1204 has been recently identified as an oncogenic miRNA in breast cancer. Our study aims to investigate the role of miR-1204 in ovarian squamous cell carcinoma. Expression of miR-1204 and glucose transporter 1 in ovarian biopsies and plasma of both OC patients and healthy controls was detected by qRT-PCR. Correlations between patients' clinicopathological data were analyzed by Chi square test. MiR-1204 overexpression OC cell lines were established. Expression of GLUT-1 protein was detected by western blot. Glucose uptake was measured by glucose uptake assay. Cell proliferation was detected by CCK-8 assay. We found that miR-1204 expression was significantly correlated with tumor size. Expression levels of miR-1204 and GLUT-1 were significantly high in OC patients. Expression levels of miR-1204 were positively correlated with expression levels of GLUT-1 in OC patients. MiR-1204 overexpression significantly promoted GLUT-1 expression, glucose uptake and cell proliferation. MiR-1204 may promote ovarian squamous cell carcinoma growth by increasing glucose uptake. PMID- 30304997 TI - Emotion Regulation Strategies in Depression and Somatization Disorder. AB - Scant research has investigated emotion regulation strategies in somatization disorder, despite its high comorbidity with depression and the growing interest in this topic in depression. The present study investigated emotion regulation strategies in patients with major depression and somatization disorder using clinical samples to examine common vulnerability factors and to provide evidence for difficulties in emotion regulation as transdiagnostic factors in these disorders. Patients with major depressive disorder ( n = 30) and patients with somatization disorder ( n = 30) completed measures of putatively adaptive and maladaptive emotion regulation strategy use. Patients with somatization disorder showed higher scores on measures of regulatory strategies, as measured by the sum of adaptive strategies in the Cognitive Emotion Regulation Questionnaire as well as the following subscales: positive refocusing, positive reappraisal, and refocusing on a plan. After controlling for levels of current depression, the significant effects remained for positive refocusing. Depression symptom severity was significantly and negatively correlated with most adaptive strategies and positively correlated with most maladaptive strategies. The current results provide preliminary data for a similar pattern of adaptive and maladaptive emotion regulation strategies usage in these two disorders. The results also contribute to theories of psychopathology and our understanding of critical cognitive and emotional processes. PMID- 30304998 TI - Facilitators and Barriers of Participation in "Uptime" Activities in Girls and Women With Rett Syndrome: Perspectives From Parents and Professionals. AB - Rett syndrome (RTT) is a rare neurodevelopmental disorder usually affecting females. It is associated with intellectual and multiple disabilities leading to a high level of dependency in all aspects of daily living including participation in physical activities. This study explored facilitators and barriers to "uptime" (non-sedentary) activities in Danish girls and women with RTT as perceived by parents and professionals using focus groups. Through thematic analysis, one central theme emerged: a constant balance to do the best thing for the girl or woman. Within the central theme, five subthemes of facilitators and barriers were identified relating to the individual and the physical, organizational, social, and attitudinal environments. Environmental barriers can be reduced through policy and management-level changes in health promotion and strong advocacy of physical activity by health professionals. Targeting both facilitators and barriers of "uptime" activities enables the planning and implementing of health promoting interventions in individuals with RTT. PMID- 30304999 TI - Crystal structure of a dimerization domain of human Caprin-2: similar overall dimeric fold but different molecular surface properties to that of human Caprin 1. AB - Human Caprin-1 and Caprin-2 are prototypic members of the caprin (cytoplasmic activation/proliferation-associated protein) protein family. Vertebrate caprin proteins contain two highly conserved homologous regions (HR1 and HR2) and C terminal RGG motifs. Drosophila caprin (dCaprin) shares HR1 and RGG motifs but lacks HR2. Caprin-1 and Caprin-2 have important and non-redundant functions. The detailed molecular mechanism s of their actions remain largely unknown. Previously, we determined the crystal structure of a ~120-residue fragment of Caprin-1 within the HR1 region. The structure has a novel all alpha-helical fold that self-associates to form a homodimer. In this study, the crystal structure of a corresponding fragment from Caprin-2 is reported. The Caprin-2 fragment has similar protein fold and dimeric structure as that of the Caprin-1 fragment. Structural comparison reveals that the molecular interactions mediating homodimerization of Caprin-1 and Caprin-2 are largely conserved in the two systems. Structural modelling study of the corresponding dCaprin fragment indicates that dCaprin may also adopt similar dimeric structure. Presence of a dimerization domain within HR1 may represent an evolutionarily conserved feature of the caprin protein family. Interestingly, while Caprin-1 and Caprin-2 adopt similar overall dimeric structures, the two structures have quite different molecular surface properties. In the Caprin-1 dimeric structure, some of the surface areas are known or suspected to function as binding sites for Carpin-1 interacting proteins. The different surface properties of the caprin dimeric structures may dictate their intermolecular interaction with specific protein partners. PMID- 30305000 TI - Thyrotoxic hypokalemic periodic paralysis: a life-threatening disorder in Asian men. AB - Thyrotoxicosis can present as a sporadic form of hypokalaemic periodic paralysis. The condition is associated with massive intracellular shift of potassium, mainly in skeletal muscles. As the total body stores of potassium remain normal, overzealous potassium supplementation targeting serum potassium level results in a poor outcome. We present a fatal case of thyrotoxic hypokalaemic periodic paralysis. PMID- 30305001 TI - Alterations in core temperature during World Rugby Sevens Series tournaments in temperate and warm environments. AB - PURPOSE: To characterize player core temperature (Tc) across two separate World Rugby Sevens Series (WRSS) tournaments in temperate and warm environments. METHODS: Tc was collected in seventeen playing members of one men's team competing at the Singapore (n = 12) and London (n = 11) WRSS tournaments. Exertional heat illness (EHI) symptoms, cooling strategy use, playing minutes and wet blub globe temperature (WBGT) were also collected. Linear mixed models and magnitude-based inferences assessed differences in Tc between all periods within and between tournaments and were also used to assess the effect of WBGT and playing minutes on Tc. RESULTS: Several players experienced Tc in excess of 38 degrees C during warm-ups and 39 degrees C during games. The highest mean Tc values were observed in the final game on all days and in Singapore Day Two, there were substantial game-on-game increases in mean Tc. These Tc responses were associated with playing minutes (effect size; +/-90% CL = 0.38; +/-0.20), although the effect of WBGT was trivial and unclear. Further, there were no differences in Tc between the two tournaments in the different environments. Despite high individual peak Tc values (Singapore 39.9 degrees C; London 39.6 degrees C); no signs/symptoms of EHI were reported, voluntary post-game cooling usage was minimal, and pre- and mid-cooling strategies were not implemented. CONCLUSIONS: During WRSS matches, peak Tc values approached thresholds associated with EHI (>40 degrees C) and exceeded those demonstrated to reduce repeated sprint performance (>39 degrees C). Practitioners may consider the use of compatible cooling and heat acclimation strategies to minimize Tc increase and maximize player preparedness and recovery. PMID- 30305002 TI - Skin Cancer Preventive Behaviors in Iranian Farmers: Applying Protection Motivation Theory. AB - Farmers are among the most common work groups at risk of skin cancer. The protection motivation theory has been widely accepted as a framework for predicting health related behaviors. This study was conducted to determine the role of factors preventing skin cancer among farmers in Eslamabad-e Gharb district, Iran, using the protection motivation theory. In this descriptive study, 280 farmers living in this district were studied from May to June 2017. Using cluster random sampling methods, health houses where farmers received health care were selected. Each farmer within the selected health house was then enrolled into the study using simple random sampling. Data were collected by interview using an author-developed questionnaire. The questionnaire ascertained demographic information and constructs of the protection motivation theory. Almost half of the farmers had a history of sunburn (56.4%). With regard to prevention, a small proportion reported using sunscreen (8.6%), hats (3.2%), gloves 3.9%, sunglasses 4.6%, and protective clothing 15.4%. The results of regression analyses showed that with one unit of increase in the scores of self efficacy to adopt prevention behavior and perceived protection motivation resulted in an increase in the mean score of the "protective" behavior by 0.26 and 0.20, respectively. Working conditions among farmers place them at great risk and skin cancer prevention is essential. Intervention and prevention programs should fully identify the determinants of skin cancer prevention in farmers; in addition, the identified effective factors must be taken into account when designing and implementing appropriate interventions. PMID- 30305003 TI - Strong Association Between Migraine and Transient Global Amnesia: A National Inpatient Sample Analysis. AB - The purpose of this article was to explore sex- and race-specific variables and comorbidities associated with transient global amnesia (TGA) using a nationally representative database. Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines. Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia. The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/Other, compared with Caucasians. TGA was associated with lower hospital charges ($14,242 versus $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] versus 4.72 [SE=0.025]), and routine hospital discharges (91.4% versus 74.5%). Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with TGA. All minority populations showed a lower rate of diagnosis that fell short of statistical significance. PMID- 30305004 TI - Why We Still Use "Organic Causes": Results From a Survey of Psychiatrists and Residents. AB - The diagnostic category of "organic disorders" was officially removed from the psychiatric nosology in DSM-IV, published in 1994. Despite this change, physicians continue to use the term "organic causes" to refer to medical and neurological causes of psychiatric symptoms, and it remains part of the ICD-10 classification. In the context of increasing integration of psychiatric disorders within a medical and neuroscientific framework, the reasons behind the ongoing use of this term (reminiscent of mind-body dualism) have to be clarified. The authors conducted a survey of 391 Canadian psychiatrists and psychiatric residents to understand attitudes and beliefs related to this terminology and then applied qualitative and quantitative analyses. Results showed that the terminology is used by the majority (55.9%) of psychiatrists and residents for two main reasons: out of a habit that begins in residency training and because of the belief that other specialties do not fully understand alternative terminology. The authors found that some psychiatrists are concerned that their patients will not receive adequate investigation unless it is made clear through use of the "organic cause" term that other medical causes of psychiatric symptoms are suspected. Use of the "organic cause" term was predicted by being of younger age, performing emergency department calls, and finding alternative terminology difficult to use. These findings highlight the importance of reflecting on and discussing the effect of this terminology used in psychiatry. PMID- 30305005 TI - Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease. AB - Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age. PMID- 30305006 TI - The Opioid Epidemic and the Role of the Occupational Health Nurse. AB - The opioid epidemic is a national public health crisis. It began with the misuse of commonly used prescription opioid pain relievers and has led to the increased use of heroin and illicit fentanyl. Large-scale initiatives have begun on the federal and state level and place an emphasis on improved opioid prescribing, which have important implications for the workplace. Treatment of work injury may initiate the use of prescription opioids and result in misuse and possible overdose. Prescription drug abuse affects all aspects of society so potentially any workplace could be affected. A multifaceted approach is needed to reduce opioid morbidity and mortality and the occupational health nurse should be actively involved. The intent of this article is to provide an overview of the epidemic and its impact on health, the challenges for the workplace, and recommended strategies for the occupational health nurse to impact the problem. PMID- 30305007 TI - HSP20 Exerts a Protective Effect on Preeclampsia by Regulating Function of Trophoblast Cells Via Akt Pathways. AB - Preeclampsia (PE) remains the leading cause of maternal and fetal morbidity and mortality. Excessive apoptosis of the placenta and poor remodeling of spiral arteries caused by insufficient invasion of trophoblast cells into uterus have been implicated in the pathogenesis of PE. Accumulating evidence showed that heat shock protein 20 (HSP20) is closely associated with the proliferation, apoptosis, and metastasis of tumor cells. However, little is known about whether HSP20 plays a role in the development of PE. In this study, we detected the apoptosis index and the expressions of HSP20 and apoptosis-associated proteins in the placentas from PE and normal pregnancies. We found that HSP20 was reversely related to the apoptosis rate and the levels of proapoptotic proteins. Moreover, we identified that HSP20 could suppress the proliferation and apoptosis of trophoblast cells, turning them into a more invasive phenotype. Additionally, H2O2-induced oxidative stress was significantly alleviated, and several key proteins on the Akt signaling pathway were upregulated in HSP20-overexpressing trophoblast cells. These findings strongly suggested that HSP20 might play a role in the remodeling of spiral arteries through affecting the invasiveness of extravillous trophoblast cells via Akt signaling pathway, and the dysregulation of it might contribute to the pathophysiology of PE. PMID- 30305008 TI - The Impact of Childhood Abuse on the Commercial Sexual Exploitation of Youth: A Systematic Review and Meta-Analysis. AB - Scholars and practitioners have drawn attention to the issue of commercial sexual exploitation (CSE) of minors, yet we continue to lack a clear understanding of which factors increase a minor's risk to this type of victimization. The current article reviews the literature about the impact of sexual, physical, or emotional abuse on the risk of CSE. The study utilizes quantitative meta-analytical techniques to estimate an overall impact of prior abuse. Nineteen studies were selected after a comprehensive search of electronic databases covering the fields of social science, criminology, psychology, or related fields. To be included in the analyses, all articles had to measure the direct impact of sexual, physical, and/or emotional abuse on minor's risk to CSE, utilizing multivariate techniques and presenting statistical metrics to assess the impact of prior abuse. Key findings demonstrate that sexual abuse considerably increases the risk of exploitation, especially among female youth in the United States. Physical and emotional abuse show negligible or no significant independent impacts, even though a few studies have begun to suggest that experiencing multiple types of childhood abuse may aggravate a risk of sexual exploitation. Our findings can guide further research on the impact of prior victimizations and inform screening instruments that are being developed to identify youth at risk of CSE. PMID- 30305009 TI - Simple Endovascular Repair for Symptomatic Aberrant Right Subclavian Artery in a Debilitated Patient. AB - We report a simple endovascular repair for symptomatic aberrant right subclavian artery (ARSA) in an 11-year-old girl. She had undergone tracheostomy due to hypoxic encephalopathy after cardiac surgery and suffered from dyspnea. Computed tomography revealed tracheal stenosis caused by a vascular ring made with an ARSA and the right common carotid artery. Transcatheter ARSA embolization using an Amplatzer vascular plug and coils was performed. Symptoms improved within a few days after this intervention and no complications such as upper extremity ischemia were encountered. Computed tomography showed the ARSA around the trachea had reduced in size and tracheal stenosis was improved. PMID- 30305010 TI - Clinical outcomes of extended endovascular recanalization of 16 consecutive Buerger's disease patients. AB - Objective Buerger's disease is one of the worst diseases causing peripheral artery occlusions (especially lower extremity) with increased morbidity and mortality. Endovascular treatment of the diseased arteries gains preference over bypass surgery nowadays. Here, we aimed to present the clinical outcomes of 16 consecutive Buerger's disease patients underwent extended endovascular recanalization which is a new technique to restore direct blood flow to at least one foot artery, with the performance of angioplasty for each tibial and foot artery obstructions. Methods A total of 16 consecutive patients with confirmed diagnosis of Buerger's disease that percutaneously treated in our center between February 2014 and March 2018 were included in the study. The mean age of the patients was 44.25 +/- 4.28 ranging from 36 to 50 years. After physical examination and complementary diagnostic tests, performance of extended angioplasty for occluded arteries was intended to restore direct blood flow to at least one of the blow-the-knee arteries. Results A successful extended endovascular treatment was performed in 20 of 22 limbs, achieving a technical success of 91%. All patients were successfully discharged without any complication. Mean follow-up duration was 21.43 +/- 7.08 months. Reintervention was performed in one patient and minor amputation was needed in one of the failed limbs. Limb salvage rate was 100%. A significant difference was observed based on Rutherford classification, ankle brachial index, direct blood flow to foot, presence of ulcer and rest pain when compared before and after the intervention. Conclusion We showed successful extended endovascular recanalization of Buerger's disease patients with a high technical success rate and sustained clinical improvement. Extended endovascular recanalization could be a therapeutic option in Buerger's disease patients, since they are not good candidates for surgery. PMID- 30305011 TI - A comparative study of geometry-based methods and intra-arterial pressure measurements to assess the hemodynamic significance of equivocal iliac artery stenoses. AB - Objectives To date, the ultimate decision to treat iliac artery stenoses in patients suffering from symptomatic peripheral arterial disease is based on the patient's symptoms and on visual inspection of angiographical images. The primary aim of this study was to investigate the accuracy of geometry-based methods (i.e. visual inspection and quantitative vascular analysis (Viewforum version R7.2v1 Advanced vessel analysis, Philips Healthcare, Best, The Netherlands) of 3D rotational angiography) to identify the severity of equivocal iliac artery stenosis in peripheral arterial disease patients with intra-arterial hyperemic pressure measurements (gold standard) as a reference. Methods Twenty patients with symptomatic iliac artery stenoses were subjected to 3D rotational angiography. Intra-arterial pressure measurements under hyperemic conditions were performed across 24 visually identified iliac artery stenoses. Three experienced interventional-radiologists retrospectively estimated the lumen diameter reduction by visual inspection. Furthermore, quantitative vascular analysis was performed on the 3D rotational angiography data. Geometry-based estimates were classified into two groups: lumen diameter reduction of <50% (non-significant) and diameter reduction [Formula: see text]50% (significant), and compared to the intra-arterial hyperemic pressure gradients. A stenosis causing a pressure gradient (Deltap) >=10 mmHg was considered hemodynamically significant. Results Visual inspection and quantitative vascular analysis correctly identified hemodynamically significant stenoses in, respectively, 83% and 67% of the 24 iliac artery stenoses. Quantitative vascular analysis-based identification of hemodynamic significant stenoses (Deltap >= 10 mmHg) could be optimized by lowering the threshold to a 42% lumen diameter reduction which improved the accuracy from 67% to 83%. Conclusions Visual inspection of 3D rotational angiography by experienced interventional-radiologists has an 83% accuracy to identify hemodynamic significant iliac artery stenoses (Delta p >=10 mmHg). The use of quantitative vascular analysis software did not improve accuracy. PMID- 30305012 TI - Genome-wide analysis of fitness data and its application to improve metabolic models. AB - BACKGROUND: Synthetic biology and related techniques enable genome scale high throughput investigation of the effect on organism fitness of different gene knock-downs/outs and of other modifications of genomic sequence. RESULTS: We develop statistical and computational pipelines and frameworks for analyzing high throughput fitness data over a genome scale set of sequence variants. Analyzing data from a high-throughput knock-down/knock-out bacterial study, we investigate differences and determinants of the effect on fitness in different conditions. Comparing fitness vectors of genes, across tens of conditions, we observe that fitness consequences strongly depend on genomic location and more weakly depend on gene sequence similarity and on functional relationships. In analyzing promoter sequences, we identified motifs associated with conditions studied in bacterial media such as Casaminos, D-glucose, Sucrose, and other sugars and amino acid sources. We also use fitness data to infer genes associated with orphan metabolic reactions in the iJO1366 E. coli metabolic model. To do this, we developed a new computational method that integrates gene fitness and gene expression profiles within a given reaction network neighborhood to associate this reaction with a set of genes that potentially encode the catalyzing proteins. We then apply this approach to predict candidate genes for 107 orphan reactions in iJO1366. Furthermore - we validate our methodology with known reactions using a leave-one-out approach. Specifically, using top-20 candidates selected based on combined fitness and expression datasets, we correctly reconstruct 39.7% of the reactions, as compared to 33% based on fitness and to 26% based on expression separately, and to 4.02% as a random baseline. Our model improvement results include a novel association of a gene to an orphan cytosine nucleosidation reaction. CONCLUSION: Our pipeline for metabolic modeling shows a clear benefit of using fitness data for predicting genes of orphan reactions. Along with the analysis pipelines we developed, it can be used to analyze similar high-throughput data. PMID- 30305013 TI - Thirty biologically interpretable clusters of transcription factors distinguish cancer type. AB - BACKGROUND: Transcription factors are essential regulators of gene expression and play critical roles in development, differentiation, and in many cancers. To carry out their regulatory programs, they must cooperate in networks and bind simultaneously to sites in promoter or enhancer regions of genes. We hypothesize that the mRNA co-expression patterns of transcription factors can be used both to learn how they cooperate in networks and to distinguish between cancer types. RESULTS: We recently developed a new algorithm, Thresher, that combines principal component analysis, outlier filtering, and von Mises-Fisher mixture models to cluster genes (in this case, transcription factors) based on expression, determining the optimal number of clusters in the process. We applied Thresher to the RNA-Seq expression data of 486 transcription factors from more than 10,000 samples of 33 kinds of cancer studied in The Cancer Genome Atlas (TCGA). We found that 30 clusters of transcription factors from a 29-dimensional principal component space were able to distinguish between most cancer types, and could separate tumor samples from normal controls. Moreover, each cluster of transcription factors could be either (i) linked to a tissue-specific expression pattern or (ii) associated with a fundamental biological process such as cell cycle, angiogenesis, apoptosis, or cytoskeleton. Clusters of the second type were more likely also to be associated with embryonically lethal mouse phenotypes. CONCLUSIONS: Using our approach, we have shown that the mRNA expression patterns of transcription factors contain most of the information needed to distinguish different cancer types. The Thresher method is capable of discovering biologically interpretable clusters of genes. It can potentially be applied to other gene sets, such as signaling pathways, to decompose them into simpler, yet biologically meaningful, components. PMID- 30305014 TI - Transcriptional defects and reprogramming barriers in somatic cell nuclear reprogramming as revealed by single-embryo RNA sequencing. AB - BACKGROUND: Nuclear reprogramming reinstates totipotency or pluripotency in somatic cells by changing their gene transcription profile. This technology is widely used in medicine, animal husbandry and other industries. However, certain deficiencies severely restrict the applications of this technology. RESULTS: Using single-embryo RNA-seq, our study provides complete transcriptome blueprints of embryos generated by cumulus cell (CC) donor nuclear transfer (NT), embryos generated by mouse embryonic fibroblast (MEF) donor NT and in vivo embryos at each stage (zygote, 2-cell, 4-cell, 8-cell, morula, and blastocyst). According to the results from further analyses, NT embryos exhibit RNA processing and translation initiation defects during the zygotic genome activation (ZGA) period, and protein kinase activity and protein phosphorylation are defective during blastocyst formation. Two thousand three constant genes are not able to be reprogrammed in CCs and MEFs. Among these constant genes, 136 genes are continuously mis-transcribed throughout all developmental stages. These 136 differential genes may be reprogramming barrier genes (RBGs) and more studies are needed to identify. CONCLUSIONS: These embryonic transcriptome blueprints provide new data for further mechanistic studies of somatic nuclear reprogramming. These findings may improve the efficiency of somatic cell nuclear transfer. PMID- 30305015 TI - Transcriptome analysis reveals the molecular mechanisms of the defense response to gray leaf spot disease in maize. AB - BACKGROUND: Gray leaf spot (GLS), which is caused by the necrotrophic fungi Cercospora zeae-maydis and Cercospora zeina, is one of the most impactful diseases in maize worldwide. The aim of the present study is to identify the resistance genes and understand the molecular mechanisms for GLS resistance. RESULTS: Two cultivars, 'Yayu889' and 'Zhenghong532,' which are distinguished as resistant and susceptible cultivars, respectively, were challenged with the GLS disease and a RNA-seq experiment was conducted on infected plants at 81, 89, 91, and 93 days post planting (dap). Compared with the beginning stage at 81 dap, 4666, 1733, and 1166 differentially expressed genes (DEGs) were identified at 89, 91, and 93 dap, respectively, in 'Yayu889,' while relatively fewer, i.e., 4713, 881, and 722 DEGs, were identified in 'Zhenghong532.' Multiple pathways involved in the response of maize to GLS, including 'response to salicylic acid,' 'protein phosphorylation,' 'oxidation-reduction process,' and 'carotenoid biosynthetic process,' were enriched by combining differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The expression of 12 candidate resistance proteins in these pathways were quantified by the multiple reaction monitoring (MRM) method. This approach identified two candidate resistance proteins, a calmodulin-like protein and a leucine-rich repeat receptor like protein kinase with SNPs that were located in QTL regions for GLS resistance. Metabolic analysis showed that, compared with 'Zhenghong532,' the amount of salicylic acid (SA) and total carotenoids in 'Yayu889' increased, while peroxidase activity decreased during the early infection stages, suggesting that increased levels of SA, carotenoids, and reactive oxygen species (ROS) may enhance the defense response of 'Yayu889' to GLS. CONCLUSION: By combining transcriptome and proteome analyses with comparisons of resistance QTL regions, calmodulin-like protein and leucine-rich repeat receptor-like protein kinase were identified as candidate GLS resistance proteins. Moreover, we found that the metabolic pathways for ROS, SA, and carotenoids are especially active in the resistant cultivar. These findings could lead to a better understanding of the GLS resistance mechanisms and facilitate the breeding of GLS-resistant maize cultivars. PMID- 30305016 TI - Factors for inhibition of early discharge from the psychiatric emergency ward for elderly patients. AB - BACKGROUND: As society is aging, the number of elderly patients with psychiatric disorder, such as dementia, is increasing. The hospitalization period of elderly patients in psychiatric wards tends to be prolonged. In this study, we have determined the factors that inhibit early discharge from the psychiatric emergency ward for elderly patients in Japan. METHODS: The information was collected from patients admitted to our hospital's emergency ward for elderly patients with psychiatric disorders between May 2015 and April 2016. We compared various factors between the early discharge group and the non-early discharge group. In addition, we used a multiple logistic regression model to clarify the risk factors for non-early discharge. RESULTS: Of the 208 elderly patients, body mass index (BMI) and serum albumin level were significantly lower in the non early discharge group. In addition, we also showed that higher serum C-reactive protein (CRP) (> 0.5 mg/dL) and use of seclusion or physical restraint significantly inhibited the early discharge of patients. The results of multiple logistic analysis showed that the BMI <= 17.5 kg/m2 (OR, 2.41 [95% confidence interval (CI) 1.06-5.46]), serum albumin level <= 30 g/L (OR, 3.78 [95% CI 1.28 11.16]), and use of seclusion or physical restraint (OR 3.78 [95% CI 1.53-9.37]) are particularly important explanatory factors. CONCLUSIONS: Hypoalbuminemia, low BMI, and the use of seclusion or physical restraint were identified as the factors that inhibit early discharge from the psychiatric emergency ward for elderly patients. These factors reflect malnutrition and extremely serious psychiatric symptoms. PMID- 30305017 TI - Effects of alleles in crossbred pigs estimated for genomic prediction depend on their breed-of-origin. AB - BACKGROUND: This study investigated if the allele effect of a given single nucleotide polymorphism (SNP) for crossbred performance in pigs estimated in a genomic prediction model differs depending on its breed-of-origin, and how these are related to estimated effects for purebred performance. RESULTS: SNP-allele substitution effects were estimated for a commonly used SNP panel using a genomic best linear unbiased prediction model with breed-specific partial relationship matrices. Estimated breeding values for purebred and crossbred performance were converted to SNP-allele effects by breed-of-origin. Differences between purebred and crossbred, and between breeds-of-origin were evaluated by comparing percentage of variance explained by genomic regions for back fat thickness (BF), average daily gain (ADG), and residual feed intake (RFI). From ten regions explaining most additive genetic variance for crossbred performance, 1 to 5 regions also appeared in the top ten for purebred performance. The proportion of genetic variance explained by a genomic region and the estimated effect of a haplotype in such a region were different depending upon the breed-of-origin. To illustrate underlying mechanisms, we evaluated the estimated effects across breeds-of-origin for haplotypes associated to the melanocortin 4 receptor (MC4R) gene, and for the MC4Rsnp itself which is a missense mutation with a known effect on BF and ADG. Although estimated allele substitution effects of the MC4Rsnp mutation were very similar across breeds, explained genetic variance of haplotypes associated to the MC4R gene using a SNP panel that does not include the mutation, was considerably lower in one of the breeds where the allele frequency of the mutation was the lowest. CONCLUSIONS: Similar regions explaining similar additive genetic variance were observed across purebred and crossbred performance. Moreover, there was some overlap across breeds-of-origin between regions that explained relatively large proportions of genetic variance for crossbred performance; albeit that the actual proportion of variance deviated across breeds-of-origin. Results based on a missense mutation in MC4R confirmed that even if a causal locus has similar effects across breeds-of-origin, estimated effects and explained variance in its region using a commonly used SNP panel can strongly depend on the allele frequency of the underlying causal mutation. PMID- 30305018 TI - Effects of evolutionary history on genome wide and phenotypic convergence in Drosophila populations. AB - BACKGROUND: Studies combining experimental evolution and next-generation sequencing have found that adaptation in sexually reproducing populations is primarily fueled by standing genetic variation. Consequently, the response to selection is rapid and highly repeatable across replicate populations. Some studies suggest that the response to selection is highly repeatable at both the phenotypic and genomic levels, and that evolutionary history has little impact. Other studies suggest that even when the response to selection is repeatable phenotypically, evolutionary history can have significant impacts at the genomic level. Here we test two hypotheses that may explain this discrepancy. Hypothesis 1: Past intense selection reduces evolutionary repeatability at the genomic and phenotypic levels when conditions change. Hypothesis 2: Previous intense selection does not reduce evolutionary repeatability, but other evolutionary mechanisms may. We test these hypotheses using D. melanogaster populations that were subjected to 260 generations of intense selection for desiccation resistance and have since been under relaxed selection for the past 230 generations. RESULTS: We find that, with the exception of longevity and to a lesser extent fecundity, 230 generations of relaxed selection has erased the extreme phenotypic differentiation previously found. We also find no signs of genetic fixation, and only limited evidence of genetic differentiation between previously desiccation resistance selected populations and their controls. CONCLUSION: Our findings suggest that evolution in our system is highly repeatable even when populations have been previously subjected to bouts of extreme selection. We therefore conclude that evolutionary repeatability can overcome past bouts of extreme selection in Drosophila experimental evolution, provided experiments are sufficiently long and populations are not inbred. PMID- 30305019 TI - Genome-wide transcriptome profiling of transgenic hop (Humulus lupulus L.) constitutively overexpressing HlWRKY1 and HlWDR1 transcription factors. AB - BACKGROUND: The hop plant (Humulus lupulus L.) is a valuable source of several secondary metabolites, such as flavonoids, bitter acids, and essential oils. These compounds are widely implicated in the beer brewing industry and are having potential biomedical applications. Several independent breeding programs around the world have been initiated to develop new cultivars with enriched lupulin and secondary metabolite contents but met with limited success due to several constraints. In the present work, a pioneering attempt has been made to overexpress master regulator binary transcription factor complex formed by HlWRKY1 and HlWDR1 using a plant expression vector to enhance the level of prenylflavonoid and bitter acid content in the hop. Subsequently, we performed transcriptional profiling using high-throughput RNA-Seq technology in leaves of resultant transformants and wild-type hop to gain in-depth information about the genome-wide functional changes induced by HlWRKY1 and HlWDR1 overexpression. RESULTS: The transgenic WW-lines exhibited an elevated expression of structural and regulatory genes involved in prenylflavonoid and bitter acid biosynthesis pathways. In addition, the comparative transcriptome analysis revealed a total of 522 transcripts involved in 30 pathways, including lipids and amino acids biosynthesis, primary carbon metabolism, phytohormone signaling and stress responses were differentially expressed in WW-transformants. It was apparent from the whole transcriptome sequencing that modulation of primary carbon metabolism and other pathways by HlWRKY1 and HlWDR1 overexpression resulted in enhanced substrate flux towards secondary metabolites pathway. The detailed analyses suggested that none of the pathways or genes, which have a detrimental effect on physiology, growth and development processes, were induced on a genome-wide scale in WW-transgenic lines. CONCLUSIONS: Taken together, our results suggest that HlWRKY1 and HlWDR1 simultaneous overexpression positively regulates the prenylflavonoid and bitter acid biosynthesis pathways in the hop and thus these transgenes are presented as prospective candidates for achieving enhanced secondary metabolite content in the hop. PMID- 30305021 TI - Data integration by multi-tuning parameter elastic net regression. AB - BACKGROUND: To integrate molecular features from multiple high-throughput platforms in prediction, a regression model that penalizes features from all platforms equally is commonly used. However, data from different platforms are likely to differ in effect sizes, the proportion of predictive features, and correlations structures. Subtle but important features may be missed by shrinking all features equally. RESULTS: We propose an Elastic net (EN) model with separate tuning parameter penalties for each platform that is fit using standard software. In a comprehensive simulation study, we evaluated the performance of EN logistic regression with multiple tuning penalties. We found that when the number of informative features differs among the platforms, and when there is no notable correlation between the features from different platforms, the multi-tuning parameter EN yields more predictive models. Moreover, the multi-tuning parameter EN is robust, in the sense that there is no loss of predictivity relative to a single tuning parameter EN when features across all platforms have similar effects. We also investigated the performance of multi-tuning parameter EN using real cancer datasets. CONCLUSION: The proposed multi-tuning parameter EN model, fit using standard penalized regression software, can achieve better prediction in sample classification when integrating multiple genomic platforms, compared to the traditional method where a single penalty parameter is used for all features in different platforms. PMID- 30305022 TI - Cloning and characterization of the homoeologous genes for the Rec8-like meiotic cohesin in polyploid wheat. AB - BACKGROUND: Meiosis is a specialized cell division critical for gamete production in the sexual reproduction of eukaryotes. It ensures genome integrity and generates genetic variability as well. The Rec8-like cohesin is a cohesion protein essential for orderly chromosome segregation in meiotic cell division. The Rec8-like genes and cohesins have been cloned and characterized in diploid models, but not in polyploids. The present study aimed to clone the homoeologous genes (homoeoalleles) for Rec8-like cohesin in polyploid wheat, an important food crop for humans, and to characterize their structure and function under a polyploid condition. RESULTS: We cloned two Rec8-like homoeoalleles from tetraploid wheat (TtRec8-A1 and TtRec8-B1) and one from hexaploid wheat (TaRec8 D1), and performed expression and functional analyses of the homoeoalleles. Also, we identified other two Rec8 homoeoalleles in hexaploid wheat (TaRec8-A1 and TaRec8-B1) and the one in Aegilops tauschii (AetRec8-D1) by referencing the DNA sequences of the Rec8 homoeoalleles cloned in this study. The coding DNA sequences (CDS) of these six Rec8 homoeoalleles are all 1,827 bp in length, encoding 608 amino acids. They differed from each other primarily in introns although single nucleotide polymorphisms were detected in CDS. Substantial difference was observed between the homoeoalleles from the subgenome B (TtRec8-B1 and TaRec8-B1) and those from the subgenomes A and D (TtRec8-A1, TaRec8-A1, and TaRec8-D1). TtRec8-A1 expressed dominantly over TtRec8-B1, but comparably to TaRec8-D1, in polyploid wheat. In addition, we developed the antibody against wheat Rec8 and used the antibody to detect Rec8 cohesin in the Western blotting and subcellular localization analyses. CONCLUSIONS: The Rec8 homoeoalleles from the subgenomes A and D are transcriptionally more active than the one from the subgenome B in polyploid wheat. The structural variation and differential expression of the Rec8 homoeoalleles indicate a unique cross-genome coordination of the homoeologous genes in polyploid wheat, and imply the distinction of the wheat subgenome B from the subgenomes A and D in the origin and evolution. PMID- 30305023 TI - A recessive lethal chondrodysplasia in a miniature zebu family results from an insertion affecting the chondroitin sulfat domain of aggrecan. AB - BACKGROUND: Congenital skeletal malformations represent a heterogeneous group of disorders affecting bone and cartilage development. In cattle, particular chondrodysplastic forms have been identified in several miniature breeds. In this study, a phenotypic characterization was performed of an affected Miniature Zebu calf using computed tomography, necropsy and histopathological examinations, whole genome sequencing of the case and its parents on an Illumina NextSeq 500 in 2 * 150 bp paired-end mode and validation using Sanger sequencing and a Kompetitive Allele Specific PCR assay. Samples from the family of an affected Miniature Zebu with bulldog syndrome including parents and siblings, 42 healthy Miniature Zebu not related with members of the herd and 88 individuals from eight different taurine cattle breeds were available for validation. RESULTS: A bulldog like Miniature Zebu calf showing a large bulging head, a short and compressed body and extremely short and stocky limbs was delivered after a fetotomy. Computed tomography and necropsy revealed severe craniofacial abnormalities including a shortening of the ventral nasal conchae, a cleft hard palate, rotated limbs as well as malformed and fused vertebrae and ribs. Histopathologic examination showed a disorganization of the physeal cartilage with disorderly arranged chondrocytes in columns and a multifocal closed epiphyseal plate. Whole genome sequencing of this malformed Miniature Zebu calf, its dam and sire and subsequent comparative sequence analysis revealed a one base pair insertion (ACAN:c.5686insC) located within the cartilage development gene aggrecan (ACAN) exclusively homozygous in the affected calf and heterozygous in its parents. This variant was predicted to cause a frameshift (p.Val1898fsTer9) and thus a truncation of the chondroitin sulfate domain as well as a loss of the C-terminal globular domain of ACAN. It perfectly co-segregated with the lethal bulldog syndrome in Miniature Zebus. CONCLUSIONS: We found a novel mutation in ACAN causing a recessive lethal chondrodysplasia in Miniature Zebu cattle. A diagnostic test for this mutation is now available for Miniature Zebu breeders preventing further cases of bulldog syndrome by targeted matings. To the authors' best knowledge, this is the first case of a Miniature Zebu associated with an ACAN mutation. PMID- 30305020 TI - Exposure to maternal obesity alters gene expression in the preimplantation ovine conceptus. AB - BACKGROUND: Embryonic and fetal exposure to maternal obesity causes several maladaptive morphological and epigenetic changes in exposed offspring. The timing of these events is unclear, but changes can be observed even after a short exposure to maternal obesity around the time of conception. The hypothesis of this work is that maternal obesity influences the ovine preimplantation conceptus early in pregnancy, and this exposure will affect gene expression in embryonic and extraembryonic tissues. RESULTS: Obese and lean ewe groups were established by overfeeding or normal feeding, respectively. Ewes were then bred to genetically similar rams. Conceptuses were collected at day 14 of gestation. Morphological assessments were made, conceptuses were sexed by genomic PCR analysis, and samples underwent RNA-sequencing analysis. While no obvious morphological differences existed between conceptuses, differentially expressed genes (>= 2-fold; >= 0.2 RPKM; <= 0.05 FDR) were detected based on maternal obesity exposure (n = 21). Also, differential effects of maternal obesity were noted on each conceptus sex (n = 347). A large portion of differentially expressed genes were associated with embryogenesis and placental development. CONCLUSIONS: Findings reveal that the preimplantation ovine conceptus genome responds to maternal obesity in a sex-dependent manner. The sexual dimorphism in response to the maternal environment coupled with changes in placental gene expression may explain aberrations in phenotype observed in offspring derived from obese females. PMID- 30305024 TI - High throughput small RNA and transcriptome sequencing reveal capacitation related microRNAs and mRNA in boar sperm. AB - BACKGROUND: Capacitation, a prerequisite for oocyte fertilization, is a complex process involving series of structural and functional changes in sperms such as membrane modifications, modulation of enzyme activities, and protein phosphorylation. In order to penetrate and fertilize an oocyte, mammalian sperms must undergo capacitation. Nevertheless, the process of sperm capacitation remains poorly understood and requires further elucidation. In the current study, via high throughput sequencing, we identified and explored the differentially expressed microRNAs (miRNAs) and mRNAs involved in boar sperm capacitation. RESULTS: We identified a total of 5342 mRNAs and 204 miRNAs that were differentially expressed in fresh and capacitated boar sperms. From these, 12 miRNAs (8 known and 4 newly identified miRNAs) and their differentially expressed target mRNAs were found to be involved in sperm capacitation-related PI3K-Akt, MAPK, cAMP-PKA and Ca2+signaling pathways. CONCLUSIONS: Our study is first to provide the complete miRNA and transcriptome profiles of boar sperm. Our findings provide important insights for the understanding of the RNA profile in boar sperm and future elucidation of the underlying molecular mechanism relevant to mammalian sperm capacitation. PMID- 30305025 TI - The gut bacteria across life stages in the synanthropic fly Chrysomya megacephala. AB - BACKGROUND: Gut bacteria are closely associated with host. Chrysomya megacephala, as a vector and resource insect, can transmit various pathogenic bacteria and consume manure to produce biofertilizer and larva biomass. However, the gut bacteria composition and abundance of C. megacephala remain unclear. RESULTS: Illumina MiSeq platform was used to compare composition of gut bacterial community in eggs, 1-day-old larvae, 5-day-old larvae, pupae, adult females and males by sequencing with variation in V4 region of 16S ribosomal DNA gene. In total, 928 operational taxonomic units (OTUs) were obtained. These OTUs were annotated into 19 phyla, 42 classes, 77 orders, 153 families and 289 genera. More than 0.5% abundance of 32 OTU core genera were found across all life stages. At class level, Alphaproteobacteria, Bacilli, Bacteroidia, Betaproteobacteria, Flavobacteriia and Gammaproteobacteria were the most abundant in C. megacephala. Eight species were identified to have significantly different abundance between 1 d-larvae and 5-day-larvae and took 28.95% of shared species between these two groups. Sex-specific bacterial species were identified that Faecalibacterium prausnitzii was merely present in females, while Rhodococcus fascians was merely present in males. CONCLUSION: Gut bacteria of C. megacephala varied across life stages. The composition and community structure of the bacterial community differed from young larvae to mature larvae, while that were similar in adult females and males. These data will provide an overall view of bacterial community across life stages in C. megacephala with attention on manure associated and pathogenic bacteria. PMID- 30305026 TI - Global identification and characterization of lncRNAs that control inflammation in malignant cholangiocytes. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, and associated with chronic inflammation and damage to the biliary epithelium. This study determined whether lncRNAs were dysregulated and participated in disease diagnosis or pivotal inflammation pathways through a genome-wide lncRNA screening and functional analysis. RESULTS: We firstly identified a large number of lncRNAs abnormally expressed between 9 pairs of cancerous and adjacent tissues of CCA, and between intra-hepatic CCA and extra hepatic CCA through a genome-wide profiling. A set of aberrant differentially expressed lncRNAs were further validated in a training set (16 pairs) and a test set (11 pairs) of CCA patient samples. Following assessment of the diagnostic value of the 7 differentially expressed lncRNAs, we confirmed the optimal combination of H19, C3P1, AC005550.3, PVT1, and LPAL2 with area under the curve of 0.8828 [95% CI: 0.7441-1.021, P < 0.001], with 93.75% sensitivity and 81.25% specificity, at the cutoff point of - 0.2884 to distinguish the CCA tissue from the normal ones, suggesting that specific lncRNAs may have potential for detecting CCA. More importantly, the genome-wide locus and lncRNA/mRNA co expression analyses revealed a set of lncRNAs that participated in inflammation and oxidative stress response pathways by regulating genes in cis or in trans. Finally, APOC1P1, PVT1, and LPAL2 were validated to regulate the migration and some pivotal inflammation genes under the CCA pathogenesis. CONCLUSIONS: Our findings are the first to show that lncRNAs may not only be potential biomarkers of CCA progression but also respond to inflammation in CCA. PMID- 30305028 TI - Escovopsioides as a fungal antagonist of the fungus cultivated by leafcutter ants. AB - BACKGROUND: Fungus gardens of fungus-growing (attine) ants harbor complex microbiomes in addition to the mutualistic fungus they cultivate for food. Fungi in the genus Escovopsioides were recently described as members of this microbiome but their role in the ant-fungus symbiosis is poorly known. In this study, we assessed the phylogenetic diversity of 21 Escovopsioides isolates obtained from fungus gardens of leafcutter ants (genera Atta and Acromyrmex) and non-leafcutter ants (genera Trachymyrmex and Apterostigma) sampled from several regions in Brazil. RESULTS: Regardless of the sample locality or ant genera, phylogenetic analysis showed low genetic diversity among the 20 Escovopsisoides isolates examined, which prompted the identification as Escovopsioides nivea (the only described species in the genus). In contrast, one Escovopsioides isolate obtained from a fungus garden of Apterostigma megacephala was considered a new phylogenetic species. Dual-culture plate assays showed that Escovopsioides isolates inhibited the mycelium growth of Leucoagaricus gongylophorus, the mutualistic fungus cultivated by somes species of leafcutter ants. In addition, Escovopsioides growth experiments in fungus gardens with and without ant workers showed this fungus is detrimental to the ant-fungus symbiosis. CONCLUSIONS: Here, we provide clues for the antagonism of Escovopsioides towards the mutualistic fungus of leafcutter ants. PMID- 30305029 TI - Bio efficacy of indigenous biological agents and selected fungicides against branch canker disease of (Macrophoma theicola) tea under field level. AB - BACKGROUND: Branch canker caused by Macrophoma theicola is a major stem disease of tea plants (Camellia spp.). In tea plantations, this disease causes crop loss and it is one of the major limiting factor for yield stagnation. In very few instances it causes considerable damage in new clearings (about 3 or 4 years old) and large number of bushes have been killed. As there is no control measures for branch canker disease in south Indian tea plantation, this field study was conducted in naturally infected pruned tea field at UPASI Tea Research Institute (Good Agricultural Practice), Valparai, Tamil Nadu, India. METHODS: The chemical fungicides, biological agents and bio products were evaluated under naturally infected field of seedling plants for two consecutive disease seasons (2014-2015) and there was 11 treatments with three applications. All the treatments were carried out in the time of February-March and October-November (2014-2015). The two set of application was conducted per year. Each set contains eight rounds during the month of February-March as well as October-November (2014-2015). The chemical fungicides, biological agents and commercial bio products were measured as per UPASI- TRF, recommendation viz., COC (50 g/ha and 0.2 g/plot), Companion (20 g/ha and 0.08 g/plot), biological agent of Bacillus amyloliquefaciens, Tichoderma harzianum, Gliocladium virens and Beauveria bassiana (5 kg/ha and 20.8 g/plot) and bio product of Tari (1 L/ha and 4.2 ml/plot) and Tricure (1 L/ha and 4.2 ml/plot). RESULTS: The present investigation revealed the integrated application of Companion/Bacillus amyloliquefaciens showed superior control of branch canker disease followed by the treatment with Companion alone under field condition. Copper oxychloride/Bacillus amyloliquefaciens was moderately effective followed by Copper oxychloride. The significantly reduced canker size was recorded with treatment of Bacillus amyloliquefaciens followed by commercial organic fungicides of Tari (Organic Tea Special) and Tricure (0.03% Azadirachtin). The least canker size was observed with Gliocladium virens followed by Beauveria bassiana. Branch canker disease incidence was increased in untreated control plants when compared to treated plants. CONCLUSION: Among these 11 treatments, the integrated treatment of companion at rate of 0.08 g and Bacillus amyloliquefaciens (20.8 g) showed the most significantly decreased canker size (DPL, 5.76) followed by another treatment with companion (0.08 g) (DPL, 4.11). The moderate reduction of canker size was observed by the treatment with Copper oxychloride (0.2 g)/Bacillus amyloliquefaciens (20.8 g) (DPL, 3.05) followed by the treatment of copper oxychloride alone (DPL, 1.74). Therefore, the integrated application of Companion/Bacillus amyloliquefaciens proved significantly effective in the management of branch canker disease under the field conditions. PMID- 30305027 TI - Non-target site-based resistance to tribenuron-methyl and essential involved genes in Myosoton aquaticum (L.). AB - BACKGROUND: Water chickweed (Myosoton aquaticum (L.)) is a dicot broadleaf weed that is widespread in winter fields in China, and has evolved serious resistance to acetolactate synthase (ALS) inhibiting herbicides. RESULTS: We identified a M. aquaticum population exhibiting moderate (6.15-fold) resistance to tribenuron methyl (TM). Target-site ALS gene sequencing revealed no known resistance mutations in these plants, and the in vitro ALS activity assays showed no differences in enzyme sensitivity between susceptible and resistant populations; however, resistance was reversed by pretreatment with the cytochrome P450 (CYP) monooxygenase inhibitor malathion. An RNA sequencing transcriptome analysis was performed to identify candidate genes involved in metabolic resistance, and the unigenes obtained by de novo transcriptome assembly were annotated across seven databases. In total, 34 differentially expressed genes selected by digital gene expression analysis were validated by quantitative real-time (qRT)-PCR. Ten consistently overexpressed contigs, including four for CYP, four for ATP-binding cassette (ABC) transporter, and two for peroxidase were further validated by qRT PCR using additional plants from resistant and susceptible populations. Three CYP genes (with homology to CYP734A1, CYP76C1, and CYP86B1) and one ABC transporter gene (with homology to ABCC10) were highly expressed in all resistant plants. CONCLUSION: The mechanism of TM resistance in M. aquaticum is controlled by NTSR rather than TSR. Four genes, CYP734A1, CYP76C1, CYP86B1, and ABCC10 could play essential role in metabolic resistance to TM and justify further functional studies. To our knowledge, this is the first large-scale transcriptome analysis of genes associated with NTSR in M. aquaticum using the Illumina platform. Our data provide resource for M. aquaticum biology, and will facilitate the study of herbicide resistance mechanism at the molecular level in this species as well as in other weeds. PMID- 30305030 TI - Complete genomic sequence of the Vibrio alginolyticus bacteriophage Vp670 and characterization of the lysis-related genes, cwlQ and holA. AB - BACKGROUND: Biocontrol of bacterial pathogens by bacteriophages (phages) represents a promising strategy. Vibrio alginolyticus, a gram-negative bacterium, is a notorious pathogen responsible for the loss of economically important farmed marine animals. To date, few V. alginolyticus phages have been successfully isolated, and only three complete genome sequences of them have been released. The limited available phage resources and poor genomic data hamper research on V. alginolyticus phages and their applications for the biocontrol of V. alginolyticus. RESULTS: We isolated a phage, Vp670, against the V. alginolyticus strain E06333 and obtained its full genomic sequence. It contains 43,121 nucleotides with a GC content of 43.4%, and codes for 49 predicted open reading frames. Observation by electron microscope combined with phylogenetic analysis of DNA polymerase indicates that Vp670 belongs to the subfamily Autographivirinae in the family Podoviridae. orf3 (designated holA) and orf8 (designated cwlQ) are predicted to encode a holin (HolA) and an endolysin (CwlQ), respectively. Expression of holA alone or coexpression of holA and cwlQ from within arrested the growth of Escherichia coli and V. alginolyticus while the expression of cwlQ alone had no effect on the growth of them. Further observation by transmission electron microscopy revealed that the expression of holA vanished the outer membrane and caused the release of cellular contents of V. alginolyticus and the coexpression of holA and cwlQ directly burst the cells and caused a more drastic release of cellular contents. Expression of cwlQ alone in V. alginolyticus did not cause cytomorphological changes. CONCLUSIONS: Phage Vp670 is a V. alginolyticus phage belonging to the family of Podoviridae. The genome of Vp670 contains a two-component lysis module, which is comprised of holA and cwlQ. holA is predicted to encode for the holin protein, HolA, and cwlQ is predicted to encode for the endolysin protein, CwlQ. Both holA and cwlQ likely play important roles during the release of phage progeny. PMID- 30305031 TI - Architecture of divergent flagellar promoters controlled by CtrA in Rhodobacter sphaeroides. AB - BACKGROUND: Rhodobacter sphaeroides has two sets of flagellar genes, fla1 and fla2, that are responsible for the synthesis of two different flagellar structures. The expression of the fla2 genes is under control of CtrA. In several alpha-proteobacteria CtrA is also required for the expression of the flagellar genes, but the architecture of CtrA-dependent promoters has only been studied in detail in Caulobacter crescentus. In many cases the expression of fla genes originates from divergent promoters located a few base pairs apart, suggesting a particular arrangement of the cis-acting sites. RESULTS: Here we characterized several control regions of the R. sphaeroides fla2 genes and analyzed in detail two regions containing the divergent promoters flgB2p-fliI2p, and fliL2p-fliF2p. Binding sites for CtrA of these promoters were identified in silico and tested by site directed mutagenesis. We conclude that each one of these promoter regions has a particular arrangement, either a single CtrA binding site for activation of fliL2p and fliF2p, or two independent sites for activation of flgB2p and fliI2p. ChIP experiments confirmed that CtrA binds to the control region containing the flgB2 and fliI2 promoters, supporting the notion that CtrA directly controls the expression of the fla2 genes. The flgB and fliI genes are syntenic and show a short intercistronic region in closely related bacterial species. We analyzed these regions and found that the arrangement of the CtrA binding sites varies considerably. CONCLUSIONS: The results in this work reveal the arrangement of the fla2 divergent promoters showing that CtrA promotes transcriptional activation using more than a single architecture. PMID- 30305033 TI - Rapid detection of respiratory organisms with the FilmArray respiratory panel in a large children's hospital in China. AB - BACKGROUND: Respiratory tract infections (RTIs) are the most common illness in children, and rapid diagnosis is required for the optimal management of RTIs, especially severe infections. METHODS: Nasopharyngeal swab or sputum specimens were collected from children aged 19 days to 15 years who were admitted to a hospital in Shanghai and diagnosed with RTIs. The specimens were tested with the FilmArray Respiratory Panel, a multiplex PCR assay that detects 16 viruses, Mycoplasma pneumoniae (M. pneumoniae), Bordetella pertussis (B. pertussis) and Chlamydophila pneumoniae (C. pneumoniae). RESULTS: Among the 775 children studied, 626 (80.8%, 626/775) tested positive for at least one organism, and multiple organisms were detected in 198 (25.5%). Rhinoviruses/enteroviruses (25.5%, 198/775) were detected most often, followed by respiratory syncytial virus (19.5%, 151/775), parainfluenza virus 3 (14.8%, 115/775), influenza A or B (10.9%), adenovirus (10.8%), M. pneumoniae (10.6%) and B. pertussis (6.3%). The prevalence of organisms differed by age, and most of the viruses were more common in winter. Of the 140 children suspected of having pertussis, 35.0% (49/140) tested positive for B. pertussis. CONCLUSIONS: FilmArray RP allows the rapid simultaneous detection of a wide number of respiratory organisms, with limited hands-on time, in Chinese pediatric patients with RTIs. PMID- 30305032 TI - Characterization and subcellular localization of histone deacetylases and their roles in response to abiotic stresses in soybean. AB - BACKGROUND: Histone deacetylases (HDACs) function as key epigenetic factors in repressing the expression of genes in multiple aspects of plant growth, development and plant response to abiotic or biotic stresses. To date, the molecular function of HDACs is well described in Arabidopsis thaliana, but no systematic analysis of this gene family in soybean (Glycine max) has been reported. RESULTS: In this study, 28 HDAC genes from soybean genome were identified, which were asymmetrically distributed on 12 chromosomes. Phylogenetic analysis demonstrated that GmHDACs fall into three major groups previously named RPD3/HDA1, SIR2, and HD2. Subcellular localization analysis revealed that YFP tagged GmSRT4, GmHDT2 and GmHDT4 were predominantly localized in the nucleus, whereas GmHDA6, GmHDA13, GmHDA14 and GmHDA16 were found in both the cytoplasm and nucleus. Real-time quantitative PCR showed that GmHDA6, GmHDA13, GmHDA14, GmHDA16 and GmHDT4 were broadly expressed across plant tissues, while GmHDA8, GmSRT2, GmSRT4 and GmHDT2 showed differential expression across various tissues. Interestingly, we measured differential changes in GmHDACs transcripts accumulation in response to several abiotic cues, indicating that these epigenetic modifiers could potentially be part of a dynamic transcriptional response to stress in soybean. Finally, we show that the levels of histone marks previously reported to be associated with plant HDACs are modulated by cold and heat in this legume. CONCLUSION: We have identified and classified 28 HDAC genes in soybean. Our data provides insights into the evolution of the HDAC gene family and further support the hypothesis that these genes are important for the plant responses to environmental stress. PMID- 30305034 TI - High rates of central obesity and sarcopenia in CKD irrespective of renal replacement therapy - an observational cross-sectional study. AB - BACKGROUND: Poor nutritional status of patients with renal disease has been associated with worsening of renal function and poor health outcomes. Simply measuring weight and height for calculation of the body mass index does however not capture the true picture of nutritional status in these patients. Therefore, we measured nutritional status by BMI, body composition, waist circumference, dietary intake and nutritional screening in three groups of renal patients. METHODS: Patients with chronic kidney disease not on renal replacement therapy (CKD stages 3-5, n = 112), after renal transplantation (n = 72) and patients treated with hemodialysis (n = 24) were recruited in a tertiary hospital in Bergen, Norway in a cross-sectional observational study. Dietary intake was assessed by a single 24 h recall. All patients underwent nutritional screening, anthropometric measurements, body composition measurement andfunctional measurements (hand grip strength). The prevalence of overweight and obesity, central obesity, sarcopenia, sarcopenic obesity and nutritional risk was calculated. RESULTS: Central obesity and sarcopenia were present in 49% and 35% of patients, respectively. 49% of patients with central obesity were normal weight or overweight according to their BMI. Factors associated with central obesity were a diagnosis of diabetes and increased fat mass, while factors associated with sarcopenia were age, female gender, number of medications. An increase in the BMI was associated with lower risk for sarcopenia. CONCLUSION: Central obesity and sarcopenia were present in renal patients at all disease stages. More attention to these unfavorable nutritional states is warranted in these patients. PMID- 30305035 TI - Diagnosis and management of non-dialysis chronic kidney disease in ambulatory care: a systematic review of clinical practice guidelines. AB - BACKGROUND: Chronic kidney disease (CKD) is age-dependent and has a high prevalence in the general population. Most patients are managed in ambulatory care. This systematic review provides an updated overview of quality and content of international clinical practice guidelines for diagnosis and management of non dialysis CKD relevant to patients in ambulatory care. METHODS: We identified guidelines published from 2012-to March 2018 in guideline portals, databases and by manual search. Methodological quality was assessed with the Appraisal of Guidelines for Research and Evaluation II instrument. Recommendations were extracted and evaluated. RESULTS: Eight hundred fifty-two publications were identified, 9 of which were eligible guidelines. Methodological quality ranged from 34 to 77%, with domains "scope and purpose" and "clarity of presentation" attaining highest and "applicability" lowest scores. Guidelines were similar in recommendations on CKD definition, screening of patients with diabetes and hypertension, blood pressure targets and referral of patients with progressive or stage G4 CKD. Definition of high risk groups and recommended tests in newly diagnosed CKD varied. CONCLUSIONS: Guidelines quality ranged from moderate to high. Guidelines generally agreed on management of patients with high risk or advanced CKD, but varied in regarding the range of recommended measurements, the need for referrals to nephrology, monitoring intervals and comprehensiveness. More research is needed on efficient management of patients with low risk of CKD progression to end stage renal disease. PMID- 30305036 TI - Sickle cell disease: a case report of renal amyloidosis. AB - BACKGROUND: The development of proteinuria and reduced glomerular filtration rate is associated with higher mortality among patients with sickle cell disease (SCD). AA amyloidosis, also associated with increased mortality, in SCD is rare. We present a case of a woman with homozygous sickle cell disease with nephrotic syndrome and antibodies to double stranded DNA without clinical features of systemic lupus erythematosus. Kidney biopsy reveals AA amyloidosis and is the first report of concomitant AA amyloidosis with antibodies to double stranded DNA in SCD. CASE PRESENTATION: A 40-year-old Central African woman with homozygous sickle cell disease and history of vaso-occlusive pain crises undergoes kidney biopsy for nephrotic-range proteinuria. Kidney biopsy reveals AA type amyloidosis, which is a rare manifestation of SCD in the kidney. Her anemia worsens with an ACE inhibitor, initiated to reduce proteinuria and limit GFR decline, so it was discontinued. Hydroxyurea, shown to decrease the frequency of vaso-occlusive crises and lower proteinuria, was subsequently initiated but then discontinued due to worsening anemia. Unfortunately, her glomerular filtration rate worsens. CONCLUSIONS: AA amyloidosis and antibodies to double stranded DNA can occur in sickle cell disease. ACE inhibition and hydroxyurea decrease proteinuria so they may limit progression of chronic kidney disease. Hydroxyurea also decreases frequency of vaso-occlusive pain crises so it might be helpful in limiting progression of renal AA amyloidosis. However, further studies are needed to determine optimal treatment strategies for AA amyloidosis in sickle cell disease. PMID- 30305037 TI - Efficacy and safety of cefazolin versus antistaphylococcal penicillins for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia: a systematic review and meta-analysis. AB - BACKGROUND: Antistaphylococcal penicillins (ASPs) and cefazolin have become the most frequent choices for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, the best therapeutic agent to treat MSSA bacteremia remains to be established. METHODS: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these two regimens for the treatment of MSSA bacteremia. PubMed, EMBASE and the Cochrane Library from inception to February 2018 were searched. The primary outcome was mortality. The secondary outcomes included treatment failure, recurrence of bacteremia, adverse effects (AEs) and discontinuation due to AEs. Data were extracted and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of ten observational studies met the inclusion criteria. The results indicate that compared to ASPs, cefazolin was associated with significant reduction in mortality (OR, 0.69; 95% CI, 0.58 to 0.82; I2 = 3.4%) and clinical failure (OR, 0.56; 95% CI, 0.37 to 0.85; I2 = 44.9%) without increasing the recurrence of bacteremia (OR, 1.12; 95% CI, 0.94 to 1.34; I2 = 0%). There were no significant differences for the risk of anaphylaxis (OR, 0.91; 95% CI, 0.36 to 2.99; I2 = 0%) or hematotoxicity (OR, 0.56; 95% CI, 0.17 to 1.88; I2 = 0%). However, nephrotoxicity (OR, 0.36; 95% CI, 0.16 to 0.81; I2 = 0%) and hepatotoxicity (OR, 0.12; 95% CI, 0.04 to 0.41; I2 = 0%) were significantly lower in the cefazolin group. Moreover, cefazolin was associated with lower probability of discontinuation due to AEs compared with the ASPs (OR, 0.24; 95% CI, 0.12 to 0.48; I2 = 18%). CONCLUSION: The results of present study favor the application of cefazolin and should be regarded as important evidence to help make clinical decisions in choosing a treatment option for treating MSSA bacteremia. PMID- 30305038 TI - Prevalence, socio-demographic characteristics, and comorbid health conditions in pre-dialysis chronic kidney disease: results from the Manitoba chronic kidney disease cohort. AB - BACKGROUND: Chronic Kidney Disease (CKD) is common and its prevalence has increased steadily over several decades. Monitoring of rates and severity of CKD across populations is critical for policy development and resource planning. Administrative health data alone has insufficient sensitivity for this purpose, therefore utilizing population level laboratory data and novel methodology is required for population-based surveillance. The aims of this study include a) develop the Manitoba CKD Cohort, b) estimate CKD prevalence, c) identify individuals at high risk of progression to kidney failure and d) determine rates of comorbid health conditions. METHODS: Administrative health and laboratory data from April 1996 to March 2012 were linked from the data repository at the Manitoba Centre for Health Policy. Prevalence was estimated using three methods: a) all CKD cases in administrative and laboratory databases; b) all CKD cases captured only through the laboratory data; c) and the capture-recapture method. Patients were stratified by risk by estimated Glomerular Filtration Rate (eGFR) and albuminuria based on Kidney Disease Improving Global Outcomes (KDIGO) criteria. For comorbid health conditions, the counts were modelled using a Generalized Linear Model (GLM). RESULTS: The Manitoba CKD Cohort consisted of 55,876 people with CKD. Of these, 18,342 were identified using administrative health data, 27,393 with laboratory data, and 10,141 people were identified in both databases. The CKD prevalence was 5.6% using the standard definition, 10.6% using only people captured by the laboratory data and 10.6% using the capture recapture method. Of the identified cases, 46% were at high risk of progression to end-stage kidney disease (ESKD), 41% were at low risk and 13% were not classified, due to unavailable laboratory data. High risk cases had a higher burden of comorbid conditions. CONCLUSION: This study reports a novel methodology for population based CKD surveillance utilizing a combination of administrative health and laboratory data. High rates of CKD at risk of progression to ESKD have been identified with this approach. Given the high rates of comorbidity and associated healthcare costs, these data can be used to develop a targeted and comprehensive public health surveillance strategy that encompass a range of interrelated chronic diseases. PMID- 30305039 TI - Prevalence and anatomical sites of human papillomavirus, Epstein-Barr virus and herpes simplex virus infections in men who have sex with men, Khon Kaen, Thailand. AB - BACKGROUND: Human papillomavirus (HPV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV) cause sexually transmitted diseases (STDs) that are frequently found in men who have sex with men (MSM) with human immunodeficiency viral (HIV) infection. METHODS: This study investigated the prevalence of infection and anatomical site distribution of these viruses in asymptomatic MSM. DNA, extracted from cells collected from the anorectum, oropharynx and urethra of 346 participants, was investigated for the presence of EBV, HPV and HSV using real-time PCR. Demographic data from the participants were analyzed. RESULTS: All three viruses were found in all sampled sites. EBV was the commonest virus, being detected in the anorectum (47.7% of participants), oropharynx (50.6%) and urethra (45.6%). HPV and HSV were found in 43.9% and 2.9% of anorectum samples, 13.8% and 3.8% of oropharynx samples and 25.7% and 2% of urethra samples, respectively. HPV infection of the anorectum was significantly associated with age groups 21-30 (odds = 3.043, 95% CI = 1.643-5.638 and P = 0.001) and 46-60 years (odds = 2.679, 95% CI = 1.406-5.101 and P = 0.03). EBV infection of the urethra was significantly correlated with age group 21-30 years (odds = 1.790, 95% CI = 1.010 3.173 and P = 0.046). EBV/HPV co-infection of the anorectum (odds = 3.211, 95% CI = 1.271-8.110, P = 0.014) and urethra (odds = 2.816, 95% CI = 1.024-7.740, P = 0.045) was also associated with this age group. Among HIV-positive MSM, there was a significant association between age-group (odds = 21.000, 95% CI = 1.777 248.103, P = 0.016) in HPV infection of the anorectum. A failure to use condoms was significantly associated with HPV infection of the anorectum (odds = 4.095, 95% CI = 1.404-11.943, P = 0.010) and urethra (odds = 7.187, 95% CI = 1.385 37.306, P = 0.019). Similarly, lack of condom use was significantly associated with EBV infection of the urethra (odds = 7.368, 95% CI = 1.580-34.371, P = 0.011). CONCLUSION: These results indicate that asymptomatic MSM in Northeast Thailand form a potential reservoir for transmission of STDs, and in particular for these viruses. PMID- 30305040 TI - Incidence of glomerulonephritis and non-diabetic end-stage renal disease in a developing middle-east region near armed conflict. AB - BACKGROUND: Estimates of the incidence of glomerulonephritis (GN) and end-stage renal disease (ESRD) in an Iraqi population are compared with the United States (US) and Jordan. METHODS: The study set consist of renal biopsies performed in 2012 and 2013 in the Kurdish provinces of Northern Iraq. The age specific and age standardized incidence of GN was calculated from the 2011 population. ESRD incidence was estimated from Sulaimaniyah dialysis center records of patient's inititating hemodialysis in 2017. RESULTS: At an annual biopsy rate of 7.8 per 100,000 persons in the Kurdish region, the number of diagnoses (2 years), the average age of diagnosis, and annual age standardized incidence (ASI)/100,000 for focal segmental glomerulosclerosis (FSGS) was n = 135, 27.3 +/- 17.6 years, ASI = 1.6; and for all glomerulonephritis (GN) was n = 384, 30.4 +/- 17.0 years, ASI = 5.1. FSGS represented 35% of GN biopsies, membranous glomerulonephritis 18%, systemic lupus erythematosus 13%, and immunoglobulin A nephropathy 7%. For FSGS and all GN, the peak age of diagnoses was 35-44 years of age with age specific rates declining after age 45. The unadjusted annual ESRD rate was 60 per million with an age specific peak at 55-64 years and a decline after age 65. The assigned cause of ESRD was 23% diabetes, 18% hypertension, and 12% GN with FSGS comprising 41% of biopsy-diagnosed, non-diabetic ESRD. CONCLUSIONS: The regional incidence of ESRD in Northern Iraq is much lower than the crude incidences of 100 and 390 per million for Jordan and the US respectively. This is associated with low renal disease rates in the Iraqi elderly and an apparent major contribution of FSGS to ESRD. PMID- 30305042 TI - De novo mutations in SCN1A are associated with classic Rett syndrome: a case report. AB - BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, there has not been reported any other gene that may account for the majority of these cases. CASE PRESENTATION: We describe two females who fulfill the diagnostic criteria for classic RTT, with pathogenic de novo mutations in SCN1A, which usually leads to Dravet syndrome. The developmental history and clinical features of these two females fits well with RTT, but they do have an unusual epileptic profile with early onset of seizures. Investigation of mRNA from one of the females showed a significantly reduced level of MECP2 mRNA. CONCLUSIONS: To our knowledge, this is the first report suggesting that SCN1A mutations could account for a proportion of the females with classic RTT without MECP2 mutations. As a consequence of these findings SCN1A should be considered in the molecular routine screening in MECP2-negative individuals with RTT and early onset epilepsy. PMID- 30305041 TI - Genomic analysis of DNA repair genes and androgen signaling in prostate cancer. AB - BACKGROUND: The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications. METHODS: We generated RNA-seq data from multiple prostate cancer lines and used bioinformatic analyses to characterize androgen-regulated gene expression. We compared the results from cell lines with gene expression data from prostate cancer xenografts, and patient samples, to query how androgen signaling and prostate cancer progression influences the expression of DNA repair genes. We performed whole genome sequencing to help characterize the status of the DNA repair machinery in widely used prostate cancer lines. Finally, we tested a DNA repair enzyme inhibitor for effects on androgen-dependent transcription. RESULTS: Our data indicates that androgen signaling regulates a subset of DNA repair genes that are largely specific to the respective model system and disease state. We identified deleterious mutations in the DNA repair genes RAD50 and CHEK2. We found that inhibition of the DNA repair enzyme MRE11 with the small molecule mirin inhibits androgen-dependent transcription and growth of prostate cancer cells. CONCLUSIONS: Our data supports the view that crosstalk between androgen signaling and DNA repair occurs at multiple levels, and that DNA repair enzymes in addition to PARPs, could be actionable targets in prostate cancer. PMID- 30305043 TI - Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease. AB - BACKGROUND: Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. METHODS: In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. RESULTS: Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. CONCLUSIONS: We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. PMID- 30305044 TI - The effect of whole body vibration training on quadriceps voluntary activation level of people with age-related muscle loss (sarcopenia): a randomized pilot study. AB - BACKGROUND: Whole body vibration was an effective training for improving muscle performance. The purpose of this study was to explore the effects of 12-week whole-body vibration training program on voluntary activation of quadriceps muscles of older people with age-related muscle loss (sarcopenia). METHODS: Twelve community dwelling seniors with age-related muscle loss were randomly allocated into whole body vibration training group and control group. The training lasted for 12 weeks. Twitch interpolation were conducted to examine the voluntary activation of quadriceps at pre- and post-intervention. RESULTS: Although there was no significant difference between whole body vibration training group and control group on the absolute values of the interpolated twitch ratio after 12 weeks of training. The changed values of ratio (Post minus Pre) were significantly different between the two groups (p = 0.044). CONCLUSIONS: The voluntary activation of quadriceps muscles of older people with age-related muscle loss was facilitated after 12 weeks of WBV training with 40 Hz * 4 mm * 360 s. Considering the small sample size of this study, it may only provide a piece of evidence that WBV is effective for facilitating the central motor drive in seniors with age-related muscle loss. More subjects are needed to confirm the present finding. TRIAL REGISTRATION: ISRCTN63583948 , registered on 16th January 2017, retrospectively registered. PMID- 30305045 TI - Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) seriously reduces quality of life and is associated with increased morbidity and mortality. The causes and neuropathogenesis of POCD remain largely unknown. Resveratrol, a sirtuin 1 (Sirt1) activator, is a polyphenol compound found in red wine that has protective functions in neuropathology paradigms. Endoplasmic reticulum stress (ERS) is a primary cellular response that activates the unfolded protein response (UPR). ERS and UPR mediate molecular and biochemical mechanisms related to neurodegeneration; however, the roles of ERS and Sirt1 in POCD remain unclear. The properties of resveratrol might be useful in the setting of POCD. METHODS: In the present study, we investigated learning and memory function and ERS pathways in aged mice after surgery under local anesthesia, and we evaluated the effects of resveratrol pretreatment. RESULTS: We found that resveratrol attenuated postoperative learning and memory impairment in aged mice postoperatively but did not alter locomotor activity. Resveratrol significantly decreased postoperative expression of ERS pathway UPR-related proteins and inflammatory mediators including nuclear factor-kappaB (NF-kappaB) in the hippocampus. This was accompanied by higher Sirt1 protein expression levels. Pretreatment with resveratrol did not affect the number of hippocampal neurons in aged mice after surgery. CONCLUSION: Overall, resveratrol pretreatment attenuated short-term learning and memory impairment and the ERS pathway UPR in aged mice after surgery under local anesthesia. PMID- 30305046 TI - Assessment of research waste part 1: an exemplar from examining study design, surrogate and clinical endpoints in studies of calcium intake and vitamin D supplementation. AB - BACKGROUND: Research waste is estimated to be very common, but assessments of its prevalence and scope are rare. As an example, we assessed research waste in clinical research on calcium intake (assessing study design and endpoint type) and vitamin D supplementation (assessing endpoint type). METHODS: We examined 404 randomised controlled trials (RCTs) and observational studies of calcium intake (diet or supplements) and bone mineral density (BMD) or fracture, and 547 RCTs of vitamin D supplements, and assessed the proportion of studies that used surrogate or clinical endpoints. For studies with BMD or fracture as an endpoint, we estimated when the 'tipping' point occurred indicating the need for RCTs with fracture as an endpoint (based on cumulative meta-analyses of BMD RCTs, and chronological review of observational studies), and whether each study published at least 5y after the tipping point was novel, added new clinical knowledge or was research waste. RESULTS: Observational studies of calcium intake and BMD or fracture outnumbered RCTs by 3.3-4.5 times. For both calcium intake and vitamin D supplements, studies using surrogate endpoints outnumbered studies using clinical endpoints by 1.6-3 times. Of 41 RCT publications of calcium intake and BMD or fracture published at least 5y after the tipping point in 1994, we considered that 19 (46%) lacked novelty, another 13 (32%) added no new clinical knowledge, and 30 (73%) were research waste. Of 204 observational study publications of calcium intake and BMD or fracture, 197 (96%) lacked novelty, another 5 (2%) added no new clinical knowledge, and 202 (99%) were research waste. Of 39 RCTs of vitamin D supplementation and BMD or fracture published at least 5y after the tipping point in 1999, 14 (36%) lacked novelty, another 13 (33%) added no new clinical knowledge, and 27 (69%) were research waste. CONCLUSIONS: A high proportion of studies of calcium intake since 2000 (95%) and trials of vitamin D supplements since 2005 (69%) on BMD or fracture represent research waste. PMID- 30305048 TI - An anticholinergic burden score for German prescribers: score development. AB - BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation. PMID- 30305047 TI - Transcriptome analysis of radish sprouts hypocotyls reveals the regulatory role of hydrogen-rich water in anthocyanin biosynthesis under UV-A. AB - BACKGROUND: Hydrogen gas (H2) is the most abundant element in the universe, and has been reported to act as a novel beneficial gaseous molecule in plant adaptive responses. Radish sprouts are popular because they contain substantial amounts of antioxidants and health-promoting compounds, such as anthocyanin and glucosinolates. Although radish sprouts accumulated more anthocyanin under UV-A after treatment with hydrogen-rich water (HRW), the molecular mechanism responsible is still elusive. To explore these mechanisms, RNA-seq analysis was used. RESULTS: Four cDNA libraries from radish sprout hypocotyls were constructed, and a total of 14,564 differentially expressed genes (DEGs) were identified through pairwise comparisons. By Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, these unigenes were found to be implicated in light signal perception and transduction, starch and sucrose metabolism, photosynthesis, nitrogen metabolism and biosynthesis of secondary metabolites. The MYB-bHLH-WD40 complex accounted for the majority of the transcription factors found to be involved in anthocyanin biosynthesis, and levels of transcripts for this complex were in accordance with the anthocyanin concentrations observed. In addition, other transcription factors (such as NAC, bZIP and TCP) might participate in HRW-promoted anthocyanin biosynthesis. Furthermore, the signaling processes of plant hormones, MAPKs and Ca2+ might be involved in HRW-promoted anthocyanin biosynthesis under UV-A. The expression patterns of 16 selected genes were confirmed using qRT-PCR analysis. CONCLUSIONS: Taken together, the results of this study may expand our understanding of HRW promoted anthocyanin accumulation under UV-A in radish sprouts. PMID- 30305049 TI - Risks and rewards of using prepaid vs. postpaid incentive checks on a survey of physicians. AB - BACKGROUND: Survey researchers use monetary incentives as a strategy to motivate physicians' survey participation. Experiments from general population surveys demonstrate that prepaid incentives increase response rates and lower survey administration costs relative to postpaid incentives. Experiments comparing these two incentive strategies have rarely been attempted with physician samples. METHODS: A nationally representative sample of oncologists was recruited to participate in the National Survey of Precision Medicine in Cancer Treatment. To determine the optimal strategy for survey incentives, sample members were randomly assigned to receive a $50 prepaid incentive check or a $50 promised (postpaid) incentive check. Outcome measures for this incentives experiment include cooperation rates, speed of response, check-cashing behavior, and comparison of hypothetical costs for different incentive strategies. RESULTS: Cooperation rates were considerably higher for sample members in the prepaid condition (41%) than in the postpaid condition (29%). Similar differences in cooperation rates were seen for physicians when stratified by region, size of the physician's metropolitan statistical area, specialty, and gender by age. Survey responders in the prepaid condition responded earlier in the field period than those in the postpaid condition, thus requiring fewer contacts. In the prepaid group, 84% of sample members who responded with a completed survey cashed the incentive check and only 6% of nonresponders cashed the check. In the postpaid condition, 72% of survey responders cashed the check; nonresponders were not given a check. The relatively higher cooperation rates and earlier response of the responders in the prepaid condition was associated with a 30% cost savings for the prepaid condition compared to the postpaid incentive condition. CONCLUSIONS: The results of this study suggest that the rewards of offering physicians a prepaid incentive check outweigh the possible risks of nonresponders cashing the check. The relative cost benefit of this strategy is likely to vary depending on the amount of the incentive relative to the costs of additional contact attempts to nonresponders. PMID- 30305050 TI - Breech birth at home: outcomes of 60 breech and 109 cephalic planned home and birth center births. AB - BACKGROUND: Research on outcomes of out-of-hospital breech birth is scarce. This study evaluates the outcomes of singleton term breech and cephalic births in a home or birth center setting. METHODS: This is a retrospective observational cohort study of 60 breech and 109 cephalic planned out-of-hospital term singleton births during a 6 year period with a single obstetrician. Outcomes measured included mode of delivery; birth weights; 1 & 5-min Apgar scores; ante-, intra-, and post-partum transports; perineal integrity; and other maternal and neonatal morbidity. RESULTS: 50 breech and 102 cephalic presentations were still in the obstetrician's care at the onset of labor; of those, 10 breech and 11 cephalic mothers required transport during labor. 76% of breech and 92.2% of cephalic births were planned to occur at home, with the remainder at a freestanding birth center. When compared to the cephalic group, the breech group had a higher rate of antepartum and in-labor transfer of care and cesarean section. Among completed out-of-hospital births, the breech group had a significantly higher rate of 1-min Apgar scores < 7 but no significant difference at 5 min. Rates of vaginal birth for both groups were high, with 84% of breech and 97.1% of cephalic mothers giving birth vaginally in this series. Compared to primiparas, multiparas in both groups had less perineal trauma and higher rates of out-of-hospital birth, vaginal birth, and spontaneous vaginal birth. No breech infant or mother required postpartum hospital transport, while one cephalic infant and one cephalic mother required postpartum transport. Of the babies born out-of-hospital, there was one short-term and one longer-term birth injury among the breech group and one short term brachial plexus injury in the cephalic group. CONCLUSIONS: A home or birth center setting leads to high rates of vaginal birth and good maternal outcomes for both breech and cephalic term singleton presentations. Out-of-hospital vaginal breech birth under specific protocol guidelines and with a skilled provider may be a reasonable choice for women wishing to avoid a cesarean section especially when there is no option of a hospital breech birth. However, this study is underpowered to calculate uncommon adverse neonatal outcomes. PMID- 30305052 TI - Parents' knowledge, awareness and attitudes of cord blood donation and banking options: an integrative review. AB - BACKGROUND: For over 25 years cord blood has been used as an alternative to bone marrow for therapeutic use in conditions of the blood, immune system and metabolic disorders. Parents can decide if they would like to privately store their infant's cord blood for later use if needed or to publicly donate it. Parents need to be aware of the options that exist for their infant's cord blood and have access to the relevant information to inform their choice. The aim of this paper is to identify parent's knowledge and awareness of cord blood donation, private banking options and stem cell use, and parent sources and preferred sources of this information. METHODS: An integrative review was conducted using several electronic databases to identify papers on parents' knowledge, attitudes and attitudes towards umbilical cord blood donation and banking. The CASP tool was used to determine validity and quality of the studies included in the review. RESULTS: The search of the international literature identified 25 papers which met review inclusion criteria. This integrative review identified parents' knowledge of cord banking and/or donation as low, with awareness of cord blood banking options greater than knowledge. Parents were found to have positive attitudes towards cord blood donation including awareness of the value of cord blood and its uses, with the option considered to be an ethical and altruistic choice. Knowledge on cord blood use were mixed; many studies' participants did not correctly identify uses. Information sources for parents on cord blood was found to be varied, fragmented and inconsistent. Health professionals were identified as the preferred source of information on cord blood banking for parents. CONCLUSIONS: This integrative review has identified that further research should focus on identifying information that expectant parents require to assist them to make informed choices around cord blood banking; and identifying barriers present for health professionals providing evidence based information on cord blood use and banking options. PMID- 30305053 TI - Home and community-based services coordination for homebound older adults in home based primary care. AB - BACKGROUND: Medically complex vulnerable older adults often face social challenges that affect compliance with their medical care plans, and thus require home and community-based services (HCBS). This study describes how non-medical social needs of homebound older adults are assessed and addressed within home based primary care (HBPC) practices, and to identify barriers to coordinating HCBS for patients. METHODS: An online survey of members of the American Academy of Home Care Medicine (AAHCM) was conducted between March through November 2016 in the United States. A 56-item survey was developed to assess HBPC practice characteristics and how practices identify social needs and coordinate and evaluate HCBS. Data from 101 of the 150 surveys received were included in the analyses. Forty-four percent of respondents were physicians, 24% were nurse practitioners, and 32% were administrators or other HBPC team members. RESULTS: Nearly all practices (98%) assessed patient social needs, with 78% conducting an assessment during the intake visit, and 88% providing ongoing periodic assessments. Seventy-four percent indicated 'most' or 'all' of their patients needed HCBS in the past 12 months. The most common needs were personal care (84%) and medication adherence (40%), and caregiver support (38%). Of the 86% of practices reporting they coordinate HCBS, 91% followed-up with patients, 84% assisted with applications, and 83% made service referrals. Fifty-seven percent reported that coordination was 'difficult.' The most common barriers to coordinating HCBS included cost to patient (65%), and eligibility requirements (63%). Four of the five most frequently reported barriers were associated with practices reporting it was 'difficult' or 'very difficult' to coordinate HCBS (OR from 2.49 to 3.94, p-values < .05). CONCLUSIONS: Despite the barriers to addressing non-medical social needs, most HBPC practices provided some level of coordination of HCBS for their high-need, high-cost homebound patients. More efforts are needed to implement and scale care model partnerships between medical and non-medical service providers within HBPC practices. PMID- 30305051 TI - The effect of body position on pulmonary function: a systematic review. AB - BACKGROUND: Pulmonary function tests (PFTs) are routinely performed in the upright position due to measurement devices and patient comfort. This systematic review investigated the influence of body position on lung function in healthy persons and specific patient groups. METHODS: A search to identify English language papers published from 1/1998-12/2017 was conducted using MEDLINE and Google Scholar with key words: body position, lung function, lung mechanics, lung volume, position change, positioning, posture, pulmonary function testing, sitting, standing, supine, ventilation, and ventilatory change. Studies that were quasi-experimental, pre-post intervention; compared >=2 positions, including sitting or standing; and assessed lung function in non-mechanically ventilated subjects aged >=18 years were included. Primary outcome measures were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC, FEV1/FVC), vital capacity (VC), functional residual capacity (FRC), maximal expiratory pressure (PEmax), maximal inspiratory pressure (PImax), peak expiratory flow (PEF), total lung capacity (TLC), residual volume (RV), and diffusing capacity of the lungs for carbon monoxide (DLCO). Standing, sitting, supine, and right- and left-side lying positions were studied. RESULTS: Forty-three studies met inclusion criteria. The study populations included healthy subjects (29 studies), lung disease (nine), heart disease (four), spinal cord injury (SCI, seven), neuromuscular diseases (three), and obesity (four). In most studies involving healthy subjects or patients with lung, heart, neuromuscular disease, or obesity, FEV1, FVC, FRC, PEmax, PImax, and/or PEF values were higher in more erect positions. For subjects with tetraplegic SCI, FVC and FEV1 were higher in supine vs. sitting. In healthy subjects, DLCO was higher in the supine vs. sitting, and in sitting vs. side-lying positions. In patients with chronic heart failure, the effect of position on DLCO varied. CONCLUSIONS: Body position influences the results of PFTs, but the optimal position and magnitude of the benefit varies between study populations. PFTs are routinely performed in the sitting position. We recommend the supine position should be considered in addition to sitting for PFTs in patients with SCI and neuromuscular disease. When treating patients with heart, lung, SCI, neuromuscular disease, or obesity, one should take into consideration that pulmonary physiology and function are influenced by body position. PMID- 30305054 TI - Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial. AB - BACKGROUND: We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. METHODS: Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. RESULTS: Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. CONCLUSIONS: De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. TRIAL REGISTRATION: Retrospectively registered on EudraCT N degrees 2009-017020-59 and NCT01303497 (February 24, 2011). PMID- 30305055 TI - Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. AB - BACKGROUND: Lapatinib has clinical efficacy in the treatment of trastuzumab refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. METHODS: We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. RESULTS: In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL 2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. CONCLUSIONS: Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies. PMID- 30305056 TI - Barriers to cervical cancer screening faced by immigrant women in Canada: a systematic scoping review. AB - BACKGROUND: The objective of this scoping study is to review the published literature and summarize findings related to barriers experienced by immigrant women in Canada while accessing cervical cancer screening. METHODS: Electronic databases of peer-reviewed articles and grey literature were searched using comprehensive sets of keywords, without restricting the time period or language. Articles were selected based on the following criteria: (a) the study population consisted of Canadian immigrant women and healthcare providers and other stakeholders serving immigrant women, (b) the research focused on the barriers to accessing cervical cancer screening, and (c) the study was conducted in Canada. RESULTS: Extracted data were grouped and analyzed, resulting in barriers comprised of six themes: economic barriers, cultural barriers, language barriers, healthcare system-related barriers, knowledge-related barriers, and individual level barriers. Lack of education, low income, preference for a female physician, lack of knowledge, lack of effective communication, and embarrassment were some of the most common barriers mentioned. CONCLUSIONS: Immigrant access to health services, including cervical cancer screening, is a complex issue concerning a wide range of barriers. Our findings offer insights into barriers to cervical cancer screening in immigrant communities in Canada that can be used to assist policymakers, healthcare providers, and researchers enhance the health and well being of these populations by mitigating barriers and improving screening. PMID- 30305057 TI - Development of a benchmark tool for cancer centers; results from a pilot exercise. AB - BACKGROUND: Differences in cancer survival exist between countries in Europe. Benchmarking of good practices can assist cancer centers to improve their services aiming for reduced inequalities. The aim of the BENCH-CAN project was to develop a cancer care benchmark tool, identify performance differences and yield good practice examples, contributing to improving the quality of interdisciplinary care. This paper describes the development of this benchmark tool and its validation in cancer centers throughout Europe. METHODS: A benchmark tool was developed and executed according to a 13 step benchmarking process. Indicator selection was based on literature, existing accreditation systems, and expert opinions. A final format was tested in eight cancer centers. Center visits by a team of minimally 3 persons, including a patient representative, were performed to verify information, grasp context and check on additional questions (through semi-structured interviews). Based on the visits, the benchmark methodology identified opportunities for improvement. RESULTS: The final tool existed of 61 qualitative and 141 quantitative indicators, which were structured in an evaluative framework. Data from all eight participating centers showed inter-organization variability on many indicators, such as bed utilization and provision of survivorship care. Subsequently, improvement suggestions for centers were made; 85% of which were agreed upon. CONCLUSION: A benchmarking tool for cancer centers was successfully developed and tested and is available in an open format. The tool allows comparison of inter-organizational performance. Improvement opportunities were successfully identified for every center involved and the tool was positively evaluated. PMID- 30305058 TI - Maternal mortality in the Gaza strip: a look at causes and solutions. AB - BACKGROUND: Maternal mortality is an important health indicator for the overall health of a population. This study assessed the causes and contributing factors to maternal mortality that occurred in the Gaza-Strip between July 2014 and June 2015. METHODS: This is a retrospective study that used both quantitative and qualitative data. The data were collected from available medical records, investigation reports, death certificates, and field interviews with healthcare professionals as well as families. RESULTS: A total of 18 maternal mortalities occurred in Gaza between 1st July 2014 and June 30th 2015. Age at time of death ranged from 18 to 44 years, with 44.4% occurring before the age of 35 years. About 22.2% were primiparous, while 55.6% were grand multiparous women. The most common causes of death were sepsis, postpartum haemorrhage, and pulmonary embolism. The most striking deficiency was very poor medical documentation which was observed in 17 cases (94%). In addition, poor communication between doctors and women and their families or among healthcare teams was noticed in nine cases (50%). These were repeatedly described by families during interviews. Further aspects surfacing in many interviews were distrust by families towards clinicians and poor understanding of health conditions by women. Other factors included socioeconomic conditions, poor antenatal attendance and the impact of the 2014 war. Low morale among medical staff was expressed by most interviewed clinicians, as well as the fear of being blamed by families and management in case of adverse events. Substandard care and lack of appropriate supervision were also found in some cases. CONCLUSIONS: This study revealed deficiencies in maternity care, some of which were linked to the socioeconomic situation and the 2014 war. Others show poor implementation of clinical guidelines and lack of professional skills in communication and teamwork. Specialised training should be offered for clinicians in order to improve these aspects. However, the most striking deficiency was the extremely poor documentation, reflecting a lack of awareness among clinicians regarding its importance. Local policymakers should focus on systematic application of quality improvement strategies in order to achieve greater patient safety and further reductions in the maternal mortality rate. PMID- 30305059 TI - Combining genomic analyses with tumour-derived slice cultures for the characterization of an EGFR-activating kinase mutation in a case of glioblastoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) gene alterations and amplification are frequently reported in cases of glioblastoma (GBM). However, EGFR-activating mutations that confer proven sensitivity to tyrosine kinase inhibitors (TKIs) in lung cancer have not yet been reported in GBM. CASE PRESENTATION: Using next-generation sequencing, array comparative genomic hybridization and droplet digital PCR, we identified the p.L861Q EGFR mutation in a case of GBM for the first time. The mutation was associated with gene amplification. L861Q may be a clinically valuable mutation because it is known to sensitize non-small-cell lung cancers to treatment with the second-generation EGFR TKI afatinib in particular. Furthermore, we used slice culture of the patient's GBM explant to evaluate the tumour's sensitivity to various EGFR targeting drugs. Our results suggested that the tumour was not intrinsically sensitive to these drugs. CONCLUSIONS: Our results highlight (i) the value of comprehensive genomic analyses for identifying patient-specific, targetable alterations, and (ii) the need to combine genomic analyses with functional assays, such as tumour-derived slice cultures. PMID- 30305060 TI - Not now but later - a qualitative study of non-exercising pregnant women's views and experiences of exercise. AB - BACKGROUND: Evidence has shown that there are several physical and mental advantages of exercise during pregnancy. Despite this, the recommendations for exercise during pregnancy are poorly fulfilled. The aim of this study was to illuminate non-exercising pregnant women's views and experiences concerning exercise before and during pregnancy. METHOD: The study had a qualitative design with an inductive approach and was analysed by content analysis. A total of 16 individual and face-to-face interviews were conducted with healthy pregnant women, mainly in the third trimester and living in Sweden. The participating women had not been exercising 3 months before pregnancy or during pregnancy. RESULTS: The main category "Insurmountable now, but possible in the future" was based on the four categories: "Lost and lack of routines", "Feelings of inadequacy", "Having a different focus" and "Need for support". The women experienced that their lack of routines was a major barrier that prevented them from exercising. Other factors that contributed were, for example, pregnancy related problems, long working days and prioritizing family life. The women described it as difficult to combine exercise with their focus on the pregnancy and they missed continuous support from the antenatal care provider. The women expressed a need for suggestions concerning exercise during pregnancy and follow up on previous counselling, especially when pregnancy-related issues arose. Information about easily accessible alternatives or simple home exercises was requested. They felt immobile and were not satisfied with their inactivity and tried to partly compensate with everyday activities. The women identified the postpartum period as an important possibility for becoming more active, for their own sake, but also because they wanted to become role models for their children. CONCLUSION: Continuous support during pregnancy is needed concerning exercise. Pregnancy is mostly a barrier that prevents exercise for this group of women but, at the same time, may be a motivator and a possibility for better health. As the result showed that these women were highly motivated to a life-style change post pregnancy, it may be crucial to support previously non-exercising women postpartum. PMID- 30305061 TI - Perceived effectiveness of pictorial health warnings on changes in smoking behaviour in Asia: a literature review. AB - BACKGROUND: Several Asian countries have implemented pictorial health warnings on cigarette packs as suggested by the World Health Organization with various policies based on countries' systems. The study is aimed to analyse multiple research studies on the perceived effectiveness of Pictorial Health Warnings as a deterrent to smoking intention and as a stimulant of smoking behaviour in smokers and non-smokers in Asian countries. METHOD: Peer-reviewed articles were identified through multiple science databases indexed by Scopus, MEDLINE or PubMed. The review was limited to articles that reported original research findings, were conducted in Asian countries and were available for review by January 2010. A PRISMA Flow diagram was used to identify the articles through the process of data screening and extractions. RESULT: A total of 14 original articles which met the criteria were included in the review, consisting of 12 quantitative studies and 2 studies with both quantitative and qualitative methods from 17 jurisdictions. The reviewed studies found that pictorial health warnings were associated with a greater perception of salience (reading and noticing the warning), emotional effects, and cognitive increase. Additionally, in the reviewed studies, pictorial health warnings were perceived as more effective in deterring smoking initiation and encouraging smoking cessation than text-only warnings. Several studies also evaluated the effectiveness of a new pictorial warning compared with the old one. However, the relevance of refreshing the pictures of pictorial health warnings and the length of the effective period of the implementation of pictorial health warnings were less frequently studied. CONCLUSION: Pictorial health warnings perceived as more effective in deterring smoking initiation among non-smokers and as well as in stimulating smoking cessation among smokers. Future studies on pictorial health warnings should study the relevance of changing or refreshing pictorial health warning on cigarette packages in a period of time. PMID- 30305062 TI - Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma. AB - BACKGROUND: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar). METHODS: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1alpha) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments. RESULTS: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1alpha, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects. CONCLUSION: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer. PMID- 30305063 TI - Polycystic ovary syndrome and its impact on Iranian women's quality of life: a population-based study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a major public health concern worldwide affecting up to one in five women at reproductive age. It is associated with biochemical and hormonal disturbances as well as adverse cosmetic, reproductive, metabolic, and psychological consequences, resulting in worsened quality of life. The aim of the present study is evaluating the quality of life and determining its degrading factors among Iranian women suffering from this syndrome. METHODS: This cross-sectional study was conducted on 200 PCOS women in Hamadan, Iran. In order to measure quality of life we used the Persian version of Health-related Quality of Life Questionnaire for PCOS (PCOSQ). Descriptive statistics was used to explore the data. In addition linear regression analysis was performed to assess factors affecting health-related quality of life in this population. RESULTS: The mean score for quality of life domains (from the greatest to the least serious concern) were: infertility (3.43 +/- 1.63), emotions (3.55 +/- 1.17), menstrual problems (3.77 +/- 1.36), body hair (3.80 +/- 2.05) and weight (4.32 +/- 1.80), respectively. The higher score represents better function. However, multivariate analysis revealed that hirsutism had the strongest impact on the patients' quality of life (p < 0.001) followed by infertility (p = 0.038) and menstrual irregularity (p = 0.003). CONCLUSION: The findings showed that impairment of quality of life was associated with PCOS related conditions such as hirsutism, infertility and menstrual problems. PMID- 30305064 TI - A molecular and staging model predicts survival in patients with resected non small cell lung cancer. AB - BACKGROUND: The current TNM staging system is far from perfect in predicting the survival of individual non-small cell lung cancer (NSCLC) patients. In this study, we aim to combine clinical variables and molecular biomarkers to develop a prognostic model for patients with NSCLC. METHODS: Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on multivariable Cox regression analysis in a cohort of 152 NSCLC patients. The predictive performance of the model was assessed by the Area under the Receiver Operating Characteristic Curve (AUC) and Kaplan-Meier survival analysis. RESULTS: The survival prediction model consisting of two genes (TPX2 and MMP12) and two clinicopathological factors (tumor stage and grade) was developed. The patients could be divided into either high-risk group or low-risk group. Both disease-free survival and overall survival were significantly different among the diverse groups (P < 0.05). The AUC of the prognostic model was higher than that of the TNM staging system for predicting survival. CONCLUSIONS: We developed a novel prognostic model which can accurately predict outcomes for patients with NSCLC after surgery. PMID- 30305066 TI - Perceptions and decision-making with regard to pregnancy among HIV positive women in rural Maputo Province, Mozambique - a qualitative study. AB - BACKGROUND: In preventing the transfer of HIV to their children, the Ministry of Health in Mozambique recommends all couples follow medical advice prior to a pregnancy. However, little is known about how such women experience pregnancy, nor the values they adhere to when making childbearing decisions. This qualitative study explores perceptions and decision-making processes regarding pregnancy among HIV positive women in rural Maputo Province. METHODS: In-depth interviews and five focus group discussions with fifty-nine women who had recently become mothers were carried out. In addition, six semi-structured interviews were held with maternity and child health nurses. The ethnographic methods employed here were guided by Bourdieu's practice theory. RESULTS: The study indicated that women often perceived pregnancy as a test of fertility and identity. It was not only viewed as a rite of passage from childhood to womanhood, but also as a duty for married women to have children. Most women did not follow recommended medical advice prior to gestation. This was primarily due to perceptions that decision-making about pregnancy was regarded as a private issue not requiring consultation with a healthcare provider. Additionally, stigmatisation of women living with HIV, lack of knowledge about the need to consult a healthcare provider prior to pregnancy, and unintended pregnancy due to inadequate use of contraceptive were crucial factors. CONCLUSION: Women's experiences and decisions regarding pregnancy are more influenced by social and cultural norms than medical advice. Therefore, education concerning sexual and reproductive health in relation to HIV/AIDS and childbearing is recommended. In particular, we recommend maternal and child healthcare nurses need to be sensitive to women's perceptions and the cultural context of maternity when providing information about sexual and reproductive health. PMID- 30305065 TI - Patients with severe low back pain exhibit a low level of physical activity before lumbar fusion surgery: a cross-sectional study. AB - BACKGROUND: People with severe low back pain are at higher risk of poor health. Patients scheduled for lumbar fusion surgery are assumed to have low levels of physical activity, but few data exist. The aim of the study was firstly to investigate preoperative levels of objectively measured physical activity in patients with severe low back pain waiting for lumbar fusion surgery, and secondly to investigate whether factors in the fear-avoidance model were associated with these levels. METHODS: We included 118 patients waiting for lumbar fusion surgery (63 women and 55 men; mean age 46 years). Physical activity expressed as steps per day and total time spent in at least moderate-intensity physical activity was assessed with ActiGraph GT3X+ accelerometers. The data were compared to the WHO recommendations on physical activity for health. Whether factors in the fear-avoidance model were associated with physical activity was evaluated by two different multiple linear regression models. RESULTS: Ninety-six patients (83%) did not reach the WHO recommendations on physical activity for health, and 19 (16%) patients took fewer than 5000 steps per day, which indicates a sedentary lifestyle. On a group level, higher scores for fear of movement and disability were associated with lower numbers of steps per day. CONCLUSION: A high proportion of the patients did not reach the WHO recommendations on physical activity and are therefore at risk of poor health due to insufficient physical activity. We also found a negative association between both fear of movement and disability, and the number of steps per day. Action needs to be taken to motivate patients to be more physically active before surgery, to improve health postoperatively. There is a need for interventions aimed at increasing physical activity levels and reducing barriers to physical activity in the prehabilitation phase of this patient group. TRIAL REGISTRATION: Current Controlled Trials ISCRTN 17115599 , retrospectively Registered 18 may 2015. PMID- 30305067 TI - Vitamin D status in healthy black African adults at a tertiary hospital in Nairobi, Kenya: a cross sectional study. AB - BACKGROUND: Vitamin D has been known since the twentieth Century for its benefits in bone health. Recent observational studies have demonstrated its benefits in infectious diseases such as tuberculosis and non-communicable diseases such as diabetes mellitus, cardiovascular diseases and cancer. This has led to a dramatic increase in testing among adults. The cut-offs for vitamin D deficiency have been debated for decades and the current cut off is derived from a Caucasian population. Studies done among black African adults in Africa are few with vitamin D deficiency ranging from 5 to 91%. A few cut- offs have correlated vitamin D deficiency to physiological markers such as parathyroid hormone (PTH), calcium and phosphate with varying results. METHODS: This was a cross sectional study carried out among blood donors at Aga Khan University hospital, Nairobi (AKUHN) from March to May 2015. Vitamin D (25(OH)D) levels were assayed and correlated with PTH, calcium and phosphate. RESULTS: A total of 253 individuals were included in the final analysis. The proportion of study participants who had a 25(OH) D level of < 20 ng/ml thus classified as vitamin D deficient was 17.4% (95% C.I 12.73-22.07). The 25(OH) D level that coincided with a significant increase in PTH was 30 ng/ml. Males were less likely to be vitamin D deficient (O.R 0.48 (C.I 0.233-0.993) p 0.04). Sunshine exposure for >=3 h per day reduced the odds of being Vitamin D deficient though this was not statistically significant after multivariate regression analysis. CONCLUSIONS: We found a much lower prevalence of Vitamin D deficiency compared to many similar studies carried out in sub-Saharan Africa possibly due to the recruitment of healthy individuals and the proximity of Nairobi to the equator which allows for considerable exposure to sunshine. Vitamin D levels below 30 ng/mL was associated with a significant rise in PTH levels, suggesting that this cut off could be appropriate for defining Vitamin D deficiency in the population served by our laboratory. PMID- 30305068 TI - Allow natural death versus do-not-resuscitate: titles, information contents, outcomes, and the considerations related to do-not-resuscitate decision. AB - BACKGROUND: As the "do not resuscitate" (DNR) discussion involves communication, this study explored (1) the effects of a title that included "allow natural death", and of information contents and outcomes of the decision; and (2) the information needs and consideration of the DNR decision, and benefits and barriers of the DNR discussion. METHODS: Healthy adults (n = 524) were presented with a scenario with different titles, information contents, and outcomes, and they rated the probability of a DNR decision. A questionnaire including information needs, consideration of the decision, and benefits and barriers of DNR discussion was also used. RESULTS: There was a significantly higher probability of signing the DNR order when the title included "allow natural death" (t = - 4.51, p < 0.001), when comprehensive information was provided (F = 60.64, p < 0.001), and when there were worse outcomes (F = 292.16, p < 0.001). Common information needs included remaining life period and the prognosis. Common barriers were the families' worries and uncertainty about future physical changes. CONCLUSION: The title, information contents, and outcomes may influence the DNR decisions. Health-care providers should address the concept of natural death, provide comprehensive information, and help patients and families to overcome the barriers. PMID- 30305070 TI - Distal biceps tendon rupture: advantages and drawbacks of the anatomical reinsertion with a modified double incision approach. AB - BACKGROUND: Distal biceps tendon rupture occurs more often in middle-aged male population, involving the dominant arm. In this retrospective study, it's been described the occurrence of the most frequent adverse events and the clinical outcomes of patients undergoing surgical repair of distal biceps tendon rupture with the modified Morrey's double-incision approach, to determine better indications for patients with acute tendon injury. METHODS: Sixty-three patients with acute distal biceps tendon rupture treated with a modified double-incision technique between 2003 and 2015 were retrospectively evaluated at a mean 24 months of follow-up. Clinical evaluation including range of motion (ROM) and isometric strength recovery compared to the healthy contralateral side assessment, together with documentation of nerve injury, was performed. Patients were asked to answer DASH, OES and MEPS scores. RESULTS: The ROM recovery showed excellent results compared to the healthy contralateral side. The reported major complications included: one case of proximal radio-ulnar synostosis, 3 cases of posterior interosseous nerve (PIN) palsy and one case of a-traumatic tendon re rupture. Concerning minor complications, intermittent pain, ROM deficiency < 30 degrees in flexion/extension and pronation/supination, isometric flexion strength deficiency < 30% and isometric supination strength deficiency < 60%, lateral antebrachial cutaneous nerve (LACBN) injury, were observed. The average DASH score was 8.5; the average OES was 41.5 and the MEPS was 96.3. CONCLUSION: The Morrey modified double-incision technique finds its indication in young and active patients if performed within 2 weeks from injury. If performed by experienced surgeons, the advantages can exceed the drawbacks of possible complications. PMID- 30305069 TI - The Next Generation Scientist program: capacity-building for future scientific leaders in low- and middle-income countries. AB - BACKGROUND: Scientific and professional development opportunities for early career scientists in low- and middle- income countries (LMICs) are limited and not consistent. There is a disproportionately low number of biomedical and clinical researchers in LMIC's relative to their high burden of disease, a disparity that is aggravated by emigration of up to 70% of scientists from their countries of birth for education and employment elsewhere. To help address this need, a novel University-accredited, immersive fellowship program was established by a large public-academic-private network. We sought to describe the program and summarize progress and lessons learned over its first 7-years. METHODS: Hallmarks of the program are a structured learning curriculum and bespoke research activities tailored to the needs of each fellow. Research projects expose the scientists to state-of-the-art methodologies and leading experts in their fields while also ensuring that learnings are implementable within their home infrastructure. Fellows run seminars on drug discovery and development that reinforce themes of scientific leadership and teamwork together with practical modules on addressing healthcare challenges within their local systems. Industry mentors achieve mutual learning to better understand healthcare needs in traditionally underserved settings. We evaluated the impact of the program through an online survey of participants and by assessing research output. RESULTS: More than 140 scientists and clinicians from 25 countries participated over the 7-year period. Evaluation revealed strong evidence of knowledge and skills transfer, and beneficial self-reported impact on fellow's research output and career trajectories. Examples of program impact included completion of post graduate qualifications; establishment and implementation of good laboratory- and clinical- practice mechanisms; and becoming lead investigators in local programs. There was a high retention of fellows in their home countries (> 75%) and an enduring professional network among the fellows and their mentors. CONCLUSIONS: Our experience demonstrates an example for how multi-sectoral partners can contribute to scientific and professional development of researchers in LMICs and supports the idea that capacity-building efforts should be tailored to the specific needs of beneficiaries to be maximally effective. Lessons learned may be applied to the design and conduct of other programs to strengthen science ecosystems in LMICs. PMID- 30305071 TI - Establishing the international prevalence of self-reported child maltreatment: a systematic review by maltreatment type and gender. AB - BACKGROUND: Estimating the prevalence of child maltreatment is challenging due to the absence of a clear 'gold standard' as to what constitutes maltreatment. This systematic review aims to review studies using self-report maltreatment to capture prevalence rates worldwide. METHODS: PubMed, Ovid SP and grey literature from the NSPCC, UNICEF, The UK Government, and WHO from 2000 to 2017 were searched. The literature review focused on the variation found in self-reported lifetime prevalence for each type of maltreatment between studies by continent and gender, and how methodological differences may explain differences found. RESULTS: Sexual abuse is the most commonly studied form of maltreatment across the world with median (25th to 75th centile) prevalence of 20.4% (13.2% to 33.6%) and 28.8% (17.0% to 40.2%) in North American and Australian girls respectively, with lower rates generally for boys. Rates of physical abuse were more similar across genders apart from in Europe, which were 12.0% (6.9% to 23.0%) and 27.0% (7.0% to 43.0%) for girls and boys respectively, and often very high in some continents, for example, 50.8% (36.0% to 73.8%) and 60.2% (43.0% to 84.9%) for girls and boys respectively in Africa. Median rates of emotional abuse were nearly double for girls than boys in North America (28.4% vs 13.8% respectively) and Europe (12.9% vs 6.2% respectively) but more similar across genders groups elsewhere. Median rates of neglect were highest in Africa (girls: 41.8%, boys: 39.1%) and South America (girls: 54.8%, boys: 56.7%) but were based on few studies in total, whereas in the two continents with the highest number of studies, median rates differed between girls (40.5%) and boys (16.6%) in North America but were similar in Asia (girls: 26.3%, boys: 23.8%). CONCLUSIONS: Median prevalence rates differ substantially by maltreatment category, gender and by continent. The number of studies and available data also varies and relatively little is known about prevalence for some forms of maltreatment, particularly outside of the North American context. Prevalence rates require caution in interpretation as some variation will reflect methodological differences, including the data collection methods, and how the maltreatment is defined. PMID- 30305072 TI - Effect of high body mass index on knee muscle strength and function after anterior cruciate ligament reconstruction using hamstring tendon autografts. AB - BACKGROUND: Increased body mass index (BMI) has been associated with poorer function in patients who have undergone anterior cruciate ligament (ACL) reconstruction. However, the effect of high BMI on muscle strength in these patients remained unclear. The current study aimed to compare knee muscle strength and Knee injury and Osteoarthritis Outcome Score (KOOS) in ACL reconstructed patients with a variety of different BMIs. METHODS: From November 2013 to March 2016, we prospectively enrolled 30 patients who underwent ACL reconstruction (18-60 years of age). Anthropometric parameters, body compositions, isokinetic muscle strength and KOOS were assessed preoperatively, and at post-operative 16th week and 28th week. The patients were stratified into two groups by BMI, i.e. normal BMI (18.5-24.9 kg/m2) and high BMI (>=25.0 kg/m2). RESULTS: Twelve patients in the normal BMI group completed the follow-up, while sixteen patients did so in the high BMI group. In comparison of muscle strength between baseline and 28th week follow-up, the normal BMI group had significant increases in overall knee muscle strength, while the high BMI group only had increases in extensors of uninjured knee and flexors of the injured knee. However, there were significant increases in all KOOS subscales for the high BMI group. The high BMI patients reported increased KOOS, which may reflect the contribution of ligament stability in the presence of inadequate muscle strength. CONCLUSIONS: The normal BMI patients had improvement in all knee muscle strength following ACL reconstruction, while high BMI patients only had increases in certain knee muscles. High BMI patients had a decreased quadriceps muscle symmetry index, as compared to their normal BMI counterparts. Increases in quadriceps muscle strength of the uninjured knee and ACL reconstruction were associated with improvements in KOOS in high BMI patients. PMID- 30305073 TI - Comparison of postoperative ciliary body changes associated with the use of 23 gauge and 20-gauge system for pars plana vitrectomy. AB - BACKGROUND: To compare the ciliary body changes associated with the use of 23 gauge (23G) and 20-gauge (20G) systems for pars plana vitrectomy. METHODS: A total of 60 patients (60 eyes) with idiopathic epiretinal membrane who were scheduled for surgical treatment were selected and randomly assigned to 20G group or 23G group. Time required for incision making, vitrectomy, and incision closure was compared between the two groups. Changes in ciliary body were evaluated by ultrasound microscopy (UBM). Anterior chamber inflammation was assessed with laser flare meter instrument. RESULTS: Incision-making time (4.5 +/- 0.9 min) and incision-closure time (2.8 +/- 0.7 min) in the 23G group were significantly shorter than those in the 20G group (10.1 +/- 1.5 min and 11.3 +/- 2.2 min, respectively). No significant intergroup difference was observed with respect to time required for vitrectomy (21.6 +/- 3.3 min and 20.7 +/- 3.2 min, respectively). Ciliary body thickness in the 23G group recovered back to preoperative levels after 4 weeks, as against 8 weeks in the 20G group. Postoperative ciliary body thickness in the 20G group was significantly higher than that in the 23G group (p < 0.05). The aqueous protein concentration in 23G group recovered back to preoperative levels after 2 weeks, as against 4 weeks in the 20G group. Postoperative aqueous protein concentration in the 20G group was significantly higher than that in the 23G group (p < 0.05). CONCLUSIONS: The use of 23G system was associated with significantly milder injury to the ciliary body as compared to that associated with the use of 20G system. TRIAL REGISTRATION: The study was retrospectively registered on Chinese Clinical Trial Registry. The clinical study registration number was ChiCTR-INR-17011082 . Date of registration: 2017-04-07. PMID- 30305074 TI - Treatment of colon cancer in a patient with systemic lupus erythematosus: a case report. AB - BACKGROUND: Gastrointestinal symptoms occur in approximately 50% of patients with systemic lupus erythematous with low specificity. Although it is well established that colon cancer is one of the many gastrointestinal manifestations associated with systemic lupus erythematous, the diagnosis and treatment remains complex due to adrenal insufficiency symptoms. CASE PRESENTATION: A 43-year-old Chinese woman with a five-year history of systemic lupus erythematous was diagnosed with colon cancer based on imaging test. A radical bowel resection was performed successfully. To avoid serious complications during surgery, prednisone was replaced with methylprednisolone therefore avoiding adrenal insufficiency. The patient was subsequently treated with mFOLFOX6 chemotherapy and recovered well. CONCLUSION: There is a lack of reports for treatment of colon cancer in patients with systemic lupus erythematous. This report provides an effective way to diagnose colon cancer in patients with systemic lupus erythematous and illustrates a successful therapy strategy for this complex medical condition. PMID- 30305075 TI - Risk factors of presenile nuclear cataract in health screening study. AB - BACKGROUND: To identify risk factors for the development of presenile nuclear cataract in health screening test. METHODS: The cross sectional study included a total of 532 eyes of 266 participants aged 30 to 49 years of Samsung Medical Center from February 2013 to April 2015. Presence of nuclear cataract was defined when the log MAR visual acuity with correction was greater than or equal to 0.2 and one or more of the following were met: Pentacam Nuclear Staging (PNS) grading score >= 1, average value of nuclear density >= 15%, maximum value of nuclear density >= 30%. Possible risk factors were obtained from blood tests and questionnaires of a health screening test of Samsung Medical Center. Association between nuclear cataract and risk factors was investigated using univariate and multivariate logistic regression analysis by generalized estimating equation (GEE) models. RESULTS: Five factors were significantly associated with presenile nuclear cataract: current smoking [odds ratio (OR) = 2.80, 95% confidence interval (CI), 1.10-7.12, p = 0.0310], non-exercise and high amount of daily physical exercise (OR = 3.99, 95% CI, 1.27-12.52, p = 0.0178; OR = 2.92, 95% CI, 1.38-6.22, p = 0.0053), asthma (OR = 8.93, 95% CI, 1.12-71.15, p = 0.0386), tuberculosis (OR = 4.28, 95% CI, 1.36-13.50, p = 0.0131), and higher total iron binding capacity (OR = 1.01, 95% CI, 1.00-1.02, p = 0.0059). CONCLUSIONS: Presenile nuclear cataract is related to current smoking, non-exercise or high amount of physical exercise, asthma, tuberculosis, and iron deficiency status. The association of non-exercise group and presenile nuclear cataract seems to be related to co-morbidity. Patients with asthma, tuberculosis, or iron deficiency anemia are recommended to receive frequent ophthalmic examination to detect cataract. PMID- 30305077 TI - Characteristics of patients with acute myocardial infarction contacting primary healthcare before hospitalisation: a cross-sectional study. AB - BACKGROUND: The characteristics of patients with on-going myocardial infarction (MI) contacting the primary healthcare (PHC) centre before hospitalisation are not well known. Prompt diagnosis is crucial in patients with MI, but many patients delay seeking medical care. The aims of this study was to 1) describe background characteristics, symptoms, actions and delay times in patients contacting the PHC before hospitalisation when falling ill with an acute MI, 2) compare those patients with acute MI patients not contacting the PHC, and 3) explore factors associated with a PHC contact in acute MI patients. METHODS: This was a cross-sectional multicentre study, enrolling consecutive patients with MI within 24 hours of admission to hospital from Nov 2012 until Feb 2014. RESULTS: A total of 688 patients with MI, 519 men and 169 women, were included; the mean age was 66+/-11 years. One in five people contacted PHC instead of the recommended emergency medical services (EMS), and 94% of these patients experienced cardinal symptoms of an acute MI; i.e., chest pain, and/or radiating pain in the arms, and/or cold sweat. Median delay time from symptom-onset-to-decision-to-seek-care was 2:15 hours in PHC patients and 0:40 hours in non-PHC patients (p<0.01). The probability of utilising the PHC before hospitalisation was associated with fluctuating symptoms (OR 1.74), pain intensity (OR 0.90) symptoms during off hours (OR 0.42), study hospital (OR 3.49 and 2.52, respectively, for two of the county hospitals) and a final STEMI diagnosis (OR 0.58). CONCLUSIONS: Ambulance services are still underutilized in acute MI patients. A substantial part of the patients contacts their primary healthcare centre before they are diagnosed with MI, although experiencing cardinal symptoms such as chest pain. There is need for better knowledge in the population about symptoms of MI and adequate pathways to qualified care. Knowledge and awareness amongst primary healthcare professionals on the occurrence of MI patients is imperative. PMID- 30305076 TI - Low lymphocyte count and high monocyte count predicts poor prognosis of gastric cancer. AB - BACKGROUND: Existing data about the prognostic value of absolute count of blood cells in gastric cancer was limited. Thus, the present study aims to investigate the prognostic value of absolute count of white blood cell (WBC), neutrophil, lymphocyte, monocyte and platelet in gastric cancer patients. METHODS: From September 2008 to March 2015, 3243 patients treated with radical gastrectomy were enrolled in the present study. Clinicopathological characteristics were recorded. The prognostic value of blood test in gastric cancer patients were analyzed. RESULTS: There were 2538 male and 705 female. The median age was 58 years (range 20-90). The median follow-up time was 24.9 months (range 1-75). The 1-, 3- and 5 year overall survival rate was 88.9%, 65.8% and 57.2%, respectively. The optimal cut off value was 6.19 * 109/L for WBC (P = 0.146), 4.19 * 109/L for neutrophil (P = 0.004), 1.72 * 109/L for lymphocyte (P = 0.000), 0.51 * 109/L for monocyte (P = 0.019) and 260.0 * 109/L for platelet (P = 0.002), respectively. Neutrophil, lymphocyte, monocyte and platelet were risk factors for the prognosis of gastric cancer (all P < 0.05). However, only lymphocyte and monocyte were independent risk factors (both P < 0.05). Combination of lymphocyte and monocyte could increase the prognostic value for gastric cancer patients, especially in stage II/III gastric cancer patients. CONCLUSIONS: High absolute count of neutrophil, monocyte and platelet, and low absolute count of lymphocyte were associated with poor prognosis of gastric cancer. However, only lymphocyte and monocyte count were independent prognostic predictors. Combination of lymphocyte and monocyte count could further increase the predictive value for gastric cancer. PMID- 30305079 TI - Providers' perspectives on denial of abortion care in Nepal: a cross sectional study. AB - BACKGROUND: Despite legalization of abortion in Nepal in 2002, many women are still unable to access legal services. This paper examines providers' views, experiences with abortion denial, and knowledge related to abortion provision, and identifies areas for improvement in quality of care. METHODS: We conducted a structured survey with 106 abortion care providers at 55 government-approved safe abortion facilities across five districts of Nepal in 2017. We assessed reasons for denial of abortion care, knowledge about laws, barriers to provision and attitudes towards abortion. RESULTS: Almost all providers (96%) reported that they have ever refused clients for abortion services. Common reasons included beyond 12 weeks gestation (93%), sex selective abortion (86%), and medical contraindications (85%). One in four providers denied abortion for lack of drugs or trained personnel, and one third denied services when they perceived that the woman's reasons for abortion were insufficient. Only a third of providers knew all three legal indications for abortion -- less than or equal to 12 weeks of pregnancy on request, up to 18 weeks for rape or incest, and any time for maternal or fetal health risk. Overall, providers were in favor of legal abortion but a substantial proportion had mixed or negative attitudes about the service. CONCLUSIONS: Improvements in training to address providers' inadequate knowledge about the abortion law may reduce inappropriate denial of abortion. Establishing referral networks in the case of abortion denial and ensuring regular supply of medical abortion drugs would help more women access abortion care in Nepal. PMID- 30305078 TI - Integrated motivational interviewing and cognitive behaviour therapy can increase physical activity and improve health of adult ambulatory care patients in a regional hospital: the Healthy4U randomised controlled trial. AB - BACKGROUND: The aim of this study was to determine whether a twelve-week, health coaching intervention could result in changes in physical activity, anthropometrics and health-related outcomes in adults presenting to an ambulatory hospital clinic. METHODS: Seventy-two participants who reported being insufficiently active were recruited from an ambulatory hospital clinic and randomised to an intervention group that received an education session and eight 30-min telephone sessions of integrated motivational interviewing and cognitive behaviour therapy (MI-CBT), or to a control group that received the education session only. ActiGraph GT3X accelerometers were used to measure moderate-to vigorous physical activity at baseline, post-intervention (3-months) and follow up (6-months). Secondary outcome measures (anthropometrics, physical activity self-efficacy, health-related quality of life, type 2 diabetes risk) were also assessed at the three time points. RESULTS: At baseline, the mean age and body mass index of participants (n = 72, 75% females) were 53 +/- 8 years and 30.8 +/- 4.1 kg/m2, respectively. Treatment group influenced the pattern of physical activity over time (p < 0.001). The intervention group increased moderate-to vigorous physical activity from baseline to post-intervention and remained elevated at follow-up by 12.9 min/day (95%CI: 6.5 to 19.5 min/day). In contrast, at follow-up the control group decreased moderate-to-vigorous physical activity by 9.9 min/day (95%CI: -3.7 to -16.0 min/day). Relative to control, at follow-up the intervention group exhibited beneficial changes in body mass (p < 0.001), waist circumference (p < 0.001), body mass index (p < 0.001), physical activity self-efficacy (p < 0.001), type 2 diabetes risk (p < 0.001), and health-related quality of life (p < 0.001). CONCLUSIONS: This study demonstrates that a low contact coaching intervention results in beneficial changes in physical activity, anthropometrics and health-related outcomes that were maintained at follow-up in adults who report being insufficiently active to an ambulatory care clinic. TRIAL REGISTRATION: ANZCTR: ACTRN12616001331426 . Registered 23 September 2016. PMID- 30305080 TI - Medication administration error and contributing factors among pediatric inpatient in public hospitals of Tigray, northern Ethiopia. AB - BACKGROUND: Medication administration error is a medication error that occurs while administering a medication to a patient. A variety of factors make pediatrics more susceptible to medication errors and its consequences. In low income countries, like Ethiopia, there is no sufficient evidence regarding medication administration error among pediatrics. The aim of this study is, therefore, to determine the magnitude and factors associated with medication administration error among pediatric population. METHODS: A prospective observational based cross sectional study design was conducted from January to April 2017. Data collection was done using pre-tested structured questionnaire and blind observation checklist to health professionals in charge of administering selected medications. A total of 1282 medication administrations were obtained using single population proportion formula from patients in the selected public hospitals and the samples were selected using multistage sampling technique. Multivariable logistic regression using odds ratio and 95% confidence interval was used to determine the relationship between the independent and dependent variables. Variables with p-value < 0.05 were considered as independent factors for medication administration error. RESULT: A total of 1251 medication administrations were observed from 1251 patients. The occurrence of medication administration error was 62.7% with 95% CI (59.6%, 65.0%), wrong dose being the most common type of medication administration error with an occurrence rate of 53.7%. Medications administered for pediatric patients less than 1 month age, administered by bachelor degree holder health professionals, prepared in facilities without medication preparation room, prepared in facilities without medication administration guide and administer for patients who have two or more prescribed medications were more likely to have medication administration error than their counterparts with AOR (95% CI) of 7.54(2.20-25.86), 1.52 (1.07-2.17), 13.45 (8.59-21.06), 4.11 (2.89-5.85), and 2.42 (1.62-3.61), respectively. CONCLUSION: This study has revealed that there is high occurrence of medication administration error among pediatric inpatients in public hospitals of Tigray, Northern Ethiopia.. Age of patients, educational level of medication administrators, availability of the medication preparation room and guide, and the number of medications given per single patient were statistically significant factors associated with occurrence of medication administration error. PMID- 30305081 TI - Palestinian doctors' views on patient-centered care in hospitals. AB - BACKGROUND: Understanding the perceived importance of Patient-Centered Care (PCC) among Palestinian doctors and how the provider and other clinical characteristics may impact their views on PCC is essential to determine the extent to which PCC can be implemented. This study investigates the provision of PCC among hospital doctors in a developing and unstable country, namely, Palestine. METHODS: This descriptive, cross-sectional research employed self-report survey among 369 Palestinian doctors working in hospitals in 2016. Respondents completed the Provider-Patient Relationship Questionnaire (PPRQ) and were asked to rate the importance of 16 PCC subjects in a context-free manner. Then they scored the existence of eight contextual attributes in their workplace. RESULTS: Although 71.4% of the participants got training in communication, only 45% of the participants knew about PCC. 48.8% of doctors considered the "exchange of information" with patients most important PCC component. Clustering identified three groups of doctors: 32.4% of doctors reported good perceptions of PCC, 47.5% moderate; and 20.1% poor. Older, married, and specialist doctors and those familiar with PCC are more likely classified in the "good" cluster. Results revealed a significant difference between doctors' views based on their gender, experience, marital status, previous knowledge about PCC, and type of hospital in favor of males, experienced, married, familiar with PCC, and doctors in private hospital respectively. The level of job interest, nurses' cooperation, the tendency of patients to hide information, and doctor's friendly style were positively related with more perceived importance of PCC. CONCLUSION: We identified benchmark doctors who perceive the high relative importance of PCC. Our results highlighted knowledge gaps and training weaknesses among doctors in public and private hospitals in respect to their views on PCC. Decision makers may invest in the determined contextual predictors to enhance attitudes towards PCC. This work doesn't address patients' views on PCC. PMID- 30305082 TI - Quality assurance for care of the dying: engaging with clinical services to facilitate a regional cross-sectional survey of bereaved relatives' views. AB - BACKGROUND: Globally, having the 'patient and /or family voice' engaged when measuring quality of care for the dying is fundamentally important. This is particularly pertinent within the United Kingdom, where changes to national guidance about care provided to dying patients has heightened the importance of quality assurance and user-feedback. Our main aim was to engage with clinical services (hospice, hospital and community settings) within a specific English region and conduct a bereaved relatives' cross-sectional survey about quality of care. Our secondary aim was to explore levers and barriers to project participation as perceived by organisational representatives. METHODS: Each organisation identified a consecutive sample of next-of-kin to adult patients who died between 1st September and 30th November 2014. Those who had an unexpected death or were involved in a formal complaint were excluded. The 'Care Of the Dying Evaluation' (CODETM) questionnaire was posted out three months following the bereavement. One-to-one interviews were undertaken with a purposive sample of organisational representatives to explore experiences about project participation. RESULTS: Of the 30 invited organisations, 18 were able to participate comprising: 7 hospitals, 7 hospices and 4 community settings. There were 1774 deaths which met the inclusion criteria but 460 (26%) were excluded due to inaccurate next-of-kin details. Subsequently, 1283 CODETM questionnaires were sent out, with 354 completed (27% response rate). Overall, most participants perceived good quality of care. A notable minority reported poor care for symptom control and communication especially within the hospital. Nine interviews were conducted - levers to project participation included the 'significance of user feedback and the opportunity to use results in a meaningful way'; the main barrier was related to 'concern about causing distress to bereaved relatives'. CONCLUSIONS: Overall, being able to engage with 18 (60%) organisations within the region and conduct the bereaved relatives' survey showed success of this initiative and was supported by interview findings. The potential to be able to benchmark user-feedback against other organisations was thought to help focus on areas to develop services. This type of quality assurance project could form a template model and be replicated on a national and international level. PMID- 30305083 TI - Patient-reported outcome domains for the esophageal CONDUIT report card: a prospective trial to establish domains. AB - BACKGROUND: Health-related quality of life (QoL) deteriorates immediately after esophagectomy. Patients may benefit from periodic assessments to detect increased morbidity on the basis of subjective self-reports. Using input from patients and health care providers, we developed a brief prototype for the esophageal conduit questionnaire (Mayo Clinic Esophageal Conduit Outcomes Noting Dysphagia/Dumping, and Unknown outcomes with Intermittent symptoms over Time after esophageal reconstruction [CONDUIT] Report Card) and previously used it in comparative research. The present study aimed to expand its content and establish health related QoL and symptom domains of a patient-reported postesophagectomy conduit evaluation tool. METHODS: We expanded tool content by selecting items measuring patient-reported symptoms from existing questionnaires or written de novo. A multidisciplinary group of clinician content-matter experts approved the draft tool, together with a designated patient advocate. The expanded tool was administered to patients postesophagectomy from March 1 to November 30, 2016. We established domains of conduit performance for score reporting through data analysis with exploratory factor analyses. We assessed psychometric properties such as dimensionality, internal consistency, and inter-item correlations in each domain and compared content coverage with other existing measures intended for this patient population. For data that were missing less than 50% of patient responses, the missing values were imputed. RESULTS: Five multi-item domains were established from data of 76 patients surveyed after esophagectomy; single items were used to assess stricture and conduit emptying. For every multi-item domain, dominance of 1 factor was present. Internal consistency reliability estimates for the domains were 0.87, 0.78, 0.75, 0.80, and 0.83 and average inter-item correlations were 0.40, 0.50, 0.40, 0.33, and 0.73 for dysphagia, reflux, dumping gastrointestinal symptoms, dumping-hypoglycemia, and pain, respectively. Some items observed to have lower inter-item correlation were reworded or flagged for removal at future validation. For reflux and dumping-related hypoglycemia, additional items were written after these analyses. CONCLUSIONS: The CONDUIT Report Card is a novel questionnaire for assessing QoL and symptoms of patients after esophageal reconstruction. It covers major symptoms of these patients and has good content validity and psychometric properties. The tool can be used to help direct patient care, guide intervention, and compare efficacy of different treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier No. 02530983 on 8/18/2015. PMID- 30305084 TI - Cardiovascular risk assessment of dyslipidemic middle-aged adults without overt cardiovascular disease over the period of 2009-2016 in Lithuania. AB - BACKGROUND: Cardiovascular mortality in Lithuania is extremely high and abnormal lipid levels are very common among Lithuanian adults. Dyslipidemia is one of the main independent risk factors for cardiovascular diseases (CVD) leading to high absolute CVD risk. The aim of this study was to assess CVD risk in dyslipidemic middle-aged subjects. METHODS: During the period of 2009-2016 a total of 92,373 people (58.4% women and 41.6% men) were evaluated. This study included men aged 40-54 and women aged 50-64 without overt CVD. RESULTS: Any type of dyslipidemia was present in 89.7% of all study population. 7.5% of dyslipidemic patients did not have any other conventional risk factors. Three and more risk factors were detected in 60.1% of dyslipidemic subjects. All analyzed risk factors, except smoking, were more common in dyslipidemic adults compared to subjects without dyslipidemia: arterial hypertension (55.8% vs. 43.3%, p < 0.001), diabetes (11.1% vs. 7.3%, p < 0.001), abdominal obesity (45.3% vs. 30.2%, p < 0.001), BMI >=30 kg/m2 (35.8% vs. 23.7%, p < 0.001), metabolic syndrome (34.0% vs. 9.2%, p < 0.001), family history of coronary heart disease (26.3% vs. 23.1%, p < 0.001), unbalanced diet (62.5% vs. 52.9%, p < 0.001) and insufficient physical activity (52.0% vs. 44.2%, p < 0.001). The prevalence of all evaluated risk factors, except smoking, increased with age. Average SCORE index was 1.87 in all study population, while dyslipidemic subjects had higher SCORE compared to control group (1.95 vs 1.20, p < 0.001). CONCLUSIONS: Almost two thirds of dyslipidemic middle-aged Lithuanian adults without overt cardiovascular disease had three or more other CVD risk factors, which synergistically increase absolute risk of CVD. The average 10-year risk of CVD death in patients with dyslipidemia was 1.95%. The importance of managing dyslipidemia as well as other risk factors in order to reduce burden of cardiovascular disease in Lithuania is evident. PMID- 30305085 TI - Shared decision making and experiences of patients with long-term conditions: has anything changed? AB - BACKGROUND: Medication problems among patients with long-term conditions (LTCs) are well documented. Measures to support LTC management include: medicine optimisation services by community pharmacists such as the Medicine Use Review (MUR) service in England, implementation of shared decision making (SDM), and the availability of rapid access clinics in primary care. This study aimed to investigate the experience of patients with LTCs about SDM including medication counselling and their awareness of community pharmacy medication review services. METHODS: A mixed research method with a purposive sampling strategy to recruit patients was used. The quantitative phase involved two surveys, each requiring a sample size of 319. The first was related to SDM experience and the second to medication counselling at discharge. Patients were recruited from medical wards at St. George's and Croydon University Hospitals.The qualitative phase involved semi-structured interviews with 18 respiratory patients attending a community rapid access clinic. Interviews were audio-recorded and transcribed verbatim. Thematic analysis using inductive/deductive approaches was employed. Survey results were analysed using descriptive statistics. RESULTS: The response rate for surveys 1 and 2 survey was 79% (n = 357/450) and 68.5% (240/350) respectively. Survey 1 showed that although 70% of patients had changes made to their medications, only 40% were consulted about them and two-thirds (62.2%) wanted to be involved in SDM. In survey 2, 37.5% of patients thought that medication counselling could be improved. Most patients (88.8%) were interested in receiving the MUR service; however 83% were not aware of it. The majority (57.9%) were interested in receiving their discharge medications from community pharmacies. The interviews generated three themes; lack of patient-centered care and SDM, minimal medication counselling provided and lack of awareness about the MUR service. CONCLUSION: Although patients wanted to take part in SDM, yet SDM and medication counselling are not optimally provided. Patients were interested in the MUR service; however there was lack of awareness and referral for this service. The results propose community pharmacy as a new care pathway for medication supply and counselling post discharge. This promotes a change of health policy whereby community-based services are used to enhance the performance of acute hospitals. PMID- 30305086 TI - Establishment of urinary exosome-like vesicles isolation protocol for FHHNC patients and evaluation of different exosomal RNA extraction methods. AB - BACKGROUND: Molecular and cellular pathophysiological events occurring in the majority of rare kidney diseases remain to be elucidated. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in either CLDN16 or CLDN19 genes. This disease is characterized by massive urinary wasting of magnesium and calcium, osmosis deregulation and polyuria. Patients with p.G20D homozygous mutation in CLDN19 gene exhibit different progression to kidney failure suggesting that beyond the pathogenic mutation itself, other molecular events are favoring disease progression. Due to the fact that biopsy is not clinically indicated in these patients, urinary exosome-like vesicles (uEVs) can be envisioned as a valuable non-invasive source of information of events occurring in the kidney. Exosome research has increased notably to identify novel disease biomarkers but there is no consensus standardized protocols for uEVs isolation in patients with polyuria. For this reason, this work was aimed to evaluate and refine different uEVs isolation methods based on differential centrifugation, the gold standard method. RESULTS: Characterization by NTA, cryo-TEM and immunoblotting techniques identified the most appropriate protocol to obtain the highest yield and purest uEVs enriched fraction possible from urine control samples and FHHNC patients. Moreover, we tested five different RNA extraction methods and evaluated the miRNA expression pattern by qRT-PCR. CONCLUSIONS: In summary, we have standardized the conditions to proceed with the identification of differentially expressed miRNAs in uEVs of FHHNC patients, or other renal diseases characterized by polyuria. PMID- 30305087 TI - Evaluation of a consulting training course for international development assistance for health. AB - BACKGROUND: Development assistance for health (DAH) is an important component of foreign assistance. International health consultants usually play a key role in the international DAH field. However, there is still a shortage of consulting training in China. To address this issue and develop new backup force of DAH for China, the Global Health Institute of Wuhan University (GHIWHU) launched a training program called the "Consulting Training Course for International Development Assistance for Health". The purpose of this article is to evaluate the impact of the training on participants. METHODS: We conducted the analysis using Kirkpatrick's model. An evaluation survey examining participants' reaction (level 1) and learning (level 2) was carried out among trainees following the training, and a follow-up telephone interview of application (level 3) was made in three months after the training. RESULTS: A total of 25 participants from Chinese Consortium of Universities for Global Health (CCUGH) attended the training program. Results of satisfaction evaluation indicated that the training program was well received, with more than 85% of participants felt satisfied or relatively satisfied with the training. Trainees' self-ratings of the consulting knowledge and skills showed a significant increase (p < 0.001) from pre- to post training. The follow-up interview revealed that the majority of participants applied the acquired knowledge and skills under various circumstances such as consulting program, teaching processes, writing reports, and et al. Meanwhile, participants considered that the lack of opportunities was one of the major application barriers. In addition, they expressed the willingness to participate in more relevant training and the need for more practice opportunities. CONCLUSIONS: This is the first study evaluating a consulting training program in China. The results show that the training course has been successfully implemented and participants have been given consulting knowledge and skills. Future research should use better-designed training methods based on demand surveys and consider providing participants with practice or practicum opportunities. Also, it is necessary to conduct both primary and advanced training courses and evaluate participants' long-term behavior changes resulting from the training. PMID- 30305088 TI - Participatory design of an improvement intervention for the primary care management of possible sepsis using the Functional Resonance Analysis Method. AB - BACKGROUND: Ensuring effective identification and management of sepsis is a healthcare priority in many countries. Recommendations for sepsis management in primary care have been produced, but in complex healthcare systems, an in-depth understanding of current system interactions and functioning is often essential before improvement interventions can be successfully designed and implemented. A structured participatory design approach to model a primary care system was employed to hypothesise gaps between work as intended and work delivered to inform improvement and implementation priorities for sepsis management. METHODS: In a Scottish regional health authority, multiple stakeholders were interviewed and the records of patients admitted from primary care to hospital with possible sepsis analysed. This identified the key work functions required to manage these patients successfully, the influence of system conditions (such as resource availability) and the resulting variability of function output. This information was used to model the system using the Functional Resonance Analysis Method (FRAM). The multiple stakeholder interviews also explored perspectives on system improvement needs which were subsequently themed. The FRAM model directed an expert group to reconcile improvement suggestions with current work systems and design an intervention to improve clinical management of sepsis. RESULTS: Fourteen key system functions were identified, and a FRAM model was created. Variability was found in the output of all functions. The overall system purpose and improvement priorities were agreed. Improvement interventions were reconciled with the FRAM model of current work to understand how best to implement change, and a multi-component improvement intervention was designed. CONCLUSIONS: Traditional improvement approaches often focus on individual performance or a specific care process, rather than seeking to understand and improve overall performance in a complex system. The construction of the FRAM model facilitated an understanding of the complexity of interactions within the current system, how system conditions influence everyday sepsis management and how proposed interventions would work within the context of the current system. This directed the design of a multi-component improvement intervention that organisations could locally adapt and implement with the aim of improving overall system functioning and performance to improve sepsis management. PMID- 30305090 TI - Protection against the overuse and underuse of health care - methodological considerations for establishing prioritization criteria and recommendations in general practice. AB - BACKGROUND: Initiatives such as "Choosing Wisely" in the USA and "Smarter Medicine" in Switzerland have published lists of widely overused health care services. The German initiative "Choosing Wisely Together (Gemeinsam Klug Entscheiden)" follows this example. The goal of our study was to prioritize important recommendations against the overuse and underuse of health care services. The final list of recommendations will be published in the German guideline "Protection against the overuse and underuse of health care". METHODS: First, a multidisciplinary expert panel established a catalogue of prioritization criteria. Second, we extracted all the recommendations from evidence- and consensus-based German College of General Practice and Family Medicine (DEGAM) guidelines and National Health Care Guidelines (NVL). Third, the recommendations were rated by two independent panels (general practitioners and other health care professionals involved/not involved in guideline development). The prioritization process was finalized in a consensus conference held by DEGAM's Standing Guideline Committee (SLK). RESULTS: Eleven prioritization criteria were established. A total of 782 recommendations were extracted and rated by 98 physicians and other health care professionals in a survey. In the voting process, more than 80% of the recommendations were eliminated. After the final consensus conference, twelve recommendations from DEGAM guidelines, nine DEGAM addenda and 17 NVL recommendations were chosen for inclusion in the guideline, for a total of 38 recommendations. CONCLUSION: The selection procedure proved helpful in identifying the highest priority recommendations with which to combat the overuse and underuse of health care services. To date, in Germany there has been no attempt to compile such a list by using a systematic and transparent methodology. Hence, the guideline that results from this process can fill an important gap. PMID- 30305089 TI - Tailoring cells for clinical needs: Meeting report from the Advanced Therapy in Healthcare symposium (October 28-29 2017, Doha, Qatar). AB - New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called "living drugs". Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report. PMID- 30305091 TI - Factors associated with social casino gaming among adolescents across game types. AB - BACKGROUND: With the proliferation of social casino games (SCGs) online, which offer the opportunity to gamble without monetary gains and losses, comes a growing concern regarding the effects of these unregulated games on public health, particularly among adolescents. However, given the limited research pertaining to SCG use, little is currently known about the manner in which adolescents engage with this new gambling medium. The present study aims to identify the factors that characterize adolescent social casino gamers, and to determine whether these factors differ by SCG type. Moreover, the study examines the extent to which social casino gaming is associated with monetary gambling and problem gambling in this cohort. METHOD: Data were obtained from students in Grades 9 to 12 (n = 10,035) residing in the Canadian provinces of Ontario, Saskatchewan, and Newfoundland and Labrador. Participants completed the Youth Gambling Survey (YGS), which is a supplementary instrument administered alongside the Canadian Student Tobacco, Alcohol and Drugs Survey (CSTADS). Logistic regression was used to assess the factors associated with SCG play. RESULTS: Overall, 12.4% of respondents reported having participated in SCGs in the past three months. Compared to adolescents who did not report playing SCGs, SCG players were typically more likely to participate in monetary gambling activities, and were more prevalently classified as problem gamblers of low-to moderate severity or high severity. Although profiles of SCG players differed across SCG game types, factors significantly associated with the playing of SCGs were gender, weekly spending money, having friends and parents who gamble, and screen time. It was also shown that current smokers were significantly more likely to participate in simulated slots online relative to adolescents who did not play SCGs. CONCLUSION: Significant associations exist between SCG play, monetary gambling, and problem gambling among adolescents. Gambling intervention efforts directed at this population should aim to identify personal and environmental factors associated with social casino gaming, and should be tailored to different types of SCGs. PMID- 30305092 TI - A randomized, controlled, single-blinded, multicenter evaluation of the efficacy and safety of a once weekly two dose otic gel containing florfenicol, terbinafine and betamethasone administered for the treatment of canine otitis externa. AB - BACKGROUND: Otitis externa is a common problem in small animal practice. Compliance with daily treatment is a major cause of treatment failure. The hypothesis tested is that a novel otic gel applied to the ear canal twice with a one-week interval is as efficacious as a daily otic suspension in the treatment of canine otitis externa. The study included 286 privately owned dogs with otitis externa. In this single blinded randomized study, enrolled dogs received either an otic gel containing 1% florfenicol, 1% terbinafine and 0.1% betamethasone acetate twice with a one-week interval or a suspension containing hydrocortisone aceponate, miconazole and gentamicin daily for 5 days. Ears were cleaned with saline prior to administration of the first dose of medication. Dogs were evaluated at day (D) 0, 7, 28 and 56 with an otitis index score (OTIS-3), otic culture and cytology, pain and pruritus, and overall response to treatment (owner and investigator evaluation). Outcome measures were improvement of the OTIS-3 and number of dogs in clinical remission at each time point. RESULTS: OTIS-3 decreased significantly (p < 0.0001) by 63 and 64% for the otic gel and by 63 and 61% for the suspension on D28 and D56 respectively. There was no significant difference between groups at any time point with regard to clinical success, pain, pruritus, overall assessments or otic cytology and culture. The treatment response was considered excellent or good by approximately three quarters of both the clinicians and Owners. Otitis recurrence at D56 was seen in 11% of both groups. Adverse events attributable to the ear medications were not noted. CONCLUSIONS: Administering an otic gel twice at a one-week interval is an effective, safe and convenient way to treat canine otitis externa. PMID- 30305093 TI - Global research output on HIV/AIDS-related medication adherence from 1980 to 2017. AB - BACKGROUND: "Human Immunodeficiency Virus (HIV)" and Acquired Immunodeficiency Syndrome (AIDS) are global health burden. Medication adherence in people living with HIV (PLWH) is a key element in reducing morbidity and mortality. Quantitative and qualitative assessment of research activity helps identify research gaps as well as efforts implemented to improve adherence behaviors in PLWH. The aim of the current study was to assess and analyze literature on HIV/AIDS-related medication adherence using bibliometric methods. METHODS: SciVerse Scopus was used to accomplish the purpose of the current study. The study period included all times up to 2017. The analysis was restricted to documents published in academic journals. RESULTS: Search strategy retrieved 3021 documents with an average of 32.5 citations per document, an h-index of 136, and an average of 4.4 authors per documents. The volume of literature on HIV/AIDS related medication adherence constituted 1.3% of the overall HIV/AIDS literature. There was a significant (p < 0.01; r = 0.9) correlation between the growth of publications in AIDS-related stigma and medication adherence. The regions of America (567.9) had the highest research output per one million infected people (567.9) followed by the European region (314.3), Western Pacific Region (70.7), Eastern Mediterranean region (31.4), South East Asia (34.0), and Africa (19.3). Geographical distribution of publications showed an active contribution of certain countries in the Southern and Eastern region of Sub-Saharan Africa. Harvard University (8.4%; n = 254) was the most active institution. The top cited documents focused on the impact of adherence on disease outcome and the impact of text messages on improving medication adherence. CONCLUSION: Research on medication adherence in PLWH showed regional variations. International research collaboration with high burden regions such as Sub-Saharan Africa needs to be strengthened to achieve the global target of ending AIDS as a public health threat by 2030. PMID- 30305094 TI - Comparison of the prevalence of incidental and non-incidental papillary thyroid microcarcinoma during 2008-2016: a single-center experience. AB - BACKGROUND: The incidence of papillary thyroid microcarcinoma (PTMC) is increasing; however, it is not clear whether this reflects an increase in the incidence of incidental or in that of non-incidentally (presurgically) discovered PTMC (IPTMC vs. NIPTMC). We assessed the incidence of IPTMC and NIPTMC over the past 9 years, to discern whether the increase in PTMC incidence is due to improved diagnostics or to a real increase in the incidence. METHODS: We performed a retrospective chart review of 4327 patients who were consecutively admitted to and surgically treated for thyroid pathology at a single institution. As a main presurgical diagnostic test, all patients underwent ultrasound-guided fine-needle aspiration biopsy (UG-FNAB). The analyzed time frame was divided into three equal periods (I: 2008-2010, II: 2011-2013, III: 2014-2016), and IPTMCs and NIPTMCs were assessed and compared in each period. RESULTS: We evaluated 393 (9.08%) patients with thyroid malignancy, of which 156 (3.60% of all thyroid tumors [TTs]; 39.69% of all thyroid cancers [TCs]) were diagnosed as PTMC. The prevalence of NIPTMC among all TCs increased from 16.66% in 2008 to 33.75% in 2016, while that of IPTMC decreased from 20.83% in 2008 to 13.75% in 2016. The incidence rates of NIPTMC and IPTMC in period III differed statistically significantly (p < 0.0001). The prevalence rate of NIPTMC in period III was higher than that in period II, yet comparable to that in period I (p = 0.0014; p = 0.2804, respectively). CONCLUSIONS: The prevalence of NIPTMC, rather than that of IPTMC, is escalating; this may be due to better presurgical diagnosis. PMID- 30305095 TI - QTL detection for growth and latex production in a full-sib rubber tree population cultivated under suboptimal climate conditions. AB - BACKGROUND: Rubber tree is cultivated in mainly Southeast Asia and is by far the most significant source of natural rubber production worldwide. However, the genetic architecture underlying the primary agronomic traits of this crop has not been widely characterized. This study aimed to identify quantitative trait loci (QTLs) associated with growth and latex production using a biparental population established in suboptimal growth conditions in Brazil. RESULTS: A full-sib population composed of 251 individuals was developed from crossing two high producing Asiatic rubber tree cultivars, PR 255 and PB 217. This mapping population was genotyped with microsatellite markers from enriched genomic libraries or transcriptome datasets and single-nucleotide polymorphism (SNP) markers, leading to construction of a saturated multipoint integrated genetic map containing 354 microsatellite and 151 SNP markers. Height and circumference measurements repeated over a six-year period and registration of cumulative latex production during six consecutive months on the same individuals allowed in-depth characterization of the genetic values of several growth traits and precocious latex production. Growth traits, circumference and height, were overall positively correlated, whereas latex production was not correlated or even negatively correlated with growth traits. A total of 86 distinct QTLs were identified, most of which were detected for only one trait. Among these QTLs, 15 were linked to more than one phenotypic trait (up to 4 traits simultaneously). Latex production and circumference increments during the last wintering period were associated with the highest numbers of identified QTLs (eleven and nine, respectively), jointly explaining the most significantly observed phenotypic variances (44.1% and 44.4%, respectively). The most important QTL for latex production, located on linkage group 16, had an additive effect of the male parent PB 217 and corresponded to a QTL at the same position detected in a previous study carried out in Thailand for the biparental population RRIM 600 x PB 217. CONCLUSIONS: Our results identified a set of significant QTLs for rubber tree, showing that the performance of modern Asiatic cultivars can still be improved and paving the way for further marker-assisted selection, which could accelerate breeding programs. PMID- 30305096 TI - Glomus tumor in the floor of the mouth: a case report and review of the literature. AB - BACKGROUND: Glomus tumors are rare benign neoplasms that usually occur in the upper and lower extremities. Oral cavity involvement is exceptionally rare, with only a few cases reported to date. CASE PRESENTATION: A 24-year-old woman with complaints of swelling in the left floor of her mouth for 6 months was referred to our institution. Her swallowing function was slightly affected; however, she did not have pain or tongue paralysis. Enhanced computed tomography revealed a 2.8 * 1.8 * 2.1 cm-sized well-defined, solid, heterogeneous nodule above the mylohyoid muscle. The mandible appeared to be uninvolved. The patient underwent surgery via an intraoral approach; histopathological examination revealed a glomus tumor. The patient has had no evidence of recurrence over 4 years of follow-up. CONCLUSIONS: Glomus tumors should be considered when patients present with painless nodules in the floor of the mouth. PMID- 30305097 TI - A lipidated bi-epitope vaccine comprising of MHC-I and MHC-II binder peptides elicits protective CD4 T cell and CD8 T cell immunity against Mycobacterium tuberculosis. AB - BACKGROUND: The clinical trials conducted at Chingleput India suggest that BCG fails to protect against tuberculosis (TB) in TB-endemic population. Recent studies advocate that non-tuberculous mycobacteria and latent Mycobacterium tuberculosis (Mtb) infection interferes in the antigen processing and presentation of BCG in inducing protective immunity against Mtb. Thereby, indicating that any vaccine that require extensive antigen processing may not be efficacious in TB-endemic zones. Recently, we have demonstrated that the vaccine candidate L91, which is composed of lipidated promiscuous MHC-II binder epitope, derived from latency associated Acr1 antigen of Mtb is immunogenic in the murine and Guinea pig models of TB and conferred better protection than BCG against Mtb. METHODS: In this study, we have used a multi-stage based bi-epitope vaccine, namely L4.8, comprising of MHC-I and MHC-II binding peptides of active (TB10.4) and latent (Acr1) stages of Mtb antigens, respectively. These peptides were conjugated to the TLR-2 agonist Pam2Cys. RESULTS: L4.8 significantly elicited both CD8 T cells and CD4 T cells immunity, as evidenced by increase in the enduring polyfunctional CD8 T cells and CD4 T cells. L4.8 efficiently declined Mtb-burden and protected animals better than BCG and L91, even at the late stage of Mtb infection. CONCLUSIONS: The BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. This study emphatically denotes that L4.8 can be a promising future vaccine candidate for controlling active and latent TB. PMID- 30305098 TI - Conceptualization, operationalization, and content validity of the EQOL questionnaire measuring quality of life and participation for persons with disabilities. AB - BACKGROUND: Measurement of quality of life demands thoroughly developed and validated instruments. The development steps from theory to concepts and from empirical data to items are sparsely described in the literature of questionnaire development. Furthermore, there seems to be a need for an instrument measuring quality of life and participation in a population with diverse disabilities. The aim of this paper was to present and discuss the initial steps in the development of the Electronic Quality of Life questionnaire (EQOL). METHODS: The development of EQOL included six steps: 1) Establishing conceptual understanding; 2) Development of interview guides which build on the conceptual understanding; 3) Qualitative interviews of 55 participants (10-40 years old) with different types and severities of disabilities; 4) Conceptualization of domains identified in the qualitative data through thematic analysis; 5) Operationalization of the identified domains into items and; 6) Evaluation of content validity of the first version of the EQOL-measure. Content validity was examined by cognitive interviews with participants in the target group as well as by continuous feedback from an advisory board. RESULTS: We identified six domains (function and health, environment (physical and social), social network, wellbeing, occupation, and managing strategies) based on themes derived from the qualitative interviews and on conceptual discussions within the author group. These domains were incorporated in a conceptual model and items were generated to measure the content of each domain. Participants expressed satisfaction with EQOL but most participants felt that there were too many items. CONCLUSIONS: In total, 191 items were included in the questionnaire. Participants felt that the EQOL questionnaire was relevant to their quality of life and participation. We have shown that it is possible to include quality of life and participation for people with various disabilities in one instrument. Although capturing less detail than a condition specific instrument, EQOL includes aspects perceived important for people with disabilities who are not included in general surveys. This is relevant when for example evaluating environmental adaptations and when comparing populations with various disabilities. PMID- 30305099 TI - Image and perception of physicians as barriers to inter-disciplinary cooperation? - the example of German occupational health physicians in the rehabilitation process: a qualitative study. AB - BACKGROUND: In the German rehabilitation system, primary care physicians (PCPs), occupational health physicians (OPs), and rehabilitation physicians (RPs) fulfill different distinct functions and roles. While effective cooperation can improve outcomes of rehabilitation, the cooperation between these groups of stakeholders has been criticized as lacking or insufficient. This article proposes an approach to understand the low levels of cooperation by examining the role of group perception and group identity in intra-professional cooperation as a barrier to cooperation between physicians in different roles. Group perception was evaluated in terms of (1) negative views about another group of medical specialists and (2) differences between the perception of members and non-members of a medical specialty group. To examine this issue, we focused on the role of OPs in the German rehabilitation process. METHODS: We implemented a qualitative study design with eight focus group discussions with PCPs, OPs, RPs, and patients (two focus group discussions per stakeholder group; 4-10 participants) and qualitative content analysis. We used the Social Identity Approach by Tajfel and Turner as a theoretical underpinning. RESULTS: While all protagonists reported a positive perception of their own professional group, we found numerous negative perceptions about other groups, especially regarding OPs. Negative perceptions of OPs included 1) apparent conflict of interest between employer and employee, 2) lack of commitment to patient outcomes, 3) lack of useful specialized knowledge which could have a bearing on rehabilitation outcomes, and 4) distrust on the part of their patients. We also found divergent perceptions regarding roles, responsibilities, and capabilities among the specialist groups. Both negative and conflicting perceptions about roles were characterized as barriers to cooperation by study participants. CONCLUSION: This example of cooperation between RPs, OPs, and PCPs suggests that negative and diverging perceptions about an out-group could create barriers in intra-professional and inter-disciplinary cooperation between physicians. These perspectives might also be useful in explaining problems at intersections between different specialties. We suggest examining the inter-group dimension of perception-based barriers to cooperation in future interventions to overcome problems caused by intra-professional and inter disciplinary conflicts in addition to other barriers (i.e. organizational hurdles). PMID- 30305100 TI - A role for RASSF1A in tunneling nanotube formation between cells through GEFH1/Rab11 pathway control. AB - BACKGROUND: By allowing intercellular communication between cells, tunneling nanotubes (TNTs) could play critical role in cancer progression. If TNT formation is known to require cytoskeleton remodeling, key mechanism controlling their formation remains poorly understood. METHODS: The cells of human bronchial (HBEC 3, A549) or mesothelial (H2452, H28) lines are transfected with different siRNAs (inactive, anti-RASSF1A, anti-GEFH1 and / or anti-Rab11). At 48 h post transfection, i) the number and length of the nanotubes per cell are quantified, ii) the organelles, previously labeled with specific tracers, exchanged via these structures are monitored in real time between cells cultured in 2D or 3D and in normoxia, hypoxia or in serum deprivation condition. RESULTS: We report that RASSF1A, a key-regulator of cytoskeleton encoded by a tumor-suppressor gene on 3p chromosome, is involved in TNTs formation in bronchial and pleural cells since controlling proper activity of RhoB guanine nucleotide exchange factor, GEF-H1. Indeed, the GEF-H1 inactivation induced by RASSF1A silencing, leads to Rab11 accumulation and subsequent exosome releasing, which in turn contribute to TNTs formation. Finally, we provide evidence involving TNT formation in bronchial carcinogenesis, by reporting that hypoxia or nutriment privation, two almost universal conditions in human cancers, fail to prevent TNTs induced by the oncogenic RASSF1A loss of expression. CONCLUSIONS: This finding suggests for the first time that loss of RASSF1A expression could be a potential biomarker for TNTs formation, such TNTs facilitating intercellular communication favoring multistep progression of bronchial epithelial cells toward overt malignancy. PMID- 30305102 TI - A biomarker basing on radiomics for the prediction of overall survival in non small cell lung cancer patients. AB - BACKGROUND: This study aimed at predicting the survival status on non-small cell lung cancer patients with the phenotypic radiomics features obtained from the CT images. METHODS: A total of 186 patients' CT images were used for feature extraction via Pyradiomics. The minority group was balanced via SMOTE method. The final dataset was randomized into training set (n = 223) and validation set (n = 75) with the ratio of 3:1. Multiple random forest models were trained applying hyperparameters grid search with 10-fold cross-validation using precision or recall as evaluation standard. Then a decision threshold was searched on the selected model. The final model was evaluated through ROC curve and prediction accuracy. RESULTS: From those segmented images of 186 patients, 1218 features were obtained via feature extraction. The preferred model was selected with recall as evaluation standard and the optimal decision threshold was set 0.56. The model had a prediction accuracy of 89.33% and the AUC score was 0.9296. CONCLUSION: A hyperparameters tuning random forest classifier had greater performance in predicting the survival status of non-small cell lung cancer patients, which could be taken for an automated classifier promising to stratify patients. PMID- 30305101 TI - Dynamics of Plasmodium falciparum gametocyte carriage in pregnant women under intermittent preventive treatment with sulfadoxine-pyrimethamine in Benin. AB - BACKGROUND: In sub-Saharan Africa, malaria is a major cause of morbidity and mortality, in particular in children and pregnant women. During pregnancy, Plasmodium falciparum infected red blood cells expressing VAR2CSA are selected from circulation by selective cytoadherence to chondroitin sulfate proteoglycan receptors expressed in the placenta, leading to an increased susceptibility to malaria, long-lasting infections and poor pregnancy outcome. Partly because of these long-lasting infections, women were reported to have a higher density of gametocytes in their peripheral blood, and are considered as a potential reservoir for malaria transmission. To improve pregnancy outcome in areas of high malaria transmission, The WHO recommends intermittent preventive treatment with sulfadoxine/pyrimethamine (IPTp-SP) during antenatal care visits. The effect of IPTp-SP on gametocyte carriage in infected pregnant women was studied. METHODS: The levels of transcription of three gametocytes stage-specific genes Pfs16 (expressed by sexually-committed ring stage parasites and fully matured gametocytes), Pfs25 (expressed by female mature gametocytes) and Pfs230 (expressed by male mature gametocytes) were assessed by real-time PCR in 50 P. falciparum infected women at early pregnancy (before implementation of IPTp-SP), and in 50 infected women at delivery. Sex ratios of male and female gametocytes were determined in these women to assess the effect of IPTp-SP on the gametocyte populations. RESULTS: The data show that the three transcript types specific to Pfs16, Pfs25 and Pfs230 were detected in all samples, both at inclusion and delivery. Levels of Pfs25 and Pfs230 transcripts were higher at delivery than at inclusion (p = 0.042 and p = 0.003), while the opposite was observed for Pfs16 (p = 0.048). The ratio of male/female gametocyte transcript levels was higher at delivery than at inclusion (p = 0.018). Since a mixed gender late stage gametocyte culture was used as a positive control, male and female gametocytes could not be quantified in an absolute way in the samples. However, the amplification reliability of the Pfs25 and Pfs230 markers in the samples could be checked. A relative quantity of each type of Pfs transcript was, therefore, used to calculate the sex ratio proxy. CONCLUSION: This study demonstrates that IPTp SP treatment contributes to modify the parasite populations' structure during pregnancy. In line with previous studies, we suggest that the continued use of SP in pregnant women as IPTp, despite having a beneficial effect on the pregnancy outcome, could be a risk factor for increased transmission. This reinforces the need for an alternative to the SP drug for malaria prevention during pregnancy. PMID- 30305103 TI - Extending research on Emotion Regulation Individual Therapy for Adolescents (ERITA) with nonsuicidal self-injury disorder: open pilot trial and mediation analysis of a novel online version. AB - BACKGROUND: Nonsuicidal self-injury (NSSI) is common among adolescents and associated with negative outcomes. However, treatments developed specifically for NSSI and the proposed NSSI disorder (NSSID) are scarce, and access to empirically supported treatments for NSSI in many areas is limited. Online treatments carry the potential to increase the availability of evidence-based treatments. Emotion regulation individual therapy for adolescents (ERITA) has shown promise in the treatment of adolescents with NSSID. METHOD: The present study examined the feasibility, acceptability, and utility of an online version of ERITA. Twenty five adolescents (aged 13-17) with NSSID and their parents were included in an uncontrolled open trial. Self-report and clinician-rated assessments of outcomes such as NSSI, self-destructive behaviors, emotion dysregulation, and global functioning were administered at pre-treatment, post-treatment, 3- and 6- month follow-up. Measures of NSSI, self-destructive behaviors, and emotion dysregulation were also assessed weekly during treatment. RESULTS: Ratings of treatment credibility, expectancy, and satisfaction were acceptable, and the therapeutic alliance and treatment completion rate (96%) were high. Adolescent participation in the treatment was associated with a statistically significant increase in past-month NSSI abstinence (p = .007), large-sized improvements in past-month NSSI frequency (55% reduction, 95% confidence interval [CI]: 29, 72; Cohen's d = 0.88, 95% CI: 0.73, 1.06) and global functioning (d = 1.01, 95% CI: 0.77, 1.32), and medium-sized improvements in emotion dysregulation (d = 0.75, 95% CI: 0.59, 0.90) and NSSI versatility (d = 0.63, 95% CI: 0.54, 0.77) from pre- to post-treatment. These improvements were further strengthened at 3-month follow up and maintained at 6-month follow-up. The online therapist-guided parent program was associated with small- to large-sized (ds = 0.47-1.22) improvements in adaptive parent behaviors, and these improvements were maintained or further improved upon at 6-month follow-up. Moreover, in line with the theoretical model underlying ERITA, change in emotion dysregulation mediated changes in both NSSI frequency and self-destructive behaviors over the course of treatment. CONCLUSIONS: Together, results suggest that online ERITA is an acceptable, feasible, and promising low-intensity treatment for adolescents with NSSID. The results of this open trial must be replicated in controlled studies. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02697019 ). Registered 2 March 2016. PMID- 30305104 TI - Elderly at risk in care transitions When discharge summaries are poorly transferred and used -a descriptive study. AB - BACKGROUND: Discharge summary with medication report effectively counteracts drug related problems among elderly patients due to insufficient information transfer in care transitions. However, this requires optimal transfer and use of the discharge summaries. This study aimed to examine information transfer with discharge summaries from hospital to primary care. METHODS: A descriptive study with data consisting of discharge summaries of 115 patients, 75 years or older, using five or more drugs, collected during one week from 28 different hospital wards in Skane county, Sweden. Two weeks after discharge, information transfer was examined via review of primary care medical records. It was noted whether the discharge summary was received (i.e. scanned to the primary care medical records), if the medication list was updated with drug changes and if a patient chart entry regarding medication or its follow-up was made in the primary care medical records. An electronic survey, which was sent to 151 primary care units in Skane county, was used to examine experiences of the information transfer. RESULTS: Out of 115 discharge summaries, 47 (41%) were found in the primary care medical records. Patient chart entries regarding medication or its follow-up were seen in 53 (46%) cases. Drug changes during hospitalisation were seen in 51 out of 76 patients without multidose drug dispensing. In 16 (31%) out of these cases, medication lists were updated in primary care medical records. In the electronic survey, 22 (21%) out of the 107 responding primary care units reported the discharge summary was often received on the day of discharge, while 71 (66%) respondents indicated the discharge summary was always/often received but later. Medication list updates and patient chart entries in the primary care medical records were always/often done upon receipt of the discharge summary according to 61 (57%) respondents. CONCLUSION: The transfer of information was often deficient and the discharge summaries were insufficiently used. Many discharge summaries were lost, an insufficient proportion of medication lists were updated and patient chart entries were often lacking. These findings may increase the risk of medication errors and drug-related problems for elderly in care transitions. PMID- 30305105 TI - Study on the cost attributable to central venous catheter-related bloodstream infection and its influencing factors in a tertiary hospital in China. AB - BACKGROUND: Central venous catheters (CVC) have been widely used for patients with severe conditions. However, they increase the risk of catheter-related bloodstream infection (CRBSI), which is associated with high economic burden. Until now, no study has focused on the cost attributable to CRBSI in China, and data on its economic burden are unavailable. The aim of this study was to assess the cost attributable to CRBSI and its influencing factors. METHODS: A retrospective matched case-control study and multivariate analysis were conducted in a tertiary hospital, with 94 patients (age >= 18 years old) from January 2011 to November 2015. Patients with CRBSI were matched to those without CRBSI by age, principal diagnosis, and history of surgery. The difference in cost between the case group and control group during the hospitalization was calculated as the cost attributable to CRBSI, which included the total cost and five specific cost categories: drug, diagnostic imaging, laboratory testing, health care technical services, and medical material. The relation between the total cost attributable to CRBSI and its influencing factors such as demographic characteristics, diagnosis and treatment, and pathogenic microorganism, was analysed with a general linear model (GLM). RESULTS: The total cost attributable to CRBSI was $3528.6, and the costs of specific categories including drugs, diagnostic imaging, laboratory testing, health care technical services, and medical material, were $2556.4, $112.1, $321.7, $268.7, $276.5, respectively. GLM analysis indicated that the total cost was associated with the intensive care unit (ICU), pathogenic microorganism, age, and catheter number, according to the sequence of standardized estimate (beta). ICU contributed the most to the model R square. CONCLUSION: Central venous catheter-related bloodstream infection represents a great economic burden for patients. More attentions should be paid to further prevent and control this infection in China. PMID- 30305107 TI - Home treatment and use of informal market of pharmaceutical drugs for the management of paediatric malaria in Cotonou, Benin. AB - BACKGROUND: Malaria is the main cause of hospital admissions in Benin and a leading cause of death in childhood. Beside consultations, various studies have underlined the management of the disease through home treatment. The medicines used can be purchased in informal market of pharmaceutical drugs (IMPD) without prescription or any involvement of healthcare professional. Pharmaceutical drugs are sold by informal private vendors, who operate at any time in the immediate environment of the patients. The present study was conducted in Cotonou to study the health-seeking behaviour of caregivers to treat malaria in children under 12 years old. Factors associated with malaria home treatment and drugs purchase in IMPD were studied. METHODS: A cross-sectional study was carried out among 340 children's caregivers who were interviewed about their socio-demographic characteristics and their care-seeking behaviour during the most recent episode of malaria in their children under 12. Medicines used and purchase place were also collected. Multivariate logistic regression model was used to determine factors associated with malaria home treatment and drug purchase in IMPD. RESULTS: Beyond all the 340 caregivers, 116 (34%) consulted healthcare professional, 224 (66%) home treat the children, among whom 207 (61%) gave pharmaceutical drugs and 17 (5%) gave traditional remedies to children. Malaria home treatment was associated with family size, health insurance (OR = 0.396, 95% CI 0.169-0.928), and wealth quintiles where home treatment was less used by the richest (OR = 0.199, 95% CI 0.0676-0.522) compared to those in the poorest quintile. The caregivers age group 30-39 years was associated to the use of IMPD (OR = 0.383, 95% CI 0.152-0.964), the most economically wealthy people were less likely to use IMPD (wealth quintile richest: OR = 0.239, 95% CI 0.064-0.887; wealth quintile fourth OR = 0.271, 95% CI 0.100-0.735) compared to those in the poorest quintile. All caregivers who benefited from health insurance did not use IMPD. CONCLUSION: This study highlights the link between worse economic conditions and accessibility to medical care as one of the main factors of malaria home treatment and drug purchase in IMPD, even if those two phenomena need to be understood apart. PMID- 30305106 TI - Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease. AB - BACKGROUND: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions. RESULTS: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. CONCLUSIONS: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine. PMID- 30305111 TI - Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. AB - Two recent publications by Sheikh and Horner and Teng et al. reviewed studies on incorporating vitamin C to treat septic patients; however, a meta-analysis was not offered in either report. This commentary extends both reviews by integrating a meta-analysis and sharing aggregated results. Pooled analyses demonstrated a marked reduction in mortality and duration of vasopressor administration in the group with the use of vitamin C. PMID- 30305109 TI - Upregulation of microRNA-17-5p contributes to hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of p21 and PTEN. AB - BACKGROUND: Pulmonary arterial smooth muscle cell (PASMC) proliferation in response to hypoxia plays an important role in the vascular remodelling that occurs in hypoxic pulmonary hypertension. MicroRNAs (miRs) are emerging as important regulators in the progression of pulmonary hypertension. In this study, we investigated whether the expression of miR-17-5p is modulated by hypoxia and is involved in the hypoxia-induced proliferation of PASMCs. METHODS: Human PASMCs were cultured under hypoxic conditions. miR-17-5p expression was determined by real-time RT-PCR. A BrdU incorporation assay and time-lapse recording were utilized to determine cell proliferation and migration. RESULTS: PASMC proliferation was increased by moderate hypoxia (3% oxygen) but was reduced by severe hypoxia (0.1% oxygen) after 48 h. Moderate hypoxia induced miR-17-5p expression. Overexpression of miR-17-5p by transfection with miR-17-5p enhanced cell proliferation and migration in normoxia, whereas knockdown of miR-17-5p with anti-miR-17-5p inhibitors significantly reduced cell proliferation and migration. The expression of miR-17-5p target genes, specifically phosphatase and tensin homologue (PTEN) and cyclin-dependent kinase inhibitor 1 (p21WAF1/Cip1, p21), was reduced under moderate hypoxia in PASMCs. Under normoxia, overexpression of miR 17-5p in PASMCs reduced the expression of PTEN and p21. CONCLUSION: Our data indicate that miR-17-5p might play a significant role in hypoxia-induced pulmonary vascular smooth muscle cell proliferation by regulating multiple gene targets, including PTEN and p21, and that miR-17-5p could be a novel therapeutic target for the management of hypoxia-induced PH. PMID- 30305110 TI - A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates. AB - BACKGROUND: The collective cognitive and motor deficits known as HIV-associated neurocognitive disorders (HAND) remain high even among HIV+ individuals whose antiretroviral therapy is optimized. HAND is worsened in the context of opiate abuse. The mechanism of exacerbation remains unclear but likely involves chronic immune activation of glial cells resulting from persistent, low-level exposure to the virus and viral proteins. We tested whether signaling through C-C chemokine receptor type 5 (CCR5) contributes to neurotoxic interactions between HIV-1 transactivator of transcription (Tat) and opiates and explored potential mechanisms. METHODS: Neuronal survival was tracked in neuronal and glial co cultures over 72 h of treatment with HIV-1 Tat +/- morphine using cells from CCR5 deficient and wild-type mice exposed to the CCR5 antagonist maraviroc or exogenously-added BDNF (analyzed by repeated measures ANOVA). Intracellular calcium changes in response to Tat +/- morphine +/- maraviroc were assessed by ratiometric Fura-2 imaging (analyzed by repeated measures ANOVA). Release of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF from CCR5 deficient and wild-type glia was measured by ELISA (analyzed by two-way ANOVA). Levels of CCR5 and MU-opioid receptor (MOR) were measured by immunoblotting (analyzed by Student's t test). RESULTS: HIV-1 Tat induces neurotoxicity, which is greatly exacerbated by morphine in wild-type cultures expressing CCR5. Loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions. Unexpectedly, when CCR5 was lost from glia, morphine appeared to entirely protect neurons from Tat-induced toxicity. Maraviroc pre-treatment similarly eliminated neurotoxicity and attenuated neuronal increases in [Ca2+]i caused by Tat +/- morphine. proBDNF/BDNF ratios were increased in conditioned media from Tat +/- morphine-treated wild-type glia compared to CCR5-deficient glia. Exogenous BDNF treatments mimicked the pro-survival effect of glial CCR5 deficiency against Tat +/- morphine. CONCLUSIONS: Our results suggest a critical role for glial CCR5 in mediating neurotoxic effects of HIV-1 Tat and morphine interactions on neurons. A shift in the proBDNF/BDNF ratio that favors neurotrophic support may occur when glial CCR5 signaling is blocked. Some neuroprotection occurred only in the presence of morphine, suggesting that loss of CCR5 may fundamentally change signaling through the MOR in glia. PMID- 30305112 TI - Screening for Zika virus RNA in sera of suspected cases: a retrospective cross sectional study. AB - BACKGROUND: Zika virus (ZIKV) became a global human health concern owing to its rapid spread worldwide and its association with congenital and neurological disorders. The current epidemiological profile of arboviruses in Brazil is characterized by widespread co-circulation of Dengue virus, Chikungunya virus, and ZIKV throughout the country. These viruses cause acute diseases frequently with overlapping symptoms, which could result in an inaccurate diagnosis based solely on clinical and epidemiological grounds. Here we conducted a screening for ZIKV RNA in serum samples from patients across Brazil with suspected ZIKV infection. METHODS: Using RT-qPCR, we investigated ZIKV RNA in 3001 serum samples. Samples were passively acquired through a private laboratory network, between December 2015 and August 2016, from 27 Brazilian Federative Units. We performed descriptive statistics on demographic variables including sex, age, and geographic location. RESULTS: ZIKV was detected in 11.4% (95%CI = 10.3-12.6%) of the sera. ZIKV RNA was detected in sera collected throughout the country, but during the analyzed period, RNA was more frequently detected in samples from the Southeast, Midwest, and North regions (3.9 to 5.8 times higher) when compared to the Northeast and South regions. CONCLUSIONS: These data reinforce the importance of laboratory diagnosis, surveillance systems, and further epidemiological studies to understand the dynamics of outbreaks and diseases associated with ZIKV and other arboviruses. PMID- 30305108 TI - Association between fluid management and dilutional coagulopathy in severe postpartum haemorrhage: a nationwide retrospective cohort study. AB - BACKGROUND: The view that 2 l of crystalloid and 1.5 l of colloid can be infused while awaiting compatible blood for patients with major postpartum haemorrhage is based on expert opinion documents. We describe real-world changes in levels of coagulation parameters after the administration of different volumes of clear fluids to women suffering from major postpartum haemorrhage. METHODS: We performed a nationwide retrospective cohort study in the Netherlands among 1038 women experiencing severe postpartum haemorrhage who had received at least four units of red cells or fresh frozen plasma or platelets in addition to red cells. The volume of clear fluids administered before the time of blood sampling was classified into three fluid administration strategies, based on the RCOG guideline: < 2 L, 2-3.5 L and > 3.5 L. Outcomes included haemoglobin, haematocrit, platelet count, fibrinogen, aPTT and PT levels. RESULTS: Haemoglobin, haematocrit, platelet count, fibrinogen and aPTT were associated with volumes of clear fluids, which was most pronounced early during the course of postpartum haemorrhage. During the earliest phases of postpartum haemorrhage median haemoglobin level was 10.1 g/dl (IQR 8.5-11.6) among the women who received < 2 L clear fluids and 8.1 g/dl (IQR 7.1-8.4) among women who received > 3.5 L of clear fluids; similarly median platelet counts were 181 * 109/litre (IQR 131-239) and 89 * 109/litre (IQR 84-135), aPTT 29 s (IQR 27-33) and 38 s (IQR 35 55) and fibrinogen 3.9 g/L (IQR 2.5-5.2) and 1.6 g/L (IQR 1.3-2.1). CONCLUSIONS: In this large cohort of women with severe postpartum haemorrhage, administration of larger volumes of clear fluids was associated with more severe deterioration of coagulation parameters corresponding to dilution. Our findings provide thus far the best available evidence to support expert opinion-based guidelines recommending restrictive fluid resuscitation in women experiencing postpartum haemorrhage. TRIAL REGISTRATION: Netherlands Trial Register ( NTR4079 ), registration date July 17, 2013. PMID- 30305113 TI - Condom use at last sex by young men in Ethiopia: the effect of descriptive and injunctive norms. AB - BACKGROUND: Condoms are an important prevention method in the transmission of HIV and sexually transmitted infections as well as unintended pregnancy. Individual level factors associated with condom use include family support and connection, strong relationships with teachers and other students, discussions about sexuality with friends and peers, higher perceived economic status, and higher levels of education. Little, however, is known about the influence of social norms on condom use among young men in Ethiopia. This study examines the effect of descriptive and injunctive norms on condoms use at last sex using the theory of normative social behavior. METHODS: A cross-sectional survey was implemented with 15-24 year old male youth in five Ethiopian regions in 2016. The analytic sample was limited to sexually active single young men (n = 260). Descriptive statistics, bivariate and multivariate logistic regressions were conducted. An interaction term was included in the multivariate model to assess whether injunctive norms moderate the relationship between descriptive norms and condom use. RESULTS: The descriptive norm of knowing a friend who had ever used condoms significantly increased respondents' likelihood of using condoms at last sex. The injunctive norm of being worried about what people would think if they learned that the respondent needed condoms significantly decreased their likelihood to use condoms. The injunctive norm did not moderate the relationship between descriptive norms and condom use. Young men who lived closer to a youth friendly service (YFS) site were significantly more likely to have used condoms at last sex compared to those who lived further away from a YFS site. CONCLUSIONS: Social norms play an important role in decision-making to use condoms among single young men in Ethiopia. The interplay between injunctive and descriptive norms is less straightforward and likely varies by individual. Interventions need to focus on shifting community-level norms to be more accepting of sexually active, single young men's use of condoms and need to be a part of a larger effort to delay sexual debut, decrease sexual violence, and increase gender equity in relationships. PMID- 30305114 TI - The LEAD trial - the effectiveness of a decision aid on decision making among citizens with lower educational attainment who have not participated in FIT-based colorectal cancer screening in Denmark: study protocol for a randomized controlled trial. AB - BACKGROUND: Colorectal cancer screening participation is a preference-sensitive choice, in which trade-offs between benefits and harms must be made by individual citizens. Often the decision is made without any contact with healthcare professionals. Citizens with lower educational attainment tend to participate less in colorectal cancer screening than citizens with average educational attainment. Further, they tend to have lower levels of knowledge about colorectal cancer screening. Providing lower educational attainment citizens with a targeted decision aid embracing their diverse information needs might increase these citizens' ability to make informed decisions. The aim of this trial is to test the effectiveness of such a newly developed self-administered decision aid. METHODS: The LEAD (Lower Educational Attainment Decision aid) trial will be conducted as a two-arm randomized controlled trial among 10,000 50-74-year-old citizens, resident in the Central Denmark Region not yet invited to take up colorectal cancer screening. Citizens will receive a baseline questionnaire. Respondents will be allocated into the intervention or the control groups. Citizens in the intervention group will receive the decision aid whereas the control group will not. Those who return a stool sample within 45 days after receiving the screening invitation and those with medium or higher educational attainment are excluded. Both groups will receive a follow-up questionnaire 90 days after being invited to colorectal cancer screening. A historic cohort consisting of 5000 50-74-year-old citizens resident in the Central Denmark Region, having received their screening invitation in the beginning of 2017 will be included. This cohort will receive a follow-up questionnaire 6-9 months after they received the screening invitation. Informed choice will be evaluated by assessing levels of knowledge, attitudes, and screening uptake. Analyses will be conducted as intention-to-treat analyses. Additionally, differences between levels of worry and decisional conflict between groups will be assessed as secondary outcomes. DISCUSSION: This trial will evaluate whether a targeted decision aid is a feasible way of enhancing informed choice among lower educational attainment citizens in colorectal cancer screening. Further, it may guide decisions about providing information material in cancer screening in general. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03253888 . Registered on 17 August 2017. PMID- 30305115 TI - Molecular profiling of hormone receptor-positive, HER2-negative breast cancers from patients treated with neoadjuvant endocrine therapy in the CARMINA 02 trial (UCBG-0609). AB - BACKGROUND: Postmenopausal women with large, hormone receptor (HR)-positive/HER2 negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis. METHODS: Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse free survival. RESULTS: The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARgamma is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors. CONCLUSIONS: The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov ( NCT00629616 ) on March 6, 2008, retrospectively registered. PMID- 30305117 TI - Correction to: Cytokines induced killer cells produced in good manufacturing practices conditions: identification of the most advantageous and safest expansion method in terms of viability, cellular growth and identity. AB - Following publication of the original article [1], the authors reported that all of the authors' names were processed incorrectly so that their given and family names were interchanged. In this Correction the correct author names are shown. The original publication of this article has been corrected. PMID- 30305118 TI - Predictive value of pediatric respiratory-induced diaphragm motion quantified using pre-treatment 4DCT and CBCTs. AB - BACKGROUND: In adults, a single pre-treatment four-dimensional CT (4D-CT) acquisition is often used to account for respiratory-induced target motion during radiotherapy. However, studies have indicated that a 4D-CT is not always representative for respiratory motion. Our aim was to investigate whether respiratory-induced diaphragm motion in children on a single pre-treatment 4DCT can accurately predict respiratory-induced diaphragm motion as observed on cone beam CTs (CBCTs). METHODS: Twelve patients (mean age 14.5 yrs.; range 8.6-17.9 yrs) were retrospectively included based on visibility of the diaphragm on abdominal or thoracic imaging data acquired during free breathing. A 4DCT for planning purposes and daily/weekly CBCTs (total 125; range 4-29 per patient) acquired prior to dose delivery were available. The amplitude, corresponding to the difference in position of the diaphragm in cranial-caudal direction in end inspiration and end-expiration phases, was extracted from the 4DCT (A4DCT). The amplitude in CBCTs (ACBCT) was defined as displacement between averaged in- and expiration diaphragm positions on corresponding projection images, and the distribution of ACBCT was compared to A4DCT (one-sample t-test, significance level p < 0.05). RESULTS: Over all patients, the mean A4DCT was 10.4 mm and the mean ACBCT 11.6 mm. For 9/12 patients, A4DCT differed significantly (p < 0.05) from ACBCT. Differences > 3 mm were found in 69/125 CBCTs (55%), with A4DCT mostly underestimating ACBCT. For 7/12 patients, diaphragm positions differed significantly from the baseline position. CONCLUSION: Respiratory-induced diaphragm motion determined on 4DCT does not accurately predict the daily respiratory-induced diaphragm motion observed on CBCTs, as the amplitude and baseline position differed statistically significantly in the majority of patients. Regular monitoring of respiratory motion during the treatment course using CBCTs could yield a higher accuracy when a daily adaptation to the actual breathing amplitude takes place. PMID- 30305119 TI - Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. AB - BACKGROUND: The pathogenic roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling in cerebral ischemia have been evidenced mainly through the efficacy of FTY720 that binds non-selectively to four of the five S1P receptors (S1P1,3,4,5). Recently, S1P1 and S1P2 were identified as specific receptor subtypes that contribute to brain injury in cerebral ischemia; however, the possible involvement of other S1P receptors remains unknown. S1P3 can be the candidate because of its upregulation in the ischemic brain, which was addressed in this study, along with underlying pathogenic mechanisms. METHODS: We used transient middle cerebral artery occlusion/reperfusion (tMCAO), a mouse model of transient focal cerebral ischemia. To identify S1P3 as a pathogenic factor in cerebral ischemia, we employed a specific S1P3 antagonist, CAY10444. Brain damages were assessed by brain infarction, neurological score, and neurodegeneration. Histological assessment was carried out to determine microglial activation, morphological transformation, and proliferation. M1/M2 polarization and relevant signaling pathways were determined by biochemical and immunohistochemical analysis. RESULTS: Inhibiting S1P3 immediately after reperfusion with CAY10444 significantly reduced tMCAO-induced brain infarction, neurological deficit, and neurodegeneration. When S1P3 activity was inhibited, the number of activated microglia was markedly decreased in both the periischemic and ischemic core regions in the ischemic brain 1 and 3 days following tMCAO. Moreover, inhibiting S1P3 significantly restored the microglial shape from amoeboid to ramified microglia in the ischemic core region 3 days after tMCAO, and it attenuated microglial proliferation in the ischemic brain. In addition to these changes, S1P3 signaling influenced the proinflammatory M1 polarization, but not M2. The S1P3-dependent regulation of M1 polarization was clearly shown in activated microglia, which was affirmed by determining the in vivo activation of microglial NF-kappaB signaling that is responsible for M1 and in vitro expression levels of proinflammatory cytokines in activated microglia. As downstream effector pathways in an ischemic brain, S1P3 influenced phosphorylation of ERK1/2, p38 MAPK, and Akt. CONCLUSIONS: This study identified S1P3 as a pathogenic mediator in an ischemic brain along with underlying mechanisms, involving its modulation of microglial activation and M1 polarization, further suggesting that S1P3 can be a therapeutic target for cerebral ischemia. PMID- 30305120 TI - Long non-coding RNA H19 and MALAT1 gene variants in patients with ischemic stroke in a northern Chinese Han population. AB - Objectives Long non-coding RNAs (lncRNAs) have been identified as key regulators in the development of atherosclerosis, which is a major cause of ischemic stroke. However, to date, there are no reports on the association between lncRNA gene variation and the risk of ischemic stroke. Therefore, we assessed the association between H19 and MALAT1 gene polymorphisms and susceptibility to ischemic stroke in a northern Chinese Han population. Methods In our study, we genotyped four genetic variations in lncRNA-H19 and -MALAT1 (rs217727, rs2251375, rs619586, and rs3200401) in a case-control study of 567 ischemic stroke patients and 552 control subjects. Results We found that the TT genotype of the rs217727 polymorphism within H19 was significantly associated with increased risk of ischemic stroke in our northern Chinese Han population (odds ration (OR) = 1.519, 95% confidence interval (CI) = 1.072-2.152, p = 0.018). Stratified analysis based on stroke subtype revealed that the increased risk was more evident in small vessel ischemic stroke (OR = 1.941, 95% CI = 1.260-2.992, p = 0.02). Individuals with the TT genotype had a 1.941 times higher risk of small vessel ischemic stroke when compared with the subjects of CC + CT. These correlations remained after adjusting for confounding risk factors of stroke (OR = 1.913, 95% CI = 1.221-2.998, p = 0.005). However, there was no significant association between H19 rs2251375 or MALAT1 rs3200401 and ischemic stroke in either total population analysis or subgroup analysis. Conclusion In conclusion, our findings suggest that the H19 rs217727 gene polymorphism contributes to small vessel ischemic stroke susceptibility in the Chinese Han population and may serve as a potential indicator for ischemic stroke susceptibility. PMID- 30305121 TI - Epidemiology of subsequent bloodstream infections in the ICU. AB - Subsequent bloodstream infections (sBSI) occur with a delay after removal of the intravascular catheter (IVC) whose tip revealed microbial growth. Here we describe the epidemiology of sBSI in the intensive care setting. Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, and yeast were the pathogens most frequently associated with sBSI. In contrast, Enterococci were rarely found in sBSI. PMID- 30305116 TI - Role of platelets and platelet receptors in cancer metastasis. AB - The interaction of tumor cells with platelets is a prerequisite for successful hematogenous metastatic dissemination. Upon tumor cell arrival in the blood, tumor cells immediately activate platelets to form a permissive microenvironment. Platelets protect tumor cells from shear forces and assault of NK cells, recruit myeloid cells by secretion of chemokines, and mediate an arrest of the tumor cell platelet embolus at the vascular wall. Subsequently, platelet-derived growth factors confer a mesenchymal-like phenotype to tumor cells and open the capillary endothelium to expedite extravasation in distant organs. Finally, platelet secreted growth factors stimulate tumor cell proliferation to micrometastatic foci. This review provides a synopsis on the current literature on platelet mediated effects in cancer metastasis and particularly focuses on platelet adhesion receptors and their role in metastasis. Immunoreceptor tyrosine-based activation motif (ITAM) and hemi ITAM (hemITAM) comprising receptors, especially, glycoprotein VI (GPVI), FcgammaRIIa, and C-type lectin-like-2 receptor (CLEC-2) are turned in the spotlight since several new mechanisms and contributions to metastasis have been attributed to this family of platelet receptors in the last years. PMID- 30305122 TI - Association between diuretics and successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury. AB - BACKGROUND: Despite aggressive application of continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury (AKI), there is no consensus on diuretic therapy when discontinuation of CRRT is attempted. The effect of diuretics on discontinuation of CRRT in critically ill patients was evaluated. METHODS: This retrospective cohort study enrolled 1176 adult patients who survived for more than 3 days after discontinuing CRRT between 2009 and 2014. Patients were categorized depending on the re-initiation of renal replacement therapy within 3 days after discontinuing CRRT or use of diuretics. Changes in urine output (UO) and renal function after discontinuing CRRT were outcomes. Predictive factors for successful discontinuation of CRRT were also analyzed. RESULTS: The CRRT discontinuation group had a shorter duration of CRRT, more frequent use of diuretics after discontinuing CRRT, and greater UO on the day before CRRT discontinuation [day minus 1 (day - 1)]. The diuretics group had greater increases in UO and serum creatinine elevation after discontinuing CRRT. In the CRRT discontinuation group, continuous infusion of furosemide tended to increase UO more effectively. Multivariable regression analysis identified high day - 1 UO and use of diuretics as significant predictors of successful discontinuation of CRRT. Day - 1 UO of 125 mL/day was the cutoff value for predicting successful discontinuation of CRRT in oliguric patients treated with diuretics following CRRT. CONCLUSIONS: Day - 1 UO and aggressive diuretic therapy were associated with successful CRRT discontinuation. Diuretic therapy may be helpful when attempting CRRT discontinuation in critically ill patients with AKI, by inducing a favorable fluid balance, especially in oliguric patients. PMID- 30305123 TI - Integration of postpartum care into child health and immunization services in Burkina Faso: findings from a cross-sectional study. AB - BACKGROUND: The Missed Opportunities for Maternal and Infant Health (MOMI) project, which aimed at upgrading maternal and infant postpartum care (PPC), implemented a package of interventions including the integration of maternal PPC in infant immunization services in 12 health facilities in Kaya Health district in Burkina Faso from 2013 to 2015. This paper assesses the coverage and the quality of combined mother-infant PPC in reproductive, maternal, newborn and child health services (RMNCH). METHODS: We conducted a mixed methods study with cross-sectional surveys before and after the intervention in the Kaya health and demographic surveillance system. On the quantitative side, two household surveys were performed in 2012 (N = 757) and in 2014 (N = 754) among mothers within one year postpartum. The analysis examines the result of the intervention by the date of delivery at three key time points in the PPC schedule: the first 48 h, days 6 10 and during weeks 6-8 and beyond. On the qualitative side, in depth interviews, focus group discussions and observations were conducted in four health facilities in 2012 and 2015. They involved mothers in the postpartum period, facility and community health workers, and other stakeholders. We performed a descriptive analysis and a two-sample test of proportions of the quantitative data. The qualitative data were recorded, transcribed and analysed along the themes relevant for the intervention. RESULTS: The findings show that the WHO guidelines, in terms of content and improvement of maternal PPC, were followed for physical examinations and consultations. They also show a significant increase in the coverage of maternal PPC services from 50% (372/752) before the intervention to 81% (544/672) one year after the start of the intervention. However, more women were assessed at days 6-10 than at later visits. Integration of maternal PPC was low, with little improvements in history taking and physical examination of mothers in immunization services. While health workers are polyvalent, difficulties in restructuring and organizing services hindered the integration. CONCLUSION: Unless a comprehensive strategy of integration within RMNCH services is implemented to address the primary health care challenges within the health system, integration will not yield the desired results. PMID- 30305124 TI - Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis. AB - BACKGROUND: The efficacy of intravenous acetaminophen in multimodal pain management in patients undergoing total knee arthroplasty (TKA) is controversial. The purpose of this meta-analysis was to compare the efficacy of intravenous acetaminophen versus placebo in TKA. METHODS: Randomized controlled trials (RCTs) or retrospective cohort studies (RCSs) concerning related topics were retrieved from PubMed (1996-June 2018), Embase (1980-June 2018), and the Cochrane Library (CENTRAL June 2018). Any studies comparing intravenous acetaminophen with a placebo were included in this meta-analysis. Meta-analysis results were collected and analyzed by Stata 12.0. Subgroup analysis was performed according to the general characteristics of the patients. RESULTS: In total, the patients from six studies met the inclusion criteria. Our meta-analysis results indicated that compared with a control group, intravenous acetaminophen was associated with reductions in total morphine consumption and visual analogue scale (VAS) score at postoperative day (POD) 3. However, there was no significant difference in morphine consumption at POD 1 or in VAS at POD 1 or POD 2. Moreover, there was no significant difference in the length of hospital stay. CONCLUSIONS: Based on our results, intravenous acetaminophen in multimodal management has shown better efficacy in pain relief at POD 3 and has morphine-sparing effects. High-quality studies with more patients are needed in the future. PMID- 30305125 TI - Clinical outcomes of image-guided proton therapy for histologically confirmed stage I non-small cell lung cancer. AB - BACKGROUND: Two prospective phase II trials were designed to assess the efficacy and safety of image-guided proton therapy (IGPT) for either medically inoperable or operable stage I non-small cell lung cancer (NSCLC). The present study reports the interim results of these trials. METHODS: Fifty-five patients with histologically confirmed stage I NSCLC (IA in 33 patients and IB in 22 patients; inoperable in 21 patients and operable in 34 patients) who received IGPT between July 2013 and February 2017 were analyzed. The median patient age was 71 years (range: 48-88 years). IGPT with fiducial metallic marker matching was performed for suitable patients, and a respiratory gating method for motion management was used for all treatments. Peripherally located tumors were treated with 66 Gy relative biological effectiveness equivalents (Gy(RBE)) in 10 fractions (n = 49) and centrally located tumors were treated with 72.6 Gy(RBE) in 22 fractions (n = 6). Treatment associated toxicities were evaluated using Common Toxicity Criteria for Adverse Events (v.4.0). RESULTS: Median follow-up was 35 months (range: 12-54 months) for survivors. For all patients, the 3-year overall survival, progression free survival, and local control rates were 87% (95% confidence interval: 73 94%), 74% (58-85%), and 96% (83-99%), respectively. Fiducial marker matching was used in 39 patients (71%). Grade 2 toxicities observed were radiation pneumonitis in 5 patients (9%), rib fracture in 2 (4%), and chest wall pain in 5 (9%). There were no grade 3 or higher acute or late toxicities. CONCLUSIONS: IGPT appears to be effective and well tolerated for all patients with stage I NSCLC. TRIAL REGISTRATION: Lung-001, 13-02-09 (9), registered 11 June 2013 and Lung-002, 13-02 10 (10), registered 11 June 2013. PMID- 30305126 TI - Effect of pedicle screw augmentation with a self-curing elastomeric material under cranio-caudal cyclic loading-a cadaveric biomechanical study. AB - BACKGROUND: Pedicle screws can be augmented with polymethylmethacrylate (PMMA) cement through cannulated and fenestrated pedicle screws to improve screw anchorage. To overcome the drawbacks of PMMA, a modified augmentation technique applying a self-curing elastomeric material into a balloon-created cavity prior to screw insertion was developed and evaluated. The aim of the study was to compare the effect of the established and novel augmentation technique on pedicle screw anchorage in a biomechanical in vitro experiment. METHODS: In ten lumbar vertebral bodies, the right pedicles were instrumented with monoaxial cannulated and fenestrated pedicle screws and augmented in situ with 2 ml PMMA. The left pedicles were instrumented with monoaxial cannulated pedicle screws. Prior to left screw insertion, a balloon cavity was created and filled with 3 ml of self curing elastomer (silicone). Each screw was subjected to a cranio-caudal cyclic load starting from - 50 to 50 N while the upper load was increased by 5 N every 100 load cycles until loosening or 11,000 cycles (600 N). After cyclic loading, a pullout test of the screws was conducted. RESULTS: The mean cycles to screw loosening were 9824 +/- 1982 and 7401 +/- 1644 for the elastomer and PMMA group, respectively (P = 0.012). The post-cycling pullout test of the loosened screws showed differences in the failure mode and failure load, with predominantly pedicle/vertebrae fractures in the PMMA group (1188.6 N +/- 288.1) and screw pullout through the pedicle (671.3 N +/- 332.1) in the elastomer group. CONCLUSION: The modified pedicle screw augmentation technique involving a balloon cavity creation and a self-curing elastomeric silicone resulted in a significantly improved pedicle screw anchorage under cyclic cranio-caudal loading when compared to conventional in situ PMMA augmentation. PMID- 30305127 TI - Assessing whether universal coverage with insecticide-treated nets has been achieved: is the right indicator being used? AB - BACKGROUND/METHODS: Insecticide-treated nets (ITNs) are the primary tool for malaria vector control in sub-Saharan Africa, and have been responsible for an estimated two-thirds of the reduction in the global burden of malaria in recent years. While the ultimate goal is high levels of ITN use to confer protection against infected mosquitoes, it is widely accepted that ITN use must be understood in the context of ITN availability. However, despite nearly a decade of universal coverage campaigns, no country has achieved a measured level of 80% of households owning 1 ITN for 2 people in a national survey. Eighty-six public datasets from 33 countries in sub-Saharan Africa (2005-2017) were used to explore the causes of failure to achieve universal coverage at the household level, understand the relationships between the various ITN indicators, and further define their respective programmatic utility. RESULTS: The proportion of households owning 1 ITN for 2 people did not exceed 60% at the national level in any survey, except in Uganda's 2014 Malaria Indicator Survey (MIS). At 80% population ITN access, the expected proportion of households with 1 ITN for 2 people is only 60% (p = 0.003 R2 = 0.92), because individuals in households with some but not enough ITNs are captured as having access, but the household does not qualify as having 1 ITN for 2 people. Among households with 7-9 people, mean population ITN access was 41.0% (95% CI 36.5-45.6), whereas only 6.2% (95% CI 4.0 8.3) of these same households owned at least 1 ITN for 2 people. On average, 60% of the individual protection measured by the population access indicator is obscured when focus is put on the household "universal coverage" indicator. The practice of limiting households to a maximum number of ITNs in mass campaigns severely restricts the ability of large households to obtain enough ITNs for their entire family. CONCLUSIONS: The two household-level indicators-one representing minimal coverage, the other only 'universal' coverage-provide an incomplete and potentially misleading picture of personal protection and the success of an ITN distribution programme. Under current ITN distribution strategies, the global malaria community cannot expect countries to reach 80% of households owning 1 ITN for 2 people at a national level. When programmes assess the success of ITN distribution activities, population access to ITNs should be considered as the better indicator of "universal coverage," because it is based on people as the unit of analysis. PMID- 30305128 TI - A child with intellectual disability and dysmorphism due to complex ring chromosome 6: identification of molecular mechanism with review of literature. AB - BACKGROUND: Ring chromosome 6 (r(6)) is a rare disorder that mainly occurs as a 'de novo' event. Nonetheless, a wide phenotypic spectrum has been reported in r(6) cases, depending on breakpoints, size of involved region, copy number alterations and mosaicism of cells with r(6) and/or monosomy 6 due to loss of r(6). CASE PRESENTATION: An 11-year-old male was referred with developmental delay, intellectual disability and microcephaly. Physical examination revealed additionally short stature and multiple facial dysmorphisms. Banding cytogenetic studies revealed a karyotype of mos 46,XY,r(6)(p25.3q27)[54]/45,XY, 6[13]/46,XY,r(6)(::p25.3->q27::p25.3 >q27::)[13]/46,XY[6]/47,XY,r(6)(p25.3q27)*2[2]dn. Additionally, molecular karyotyping and molecular cytogenetics confirmed the breakpoints and characterized a 1.3 Mb contiguous duplication at 6p25.3. CONCLUSION: The present study has accurately identified copy number alterations caused by ring chromosome formation. A review of the literature suggests that hemizygous expression of TBP gene in 6q27~qter, is likely to be the underlying cause of the phenotype. The phenotypic correlation and clinical severity in r(6) cases continue to remain widely diverse in spite of numerous reports of genomic variations. PMID- 30305129 TI - A systematic review of person-centered care interventions to improve quality of facility-based delivery. AB - INTRODUCTION: We conducted a systematic review to summarize the global evidence on person-centered care (PCC) interventions in delivery facilities in order to: (1) map the PCC objectives of past interventions (2) to explore the impact of PCC objectives on PCC and clinical outcomes. METHODS: We developed a search strategy based on a current definition of PCC. We searched for English-language, peer reviewed and original research articles in multiple databases from 1990 to 2016 and conducted hand searches of the Cochrane library and gray literature. We used systematic review methodology that enabled us to extract and synthesize quantitative and qualitative data. We categorized interventions according to their primary and secondary PCC objectives. We categorized outcomes into person centered and clinical (labor and delivery, perinatal, maternal mental health). RESULTS: Our initial search strategy yielded 9378 abstracts; we conducted full text reviews of 32 quantitative, 6 qualitative, 2 mixed-methods studies, and 7 systematic reviews (N = 47). Past interventions pursued these primary PCC objectives: autonomy, supportive care, social support, the health facility environment, and dignity. An intervention's primary and secondary PCC objectives frequently did not align with the measured person-centered outcomes. Generally, PCC interventions either improved or made no difference to person-centered outcomes. There was no clear relationship between PCC objectives and clinical outcomes. CONCLUSIONS: This systematic review presents a comprehensive analysis of facility-based delivery interventions using a current definition of person centered care. Current definitions of PCC propose new domains of inquiry but may leave out previous domains. PMID- 30305131 TI - A matched-pair analysis of stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer versus early stage non-small cell lung cancer. AB - BACKGROUND: The use of stereotactic body radiotherapy (SBRT) for early-stage primary non-small cell lung cancer (NSCLC) reported excellent local control rates. But the optimal SBRT dose for oligometastatic lung tumors (OLTs) from colorectal cancer (CRC) has not yet been determined. This study aimed to evaluate whether SBRT to a dose of 48-60 Gy in 4-5 fractions could result in similar local outcomes for OLTs from CRC as compared to early-stage NSCLC, and to examine potential dose-response relationships for OLTs from CRC. METHODS: OLTs from CRC and primary NSCLCs treated with SBRT to 48-60 Gy in 4-5 fractions at a single institution were evaluated, and a matched-pair analysis was performed. Local recurrence-free survival (LRFS) was estimated by the Kaplan-Meier method. Univariate Cox regression was performed to identify significant predictors. RESULTS: There were 72 lung lesions in 61 patients (24 OLTs from CRC in 15 patients and 48 NSCLCs in 46 patients) were analyzed with a median follow-up of 30 months. LRFS for OLTs from CRC was significantly worse than that of NSCLC when treated with 48-60 Gy/4-5 fx (p = 0.006). The 1, 3 and 5-year LRFS of OLTs from CRC vs NSCLC were 80.6% vs. 100%, 68.6% vs. 97.2%, and 68.6% vs. 81.0%, respectively. On univariate analysis, OLTs from CRC treated with higher dose (BED10 = 132 Gy) exhibited significantly better local recurrence-free survival than those treated to lower doses (BED10 <= 105.6 Gy) (p = 0.0022). The 1 and 3 year LRFS rates for OLTs treated to a higher dose (BED10 = 132 Gy) were 88.9% and 81.5%, vs 33.3%, and not achieved for lower doses (BED10 <= 105.6 Gy). CONCLUSION: The LRFS of OLTs from CRC after SBRT of 48-60 Gy/4-5 fx was significantly worse than that of primary NSCLC. Lower dose SBRT appeared to have inferior control for OLTs of CRC in this cohort. Further studies with larger sample sizes are needed. PMID- 30305132 TI - Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis and is defined by organ failure and high rates of short-term mortality. Patients with ACLF are managed with multiorgan support in the intensive care unit (ICU). Currently, it is unclear when this supportive care becomes futile, particularly in patients who are not candidates for liver transplant. The aim of this study was to determine whether the currently available prognostic scores can identify patients with ACLF in whom prolonged ICU care is likely to be futile despite maximal treatment efforts. METHODS: Data of 202 consecutive patients with ACLF admitted to the ICU at the Royal Free Hospital London between 2005 and 2012 were retrospectively analyzed. Prognostic scores for chronic liver diseases, such as Child-Pugh, Model for End-Stage Liver Disease (MELD), European Foundation for the study of chronic liver failure (CLIF-C) organ failure (OF), and CLIF-C ACLF, were calculated 48 hours after ICU admission and correlated with patient outcome after 28 days. RESULTS: The CLIF-C ACLF score, compared with all other scores, most accurately predicted 28-day mortality, with an area under the receiver operator characteristic of 0.8 (CLIF-C OF, 0.75; MELD, 0.68; Child-Pugh, 0.66). A CLIF-C ACLF score cutoff >= 70 identified patients with a 100% mortality within 28 days. These patients had elevated inflammatory parameters representing a systemic inflammatory response, most often renal failure, compared with patients below this cutoff. CONCLUSIONS: Patients with ACLF and high CLIF-C ACLF score (>= 70) after 48 hours of intensive care may reach a threshold of futility for further ongoing intensive support. The best treatment options in this scenario remain to be determined but may include palliative care. PMID- 30305130 TI - Adoptive cell transfer: new perspective treatment in veterinary oncology. AB - Cancer immunotherapy is recently considered the most promising treatment for human patients with advanced tumors and could be effectively combined with conventional therapies such as chemotherapy or radiotherapy. Patients with hematological malignancies and melanoma have benefited greatly from immunotherapies such as, adoptive cell transfer therapy, experiencing durable remissions and prolonged survival. In the face of increasing enthusiasm for immunotherapy, particularly for the administration of tumor-specific T lymphocytes, the question arises whether this method could be employed to improve treatment outcomes for canine patients. It is warranted to determine whether veterinary clinical trials could support comparative oncology research and thus facilitate the development of new cell-based therapies for humans. Herein, we discuss adoptive transfer of T lymphocytes and lymphokine-activated cells for application in veterinary oncology, in the context of human medicine achievements. Furthermore, we discuss potential benefits of using domestic dog as a model for immunotherapy and its advantages for translational medicine. We also focus on an emerging genome-editing technology as a useful tool to improve a T cells' phenotype. PMID- 30305133 TI - Performance comparison of new Veris and Xpert random access HIV-1 RNA quantification assays. AB - BACKGROUND: Recent systems for Human Immunodeficiency Virus 1 (HIV-1) viral load (VL) monitoring allow one-by-one analysis and fast turn-around-time for results. VL measurement on two rapid recently commercialized systems, GeneXpert (Cepheid) and Veris (Beckman Coulter) was compared to classical methods. METHODS: Plasma specimen from HIV-1 (group M) positive patients (n = 129) initially quantified with Abbott RealTime HIV-1 and Generic HIV-VL Biocentric assays were retrospectively tested with GeneXpert and Veris. RESULTS: Valid results on all techniques were obtained for 116/129 specimens composed of 89 Abbott quantifiable VL (38 B, 51 non-B subtypes) [range: 2.09-7.20 log cp/mL] and 27 plasma (9 B, 18 non-B) with Abbott-VL below the limit of quantification (LLQ). All techniques showed good correlation and agreement with a lowest Spearman correlation coefficient of 0.86. Compared to Abbott, the mean bias was 0.35 (95% CI: 0.25 0.45), 0.44 (0.36-0.53) and - 0.04 (- 0.13-0.05) for Biocentric, Beckman and Cepheid, respectively. A difference over 0.5 log cp/mL between VL-quantification of the same sample was observed for 19, 9 and 6 samples with Biocentric, Beckman and Cepheid, respectively. No influence of HIV-1 subtypes on VL was identified. Among 29 samples below LLQ on Abbott, only one was detected and quantified with the Veris assay (38 cp/mL), none with Cepheid. CONCLUSION: Both random access systems from Cepheid and Beckman appear well designed for quantifying plasma HIV 1 VL, are easy to handle, fast and fully automated. The slight observed differences suggest to follow the current guidelines recommending the use of the same technique over time for patient viral load monitoring. PMID- 30305134 TI - Subclinical acute kidney injury is associated with adverse outcomes in critically ill neonates and children. AB - BACKGROUND: Research on acute kidney injury (AKI) has focused on identifying early biomarkers. However, whether AKI could be diagnosed in the absence of the classic signs of clinical AKI and whether the condition of subclinical AKI, identified by damage or functional biomarkers in the absence of oliguria or increased serum creatinine (sCr) levels, is clinically significant remains to be elucidated in critically ill children. The aims of the study were to investigate the associations between urinary cystatin C (uCysC) levels and AKI and mortality and to determine whether uCysC-positive subclinical AKI is associated with adverse outcomes in critically ill neonates and children. METHODS: In this prospective cohort study, uCysC levels were serially measured during the first week after intensive care unit (ICU) admission in a heterogeneous group of patients (n = 510) presenting to a tertiary neonatal and pediatric ICU. The diagnosis of neonatal AKI that developed during the first week after admission was based on neonatal KDIGO criteria or sCr >1.5 mg/dL, and pediatric AKI was based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The term "uCysC(-)" or "uCysC(+)", indicating the absence or presence of tubular injury, was defined by the optimal peak uCysC cutoff value for predicting ICU mortality. RESULTS: The initial and peak uCysC levels were significantly associated with AKI and mortality, and had an area under the receiver operating characteristic curve of 0.76 and 0.81, respectively, for predicting mortality. At the optimal cutoff value of 1260 ng/mg uCr, the peak uCysC displayed sensitivity of 79.2% and specificity of 72.3% for predicting mortality. Among all patients, 130 (25.5%) developed uCysC(+)/AKI(-) status during the first week after admission. The adjusted odds ratio for patients with uCysC(+)/AKI(-) status in association with an increased risk of mortality compared with that for patients with uCysC(-)/AKI( ) was 9.34 (P < 0.001). Patients with uCysC(+)/AKI(-) spent 2.8 times as long in the ICU as those with uCysC(-)/AKI(-) (P < 0.001). CONCLUSIONS: Both initial and peak uCysC levels are associated with AKI and mortality and are independently predictive of mortality in critically ill neonates and children. Subclinical AKI may occur without detectable loss of kidney function, and uCysC-positive subclinical AKI is associated with worse clinical outcomes in this population. PMID- 30305135 TI - Mechanism of piR-DQ590027/MIR17HG regulating the permeability of glioma conditioned normal BBB. AB - BACKGROUND: The blood-brain barrier (BBB) strongly restricts the entry of anti glioma drugs into tumor tissues and thus decreases chemotherapy efficacy. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumor form. Because regulation of the effect of noncoding RNA on BBB function is attracting growing attention, we investigated the effects of noncoding RNA on the permeability of glioma conditioned normal BBB and the mechanism involved using PIWI-associated RNA piR DQ590027 as a starting point. METHODS: The mRNA levels of MIR17HG, miR-153, miR 377, ZO-1, occludin, and claudin-5 were determined using real-time PCR. Transient cell transfection was performed using Lipofectamine 3000 reagent. TEER and HRP flux were applied to measure the permeability of glioma conditioned normal BBB. Western blotting and immunofluorescence assays were used to measure ZO-1, occludin, and claudin-5 levels. Reporter vector construction and a luciferase reporter assay were performed to detect the binding sites of MIR17HG and piR DQ590027, MIR17HG and miR-153 (miR-377), and FOXR2 and miR-153 (miR-377). RNA immunoprecipitation was used to test the interaction between miR-153 (miR-377) and its target proteins. Chromatin immunoprecipitation was performed to detect the interaction between the transcription factor FOXR2 and ZO-1, occludin, and claudin-5. RESULTS: piR-DQ590027 was expressed at low levels in glioma conditioned ECs (GECs) of the in vitro glioma conditioned normal BBB model. Overexpression of piR-DQ590027 down-regulated the expressions of ZO-1, occludin, and claudin-5 and increased the permeability of glioma conditioned normal BBB. MIR17HG had high expression in GECs but miR-153 and miR-377 had low expression. piR-DQ590027 bound to and negatively regulated MIR17HG. FOXR2 was a downstream target of miR-153 and miR-377; MIR17HG bound separately to miR-153 and miR-377 and negatively regulated their ability to mediate FOXR2 expression. FOXR2 associated with the promoter regions of ZO-1, occludin, and claudin-5 in GECs to promote their transcription. CONCLUSION: The piR-DQ590027/MIR17HG/miR-153 (miR 377)/FOXR2 pathway plays an important role in regulating glioma conditioned normal BBB permeability and provides a new target for the comprehensive treatment of glioma. PMID- 30305136 TI - The meaning of blood pressure. AB - Measurement of arterial pressure is one of the most basic elements of patient management. Arterial pressure is determined by the volume ejected by the heart into the arteries, the elastance of the walls of the arteries, and the rate at which the blood flows out of the arteries. This review will discuss the three forces that determine the pressure in a vessel: elastic, kinetic, and gravitational energy. Emphasis will be placed on the importance of the distribution of arterial resistances, the elastance of the walls of the large vessels, and critical closing pressures in small arteries and arterioles. Regulation of arterial pressure occurs through changes in cardiac output and changes in vascular resistance, but these two controlled variables can sometimes be in conflict. PMID- 30305137 TI - Integrated fever management: disease severity markers to triage children with malaria and non-malarial febrile illness. AB - Febrile symptoms in children are a leading cause of health-care seeking behaviour worldwide. The majority of febrile illnesses are uncomplicated and self-limited, without the need for referral or hospital admission. However, current diagnostic tools are unable to identify which febrile children have self-limited infection and which children are at risk of progressing to life-threatening infections, such as severe malaria. This paper describes the need for a simple community based tool that can improve the early recognition and triage of febrile children, with either malarial or non-malarial illness, at risk of critical illness. The integration of a disease severity marker into existing malaria rapid diagnostic tests (RDT) could enable detection of children at risk of severe infection in the hospital and community, irrespective of aetiology. Incorporation of a disease severity marker could inform individualized management and early triage of children at risk of life-threatening infection. A child positive for both malaria and a disease severity marker could be prioritized for urgent referral/admission and parenteral therapy. A child positive for malaria and negative for a disease severity marker could be managed conservatively, as an out-patient, with oral anti-malarial therapy. An RDT with a disease severity marker could facilitate an integrated community-based approach to fever syndromes and improve early recognition, risk stratification, and prompt treatment of severe malaria and other life-threatening infections. PMID- 30305138 TI - GLI2 promotes cell proliferation and migration through transcriptional activation of ARHGEF16 in human glioma cells. AB - BACKGROUND: The Hedgehog (Hh) signaling pathway plays critical roles in modulating embryogenesis and maintaining tissue homeostasis, with glioma associated oncogene (GLI) transcription factors being the main mediators. Aberrant activation of this pathway is associated with various human malignancies including glioblastoma, although the mechanistic details are not well understood. METHODS: We performed a microarray analysis of genes that are differentially expressed in glioblastoma U87 cells overexpressing GLI2A, the active form of GLI2, relative to the control cells. Chromatin immunoprecipitation and dual luciferase assays were used to determine whether Rho guanine nucleotide exchange factor 16 (ARHGEF16) is a downstream target of GLI2. Then, transwell migration, EdU and soft-agar colony formation assays were employed to test effects of ARHGEF16 on glioma cancer cell migration and proliferation, and the effects of GLI2/ARHGEF16 signaling on tumor growth were examined in vivo. Finally, we performed yeast two-hybrid assay, Co-IP and GST-pull down to identify factors that mediate effects of ARHGEF16. RESULTS: We found that ARHGEF16 mRNA level was upregulated in U87 cells overexpressing GLI2A relative to control cells. GLI2 binds to the ARHGEF16 promoter and activates gene transcription. Glioma cells U87 and U118 overexpressing ARHGEF16 showed enhanced migration and proliferation relative to the control cells, while knockdown of ARHGEF16 in H4 cells led to decreased cell proliferation compared to the control H4 cells. In contrast to the promoting effect of GLI2A overexpression on glioma xenograft growth, both GLI2 inhibition and ARHGEF16 knockdown retarded tumor growth. Cytoskeleton-associated protein 5 (CKAP5) was identified as an interaction protein of ARHGEF16, which is important for the stimulatory effects of ARHGEF16 on glioma cell migration and proliferation. CONCLUSIONS: These results suggest that therapeutic strategies targeting the GLI2/ARHGEF16/CKAP5 signaling axis could inhibit glioma progression and recurrence. PMID- 30305139 TI - Consistent and reproducible cultures of large-scale 3D mammary epithelial structures using an accessible bioprinting platform. AB - BACKGROUND: Standard three-dimensional (3D) in vitro culture techniques, such as those used for mammary epithelial cells, rely on random distribution of cells within hydrogels. Although these systems offer advantages over traditional 2D models, limitations persist owing to the lack of control over cellular placement within the hydrogel. This results in experimental inconsistencies and random organoid morphology. Robust, high-throughput experimentation requires greater standardization of 3D epithelial culture techniques. METHODS: Here, we detail the use of a 3D bioprinting platform as an investigative tool to control the 3D formation of organoids through the "self-assembly" of human mammary epithelial cells. Experimental bioprinting procedures were optimized to enable the formation of controlled arrays of individual mammary organoids. We define the distance and cell number parameters necessary to print individual organoids that do not interact between print locations as well as those required to generate large contiguous organoids connected through multiple print locations. RESULTS: We demonstrate that as few as 10 cells can be used to form 3D mammary structures in a single print and that prints up to 500 MUm apart can fuse to form single large structures. Using these fusion parameters, we demonstrate that both linear and non-linear (contiguous circles) can be generated with sizes of 3 mm in length/diameter. We confirm that cells from individual prints interact to form structures with a contiguous lumen. Finally, we demonstrate that organoids can be printed into human collagen hydrogels, allowing for all-human 3D culture systems. CONCLUSIONS: Our platform is adaptable to different culturing protocols and is superior to traditional random 3D culture techniques in efficiency, reproducibility, and scalability. Importantly, owing to the low-cost accessibility and computer numerical control-driven platform of our 3D bioprinter, we have the ability to disseminate our experiments with absolute precision to interested laboratories. PMID- 30305140 TI - Chemokine analysis as a novel diagnostic modality in the early prediction of the outcome of non-union therapy: a matched pair analysis. AB - BACKGROUND: Despite the regenerative capability of skeletal tissue fracture, non union is common. Treatment of non-unions remains challenging, and early determination of the outcome is impossible. Chemokines play an important role in promoting the formation of new bone and remodeling existing bone. Despite their importance regarding the regulation of bone biology, the potential of chemokines as biological markers reflecting osseous regeneration is unknown. The purpose of this study was to determine (1) if serum chemokine expression levels correlate with the outcome of non-union surgery and (2) if chemokine expression analysis can be used to identify patients at risk for treatment failure. METHODS: Non union patients receiving surgical therapy in our institution between March 2012 and March 2014 were prospectively enrolled in a clinical observer study. Regular clinical and radiological follow-up was conducted for 12 months including collection of blood during the first 12 weeks. Based on the outcome, patients were declared as responders or non-responders to the therapy. To minimize biases, patients were matched (age, sex, body mass index (BMI)) and two groups of patients could be formed: responders (R, n = 10) and non-responders (NR, n = 10). Serum chemokine expression (CCL-2, CCL-3, CCL-4, CXCL-10, CCL-11, and interferon gamma (IFN-gamma)) was analyzed using Luminex assays. Data was compared and correlated to the outcome. RESULTS: CCL-3 expression in NR was significantly higher during the course of the study compared to R (p = 0.002), and the expression pattern of CCL-4 correlated with CCL-3 in both groups (NR: p < 0.001 and r = 0.63). IFN-gamma expression in NR was continuously higher than in R (p < 0.001), and utilization of CCL-3 and IFN-gamma serum expression levels 2 weeks after the treatment resulted in a predictive model that had an AUC of 0.92 (CI 0.74-1.00). CONCLUSION: Serum chemokine expression analysis over time is a valid and promising diagnostic tool. The chemokine expression pattern correlates with the outcome of the Masquelet therapy of lower limb non-unions. Utilization of the serum analysis of CCL-3 and IFN-gamma 2 weeks after the treatment resulted in an early predictive value regarding the differentiation between patients that are likely to heal and those that are prone to high risk of treatment failure. PMID- 30305141 TI - Visualisation and characterisation of mononuclear phagocytes in the chicken respiratory tract using CSF1R-transgenic chickens. AB - The respiratory tract is a key organ for many avian pathogens as well as a major route for vaccination in the poultry industry. To improve immune responses after vaccination of chickens through increased uptake of vaccines and targeting to antigen presenting cells, a better understanding of the avian respiratory immune system is required. Transgenic MacReporter birds were used expressing a reporter gene (eGFP or mApple) under the control of the CSF1R promoter and enhancer in cells of the mononuclear phagocyte (MNP) lineage to visualize the ontogeny of the lymphoid tissue, macrophages and dendritic cells, in the trachea, lung and air sac of birds from embryonic day 18-63 weeks of age. Small aggregates of CSF1R transgene+ cells start to form at the openings of the secondary bronchi at 1 week of age, indicative of the early development of the organised bronchus-associated lymphoid tissue. Immunohistochemical staining revealed subpopulations of MNPs in the lung, based on expression of CSF1R-transgene, CD11, TIM4, LAMP1, and MHC II. Specialised epithelial cells or M cells covering the bronchus-associated lymphoid tissue expressed CSF1R-transgene and type II pneumocytes expressed LAMP1 suggesting that these epithelial cells are phagocytic and transcytose antigen. Highly organised lymphoid tissue was seen in trachea from 4 weeks onwards. Throughout the air sacs at all ages, CSF1R-transgene+ cells were scattered and at later stages, CSF1R-transgene+ cells lined capillaries. These results will serve as a base for further functional characterization of macrophages and dendritic cells and their role in respiratory diseases and vaccine responses. PMID- 30305143 TI - Investigating psychometric properties and dimensional structure of an educational environment measure (DREEM) using Mokken scale analysis - a pragmatic approach. AB - BACKGROUND: Questionnaires and surveys are used throughout medical education. Nevertheless, measuring psychological attributes such as perceptions of a phenomenon among individuals may be difficult. The aim of this paper is to introduce the basic principles of Mokken scale analysis (MSA) as a method for the analysis of questionnaire data and to empirically apply MSA to a real-data example. METHODS: MSA provides a set of statistical tools for exploring the relationship between items and latent traits. MSA is a scaling method of item selection algorithms used to partition an array of items into scales. It employs various methods to probe the assumptions of two nonparametric item response theory models: the monotone homogeneity model and the double monotonicity model. The background and theoretical framework underlying MSA are outlined in the paper. MSA for polytomous items was applied to a real-life data example of 222 undergraduate students who had completed a 50-item self-administered inventory measuring the educational environment, the Dundee Ready Educational Measure (DREEM). RESULTS: A pragmatic and parsimonious approach to exploring questionnaires and surveys from an item response theory (IRT) perspective is outlined. The use of MSA to explore the psychometric properties of the Swedish version of the DREEM failed to yield strong support for the scalability and dimensional structure of the instrument. CONCLUSIONS: MSA, a class of simple nonparametric IRT models - for which estimates can be easily obtained and whose fit to data is relatively easily investigated - was introduced, presented, and tested. Our real-data example suggests that the psychometric properties of DREEM are not adequately supported. Thus, the empirical application depicted a potential and feasible approach whereby MSA could be used as a valuable method for exploring the behavior of scaled items in response to varying levels of a latent trait in medical education research. PMID- 30305142 TI - Improved simplified clinical algorithm for identifying patients eligible for immediate initiation of antiretroviral therapy for HIV (SLATE II): protocol for a randomized evaluation. AB - BACKGROUND: The World Health Organization recommends rapid (<= 7 days) or same day initiation of antiretroviral treatment (ART) for HIV-positive patients. South Africa adopted this recommendation in 2017, but multiple clinic visits, long waiting times, and delays for laboratory tests remain common. Streamlined approaches to same-day initiation that allow the majority of patients to start ART immediately, while ensuring that patients who do require additional services receive them, are needed to achieve national and international treatment program goals. METHODS/DESIGN: The SLATE II (Simplified Algorithm for Treatment Eligibility) study is an individually randomized evaluation of a clinical algorithm to reliably determine a patient's eligibility for immediate ART initiation without waiting for laboratory results or additional clinic visits. It differs from the earlier SLATE I study in management of patients with symptoms of tuberculosis (under SLATE II these patients may be started on ART immediately) and other criteria for immediate initiation. SLATE II will randomize (1:1) 600 adult, HIV-positive patients who present for HIV testing or care and are not yet on ART in South Africa. Patients randomized to the standard arm will receive standard-of-care ART initiation from clinic staff. Patients randomized to the intervention arm will be administered a symptom report, medical history, brief physical exam, and readiness assessment. Symptomatic patients will also have a tuberculosis (TB) module with lipoarabinomannan antigen of mycobacteria test. Patients who have satisfactory results for all four components will be dispensed antiretrovirals (ARVs) immediately, at the same clinic visit. Patients who have any negative results will be referred for further investigation, care, counseling, tests, or other services prior to being dispensed ARVs. Follow-up will be by passive medical record review. The primary outcomes will be ART initiation in <= 7 days and retention in care 8 months after study enrollment. DISCUSSION: SLATE II improves upon the SLATE I study by reducing the number of reasons for delaying ART initiation and allowing more patients with TB symptoms to start ART on the day of diagnosis. If successful, SLATE II will provide a simple and streamlined approach that can readily be adopted in other settings without investment in additional technology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03315013 . Registered on 19 October 2017. PMID- 30305144 TI - The role of insulin receptor substrate 1 gene polymorphism Gly972Arg as a risk factor for ischemic stroke among Indonesian subjects. AB - OBJECTIVE: The identification of new genetic-associated risk factor of ischemic stroke could improves strategies for stroke prevention. This study aims to identify insulin receptor substrate 1 (IRS-1) gene polymorphism Gly972Arg as the risk factor for ischemic stroke among Indonesian subjects. The case-control study was conducted by matching the gender and race on 85 cases of patients with ischemic stroke and 86 healthy non-stroke control subjects. Ischemic stroke was established by the complete neurology examination and brain computed tomography scan or magnetic resonance imaging. Polymerase chain reaction-Restriction Fragment Length Polymorphism was performed to analyze IRS-1 gene Gly972Arg genotype. RESULTS: There were 85 ischemic stroke cases and 86 control subjects. The distribution of nucleotide IRS-1 gene polymorphism Gly972Arg in the ischemic stroke vs health controls for GG were 32.2% vs 41.5%, for GR were 16% vs 7.6%, and for RR were 0.5% vs 1.9%. IRS-1 gene polymorphism Gly972Arg was found as significant risk factor for ischemic stroke [odds ratio of 2.6 (1.27-5.27); CI 95%, p = 0.008]. Conclusively, the IRS-1 gene polymorphism Gly972Arg should be considered as an important factor in the prevention and treatment of ischemic stroke. PMID- 30305145 TI - Poliovirus excretion following vaccination with live poliovirus vaccine in patients with primary immunodeficiency disorders: clinicians' perspectives in the endgame plan for polio eradication. AB - OBJECTIVE: Primary immunodeficiency (PID) patients are prone to developing viral infections and should not be vaccinated with live vaccines. In such patients, prolonged excretion and viral divergence may occur and they may subsequently act as reservoirs in the community introducing mutated virus and jeopardizing polio eradication. One hundred and thirty PID cases were included for poliovirus detection in stool with assessment of divergence of detected polioviruses from oral polio vaccine (OPV) virus. Clinical presentations of PID patients with detectable poliovirus in stool specimens are described. RESULTS: Six PID patients (4.5%) had detectable vaccine-derived poliovirus (VDPV) excretion in stool specimens; of these, five patients had severe combined immunodeficiency (two with acute flaccid paralysis, one with meningoencephalitis and two without neurological manifestations), and one patient had X-linked agammaglobulinemia (paralysis developed shortly after diagnosis of immunodeficiency). All six case patients received trivalent OPV. Five case-patients had type 2 immunodeficiency related vaccine-derived polioviruses (iVDPV2) excretion; one had concomitant excretion of Sabin like type 3 virus and one was identified as iVDPV1 excretor. Surveillance for poliovirus excretion among PID patients is critical as these patients represent a potential source to reseed polioviruses into populations. PMID- 30305146 TI - A study of target effect sizes in randomised controlled trials published in the Health Technology Assessment journal. AB - BACKGROUND: When designing a randomised controlled trial (RCT), an important consideration is the sample size required. This is calculated from several components; one of which is the target difference. This study aims to review the currently reported methods of elicitation of the target difference as well as to quantify the target differences used in Health Technology Assessment (HTA)-funded trials. METHODS: Trials were identified from the National Institute of Health Research Health Technology Assessment journal. A total of 177 RCTs published between 2006 and 2016 were assessed for eligibility. Eligibility was established by the design of the trial and the quality of data available. The trial designs were parallel-group, superiority RCTs with a continuous primary endpoint. Data were extracted and the standardised anticipated and observed effect size estimates were calculated. Exclusion criteria was based on trials not providing enough detail in the sample size calculation and results, and trials not being of parallel-group, superiority design. RESULTS: A total of 107 RCTs were included in the study from 102 reports. The most commonly reported method for effect size derivation was a review of evidence and use of previous research (52.3%). This was common across all clinical areas. The median standardised target effect size was 0.30 (interquartile range: 0.20-0.38), with the median standardised observed effect size 0.11 (IQR 0.05-0.29). The maximum anticipated and observed effect sizes were 0.76 and 1.18, respectively. Only two trials had anticipated target values above 0.60. CONCLUSION: The most commonly reported method of elicitation of the target effect size is previous published research. The average target effect size was 0.3. A clear distinction between the target difference and the minimum clinically important difference is recommended when designing a trial. Transparent explanation of target difference elicitation is advised, with multiple methods including a review of evidence and opinion-seeking advised as the more optimal methods for effect size quantification. PMID- 30305147 TI - Proportional decline of Anopheles quadriannulatus and increased contribution of An. arabiensis to the An. gambiae complex following introduction of indoor residual spraying with pirimiphos-methyl: an observational, retrospective secondary analysis of pre-existing data from south-east Zambia. AB - BACKGROUND: Across most of sub-Saharan Africa, malaria is transmitted by mosquitoes from the Anopheles gambiae complex, comprising seven morphologically indistinguishable but behaviourally-diverse sibling species with ecologically distinct environmental niches. Anopheles gambiae and An. arabiensis are the mostly widely distributed major malaria vectors within the complex, while An. quadriannulatus is sparsely distributed. METHODS: Indoor residual spraying (IRS) with the organophosphate pirimiphos-methyl (PM) was conducted four times between 2011 and 2017 in the Luangwa Valley, south-east Zambia. Anopheles mosquitoes were repeatedly collected indoors by several experiments with various objectives conducted in this study area from 2010 onwards. Indoor mosquito collection methods included human landing catches, Centres for Disease Control and Prevention miniature light traps and back pack aspirators. Anopheles gambiae complex mosquitoes were morphologically identified to species level using taxonomic keys, and to molecular level by polymerase chain reaction. These multi study data were collated so that time trends in the species composition of this complex could be assessed. RESULTS: The proportion of indoor An. gambiae complex accounted for by An. quadriannulatus declined from 95.1% to 69.7% following two application PM-IRS rounds with an emulsifiable concentrate formulation from 2011 to 2013, while insecticidal net utilisation remained consistently high throughout that period. This trend continued after two further rounds of PM-IRS with a longer-lasting capsule suspension formulation in 2015 and 2016/2017, following which An. quadriannulatus accounted for only 4.5% of the complex. During the same time interval there was a correspondingly steady rise in the proportional contribution of An. arabiensis to the complex, from 3.9 to 95.1%, while the contribution of nominate An. gambiae remained stable at <= 0.9%. CONCLUSION: It seems likely that An. arabiensis is not only more behaviourally resilient against IRS than An. gambiae, but also than An. quadriannulatus populations exhibiting indoor-feeding, human-feeding and nocturnal behaviours that are unusual for this species. Routine, programmatic entomological monitoring of dynamic vector population guilds will be critical to guide effective selection and deployment of vector control interventions, including supplementary measures to tackle persisting vectors of residual malaria transmission like An. arabiensis. PMID- 30305148 TI - Psychological Support for Personality (PSP) versus treatment as usual: study protocol for a feasibility randomized controlled trial of a low intensity intervention for people with personality disorder. AB - BACKGROUND: Previous research has demonstrated the clinical effectiveness of long term psychological treatment for people with some types of personality disorder. However, the high intensity and cost of these interventions limit their availability. Lower-intensity interventions are increasingly being offered to people with personality disorder, but their clinical and cost effectiveness have not been properly tested in experimental studies. We therefore set out to develop a low intensity intervention for people with personality disorder and to test the feasibility of conducting a randomized controlled trial to compare the clinical effectiveness of this intervention with that of treatment as usual (TAU). METHODS: A two-arm, parallel-group, single-blind, randomized controlled trial of Psychological Support for Personality (PSP) versus TAU for people aged over 18 years, who are using secondary care mental health services and have personality disorder. We will exclude people with co-existing organic or psychotic mental disorders (dementia, bipolar affective disorder, delusional disorder, schizophrenia, schizoaffective disorder, or schizotypal disorder), those with cognitive or language difficulties that would preclude them from providing informed consent or compromise participation in study procedures, and those who are already receiving psychological treatment for personality disorder. Participants will be randomized via a remote system in a ratio of PSP to TAU of 1:1. Randomization will be stratified according to the referring team and gender of the participant. A single follow-up assessment will be conducted by masked researchers 24 weeks after randomization to assess mental health (using the Warwick and Edinburgh Well-Being Schedule), social functioning (using the Work and Social Adjustment Scale), health-related quality of life (EQ-5D-5 L), incidence of suicidal behavior, satisfaction with care (Client Satisfaction Questionnaire), and resource use and costs using a modified version of the Adult Service Use Schedule. In addition to this, each participant will be asked to complete the patient version of the Clinical Global Impression Scale. Feasibility and acceptability will primarily be judged by study recruitment rate and engagement and retention in treatment. The analysis will focus principally on descriptive data on the rate of recruitment, characteristics of participants, attrition, adherence to therapy, and follow-up. We will explore the distribution of study outcomes to investigate assumptions of normality in order to plan the analysis and sample size of a future definitive trial. DISCUSSION: Most people with personality disorder do not currently receive evidence-based interventions. While a number of high intensity psychological treatments have been shown to be effective, there is an urgent need to develop effective low intensity approaches to help people unable to use existing treatments. PSP is a low intensity intervention for individuals, which was developed following extensive consultation with users and providers of services for people with personality disorder. This study aims to examine the feasibility of a randomized trial of PSP compared to TAU for people with personality disorder. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN14994755 . Registered on 18 July 2017. PMID- 30305149 TI - Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. AB - BACKGROUND: The optimal strategy for adjuvant therapy after curative resection for hepatocellular carcinoma (HCC) patients with solitary tumor and microvascular invasion (MVI) is controversial. This trial evaluated the efficacy and safety of adjuvant transcatheter arterial chemoembolization (TACE) after hepatectomy versus hepatectomy alone in HCC patients with a solitary tumor >= 5 cm and MVI. METHODS: In this randomized, open-labeled, phase III trial, HCC patients with a solitary tumor >= 5 cm and MVI were randomly assigned (1:1) to receive either 1-2 cycles of adjuvant TACE after hepatectomy (Hepatectomy-TACE) or hepatectomy alone (Hepatectomy Alone). The primary endpoint was disease-free survival (DFS); the secondary endpoints included overall survival (OS) and adverse events. RESULTS: Between June 1, 2009, and December 31, 2012, 250 patients were enrolled and randomly assigned to the Hepatectomy-TACE group (n = 125) or the Hepatectomy Alone group (n = 125). Clinicopathological characteristics were balanced between the two groups. The median follow-up time from randomization was 37.5 months [interquartile range 18.3-48.2 months]. The median DFS was significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [17.45 months (95% confidence interval [CI] 11.99-29.14) vs. 9.27 months (95% CI 6.05-13.70), hazard ratio [HR] = 0.70 (95% CI 0.52-0.95), P = 0.020], respectively. The median OS was also significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [44.29 months (95% CI 25.99-62.58) vs. 22.37 months (95% CI 10.84-33.91), HR = 0.68 (95% CI 0.48-0.97), P = 0.029]. Treatment-related adverse events were more frequently observed in the Hepatectomy-TACE group, although these were generally mild and manageable. The most common grade 3 or 4 adverse events in both groups were neutropenia and liver dysfunction. CONCLUSION: Hepatectomy followed by adjuvant TACE is an appropriate option after radical resection in HCC patients with solitary tumor >= 5 cm and MVI, with acceptable toxicity. PMID- 30305150 TI - Evaluation of methods to detect in vitro biofilm formation by staphylococcal clinical isolates. AB - OBJECTIVE: Staphylococcus genus comprising both Staphylococcus aureus and coagulase negative staphylococci (CoNS) are widely distributed in nature and can infect diversity of hosts. Indeed, staphylococci are the major pathogens causing biofilm associated infections caused by contaminated hospital indwelling devices. These infections are persistent in nature being highly refractory to various stresses including antibiotics. Implementation of efficient diagnostic techniques for the biofilm production would help minimize the disease burden. Thus, early detection of pathogenic strains producing biofilms warrant the utmost importance in diagnostic laboratories especially in resource limited settings. RESULT: Among 375 isolates collected from different clinical specimens, 214 (57%) were identified as coagulase negative staphylococci and 161 (43%) S. aureus. Detection of In-vitro biofilm formation in these isolates were carried out by three commonly used phenotypic assays and a genotypic assay. While evaluating the results, tissue-culture method with supplemented glucose and sucrose showed the best correlation with the results of genotypic assay. PMID- 30305152 TI - Advanced colorectal carcinoma with testicular metastasis in an adolescent: a case report. AB - BACKGROUND: Colorectal carcinoma in the pediatric age group is rare and tends to be very aggressive and present late, due to which it has a very poor prognosis. It may present with distant metastasis; however, metastasis to the testes is very rare and signifies an advanced stage of the disease. Surgery is the only effective modality to cure patients with localized colorectal carcinomas. However, statistics show a higher incidence of unresectable disease and a higher metastasis rate in childhood colorectal carcinomas. We present a case of advanced colorectal carcinoma with testicular metastasis in an adolescent. CASE PRESENTATION: A 15-year-old Indian Hindu boy presented to surgical emergency with signs and symptoms of intestinal obstruction. He also had a history of passing blood and mucus per rectum. On examination he had abdominal distension. On digital rectal examination, a circumferential proliferative growth was felt 1 cm above the anal verge. On scrotal examination, a small nodule was felt in his right testis. In view of intestinal obstruction, he was taken into our emergency operation theater and a diverting loop sigmoid colostomy was performed to relieve the obstruction. A punch biopsy from anorectal growth was taken which suggested signet ring cell adenocarcinoma. Contrast-enhanced computed tomography of his chest, abdomen, and pelvis showed advanced colorectal carcinoma with distant metastasis. Ultrasonography of his testes showed a hypoechoic nodule in the right testis from which a needle aspiration biopsy was done which revealed metastatic adenocarcinoma. CONCLUSIONS: Childhood colorectal carcinomas have a very poor prognosis due to their aggressive nature and late presentation. In spite of all the advances in diagnosis and treatments, the overall long-term survival is still dismal in these patients. Due to the rarity of this disease, screening is not recommended for individuals under the age of 50. Thus, to improve outcome, early diagnosis and treatment is paramount. For that to happen, awareness needs to be created regarding pediatric colorectal carcinoma and its signs and symptoms. PMID- 30305151 TI - Aerobic exercise program with or without motor complexity as an add-on to the pharmacological treatment of depression - study protocol for a randomized controlled trial. AB - BACKGROUND: Patients with major depression disorder presents increased rates of cognitive decline, reduced hippocampal volume, poor sleep quality, hypertension, obesity, suicidal ideation and behavior, and decreased functionality. Although continuous aerobic exercise (CAE) improves some of the aforementioned symptoms, comorbidities, and conditions, recent studies have suggested that performing aerobic exercise with motor complexity (AEMC) may be more beneficial for cognitive decline, hippocampal volume, and functionality. Therefore, this randomized controlled trial will compare the effects of CAE and AEMC on depression score, cognitive function, hippocampal volume, brain-derived neurotrophic factor expression, sleep parameters, cardiovascular risk parameters, suicidal behavior, functionality, and treatment costs in patients with depression. METHODS/DESIGN: Seventy-five medicated patients with depression will be recruited from a Basic Healthcare Unit to participate in this prospective, parallel group, single blinded, superiority, randomized controlled trial. Patients with depression according to DSM-V criteria will be balanced and randomly assigned (based on depression scores and number of depressive episodes) to a non-exercising control (C), CAE, and AEMC groups. The CAE and AEMC groups will exercise for 60 min, twice a week for 24 weeks (on non-consecutive days). Exercise intensity will be maintained between 12 and 14 points of the rating of perceived exertion scale (~ 70-80% of the maximum heart rate). The CAE group will perform a continuous aerobic exercise while the AEMC group will perform exercises with progressively increased motor complexity. Blinded raters will assess patients before and after the intervention period. The primary outcome measure will be the change in depression score measured by the Montgomery-Asberg Depression Rating Scale. Secondary outcomes will include measures of cognitive function, hippocampal volume, brain-derived neurotrophic factor expression, sleep parameters, cardiovascular risk parameters, suicidal behavior, functionality, and treatment costs. DISCUSSION: This study was selected in the call of public policy programs for the Brazilian Unified National Health System - "PPSUS 2015". To our knowledge, this is the first pragmatic trial to test the effect of adding AEMC to the pharmacological treatment of patients with depression and to evaluate the possible reductions in depression symptoms and healthcare costs. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (ReBec) - RBR-9zgxzd - Registered on 4 Jan. 2017. PMID- 30305153 TI - Cognitive aids for people with early stage dementia versus treatment as usual (Dementia Early Stage Cognitive Aids New Trial (DESCANT)): study protocol for a randomised controlled trial. AB - BACKGROUND: There is a growing need for an evidence-based approach to home support for people with dementia and their carers following diagnosis but research on the effectiveness and cost-effectiveness of different approaches is sparse. The Dementia Early Stage Cognitive Aids New Trial (DESCANT) will evaluate the clinical and cost-effectiveness of a range of memory aids, training and support to people with mild to moderate dementia and their carers at home and compares that intervention with treatment as usual. METHODS/DESIGN: This is a multi-site, pragmatic randomised trial preceded by a feasibility study and internal pilot. We aim to allocate at random 360 pairs comprising a person with mild to moderate dementia and an identified carer between the DESCANT intervention and treatment as usual. We assess participants at baseline, 13 and 26 weeks. The primary outcome measure is the Bristol Activities of Daily Living Scale; other participant outcomes include cognition, quality of life, activities of daily living and social networking; carer outcomes include quality of life, sense of competence and mental health. To enhance this quantitative evaluation we are conducting a qualitative component and a process evaluation to assess the implementation process and identify contextual factors associated with variation. DISCUSSION: The DESCANT intervention reflects current policy to enhance the capabilities of people with dementia after diagnosis and their carers. If it is clinically and cost-effective, its modest nature and cost will enhance the likelihood of it being incorporated into mainstream practice. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN12591717 . Registered on 29 July 2016. Protocol number: 31288: North West - Haydock Research Ethics Committee, 20/06/2016, ref.: 16/NW/0389. PMID- 30305155 TI - Choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial - the development of the DELTA2 guidance. AB - BACKGROUND: A key step in the design of a randomised controlled trial is the estimation of the number of participants needed. The most common approach is to specify a target difference in the primary outcome between the randomised groups and then estimate the corresponding sample size. The sample size is chosen to provide reassurance that the trial will have high statistical power to detect the target difference at the planned statistical significance level. Alternative approaches are also available, though most still require specification of a target difference. The sample size has many implications for the conduct of the study, as well as incurring scientific and ethical aspects. Despite the critical role of the target difference for the primary outcome in the design of a randomised controlled trial (RCT), the manner in which it is determined has received little attention. This article reports the development of the DELTA2 guidance on the specification and reporting of the target difference for the primary outcome in a sample size calculation for a RCT. METHODS: The DELTA2 (Difference ELicitation in TriAls) project has five components comprising systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2), a Delphi study (stage 3), a 2-day consensus meeting bringing together researchers, funders and patient representatives (stage 4), and the preparation and dissemination of a guidance document (stage 5). RESULTS: The project started in April 2016. The literature search identified 28 articles of methodological developments relevant to a method for specifying a target difference. A Delphi study involving 69 participants, along with a 2-day consensus meeting were conducted. In addition, further engagement sessions were held at two international conferences. The main guidance text was finalised on April 18, 2018, after revision informed by feedback gathered from stages 2 and 3 and from funder representatives. DISCUSSION: The DELTA2 Delphi study identified a number of areas (such as practical recommendations and examples, greater coverage of different trial designs and statistical approaches) of particular interest amongst stakeholders which new guidance was desired to meet. New relevant references were identified by the review. Such findings influenced the scope, drafting and revision of the guidance. While not all suggestions could be accommodated, it is hoped that the process has led to a more useful and practical document. PMID- 30305154 TI - Prophylactic management of postpartum haemorrhage in the third stage of labour: an overview of systematic reviews. AB - BACKGROUND: Postpartum haemorrhage is a direct cause of maternal death worldwide and usually occurs during the third stage of labour. Most women receive some type of prophylactic management, which may include pharmacological or non pharmacological interventions. The objective of this study was to summarize systematic reviews that assessed the effects of postpartum haemorrhage prophylactic management during the third stage of labour. METHODS: We applied the guidelines for conducting an overview of reviews from the Cochrane Handbook for Systematic Reviews of Interventions. We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews to identify all relevant systematic reviews of randomized controlled trials of prophylactic management of postpartum haemorrhage in the third stage of labour compared with no treatment, placebo, or another management technique. Two review authors independently extracted data and assessed methodological quality using a measurement tool to assess reviews and quality of evidence using the Grades of Recommendation, Assessment, Development, and Evaluation for primary outcomes, summarizing results narratively. RESULTS: We identified 29 systematic reviews: 18 Cochrane and 11 non-Cochrane. Cochrane systematic reviews were high quality, while the quality of non-Cochrane systematic reviews varied. The following techniques suggested effective, third stage interventions to reduce the incidence of severe postpartum haemorrhage: active management of the third stage of labour compared to physiological management, active management compared to expectant management, administration of oxytocin compared to placebo, and use of tranexamic acid compared to placebo. The following third-stage management approaches reduced the need for blood transfusion: active management compared to physiological management, active management compared to expectant management, oral misoprostol compared to placebo, and tranexamic acid compared to placebo. CONCLUSIONS: No effective prophylactic management techniques were identified for maternal mortality. Most methods of effective prophylactic management of postpartum haemorrhage were supported by evidence; however, they were limited to low- or moderate-quality evidence, and high-quality studies are therefore needed. Outcome measures of the included systematic reviews varied. It is recommended that outcome measures in preventive postpartum haemorrhage intervention trials align with the World Health Organization guidelines. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42016049220 . PMID- 30305156 TI - What is the value of musculoskeletal ultrasound in patients presenting with arthralgia to predict inflammatory arthritis development? A systematic literature review. AB - OBJECTIVE: Musculoskeletal ultrasound (US) is frequently used in several rheumatology practices to detect subclinical inflammation in patients with joint symptoms suspected for progression to inflammatory arthritis. Evaluating the scientific basis for this specific US use, we performed this systematic literature review determining if US features of inflammation are predictive for arthritis development and which US features are of additive value to other, regularly used biomarkers. METHODS: Medical literature databases were systematically searched up to May 2017 for longitudinal studies reporting on the association between greyscale (GSUS) and Power Doppler (PDUS) abnormalities and inflammatory arthritis development in arthralgia patients. Quality of studies was assessed by two independent reviewers using a set of 18 criteria. Studies were marked high quality if scored >= 80.6% (which is the median score). Best-evidence synthesis was performed to determine the level of evidence (LoE). Positive and negative likelihood ratios (LR+, LR-) were determined. RESULTS: Of 3061 unique references, six fulfilled inclusion criteria (three rated high quality), of which two reported on the same cohort. Heterogeneity in arthralgia populations, various US machines and scoring systems hampered the comparability of results. LoE for GSUS as predictor was limited and moderate for PDUS; LoE for the additive value of GSUS and PDUS with other biomarkers was limited to moderate. Estimated LR+ values were mostly < 4 and LR- values > 0.5. CONCLUSIONS: Data on the value of GSUS and PDUS abnormalities for predicting inflammatory arthritis development are sparse. Although a potential benefit is not excluded, current LoE is limited to moderate. Future studies are required, preferably performed in clearly defined, well-described arthralgia populations, using standardized US acquisition protocols and scoring systems. PMID- 30305158 TI - Persistence and adverse events of biological treatment in adult patients with juvenile idiopathic arthritis: results from BIOBADASER. AB - BACKGROUND: Biologic therapy has changed the prognosis of patients with juvenile idiopathic arthritis (JIA). The aim of this study was to examine the pattern of use, drug survival, and adverse events of biologics in patients with JIA during the period from diagnosis to adulthood. METHODS: All patients included in BIOBADASER (Spanish Registry for Adverse Events of Biological Therapy in Rheumatic Diseases), a multicenter prospective registry, diagnosed with JIA between 2000 and 2015 were analyzed. Proportions, means, and SDs were used to describe the population. Incidence rates and 95% CIs were calculated to assess adverse events. Kaplan-Meier analysis was used to compare the drug survival rates. RESULTS: A total of 469 patients (46.1% women) were included. Their mean age at diagnosis was 9.4 +/- 5.3 years. Their mean age at biologic treatment initiation was 23.9 +/- 13.9 years. The pattern of use of biologics during their pediatric years showed a linear increase from 24% in 2000 to 65% in 2014. Biologic withdrawal for disease remission was higher in patients who initiated use biologics prior to 16 years of age than in those who were older (25.7% vs 7.9%, p < 0.0001). Serious adverse events had a total incidence rate of 41.4 (35.2-48.7) of 1000 patient-years. Patients younger than 16 years old showed significantly increased infections (p < 0.001). CONCLUSIONS: Survival and suspension by remission of biologics were higher when these compounds were initiated in patients with JIA who had not yet reached 16 years of age. The incidence rate of serious adverse events in pediatric vs adult patients with JIA treated with biologics was similar; however, a significant increase of infection was observed in patients under 16 years old. PMID- 30305159 TI - Correlates of facility-based delivery among women of reproductive age from the Digo community residing in Kwale, Kenya. AB - OBJECTIVE: This study sought to describe factors associated with facility-based delivery among women of reproductive age in Kwale County, Kenya. RESULTS: Between March and December 2015, 745 women from 15 villages were interviewed through a cross-sectional household survey. Respondents were selected using stratified, systematic sampling and completed a sexual and reproductive health questionnaire. Of 632 (85%) women who had a previous birth, 619 (98%) reported antenatal care attendance. Of these, 491 (79%) subsequently had a facility-based delivery. Factors associated with increased likelihood of facility delivery included respondent's education (odds ratio, OR = 2.0, 95% confidence interval, CI 1.2 3.2, P = 0.004), ideal antenatal care attendance (OR = 2.3, 95% CI 1.4-3.7, P = 0.001) and pregnancy intention (OR = 1.5, 95% CI 1.0-2.2, P = 0.040). Being in a polygamous relationship (OR = 0.6, 95% CI 0.3-0.9, P = 0.024) and having a husband >= 40 years (OR = 0.5, 95% CI 0.3-0.9, P = 0.013) were associated with reduced likelihood of facility delivery. Respondent's education (aOR = 1.9, 95% CI 1.1-3.3, P = 0.030) as well as ideal ANC attendance (aOR = 2.0, 95% CI 1.0 3.8, P = 0.040) remained significantly associated with facility delivery in multivariate analyses. PMID- 30305157 TI - Sex influences the association between haemostasis and the extent of lung lesions in tuberculosis. AB - BACKGROUND: Worldwide tuberculosis (TB) reports show a male bias in morbidity; however, the differences in pathogenesis between men and women with TB, as well as the mechanisms associated with such differences, are poorly investigated. We hypothesized that comparison of the degree of lung injury and clinical indices of well-matched men and women with newly diagnosed TB, and statistical analysis of the correlation between these indices and the extent of lung lesions, can provide insights into the mechanism of gender bias in TB. METHODS: We evaluated the acid fast bacilli grading of sputum samples and compiled computed tomography (CT) data of the age-matched, newly diagnosed male and female TB patients without history of smoking or comorbidities. Inflammatory biomarker levels and routine haematological and coagulation-associated parameters were compared. Binary logistic regression analysis was used to define the association between the indices and lung lesions, and the influence of sex adjustment. RESULTS: Women with TB have a longer delay in seeking healthcare than men after onset of the TB associated symptoms. Men with TB have significantly more severe lung lesions (cavities and healing-associated features) and higher bacterial counts compared to women with TB. Scoring of the CT images before and after anti-TB treatment showed a faster response to therapy in women than in men. Coagulation- and platelet-associated indices were in models from multivariate regression analysis with groups of males or females with TB or in combination. In univariate regression analysis, lower lymphocyte counts were associated with both cavity and more bacterial counts, independent of sex, age and BMI. The association of international normalized ratios (INR), prothrombin times (PTs), mean platelet volumes (MPVs) and fibrinogen (FIB) level with lung lesions was mostly influenced by sex adjustment. CONCLUSIONS: Sex influences the association between haemostasis and extent of TB lung lesions, which may be one mechanism involved in sex bias in TB pathogenesis. PMID- 30305160 TI - Lumen-apposing metal stents (LAMS) versus plastic stents for EUS-guided drainage of walled-off necrosis (WON) (LVPWON): study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Endoscopic ultrasonography (EUS)-guided drainage has become the first line therapy for late peri-pancreatic fluid collection (PFC). Double pigtail plastic stents (DPPS) and lumen-apposing metal stents (LAMS) are commonly used for PFC drainage. Recently, a multi-institutional consensus on PFC drainage has recommended that LAMS should be the standard care for patients with walled-off necrosis (WON). However, given the poor quality of evidence, we aim to perform a large-scale randomized controlled trial to determine whether LAMS is superior to DPPS for WON drainage. METHODS/DESIGN: The study is an open-label, prospective, parallel-group, superiority, multicenter randomized controlled trial. Two hundred and fifty-six patients with WON who will attend 18 tertiary hospitals in China will be randomly allocated to the LAMS or DPPS group before the procedure. The primary endpoint is the clinical success at one month after drainage (reduction in the size of WON to < 2 cm). Secondary endpoints include technical success, operation time, recurrence, adverse events, and secondary interventions. DISCUSSION: The LVPWON trial is designed to determine whether LAMS is effective, safe, and superior to DPPS for WON drainage. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03027895 . Registered on 14 January 2017. PMID- 30305161 TI - Safety culture in the primary health care settings based on workers with a leadership role: the psychometric properties of the Slovenian-language version of the safety attitudes questionnaire - short form. AB - BACKGROUND: Safety culture describes leader and staff interactions, attitudes, routines, awareness, and practices within an organisation. With this study, we aimed to determine the psychometric properties of the Slovenian-language version of the Safety Attitudes Questionnaire (SAQ) - Short Form in primary health care settings. METHODS: This was a cross-sectional study in the largest primary health care in Slovenia. We invited all employees with a leadership role to participate in the study (N = 211). We used the Slovenian-language version of the SAQ - Short Form. RESULTS: There were 154 participants in the final sample (73.0% response rate), of which 136 (88.3%) were women. The mean age of the sample was 46.2 +/- 10.0 years. Exploratory factor analysis put forward six factors: 1) Perceptions of Management; 2) Stress recognition; 3) Teamwork Climate; 4) Communication; 5) Safety Climate; 6) Working Conditions and Satisfaction. This model explained 61.7% of the variance of the safety culture in the primary health care setting. The reliability of the whole scale and of the six factors, assessed using Cronbach's alpha, was all above 0.78. CONCLUSION: The results of our study suggests that the Slovenian-language version of the SAQ - Short Form with six factors could be a reliable and valid tool for measuring the safety culture in the primary health care workers with leadership role In Slovenia. The Slovenian version differed from the original SAQ - Short Form and the majority of other translated versions. Also, the data was from one health centre only and therefore we cannot draw strong conclusions on its external validity. PMID- 30305162 TI - A perforated anodised aluminium slide for improved specimen clearing and imaging for confocal laser scanning microscopy. AB - OBJECTIVE: The bleaching, clearing and handling of tiny specimens with soft tissue and cuticular components for confocal laser scanning microscopy is difficult, because after cuticle bleaching and tissue clearing the specimens are virtually invisible. We have adjusted the design of the specimen container described by Smolla et al. (Arthropod Struct Dev 43:175-81, 2014) to handle tiny specimens. RESULTS: We describe a perforated and anodised aluminium slide that was designed to hold the distal tips of the pedipalp appendages of the spider Parasteatoda tepidariorum during clearing, and that can then be used directly for confocal laser scanning microscopy. We believe that this slide design will be helpful for others who want to visualise specimens between 500 and 800 um with confocal laser scanning microscopy. PMID- 30305163 TI - Spontaneous seizure and partial lethality of juvenile Shank3-overexpressing mice in C57BL/6 J background. AB - The SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene encodes core scaffolds in neuronal excitatory postsynapses. SHANK3 duplications have been identified in patients with hyperkinetic disorders and early-onset generalized tonic-clonic seizures. Consistently, Shank3 transgenic (TG) mice, which mildly overexpress Shank3 proteins exhibit hyperkinetic behavior and spontaneous seizures. However, the seizure phenotype of Shank3 TG mice has only been investigated in adults of the seizure-sensitive strain FVB/N. Therefore, it remains unknown if spontaneous seizures occur in Shank3 TG mice from the early postnatal stages onward, or even in seizure-resistant strains. Clinically, generalized tonic-clonic seizures are the critical risk factor for epilepsy associated mortality. However, the potential association between Shank3 overexpression and mortality, at least in mice, has not been investigated in detail. In the present study, we backcrossed Shank3 TG mice in seizure-resistant C57BL/6 J strain and monitored their home-cage activities at 3 weeks of age. Of the 15 Shank3 TG mice monitored, two exhibited spontaneous tonic-clonic seizures, and one died immediately after the seizure event. Based on this observation, we determined the survival rate of the Shank3 TG mice from 3 to 12 weeks of age. We found that approximately 40-45% of the Shank3 TG mice, both males and females, died before reaching 12 weeks of age. Notably, 53% and 70% of the total deaths in male and female Shank3 TG mice, respectively, occurred in the juvenile stages. These results suggest spontaneous seizure and partial lethality of juvenile Shank3 TG mice in seizure-resistant background, further supporting the validity of this model. PMID- 30305164 TI - Echinococcus granulosus hydatid cyst location is modified by Fasciola hepatica infection in cattle. AB - BACKGROUND: Natural parasite infection occurs in wild and domestics animals with more than one parasite species at the same time, generating an infection called polyparasitism. Cystic echinococcosis reports are usually based only on infection with Echinoccocus granulosus leaving aside other internal parasitoses that could modulate both the immune response and pathogenesis of the natural infection. Fasciola hepatica is another cosmopolitan parasite in ruminants with a similar distribution to E. granulosus in different parts of the world, but no information of the effect of co-infection with E. granulosus has been described. The aims of this report were to establish E. granulosus prevalence and explore the association of F. hepatica co-infection and natural E. granulosus infections in cattle. RESULTS: From 1725 animals, the prevalence of E. granulosus and F. hepatica was 21.16 and 51.3%, respectively. Considering both infections, older cattle (> 4 years) presented higher prevalence compared to younger animals. In E. granulosus-infected cattle, 5.21% had fertile cysts, 71.78% infertile cysts, and in 23.01% cysts were smaller than 1 cm in diameter. Considering cyst location, 39.72% had lungs cysts, 24.72% had liver cysts and 36.94% had cysts in both organs. Cyst location significantly differed between age groups: 44.68% of younger animals had cysts only in the lungs, while older animals presented hydatid cyst in the lungs and liver simultaneously (44.15%). With E. granulosus infection alone, 30.26% of cysts were found in the lungs, 31.79% in the liver and 37.95% in both organs. Regarding the co-infection of E. granulosus with F. hepatica, the proportion was significantly different (P < 0.05) with most animals having cysts only in the lungs (49.41%) and a lower level of liver infection (15.88%). Analyzing organ cyst distribution and F. hepatica absence/presence ratio within each cyst type, small cysts showed the highest difference in ratio. CONCLUSIONS: To the best of our knowledge, this is the first report indicating that F. hepatica co-infection in cattle could be affecting the instate of hydatid cysts in the liver, displacing toward lung localization, suggesting an antagonistic relationship. PMID- 30305166 TI - Multi-scale characterization of symbiont diversity in the pea aphid complex through metagenomic approaches. AB - BACKGROUND: Most metazoans are involved in durable relationships with microbes which can take several forms, from mutualism to parasitism. The advances of NGS technologies and bioinformatics tools have opened opportunities to shed light on the diversity of microbial communities and to give some insights into the functions they perform in a broad array of hosts. The pea aphid is a model system for the study of insect-bacteria symbiosis. It is organized in a complex of biotypes, each adapted to specific host plants. It harbors both an obligatory symbiont supplying key nutrients and several facultative symbionts bringing additional functions to the host, such as protection against biotic and abiotic stresses. However, little is known on how the symbiont genomic diversity is structured at different scales: across host biotypes, among individuals of the same biotype, or within individual aphids, which limits our understanding on how these multi-partner symbioses evolve and interact. RESULTS: We present a framework well adapted to the study of genomic diversity and evolutionary dynamics of the pea aphid holobiont from metagenomic read sets, based on mapping to reference genomes and whole genome variant calling. Our results revealed that the pea aphid microbiota is dominated by a few heritable bacterial symbionts reported in earlier works, with no discovery of new microbial associates. However, we detected a large and heterogeneous genotypic diversity associated with the different symbionts of the pea aphid. Partitioning analysis showed that this fine resolution diversity is distributed across the three considered scales. Phylogenetic analyses highlighted frequent horizontal transfers of facultative symbionts between host lineages, indicative of flexible associations between the pea aphid and its microbiota. However, the evolutionary dynamics of symbiotic associations strongly varied depending on the symbiont, reflecting different histories and possible constraints. In addition, at the intra-host scale, we showed that different symbiont strains may coexist inside the same aphid host. CONCLUSIONS: We present a methodological framework for the detailed analysis of NGS data from microbial communities of moderate complexity and gave major insights into the extent of diversity in pea aphid-symbiont associations and the range of evolutionary trajectories they could take. PMID- 30305168 TI - Limitations in the isolation and stimulation of splenic mononuclear cells in a dasyurid marsupial, Phascogale calura. AB - OBJECTIVE: Marsupials suffer from an increasing number of stressors in this changing world. Functional studies are thus needed to broaden our understanding of the marsupial immune system. The red-tailed phascogale (Phascogale calura) is a small Australian marsupial previously used in descriptive immunological studies. Here, we aimed to develop functional assays by isolating and stimulating blood and spleen mononuclear cells in vitro. RESULTS: While peripheral blood mononuclear cell (PBMC) were relatively easy to isolate, only 105 mononuclear cells (> 90% purity and > 75% viability) could be recovered from the spleen, independently of the sex and age of the animal or the centrifugation time and speed tested. The pores of the mesh sieve used for tissue homogenization might have been too big to yield a single cell suspension. Nevertheless, in spite of the overall low number of cells recovered, PBMC and splenic mononuclear cells were successfully activated in preliminary trials with phytohemaglutinin. This activation state was evidenced by a change in shape and the presence of small cell aggregations in the mitogen-stimulated cultures. A non-radioactive colorimetric assay was also performed to confirm cell proliferation in these wells. This work highlights the importance of developing and reporting detailed methodological protocols in non-traditional research species. PMID- 30305167 TI - Effects of long-term methylphenidate use on growth and blood pressure: results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). AB - BACKGROUND: Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure. METHODS: Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6 15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non ADHD control group regarding low weight (BMI <= 3rd percentile), low height (<=3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (< 11 years/>=11 years, to account for pubertal maturation). Multivariable logistic regression was conducted to test for associations. RESULTS: 4244 boys were included in the study; MPH < 12 months: n = 65 (n = 36 < 11 years), MPH >= 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI <= 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter. CONCLUSION: The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (<=3rd percentile) and changes in blood pressure. PMID- 30305170 TI - Media multitasking is associated with altered processing of incidental, irrelevant cues during person perception. AB - BACKGROUND: Media multitasking (MMT)-using and switching between unrelated forms of media-has been implicated in altered processing of extraneous stimuli, resulting in performance deficits. Here, we sought to extend our prior work to test the hypothesis that MMT might be associated with enhanced processing of incidental environmental cues during person perception. METHOD: We tested the relationship between individual differences in MMT and person perception, by experimentally manipulating the relevance of environmental cues that participants could use to make trait and personality judgements of an unfamiliar social target. Relevant environmental cues consisted of neat or messy arrangements of the target's belongings, whereas irrelevant cues consisted of similarly neat or messy arrangements of the testing room in which participants viewed a video of the target. RESULTS: In general, relevant cues affected ratings of the target's conscientiousness. Additionally, and consistent with our hypothesis, there was a significant interaction between irrelevant cue condition and MMT, such that high media multitaskers more readily incorporated irrelevant environmental cues into their evaluations of the target's conscientiousness. CONCLUSIONS: These results suggest that high media multitaskers are more responsive to irrelevant environmental cues, which in turn can lead them to form inaccurate impressions of others. PMID- 30305169 TI - Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients. AB - BACKGROUND: Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. METHODS: Next generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients. RESULTS: Genetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes. CONCLUSION: Our study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes. PMID- 30305165 TI - Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. AB - The scientific premise, design, and structure-function analysis of chemical-based muscle membrane stabilizing block copolymers are reviewed here for applications in striated muscle membrane injury. Synthetic block copolymers have a rich history and wide array of applications from industry to biology. Potential for discovery is enabled by a large chemical space for block copolymers, including modifications in block copolymer mass, composition, and molecular architecture. Collectively, this presents an impressive chemical landscape to leverage distinct structure-function outcomes. Of particular relevance to biology and medicine, stabilization of damaged phospholipid membranes using amphiphilic block copolymers, classified as poloxamers or pluronics, has been the subject of increasing scientific inquiry. This review focuses on implementing block copolymers to protect fragile muscle membranes against mechanical stress. The review highlights interventions in Duchenne muscular dystrophy, a fatal disease of progressive muscle deterioration owing to marked instability of the striated muscle membrane. Biophysical and chemical engineering advances are presented that delineate and expand upon current understanding of copolymer-lipid membrane interactions and the mechanism of stabilization. The studies presented here serve to underscore the utility of copolymer discovery leading toward the therapeutic application of block copolymers in Duchenne muscular dystrophy and potentially other biomedical applications in which membrane integrity is compromised. PMID- 30305171 TI - Plasma interleukin-37 is increased and inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells in systemic juvenile idiopathic arthritis patients. AB - BACKGROUND: Interleukin (IL)-37 has emerged as a novel anti-inflammatory cytokine that play an immunosuppressive role in regulating inflammatory response. This study aimed to measure IL-37 levels in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with systemic juvenile idiopathic arthritis (sJIA), and to establish the correlation between IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines. METHODS: The mRNA levels of IL-37 in PBMCs and plasma IL-37 concentrations in 46 sJIA patients and 30 age- and sex-matched healthy controls were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The correlations between plasma IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines in sJIA were analyzed by Spearman correlation test. PBMCs from the sJIA patients were stimulated with recombinant human IL-37 (rhIL-37) protein, expressions of IL-1beta, IL-6, TNF alpha and IL-17 were detected by RT-PCR and ELISA. RESULTS: Plasma levels of IL 37 and relative IL-37 mRNA expression were significantly elevated in sJIA patients, especially in active sJIA patients, when compared with the healthy controls (P < 0.001). Furthermore, patients with active disease showed higher IL 37 mRNAs and plasma protein levels than those with inactive disease as well as healthy controls. Plasma IL-37 levels were correlated with disease activity and inflammatory cytokines (IL-6, TNF-alpha, IL-17 and GM-CSF) in sJIA patients. The productions of inflammatory cytokines such as IL-6, TNF-alpha, IL-17 in PBMCs from sJIA patients were obviously decreased after recombinant IL-37 stimulation, whereas the production of IL-1beta was not changed. CONCLUSIONS: Our results demonstrate that levels of IL-37 were higher in sJIA patients, which were correlated with disease activity and sJIA related inflammatory cytokines. In addition, rhIL-37 down-regulates the expressions of inflammatory cytokines form PBMCs in sJIA patients, suggesting that IL-37 may have the potential role as a natural inhibitor for the pathogenesis and therapy of sJIA. PMID- 30305172 TI - Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series. AB - BACKGROUND: The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described. CASE PRESENTATIONS: In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked. CONCLUSIONS: This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation. PMID- 30305173 TI - Short-term effects of fine particulate matter and ozone on the cardiac conduction system in patients undergoing cardiac catheterization. AB - BACKGROUND: Air pollution-induced changes in cardiac electrophysiological properties could be a pathway linking air pollution and cardiovascular events. The evidence of air pollution effects on the cardiac conduction system is incomplete yet. We investigated short-term effects of particulate matter <= 2.5 MUm in aerodynamic diameter (PM2.5) and ozone (O3) on cardiac electrical impulse propagation and repolarization as recorded in surface electrocardiograms (ECG). METHODS: We analyzed repeated 12-lead ECG measurements performed on 5,332 patients between 2001 and 2012. The participants came from the Duke CATHGEN Study who underwent cardiac catheterization and resided in North Carolina, United States (NC, U.S.). Daily concentrations of PM2.5 and O3 at each participant's home address were predicted with a hybrid air quality exposure model. We used generalized additive mixed models to investigate the associations of PM2.5 and O3 with the PR interval, QRS interval, heart rate-corrected QT interval (QTc), and heart rate (HR). The temporal lag structures of the associations were examined using distributed-lag models. RESULTS: Elevated PM2.5 and O3 were associated with four-day lagged lengthening of the PR and QRS intervals, and with one-day lagged increases in HR. We observed immediate effects on the lengthening of the QTc interval for both PM2.5 and O3, as well as delayed effects for PM2.5 (lagged by 3 - 4 days). The associations of PM2.5 and O3 with the PR interval and the association of O3 with the QRS interval persisted until up to seven days after exposure. CONCLUSIONS: In patients undergoing cardiac catheterization, short-term exposure to air pollution was associated with increased HR and delays in atrioventricular conduction, ventricular depolarization and repolarization. PMID- 30305174 TI - A cognitive versus behavioral approach to emotion regulation training for externalizing behavior problems in adolescence: Study protocol of a randomized controlled trial. AB - BACKGROUND: Interventions for adolescents with externalizing behavior problems are generally found to be only moderately effective, and treatment responsiveness is variable. Therefore, this study aims to increase intervention effectiveness by examining effective approaches to train emotion regulation, which is considered to be a crucial mechanism involved in the development of externalizing behavior problems. Specifically, we aim to disentangle a cognitive and behavioral approach to emotion regulation training. METHODS: A randomized controlled parallel-group study with two arms will be used. Participants are adolescents between 12 and 16 years old, with elevated levels of externalizing behavior problems. Participants will be randomly assigned to either the control condition or the intervention condition. Participants in the intervention condition receive both a cognitive and behavioral emotion regulation module, but in different sequences. Primary outcome measures are emotion regulation skills, emotion regulation strategies, and externalizing behavior problems. Questionnaires will be completed at pre test, in-between modules, and post-test. Moreover, intensive longitudinal data is collected, as adolescents will complete weekly and daily measures. DISCUSSION: Gaining insight into which approaches to emotion regulation training are more effective, and for whom, is important because it may lead to the adaptation of effective intervention programs for adolescents with externalizing behavior problems. Eventually, this could lead to individually tailored evidence-based interventions. TRIAL REGISTRATION: The trial is registered at the Central Committee on Research Involving Human Subjects ( NL61104.041.17 , September 20th, 2017) and the Dutch Trial Register ( NTR7334 , July 10th, 2018). PMID- 30305176 TI - Efficacy and safety of the switch of Triumeq(r) to generic (abacavir + lamivudine) + Tivicay(r): data at 24 weeks. AB - BACKGROUND: Generic drugs may help to support antiretroviral treatment. We want to assess the efficacy and safety at 24 weeks of the change of coformulated (abacavir + lamivudine + dolutegravir) to (abacavir + lamivudine) coformulated as a generic pharmaceutical specialty + dolutegravir. METHODS: Between February and June 2017, switch from Triumeq(r) to a generic pharmaceutical specialty co formulated tablet (abacavir + lamivudine) plus Tivicay(r) was made. Demographic, viroimmunological characteristics and the Charlson index were collected. Six months after switching, efficacy and safety were evaluated. RESULTS: Switch was made in 93 patients, with a mean age of 47 years, after six months there were five patients (5.4%) with viral loads between 50 and 400 copies, no patient had viral loads of greater amount. There were 2 interruptions due to toxicity (2.15%), in relation to symptoms of the central nervous system. There were no differences in the amount of years with HAART, nor in the previous months with the STR regimen based on abacavir + lamivudine + dolutegravir, nor in the Charlson index. The effective saving in 2017 derived from the change in these 93 patients was ? 125.512. CONCLUSIONS: The change from a regimen of abacavir + lamivudine + dolutegravir seems to be safe and effective at 24 weeks. PMID- 30305175 TI - Fluorine-19 MRI for detection and quantification of immune cell therapy for cancer. AB - Over the past two decades, immune cell therapy has emerged as a potent treatment for multiple cancers, first through groundbreaking leukemia therapy, and more recently, by tackling solid tumors. Developing successful therapeutic strategies using live cells could benefit from the ability to rapidly determine their in vivo biodistribution and persistence. Assaying cell biodistribution is unconventional compared to traditional small molecule drug pharmacokinetic readouts used in the pharmaceutical pipeline, yet this information is critical towards understanding putative therapeutic outcomes and modes of action. Towards this goal, efforts are underway to visualize and quantify immune cell therapy in vivo using advanced magnetic resonance imaging (MRI) techniques. Cell labeling probes based on perfluorocarbon nanoemulsions, paired with fluorine-19 MRI detection, enables background-free quantification of cell localization and survival. Here, we highlight recent preclinical and clinical uses of perfluorocarbon probes and 19F MRI for adoptive cell transfer (ACT) studies employing experimental T lymphocytes, NK, PBMC, and dendritic cell therapies. We assess the forward looking potential of this emerging imaging technology to aid discovery and preclinical phases, as well as clinical trials. The limitations and barriers towards widespread adoption of this technology, as well as alternative imaging strategies, are discussed. PMID- 30305177 TI - Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. AB - BACKGROUND: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-alpha inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. METHODS: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. RESULTS: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group. CONCLUSIONS: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted. PMID- 30305179 TI - Serially transplantable mammary epithelial cells express the Thy-1 antigen. AB - BACKGROUND: Recent studies in murine mammary tissue have identified functionally distinct cell populations that may be isolated by surface phenotype or lineage tracing. Previous groups have shown that CD24medCD49fhigh cells enriched for long lived mammary epithelial cells can be serially transplanted. METHODS: Flow cytometry-based enrichment of distinct phenotypic populations was assessed for their gene expression profiles and functional proliferative attributes in vitro and in vivo. RESULTS: Here, we show Thy-1 is differentially expressed in the CD24medCD49fhigh population, which allowed us to discern two functionally different populations. The Thy-1+CD24medCD49fhigh phenotype contained the majority of the serially transplantable epithelial cells. The Thy-1 CD24medCD49fhigh phenotype contains a rare progenitor population that is able to form primary mammary outgrowths with significantly decreased serial in vivo transplantation potential. CONCLUSIONS: Therefore, Thy-1 expression in the immature cell compartment is a useful tool to study the functional heterogeneity that drives mammary gland development and has implications for disease etiology. PMID- 30305180 TI - Self-medication during pregnancy and associated factors among pregnant women in Goba town, southeast Ethiopia: a community based cross sectional study. AB - OBJECTIVE: The use of self-medications during pregnancy results in serious structural as well as functional adverse effects on mothers and unborn children. But little is known about the practice of self-medication used during pregnancy in Ethiopia. Therefore, this research aimed to assess the prevalence of self medication practice and associated factors during pregnancy among pregnant women in Goba town, southeast Ethiopia. RESULTS: The prevalence of self-medication was 15.5% (95% CI 0.116, 0.195) in Goba town. Women who had health problems during pregnancy (AOR = 6.1, 95% CI 2.67, 13.9), women unable to read and write (AOR = 8.87, 95% CI 1.84, 41.95), those who can read and write (AOR = 5.26, 95% CI 1.34, 20.66) and had primary education (AOR = 3.57, 95% CI 1.42, 9.02) were more likely to use self-medication, while women who visited ANC for pregnancy (AOR = 0.028, 95% CI 0.09, 0.87) were less likely to indulge on such practices. In conclusion, the prevalence of self-medication noted in this work is medium compared to the react of other studies. Health institutions have to give health education to all pregnant women attending ANC services regardless of gestational age and types of health problem. PMID- 30305181 TI - Phenotypic and genotypic characterization of macrolide, lincosamide and streptogramin B resistance among clinical isolates of staphylococci in southwest of Iran. AB - OBJECTIVE: The present study aimed to determine the phenotypic and genotypic profile of macrolide, lincosamide and streptogramin B (MLSB) resistance in clinical isolates of staphylococci. RESULTS: This cross-sectional study was conducted on 164 non-duplicated staphylococci isolates collected during August 2015 to February 2016 from two tertiary care hospitals in Shiraz, southwest of Iran. Of the 164 isolates, 86 erythromycin-resistant isolates consist of 35 Staphylococcus aureus and 51 coagulase negative staphylococci (CoNS) were included in the study. Of the 35 S. aureus, the prevalence of cMLS (constitutive), iMLS (inducible), and MS phenotypes were found 82.9%, 8.6% and 8.6%, respectively. Among 51 CoNS, the frequencies of cMLS, iMLS, and MS phenotypes were detected 66.7%, 11.8% and 21.6%, respectively. Among S. aureus isolates, the predominant genes were ermC in 82.9% isolates, followed by ermA in 57.1% and msrA in 28.6% of isolates. Among CoNS isolates, the most frequent genes were diagnosed ermC in 70.6% isolates followed by msrA in 68.6% and ermA in 11.8% of isolates. In conclusion, regarding the presence of MLSB resistance in our region, diagnosis of this resistance type on a routine basis in staphylococcal clinical isolates is of particular importance. PMID- 30305182 TI - Triatominae: does the shape change of non-viable eggs compromise species recognition? AB - BACKGROUND: Eggs have epidemiological and taxonomic importance in the subfamily Triatominae, which contains Chagas disease vectors. The metric properties (size and shape) of eggs are useful for distinguishing between close species, or different geographical populations of the same species. METHODS: We examined the effects of egg viability on its metric properties, and the possible consequences on species recognition. Four species were considered: Panstrongylus chinai, P. howardi and Triatoma carrioni (tribe Triatomini), and Rhodnius ecuadoriensis (tribe Rhodniini). Digitization was performed on pictures taken when the viability of the egg could not clearly be predicted by visual inspection. We then followed development to separate viable from non-viable eggs, and the metric changes associated with viability status of the eggs were tested for species discrimination (interspecific difference). RESULTS: The shape of the complete contour of the egg provided satisfactory species classification (95% of correct assignments, on average), with improved scores (98%) when discarding non-viable eggs from the comparisons. Using only non-viable eggs, the scores dropped to 90%. The morphometric differences between viable and non-viable eggs were also explored (intraspecific comparison). A constant metric change observed was a larger variance of size and shape in non-viable eggs. For all species, larger eggs, or eggs with larger operculum, were more frequently non-viable. However, these differences did not allow for an accurate prediction regarding egg viability. CONCLUSIONS: The strong taxonomic signal present in egg morphology was affected by the level of viability of the eggs. The metric properties as modified in non-viable eggs presented some general trends which could suggest the existence of an optimum phenotype for size and for shape. Globally, viable eggs tended to have intermediate or small sizes, and presented a less globular shape in the Triatomini, or a relatively wider neck in Rhodnius ecuadoriensis. PMID- 30305183 TI - Skeletonized internal thoracic artery harvesting: a low thermal damage electrosurgical device provides improved endothelial layer and tendency to better integrity of the vessel wall compared to conventional electrosurgery. AB - BACKGROUND: Electrosurgery is fundamental to the precise, fast and bloodless preparation of internal thoracic artery grafts in cardiac surgery. The PEAK PlasmaBlade is a monopolar electrosurgical device that uses pulsed radiofrequency energy to generate a plasma-mediated discharge along an insulated electrode, creating a cutting edge while the blade stays near body temperature. The aim of this study is to compare the histological samples, cardiac computed-tomography of graft patency, and clinical outcomes of patients after off-pump coronary artery bypass grafting with preparation of the internal thoracic arteries by a conventional electrosurgical device and the PlasmaBlade. METHODS: In twenty subjects one internal thoracic artery was prepared with PlasmaBlade and the other artery with a conventional electrosurgical device. Histological samples were evaluated for three factors for potential graft failure: endothelial damage, integrity of the vessel wall and adventitial hemorrhage. Five samples per artery were evaluated by a novel scoring method based on the exposed circumference of the histological sample ("0": 0%, "1": 1-25%, "2": 26-50%, "3": 51-75%, "4": >=76% of the circumference). The Wilcoxon signed ranks test for mean scores within subjects was performed. Six-month-follow up by cardiac computed tomography for evaluation of graft patency was completed in 16 patients. RESULTS: Histological results demonstrated significantly less endothelial damage after PlasmaBlade (83% vs 60%, absolute: 75/90 vs. 53/89 samples with score "0-1", p = 0.04). PlasmaBlade samples demonstrated a tendency to better wall integrity (72% vs. 54%, absolute: 64/89 vs. 47/87 samples with score "0-1", p = 0.32). There were no differences in endothelial bleeding (PlasmaBlade 46% vs. electrosurgery 53%, absolute: 41/88 vs. 48/90 samples with score "0-1", p = 0.63). Computed tomography confirmed non-inferiority of the PlasmaBlade to conventional electrosurgery with a patency rate of 94%. CONCLUSION: Histologically, internal thoracic arteries harvested with PlasmaBlade demonstrate a more intact endothelial layer and a tendency to better wall integrity. Computed tomography of graft patency speaks for non-inferiority to conventional electrosurgery. PlasmaBlade may be preferable to conventional electrosurgery, if further follow up confirms patency of internal thoracic arteries. TRIAL REGISTRATION: NCT03510026 , registered 4th April 2018 (retrospectively registered). PMID- 30305184 TI - Identifying key bird species and geographical hotspots of avian influenza A (H7N9) virus in China. AB - BACKGROUND: In China since the first human infection of avian influenza A (H7N9) virus was identified in 2013, it has caused serious public health concerns due to its wide spread and high mortality rate. Evidence shows that bird migration plays an essential role in global spread of avian influenza viruses. Accordingly, in this paper, we aim to identify key bird species and geographical hotspots that are relevant to the transmission of avian influenza A (H7N9) virus in China. METHODS: We first conducted phylogenetic analysis on 626 viral sequences of avian influenza A (H7N9) virus isolated in chicken, which were collected from the Global Initiative on Sharing All Influenza Data (GISAID), to reveal geographical spread and molecular evolution of the virus in China. Then, we adopted the cross correlation function (CCF) to explore the relationship between the identified influenza A (H7N9) cases and the spatiotemporal distribution of migratory birds. Here, the spatiotemporal distribution of bird species was generated based on bird observation data collected from China Bird Reports, which consists of 157 272 observation records about 1145 bird species. Finally, we employed a kernel density estimator to identify geographical hotspots of bird habitat/stopover that are relevant to the influenza A (H7N9) infections. RESULTS: Phylogenetic analysis reveals the evolutionary and geographical patterns of influenza A (H7N9) infections, where cases in the same or nearby municipality/provinces are clustered together with small evolutionary differences. Moreover, three epidemic waves in chicken along the East Asian-Australasian flyway in China are distinguished from the phylogenetic tree. The CCF analysis identifies possible migratory bird species that are relevant to the influenza A(H7N9) infections in Shanghai, Jiangsu, Zhejiang, Fujian, Jiangxi, and Guangdong in China, where the six municipality/provinces account for 91.2% of the total number of isolated H7N9 cases in chicken in GISAID. Based on the spatial distribution of identified bird species, geographical hotspots are further estimated and illustrated within these typical municipality/provinces. CONCLUSIONS: In this paper, we have identified key bird species and geographical hotspots that are relevant to the spread of influenza A (H7N9) virus. The results and findings could provide sentinel signal and evidence for active surveillance, as well as strategic control of influenza A (H7N9) transmission in China. PMID- 30305178 TI - Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword. AB - Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis. PMID- 30305186 TI - Assessment of partograph utilization and associated factors among obstetric care givers at public health institutions in central zone, Tigray, Ethiopia. AB - OBJECTIVES: Partograph is one of the best effective obstetric tools used to monitoring labor and prevent prolonged or obstructed labor which accounts for about 22% of maternal deaths in Ethiopia. This study was aimed to assess partograph utilization and associated factors among obstetric care givers. Facility based cross sectional study was used in the randomly selected health facilities. Total 220 obstetric care givers were selected using simple random sampling technique. Data were entered and analyzed using SPSS version 22.0. Bivariate and multivariate logistic regression analysis was used to identify the associations of each explanatory variable with the outcome variable. Finally, odds ratio with its 95% confidence interval and p-value of 0.05 was used to identify significant variables. RESULT: Out of 198 obstetric care providers, 73.3% used partograph to monitor progress of labor. Those who were diploma holders (AOR = 3.8, CI = 2.2-6.2), receiving basic emergency obstetrics and new born care training (AOR = 5.6, CI 1.1-28.5), age between 20 and 29 years-old (AOR = 0.1, CI = 0.01-0.50), and male health care providers (AOR = 0.37, CI = 0.44 0.95) were factors significantly associated with partograph utilization. Partograph utilization in this study was below the WHO recommendation. Especial emphasizes and interventions should be given to increase partograph utilization. PMID- 30305188 TI - Response to 'Clinical relevance and validity of obesity risk prediction tools' by Redsell et al. PMID- 30305187 TI - Hypocalcaemia following laryngectomy: prevalence and risk factors. AB - OBJECTIVES: To establish the prevalence of hypocalcaemia following laryngectomy and demonstrate that total thyroidectomy is a risk factor. METHODS: A retrospective cohort study was conducted that included all patients who underwent total laryngectomy from 1st January 2006 to 1st August 2017. Exclusion criteria were: pre-operative calcium derangement, previous thyroid or parathyroid surgery, concurrent glossectomy, pharyngectomy, or oesophagectomy. RESULTS: Ninety patients were included. Sixteen patients had early hypocalcaemia (18 per cent), seven had protracted hypocalcaemia (8 per cent) and six had permanent hypocalcaemia (10 per cent). Exact logistic regression values for hypocalcaemia following total thyroidectomy compared to other patients were: early hypocalcaemia, odds ratio = 15.5 (95 per cent confidence interval = 2.2-181.9; model p = 0.002); protracted hypocalcaemia, odds ratio = 13.3 (95 per cent confidence interval = 1.5-117.1; model p = 0.01); and permanent hypocalcaemia, odds ratio = 22.7 (95 per cent confidence interval = 1.9-376.5; model p = 0.005). CONCLUSION: This is the largest study to investigate the prevalence of hypocalcaemia following laryngectomy and the first to include follow up of longer than three months. Total thyroidectomy significantly increased the risk of hypocalcaemia at all time frames and independent of other variables. PMID- 30305189 TI - Assessment of nasal functions and their relationship with cholesteatoma formation in patients with unilateral chronic otitis media. AB - OBJECTIVES: To evaluate the nasal functions of patients with unilateral chronic otitis media using rhinomanometry, comparing chronic otitis media sides with healthy sides, chronic otitis media patients with cholesteatoma and without cholesteatoma, and patients with healthy individuals. METHODS: This prospective study included 102 patients with unilateral chronic otitis media (48 with and 54 without cholesteatoma). The control group comprised 40 individuals without any ear or nasal pathologies. All patients underwent active anterior rhinomanometry to measure nasal airway resistance and a saccharin test to measure mucociliary transport times. RESULTS: There were no significant differences in nasal airway resistance and mucociliary transport time between the chronic otitis media sides and unaffected sides in the 102 patients (p = 0.72 and p = 0.28, respectively), between the non-suppurative chronic otitis media patients (without cholesteatoma) and chronic otitis media with cholesteatoma patients (p > 0.05), or between the study and control groups (p > 0.05). CONCLUSION: The present study, with a larger sample size compared to previously published literature, supports the conclusion that unilateral nasal obstruction is unlikely to lead to chronic otitis media on the same side. The results also suggest that nasal functions do not contribute to the development of cholesteatoma. PMID- 30305185 TI - Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells. AB - BACKGROUND: In the bone marrow, MSCs reside in a hypoxic milieu (1-5% O2) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs. METHODS: Human and porcine bone marrow MSCs were obtained from fresh mononuclear cells. The first study evaluated MSC function following both long-term (10 days) and short-term (48 h) hypoxia (1% O2) culture. In our second study, we evaluated the functional characteristics of MSC cultured under short-term 2% and 5% hypoxia. MSCs were evaluated for their metabolic activity, proliferation, viability, clonogenicity, gene expression, and secretory capacity. RESULTS: In long-term culture, common MSC surface marker expression (CD44 and CD105) dropped under hypoxia. Additionally, in long-term culture, MSCs proliferated significantly slower and provided lower yields under hypoxia. Conversely, in short-term culture, MSCs proliferated significantly faster under hypoxia. In both long-term and short-term cultures, MSC metabolic activity was significantly higher under hypoxia. Furthermore, MSCs cultured under hypoxia had upregulated expression of VEGF with concomitant downregulation of HMGB1 and the apoptotic genes BCL-2 and CASP3. Finally, in both hypoxia cultures, the pro-inflammatory cytokine, IL-8, was suppressed, while levels of the anti-inflammatories, IL-1ra and GM-CSF, were elevated in short-term hypoxia only. CONCLUSIONS: In this study, we demonstrate that hypoxia augments the therapeutic characteristics of both porcine and human MSCs. Yet, short-term 2% hypoxia offers the greatest benefit overall, exemplified by the increase in proliferation, self-renewing capacity, and modulation of key genes and the inflammatory milieu as compared to normoxia. These data are important for generating robust MSCs with augmented function for clinical applications. PMID- 30305190 TI - Supplemental Nutrition Assistance Program participation and racial/ethnic disparities in food and beverage purchases. AB - OBJECTIVE: The current study aimed to (i) describe racial/ethnic disparities in household food and beverage purchases among participants and non-participants in the Supplemental Nutrition Assistance Program (SNAP) and (ii) examine longitudinal associations between SNAP participation and purchases by race/ethnicity. DESIGN: To describe disparities, we estimated sociodemographic adjusted mean purchases of seven unhealthy food and beverage groups (e.g. junk food, sugar-sweetened beverages) and four nutrients (e.g. sugar, Na) among white, black and Hispanic SNAP-participating and non-participating households. To examine longitudinal associations, we used multivariable linear regression with household fixed effects. SETTING: USA, 2010-2014. SUBJECTS: Food and beverage purchases among low-income (<=250 % federal poverty line) US households (n 30 403) participating in the Nielsen Homescan Panel. RESULTS: Among non participants, there were significant black-white disparities (i.e. differences favouring white households) in households' adjusted mean purchases of processed meat, sweeteners, sugar-sweetened beverages, energy and Na. These disparities persisted among SNAP participants. In contrast, the only significant Hispanic white disparity among non-participants was for Na purchases; this disparity was reduced in magnitude and no longer significant among SNAP-participating households. Additionally, Hispanic households purchased less energy from junk foods than white households, regardless of SNAP status. In longitudinal models accounting for household fixed effects, SNAP participation was associated with increased energy purchased among black households. No other significant longitudinal associations between SNAP and purchase outcomes were observed. CONCLUSIONS: SNAP may not be meeting its potential to improve food and beverage purchases or reduce disparities. Research is needed to identify strategies for ensuring nutritious purchases across all racial/ethnic groups. PMID- 30305191 TI - Strategies to reduce sugar-sweetened beverage consumption and increase water access and intake among young children: perspectives from expert stakeholders. AB - OBJECTIVES: To summarize stakeholder recommendations and ratings of strategies to reduce sugar-sweetened beverage (SSB) consumption and increase water access and intake among young children (0-5 years). DESIGN: Two online surveys: survey 1 asked respondents to recommend novel and innovative strategies to promote healthy beverage behaviour; survey 2 asked respondents to rank each of these strategies on five domains (overall importance, feasibility, effectiveness, reach, health equity). Open-ended questions were coded and analysed for thematic content. SETTING: Using a snowball sampling approach, respondents were invited to complete the survey through an email invitation or an anonymous listserv link. Of the individuals who received a private email invitation, 24 % completed survey 1 and 29 % completed survey 2. SUBJECTS: Survey 1 (n 276) and survey 2 (n 182) included expert stakeholders who work on issues related to SSB and water consumption. RESULTS: Six overarching strategies emerged to change beverage consumption behaviours (survey 1): education; campaigns and contests; marketing and advertising; price changes; physical access; and improving the capacity of settings to promote healthy beverages. Labelling and sugar reduction (e.g. reformulation) were recommended as strategies to reduce SSB consumption, while water testing and remediation emerged as a strategy to promote water intake. Stakeholders most frequently recommended (survey 1) and provided higher ratings (survey 2) to strategies that used policy, systems and/or environmental changes. CONCLUSIONS: The present study is the first to assess stakeholder opinions on strategies to promote healthy beverage consumption. This knowledge is key for understanding where stakeholders believe resources can be best utilized. PMID- 30305192 TI - Celebrity Role in Sarpol-e Zahab Earthquake in Iran 2017. PMID- 30305193 TI - Food insufficiency is associated with depression among street-involved youth in a Canadian setting. AB - OBJECTIVE: Food insufficiency, defined by the experience of hunger, is known to be prevalent and a source of health-related harm among-street involved youth, but little is known about its relationship with depression in this population. Therefore, we sought to assess the association between food insufficiency and symptoms of depression among a cohort of street-involved youth. DESIGN: Multivariable logistic regression was used to assess the relationship between food insufficiency, defined as being hungry but not having enough money to buy food, and depression as measured by the Center for Epidemiological Studies Depression (CES-D) scale. SETTING: Data from April 2006 to November 2013 were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street involved youth who use illicit drugs in Vancouver, Canada. SUBJECTS: There were 1066 street-involved youth enrolled in the study, including 340 (31.9 %) females. RESULTS: Of 1066 youth enrolled in the study, 724 (67.9 %) reported some food insufficiency and 565 (53.0 %) met criteria for depression. Compared with youth who did not report food insufficiency, those who reported often experiencing food insufficiency had a higher likelihood of reporting depression (adjusted OR=2.52; 95 % CI 1.74, 3.67), as did those who reported sometimes experiencing food insufficiency (adjusted OR=1.99; 95 % CI 1.47, 2.70). CONCLUSIONS: Food insufficiency was prevalent and associated in a dose-dependent trend with symptoms of depression among street-involved youth in our setting. Findings highlight the need to address the nutritional and mental health needs of youth and identify pathways by which food insufficiency may contribute to depression among vulnerable populations. PMID- 30305195 TI - Successful Renovation of a Closed School Into a Long-Term Care Facility in the Affected Area After the 2011 Fukushima Disaster. PMID- 30305194 TI - Interventions to reduce unnecessary central venous catheter use to prevent central-line-associated bloodstream infections in adults: A systematic review. AB - OBJECTIVE: To identify, describe, and evaluate interventions to reduce unnecessary central venous catheter (CVC) use to prevent central-line-associated bloodstream infections (CLABSIs) in adults. DESIGN: Systematic review. METHODS: The review has been registered in PROSPERO, an international prospective register of systematic reviews. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Cumulative Index to Nursing and Allied Health (CINAHL) from inception until August 28, 2018, to collect experimental and observational studies. We included all studies that implemented interventions to reduce unnecessary CVC use, defined as interventions aimed at improving appropriateness, awareness of device presence, or prompt removal of devices. RESULTS: In total, 1,892 unique citations were identified. Among them, 1 study (7.1%) was a randomized controlled trial, 9 studies (64.3%) were quasi experimental studies, and 4 studies (28.6%) were cohort studies. Furthermore, 13 studies (92.9%) demonstrated a decrease in CVC use after intervention despite different reporting methods, and the reduction rate varied from 6.8% to 85%. Also, 7 studies (50.0%) that reported the incidence of CLABSI described a reduction in CLABSIs ranging from 24.4% to 100.0%. Data on secondary outcomes were limited, and results of the descriptive analysis showed 70%-84% compliance with these interventions, less catheter occlusion, shorter duration of hospitalization, and cost savings. CONCLUSIONS: Interventions to reduce unnecessary CVC use significantly decrease the rate of CLABSI. Healthcare providers should strongly consider implementing these interventions for prevention of CLABSI in adults. PMID- 30305196 TI - Interpreting Neuroendocrine Hormones, Corticosterone, and Blood Glucose to Assess the Wellbeing of Anesthetized Rats during Euthanasia. AB - Current recommendations for assessing animal wellbeing during euthanasia suggest that measuring neuroendocrine hormones-such as ACTH, noradrenaline, and adrenaline-is preferable to measuring corticosterone and blood glucose because of the sensitivity of neuroendocrine hormones to the acute stress associated with rapid methods of euthanasia. However, theseneuroendocrine hormones can be stimulated in ways that confound interpretation of welfare assessment in euthanasia studies.Although this property does not negate the usefulness of neuroendocrine hormones as tools of assessment, it is importantto differentiate the stress associated with the induction of anesthesia before the loss of consciousness (an animal wellbeingconcern) with the physiologic responses that occur after the loss of consciousness (not an animal wellbeing concern). In thisstudy, rats were anesthetized by using a ketamine-xylazine combination. Once the rats achieved a surgical plane of anesthesia,they were exposed to O2, CO2, or isoflurane, followed by terminal blood collection to assess concentrations of ACTH,noradrenaline, corticosterone, and blood glucose. Compared with animals exposed to O2 or isoflurane, rats exposed to CO2had significant increases in their serum concentrations of ACTH and noradrenaline, but blood glucose and corticosteronedid not differ between groups. These findings indicate that noradrenaline and ACTH should be used with caution to assessanimal wellbeing when the method of euthanasia might confound that assessment. PMID- 30305197 TI - System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta). AB - We developed a clinical assessment tool for use in an NHP radiation model to 1) quantify severity responses for subsyndromes of the acute radiation syndrome (ARS; that is, hematopoietic and others) and 2) identify animals that required enhanced monitoring. Our assessment tool was based primarily on the MEdical TREatment ProtocOLs for Radiation AccidentVictims (METREPOL) scoring system but was adapted for NHP to include additional indices (for example, behaviors) for usein NHP studies involving limited medical intervention. Male (n = 16) and female (n = 12) rhesus macaques (Macaca mulatta;5 groups: sham and 1.0, 3.5, 6.5, and 8.5 Gy; n = 6 per group) received sham- or bilateral 60Co gamma-irradiation at approximately 0.6 Gy/mn. Clinical signs of ARS and blood analysis were obtained before and serially for clinical assessment during the periodof 6 h to 60 d after sham or 60Co irradiation. Minimal supportive care (that is, supplemental nutrition, subcutaneous fluid,loperamide, acetaminophen, and topical antibiotic ointment) was prescribed based on clinical observations. Results fromclinical signs and assays for assessment of relevant organ systems in individual animals were stratified into ARS severityscores of normal (0), mild (1), moderate (2), and severe (3 or 4). Individual NHP were scored for maximal subsyndrome ARSseverity in multiple organ systems by using the proposed ARS scoring system to obtain an overall ARS response category.One NHP died unexpectedly. The multiple-parameter ARS severity scoring tool aided in the identification of animals in thehigh-dose (6.5 and 8.5 Gy) groups that required enhanced monitoring. PMID- 30305198 TI - Home Cage Compared with Induction Chamber for Euthanasia of Laboratory Rats. AB - This study compared behavioral and physiologic changes in Sprague-Dawley and Brown Norway rats that were euthanizedby using a 30% volume displacement rate of CO2 in either their home cage or an induction chamber; rats euthanized in thehome cage were hypothesized to demonstrate a higher level of animal wellbeing. No significant differences were detectedin the physiologic responses to home cage versus induction chamber euthanasia groups. A few strain-related behavioraldifferences occurred. The number of digs per second was higher in Brown Norway compared with Sprague-Dawley rats when in the home cage, where a digging substrate was present. Rearing frequency was higher in both Brown Norway and Sprague-Dawley rats in the induction chamber compared with the home cage. This study demonstrated that although strainspecific differences were associated with the process of euthanasia, there were no significant differences between the treatment groups of home cage compared with induction chamber. This finding suggests that-from the perspective of a rat-either the home cage or an induction chamber can be used for euthanasia, with likely extension of this conclusion to use of either method to the induction of anesthesia. PMID- 30305199 TI - Response Surface Optimization of Supercritical Carbon Dioxide Extraction of Tea Polyphenols from Green Tea Scraps. AB - Background: The green tea scraps are the waste materials during the process of green tea production, and it is significant to extract valuable tea polyphenols (TP) for reuse. Objective: The objective of this study was to extract valuable TP from green tea scraps, and the extraction conditions were optimized to obtain maximum yield of TP. Methods: The TP were extracted by supercritical carbon dioxide (SC-CO2) with 65% (v/v) aqueous ethanol solution as cosolvent. The content of TP was determined with the Folin-Ciocalteu method. The key factors of the extraction process, including temperature (313.15-323.15 K), pressure (20-30 Mpa), and amount of cosolvent (50-150 mL) were optimized by response surface methodology (RSM). Results: These key factors showed the extremely complex effects on the extraction yield of TP. A second-order polynomial mathematical model was developed for the response with high R-squared value (R2 = 0.9946) and used to predict the optimal conditions (i.e., temperature of 322.15 K, pressure of 23.60 MPa, and amount of cosolvent of 150 mL). The verification experiments showed that the maximum yield of TP was 23.07 +/- 0.82% under the optimal conditions, which was in good agreement with the predicted value. Conclusions: TP can be successfully extracted from green tea scraps by SC-CO2, and RSM could be used to optimize the extraction process. Highlights: SC-CO2 extraction of TP from green tea scraps was developed. The operating conditions, including pressure, temperature, and amount of cosolvent, were optimized. RSM could successfully predict the optimal operating conditions. PMID- 30305200 TI - Using Hysterectomy Rederivation to Produce Guinea Pigs (Cavia porcellus) Free of Guinea Pig Cytomegalovirus. AB - Due to similarities in placentation, guinea pigs can be used as models of human cytomegalovirus infection, but they mustbe free of guinea pig cytomegalovirus. Many commercial guinea pig colonies are enzootically infected with guinea pigcytomegalovirus, which can be transmitted vertically as well as horizontally through saliva, vaginal secretions, and milk.These characteristics make its eradication in a commercial setting challenging. Because embryo transfer technology in guineapigs is in its infancy, it is not generally a viable option for obtaining animals free of guinea pig cytomegalovirus. However,a combination of hysterectomy rederivation and testing by PCR assay and serology of both dams and offspring from anenzootically infected colony produced offspring free of guinea pig cytomegalovirus. PMID- 30305201 TI - Single-Laboratory Validation of a Method for Determination of Ergocalciferol in Protein Drink Powders and Tablets by LC-MS/MS. AB - Background: Currently, there is a lack of validation studies available in the literature for the determination of ergocalciferol, especially for those using a direct extraction technique. The current official methodologies for the quantification of ergocalciferol require saponification, liquid-liquid extraction, or both, thus requiring experienced technicians and specialized reflux equipment. This work provides a method that is more easily accessible to laboratories without these resources while still achieving the robustness needed for a successful validation of low levels of ergocalciferol in complex matrixes. Objective: A single-laboratory validation study was conducted for a rapid quantification method of ergocalciferol in protein drink powders and tablets. Methods: The method uses an LC-MS/MS with multimode source utilizing atmospheric pressure chemical ionization positive ionization mode. For both protein drink powders and tablets, the procedure consisted of a liquid extraction step using dimethyl sulfoxide and methanol. Isotopically labeled ergocalciferol was used as an internal standard to correct for signal depression caused by matrix interference. Results: This LC-MS/MS method was found to be accurate, precise, linear (from 0.01 to 0.3 MUg/mL), rugged, and suitable for protein drink powders and tablets. Conclusions: The method was validated and is suitable for accurate quantification of ergocalciferol in tablet and protein powder products. Highlights: This work provides a validated method for accurate quantification of ergocalciferol in complex matrixes using a direct extraction technique. This may benefit quality control laboratories in the food and nutraceutical industries, where simple and efficient methodology is key to optimal functioning. PMID- 30305202 TI - Determination of Unsulfonated Aromatic Amines in FD&C Yellow No. 5 and FD&C Yellow No. 6 by Liquid Chromatography-Triple Quadrupole Mass Spectrometry. AB - Background: This paper describes a simple and sensitive ultra-HPLC-triple quadrupole MS (LC-MS/MS) method for the determination of six unsulfonated aromatic amines in the color additives FD&C Yellow No. 5 (Y5) and FD&C Yellow No. 6 (Y6). The six amines determined by this method are aniline (ANL), benzidine (BNZ), 4-aminobiphenyl (4ABP), 4-aminoazobenzene (4AAB), 2-aminobiphenyl (2ABP), and 4-aminobenzonitrile (4ABN). Objective: This method is intended for use in batch certification of the color additives by the U.S. Food and Drug Administration (FDA) to ensure that each lot meets published specifications for coloring foods, drugs, and cosmetics. Methods: A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure is used for extraction of the amines. Quantitative determination was performed in electrospray positive ionization and multiple-reaction monitoring modes. Results: Validation of the method demonstrated overall recovery of 101-115% and precision of 1.74-9.78% for all analytes. Excellent regression coefficients were obtained, with values >0.999. Conclusions: The validated method was successfully used for the analyses of 30 Y5 and Y6 samples and provided results that are consistent with results from the current method used by FDA, with greater sensitivity and low matrix effects. Highlights: The validation results demonstrate that the new LC-MS/MS method is applicable for use in routine batch certification. PMID- 30305203 TI - Application of Stable Isotope Dilution and Liquid Chromatography Tandem Mass Spectrometry for Multi-Mycotoxin Analysis in Edible Oils. AB - Background: Mycotoxin contamination in oils remains an important food safety issue. To monitor the occurrence of mycotoxins in edible oils, it is important to develop analytical methods that can determine multiple mycotoxins in oil products. A stable isotope dilution LC-tandem MS (LC-MS/MS) method for the simultaneous determination of 12 mycotoxins in five edible oil matrixes (canola, corn, olive, peanut, and soybean oil) was developed and validated. Methods: Prior to extraction, the oil samples were fortified with 13C uniformly labeled internal standards (13C-IS) for 12 target mycotoxins, followed by extraction and LC-MS/MS analysis. Quantitation was achieved using solvent-only calibration standards, relative response factors of 13C-IS, and target mycotoxins. Results: The majority of recoveries in oil for ochratoxin A and aflatoxins B1, B2, G1, and G2 fortified at 1, 10, and 100 ng/g as well as deoxynivalenol; fumonisins B1, B2, and B3; T-2 toxin; HT-2 toxin; and zearalenone fortified at 10, 100, and 1000 ng/g ranged from 80 to 120% with RSDs of <20%. The method LOQs ranged from 0.1 ng/g (aflatoxin B1) to 6.4 ng/g (zearalenone). Among 16 U.S. market samples, zearalenone was detected in three corn oil samples at 37, 185, and 317 ng/g, respectively. T-2 toxin was found in two corn oil samples at 7 and 10 ng/g, respectively. Conclusions: The method provides sufficient selectivity, sensitivity, accuracy, and repeatability to screen edible oils for regulated mycotoxins such as aflatoxins at low nanogram per gram concentrations without using conventional standard addition or matrix-matched calibration standards to correct for matrix effects. PMID- 30305204 TI - Utilization of FT-NIR Spectroscopy to Check Acidity of Various Types of Cheeses. AB - Background: Monitoring the acidity of cheese is an important control mechanism in various stages of manufacture, including aging. Acid development in cheesemaking is essential to cheese flavor, texture, and safety. Objective: The aim of the work was to develop and validate calibration models by using NIR spectroscopy, which allows for the monitoring of changes in cheese acidity (pH and titration acidity) during cheese ripening. Methods: Cheeses were analyzed by an FT-NIR spectrometer. Each of the samples was analyzed three times, and for calibration, an average spectrum was used. A partial least-squares regression was used to develop calibration models. The constructed calibration models were validating by full cross-validation. Results: Calibration models were created with a high correlation coefficient for the following cheese pH levels: blue cheese (0.966), Olomouc curd read smear cheese (0.984), and fresh goat cheese (0.980). Results of the calibration of titratable acidity are functional for fresh goat cheese (0.953) and mozzarella (0.999). Conclusions: The results of these new calibration methods showed the possibility of NIR technology for the fast determination of pH and titratable acidity. Highlights: Detection of cheese acidity using FT-NIR spectrometry enables rapid evaluation of the process of lactic acidification in particular cheese technological operations, including the maturing of cheeses. PMID- 30305205 TI - Vitamin A Analysis by Ultra-Performance Convergence Chromatography. PMID- 30305206 TI - Validation of the Listeria Right NowTM Test for Detection of Listeria spp. from Selected Environmental Surfaces Without Enrichment. AB - Background: Listeria Right NowTM is a novel, enrichment-free molecular method for detection of Listeria spp. in swab samples from environmental surfaces. The test provides results in real time, indicating the current or recent presence of Listeria spp. in the environment. After sampling, the entire contents of the swab are subject to sample processing, releasing large quantities of target ribosomal RNA molecules into the lysate. A portion of the lysate is then tested using the ANSR(r)for Listeria isothermal nucleic acid amplification assay. Objective: A Performance Tested MethodSM study was conducted to validate the method for detection of Listeria spp. in swab samples from stainless steel and sealed concrete surfaces. Methods and Results: In inclusivity testing, 60 of 60 Listeria spp. strains tested positive. In exclusivity testing, 31 of 31 nontarget bacterial strains tested negative. In LOD testing, the test was able to detect as few as 2 CFU of L. monocytogenes applied to a stainless steel surface. In matrix testing of inoculated stainless steel and sealed concrete surfaces, there were no statistically significant differences in method performance comparing the Listeria Right Now and U.S. Food and Drug Administration Bacteriological Analytical Manual reference culture procedures as determined by probability of detection analysis. In robustness testing, modest changes to three assay operating parameters simultaneously did not significantly affect performance of the test. Conclusions and Highlights: Results can be obtained in less than 1 h using the Listeria Right Now test, allowing food industry personnel to take immediate corrective action in the case of Listeria contamination incidents. PMID- 30305207 TI - Automated Determination of Xenobiotics (Pesticides, PCBs, PAHs, and PBDEs) in Sediment Samples Applying HS-SPME-GC-HRMS. AB - Background: Automated methods are needed for the reliable determination of xenobiotics in environmental samples. Objective: Optimization and application of an automated method for the ultra-trace analysis of 34 organic contaminants including polycyclic aromatic hydrocarbons (PAHs), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), organochlorinated (OCPs), and organophosphorus pesticides (OPPs) in sediment samples have been performed. Methods: Automated method based on headspace solid-phase microextraction (SPME) coupled to GC-high-resolution MS (GC-HRMS) for the ultra-trace analysis of the targeted compounds has been developed. Conclusions: Suitable validation parameters in terms of linearity, trueness, selectivity, intraday and interday precision, LODs, and LOQs were obtained. Relative recovery values between 70 and 120% were achieved for all compounds (concentration levels assayed 1 and 10 MUg/kg). RSD values were always lower than 25% for intra- and interday precision, and LODs and LOQs were 0.1 and 1.0 MUg/kg, respectively, for all analytes. Highlights: The proposed method was applied to the analysis of sediments collected in Andalusia, Spain, and Poland, finding PCB 18 in one sample (15.9 MUg/kg) and p,p'-DDE in several samples at concentrations ranging from 27.6 to 297.2 MUg/kg. PMID- 30305208 TI - Multiresidue Determination of Carbamate, Organophosphate, Neonicotinoid and Triazole Pesticides in Roasted Coffee Using Ultrasonic Solvent Extraction and Liquid Chromatography-Tandem Mass Spectrometry. AB - Background: A simple and effective extraction method based on ultrasonic solvent extraction and liquid-liquid microextraction (as the cleaning step) was developed to determine seven pesticide residues in roasted coffee (Coffea arabica) using ultra-performance LC-tandem MS. Objective: Different parameters of the method were evaluated, including solvent type and amount and sonication time. The best results were obtained using 1.0 g roasted coffee and acetonitrile (5 mL) as the extraction solvent with sonication for 15 min. The method was validated using roasted coffee samples fortified with pesticides at different concentration levels (0.1, 0.2, 0.3, and 0.5 MUg/kg). Average recoveries (three replicates) ranged from 74.3 to 99.9%, with RSDs between 0.7 and 10.2%. Results: The method showed good linearity for all the pesticides studied, with correlation coefficients >0.99. The detection limits ranged from 0.02 to 0.05 MUg/kg, and the quantification limit for all the compounds was 0.10 MUg/kg. The proposed method was applied for analysis of the compounds in commercial coffee samples from a producer in Minas Gerais State, Brazil. No residues of the pesticides were detected in the samples. Highlights: Ultrasonic solvent extraction was effective in the analysis of pesticides in roasted coffee. PMID- 30305209 TI - Self-Assembled Hydroxyapatite-Graphene Scaffold for Photothermal Cancer Therapy and Bone Regeneration. AB - Repairing large tumor-related bone defects remains a difficult clinical problem because of the significant risk of locoregional relapse after surgical curettage. In this study, a composite scaffold of nano-hydroxyapatite (nHA) and reduced graphene oxide (rGO) sheets was fabricated by self-assembly, and a 20 wt% nHA-rGO sheet solution formed the most stable hydrogel. In vitro, nHA-rGO scaffolds killed all but 8% of osteosarcoma cells (MG-63) under 808 nm near-infrared laser irradiation for 20 min. SEM images and live/dead staining of MG-63 cells in nHA rGO also confirmed the therapeutic efficacy of the scaffolds. Tumors implanted with nHA-rGO scaffolds reached 60 degrees C after 4 min. of irradiation; xenografted tumors stopped growth or even decreased in size after photothermal therapy. In vitro the scaffolds promoted adhesion, proliferation, and osteogenic mineralization of rat bone marrow stem cells (rBMSCs). Live cell staining and CCK 8 showed good proliferation for rBMSCs in nHA-rGO scaffolds. Alkaline phosphatase activity and qPCR demonstrated osteogenic mineralization of rBMSCs in nHA-rGO scaffolds. Micro-CT and histology verified that the scaffold promotes bone regeneration in rat cranial defects. At 8 weeks, 35% of the cranial defect area remained in the scaffold-implanted group, while 80% remained for the control. Bone mineral density of the scaffold-implanted group reached 284.58+/-20.78 mg/cm3, indicating new bone mineral deposition, versus only 96.04+/-2.67 mg/cm3 for the control. Histology showed scaffold stimulation of osteoblast mineralization and collagen deposition. Therefore, nHA-rGO scaffolds may be an effective treatment of large tumor-related bone defects due to their excellent photothermal and osteogenic effects. PMID- 30305210 TI - Redox-Sensitive Folate-Conjugated Polymeric Nanoparticles for Combined Chemotherapy and Photothermal Therapy Against Breast Cancer. AB - We have developed redox-sensitive folic acid-conjugated PCL-PEG-PCL (PCEP) nanoparticles for co-delivering chemotherapeutic agent doxorubicin (DOX) and imaging and hyperthermia agent indocyanine green (ICG) with simultaneous imaging and combined therapy for breast cancer. DOX and ICG were entrapped into PCEP nanoparticles through the thin-film hydration and ultrasonic dispersion. Then nanoparticles were surface decorated with folic acid ligands against FR overexpressing breast cancers. Drug-loading nanoparticles exhibited an enhanced reduction-sensitivity in the presence of 10 mM glutathione. Nanoparticle-mediated treatment had synergistic cytotoxicity against mammary cancer cells. The conjugation of folic acid improved the uptake of nanoparticles in EMT-6 breast cancer overexpressing cell lines, and the uptake efficacy of DOX was remarkably increased by the laser irradiation. Furthermore, ex vivo fluorescence imaging confirmed that folate conjugation also improved drug accumulation in tumor. Our unique FA-DINPs system has potential for combination of chemotherapy and photothermal therapy for breast cancer. PMID- 30305211 TI - Noninvasive and Local Delivery of Adenoviral-Mediated Herpes Simplex Virus Thymidine Kinase to Treat Glioma Through Focused Ultrasound-Induced Blood-Brain Barrier Opening in Rats. AB - Adenoviral-mediated gene therapy has been shown great prospects for tumor treatment. However, it is still a great challenge for its application in the glioma. A main cause is the blood-brain barrier (BBB) limits the delivery of adenoviral vectors, greatly compromising their efficacy. Here, we used focused ultrasound (FUS) induced microbubble cavitation to locally and reversibly open BBB for enhancing gene delivery. In this study, Ad-CMV-TK-IRES-EGFP (Ad-HSV-TK EGFP) carrying the herpes simplex virus thymidine kinase (HSV-TK) and EGFP transgenes was chose as gendicine and Ad-CMV-IRES-EGFP (Ad-EGFP) as the control. The in vitro experiments showed that Ad-HSV-TK-EGFP had a high infection efficiency for C6 glioma cells, producing good tumor cell killing effects when these cells were exposed to more than 10 MUg/ml ganciclovir (GCV). Taking advantage of FUS-induced BBB opening, Ad-HSV-TK-EGFP could be effectively delivered into the brain tumors, getting the overexpression of HSV-TK gene in the tumor cells. After exposure to GCV, the significantly stronger anti-tumor efficacy and longer survival time were observed in tumor-bearing mice treated with Ad-HSV-TK-EGFP + FUS than those treated with Ad-EGFP + FUS or only Ad-HSV-TK EGFP. Histological examination indicated that the reduced expression level of Ki67 proteins and the increased apoptotic tumor cells in tumor xenografts, causing the inhibition of tumor growth. In conclusion, our study provided a new strategy to efficiently and locally deliver recombinant adenoviral vector mediated HSV-TK gene into the brain to treat glioma. PMID- 30305212 TI - Study of Key Biological Pathways and Important microRNAs Involved in Silver Nanoparticles Induced Cytotoxicity Based on microRNA Sequencing Technology. AB - The aim of this study was to screen and research key biological pathways and important microRNAs (miRNAs) involved in silver nanoparticles (SNPs) induced cytotoxicity using miRNA sequencing technology. First, the influences of five SNPs with different sizes (~5, ~20, ~50, ~100 and ~200 nm), named as SNP-5, SNP 20, SNP-50, SNP-100, and SNP-200, on human dermal fibroblasts (HDFs) proliferation were evaluated by MTT assay after 4, 8, 12, 24, 48 and 72 h. miRNA sequencing technology was then utilized to screen differentially expressed miRNAs in SNPs treated HDFs for 4 h. Bioinformatics analysis was performed to screen key biological pathways and important miRNAs in SNP-induced cytotoxicity. Finally, the functions of key biological pathways and expression level of important miRNAs were verified using different cellular/molecular biology experiments. MTT results showed that the effect of SNP-5 on cell proliferation was greatest at all-time points, while the effect of SNP-20 was minimal. miRNA sequencing results showed that 457, 76, 177, 461 and 341 miRNAs were found to be differentially expressed in HDFs after treatment with five SNPs. Biological pathway analysis for differentially expressed miRNAs revealed that MAPK signaling pathway played a key role in SNP-induced cytotoxicity and its functions were verified by cell cycle and cell apoptosis tests. Four important miRNAs (miR-424-5p, miR-340-5p, miR-30b 5p, and miR-132-3p) were screened and expressions of miR-424-5p and miR-340-5p were confirmed by qRT-PCR. In conclusion, results from this study suggested that the SNPs arrested cell cycle, promoted cell apoptosis and finally induced cytotoxicity mainly through the MAPK signaling pathway. The expression of two important miRNAs had strong correlation with cytotoxicity of differently sized SNPs. PMID- 30305213 TI - Preparation of Graphene Oxide-Based Supramolecular Hybrid Nanohydrogel Through Host-Guest Interaction and Its Application in Drug Delivery. AB - Graphene oxide (GO) has attracted a wide attention for its excellent mechanical, thermal properties and unique two-dimensional structure. In this work, A new GO based supramolecular hybrid nanohydrogel was prepared, in which GO as the cross links was incorporated into the above hydrogel through non-covalent functionalization to enhance the mechanical properties and control morphology. A 1-pyrenebutyric acid (Py) modified low-molecular weight (MW) mPEG was firstly synthesized via a simple esterification reaction. Then, low-MW mPEG functionalized GO (GO-Py-PEG) was obtained due to the strong pi-pi stacking interaction between Py and GO. The combination of the host-guest interaction between mPEG and -CD and addition of GO lastly leaded to the formation of supramolecular hybrid nanohydrogel. Various techniques including UV-vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA) and transmission electron microscopy (TEM) were used to thoroughly characterize the hybrid hydrogel. More interestingly, the results of rheology studies and scanning electron microscopy (SEM) revealed that the mechanical strength and morphology of hybrid hydrogel was improved by the incorporation of GO. Meanwhile, doxorubicin hydrochloride (DOX) as a model drug was loaded into hybrid hydrogel, and the in vitro released behavior was studied under different pH values. The results showed that the formed hybrid hydrogel could release DOX over 50 h in a sustained manner. In addition, in vitro and in vivo experiments, GO-Py-PEG-alpha-CD@DOX hydrogel (hydrogel@DOX) dramatically shows the inhibition of tumor cell proliferation and tumor growth. At the same time, HE staining results show hydrogel@DOX can significantly reduce the side effects of DOX. We believe that the development of such hybrid hydrogels will provide important potential for medical applications. PMID- 30305214 TI - Delivering the Acetylcholine Neurotransmitter by Nanodrugs as an Effective Treatment for Alzheimer's Disease. AB - The current clinical symptomatic therapy for Alzheimer's disease involves increasing acetylcholine levels in the brain by inhibiting acetylcholinesterase. However, the effectiveness of acetylcholinesterase inhibitors decreases as the disease progresses, leading to many side effects including over-inhibition of other enzymes and hepatic injury. Herein, we investigate the effects of the direct delivery of a low-dose of acetylcholine via human serum albumin nanoparticles to brain. This novel nanodrug improved both spatial learning and memory capability, whereas it reduced oxidative damage in mice. More importantly, damage to the liver or interference with the inherent neurotransmitter generation due to supplementation were almost absent. Our study is the first to demonstrate that supplementation of acetylcholine-loaded nanoparticles might offer a better therapeutic option in the ease of Alzheimer's disease. PMID- 30305215 TI - Oral Administration of Liposome-Apatinib and Locally Delivery of Docetaxel/MPEG PCL by Fibrin Glue Synergistically Improve Therapeutic Effect in Colorectal Cancer. AB - Colorectal cancer is one of the most common and malignant cancer in the world wide. Recently, combination of target therapy and chemotherapy has generated new promise for colorectal cancer. Apatinib mesylate is a novel and highly selective VEGFR-2 inhibitor, presented with an outstanding activity of anti-angiogensis, which has the potential for treating various tumors. As a traditional chemotherapeutic drug, docetaxel (Taxotere) is a widely used semisynthetic taxoid in solid tumors. In this study, Liposome and Methoxy poly(ethylene glycol) poly(epsilon-caprolactone) (MPEG-PCL) were constructed as drug delivery system for the delivery of apatinib (Lipo-Apa) and docetaxel (DOC/M), respectively. Co administration of Lipo-Apa and DOC/M showed synergistically effects on inhibiting cell proliferation and inducing cell apoptosis of CT26 cells in vitro. Moreover, fibrin glue, as a biocompatible adherent hemostat, was used as a kind of vehicle for locally delivery of DOC/M in animal models, for achieving locally high concentration and prolonging releasing time. Combination of Lipo-Apa by gavage and locally delivery of DOC/M showed significantly improved anti-tumor activity in a subcutaneous xenograft model as well as in the abdominal metastasis model of colorectal cancer. In addition, promoted tumor apoptosis, inhibited proliferation and decreased tumor angiogenesis were presented by the co-administration. Finally, our study suggested that combination of oral administration of Lipo-Apa and locally delivery of DOC/M by fibrin glue, has the potential to be applied clinically in colorectal cancer therapy. PMID- 30305216 TI - Self-Assembled Nanoparticle Mediated Survivin-T34A for Ovarian Cancer Therapy. AB - Gene therapy is emerging as a promising tool for cancer treatment. Down regulation of survivin gene can lead to the cancer inhibition. However, the lack of efficient and safe gene delivery system is still a critical obstacle to clinical gene therapy. In this study, we use a biodegradable nanoparticle to deliver human survivin-T34A (T34A) to dominant-negatively regulate survivin gene for ovarian cancer therapy. This nanoparticle, self-assembled from monomethoxy poly(ethylene glycol)-poly(D,L-lactide) (MPEG-PLA) copolymer and N-[1-(2,3 dioleoyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTAP), has high transfection capability and negligible cytotoxicity. The nanoparticle-delivered T34A gene can efficiently inhibit the growth of SKOV3 ovarian cancer cells through induction of apoptosis in vitro. After intraperitoneal injection, the nanoparticle-delivered T34A gene significantly inhibited the growth of intraperitoneal metastasis of SKOV3 ovarian cancer, with no obvious adverse effects. Our data suggest that the nanoparticle-delivered T34A gene has promising clinical applications in ovarian cancer treatment. PMID- 30305217 TI - Polylactide-Cholesterol Stereocomplex Micelle Encapsulating Chemotherapeutic Agent for Improved Antitumor Efficacy and Safety. AB - For efficient therapy, optimized polymer micelle drug delivery systems require stability during circulation, appropriate diameters for targeting, and controlled drug release at the lesion site. To enhance the stability, adjust the sizes, and improve the selectivity of drug release of micelles from polylactides and polypeptides, stereocomplex interaction has been introduced. Herein, the cholesterol (CHOL)-enhanced doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (CDM/DOX), poly(L-lactide)-based micelle (CLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric 4-armed poly(ethylene glycol)-polylactide copolymers were reported to enhance tumor cell uptake and control drug release for treatment of cervical carcinoma. The introduction of hydrophobic CHOL further upregulated the stability, drug-loading capability, and cell uptake of micelles. All these DOX-loaded micelles showed appropriate sizes of ~100 nm for the enhanced permeability and retention (EPR) effect. Compared to CDM/DOX and CLM/DOX, SCM/DOX exhibited the highest cell uptake and the most efficient antitumor efficacy in vitro. For U14 cervical carcinoma mouse model, all of the DOX-loaded micelles, especially SCM/DOX, effectively inhibited the progression of cervical carcinoma, as demonstrated by nearly stagnant tumor growth and increased apoptosis and necrosis areas within tumor tissue. Furthermore, these DOX-loaded micelles effectively alleviated the systemic toxicity of DOX. All the above results suggest that the DOX-loaded micelles, especially SCM/DOX, are an ideal drug delivery system for combating cervical carcinoma. PMID- 30305218 TI - Synthesis, Characterization, and Biological Study of Carboxyl- and Amino-Rich g C3N4 Nanosheets by Different Processing Routes. AB - Graphitic-phase carbon nitride (g-C3N4) is a graphene analogue, which has attracted much attention for its unique physicochemical properties. The bulk g C3N4 is often fragmented and ionized to nanosheets, obtaining improved performance or confer novel properties. It is reported that g-C3N4 nanosheets using different processing methods can be modified with different functional groups, resulting in different electrical characteristics. However, the surface charge of g-C3N4 nanosheets is seldom mentioned as a factor influencing their biological applications. In our present study, we prepared two kinds of uniformly dispersed g-C3N4 nanosheets of high quality, the carboxyl- and amino-rich g-C3N4 nanosheets. Although both the carboxyl- and amino-rich g-C3N4 nanosheets displayed good biocompatibility in vitro and in vivo, however, they are at very different levels of surface charge, which are relative to different cellular uptake, penetration mechanism and lysosome escape ability of the nanosheets. PMID- 30305219 TI - Wnt Pathway-Mediated Nano TiO2-Induced Toxic Effects on Rat Primary Cultured Sertoli Cells. AB - Nanosized titanium dioxide (Nano TiO2) has been widely used in daily lives, medicine, industry, and caused the potential reproduction toxicity for animals and human, however, the underlying molecular mechanisms for the reproductive toxicity of nano TiO2 are still largely unclear. In the present study, when primary cultured rat Sertoli cells (SCs) were exposed to nano TiO2, cell injury and alterations in wingless related MMTV integration site (Wnt) pathway-related factors including Wnt1, Wnt3a, Wnt5a, Wnt11, beta-catenin, and p-GSK-3beta expression were investigated. The results suggested that nano TiO2 could be translocated to cytoplasm or nucleus, and decreased cell viability, and impaired morphological structures of SCs, induced apoptosis and dead of primary cultured rat SCs. Furthermore, nano TiO2-induced the toxicity of primary cultured rat SCs was associated with increased expression of Wnt1, Wnt3a, Wnt5a, Wnt11, and beta catenin and involved with reduced p-GSK-3beta expression. Therefore, this implies that nano TiO2-induced toxic effects on SCs may be associated with Wnt signaling pathways. PMID- 30305220 TI - Pulsed Magnetic Field Stimuli Can Promote Chondrogenic Differentiation of Superparamagnetic Iron Oxide Nanoparticles-Labeled Mesenchymal Stem Cells in Rats. AB - Mesenchymal stem cells (MSCs) have potential uses for cartilage repair due to the potential of chondrogenic differentiation. However, developing effective approaches to regulate chondrogenesis in vivo remains a big challenging. To address the limitations, we propose the application of magnetic fields, which features excellent performance for tissue penetration, good biocompatibility even at high magnetic strength, and wireless remote control. To test this concept, a pulsed magnetic field (PMF) was used to enhance the chondrogenesis of SPIO labeled MSCs in a rat model of cartilage defects. The SPIO labeling not only efficiently strengthens the responsiveness of MSCs to the externally applied PMF but also enables in vivo non-invasive monitoring of MSCs with magnetic resonance imaging (MRI). Importantly, biochemical and gene expression analysis reveal the upregulation of certain cartilage biomarkers (i.e., SOX9 and COL2A1), showing that the PMF improves the chondrogenesis of MSCs via activation of the TGF beta/SMAD signaling pathways. These results indicate a promising scheme for stem cell-based cartilage repair. PMID- 30305221 TI - Hypoglycemic Bioactivity of Novel Eco-Friendly Carbon Dots Derived from Traditional Chinese Medicine. AB - Although recent research on intrinsic bioactivities of carbon dots is expanding, it is focused on basic aspects, which creates the need for broadening our knowledge about carbon dots to expand their uses in biomedical sciences and facilitate their application in clinical practice. Jiaosanxian is a charcoal traditional Chinese medicine with a pronounced effect on promoting appetite and digestion that is widely used as dyspepsia therapy in China. To study the underlying mechanism and the material requirements, we investigated carbon dots which was generated in the charcoal processing. In this study, we developed Jiaosanxian-derived carbon dots (JSX-CDs) with an average diameter of 4.4-6.4 nm. No further modifications or external surface passivation agents were required because Jiaosanxian naturally contains carbon, nitrogen, and oxygen. We found that carbon dots derived from different charcoal traditional Chinese medicines had both similarities and differences in their structural features, physicochemical properties, and bioactivities. Due to an abundance of surface groups, JSX-CDs showed a distinct solubility and bioactivity. In this study, we established a modified hyperglycemia model in mice to evaluate the hypoglycemic activity of JSX-CDs. We found that JSX-CDs were effective in regulating blood sugar and appeared to be very safe, indicating its potential use as a hypoglycemic agent. Our results do not only provide guidance for further research on intrinsic bioactivities of CDs but also give new insights into their potential biomedical and healthcare applications. PMID- 30305222 TI - Aptamer-Based Electrochemical Biosensor for Mercury Ions Detection Using AuNPs Modified Glass Carbon Electrode. AB - A mercury ion aptamer electrochemical biosensor based on a Thymine-Hg2+-Thymine (T-Hg2+-T) structure has been constructed and successfully used to detect mercury ions in tap water samples. The aptamer electrochemical biosensor was assembled using a mercury ion aptamer-functionalized AuNPs-modified glass carbon electrode (aptamer/(AuNPs/CS)2/GCE) capable of specifically detecting mercury ions through a T-Hg2+-T structure. The experimental results indicated the optimum electrochemical performance of the prepared aptamer biosensor when the (AuNPs/CS)2/GCE surface was modified with 1.0 MUM aptamer and incubated with Hg2+ for 60 min. Moreover, the aptamer biosensor exhibits a good linear relationship between the logarithm of the Hg2+ concentration and the DPV peak current in the range from 0.01 to 500 nM following the linearization equation Ip (MUA) = 2.59902 + 0.2097logC (R2 = 0.9994) with a limit of detection as low as 0.005 nM. Therefore, the constructed aptamer biosensor provides a simple and sensitive approach for Hg2+ detection in aqueous solution with promising application for trace Hg2+ detection in real samples. PMID- 30305223 TI - Perfluorocarbon Nanocapsules Improve Hypoxic Microenvironment for the Tumor Ultrasound Diagnosis and Photodynamic Therapy. AB - Amelioration of hypoxia is an important factor increasing the effects of anti tumor therapies. In the present experiments, nanocapsules of poly(lactide-co glycolide)-poly(ethylene glycol)/perfluorooctyl bromide (PFOB)/photosensitizers (IR780) have been developed to increase oxygen concentration inside the tumor and improve the outcome of photodynamic therapy (PDT). PFOB has high oxygen solubility, and IR780 is a photosensitizer particularly suited for a highly effective photodynamic therapy under the 808-nm laser irradiation. Thus, PFOB provides sufficient oxygen for the reaction with the photosensitizer, producing more singlet oxygen to induce cell apoptosis. The photodynamic effect of nanocapsules was confirmed to be enhanced after addition of PFOB through simulation experiments in vitro in the hypoxic microenvironment. The results have demonstrated that due to the addition of PFOB the nanocapsules can provide a contrast-enhanced ultrasound diagnosis and ensure more notable inhibition of the growth of lung tumors following the 808 nm laser irradiation. Furthermore, the nanocapsules allowed the photosensitizers to achieve sufficient therapeutic potential, which was optimal under the conditions of modest hypoxia with about 5% oxygen concentration. PMID- 30305224 TI - Fine Particulate Matter (PM2.5) Promoted the Invasion of Lung Cancer Cells via an ARNT2/PP2A/STAT3/MMP2 Pathway. AB - Accumulating evidence indicates that fine particulate matter (PM2.5) exposure is associated with many cardiopulmonary diseases, particularly lung carcinoma. Nevertheless, the underlying biological mechanisms by which PM2.5 exposure initiates and aggravates lung carcinoma remain elusive. In the present study, we collected PM2.5 in Nanjing and explored the mechanisms underlying the oncogenic roles of PM2.5 in the murine lung carcinoma cell line LLC in vitro and in vivo. PM2.5 was closely attached to and internalized by lung cancer cells. Moreover, PM2.5 increased the production of ARNT2 and the inactivation of the tumor suppressor B56gamma-PP2A, which was followed by the activation of ps727STAT3 and the enhancement of invasive ability by MMP-2. Furthermore, we took advantage of an orthotopic lung carcinoma metastasis mouse model to illustrate the prometastatic effect of PM2.5 in vivo; our results suggested that the ARNT2/PP2A/STAT3/MMP-2 cascade played a key role in PM2.5-related oncogenicity. Finally, we observed that PM2.5 was deposited in human lung carcinoma tissues, indicating that this potential pathway may also be involved in human lung carcinoma. These findings demonstrated that fine particulate matter, or PM2.5, promoted the invasion of lung cancer cells via an ARNT2/PP2A/STAT3/MMP2 pathway, which may be targeted to alleviate the tumorigenic effect of PM2.5 in lung cancer. PMID- 30305225 TI - Antibody Modified Nanoparticle-Mediated Delivery of miR-124 Regulates Apoptosis via Repression the Stat3 Signal in Mycobacterial-Infected Microglia. AB - The mechanism of Mycobacterium tuberculosis (M.tb) evasion of host cell remains elusive. Several microRNAs that are involved in this complex process were identified. miRNA interference-based therapeutics represents an attractive challenge and shows huge potential for disorder treatment. In this study, we found that miR-124-3p expression is significantly decreased in microglia after Mycobacterium marinum (M.m) infection. To achieve better target transfection effect, a CD11b antibody and PEI modified nanoparticles-based Nano platform had been developed. This system was equipped by conjugation of miRNA-124-3p onto the surface of nanoparticles with a PEI/CD11b antibody coating. Transfection with miR 124-3p promoted microglia apoptosis through upregulation of Caspase3 or downregulation of Bcl-2 and Bcl-xl. More importantly, transfection with miR-124 3p inhibitor increases the mycobacterium proliferation in microglia. Based on the above, we further found miRNA-124-3p to bind to 3'untranslated region of Stat3, resulting in the downregulation of its protein to trigger cells apoptosis through Stat3-related pathway. As such, our research might provide new insights towards target delivering miRNA through the bold-brain barrier (BBB) and exploiting highly effective anti-tuberculous meningitis drugs. Taken together, our findings suggest how Mycobacterium can manipulate host miRNA expression to regulate cell survival for its own proliferation, and highlight the importance to develop novel therapeutic strategies against tuberculous meningitis. PMID- 30305226 TI - The Response of Liposomes Modified with Lysosomal Membrane Proteins to the Targeting Ability Associated with Antimicrobial Activity. AB - Liposomes were modified using two different methods. In Method 1, liposomes were modified by mixing whole lysosomal proteins, lipid, and cholesterol before preparation. For Method 2, the liposomes were modified by mixing whole lysosomal proteins after liposome preparation. Method 1-modified liposomes exhibited improved cell mortality compared to Method 2-modified liposomes. The modified liposomes were then evaluated for their antimicrobial activity against lysosomal enzymes, and Escherichia coli did not modify the liposome surface. The whole lysosomal membrane proteins extracted from the lysosomes in Saccharomyces cerevisiae were analyzed using two-dimensional electrophoresis to find specific proteins associated with antimicrobial activity and to construct recombinant S. cerevisiae proteins. Additionally, genes related to antimicrobial activity were identified, and the liposomes modified by lysosomal membrane proteins of recombinant S. cerevisiae tagged with green fluorescence proteins were prepared and overexpressed. The modified liposomes exhibited improved antimicrobial activity with an almost two-fold increase in the cell mortality rate, suggesting crucial roles as potential therapeutics. PMID- 30305227 TI - Magnolol Nanoparticles Exhibit Improved Water Solubility and Suppress TNF-alpha Induced VCAM-1 Expression in Endothelial Cells (Journal of Biomedical Nanotechnology, Vol. 13(3), pp. 255-268 (2017)). PMID- 30305229 TI - Author Index to Volume 14, Numbers 1-12, 2018. PMID- 30305228 TI - Table of Contents to Volume 14, Numbers 1-12, 2018. PMID- 30305231 TI - Update on neuroblastoma. AB - : Neuroblastoma is an embryonic cancer arising from neural crest stem cells. This cancer is the most common malignancy in infants and the most common extracranial solid tumor in children. The clinical course may be highly variable with the possibility of spontaneous regression in the youngest patients and increased risk of aggressive disease in older children. Clinical heterogeneity is a consequence of the diverse biologic characteristics that determine patient risk and survival. This review will focus on current progress in neuroblastoma staging, risk stratification, and treatment strategies based on advancing knowledge in tumor biology and genetic characterization. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level II. PMID- 30305232 TI - Two-point ultrasound-guided transversus abdominis plane injection in canine cadavers - a pilot study. AB - OBJECTIVE: This study evaluated the spread of a two-point transversus abdominis plane (TAP) injection in canine cadavers. Compared with previous techniques, the two-point TAP injection was developed to increase the consistency of local anaesthetic spread to the nerve segments T11, T12, L1, L2 and L3. STUDY DESIGN: Prospective experimental trial. ANIMALS: Five fresh canine cadavers. METHODS: Two point TAP injections were performed under ultrasound guidance by a single trained individual in canine cadavers (15.7-43.0 kg). Each hemi-abdomen was infiltrated and evaluated independently for a total of 10 evaluations of the technique. The first injection was performed at the level of the costo-chondral junction of the thirteenth rib, and the second injection was performed cranial to the tuber coxae. Each injection comprised 0.3 mL kg-1 methylene blue solution (0.0015 mg mL 1). Ten minutes after the injections, abdominal wall dissection was performed, and any nerves stained for a minimum of 10 mm along their long axis were identified and recorded. RESULTS: During all injections, separation of the internal oblique and transversus abdominis muscles was observed on ultrasound. On dissection, branches of T12, T13, L1, L2 and L3 were adequately stained in 30%, 100%, 100%, 90% and 90% of injections, respectively. No staining of branches of T11 occurred in any of the cadavers. In one hemi-abdomen, branches of L1 and L3, but not L2, were stained. CONCLUSIONS AND CLINICAL RELEVANCE: This study indicates that the two-point TAP injection delivers consistent dye dispersion to adequately stain branches of T13, L1, L2 and L3, with no coverage of T11 and poor coverage of T12, in fresh canine cadavers. An in vivo study using local anaesthetic should be performed to evaluate the analgesic efficacy of this technique in mid to caudal abdominal surgeries. PMID- 30305233 TI - The use of rapamycin in patients with tuberous sclerosis complex: Long-term results. AB - PURPOSE: The purpose of this study was to evaluate the long-term results of eight cases diagnosed with tuberous sclerosis complex (TSC) and receiving rapamycin therapy because of epileptic seizures and/or accompanying TSC findings. METHOD: Rapamycin therapy was initiated at a dose of 1.5 mg/m2. Seizure frequency, electroencephalographic (EEG) findings, renal and cranial imaging findings, and cutaneous lesions over 3- to 6-month periods during follow-up and treatment were evaluated. RESULTS: Four girls and four boys aged 4-16 years at the start of rapamycin therapy and now aged 9-24 years were evaluated. Duration of rapamycin therapy was 1-5 years, and the monitoring period after commencement of rapamycin therapy lasted 5-8 years. Positive effects were observed at 9-12 months in three out of six cases of renal angiomyolipoma (AML) and in the second year of treatment in one. An increase in AML dimensions was observed in three cases after treatment was stopped. Seizure control was established in the first year of rapamycin therapy in all cases. An increased frequency of seizures was observed in three cases after the second year of treatment. No seizure recurrence was determined in the second year of treatment with rapamycin in five out of eight cases. Recurrence of seizure was observed in 6-12 months after the discontinuation of rapamycin in three cases. CONCLUSION: Rapamycin therapy exhibits positive effects on epileptic seizures in cases of TSC in 1-2 years but these positive effects on seizure control of rapamycin therapy decline after the second year. Larger case series are still needed to determine the duration and effectiveness of treatment in childhood. PMID- 30305234 TI - Novel Xp21.1 deletion associated with unusual features in a large McLeod syndrome kindred. PMID- 30305235 TI - The association between fat mass and the risk of breast cancer: A systematic review and meta-analysis. AB - BACKGROUND & AIMS: Several cohort and case-control studies examined the association between fat mass (FM) and the risk of breast cancer; however, findings are conflicting. The purpose of the present study was to systematically review this association and conducted a meta-analysis, if possible. METHOD: A systematic search of PubMed/Medline, Scopus, Web of Science and Embase databases was conducted for cohort and case-control studies, between January 2000 and 31 March 2018 with no language limitations. Multivariate adjusted relative risk (RR) estimates with 95% confidence intervals (CI) for each category of FM were pooled to examine the association. RESULTS: Finally, 12 papers were considered for quantitative synthesis. The pooled RR for the highest vs. the lowest FM (%) of cohort studies was 1.44 (95% CI: 1.33, 1.56; I2: 63.3%, p = 0.008). The overall effect size for adjusted case-control studies showed no significant association (1.49, 95% CI: 0.77, 2.90; I2: 93.2%; p = 0.001). After stratification by menopause, it was revealed that the association between FM and the risk of breast cancer in post menopausal women (2.29, 95% CI: 1.12, 4.68; I2: 92%, p = 0.0001) was significant, while there was no significant association in pre-menopausal women (0.68, 95% CI: 0.18, 2.58; I2: 81.3%; p = 0.02). CONCLUSION: Cohort studies showed that higher FM is positively associated with the risk for breast cancer. However, only case-control studies on post-menopausal women showed a positive link. Due to limited studies and high heterogeneity, findings should be interpreted with caution. More cohort studies are needed to clarify this association. PMID- 30305236 TI - Biometrics and public health surveillance in criminalised and key populations: policy, ethics, and human rights considerations. AB - Widespread public health surveillance efforts focused on key populations (men who have sex with men, sex workers, people who inject drugs, and others) gather data on population sizes, HIV prevalence, and other information for planning and resource allocation. Biometric identification might improve this data gathering. However, in the context of extensive criminalisation of these populations, the use of biometrics such as fingerprints raises concerns that are insufficiently addressed in current policies. These concerns include infringing privacy, exposing participants to risks of legal action or violence, biasing surveillance results, and undermining trust in the health system. We set out key ethics and human rights considerations regarding the use of biometrics in HIV surveillance among these populations, and outline a typology of jurisdictions wherein such methods might be considered, based on data about legal, political, and social environments. In this Review, we suggest that the biometrics approach is not currently likely to be appropriate in many jurisdictions. PMID- 30305237 TI - Corrigendum to "Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model." [Atherosclerosis 274 (July 2018) 120-127]. PMID- 30305238 TI - Depression, treatable cardiovascular risk factors and incident cardiac events in the Gazel cohort. AB - BACKGROUND: Depression is an important risk factor of cardiovascular disease (CVD), a leading cause of death worldwide. One of the reasons underlying this association may be that depression modifies the association between treatable cardiovascular risk factors and cardiac events (angina pectoris or myocardial infarction). We tested this hypothesis in a cohort study of middle-aged men and women in France followed for 20 years. METHODS: 10,541 Gazel working men and women free of cardiovascular disease at baseline (1993) were followed-up over 20 years for validated incident cardiac events. Depression was measured at baseline and every three years with the Center for Epidemiological Studies-Depression (CES D). We used time-dependent Cox regression models to calculate hazard ratios (HR) of cardiac events associated with depression, main treatable cardiovascular risk factors (hypertension, diabetes, and dyslipidemia), and their interactions, adjusting for demographic, lifestyle and clinical characteristics. RESULTS: Over 20 years of follow-up, 592 incident cases of cardiac events were identified. Depression was significantly associated with incident cardiac events (HR 1.55, P = 0.002), as was hypertension (HR 1.49, P = 0.02), diabetes (HR 2.54, P = 0.001), and dyslipidemia (HR 1.55, P = 0.003). No statistically significant interactions were observed between depression and hypertension, diabetes or dyslipidemia in relation to incident cardiac events (all P >= 0.16). CONCLUSIONS: The association between depression and cardiac events is unlikely to be explained by a heightened impact of hypertension, diabetes or dyslipidemia. PMID- 30305241 TI - Role of early life nutrition on regulating the hypothalamic-anterior pituitary testicular axis of the bull AB - The objective of this study was to examine the effect of nutrition during the first 18 weeks of life on the physiological and transcriptional functionality of the hypothalamic (arcuate nucleus region), anterior pituitary and testes in Holstein-Friesian bull calves. Holstein-Friesian bull calves with a mean (+/ S.D.) age and bodyweight of 19 (+/-8.2) days and 47.5 (+/-5.3) kg, respectively, were assigned to either a HIGH (n = 10) or LOW (n = 10) plane of nutrition, to achieve an overall target growth rate of 1.2 or 0.5 kg/day, respectively. At 126 +/- 1.1 days of age, all calves were euthanised. Animal performance (weekly) and systemic concentrations of metabolic (monthly) and reproductive hormones (fortnightly) were assessed. Testicular histology, targeted gene and protein expression of the arcuate nucleus region, anterior pituitary and testes were also assessed using qPCR and immunohistochemistry, respectively. The expression of candidate genes in testicular tissue from post pubertal 19-month-old Holstein Friesian bulls (n = 10) was compared to that of the 18-week-old calves. Metabolite and metabolic hormone profiles generally reflected the improved metabolic status of the calves on the HIGH (P< 0.001). Calves offered a HIGH plane of nutrition were heavier at slaughter (P < 0.001), had larger testes (P < 0.001), larger seminiferous tubule diameter (P < 0.001), more mature spermatogenic cells (P < 0.001) and more Sertoli cells (P < 0.05) in accordance with both morphological and transcriptional data. Overall, testicular gene expression profiles suggested a more mature stage of development in HIGH compared with LOW and were more closely aligned to that of mature bulls. Ghrelin receptor was the only differentially expressed gene between LOW and HIGH calves in either the anterior pituitary (P < 0.05) or arcuate nucleus region of the hypothalamus (P < 0.10) and was upregulated in LOW for both tissues. This study indicates that an enhanced plane of nutrition during early calfhood favourably alters the biochemical regulation of the hypothalamus-anterior pituitary-testicular axis, advancing testicular development and hastening spermatogenesis. PMID- 30305239 TI - Genetic contributors to serum uric acid levels in Mexicans and their effect on premature coronary artery disease. AB - BACKGROUND: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS: Only two loci were associated with SUA levels: SLC2A9 (beta = -0.47 mg/dl, P = 1.57 * 10-42 for lead SNP rs7678287) and ABCG2 (beta = 0.23 mg/dl, P = 2.42 * 10-10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS: SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD. PMID- 30305242 TI - Spexin: A novel regulator of adipogenesis and fat tissue metabolism. AB - Spexin (SPX, NPQ) is a novel peptide involved in the regulation of energy metabolism. SPX inhibits food intake and reduces body weight. In obese humans, SPX is the most down-regulated gene in fat. Therefore, SPX might be involved in the regulation of lipid metabolism. Here, we study the effects of SPX on lipolysis, lipogenesis, glucose uptake, adipogenesis, cell proliferation and survival in isolated human adipocytes or murine 3T3-L1 cells. SPX and its receptors, GALR2 and GALR3, are present at mRNA and protein levels in murine 3T3 L1 cells and human adipocytes. SPX inhibits adipogenesis and down-regulates mRNA expression of proadipogenic genes such as Ppargamma, C/ebpalpha, C/ebpbeta and Fabp4. SPX stimulates lipolysis by increasing the phosphorylation of hormone sensitive lipase (HSL). Simultaneously, SPX inhibits lipogenesis and glucose uptake in human adipocytes and murine 3T3-L1 cells. SPX has no effect on murine 3T3-L1 cell proliferation and viability. Moreover, our research showed that the SPX effect on adipocytes metabolism is mediated via GALR2 and GALR3 receptors. SPX is a novel regulator of lipid metabolism in murine 3T3-L1 and human adipocytes. PMID- 30305243 TI - A critical appraisal of the measurement of serum 'cholesterol efflux capacity' and its use as surrogate marker of risk of cardiovascular disease. AB - The 'cholesterol efflux capacity (CEC)' assay is a simple in vitro measure of the capacities of individual sera to promote the first step of the reverse cholesterol transport pathway, the delivery of cellular cholesterol to plasma HDL. This review describes the cell biology of this model and critically assesses its application as a marker of cardiovascular risk. We describe the pathways for cell cholesterol export, current cell models used in the CEC assay with their limitations and consider the contribution that measurement of serum CEC provides to our understanding of HDL function in vivo. PMID- 30305245 TI - Extended-resolution imaging of the interaction of lipid droplets and mitochondria. AB - Physical contacts between organelles play a pivotal role in intracellular trafficking of metabolites. Monitoring organelle interactions in living cells using fluorescence microscopy is a powerful approach to functionally assess these cellular processes. However, detailed target acquisition is typically limited due to light diffraction. Furthermore, subcellular compartments such as lipid droplets and mitochondria are highly dynamic and show significant subcellular movement. Thus, high-speed acquisition of these organelles with extended resolution is appreciated. Here, we present an imaging informatics pipeline enabling spatial and time-resolved analysis of the dynamics and interactions of fluorescently labeled lipid droplets and mitochondria in a fibroblast cell line. The imaging concept is based on multispectral confocal laser scanning microscopy and includes high-speed resonant scanning for fast spatial acquisition of organelles. Extended-resolution is achieved by the recording of images at minimized pinhole size and by post-processing of generated data using a computational image restoration method. Computation of inter-organelle contacts is performed on basis of segmented spatial image data. We show limitations of the image restoration and segmentation part of the imaging informatics pipeline. Since both image processing methods are implemented in other related methodologies, our findings will help to identify artifacts and the false interpretation of obtained morphometric data. As a proof-of-principle, we studied how lipid load and overexpression of PLIN5, considered to be involved in the tethering of LDs and mitochondria, affects organelle association. PMID- 30305244 TI - Intake of stigmasterol and beta-sitosterol alters lipid metabolism and alleviates NAFLD in mice fed a high-fat western-style diet. AB - OBJECTIVE: To investigate and compare the effects of two common dietary phytosterols, stigmasterol and beta-sitosterol, in altering lipid metabolism and attenuating nonalcoholic fatty liver disease (NAFLD). METHODS: Stigmasterol and beta-sitosterol were administered to mice at 0.4% in a high-fat western-style diet (HFWD) for 17 weeks. RESULTS: Stigmasterol and beta-sitosterol significantly ameliorated HFWD-induced fatty liver and metabolic abnormalities, including elevated levels of hepatic total lipids, triacylglycerols, cholesterol and liver histopathology. Both phytosterols decreased the levels of intestinal bile acids, accompanied by markedly increased fecal lipid levels. In addition, they altered the expression of genes involved in lipid metabolism. beta-Sitosterol was less effective in affecting most of these parameters. Lipidomic analysis of liver and serum samples showed that stigmasterol prevented the HFWD-induced elevation of some di- and triacylglycerol species and lowering of some phospholipid species. Stigmasterol also decreased serum levels of ceramides. CONCLUSION: Stigmasterol and beta-sitosterol, at a dose corresponding to that suggested for humans by the FDA for lowering cholesterol levels, are shown to alleviate HFWD-induced NAFLD. Stigmasterol was more effective than beta-sitosterol, possibly because of its suppression of hepatic lipogenic gene expression and modulation of circulating ceramide levels. PMID- 30305246 TI - Plant hydroperoxide-cleaving enzymes (CYP74 family) function as hemiacetal synthases: Structural proof of hemiacetals by NMR spectroscopy. AB - Hydroperoxide lyases (HPLs) of the CYP74 family (P450 superfamily) are widely distributed enzymes in higher plants and are responsible for the stress-initiated accumulation of short-chain aldehydes. Fatty acid hydroperoxides serve as substrates for HPLs; however, details of the HPL-promoted conversion are still incompletely understood. In the present work, we report first time the micropreparative isolation and the NMR structural studies of fatty acid hemiacetal (TMS/TMS), the short-lived HPL product. With this aim, linoleic acid 9(S)-hydroperoxide (9(S)-HPOD) was incubated with recombinant melon hydroperoxide lyase (CmHPL, CYP74C2) in a biphasic system of water/hexane for 60 s at 0 degrees C, pH 4.0. The hexane layer was immediately decanted and vortexed with a trimethylsilylating mixture. Analysis by GC-MS revealed a major product, i.e. the bis-TMS derivative of a hemiacetal which was conclusively identified as 9-hydroxy 9-[(1'E,3'Z)-nonadienyloxy]-nonanoic acid by NMR-spectroscopy. Further support for the hemiacetal structure was provided by detailed NMR-spectroscopic analysis of the bis-TMS hemiacetal generated from [13C18]9(S)-HPOD in the presence of CmHPL. The results obtained provide incontrovertible evidence that the true products of the HPL group of enzymes are hemiacetals, and that the short-chain aldehydes are produced by their rapid secondary chain breakdown. Therefore, we suggest replacing the name "hydroperoxide lyase", which does not reflect the factual isomerase (intramolecular oxidoreductase) activity, with "hemiacetal synthase" (HAS). PMID- 30305247 TI - FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism. AB - N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes. Loss of m6A demethylase FTO increases m6A levels and inhibits adipogenesis of preadipocytes. However, its underlying mechanism remains elusive. Here, we demonstrated that silencing FTO inhibited adipogenesis of preadipocytes through impairing cell cycle progression at the early stage of adipogenesis. FTO knockdown markedly decreased the expression of CCNA2 and CDK2, crucial cell cycle regulators, leading to delayed entry of MDI-induced cells into G2 phase. Furthermore, the m6A levels of CCNA2 and CDK2 mRNA were significantly upregulated following FTO knockdown. m6A-binding protein YTHDF2 recognized and decayed methylated mRNAs of CCNA2 and CDK2, leading to decreased protein expression, thereby prolonging cell cycle progression and suppressing adipogenesis. Our work unravels that FTO regulates adipogenesis by controlling cell cycle progression in an m6A-YTHDF2 dependent manner, which provides insights into critical roles of m6A methylation in adipogenesis. PMID- 30305250 TI - Join us at The Lancet Clinic. PMID- 30305251 TI - 2015 European Cancer Congress. PMID- 30305252 TI - Do visual aids influenced patients' risk perceptions for rare and very rare risks? AB - OBJECTIVE: To examine whether visual aids (a graphic representation and/or conceptual illustrations) influence patients' risk perceptions for rare and very rare risks. METHODS: Participants were randomized to a scenario which varied by probability of infection (2% or 0.2%) and visual aid: numbers only, numbers + graphic representation, numbers + conceptual illustrations, or numbers + graphic representation + conceptual illustrations. Risk perceptions and likelihood of starting the medication were examined across the four formats, separately, in participants with and without a college education. RESULTS: Adding a graphic representation and/or conceptual illustrations did not affect risk perceptions among those with a higher level of education. Adding both a graphic representation + conceptual illustrations decreased risk perceptions and increased likelihood of starting the medication among participants randomized to the 2%, but not 0.2% scenario, among participants with lower levels of education. CONCLUSION: Adding a graphic representation + conceptual illustrations to numbers may influence perceptions for rare, but not very rare, risks among patients with lower education. PRACTICE IMPLICATIONS: Clinicians should be aware of the differential effects of visual aids developed to facilitate risk communication. Patients with higher levels of education may be less responsive to visual aids than those with lower education. PMID- 30305253 TI - Online health information seeking by adults hospitalized for acute coronary syndromes: Who looks for information, and who discusses it with healthcare providers? AB - OBJECTIVE: To describe characteristics associated with online health information seeking and discussing resulting information with healthcare providers among adults with acute coronary syndromes (ACS). METHODS: Consecutive patients hospitalized with ACS in 6 hospitals in Massachusetts and Georgia who reported Internet use in the past 4 weeks (online patients) were asked about online health information-seeking and whether they discussed information with healthcare providers. Participants reported demographic and psychosocial characteristics; clinical characteristics were abstracted from medical records. Logistic regression models estimated associations with information-seeking and provider communication. RESULTS: Online patients (N = 1142) were on average aged 58.8 (SD: 10.6) years, 30.3% female, and 82.8% non-Hispanic white; 56.7% reported online health information-seeking. Patients with higher education and difficulty accessing medical care were more likely to report information-seeking; patients hospitalized with myocardial infarction, and those with impaired health numeracy and limited social networks were less likely. Among information-seekers, 33.9% discussed information with healthcare providers. More education and more frequent online information-seeking were associated with provider discussions. CONCLUSION: Over half of online patients with ACS seek health information online, but only 1 in 3 of these discuss information with healthcare providers. PRACTICE IMPLICATIONS: Clinician awareness of patient information-seeking may enhance communication including referral to evidence-based online resources. PMID- 30305255 TI - Predicting Adherence to Internet-Delivered Psychotherapy for Symptoms of Depression and Anxiety After Myocardial Infarction: Machine Learning Insights From the U-CARE Heart Randomized Controlled Trial. AB - BACKGROUND: Low adherence to recommended treatments is a multifactorial problem for patients in rehabilitation after myocardial infarction (MI). In a nationwide trial of internet-delivered cognitive behavior therapy (iCBT) for the high-risk subgroup of patients with MI also reporting symptoms of anxiety, depression, or both (MI-ANXDEP), adherence was low. Since low adherence to psychotherapy leads to a waste of therapeutic resources and risky treatment abortion in MI-ANXDEP patients, identifying early predictors for adherence is potentially valuable for effective targeted care. OBJECTIVES: The goal of the research was to use supervised machine learning to investigate both established and novel predictors for iCBT adherence in MI-ANXDEP patients. METHODS: Data were from 90 MI-ANXDEP patients recruited from 25 hospitals in Sweden and randomized to treatment in the iCBT trial Uppsala University Psychosocial Care Programme (U-CARE) Heart study. Time point of prediction was at completion of the first homework assignment. Adherence was defined as having completed more than 2 homework assignments within the 14-week treatment period. A supervised machine learning procedure was applied to identify the most potent predictors for adherence available at the first treatment session from a range of demographic, clinical, psychometric, and linguistic predictors. The internal binary classifier was a random forest model within a 3*10-fold cross-validated recursive feature elimination (RFE) resampling which selected the final predictor subset that best differentiated adherers versus nonadherers. RESULTS: Patient mean age was 58.4 years (SD 9.4), 62% (56/90) were men, and 48% (43/90) were adherent. Out of the 34 potential predictors for adherence, RFE selected an optimal subset of 56% (19/34; Accuracy 0.64, 95% CI 0.61-0.68, P<.001). The strongest predictors for adherence were, in order of importance, (1) self-assessed cardiac-related fear, (2) sex, and (3) the number of words the patient used to answer the first homework assignment. CONCLUSIONS: For developing and testing effective iCBT interventions, investigating factors that predict adherence is important. Adherence to iCBT for MI-ANXDEP patients in the U-CARE Heart trial was best predicted by cardiac related fear and sex, consistent with previous research, but also by novel linguistic predictors from written patient behavior which conceivably indicate verbal ability or therapeutic alliance. Future research should investigate potential causal mechanisms and seek to determine what underlying constructs the linguistic predictors tap into. Whether these findings replicate for other interventions outside of Sweden, in larger samples, and for patients with other conditions who are offered iCBT should also be investigated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01504191; https://clinicaltrials.gov/ct2/show/NCT01504191 (Archived at Webcite at http://www.webcitation.org/6xWWSEQ22). PMID- 30305254 TI - Characterizing Websites That Provide Information About Complementary and Integrative Health: Systematic Search and Evaluation of Five Domains. AB - BACKGROUND: In recent years, there has been an increase in the utilization of complementary and integrative health (CIH) care, and an increase in information seeking behavior focused on CIH. Thus, understanding the quality of CIH information that is available on the internet is imperative. Although there have been a limited number of studies evaluating the quality of websites providing information about specific CIH-related topics, a broad evaluation of CIH websites has not been conducted. OBJECTIVE: This study was designed to fill that gap. We set out to assess website quality in 5 CIH domains: (1) acupuncture, (2) homeopathy, (3) massage, (4) reiki, and (5) yoga. This study aimed to 1) characterize the websites by type and quality; 2) evaluate website characteristics which may affect readers' perceptions, specifically message content, structural features, and presentation style, and 3) investigate the extent to which harms, benefits and purposes of use are stated on websites. METHODS: This study employed a systematic search strategy to identify websites in each of the target domains to be evaluated. The websites were then classified by type, and a set of checklists focusing on quality, message content, structural features, and presentation style was used to evaluate the websites. Lastly, we performed content analysis to identify harms, benefits, and perceived purposes of use. RESULTS: There were similarities across domains regarding their overall quality and their message content. Across all domains, a high proportion of websites received strong scores in terms of ownership, currency, interactivity and navigability. Scores were more variable concerning authorship, balanced presentation of information and the use of sources of information. However, there were differences regarding their structural features and presentation style. Acupuncture and reiki sites tended to include more external links, and yoga, fewer. There was variation across domains in the extent to which the websites contained domain-specific terminology. Websites tended to provide an extensive list of potential benefits, while reporting of harms was scarce. CONCLUSIONS: This is the first study to perform a multidimensional assessment of websites in multiple CIH domains. This review showed that while there are similarities among websites of different CIH domains, there are also differences. The diverse distribution of website types suggests that, regardless of CIH domain, the public encounters information through many different types of media, and it would be useful to consider how the presentation of this content may differ depending on the medium. The characteristics for which variability exist are areas that warrant greater attention from researchers, policy makers, clinicians and patients. There is also a need to better understand how individuals may interact with CIH websites, and to develop tools to assist people to interpret the CIH related information that they encounter. PMID- 30305256 TI - Developing Culturally Sensitive mHealth Apps for Caribbean Immigrant Women to Use During Pregnancy: Focus Group Study. AB - BACKGROUND: A valuable addition to the mobile health (mHealth) space is an exploration of the context of minorities in developed countries. The transition period postmigration, culture, and socioeconomic uniqueness of migratory groups can shed light on the problems with existing prenatal mHealth apps. OBJECTIVE: The objectives of this study were to (1) use the theoretical concept of pregnancy ecology to understand the emotional, physical, information, and social challenges affecting low-income Caribbean immigrant women's prenatal well-being practices and (2) develop a deep understanding of challenges worthy of consideration in mHealth design for these women. METHODS: This qualitative interpretive approach using analytical induction presents the findings of 3 focus group sessions with 12 Caribbean immigrant women living in South Florida in the United States. The study took place from April to September 2015. RESULTS: The participants revealed problematic tiers and support needs within the pregnancy ecology including emotional stressors caused by family separation, physical challenges, information gaps, and longing for social support. CONCLUSIONS: mHealth interventions for low income Caribbean immigrant women must be designed beyond the conventional way of focusing on the events surrounding the unborn child. It can be tailored to the needs of the expecting mother. Pregnancy information should be customized on the basis of the variability of lifestyle, cultural practices, socioeconomic status, and social ties while still being able to deliver appropriate guidelines and clear cultural misconceptions. PMID- 30305257 TI - Collecting Health and Exposure Data in Australian Olympic Combat Sports: Feasibility Study Utilizing an Electronic System. AB - BACKGROUND: Electronic methods are increasingly being used to manage health related data among sporting populations. Collection of such data permits the analysis of injury and illness trends, improves early detection of injuries and illnesses, collectively referred to as health problems, and provides evidence to inform prevention strategies. The Athlete Management System (AMS) has been employed across a range of sports to monitor health. Australian combat athletes train across the country without dedicated national medical or sports science teams to monitor and advocate for their health. Employing a Web-based system, such as the AMS, may provide an avenue to increase the visibility of health problems experienced by combat athletes and deliver key information to stakeholders detailing where prevention programs may be targeted. OBJECTIVE: The objectives of this paper are to (1) report on the feasibility of utilizing the AMS to collect longitudinal injury and illness data of combat sports athletes and (2) describe the type, location, severity, and recurrence of injuries and illnesses that the cohort of athletes experience across a 12-week period. METHODS: We invited 26 elite and developing athletes from 4 Olympic combat sports (boxing, judo, taekwondo, and wrestling) to participate in this study. Engagement with the AMS was measured, and collected health problems (injuries or illnesses) were coded using the Orchard Sports Injury Classification System (version 10.1) and International Classification of Primary Care (version 2). RESULTS: Despite >160 contacts, athlete engagement with online tools was poor, with only 13% compliance across the 12-week period. No taekwondo or wrestling athletes were compliant. Despite low overall engagement, a large number of injuries or illness were recorded across 11 athletes who entered data-22 unique injuries, 8 unique illnesses, 30 recurrent injuries, and 2 recurrent illnesses. The most frequent injuries were to the knee in boxing (n=41) and thigh in judo (n=9). In this cohort, judo players experienced more severe, but less frequent, injuries than boxers, yet judo players sustained more illnesses than boxers. In 97.0% (126/130) of cases, athletes in this cohort continued to train irrespective of their health problems. CONCLUSIONS: Among athletes who reported injuries, many reported multiple conditions, indicating a need for health monitoring in Australian combat sports. A number of factors may have influenced engagement with the AMS, including access to the internet, the design of the system, coach views on the system, previous experiences with the system, and the existing culture within Australian combat sports. To increase engagement, there may be a requirement for sports staff to provide relevant feedback on data entered into the system. Until the barriers are addressed, it is not feasible to implement the system in its current form across a larger cohort of combat athletes. PMID- 30305258 TI - Research Ethics in the European Influenzanet Consortium: Scoping Review. AB - BACKGROUND: Influenzanet was launched in several European countries to monitor influenza-like illness during flu seasons with the help of volunteering participants and Web-based technologies. As in the case of developing fields, ethical approaches are not well developed in the collection, processing, and analysis of participants' information. Existing controversies and varying national ethical regulations can, thus, hamper efficient cross-border research collaboration to the detriment of quality disease surveillance. OBJECTIVE: This scoping review characterizes current practices on how ethical, legal, and social issues (ELSIs) pertinent to research ethics are handled by different Influenzanet country groups to analyze similarities and identify the need for further harmonization of ethical approaches. METHODS: A literature search was carried out on PubMed, Web of Science, Global Digital Library on Ethics, and Bioethics Literature Database to identify ELSIs for Influenzanet country platforms. Only English-language papers were included with publication dates from 2003 to 2017. Publications were screened for the application of bioethics principles in the implementation of country platforms. Additional publications gathered from the Influenzanet Consortium website, reference screening, and conference proceeding were screened for ELSIs. RESULTS: We gathered 96 papers from our search methodology. In total, 28 papers that mentioned ELSIs were identified and included in this study. The Research Ethics Committee (REC) approvals were sought for recruiting participants and collecting their data in 8 of 11 country platforms and informed e-consent was sought from participants in 9 of 11 country platforms. Furthermore, personal data protection was ensured throughout the Consortium using data anonymization before processing and analysis and using aggregated data. CONCLUSIONS: Epidemics forecasting activities, such as Influenzanet, are beneficial; however, its benefits could be further increased through the harmonization of data gathering and ethical requirements. This objective is achievable by the Consortium. More transparency should be promoted concerning REC-approved research for Influenzanet-like systems. The validity of informed e-consent could also be increased through the provision of a user friendly and standard information sheet across the Consortium where participants agree to its terms, conditions, and privacy policies before being able to fill in the questionnaire. This will help to build trust in the general public while preventing any decline in participation. PMID- 30305259 TI - Using Social Media and Web-Based Networking in Collaborative Research: Protocol for the Geriatric Medicine Research Collaborative. AB - BACKGROUND: Traditional pathways to promote research collaboration typically take years to expand beyond individual institutions. Social media and online networking provide an innovative approach to promote research collaboration. OBJECTIVE: The objective of this paper is to present the formation of the Geriatric Medicine Research Collaborative, United Kingdom - a national trainee led research collaborative. This collaborative aims to facilitate research projects that will directly benefit older patients, improve research skills of geriatric medicine trainees, and facilitate recommendations for health care policy for older adults. METHODS: Our methods of collaboration comprised trainee led meetings regionally and at national conferences, email communication, direct uploading of project material to our website, social media, and virtual meetings. Structured use of local, regional, and network leads has facilitated this collaboration. Having a clear virtual presence has been the key to the rapid development of the network. RESULTS: The use of social media and online networking encouraged the involvement of multiple regions early in the development of the collaborative and allowed rapid dissemination of project ideas. This facilitated the collection of large datasets and enhanced scientific validity of project outcomes. Furthermore, this has the potential to transform geriatric medicine research, as older patients have been historically excluded from large commercial trials due to multimorbidity, frailty, and cognitive impairment. CONCLUSIONS: Perceived limitations to predominantly online or virtual collaboratives, including reduced accountability, and loss of interpersonal relationships are balanced by increased trainee engagement, high frequency of communication, and rapid access to a breadth of expertise. Utilization of virtual communication has the potential to lead to future interspecialty, interprofessional, and international collaboration, and to accelerate research that improves outcomes for older adults. PMID- 30305261 TI - Utilization of Electronic Medical Records and Biomedical Literature to Support the Diagnosis of Rare Diseases Using Data Fusion and Collaborative Filtering Approaches. AB - BACKGROUND: In the United States, a rare disease is characterized as the one affecting no more than 200,000 patients at a certain period. Patients suffering from rare diseases are often either misdiagnosed or left undiagnosed, possibly due to insufficient knowledge or experience with the rare disease on the part of clinical practitioners. With an exponentially growing volume of electronically accessible medical data, a large volume of information on thousands of rare diseases and their potentially associated diagnostic information is buried in electronic medical records (EMRs) and medical literature. OBJECTIVE: This study aimed to leverage information contained in heterogeneous datasets to assist rare disease diagnosis. Phenotypic information of patients existed in EMRs and biomedical literature could be fully leveraged to speed up diagnosis of diseases. METHODS: In our previous work, we advanced the use of a collaborative filtering recommendation system to support rare disease diagnostic decision making based on phenotypes derived solely from EMR data. However, the influence of using heterogeneous data with collaborative filtering was not discussed, which is an essential problem while facing large volumes of data from various resources. In this study, to further investigate the performance of collaborative filtering on heterogeneous datasets, we studied EMR data generated at Mayo Clinic as well as published article abstracts retrieved from the Semantic MEDLINE Database. Specifically, in this study, we designed different data fusion strategies from heterogeneous resources and integrated them with the collaborative filtering model. RESULTS: We evaluated performance of the proposed system using characterizations derived from various combinations of EMR data and literature, as well as with sole EMR data. We extracted nearly 13 million EMRs from the patient cohort generated between 2010 and 2015 at Mayo Clinic and retrieved all article abstracts from the semistructured Semantic MEDLINE Database that were published till the end of 2016. We applied a collaborative filtering model and compared the performance generated by different metrics. Log likelihood ratio similarity combined with k-nearest neighbor on heterogeneous datasets showed the optimal performance in patient recommendation with area under the precision recall curve (PRAUC) 0.475 (string match), 0.511 (systematized nomenclature of medicine [SNOMED] match), and 0.752 (Genetic and Rare Diseases Information Center [GARD] match). Log likelihood ratio similarity also performed the best with mean average precision 0.465 (string match), 0.5 (SNOMED match), and 0.749 (GARD match). Performance of rare disease prediction was also demonstrated by using the optimal algorithm. Macro-average F-measure for string, SNOMED, and GARD match were 0.32, 0.42, and 0.63, respectively. CONCLUSIONS: This study demonstrated potential utilization of heterogeneous datasets in a collaborative filtering model to support rare disease diagnosis. In addition to phenotypic-based analysis, in the future, we plan to further resolve the heterogeneity issue and reduce miscommunication between EMR and literature by mining genotypic information to establish a comprehensive disease-phenotype-gene network for rare disease diagnosis. PMID- 30305262 TI - Using Facebook for Improving the Psychological Well-Being of Individuals Experiencing Homelessness: Experimental and Longitudinal Study. AB - BACKGROUND: Web-based social networks are a powerful communicative element and their use is increasingly widespread. Persons living in extreme social exclusion such as individuals experiencing homelessness can benefit from the positive elements of communication and relationship associated with social networking sites. OBJECTIVE: This study aimed to suggest the comparison of a Facebook training course and an office software course and their effect on psychological well-being in a group of individuals experiencing homelessness. METHODS: An experimental and longitudinal study was designed. Individuals experiencing homelessness were randomly assigned to either the Facebook group or the office software group, and their social skills, self-esteem, self-efficacy, and satisfaction with life were measured on 4 occasions: pretest, at the end of the training course, 1 month later, and 3 months later. A mixed analysis of variance of repeated measures (2*4) was performed. RESULTS: A total of 92 individuals experiencing homelessness participated in the study. The number of cases in which the 4 measurements were completed was 71 (35 in the intervention group and 36 in the control group). The mixed analysis of variance of repeated measures and the multiple regression analysis indicated a significant increase of the 4 analyzed parameters, with greater significance in the areas of social skills and self esteem. The critical levels associated to the interaction Time*Program were significant in all variables and levels. Therefore, the scores in the 4 analyzed constructs were not equal according to the program carried out throughout the work. The effect size associated to the interaction Time*Program in the social skills scores was large (eta2=0.32); in the self-esteem and self-efficacy scores, it was medium, (eta2=0.13); and in the satisfaction with life scores, it was small (eta2=0.09). The results of the adjustment of the different models of multiple linear regression indicate that the number of hours devoted weekly to the use of Facebook was a predictor of the increase in the scores of social skills (B=3.43, r2=.405) and self-esteem (B=.382). Age (B=.175) and self-efficacy (B=.09) were also variables, which with independence and in equal conditions, predicted self-esteem (r2=.29). Finally, self-esteem (B=.69) was also a predictor variable of the increase of satisfaction with life (r2=.195). CONCLUSIONS: These findings suggest that Facebook could be a key element in homeless psychological well-being and socialization. PMID- 30305260 TI - Assessing the Attitudes and Perceptions Regarding the Use of Mobile Health Technologies for Living Kidney Donor Follow-Up: Survey Study. AB - BACKGROUND: In 2013, the Organ Procurement and Transplantation Network began requiring transplant centers in the United States to collect and report postdonation living kidney donor follow-up data at 6 months, 1 year, and 2 years. Despite this requirement, <50% of transplant centers have been able to collect and report the required data. Previous work identified a number of barriers to living kidney donor follow-up, including logistical and administrative barriers for transplant centers and cost and functional barriers for donors. Novel smartphone-based mobile health (mHealth) technologies might reduce the burden of living kidney donor follow-up for centers and donors. However, the attitudes and perceptions toward the incorporation of mHealth into postdonation care among living kidney donors are unknown. Understanding donor attitudes and perceptions will be vital to the creation of a patient-oriented mHealth system to improve living donor follow-up in the United States. OBJECTIVE: The goal of this study was to assess living kidney donor attitudes and perceptions associated with the use of mHealth for follow-up. METHODS: We developed and administered a cross sectional 14-question survey to 100 living kidney donors at our transplant center. All participants were part of an ongoing longitudinal study of long-term outcomes in living kidney donors. The survey included questions on smartphone use, current health maintenance behaviors, accessibility to health information, and attitudes toward using mHealth for living kidney donor follow-up. RESULTS: Of the 100 participants surveyed, 94 owned a smartphone (35 Android, 58 iPhone, 1 Blackberry), 37 had accessed their electronic medical record on their smartphone, and 38 had tracked their exercise and physical activity on their smartphone. While 77% (72/93) of participants who owned a smartphone and had asked a medical question in the last year placed the most trust with their doctors, nurses, or other health care professionals regarding answering a health-related question, 52% (48/93) most often accessed health information elsewhere. Overall, 79% (74/94) of smartphone-owning participants perceived accessing living kidney donor information and resources on their smartphone as useful. Additionally, 80% (75/94) perceived completing some living kidney donor follow-up via mHealth as useful. There were no significant differences in median age (60 vs 59 years; P=.65), median years since donation (10 vs 12 years; P=.45), gender (36/75, 36%, vs 37/75, 37%, male; P=.57), or race (70/75, 93%, vs 18/19, 95%, white; P=.34) between those who perceived mHealth as useful for living kidney donor follow-up and those who did not, respectively. CONCLUSIONS: Overall, smartphone ownership was high (94/100, 94.0%), and 79% (74/94) of surveyed smartphone-owning donors felt that it would be useful to complete their required follow-up with an mHealth tool, with no significant differences by age, sex, or race. These results suggest that patients would benefit from an mHealth tool to perform living donor follow up. PMID- 30305264 TI - Discourse on Exposure to Pornography Content Online Between Arab Adolescents and Parents: Qualitative Study on its Impact on Sexual Education and Behavior. AB - BACKGROUND: The internet revolution of the 21st century has made sexual content available and accessible on a scale that has never existed before. Many studies have indicated that the use of pornography was associated with more permissive sexual attitudes and tended to be linked with stronger gender-stereotypical sexual beliefs. It also seemed to be associated with other risky behaviors and sexual promiscuity. Pornography exposure in conservative societies leads to conflicts with religious and cultural taboos. OBJECTIVE: The aim of this study was to characterize the barriers and difficulties that prevent sexual discourse in the Arab society and enable pornography viewing according to the perceptions of adolescents and mothers. METHODS: This study involved qualitative research methods and in-depth interviews with 40 participants. This study included 20 Arab adolescents, sampled by 2 age groups (14-16 years and 16-18 years), and 20 mothers of adolescents from both sexes. RESULTS: The findings indicate that mothers "turn a blind eye" to porn viewing and sexual activity by boys; however, they show a sweeping prohibition and denial of such behavior by girls. Boys reported viewing porn routinely, whereas girls denied doing so, but admitted that their female friends watched porn. The study also found that boys experienced guilt during and after viewing porn as a result of the clash between modernity and traditional values. The mothers and adolescents emphasized the need for an open sexual discourse to reduce violent behaviors such as Web-based sexual harassment, including sending videos and pictures of naked girls, often accompanied by threats and blackmail. CONCLUSIONS: It is necessary to find a way to encourage a significant sexual discourse to prevent the violent consequences of its absence in the Arab society. A controlled, transparent, and critical sexual discourse could help youth make more informed decisions concerning the search for sexual content, porn viewing, and sexual behavior. PMID- 30305263 TI - Combining Technology and Research to Prevent Scald Injuries (the Cool Runnings Intervention): Randomized Controlled Trial. AB - BACKGROUND: New technologies, internet accessibility, social media, and increased smartphone ownership provide new opportunities for health researchers to communicate and engage target audiences. An innovative burn prevention intervention was developed using these channels. OBJECTIVE: The aim of this study was to evaluate the efficacy of Cool Runnings, an app-based intervention to increase knowledge of childhood burn risk (specifically hot beverage scalds) and correct burn first aid among mothers of young children. METHODS: This was a 2 group, parallel, single-blinded randomized controlled trial (RCT). Participants were women aged 18 years and above, living in Queensland, Australia, with at least 1 child aged 5-12 months at time of enrollment. The primary outcome measures were change in knowledge about risk of burns and correct burn first aid assessed via 2 methods: (1) overall score and (2) categorized as adequate (score=4) versus inadequate (score<4). Efficacy of gamification techniques was also assessed. RESULTS: In total, 498 participants were recruited via social media and enrolled. At the 6-month follow-up, 244 participants completed the posttest questionnaire. Attrition rates in both groups were similar. Participants who remained in the study did not differ from those lost to follow-up on any characteristics except education level. Although similar at baseline, intervention group participants achieved significantly greater improvement in overall knowledge posttest than control group participants on both primary outcome measures (overall knowledge intervention: mean [SD] of overall knowledge 2.68 [SD 1.00] for intervention vs 2.13 [SD 1.03] for control; 20.7% [25/121] adequate in intervention vs 7.3% [2/123] in control). Consequently, the number needed to treat was 7.46. Logistic regression showed participants exposed to the highest level of disadvantage had 7.3 times higher odds of improved overall knowledge scores than participants in other levels of disadvantage. There were also significant correlations between gamification techniques and knowledge change (P<.001). In addition, odds of knowledge improvement between baseline and 6-month follow-up was higher in participants with low-moderate app activity compared with no app activity (odds ratio [OR] 8.59, 95% CI 2.9-25.02) and much higher in participants with high app activity (OR 18.26, 95% CI 7.1-46.8). CONCLUSIONS: Despite substantial loss to follow-up, this RCT demonstrates the Cool Runnings app was an effective intervention for improving knowledge about risks of hot beverage scalds and burn first aid in mothers of young children. The benefits of combining gamification elements in the intervention were also highlighted. Given the low cost and large reach of smartphone apps to deliver content to and engage with targeted populations, the results from this RCT provide important information on how smartphone apps can be used for widespread injury prevention campaigns and public health campaigns generally. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000019404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369745&showOrigi al=true&isReview=true (Archived by WebCite at http://www.webcitation.org/72b1E8gTW). PMID- 30305265 TI - The Phased Implementation of a National Telehealth Weight Management Program for Veterans: Mixed-Methods Program Evaluation. AB - BACKGROUND: The burden of obesity is high among US veterans, yet many face barriers to engaging in in-person, facility-based treatment programs. To improve access to weight-management services, the Veterans Health Administration (VHA) developed TeleMOVE, a home-based, 82-day curriculum that utilizes in-home messaging devices to promote weight loss in VHA patients facing barriers to accessing facility-based services. OBJECTIVE: The primary aim was to establish preliminary evidence for the program by comparing outcomes for TeleMOVE with standard, facility-based MOVE weight-management services (group, individual modalities) over the evaluation period based on the number of patients enrolled per site and the program's clinical effectiveness, as demonstrated by average weight lost per patient. The secondary aim was to understand factors influencing TeleMOVE implementation variability across demonstration sites to develop recommendations to improve national program dissemination. METHODS: We employed a formative mixed-methods design to evaluate the phased implementation of TeleMOVE at 9 demonstration sites and compare patient- and site-level measures of program uptake. Data were collected between October 1, 2009 and September 30, 2011. Patient-level program outcomes were extracted from VHA patient care databases to evaluate program enrollment rates and clinical outcomes. To assess preliminary clinical effectiveness, weight loss outcomes for veterans who enrolled in TeleMOVE were compared with outcomes for veterans enrolled in standard MOVE! at each demonstration site, as well as with national averages during the first 2 years of program implementation. For the secondary aim, we invited program stakeholders to participate in 2 rounds of semistructured interviews about aspects of TeleMOVE implementation processes, site-level contextual factors, and program delivery. Twenty-eight stakeholders participated in audio-recorded interviews. RESULTS: Although stakeholders at 3 sites declined to be interviewed, objective program uptake was high at 2 sites, delayed-high at 2 sites, and low at 5 sites. At 6 months post enrollment, the mean weight loss was comparable for TeleMOVE (n=417) and MOVE! (n=1543) participants at -5.2 lb (SD 14.4) and -5.1 lb (SD 12.2), respectively (P=.91). All sites reported high program complexity because TeleMOVE required more staff time per participant than MOVE! due to logistical and technical assistance issues related to the devices. High-uptake sites overcame implementation challenges by leveraging communication networks with stakeholders, adapting the program to patient needs whenever possible, setting programmatic goals and monitoring feedback of results, and taking time to reflect and evaluate on delivery to foster incremental delivery improvements, whereas low-uptake sites reported less leadership support and effective communication among stakeholders. CONCLUSIONS: This implementation evaluation of a clinical telehealth program demonstrated the value of partnership-based research in which researchers not only provided operational leaders with feedback regarding the effectiveness of a new program but also relevant feedback into contextual factors related to program implementation to enable adaptations for national deployment efforts. PMID- 30305266 TI - Promoting Self-Care of Diabetic Foot Ulcers Through a Mobile Phone App: User Centered Design and Evaluation. AB - BACKGROUND: Without effective self-care, people with diabetic foot ulcers (DFUs) are at risk of prolonged healing times, hospitalization, amputation, and reduced quality of life. Despite these consequences, adherence to DFU self-care remains low. New strategies are needed to engage people in the self-care of their DFUs. OBJECTIVE: This study aimed to evaluate the usability and potential usefulness of a new mobile phone app to engage people with DFUs in self-care. METHODS: We developed a new mobile phone app, MyFootCare, to engage people with DFUs through goals, progress monitoring, and reminders in self-care. Key features included novel visual analytics that automatically extract and monitor DFU size information from mobile phone photos of the foot. A functional prototype of MyFootCare was created and evaluated through a user-centered design process with 11 participants with DFUs. Data were collected through semistructured interviews discussing existing self-care practices and observations of MyFootCare with participants. Data were analyzed qualitatively through thematic analysis. RESULTS: Key themes were as follows: (1) participants already used mobile phone photos to monitor their DFU progress; (2) participants had limited experience with using mobile phone apps; (3) participants desired the objective DFU size data provided by the tracking feature of MyFootCare to monitor their DFU progress; (4) participants were ambivalent about the MyFootCare goal image and diary features, commenting that these features were useful but also that it was unlikely that they would use them; and (5) participants desired to share their MyFootCare data with their clinicians to demonstrate engagement in self-care and to reflect on their progress. CONCLUSIONS: MyFootCare shows promising features to engage people in DFU self-care. Most notably, ulcer size data are useful to monitor progress and engage people. However, more work is needed to improve the usability and accuracy of MyFootCare, that is, by refining the process of taking and analyzing photos of DFUs and removing unnecessary features. These findings open the door for further work to develop a system that is easy to use and functions in everyday life conditions and to test it with people with DFUs and their carers. PMID- 30305268 TI - Lee J, Zhang LL, Wu W, et al. Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma. Blood Adv. 2018;2(16):2039-2051. PMID- 30305267 TI - Sensing of red blood cells with decreased membrane deformability by the human spleen. AB - The current paradigm in the pathogenesis of several hemolytic red blood cell disorders is that reduced cellular deformability is a key determinant of splenic sequestration of affected red cells. Three distinct features regulate cellular deformability: membrane deformability, surface area-to-volume ratio (cell sphericity), and cytoplasmic viscosity. By perfusing normal human spleens ex vivo, we had previously showed that red cells with increased sphericity are rapidly sequestered by the spleen. Here, we assessed the retention kinetics of red cells with decreased membrane deformability but without marked shape changes. A controlled decrease in membrane deformability (increased membrane rigidity) was induced by treating normal red cells with increasing concentrations of diamide. Following perfusion, diamide-treated red blood cells (RBCs) were rapidly retained in the spleen with a mean clearance half-time of 5.9 minutes (range, 4.0-13.0). Splenic clearance correlated positively with increased membrane rigidity (r = 0.93; P < .0001). To determine to what extent this increased retention was related to mechanical blockade in the spleen, diamide-treated red cells were filtered through microsphere layers that mimic the mechanical sensing of red cells by the spleen. Diamide-treated red cells were retained in the microsphilters (median, 7.5%; range, 0%-38.6%), although to a lesser extent compared with the spleen (median, 44.1%; range, 7.3%-64.0%; P < .0001). Taken together, these results have implications for understanding the sensitivity of the human spleen to sequester red cells with altered cellular deformability due to various cellular alterations and for explaining clinical heterogeneity of RBC membrane disorders. PMID- 30305270 TI - Role model: Abdallah Al-Mohammad. PMID- 30305271 TI - Living with Buildings: new Wellcome show looks at urban architecture and health. PMID- 30305269 TI - Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts. AB - OBJECTIVE: To systematically test dietary components for association with serum urate levels and to evaluate the relative contributions of estimates of diet pattern and inherited genetic variants to population variance in serum urate levels. DESIGN: Meta-analysis of cross sectional data from the United States. DATA SOURCES: Five cohort studies. REVIEW METHODS: 16 760 individuals of European ancestry (8414 men and 8346 women) from the US were included in analyses. Eligible individuals were aged over 18, without kidney disease or gout, and not taking urate lowering or diuretic drugs. All participants had serum urate measurements, dietary survey data, information on potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome wide genotypes. The main outcome measures were average serum urate levels and variance in serum urate levels. beta values (95% confidence intervals) and Bonferroni corrected P values from multivariable linear regression analyses, along with regression partial R2 values, were used to quantitate associations. RESULTS: Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained <=0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation. CONCLUSION: In contrast with genetic contributions, diet explains very little variation in serum urate levels in the general population. PMID- 30305272 TI - Once you label me, you negate me. PMID- 30305275 TI - Reducing sedentary behaviour in the workplace. PMID- 30305276 TI - The role of diet in serum urate concentration. PMID- 30305274 TI - Lens-regulated retinoic acid signalling controls expansion of the developing eye. AB - Absence of the developing lens results in severe eye defects, including substantial reductions in eye size. How the lens controls eye expansion and the underlying signalling pathways are very poorly defined. We identified RDH10, a gene crucial for retinoic acid synthesis during embryogenesis, as a key factor downregulated in the peripheral retina (presumptive ciliary body region) of lens removed embryonic chicken eyes prior to overt reductions in eye size. This is associated with a significant decrease in retinoic acid synthesis by lens-removed eyes. Restoring retinoic acid signalling in lens-removed eyes by implanting beads soaked in retinoic acid or retinal, but not vitamin A, rescued eye size. Conversely, blocking retinoic acid synthesis decreased eye size in lens containing eyes. Production of collagen II and collagen IX, which are major vitreal proteins, is also regulated by the lens and retinoic acid signalling. These data mechanistically link the known roles of both the lens and retinoic acid in normal eye development, and support a model whereby retinoic acid production by the peripheral retina acts downstream of the lens to support vitreous production and eye expansion. PMID- 30305273 TI - The balance of poly(U) polymerase activity ensures germline identity, survival and development in Caenorhabditis elegans. AB - Poly(U) polymerases (PUPs) catalyze 3' uridylation of mRNAs and small RNAs, a modification often correlating with decreased RNA stability. We have investigated the importance of three proteins with in vitro PUP activity, PUP-1/CDE-1, PUP-2 and PUP-3, in C. elegans germline development. Genetic analysis indicates that PUP-1/CDE-1 and PUP-2 are developmentally redundant under conditions of temperature stress during which they ensure germline viability and development. Multiple lines of evidence indicate that pup-1/-2 double mutant germ cells fail to maintain their identity as distinct from soma. Consistent with phenotypic data, PUP-1 and PUP-2 are expressed in embryonic germ cell precursors and throughout germline development. The developmental importance of PUP activity is presumably in regulating gene expression as both a direct and indirect consequence of modifying target RNAs. PUP-3 is significantly overexpressed in the pup-1/-2 germline, and loss of pup-3 function partially suppresses pup-1/-2 germline defects. We conclude that one major function of PUP-1/-2 is to limit PUP 3 expression. Overall, the balance of PUP-1, PUP-2 and PUP-3 activities appears to ensure proper germline development. PMID- 30305277 TI - The Fentanyl Epidemic and Evolution of Fentanyl Analogs in the United States and the European Union. AB - BACKGROUND: Since 2013, an unprecedented surge in fentanyl overdose deaths has been caused by heroin laced with illicitly produced fentanyl and/or fentanyl analogs (FAs) sold as heroin. The US Drug Enforcement Agency's National Forensic Laboratory Information System reported a >300% increase in fentanyl encounters from 4697 in 2014 to 14440 in 2015. In 2015, the CDC reported 9580 deaths caused by synthetic opioids, primarily fentanyl, a 72% increase from 2014. The European Monitoring Centre for Drugs and Drug Addiction has also encountered several new FAs in the heroin supply. Counterfeit pharmaceuticals containing mixtures of fentanyl and FAs continue to be a poorly recognized worldwide problem despite the WHO classifying several FAs as a serious threat to public health. CONTENT: This review covers the epidemiology of fentanyl abuse and discusses the clinical practice implications of widespread fentanyl abuse. It includes a historical perspective on the illicit FAs that have appeared in the US and European Union and reviews the methods available to identify FAs and emerging technologies useful for identifying previously undescribed analogs. A compilation of structural and mass spectral data on FAs reported thus far is provided. SUMMARY: Fentanyl and FAs have evolved into a global public health threat. It is important to understand the analytical, clinical, and regulatory efforts underway to assist communities affected by the current fentanyl epidemic. PMID- 30305279 TI - Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor. AB - Von Willebrand factor (VWF) is a key player in the regulation of hemostasis by promoting recruitment of platelets to sites of vascular injury. An array of six C domains forms the dimeric C-terminal VWF stem. Upon shear force activation, the stem adopts an open conformation allowing the adhesion of VWF to platelets and the vessel wall. To understand the underlying molecular mechanism and associated functional perturbations in disease-related variants, knowledge of high resolution structures and dynamics of C domains is of paramount interest. Here, we present the solution structure of the VWF C4 domain, which binds to the platelet integrin and is therefore crucial for the VWF function. In the structure, we observed five intra- and inter-subdomain disulfide bridges, of which one is unique in the C4 domain. The structure further revealed an unusually hinged two-subdomain arrangement. The hinge is confined to a very short segment around V2547 connecting the two subdomains. Together with two nearby inter subdomain disulfide bridges, this hinge induces slow conformational changes and positional alternations of both subdomains with respect to each other. Furthermore, the structure demonstrates that a clinical gain-of-function VWF variant (Y2561) (Schneppenheim et al., submitted) is more likely to have an effect on the arrangement of the C4 domain with neighboring domains rather than impairing platelet integrin binding. PMID- 30305278 TI - Effectiveness of the Stand More AT (SMArT) Work intervention: cluster randomised controlled trial. AB - OBJECTIVES: To evaluate the impact of a multicomponent intervention (Stand More AT (SMArT) Work) designed to reduce sitting time on short (three months), medium (six months), and longer term (12 months) changes in occupational, daily, and prolonged sitting, standing, and physical activity, and physical, psychological, and work related health. DESIGN: Cluster two arm randomised controlled trial. SETTING: National Health Service trust, England. PARTICIPANTS: 37 office clusters (146 participants) of desk based workers: 19 clusters (77 participants) were randomised to the intervention and 18 (69 participants) to control. INTERVENTIONS: The intervention group received a height adjustable workstation, a brief seminar with supporting leaflet, workstation instructions with sitting and standing targets, feedback on sitting and physical activity at three time points, posters, action planning and goal setting booklet, self monitoring and prompt tool, and coaching sessions (month 1 and every three months thereafter). The control group continued with usual practice. MAIN OUTCOME MEASURES: The primary outcome was occupational sitting time (thigh worn accelerometer). Secondary outcomes were objectively measured daily sitting, prolonged sitting (>=30 minutes), and standing time, physical activity, musculoskeletal problems, self reported work related health (job performance, job satisfaction, work engagement, occupational fatigue, sickness presenteeism, and sickness absenteeism), cognitive function, and self reported psychological measures (mood and affective states, quality of life) assessed at 3, 6, and 12 months. Data were analysed using generalised estimating equation models, accounting for clustering. RESULTS: A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (-83.28 min/workday, 95% confidence interval -116.57 to -49.98, P=0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (-50.62 min/workday, -78.71 to -22.54, P<0.001) and six months (-64.40 min/workday, -97.31 to -31.50, P<0.001) and daily sitting time at six months (-59.32 min/day, -88.40 to -30.25, P<0.001) and 12 months (-82.39 min/day, -114.54 to -50.26, P=0.001). Group differences (in favour of the intervention group compared with control) were found for prolonged sitting time, standing time, job performance, work engagement, occupational fatigue, sickness presenteeism, daily anxiety, and quality of life. No differences were seen for sickness absenteeism. CONCLUSIONS: SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10967042. PMID- 30305280 TI - Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. AB - Azacitidine treatment for (MDS) generally exacerbates thrombocytopenia during the first treatment cycles. SUPPORT, a Phase III, randomized, double-blind, placebo controlled study (NCT02158936), investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. IPSS intermediate-1, intermediate-2 or high-risk MDS patients with baseline platelets <75x109/L were randomized 1:1 to eltrombopag (starting 200 mg/day [East Asians: 100 mg/day], maximum 300 mg/day [East Asians: 150 mg/day]) or placebo, plus azacitidine (75 mg/m2 sc once daily for 7 days, every 28 days). Primary endpoint was the proportion of patients platelet transfusion-free during cycles 1-4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely as efficacy outcomes crossed the predefined futility threshold, and for safety reasons. At final termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary endpoint (OR 0.37; 95%CI 0.21, 0.65; two-sided P=0.001). Overall response (IWG criteria; complete, marrow or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment (OR 0.51; 95%CI 0.30, 0.86; nominal P=0.005). There was no difference in hematologic improvement in any cell lineage between the two arms. There was no improvement in overall survival (HR 1.42; 95%CI 0.97, 2.08; nominal P=0.164) or progression-free survival (HR 1.47; 95%CI 1.05, 2.07; nominal P=0.060). AEs with greater occurrence (>=10%) in the eltrombopag versus placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to AML. PMID- 30305281 TI - Trends in lung cancer and cigarette smoking: California compared to the rest of the United States. AB - Three cigarette smoking behaviors influence lung cancer rates: how many people start, the amount they smoke, and the age they quit. California has reduced smoking faster than the rest of the US and trends in these 3 smoking behaviors should inform lung cancer trends. We examined trends in smoking behavior (initiation, intensity, and quitting) in California and the rest of US by regression models using the 1974-2014 National Health Interview Surveys (n=962,174). Lung cancer mortality data for 1970-2013 was obtained from the national Surveillance, Epidemiology, and End Results (SEER) Program. Among those aged 18- 35 years, California had much larger declines than the rest of the US in smoking initiation and intensity, and increased quitting. In 2012-14, among this age group, only 18.6% (95% CI, 16.8%-20.3%) had ever smoked; smokers consumed only 6.3 cigarettes/d (95% CI, 5.6-7.0); and 45.7% (95% CI, 41.1%-50.4%) of ever smokers had quit by age 35. Each of these metrics was at least 24% better than in the rest of the US. There was no marked California effect on quitting or intensity among seniors. From 1986-2013, annual lung cancer mortality decreased more rapidly in California and by 2013 was 28% lower (62.6 vs 87.5/100,000) than in the rest of the US. California's tobacco control efforts were associated with a major reduction in cigarette smoking among those under age 35 years. These changes will further widen the lung cancer gap that already exists between California and the rest of the US. PMID- 30305283 TI - Model-based serial blood sampling protocol for minimal mortality and better recovery in small to medium sized tilapia. AB - Serial blood sampling involving sampling blood from the same individual at different time points is essential in time-based studies including xenobiotic toxicokinetics and biochemical studies. However, high fish mortality due to phlebotomy-induced anaemia (PIA) constrains serial blood sampling in small to medium sized fish. The aim of the study was to develop and implement a model based serial blood sampling protocol that minimises fish mortality by regulating anaemia within levels that sustain fish survival and recovery. A model simulating the reduction in haemoglobin was developed from blood sampling data of sixteen (N=16) medium sized Oreochromis mossambicus The model was incorporated into a serial blood sampling protocol whose performance was tested on eight (N=8) fish. The protocol avoided fish mortality and the fish recovered from PIA within three weeks of the post-sampling period. Therefore, managing anaemia minimises mortality and improves the applicability of serial blood sampling in small to medium sized fish.This article has an associated First Person interview with the first author of the paper. PMID- 30305284 TI - Study: Atezolizumab Improves Survival in SCLC. AB - Combining the PD-L1 inhibitor atezolizumab with platinum-based chemotherapy improves overall survival among patients with extensive-stage small cell lung cancer relative to chemotherapy alone. These findings could lead to a new first line treatment option for patients with the disease. PMID- 30305282 TI - Basal constriction during midbrain-hindbrain boundary morphogenesis is mediated by Wnt5b and focal adhesion kinase. AB - Basal constriction occurs at the zebrafish midbrain-hindbrain boundary constriction (MHBC) and is likely a widespread morphogenetic mechanism. 3D reconstruction demonstrates that MHBC cells are wedge-shaped, and initially constrict basally, with subsequent apical expansion. wnt5b is expressed in the MHB and is required for basal constriction. Consistent with a requirement for this pathway, expression of dominant negative Gsk3beta overcomes wnt5b knockdown. Immunostaining identifies focal adhesion kinase (Fak) as active in the MHB region, and knockdown demonstrates Fak is a regulator of basal constriction. Tissue specific knockdown further indicates that Fak functions cell autonomously within the MHBC. Fak acts downstream of wnt5b, suggesting that Wnt5b signals locally as an early step in basal constriction and acts together with more widespread Fak activation. This study delineates signaling pathways that regulate basal constriction during brain morphogenesis. PMID- 30305285 TI - EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. AB - Translation initiation is orchestrated by the cap binding and 43S pre-initiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX is enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113spl variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2alpha phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113spl. ATF4 and c-MYC induce expression of aminoacid transporters and enhance sensitivity of mTOR to aminoacid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors. PMID- 30305286 TI - Surgical mesh and patient safety. PMID- 30305287 TI - Vaginal mesh implants: putting the relations between UK doctors and industry in plain sight. PMID- 30305288 TI - Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage. AB - The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common side effect incurred by head and neck cancer patients receiving radiotherapy. Yet, whether the ducts are capable of regenerating after genotoxic injury, or whether damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, using the murine salivary gland, we show that two ductal progenitor populations, marked exclusively by KRT14 and KIT, maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14+ progenitor cells are fast-cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT+ intercalated duct cells are long-lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture with slow rates of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture. PMID- 30305291 TI - The trial that launched millions of mesh implant procedures: did money compromise the outcome? PMID- 30305289 TI - Lats1/2 inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing. AB - Lung growth to its optimal size at birth is driven by reiterative airway branching followed by differentiation and expansion of alveolar cell types. How this elaborate growth is coordinated with the constraint of the chest is poorly understood. Here, we investigate the role of Hippo signaling, a cardinal pathway in organ size control, in mouse lung development. Unexpectedly, we found that epithelial loss of the Hippo kinase genes Lats1 and Lats2 (Lats1/2) leads to a striking reduction of lung size owing to an early arrest of branching morphogenesis. This growth defect is accompanied by abnormalities in epithelial cell polarity, cell division plane and extracellular matrix deposition, as well as precocious and increased expression of markers for type 1 alveolar epithelial cells (AEC1s), an indicator of terminal differentiation. Increased AEC1s were also observed in transgenic mice with overexpression of a constitutive nuclear form of downstream transcriptional effector YAP. Conversely, loss of Yap and Taz led to decreased AEC1s, demonstrating that the canonical Hippo signaling pathway is both sufficient and necessary to drive AEC1 fate. These findings together reveal unique roles of Hippo-LATS-YAP signaling in the developing mouse lung. PMID- 30305292 TI - Workplace gyms and canteens should suit doctors' working patterns, says BMA report. PMID- 30305290 TI - Prepubertal skeletal muscle growth requires Pax7-expressing satellite cell derived myonuclear contribution. AB - The functional role of Pax7-expressing satellite cells (SCs) in postnatal skeletal muscle development beyond weaning remains obscure. Therefore, the relevance of SCs during prepubertal growth, a period after weaning but prior to the onset of puberty, has not been examined. Here, we have characterized mouse skeletal muscle growth during prepuberty and found significant increases in myofiber cross-sectional area that correlated with SC-derived myonuclear number. Remarkably, genome-wide RNA-sequencing analysis established that post-weaning juvenile and early adolescent skeletal muscle have markedly different gene expression signatures. These distinctions are consistent with extensive skeletal muscle maturation during this essential, albeit brief, developmental phase. Indelible labeling of SCs with Pax7CreERT2/+ ; Rosa26nTnG/+ mice demonstrated SC derived myonuclear contribution during prepuberty, with a substantial reduction at puberty onset. Prepubertal depletion of SCs in Pax7CreERT2/+ ; Rosa26DTA/+ mice reduced myofiber size and myonuclear number, and caused force generation deficits to a similar extent in both fast and slow-contracting muscles. Collectively, these data demonstrate SC-derived myonuclear accretion as a cellular mechanism that contributes to prepubertal hypertrophic skeletal muscle growth. PMID- 30305293 TI - PRMT5 Circular RNA Promotes Metastasis of Urothelial Carcinoma of the Bladder through Sponging miR-30c to Induce Epithelial-Mesenchymal Transition. AB - Purpose: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn lots of attention in the pathogenesis of human cancers. However, the role of circRNAs in cancer cells epithelial-mesenchymal transition (EMT) remains unclear. In this study, we aimed to identify novel circRNAs that regulate urothelial carcinoma of the bladder (UCB) cells' EMT and explored their regulatory mechanisms and clinical significance in UCBs.Experimental Design: We first screened circRNA expression profiles using a circRNA microarray in paired UCB and normal tissues, and then studied the clinical significance of an upregulated circRNA, circPRMT5, in a large cohort of patients with UCB. We further investigated the functions and underlying mechanisms of circPRMT5 in UCB cells' EMT. Moreover, we evaluated the regulation effect of circPRMT5 on miR-30c, and its target genes, SNAIL1 and E-cadherin, in two independent cohorts from our institute and The Cancer Genome Atlas (TCGA).Results: We demonstrated that upregulated expression of circPRMT5 was positively associated with advanced clinical stage and worse survival in patients with UCB. We further revealed that circPRMT5 promoted UCB cell's EMT via sponging miR-30c. Clinical analysis from two independent UCB cohorts showed that the circPRMT5/miR-30c/SNAIL1/E-cadherin pathway was essential in supporting UCB progression. Importantly, we identified that circPRMT5 was upregulated in serum and urine exosomes from patients with UCB, and significantly correlated with tumor metastasis.Conclusions: CircPRMT5 exerts critical roles in promoting UCB cells' EMT and/or aggressiveness and is a prognostic biomarker of the disease, suggesting that circPRMT5 may serve as an exploitable therapeutic target for patients with UCB. Clin Cancer Res; 1-13. (c)2018 AACR. PMID- 30305294 TI - Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities. AB - Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence. Clin Cancer Res; 1-9. (c)2018 AACR. PMID- 30305295 TI - What treatments are effective for common cold in adults and children? PMID- 30305296 TI - Diagnosis of "mystery" conditions improves with advanced US network approach. PMID- 30305298 TI - Mahua Chakrabarti: Blissful operator. PMID- 30305297 TI - Noise pollution: WHO sets limits on exposure to minimise adverse health effects. PMID- 30305299 TI - Europe's new device regulations fail to protect the public. PMID- 30305300 TI - Illicit drug use should be decriminalised and regarded as part of the spectrum of mental health disorders. PMID- 30305301 TI - Overdiagnosis: interpreting biochemistry results. PMID- 30305302 TI - 17-DMAG regulates p21 expression to induce chondrogenesis in vitro and in vivo. AB - Cartilage degeneration after injury affects a significant percentage of the population, including those that will go on to develop osteoarthritis (OA). Like humans, most mammals, including mice, are incapable of regenerating injured cartilage. Interestingly, it has previously been shown that p21 (Cdkn1a) knockout (p21-/-) mice demonstrate auricular (ear) cartilage regeneration. However, the loss of p21 expression is highly correlated with the development of numerous types of cancer and autoimmune diseases, limiting the therapeutic translation of these findings. Therefore, in this study, we employed a screening approach to identify an inhibitor (17-DMAG) that negatively regulates the expression of p21. We also validated that this compound can induce chondrogenesis in vitro (in adult mesenchymal stem cells) and in vivo (auricular cartilage injury model). Furthermore, our results suggest that 17-DMAG can induce the proliferation of terminally differentiated chondrocytes (in vitro and in vivo), while maintaining their chondrogenic phenotype. This study provides new insights into the regulation of chondrogenesis that might ultimately lead to new therapies for cartilage injury and/or OA. PMID- 30305303 TI - Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation. AB - Separase halves eukaryotic chromosomes in M-phase by cleaving cohesin complexes holding sister chromatids together. Whether this essential protease functions also in interphase and/or impacts carcinogenesis remains largely unknown. Here, we show that mammalian separase is recruited to DNA double-strand breaks (DSBs) where it is activated to locally cleave cohesin and facilitate homology-directed repair (HDR). Inactivating phosphorylation of its NES, arginine methylation of its RG-repeats, and sumoylation redirect separase from the cytosol to DSBs. In vitro assays suggest that DNA damage response-relevant ATM, PRMT1, and Mms21 represent the corresponding kinase, methyltransferase, and SUMO ligase, respectively. SEPARASE heterozygosity not only debilitates HDR but also predisposes primary embryonic fibroblasts to neoplasia and mice to chemically induced skin cancer. Thus, tethering of separase to DSBs and confined cohesin cleavage promote DSB repair in G2 cells. Importantly, this conserved interphase function of separase protects mammalian cells from oncogenic transformation. PMID- 30305304 TI - Apolipoprotein E deficiency accelerates atherosclerosis development in miniature pigs. AB - Miniature pigs have advantages over rodents in modeling atherosclerosis because their cardiovascular system and physiology are similar to that of humans. Apolipoprotein E (ApoE) deficiency has long been implicated in cardiovascular disease in humans. To establish an improved large animal model of familial hypercholesterolemia and atherosclerosis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 system (CRISPR/Cas9) was used to disrupt the ApoE gene in Bama miniature pigs. Biallelic-modified ApoE pigs with in-frame mutations (ApoEm/m ) and frameshift mutations (ApoE-/- ) were simultaneously produced. ApoE-/- pigs exhibited moderately increased plasma cholesterol levels when fed with a regular chow diet, but displayed severe hypercholesterolemia and spontaneously developed human-like atherosclerotic lesions in the aorta and coronary arteries after feeding on a high-fat and high cholesterol (HFHC) diet for 6 months. Thus, these ApoE-/- pigs could be valuable large animal models for providing further insight into translational studies of atherosclerosis. PMID- 30305307 TI - Correction to "Antagonism of Aryl Hydrocarbon Receptor Signaling by 6, 2',4' Trimethoxyflavone". PMID- 30305305 TI - ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters. AB - Antigen recognition by the T cell receptor (TCR) directs the assembly of essential signaling complexes known as SLP-76 (also known as LCP2) microclusters. Here, we show that the interaction of the adhesion and degranulation-promoting adaptor protein (ADAP; also known as FYB1) with SLP-76 enables the formation of persistent microclusters and the stabilization of T cell contacts, promotes integrin-independent adhesion and enables the upregulation of CD69. By analyzing point mutants and using a novel phospho-specific antibody, we show that Y595 is essential for normal ADAP function, that virtually all tyrosine phosphorylation of ADAP is restricted to a Y595-phosphorylated (pY595) pool, and that multivalent interactions between the SLP-76 SH2 domain and its binding sites in ADAP are required to sustain ADAP phosphorylation. Although pY595 ADAP enters SLP-76 microclusters, non-phosphorylated ADAP is enriched in protrusive actin-rich structures. The pre-positioning of ADAP at the contact sites generated by these structures favors the retention of nascent SLP-76 oligomers and their assembly into persistent microclusters. Although ADAP is frequently depicted as an effector of SLP-76, our findings reveal that ADAP acts upstream of SLP-76 to convert labile, Ca2+-competent microclusters into stable adhesive junctions with enhanced signaling potential. PMID- 30305308 TI - Broadening Our Perspectives: CKD Care and the Dialysis Transition. PMID- 30305306 TI - A severe atherosclerosis mouse model on the resistant NOD background. AB - Atherosclerosis is a complex disease affecting arterial blood vessels and blood flow that could result in a variety of life-threatening consequences. Disease models with diverged genomes are necessary for understanding the genetic architecture of this complex disease. Non-obese diabetic (NOD) mice are highly polymorphic and widely used for studies of type 1 diabetes and autoimmunity. Understanding atherosclerosis development in the NOD strain is of particular interest as human atherosclerosis on the diabetic and autoimmune background has not been successfully modeled. In this study, we used CRISPR/Cas9 genome editing to genetically disrupt apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) expression on the pure NOD background, and compared phenotype between single-gene-deleted mice and double-knockout mutants with reference to ApoE-deficient C57BL/6 mice. We found that genetic ablation of Ldlr or Apoe in NOD mice was not sufficient to establish an atherosclerosis model, in contrast to ApoE-deficient C57BL/6 mice fed a high-fat diet (HFD) for over 12 weeks. We further obtained NOD mice deficient in both LDLR and ApoE, and assessed the severity of atherosclerosis and immune response to hyperlipidemia in comparison to ApoE-deficient C57BL/6 mice. Strikingly, the double-knockout NOD mice treated with a HFD developed severe atherosclerosis with aorta narrowed by over 60% by plaques, accompanied by destruction of pancreatic islets and an inflammatory response to hyperlipidemia. Therefore, we succeeded in obtaining a genetic model with severe atherosclerosis on the NOD background, which is highly resistant to the disease. This model is useful for the study of atherosclerosis in the setting of autoimmunity. PMID- 30305309 TI - Addressing Financial Disincentives to Improve CKD Care. PMID- 30305311 TI - The Science of Fistula Maturation. PMID- 30305312 TI - Curli-Containing Enteric Biofilms Inside and Out: Matrix Composition, Immune Recognition, and Disease Implications. AB - Biofilms of enteric bacteria are highly complex, with multiple components that interact to fortify the biofilm matrix. Within biofilms of enteric bacteria such as Escherichia coli and Salmonella species, the main component of the biofilm is amyloid curli. Other constituents include cellulose, extracellular DNA, O antigen, and various surface proteins, including BapA. Only recently, the roles of these components in the formation of the enteric biofilm individually and in consortium have been evaluated. In addition to enhancing the stability and strength of the matrix, the components of the enteric biofilm influence bacterial virulence and transmission. Most notably, certain components of the matrix are recognized as pathogen-associated molecular patterns. Systemic recognition of enteric biofilms leads to the activation of several proinflammatory innate immune receptors, including the Toll-like receptor 2 (TLR2)/TLR1/CD14 heterocomplex, TLR9, and NLRP3. In the model of Salmonella enterica serovar Typhimurium, the immune response to curli is site specific. Although a proinflammatory response is generated upon systemic presentation of curli, oral administration of curli ameliorates the damaged intestinal epithelial barrier and reduces the severity of colitis. Furthermore, curli (and extracellular DNA) of enteric biofilms potentiate the autoimmune disease systemic lupus erythematosus (SLE) and promote the fibrillization of the pathogenic amyloid alpha-synuclein, which is implicated in Parkinson's disease. Homologues of curli-encoding genes are found in four additional bacterial phyla, suggesting that the biomedical implications involved with enteric biofilms are applicable to numerous bacterial species. PMID- 30305314 TI - Child mental health: government has "long way to go" to improve access, NAO finds. PMID- 30305310 TI - Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis. AB - BACKGROUND: The bile acid-activated receptors, including the membrane G protein coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms. METHODS: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the in vivo effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and Tgr5 knockout (Tgr5 -/-) mice. RESULTS: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells via a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. Tgr5 -/- mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium treated Tgr5 -/- mice, LCA treatment failed to prevent reduction of AQP2 expression. CONCLUSIONS: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney. PMID- 30305313 TI - A tent pole twist on membrane ruffles. AB - Macropinocytosis or "cell drinking" involves the elaboration of membrane ruffles that enclose and internalize extracellular fluids. Using lattice light sheet microscopy, Condon et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201804137) reveal the presence of parallel membrane protrusions termed "tent poles" that flank and direct membrane ruffle formation. PMID- 30305315 TI - How mesh became a four letter word. PMID- 30305316 TI - Cutaneous immunohistochemical staining pattern of p53beta isoforms. AB - p53 is considered the guardian of the genome and as such has numerous functions. The TP53 gene is the most commonly mutated gene in cancer, and yet the exact biological significance of such mutations remains unclear. There are at least 12 different isoforms of p53, and the complexity of the p53 pathway may be in part related to these isoforms. Prior research has often not teased out what isoforms of p53 are being studied, and there is evidence in the literature that p53 isoforms are expressed differently. In this paper, we document the staining pattern of p53beta isoforms in the skin and correlate it with mutational status in a subgroup of squamous proliferations of the skin. p53beta isoforms are present in the cytoplasm of the differentiated layer of the epidermis and hair follicles (granular layer, infundibular and isthmus-catagen). p53beta isoforms are diffusely expressed within the cytoplasm of well-differentiated squamous tumours with tetramerisation (C-terminal) domain mutations in TP53 Our results lend support to p53beta isoforms being a marker of differentiation in keratinocytes. PMID- 30305317 TI - Structure of the Recombinant Neisseria gonorrhoeae Adhesin Complex Protein (rNg ACP) and Generation of Murine Antibodies with Bactericidal Activity against Gonococci. AB - Neisseria gonorrhoeae (gonococcus [Ng]) is the causative organism of the sexually transmitted disease gonorrhoea, and no effective vaccine exists currently. In this study, the structure, biological properties, and vaccine potential of the Ng adhesin complex protein (Ng-ACP) are presented. The crystal structure of recombinant Ng-ACP (rNg-ACP) protein was solved at 1.65 A. Diversity and conservation of Ng-ACP were examined in different Neisseria species and gonococcal isolates (https://pubmlst.org/neisseria/ database) in silico, and protein expression among 50 gonococcal strains in the Centers for Disease Control and Prevention/Food and Drug Administration (CDCP/FDA) AR Isolate Bank was examined by Western blotting. Murine antisera were raised to allele 10 (strain P9 17)-encoded rNg-ACP protein with different adjuvants and examined by enzyme linked immunosorbent assay (ELISA), Western blotting, and a human serum bactericidal assay. Rabbit antiserum to rNg-ACP was tested for its ability to prevent Ng-ACP from inhibiting human lysozyme activity in vitro. Ng-ACP is structurally homologous to Neisseria meningitidis ACP and MliC/PliC lysozyme inhibitors. Gonococci expressed predominantly allele 10- and allele 6-encoded Ng ACP (81% and 15% of isolates, respectively). Murine antisera were bactericidal (titers of 64 to 512, P < 0.05) for the homologous P9-17 strain and heterologous (allele 6) FA1090 strain. Rabbit anti-rNg-ACP serum prevented Ng-ACP from inhibiting human lysozyme with ~100% efficiency. Ng-ACP protein was expressed by all 50 gonococcal isolates examined with minor differences in the relative levels of expression. rNg-ACP is a potential vaccine candidate that induces antibodies that (i) are bactericidal and (ii) prevent the gonococcus from inhibiting the lytic activity of an innate defense molecule.IMPORTANCE Neisseria gonorrhoeae (gonococcus [Ng]) is the causative organism of the sexually transmitted disease gonorrhoea, and the organism is listed by the World Health Organization as a high priority pathogen for research and development of new control measures, including vaccines. In this study, we demonstrated that the N. gonorrhoeae adhesin complex protein (Ng-ACP) was conserved and expressed by 50 gonococcal strains and that recombinant proteins induced antibodies in mice that killed the bacteria in vitro We determined the structure of Ng-ACP by X-ray crystallography and investigated structural conservation with Neisseria meningitidis ACP and MliC/PliC proteins from other bacteria which act as inhibitors of the human innate defense molecule lysozyme. These findings are important and suggest that Ng-ACP could provide a potential dual target for tackling gonococcal infections. PMID- 30305318 TI - The Genetic Transformation of Chlamydia pneumoniae. AB - We demonstrate the genetic transformation of Chlamydia pneumoniae using a plasmid shuttle vector system which generates stable transformants. The equine C. pneumoniae N16 isolate harbors the 7.5-kb plasmid pCpnE1. We constructed the plasmid vector pRSGFPCAT-Cpn containing a pCpnE1 backbone, plus the red-shifted green fluorescent protein (RSGFP), as well as the chloramphenicol acetyltransferase (CAT) gene used for the selection of plasmid shuttle vector bearing C. pneumoniae transformants. Using the pRSGFPCAT-Cpn plasmid construct, expression of RSGFP in koala isolate C. pneumoniae LPCoLN was demonstrated. Furthermore, we discovered that the human cardiovascular isolate C. pneumoniae CV 6 and the human community-acquired pneumonia-associated C. pneumoniae IOL-207 could also be transformed with pRSGFPCAT-Cpn. In previous studies, it was shown that Chlamydia spp. cannot be transformed when the plasmid shuttle vector is constructed from a different plasmid backbone to the homologous species. Accordingly, we confirmed that pRSGFPCAT-Cpn could not cross the species barrier in plasmid-bearing and plasmid-free C. trachomatis, C. muridarum, C. caviae, C. pecorum, and C. abortus However, contrary to our expectation, pRSGFPCAT-Cpn did transform C. felis Furthermore, pRSGFPCAT-Cpn did not recombine with the wild type plasmid of C. felis Taken together, we provide for the first time an easy-to handle transformation protocol for C. pneumoniae that results in stable transformants. In addition, the vector can cross the species barrier to C. felis, indicating the potential of horizontal pathogenic gene transfer via a plasmid.IMPORTANCE The absence of tools for the genetic manipulation of C. pneumoniae has hampered research into all aspects of its biology. In this study, we established a novel reproducible method for C. pneumoniae transformation based on a plasmid shuttle vector system. We constructed a C. pneumoniae plasmid backbone shuttle vector, pRSGFPCAT-Cpn. The construct expresses the red-shifted green fluorescent protein (RSGFP) fused to chloramphenicol acetyltransferase in C. pneumoniae C. pneumoniae transformants stably retained pRSGFPCAT-Cpn and expressed RSGFP in epithelial cells, even in the absence of chloramphenicol. The successful transformation in C. pneumoniae using pRSGFPCAT-Cpn will advance the field of chlamydial genetics and is a promising new approach to investigate gene functions in C. pneumoniae biology. In addition, we demonstrated that pRSGFPCAT Cpn overcame the plasmid species barrier without the need for recombination with an endogenous plasmid, indicating the potential probability of horizontal chlamydial pathogenic gene transfer by plasmids between chlamydial species. PMID- 30305319 TI - Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug Induced and Viral Hepatitis. AB - Cytochrome p4502E1 (CYP2E1) autoantibodies are biomarkers for drug-induced hepatitis and chronic hepatitis C. However, major histocompatibility-restricted CYP2E1 epitopes associated with these diseases have not been identified. We hypothesized that CYP2E1 epitopes associated with different types of hepatitis may be shared and may impact immune responses and metabolism. SYFPEITHI epitope prediction identified CYP2E1 candidate epitopes that would be recognized by MHC II haplotypes. Candidate epitopes were tested for induction of hepatitis and CYP2E1 autoantibodies in mice and recognition by sera from patients with anesthetic drug-induced and viral hepatitis. Human liver cells treated with epitope hybridoma serum were analyzed for mitochondrial stress. CYP2E1 activity was measured in human microsomes similarly treated. Epitope antibodies in viral hepatitis sera were analyzed using linear regression to uncover associations with liver pathology. A P value of <0.05 was considered significant. One epitope (Gly113-Leu135) induced hepatitis and CYP2E1 autoantibodies in mice after modification of Lys123 (P < 0.05). Gly113-Leu135 antiserum recognized mitochondria and endoplasmic reticula (P < 0.05), upregulated HSP27 (P < 0.01) and mitochondrial oxidative stress via complex 1 inhibition (P < 0.001), and inhibited CYP2E1 activity. Gly113-Leu135 IgG4 detected in viral hepatitis sera was associated with severe hepatic fibrosis (P = 0.0142). We found a novel CYP2E1 epitope that was detected in anesthetic and viral hepatitis and that triggered hepatitis in mice. Our findings may improve understanding of hepatic immune responses triggered by metabolism or viruses.IMPORTANCE Drug-induced hepatitis is the leading reason that an approved drug is removed from the commercial market. Halogenated anesthetics can induce hepatitis in susceptible persons, and cytochrome p4502E1 (CYP2E1) enzymes responsible for their metabolism induce antibodies in addition to hepatitis. CYP2E1 antibodies detected in anesthetic hepatitis patients have been detected in patients with viral hepatitis, suggesting that these different forms of hepatitis could develop immune reactions to a common segment or epitope of CYP2E1. We have found a common MHC-restricted CYP2E1 epitope in anesthetic and viral hepatitis that is a dominant epitope in anesthetic hepatitis and is significantly associated with fibrosis in patients with viral hepatitis. Along with conformational epitopes, our identification of MHC-restricted CYP2E1 epitopes can be used to develop specific diagnostic tests for drug-induced or viral hepatitis or associated fibrosis or to predict individuals at risk for developing these diseases or their sequelae. PMID- 30305322 TI - Retrotransposons in the development and progression of amyotrophic lateral sclerosis. AB - Endogenous retrotransposon sequences constitute approximately 42% of the human genome, and mobilisation of retrotransposons has resulted in rearrangements, duplications, deletions, novel transcripts and the introduction of new regulatory domains throughout the human genome. Both germline and somatic de novo retrotransposition events have been involved in a range of human diseases, and there is emerging evidence for the modulation of retrotransposon activity during the development of specific diseases. Particularly, there is unequivocal consensus that endogenous retrotransposition can occur in neuronal lineages. This review addresses our current knowledge of the different mechanisms through which retrotransposons might influence the development of and predisposition to amyotrophic lateral sclerosis. PMID- 30305320 TI - Most Sinorhizobium meliloti Extracytoplasmic Function Sigma Factors Control Accessory Functions. AB - Bacteria must sense alterations in their environment and respond with changes in function and/or structure in order to cope. Extracytoplasmic function sigma factors (ECF sigmas) modulate transcription in response to cellular and environmental signals. The symbiotic nitrogen-fixing alphaproteobacterium Sinorhizobium meliloti carries genes for 11 ECF-like sigmas (RpoE1 to -E10 and FecI). We hypothesized that some of these play a role in mediating the interaction between the bacterium and its plant symbiotic partner. The bacterium senses changes in its immediate environment as it establishes contact with the plant root, initiates invasion of the plant as the root nodule is formed, traverses several root cell layers, and enters plant cortical cells via endocytosis. We used genetics, transcriptomics, and functionality to characterize the entire S. meliloti cohort of ECF sigmas. We discovered new targets for individual sigmas, confirmed others by overexpressing individual ECF sigmas, and identified or confirmed putative promoter motifs for nine of them. We constructed precise deletions of each ECF sigma gene and its demonstrated or putative anti sigma gene and also a strain in which all 11 ECF sigma and anti-sigma genes were deleted. This all-ECF sigma deletion strain showed no major defects in free living growth, in Biolog Phenotype MicroArray assays, or in response to multiple stresses. None of the ECF sigmas were required for symbiosis on the host plants Medicago sativa and Medicago truncatula: the strain deleted for all ECF sigma and anti-sigma genes was symbiotically normal.IMPORTANCE Fixed (reduced) soil nitrogen plays a critical role in soil fertility and successful food growth. Much soil fertility relies on symbiotic nitrogen fixation: the bacterial partner infects the host plant roots and reduces atmospheric dinitrogen in exchange for host metabolic fuel, a process that involves complex interactions between the partners mediated by changes in gene expression in each partner. Here we test the roles of a family of 11 extracytoplasmic function (ECF) gene regulatory proteins (sigma factors [sigmas]) that interact with RNA polymerase to determine if they play a significant role in establishing a nitrogen-fixing symbiosis or in responding to various stresses, including cell envelope stress. We discovered that symbiotic nitrogen fixation occurs even when all 11 of these regulatory genes are deleted, that most ECF sigma factors control accessory functions, and that none of the ECF sigma factors are required to survive envelope stress. PMID- 30305323 TI - Apraxia screening predicts Alzheimer pathology in frontotemporal dementia. AB - OBJECTIVES: Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome linked to diverse types of underlying neuropathology. Diagnosis is mainly based on clinical presentation and accurate prediction of underlying neuropathology remains difficult. METHODS: We present a large cohort of patients with FTD spectrum diseases (n=84). All patients were thoroughly characterised by cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, neuroimaging, neuropsychological testing and standardised apraxia screening. RESULTS: A potential AD pathology was found in 43% of patients with FTD. CSF AD biomarker levels positively correlated with AD-typical apraxia scores in patients with FTD. The discriminative power of apraxia test results indicative of AD pathology was high (sensitivity: 90%, specificity: 66%). CONCLUSIONS: Apraxia is common in neurodegenerative dementias but under-represented in clinical workup and diagnostic criteria. Standardised apraxia screening may serve as bedside test to objectify an AD-typical apraxia profile as an early and robust sign of AD pathology in patients with FTD. PMID- 30305321 TI - Discovery of mcr-1-Mediated Colistin Resistance in a Highly Virulent Escherichia coli Lineage. AB - Resistance to last-line polymyxins mediated by the plasmid-borne mobile colistin resistance gene (mcr-1) represents a new threat to global human health. Here we present the complete genome sequence of an mcr-1-positive multidrug-resistant Escherichia coli strain (MS8345). We show that MS8345 belongs to serotype O2:K1:H4, has a large 241,164-bp IncHI2 plasmid that carries 15 other antibiotic resistance genes (including the extended-spectrum beta-lactamase bla CTX-M-1) and 3 putative multidrug efflux systems, and contains 14 chromosomally encoded antibiotic resistance genes. MS8345 also carries a large ColV-like virulence plasmid that has been associated with E. coli bacteremia. Whole-genome phylogeny revealed that MS8345 clusters within a discrete clade in the sequence type 95 (ST95) lineage, and MS8345 is very closely related to the highly virulent O45:K1:H4 clone associated with neonatal meningitis. Overall, the acquisition of a plasmid carrying resistance to colistin and multiple other antibiotics in this virulent E. coli lineage is concerning and might herald an era where the empirical treatment of ST95 infections becomes increasingly more difficult.IMPORTANCE Escherichia coli ST95 is a globally disseminated clone frequently associated with bloodstream infections and neonatal meningitis. However, the ST95 lineage is defined by low levels of drug resistance amongst clinical isolates, which normally provides for uncomplicated treatment options. Here, we provide the first detailed genomic analysis of an E. coli ST95 isolate that has both high virulence potential and resistance to multiple antibiotics. Using the genome, we predicted its virulence and antibiotic resistance mechanisms, which include resistance to last-line antibiotics mediated by the plasmid-borne mcr-1 gene. Finding an ST95 isolate resistant to nearly all antibiotics that also has a high virulence potential is of major clinical importance and underscores the need to monitor new and emerging trends in antibiotic resistance development in this important global lineage. PMID- 30305324 TI - Revolution or redux? Assessing IQOS through a precursor product. AB - BACKGROUND: Philip Morris International (PMI) currently claims that its heated tobacco product, IQOS, reduces health risk by reducing users' exposure to harmful and potentially harmful constituents present in tobacco smoke. Given the tobacco industry's long history of misrepresenting and obfuscating research, independent assessment of PMI's claims is important. Analysis of Accord, a failed but strikingly similar precursor to IQOS, may help contextualise PMI's claims in its Modified Risk Tobacco Product (MRTP) application. METHODS: We analysed previously secret internal Philip Morris (PM) and PMI documents, public communications and MRTP application. RESULTS: PM marketed Accord as a 'cleaner' tobacco product in an attempt to address smokers' growing health concerns without making explicit health claims. While PM communications asserted that Accord reduced users' exposure to harmful constituents, company scientists and executives consistently stressed to both regulators and the public that such reductions did not render Accord safer. IQOS's design and marketing are similar to Accord's. On the basis of aerosol chemistry data, IQOS reduces user exposure to some compounds compared with Accord but raises them for others. DISCUSSION: IQOS appears to be a variant of Accord without consistent improvements in exposure to aerosol toxic compounds. In contrast to PM's past claims for Accord, PMI now claims in its MRTP application that IQOS reduces health risk. This shift in stance is likely not the result of any toxicological difference between Accord and IQOS, but rather a change in the social and regulatory landscape permitting these claims. PMID- 30305327 TI - Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40. AB - New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto oligomerizing CD40 derivatives to induce strong activation of APCs in a ligand independent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-gamma secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-gamma, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-gamma and TNF-alpha production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family. PMID- 30305325 TI - Cutting Edge: IL-1alpha and Not IL-1beta Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality. AB - Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1alpha and IL-1beta, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1alpha or IL-1beta in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1alpha and IL-1beta, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1alpha and not IL-1beta is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates. PMID- 30305329 TI - B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation. AB - BCR engagement leads to activation and clonal expansion of B cells. The I-A12% mutant mouse possesses a branch site point mutation in the H2-Aa gene that causes highly reduced I-Aa protein expression. As I-A is a heterodimer made up of I-Aa and I-Ab, reduced I-Aa results not only in reduced surface I-A expression but also in an excess of unpaired I-Ab. B cells that develop in I-A12% mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A12% B cells were engaged in unfolded protein response due to an excess of unpaired I-Ab. BCR responsiveness was restored by transduced I-Aa expression and by BiP, the unfolded protein response sensor. Reducing the load of unpaired I-Ab also restored BCR responsiveness of I-A12% B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A12% B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A12% B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A12% B cells restored BCR responsiveness. Our results point to a generalized incompatibility between BCR responsiveness and increased Skp2 stability. They also imply the existence of regulatory mechanisms other than Ig gene rearrangement that govern Mef2c turnover in a specific, exquisite, and dynamic fashion. PMID- 30305326 TI - Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in Drosophila. AB - Zika virus (ZIKV) outbreaks pose a massive public health threat in several countries. We have developed an in vivo model to investigate the host-ZIKV interaction in Drosophila We have found that a strain of ZIKV replicates in wild type flies without reducing their survival ability. We have shown that ZIKV infection triggers RNA interference and that mutating Dicer-2 results in enhanced ZIKV load and increased susceptibility to ZIKV infection. Using a flavivirus specific Ab, we have found that ZIKV is localized in the gut and fat body cells of the infected wild-type flies and results in their perturbed homeostasis. In addition, Dicer-2 mutants display severely reduced insulin activity, which could contribute toward the increased mortality of these flies. Our work establishes the suitability of Drosophila as the model system to study host-ZIKV dynamics, which is expected to greatly advance our understanding of the molecular and physiological processes that determine the outcome of this disease. PMID- 30305328 TI - Androgen and Androgen Receptor as Enhancers of M2 Macrophage Polarization in Allergic Lung Inflammation. AB - Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4-stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (ARfloxLysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment. PMID- 30305331 TI - Hands are vehicles for transmission of Streptococcus pneumoniae in novel controlled human infection study. PMID- 30305332 TI - The European Sleep Apnoea Database (ESADA) ERS Clinical Research Collaboration: past, present and future. PMID- 30305330 TI - Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease. AB - The long-term effects of chronic blood exchange transfusions (BETs) on pre capillary pulmonary hypertension complicating sickle cell disease (SCD) are unknown.13 homozygous SS SCD patients suffering from pre-capillary pulmonary hypertension and treated by chronic BETs were evaluated retrospectively. Assessments included haemodynamics, New York Heart Association Functional Class (NYHA FC), 6-min walk distance (6MWD) and blood tests.Before initiating BETs, all patients were NYHA FC III or IV, median (range) 6MWD was 223 (0-501) m and median (range) pulmonary vascular resistance (PVR) was 3.7 (2-12.5) Wood Units. After a median number of 4 BET sessions, all patients had improved to NYHA FC II or III. Significant improvements in haemodynamics were observed, including a decrease in PVR (p=0.01). There was a trend to higher 6MWD (p=0.09). Median (range) follow-up time after initiation of BETs was 25 (6-53) months. During this period, two patients decided to stop BETs. One of them died from acute right heart failure and the other experienced worsening pulmonary hypertension. Two other patients died during follow-up at 25 and 54 months after BET initiation.Chronic BETs may be a potential therapeutic option in pre-capillary pulmonary hypertension complicating SCD, leading to significant clinical and haemodynamic improvements. These data must be confirmed in a prospective study. PMID- 30305333 TI - Physical activity: the key to cardiometabolic risk reduction in obstructive sleep apnoea. PMID- 30305334 TI - Digital Health and Health Systems of the Future. PMID- 30305335 TI - Establishing Standards to Evaluate the Impact of Integrating Digital Health into Health Systems. PMID- 30305336 TI - What Does It Take to Be an Effective National Steward of Digital Health Integration for Health Systems Strengthening in Low- and Middle-Income Countries? AB - BACKGROUND: Digital innovations have evolved over the last 15 years to support health activities, and their introduction in low- and middle-income countries has shown the potential to catalyze gains in health systems and service delivery. Despite widespread efforts to roll out these technologies, standardized approaches for formalizing national stewardship responsibilities and ensuring that digital health is a routine, mature, sustainable, and country-owned component of the health system are lacking. In this paper, we define digital health stewardship, with a focus on the ministry of health's role; describe practices undertaken to date; and identify gaps where increased attention could improve sustainability, impact, and local ownership. METHODS: We conducted a purposeful review of peer-reviewed and gray literature. Of the 404 identified resources from the peer-reviewed literature, 12 met all of the inclusion criteria. After searching various online gray literature repositories, we identified 6 sources based on their quality, source, and relevance. Selected resources were abstracted for relevance to our stewardship themes and synthesized. RESULTS: Findings are presented in 4 broad thematic areas: strategic direction, policies and procedures, roles and responsibilities, and health service delivery implications. Evidence related to strategic direction offers guidance on the main responsibilities under digital health stewardship, including regulations and incentives to promote compliance with standards, mechanisms for oversight, and structures to support evidence-based decisions, and the potential institutional structures and goals that could be used to achieve them. A number of examples of high-level policies and implementation-oriented procedures, such as from the European Commission and the World Health Organization, demonstrate how to operationalize the strategic direction. Available evidence for the remaining themes was sparse, drawing attention to key areas for future work. CONCLUSIONS: Despite the importance of country-owned stewardship of digital health, the guidance available is limited and aspirational. Concrete recommendations, including how to adapt existing innovations to the local context, are needed. In particular, the role of external partners needs to be oriented toward building and supporting country capacity to achieve digital health stewardship's potential to support health systems into the future. PMID- 30305337 TI - The Role of Digital Strategies in Financing Health Care for Universal Health Coverage in Low- and Middle-Income Countries. AB - Countries finance health care using a combination of 3 main functions: raising resources for health, pooling resources, and purchasing health services. In this paper, we examine how digital health technologies can be used to enhance these health financing functions in low- and middle-income countries and can thus contribute to progress toward universal health coverage. We illustrate our points by presenting some recent innovations in digital technologies for financing health care, identifying their contributions and their limits. Some examples include a mobile-health wallet application used in Kenya that encourages households to put money aside for future health expenses; an online software platform developed by a startup in Tanzania in partnership with a private insurance provider to give individuals and families the opportunity to choose among different health coverage options; and digital maps by a number of startups that bring together data on health facility locations and capacity, including equipment, staff, and types of services offered. We also sketch an agenda for future research and action for digital strategies for health financing. The development and adoption of effective solutions that align well with the universal health coverage agenda will require strong partnerships between stakeholders and enough proactive stewardship by authorities. PMID- 30305338 TI - Digital Technologies for Health Workforce Development in Low- and Middle-Income Countries: A Scoping Review. AB - The collection of journal articles, systematic reviews, and reports published over the last decade that attest to the potential of digital technologies to achieve health workforce improvements across all aspects of the health system is vast. As a capacity-building mechanism, digital technology has potential for low- and middle-income countries (LMICs) to support development of the health workforce, including those health workers based in remote or rural areas, to train, motivate, support, monitor, and pay them. The purpose of this scoping review to present, at a high level, the state of the evidence and best practices in digital strategies for human resources for health and to propose a roadmap for a research agenda to fill identified gaps in the evidence. A variety of peer reviewed and gray literature sources were searched using selected key terms related to digital health and health workforce, limited to materials published from 2010 to 2018. More than 70 articles, reports, and blog posts were reviewed, with in-depth analysis of 29 articles. Findings show that a range of digital health solutions for health workforce development have been tested and used, such as for health worker training, provider-to-provider communication and professional networking, and supervision of and performance feedback to health workers. There is some evidence of improved efficiency and effectiveness, at least at the level of pilots or small-scale projects. There is, however, a growing urgency in global health to move beyond small-scale demonstration projects and to define the capital and recurring costs of implementation and scale up of digital health interventions, including the return on investment. The next frontier is to select, adapt, and implement at scale those digital health interventions for health worker development and management found to be most promising. PMID- 30305339 TI - The State of Digital Interventions for Demand Generation in Low- and Middle Income Countries: Considerations, Emerging Approaches, and Research Gaps. AB - The recent introduction of digital health into generating demand for health commodities and services has provided practitioners with an expanded universe of potential tools to strengthen demand and ensure service delivery receipt. However, considerable gaps remain in our understanding of which interventions are effective, which characteristics mediate their benefit for different target populations and health domains, and what is necessary to ensure effective deployment. This paper first provides an overview of the types of digital health interventions for demand generation, including untargeted client communication, client-to-client communication, on-demand information services, personal health tracking, client financial transactions, and targeted client communication. It then provides a general overview of 118 studies published between January 1, 2010, and October 3, 2017, that used digital interventions to generate demand for health interventions. The majority (61%) of these studies used targeted client communication to provide health education or reminders to improve treatment adherence, and the most frequently (27%) studied health condition was HIV/AIDS. Intervention characteristics that have been found to have some effect on gains in demand generation include modality, directionality, tailoring, phrasing, and schedule. The paper also explores new emergent digital approaches that expand the potential effect of traditional demand generation in terms of personalization of content and services, continuity of care, and accountability tracking. Applying existing frameworks for monitoring and evaluation and reporting, research on emerging approaches will need to consider not only their feasibility but also their effectiveness in achieving demand generation outcomes. We propose a research agenda to help guide the field of digital demand generation studies and programs within a broader health systems strengthening agenda, including establishing and documenting the influence of intervention characteristics within different populations and health domains and examining the long-term effects and cost-effectiveness of digital demand generation interventions, as well as equity in access to such interventions. PMID- 30305342 TI - A four-gene decision tree signature classification of triple-negative breast cancer: Implications for targeted therapeutics. AB - The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterise this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1 and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumours (~50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum-sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the mitogen-activated protein kinase (MAPK) signalling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials. PMID- 30305340 TI - Strengthening Delivery of Health Services Using Digital Devices. AB - BACKGROUND: Delivery of high-quality efficient health services is a cornerstone of the global agenda to achieve universal health coverage. According to the World Health Organization, health service delivery is considered good when equitable access to a comprehensive range of high-quality health services is ensured within an integrated and person-centered continuum of care. However, good health service delivery can be challenging in low-resource settings. In this review, we summarize and discuss key advances in health service delivery, particularly in the context of using digital health strategies for mitigating human resource constraints. METHODS: The review updates the foundational systematic review conducted by Agarwal et al. in 2015. We used PubMed, EMBASE, and CINAHL to find relevant English-language peer-reviewed articles published 2018. Our search strategy for MEDLINE was based on MeSH (medical subject headings) terms and text words of key articles that we identified a priori. Our search identified 92 articles. After screening, we selected 24 articles for abstract review, of which only 6 met the eligibility criteria and were ultimately included in this review. RESULTS: Despite encouraging advances in the evidence base on digital strategies for health service delivery, the current body of evidence is still quite limited in 3 main areas: the effectiveness of interventions on health outcomes, improvement in health system efficiencies for service delivery, and the human capacity required to implement and support digital health strategies at scale. Two particular areas, digital health-enhanced referral coordination and mobile clinical decision support systems, demonstrate considerable potential to improve the quality and comprehensiveness of care received by patients, but they require a greater level of standardization and an expanded scope of health worker engagement across the health system in order to scale them up effectively. CONCLUSIONS: Additional research is urgently needed to inform the effectiveness of interventions on health outcomes, improvement in health system efficiencies, and cost-effectiveness of service delivery. In particular, more documentation and research on ways to standardize and engage health workers in digital referral and clinical decision support systems can provide the foundation needed to scale these promising approaches in low- and middle-income settings. PMID- 30305341 TI - PRKRA/PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer. AB - For mucinous ovarian cancer (MOC), standard platinum based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based small interfering RNA (siRNA) library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant anti tumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515 3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin. PMID- 30305343 TI - Efficacy of an Education Program for People With Diabetes and Insulin Pump Treatment (INPUT): Results From a Randomized Controlled Trial. AB - OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) is the most advanced form of insulin delivery, but it requires structured education to provide users with the necessary knowledge/skills and to support their motivation. Currently, no structured education program designed to provide this training has been evaluated. We developed a CSII-specific, structured education program (Insulin Pump Treatment [INPUT]) and evaluated its impact on glycemic control, behavior, and psychosocial status. RESEARCH DESIGN AND METHODS: This was a multicenter, randomized, parallel trial with a 6-month follow-up. Eligible participants (age 16-75 years) currently were treated with insulin pump therapy. Participants were randomly assigned (1:1) to the INPUT program or to usual care using a computer generated algorithm, with study center as the stratification factor. The primary outcome was HbA1c change from baseline to 6 months. Secondary outcomes were incidence of severe hypoglycemia and changes in behavioral and psychosocial measures. RESULTS: Between 1 April 2016 and 26 April 2016, 268 people with diabetes and a mean duration of CSII therapy of 9.5 years were randomly assigned to the INPUT group (n = 135) or control group (n = 133). At 6 months, HbA1c improved in the INPUT group (8.33 +/- 0.8 vs. 8.04 +/- 0.9; P < 0.0001) but not in the control group (8.33 +/- 1.0 vs. 8.27 +/- 1.0; P = 0.11). The between-group difference in HbA1c reduction was significant, favoring INPUT (-0.28% vs. -0.06%, Delta -0.22%, 95% CI -0.38 to -0.06; P = 0.0029). The incidence rate ratio of severe hypoglycemia was 3.55 times higher for participants in the control group than for those in the INPUT group (95% CI 1.50-8.43; P = 0.0041). CONCLUSIONS: The INPUT education program led to a significant improvement in glycemic control and incidence of severe hypoglycemia in insulin pump users. PMID- 30305345 TI - Pharmacokinetics, Pharmacodynamics, and Modulation of Hepatic Glucose Production With Insulin Glargine U-300 and Glargine U-100 at Steady State With Individualized Clinical Doses in Type 1 Diabetes. AB - OBJECTIVE: This study characterized the pharmacokinetics (PK), pharmacodynamics (PD), and endogenous (hepatic) glucose production (EGP) of clinical doses of glargine-U300 (Gla-300) and glargine-U100 (Gla-100) under steady-state conditions (SS) in type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: T1DM subjects (N = 18, age 40 +/- 12 years, T1DM duration 26 +/- 12 years, BMI 23.4 +/ 2 kg/m2, A1C 7.19 +/- 0.52% [55 +/- 5.7 mmol/mol]), were studied after 3 months of Gla-300 or Gla-100 (evening dosing) titrated to fasting euglycemia (random, crossover) with the euglycemic clamp using individualized doses (Gla-300 0.35 +/- 0.08, Gla-100 0.28 +/- 0.07 units . kg-1). RESULTS: Plasma free insulin concentrations (free immunoreactive insulin area under the curve) were equivalent over 24 h with Gla-300 versus Gla-100 (point estimate 1.11 [90% CI 1.03-1.20]) but were reduced in the first 6 h (0.91 [90% CI 0.86-0.97]) and higher in the last 12 h postdosing (1.38 [90% CI 1.21-1.56]). Gla-300 and Gla-100 both maintained 24 h euglycemia (0.99 [90% CI 0.98-1.0]). The glucose infusion rate was equivalent over 24 h (1.03 [90% CI 0.88-1.21]) but was lower in first (0.77 [90% CI 0.62-0.95]) and higher (1.53 [90% CI 1.23-1.92]) in the second 12 h with Gla-300 versus Gla-100. EGP was less suppressed during 0-6 h but more during 18 24 h with Gla-300. PK and PD within-day variability (fluctuation) was 50% and 17% lower with Gla-300. CONCLUSIONS: Individualized, clinical doses of Gla-300 and Gla-100 resulted in a similar euglycemic potential under SS conditions. However, Gla-300 exhibited a more stable profile, with lower variability and more physiological modulation of EGP compared with Gla-100. PMID- 30305344 TI - Fasting Glucose Variability in Young Adulthood and Cognitive Function in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - OBJECTIVE: To determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG. RESEARCH DESIGN AND METHODS: We studied 3,307 CARDIA (Coronary Artery Risk Development in Young Adults) Study participants (age range 18-30 years and enrolled in 1985-1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements (average real variability [ARV-FG]) before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010-2011) and 30 (2015-2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FG level, and diabetes development, medication use, and duration. RESULTS: After multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient -0.95 (95% CI -1.54, -0.36); RAVLT, -0.14 (95% CI -0.27, -0.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values. CONCLUSIONS: Higher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels. PMID- 30305346 TI - First Look at Control-IQ: A New-Generation Automated Insulin Delivery System. AB - OBJECTIVE: To pilot test a new closed-loop control technology to validate it for a further large clinical trial. RESEARCH DESIGN AND METHODS: The t:slim X2 insulin pump with Control-IQ Technology (Tandem Diabetes Care) includes a Dexcom G6 sensor and a closed-loop algorithm implemented in the pump that 1) automates insulin correction boluses, 2) has a dedicated hypoglycemia safety system, and 3) gradually intensifies control overnight, aiming for blood glucose levels of approximately 100-120 mg/dL every morning. RESULTS: Five patients with type 1 diabetes (mean age 52.8 years, 2/3 male/female, mean A1C 6.5%) used Control-IQ in an outpatient setting (hotel) for approximately 37 h. During the closed loop, mean glucose was 129 mg/dL (135/121 mg/dL during the day/night), time within target range 70-180 mg/dL was 87% (82%/94% during the day/night), and time <60 mg/dL was 1.1% (2.0%/0.0% during the day/night). CONCLUSIONS: Following this pilot trial, Control-IQ was deployed in several studies, including the large scale National Institutes of Health International Diabetes Closed-Loop (iDCL) Trial. PMID- 30305347 TI - Risk Factors for the Presence and Progression of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: ADDITION-Denmark. AB - OBJECTIVE: To examine the course of cardiovascular autonomic neuropathy (CAN) and related cardiometabolic risk factors in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: CAN and cardiometabolic risk factors were assessed in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) at 6-year (n = 777) and 13-year (n = 443) follow-up examinations. Cardiovascular autonomic reflex tests (CARTs)-that is, lying to standing, deep breathing, and the Valsalva maneuver-and 2-min resting heart rate variability (HRV) indices were obtained as the main measures of CAN. Risk factors related to CAN status, as determined by CARTs, were studied by using multivariate logistic regressions. The effects of risk factors on continuous CARTs and HRV indices, and their changes over time, were estimated in linear mixed models. RESULTS: A progressive yet heterogeneous course of CAN occurred between the 6- and 13-year follow-ups. Higher HbA1c, weight, BMI, and triglycerides were associated with prevalent CAN. No significant effect of risk factors on CARTs was found when they were analyzed as continuous variables. CART indices decreased over time, and a trend of decreasing HRV indices was seen. Higher HbA1c and BMI were associated with lower HRV index values, but these differences diminished over time. CONCLUSIONS: These data confirm that hyperglycemia, obesity, and hypertriglyceridemia are negatively related to indices of CAN, although these effects diminish over time. The observed heterogeneous course of CAN may challenge the present clinical approach of categorically classifying CARTs to diagnose CAN and the notion of CAN being irreversible. PMID- 30305348 TI - Increased Reporting of Immune Checkpoint Inhibitor-Associated Diabetes. PMID- 30305349 TI - Economic Costs Attributable to Diabetes in Each U.S. State. AB - OBJECTIVE: To estimate direct medical and indirect costs attributable to diabetes in each U.S. state in total and per person with diabetes. RESEARCH DESIGN AND METHODS: We used an attributable fraction approach to estimate direct medical costs using data from the 2013 State Health Expenditure Accounts, 2013 Behavioral Risk Factor Surveillance System, and the Centers for Medicare & Medicaid Services' 2013-2014 Minimum Data Set. We used a human capital approach to estimate indirect costs measured by lost productivity from morbidity (absenteeism, presenteeism, lost household productivity, and inability to work) and premature mortality, using the 2008-2013 National Health Interview Survey, 2013 daily housework value data, 2013 mortality data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research, and mean wages from the 2014 Bureau of Labor Statistics. Costs were adjusted to 2017 U.S. dollars. RESULTS: The estimated median state economic cost was $5.9 billion, ranging from $694 million to $55.5 billion, in total and $18,248, ranging from $15,418 to $30,915, per person with diabetes. The corresponding estimates for direct medical costs were $2.8 billion (range $0.3-22.9) and $8,544 (range $6,591 12,953) and for indirect costs were $3.0 billion (range $0.4-32.6) and $9,672 (range $7,133-17,962). In general, the estimated state median indirect costs resulting from morbidity were larger than costs from mortality both in total and per person with diabetes. CONCLUSIONS: Economic costs attributable to diabetes were large and varied widely across states. Our comprehensive state-specific estimates provide essential information needed by state policymakers to monitor the economic burden of the disease and to better plan and evaluate interventions for preventing type 2 diabetes and managing diabetes in their states. PMID- 30305350 TI - Identification of anti-norovirus genes in human cells using genome-wide CRISPR activation screening. AB - Noroviruses (NoVs) are a leading cause of gastroenteritis world-wide, yet host factors that restrict NoV replication are not well understood. Here, we use a CRISPR activation (CRISPRa) genome-wide screening to identify host genes that can inhibit murine norovirus (MNoV) replication in human cells. Our screens identified with high confidence 49 genes that can inhibit MNoV infection when overexpressed. A significant number of these genes are in interferon and immune regulation signaling networks, but surprising, the majority of the genes identified are not associated with innate or adaptive immunity nor with any antiviral activity. Confirmatory studies of eight of the genes validate the initial screening data. Mechanistic studies on TRIM7 demonstrated a conserved role of the molecule in mouse and human cells in restricting MNoV in a step of infection after viral entry. Furthermore, we demonstrate that two isoforms of TRIM7 have differential antiviral activity. Taken together these data provide a resource for understanding norovirus biology and demonstrate a robust methodology for identifying new antiviral molecules.Importance: Norovirus is one of the leading causes of foodborne illness world-wide. Despite its prevalence, our understanding of norovirus biology is limited due to the difficulty in growing human norovirus in vitro and a lack of an animal model. Murine norovirus (MNoV) is a model norovirus system because MNoV replicates robustly in cell culture and in mice. To identify host genes that can restrict norovirus replication when overexpressed we performed genome-wide CRISPR activation (CRISPRa) screens to induce gene overexpression at the native locus through recruitment of transcriptional activators to individual gene promoters. We found 49 genes could block murine norovirus replication in human cells. Several of these genes are associated with classical immune signaling pathways, while many of the molecules we identified have not been previously associated with antiviral activity. Our data is a resource for those studying norovirus and we provide a robust approach to identify novel antiviral genes. PMID- 30305351 TI - Structure-based classification defines the discrete conformational classes adopted by the arenaviral GP1. AB - The emergence of Old and New World arenaviruses from rodent reservoirs persistently threatens human health. The GP1 subunit of the envelope-displayed arenaviral glycoprotein spike complex, GPC, mediates host-cell recognition and is an important determinant of cross-species transmission. Previous structural analyses of Old World arenaviral GP1 glycoproteins, alone and in complex with a cognate GP2 subunit, have revealed that GP1 adopts two distinct conformational states, distinguished by differences in orientation of helical regions of the molecule. Here, through comparative study of the GP1 glycoprotein architectures of Old World Loei River virus and New World Whitewater Arroyo virus, we show that these rearrangements are restricted to Old World arenaviruses and are not solely induced by the pH change that is associated with virus endosomal trafficking. Our structure-based phylogenetic analysis of arenaviral GP1s provides a blueprint for understanding the discrete structural classes adopted by these therapeutically important targets.IMPORTANCE The genetically and geographically diverse group of viruses within the Arenaviridae family includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multi-subunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and the primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 sub-component of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure based approach for understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC, as presented on the mature virion surface. PMID- 30305352 TI - Influenza A virus utilizes low affinity, high avidity interactions with the nuclear import machinery to ensure infection and immune evasion. AB - The incoming influenza A virus (IAV) genome must pass through two distinct barriers in order to establish infection in the cell- the plasma membrane and the nuclear membrane. A precise understanding of the challenges imposed by the nuclear barrier remain outstanding. Passage across is mediated by host karyopherins (KPNAs), which bind to the viral nucleoprotein (NP) via its N terminal nuclear localization sequence (NLS). Binding affinity between the two molecules is low but NP is present in high copy number, which suggests that binding avidity plays a compensatory role during import. Using nanobody-based technology, we demonstrate that high binding avidity is required for infection though the absolute value differs between cell types and correlates with their relative susceptibility to infection. In addition, we demonstrate that increasing the affinity level caused a decrease in avidity requirements for some cell types but blocked infection in others. Finally, we show that genomes that become frustrated by low avidity and remain cytoplasmic trigger the Type-I interferon response. Based on these results, we conclude that IAV balances affinity and avidity considerations in order to overcome the nuclear barrier across a broad range of cell types. Furthermore, these results provide evidence to support the long-standing hypothesis that IAV's strategy of import and replication in the nucleus facilitates immune evasion.ImportanceWe used intracellular nanobodies to block influenza virus infection at the step prior to nuclear import of its ribonucleoproteins. By doing so, we were able to answer an important but outstanding question that could not be addressed with conventional tools- how many of the ~500 available NLS motifs are needed to establish infection? Furthermore, by controlling the sub-cellular localization of the incoming vRNPs and measuring the cell's antiviral response, we were able to provide direct evidence for the longstanding hypothesis that influenza virus exploits nuclear localization to delay activation of the innate immune response. PMID- 30305353 TI - Synergistic activation of bovine herpesvirus 1 productive infection and viral regulatory promoters by the progesterone receptor and Kruppel-like transcription factor 15. AB - Bovine herpesvirus 1 (BoHV-1), including modified live vaccines, readily infect the fetus and ovaries, which can lead to reproductive failure. The BoHV-1 latency reactivation cycle in sensory neurons may further complicate reproductive failure in pregnant cows. The immediate early transcription unit 1 (IEtu1) promoter drives expression of important viral transcriptional regulators (bICP0 and bICP4). This promoter contains two functional glucocorticoid receptor (GR) response elements (GREs) that have the potential to stimulate productive infection following stressful stimuli. Since progesterone and the progesterone receptor (PR) can activate many GREs, we hypothesized that the PR and/or progesterone regulates productive infection and viral transcription. New studies demonstrated that progesterone stimulated productive infection. Additional studies revealed the PR and Kruppel-like transcription factor 15 (KLF15) cooperated to stimulate productive infection and IEtu1 promoter activity. IEtu1 promoter activation required both GREs, which correlated with the ability of the PR to interact with wt GREs, but not mutant GREs. KLF15 also cooperated with the PR to trans-activate the bICP0 early promoter, a promoter that maintains bICP0 protein expression during productive infection. Intergenic viral DNA fragments (less than 400 bp) containing two GREs and putative KLF binding sites present within genes encoding unique long 52 (UL-52; component of DNA primase/helicase complex), Circ, bICP4, and IEtu2 were stimulated by KLF15 and the PR more than 10 fold suggesting additional viral promoters are activated by these transcription factors. Collectively, these studies suggest progesterone and the PR promote BoHV 1 spread to reproductive tissues, thus increasing the incidence of reproductive failure.IMPORTANCEBovine herpesvirus 1 (BoHV-1) is the most frequently diagnosed cause of abortions in pregnant cows and can cause "abortion storms" in susceptible herds. Virulent field strains and even commercially available modified live vaccines can induce abortion, in part because BoHV-1 replicates efficiently in the ovary and corpus luteum. We now demonstrate that progesterone and the progesterone receptor (PR) stimulate productive infection. The BoHV-1 genome contains approximately 100 glucocorticoid receptor (GR) response elements (GREs). Interestingly, the PR can bind and activate many promoters that contain GREs. The PR and Kruppel-like transcription factor 15 (KLF15), which regulate key steps during embryo implantation, cooperate to stimulate productive infection and two viral promoters that drive expression of key viral transcriptional regulators. These studies suggest that the ability of progesterone and the PR to stimulate productive infection has the potential to promote virus spread in reproductive tissue and induce reproductive failure. PMID- 30305354 TI - Genotypic and Mechanistic Characterization of Subtype-specific HIV Adaptation to Host Cellular Immunity. AB - The extent to which viral genetic context influences HIV adaptation to Human Leukocyte Antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D co-circulate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtypes A1 or D. Using phylogenetically-informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtypes A1 and/or D had previously been reported in subtypes B, C and/or Circulating Recombinant Form (CRF) 01_AE, confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of identified HLA associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm HIV genetic context as a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies.ImportanceThe identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles, and the elucidation of their impact on viral function, can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B, and to a lesser extent C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. Results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational CTL-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines. PMID- 30305355 TI - Defining HIV-1 Envelope N-glycan Microdomains Through Site-specific Heterogeneity Profiles. AB - The HIV-1 envelope (Env) glycans shield the surface of Env from the immune system and form integral interactions important for a functional Env. To understand how individual N-glycosylation sites (NGS) coordinate to form a dynamic shield and evade the immune system through mutations, we tracked 20 NGS in Env from HIV transmitted/founder (T/F) and immune-escape variants and their mutants involving the N262 glycan. NGS were profiled in a site-specific manner using a high resolution mass spectrometry (MS)-based workflow. Using this site-specific quantitative heterogeneity profiling, we empirically characterized the interdependent NGS of a microdomain in the high-mannose patch (HMP). The changes (shifts) in NGS heterogeneity between the T/F and immune-escape variants defined a range of NGS that we further probed for exclusive combinations of sequons in the HMP microdomain using the Los Alamos HIV sequence database. The resultant sequon combinations, including the highly conserved NGS N262, N448, and N301, created an immune-escape map of the conserved and variable sequons in the HMP microdomain. This report provides details on how some clustered NGS form microdomains that can be identified and tracked across Env variants. These microdomains have a limited number of N-glycan-sequon combinations that may allow the anticipation of immune-escape variants.ImportanceThe Env of HIV is highly glycosylated and the sites of glycosylation can change as the virus mutates during immune evasion. Due to these changes, the glycan location and heterogeneity of surrounding N-glycosylation sites can be altered resulting in exposure of different glycan or proteoglycan surfaces while still producing a viable HIV variant. These changes present a need for vaccine developers to identify Env variants with epitopes most likely to induce durable protective responses. Here, we describe a means of anticipating HIV-1 immune evasion by dividing Env into N-glycan microdomains that have a limited number of N-glycan sequon combinations. PMID- 30305356 TI - A 1000 year-old RNA virus. AB - Only a few RNA viruses have been discovered from archaeological samples, the oldest dating from about 750 years ago. Using ancient maize cobs from Antelope house, Arizona, dating from circa 1,000 CE, we discovered a novel plant virus with a double-stranded RNA genome. The virus is a member of the family Chrysoviridae that infect plants and fungi in a persistent manner. The extracted double-stranded RNA from 312 maize cobs was converted to cDNA and sequences were determined on Illumina HiSeq 2000. Assembled contigs from many samples showed similarity to Anthurium mosaic-associated virus and Persea americana chrysovirus, putative species in the Chrysovirus genus, and nearly complete genomes were found in three ancient maize samples. We named this new virus Zea mays chrysovirus 1. Using specific primers, we were able to recover sequences of a closely related virus from modern maize and obtained the nearly complete sequences of the three genomic RNAs. Comparing the nucleotide sequences of the three genomic RNAs of the modern and ancient viruses showed 98%, 96.7%, and 97.4% identity, respectively. Hence, in 1,000 years of maize cultivation, this virus has undergone about 3% divergence.ImportanceA virus related to plant chrysoviruses was found in numerous ancient samples of maize, with nearly complete genomes in three samples. The age of the ancient samples (about 1,000 years old) was confirmed by carbon dating. Chrysoviruses are persistent plant viruses. They infect their hosts from generation to generation by transmission through seeds, and can remain in their hosts for very long time periods. When modern corn samples were analyzed, a closely related chrysovirus was found with only about 3% divergence from the ancient sequences. This virus represents the oldest known plant virus. PMID- 30305357 TI - Bone marrow-derived CD4+ T cells are depleted in SIV-infected macaques and contribute to the size of the replication competent reservoir on ART. AB - The bone marrow (BM) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature T cells. However, very little is known on the phenotype of BM-derived CD4+ T cells, their fate during SIV infection, and their contribution to viral persistence during antiretroviral therapy (ART). Here, we characterized the immunologic and virologic status of BM derived CD4+ T cells in rhesus macaques prior to SIV infection, during the early chronic phase of infection, and after ART. We found that BM memory CD4+ T cells are significantly depleted following SIV infection, at levels that are similar to those measured in PB. In addition, BM-derived memory CD4+ T cells include a high frequency of cells that express the co-inhibitory receptors CTLA-4 and PD-1, two subsets previously shown to be enriched in viral reservoir; these cells appear to have a more resting phenotype then the same cells in the blood (PB). Finally, when we analyzed SIV-infected RMs in which viral replication was effectively suppressed by 12-months of ART-treatment, we found that BM CD4+ T cells harbor SIV-DNA and SIV-RNA at levels comparable to those of PB CD4+ T cells, including replication competent SIV. Thus, BM is a largely understudied anatomic site of the latent reservoir which contributes to viral persistence during ART and needs to be further characterized and targeted when designing therapies for a functional or sterilizing cure to HIV.Importance The latent viral reservoir is one of the major obstacles in purging the immune system of HIV. It is paramount that we elucidate which anatomic compartments harbor replication competent virus, that upon ART-treatment interruption results in viral rebound and pathogenesis. Here, using the rhesus macaque model of SIV infection and ART treatment, we examined the immunologic status of the BM and its role as a potential sanctuary for latent virus. We found that the BM compartment undergoes a similar depletion of memory CD4+ T cells as PB, and during ART treatment the BM-derived memory CD4+ T cells contain high levels of cells expressing CTLA-4 and PD-1, as well as comparable amounts of cell-associated SIV-DNA, SIV-RNA, and replication competent virus as PB. These results enrich our understanding of which anatomic compartments harbor replication virus and suggests that BM-derived CD4+ T cells need to be targeted by therapeutic strategies aimed at achieving an HIV cure. PMID- 30305358 TI - Going the distance: optimizing RNA-Seq strategies for transcriptomic analysis of complex viral genomes. AB - Transcriptome profiling has become routine in studies of many biological processes. However, favored approaches such as short-read Illumina RNA sequencing are giving way to long-read sequencing platforms better suited to interrogating the complex transcriptomes typical of many RNA and DNA viruses. Here, we provide a guide - tailored to molecular virologists - to the ins-and-outs of viral transcriptome sequencing and discuss the strengths and weaknesses of the major RNA sequencing technologies as tools to analyze the abundance and diversity of viral transcripts made during infection. PMID- 30305359 TI - Risk assessment of fifth-wave H7N9 influenza A viruses in mammalian models. AB - The fifth-wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth-wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and HA cleavability. Here, several low pathogenic avian influenza (LPAI) and HPAI H7N9 human isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that a LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold compared with other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets, but exhibited a limited capacity to transmit by respiratory droplets and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models, and with further adaptation may acquire the ability to cause an H7N9 pandemic.ImportanceThe potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increased number of human infections and the emergence of antigenically distinct LPAI and HPAI H7N9 viruses. In this study, a group of fifth-wave HPAI and LPAI viruses were evaluated for their ability to infect, cause disease, and transmit in small animal models. The ability of HPAI H7N9 viruses to cause more severe disease and to replicate in brain tissues in animal models as well as their ability to fuse at a lower pH threshold compared to LPAI H7N9 viruses suggest that the fifth-wave H7N9 viruses have evolved to acquire novel traits with the potential to pose a higher risk to humans. Although the fifth-wave H7N9 viruses have not yet gained the ability to transmit efficiently by air, continuous surveillance and risk assessment remain essential parts of our pandemic preparedness efforts. PMID- 30305361 TI - The interaction between ORF18 and ORF30 is required for late gene expression in Kaposi's sarcoma-associated herpesvirus. AB - In the beta- and gammaherpesviruses, a specialized complex of viral transcriptional activators (vTAs) coordinate to direct expression of virus encoded late genes, which are critical for viral assembly and whose transcription initiates only after the onset of viral DNA replication. The vTAs in Kaposi's sarcoma-associated herpesvirus (KSHV) are ORF18, ORF24, ORF30, ORF31, ORF34, and ORF66. While the general organization of the vTA complex has been mapped, the individual roles of these proteins, and how they coordinate to activate late gene promoters, remains largely unknown. Here, we performed a comprehensive mutational analysis of the conserved residues in ORF18, which is a highly interconnected vTA component. Surprisingly, the mutants were largely selective for disrupting the interaction with ORF30 but not the other three ORF18 binding partners. Furthermore, disrupting the ORF18-ORF30 interaction weakened the vTA complex as a whole, and an ORF18 point mutant that failed to bind ORF30 was unable to complement an ORF18 null virus. Thus, contacts between individual vTAs are critical, as even small disruptions in this complex result in profound defects in KSHV late gene expression.ImportanceKaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma and other B-cell cancers and remains a leading cause of death in immunocompromised individuals. A key step in the production of infectious virions is the transcription of viral late genes, which generates capsid and structural proteins and requires the coordination of six viral proteins that form a complex. The role of these proteins during transcription complex formation and the importance of protein-protein interactions are not well understood. Here, we focused on a central component of the complex, ORF18, and revealed that disruption of its interaction with even a single component of the complex (ORF30) prevents late gene expression and completion of the viral lifecycle. These findings underscore how individual interactions between the late gene transcription components are critical for both the stability and function of the complex. PMID- 30305360 TI - P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL 10 and IL-1beta in a human tonsil explant model. AB - HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1beta) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1beta. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1 stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE:Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here we describe a class of drugs that target the P2X pro-inflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to both block HIV-1 infection and production of IL-10 and IL-1beta in lymphoid tissue suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted. PMID- 30305362 TI - Correction: Evolution of neuropeptide signalling systems (doi:10.1242/jeb.151092). PMID- 30305363 TI - Erratum. The Adiponectin Paradox for All-Cause and Cardiovascular Mortality. Diabetes 2018;67:12-22. PMID- 30305364 TI - Increase Functional beta-Cell Mass in Subcutaneous Alginate Capsules With Porcine Prenatal Islet Cells but Loss With Human Adult Islet Cells. AB - Alginate (Alg)-encapsulated porcine islet cell grafts are developed to overcome limitations of human islet transplantation. They can generate functional implants in animals when prepared from fetal, perinatal, and adult pancreases. Implants have not yet been examined for efficacy to establish sustained, metabolically adequate functional beta-cell mass (FBM) in comparison with human islet cells. This study in immune-compromised mice demonstrates that subcutaneous implants of Alg-encapsulated porcine prenatal islet cells with 4 * 105 beta-cells form, over 10 weeks, a FBM that results in glucose-induced plasma C-peptide >2 ng/mL and metabolic control over the following 10 weeks, with higher efficiency than nonencapsulated, while failing in peritoneum. This intracapsular FBM formation involves beta-cell replication, increasing number fourfold, and maturation toward human adult beta-cells. Subcutaneous Alg-encapsulated human islet cells with similar beta-cell number establish implants with plasma C-peptide >2 ng/mL for the first 10 weeks, with nonencapsulated cells failing; their beta-cells do not replicate but progressively die (>70%), explaining C-peptide decline and insufficient metabolic control. An Alg matrix thus helps establish beta-cell functions in subcutis. It allows formation of sustained metabolically adequate FBM by immature porcine beta-cells with proliferative activity but not by human adult islet cells. These findings define conditions for evaluating its immune protecting properties. PMID- 30305366 TI - Pancreatic beta-Cell Rest Replenishes Insulin Secretory Capacity and Attenuates Diabetes in an Extreme Model of Obese Type 2 Diabetes. AB - The onset of common obesity-linked type 2 diabetes (T2D) is marked by exhaustive failure of pancreatic beta-cell functional mass to compensate for insulin resistance and increased metabolic demand, leading to uncontrolled hyperglycemia. Here, the beta-cell deficient obese hyperglycemic/hyperinsulinemic KS db/db mouse model was used to assess consequential effects on beta-cell functional recovery by lowering glucose homeostasis and/or improving insulin sensitivity following treatment with thiazolidinedione (TZD) therapy or glucagon-like-peptide-1 receptor (GLP-1R) agonism alone, or in combination with sodium/glucose cotransporter-2 inhibition (SGLT-2i). SGLT-2i combination therapies improved glucose homeostasis, independent of changes in body weight, resulting in a synergistic increase in pancreatic insulin content marked by significant recovery of the beta-cell mature insulin secretory population, but with limited changes in beta-cell mass and no indication of beta-cell dedifferentiation. Restoration of beta-cell insulin secretory capacity also restored biphasic insulin secretion. These data emphasize that by therapeutically alleviating the demand for insulin in vivo, irrespective of weight loss, endogenous beta-cells recover significant function that can contribute to attenuating diabetes. Thus, this study provides evidence that alleviation of metabolic demand on the beta-cell, rather than targeting the beta-cell itself, could be effective to delay the progression of T2D. PMID- 30305365 TI - Syntaxin 4 Expression in Pancreatic beta-Cells Promotes Islet Function and Protects Functional beta-Cell Mass. AB - Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves the success of transplants in reversing streptozotocin (STZ)-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward a further understanding of this, human islets and inducible transgenic mice that selectively overexpress Stx4 in islet beta-cells (betaTG-Stx4) were challenged with proinflammatory stressors in vitro and in vivo. Remarkably, betaTG-Stx4 mice resisted the loss of beta-cell mass and the glucose intolerance that multiple low doses of STZ induce. Under standard conditions, glucose tolerance was enhanced and mice maintained normal fasting glycemia and insulinemia. Conversely, Stx4 heterozygous knockout mice succumbed rapidly to STZ-induced glucose intolerance compared with their wild-type littermates. Human islet beta-cells overexpressing Stx4 exhibited enhanced insulin secretory capability; resilience against proinflammatory cytokine-induced apoptosis; and reduced expression of the CXCL9, CXCL10, and CXCL11 genes coordinate with decreased activation/nuclear localization of nuclear factor-kappaB. Finding ways to boost Stx4 expression presents a novel potential therapeutic avenue for promoting islet function and preserving beta-cell mass. PMID- 30305367 TI - Loss of Nuclear and Membrane Estrogen Receptor-alpha Differentially Impairs Insulin Secretion and Action in Male and Female Mice. AB - Estrogens favor glucose homeostasis primarily through the estrogen receptor alpha (ERalpha), but the respective importance of nuclear and membrane ERalpha pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion and insulin sensitivity in male and female mice expressing either the nuclear ERalpha (NOER) or the membrane ERalpha (MOER). Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose stimulated-insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERalpha signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERalpha alters the central control of insulin sensitivity in females, and predominantly impairs the central regulation of insulin secretion in males. PMID- 30305368 TI - MANF is Required for the Postnatal Expansion and Maintenance of the Pancreatic beta-Cell Mass in Mice. AB - Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of beta-cells mass and insulin-dependent diabetes in mice. Similarly to Manf -/- mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of the pancreatic beta-cell mass and for adult beta-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/- ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreases and significant correlation between the number of MANF-positive beta-cells and beta-cell mass in individual mice. In vitro, recombinant MANF induced beta-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from beta-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced beta-cell mass and diabetes caused largely by beta-cell ER stress and apoptosis, possibly accompanied by beta cell de-differentiation and reduced rates of beta-cell proliferation. Thus, MANF expression in adult mouse beta-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress, and inflammatory signaling pathways leading to beta-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes. PMID- 30305369 TI - Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects with Type 2 Diabetes. AB - Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2DM) and its associated microvascular complications. This study aimed to (i) identify the genetic determinants influencing circulating PEDF level in a clinical setting of T2DM; (ii) examine the relationship between circulating PEDF and diabetic complications; and (iii) explore the causal relationship between PEDF and diabetic complications. An exome chip association study on circulating PEDF leve1 was conducted in 5385 Chinese subjects with T2DM. A meta-analysis of the association results of the discovery stage (n=2936) and replication stage (n=2449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; P combined =2.06x10-57; beta[SE]:-0.33[0.02]). Two missense variants of SMYD4 (p.Arg131Ile; P combined =7.56x10-25; beta[SE]:0.21[0.02]) and SERPINF2 (p.Arg33Trp; P combined =8.22x10 10; beta[SE]:-0.15[0.02]) respectively, showed novel associations at genome-wide significance. Elevated circulating PEDF level was associated with increased risks of diabetic nephropathy (DN) and sight-threatening diabetic retinopathy (STDR). Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on STDR (P=0.085). Our study had provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for DN and STDR. Further studies to explore the causal relationship of PEDF with diabetic complications are warranted. PMID- 30305370 TI - Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children. AB - Progression to clinical type 1 diabetes varies between children developing beta cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles using a novel wavelet-based algorithm. We identified clusters of similar profiles, associated with different types of progression, among 600 children from The Environmental Determinants of Diabetes in the Young birth cohort study who developed persistent autoantibodies against insulin (IAA), GAD (GADA) and/or insulinoma-associated antigen-2 (IA-2A), and were followed prospectively in 3 to 6 months intervals (median follow-up 6.5 years). Among multiple autoantibody positive children (n=370), progression from seroconversion to clinical diabetes ranged between clusters from 6% (95%CI [0, 17.4]) to 84% (59.2, 93.6) within 5 years. Highest diabetes risks had children who seroconverted early in life (median age <2 years) and developed IAA and IA-2A that were stable-positive on follow-up, and these risks were unaffected by GADA status. Clusters lacking stable-positive GADA responses showed higher proportions of boys and lower frequencies of the HLA-DR3 allele. Our novel algorithm allows refined grouping of beta-cell autoantibody-positive children with distinct progression to clinical type 1 diabetes and provides new opportunities in searching for etiological factors and elucidating complex disease mechanisms. PMID- 30305371 TI - The wheat Lr67 gene of the Sugar Transport Protein family confers multipathogen resistance in barley. AB - Fungal pathogens are a major constraint to global crop production; hence, plant genes encoding pathogen resistance are important tools for combating disease. A few resistance genes identified to date provide partial, durable resistance to multiple pathogens and the wheat (Triticum aestivum) Lr67 hexose transporter variant (Lr67res) fits into this category. Two amino acids differ between the wild-type and resistant alleles - G144R and V387L. Exome sequence data from 267 barley (Hordeum vulgare) landraces and wild accessions was screened and neither of the Lr67res mutations was detected. The barley orthologue of Lr67, HvSTP13, was functionally characterised in yeast as a high affinity hexose transporter. The G144R mutation was introduced into HvSTP13 and abolished glucose uptake, whereas the V387L mutation reduced glucose uptake by ~50%. Glucose transport by HvSTP13 heterologously expressed in yeast was reduced when co-expressed with Lr67res. Stable transgenic Lr67res barley lines exhibited seedling resistance to the barley-specific pathogens Puccinia hordei and Blumeria graminis f. sp. hordei, which cause leaf rust and powdery mildew, respectively. Barley plants expressing Lr67res exhibited early senescence and higher pathogenesis-related (PR) gene expression. Unlike previous observations implicating flavonoids in the resistance of transgenic sorghum (Sorghum bicolor) expressing Lr34res, another wheat multipathogen resistance gene, barley flavonoids are unlikely to have a role in Lr67res-mediated resistance. Similar to observations made in yeast, Lr67res reduced glucose uptake in planta. These results confirm that the pathway by which Lr67res confers resistance to fungal pathogens is conserved between wheat and barley. PMID- 30305372 TI - Enhancer-promoter interaction of SELF PRUNING 5G shapes photoperiod adaptation. AB - Tomato (Solanum lycopersicum) is a major vegetable fruit grown and consumed worldwide. Modern cultivated tomatoes are derived from their wild relative, Solanum pimpinellifolium, a short-day plant that originated from the Andean region of South America. The molecular underpinnings of the regional adaptation and expansion of domesticated tomato remain largely unclear. In this study, we examined flowering time in wild and cultivated tomatoes under both long-day (LD) and short-day (SD) conditions. Using QTL mapping in a recombinant inbred line (RIL) population, we identified SELF PRUNING 5G (SP5G) as a major locus influencing day-length adaptation in tomato. Genetic diversity analysis revealed that the genomic region harboring SP5G shows signatures of a domestication sweep. We found that a 52-bp sequence within the 3' untranslated region (3' UTR) of SP5G is essential for enhanced expression of this gene, leading to delayed flowering time in tomatoes through a promoter-enhancer interaction that occurs only under LD conditions. We further demonstrate that the absence of the 52-bp sequence attenuates the promoter-enhancer interaction and reduces SP5G expression in cultivated tomatoes, making their flowering time insensitive to day length. Our findings demonstrate that cis-regulatory variation at the enhancer region of the SP5G 3' UTR confers reduced photoperiodic response in cultivated tomatoes, uncovering a regulatory mechanism that could potentially be used to manipulate flowering time in tomato through novel biotechnological approaches. PMID- 30305373 TI - An organellar thymidine kinase is required for the efficient replication of the maize plastidial genome. AB - Thymidine kinase (TK) is a key enzyme of the salvage pathway that recycles thymidine nucleosides to produce dTTP. We identified the single TK of maize, denoted CPTK1, as an essential factor in the replication of the plastidial genome (cpDNA), demonstrating the essential function of the salvage pathway during chloroplast biogenesis. CPTK1 localizes to both plastids and mitochondria. Its absence results in an albino phenotype, reduced cpDNA copy number, and a severe deficiency for plastidial ribosomes. No significant effect was found on mitochondria, indicating that they are less reliant on the salvage pathway. Arabidopsis has two thymidine kinases, TK1A and TK1B, that apparently resulted from a gene duplication after the divergence of monocots and dicots. Similar but less severe effects were observed for Arabidopsis tk1a tk1b double mutants in comparison to those in maize cptk1. We found that TK1B is important not only for cpDNA replication, but also for its repair in conditions of replicative stress, and that it has little impact on the mitochondrial phenotype. In the maize cptk1 mutant, the DNA from the small single copy region of the plastidial genome was reduced to a greater extent than other regions, suggesting preferential abortion of replication in this region. This is accompanied by the accumulation of truncated genomes that result, at least in part, from unfaithful microhomology mediated repair. These and other results suggest that the loss of normal cpDNA replication elicits the mobilization of new replication origins around the rpoB transcription unit, and imply that increased transcription at rpoB is associated with the initiation of cpDNA replication. PMID- 30305374 TI - Latency for facultative expression of male-typical courtship behaviour by female bluehead wrasses depends on social rank: the 'priming/gating' hypothesis. AB - Although socially controlled sex transformation in fishes is well established, the underlying mechanisms are not well understood. Particularly enigmatic is behavioural transformation, in which fish can rapidly switch from exhibiting female to male-typical courtship behaviours following removal of 'supermales'. Bluehead wrasses are a model system for investigating environmental control of sex determination, particularly the social control of sex transformation. Here, we show that the onset of this behavioural transformation was delayed in females that occupied low-ranking positions in the female dominance hierarchy. We also establish that expression of male-typical courtship behaviours in competent initial-phase (IP) females is facultative and gated by the presence of terminal phase (TP) males. Dominant females displayed reliable TP male-typical courtship behaviours within approximately 2 days of the removal of a TP male; immediately following reintroduction of the TP male, however, females reverted back to female typical behaviours. These results demonstrate a remarkable plasticity of sexual behaviour and support a 'priming/gating' hypothesis for the control of behavioural transformation in bluehead wrasses. PMID- 30305375 TI - High-frequency temperature variability mirrors fixed differences in thermal limits of the massive coral Porites lobata (Dana, 1846). AB - Spatial heterogeneity in environmental characteristics can drive adaptive differentiation when contrasting environments exert divergent selection pressures. This environmental and genetic heterogeneity can substantially influence population and community resilience to disturbance events. Here, we investigated corals from the highly variable back reef habitats of Ofu Island in American Samoa that thrive in thermal conditions known to elicit widespread bleaching and mortality elsewhere. To investigate the relative importance of acclimation vs. site of origin in shaping previously observed differences in coral tolerance limits in Ofu, specimens of the common Indo-Pacific coral Porites lobata (Dana, 1846) from locations with differing levels of thermal variability were acclimated to low and high thermal variation in controlled common garden aquaria. Overall, there were minimal effects of the acclimation exposure. Corals native to the site with the highest level of daily variability grew fastest, regardless of acclimation treatment. When exposed to lethal thermal stress, corals native to both variable sites contained elevated levels of heat shock proteins and maintained photosynthetic performance for 1-2 days longer than corals from the stable environment. Despite being separated by<5 km, there was significant genetic differentiation among coral colonies (F ST =0.206, p<0.0001; nuclear ribosomal DNA), while Symbiodiniaceae were all Cladocopium sp. (ITS-type C15). Our study demonstrates consistent signatures of adaptation in growth and stress resistance in corals from naturally thermally variable habitats, suggesting that differences in the amount of thermal variability may be an important contributor to adaptive differentiation in reef building corals. PMID- 30305376 TI - Evidence that Rh proteins in the anal papillae of the freshwater mosquito Aedes aegypti are involved in the regulation of acid-base balance in elevated salt and ammonia environments. AB - Aedes aegypti commonly inhabit ammonia-rich sewage effluents in tropical regions of the world where the adults are responsible for the spread of disease. Studies have shown the importance of the anal papillae of A. aegypti in ion uptake and ammonia excretion. The anal papillae express ammonia transporters and Rhesus (Rh) proteins which are involved in ammonia excretion and studies have primarily focused on understanding these mechanisms in freshwater. In this study, effects of rearing larvae in salt (5 mmol l-1 NaCl) or ammonia (5 mmol l-1 NH4Cl) on physiological endpoints of ammonia and ion regulation were assessed. In anal papillae of NaCl-reared larvae, Rh protein expression increased, NHE3 transcript abundance decreased and NH4 + excretion increased, and this coincided with decreased hemolymph [NH4 +] and pH. We propose that under these conditions, larvae excrete more NH4 + through Rh proteins as a means of eliminating acid from the hemolymph. In anal papillae of NH4Cl-reared larvae, expression of an apical ammonia transporter and the Rh proteins decreased, the activities of NKA and VA decreased and increased, respectively, and this coincided with hemolymph acidification. The results present evidence for a role of Rh proteins in acid base balance in response to elevated levels of salt, whereby ammonia is excreted as an acid equivalent. PMID- 30305377 TI - Anti-NMDAR encephalitis complicating pregnancy. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first reported in 2005 in four patients with ovarian teratomas; there have been many further cases reported since the antigen for the NMDAR antibody was confirmed in 2007. Patients characteristically have a well-defined set of features, characterised by psychiatric disturbance, seizures and cognitive disturbance, followed by movement disorders, disorders of consciousness and dysautonomia. To date, 14 cases of NMDAR encephalitis have been described in the context of pregnancy. We report a case of NMDAR encephalitis in a 34-year-old woman at 8 weeks' gestation. She had a turbulent clinical course and was initially admitted to a psychiatric unit. She was successfully treated with first-line immunomodulatory therapies and surgical resection of an ovarian teratoma. Following discharge she delivered a healthy baby and made a complete clinical recovery. PMID- 30305378 TI - How to do it: investigate exertional rhabdomyolysis (or not). AB - Rhabdomyolysis is the combination of symptoms (myalgia, weakness and muscle swelling) and a substantial rise in serum creatine kinase (CK) >50 000 IU/L; there are many causes, but here we specifically address exertional rhabdomyolysis. The consequences of this condition can be severe, including acute kidney injury and requirement for higher level care with organ support. Most patients have 'physiological' exertional rhabdomyolysis with no underlying disease; they do not need investigation and should be advised to return to normal activities in a graded fashion. Rarely, exertional rhabdomyolysis may be the initial presentation of underlying muscle disease, and we review how to identify this much smaller group of patients, who do require investigation. PMID- 30305379 TI - Disseminated cerebral hydatid disease (multiple intracranial echinococcosis). AB - Intracranial echinococcosis is relatively uncommon and usually occurs in the context of echinococcal lesions elsewhere in the body, mostly liver and lung. Multiple intracranial lesions can result from rupture of an initial single intracranial cyst (in cystic echinococcosis) or from dissemination of systemic disease of the lung, liver or heart (cystic and alveolar echinococcosis). The two main subtypes, cystic and alveolar echinococcosis, present differently and have distinct imaging features in the brain. We discuss the presentation, imaging findings and clinical course of three cases (two cystic and one alveolar) of intracranial echinococcal disease in adults. PMID- 30305380 TI - The prognostic roles of circulating ALDH1+ tumor cell in the patients with non small cell lung cancer. AB - Circulating tumor cells can provide important diagnostic and prognostic information of the patients with non-small cell lung cancer (NSCLC). Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, has been used in various tumors, including NSCLC. In the present study, we isolated the circulating ALDH1+ tumor cells from the NSCLC patients using ALDH1 as a potential marker. Higher percentage of ALDH1+ tumor cells was identified in blood samples from the NSCLC patients compared with normal controls. ALDH1+ cells were correlated with the poor prognosis of these patients by using Kaplan-Meier analysis. In the last, the tumorigenic properties of ALDH1+ tumor cells were determined in vitro and in vivo by using sphere assay and xenograft tumor mouse models. Our in vitro and in vivo experiments demonstrated that ALDH1 could drive the stemness of circulating NSCLC cells. Circulating ALDH1+ cells could be used as a prognostic marker for NSCLC. PMID- 30305382 TI - Impact of gender on the survival of patients with glioblastoma. AB - Background: Preclinical models have suggested a role for sex hormones in the development of glioblastoma multiforme (GBM). However, the impact of gender on the survival time of patients with GBM has not been fully understood. The objective of the present study was to clarify the association between gender and survival of patients with GBM by analyzing population-based data.Methods: We searched the Surveillance, Epidemiology, and End-Results database who were diagnosed with GBM between 2000 and 2008 and were treated with surgery. Five-year cancer specific survival data were obtained. Kaplan-Meier methods and multivariable Cox regression models were used to analyze long-term survival outcomes and risk factors.Results: A total of 6586 patients were identified; 61.5% were men and 38.5% were women. The 5-year cancer-specific survival (CSS) rates in the male and female groups were 6.8% and 8.3%, respectively (P=0.002 by univariate and P<0.001 by multivariate analysis). A stratified analysis showed that male patients always had the lowest CSS rate across localized cancer stage and different age subgroups.Conclusions: Gender has prognostic value for determining GBM risk. The role of sex hormones in the development of GBM warrants further investigation. PMID- 30305381 TI - Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme. AB - Insulin-degrading enzyme (IDE) is a zinc metalloprotease that selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease (AD). As such, IDE is an attractive target for therapeutic innovations. A major requirement is an understanding of how other molecules present in cells regulate the activity of the enzyme toward insulin, IDE's most important physiologically relevant substrate. Previous kinetic studies of the IDE dependent degradation of insulin in the presence of potential regulators have used iodinated insulin, a chemical modification that has been shown to alter the biological and biochemical properties of insulin. Here, we present a novel kinetic assay that takes advantage of the loss of helical circular dichroic signals of insulin with IDE-dependent degradation. As proof of concept, the resulting Michaelis-Menten kinetic constants accurately predict the known regulation of IDE by adenosine triphosphate (ATP). Intriguingly, we found that when Mg2+ is present with ATP, the regulation is abolished. The implication of this result for the development of preventative and therapeutic strategies for AD is discussed. We anticipate that the new assay presented here will lead to the identification of other small molecules that regulate the activity of IDE toward insulin. PMID- 30305383 TI - Limited Marginal Utility of Deep Sequencing for HIV Drug Resistance Testing in the Age of Integrase Inhibitors. AB - HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect low-frequency alleles. However, the clinical value added from NGS approaches to antiviral resistance testing remains to be demonstrated. We compared the variant detection capacity of NGS versus Sanger sequencing methods for resistance genotyping in 144 drug resistance tests (105 protease-reverse transcriptase tests and 39 integrase tests) submitted to our clinical virology laboratory over a four-month period in 2016 for Sanger based HIV drug resistance testing. NGS detected all true high-frequency drug resistance mutations (>20% frequency) found by Sanger sequencing, with greater accuracy in one instance of a Sanger-detected false positive. Freely available online NGS variant callers HyDRA and PASeq were superior to Sanger methods for interpretations of allele linkage and automated variant calling. NGS additionally detected low-frequency mutations (1 to 20% frequency) associated with higher levels of drug resistance in 30/105 (29%) protease-reverse transcriptase tests and 4/39 (10%) integrase tests. In clinical follow-up of 69 individuals for a median of 674 days, we did not find a difference in rates of virological failure between individuals with and without low-frequency mutations, although rates of virological failure were higher for individuals with drug-relevant low-frequency mutations. However, all 27 individuals who experienced virological failure reported poor adherence to their drug regimen during the preceding follow-up time, and all 19 who subsequently improved their adherence achieved viral suppression at later time points, consistent with a lack of clinical resistance. In conclusion, in a population with low antiviral resistance emergence, NGS methods detected numerous instances of minor alleles that did not result in subsequent bona fide virological failure due to antiviral resistance. PMID- 30305385 TI - Taxonomic Changes for Human and Animal Viruses, 2016 to 2018. AB - The classification of viruses provides the structure necessary to appreciate their biological diversity. Herein, we provide an update to our previous review of changes in viral taxonomy, covering changes between 2016 and 2018. PMID- 30305384 TI - Corynebacterium Species Rarely Cause Orthopedic Infections. AB - Corynebacterium spp. are rarely considered pathogens, but data on Corynebacterium spp. as a cause of orthopedic infections are sparse. Therefore, we asked how often Corynebacterium spp. caused an infection in a defined cohort of orthopedic patients with a positive culture. In addition, we aimed to determine the species variety and the susceptibility of isolated strains to define potential treatment strategies. We retrospectively assessed all bone and joint samples that were collected between 2006 and 2015 from an orthopedic ward and that were positive for Corynebacterium spp. by culture. The isolates were considered relevant to an infection if the same Corynebacterium sp. was present in at least two samples. We found 97 orthopedic cases with isolation of Corynebacterium spp. (128 positive samples). These were mainly Corynebacterium tuberculostearicum (n = 26), Corynebacterium amycolatum (n = 17), Corynebacterium striatum (n = 13), and Corynebacterium afermentans (n = 11). Compared to the species found in a cohort of patients with positive blood cultures hospitalized in nonorthopedic wards, we found significantly more C. striatum- and C. tuberculostearicum-positive cases but no C. jeikeium-positive cases in our orthopedic cohort. Only 16 out of 66 cases (24.2%) with an available diagnostic set of at least two samples had an infection. Antibiotic susceptibility testing (AST) showed various susceptibility results for all antibiotics except vancomycin and linezolid, to which 100% of the isolates were susceptible. The rates of susceptibility of corynebacteria isolated from orthopedic samples and of isolates from blood cultures were comparable. In conclusion, our study results confirmed that a Corynebacterium sp. is most often isolated as a contaminant in a cohort of orthopedic patients. AST is necessary to define the optimal treatment in orthopedic infections. PMID- 30305386 TI - Designing Studies Acceptable for Abstraction and Inclusion in Evidence-Based Laboratory Practice Guidelines. AB - Expansion of technologies, changing infrastructure and dwindling resources have caused the need for healthcare reform and changes in the clinical laboratory. The healthcare model will have to shift more and more from a fee-for-service model to a value-based model. Laboratories will have to focus more on evidence-based outcome studies evaluating the effect of their pre- and post-analytic practices on real patient outcomes. Although well designed clinical trials and multicenter studies are needed to determine the effect of laboratory processes on outcomes, there has been concern that too few well-designed studies have been published. To help improve the quality of study design and to aid reporting transparency, several method statements have been developed. The Standards for Reporting of Diagnostic Accuracy Studies (STARD) initiative was recently updated, listing 30 items deemed crucial to transparent reporting in studies, thereby allowing the creation of a robust data base for clinical practice guidelines. Three methods are also available describing the assessment of quality of data on which to base recommendations for such guidelines. Close attention must be given to the design of a study so that parameters assuring study quality are met, thereby allowing its inclusion in formulation of evidence-based laboratory best practices guidelines. PMID- 30305387 TI - Performance of Xpert MTB/RIF, Xpert Ultra, and Abbott RealTime MTB for Diagnosis of Pulmonary Tuberculosis in a High-HIV-Burden Setting. AB - More sensitive tests are needed for the diagnosis of smear-negative and HIV associated tuberculosis. This study compares the sensitivities and specificities of three molecular tests, namely, the Xpert MTB/RIF test, the Xpert Ultra (Ultra), and RealTime MTB (RT-MTB), in a high HIV prevalence setting. Symptomatic adults were recruited from three outpatient sites, and each provided 4 sputum specimens. The diagnostic performance of Xpert MTB/RIF, Ultra, and RT-MTB was evaluated, with culture as a reference standard. HIV infection occurred in 62% of patients, with a median CD4 count of 220 cells/ul. The Ultra test had the highest sensitivity of 89.3% (95% confidence interval [CI], 78.1 to 96) compared to those of the Xpert MTB/RIF at 82.1% (95% CI, 69.6 to 91.1; P = 0.12) and RT-MTB at 78.6% (95% CI, 65.6 to 88.4; P = 0.68). The specificity was highest with the Xpert MTB/RIF at 100% (95% CI, 98 to 100), followed by RealTime MTB at 96.7% (95% CI, 92.9 to 98.8; P = 0.03) and the Ultra at 95.6% (95% CI, 91.5 to 98.1; P = 0.08). In patients with smear-negative disease, the Ultra was more sensitive than the Xpert MTB/RIF (64.7% [95% CI, 38.3 to 85.8] versus 41.2% [95% CI, 18.4 to 67.1], respectively; P = 0.12), and RT-MTB performed equally to Xpert MTB/RIF. In a comparison of the Ultra and RT-MTB on the same sputum specimen pellets, the Ultra was more sensitive than RT-MTB in the overall cohort (88.9% [95% CI, 77.4 to 95.8] versus 77.8% [95% CI, 64.4 to 88], respectively; P = 0.03) and among people with HIV (87.5% [95% CI, 71 to 96.5] versus 68.6% [95% CI, 50 to 83.9], respectively; P = 0.03). Although these results did not reach statistical significance, they suggest that the Ultra is more sensitive than the Xpert MTB/RIF and RT-MTB, most prominently in smear-negative disease. This was accompanied by a loss of specificity. PMID- 30305388 TI - Gaps in Well-Child Care Attendance Among Primary Care Clinics Serving Low-Income Families. AB - BACKGROUND AND OBJECTIVES: It is unclear which specific well-child visits (WCVs) are most frequently missed and whether age-specific patterns of attendance differ by race or insurance type. METHODS: We conducted a retrospective cohort study of children 0 to 6 years old between 2011 and 2016 within 2 health networks spanning 20 states. WCVs were identified by using International Classification of Diseases, Ninth and 10th Revisions and Current Procedural Terminology codes. We calculated adherence to the 13 American Academy of Pediatrics-recommended WCVs from birth to age 6 years. To address data completeness, we made 2 adherence calculations after a child's last recorded WCV: 1 in which we assumed all subsequent WCVs were attended outside the network and 1 in which we assumed none were. RESULTS: We included 152 418 children in our analysis. Most children were either publicly insured (77%) or uninsured (14%). The 2-, 4-, and 6-month visits were the most frequently attended (63% [assuming no outside care after the last recorded WCV] to 90% [assuming outside care]), whereas the 15- and 18-months visits (41%-75%) and 4-year visit (19%-49%) were the least frequently attended. Patients who were publicly insured and uninsured (versus privately insured) had higher odds of missing WCVs. Hispanic and Asian American (versus non-Hispanic white) patients had higher odds of attending WCVs. DISCUSSION: The 15- and 18 month WCVs as well as the 4-year WCV are the least frequently attended WCVs. The former represent opportunities to identify developmental delays, and the latter represents an opportunity to assess school readiness. PMID- 30305389 TI - Rapid and low-cost multiplex synthesis of chemokine analogs. AB - Peptides represent a promising source of new medicines, but improved technologies are needed to facilitate discovery and optimization campaigns. In particular, longer peptides with multiple disulfide bridges are challenging to produce, and producing large numbers of structurally related variants is dissuasively costly and time consuming. The principal cost and time drivers are the multiple column chromatography purification steps that are used during the multi-step chemical synthesis procedure, which involves both ligation and oxidative refolding steps. In this study we developed a method for multiplex parallel synthesis of complex peptide analogs in which the structurally variant region of the molecule is produced as a small peptide on a 384-well synthesizer, with subsequent ligation to the longer, structurally invariant region and oxidative refolding carried out in-well without any column purification steps. To test the method we used a panel of 96 analogs of the chemokine RANTES/CCL5 (69 residues, two disulfide bridges) were synthesized using standard approaches and characterized pharmacologically in an earlier study. Although, as expected, the multiplex method generated chemokine analogs of lower purity than those produced in the original study, it was nonetheless possible to closely match the pharmacological attributes (anti-HIV potency, capacity to elicit G protein signaling, capacity to elicit intracellular receptor sequestration) of each chemokine analog to reference data from the earlier study. This rapid, low-cost approach has the potential to support discovery and optimization campaigns based on analogs of other chemokines, as well as those of other complex peptide and small protein targets of a similar size. PMID- 30305390 TI - DNA-unwinding activity of Saccharomyces cerevisiae Pif1 is modulated by thermal stability, folding conformation, and loop lengths of G-quadruplex DNA. AB - G-quadruplexes (G4s) are four-stranded DNA structures formed by Hoogsteen base pairing between stacked sets of four guanines. Pif1 helicase plays critical roles in suppressing genomic instability in the yeast Saccharomyces cerevisiae by resolving G4s. However, the structural properties of G4s in S. cerevisiae and the substrate preference of Pif1 for different G4s remain unknown. Here, using CD spectroscopy and 83 G4 motifs from S. cerevisiae ranging in length from 30 to 60 nucleotides, we first show that G4 structures can be formed with a broad range of loop sizes in vitro and that a parallel conformation is favored. Using single molecule FRET analysis, we then systematically addressed Pif1-mediated unwinding of various G4s and found that Pif1 is sensitive to G4 stability. Moreover, Pif1 preferentially unfolded antiparallel G4s rather than parallel G4s having similar stability. Furthermore, our results indicate that most G4 structures in S. cerevisiae sequences have long loops and can be efficiently unfolded by Pif1 because of their low stability. However, we also found that G4 structures with short loops can be barely unfolded. This study highlights the formidable capability of Pif1 to resolve the majority of G4s in S. cerevisiae sequences, narrows the fractions of G4s that may be challenging for genomic stability, and provides a framework for understanding the influence of different G4s on genomic stability via their processing by Pif1. PMID- 30305391 TI - The deletion of the protein phosphatase 1 regulator NIPP1 in testis causes hyperphosphorylation and degradation of the histone methyltransferase EZH2. AB - Germ cell proliferation is epigenetically controlled, mainly through DNA methylation and histone modifications. However, the pivotal epigenetic regulators of germ cell self-renewal and differentiation in postnatal testis are still poorly defined. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, represses target genes through trimethylation of histone H3 at Lys-27 (H3K27me3), and interacts (in)directly with both protein phosphatase 1 (PP1) and nuclear inhibitor of PP1 (NIPP1). Here, we report that postnatal, testis-specific ablation of NIPP1 in mice results in loss of EZH2 and reduces H3K27me3 levels. Mechanistically, the NIPP1 deletion abrogated PP1-mediated EZH2 dephosphorylation at two cyclin dependent kinase sites (Thr-345/487), thereby generating hyperphosphorylated EZH2, which is a substrate for proteolytic degradation. Accordingly, alanine mutation of these residues prolonged the half-life of EZH2 in male germ cells. Our study discloses a key role for the PP1:NIPP1 holoenzyme in stabilizing EZH2 and maintaining the H3K27me3 mark on genes that are important for germ cell development and spermatogenesis. PMID- 30305392 TI - 2-Hydroxy-oleic acid does not activate sphingomyelin synthase activity. AB - 2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis. Previous studies have suggested that 2OHOA's anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. To confirm this phenomenon, in this study, we treated both A549 and U118 cells with 2OHOA and measured SMS activity. To our surprise, we found neither 2OHOA-mediated SMS activation nor sphingomyelin accumulation in the cells. However, we noted that 2OHOA significantly reduces phosphatidylcholine in these cells. We also did not observe 2OHOA-mediated SMS activation in mouse tissue homogenates. Importantly, 2OHOA inhibited rather than activated recombinant SMS1 (rSMS1) and rSMS2 in a dose-dependent fashion. Intra-gastric treatment of C57BL/6J mice with 2OHOA for 10 days had no effects on liver and small intestine SMS activities and plasma sphingomyelin levels. The treatment inhibited lysophosphatidylcholine acyltransferase (LPCAT) activity, consistent with the aforementioned reduction in plasma phosphatidylcholine. Because total cellular phosphatidylcholine is used as a predictive biomarker for monitoring tumor responses, the previously reported 2OHOA-mediated cancer suppression could be related to this phosphatidylcholine reduction, which may influence cell membrane structure and properties. We conclude that 2OHOA is not a SMS activator and that its anticancer property may be related to an effect on phosphatidylcholine metabolism. PMID- 30305393 TI - Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity. AB - An increase in oxidative protein damage is a leading contributor to age associated decline in oocyte quality. By removing such damaged proteins, the proteasome plays an essential role in maintaining the fidelity of oocyte meiosis. In this study, we established that decreased proteasome activity in naturally aged, germinal vesicle (GV) mouse oocytes positively correlates with increased protein modification by the lipid aldehyde 4-hydroxynonenal (4-HNE). Further, attenuation of proteasome activity in GV oocytes of young animals was accompanied by an increase in 4-HNE-modified proteins, including alpha-tubulin, thereby contributing to a reduction in tubulin polymerization, microtubule stability, and integrity of oocyte meiosis. A decrease in proteasome activity was also recapitulated in the GV oocytes of young animals following exposure to oxidative insults in the form of either hydrogen peroxide (H2O2) or 4-HNE. We also observed that upon oxidative insult, 4-HNE exhibits elevated adduction to multiple proteasomal subunits. Notably, the inclusion of the antioxidant penicillamine, to limit propagation of oxidative stress cascades, led to a complete recovery of proteasome activity and enhanced clearance of 4-HNE-adducted alpha-tubulin during a 6 h post-treatment recovery period. This strategy also proved effective in reducing the incidence of oxidative stress-induced aneuploidy following in vitro oocyte maturation, but was ineffective for naturally aged oocytes. Taken together, our results implicate proteasome dysfunction as an important factor in the accumulation of oxidatively induced damage in the female germline. This discovery holds promise for the design of therapeutic interventions to address the age-dependent decline in oocyte quality. PMID- 30305395 TI - Insulin and 20-hydroxyecdysone oppose each other in the regulation of phosphoinositide-dependent kinase-1 expression during insect pupation. AB - Insulin promotes larval growth of insects by stimulating the synthesis of the steroid hormone 20-hydroxyecdysone (20E), which induces pupation and apoptosis. However, the mechanism underlying the coordinate regulation of insect pupation and apoptosis by these two functionally opposing hormones is still unclear. Here, using the lepidopteran insect and serious agricultural pest Helicoverpa armigera (cotton bollworm) as a model, we report that phosphoinositide-dependent kinase-1 (PDK1) and forkhead box O (FoxO) play key roles in these processes. We found that the transcript levels of the PDK1 gene are increased during the larval feeding stages. Moreover, PDK1 expression was increased by insulin, but repressed by 20E. dsRNA-mediated PDK1 knockdown in the H. armigera larvae delayed pupation and resulted in small pupae and also decreased Akt/protein kinase B expression and increased FoxO expression. Furthermore, the PDK1 knockdown blocked midgut remodeling and decreased 20E levels in the larvae. Of note, injecting larvae with 20E overcame the effect of the PDK1 knockdown and restored midgut remodeling. FoxO overexpression in an H. armigera epidermal cell line (HaEpi) did not induce apoptosis, but promoted autophagy and repressed cell proliferation. These results reveal cross-talk between insulin and 20E and that both hormones oppose each other's activities in the regulation of insect pupation and apoptosis by controlling PDK1 expression and, in turn, FoxO expression. We conclude that sufficiently high 20E levels are a key factor for inducing apoptosis during insect pupation. PMID- 30305394 TI - The GTPase BipA expressed at low temperature in Escherichia coli assists ribosome assembly and has chaperone-like activity. AB - BPI-inducible protein A (BipA) is a conserved ribosome-associated GTPase in bacteria that is structurally similar to other GTPases associated with protein translation, including IF2, EF-Tu, and EF-G. Its binding site on the ribosome appears to overlap those of these translational GTPases. Mutations in the bipA gene cause a variety of phenotypes, including cold and antibiotics sensitivities and decreased pathogenicity, implying that BipA may participate in diverse cellular processes by regulating translation. According to recent studies, a bipA deletion strain of Escherichia coli displays a ribosome assembly defect at low temperature, suggesting that BipA might be involved in ribosome assembly. To further investigate BipA's role in ribosome biogenesis, here, we compared and analyzed the ribosomal protein compositions of MG1655 WT and bipA-deletion strains at 20 degrees C. Aberrant 50S ribosomal subunits (i.e. 44S particles) accumulated in the bipA-deletion strain at 20 degrees C, and the ribosomal protein L6 was absent in these 44S particles. Furthermore, bipA expression was significantly stimulated at 20 degrees C, suggesting that it encodes a cold shock-inducible GTPase. Moreover, the transcriptional regulator cAMP receptor protein (CRP) positively promoted bipA expression only at 20 degrees C. Importantly, GFP and alpha-glucosidase refolding assays revealed that BipA has chaperone activity. Our findings indicate that BipA is a cold shock-inducible GTPase that participates in 50S ribosomal subunit assembly by incorporating the L6 ribosomal protein into the 44S particle during the assembly. PMID- 30305397 TI - The long non-coding RNA NEAT1 and nuclear paraspeckles are upregulated by the transcription factor HSF1 in the heat shock response. AB - The long non-coding RNA (lncRNA) NEAT1 is the architectural component of nuclear paraspeckles, and has recently gained considerable attention as it is abnormally expressed in pathological conditions such as cancer and neurodegenerative diseases. NEAT1 and paraspeckle formation are increased in cells upon exposure to a variety of environmental stressors, and believed to play an important role in cell survival. The present study was undertaken to further investigate the role of NEAT1 in cellular stress response pathways. We show that NEAT1 is a novel target gene of heat shock transcription factor 1 (HSF1), and upregulated when the heat shock response pathway is activated by Sulforaphane (SFN) or elevated temperature. HSF1 binds specifically to a newly identified conserved heat shock element (HSE) in the NEAT1 promoter. In line with this, SFN induced the formation of NEAT1-containing paraspeckles via a HSF1-dependent mechanism. HSF1 plays a key role in the cellular response to proteotoxic stress by promoting the expression of a series of genes, including those encoding molecular chaperones. We have found that the expression of HSP70, HSP90, and HSP27 is amplified and sustained during heat shock in NEAT1-depleted cells compared to control cells, indicating that NEAT1 feeds back via an unknown mechanism to regulate HSF1 activity. This interrelationship is potentially significant in human diseases such as cancer and neurodegenerative disorders. PMID- 30305396 TI - Substrate priming enhances phosphorylation by the budding yeast kinases Kin1 and Kin2. AB - Multisite phosphorylation of proteins is a common mechanism for signal integration and amplification in eukaryotic signaling networks. Proteins are commonly phosphorylated at multiple sites in an ordered manner, whereby phosphorylation by one kinase primes the substrate by generating a recognition motif for a second kinase. Here we show that substrate priming promotes phosphorylation by Saccharomyces cerevisiae Kin1 and Kin2, kinases that regulate cell polarity, exocytosis, and the endoplasmic reticulum (ER) stress response. Kin1/Kin2 phosphorylated substrates within the context of a sequence motif distinct from those of their most closely related kinases. In particular, the rate of phosphorylation of a peptide substrate by Kin1/Kin2 increased >30-fold with incorporation of a phosphoserine residue two residues downstream of the phosphorylation site. Recognition of phosphorylated substrates by Kin1/Kin2 was mediated by a patch of basic residues located in the region of the kinase alphaC helix. We identified a set of candidate Kin1/Kin2 substrates reported to be dually phosphorylated at sites conforming to the Kin1/Kin2 consensus sequence. One of these proteins, the t-SNARE protein Sec9, was confirmed to be a Kin1/Kin2 substrate both in vitro and in vivo Sec9 phosphorylation by Kin1 in vitro was enhanced by prior phosphorylation at the +2 position. Recognition of primed substrates was not required for the ability of Kin2 to suppress the growth defect of secretory pathway mutants but was necessary for optimal growth under conditions of ER stress. These results suggest that at least some endogenous protein substrates of Kin1/Kin2 are phosphorylated in a priming-dependent manner. PMID- 30305400 TI - Contraception after medication abortion should be determined by convenience and choice. PMID- 30305401 TI - Patient and public involvement in sexual and reproductive health: a new editor, and a new tool. PMID- 30305398 TI - Depletion of plasma membrane-associated phosphoinositides mimics inhibition of TRPM7 channels by cytosolic Mg2+, spermine, and pH. AB - Transient receptor potential cation channel subfamily M member 7 (TRPM7) is an ion channel/protein kinase belonging to the TRP melastatin and eEF2 kinase families. Under physiological conditions, most native TRPM7 channels are inhibited by cytoplasmic Mg2+, protons, and polyamines. Currents through these channels (ITRPM7) are robustly potentiated when the cell interior is exchanged with low Mg2+-containing buffers. ITRPM7 is also potentiated by phosphatidyl inositol bisphosphate (PI(4,5)P2) and suppressed by its hydrolysis. Here we characterized internal Mg2+- and pH-mediated inhibition of TRPM7 channels in HEK293 cells overexpressing WT voltage-sensing phospholipid phosphatase (VSP) or its catalytically inactive variant VSP-C363S. VSP-mediated depletion of membrane phosphoinositides significantly increased channel sensitivity to Mg2+ and pH. Proton concentrations that were too low to inhibit ITRPM7 when the VSP-C363S variant was expressed (pH 8.2) became inhibitory in WT VSP-expressing cells. At pH 6.5, protons inhibited ITRPM7 both in WT and VSP C363S-expressing cells but with a faster time course in the WT VSP-expressing cells. Inhibition by 150 MUm Mg2+ was also significantly faster in the WT VSP-expressing cells. Cellular PI(4,5)P2 depletion increased the sensitivity of TRPM7 channels to the inhibitor 2-aminoethyl diphenyl borinate, which acidifies the cytosol. Single substitutions at Ser-1107 of TRPM7, reducing its sensitivity to Mg2+, also decreased its inhibition by spermine and acidic pH. Furthermore, these channel variants were markedly less sensitive to VSP-mediated PI(4,5)P2 depletion than the WT. We conclude that the internal Mg2+-, polyamine-, and pH-mediated inhibition of TRPM7 channels is not direct but, rather, reflects electrostatic screening and resultant disruption of PI(4,5)P2-channel interactions. PMID- 30305404 TI - Making the unbearable bearable: a relative's tips to clinicians. PMID- 30305405 TI - Comment on 'Early medical abortion: best practice now lawful in Scotland and Wales but not available to women in England'. PMID- 30305406 TI - Home use of misoprostol: is it really safe and appreciated? PMID- 30305407 TI - Response to 'Home use of misoprostol: is it really safe and appreciated?' PMID- 30305408 TI - Endometrial sampling has been undertaken for many years in some general practices. PMID- 30305409 TI - Perforation of the anterior cervix by the threads of an intrauterine device. PMID- 30305410 TI - Manufacturer's response to letter about 'Sayana Press and a case of likely lipoatrophy'. PMID- 30305411 TI - Essential anatomy: why anatomical words matter when it comes to subdermal implants. PMID- 30305413 TI - Venus. PMID- 30305412 TI - Case in point: Natural Cycles Facebook advertisement withdrawn. PMID- 30305414 TI - Magnetic Resonance Imaging-Based Screening for Asymptomatic Brain Tumors: A Review. AB - : Brain tumors comprise 2% of all cancers but are disproportionately responsible for cancer-related deaths. The 5-year survival rate of glioblastoma, the most common form of malignant brain tumor, is only 4.7%, and the overall 5-year survival rate for any brain tumor is 34.4%. In light of the generally poor clinical outcomes associated with these malignancies, there has been interest in the concept of brain tumor screening through magnetic resonance imaging. Here, we will provide a general overview of the screening principles and brain tumor epidemiology, then highlight the major studies examining brain tumor prevalence in asymptomatic populations in order to assess the potential benefits and drawbacks of screening for brain tumors. IMPLICATIONS FOR PRACTICE: Magnetic resonance imaging (MRI) screening in healthy asymptomatic adults can detect both early gliomas and other benign central nervous system abnormalities. Further research is needed to determine whether MRI will improve overall morbidity and mortality for the screened populations and make screening a worthwhile endeavor. PMID- 30305415 TI - A Prospective Trial Evaluating the Safety of a Shortened Infusion of Ramucirumab in Patients with Gastrointestinal Cancer. AB - LESSONS LEARNED: A shortened infusion of ramucirumab (from 60 to 20 minutes) was safe and feasible without infusion-related reactions.Twenty-minute infusions of ramucirumab can be an option for patients with no infusion-related reactions during the first 60-minute treatment. BACKGROUND: Ramucirumab is usually administered over 60 minutes, during which it is unlikely to cause infusion related reactions (IRRs). This prospective study evaluated the safety of a shortened infusion of ramucirumab. METHODS: Patients who received their first dose of ramucirumab in a 60-minute infusion without developing IRRs were eligible and received their second ramucirumab dose for 20 minutes. The primary study endpoint was incidence of IRR during the first short-term infusion, and the secondary endpoints were incidence of IRR at any time and adverse events other than IRR. RESULTS: Of the 40 patients enrolled (median age, 68.5 years), 20 (55%) were male, 27 (67.5%) had stage IV gastric cancer, 25 (62.5%) received ramucirumab in combination with taxane-based chemotherapy, and 24 (60%) received only a single administration of ramucirumab prior to their enrollment. Notably, no IRR was observed during the first short-term infusion (IRR rate, 0%; 95% confidence interval [CI], 0%-0.72%). Among the 149 short-term infusions performed, there were no instances of IRRs or unexpected adverse events related to the treatment (Table 1). CONCLUSION: For patients without development of IRRs upon the first ramucirumab administration, shortening infusion time (from 60 to 20 minutes) is safe and feasible. PMID- 30305416 TI - In Reply. PMID- 30305417 TI - Use of daily Internet search query data improves real-time projections of influenza epidemics. AB - Seasonal influenza causes millions of illnesses and tens of thousands of deaths per year in the USA alone. While the morbidity and mortality associated with influenza is substantial each year, the timing and magnitude of epidemics are highly variable which complicates efforts to anticipate demands on the healthcare system. Better methods to forecast influenza activity would help policymakers anticipate such stressors. The US Centers for Disease Control and Prevention (CDC) has recognized the importance of improving influenza forecasting and hosts an annual challenge for predicting influenza-like illness (ILI) activity in the USA. The CDC data serve as the reference for ILI in the USA, but this information is aggregated by epidemiological week and reported after a one-week delay (and may be subject to correction even after this reporting lag). Therefore, there has been substantial interest in whether real-time Internet search data, such as Google, Twitter or Wikipedia could be used to improve influenza forecasting. In this study, we combine a previously developed calibration and prediction framework with an established humidity-based transmission dynamic model to forecast influenza. We then compare predictions based on only CDC ILI data with predictions that leverage the earlier availability and finer temporal resolution of Wikipedia search data. We find that both the earlier availability and the finer temporal resolution are important for increasing forecasting performance. Using daily Wikipedia search data leads to a marked improvement in prediction performance compared to weekly data especially for a three- to four-week forecasting horizon. PMID- 30305418 TI - Modularity speeds up motor learning by overcoming mechanical bias in musculoskeletal geometry. AB - We can easily learn and perform a variety of movements that fundamentally require complex neuromuscular control. Many empirical findings have demonstrated that a wide range of complex muscle activation patterns could be well captured by the combination of a few functional modules, the so-called muscle synergies. Modularity represented by muscle synergies would simplify the control of a redundant neuromuscular system. However, how the reduction of neuromuscular redundancy through a modular controller contributes to sensorimotor learning remains unclear. To clarify such roles, we constructed a simple neural network model of the motor control system that included three intermediate layers representing neurons in the primary motor cortex, spinal interneurons organized into modules and motoneurons controlling upper-arm muscles. After a model learning period to generate the desired shoulder and/or elbow joint torques, we compared the adaptation to a novel rotational perturbation between modular and non-modular models. A series of simulations demonstrated that the modules reduced the effect of the bias in the distribution of muscle pulling directions, as well as in the distribution of torques associated with individual cortical neurons, which led to a more rapid adaptation to multi-directional force generation. These results suggest that modularity is crucial not only for reducing musculoskeletal redundancy but also for overcoming mechanical bias due to the musculoskeletal geometry allowing for faster adaptation to certain external environments. PMID- 30305419 TI - Segment-specific associations between local haemodynamic and imaging markers of early atherosclerosis at the carotid artery: an in vivo human study. AB - Low and oscillatory wall shear stress (WSS) has long been hypothesized as a risk factor for atherosclerosis; however, evidence has been inferred primarily from model and post-mortem studies, or clinical studies of patients with already developed plaques. This study aimed to identify associations between local haemodynamic and imaging markers of early atherosclerosis. Comprehensive magnetic resonance imaging allowed quantification of contrast enhancement (CE) (a marker of endothelial dysfunction) and vessel wall thickness at two distinct segments: the internal carotid artery bulb and the common carotid artery (CCA). Strict criteria were applied to a large dataset to exclude inward remodelling, resulting in 41 cases for which personalized computational fluid dynamic simulations were performed. After controlling for cardiovascular risk factors, bulb wall thickening was found to be weakly, but not significantly, associated with oscillatory WSS. CE at the bulb was significantly associated with low WSS (p < 0.001) and low flow helicity (p < 0.05). No significant associations were found for the CCA segment. Local haemodynamics at the bulb were significantly correlated with blood flow rates and heart rates, but not carotid bifurcation geometry (flare and curvature). Therefore low, but not oscillatory, WSS is an early independent marker of atherosclerotic changes preceding intimal thickening at the carotid bulb. PMID- 30305420 TI - Biodiversity, functional redundancy and system stability: subtle connections. AB - The relationship between biodiversity and functional redundancy has remained ambiguous for over a half-century, likely due to an inability to distinguish between positivist and apophatic (that which is missing) properties of ecosystems. Apophases are best addressed by mathematics that is predicated upon absence, such as information theory. More than 40 years ago, the conditional entropy of a flow network was proposed as a formulaic way to quantify trophic functional redundancy, an advance that has remained relatively unappreciated. When applied to a collection of 25 fully quantified trophic networks, this authoritative index correlates only poorly and transitively with conventional Hill numbers used to represent biodiversity. Despite such a weak connection, the underlying biomass distribution remains useful in conjunction with the qualitative diets of system components for providing a quick and satisfactory emulation of a system's functional redundancy. Furthermore, an information theoretic cognate of the Wigner Semicircle Rule can be formulated using network conditional entropy to provide clues to the relative stability of any ecosystem under study. The necessity for a balance between positivist and apophatic attributes pertains to the functioning of a host of other living ensemble systems. PMID- 30305421 TI - Chordwise wing flexibility may passively stabilize hovering insects. AB - Insect wings are flexible, and the dynamically deforming wing shape influences the resulting aerodynamics and power consumption. However, the influence of wing flexibility on the flight dynamics of insects is unknown. Most stability studies in the literature consider rigid wings and conclude that the hover equilibrium condition is unstable. The rigid wings possess an unstable oscillatory mode mainly due to their pitch sensitivity to horizontal velocity perturbations. Here, we show that a flapping wing flyer with flexible wings exhibits stable hover equilibria. The free-flight insect flight dynamics are simulated at the fruit fly scale in the longitudinal plane. The chordwise wing flexibility is modelled as a linear beam. The two-dimensional Navier-Stokes equations are solved in a tight fluid-structure integration scheme. For a range of wing flexibilities similar to live insects, all eigenvalues of the system matrix about the hover equilibrium have negative real parts. Flexible wings appear to stabilize the unstable mode by passively deforming their wing shape in the presence of perturbations, generating significantly more horizontal velocity damping and pitch rate damping. These results suggest that insects may passively stabilize their hover flight via wing flexibility, which can inform designs of synthetic flapping wing robots. PMID- 30305422 TI - Transitions in synchronization states of model cilia through basal-connection coupling. AB - Despite evidence for a hydrodynamic origin of flagellar synchronization between different eukaryotic cells, recent experiments have shown that in single multi flagellated organisms, coordination hinges instead on direct basal body connections. The mechanism by which these connections lead to coordination, however, is currently not understood. Here, we focus on the model biflagellate Chlamydomonas reinhardtii, and propose a minimal model for the synchronization of its two flagella as a result of both hydrodynamic and direct mechanical coupling. A spectrum of different types of coordination can be selected, depending on small changes in the stiffness of intracellular couplings. These include prolonged in phase and anti-phase synchronization, as well as a range of multi-stable states induced by spontaneous symmetry breaking of the system. Linking synchrony to intracellular stiffness could lead to the use of flagellar dynamics as a probe for the mechanical state of the cell. PMID- 30305423 TI - A topographic mechanism for arcing of dryland vegetation bands. AB - Banded patterns consisting of alternating bare soil and dense vegetation have been observed in water-limited ecosystems across the globe, often appearing along gently sloped terrain with the stripes aligned transverse to the elevation gradient. In many cases, these vegetation bands are arced, with field observations suggesting a link between the orientation of arcing relative to the grade and the curvature of the underlying terrain. We modify the water transport in the Klausmeier model of water-biomass interactions, originally posed on a uniform hillslope, to qualitatively capture the influence of terrain curvature on the vegetation patterns. Numerical simulations of this modified model indicate that the vegetation bands arc convex-downslope when growing on top of a ridge, and convex-upslope when growing in a valley. This behaviour is consistent with observations from remote sensing data that we present here. Model simulations show further that whether bands grow on ridges, valleys or both depends on the precipitation level. A survey of three banded vegetation sites, each with a different aridity level, indicates qualitatively similar behaviour. PMID- 30305424 TI - SUMO protease SENP1 deSUMOylates and stabilizes c-Myc. AB - Posttranslational modifications play a crucial role in the proper control of c Myc protein stability and activity. c-Myc can be modified by small ubiquitin-like modifier (SUMO). However, how SUMOylation regulates c-Myc stability and activity remains to be elucidated. The deSUMOylation enzyme, SENP1, has recently been shown to have a prooncogenic role in cancer; however, mechanistic understanding of this is limited. Here we show that SENP1 is a c-Myc deSUMOylating enzyme. SENP1 interacts with and deSUMOylates c-Myc in cells and in vitro. Overexpression of wild-type SENP1, but not its catalytically inactive C603S mutant, markedly stabilizes c-Myc and increases its levels and activity. Knockdown of SENP1 reduces c-Myc levels, induces cell cycle arrest, and drastically suppresses cell proliferation. We further show that c-Myc can be comodified by both ubiquitination and SUMOylation. SENP1-mediated deSUMOylation reduces c-Myc polyubiquitination, suggesting that SUMOylation promotes c-Myc degradation through the proteasome system. Interestingly, SENP1-mediated deSUMOylation promotes the accumulation of monoubiquitinated c-Myc and its phosphorylation at serine 62 and threonine 58. SENP1 is frequently overexpressed, correlating with the high expression of c-Myc, in breast cancer tissues. Together, these results reveal that SENP1 is a crucial c-Myc deSUMOylating enzyme that positively regulates c-Myc's stability and activity. PMID- 30305425 TI - The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1. AB - SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies. PMID- 30305426 TI - XBP1s activation can globally remodel N-glycan structure distribution patterns. AB - Classically, the unfolded protein response (UPR) safeguards secretory pathway proteostasis. The most ancient arm of the UPR, the IRE1-activated spliced X-box binding protein 1 (XBP1s)-mediated response, has roles in secretory pathway maturation beyond resolving proteostatic stress. Understanding the consequences of XBP1s activation for cellular processes is critical for elucidating mechanistic connections between XBP1s and development, immunity, and disease. Here, we show that a key functional output of XBP1s activation is a cell type dependent shift in the distribution of N-glycan structures on endogenous membrane and secreted proteomes. For example, XBP1s activity decreased levels of sialylation and bisecting GlcNAc in the HEK293 membrane proteome and secretome, while substantially increasing the population of oligomannose N-glycans only in the secretome. In HeLa cell membranes, stress-independent XBP1s activation increased the population of high-mannose and tetraantennary N-glycans, and also enhanced core fucosylation. mRNA profiling experiments suggest that XBP1s mediated remodeling of the N-glycome is, at least in part, a consequence of coordinated transcriptional resculpting of N-glycan maturation pathways by XBP1s. The discovery of XBP1s-induced N-glycan structural remodeling on a glycome-wide scale suggests that XBP1s can act as a master regulator of N-glycan maturation. Moreover, because the sugars on cell-surface proteins or on proteins secreted from an XBP1s-activated cell can be molecularly distinct from those of an unactivated cell, these findings reveal a potential new mechanism for translating intracellular stress signaling into altered interactions with the extracellular environment. PMID- 30305427 TI - Lipocalin-Like Prostaglandin D Synthase but Not Hemopoietic Prostaglandin D Synthase Deletion Causes Hypertension and Accelerates Thrombogenesis in Mice. AB - Prostaglandin (PG) D2 is formed by two distinct PGD synthases (PGDS): lipocalin type PGDS (L-PGDS), which acts as a PGD2-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a sigma glutathione-S transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS- and H-PGDS-dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ~35%, whereas deletion of H-Pgds does so by ~90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS-dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein. PMID- 30305428 TI - Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators. AB - Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3 hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4 chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD 1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED50 values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders. PMID- 30305429 TI - Controllable oxidative stress and tissue specificity in major tissues during the torpor-arousal cycle in hibernating Daurian ground squirrels. AB - Mammalian hibernators experience repeated hypoxic ischaemia and reperfusion during the torpor-arousal cycle. We investigated levels of oxidative stress, antioxidant capacity, and the underlying mechanism in heart, liver, brain and kidney tissue as well as plasma during different periods of hibernation in Daurian ground squirrels (Spermophilus dauricus). Our data showed that the levels of hydrogen peroxide significantly increased in the heart and brain during late torpor (LT) compared with levels during the summer active (SA) state. The content of malondialdehyde (MDA) was significantly lower during interbout arousal (IBA) and early torpor (ET) than that during SA or pre-hibernation (PRE), and MDA levels in the LT brain were significantly higher than the levels in other states. Superoxide dismutase 2 protein levels increased markedly in the heart throughout the entire torpor-arousal cycle. Catalase expression remained at an elevated level in the liver during the hibernation cycle. Superoxide dismutase 1 and glutathione peroxidase 1 (GPx1) expression increased considerably in all tissues during the IBA and ET states. In addition, the activities of the various antioxidant enzymes were higher in all tissues during IBA and ET than during LT; however, GPx activity in plasma decreased significantly during the hibernation season. The expression of p-Nrf2 decreased in all tissue types during IBA, but significantly increased during LT, especially in liver tissue. Interestingly, most changed indicators recovered to SA or PRE levels in post-hibernation (POST). These results suggest that increased reactive oxygen species during LT may activate the Nrf2/Keap1 antioxidant pathway and may contribute to the decreased MDA levels found during the IBA and ET states, thereby protecting organisms from oxidative damage over the torpor-arousal cycle of hibernation. This is the first report on the remarkable controllability of oxidative stress and tissue specificity in major oxidative tissues of a hibernator. PMID- 30305430 TI - IDH1 mutation promotes lung cancer cell proliferation through methylation of Fibulin-5. AB - Mutation in isocitrate dehydrogenase (IDH) leads to an aberrant function of the enzyme, leading to the production of hydroxyglutarate, as well as changes in cellular metabolism, DNA methylation and histone modification. Previous studies uncovered mutations in IDH1 in several malignancies, with the most frequent mutation being IDH1 R132H. It has been demonstrated that IDH1 expression is induced in non-small-cell lung cancer (NSCLC). However, the contribution of IDH1 mutation in the malignant transformation and development of NSCLC is unclear. In our study, we show that IDH1 R132H enhanced the migration and proliferation of NSCLC cells. Moreover, IDH1 R132H was a crucial modulator of 2-hydroxyglutarate, whose production from cells with IDH1 mutation promoted the binding of DNA methyltransferase 1 (DNMT1) to the Fibulin-5 promoter, leading to its methylation. As a result, Fibulin-5 silencing in cells with IDH1 mutation enhanced the migration and proliferation of NSCLC cells. We show that the IDH1 mutation was present in tissues sampled from patients with NSCLC, which was reversely linked to Fibulin-5 expression. In this study, we suggest an innovative model for IDH1 R132H/Fibulin-5 pathway, which could throw light upon the activity of IDH1 R132H in NSCLC. PMID- 30305432 TI - Two pulses of morphological diversification in Pacific pelagic fishes following the Cretaceous-Palaeogene mass extinction. AB - Molecular phylogenies suggest some major radiations of open-ocean fish clades occurred roughly coincident with the Cretaceous-Palaeogene (K/Pg) boundary, however the timing and nature of this diversification is poorly constrained. Here, we investigate evolutionary patterns in ray-finned fishes across the K/Pg mass extinction 66 million years ago (Ma), using microfossils (isolated teeth) preserved in a South Pacific sediment core spanning 72-43 Ma. Our record does not show significant turnover of fish tooth morphotypes at the K/Pg boundary: only two of 48 Cretaceous tooth morphotypes disappear at the event in the South Pacific, a rate no different from background extinction. Capture-mark-recapture analysis finds two pulses of origination in fish tooth morphotypes following the mass extinction. The first pulse, at approximately 64 Ma, included short-lived teeth, as well as forms that contribute to an expansion into novel morphospace. A second pulse, centred at approximately 58 Ma, produced morphotype novelty in a different region of morphospace from the first pulse, and contributed significantly to Eocene tooth morphospace occupation. There was no significant increase in origination rates or expansion into novel morphospace during the early or middle Eocene, despite a near 10-fold increase in tooth abundance during that interval. Our results suggest that while the K/Pg event had a minor impact on fish diversity in terms of extinction, the removal of the few dominant Cretaceous morphotypes triggered a sequence of origination events allowing fishes to rapidly diversify morphologically, setting the stage for exceptional levels of ray-finned fish diversity in the Cenozoic. PMID- 30305431 TI - Reduced miR-125a-5p level in non-small-cell lung cancer is associated with tumour progression. AB - Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumourigenesis and development. Although the low expression of miR-125a-5p in non small-cell lung cancer (NSCLC) has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in NSCLC was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the CpG island in the miR-125a-5p region was hypermethylated in the tumour tissues, and the hypermethylation was negatively correlated with miR-125a 5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR 125a-5p could directly suppress Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a 5p could also self-activate the silenced miR-125a-5p in NSCLC cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo Thus, we found that the epigenetic silenced miR-125a 5p could be self-activated through targeting Suv39H1 in NSCLC, suggesting that miR-125a-5p might not only have the potential prognostic value as a tumour biomarker but also be a potential therapeutic target in NSCLC. PMID- 30305433 TI - Explaining the ocean's richest biodiversity hotspot and global patterns of fish diversity. AB - For most marine organisms, species richness peaks in the Central Indo-Pacific region and declines longitudinally, a striking pattern that remains poorly understood. Here, we used phylogenetic approaches to address the causes of richness patterns among global marine regions, comparing the relative importance of colonization time, number of colonization events, and diversification rates (speciation minus extinction). We estimated regional richness using distributional data for almost all percomorph fishes (17 435 species total, including approximately 72% of all marine fishes and approximately 33% of all freshwater fishes). The high diversity of the Central Indo-Pacific was explained by its colonization by many lineages 5.3-34 million years ago. These relatively old colonizations allowed more time for richness to build up through in situ diversification compared to other warm-marine regions. Surprisingly, diversification rates were decoupled from marine richness patterns, with clades in low-richness cold-marine habitats having the highest rates. Unlike marine richness, freshwater diversity was largely derived from a few ancient colonizations, coupled with high diversification rates. Our results are congruent with the geological history of the marine tropics, and thus may apply to many other organisms. Beyond marine biogeography, we add to the growing number of cases where colonization and time-for-speciation explain large-scale richness patterns instead of diversification rates. PMID- 30305434 TI - How many faces do people know? AB - Over our species history, humans have typically lived in small groups of under a hundred individuals. However, our face recognition abilities appear to equip us to recognize very many individuals, perhaps thousands. Modern society provides access to huge numbers of faces, but no one has established how many faces people actually know. Here, we describe a method for estimating this number. By combining separate measures of recall and recognition, we show that people know about 5000 faces on average and that individual differences are large. Our findings offer a possible explanation for large variation in identification performance. They also provide constraints on understanding the qualitative differences between perception of familiar and unfamiliar faces-a distinction that underlies all current theories of face recognition. PMID- 30305435 TI - Acoustic adaptation to city noise through vocal learning by a songbird. AB - Anthropogenic noise imposes novel selection pressures, especially on species that communicate acoustically. Many animals-including insects, frogs, whales and birds produce sounds at higher frequencies in areas with low-frequency noise pollution. Although there is support for animals changing their vocalizations in real time in response to noise (i.e. immediate flexibility), other evolutionary mechanisms for animals that learn their vocalizations remain largely unexplored. We hypothesize that cultural selection for signal structures less masked by noise is a mechanism of acoustic adaptation to anthropogenic noise. We test this hypothesis by presenting nestling white-crowned sparrows (Zonotrichia leucophyrs) with less-masked (higher-frequency) and more-masked (lower-frequency) tutor songs either during playback of anthropogenic noise (noise-tutored treatment) or at a different time from noise playback (control treatment). As predicted, we find that noise-tutored males learn less-masked songs significantly more often, whereas control males show no copying preference, providing strong experimental support for cultural selection in response to anthropogenic noise. Further, noise tutored males reproduce songs at higher frequencies than their tutor, indicating a distinct mechanism to increase signal transmission in a noisy environment. Notably, noise-tutored males achieve lower performance songs than their tutors, suggesting potential costs in a sexual selection framework. PMID- 30305436 TI - Staggered Hox expression is more widespread among molluscs than previously appreciated. AB - Hox genes are expressed along the anterior-posterior body axis in a colinear fashion in the majority of bilaterians. Contrary to polyplacophorans, a group of aculiferan molluscs with conserved ancestral molluscan features, gastropods and cephalopods deviate from this pattern by expressing Hox genes in distinct morphological structures and not in a staggered fashion. Among conchiferans, scaphopods exhibit many similarities with gastropods, cephalopods and bivalves, however, the molecular developmental underpinnings of these similar traits remain unknown. We investigated Hox gene expression in developmental stages of the scaphopod Antalis entalis to elucidate whether these genes are involved in patterning morphological traits shared by their kin conchiferans. Scaphopod Hox genes are predominantly expressed in the foot and mantle but also in the central nervous system. Surprisingly, the scaphopod mid-stage trochophore exhibits a near to staggered expression of all nine Hox genes identified. Temporal colinearity was not found and early-stage and late-stage trochophores, as well as postmetamorphic individuals, do not show any apparent traces of staggered expression. In these stages, Hox genes are expressed in distinct morphological structures such as the cerebral and pedal ganglia and in the shell field of early stage trochophores. Interestingly, a re-evaluation of previously published data on early-stage cephalopod embryos and of the gastropod pre-torsional veliger shows that these developmental stages exhibit traces of staggered Hox expression. Considering our results and all gene expression and genomic data available for molluscs as well as other bilaterians, we suggest a last common molluscan ancestor with colinear Hox expression in predominantly ectodermal tissues along the anterior-posterior axis. Subsequently, certain Hox genes have been co-opted into the patterning process of distinct structures (apical organ or prototroch) in conchiferans. PMID- 30305438 TI - Social bonds facilitate cooperative resource sharing in wild chimpanzees. AB - Why share when access to benefits is uncertain is crucial to our understanding of the evolution of humans' extensive cooperation. Here, we investigated some of the different human sharing hypotheses and potential neuroendocrine mechanisms, in one of our closest living relatives, chimpanzees. The strongest predictor of sharing across food types was the presence of enduring and mutually preferred grooming partners, more than harassment, direct signalling, or trade. Moreover, urinary oxytocin levels were higher after the sharing of both individually and jointly acquired resources compared with controls. We conclude that the emotional connection inherent in social bonds was a key factor determining sharing patterns, with the oxytocinergic system potentially facilitating long-term cooperative exchanges. Testing for the role of social bonds in increasing predictability of sharing behaviour, a feature frequently overlooked, may help us to identify the evolutionary drivers of resource sharing and mechanisms that sustain delayed reciprocity between non-kin. PMID- 30305437 TI - Ancient plants with ancient fungi: liverworts associate with early-diverging arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizas are widespread in land plants including liverworts, some of the closest living relatives of the first plants to colonize land 500 million years ago (MYA). Previous investigations reported near-exclusive colonization of liverworts by the most recently evolved arbuscular mycorrhizal fungi, the Glomeraceae, indicating a recent acquisition from flowering plants at odds with the widely held notion that arbuscular mycorrhizal-like associations in liverworts represent the ancestral symbiotic condition in land plants. We performed an analysis of symbiotic fungi in 674 globally collected liverworts using molecular phylogenetics and electron microscopy. Here, we show every order of arbuscular mycorrhizal fungi colonizes early-diverging liverworts, with non Glomeraceae being at least 10 times more common than in flowering plants. Arbuscular mycorrhizal fungi in liverworts and other ancient plant lineages (hornworts, lycopods, and ferns) were delimited into 58 taxa and 36 singletons, of which at least 43 are novel and specific to liverworts. The discovery that early plant lineages are colonized by early-diverging fungi supports the hypothesis that arbuscular mycorrhizas are an ancestral symbiosis for all land plants. PMID- 30305439 TI - Reciprocal facilitation between large herbivores and ants in a semi-arid grassland. AB - While positive interactions have been well documented in plant and sessile benthic marine communities, their role in structuring mobile animal communities and underlying mechanisms has been less explored. Using field removal experiments, we demonstrated that a large vertebrate herbivore (cattle; Bos tarurs) and a much smaller invertebrate (ants; Lasius spp.), the two dominant animal taxa in a semi-arid grassland in Northeast China, facilitate each other. Cattle grazing led to higher ant mound abundance compared with ungrazed sites, while the presence of ant mounds increased the foraging of cattle during the peak of the growing season. Mechanistically, these reciprocal positive effects were driven by habitat amelioration and resource (food) enhancement by cattle and ants (respectively). Cattle facilitated ants, probably by decreasing plant litter accumulation by herbivory and trampling, allowing more light to reach the soil surface leading to microclimatic conditions that favour ants. Ants facilitated cattle probably by increasing soil nutrients via bioturbation, increasing food (plant) biomass and quality (nitrogen content) for cattle. Our study demonstrates reciprocal facilitative interactions between two animal species from phylogenetically very distant taxa. Such reciprocal positive interactions may be more common in animal communities than so far assumed, and they should receive more attention to improve our understanding of species coexistence and animal community assembly. PMID- 30305441 TI - Correction to 'Dodging silver bullets: good CRISPR gene-drive design is critical for eradicating exotic vertebrates'. PMID- 30305442 TI - Correction to 'Tree species richness increases ecosystem carbon storage in subtropical forests'. PMID- 30305443 TI - Atrial fibrillation, antithrombotic treatment, and cognitive aging: A population based study. AB - OBJECTIVE: To examine the association of atrial fibrillation (AF) with cognitive decline and dementia in old age, and to explore the cognitive benefit of antithrombotic treatment in patients with AF. METHODS: This population-based cohort study included 2,685 dementia-free participants from the Swedish National Study on Aging and Care in Kungsholmen, who were regularly examined from 2001 2004 to 2010-2013. AF was ascertained from clinical examination, ECG, and patient registry. Global cognitive function was assessed using the Mini-Mental State Examination. We followed the DSM-IV criteria for the diagnosis of dementia, the NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences) criteria for vascular dementia, and the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer disease. Data were analyzed using multiple linear mixed-effects and Cox regression models. RESULTS: We identified 243 participants (9.1%) with AF at baseline. During the 9-year follow-up period, 279 participants (11.4%) developed AF and 399 (14.9%) developed dementia. As a time-varying variable, AF was significantly associated with a faster annual Mini-Mental State Examination decline (beta coefficient = -0.24, 95% confidence interval [CI]: -0.31 to -0.16) and an increased hazard ratio (HR) of all-cause dementia (HR = 1.40, 95% CI: 1.11-1.77) and vascular and mixed dementia (HR = 1.88, 95% CI: 1.09-3.23), but not Alzheimer disease (HR = 1.33, 95% CI: 0.92-1.94). Among people with either prevalent or incident AF, use of anticoagulant drugs, but not antiplatelet treatment, was associated with a 60% decreased risk of dementia (HR = 0.40, 95% CI: 0.18-0.92). CONCLUSION: AF is associated with a faster global cognitive decline and an increased risk of dementia in older people. Use of anticoagulant drugs may reduce dementia risk in patients with AF. PMID- 30305444 TI - Burnout in neurology: Extinguishing the embers and rekindling the joy in practice. PMID- 30305440 TI - Wild chimpanzees select tool material based on efficiency and knowledge. AB - Some animals have basic culture, but to date there is not much evidence that cultural traits evolve as part of a cumulative process as seen in humans. This may be due to limits in animal physical cognition, such as an inability to compare the efficiency of a novel behavioural innovation with an already existing tradition. We investigated this possibility with a study on a natural tool innovation in wild chimpanzees: moss-sponging, which recently emerged in some individuals to extract mineral-rich liquids at a natural clay-pit. The behaviour probably arose as a variant of leaf-sponging, a tool technique seen in all studied chimpanzee communities. We found that moss-sponges not only absorbed more liquid but were manufactured and used more rapidly than leaf-sponges, suggesting a functional improvement. To investigate whether chimpanzees understood the advantage of moss- over leaf-sponges, we experimentally offered small amounts of rainwater in an artificial cavity of a portable log, together with both sponge materials, moss and leaves. We found that established moss-spongers (having used both leaves and moss to make sponges) preferred moss to prepare a sponge to access the rainwater, whereas leaf-spongers (never observed using moss) preferred leaves. Survey data finally demonstrated that moss was common in forest areas near clay-pits but nearly absent in other forest areas, suggesting that natural moss-sponging was at least partly constrained by ecology. Together, these results suggest that chimpanzees perceive functional improvements in tool quality, a crucial prerequisite for cumulative culture. PMID- 30305445 TI - Reduced risk of dementia among patients with atrial fibrillation receiving oral anticoagulants. PMID- 30305446 TI - Golgin A4 in CSF and granulovacuolar degenerations of patients with Alzheimer disease. AB - OBJECTIVE: To isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease. METHODS: We immunized mice with human CSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls. RESULTS: We generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125-155] vs 115 [ 99-128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67-0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs). CONCLUSIONS: These results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that elevated CSF golgin A4 levels identify patients with Alzheimer disease. PMID- 30305447 TI - Contralesional macrostructural plasticity of the insular cortex in patients with glioma: A VBM study. AB - OBJECTIVE: To assess the homotopic structural plasticity in case of unilateral damage of the insula. METHODS: To detect changes in gray matter volumes of the contralesional insula from structural MRIs, we used voxel-based morphometry (VBM) in a sample of 84 patients with a diffuse low-grade glioma invading the left insula (insL group; n = 47) or the right insula (insR group; n = 37). RESULTS: The region of interest-based VBM analysis highlighted a large cluster of voxels with gray matter volume increase in the contralesional insula in both patient groups (k = 2,214 voxels for insL and k = 879 voxels for insR, p < 0.05, family wise error corrected) compared with 24 age-matched healthy controls. Gray matter volume was increased for the entire insula (t 69 = 3.63, p = 0.0016 for insL; t 59 = 3.54, p = 0.0024 for insR, Bonferroni corrected), whereas no significant changes were found in 2 control regions for both patient groups. Furthermore, an increase of 24.6% and 31.6% in the gray matter volume was observed in the insula related VBM cluster for insL and insR patients, respectively, compared with healthy controls (t 69 = 7.39, p = 2.59 * 10-10 and t 59 = 7.51, p = 3.61 * 10 10). CONCLUSIONS: The reported results demonstrate that slow-growing but massive lesion infiltration of the insula induces marked increase of gray matter volume in the contralateral one. Our findings give support for a homotopic reorganization that might be a physiologic basis for the high level of functional compensation observed in patients with glioma. PMID- 30305448 TI - Age and sex differences in burnout, career satisfaction, and well-being in US neurologists. AB - OBJECTIVE: To examine age and sex differences in burnout, career satisfaction, and well-being in US neurologists. METHODS: Quantitative and qualitative analyses of men's (n = 1,091) and women's (n = 580) responses to a 2016 survey of US neurologists. RESULTS: Emotional exhaustion in neurologists initially increased with age, then started to decrease as neurologists got older. Depersonalization decreased as neurologists got older. Fatigue and overall quality of life in neurologists initially worsened with age, then started to improve as neurologists got older. More women (64.6%) than men (57.8%) met burnout criteria on univariate analysis. Women respondents were younger and more likely to work in academic and employed positions. Sex was not an independent predictive factor of burnout, fatigue, or overall quality of life after controlling for age. In both men and women, greater autonomy, meaning in work, reasonable amount of clerical tasks, and having effective support staff were associated with lower burnout risk. More hours worked, more nights on call, higher outpatient volume, and higher percent of time in clinical practice were associated with higher burnout risk. For women, greater number of weekends doing hospital rounds was associated with higher burnout risk. Women neurologists made proportionately more negative comments than men regarding workload, work-life balance, leadership and deterioration of professionalism, and demands of productivity eroding the academic mission. CONCLUSIONS: We identified differences in burnout, career satisfaction, and well being in neurologists by age and sex. This may aid in developing strategies to prevent and mitigate burnout and promote professional fulfillment for different demographic subgroups of neurologists. PMID- 30305450 TI - Gray matter differences in patients with functional movement disorders. AB - OBJECTIVE: To explore alterations in gray matter volume in patients with functional movement disorders. METHODS: We obtained T1-weighted MRI on 48 patients with clinically definite functional movement disorders, a subset of functional neurologic symptom disorder characterized by abnormal involuntary movements, and on 55 age- and sex-matched healthy controls. We compared between group differences in gray matter volume using voxel-based morphometry across the whole brain. All participants in addition underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression Scales and the Childhood Trauma Questionnaire. To determine whether confounding factors such as comorbid depression, anxiety, or childhood trauma exposure contributed to the observed structural changes, nonparametric correlation analysis was performed. RESULTS: Patients with functional movement disorders exhibited increased volume of the left amygdala, left striatum, left cerebellum, left fusiform gyrus, and bilateral thalamus, and decreased volume of the left sensorimotor cortex (whole-brain corrected p <= 0.05). Volumetric differences did not correlate with measures of disease duration or patient-rated disease severity. CONCLUSION: This study demonstrates that patients with functional movement disorders exhibit structural gray matter abnormalities in critical components of the limbic and sensorimotor circuitry. These abnormalities may represent a premorbid trait rendering patients more susceptible to disease, the disease itself, or a compensatory response to disease. PMID- 30305449 TI - Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study. AB - OBJECTIVES: To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period. METHODS: Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months. RESULTS: Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers. CONCLUSIONS: Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy. CLINICALTRIALSGOV IDENTIFIER: NCT01719159. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections. PMID- 30305451 TI - Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults. AB - OBJECTIVE: To assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults. METHODS: One hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30-89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status. RESULTS: In initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical, hippocampal, and Alzheimer disease signature cortical volume. CONCLUSION: Our results indicate that assessing regional changes in amyloid, particularly in posterior cortical regions, can aid in the early detection of subclinical amyloid related decline in episodic memory as early as middle age. Future research incorporating tau and other markers of neurodegeneration is needed to clarify the sequence of events that lead to this early, subclinical memory decline. PMID- 30305452 TI - Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-beta/Smad3 pathway. AB - Transforming growth factor-beta (TGF-beta) is a well-established central mediator of renal fibrosis, a common outcome of almost all progressive chronic kidney diseases. Here, we identified a poorly conserved and kidney-enriched long noncoding RNA in TGF-beta1-stimulated human tubular epithelial cells and fibrotic kidneys, which we termed TGF-beta/Smad3-interacting long noncoding RNA (lnc-TSI). Lnc-TSI was transcriptionally regulated by Smad3 and specifically inhibited TGF beta-induced Smad3 phosphorylation and downstream profibrotic gene expression. Lnc-TSI acted by binding with the MH2 domain of Smad3, blocking the interaction of Smad3 with TGF-beta receptor I independent of Smad7. Delivery of human lnc-TSI into unilateral ureteral obstruction (UUO) mice, a well-established model of renal fibrosis, inhibited phosphorylation of Smad3 in the kidney and attenuated renal fibrosis. In a cohort of 58 patients with biopsy-confirmed IgA nephropathy (IgAN), lnc-TSI renal expression negatively correlated with the renal fibrosis index (r = -0.56, P < 0.001) after adjusting for cofounders. In a longitudinal study, 32 IgAN patients with low expression of renal lnc-TSI at initial biopsy had more pronounced increases in their renal fibrosis index and experienced stronger declines in renal function at repeat biopsy at a mean of 48 months of follow-up. These data suggest that lnc-TSI reduced renal fibrogenesis through negative regulation of the TGF-beta/Smad pathway. PMID- 30305453 TI - GDP-l-fucose synthase is a CD4+ T cell-specific autoantigen in DRB3*02:02 patients with multiple sclerosis. AB - Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)-l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid-infiltrating CD4+ T cells from HLA-DRB3*-positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis. PMID- 30305455 TI - T cells take aim at a ubiquitous autoantigen in multiple sclerosis. AB - CD4+ T cells from multiple sclerosis lesions target a ubiquitous self-antigen that is shared by gut commensal bacteria (Planas et al, this issue). PMID- 30305454 TI - ITGBL1 modulates integrin activity to promote cartilage formation and protect against arthritis. AB - Developing and mature chondrocytes constantly interact with and remodel the surrounding extracellular matrix (ECM). Recent research indicates that integrin ECM interaction is differentially regulated during cartilage formation (chondrogenesis). Integrin signaling is also a key source of the catabolic reactions responsible for joint destruction in both rheumatoid arthritis and osteoarthritis. However, we do not understand how chondrocytes dynamically regulate integrin signaling in such an ECM-rich environment. Here, we found that developing chondrocytes express integrin-beta-like 1 (Itgbl1) at specific stages, inhibiting integrin signaling and promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 is secreted and physically interacts with integrins to down-regulate activity. We observed that Itgbl1 expression was strongly reduced in the damaged articular cartilage of patients with osteoarthritis (OA). Ectopic expression of Itgbl1 protected joint cartilage against OA development in the destabilization of the medial meniscus-induced OA mouse model. Our results reveal ITGBL1 signaling as an underlying mechanism of protection against destructive cartilage disorders and suggest the potential therapeutic utility of targeting ITGBL1 to modulate integrin signaling in human disease. PMID- 30305456 TI - PIEZO2 mediates injury-induced tactile pain in mice and humans. AB - Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia. PMID- 30305457 TI - The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. AB - The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of Piezo2-expressing sensory neurons induced nociception in mice. Mice lacking Piezo2 in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Adelta-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia. PMID- 30305458 TI - Correction to 'Spatial spread of Wolbachia in Rhagoletis cerasi populations'. PMID- 30305459 TI - Genetic data reveal mixed-stock aggregations of gray whales in the North Pacific Ocean. AB - Gray whales (Eschrichtius robustus) in the Western Pacific are critically endangered, whereas in the Eastern Pacific, they are relatively common. Holocene environmental changes and commercial whaling reduced their numbers, but gray whales in the Eastern Pacific now outnumber their Western counterparts by more than 100-fold. Herein, we investigate the genetic diversity and population structure within the species using a panel of genic single nucleotide polymorphisms. Results indicate the gray whale gene pool is differentiated into two substocks containing similar levels of genetic diversity, and that both our Eastern and Western geographical samples represent mixed-stock aggregations. Ongoing or future gene flow between the stocks may conserve genetic diversity overall, but admixture has implications for conservation of the critically endangered Western gray whale. PMID- 30305460 TI - Environmental heterogeneity promotes spatial resilience of phototrophic biofilms in streambeds. AB - The loss of environmental heterogeneity threatens biodiversity and ecosystem functioning. It is therefore important to understand the relationship between environmental heterogeneity and spatial resilience as the capacity of ecological communities embedded in a landscape matrix to reorganize following disturbance. We experimented with phototrophic biofilms colonizing streambed landscapes differing in spatial heterogeneity and exposed to flow-induced disturbance. We show how streambed roughness and related features promote growth-related trait diversity and the recovery of biofilms towards carrying capacity (CC) and spatial resilience. At the scale of streambed landscapes, roughness and exposure to water flow promoted biofilm CC and growth trait diversity. Structural equation modelling identified roughness, post-disturbance biomass and a 'neighbourhood effect' to drive biofilm CC. Our findings suggest that the environment selecting for adaptive capacities prior to disturbance (that is, memory effects) and biofilm connectivity into spatial networks (that is, mobile links) contribute to the spatial resilience of biofilms in streambed landscapes. These findings are critical given the key functions biofilms fulfil in streams, now increasingly experiencing shifts in sedimentary and hydrological regimes. PMID- 30305461 TI - Inclusive fitness for in-laws. AB - Cooperation among kin is common across the natural world and can be explained in terms of inclusive fitness theory, which holds that individuals can derive indirect fitness benefits from aiding genetically related individuals. However, human kinship includes not only genetic kin but also kin by marriage: our affines (in-laws) and spouses. Can cooperation between these genetically unrelated kin be reconciled with inclusive fitness theory? Here, we argue that although affinal kin and spouses do not necessarily share genetic ancestry, they may have shared genetic interests in future reproduction and, as such, can derive indirect fitness benefits though cooperating. We use standard inclusive fitness theory to derive a coefficient of shared reproductive interest (s) that predicts altruistic investment both in genetic kin and in spouses and affines. Specifically, a behaviour that reduces the fitness of the actor by c and increases the fitness of the recipient by b will be favoured by natural selection when sb > c We suggest that the coefficient of shared reproductive interest may provide a valuable tool for understanding not only the evolution of human kinship but also cooperation and conflict across the natural world more generally. PMID- 30305462 TI - Experimental evidence for reduced male allocation under selfing in a simultaneously hermaphroditic animal. AB - Self-fertilization is widespread among simultaneously hermaphroditic animals and plants, but is often only facultatively deployed under circumstances that constrain outcrossing. A central prediction of sex allocation (SA) theory is that because exclusive selfing reduces sperm or pollen competition to zero, this should favour extreme economy in resources channelled to the male sex function. We can therefore expect that organisms switching from outcrossing to selfing should reduce their male allocation. However, to date this prediction has received relatively little support in animal taxa, especially compared to plants. Here we show that isolated individuals (under enforced selfing conditions) have a less male-biased SA than do grouped conspecifics (under outcrossing conditions) in the preferentially outcrossing flatworm Macrostomum hystrix This shift arises from a reduced male allocation (testis area) in isolated individuals, although we did not find any evidence for a re-allocation of these resources to the female sex function (i.e. ovary area was unaffected by selfing/outcrossing conditions). Our results provide some of the clearest experimental evidence to date for reduced male allocation under selfing in simultaneously hermaphroditic animals, extending previous findings comparing SA between populations differing in selfing rates to the level of individual plasticity in gametogenesis. PMID- 30305463 TI - Spontaneously Cleavable Glycosylated Linker Capable of Extended Release of its Conjugated Peptide. AB - Reversibly glycosylated conjugates were developed by adding complex-type N-linked oligosaccharides to peptides through self-cleavable linkers with the aim of increasing the solubility and stability of the peptides in plasma. The amino or carboxyl group of the peptide was connected to a glycosylated Ascendis or ester/thioester-type linker, respectively. Use of the linkers enabled extended release of the peptides depending on the pH and temperature of the buffer according to a first order reaction, and their cleavage rate was also affected by the structure of the peptide-linker coupling. This tunability will allow optimization towards the intended use of the peptides to be released. Furthermore, because glycosylation is a reliable method of greatly increasing the solubility of a peptide, the presented glycosylated linkers are expected to permit the preparation of antibodies in aqueous buffers even in the case of sparingly soluble antigen peptides. PMID- 30305464 TI - Postprandial Hyperlipemia is an Indication for Additional Risk in Sitosterolemia. PMID- 30305465 TI - Time-action profiles of insulin degludec in healthy dogs and its effects on glycemic control in diabetic dogs. AB - Insulin degludec (IDeg) is a new insulin formulation that facilitates long-term control of glucose level in humans. In this study, we investigated the effects of IDeg on glycemic control in dogs. Its time-action profiles were monitored in healthy dogs using an artificial pancreas apparatus under euglycemic conditions. At 9.0-13.5 hr post-IDeg injection, an indistinct peak of glucose level was detected. Moreover, the action of IDeg was persistent for >20 hr. Both IDeg and neutral protamine Hagedorn insulin (NPH) lowered blood glucose concentrations in diabetic dogs, but IDeg caused postprandial hyperglycemia and a somewhat lower preprandial glucose level than that caused by NPH. IDeg might be ineffective in concurrently preventing postprandial hyperglycemia and preprandial hypoglycemia in a single-agent administration. PMID- 30305466 TI - Prognostic significance of midline shift of the olfactory or frontal lobes of the brain in canine nasal carcinomas treated by palliative radiotherapy: a pilot study. AB - Canine nasal carcinomas are often treated with radiotherapy. Presence of lysis of the cribriform plate by tumor invasion (stage 4 by modified Adams's staging system) is a well-known prognostic factor. In this study, dogs with stage 4 disease were divided into two subgroups based on the presence or absence of midline shift of the olfactory or frontal lobes of the brain (Stage 4a: without presence of midline shift. Stage 4b: with midline shift). The median survival time of dogs with midline shift was significantly shorter than that of dogs without midline shift (64 vs. 208 days). Our results indicate that the finding of a midline shift might have a prognostic significance in dogs with nasal carcinoma treated with radiotherapy. PMID- 30305474 TI - Rare concurrent indolent B-cell lymphoma and plasmablastic transformation of myeloma. PMID- 30305467 TI - ELISA using a recombinant chimera of ESAT-6/MPB70/MPB83 for Mycobacterium bovis diagnosis in naturally infected cattle. AB - Bovine tuberculosis (bTB) control programs generally rely on intradermal tuberculin tests for the antemortem diagnosis of Mycobacterium bovis infection in cattle, but these tests detect only a portion of the infected animals. The aim of the present study was to evaluate the diagnostic coverage of a combination of the bTB antemortem techniques known as the comparative intradermal tuberculin test (CITT) and an ELISA based on a recombinant chimera of ESAT-6/MPB70/MPB83 as the antigen in cattle. The results were compared to postmortem findings based on M. bovis culturing and PCR. Paired comparisons of all data (n=92) demonstrated that ELISA and LST results compared to the culturing results did not present significant differences (P=0.27 on McNemar's test and P=0.12 on Fisher's exact test, respectively). Using culturing as the gold standard, the sensitivity and specificity of ELISA were 79.5% (95% CI: 64.5-89.2%) and 75.5% (95% CI: 62.4 85.1%), respectively, whereas LST demonstrated 100% sensitivity (95% CI: 91.03 100%) and 92.5% specificity (95% CI: 82.1-97.0%). The ELISA results did not reveal significant differences in relation to the LST results (P>0.99 on Fisher's exact test). Using the latter as the gold standard, the sensitivity and specificity of ELISA were 79.1% (95% CI: 64.8-88.6%) and 79.6% (95% CI: 66.4 88.5%), respectively. The use of ELISA with the recombinant chimera of ESAT 6/MPB70/MPB83 as the antigen complements the diagnostic coverage provided by CITT and increases the removal of infected animals from herds. PMID- 30305475 TI - Cladribine treatment for Erdheim-Chester disease involving the central nervous system and concomitant polycythemia vera: A case report. AB - Erdheim-Chester disease (ECD), a rare form of non-Langerhans cell histiocytosis, is characterized by the infiltration of foamy CD68+ and CD1a- histiocytes into multiple organ systems. Central nervous system (CNS) involvement has recently been reported to be a poor prognostic factor when treating ECD with interferon alpha. We report the case of a 66-year-old Japanese patient with ECD involving the CNS who harbored the BRAF V600E mutation and also concomitantly developed polycythemia vera with the JAK2 V617F mutation. We confirmed 2 chlorodeoxyadenosine (cladribine) therapy to be effective for the patient in this case. PMID- 30305476 TI - Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) chemotherapy. PMID- 30305477 TI - The neutral N-linked glycans of the Basidiomycetous yeasts Pseudozyma antarctica and Malassezia furfur (Subphylum Ustilaginomycotina). AB - Pseudozyma antarctica and Malassezia furfur are basidiomycetous yeasts under the subphylum Ustilaginomycotina. P. antarctica is a commensal organism found in certain plant species, while M. furfur is associated with several skin diseases of animals including humans. N-linked glycans of P. antarctica and M. furfur were prepared, digested with glycosidases, and structurally analyzed using high performance liquid chromatography (HPLC) and mass spectrometry (MS). Analyses revealed the presence of neutral N-linked glycans ranging in length from Man3GlcNAc2-PA to Man9GlcNAc2-PA. The two species shared the most abundant neutral N-linked glycan: Manalpha1-2Manalpha1-6(Manalpha1-3)Manalpha1-6(Manalpha1 2Manalpha1-2Manalpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc (M8A). The second and third most abundant neutral N-linked glycans for P. antarctica were Manalpha1 2Manalpha1-6(Manalpha1-2Manalpha1-3)Manalpha1-6(Manalpha1-2Manalpha1-2Manalpha1 3)Manbeta1-4GlcNAcbeta1-4GlcNAc (M9A) and Manalpha1-6(Manalpha1-3)Manalpha1 6(Manalpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc (M5A), respectively. In the case of M. furfur, Manalpha1-2Manalpha1-6(Manalpha1-3)Manalpha1-6(Manalpha1-2Manalpha1 3)Manbeta1-4GlcNAcbeta1-4GlcNAc (M7A) was the second most abundant, while both M8A and M9A were tied for the third most abundant. The presence of putative galactose residues in the hypermannosylated neutral N-linked glycans is also discussed. This report is the first to analyze the neutral N-linked glycans of P. antarctica and M. furfur. PMID- 30305479 TI - Assessing Aortic Remodeling after Thoracic Endovascular Aortic Repair (TEVAR) in DeBakey IIIb Aortic Dissection: A Retrospective Study. AB - PURPOSE: This study analyzed the different levels of aortic remodeling in patients with DeBakey IIIb aortic dissection (AD) after thoracic endovascular aortic repair (TEVAR) at a single center. METHODS: In all, 66 patients with DeBakey IIIb AD who underwent TEVAR in the acute (Group A) or subacute phase (Group SA) from January 2012 to October 2016 were included in the study. The change in aortic lumen (A), true lumen (TL), false lumen (FL), and true lumen index (TLi) at different levels were analyzed. RESULTS: There was no statistically significant difference in the clinical information and morphologic imaging findings in Groups A and SA. At proximal levels (levels A-C), there was no difference in aortic remodeling parameters, that is, increased TL, decreased FL, and increased TLi at levels B and C and stable A at levels A-C, in both groups. Moreover, the above parameters were illustrated using a box-and-whisker plot, which revealed the unstable acute phase by the larger distribution interval and the median and abnormal values of the right skew distribution in Group A. CONCLUSION: Postoperative surveillance is important for patients of both acute and subacute AD. PMID- 30305480 TI - Employment status changes of workers after referral to an occupational disease clinic. AB - OBJECTIVE: Occupational diseases (OD) are among the most significant issues of work life, with economic, medical, social, and ethical aspects. The majority of studies concerning OD focus on the causes or medical outcomes of OD. There are a limited number of studies investigating the social and economic impacts of being diagnosed with an OD. One of the important social aspects of OD is the employability of workers after an OD diagnosis. The aim of this study is to evaluate the changes in employment status after the OD diagnosis process. METHODS: This is a cross sectional study. There were 204 eligible cases, and 198 (97%) completed the study. The study data were obtained from patient files, including OD Committee reports and questionnaires applied via telephone interview. RESULTS: Among the 198 applicants, 170 (85.9%) were male and 146 (73.7%) were diagnosed with an OD. Of these workers, 106 (53.5%) had quit their current jobs. Of those workers, 89 out of 106 were in the OD group, and 17 were in the non-OD group. Diagnosis with OD (OR: 3.1 CI: 1.4-6.8) and non-union membership (OR: 11.1 CI: 5.2-23.5) increased the likelihood of quitting the job after an OD diagnosis. CONCLUSION: The short-term prognosis of OD was relatively poor. OD diagnosis or even referral to an outpatient clinic may cause quitting the job. Policies should account for the risk of unemployment after an OD diagnosis, and OD surveillance systems should obtain data on the employment status of workers following diagnosis. PMID- 30305481 TI - A new DNA marker of the TMIGD1 gene used to identify high fertilization rates in Tsaiya ducks (Anas platyrhynchos). AB - In a prior study, comparisons of individuals of Anas platyrhynchos with higher/lower reproductive performances showed that the expression of the transmembrane and immunoglobulin domain containing 1 (TMIGD1) gene significantly differed between the two groups. Here, we demonstrate that ducks with the TMIGD1 GG genotype have a significantly higher fertilization rate than other TMIGD1 genotypes. Primers designed based on the TMIGD1 sequence of Pekin duck were able to successfully amplify a TMIGD1 fragment from Tsaiya ducks, and sequencing results indicated that a single nucleotide polymorphism (SNP) of the TMIGD1 gene existed. We also developed a cost-effective method of restriction fragment length polymorphism. Using the above methods, ducks were classified into three genotypes. To identify the relationships between genotypes and traits, we recorded the ducks' performance; to ensure the coverage of the entire duration of the fertile period, the egg collection period was extended to 18 days, and therefore, lower than usual fertilization rates were observed. Further assessment using a high-throughput system showed that the ducks with the GG genotype exhibited the highest fertilization rates among genotypes (P < 0.05). We suggest that TMIGD1 may affect the release of sperm protection factors from the female genital tract, and thus alter fertilization rate. In conclusion, the results of this study demonstrate that the TMIGD1 GG genotype can be used as a new DNA marker to identify animals with high fertilization rates at a young age, a process which could improve farming efficiency. PMID- 30305478 TI - Transcriptional regulation of the 26S proteasome by Nrf1. AB - The 26S proteasome is a large protease complex that selectively degrades ubiquitinated proteins. It comprises 33 distinct subunits, each of which differ in function and structure, and which cannot be substituted by the other subunits. Owing to its complicated structure, the biogenesis of the 26S proteasome is elaborately regulated at the transcription, translation, and molecular assembly levels. Recent studies revealed that Nrf1 (NFE2L1) is a transcription factor that upregulates the expression of all the proteasome subunit genes in a concerted manner, especially during proteasome impairment in mammalian cells. In this review, we summarize current knowledge regarding the transcriptional regulation of the proteasome and recent findings concerning the regulation of Nrf1 transcription activity. PMID- 30305482 TI - Different daily glycemic profiles after switching from once-daily alogliptin plus twice-daily metformin to their once-daily fixed-dose combination in Japanese type 2 diabetic patients. AB - The aim of this study was to investigate whether daily glycemic profiles and treatment satisfaction would be changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the fixed-dose combination of 25 mg alogliptin and 500-mg metformin once daily in type 2 diabetic patients. Twenty adult Japanese type 2 diabetic patients in whom once-daily 25-mg alogliptin plus twice-daily 250-mg metformin were switched to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily participated. Before and one month after the switch, participants were asked to perform one day of seven-point self monitoring of blood glucose (SMBG), to wear a sensor of flash glucose monitoring for up to 14 days, and to respond to a questionnaire for treatment satisfaction. As a result, the SMBG profiles were significantly changed after the switch (p = 0.021); blood glucose levels 2 hours after breakfast were significantly elevated (p = 0.022), whereas those 2 hours after lunch were significantly reduced (p = 0.036). The flash glucose monitoring also demonstrated a significant change of daily glucose profiles (p < 0.001). The risk of glucose levels <80 mg/dL were decreased from evening to morning, while the risk of glucose levels >=140 mg/dL were increased. Mean 24-hour glucose values were increased by 5 mg/dL on average (p < 0.001). Treatment satisfaction was significantly improved after the switch (p < 0.001). In conclusion, daily glycemic profiles were significantly changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the once-daily fixed-dose combination in Japanese type 2 diabetic patients. Treatment satisfaction was significantly improved after the switch. PMID- 30305483 TI - Lower serum total bilirubin concentration is associated with higher prevalence of gestational diabetes mellitus in Japanese pregnant women. AB - We aimed to clarify the pathophysiological significance of total bilirubin (TB) in gestational diabetes mellitus (GDM). This was a cross-sectional study that included 616 pregnant Japanese women (368 normal glucose tolerance [NGT] and 248 GDM). Serum TB concentration, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were compared in NGT and GDM women. TB concentration was also compared according to the number of abnormal OGTT values. Logistic regression analysis was used to evaluate the association between TB and GDM prevalence. A multiple linear regression model was used to evaluate the association between TB and HOMA-IR. TB concentrations were significantly lower in GDM women than in NGT women. This result did not change after adjustments for TB sampling timing were made. Out of 248 GDM women, the prevalences of 1- and 2/3- abnormal OGTT values (1- and 2/3-AV) GDM were 72.2% (n = 179) and 27.8% (n = 69), respectively. In the multiple comparisons, TB concentrations were significantly lower in women with 2/3-AV GDM than in women with NGT and 1-AV GDM. Multiple logistic regression analysis showed that TB was a significantly associated factor for 2/3-AV, but not for total GDM. HOMA-IR was significantly higher in GDM women than in NGT women. The univariate, but not multivariate, analysis showed that TB was a significantly associated factor for HOMA-IR. Our findings suggest that hypobilirubinemia may be involved in the pathogenesis of GDM. PMID- 30305484 TI - Percutaneous WATCHMAN Left Atrial Appendage Closure for Japanese Patients With Nonvalvular Atrial Fibrillation at Increased Risk of Thromboembolism - First Results From the SALUTE Trial. AB - BACKGROUND: The PROTECT AF and PREVAIL trials demonstrated that the WATCHMAN left atrial appendage (LAA) closure device is a reasonable alternative to warfarin therapy for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the USA and Europe. We conducted the SALUTE trial to confirm the safety and efficacy of the LAA closure therapy for patients with NVAF in Japan. Methods and Results: A total of 54 subjects (including 12 Roll-in) with NVAF who had a CHA2DS2-VASc score >=2 were enrolled. All subjects were successfully implanted with the LAA closure device. No serious adverse events related to the primary procedure-safety endpoint occurred. The 2nd co-primary endpoint was a composite of all stroke, systemic embolism and cardiovascular/unexplained death. One ischemic stroke (1/42) occurred during the 6-month follow-up. The effective LAA closure rate defined as the 3rd co-primary endpoint was 100% (42/42) at both 45 day and 6-month follow-up. CONCLUSIONS: The procedural safety and 6-month results from the SALUTE trial demonstrated that the LAA closure device was safe and effective, similar to the results of large-scale randomized clinical trials, and provides a novel perspective of LAA closure for Japanese patients with NVAF in need of an alternative to long-term oral-anticoagulation. (Trial Registration: clinicaltrials.gov Identifier NCT 03033134). PMID- 30305485 TI - Clinical Predictors of Recurrent Ventricular Arrhythmias in Secondary Prevention Implantable Cardioverter Defibrillator Recipients With Coronary Artery Disease - Lower Left Ventricular Ejection Fraction and Incomplete Revascularization. AB - BACKGROUND: The implantable cardioverter defibrillator (ICD) is a standard prevention therapy for patients at high risk for sudden cardiac death (SCD) due to life-threatening ventricular arrhythmia (VA), that is, ventricular fibrillation and ventricular tachycardia. However, clinical predictors of recurrent VA in secondary prevention ICD recipients with coronary artery disease (CAD) remain unknown. Methods and Results: We followed up 96 consecutive patients with CAD undergoing ICD implantation for secondary prevention of SCD. Long-term rates and clinical predictors of appropriate ICD therapy (ICD-Tx) for VA were analyzed. Appropriate ICD-Tx occurred in 41 (42.7%) patients during a median follow-up of 2.4 years (interquartile range, 0.9-6.1). These patients had significantly greater left ventricular end-diastolic diameter (62.3+/-1.3 vs. 54.6+/-1.1 mm, P<0.001), lower left ventricular ejection fraction (LVEF; 36.3+/ 2.0% vs. 45.7+/-1.8%, P<0.001), and more incomplete revascularization (ICR; 70.7% vs. 45.5%, P=0.014) than those without appropriate ICD-Tx. Multivariable analysis showed that LVEF (hazards ratio [HR], 0.950; 95% CI: 0.925-0.975; P<0.001) and ICR (HR, 2.293; 95% CI: 1.133-4.637; P=0.021) were significant predictors of appropriate ICD-Tx for VA. CONCLUSIONS: Lower LVEF and ICR were independent predictors of recurrent VA in secondary prevention ICD recipients with CAD. PMID- 30305487 TI - [Hematopoietic cell differentiation orchestrated by transcription factor network and its related pathogenesis]. AB - It has long been considered that hematopoietic system development is based on hematopoietic stem cell differentiation with a gradual loss of multipotency. However, recent studies have indicated that hematopoietic stem cells are composed of subsets that exhibit lineage skewing, thereby comprising a heterogeneous population. Therefore, the present hierarchical development model of the hematopoietic system may be reconsidered. Appropriate transcription regulators and epigenetic influences are required for cell differentiation. To this end, transcription factors, such as GATA1 for erythropoiesis and PU.1 for myelopoiesis, have been believed to play key roles at the initiation of hematopoietic cell differentiation. However, the mechanisms controlling the expression of these transcription factors are controlled, and the points at which the lineage commitments occur from hematopoietic stem cells through to progenitor cells are not fully elucidated. As per the findings of this study, we propose that the regulation of transcription and epigenetic factors are central events in hematopoietic cell differentiation. PMID- 30305486 TI - [Updated human hematopoietic stem cell findings: purification of human hematopoietic stem cells and elucidation of their hierarchy]. AB - Hematopoietic stem cell (HSC) biology is a current topic of interest having significant implications for clinical HSC transplantation and basic HSC research. It was long believed that the most primitive HSCs in mammals, including those in mice and humans, were CD34 antigen-positive (CD34+) cells. However, Nakauchi et al. reported that murine long-term lymphohematopoietic reconstituting HSCs were lineage marker-negative (Lin-) c-kit+Sca-1+CD34-low/negative (CD34low/-), known as CD34low/-KSL cells. We have previously identified very primitive human cord blood (CB) -derived CD34-negative (CD34-) severe combined immunodeficiency (SCID) -repopulating cells (SRCs) utilizing an intra-bone marrow injection method and have proposed a new concept that CD34-SRCs (HSCs) reside at the apex of human HSC hierarchy. Recently, we developed an ultra-high-resolution purification method using the two positive/enrichment markers CD133 and GPI-80 and succeeded in purifying CD34+/-HSCs on a single-cell level. On the basis of these data, we propose a revised roadmap for the commitment of human CD34-HSCs. This review updates the concept of the stem cell nature of human CB-derived primitive CD34+/ HSCs. PMID- 30305488 TI - [Risk assessment of age-associated diseases using telomere and microRNA technologies]. AB - Prevention and early detection of age-associated diseases are critical to achieve healthy longevity among the super-aged individuals. To this end, technology that can assess the risk of diseases before onset and that can detect diseases at an early stage for early treatment intervention is essential. Technology that measures telomere G-tail length can be used to examine the risk of age-associated diseases, while miRNAs may serve as a novel diagnostic marker for the early detection of diseases, such as cancer and dementia. In this review, the potential of telomere and microRNA technologies as disease risk assessment tools is explored. PMID- 30305489 TI - [Niche signals regulate differentiation and functions of tissue resident macrophages]. AB - Emerging evidence has revealed that tissue-resident macrophages (TRMs) are differentiated from fetal precursors, including yolk sac macrophages, and late erythro-myeloid progenitors (EMPs) derived from fetal monocytes. Furthermore, TRMs can locally undergo self-renewal independent of circulating bone marrow derived monocytes. Recent data has indicated the existence of a TRM niche that controls TRM differentiation, maintenance, and diversification. Niche availability and accessibility for different TRM precursors determine the cell origin of each TRM. Furthermore, the TRM niche in each organ induces epigenetic and gene expression programing to develop the specific functions of each TRM, which are critical for homeostasis maintenance in the corresponding organs. In this review article, we discuss the recent findings concerning TRM differentiation and maintenance from the perspective of TRM niche function. PMID- 30305490 TI - [Strategical consideration of the interaction between tumor microenvironment and tumor immunity]. AB - In cancer immunotherapy, the importance of tumor microenvironment (TME) has recently been highlighted. TME, where trafficked T lymphocytes with tumoricidal activity, particularly endowed by dendritic cells in the sentinel lymph nodes, suppress cancer cells, consists of multiple cellular components, such as fibroblasts, macrophages, myeloid-derived suppressor cells, monocytes, neutrophils, regulatory T cells, and NK cells, and non-cellular components, such as extracellular matrix and blood and lymphatic vessels. These stroma-forming components have been demonstrated to be mutually interrelated and to provide pro cancer propensity. The recent clinical success of immune checkpoint inhibitors in cancer treatment has again highlighted the importance of controlling the immunosuppressive milieu of TME to achieve an improved clinical outcome. Simultaneously, understanding the unsuccessful clinical efficacy mediated by adoptively transferred cancer antigen receptor gene-modified T cells against solid tumors has similarly drawn a conclusion. This review presents some recent and notable progresses in cancer immunotherapy, thus aiming at an opportunity to understand the interrelation between tumor immunity in cancer-bearing host and TME. PMID- 30305491 TI - [Ex vivo platelet production from induced pluripotent stem cells]. AB - Platelet transfusion products derived from induced pluripotent stem cells (iPSCs) have been pursued as a blood donor-independent and genetically manipulative measure to complement or as an alternative to current platelet products. Platelets are enucleate blood cells indispensable for hemostasis. Thus, platelet transfusions have been clinically established to treat patients with severe thrombocytopenia. However, current blood products face issues in the balance of supply and demand, alloimmune responses, and infections and are expected to meet the shortage of donors in aging societies. iPSc-derived platelet products are qualitatively and quantitatively approaching a clinically applicable level, owing to advances and novel findings in expandable megakaryocyte cell lines, turbulence incorporating bioreactors, and reagents that enable feeder cell-free production and improve platelet quality. Currently, the establishment of guidelines to assure the quality of iPSC-derived blood products for clinical application is in process. Considering the low risk of tumorigenicity and the large demand, ex vivo production of iPSC-derived platelets could lead to iPSC-based regenerative medicine becoming a common clinical practice and the development of a future system in which anyone can safely receive a platelet transfusion in their time of need. PMID- 30305492 TI - [Hepatitis E in patients with hematological disorders]. AB - Hepatitis E virus (HEV), a causative agent of hepatitis E, is indigenous to Japan, and pigs and wild boars are established as primary reservoirs of HEV. As HEV is present in the circulating blood of infected hosts, blood-borne HEV transmission is possible. Patients with hematological disorders are at considerable risk of transmission from blood-borne sources. Although HEV viremia is typically transient, cases of chronic HEV infection are increasingly reported in immunocompromised patients, including solid-organ transplant recipients and patients with hematological disorders. In Japan, although nationwide studies have reported the presence of chronic HEV infection in solid-organ transplant recipients, no such study has been conducted on patients with hematological disorders, including those after hematopoietic stem cell transplantation (HSCT). To date, at least 13 cases with hematological disorders acquiring HEV infection have been reported in Japan, mostly through blood transfusion, including those with chronic hepatitis E and fatal fulminant hepatitis E. Thus, clinicians should be aware of the potential for HEV to present as either acute or chronic infection, with mild or absent clinical symptoms. Overall, HEV testing should be considered in at-risk immunosuppressed patients with hematological disorders, even when the liver function test reveals only moderate elevation or should better be performed as part of routine testing. PMID- 30305493 TI - [Implementing next-generation sequencing for precision hematology/oncology]. AB - In January 2015, President Obama announced his plan to launch the Precision Medicine Initiative. While precision medicine originally refers to a medical model wherein treatments are tailored to individual patients based on their lifestyle, genetic background, and other molecular and physiological test results, genomics-based oncology is most advanced in terms of clinical implementation. Herein, I discuss the benefit of cancer genome sequencing in the field of hematology/oncology and the associated technical and sociomedical challenges. PMID- 30305494 TI - [Current basic understanding and clinical application of mesenchymal stromal/stem cells]. AB - Mesenchymal stromal/stem cells (MSCs) exhibit various biological characteristics, including immunomodulation, tissue regeneration, anti-inflammation, and hematopoietic support. Extensive efforts have been made toward the development of cell therapy using MSCs to treat various diseases. In Japan, off-the-shelf allogeneic human bone marrow-derived MSC products from third-party donors are clinically available for treating patients with steroid-resistant/refractory acute graft-versus-host disease (GVHD). In this manuscript, we present an overview of the current status of clinical development of MSC-based cell therapy and the basic understanding of MSCs. We also introduce a novel approach to obtain the anti-GVHD effect utilizing bone marrow MSC-derived extracellular vesicles. PMID- 30305495 TI - [Cancer therapy using bispecific antibodies]. AB - Bispecific antibodies comprise two antigen-binding sites that recognize different antigens or epitopes. Blinatumomab, a bispecific T-cell engager (BiTE) that lacks the Fc portion, recognizes CD19 on B tumor cells and CD3 on T cells and induces the T cell-mediated killing of the B tumor cells. The Food and Drug Administration has approved the use of blinatumomab for the treatment of precursor B-cell acute lymphoblastic leukemia (ALL) with minimal residual disease and relapsed/refractory ALL. Various bispecific antibodies have been developed, including BiTEs that target surface molecules on myeloma cells or intracellular antigens presented on the major histocompatibility complex and Fc portion containing bispecific antibodies that have a potent T cell-activating capacity and a long half-life. These efforts could lead to the development of potent, off the-shelf bispecific antibodies for the treatment of a broad array of hematological malignancies. PMID- 30305496 TI - [Chimeric antigen receptor T cell (CAR-T) therapy for refractory/relapsed hematological malignancy]. AB - Anti-tumor drugs have been the mainstay of cancer treatment; however, immunotherapy has been considered as supplementary, often less effective, and associated with toxicity. However, over the recent years, new types of immunotherapies have been developed, some of which are proving pivotal in current cancer treatment. Of these, chimeric antigen receptor T (CAR-T) cell therapy represents one of the promising types of immunotherapy, particularly for B lineage malignancy treatment. Notably, many researchers are utilizing this technology for other types of cancer as well. Although it has some drawbacks such as lethal side-effects and extremely high costs, CAR-T cell therapy is estimated to be a potential game changer in the field of cancer treatment. This review provides an overview of the current status and future prospects of CAR-T therapy. PMID- 30305498 TI - [Clonal hematopoiesis in aplastic anemia]. AB - Aplastic anemia (AA) is an autoimmune-mediated bone marrow failure syndrome. While AA is not a malignant disease, clonal hematopoiesis is commonly detected via next-generation sequencing and single nucleotide polymorphism (SNP) array. Clonal hematopoiesis in AA has been confirmed by the detection of classic X chromosome skewing, PNH clones, UPD6p, and various mutations. The most frequent genetic events in AA are UPD6p and somatic mutations in BCOR/BCORL1, PIGA, DNMT3A, and ASXL1. While some mutations are common between patients with AA and healthy elderly donors, UPD6p and PIGA mutations are specific to clonal cells in AA, which need to manage their highly autoimmune extrinsic environment. During the evolution of AA into myelodysplastic syndrome (MDS), additional genetic events are frequently acquired that provide MDS cells with intrinsic survival benefits. Hematopoietic cells in AA appear to achieve clonal expansion by their escape from recognition and cytotoxicity by CD8 T-cells, accounting for the distinct landscape of genetic events observed in AA. PMID- 30305497 TI - [Inflammation and early hematopoiesis]. AB - Lifelong, self-renewing, and, multilineage-differentiating hematopoietic stem cells (HSCs) gradually divide in steady-state bone marrow (BM). Conversely, in cases of hematopoietic stress, including infection and inflammation, hematopoiesis is highly demanded due to massive cell consumption in the stressed tissues and involves HSC recruitment to fulfil the hematopoietic demand. Accumulating evidence indicates that infection-related inflammation acts on blood forming HSCs and progenitors within the BM to facilitate hematopoiesis for self defense. In this review, we discuss the mechanisms used by various inflammatory responses involving not only HSCs but also the niche cells in the BM, a site that has long been considered an immune-privileged organ. PMID- 30305499 TI - [Treatment strategy for acquired aplastic anemia]. AB - "The guidelines for the diagnosis and treatment of aplastic anemia (AA) in Japan" have recently been revised. Former stage 2 has been divided into stage 2a, which does not require red blood cell (RBC) transfusions, and stage 2b, which requires <2 units of RBC transfusions per month. In addition, the guidelines recommend treating stage 2b similar to stages 3 or higher severity. The standard immunosuppressive therapy for transfusion-dependent AA has been changed from ATG plus cyclosporine (CsA) to ATG+CsA+eltrombopag. For patients with stage 1 and stage 2b AA, initiating CsA as early as possible after the diagnosis is recommended. Notably, high-dose (200 mg/kg) cyclophosphamide (CY), which has been used as the standard conditioning regimen for allogeneic stem cell transplantation (SCT), is less frequently used than a reduced-dose CY regimen that contains fludarabine for avoiding cardiotoxicity. Among transplant regimens from alternative donors, HLA-haploidentical SCT from related donors using post transplant CY is presently garnering recognition because of its low transplant related mortality and the low incidence of chronic GVHD. PMID- 30305500 TI - [Molecular pathophysiology of sideroblastic anemia]. AB - Sideroblastic anemias (SAs) are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ring sideroblasts in bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations in genes that are involved in heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The most common form of CSA is X-linked sideroblastic anemia; it occurs because of mutations in the erythroid specific delta-aminolevulinate synthase gene (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. Additionally, SAs can occur after exposure to certain drugs or alcohol and with copper deficiency (secondary SA) ; they are also detected in association with myelodysplastic syndrome (idiopathic SA). Among all types of SAs, idiopathic SA is the most common form. This review encompasses the current understanding of the molecular pathophysiology of SA. PMID- 30305501 TI - [Incorporation of novel agents into the treatment for acute myeloid leukemia]. AB - The mainstay of therapeutic modalities of acute myeloid leukemia (AML) includes intensive chemotherapies and allogeneic hematopoietic cell transplantation. The gold standard of the induction treatment is a regular dose of cytarabine plus anthracycline, and several courses of consolidation therapy are administered. Allogeneic hematopoietic cell transplantation is employed in patients with intermediate-poor risks. No new drugs have been introduced to the treatment of AML for nearly 30 years. However, in 2017, the US Food and Drug Administration approved four novel drugs for treating AML: FLT3 inhibitor midostaurin, IDH2 inhibitor enasidenib, liposomal cytarabine-daunorubicin CPX-351, and revived antibody-drug conjugate gemtuzumab ozogamicin. In Japan, several new agents are also undergoing clinical trials, including Bcl-2 inhibitor venetoclax, CDK9 inhibitor alvocidib, smoothened (SMO) inhibitor glasdegib, hypomethylating agents guadecitabine and azacitidine, NEDD8 inhibitor pevonedistat, and FLT3 inhibitors quizartinib and gilteritinib. These agents will be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents or low-dose cytarabine to improve the therapeutic outcomes of AML. PMID- 30305502 TI - [Molecular pathogenesis and treatment of core binding factor-acute myeloid leukemia]. AB - Core binding factor-acute myeloid leukemia (CBF-AML) comprises AML with t (8;21) (p22;q22) and inv16 (q16q16) /t (16;16) (q16;q16) and accounts for 20% of AML cases. The 2016 WHO classification categorized CBF-AML under AML with recurrent genetic abnormalities and considered it as a favorable risk group with a higher remission rate and better overall survival with high-dose cytarabine post remission therapy. However, relapse occurs in approximately 40% of patients, thereby necessitating the establishment of risk stratification and risk-adapted therapy in CBF-AML. In CBF-AML, activating kinase mutations in KIT, FLT3, and NRAS have frequently been detected, and their clinical impact on the prognosis has been discussed for a decade. Recent clinical trials have evaluated the clinical significance of minimal residual disease (MRD) and the efficacy of molecular-targeted therapy to enhance the outcome. However, recent comprehensive genetic studies have revealed several additional genetic alterations in CBF-AML. While t (8;21) -AML and inv (16) -AML have different characteristics in coexisting gene mutations, their biological and clinical significance remain largely unknown. Overall, CBF-AML is a genetically and clinically heterogeneous disease entity, and it is imperative to elucidate its leukemogenesis and the mechanisms of resistance to develop a new treatment strategy based on the molecular basis. PMID- 30305503 TI - [State-of-the-art treatment of acute promyelocytic leukemia]. AB - Acute promyelocytic leukemia (APL) with PML-RARA is an acute myeloid leukemia (AML) with a predominance of abnormal promyelocytes. Both hypergranular (typical) and microgranular (hypogranular) types exist. Previously, APL was associated with an extremely high mortality rate due to hemorrhage. However, since the advent of anthracycline, all-trans retinoic acid (ATRA) has been introduced into therapy, resulting in the transformation of APL into AML with a higher probability of cure. Furthermore, for the last 30 years, molecular-targeted drugs, such as arsenic acid (ATO), tamibarotene (Am80), and gemtuzumab ozogamicin (GO), have been developed in succession in addition to ATRA. In recent years, molecular targeted drugs with different mechanisms of action are being combined, and the APL treatment outcome is revolutionary. In this review, we introduce previously used APL therapies and those at the forefront of APL treatment. PMID- 30305504 TI - [Strategy for treatment of acute lymphoblastic leukemia]. AB - The treatment outcomes of adult acute lymphoblastic leukemia (ALL) have improved. Furthermore, the introduction of pediatric specific therapies has enhanced ALL treatment results in adolescents and young adult (AYAs). Age-related molecular signatures have also been identified, such as Philadelphia chromosome (Ph)-like ALL and DUX4/ERG gene-associated ALL. The measurement of minimal residual disease (MRD) has enabled the early detection of patients susceptible to relapse, and they become candidates for hematopoietic stem cell transplantation (HSCT). However, new generation tyrosine kinase inhibitor (TKI) therapy has enabled the avoidance of HSCT in Ph-positive ALL cases. Novel agents targeting CD19 and CD22 molecules will be available in the near future that should improve treatment outcomes in patients newly diagnosed with ALL. PMID- 30305505 TI - [Current management of adult Philadelphia chromosome-positive acute lymphoblastic leukemia]. AB - Tyrosine kinase inhibitors (TKIs) have improved the response and survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) (Ph+ALL). Although the second and third generation TKIs are expected to greatly enhance treatment outcomes, no study has demonstrated the inferiority of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to chemotherapy combined with TKIs in any subgroup of adults with Ph+ALL. Because the PCR-based detection of minimal residual disease (MRD) is easy and reliable, physicians can judge the level of treatment response. Recently, the molecular genetics risk factors of Ph+ALL in the TKI era have been revealed. These diagnostic advancements have enabled physiciansto precisely evaluate the disease risk before commencing initial treatment and to select the most suitable therapy via MRD monitoring during the treatment. Currently, new antibody therapies have been included as candidate therapies for Ph+ALL. This review discusses available treatments for adult patients with Ph+ALL. PMID- 30305506 TI - [Dyserythropoiesis in myelodysplastic syndrome]. AB - Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis including dyserythropoiesis. Recently, several signaling pathways have been implicated in dyserythropoiesis in MDS, such as the p53-S100A8/9-TLR4 pathway, which is involved in ineffective erythropoiesis in 5q- syndrome. Somatic mutations that target SF3B1, which encodes a component of the mRNA splicing machinery, have been identified in approximately 85% of patients with MDS presenting with ring sideroblasts (MDS-RS). SF3B1 mutations confer a change-of function and cause aberrant splicing of genes that may be involved in the pathogenesis of MDS-RS. Recurrent mutations have also been identified in epigenetic regulator genes in MDS, including polycomb repressive complex 2 (PRC2) genes, and the loss of Ezh2, an enzymatic component of PRC2, enhances ineffective hematopoiesis and induces impaired erythropoiesis. A better understanding of the molecular mechanisms underlying dyserythropoiesis in MDS may lead to innovative novel therapeutic modalities. PMID- 30305507 TI - [Myelodysplastic syndromes and iron metabolism]. AB - Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis in bone marrow and cytopenias in peripheral blood. In patients with MDS, iron overload is frequent due to red blood cell transfusions and ineffective erythropoiesis. Dysplastic erythroblasts in MDS secrete humoral factors such as erythroferrone, which suppress hepatic expression of hepcidin. Hepcidin is the key regulator of systemic iron homeostasis, and suppression of hepcidin expression leads to an increase in iron absorption from the intestines, exacerbating systemic iron overload. Patients with MDS with ring sideroblasts (MDS-RS) are prone to iron overload, with most harboring splicing factor 3B subunit 1 (SF3B1) mutations in hematopoietic cells. SF3B1 mutations may induce ring sideroblasts by downregulating ATP binding cassette subfamily B member 7, which exports iron-sulfur clusters from the mitochondria to the cytoplasm. Iron overload in MDS causes hepatic dysfunction, diabetes, cardiac failure, and atherosclerosis, whereas excess iron may suppress normal hematopoiesis. Though randomized control studies are lacking, results from retrospective and cohort studies indicate that iron chelation therapy is appropriate for lower-risk MSD patients with transfusion-related iron overload, although it is not recommended for higher-risk MSD patients with short life expectancy. PMID- 30305508 TI - [Treatment for low-risk myelodysplastic syndromes]. AB - Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenia and leukemic transformation. Allogeneic hematopoietic stem cell transplantation is the only potential curative therapy for MDS; however, the first treatment option for transfusion-independent patients with low risk MDS remains limited. Recently, lenalidomide has become available for patients with low-risk MDS and symptomatic anemia with del (5q) (5q-syndrome), darbepoetin (DA) for those with anemia without del (5q), and azacitidine for those with DA-resistant anemia or anemia with thrombocytopenia. DA may be the first treatment option for anemic patients with low-risk MDS because the incidence of 5q-syndrome is rare in Japan in contrast to western countries. It has been reported that primary or secondary failure of Erythropoiesis-stimulating agents (ESA) correlated with a higher risk of acute myeloid leukemia, and none of the leading second-line treatments significantly improved survival. In this review, I have described the treatment strategies in using such drugs and future perspectives for low-risk MDS. PMID- 30305509 TI - [Novel therapies for higher-risk myelodysplastic syndromes]. AB - Recent advances in drug treatment for higher-risk myelodysplastic syndromes (MDS) have focused on DNA hypomethylating agents (HMAs). Azacitidine (AZA), a representative HMA available in Japan, has demonstrated a survival benefit over conventional treatment. However, unsatisfactory treatment profiles of AZA exemplified by a low response rate of <20% complete remission (CR), a short duration of response (usually <1 year), and dismal outcomes after the failure to fulfil unmet needs in AZA treatments have highlighted the urgent need for the development of novel therapeutic modalities. In this manuscript, an array of novel agents under clinical investigation for higher-risk MDS is introduced. The drugs in the most advanced phase of development include SGI-110, a next generation DNA hypomethylating agent that is designed to prolong cellular exposure time, and the multi-kinase inhibitor rigosertib, which is specifically active against patients with higher-risk MDS who fail to respond to conventional HMAs. Other lines of agents under investigation include a combination of histone deacetylase inhibitors and hypomethylating agents, immune checkpoint inhibitors, spliceosome inhibitors, BCL2 inhibitors, and IDH1/2 inhibitors, all of which have been developed by exploiting the recent understanding of the molecular pathogenesis of MDS, including the tumorigenic role of common mutations and disturbance of tumor immunity. PMID- 30305510 TI - [The role of HMGA2 in myeloproliferative neoplasms]. AB - Myeloproliferative neoplasms (MPNs) are characterized by the activation of the JAK-STAT pathway due to driver mutations, including JAK2V617F, but some additional abnormalities may be necessary to maintain an MPN clone and develop a more advanced disease. The HMGA2 proto-oncogene, which regulates the expression of various genes, is often overexpressed due to downregulation of let-7 microRNAs or EZH2 mutations in advanced MPNs such as myelofibrosis. In mice with JAK2V617F, Ezh2 deletion deregulates Hmga2, which plays a crucial role in MPN progression. Correspondingly, Hmga2 overexpression causes massive splenomegaly and severe anemia in mice carrying JAK2V617F, mimicking severe MPN. Herein, we discuss the mechanisms of HMGA2 deregulation and its possible use as a therapeutic target. PMID- 30305511 TI - [Pathogenesis of myeloproliferative neoplasms: insights from mouse models]. AB - One of the main molecular features of myeloproliferative neoplasms (MPNs) is the high frequency of JAK2V617F or CALRexon 9 mutations. The mouse models driven by these mutations suggest that they are the direct cause of MPNs and that the expression levels of mutated genes define the disease phenotype. The function of MPN-initiating cells was also elucidated using these mouse models. Furthermore, these mouse models play important roles as disease models to investigate the effects and mechanisms of action of therapeutic drugs such as JAK2 inhibitors and interferon alpha against MPNs. The mutation landscape of hematological tumors has already been clarified using next-generation sequencing technology, and future research on the importance of the functional analysis of mutant genes in vivo should be emphasized. Thus, it is necessary to promote rapid genetic modification techniques such as genome editing. PMID- 30305512 TI - [Myelodysplastic/myeloproliferative neoplasm: a histopathological review]. AB - Myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) is a type of myeloid neoplasm where at least one hematopoietic lineage exhibiting cytopenia clinically coexists with other (s) exhibiting hypercytosis. There is ineffective erythropoiesis and bone marrow coexistence of at least one hematopoietic lineage morphologically characterized by dysplasia of blood cells and other (s) characterized by pronounced proliferation. At a molecular level, various abnormalities have been identified that overlap with related diseases, and a prerequisite for MDS/MPN diagnosis includes ruling out various hematopoietic tumors and reactive conditions. Therefore, a multilateral approach involving clinical findings, morphology, and molecular biology is needed. Herein, we introduce the pathological features of MDS/MPN and the relationship between molecular abnormalities and morphological characteristics. PMID- 30305513 TI - [Adverse events of ABL tyrosine kinase inhibitors in chronic myeloid leukemia therapy]. AB - Fatal events during treatment with ABL tyrosine kinase inhibitors (ABL TKIs) have been reported, and there have been concerns of high mortality rate in patients with chronic myeloid leukemia receiving ABL TKIs. The predictive factors of patients treated with ABL TKIs who are at risk of potentially fatal toxicities remain unknown. Although this scenario appears discouraging, the risk of severe toxicity might be predicted by investigating the effect of genetic variation on the disposition of ABL TKIs. Global genomic surveys should be conducted to identify factors contributing to an increased risk of toxicity using multivariable analyses with particular reference to ABL TKIs pharmacokinetics and baseline clinical characteristics. PMID- 30305514 TI - [Tyrosine kinase inhibitor therapy discontinuation for chronic myelogenous leukemia to achieve clinical cure: current status and future perspectives]. AB - Tyrosine kinase inhibitors (TKIs) markedly improve the prognosis of patients with chronic myelogenous leukemia (CML) by potentially helping to achieve a deep molecular response (DMR). In many clinical trials, beginning with the French Stop Imatinib (STIM1) trial, approximately 40%-60% patients with chronic CML who sustained a long DMR could discontinue TKI therapy and achieve long-term treatment-free remission (TFR). These trials have proposed many predictive factors for successful TKI therapy discontinuation, including deeper molecular response, longer duration of DMR and lack of TKI resistance prior to the discontinuation, and greater numbers of natural killer (NK) cells during the discontinuation. However, further investigations are necessary because only 20% 30% patients with chronic CML could achieve TFR. Recent studies have suggested that the recovery and reconstitution of immune effector cells against CML, including NK cells, and the elimination of CML cells using aberrant clones that are resistant to TKI are crucial for successfully achieving DMR and subsequent TFR. CML stem cells are not sensitive to TKI and could potentially interfere with TFR. Therefore, therapies targeting CML stem cells are being investigated, and the results are highly anticipated. PMID- 30305515 TI - [Follicular lymphoma: recent advances]. AB - Follicular lymphoma (FL) is a neoplasm comprising germinal center B cells, which typically has, at least, a partially follicular pattern. Although the natural course of the disease is indolent, the chemosensitivity is low, which results in frequent relapse and immunosuppression. Therefore, the tumor stage and tumor burden are essential criteria for deciding on the treatment strategy. For advanced-stage patients with a low tumor burden, watchful waiting is a standard option. The optimal timing for administrating rituximab is a critical clinical question. For advanced-stage patients with a high tumor burden, R-CHOP, R-CVP, and BR are the standard options. Recently, the second-generation CD20 antibody was added to the options. Several new agents are now under development for relapsed FL. PMID- 30305516 TI - [Treatment strategy for high-grade B-cell lymphoma]. AB - High-grade B-cell lymphoma (HGBL) is a newly defined entity in the latest WHO classification. HGBL is classified into two categories as follows: HGBL with MYC and BCL2 and/or BCL6 [so-called "double-hit" (DH)] rearrangements; and HGBL, not otherwise specified. At present, no standard induction treatment regimen and treatment strategy, including the role of upfront stem cell transplantation, exist for patients with HGBL. As the prognosis of patients with HGBL, especially those with DH, who were treated with R-CHOP therapy is relatively poor, recently several retrospective and prospective studies have been conducted. Thus, this session aims to review the clinical data and consider the reasonable treatment strategy for patients with HGBL. PMID- 30305517 TI - [Treatment strategy for newly diagnosed Hodgkin lymphoma: current evidence]. AB - Interim positron emission tomography (PET) -guided therapy and brentuximab vedotin (BV) combined systemic chemotherapy have been developed for newly diagnosed classical Hodgkin's lymphoma (cHL). A majority of recent trials using interim PET response-adapted approaches have assessed the treatment strategies for cHL and reported that the initial treatment could be suitably altered to intensive treatment in an early phase, thereby enhancing the efficacy in interim PET-positive patients, whereas the simplified treatment regimen, such as omitting drugs or radiation, could minimize the risk of toxicity in interim PET-negative patients. This review includes the current evidence primarily focusing on randomized clinical trials including patients with newly diagnosed cHL to investigate the efficacy and safety of interim PET-guided therapy or BV combined regimen and also mentions that issues. PMID- 30305518 TI - [Genetic analysis and its clinical implication in adult T-cell leukemia/lymphoma]. AB - Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. This disease is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. Not only viral proteins, such as Tax and HBZ, but also additional genetic and epigenetic aberrations, including gain-of-function alterations in the components of T-cell receptor/NF-kappaB pathway or deteriorating alterations responsible for immune surveillance, are essential for ATL development and progression. Furthermore, recent investigation has demonstrated the effects of genetic and epigenetic alterations prevalently identified in ATL on the disease phenotype and its clinical outcomes. Aggressive ATL is associated with an increased burden of genetic and epigenetic abnormalities. Higher frequencies of TP53 and IRF4 mutations and several copy number alterations, including PD-L1 amplifications and CDKN2A deletions, are more predominant in aggressive than indolent diseases. In contrast, STAT3 mutations are more frequent in indolent ATL. Several genetic alterations, such as PD-L1 amplification, can predict the clinical outcomes independent of established clinical factors. Therefore, ATL subtypes can further be subdivided into genetically distinct subgroups with different prognoses. The genetic profiling of ATL cases has revealed its molecular pathology and should contribute to improved prognostication and management of patients with ATL. PMID- 30305519 TI - [Current status and future directions of ATL]. AB - Patients with adult T-cell leukemia/lymphoma (ATL), which is caused by human T cell lymphotropic virus type 1, exhibit an extremely poor prognosis. ATL was first reported in 1977 in Japan as a distinct T-cell neoplasm, and its basic and clinical research have been led by Japanese investigators. This study aims to review the scenario since the discovery of ATL/HTLV-1 to the current status of ATL research and medicine and to consider its future directions. PMID- 30305521 TI - [Methods and clinical values for minimal residual disease detection in patients with multiple myeloma]. AB - The complete response (CR) rates in patients with multiple myeloma (MM) have been rapidly increasing after the approval of novel agents such as proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies. Recently, patients administered with a combination of novel agents with autologous stem-cell transplantation achieved a 70% CR rate. The assessment of minimal residual disease (MRD) is necessary for effective stratification of the CR cases and the generation of accurate prognoses. This review summarizes recent topics pertaining to MRD detection methods (multiparameter flow cytometry, allele-specific oligonucleotide real-time quantitative polymerase chain reaction, droplet digital PCR, and next-generation sequencing) and the prognostic value of MRD assessment in patients with MM. PMID- 30305520 TI - [Revision of JSH Guideline for Tumors of Hematopoietic and Lymphoid Tissues 2018: lymphoma]. AB - The Japanese Society of Hematology has revised its clinical practice guidelines for Tumors of Hematopoietic and Lymphoid Tissues, and this version will be published in 2018. In the lymphoma section, the revised 4th edition (2017) of the WHO classification was adopted and reflected in all issues. The descriptions of all clinical questions (CQs) were thoroughly updated according to the latest published studies. The CQs were modified to reflect recent progress in the treatment of follicular, diffuse large B-cell, and Hodgkin lymphomas. Some of the treatment algorithms were amended aiming to become more useful tools in clinical practices. Because of rapid advances in lymphoma treatment, continuous revision of these clinical practice guidelines is critical. PMID- 30305522 TI - [Role of novel proteasome inhibitors in the treatment of relapsed/refractory multiple myeloma]. AB - Multiple myeloma (MM) is a mature plasma cell neoplasm characterized by the excessive production of monoclonal antibodies and various cytokines. Therefore, MM cells are highly dependent on the ubiquitin-proteasome pathway and the well differentiated unfolded protein response in the endoplasmic reticulum. Bortezomib, the first approved proteasome inhibitor (PI) for the treatment of MM, is widely used as a therapeutic agent for patients with MM, including newly diagnosed and relapsed/refractory (RR) cases. However, severe peripheral neuropathy and gastrointestinal disorders often occur during bortezomib treatment, which leads to inadequate treatment of MM owing to the interruption or reduction in bortezomib administration. Novel PIs, carfilzomib and ixazomib, have been developed as less toxic and more effective PIs than bortezomib, and these novel PIs are expected to be potent options for the treatment of RR MM. The use of novel PIs, which is based on the characteristics of each agent and the condition of each patient, is considered an effective treatment, and it can improve the outcomes in patients with RR MM, particularly those who cannot tolerate bortezomib. PMID- 30305523 TI - [Immunopathogenesis and appropriate use of monoclonal antibody agents in multiple myeloma]. AB - Multiple myeloma (MM) involves the immune dysregulation not only of B cells but also of NK, T, and dendritic cells. Furthermore, the number of regulatory T and myeloid-derived immunosuppressive cells, which are associated with disease progression, also increases. Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide exhibit an antimyeloma effect and improve the immune status. Thus, IMiD-enhanced antibody-dependent cell cytotoxicity increases the cytotoxic activity of monoclonal antibody treatment. Among many antibodies, anti-SLAMF7 elotuzumab and anti-CD38 daratumumab have been approved in Japan, and their targeted antigens are responsible for functions that may influence clinical efficacy. Daratumumab exerts various mechanisms of antitumor activity and enhances T-cell immunity by inhibiting immunosuppressive cells. New monoclonal antibodies, including the anti-CD38 antibody isatuximab and anti-BCMA antibody drug conjugate, are being developed and are expected to demonstrate clinical efficacy. To improve long-term prognosis and achieve cure for MM, immunotherapies such as IMiD-intensified antibody treatment, which resulted in better response rates and longer survival in refractory/relapsed MM, are essential. PMID- 30305524 TI - [Treatment strategy for relapsed or refractory myeloma according to the new Guidelines]. AB - The development of novel agents for treating multiple myeloma (MM) has markedly improved the treatment outcome and has caused a major paradigm shift in treatment strategies. In Japan, bortezomib and lenalidomide have been approved for the initial treatment; additionally, seven novel drugs, including next-generation proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies, have been approved for relapsed and/or refractory MM treatment. Of these novel agents, daratumumab-containing regimens have been reported to induce a deep response, such as minimal residual disease-negative status, even in relapsed patients. Thus, compared with the initial therapy, many efficacious choices are available for treatment at the time of MM relapse; and salvage therapy is currently considered to be the most important treatment strategy for MM. In clinical practice, it is desirable to consider patient, disease, and therapeutic factors to make an optimal treatment decision for each patient. PMID- 30305525 TI - [Chimeric antigen receptor T-cell therapy for multiple myeloma]. AB - CAR T-cell therapy is a novel cancer immunotherapy targeting cancer-specific cell surface antigen. CD19-CAR T cells have been demonstrated to be highly efficacious in treating B-cell leukemia/lymphoma. Currently, several researchers are developing CAR T cells for multiple myeloma. In some early-phase clinical trials, CAR T cells targeting B-cell maturation antigen have exhibited promising efficacy. Recently, we reported that CAR T cells targeting the activated integrin 7 can selectively eradicate MM cells including CD19+ clonotypic B cells; a clinical trial for further assessment regarding this study is in process. PMID- 30305526 TI - [The forefront of primary immunodeficiencies]. AB - Primary immunodeficiencies (PIDs) are inherited disorders caused by an impaired immune system. Because the immune system effects various immune reactions, PIDs present various clinical phenotypes including increased susceptibility to infections, autoimmunity, and malignancies. For adequate diagnosis of PIDs, a systematic approach using clinical genetic sequencing is required. New technologies including next-generation sequencing have become widely available and have led to the identification of novel genetic defects underlying PIDs. In the clinical setting, the identification of genes responsible for impaired immune system function for each PID enables the proposition of more disease-specific treatment options that target the affected signaling pathway. Research on PIDs not only benefits clinical treatment, it also provides a deeper understanding of the human immune system. PMID- 30305527 TI - [Primary immunodeficiency and inherited bone marrow failure syndrome in adults]. AB - Primary immunodeficiency is a group of heterozygous disorders with intrinsic defects in immune cells or molecules associated with immune function. Inherited bone marrow failure syndrome is characterized by at least one defective hematopoietic cell lineage. Clinical symptoms in these patients are usually observed in childhood, but the symptoms may infrequently first occur in adulthood. Although these patients tend to develop autoimmune diseases and cancer in adulthood, recent treatment advances can ensure long-term survival. Therefore, diagnosis should not be delayed, and disease management with a view to lifelong treatment should have a long-term outlook. Therefore, we need to fully understand the pathogenesis of associated underlying complications. PMID- 30305529 TI - [Diagnosis and management of von Willebrand disease]. AB - von Willebrand disease (VWD) is an inherited bleeding disorder resulting from either a quantitative or a qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). A diagnosis of VWD can be made when a patient presents with appropriate bleeding and VWF <30 IU/dl. However, persons with VWF levels of 30-50 IU/dl cannot be precluded from the diagnosis of VWD. Desmopressin acetate (DDAVP) or VWF-containing factor VIII (pdVWF/FVIII) concentrate is used for treating VWD. The effect of DDAVP varies among individuals; a trial should be performed while in a nonbleeding state. For patients in whom DDAVP is invalid or those that require long-term management of hemostasis, pdVWF/FVIII is administered. The treatment of the hype rmenorrhea is the hope of every pregnant patient with VWD. When a patient with VWD becomes pregnant, VWF and FVIII should be regularly monitored throughout pregnancy. During childbirth, pdVWF/FVIII concentrate should be administered to achieve VWF and FVIII levels of >=50 IU/dl before delivery. PMID- 30305528 TI - [Treatment of DIC associated with hematological malignancies]. AB - To improve the prognosis of patients with hematological malignancies, close attention should be paid to major hemorrhage in the clinical management of patients with disseminated intravascular coagulation (DIC) associated with hematological malignancies, especially from diagnosis to induction therapy. Cerebral, alveolar, and GI tract hemorrhages may cause a life-threatening event. Therefore, DIC should always be suspected, and careful observation for hemorrhage and hemostatic examination should be performed. The diagnostic criteria for DIC according to the Japanese Ministry of Health and Welfare and the Japanese Society on Thrombosis and Hemostasis (2017) are useful resources for the diagnosis of DIC associated with hematological malignancies. Following diagnosis, treatment for DIC should be initiated as soon as possible, and the risk of hemorrhage should be considered when choosing the anticoagulant. Sufficient amount of fresh frozen plasma or platelet concentrates should be used if necessary. Recombinant human soluble thrombomodulin has promising potential for use as a drug for the treatment of DIC associated with hematological malignancies that can manage a wide range of pathologic processes such as hypercoagulable states, inflammation, excessive fibrinolysis, and easy hemorrhage caused by endothelial cell damage. PMID- 30305530 TI - [A hemostatic disorder caused by high shear stress: acquired von Willebrand syndrome]. AB - The von Willebrand factors (VWFs) play critical role in hemostasis and thrombosis formation. VWFs are produced in and secreted as large multimers from endothelial cells, and shear stress-dependently cleaved into 2-80 multimers by their specific protease, ADATS13. Because high molecular weight VWFs play important roles in platelet aggregation, the loss of high molecular weight VWFs caused by pathological high-shear stress induces a hemostatic disorder known as acquired von Willebrand syndrome (AVWS) type IIA. The most well-known cause of this loss is aortic stenosis, which is accompanied by gastrointestinal bleeding most often as a result of angiodysplasia; this comprises a condition known as Heyde's syndrome. Additionally, various cardiovascular diseases that generate excessive high-shear stress in the blood stream, such as hypertrophic obstructive cardiomyopathy (HOCM), mitral regurgitation, pulmonary hypertension, and some congenital heart diseases, and mechanical circulatory support systems, such as left ventricular assist device (LVAD), cause AVWS. PMID- 30305531 TI - [Development of gene therapy for hemophilia: current states and future perspectives]. AB - Hemophilia is congenital hemorrhagic disease due to genetic abnormality of blood coagulation factor VIII or factor IX. Hemophilia appears suitable for gene therapy because it is caused by a single gene abnormality, and therapeutic coagulation factor levels vary across a broad range. Since the success of gene therapy eliminates the need for regular administration of factor concentrates, the development has been met with great expectation from patients and their families. In fact, several clinical trials using adeno-associated virus (AAV) vectors have been started in Western countries, and long-term therapeutic effect could be obtained by single injection. More recently, the modifications of therapeutic gene and AAV serotypes have further improved therapeutic effects, and it appears to have reached the level of "cure". However, gene therapy using AAV vectors presents difficulties such as the existence of anti AAV capsid neutralizing antibody and hepatic injury due to cellular immunity with CD8+ T cells. Thus, it is essential to develop technologies adapted to a wide range of hemophilia patients, and to observe long-term safety and therapeutic effect after the gene therapy. PMID- 30305532 TI - [A diagnostic approach to relatively common mild bleeding symptoms: screening of congenital mild bleeding disorders]. AB - Although mild skin and mucosal bleeding symptoms are common in patients with inherited bleeding disorders, both can also be observed in healthy individuals. These bleeding symptoms may be caused by disorders of primary hemostasis (i.e., von Willebrand disease and platelet function disorders), mild deficiencies of clotting factors and some rare hyper fibrinolytic disorders are also included. To date, mild bleeding symptoms pose a frequent and substantial diagnostic challenge, and the definitive diagnosis of inherited bleeding disorders is not feasible in a vast majority of individuals despite an extensive laboratory workup. However, it must be diagnosed precisely to avoid severe complications and decrease bleeding risks before invasive procedures. Thus, a comprehensive diagnostic approach, from structured patient history to highly specialized laboratory diagnosis, is warranted to establish diagnosis of inherited bleeding disorders. Furthermore, the prophylaxis should be offered to prevent excessive bleeding in these patients with bleeding symptoms, even if they remain undiagnose of bleeding disorders. PMID- 30305533 TI - [Severe fever with thrombocytopenia syndrome: epidemiology, pathophysiology, and development of specific treatment and prevention measures]. AB - Severe fever with thrombocytopenia syndrome (SFTS) was first reported in 2011 as an emerging virus infection caused by a novel Phlebovirus in the Bunyaviridae family [SFTS virus (SFTSV)]. In addition, it was reported to be endemic to Hubei, Henan, Shandong, and Heilongjiang provinces in China. The primary symptoms of SFTS are gastrointestinal symptoms such as fever, general fatigue, nausea, vomiting, and diarrhea. The total blood cell counts in patients with SFTS reveal thrombocytopenia and leukopenia. A woman in her 50s died due to multiorgan failure, intestinal hemorrhage, and hemophagocytosis in the autumn of 2012. She was retrospectively diagnosed with SFTS, suggesting that SFTS was endemic not only to China but also to Japan. Subsequently, SFTS was reported to be endemic to South Korea as well. Approximately 5 years have passed since the discovery of SFTS endemicity in Japan. To date, 40-100 patients with SFTS from the western part of Japan have been reported annually to the National Institute of Infectious Diseases. The case-fatality rate of SFTS is approximately 20%. This high case fatality rate could be attributed to multiorgan failure, coagulopathy, and hemophagocytosis, which are induced in most patients with SFTS. Reportedly, an antiviral drug, favipiravir, was effective in treating SFTSV infection in an animal infection model. SFTSV has been found to circulate between wild animals and several species of ticks in nature, suggesting that we cannot escape the risk of infection with SFTSV and that SFTS will continue to occur in endemic areas. Hence, the development of specific treatment and preventive measures with SFTS vaccines is imperative. PMID- 30305534 TI - [Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia]. AB - The pathogenesis of acute myeloid leukemia (AML) is heterogeneous and caused by various chromosomal aberrations, gene mutations or epigenetic modifications, and deregulated or overregulated gene expression, leading to increased proliferation and decreased hematopoietic progenitor cell differentiation. Although most of these aberrations are correlated with prognosis, accurate risk stratification remains challenging even after incorporating these molecular markers. The development of analytical techniques using microarrays and massive parallel sequencing has identified some gene mutations in adult AML, including DNMT3A and TET2 mutations. However, these mutations are rare in pediatric AML cases. However, a considerable amount of gene fusions was detected in pediatric AML, indicating that a different pathogenesis may exist between adult and pediatric AML. To facilitate genome-based treatment, we should revise the risk classification of AML more appropriately, adopting mutations of NPM1, biallelic CEBPA, and KMT2A-PTD and novel gene fusions, including CBFA2T3-GLIS2 and NUP98 JARID1A. Furthermore, new promising molecular-targeted drugs without side effects are recommended to improve the prognosis of AML. PMID- 30305535 TI - [Genetic background and treatment of pediatric ALL]. AB - Molecular genomic studies for acute lymphoblastic leukemia (ALL) have been focused on genetic alterations in leukemic cells, while germline cells are mainly used as a control to identify the somatic mutation. However, recent studies demonstrate that germline mutations may contribute to the pathogenesis of ALL, and currently, the genetic background has been found to play an essential role in the development of pediatric ALL. An association between polymorphism and adverse events has already been reported, and recent genomic analyses of familial ALL cases identified inherited causative genes for ALL. Moreover, non syndromic/familial ALL cases may present pathogenic germline variants in cancer predisposition genes. These variants could not only contribute to poor response to treatment but also lead to an increased risk of secondary neoplasms. Comprehensive understanding of the biology in both ALL cells and germline cells is required. PMID- 30305536 TI - [Therapeutic approaches to hematological malignancies in adolescents and young adults]. AB - Hematological malignancies (HM) comprise the major proportion of the cancer incidence and mortality in the adolescent and young adult (AYA) age group. Even though age-related differences in tumor biology have been reported in HM, further biological studies are warranted for elucidating age-related differences in AYAs. Hemato-oncologists and pediatric oncologists frequently follow various treatment strategies for HM, as the treatment strategy that is more suitable for this age group remains unclear. Recently, the involvement of pediatric oncologists has increased because the advantage of pediatric-type treatment has been demonstrated in acute lymphoblastic leukemia (ALL) and the significance of long-term follow-up has been clarified. However, for HM, except for ALL, the pediatric- and adult type therapy that is more suitable for AYAs remains unclear. This review aimed to describe the challenges in the context of major HM affecting the AYA age group (acute leukemia and lymphoma). For assessing the outcome of AYAs with HM, we need to consider not only the treatment strategy but also other factors such as differences in aging and tumor biology. Furthermore, it is imperative to develop a therapy that resolves psychosocial problems peculiar to AYAs. PMID- 30305537 TI - [Progress in research of the pathogenesis of childhood MDS/MPN]. AB - Recent research reveals novel insights into the pathogenesis of childhood myelodysplastic syndromes (MDS) in addition to that of juvenile myelomonocytic leukemia (JMML). In pediatric MDS, the genetic characteristics of which have been barely elucidated previously, germline mutations, particularly those in GATA2, SAMD9, and SAML9L, have been frequently identified, indicating the importance of germline predisposition in childhood MDS compared with adult MDS. In JMML, in addition to the known Ras-pathway mutations, novel secondary mutations and causative fusion genes have been reported. This review aims to summarize the recent progress in the research of the pathogenesis of childhood MDS and JMML. PMID- 30305539 TI - [2018 update on chronic graft-versus-host disease]. AB - Chronic graft-versus-host disease (GVHD) occurs in 30-40% of patients who undergo allogeneic hematopoietic cell transplantation. The symptoms of chronic GVHD resemble those of autoimmune diseases, and many sites, including the eyes, mouth, skin, gastrointestinal tract, liver, lungs, joints, and fascia, can be affected. Severe chronic GVHD increases patients' mortality and decreases their quality of life. The 2014 National Institutes of Health (NIH) Consensus has proposed a three step model for classification of the mechanisms of chronic GVHD: early acute inflammation, chronic inflammation with dysregulated immunity, and tissue fibrosis. Many drugs targeting specific biological pathways for treating chronic GVHD are under development. The NIH Consensus has also clarified objective response measures, optimal endpoints, and clinical trial designs to be used for drug approval. More than 30 novel drugs for GVHD treatment are currently being tested in over 80 clinical trials worldwide. PMID- 30305538 TI - [Diagnosis, surveillance, and management of familial leukemia]. AB - Recently, the modern technique of comprehensive genomic analysis has identified both somatic mutations originating from tumor cells and germline mutations as causative genes of inherited familial leukemias among which Fanconi anemia and Li Fraumeni syndrome are well known. Pathogenic germline mutations occur in various pathways, affecting DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, neutrophil development, and other critical cellular processes. The clinical manifestations of germline mutations present a wide phenotypic spectrum of patients displaying congenital anomalies, early-onset myelodysplastic syndrome, or no medical problems until the developing leukemia. The use of genetic tests to identify these affected persons will significantly benefit cancer surveillance and subsequent therapeutic interventions. Although familial leukemia treatment usually focuses on children, it is important for clinicians to recognize that familial leukemias can occur at any age, even among older adults. Genetic counseling after diagnosis is essential, and an immediate referral to experts in each disease is recommended. PMID- 30305540 TI - [Management of transplant-associated thrombotic microangiopathy]. AB - The clinical features of transplant-associated thrombotic microangiopathy (TA TMA) include microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ dysfunction caused by thrombi in microvessels. The pathogenesis of TA-TMA is based on vascular endothelial insults caused by various factors, including chemotherapy and total-body irradiation used for transplant pre-conditioning, calcineurin inhibitors, cytokines release associated with infection, and complement factors. The incidence of TA-TMA is approximately 15-30% among allogeneic transplant patients, and the mortality rate reaches 100% in severe cases with multi-organ dysfunction. This review describes the current understanding of the pathogenesis, diagnostic criteria, and treatment strategies of this potentially lethal transplant-associated complication. PMID- 30305541 TI - [Cord blood transplantation for leukemia in nonremission]. AB - Cure rates achieved with allogeneic hematopoietic cell transplantation (allo-HCT) for nonremission leukemia have been largely unsatisfactory (10-20%). Cord blood (CB) transplantation has long been thought to have a low propensity for graft versus-leukemia (GVL) effect because of the low incidence of graft-versus-host disease (GVHD). However, several retrospective studies have revealed that GVL effect of CB transplantation is comparable to or even greater than that of peripheral blood (PB) or bone marrow (BM) transplantation. The underlying mechanism of this phenomenon remains unclear; however, basic research has revealed some unique characteristics of immune cells in CB which are distinct from those of PB or BM. In clinical transplantation, the observed systemic immune mediated manifestations in the pre-engraftment phase are also specific to CB transplantation. These findings suggest that CB is a potential donor source for patients in nonremission due to its unique immunological potential as well as rapid availability for nearly all patients in the near future. PMID- 30305542 TI - [Introduction and the current status of unrelated peripheral blood stem cells transplantation in Japan]. AB - In other countries, unrelated donor peripheral blood stem cell transplantation (PBSCT) is more prevalent than bone marrow transplantation; however, in Japan, it was introduced in 2010 after confirming the safety of donors. PBSCT does not require blood donation, general anesthesia, or frequent bone marrow aspiration of the donor. After PBSCT, numerous hematopoietic cells can prompt blood recovery and engraftment, which has enabled reduced intensity transplantation in elderly patients and patients with concurrent diseases, such as infection. In addition, GVL effect by a large number of donor lymphocytes is expected, however, chronic GVHD is a major concern. When introducing PBSCT in Japan, manuals were drafted considering the short-term safety of donors, and data were collected on the occurrence of long- and short-term adverse events. A randomized trial reported no difference in the survival rate between bone marrow transplantation and PBSCT at 5 years; however, it revealed that QOL was better in the former. PB is a essential transplant source option, and attempts are being made to overcome chronic GVHD. PBSC contains abundant stem cells, progenitor cells, and immunocompetent cells and is indispensable for the development of cell therapy for blood diseases in the future. PMID- 30305543 TI - [Hematopoietic stem cell transplantation in the era of new molecular-targeted therapies]. AB - Recent advances in the field of molecular-targeted therapy have revolutionized the treatment of hematological malignancies. Consequentially, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically changed. However, allo-HSCT remains vital in the treatment of hematological malignancies because cure is rarely achieved by targeted therapy only. In the new era of molecular-targeted treatment, its incorporation into allo-HSCT is key to achieving therapeutic success. In particular, the understanding of the immune impact of molecular-targeted therapy on graft-versus-host-disease and graft versus-leukemia is essential to improve the outcome of allo-HSCT. PMID- 30305544 TI - [The ABCs of transfusion for hematologists]. AB - "Guidelines for the use of red blood cell products, platelet transfusion concentrates and fresh frozen plasma based on scientific evidence" was published by the Japan Society of Transfusion Medicine and Cell Therapy. Each transfused blood product carries a certain risk of an acute or late adverse event. Hematologists must be familiar with transfusion-associated adverse events, such as transfusion-related acute lung injury, transfusion-associated circulatory overload, post-transfusion graft-versus-host disease, transfusion-transmitted viral infection, etc. Thus, these guidelines should be followed for the appropriate use of blood products according to trigger values and indications for transfusion. PMID- 30305545 TI - [Guidelines based on scientific evidence for the application of platelet transfusion concentrates]. AB - Platelet transfusion concentrates are commonly used to prevent and treat bleeding due to thrombocytopenia and abnormal platelet function. Although these concentrates are indispensable while safely conducting anticancer chemotherapy and surgery, their use may cause certain adverse effects, including fever, urticaria, anaphylaxis, and transfusion-related acute lung injury. In addition, repeated platelet transfusions may induce allogeneic antibodies, possibly resulting in platelet transfusion refractoriness (PTR). Intrinsically, the use of platelet transfusion concentrates should be carefully administered and reserved to a minimum. This chapter introduces the guidelines based on scientific evidence for the therapeutic use of platelet transfusion concentrates, which The Japan Society of Transfusion Medicine and Cell Therapy recently established. PMID- 30305546 TI - [Transfusion of patients with autoimmune hemolytic anemia]. AB - Autoimmune hemolytic anemia (AIHA) is caused by the generation of autoantibodies against red cells. Sometimes, the destruction of red cells occurs in the intravascular space following the autoantibody-mediated activation of the complement cascade. More frequently, extravascular hemolysis occurs when macrophages phagocytose autoantibodies and complements bearing red cells. The direct antiglobulin test results (DAT) are usually positive. When the serum of patients with AIHA frequently reacts with all normal red cells, it is impossible to find compatible blood for transfusion. It is necessary to adsorb autoantibodies by autologous or allogeneic red cells for detecting alloantibodies in patients with AIHA. In addition, it is essential to accurately detect alloantibodies and intentionally avoid the generation of new alloantibodies for performing safer transfusion in the future. Although transfusion of phenotypically matched blood is desirable, it is challenging to obtain such blood in time. Moreover, the transfusion of partially phenotypically matched blood (ABO, D, C, E, c, e, Jka, Jkb) and the exclusion of alloantibody-related phenotype appear to be appropriate to avoid the severe transfusion reaction in the clinical setting. Furthermore, small volume, slow, and inevitable transfusion is recommended to avoid unexpected complications. In cases of cold reactive AIHAs, the application of blood warmer is recommended for transfusion. PMID- 30305547 TI - [Clinical application of mesenchymal stem cells for hematological diseases]. AB - Mesenchymal stem cells (MSCs) perform multiple functions, such as immunomodulation and tissue repair, and they are also capable of differentiation into bone, cartilage, and fat cells. Furthermore, an MSC culture method has been established, and clinical safety is guaranteed; therefore, MSCs can be clinically applied for the treatment of many diseases. MSC treatment for hematological diseases is expected to be effective against refractory acute graft-versus-host disease (GVHD). It is presently used for treating chronic GVHD, preventing GVHD, promoting the engraftment of hematopoietic stem cells, and treating refractory aplastic anemia. However, owing to the cellular properties of MSCs, there are some concerns including increases in relapse, the deterioration of infectious diseases, and tumor formation or malignant transformation of MSCs. In the present review, I describe the present situation, problems, and prospects of the clinical application of MSCs for treating hematological diseases, including recent topics such as placental-derived decidual stromal cells and highly purified MSCs. PMID- 30305548 TI - [Immunotherapy using T cells for treating viral infections]. AB - Recipients of hematopoietic stem cell transplantation suffering from severe immunosuppression and immune dysregulation because of GVHD or other causes are at higher risk of viral infection. Often, cytomegalovirus and EB virus are reactivated from their latent state in these patients ; viral infections thus remain a primary cause of severe morbidity and mortality. Since the 1990s, virus specific T cells have been generated by different methods using immunogenic epitope peptides or EBV-LCL from transplant donors, and studies have demonstrated the efficacy of these methods. However, establishing such order-made, virus specific T cells requires 8-10 weeks, which is not feasible for application in the frontline of clinics. Recent advances, such as direct donor T cell selection using peptide-HLA multimers or cytokine capture method and virus-specific T cells bank generated using third-party donors, facilitated the broadening of the applicability of this method. The clinical development of virus-specific T-cell therapy is considered as the prototype of future T-cell immunotherapy for various infections or malignant diseases. PMID- 30305549 TI - [The principles and practice of research ethics]. AB - Medical research is conducted by doctors as medical professionals with inspirational ideas and high ethical standards to gain knowledge for the future of medicine. Therefore, doctors must properly understand the three principles of ethics, i.e., respect for persons, beneficence, and justice, and appropriately practice them in the clinical research field. The Japan Clinical Research Act was established to restore the public confidence in clinical research that has been lost due to repeated research misconduct. Rather than being pessimistic towards the legal regulation of research, we should initiate a discussion regarding a framework to effectively utilize the evidence obtained in clinical research conducted under the law that could lead to innovative medical development. Amid changes in the global environment surrounding clinical research, we must continue generating evidence from our country, Japan, where medical resources are extremely limited, via high-quality clinical research with ethical validity and scientific rationality. PMID- 30305550 TI - [Japanese Society of Hematology conflict of interest management in medical research]. AB - In March 2017, considering the recent social trend, the Japanese Association of Medical Sciences (JAMS) officially announced the "JAMS Conflicts of Interest (COI) Management Guideline" and the "JAMS Guidance on Criteria for Qualification to Practice Guideline." In response to this announcement, the Japanese Society of Internal Medicine partially revised and announced the "Common Guideline on the Policy of COI in Medical Research," including the "COI Management to Practice Guideline" and the "Treatment Guideline," for its affiliated societies in September 2017. To ensure consistency with the Japanese Society of Internal Medicine, the Japanese Society of Hematology (JSH) has adopted and implemented the "Common Guideline of the Policy of COI in Medical Research of JSH," which matches that of the Japanese Society of Internal Medicine, and revised "Bylaws Concerning Conflict of Interest Policy in Clinical Research of JSH" to "Disclosure of COI in Conferences or Official Journals of JSH." Clinical Trials Act came into effect in April 2018, and the Japanese Ministry of Health, Labour, and Welfare has published "Guidance on COI Management according to Clinical Trials Act." PMID- 30305551 TI - Special Issue: Symposium on the Chemistry of Terpenes, Essential Oils and Aromatics (TEAC). PMID- 30305552 TI - Solubility of Tannins and Preparation of Oil-Soluble Derivatives. AB - Tannins are plant defense substances that exhibit a strong astringent taste and precipitate proteins, leading to the inhibition of protein functions; however, owing to their relatively low toxicity, tannins must be accumulated in high concentrations in cell vacuoles. Therefore, the solubility of tannins is crucial for their functions. In this review, the structure and reactions of tannins related to solubility; insolubilization of persimmon proanthocyanidins on fruit ripening; pigment formation from cinnamon procyanidins by reaction with cinnamaldehyde in case of wounding; and insolubilization of ellagitannins in chestnut wood is discussed. In addition, the development of functional polyphenols including oil-soluble tea catechins is introduced. PMID- 30305553 TI - Solvent-Free Synthesis of 2-Alkylbenzothiazoles and Bile Acid Derivatives Containing Benzothiazole Ring by Using Active Carbon/Silica Gel and Microwave. AB - A highly efficient and simple method for the synthesis of 2-alkylbenzothiazoles through the condensation of 2-aminothiophenol and aliphatic aldehydes in the presence of active carbon/silica gel is described. The reaction proceeded under solvent-free and microwave irradiation to afford 2-alkylbenzothiazoles in high yields. This method was extended to the synthesis of bile acid derivatives containing a benzothiazole ring and obtained the desired products in high yields. The anti-inflammatory activity and cytotoxicity of the newly synthesized benzothiazole derivatives of bile acid were tested; the results showed that anti inflammatory activities of all tested compounds tested were higher than that of standard drugs, such as indomethacin. PMID- 30305554 TI - Isolation and Identification of a Volatile Compound in Habanero Pepper (Capsicum chinense). AB - A volatile compound was isolated from the fruit of Habanero pepper (Capsicum chinense) and related varieties and identified as 6-methyl-(E)-4-heptenyl 3 methylbutyrate by 1H and 13C NMR spectroscopy and two-dimensional NMR experiments, including HMQC, HMBC, and 1H-1H COSY. The compound has a retention index of 1387 and is one of the major volatile compounds in Habanero pepper. This compound would be useful as a new flavor. PMID- 30305555 TI - Utilization of the Japanese Peppermint Herbal Water Byproduct of Steam Distillation as an Antimicrobial Agent. AB - The present study provides valuable data that the herbal water byproduct of Japanese peppermint, produced during the steam distillation extraction of an essential oil, can be utilized as an antibacterial agent. The major ingredient in the herbal water from Japanese peppermint 'Hokuto' was menthol, with a concentration close to its water solubility. The herbal water produced showed excellent antibacterial efficacy against typical gram-negative and gram-positive bacterial strains of Escherichia coli and Staphylococcus aureus, respectively, and the antibacterial efficacy was maintained even when the herbal water was diluted up to an appropriate concentration of 50%. The efficacy of the herbal water against E. coli was higher than that against S. aureus, which is likely because of the difference in the efficacy of menthol against these two different bacterial strains. The excellent antibacterial efficacy of the herbal water is mainly attributed to the function of menthol, while other trace ingredients also contributed to the antibacterial efficacy. The Japanese peppermint herbal water byproduct, generally treated as industrial waste and disposed, can be easily commercialized as an antibacterial agent if efforts are made to maintain a constant menthol concentration throughout the steam distillation essential oil extraction process. PMID- 30305556 TI - Isolation and Functional Characterization of New Terpene Synthase Genes from Traditional Edible Plants. AB - Terpene synthase (TPS) genes were isolated and functionally characterized from three traditional edible plants, Acanthopanax sciadophylloides ("Koshiabura") and Acanthopanax sieboldianus ("Himeukogi"), belonging to the family Araliaceae, and Curcuma zedoaria (zedoary, "Gajutsu"), belonging to the family Zingiberaceae. These plants emit characteristic fragrances and are used for traditional foods and folk medicines. From their fragrant tissues, i.e., sprouts of Araliaceae plants and developing rhizomes of zedoary, total RNAs were extracted and reverse transcribed. The resultant cDNAs were used for degenerate PCR followed by rapid amplification of cDNA ends. From the contig sequences obtained, full-length Tps genes were amplified by PCR with newly synthesized primer sets. The isolated full length genes were introduced into engineered Escherichia coli cells, which can utilize acetoacetate to synthesize farnesyl diphosphate, the substrate for TPSs, through the mevalonate pathway. TPS products synthesized in the transformed E. coli cells were analysed by gas chromatography-mass spectrometry, nuclear magnetic resonance, and optical rotation. Consequently, the isolated Tps genes were found to encode beta-caryophyllene synthase, germacrene D synthase, linalool/(3S)-(+)-nerolidol synthase, beta-eudesmol synthase, and germacrene B synthase. These results lead us to expect that some of the effective ingredients in folk medicines are volatile terpenes and that intake of traditional foods including these edible plants would have some positive effects on our health. PMID- 30305557 TI - Inhibition of Polymorphic Property of Naphthoquinonepigment Derived from Vitamin K. AB - Organicpigment, 2-Methyl-3-(4-fluorophenylthio)-1,4-naphthalenedione (2), that is a new Vitamin K derivative bearing a fluorine group, did not show any polymorphism disregard of three different solvents. For comparison, its naphthoquinone analogue with a bromine group (1) showed clearly polymorphism susceptible to these solvents. PMID- 30305558 TI - New Acetylenic Carotenoid 6'-Epimonadoxanthin from the Rosary Goby Gymnogobius castaneus. AB - Carotenoids of the rosary goby Gymnogobius castaneus (juzukakehaze in Japanese) were investigated. A new acetylenic carotenoid, (3R,3'R,6'S)-7,8-didehydro beta,epsilon-carotene-3,3'-diol (1), named 6'-epimonadoxanthin, was isolated along with 18 known carotenoids. The structure of 6'-epimonadoxanthin was determined by UV-VIS, ESI-TOF MS, 1H-NMR, and CD spectral data. The metabolic pathway from diatoxanthin to 6'-epimonadoxanthin is also discussed. PMID- 30305559 TI - Characteristic Scent from the Tahitian Liverwort, Cyathodium foetidissimum. AB - The volatile components of the Tahitian liverwort Cyathodium foetidissimum was analyzed using headspace solid phase micro-extraction (SPME) and GC-MS. Three volatile components, 4-methoxystyrene (24.4%), 3,4-dimethoxystyrene (28.7%), and skatole (15.9%) were identified as the major components from the fresh C. foetidissimum, along with several aliphatic aldehydes, n-octanal, n-nonanal, and n-decanal. However, (E)-2-nonenal recognized as aged malodor was not identified. In GC-O analysis, 2-aminoacetophenone was detected as one of the minor components with a strong aging note. In fact, C. foetidissimum showed the characteristic aging odor reminiscent the damp smell from old chest of drawers, or the civet like note with very strong feces and urine odor. The mixture consisted of 4 methoxystyrene, 3,4-dimethoxystyrene, and skatole in the detected ratio showed the sedative effect on CNV (contingent negative variation) measurement. PMID- 30305560 TI - Collagen Synthesis-Promoting Effects of Andiroba Oil and its Limonoid Constituents in Normal Human Dermal Fibroblasts. AB - The seed oil of andiroba (Carapa guianensis, Meliaceae) was found to promote collagen synthesis in normal human dermal fibroblasts. To characterize the active constituents of this oil, the collagen synthesis-promoting activities of 10 principal limonoid constituents, gedunin (1), 6alpha-acetoxygedunin (2), 7 deacetoxy-7-oxogedunin (3), 7-deacetoxy-7alpha-hydroxygedunin (4), andirolide H (5), 6alpha-hydroxygedunin (6), methyl angolensate (7), 17beta hydroxyazadiradione (8), and carapanosides C (9) and R (10), were examined. Among them, 1-4, 6, 7, and 9 were found to significantly promote collagen synthesis without cytotoxicity at the effective concentrations. PMID- 30305561 TI - Surface Activity and Ca2+-Dependent Aggregation Property of Lichenysin Produced by Bacillus licheniformis NBRC 104464. AB - Bacillus licheniformis NBRC 104464 produces a cyclic lipopeptide different from surfactin. After we performed liquid chromatography fractionation and purification, we used structural analyses to identify the cyclic lipopeptide as lichenysin. Surface tension measurements of lichenysin sodium salt in water yielded a critical micelle concentration (CMC) of 1.0*10-5 M. The surface tension at the CMC was 28.9 mN/m. Comparative analysis of Ca2+-influenced micellar aggregation of lichenysin and surfactin revealed that the formation rate of the lichenysin-Ca2+ complex aggregate remained low up to a [Ca2+]/[lichenysin] molar ratio of 80, whereas the surfactin-Ca2+ complex formed micellar aggregates at the same molar ratio. Further excessive addition of Ca2+ to the micellar solution of lichenysin induced higher turbidity than surfactin. PMID- 30305562 TI - Nephroprotective Effect of Essential Oils from Ginger (Zingiber officinale) and Turmeric (Curcuma longa) Rhizomes against Cadmium-induced Nephrotoxicity in Rats. AB - Several studies have shown that cadmium (Cd) induces nephrotoxicity and many plant foods phytochemicals have been found useful but their possible mechanism of action still remains unexplored. Hence, this study aimed to investigate the nephroprotective effect of essential oils from Nigeria ginger and turmeric rhizomes in cadmium-treated rats by examining their effect on renal function biomarkers (creatinine, urea and BUN), inflammatory cytokines (IL-6, IL-10 and TNF-Alpha) and renal adenosine deaminase (ADA) activity. The result revealed that essential oils from ginger and turmeric rhizomes exert anti-inflammatory effect by preventing alterations of renal function markers and cytokines (IL-6, IL-10 and TNF-Alpha) levels in Cd-treated rats. In addition, the essential oils inhibited renal ADA activity in Cdtreated rats. In conclusion, inhibition of ADA activity and modulation of inflammatory cytokines could be suggested as the possible mechanism of action by which essential oils from ginger and turmeric rhizomes exert their nephroprotective activities. PMID- 30305563 TI - EPR and HPLC Investigation of Pigments in Thai Purple Rice. AB - We investigated the pigments in Thai purple rice using electron paramagnetic resonance (EPR), X-band (9 GHz) EPR imaging (EPRI), and HPLC. The location and spatial distribution of the paramagnetic species in purple and white rice were determined by EPR and EPRI. EPR primarily detected three paramagnetic species in purple rice, which were identified as stable radicals, Mn2+, and Fe3+ based on the gvalues and hyperfine components of the EPR signals. Subsequent noninvasive two-dimensional (2D) EPRI revealed that these stable radicals are primarily located in the pigmented region of purple rice, while very few radicals were observed in the interior of the rice. HPLC revealed that the major compounds were cyanidin-3-O-glucoside and peonidin-3-O-glucoside. Scavenging activities, EPR, and EPR imaging results indicate that the stable radicals contain the radical state of anthocyanins and are mostly found within the pigmented embryo region of purple rice. They could be either associated with scavenging activities or could be one of the products of their oxidative decomposition. PMID- 30305564 TI - [Current status and problems of diagnosis of superficial cancer of the esophagus and the head and neck in Japan]. PMID- 30305565 TI - [The role of ESD in the multimodal treatment for esophageal cancer]. PMID- 30305567 TI - [Pathological diagnosis of superficial esophageal squamous cell carcinoma and superficial squamous cell carcinoma of head and neck]. PMID- 30305566 TI - [ELPS (endoscopic laryngo-pharyngeal surgery) for superficial head and neck cancer]. PMID- 30305568 TI - [Risk factors and field cancerization of esophageal squamous cell carcinoma in Japan]. PMID- 30305569 TI - ? PMID- 30305570 TI - [Hemobilia caused by hepatic artery pseudoaneurysm after endoscopic biliary stenting for malignant hilar biliary strictures:a case report]. AB - A 78-year-old female presented at our hospital with hilar biliary strictures caused by gallbladder cancer. Metal stents with a dilated diameter of 8mm were placed in a side-by-side fashion in the left and right hepatic ducts. However, 3 months after stenting, the patient experienced a sudden onset of hematemesis. Emergent enhanced abdominal angiography revealed a right hepatic arterial pseudoaneurysm that had likely ruptured, thus causing the hemobilia. Probable association of biliary stents with pseudoaneurysm was also demonstrated. Selective angiography revealed bleeding from the pseudoaneurysm into the biliary stents, which was controlled by coil embolization. The patient was subsequently discharged on hospital day 15. PMID- 30305571 TI - [Subcapsular hepatic hematoma due to vessel injury from the rigid portion of a guidewire during endoscopic retrograde cholangiopancreatography]. AB - A 58-year-old male receiving two types of antithrombotic medication developed acute obstructive suppressive cholangitis due to choledocholithiasis. During the first endoscopic retrograde cholangiopancreatography (ERCP) procedure, we performed biliary plastic stenting. Seven days after this procedure and with continued antithrombotic treatment, we performed ERCP with endoscopic sphincterotomy and stone extraction. Twelve hours after this procedure, the patient suffered transient unconsciousness and progression of anemia. Sixty hours after the procedure, he experienced right hypochondralgia and hiccups. Ultrasonography and computed tomography revealed a subcapsular hepatic hematoma. Bleeding was successfully arrested with selective arterial embolization. We suspected that the cause of these problems was vessel injury from the rigid portion of the guidewire during the ERCP procedure. PMID- 30305572 TI - [Successful curative resection after chemotherapy for initially unresectable advanced gallbladder cancer with rectal metastasis:a case report]. AB - A 42-year-old male was referred to our hospital with bloody feces and lower back pain. He was diagnosed with unresectable gallbladder cancer with rectal metastasis (T3aN1M1, Stage IVB). The patient was administered gemcitabine plus cisplatin (GC). After nine courses of GC, computed tomography showed regression of the tumor and the patient's tumor marker levels had decreased. Therefore, curative resection was performed. Ten months after the operation, recurrence was observed in the rectal margin and GC was restarted. Because the total dose of cisplatin was 1040mg, we stopped cisplatin and continued to administer only gemcitabine (at the same dose). A follow-up examination 2 years after the operation showed no evidence of recurrence. Conversion therapy might be an effective multidisciplinary treatment for advanced gallbladder cancer that is initially unresectable. Herein, we report the case of a patient with advanced gallbladder cancer and rectal metastasis who was successfully treated by curative resection after chemotherapy;we also review the relevant literature. PMID- 30305574 TI - [A case of a collision tumor comprising gastric cancer and a malignant lymphoma treated by endoscopic submucosal dissection]. PMID- 30305573 TI - [A case of obstructive pancreatitis induced by extramedullary pancreatic metastasis in a patient with immunoglobulin D multiple myeloma]. AB - A 51-year-old Brazilian female who had IgD-lambda type multiple myeloma presented with epigastralgia and obstructive jaundice during her follow-up. Contrast enhanced computed tomography (CT) showed an enhanced mass of 25mm in the pancreatic head, and endoscopic retrograde cholangiopancreatography revealed smooth stenoses in the lower bile duct and main pancreatic duct (MPD) of the head. We diagnosed the patient with extramedullary pancreatic metastasis of multiple myelomas. Plastic stents were endoscopically placed into both the common bile duct and MPD. One week later, she suffered a repeat episode of epigastralgia. A subsequent CT scan showed obstructive pancreatitis due to another mass, 30mm in size, emerging rapidly in the pancreatic body. Pancreatitis improved after we replaced the plastic stent with a longer one so that the distal end reached beyond the stenosis at the MPD of the body. Although both the tumors were treated with radiotherapy and showed temporary reduction, the patient died 1 month later due to progression of the disease. While cases involving obstructive pancreatitis induced by extramedullary pancreatic metastasis of multiple myelomas are very rare, it is crucial that such patients are rapidly diagnosed and treated. PMID- 30305575 TI - The Inflammatory Transcription Factor C/EBPbeta Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis. AB - The aim of the present study was to investigate the mechanisms of CCAAT/enhancer binding protein beta (C/EBPbeta) in cardiac myofibroblast (CMF) differentiation and in a rat model of cardiac fibrosis induced by experimental autoimmune myocarditis (EAM).In vitro studies performed in primary neonatal rat CMF revealed that silencing of C/EBPbeta expression (via lentiviral mediated shRNA strategies) was sufficient to reduce C/EBPbeta mRNA and protein levels as well as to decrease the expressions of actin cytoskeletal proteins, cofilin, and filamin A (FLNA). TGFbeta increased IL-1beta, IL-6 and TNF-a production in cardiac fibroblasts (CF), while C/EBPbeta knockdown reduced the secretion of these inflammatory mediators. In vivo studies performed in rats exhibiting EAM revealed that lentiviral-mediated silencing of C/EBPbeta was sufficient to reduce the expression of C/EBPbeta as well as inflammation and fibrosis in the hearts of EAM rats, when compared to controls. Echocardiography further revealed that C/EBPbeta knockdown was sufficient to significantly improve cardiac dimensions and function in EAM rats. Immunohistochemical results showed that C/EBPbeta knockdown attenuated the expression of C/EBPbeta protein as well as the expressions of collagen I, collagen III, MMP-2, MMP-9, and alpha-SMA in heart tissue sections from rats in the EAM + Lenti-shC/EBPbeta group.Strategies targeted at inhibiting C/EBPbeta expression can be potentially exploited to regulate cofilin and FLNA expression, thereby regulating actin polymerization/depolymerization, cytoskeleton rearrangement, and CF differentiation into CMF and the production of inflammatory cytokines. C/EBPbeta knock down reduces the degree of inflammation mediated myocardial fibrosis in a rat model of EAM. PMID- 30305576 TI - Increased Bioavailable Berberine Protects Against Myocardial Ischemia Reperfusion Injury Through Attenuation of NFkappaB and JNK Signaling Pathways. AB - Activation of Janus kinase (JNK) is involved in the pathogenesis of cardiac ischemia reperfusion injury. We previously demonstrated that oral treatment of rats with high doses of berberine (BBR) improved cardiac function in ischemia reperfusion injury. It is unknown if BBR modulates JNK activation. We developed a new formula, solid dispersion of BBR with sodium caprate (HGSD), which increases its bioavailability and membrane permeability. The present study examined if HGSD mediated inhibition of JNK protects the heart from ischemia reperfusion injury.The cardioprotective effect of HGSD was examined in rat hearts subjected to global 45 minutes ischemia followed by 30 minutes reperfusion. Hemodynamic parameters and troponin levels in the perfusate, and TNF-alpha, IL-6, JNK, and NFkappaB levels in the heart were determined. To further explore the cardioprotective mechanism of HGSD, H9c2 cells subjected to hypoxia/reoxygenation were incubated with serum containing HGSD in the absence or presence of an activator or inhibitor of JNK.Pretreatment of rats with HGSD for 7 days significantly improved recovery of heart function in animals subjected to ischemia reperfusion injury compared to untreated controls. In addition, HGSD pretreatment inhibited cardiac production of TNF-alpha and IL-6, and attenuated ischemia reperfusion induced cardiac JNK activation and nuclear translocation of NFkappaB compared to untreated controls. In H9c2 cells subjected to hypoxia/reoxygenation, the presence of JNK activator diminished the release of TNF-alpha and IL-6 and the nuclear translocation of NFkappaB.HGSD treatment protects the heart from ischemia reperfusion injury through attenuation of NFkappaB and JNK signaling pathways. PMID- 30305577 TI - Lower Circulating Omega-3 Polyunsaturated Fatty Acids Are Associated with Coronary Microvascular Dysfunction Evaluated by Hyperemic Microvascular Resistance in Patients with Stable Coronary Artery Disease. AB - The consumption of omega-3 polyunsaturated fatty acids (PUFAs) reduces the incidence of cardiovascular events and sudden cardiac death. Coronary microvascular dysfunction (CMD) is a predictor of cardiac mortality, but little information is known on the relationship between CMD and omega-3 PUFAs. This study aimed to identify the relationship between the serum levels of omega-3 PUFAs and the CMD evaluated by the hyperemic microvascular resistance index (hMVRI) to assess coronary microvascular function in patients with stable coronary artery disease (CAD).Intracoronary physiological variables (fractional flow reserve (FFR), hMVRI, mean distal coronary pressure (Pd), and average peak velocity (APV)) were measured in 108 patients. These parameters were evaluated in 150 coronary arteries with stenosis of intermediate severity and without significant ischemia (FFR > 0.80). The PUFA levels and atherosclerotic risk factors were also measured. Univariate analysis shows that hMVRI was negatively correlated with eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (beta = 0.31, P = 0.001) and EPA (beta = -0.25, P = 0.009) and was positively correlated with dihomo-gamma-linolenic acid (beta = 0.26, P = 0.006). Multivariate regression analysis shows that the EPA/AA ratio was the only independent determinant of hMVRI (beta = -0.234, SE = 0.231, P = 0.024). Furthermore, hMVRI decreased significantly from the lowest to highest tertiles of the EPA/AA ratio (P = 0.007). The EPA/AA ratio was positively correlated with APV at hyperemia (beta = 0.26, P = 0.008) but not with Pd at hyperemia.A lower serum EPA/AA ratio may cause CMD in patients with stable CAD. PMID- 30305578 TI - RoPE Score as a Predictor of Recurrent Ischemic Events After Percutaneous Patent Foramen Ovale Closure. AB - The benefits of patent foramen ovale (PFO) closure for cryptogenic stroke secondary prevention are still debated. The Risk of Paradoxical Embolism (RoPE) study developed a score to improve patient selection for this procedure. We proposed to assess the validity of this score to assess the prognostic impact of PFO closure.From 2000 to 2014, all consecutive patients submitted to PFO closure were included in a prospective registry in a university center. The primary endpoint was recurrent ischemic cerebrovascular events and the secondary endpoints were all-cause, neurological, and cardiac mortality rates and new-onset atrial fibrillation (NOAF) rates. In total, 403 patients were included in the study (women: 52.1%; mean age: 44.7 +/- 10.9 years). The mean follow-up period was 6.4 +/- 3.7 years. Immediate success was achieved in 97% patients. There were 23 (5.8%) ischemic cerebrovascular events, 8 (2.0%) deaths, and 17 (4.3%) NOAFs. The mean RoPE score was 6.10 +/- 1.79. Smoker status, coronary artery disease, lower RoPE score, and higher left atrial dimensions were predictors of the primary endpoint. However, a lower RoPE score and coronary artery disease remained independent predictors in multivariate analysis.RoPE score was shown to be an independent predictor of recurrent ischemic cerebrovascular events, and a score of <= 6 was shown to identify patients with significantly higher risk of mortality and recurrent ischemic events. PMID- 30305579 TI - Ubiquitin Carboxyl Terminal Hydrolase L1 Attenuates TNF-alpha-Mediated Vascular Smooth Muscle Cell Migration Through Suppression of NF-kappaB Activation. AB - Ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) is one of the deubiquitinating enzymes in the ubiquitin-proteasome system. It has been shown that UCH-L1 could markedly decrease neointima formation through suppressing vascular smooth muscle cell (VSMC) proliferation in the balloon-injured rat carotid. However, whether UCH-L1 plays roles in VSMC migration remains to be determined. In this study, the primary VSMCs were isolated from aortic media of rats and TNF-alpha to was used to induce VSMC migration. Using a modified Boyden chamber and wound healing assay, it was found that TNF-alpha can dose and time-dependently induce VSMC migration with a maximal effect at 10 ng/mL. Moreover, UCH-L1 expression increased gradually with the prolonged induction time at 10 ng/mL of TNF-alpha. UCH-L1 content in VSMC was then modulated by recombinant adenoviruses expressing UCH-L1 or RNA interference to evaluate its roles in cell migration. The results showed that over-expression of UCH-L1 attenuated VSMC migration, while knockdown of it enhanced cell migration significantly no matter whether TNF-alpha treatment or not. Finally, the effect of UCH-L1 on NF-kappaB activation was demonstrated by NF-kappaB nuclear translocation and DNA binding activity, and the levels of IL-6 and IL-8 in cell culture media were examined by ELISA. It was showed that UCH-L1 over-expression inhibited NF-kappaB activation and decrease IL-6 and IL-8 levels, while knockdown of it enhanced NF-kappaB activation and increase IL-6 and IL-8 levels during TNF-alpha treatment. These data suggest that UCH-L1 can inhibit TNF alpha-induced VSMCs migration, and this kind of effect may partially due to its suppression role in NF-kappaB activation. PMID- 30305580 TI - Strain Values of Left Ventricular Segments Reduce Non-homogeneously in Dilated Cardiomyopathy with Moderately and Severely Deteriorated Heart Function Assessed by MRI Tissue Tracking Imaging. AB - Changes of global and segmental ventricular strain at different deterioration levels of cardiac function in patients with dilated cardiomyopathy (DCM) using cardiac magnetic resonance (CMR) have not yet been explored. In total, 101 patients diagnosed with DCM consecutively underwent CMR. They were categorized according to the reduction in left ventricular ejection fraction (LVEF) into the following groups: moderately reduced (n = 43) and severely reduced group (n = 58). LV global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS), and segmental strain values were assessed using tissue tracking technique. LV segmental circumferential strain (CS) and radial strain (RS) in healthy volunteers increased from base to apex stepwisely. The LV base-to-apex increasing pattern disappeared in the moderate DCM group (RS: 26.61% +/- 20.63% versus 21.97% +/- 4.85% versus 29.05% +/- 9.90%, P > 0.05; CS: -13.16% +/- 6.40% versus -12.96%+/- 2.45% versus -15.32% +/- 3.89%, P > 0.05). While in the severe group, CS and RS of base segment had the highest values, there was no significant difference between mid and apex segments. GLSLV, GRSLV, and GCSLV were significantly reduced in moderate and severe groups in steps, similar to the three parameters of RV. During a 17-month median follow-up, 25 patients had an index composite outcome event. GLSLV > -11.62%, GCSLV > -9.35%, and GRSLV<= 12.42% were significantly associated with the occurrence of cardiac events in DCM patients. LV segmental values reduce non-homogeneously in DCM patients with moderately and severely deteriorated heart function. PMID- 30305581 TI - Endothelial Dysfunction of Conduit Arteries in Patients with Repaired Coarctation of the Aorta. AB - Adult patients with repaired coarctation of the aorta (r-CoA) show high prevalence of late hypertension, but the exact mechanisms of this phenomenon are unknown. Endothelial dysfunction has been implicated in this paradoxical hypertension. We evaluated the endothelial function of both conduit and resistance arteries by using flow-mediated dilation (FMD) and digital peripheral artery tonometry (PAT).Seventeen patients with r-CoA and one patient with repaired interrupted aortic arch (r-CoA group) aged 22.0 +/- 6.9 years (5 females) underwent FMD of the right brachial artery, PAT of the right finger, blood marker tests, ambulatory blood pressure monitoring, echocardiography, carotid ultrasonography, and brachio-ankle pulse wave velocity measurement. The median age at aortic arch reconstruction was 2.0 months (interquartile range: 15 days to 7.0 years). Results were compared with 17 age-matched healthy subjects (control group).Eight (44%) patients of the r-CoA group were hypertensive (5 received antihypertensive drugs). Patients in the r-CoA group showed significantly lower FMD (3.8 +/- 1.5 versus 6.6 +/- 2.5%, P < 0.001), larger intima-media thickness (0.63 +/- 0.17 versus 0.47 +/- 0.09 mm, P = 0.001), and higher left ventricular mass index (91.4 +/- 24.6 versus 73.4 +/- 17.3 g/m2, P = 0.017) than those in the control group. There were no significant differences in PAT (refractory hyperemia index, 1.86 +/- 0.43 versus 1.99 +/- 0.59, P = 0.48) and brachio-ankle pulse wave velocity between the two groups.Vascular dysfunction in r-CoA patients, particularly endothelial dysfunction, tends to occur more significantly in conduit arteries than in resistance arteries. PMID- 30305582 TI - Novel ASK1 Inhibitor AGI-1067 Attenuates AGE-Induced Fibrotic Response by Suppressing the MKKs/p38 MAPK Pathway in Human Coronary Arterial Smooth Muscle Cells. AB - The phenotype shifting of vascular smooth muscle cells (VSMCs) was indicated to play a role during the initial stage of atherosclerotic plaque formation by facilitating extracellular matrix deposition. This study was aimed at investigating the involvement of the apoptosis signal-regulating kinase 1 (ASK1) /mitogen-activated protein kinase (MAPK) kinases (MKKs) /p38 MAPK pathway in the advanced glycation end product (AGE) -induced fibrotic response of VSMCs. The effect of the novel ASK1 inhibitor AGI-1067 was also studied.Cultured human coronary smooth muscle cells (HCSMCs) were exposed to AGEs. AGI-1067 and siRNAs silencing mkk3, mkk6, and p38 mapk were used to treat the cells. The activation of MKK3, MKK6, and p38 MAPK was assessed by immunoblotting. Fibrotic response was assessed by the fluorescence immunohistochemistry staining of collagen I and collagen VIII. Activation of immunoprecipitation determined the association of ASK1 and its inhibitor thioredoxin. A kinase assay was used to determine ASK1 activity.AGE incubation significantly activated ASK1, MKK3, and MKK6, which led to activation of p38 MAPK, resulting in upregulated fibrotic response in HCSMCs. However, siRNAs knocking down mkk3, mkk6, and p38 mapk impaired this fibrotic response. AGI-1067 administration not only dramatically inhibited the activation of ASK1/MKKs/p38 MAPK but also suppressed the expression of the downstream proteins, including transforming growth factor-beta1, connective tissue growth factor, collagen I, and collagen VIII in HCSMCs exposed to AGEs.The ASK1/MKKs/p38 MAPK pathway was activated by AGEs, leading to the fibrotic response in VSMCs. AGI-1067 reversed this process by maintaining the inactive state of ASK1. PMID- 30305583 TI - Postural Orthostatic Tachycardia in a Patient with Type 2 Diabetes with Diabetic Neuropathy. AB - A 24-year-old Japanese man with type 2 diabetes mellitus and diabetic neuropathy was admitted to our ward to evaluate the cause of orthostatic intolerance. During a head-up tilt test, his heart rate increased from 105 to 155 beats/minute within 3 minutes, and chest discomfort began. He was diagnosed with postural orthostatic tachycardia syndrome (POTS), and orthostatic intolerance disappeared after beta blocker treatment. Scintigraphy using 123I-metaiodobenzylguanidine showed decreased cardiac uptake. Power spectral analysis of heart rate variability for 24 hours in Holter electrocardiography demonstrated decreases in both sympathetic and parasympathetic nervous system activities, with a greater decrease in parasympathetic activity than sympathetic activity. The relative sympathetic hyperactivity in the present patient with diabetic neuropathy seemed to be related to POTS. PMID- 30305584 TI - Persistent QT Prolongation in a Child with Gitelman Syndrome and SCN5A H558R Polymorphism. AB - Gitelman syndrome (GS) is an inherited renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and low urinary calcium excretion. While it is considered a benign disease, severe ventricular arrhythmia and sudden cardiac death related to the prolongation of the QT interval have been reported in rare cases. Herein we report a 13-year-old girl with GS who presented with persistent prolongation of the QT interval, even after being treated for hypokalemia and hypomagnesemia. Genetic analysis identified SCN5A H558R polymorphism, which modulates the function of myocardial sodium channel, and SLC12A3 A588V mutation, which causes GS. The SCN5A polymorphism and GS-related electrolyte disturbance might have contributed to the persistent QT prolongation in this patient. Although no ventricular arrhythmias were recorded in this case, careful cardiac surveillance should be applied for avoiding life-threatening cardiac events. PMID- 30305585 TI - Sequential Saphenous Vein Coronary Bypass Grafting. AB - The enormous majority of previous reports focused on evaluating the safety and efficacy of sequential saphenous vein (SV) coronary bypass grafting; however, no reports to date have revealed concern regarding the impacts of the number of distal anastomoses of sequential SV grafting on graft patency after coronary artery bypass grafting (CABG). This single-center retrospective study aimed to evaluate the impacts of three versus two distal anastomoses per single SV conduit on SV graft patency after off-pump CABG, and to determine the independent risk factors for sequential SV graft failure.From January 2011 to December 2014, 1320 eligible patients were assigned to either a triple group (three distal anastomoses of sequential SV grafting, n = 758) or a double group (two distal anastomoses of sequential SV grafting, n = 562). The primary endpoint was over a 2-year follow-up SV graft failure after off-pump CABG.The triple and double group received a similar total patency rate of sequential SV conduits (86.5% versus 87.1%, P = 0.757). The number of distal anastomoses of sequential SV grafting (three versus two) was not a predictive factor for the follow-up graft failure of sequential SV conduits (HR = 0.91, 95% CI: 0.66-2.29, P = 0.137). Moreover, the two groups received a similar follow-up survival freedom from repeat revascularization (chi2 = 1.881, log-rank P = 0.170).Three versus two distal anastomoses per single SV conduit received a similar SV graft patency. The number of distal anastomoses of sequential SV grafting was not an independent risk factor for graft failure. PMID- 30305586 TI - Bifurcation Intervention in Single Coronary Artery. AB - A 77-year-old man was referred to our hospital for angina on effort. Coronary angiography and computed tomography demonstrated a single coronary artery arising from the right sinus of Valsalva. The left circumflex coronary artery (LCx) anomalously deriving near from the ostium of right coronary artery exhibited severe stenosis in the bifurcation of the obtuse marginal branch. Although the bifurcation lesion still remains a therapeutic challenge for guide extension catheter (GEC)-based percutaneous coronary intervention, under the guidance of intravascular ultrasound imaging, we successfully implanted an everolimus-eluting stent at the bifurcated LCx lesion and performed kissing balloon inflation using 0.014- and 0.010-inch systems through GECs. PMID- 30305587 TI - Sildenafil Reduces the Risk of Thromboembolic Events in HeartMate II Patients with Low-Level Hemolysis and Significantly Improves the Pulmonary Circulation. AB - Low-level hemolysis (LLH) after left ventricular assist device implantation contributes to thromboembolic events (TE). Free plasma hemoglobin (fHb) scavenges nitric oxide (NO), which causes endothelial dysfunction and activates platelets. fHb also interacts with von Willebrand factor (vWF). We hypothesized that improved hemodynamic and enhanced NO signaling in HeartMate II (HMII) patients with LLH taking the phosphodiesterase-5 inhibitor sildenafil may reduce the risk of TE.From 2011 to 2015, 83 patients underwent HMII implantation. Patients with LLH as defined by elevated lactate dehydrogenase (400 < LDH <= 700 U/L) at hospital discharge were identified. Patients were categorized into 4 groups: 1) LLH + sildenafil, 2) LLH no sildenafil, 3) no LLH + sildenafil, and 4) no LLH no sildenafil. Adverse event-free survival was compared between the groups.Thirty four patients (40.9%) were discharged with LLH and 22 (64.7%) of them took sildenafil. LDH and fHb remained significantly elevated in both LLH groups compared to the no LLH patients (P < 0.0001). Overall incidence of pump thrombosis (PT) was 4.8% and of ischemic stroke (IS) was 8.4%. HMII patients with LLH not on sildenafil had higher risk of TE (hazard ratio (HR): 14.4, 95%-CI: 1.8 117.1, P = 0.001). vWF activity and bleeding incidence did not differ between the LLH and no LLH patients. Mean pulmonary artery pressure and pulmonary vascular resistance decreased significantly in HMII taking sildenafil (P < 0.0001) while cardiac index increased (P < 0.0001).Sildenafil treatment among HMII patients with LLH reduced the risk of thromboembolic events and significantly improved and decompressed the pulmonary circulation during HMII support. PMID- 30305588 TI - Determinants of Slow Flow in Percutaneous Coronary Intervention to the Culprit Lesion of Non-ST Elevation Myocardial Infarction. AB - Slow flow is a serious complication in percutaneous coronary intervention (PCI) and is associated with poor clinical outcomes. Our previous study revealed that the ratio of stent diameter to vessel diameter was the determinant of slow flow in intravascular ultrasound (IVUS)-guided PCI to the culprit lesion of ST elevation myocardial infarction (STEMI). The purpose of this study was to verify whether the ratio of stent diameter to vessel diameter is the determinant of slow flow in IVUS-guided PCI to the culprit lesion of non-STEMI (NSTEMI). We included 150 NSTEMI patients and divided into the slow flow group (n = 17) and the non slow flow group (n = 133). The ratio of stent diameter to vessel diameter was significantly larger in the slow flow group (0.77 +/- 0.11) than the non-slow flow group (0.71 +/- 0.11) (P = 0.03). Multivariate logistic regression analysis revealed that the ratio of stent diameter to vessel diameter (per 0.1 increase: OR 2.06, 95% CI 1.23-3.46, P = 0.006) was the determinant of slow flow after controlling covariates. In conclusion, the ratio of stent diameter to vessel diameter was the determinant of slow flow in IVUS-guided PCI to the culprit lesion of NSTEMI. Unlike other parameters, the ratio of stent diameter to vessel diameter is the modifiable parameters. We may consider the modest stent expansion strategy rather than the aggressive stent expansion strategy in IVUS-guided PCI to the culprit lesion of NSTEMI. PMID- 30305590 TI - A Highly Selective and Sensitive Colorimetric Probe for Cu2+ Determination in Aqueous Media Based on Derivative of Tryptanthrin. AB - A new colorimetric probe, based on tryptanthrin derivative (TR-A), has been successfully synthesized. The probe shows good selectivity and sensitivity for Cu2+ over 12 competing metal ions in a 10 mM Tris-HCl buffer solution (pH 5.5). A significant peak at 623nm appears in the UV-Vis absorption of TR-A-Cu2+, and a noteworthy color change is observed with the naked eye from aquamarine blue to light orange. The interaction of TR-A and Cu2+ are proven to form a 1:1 binding stoichiometry; this identifying is expected to be completed within 1 min. The probe with a limit of detection (16 nM, R2 = 0.9934) shows excellent potential to determine Cu2+ in analysis systems. PMID- 30305589 TI - Derivatization Techniques for Chromatographic Analysis. PMID- 30305591 TI - Separation and Preconcentration of Nickel(II) from Drinking, Spring, and Lake Water Samples with Amberlite CG-120 Resin and Determination by Flame Atomic Absorption Spectrometry. AB - In this study, Amberlite CG-120 adsorbent was used for the separation/preconcentration of Ni(II) ions in commercial drinking, spring and lake water samples before detection by flame atomic absorption spectrometry. Various optimization parameters for Ni(II) determination, such as pH, eluent type and concentration, sample and eluent flow rates, amount of adsorbent, were investigated to obtain better sensitivity, accuracy, precision and quantitative recovery. Furthermore, the interference effects of some ions on the recovery efficiency of Ni(II) were also investigated. The optimum experimental parameters were obtained in the case of pH 1; 5 mL of 4 mol L-1 HCl for eluent and 0.3 g for the adsorbent amount. The limit of detection was found to be 0.58 MUg L-1 and linearity ranged from 5 to 50 MUg L-1. The accuracy of the method was tested by the certified reference material of TMDA-70.2 Ontario Lake Water at a 95% confidence level. PMID- 30305592 TI - Ultrasensitive Biosensor for Detection of Mercury(II) Ions Based on DNA-Cu Nanoclusters and Exonuclease III-assisted Signal Amplification. AB - This paper describes a novel method for label-free mercury(II) ion detection based on exonuclease III-induced target signal recycling amplification using double-stranded DNA templated copper nanoclusters. The synthesized DNA-Cu nanoclusters were used with exonuclease III loop amplification technology for ultra-high sensitivity detection of mercury(II) ions, which were detected by significantly decreased fluorescence intensity. Under the optimal experimental conditions, there was a clear linear relationship between Hg2+ concentration in the range of 0.04 to 8 nM and fluorescence intensity. The detection limit for Hg2+ was 4 pM. In addition, the interference of other metal ions on the mercury(II) ion detection was also studied. To confirm the application of the fluorescent sensor, it was applied to determine the concentrations of mercury(II) ions in tap water, and the results showed that the method can be used to detect mercury(II) ions in water samples successfully. PMID- 30305594 TI - Determination of Allura Red in the Presence of Cetylpyridinium Bromide by Square wave Adsorptive Stripping Voltammetry on a Glassy Carbon Electrode. AB - A simple method to determine Allura Red (AR) in cherry gelatin, chili sauce and strawberry juice by square-wave adsorptive stripping voltammetry (SWAdV) in the presence of cetylpyridinium bromide (CPB) is reported. Using a glassy carbon electrode (GCE), Amaranth (AM), Ponceau 4R (P-4R) and AR were oxidized to very close potential values in medium acid pH 3.0 with phosphate buffer solution (PBS), making selective AR detection impossible. Under these conditions AM, P-4R and AR were oxidized at 0.80, 0.77 and 0.81 V, respectively. When small amounts of CPB were added, an AR-CPB aggregate was formed. This change displaced the oxidation almost 0.14 V in the direction of the most positive potential and increased the current almost 50%, while AM and P-4R were oxidized at almost the same potential. Under these conditions, the selective determination of AR in food was possible. Detection limit was 0.032 MUmol L-1. Finally, the method was successfully applied to the determination of AR in these foods. PMID- 30305593 TI - Surface Functionalized Prussian Blue-coated Nanostructured Nickel Oxide as a New Biosensor Platform for Catechol Detection. AB - An amperometric biosensor has been developed for highly efficient and sensitive detection of catechol using Prussian blue (PB)-coated nickel oxide (NiO) nanoparticles (NPs) as a matrix for the immobilization of tyrosinase enzyme. The NiO NPs were synthesized by sol-gel method using sodium dodecyl sulphate as anionic surfactant and the surface of the synthesized NiO NPs was modified with PB to enhance electrocatalytic activity and to prevent surface aggregation. After confirmation of successful synthesis of the PB-NiO NPs from transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopic (EDS) studies, the prepared NPs were deposited onto a working electrode of a commercially available screen printed carbon electrode (SPCE) substrate. The tyrosinase enzyme was covalently immobilized onto the PB-NiO deposited SPCE for selective detection and estimation of catechol through electrochemical methods via cyclic voltammetry (CV) and chronoamperometric techniques. The functionalization of tyrosinase on the electrode surface was verified by atomic force microscopy (AFM) and scanning electron microscopic (SEM) techniques and the electrochemical response studies of the proposed biosensor showed high sensitivity of 0.954 MUA/MUM for catechol in a wide linear range (1 - 50 MUM) with low detection limit (LOD) of 0.087 MUM. The developed sensor also exhibited a fast response time of 27 s and decent selectivity for catechol detection. PMID- 30305595 TI - The Utility of Sonogashira Coupling Reaction for the Derivatization of Aryl Halides with Fluorescent Alkyne. AB - Aryl halides are a very important category of compounds that include many vital drugs and key industrial additives, such as clofibrate and bromobenzene, respectively. Due to their importance, our research group previously developed a novel fluorescence labeling approach for their analysis using a fluorescent aryl boronic acid as a reagent, based on the Suzuki coupling reaction. This coupling reaction was successfully applied for the determination of aryl halides in biological fluids; however, there was a limitation of low reactivity towards ortho-substituted aryl halides. In the present study, a novel fluorescence derivatization approach for aryl halides was developed using, 2-(4-ethynylphenyl) 4,5-diphenyl-1H-imidazole (DIB-ET) as a fluorescent alkyne reagent, based on the Sonogashira coupling reaction. DIB-ET reacted with aryl bromides in the presence of palladium and copper as catalysts, yielding fluorescent derivatives that could be subsequently determined by an HPLC system with fluorescence detection. The detection limits (S/N = 3) for aryl bromides were in the range of 14 - 23 nM, which is 3.5 - 18-times more sensitive than our previously developed approach, Suzuki coupling derivatization. Moreover, in contrast to the previous technique, the reactivity of DIB-ET to ortho-substituted aryl bromides was almost equivalent to that of the para-substituted aryl bromides. Hence, by using this newly developed approach we could label the aryl halides with more sensitivity and reactivity. Finally, the proposed method was successfully applied for the selective determination of aryl bromides in human serum with good recovery (84.6 107%), which proves the ability of the developed method to determine occupational exposure to aryl halides. PMID- 30305596 TI - One Hour In Vivo-like Phenotypic Screening System for Anti-cancer Drugs Using a High Precision Surface Plasmon Resonance Device. AB - In anti-cancer drug (candidate) screening, there is the need for evaluation at physiological concentrations similar to in vivo. This is often performed by three dimensionally (3D) cultured cells; however, it requires a long culture period of 2 - 4 weeks with tedious experimental procedures. Here, we report on a high precision surface plasmon resonance (HP-SPR)-3D system. We developed the system with average fluctuation of 50 ndeg s-1 using two-dimensionally cultured cells attached onto a sensor chip by applying collagen on the top to change their activity into in vivo-like conditions without cell division. It allowed in vivo like phenotypic screening for anti-cancer drugs within 1 h of drug addition. The data were collected as the stable linear signal change parts for at least 5 min after 25 min following drug addition. The results provided compatibility to clinically related chemosensitivity test for anti-cancer (P <0.001) using two cell lines of pancreatic cancer and three anti-cancer drugs to represent differences in individual gene expression and drug mode of action. PMID- 30305597 TI - Process for the Purification of cis-p-Coumaric Acid by Cellulose Column Chromatography after the Treatment of the trans Isomer with Ultraviolet Irradiation. AB - A methanolic solution of trans-p-coumaric acid was exposed to ultraviolet radiation and a mixture solution of the trans and cis isomers was subjected to cellulose column chromatography, eluting with an aqueous 0.1% trifluoroacetic acid solution containing methanol (90:10, v/v). Separation of the trans and cis isomers was achieved. The identity of the cis isomer was confirmed by TLC, HPLC, and NMR. Since both the support and eluent are inexpensive, the cis isomers can be obtained economically on both the laboratory and industrial scales. PMID- 30305598 TI - Retention of Fluorescent Amino Acid Derivatives in Ion-pairing Reversed-phase Liquid Chromatography. AB - Recent studies have shown that pillar array columns enable fast and quantitative analysis of amino acids. However, hydrophilic amino acids still cannot be retained on pillar array columns since they have limited retention ability. Ion pairing liquid chromatography is a promising means of increasing analyte retention. In this study, the effects of ion-pairing reagents on the retention of eight hydrophilic amino acids (histidine, asparagine, glutamine, serine, arginine, aspartic acid, glycine, and glutamic acid) derivatized with 4-fluoro-7 nitro-2,1,3-benzoxadiazole (NBD-F) under reversed-phase conditions on a conventional ODS column were studied. Among the ion-pairing reagents investigated, tetraheptylammonium bromide proved to be the most effective for increasing analyte retention. With a mobile phase consisting of 20 mM citrate buffer (pH 6.3)-acetonitrile (100:40, v/v) and 2 mM tetraheptylammonium bromide, the retention times of the eight NBD-amino acids-except NBD-arginine-were longer than 19.4 min, which was the retention time of NBD-valine when eluted without an ion-pairing reagent. As NBD-valine was well retained on pillar array columns, the chromatographic conditions may thus be applied in the analysis of hydrophilic amino acids using pillar array columns. PMID- 30305599 TI - Building a Low-cost Standalone Electrochemical Instrument Based on a Credit Card sized Computer. AB - A low-cost, standalone electrochemical instrument was built from a credit card sized computer and inexpensive A/D and D/A converter chips. The instrument is capable of cyclic voltammetry and constant potential electrolysis, with the potential range of -4 to +4 V and the current range of 1 MUA to 20 mA. PMID- 30305601 TI - Importance of Risk Control on the Incidence of Aortic Artery Disease-Related Disease in Epidemiological Studies. PMID- 30305602 TI - Effects of Enhancer of Zeste Homolog 2 (EZH2) Expression on Brain Glioma Cell Proliferation and Tumorigenesis. AB - BACKGROUND Brain glioma is a type of common primary intracranial malignant tumor, the prognosis of which is frequently unfavorable. Enhancer of zeste homolog 2 (EZH2) belongs to poly-sulfur protein family and can mediate cell proliferation and differentiation via the modulation of various genes expressions. In addition, it is further related with occurrence and metastasis of malignant tumors. This study investigated the effect of EZH2 expression on proliferation and tumorigenesis of brain glioma cells. MATERIAL AND METHODS Glioma tumor tissues were collected from 3 patients who received surgery, and the glioma stem cells were then separated, cultured, and identified by flow cytometry. RNA interference approach was used to suppress EZH2 expression, which was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Clonal formation assay analyzed the change of cell proliferation potency. The effect on tumorigenesis potency of glioma stem cells was determined by mouse transplantation assay. Western blot investigated the effect of EZH2 on levels of oncogenes such as HER-2, c-myc, PI3K, and Akt. RESULTS Flow cytometry revealed cancer stem cells in glioma tissues took up 39.4%, and qRT-PCR showed that EZH2 expression was decreased by 72% after the treatment of RNA interference in glioma cells (P<0.05). Both cell clonal formation and xenograft assays showed that the downregulation of EZH2 inhibited glioma cell proliferation (P<0.05) and weakened tumorigenesis potency (P<0.05). Western blot results showed that the reduction of EZH2 also suppressed expressions of oncogenes including c-myc and Akt (P<0.05). CONCLUSIONS Our data demonstrated that in brain glioma cells, the decrease of EZH2 level could suppress cell proliferation and tumorigenesis potency, and meanwhile inhibit the expressions of oncogenes including c-myc and Akt. PMID- 30305603 TI - Hepatic Involvement in Systemic Sarcoidosis. AB - BACKGROUND Sarcoidosis is a systemic disease that can affect any organ, including the liver. It is manifested by the presence of non-caseating granulomas within involved organs, most commonly the pulmonary, lymphatic, and hepatic system. Unlike pulmonary or lymphatic involvement, hepatic involvement is usually asymptomatic and it is underdiagnosed. Here, we report a case of a patient with a history of pulmonary sarcoidosis who developed hepatic sarcoidosis. CASE REPORT 68-year-old female with pulmonary sarcoidosis with a 2-week history of severe abdominal pain and epigastric tenderness presented to our center. Abdominal magnetic resonance imaging (MRI) demonstrated mild hepatic fibrosis and cirrhosis. A thorough workup was performed including a liver biopsy which showed chronic non-necrotizing granulomas consistent with sarcoidosis. She was started on prednisone and subsequently improved. The patient was symptom-free on follow up 1 month later. CONCLUSIONS The majority of patients with hepatic sarcoidosis are usually asymptomatic, with only 5-30% presenting with abdominal pain, jaundice, nausea, vomiting, and hepatosplenomegaly. In rare cases, hepatic sarcoidosis can lead to cholestasis, portal hypertension, cirrhosis, or Budd Chiari syndrome. Treatment with steroids is the mainstay of therapy; however, in severe cases, patients may require liver transplantation. This case report demonstrates that hepatic sarcoidosis is a serious condition, and if not treated, can lead to portal hypertension and cirrhosis. In patients with sarcoidosis, early detection and longitudinal follow-up is important in preventing overt liver failure. PMID- 30305604 TI - Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota. AB - Diosgenin, a natural steroidal saponin, can exert antitumor effect by regulating immune function and improving intestinal microbiota. The response to anti-PD-1 immunotherapy is associated with intestinal microbiota and effector T cells in tumor microenvironment. We hypothesize that the modulation of diosgenin on intestinal microbiota can facilitate antitumor immunity and the therapeutic efficacy of PD-1 antibody. In melanoma-bearing C57BL/6 mice, we observed that the anti-melanoma effect of diosgenin relied more on antitumor immunity than direct tumor inhibition activity evidenced by obvious CD4+/CD8+ T-cell infiltration and IFN-gamma expression in tumor tissues, and it could improve the compositions of intestinal microbiota. Antibiotics impaired the therapeutic efficacy and immunity responses of diosgenin through disturbing intestinal microbiota, indicating the importance of intestinal microbiota in diosgenin's in vivo antitumor activity. More importantly, the combined administration of PD-1 antibody with diosgenin aggravated the tumor necrosis and apoptosis by eliciting augmented T-cell responses. Taken together, diosgenin can be used as a microecological regulator to induce antitumor immunity and improve the efficacy of immune checkpoint antibody, making it more suitable for the treatment of malignant tumors. PMID- 30305605 TI - Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice. AB - Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas. PMID- 30305606 TI - Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death. AB - Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1gamma (HP1gamma) as another required coactivator. Here, we used a genome-wide analysis to show that HP1gamma is selectively required for GC-regulated expression of the great majority of GR target genes that require G9a and GLP. To further address the importance of G9a and GLP methylation in this process and in cell physiology, we found that JIB-04, a selective JmjC family lysine demethylase inhibitor, increased G9a methylation and thereby increased G9a binding to HP1gamma. This led to increased expression of GR target genes regulated by G9a, GLP and HP1gamma and enhanced Nalm6 cell death. Finally, the KDM4 lysine demethylase subfamily demethylates G9a in vitro, in contrast to other KDM enzymes tested. Thus, inhibiting G9a/GLP demethylation potentially represents a novel method to restore sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death. PMID- 30305607 TI - DNA-methylation-mediated silencing of miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/beta-catenin signal pathways. AB - As one of the most common cancers worldwide, colorectal cancer (CRC) causes a large number of mortality annually. Aberrant expression of microRNAs (miRNAs) is significantly associated with the initiation and development of CRC. Further investigations regarding the regulatory mechanism of miRNAs is warranted. In this study, we discovered that miR-486-5p was remarkably downregulated in CRC, which partially results from higher DNA methylation in the promoter region detected by using methylation-specific PCR, bisulfite sequencing PCR, and DNA demethylation treatment. Besides, decreased miR-486-5p was obviously associated with advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis in CRC. Upregulated miR-486-5p inhibited the proliferation and migration of CRC through targeting PLAGL2 expression and subsequent repressing IGF/beta-catenin signal pathways both in vitro and in vivo. Notably, plasma miR-486-5p expression was significantly upregulated in CRC patients and we identified plasma miR-486-5p as a novel diagnostic biomarker of CRC using receiver operating characteristic (ROC) curve analysis. Moreover, exploration in GEO dataset revealed that circulating miR-486-5p is tumor derived through being packaged into secretory exosomes. Taken together, our data demonstrated that miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/beta-catenin signal pathway, which is a promising therapeutic target of CRC treatment. PMID- 30305608 TI - Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry. AB - Multiple myeloma (MM) is two- to three-fold more common in African Americans (AAs) compared to European Americans (EAs). This striking disparity, one of the highest of any cancer, may be due to underlying genetic predisposition between these groups. There are multiple unique cytogenetic subtypes of MM, and it is likely that the disparity is associated with only certain subtypes. Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry, which may result in bias. To mitigate these difficulties, we studied 881 patients with monoclonal gammopathies who had undergone uniform testing to identify primary cytogenetic abnormalities. DNA from bone marrow samples was genotyped on the Precision Medicine Research Array and biogeographical ancestry was quantitatively assessed using the Geographic Population Structure Origins tool. The probability of having one of three specific subtypes, namely t(11;14), t(14;16), or t(14;20) was significantly higher in the 120 individuals with highest African ancestry (>=80%) compared with the 235 individuals with lowest African ancestry (<0.1%) (51% vs. 33%, respectively, p value = 0.008). Using quantitatively measured African ancestry, we demonstrate a major proportion of the racial disparity in MM is driven by disparity in the occurrence of the t(11;14), t(14;16), and t(14;20) types of MM. PMID- 30305609 TI - Comparison of breast cancer metastasis models reveals a possible mechanism of tumor aggressiveness. AB - In breast cancer patients, the lungs are among the first sites of cancer metastasis, and in nearly one quarter of metastatic patients, the exclusive first event. Two common mouse models mimic breast cancer lung colonization and distal metastasis: an orthotopic model and intravenous (IV) cell injections. Gene expression analysis of pulmonary lesions from these two methods demonstrated high inter-model resemblance. However, microRNA (miRNA) expression profiles were not compared. In this study, we compared the overall miRNA expression profiles (miRNome) of the orthotopic and IV breast cancer metastasis models and identified significant miRNome changes between the two models. Overexpression of the most significant candidate, miR-96 or downregulation of its validated gene-target, ABCE1 reduced cancer cells 2D/3D cell movement and proliferation in vitro, and abated tumor growth and metastasis formation in vivo. Human data analysis further strengthened miR-96/ABCE1 role in breast cancer tumor aggression. Taken together, our results indicate that IV- and orthotopic models differ by their miRNome. Specifically in our study, breast cancer aggressiveness was dictated by miR-96 regulating ABCE1. Overall, miRNome analysis of various metastatic cancer models may lead to the identification of candidate genes critical to metastasis development. PMID- 30305610 TI - Degranulation of mast cells induced by gastric cancer-derived adrenomedullin prompts gastric cancer progression. AB - Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, their precise mechanism of communication in gastric cancer remains largely unclear. Here, we found that patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. Tumor-derived adrenomedullin (ADM) induced mast cell degranulation via PI3K-AKT signaling pathway, which effectively promoted the proliferation and inhibited the apoptosis of GC cells in vitro and contributed to the growth and progression of GC tumors in vivo, and the effect could be reversed by blocking interleukin (IL)-17A production from these mast cells. Our results illuminate a novel protumorigenic role and associated mechanism of mast cells in GC, and also provide functional evidence for these mast cells to prevent, and to treat this immunopathogenesis feature of GC. PMID- 30305611 TI - Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis. AB - Glioma is the most common and malignant form of primary brain tumour, and is characterised by high proliferation and extensive invasion and neurological destruction. Demethylzeylasteral (T-96), which is extracted from Tripterygium wilfordii, is considered to have immunosuppressive, anti-inflammatory and anti angiogenic effects. Here, the anti-tumour effect of T-96 on glioma was evaluated. Our results demonstrated that T-96 significantly inhibited glioma cell growth and induced cell cycle arrest in G1 phase but did not induce apoptosis. Cell invasion and migration were dramatically suppressed after treatment with T-96. Almost all genes related to cell cycle and DNA replication were downregulated after treatment with T-96. Our results showed that miR-30e-5p was noticeably upregulated after T-96 treatment, and MYBL2, which is involved in cell cycle progression and is a target gene of miR-30e-5p, was significantly reduced in synchrony. Overexpression of MYBL2 partially rescued the T-96-induced inhibition of cell growth and proliferation. Moreover, a miR-30e-5p antagomir significantly reduced the upregulation of miR-30e-5p expression induced by T-96, leading to recovery of MYBL2 expression, and partially rescued the T-96-induced inhibition of cell growth and proliferation. More important, T-96 effectively upregulated miR-30e-5p expression and downregulated MYBL2 expression, thus inhibiting LN-229 cell tumour growth in a mouse model. These results indicated that T-96 might inhibit glioma cell growth by regulating the miR-30e-5p/MYBL2 axis. Our study demonstrated that T-96 might act as a promising agent for malignant glioma therapy. PMID- 30305612 TI - BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways. AB - Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC. PMID- 30305614 TI - Electrically reconfigurable terahertz signal processing devices using liquid metal components. AB - Many applications of terahertz (THz) technology require the ability to actively manipulate a free space THz beam. Yet, although there have been many reports on the development of devices for THz signal processing, few of these include the possibility of electrical control of the functionality, and novel ideas are needed for active and reconfigurable THz devices. Here, we introduce a new approach, based on the integration of electrically actuated liquid metal components in THz waveguides. This versatile platform offers many possibilities for control of THz spectral content, wave fron"ts, polarization, and power flow. We demonstrate two illustrative examples: the first active power-splitting switch, and the first channel add-drop filter. We show that both of these devices can be used to electrically switch THz communication signals while preserving the information in a high bit-rate-modulated data stream. PMID- 30305613 TI - Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages. AB - The establishment of the embryonic and trophoblast lineages is a developmental decision underpinned by dramatic differences in the epigenetic landscape of the two compartments. However, it remains unknown how epigenetic information and transcription factor networks map to the 3D arrangement of the genome, which in turn may mediate transcriptional divergence between the two cell lineages. Here, we perform promoter capture Hi-C experiments in mouse trophoblast (TSC) and embryonic (ESC) stem cells to understand how chromatin conformation relates to cell-specific transcriptional programmes. We find that key TSC genes that are kept repressed in ESCs exhibit interactions between H3K27me3-marked regions in ESCs that depend on Polycomb repressive complex 1. Interactions that are prominent in TSCs are enriched for enhancer-gene contacts involving key TSC transcription factors, as well as TET1, which helps to maintain the expression of TSC-relevant genes. Our work shows that the first developmental cell fate decision results in distinct chromatin conformation patterns establishing lineage specific contexts involving both repressive and active interactions. PMID- 30305615 TI - Structural basis for PtdInsP2-mediated human TRPML1 regulation. AB - Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a pi-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels. PMID- 30305616 TI - Compact folded metasurface spectrometer. AB - An optical design space that can highly benefit from the recent developments in metasurfaces is the folded optics architecture where light is confined between reflective surfaces, and the wavefront is controlled at the reflective interfaces. In this manuscript, we introduce the concept of folded metasurface optics by demonstrating a compact spectrometer made from a 1-mm-thick glass slab with a volume of 7 cubic millimeters. The spectrometer has a resolution of ~1.2 nm, resolving more than 80 spectral points from 760 to 860 nm. The device is composed of three reflective dielectric metasurfaces, all fabricated in a single lithographic step on one side of a substrate, which simultaneously acts as the propagation space for light. The folded metasystem design can be applied to many optical systems, such as optical signal processors, interferometers, hyperspectral imagers, and computational optical systems, significantly reducing their sizes and increasing their mechanical robustness and potential for integration. PMID- 30305617 TI - LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival. AB - Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier. Human LRH-1 (hLRH-1) rescues epithelial integrity and when overexpressed, mitigates inflammatory damage in murine and human intestinal organoids, including those derived from IBD patients. Finally, hLRH-1 greatly reduces disease severity in T cell-mediated murine colitis. Together with the failure of a ligand-incompetent hLRH-1 mutant to protect against TNFalpha-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease. PMID- 30305618 TI - A growing bacterial colony in two dimensions as an active nematic. AB - How a single bacterium becomes a colony of many thousand cells is important in biomedicine and food safety. Much is known about the molecular and genetic bases of this process, but less about the underlying physical mechanisms. Here we study the growth of single-layer micro-colonies of rod-shaped Escherichia coli bacteria confined to just under the surface of soft agarose by a glass slide. Analysing this system as a liquid crystal, we find that growth-induced activity fragments the colony into microdomains of well-defined size, whilst the associated flow orients it tangentially at the boundary. Topological defect pairs with charges [Formula: see text] are produced at a constant rate, with the [Formula: see text] defects being propelled to the periphery. Theoretical modelling suggests that these phenomena have different physical origins from similar observations in other extensile active nematics, and a growing bacterial colony belongs to a new universality class, with features reminiscent of the expanding universe. PMID- 30305619 TI - GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. AB - Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracellular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, suggesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection. PMID- 30305621 TI - Ischemic postconditioning confers cerebroprotection by stabilizing VDACs after brain ischemia. AB - Ischemic postconditioning provides robust neuroprotection, therefore, determining the molecular events may provide promising targets for stroke treatment. Here, we showed that the expression of functional mitochondrial voltage-dependent anion channel proteins (VDAC1, VDAC2, and VDAC3) reduced in rat vulnerable hippocampal CA1 subfield after global ischemia. Ischemic postconditioning restored VDACs to physiological levels. Stabilized VDACs contributed to the benefits of postconditioning. VDAC1 was required for maintaining neuronal Ca2+ buffering capacity. We found that microRNA-7 (miR-7) was responsible for postischemic decline of VDAC1 and VDAC3. Notably, miR-7 was more highly expressed in the peripheral blood of patients with acute ischemic stroke compared to healthy controls. Inhibition of miR-7 attenuated neuronal loss and ATP decline after global ischemia, but also diminished the infarct volume with improved neurological functions after focal ischemia. Thus, ischemic postconditioning protects against mitochondrial damage by stabilizing VDACs. MiR-7 may be a potential therapeutic target for ischemic stroke. PMID- 30305620 TI - SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. AB - Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1. SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression. SIRT1 interacts with the Polycomb silencing complex to decrease Kiss1 promoter activity. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive switch in chromatin landscape. Early-onset overnutrition accelerates these changes, enhances Kiss1 expression and advances puberty. In contrast, undernutrition raises SIRT1 levels, protracts Kiss1 repression and delays puberty. This delay is mimicked by central pharmacological activation of SIRT1 or SIRT1 overexpression, achieved via transgenesis or virogenetic targeting to the ARC. Our results identify SIRT1 mediated inhibition of Kiss1 as key epigenetic mechanism by which nutritional cues and obesity influence mammalian puberty. PMID- 30305622 TI - Host-associated niche metabolism controls enteric infection through fine-tuning the regulation of type 3 secretion. AB - Niche-adaptation of a bacterial pathogen hinges on the ability to recognize the complexity of signals from the environment and integrate that information with the regulation of genes critical for infection. Here we report the transcriptome of the attaching and effacing pathogen Citrobacter rodentium during infection of its natural murine host. Pathogen gene expression in vivo was heavily biased towards the virulence factor repertoire and was found to be co-ordinated uniquely in response to the host. Concordantly, we identified the host-specific induction of a metabolic pathway that overlapped with the regulation of virulence. The essential type 3 secretion system and an associated suite of distinct effectors were found to be modulated co-ordinately through a unique mechanism involving metabolism of microbiota-derived 1,2-propanediol, which dictated the ability to colonize the host effectively. This study provides novel insights into how host specific metabolic adaptation acts as a cue to fine-tune virulence. PMID- 30305624 TI - Quantum machine learning for electronic structure calculations. AB - Considering recent advancements and successes in the development of efficient quantum algorithms for electronic structure calculations-alongside impressive results using machine learning techniques for computation-hybridizing quantum computing with machine learning for the intent of performing electronic structure calculations is a natural progression. Here we report a hybrid quantum algorithm employing a restricted Boltzmann machine to obtain accurate molecular potential energy surfaces. By exploiting a quantum algorithm to help optimize the underlying objective function, we obtained an efficient procedure for the calculation of the electronic ground state energy for a small molecule system. Our approach achieves high accuracy for the ground state energy for H2, LiH, H2O at a specific location on its potential energy surface with a finite basis set. With the future availability of larger-scale quantum computers, quantum machine learning techniques are set to become powerful tools to obtain accurate values for electronic structures. PMID- 30305623 TI - Efficient carrier multiplication in CsPbI3 perovskite nanocrystals. AB - The all-inorganic perovskite nanocrystals are currently in the research spotlight owing to their physical stability and superior optical properties-these features make them interesting for optoelectronic and photovoltaic applications. Here, we report on the observation of highly efficient carrier multiplication in colloidal CsPbI3 nanocrystals prepared by a hot-injection method. The carrier multiplication process counteracts thermalization of hot carriers and as such provides the potential to increase the conversion efficiency of solar cells. We demonstrate that carrier multiplication commences at the threshold excitation energy near the energy conservation limit of twice the band gap, and has step like characteristics with an extremely high quantum yield of up to 98%. Using ultrahigh temporal resolution, we show that carrier multiplication induces a longer build-up of the free carrier concentration, thus providing important insights into the physical mechanism responsible for this phenomenon. The evidence is obtained using three independent experimental approaches, and is conclusive. PMID- 30305625 TI - MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging. AB - Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, we have pursued analysis of miR-34 mutants in Drosophila. The miR-34 mutant brain displays a gene expression profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We demonstrate that Pcl and Su(z)12, two components of polycomb repressive complex 2, (PRC2), are targets of miR-34, with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, we hypothesize that miR-34 modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age. PMID- 30305626 TI - Structural insights on TRPV5 gating by endogenous modulators. AB - TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-pi interaction between Lys116 on the C-lobe of calcium activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery. PMID- 30305628 TI - Contact angle measurement of free-standing square-millimeter single-layer graphene. AB - Square millimeters of free-standing graphene do not exist per se because of thermal fluctuations in two-dimensional crystals and their tendency to collapse during the detachment from the substrate. Here we form millimeter-scale freely suspended graphene by injecting an air bubble underneath a graphene monolayer floating at the water-air interface, which allowed us to measure the contact angle on fully free-standing non-contaminated graphene. A captive bubble measurement shows that free-standing clean graphene is hydrophilic with a contact angle of 42 degrees +/- 3 degrees . The proposed design provides a simple tool to probe and explore the wettability of two-dimensional materials in free standing geometries and will expand our perception of two-dimensional materials technologies from microscopic to now millimeter scales. PMID- 30305629 TI - Prevention of pancreatic acinar cell carcinoma by Roux-en-Y Gastric Bypass Surgery. AB - Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female Ngn3-Tsc1-/- mice. Ngn3 directed Cre deletion of Tsc1 gene induced the development of pancreatic ACC. The transgenic mice with sham surgery demonstrated a cancer incidence of 96.7 +/- 3.35% and survival rate of 67.0 +/- 1.4% at the age of 300 days. Metastasis to liver and kidney was observed in 69.7 +/- 9.7% and 44.3 +/- 8.01% of these animals, respectively. All animals with RYGB performed at the age of 16 weeks survived free of pancreatic ACC up to the age of 300 days. RYGB significantly attenuated the activation of mTORC1 signaling and inhibition of tumor suppressor genes: p21, p27, and p53 in pancreatic ACC. Our studies demonstrate that bariatric surgery may limit the occurrence and growth of pancreatic ACC through the suppression of mTORC1 signaling in pancreas. RYGB shows promise for intervention of both metabolic dysfunction and organ cancer. PMID- 30305627 TI - MSK1 functions as a transcriptional coactivator of p53 in the regulation of p21 gene expression. AB - Mitogen- and stress-activated kinase 1 (MSK1) is a chromatin kinase that facilitates activator-dependent transcription by altering chromatin structure through histone H3 phosphorylation. The kinase activity of MSK1 is activated by intramolecular autophosphorylation, which is initially triggered by the activation of upstream mitogen-activated protein kinases (MAPKs), such as p38 and ERK1/2. MSK1 has been implicated in the expression of p21, a p53 target gene; however, the precise connection between MSK1 and p53 has not been clearly elucidated. Here, using in vitro and cell-based transcription assays, we show that MSK1 functions as a transcriptional coactivator of p53 in p21 expression, an action associated with MAPK-dependent phosphorylation of MSK1 and elevated kinase activity. Of special significance, we show that MSK1 directly interacts with p53 and is recruited to the p21 promoter, where it phosphorylates histone H3 in a p53 dependent manner. In addition, phosphomimetic mutant analysis demonstrated that negative charges in the hydrophobic motif are critical for serine 212 phosphorylation in the N-terminal kinase domain, which renders MSK1 competent for histone kinase activity. These studies suggest that MSK1 acts through a direct interaction with p53 to function as a transcriptional coactivator and that MSK1 activation by upstream MAPK signaling is important for efficient p21 gene expression. PMID- 30305630 TI - Relativistic and resonant effects in the ionization of heavy atoms by ultra intense hard X-rays. AB - An accurate description of the interaction of intense hard X-ray pulses with heavy atoms, which is crucial for many applications of free-electron lasers, represents a hitherto unresolved challenge for theory because of the enormous number of electronic configurations and relativistic effects, which need to be taken into account. Here we report results on multiple ionization of xenon atoms by ultra-intense (about 1019 W/cm2) femtosecond X-ray pulses at photon energies from 5.5 to 8.3 keV and present a theoretical model capable of reproducing the experimental data in the entire energy range. Our analysis shows that the interplay of resonant and relativistic effects results in strongly structured charge state distributions, which reflect resonant positions of relativistically shifted electronic levels of highly charged ions created during the X-ray pulse. The theoretical approach described here provides a basis for accurate modeling of radiation damage in hard X-ray imaging experiments on targets with high-Z constituents. PMID- 30305632 TI - A guanine-flipping and sequestration mechanism for G-quadruplex unwinding by RecQ helicases. AB - Homeostatic regulation of G-quadruplexes (G4s), four-stranded structures that can form in guanine-rich nucleic acids, requires G4 unwinding helicases. The mechanisms that mediate G4 unwinding remain unknown. We report the structure of a bacterial RecQ DNA helicase bound to resolved G4 DNA. Unexpectedly, a guanine base from the unwound G4 is sequestered within a guanine-specific binding pocket. Disruption of the pocket in RecQ blocks G4 unwinding, but not G4 binding or duplex DNA unwinding, indicating its essential role in structure-specific G4 resolution. A novel guanine-flipping and sequestration model that may be applicable to other G4-resolving helicases emerges from these studies. PMID- 30305631 TI - Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism. AB - The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men. PMID- 30305633 TI - Low threshold and efficient multiple exciton generation in halide perovskite nanocrystals. AB - Multiple exciton generation (MEG) or carrier multiplication, a process that spawns two or more electron-hole pairs from an absorbed high-energy photon (larger than two times bandgap energy Eg), is a promising way to augment the photocurrent and overcome the Shockley-Queisser limit. Conventional semiconductor nanocrystals, the forerunners, face severe challenges from fast hot-carrier cooling. Perovskite nanocrystals possess an intrinsic phonon bottleneck that prolongs slow hot-carrier cooling, transcending these limitations. Herein, we demonstrate enhanced MEG with 2.25Eg threshold and 75% slope efficiency in intermediate-confined colloidal formamidinium lead iodide nanocrystals, surpassing those in strongly confined lead sulfide or lead selenide incumbents. Efficient MEG occurs via inverse Auger process within 90 fs, afforded by the slow cooling of energetic hot carriers. These nanocrystals circumvent the conundrum over enhanced Coulombic coupling and reduced density of states in strongly confined nanocrystals. These insights may lead to the realization of next generation of solar cells and efficient optoelectronic devices. PMID- 30305634 TI - A non-randomised controlled pilot study of clinical pharmacist collaborative intervention for community dwelling patients with COPD. AB - UK, home-based patients with COPD receive specialist care from respiratory physicians, nurses, and general practitioners (GPs), but increasing complexity of therapeutic options and a GP/Nurse workforce crisis suggests merit in testing the role of home visits by a clinical pharmacist. We conducted a non-randomised intervention study with a contemporaneous comparator group, in Glasgow (Scotland). A clinical pharmacist (working closely with a consultant respiratory physician) visited patients with COPD living at home, assessing respiratory and other co-morbid conditions, and medicines then, with patient approval, agreed treatment modifications with a consultant physician. Comparator group-patients were drawn from another hospital out-patient clinic. Main outcomes were exacerbations during 4-months of follow-up and respiratory hospitalisations (number and duration) after 1 year. In the intervention group, 86 patients received a median of three home visits; 87 received usual care (UC). At baseline, patients in the intervention group were similar to those in UC in terms of respiratory hospitalisations although slightly younger, more likely to receive specific maintenance antibiotics/Prednisolone and to have had exacerbations. Sixty-two (72.1%) of the intervention group received dose changes; 45 (52.3%) had medicines stopped/started and 21 (24.4%) received an expedited review at the specialist respiratory consultant clinic; 46 (53.5%) were referred to other healthcare services. Over one-third were referred for bone scans and 11% received additional investigations. At follow-up, 54 (63.5%) of intervention group participants had an exacerbation compared with 75 (86.2%) in the UC group (p = 0.001); fewer had respiratory hospitalisations (39 (45.3%) vs. 66 (76.7%); p < 0.001). Hospitalisations were shorter in the intervention group. Pharmacist consultant care for community dwelling patients with COPD, changed clinical management and improved outcomes. A randomised controlled trial would establish causality. PMID- 30305636 TI - Nanoporous aramid nanofibre separators for nonaqueous redox flow batteries. AB - Redox flow batteries are attractive for large-scale energy storage due to a combination of high theoretical efficiencies and decoupled power and energy storage capacities. Efforts to significantly increase energy densities by using nonaqueous electrolytes have been impeded by separators with low selectivities. Here, we report nanoporous separators based on aramid nanofibres, which are assembled using a scalable, low cost, spin-assisted layer-by-layer technique. The multilayer structure yields 5 +/- 0.5 nm pores, enabling nanofiltration with high selectivity. Further, surface modifications using polyelectrolytes result in enhanced performance. In vanadium acetylacetonate/acetonitrile-based electrolytes, the coated separator exhibits permeabilities an order of magnitude lower and ionic conductivities five times higher than those of a commercial separator. In addition, the coated separators exhibit exceptional stability, showing minimal degradation after more than 100 h of cycling. The low permeability translates into high coulombic efficiency in flow cell charge/discharge experiments performed at cycle times relevant for large-scale applications (5 h). PMID- 30305635 TI - Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination. AB - The DNA-damage repair pathway homologous recombination (HR) requires factors that promote the activity of strand-exchange protein RAD51 and its meiosis-specific homolog DMC1. Here we show that the Shu complex SWS1-SWSAP1, a candidate for one such HR regulator, is dispensable for mouse viability but essential for male and female fertility, promoting the assembly of RAD51 and DMC1 on early meiotic HR intermediates. Only a fraction of mutant meiocytes progress to form crossovers, which are crucial for chromosome segregation, demonstrating crossover homeostasis. Remarkably, loss of the DNA damage checkpoint kinase CHK2 rescues fertility in females without rescuing crossover numbers. Concomitant loss of the BRCA2 C terminus aggravates the meiotic defects in Swsap1 mutant spermatocytes, suggesting an overlapping role with the Shu complex during meiotic HR. These results demonstrate an essential role for SWS1-SWSAP1 in meiotic progression and emphasize the complex interplay of factors that ensure recombinase function. PMID- 30305638 TI - Singular sublimation of ice and snow crystals. AB - The evaporation (sublimation) of ice and snow has a major impact on global climate, since the amount of ice and snow determines Earth's albedo. Yet, due to their complex geometry with several sharp regions which are singular for the evaporation, the precise evaporation dynamics of snow and ice crystals remains challenging to predict. Here, we study the sublimation of snowflakes and pointy ice drops. We show that the evaporation rates of water and ice drops are similar; they are both limited by the diffusive transport of the vapour. This allows us to predict ice and snowflake evaporation quantitatively by solving the diffusive free-boundary problem, which correctly predicts the rapid self-similar evolution of sharp edges and points. Beyond providing a conceptual picture to understand the sublimation of ice crystals, our results are more generally applicable to other diffusion problems such as the dissolution of salt crystals or pharmaceuticals. PMID- 30305639 TI - Author Correction: Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine. AB - The original version of this Article contained an error in the spelling of the author Bin Geng, which was incorrectly given as Bing Geng. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30305641 TI - Fabrication of buried nanostructures by atomic layer deposition. AB - We present a method for fabricating buried nanostructures by growing a dielectric cover layer on a corrugated surface profile by atomic layer deposition of TiO2. Selecting appropriate process parameters, the conformal growth of TiO2 results in a smooth, nearly flat-top surface of the structure. Such a hard surface can be easily cleaned without damage, making the nanostructure reusable after contamination. The technique has wide applicability in resonance-domain diffractive optics and in realization of quasi-planar metamaterials. We discuss design issues of such optical elements and demonstrate the method by fabricating narrow-band spectral filters based on the guided-mode resonance effect. These elements have strong potential for, e.g., sensing applications in harsh conditions. PMID- 30305640 TI - Deciphering molecular details in the assembly of alpha-type carboxysome. AB - Bacterial microcompartments (BMCs) are promising natural protein structures for applications that require the segregation of certain metabolic functions or molecular species in a defined microenvironment. To understand how endogenous cargos are packaged inside the protein shell is key for using BMCs as nano-scale reactors or delivery vesicles. In this report, we studied the encapsulation of RuBisCO into the alpha-type carboxysome from Halothiobacillus neapolitan. Our experimental data revealed that the CsoS2 scaffold proteins engage RuBisCO enzyme through an interaction with the small subunit (CbbS). In addition, the N domain of the large subunit (CbbL) of RuBisCO interacts with all shell proteins that can form the hexamers. The binding affinity between the N domain of CbbL and one of the major shell proteins, CsoS1C, is within the submicromolar range. The absence of the N domain also prevented the encapsulation of the rest of the RuBisCO subunits. Our findings complete the picture of how RuBisCOs are encapsulated into the alpha-type carboxysome and provide insights for future studies and engineering of carboxysome as a protein shell. PMID- 30305643 TI - Electrochemical Preparation and Post-treatment of Composite Porous Foam NiZn Alloy Electrodes with High Activity for Hydrogen Evolution. AB - Composite porous foam NiZn alloy electrodes with nano pore structure were prepared by the combination of eletrodeposition, heat treatment and HCl etching. The morphology of the electrodes was examined by scanning electron microscopy (SEM). And the component of the electrodes was analyzed by Energy Dispersive Spectrum (EDS). The specific surface area and pore size of the electrode were investigated by nitrogen adsorption. The phase constituents were analyzed by X ray diffraction (XRD), and the electrocatalytic characteristics for hydrogen evolution reaction of the electrodes in 30% (mass fraction) KOH solution were investigated by cathode polarization curve. The experimental results showed that the pores were formed on surface of the foam NiZn alloy electrodes after heat treatment at 600 degrees C, and with the etching by 10% HCl, nano layered structure was formed on the surface of the porous skeleton. Compared with the nickel foam, the surface area of the NiZn foam alloy electrode became larger, and the nano pore structure had good catalytic activity. At current density of 200 mA.dm-2, the hydrogen evolution overpotential of the NiZn foam alloy electrodes were reduced by 222 mV and 276 mV, respectively, through heat treatment of 600 degrees C and etching in 10% HCl solution, which indicated that the hydrogen evolution overpotential was effectively reduced because of the composite nano porous structure, while the activity of hydrogen evolution of the electrodes was obviously improved. PMID- 30305642 TI - Spatio-temporal dynamics and aetiology of proliferative leg skin lesions in wild British finches. AB - Proliferative leg skin lesions have been described in wild finches in Europe although there have been no large-scale studies of their aetiology or epizootiology to date. Firstly, disease surveillance, utilising public reporting of observations of live wild finches was conducted in Great Britain (GB) and showed proliferative leg skin lesions in chaffinches (Fringilla coelebs) to be widespread. Seasonal variation was observed, with a peak during the winter months. Secondly, pathological investigations were performed on a sample of 39 chaffinches, four bullfinches (Pyrrhula pyrrhula), one greenfinch (Chloris chloris) and one goldfinch (Carduelis carduelis) with proliferative leg skin lesions and detected Cnemidocoptes sp. mites in 91% (41/45) of affected finches and from all species examined. Fringilla coelebs papillomavirus (FcPV1) PCR was positive in 74% (23/31) of birds tested: a 394 base pair sequence was derived from 20 of these birds, from all examined species, with 100% identity to reference genomes. Both mites and FcPV1 DNA were detected in 71% (20/28) of birds tested for both pathogens. Histopathological examination of lesions did not discriminate the relative importance of mite or FcPV1 infection as their cause. Development of techniques to localise FcPV1 within lesions is required to elucidate the pathological significance of FcPV1 DNA detection. PMID- 30305637 TI - Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 * 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 * 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy. PMID- 30305644 TI - First passage events in biological systems with non-exponential inter-event times. AB - It is often possible to model the dynamics of biological systems as a series of discrete transitions between a finite set of observable states (or compartments). When the residence times in each state, or inter-event times more generally, are exponentially distributed, then one can write a set of ordinary differential equations, which accurately describe the evolution of mean quantities. Non exponential inter-event times can also be experimentally observed, but are more difficult to analyse mathematically. In this paper, we focus on the computation of first passage events and their probabilities in biological systems with non exponential inter-event times. We show, with three case studies from Molecular Immunology, Virology and Epidemiology, that significant errors are introduced when drawing conclusions based on the assumption that inter-event times are exponentially distributed. Our approach allows these errors to be avoided with the use of phase-type distributions that approximate arbitrarily distributed inter-event times. PMID- 30305645 TI - Hesperidin and capsaicin, but not the combination, prevent hepatic steatosis and other metabolic syndrome-related alterations in western diet-fed rats. AB - We aimed to assess the potential effects of hesperidin and capsaicin, independently and in combination, to prevent the development of obesity and its related metabolic alterations in rats fed an obesogenic diet. Three-month-old male Wistar rats were divided into 5 groups: Control (animals fed a standard diet), WD (animals fed a high fat/sucrose (western) diet), HESP (animals fed a western diet + hesperidin (100 mg/kg/day)), CAP (animals fed a western diet + capsaicin (4 mg/kg/day)), and HESP + CAP (animals fed a western diet + hesperidin (100 mg/kg/day) + capsaicin (4 mg/kg/day)). Hesperidin and capsaicin were administered by gavage. Capsaicin decreased body fat gain and prevented insulin resistance, whereas hesperidin showed little effect on body fat gain and no apparent effects on insulin resistance. No additive effects were observed with the combination. Capsaicin and hesperidin, separately, improved blood lipid profile, diminished hepatic lipid accumulation, and prevented non-alcoholic steatohepatitis in western diet-fed rats, but the combination showed lower effects. Hesperidin alone, and to a lesser extent capsaicin or the combination, displayed hypotensive effects in western diet-fed rats. In conclusion, capsaicin and hesperidin, separately, exhibit health beneficial effects on metabolic syndrome-related alterations in western diet-fed rats, but the effects are mitigated with the combination. PMID- 30305647 TI - Genome-wide expression profiling of glioblastoma using a large combined cohort. AB - Glioblastomas (GBMs), are the most common intrinsic brain tumors in adults and are almost universally fatal. Despite the progresses made in surgery, chemotherapy, and radiation over the past decades, the prognosis of patients with GBM remained poor and the average survival time of patients suffering from GBM was still short. Discovering robust gene signatures toward better understanding of the complex molecular mechanisms leading to GBM is an important prerequisite to the identification of novel and more effective therapeutic strategies. Herein, a comprehensive study of genome-scale mRNA expression data by combining GBM and normal tissue samples from 48 studies was performed. The 147 robust gene signatures were identified to be significantly differential expression between GBM and normal samples, among which 100 (68%) genes were reported to be closely associated with GBM in previous publications. Moreover, function annotation analysis based on these 147 robust DEGs showed certain deregulated gene expression programs (e.g., cell cycle, immune response and p53 signaling pathway) were associated with GBM development, and PPI network analysis revealed three novel hub genes (RFC4, ZWINT and TYMS) play important role in GBM development. Furthermore, survival analysis based on the TCGA GBM data demonstrated 38 robust DEGs significantly affect the prognosis of GBM in OS (p < 0.05). These findings provided new insights into molecular mechanisms underlying GBM and suggested the 38 robust DEGs could be potential targets for the diagnosis and treatment. PMID- 30305646 TI - Glucocorticoids Induce Stress Oncoproteins Associated with Therapy-Resistance in African American and European American Prostate Cancer Cells. AB - Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities. PMID- 30305648 TI - The role of acetyltransferases for the temporal-specific accessibility of beta catenin to the myogenic gene locus. AB - Molecules involved in WNT/beta-catenin signaling show spatiotemporal-specific expression and play vital roles in muscle development. Our previous study showed that WNT/beta-catenin signaling promotes myoblast proliferation and differentiation through the regulation of the cyclin A2 (Ccna2)/cell division cycle 25C (Cdc25c) and Fermitin family homolog 2 (Fermt2) genes, respectively. However, it remains unclear how beta-catenin targets different genes from stage to stage during myogenesis. Here, we show that the accessibility of beta-catenin to the promoter region of its target genes is regulated by developmental stage specific histone acetyltransferases (HATs), lysine acetyltransferase 2B (KAT2B), and cAMP-response element-binding protein (CREB)-binding protein (CBP). We found that KAT2B was specifically expressed at the myoblast proliferation stage and formed a complex with beta-catenin to induce Ccna2/Cdc25c expression. On the other hand, CBP was specifically expressed during myoblast differentiation and formed a complex with beta-catenin to induce Fermt2 expression. Our findings indicate that beta-catenin efficiently accesses to its target gene's promoters by forming a complex with developmental stage-specific acetyltransferases during myogenesis. PMID- 30305649 TI - Changes in brain arousal (EEG-vigilance) after therapeutic sleep deprivation in depressive patients and healthy controls. AB - Depressed patients frequently exhibit a hyperstable brain arousal regulation. According to the arousal regulation model of affective disorders, the antidepressant effect of therapeutic sleep deprivation could be achieved by counter-acting this dysregulation. We investigated the impact of partial sleep deprivation (PSD) on EEG-vigilance (an indicator of brain arousal regulation) in depressed patients (n = 27) and healthy controls (n = 16). PSD was hypothesized to cause a more prominent destabilisation of brain arousal regulation in depressed patients (reflected by increased occurrence of lower EEG-vigilance stages). Furthermore, it was studied whether responders (n = 17) exhibit a more stable baseline brain arousal regulation and would show a more prominent arousal destabilisation after PSD than non-responders (n = 10). Before PSD, patients showed a more stable EEG-vigilance with less declines to lower vigilance stages compared to controls. Contrary to the hypothesis, a greater destabilisation of brain arousal after PSD was seen in controls. Within the patient sample, responders generally showed a less stable EEG-vigilance, especially after PSD when we found significant differences compared to non-responders. EEG-vigilance in non-responders showed only little change from baseline to after PSD. In summary, PSD had a destabilizing impact on brain arousal regulation in healthy controls whereas depressed patients reacted heterogeneously depending on the outcome of treatment. PMID- 30305650 TI - Improved Parallel Magnertic Resonance Imaging reconstruction with Complex Proximal Support Vector Regression. AB - Generalized Auto-calibrating Partially Parallel Acquisitions (GRAPPA) has been widely used to reduce imaging time in Magnetic Resonance Imaging. GRAPPA synthesizes missing data by using a linear interpolation of neighboring measured data over all coils, thus accuracy of the interpolation weights fitting to the auto-calibrating signal data is crucial for the GRAPPA reconstruction. Conventional GRAPPA algorithms fitting the interpolation weights with a least squares solution are sensitive to interpolation window size. MKGRAPPA that estimates the interpolation weights with support vector machine reduces the sensitivity of the k-space reconstruction to interpolation window size, whereas it is computationally expensive. In this study, a robust GRAPPA reconstruction method is proposed that applies an extended proximal support vector regression (PSVR) to fit the interpolation weights with wavelet kernel mapping. Experimental results on in vivo MRI data show that the proposed PSVR-GRAPPA method visually improves overall quality compared to conventional GRAPPA methods, while it has faster reconstruction speed compared to MKGRAPPA. PMID- 30305651 TI - Uni- and triaxial accelerometric signals agree during daily routine, but show differences between sports. AB - Accelerometers objectively monitor physical activity, and ongoing research suggests they can also detect patterns of body movement. However, different types of signal (uniaxial, captured by older studies, vs. the newer triaxial) and or/device (validated Actigraph used by older studies, vs. others) may lead to incomparability of results from different time periods. Standardization is desirable. We establish whether uniaxial signals adequately monitor routine activity, and whether triaxial accelerometry can detect sport-specific variations in movement pattern. 1402 adolescents wore triaxial Actigraphs (GT3X) for one week and diaried sport. Uni- and triaxial counts per minute were compared across the week and between over 30 different sports. Across the whole recording period 95% of variance in triaxial counts was explained by the vertical axis (5th percentile for R2, 91%). Sport made up a small fraction of daily routine, but differences were visible: even when total acceleration was comparable, little was vertical in horizontal movements, such as ice skating (uniaxial counts 41% of triaxial) compared to complex movements (taekwondo, 55%) or ambulation (soccer, 69%). Triaxial accelerometry captured differences in movement pattern between sports, but so little time was spent in sport that, across the whole day, uni- and triaxial signals correlated closely. This indicates that, with certain limitations, uniaxial accelerometric measures of routine activity from older studies can be feasibly compared to triaxial measures from newer studies. Comparison of new studies based on raw accelerations to older studies based on proprietary devices and measures (epochs, counts) will require additional efforts which are not addressed in this paper. PMID- 30305653 TI - GOGO: An improved algorithm to measure the semantic similarity between gene ontology terms. AB - Measuring the semantic similarity between Gene Ontology (GO) terms is an essential step in functional bioinformatics research. We implemented a software named GOGO for calculating the semantic similarity between GO terms. GOGO has the advantages of both information-content-based and hybrid methods, such as Resnik's and Wang's methods. Moreover, GOGO is relatively fast and does not need to calculate information content (IC) from a large gene annotation corpus but still has the advantage of using IC. This is achieved by considering the number of children nodes in the GO directed acyclic graphs when calculating the semantic contribution of an ancestor node giving to its descendent nodes. GOGO can calculate functional similarities between genes and then cluster genes based on their functional similarities. Evaluations performed on multiple pathways retrieved from the saccharomyces genome database (SGD) show that GOGO can accurately and robustly cluster genes based on functional similarities. We release GOGO as a web server and also as a stand-alone tool, which allows convenient execution of the tool for a small number of GO terms or integration of the tool into bioinformatics pipelines for large-scale calculations. GOGO can be freely accessed or downloaded from http://dna.cs.miami.edu/GOGO/ . PMID- 30305654 TI - Spiral magnetic domain structure in cylindrically-shaped microwires. AB - Identification and characterisation of novel and unusual magnetization states remains a topic of research in modern magnetism. Recently, control of the magnetization state between the surface and volume in cylindrical microwires with the giant magneto-impedance effect has been demonstrated. Herein, the phenomenon of spatial migration of spiral magnetic domains inside a microwire is demonstrated using the magneto-optical Kerr effect. The main properties of the inclined spiral structure were determined, where the surface domain structure possessed a length limited only by actual sample length. Transformation of the structure from a spiral to an elliptical structure could be controlled by external torsion stress. Hysteresis and magnetic images were simulated based on a model assuming a spatial distribution of the internal stress inside the microwire, whose results were consistent with the experimental results. A consistent interpretation of the results in terms of the formation and transformation of the spiral magnetic domain structure is proposed. PMID- 30305652 TI - The impact of frequent napping and nap practice on sleep-dependent memory in humans. AB - Napping benefits long-term memory formation and is a tool many individuals use to improve daytime functioning. Despite its potential advantages, approximately 47% of people in the United States eschew napping. The goal of this study was to determine whether people who endorse napping at least once a week (nap+) show differences in nap outcomes, including nap-dependent memory consolidation, compared with people who rarely or never nap (nap-). Additionally, we tested whether four weeks of nap practice or restriction would change sleep and performance profiles. Using a perceptual learning task, we found that napping enhanced performance to a greater degree in nap+ compared with nap- individuals (at baseline). Additionally, performance change was associated with different electrophysiological sleep features in each group. In the nap+ group, spindle density was positively correlated with performance improvement, an effect specific to spindles in the hemisphere contralateral to the trained visual field. In the nap- group, slow oscillatory power (0.5-1 Hz) was correlated with performance. Surprisingly, no changes to performance or brain activity during sleep emerged after four weeks of nap practice or restriction. These results suggest that individual differences may impact the potential benefits of napping on performance and the ability to become a better napper. PMID- 30305656 TI - Direct Enzymatic Glucose/O2 Biofuel Cell based on Poly-Thiophene Carboxylic Acid alongside Gold Nanostructures Substrates Derived through Bipolar Electrochemistry. AB - Bipolar electrochemistry (BPE) has been lately explored as a simple, reliable and novel electrochemical technique for the adjustment of various conductive substrates. Herein, BPE is performed to derive both of cathode and anode electrodes for the development of mediatorless/membraneless biofuel cell (BFC). On one hand, a preferable substrate for immobilization of bilirubin oxidase enzyme is prepared based on the electropolymerization of thiophene-3-carboxcylic acid (TCA) on an Au microfilm as a bipolar electrode. The resulted biocathode as novel bioelectrocatalyst offers a high electrocatalytic activity toward direct oxygen reduction reaction (ORR) with onset potential and current density of 0.55 V (vs. Ag/AgCl) and 867 MUA cm-2, respectively. On the other hand, another analogous Au bipolar electrode is electroplated through BPE to derive Au nanostructures (AuNSs). This modified Au electrode is utilized as an anodic platform for immobilization of flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) enzyme aimed at electrocatalytic glucose oxidation. The prepared bioanode displays a current density of 2.7 mA cm-2 with onset potential of -0.03 V. Finally, the proposed bioanode and biocacthode in an assembled membraneless glucose/O2 BFC offers a power output of 146 MUW cm-2 with open circuit voltage of 0.54 V. This novel BPE method provides disposable electrochemical platforms for design of novel sensors, biosensors or other devices. PMID- 30305655 TI - 13C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI. AB - Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1 13C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-13C]pyruvate and ethyl-[1-13C]pyruvate in naive brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well characterised rat model of brain metastasis that the appearance of hyperpolarized [1-13C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-13C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies. PMID- 30305658 TI - Bone mineral density assessment using iterative reconstruction compared with quantitative computed tomography as the standard of reference. AB - This study examines the influence of iterative reconstruction on bone mineral density (BMD) measurement by comparison with standard quantitative computed tomography (QCT; reference) and two other protocols based on filtered back projection. Ten human cadaver specimens of the lumbar spine with a hydroxyapatite calibration phantom underneath, were scanned with 4 protocols: 1. standard QCT, 2. volume scan with FBP, 3. helical scan with FBP, and 4. helical scan with IR (Adaptive Iterative Dose Reduction 3D (AIDR3D)). Radiation doses were recorded as CT dose index (CTDIvol) and BMD, signal-to-noise and contrast-to-noise ratio were calculated. Mean hydroxyapatite concentration (HOA) did not differ significantly between protocols, ranging from 98.58 +/- 31.09 mg cm3 (protocol 4) to 100.47 +/- 30.82 mg cm3 (protocol 2). Paired sample correlations of HOA values for protocol 4 and protocols 1, 2 and 3 were nearly perfect with coefficients of 0.980, 0.979 and 0.982, respectively (p < 0.004). CTDIvol were 7.50, 5.00, 6.82 (+/-2.03) and 1.72 (+/-0.50) mGy for protocols 1, 2, 3 and 4 respectively. Objective image quality was highest for protocol 4. The use of IR for BMD assessment significantly lowers radiation exposure compared to standard QCT and protocols with FBP while not degrading BMD measurement. PMID- 30305657 TI - Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans. AB - Active matrix Gla protein (MGP), a potent inhibitor of calcification in large arteries, protects against macrovascular complications. Recent studies suggested that active MGP helps maintaining the integrity of the renal and myocardial microcirculation, but its role in preserving the retinal microcirculation remains unknown. In 935 randomly recruited Flemish participants (mean age, 40.9 years; 50.3% women), we measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker of poor vitamin K status using an ELISA-based assay at baseline (1996 2010) and retinal microvascular diameters using IVAN software (Vasculomatic ala Nicola, version 1.1) including the central retinal arteriolar (CRAE) and venular (CRVE) equivalent and the arteriole-to-venule ratio (AVR) at follow-up (2008 2015). CRAE (P = 0.005) and AVR (P = 0.080) at follow-up decreased across tertiles of the dp-ucMGP distribution. In unadjusted models, for a doubling of dp ucMGP at baseline, CRAE and AVR at follow-up respectively decreased by 1.40 um (95% confidence interval [CI], 0.32 to 2.48; P = 0.011) and 0.006 (CI, 0.001 to 0.011; P = 0.016). In multivariable-adjusted models accounting for sex, baseline characteristics and follow-up duration, these estimates were -1.03 um (CI, -1.96 to -0.11; P = 0.028) and -0.007 (CI, -0.011 to -0.002; P = 0.007). Additional adjustment for changes from baseline to follow-up in major baseline characteristics yielded as estimates -0.91 um (CI, -1.82 to -0.01; P = 0.048) and -0.006 (95% CI, -0.011 to -0.001; P = 0.014), respectively. Circulating inactive dp-ucMGP is a long-term predictor of smaller retinal arteriolar diameter in the general population. Our observations highlight the possibility that vitamin K supplementation might promote retinal health. PMID- 30305659 TI - Mobility of A Water Droplet on Liquid Phase of N-Octadecane Coated Hydrophobic Surface. AB - A water droplet behavior on the liquid n-octadecane film is investigated. The coating of hydrophobic surface by N-octadecane film provides exchange of wetting state on the surface. The polycarbonate surface is crystallized and the functionalized silica particles are placed on the resulting surface prior to thin film coating of n-octadecane. A high-speed camera is used to monitor dynamic characteristics of the droplet on the inclined film. The findings reveal that deposition of thin n-octadecane film on hydrophobic surface results in reversibly exchange of the wetting state at the surface, which remains hydrophobic when n octadecane film is in solid phase while it becomes hydrophilic when n-octadecane film liquefies. Droplet transition velocity predicted agrees well with the experimental data. Sliding mode of the water droplet governs droplet transition on the liquid surface. Droplet pinning force, due to interfacial tension, dominates over the other retention forces including drag and shear. PMID- 30305660 TI - High temperature tribology of polymer derived ceramic composite coatings. AB - Polymer derived ceramic (PDC) composite coatings were deposited on AISI 304 substrates using siloxane based preceramic polymer polymethlysilsquioxane (PMS) and ZrSi2 as active filler or Ag as passive filler. The tribological performance of the composite coatings was evaluated at room temperature and moderately high temperatures (150 degrees C, 200 degrees C, 300 degrees C and 400 degrees C). The composite coatings showed low coefficient of friction (COF), u, from 0.08 to 0.2 for SiOC-ZrSi2 composite coatings, and from 0.02 to 0.3 for SiOC-Ag composite coatings, at room temperature with increasing normal load from 1 to 5 N. High temperature tribology tests showed high COF values from 0.4 to 1 but low wear for SiOC-ZrSi2 coating, and low COF from 0.2 to 0.3 for SiOC-Ag coatings at lower temperature ranges. Low load friction tests at room temperature showed negligible wear in SiOC-ZrSi2 coatings, suggesting good wear resistant and lubricating properties due to formation of t-ZrO2 and carbon. Low COF and high amount of wear was observed in SiOC-Ag composite coatings at room temperature due to high ductility of Ag and smearing of wear debris in the wear track. The coatings and wear tracks were characterized to evaluate the lubrication and wear behavior. PMID- 30305661 TI - In silico-prediction of protein-protein interactions network about MAPKs and PP2Cs reveals a novel docking site variants in Brachypodium distachyon. AB - Protein-protein interactions (PPIs) underlie the molecular mechanisms of most biological processes. Mitogen-activated protein kinases (MAPKs) can be dephosphorylated by MAPK-specific phosphatases such as PP2C, which are critical to transduce extracellular signals into adaptive and programmed responses. However, the experimental approaches for identifying PPIs are expensive, time consuming, laborious and challenging. In response, many computational methods have been developed to predict PPIs. Yet, these methods have inherent disadvantages such as high false positive and negative results. Thus, it is crucial to develop in silico approaches for predicting PPIs efficiently and accurately. In this study, we identified PPIs among 16 BdMAPKs and 86 BdPP2Cs in B. distachyon using a novel docking approach. Further, we systematically investigated the docking site (D-site) of BdPP2C which plays a vital role for recognition and docking of BdMAPKs. D-site analysis revealed that there were 96 pairs of PPIs including all BdMAPKs and most BdPP2Cs, which indicated that BdPP2C may play roles in other signaling networks. Moreover, most BdPP2Cs have a D-site for BdMAPKs in our prediction results, which suggested that our method can effectively predict PPIs, as confirmed by their 3D structure. In addition, we validated this methodology with known Arabidopsis and yeast phosphatase-MAPK interactions from the STRING database. The results obtained provide a vital research resource for exploring an accurate network of PPIs between BdMAPKs and BdPP2Cs. PMID- 30305663 TI - Evaluation of the thermal aging of delta-ferrite in austenitic stainless steel welds by electrochemical analysis. AB - Cr-segregation by spinodal decomposition and G-phase precipitation were observed in delta-ferrite of austenitic stainless steel welds thermally aged at 400 degrees C for up to 20,000 h. A reversion heat treatment (R-HT) at 550 degrees C for 1 h dissolved the Cr-segregation in the aged welds while some intermetallic precipitates were present. The double-loop electrochemical potentiokinetic reactivation (DL-EPR) analysis showed no significant differences among them. However, after selective etching of the austenite phase, the DL-EPR values of delta-ferrite phase steadily increased with aging time due to the growth of Cr depleted regions by spinodal decomposition. The electrochemical behavior of delta ferrite after R-HT condition was similar to that of unaged welds, indicating the intermetallic precipitates did not affect the corrosion resistance in this case. Overall, DL-EPR analysis of delta-ferrite phase provided better correlation with spinodal decomposition. PMID- 30305662 TI - Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice. AB - Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E deficient (Apoe-/-) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe-/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe-/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content. PMID- 30305664 TI - High extinction ratio super pixel for long wavelength infrared polarization imaging detection based on plasmonic microcavity quantum well infrared photodetectors. AB - Polarization imaging detection has its unique advantage in discriminating the man made objects from natural objects. Grating integrated super pixel for polarization imaging detection can simultaneously obtain the first three elements of the Stokes vector, which is the trend of infrared polarization imaging detection in recent years. Here, we demonstrate the first super pixel for long wavelength infrared polarization imaging detection with the extinction ratio of its four polarization directions more than 100. The measured highest polarization extinction ratio is as high as 136, which is the highest reported value of long wavelength infrared polarization imaging detection super pixel. The mechanism is attributed to the excellent mode selectivity of plasmonic microcavity according to the results of three-dimensional theoretical simulation. The experimental responses of the super pixel with four polarization directions are in good agreement with the Malus' Law. In addition, the super pixel can accurately resolve the Stokes parameters at the same time. It is expected to develop the super pixel into a new generation of practical high-polarization-discriminating long wavelength infrared focal plane array. PMID- 30305665 TI - Volatiles from Aquilaria sinensis damaged by Heortia vitessoides larvae deter the conspecific gravid adults and attract its predator Cantheconidea concinna. AB - The effects of induced plant responses on herbivores are categorised as direct, by reducing herbivore development, or indirect, by affecting the performance of natural enemies. Here, we investigated a tritrophic system, which included the herbivore Heortia vitessoides, its host plant Aquilaria sinensis, and its predator Cantheconidea concinna. Herbivore-damaged A. sinensis plants released significantly greater amounts of volatiles than undamaged and mechanically damaged plants, with an obvious temporal trend. One day after initial herbivore damage, A. sinensis plants released large amounts of volatile compounds. Volatile compounds release gradually decreased over the next 3 d. The composition and relative concentrations of the electroantennographic detection (EAD)-active compounds, emitted after herbivore damage, varied significantly over the 4-d measurement period. In wind tunnel bioassays, mated H. vitessoides females showed a preference for undamaged plants over herbivore and mechanically damaged A. sinensis plants. In Y-tube bioassays, C. concinna preferred odours from herbivore damaged plants to those from undamaged plants, especially after the early stages of insect attack. Our results indicate that the herbivore-induced compounds produced in response to attack by H. vitessoides larvae on A. sinensis plants could be used by both the herbivores themselves and their natural enemies to locate suitable host plants and prey, respectively. PMID- 30305666 TI - Distinguishing Ewing sarcoma and osteomyelitis using FTIR spectroscopy. AB - The differential diagnosis of Ewing sarcoma and osteomyelitis can be challenging and can lead to delays in treatment with possibly devastating results. In this retrospective, small-cohort study we demonstrate, that the Fourier Transformed Infrared (FTIR) spectra of osteomyelitis bone tissue can be differentiated from Ewing sarcoma and normal bone tissue sampled outside tumour area. Significant differences in osteomyelitis samples can be seen in lipid and protein composition. Supervised learning using a quadratic discriminant analysis classifier was able to differentiate the osteomyelitis samples with high accuracy. FTIR spectroscopy, alongside routine radiological and histopathological methods, may offer an additional tool for the differential diagnosis of osteomyelitis and ES. PMID- 30305668 TI - MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1 alpha signalling in beige adipocytes. AB - Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and beta3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown. We investigated the role of miR-494-3p in mitochondrial biogenesis during adipogenesis and browning. Intermittent mild cold exposure of mice induced PPARgamma coactivator1-alpha (PGC1-alpha) and mitochondrial TFAM, PDH, and ANT1/2 expression along with uncoupling protein-1 (Ucp1) in inguinal white adipose tissue (iWAT). miR-494-3p levels were significantly downregulated in iWAT upon cold exposure (p < 0.05). miR-494-3p overexpression substantially reduced PGC1-alpha expression and its downstream targets TFAM, PDH and MTCO1 in 3T3-L1 white and beige adipocytes (p < 0.05). miR 494-3p inhibition in 3T3-L1 white adipocytes resulted in increased PDH (p < 0.05). PGC1-alpha, TFAM and Ucp1 mRNA levels were robustly downregulated by miR 494-3p overexpression in 3T3-L1 beige adipocytes, along with strongly decreased oxygen consumption rate. PGC1-alpha and Ucp1 proteins were downregulated by miR 494-3p in primary beige cells (p < 0.05). Luciferase assays confirmed PGC1-alpha as a direct gene target of miR-494-3p. Our findings demonstrate that decreased miR-494-3p expression during browning regulates mitochondrial biogenesis and thermogenesis through PGC1-alpha. PMID- 30305667 TI - Gut microbiome modulation during treatment of mucositis with the dairy bacterium Lactococcus lactis and recombinant strain secreting human antimicrobial PAP. AB - Mucositis is an inflammatory condition of the gut, caused by an adverse effect of chemotherapy drugs, such as 5-fluorouracil (5-FU). In an attempt to develop alternative treatments for the disease, several research groups have proposed the use of probiotics, in particular, Lactic Acid Bacteria (LAB). In this context, the use of recombinant LAB, for delivering anti-inflammatory compounds has also been explored. In previous work, we demonstrated that either Lactococcus lactis NZ9000 or a recombinant strain expressing an antimicrobial peptide involved in human gut homeostasis, the Pancreatitis-associated Protein (PAP), could ameliorate 5-FU-induced mucositis in mice. However, the impact of these strains on the gut microbiota still needs to be elucidated. Therefore, in the present study, we aimed to characterize the effects of both Lactococci strains in the gut microbiome of mice through a 16 S rRNA gene sequencing metagenomic approach. Our data show 5-FU caused a significant decrease in protective bacteria and increase of several bacteria associated with pro-inflammatory traits. The Lactococci strains were shown to reduce several potential opportunistic microbes, while PAP delivery was able to suppress the growth of Enterobacteriaceae during inflammation. We conclude the strain secreting antimicrobial PAP was more effective in the control of 5-FU-dysbiosis. PMID- 30305669 TI - Lying down frequency as a discomfort index in heat stressed Holstein bull calves. AB - Changes in lying behaviour in response to extreme ambient temperatures have not been examined in dairy calves so far. In this study, lying time, and frequency of lying down were investigated in shaded (n = 8) and non-shaded (n = 8) Holstein bull calves during a 5-d period [temperature, average/max ( degrees C); Day 1 (control, all calves shaded): 22.9/29.4, Day 2 (heat stress day): 28.3/38.8, Day 3: 26.2/33.5, Day 4: 23.7/28.7, and Day 5: 21.2/24.7]. The thermal environment around the calves was characterized by the temperature-humidity index (THI). A three-dimension accelerometer was used to record posture of the calves and lying time and lying down frequency were analysed with 4-h sampling intervals. On Day 1 no differences were found in THI between the shaded and non-shaded environments. On Days 2, 3 and 4 maximal and average THI were higher in the shaded than those recorded for the non-shaded environment. On Day5 no significant differences in THI were observed between calf environments. A similar diurnal pattern of lying time and lying down frequency was observed in both groups. Lying times were shorter during the afternoon (P = 0.003); however, no group differences were found in lying time (P = 0.551). During the daytime (between 8:00 and 20:00), the frequency of lying down was 50, 33, and 41% higher, respectively, than during the nighttime on Days 2, 3 and 4 (P < 0.001, P = 0.011, and P < 0.001). On the heat stress day, non-shaded calves changed posture 88.4 and 76.6% more often than shaded ones between 8:00 and 12:00 and 12:00 and 16:00, respectively (P < 0.001 for both intervals). Similar group differences were observed for Day 3 between 8:00 and 12:00 (71.2%) and Day 4 between 12:00 and 16:00 (76.6%), respectively (P = 0.003, and P = 0.001). On Day 5, there was no difference between groups (P = 0.732). As indicated by our results, heat stress causes changes in lying down frequency and lying time in dairy calves. Supplemental shading reduces discomfort as indicated by lying down frequency, but not by lying time. PMID- 30305671 TI - The distribution and lifetime of powerful radio galaxies as a function of environment and redshift. AB - Correlations between jet power and active time for z < 0.1 high excitation and low excitation radio galaxies are explored as well as evidence in favor of a specific, non-random distribution for these objects including mid-infrared emitting radio galaxies as a function of environment and redshift. In addition, so-called weak line radio galaxies with FRII jet morphology have been identified as a class of active galaxies in the process of shutting down. This paper identifies common features between these seemingly disparate phenomena described above for the population of radio galaxies, and strings them together by way of a simple phenomenological framework that has shed light on the radio loud/radio quiet dichotomy, the jet-disk connection, and the distribution of all active galaxies as a function of redshift. PMID- 30305670 TI - Expression analysis of Cell wall invertase under abiotic stress conditions influencing specialized metabolism in Catharanthus roseus. AB - Catharanthus roseus is a commercial source for anti-cancer terpenoid indole alkaloids (TIAs: vincristine and vinblastine). Inherent levels of these TIAs are very low, hence research studies need to focus on enhancing their levels in planta. Since primary metabolism provides precursors for specialized-metabolism, elevating the former can achieve higher amounts of the latter. Cell Wall Invertase (CWIN), a key enzyme in sucrose-metabolism catalyses the breakdown of sucrose into glucose and fructose, which serve as carbon-skeleton for specialized metabolites. Understanding CWIN regulation could unravel metabolic-engineering approaches towards enhancing the levels of TIAs in planta. Our study is the first to characterize CWIN at gene-expression level in the medicinal plant, C. roseus. The CWINs and their inter-relationship with sucrose and TIA metabolism was studied at gene and metabolite levels. It was found that sucrose-supplementation to C. roseus leaves significantly elevated the monomeric TIAs (vindoline, catharanthine) and their corresponding genes. This was further confirmed in cross species, wherein Nicotiana benthamiana leaves transiently-overexpressing CrCWIN2 showed significant upregulation of specialized-metabolism genes: NbPAL2, Nb4CL, NbCHS, NbF3H, NbANS, NbHCT and NbG10H. The specialized metabolites- cinnamic acid, coumarin, and fisetin were significantly upregulated. Thus, the present study provides a valuable insight into metabolic-engineering approaches towards augmenting the levels of therapeutic TIAs. PMID- 30305674 TI - Marine microalgae commercial production improves sustainability of global fisheries and aquaculture. AB - A method is described for saving 30% of the world fish catch by producing fishmeal and fish oil replacement products from marine microalgae, the natural source of proteins and oils in the marine food web. To examine the commercial aspects of such a method, we adapt a model based on results of microalgae production in Hawaii and apply it to Thailand, the world's fourth largest producer of fishmeal. A model facility of 111 ha would produce 2,750 tonnes yr-1 of protein and 2,330 tonnes yr-1 of algal oil, at a capital cost of $29.3 M. Such a facility would generate $5.5 M in average annual net income over its 30-year lifetime. Deployment of 100 such facilities in Thailand would replace all domestic production of fishmeal, 10% of world production, on ~1.5% of the land now used to cultivate oil palm. Such a global industry would generate ~$6.5 billion in annual net income. PMID- 30305673 TI - Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis - Tampere Vascular Study. AB - alpha-melanocyte-stimulating hormone (alpha-MSH) is processed from pro opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. alpha-MSH also promotes macrophage reverse cholesterol transport by inducing ATP binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and alpha-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. alpha-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating alpha-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque alpha-MSH levels. Second, immunohistochemical analyses revealed the presence of alpha-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of alpha-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, alpha-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of alpha-MSH might protect against atherosclerosis. PMID- 30305672 TI - CX3CR1 differentiates F4/80low monocytes into pro-inflammatory F4/80high macrophages in the liver. AB - The expression of chemokine receptor CX3CR1 is related to migration and signaling in cells of the monocyte-macrophage lineage. The precise roles of CX3CR1 in the liver have been investigated but not clearly elucidated. Here, we investigated the roles of CX3CR1 in hepatic macrophages and liver injury. Hepatic and splenic CX3CR1lowF4/80low monocytes and CX3CR1lowCD16- monocytes were differentiated into CX3CR1highF4/80high or CX3CR1highCD16+ macrophages by co-culture with endothelial cells. Moreover, CX3CL1 deficiency in human umbilical vein endothelial cells (HUVECs) attenuated the expression of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), whereas recombinant CX3CL1 treatment reversed this expression in co-cultured monocytes. Upon treatment with clodronate liposome, hepatic F4/80high macrophages were successfully depleted at day 2 and recovered similarly in CX3CR1+/GFP and CX3CR1GFP/GFP mice at week 4, suggesting a CX3CR1-independent replacement. However, F4/80high macrophages of CX3CR1+/GFP showed a stronger pro-inflammatory phenotype than CX3CR1GFP/GFP mice. In clodronate-treated chimeric CX3CR1+/GFP and CX3CR1GFP/GFP mice, CX3CR1+F4/80high macrophages showed higher expression of IL-1beta and TNF-alpha than CX3CR1 F4/80high macrophages. In alcoholic liver injury, despite the similar frequency of hepatic F4/80high macrophages, CX3CR1GFP/GFP mice showed reduced liver injury, hepatic fat accumulation, and inflammatory responses than CX3CR1+/GFP mice. Thus, CX3CR1 could be a novel therapeutic target for pro-inflammatory macrophage mediated liver injury. PMID- 30305675 TI - Revealing particle-scale powder spreading dynamics in powder-bed-based additive manufacturing process by high-speed x-ray imaging. AB - Powder spreading is a key step in the powder-bed-based additive manufacturing process, which determines the quality of the powder bed and, consequently, affects the quality of the manufactured part. However, powder spreading behavior under additive manufacturing condition is still not clear, largely because of the lack of particle-scale experimental study. Here, we studied particle-scale powder dynamics during the powder spreading process by using in-situ high-speed high energy x-ray imaging. Evolution of the repose angle, slope surface speed, slope surface roughness, and the dynamics of powder clusters at the powder front were revealed and quantified. Interactions of the individual metal powders, with boundaries (substrate and container wall), were characterized, and coefficients of friction between the powders and boundaries were calculated. The effects of particle size on powder flow dynamics were revealed. The particle-scale powder spreading dynamics, reported here, are important for a thorough understanding of powder spreading behavior in the powder-bed-based additive manufacturing process, and are critical to the development and validation of models that can more accurately predict powder spreading behavior. PMID- 30305676 TI - Trypsinogen isoforms in the ferret pancreas. AB - The domestic ferret (Mustela putorius furo) recently emerged as a novel model for human pancreatic diseases. To investigate whether the ferret would be appropriate to study hereditary pancreatitis associated with increased trypsinogen autoactivation, we purified and cloned the trypsinogen isoforms from the ferret pancreas and studied their functional properties. We found two highly expressed isoforms, anionic and cationic trypsinogen. When compared to human cationic trypsinogen (PRSS1), ferret anionic trypsinogen autoactivated only in the presence of high calcium concentrations but not in millimolar calcium, which prevails in the secretory pathway. Ferret cationic trypsinogen was completely defective in autoactivation under all conditions tested. However, both isoforms were readily activated by enteropeptidase and cathepsin B. We conclude that ferret trypsinogens do not autoactivate as their human paralogs and cannot be used to model the effects of trypsinogen mutations associated with human hereditary pancreatitis. Intra-pancreatic trypsinogen activation by cathepsin B can occur in ferrets, which might trigger pancreatitis even in the absence of trypsinogen autoactivation. PMID- 30305677 TI - Mechanisms Underlying the Regulation of HP1gamma by the NGF-PKA Signaling Pathway. AB - Heterochromatin protein 1 gamma (HP1gamma) is a well-known chromatin protein, which regulates gene silencing during the execution of processes associated with embryogenesis, organ maturation, and cell differentiation. We find that, in vivo, the levels of HP1gamma are downregulated during nervous system development. Similar results are recapitulated in vitro during nerve growth factor (NGF) induced neuronal cell differentiation in PC12 cells. Mechanistically, our experiments demonstrate that in differentiating PC12 cells, NGF treatment decreases the association of HP1gamma to silent heterochromatin, leads to phosphorylation of this protein at S83 via protein kinase A (PKA), and ultimately results in its degradation. Genome-wide experiments, using gain-of-function (overexpression) and loss-of-function (RNAi) paradigms, demonstrate that changing the level of HP1gamma impacts on PC12 differentiation, at least in part, through gene networks involved in this process. Hence, inactivation of HP1gamma by different post-translational mechanisms, including reduced heterochromatin association, phosphorylation, and degradation, is necessary for neuronal cell differentiation to occur. Indeed, we show that the increase of HP1gamma levels has the reverse effect, namely antagonizing neuronal cell differentiation, supporting that this protein acts as a barrier for this process. Thus, these results describe the regulation and participation of HP1gamma in a novel membrane to-nucleus pathway, through NGF-PKA signaling, which is involved in NGF-induced neuronal cell differentiation. PMID- 30305678 TI - Neck Lymph Node Metastasis as A Poor Prognostic Factor in Thoracic Esophageal Squamous Cell Carcinoma Patients Receiving Concurrent Chemoradiotherapy: A Propensity Score-Matched Analysis. AB - The present study investigated the clinical impact of neck lymph node (LN) metastasis in locally advanced inoperable thoracic esophageal squamous cell carcinoma (ESCC) patients who underwent concurrent chemoradiotherapy (CCRT) with a curative intent. There were 404 ESCC patients enrolled, including 35 patients with neck LN metastasis and 369 patients without such metastasis. Through the propensity score matching method, 35 patients of the 369 patients without neck LN metastasis were matched to the 35 patients with neck LN metastasis. Progression free survival (PFS) and overall survival (OS) were found to be significantly worse in the neck LN metastasis group compared to the full non-neck LN metastasis group (9.8 months versus 5.9 months, P < 0.001, and 18.2 months versus 9.7 months, P = 0.001) and the matched non-neck LN metastasis group (9.9 months versus 5.9 months, P = 0.006, and 19.4 months versus 9.7 months, P = 0.007). In order to determine the difference between neck LN and supraclavicular LN metastasis, seventy patients with supraclavicular LN metastasis were also selected from the 369 patients without neck LN metastasis for comparison. Subsequently, when compared to the ESCC patients with supraclavicular LN metastasis, significantly worse PFS (8.5 months versus 5.9 months, P = 0.026) and OS (17.2 months versus 9.7 months, P = 0.047) were still found in the ESCC patients with neck LN metastasis. Our study indicates that neck LN metastasis is an independent poor prognostic factor for locally advanced inoperable thoracic ESCC patients who have undergone CCRT. PMID- 30305679 TI - Current noninvasive liver reserve models do not predict histological fibrosis severity in hepatocellular carcinoma. AB - The Ishak scoring system has been used to stage liver fibrosis. Ten noninvasive liver reserve models were proposed to assess the severity of liver fibrosis, but their performance in hepatocellular carcinoma (HCC) is unknown. We aimed to evaluate the correlation between these models and severity of fibrosis in patients with HCC. A total 464 patients with HCC undergoing surgical resection were retrospectively analyzed. Multivariate logistic regression analysis was performed to determine independent factors associated with advanced fibrosis (Ishak score 4 or higher). There were no significant correlations between all noninvasive models and severity of fibrosis in HCC (p for trend all >0.1). In subgroup analysis, cirrhosis discriminant index (CDS) and Lok's index in hepatitis B-, and fibrosis index based on 4 factors (FIB-4), CDS and Lok's index in hepatitis C-associated HCC, best correlated with the severity of liver fibrosis. Low platelet count, prolonged prothrombin time, hepatitis C and multiple tumors were independently associated with advanced fibrosis. Among the 10 models, CDS was the best model to predict cirrhosis. Currently used noninvasive liver reserve models do not well correlate with severity of histological fibrosis in HCC. New noninvasive models are required to improve the predictive accuracy of liver fibrosis in HCC. PMID- 30305680 TI - A generalised framework for detailed classification of swimming paths inside the Morris Water Maze. AB - The Morris Water Maze is commonly used in behavioural neuroscience for the study of spatial learning with rodents. Over the years, various methods of analysing rodent data collected during this task have been proposed. These methods span from classical performance measurements to more sophisticated categorisation techniques which classify the animal swimming path into behavioural classes known as exploration strategies. Classification techniques provide additional insight into the different types of animal behaviours but still only a limited number of studies utilise them. This is primarily because they depend highly on machine learning knowledge. We have previously demonstrated that the animals implement various strategies and that classifying entire trajectories can lead to the loss of important information. In this work, we have developed a generalised and robust classification methodology to boost classification performance and nullify the need for manual tuning. We have also made available an open-source software based on this methodology. PMID- 30305681 TI - MiR-323b-5p acts as a novel diagnostic biomarker for critical limb ischemia in type 2 diabetic patients. AB - Type 2 diabetes mellitus (T2DM) is a major contributor to peripheral artery disease (PAD), especially in cases that advance to critical limb ischemia (CLI). Accumulating evidence indicates that miRNAs play an important role in the development of PAD and T2DM. Due to the limited value of current diagnostic methods for CLI in T2DM patients, we compared the miRNA expression profiles of Chinese T2DM patients with or without CLI to find out whether distinctive miRNAs could serve as potential diagnostic biomarkers. We statistically identified 7 miRNAs (hsa-miR-200b-3p, hsa-miR-2115-3p, hsa-miR-431-5p, hsa-miR-486-5p, hsa-miR 210-3p, hsa-miR-1264, hsa-miR-323b-5p) which were up-regulated in the CLI group, whereas other 4 miRNAs (hsa-miR-5579-3p, hsa-miR-665, hsa-miR-4285, hsa-miR-500a 3p) were down-regulated. Our validation test suggested a relatively high diagnostic accuracy of serum hsa-miR-323b-5p levels for the detection of CLI in T2DM patients, with a sensitivity of 62.67% and a specificity of 80.65%. The area under the curve (AUC) for miR-323b-5p + confounding risk factors was 0.94 (95% CI: 0.884-0.994, P < 0.001), which was higher than that for miR-323b-5p. Taken together, our results indicate that circulating hsa-miR-323b-5p could be a promising serum biomarker for the diagnosis of critical limb ischemia in type 2 diabetic patients. PMID- 30305682 TI - Tolloid-like 1 genetic variants determine fibrosis regression in chronic hepatitis C patients with curative antivirals. AB - Hepatitis C virus (HCV) eradication by antivirals promote fibrosis modification. Whether host genetics determined fibrosis regression in chronic hepatitis C (CHC) patients with sustained virological response (SVR) is to be determined. One hundred and fifty-six SVR patients with paired liver biopsy before and after antivirals were enrolled. Host genetic factors including single nucleotide polymorphism rs17047200 of tolloid-like 1(TLL-1) were analyzed for their association with fibrosis modification. The proportions of improved, unchanged and worsening fibrotic stags were 39.1% (n = 61), 39.1% (n = 61), and 21.8% (n = 34), respectively. The rate of annual fibrotic improvement was 0.16 +/- 0.79. There was a significant trend of increased fibrotic improvement rate in patients from F01 to F4 (P < 0.001). However, the rate of improvement seemed more limited in cirrhotic patients among those with advanced liver disease. Patients with fibrotic improvement had a significantly higher proportion of TLL-1 rs17047200 AA genotype compared to those without (92.5% vs. 79.3%, p = 0.039). Logistic regression analysis revealed that the TLL-1 rs17047200 AA genotype was the only independent factor associated with fibrosis improvement (odds ratio/95% confidence intervals: 3.2/1.01-10.12, p = 0.047). Compared with TLL-1 rs17047200 non-AA carriers, a significantly higher proportion of fibrosis improvement in AA genotype carriers was observed among patients with F0-2 (33.3% vs. 0%, p = 0.005) but not with F34 (70% vs. 80%, p = 1). We concluded that TLL-1 genetic variants determined fibrotic improvement in CHC with curative antivirals, particularly in patients with mild liver disease. PMID- 30305683 TI - Changing characteristics of the empathic communication network after empathy enhancement program for medical students. AB - The Empathy-Enhancement Program for Medical Students (EEPMS) comprises five consecutive weekly sessions and aims to improve medical students' empathic ability, an essential component of humanistic medical professionalism. Using a graph theory approach for the Ising network (based on l1-regularized logistic regression) comprising emotional regulation, empathic understanding of others' emotion, and emotional expressivity, this study aimed to identify the central components or hubs of empathic communication and the changed profile of integration among these hubs after the EEPMS. Forty medical students participated in the EEPMS and completed the Depression Anxiety Stress Scale-21, the Empathy Quotient-Short Form, the Jefferson Scale of Empathy, and the Emotional Expressiveness Scale at baseline and after the EEPMS. The Ising model-based network of empathic communication was retrieved separately at two time points. Agitation, self-efficacy for predicting others' feelings, emotional concealment, active emotional expression, and emotional leakage ranked in the top 20% in terms of nodal strength and betweenness and closeness centralities, and they became hubs. After the EEPMS, the 'intentional emotional expressivity' component became less locally segregated (P = 0.014) and more directly integrated into those five hubs. This study shows how to quantitatively describe the qualitative item-level effects of the EEPMS. The key role of agitation in the network highlights the importance of stress management in preserving the capacity for empathic communication. The training effect of EEPMS, shown by the reduced local segregation and enhanced integration of 'intentional emotional expressivity' with hubs, suggests that the EEPMS could enable medical students to develop competency in emotional expression, which is an essential component of empathic communication. PMID- 30305684 TI - Graphene Oxide-Gold Nanosheets Containing Chitosan Scaffold Improves Ventricular Contractility and Function After Implantation into Infarcted Heart. AB - Abnormal conduction and improper electrical impulse propagation are common in heart after myocardial infarction (MI). The scar tissue is non-conductive therefore the electrical communication between adjacent cardiomyocytes is disrupted. In the current study, we synthesized and characterized a conductive biodegradable scaffold by incorporating graphene oxide gold nanosheets (GO-Au) into a clinically approved natural polymer chitosan (CS). Inclusion of GO-Au nanosheets in CS scaffold displayed two fold increase in electrical conductivity. The scaffold exhibited excellent porous architecture with desired swelling and controlled degradation properties. It also supported cell attachment and growth with no signs of discrete cytotoxicity. In a rat model of MI, in vivo as well as in isolated heart, the scaffold after 5 weeks of implantation showed a significant improvement in QRS interval which was associated with enhanced conduction velocity and contractility in the infarct zone by increasing connexin 43 levels. These results corroborate that implantation of novel conductive polymeric scaffold in the infarcted heart improved the cardiac contractility and restored ventricular function. Therefore, our approach may be useful in planning future strategies to construct clinically relevant conductive polymer patches for cardiac patients with conduction defects. PMID- 30305685 TI - Improved safety standards are needed to better protect younger children at playgrounds. AB - Playground-related traumatic brain injuries (TBIs) in children remain a considerable problem world-wide and current safety standards are being questioned due to historical reasons where the injury thresholds had been perpetuated from automobile industry. Here we investigated head injury mechanisms due to falls on playgrounds using a previously developed and validated age-scalable and positionable whole body child model impacted at front, back and side of the head simulating head-first falls from 1.59 meters (m). The results show that a playground material passing the current testing standards (HIC < 1000 and resultant linear acceleration <200 g) resulted in maximum strain in the brain higher than known injury thresholds, thus not offering sufficient protection especially for younger children. The analysis highlights the age dependence of head injuries in children due to playground falls and the youngest have a higher risk of brain injury and skull fracture. Further, the results provide the first biomechanical evidence guiding age-dependent injury thresholds for playground testing standards. The results also have direct implications for novel designs of playground materials for a better protection of children from TBIs. Only making the playground material thicker and more compliant is not sufficient. This study represents the first initiative of using full body human body models of children as a new tool to improve playground testing standards and to better protect the children at playgrounds. PMID- 30305686 TI - Helvamide, a new inhibitor of sterol O-acyltransferase produced by the fungus Aspergillus nidulans BF-0142. AB - A new piperazine derivative designated helvamide was isolated as a pair of rotamers (1 and 2) from the culture broth of the fungus Aspergillus nidulans BF 0142 along with a known helvafuranone (3). The structures of 1 and 2 were elucidated based on spectroscopic analyses by the interpretation of one dimensional and two-dimensional nuclear magnetic resonance data, ROESY (rotational Overhauser effect spectroscopy) correlations, and a chemical method. Helvamide existed as a rotameric mixture (1 and 2) in dimethyl sulfoxide. Helvamide inhibited sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT2) in enzyme based and cell-based assays using SOAT1-expressing and SOAT2-expressing Chinese hamster ovary (CHO) cells. PMID- 30305687 TI - TRSP is dispensable for the Plasmodium pre-erythrocytic phase. AB - Plasmodium sporozoites deposited in the skin following a mosquito bite must migrate and invade blood vessels to complete their development in the liver. Once in the bloodstream, sporozoites arrest in the liver sinusoids, but the molecular determinants that mediate this specific homing are not yet genetically defined. Here we investigate the involvement of the thrombospondin-related sporozoite protein (TRSP) in this process using knockout Plasmodium berghei parasites and in vivo bioluminescence imaging in mice. Resorting to a homing assay, trsp knockout sporozoites were found to arrest in the liver similar to control parasites. Moreover, we found no defects in the establishment of infection in mice following inoculation of trsp knockout sporozoites via intravenous and cutaneous injection or mosquito bite. Accordingly, mutant sporozoites were also able to successfully invade hepatocytes in vitro. Altogether, these results suggest TRSP may have a redundant role in the completion of the pre-erythrocytic phase of the malaria parasite. Nonetheless, identifying molecules with paramount roles in this phase could aid in the search for new antigens needed for the design of a protective vaccine against malaria. PMID- 30305688 TI - 3'RR and 5'EMU immunoglobulin heavy chain enhancers are independent engines of locus remodeling. PMID- 30305689 TI - Weight management interventions for youth with autism spectrum disorder: a systematic review. AB - BACKGROUND AND OBJECTIVE: In response to the elevated levels of overweight and obesity among children with autism spectrum disorder (ASD), this article provides a systematic review of the extant empirical literature reporting the effect of weight management interventions (including exercise, diet, and medication) for youth with ASD. DESIGN: A systematic review of published studies. The databases CINAHL, Web of Science, ERIC, Pubmed, and PsychINFO were searched, revealing 12 studies that were eligible for review. RESULTS: Of the included studies, half (n = 6) demonstrated significant weight loss; including comprehensive (n = 3), pharmaceutical (n = 2), and exercise (n = 1) interventions. Of relevance, and concern, was that only one of the included studies was determined to be of strong research quality, with the majority (n = 8) determined as being of weak study quality. Furthermore, studies included highly heterogeneous treatment approaches, study designs, and sample characteristics. CONCLUSIONS: This review demonstrates the potential of interventions (particularly individualized, comprehensive, and multidisciplinary team- based interventions) to effectively impact on weight among youth with ASD. It is imperative to rigorously test these interventions in individuals with ASD given the rates of obesity in this population and complications that ensue. PMID- 30305690 TI - A statistical description of scattering at the quantum level. AB - Quantum physics is undoubtedly the most successful theory of the microscopic world, yet the complexities which arise in applying it even to simple atomic and molecular systems render the description of basic collision probabilities a formidable task. For this reason, approximations are often employed, the validity of which may be restricted to given energy regimes and/or targets and/or projectiles. Now we have found that the lognormal function, widely used for the probability distribution of macroscopic stochastic events (as diverse as periods of incubation of and recovery from diseases, size of grains, abundance of species, fluctuations in economic quantities, etc.) may also be employed to describe the energy dependence of inelastic collisions at the quantum level (including ionization, electron capture and excitation by electrons, positrons, protons, antiprotons, etc.), by allowing for the relevant threshold energy. A physical interpretation is discussed in this article by analogy with the heat capacity of few-level systems in solid state physics. We find the generality of the analysis to extend also to nuclear reactions. As well as aiding the description of collision probabilities for quantum systems, this finding is expected to impact also on the fundamental understanding of the interface between the classical and quantum domains. PMID- 30305692 TI - How does lorcaserin facilitate weight loss and who will benefit? PMID- 30305691 TI - Non-uniform Excitation States in Photoinduced Deformation of Amorphous Carbon Nitride Films. AB - Amorphous carbon nitride (a-CNx) films prepared via reactive radio frequency magnetron sputtering deform under on-off visible light illumination. We investigate the relationship between photoinduced deformation and surface electrical states via scanning electron microscopy with Ar+ laser irradiation (SEM-L). Two samples with different levels of photoinduced deformation are prepared. For the film with small photoinduced deformation, uniform secondary electron emission is observed on the film surface, regardless of whether the laser is on or off. On the a-CNx film, which has fifty times larger photoinduced deformation than the previous film, light and dark patches, similar to a speckle pattern, appear on the film surface in SEM-L images. This anomalous phenomenon indicates non-uniformity of the electrical states excited by laser light irradiation. A size of the patches is well correlated with an inhomogeneous distribution of sp3C and sp2C, Isp3C/Isp2C, obtained using soft X-ray emission spectroscopy (SXES). Simultaneously, temporal decrease in the sp3C component under illumination is obtained via SXES. PMID- 30305694 TI - Neonatal regulatory behavior problems are predicted by maternal early pregnancy overweight and obesity: findings from the prospective PREDO Study. AB - INTRODUCTION: Maternal overweight/obesity and comorbid hypertensive disorders and gestational diabetes associate with neurodevelopmental delay in the offspring in childhood. We hypothesize that these maternal conditions associate also with the offspring regulatory behavior problems and impact on neurodevelopment via the offspring regulatory behavior. METHODS: A number of 3117 women of the PREDO Study filled in a questionnaire on regulatory behavior problems at the child's mean age of 16.9 days and 2116 of them a questionnaire on developmental milestones at the child's mean age of 42.2 months. Data on maternal BMI and comorbid disorders come from the Finnish Medical Birth Register. RESULTS: Offspring of overweight/obese mothers in comparison to normal weight mothers had higher levels of regulatory behavior problems and 22% (95% confidence interval 5-42%) higher odds of having problems on multiple domains of behavioral regulation at the mean age of 16.9 days. Offspring regulatory behavior problems partially mediated the association between maternal overweight/obesity and developmental milestones comprising communication, gross motor, fine motor, problem solving, and personal/social domains of development. Comorbid disorders did not associate with offspring regulatory behavior problems. CONCLUSION: Regulatory behavior problems of the offspring have prenatal origins and partially mediate the effects of maternal overweight/obesity on offspring neurodevelopment. PMID- 30305695 TI - Hyperferritinaemia and hyperuricaemia - a causal connection? PMID- 30305693 TI - Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice. AB - The standard treatment for high-risk non-muscle invasive bladder cancer (BC) is the intravesical administration of live Mycobacterium bovis BCG. Previous studies suggest improving this therapy by implementing non-pathogenic mycobacteria, such as Mycobacterium brumae, and/or different vehicles for mycobacteria delivery, such as an olive oil (OO)-in-water emulsion. While it has been established that BCG treatment activates the immune system, the immune effects of altering the mycobacterium and/or the preparation remain unknown. In an orthotopic murine BC model, local immune responses were assessed by measuring immune cells into the bladder and macromolecules in the urine by flow cytometry and multiplexing, respectively. Systemic immune responses were analyzed by quantifying sera anti mycobacteria antibody levels and recall responses of ex vivo splenocytes cultured with mycobacteria antigens. In both BCG- and M. brumae-treated mice, T, NK, and NKT cell infiltration in the bladder was significantly increased. Notably, T cell infiltration was enhanced in OO-in-water emulsified mycobacteria-treated mice, and urine IL-6 and KC concentrations were elevated. Furthermore, mycobacteria treatment augmented IgG antibody production and splenocyte proliferation, especially in mice receiving OO-in-water emulsified mycobacteria. Our data demonstrate that intravesical mycobacterial treatment triggers local and systemic immune responses, which are most significant when OO-in-water emulsified mycobacteria are used. PMID- 30305696 TI - Ustekinumab - a novel treatment? PMID- 30305698 TI - Long-term safety of canakinumab in systemic JIA. PMID- 30305697 TI - IL-1beta blockade prevents gout attacks. PMID- 30305699 TI - DMARD-related adverse events lower persistence. PMID- 30305700 TI - New insights into the genetics and epigenetics of systemic sclerosis. AB - Systemic sclerosis (SSc) is a severe autoimmune disease that is characterized by vascular abnormalities, immunological alterations and fibrosis of the skin and internal organs. The results of genetic studies in patients with SSc have revealed statistically significant genetic associations with disease manifestations and progression. Nevertheless, genetic susceptibility to SSc is moderate, and the functional consequences of genetic associations remain only partially characterized. A current hypothesis is that, in genetically susceptible individuals, epigenetic modifications constitute the driving force for disease initiation. As epigenetic alterations can occur years before fibrosis appears, these changes could represent a potential link between inflammation and tissue fibrosis. Epigenetics is a fast-growing discipline, and a considerable number of important epigenetic studies in SSc have been published in the past few years that span histone post-translational modifications, DNA methylation, microRNAs and long non-coding RNAs. This Review describes the latest insights into genetic and epigenetic contributions to the pathogenesis of SSc and aims to provide an improved understanding of the molecular pathways that link inflammation and fibrosis. This knowledge will be of paramount importance for the development of medicines that are effective in treating or even reversing tissue fibrosis. PMID- 30305701 TI - Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management. AB - Osteoarthritis (OA) is a highly prevalent condition, and the hand is the most commonly affected site. Patients with hand OA frequently report symptoms of pain, functional limitations and frustration in undertaking everyday activities. The condition presents clinically with changes to the bone, ligaments, cartilage and synovial tissue, which can be observed using radiography, ultrasonography or MRI. Hand OA is a heterogeneous disorder and is considered to be multifactorial in aetiology. This Review provides an overview of the epidemiology, presentation and burden of hand OA, including an update on hand OA imaging (including the development of novel techniques), disease mechanisms and management. In particular, areas for which new evidence has substantially changed the way we understand, consider and treat hand OA are highlighted. For example, genetic studies, clinical trials and careful prospective imaging studies from the past 5 years are beginning to provide insights into the pathogenesis of hand OA that might uncover new therapeutic targets in the disease. PMID- 30305702 TI - Publisher Correction: Assessing spatial pattern separation in rodents using the object pattern separation task. AB - In the HTML version of this paper originally published online, text in Table 6 was misaligned in a way that made it difficult to determine which entries in the "Problem," "Possible reason," and "Solution" columns corresponded to one another. Additional but less severe alignment problems were also present in the PDF and print articles. These errors have been corrected in the HTML and PDF versions of the paper. PMID- 30305704 TI - The phylogenomics of evolving virus virulence. AB - How virulence evolves after a virus jumps to a new host species is central to disease emergence. Our current understanding of virulence evolution is based on insights drawn from two perspectives that have developed largely independently: long-standing evolutionary theory based on limited real data examples that often lack a genomic basis, and experimental studies of virulence-determining mutations using cell culture or animal models. A more comprehensive understanding of virulence mutations and their evolution can be achieved by bridging the gap between these two research pathways through the phylogenomic analysis of virus genome sequence data as a guide to experimental study. PMID- 30305703 TI - Oxaliplatin induces pH acidification in dorsal root ganglia neurons. AB - Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin. Reversal of the acidification indeed leads to a significantly reduced activity of TRPA1 channels. Last, acidification occurs also in vivo after a single injection of therapeutically-relevant doses of oxaliplatin. PMID- 30305706 TI - Choroidal morphology and short-term outcomes of combination photodynamic therapy in polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate outcomes of combined photodynamic therapy (PDT) and intravitreal bevacizumab in association with choroidal morphology in polypoidal choroidal vasculopathy (PCV). METHOD: Eighty-six PCV eyes (83 patients) treated with PDT in combination with intravitreal bevacizumab and followed for 1 year were evaluated. Choroidal morphological features including subfoveal choroidal thicknesses, diameter of pachyvessel, and choroidal vascularity were analyzed for association with responsiveness and recurrence. RESULT: Total choroid, Haller's layer, and pachyvessel were thicker in responders (n = 70) compared with non responders (n = 16) at baseline (298 vs. 227 MUm, 213 vs. 144 MUm, and 276 vs. 210 MUm, respectively; all P <= 0.001). Choroidal vascularity was significantly higher (0.68 vs 0.60, P < 0.001) and choroidal hyperpermeability was more frequent in responders (44 vs 13%, P = 0.018). Significant thinning of total choroid was observed in both responders and non-responders at 3 months after combination PDT (both P < 0.05), but the reduction was greater in responders (- 33 MUm vs. - 10 MUm, P = 0.036). In recurrent eyes (n = 26), increase in pachyvessel diameter and choroidal vascularity was observed at recurrence. CONCLUSION: Choroidal morphology including characteristic features of pachychoroid and high vascularity can serve as predictive factors for outcomes after combination PDT in eyes with PCV. PMID- 30305707 TI - 21st century glaucoma care. AB - Glaucoma care has evolved dramatically over the past generation, with changes that have incorporated new technology and improved understanding of the disease process. A major need is to construct a useful definition of glaucomatous optic neuropathy that can be used to compare data across clinical research studies. The treatment of glaucoma should now be based on achievement of a goal target for intraocular pressure, unique to each patient. Adherence with eye drop treatment is far from ideal and can be improved using reminder systems. Sustained delivery of glaucoma medication is on the horizon. New surgical approaches to glaucoma are being actively studied but have not as yet found their place in its care, with rigorous testing against present treatments needed. PMID- 30305705 TI - Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans. AB - Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive-compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits. PMID- 30305708 TI - A new STAT3 function: pH regulation. PMID- 30305710 TI - Linking cellular stress responses to systemic homeostasis. AB - Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses - which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy - as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells - such as cell senescence and regulated cell death - are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease. PMID- 30305709 TI - Accurate annotation of accessible chromatin in mouse and human primordial germ cells. AB - Extensive and accurate chromatin remodeling is essential during primordial germ cell (PGC) development for the perpetuation of genetic information across generations. Here, we report that distal cis-regulatory elements (CREs) marked by DNase I-hypersensitive sites (DHSs) show temporally restricted activities during mouse and human PGC development. Using DHS maps as proxy, we accurately locate the genome-wide binding sites of pluripotency transcription factors in mouse PGCs. Unexpectedly, we found that mouse female meiotic recombination hotspots can be captured by DHSs, and for the first time, we identified 12,211 recombination hotspots in mouse female PGCs. In contrast to that of meiotic female PGCs, the chromatin of mitotic-arrested male PGCs is permissive through nuclear transcription factor Y (NFY) binding in the distal regulatory regions. Furthermore, we examined the evolutionary pressure on PGC CREs, and comparative genomic analysis revealed that mouse and human PGC CREs are evolutionarily conserved and show strong conservation across the vertebrate tree outside the mammals. Therefore, our results reveal unique, temporally accessible chromatin configurations during mouse and human PGC development. PMID- 30305711 TI - Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. AB - Cognitive ageing research examines the cognitive abilities that are preserved and/or those that decline with advanced age. There is great individual variability in cognitive ageing trajectories. Some older adults show little decline in cognitive ability compared with young adults and are thus termed 'optimally ageing'. By contrast, others exhibit substantial cognitive decline and may develop dementia. Human neuroimaging research has led to a number of important advances in our understanding of the neural mechanisms underlying these two outcomes. However, interpreting the age-related changes and differences in brain structure, activation and functional connectivity that this research reveals is an ongoing challenge. Ambiguous terminology is a major source of difficulty in this venture. Three terms in particular - compensation, maintenance and reserve - have been used in a number of different ways, and researchers continue to disagree about the kinds of evidence or patterns of results that are required to interpret findings related to these concepts. As such inconsistencies can impede progress in both theoretical and empirical research, here, we aim to clarify and propose consensual definitions of these terms. PMID- 30305712 TI - Imaging-based parcellations of the human brain. AB - A defining aspect of brain organization is its spatial heterogeneity, which gives rise to multiple topographies at different scales. Brain parcellation - defining distinct partitions in the brain, be they areas or networks that comprise multiple discontinuous but closely interacting regions - is thus fundamental for understanding brain organization and function. The past decade has seen an explosion of in vivo MRI-based approaches to identify and parcellate the brain on the basis of a wealth of different features, ranging from local properties of brain tissue to long-range connectivity patterns, in addition to structural and functional markers. Given the high diversity of these various approaches, assessing the convergence and divergence among these ensuing maps is a challenge. Inter-individual variability adds to this challenge but also provides new opportunities when coupled with cross-species and developmental parcellation studies. PMID- 30305714 TI - Can laryngeal mask airway be used for surfactant administration in neonates? PMID- 30305713 TI - First evidence for a possible invasional meltdown among invasive fish parasites. AB - Biological invasions are frequently studied topics in ecological research. Unfortunately, within invasion ecology parasite-associated aspects such as parasite impacts on new environments and on local host populations are less well studied. Round gobies migrating from the Ponto-Caspian region into the Rhine River system are heavily infested with the Ponto-Caspian acanthocephalan parasite Pomphorhynchus laevis. As shown by experimental infestations the acanthocephalans occur as pre-adults in host-encapsulated cysts within the internal organs of the migrating gobies, but remain infective for their definitive host chub. Recently, we described the occurrence of larvae of another parasite, the invasive eel swim bladder nematode Anguillicola crassus, in these Pomphorhynchus cysts. In the present study, we could prove the infectivity of the nematode larvae for European eels for the first time. After experimental inoculation of Pomphorhynchus cysts occasionally infested with A. crassus larvae, the nematodes grow to maturity and reproduce whereas all P. laevis were unviable. We therefore postulate that the nematode larvae behave like immunological hitchhikers that follow a "Trojan horse strategy" in order to avoid the paratenic host's immune response. Accordingly, the interaction between both invasive parasites gives first evidence that the invasional meltdown hypothesis may also apply to parasites. PMID- 30305715 TI - Neonatal hypoglycemia: is there a neurodevelopmental impact in early childhood? PMID- 30305716 TI - Structural Analysis of an Epitope Candidate of Triosephosphate Isomerase in Opisthorchis viverrini. AB - Opisthorchis viverrini, a parasitic trematode, was recategorized as a group 1 biological carcinogen because it causes opisthorchiasis, which may result in cholangiocarcinoma. A new strategy for controlling opisthorchiasis is needed because of issues such as drug resistance and reinfection. Triosephosphate isomerase (TIM), a key enzyme in energy metabolism, is regarded as a potential drug target and vaccine candidate against various pathogens. Here, we determined the crystal structures of wild-type and 3 variants of TIMs from O. viverrini (OvTIM) at high resolution. The unique tripeptide of parasite trematodes, the SAD motif, was located on the surface of OvTIM and contributed to forming a 310-helix of the following loop in a sequence-independent manner. Through thermal stability and structural analyses of OvTIM variants, we found that the SAD motif induced local structural alterations of the surface and was involved in the overall stability of OvTIM in a complementary manner with another parasite-specific residue, N115. Comparison of the surface characteristics between OvTIM and Homo sapiens TIM (HsTIM) and structure-based epitope prediction suggested that the SAD motif functions as an epitope. PMID- 30305717 TI - Non-invasive imaging of disrupted protein homeostasis induced by proteasome inhibitor treatment using chemical exchange saturation transfer MRI. AB - Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types. PMID- 30305718 TI - High-Efficiency Reverse (5'->3') Synthesis of Complex DNA Microarrays. AB - DNA microarrays are important analytical tools in genetics and have recently found multiple new biotechnological roles in applications requiring free 3' terminal hydroxyl groups, particularly as a starting point for enzymatic extension via DNA or RNA polymerases. Here we demonstrate the highly efficient reverse synthesis of complex DNA arrays using a photolithographic approach. The method is analogous to conventional solid phase synthesis but makes use of phosphoramidites with the benzoyl-2-(2-nitrophenyl)-propoxycarbonyl (BzNPPOC) photolabile protecting group on the 3'-hydroxyl group. The use of BzNPPOC, with more than twice the photolytic efficiency of the 2-(2-nitrophenyl) propoxycarbonyl (NPPOC) previously used for 5'->3' synthesis, combined with additional optimizations to the coupling and oxidation reactions results in an approximately 3-fold improvement in the reverse synthesis efficiency of complex arrays of DNA oligonucleotides. The coupling efficiencies of the reverse phosphoramidites are as good as those of regular phosphoramidites, resulting in comparable yields. Microarrays of DNA surface tethered on the 5' end and with free 3' hydroxyl termini can be synthesized quickly and with similarly high stepwise coupling efficiency as microarrays using conventional 3'->5' synthesis. PMID- 30305720 TI - Reviewer recognition. AB - In this issue we would like to thank all those listed below for taking the time to review for Cancer Gene Therapy in 2017-your generosity is much appreciated and we hope your association with the journal continues in the future. PMID- 30305719 TI - A Reversible Rocksalt to Amorphous Phase Transition Involving Anion Redox. AB - The charge-discharge capacity of lithium secondary batteries is dependent on how many lithium ions can be reversibly extracted from (charge) and inserted into (discharge) the electrode active materials. In contrast, large structural changes during charging/discharging are unavoidable for electrode materials with large capacities, and thus there is great demand for developing materials with reversible structures. Herein, we demonstrate a reversible rocksalt to amorphous phase transition involving anion redox in a Li2TiS3 electrode active material with NaCl-type structure. We revealed that the lithium extraction during charging involves a change in site of the sulfur atom and the formation of S-S disulfide bonds, leading to a decrease in the crystallinity. Our results show great promise for the development of long-life lithium insertion/extraction materials, because the structural change clarified here is somewhat similar to that of optical phase change materials used in DVD-RW discs, which exhibit excellent reversibility of the transition between crystalline and amorphous phase. PMID- 30305721 TI - Correction: Advances in development of new tools for the study of phosphohistidine. AB - Since the publication of the paper the authors have noted some errors in the text (please read the full correction for more information). These errors have now been corrected in both the HTML and PDF versions of the paper. PMID- 30305722 TI - Non-canonical activation of beta-catenin by PRL-3 phosphatase in acute myeloid leukemia. AB - Aberrant activation of Wnt/beta-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine dephosphorylated form of Leo1 binds directly to beta-catenin, promoting the nuclear accumulation of beta-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards beta-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to beta-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant beta-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with beta-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or beta-catenin hyperactivation. PMID- 30305723 TI - Family-based germline sequencing in children with cancer. AB - The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology. PMID- 30305725 TI - IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell like properties in colon and lung cancer cells. AB - Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose 6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs. PMID- 30305724 TI - Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition. AB - Tumor responses to cancer therapeutics are generally monitored every 2-3 months based on changes in tumor size. Dynamic biomarkers that reflect effective engagement of targeted therapeutics to the targeted pathway, so-called "effect sensors", would fulfill a need for non-invasive, drug-specific indicators of early treatment effect. Using a proteomics approach to identify effect sensors, we demonstrated MUC1 upregulation in response to epidermal growth factor receptor (EGFR)-targeting treatments in breast and lung cancer models. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3. We validated these results in erlotinib-sensitive human breast and non-small lung cancer cell lines. Importantly, erlotinib treatment of mice bearing SUM149 xenografts resulted in increased MUC1 shedding into plasma. Analysis of MUC1 using serial blood sampling may therefore be a new, relatively non-invasive tool to monitor early and drug-specific effects of EGFR-targeting therapeutics. PMID- 30305726 TI - Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment. AB - Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion. This closes a feedback loop in which senescence acts as a crosspoint for the generation of CSCs mediated by phospholipid metabolism. We also demonstrate the connexion of both phenomena in mouse models in vivo showing that a high PLD2 expression increased stemness and tumorigenesis. Thus, the patients with colon cancer show high levels of PLD2 and SASP factor genes expression correlating with Wnt pathway activation. Therefore, we demonstrate that tumor cell-secreted PLD2 contributes to tumor development by modifying the microenvironment, making it a possible therapeutic target for cancer treatment. This mechanism may also explain the high levels of Wnt pathway activation in colon cancer. PMID- 30305727 TI - Hsp90ab1 stabilizes LRP5 to promote epithelial-mesenchymal transition via activating of AKT and Wnt/beta-catenin signaling pathways in gastric cancer progression. AB - Hsp90ab1 is upregulated in numerous solid tumors, which is thought to induce the angiogenesis and promote cancer metastasis. However, it's actions in gastric cancer (GC) has not been exhibited. In this study, Hsp90ab1 was demonstrated to be overexpressed and correlated with the poor prognosis, proliferation and invasion of GC. Ectopic expression of Hsp90ab1 promoted the proliferation and metastasis of GC cells both in vitro in cell line models of GC and in vivo using two different xenograft mouse models, while opposite effects were observed in Hsp90ab1 silenced cells. Moreover, the underlining molecular mechanism was explored by the co-immunoprecipitation, immunofluorescence, GST pull-down and in vitro ubiquitination assay. Namely, Hsp90ab1 exerted these functions via the interaction of LRP5 and inhibited ubiquitin-mediated degradation of LRP5, an indispensable coreceptor of the Wnt/beta-catenin signaling pathway. In addition, the crosstalk between Hsp90ab1 and LRP5 contributed to the upregulation of multiple mesenchymal markers, which are also targets of Wnt/beta-catenin. Collectively, this study uncovers the details of the Hsp90ab1-LRP5 axis, providing novel insights into the role and mechanism of invasion and metastasis in GC. PMID- 30305728 TI - Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis. AB - Argonaute2 (AGO2) is an effector of small RNA mediated gene silencing. Increasing evidence show that post-translational modifications of AGO2 can change miRNA activity at specific or global levels. Among the six mature miRNAs that are encoded by miR-17-92, miR-19b1 is the most powerful to exert the oncogenic properties of the entire cluster. Here we identify that AGO2 can be acetylated by P300/CBP and deacetylated by HDAC7, and that acetylation occurs at three sites K720, K493, and K355. Mutation of K493R/K720R, but not K355R at AGO2, inhibits miR-19b biogenesis. We demonstrate that acetylation of AGO2 specifically increases its recruiting pre-miR-19b1 to form the miPDC (miRNA precursor deposit complex), thereby to enhance miR-19b maturation. The motif UGUGUG in the terminal loop of pre-miR-19b1, as a specific processing feature that is recognized and bound by acetylated AGO2, is essential for the assembly of miRISC (miRNA-induced silencing complex) loading complex. Analyses on public clinical data, xenograft mouse models, and IHC and ISH staining of lung cancer tissues, further confirm that the high levels of both AGO2 acetylation and miR-19b correlate with poor prognosis in lung cancer patients. Our finding reveals a novel function of AGO2 acetylation in increasing oncogenic miR-19b biogenesis and suggests that modulation of AGO2 acetylation has potential clinical implications. PMID- 30305729 TI - Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth. AB - Ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) produce not only high levels of interleukin-6 (IL6) but also the related cytokine leukemia inhibitory factor (LIF). IL6-mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy. Less is known about the role of LIF, which can similarly activate STAT3, in ovarian cancer. We therefore sought to evaluate the tumorigenic effects of CA-MSC paracrine LIF signaling and the redundancy of IL6 and LIF in activating ovarian cancer STAT3 mediated cancer growth. As expected, we found that both IL6 and LIF induce STAT3 phosphorylation in tumor cells. In addition, both IL6 and LIF increased the percentage of ALDH+ ovarian cancer stem-like cells (CSC). Supporting redundancy of function by the two cytokines, CA-MSC induced STAT3 phosphorylation and increased cancer cell "stemness". This effect was not inhibited by LIF or IL6 blocking antibodies alone, but was prevented by dual IL6/LIF blockade or JAK2 inhibition. Similarly, small hairpin RNA (shRNA)-mediated reduction of IL6 or LIF in CA-MSC partially decreased but could not completely abrograte the ability of CA-MSC to induce STAT3 phosphorylation and stemness. Importantly, the in vivo pro-tumorigenic effect of CA-MSC is abrogated by dual blockade with the JAK2 inhibitor ruxolitinib to a much greater extent than treatment with anti-IL6 or anti-LIF antibody alone. Ruxolitinib treatment also improves survival in the immunocompetent ovarian cancer mouse model system with ID8 tumor cells plus MSC. Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and increase tumor cell stemness. This functional redundancy suggests that therapeutic targeting of a single cytokine may be less effective than strategies such as dual inhibitor therapy or targeting shared downstream factors of the JAK/STAT pathway. PMID- 30305731 TI - Options for keeping the food system within environmental limits. AB - The food system is a major driver of climate change, changes in land use, depletion of freshwater resources, and pollution of aquatic and terrestrial ecosystems through excessive nitrogen and phosphorus inputs. Here we show that between 2010 and 2050, as a result of expected changes in population and income levels, the environmental effects of the food system could increase by 50-90% in the absence of technological changes and dedicated mitigation measures, reaching levels that are beyond the planetary boundaries that define a safe operating space for humanity. We analyse several options for reducing the environmental effects of the food system, including dietary changes towards healthier, more plant-based diets, improvements in technologies and management, and reductions in food loss and waste. We find that no single measure is enough to keep these effects within all planetary boundaries simultaneously, and that a synergistic combination of measures will be needed to sufficiently mitigate the projected increase in environmental pressures. PMID- 30305732 TI - The dispersion-brightness relation for fast radio bursts from a wide-field survey. AB - Despite considerable efforts over the past decade, only 34 fast radio bursts intense bursts of radio emission from beyond our Galaxy-have been reported1,2. Attempts to understand the population as a whole have been hindered by the highly heterogeneous nature of the searches, which have been conducted with telescopes of different sensitivities, at a range of radio frequencies, and in environments corrupted by different levels of radio-frequency interference from human activity. Searches have been further complicated by uncertain burst positions and brightnesses-a consequence of the transient nature of the sources and the poor angular resolution of the detecting instruments. The discovery of repeating bursts from one source3, and its subsequent localization4 to a dwarf galaxy at a distance of 3.7 billion light years, confirmed that the population of fast radio bursts is located at cosmological distances. However, the nature of the emission remains elusive. Here we report a well controlled, wide-field radio survey for these bursts. We found 20, none of which repeated during follow-up observations between 185-1,097 hours after the initial detections. The sample includes both the nearest and the most energetic bursts detected so far. The survey demonstrates that there is a relationship between burst dispersion and brightness and that the high-fluence bursts are the nearby analogues of the more distant events found in higher-sensitivity, narrower-field surveys5. PMID- 30305734 TI - Neural blastocyst complementation enables mouse forebrain organogenesis. AB - Genetically modified mice are commonly generated by the microinjection of pluripotent embryonic stem (ES) cells into wild-type host blastocysts1, producing chimeric progeny that require breeding for germline transmission and homozygosity of modified alleles. As an alternative approach and to facilitate studies of the immune system, we previously developed RAG2-deficient blastocyst complementation2. Because RAG2-deficient mice cannot undergo V(D)J recombination, they do not develop B or T lineage cells beyond the progenitor stage2: injecting RAG2-sufficient donor ES cells into RAG2-deficient blastocysts generates somatic chimaeras in which all mature lymphocytes derive from donor ES cells. This enables analysis, in mature lymphocytes, of the functions of genes that are required more generally for mouse development3. Blastocyst complementation has been extended to pancreas organogenesis4, and used to generate several other tissues or organs5-10, but an equivalent approach for brain organogenesis has not yet been achieved. Here we describe neural blastocyst complementation (NBC), which can be used to study the development and function of specific forebrain regions. NBC involves targeted ablation, mediated by diphtheria toxin subunit A, of host-derived dorsal telencephalic progenitors during development. This ablation creates a vacant forebrain niche in host embryos that results in agenesis of the cerebral cortex and hippocampus. Injection of donor ES cells into blastocysts with forebrain-specific targeting of diphtheria toxin subunit A enables donor-derived dorsal telencephalic progenitors to populate the vacant niche in the host embryos, giving rise to neocortices and hippocampi that are morphologically and neurologically normal with respect to learning and memory formation. Moreover, doublecortin-deficient ES cells-generated via a CRISPR-Cas9 approach-produced NBC chimaeras that faithfully recapitulated the phenotype of conventional, germline doublecortin-deficient mice. We conclude that NBC is a rapid and efficient approach to generate complex mouse models for studying forebrain functions; this approach could more broadly facilitate organogenesis based on blastocyst complementation. PMID- 30305733 TI - Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. AB - The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death-most often of OHCs-is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1-3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC specific differentiation. PMID- 30305735 TI - Cervical excitatory neurons sustain breathing after spinal cord injury. AB - Dysfunctional breathing is the main cause of morbidity and mortality after traumatic injury of the cervical spinal cord1,2 and often necessitates assisted ventilation, thus stressing the need to develop strategies to restore breathing. Cervical interneurons that form synapses on phrenic motor neurons, which control the main inspiratory muscle, can modulate phrenic motor output and diaphragmatic function3-5. Here, using a combination of pharmacogenetics and respiratory physiology assays in different models of spinal cord injury, we show that mid cervical excitatory interneurons are essential for the maintenance of breathing in mice with non-traumatic cervical spinal cord injury, and are also crucial for promoting respiratory recovery after traumatic spinal cord injury. Although these interneurons are not necessary for breathing under normal conditions, their stimulation in non-injured animals enhances inspiratory amplitude. Immediately after spinal cord injury, pharmacogenetic stimulation of cervical excitatory interneurons restores respiratory motor function. Overall, our results demonstrate a strategy to restore breathing after central nervous system trauma by targeting a neuronal subpopulation. PMID- 30305737 TI - Social regulation of a rudimentary organ generates complex worker-caste systems in ants. AB - The origin of complex worker-caste systems in ants perplexed Darwin1 and has remained an enduring problem for evolutionary and developmental biology2-6. Ants originated approximately 150 million years ago, and produce colonies with winged queen and male castes as well as a wingless worker caste7. In the hyperdiverse genus Pheidole, the wingless worker caste has evolved into two morphologically distinct subcastes-small-headed minor workers and large-headed soldiers8. The wings of queens and males develop from populations of cells in larvae that are called wing imaginal discs7. Although minor workers and soldiers are wingless, vestiges or rudiments of wing imaginal discs appear transiently during soldier development7,9-11. Such rudimentary traits are phylogenetically widespread and are primarily used as evidence of common descent, yet their functional importance remains equivocal1,12-14. Here we show that the growth of rudimentary wing discs is necessary for regulating allometry-disproportionate scaling-between head and body size to generate large-headed soldiers in the genus Pheidole. We also show that Pheidole colonies have evolved the capacity to socially regulate the growth of rudimentary wing discs to control worker subcaste determination, which allows these colonies to maintain the ratio of minor workers to soldiers. Finally, we provide comparative and experimental evidence that suggests that rudimentary wing discs have facilitated the parallel evolution of complex worker-caste systems across the ants. More generally, rudimentary organs may unexpectedly acquire novel regulatory functions during development to facilitate adaptive evolution. PMID- 30305736 TI - Pathogen elimination by probiotic Bacillus via signalling interference. AB - Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are thought to reduce intestinal colonization by pathogens, and thus to reduce susceptibility to infection. However, the mechanisms that underlie these effects remain poorly understood. Here we report that the consumption of probiotic Bacillus bacteria comprehensively abolished colonization by the dangerous pathogen Staphylococcus aureus in a rural Thai population. We show that a widespread class of Bacillus lipopeptides, the fengycins, eliminates S. aureus by inhibiting S. aureus quorum sensing-a process through which bacteria respond to their population density by altering gene regulation. Our study presents a detailed molecular mechanism that underlines the importance of probiotic nutrition in reducing infectious disease. We also provide evidence that supports the biological significance of probiotic bacterial interference in humans, and show that such interference can be achieved by blocking a pathogen's signalling system. Furthermore, our findings suggest a probiotic-based method for S. aureus decolonization and new ways to fight S. aureus infections. PMID- 30305738 TI - IRE1alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. AB - Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1alpha-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1alpha-XBP1 activation that suppressed mitochondrial activity and IFNgamma production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1alpha-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1alpha-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts. PMID- 30305739 TI - The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter. AB - Synthetic cathinones are common constituents of abused "bath salts" preparations and represent a large family of structurally related compounds that function as cocaine-like inhibitors or amphetamine-like substrates of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters. Preclinical evidence suggests that some cathinones (e.g., MDPV and alpha-PVP) are more effective reinforcers than prototypical stimulant drugs of abuse, such as cocaine or methamphetamine. Although the reinforcing potency of these cathinones is related to their potency to inhibit DAT, less is known about the pharmacological determinants of their unusually high reinforcing effectiveness. To this end, we tested the hypothesis that reinforcing effectiveness of cathinone stimulants is positively correlated with their selectivity for DAT relative to SERT. Uptake inhibition assays in rat brain synaptosomes were used to directly compare the potency of MDPV, MDPBP, MDPPP, alpha-PVP, alpha-PPP, and cocaine at DAT, NET, and SERT, whereas intravenous self-administration in rats was used to quantify relative reinforcing effectiveness of the drugs using progressive ratio (PR) and behavioral economic procedures. All cathinones were more potent at DAT than NET or SERT, with a rank order for selectivity at DAT over SERT of alpha-PVP > alpha PPP > MDPV > MDPBP > MDPPP > cocaine. These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT. Together, these studies provide strong and convergent evidence that the abuse potential of stimulant drugs is mediated by uptake inhibition at DAT, with activity at SERT serving as a negative modulator of reinforcing effectiveness. PMID- 30305740 TI - Genome-wide association studies of brain imaging phenotypes in UK Biobank. AB - The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing. PMID- 30305741 TI - Perovskite light-emitting diodes with external quantum efficiency exceeding 20 per cent. AB - Metal halide perovskite materials are an emerging class of solution-processable semiconductors with considerable potential for use in optoelectronic devices1-3. For example, light-emitting diodes (LEDs) based on these materials could see application in flat-panel displays and solid-state lighting, owing to their potential to be made at low cost via facile solution processing, and could provide tunable colours and narrow emission line widths at high photoluminescence quantum yields4-8. However, the highest reported external quantum efficiencies of green- and red-light-emitting perovskite LEDs are around 14 per cent7,9 and 12 per cent8, respectively-still well behind the performance of organic LEDs10-12 and inorganic quantum dot LEDs13. Here we describe visible-light-emitting perovskite LEDs that surpass the quantum efficiency milestone of 20 per cent. This achievement stems from a new strategy for managing the compositional distribution in the device-an approach that simultaneously provides high luminescence and balanced charge injection. Specifically, we mixed a presynthesized CsPbBr3 perovskite with a MABr additive (where MA is CH3NH3), the differing solubilities of which yield sequential crystallization into a CsPbBr3/MABr quasi-core/shell structure. The MABr shell passivates the nonradiative defects that would otherwise be present in CsPbBr3 crystals, boosting the photoluminescence quantum efficiency, while the MABr capping layer enables balanced charge injection. The resulting 20.3 per cent external quantum efficiency represents a substantial step towards the practical application of perovskite LEDs in lighting and display. PMID- 30305742 TI - Perovskite light-emitting diodes based on spontaneously formed submicrometre scale structures. AB - Light-emitting diodes (LEDs), which convert electricity to light, are widely used in modern society-for example, in lighting, flat-panel displays, medical devices and many other situations. Generally, the efficiency of LEDs is limited by nonradiative recombination (whereby charge carriers recombine without releasing photons) and light trapping1-3. In planar LEDs, such as organic LEDs, around 70 to 80 per cent of the light generated from the emitters is trapped in the device4,5, leaving considerable opportunity for improvements in efficiency. Many methods, including the use of diffraction gratings, low-index grids and buckling patterns, have been used to extract the light trapped in LEDs6-9. However, these methods usually involve complicated fabrication processes and can distort the light-output spectrum and directionality6,7. Here we demonstrate efficient and high-brightness electroluminescence from solution-processed perovskites that spontaneously form submicrometre-scale structures, which can efficiently extract light from the device and retain wavelength- and viewing-angle-independent electroluminescence. These perovskites are formed simply by introducing amino acid additives into the perovskite precursor solutions. Moreover, the additives can effectively passivate perovskite surface defects and reduce nonradiative recombination. Perovskite LEDs with a peak external quantum efficiency of 20.7 per cent (at a current density of 18 milliamperes per square centimetre) and an energy-conversion efficiency of 12 per cent (at a high current density of 100 milliamperes per square centimetre) can be achieved-values that approach those of the best-performing organic LEDs. PMID- 30305743 TI - The UK Biobank resource with deep phenotyping and genomic data. AB - The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases. PMID- 30305744 TI - Trade-offs in using European forests to meet climate objectives. AB - The Paris Agreement promotes forest management as a pathway towards halting climate warming through the reduction of carbon dioxide (CO2) emissions1. However, the climate benefits from carbon sequestration through forest management may be reinforced, counteracted or even offset by concurrent management-induced changes in surface albedo, land-surface roughness, emissions of biogenic volatile organic compounds, transpiration and sensible heat flux2-4. Consequently, forest management could offset CO2 emissions without halting global temperature rise. It therefore remains to be confirmed whether commonly proposed sustainable European forest-management portfolios would comply with the Paris Agreement-that is, whether they can reduce the growth rate of atmospheric CO2, reduce the radiative imbalance at the top of the atmosphere, and neither increase the near-surface air temperature nor decrease precipitation by the end of the twenty-first century. Here we show that the portfolio made up of management systems that locally maximize the carbon sink through carbon sequestration, wood use and product and energy substitution reduces the growth rate of atmospheric CO2, but does not meet any of the other criteria. The portfolios that maximize the carbon sink or forest albedo pass only one-different in each case-criterion. Managing the European forests with the objective of reducing near-surface air temperature, on the other hand, will also reduce the atmospheric CO2 growth rate, thus meeting two of the four criteria. Trade-off are thus unavoidable when using European forests to meet climate objectives. Furthermore, our results demonstrate that if present-day forest cover is sustained, the additional climate benefits achieved through forest management would be modest and local, rather than global. On the basis of these findings, we argue that Europe should not rely on forest management to mitigate climate change. The modest climate effects from changes in forest management imply, however, that if adaptation to future climate were to require large-scale changes in species composition and silvicultural systems over Europe5,6, the forests could be adapted to climate change with neither positive nor negative climate effects. PMID- 30305745 TI - Electronic noise due to temperature differences in atomic-scale junctions. AB - Since the discovery a century ago1-3 of electronic thermal noise and shot noise, these forms of fundamental noise have had an enormous impact on science and technology research and applications. They can be used to probe quantum effects and thermodynamic quantities4-11, but they are also regarded as undesirable in electronic devices because they obscure the target signal. Electronic thermal noise is generated at equilibrium at finite (non-zero) temperature, whereas electronic shot noise is a non-equilibrium current noise that is generated by partial transmission and reflection (partition) of the incoming electrons8. Until now, shot noise has been stimulated by a voltage, either applied directly8 or activated by radiation12,13. Here we report measurements of a fundamental electronic noise that is generated by temperature differences across nanoscale conductors, which we term 'delta-T noise'. We experimentally demonstrate this noise in atomic and molecular junctions, and analyse it theoretically using the Landauer formalism8,14. Our findings show that delta-T noise is distinct from thermal noise and voltage-activated shot noise8. Like thermal noise, it has a purely thermal origin, but delta-T noise is generated only out of equilibrium. Delta-T noise and standard shot noise have the same partition origin, but are activated by different stimuli. We infer that delta-T noise in combination with thermal noise can be used to detect temperature differences across nanoscale conductors without the need to fabricate sophisticated local probes. Thus it can greatly facilitate the study of heat transport at the nanoscale. In the context of modern electronics, temperature differences are often generated unintentionally across electronic components. Taking into account the contribution of delta-T noise in these cases is likely to be essential for the design of efficient nanoscale electronics at the quantum limit. PMID- 30305746 TI - Mobile hack. PMID- 30305747 TI - Why working as a travel guide or cruise lecturer can be an effective form of science outreach. PMID- 30305748 TI - The best supervisor. PMID- 30305749 TI - Protect Denmark's groundwater from pesticides. PMID- 30305750 TI - Universities fund off-the-wall research from their own pockets. PMID- 30305751 TI - Funding mechanisms risk promoting conscious bias. PMID- 30305752 TI - Mouse avatars take off as cancer models. PMID- 30305753 TI - First report of antimicrobial resistance pre-dates penicillin. PMID- 30305754 TI - UK Biobank shares the promise of big data. PMID- 30305755 TI - LED technology breaks performance barrier. PMID- 30305756 TI - Unexpected noise from hot electrons. PMID- 30305758 TI - An alternative Japan experience. PMID- 30305759 TI - The approach to predictive medicine that is taking genomics research by storm. PMID- 30305760 TI - Economics Nobel for climate change, Hubble trouble and o pen-access ups and downs. PMID- 30305761 TI - Influence of preoperative information support on anxiety, pain and satisfaction with postoperative analgesia in children and adolescents after thoracic surgery: a randomized double blind study. AB - AIMS/BACKGROUND: The proportion of patients who experience anxiety prior to planned surgery, even a minimally invasive one, is estimated at 50-70%. Thoracic surgery, causes significant preoperative anxiety, especially in children. The aim of this study was to determine the effect of an important component of psychological preparation for a surgery as information support on levels of anxiety, pain and satisfaction with postoperative analgesia. METHODS: The randomized double blind study including patients aged 9-18 years qualified for lateral thoracotomy or Ravitch procedure. The subjects were randomized to the control group (n=56) provided with a routine preoperative information by a nurse, and the experimental group (n=56) offered additional psychological consultation. Data were collected via the State-Trait Anxiety Inventory. RESULTS: In the experimental group, the level of state anxiety at 48 h post-surgery was significantly lower than prior to the procedure, but only in subjects with preoperative trait anxiety <7/10 sten. In the control group, the level of postoperative anxiety was significantly higher than prior to the surgery; this effect was observed irrespectively of preoperative trait anxiety level. Lack of preoperative psychological consultation (beta=-0.23), trait anxiety >=7 sten (beta=0.25), and higher level of preoperative state anxiety (beta=0.65) were independent predictors of greater state anxiety at 48 h post-surgery. Patients from the experimental group did not differ significantly from the controls in terms of their median pain scores and satisfaction with postoperative analgesia. Greater state anxiety was associated with 22% lesser likelihood of complete satisfaction with the analgesia. CONCLUSION: Information support from a psychologist offered prior to a thoracic surgery decrease the level of postoperative state anxiety solely in children with lower levels of trait anxiety. Higher level of postoperative state anxiety negatively affect patients' satisfaction with post-surgical analgesia. TRIAL REGISTRATION: ClinicalTrials.gov; Influence of Preoperative Support on Anxiety, Pain and Satisfaction With Postoperative Analgesia; NCT03488459, https://clinicaltrials.gov/ct2/show/record/NCT03488459?cntry=PL&city=Rabka Zdr%C3%B3j&rank=1. PMID- 30305762 TI - Heart failure disease management program, its contribution to established pharmacotherapy and long-term prognosis in real clinical practice - retrospective data analysis. AB - BACKGROUND AND AIMS: The prognosis of patients with heart failure (HF) is still generally unfavorable. HF with reduced ejection fraction (HFrEF) patients reach target medication doses in very low percentages in daily clinical practice. HF disease management programs (DMP), including nurse and telemedicine support that facilitate achieving target medication doses, may improve the unfavorable prognosis. METHODS: We retrospectively analyzed the data of 738 patients with HFrEF who were followed in a single HF center during the years 1975-2011, for 6.4 (median) years. DMP, nurse and telemedicine support is established at this center. RESULTS: The group achieved left ventricle (LV) recovery after the HF treatment. The median LV ejection fraction improved from 25.0% at baseline to 50.0% at the time of the latest data collection. The proportion of NYHA II, III and IV classes decreased from 27.6%, 30.2% and 29.7% to 26.6%, 7.2% and 0.1%, respectively while the proportion of NYHA class I increased from 12.5% to 66.1%. Median NT-proBNP decreased from 975.0 to 324.0 pg/mL. The survival of the patient group was favorable; 79.7% survived 18.1 years after diagnosis of HF. A high percentage of the patients received recommended target or higher than target doses of angiotensin-converting enzyme inhibitors (82.0%) and beta-blockers (78.1%). CONCLUSION: The established pharmacotherapy resulted from an effective DMP and this contributed to the favorable prognosis. PMID- 30305763 TI - The prevalence and characteristics of HIV/AIDS patients presenting at a chiropractic outpatient clinic in Toronto, Ontario. A retrospective, observational study. AB - Objective: To determine the prevalence and presenting complaints of HIV/AIDS patients attending a chiropractic outpatient teaching clinic in downtown Toronto, and explore their self-reported comorbidities, medications used, and consumption of other complementary health care. Methods: A random sample was drawn from the entire clinic file collection spanning the years 2007 to 2013. Files were anonymized and coded to ensure confidentiality. Results: A total of 264 files were radomly pulled from approxinately 3750 clinic files. The prevalence of HIV positive patients was 5.7% (15/264), predominantly males, with 3 patients having developed AIDS. Co-infection with Hepatitis B and/or C was identified in 5/15 patients. The most common presenting complaint was neck pain (80%), followed by low back pain (47%) compared to 20% and 43% respectively for the general cohort. Eleven of 15 patients were on antiretroviral treatment (ART); The frequency of comorbidities was 8/15 (53%) however, none were identified as being dominant. In addition to chiropractic, 7/15 patients reported receiving other complementary therapies. Conclusions: A relatively small proportion of HIV/ AIDS patients were found to be receiving treatments in this downtown chiropractic clinic situated within a community health clinic setting. The principal presenting complaint was neck pain. PMID- 30305764 TI - Does the Gillet test assess sacroiliac motion or asymmetric one-legged stance strategies? AB - Objective: The purpose of this study was to quantify the extent to which apparent movements of the posterior superior iliac spine and sacral base areas Gillet sacroiliac motion testing were related to (a) degree of hip flexion and (b) the examiner's palpatory pressure. Methods: A preliminary exploratory study quantified relative PSIS/S2 displacements in 10 sacroiliac joints among 5 asymptomatic subjects at 10 degrees increments of hip flexion from 0-90 degrees . A comprehensive follow-up asymptomatic study quantified PSIS/S2 displacements at 0 degrees vs. 30 degrees vs. 90 degrees hip flexion, and for light vs. firm pressure at 30 degrees hip flexion. Displacements measured in pixels on digital photographs were transformed to mm. Mean differences for the various test conditions were evaluated for statistical significance using paired t-testing and Wilcoxon signed rank test. Results: With light pressure, the left PSIS moved caudal for hip flexion <=30 degrees during right-legged stance, whereas the right PSIS moved cephalad relative to the sacral base. For hip flexion =90 degrees , both PSISs moved cephalad. The use of firm palpatory pressure abolished the initial caudal movement of the left PSIS, as well as differences in the amount of cephalad PSIS movement at 30 degrees vs. 90 degrees hip flexion. Conclusions: The results are consistent with there being left-right differences in gluteus medius and biceps femoris activation among asymptomatic individuals that result in different balancing strategies during one-legged stance. This may create the appearance of relative PSIS/SB displacement, even though the results of Gillet testing can be wholly or partially explained by pelvic obliquity owing to muscle function asymmetry. This study questions the validity of the upright Gillet test for sacroiliac motion. PMID- 30305765 TI - Tendon neuroplastic training for lateral elbow tendinopathy: 2 case reports. AB - Objective: To report 2 cases of lateral elbow tendinopathy treated with a novel adaptation of tendon neuroplastic training (TNT). Clinical features: Patient 1: A 61-year-old male machine operator presented with one year of bilateral lateral elbow pain related to his occupation of using torque wrenches.Patient 2: A 37 year-old male electrician presented with two months of recurrent left lateral elbow pain related to repetitive motions of gripping and pulling at work. Intervention and outcome: Both patients underwent 8 weeks of a novel rehabilitation program, including TNT, which involved pacing their resistance exercises to a metronome. Both patients experienced clinically meaningful improvements in pain and functional outcome scores that were sustained at the 3 month follow-up. Summary: Recent evidence suggests that the central nervous system may play a role in chronic tendinopathies. It is possible that TNT may address the central nervous system component of chronic/recurrent tendinopathy that is not addressed by traditional passive therapies. However, further research is needed. PMID- 30305766 TI - Adolescent knee pain: fracture or normal? A case report. AB - Background: Knee injuries are the second to fourth most common injuries in youth soccer. In this population, sprains/strains, fractures and contusions are most common. Due to variations in the developing skeleton, it can be difficult to rule out fractures. Case Summary: We present a case of a 13-year-old presenting to the emergency department (ED) with patellar pain after pivoting during a soccer game. After radiographic clearance, he was allowed to return to sport. Following another fall and ED visit, his full leg was casted. He presented to a chiropractor after cast removal, who made recommendations for progressive rehabilitation owing to the lack of evidence for fracture on radiographs. Summary: We suggest a thorough history, physical and Ottawa knee rules to determine whether radiographs are indicated in the management of a pediatric knee injury. Due to normal skeletal variance, we recommend bilateral radiographs and if findings are ambiguous, consultation with a radiologist to confirm clinical suspicions. PMID- 30305767 TI - Conservative management of a chronic recurrent flexor hallucis longus stenosing tenosynovitis in a pre-professional ballet dancer: a case report. AB - Objective: To describe the successful conservative management of a chronic recurrent flexor hallucis longus (FHL) stenosing tenosynovitis. Clinical Features: A 20-year-old female pre-professional ballet dancer presented with medial ankle and mid-foot pain of 7.5 months duration. Pain was constant but exacerbated with training and assuming the en pointe and demi-pointe dance positions. Plantar flexion of the great toe was pain provoking. Triggering of the great toe and audible and palpable crepitus were noted with active and passive great toe range of motion. A diagnosis of a chronic recurrent FHL stenosing tenosynovitis was made based on the history and physical exam. Intervention and Outcome: Soft tissue and joint mobilization and manipulation, laser therapy, kinesiology tape application and rehabilitative exercise was used over 4 months. The patient reported an 8-point decrease in her numeric pain rating scale score and a 15-point improvement in her Lower Extremity Functional Scale score. PMID- 30305768 TI - A scoping review of chiropractic management of female patients with infertility. AB - Background: Debate concerning chiropractic management of female infertility occurs largely in the absence of reference to the extant literature. Methods: A scoping review was conducted of primary (original) data publications on the chiropractic management of female infertility based on searches of the Index to Chiropractic Literature and Pubmed, supplemented by papers from one author's archive. Results: Ten articles, all case studies, met the review's inclusion criteria and documented the experiences of 11 women (mean age 31 years; mean period of infertility 3 years). Pregnancy occurred, on average, after 5 months of treatment with spinal manipulation and adjunctive modalities. No adverse events were reported. Discussion: There are very few original data articles documenting responses of infertile females treated with spinal manipulation. Conclusions: In the absence of a robust body of primary data literature, the use of spinal manipulation the management of female infertility should be approached with caution. PMID- 30305769 TI - An Efficient Synthesis of Functionalized Urethanes from Azides. AB - Catalytic hydrogenation of various azides in the presence of functionalized mixed carbonates afforded the corresponding urethanes in high yields. PMID- 30305770 TI - A Corpus with Multi-Level Annotations of Patients, Interventions and Outcomes to Support Language Processing for Medical Literature. AB - We present a corpus of 5,000 richly annotated abstracts of medical articles describing clinical randomized controlled trials. Annotations include demarcations of text spans that describe the Patient population enrolled, the Interventions studied and to what they were Compared, and the Outcomes measured (the 'PICO' elements). These spans are further annotated at a more granular level, e.g., individual interventions within them are marked and mapped onto a structured medical vocabulary. We acquired annotations from a diverse set of workers with varying levels of expertise and cost. We describe our data collection process and the corpus itself in detail. We then outline a set of challenging NLP tasks that would aid searching of the medical literature and the practice of evidence-based medicine. PMID- 30305771 TI - A Dose Falloff Gradient Study in RapidArc Planning of Lung Stereotactic Body Radiation Therapy. AB - Introduction: Radiation Therapy Oncology Group (RTOG) report #0813 and 0915 recommends using D2cm and R50% as plan quality metrics for evaluation of normal tissue sparing in stereotactic body radiation therapy (SBRT) of lung lesion. This study introduces dose falloff gradient (DFG) as a tool for analyzing the dose beyond the planning target volume (PTV) extending into normal tissue structures. In ascertaining the impact of PTV size and SBRT planning techniques in DFG, this study questions the independence of the RTOG recommended metrics. Materials and Methods: In this retrospective study, 41 RapidArc lung SBRT plans with 2 or 3 complete or partial arcs were analyzed. PTV volumes ranged between 5.3 and 113 cm3 and their geographic locations were distributed in both lungs. 6MV, 6 MV-FFF, 10 MV, or 10 MV-FFF energies were used. RTOG-0915 metrics conformity index, homogeneity index, D2cm, R50%, and HDloc were evaluated. DFG was computed from the mean and maximum dose in seven concentric 5 mm wide rings outside the PTV. DFG was investigated against the volume of normal lung irradiated by 50% isodose volume. Treatment plans with alternate energy and couch rotations were generated. Results: The dose falloff beyond PTV was modeled using a double exponential fit and evaluated for relationship with intermediate lung dose. Photon energy and beam configuration had a minimal impact on the dose falloff outside. The product of normalized D2cm and R50% was estimated to have a slowly varying value. Conclusions: Dose falloff outside PTV has been studied as a function of radial distance and ascertained by intermediate dose to normal lung. DFG can serve as a complementary plan quality metric. PMID- 30305772 TI - Voxel based BED and EQD2 Evaluation of the Radiotherapy Treatment Plan. AB - Introduction: Three-dimensional (3D) treatment planning of patient undergoing radiotherapy uses complex and meticulous computational algorithms. These algorithms use 3D voxel data of the patient to calculate the radiation dose distribution and display it over the CT image dataset for treatment plan evaluation. Aims and Objective: The purpose of the present study is the development and implementation of radiobiological evaluation of the radiotherapy treatment plan incorporating the tissue-specific radiobiological parameters. Material and Method: An indigenous program was written in MATLAB(r) software (version 2011b of Mathworks Inc.) to extract the patient treatment plan data from DICOM-RT files which are exported from the treatment planning system. CT-, Structures- and Dose-Cube matrices are reconstructed from the exported patient plan data. BED and EQD2 based dose volume histograms (DVHs), colorwash and iso effective dose curves were generated from the physical Dose-Cube using the linear quadratic (LQ) formalism and tissue-specific radiobiological parameters (alpha/beta). Results and Conclusion: BED-and EQD2-colorwash and iso-effective curves along with BED and EQD2 dose volume histograms provide superior radiobiological information as compared to those of physical doses. This study provides supplementary recipes of radiobiological doses along with the physical doses which are useful for the evaluation of complex radiotherapy treatment plan of the patients. PMID- 30305773 TI - Comparison of Measured and Monte Carlo Calculated Dose Distributions from Indigenously Developed 6 MV Flattening Filter Free Medical Linear Accelerator. AB - Purpose: Monte Carlo simulation was carried out for a 6 MV flattening filter-free (FFF) indigenously developed linear accelerator (linac) using the BEAMnrc user code of the EGSnrc code system. The model was benchmarked against the measurements. A Gaussian distributed electron beam of kinetic energy 6.2 MeV with full-width half maximum of 1 mm was used in this study. Methods: The simulation of indigenously developed linac unit has been carried out by using the Monte Carlo-based BEAMnrc user-code of the EGSnrc code system. Using the simulated model, depth and lateral dose profiles were studied using the DOSXYZnrc user code. The calculated dose data were compared against the measurements using an RFA dosimertic system made by PTW, Germany (water tank MP3-M and 0.125 cm3 ion chamber). Results: The BEAMDP code was used to analyze photon fluence spectra, mean energy distribution, and electron contamination fluence spectra. Percentage depth dose (PDD) and beam profiles (along both X and Y directions) were calculated for the field sizes 5 cm * 5 cm - 25 cm * 25 cm. The dose difference between the calculated and measured PDD and profile values were under 1%, except for the penumbra region where the maximum deviation was found to be around 3%. Conclusions: A Monte Carlo model of indigenous FFF linac (6 MV) has been developed and benchmarked against the measured data. PMID- 30305774 TI - Incidence of Suboptimal Applicator Placement and the Resulting Dosimetric Impact in Image-Based Intracavitary Brachytherapy. AB - Aim: With the advent of computed tomography (CT)-based brachytherapy, it is possible to view the appropriate placement of the applicator within the uterine canal and detect uterine perforation. In this study, the incidence of suboptimal placement of the intracavitary applicator and the resulting dosimetric impact were analyzed and compared with a similar set of ideal applicator placement. Materials and Methods: CT datasets of 282 (141 patients) high dose rate brachytherapy insertions between January and April 2016 were analyzed. The target volumes and organs at risk (OAR) were contoured as per the Groupe Europeen de Curietherapie European Society of Therapeutic Radiation Oncology guidelines. The position of the applicator in the uterine cavity was analyzed for each application. Results: The suboptimal insertion rate was 11.7%. There were 26 perforations and 7 subserosal insertions. The most common site of perforation was through the posterior wall of the uterus (42.4%). Fundus perforation and anterior wall perforation were seen in 24.2% and 12.1% of patients, respectively. The average dose to 90% of the target volume (D90 to high-risk clinical target volume) was the highest (9.15 Gy) with fundal perforation. Average dose to 2 cc (D2cc) bladder was highest for fundus perforation (7.65 Gy). The average dose received by 2 cc of rectum (D2cc) was highest (4.49 Gy) with posterior wall perforation. The average D2cc of the sigmoid was highest with anterior perforation (3.18 Gy). Conclusion: In order to achieve better local control and to decrease doses to OAR, it is important to perform a technically accurate applicator placement. A cost-effective, real-time image guidance modality like ultrasound is recommended for all insertions to ensure optimal applicator insertion. PMID- 30305776 TI - A Pilot Study on the Comparison between Planning Target Volume-based Intensity Modulated Proton Therapy Plans and Robustly Optimized Intensity-Modulated Proton Therapy Plans. AB - The objective of this work is to compare the planning target volume (PTV)-based intensity-modulated proton therapy (IMPT) plans with robustly optimized IMPT plans using the robust optimization tools available in Pinnacle Treatment Planning System. We performed the study in five cases of different anatomic sites (brain, head and neck, lung, pancreas, and prostate). Pinnacle IMPT nonclinical version was used for IMPT planning. Two types of IMPT plans were created for each case. One is PTV-based conventionally optimized IMPT plan and the other is robustly optimized plan considering setup uncertainties. For the PTV-based plans, margins were on top of clinical target volume (CTV) to account for the setup errors, whereas in the robustly optimized plan, the setup errors were directly incorporated into the optimization process. The plan evaluation included target (CTV) coverage and dose uniformity. Our interest was to see how the target coverage and dose uniformity were perturbed on imposing setup errors in +X, -X, +Y, -Y, +Z, and -Z directions for both PTV-based and robust optimization (RO) based plans. On the average, RO-based IMPT plans have shown a good consistency of target coverage and dose uniformity for all six setup errors scenarios as compared to PTV-based plans. In addition, RO-based plans have a better target coverage and dose uniformity under uncertainty conditions as compared to the PTV based plans. The study demonstrates the superiority of robustly optimized IMPT plans over the PTV-based IMPT plans in terms of dose distribution under the uncertainty conditions. PMID- 30305777 TI - Optimization of Variance Reduction Techniques used in EGSnrc Monte Carlo Codes. AB - Monte Carlo (MC) simulations are often used in calculations of radiation transport to enable accurate prediction of radiation-dose, even though the computation is relatively time-consuming. In a typical MC simulation, significant computation time is allocated to following non-important events. To address this issue, variance reduction techniques (VRTs) have been suggested for reducing the statistical variance for the same computation time. Among the available MC simulation codes, electron gamma shower (National Research Council of Canada) (EGSnrc) is a general-purpose coupled electron-photon transport code that also features an even-handed, rich set of VRTs. The most well-known VRTs are the photon splitting, Russian roulette (RR), and photon cross-section enhancement (XCSE) techniques. The objective of this work was to determine the optimal combination of VRTs that increases the simulation speed and the efficiency of simulation, without compromising its accuracy. Selection of VRTs was performed using EGSnrc MC User codes, such as cavity and egs_chamber, for simulating various ion chamber geometries using 6 MV photon beams and 1.25 MeV 60Co photon beams. The results show that the combination of XCSE and RR yields the highest efficiency for ion-chamber dose calculations inside a 30 cm * 30 cm * 30 cm water phantom. Hence, properly selecting a different VRT without altering the underlying physics increases the efficiency of MC simulations for ion-chamber dose calculation. PMID- 30305775 TI - Dosimetry of 175Ytterbium-poly (amidoamine) Therapy for Humans' Organs. AB - Purpose: This investigation focuses on biodistribution of irradiated dendrimer encapsulated ytterbium-175 (175Yb) and to estimate the absorbed dose from intravenous injection of PAMAM encapsulated 175Yb to human organs. Methods: A dendrimer compound containing an average of 55 Yb+3 ions per dendrimer was prepared and irradiated with neutrons for 2h at 3*1011 n.cm-2s-1 neutron flux. The resulting mixture was injected into a group of tumor bearing mice and the mice were excised, weighed and counted at certain times to study the biodistribution. The human organs absorbed dose was assessed by MIRD schema and MCNP simulation. Results: The specific activity and radiochemical purity of the irradiated nano-composite were 7MBq/mg and >99% respectively. The rapid up take of dendrimer was in liver, lung, and, spleen. MIRD and MCNPX were applied for dose estimation. The human absorbed dose in liver, lung, spleen, kidney and bone that simulated by MCNP are 1.266, 0.8081, 0.8347, 0.03979 and 0.01706 mGy/MBq respectively and these values for MIRD schema are 1.351, 0.73, 1.03, 0.039, and 0.0097 mGy/MBq respectively. Conclusion: The results showed that 175Yb-PAMAM nano radiopharmaceutical has potential of application for liver and lung tumors. PMID- 30305778 TI - Monte Carlo Simulation on the Imaging Contrast Enhancement in Nanoparticle enhanced Radiotherapy. AB - This study focused on the imaging in radiotherapy by finding the relationship between the imaging contrast ratio and appropriate gold, iodine, iron oxide, silver, and platinum nanoparticle concentrations; the relationship between the imaging contrast ratio and different beam energies for the different nanoparticle concentrations; the relationship between the contrast ratio and various beam energies for gold nanoparticles; and the relationship between the contrast ratio and different thicknesses of the incident layer of the phantom including variety of gold nanoparticles (GNPs) concentration. Monte Carlo simulation was used to model the gold, iodine, iron oxide, silver, and platinum nanoparticle concentration which were infused within a heterogeneous phantom (50 cm * 50 cm * 10.5 cm) choosing different concentrations (3, 7, 18, 30, and 40 mg), and beams (100, 120, 130, and 140 kVp) correspondingly that were delivered into the phantom. The results showed obvious connection between the high concentration and having a high imaging contrast ratio, low energy and a high contrast ratio, small thickness, and a high contrast ratio. The superior nanoparticle obtained was GNP, the better concentration was 40 mg, the better beam energy was 100 kVp, and the better thickness was 0.5 cm. It is concluded that our study successfully proved that medical imaging contrast could be improved by increasing the contrast ratio using GNP as the finest choice to accomplish this improvement considering a high concentration, low beam energy, and a small thickness. PMID- 30305779 TI - Assessment of Diagnostic Reference Level in Radiography of Neonatal Chest Anteroposterior Examination: A Hospital-based Study. AB - Radiological imaging is an important modality of today's overall practicum. Imaging can begin as early as the 1st day of life. Neonates are 3-4 times more sensitive to radiation than adults. The purpose of the work was to assess the diagnostic reference level (DRL), the radiation organ dose, and effective organ dose for both sexes from chest anteroposterior radiograph, which is the most common radiographic examination performed at the Neonatal Intensive Care Unit (NICU). The entrance air kerma was measured using a solid-state PIN type detector, and the value was used as the input factor to PCXMC-2.0 software to calculate the entrance surface air kerma (ESAK), patient-specific organ dose, and effective dose originated from chest anteroposterior examinations of neonates at NICU. The mean value of ESAK is taken as a diagnostic reference level (DRL) for neonates (both male and female). The mean ESAK value of male neonates is (79.6 +/ 1.4) MUGy and for female is (79.9 +/- 1.9) MUGy, and the institutional diagnostic reference level (DRL) is 80.35 MUGy for male and 81.2 MUGy for female (i.e., third quartile value). A statistical dependency (correlation) between neonates body mass index (BMI) and ESAK was defined for both the sexes. Significant positive correlation was found between ESAK per patient with respect to BMI of both male (R = 0.83, P = 0.00001) and female (R = 0.72, P = 0.00055) neonates. The results for neonatal dose in NICU were compatible with the literature. The result presented will serve as baseline data for the selection of technical parameters in neonatal chest anteroposterior X-ray examination. PMID- 30305780 TI - Individualizing medical treatment of overactive bladder. AB - Overactive bladder (OAB) syndrome is highly prevalent in both men and women and might have negative impact on quality of life. Clinical trials of OAB usually highly select participants that may not reflect the real-world practice of OAB patients. The spectrum of OAB includes patients with idiopathic, neuropathic, with bladder outlet obstruction, and patients in elderly and medical comorbidities. Patients might have poor response to OAB medication or have adverse events after treatment. Therefore, treatment of OAB should be individualized to obtain therapeutic efficacy and avoid unacceptable adverse events. This article reviews the recently published literature and provides a guide for physicians to choose the appropriate treatment for different OAB patients. PMID- 30305781 TI - Impact of vegan diets on gut microbiota: An update on the clinical implications. AB - Numerous studies indicate that microbiota plays an important role in human health. Diet is a factor related to microbiota which also influences human health. The relationships between diet, microbiota, and human health are complex. This review focuses on the current literature on vegan diets and their unique impact on gut microbiota. We also report on the health benefits of a vegan diet for metabolic syndrome, cardiovascular disease, and rheumatoid arthritis concerning relevant impacts from gut microbiota. Despite evidence supporting the clinical relevance of vegan gut microbiota to human health, the whole mechanism awaits further investigation. PMID- 30305782 TI - Treatment strategies for neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an autoimmune demyelinating disease with pathogenic autoantibodies that act against the astrocyte water channel protein, i.e. aquaporin-4: the disease is associated with recurrent episodes of optic neuritis (ON) and transverse myelitis, often resulting in severe disability. The main goals in treatment of NMO include acute symptomatic therapy and long-term stabilization of symptoms by preventing relapse. In recent years, ongoing randomized controlled trials in NMO patients have studied evidence for treatment. Briefly, acute-stage management (with pulse therapy using corticosteroids and/or plasmapheresis) and maintenance therapy (including rituximab, mycophenolate mofetil, and azathioprine) have been recommended in some case series and retrospective studies. Because of the high prevalence of liver disease, all NMO patients in Taiwan should be screened for hepatitis B and C before treatment is initiated. Although immunosuppression and plasma exchange are the mainstays of therapy for NMO ON, several selective and potentially therapeutic strategies targeting specific steps in NMO pathogenesis including blockers of NMO-IgG binding and inhibitors of granulocyte function have been evaluated in recent years. PMID- 30305784 TI - Sensorineural hearing loss in patients with chronic renal failure on hemodialysis in Basrah, Iraq. AB - Objectives: The objective of this study is to determine the effect of hemodialysis on the hearing threshold in patients with chronic renal failure (CRF). Materials and Methods: Fifty-nine patients with CRF on regular hemodialysis were followed up for 1 year with a pure-tone audiometric examination every 6 months. Results: The mean age of the patients was 41.8 +/- 9.2 years (range: 17-50 years). At the beginning of the study, 39 patients (66.1%) had sensorineural hearing loss (SNHL). During the 12-month follow-up, 6 more patients developed SNHL giving a point prevalence rate of 76.3% at the end of the study. The hearing loss was more evident in the higher frequencies. Of the studied patients, 64.4% showed deterioration of the hearing threshold. The mean hearing threshold at the beginning of the study was 29.2 +/- 21.1 dB versus 36.9 +/- 17.3 dB at the end of the study (P < 0.001). No significant relation was found between age, sex, serum electrolytes, blood urea, and duration of CRF and hearing loss. Multivariate analysis showed that the duration of hemodialysis was the only significant independent predictor of SNHL. Conclusion: SNHL is common in patients with CRF on hemodialysis. It was mild to moderate in the majority of patients. Hearing impairment was most obvious at the high frequencies. Most of the patients showed further deterioration in the hearing threshold with the duration of dialysis. PMID- 30305783 TI - Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury. AB - Acute myocardial ischemia/reperfusion (I/R) injury is a significant, unsolved clinical puzzle. In the disease context of acute myocardial infarction, reperfusion remains the only effective strategy to salvage ischemic myocardium, but it also causes additional damage. Myocardial I/R injury is composed of four types of damage, and these events attenuate the benefits of reperfusion therapy. Thus, inventing new strategies to conquer I/R injury is an unmet clinical need. A variety of pathological processes and mediators, including changes in the pH, generation of reactive oxygen radicals, and intracellular calcium overload, are proposed to be crucial in I/R-related cell injury. Among the intracellular events that occur during I/R, we stress the importance of protein phosphorylation signaling and elaborate its regulation. A variety of protein kinase pathways could be activated in I/R, including reperfusion injury salvage kinase and survivor-activating factor enhancement pathways, which are critical to cardiomyocyte survival. In addition to serine/threonine phosphorylation signaling, protein tyrosine phosphorylation is also critical in multiple cell functions and survival. However, the roles of protein kinases and phosphatases in I/R have not been extensively studied yet. By better understanding the mechanisms of I/R injury, we may have a better chance to develop new strategies for I/R injury and apply them in the clinical patient care. PMID- 30305785 TI - Assessment of perceived stress and association with sleep quality and attributed stressors among 1st-year medical students: A cross-sectional study from Karwar, Karnataka, India. AB - Objectives: The objective is to study the extent of perceived stress among 1st year medical students using the Perceived Stress Scale-14 (PSS-14) and its association with sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) and attributed stressors. Materials and Methods: A cross-sectional study was conducted of 121 1st-year medical students at Karwar Institute of Medical Sciences, Karwar, Karnataka, India. The extent of their stress was assessed using the PSS-14 and their sleep quality was assessed using the PSQI. Graded stress exerted by the attributed stressors was also assessed. Results: A total of 33.8% of participants had perceived stress scores of >28. Among academic stressors, performance in examinations (34.7%), lack of time for recreation (30.6%), curriculum (24.8%), and frequency of examinations (24.8%) were the highest rated stressors. Quality of food in the mess (50.4%) and lack of entertainment in the institution (39.7%) were the highest rated psychosocial stressors. There was a positive correlation between the PSS-14 scores and various academic stressors and the global PSQI score. Conclusion: First-year medical students reported a high level of stress, including academic and psychosocial stressors. Effective changes in the curriculum and living conditions can reduce the level of stress among these students. PMID- 30305786 TI - High serum leptin levels are associated with central arterial stiffness in geriatric patients on hemodialysis. AB - Objective: Central arterial stiffness predicts cardiovascular (CV) mortality in hemodialysis (HD) patients. The aging process transforms lipid distribution and thus alters adipokine secretion. The harmful effects of leptin on CV events may change in the elderly. The purpose of this study was to investigate the relationship between leptin and central arterial stiffness markers through carotid-femoral pulse wave velocity (cfPWV) in geriatric HD patients. Materials and Methods: Patients over 65 years old on chronic HD were recruited. Blood samples were collected, and the cfPWV was measured with the SphygmoCor system. The patients with cfPWV values >10 m/s were defined as the high arterial stiffness group. Results: In total, 30 (51.7%) of the 58 geriatric patients on chronic HD in this study were in the high arterial stiffness group. The high arterial stiffness group had higher rates of diabetes mellitus (P = 0.019), hypertension (P = 0.019), and higher systolic blood pressure (P = 0.018), pulse pressure (P = 0.019), body mass index (P = 0.018), serum leptin levels (P = 0.008), and hemoglobin levels (P = 0.040) than those in the low arterial stiffness group. Multivariable forward stepwise linear regression analysis showed logarithmically transformed leptin (log-leptin, beta =0.408, adjusted R 2 change = 0.164; P = 0.001) and diabetes (beta =0.312, adjusted R 2 change = 0.085; P = 0.009) were associated with cfPWV values in geriatric HD patients. Moreover, an increased serum leptin level (odds ratio: 1.053; 95% confidence interval: 1.007 1.100; P = 0.023) was an independent factor for central arterial stiffness among geriatric HD patients after multivariate logistic regression analysis. Conclusion: In this study, a higher serum leptin level was correlated with central arterial stiffness in geriatric HD patients. PMID- 30305787 TI - Increased prevalence of obstructive sleep apnea in patients with pectus excavatum: A pilot study. AB - Objective: Laryngomalacia is the most common congenital laryngeal anomaly and is associated with pectus excavatum (PE). Patients with laryngomalacia and patients with obstructive sleep apnea (OSA) both experience upper airway obstruction, and patients with laryngomalacia had been found to have a higher prevalence of PE. However, no studies have established the prevalence of OSA in patients with PE. We conducted this pilot study to evaluate the prevalence of OSA in patients with PE. Materials and Methods: A total of 42 patients >=20 years old with PE who were admitted for Nuss surgery to correct PE in Taipei Tzu Chi Hospital between October 2015 and September 2016 were invited to participate in the study; 31 of the 42 patients agreed. All 31 patients completed an Epworth sleepiness scale questionnaire to evaluate excessive daytime sleepiness (EDS) and underwent overnight polysomnography to evaluate OSA before Nuss surgery. Results: The prevalence of snoring in the study participants was 100%. Ten of 31 patients (32.3%) reported EDS. The overall prevalence of OSA with an apnea/hypopnea index >=5/h was 25.8%, and all patients with OSA were men. Conclusions: The prevalence of OSA in patients with PE seemed to be higher than that previously reported in the general population, implying that OSA might be a potential etiology or, at least, an aggravating factor for the development or progression of PE or might be responsible for the postoperative recurrence of PE in some patients. Further studies are needed to clarify this relationship. PMID- 30305788 TI - Passive limb movement test facilitates subthalamic deep brain stimulation under general anesthesia without influencing awareness. AB - Objectives: We have shown that neuronal activity in the subthalamic nucleus (STN) in patients with Parkinson's disease can be accurately recorded during deep brain stimulation (DBS) with general anesthesia (GA). However, a vigorous passive range of motion (PROM) test might exert awakening effects on patients who are lightly anesthetized. We will explore the effects of PROM on the heart rate (HR) and mean arterial pressure (MAP) during microelectrode recording (MER) and confirm whether it facilitates identifying the sensory motor portion of the STN under GA. Materials and Methods: 3T magnetic resonance image targeting of the STN was done to guide MER during frame-based stereotactic procedures for DBS. Regular induction and endotracheal intubation for GA were performed and then maintained with a volatile anesthetic agent and muscle relaxant only. The depth of anesthesia was monitored by the bispectral index (BIS). Results: A total of ten patients were enrolled in this study. Their mean age was 48.5 +/- 10.8 years old with a disease duration 8.6 +/- 2.4 years at the time of surgery. During MER, PROM significantly decreased recording tract numbers and still reached the STN at a recorded length at 5.5 +/- 0.8 mm. Compared with baseline, PROM increased HR by a mean 0.5 beats/min and MAP by a mean 1.4 mmHg (P = 0.1178 and 0.0525). The change in BIS was -0.7 (P = 0.4941), and the mean alveolar concentration of the anesthetic agent changed little throughout surgery. Conclusions: PROM was effective in triggering and magnifying neuronal firing signal without influencing patient awareness during MER for STN-DBS under GA. PMID- 30305790 TI - Spontaneous colonic rupture related to the segmental absence of muscularis propria in an adult. AB - Colonic perforation is a medical emergency that may be fatal if surgery cannot be performed in a timely manner. Colonic rupture in adults is caused by primary (idiopathic) and secondary factors. Although the segmental absence of muscularis propria (SAMP) is a recognized cause of secondary colonic rupture in neonates and infants, few cases have been reported in adults. Here, we present the case of a large colonic rupture caused by SAMP in a 60-year-old woman and a review of the literature. We suggest that SAMP should be included in the differential diagnosis of large perforation and/or periperforation membranous thinning of the colonic wall in adults. PMID- 30305789 TI - Open reduction and internal fixation with plating is beneficial in the early recovery stage for displaced midshaft clavicular fractures in patients aged 30-65 years old. AB - Objectives: Midshaft clavicular fractures are increasingly treated operatively rather than nonoperatively. Studies have shown mixed results for both types of treatment. The aim of this study was to compare the early-stage functional status associated with open reduction and internal fixation (ORIF) with plating and that associated with conservative treatment for displaced midshaft clavicular fractures. Materials and Methods: A single-center retrospective review of the results of 120 cases of displaced midshaft clavicular fractures in patients aged 30-65 years old was conducted. The primary outcome was fracture union status at 6 months. Other outcomes were subjective shoulder value (SSV) scores, visual analog scale (VAS) scores, and radiographic shortening at 6 weeks, 3 months, and 6 months. The complication rates in the operative and nonoperative groups were recorded. Results: The delayed union rate at 6-month postoperatively and VAS scores at 6 weeks, 3 months, and 6 months postinjury were significantly higher in the conservative treatment group than in the ORIF group. SSV scores were significantly improved at 6-month postinjury in the ORIF group. Conclusions: This is the first study to discuss the importance of early-stage functional restoration after ORIF with plating for displaced midshaft clavicular fractures. This surgery leads to lower pain complications in the earlier stages of bone healing and lower delayed union rates compared with conservative treatment, in patients aged 30-65 years old. PMID- 30305791 TI - Early renal arterial rupture and arterial pseudoaneurysm in graft kidneys from the same deceased donor. AB - Vascular complications are serious problems after kidney transplantation. An aneurysm or rupture in a graft artery is a rare but potentially devastating complication, which may lead to renal function impairment, graft loss, or even death. In this paper, we present two rare vascular complications in the early postoperative course after renal transplantation from the same deceased donor. In the first case, a 49-year-old woman who had spontaneous graft arterial rupture 13 days after kidney transplantation presented with sudden distension in the right lower abdomen. In the second case, a 56-year-old woman recipient with a graft renal arterial pseudoaneurysm presented with decreased urine output and deteriorating renal function 32 days after transplantation. Immediate surgical repair was performed, and fibrin sealant was applied to strengthen the fragile renal arterial wall. Although the function of both graft kidneys recovered well after surgery, the first graft kidney was removed 2 months later because of repeated fungal and bacterial infections. Aggressive surgical reconstruction may preserve graft kidneys in patients with vascular complications after kidney transplantation, but recovery of the graft condition remains a demanding challenge in renal transplantation. PMID- 30305793 TI - Corrigendum: Open reduction and internal fixation with plating is beneficial in the early recovery stage for displaced midshaft clavicular fractures in patients aged 30-65 years old. AB - [This corrects the article on p. 242 in vol. 30.]. PMID- 30305792 TI - Multiple preretinal yellowish dots in a patient with syphilis. PMID- 30305794 TI - A Visually Interpretable, Dictionary-Based Approach to Imaging-Genomic Modeling, With Low-Grade Glioma as a Case Study. AB - Radiomics is a rapidly growing field in which sophisticated imaging features are extracted from radiology images to predict clinical outcomes/responses, genetic alterations, and other outcomes relevant to a patient's prognosis or response to therapy. This approach can effectively capture intratumor phenotypic heterogeneity by interrogating the "larger" image field, which is not possible with traditional biopsy procedures that interrogate specific subregions alone. Most models in radiomics derive numerous imaging features (eg, texture, shape, size) from a radiology data set and then learn complex nonlinear hypotheses to solve a given prediction task. This presents the challenge of visual interpretability of radiomic features necessary for effective adoption of radiomic models into the clinical decision-making process. To this end, we employed a dictionary learning approach to derive visually interpretable imaging features relevant to genetic alterations in low-grade gliomas. This model can identify regions of a medical image that potentially influence the prediction process. Using a publicly available data set of magnetic resonance imaging images from patients diagnosed with low-grade gliomas, we demonstrated that the dictionary-based model performs well in predicting 2 biomarkers of interest (1p/19q codeletion and IDH1 mutation). Furthermore, the visual regions (atoms) associated with these dictionaries show association with key molecular pathways implicated in gliomagenesis. Our results show that dictionary learning is a promising approach to obtain insights into the diagnostic process and to potentially aid radiologists in selecting physiologically relevant biopsy locations. PMID- 30305795 TI - Predicting Factors for Smoking Behavior among Women Who Frequent Nightlife Entertainment Venues around a University in the Northern Region of Thailand. AB - This cross-sectional survey aims to study the behaviors and predictors for smoking behaviors among women who frequent nightlife entertainment venues around a university in the northern region of Thailand. Samples comprised 279 women who visited nightlife venues around a university in the northern region of Thailand. A questionnaire was used for data collection. Data were analyzed by chi-square and binary logistic regression. The results found that women who frequented nightlife venues and smoked accounted for 32% and 22% of those who smoked inside such venues. Furthermore, the factors identified as predictive of smoking behavior among women who frequented nightlife entertainment venues included frequently visiting nightlife venues more than 3 days per week (odds ratio (OR) = 8.89, 95% confidence interval (CI): 3.31-23.90), having a positive attitude toward smoking (OR = 3.13, 95% CI: 1.56-6.28), having a smoking family member (OR = 2.78, 95% CI: 1.37-5.66), and having a smoking partner (OR = 4.86, 95% CI: 2.38 9.93). Therefore, relevant agencies should continuously promote the right attitudes about smoking to Thai women who frequent nightlife entertainment venues. PMID- 30305797 TI - Impact of Video Aid on Quality of Bowel Preparation Among Patients Undergoing Outpatient Screening Colonoscopy. AB - Aim: To investigate the effect of video aid on quality of bowel preparation. Study: A retrospective study was done on patients undergoing outpatient screening colonoscopy. All subjects received educational video prior to colonoscopy in addition to the standard counseling. Patient charts were reviewed to collect data regarding quality of bowel preparation (adequate or inadequate). The study population was stratified into four groups according to viewing status: Group I 0% (control group), Group II <50%, Group III >50% to <75%, and Group IV watched ?75% of the video. Results: A total of 338 patients with an average age of 59.1 years and 60.3% females were included in the final study cohort. Of the patients in Groups I, II, III, and IV, 94.3%, 90.9%, 100%, and 91.7%, respectively, had adequate preparation (P value = .827). Adenoma detection rate (ADR) for Groups I, II, III, and IV was 28.8%, 50%, 50%, and 22.6%, respectively (P value = .305). The mean cecal intubation time was 20.7, 16.4, 16.57, and 17 minutes for Groups I, II, III, and IV, respectively (P value = .041). Conclusions: Video aid use for patients undergoing screening colonoscopy lacked a statistically significant impact on the quality of bowel preparation, ADR, and advanced adenoma detection rate when compared with standard practice. PMID- 30305798 TI - Thesiumnautimontanum, a new species of Thesiaceae (Santalales) from South Africa. AB - Thesiumnautimontanum M.A. Garcia, Nickrent & Mucina, a new species from the Matroosberg Mt. of Western Cape Province of South Africa, is described and illustrated. This species shows several morphological features unusual for the genus including stem sympodial branching, indeterminate spicate inflorescences subtended by numerous bracts and fleshy, non-trichome tissue lining the inside of the corolla lobes. Molecular phylogenetic analyses using nuclear ribosomal internal transcribed spacer sequences place this taxon as sister to all African, Madagascan and South American Thesium species. Given that only two proximal populations are known, this species is of conservation concern. PMID- 30305796 TI - The Amylases of Insects. AB - Alpha-amylases are major digestive enzymes that act in the first step of maltopolysaccharide digestion. In insects, these enzymes have long been studied for applied as well as purely scientific purposes. In many species, amylases are produced by multiple gene copies. Rare species are devoid of Amy gene. They are predominantly secreted in the midgut but salivary expression is also frequent, with extraoral activity. Enzymological parameters are quite variable among insects, with visible trends according to phylogeny: Coleopteran amylases have acidic optimum activity, whereas dipteran amylases have neutral preference and lepidopteran ones have clear alkaline preference. The enzyme structure shows interesting variations shaped by evolutionary convergences, such as the recurrent loss of a loop involved in substrate handling. Many works have focused on the action of plant amylase inhibitors on pest insect amylases, in the frame of crop protection by transgenesis. It appears that sensitivity or resistance to inhibitors is finely tuned and very specific and that amylases and their inhibitors have coevolved. The multicopy feature of insect amylases appears to allow tissue-specific or stage-specific regulation, but also to broaden enzymological abilities, such as pH range, and to overcome plant inhibitory defenses. PMID- 30305799 TI - OpenNahele: the open Hawaiian forest plot database. AB - Background: This data paper provides a description of OpenNahele, the open Hawaiian forest plot database. OpenNahele includes 530 forest plots across the Hawaiian archipelago containing 43,590 individuals of 185 native and alien tree, shrub and tree fern species across six islands. We include estimates of maximum plant size (D950.1 and Dmax3) for 58 woody plant species, a key functional trait associated with dispersal distance and competition for light. OpenNahele can serve as a platform to test key ecological, evolutionary and conservation questions in a hotspot archipelago. New information: OpenNahele is the first database that compiles data from a large number of forest plots across the Hawaiian archipelago to allow broad and high resolution studies of biodiversity patterns.Keywords: Hawaii, forests, islands, biodiversity, community ecology, evolutionary ecology. PMID- 30305800 TI - Aggregated occurrence records of the federally endangered Poweshiek skipperling (Oarisma poweshiek). AB - Background: Primary biodiversity data records that are open access and available in a standardised format are essential for conservation planning and research on policy-relevant time-scales. We created a dataset to document all known occurrence data for the Federally Endangered Poweshiek skipperling butterfly [Oarisma poweshiek (Parker, 1870; Lepidoptera: Hesperiidae)]. The Poweshiek skipperling was a historically common species in prairie systems across the upper Midwest, United States and Manitoba, Canada. Rapid declines have reduced the number of verified extant sites to six. Aggregating and curating Poweshiek skipperling occurrence records documents and preserves all known distributional data, which can be used to address questions related to Poweshiek skipperling conservation, ecology and biogeography. Over 3500 occurrence records were aggregated over a temporal coverage from 1872 to present. Occurrence records were obtained from 37 data providers in the conservation and natural history collection community using both "HumanObservation" and "PreservedSpecimen" as an acceptable basisOfRecord. Data were obtained in different formats and with differing degrees of quality control. During the data aggregation and cleaning process, we transcribed specimen label data, georeferenced occurrences, adopted a controlled vocabulary, removed duplicates and standardised formatting. We examined the dataset for inconsistencies with known Poweshiek skipperling biogeography and phenology and we verified or removed inconsistencies by working with the original data providers. In total, 12 occurrence records were removed because we identified them to be the western congener Oarisma garita (Reakirt, 1866). This resulting dataset enhances the permanency of Poweshiek skipperling occurrence data in a standardised format. New information: This is a validated and comprehensive dataset of occurrence records for the Poweshiek skipperling (Oarisma poweshiek) utilising both observation and specimen-based records. Occurrence data are preserved and available for continued research and conservation projects using standardised Darwin Core formatting where possible. Prior to this project, much of these occurrence records were not mobilised and were being stored in individual institutional databases, researcher datasets and personal records. This dataset aggregates presence data from state conservation agencies, natural heritage programmes, natural history collections, citizen scientists, researchers and the U.S. Fish & Wildlife Service. The data include opportunistic observations and collections, research vouchers, observations collected for population monitoring and observations collected using standardised research methodologies. The aggregated occurrence records underwent cleaning efforts that improved data interoperablitity, removed transcription errors and verified or removed uncertain data. This dataset enhances available information on the spatiotemporal distribution of this Federally Endangered species. As part of this aggregation process, we discovered and verified Poweshiek skipperling occurrence records from two previously unknown states, Nebraska and Ohio. PMID- 30305801 TI - Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer. AB - Background: p16 and p53 genes are frequently mutated in triple negative breast cancer & prognostic value of these mutations have been shown; however, their role as immunohistochemical overexpression has not been fully validated. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters. Methods: Total 150 cases of triple negative breast cancers were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. ER, PR and Her2neu immunohistochemistry were re-performed to confirm triple negative status. p16 & p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined. Results: Mean age of the patients involved in the study was 48.9 years. Most of the patients presented at stage T2 with a high mean ki67 index i.e. 46.9%. 42.7% of cases had nodal metastasis. Although 84% cases were of invasive ductal carcinoma; however a significant proportion of cases were of metaplastic histology (9.3%). Fifty-one percent (76 cases) of cases showed positive p53 expression while 49% (74 cases) were negative. Higher percentage of p53 expression was found to correlate with higher T stage, high ki67 index and higher nodal stage. On the other hand, strong intensity of p53 expression was positively correlated with higher tumor grade and ki67 index. Seventy-one percent (98 cases) of cases showed positive p16 expression, whereas 24.8% (34 cases) were negative and 3.6% (5 cases) showed focal positive p16 expression. However, no significant association was found between p16 expression and various clinical and pathologic parameters. Similarly, no significant association of either p16 or p53 over-expression was noted with recurrence status of patients. Conclusion: On the basis of significant association of p53 over-expression with worse prognostic factors in triple negative breast cancer, therefore we suggest that more large scale studies are needed to validate this finding in loco-regional population. Moreover, high expression of p16 in triple negative breast cancer suggests a potential role of this biomarker in triple negative breast cancer pathogenesis which should be investigated with molecular based research in our population. PMID- 30305802 TI - Prognostic value of microvessel density in cervical cancer. AB - Background: Several epidemiological researches have indicated that microvessel density (MVD), reflecting angiogenesis, was a negatively prognostic factor of cervical cancer. However, the results were inconsistent. Therefore, we performed a meta-analysis to evaluate the association between microvessel density and the survival probability of patients with cervical cancer. Method: There was a comprehensive search of the PubMed, EMBASE and Cochrane databases up to August 31, 2017. Based on a fixed-effects or random-effects model, the hazard ratio (HR) and 95% confidence intervals (CIs) were calculated from researches on overall survival (OS) and disease-free survival (DFS). Result: Totally, we included 13 observational researches, involving 1097 patients with cervical cancer. The results showed that high level of microvessel density was negatively correlated with OS (HR = 1.79, 95% CIs 1.31-2.44, I 2 = 60.7%, P = 0.003) and DFS (HR = 1.47, 95% CIs 1.13-1.80, I 2 = 0%, P = 0.423) of cervical cancer patients. In subgroup analysis, high counts of MVD were significantly associated with a poor survival (including OS and DFS) of the patients detected by anti-factor VIII antibodies or in European origin. Conclusion: The present meta-analysis indicated that survival with high level of MVD was significant poorer than with low MVD in cervical cancer patient. Standardization of MVD assessment is needed. PMID- 30305803 TI - The predictive and prognostic role of a novel ADS score in esophageal squamous cell carcinoma patients undergoing esophagectomy. AB - Background: Chronic inflammation is deemed to play a significant effect on initiation and progression of esophageal squamous cell carcinoma (ESCC). In current study, we investigated the prognostic and predictive role of albumin (Alb) to fibrinogen (Fib) ratio (AFR) and a novel AFR-Alb-derived neutrophil/lymphocyte ratio (dNLR) score (ADS) in ESCC patients undergoing esophagectomy and compared them with Fib, Alb, neutrophil to lymphocyte ratio (NLR), dNLR, platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR). Materials and methods: A total of 153 clinical confirmed ESCC patients undergoing esophagectomy between January 2011 and December 2013 were included in present study. We detected preoperative Alb, Fib and neutrophil, monocyte, lymphocyte and platelet count, and obtained overall survival (OS) by 3 years' follow-up in the cases. X-tile software, Kaplan-Meier curve, Cox regression and predicted nomogram were used to evaluate the predictive and prognostic role of them in ESCC patients. Results: The optimal cut-off values of Fib, Alb, AFR, NLR, dNLR, PLR and LMR were 3.2 mg/dL, 38.2 g/L, 9.3, 2.1, 4.3, 145.9 and 2.3, respectively. High levels of Fib [(adjusted hazard ratio (HR) = 2.148, 95% confidential interval (CI) (1.229-3.753)], dNLR (adjusted HR = 2.338, 95% CI 1.626-5.308) and PLR (adjusted HR = 1.964, 95% CI 1.129-3.415) as well as low AFR (adjusted HR = 2.381, 95% CI 1.152-4.926) and Alb (adjusted HR = 2.398, 95% CI 1.342-4.273) were significantly associated with decreased OS in ESCC patients. The survival predictive areas under the time-dependent receiver operating characteristics curve of AFR, dNLR and Alb were higher than Fib and PLR, respectively. High ADS score was significantly associated with short 3 years' OS of ESCC patients (adjusted HR = 2.94, 95% CI 1.70-5.08). Moreover, OS of ESCC patients receiving adjuvant radio-chemotherapy was longer than those without the treatment in high ADS score subgroup (p = 0.001), however, no significant survival difference was observed in the patients with or without treatment radio chemotherapy (p = 0.297). Additionally, a significant difference was observed in c-index values of the nomograms including or without ADS (0.720 vs. 0.670, p < 0.05). Conclusions: Preoperative ADS was a prospective biomarker to predict clinical efficacy of adjuvant radio-chemotherapy and clinical prognosis of ESCC patients undergoing esophagectomy, and the score could apparently improve predicted efficacy of the nomogram. PMID- 30305804 TI - Drug induced Kounis syndrome: does oxidative stress play a role? AB - Background: Kounis syndrome (KS) has been described as the coincidental occurrence of acute coronary syndromes during an allergic reaction with cardiac anaphylaxis. It is caused by inflammatory mediators released after exposure to drugs, food, environmental and other triggers. Oxidative stress occurring in various inflammatory disorders causes molecular damage with the production of advanced oxidation products (AOPPs) and advanced glycation end products (AGEs). Case presentation: Markers of oxidative stress were evaluated in a patient who had experienced KS after antibiotic administration in order to investigate the possible role of these molecules in KS. No data, up to now, are available on biomarkers of oxidative stress in patients with drug-induced KS. Conclusions: AOPPs, but not AGEs, were significantly increased in the KS affected patient compared to controls as already reported in mastocytosis affected patients. PMID- 30305806 TI - stpm2cr: A flexible parametric competing risks model using a direct likelihood approach for the cause-specific cumulative incidence function. AB - In a competing risks analysis, interest lies in the cause-specific cumulative incidence function (CIF) which is usually obtained in a modelling framework by either (1) transforming on all of the cause-specific hazard (CSH) or (2) through its direct relationship with the subdistribution hazard (SDH) function. We expand on current competing risks methodology from within the flexible parametric survival modelling framework (FPM) and focus on approach (2). This models all cause-specific CIFs simultaneously and is more useful when prognostic related questions are to be answered. We propose the direct FPM approach for the cause specific CIF which models the (log-cumulative) baseline hazard without the requirement of numerical integration leading to benefits in computational time. It is also easy to make out-of-sample predictions to estimate more useful measures and alternative link functions can be incorporated, for example, the logit link. To implement the methods, a new estimation command, stpm2cr, is introduced and useful predictions from the model are demonstrated through an illustrative Melanoma dataset. PMID- 30305805 TI - Sickle cell disease, sickle trait and the risk for venous thromboembolism: a systematic review and meta-analysis. AB - Background: Globally, sickle cell disease (SCD) is one of the most common haemoglobinopathy. Considered a public health problem, it leads to vessel occlusion, blood stasis and chronic activation of the coagulation system responsible for vaso-occlussive crises and venous thromboembolism (VTE) which may be fatal. Although contemporary observational studies suggest a relationship between SCD or sickle trait (SCT) and VTE, there is lack of a summary or meta analysis data on this possible correlation. Hence, we propose to summarize the available evidence on the association between SCD, SCT and VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: We searched PubMed and Scopus to identify all cross-sectional, cohort and case-control studies reporting on the association between SCD or SCT and VTE, DVT or PE in adults or children from inception to April 25, 2017. For measuring association between SCD or SCT and VTE, DVT, or PE, a meta-analysis using the random-effects method was performed to pool weighted odds ratios (OR) of risk estimates. Results: From 313 records initially identified from bibliographic databases, 10 studies were eligible and therefore included the meta-analysis. SCD patients had significantly higher risk for VTE (pooled OR 4.4, 95%CI 2.6-7.5, p < 0.001), DVT (OR 1.1, 95% CI 1.1-1.2, p < 0.001) and PE (pooled OR 3.7, 95% CI 3.6-3.8, p < 0.001) as compared to non SCD-adults. A higher risk of VTE (OR 33.2, 95% CI 9.7-113.4, p < 0.001) and DVT (OR 30.7, 95% CI 1.6-578.2, p = 0.02) was found in pregnant or postpartum women with SCD as compared to their counterparts without SCD. Compared to adults with SCT, the risk of VTE was higher in adults with SCD (pooled OR 3.1, 95% CI 1.8-5.3, p < 0.001), and specifically in SCD pregnant or postpartum women (OR 20.3, 95% CI 4.1-102, p = 0.0003). The risk of PE was also higher in adults with SCD (OR 3.1, 95% CCI 1.7-5.9, p = 0.0004) as compared to those with SCT. The risk of VTE was higher in individuals with SCT compared to controls (pooled OR 1.7, 95% CI 1.3-2.2, p < 0.0001), but not in pregnant or postpartum women (OR 0.9, 95% CI 0.3-2.9, p = 0.863). Compared to controls, SCT was associated with a higher risk of PE (pooled OR 2.1, 95% CI 1.2-3.8, p = 0.012) but not of DVT (pooled OR 1.2, 95% CI 0.9-1.7, p = 0.157). Conclusion: Individuals with SCD, especially pregnant or postpartum women, might have a higher risk of VTE compared to the general population. SCT might also increases the risk of VTE. However, currently available data are not sufficient to allow a definite conclusion. Further larger studies are needed to provide a definitive conclusion on the association between SCD, SCT and VTE. PMID- 30305807 TI - Acute Effects of Whole-Body Vibration on the Pain Level, Flexibility, and Cardiovascular Responses in Individuals With Metabolic Syndrome. AB - The aim of the study was to assess the acute effect of whole-body vibration (WBV) exercise, with low frequency (5 Hz), on the pain level (PL), trunk flexibility, and cardiovascular responses (blood pressure [BP] and heart rate [HR]) in individuals with metabolic syndrome (MetS). Forty-four individuals were included in the study (control: 15) or in (WBV exercise: 29) groups. They were submitted to 3 bouts (1 minute each) of WBV exercise (5 Hz and peak-to-peak displacements of 2.5, 5.0, and 7.5 mm, corresponding to peak accelerations of 0.12, 0.25, and 0.35 g, respectively, sitting in a chair with the feet on the platform with knees flexed, followed by 1 minute of interset rest. The Control Group performed the same protocol, but the platform was turned off. The PL was measured through the visual analog pain scale, and the flexibility was measured through the anterior trunk flexion test. Significant improvements on PL (P = .031) and flexibility (P = .004) were found only in the WBV exercise group. The BP and HR remained at physiological levels. In conclusion, the WBV exercise would lead to physiological response decreasing PL and increasing flexibility as well as maintaining the cardiovascular responses in individuals with MetS. PMID- 30305808 TI - Can Whole-Body Vibration Exercises in Different Positions Change Muscular Activity of Upper Limbs? A Randomized Trial. AB - The aim of this study was to investigate the acute effects of whole-body vibration exercises (WBVE) in different positions on muscular activity of flexor digitorum superficialis (FD), wrist extensor (ED), and handgrip strength (HG) of healthy men. Fifteen participants have performed 5 test sets each one consisting of HG strength measurement and 1-minute WBVE intervention (frequency: 50 Hz, amplitude: 1.53 mm, synchronous tri-planar oscillating/vibratory platform), that could be control (no exposition to vibration), squat (30 seconds of rest and 30 seconds of WBVE in squat position), or push-up (30 seconds of rest, and 30 seconds of WBVE in push-up position). After testing, participants had 2 minutes of rest and then were encouraged to keep themselves on a pull-up bar for 30 seconds. During all procedures, muscular activity of FD and ED was measured by surface electromyography (EMG). Statistical analysis has revealed that the EMG measured in the FD during the static pull-up bar exercise after SQUAT condition was significantly higher (P = .004) than the CONTROL and PUSH-UP conditions. Whole-body vibration exercises in squat position increase acutely muscle activation of the FD during isometric exercises of longer duration, while muscle activation of ED and HG strength are not affected by WBVE. PMID- 30305810 TI - Effectiveness of Coenzyme Q10 Supplementation for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - Objective: To evaluate the effectiveness and safety of coenzyme Q10 for patients with type 2 diabetes mellitus (T2DM). Methods: Data from randomized controlled trials were obtained to assess the effects of coenzyme Q10 versus placebo or western medicine on patients with T2DM. The study's registration number is CRD42018088474. The primary outcomes included glycosylated hemoglobin, fasting blood glucose, and fasting insulin. Result: Thirteen trials involving 765 patients were included. Compared with the control group, coenzyme Q10 may decrease the HbA1c (WMD -0.29; 95% CI -0.54, -0.03; P = 0.03) and the fasting blood glucose (WMD -11.21; 95% CI -18.99, -3.43; P = 0.005). For fasting insulin, there is also not strong evidence that confirms which one is better because there was no statistical difference (WMD -0.48; 95% CI -2.54, 1.57; P = 0.65). Conclusion: Based on current evidence, coenzyme Q10 may assist glycemic control, decrease TG, and improve HDL-C in patients with T2DM. PMID- 30305809 TI - Enhancement of grain number per spike by RNA interference of cytokinin oxidase 2 gene in bread wheat. AB - Background: This study aimed to validate the function of CKX gene on grain numbers in wheat. Methods: we constructed and transformed a RNA interference expression vector of TaCKX2.4 in bread wheat line NB1. Southern blotting analysis was used to select transgenic plants with single copy. The expression of TaCKX2.4 gene was estimated by Quantitative real-time PCR (qRT-PCR) analysis. Finally, the relation between expression of TaCKX2.4 gene and grain numbers was validated. Results: Totally, 20 positive independent events were obtained. Homozygous lines from 5 events with a single copy of transformed gene each were selected to evaluate the expression of TaCKX2.4 and grain numbers per spike in T3 generation. Compared with the control NB1, the average grain numbers per spike significantly increased by 12.6%, 8.3%, 6.5% and 5.8% in the T3 lines JW39-3A, JW1-2B, JW1-1A and JW5-1A, respectively. Conclusion: Our study indicated that the expression level of TaCKX2.4 was negatively correlated with the grain number per spike, indicating that the reduced expression of TaCKX2.4 increased grain numbers per spike in wheat. PMID- 30305811 TI - Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis. AB - Purpose: We aimed to identify new predictive biomarkers for cetuximab in first line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations. PMID- 30305812 TI - Matrix Metalloproteinase-8 as an Inflammatory and Prevention Biomarker in Periodontal and Peri-Implant Diseases. AB - Levels of and especially the degree of activation of matrix metalloproteinase (MMP-8) in oral fluids (i.e., saliva, mouth rinse, gingival crevicular fluid (GCF) and peri-implantitis sulcular fluid (PISF)) increase to pathologically elevated levels in the periodontal and peri-implant diseases. This study aimed at collecting and collating data from previously published studies and determining whether active MMP-8 (aMMP-8) could serve as a biomarker for the diagnosis and prevention of periodontal and peri-implant diseases. The literature search identified a total of 284 articles. Out of 284 articles, 61 articles were found to be relevant. Data obtained from the selected studies were combined, and it indicated that aMMP-8 in oral fluids exerts the strong potential to serve as a useful adjunctive diagnostic and preventive biotechnological tool in periodontal and peri-implant diseases. aMMP-8 can be used alone or in combination with other proinflammatory and/or microbiological biomarkers. PMID- 30305813 TI - Vitamin D and Nonskeletal Complications among Egyptian Sickle Cell Disease Patients. AB - Lower levels of vitamin D have been documented in many patients with sickle cell disease (SCD), but data are still inconclusive regarding the association between vitamin D deficiency (VDD) and the occurrence or the severity of various SCD complications. Our study aimed to detect the prevalence of vitamin D deficiency among Egyptian patients with SCD and to associate it with the clinical course of the disease. We measured the level of 25-hydroxy vitamin D in 140 children (age from 4.3 to 15.5years), 80 patients with SCD and 60 controls using enzyme-linked immunosorbent assay. Vitamin D was deficient in 60% of SCD compared to 26.7% of controls. Severe VDD was significantly higher in SCD patients than controls. Patients were divided into 2 groups; Normal group (32 patients) and Deficient group (48 patients). There were statistically significant differences between the 2 groups regarding their age, height percentile, the presence of clinical jaundice, and osseous changes (P values 0.043, 0.024, 0.001, and 0.015, respectively). Hemoglobin and hematocrit values were significantly lower in Deficient group (P values 0.022 and 0.004, respectively) while the levels of aspartate aminotransferase, lactate dehydrogenase, and total and indirect bilirubin were significantly higher in the same group (P values 0.006, 0.001, 0.038, and 0.016, respectively). The frequency of blood transfusions, hospitalization, and vasoocclusive crisis previous year as well as the history of bone fracture and recurrent infections proved to be significantly higher in Deficient group. These findings suggest that VDD may play a role in the pathogenesis of hemolysis and other complication of SCD. Vitamin D monitoring and supplementation in patients with SCD should be implemented as a standard of care to potentially improve health outcomes in these affected patients. PMID- 30305815 TI - The First Report of Multicentric Carpotarsal Osteolysis Syndrome Caused by MAFB Mutation in Asian. AB - Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by aggressive osteolysis associated with progressive nephropathy. The early clinical presentation can mimic polyarticular juvenile idiopathic arthritis. Since 2012, MAFB mutations have been discovered in all MCTO patients. Therefore, the early diagnosis can be made based on genetic confirmation. We report the clinical manifestation of mineral bone disease and the molecular genetic study of a Thai female adolescent with MCTO. She presented with end-stage renal disease, bilateral wrist and ankle joint deformities, and subtle facial dysmorphic features. We identified a heterozygous missense MAFB mutation at nucleotide 197 from C to G (NM_005461.4; c.197C>G), predicting the change of amino acid at codon 66 from serine to cysteine (p.Ser66Cys), and the mutation was absent in the parents, indicating a de novo mutation. This report confirms the previous link between MAFB mutation and MCTO. Her unexplained hypercalcemia after a regular dose of calcium and active vitamin D supported an important role of MafB in the negative regulation of RANKL-mediated osteoclast differentiation. Therefore, we would encourage the physicians who take care of MCTO patients to closely monitor serum calcium level and perform a genetic study as a part of the management and investigation. PMID- 30305814 TI - Prevalence of Multidrug Resistance and Extended-Spectrum beta-Lactamase Carriage of Clinical Uropathogenic Escherichia coli Isolates in Riyadh, Saudi Arabia. AB - The prevalence of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli) has recently increased worldwide. This study aims at determining the antimicrobial susceptibility patterns of a collection of clinical E. coli urine isolates and evaluating the ESBL carriage of these isolates at phenotypic and genotypic levels. A total of 100 E. coli urine isolates were collected at a tertiary healthcare centre in Riyadh from January 2018 to March 2018. Antimicrobial susceptibility testing was carried out for all isolates. ESBL production was characterized at phenotypic and genotypic levels using double-disc synergy test and polymerase chain reaction, respectively. Detection of different ESBL variants was performed using DNA sequencing. Of 100 E. coli isolates, 67 were associated with multidrug resistance (MDR) phenotype. All isolates showed variable resistance levels to all antibiotics used here expect to imipenem, where they were all imipenem-sensitive. 33 out of 100 E. coli isolates were positive for ESBLs by phenotypic and genotypic methods. Among all ESBL-positive E. coli isolates, the CTX-M was the most prevalent ESBL type (31/33 isolates; 93.94%). CTX-M-15 variant was detected in all isolates associated with CTX-M carriage. Multiple ESBL gene carriage was detected in 15/33 isolates (45.45%), where 11 (33.33%) isolates produced two different ESBL types while 4 isolates (12.12%) associated with carrying three different ESBL types. Our study documented the high antimicrobial resistance of ESBL-producing E. coli to many front-line antibiotics currently used to treat UTI patients, and this implies the need to continuously revise the local guidelines used for optimal empirical therapy for UTI patients. It also showed the high prevalence of ESBL carriage in E. coli urine isolates, with CTX-M-15 being the most predominant CTX-M variant. PMID- 30305816 TI - When a Seemingly Harmless Prescription Turns into Toxicity. AB - Valacyclovir neurotoxicity is commonly seen in the elderly and those with impaired renal function. Differential diagnosis can be challenging as a myriad of medical conditions, including herpes zoster virus associated encephalitis, may present in a similar fashion. We present a case of a 71-year-old male who presented with altered mental status in the setting of recent herpes zoster eruption. His condition was attributed to valacyclovir neurotoxicity, and initiation of appropriate supportive therapy was met with complete resolution of symptoms and normalization of cognitive function. PMID- 30305817 TI - Application of Stem Cells and Advanced Materials in Nerve Tissue Regeneration. PMID- 30305819 TI - New Approaches to Treat Osteoarthritis with Mesenchymal Stem Cells. AB - Osteoarthritis is one of the most common chronic health problems in the world that causes disability and chronic pain with reduced mobility and is a progressive degenerative disease in weight-bearing joints such as the knee. The pathology of the joint resulting from OA includes loss of cartilage volume and cartilage lesions leading to inflammation of the articular joint structures; its incidence and progression are associated with a variety of risk factors. Most of the current treatments focus on symptom management such as physical and occupational therapies, pharmacological intervention for pain management, and surgical intervention with limited success and do not address nor halt the progression of the disease. In this review, we will describe the current treatment options for OA and the exciting new translational medical research currently underway utilising mesenchymal stem cells for OA therapy. PMID- 30305820 TI - Mechanobiology of Periodontal Ligament Stem Cells in Orthodontic Tooth Movement. AB - Periodontal ligament stem cells (PDLSCs) possess self-renewal, multilineage differentiation, and immunomodulatory properties. They play a crucial role in maintaining periodontal homeostasis and also participated in orthodontic tooth movement (OTM). Various studies have applied controlled mechanical stimulation to PDLSCs and investigated the effects of orthodontic force on PDLSCs. Physical stimuli can regulate the proliferation and differentiation of PDLSCs. During the past decade, a variety of studies has demonstrated that applied forces can activate different signaling pathways in PDLSCs, including MAPK, TGF-beta/Smad, and Wnt/beta-catenin pathways. Besides, recent advances have highlighted the critical role of orthodontic force in PDLSC fate through mediators, such as IL 11, CTHRC1, miR-21, and H2S. This perspective review critically discusses the PDLSC fate to physical force in vitro and orthodontic force in vivo, as well as the underlying molecular mechanism involved in OTM. PMID- 30305818 TI - Mesenchymal Stem Cells in Primary Sjogren's Syndrome: Prospective and Challenges. AB - Primary Sjogren's syndrome (pSS) is a chronic systemic inflammatory autoimmune disease characterized by lymphocytic infiltrates in exocrine glands. Current approaches do not control harmful autoimmune attacks or prevent irreversible damage and have considerable side effects. Mesenchymal stem cells (MSCs) have been effective in the treatment of several autoimmune diseases. The objective of this review is to illustrate the potential therapeutic role of MSCs in pSS. We summarize the recent advances in what is known about their immunomodulatory function and therapeutic applications in pSS. MSC transfusion can suppress autoimmunity and restore salivary gland secretory function in mouse models and patients with pSS by inducing regulatory T cells, suppressing Th1, Th17, and T follicular helper cell responses. In addition, MSCs can differentiate into salivary epithelial cells, presenting an option as a suitable alternative treatment. We also discuss current bioengineering methods which improve functions of MSCs for pSS. However, there remain many challenges to overcome before their wide clinical application. PMID- 30305821 TI - Human Neonatal Thymus Mesenchymal Stem Cells Promote Neovascularization and Cardiac Regeneration. AB - Newborns with critical congenital heart disease are at significant risk of developing heart failure later in life. Because treatment options for end-stage heart disease in children are limited, regenerative therapies for these patients would be of significant benefit. During neonatal cardiac surgery, a portion of the thymus is removed and discarded. This discarded thymus tissue is a good source of MSCs that we have previously shown to be proangiogenic and to promote cardiac function in an in vitro model of heart tissue. The purpose of this study was to further evaluate the cardiac regenerative and protective properties of neonatal thymus (nt) MSCs. We found that ntMSCs expressed and secreted the proangiogenic and cardiac regenerative morphogen sonic hedgehog (Shh) in vitro more than patient-matched bone-derived MSCs. We also found that organoid culture of ntMSCs stimulated Shh expression. We then determined that ntMSCs were cytoprotective of neonatal rat cardiomyocytes exposed to H2O2. Finally, in a rat left coronary ligation model, we found that scaffoldless cell sheet made of ntMSCs applied to the LV epicardium immediately after left coronary ligation improved LV function, increased vascular density, decreased scar size, and decreased cardiomyocyte death four weeks after infarction. We conclude that ntMSCs have cardiac regenerative properties and warrant further consideration as a cell therapy for congenital heart disease patients with heart failure. PMID- 30305822 TI - Thyroid Function in Chronically Transfused Children with Beta Thalassemia Major: A Cross-Sectional Hospital Based Study. AB - Background: Thalassemia is the most common genetic disorder worldwide. Use of iron chelators has improved survival but endocrine complications have become more frequent. The frequency of hypothyroidism in Beta Thalassemia Major (BTM) children ranges from 6 to 30 %. Thyroid dysfunction mainly occurs by gland infiltration, chronic tissue hypoxia, free radical injury, and organ siderosis. Objectives: (a) To evaluate the thyroid function status in chronically transfused children with BTM, in the first and second decade of life and (b) to study the influence of factors like duration and amount of blood transfusions, serum ferritin level, and iron chelation therapy on thyroid function. Methodology: BTM children, 3 years old and above, on regular blood transfusions with serum ferritin > 1500 mcg/l were included in the study. Thyroid function and ferritin assessment was done using ELISA kits. Autoimmune thyroiditis was ruled out by antithyroid peroxidase and antithyroglobulin antibody testing. Results: A study population of 83 children consisted of 49 boys (59%) and 34 girls (41%). 4.8% of the children had evidence of subclinical hypothyroidism. Among them two belonged to the first decade and the other two to the second decade of life. Mean TSH, FT4, and ferritin values among children with thyroid dysfunction were 6.38 +/- 0.83 mIU/ml, 1.08 +/- 0.45 ng/dl, and 3983.0+/-1698.30 ng/ml, respectively. The severity of thyroid dysfunction was statistically significantly associated with higher serum TSH values in children in the second decade of life with a p value = 0.001. No other significant correlation was found between oral chelation, amount and duration of blood transfusion, or serum ferritin levels. Conclusion: Subclinical hypothyroidism was the thyroid dysfunction observed in our study. Regular blood transfusions with adequate chelation may decrease incidence of thyroid dysfunction. PMID- 30305823 TI - Computer Vision Syndrome and Associated Factors among Computer Users in Debre Tabor Town, Northwest Ethiopia. AB - Background: Globally, computer is one of the common office tools used in various institutions. Using computer for prolonged time led to the users at greater health risk of computer vision syndrome (CVS). Computer vision syndrome is the leading occupational health problem of the twenty-first century. About 70 percent of computer users are suffered from CVS. Besides the health problems, CVS causes inefficiency at workplace and deteriorate quality of work. The problem of CVS and its risk factors are not well known in Ethiopia. Method: A cross-sectional study was conducted to assess the prevalence of CVS and associated factors among computer user government employees in Debre Tabor town from February to March, 2016. Multistage random sampling method was applied to select 607 study participants, and the data were collected by using a structured questionnaire. Computer vision syndrome was measured by self-reported method. Bivariate and multivariable binary logistic regression analyses were performed using SPSS version 20. Significance level was obtained at 95% CI and p value < 0.05. Results: The prevalence of CVS was 422 (69.5%) with 95% CI of 65.60, 73.0%. Blurred vision, eyestrain, and eye irritation were the commonest reported symptoms of CVS with proportion of 62.60%, 47.63%, and 47.40%, respectively. Occupation: officer (adjusted odds ratio (AOR) = 4.74) and secretary (AOR = 9.17), daily computer usage (AOR: 2.29), and preexisting eye disease (AOR = 3.19) were risk factors for CVS. However, computer users with high payment, who took regular health break, and with good knowledge on computer safety measures were less impacted by CVS. Conclusion: The prevalence of computer vision syndrome was found to be higher in Debre Tabor town. Monthly income, occupation, daily computer usage, regular health break, knowledge, and preexisting eye disease were predictor variables for CVS. Optimizing exposure time, improving awareness on safety measures, and management support are important to tackle CVS. PMID- 30305824 TI - Dietary Intake and Obesity among Filipino Americans in New Jersey. AB - The prevalence of obesity is a public concern and is linked to chronic diseases. Filipino Americans have a high prevalence rate of hypertension and diabetes. This study investigated the dietary intake of first-generation Filipino Americans (n=210). In addition, it provides a comparison of the obesity rates using the International guideline and the WHO Asian recommendation. The dietary intake included caloric, carbohydrate, and fat intake and was determined using the Block Brief Food Frequency Questionnaire. The anthropometric measurements included actual height, weight, and waist measurements. The body mass index (BMI) and waist circumference were categorized using the International guideline and the WHO Asian recommendation to determine obesity. The caloric and carbohydrate intake were normal; however, fat intake was increased. The BMI and waist circumference showed substantial difference when using the International and Asian guidelines to determine obesity. The results highlight the increased health risks of Filipino American immigrants including a high dietary fat intake and an increased obesity rate. PMID- 30305825 TI - Assessment of Quality of Life among Children with End-Stage Renal Disease: A Cross-Sectional Study. AB - Background: Measuring health-related quality of life is considered an important outcome indicator in evaluating health-care interventions and treatments and in understanding the burden of diseases. Objectives: This study aimed at assessing quality of life among children with end-stage renal disease, either undergoing hemodialysis or had renal transplantation therapy and comparing it with healthy controls. Methods: A cross-sectional study was conducted between December 2016 and May 2017 in Abo El-Reesh Pediatric Hospital using parent/child reports of generic module for QoL assessment: PedsQLTM Inventory version 4 for both cases and controls. Disease-specific module: PedsQLTM ESRD version 3 was used for ESRD cases. 55 ESRD cases and 86 controls were enrolled in the study. Results: Statistically significant difference between ESRD cases and controls regarding all aspects of QoL was found; total QoL mean score was 58.4 +/- 15.3 and 86.8 +/- 10 among cases and controls, respectively. All individual QoL domains were significantly worse in ESRD cases. Transplantation group had better Spearman's correlation between child and parents' scores which showed significant positive moderate correlation. Conclusions: ESRD and its treatment modalities are affecting negatively all aspects of quality of life; incorporating QoL assessment and management is highly recommended. PMID- 30305826 TI - Experimental research into the potential therapeutic effect of GYY4137 on Ovariectomy-induced osteoporosis. AB - Background: Evidence has shown that endogenous H2S plays an important role in the physiological and pathophysiological processes of many organs. The study aimed to explore whether exogenous H2S has a potential therapeutic effect on a rat ovariectomy-induced model of osteoporosis. Methods: The OVX osteoporosis model was established in female Sprague-Dawley rats by full bilateral ovariectomy. The rats were randomly divided into four groups, with the two experimental groups receiving an intraperitoneal injection of GYY4137 or sodium alendronate. The level of H2S in the plasma was determined and common laboratory indicators to diagnose osteoporosis, such as alkaline phosphatase (ALP) activity and the levels of osteocalcin (OCN), calcitonin, parathyroid hormone and leptin were measured. The bone mineral density (BMD) of the 4th and 5th lumbar vertebrae was measured using dual-energy X-ray absorptiometry. The maximum stress of femoral fracture was obtained through a three-point bending test of the femur. Results: The OVX osteoporosis model was successfully established. GYY4137 was injected to increase the level of H2S in the plasma in one group, designated OVX-GYY during the observation period (p < 0.05). At 12 weeks, the BMD value of the fourth lumbar vertebra in the OVX-GYY group had increased (p < 0.05). The BMD femur value in the OVX-vehicle group had decreased (p < 0.05). Bilateral ovariectomy leads to biochemical disorders related to bone metabolism and hormone levels in rat plasma (all p < 0.05). Ovariectomy also reduced blood calcium, blood phosphate and calcitonin, and increased parathyroid hormone and leptin. The opposite results were obtained for the groups with alendronate sodium or GYY4137 treatment (all p < 0.05). Conclusions: Through the slow release of H2S, GYY4137 did an excellent job of simulating endogenous neuroendocrine gaseous signaling molecules. Exogenous H2S had a regulatory effect on osteoporosis in ovariectomized rats, showing potential value for the treatment of human postmenopausal osteoporosis. PMID- 30305827 TI - Hypoxic stabilization of mRNA is HIF-independent but requires mtROS. AB - Background: Tissue ischemia can arise in response to numerous physiologic and pathologic conditions. The cellular response to decreased perfusion, most notably a decrease in glucose and oxygen, is important for cellular survival. In response to oxygen deprivation or hypoxia, one of the key response elements is hypoxia inducible factor (HIF) and a key protein induced by hypoxia is vascular endothelial growth factor (VEGF). Under hypoxia, we and others have reported an increase in the half-life of VEGF and other hypoxia related mRNAs including MYC and CYR61; however, the mediator of this response has yet to be identified. For this study, we sought to determine if HIF-mediated transcriptional activity is involved in the mRNA stabilization induced by hypoxia. Methods: HEK293T or C6 cells were cultured in either normoxic or hypoxic (1% oxygen) conditions in the presence of 1 g/L glucose for all experiments. Pharmacological treatments were used to mimic hypoxia (desferroxamine, dimethyloxaloglutamate, CoCl2), inhibit mitochondrial respiration (rotenone, myxothiazol), scavenge reactive oxygen species (ROS; ebselen), or generate mitochondrial ROS (antimycin A). siRNAs were used to knock down components of the HIF transcriptional apparatus. mRNA half life was determined via actinomycin D decay and real time PCR and western blotting was used to determine mRNA and protein levels respectively. Results: Treatment of HEK293T or C6 cells with hypoxic mimetics, desferroxamine, dimethyloxaloglutamate, or CoCl2 showed similar induction of HIF compared to hypoxia treatment, however, in contrast to hypoxia, the mimetics caused no significant increase in VEGF, MYC or CYR61 mRNA half-life. Knockdown of HIF-alpha or ARNT via siRNA also had no effect on hypoxic mRNA stabilization. Interestingly, treatment of HEK293T cells with the mitochondrial inhibitors rotenone and myxothiazol, or the glutathione peroxidase mimetic ebselen did prevent the hypoxic stabilization of VEGF, MYC, and CYR61, suggesting a role for mtROS in the process. Additionally, treatment with antimycin A, which has been shown to generate mtROS, was able to drive the normoxic stabilization of these mRNAs. Conclusion: Overall these data suggest that hypoxic mRNA stabilization is independent of HIF transcriptional activity but requires mtROS. PMID- 30305829 TI - Hypoglycemic Properties of the Aqueous Extract from the Stem Bark of Ceiba pentandra in Dexamethasone-Induced Insulin Resistant Rats. AB - Parts of Ceiba pentandra are wildly used in Africa to treat diabetes and previous works have demonstrated their in vivo antidiabetic effects on type 1 diabetes models. In addition, it has been recently shown that the decoction and the methanol extract from the stem bark of C. pentandra potentiate in vitro, the peripheral glucose consumption by the liver and skeletal muscle slices. But nothing is known about its effect on type II diabetes, especially on insulin resistance condition. We investigated herein the antihyperglycemic, insulin sensitizing potential, and cardioprotective effects of the dried decoction from the stem bark of Ceiba pentandra (DCP) in dexamethasone-induced insulin resistant rats. DCP phytochemical analysis using LC-MS showed the presence of many compounds, including 8-formyl-7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4 naphthaquinone, 2,4,6-trimethoxyphenol, and vavain. Wistar rats were given intramuscularly (i.m.) dexamethasone (1 mg/kg/day) alone or concomitantly with oral doses of DCP (75 or 150 mg/kg/day) or metformin (40 mg/kg/day) for 9 days. Parameters such as body weight, glycemia, oral glucose tolerance, plasma triglycerides and cholesterol, blood pressure, and heart rate were evaluated. Moreover, cardiac, hepatic and aortic antioxidants (reduced glutathione, catalase, and superoxide dismutase), malondialdehyde level, and nitric oxide content were determined. DCP decreased glycemia by up to 34% and corrected the impairment of glucose tolerance induced by dexamethasone but has no significant effect on blood pressure and heart rate. DCP reduced the total plasma cholesterol and triglycerides as compared to animals treated only with dexamethasone. DCP also increased catalase, glutathione, and NO levels impaired by dexamethasone, without any effect on SOD and malondialdehyde. In conclusion, the decoction of the stem bark of Ceiba pentandra has insulin sensitive effects as demonstrated by the improvement of glucose tolerance, oxidative status, and plasma lipid profile. This extract may therefore be a good candidate for the treatment of type II diabetes. PMID- 30305830 TI - Evaluation of the Effectiveness of Protective Patches on Acupoints to Preserve the Bioenergetic Status against Magnetic Fields. AB - The potentially harmful nature of electromagnetic fields (EMF) and static magnetic fields (SMF) has become a major problem in recent years. All these elements could be combined to produce cellular responses. For example, the orientation of molecules of water or other complex molecules, growth and cell viability, cell morphology, and intracellular metabolic pathways have demonstrated binding to magnetic fields. The effect of EMF and SMF on humans is a topic of great importance, especially because modern technology has introduced artificial magnetic fields such as those generated by power lines, mobile communications, and medical imaging equipment. A relevant problem is certainly that of professional exposure. The aim of this study was the evaluation of the effectiveness of a commercially available device, Skudo(r) patches (Edil Natura S.r.l., Novara, Italy), in protecting magnetic resonance operators from the influence of magnetic fields such as those present in the workplace. Skudo(r) patches are designed to protect microareas of the body from external electromagnetic disturbances. In this study, 10 male Italian volunteers aged between 50 and 60 were enrolled in the hospital. All participants were subjected to measurements at 4 specific time points to evaluate the effectiveness of Skudo(r) to counteract both EMF and SMF magnetic fields by evaluating the level of bioenergetic reactivity. To perform the measurements, a variant of the Ryodoraku method has been used, based upon the assessment of electropermeability. In particular, 12 acupoints were measured, one for each of the main meridians. This study shows that both SMF and EMF cause an alteration of the body's water system. The application of Skudo(r) patches determines a regularization of bioenergetic levels related to the water system. The application of Skudo(r) on the EMF source has suppressed the imbalance effect of the water system found in the subject without any protection. PMID- 30305828 TI - A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation. AB - Background: Asthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase activating protein in an acute neutrophilic model of lung inflammation. Methods: Wild type and Rgs2 -/- C57Bl6 mice were exposed to nebulized lipopolysaccharide (LPS). Lung function (respiratory system resistance and compliance) was measured using a SCIREQ flexivent small animal ventilator. Lung inflammation was assessed by histochemistry, cell counting and by cytokine and chemokine expression in bronchoalveolar lavage (BAL) fluid. Results: Lipopolysaccharide inhalation induced transient airways hyperreactivity (AHR) and neutrophilic lung inflammation. While AHR and inflammation was greatest 3 h post-LPS exposure, BAL neutrophils persisted for 24 h. At 3 h post-LPS inhalation, multiple inflammatory cytokines (CSF2, CSF3, IL6, TNF) and chemokines (CCL3, CCL4, CXCL1, CXCL2) were highly expressed in the BAL fluid, prior to declining by 24 h. Compared to wild type counterparts, Rgs2 -/- mice developed significantly greater airflow resistance in response to inhaled methacholine (MCh) at 3 h post-LPS exposure. At 24 h post-LPS exposure, when lung function was recovering in the wild type animals, MCh-induced resistance was increased, and compliance decreased, in Rgs2 /- mice. Thus, Rgs2 -/- mice show AHR and stiffer lungs 24 h post-LPS exposure. Histological markers of inflammation, total and differential cell counts, and major cytokine and chemokine expression in BAL fluid were similar between wild type and Rgs2 -/- mice. However, 3 and 24 h post-LPS exposure, IL12B expression was significantly elevated in BAL fluid from Rgs2 -/- mice compared to wild type animals. Conclusions: While Rgs2 is bronchoprotective in acute neutrophilic inflammation, no clear anti-inflammatory effect was apparent. Nevertheless, elevated IL12B expression in Rgs2 -/- animals raises the possibility that RGS2 could dampen Th1 responses. These findings indicate that up-regulation of RGS2, as occurs in response to inhaled corticosteroids and long-acting beta2 adrenoceptor agonists, may be beneficial in acute neutrophilic exacerbations of airway disease, including asthma. PMID- 30305831 TI - Ameliorative Effects of Infantile Feire Kechuan Oral Solution on Mycoplasma Pneumoniae Pneumonia in Infant Mouse and Rat Models. AB - Mycoplasma pneumoniae (MP) infection is a major pathogen of community-acquired pneumonia (CAP) in children worldwide. Infantile Feire Kechuan Oral Solution (IFKOS) has been used for the treatment of MP pneumonia clinically in China for many years. The present study was designed to investigate the therapeutic effect of IFKOS on MP pneumonia and explore the potential mechanism of the actions. The infant BALB/c mouse and Wistar rat models of MP infection were successfully established to confirm the therapeutic effects of IFKOS, followed by assays for related cytokines and investigations of the IgM response involved. The results showed that IFKOS exhibited an inhibitory effect on pulmonary index (PI) and effectively reduced the degree of lesions in the lungs. The lethal rate of mice was significantly decreased while survival time of mice was dramatically increased by IFKOS treatment in comparison to infection control, respectively. IFKOS treatment (40, 20, and 10ml/kg) significantly decreased the level of MP-IgM in a dose-dependent manner, whereas IFKOS showed no obvious inhibitory effect on the increase of relative expression of MP-DNA. In addition, the elevated IL-2 and TNF-alpha levels were significantly reduced and the decreased IL-6 level was significantly enhanced by IFKOS treatment. Our study demonstrates that IFKOS has inhibitory effect on MP infection in infant mouse and rat models of MP pneumonia and protective effect from lethal MP challenge in infant murine model. These anti MP effects might be related to suppression of the IgM response and a reversal the imbalance of Th1/Th2 cytokines induced by MP infection. PMID- 30305832 TI - Expression changes of autophagy-related proteins in AKI patients treated with CRRT and their effects on prognosis of adult and elderly patients. AB - Background: Sepsis is one of the common death factors in intensive care unit, which refers to the systemic inflammatory response syndrome caused by infection. It has many complications such as acute renal injury, shock, multiple organ dysfunction, and failure. The mortality of acute renal injury is the highest among the complications, which is a serious threat to the safety of patients and affects the quality of life. This study aimed to observe the changes in autophagy related protein expressions in patients with acute kidney injury (AKI) after continuous renal replacement therapy (CRRT) and their impacts on prognosis. Methods: 207 AKI patients visiting the Emergency Department of The First People's Hospital of Xuzhou from January 2014 to February 2018 were recruited and treated with CRRT. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied to detect the expression of autophagy-related genes, including light chain 3 type II (LC3-II), autophagy-related 5 (Atg-5) and Beclin-1, in the monocytes of the patient's peripheral blood before and after treatment. The levels of inflammatory mediators interleukin (IL)-1beta and IL-6 were determined via enzyme-linked immunosorbent assay before and after treatment. The patient's serum creatinine (Scr) level before and after treatment was measured using a full automatic biochemistry analyser. Moreover, the treatment effect was graded after CRRT, and the relationship between the prognosis of patients and the autophagy related proteins was observed. Results: The Scr levels in the patients were significantly decreased after treatment with CRRT. Before treatment, the IL-1beta and IL-6 blood levels were high in the patients, while the amounts were significantly reduced after CRTT. The expressions of LC3-II, Atg-5 and Beclin-1 in the monocytes of patients after treatment were significantly decreased compared with those before treatment. Compared with those in survived patients, the expression of autophagy-related proteins was significantly elevated in in patients died after one to three weeks after the treatment. IL-1beta, IL-6, LC3 II and Beclin-1, but not Atg-5 values were significantly correlated with Scr. Conclusion: The expression of LC3-II, Atg-5 and Beclin-1 in the monocytes of patients may change prominently after treatment with CRRT, so they are expected to be regarded as new prognostic indicators for AKI patients. PMID- 30305833 TI - A consistent long-lasting pattern of spatial variation in egg size and shape in blue tits (Cyanistes caeruleus). AB - Background: Interspecies variation in avian egg shape and size is understandable in terms of adaptation, allometry and phylogeny. Within-species variation in egg properties influences offspring fitness and can be explained by differences in allocation of resources into reproductive components of life history in mulidimensionally variable environments. Egg size is inherently traded-off with clutch size, which may also be true of egg shape in some cases. We investigated long-term variation in egg shape and size between two geographically close populations of blue tits Cyanistes caeruleus in relation to clutch size and habitat differences. Results: The main finding is that there exists a persistent long-lasting pattern of spatial variation of egg size and shape between the two study populations of blue tits, 10 km apart, controlling for clutch size. Eggs in the urban park site were on average larger in volume and less spherical in shape than eggs in the forest site over 12 years of this study. Egg sizes were negatively associated with clutch sizes. Egg shape was not correlated with clutch size. Conclusions: Our findings suggest that the pattern of variation in egg size and shape results from different trophic richness of the breeding habitats of the study populations, demanding different allocation of resources and, especially, from the contrasting difference in the availability of calcium. PMID- 30305834 TI - Estimation of pack density in grey wolf (Canis lupus) by applying spatially explicit capture-recapture models to camera trap data supported by genetic monitoring. AB - Background: Density estimation is a key issue in wildlife management but is particularly challenging and labour-intensive for elusive species. Recently developed approaches based on remotely collected data and capture-recapture models, though representing a valid alternative to more traditional methods, have found little application to species with limited morphological variation. We implemented a camera trap capture-recapture study to survey wolf packs in a 560 km2 area of Central Italy. Individual recognition of focal animals (alpha) in the packs was possible by relying on morphological and behavioural traits and was validated by non-invasive genotyping and inter-observer agreement tests. Two types (Bayesian and likelihood-based) of spatially explicit capture-recapture (SCR) models were fitted on wolf pack capture histories, thus obtaining an estimation of pack density in the area. Results: In two sessions of camera trapping surveys (2014 and 2015), we detected a maximum of 12 wolf packs. A Bayesian model implementing a half-normal detection function without a trap specific response provided the most robust result, corresponding to a density of 1.21 +/- 0.27 packs/100 km2 in 2015. Average pack size varied from 3.40 (summer 2014, excluding pups and lone-transient wolves) to 4.17 (late winter-spring 2015, excluding lone-transient wolves). Conclusions: We applied for the first time a camera-based SCR approach in wolves, providing the first robust estimate of wolf pack density for an area of Italy. We showed that this method is applicable to wolves under the following conditions: i) the existence of sufficient phenotypic/behavioural variation and the recognition of focal individuals (i.e. alpha, verified by non-invasive genotyping); ii) the investigated area is sufficiently large to include a minimum number of packs (ideally 10); iii) a pilot study is carried out to pursue an adequate sampling design and to train operators on individual wolf recognition. We believe that replicating this approach in other areas can allow for an assessment of density variation across the wolf range and would provide a reliable reference parameter for ecological studies. PMID- 30305836 TI - A comparison of three-factor structure models using WISC-III in Greek children with learning disabilities. AB - Background: Children with learning disabilities are a heterogeneous group of children with a common characteristic discrepancy on the progress and development of their individual learning abilities. A few statistical analyses have been published regarding the factor analysis of the Greek Edition of Wechsler Intelligence Scale for Children-III. The aim of the research is the emergence of a new factorial model which describes the General Intelligence (g) of children and adolescents with learning disabilities, and that differs from the already existing intelligence models. This study aims to compare three-factor structure models of WISC-III in children with learning disabilities in the Greek population. Methods: A sample of 50 children were selected on the basis of research criteria from a total of 122 children who evaluated in a child psychiatric service in a general hospital, in a residential area in Greece. The Wechsler Intelligence Scale for Children-Third Edition was used to assess children's cognitive function. Using multi-factor analysis, three alternative factor models were compared. Results: Analysis of factor structure models suggests a new bi-factorial model that more appropriately describes the areas of cognitive development of children with learning disabilities. The first factor includes Comprehension, Picture Arrangement, Coding, Block Design, and Object Assembly, whereas the second one combines Information, Similarities, Arithmetic, Vocabulary, and Picture Arrangement. Conclusions: The present study shows the existence of a factorial model with two factors: one aggregating the Comprehension verbal subtest with four performance subtests and the other the Picture Arrangement performance subtest with four verbal subtests. This two factor model includes the loadings in two factors that relate to sequencing abilities and verbal reasoning abilities of children. These findings assert the clinical utility of the intelligence evaluation in the specific population. PMID- 30305835 TI - Effect of personalized moderate exercise training on Wistar rats fed with a fructose enriched water. AB - Background: Metabolic Syndrom has become a public health problem. It mainly results from the increased consumption of fat and sugar. In this context, the benefits of personalized moderate exercise training were investigated on a metabolic syndrome male wistar rat model food with fructose drinking water (20 25% w/v). Different markers including body weight, metabolic measurements, blood biochemistry related to metabolic syndrome complications have been evaluated. Methods: Male Wistar rats were randomly allocated to 4 groups: control (sedentary (C, n = 8) and exercise trained (Ex, n = 8)), fructose fed (sedentary (FF, n = 8) and exercise trained fructose fed rats (ExFF, n = 10)). ExFF and Ex rats were trained at moderate intensity during the last 6 weeks of the 12 weeks-long protocol of fructose enriched water. Metabolic control was determined by measuring body weight, fasting blood glucose, HOMA 2-IR, HIRI, MISI, leptin, adiponectin, triglyceridemia and hepatic dysfunction. Results: After 12 weeks of fructose enriched diet, rats displayed on elevated fasting glycaemia and insulin resistance. A reduced food intake, as well as increased body weight, total calorie intake and heart weight were also observed in FF group. Concerning biochemical markers, theoretical creatinine clearance, TG levels and ASAT/ALAT ratio were also affected, without hepatic steatosis. Six weeks of 300 min/week of moderate exercise training have significantly improved overweight, fasting glycaemia, HOMA 2-IR, MISI without modify HIRI. Exercise also decreased the plasma levels of leptin, adiponectin and the ratio leptin/adiponectin. Regarding liver function and dyslipidemia, the results were less clear as the effects of exercise and fructose-enriched water interact together, and, sometimes counteract each other. Conclusion: Our results indicated that positive health effects were achieved through a personalized moderate training of 300 min per week (1 h/day and 5 days/week) for 6 weeks. Therefore, regular practice of aerobic physical exercise is an essential triggering factor to attenuate MetS disorders induced by excessive fructose consumption. PMID- 30305837 TI - Comparison of attitudes to breastfeeding among Spanish-born and Chinese-born postpartum women in Madrid. AB - Background: Maternal breastfeeding is a practice that is associated with multiple health benefits for mothers and children. One of the lowest rates of breastfeeding has been observed among Chinese women who immigrate to high income countries. At present, there is a lack of comparative information between this group and that of Spanish-born women. Considering the relationship between the attitude of women towards breastfeeding and the initiation of breastfeeding, the aim of the study was to determine whether the attitude towards breastfeeding among Chinese postpartum women who have immigrated to Spain differs from that of Spanish-born postpartum women. Methods: Cross-sectional study, with between-group comparison, of 73 postpartum Spanish-born and Chinese immigrant women admitted to the maternity units of "12 de Octubre" Hospital (Spain) between April and November 2016. Attitudes toward breastfeeding were analyzed using the Spanish or Chinese version of the Iowa Infant Feeding Attitude Scale (IIFAS). A wide set of socioeconomic, biological, working and attitudinal conditions were considered as covariates. The association between IIFAS and country of origin was assessed by three multiple linear regression models (B, SE, and 95% confidence interval were calculated). Results: All Chinese women were first generation immigrants. Chinese born women were four years younger than Spanish-born mothers, had a lower educational level, more frequently had a paid job (mainly self-employed), and planned to return to work almost two months earlier than Spanish-born mothers did. Most Chinese women did not breastfeed exclusively.Chinese immigrant women obtained scores of approximately 9 points less in the Iowa Infant Feeding Attitude Scale (IIFAS) when compared to Spanish-born women [95% CI -15.59, 2.48], after adjusting for the different socioeconomic, educational and work related factors. Conclusions: Chinese-born women resident in Spain present a lower score on the IIFAS, when compared to Spanish-born women, which implies a more negative attitude towards breastfeeding. The between-groups difference is consistent, even when adjusting for known confounders and other factors which could affect the attitude of the mothers. It is therefore striking that, despite being in Spain, Chinese-born women maintain these preferences/attitudes regarding breastfeeding, compared with Spanish-born women, who obtain overall high scores. PMID- 30305838 TI - Hyperspectral imaging: a novel approach for plant root phenotyping. AB - Background: Root phenotyping aims to characterize root system architecture because of its functional role in resource acquisition. RGB imaging and analysis procedures measure root system traits via colour contrasts between roots and growth media or artificial backgrounds. In the case of plants grown in soil filled rhizoboxes, where the colour contrast can be poor, it is hypothesized that root imaging based on spectral signatures improves segmentation and provides additional knowledge on physico-chemical root properties. Results: Root systems of Triticum durum grown in soil-filled rhizoboxes were scanned in a spectral range of 1000-1700 nm with 222 narrow bands and a spatial resolution of 0.1 mm. A data processing pipeline was developed for automatic root segmentation and analysis of spectral root signatures. Spectral- and RGB-based root segmentation did not significantly differ in accuracy even for a bright soil background. Best spectral segmentation was obtained from log-linearized and asymptotic least squares corrected images via fuzzy clustering and multilevel thresholding. Root axes revealed major spectral distinction between center and border regions. Root decay was captured by an exponential function of the difference spectra between water and structural carbon absorption regions. Conclusions: Fundamentals for root phenotyping using hyperspectral imaging have been established by means of an image processing pipeline for automated segmentation of soil-grown plant roots at a high spatial resolution and for the exploration of spectral signatures encoding physico-chemical root zone properties. PMID- 30305839 TI - Optimization of CRISPR/Cas9 genome editing in cotton by improved sgRNA expression. AB - Background: When developing CRISPR/Cas9 systems for crops, it is crucial to invest time characterizing the genome editing efficiency of the CRISPR/Cas9 cassettes, especially if the transformation system is difficult or time consuming. Cotton is an important crop for the production of fiber, oil, and biofuel. However, the cotton stable transformation is usually performed using Agrobacterium tumefaciens taking between 8 and 12 months to generate T0 plants. Furthermore, cotton is a heterotetraploid and targeted mutagenesis is considered to be difficult as many genes are duplicated in this complex genome. The application of CRISPR/Cas9 in cotton is severely hampered by the long and technically challenging genetic transformation process, making it imperative to maximize its efficiency. Results: In this study, we provide a new system to evaluate and validate the efficiency of CRISPR/Cas9 cassettes in cotton using a transient expression system. By using this system, we could select the most effective CRISPR/Cas9 cassettes before the stable transformation. We have also optimized the existing cotton CRISPR/Cas9 system to achieve vastly improved mutagenesis efficiency by incorporating an endogenous GhU6 promoter that increases sgRNA expression levels over the Arabidopsis AtU6-29 promoter. The 300 bp GhU6.3 promoter was cloned and validated using the transient expression system. When sgRNAs were expressed under the control of the GhU6.3 promoter in CRISPR/Cas9 cassettes, expression levels were 6-7 times higher than those provided by the AtU6-29 promoter and CRISPR/Cas9-mediated mutation efficiency was improved 4-6 times. Conclusions: This study provides essential improvements to maximize CRISPR/Cas9-mediated mutation efficiency by reducing risk and workload for the application of CRISPR/Cas9 approaches in the targeted mutagenesis of cotton. PMID- 30305840 TI - Hyperspectral band selection using genetic algorithm and support vector machines for early identification of charcoal rot disease in soybean stems. AB - Background: Charcoal rot is a fungal disease that thrives in warm dry conditions and affects the yield of soybeans and other important agronomic crops worldwide. There is a need for robust, automatic and consistent early detection and quantification of disease symptoms which are important in breeding programs for the development of improved cultivars and in crop production for the implementation of disease control measures for yield protection. Current methods of plant disease phenotyping are predominantly visual and hence are slow and prone to human error and variation. There has been increasing interest in hyperspectral imaging applications for early detection of disease symptoms. However, the high dimensionality of hyperspectral data makes it very important to have an efficient analysis pipeline in place for the identification of disease so that effective crop management decisions can be made. The focus of this work is to determine the minimal number of most effective hyperspectral wavebands that can distinguish between healthy and diseased soybean stem specimens early on in the growing season for proper management of the disease. 111 hyperspectral data cubes representing healthy and infected stems were captured at 3, 6, 9, 12, and 15 days after inoculation. We utilized inoculated and control specimens from 4 different genotypes. Each hyperspectral image was captured at 240 different wavelengths in the range of 383-1032 nm. We formulated the identification of best waveband combination from 240 wavebands as an optimization problem. We used a combination of genetic algorithm as an optimizer and support vector machines as a classifier for the identification of maximally-effective waveband combination. Results: A binary classification between healthy and infected soybean stem samples using the selected six waveband combination (475.56, 548.91, 652.14, 516.31, 720.05, 915.64 nm) obtained a classification accuracy of 97% for the infected class. Furthermore, we achieved a classification accuracy of 90.91% for test samples from 3 days after inoculation using the selected six waveband combination. Conclusions: The results demonstrated that these carefully-chosen wavebands are more informative than RGB images alone and enable early identification of charcoal rot infection in soybean. The selected wavebands could be used in a multispectral camera for remote identification of charcoal rot infection in soybean. PMID- 30305841 TI - Health status of returning refugees, internally displaced persons, and the host community in a post-conflict district in northern Sri Lanka: a cross-sectional survey. AB - Background: Although the adverse impacts of conflict-driven displacement on health are well-documented, less is known about how health status and associated risk factors differ according to displacement experience. This study quantifies health status and quality of life among returning refugees, internally displaced persons, and the host community in a post-conflict district in Northern Sri Lanka, and explores associated risk factors. Methods: We analysed data collected through a household survey (n = 570) in Vavuniya district, Sri Lanka. The effect of displacement status and other risk factors on perceived quality of life as estimated from the 36-item Short Form Questionnaire, mental health status from 9 item Patient Health Questionnaire, and self-reported chronic disease status were examined using univariable analyses and multivariable regressions. Results: We found strong evidence that perceived quality of life was significantly lower for internally displaced persons than for the host community and returning refugees, after adjusting for covariates. Both mental health status and chronic disease status did not vary remarkably among the groups, suggesting that other risk factors might be more important determinants of these outcomes. Conclusions: Our study provides important insights into the overall health and well-being of the different displaced sub-populations in a post-conflict setting. Findings reinforce existing evidence on the relationship between displacement and health but also highlight gaps in research on the long-term health effects of prolonged displacement. Understanding the heterogeneity of conflict-affected populations has important implications for effective and equitable humanitarian service delivery in a post-conflict setting. PMID- 30305842 TI - Collagen and fibronectin surface modification of nanoporous anodic alumina and macroporous silicon for endothelial cell cultures. AB - Background: The ability to direct the cellular response by means of biomaterial surface topography is important for biomedical applications. Substrate surface topography has been shown to be an effective cue for the regulation of cellular response. Here, the response of human aortic endothelial cells to nanoporous anodic alumina and macroporous silicon with collagen and fibronectin functionalization has been studied. Methods: Confocal microscopy and scanning electron microscopy were employed to analyse the effects of the material and the porosity on the adhesion, morphology, and proliferation of the cells. Cell spreading and filopodia formation on macro- and nanoporous material was characterized by atomic force microscopy. We have also studied the influence of the protein on the adhesion. Results: It was obtained the best results when the material is functionalized with fibronectin, regarding cells adhesion, morphology, and proliferation. Conclusion: These results permit to obtain chemical modified 3D structures for several biotechnology applications such as tissue engineering, organ-on-chip or regenerative medicine. PMID- 30305843 TI - Correction to: Genome-resolved metagenomics of sugarcane vinasse bacteria. AB - [This corrects the article DOI: 10.1186/s13068-018-1036-9.]. PMID- 30305844 TI - Dynamical assessment of fluorescent probes mobility in poplar cell walls reveals nanopores govern saccharification. AB - Background: Improving lignocellulolytic enzymes' diffusion and accessibility to their substrate in the plant cell walls is recognised as a critical issue for optimising saccharification. Although many chemical features are considered as detrimental to saccharification, enzymes' dynamics within the cell walls remains poorly explored and understood. To address this issue, poplar fragments were submitted to hot water and ionic liquid pretreatments selected for their contrasted effects on both the structure and composition of lignocellulose. In addition to chemical composition and porosity analyses, the diffusion of polyethylene glycol probes of different sizes was measured at three different time points during the saccharification. Results: Probes' diffusion was mainly affected by probes size and pretreatments but only slightly by saccharification time. This means that, despite the removal of polysaccharides during saccharification, diffusion of probes was not improved since they became hindered by changes in lignin conformation, whose relative amount increased over time. Porosity measurements showed that probes' diffusion was highly correlated with the amount of pores having a diameter at least five times the size of the probes. Testing the relationship with saccharification demonstrated that accessibility of 1.3-1.7-nm radius probes measured by FRAP on non-hydrolysed samples was highly correlated with poplar digestibility together with the measurement of initial porosity on the range 5-20 nm. Conclusion: Mobility measurements performed before hydrolysis can serve to explain and even predict saccharification with accuracy. The discrepancy observed between probes' size and pores' diameters to explain accessibility is likely due to biomass features such as lignin content and composition that prevent probes' diffusion through non-specific interactions probably leading to pores' entanglements. PMID- 30305846 TI - Using a trait-based approach to optimize mixotrophic growth of the red microalga Porphyridium purpureum towards fatty acid production. AB - Background: Organic carbon sources have been reported to simultaneously increase the growth and lipid accumulation in microalgae. However, there have been no studies of the mixotrophic growth of Porphyridium purpureum in organic carbon media. In this study, three organic carbon sources, glucose, sodium acetate, and glycerol were used as substrates for the mixotrophic growth of P. purpureum. Moreover, a novel trait-based approach combined with Generalized Additive Modeling was conducted to determine the dosage of each organic carbon source that optimized the concentration of cell biomass or fatty acid. Results: A 0.50% (w/v) dosage of glucose was optimum for the enhancement of the cell growth of P. purpureum, whereas sodium acetate performed well in enhancing cell growth, arachidonic acid (ARA) and eicosapentaenoic acid (EPA) content, and glycerol was characterized by its best performance in promoting both cell growth and ARA/EPA ratio. The optimum dosages of sodium acetate and glycerol for the ARA concentration were 0.25% (w/v) and 0.38% (v/v), respectively. An ARA concentration of 211.47 mg L-1 was obtained at the optimum dosage of glycerol, which is the highest ever reported. Conclusions: The results suggested that a comprehensive consider of several traits offers an effective strategy to select an optimum dosage for economic and safe microalgae cultivation. This study represents the first attempt of mixotrophic growth of P. purpureum and proved that both biomass and ARA accumulation could be enhanced under supplements of organic carbon sources, which brightens the commercial cultivation of microalgae for ARA production. PMID- 30305847 TI - Cost-effectiveness of sacral nerve stimulation and percutaneous tibial nerve stimulation for faecal incontinence. AB - Background: Subcutaneous sacral nerve stimulation is recommended by the United Kingdom (UK) National Institute for Health and Care Excellence (NICE) as a second line treatment for patients with faecal incontinence who failed conservative therapy. Sacral nerve stimulation is an invasive procedure associated with complications and reoperations. This study aimed to investigate whether delivering less invasive and less costly percutaneous tibial nerve stimulation prior to sacral nerve stimulation is cost-effective. Methods: A decision analytic model was developed to estimate the cost-effectiveness of percutaneous tibial nerve stimulation with subsequent subcutaneous sacral nerve stimulation versus subcutaneous sacral nerve stimulation alone. The model was populated with effectiveness data from systematic reviews and cost data from randomized studies comparing both procedures in a UK National Health Service (NHS) setting. Results: Offering percutaneous tibial nerve stimulation prior to sacral nerve stimulation (compared with delivering sacral nerve stimulation straight away) was both more effective and less costly in all modeled scenarios. The estimated savings from offering percutaneous tibial nerve stimulation first were L662-L5,697 per patient. The probability of this strategy being cost-effective was around 80% at L20,000-L30,000 per quality-adjusted life-year (QALY). Conclusion: Our analyses suggest that offering patients percutaneous tibial nerve stimulation prior to sacral nerve stimulation can be both cost-effective and cost-saving in the treatment of faecal incontinence. PMID- 30305845 TI - Microalgae for the production of lipid and carotenoids: a review with focus on stress regulation and adaptation. AB - Microalgae have drawn great attention as promising sustainable source of lipids and carotenoids. Their lipid and carotenoids accumulation machinery can be trigged by the stress conditions such as nutrient limitation or exposure to the damaging physical factors. However, stressful conditions often adversely affect microalgal growth and cause oxidative damage to the cells, which can eventually reduce the yield of the desired products. To overcome these limitations, two stage cultivation strategies and supplementation of growth-promoting agents have traditionally been utilized, but developing new highly adapted strains is theoretically the simplest strategy. In addition to genetic engineering, adaptive laboratory evolution (ALE) is frequently used to develop beneficial phenotypes in industrial microorganisms during long-term selection under specific stress conditions. In recent years, many studies have gradually introduced ALE as a powerful tool to improve the biological properties of microalgae, especially for improving the production of lipid and carotenoids. In this review, strategies for the manipulation of stress in microalgal lipids and carotenoids production are summarized and discussed. Furthermore, this review summarizes the overall state of ALE technology, including available selection pressures, methods, and their applications in microalgae for the improved production of lipids and carotenoids. PMID- 30305848 TI - Primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells. PMID- 30305849 TI - Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy. AB - Background: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) and the first approved drug for the treatment of spinal muscular atrophy (SMA). However, progressive neuromyopathic scoliosis and the presence of spondylodesis can impede lumbar punctures in SMA patients. Our aim was to assess the feasibility and safety of the treatment in adults with SMA. Methods: For the intrathecal administration of nusinersen, we performed conventional, fluoroscopy assisted and computer tomography (CT)-guided lumbar punctures in adult patients with type 2 and type 3 SMA. We documented any reported adverse events and performed blood tests. Results: We treated a total of 28 adult SMA patients (9 patients with SMA type 2 and 19 patients with SMA type 3) aged between 18-61 years with nusinersen. The mean Revised Upper Limb Module (RULM) score at baseline in SMA type 2 and SMA type 3 patients was 9.9 +/- 4.6 and 29.5 +/- 8.5, respectively. The mean Hammersmith Functional Motor Scale Expanded (HFMSE) score at baseline was 3.1 +/- 2.5 and 31.2 +/- 18.1, respectively. Half of the SMA type 3 patients were ambulatory at treatment onset. In total, we performed 122 lumbar punctures with 120 successful intrathecal administrations of nusinersen. Lumbar punctures were well tolerated, and no serious adverse events occurred. Conclusions: Our data demonstrate the feasibility and tolerability of intrathecal treatment with nusinersen in adults with SMA type 2 and type 3. However, treatment can be medically and logistically challenging, particularly in patients with SMA type 2 and in patients with spondylodesis. PMID- 30305850 TI - Prolonged-release fampridine in multiple sclerosis: clinical data and real-world experience. Report of an expert meeting. AB - Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4-7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and re-treatment, and stopping criteria. This article summarizes the experts' opinions on how PR-fampridine can be used in real world clinical practice to optimize the benefits to people with MS with impaired walking ability. PMID- 30305851 TI - Salvage surgery for recurrent or persistent tumour after radical (chemo)radiotherapy for locally advanced non-small cell lung cancer: a systematic review. AB - Background: Once recurrent or persistent locoregional tumour after radical chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is identified, few curative-intent treatment options are available. Selected patients might benefit from surgical salvage. We performed a systematic review of the available literature for this emerging treatment option. Methods: A systematic literature search was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Publications about persistent or (locoregional) recurrent disease after radical/definitive CRT for locally advanced non-small cell lung cancer were identified. Results: Eight full papers were found, representing 158 patients. All were retrospective series and data were heterogeneous: definition and indication for salvage surgery varied and the median time from radiotherapy to surgery was 4.1-33 months. Complete resection (R0) was achieved in 85-100%, with vital tumour in 61-100%. A large number of pneumonectomies were performed, and additional structures were often resected. Where reported, 90-day mortality was 0-11.4%. Reported survival metrics varied but included median overall survival 9-46 months and 5-year survival 20-75%. Conclusion: There are limited, low-level, heterogeneous data in support of salvage surgery after radical CRT. Based on this, perioperative mortality appears acceptable and long-term survival is possible in (highly) selected patients. In suitable patients (fit, no distant metastases, tumour appears completely resectable and preferably with confirmed viable tumour), this treatment option should be discussed in an experienced multidisciplinary lung cancer team. PMID- 30305853 TI - The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2alpha and ATF4 in Lung Cancer. AB - Introduction: The expression of programmed death 1 (PD1) and programmed death ligand 1 (PDL1) can be induced by the interferon (IFN)/signal transducer and activator of transcription (STAT) pathway. The PD1/PDL1 reverse signaling can activate the eukaryotic translation initiation factor 2 (eIF2alpha)/activating transcription factor 4 (ATF4) pathway which in turn regulates the expression of IFN regulatory factor (IRF) 7 and IFNalpha. The eIF2alpha/ATF4 pathway is responsible for the integrated stress response (ISR) of unfolded protein response (UPR) which can affect immune cell function in tumor microenvironment. Materials and Methods: The protein levels of PDL1, IRF1, IRF7, STAT1, STAT2, IFNAR1, eIF2alpha, and ATF4 in the normal and tumor tissues of 27 subjects with lung cancer were determined by Western blot. Results: The protein level of PDL1 was significantly correlated with those of IRF1, eIF2alpha, and ATF4 in the tissues of all subjects and the subgroup of squamous cell carcinoma but not in the normal tissue of adenocarcinoma. The protein levels of IRF1, eIF2alpha, and ATF4 were consistently correlated in the tumor tissues but to various extents in the normal ones. The protein level of PDL1 was not correlated with those of STAT1 and STAT2 in all the tissues. Conclusion: The PDL1 expression in lung cancer may be independent of STAT1 and STAT2. The PD1/PDL1 axis and UPR/ISR may be closely associated in the tumor tissues of lung cancer. PMID- 30305852 TI - Effects of physical, virtual reality-based, and brain exercise on physical, cognition, and preference in older persons: a randomized controlled trial. AB - Background: Physical exercise (PE), virtual reality-based exercise (VRE), and brain exercise (BE) can influence physical and cognitive conditions in older persons. However, it is not known which of the three types of exercises provide the best effects on physical and cognitive status, and which exercise is preferred by older persons. This study compared the effects of PE, VRE, and BE on balance, muscle strength, cognition, and fall concern. In addition, exercise effort perception and contentment in older persons was evaluated. Methods: Eighty four older persons (n = 84) were randomly selected for PE, VRE, BE, and control groups. The exercise groups received 8-week training, whereas the control group did not. Balance was assessed by Berg Balance Scale (BBS) and Timed Up and Go test (TUG), muscle strength by 5 Times Sit to Stand (5TSTS) and left and right hand grip strength (HGS), cognition by Montreal Cognitive Assessment (MoCA) and Timed Up and Go test Cognition (TUG-cog), fall concern by Fall Efficacy Scale International (FES-I), exercise effort perception by Borg category ratio scale (Borg CR-10), and exercise contentment by a questionnaire. Results: After exercise, PE significantly enhanced TUG and 5TSTS to a greater extent than VRE (TUG; p = 0.004, 5TSTS; p = 0.027) and BE (TUG; p = 0,012, 5TSTS; p < 0.001). VRE significantly improved MoCA (p < 0.001) and FES-I (p = 0.036) compared to PE, and 5TSTS (p < 0.001) and FES-I (p = 0.011) were improved relative to BE. MoCA was significantly enhanced by BE compared to PE (p < 0.001) and both MoCA and TUG-cog were improved compared to VRE (p = 0.04). PE and VRE significantly (p < 0.001) increased Borg CR-10 in all exercise sessions, whereas BE showed a significant improvement (p < 0.001) in the first 4 sessions. Participants had a significantly greater satisfaction with BE than controls (p = 0.006), and enjoyed VRE and BE more than PE (p < 0.001). Subjects in all exercise groups exhibited benefits compared to the control group (p < 0.001). Conclusions: PE provided the best results in physical tests, VRE produced measurable improvements in physical and cognition scores, while BE enhanced cognition ability in older persons. Older persons preferred VRE and BE compared to PE. Both exercises are suggested to older persons to improve physical and cognitive conditions. PMID- 30305855 TI - New Frontiers in Orofacial Pain and Its Management. PMID- 30305856 TI - The Effect of Anterior Uterocervical Angle on Primary Dysmenorrhea and Disease Severity. AB - Background: Primary dysmenorrhea, defined as painful menstrual cramps originating in the uterus without underlying pathology, is a gynecological disease that affects quality of life and school success. Our goal was to determine the effect of anterior uterocervical angle on primary dysmenorrhea and disease severity. Methods: A total of 200 virgin adolescents, 16 to 20 years of age, were included in the study. The Andersch and Milsom scale was used to determine dysmenorrhea severity. Those with pathologies causing secondary dysmenorrhea were excluded from the study. Study subjects were grouped based on severity of pain. Demographic characteristics and uterocervical ultrasonographic measurements were compared among groups. Results: Of the 200 participants enrolled in the study, 50 were healthy controls and 150 had primary dysmenorrhea. Those with primary dysmenorrhea had a significant family history of primary dysmenorrhea compared with controls (P < 0.001). Age (P=0.668), body mass index (P=0.898), menarche age (P=0.915), and length of menstrual cycles (P=0.740) were similar in all groups. The uterine corpus longitudinal axis, uterine corpus transverse axis, and uterine cervix longitudinal axis were also similar (P=0.359, P=0.279, and P=0.369, resp.). The mean uterocervical angle was 146.8 +/- 6.0 in controls and 143.3 +/- 7.3 in those with mild pain with no significant difference between the groups. In those with moderate pain, the mean uterocervical angle was 121.2 +/- 7.3 compared with 101 +/- 9.2 in those with severe pain, which was a significant difference. Additionally, there was also a significant difference in the uterocervical angle among those with mild, moderate, and severe pain (P < 0.001). Conclusion: Our results indicate that a narrower anterior uterocervical angle is associated with primary dysmenorrhea and disease severity. PMID- 30305854 TI - Considerations in hiPSC-derived cartilage for articular cartilage repair. AB - Background: A lack of cell or tissue sources hampers regenerative medicine for articular cartilage damage. Main text: We review and discuss the possible use of pluripotent stem cells as a new source for future clinical use. Human induced pluripotent stem cells (hiPSCs) have several advantages over human embryonic stem cells (hESCs). Methods for the generation of chondrocytes and cartilage from hiPSCs have been developed. To reduce the cost of this regenerative medicine, allogeneic transplantation is preferable. hiPSC-derived cartilage shows low immunogenicity like native cartilage, because the cartilage is avascular and chondrocytes are segregated by the extracellular matrix. In addition, we consider our experience with the aberrant deposition of lipofuscin or melanin on cartilage during the chondrogenic differentiation of hiPSCs. Short conclusion: Cartilage generated from allogeneic hiPSC-derived cartilage can be used to repair articular cartilage damage. PMID- 30305857 TI - Management of radial artery pseudoaneurysm in radial forearm free flap: case report and review of the literature. AB - The formation of a pseudoaneurysm in a revascularized free flap is an extremely rare complication in microsurgery. The most effective treatment modality is still the subject of debate. We present the management of a case of pseudoaneurysm of the arterial pedicle of a radial free flap used after hemiglossopelvectomy in a patient with squamous cell carcinoma of the tongue. In our case, a 74-year-old man with the pseudoaneurism was successfully treated by endovascular stenting. Endovascular stenting can be considered an effective and safe procedure and a relevant alternative to open neck surgical treatment. PMID- 30305858 TI - Transplant uretero-inguinal hernia resulting in urosepsis. AB - Uretero-inguinal hernias are rare and can be difficult to diagnose. We present a case of a rare transplant kidney uretero-inguinal hernia. An 81-year-old male presented with urosepsis and was found to have an obstructed transplanted kidney secondary to herniation of the ureter into an inguinal hernia. The patient required interventional radiology decompression of the urinary system with a percutaneous nephrostomy tube. In this case, the patient's uretero-inguinal hernia was the extraperitoneal subtype allowing the diagnosis to be made easily on computed tomography imaging of the abdomen and pelvis which facilitated rapid treatment. PMID- 30305859 TI - Traction apophysitis of the knee: A case report. AB - We report a case of a 12-year-old boy who presented with infrapatellar pain, with subsequent diagnosis of traction apophysitis of the knee (Sinding-Larsen Johansson disease). Conventional radiographs are frequently reported with no significant findings in the acute setting, leading to ultrasound as the modality of choice for diagnostic efficacy of apophyseal traction injuries in young athletes. Sinding-Larsen-Johansson disease has a 2%-5% incidence in children aged 10-15 years, with the most common cause related to sporting activities related to jumping. PMID- 30305860 TI - Primary diffuse large B-cell non-Hodgkin's lymphoma of the breast-A case report and review of the literature. AB - Primary breast lymphoma (PBL) is considered a rare clinical entity forming about 0.4%-0.5% of all breast tumors. In this report we have presented a case of PBL in a 56-year-old female complaining of a mass in the upper medial quadrant of the breast. PBL suspicion of our case was made by breast radiology and the sure diagnosis was reached by the immunohistochemistry results; CD (cluster of differentiation) 20: was diffusely positive; Pan-CK (pan-cytokeratin): was diffusely negative in tumor cells. Hence, the case was finally diagnosed as a primary breast a primary breast diffuse large B-cell non-Hodgkin's lymphoma of lymphoma. The management and outcome of PBL and carcinoma are totally different. Accurate diagnosis of PBL by true cut needle biopsy and immunocytochemistry is important to avoid unnecessary mastectomies. PMID- 30305861 TI - Primary perirenal angiosarcoma: A rare presentation of a perirenal mass. PMID- 30305862 TI - Perforated cecal diverticulitis with CT diagnosis and medical management. AB - Acute diverticulitis is a painful condition of the gastrointestinal tract that results from sudden inflammation of one or more diverticula in the bowel wall. Right-sided acute diverticulitis, such as cecal diverticulitis, is uncommon diagnosis that can be easily misdiagnosed as acute appendicitis as it shares similar clinical presentation. An unusual complication of right-sided acute diverticulitis such as perforated cecal diverticulitis has different management from acute appendicitis. Thus, definitive diagnosis of this clinical condition with imaging is crucial to optimal management. We report a case of 43-year-old man who presented to the Emergency Department with acute onset severe right lower quadrant abdominal pain associated with anorexia, fever, and nausea. Computed tomography scans obtained showed findings consistent with perforated diverticulitis limited to the cecum, and normal caliber appendix. Conservative medical treatment was decided based on localized imaging findings with excellent outcome. PMID- 30305863 TI - Pelvic congestion syndrome due to agenesis of the infrarenal inferior vena cava. AB - The inferior vena cava (IVC) is the main conduit of venous return to the right atrium from the lower extremities and abdominal organs. Agenesis of the IVC has an incidence of <1% in the general population [1], although it has been reported in the literature as occurring in up to 8.7% of the population [2]. Patients with absent IVC may present with symptoms of lower extremity venous insufficiency [6], idiopathic deep venous thrombosis [7], or pelvic congestion syndrome. To our knowledge there have only been a few cases reported in the literature of agenesis of the IVC associated with pelvic congestion syndrome [3,10,11]. We present another interesting case of pelvic congestion syndrome due to absent IVC. PMID- 30305864 TI - Unintended intra-arterial injection of contrast of an intracranial CT angiography. AB - Computed tomography angiography (CTA) is widely used to evaluate intracranial vascular disease. We report a case of intracranial CTA with unintended intra arterial (IA) injection of contrast due to IA placement of an intravenous cannula, which results in a selective left vertebral artery IA CTA. Knowledge of anatomy is essential in analyzing the whole study and identifying the error. In clinical practice, it is important to avoid and recognize a wrongly placed intravenous cannula. And bolus tracking protocol might play a role as a gatekeeper. PMID- 30305866 TI - Weanling Offspring of Dams Maintained on Serine-Deficient Diet Are Vulnerable to Oxidative Stress. AB - Serine plays an important role in the antioxidant defense system. However, the effects of maternal serine deficiency on the antioxidant ability of weanling offspring have not been reported. In the present study, we investigated the oxidative status of offspring of dams that are maintained on serine-deficient diet and subjected to diquat challenge. Individual pregnant animals were randomly divided into two dietary groups, namely, the control diet group and the serine- and glycine-deficient diet group. Samples were collected from weanling offspring at the age of 3 weeks after diquat challenge. Our results showed that maternal serine deficiency did not affect the levels of antioxidant enzymes and reactive oxygen species, as well as the expression of cellular and mitochondrial stress markers (Hspd1 and Hspa1a), which indicated that maternal serine deficiency did not affect basal oxidative status in weanling offspring. However, the weanling offspring were found to be vulnerable to oxidative challenges. Furthermore, our results suggested that the dysfunctional antioxidant system in response to oxidative stress in offspring of dams fed with serine-deficient diet was primarily caused by reduced availability of nicotinamide adenine dinucleotide phosphate. Furthermore, impairment of the antioxidant defense system caused by maternal serine deficiency was mediated by the Akt/AMPK/Sirt1 pathway. Our results indicated that maternal serine availability is important for maintaining antioxidant defense against oxidative challenge in weanling offspring. PMID- 30305868 TI - Tridimensional assessment of the dental follicle dimensions of impacted mandibular third molars using cone-beam CT. AB - Background: The present study was performed to compare follicle dimensions of impacted mandibular third molar (IMTM) with different impaction angulations using cone beam computed tomography (CBCT). Material and Methods: Forty-nine individuals with IMTM (24 male, 25 female) were selected. Their age range was 25 55 years. The sample was divided into three IMTM groups either vertical (n=16), mesioangular (n=18) or horizontal (n=15) position based on Winter's classification (the angle between the longitudinal axis of the second and third molars). Follicular spaces (FS) from available CBCT imaging were measured from the midpoint of the teeth's crown in several dimensions (mesial, distal, occlusal, apical, vestibular and lingual) in axial, sagittal and coronal planes. An ANOVA, T-student, Kruskal-Wallis and Mann-Whitney U tests were used. Results: A comparison of the mesial FS for all groups revealed significant differences (p<0.001). Significant difference was also found for vestibular FS between the vertical and mesioangular IMTM groups (p=0.04). Buccolingual FS for all groups revealed no significant differences (p=0.074), whereas significant difference was found for the vertical and horizontal IMTM groups (p=0.02). No significant statistical differences were found for occlusal (p=0.54), apical (p=0.06), and lingual (p=0.64) FS. Conclusions: In this sample IMTM follicles have different dimensions according to their degree of angulation. Mesioagulated and horizontally positioned IMTMs seems to consistently have some increased FS dimensions (mesial and vestibular aspects). Key words:Dental follicle, impacted tooth, third molar, cone-beam computed tomography. PMID- 30305867 TI - Complete genome sequence of the halophile bacterium Kushneria konosiri X49T, isolated from salt-fermented Konosirus punctatus. AB - Kushneria konosiri X49T is a member of the Halomonadaceae family within the order Oceanospirillales and can be isolated from salt-fermented larval gizzard shad. The genome of K. konosiri X49T reported here provides a genetic basis for its halophilic character. Diverse genes were involved in salt-in and -out strategies enabling adaptation of X49T to hypersaline environments. Due to resistance to high salt concentrations, genome research of K. konosiri X49T will contribute to the improvement of environmental and biotechnological usage by enhancing understanding of the osmotic equilibrium in the cytoplasm. Its genome consists of 3,584,631 bp, with an average G + C content of 59.1%, and 3261 coding sequences, 12 rRNAs, 66 tRNAs, and 8 miscRNAs. PMID- 30305869 TI - Effects of different etching strategies on the microtensile repair bond strength of beautifil II giomer material. AB - Background: Considering the differences in the filler particles between giomer and conventional composite resins and the importance of these fillers in the repair bond strength, the aim was to evaluate the effects of different etching strategies with phosphoric acid (PA) and hydrofluoric acid (HF) on the microtensile repair bond strength (uTRBS) of giomer. Material and Methods: Ten giomer blocks were randomly assigned into 10: 1) control; 2) 37%PA-20s; 3) 3%HF 20s; 4) 3%HF-120s; 5) 9.6%HF-20s; 6) 9.6%HF-120s; 7) 37%PA-20s + 3%HF-120s; 8) 37%PA-20s + 9.6%HF-120s; 9) 3%HF-120s + 37%PA-20s; 10) 9.6%HF-120s + 37%PA-20s. In all groups, the One-Step Plus bonding system was applied and the new giomer block was bonded to the existing giomer. After cross-sectional cutting, 18 samples were prepared from each block and the uTRBS of the samples was measured at a strain rate of 0.5 mm/min. Data were analyzed with one-way ANOVA and post hoc Tukey tests (P<0.05). Results: The uTRBS in groups 4, 5, 6, 7, 8 and 10 were significantly higher than that in the control group (P<0.05). The uTRBS in group 2 was even less than that in the control group (P<0.001). The highest uTRBS was recorded in group 10, which was significantly different from those in groups 3, 4 and 9 (P<0.05). In addition, the differences between group 9 and groups 6, 7 and 8 were significantly different (P<0.05). Conclusions: Etching with PA resulted in a decrease in uTRBS. Etching with HF, except for 3%HF-20s and HF after etching with PA, resulted in a significant increase in giomer's uTRBS. An increase in the application time of 3%HF resulted in a significant increase in the uTRBS. Key words:Dental restoration repair, Hydrofluoric acid, Phosphoric acid, etching. PMID- 30305870 TI - Shear bond strength of metal brackets to ceramic surfaces using a universal bonding resin. AB - Background: Assure Plus is a recently introduced universal adhesive with the ability to bond to various restorations. This study compared the shear bond strength of brackets bonded to two types of ceramics using conventional bonding agent and Assure Plus. Surface damage caused by debonding was also evaluated. Material and Methods: In this in vitro study, 40 feldspathic and lithium disilicate ceramic discs were sandblasted, etched with 9.6% hydrofluoric acid and divided into two groups. In group 1, silane was applied and air-dried followed by application of Transbond XT primer, which was light-cured. In group 2, Assure Plus was applied and air-dried. In both groups, maxillary central incisor brackets were bonded. After incubation in distilled water at 37 degrees C for 24 hours and 2000 thermal cycles, bond strength was measured using a universal testing machine, and the adhesive remnant index (ARI) and failure modes were determined. ANOVA and LSD tests were used to compare bond strength values; chi squared test was used to compare ARI scores. Results: Bracket bond to lithium disilicate by Assure Plus was significantly stronger than that to Feldspathic porcelain (P=0.041). Only in the Assure Plus/lithium disilicate group did some adhesive remain on the surface following debonding (40% of samples, P<0.05). Cohesive porcelain fracture had the lowest frequency in the lithium disilicate/Assure Plus group. Conclusions: Assure Plus provided high bond strength between ceramic and brackets and minimized damage to lithium disilicate ceramic during debonding. Assure Plus is recommended for use in orthodontic treatment of adults with ceramic restorations. Key words:Adhesives, ceramics, dental bonding, shear bond strength. PMID- 30305871 TI - Nonsyndromic cleft lip and/or palate: A multicenter study of the dental anomalies involved. AB - Background: Nonsyndromic cleft lip and/or palate (NSCL/P) is the most common craniofacial malformation. Due to the anatomical defect present in the alveolar process, these patients tend to exhibit more dental anomalies. The aim of this study was to identify the prevalence of dental anomalies in patients with NSCL/P by obtaining orthodontic documentation from Brazilian Centers for cleft lip and palate treatment. Material and Methods: A retrospective analysis (2000-2014) was conducted on orthodontic archives, radiographs and medical records of NSCL/P of 524 patients under orthodontic treatment. Panoramic radiographs and intra-oral photographs were examined to identify these anomalies. Categorical variables were expressed in terms of frequencies and percentages and analyzed using the Chi Square test. The level of significance was set at p<=0.05 in all analyses. Results: Approximately 83.3% of the individuals had at least one dental anomaly. Tooth agenesis was the most common abnormality found in those patients (87.8%) (p<0.001). Also, the largest number of dental anomalies was detected in the group of unilateral left clefts. The prevalence of dental anomalies in the present sample of NSCL/P patients was high and reached the highest levels in patients with alveolar bone clefts. Conclusions: This study describes the most common dental anomalies observed in patients with NSCL/P. These abnormalities can cause significant problems that may be solved or minimized by early diagnosis and treatment. Key words:Cleft lip and/or palate, dental care for children, epidemiology, craniofacial abnormalities. PMID- 30305872 TI - Criteria and treatment decisions in the management of deep caries lesions: Is there endodontic overtreatment? AB - Background: The aim of this study was to investigate the diagnostic criteria and treatment decisions in the management of deep caries lesions (DCLs). The null hypothesis tested was that DCLs are managed according to the current scientific evidence. Material and Methods: A total of 288 dentists were contacted directly or by mail, and 125 (43%) were included in the study. Dentists were requested to answer a questionnaire about the routine approach to the diagnosis and treatment of DCLs. Logistic regression analyses were carried out to calculate odds ratios (OR). Results: Pulp sensitivity tests were used by 65% of dentists when assessing pulpal health in cases of DCLs, particularly those who had followed courses in cariology (OR = 3.8; p = 0.005). Dentine hardness was the most frequent criterion used during DCLs excavation (98%). Two thirds of the respondents (65%) removed carious tissue until they felt hard dentine, and feeling hard dentine correlated with caries removal even at the risk of pulpal exposure (OR = 15.8; p = 0.0000). Acute transient pain or sensitivity to cold or heat (reversible pulpitis) were considered by 58% of respondents as a reason to provide endodontic therapy. Conclusions: The null hypothesis tested is rejected. The evidence-based more conservative approach on the management of DCLs is not being translated to clinical dentistry. Root canal treatment is being indicated in cases of DCLs in which the diagnosis is reversible pulpitis. Likewise, it can be concluded that non-conservative management of DCLs, with endodontic overtreatment, could be occurring. Key words:Deep caries lesions, dental pulp capping, dental pulp health, dentists, endodontic therapy, pulpal diagnosis, reversible pulpitis, treatment decisions. PMID- 30305873 TI - In-vivo effects of flapless osteopuncture-facilitated tooth movement in the maxilla and the mandible. AB - Background: This study aimed to investigate the effects of a minimally invasive, flapless procedure to enhance tooth movement in both jaws and to determine whether this triggers the acceleration when repeated monthly. Material and Methods: The sample consisted of thirty-two individuals whose orthodontic treatment required canine retraction. They were divided into an experimental group and control group. Osteopunctures were performed using orthodontic mini screws at the distal aspects of the canine teeth at the beginning and on the fourth week of distalization in the experimental group. The control group was treated with conventional mechanics. All canines were retracted. The rates of canine distalization, rotation, and tipping were measured on the first, fourth, and eighth weeks of distalization. First molar anchorage loss was also measured. Intergroup and intragroup analyses were performed. Results: Flapless osteopuncture-facilitated tooth movement resulted in greater canine distalization and reduced molar movement in the maxilla in the experimental than in the control group during the first month of distalization. In addition, the extent of upper canine movement was significantly higher in the experimental group in the first month than in the second. No differences in canine and molar movement in the mandible were observed between the two groups. Conclusions: OP, as applied in this study, is an effective method for increasing the rate of tooth movement in the maxilla. Repeating the procedure monthly does not appear to show a major advance of tooth movement. Key words:Accelerated tooth movement, flapless osteopuncture. PMID- 30305865 TI - Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases. AB - Mechanistic/mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase of the phosphoinositide 3-kinase- (PI3K-) related kinase family, elicits a vital role in diverse cellular processes, including cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of both physiological and pathological processes. MicroRNAs (miRs), a class of short noncoding RNA, are an emerging intricate posttranscriptional modulator of critical gene expression for the development and maintenance of homeostasis across a wide array of tissues, including the cardiovascular system. Over the last decade, numerous studies have revealed an interplay between miRNAs and the mTOR signaling circuit in the different cardiovascular pathophysiology, like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation, and atherosclerosis. In this review, we provide a comprehensive state of the current knowledge regarding the mechanisms of interactions between the mTOR signaling pathway and miRs. We have also highlighted the latest advances on mTOR-targeted therapy in clinical trials and the new perspective therapeutic strategies with mTOR-targeting miRs in cardiovascular diseases. PMID- 30305874 TI - Study of the influence of crossbite on the size of the apical area in a child population by analyzing panoramic X-ray. AB - Background: The apical area is the space in the maxillary bones that contains teeth during formation and is subsequently occupied by the apices of the permanent teeth. Its dimensions are easy to perceive and determine by observing a panoramic X-ray. Our objective was to analyze the influence of crossbite on the size of the anterior and mesial apical area in Caucasian children. Material and Methods: Based on the ortopantomograph of 353 patients in mixed dentition and crossbite, the sizes of the apical areas of the four hemiarches were studied using the Tps Dig Version 2(r) computer program. These data were subjected to statistical analysis using the SPSS 22.0 for Windows program and applying the methods of descriptive statistics of quantitative variables, the Kolmogorov Smirnov test, the non-parametric test Mann-Whitney-Wilcoxon test, and the paired Student t-test. Results: In the group of boys, average values in the superior mesial, superior-anterior, inferior-mesial and inferior-anterior apical areas of the crossbite were 173.43, 99.85, 180.32 and 87.56 respectively, with the lower values being in the hemiarch without malocclusion. In the group of girls, for the same apical areas, average values were 165.64, 94.24, 168.62 and 83.34 respectively, with all the highest values being in the hemiarch with crossbite, except for the inferior-mesial apical area. Statistically significant differences were found in the hemiarch with crossbite between both genders in the superior anterior, inferior-anterior and inferior-mesial apical areas, with the significance being 0.001, 0.029 and 0.001 respectively, while in the hemiarch without malocclusion significance was observed in the superior-mesial, superior anterior and inferior-mesial apical areas, with values of 0.004, 0.001 and 0.004, respectively. Conclusions: Crossbite affects the size of the anterior apical area in both arches and in both genders. The mesial apical area is influenced by this malocclusion in the jaw in boys and in the maxilla girls. Key words:Apical area, ortopantomography, crossbite. PMID- 30305875 TI - Effect of different bleaching protocols on whitening efficiency and enamel superficial microhardness. AB - Background: Tooth bleaching is a popular aesthetic treatment to modify the color of teeth. Despite the extensive literature concerning the subject, there is still no consensus regarding the application mode of the different bleaching agents and their effect on enamel. Therefore, this study evaluated the influence of different bleaching protocols on whitening efficiency and enamel superficial hardness. Material and Methods: Bovine enamel fragments were embedded in acrylic resin and wet-sanded to obtain a flat buccal surface. The specimens were then randomly divided into 6 groups (n=10), based on the bleaching material [HP Maxx 35% (35% hydrogen peroxide), HP Blue 35% (35% hydrogen peroxide + Ca) and Whiteness Perfect 10% (10% carbamide peroxide)] and application mode (3 applications of 15 min, 1 application of 45 min, 1 application of 1h30 or 1 application of 3h30). The color and superficial hardness were assessed before and after bleaching. The color was assessed by means of a digital spectrophotometer, using CIELab parameters. Vickers hardness was determined using a load of 200g for 10s. Data were statistically analyzed by one-way ANOVA with repeated measures and Tukey's test (alpha = 0.05). Results: Concerning the color alteration, the groups were similar to each other, except for at-home bleaching protocols, which were statistically different from each other. Similarly, there was a reduction in hardness values comparing the initial and final periods, with lowest final hardness for the at-home bleaching protocol group applied for 3h30. Conclusions: It can be concluded that the bleaching protocols influenced the final color and enamel surface hardness, evidencing that lower gel concentrations applied for longer periods promoted greater variation in color and lower final hardness. Key words:Tooth bleaching, roughness, microhardness, in-office, at-home bleaching. PMID- 30305876 TI - Anti-erosive effect of calcium carbonate suspensions. AB - Background: This study aimed to investigate the ability of different concentrations of calcium carbonate (CaCO3) suspensions to control enamel surface loss. Material and Methods: Seventy-five enamel slabs were embedded, ground and polished in a pneumatic grinder-polisher machine. Reference areas were created with UPVC tape and the specimens were randomly allocated into five groups (n = 15) for exposure to hydrochloric acid solution to simulate gastric juice (0.01 M, pH 2) for 2 minutes. The samples were then exposed to suspensions containing 0.0001, 0.001, 0.01 or 0.1 mmol/L CaCO3 for 1 minute. Artificial saliva was used as control. The samples were subjected to a total of five erosive cycles followed by treatment with CaCO3 suspension. Surface loss was measured (in um) using optical profilometry. Results: One-way ANOVA (p = 0.009) and Tukey's test showed a significant reduction in surface loss when compared to the group not exposed to CaCO3 (0.74, +/- 0.23 um), and the 0.01 mmol/L (0.40; +/- 0.23 um) and 0.1 mmol/L suspensions (0.37; +/- 0.26 um). Conclusions: The lower concentrated suspensions were incapable of significantly reducing enamel surface loss. Rinsing with 0.01 and 0.1 mmol/L calcium carbonate suspensions was revealed as a potentially promising strategy to prevent enamel erosion. Key words:Tooth erosion, gastric acid, calcium carbonate, prevention and control. PMID- 30305877 TI - Comparison of three adhesive systems in class II composite restorations in endodontically treated teeth: Influence of Er:YAG laser conditioning and gingival margin levels on microleakage. AB - Background: Dental surface conditioning by Er:YAG laser is currently being investigated, as not all of the mechanisms and effects of this technique have been clearly studied. Thus, the aim of the present study was to assess the cervical microleakage of Class II resin composite restorations in endodontically treated teeth following either the respective conventional conditioning or additional Er:YAG laser conditioning, in association with varied adhesives. Material and Methods: Standardized mesial-occlusal-distal cavities (two gingival walls positioned in dentin and enamel, respectively) were created in 60 extracted human premolar teeth. Following the completion of the endodontic therapy, the teeth were grouped into six categories based on conditioning modality and adhesive strategy as follows: group 1-37% phosphoric acid/Adper Single Bond 2 (ASB2); group 2-Er:YAG laser/37% phosphoric acid/ASB2; group 3-Clearfil SE Bond (CSE); group 4-Er:YAG laser/CSE; group 5-Adper Easy One (AEO); and group 6-Er:YAG laser/AEO. Specimens were submitted to thermocycling and dye penetration, followed by longitudinal sectioning. The dye penetration was evaluated using a stereomicroscope. One specimen from each group was assessed under a scanning electron microscope for adhesive interface analysis. Results: No significant differences were found between the conditioning modalities, nor between the adhesive systems at both margins. Groups 1 and 2 showed a lower degree of microleakage in the enamel vs. dentin (p = 0.002). Group 2 showed a significantly lower incidence of microleakage in enamel vs. dentin (p = 0.005). Conclusions: CSE and AEO were comparable with that of ASB2 regarding sealing ability. Additional Er:YAG laser conditioning may be beneficial before ASB2 application in enamel. Key words:Endodontically treated teeth, etch-and-rinse adhesive, Er:YAG laser, gingival level, sealing ability, self-etch adhesive. PMID- 30305878 TI - The effect of orthodontic bracket pad shape on shear bond strength, an in vitro study on human enamel. AB - Background: To evaluate the effect of bracket pad shape on shear bond strength (SBS) of orthodontic brackets bonded to human enamel. Material and Methods: One hundred and five extracted human maxillary permanent molars were divided into 7 groups of 15 specimens per group (n=15). Each group of teeth was bonded with 6 different shaped WildSmiles(r) brackets (Star, Heart, Soccer ball, Football, Flower, and Diamond) and GAC(r) rectangle shaped brackets. Shear debonding force was measured with an Instron universal testing machine using a knife-edged chisel 24 hours after initial bonding. Descriptive statistics (mean, standard deviation, and range) for each bracket pad shape was calculated. Analysis of variance (ANOVA) using SPSS software version 24.0 was performed with P-value set at 0.05. Post-Hoc Tukey analysis was used to analyze differences among groups. Differences in Adhesive Remnant Index (ARI) scores among groups were analyzed using Chi square test. Results: Debonding force values (N +/- SD) ranged from 205.51 +/- 49.12 (Star) and 275.96 +/- 69.05 (Soccer). SBS values (MPa +/- SD) ranged from 13.34 +/- 3.18 (Star) and 17.77 +/- 6.94 (Rectangle). Even though intergroup comparison of SBS in Newtons revealed statistical significance (p = 0.014) between Star-Soccer and Star-Football group, it does not have any clinical significance since ranges of SBS of all groups are clinically acceptable. Analysis of ARI scores showed no significant differences in mode of bond failure among groups (P = 0.82). Conclusions: Orthodontic bracket pad shape has no effect on SBS and does not affect the mode of fracture pattern. Key words:Shear bond strength, orthodontic bracket, bracket pad shape, orthodontic bracket base shape, adhesive remnant index. PMID- 30305879 TI - Effect of sintering process on color parameters of nano-sized yttria partially stabilized tetragonal monolithic zirconia. AB - Background: Sintering process is responsible for aesthetic of zirconia restoration. This study evaluated the effect of different sintering temperatures and sintered-holding times on color parameters of monolithic zirconia. Material and Methods: One hundred and thirty five zirconia bar specimens (width-length thickness = 10*20*1.5 mm) were prepared from yttria-stabilized tetragonal zirconia polycrystalline (Y-TZP) ceramic and randomly divided into nine groups to be sintered at different temperatures [decreasing- (SD, 1350 degrees C), regular- (SR, 1450 degrees C), and increasing- (SI, 1550 degrees C) sintering temperature] and different sintered-holding times [shortening- (HS, 60 min), regular- (HR, 120 min), and prolonged- (HP, 180 min) sintered-holding time]. Color appearance (DeltaE), translucency parameter (TP), contrast ratio (CR), and opalescence parameter (OP) were determined with spectrophotometer. An analysis of variance (ANOVA) and Tukey's multiple comparisons were used to determine for statistically significant difference of color parameters (alpha=0.05). Crystal sizes were microscopically examined using scanning electron microscope (SEM), and phase composition of zirconia was determined using X-ray diffraction (XRD). Results: The mean+/-sd for DeltaE, TP, CR, OP were 82.28+/-1.27, 1.4+/-0.13, 0.982+/ 0.004, 1.25+/-0.15 for SDHS, 78.38+/-0.74, 2.16+/-0.10, 0.967+/-0.005, 1.90+/ 0.11 for SDHR, 74.43+/-0.91, 2.24+/-0.10, 0.964+/-0.004, 1.94+/-0.09 for SDHP, 76.31+/-1.22, 3.03+/-0.10, 0.945+/-0.003, 2,50+/-0.09 for SRHS, 74.51+/-1.27, 3.19+/-0.17, 0.942+/-0.003, 2.65+/-0.16 for SRHR, 73.94+/-0.49, 3.42+/-0.10, 0.937+/-0.003, 2,83+/-0.09 for SRHP, 76.30+/-0.43, 3.16+/-0.09, 0.937+/-0.002, 2.48+/-0.09 for SIHS 76.73+/-1.15, 3.05+/-0.20, 0.939+/-0.005, 2.38+/-0.17 for SIHR, and 75.32+/-1.37, 2.95+/-0.18, 0.942+/-0.006, 2.33+/-0.15 for SIHP. The DeltaE, TP, CR, and OP were significantly affected by altering sintering temperatures and holding times (p<0.05). Increasing sintering temperature and extending sintering time significantly improved color appearance, translucency, contrast, and opalescence of Y-TZP (p<0.05) as evidenced by enlarging grain size and increasing t->m phase shift. Conclusions: Raising sintering temperature and prolonging sintering time lead to better color appearance, translucency, contrast and opalescence of nano-sized monolithic Y-TZP, and are suggested for sintering process. Key words:Color appearance, contrast, monolithic zirconia, opalescence, sintering process, translucency. PMID- 30305880 TI - An in vitro cyclic fatigue resistance comparison of conventional and new generation nickel-titanium rotary files. AB - Background: New designs and processing of Niquel-Titanium (NiTi) have been introduced to increase resistance to cyclic fatigue. The purpose of this study was to compare the cyclic fatigue resistance of 3 NiTi rotary instruments, ProTaper Next (PTN; Dentsply Maillefer, Ballaigues, Switzerland), Profile Vortex Blue (PVB; Dentsply Tulsa Dental, Tulsa, OK, USA) and ProTaper Universal (PTU; Dentsply Maillefer, Ballaigues, Switzerland). Material and Methods: A cyclic fatigue test was conducted operating instruments from ProTaper Next X2, Profile Vortex Blue 25.06 and ProTaper F2. A total of 234 instruments were rotated in 2 simulated stainless steel curved canals with different angles of curvature (45o and 60 degrees ) and 5-mm radius of curvature. The number of cycles to fracture (NCF) was calculated. Data were compared using 2-way analysis of variance and post-hoc Bonferroni test in software (SPSS 15.0, Chicago, IL). Statistical significance was set at P<0.05. Results: Profile Vortex Blue showed higher resistance to cyclic fatigue in both curved canals than ProTaper Next and ProTaper Universal (P<0.001). ProTaper Universal obtained the lowest resistance to cyclic fatigue in both canals (P<0.001). Conclusions: Profile Vortex Blue was the most resistant to cyclic fatigue failure, followed by ProTaper Next and ProTaper Universal. Anatomical complexity (angle of curvature) and manufacturing process of NiTi are important factors for resistance to cyclic fatigue. Key words:Cyclic fatigue, M-Wire, Protaper Next, ProTaper Universal, Profile Vortex Blue. PMID- 30305881 TI - Evaluation of the time required to perform three retreatment techniques with dental microscope and ultrasonic activation for removing filling material from the oval root canal. AB - Background: When endodontic treatment fails, retreatment consists of the complete removal of the root canal filling material for thorough cleaning and reobturation. Various techniques are available for the filling removal procedure, which present varying degrees of efficacy, and take a varying length of time to perform. The aim of this study was to compare the time required to carry out reciprocating, rotary, and manual techniques with dental microscope and ultrasonic activation for removing filling material from root canals. Material and Methods: Ninety-nine extracted single-rooted teeth with straight and oval shaped canals were selected. The samples were instrumented with ProTaper Gold System up to file F2 and obturated with AH Plus sealer and GuttaCore. The teeth were randomly divided into three groups (n=33) according to the instruments used for removal of filling material: Group (1) Reciproc blue R50 instrument; Group (2) ProTaper Retreatment instruments; Group (3) manual (Hedstrom files and Gates Glidden drills), under dental microscope at X10 magnification with Ultrasonic retreatment tip. The time required to remove the filling materials was measured with a chronometer. Data were analyzed statistically applying the Kruskal-Wallis test followed by the Mann-Whitney U-test (p<0.05). Results: The time required to remove filling material was significantly shorter in Group 1, followed by Group 2, the slowest being Group 3 (P<0.05). Conclusions: The reciprocating technique was the fastest method for removing root canal filling material. Key words:Endodontic retreatment, hedstrom file, ProTaper retreatment, reciproc blue. PMID- 30305882 TI - Correlation between alteration of enamel roughness and tooth color. AB - Background: To establish the correlation between enamel roughness and color change of tooth. Material and Methods: Enamel/dentin blocks (5 x 5 x 3.2 mm) were serially ground with the following abrasive paper: 1200-grit, 800-grit, and 600 grit SiC papers. In the paired model, the analyses of color (L*, a*, b*, DeltaE) and roughness (Ra) were performed among the sandpaper exposure. The data were subjected to ANOVA using models for repeated measures followed by the Tukey test. The Pearson correlation test was used to determine whether there was a relationship between Ra values and color results (alpha = 0.05). Results: The L* values decreased in accordance with the increase of Ra, with statistical difference between all the times (p<0.05). A correlation was found between the Ra vs. the L* values (r = -0.67; p<0.0001) and ?Ra vs. ?a* values (r = 0.29; p = 0.05); besides that, there was no significant correlation with b* values or significant alteration in the ?E values (p>0.05). Conclusions: The alteration of enamel roughness acted on the lightness and the green-red axis of tooth color. However, there was no significant correlation between the alteration of roughness of enamel and general color change of tooth. Key words:Surface properties, tooth discoloration, color. PMID- 30305884 TI - Non syndromic synchronous multiple odontogenic keratocysts in a western Indian population: A series of four cases. AB - Odontogenic keratocysts (OKCs) are developmental odontogenic cysts affecting the maxillofacial region and their association with a syndrome especially Naevoid basal cell carcinoma syndrome (NBCCS) is a common occurrence in comparison to non syndromic multiple OKCs. In a first, we present a series of four non syndromic cases with multiple OKCs in western Indian population. The presence of multiple OKC in our present case series may be because of the multifocal nature of the lesion rather than its association with any syndrome. Thus, a comprehensive evaluation of any patients reporting with multiple cysts/OKCs always has to be undertaken and the dental practitioner may be the play a key role in early detection and subsequent follow-up. Key words:Abnormalities, multiple; basal cell nevus syndrome, India, odontogenic cysts. PMID- 30305883 TI - Effect of different sintering process on flexural strength of translucency monolithic zirconia. AB - Background: Sintering process is responsible for the strength of zirconia restoration. This study evaluated the effect of different sintering temperatures and sintered-holding times on flexural strength of translucency monolithic zirconia. Material and Methods: One hundred and thirty five zirconia bar specimens (width-length-thickness = 10*20*1.5 mm) were prepared from yttria stabilized tetragonal zirconia polycrystalline (Y-TZP) ceramic and randomly divided into nine groups to be sintered at different temperatures [decreasing- (SD, 1350 degrees C), regular- (SR, 1450 degrees C), and increasing- (SI, 1550 degrees C) sintering temperature] and different sintered-holding times [shortening- (HS, 60 min), regular- (HR, 120 min), and prolonged- (HP, 180 min) sintered-holding time]. Flexural strength was determined using three-point bending test in a universal testing machine at 1 mm/min crosshead speed. An analysis of variance (ANOVA) and Tukey's multiple comparisons were used to determine for statistically significant difference of flexural strength (alpha=0.05). Weibull analysis was applied for survival probability, Weibull modulus (m), and characteristics strength (sigmao) of the flexural strength. The crystal sizes were microscopically examined using scanning electron microscope (SEM). The phase composition of zirconia was determined using X-ray diffraction (XRD). Results: The mean+/-sd (MPa), m, and sigmao of flexural strength were 1080.25+/-217.19, 5.54, and 1167.53 for SDHS, 1243.41+/-233.17, 5.19, and 1352.30 for SDHR, 1298.92+/-235.68, 6.24, and 1394.79 for SDHP, 1303.34+/-171.87, 8.40, and 1377.90 for SRHS, 1331.73+/-278.84, 5.31, and 1444.50 for SRHR, 1348.13+/ 283.35, 5.32, and 1460.68 for SRHP, 1458.45+/-289.19, 4.51, and 1604.41 for SIHS 1581.34+/-190.56, 8.20, and 1675.21 for SIHR and, 1604.10+/-139.52, 12.57, and 1667.90 for SIHP. The flexural strength was significantly affected by altering sintering temperatures and holding times (p<0.05). Enlarging grain size and increasing t->m phase shifting related with raising temperatures and times. Conclusions: Increasing sintering temperature and prolonged sintered-holding time lead to enhancing flexural strength of translucency monolithic zirconia, and are suggested for sintering process to achieve durable restoration. Key words:Flexural strength, monolithic zirconia, sintering temperature, sintered holding time. PMID- 30305885 TI - Structural stability of DNA origami nanostructures under application-specific conditions. AB - With the introduction of the DNA origami technique, it became possible to rapidly synthesize almost arbitrarily shaped molecular nanostructures at nearly stoichiometric yields. The technique furthermore provides absolute addressability in the sub-nm range, rendering DNA origami nanostructures highly attractive substrates for the controlled arrangement of functional species such as proteins, dyes, and nanoparticles. Consequently, DNAorigami nanostructures have found applications in numerous areas of fundamental and applied research, ranging from drug delivery to biosensing to plasmonics to inorganic materials synthesis. Since many of those applications rely on structurally intact, well-definedDNA origami shapes, the issue of DNA origami stability under numerous application-relevant environmental conditions has received increasing interest in the past few years. In this mini-review we discuss the structural stability, denaturation, and degradation of DNA origami nanostructures under different conditions relevant to the fields of biophysics and biochemistry, biomedicine, and materials science, and the methods to improve their stability for desired applications. PMID- 30305887 TI - Efficacy of collagen and alginate hydrogels for the prevention of rat chondrocyte dedifferentiation. AB - Dedifferentiation of chondrocytes remains a major problem in cartilage tissue engineering. The development of hydrogels that can preserve chondrogenic phenotype and prevent chondrocyte dedifferentiation is a meaningful strategy to solve dedifferentiation problem of chondrocytes. In the present study, three gels were prepared (alginate gel (Alg gel), type I collagen gel (Col gel), and their combination gel (Alg/Col gel)), and the in vitro efficacy of chondrocytes culture while preserving their phenotypes was investigated. While Col gel became substantially contracted with time, the cells encapsulated in Alg gel preserved the shape over the culture period of 14 days. The mechanical and cell-associated contraction behaviors of Alg/Col gel were similar to those of Alg. The cells in Alg and Alg/Col gels exhibited round morphology, whereas those in Col gel became elongated (i.e. fibroblast-like) during cultures. The cells proliferated with time in all gels with the highest proliferation being attained in Col gel. The expression of chondrogenic genes, including SOX9, type II collagen, and aggrecan, was significantly up-regulated in Alg/Col gel and Col gel, particularly in Col gel. However, the chondrocyte dedifferentiation markers, type I collagen and alkaline phosphatase (ALP), were also expressed at significant levels in Col gel, which being contrasted with the events in Alg and Alg/Col gels. The current results suggest the cells cultured in hydrogels can express chondrocyte dedifferentiation markers as well as chondrocyte markers, which draws attention to choose proper hydrogels for chondrocyte-based cartilage tissue engineering. PMID- 30305886 TI - Bioprinting of tissue engineering scaffolds. AB - Bioprinting is the process of creating three-dimensional structures consisting of biomaterials, cells, and biomolecules. The current additive manufacturing techniques, inkjet-, extrusion-, and laser-based, create hydrogel structures for cellular encapsulation and support. The requirements for each technique, as well as the technical challenges of printing living cells, are discussed and compared. This review encompasses the current research of bioprinting for tissue engineering and its potential for creating tissue-mimicking structures. PMID- 30305888 TI - Mediating Effect of Mutuality on Health-Related Quality of Life in Patients with Parkinson's Disease. AB - The relationship quality, mutuality, has been identified as a protective factor in family care situations, but its role in mediating health-related quality of life (HRQoL) in patients having Parkinson's disease (PD) is not known. Data on patients' and partners' mutuality (MS), motor signs (UPDRS III), non-motor symptoms (NMSQuest), impaired cognition (IQCODE), dependency in activities of daily life (ADL), and HRQoL (PDQ8) were collected from 51 dyads. Structural equation model with manifest variables was applied to explore if the MS score mediated the effect of UPDRS III, NMSQuest, IQCODE, and dependency in ADL on PDQ8. The results suggest that increasing severity of motor and non-motor symptoms decreases patients' mutuality which leads to worse HRQoL. Partners' mutuality mediated the effect of impaired cognition which in turn decreased patients' mutuality. The findings enhance our understanding of how various symptoms may influence PD patients' HRQoL. This may help clinicians to personalize interventions to provide more effective interventions to improve the lives of patients with PD. PMID- 30305889 TI - The evaluation of three treatment protocols using oral prednisone and oral meloxicam for therapy of canine idiopathic lymphoplasmacytic rhinitis: a pilot study. AB - Background: Idiopathic lymphoplasmacytic rhinitis (LPR) is a common inflammatory disorder of the nasal cavity in dogs due to unknown etiology. It is characterised by non-specific clinical signs, including nasal discharge, epistaxis and breathing problems. Diagnosis is usually based on the histopathologic identification of infiltrating plasmocytes and lymphocytes in the nasal mucosa and the exclusion of other underlying diseases. Treatment strategies include glucocorticoids, non-steroidal anti-inflammatory drugs, antibiotics and antifungal medications. The aim of this study was to evaluate the efficacy of various therapeutic protocols for managing canine lymphoplasmacytic rhinitis based on the results of clinical, endoscopic and histological examinations, and to determine the relapse rate for LPR in dogs.Twenty dogs of different breeds and both sexes, aged 1 to 14 years, were divided into four groups, each consisting of five dogs, including three experimental groups diagnosed with LPR and a control group.The dogs from the first experimental group were administered prednisone orally at 1 mg/kg/day in the first 4 weeks and 0,5 mg/kg/day in the following 2 weeks. The second group of dogs was administered meloxicam orally at 0,1 mg/kg/day in the first 3 weeks, followed by prednisone at 1 mg/kg/day in the following 2 weeks and 0,5 mg/kg/day in the last week of the treatment. The dogs from the third experimental group were administered meloxicam orally at 0,1 mg/kg/day for 6 weeks. The control group of dogs was administered empty gelatin capsules (placebo) orally for 6 weeks. Clinical signs, endoscopic and histopathologic lesions were scored before and after treatment. Groups were compared using Chi- squared statistics in a 2 * 2 table for pre- versus post treatment scores. Results: Clinical signs persisted in the group treated with meloxicam and were mostly resolved in prednisone-treated dogs. However, endoscopic and histological changes were still observed in these two groups after treatment. The severity of all diagnostic features was reduced in the group treated with meloxicam for 3 weeks followed by prednisone for 3 weeks. The significant differences (p < 0.05) were noted between experimental and control groups. The dogs showed a statistically significant reduction in characteristics of the LPR before and after treatment, as measured by clinical signs (Group 1vs.4 p = 0.00, group 2 vs 4 p = 0.00, group 3 vs 4 p = 0,01), by endoscopy (1 vs 4 p = 0,01, 2 vs 4 p = 0,00, 3 vs 4 p = 0,03), and by histopathology (groups 1 vs 4 p = 0,00, 2 vs 4 p = 0,00, 3 vs 4 p = 0,03). The significant differences were noted between experimental groups, as measured by endoscopy (group 2vs 3 p = 0,04), and by relapse rate (groups 1 and 2 p = 0,03, groups 2 and 3 p = 0,01). Conclusions: The three treatment protocols administered to dogs improved clinical, endoscopic and histological status. However, oral administration of meloxicam for 3 weeks, followed by prednisone for 3 weeks, appeared to be the most successful treatment. These patients remained asymptomatic for 6 months. PMID- 30305890 TI - Clinical and economic impact of goal-directed fluid therapy during elective gastrointestinal surgery. AB - Background: Several randomized controlled trials suggest that goal-directed fluid therapy (GDFT) may result in improved postoperative outcomes. The aim of this study was to assess the clinical and financial impact of the real-life implementation of intraoperative GDFT in patients undergoing elective gastrointestinal surgery in a Chinese tertiary medical center. Methods: This Quality Improvement Program (QIP) study comprised three phases of 5, 1, and 5 months, respectively. During the first phase, we retrospectively collected perioperative data from patients who received standard intraoperative fluid management from January to May 2016. Then a 1-month training period allowed the clinical staff to become familiar with the GDFT protocol. After the training phase, GDFT was used from July to November 2016. In the GDFT group, stroke volume (SV) was continuously monitored and optimized towards the plateau of the Frank Starling curve. The primary outcome measure was postoperative morbidity (the proportion of patients with one or more complications within 30 days after surgery). Secondary outcomes were total hospital cost, postoperative length of hospital stay, and 30-day mortality. Results: Data from 200 patients before (control group) and 201 patients after the implementation of GDFT (GDFT group) were collected and compared. There was no significant difference in demographics and surgical procedures between the two groups. Postoperative morbidity was significantly lower in the GDFT group than in the control group (30.8% vs. 44.0%, p = 0.006). No significant differences were observed for mean total hospital cost (76,793 RMB vs. 74,444 RMB; p = 0.430), median postoperative length of hospital stay (10 days vs. 10 days; p = 0.104), and 30-day mortality (1% vs. 0.5%; p = 0.565). Conclusion: In patients undergoing gastrointestinal surgery, the implementation of a GDFT protocol was associated with a reduction in postoperative morbidity without increasing costs. Trial registration: clinicaltrials.gov, NCT02507557. Registered 13 July 2015. PMID- 30305893 TI - Patients with primary membranous nephropathy lack auto-antibodies against LDL receptor, the homologue of megalin in human glomeruli. PMID- 30305892 TI - Effects of gene polymorphisms of metabolic enzymes on the association between red and processed meat consumption and the development of colon cancer; a literature review. AB - The role of environmental factors and genetic susceptibility in the development of colon cancer (CC) has been already proven, but the role of gene polymorphisms in modifying the risk of environmental factors such as nutritional factors is still unknown. This study aimed to investigate the effect of polymorphisms of involved genes in the association between red meat consumption and the development of CC. The present review was carried out using keywords such as polymorphism and/or protein and/or red meat and/or processed meat and/or colon cancer. PubMed and Science Direct databases were used to collect all related articles published from 2001 to 2017. The presence of SNP in the coding genes of proteins involved in metabolism of nutrients could play significant roles in the extent of the effects of nutrition in the development of CC. The effect of dietary proteins greatly depends on the polymorphisms in the metabolising genes of these substances. Gene polymorphisms may have a role in colorectal cancer risk, especially in people with high meat intake, and this leads to a difference in the effects of meat consumption in different individuals. To conclude, dietary recommendations for the prevention and control of CC should be modified based on the genotype of different individuals. Increasing our knowledge on this field of nutritional genomics can lead to personalised preventive and therapeutic recommendations for CC patients. PMID- 30305891 TI - Antibiotic resistance, virulence factors and genotyping of Uropathogenic Escherichia coli strains. AB - Background: The way of treating different types of infectious diseases is really important. Using genotyping method, we can determine the genetic relatedness between the organisms with different resistance profile from different sources. The aim of this study was to determine antibiotic resistance and genotyping of uropathogenic Escherichia coli (UPEC) strains using pulsed field gel electrophoresis (PFGE). Method: Escherichia coli (E. coli) strains were recovered from the patients with urinary tract infections (UTI) whom admitted in several major hospitals in Tehran. Antibiotic susceptibility testing was done according to CLSI guideline. The present of some virulence factor have been detected using PCR assay. Genotyping of the strains was performed by PFGE and all PFGE profiles were subjected to data processing. Result: In total, 60 E. coli strains were subjected to the study. Most of E. coli isolates were resistant to cefepime (100%) and cephalothin (74%) and susceptible to imipenem (100%), vancomycin (100%) and doxycycline (100%). Among the UPEC isolates the prevalence of fimbriae type I (fimH), hemolysin (hlyA) and aerobactin (aer) genes were 89%, 60% and 90%, respectively. The PFGE differentiated E. coli strains into 33 different genetic clusters. Majority (30%) of them including PFGE type 11 generated 15 bands, while PFGE type 2 was the lowest (2%) prevalent group with 9 bands. Conclusion: The result showed that the antibiotic resistance is escalating rapidly. UPEC strains causing infections are more likely to harbor certain virulence genes. Our finding also showed E. coli strains isolated under the study were belonged to the diverse clones. PMID- 30305894 TI - Familial hepatocellular carcinoma: 'A model for studying preventive and therapeutic measures'. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with more than 80% of cases found in endemic areas of hepatitis B such as Africa or East Asia. A family history of liver cancer increases HCC risk, independently of hepatitis. The combination of family history of liver cancer and hepatitis B/C serum markers is associated with an over 70-fold elevated HCC risk and poor prognosis. Only limited attention has been given to the role of primary genetic factors in HCC, but scattered anecdotal reports have identified familial aggregations of HCC. This article reviewed the literature on familial hepatocellular carcinoma and suggest that familial HCC may be a good model for studying preventive and therapeutic measures. PMID- 30305895 TI - Atypical angiofibroma in a patient with compromised general health: A case report. AB - Introduction: The nasopharyngeal angiofibroma (NA) is a benign tumor that originates from the pterygopalatine fossa and extends to the adjacent anatomical structures and affects frequently young individuals. The basic treatment for NA is surgical resection, but in some cases the tumor is surgically inaccessible. Case presentation: We describe the case of a 45-year-old male with respiratory difficulty after the appearance of a soft palate lesion. The clinical appearance of NA was not specific. Discussion: There are still discussions about the best therapeutic strategy and controversies about performing incisional biopsy. To our knowledge, this is the first report of a NA in an adult patient in which the general health conditions prevented the therapeutic approach, besides the extension of the lesion and its complications. Conclusion: Our case shows that NA may reach high proportions and its involvement in older patients should be considered. In this report, we showed the limitation of the therapeutic strategy for advanced cases of NA. PMID- 30305896 TI - Primary acinic cell carcinoma of the breast: A case report with a clinicopathological and immunohistochemical study of a rare breast cancer subtype. AB - Acinic cell carcinoma (ACC) of the breast is extremely rare subtype of triple negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. Herein, we report a case of acinic cell carcinoma of the breast in a 41-year old female presenting with a palpable breast mass along with significant morphological and immunohistochemical findings. Histologically, ACC showed a diffuse glandular infiltrative pattern, with small acinar or glandular structures mixed with solid nests. Both glandular and solid tumor cell populations were strongly positive for lysozyme. The immunohistochemical profile of the tumor was also similar to that of salivary gland acinic cell carcinoma. She received postoperative chemoradiation therapy and has been doing well. As studies on large series are lacking, further studies are needed to elucidate the biological characteristics of acinic cell carcinoma of the breast. In this study, we perform a detailed morphologic and immunohistochemical description of cases of this rare entity and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. PMID- 30305898 TI - Evidence-based campaigning. AB - Background: When promoting public health measures, such as reducing smoking, there are many different approaches, for example providing information, imposing legal restrictions, taxing products, and changing cultures. By analogy with evidence-based medicine, different approaches to campaigning for health promotion can be compared by obtaining evidence of effectiveness. However, evaluating the effectiveness of campaigning approaches is far more difficult than evaluating drugs or medical procedures, because controls are seldom possible, endpoints are difficult to specify, multiple factors influence outcomes, and the targets of campaigns are people or organizations that may resist. Methods: Ten ideal campaigning types are proposed: positive and negative approaches to the five categories of information, attitude, arguments, authorities and incentives. To illustrate the ideal types and the complexities of evaluating approaches to campaigning, three contrasting Australian strategies to promote vaccination are examined. Results: Each of the three vaccination-promotion strategies showed the presence of several ideal campaigning types, but with distinct differences in emphasis. With available evidence, it is difficult to assess the relative effectiveness of the three strategies. Conclusion: Because of the difficulty in obtaining evidence, claims about the effectiveness of general approaches to health promotion should be treated with scepticism, especially when presented by partisans. There are inherent difficulties in making campaigning evidence-based. PMID- 30305897 TI - Ascorbic acid synthesis and transportation capacity in old laying hens and the effects of dietary supplementation with ascorbic acid. AB - Background: Laying hens over 75 weeks of age commonly show great declines in immunity and production performance. It is unclear whether these declines can be relieved by supplementing with ascorbic acid (AA) in feed. Two trials were conducted to investigate the synthesis and metabolism of AA in layers of different ages and the effects of dietary supplemental AA on the performance and the immune and antioxidant statuses of 78 weeks old hens. Methods: In Exp. 1, equal numbers (24 hens) of 35 weeks old (Young) and 75 weeks old (Old) layers were fed the same diet without AA supplementation for 4 weeks. In Exp. 2, 360 healthy 78 weeks old laying hens were randomly assigned to 4 treatments (basal diet supplemented with 0, 0.25, 0.5, or 1 g AA/kg diet) in an 8-week feeding trial. Results: The old hens tended to have decreased L-gulonolactone oxidase (GLO) synthase activity in the kidney and liver than that of the young hens (P = 0.07 and P = 0.05, respectively). Compared with the young hens, the old hens had lower hepatic antioxidant capacity allowing for the lower thioredoxin (TXN), thioredoxin reductase (TXNR) and cytochrome b5 reductase (CYB5R) gene expression (P < 0.05), whereas increased sodium-dependent vitamin C transporter (SVCT) 1 expression levels in the ileum and kidney and enhanced splenic and hepatic AA concentrations (P < 0.05). Dietary supplementation with AA significantly decreased GLO enzyme activity but increased splenic AA concentration and anti bovine serum albumin IgG levels (P < 0.05) and tended to increase CD4+ T lymphocyte numbers (P = 0.06) in serum. Supplementation of 0.25 g AA/kg diet significantly increased hepatic total antioxidant capacity (T-AOC, P < 0.05) relative to the control group. Conclusions: Laying hens could synthesize AA in both the kidney and the liver, though the GLO enzyme activities were 100 times greater in kidneys than in livers. The old laying hens had greater absorption and reabsorption capacity and higher AA retention in some tissues that did the young hens. Dietary supplementation of AA can improve the health of old layers by enhancing immunity and antioxidant capacity. PMID- 30305899 TI - Reducing amount and frequency of meal as a major coping strategy for food insecurity. AB - Background: Food insecurity is a global problem affecting many people worldwide, including approximately 220 million people in sub-Saharan Africa. Ethiopia is among the countries severely affected by hunger. However, evidence on how populations within Ethiopia cope with hunger and food insecurity is limited. This study aimed to identify household coping mechanisms in response to food insecurity at a Dabat Health and Demographic Surveillance System site. Methods: This study used data from a re-census collected between October 2014 and December 2014.15,159 household members in thirteen kebeles of the Dabat Health and Demographic surveillance system were included. The outcome variables of the study were food insecurity and coping strategies. Household Food Insecurity Access Scale (HFIAS) was used to assess food insecurity. If food insecurity was found, families were asked about coping mechanisms used. Binary logistic regression analysis was applied to identify socio-demographic determinants of reducing amount and frequency of meal as a coping mechanism in response to food insecurity. Result: Of the 15,159 households surveyed, 6671 (44.01%) reported the presence of a food insecurity in their household. Decreasing meal frequency and portions (3733 (55.96%)), borrowing money and food (2542 (38.11%)), and receiving food and money aid (1779 (26.67%)) were among the major coping strategies used by the households. Urban dwellers (AOR 2.07: 95% CI 1.74, 2.46), mid-altitude (weyina-dega) and high-land (dega) dwellers (AOR 2.46: 95% CI 2.08, 2.92 and AOR 1.22 95% CI 1.08, 1.38 respectively), and not married persons (AOR 1.60: 95% CI 1.07, 2.39) were more likely to consume less when faced with a food insecurity (using reducing amount and frequency of meal as a coping strategy). Conclusion: Households in the study area experienced a very high rate of food insecurity. Decreasing meal frequency and portions was the primary coping mechanism used by the households. Due to the severe insecurity of food in their household, many people chose to reduce the amount and frequency of their meal in order to prolong the small amount of food in their house. This finding indicates a high risk for undernourishment which can exacerbate the burden of malnutrition and related diseases in the region. PMID- 30305900 TI - Breathlessness, but not cough, suggests chronic obstructive pulmonary disease in elderly smokers with stable heart failure. AB - Chronic obstructive pulmonary disease (COPD) is a common comorbidity of heart failure (HF), but remains often undiagnosed, and we aimed to identify symptoms predicting COPD in HF. As part of an observational, prospective study, we investigated stable smokers with a confirmed diagnosis of HF, using the 8-item COPD-Assessment-Test (CAT) questionnaire to assess symptoms. All the items were correlated with the presence of COPD, and logistic regression models were used to identify independent predictors. 96 HF patients were included, aged 74, 33% with COPD. Patients with HF and COPD were more symptomatic, but only breathlessness when walking up a hill was an independent predictor of COPD (odds ratio = 1.33, p = 0.0484). Interestingly, COPD-specific symptoms such as cough and phlegm were not significant. Thus, in elderly smokers with stable HF, significant breathlessness when walking up a hill is most indicative of associated COPD, and may indicate the need for further lung function evaluation. PMID- 30305901 TI - Prevalence, risk factors, and impact of lung Cancer on outcomes of idiopathic pulmonary fibrosis: a study from the Middle East. AB - Background: No studies have addressed the impact of lung cancer (LC) on prognosis of patients with idiopathic pulmonary fibrosis (IPF) in Upper Egypt. We aimed to evaluate the prevalence and risk factors for LC among IPF patients and its impact on their outcomes and survival in Upper Egypt. Methods: A total of 246 patients with IPF who had complete clinical and follow up data were reviewed. They were categorized into 2 groups: 34 patients with biopsy-proven LC and IPF (LC-IPF) and 212 patients with IPF only (IPF). Survival and clinical characteristics of the two groups were compared. Results: Prevalence of LC was 13.8%. Pack/years was the most significant predictor for LC development in IPF (Odds ratio; 3.225, CI 1.257 1.669, p = 0.001). Survival in patients with LC-IPF was significantly worse than in patients with IPF without LC; median survival, 35 months vs 55 months; p = 0.000. LC accompanying IPF was one of the most significant independent predictors of survival in IPF patients (Hazard ratio 5.431, CI 2.186-13.492, p = 0.000). Mortality in LC-IPF patients was mainly due to LC progression in 36% and LC therapy-related complications in 22%. Conclusions: Prevalence of LC in IPF patients was 13.8%. Lung cancer has significant impacts on patients with IPF in Upper Egypt, in terms of clinical outcomes and survival. Smoking is the most significant independent predictor of LC development in IPF patients. A poorer survival was observed for patients with IPF developing LC, mainly due to LC progression, and to complications of its therapies. Further prospective, multicenter and larger studies are warranted. PMID- 30305902 TI - From bingeing to cutting: the substitution of a mal-adaptive coping strategy after bariatric surgery. AB - Background: An increase in self-harm emergencies after bariatric surgery have been documented, but understanding of the phenomenon is missing. Case presentation: The following case report describes a 26-year-old woman with obesity, who initiated self-harm behaviour after bariatric surgery. The patient reported that the self-harm was a substitute for binge eating, which was anatomically impeded after bariatric surgery.Pre-surgical psychosocial assessment revealed Anorexia Nervosa in youth, which had later migrated to Binge Eating Disorder. At the time of surgery, the patient was not fulfilling the diagnostic criteria for Binge Eating Disorder because of a low frequency of binges. The remaining binges occurred when experiencing negative affect. Conclusions: Previous eating disorder pathology is an important consideration in pre-surgical assessments. For patients with affect-driven pre-surgical Binge Eating Disorder, therapeutic intervention before and after bariatric surgery could be indicated in order to secure the development of adaptive coping strategies. Furthermore, body weight as the only outcome measure for the success of surgery seems insufficient. PMID- 30305903 TI - Self-injurious behaviour in patients with anorexia nervosa: a quantitative study. AB - Background: Many patients with an eating disorder report difficulties in regulating their emotions and show a high prevalence of self-injurious behaviour. Several studies have stated that both eating disorder and self-injurious behaviour help emotion regulation, and are thus used as coping mechanisms for these patients. We aimed to determine the prevalence of self-injurious behaviour, its characteristics and its emotion-regulation function in patients with anorexia nervosa or an eating disorder not otherwise specified (n = 136). Methods: A cross sectional design using a self-report questionnaire. Mann-Whitney U-tests were conducted to compare the background and clinical variables between patients with self-injurious behaviour and patients without this type of behaviour. Changes in emotional state before and after self-injurious behaviour were tested by Wilcoxon signed rank tests. Results: Our results showed a 41% prevalence of self-injurious behaviour in the previous month. Patients who performed self-injurious behaviour had a statistically significant longer treatment history for their eating disorder than those who did not. Whereas 55% of self-injuring patients had a secondary psychiatric diagnosis, only 21% of participants without self-injurious behaviour did. Regarding the impact of self-injurious behaviour, our results showed a significant increase in "feeling relieved" and a significant decrease in "feeling angry at myself", "feeling anxious" and "feeling angry at others". This indicates that self-injurious behaviour can be regarded as an emotion-regulation behaviour. Participants were usually aware of the causes of their self-injurious behaviour acts. Conclusions: Professionals should systematically assess the occurrence of self-injurious behaviour in eating disorder patients, pay special attention to patients with more severe and comorbid psychopathology, and those with a long treatment history. This assessment should be followed by a functional analysis of the self-injurious behaviour and by effective therapeutic interventions alongside the eating disorder treatment. PMID- 30305904 TI - Miniaturized multi-sensor loggers provide new insight into year-round flight behaviour of small trans-Sahara avian migrants. AB - Background: Over the past decade, the miniaturisation of animal borne tags such as geolocators and GPS-transmitters has revolutionized our knowledge of the whereabouts of migratory species. Novel light-weight multi-sensor loggers (1.4 g), which harbour sensors for measuring ambient light intensity, atmospheric pressure, temperature and acceleration, were fixed to two long-distance migrant bird species - eurasian hoopoe (Upupa epops) and great reed warbler (Acrocephalus arundinaceus). Using acceleration and atmospheric pressure data recorded every 5 and 30 min, respectively, we aimed at reconstructing individual diurnal and seasonal patterns of flight activity and flight altitude and thereby, at describing basic, yet hitherto unknown characteristics of migratory flight behaviour. Furthermore, we wanted to characterise the variability in these migration characteristics between individuals, species and migration periods. Results: The flight duration from breeding to sub-Saharan African non-breeding sites and back was more variable within than between the species. Great reed warblers were airborne for a total of 252 flight hours and thus, only slightly longer than eurasian hoopoes with 232 h. With a few exceptions, both species migrated predominantly nocturnally - departure around dusk and landing before dawn. Mean flight altitudes were higher during pre- than during post-breeding migration (median 1100 to 1600 m a.s.l.) and flight above 3000 m occurred regularly with a few great reed warblers exceeding 6000 m a.s.l. (max. 6458 m a.s.l.). Individuals changed flight altitudes repeatedly during a flight bout, indicating a continuous search for (more) favourable flight conditions. Conclusions: We found high variation between individuals in the flight behaviour parameters measured - a variation that surprisingly even exceeded the variation between the species. More importantly, our results have shown that multi-sensor loggers have the potential to provide detailed insights into many fundamental aspects of individual behaviour in small aerial migrants. Combining the data recorded on the multiple sensors with, e.g., remote sensing data like weather and habitat quality on the spatial and temporal scale will be a great step forward to explore individual decisions during migration and their consequences. PMID- 30305905 TI - A whole of school intervention for personality disorder and self-harm in youth: a pilot study of changes in teachers' attitudes, knowledge and skills. AB - Background: The school environment offers an ideal opportunity for early identification and intervention for youth with self-harm and complex mental health issues, such as borderline personality disorder (BPD). Yet, class teachers often report minimal knowledge, feeling ill-equipped to respond, and experience high levels of stress when exposed to such challenges. Research is required to understand how training and development activities led by school counsellors may enhance teacher attitudes, confidence and knowledge of self-harm and complex mental health issues, such as BPD. We aimed to explore the extent that a whole of school initiative might enhance capacity for early identification and intervention. Method: 18 secondary schools implemented a manualised program, Project Air Strategy for Schools. N = 400 class teachers (71.3% female, mean age 42 years) across city and rural locations were evaluated before and after program implementation on attitudes, knowledge and skills. Results: Providing class teachers with additional training on complex mental health issues and associated behaviours such as self-harm was well received. Participants reported post program improvements in their optimism (d = .35), confidence (d = .63), knowledge (d = .73) and skills (d = 0.67) in working with young people with complex mental health issues, such as BPD. Conclusions: Providing school counsellor led structured approaches, to help class teachers identify and respond to youth in distress, closed identified gaps. Results indicated improvements in class teachers' knowledge and attitudes towards self-harm and BPD. The intervention also improved the capacity of schools to plan and implement strategies to reduce the impact of mental health problems on the young person and their peers. A stay at-school psychological care approach was fostered by enhancing partnerships between class teachers and school counsellors. PMID- 30305906 TI - The future of driving pressure: a primary goal for mechanical ventilation? AB - Background: Management of patients with acute respiratory distress syndrome (ARDS) remains supportive with lung protective mechanical ventilation. In this article, we discuss the physiological concept of driving pressure, current data, ongoing trials, and future directions needed to clarify the role of driving pressure in patients with ARDS. Body: Driving pressure is the plateau airway pressure minus PEEP. It can also be expressed as the ratio of tidal volume to respiratory system compliance, indicating the decreased functional size of the lung observed in patients with ARDS (i.e., baby lung). Driving pressure as a strong predictor of mortality in patients with ARDS is supported by a post hoc analysis of previous randomized controlled trials and a subsequent meta-analysis. Importantly, the meta-analysis suggested targeting driving pressure below 13-15 cmH2O. Ongoing clinical trials of driving pressure in patients with ARDS focus mainly on physiological rather than clinical outcome but will provide important insights for the design of future clinical trials. Conclusion: Currently, no definite clinical recommendations on the routine use of driving pressure in patients with ARDS can be made, as the available data are hypothesis-generating. Randomized controlled trials are needed to evaluate the efficacy of a driving pressure-based ventilation strategy. PMID- 30305907 TI - Thoracic ultrasound: it's not all about the pleura. PMID- 30305908 TI - Improved diabetes medication convenience and satisfaction in persons with type 2 diabetes after switching to insulin glargine 300 U/mL: results of the observational OPTIN-D study. AB - Objective: Insulin glargine 300 (Gla-300) provides less hypoglycemia risk and more flexibility in injection time. The extent to which these effects translate into improved patient-reported outcomes (PROs) is unknown, and is the subject of this observational study. Research design and methods: Adults with type 2 diabetes treated with basal insulin for at least 6 months initiating Gla-300 were included. Data were collected at baseline (start Gla-300) and at 3-month and 6 month follow-up. Patients and physicians gave reasons for switching to Gla-300 at baseline and the extent to which Gla-300 fulfilled their expectations at 6 months. Mixed model analyses examined PRO changes over time, with emotional well being (WHO-5 Well-Being Index) as the primary outcome. The secondary outcomes were hypoglycemia incidence, hemoglobin A1c (HbA1c), hypoglycemia worries (worry subscale of the Hypoglycemia Fear Survey), diabetes distress (short form of the Dutch version of the Problem Areas In Diabetes Scale), diabetes medication convenience (Diabetes Medication System Rating Questionnaire (DMSRQ)), sleep quality and duration (Pittsburgh Sleep Quality Index), and adherence (Summary of Diabetes Self-Care Activities). Results: 162 patients participated: 53.70% were men, the mean age was 65.54 years (9.05), baseline mean HbA1c was 7.87% (1.15) (62.48 mmol/mol (12.61)), and mean diabetes duration was 15.14 years (6.65). Mean WHO-5 Well-Being Index scores improved non-significantly from 61.94 (19.52) at baseline (T0) to 63.83 (19.67) at 6 months (T2). Mean DMSRQ scores improved significantly from 32.96 (9.02) (T0) to 36.70 (8.85) (T2) (p<0.001). Dose (less volume) was a switching reason in 69.60% of patients and 63% of physicians, and flexibility in 33.30% and 24.70%, respectively. Gla-300 fulfilled the expectations or even better than expected in 92.30% of patients and 88.90% of physicians. Conclusion: In a relatively well-controlled sample of adults with type 2 diabetes, switching to Gla-300 improves diabetes medication convenience. PMID- 30305910 TI - Role of cardiovascular imaging for the diagnosis and prognosis of cardiac amyloidosis. AB - Cardiac amyloidosis (CA) describes the pathological process of amyloid protein deposition in the extracellular space of the myocardium. Unfortunately, the diagnosis of CA is often made late and when the disease process is advanced. However, advances in cardiovascular imaging have allowed for better prognostication and establishing diagnostic pathways with high sensitivity and specificity. This review discusses the role of echocardiography, cardiac MRI and nuclear cardiology in current clinical practice for diagnosis and prognosis of CA. PMID- 30305909 TI - Complex patterns of direct and indirect association between the transcription Factor-7 like 2 gene, body mass index and type 2 diabetes diagnosis in adulthood in the Hispanic Community Health Study/Study of Latinos. AB - Background: Genome-wide association studies have implicated the transcription factor 7-like 2 (TCF7L2) gene in type 2 diabetes risk, and more recently, in decreased body mass index. Given the contrary direction of genetic effects on these two traits, it has been suggested that the observed association with body mass index may reflect either selection bias or a complex underlying biology at TCF7L2. Methods: Using 9031 Hispanic/Latino adults (21-76 years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 2008-2011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at TCF7L2 (rs7903146-T) and body mass index. We then used structural equation models to simultaneously model the genetic association on changes in body mass index across the life course and estimate the odds of type 2 diabetes per TCF7L2 risk allele. Results: We observed both significant increases in type 2 diabetes prevalence at examination (independent of body mass index) and decreases in mean body mass index and waist circumference across genotypes at rs7903146. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45 years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood. Conclusions: Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple time points in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. The robust replication of the negative effects of TCF7L2 on body mass index in multiple samples, including in our diverse Hispanic/Latino community-based sample, supports a growing body of literature on the complex biologic mechanism underlying the functional consequences of TCF7L2 on obesity and type 2 diabetes across the life course. PMID- 30305911 TI - A small molecule inhibitor of the perinucleolar compartment, ML246, attenuates growth and spread of ovarian cancer. AB - Background: Ovarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease. There are limited therapeutic agents and survival rates remain poor. The perinucleolar compartment (PNC) has been shown to be associated with malignancy and is considered a surrogate phenotypic marker for metastatic cancer cells. A small molecule, ML246, was derived from a screen against PNCs. In this study, the effect of ML246 on ovarian cancer growth and spread was investigated. Methods: SKOV3 or OVCAR3 cells were treated with ML246 in vitro and PNC was visualized with immunofluorescent staining. Cell invasion was assessed using Matrigel-coated transwell systems. SKOV3 cells were xenografted orthotopically under the ovarian bursa of immunocompromised mice. Additionally, a patient derived ovarian cancer cell line was grafted subcutaneously. Mice were treated with ML246 and tumor growth and spread was assessed. Results: PNCs were prevalent in the ovarian cancer cell lines OVCAR3 and SKOV3 with higher prevalence in OVCAR3 cells. Treatment with ML246 significantly reduced PNC prevalence in OVCAR3 and SKOV3 cells. Moreover, the invasive activity of both cell lines was significantly inhibited in vitro. Orthotopic implantation of SKOV3 cells resulted in growth of the tumor on the ovary as well as spread of tumor tissues outside of the primary site on organs into the abdominal cavity. Treatment with ML246 decreased the incidence of tumors outside of the ovary. In addition, a patient-derived xenograft (PDX) line was grafted subcutaneously to monitor tumor growth. ML246 significantly attenuated growth of tumors over a 5-week treatment period. Conclusions: PNC's are present in ovarian cancer cells and treatment with ML246 decreases invasion in vitro and tumor growth and spread in vivo. Additional studies are warranted to determine the efficacy of ML246 as an inhibitor of metastatic disease in ovarian cancer and to determine its precise mechanism of action. PMID- 30305912 TI - Increased alloreactive and autoreactive antihuman leucocyte antigen antibodies associated with systemic lupus erythematosus and rheumatoid arthritis. AB - Objectives: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) disproportionately affect women during and following childbearing years. Antihuman leucocyte antigen (HLA) alloantibody responses are common in healthy parous women, and as these diseases are both linked with HLA and immune dysregulation, we sought to evaluate anti-HLA antibodies in RA and SLE. Methods: Anti-HLA antibodies were measured among parous SLE cases (n=224), parous RA cases (n=202) and healthy parous controls (n=239) and compared with each other as well as with nulliparous female and male controls. Antibody specificities were identified and compared against subject HLA types to determine autoreactivity versus alloreactivity. The association of anti-HLA antibodies with clinical outcomes was evaluated. Results: Levels and frequencies of anti-HLA antibodies were significantly higher among parous females with SLE (52%) or RA (46%) compared with controls (26%), and anti-HLA antibodies were also found among nulliparous females and males with SLE and RA. Autoreactive anti-HLA antibodies were observed among SLE and RA antibody-positive subjects, but not healthy controls, with the highest frequency of autoreactive anti-HLA antibodies found in the SLE subjects. Higher levels of anti-HLA antibodies were associated with nephritis among the nulliparous SLE cases (p<0.01). The presence of anti-class I HLA antibodies was associated with younger age at diagnosis among both the RA and SLE nulliparous cases. Conclusions: Both autoreactive and alloreactive anti-HLA antibodies were found at high levels in RA and SLE subjects. These occurred even in the absence of alloexposure, particularly among SLE subjects and may be linked with disease severity. PMID- 30305913 TI - Translocated duplication of a targeted chromosomal segment enhances gene expression at the duplicated site and results in phenotypic changes in Aspergillus oryzae. AB - Background: Translocated chromosomal duplications occur spontaneously in many organisms; segmental duplications of large chromosomal regions are expected to result in phenotypic changes because of gene dosage effects. Therefore, experimentally generated segmental duplications in targeted chromosomal regions can be used to study phenotypic changes and determine the functions of unknown genes in these regions. Previously, we performed tandem duplication of a targeted chromosomal segment in Aspergillus oryzae. However, in tandem chromosomal duplication, duplication of chromosomal ends and multiple chromosomal duplication are difficult. In this study, we aimed to generate fungal strains with a translocated duplication or triplication of a targeted chromosomal region via break-induced replication. Results: Double-strand breaks were introduced into chromosomes of parental strains by treating protoplast cells with I-SceI meganuclease. Subsequently, strains were generated by nonreciprocal translocation of a 1.4-Mb duplicated region of chromosome 2 to the end of chromosome 4. Another strain, containing a triplicated region of chromosome 2, was generated by translocating a 1.4-Mb region of chromosome 2 onto the ends of chromosomes 4 and 7. Phenotypic analyses of the strains containing segmental duplication or triplication of chromosome 2 showed remarkable increases in protease and amylase activities in solid-state cultures. Protease activity was further increased in strains containing the duplication and triplication after overexpression of the transcriptional activator of proteases prtT. This indicates that the gene-dosage effect and resulting phenotypes of the duplicated chromosomal region were enhanced by multiple duplications, and by the combination of the structural gene and its regulatory genes. Gene expression analysis, conducted using oligonucleotide microarrays, showed increased transcription of a large population of genes located in duplicated or triplicated chromosomal regions. Conclusion: In this study, we performed translocated chromosomal duplications and triplications of a 1.4-Mb targeted region of chromosome 2. Strains containing a duplication of chromosome 2 showed significant increases in protease and amylase activities; these enzymatic activities were further increased in the strain containing a triplication of chromosome 2. This indicates that segmental duplications of chromosomes enhance gene-dosage effects, and that the resulting phenotypes play important phenotypic roles in A. oryzae. PMID- 30305914 TI - Severe Acute Kidney Injury and Multiple Organ Failure in a 17-Day-Old Newborn: When Pathology Makes the Difference. AB - Rationale: Acute tubulointerstitial nephritis (ATIN) in children is most commonly due to allergic drug reactions. In neonates, diagnosis of ATIN is clinically suspected and a kidney biopsy is not routinely performed. Presenting concern: A 17-day-old newborn presented with vomiting and dehydration, along with anuric acute kidney injury, severe electrolyte disturbances, hypocomplementemia, and thrombocytopenia. Abdominal ultrasound revealed bilateral nephromegaly and hepatosplenomegaly. The patient was promptly started on intravenous (IV) fluid and broad-spectrum antibiotics. His electrolyte disturbances were corrected as per standard guidelines. The rapid progressive clinical deterioration despite maximal treatment and the unclear etiology influenced the decision to proceed to a kidney biopsy. Histopathological findings revealed diffuse interstitial edema with a massive polymorphic cellular infiltrate and destruction of tubular structures, consistent with severe ATIN. Elements of thrombotic microangiopathy (TMA) were observed. Diagnosis: The clinical presentation combined with imaging and histopathological findings was suggestive of ATIN caused by a severe acute bacterial pyelonephritis. Intervention: Methylprednisolone pulses followed by oral prednisolone were administered. Antibiotics were continued for 10 days. The patient was kept on invasive mechanical ventilation and on peritoneal dialysis for 12 days. Outcome: His condition stabilized following steroid pulses. His renal function progressively improved, and renal replacement therapy was weaned off. His renal ultrasound normalized. He has maintained a normal blood pressure, urinalysis, and renal function over the past 5 years. Novel finding: This case reports a severe presentation of acute bacterial pyelonephritis in a neonate. It highlighted the involvement of complement activation in severe infectious process. Histopathological findings of ATIN and TMA played a crucial role in understanding the physiopathology and severity of the disease. PMID- 30305915 TI - Magnitude and associated factors of postpartum morbidity in public health institutions of Debre Markos town, North West Ethiopia. AB - Background: Postpartum maternal morbidity is maternal illness that occurs after one hour of expulsion of placenta up to six weeks of childbirth. Though the true burden of this problem is not well known estimates of WHO, UNICEF and UNFPA showed that 1.4 million women experience acute obstetric morbidity annually. Knowledge of magnitude and predicting factors postpartum morbidity is central to understand the extent of the problem and will help as a cornerstone in designing and implementing better preventive strategies. Objectives: To assess the magnitude and factors associated with postpartum morbidity in public health institutions in Debre Markos town. Method: Institutional based cross sectional study was conducted in Debre Markos town public health institutions by reviewing delivery charts, delivery records and reporting log books. Total deliveries in each health institution in the previous year were identified and number of records to be included from each institution was determined by probability proportion to size. Systematic sampling technique was employed to select 308 charts for review. Data was collected by trained midwifes using structured checklist; entered by epi info and analyzed using SPSS 20. To present findings descriptive statistics using frequencies, charts and figures were used accordingly. Finally binary and multiple logistic regressions were performed to identify predicting factors. Results: The magnitude of postpartum morbidity was found to be 101(32.8%). Divorced/widowed women [AOR = 10.920, 95% CI: (2.168, 54.998)], women who didn't have ANC follow up [AOR = 3.710, 95% CI: (1.749, 7.870)], abnormal labour [AOR =3.496, 95% CI: (1.69, 7.22)], women delivered by doctor [AOR =0.111, 95% CI: (0.027, 0.454)] and women who were not attended postpartum visit [AOR =0.088, 95% CI: (0.040, 0.194)] were the factors associated with postpartum maternal morbidity. Conclusion: Maternal morbidity in Debre Markos health institution was found to be major maternal health issue. Being divorced/widowed, absence of ANC visit, intrapartum abnormalities, delivery attended by skilled professionals and no post-partum visit were important predictors of maternal postpartum morbidity. PMID- 30305917 TI - Diabetes and the direct secondary use of electronic health records: Using routinely collected and stored data to drive research and understanding. AB - Introduction: Electronic health records provide an unparalleled opportunity for the use of patient data that is routinely collected and stored, in order to drive research and develop an epidemiological understanding of disease. Diabetes, in particular, stands to benefit, being a data-rich, chronic-disease state. This article aims to provide an understanding of the extent to which the healthcare sector is using routinely collected and stored data to inform research and epidemiological understanding of diabetes mellitus. Methods: Narrative literature review of articles, published in both the medical- and engineering-based informatics literature. Results: There has been a significant increase in the number of papers published, which utilise electronic health records as a direct data source for diabetes research. These articles consider a diverse range of research questions. Internationally, the secondary use of electronic health records, as a research tool, is most prominent in the USA. The barriers most commonly described in research studies include missing values and misclassification, alongside challenges of establishing the generalisability of results. Discussion: Electronic health record research is an important and expanding area of healthcare research. Much of the research output remains in the form of conference abstracts and proceedings, rather than journal articles. There is enormous opportunity within the United Kingdom to develop these research methodologies, due to national patient identifiers. Such a healthcare context may enable UK researchers to overcome many of the barriers encountered elsewhere and thus to truly unlock the potential of electronic health records. PMID- 30305918 TI - Formative research implications on design of a randomized controlled trial for oral health promotion in children. AB - Background: The COordinated Oral health Promotion (CO-OP) Chicago trial will test the efficacy of a community health worker (CHW) intervention to improve oral health behaviors for children at high risk for early childhood caries. Before implementing the cluster-randomized controlled trial, we conducted a formative assessment to determine the final design. We used qualitative methods to assess the feasibility and acceptability of the proposed recruitment, data collection, and intervention plan. Methods: Key informant interviews (N = 37) and site observations were conducted at 10 pediatric primary care clinics and 10 Special Supplemental Nutrition Program for Women Infant and Children (WIC) centers to gain insight from providers and administrators at the locations where recruitment and intervention will occur. Eight focus groups (N = 68) were conducted with caregivers of children to capture the parent perspective. Conceptual coding methods from grounded theory were applied to organize the data into the final themes. Results: Families, clinics, and WIC centers were all very interested in additional supports for oral health and were enthusiastic about CHWs. Challenges included competing family priorities that might interfere in study enrollment and intervention efficacy. Physical space for enrollment and intervention delivery was a major barrier for some sites. Home visits for data collection and intervention delivery would be unacceptable for some families. These challenges and barriers prompted us to make major changes in our trial design. We opened the option for data collection to occur in multiple locations. We eliminated the home only arm of the trial. Clinics and WIC centers that are randomized to the non intervention arm will now have CHWs available at the study conclusion. Finally, we aligned the CHW oral health topics to the needs of families. Conclusions: We conducted this comprehensive formative assessment to determine the feasibility and acceptability of the CO-OP Chicago trial. While overall acceptance of the trial was high, the results highlighted specific issues with the proposed trial implementation plan and led to several critical design changes. This type of formative work requires a significant upfront investment but we expect it will translate into savings through better recruitment, retention, intervention implementation and adherence, and result dissemination. PMID- 30305916 TI - Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. AB - The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome. PMID- 30305919 TI - Using a peanut ball during labour versus not using a peanut ball during labour for women using an epidural: study protocol for a randomised controlled pilot study. AB - Background: The peanut ball has only been recently used as a support for women labouring with epidurals. The peanut ball is shaped like a peanut and fits snugly between the woman's legs so that both legs are maintained as opening the pelvic outlet to increase the progress of labour and facilitate descent of the fetal head. Using position changes during labour to enhance widening of the pelvic outlet can be beneficial but a woman who has an epidural is limited in the number of positions she can adopt. No randomised controlled trial has been implemented in Australia to establish the effectiveness of a peanut ball specifically for women using epidurals during labour, and this project addresses this gap. The main aim of this pilot study is to assess the feasibility and practicality of conducting and replicating this trial to a definitive randomised controlled trial (RCT). Methods: A minimum number of 50 women (25 in each trial arm), who are using an epidural in labour at two hospitals in NSW over a 1-year period, will be recruited and randomly allocated into a group that uses the peanut ball or into a group that does not use the peanut ball. Primary study objectives include assessing the proportion of women willing to be randomised, retention/attrition rates, and with associated reasons. Data will be collected on key clinical outcomes (natural birth rate, length of stay) with means and variances estimated between trial arms. This will inform the appropriate powering of a future definitive RCT. Secondary study objectives will include investigating the completion and acceptability of health and satisfaction surveys and assess the feasibility of conducting an economic evaluation alongside a future trial. Discussion: This is a two-armed randomised controlled pilot trial. Outcomes from this pilot will inform a larger trial at a tertiary hospital. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000662268. PMID- 30305920 TI - Application of black phosphorus nanodots to live cell imaging. AB - Background: Black phosphorus (BP) has emerged as a novel class of nanomaterials owing to its unique optical and electronic properties. BP, a two-dimensional (2D) nanomaterial, is a structure where phosphorenes are stacked together in layers by van der Waals interactions. However, although BP nanodots have many advantages, their biosafety and biological effect have not yet been elucidated as compared to the other nanomaterials. Therefore, it is particularly important to assess the cytotoxicity of BP nanodots for exploring their potentials as novel biomaterials. Methods: BP nanodots were prepared by exfoliation with a modified ultrasonication assisted solution method. The physicochemical properties of BP nanodots were characterized by transmission electron microscopy, dynamic light scattering, Raman spectroscopy, and X-ray diffractometry. In addition, the cytotoxicity of BP nanodots against C2C12 myoblasts was evaluated. Moreover, their cell imaging potential was investigated. Results: Herein, we concentrated on evaluating the cytotoxicity of BP nanodots and investigating their cell imaging potential. It was revealed that the BP nanodots were cytocompatible at a low concentration, although the cell viability was decreased with increasing BP nanodot concentration. Furthermore, our results demonstrated that the cells took up the BP nanodots, and the BP nanodots exhibited green fluorescence. Conclusions: In conclusion, our findings suggest that the BP nanodots have suitable biocompatibility, and are promising candidates as fluorescence probes for biomedical imaging applications. PMID- 30305921 TI - Heart rate variability following youth concussion: how do autonomic regulation and concussion symptoms differ over time postinjury? AB - Objectives: Following youth concussion, objective physiological indicators are needed to corroborate changes in subjective clinical measures. The objectives of the current study were to: (1) explore the effect of concussion on heart rate variability (HRV) across days postinjury in youth athletes aged 13-18 years old, compared with healthy age-matched and sex-matched controls and (2) examine the relationship between postconcussion symptom domains (physical, cognitive, fatigue and emotional) and HRV. Methods: Prospective, longitudinal, case-control study (N=44). This study comprised 29 concussed athletes between the ages of 13 and 18 years old (21 females, 8 males) and 15 age-matched and sex-matched controls). All participants completed baseline testing, which included demographic information (age, sex, concussion history), self-reported concussion symptoms (Post Concussion Symptom Inventory [PCSI]) and a 24-hour heart rate recording via the Polar RS800CX system. The PCSI and HRV were collected weekly while the participant was symptomatic and then 1, 3 and 6 months following symptom resolution. HRV variables included time and frequency domain measures. Data visualisations and mixed effects modelling were used to derive parsimonious models. Results: HRV increased across days postinjury. Concussion symptom domains (physical, cognitive, fatigue and emotional) all had a significant main effect on HRV; concussed participants who reported more symptoms had higher HRV compared with those who reported fewer symptoms. Visualisations of HRV depict the recovery trajectory as non-linear across time. No significant differences on HRV measures were found between concussed and control participants. Conclusion: These preliminary findings provide the foundation to understand the varied trajectory and relationship between objective physiological measures and subjective symptom reporting. PMID- 30305922 TI - Perceptual-cognitive three-dimensional multiple-object tracking task can help the monitoring of sport-related concussion. AB - Objectives: While the rate of sport-related concussion is increasing, more effective tools are needed to help monitor the diagnosis and return to play of athletes. The three-dimensional multiple-object tracking (3D-MOT) exercise is a perceptual-cognitive task that has shown predictive power towards the dynamic requirements of real-world activities such as sport. This study introduced the use of the 3D-MOT task, along with the Standardized Assessment of Concussion (SAC) and Modified Balance Error Scoring System (M-BESS) tests, for diagnosis and return to play in professional sports. Methods: Fifty-nine professional athletes were tested with the 3D-MOT, SAC and M-BESS tests at 48 hours following the injury. The same measures were employed to evaluate the return to play following the standard concussion management protocol. The SAC and M-BESS tests were also performed in pre-season (baseline) in 32 out of the 59 athletes. Results: The injured athletes exhibited poor performance on 3D-MOT at 48 hours post injury compared with return to play (p<0.001) as well as compared with healthy professionals' performance scores (p<0.001). Importantly, learning rate, which participants are thought to have an expert advantage on this perceptual-cognitive task, was totally disrupted at 48 hours post injury compared with healthy professionals (p<0.001). The 3D-MOT performance was also correlated to the total number of symptoms (p=0.020), SAC (p=0.031) and M-BESS (p=0.004) scores at 48 hours. Not surprisingly, SAC and M-BESS tests' usefulness for monitoring concussion was found to be weak, particularly when test performance following the injury was compared to baseline (p=0.056 and 0.349 for SAC and M-BESS, respectively). Conclusion: 3D-MOT could help monitor sport-related concussion in professional athletes. The discussion also covers the critical importance of perceptual-cognitive assessment following concussion in the athletic population. PMID- 30305923 TI - Top 50 most-cited articles in medicine and science in football. AB - Objectives: To conduct a comprehensive mapping analysis to the scientific literature published in football aiming to identify the areas of bigger interest and potential for further exploration. Methods: The data were obtained by a search conducted on the Web of Science. Articles were listed based on citation frequency. We used an open-source bibliometrix R-package for the comprehensive bibliometric analyses. Results: The number of citations per article ranged from 251 to 869 (median 323; IQR 125). The yearly number of citations ranged from 8 to 54 (median 26; IQR 11). Most of the articles (76%) were of level III of evidence, 10% were level II and 14% were level IV. Within the top 50 most-cited articles, 40 articles were original research (37 observational and 3 experimental studies), 9 were review articles and 1 was a thesis. From the 40 original research articles, 50% involved elite players, 73% were exclusive to male players and 80% involved adult players only. The topic area with the highest number of articles was sports medicine (44%), followed by training and testing (32%), performance analysis (14%) and physiology (10%). No study within the top 50 was devoted to biomechanics, nutrition, sport psychology, coaching or social sciences. Conclusions: The lack of experimental studies within the top 50 most-cited articles in football clearly underpins how far we still are from establishing the theoretical and methodological guidelines for the applied science and medicine in football. PMID- 30305924 TI - Effect of moderate-intensity exercise bouts lasting <10 minutes on body composition in sedentary Kenyan adults aged >=50 years. AB - Background: Sedentary lifestyles and related morbidities are rising among adults despite existing exercise recommendations. Appealing exercise regimes yielding similar/better body composition should be sought. Objective: We investigated the effect of moderate-intensity exercise bouts of <10 min on body composition in previously sedentary adults. Methods: This unblinded study enrolled 53 healthy sedentary volunteers aged >=50 years, randomised into one of two gender-balanced exercise interventions: (1) male and (2) female short-duration bouts (MS, n=14; FS, n = 13), and (3) male and (4) female long-duration bouts (ML, n=13; FL, n=13). Short-duration bouts entailed 5-10 min of jogging thrice daily; long duration bouts, 30-60 min 3-5 days weekly. Body composition was determined at recruitment and 8-weekly thereafter, for 24 weeks. Results: At baseline, 14.3% of MS, 38.5% of ML, 92.3% of FS and 69.2% of FL were obese, dropping to 7.1%, 15.4%, 61.5% and 30.8%, respectively. For waist:height ratio, 64.3 % of MS, 76.9% of ML, 100% of FS and 84.6.3% of FL had ratios >0.5, dropping to 42.9%, 30.8%, 92.9% and 26.2%, respectively. While baseline MS and ML waist:hip ratio (WHR) >=0.9 were 64.3% and 69.2%, respectively, they correspondingly dropped to 23.1% and 21.4%. The FS and FL with WHR >=0.85 dropped from 46.2% to 15.4% and from 30.8% to 7.7%, respectively. Body composition variables improved for both sexes (all p <0.05) and mean change between exercise regimes was comparable for both sexes. Conclusion: In equal cumulative times, moderate-intensity exercise bouts lasting <10 min are comparable with current 30-60 min bouts in body composition modification for adults of >=50 years. PMID- 30305926 TI - 10-year follow-up after standardised treatment for Achilles tendinopathy. AB - Background: Achilles tendinopathy is a common and often long-lasting injury. We present a 10-year follow-up on a pragmatic study on Achilles tendinopathy treated with controlled exercises supplemented with corticosteroid injections if necessary in order to continue training. Methods: All patients who completed the original study (n=93) were invited for a 10-year follow-up. 83% participated. Patients were evaluated with ultrasound scanning (n=58) and with a questionnaire (n=77) using the same outcome measures as in the primary study. The 10-year overall outcome on a 4-point scale (excellent, good, fair, poor), other treatments and adverse event and present activity level were recorded. Results: Excellent outcome was reported in 63% and good outcome in 27%. 76% reported an activity level at 75%-100% of preinjury level. The average Victorian Institute of Sports Assessment-Achilles score for all patients was 84 (SD 19). 16% had surgery. Three ruptures occurred 5-8 years after the primary study. The improvement from entry to 6 months in the primary study was maintained until 10 year follow-up. Insertional tendinopathy did not differ from mid-substance tendinopathy in any outcome measure (short term and long term). We encountered no prognostic markers on ultrasound for the long-term outcome; however, present heterogeneity and increased flow resemble present pain. Thickened tendons seem to maintain their thickness despite improvement of symptoms. Conclusion: One to two corticosteroid injections are a safe and effective supplement to controlled exercises in the treatment of Achilles tendon pain with no signs of deterioration in the very long term. Mid-substance and insertional tendinopathies benefit equally from this treatment. PMID- 30305925 TI - Effects of exercise training on physical and psychosocial health in children with chronic respiratory disease: a systematic review and meta-analysis. AB - Introduction: Chronic disease in children is increasing, including the prevalence of chronic respiratory diseases such as asthma, cystic fibrosis (CF), bronchiectasis and bronchopulmonary dysplasia (BPD). The aim of this systematic review and meta-analysis was to evaluate the effects of exercise training on health outcomes in children with chronic respiratory disease. Method: Five databases were searched for randomised controlled trials investigating the effects of exercise training on children with chronic respiratory disease. Following the PRISMA guidelines, eligible studies were identified and data were extracted. A meta-analysis was conducted for the outcomes cardiovascular fitness, lung function and quality of life (QoL). Results: The initial search returned 3688 papers. Twenty-seven (17 in children with asthma, 10 in children with CF) were included in the systematic review and 24 of these were included in the meta analysis. No studies were identified in children with bronchiectasis or BPD. Included papers had a total of 1009 participants aged 8-20 years. In addition to cardiovascular fitness, lung function and QoL, studies also assessed pulmonary function, respiratory muscle strength, muscular strength and inflammation. Meta analysis showed a large significant effect size in favour of exercise for cardiovascular fitness (peak VO2) (standard mean difference (SMD)=1.16, 95% CI 0.61 to 1.70) and QoL (SMD=1.27, 95% CI 0.72 to 1.82) as well as a small, non significant effect size for lung function (FEV1) (SMD=0.02, 95% CI -0.38 to 0.42). Conclusion: Exercise training significantly improves cardiovascular fitness and QoL in children with asthma and CF. Further research is needed, particularly in children with bronchiectasis and BPD. PMID- 30305927 TI - Positioning of the femoral tunnel in anterior cruciate ligament reconstruction: functional anatomical reconstruction. AB - The aim of this study was to review and update the literature in regard to the anatomy of the femoral origin of the ACL, the concept of the double band and its respective mechanical functions, and the concept of direct and indirect fibres in the ACL insertion. These topics will be used to help determine which might be the best place to position the femoral tunnel and how this should be achieved, based on the idea of functional positioning, that is, where the most important ACL fibres in terms of knee stability are positioned. Low positioning of the femoral tunnel, reproducing more of the posterolateral band, and positioning the tunnel away from the lateral intercondylar ridge, that is, in the indirect fibres, would theoretically rebuild a ligament that is less effective in relation to knee stability. The techniques described to determine the femoral tunnel's centre point all involve some degree of subjectivity; the point is defined manually and depends on the surgeon's expertise. The centre of the ACL insertion in the femur should be used as a parameter. Once the centre of the ligament in its footprint is marked, the centre of the tunnel must be defined, drawing the marking toward the intercondylar ridge and anteromedial band. This will allow the femoral tunnel to occupy the region containing the most important original ACL fibres in terms of this ligament's function. PMID- 30305928 TI - Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes. AB - Objective: A growing number of ultra-endurance athletes have switched to a very low-carbohydrate/high-fat eating pattern. We compared markers of cholesterol and the lipoprotein profile in a group of elite ultra-runners consuming a high carbohydrate (HC) or low-carbohydrate (LC) diet. Methods: Fasting blood was obtained from competitive male ultra-endurance runners habitually consuming a very low-carbohydrate (LC; n=10) or high-carbohydrate (HC; n=10) diet to determine blood cholesterol profile, lipoprotein particle distribution and sterol biomarkers of cholesterol balance. Results: Plasma total cholesterol, low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) cholesterol were all significantly greater (p<0.000) in the LC group (65%, 83% and 60%, respectively). There were also significant differences in lipoprotein particle distribution as evidenced by a greater size and concentration of large HDL and LDL particles, and total LDL particle concentration was significantly greater in the LC group, but they had significantly fewer small LDL particles. Conclusion: Ultra-endurance athletes habitually consuming a very low-carbohydrate/high-fat diet for over a year showed unique cholesterol profiles characterised by consistently higher plasma LDL-C and HDL-C, less small LDL particles, and lipoprotein profiles consistent with higher insulin sensitivity. There may be a functional purpose to the expansion of the circulating cholesterol pool to meet the heightened demand for lipid transport in highly trained, keto-adapted athletes. PMID- 30305929 TI - Chinese translation and validation of the Sport Concussion Assessment Tool 3 (SCAT3). AB - Objective: The aim of this study was to translate, adapt and validate the Sport Concussion Assessment Tool 3rd edition (SCAT3), a test for assessing athletes for concussion, into the Chinese context. Methods: Translation and adaptation were performed in several stages, which included forward translation by two independent teams, translation merging, backward translation, reviews by both native Cantonese-speaking and Mandarin-speaking multidisciplinary expert panels (n=49) for semantic and conceptual equivalence and reviews by pitch-side physiotherapists (n=18) as end-users of the SCAT3 and rugby players (n=11) for face validity. The Serial 3 s subtraction test was used as a substitute for the Months Backward Test (MBT) for measures of concentration in the Standardized Assessment of Concussion subscale. English-speaking and Chinese-speaking rugby players (n=52) were recruited to perform these tests to assess the level of difficulty, time for completion and accuracy. Inter-rater and test-retest reliability were assessed in 33 and 38 healthy young individuals, respectively. Results: Despite the longer mean completion time (p<0.05) for the Serial 3 s test, no significant difference was found in the percentage accuracy between MBT and the Serial 3 s test. No significant difference was found in either the percentage accuracy or completion time between English-speaking and Cantonese speaking rugby players. All subscales in the Chinese SCAT3 had excellent levels of inter-rater reliability for all items (ICC2,1 range: 0.96-0.99) but a low to moderate test-retest reliability (ICC3,2 range: 0.32-0.65). The mean completion time of the Chinese SCAT3 was 10.6+/-1.1 min. Conclusion: Chinese SCAT3 is a valid instrument for pitch-side assessment of concussed Chinese-speaking athletes. PMID- 30305930 TI - Low salivary cortisol levels in patients with rheumatoid arthritis exposed to oral glucocorticoids: a cross-sectional study set within UK electronic health records. AB - Background: Glucocorticoids (GCs) suppress endogenous cortisol levels which can lead to adrenal insufficiency (AI). The frequency of GC-induced AI remains unclear. In this cross-sectional study, low morning salivary cortisol (MSC) levels were used as a measure of adrenal function. The study aim was to investigate the prevalence of low MSC in patients with rheumatoid arthritis (RA) currently and formerly exposed to oral GCs, and the association with potential risk factors. Methods: Sample collection was nested within UK primary care electronic health records (from the Clinical Practice Research Datalink). Participants were patients with RA with at least one prescription for oral GCs in the past 2 years. Self-reported oral GC use was used to define current use and current dose; prescription data were used to define exposure duration. MSC was determined from saliva samples; 5 nmol/L was the cut-off for low MSC. The prevalence of low MSC was estimated, and logistic regression was used to assess the association with potential risk factors. Results: 66% of 38 current and 11 % of 38 former GC users had low MSC. Among former users with low MSC, the longest time since GC withdrawal was 6 months. Current GC dose, age and RA duration were significantly associated with increased risk of low MSC. Conclusion: The prevalence of low MSC among current GC users is high, and MSC levels may remain suppressed for several months after GC withdrawal. Clinicians should therefore consider the risk of suppressed cortisol and remain vigilant for symptoms of AI following GC withdrawal. PMID- 30305932 TI - Peripheral retinal nonperfusion using widefield imaging with von Hippel-Lindau disease. AB - Background: To describe a case of von Hippel-Lindau disease with peripheral retinal nonperfusion. Case presentation: A 66-year-old female with known cerebellar and midbrain hemangioblastomas was evaluated for a retinal hemangioblastoma in the right eye. She underwent widefield fluorescein angiography, which showed hyperfluorescence localized to the hemangioblastoma surrounded by peripheral retinal nonperfusion in the same quadrant. Conclusions: Further widefield imaging studies are required to determine if peripheral retinal nonperfusion is a common finding in von Hippel-Lindau disease. PMID- 30305931 TI - Feasibility of cardiovascular disease risk assessments in rheumatology outpatient clinics: experiences from the nationwide NOCAR project. AB - Objective: The European League Against Rheumatism recommends implementing cardiovascular disease (CVD) risk assessments for patients with inflammatory joint diseases (IJDs) into clinical practice. Our goal was to design a structured programme for CVD risk assessments to be implemented into routine rheumatology outpatient clinic visits. Methods: The NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR) started in April 2014 as a quality assurance project including 11 Norwegian rheumatology clinics. CVD risk factors were recorded by adding lipids to routine laboratory tests, self reporting of CVD risk factors and blood pressure measurements along with the clinical joint examination. The patients' CVD risks, calculated by the European CVD risk equation SCORE, were evaluated by the rheumatologist. Patients with high or very high CVD risk were referred to their primary care physician for initiation of CVD preventive measures. Results: Data collection (autumn 2015) showed that five of the NOCAR centres had implemented CVD risk assessments. There were 8789 patients eligible for CVD risk evaluation (rheumatoid arthritis (RA), 4483; ankylosing spondylitis (AS), 1663; psoriatic arthritis (PsA), 1928; unspecified and other forms of spondyloarthropathies (SpA), 715) of whom 41.4 % received a CVD risk assessment (RA, 44.7%; AS, 43.4%; PsA, 36.3%; SpA, 30.6%). Considerable differences existed in the proportions of patients receiving CVD risk evaluations across the NOCAR centres. Conclusion: Patients with IJD represent a patient group with a high CVD burden that seldom undergoes CVD risk assessments. The NOCAR project lifted the offer of CVD risk evaluation to over 40% in this high-risk patient population. PMID- 30305933 TI - The enigma of atypical femoral fractures: A summary of current knowledge. AB - Atypical femoral fractures (AFF) are stress or 'insufficiency' fractures, often complicated by the use of bisphosphonates or other bone turnover inhibitors. While these drugs are beneficial for the intact osteoporotic bone, they probably prevent a stress fracture from healing which thus progresses to a complete fracture.Key features of atypical femoral fractures, essential for the diagnosis, are: location in the subtrochanteric region and diaphysis; lack of trauma history and comminution; and a transverse or short oblique configuration.The relative risk of patients developing an atypical femoral fracture when taking bisphosphonates is high; however, the absolute risk of these fractures in patients on bisphosphonates is low, ranging from 3.2 to 50 cases per 100,000 person-years.Treatment strategy in patients with AFF involves: radiograph of the contralateral side (computed tomography and magnetic resonance imaging should also be considered); dietary calcium and vitamin D supplementation should be prescribed following assessment; bisphosphonates or other potent antiresorptive agents should be discontinued; prophylactic surgical treatment of incomplete AFF with cephalomedullary nail, unless pain free; cephalomedullary nailing for surgical fixation of complete fractures; avoidance of gaps in the lateral and anterior cortex; avoidance of varus malreduction. Cite this article: EFORT Open Rev 2018;3:494-500. DOI: 10.1302/2058-5241.3.170070. PMID- 30305934 TI - Turf toe: A clinical update. AB - Turf toe is a condition that describes injury to the plantar metatarsophalangeal sesamoid complex of the great toe.It is a relatively rare and debilitating condition, particularly seen in American footballers after the introduction of harder, artificial 'turf' surfaces.Turf toe represents a significant injury to the hallux and requires a high index of suspicion.If unrecognized, it can lead to chronic problems including reduced push-off strength, persistent pain, progressive deformity and eventual joint degeneration.Patients with chronic injuries may have worse outcomes, and therefore early, accurate diagnosis and initiation of treatment play a vital role.A multidisciplinary team approach is key for successful return to sport. Cite this article: EFORT Open Rev 2018;3:501 506. DOI: 10.1302/2058-5241.3.180012. PMID- 30305935 TI - Total hip arthroplasty outcomes in morbidly obese patients: A systematic review. AB - The increasing prevalence of obesity has resulted in a marked increase in the number of total hip arthroplasties (THAs) carried out in patients with a high body mass index (BMI).THA in morbidly obese patients is often technically challenging owing to the associated co-morbidities and anatomical factors. Furthermore, the long-term clinical and functional outcomes of the procedure in these patients are not clear.The aim of this systematic review was to compare the long-term failure rate and functional outcomes of THA in morbidly obese versus non-obese patients.A literature search of PubMed, EMBASE and PubMed Central was conducted to identify studies that compared the outcomes of THA in patients defined as morbidly obese (BMI >= 35) to a control group (BMI < 30). The primary and secondary outcome measures were rate of revision and functional outcome, respectively, in the long term.Eight studies were included in this review. There were 66,238 THAs in morbidly obese patients and 705,619 THAs in patients with a BMI < 30. The overall revision rate was 7.99% in the morbidly obese patients versus 2.75% in the non-obese controls. The functional outcome was at least comparable to non-obese patients.This review suggests that morbidly obese patients have a slightly increased revision rate following THA. Importantly, these patients have a functional recovery at least comparable to those with a BMI < 30. Morbidly obese patients should be fully informed of these issues prior to undergoing surgery. Cite this article: EFORT Open Rev 2018;3:507-512. DOI: 10.1302/2058-5241.3.180011. PMID- 30305937 TI - A novel biosimulation task trainer for the deliberate practice of resuscitative hysterotomy. AB - Resuscitative hysterotomy is a daunting and rarely performed procedure in the emergency department (ED). Given the paucity of clinical exposure to this intervention, resuscitative hysterotomy is an ideal opportunity for simulation mediated deliberate practice. The authors propose a novel training program using a homegrown, realistic, simulation device as a means to practice resuscitative hysterotomy. Two high-fidelity, tissue-based task-trainer models were constructed and tested on a convenience sample of 14 emergency medicine (EM) residents. The simulated human placenta, bladder, amniotic sac, and uterus were constructed through the use of porcine skin, porcine stomach, transparent plastic bag, Foley tubing, and squid mantle, all secured with nylon sutures. A Gaumard S500 Articulating Newborn was inserted in the simulated uterus, and the entire model was placed into a Gaumard S500 Childbirth Simulator. Each model required less than 1 h for assembly. Emergent hysterotomy was first demonstrated by an EM faculty facilitator, followed by hands-on deliberate practice. Formal feedback on the learners' self-reported confidence and satisfaction levels was solicited at the end of the workshop through a survey previously cited for use with a low fidelity resuscitative hysterotomy. Quantitative evaluation of the simulated training session was extracted through a 5-item questionnaire using a 5-point Likert-type scale (i.e., from 1, strongly disagree, to 5, strongly agree). Item scores were added for a cumulative total score, with a possible maximum score of 25 and minimum score of 5. Responses were overwhelmingly positive [24.13 (+/- 1.36)]. Qualitative feedback was extracted from the survey through open-ended questions; these responses highlighted learners' appreciation for hands-on practice and the development of a novel, tissue-based simulation task trainer. All participants recommended the training session be available to future learners. Resuscitative hysterotomy is a high-stakes, low-frequency procedure that demands provider practice and confidence. Our hybrid, tissue-based hysterotomy model represents a feasible opportunity for training. The model is cost conscious, easily reproducible, and portable and allows for ample deliberate practice. PMID- 30305938 TI - Life on a knife edge: using simulation to engage young people in issues surrounding knife crime. AB - Background: Knife-related behaviour among young people is an increasing social concern with a total of 35 teenagers killed by knife attacks in England in 2017. Distributed simulation has been shown to be a valid method of portable simulation for medical professionals; however, its role in delivering a socially educational message to members of the public has not been previously studied. This paper explores how the novel use of simulation could be used to address a serious social issue amongst young people at risk of criminal knife behaviour. Methods: A qualitative approach was used to study a two-part workshop attended by two groups of young people vulnerable to knife crime. Based on the concepts of sequential simulation and distributed simulation previously developed at the Imperial College Centre for Engagement and Simulation Science, the first part of the workshop showed the patient journey of a young man stabbed in the abdomen, attended by policemen and paramedics, followed by the participants witnessing a simulated emergency abdominal operation on a silicone model and concluded with a dialogue between the surgeon, the victim (who required an intestinal stoma as a result of the knife injury) and his mother. The second part of the workshop involved further discussion with the participants regarding the role of knives from the personal and community perspective. Visual data was recorded during the workshops and qualitative data obtained from group and individual interviews were thematically analysed. Results: A total of sixty teenagers aged 13-19 took part in the two workshops. The participant feedback suggested that the workshops provided a safe environment where young people could learn about and explore the consequences surrounding knife crime. Furthermore, participant recollection of key points was assessed between 4 and 6 weeks after the second workshop and the data suggested that the workshop could promote learning and a change in the participants' knife-related behaviour in the future. Conclusions: The findings support further exploration of simulation as a modality for engaging young people about the issues surrounding criminal knife behaviour in a safe and cooperative environment. Moreover, the findings suggest that the workshop could be used as an educational tool that may facilitate behavioural change. PMID- 30305936 TI - Current concepts for the evaluation and management of diabetic foot ulcers. AB - The lifetime risk for diabetic patients to develop a diabetic foot ulcer (DFU) is 25%. In these patients, the risk of amputation is increased and the outcome deteriorates.More than 50% of non-traumatic lower-extremity amputations are related to DFU infections and 85% of all lower-extremity amputations in patients with diabetes are preceded by an ulcer; up to 70% of diabetic patients with a DFU related amputation die within five years of their amputation.Optimal management of patients with DFUs must include clinical awareness, adequate blood glucose control, periodic foot inspection, custom therapeutic footwear, off-loading in high-risk patients, local wound care, diagnosis and control of osteomyelitis and ischaemia. Cite this article: EFORT Open Rev 2018;3:513-525. DOI: 10.1302/2058 5241.3.180010. PMID- 30305939 TI - BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance. AB - Background: The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials. Materials and methods: The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines. Results: Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines. Conclusion: Our data provide the rationale to evaluate birabresib in patients affected by MCL. PMID- 30305940 TI - Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature. AB - Background: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%-90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy. Patients and methods: A systematic review was done. We searched for documents and articles published in English language and registered in Cochrane Library, National Health Service (NHS) Centre for Reviews and Dissemination (CRD), Embase or Medline. The search terms were (A) (Lung cancer or NSCLC) with (pembrolizumab or nivolumab) with PD-L1 with (tobacco or smoking) and (B) Lung Neoplasms and Immunotherapy and (smoking cessation or patient compliance). 68 papers were detected and two more were added during review process (references) and six based on information from the manufacturers. Results: Nine papers were selected. High PD-L1 expression (>=50%) was correlated with current/ever smoking history in three studies. Six studies revealed a higher overall response rate (ORR) among current/former smokers. The ORR was generally (six studies) better among the current/former smoker group. So also when tumours had a molecular 'smoking signature' (one study). This was probably due to a higher mutational burden. In two studies, minor or no difference was revealed.One study (KEYNOTE-024) compared former and current smokers, and documented pembrolizumab being more effective among former smokers than current smokers. Conclusions: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation. PMID- 30305942 TI - Atrial septal defects: an overview. PMID- 30305941 TI - The 5S-5M-5C schematic: transforming primary care inputs to outcomes in low income and middle-income countries. PMID- 30305943 TI - Anatomy of the atrial septum and interatrial communications. AB - Deficiencies in the septum separating the two atrial chambers are among the most common of congenital heart malformations. This article reviews the developmental aspects of the partitioning of the primitive atrium into right and left atrial chambers, the anatomical components of the atrial septum, and deficiencies that produce the various types of interatrial communications. Knowledge of the components of the true atrial septum in the developed heart clarifies the morphology of various types of interatrial communications. The oval fossa defect (also termed secundum ASD) is located within the true septum. The patent foramen ovale (PFO) is a tunnel-like passageway between the free edge of the overlapping ovale fossa valve and its muscular rim. Other defects such as superior and inferior sinus venosus defects, coronary sinus defects, and ostium primum defects lie outside the area of the true septum. PMID- 30305944 TI - Electrical disorders in atrial septal defect: genetics and heritability. AB - Atrial septal defect (ASD) is one of the most common types of congenital heart diseases (CHDs). Most ASDs occur sporadically, but some are inherited and associated with cardiac conduction defects such as atrioventricular block (AVB) or bundle branch block. Mutations in genes encoding transcription factor gene TBX5 and NKX2-5, were found in Holt-Oram syndrome (HOS) and ASD with atrioventricular (AV) conduction defects, respectively. HOS is characterized by upper limb anomaly in addition to ASD and AVB (heart-hand syndrome). ASD associated with NKX2-5 is rare but is reported to cause sudden cardiac death (SCD) or cardiomyopathy. We provide a review of these two diseases. PMID- 30305945 TI - Pathophysiology and natural history of atrial septal defect. AB - Atrial septal defects are among the third most common types of congenital heart disease. This group of malformations includes several types of atrial communications allowing shunting of blood between the systemic and the pulmonary circulations. The nature of shunting across the defect in patients with atrial septal defect is of particular interest. Understanding the underlying mechanisms of interatrial shunts and their natural history will help selecting the best timing for closure, before irreversible cardiac and pulmonary injury occur. This review describes the different pathophysiologic mechanisms involved in the direction and magnitude of blood flow through atrial septal defects. The natural history of an individual born with an isolated atrial septal defect is then discussed, including the impact of a longstanding shunt on survival. PMID- 30305947 TI - Atrial septal defect closure: indications and contra-indications. AB - Transcatheter closure has become an accepted alternative to surgical repair for ostium secundum atrial septal defects (ASD). However, large ASDs (>38 mm) and defects with deficient rims are usually not offered transcatheter closure but are referred for surgical closure. Transcatheter closure also remains controversial for other complicated ASDs with comorbidities, additional cardiac features and in small children. This article not only provides a comprehensive, up-to-date description of the current indications and contra-indications for ASD device closure, but also further explores the current limits for transcatheter closure in controversial cases. With the devices and technology currently available, several cohort studies have reported successful percutaneous closure in the above mentioned complex cases. However the feasibility and safety of transcatheter technique needs to be confirmed through larger studies and longer follow-up. PMID- 30305946 TI - Atrial septal defect and exercise capacity: value of cardio-pulmonary exercise test in assessment and follow-up. AB - Nearly four decades ago, the World Health Organization stated that functional capacity explorations best reflected the impact of a chronic disease on quality of life. Today, cardio-pulmonary exercise test (CPET) is recommended in the follow-up of patients with congenital heart diseases (CHDs). Indeed, the maximum oxygen uptake (VO2max) and the ventilatory efficiency (VE/VCO2 slope) correlate with both the prognosis and the quality of life in this population. Atrial septal defects (ASDs) represent the second most frequent CHD and are usually considered as simple CHDs. However, the exercise capacity of ASD patients may be impaired. Therefore, the CPET provides important information in assessment and follow-up of patients with ASDs, for both children and adults. Exercise capacity of patients with unrepaired ASDs depends on the importance of the shunt, the right ventricular (RV) function and volume overload, the level of pulmonary arterial pressure, and the occurrence of arrhythmias. For repaired ASDs, exercise capacity also depends on the delay before closure and the type of procedure (catheter or surgery). In most cases, the exercise capacity is nearly normal and CPET contributes to promote sports participation. In addition, a regular CPET follow up is necessary to evaluate the occurrence, severity and physiological mechanisms of comorbidities, i.e., heart failure, pulmonary hypertension and arrhythmia. Furthermore, CPET follow-up in patients with ASDs may detect early onset of muscular deconditioning, for which cardiac rehabilitation may be considered. PMID- 30305948 TI - Hemodynamic assessment of atrial septal defects. AB - Atrial septal defect (ASD) is one of the most common congenital cardiac anomalies. ASD can present as an isolated lesion in an otherwise normal heart or in association with other congenital heart conditions. Regardless of the type of ASD, the direction and degree of shunting across the communication is mainly determined by the difference in compliance between the right and left ventricle. Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP). Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction. Diagnostic catheterization is usually not indicated unless there is suggestion of pulmonary hypertension on echocardiography. In older patients and/or in those with ventricular dysfunction, measurement of left heart pressures during temporary balloon occlusion is recommended prior to device closure as it may not be tolerated. In ASD associated with other congenital malformations, shunting degree and direction will depend upon underlying condition. Restrictive ASD can result in significant hemodynamic compromise in neonates with conditions such as hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA). In most cases, hemodynamics can be estimated with echocardiography only. PMID- 30305949 TI - Atrial septal defect with pulmonary hypertension: when/how can we consider closure? AB - Patients having atrial septal defect (ASD) with moderate and more importantly severe pulmonary arterial hypertension (PAH) pose a clinical dilemma. Closing ASD in those with irreversible PAH and not closing it when the PAH is reversible can cost patients dearly, both in terms of quality of life and longevity. In our experience, there is no single parameter that can help in decision making in this difficult subset of patients and therefore we recommend a multi-dimensional approach, which takes into consideration clinical, radiological, electrocardiographic and hemodynamic variables as a whole. ASD with restrictive left ventricular (LV) physiology can lead to pulmonary venous hypertension, which can manifest as life threatening acute pulmonary edema following device closure. All high-risk candidates prone to having this combination should be prepared with diuretics and vasodilators prior to bringing them to catheterization laboratory and should be assessed with temporary balloon/device occlusion prior to permanent closure of the defect. In those cases of ASD with borderline operability either due to severe PAH or LV restrictive physiology, perforated device may be helpful in preventing acute or long-term complications of complete closure. PMID- 30305950 TI - Echocardiography guidance of atrial septal defect closure. AB - Transcatheter procedures offer less invasive approaches allowing rapid recovery and earlier hospital discharge. A number of international guidelines have defined the role of echocardiography spanning diagnosis, detailed anatomical assessment, device sizing and selection, peri-procedure guidance and post device surveillance. This review discusses the role of echocardiography in transcatheter atrial septal defect (ASD) closure. It describes a systematic approach to assessment including the crucial role of three dimensional echo and provides the reader with key information required during device sizing and procedure guidance. PMID- 30305951 TI - Transcatheter closure of atrial septal defect: principles and available devices. AB - There has been a remarkable improvement in the treatment strategy of secundum atrial septal defect (ASD) over the last few decades. Indebted to the improvement in device technology and procedural techniques, transcatheter closure of ASD is currently accepted as the treatment of choice in most patients with secundum ASD. Recent generation devices enable easy and safe deployment of device with the properties of adequate flexibility, re-capturability and repositioning. Use of biocompatible materials with improved device design and refined equipment finish may promote re-endothelialization and reduce potential damage to nearby structures. Most of currently available devices show excellent efficacy and comparable outcome with its own advantages and disadvantages. In addition to improvement of device properties and performance, there has been distinct improvement in procedural technique from numerous experiences of device closure of ASD. Nowadays there are well established principles regarding patient selection, pre-procedural evaluation, step-by-step details of procedure as well as post-procedural follow-up. However, an operator may encounter pitfalls in closing complex lesions such as large defect, rim deficiencies and multiple defects, so every operator has to be familiar with each available device, general principle as well as special issues for complex lesions. PMID- 30305953 TI - Surgical closure of atrial septal defects. AB - Surgical repair of an atrial septal defect (ASD) is a safe and effective operation with little to no morbidity and mortality. In an effort to reduce the trauma of surgery, current approaches focus on less invasive surgical techniques, rather than the intracardiac repair. We will describe the different types of ASD, techniques for repair, and options for minimally invasive repair. PMID- 30305954 TI - Arrhythmias and conduction disorders associated with atrial septal defects. AB - Atrial septal defects (ASDs) are the most common form of congenital heart disease. There are 4 embryologic types of ASDs, and rhythm considerations vary based on type. ASDs have left-to-right shunt and primarily right-sided volume overload. This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders. Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions. Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population. Medical and procedural therapy for arrhythmias should consider type and timing of ASD repair. Conduction disorders are rare. Sinus node dysfunction may be seen with late age of repair and large shunt size. Sinus venosus ASD exhibits a higher rate of sinus node dysfunction, especially with older surgical techniques. Ostium primum ASD has higher risk of spontaneous or post-operative AV block, though this is rare with current surgical techniques. Risk of AV block with surgical repair or device closure of secundum ASD is rare. Familial ASDs and other forms of congenital heart disease may be seen with mutations in associated myocardial transcription factors NKX2.5, GATA4, TBX6, along with conduction disorders such as AV block. PMID- 30305952 TI - Atrial septal defect (ASD) device trans-catheter closure: limitations. AB - Transcatheter closure is a widespread technique used to treat secundum atrial septal defects (ASDs). When compared to surgery, it provides a less invasive approach with quicker recovery and reduced physical and psychological impact. Nowadays, almost 85-90% of all secundum ASD can be closed by using a transcatheter approach. However, several limitations may have a significant impact on the feasibility and success of percutaneous ASD closure. Limitations can be grouped as: (I) anatomical; (II) device-related; (III) associated defects and natural history associated issues; (IV) physiological; (V) complications. Physician should be aware of potential limits of percutaneous ASD closure. PMID- 30305955 TI - Pregnancy in adults with repaired/unrepaired atrial septal defect. AB - Atrial septal defect (ASD) is the most common form of congenital heart disease. Left-to-right shunting leads to right ventricular (RV) volume overload with excessive pulmonary blood flow. Complications include exercise intolerance, pulmonary vascular disease, RV dysfunction, paradoxical thromboemboli, and atrial arrhythmias. Women with coexisting severe pulmonary hypertension should be counselled against pregnancy due to high incidence of maternal and fetal morbidity and mortality. In the absence of pulmonary hypertension, pregnancy is generally well tolerated in the setting of an ASD. Nevertheless, hemodynamic changes throughout gestation may increase the risk for complications, particularly in those with unrepaired ASDs. Arrhythmias are the most common cardiac event and occur in 4-5%, followed by paradoxical emboli in 2-5%. Obstetrical and neonatal complications include preeclampsia, a higher incidence of infants born small for gestational age, and higher fetal/perinatal mortality. Although there is no definitive evidence demonstrating superiority of an aggressive approach to ASD closure prior to pregnancy, it is currently common practice to electively close asymptomatic but large and/or hemodynamically significant ASDs prior to childbearing. Cardiology follow up during pregnancy should be adapted to clinical circumstances and includes transthoracic echocardiography during the second trimester and arrhythmia monitoring in the event of symptoms. PMID- 30305956 TI - Atrial septal defects and pulmonary arterial hypertension. AB - Atrial septal defects (ASD) are a common congenital heart defect. The majority of patient with ASDs often follow an uncomplicated course of events. However, a proportion of patients with ASDs, may have their condition complicated by pulmonary hypertension (PH), with a subsequent significant impact on management, morbidity and mortality. The presence of PH, influences the suitability for defect closure. In this review we describe the different types of ASDs, the classification of PH related to congenital heart disease (CHD), when ASD closure is contraindicated and the management of patients who develop pulmonary arterial hypertension (PAH), including the most extreme form, Eisenmenger syndrome (ES). PMID- 30305957 TI - Role of animal models for percutaneous atrial septal defect closure. AB - As for any preclinical development of new implantable device, bench testing has been followed by experimental studies on large animal models for the development of atrial septal defect closure devices. Various models have been used according to studied species (porcine, ovine or canine model) and whether the septal defect was percutaneously or surgically created. Animal models of percutaneous atrial septal defect closure aim to assess the healing process and device endothelialisation, as well as the development of magnetic resonance imaging guided procedures, the short-term effects of volume overload on right ventricular contractility through haemodynamic studies and the understanding of other complications such as nickel hypersensitivity. Each technique has its own advantages and drawbacks, and leads to different punch-related, acute septal injuries that could have an effect on the healing process after device implantation. It has been suggested that some long-term, major device-related complications such as thrombosis or infective endocarditis may be associated with an inappropriate healing process or insufficient endothelialisation of the device, leading industrial companies to pay a great deal of attention to the healing process. Tissue reactions in animal models were shown to adequately reproduce the healing response after device implantation in humans, with an endothelial device coverage observed as early as 30 days after implantation and complete after 3 to 6 months. Research perspectives may evaluate both animal models and in-vitro studies in parallel with a view to clarify the endothelialisation process using human endothelial cells through in-vitro experiments. Self-sensing device for detecting the presence of endothelial cells on the surface of intracardiac occluders and high-resolution imaging techniques that could non-invasively assess the complete endothelialisation of a device would also be promising tools which would need large animal models studies before their clinical application. PMID- 30305959 TI - Retrospective Comparison of 27-Gauge and 25-Gauge Microincision Vitrectomy Surgery with Silicone Oil for the Treatment of Primary Rhegmatogenous Retinal Detachment. AB - Aim: To retrospectively compare the safety and effectiveness of 27-gauge (27G) microincision vitrectomy surgery (MIVS) with 25-guage (25G) MIVS for the treatment of primary rhegmatogenous retinal detachment (RRD) with silicone oil tamponade. Methods: Ninety-two patients with RRD who underwent MIVS from May 1, 2015, to June 30, 2017, were included in this study. Fifty-eight eyes underwent 25G MIVS and 34 eyes underwent 27G MIVS. We analyzed the characteristics of the patients, surgical time, main clinical outcomes, and rate of complications. Results: The mean surgical time was 56.7 +/- 35.9 min for the 25G MIVS and 55.7 +/- 36.1 min for the 27G MIVS, and there was no significant difference (P=0.894) between the two groups. The primary anatomical success rate after a single operation was 94.8% for 25G MIVS and 91.2% for 27G MIVS (P=0.666). Baseline and final visit best-corrected visual acuity (BCVA) were 1.9 +/- 1.1 and 1.0 +/- 0.8 in the 25G group, and 1.7 +/- 1.0 and 1.1 +/- 0.8 in the 27G group. Last visit BCVA increased significantly in both groups (P < 0.001). However, there were no significant differences in terms of visual improvement ratio (>0.2 logMAR) between the two groups (P=0.173). No severe intraoperative complication was observed. Iatrogenic retinal breaks occurred in 2 eyes (3.4%) in the 25G group and 1 eye (2.9%) in the 27G group during the peripheral vitreous base shaving. The transient ocular hypertension (>25 mmHg) within postoperative week 1 was 25.9% in the 25G group and 11.8% in the 27G group (P=0.120). Conclusions: This study found no significant anatomical or functional difference between 27G and 25G MIVS in the treatment of primary RRD. Therefore, 27G vitrectomy appears to be a safe and effective surgery for the treatment of primary RRD. PMID- 30305958 TI - Vascular Endothelial Growth Factor (VEGF) Serological and Lacrimal Signaling in Patients Affected by Vernal Keratoconjunctivitis (VKC). AB - Background: Vernal keratoconjunctivitis (VKC) is a rare inflammatory disease involving the ocular surface, with seasonally exacerbated symptoms. Both type-1 and type-4 hypersensitivity reactions play a role in the development of VKC. Purpose: The aim of the present study was to assess the presence and evaluate the concentration of the vascular endothelial growth factor (VEGF) in tear and blood samples from patients with VKC, during the acute phase, based on the histopathological vasculostromal structure of the tarsal papillae. Methods: Two groups of children aged between 6 and 16 years of life were enrolled: 21 patients (16 males, 76%) affected by VKC, tarsal or mixed form, and 13 healthy children (5 males, 38%) used as controls. Blood and tear samples were obtained from all patients, in order to specifically assess the presence of VEGF. Statistical analyses were performed with one-way ANOVA, followed by post hoc comparisons with the Bonferroni tests. Pearson's correlation was chosen as statistical analysis to assess the relationship between the expression levels of VEGF in tears and blood and the clinical parameters measured. Results: Comparing the 2 groups for VEGF concentration, a statistically significant difference was found in tear samples: the mean value was 12.13 pg/mL (+/-5.54 SD) in the patient group and 7 pg/ml (+/ 4.76 SD) in controls (p < 0.05). However, no statistically significant difference was found when comparing VEGF concentration in blood samples (p > 0.05), with a mean value of 45.17 pg/mL (+/-18.67 SD) in VKC patients and 38.08 pg/mL (+/-19.43 SD) in controls. Conclusions: This pilot study highlights the importance of lacrimal and vascular inflammatory biomarkers that can be detected in VKC patients during the acute phase, but not in healthy children. The small group of patients warrants additional studies on a larger sample, not only to further investigate the role of VEGF but also to evaluate the angiogenic biomarkers before and after topical treatment. PMID- 30305960 TI - The Effect of Strabismus Muscle Surgery on Corneal Biomechanics. AB - Purpose: Studying the early effect of different extraocular muscle (EOM) surgeries on corneal biomechanics. Subjects and methods: This is a prospective, nonrandomized, interventional study, in which 42 eyes of 29 candidates for EOM surgery for strabismus correction at Cairo university hospitals, aged 14-37 years, were recruited. All participants had measuring of the visual acuity, refraction (spherical equivalent (SE)), assessment of the EOM motility and muscle balance, sensory evaluation, fundus examination, and assessing the ocular biomechanics using the Ocular response analyzer (ORA, Reichert, INC., Depew, NY) noting the corneal hysteresis (CH) and corneal resistance factor (CRF) preoperatively. Same patients were reassessed using ORA 4 weeks postoperatively following a different standard EOM surgery (recti weakening/strengthening and inferior oblique weakening either (graded recession) according to the surgical indication, and ?CH and ?CRF were calculated, each is the preoperative - the postoperative value. Results: ?CH and ?CRF = -0.78 +/- 1.56 and -0.72 +/- 2.15, respectively, and a highly significant difference was found between each of the pre- and postoperative CH and CRF (p < 0.001). 18 eyes had single EOM surgery, while 24 had multiple (2 or 3) EOM surgery; ?CH in the single group = -1.28 +/- 1.5, and ?CH in the multiple group = 0.4 +/- 1.49 (p=0.07). 23 eyes had EOM weakening surgery, while 18 had combined weakening and strengthening EOM surgery: ?CH in the weakening group = -1.24 +/- 1.77 and ?CH in combined group = -0.26 +/- 1.07 (p=0.04). A nonsignificant difference was found for ?CRF (p=0.53). Conclusion: A different EOM surgery has an early tendency for increase of the postoperative CH specially for muscle weakening procedures (recti recession/inferior oblique muscle weakening). PMID- 30305961 TI - Nitrate-Rich Fruit and Vegetable Supplement Reduces Blood Pressure in Normotensive Healthy Young Males without Significantly Altering Flow-Mediated Vasodilation: A Randomized, Double-Blinded, Controlled Trial. AB - Nitric oxide (NO) is a primary vasodilatory factor released from endothelial cells of the peripheral vasculature. NO production is stimulated through enzymatic-dependent mechanisms via NO synthase and from dietary intake of nitrate containing foods or supplements. We evaluated the efficacy of a nitrate-rich fruit and vegetable liquid supplement (FVS, AMPED NOx, Isagenix International LLC) versus a juice low in nitrates (prune juice, PRU) on circulating nitrates/nitrites as well as cardiovascular parameters in 45 healthy normotensive men (18-40 y). Blood pressure, flow-mediated dilation (FMD), and plasma nitrates and nitrites were measured at baseline and after two weeks of supplementation (2 oz/d). Subjects also completed questionnaires on sleep quality and mood since these measures have been associated with endothelial function. In contrast to PRU, FVS significantly increased plasma nitrates and nitrites (+67%, p < 0.001) and decreased diastolic blood pressure (-9%, p=0.029) after two weeks. The change in FMD for FVS supplementation versus PRU supplementation was not significant (+2% vs. -9%, respectively, p=0.145). Changes in sleep quality or total mood state did not differ between groups after the 2-week study. Thus, the nitrate rich FVS supplement increased plasma NO and reduced diastolic blood pressure in young normotensive men, but increased plasma NO was not associated with improvements in FMD, mood, or sleep. This trial is registered with ClinicalTrials.gov NCT03486145. PMID- 30305963 TI - Oral Rehabilitation of Oral Cancer Patients Using Zygomatic Implant-Supported Maxillary Prostheses with Magnetic Attachment: Three Case Reports. AB - Maxillectomy for malignant tumor often results in a maxillary defect and serious oral dysfunction. A prosthesis is usually provided for postoperative oral rehabilitation of such patients with maxillary defects. However, the further the resected region extends, the less stable the prosthesis becomes, due to insufficient bone and tooth support. Therefore, in many cases, conventional resection dentures may not be adequate to restore the oral function. Effective utilization of dental and zygomatic implants may help to restore oral function in patients with severe maxillary defects. This clinical report describes the management of three patients with severe maxillary defects following cancer ablative surgery who were rehabilitated using maxillary prostheses with magnetic attachments supported by dental and zygomatic implants. Occlusal reconstruction was performed with removable prostheses supported with two or four implants and magnetic attachment. The oral function was evaluated before and after prosthodontic treatment with implants using the Oral Health Impact Profile (OHIP 14) and functional chewing score. Results indicated improvement in all cases. These findings show that quality of life (QOL) and oral function were improved. PMID- 30305962 TI - Prevalence and Risk Factors for Depression among Caregivers of Alzheimer's Disease Patients in Saudi Arabia. AB - Objectives: To identify prevalence and risk factors of depression among caregivers of Alzheimer' disease (AD) patients. Methods: In a cross-sectional study, 110 caregivers of AD patients participated in this study (51 males and 59 females). Patients data were obtained from patients' records at Aseer Central Hospital. Depression among caregivers was assessed by using the Hamilton Rating Scale for Depression. Results: The age of caregivers ranged from 17 to 85 years (Mean+/-SD: 41.1+/-14.0 years). Prevalence of depression among caregivers was 70%. Caregivers were mainly sons/daughters (69.1%) or spouses (11.8%). A total of 33 caregivers (30%) had mild depression while 44 (40%) had moderate depression. Prevalence of depression was significantly higher among caregivers of AD patients who were exposed to repeated falling down (p=0.003), but did not differ significantly among caregivers who were exposed to repeated pneumonia or getting lost. Caregivers' scores of depression positively correlated with duration of caregivers' daily stay with AD patients (r=0.272, p=0.004), but did not correlate significantly with either caregivers' age or patients' age. Moreover, caregivers' depression did not differ significantly according to their marital status, educational status, employment status, or monthly income. Conclusions: Prevalence of depression among AD caregiver is high. Risk factors for depression include patients' exposure to repeated falls and prolonged stay with patients. Therefore, psychiatric care should be provided to caregivers, home safety should be maintained to avoid falls, and several persons should interchangeably provide care to AD patients. PMID- 30305964 TI - Unexpected Complication Ten Years after Initial Treatment: Long-Term Report and Fate of a Maxillary Premolar Rehabilitation. AB - Full-coverage restorations represent a well-known rehabilitation strategy for compromised posterior teeth; in the last years, new ceramic materials like zirconia have been introduced and widely adopted for the prosthetic management of molar and premolar areas. A long-term follow-up of a maxillary premolar rehabilitation using a veneered zirconia crown is presented; after ten years of uneventful clinical service of the tooth-restoration complex, a serious complication-namely, a vertical root fracture (VRF)-occurred. An extended time lapse (9 years) between the end of restorative procedures and development of symptoms due to VRF has been observed. On the other hand, a complete functional and esthetic integrity of the zirconia crown (without chippings or crack development) is documented along the follow-up period. Due to periodontal breakdown and severity of fracture, the premolar was extracted. The illustrations of our late failure, aetiological factors, and available data on the literature regarding VRF are addressed. Patients and clinicians should be aware of potential occurrences of some long-term, serious complications when dealing with previously treated and/or structurally weakened teeth. The development of a VRF might be unexpected and might occur many years after the end of tooth rehabilitation, despite adoption of contemporary restorative protocols and techniques. PMID- 30305965 TI - Two Cases of Catastrophic AAA Rupture in Young Women with Systemic Lupus Erythematosus. AB - We present two cases of young women with a past medical history significant for systemic lupus erythematosus (SLE), who presented to the Emergency Department with a ruptured abdominal aortic aneurysm (AAA). These cases are of particular interest because the patients did not fit the typical demographic for patients who present with a ruptured AAA. Based on these cases and a review of the relevant literature, ED providers should maintain a higher index of suspicion for AAA rupture in patients with autoimmune diseases, especially SLE. PMID- 30305966 TI - Simultaneous Occurrence of Rosai-Dorfman Disease and Nodal Marginal Zone Lymphoma in a Patient with Sjogren's Syndrome. AB - We present an exceptionally rare case of co-occurrence of Rosai-Dorfman disease (RDD) and nodal marginal zone lymphoma (NMZL) in a 60-year-old Caucasian female with a 20-year course of Sjogren's syndrome (SS). In response to treatment for lymphoma, the patient presented a short positive response, followed by a rapid progression of the disease accompanied by the development of the peripheral facial nerve palsy. We failed to detect Epstein-Barr virus (EBV) in the NMZL/RDD sample by EBV-encoded RNA (EBER) in situ hybridization but identified genomic DNA of EBV by polymerase chain reaction. A second biopsy revealed EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified. The identical clonal immunoglobulin heavy chain gene rearrangements in the NMZL and DLBCL pointed to their clonal relationship. Though the role of EBV in the pathogenesis of some lymphomas is well-known, there have been only few cases of EBV-induced transformation of low-grade B-cell lymphoma into high-grade lymphoma and no cases of a patient with an NMZL background. To our knowledge, this is the first report of a concomitant occurrence of RDD and NMZL in a SS patient. PMID- 30305967 TI - Successful Antimicrobial Treatment of Phlegmonous Gastritis: A Case Report and Literature Review. AB - Phlegmonous gastritis is an uncommon acute bacterial infection of the stomach that carries a fatal prognosis in spite of the advent of antibiotics. A high index of suspicion is required in patients with risk factors. An immunocompromised state is identified as one of the most important risk factors. We hereby report a case of successful antimicrobial treatment of phlegmonous gastritis in a patient who was receiving intensive chemotherapy for acute myelogenous leukemia. We have also carried out a review of literature over the past ten years. Streptococcus pyogenes is identified as the most common causative organism, and patient presentation is usually nonspecific. Conservative treatment with prompt institution of antibiotics can lead to rapid resolution in the majority of patients. PMID- 30305968 TI - A Rare Case of Burkholderia cepacia Complex Septic Arthritis. AB - Bacteria of the Burkholderia cepacia complex have rarely been reported to cause septic arthritis. Cases have been reported in patients who were immunocompromised, at extremes of age or who had history of steroid injection or penetrating trauma. A 67-year-old man with a history of opioid use disorder, osteoarthritis, and gout but no known immunocompromise was admitted to hospital with pain and swelling of his right knee. Cultures of synovial fluid and urine grew Burkholderia cepacia complex. Microscopy of synovial fluid also identified intracellular calcium pyrophosphate crystals. The patient's symptoms improved with joint irrigation and debridement and prolonged antimicrobial therapy. This case highlights the importance of diagnostic aspiration of an acutely inflamed joint to obtain a specific etiological diagnosis. PMID- 30305969 TI - Remote Cerebellar Haemorrhage: A Potential Iatrogenic Complication of Spinal Surgery. AB - We report the case of a 51-year-old man with no significant past medical history, who underwent elective revision spinal surgery and subsequently developed intracranial hypotension, remote cerebellar haemorrhage (RCH), and mild hydrocephalus on the fourth postoperative day. Remote cerebellar haemorrhage is a known complication of supratentorial surgery. This iatrogenic phenomenon may also occur following spinal surgery, due to dural tearing and rapid cerebral spinal fluid (CSF) leakage, resulting in intracranial hypotension and cerebellar haemorrhage. This complication may result in severe permanent neurologic sequelae; hence, it is of pertinence to diagnose and manage it rapidly in order to optimise patient outcome. PMID- 30305970 TI - Bilateral Hypoglossal Nerve Palsy due to Brainstem Infarction: A Rare Presentation of Presumed Pyogenic Meningitis. AB - Background: Cranial nerve palsies are well-known complications of basal meningitis, especially in patients with tuberculous meningitis. However, a minority of bacterial meningitis gets complicated with cranial nerve palsies. Although cerebral infarctions are known to occur with acute bacterial meningitis, infarctions occurring in the brainstem are infrequently described. Case Presentation: We report a 46-year-old healthy female who presented with dysarthria with fever, headache, and vomiting and was diagnosed to have acute pyogenic meningitis complicated with a brainstem infarction resulting in bilateral hypoglossal palsy. Her MRI revealed an infarction in the lower part of the medulla oblongata, probably involving the bilateral hypoglossal nuclei. Conclusion: Isolated bilateral hypoglossal nerve palsy is an extremely rare cranial nerve palsy, secondary to pyogenic meningitis. To our knowledge, this should be the first reported case of isolated bilateral hypoglossal nerve palsy due to a brainstem infarct in the background of pyogenic meningitis. PMID- 30305971 TI - Recurrent Nausea and Vomiting in a Pregnant Woman with Chronic Marijuana Use. AB - Background: Cannabinoid hyperemesis syndrome is a condition characterized by chronic cannabis use and cyclic episodes of nausea, vomiting, and abdominal pain, relieved by compulsive bathing. The syndrome is likely to be underdiagnosed in pregnant women due to its similarity with hyperemesis gravidarum in the presentation. Case: We report a 20-year-old pregnant woman with multiple admissions for recurrent nausea and vomiting who was observed to be taking frequent hot showers. Without other identifiable causes, she was diagnosed with cannabinoid hyperemesis syndrome and managed with antiemetics and abstinence. Conclusion: Abstinence from cannabis use is highly recommended in pregnant women due to its potential harm in fetal development and stimulation of intractable nausea and vomiting. Recognizing the symptoms and proper history taking prompt early diagnosis, allowing timely and adequate treatment. PMID- 30305972 TI - Rosai-Dorfman Disease: Self-Resolving Unilateral Lymphadenopathy and a Brief Review of Literature. AB - Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a disease of histiocytic proliferation with no known pathogenesis. This disease is defined by histological and cytological characteristics, including emperipolesis and positive S100 and CD68 markers. Although the disease typically presents clinically with massive bilateral lymphadenopathy due to sinus expansion from excessive histiocytosis, only unilateral lymphadenopathy was observed in this patient. The case involves a 40 year-old Caucasian male from the Netherlands presenting with unilateral lymphadenopathy suspicious for malignancy. Subsequent histological and laboratory testing led to the rare diagnosis of RDD. The lymphadenopathy resolved spontaneously over the course of several weeks following the initial presentation. Rosai-Dorfman disease reportedly has a benign prognosis with approximately 20% of patients experiencing spontaneous disease resolution (as was the case for this patient) with 70% experiencing chronic symptoms that may last years but not require intervention. We therefore advocate observation as a mainstay of treatment for most cases of this rare disease with intervention only being pursued in symptomatic cases. A review of recent literature regarding pathogenesis, epidemiology, diagnostic factors, prognosis, and treatment is provided and discussed. PMID- 30305973 TI - Periprosthetic Fracture through a Unicortical Tracking Pin Site after Computer Navigated Total Knee Replacement. AB - A rare complication from computer-navigated total knee arthroplasty is a fracture through the insertion site of a tracking pin. These pins are inserted across the femoral and tibial shafts either bicortically, transcortically, or unicortically and have a reported fracture incidence of 1.38%, with all published cases occurring after bicortical pin placement. In this case, a 60-year-old female suffered a femoral shaft fracture through a unicortically inserted computer navigation tracking pin 6 weeks after total knee arthroplasty. Her fracture was successfully fixated with an intramedullary nail with retention of the knee prosthesis. This case is important as it records the risk for a postoperative fracture through a unicortically inserted computer navigation pin. PMID- 30305974 TI - IgG4-Related Sclerosing Cholangitis Involving the Intrahepatic Bile Ducts Diagnosed with Liver Biopsy. AB - IgG4-related disease is characterized by lymphoplasmacytic inflammation and fibrosis, often leading to mass-forming lesions in different organs. When IgG4 related disease affects the bile ducts, it is called IgG4-related sclerosing cholangitis. A 74-year-old male complained of dysphagia and abdominal pain. Endoscopic retrograde cholangiography and magnetic resonance cholangiography revealed bile duct changes suspicious of a bile duct carcinoma or cholangitis. Liver biopsy showed storiform fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, and a portal-based inflammatory nodule with expansion of a portal tract. Hot spots revealed 339 IgG4-positive cells per high power field (HPF) and an IgG4/IgG ratio of 72%. Eight months earlier, an inguinal lymph node had been removed, showing expanded interfollicular zones and increased plasma cells. Hot spots revealed 593 IgG4-positive cells and an IgG4/IgG ratio of 92%. The serum IgG4 of the patient was elevated nearly 10 times upper limit of normal. The diagnosis of IgG4-related sclerosing cholangitis associated with IgG4-related lymphadenopathy was made. There was good response to treatment with prednisolone and azathioprine. The differentiation of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis and bile duct carcinoma is often difficult. Liver biopsy only rarely contributes to this setting, but we describe and report in detail a case where liver biopsy showed a portal-based inflammatory nodule with the characteristic features of this disease. PMID- 30305975 TI - Concurrent Polycythemia of Undetermined Etiology and Smouldering Plasma Cell Myeloma. AB - The combination of polycythemia and plasma cell myeloma occurring concurrently is very rare and few cases have been reported in the literature. Further, the vast majority of these cases are cases of polycythemia vera and myeloma. Here, we present a case of polycythemia of undetermined etiology and myeloma. The patient is a 48-year-old Caucasian male who was originally diagnosed with polycythemia of undetermined etiology. Twelve years later, when a bone marrow biopsy was performed in an attempt to determine the etiology of the polycythemia, findings diagnostic of plasma cell myeloma were discovered. Subsequent serum studies were also consistent with a plasma cell neoplasm, while evaluation for end-organ damage was negative. A battery of genetic and biochemical tests ruled out various congenital polycythemias, leading to a final diagnosis of polycythemia of undetermined etiology and smouldering plasma cell myeloma. This case highlights that while being unusual, polycythemia and plasma cell myeloma can occur concurrently, and, in this report, we discuss both entities and potential mechanisms of the pathophysiology of the concurrent presentation. PMID- 30305976 TI - Systemic Lupus Erythematosus Presenting with Alveolar Hemorrhage. AB - Introduction: Diffuse alveolar hemorrhage is a rare presentation of systemic lupus erythematosus. Early diagnosis and appropriate treatment can improve outcome. Case Report: An 18-year-old male presented with hemoptysis and respiratory distress requiring orotracheal intubation. Laboratory tests showed positive anti-nuclear antibody and anti-dsDNA and low C3 and C4. Bronchoalveolar lavage became progressively hemorrhagic after each aliquot. He was treated with pulse methylprednisolone, cyclophosphamide, and plasma exchanges. Discussion: Alveolar hemorrhage is a rare initial presentation of lupus, with mortality rates reported at about 50%. Lupus should be considered in those presenting with alveolar hemorrhage since delay in therapy may cause a rapid deterioration of the patient. The diagnosis of SLE is illusive when DAH is the presenting symptom. Since early diagnosis and appropriate institution of treatment improve outcome, it is important to keep lupus in mind as an etiology of alveolar hemorrhage. Pulse methylprednisolone, cyclophosphamide, and plasmapheresis therapy resulted in rapid improvement of respiratory function in our patient. PMID- 30305977 TI - Necrotizing Fasciitis Resulting from an Anastomotic Leak after Colorectal Resection. AB - One of the most feared complications in colorectal surgery is an anastomotic leak (AL) following a colorectal resection. While various recommendations have been proposed to prevent this potentially fatal complication, anastomotic leaks still occur. We present a case of an AL resulting in a complicated and fatal outcome. This case demonstrates the importance of high clinical suspicion, early recognition, and immediate management. PMID- 30305978 TI - Serious Hypokalemia Associated with Abiraterone Acetate in Patients with Castration-Resistant Prostate Cancer. AB - Introduction: The treatment strategy for castration-resistant prostate cancer (CRPC) has changed with the approval of several new agents. In 2011, abiraterone acetate was approved for the treatment of metastatic CRPC; however abiraterone is known to cause mineralocorticoid excess syndrome characterized by hypokalemia, fluid retention, and hypertension. We experienced two cases of grade 4 hypokalemia associated with abiraterone treatment. Case Presentation: Case 1: a 71-year-old male with metastatic CRPC presented with convulsive seizures two weeks after receiving abiraterone plus prednisone. The serum potassium level was 2.1mEq/l. We determined that convulsive seizure was caused by hypokalemia associated with abiraterone. Case 2: a 68-year-old male with metastatic CRPC presented with severe lethargy one month after receiving abiraterone plus prednisone. The serum potassium level was 1.7mEq/l and we concluded that severe lethargy was caused by hypokalemia associated with abiraterone. They were treated with potassium supplementation and increased prednisone following withdrawal of abiraterone. Discussion: The two patients had been on glucocorticoid therapy before abiraterone therapy. Prolonged administration of exogenous glucocorticoid can lead adrenocortical insufficiency and consequently reduce endogenous glucocorticoid production. This situation may increase the risk of abiraterone induced mineralocorticoid excess. To reduce the risk of abiraterone-induced hypokalemia, evaluation of adrenocortical insufficiency is required. PMID- 30305979 TI - Augmentation of a Locking Plate System Using Bioactive Bone Cement-Experiment in a Proximal Humeral Fracture Model. AB - Introduction: The purpose of this study was to test whether local filling of a novel strontium-containing hydroxyapatite (Sr-HA) bone cement can augment the fixation of a locking plate system in a cadaveric proximal humeral facture model. Materials and Methods: Twelve pairs of formalin-treated cadaveric humeri were used. One side in each pair was for cemented group, while the other side was for the control group. The bone mineral density (BMD) of the samples was tested. A 3 part facture model was created and then reduced and fixed by a locking plate system. In the cemented group, the most proximal 4 screw holes were filled with 0.5 mL bone cement. In the control group, the screw holes were not filled by cement. Locking screws were inserted in a standard manner before the cement hardened. X-ray was taken before all the specimens being subjected to mechanical study, in which 6 pairs were used for axial loading (varus bending) test, while other 6 pairs were used for axial rotational test. Results: There is no difference in BMD between the cemented side and the control side. The X-ray shows that the implant is in position. Cement filling was noted in the most proximal 4 screws in the cemented group. Better mechanical outcome was seen in the cemented groups, in terms of less maximal displacement per cycle and higher failure point and stiffness in varus bending test. However, no difference was found between the cemented group and the control group in the axial rotation test. Discussion: In similarity with the previous studies, our results showed better mechanical results in the cemented group. However, due to the limitations (e.g. sample size, fracture model, testing protocol, etc), we still cannot directly extrapolate current mechanical results to clinical practice at the present moment. Furthermore, it is still unknown whether better primary outcome may lead to better long-term results, even though the local release of strontium may enhance the local bone formation. Conclusion: The local filling of Sr-HA bone cement augments the fixation of the locking plate system in current proximal humeral fracture model. PMID- 30305980 TI - Randomized Trials of Nasal Patency and Dermal Tolerability With External Nasal Dilators in Healthy Volunteers. AB - Background: External nasal dilator strips are used as nonpharmacological therapy to reduce snoring and daytime sleepiness. In a product improvement initiative, a marketed strip (BRNS) and 2 prototype nasal strips were evaluated. Objective: To compare the nasal patency and multiple-use dermal tolerability of the BRNS and prototype nasal strips using both objective and subject-reported outcome measures. Methods: Two studies were conducted separately in healthy volunteers >=18 years of age. A single-day nasal patency randomized crossover study assessed minimal cross-sectional area (MCA; second restriction) and nasal volume (using acoustic rhinometry); nasal inspiratory flow and resistance (using posterior rhinomanometry); and subject-reported evaluations of the BRNS compared with the butterfly strip and teardrop strip prototypes. A single-center, randomized, controlled, parallel-group, evaluator-blinded study assessed dermal tolerability of the BRNS and the butterfly strip over 7 consecutive nights of use, using the Dermal Response Scale (DRS) and subject-reported comfort and ease of removal. Results: In the Patency study (N = 50), all 3 strips demonstrated significant improvement from baseline in MCA, nasal volume, and nasal flow parameters (resistance and peak flow). The prototype strips demonstrated significantly more improvement in nasal volume than the BRNS, and the butterfly strip showed significantly more improvement in MCA than the BRNS; all strips were similar with respect to nasal flow and subject-reported nasal breathing outcomes. In the Dermal Tolerability study (N = 82), all subjects scored 0 (no evidence of irritation) on the DRS at all 7 morning assessments; the BRNS was numerically, but not significantly, superior to the butterfly strip on subject-reported outcomes. Conclusion: The Patency study demonstrated significant improvement from baseline in nasal dimensions and flow for all 3 evaluated strips; between-strip differences were confined to nasal dimensions. Both the BRNS and butterfly strip were generally well tolerated, with no evidence of dermal response over 7 consecutive nights of use.ClinicalTrials.gov identifiers: NCT01105949 and NCT01495494. PMID- 30305981 TI - Hand Rehabilitation Treatment for Charcot-Marie-Tooth Disease: An Open Label Pilot Study. AB - Objective: Charcot-Marie-Tooth neuropathy affects mainly and early the lower limbs, but hands deformities are a relevant problem, which involves the quality of life of the patients. Unfortunately, there are few studies about the evaluation of the upper limbs and very rare works about the rehabilitation. A treatment study at the moment is missing and it is important to search rehabilitation exercises to improve the dexterity and the quality of life of the patients. Methods: We recruited 9 patients with clinical and genetic diagnosis of CMT and we proposed a rehabilitation protocol which includes muscle recruitment, stretching and proprioceptive exercises for the hand with the duration of 4 weeks (two sessions for week). We evaluated the patients before and one week after the treatment with Thumb Opposition Test, Sollerman Hand Function Scale, dynamometry (tripod pinch and hand grip). Results: The rehabilitation protocol has been well tolerated and there were not dropouts. We did not observe any worsening in every scale we used. Every parameter tested showed an improvement especially in the right/dominant hand. Conclusion: This study demonstrates that this three phases treatment is well tolerated by patients, it is not detrimental for the hands status and perfectly reproducible by professionals. Moreover, this could be the basis for future randomized single blind projects. PMID- 30305982 TI - Fetal Congenital Peripheral Bronchial Atresia Diagnosed by Magnetic Resonance Imaging: Two Case Reports. AB - Two types of congenital bronchial atresia (proximal and peripheral) have been classified. We report two cases of peripheral bronchial atresia diagnosed by prenatal ultrasonography (US) and magnetic resonance imaging (MRI). Evaluating an enlarged lung mass that is homogeneously hyperechoic on US and hyperintense on T2 weighted MRI can help in determining whether bronchial atresia is present. Proximal type is suggested when a dilated main bronchus is observed as a tubule structure of an involved lung hilum. In our cases, T2-weighted MRI revealed homogeneously hyperintense lung lesion with decreased signal intensity of adjacent lobe, flattening diaphragm, and mediastinal shift. Dilatation of the main bronchus was not observed and the opposite lung was normal in appearance. These findings were explained by secondary compression due to enlargement of the involved lung. The preservation of vascular structure and the retained normal shape, though enlarged, in the affected lobe were observed, which demonstrated undisrupted pulmonary architecture of the lobe. Thus, congenital cystic adenomatoid malformation was excluded because pulmonary architecture was relatively preserved. Finally, presumed diagnoses of the peripheral bronchial atresia were made and confirmed by postnatal chest computed tomography. PMID- 30305983 TI - Visual Estimation of Force Applied During Simulated Deliveries Complicated by Shoulder Dystocia. AB - Background Shoulder dystocia occurs when the fetal head delivers, but the shoulder is lodged behind the pubic symphysis. Training for these emergency deliveries is not optimized, and litigation can occur around a shoulder dystocia delivery. Objective Evaluate the ability of an outside observer to visually estimate the amount of traction applied to the fetal head during simulated deliveries complicated by shoulder dystocia. Study Design Simulated deliveries with an objective measurement of traction were randomly organized for estimation of traction applied. Videos show providers applying a "normal" (75 N) and "excessive" (150 N) amount of force in both a "calm" and "stressed" delivery. Results Fifty participants rated the amount of force applied. Observers estimated traction, on a scale from 1 to 5, higher in the 150-N deliveries as compared with 75-N deliveries ("calm" environment: 3.1 vs. 2.8, p < 0.001; and "stressed" environment: 3.2 vs. 2.8, p < 0.001). Only 15% of observers rated force "above average" or "excessive" in a "calm" environment, as opposed to 30% of observers in the "stressed" environment. Conclusion Observers are not able to determine when "excessive force" is used and are twice as likely to overestimate the force applied to a fetal head when an average amount of force is used and the delivery environment is stressful. Precis Observers are unable to determine when excessive traction is applied to the fetal head during simulated deliveries complicated by shoulder dystocia. PMID- 30305984 TI - Determinants of Infant Mortality in Southeast Nigeria: Results from the Healthy Beginning Initiative, 2013-2014. AB - Background: Neonatal mortality due to preventable factors occurs at high rates throughout sub-Saharan Africa. Community-based interventions increase opportunities for prenatal screening and access to antenatal care services (ANC) services. The Healthy Beginning Initiative (HBI) provided congregation-based prenatal screening and health counseling for 3,047 women in Enugu State. The purpose of this study was to identify determinants for infant mortality among this cohort. Methods: This was a prospective cohort study of post-delivery outcomes at 40 churches in Enugu State, Nigeria between 2013 and 2014. Risk factors for infant mortality were assessed using chi square, odds ratios, and multiple logistic regression. Results: There were 2,436 live births from the 2,379 women who delivered (55 sets of twins and one set of triplets), and 99 cases of neonatal/early postneonatal mortality. The neonatal mortality rate was 40.6 per 1,000 live births. Risk factors associated with neonatal mortality were lack of access to ANC services [OR= 8.81], maternal mortality [OR= 15.28], caesarian section [OR= 2.47], syphilis infection [OR= 6.46], HIV-positive status [OR= 3.87], and preterm birth [OR= 14.14]. Conclusions and Global Health Implications: These results signify that culturally-acceptable community-based interventions targeted to increase access to ANC services, post-delivery services for preterm births, and HIV and syphilis screening for expectant mothers are needed to reduce infant mortality in resource-limited settings. PMID- 30305985 TI - Nutritional Assessment and Maternal Perception of Toddler Body Size using Toddler Silhouette Scale in Nigeria a Developing Country. AB - Background and Objectives: The toddler silhouettes scales have been validated in the caucascian population in developing countries but in the African population, the use of these scales is yet to be evaluated. The aim of this study was to determine the perception of mothers on the body size of toddlers using a validated scale in an African population. Methods: This was a cross sectional study of 241 mothers and their toddlers. Study participants were recruited from the immunization and pediatric clinics. The mothers' perceptions of the body sizes of toddlers and their own child was determined with the use of a validated 7-scale toddler silhouette. Each mother also assessed their own child with the scale. Each child's anthropometry was documented. Results: Majority of the mothers were able to correctly classify the underweight (95.0%) and overweight toddler silhouettes (95.7%). However, 30% of the respondents misclassified Silhouette 6 (overweight silhouette) as normal and 48.2% of the respondents misclassified a normal silhouette as underweight. The overall maternal accuracy in assessing their toddler size was 41.1%. There was a significant relationship between maternal accuracy and the maternal educational status, tribe, and toddler size. Conclusions and Global Health implications: Toddler silhouette scales is a quick way of assessing the body size of children and could be of significant use in the developing countries. There is a need for caregivers to accurately assess the body size of their children as this will significantly influence the food mothers will give their children and thus children's eventual growth and development. PMID- 30305986 TI - Acceptance of Cervical Cancer Screening and its Correlates Among Women of a Peri Urban High-Density Residential Area in Ndola, Zambia. AB - Background: Zambia has one of the highest cervical cancer incidence and mortality rates in the world. Cervical cancer screening leads to reduction in the incidence of invasive disease. The objectives of the study were to determine the level of acceptance of cervical cancer screening and its correlates among women of a peri urban high-density residential area in Ndola, Zambia. Methods: A cross sectional study was conducted. With a population size of 12,000 women in reproductive age and using an expected frequency of 50 + 5% and at 95% confidence interval, the required sample size was 372. A stratified sampling method was used to select participants. Independent factors that were associated with the outcome were established using multi-variate logistic regression. Adjusted odds ratios and their 95% confidence intervals are reported. Results: In total, 355 out of 372 questionnaires were administered, achieving a response rate of 95.4%. Out of 355 participants, 9 (2.5%) had ever been screened for cervical cancer. In bivariate analyses, factors associated with screened were knowledge of body part affected, screening as a prevention tool, whether cervical cancer was curable in its early stages or not, awareness of cervical cancer screening, knowledge on frequency of screening and cervical cancer screening causing harm. However, in multivariate analysis, participants who knew that cervical cancer screening prevented cervical cancer were 3.58 (95% CI [1.49, 8.64]) times more likely to have been screened than those who did not have the knowledge. Participants who knew that cervical cancer is curable were 2.76 (95% CI [1.92, 8.31]) times more likely to have been screened than those who did not have the knowledge. Conclusion and Global Health Implications: The uptake of screening was low. Interventions should be designed to increase uptake of screening for cervical cancer by considering factors that have been identified in the current study that are independently associated with cervical cancer screening among this population. PMID- 30305987 TI - The Tentorium Cerebelli: A Comprehensive Review Including Its Anatomy, Embryology, and Surgical Techniques. AB - The tentorium cerebelli functions as a partition, dispelling the burden of weight from supratentorial structures upon inferior brain matter. Clinicians and neurosurgeons, when assessing pathological findings, should have knowledge regarding the tentorium cerebelli anatomy. This work of literature is a comprehensive review of the tentorium cerebelli, including its anatomy, embryology, and clinical and surgical implications. The evolutionary pattern demonstrates sequential stages to higher mammalian lineage. An understanding of the complexity of the neurovascular structures and the anatomy of the tentorium cerebelli is crucial for surgical procedures by neurosurgeons. PMID- 30305988 TI - The Use of Vedolizumab in Patients with Concomitant Cirrhosis and Crohn's Disease. AB - Vedolizumab is a humanized monoclonal alpha4beta7 integrin antibody used in patients with Crohn's disease (CD) and ulcerative colitis (UC). Limited data are available on the use of vedolizumab in patients with concurrent cirrhosis and inflammatory bowel disease (IBD). Patients with cirrhosis are unique, as they have a predilection for developing opportunistic infections and malignancies. Additionally, it is not known if vedolizumab alters the natural course of cirrhosis. We report our experience in three patients with concomitant CD and cirrhosis, who were treated with vedolizumab. In our limited cohort, all the three patients tolerated vedolizumab well. None of them experienced significant infectious complications, nor did any have decompensated cirrhosis. Our limited series suggest that vedolizumab is well tolerated in patients with compensated cirrhosis. PMID- 30305989 TI - Subtrochanteric Fracture of the Femur Accompanying Pre-existing Ipsilateral Osteoarthritis of the Hip Successfully Treated with Intramedullary Nailing in the Lateral Decubitus Position: A Case Report. AB - A subtrochanteric fracture of the femur accompanying pre-existing osteoarthritis of the ipsilateral hip is rare. A deformity of the hip joint complicates the insertion of the intramedullary nail and varus malreduction is anticipated when surgery is performed on a fracture table with a perineal post. We report a successful case of intramedullary fixation performed in the lateral decubitus position and discuss the importance of avoiding varus and the superiority of the lateral position in surgery. PMID- 30305990 TI - Biotransformation of phenol in synthetic wastewater using the functionalized magnetic nano-biocatalyst particles carrying tyrosinase. AB - Low conversion efficiency and long-processing time are some of the major problems associated with the use of biocatalysts in industrial processes. In this study, modified magnetic iron oxide nanoparticles bearing tyrosinase (tyrosinase-MNPs) were employed as a magnetic nano-biocatalyst to treat phenol-containing wastewater. Different factors affecting the phenol removal efficiency of the fabricated nano-biocatalyst such as catalyst dosage, pH, temperature, initial phenol concentration, and reusability were investigated. The results proved that the precise dosage of nano-biocatalyst was able to degrade phenol at the wide range of pHs and temperatures. The immobilized tyrosinase showed proper phenol degradation more than 70%, where the substrate with a high concentration of 2500 mg/L was subjected to phenol removal. The nano-biocatalyst was highly efficient and reusable, since it displayed phenol degradation yields of 100% after the third reuse cycle and about 58% after the seventh cycle. Moreover, the immobilized tyrosinase was able to degrade phenol dissolved in real water samples up to 78% after incubation for 60 min. It was also reusable at least seven cycles in the real water sample. The results proved the effectiveness and applicability of the fabricated nano-biocatalyst to treat phenol-containing wastewaters in a shorter time and higher efficiency even at high phenol concentration. The developed nano-biocatalyst can be promising for the micropollutants removal and an alternative for the catalysts used in traditional treatment processes. PMID- 30305991 TI - Anatomical and biochemical analyses reveal the mechanism of double-color formation in Paeonia suffruticosa 'Shima Nishiki'. AB - Paeonia suffruticosa 'Shima Nishiki' is a very precious double-color cultivar because of its distinctive and colorful flowers. However, our understanding of the underlying mechanisms of its double-color formation is limited. The present study investigated the soluble sugar content, cell sap pH value and anatomical structure, anthocyanin composition and content and expression patterns of genes related to anthocyanin biosynthesis in the red and pink petals of the 'Shima Nishiki' cultivar. Here, we found that soluble sugar content, cell sap pH and the shape of outer epidermal cells were not the key factors that determine double color formation. Five different anthocyanins were detected in both the red and pink petals, and the pelargonidin-3,5-di-O-glucoside (Pg3G5G) and pelargonidin-3 O-glucoside (Pg3G) contents in the red petals were significantly higher than those in the pink petals at every developmental stage. In addition, these gene expression patterns suggested that the significant differential expression of the dihydroflavonol 4-reductase gene (PsDFR) gene might play a key role in double color formation. These results will provide a valuable resource for further studies unraveling the underlying genetic mechanisms of double-color formation in P. suffruticosa 'Shima Nishiki'. PMID- 30305992 TI - Production of succinate by recombinant Escherichia coli using acetate as the sole carbon source. AB - Acetate is a potential low-cost carbon source that can be generated by biological and chemical processes. In this study, deletion of sdhAB encoding succinate dehydrogenase, iclR encoding the isocitrate lyase regulator, and maeB encoding the malic enzyme, and overexpression of acs encoding acetyl-CoA synthetase, gltA encoding citrate synthase, and acnB encoding aconitate hydratase in the wild-type Escherichia coli MG1655 strain yielded the recombinant E. coli strain WCY-7, which could synthesize succinate from acetate. After 48 h batch fermentation, this strain accumulated 11.23 mM succinate from 50 mM sodium acetate. This work indicates that microbial fermentation using acetate as the sole carbon source may be a suitable route to produce high yields of the valuable chemicals. PMID- 30305994 TI - Enzymatic detoxification of azo dyes by a multifarious Bacillus sp. strain MR-1/2 bearing plant growth-promoting characteristics. AB - This study was conducted to elucidate the inherent potential of Bacillus sp. MR 1/2, which was isolated from root zone of maize crop grown on a textile wastewater-irrigated soil. The isolated strain was identified through its ribosomal RNA sequence. Under in vitro conditions, the strain demonstrated its tolerance for high concentrations of various heavy metal ions as determined by minimum inhibitory concentration. Moreover, the strain MR-1/2 exhibited many important phytobeneficial traits such as inorganic P solubilization and 1 aminocyclopropane-1-carboxylate (ACC) deaminase ability even under high metal and salt stress. Results showed that the strain proficiently decolorizes various azo dye compounds, e.g., reactive black-5, reactive red-120, and direct blue-1 and congo red, in broth culture. The bioremediation potential of the strain MR-1/2 was further confirmed by analyzing the retrieved azoreductase gene sequence through bioinformatics tools, whereby a subsequent prediction revealed that the azoreductase enzyme activity was involved in decolorization process. When mung bean seeds were grown in pots under various concentrations of decolorized and non decolorized azo dye, the Bacillus sp. MR-1/2 not only alleviated the azo dye toxicity, but also increased the plant growth parameters. In conclusion, the strain MR-1/2 efficiently decolorized the azo dyes and helped in mung bean plant growth by alleviating azo dye toxicity. PMID- 30305993 TI - Complex gene response of herbicide-resistant Enterobacter strain NRS-1 under different glyphosate stresses. AB - Knowledge of biological evolution and genetic mechanisms is gained by studying the adaptation of bacteria to survive in adverse environmental conditions. In this regard, transcriptomic profiling of a glyphosate-tolerant Enterobacter strain NRS-1 was studied under four different treatments to investigate the gene regulatory system for glyphosate tolerance. A total of 83, 83, 60 and 74 genes were up-regulated and 108, 87, 178 and 117 genes down-regulated under 60-NPG, 110 NPG, NaCl (355 mM) and HCl (pH 4.46) stress treatments, respectively. Complex gene network was identified to be involved in regulating tolerance to glyphosate. This study revealed that NRS-1 has gained glyphosate tolerance at the cost of osmotic and acidic resistance. The 25 differentially expressed genes are reported to may have partly changed the function for providing resistance to glyphosate directly, among them genes metK, mtbK, fdnG and wzb that might detoxify/degrade the glyphosate. However, under 110-NPG condition, NRS-1 might have utilized economical and efficient ways by depressing its metabolism and activity to pass through this stress. Hence, the present study provides insights into the genes involved in glyphosate tolerance, which can be effectively utilized to engineer herbicide-resistant crop varieties after their proper validation to manage weed growth. PMID- 30305996 TI - Antimycobacterial potentials of quercetin and rutin against Mycobacterium tuberculosis H37Rv. AB - Quercetin and rutin, two flavonoids were examined for antimycobacterial activities against M. tuberculosis H37Rv (ATCC 27294). The quercetin exhibited (99.30 +/- 0.268%) in (LRP) assay at 200 ug/ml and 56.21 +/- 0.97% inhibition in (BMD) at 50 ug/ml, whereas rutin exhibited (90.40 +/- 0.68%) in LRP assay at 200 ug/ml and 56.10 +/- 0.67% inhibition in BMD at 50 ug/ml. The minimum inhibitory concentration (MIC) was found to be 6.25 ug ml-1 and 25 ug ml-1 respectively. The current investigation suggests that quercetin has better inhibitory activity than rutin. PMID- 30305997 TI - Effective bioremediation and toxicity assessment of tannery wastewaters treated with indigenous bacteria. AB - This study evaluated the bioremediation capacity of indigenous bacteria isolated from tannery sludge for two different tannery wastewaters collected from Kanpur and Chennai. To identify bacteria which can efficiently degrade a mixture of different pollutants, the isolates were grown in hazardous 100% tannery wastewaters. The reductions in toxicants such as chromium, sulphate, biochemical oxygen demand (BOD) and chemical oxygen demand (COD) of the wastewater were analysed post-bioremediation. Amongst the isolates, Citrobacter freundii was able to reduce the concentration of multiple toxicants such as chromium by 73% and sulphate was reduced by 68% bringing down the level much below the permissible limit stipulated by Bureau of Indian Standards (BIS). Notably, the organic load characterized by BOD and COD was also lowered by 86 and 80%, respectively. The indigenous isolates, not only bioremediated the Kanpur effluent but, also significantly detoxified the Chennai effluent having higher toxicant load. An interesting observation made during the study was better survival and growth along with the development of appendages of Artemia nauplii in the treated wastewaters which thus further confirmed reduction in toxicity of the effluents. The results thus demonstrate that the tested indigenous strains are promising for bioremediation of tannery wastewater and effectively improve the water quality for safe discharge. PMID- 30305995 TI - DREB2 (dehydration-responsive element-binding protein 2) type transcription factor in sorghum (Sorghum bicolor): genome-wide identification, characterization and expression profiles under cadmium and salt stresses. AB - Biotic and abiotic stresses negatively affect fitness, biomass production, and crop yield in plants. The dehydration-responsive element-binding proteins (DREB) are important transcription factors (TFs), and are induced by abiotic and biotic stresses. In this study, genome-wide identification, in silico sequence, and phylogenetic analyses and expression analyses of DREB2 genes under cadmium (Cd) and salt (NaCl) stresses in sorghum (Sorghum bicolor, Sb) were performed. Six putative SbDREB2 genes were identified in sorghum genome and all contained AP2 domain (PF00847). Nucleotide diversities in SbDREB2 genes were calculated as pi: 0.53 and theta: 0.39, respectively. While exon numbers of them were either one or two, length of SbDREB2 proteins ranged from 238 to 388 amino acid residues. Fifty six cis-acting regulatory elements, which are tissue specific, light, hormone, and stress responsive, were identified in the promotor regions of SbDREB2 genes. Analyses on digital expression data indicated that SbDREB2A and SbDREB2B are more expressed genes than other SbDREB genes in sorghum. Under Cd and NaCl stresses, expressions of SbDREB2 genes were induced at different levels. All SbDREB2 genes in root were up-regulated under salt stress. In case of Cd stress, SbDREB2D gene was particularly up-regulated in leaves and roots. Co-expression analyses revealed four of TFs in co-expression network, indicating that they have roles in transcriptional cascade. Furthermore, five miRNA target regions were identified for four SbDREB2 genes, indicating their roles in post-transcriptional regulation. The predicted 3D structure of SbDREB2 proteins showed some structural divergences and structure overlap between rice and sorghum varied at between 26.58 and 50%. Finally, obtained data could be used in breeding of stress tolerant plants, particularly genetically engineered DREB2 expressing plants. Findings in this study would also contribute to the understanding of DREB2 genes in plants, especially in sorghum. PMID- 30305998 TI - Growth, substrate consumption, and product formation kinetics of Phanerochaete chrysosporium and Schizophyllum commune mixed culture under solid-state fermentation of fruit peels. AB - Kinetic analysis of solid-state fermentation (SSF) of fruit peels with Phanerochaete chrysosporium and Schizophyllum commune mixed culture was studied in flask and 7 kg capacity reactor. Modified Monod kinetic model suggested by Haldane sufficiently described microbial growth with co-efficient of determination (R 2) reaching 0.908 at increased substrate concentration than the classical Monod model (R 2 = 0.932). Leudeking-Piret model adequately described product synthesis in non-growth-dependent manner (R 2 = 0.989), while substrate consumption by P. chrysosporium and S. commune fungal mixed culture was growth dependent (R 2 = 0.938). Hanes-Woolf model sufficiently represented alpha-amylase and cellulase enzymes synthesis (R 2 = 0.911 and 0.988); alpha-amylase had enzyme maximum velocity (V max) of 25.19 IU/gds/day and rate constant (K m) of 11.55 IU/gds/day, while cellulase enzyme had V max of 3.05 IU/gds/day and K m of 57.47 IU/gds/day. Product yield in the reactor increased to 32.65 mg/g/day compared with 28.15 mg/g/day in shake flask. 2.5 cm media thickness was adequate for product formation within a 6 day SSF in the tray reactor. PMID- 30305999 TI - Identification and characterization of the myeloid differentiation factor 88 gene in yellow catfish. AB - Myeloid differentiation factor 88 (MyD88) is an important adapter protein of the innate immune system, but it has never before been reported in yellow catfish (Pelteobagrus fulvidraco). In this study, we cloned and characterized the yellow catfish MyD88 gene. The gene was 1230 bp in length and contained an 876-bp open reading frame which encodes a polypeptide of 291 amino acid residues. The theoretical molecular mass and isoelectric point of this polypeptide were 33.4341 kDa and 5.17, respectively. Furthermore, bioinformatic and phylogenetic analyses grouped yellow catfish MyD88 with MyD88 of other fish. We found that the deduced amino acid sequence showed that the conserved N-terminal death domain and the C terminal typical Toll/interleukin-1 receptor domain were very similar to those of other fish. Moreover, reverse transcription PCR showed that yellow catfish MyD88 is ubiquitously expressed in all tissues examined, with highest expression levels observed in the spleen and lowest levels in the intestine. Importantly, MyD88 was shown to be significantly up-regulated in the intestines after 30-day dietary supplement of Clostridium butyricum. Collectively, these results indicate that yellow catfish MyD88 has a conserved structure and is probably an important component of innate immunity in yellow catfish. This study is the first to identify and characterize MyD88 in yellow catfish, thereby providing a reference for further research into the yellow catfish innate immune system. PMID- 30306000 TI - Differential expression of anthocyanin biosynthesis genes in Daucus carota callus culture in response to ammonium and potassium nitrate ratio in the culture medium. AB - Anthocyanins are major water-soluble and dynamic colouring plant pigment present in plant tissues with the high antioxidant properties. The role of ammonium and potassium nitrate in the culture medium on anthocyanin augmentation is probed thoroughly, but the mechanism of its biosynthesis continues to be unclear. Hence, the present study was undertaken to optimise nitrate ratio in the culture medium for anthocyanin augmentation and examination of its biosynthesis pathway in callus culture of Daucus carota. MS basal medium fortified with various ratio of NH4NO3:KNO3 was employed to find their impact on biomass, anthocyanin augmentation and the expression profile of anthocyanin biosynthesis genes in the callus culture. The data indicated that the highest anthocyanin content (9.30 +/- 0.25 mg/100 g FW) was seen in callus grown on the medium supplemented with 20.0 mM NH4NO3:37.6 mM KNO3 and the least was seen in the medium which contained 40.0 mM NH4NO3:18.8 mM KNO3 (2.74 +/- 0.27 mg/100 g FW). This indicates an optimal concentration of NH4NO3:KNO3 ratio is essential to produce a higher amount of anthocyanin in in vitro culture. Meanwhile, anthocyanin biosynthesis genes were differentially expressed as confirmed by qRT-PCR in the time interval of 5, 10, 15, 20 and 25 days. The transcript levels of nine anthocyanin biosynthesis genes were increased in the response of varying NH4NO3:KNO3 ratio in the medium. The transcript level of early genes PAL, 4CL, CHS and CHI increased by 19.5, 21.0, 16.2 and 9.98-fold, respectively, compared with control. In addition, late biosynthesis genes LDOX and UFGT resulted in the transcript level of 11.3 and 13.6-fold, respectively. PMID- 30306001 TI - Expression of defense-related genes in mung bean varieties in response to Trichoderma virens alone and in the presence of Rhizoctonia solani infection. AB - Web blight/wet root rot caused by Rhizoctonia solani is one of the major constraints for mung bean (Vigna radiata) production. Growing of resistant varieties and use of biocontrol agents are the feasible options available to manage the disease. The present study was conducted to determine the variation in the expression of various defense-related genes in susceptible and resistant mung bean varieties in response to biocontrol agent Trichoderma virens and R. solani interactions. The primers were designed using sequences of defense-related genes, namely PR 10, epoxide hydrolase (EH), catalase and calmodulin available in NCBI database and evaluated against cDNA obtained from both susceptible and resistant mung bean plants at 1-4 days post-inoculation (dpi) with the test pathogen R. solani and biocontrol agent T. virens using conventional PCR and qPCR analyses. R. solani inoculation upregulated the mean expression of PR 10 and calmodulin in susceptible and resistant varieties, respectively, whereas downregulated in the rest of the treatments. Quantitative PCR analysis showed that except catalase in the susceptible variety, which is downregulated, the expression of PR 10, EH, catalase and calmodulin was upregulated in both resistant and susceptible varieties in response to T. virens alone and in the presence of R. solani. In general, the expression of PR 10 and calmodulin was highest at 1 dpi whereas EH and catalase expression were maximum at 4 dpi. The application of T. virens suppressed the development of disease in the presence of R. solani in both susceptible and resistant varieties with more pronounced effect in resistant variety. Thus, the application of biocontrol agent T. virens upregulated the expression of defense-related genes and reduced disease development. PMID- 30306002 TI - Identification and genome analysis of Deinococcus actinosclerus SJTR1, a novel 17beta-estradiol degradation bacterium. AB - Biodegradation with microorganisms is considered as an efficient strategy to remove the environmental pollutants. In this work, Deinococcus actinosclerus SJTR1 isolated from the wastewater was confirmed with great degradation capability to 17beta-estradiol, one typical estrogen chemical. It could degrade nearly 90% of 17beta-estradiol (10 mg/L) in 5 days and transform it into estrone; its degradation kinetics fitted for the first-order kinetic equation. The whole genome sequence of D. actinosclerus SJTR1 was obtained and annotated, containing one chromosome (3,315,586 bp) and four plasmids (ranging from 17,267 bp to 460,244 bp). A total of 3913 CDSs and 73 RNA genes (including 12 rRNA genes, 50 tRNA genes, and 11 ncRNA genes) were identified in its whole genome sequence. On this basis, a series of potential genes involved in steroid metabolism and stress responses of D. actinosclerus SJTR1 were predicted. It is the first report of Deinococcus strain with the degradation capability to estrogens. This work could enrich the genome sources of the estrogen-degrading strains and promote the degradation mechanism study of 17beta-estradiol in bacteria. PMID- 30306003 TI - Comparative analysis of biodiesel produced by acidic transesterification of lipid extracted from oleaginous yeast Rhodosporidium toruloides. AB - This study investigated the potential of oleaginous yeast Rhodosporidium toruloides strain (ATCC20409) for the sustainable production of microbial lipids as biodiesel feedstock and other economically important fatty acids in comparison to algal or plant-based biodiesel. The strain exhibited high lipid content (76% of dry cell weight biomass) through consolidated bioprocessing which was transesterified to produce biodiesel. Physico-chemical properties of the biodiesel produced showed that they were in accordance with ASTM standards, although few parameters such as acid value, calorific value and free fatty acid value differed to some extent, as also reported in plant-based/microalgal biodiesel. Fatty acid methyl esters analysis of biodiesel showed 50.18% unsaturated fatty acid and 49.81% saturated fatty acid. Total content of (monounsaturated fatty acid) MUFA was higher than (polyunsaturated fatty acid) PUFA, being 44.36% and 2.69%, respectively. Considering the yield and cost, lipid extracted from R. toruloides may become a promising alternative feed in biodiesel production. PMID- 30306004 TI - Pseudogene product YqiG is important for pflB expression and biohydrogen production in Escherichia coli BW25113. AB - Pseudogenes in the Escherichia coli genome are assumed to be non-functional. In this study, Keio collection BW25113?yqiG and YqiG-producing strain (BW25113/pCA24N-YqiG) were used to evaluate the importance of pseudogene yqiG in hydrogen metabolism. Our results show pseudogene protein YqiG was identified as an essential protein in the production of biohydrogen from glucose. The mutant yqiG decreased biohydrogen production from 37 umol mg-1 protein to 6 umol mg-1 protein compared to the wild-type strain, and glucose consumption was reduced by 80%. Through transcriptional analysis, we found that the yqiG mutation represses pflB transcription tenfold; pflB encodes pyruvate-formate lyase, one of the key enzymes in the anaerobic metabolism of E. coli. Moreover, production of YqiG stimulated glycolysis and increased biohydrogen productivity 1.5-fold compared to that of the wild-type strain. Thus, YqiG is important for the central glycolysis reaction and is able to influence hydrogen metabolism activity in E. coli. PMID- 30306005 TI - Taxonomic diversity of bacteria from mangrove sediments of Goa: metagenomic and functional analysis. AB - The present study compared the taxonomic diversity and evaluated the functional attributes of the bacterial species from Mandovi and Zuari mangrove sediments, Goa, using paired-end amplicon sequencing of 16S rDNA and culture-based analyses, respectively. 16S rDNA sequencing revealed Proteobacteria, Firmicutes, and Actinobacteria as the dominant phyla in both the sediments. However, the abundance of these phyla significantly differed between the samples. Bacteroidetes from Mandovi sediment, and Acidobacteria and Gemmatimonadetes from Zuari sediment were the other exclusive major phyla. Chloroflexi, Cyanobacteria, Nitrospirae, Planctomycetes, Verrucomicrobia, and WS3 were the minor phyla observed in both. However, a significant difference in the distribution of minor phyla and lower bacterial taxa under each phylum was noted between the sediments, indicating that the resident microbial flora completely differed between them. This was further validated by high values from distance matrix analyses between the samples. In addition, the pathogenic Vibrio sp. was recorded exclusively in Mandovi sediment, while higher abundance of ecologically important bacterial classes including Gammaproteobacteria, Alphaproteobacteria, Deltaproteobacteria, and Bacilli was observed in Zuari sediment. Taken together, the data indicated that Zuari sediment was taxonomically richer than Mandovi sediment, while a greater incidence of anthropogenic activities occurred in the latter. This observation was further validated by non-parametric richness estimators which were found to be higher for Zuari sediment. The cultured bacterial isolates, all identified as Firmicutes, were tested for activities related to biofertilization and production of enzymes to be used for bioremediation and chemotherapeutic applications. Higher number of bacterial isolates from Mandovi was found to produce indole-acetic-acid, tannase, xylanase, and glutaminase enzymes, and could solubilize phosphate. In contrast, higher proportion of bacterial isolates from Zuari sediment were capable of producing amylase, cellulase, gelatinase, laccase, lipase, protease, and asparaginase enzymes, emphasizing the fact that the Zuari mangrove sediment is a rich reservoir for economically and biotechnologically important bacterial species. PMID- 30306006 TI - Deriving electricity from dye processing wastewater using single chamber microbial fuel cell with carbon brush anode and platinum nano coated air cathode. AB - Single chamber air cathode microbial fuel cell (MFC) is a promising and sustainable technology to generate electricity. In the present study, the potential of air cathode MFC treating dye processing wastewater was investigated at various organic loads with interest focused on power densities, organic removal and coulombic efficiencies. The highest power density of about 515 mW/m2 (6.03 W/m3) with 56% of coulombic efficiency was procured at 1.0 (g COD/L) organic load. The high potency of TCOD (total chemical oxygen demand), SCOD (soluble chemical oxygen demand) and TSS (Total Suspended Solids) removal of about 85%, 73% and 68% respectively was achieved at the organic load of 1.0 (g COD/L). The bacterial strains in anode region at the initial stage of MFC operation were reported to be responsible for potential organic removal. The bacterial strains in air cathode MFC were identified as Paenibacillus sp. strain JRA1 (MH27077), Pseudomonas sp. strain JRA2 (MH27078), Ochrobactrum sp. strain JRA3 (MH27079), Sphingobacterium sp. strain JRA4 (MH27080), Stenotrophomonas sp. strain JRA5 (MH27081), Bacillus sp. strain JRA6 (MH27082) and Clostridium sp. strain JRA7 (MH27083) using phylogenetic analysis. After 60 days of air cathode MFC operation, the bacterial community in biofilm samples was dominated by Bacillus, Ochrobactrum and Pseudomonas (20-22%). The biofilm sample collected from the carbon brush consisted of Bacillus (33%), Ochrobactrum (30%), Pseudomonas (28%), Clostridium (6%) and Stenotrophomonas (3%). The present study revealed the treatment efficiency of dye processing wastewater along with power generation in single chambered air cathode MFC. PMID- 30306007 TI - Moderate levels of glyphosate and its formulations vary in their cytotoxicity and genotoxicity in a whole blood model and in human cell lines with different estrogen receptor status. AB - In vitro studies were conducted to determine the short-term cytotoxic and genotoxic effects of pure glyphosate and two glyphosate formulations (Roundup(r) and Wipeout(r)) at concentrations relevant to human exposure using whole blood (cytotoxicity) and various cancer cell lines (cytotoxicity and genotoxicity). Pure glyphosate (pure glyph) and Roundup(r) (Ro) showed similar non-monotonic toxicological profiles at low dose exposure (from 10 ug/ml), whereas Wipeout(r) (Wo) demonstrated a monotonic reduction in cell viability from a threshold concentration of 50 ug/ml, when tested in whole blood. We evaluated whether using various cancer cells (the estrogen-E2-responsive HEC1A, MCF7 and the estrogen insensitive MDA-MB-231) exposed to moderate doses (75-500 ug/ml) would indicate varied toxicity and results indicated significant effects in the HEC1A cancer cells. A non-monotonic reduction in cell viability was observed in HEC1A exposed to pure glyph (75-500 ug/ml) and proliferative effects were observed after exposure to Wo (75, 125 and 250 ug/ml). Genotoxicity assessment (test concentration 500 ug/ml) demonstrated DNA damage in the HEC1A and MDA-MB-231 cells. Adjuvants and/or glyphosate impurities were potential contributing factors of toxicity based on the differential toxicities displayed by Ro and Wo in human whole blood and the HEC1A cells. This study contributes to the existing knowledge about in vitro exposure to moderate concentrations of glyphosate or glyphosate formulations at cytotoxic and genotoxic levels. In addition, a suggestion on the relevance of the estrogen receptor status of the cell lines used is provided, leading to the need to further investigate a potential endocrine disruptive role. PMID- 30306008 TI - In vitro antibacterial and early stage biofilm inhibitory potential of an edible chitosan and its phenolic conjugates against Pseudomonas aeruginosa and Listeria monocytogenes. AB - In the present study, the antibacterial potential of chitosan grafted with phenolics (CPCs) such as caffeic acid (CCA), ferulic (CFA), and sinapic acid (CSA) were evaluated against foodborne pathogens like Pseudomonas aeruginosa (PA) and Listeria monocytogenes (LM). The geometric means of minimum inhibitory concentration (MIC range 0.05-0.33 mg/ml), bactericidal concentration (MBC range 0.30-0.45 mg/ml), biofilm inhibitory concentration (BIC range 0.42-0.83 mg/ml), and biofilm eradication concentration (BEC range 1.71-3.70 mg/ml) of CPCs were found to be lower than the MIC (0.12-1.08 mg/ml), MBC (0.17-1.84 mg/ml), BIC (4.0 4.50 mg/ml), and BEC (17.4-23.0 mg/ml) of unmodified chitosan against PA and LM. CPCs attenuated the biofilms of PA and LM by increasing the membrane permeability of bacteria embedded within the biofilms. Further, sub MIC of CPCs (0.5 * MIC) significantly reduced the biofilm adhesion (p < 0.001) by representative strains of LM (CCA: 72.2 +/- 3.5, CFA: 79.3 +/- 0.9, and CSA: 74.9 +/- 1.5%) and PA (CCA: 64 +/- 1.1, CFA: 67.8 +/- 0.8, and CSA: 65.7 +/- 4.9%). These results suggested the antibacterial and anti-biofilm potential of CPCs that can be exploited to control foodborne pathogenic infections. PMID- 30306009 TI - Genome-wide overview of Trichosporon akiyoshidainum HP-2023, new insights into its mechanism of dye discoloration. AB - Trichosporon akiyoshidainum HP-2023 completely discolorised Reactive Black 5 (200 mg/l) in 24 h. Manganese peroxidase and phenoloxidase, but no laccase activities were detected throughout the incubation. Total aromatic amines in media with Reactive Black 5 decreased 83% after 24 h, supporting an oxidative mechanism of azo dye discoloration. To unravel the genetic basis of these activities, the genome of Trichosporon akiyoshidainum HP-2023 was sequenced, assembled and annotated de novo. T. akiyoshidainum HP-2023 genome comprises 30 MB with a G+C content of 60.75% and 9019 gene models. Thirty-three putative carbohydrate-active enzymes with auxiliary activities, probably involved in lignin degradation and dye discoloration, were identified in the annotated genome, including two laccases, four extracellular fungal heme-peroxidases, nineteen hydrogen peroxide producing enzymes, and four benzoquinone oxidoreductases. This report will facilitate further studies of textile-dye discoloration with this and closely related strains and poses questions about the ligninolytic potential of Trichosporon akiyoshidainum HP-2023 and related species. PMID- 30306010 TI - In vivo toxicity evaluation of biologically synthesized silver nanoparticles and gold nanoparticles on adult zebrafish: a comparative study. AB - In this study, toxicity of biologically synthesized silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) was compared using zebrafish as a model organism. At 96 h, LC50 of AgNPs and AuNPs was found to be 24.5 ug/L and 41 mg/L, respectively. Following the LC50 determination, half of the LC50 of AgNPs (12.25 ug/L) and AuNPs (20.5 mg/L) was exposed to adult zebrafishes for 14 days. Morphological changes, liver marker enzymes, reactive oxygen species (ROS) generation, genotoxic effects and mRNA expression levels of oxidative stress and innate immune response related genes were studied using nanoparticle treated gill, liver and blood cells. In this study, AgNP-treated gill and liver tissues showed a number of morphological changes such as cell membrane damage, irregular cell outlines, pyknotic nuclei and complete disruption of gill and liver cells; on the contrary, AuNPs treated liver tissues alone showed such changes. The levels of liver marker enzymes such as alanine aminotransferase and aspartate aminotransferase were increased after AgNPs treatment when compared to AuNPs treatment. AgNP-treated liver cells showed higher levels of ROS generation than the control; on the other hand, AuNPs treatment exhibited lower levels of ROS generation than the control. Interestingly, AgNP-treated blood cells showed micronuclei formation and nuclear abnormalities, while AuNPs treatment did not show such effects. Based on these observations, it is clear that AgNPs may cause oxidative stress and immunotoxicity to adult zebrafish than the AuNPs. However, these results clearly reveal the significance of relatively safe and less toxic bionanomaterials for possible biomedical applications. PMID- 30306011 TI - Rapid and sensitive detection of Pseudocercospora eumusae pathogen causing eumusae leaf spot disease of banana by loop-mediated isothermal amplification (LAMP) method. AB - A rapid and sensitive loop-mediated isothermal amplification (LAMP) method was developed for the specific detection of Pseudocercospora eumusae. The LAMP primers designed based on the specific SCAR (Sequence Characterized Amplified Region) marker sequence of P. eumusae proved highly specific to P. eumusae and there was no cross reactivity with closely related Pseudocercospora spp. (P. fijiensis and P. musicola) and 17 other leaf spot causing fungal pathogens of banana. The developed LAMP method exhibited greater sensitivity as the minimum detectable concentration of P. eumusae genomic DNA was 10 pg/ul which was 100 times lower than that of conventional PCR (1 ng/ul).This method also detected the target pathogen from crude DNA of the mycelium and single leaf spot tissues which eliminates laborious purification steps in DNA isolation and requires less operational time. To the best of our knowledge, this is the first report on the development of this LAMP method to specifically detect and diagnose P. eumusae pathogen from pure cultures and leaf spot tissues. PMID- 30306012 TI - Actual neighborhood-level crime predicts body mass index z-score changes in a multi-racial/ethnic sample of children. AB - Longitudinal studies are warranted to clarify the influence crime has on health outcomes in children especially children representing multiple racial/ethnic backgrounds. To address this need, the current study examined whether neighborhood-level crime predicted changes in body mass index z (BMIz) scores in 373 White (W), 627 African American (AA), 1020 Hispanic (H), and 88 Asian (A), five to ten year-old boys and girls living in urban neighborhoods. Heights and weights were assessed at baseline (2012) and three-years later and used to calculate BMIz scores. Characteristics of zip codes where students lived during the three-year period were obtained at baseline from various sources. The Crime Risk Index (CRI) for each zip code was calculated using actual crime statistics. Multiple linear regression analyses were conducted to examine associations between baseline CRI and follow-up BMIz scores while controlling for other variables including BMIz at baseline. The CRI and BMIz scores differed significantly by race/ethnicity with the highest values for both noted in H. Regression analyses indicated that the CRI accounted for a significant percentage of the variance in follow-up BMIz scores in the overall sample. When race/ethnicity was considered, the CRI predicted follow-up BMIz scores only in W children. The CRI was not significantly associated with BMIz scores in the other races/ethnicities. The impact actual, neighborhood-level crime has on BMI in children is complex. Based on the existing evidence, considering actual crime as a primary target in obesity prevention would be premature especially in racial/ethnicity minority children living in urban areas. PMID- 30306013 TI - Longer afterschool active commutes and the travel environment of middle schools in Shenzhen, China. AB - The afterschool commute is a major part of children's daily activity. This study examines the relationship between student extended active travel routes and route environment characteristics. Route environment characteristics may be related to an extended route for students who walk or bike home. Self-reported itineraries were collected from 12 to 15-year old students in 3 middle schools in Shenzhen in May and June (n = 1257). Itineraries involving a detour from the shortest possible route home (n = 437) were compared with the shortest route. A field study coded all possible routes within the school districts by playable open spaces, sidewalk width, controlled crossings, road category, and public transit stops. Binary logistic regression reveals that routes with greater intersection density and number of open spaces are related to active travel choice. Sidewalk width, number of traffic lights and proportion of arterial roads are positively related to motorized travel. Linear regression reveals that travel distance, sidewalk width, number of open spaces and street crossings, as well as the proportion of secondary roads and pathways are positively related to detour distance. Higher numbers of public transit stops and traffic lights are related to shorter detours. Attending cram school is also negatively associated with active travel and detour. Younger students, females and students with longer moderate-to-vigorous physical activity time have extended active travel. Specific route environment characteristics are associated with longer and more active middle school student commutes and may be implemented to raise overall activity levels in children. PMID- 30306015 TI - "I'm gonna get me a loosie" Understanding single cigarette purchases by adult smokers in a disadvantaged section of New York City. AB - This study seeks to update and expand our understanding of the perceptions and purchasing patterns of smokers of single cigarettes ('loosies') in disadvantaged urban areas. Semi-structured guides were used in thirteen focus groups with 67 self-identified adult smokers from the South Bronx section of New York City in summer 2013. There is wide availability of single cigarettes in the South Bronx, with legitimate stores overwhelmingly being the preferred venue for purchases. Single cigarettes are sold at higher per-unit prices than illicit packs. However, buyers of single cigarettes can achieve cost savings compared to legal, fully taxed cigarette packs. Apart from cost-savings, smokers opt for single cigarettes to reduce their personal cigarette consumption. There is a general perception of market resilience despite law enforcement intervention. However, law enforcement has a limiting effect on access to single cigarettes outside of an individual smoker's immediate neighborhood. The findings suggest that single cigarette sales are an important element of the illicit cigarette market in disadvantaged communities which should not be ignored in future research on the nature and extent of cigarette tax avoidance and evasion. PMID- 30306014 TI - Evaluation of the impact of a public bicycle share program on population bicycling in Vancouver, BC. AB - Public bicycle share programs have been implemented in cities around the world to encourage bicycling. However, there are limited evaluations of the impact of these programs on bicycling at the population level. This study examined the impact of a public bicycle share program on bicycling amongst residents of Vancouver, BC. Using an online panel, we surveyed a population-based sample of Vancouver residents three times: prior to the implementation of the public bicycle share program (T0, October 2015, n = 1111); in the early phase of implementation (T1, October 2016, n = 995); and one-year post implementation (T2, October 2017, n = 966). We used difference in differences estimation to assess whether there was an increase in bicycling amongst those living and/or working in close proximity (<=500 m) to Vancouver's Mobi by Shaw Go public bicycle share program, compared to those living and working outside this area. Results suggest that only living or only working inside the bicycle share service area was not associated with increases in bicycling at T1 or T2 relative to those outside the service area. Both living and working inside the bicycle share service area was associated with increases in bicycling at T1 (OR: 2.26, 95% CI: 1.07, 4.80), however not at T2 (OR: 1.37, 95% CI: 0.67, 2.83). These findings indicate that the implementation of a public bicycle share program may have a greater effect on bicycling for residents who both live and work within the service area, although this effect may not be sustained over time. PMID- 30306016 TI - The effect of ingredient-specific calorie information on calories ordered. AB - Providing calorie labeling is a widely used strategy to combat obesity. However, there is little evidence that the availability of calorie information at food away-from-home establishments has an effect on food choices. Listing calorie information for each ingredient, though, may allow customers to avoid high calorie items that add little to their enjoyment. Data from a natural experiment were used to compare total calories ordered before and after the provision of per ingredient versus for build-your-own sandwiches, and per-sandwich for pre-defined sandwiches, at a supermarket sandwich counter. Sandwich order slips from a Lincoln, Neb. supermarket were collected from December 15, 2016 to February 4, 2018. In June 2017, calorie information was introduced. A total of 1134 build your-own orders and 559 pre-defined orders were collected. Calories ordered before and after the provision of calorie information were examined for build your-own and pre-defined sandwiches using two-sample t-tests. Orders post-calorie information were split into three periods to examine whether responses to information changed over time. Ingredients ordered were also examined before and after information was provided. Customers decrease calories ordered by 7.8% for build-your-own sandwiches when per-ingredient calorie information is introduced. There is no significant change in calories ordered for pre-defined sandwiches. Calorie reduction appears to result from substitution away from some higher calorie items, e.g., mayonnaise, towards lower calorie ingredients, like mustard. Despite low calorie content, customers did not increase the number of vegetables ordered. Finally, there is no attenuation of the effect of calorie information over time. PMID- 30306017 TI - How to Write a Research Protocol: Tips and Tricks. PMID- 30306018 TI - Stress Echocardiography: Need to Optimize its Appropriate Use in Suspected Angina and a Review of Available Additional Tools for its Clinical Application in 2018: First do no Harm! Second do it at the Highest Possible Accuracy. AB - There is a need to reassess the most appropriate indications for stress echocardiography in the current era, in patients with suspect or known coronary artery disease (CAD), and also the most helpful additional parameters that can be easily calculated in clinical practice to increase the known suboptimal sensitivity for obstructive CAD of this test. The current review tries to clarify what is and what should be the proper role for functional testing in general, but specifically regarding modern stress echocardiography in the current practice, for suspected CAD and/or atypical chest pain. Few candidate additional parameters beyond wall motion assessment are here suggested to improve diagnostic accuracy of stress echocardiography, and pertinent literature is briefly reviewed, together with a more personal view of the author regarding the characteristics of each parameter, as far as ease of acquisition, cost, and true diagnostic or prognostic clinical usefulness are concerned. The reviewed additional parameters, which can be acquired during stress echocardiography, are Doppler coronary flow reserve in the left anterior descending artery, cardiac calcium score, global longitudinal strain, ventricular elastance, and contrast myocardial perfusion. Each of them finds a potential place in the current practice or may find a place in the future practice of stress echocardiography. PMID- 30306019 TI - The Association of Epicardial Adipose Tissue and the Metabolic Syndrome in Community Participants in South Africa. AB - Background: We sought to determine the association of echocardiographically derived epicardial adipose tissue (EAT) thickness, which is a component of visceral adipose tissue, with the metabolic syndrome (MetS) in a cohort of randomly selected community participants. Methods: South African-Asian Indians aged 15-64 years were recruited over a 2-year period after informed consent was obtained. All participants who had complete measurements done for biochemistry and echocardiography (using established criteria), were dichotomized into the MetS or non-MetS groups defined according to the harmonized criteria. Results: Of the 953 (232 men and 721 women) participants recruited, 47.1% (448) were classified with the MetS. These participants had larger waist circumference and body mass index (P < 0.001), with larger LA volumes and diameter, thicker ventricular walls, higher left ventricular mass, relative wall thickness, and EAT (P < 0.001). There was a corresponding increase in EAT thickness with increasing number of MetS risk factors at the transition from 0 MetS factors to 1 (95% confidence interval [CI] -0.8; -0.2) and from 2 to 3 MetS factors (95% CI -0.9; 0.4). The AUC of the receiver operator curve was highest for triglycerides (0.845), followed by fasting plasma glucose (0.795) and then EAT (0.789). An EAT value of <3.6 mm predicted the presence of the MetS with a 78% sensitivity and 70% specificity. Using backward stepwise logistic regression, the most significant independent determinants of the MetS after adjusting for age, gender, and type 2 diabetes mellitus, was fasting plasma glucose (odds ratio [OR] = 1.2), triglycerides (OR = 7.1), and EAT (OR = 2.3). Conclusion: Although EAT is associated with the MetS, and can identify individuals at increased cardiometabolic risk, it has a limited additional role compared to current risk markers. PMID- 30306020 TI - Early Recovery of Left Ventricular Systolic Function after Transcatheter Aortic Valve Implantation. AB - Background: A lot of studies have shown a positive effect of transcatheter aortic valve implantation (TAVI) on left ventricular ejection fraction (LVEF). Objectives: We aimed to investigate the effect of TAVI on left ventricular function and correlate this phenomenon with hypertrophy degree in an early follow up. Materials and Methods: Between August 2015 and July 2016, 250 consecutive patients with symptomatic severe aortic stenosis (AS) underwent TAVI in our institution. Given the aim of this analysis, only patients with an LVEF <50%, no more than moderate mitral valve regurgitation, successful valve implantation, and 1-month follow-up available were included in the study (n = 46). Patients were enrolled in a prospective database, with clinical and echocardiographic evaluations at 1 month after TAVI. Results: All patients had severe symptomatic AS (mean transaortic pressure gradients: 44.1 +/- 13.8 mmHg and mean aortic valve area: 0.66 +/- 0.19 cm2). Mean baseline LVEF was 39.3 +/- 8.8%. Significant hemodynamic improvement was observed after TAVI. Mean transvalvular aortic gradient decreased significantly from 44.1 +/- 13.8 mmHg to 8.9 +/- 4.2 mmHg (P < 0.005). A statistically significant improvement in LVEF compared to baseline was observed in the 1st month of follow-up (39.3 +/- 8.8% vs. 44.1 +/- 10.1%, P < 0.019). Overall, 52.2% of patients showed an increase in LVEF, 32.6% had no change, while only 2.2% had a decrease in LVEF. Interestingly, we found a significant reverse correlation between LVEF improvement and ventricular hypertrophy measured as diastolic interventricular septum thickness (Pearson index r = -0.42). Patients showing greater improvement in LVEF were those with less than moderate hypertrophy. Conclusions: Patients with depressed systolic function show a consistent and early LVEF recovery after TAVI. An impaired LVEF recovery is most likely among patients with more than moderate hypertrophy, probably responsible of left ventricular fibrosis that irremediably compromises systolic function. PMID- 30306022 TI - Reference Values of Longitudinal Systolic Right and Left Ventricular Function Measured by M-mode Echocardiography in Healthy Preterm and Term Neonates. AB - Background: The mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) are parameters for evaluating systolic function, which is directly affected by ventricular morphology and geometry. Materials and Methods: A cross-sectional study in term and preterm neonates calculated TAPSE and MAPSE at the lateral and septal (LAT/SEP) mitral. The study groups were divided into three classes based on birth age: two preterm groups, 30 33 weeks and 34-37 weeks, and one term group, 38-40 weeks. Results: This study included 21 term neonates and 31 preterm neonates. The mean LAT MAPSE was 0.63 +/ 0.11 cm for gestational age (GA) of 30-33 weeks, 0.76 +/- 0.03 cm among GA of 34 36 weeks, and 0.84 +/- 0.08 cm for GA of 37-40 weeks; the mean SEP MAPSE was 0.39 +/- 0.14 cm, 0.51 +/- 0.06 cm, and 0.65 +/- 0.09 cm, respectively; and the mean TAPSE was 0.47 +/- 0.13 cm, 0.62 +/- 0.07 cm and 0.88 +/- 0.15 cm, respectively. The mean LAT MAPSE was 0.63 +/- 0.09 cm for neonates weighing 1500-2500 g and 0.82 +/- 0.06 cm for those weighing 2500-3600 g; the mean SEP MAPSE was 0.39 +/- 0.11 cm and 0.61 +/- 0.09 cm, respectively. The LAT MAPSE showed a positive correlation with body surface area (BSA) and body weight (BW) (P = 0.0001). In addition, the SEP MAPSE indicated a positive correlation with BSA and BW (P = 0.0001). The TAPSE had a positive correlation with BSA (P = 0.0001) and BW (r = 0.876, P = 0.0001). Conclusions: The TAPSE and MAPSE values were calculated to establish the reference values for assessing global ventricular systolic function in neonate's health. PMID- 30306021 TI - Impaired Cardiac Functions and Aortic Elastic Properties in Patients with Severe Vitamin D Deficiency. AB - Background: The study explored the effect of severe Vitamin D deficiency on cardiac functions and aortic elastic properties determined by echocardiography. Patients and Methods: It included 56 patients with Vitamin D deficiency (Group 1; 16 men, 40 women; mean age 43.1 +/- 11.4 years) and 42 healthy individuals with normal Vitamin D levels (Group 2; 11 men, 31 women; mean age 40.0 +/- 7.5 years). Calcium, parathormone, alkaline phosphatase, and Vitamin D levels were measured from blood samples, and all participants underwent echocardiographic examination. Results: Left ventricular diastolic functions were determined by both conventional and tissue Doppler methods and were found to be impaired in Group 1 compared to Group 2. Aortic distensibility was significantly reduced in Group 1 compared to Group 2, whereas aortic stiffness index was significantly increased. Left atrial active emptying volume and fraction (LAAEV and LAAEF) were significantly higher in Group 1 than in Group 2. There were significant negative correlations between Vitamin D level and LAAEV, LAAEF, and septal E/E' ratio and significant positive correlations between Vitamin D level and septal, lateral, anterior, and right ventricular annular E' velocities. Conclusion: In severe Vitamin D deficiency, echocardiographically assessed diastolic functions appeared particularly impaired, and ventricular myocardial velocities and aortic elastic parameters were also adversely affected. In addition, LA mechanical functions were impaired, probably secondary to disturbed diastolic functions. PMID- 30306023 TI - Multimodality Imaging of Left Ventricular Clefts in an Asymptomatic Teenager. AB - Left ventricular clefts (LVCs) are defined as deep, tight blood-filled invaginations within the ventricular myocardium localized predominantly in the basal posterior septum and LV-free wall. Usually, they are asymptomatic and incidentally discovered during diagnostic imaging procedures. LVC has been reported both in healthy volunteers and in patients affected with hypertrophic cardiomyopathy. Clinicians should be able to recognize LVC and to distinguish this entity from other myocardial wall defects with different pathological profile and clinical significance. We describe a case of multimodality imaging of multiple septal myocardial clefts in an asymptomatic teenager. PMID- 30306024 TI - Right Cardiac Chambers' Involvement as the First Manifestation of Recurrent Complex Karyotype Acute Myeloid Leukemia. AB - We describe a case of a 21-year-old male, with a history of acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation, referred to our department for atypical chest pain and dyspnea. Echocardiography revealed an extensive mass involving right cardiac chambers and tricuspid valve annulus, with increased thickness and impairment of right ventricle. Cardiac magnetic resonance confirmed the presence of cardiac mass involving pulmonary artery trunk, pericardial sleeves, and lung parenchyma. These findings were attributed to a manifestation of recurrent AML involving the right heart. PMID- 30306025 TI - Pericardial Agenesis as a Rather Unusual Cause of Palpitations: We Only See What we Know. AB - Cardiac palpitations secondary to ventricular ectopic beats are a frequent clinical indication for a cardiac magnetic resonance (CMR) scan. CMR has already demonstrated its additive diagnostic value in patients with frequent arrhythmias even when echocardiogram appears normal. Hereby, we describe a case of a middle aged male patient referred to our laboratory because of frequent ventricular ectopic beats and an inconclusive echocardiogram due to an extremely poor acoustic window. A diagnosis of pericardial agenesis (PA) was made explaining patient symptoms and arrhythmias previously detected. Furthermore, at the case report description, PA prevalence, associated cardiac pathologies, and novel CMR diagnostic criteria are being described. PMID- 30306026 TI - Traumatic Ventricular Septal Defect Resulting from a Motor Vehicle Collision. AB - This case report describes a rare case of ventricular septal defect due to non penetrating trauma in a 43 year old male involved in a motor vehicle collision. The diagnosis was made by echocardiogram and the patient was taken immediately to the operating room for emergent surgical repair of the ventricular septal defect and survived. PMID- 30306027 TI - Aortic Valve Thrombosis after Valve-Sparing Aortic Root Replacement and Insertion of an Extracorporeal Left Ventricular Assist Device, Masked by Mediastinal Packing. AB - Aortic valve (AV) or aortic root thrombus related to a left ventricular assist device (LVAD) is a relatively uncommon but potentially life-threatening complication. In the present report, we describe a complex case where echocardiographic diagnosis of AV thrombosis was obscured by the presence of mediastinal packing in a patient who underwent valve-sparing aortic root replacement and insertion of the CentriMagTM LVAD for postcardiotomy cardiogenic shock. A large AV thrombus may develop rapidly in patients with LVADs. This case highlights the importance of a careful and thorough transesophageal echocardiography examination in detecting this complication and in altering surgical management. PMID- 30306028 TI - Incidental Discovery of an Atypical Cardiac Tumor. AB - Primary cardiac tumors are rare, present in roughly 0.05% of the population. Cardiac papillary fibroelastoma (CPF) is the second most common, accounting for 10% of primary cardiac tumors.[1] Most cases of CPFs are discovered incidentally on autopsy; however, they may present clinically with systemic embolization or heart failure symptoms. The recommended treatment for symptomatic CPF patients is surgical resection.[1] Treatment in asymptomatic patients remains somewhat controversial with incidentally discovered tumors presenting a clinical dilemma. We present a case of an atypically located CPF that was discovered incidentally on intraoperative transesophageal echocardiography (TEE) during a routine coronary artery bypass graft operation. This case highlights several important points for cardiac anesthesiologists. The first is the importance of performing a comprehensive intraoperative TEE. Next, this case reinforces the broad utility of TEE for evaluation of intracardiac tumors. Finally, this case demonstrates the importance of precise localization of intracardiac tumors. PMID- 30306030 TI - A Rare Case of Dense Spontaneous Echo Contrast within Inferior Vena Cava. AB - A 33-year-old gentleman was examined because of fatigue and progressive right heart failure. A striking finding in his echocardiogram was intense and slow moving dense echo contrast in the inferior vena cava (IVC). Cardiac catheterization revealed constrictive pericarditis, and pericardiectomy was performed. Postoperatively spontaneous echo contrast in IVC have resolved. This case helps explain the origin of spontaneous IVC contrast. PMID- 30306029 TI - Spontaneous Rupture of Sinus of Valsalva Aneurysm Presenting as Perivalvular Hematoma. AB - Acute rupture of sinus of Valsalva often presents as an acute emergency with significant hemodynamic compromise whereas contained rupture of sinus of Valsalva with a perivalvular hematoma formation is rarely seen. We describe the case of a 63-year-old male who presented with acute shortness of breath and was found to have rupture of sinus of Valsalva aneurysm (SVA) with a perivalvular hematoma and severe aortic regurgitation. We also review the presentation, diagnosis, and management of SVAs. PMID- 30306031 TI - A Powerful Value of Hysteroscopy. PMID- 30306032 TI - Loop Electrosurgical Excision Procedure versus Cryotherapy in the Treatment of Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Aim: Invasive cervical cancer is proceeded by a phase of preinvasive disease that is slow to progress and can be detected, treated, and collectively referred to as cervical intraepithelial neoplasia (CIN). Several excisional and ablative treatments for CIN have been studied, with loop electrosurgical excision procedure (LEEP) and cryotherapy being the two most commonly utilized. The objective of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to compare the compare harms and benefits of LEEP versus cryotherapy in women with CIN. Methods: Electronic databases were searched from their inception until May 2018. We included all RCTs comparing cryotherapy versus LEEP in women with CIN. We included trials evaluating both HIV-seropositive and HIV-seronegative women. The primary outcome was the persistence of the disease at 6-month follow-up. Meta-analysis was performed using the random-effects model to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). Results: Four trials, including 1035 women with CIN, were identified as relevant and included in the meta-analysis. Women who received LEEP for CIN had a significantly lower persistence at 6-month follow-up biopsy (RR: 0.87, 95% CI: 0.76-0.99) and significantly lower recurrence at 12-month follow-up biopsy (RR: 0.91, 95% CI: 0.84-0.99) compared to those who received cryotherapy. No between-group differences were found in the complications rate, but the analyses were not powered for these outcomes. Conclusions: In women with CIN, treatment with LEEP was associated with a significantly lower risk of persistence disease at 6 months and recurrence disease at 12 months compared to treatment with cryotherapy. PMID- 30306033 TI - Utility of Laparoscopic Uterine Myomectomy as a Treatment for Infertility with No Obvious Cause Except for Uterine Fibroids. AB - Objectives: Uterine fibroids are capable of causing infertility, but there are no definite criteria for which laparoscopic uterine myomectomy (LM) is known to be beneficial. To investigate the usefulness of LM, we examined pregnancy rates in patients with infertility with no obvious cause except for the presence of uterine fibroids. Materials and Methods: We retrospectively reviewed the clinical records at Suzuki Memorial Hospital between June 2010 and August 2014. We found 60 eligible patients (LM group, 46; non-LM group, 14). The criteria for performing LM were a maximal fibroid diameter of 40 mm or more or the presence of >4 fibroids. Results: The duration of infertility before the first visit was significantly longer in the LM group; although there was no significant difference in the mean patient age and body mass index. Pregnancy was achieved in 45.7% of patients (21/46) in the LM group and 28.6% (4/14) in the non-LM group. There were no pregnancies in patients with >10 fibroids. The postoperative pregnancy rate in the LM group was comparable to previously reported pregnancy rates. Conclusions: Our criteria for performing LM in patients with no obvious cause for infertility except for uterine fibroids seem appropriate, especially when the fibroids are large and the number of fibroids is between 4 and 9. However, our results suggest that the effectiveness of LM is low in patients with 10 or more uterine fibroids. PMID- 30306034 TI - A Randomized Controlled Trial Comparing Laparoscopic Lens Defogging Techniques through Simulation Model. AB - Context: Current literature demonstrates a lack of comparative studies regarding effective techniques for reducing laparoscopic lens fogging. Aim: Our primary objective is to determine the efficacy of various laparoscopic defogging techniques (LDT) through a randomized controlled trial that employs a novel simulation model of the abdominopelvic cavity. Settings and Design: This study was conducted at academic community hospital. This study design was a randomized controlled trial through simulation. Subjects and Methods: A chamber was constructed that simulated the abdominopelvic cavity. We used 5 and 10 mm 0 degrees laparoscopes. A 10 cm visual analog scale was developed to assign visual clarity (VC) scores. The 10 cm mark indicated perfect VC. We employed the following LDTs: (1) glove warming (GLOVE), (2) surfactant solution (Fog Reduction and Elimination Device [FRED]), (3) chlorhexidine solution (SOAP), (4) warm saline (SALINE), and (5) control. Three observers were blinded to the LDT used. Primary outcomes included VC scores at designated time intervals (5, 30, and 60 s) for each LDT. A minimum of 10 observations per time interval were required to achieve adequate power based on a 2.5 cm difference in VC scores. Results: For the 10 mm laparoscope, FRED, SOAP, and SALINE had a VC score at 60 s (VC60) higher than control (4.8 +/- 2.2, 7.8 +/- 0.8, 7.9 +/- 0.7 vs. 2.4 +/- 0.72, P < 0.05). Both SOAP and SALINE VC60 scores were higher than FRED (7.8 +/- 0.8, 7.9 +/- 0.7 vs. 4.8 +/- 2.2, P < 0.05). No differences were noted in VC60 scores between control and GLOVE (2.4 +/- 0.72 vs. 3.1 +/- 2.2, P > 0.05) and between SOAP and SALINE (7.8 +/- 0.8 vs. 7.9 +/- 0.7, P > 0.05). Similar results were noted with the 5 mm laparoscope. Conclusions: Common LDTs such as SALINE and SOAP were more effective than FRED, while GLOVE was no different than control. These results demonstrate that the use of effective LDTs can potentially translate into improved patient care and operative outcomes during surgery. PMID- 30306035 TI - Five-Year Lapsed: Review of Laparoscopic Myomectomy versus Open Myomectomy in Putrajaya Hospital. AB - Study Objective: This study aimed to investigate the morbidity of laparoscopic myomectomy (LM) versus open myomectomy (OM), including intraoperative blood loss, duration of surgery, hospital stay, and complications and to evaluate the criteria for selection of cases suitable for LM. Design: This was a retrospective study. Setting: This study was conducted at tertiary hospital. Participants: The records of 67 women who underwent LM, 22 women who underwent OM, and 14 women who had laparo-conversion from January 2010 to November 2014 were reviewed. Measurement and Main Results: Fibroids up to 10 cm were removed by LM, while most fibroids more than 10 cm were managed through OM. The number and weight of myomas are significantly associated with laparo-conversion, with a rate of 17%. Mean blood loss was significantly reduced in LM group than the OM and laparo conversion groups. Duration of hospital stay was also significantly less in LM (2 +/- 1 days) compared to both OM and laparo-conversion groups (3 +/- 1 days). Most women underwent LM (88%) had no postoperative complications compared to OM (50%) and laparo-conversion (57.1%). The number of fibroids removed and duration of surgery was positively correlated with blood loss in the women who underwent myomectomy. Conclusion: LM is an ideal surgical approach for removal of fibroids which are up to 10 cm diameter and <5 in number, while OM is useful for cases with multiple (5 or more), larger fibroids (>10 cm), and deeply located fibroids. Preoperative evaluation of the size and number of myomas is necessary to avoid laparo-conversion and to reduce intraoperative and postoperative complications. PMID- 30306036 TI - New Continuous Barbed Suture Device with Stratafix for the Vaginal Stump in Laparoscopic Hysterectomy. AB - Aims: Closure of the vaginal stump in total laparoscopic hysterectomy (TLH) performed by interrupted suture is time-consuming and requires sufficient experience. Stratafix (SF) is a new type of antibacterial monofilament absorbable suture which has multiple small anchors on the string surface. There is no information concerning the efficacy of SF for vaginal stump suture in minimally invasive hysterectomy. Materials and Methods: We retrospectively evaluated the operative complications and SF (n = 20) advantages for the vaginal stump in TLH and compared with a cohort of patients with conventional sutures (n = 20). The differences in performance based on operators' skill levels were also considered. Results: The time taken to close vaginal stump in the SF suture group was significantly lower than the conventional group (median times: 13.1 vs. 18.0 min, respectively; P = 0.038). Closure by a less experienced operator using SF suture was reduced by 7.2 min. The junior operator median vaginal suture time was only 2.6 min longer than the senior operator median time in SF suture group (P = 0.218), whereas an 8.4 min difference was recorded in the conventional suture group (P = 0.043). Total operation times did not significantly correlate with vaginal suturing techniques (median times: 126 vs. 145 min, respectively; P = 0.718). Complications regarding the vaginal stump closure techniques including organ injury, bleeding, wound separation, and pain did not occur in both groups. Conclusions: SF suturing facilitates the vaginal stump closure in TLH without increasing the complications. SF allowed vaginal stump approximation and reduced the operative burden, especially in less experienced operators. PMID- 30306037 TI - Successful Procedure in Conservative Management of Interstitial (Cornual) Ectopic Pregnancy. AB - A 35-year-old woman presented with spotting and lower abdominal pain. Follow-up sonography was suggestive of interstitial ectopic pregnancy. Laparoscopic cornuostomy was carried out. Before incision, diluted vasopressin was injected around the site of interstitial pregnancy. Removal of the conceptual tissues was conducted smoothly through a 1.5 cm incision. The overall blood loss was 50 mL. The operative time was 50 min, and there were no intraoperative complications. We successfully performed laparoscopic cornuostomy, which was followed by an unremarkable postoperative course. Laparoscopic surgery is a safe and effective minimally invasive surgical intervention for interstitial ectopic pregnancy if performed by the experienced surgeon. Local vasopressin injection is a good alternative for bleeding control in conservative laparoscopic surgery. PMID- 30306038 TI - Surgical Planning and Counseling in Adolescence: A Case Report of a 16-Year-Old with an Aborting Pelvic Mass. AB - This case illustrates a rare finding and successful treatment of an aborting fibroid in a virginal adolescent. Careful consideration for the exam process, specific counseling, surgical planning and approach in this case are presented. PMID- 30306039 TI - Single-Phase Focused Ultrasound Surgery for 15-Leiomyoma and Huge Leiomyoma Patients. AB - Focused ultrasound surgery is a potential noninvasive surgery for eliminating leiomyoma. In this clinical image, we introduced an alternative role of this method for cases of multiple leiomyomas and huge leiomyoma with effective outcomes. PMID- 30306040 TI - Port-site Hernia: An Individualized Approach to Port Closure. PMID- 30306041 TI - A Novel Non Invasive Screening Tool for Triaging Endometrial Pathologies in Abnormal Uterine Bleeding: Diseases of Endometrium - Evaluation and Risk Scoring. PMID- 30306042 TI - Hysteroscopy for Pyometra - Treading on Treacherous Grounds. PMID- 30306043 TI - Clinical optoacoustic imaging combined with ultrasound for coregistered functional and anatomical mapping of breast tumors. AB - Optoacoustic imaging, based on the differences in optical contrast of blood hemoglobin and oxyhemoglobin, is uniquely suited for the detection of breast vasculature and tumor microvasculature with the inherent capability to differentiate hypoxic from the normally oxygenated tissue. We describe technological details of the clinical ultrasound (US) system with optoacoustic (OA) imaging capabilities developed specifically for diagnostic imaging of breast cancer. The combined OA/US system provides co-registered and fused images of breast morphology based upon gray scale US with the functional parameters of total hemoglobin and blood oxygen saturation in the tumor angiogenesis related microvasculature based upon OA images. The system component that enabled clinical utility of functional OA imaging is the hand-held probe that utilizes a linear array of ultrasonic transducers sensitive within an ultrawide-band of acoustic frequencies from 0.1 MHz to 12 MHz when loaded to the high-impedance input of the low-noise analog preamplifier. The fiberoptic light delivery system integrated into a dual modality probe through a patented design allowed acquisition of OA images while minimizing typical artefacts associated with pulsed laser illumination of skin and the probe components in the US detection path. We report technical advances of the OA/US imaging system that enabled its demonstrated clinical viability. The prototype system performance was validated in well defined tissue phantoms. Then a commercial prototype system named ImagioTM was produced and tested in a multicenter clinical trial termed PIONEER. We present examples of clinical images which demonstrate that the spatio-temporal co registration of functional and anatomical images permit radiological assessment of the vascular pattern around tumors, microvascular density of tumors as well as the relative values of the total hemoglobin [tHb] and blood oxygen saturation [sO2] in tumors relative to adjacent normal breast tissues. The co-registration technology enables increased accuracy of radiologist assessment of malignancy by confirming, upgrading and/or downgrading US categorization of breast tumors according to Breast Imaging Reporting And Data System (BI-RADS). Microscopic histologic examinations on the biopsied tissue of the imaged tumors served as a gold standard in verifying the functional and anatomic interpretations of the OA/US image feature analysis. PMID- 30306044 TI - Osteoporotic vertebral endplate and cortex fractures: A pictorial review. AB - : Despite years' research, the radiographic criteria for osteoporotic vertebral fracture and its grading remain debated. The importance of identifying vertebral endplate/cortex fracture (ECF) is being recognised; however, evaluation of osteoporotic ECF requires training and experience. This article aims to serve as a teaching material for radiologists/physicians or researchers to evaluate osteoporotic ECF. Emphasis is particularly dedicated to identifying ECF that may not be associated with apparent vertebral body collapse. We suggest a combined approach based on standardised radiologic evaluation by experts and morphometry measurement is the most appropriate approach to detect and classify osteoporotic vertebral fractures. The translational potential: A good understanding of radiologic anatomy of vertebrae and fracture signs of endplate/cortex are essential for spine fragility fracture assessment. PMID- 30306046 TI - Emphysematous infection of a solitary renal cyst: A case report and literature review. PMID- 30306047 TI - Epididymal filariasis a rare presentation of testicular pain. PMID- 30306045 TI - Biomechanical properties of novel transpedicular transdiscal screw fixation with interbody arthrodesis technique in lumbar spine: A finite element study. AB - Purpose: The purpose of this study was to investigate finite element biomechanical properties of the novel transpedicular transdiscal (TPTD) screw fixation with interbody arthrodesis technique in lumbar spine. Methods: An L4-L5 finite element model was established and validated. Then, two fixation models, TPTD screw system and bilateral pedicle screw system (BPSS), were established on the validated L4-L5 finite element model. The inferior surface of the L5 vertebra was set immobilised, and moment of 7.5 Nm was applied on the L4 vertebra to test the range of motion (ROM) and stress at flexion, extension, lateral bending and axial rotation. Results: The intact model was validated for prediction accuracy by comparing two previously published studies. Both of TPTD and BPSS fixation models displayed decreased motion at L4-L5. The ROMs of six moments of flexion, extension, left lateral bending, right lateral bending, left axial rotation and right axial rotation in TPTD model were 1.92, 2.12, 1.10, 1.11, 0.90 and 0.87 degrees , respectively; in BPSS model, they were 1.48, 0.42, 0.35, 0.38, 0.74 and 0.75 degrees , respectively. The screws' peak stress of above six moments in TPTD model was 182.58, 272.75, 133.01, 137.36, 155.48 and 150.50 MPa, respectively; and in BPSS model, it was 103.16, 129.74, 120.28, 134.62, 180.84 and 169.76 MPa, respectively. Conclusion: Both BPSS and TPTD can provide stable biomechanical properties for lumbar spine. The decreased ROM of flexion, extension and lateral bending was slightly more in BPSS model than in TPTD model, but TPTD model had similar ROM of axial rotation with BPSS model. The screws' peak stress of TPTD screw focused on the L4-L5 intervertebral space region, and more caution should be put at this site for the fatigue breakage. The translational potential of this article: Our finite element study provides the biomechanical properties of novel TPTD screw fixation, and promotes this novel transpedicular transdiscal screw fixation with interbody arthrodesis technique be used clinically. PMID- 30306048 TI - Giant cystic lymphangioma of adrenal gland: A case report and review of the literature. PMID- 30306049 TI - Atypical presentation of renal medullary carcinoma: A case report and review of the literature. PMID- 30306050 TI - Prostate surgery in severe congenital factor VII deficiency: A case report. PMID- 30306051 TI - Well-differentiated papillary mesothelioma of the tunica vaginalis: Case report and literature review. PMID- 30306052 TI - Rosai-Dorfman-Destombes disease with renal involvement and secondary glomerulopathy: Report of an exceptional case. PMID- 30306053 TI - Advances in super-resolution photoacoustic imaging. PMID- 30306054 TI - Responsive alginate-cisplatin nanogels for selective imaging and combined chemo/radio therapy of proliferating macrophages. AB - Background: Atherosclerosis is a major global health concern. Targeting macrophages is hypothesized as an alternative treatment for atherosclerosis. Methods: We synthesized alginate-based cisplatin-loaded nanogels (TANgel) as a pH responsive drug-releasing theranostic nanoplatform for macrophage cells. Carboxylic acid groups of alginic acid were modified with iminodiacetic acid (IDA) to enhance chelation of platinum ions. The near infrared (NIR) fluorophore ATTO655 was conjugated to the modified alginic acid. Cisplatin was used as an antiproliferation drug and as a crosslinking agent between alginate molecules to form TANgel. Release behavior of cisplatin from TANgel was analyzed under different pH conditions. Cellular uptake and therapeutic efficacy of TANgel were tested in the macrophage cell line J774A.1 and normal human cell lines such as HDMVECn. Results: The nanogel had a narrow size distribution of approximately 100 nm. The nanogel showed highly pH-responsive drug release behavior. All incorporated cisplatin was released at pH 5 within 48 h, while less than 15% was released at pH 7.4. The nanogel was preferentially taken up by J774A.1 cells compared to normal human cells, enabling selective NIR fluorescence imaging and chemotherapy of macrophage cells. In addition, the nanogel formulation lowered the therapeutic concentration of the drug with and without low dose radiation therapy (RT) compared to the free drug form. Conclusions: This nanogel system may have potential utility for selective NIR fluorescence imaging and combined chemo/radio therapy of proliferating macrophage cells in atherosclerotic regions, allowing for reduction of systemic toxicity. PMID- 30306055 TI - Ultra-wide optical coherence tomography angiography in diabetic retinopathy. AB - Background: To implement an ultra-wide optical coherence tomography angiography imaging (UW-OCTA) modality in eyes with diabetic retinopathy (DR) with the aim of quantifying the burden of microvascular disease at baseline and subsequent clinic visits. Methods: UW-OCTA was implemented on a 1,060 nm swept source (SS) OCTA engine running at 100 kHz A-line rate with a motion tracking mechanism. A montage scanning protocol was used to capture a 100-degree field of view (FOV) using a 4*4 grid of sixteen total individual 6*6 mm2 scans. Typical OCTA images with a FOV of 3*3, 6*6 and 12*12 mm2 were obtained for comparison. DR patients were scanned at baseline and follow-up. They were treated at the clinician's discretion. Vessel density and non-perfusion area maps were calculated based on the UW-OCTA images. Results: Three proliferative DR patients were included in the study. UW-OCTA images provided more detailed visualization of vascular networks compared to 50-degree fluorescein angiography (FA) and showed higher burden of pathology in the retinal periphery that was not captured by typical OCTA. Neovascularization complexes were clearly detected in the two patients with active PDR. Vessel density and non-perfusion maps were used to measure progressive capillary non-perfusion and regression of neovascularization between visits. Conclusions: UW-OCTA provides approximately 100-degree OCTA images of the fundus comparable to that of wide-angle fundus photography, and may be more applicable in conditions such as DR which affect the peripheral retina in contrast to standard OCTA. PMID- 30306056 TI - Monitoring reperfused myocardial infarction with delayed left ventricular systolic dysfunction in rabbits by longitudinal imaging. AB - Background: An experimental imaging platform for longitudinal monitoring and evaluation of cardiac morphology-function changes has been long desired. We sought to establish such a platform by using a rabbit model of reperfused myocardial infarction (MI) that develops chronic left ventricle systolic dysfunction (LVSD) within 7 weeks. Methods: Fifty-five New Zeeland white (NZW) rabbits received sham-operated or 60-min left circumflex coronary artery (LCx) ligation followed by reperfusion. Cardiac magnetic resonance imaging (cMRI), transthoracic echocardiography (echo), and blood samples were collected at baseline, in acute (48 hours or 1 week) and chronic (7 weeks) stage subsequent to MI for in vivo assessment of infarct size, cardiac morphology, LV function, and myocardial enzymes. Seven weeks post MI, animals were sacrificed and heart tissues were processed for histopathological staining. Results: The success rate of surgical operation was 87.27%. The animal mortality rates were 12.7% and 3.6% both in acute and chronic stage separately. Serum levels of the myocardial enzyme cardiac Troponin T (cTnT) were significantly increased in MI rabbits as compared with sham animals after 4 hours of operation (P<0.05). According to cardiac morphology and function changes, 4 groups could be distinguished: sham rabbits (n=12), and MI rabbits with no (MI_NO_LVSD; n=10), moderate (MI_M_LVSD; n=9) and severe (MI_S_LVSD; n=15) LVSD. No significant differences in cardiac function or wall thickening between sham and MI_NO_LVSD rabbits were observed at both stages using both cMRI and echo methods. cMRI data showed that MI_M_LVSD rabbits exhibited a reduction of ejection fraction (EF) and an increase in end-systolic volume (ESV) at the acute phase, while at the chronic stage these parameters did not change further. Moreover, in MI_S_LVSD animals, these observations were more striking at the acute stage followed by a further decline in EF and increase in ESV at the chronic stage. Lateral wall thickening determined by cMRI was significantly decreased in MI_M_LVSD versus MI_NO_LVSD animals at both stages (P<0.05). As for MI_S_LVSD versus MI_M_LVSD rabbits, the thickening of anterior, inferior and lateral walls was significantly more decreased at both stages (P<0.05). Echo confirmed the findings of cMRI. Furthermore, these in vivo outcomes including those from vivid cine cMRI could be supported by exactly matched ex vivo histomorphological evidences. Conclusions: Our findings indicate that chronic LVSD developed over time after surgery-induced MI in rabbits can be longitudinally evaluated using non-invasive imaging techniques and confirmed by the entire-heart-slice histomorphology. This experimental LVSD platform in rabbits may interest researchers in the field of experimental cardiology and help strengthen drug development and translational research for the management of cardiovascular diseases. PMID- 30306057 TI - SPIO-loaded nanostructured lipid carriers as liver-targeted molecular T2-weighted MRI contrast agent. AB - Background: Superparamagnetic iron oxide (SPIO) acts as a negative contrast agent in magnetic resonance imaging (MRI), and is widely used in clinical applications, including the diagnosis of hepatic diseases. Hepatocyte-targeted magnetic resonance contrast agents (MRCAs) can provide useful information for evaluating hepatic diseases. We prepared targeted magnetic nanostructured lipid carriers (MNLCs) to enhance the hepatocytes targeting efficiency. Methods: In vitro characterizations of MNLCs were determined by transmission electron microscopy (TEM). The cytotoxicity assay of the MNLCs was measured by methyl tetrazolium (MTT) method. The uptaken study was measured by confocal microscopy, flow cytometry and MRI in vitro. The enhanced liver-targeting efficiency of MNLCs was measured by fluorescence imaging and MRI in vivo. Results: Gal-NLC-SPIO was prepared successfully. The cytotoxicity assay of the MNLCs demonstrated that the MNLC had relatively low cytotoxicity and high biocompatibility for LO2 cells. More importantly, we confirmed that Gal-NLC-SPIO had greater uptake by LO2 cells than Gal-NLC-SPIO/PEG and free Gal in vitro. A liver distribution study of MNLCs in normal mice demonstrated that the fluorescent signal values to livers of the Gal-NLC-SPIO were significantly stronger than those of NLC-SPIO and Gal-NLC SPIO/PEG. The liver targeting efficiency of Gal-NLC-SPIO was confirmed both in vitro and in vivo. Conclusions: We successfully developed liver-targeting MNLCs, which showed accurate hepatocytes targeting, and thus have the potential to be a new MRI contrast agent to help the diagnosis of liver diseases. PMID- 30306058 TI - Sonographic appearance of fluid in peripheral joints and bursae of healthy asymptomatic Chinese population. AB - Background: High frequency ultrasound is often used to measure the thickness of fluid in peripheral joints and bursae of healthy asymptomatic populations. Two major steps critical to this procedure are obtaining the detection rates and analyzing the relevant factors. Methods: Healthy Chinese adult volunteers with no history of arthritis, past trauma or surgery and joint pain were enrolled in this study. Ultrasonography was performed on the bilateral shoulders, elbows, wrists, metacarpophalangeal joints (MCP) 1-5, proximal interphalangeal joints (PIP) 1-5, distal interphalangeal joints (DIP) 2-5, suprapatellar knees, ankles, metatarsophalangeal joints (MTP) 1-5, subacromial and subdeltoid bursae, deep infrapatellar bursae, retrocalcaneal bursae and long biceps tendons in B mode. Average size of fluid thickness and detection rate were calculated and correlated with demographic parameters. Mean + 1.64 SD was defined as the upper limit of the 95% reference range. Results: One hundred and fifty-two volunteers (71 males and 81 females) with mean age of 48.0+/-14.1 years were enrolled. Both the highest detection rate and the thickest fluid were found in the suprapatellar knee (82.9%, 3.7+/-1.7 mm). There was no significant difference between the left and right side of the same structure in the detection rate and the fluid thickness. Females had a higher detection rate and fluid thickness than males in most examined structures, especially in the upper-limb joints. The greatest number of examined structures was found to be affected by age, and all of the correlations were positive (r from 0.118 to 0.510, P<0.05). Positive correlations were found in the long biceps tendon and MTP1 between detection rate and body mass index (BMI) (r=0.251 and 0.123, respectively, P<0.05), and in the long biceps tendon between effusion thickness and BMI (r=0.228, P<0.05). The upper limits of the 95% reference range for peripheral joints and bursae were determined. Conclusions: Fluid in certain peripheral joints of healthy asymptomatic populations can be associated with gender, age or BMI. This study provided reference values for future comparisons with pathological conditions among Chinese populations. PMID- 30306059 TI - Semi-quantitative analysis of pre-treatment morphological and intratumoral characteristics using 18F-fluorodeoxyglucose positron-emission tomography as predictors of treatment outcome in nasal and paranasal squamous cell carcinoma. AB - Background: To investigate the utility of quantitative morphological and intratumoral characteristics obtained by 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) for the prediction of treatment outcome in patients with nasal or paranasal cavity squamous cell carcinoma (SCC). Methods: Twenty-four patients with nasal or paranasal cavity SCC who received curative non-surgical therapy (a combination of super-selective arterial cisplatin infusion and radiotherapy) were retrospectively analyzed. From pre treatment FDG-PET data, a total of 13 parameters of quantitative morphological characteristics (tumor volume, surface area and sphericity), intratumoral characteristics (the maximum and mean standard uptake value, three intratumoral histogram and four textural parameters) and total lesion glycolysis (TLG) were respectively calculated. Information regarding the treatment outcome was determined from the histological diagnosis or clinical follow-up. Each of the 13 quantitative parameters as well as T- and N-stage was assessed for its relation to treatment outcome of local control or failure. Results: In univariate analysis, significant differences in surface area and sphericity between the local control and failure groups were observed. The receiver operating characteristic (ROC) curve analysis showed that sphericity had the highest accuracy of 0.88. In the multivariate analysis, sphericity was revealed as an independent predictor of the local control or failure. Conclusions: The quantitative parameters of sphericity are useful to predict the treatment outcome in patients with nasal or paranasal SCC. PMID- 30306060 TI - Percutaneous ultrasound-guided balloon-assisted embolization of iatrogenic femoral artery pseudoaneurysms with Glubran(r)2 cyanoacrylate glue: safety, efficacy and outcomes. AB - Background: Femoral pseudoaneurysm (PA) is a frequent complication of arterial access for endovascular procedures. Surgery has traditionally been considered as the gold standard of therapy. We aimed to report our experience of percutaneous ultrasound (US)-guided balloon-assisted embolization with cyanoacrylate glue for the treatment of iatrogenic femoral PAs. Methods: Retrospective two-center study of patients with femoral iatrogenic PAs treated by N-butyl cyanoacrylate methacryloxy sulfolane (NBCA-MS) Glubran(r)2 glue embolization between July 2013 and November 2017. All patients underwent contralateral arterial access with balloon placement of an appropriate size in front of the PA neck before glue/lipiodol embolization in a 1:1 ratio by percutaneous US-guided puncture of the aneurysmal sac under fluoroscopy control. Results: Twenty-three patients (12 females, 11 males; median age, 79 years; range, 18-93 years) were included. Median PA size was 34 mm (range, 17-60 mm). The median time to treatment was 5 days (range, 1-30 days). Twenty patients (86.9%) were successfully treated by glue injection alone. The three remaining patients (13.1%) with persistent PA or associated arterial-venous fistula were immediately treated during the same procedure by additional stent-graft. Then, overall immediate and 1-month clinical success rates were 100%. No surgical conversion was necessary. No recurrence was reported during the median follow-up of 11 months (range, 2-73 months). Two (8.7%) puncture-related complications occurred at the contralateral arterial access site, which spontaneously resolved. No non-target glue embolization occurred. Conclusions: US-guided balloon-assisted glue embolization is safe and effective to treat iatrogenic femoral PAs in most cases, offering complete exclusion of the PA and avoiding the morbidity of open surgery. PMID- 30306061 TI - CT cinematic rendering for pelvic primary tumor photorealistic visualization. AB - Pelvic tumors can be both complicated and challenging, and computed tomography (CT) has played an important role in the diagnosis and treatment planning of these conditions. Cinematic rendering (CR) is a new method of 3D imaging using CT volumetric data. Unlike traditional 3D methods, CR uses the global illumination model to produce high-definition surface details and shadow effects to generate photorealistic images. In this pictorial review, a series of primary pelvic tumor cases are presented to demonstrate the potential value of CR relative to conventional volume rendering (VR). This technique holds great potential in disease diagnosis, preoperative planning, medical education and patient communication. PMID- 30306063 TI - Functional probes for cardiovascular molecular imaging. AB - Cardiovascular diseases (CVDs) are a severely threatening disorder and frequently cause death in industrialized countries, posing critical challenges to modern research and medicine. Molecular imaging has been heralded as the solution to many problems encountered in individuals living with CVD. The use of probes in cardiovascular molecular imaging is causing a paradigmatic shift from regular imaging techniques, to future advanced imaging technologies, which will facilitate the acquisition of vital information at the cellular and molecular level. Advanced imaging for CVDs will help early detection of disease development, allow early therapeutic intervention, and facilitate better understanding of fundamental biological processes. To promote a better understanding of cardiovascular molecular imaging, this article summarizes the current developments in the use of molecular probes, highlighting some of the recent advances in probe design, preparation, and functional modification. PMID- 30306062 TI - Concurrent mapping of brain activation from multiple subjects during social interaction by hyperscanning: a mini-review. AB - Social interaction plays an essential role in acquiring knowledge and developing our own personalities in our daily life. Meanwhile, functional magnetic resonance imaging (fMRI)-, electroencephalograph (EEG)-, and functional near inferred spectroscopy (fNIRS)-hyperscanning, enables us to concurrently map brain activation from two or more participants who are engaged in social interaction simultaneously. In this review, we first highlight the recent technologies advances and the most significant findings towards social interaction by using the hyperscanning method. In addition, we also illustrate several well-designed hyperscanning tasks that have been extensively adopted for the study of social interaction. Basically, hyperscanning contains six categories of experimental paradigms that can track the interactive neural process of interest. Furthermore, it contains two main elucidated neural systems which are involved in social interaction, including the mirror neuron system (MNS) and mentalizing system (MS). Finally, future research directions and clinical implications that are associated with hyperscanning are also highlighted and discussed. PMID- 30306064 TI - CT and MRI of adrenal gland pathologies. AB - Besides ultrasound and nuclear medicine techniques, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used to examine adrenal lesions in both symptomatic and asymptomatic patients. Some adrenal lesions have characteristic radiological features. If an adrenal nodule is discovered incidentally, determining whether the lesion is benign or malignant is of great importance. According to their biological behavior, lesions can be divided into benign (mainly: adenoma, hyperplasia, pheochromocytoma, cyst, hemorrhage, cystic lymphangioma, myelolipoma, hemangioma, ganglioneuroma, teratoma) and malignant (mainly: metastases, adrenal cortical carcinoma, neuroblastoma, lymphoma) conditions. In this paper, we review CT/MRI findings of common adrenal gland lesions. PMID- 30306065 TI - Informed communication with study subjects of radiographically detected osteoporotic vertebral deformity. PMID- 30306066 TI - Incidental abnormal bone marrow signal on magnetic resonance imaging and reflexive testing for the JAK2 V617F mutation. PMID- 30306068 TI - Rare diseases: the paradox of an emerging challenge. PMID- 30306067 TI - MicroRNA expression profile of urinary exosomes in Type IV lupus nephritis complicated by cellular crescent. AB - Background: Type IV lupus nephritis (LNIV) is a severe disease characterized by diffuse proliferative lesions, and its prognosis is worse with cellular crescent (LNIV-CC) involvement. Urinary exosomes have been shown to reflect the degree of kidney injury. This study was aimed to identify non-invasive diagnostic markers for LNIV-CC. We analysed the expression profile of microRNAs (miRNAs) isolated from urinary exosomes in patients with LNIV-CC and LNIV, and healthy individuals using high-throughput sequencing. Results: A total of 66 differentially expressed miRNAs were identified, which were significantly enriched in 15 signalling pathways. Bioinformatic analysis revealed a co-expression network of miRNAs, predicted transcription factors and target mRNAs. Expression of three miRNAs including miR-3135b, miR-654-5p, and miR-146a-5p were further analysed and validated by reverse transcription-quantitative polymerase chain reaction. ROC analysis suggested these as candidate biomarkers for LNIV-CC. Conclusions: LNIV CC has a unique miRNA expression profile of urinary exosome and complex regulatory network. miR-3135b, miR-654-5p and miR-146a-5p in urinary exosomes could be used as novel non-invasive diagnostic markers for LNIV-CC. PMID- 30306069 TI - The burden of cardiac arrhythmias in sarcoidosis: a population-based inpatient analysis. AB - Background: Cardiac involvement in the sarcoidosis is known to ensue with diverse clinical forms and its investigation is challenging at times. This article features the under-perceived burden, patterns, and outcomes of different arrhythmias, which may have a prognostic significance in patients with sarcoidosis. Methods: We queried the National Inpatient Sample (NIS) for 2010 2014 to recognize sarcoidosis, arrhythmia, and comorbidities affecting hospitalizations. The nationwide estimates were attained using discharge records. We assessed incidence and trends in sarcoidosis-related arrhythmia and consequential inpatient mortality, hospital length of stay (LOS), hospitalization charges and predictors of mortality with multivariate analysis. Results: We identified 369,285 sarcoidosis-related hospitalizations. Of these, nearly one fifth suffered from arrhythmias (n=73,424). The sarcoidosis patients developing arrhythmias were older (61.9 vs. 56.0 years) compared to those without. Males had the higher incidence of arrhythmias compared to females. Atrial fibrillation (Afib) (10.97%) was the most common subtype, followed by ventricular tachycardia (1.97%). There was a rising trend in arrhythmia-related hospital admissions and mortality among sarcoidosis, with Afib incidence displaying the highest increase. Traditional cardiac comorbidities were higher in the sarcoid-arrhythmia group. The arrhythmia group had significantly higher mortality (3.7% vs. 1.5%), mean hospital LOS (6.4 vs. 5.2 days) and hospital charges ($64,118 vs. $41,565) compared to non-arrhythmia group (P<0.001). Incident arrhythmia significantly increased the mortality odds in sarcoidosis (adjusted odds ratio, 2.06). Conclusions: The growing trend, deteriorating outcomes and higher mortality associated with sarcoid-related arrhythmias highlight the importance of timely diagnosis and aggressive management in this population. PMID- 30306070 TI - Rare congenital bleeding disorders. AB - The rare congenital bleeding disorders are a heterogeneous group of diseases which include deficiencies of fibrinogen, prothrombin and factors V, V + VIII, VII, X, XI and XIII. They are usually transmitted as autosomal recessive disorders, and the prevalence of the severe forms ranges from one case in 500,000 for factor VII up to one in 2,000,000 for factor XIII in the general population. Patients with rare congenital bleeding disorders may have a broad spectrum of clinical symptoms, ranging from mucocutaneous bleeding to life-threatening haemorrhages, such as those occurring in the central nervous system. The treatment of these disorders is based principally on the replacement of the deficient factor using, when available, specific plasma-derived or recombinant products. The aim of this narrative review is to summarise current knowledge about these rare bleeding conditions. PMID- 30306072 TI - Current and future roles of mucins in cholangiocarcinoma-recent evidences for a possible interplay with bile acids. AB - Cholangiocarcinoma (CCA) is rare but highly malignant tumour. The diagnosis is difficult due to its silent clinical character and the inefficiency of currently available diagnostic markers. An enhanced understanding of the molecular pathways involved in CCA carcinogenesis would herald targeted, individualized therapies, as well as new early diagnostic tool with improvement of patient survival. Recently, two mucin proteins, MUC4 and MUC5 have gained interest for their involvement in tumour growth and progression and possible use as diagnostic and prognostic cancer biomarkers. Moreover, a number of studies have demonstrated an association between biliary or serum bile acids (BAs) and some forms of cancers including CCA. More importantly, BAs have been shown to participate in tumour progression by inducing alterations in the expression of oncogenic mucins. This review summarizes the most important findings regarding the possible use of mucin glycoproteins and BAs in the diagnosis and prognostication of CCA and discuss evidences suggesting a role of BAs in regulating the expression of transmembrane and secreted mucins. PMID- 30306071 TI - Anaphylactic cardiovascular collapse and Kounis syndrome: systemic vasodilation or coronary vasoconstriction? AB - The first reported human anaphylactic death is considered to be the Pharaoh Menes death, caused by a wasp sting. Currently, anaphylactic cardiovascular events represent one of most frequent medical emergencies. Rapid diagnosis, prompt and appropriate treatment can be life saving. The main concept beyond anaphylaxis lies to myocardial damage and ventricular dysfunction, thus resulting in cardiovascular collapse. Cardiac output depression due to coronary hypoperfusion from systemic vasodilation, leakage of plasma and volume loss due to increased vascular permeability, as well as reduced venous return, are regarded as the main causes of cardiovascular collapse. Clinical reports and experiments indicate that the human heart, in general, and the coronary arteries, in particular, could be the primary target of the released anaphylactic mediators. Coronary vasoconstriction and thrombosis induced by the released mediators namely histamine, chymase, tryptase, cathepsin D, leukotrienes, thromboxane and platelet activating factor (PAF) can result to further myocardial damage and anaphylaxis associated acute coronary syndrome, the so-called Kounis syndrome. Kounis syndrome with increase of cardiac troponin and other cardiac biomarkers, can progress to heart failure and cardiovascular collapse. In experimental anaphylaxis, cardiac reactions caused by the intracardiac histamine and release of other anaphylactic mediators are followed by secondary cardiovascular reactions, such as cardiac arrhythmias, atrioventricular block, acute myocardial ischemia, decrease in coronary blood flow and cardiac output, cerebral blood flow, left ventricular developed pressure (LVdp/dtmax) as well as increase in portal venous and coronary vascular resistance denoting vascular spasm. Clinically, some patients with anaphylactic myocardial infarction respond satisfactorily to appropriate interventional and medical therapy, while anti allergic treatment with antihistamines, corticosteroids and fluid replacement might be ineffective. Therefore, differentiating the decrease of cardiac output due to myocardial tissue hypoperfusion from systemic vasodilation and leakage of plasma, from myocardial tissue due to coronary vasoconstriction and thrombosis might be challenging during anaphylactic cardiac collapse. Combined antiallergic, anti-ischemic and antithrombotic treatment seems currently beneficial. Simultaneous measurements of peripheral arterial resistance and coronary blood flow with newer diagnostic techniques including cardiac magnetic resonance imaging (MRI) and myocardial scintigraphy may help elucidating the pathophysiology of anaphylactic cardiovascular collapse, thus rendering treatment more rapid and effective. PMID- 30306075 TI - Sclerosing mesenteritis: a comprehensive clinical review. AB - Sclerosing mesenteritis is a rare disease entity initially described in 1924 with a prevalence reported to be less than 1%. Sclerosing mesenteritis is a comprehensive term used to describe three almost similar clinical entities including mesenteric panniculitis, retractile mesenteritis, and mesenteric lipodystrophy which only differ by their histology. The etiology of sclerosing mesenteritis is uncertain, but the disease has been associated with trauma, autoimmune disease, surgery, and malignancy. The typical presenting symptom is the abdominal pain, but sclerosing mesenteritis has a broad constellation of presenting symptoms which often makes consideration of the diagnosis unlikely. Treatment for this little-understood disease ranges from surgical intervention for patients presenting with obstructive symptoms to immunosuppressive medical therapy for patients presenting with pain. The purpose of this article is to provide an overview of the literature relevant to the diagnosis, etiology, and management of this condition in hopes of making physicians aware of this unique condition. PMID- 30306073 TI - Molecular basis of cystic fibrosis: from bench to bedside. AB - Cystic fibrosis (CF), is an autosomal recessive disease affecting different organs. The lung disease, characterized by recurrent and chronic bacterial infection and inflammation since infancy, is the main cause of morbidity and precocious mortality of these individuals. The innovative therapies directed to repair the defective CF gene should account for the presence of more than 200 disease-causing mutations of the CF transmembrane conductance regulator (CFTR) gene. The review will recall the different experimental approaches in discovering CFTR protein targeted molecules, such as the high throughput screening on chemical libraries to discover correctors and potentiators of CFTR protein, dual acting compounds, read-through molecules, splicing defects repairing tools, CFTR "amplifiers". PMID- 30306074 TI - Insulin autoimmune syndrome: from diagnosis to clinical management. AB - Autoimmune forms of hypoglycemia are a rare cause of low blood sugar levels among Caucasians, and often go misdiagnosed, exposing patients to lengthy series of pointless, potentially harmful and expensive tests. There are two types of autoimmune hypoglycemia. One is insulin autoimmune syndrome (IAS), which is characterized by hyperinsulinemic hypoglycemia, elevated insulin autoantibody (IAA) titers, no prior exposure to exogenous insulin, and no of pathological abnormalities of the pancreatic islets. This condition is also known as "Hirata's disease". The other is type B insulin resistance syndrome (TBIRS), a rare autoimmune disorder resulting in a broad array of abnormalities in glucose homeostasis-from hypoglycemia to extremely insulin-resistant hyperglycemia-caused by the presence of insulin receptor autoantibodies (IRAbs). This review focuses on these two syndromes, describing their epidemiology, possible genetic background, clinical presentation, pathophysiology, diagnosis and treatment. PMID- 30306077 TI - Metabolomics: a challenge for detecting and monitoring inborn errors of metabolism. AB - Timely newborn screening and genetic profiling are crucial in early recognition and treatment of inborn errors of metabolism (IEMs). A proposed nosology of IEMs has inserted 1,015 well-characterized IEMs causing alterations in specific metabolic pathways. With the increasing expansion of metabolomics in clinical biochemistry and laboratory medicine communities, several research groups have focused their interest on the analysis of metabolites and their interconnections in IEMs. Metabolomics has the potential to extend metabolic information, thus allowing to achieve an accurate diagnosis for the individual patient and to discover novel IEMs. Structural and functional information on 247 metabolites associated with 147 IEMs and 202 metabolic pathways involved in various IEMs have been reported in the human metabolome data base (HMDB). For each metabolic gene, a new computational approach can be developed for predicting a set of metabolites, whose concentration is predicted to change after gene knockout in urine, blood and other biological fluids. Both targeted and untargeted mass spectrometry (MS)-based metabolomic approaches have been used to expand the range of disease-associate metabolites. The quantitative targeted approach, in conjunction with chemometrics, can be considered a basic tool for validating known diagnostic biomarkers in various metabolic disorders. The untargeted approach broadens the identification of new biomarkers in known IEMs and allows pathways analysis. Urine is an ideal biological fluid for metabolomics in neonatology; however, the lack of standardization of preanalytical phase may generate potential interferences in metabolomic studies. The integration of genomic and metabolomic data represents the current challenge for improving diagnosis and prognostication of IEMs. The goals consist in identifying both metabolically active loci and genes relevant to a disease phenotype, which means deriving disease-specific biological insights. PMID- 30306076 TI - Diagnostic insights into chronic-inflammatory demyelinating polyneuropathies. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune mediated neuropathy with demyelination of nerve fibers as leading morphological feature. The course of disease can be chronic progressive or remitting relapsing. Whereas for acute immune-mediated neuropathies several serological markers have been identified and used successfully in clinical routine, the serological diagnosis of chronic variants such as CIDP has not yet been evolved satisfactory. The typical CIDP and its various atypical variants are characterized by a certain diversity of clinical phenotype and response to treatment. Thus, diagnostic markers could aid in the differential diagnosis of CIDP variants and stratification of patients for a better treatment response. Most patients respond well to a causal therapy including steroids, intravenous immunoglobulins and plasmapheresis. Apart from electrophysiological and morphological markers, several autoantibodies have been reported as candidate markers for CIDP, including antibodies against glycolipids or paranodal/nodal molecules. The present review provides a summary of the progress in autoantibody testing in CIDP and its possible implication on the stratification of the CIDP variants and treatment response. PMID- 30306079 TI - Diagnosis of neurodegenerative dementia: where do we stand, now? AB - After many years of large efforts made for understanding the pathogenesis of dementias, the early diagnosis of these degenerative diseases remains an open challenge. Alzheimer's disease (AD) represents the most common form of dementia, followed by Lewy body disease and frontotemporal degeneration. Actually, different pathological processes can determine similar and overlapping clinical syndrome. To detect in vivo the pathological process underlying progressive cognitive and behavior impairment, the Internationals guidelines recommend the use of biological and topographical markers, which can reflect neuropathological modifications in brain. In cerebrospinal fluid (CSF), decrease of amyloid beta 1 42 (Abeta42) and a low ratio of Abeta42 with amyloid beta 1-40 (Abeta42/Abeta40), together with the increase of both total tau protein (t-tau) and phosphorylated tau (p-tau), contribute to define the "Alzheimer's signature". This review points out on the evolution of the concept for early diagnosis of AD, and on the current use of CSF proteins for research purposes and in clinical setting. Then, we discuss the limitations and drawbacks in wide application of CSF biomarkers for diagnosing degenerative dementias, and on the role of laboratory medicine to convey these biomarkers from "research" toward "clinical practice". PMID- 30306078 TI - Old and new insights into the diagnosis of hereditary spherocytosis. AB - Hereditary spherocytosis (HS) belongs to the group of congenital hemolytic anemias resulting from plasma membrane protein deficiency. When diagnosed too late, HS bares the risk of long-term complications including gall stones and severe anemia. Here, there are discussed advances in HS screening and diagnostics, with a particular focus on methodologies, most of which are available in clinical laboratories worldwide. PMID- 30306080 TI - Biochemical markers of acute intestinal ischemia: possibilities and limitations. AB - Acute intestinal ischemia is a relative rare abdominal emergency, associated with considerably high morbidity and mortality rates. Although the conventional diagnostic approach to acute intestinal ischemia entails a preliminary evaluation of signs and symptoms, followed by radiological and laboratory investigations, a definitive diagnosis is can usually be made after laparotomy, which still remains the gold standard diagnostic (and therapeutic) procedure. Several potential laboratory biomarkers have been investigated over the past decades, but none of these seems to reach a suitable diagnostic accuracy for an early and reliable diagnosis of intestinal ischemia. The aim of this narrative review is to provide an overview on traditional laboratory tests for diagnosing acute intestinal ischemia (i.e., complete blood count, D-dimer, blood gas analysis, total lactic acid, C-reactive protein and procalcitonin), and summarize current evidence regarding some emerging and potentially useful biomarkers such as D-lactate, intestinal fatty acid-binding protein (I-FABP), ischemia modified albumin (IMA), alpha-glutathione S-transferase (alpha-GST), interleukin-6 (IL-6), citrulline and smooth muscle protein of 22 kDa (SM22). Among the various tests, D-lactate, IMA and I-FABP are perhaps the most promising, since they are characterized by optimal sensitivity and relatively good specificity, early kinetics, and can be measured with assays suited for a rapid diagnosis. PMID- 30306081 TI - Rare thrombophilic conditions. AB - Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other conditions have been described so far, which have then allowed to currently detect an inherited or acquired predisposition in approximately 60-70% of patients with thromboembolic disorders. These prothrombotic risk factors mainly include qualitative or quantitative defects of endogenous coagulation factor inhibitors, increased concentration or function of clotting proteins, defects in the fibrinolytic system, impaired platelet function, and hyperhomocysteinemia. In this review article, we aim to provide an overview on epidemiologic, clinic and laboratory aspects of both acquired and inherited rare thrombophilic risk factors, especially including dysfibrinogenemia, heparin cofactor II, thrombomodulin, lipoprotein(a), sticky platelet syndrome, plasminogen activator inhibitor-1 apolipoprotein E, tissue factor pathway inhibitor, paroxysmal nocturnal haemoglobinuria and heparin induced thrombocytopenia. PMID- 30306083 TI - e-thrombosis: epidemiology, physiopathology and rationale for preventing computer related thrombosis. AB - The large availability of computers (personal, laptop and tablet) has revolutionized human life more than any other discovery or invention over the past century. Nevertheless, prolonged use of computers may both directly and indirectly promote the onset of some serious human pathologies, thus including venous thromboembolism (VTE). Convincing epidemiological and biological evidence has been published that computer-related thrombosis (also known as "e thrombosis") should now be regarded as an independent clinical entity, deserving enhanced healthcare focus and interventions, due to the growing worldwide diffusion of computer devices, which may ultimately contribute to enhance the risk of computer-related thrombosis, and turn it from a relatively rare disease to a noticeably frequent pathology. A set of preventive measures can thus be suggested, such as designing and setting up ergonomically suitable computer workstations, using comfortable sitting positions, avoiding long and uninterrupted computer-seated immobility, and avoiding the wearing of restrictive clothing on the legs. Reinforced measures should then be advised in patients with acquired, or inherited prothrombotic conditions, in whom the risk of computer related thrombosis may be substantially magnified. PMID- 30306082 TI - Sleep-disordered breathing in paediatric setting: existing and upcoming of the genetic disorders. AB - Childhood obstructive sleep apnea syndrome (OSAS) is characterized by anatomical and functional upper airway abnormalities as pathophysiological determinants, and clinical symptoms are frequently clear. OSAS is widely described in rare genetic disorders, such as achondroplasia, Down syndrome, Prader-Willi syndrome, Pierre Robin sequence, and mucopolysaccharidosis. Craniofacial and upper airway involvement is frequently morbid conditions. In children with genetic diseases, the clinical symptoms of OSAS are often slight or absent, and related morbidities are usually more severe and can be observed at any age. The present review is aimed to updating the discoveries regarding OSAS on Achondroplasia, Down syndrome, Prader-Willi syndrome, Pierre Robin sequence, Sickle cell disease, or encountered in our clinical practice (Ehlers-Danlos syndrome, Ellis-van Creveld syndrome, Noonan syndrome). Two additional groups of genetic disorders will be focused (mucopolysaccharidoses and osteogenesis imperfecta). The flowing items are covered for each disease: (I) what is the pathophysiology of OSAS? (II) What is the incidence/prevalence of OSAS? (III) What result from the management and prognosis? (IV) What are the recommendations? Considering the worries of OSAS, such as inattention and behavioural problems, daytime sleepiness, failure to thrive, cardiological and metabolic complications, the benefit of a widespread screening and the treatment in children with genetic diseases is undoubtful. The goals of the further efforts can be the inclusion of various genetic diseases into guidelines for the screening of OSAS, updating the shreds of evidence based on the research progression. PMID- 30306084 TI - Rare forms of von Willebrand disease. AB - von Willebrand disease (VWD) arises from deficiency and/or defect(s) of plasma von Willebrand factor (VWF). In turn, plasma VWF is an adhesive protein which primarily functions by anchoring platelets to regions of vascular injury, thereby assisting prevention of bleeding. There is a proportional reduction also in Factor VIII, due to the absence of the stabilizing and anti-proteolytic effect that VWF normally exerts. VWD is reportedly the most common inherited bleeding disorder and can be classified into quantitative and qualitative defects, with type 1 and 3 VWD respectively identifying partial and total quantitative deficiency of VWF, and type 2 VWD identifying qualitative defects of VWF. The relative incidence of each subtype of VWD differs according to the locality and the ability of clinicians and laboratories to correctly diagnose and classify cases. In general, type 1 VWD is considered the most common type of VWD, whereas types 2 and 3 represent rarer forms. However, in developing countries, and partly because of consanguinity, type 3 VWD is over-represented. This review primarily focuses on the rarer forms of VWD, which typically comprise types 2 (A, B, M and N) and 3 VWD. The review also mentions type 1 VWD, largely for completeness and comparability, and since purportedly "severe" type 1 VWD, albeit not a formally recognized subtype of type 1 VWD, would represent a relatively "rare" form of VWD. PMID- 30306085 TI - Effect of MDP-Based Primers on the Luting Agent Bond to Y-TZP Ceramic and to Dentin. AB - Purpose: The aim of this study was to evaluate the influence of multimode MDP based primers and different application protocols on the bond strength of a representative resin cement to an yttrium stabilized tetragonal zirconia (Y-TZP) ceramic. Materials and Methods: The occlusal dentin from 60 human molars was exposed. The teeth and zirconia cylinders (N = 60) (3 mm of diameter; 4 mm of height) were divided into six groups (n = 10) according to the ceramic surface conditioning: (1) air abraded with SiO2 particles; (2) Z-Prime Plus; (3) air abraded with SiO2 particles + Z-Prime Plus; (4) air abraded with SiO2 particles + All-Bond Universal; (5) air abraded with SiO2 particles + ScotchBond Universal Adhesive; and (6) untreated zirconia. The luting agent (Duo-Link cement) was applied on the treated dentin surface. Specimens were stored in water (37 degrees C, 24 h) and tested in shear bond strength. Data were statistically analyzed using 2-way ANOVA and Post hoc Tukey tests (alpha = 0.05). Results: Significant effects of ceramic conditioning were found (p < 0.0001). The specimens sandblasted with silica particles followed by the application of Z-Prime Plus or All-Bond Universal presented greater bond strength values. For the untreated zirconia, several specimens failed prematurely prior to testing. Conclusions: Sandblasting with silica particles combined with Z-Prime Plus increased the bond strength. PMID- 30306086 TI - The Dental Management of Patients at Risk of Medication-Related Osteonecrosis of the Jaw: New Paradigm of Primary Prevention. AB - Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is a potentially painful and debilitating condition that can considerably affect the quality of life of patients. Furthermore, even if its epidemiology and pathogenesis have still not been fully clarified, several risk factors related to MRONJ have been recognized in prevention protocols. Three main risk factors are as follows: (i) the type of ONJ-related medications: antiresorptive (e.g., Bisphosphonates, Denosumab) and antiangiogenic drugs (e.g., Bevacizumab, Sunitinib); (ii) the category of patient at MRONJ risk: cancer versus non-cancer patient; (iii) the typologies and timing of dental treatments (e.g., before, during, or after the drug administration). The aim of this paper is to describe the new paradigm by the Italian Society of Oral Pathology and Medicine (SIPMO) on preventive dental management in patients at risk of MRONJ, prior to and during/after the administration of the aforementioned ONJ-related drugs. In reducing the risk of MRONJ, dentists and oral hygienists are key figures in applying a correct protocol of primary prevention for pre-treatment and in-treatment patients. However, the necessity of a multidisciplinary standardized approach, with a sustained dialogue among specialists involved, should be always adopted in order to improve the efficacy of preventive strategies and to ameliorate the patient's quality of life. PMID- 30306088 TI - Comment on "Optic Nerve Sheath Diameter Ultrasound Evaluation in Intensive Care Unit: Possible Role and Clinical Aspects in Neurological Critical Patients' Daily Monitoring". PMID- 30306087 TI - The Augment of the Stability in Locking Compression Plate with Intramedullary Fibular Allograft for Proximal Humerus Fractures in Elderly People. AB - Objective: The objective of this study was to compare the clinical outcomes and complications between the locking compression plate (LCP) and LCP with fibular allograft in the treatment of patients with displaced proximal humerus fracture (PHF) in elderly people. Material and Methods: Between January 2010 and December 2013, a total of 97 elderly patients with displaced PHF were treated by LCP or LCP with fibular allograft, and finally 89 patients were included in our study. All the patients were divided into Group I (patients treated by LCP) and Group II (patients treated by LCP with fibular allograft). Function results were assessed by the disability of the arm, shoulder, and hand (DASH) score and Constant-Murley score (CMS), and complications were also recorded in each group. Results: The average follow-up was 35.2 months (range, 24-48 months) in Group I and 33.5 months (range, 24-48 months) in Group II. DASH in patients of Group I was significantly higher than that in patients in Group II and patients of Group I had CMS scores significantly lower than patients in Group II (P<0.05). The rates of varus malunion, screw perforation, and loss of reduction>5mm were significantly higher in Group I than in Group II (P<0.05). Conclusions: The present results showed that that patients treated by LCP with fibular allograft had a better functional outcome and a lower complication rate compared to patients treated by LCP alone. Suitable void filler in the proximal humerus for supporting the head fragment, medial cortical bone, and greater tuberosity might play a key role in reducing the incidence of the complications in elderly patients, especially with osteoporosis. PMID- 30306090 TI - Multicriteria Decision Model and Thermal Pretreatment of Hotel Food Waste for Robust Output to Biogas: Case Study from City of Jaipur, India. AB - The anaerobic batch test (45 days at 37 degrees C) was performed to describe the effect of thermal pretreatment at moderate temperatures (60, 80, and 100 degrees C) over durations of 10 and 20 minutes on the enhancement of biogas production using hotel food waste from city of Jaipur, India. The results showed that the total cumulative biogas production with thermal pretreatment (100 degrees C, 10 minutes) was 41% higher than the control. Also, this alternative gets first rank using multicriteria decision making model, VIKOR. This outcome was obtained due to the enhancement of degradation of organic compounds such as protein and volatile solids that occurred in the linear trend. Modified Gompertz and Logistic models were used to study the effect of different pretreatment parameters on lag time and biogas yield. Scanning electron microscopy and Fourier transform infrared spectroscopy were also employed to investigate the effect of thermal pretreatment on the physiochemical properties of food waste. PMID- 30306091 TI - Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients. AB - Objective: To characterize the genotype and phenotype of Chinese patients with congenital hyperinsulinism (CHI) caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Methods: The clinical data of glutamate dehydrogenase hyperinsulinism (GDH-HI) patients were reviewed, and gene mutations were confirmed by whole exome sequencing (WES) and Sanger DNA sequencing. Results: Twenty-six patients with GDH-HI heterozygous missense mutations were identified from 240 patients diagnosed as congenital hyperinsulinism over past 15 years. The median age at onset was 8 months (range: 1 day of life to 3 years). Seizure disorder was common in our cohort of patients (23/26). Four patients had normal serum ammonia levels; the median serum concentration was 101 MUmol/L (range: 37-190 MUmol/L). Hypoglycemic symptoms could be triggered by fasting or protein meals in all patients while blood glucose could be well controlled in all patients with diazoxide. Dosage of diazoxide could be reduced by protein restriction. Attempts to lower ammonia levels failed with different therapies such as protein restriction, benzoate, or N-carbamoyl glutamate. In follow-up, 15 of 26 patients had normal intelligence. Eleven patients developed epilepsy at the age of 6 months to 11 years. De novo mutations in GLUD1 were found in 24 cases, and dominant inheritance was observed in the other two; all were heterozygous. A total of 35% (9/26) patients carried c.1493C>T (p.S445L) mutation. Conclusions: Phenotypic heterogeneity of GDH-HI patients was observed within the Chinese cohort in the present study. The fact that most patients had a GLUD1 p. S445L mutation implies that this site could be a hotspot in Chinese patients. A high frequency of GDH-HI with normal ammonia has been reported in this study. Hence, GLUD1 mutational analysis may be an important method to differential diagnosis of GDH-HI from other diazoxide-responsive CHI in Chinese patients. PMID- 30306089 TI - Prognostic Value and Therapeutic Perspectives of Coronary CT Angiography: A Literature Review. AB - Coronary stenosis severity is both a powerful and a still debated predictor of prognosis in coronary artery disease. Coronary computed tomographic angiography (CCTA) has emerged as a noninvasive technique that enables anatomic visualization of coronary artery disease (CAD). CCTA with newer applications, plaque characterization and physiologic/functional evaluation, allows a comprehensive diagnostic and prognostic assessment of otherwise low-intermediate subjects for primary prevention. CCTA measures the overall plaque burden, differentiates plaque subtypes, and identifies high-risk plaque with good reproducibility. Research in this field may also advance towards an era of personalized risk prediction and individualized medical therapy. It has been demonstrated that statins may delay plaque progression and change some plaque features. The potential effects on plaque modifications induced by other medical therapies have also been investigated. Although it is not currently possible to recommend routinely serial scans to monitor the therapeutic efficacy of medical interventions, the plaque modulation, as a part of risk modification, appears a feasible strategy. In this review we summarize the current evidence regarding vulnerable plaque and effects of lipid lowering therapy on morphological features of CAD. We also discuss the potential ability of CCTA to characterize coronary atherosclerosis, stratify prognosis of asymptomatic subjects, and guide medical therapy. PMID- 30306092 TI - Diabetic Enteropathy: From Molecule to Mechanism-Based Treatment. AB - The incidence of the micro- and macrovascular complications of diabetes is rising, mirroring the increase in the worldwide prevalence. Arguably, the most common microvascular complication is neuropathy, leading to deleterious changes in both the structure and function of neurons. Amongst the various neuropathies with the highest symptom burden are those associated with alterations in the enteric nervous system, referred to as diabetic enteropathy. The primary aim of this review is to provide a contemporaneous summary of pathophysiology of diabetic enteropathy thereby allowing a "molecule to mechanism" approach to treatment, which will include 4 distinct aspects. Firstly, the aim is to provide an overview of the diabetes-induced structural remodelling, biochemical dysfunction, immune-mediated alterations, and inflammatory properties of the enteric nervous system and associated structures. Secondly, the aim is to provide a synopsis of the clinical relevance of diabetic enteropathy. Thirdly, the aim is to discuss the various patient-reported outcome measures and the objective modalities for evaluating dysmotility, and finally, the aim is to outline the clinical management and different treatment options that are available. Given the burden of disease that diabetic enteropathy causes, earlier recognition is needed allowing prompt investigation and intervention, which may lead to improvements in quality of life for sufferers. PMID- 30306094 TI - Evaluation of Soluble CD48 Levels in Patients with Allergic and Nonallergic Asthma in Relation to Markers of Type 2 and Non-Type 2 Immunity: An Observational Study. AB - CD48 is a costimulatory receptor associated with human asthma. We aimed to assess the significance of the soluble form of CD48 (sCD48) in allergic and nonallergic asthma. Volunteer patients completed an asthma and allergy questionnaire, spirometry, methacholine challenge test, a common allergen skin prick test, and a complete blood count. sCD48, IgE, IL5, IL17A, IL33, and IFNgamma were quantitated in serum by ELISA. Asthma was defined as positive methacholine challenge test or a 15% increase in FEV1 post bronchodilator in symptomatic individuals. Allergy was defined as positive skin test or IgE levels > 200 IU/l in symptomatic individuals. 137 individuals participated in the study: 82 (60%) were diagnosed with asthma of which 53 (64%) was allergic asthma. sCD48 levels were significantly elevated in patients with nonallergic asthma compared to control and to the allergic asthma cohort (median (IQR) pg/ml, 1487 (1338-1758) vs. 1308 (1070-1581), p < 0.01, and 1336 (1129-1591), p = 0.02, respectively). IL17A, IL33, and IFNgamma levels were significantly elevated in allergic and nonallergic asthmatics when compared to control. No correlation was found between sCD48 level and other disease markers. sCD48 is elevated in nonallergic asthma. Additional studies are required for understanding the role of sCD48 in airway disease. PMID- 30306096 TI - Stress Fractures of the Elbow in the Throwing Athlete: A Systematic Review. AB - Background: Stress fractures of the elbow are rare in throwing athletes and present a challenge from both a management and rehabilitation perspective. Although the incidence of stress fractures of the elbow is increasing, there is a lack of data in the literature focused on throwers. Purpose: To evaluate studies regarding the management and outcomes of stress fractures of the elbow in throwing athletes. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was conducted by searching the Scopus, PubMed, and Cochrane Library electronic databases to identify studies reporting on the management and outcomes of stress fractures in overhead-throwing athletes. Management data included nonoperative and operative modalities, and outcome data included return to play, encompassing the timing and level of activity. Studies were excluded if the stress fracture of the elbow was not a result of a sport injury attributed to throwing or if the study failed to report whether an athlete returned to play. Results: Fourteen studies met the inclusion criteria and were included in this analysis. There were 52 patients in total (50 male, 2 female) with a mean age of 19.7 years (range, 13-29.1 years). The olecranon was the most common location of the stress fracture (51 patients; 98.1%), followed by the distal humerus (1 patient; 1.9%). The majority of patients (n = 40; 76.9%) were treated operatively. Of the 40 patients who were treated surgically, 14 (35.0%) underwent a period of conservative treatment preoperatively that ultimately failed because of persistent nonunion or continued elbow pain. A total of 50 patients (96.2%) returned to sport either at or above their preinjury level. Of the 2 patients (3.8%) who did not return to sport, 1 did not return because of continued elbow pain postoperatively, and the other was lost to follow-up. Complications occurred in 9 patients (17.3%), all of whom were treated surgically. Conclusion: On the basis of this systematic review, the majority of elbow stress fractures were treated operatively and approximately one-third after a period of failed nonoperative management. The return-to-sport rate was high. Further, higher level studies are needed to optimize management and return-to sport rates in this population. PMID- 30306095 TI - Human Botfly: A Case Report and Overview of Differential Diagnosis. AB - Dermatobia hominis, commonly known as the human botfly, is native to Tropical America. As such, cutaneous infestation by its developing larvae, or myiasis, is quite common in this region. The distinct dermatological presentation of D hominis myiasis allows for its early recognition and noninvasive treatment by locals. However, it can prove quite perplexing for those unfamiliar with the lesion's unique appearance. Common erroneous diagnoses include the following: folliculitis, benign dermatocyst, and embedded foreign body with localized infection. We present a patient who acquired D hominis while she was in Belize. In this report, we discuss the presentation, differential diagnosis, diagnostic tests, and therapeutic approaches of human botfly lesion to raise the awareness about human botfly. PMID- 30306097 TI - Patient Preferences for the Treatment of Shoulder and Proximal Biceps Disorders Are Associated With Patient Age, Race, Sex, and Activity Level. AB - Background: Patient preference information has become increasingly more important in clinical decision making. Purpose: To assess patient preferences when making treatment decisions in the shoulder to determine which features are more important according to patient age, race, activity level, and sex. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Study participants aged >=18 years were surveyed as to their preferences regarding surgical treatment for shoulder and proximal biceps abnormalities. Survey features included time to return to unrestricted activities, time to return to work, size and appearance of scars, the potential for persistent pain in the upper arm or shoulder, fatigue in the biceps with repetitive lifting, potential for muscle cramping, and deformity in the proximal biceps. Participants also completed a validated shoulder activity scale, and demographic data regarding age, race, and sex were collected. Results: A total of 349 participants (166 female, 183 male) with a mean age of 45 years (range, 18-81 years) completed the survey. Overall, time to return to unrestricted activities and residual pain were considered very important to the majority of the respondents, while the size and appearance of surgical scars were of little importance. Prior shoulder pain (rho = -0.17; P = .01) and prior shoulder surgery (rho = -0.16; P = .03) correlated to concern about time to return to unrestricted activities. Younger age (rho = -0.11; P = .04) and a higher level of education (rho = 0.14; P = .03) correlated with greater concern for time to return to work. Women and African Americans were more concerned about the size and appearance of surgical scars (rho = -0.28; P < .0001 and rho = 0.20; P = .0002, respectively) and biceps deformity. Respondents with a higher activity level (rho = 0.20; P = .0002) and men (rho = 0.11; P = .04) were more concerned about fatigue. Conclusion: Concerns about residual pain, time to return to unrestricted activities, and time away from work are important to patients when considering the treatment for shoulder lesions. Patient preferences are associated with age, sex, race, and shoulder activity level. These features should be considered when discussing treatment options for shoulder and proximal biceps tendon disorders. PMID- 30306098 TI - Impact of Transcranial Direct Current Stimulation on Reading Skills of Children and Adolescents With Dyslexia. AB - Introduction: Rehabilitation techniques have been used to facilitate reading acquisition in dyslexia. However, many individuals continue to present academic impairment throughout life. New intervention strategies are necessary to further help this population. Objectives: Assess the impact of transcranial direct current stimulation on reading skills in children and adolescents with dyslexia. Methods: The study was conducted with one-group pretest-posttest. Participants received 2 mA transcranial direct current stimulation during 30 minutes for 5 consecutive days. Reading performance was measured by a group of tasks (identification and reading of letters, syllables, words, nonwords, and text). Results: A significant increase in the number of correct answers for nonwords and text tasks was observed after transcranial direct current stimulation (P = .035 and P = .012, respectively). Conclusion: The transcranial direct current stimulation seems to be a promising tool for the treatment of reading problems in dyslexia. Future studies are necessary to confirm the effects of transcranial direct current stimulation and to establish optimal intervention protocol in this population. PMID- 30306093 TI - Viral and Nonviral Engineering of Natural Killer Cells as Emerging Adoptive Cancer Immunotherapies. AB - Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors. In addition, the short postinfusion persistence of NK cells in vivo has limited their clinical efficacy. Enhancing the antitumor immunity of NK cells through genetic engineering has been fueled by the promise that impaired cytotoxic functionality can be restored or augmented with the use of synthetic genetic approaches. Alongside expressing chimeric antigen receptors to overcome immune escape by cancer cells, enhance their recognition, and mediate their killing, NK cells have been genetically modified to enhance their persistence in vivo by the expression of cytokines such as IL-15, avoid functional and metabolic tumor microenvironment suppression, or improve their homing ability, enabling enhanced targeting of solid tumors. However, NK cells are notoriously adverse to endogenous gene uptake, resulting in low gene uptake and transgene expression with many vector systems. Though viral vectors have achieved the highest gene transfer efficiencies with NK cells, nonviral vectors and gene transfer approaches-electroporation, lipofection, nanoparticles, and trogocytosis-are emerging. And while the use of NK cell lines has achieved improved gene transfer efficiencies particularly with viral vectors, challenges with primary NK cells remain. Here, we discuss the genetic engineering of NK cells as they relate to NK immunobiology within the context of cancer immunotherapy, highlighting the most recent breakthroughs in viral vectors and nonviral approaches aimed at genetic reprogramming of NK cells for improved adoptive immunotherapy of cancer, and, finally, address their clinical status. PMID- 30306099 TI - Selecting a Grounded Theory Approach for Nursing Research. AB - Grounded theory is a commonly used research methodology. There are three primary approaches to grounded theory in nursing research: those espoused by Glaser, Strauss and Corbin, and Charmaz. All three approaches use similar procedures, yet there are important differences among them, which implies that researchers need to make careful choices when using grounded theory. Researchers new to grounded theory need to find the most appropriate approach that fits their research field, topic, and researcher position. In this article, we compare the three grounded theory approaches. Choices of a grounded theory approach will depend on the researcher's understanding of the philosophical underpinnings of all three approaches. Practical aspects of grounded theory approaches should match the information processing styles and analytical abilities of the researcher and the intended use of the theory. We illustrate key aspects of decision making about which method to select by drawing upon the first author's experiences in his doctoral research. PMID- 30306101 TI - Water vapor sorption and glass transition temperatures of phase-separated amorphous blends of hydrophobically-modified starch and sucrose. AB - This article contains water vapor sorption data obtained on amorphous blends of octenyl succinic acid-modified (denoted as hydrophobically modified starch; HMS) and sucrose (S) in the anhydrous weight HMS/S ratios between 100/0 and 27/75. The water vapor sorption data was obtained gravimetrically. The amorphous state of the blends was confirmed by X-ray diffraction. The glass transition temperatures of the phase-separated blends are listed; the blends show phase separation into a sucrose-rich phase and a HMS-rich phase, the composition of which varies with the blend ratios. The sucrose-rich phase is characterized by a glass transition temperature T g,lower that is 40 to 90 K lower than the glass transition temperature T g,upper of the HMS-rich phase. PMID- 30306100 TI - Glucocorticoids cause mandibular bone fragility and suppress osteocyte perilacunar-canalicular remodeling. AB - Osteocytes support dynamic, cell-intrinsic resorption and deposition of bone matrix through a process called perilacunar/canalicular remodeling (PLR). In long bones, PLR depends on MMP13 and is tightly regulated by PTH, sclerostin, TGFbeta, and glucocorticoids. However, PLR is regulated differently in the cochlea, suggesting a mechanism that is anatomically distinct. Unlike long bones, the mandible derives from neural crest and exhibits unique susceptibility to medication and radiation induced osteonecrosis. Therefore, we sought to determine if PLR in the mandible is suppressed by glucocorticoids, as it is in long bone. Hemimandibles were collected from mice subcutaneously implanted with prednisolone or vehicle containing pellets for 7, 21, or 55 days (n = 8/group) for radiographic and histological analyses. Within 21 days, micro-computed tomography revealed a glucocorticoid-dependent reduction in bone volume/total volume and trabecular thickness and a significant decrease in bone mineral density after 55 days. Within 7 days, glucocorticoids strongly and persistently repressed osteocytic expression of the key PLR enzyme MMP13 in both trabecular and cortical bone of the mandible. Cathepsin K expression was significantly reduced only after 55 days of glucocorticoid treatment, at which point histological analysis revealed a glucocorticoid-dependent reduction in the lacunocanalicular surface area. In addition to reducing bone mass and suppressing PLR, glucocorticoids also reduced the stiffness of mandibular bone in flexural tests. Thus, osteocyte PLR in the neural crest-derived mandible is susceptible to glucocorticoids, just as it is in the mesodermally-derived femur, highlighting the need to further study PLR as a target of drugs, and radiation in mandibular osteonecrosis. PMID- 30306103 TI - Change of permanent grasslands extent (1996-2015) and national grassland dataset of Switzerland. AB - So far, neither a grassland map, temporal analysis of the conversion of permanent grassland (PG) to other land uses nor the differentiation of permanent and temporal grassland exists for Switzerland. For the first time in Switzerland, we present a Swiss national grassland map for the year 2015 capturing the extent of both, permanent and temporal grasslands (here called grasslands) by intersecting the information of three datasets. We blended the high temporal resolution Climate Change Initiate (CCI) Land Cover of 2015 (processed by the European Space Agency (ESA)), with the high spatial resolution Swiss topographical landscape model "SwissTLM3D" and the landscape model "vector25" both provided by Swisstopo. The final data presents the spatial patterns and the national extent of Swiss grasslands. Furthermore, the recently published (April 2017) CCI Land Cover dataset allow extracting the extent of grasslands for 24 years (1992-2015) with a coarse spatial resolution of 300 m. We used the time series data of the grassland extent to produce annual PG maps from 1996 to 2015. That data enables the identification of the development of grassland extent over two decades. The Swiss national grassland map is used for investigating the spatio-temporal patterns of the soil erosion risk of Swiss grasslands (see Mapping spatio-temporal dynamics of the cover and management factor (C-factor) for grasslands in Switzerland, doi:10.1016/j.rse.2018.04.008 (Schmidt el al., 2018)). PMID- 30306102 TI - Collated data of mutation frequencies and associated genetic variants of bedaquiline, clofazimine and linezolid resistance in Mycobacterium tuberculosis. AB - A comprehensive literature search was conducted to obtain previously published resistance associated mutations for bedaquiline, clofazimine and linezolid for Mycobacterium tuberculosis. Where possible, mutation frequencies for these three drugs were also identified. This catalog of previously published mutations could serve as a reference for comparing mutations associated with either in vitro or clinical resistant mutants. The usage of these data was seen in our study relating to approaches for resistance mutant creation (in vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variants (Ismail et al., 2018 in press). Previously published mutations for clofazimine were described in the rv0678 and rv1979c genes, for bedaquiline in atpE, rv0678 and rv2535c (pepQ) genes and for linezolid in the rplC and rrl genes. PMID- 30306104 TI - Sandwich-like Ni2P nanoarray/nitrogen-doped graphene nanoarchitecture as a high performance anode for sodium and lithium ion batteries. AB - The data presented in this article are related to the research article entitled "Sandwich-like Ni2P Nanoarray/Nitrogen-Doped Graphene Nanoarchitecture as a High Performance Anode for Sodium and Lithium Ion Batteries (Dong et al., 2018)". This work shows the morphology and structural of Ni2P/NG/Ni2P and the electrochemial performance of Ni2P/NG/Ni2P. PMID- 30306105 TI - Data on the effect of temperature variation tendency on the inhibitive absorption of Lasienthera africanum in 0.5M HCl: A necessity. AB - The assessment of Lasienthera africanum as corrosion inhibitor for aluminium alloy in 0.5M HCl acid solution using weight loss method was investigated at 303 and 313 K to check its behaviour at high temperature application. Inhibitor efficiency (IE) as high as 93.8, 87.3% both at 303 and 313 K, respectively, was obtained. It can be seen that the inhibition efficiency values increase with increase in extract concentration which suggests that the inhibition is due to the adsorption of the inhibitor on the metal surface. A straight line is obtained when C/theta is plotted against C with linear correlation coefficient of the fitted data close to 1. The adsorption of the inhibitor molecules obey Lanqmuir's adsorption isotherm. PMID- 30306106 TI - Data of root anatomical responses to periodic waterlogging stress of tobacco (Nicotiana tabacum) varieties. AB - The data of root anatomical structure and the formation of aerenchyma tissues of five varieties of tobacco under waterlogging stress were obtained by modified paraffin method. Each tobacco varieties performed distinct anatomical adaptation response, including changes of cortical tissue, stele diameter, xylem diameter and the formation of aerenchyma under periodic waterlogging stress. PMID- 30306107 TI - Personality variables in risk perception, learning and risky choice after safety training: Data of two empirical intervention studies contrasting immersive VR and PowerPoint. AB - The data provided contains personality variables as well as risk perception, choice data and learning outcomes after safety training which differed between subject regarding whether it was carried out in immersive virtual reality (VR) or as a PowerPoint. The data presented here is reported in the study of Leder et al. (in press) [3] where the impact of presentation medium on safety training effectiveness was investigated. The data is hosted on the open science project: https://osf.io/rxq5w/?view_only=cd42aa4b97514f16af8884697450d2a6. PMID- 30306108 TI - Data on the porphyrin effect and influence of dopant ions on Thaumatococcus daniellii dye as sensitizer in dye-sensitized solar cells. AB - In this work, data on the effect of porphyrin characteristic of UV/VIS absorption of Thaumatococcus daniellii (T. daniellii) dye-sensitized solar cells sensitized with different electrolytes were presented. The influence of dopants from 1 g/100 ml electrolyte: distilled water and applied time difference of 3 min is observed on the photovoltaic characteristics and performance of the deposited thin film. The output efficiency and incident photon to conversion efficiency of T. daniellii dye-sensitized solar cells was acquired and could be further used as a model for designing dye-sensitized solar models as substitute for silicon solar cells. PMID- 30306109 TI - Occurrence of an invasive cervical epidermoid carcinoma in a patient receiving TNF-alpha blocking therapy for hidradenitis suppurativa. PMID- 30306110 TI - Dupilumab in the management of topical corticosteroid withdrawal in atopic dermatitis: A retrospective case series. PMID- 30306111 TI - A case of Vogt-Koyanagi-Harada disease as a sequela of drug reaction with eosinophilia and systemic symptoms. PMID- 30306112 TI - Chronic verrucous sarcoidosis associated with human papillomavirus infection: Improvement with adalimumab. PMID- 30306113 TI - Aggressive squamous cell carcinoma as a harbinger of non-Hodgkin lymphoma. PMID- 30306114 TI - Anaphylaxis to diphenylcyclopropenone during sensitization for wart treatment-A case report. PMID- 30306115 TI - Pretibial myxedema successfully treated with intralesional hyaluronidase. PMID- 30306116 TI - Acute syndrome of pan-epidermolysis and thrombotic storm arising in a patient with systemic lupus erythematosus. PMID- 30306117 TI - Long-term follow-up of early-onset Sneddon syndrome: A case report. PMID- 30306118 TI - IgG4 expression in cutaneous marginal zone lymphoma with plasmacytic differentiation and localized amyloid deposition: A useful clue to cutaneous origin. PMID- 30306119 TI - Endocrine mucin-producing sweat gland carcinoma of the scalp treated with Mohs micrographic surgery. PMID- 30306120 TI - Treatment of an ulcerated hemangioma with dehydrated human amnion/chorion membrane allograft. PMID- 30306121 TI - A rapidly growing violaceous tumor in a neonate. PMID- 30306122 TI - Thalidomide as an effective treatment for adult multiple xanthogranuloma. PMID- 30306123 TI - The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. PMID- 30306124 TI - Esophageal leaks: I thought that glue was not effective. PMID- 30306126 TI - The benefits of grouping as a main driver of social evolution in a halictine bee. AB - Over the past decade, the cause of sociality has been much debated. Inclusive fitness [br in Hamilton's rule (br - c > 0)] has been criticized but is still useful in the organization of a framework by elucidating mechanisms through which br (benefit * relatedness) becomes larger than c (cost). The bee Lasioglossum baleicum is suitable for investigation of this issue because of the sympatric occurrence of both social and solitary nesting in its populations. We show that a large part (approximately 92%) of the inclusive fitness of a eusocial worker can be attributed to the benefits of grouping. A 1.5-fold relatedness asymmetry benefit in singly mated haplo-diploids explains a small part (approximately 8.5%) of the observed inclusive fitness. Sociality enables this species to conduct foraging and nest defense simultaneously, which is not the case in solitary nests. Our results indicate that this benefit of grouping is the main source of the increased inclusive fitness of eusocial workers. PMID- 30306127 TI - Opening the window to the Southern Ocean: The role of jet dynamics. AB - The surface waters of the Southern Ocean act as a control valve through which climatically important tracers such as heat, freshwater, and CO2 are transferred between the atmosphere and the ocean. The process that transports these tracers through the surface mixed layer into the ocean interior is known as ocean ventilation. Changes in ocean ventilation are thought to be important for both rapid transitions of the ocean's global overturning circulation during the last deglaciation and the uptake and storage of excess heat and CO2 as a consequence of anthropogenic climate change. I show how the interaction between Southern Ocean jets, topographic features, and ocean stratification can lead to rapid changes in Southern Ocean ventilation as a function of wind stress. For increasing winds, this interaction leads from a state in which tracers are confined to the surface mixed layer to a state in which tracers fill the ocean interior. For sufficiently high winds, the jet dynamics abruptly change, allowing the tracer to ventilate a water mass known as Antarctic Intermediate Water in the mid-depth Southern Ocean. Abrupt changes in Antarctic Intermediate Water ventilation have played a major role in rapid climate transitions in Earth's past, and combined with the results presented here, this would suggest that jet dynamics could play a prominent role in contributing to, or even triggering, rapid transitions of the global climate system. PMID- 30306125 TI - Checkpoint Blockade Reverses Anergy in IL-13Ralpha2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. AB - We generated two humanized interleukin-13 receptor alpha2 (IL-13Ralpha2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL 13Ralpha2, but not IL-13Ralpha1. Hu08BBz also recognized canine IL-13Ralpha2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Ralpha2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Ralpha2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Ralpha2 and were recognized by Hu08BBz. Canine IL-13Ralpha2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre clinical trial to evaluate the safety of canine IL-13Ralpha2 CAR T cells in dog with spontaneous IL-13Ralpha2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Ralpha2 targeting CAR T cells. PMID- 30306128 TI - Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. AB - The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m6A levels by silencing either N 6 adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m6A levels of key epithelial mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor-beta signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m6A modifications, as altered m6A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m6A status of target genes by controlling each other's expression and by inhibiting m6A reader YTHDF3 (YTH N 6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression. PMID- 30306129 TI - Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input. AB - Pavlovian eyeblink conditioning has been used extensively to study the neural mechanisms underlying associative and motor learning. During this simple learning task, memory formation takes place at Purkinje cells in defined areas of the cerebellar cortex, which acquire a strong temporary suppression of their activity during conditioning. Yet, it is unknown which neuronal plasticity mechanisms mediate this suppression. Two potential mechanisms include long-term depression of parallel fiber to Purkinje cell synapses and feed-forward inhibition by molecular layer interneurons. We show, using a triple transgenic approach, that only concurrent disruption of both these suppression mechanisms can severely impair conditioning, highlighting that both processes can compensate for each other's deficits. PMID- 30306130 TI - Assessing bimanual motor skills with optical neuroimaging. AB - Measuring motor skill proficiency is critical for the certification of highly skilled individuals in numerous fields. However, conventional measures use subjective metrics that often cannot distinguish between expertise levels. We present an advanced optical neuroimaging methodology that can objectively and successfully classify subjects with different expertise levels associated with bimanual motor dexterity. The methodology was tested by assessing laparoscopic surgery skills within the framework of the fundamentals of a laparoscopic surgery program, which is a prerequisite for certification in general surgery. We demonstrate that optical-based metrics outperformed current metrics for surgical certification in classifying subjects with varying surgical expertise. Moreover, we report that optical neuroimaging allows for the successful classification of subjects during the acquisition of these skills. PMID- 30306131 TI - Couples showing off: Audience promotes both male and female multimodal courtship display in a songbird. AB - Social environments can shape animal communication. Although mutual courtship displays are generally thought to function in private communication between a male and a female, we provide experimental evidence that they work in a broader social context than previously thought. We examined the audience effect on mutual courtship in blue-capped cordon-bleus, a socially monogamous songbird. This species is characterized by conspicuous courtship shared between sexes: Both sexes sing songs and sometimes add a unique dance display that looks like human tap dancing. We found that in both sexes, multimodal courtship displays (song accompanied by dance) were promoted in the presence of an audience, especially if it was the opposite sex. In contrast, unimodal displays (song without dance) were suppressed by audiences. Because birds directed the courtship dancing toward their partners (but not the audience), multimodal courtship displays are likely meant to advertise their current mating status to other cordon-bleus. PMID- 30306132 TI - Fruit scent as an evolved signal to primate seed dispersal. AB - The tremendous diversity of floral and fruit traits is, to a large extent, a set of adaptations that promote plant reproduction through animal pollinators and seed dispersers. Yet, it is still unknown whether fruit scent is a by-product of fruit maturation or an evolved communication channel with animal mutualists. We show that in species that specialize on seed dispersal by lemurs-an olfactorily oriented primate-fruits increase scent production and change their chemical composition significantly more than sympatric species whose seeds are largely dispersed by birds. We further show that lemurs use these shifts in fruit scent to identify ripe fruits. These results show that fruit scent is an evolved communication system that facilitates animal-plant mutualism. PMID- 30306133 TI - Artelle et al. (2018) miss the science underlying North American wildlife management. AB - Artelle et al. (2018) conclude that "hallmarks of science" are largely missing from North American wildlife management based on a desk review of selected hunting management plans and related documents found through Internet searches and email requests to state and provincial wildlife agencies. We highlight three fundamental problems that compromise the validity of the conclusions posited: missing information to support selection of "hallmarks of science," confusion about the roles and nature of science and management, and failure to engage effectively with the scientists and managers actively managing wildlife populations in North America. PMID- 30306135 TI - Evidence for a large exomoon orbiting Kepler-1625b. AB - Exomoons are the natural satellites of planets orbiting stars outside our solar system, of which there are currently no confirmed examples. We present new observations of a candidate exomoon associated with Kepler-1625b using the Hubble Space Telescope to validate or refute the moon's presence. We find evidence in favor of the moon hypothesis, based on timing deviations and a flux decrement from the star consistent with a large transiting exomoon. Self-consistent photodynamical modeling suggests that the planet is likely several Jupiter masses, while the exomoon has a mass and radius similar to Neptune. Since our inference is dominated by a single but highly precise Hubble epoch, we advocate for future monitoring of the system to check model predictions and confirm repetition of the moon-like signal. PMID- 30306134 TI - Genomic and functional evidence reveals molecular insights into the origin of echolocation in whales. AB - Echolocation allows toothed whales to adapt to underwater habitats where vision is ineffective. Because echolocation requires the ability to detect exceptional high-frequency sounds, fossils related to the auditory system can help to pinpoint the origin of echolocation in whales. However, because of conflicting interpretations of archaeocete fossils, when and how whales evolved the high frequency hearing correlated with echolocation remain unclear. We address these questions at the molecular level by systematically investigating the convergent evolution of 7206 orthologs across 16 mammals and find that convergent genes between the last common ancestor of all whales (LCAW) and echolocating bats are not significantly enriched in functional categories related to hearing, and that convergence in hearing-related proteins between them is not stronger than that between nonecholocating mammalian lineages and echolocating bats. However, these results contrast with those of parallel analyses between the LCA of toothed whales (LCATW) and echolocating bats. Furthermore, we reconstruct the ancestral genes for the hearing protein prestin for the LCAW and LCATW; we show that the LCAW prestin exhibits the same function as that of nonecholocating mammals, but the LCATW prestin shows functional convergence with that of extant echolocating mammals. Mutagenesis shows that functional convergence of prestin is driven by convergent changes in the prestins S392A and L497M in the LCATW and echolocating bats. Our results provide genomic and functional evidence supporting the origin of high-frequency hearing in the LCAW, not the LCATW, and reveal molecular insights into the origin and evolutionary trajectories of echolocation in whales. PMID- 30306136 TI - Working constructively toward an improved North American approach to wildlife management. AB - Mawdsley et al. (2018) respond disapprovingly to our 2018 review of 667 wildlife management systems across Canada and the United States, which found that many of these systems lacked the scientific hallmarks of clear objectives, evidence, transparency, and independent review. Although we strongly agree with several of Mawdsley et al.'s points about the role of science in management, their response suggests confusion about three elements of our approach that we clarify herein: (i) the selection of hallmarks, (ii) the role of science in wildlife management, and (iii) our engagement with wildlife agencies. We contend that both critics and defenders of the current approach to wildlife management in Canada and the United States similarly desire rigorous management that achieves social and ecological benefits. Our original study-which used a clear approach to define hallmarks of science-based management, employed a reasonable set of indicator criteria to test for them, and was based on data available to the general public on whose behalf management is conducted-found evidence that the current approach falls short. However, it also provided a framework for addressing shortcomings moving forward. We suggest that advancing discussion on the operational role of science in management, including clarifying what "science-based management" actually means, could curtail practitioners and critics of the status quo talking over each other's heads and encourage all parties to work constructively to improve the governance of wildlife at a continental scale. PMID- 30306137 TI - Atypical Carcinoid Neuroendocrine Tumor of the Ureter: A Case Report and Literature Review. AB - Neuroendocrine tumors (NETs) of the ureter are rare, with less than 40 cases described in the literature. A majority of tumors described are poorly differentiated tumors with a poor prognosis. We present the case of a moderately differentiated atypical carcinoid NET of the ureter with a good postoperative outcome. A literature review was also performed to identify similar cases to compare their management and postoperative outcomes. PMID- 30306138 TI - Use of REBOA to stabilize in-hospital iatrogenic intra-abdominal hemorrhage. AB - : Resuscitative endovascular balloon occlusion of the aorta (REBOA) has become an increasingly popular alternative to emergency thoracotomy and aortic cross clamping in patients with exsanguinating hemorrhage.1 This new capability is increasingly being used in non-trauma situations.2 3 This report demonstrates another novel use of REBOA for iatrogenic intra-abdominal hemorrhage. An 83-year old man with multiple medical comorbidities and a history of chronic mesenteric ischemia was admitted to our institution for an elective mesenteric revascularization. Revascularization was unsuccessful, despite attempts to cross the lesion. Postprocedure, the patient developed a right groin hematoma, and CT on postprocedure day 0 demonstrated a femoral artery pseudoaneurysm and subintimal contrast at the level of the celiac artery, representing an iatrogenic dissection. The following day, he complained of dizziness. Physical examination revealed a blood pressure of 68/35 mm Hg, heart rate of 100 beats per minute, and a distended abdomen. Because the surgical intensive care unit (SICU) was full, he was transferred to the neurotrauma intesive care unit (NTICU) and intubated for hemodynamic instability. A chest X-ray revealed a prior thoracic endovascular aortic repair (figure 1), but no intrathoracic hemorrhage or pathology. Bedside ultrasonography revealed intra-abdominal fluid. Laboratory workup showed hemoglobin of 6.1 g/dL, from 10.9 the previous day. The patient was given two units of packed red blood cells, without response. The intensive care unit (ICU) team initiated norepinephrine, with minimal improvement despite increasing doses. Figure 1Chest X-ray with catheter in zone 1. Arrows mark the proximal and distal markers of the resuscitative endovascular balloon occlusion of the aorta. What would you do?: Transfuse two units of packed red blood cells and observe.Proceed to the operating room (OR) for exploratory laparotomy.Endovascular balloon occlusion of the aorta (zone 1). PMID- 30306139 TI - E-referrals: improving the routine interspecialty inpatient referral system. AB - Interspecialty referrals are an essential part of most inpatient stays. With over 130 referrals occurring per week at the Royal Devon and Exeter Hospital, the process must be efficient and safe. The current paper-based 'white card' system was felt to be inefficient, and a Trust incident highlighted patient safety concerns. Questionnaires reinforced the need for improvement, with concerns such as a lack of referral traceability and delays in the referral delivery due to workload. The aims of the project were to improve patient safety and junior doctor efficiency in the referral process. Through appreciative enquiry and the PDSA (Plan-Do-Study-Act) model, an electronic referral system was developed, piloted within two specialties and later expanded to others with improvements made along the way based on user feedback. The system includes novel features including specialties 'acknowledging' a referral to allow referral progress to be tracked. The system stores all referrals, creating a fully auditable inpatient referral pathway. Qualitative data indicated improvement to patient safety and user experience (n=31). Timings for referrals were measured over a 6-month period; referrals became faster with the electronic system, with average time from decision to refer to referral submission improving from 2.1 hours to 1.9 hours, with a noted statistically significant improvement in timings on a statistical process control chart. An unexpected benefit was that patients were also reviewed faster by specialties. Measuring these changes presented a significant challenge due to the complexity of the referral process, and this was a big limitation. Overall, the re-design of a paper-based referral system into an electronic system has been proven to be more efficient and felt to be safer for patients. This is a sustainable change which is being rolled out Trust-wide. We hope that the reporting of this project will help others considering reviewing their inpatient referral pathways. PMID- 30306140 TI - Emergency department checklist: an innovation to improve safety in emergency care. PMID- 30306141 TI - Systematic review and meta-analysis of community pharmacy error rates in the USA: 1993-2015. AB - Importance: While much is known about hospital pharmacy error rates in the USA, comparatively little is known about community pharmacy dispensing error rates. Objective: The aim of this study was to determine the rate of community pharmacy dispensing errors in the USA. Methods: English language, peer-reviewed observational and interventional studies that reported community pharmacy dispensing error rates in the USA from January 1993 to December 2015 were identified in 10 bibliographic databases and topic-relevant grey literature. Studies with a denominator reflecting the total number of prescriptions in the sample were necessary for inclusion in the meta-analysis. A random effects meta analysis was conducted to estimate an aggregate community pharmacy dispensing error rate. Heterogeneity was assessed using the I2 statistic prior to analysis. Results: The search yielded a total of 8490 records, of which 11 articles were included in the systematic review. Two articles did not have adequate data components to be included in the meta-analysis. Dispensing error rates ranged from 0.00003% (43/1 420 091) to 55% (55/100). The meta-analysis included 1 461 128 prescriptions. The overall community pharmacy dispensing error rate was estimated to be 0.015 (95% CI 0.014 to 0.018); however, significant heterogeneity was observed across studies (I2=99.6). Stratification by study error identification methodology was found to have a significant impact on dispensing error rate (p<0.001). Conclusion and relevance: There are few published articles that describe community pharmacy dispensing error rates in the USA. Thus, there is limited information about the current rate of community pharmacy dispensing errors. A robust investigation is needed to assess dispensing error rates in the USA to assess the nature and magnitude of the problem and establish prevention strategies. PMID- 30306142 TI - Postpartum quality improvement strategy for increasing long-acting contraception uptake at a University Hospital in Haiti. AB - To address the gap in the uptake of long-acting contraception (LAC) methods among high-risk postpartum women who fail to return for a family planning method at HopitalUniversitaire de Mirebalais in the Central Plateau Department of Haiti, contraceptive implant trainings were held for providers on the Labour and Delivery, Post-Partum and Internal Medicine inpatient wards. A very high maternal mortality rate affects large numbers of women in Haiti; however, contraceptive use can reduce maternal mortality significantly. A quality improvement strategy to offer LAC methods to immediate postpartum women at a University Hospital in rural Haiti was initiated in March 2016. This new strategy produced an average improvement from 5% to 32% of women delivering at the hospital, accepting a long acting method (including bilateral tubal ligations) by the end of the project and which has proved sustainable at an average of 20% to date. PMID- 30306143 TI - Improving anticoagulation of patients with an implantable left ventricular assist device. AB - Patients supported with implantable left ventricular assist devices (LVAD) have a significant risk of bleeding and thromboembolic complications. All patients require anticoagulation with warfarin, aiming for a target international normalised ratio (INR) of 2.5 and most patients also receive antiplatelet therapy. We found marked variation in the frequency of INR measurements and proportion of time outside the therapeutic INR range in our LVAD-supported patients. As part of a quality improvement initiative, home INR monitoring and a networked electronic database for recording INR results and treatment decisions were introduced. These changes were associated with increased frequency of INR measurement. We anticipate that changes introduced in this quality improvement project will reduce the likelihood of adverse events during long-term LVAD support. PMID- 30306145 TI - Impact of punitive immigration policies, parent-child separation and child detention on the mental health and development of children. AB - In April 2018, the US government introduced a 'zero tolerance' illegal immigration control strategy at the US-Mexico border resulting in the detention of all adults awaiting federal prosecution for illegal entry and the subsequent removal of their children to separate child shelters across the USA. By June 2018, over 2300 immigrant children, including infants, had been separated from their parents for immigration purposes. Media reports and scenes of distraught families ignited global condemnation of US immigration policy and fresh criticism of immigration detention practices. Detention of children for immigration purposes is known to be practised in over 100 countries worldwide, despite a significant body of research demonstrating the extensive harm of such policies. This review explores and contextualises the key potential impacts of family separation and detention of children for immigration purposes including damaged attachment relationships, traumatisation, toxic stress and wider detrimental impacts on immigrant communities. As such, it is critical for host nation governments to cease the practice of family separation and child detention for immigration control and promote postmigration policies that protect children from further harm, promote resilience and enable recovery. PMID- 30306144 TI - Developmental outcomes of an individualised complementary feeding intervention for stunted children: a substudy from a larger randomised controlled trial in Guatemala. AB - Objective: Stunting is a common cause of early child developmental delay; Guatemala has the fourth highest rate of stunting globally. The goal of this study was to examine the impact of an intensive community health worker-led complementary feeding intervention on early child development in Guatemala. We hypothesised that the intervention would improve child development over usual care. Design: A substudy from a larger individually randomised (1:1 allocation ratio), parallel-group superiority trial, with blinding of study staff collecting outcomes data. Setting: Rural, indigenous Maya communities in Guatemala. Participants: 210 stunted children (height-for-age z-score <=-2.5) aged 6-24 months, previously randomised to usual care (106) or an intensive complementary feeding intervention (104). 84 in the intervention and 91 in the usual care arm agreed to participate. Interventions: Community health workers conducted monthly home visits for 6 months, providing usual care or individualised complementary feeding education. Main outcome measures: The primary outcomes were change in z scores for the subscales of the Bayley Scales of Infant Development (BSID), Third Edition. Results: 100 individuals were included in the final analysis, 47 in the intervention and 53 in the usual care arm. No statistically significant differences in age-adjusted scores between the arms were observed for any subscale. However, improvements within-subjects in both arms were observed (median duration between measurements 189 days (IQR 182-189)). Mean change for subscales was 0.45 (95% CI 0.23 to 0.67) z-scores in the intervention, and 0.43 (95% CI 0.25 to 0.61) in the usual care arm. Conclusions: An intensive complementary feeding intervention did not significantly improve developmental outcomes more than usual care in stunted, indigenous Guatemalan children. However, both interventions had significant positive impacts on developmental outcomes. Trial registration number: NCT02509936. Stage: Results. PMID- 30306146 TI - Knowledge, attitude and practice with respect to soil contamination by Soil Transmitted Helminths in Ibadan, Southwestern Nigeria. AB - Ancylostoma duodenale, Necator americanus, Ascaris lumbricoides and Trichuris trichiura, the four major Soil-transmitted helminths (STHs) and also Strongyloides stercoralis infect humans worldwide. Most studies on Soil transmitted helminths (STHs) carried out in Ibadan were faecal examination based while relatively few soil examination based studies were carried out mostly around school premises using limited number of sampling locations. This study was therefore designed to assess the level of soil contamination with STH and associated risk factors in the eleven local government areas of Ibadan. A total of 1980 soil samples were purposively collected monthly, between January and December 2017, from toilet areas, refuse dump sites, house vicinities, playgrounds, roadsides/walk ways, and examined for the presence of parasite eggs or larvae using automated analysis of light microscopy images by computer. Well structured questionnaires were administered to 620 consenting participants to obtain information on the Knowledge of STH infections, Attitudes and Practices towards the infections. Data were analyzed using SPSS version 21, Chi-square and ANOVA were used in the analysis at p < 0.05. Out of soil samples examined, 1087 (54.9%) had at least one species of parasite. The prevalence of hookworm was 74.5% followed by 50.2% and 37.2% for Strongyloides species larvae and adult respectively, and 25.1% for Ascaris species. The highest prevalence was observed in the refuse dump (74.2%) followed by toilet area (36.5%) while the lowest was at house vicinities (1.6%). Fifty-seven percent of the respondents use pit latrine while 20.6% still practice open defecation. A high transmission risk was observed as large percentage (66.8%) of the respondents showed inadequate knowledge of how to avoid STH infections. Moreover, 64.0% and 25.2% reported that they often walk barefooted and suck fingers respectively. The high prevalence of parasitic contamination of soil observed in the present study and the high proportion of respondent with inadequate knowledge of how to prevent transmission of STH pose a high risk of re-infections in the study area even after treatment. Therefore there is a need for proper education on parasite transmission in the area. PMID- 30306147 TI - Syntactic Patterns Improve Information Extraction for Medical Search. AB - Medical professionals search the published literature by specifying the type of patients, the medical intervention(s) and the outcome measure(s) of interest. In this paper we demonstrate how features encoding syntactic patterns improve the performance of state-of-the-art sequence tagging models (both linear and neural) for information extraction of these medically relevant categories. We present an analysis of the type of patterns exploited, and the semantic space induced for these, i.e., the distributed representations learned for identified multi-token patterns. We show that these learned representations differ substantially from those of the constituent unigrams, suggesting that the patterns capture contextual information that is otherwise lost. PMID- 30306148 TI - The electronic structure of f-element Prussian blue analogs determined by soft X ray absorption spectroscopy. AB - In molecular solids derived from Prussian blue, intermetallic charge transfer is fostered through a cyano bridge two metal ions. In this study, isostructural trivalent lanthanide and tetravalent actinide Prussian blue analogs' valence orbitals are probed by soft X-ray absorption measurements. PMID- 30306153 TI - Fluorinated polymeric micelles to overcome hypoxia and enhance photodynamic cancer therapy. AB - Photodynamic therapy (PDT) as an alternative choice of cancer treatment method has attracted increasing attention in the past few decades. A sufficient amount of oxygen is essential for the production of singlet oxygen (1O2) in successful PDT; however, hypoxia is a typical hallmark of cancer, which is one of the most important limitation factors of PDT. To overcome the hypoxic tumour microenvironment and achieve highly efficient photodynamic cancer therapy, herein, a photosensitizer Ce6-loaded fluorinated polymeric micelle (Ce6-PFOC-PEI M) was constructed via the self-assembly of an amphiphilic polymer prepared from perfluorooctanoic acid and branched polyethyleneimine (10 kDa). The introduction of perfluoroalkyl groups in the polymeric micelle Ce6-PFOC-PEI-M retained the oxygen-carrying capacity similar to perfluorocarbon, increased the oxygen level and overcame the hypoxia in C6 glioma cells under oxygen-deficient conditions. As a control, Ce6-OC-PEI-M without a perfluoroalkyl group could not increase the oxygen level in C6 glioma cells under the same conditions. With laser irradiation, Ce6-PFOC-PEI-M generated much more reactive oxygen species (ROS) in C6 glioma cells than Ce6-OC-PEI-M, leading to a higher phototoxicity in vitro and photodynamic tumour growth inhibition in vivo than Ce6-OC-PEI-M. Furthermore, there were no differences in the contents of Ce6 in tumour tissue between Ce6 PFOC-PEI-M and Ce6-OC-PEI-M. The higher efficacy of Ce6-PFOC-PEI-M in PDT is ascribed to its oxygen-carrying ability rather than higher content of Ce6 in the tumour. The presented fluorinated polymeric micelle could provide a new platform in the delivery of various photosensitizers and has great potential to improve the efficacy of PDT cancer therapy. PMID- 30306159 TI - A ratiometric fluorescent probe for bioimaging and biosensing of HBrO in mitochondria upon oxidative stress. AB - A novel ratiometric fluorescent probe with high selectivity and sensitivity was designed and developed for bioimaging and biosensing of HBrO in mitochondria. Using this useful tool with low cytotoxicity and good biocompatibility, it was found that O2--induced oxidative stress triggered the burst of HBrO in mitochondria. PMID- 30306161 TI - Light-induced cargo release from a cucurbit[8]uril host by means of a sequential logic operation. AB - The logically controlled and light-induced release of a tripeptide model cargo from a cucurbit[8]uril host macrocycle by means of a photoswitch was shown in water. This provides a new approach to photoresponsive and selective release in a meaningful pH window. PMID- 30306163 TI - Thousand-atom ab initio calculations of excited states at organic/organic interfaces: toward first-principles investigations of charge photogeneration. AB - Predicting electronically excited states across electron-donor/electron acceptor interfaces is essential for understanding the charge photogeneration process in organic solar cells. However, organic solar cells are large and disordered systems, and their excited states cannot be easily accessed by conventional quantum chemistry approaches. Moreover, a large number of excited states must be obtained to fully understand the charge separation mechanism. Recently, we have developed a novel fragment-based excited state method which can efficiently calculate a large number of states in molecular aggregates. In this article, we demonstrate the large-scale excited-state calculations by investigating interfacial charge transfer (ICT) states across the electron-donor/electron acceptor interfaces. As the model systems, we considered the face-on and edge-on configurations of pentacene/C60 bilayer heterojunction structures. These model structures contain approximately 1.8 * 105 atoms, and their local interface regions containing 2000 atoms were treated quantum mechanically, embedded in the electrostatic potentials from the remaining parts. Therefore, the charge delocalization effect, structural disorder, and the resulting heterogeneous electrostatic and polarizable environments were taken into account in the excited state calculations. The computed energies of the low-lying ICT states are in reasonable agreement with experimental estimates. By comparing the edge-on and face-on configurations of the pentacene/C60 interfaces, we discuss the influence of interfacial morphologies on the energetics and charge delocalization of ICT states. In addition, we present the detailed characterization of excited states and highlight the importance of hybridization effects between pentacene excited states and ICT states. The large-scale ab initio calculations for the interface systems enabled the exploration of the ICT states, leading to first-principles investigation of the charge separation mechanism in organic solar cells. PMID- 30306164 TI - Coarse-grained molecular dynamics simulation of the interface behaviour and self assembly of CTAB cationic surfactants. AB - In this work we study the behaviour at interfaces and the micelle self-assembly of a cationic surfactant (CTAB) by Molecular Dynamics (MD) simulations of coarse grained models. We consider both the standard (with explicit water) Martini force field and the implicit solvent version of the Martini force field (Dry Martini). First, we study the behaviour of CTAB at a water/vacuum interface, at a water/organic solvent interface and in a pre-assembled CTAB micelle using both standard and Dry Martini and all-atomic simulations. Our results indicate that there are significant quantitative differences between the predictions of the two models. Interestingly, implicit solvent simulations with Dry Martini show good quantitative agreement with all-atomic MD simulations, better than explicit solvent Martini MD simulations. The computational efficiency of the Martini and Dry Martini models allowed us to study the self-assembly of CTAB in a large system with many micelles. We observe the self-assembly of CTAB into micelles and also the exchange of CTAB molecules between micelles by events such as micelle fusion and fission which are difficult to observe in all-atomic MD simulations due to the time and length scales involved. Under the studied conditions, both Martini models predict a rather different self-assembly behaviour. The standard Martini model predicts a final equilibrium state with spherical micelles with an average size of ~70 CTAB molecules. In contrast, the Dry Martini model predicts the formation of large tubular micelles with ~330 CTAB molecules. Compared with experiments, standard Martini and Dry Martini underestimate and overestimate, respectively, the micelle size. PMID- 30306166 TI - Catalytic CO oxidation on B-doped and BN co-doped penta-graphene: a computational study. AB - The catalytic reaction of carbon monoxide oxidation on boron-doped and boron nitrogen co-doped penta-graphene materials has been systematically studied by utilizing spin-polarized density functional theory (DFT) calculations. Various pathways including the Eley-Rideal (ER), Langmuir-Hinshelwood (LH), and tri molecular Eley-Rideal (TER) mechanisms were considered in which the TER mechanism is a newly proposed reaction mechanism for CO oxidation. According to the calculation results, the ER, LH and TER mechanisms of CO oxidation can occur and compete with each other because of the related small overall reaction energy barriers (0.11-0.35 eV for the ER mechanism, 0.16-0.17 eV for the LH mechanism, and no activation energy for the TER mechanism). Our study helps to understand the various pathways for the CO oxidation process and suggests that both B-doped and BN co-doped penta-graphene sheets may serve as effective metal-free catalysts for low-temperature CO oxidation. PMID- 30306167 TI - Characterization of transglutaminase from Bacillus subtilis and its cross-linking function with a bovine serum albumin model. AB - Finding new crosslinking enzymes for enzyme-mediated protein conjugation is a great need in the food industry. In this research, the properties of Bacillus subtilis transglutaminase (BTG) were characterized in detail and its protein crosslinking functions with bovine serum albumin (BSA) as a model were studied. Compared to the commercial transglutaminase from Streptoverticillium mobaraense, BTG was more stable in a broad range of temperatures (30-60 degrees C) and pH values (pH 5.0-9.0), with its maximum enzymatic activity at 60 degrees C and pH 8.0. The protein function evaluation results demonstrated that the BTG-modified BSA showed better emulsifying and foaming properties (p < 0.05) compared with the native one. Additionally, significant improvements (p < 0.05) were observed in the rheological properties, water holding capacity, and textural properties of the BTG-treated BSA gels. With good thermal and pH stability and excellent crosslinking effects, BTG would be a potential enzyme for food structure engineering to improve the functional properties of food proteins and expand their applications. PMID- 30306168 TI - Determination of possible configurations for Li0.5CoO2 delithiated Li-ion battery cathodes via DFT calculations coupled with a multi-objective non-dominated sorting genetic algorithm (NSGA-III). AB - Here, we propose a new and logical approach to systematically treat the configurational diversity in density functional theory (DFT) calculations. To tackle this issue, we select Li0.5CoO2 as a representative example because it is one of the most extensively studied cathodes in Li-ion batteries (LIBs), and it has a huge number of disordered configurations. To delineate the configurations that will match well with the experimentally measured macro-functions of redox potential, band gap energy, and magnetic moment, we adopt a multi-objective, non dominated sorting, genetic algorithm (NSGA-III) that enables the simultaneous optimization of these three objective functions. The decision variables include configuration of the Li/vacancy, initial input for the magnetic moment distribution reflecting Co3+/Co4+ distribution, and initial input for the lattice parameter and Hubbard U. We use NSGA-III to separate the configurations that exhibit awkward objective function values, which allows us to pinpoint a set of plausible configurations that match the experimentally estimated values of the objective functions. The results reveal a plausible configuration that is a mixture of various ordered/disordered configurations rather than a simple ordered structure. PMID- 30306169 TI - Peroxidase mimicking DNAzymes degrade graphene oxide. AB - DNAzymes made of supramolecular guanine-rich G-quadruplexes and hemin are attracting a lot of interest due to their peroxidase activity mimicking the natural enzyme horseradish peroxidase (HRP). Herein, we demonstrate that DNAzyme consisting of a PS2.M-hemin complex can be an alternative to natural HRP for the oxidation and degradation of graphene oxide (GO). The degradation of GO sheets was carried out by incubating the PS2.M-hemin complex in the presence of hydrogen peroxide for 30 days. The degradation of GO has been confirmed using transmission electron microscopy and 2d Raman mapping. The current study suggests that the peroxidase activity of DNAzymes is similar to HRP and DNAzymes are able to degrade carbon-based nanomaterials. PMID- 30306170 TI - A honeycomb-like monolayer of HfO2 and the calculation of static dielectric constant eliminating the effect of vacuum spacing. AB - A novel dielectric material of monolayer 1T-HfO2 has been investigated using first-principles calculations. The stability of 1T-HfO2 has been proved by both phonon dispersions and ab initio molecular dynamics calculations, although its 2H structural counterpart is dynamically unstable. 1T-HfO2 monolayer can be cleaved from the (111) facet of cubic HfO2. It is found that 1T-HfO2 has a large band gap of 6.73 eV, exceeding the band gaps of h-BN (5.97 eV) and bulk HfO2 (5.7 eV). From the microscopic perspective of dielectric polarization, we provide an explanation for the dependence of the dielectric constant directly calculated from the supercell of a two-dimensional (2D) system on the variable vacuum spacing, and we thus obtain a rational method for accurately evaluating the dielectric constants of 2D materials based on the calculated value obtained from a supercell to meet periodic conditions. Our derivation can be verified by the data fitting of a series of calculations with different vacuum spacings. The static dielectric constants of 1T-HfO2 along the in-plane and out-of-plane directions are 27.35 and 4.80, respectively, higher than those of monolayer h-BN. The large band gap and high dielectric constant make 1T-HfO2 a promising candidate as a dielectric layer in 2D field-effect transistors and heterojunctions. PMID- 30306171 TI - Manipulation of spin and magnetic anisotropy in bilayer magnetic molecular junctions. AB - Understanding the role of spin-environment interactions in the electron transport properties of magnetic quantum systems is central to the rational design of spintronics devices. Herein, two emergent phenomena arising from such interactions, namely, the Kondo effect and magnetic anisotropy, are investigated theoretically in bilayer transition metal phthalocyanine (TMPc) (TM = Co, Fe) on a Pb(111) substrate by combining the density functional theory (DFT) and hierarchical equations of motion (HEOM) approaches. The calculation results indicate that the Kondo temperature TK and magnetic anisotropy energy in TMPc/TMPc/Pb(111) junctions can be actively tuned through the modification of the TM atom at the molecular center. In particular, the CoPc/FePc/Pb(111) composite exhibits a similar spin-1/2 Kondo effect as the CoPc/CoPc/Pb(111) composite reported previously in experiments, but TK is one order of magnitude larger with the modification of the intermediate decoupling layer from CoPc to FePc. Moreover, the magnetic anisotropy energy of the composite systems can also be switched from the easy axis of D = -12.6 meV, E = 1.56 meV in FePc/CoPc/Pb(111) to D = -11.2 meV, E = 0.0 meV in FePc/FePc/Pb(111) by changing the intermediate layer. We attribute these intriguing tunabilities to the different spin-electron coupling and symmetry of the ligand field provided by the intermediate layer. These findings demonstrate the importance of the decoupling layer for the magnetic properties of adsorbates and offer a promising strategy for the design of spintronics. PMID- 30306172 TI - Selective intracellular delivery and intracellular recordings combined in MEA biosensors. AB - Biological studies on in vitro cell cultures are of fundamental importance to investigate cell response to external stimuli, such as new drugs for the treatment of specific pathologies, or to study communication between electrogenic cells. Although three-dimensional (3D) nanostructures brought tremendous improvements on biosensors used for various biological in vitro studies, including drug delivery and electrical recording, there is still a lack of multifunctional capabilities that could help gain deeper insights in several bio related research fields. In this work, the electrical recording of large cell ensembles and the intracellular delivery of few selected cells are combined on the same device by integrating microfluidic channels on the bottom of a multi electrode array decorated with 3D hollow nanostructures. The novel platform allows the recording of intracellular-like action potentials from large ensembles of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and from the HL-1 line, while different molecules are selectively delivered into single/few targeted cells. The proposed approach shows high potential for enabling new comprehensive studies that can relate drug effects to network level cell communication processes. PMID- 30306173 TI - Novel metal doped carbon quantum dots/CdS composites for efficient photocatalytic hydrogen evolution. AB - Carbon quantum dots (CDs) are rising stars for photocatalytic applications due to their low toxicity and excellent electron transfer characteristics. Doping with heteroatoms is expected to adjust the band levels and electron transfer properties of CDs, and understanding the effect of doping on CDs can aid the rational preparation of highly efficient CD-based photocatalysts. Herein, we prepared a series of metal atom (Zn, Co, Bi, Cd, or Ti) doped CDs by pyrolysis and explored the photocatalytic application of these metal doped CDs for the first time. The metal doped CDs were combined with CdS nanowires as a co-catalyst for photocatalytic hydrogen production. The Bi, Cd and Ti doped CDs/CdS composites show much better hydrogen production performance than the undoped CDs/CdS composite. Among these composites, Bi-CDs/CdS presents the optimal interfacial charge separation and the best hydrogen production performance. The hydrogen evolution rate of Bi-CDs/CdS is 4.2 times and almost one time higher than that of pure CdS and undoped CDs/CdS, respectively. Bi doping can make the CDs metallic and promote the charge transfer of CDs. Such a great enhancement originates from the outstanding electron transfer properties of Bi-doped CDs, as well as the effective charge separation between Bi-doped CDs and CdS. Bi doping was demonstrated to be an effective strategy for optimizing the photocatalytic activity of CD based composites. PMID- 30306176 TI - Correlation between the magnetic-microstructure and microwave mitigation ability of MxCo(1-x)Fe2O4 based ferrite-carbon black/PVA composites. AB - A study of controlling the microwave mitigation properties of ferrite-carbon black/PVA composites by tuning the magnetic microstructure and spin arrangement of the ferrite particles is presented. MxCo(1-x)Fe2O4 (M: Ni2+, Mn2+ & Zn2+) nano ferrites (NFs) were synthesized by a solvothermal method and these NFs were used to fabricate NF-CB hybrids and flexible NF-CB/PVA composite films. The magnetic force microscopy studies of the NFs reveal a unique single axis oriented domain structure for Zn-NFs and multi-domain magnetic microstructures for Mn-NFs and Ni NFs. Mossbauer analysis of the NFs reveals highly distorted co-ordination of Fe3+ cations in Zn-NFs, whereas sub-lattice spins are canted in Mn-NFs and Ni-NFs. Despite the distorted magnetic lattice and broken coordination, the largest microwave shielding effectiveness (SE) of 32 dB is observed, over a bandwidth of 8 to 18 GHz, for Zn-NF-CB/PVA with a major contribution from absorption (SEA~ 25 dB). The dielectric properties and Cole-Cole plots indicate enhanced interfacial polarization in Zn-NF-CB/PVA, which is attributed to the motion of polarons across multiple heterogeneous interfaces. These polarons are thought to be generated by distorted co-ordination of Fe3+, and d-d electron transition between Co2+? Fe3+ cations at the B-site of Zn-NF. Distorted co-ordination of Fe3+ in Zn NF along with unique single axis oriented magnetic domains play a crucial role in magnetic losses, as MU'' is almost double in Zn-NF based composites as compared to other composites. Due to their excellent and tunable microwave absorption properties, NF-CB/PVA composites could be employed for next generation stealth applications. PMID- 30306175 TI - Sulfono-gamma-AA modified peptides that inhibit HIV-1 fusion. AB - The utilization of bioactive peptides in the development of highly selective and potent pharmacological agents for the disruption of protein-protein interactions is appealing for drug discovery. It is known that HIV-1 entry into a host cell is through a fusion process that is mediated by the trimeric viral glycoprotein gp120/41, which is derived from gp160 through proteolytic processing. Peptides derived from the HIV gp41 C-terminus have proven to be potent in inhibiting the fusion process. These peptides bind tightly to the hydrophobic pocket on the gp 41 N-terminus, which was previously identified as a potential inhibitor binding site. In this study, we introduce modified 23-residue C-peptides, 3 and 4, bearing a sulfono-gamma-AA residue substitution and hydrocarbon stapling, respectively, which were developed for HIV-1 gp-41 N-terminus binding. Intriguingly, both 3 and 4 were capable of inhibiting envelope-mediated membrane fusion in cell-cell fusion assays at nanomolar potency. Our study reveals that sulfono-gamma-AA modified peptides could be used for the development of more potent anti-HIV agents. PMID- 30306177 TI - Interfacial barriers to gas transport in zeolites: distinguishing internal and external resistances. AB - We use atomistic simulations of CH4, H2 and CO2 transport to elucidate the effect of internal interfacial barriers on gas transport within nanoscale zeolite crystals of different morphology; such barriers are shown here to have critical significance for the performance of ultrathin membranes and nanoscale mixed matrix composite membranes for gas separation. These interfacial resistances are seen to be confined to a narrow region within the zeolite, adjacent to the phase boundary, and are distinct from the external fluid phase resistance. Our results indicate that interfacial barriers depend on the nature of the zeolite pore network, and significantly hinder gas transport in nanocrystals. We show that interaction with dense surrounding media such as a polymer enhances the interfacial resistance internal to the zeolite, and further attenuates gas transport. The relative contribution of the interfacial resistance to the gas transport resistance is more significant at lower temperatures, and this resistance is larger than the external gas phase resistance by an order of magnitude. We determine the critical membrane thickness, below which these interfacial barriers are pronounced, and find that interfacial barriers can be significant up to a thickness of about 0.1 MUm. Furthermore, these interfacial barriers to gas transport are significantly higher for a gas with a kinetic diameter comparable to that of the limiting pore diameter of the zeolite (methane in this case), thus improving the H2/CH4 kinetic selectivity in finite crystals. We show that small finite crystals of SAS type zeolite are selective for H2 over CH4, while large crystals are selective for CH4 over H2. PMID- 30306179 TI - Tetraphenylethylene conjugated p-hydroxyphenacyl: fluorescent organic nanoparticles for the release of hydrogen sulfide under visible light with real time cellular imaging. AB - Hydrogen sulfide (H2S) behaves like a two-edged sword, at low concentrations it has beneficial and cytoprotective effects, while at higher concentrations it exhibits toxicity. Hence there is a keen interest in developing light responsive H2S donors with a spatio-temporal controlled release. Herein, we report visible light activatable tetraphenylethylene conjugated p-hydroxyphenacyl (TPE-pHP-H2S) nanoparticles for the release of hydrogen sulfide (H2S) with a real time monitoring ability. Our newly designed photoresponsive single component organic nanoparticle based H2S donor is built by integrating the tetraphenylethylene (TPE) moiety and p-hydroxyphenacyl (pHP) group so that it can display both aggregation-induced emission (AIE) and excited state intramolecular proton transfer (ESIPT) properties. Aggregation-induced emission enhancement was exhibited by our TPE-pHP-H2S NP donor, which was then explored for the cellular imaging application. The ESIPT by the pHP moiety provided unique advantages to our TPE-pHP-H2S NP donor which include (i) the excitation wavelength extended to >410 nm (ii) a large Stokes shift (iii) a low inner filter effect and (iv) real time monitoring of H2S release by a simple fluorescent colour change. In vitro studies showed that the TPE-pHP-H2S NP donor presents excellent properties like real-time monitoring, photoregulated H2S release and biocompatibility. PMID- 30306180 TI - New insights into the structure-performance relationships of mesoporous materials in analytical science. AB - Mesoporous materials are ideal carriers for guest molecules and they have been widely used in analytical science. The unique mesoporous structure provides special properties including large specific surface area, tunable pore size, and excellent pore connectivity. The structural properties of mesoporous materials have been largely made use of to improve the performance of analytical methods. For instance, the large specific surface area of mesoporous materials can provide abundant active sites and increase the probability of contact between analytes and active sites to produce stronger signals, thus leading to the improvement of detection sensitivity. The connections between analytical performances and the structural properties of mesoporous materials have not been discussed previously. Understanding the "structure-performance relationship" is highly important for the development of analytical methods with excellent performance based on mesoporous materials. In this review, we discuss the structural properties of mesoporous materials that can be optimized to improve the analytical performance. The discussion is divided into five sections according to the analytical performances: (i) selectivity-related structural properties, (ii) sensitivity related structural properties, (iii) response time-related structural properties, (iv) stability-related structural properties, and (v) recovery time-related structural properties. PMID- 30306181 TI - Hydroarylation of unsaturated carbon-carbon bonds in cross-conjugated enynones under the action of superacid CF3SO3H or acidic zeolite HUSY. Reaction mechanism and DFT study on cationic intermediate species. AB - Reactions of cross-conjugated enynones,1,5-diarylpent-1-en-4-yn-3-ones, with arenes in the system TfOH-pyridine or under the action of acidic zeolite HUSY lead regioselectively to products of hydroarylation of the acetylene bond only,1,1,5-triarylpent-1,4-dien-3-ones, in yields up to 98%. These dienones add one more arene molecule to the double carbon-carbon bond in neat TfOH forming 1,1,5,5-tetraarylpent-1-en-3-ones in high yields. Cationic reaction intermediates have been studied by means of DFT calculations to elucidate plausible reaction mechanisms. PMID- 30306182 TI - Specific protein-labeling and ligand-binding position analysis with amidopyrene probes as LDI MS tags. AB - To readily analyze the binding mode of protein-ligand interactions, we developed ligand-bound-type and ligand-dissociation-type probes having 6-amidopyrene (apy) as a detecting group. Matrix- and label-assisted laser desorption/ionization mass spectrometry (MALDI and LA-LDI MS) analyses and a covalent docking simulation using these probes precisely determined the binding position of the ligand biotin on the target protein avidin (RMSD = 0.786 and 0.332 A). Our apy-probe-labeling method may be useful for determining the unknown ligand-binding sites of various target proteins. PMID- 30306183 TI - Amorphous Y(OH)3-promoted Ru/Y(OH)3 nanohybrids with high durability for electrocatalytic hydrogen evolution in alkaline media. AB - A novel Ru/Y(OH)3 nanohybrid with high activity and excellent durability for electrocatalytic hydrogen evolution in alkaline media was developed. The enhanced performance mainly arose from the amorphous Y(OH)3 scaffold that both facilitates water dissociation and enhances the structural stability of Ru/Y(OH)3 due to the strong interaction between Ru and Y(OH)3. PMID- 30306184 TI - The catalytic Mitsunobu reaction: a critical analysis of the current state-of-the art. AB - The Mitsunobu reaction is widely regarded as the pre-eminent method for performing nucleophilic substitutions of alcohols with inversion of configuration. However, its applicability to large-scale synthesis is undermined by the fact that alcohol activation occurs at the expense of two stoichiometric reagents - a phosphine and an azodicarboxylate. The ideal Mitsunobu reaction would be sub-stoichiometric in the phosphine and azodicarboxylate species and employ innocuous terminal oxidants and reductants to achieve recycling. This Review article provides a summary and analysis of recent advances towards the development of such catalytic Mitsunobu reactions. PMID- 30306185 TI - UVA-induced neurotoxicity in Japanese medaka (Oryzias latipes). AB - Ultraviolet radiation-induced neurodegeneration has been studied in the early stages of development in fish, but not extensively in the adult stage. The present study aimed at investigating the effects of ultraviolet radiation-A (UVA) in adult Japanese medaka (Oryzias latipes). The brain, spinal cord, and retina were examined histopathologically as nervous system target organs. Japanese medaka fish were exposed to 15, 30, and 60 min day-1 UVA for 3 days, and samples were obtained 24 h and 14 days after UVA exposure. Neurohistopathological alterations in brain tissue included vacuoles, blood congestion, degeneration of neuropils, and pyknotic nuclei in neurons. Alterations in the spinal cord included neuronal cell degeneration, reduction in the spinal cord area, and degeneration of Mauthner cells. Retinal tissue showed vacuolation in the nerve fiber layer (NFL), pyknotic nuclei in the ganglion cell layer (GCL), and decreased cell populations particularly in the inner nuclear layer (INL) and GCL. The degree of degeneration was dependent on the duration of UVA exposure. The signs of degeneration decreased gradually and disappeared completely after the 14 day recovery period. In addition, p53-deficient medaka fish were more tolerant than were wild-type (Hd-rR) Japanese medaka. In conclusion, UV radiation induced neurodegeneration in the brain, spinal cord, and retina of adult Japanese medaka (Oryzias latipes) but their normal histological architecture reappeared in these tissues after 14 days. PMID- 30306186 TI - Growth of form in thin elastic structures. AB - Heterogeneous growth plays an important role in the shape and pattern formation of thin elastic structures ranging from the petals of blooming lilies to the cell walls of growing bacteria. Here we address the stability and regulation of such growth, which we modeled as a quasi-static time evolution of a metric, with fast elastic relaxation of the shape. We consider regulation via coupling of the growth law, defined by the time derivative of the target metric, to purely local properties of the shape, such as the local curvature and stress. For cylindrical shells, motivated by rod-like E. coli, we show that coupling to curvature alone is generically linearly unstable to small wavelength fluctuations and that additionally coupling to stress can stabilize these modes. Interestingly, within this framework, the longest wavelength fluctuations can only be stabilized with the mean curvature flow. Our approach can readily be extended to gain insights into the general classes of stable growth laws for different target geometries. PMID- 30306187 TI - ? PMID- 30306188 TI - Effect of arch wire size on orthodontic reverse closing loop and retraction force in canine tooth distalization : Three-dimensional finite element analysis. AB - AIM: The purpose of this study is to compare the effects of different wire size reverse closing loop and retraction forces in canine tooth distalization using the finite element analysis method. MATERIALS AND METHODS: Maxillary alveolar bone, maxillary first molar, second premolar and canine teeth were constructed in three dimensions along with their periodontal ligaments and standard edgewise brackets of 0.022 inch and stainless-steel reverse closing loop of 0.016 * 0.022 inch and 0.019 * 0.025 inch were designed. Force of 0.98 N and 1.96 N were applied to the arch wire from the posterior region of the molar tooth in the distal direction for activating the reverse closing loop. The stress distribution and displacement of the maxillary canine tooth were performed using the three dimensional finite element analysis method. RESULTS: The maximum deformation on the canine tooth was higher in the x-, y-, and z-axes in both arch wires with 1.96 N force activation. Moreover, 1.96 N caused more stress on the canine tooth in both arch wires compared to the application of 0.98 N. In terms of von Mises stress distribution on alveolar bones, the amount of stress was higher during the application of 1.96 N than the application of 0.98 N. CONCLUSION: The finite element method is a reliable instrument which allows the effects of biomechanics applied in orthodontics to be evaluated. The finite element analysis method precisely predicted the mechanical effects of reverse closing loop of different wire sizes and different retraction forces. PMID- 30306189 TI - [Emergency lung ultrasound]. AB - Acute and emergency physicians need to make rapid and far-reaching decisions on the basis of little diagnostic information. In patients with symptoms suggestive of a cardiopulmonary diagnosis, point-of-care lung ultrasound (LUS) is becoming increasingly used. In patients with acute dyspnea, chest pain and shock, LUS increases the diagnostic reliability. The BLUE protocol helps to differentiate important diagnoses of acute dyspnea (pulmonary edema, pneumonia, acute respiratory distress syndrome, pulmonary embolism, pleural effusions or pneumothorax). LUS is also used for treatment follow-up. It is clearly superior to other diagnostic measures (auscultation, chest X-ray). With ever smaller "handheld" ultrasound devices, the use of ultrasound is also being increasingly used in preclinical situations. PMID- 30306191 TI - Chronological Variation of Metals in Reclaimed Coal Mine Soil and Tissues of Eucalyptus Hybrid Tree After 25 Years of Reclamation, Jharia Coal Field (India). AB - Fast-growing metal-accumulating woody trees are potential candidates for phytoremediation of coal mine overburden (OB) dumps. The present study assessed chronological variation in metals (Pb, Zn, Mn, Cu, and Co) concentration in reclaimed mine soil (RMS) and tissues (leaf, stem bark, stem wood, root bark and root wood) of Eucalyptus hybrid tree between 3 and 25-year old OB dumps (RMS3 and RMS25) from Jharia coal field (India). Total metal concentrations of Pb, Zn, and Cu in RMS25 were 1.55, 3.46, and 1.44 times lower (p < 0.05), respectively, than RMS3. Higher concentrations of total (110%-565%) and available form (DTPA extractable) of metals (109%-480%) were observed in RMS25 than in control soil. Pb selectively accumulated in stem bark, Zn and Mn in leaves, and Cu and Co in root wood. Metal concentrations were higher (1.04-4.15 times at p < 0.05) in tree tissues growing on RMS25 than in RMS3. This study concluded that Eucalyptus hybrid could be utilized for reclamation of coal mine OB dumps. PMID- 30306192 TI - Phosphorus Enhances Cr(VI) Uptake and Accumulation in Leersia hexandra Swartz. AB - The effects of P supplementation on chromium(VI) uptake by Leersia hexandra Swartz were studied using pot-culture experiment. P-deficiency and zero-P addition controls were included. The Cr(VI) uptake followed Michaelis-Menten kinetics. Compare with the control, the P-supply decreased the Michaelis constant (Km) by 16.9% and the P-deficiency decreased the maximum uptake velocity (Vmax) by 18%, which indicated no inhibition and competition between P and Cr(VI) uptake by L. hexandra. Moreover, there were a synergistic action between P and Cr(VI) suggests that Cr(VI) uptake by the roots of L. hexandra may be an active process. The bioconcentration factor (BCF) and the transport factor (TF') increased with the increase in P supply. The highest BCF was 3.6-folds higher than the control, indicating that the additional P contribute to a higher ability of L. hexandra transporting Cr from root to the aboveground parts. PMID- 30306190 TI - Circulating prolactin concentrations and risk of type 2 diabetes in US women. AB - AIMS/HYPOTHESIS: Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of prolactin are associated with risk of type 2 diabetes remains uncertain. METHODS: We analysed the prospective relationship between circulating prolactin concentrations and type 2 diabetes risk in the Nurses' Health Study (NHS) and NHSII with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8615 women free of type 2 diabetes and cardiovascular disease at baseline blood collection (NHS 1989-1990; NHSII 1996-1999) and a subset of 998 NHS women providing a second blood sample during 2000-2002. Baseline bioactive prolactin was measured in a subset of 2478 women using the Nb2 bioassay. HRs were estimated using Cox regression. RESULTS: A total of 699 incident type 2 diabetes cases were documented during 156,140 person years of follow-up. Total plasma prolactin levels were inversely associated with type 2 diabetes risk; the multivariable HR comparing the highest with the lowest quartile was 0.73 (95% CI 0.55, 0.95; ptrend = 0.02). The associations were similar by menopausal status and other risk factors (pinteraction > 0.70). Additional adjustment for sex and growth hormones, adiponectin, and inflammatory and insulin markers did not significantly alter the results. The association of plasma bioactive prolactin with type 2 diabetes risk was non-significantly stronger than that of total prolactin (HR comparing extreme quartiles, 0.53 vs 0.81 among the subset of 2478 women, pdifference = 0.11). The inverse association of total prolactin with type 2 diabetes was significant during the first 9 years after blood draw but waned linearly with time, whereas for bioactive prolactin, the inverse relationship persisted for a longer follow-up time after blood draw. CONCLUSIONS/INTERPRETATION: A normally high circulating total prolactin concentration was associated with a lower type 2 diabetes risk within 9-10 years of follow-up since blood draw in US women. Our findings are consistent with experimental evidence, suggesting that among healthy women, prolactin within the biologically normal range may play a protective role in the pathogenesis of type 2 diabetes. PMID- 30306193 TI - Association of baseline severity of lower urinary tract symptoms with the success conservative therapy for urinary incontinence in women. AB - INTRODUCTION AND HYPOTHESIS: To identify the association between the symptom severity and outcome of conservative management for OAB, SUI and MUI. Conservative treatments are recommended for overactive bladder (OAB), stress urinary incontinence (SUI) and mixed incontinence (MUI). It is unclear whether disease severity affects treatment outcome. METHODS: Patients receiving conservative management were reviewed. Disease-specific questionnaires (OAB-q SF, ICIQ-UI SF) and bladder diaries recorded baseline symptoms. Success was defined by Patient Global Impression of Improvement questionnaire (PGI-I) response of "very much better" or "much better". Non-parametric statistical tests and logistic regression were used. RESULTS: In 50 OAB patients success was associated with lower symptom severity [30 (0-80) vs. 80 (23-100), p = 0.0001], fewer urgency episodes [4 (0-12) vs. 6 (0-11), p = 0.032] and lower ICIQ-UI SF [5.5 (0 20) vs. 15 (0-21), p = 0.002], but higher QoL [67 (20-101) vs. 24 (6-58), p = 0.0001]. In 50 MUI patients, variables were fewer urgency episodes [3 (0-10) vs. 6 (0-16), p = 0.004] and lower ICIQ-UI [11 (1-18) vs. 15 (5-21), p = 0.03]. In 40 SUI patients, variables were fewer incontinence episodes [1 (0-4) vs. 2 (0-5), p = 0.05] and lower ICIQ-UI [11 (6-16) vs. 13.5 (11-19), p = 0.003]. Multiple regression confirmed OAB-q QoL [odds ratio (OR) 1.10 (95% confidence intervals 1.04, 1.1)] for OAB, urgency episodes [OR 0.74 (0.56, 0.98)] and ICIQ-UI [OR 0.83 (0.71, 0.98] for MUI and ICIQ-UI [OR 0.57 (0.40, 0.83)] for SUI. CONCLUSIONS: Milder baseline disease severity was associated with successful outcome. There is potential for triage at initial assessment to second-line interventions for women unlikely to achieve success. PMID- 30306194 TI - Focus on sepsis: new concepts and findings in sepsis care. PMID- 30306195 TI - Assessing the Genetic Correlations Between Blood Plasma Proteins and Osteoporosis: A Polygenic Risk Score Analysis. AB - Osteoporosis is a common metabolic bone disease. The impact of global blood plasma proteins on the risk of osteoporosis remains elusive now. We performed a large-scale polygenic risk score (PRS) analysis to evaluate the potential effects of blood plasma proteins on the development of osteoporosis in 2286 Caucasians, including 558 males and 1728 females. Bone mineral density (BMD) and bone areas at ulna & radius, hip, and spine were measured using Hologic 4500W DXA. BMD/bone areas values were adjusted for age, sex, height, and weight as covariates. Genome wide SNP genotyping of 2286 Caucasian subjects was performed using Affymetrix Human SNP Array 6.0. The 267 blood plasma proteins-associated SNP loci and their genetic effects were obtained from recently published genome-wide association study (GWAS) using a highly multiplexed aptamer-based affinity proteomics platform. The polygenetic risk score (PRS) of study subjects for each blood plasma protein was calculated from the genotypes data of the 2286 Caucasian subjects by PLINK software. Pearson correlation analysis of individual PRS values and BMD/bone area value was performed using R. Additionally, gender-specific analysis also was performed by Pearson correlation analysis. 267 blood plasma proteins were analyzed in this study. For BMD, we observed association signals between 41 proteins and BMD, mainly including whole body total BMD versus Factor H (p value = 9.00 * 10-3), whole body total BMD versus BGH3 (p value = 1.40 * 10 2), spine total BMD versus IGF-I (p value = 2.15 * 10-2), and spine total BMD versus SAP (p value = 3.90 * 10-2). As for bone areas, association evidence was observed between 45 blood plasma proteins and bone areas, such as ferritin versus spine area (p value = 1.90 * 10-2), C4 versus hip area (p value = 1.25 * 10-2), and hemoglobin versus right ulna and radius area (p value = 2.70 * 10-2). Our study results suggest the modest impact of blood plasma proteins on the variations of BMD/bone areas, and identify several candidate blood plasma proteins for osteoporosis. PMID- 30306198 TI - Pseudoaneurysm after total knee arthroplasty: imaging findings in 7 patients. AB - OBJECTIVE: To describe the clinical presentation of arterial pseudoaneurysms following total knee arthroplasty (TKA) and their diagnostic imaging features on ultrasound and magnetic resonance angiography (MRA) in 7 patients. MATERIALS AND METHODS: A search of our radiology report database from 2007 to 2017 yielded 7 patients with a pseudoaneurysm diagnosed by imaging after TKA. Clinical notes and imaging were reviewed. RESULTS: All 7 patients were male and ranged in age from 53 to 68 (mean 61) years. All patients presented with a painful swollen knee and hemarthrosis within the first month following surgery. Five patients presented after primary TKA. One patient presented after explantation for septic arthritis and another after partial synovectomy for septic arthritis without explantation. Ultrasound identified the pseudoaneurysm as a hypoechoic or hyperechoic mass with a "yin-yang" appearance of turbulent arterial flow and associated complex joint effusion. On MRA, the pseudoaneurysm was a mass next to a parent artery showing avid contrast enhancement in the arterial phase that persisted into the venous phase and washed out in the late venous phase. Six pseudoaneurysms arose from lateral geniculate arteries and 1 from a medial geniculate artery. There were no popliteal artery pseudoaneurysms. Five patients were treated endovascularly, 1 patient thrombosed without intervention, and 1 patient was treated with open surgery. CONCLUSION: Pseudoaneurysm is a potential source of a painful swollen knee with hemarthrosis or a drop in hematocrit after TKA and can be identified with either ultrasound or MRA. PMID- 30306197 TI - [Possible surgical approaches to the orbit]. AB - For removal of tumors and foreign bodies from the orbit, for treatment of severe inflammatory diseases, and for repositioning of bone fragments following fractures or during reconstruction of the bony orbit, several different surgical approaches are available. During the past decade, improved understanding of the pathology and pathophysiology of particular orbital diseases, advancements in clinical endoscopy and microscopy, the introduction of modern imaging techniques for preoperative visualization of pathologic findings, modern approaches to orbital reconstruction, as well as developments in adjuvant therapy have led to a reduction in invasiveness and development of the modern minimally invasive surgical approaches to the orbit usually used today. This review article aims to describe several surgical approaches to the orbit that are nowadays commonly applied-frequently in the context of interdisciplinary therapy-as well as their indications and potential complications. Particular attention is paid to minimally invasive approaches. These different surgical approaches allow a 360 degree exposure of the internal orbital structures with the optic nerve at the center ("round the clock access to the orbit"). The review is complemented by hints and tricks for particular approaches, as well as by a review of the latest literature in the field. PMID- 30306199 TI - Contrast Echocardiogram for the Evaluation of Streaming in a Single-Ventricle Patient. AB - In cases involving single ventricles, predicting streaming characteristics is difficult. Unfavorable streaming can cause decreased oxygen saturation. Judging whether desaturation results from decreased pulmonary flow or unfavorable streaming is critical. A 20-day-old infant with a single left ventricle underwent ductus arteriosus ligation and pulmonary artery banding to control high pulmonary flow. Severe desaturation presented postoperatively, which worsened to 68% despite pure-oxygen ventilation. A bedside contrast echocardiogram helped determine whether unfavorable streaming caused desaturation. It revealed systemic venous streaming predominantly directed to the aorta. Emergent balloon atrial septostomy facilitated mixing at the atrial level. Oxygen saturation promptly increased to 85%. PMID- 30306200 TI - Functions of aldehyde reductases from Saccharomyces cerevisiae in detoxification of aldehyde inhibitors and their biotechnological applications. AB - Bioconversion of lignocellulosic biomass to high-value bioproducts by fermentative microorganisms has drawn extensive attentions worldwide. Lignocellulosic biomass cannot be efficiently utilized by microorganisms, such as Saccharomyces cerevisiae, but has to be pretreated prior to fermentation. Aldehyde compounds, as the by-products generated in the pretreatment process of lignocellulosic biomass, are considered as the most important toxic inhibitors to S. cerevisiae cells for their growth and fermentation. Aldehyde group in the aldehyde inhibitors, including furan aldehydes, aliphatic aldehydes, and phenolic aldehydes, is identified as the toxic factor. It has been demonstrated that S. cerevisiae has the ability to in situ detoxify aldehydes to their corresponding less or non-toxic alcohols. This reductive reaction is catalyzed by the NAD(P)H dependent aldehyde reductases. In recent years, detoxification of aldehyde inhibitors by S. cerevisiae has been extensively studied and a huge progress has been made. This mini-review summarizes the classifications and structural features of the characterized aldehyde reductases from S. cerevisiae, their catalytic abilities to exogenous and endogenous aldehydes and effects of metal ions, chemical protective additives, and salts on enzyme activities, subcellular localization of the aldehyde reductases and their possible roles in protection of the subcellular organelles, and transcriptional regulation of the aldehyde reductase genes by the key stress-response transcription factors. Cofactor preference of the aldehyde reductases and their molecular mechanisms and efficient supply pathways of cofactors, as well as biotechnological applications of the aldehyde reductases in the detoxification of aldehyde inhibitors derived from pretreatment of lignocellulosic biomass, are also included or supplemented in this mini-review. PMID- 30306201 TI - Staying alive: growth and survival of Bifidobacterium animalis subsp. animalis under in vitro and in vivo conditions. AB - Members of the Bifidobacterium genus are widely used as probiotics in fermented milk products. Bifidobacterium animalis subsp. animalis CNCM I-4602 grows and survives poorly in reconstituted skimmed milk (RSM). Availing of genome and transcriptome information, this poor growth and survival phenotype in milk was substantially improved by the addition of certain compounds, such as yeast extract, uric acid, glutathione, cysteine, ferrous sulfate, and a combination of magnesium sulfate and manganese sulfate. Carbohydrate utilization of CNCM I-4602 was also investigated, allowing the identification of several carbohydrate utilization gene clusters, and highlighting this strain's inability to utilize lactose, unlike the type strain of this subspecies, B. animalis subsp. animalis ATCC25527 and the B. animalis subsp. lactis subspecies. In addition, the ability of B. animalis subsp. animalis CNCM I-4602 to colonize a murine model was investigated, which showed that this strain persists in the murine gut for a period of at least 4 weeks. Associated in vivo transcriptome analysis revealed that, among other genes, a gene cluster encoding a predicted type IVb tight adherence (Tad) pilus was upregulated, indicating that this extracellular structure plays a role in the colonization/adaptation of the murine gastrointestinal tract by this strain. PMID- 30306202 TI - Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination based immunotherapy in patients with advanced cancer. AB - Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN gamma assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer. PMID- 30306203 TI - Clinical review of liver hydatid disease and its unusual presentations in developing countries. AB - Human hydatid cyst disease is an international public health issue that particularly affects the developing countries. In this article, we discuss the epidemiology of hydatid disease in third world countries, the life cycle of echinococcus granulosus and how to make the clinical diagnosis of the disease, including laboratory tests and imaging modalities as well as uncommon presentation of this entity that we have encountered at the American University of Beirut Medical Center (AUBMC). We emphasize on the new World Health Organization classification of hepatic echinococcosis with examples from our clinical practice at AUBMC, and finally we describe the treatment, including medical and interventional therapies. PMID- 30306204 TI - Robotically Assisted CBCT-Guided Needle Insertions: Preliminary Results in a Phantom Model. AB - AIM: To compare robotic-assisted needle insertions performed under CBCT guidance to standard manual needle insertions. MATERIALS AND METHODS: A homemade robotic prototype was used by two operators to perform robotic and manual needle insertions on a custom-made phantom. Both the operators had no experience with the prototype before starting the trial. The primary endpoint was accuracy (i.e., the minimal distance between the needle tip and the center of the target) between robotic and manual insertions. Secondary endpoints included total procedure time and operators' radiation exposure. The Wilcoxon test was used. A p value less than 0.05 was considered statistically significant. RESULTS: Thirty-three (17 manual, 16 robotic) needle insertions were performed. Mean accuracy for robotic insertion was 2.3 +/- 0.9 mm (median 2.1; range 0.8-4.2) versus 2.3 +/- 1 mm (median 2.1; range 0.7-4.4) for manual insertion (p = 0.84). Mean procedure time was 683 +/- 57 s (median 670; range 611-849) for the robotic group versus 552 +/- 40 s (median 548; range 486-621) for the manual group (p = 0.0002). Mean radiation exposure was 3.25 times less for the robotic insertion on comparison to manual insertion for the operator 1 (0.4 vs 1.3 uGy); and 4.15 times less for the operator 2 (1.9 vs 7.9 uGy). CONCLUSION: The tested robotic prototype showed accuracy comparable to that achieved with manual punctures coupled to a significant reduction of operators' radiation exposure. Further, in vivo studies are necessary to confirm the efficiency of the system. PMID- 30306206 TI - A review of inflammatory mechanism in airway diseases. AB - BACKGROUND: Inflammation in the lung is the body's natural response to injury. It acts to remove harmful stimuli such as pathogens, irritants, and damaged cells and initiate the healing process. Acute and chronic pulmonary inflammation are seen in different respiratory diseases such as; acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF). FINDINGS: In this review, we found that inflammatory response in COPD is determined by the activation of epithelial cells and macrophages in the respiratory tract. Epithelial cells and macrophages discharge transforming growth factor-beta (TGF-beta), which trigger fibroblast proliferation and tissue remodeling. Asthma leads to airway hyper-responsiveness, obstruction, mucus hyper production, and airway-wall remodeling. Cytokines, allergens, chemokines, and infectious agents are the main stimuli that activate signaling pathways in epithelial cells in asthma. Mutation of the CF transmembrane conductance regulator (CFTR) gene results in CF. Mutations in CFTR influence the lung epithelial innate immune function that leads to exaggerated and ineffective airway inflammation that fails to abolish pulmonary pathogens. We present mechanistic computational models (based on ordinary differential equations, partial differential equations and agent-based models) that have been applied in studying the complex physiological and pathological mechanisms of chronic inflammation in different airway diseases. CONCLUSION: The scope of the present review is to explore the inflammatory mechanism in airway diseases and highlight the influence of aging on airways' inflammation mechanism. The main goal of this review is to encourage research collaborations between experimentalist and modelers to promote our understanding of the physiological and pathological mechanisms that control inflammation in different airway diseases. PMID- 30306205 TI - Circular Permutation Obscures Universality of a Ribosomal Protein. AB - Functions, origins, and evolution of the translation system are best understood in the context of unambiguous and phylogenetically based taxonomy and nomenclature. Here, we map ribosomal proteins onto the tree of life and provide a nomenclature for ribosomal proteins that is consistent with phylogenetic relationships. We have increased the accuracy of homology relationships among ribosomal proteins, providing a more informative picture of their lineages. We demonstrate that bL33 (bacteria) and eL42 (archaea/eukarya) are homologs with common ancestry and acute similarities in sequence and structure. Their similarities were previously obscured by circular permutation. The most likely mechanism of permutation between bL33 and eL42 is duplication followed by fusion and deletion of both the first and last beta-hairpins. bL33 and eL42 are composed of zinc ribbon protein folds, one of the most common zinc finger fold-groups of, and most frequently observed in translation-related domains. Bacterial-specific ribosomal protein bL33 and archaeal/eukaryotic-specific ribosomal protein eL42 are now both assigned the name of uL33, indicating a universal ribosomal protein. We provide a phylogenetic naming scheme for all ribosomal proteins that is based on phylogenetic relationships to be used as a tool for studying the systemics, evolution, and origins of the ribosome. PMID- 30306208 TI - MYC, BCL2, and BCL6 rearrangements in primary central nervous system lymphoma of large B cell type. AB - Primary central nervous system lymphoma (PCNSL) is a rare specific subtype of non Hodgkin lymphoma limited to the brain, leptomeninges, spinal cord, or eyes without any systemic presentation and relapse which mostly takes place in CNS. In more than 95% of patients, it is of diffuse large B cell lymphoma (DLBCL) type. Categorizing PCNSL to germinal center cell like or activated B cell like, as we usually do for DLBCL NOS, may not be applicable for predicting outcome. Possible prognostic significance of MYC, BCL2, and/or BCL6 rearrangements may be important given what we know about their impact in systemic DLBCL, but we have limited knowledge about the status of double or triple hit molecular changes in PCNSL. Here, we have investigated prevalence of these molecular alterations in PCNSL. Two independent tissue microarrays constructed from 78 formalin-fixed paraffin embedded blocks of confirmed PCNSL were tested for rearrangement of MYC, BCL2, and BCL6 by interphase fluorescent in situ hybridization (FISH) using break apart dual color probes. BCL6 translocation was detected in 15 (12%) cases. Translocation involving MYC and BCL2 was identified in 3 cases (3.8%) and 1 case (1.3%) respectively. One double hit lymphoma was discovered with both MYC/BCL2 translocation (1.3%). To the best of our knowledge, few organized studies have been conducted for MYC, BCL2, and/or BCL6 rearrangement in PCNSL. This study is evaluating large number of PCNSL. Double or triple hit events which are rarely seen in PCNSL. PMID- 30306207 TI - MiR-200b attenuates IL-6 production through IKKbeta and ZEB1 in human gingival fibroblasts. AB - OBJECTIVE: MicroRNAs (miRNAs) play important roles in biological processes such as cell differentiation, development, infection, immune response, inflammation and tumorigenesis. We previously reported that the expression of miR-200b was significantly increased in inflamed gingiva compared with non-inflamed gingiva. To elucidate the roles of miR-200b in the inflamed gingiva, we have analyzed the effects of miR-200b on the expression of IL-6 in human gingival fibroblasts (HGF). MATERIALS AND METHODS: Total RNA and protein were extracted from HGF after stimulation by interleukin-1beta (IL-1beta; 1 ng/ml) or tumor necrosis factor alpha (TNF-alpha; 10 ng/ml) and transfected with miR-200b expression plasmid or miR-200b inhibitor. IL-6, IL-1beta, inhibitor of nuclear factor kappa-B kinasebeta (IKKbeta), Zinc-finger E-box-binding homeobox 1 (ZEB1) and E-cadherin mRNA and protein levels were analyzed by real-time PCR and Western blot. RESULTS: IL-1beta and TNF-alpha increased IL-6 mRNA and protein levels, and they were significantly suppressed by miR-200b overexpression, whereas they were further increased by miR-200b inhibitor in HGF. IKKbeta and ZEB1 which are target genes of miR-200b negatively regulate E-cadherin. MiR-200b suppressed the expression of IKKbeta and ZEB1 and increased E-cadherin mRNA and protein levels in HGF. CONCLUSIONS: These results suggest that miR-200b attenuates inflammatory response via IKKbeta and ZEB1 in periodontal tissue. PMID- 30306209 TI - The submental arrowhead variation of the mylohyoid and anterior belly of the digastric muscles. AB - PURPOSE: Submental anatomical variation is of clinical importance with regard to head and neck surgeries. One such anatomical variation is that of additional musculature joining the intermediate tendon of the digastric muscle to the midline of the mylohyoid musculature-a variation which this report refers to, accordingly, as an arrowhead variation. Though the arrowhead variation has been described in several case reports, it has not been subject to cross-sectional study. The purpose of this study is to determine the prevalence of the arrowhead variation. METHODS: Prevalence of the arrowhead variation was assessed in 19 cadavers via gross dissection. RESULTS: Two of the 19 cadavers (10.5%) were found to have arrowhead variations. The arrowhead variation was found in one male (1:11; 9.1%) and one female (1:8; 12.5%), respectively. CONCLUSIONS: This report demonstrates that the submental arrowhead variation of the anterior digastric and mylohyoid musculature has been reported in isolated case reports since the nineteenth century. This report is the first cross-sectional study of the arrowhead variant, identifying it in approximately one in ten individuals and in both sexes. Therefore, the presence of an arrowhead variation should be regularly considered with regard to diagnosis of submental masses. Likewise, the arrowhead variation should be considered in the preoperative planning of the myriad operations performed in the submental region. PMID- 30306210 TI - Classification of unusual insertion of the pectoralis minor muscle. AB - PURPOSE: The pectoralis minor muscle (PMi) generally originates from the third, fourth, and fifth ribs and inserts on the medial and superior margins of the anterior portion of the coracoid process. Variations in the shape and attachment point of the PMi could cause discomfort in the shoulders. The aim of this study was to observe the types of morphological insertion patterns and attachment sites of the PMi. METHODS: Seventy-four sides of fresh, embalmed Korean (42 sides; mean age 78 years) and Thai (32 sides; mean age 78 years) cadavers were dissected to analyze the morphological insertion types and attachment sites of the PMi. RESULTS: Unusual insertion patterns were evident in about 23% of the samples. When the portion of the PMi tendon ran over the coracoid process, the most common attachment site was the glenohumeral joint capsule. We also confirmed the attachment of the PMi to the clavicle. Costal attachments of the PMi that extend from the second rib to the fourth rib were observed frequently as well. CONCLUSIONS: Unusual insertion patterns of the PMi are common. Some authors consider that tendon attachment to the joint capsule can cause shoulder pain. In addition, the PMi tendon could be utilized in acromioclavicular joint reconstruction. Surgeons need to be aware of the possibility of a PMi variant being found during surgery even when this is not visible in magnetic resonance or ultrasound imaging. PMID- 30306211 TI - Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells. AB - Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol's influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders. PMID- 30306212 TI - The Janus face of HMGB1 in heart disease: a necessary update. AB - High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein involved in transcription regulation, DNA replication and repair and nucleosome assembly. HMGB1 is passively released by necrotic tissues or actively secreted by stressed cells. Extracellular HMGB1 acts as a damage-associated molecular pattern (DAMPs) molecule and gives rise to several redox forms that by binding to different receptors and interactors promote a variety of cellular responses, including tissue inflammation or regeneration. Inhibition of extracellular HMGB1 in experimental models of myocardial ischemia/reperfusion injury, myocarditis, cardiomyopathies induced by mechanical stress, diabetes, bacterial infection or chemotherapeutic drugs reduces inflammation and is protective. In contrast, administration of HMGB1 after myocardial infarction induced by permanent coronary artery ligation ameliorates cardiac performance by promoting tissue regeneration. HMGB1 decreases contractility and induces hypertrophy and apoptosis in cardiomyocytes, stimulates cardiac fibroblast activities, and promotes cardiac stem cell proliferation and differentiation. Interestingly, maintenance of appropriate nuclear HMGB1 levels protects cardiomyocytes from apoptosis by preventing DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac damage. Finally, higher levels of circulating HMGB1 are associated to human heart diseases. Hence, during cardiac injury, HMGB1 elicits both harmful and beneficial responses that may in part depend on the generation and stability of the diverse redox forms, whose specific functions in this context remain mostly unexplored. This review summarizes recent findings on HMGB1 biology and heart dysfunctions and discusses the therapeutic potential of modulating its expression, localization, and oxidative-dependent activities. PMID- 30306213 TI - [Special reduction instruments]. AB - Special and specialized instruments help perform reduction more effectively and in a tissue-preserving manner. In addition to other articles, the application and advantages of the following instruments are presented: colinear reduction forceps, cerclage, cerclage passer, distal radius reduction clamp, modular external fixator, extension table, distraction frame, joystick, manipulators, distractor and assistance of reduction with elastic nails. PMID- 30306215 TI - [Costs and proceeds from patients admitted via the emergency room with mild craniocerebral trauma]. AB - The introduction of the diagnosis-related groups (DRG) in 2003 radically changed the billing of the treatment costs. From the very beginning, trauma surgeons questioned whether the introduction of the DRG could have a negative impact on the care of the severely injured. "Trauma centers in need" was the big catchword warning against shortfalls at trauma centers due to the billing via DRG. This situation was confirmed in the first publications after introduction of the DRG, showing a clearly deficient level of care of polytrauma cases. Over the years, adjustments have led to an improvement in the remuneration for polytraumatized patients. In the emergency room, polytrauma is not always the final diagnosis. A considerable proportion of patients are only slightly injured, but must be admitted via the emergency room due to the circumstances of the accident or suspected diagnosis at the scene of the accident to exclude life-threatening injuries. In this study, patients with the billing diagnosis of mild craniocerebral trauma were selected as an example. The proportion of these patients was 22% during the period of observation in 2017. For these patients, the proportional costs during treatment were calculated. It could be shown that 60.36% of the costs during a 2-day treatment of these patients were incurred in the emergency room. Costs for material and personnel could not be considered. Despite not including these expenses, the costs were never covered for any of these patients. For patients with slight injuries after trauma management in the emergency room, the present adjustments to the DRG system by increasing the basic case value seem to be insufficient. Additional remuneration for these patients seems absolutely justified to further ensure adequate quality of care. PMID- 30306214 TI - [Reduction techniques for minimally invasive plate osteosynthesis]. AB - The technique of fracture treatment by minimally invasive plate osteosynthesis (MIPO) is today part of the treatment repertoire of any experienced trauma surgeon. The minimization of any additional iatrogenic damage to the tissues and the preservation of the osteogenic fracture hematoma are the decisive differences to open reduction and internal fixation (ORIF). The MIPO technique is particularly applied in metaphyseal and diaphyseal fractures, which cannot be treated with intramedullary nails as well as in fractures with critical soft tissue covering and complex fractures with metaphyseal extension fractures. In metaphyseal and diaphyseal fractures a distinction must always be made between relatively simple (A/B1 type) and more complex (B2/3 and C type) fracture forms. In simple fracture forms, which are treated with minimally invasive plate osteosynthesis, an anatomical (or at least gap-free) reduction should be strived for. In contrast, in more complex metaphyseal and diaphyseal fractures achievement of correct functional alignment (correct axis, length and rotation) is the goal of reduction. The minimally invasive approach by the trauma surgeon in MIPO fracture treatment is mainly defined by the selected gentle reduction technique. Because the fracture zone cannot be directly viewed, good knowledge of the anatomy and careful surgical planning including reduction on an adequate image basis are of decisive importance. This article introduces the principles of the reduction techniques in minimally invasive plate osteosynthesis and their practical application is described in detail. PMID- 30306216 TI - [Changes in age distribution and frequency of comorbidities in patients in the occupational insurance association treatment process]. AB - BACKGROUND: Due to the demographic development the proportion of older patients has increased. These show at least a higher rate of comorbidities, which affects the length of inpatient hospital stay. Until now no uniform recording exists for such comorbidities within the occupational insurance association system even if the clinical relevance is beyond dispute. Adaptations within the system with increased interdisciplinary treatment are necessary. OBJECTIVE: The aim of this study was to analyze changes in the age distribution and the frequency of comorbidities in patients in the occupational insurance association system. METHODS: The study was a retrospective analysis of age distribution and comorbidities of all operatively treated occupational insurance association patients in 2005 (n = 631), 2010 (n = 1180) and 2015/2016 (n = 2315). A comparison of the age groups <=29 years, 30-49 years, 50-65 years and >=66 years was performed. RESULTS: The proportion of patients aged 50-65 years showed a significant increase: 2005 (26.5%), 2010 (30.5%) and 2015/2016 (37.3%) (p < 0.001) and an increased proportion of patients with at least 1 comorbidity: 2005 (38.7%), 2010 (52.5%) and 2015/2016 (52.9%) (p = 0.01). This was statistically significant (p < 0.001, p = 0.005) within the age group 30-49 years (2005: 31.1%, 2015/2016: 49.0%) and the age group 50-65 years (2005: 55.7%, 2015/2016: 67.1%). Significant changes were found for arterial hypertension, morbid obesity, thyroid and respiratory diseases. In addition, there was an increase in multimorbid patients. DISCUSSION: A changing age distribution with a tendency to an increased number of older patients and an increased frequency of comorbidities could be determined. In the present documentation system of the occupational insurance association treatment procedure these comorbidities are insufficiently recorded and considered, even though their clinical relevance is indisputable. Adaptations with respect to intensified interdisciplinary cooperation are necessary. PMID- 30306218 TI - Latarjet procedure versus open capsuloplasty in traumatic anterior shoulder dislocation: long-term clinical and functional results. AB - PURPOSE: To compare the results of two different open surgical techniques (open capsuloplasty and Bristow-Latarjet procedure) at a mid- to long-term follow-up (6 years) in patients with recurrent traumatic anterior shoulder dislocations. METHODS: Seventy-three patients (73 shoulders, 48 males; 25 females) fulfilled inclusion and exclusion criteria. Patients were classified as group A if operated on with a Bristow-Latarjet procedure (40 patients, 24 males; 16 females) or group B if operated on with an open capsuloplasty (33 patients, 24 males; 9 females). All patients were followed up with physical examination and functional evaluation scores (UCLA, ROWE and WOSI). RESULTS: In group A, no further episodes of dislocation or subluxation were reported; in group B, one patient (3.3%) reported a new episode of anterior dislocation as a result of a new trauma. No statistical difference in regard of new episodes of shoulder dislocation was found between the two groups (p > 0.05). At physical examination, two patients (5%) of group A and four patients of group B (13.3%) showed a positive apprehension test (p > 0.05); anterior drawer test was positive in six patients (15%) of group A and in nine patients (30%) of group B (p > 0.05). Statistical analysis showed better external rotation in group A (Latarjet group) than in group B. (p = 0.0176). No statistical differences were detected in regard to the scale scores (UCLA, WOSI, Rowe) (p > 0.05). Regarding the return to sport, 29 patients (72.5%) of group A and 18 patients (60%) of group B reported they resumed the same sports activity at the same pre-operative level (p > 0.05). CONCLUSION: Open capsuloplasty and Bristow-Latarjet procedure are both validated surgical techniques for the treatment of recurrent shoulder anterior instability. We found no statistical difference in terms of recurrent dislocation rates, clinical shoulder stability tests, and scoring scales. The rate of patients returning to sport was similar after both techniques. However, patients with open capsuloplasty reported a significantly lower recovery of external rotation than patients operated via the Latarjet procedure. PMID- 30306217 TI - Customized implants for acetabular Paprosky III defects may be positioned with high accuracy in revision hip arthroplasty. AB - PURPOSE: In revision hip arthroplasty, custom-made implants are one option in patients with acetabular Paprosky III defects. METHODS: In a retrospective analysis, we identified 11 patients undergoing cup revision using a custom-made implant. The accuracy of the intended position of the implant was assessed on post-operative 3D CT and compared to the pre-operative 3D planning in terms of inclination, anteversion, and centre of rotation. In addition, the accuracy of post-operative plain radiographs for measuring implant position was evaluated in relation to the 3D CT standard. RESULTS: We found a mean deviation between the planned and the final position of the custom-made acetabular implant on 3D CT of 3.6 degrees +/- 2.8 degrees for inclination and of - 1.2 degrees +/- 7.0 degrees for anteversion, respectively. Restoration of center of rotation succeeded with an accuracy of 0.3 mm +/- 3.9 mm in the mediolateral (x) direction, - 1.1 mm +/- 3.8 mm in the anteroposterior (y) direction, and 0.4 mm +/- 3.2 mm in the craniocaudal (z) direction. The accuracy of the post-operative plain radiographs in measuring the position of the custom-made implant in relation to 3D CT was 1.1 degrees +/- 1.7 degrees for implant inclination, - 2.6 degrees +/- 1.3 degrees for anteversion and 1.3 mm +/- 3.5 mm in the x direction, and - 0.9 mm +/- 3.8 mm in the z-direction for centre of rotation. CONCLUSION: Custom-made acetabular implants can be positioned with good accuracy in Paprosky III defects according to the pre-operative planning. Plain radiographs are adequate for assessing implant position in routine follow-up. PMID- 30306219 TI - Screw tip augmentation leads to improved primary stability in the minimally invasive treatment of displaced intra-articular fractures of the calcaneus: a biomechanical study. AB - PURPOSE: To investigate if the stability of minimally invasive screw osteosynthesis of displaced intra-articular calcaneal fractures (DIACF) can be effectively increased by an innovative approach to screw tip augmentation. METHODS: In eight-paired human cadaver hindfoot specimens, DIACF of Sanders type IIB were treated with either standard screw osteosynthesis or with bone cement augmentation of the screw tips in the main fragments. The instrumented specimens were subjected to a cyclic loading protocol (9000 cycles, with stepwise increasing loads, 100-1000 N). The interfragment motions were quantified as tuber fragment tilt (TFT) and posterior facet inclination angle (PFIA) using a 3-D motion analysis system. Bohler's angle (BA) was evaluated from X-rays. A load-to failure test was performed after the cyclic loading protocol. RESULTS: All but one specimen of the augmented group withstood more cycles than the respective specimens of the non-augmented group. Mean cycles to failure for the failure criterion of 5 degrees TFT were 7299 +/- 1876 vs. 3864 +/- 1810, corresponding to loads of 811 N +/- 195 vs. 481 N +/- 180, (P = 0.043). There were no significant differences observed in the PFIAs. The failure criterion of 5 degrees BA was reached after a mean of 7929 cycles +/- 2004 in the augmented group and 4129 cycles +/- 2178 in the non-augmented group, corresponding to loads of 893 N +/- 200 vs. 513 N +/- 218, (P = 0,090). The mean load-to-failure of the four specimens in the augmented group that completed the cyclic loading was 1969 N over a 1742-2483 N range. CONCLUSION: Screw tip augmentation significantly improved the mechanical stability of the calcanei after osteosynthesis in terms of decreased tuber fragment tilts and less changes in Bohler's angle. PMID- 30306220 TI - Osteoporosis prevention: where are the barriers to improvement in a French general population? A qualitative study. AB - : We conducted a qualitative study with French men and women in order to provide insight into individuals' experiences, behaviors, and perceptions about osteoporosis (OP) and OP care. The data showed that both sexes, but especially men, were unfamiliar with OP, did not always feel concerned, and mistrusted pharmacological treatments. INTRODUCTION: To engage actively in osteoporosis (OP) prevention, people need to have basic knowledge about the disease. The aim of this qualitative study was to explore knowledge and representations of OP care and prevention among both men and women. METHODS: Focus groups were conducted in the Rhone-Alpes Region, France, with women aged 50-85 years and men aged 60-85 years, with or without a history of fragility fracture and/or an OP diagnosis (respectively referred to as "aware" or "unaware"). A total of 45 women (23 "aware" and 22 "unaware" in 5 and 4 focus groups, respectively) and 53 men (19 "aware" and 34 "unaware" in 3 and 4 focus groups, respectively) were included. A thematic analysis of transcripts was performed to explore knowledge and representations about OP, risk factors, prevention, and treatment. RESULTS: The data showed that both sexes, but especially men, had limited knowledge of OP and considered it as a natural aging process not related to fragility fractures. They generally did not feel concerned by OP and no important difference was observed between "aware" and "unaware" patients. Women expressed their fear of the disease, associated with aging and the end of life, while men considered it to be a women's disease only. Both sexes were aware of OP risk factors, but were suspicious towards treatments because of the associated side effects. CONCLUSION: Understanding people's representation of OP might help to provide patients with relevant information in order to optimize their preventive behavior and decrease the burden of the disease. PMID- 30306221 TI - Hepatocyte growth factor is a potential biomarker for osteoproliferation and osteoporosis in ankylosing spondylitis. AB - : We explored relations between serum hepatocyte growth factor (HGF), disease activity, osteoproliferation, and bone mineral density (BMD) in ankylosing spondylitis (AS), in comparison with healthy controls. HGF was increased especially in male AS patients and smokers and associated with both lower BMD and more chronic radiographic changes in the spine. INTRODUCTION: Ankylosing spondylitis (AS) is characterized by both osteoproliferation and increased bone loss. Biomarkers are requested to predict the processes. The aims of this study were to compare serum levels of hepatocyte growth factor (HGF), matrix metalloproteinase-3 (MMP-3), and vascular endothelial growth factor (VEGF) in AS patients with healthy controls (HC) and to explore the associations with disease activity, osteoproliferation, and bone mineral density (BMD). METHODS: Serum from AS patients (modified NY-criteria) and HC was analyzed for HGF, MMP-3, and VEGF with ELISA. Disease activity parameters were collected. Osteoproliferation was assessed with modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and BMD was measured in femoral neck. RESULTS: Totally, 204 AS patients and 80 sex and age matched HC were included. Serum HGF was higher in the AS patients compared with the HC, whereas serum MMP-3 and VEGF were not. Serum HGF was also higher in smokers and in the male AS patients positively correlated with age, BASMI, and mSASSS, and negatively correlated with BMD. The biomarkers were all positively associated with ESR, CRP, and WBC. In multiple linear regression analysis serum HGF remained associated with higher mSASSS and lower BMD, after adjusting for age, sex, CRP, smoking, and body mass index. CONCLUSIONS: Serum HGF was increased in male AS patients and associated with higher mSASSS and lower BMD. In addition, serum HGF was positively associated with risk factors for osteoproliferation such as age, CRP and smoking. HGF could be a potential biomarker of importance for the bone metabolism in AS. TRIAL REGISTRATION: NCT00858819. PMID- 30306222 TI - Acute continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, attenuates postprandial suppression of circulating osteocalcin in young overweight and obese adults. AB - : Bone remodeling markers (BRMs) are suppressed following the consumption of a meal. Our findings indicate that a single session of continuous moderate intensity exercise, but not low-volume high-intensity interval exercise, performed 1 h after a meal attenuates the postprandial suppression of BRMs. INTRODUCTION: Acute exercise transiently increases BRMs including osteocalcin (tOC) and the undercarboxylated form of osteocalcin (ucOC), a hormone that is implicated in glucose regulation. The effects of acute exercise and exercise intensity on postprandial levels of tOC and ucOC are unknown. METHODS: Twenty seven adults that were overweight or obese (age 30 +/- 1 years; BMI 30 +/- 1 kg?m 2; mean +/- SEM) were randomly allocated to perform a single session of low volume high-intensity interval exercise (LV-HIIE; nine females, five males) or continuous moderate-intensity exercise (CMIE; eightfemales, five males) 1 h after consumption of a standard breakfast. Serum tOC, ucOC, and ucOC/tOC were measured at baseline, 1 h, and 3 h after breakfast consumption on a rest day (no exercise) and the exercise day (exercise 1 h after breakfast). RESULTS: Compared to baseline, serum tOC and ucOC were suppressed 3 h after breakfast on the rest day (- 10 +/- 1% and - 6 +/- 2%, respectively; p < 0.05), whereas ucOC/tOC was elevated (2.5 +/- 1%; p = 0.08). Compared to the rest day, CMIE attenuated the postprandial-induced suppression of tOC (rest day - 10 +/- 2% versus CMIE - 5 +/- 2%, p < 0.05) and ucOC (rest day - 6 +/- 4% versus CMIE 11 +/- 2%, p < 0.05), and increased postprandial ucOC/tOC (rest day 3 +/- 2% versus CMIE 15 +/- 1%, p < 0.05). In contrast, LV-HIIE did not alter postprandial tOC, ucOC, or ucOC/tOC (all p > 0.1). CONCLUSIONS: Acute CMIE, but not LV-HIIE, attenuates the postprandial-induced suppression of tOC and ucOC. CMIE may be an effective tool to control the circulating levels of BRMs following meal consumption in overweight/obese adults. PMID- 30306223 TI - Discordant pattern of peripheral fractures in diabetes: a meta-analysis on the risk of wrist and ankle fractures. AB - : To clarify if the peripheral microarchitectural abnormalities described in diabetics have clinical consequences, we evaluated the risk of wrist and ankle fractures. The meta-analysis resulted in an increase in the risk of ankle fractures and a decrease in wrist fractures risk, suggesting that microarchitecture may not be the major fracture determinant. INTRODUCTION: There is evidence for an increase in the risk of hip fractures in diabetes (both in type 1 and 2), but the risk is not established for other skeletal sites. Microarchitecture evaluations have reported a decrease in volumetric bone mineral density and an increase in cortical porosity at the radius and tibia. To investigate if there is a clinical consequence for these microarchitectural abnormalities, we performed a systematic review and meta-analysis on the risk of ankle and wrist fractures in diabetes. METHODS: Medline and Embase were searched using the terms 'diabetes mellitus', 'fracture', 'ankle', 'radius' and 'wrist'. Relative risks and 95% confidence intervals were calculated using random effects model. RESULTS: For ankle fractures, six studies were selected including 2,137,223 participants and 15,395 fractures. For wrist fractures, 10 studies were eligible with 2,773,222 subjects and 39,738 fractures. The studies included men and women, ages 20 to 109 years for the wrist and 27 to 109 years for the ankle. The vast majority of subjects had type 2 diabetes. Diabetes was associated with an increase in the risk of ankle fractures (RR 1.30 95%CI 1.15-1.48) and a decrease in wrist fractures (RR 0.85 95%CI 0.77-0.95). In the studies that reported body mass index (BMI), the mean values were 10% higher in the diabetic groups than controls. CONCLUSION: The risk of fractures is increased in diabetes at the ankle and decreased at the wrist. The same pattern is observed in obesity. Although bone microarchitectural features are different in obesity and diabetes, the epidemiology of peripheral fractures is similar in both diseases suggesting that microarchitecture may not be the major determinant of peripheral fractures in these populations. PMID- 30306224 TI - Associations between radius low-frequency axial ultrasound velocity and bone fragility in elderly men and women. AB - : An exploratory study in elderly women and men from the Geneva Retirees Cohort indicates that low-frequency quantitative ultrasound measurement at the radius captures aBMD, bone size, and cortical tissue mineral density and might be used for screening purposes prior to DXA to evaluate fracture risk. INTRODUCTION: The contribution of distal radius bone mineral density (BMD) and cortical microstructure to fracture risk has recently been demonstrated. In this exploratory study, we investigated whether low-frequency quantitative ultrasound measurement at the distal radius may capture the peripheral determinants of bone fragility assessed with dual-energy X-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Low frequency velocity (VLF) was measured at the radius using OsCare Sono(r), a portable axial transmission ultrasonometer, in 271 community-dwelling postmenopausal women and men (age 71.5 +/- 1.4 years) from the Geneva Retirees Cohort. Cortical (Ct) and trabecular (Tb) volumetric (v) BMD and microstructure at the distal radius were assessed by HR-pQCT, in addition to areal (a) BMD by DXA, at the same time point. RESULTS: VLF was highly correlated with aBMD at the distal third radius (r = 0.72, p < 0.001). For microstructure parameters, the highest correlation was observed with cortical area (r = 0.59, p < 0.001). VLF also captured bone geometry (total area) and cortical tissue mineral density independently of aBMD. In models adjusted for age and sex, VLF was significantly associated with prevalent low-trauma fractures [OR 95%CI for one SD decrease of VLF 1.50 (1.05, 2.14), p = 0.024], with discrimination performance comparable to femoral neck or distal radius aBMD. CONCLUSION: Measurement of VLF at the radius captures aBMD, bone size, and cortical tissue mineral density and might be used for screening purposes prior to DXA to evaluate fracture risk. PMID- 30306225 TI - Prediction of incident vertebral fracture using CT-based finite element analysis. AB - : Prior studies show vertebral strength from computed tomography-based finite element analysis may be associated with vertebral fracture risk. We found vertebral strength had a strong association with new vertebral fractures, suggesting that vertebral strength measures identify those at risk for vertebral fracture and may be a useful clinical tool. INTRODUCTION: We aimed to determine the association between vertebral strength by quantitative computed tomography (CT)-based finite element analysis (FEA) and incident vertebral fracture (VF). In addition, we examined sensitivity and specificity of previously proposed diagnostic thresholds for fragile bone strength and low BMD in predicting VF. METHODS: In a case-control study, 26 incident VF cases (13 men, 13 women) and 62 age- and sex-matched controls aged 50 to 85 years were selected from the Framingham multi-detector computed tomography cohort. Vertebral compressive strength, integral vBMD, trabecular vBMD, CT-based BMC, and CT-based aBMD were measured from CT scans of the lumbar spine. RESULTS: Lower vertebral strength at baseline was associated with an increased risk of new or worsening VF after adjusting for age, BMI, and prevalent VF status (odds ratio (OR) = 5.2 per 1 SD decrease, 95% CI 1.3-19.8). Area under receiver operating characteristic (ROC) curve comparisons revealed that vertebral strength better predicted incident VF than CT-based aBMD (AUC = 0.804 vs. 0.715, p = 0.05) but was not better than integral vBMD (AUC = 0.815) or CT-based BMC (AUC = 0.794). Additionally, proposed fragile bone strength thresholds trended toward better sensitivity for identifying VF than that of aBMD-classified osteoporosis (0.46 vs. 0.23, p = 0.09). CONCLUSION: This study shows an association between vertebral strength measures and incident vertebral fracture in men and women. Though limited by a small sample size, our findings also suggest that bone strength estimates by CT based FEA provide equivalent or better ability to predict incident vertebral fracture compared to CT-based aBMD. Our study confirms that CT-based estimates of vertebral strength from FEA are useful for identifying patients who are at high risk for vertebral fracture. PMID- 30306227 TI - Timing is everything: differential effects of chronic stress on fear extinction. AB - RATIONALE: Stress disorders cause abnormal regulation of fear-related behaviors. In most rodent models of these effects, stress was administered before fear conditioning, thereby assessing its impact on both the formation and extinction of fear memories, not the latter alone. Here, we dissociated the two processes by also administering stress after fear conditioning, and then compared how pre conditioning versus post-conditioning exposure to chronic stress affects subsequent acquisition and recall of fear extinction. METHODS: Male Wistar rats were subjected to chronic immobilization stress (2 h/day, 10 days); the morphological effects of which were analyzed using modified Golgi-Cox staining across brain areas mediating the formation and extinction of fear memories. Separate groups of rats underwent fear conditioning followed by acquisition and recall of extinction, wherein stress was administered either before or after fear conditioning. RESULTS: When fear memories were formed after chronic stress, both acquisition and retrieval of extinction was impaired. Strikingly, these deficits were absent when fear memories were formed before the same stress. Chronic stress also reduced dendritic spine density in the infralimbic prefrontal cortex, but enhanced it in the basolateral amygdala. CONCLUSION: Chronic stress, administered either before or after fear learning, had distinct effects on the acquisition and recall of fear extinction memories. Stress also strengthened the structural basis of synaptic connectivity in the amygdala, but weakened it in the prefrontal cortex. Thus, despite eliciting a specific pattern of brain region-specific morphological changes, the timing of the same stress gave rise to strikingly different behavioral effects on the extinction of fear. PMID- 30306226 TI - Gene-based GWAS analysis for consecutive studies of GEFOS. AB - : By integrating the multilevel biological evidence and bioinformatics analyses, the present study represents a systemic endeavor to identify BMD-associated genes and their roles in skeletal metabolism. INTRODUCTION: Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) have already identified about 100 loci associated with bone mineral density (BMD), but these loci only explain a small proportion of heritability to osteoporosis risk. In the present study, we performed a gene-based analysis of the largest GWASs in the bone field to identify additional BMD-associated genes. METHODS: BMD-associated genes were identified by combining the summary statistic P values of SNPs across individual genes in the two consecutive meta-analyses of GWASs from the Genetic Factors for Osteoporosis (GEFOS) studies. The potential functionality of these genes to bone was partially assessed by differential gene expression analysis. Additionally, the consistency of the identification of potential bone mineral density (BMD)-associated variants were evaluated by estimating the correlation of the P values of the same single-nucleotide polymorphisms (SNPs)/genes between the two consecutive Genetic Factors for Osteoporosis Studies (GEFOS) with largely overlapping samples. RESULTS: Compared to the SNP-based analysis, the gene-based strategy identified additional BMD-associated genes with genome-wide significance and increased their mutual replication between the two GEFOS datasets. Among these BMD-associated genes, three novel genes (UBTF, AAAS, and C11orf58) were partially validated at the gene expression level. The correlation analysis presented a moderately high between-study consistency of potential BMD-associated variants. CONCLUSIONS: Gene-based analysis as a supplementary strategy to SNP based genome-wide association studies, when applied here, is shown that it helped identify some novel BMD-associated genes. In addition to its empirically increased statistical power, gene-based analysis also provides a higher testing stability for identification of BMD genes. PMID- 30306228 TI - Translational tests involving non-reward: methodological considerations. AB - This review is concerned with methods for assessing the processing of unrewarded responses in experimental animals and the mechanisms underlying performance of these tasks. A number of clinical populations, including Parkinson's disease, depression, compulsive disorders, and schizophrenia demonstrate either abnormal processing or learning from non-rewarded responses in laboratory-based reinforcement learning tasks. These effects are hypothesized to result from disturbances in modulatory neurotransmitter systems, including dopamine and serotonin. Parallel work in experimental animals has revealed consistent behavioral patterns associated with non-reward and, consistent with the human literature, modulatory roles for specific neurotransmitters. Classical tests involving an important reward omission component include appetitive extinction, ratio schedules of responding, reversal learning, and delay and probability discounting procedures. In addition, innovative behavioral tests have recently been developed leverage probabilistic feedback to specifically assay accommodation of, and learning from, non-rewarded responses. These procedures will be described and reviewed with discussion of the behavioral and neural determinants of performance. A final section focusses specifically on the benefits of trial-by-trial analysis of responding during such tasks, and the implications of such analyses for the translation of findings to clinical studies. PMID- 30306230 TI - [Endoscopic negative pressure therapy of the upper gastrointestinal tract. German version]. AB - Endoscopic negative pressure therapy (ENPT) has been adapted for upper gastrointestinal tract applications. More than 400 patients have already been treated with ENPT due to transmural defects in the upper gastrointestinal tract, with a success rate of 87%. The greatest experience exists for the treatment of anastomotic leakages and perforations of the esophagus. The ENPT is also used in the duodenum, pancreas and for complications after bariatric surgery. There are new indications that go beyond treatment in complication management. Innovative drainage types and endoscopic techniques have been developed that broaden the spectrum of applications. The aim of this article is to give an overview of the current status of ENPT in the upper gastrointestinal tract. PMID- 30306231 TI - [Learning of flexible endoscopy, particularly endoscopic vacuum therapy (EVT)]. AB - BACKGROUND: Anastomotic insufficiency and perforations in the gastrointestinal tract are severe complications associated with a high complication rate and mortality. Conventional treatment options (particularly re-operations) are often unsatisfactory. Endoscopic vacuum therapy (EVT) is increasingly being used as a promising alternative. PROBLEM: The use of EVT requires a high level of competence in interventional flexible endoscopy, which is primarily not available to every surgeon. Special training programs are required here. METHODS: Based on this need the long-proven Tubingen training system for flexible endoscopy was modified to meet the special requirements of surgeons and is currently being extended by a special training module for EVT. RESULTS: In addition to the theoretical principles, the training is focused on learning the manual skills for flexible endoscopy. A 2-stage process was developed for this purpose: 1) to become familiar with handling of the flexible endoscope and to learn spatial orientation by means of a didactically optimized abstract phantom (Tubingen Orientophant) and 2) learning and training of EVT using a newly developed patient analogous training model with various insufficiencies and abscess cavities in the upper and lower gastrointestinal tract. The procedure can be trained hands-on step by step exactly as with the patient, whereby the sponge can be applied using different methods, such as overtube and dragging procedures. The consequences of mistakes and complication management can also ideally be trained hands-on using the phantom. DISCUSSION: Evaluations of the first course series show that surgeons achieve endoscopic competence very quickly and learn to master the new procedure. The structure of such a course must, however, be designed according to long-term experience in an optimal didactic manner. Decision-makers in healthcare policy should give much more support to such courses in order to improve patient care and to increase patient safety. PMID- 30306229 TI - Effects of the experimental administration of oral estrogen on prefrontal functions in healthy young women. AB - 17-Beta-estradiol (E2) stimulates neural plasticity and dopaminergic transmission in the prefrontal cortex, which is critically involved in attentional control, working memory, and other executive functions. Studies investigating E2's actions on prefrontally mediated behavior in the course of the menstrual cycle or during hormone replacement therapy are inconclusive, with numerous null findings as well as beneficial and detrimental effects. The current study focused on the effect of E2 on attentional performance, as animal studies indicate that supraphysiological doses (i.e., above estrous cycle levels) of E2 have beneficial effects on measures of attention in female rodents. To translate these findings to humans, we administered 12 mg E2-valerate or placebo orally to 34 naturally cycling women in the low-hormone early follicular phase using a randomized, double-blinded, pre post design. Behavioral performance was tested twice during baseline and E2 peak, where E2 levels reached mildly supraphysiological levels in the E2 group. Aside from mainly prefrontally mediated tasks of attention, working memory, and other executive functions, we employed tasks of affectively modulated attention, emotion recognition, and verbal memory. E2 administration had a significant, but subtle negative impact on general processing speed and working memory performance. These effects could be related to an overstimulation of dopaminergic transmission. The negative effect of supraphysiological E2 on working memory connects well to animal literature. There were no effects on attentional performance or any other measure. This could be explained by different E2 levels being optimal for changing behavioral performance in specific tasks, which likely depends on the brain regions involved. PMID- 30306232 TI - [Genetics of pheochromocytoma and the relevance in surgery]. AB - Chromaffin tumors, e.g. pheochromocytomas and paragangliomas are caused by germline mutations of several susceptibility genes in 30-40% of the patients. The corresponding syndromes are multiple endocrine neoplasia type 2 (MEN2, RET gene), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), paraganglioma syndrome types 1-5 (PGL1-5, SDHx gene) and familial pheochromocytoma due to mutations in the MAX and TMEM127 genes. Clinically, screening for such diseases should be carried out by clinical symptoms and mutation analyses. Important indications can be found in the history of patients and their families, young age of manifestation (<30 years), extra-adrenal localization and the presence of metastatic pheochromocytomas. Organ-preserving endoscopic adrenal operations are nowadays standard for hereditary pheochromocytomas. Previous studies have shown that the reoccurrence of tumors in residual tissue is rare and can occur many years later and that metastatic tumors arising from such recurrences are very rare. When a mutation is detected in a susceptibility gene, a multidisciplinary follow-up care tailored to each individual syndrome is essential. PMID- 30306233 TI - [Open vs. laparoscopic rectal resection-2-year results of the ACOSG Z6051 study]. PMID- 30306234 TI - [Intrathoracic anastomotic leakage following esophageal and cardial resection : Definition and validation of a new severity grading classification]. AB - BACKGROUND: Anastomotic leakage is still the most frequent cause of postoperative mortality following esophageal and cardial surgery. The German Advanced Surgical Study Group recommended that endoscopy should be the first diagnostic method if leakage is suspected. The German Surgical Endoscopy Association developed and validated a definition and severity classification of anastomotic leakage following esophageal and cardial resection. MATERIAL AND METHODS: In 2010 the international study group on insufficiency published a definition and severity grading of anastomotic leakage following anterior resection of the rectum, which was validated in 2013. The severity of anastomotic leakage should be graded according to the impact on clinical management: type I requires only conservative management, type II requires interventional radiological or endoscopic treatment and type III requires surgical revision. In contrast to the rectal classification type III is divided into a category without (type IIIa) or with (type IIIb) conduit resection and diversion. The validation was carried out on a 10-year collective from the university hospitals in Heidelberg and Tubingen. RESULTS: From 2006-2015 all 92 patients who developed an anastomotic leakage following esophageal and cardial resection were enrolled in the study. We found a significant increase in the length of stay in the intensive care unit (ICU) with increasing classification type (p < 0.0143). Furthermore, there was a significant correlation with the general classification of postoperative complications according to Clavien-Dindo as well as with mortality (p < 0.001). DISCUSSION: Standardized parameters are the prerequisite to be able to compare the results between hospitals and studies. The validation of the suggested classification shows that the differentiation between the groups is substantiated by the correlation to the length of ICU stay, Clavien-Dindo and mortality and will therefore contribute to a better comparability of data on leakage following esophageal resection in the future. PMID- 30306235 TI - Identification of lignin oligomers in Kraft lignin using ultra-high-performance liquid chromatography/high-resolution multiple-stage tandem mass spectrometry (UHPLC/HRMSn). AB - Kraft lignin is the main source of technically produced lignin. For the development of valuable products based on Kraft lignin, its molecular structure is important. However, the chemical composition of Kraft lignin is still not well known. So far, the analysis of Kraft lignin by mass spectrometry (MS) has been mainly focused on monomeric compounds. Previous MS studies on lignin oligomers (LOs) considered only synthesised LO standards and/or lignins produced by processes other than the Kraft process. Furthermore, published MS methods suffer from using high resolution only in the MS1 stage in multiple-stage tandem MS methods. A high resolution in all MSn stages would provide more detailed information about LO fragmentation pathways. Since lignin samples are complex mixtures of a large number of similar phenolic compounds, the selection of tentative LOs in the MS data is challenging. In this study, we present a method for non-targeted analysis of LOs in Kraft lignin using ultra-high-performance liquid chromatography/high-resolution multiple-stage tandem mass spectrometry (UHPLC/HRMSn). A pre-selection strategy for LOs has been established based on a data-dependent neutral loss MS3 method in combination with a principal component analysis-quadratic discriminant analysis classification model (PCA-QDA). The method was optimised using a design of experiments (DOE) approach. The developed approach improved the pre-selection of tentative LOs in complex mixtures. From 587 detected peaks, 36 peaks were identified as LOs. Graphical abstract ?. PMID- 30306236 TI - Liquid chromatography-time-of-flight high-resolution mass spectrometry study and determination of the dansylated products of estrogens and their hydroxylated metabolites in water and wastewater. AB - A method combining liquid chromatography with a dual-probe ultraspray electrospray ionization (ESI) source and time-of-flight high-resolution mass spectrometry (LC-ESI-TOF/MS) was developed for the simultaneous determination of four steroidal sex hormones, estrone (E1), 17beta-estradiol (E2), 17alpha-ethinyl estradiol (EE2), and estriol (E3), as well as five of their hydroxylated metabolites, 2-hydroxyestrone (2-OHE1), 4-hydroxyestrone (4-OHE1), 16alpha hydroxyestrone (16-OHE1), 2-hydroxyestradiol (2-OHE2), and 4-hydroxyestradiol (4 OHE2), in water samples in a short chromatographic run of 10 min. Derivatization of the analytes was optimized using dansyl chloride as the derivatizing agent. Under optimal positive ionization conditions, the following signals, which had not been previously reported, were observed (with theoretical values of m/z 377.1373 for 2- and 4-OHE1 and 378.1452 for 2- and 4-OHE2), corresponding to doubly derivatized catechol estrogens in the form of [M+2H]2+. These mass spectrometric signals were more abundant than those reported previously for the [M+H]+ forms of these hydroxylated metabolites. Solid-phase extraction (SPE) with an octadecyl-endcapped sorbent was used to pretreat tap water and effluent from a wastewater treatment plant (WWTP) in Santiago, Chile. The method achieved the simple, fast, and sensitive measurement of nine estrogens with quantitative recoveries (higher than 85.4%). Detection and quantification limits were between 1 and 17 ng L-1 and between 3 and 58 ng L-1, respectively, for all compounds in water. The estrogens E1 and E2 were found in WWTP effluent at concentrations of 7 +/- 1 and 41 +/- 1 ng L-1, respectively, and EE2 was detected at a concentration below the limit of quantitation. This study shows that the proposed method is suitable for the accurate, rapid, and selective determination of all these analytes at trace levels. Graphical abstract ?. PMID- 30306237 TI - Tip-enhanced Raman spectroscopy: principles, practice, and applications to nanospectroscopic imaging of 2D materials. AB - Two-dimensional (2D) materials have been one of the most extensively studied classes of modern materials, due to their astonishing chemical, optical, electronic, and mechanical properties, which are different from their bulk counterparts. The edges, grain boundaries, local strain, chemical bonding, molecular orientation, and the presence of nanodefects in these 2D monolayers (MLs) will strongly affect their properties. Currently, it is still challenging to investigate such atomically thin 2D monolayers with nanoscale spatial resolution, especially in a label-free and non-destructive way. Tip-enhanced Raman spectroscopy (TERS), which combines the merits of both scanning probe microscopy (SPM) and Raman spectroscopy, has become a powerful analytical technique for studying 2D monolayers, because it allows very high-resolution and high-sensitivity local spectroscopic investigation and imaging and also provides rich chemical information. This review provides a summary of methods to study 2D monolayers and an overview of TERS, followed by an introduction to the current state-of-the-art and theoretical understanding the spatial resolution in TERS experiments. Surface selection rules are also discussed. We then focus on the capabilities and potential of TERS for nanoscale chemical imaging of 2D materials, such as graphene, transition metal dichalcogenides (TMDCs), and 2D polymers. We predict that TERS will become widely accepted and used as a versatile imaging tool for chemical investigation of 2D materials at the nanoscale. Graphical abstract ?. PMID- 30306239 TI - Femoral tunnel widening is similar between anteromedial portal and transtibial techniques following single-bundle anterior cruciate ligament reconstruction: a systematic review and meta-analysis. AB - PURPOSE: In anterior cruciate ligament (ACL) reconstruction, there is concern regarding the potential risk of femoral tunnel widening in the anteromedial portal (AMP) technique due to the acute graft-bending angle at the aperture and the more elliptical aperture shape of the femoral tunnel compared to the transtibial (TT) techniques. Therefore, the aim of the current systematic review and meta-analysis was to compare the femoral tunnel widening between the AMP and TT techniques in patients who underwent ACL reconstruction. METHODS: It should be included the studies that reported on femoral tunnel widening in patients who underwent single-bundle ACL reconstruction, using soft-tissue tendon graft, with AMP and/or TT techniques. Two reviewers independently recorded data from each study, including the sample size and magnitude of tunnel widening after ACL reconstruction. RESULTS: Twenty-one studies were finally included in this meta analysis. The pooled changes of absolute millimeters of tunnel widening from the immediate postoperative status to the last follow-up did not differ significantly between the AMP and TT techniques at both the aperture [3.31 mm, 95% confidence interval (CI) 1.7-5.0. mm versus 2.9 mm, 95% CI 2.4-3.4 mm, P = n.s.] and the midportion (3.5 mm, 95% CI 0.8-6.3 mm versus 3.0 mm, 95% CI 2.2-3.9 mm, P = n.s.) of the femoral tunnel. No significant difference was observed between the two techniques in the relative percentage of femoral tunnel widening (AMP; 28.8%, 95% CI 14.8-42.9% vs. TT; 29.7%, 95% CI 15.6-43.7%, P = n.s.). CONCLUSION: No significant difference in femoral tunnel widening was observed between the AMP and TT techniques, both in absolute millimeter and relative percentage, in patients who underwent single-bundle ACL reconstruction. This finding could alleviate the potential concerns associated with femoral tunnels being wider for the AMP than for the TT technique. LEVEL OF EVIDENCE: III. PMID- 30306238 TI - Hexagonal cobalt oxyhydroxide nanoflakes/reduced graphene oxide for hydrogen peroxide detection in biological samples. AB - Abnormal concentration of hydrogen peroxide (H2O2) in blood plasma and cells may lead to several diseases. Thus, it is important to develop a selective and sensitive method to monitor H2O2. In the present work, a novel nonenzymatic H2O2 sensing platform based on cobalt oxyhydroxide (CoOOH)/reduced graphene oxide (RGO) nanocomposite was fabricated. CoOOH nanoflakes were firstly synthesized via soft chemistry routes and then assembled on the surface of RGO. A series of characterizations by X-ray diffraction, X-ray photoelectron spectroscopy, and transmission electron microscopy demonstrated that hexagonal CoOOH nanoflakes were well distributed on the surface of RGO. The nanocomposite exhibited excellent electrochemical performance for H2O2 detection. Two linear ranges of 6 200 MUM and 200-1500 MUM were obtained, and the detection limit was 0.01 MUM (signal-to-noise ratio was 3). The good performance was attributed to more exposed catalytic active sites of CoOOH nanoflakes compared with zero-dimensional nanoparticles and outstanding conductivity of RGO as well as their synergistic effect. Moreover, the nanocomposite was used to detect H2O2 from human serum and HeLa cells with satisfactory results. Graphical abstract ?. PMID- 30306240 TI - Repair of the entire superior acromioclavicular ligament complex best restores posterior translation and rotational stability. AB - PURPOSE: The acromioclavicular ligament complex (ACLC) is the primary stabilizer against horizontal translation with the superior ACLC providing the main contribution. The purpose of this study was to evaluate the specific regional contributions in the superior half of ACLC, where the surgeon can easily access and repair or reconstruct, for posterior translational and rotational stability. METHODS: The superior half of ACLC was divided into three regions; Region A (0 degrees -60 degrees ): an anterior 1/3 region of the superior half of ACLC, Region B (60 degrees -120 degrees ): a superior 1/3 region of the superior half of ACLC, and Region C (120 degrees -180 degrees ): a posterior 1/3 region of the superior half of ACLC. Fifteen fresh-frozen cadaveric shoulders were used. Biomechanical testing was performed to evaluate the resistance force against passive posterior translation (10 mm) and the resistance torque against passive posterior rotation (20 degrees ) during the following the four conditions. (1) Stability was tested on all specimens in their intact condition (n = 15). (2) The ACLC was dissected and stability was tested (n = 15). (3) Specimens were randomly divided into three groups by regions of suturing. Stability was tested after suturing Region A, Region B, or Region C (n = 5 per group). (4) Stability was tested after suturing additional regions: Region A + B (0 degrees -120 degrees ), Region B + C (60 degrees -180 degrees ), or Region A + C (0 degrees -60 degrees , 120 degrees -180 degrees , n = 5 per group). RESULTS: The translational force increased after suturing Region A when compared with dissected ACLC (P = 0.025). The force after suturing Region A + B was significantly higher compared to the dissected ACLC (P < 0.001). The rotational torque increased after suturing Region A or Region B compared with dissected ACLC (P = 0.020, P = 0.045, respectively). The torque after suturing the Region A + C was significantly higher compared to the dissected ACLC (P < 0.001). CONCLUSION: The combined Region A + B contributed more to posterior translational stability than Region B + C or Region A + C. In contrast, combined Region A + C contributed more to posterior rotational stability than Region A + B or Region B + C. Based on these findings, surgical techniques restoring the entire superior ACLC are recommended to address both posterior translational and rotational stability of the AC joint. PMID- 30306241 TI - Anterior cruciate ligament reconstruction improves subjective ability but not neuromuscular biomechanics during dynamic tasks. AB - PURPOSE: The purpose of this study was to identify high-functioning anterior cruciate ligament-deficient patients and assess the effects of reconstruction on their self-reported functionality, muscle activations and biomechanical properties. METHODS: Twenty young and active patients participated pre- (11.5 +/- 14.3 months post-injury) and again 10.5 +/- 1.7 months post-reconstruction and were individually matched to 20 healthy controls. Participants completed hop and side cut movements while patient-related outcome measures, lower limb electromyography, kinetic, and whole body kinematic data were collected. One dimensional statistical parametric mapping was used to test for group differences (healthy vs deficient; deficient vs reconstructed; reconstructed vs healthy). RESULTS: When comparing healthy to anterior cruciate ligament-deficient participants, all questionnaires indicated significant lower subjective function while the only substantial biomechanical difference between these participants was a decreased knee extensor moment in both the hop (peak difference: 0.63 Nm/kg, p < 0.001) and side cut (peak difference: 0.76 Nm/kg, p < 0.001). When comparing patients' pre- and post-reconstruction, no biomechanical differences were observed whereas only half of the questionnaires (Tegner, Lysholm, KNEES ADL, KNEES-Slackness, KNEES-Looseness, KNEES-Sport Behaviour, IKDC, and KOOS-QoL) indicated higher function in the reconstructed state. When comparing the reconstructed patients to the healthy participants, all questionnaires were still significantly higher in the healthy controls. The reconstructed group also had a smaller flexion angle (peak difference: 14.5 degrees , p = 0.007) and knee extensor moment (peak difference: 0.62 Nm/kg, p < 0.001) during the hop and a smaller knee extensor moment (peak difference: 0.90 Nm/kg, p < 0.001) during the side-cut task. CONCLUSION: At 10-months post-reconstruction, the current results indicate that in high-functioning anterior cruciate ligament-deficient patients, reconstruction had little impact on objective measures of functional ability during dynamic tasks although self-reported function was improved. LEVEL OF EVIDENCE: Therapeutic prospective cohort study, Level II. PMID- 30306242 TI - Asymmetric polyethylene inserts promote favorable kinematics and better clinical outcome compared to symmetric inserts in a mobile bearing total knee arthroplasty. AB - PURPOSE: This study aims at comparing the effects of symmetric and asymmetric designs for the polyethylene insert currently available and also for mobile bearing total knee arthroplasty (TKA). The investigation was performed both clinically and biomechanically through finite element analysis. METHODS: 303 patients, with a mobile bearing TKA, were analyzed retrospectively. All patients received the same femoral and tibial components; for the insert, 151 patients received a symmetric design (SD) and 152 an asymmetric design (AD). Additionally, a 3D finite element model of a lower leg was developed, resurfaced with the same TKAs and analysed during gait and squat activities. TKA kinematics, and bone stresses were investigated for the two insert solutions. RESULTS: After surgery, patients' average flexion improved from 105 degrees , with 5 degrees of preoperative extension deficit, to 120 degrees (AD-group) and 115 degrees (SD group) at the latest follow-up. There was no postoperative extension deficit. No pain affected the AD-group, while an antero-lateral pain was reported in some patients of the SD-group. Patients of the AD-group presented a better ability to perform certain physical routines. Biomechanically, the SD induced higher tibial bone stresses than the AD. Both designs replicated similar kinematics, comparable to literature. However, SD rotates more on the tray, reducing the motion between femoral and polyethylene components, while AD permits greater insert rotation. CONCLUSION: The biomechanical analysis justifies the clinical findings. TKA kinematics is similar for the two designs, although the asymmetric solution shows less bone stress, thus resulting as more suitable to be cemented, avoiding lift off issues, inducing less pain. Clinically, and biomechanically, an asymmetric mobile bearing insert could be a valid alternative to symmetric mobile bearing insert. LEVEL OF EVIDENCE: Case-control study retrospective comparative study, III. PMID- 30306243 TI - Neuromuscular electrical stimulation increases serum brain-derived neurotrophic factor in humans. AB - Brain-derived neurotrophic factor (BDNF) plays several important roles in nervous system function including neuronal growth and plasticity. The purpose of the present study was to clarify whether neuromuscular electrical stimulation (NMES) and voluntary exercise to the same integrated force as by the NMES-induced exercise would enhance serum BDNF. Eleven healthy male subjects completed three interventions (NMES, voluntary exercise, and resting interventions) for 20 min on different days. In the NMES intervention, NMES was applied to the quadriceps femoris muscles. The stimulus intensity of NMES was progressively increased to the highest tolerated intensity during the experiment. In the voluntary exercise intervention, subjects performed an isometric knee-extension task; in this intervention, the target torque was calculated in accordance with the integrated force of knee extension obtained during the NMES intervention. In the resting intervention, subjects relaxed in a sitting posture. We measured serum BDNF, blood lactate, heart rate, oxygen uptake, respiratory ratio, and blood pressure. Serum BDNF was increased in the NMES (p = 0.003) and voluntary exercise interventions (p = 0.004) after each intervention. At the post-timepoint, serum BDNF in the NMES intervention was highest among all interventions (p = 0.038) and significantly higher than in the voluntary exercise (p = 0.036) and resting (p = 0.037) interventions. Our results showed that NMES was more effective for enhancing serum BDNF than voluntary exercise at least when employing the same method and integrated force. PMID- 30306244 TI - Looking up while reaching out: the neural correlates of making eye and arm movements in different spatial planes. AB - Standard visually guided reaching begins with foveation of a target of interest followed by an arm movement to the same spatial location. However, many visually guided arm movements, as well as a majority of imaging studies examining such movements, require participants to perform non-standard visuomotor mappings where the locations of gaze and arm movements are spatially dissociated (e.g. gaze fixation peripheral to the target of a reaching movement, or use of a tool such as a joystick while viewing stimuli on a screen). In this study, we compare brain activity associated with the production of standard visually guided arm movements to activity during a visuomotor mapping where saccades and reaches were made in different spatial planes. Multi-voxel pattern analysis revealed that while spatial patterns of voxel activity remain quite similar for the two visuomotor mappings during presentation of a cue for movement, patterns of activity become increasingly more discriminative throughout the brain as planning progresses toward motor execution. Decoding of the visuomotor mappings occurs throughout visuomotor-related regions of the brain including the premotor, primary motor and somatosensory, posterior parietal, middle occipital, and medial occipital cortices, and in the cerebellum. These results show that relative to standard visuomotor tasks, activity differs substantially in areas throughout the brain when a task requires an implicit sensorimotor recalibration. PMID- 30306245 TI - Startle evokes nearly identical movements in multi-jointed, two-dimensional reaching tasks. AB - StartReact is the ability of the startle reflex to involuntarily release a planned movement in the presence of a loud acoustic stimulus resulting in muscle activity patterns and kinematics that are tightly regulated and scaled with the intended action. Previous studies demonstrated startReact's robustness during simple single-joint reaching tasks and found no difference between startReact and voluntary movements for movement kinematics and muscle activation patterns. However, startReact has not been evaluated during multi-joint reaching movements with multiple degrees of freedom. It is unclear if startReact would evoke accurate and precise multi-joint reaching movements in an unrestricted workspace. Furthermore, if tested more rigorously, multi-joint startReact movement kinematics and muscle activation patterns might not be truly equivalent despite showing no difference through traditional ANOVAs. A previous study found multi joint startReact was possible during unrestricted elbow and shoulder movement when reaching to a forward target. Therefore, we hypothesized that startReact would evoke similar multi-joint reaching movements for movement accuracy and muscle activation patterns when compared to voluntary movements in a multi directional workspace. Expanding upon the previous study, our study uses a larger workspace and fully evaluates movement kinematics and muscle activations patterns. Results confirmed our hypothesis and found startReact movements were readily evoked in all directions. StartReact responses presented stereotypically earlier muscle activation, but the relative timing of agonist/antagonist firing pairs between startReact and voluntary movements remained similar. Results demonstrate that startReact is robustly present and equivalent in multi-joint reaching tasks and has potential clinical use for evaluating healthy and impaired movement. PMID- 30306246 TI - Effects of transcutaneous electrical nerve stimulation and visuotactile synchrony on the embodiment of an artificial hand. AB - The rubber hand illusion (RHI) is an experimental paradigm known to produce a bodily illusion. Transcutaneous electrical nerve stimulation (TENS) combined with the RHI induces a stronger illusion than the RHI alone. Visuotactile stimulus synchrony is an important aspect of the RHI. However, the effect of TENS and visuotactile stimulus synchrony in TENS combined with the RHI remains unknown. The purpose of this study was to investigate the effects of TENS and visuotactile stimulus synchrony on the embodiment of an artificial hand when using TENS combined with the RHI. The participants underwent four experimental conditions in random order: TENS/noTENS * Synchronous/Asynchronous. TENS was set at an intensity such that it generated a feeling of electrical paresthesia in the radial nerve area of the hand but did not cause pain, i.e., 100-Hz pulse frequency, 80-us pulse duration, and a constant pulse pattern. A visuotactile stimulus, either temporally synchronous or asynchronous, was generated using paintbrush strokes. To evaluate the outcome measures, the participants completed a questionnaire report and proprioceptive drift assessments (motor response and perceptual response). There were significant main effects of TENS and visuotactile synchrony, but no interaction between these factors, on the results of the questionnaire and the perceptual response. In contrast, there was no significant effect on the result of the motor response. These findings indicate that TENS and visuotactile synchrony might affect differently the embodiment of an artificial hand when using TENS combined with the RHI. PMID- 30306249 TI - Crosstalk in transition: the translocation of Akt. AB - Akt/PKB is an important crosstalk node at the junction between a number of major signalling pathways in the mammalian cell. As a significant nutrient sensor, Akt plays a central role in many cellular processes, including cell growth, cell survival and glucose metabolism. The dysregulation of Akt signalling is implicated in the development of many diseases, from diabetes to cancer. The translocation of Akt from cytosol to plasma membrane is a crucial step in Akt activation. Akt is initially synthesized on the endoplasmic reticulum, but translocates to the plasma membrane (PM) in response to insulin stimulation, where it may be activated. The Akt is then recycled to the cytoplasm. The activated Akt may propagate signals to downstream substrates both at the PM and in the cytosol, hence understanding the translocation dynamics is an important step in dissecting the signalling system. At the present time, however, knowledge concerning the translocation of either activated and unactivated Akt is scant. Here we present a simple, deterministic, three-compartment ordinary differential equation model of Akt translocation in vitro. This model can reproduce the salient features of Akt translocation in a manner consistent with the experimental data. Furthermore, we demonstrate that this system is equivalent to a damped harmonic oscillator, and analyse the steady state and transient behaviour of the model over the entire parameter space. PMID- 30306250 TI - An ant navigation model based on Weber's law. AB - We analyze an ant navigation model based on Weber's law, where the ants move across a pheromone landscape sensing the area using two antennae. The key parameter of the model is the angle [Formula: see text] representing the span of the ant's sensing area. We show that when [Formula: see text] ants are able to follow (straight) pheromone trails proving that for initial conditions close to the trail, there exists a Lyapunov function that ensures ant trajectories converge on and follow the pheromone trail, with these solutions being locally asymptotically stable. Furthermore, we indicate that the features of the ant trajectories such as convergence speed or oscillation wave length are controlled by the angle [Formula: see text]. For [Formula: see text], we present numerical evidence that indicates that ants are unable to follow pheromone trails. We also assess our model by comparing it to previous experimental results, showing that the solutions' behavior falls into biologically meaningful ranges. Our work provides solid mathematical support for experimental studies where it was found that ant perception follows a Weber's law, by proving that such models lead to the desired robust and stable trail following. PMID- 30306251 TI - Targeted silencing of genes in polyploids: lessons learned from Brassica juncea glucosinolate system. AB - KEY MESSAGE: Intron-spliced hairpin RNAi construct targeting the exonic region of BjuMYB28 driven by the native promoter is the best suited strategy for developing viable low glucosinolate lines in polyploid Brassica juncea. Targeted silencing of specific homolog(s) of a multigene family in polyploids through RNA interference (RNAi) is a challenging effort. Indian oilseed mustard (Brassica juncea), a natural allotetraploid, is expected to have 4-6 copies of every Arabidopsis gene ortholog. In the current study, we have attempted to establish the best gene silencing system suitable for BjuMYB28, a transcription factor gene, with the objective of developing low seed glucosinolate lines in B. juncea. After comparing multiple combinations of BjuMYB28 gene homologs, promoters, target regions (exon and 3' UTR) and silencing strategies (RNAi and antisense), we suggest that the intron-spliced hairpin RNAi construct targeting the specific exonic region of the BjuMYB28 gene under the control of native promoter, whose peak activity synchronises with the highest glucosinolate accumulation phase of the plant, is the best suited strategy for developing viable low glucosinolate lines in polyploid B. juncea. PMID- 30306252 TI - Let us take care of the patient! AB - Treating the patient-not only the disease itself-is important in daily clinical practice. Herein, a short text and a related cartoon on patient care are provided. PMID- 30306253 TI - The secrets of keeping fit: exercising and healthy eating. AB - Physical fitness not only requires exercising, but also healthy eating habits. Herein, a cartoon and a related text on physical fitness are submitted. PMID- 30306254 TI - Patterns of the initiation of disease-modifying antirheumatic drugs in incident rheumatoid arthritis: a German perspective based on nationwide ambulatory drug prescription data. AB - This study aimed at providing a current and nearly complete picture of the patterns of the initiation of disease-modifying antirheumatic drugs (DMARDs) in patients with newly diagnosed RA. Based on ambulatory drug prescription data and physician billing claims data covering 87% of the German population, we assembled a cohort of incident RA patients aged 15-79 years (n = 54,896) and assessed the prescription frequency of total DMARDs, conventional synthetic (csDMARDs) and biologic DMARDs (bDMARDs) within the first year of disease. Using multiple logistic regression, we estimated the chance of early DMARD receipt based on age, sex, serotype and specialty of prescribing physician while controlling for region of residence. In total, 44% of incident RA patients received a DMARD prescription within the first year of disease. In multiple regression, younger patients (< 35 years) had 1.7-fold higher chances of receiving a csDMARD than patients aged >= 65 years [odds ratio (OR): 1.65 with 95% confidence interval (CI) 1.51-1.80] and almost tenfold higher chances to receive a bDMARD [OR (95% CI) 9.5 (8.0-11.3)]. Seropositivity and a visit to a rheumatologist were positively associated with DMARD initiation [OR (95% CI) 2.8 (2.6-2.9) and 5.9 (5.6-6.2) for csDMARDs, respectively]. Based on data covering 87% of the German population, the present study revealed that less than half of incident RA patients receive DMARDs within the first year of disease and that marked differences exist according to age. The study highlights the importance of involving a rheumatologist early in the management of RA. PMID- 30306256 TI - Comparison of bonobo and chimpanzee brain microstructure reveals differences in socio-emotional circuits. AB - Despite being closely related, bonobos and chimpanzees exhibit several behavioral differences. For instance, studies indicate that chimpanzees are more aggressive, territorial, and risk-taking, while bonobos exhibit greater social tolerance and higher rates of socio-sexual interactions. To elucidate the potential neuroanatomical variation that accompanies these differences, we examined the microstructure of selected brain areas by quantifying the neuropil fraction, a measure of the relative tissue area occupied by structural elements of connectivity (e.g., dendrites, axons, and synapses) versus cell bodies. In bonobos and chimpanzees, we compared neuropil fractions in the nucleus accumbens (NAc; core and shell), amygdala (whole, accessory basal, basal, central and lateral nuclei), anterior cingulate cortex (ACC; dorsal and subgenual), anterior insular cortex (AIC), and primary motor cortex (M1). In the dorsal ACC and frontoinsular cortex (FI) we also quantified numbers of von Economo neurons (VENs), a unique subset of neurons thought to be involved in rapid information processing during social interactions. We predicted that the neuropil fraction and number of VENs in brain regions associated with socio-emotional processing would be higher in bonobos. In support of this hypothesis, we found that bonobos had significantly greater neuropil in the central and accessory basal nuclei of the amygdala, as well as layers V-VI of the subgenual ACC. However, we did not find a difference in the numbers of VENs between the two species. These findings support the conclusion that bonobo and chimpanzee brains differ in the anatomical organization of socio-emotional systems that may reflect species-specific variation in behavior. PMID- 30306255 TI - Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. AB - PURPOSE: Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research. METHODS: We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2). RESULTS: We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes. CONCLUSIONS: Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes. PMID- 30306258 TI - Relationship between physical activity and intramyocellular lipid content is different between young and older adults. AB - PURPOSE: Intramyocellular lipid (IMCL) is influenced by physical exercise; however, whether the habitual level of physical activity affects resting IMCL content remains unclear. The purpose of this study was to determine the relationship between physical activity levels and resting IMCL content in young and older adults. METHODS: In total, 15 nonobese young adults (21.0 +/- 0.0 years) and 15 older adults (70.7 +/- 3.8 years) were recruited. Time spent performing physical activities for 10 days was assessed using a three-dimensional ambulatory accelerometer, and intensity was categorized as light [< 3.0 metabolic equivalents (METs)], moderate (3.0-6.0 METs), or vigorous (> 6.0 METs). Physical activity level was calculated as the product of METs and time spent performing physical activities (MET h) at each intensity level. The IMCL content in the vastus lateralis was determined using 1H-magnetic resonance spectroscopy after overnight fasting. RESULTS: No significant differences in IMCL content were observed between young and older adults. Vigorous intensity physical activity (time and MET h) was significantly lower in older than young adults (p < 0.01); this difference was not observed for light and moderate intensity physical activity. Light intensity physical activity (time and MET h) was significantly and inversely correlated with IMCL content in young adults (r = - 0.59 and r = - 0.58; both p < 0.05), but not in older adults. CONCLUSIONS: These results suggest that daily light intensity physical activity reduces resting IMCL content in young adults, whereas no significant relationship was seen between daily physical activity and resting IMCL content in older adults. PMID- 30306260 TI - Identification of complement-related host genetic risk factors associated with influenza A(H1N1)pdm09 outcome: challenges ahead. AB - Influenza remains an important threat for human health, despite the extensive study of influenza viruses and the production of effective vaccines. In contrast to virus genetics determinants, host genetic factors with clinical impact remained unexplored until recently. The association between three single nucleotide polymorphisms (SNPs) and influenza outcome in a European population was investigated in the present study. All samples were collected during the influenza A(H1N1)pdm09 post-pandemic period 2010-11 and a sufficient number of severe and fatal cases was included. Host genomic DNA was isolated from pharyngeal samples of 110 patients from northern Greece with severe (n = 59) or mild (n = 51) influenza A(H1N1)pdm09 disease, at baseline, and the genotype of CD55 rs2564978, C1QBP rs3786054 and FCGR2A rs1801274 SNPs was investigated. Our findings suggest a relationship between the two complement-related SNPs, namely, the rare TT genotype of CD55 and the rare AA genotype of C1QBP with increased death risk. No significant differences were observed for FCGR2A genotypes neither with fatality nor disease severity. Additional large-scale genetic association studies are necessary for the identification of reliable host genetic risk factors associated with influenza A(H1N1)pdm09 outcome. Prophylactic intervention of additional high-risk populations, according to their genetic profile, will be a key achievement for the fight against influenza viruses. PMID- 30306259 TI - [Somatic risks in elderly people with severe psychiatric illnesses]. AB - BACKGROUND: Aged patients with severe mental illness (SMI) suffer from a high risk for functional impairment and a high load of somatic comorbidities. Until now, there has been a lack of systematic studies on this patient population in later life. This review summarizes the most significant somatic comorbidities and discusses the consequences for the medical care of this elderly group of patients. METHODS: A selective narrative review based on PubMed research and observations in clinical practice. RESULTS: Life expectancy is shortened by approximately 10 years in patients with SMI. The main reasons are somatic comorbidities, particularly lung and respiratory tract disorders, metabolic syndrome with its subsequent cardiovascular complications, in addition to osteoporosis and fractures with a complicated clinical course. Although life expectancy is shortened, the number of geriatric patients with SMI is increasing and requires special attention to be given to out-patient psychosocial care, self management of somatic diseases, and to age-appropriate continuation of psychiatric treatment. CONCLUSION: The life expectancy of patients with SMI is reduced because of their typically somatic comorbidity, but they are reaching increasingly advanced ages as a consequence of improved treatment possibilities. They often require special attention in their diagnostic work-up and support in the management of their treatment. Collaborative care linking medical geriatric and geronto-psychiatric treatment facilities is helpful in the the interdisciplinary therapy required. PMID- 30306261 TI - Buccal mucosa graft for simultaneous correction of severe chordee and urethroplasty as a one-stage repair of scrotal hypospadias (watch technique). AB - PURPOSE: Severe hypospadias repair still presents a great challenge. We evaluated a novel approach of using a specially shaped buccal mucosa graft for simultaneous ventral tunica grafting and new urethral plate creation, in combination with longitudinal dorsal island skin flap, as a one-stage repair of severe hypospadias. METHODS: Between July 2014 and September 2017, 26 patients (aged from 12 to 22 months) underwent scrotal hypospadias repair. Short and non-elastic urethral plate is divided. Buccal mucosa graft is harvested from the inner cheek, and designed in a special "watch" shape, with the spherical part in the middle and two rectangular parts on both sides. Tunica albuginea is opened ventrally for penile straightening and grafted to the spherical part of the "watch-shaped" buccal mucosa with 6-8 "U-shape" stitches. The rectangular parts are fixed to the tip of the glans distally and native urethral meatus proximally. Longitudinal dorsal skin flap is harvested, button-holed ventrally and joined with buccal graft. Penile skin reconstruction is performed using available penile skin. RESULTS: The mean follow-up was 22 months (range from 9 to 46 months). Satisfactory results were achieved in 22 patients. Two urethral fistulas were successfully repaired by minor surgery after 3 months, while one meatal stenosis and one urethral diverticulum were successfully treated by temporary urethral dilation. There were no cases of residual curvature. CONCLUSION: Specially shaped buccal mucosa graft for simultaneous curvature correction and urethroplasty could be a good choice for single-stage repair of scrotal hypospadias with severe curvature. PMID- 30306262 TI - Topical treatment with the bacterium-derived c-Met agonist InlB321/15 accelerates healing in the abrasion wound mouse model. AB - Studies of factors affecting wound-healing rates are encouraged by a critical need for new treatments to manage an increasing burden of non-healing wounds. The InlB protein produced by the Gram-positive bacterium Listeria monocytogenes is an agonist of the tyrosine kinase receptor c-Met and a functional analog of the hepatocyte growth factor (HGF), which is a mammalian ligand of c-Met. The recombinant InlB321 protein, which is the c-Met-binding InlB domain (amino acids 31-321), was cloned from the L. monocytogenes serovar 4b clinical strain VIMHA015 and serovar 1/2a strain EGDe (InlB321/15 and InlB321/EGDe, respectively). Both InlB321 variants stimulated proliferation of endothelial HUVEC cells. InlB321/15 was more active in Erk1/2 phosphorylation assay, and more potent than InlB321/EGDe in the 2D-scratch wound-healing assay. Scratch closure reached 86%, 29% and 72% for InlB321/15, InlB321/EGDe and HGF, respectively, 72 h post wounding (p < 0.05). Topically applied glycerol-mixed InlB321/15 (300 ug ml- 1) increased abrasion wound-healing rates in mice. The 50% wound closing time (CT50) was reduced by InlB321/15 (4.18 +/- 0.91 days; CI: 3.05; 5.31) compared with control animals (5.51 +/- 1.21 days; CI: 4.01; 7.01; p < 0.05). Taken together, obtained results suggested a potential of InlB321/15 as a means of accelerating wound healing. PMID- 30306257 TI - Macrophage-microbe interaction: lessons learned from the pathogen Mycobacterium tuberculosis. AB - Macrophages, being the cornerstone of the immune system, have adapted the ancient nutrient acquisition mechanism of phagocytosis to engulf various infectious organisms thereby helping to orchestrate an appropriate host response. Phagocytosis refers to the process of internalization and degradation of particulate material, damaged and senescent cells and microorganisms by specialized cells, after which the vesicle containing the ingested particle, the phagosome, matures into acidic phagolysosomes upon fusion with hydrolytic enzyme containing lysosomes. The destructive power of the macrophage is further exacerbated through the induction of macrophage activation upon a variety of inflammatory stimuli. Despite being the end-point for many phagocytosed microbes, the macrophage can also serve as an intracellular survival niche for a number of intracellular microorganisms. One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli. M. tuberculosis excels at circumventing destruction within macrophages, thus establishing itself successfully for prolonged times within the macrophage. In this contribution, we describe a number of general features of macrophages in the context of their function to clear an infection, and highlight the strategies employed by M. tuberculosis to counter macrophage attack. Interestingly, research on the evasion tactics employed by M. tuberculosis within macrophages not only helps to design strategies to curb tuberculosis, but also allows a better understanding of host cell biology. PMID- 30306263 TI - Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer. AB - PURPOSE: Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers. METHODS: PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC-MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA seq and qRT-PCR for KPC mice. RESULTS: Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0 infinity of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 ug/g tissue (or 13 uM), well above the cell-based IC50 of 0.4 uM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0-24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0-24h and C24h. AUC0-24h MD to AUC0-24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors. CONCLUSIONS: Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery. PMID- 30306264 TI - Functioning and quality of life in patients with neuropathy associated with anti MAG antibodies. AB - Although anti-myelin-associated glycoprotein (MAG) antibody neuropathy is reported as a slowly progressive disease, it can lead to significant disability and impairment of health-related quality of life (HR-QoL) and social participation. The aim of this cross-sectional study was to evaluate the functioning and HR-QoL determinants in 67 patients with anti-MAG neuropathy in terms of the International Classification of Functioning, Disability, and Health (ICF). Evaluations included: Medical Research Council (MRC) sum score, Sensory Modality Sum score (SMS), Berg balance scale (BBS), Fatigue Severity Scale (FSS), Visual Analogue Scale (VAS) for pain, 9-Hole Peg Test (9-HPT), 6-min Walk Distance (6MWD), Impact on Participation and Autonomy (IPA) and the physical component score (PCS) and mental component score (MCS) of the short-form-36 health status scale (SF-36) HR-QoL measure. In the regression models, 6MWD was the most reliable predictor of PCS, explaining the 52% of its variance, while the strongest determinants of 6MWD were BBS and FSS, explaining the 41% of its variance. Consistently, VAS and BBS were good predictor of PCS, explaining together 54% of its variance. FSS was the most reliable determinant of MCS, explaining 25% of its variance. SMS and MRC were not QoL determinants. The results of our study suggest that 6MWD and FSS might be considered as potential meaningful outcome measures in future clinical trials. Furthermore, neurorehabilitation interventions aimed at improving balance and walking performance, fatigue management, and specific pain relief therapy should be considered to ameliorate participation in social life and HR-QoL in anti-MAG neuropathy patients. PMID- 30306266 TI - Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. AB - The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice. Using near-infrared fluorescence imaging, we showed that tracers quickly exited the subarachnoid space by transport through the lymphatic system to the systemic circulation in awake mice, significantly limiting their spread to the paravascular spaces of the brain. Magnetic resonance imaging and fluorescence microscopy through the skull under anesthetized conditions indicated that tracers remained confined to paravascular spaces on the surface of the brain. Immediately after death, a substantial influx of tracers occurred along paravascular spaces extending into the brain parenchyma. We conclude that under normal conditions a rapid CSF turnover through lymphatics precludes significant bulk flow into the brain. PMID- 30306265 TI - Evaluation of Plasmodium vivax isolates in Thailand using polymorphic markers Plasmodium merozoite surface protein (PvMSP) 1 and PvMSP3. AB - Malaria is a significant public health problem in several tropical countries including Thailand. The prevalence of Plasmodium vivax infection has been increasing in the past decades. Plasmodium vivax merozoite surface protein (PvMSP) gene encodes a malaria vaccine candidate antigen. Its polymorphic nature leads to antigenic variation, the barrier for vaccine development, drug resistance, and potential for multiple-clone infections within the malaria patients. The objective of this study was to investigate the genetic diversity of PvMSP1 and PvMSP3 gene in P. vivax populations in Thailand. A total of 100 P. vivax isolates collected from the western (Kanchanaburi and Tak Provinces) and southern (Ranong Provinces) regions along the Thai-Myanmar border were analyzed using polymerase chain reaction and restriction fragment length polymorphism (PCR RFLP). Analysis of the F1, F2, and F3 regions of PvMSP1 revealed 5, 2, and 3 allelic variants, respectively. Three major types of PvMSP3-alpha and two major types of PvMSP3-beta were identified based on the PCR product sizes. After digestion with restriction enzymes, 29, 25, 26, and 18 patterns were distinguished by RFLP for PvMSP1 (F2, Alu I), PvMSP1 (F2, Mnl I), PvMSP3-alpha, and PvMSP3-beta, respectively. Combination of each family variant (PvMSP1 and PvMSP3) resulted in high genetic polymorphism of P. vivax population. Additionally, using PvMSP1 polymorphic marker revealed a significant association between multiple-genotype infections and P. vivax parasitemia. The results strongly supported that P. vivax populations in the endemic areas along the Thai Myanmar border are highly diverse. PMID- 30306267 TI - Correction to: Gastrointestinal juvenile-like (inflammatory/hyperplastic) mucosal polyps in neurofibromatosis type 1 with no concurrent genetic or clinical evidence of other syndromes. AB - The authors regret that the original version of this article, unfortunately, contained an error. The values "1/3 (33%)" reported in the second to last sentence of the Discussion are wrong; the correct values are "2/2 (100%)". These are presented correctly in this article. PMID- 30306268 TI - Effects of anti-osteoporosis medications on total hip arthroplasty risks in osteoporotic patients with hip osteoarthritis in Taiwan: a nationwide cohort study. AB - : This nationwide cohort study examined the potential disease-modifying effect of anti-osteoporosis medication on hip osteoarthritis. The results revealed that the usage of anti-osteoporosis medication is not associated with decreased risk in undergoing total hip arthroplasty in patient with hip osteoarthritis. PURPOSE: This study aimed to assess the association between use of anti-osteoporosis medications (AOMs) and the risk of undergoing total hip arthroplasty (THA) in patients with hip osteoarthritis (OA). METHODS: Using the 2008-2013 National Health Insurance Research Database, we identified patients who were first diagnosed as having hip OA. All identified patients were followed until THA, death of any cause, or December 31, 2013, whichever occurred first. All AOM exposures were divided into three categories: bisphosphonates use, non bisphosphonates use, and no use of AOMs and assessed in a time-varying manners. The primary outcome was THA. The secondary outcome was the differences in the longitudinal utilization of NSAIDs between AOM users and non-users. Time dependent Cox proportional hazards models were used to investigate the effect of AOM use on the risk of THA. RESULTS: We identified 35,870 patients who were first diagnosed as having hip OA and had no history of AOM use between 2009 and 2012. Among them, 3162 and 1667 patients had their first prescription of bisphosphonates and other non-bisphosphonates AOMs during the follow-up period. Mean age of bisphosphonates users, non-bisphosphonates users, and non-users was 75.62, 76.84, and 67.39 years, respectively. Bisphosphonates or non bisphosphonates users did not show significant change when compared to non-users in terms of risk of undergoing THA [adjusted hazard ratio (aHR) 0.972, 95% confidence interval (CI) 0.743-1.273; aHR 0.926, 95% CI 0.672-1.277]. CONCLUSION: Our results showed that the use of AOMs is not associated with decreased risk of THA in patients with hip OA. PMID- 30306269 TI - The effects of intrapartum synthetic oxytocin on maternal postpartum mood: findings from a prospective observational study. AB - Postpartum depression (PPD) affects up to 19% of all mothers, with detrimental effects on both mother and child. The antidepressant and anxiolytic effects of plasma oxytocin are well-documented, but it is still disputable whether synthetic oxytocin (synOT) may protect women against postpartum mood alterations. The current study examined the association between synOT intrapartum and maternal mood postpartum using a prospective design. Two hundred sixty women were screened for depressive symptoms in the last trimester of pregnancy and then again 6 weeks and 9 months postpartum using the Edinburgh Postnatal Depression Scale. They also completed Maternity Blues Questionnaire in the first postpartum week. The data concerning the intrapartum interventions and health status of the newborn were extracted from the medical records. Cox proportional hazards regression adjusted for a history of depression, mode of delivery, and childbirth experience showed that synOT predicted a significantly lower risk of PPD (HR = 0.65, 95% CI 0.45 0.95, p = 0.025). The risk factors for PPD included a history of depression (HR = 3.20, 95% CI 2.33-4.40, p < 0.001) and negative childbirth experience (HR = 1.39, 95% CI 1.01-1.90, p = 0.040). Logistic regression adjusted for the same covariates found no significant effect of synOT on maternity blues (OR = 0.64, 95% CI 0.31-1.32, p = 0.23). While synOT administered intrapartum does not affect maternal mood immediately, it may come to effect some weeks after childbirth to protect mothers from developing PPD symptoms. PMID- 30306270 TI - A structural DFT study of MM, GG, MG, and GM alginic acid disaccharides and reactivity of the MG metallic complexes. AB - The density functional theory method using the B3LYP/6-31G(d,p) level of theory was used to perform isoenergetic maps in order to determine the lower energy conformers of four disaccharides constituting alginic acids, which are based on beta-D-mannuronic (M) and alpha-L-guluronic acid (G), called MM, GG, MG, and GM. The preferred structures are combined to monovalent (Li+, Na+, and K+) cations and further fully optimized, and an isoenergetic map corresponding to the complex (MG2-, 2Na+) was performed. Then, the reactivity of MG complexes with mono- and bivalent cations was studied using the global nucleophilic index. The position selectivity was also predicted using the local nucleophilic indices. It was demonstrated that experimental trends of relative reactivity and regioselectivity of the complexes are correctly predicted using these empirical indices of reactivity. Graphical abstract MM, GG, MG, and GM alginic acid disaccharides and reactivity of the MG metallic complexes. PMID- 30306271 TI - Eight-year survival of a recurrent glioblastoma patient treated with molecularly tailored therapy: a case report. AB - Treatment options for recurrent glioblastoma are scarce; targeted therapy trials were disappointing, probably due to enrollment of patients without molecular selection. We treated with bevacizumab and erlotinib a 66-year-old male suffering from recurrent glioblastoma, IDH-wildtype and MGMT unmethylated, after three neurosurgeries. Treatment was tailored on molecular profile of recurrent tumor namely, EGFRvIII positivity, VEGF overexpression, normal PTEN, low total VEGF and VEGF-121 mRNA-and resulted in complete, exceptionally durable response (51-month progression-free survival). Notably, histology of further recurrence after therapy was reminiscent of sarcoma. We suggest a thorough molecular screening for personalization of targeted therapy in recurrent glioblastoma. PMID- 30306272 TI - Prevalence of vitamin D deficiency in postmenopausal high- and low-energy fracture patient. AB - : This study evaluated the prevalence of vitamin D deficiency in postmenopausal women with fractures and revealed a high prevalence of vitamin D deficiency regardless of whether the injury mechanism was high or low energy. However, the prescription rate of vitamin D supplementation was lower in the high-energy compared to the low-energy injury group. PURPOSE: The present study aimed to investigate the prevalence of vitamin D deficiency in postmenopausal women with fractures from low-energy and high-energy injuries and to determine differences in the prevalence of vitamin D deficiency and the rate of postoperative vitamin D supplementation between the two groups. METHODS: Medical records of postmenopausal women aged >= 50 years who presented with fractures were reviewed. One hundred and thirty-six patients were enrolled and divided into two groups according to the injury mechanism: low (107 patients) vs. high energy (29 patients). Thereafter, serum vitamin D levels, bone turnover markers, body mass index (BMI), bone mineral density, history of prior osteoporosis therapy and vitamin D supplementation, and postoperative prescription rates were compared between the two groups. Vitamin D deficiency was defined as < 20 ng/mL, insufficiency as 20-30 ng/mL, and sufficiency as 30-150 ng/mL. RESULTS: The overall average vitamin D level was 22.6 ng/mL. The prevalence of vitamin D deficiency was 61.8%, and the rate of insufficiency was 14.7%, while only 23.5% of patients showed normal vitamin D levels. The prevalence of vitamin D deficiency was 60.7% and 65.5% in the low and high-energy groups (p = 0.673), respectively. BMI and other laboratory measurements were similar between the two groups. Postoperative calcium and vitamin D supplementation was administered in 85.0% of patients with low-energy injury, as compared to 58.6% of those with high energy injury (p = 0.003). Osteoporosis medication was also prescribed more frequently in the low-energy group than in the high-energy group (73.8% vs. 48.3%, p = 0.009). In both groups, prescription rates of calcium and vitamin D supplementation and osteoporosis medication increased after the occurrence of fracture. CONCLUSION: Postmenopausal women with fractures have a high prevalence of vitamin D deficiency regardless of whether the mechanism of injury was high or low energy, but the prescription rate of vitamin D supplementation was lower in the high-energy than in the low-energy injury group. PMID- 30306275 TI - On the best partitioning of the density functional energy. AB - This essay discusses special features for two different ways of partitioning the density functional energy expression. The contribution, which is part of the special issue for Pratim Chattaraj, was stimulated by a thought-provoking suggestion by him at a recent conference. PMID- 30306274 TI - Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci. AB - Previous studies have suggested that naturally occurring genetic variation contributes to the risk of astigmatism. The purpose of this investigation was to identify genetic markers associated with corneal and refractive astigmatism in a large-scale European ancestry cohort (UK Biobank) who underwent keratometry and autorefraction at an assessment centre. Genome-wide association studies for corneal and refractive astigmatism were performed in individuals of European ancestry (N = 86,335 and 88,005 respectively), with the mean corneal astigmatism or refractive astigmatism in fellow eyes analysed as a quantitative trait (dependent variable). Genetic correlation between the two traits was calculated using LD Score regression. Gene-based and gene-set tests were carried out using MAGMA. Single marker-based association tests for corneal astigmatism identified four genome-wide significant loci (P < 5 * 10-8) near the genes ZC3H11B (1q41), LINC00340 (6p22.3), HERC2/OCA2 (15q13.1) and NPLOC4/TSPAN10 (17q25.3). Three of these loci also demonstrated genome-wide significant association with refractive astigmatism: LINC00340, HERC2/OCA2 and NPLOC4/TSPAN10. The genetic correlation between corneal and refractive astigmatism was 0.85 (standard error = 0.068, P = 1.37 * 10-35). Here, we have undertaken the largest genome-wide association studies for corneal and refractive astigmatism to date and identified four novel loci for corneal astigmatism, two of which were also novel loci for refractive astigmatism. These loci have previously demonstrated association with axial length (ZC3H11B), myopia (NPLOC4), spherical equivalent refractive error (LINC00340) and eye colour (HERC2). The shared role of these novel candidate genes for astigmatism lends further support to the shared genetic susceptibility of myopia and astigmatism. PMID- 30306273 TI - Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity. AB - PURPOSE: Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes. METHODS: First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (NH4)2SO4 - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed. RESULTS: IGLEDC showed average diameters of 172.3 +/- 2.6 nm, low PDI (0.12 +/- 0.01), mean particle concentration of 6.3 +/- 0.5 * 1012/mL and negative zeta values (-10.2 +/- 0.4 mV); parameters that remain stable during storage at 4 degrees C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts. CONCLUSION: A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGLEDC can come to be a tool to reintroduce etidocaine in clinical use. PMID- 30306276 TI - Transperineal retropubic approach in total pelvic exenteration for advanced and recurrent colorectal and anal cancer involving the penile base: technique and outcomes. AB - BACKGROUND: Complete pathological resection of locally advanced and recurrent anorectal cancer is considered the most important determinant of survival outcome. Involvement of the retropubic space with cancer threatening or involving the penile base poses specific challenges due to the potential for margin involvement and blood loss from the dorsal venous plexus. In the present study we evaluate a new transperineal surgical approach to excision of anterior compartment organs involved or threatened by cancer which facilitates exposure and visualisation of the bulbar urethra and the deep vein of the penis caudal to the retropubic space and penile base. METHODS: A retrospective study was performed on male patients with tumour extension into the penile base treated at our institution using the transperineal surgical approach. Descriptive data for patient demographics, radiology, operative details, postoperative histology, complications and outcomes were collated. RESULTS: Ten male patients with tumour extension into the penile base were identified. Two patients had recurrent anal cancer, 6 had locally advanced primary rectal cancer and 2 had recurrent rectal cancer. All patients had exenterative surgery with excision of the penile base utilising the transperineal approach. All patients had R0 resection. No local recurrence developed after a median follow up period of 15 months. CONCLUSIONS: The transperineal approach to the penile base and retropubic space allows for high rates of R0 resection margin status with direct visualisation of the dorsal venous plexus, thereby minimising blood loss. In our experience, this technique is the preferred approach to excision of cancers threatening and involving the penile base and also for most male patients requiring total pelvic exenteration. PMID- 30306277 TI - Outpatient laser treatment of primary pilonidal disease : the PiLaT technique. AB - BACKGROUND: The aim of the present study was to assess the effectiveness of the minimally invasive technique pilonidal disease laser treatment (PiLaT) in treating primary (non-recurrent) pilonidal disease in an outpatient setting under local anaesthesia. METHODS: A prospective observational study was conducted on consecutive patients suffering from primary pilonidal disease that were treated at Iasi Private Medical Center, Ioannina, Greece, between April 2015 and December 2016, using a 1.470 nm diode laser (BioLitec, Germany) emitting energy through a radial optic fiber that was inserted in the cyst and accompanying sinus tracts. Patients were discharged half an hour after completion of the procedure. Pain scores [visual analogue scale (VAS)], complications and patient satisfaction were assessed. Follow-up lasted 12 months. RESULTS: There were 60 patients, 51 males and 9 females, with a mean age of 22.7 years (range 15-58). Successful treatment (complete epithelization of cyst and tracts) was documented in 55 out of the 60 patients (92% success rate). VAS pain scores were low and no major complications were recorded. Healing was achieved in 25.4 days (range 17-40) and 53.3% of patients were able to return to work the same day (the rest within 3 days). Of the failures, four patients did not heal and one patient recurred after 5 months. All failures were treated successfully with a second laser procedure except for one who denied re-intervention. Overall patient satisfaction reached 98%. CONCLUSIONS: PiLaT seems to be very close to the ideal treatment of pilonidal disease, since it is safe, easy to perform, almost painless and highly effective. PMID- 30306279 TI - Association of high-density lipoprotein, triglycerides, and homocysteine with bone mineral density in young Indian tribal women. AB - : This study investigated association between lipids and homocysteine (Hcy) with bone mineral density (BMD) in young women as opposed to previous studies on elderly women. HDL, triglyceride, and Hcy are significantly associated with BMD in young women and tobacco and alcohol consumption have no effect on this association. PURPOSE: The present study investigates whether the association of serum lipids and homocysteine (Hcy) with bone mineral density (BMD) reported mostly in elderly population can be generalized to young or premenopausal women, consequently suggesting screening of young women with low BMD for dyslipidemia or any cardiovascular events and vice versa. METHODS: Women (n = 293, aged 20-47 years) from Northeast India belonging to Tibeto-Burman origin were enrolled. Information about their physical and clinical attributes were collected by a structured questionnaire. Their BMDs at lumbar spine and femur were measured by dual-energy X-ray absorptiometry (DXA) and sera were profiled for lipid parameters and Hcy by auto-analyzer and ELISA, respectively. Women consuming tobacco and/or alcohol were grouped as consumers and others as non-consumers for the analysis. RESULTS: Positive correlation of BMD with HDL (spine and femur r = 0.38, p < 0.0001) and triglyceride (spine r = 0.534, p < 0.0001; femur r = 0.423, p < 0.0001) was observed, whereas Hcy correlated negatively with BMD (spine r = - 0.189, p = 0.0026; femur r = - 0.273, p < 0.0001). LDL showed a weak negative correlation with BMD (spine r = - 0.128, p = 0.0283; femur r = - 0.199, p = 0.0006). However, after adjusting for age, BMI, and consumption, HDL, triglyceride, and Hcy continued to show significant correlation with BMD at both the sites. Logistic regression analyses indicated that HDL, triglyceride, and Hcy were significant predictors of osteopenia and osteoporosis in our study cohort; however, consumption did not contribute to its prediction. CONCLUSION: Low levels of HDL and triglyceride and high levels of Hcy are significantly associated with osteopenia and osteoporosis in young Northeast Indian women. PMID- 30306278 TI - Management of Overactive Bladder Symptoms After Radical Prostatectomy. AB - PURPOSE OF REVIEW: Post-prostatectomy overactive bladder (OAB) is a common and challenging condition to manage. The aim of the present report was to review the recent evidences regarding OAB symptoms that develop in men after prostatectomy and how to manage them. RECENT FINDINGS: The prevalence of OAB after radical prostatectomy may range from 15.2 to 37.8%. Recent studies have highlighted the role of the urethrogenic mechanism (facilitation of the urethrovesical reflex due to stress urinary incontinence (SUI)) in the genesis of post-prostatectomy OAB in a significant proportion of patients. Several other pathophysiological factors such as iatrogenic decentralization of the bladder, defunctionalized bladder due to severe SUI, detrusor underactivity, or bladder outlet obstruction might be involved. The evaluation should aim to identify the underlying mechanism to tailor the treatment, which could range from SUI surgery, to fixing a urethral stricture, improving bladder emptying or using the conventional spectrum of OAB therapies. There is a paucity of data for OAB therapies specific to post prostatectomy patients, with the exception of solifenacin, tolterodine, and botulinum toxin. There is currently no data on how preoperative management or surgical technique may prevent post-prostatectomy OAB. PMID- 30306281 TI - Lower limb injury prevention programs in youth soccer: a survey of coach knowledge, usage, and barriers. AB - BACKGROUND: Participation in youth soccer carries a significant risk of injury, most commonly non-contact injuries of the lower extremity. A growing body of research supports the use of neuromuscular interventions by teams to prevent such injuries, yet the uptake of these recommendations by soccer teams remains largely unexplored. The purposes of the study were to determine (1) the level of awareness by youth coaches of injury prevention programs and their efficacy; (2) the number of youth coaches that use these interventions; and (3) barriers and potential facilitators to implementing a sustainable injury prevention program. METHODS: Four hundred eighteen coaches of male and female youth soccer teams were emailed an online blinded survey. This survey consisted of 26 questions covering coaches' demographics, level of training, experience with injuries among players, and use of injury prevention programs. Question development was guided by the RE AIM Sports Setting Matrix in combination with findings from the literature review and expert experience from orthopaedic surgeons specializing in sport medicine. RESULTS: Of the 418 coaches contacted, 101 responded. Only 29.8% of respondents used an injury prevention program in the prior soccer season. Coaches that had completed one or more coaching courses were more likely to use an intervention. Of those that did not already use an intervention, coaches agreed or strongly agreed that they would consider using one if it could be used in place of the warm up and take no more than 20 min (74.0%), if they could access information about the exercises (84.0%), and if the exercises could be properly demonstrated (84.0%). Additionally, 84% of coaches that did not already use an intervention agreed or strongly agreed that knowing that interventions may reduce a player's risk of injury by 45% would affect whether they would use one. CONCLUSION: This study suggests that the current use and awareness of injury prevention programs is limited by a lack of communication and education between sporting associations and coaches, as well as perceived time constraints. The results also suggest that improving coaching education of injury prevention could increase the frequency of intervention use. PMID- 30306280 TI - A northern Chinese origin of Austronesian agriculture: new evidence on traditional Formosan cereals. AB - BACKGROUND: Genetic data for traditional Taiwanese (Formosan) agriculture is essential for tracing the origins on the East Asian mainland of the Austronesian language family, whose homeland is generally placed in Taiwan. Three main models for the origins of the Taiwanese Neolithic have been proposed: origins in coastal north China (Shandong); in coastal central China (Yangtze Valley), and in coastal south China. A combination of linguistic and agricultural evidence helps resolve this controversial issue. RESULTS: We report on botanically informed linguistic fieldwork of the agricultural vocabulary of Formosan aborigines, which converges with earlier findings in archaeology, genetics and historical linguistics to assign a lesser role for rice than was earlier thought, and a more important one for the millets. We next present the results of an investigation of domestication genes in a collection of traditional rice landraces maintained by the Formosan aborigines over a hundred years ago. The genes controlling awn length, shattering, caryopsis color, plant and panicle shapes contain the same mutated sequences as modern rice varieties everywhere else in the world, arguing against an independent domestication in south China or Taiwan. Early and traditional Formosan agriculture was based on foxtail millet, broomcorn millet and rice. We trace this suite of cereals to northeastern China in the period 6000-5000 BCE and argue, following earlier proposals, that the precursors of the Austronesians, expanded south along the coast from Shandong after c. 5000 BCE to reach northwest Taiwan in the second half of the 4th millennium BCE. This expansion introduced to Taiwan a mixed farming, fishing and intertidal foraging subsistence strategy; domesticated foxtail millet, broomcorn millet and japonica rice; a belief in the sacredness of foxtail millet; ritual ablation of the upper incisors in adolescents of both sexes; domesticated dogs; and a technological package including inter alia houses, nautical technology, and loom weaving. CONCLUSION: We suggest that the pre-Austronesians expanded south along the coast from that region after c. 5000 BCE to reach northwest Taiwan in the second half of the 4th millennium BCE. PMID- 30306282 TI - Frequency of human leukocyte antigens class II-DR alleles (HLA-DRB1) in Argentinian patients with early arthritis. AB - Patients with rheumatoid arthritis (RA) or undifferentiated arthritis (UA) in the CONAART database (Argentine Consortium for Early Arthritis) were assessed for genetic risk factors for RA, specifically for HLA-DRB1 alleles and the PTPN22 rs2476601 polymorphism associated with progression to RA. This is a case-control study. Blood samples were obtained to determine HLA-DRB1 genotypes by PCR-SSO Luminex and PTPN22 (rs2476601) polymorphism by allelic discrimination. A control group of individuals from the general Argentinian population were obtained from the national register of cadaveric organ donors. A total of 1859 individuals were included in this analysis: 399 patients from the CONAART database (347 patients with RA at study end and 52 patients with UA at study end, mean follow-up time 25 +/- 18 months) and 1460 individuals from the general Argentinian population. Compared with the controls, the HLA-DRB1*04 and DRB1*09 alleles were more commonly detected in patients with RA diagnosis (OR (95% CI) 2.23 (1.74-2.85) and 1.89 (1.26-2.81)) respectively. Both patients with UA and the general population showed higher frequency of DRB1*07, DRB1*11 and DRB1*15 alleles than patients with RA. PTPN22 rs2476601 polymorphism frequency was higher in RA and UA vs the general population; however, this was significantly different only for RA vs control group (OR [95% CI] = 1.81 [1.10-3.02], P = 0.018. HLA-DRB1 typing and PTPN22 allelic discrimination could distinguish between patients with UA, patients with early RA, and the general population in Argentina. This is the first study of HLA-DRB1 alleles and PTPN22 polymorphism associations with progression to early RA in an Argentinian population. PMID- 30306283 TI - A biomechanical comparison of all-inside cruciate ligament graft preparation techniques. AB - BACKGROUND: The all-inside cruciate ligament graft preparation technique has become popular due to its utility in sparing a growing physis, preserving a tendon in ACL surgery, and/or reduction of pain. However, few studies have compared graft preparation techniques to determine the ideal construct for cruciate ligament reconstruction. We sought to compare biomechanical properties of two quadrupled all-inside cruciate ligament graft preparation techniques and three alternative all-inside graft preparation techniques that may be used when the available tendon is too short to be quadrupled. METHODS: Fifty porcine extensor tendons were evenly divided into five groups (n = 10) representing all inside graft preparation techniques, including two quadrupled (Quad-A, Quad-B) and three alternative methods (Tripled, Folded, Two-Doubled). Each graft construct underwent preconditioning (10 loading cycles from 20 to 50 N at 0.1 Hz), cyclic loading (500 loading cycles from 50 to 250 N at 1.0 Hz) and load-to failure (tension applied at 20 mm/min). RESULTS: Quad-A and Quad-B demonstrated no significant differences in cyclic displacement (10.5 +/- 0.3 vs 11.7 +/- 0.4 mm; p = 0.915), cyclic stiffness (1086.2 +/- 487.3 vs 460.4 +/- 71.4 N/mm; p = 0.290), pullout stiffness (15.9 +/- 4.3 vs 7.4 +/- 4.4 N/mm; p = 0.443), ultimate failure load (641.2 +/- 84.7 vs 405.9 +/- 237.4 N; p = 0.672), or ultimate failure displacement (47.3 +/- 6.7 vs 55.5 +/- 0.7 mm; p = 0.778). The mean cyclic displacement of the Two-Doubled group was significantly greater than the Quad-A (29.7 +/- 2.2 vs 10.5 +/- 0.3 mm; p < 0.001), Quad-B (29.7 +/- 2.2 vs 11.7 +/- 0.4 mm; p < 0.001), Tripled (29.7 +/- 2.2 vs 11.3 +/- 0.2 mm; p < 0.001), and Folded group (29.7 +/- 2.2 vs 13.3 +/- 0.2 mm; p < 0.001). There were no other statistically significant differences between the three alternative all-inside graft preparation techniques. CONCLUSION: The current study demonstrates the biomechanical properties of two quadrupled all-inside graft constructs, Quad-A and Quad-B, are not significantly different. When the available tendon is of insufficient length, the Two-Doubled group demonstrated more than twice the cyclic displacement of all other graft preparation techniques, and is therefore not recommended for use in all-inside cruciate ligament reconstruction. PMID- 30306284 TI - Oxygen treatment for cluster headache attacks at different flow rates: a double blind, randomized, crossover study. AB - BACKGROUND: Cluster headache attacks can, in many patients, be successfully treated with oxygen via a non-rebreather mask. In previous studies oxygen at flow rates of both 7 L/min and 12 L/min was shown to be effective. The aim of this study was to compare the effect of 100% oxygen at different flow rates for the treatment of cluster headache attacks. METHODS: In a double-blind, randomized, crossover study, oxygen naive cluster headache patients, treated attacks with oxygen at 7 and 12 L/min. The primary outcome measure was the percentage of attacks after which patients (treating at least 2 attacks/day) were painfree after 15 min, in the first two days of the study. Secondary outcome measures were percentage of successfully treated attacks, percentage of attacks after which patients were painfree, drop in VAS score and patient preference in all treatment periods (14 days). RESULTS: Ninety-eight patients were enrolled, 70 provided valid data, 56 used both flow rates. These 56 patients recorded 604 attacks, eligible for the primary analysis. An exploratory analysis was conducted using all eligible attacks of 70 patients who provided valid data. We could only include 5 patients, treating 27 attacks on the first two days of the study, for our primary outcome, which did not show a significant difference (p = 0.180). Patients tended to prefer 12 L/min (p = 0.005). Contradicting this result, more patients were painfree using 7 L/min (p = 0.039). There were no differences in side effects or in our other secondary outcome measures. The exploratory analysis showed an odds ratio of being painfree using 12 L/min of 0.73 (95% CI 0.52-1.02) compared to 7 L/min (p = 0.061) as scored on a 5-point scale. The average drop in score on this 5-point scale, however, was equal between groups. Also slightly more patients noticed, no or not much, relief on 7 L/min, and found 12 L/min to be effective in all their attacks. CONCLUSION: There is lack of evidence to support differences in the effect of oxygen at a flow rate of 12 L/min compared to 7 L/min. More patients were painfree using 7 L/min, but our other outcome measures did not confirm a difference in effect between flow rates. As most patients prefer 12 L/min and treatments were equally safe, this could be used in all patients. It might be more cost-effective, however, to start with 7 L/min and, if ineffective, to switch to 12 L/min. TRIAL REGISTRATION: European Union Clinical Trials Register ( 2012-003648-59 ), registered 1 October 2012. Dutch Trial Register ( NTR3801 ), registered 14 January 2013. PMID- 30306287 TI - New Horizons for Health Care Analysis. PMID- 30306285 TI - The Diagnostic Yield, Safety, and Impact of Flexible Bronchoscopy in Non-HIV Immunocompromised Critically Ill Patients in the Intensive Care Unit. AB - BACKGROUND: Flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) have major roles in the evaluation of parenchymal lung diseases in immunocompromised patients. Given the limited evidence, lack of standardized practice, and variable perception of procedural safety, uncertainty still exists on what constitutes the best approach in critically ill patients with immunocompromised state who present with pulmonary infiltrates in the era of prophylactic antimicrobials and the presence of new diagnostic tests. OBJECTIVE: To evaluate the diagnostic yield, safety and impact of FB and BAL on management decisions in immunocompromised critically ill patients admitted to the intensive care unit (ICU). METHODS: A prospective, observational study of 106 non-HIV immunocompromised patients admitted to the intensive care unit with pulmonary infiltrates who underwent FB with BAL. RESULTS: FB and BAL established the diagnosis in 38 (33%) of cases, and had a positive impact on management in 44 (38.3%) of cases. Escalation of ventilator support was not required in 94 (81.7%) of cases, while 18 (15.7%) required invasive and 3 (2.6%) required non-invasive positive pressure ventilation after the procedure. Three patients (2.6%) died within 24 h of bronchoscopy, and 46 patients (40%) died in ICU. Significant hypoxemia developed in 5% of cases. CONCLUSION: FB can be safely performed in immunocompromised critically ill patients in the ICU. The yield can be improved when FB is done prior to initiation of empiric antimicrobials, within 24 h of admission to the ICU, and in patients with focal disease. PMID- 30306286 TI - Characterization and Triggers of Dyspnea in Patients with Chronic Obstructive Pulmonary Disease or Chronic Heart Failure: Effects of Weather and Environment. AB - BACKGROUND AND OBJECTIVES: Dyspnea is one of the most disturbing symptoms for patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF). This study investigated dyspnea triggers and factors associated with worsening dyspnea in patients with COPD or HF. METHODS: COPD support group members and HF patients with reduced ejection fraction (HFrEF) and no airway obstruction answered a questionnaire describing different weather conditions (rising/falling air pressure, sunny, foggy, rainy, windy, snowy, hazy, high ozone levels, and airborne pollen) and environmental circumstances (cooking, grilling, perfumes, cigarette smoke, gasoline odor, and flower scents) and were asked to estimate the occurrence and severity of dyspnea under these conditions using predefined scales. RESULTS: 230 patients with COPD and 90 with HFrEF (left ventricular ejection fraction 34 +/- 10%, Tiffeneau index > 70%) were analyzed. COPD patients reported dyspnea more often than HF patients in almost all weather and environmental conditions (p = 0.004 to p < 0.001), with the exception of outdoor floral scents and cigarette smoke. Severe to very severe dyspnea was reported more in COPD versus HF in all weather and environmental conditions except sunny weather (p = 0.01 to p < 0.001). COPD was associated with more severe dyspnea than HF in all conditions (all p < 0.001). CONCLUSIONS: Dyspnea was triggered by a variety of weather and other environmental triggers in patients with COPD and occurred more often than in HF patients under the same conditions. Foggy weather and exposure to perfumes were associated with severe dyspnea in the majority of COPD patients, but only a minority of HF patients. PMID- 30306288 TI - 15N transverse relaxation measurements for the characterization of us-ms dynamics are deteriorated by the deuterium isotope effect on 15N resulting from solvent exchange. AB - 15N R2 relaxation measurements are key for the elucidation of the dynamics of both folded and intrinsically disordered proteins (IDPs). Here we show, on the example of the intrinsically disordered protein alpha-synuclein and the folded domain PDZ2, that at physiological pH and near physiological temperatures amide water exchange can severely skew Hahn-echo based 15N R2 relaxation measurements as well as low frequency data points in CPMG relaxation dispersion experiments. The nature thereof is the solvent exchange with deuterium in the sample buffer, which modulates the 15N chemical shift tensor via the deuterium isotope effect, adding to the apparent relaxation decay which leads to systematic errors in the relaxation data. This results in an artificial increase of the measured apparent 15N R2 rate constants-which should not be mistaken with protein inherent chemical exchange contributions, Rex, to 15N R2. For measurements of 15N R2 rate constants of IDPs and folded proteins at physiological temperatures and pH, we recommend therefore the use of a very low D2O molar fraction in the sample buffer, as low as 1%, or the use of an external D2O reference along with a modified 15N R2 Hahn echo based experiment. This combination allows for the measurement of Rex contributions to 15N R2 originating from conformational exchange in a time window from us to ms. PMID- 30306289 TI - Age-related changes in mitochondrial membrane composition of Nothobranchius furzeri.: comparison with a longer-living Nothobranchius species. AB - Membrane compositions, particularly of mitochondria, could be critical factors in the mechanisms of growth and aging, especially during phases of high oxidative stress that result in molecular damage. Changes affecting lipid class or fatty acid (FA) compositions could affect phospholipid (PL) properties and alter mitochondrial function. In the present study, mitochondrial membrane PL compositions were analysed throughout the life-cycle of Nothobranchius furzeri, a species with explosive growth and one of the shortest-lived vertebrates. Mitochondrial PLs showed several changes with age. Proportions of total PLs and PC were reduced while an increase in PS, CL and PE was observed, mainly between the 2.5 and 5 months of fish age, the time during which animals doubled their weight. FA compositions of individual PLs in mitochondria were also significantly affected with age suggesting the existence of increasing damage to mitochondrial lipids during the life-cycle of N. furzeri that could be one of the main contributors to degraded mitochondrial function associated with aging. The peroxidation index values from N. furzeri mitochondrial PLs were significantly lower than those reported in N. rachovii, a species with a twofold longer life span than N. furzeri, which seems to contradict the membrane pacemaker theory of animal metabolism. PMID- 30306290 TI - Optimization of macrophage isolation from the Persian sturgeon and the Caspian kutum fish: a comparative study. AB - The aim of this research was a comparative study on the isolation and culture of head kidney macrophages derived from Acipenser persicous and Rutilus frisii kutum as teleost and chondrostei species of fish. The macrophages were isolated by density gradient sedimentation, followed by adherence to a plastic surface. They exhibited strong phagocytic activity against bacteria. The effect of cell density, incubation time, FBS percentage, pH and temperatures on the cell number and viability were determined and compared. Also, the effect of light/dark regimen on viability, adherence, release of reactive oxygen species (ROS) and nitric oxide (NO) in the macrophages was determined. The results showed that the Caspian kutum macrophages were more sensitive to FBS percentage and cell density whereas the Persian sturgeon macrophages were more sensitive to pH of the cell culture media. The adherence and viability of the macrophages from both fish species firstly increased (P < 0.05) after exposure to a light/dark regimen, but then significantly decreased as did ROS and NO productions. For the first time, this study has determined the optimal conditions for primary culture of macrophages derived from sturgeons, and shows the unique effect of light on the biology of fish immune cells. PMID- 30306291 TI - Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome. AB - Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFbeta) in arteries. Altered TGFbeta bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1 deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12 weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGFbeta directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease. PMID- 30306292 TI - Patient involvement in health professionals' education: a meta-narrative review. AB - More than 100 years ago, Osler inspired educators to consider health professions education (HPE) as intricately reliant on patients. Since that time, patient involvement in HPE has taken on many different meanings. The result is a disparate body of literature that is challenging to search, making it difficult to determine how to continue to build knowledge in the field. To address this problem, we conducted a review of the literature on patient involvement in HPE using a meta-narrative approach. The aim of the review was to synthesize how questions of patient involvement in HPE have been considered across various research traditions and over time. In this paper, we focus on three scholarly communities concerned with various interpretations of patient involvement in HPE patient as teachers, real patients as standardized patients, and bedside learning. Focus on these three research communities served as a way to draw out various meta-narratives in which patients are thought of in particular ways, specific rationales for involvement are offered, and different research traditions are put to use in the field. Attending to the intersections between these meta-narratives, we focus on the potentially incommensurate ways in which "active" patient engagement is considered within the broader field and the possible implications. We end by reflecting on these tensions and what they might mean for the future of patient involvement, specifically patient involvement as part of future iterations of competency based education. PMID- 30306294 TI - Editorial: The Yin and Yang of Perivascular Adipose Tissue in Vascular Disease. PMID- 30306293 TI - Purification, characterization and fine sugar specificity of a N Acetylgalactosamine specific lectin from Adenia hondala. AB - Plant lectins are gaining interest because of their interesting biological properties. Several Adenia species, that are being used in traditional medicine to treat many health ailments have shown presence of lectins or carbohydrate binding proteins. Here, we report the purification, characterization and biological significance of N-Acetyl galactosamine specific lectin from Adenia hondala (AHL) from Passifloraceae family. AHL was purified in a single step by affinity chromatography on asialofetuin Sepharose 4B column, characterized and its fine sugar specificity determined by glycan array analysis. AHL is human blood group non specific and also agglutinates rabbit erythrocytes. AHL is a glycoprotein with 12.5% of the carbohydrate, SDS-PAGE, MALDI-TOF-MS and ESI-MS analysis showed that AHL is a monomer of 31.6 kDa. AHL is devoid of DNase activity unlike other Ribosome inactivating proteins (RIPs). Glycan array analysis of AHL revealed its highest affinity for terminal lactosamine or polylactosamine of N- glycans, known to be over expressed in hepatocellular carcinoma and colon cancer. AHL showed strong binding to human hepatocellular carcinoma HepG2 cells with MFI of 59.1 expressing these glycans which was effectively blocked by 93.1% by asialofetuin. AHL showed dose and time dependent growth inhibitory effects on HepG2 cells with IC50 of 4.8 MUg/ml. AHL can be explored for its clinical potential. PMID- 30306296 TI - Non-alcoholic fatty liver disease and obesity: the role of the gut bacteria. AB - Non-alcoholic fatty-liver disease (NAFLD) is now considered one of the leading causes of liver disease worldwide and is associated with metabolic syndrome and obesity. There are several factors contributing to the disease state. Recent research suggests that the intestinal microbiota (IM) and bacterial products may play a role through several mechanisms which include increased energy uptake, intestinal permeability and chronic inflammation. In addition to diet and exercise, treatment options targeting the IM are being investigated and include the use of pre-, pro- and synbiotics as well as the possibility of fecal microbial transfers. This literature review explores the relationship between NAFLD and the IM as well as highlight new IM treatment options that may become available in the near future. PMID- 30306295 TI - German Cardiac Society Working Group on Cellular Electrophysiology state-of-the art paper: impact of molecular mechanisms on clinical arrhythmia management. AB - Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management. PMID- 30306297 TI - Correction to: A priori dietary patterns and blood pressure in the EPIC Florence cohort: a cross-sectional study. AB - In the original publication of the article have been published in an incorrect form. The correct form is given below. PMID- 30306298 TI - ? PMID- 30306299 TI - ["Blue eyes"-case report about the risks of cosmetic iris implants]. AB - A 24-year-old Iranian woman presented to our department for routine eye control. She had had cosmetic iris implants (BrightOcular(c)) implanted 5 years before in a Tunisian eye clinic in order to change the color of her eyes. Despite subjective freedom of symptoms, a dramatically reduced corneal endothelial cell count was measured in the left eye. Therefore, surgical removal of the angle supported cosmetic iris implants was necessary. Cosmetic iris implants are associated with sight-threatening complications-even years after their implantation. We report on a case of cosmetic iris implants inserted for alteration of eye color only, which gave rise to serious complications for our patient. PMID- 30306300 TI - [Acute painless visual decline in a 9-year-old boy]. PMID- 30306301 TI - [Treatment reality with ranibizumab in clinical routine use for patients with diabetic macular edema : 1-year results of the German POLARIS cohort]. AB - BACKGROUND: Currently only few data are available on the treatment reality with ranibizumab in patients with diabetic macular edema (DME). MATERIAL AND METHODS: POLARIS is an international observational study which included 983 patients who were treated with ranibizumab due to DME. The primary objective of the study was to investigate the influence of treatment and control intervals as well as resource utilization on the mean change in visual acuity. Secondary endpoints included the collation of disease activity monitoring in the clinical practice. This article describes the results of the German POLARIS population. The study was conducted in 8 European countries from October 2012 to January 2015. RESULTS: In Germany 220 patients were included in the study. Visual acuity improved by 4.3 letters within the first 3 months of treatment. At 12 months, visual acuity increased on average by 4.1 (SD +/- 12.4) letters (approximately 1 line) for 168 patients enrolled in the efficacy analysis. Patients received an average of 4.5 (SD +/- 1.9) injections, 10.3 (SD +/- 6.3) visual acuity tests and 3.3 (SD +/- 3.1) optical coherence tomography (OCT) examinations during the first year. Patients with <=3 injections showed an average improvement in visual acuity by 2.7 letters which was less improvement compared to patients with >3 injections, who achieved an average improvement of 5.4 letters. There was a correlation between the number of injections and the visual acuity achieved. DISCUSSION: For Germany, the results of the POLARIS study indicate that despite a high number of visits, patients with DME are undertreated in clinical routine practice. The injection frequency in Germany was lower than in randomized clinical trials. Almost half of the patients received less than 4 injections in the first year of treatment and thus showed an undertreatment compared to the recommendations of German and international medical societies. PMID- 30306302 TI - [Transvenous neurostimulation in central sleep apnea associated with heart failure]. AB - Sleep-related breathing disorders can be classified as either obstructive (OSA) or central sleep apnea (CSA). Whereas there is substantial knowledge about the pathophysiology and sound recommendations for the diagnosis and treatment of OSA, the origin of CSA is still incompletely understood, patient identification is difficult and the necessity for specific treatment is under debate. CSA often accompanies heart failure and is associated with an adverse prognosis. Optimized heart failure treatment reduces CSA and is thus the cornerstone of CSA treatment. In contrast to OSA, noninvasive ventilation does not lead to prognostic improvement in CSA and ASV ventilation may even lead to an increase in mortality. Transvenous neurostimuation of the phrenic nerve is currently under clinical investigation as a new therapeutic modality for CSA. Early results demonstrate positive effects on sleep parameters and quality of life without any evidence for a negative impact on mortality. However, these results await confirmation in larger studies before this new approach can be advocated for routine clinical use. PMID- 30306303 TI - [Subcutaneous implantable cardioverter-defibrillator : Current status and perspectives]. AB - The use of transvenous implantable cardioverter-defibrillators (ICD) for the prevention of sudden cardiac death has been proven in numerous randomized trials. By using a totally subcutaneous ICD (S-ICD) system, it is expected to ensure appropriate protection while avoiding long-term complications associated with transvenous leads, such as systemic infection and electrode dysfunction. Meanwhile, the safety and effectiveness of the S-ICD has been substantiated by results of large registry studies. Based on the missing option for ventricular stimulation, corresponding recommendations have been integrated into current guidelines for certain patient populations. In the future, the issue of inadequate shocks caused by oversensing may be solved using advanced screening tools and new detection algorithms. Furthermore, a combination of subcutaneous ICD and LCP (leadless cardiac pacer) seems realistic to enable antibradycardia and antitachycardia ventricular pacing. PMID- 30306304 TI - [Pulmonary artery pressure sensor for ambulatory assessment of ventricular filling pressure in advanced heart failure : What should be considered for the follow-up care?] AB - BACKGROUND: Patients with advanced heart failure suffer from frequent hospitalizations. Noninvasive hemodynamic telemonitoring for assessment of pulmonary filling pressure has been shown to reduce hospitalizations. In this article, our experience with possible control intervals and the standardization of the follow-up care of hemodynamic telemonitoring is reported. METHODS: A literature search and our own experience in the follow-up care concerning the implantable pulmonary artery pressure sensor for noninvasive hemodynamic telemonitoring in patients with advanced heart failure are presented. RESULTS: For standardized follow-up care of heart failure patients with hemodynamic monitoring a specialized team consisting of a heart failure nurse and heart failure physician is essential. These teams should ideally work based on a unique standard operating procedure (SOP) to ensure standardized control intervals and a standardized approach to classical hemodynamic changes. However, all therapeutic recommendations have to be prescribed by a physician and must be modified if individually appropriate. CONCLUSION: Optimized follow-up care for hemodynamically guided heart failure management requires the implementation of novel structures in the German health care system in order to transfer the clinical benefit from clinical trials into daily routine. PMID- 30306305 TI - [Telemonitoring of implanted cardiac devices : Clinical necessity or senseless luxury?] AB - In addition to the telemedical follow-up at a fixed point in time, there is the possibility of a close-meshed telemetric monitoring in modern devices. By transferring device and patient-specific data, errors in the integrity of the device or electrodes and cardiac arrhythmias can be detected early, in various studies significantly reducing the number of outpatient or inpatient visits and the rate of inadequate implantable cardioverter-defibrillator (ICD) therapies. Measurement of various surrogate parameters allows better clinical assessment of heart failure patients, yet no improvement in outcome with therapy guided by telemetric data has been demonstrated. Retrospective analyzes, a prospective randomized study, and various meta-analyzes identified a reduction in all-cause mortality through the use of remote monitoring. This effect is mainly due to monitoring as closely as possible, timely examination of the findings, accordingly early interventions and specification of clear therapeutic regimens in certain clinical scenarios. Such comprehensive patient care requires the creation of telemonitoring centers with appropriate structural and personal equipment, whereby the creation of such structures has not yet been remunerated in the German healthcare system. In this paper, an overview of remote monitoring and identify possibilities and limitations of device-based telemedical monitoring is provided. PMID- 30306306 TI - [German transcultural translation of the Injustice Experience Questionnaire]. AB - BACKGROUND: Occupational and social rehabilitation is influenced by perceived injustice as a result of injury. To assess perceived injustice, the Injustice Experience Questionnaire (IEQ) has been developed and is available in English. The aim of this study was to translate and culturally adapt the English version of the IEQ into German. MATERIALS AND METHODS: The IEQ was translated into German according to the criteria for the transcultural adaptation of self-assessment tools. The translation was examined in a sample of 19 pain patients as to whether the translated items were comprehensible, unacceptable or offensive, and what their meaning and the reason for the chosen response were. Data were assessed using nonparametric statistical methods. RESULTS: The German translation of the IEQ showed a high degree of comprehensibility. The items' meanings and participants' selected answer options were rated as highly plausible by two raters and the wording of the items was assessed as being neither unacceptable nor offensive by participants. Because of the slightly increased values with regard to Item 3, whose meaning was unrecognized by the raters, the term "Unachtsamkeit" was replaced by "Unaufmerksamkeit." CONCLUSION: The study attests to the cultural and linguistic intelligibility and precision of the German translation of the IEQ. In a follow-up study, the translation should be validated in a larger sample of pain patients. PMID- 30306307 TI - [Postherpetic neuralgia of the left trigeminus nerve V1 : Successful therapy with capsaicin 8% patch]. AB - A 68-year-old patient suffered from postzoster neuralgia with severe pain of the left trigeminal nerve V1. Despite medication with gabapentin 1800 mg/d, oxacarbazepine 600 mg, tapentadol 500 mg/d, amitriptyline 20 mg as well as ambroxol 20% ointment and lidocaine patch topically, the pain reached an intensity of 8-10 on the numeric rating scale (NRS). Wearing a CPAP (continuous positive airway pressure) mask at night to treat a sleep apnea was impossible or the mask was leaking under lidocaine patch, only topical ambroxol 20% brought a certain pain relief. Lack of sleep, a strongly reduced quality of life and massive exhaustion followed quickly. Due to a fall the systemic medication could not be increased. Also lidocaine infusions with dexamethasone and supraorbitalis blockades were unsuccessful, and a ganglionic local opioid analgesia (GLOA) was anatomically not feasible. Therefore, 8 weeks after the onset of the disease, treatment with capsaicin 8% for 60 min on the face was performed. After only one week, 20-30% pain relief was achieved, sometimes even freedom from pain. Six weeks after application, the average pain during the day was only NRS 3/10 despite a considerable reduction in oral medication. Three months after the second treatment, the patient was almost pain-free during the day. Topical capsaicin 8% patch is, in our opinion, also safe and successful to use on the face with appropriate experience of the user. PMID- 30306308 TI - [The effects of setting a standard in the acute pain therapy on a ward : Parameters for patient and provider satisfaction and cost structure (STANDAKU)]. AB - BACKGROUND: There is neither a "gold standard" nor commonly approved therapy goals in postoperative pain therapy. In a multi-center study, more than 80% of all patients treated stated that they suffered from postoperative pain. Moreover, patients evaluated the pain therapy as significantly worse than other medical or nursing practices. Therefore, there is a need for optimization in therapy for acute pain. OBJECTIVES: The goal of our project was to figure out if the introduction of a "pain treatment standard" would increase the satisfaction of patients, physicians, and nurses, and reduce the costs of pain-related medicine. MATERIALS AND METHODS: Overall, 2769 patients and 285 providers (202 nurses and 83 physicians) were polled. The medication costs in ten areas of the ward were evaluated and compared. The providers were offered a training course on the "pain standard" and it was officially introduced onto the wards. After some time, the satisfaction of patients and providers and the use of medicine were recorded again. RESULTS AND DISCUSSION: The maximum pain values declared by the patients significantly decreased after the introduction of the "pain standard." The satisfaction with pain therapy significantly increased for the patients and for the providers. The reported minimum pain values of the patients did not change significantly. The costs of pain medicine slightly increased. In general, there was a positive effect of introducing a "pain standard" for patients and providers. PMID- 30306309 TI - LAVH superior to TVH when concomitant salpingo-oophorectomy is intended in prolapse hysterectomy: a comparative cohort study. AB - PURPOSE: This comparative cohort study evaluated the influence of surgical route for prolapse hysterectomy (vaginal or laparoscopically assisted) on the achievement of intended elective salpingo-oophorectomy, which was a procedural goal planned with the patient before primary vaginal native-tissue prolapse surgery. METHODS: Consecutive patients who underwent total vaginal hysterectomy (TVH; n = 163) or laparoscopically assisted vaginal hysterectomy (LAVH; n = 144) and vaginal native-tissue repair for pelvic organ prolapse at Jena University Hospital were enrolled. RESULTS: Peri- and postoperative parameters, including Clavien-Dindo (CD) classification of surgical complications, were compared between groups using Student's t test, Fisher's exact test, and multivariable regression. Patient characteristics were similar, except that grade IV prolapse was more common in the LAVH group (p < 0.001). The following parameters differed between the TVH and LAVH groups: concomitant salpingectomy (1.2% vs. 34%) and salpingo-oophorectomy (45% vs. 66%), non-performance of intended salpingo oophorectomy (36% vs. 0% OR 0.006, 95% CI < 0.001-0.083), adhesiolysis (0% vs. 44%), CD II-III complications (51% vs. 14.6% p < 0.001), operating time (153 +/- 61 vs. 142 +/- 27 min), and postoperative in-patient days (9.02 +/- 4.9 vs. 4.99 +/- 0.96; all p < 0.001). CONCLUSIONS: LAVH enabled the safe performance of planned concomitant salpingo-oophorectomy in all cases. To achieve the procedural goal in such cases, laparoscopic assistance in prolapse hysterectomy should be considered. PMID- 30306310 TI - Indication of prophylactic vaccines as a tool for secondary prevention in HPV linked disease. AB - PURPOSE: To determine whether quadrivalent HPV vaccination is effective in reducing recurrent disease in women with a previous history of HPV disease. METHODS: All women under 45 years of age treated for HPV-linked disease and with negative HPV test, cytology and colposcopy 3 months after treatment were enrolled. Women were randomly assigned into two groups: a group that received HPV vaccine post treatment and a group that was only submitted to follow-up. Follow up was performed every 6 months for a duration of at least 3 years. Kaplan-Meier curve was used to estimate the overall disease-free survival during the follow-up period. Statistical analysis was performed by Fisher's exact test. RESULTS: From November 2013 to October 2014, we enrolled a total of 178 women at Careggi University Hospital in Florence and at Azienda USL in Massa Carrara. 12 out of 89 patients in the non-vaccination group recurred (13.5%), while 3 out of 89 patients in the vaccination group recurred (3.4%). The Kaplan-Meier curves showed a statistically difference in the log rank test (p = 0.0147) for the overall disease-free survival in the study groups during follow-up. The rate of recurrence was significantly higher in the non-vaccination group, with a p = 0.0279 by Fisher exact test. CONCLUSION: The introduction of anti-HPV vaccination during the follow-up post treatment for HPV-linked disease is recommended to reduce the risk of recurrence. The clinical implication of this could be very important to influence post-treatment management of HPV disease. PMID- 30306311 TI - Glucocorticoid receptor in cervical cancer: an immunhistochemical analysis. AB - PURPOSE: Cervical cancer is one of the most frequent cancers in women worldwide. In most of all cases, a persistent HPV infection is the leading cause. HPV specific sequences are able to bind glucocorticoid receptor (GR). Dexamethasone can increase the activity of early promoters in HPV16 and HPV18 interfering in transcription control of viral oncogenes. The aim of our study was to evaluate glucocorticoid receptor as transcriptional factor in its active form in the nucleus of in cervical cancer cells and to correlate the results with clinical patient specific parameters. METHODS: A total of 250 paraffin-embedded cervical cancer samples obtained from patients having undergone surgery for cervical cancer were used for the study. The expression of GR was immunhistochemical examined and evaluated by a semi-quantitative scoring. SPSS software was used for the statistical evaluation of staining results and survival analysis of patients with cervical cancer. RESULTS: GR is frequently expressed in cervical carcinoma tissue in favor of squamous cell carcinoma (SCC). An enhanced expression is correlated with rather small clinical stages. The expression of the GR is correlated with better overall survival and progression-free survival. CONCLUSIONS: The glucocorticoid receptor is frequently expressed in cervical carcinoma tissue in favor of squamous cell carcinoma. An enhanced expression is correlated with rather small clinical stages. The expression of the analyzed receptor is correlated with better overall survival. Further studies are needed to determine useful treatment targets for glucocorticoid receptor manipulation. PMID- 30306313 TI - Online and Social Media Resources for Patients with MDS. AB - PURPOSE OF REVIEW: The number of online resources for patients with MDS is exponentially increasing; this is in large part due to the advent of social media which has introduced multiple avenues for information exchange and communication. Whether this information is targeted towards the patient population or not, the wealth of information online represents a new era of patient engagement in their health care. This review aims to highlight the different online resources being used in the field of MDS. RECENT FINDINGS: Patients with MDS have access to the opinions of thought leaders in the field, advances in research and clinical trials, and the latest updates at national conferences and leading journals through social media. Social media is a powerful educational resource for patients with MDS when used conscientiously. PMID- 30306314 TI - (Z)-7-Hexadecene is an Aggregation-Sex Pheromone Produced by Males of the South American Cerambycid Beetle Susuacanga octoguttata. AB - We describe the identification, synthesis, and field bioassays of a novel aggregation-sex pheromone produced by males of Susuacanga octoguttata (Germar), a South American cerambycid beetle. Analyses of extracts of headspace volatiles produced by adult beetles revealed a sex-specific compound emitted by males which was identified as (Z)-7-hexadecene by microchemical and spectroscopic analyses. The synthesized pheromone was attractive to beetles of both sexes in field trials. This unsaturated hydrocarbon motif is unprecedented among cerambycid pheromones identified to date. During field bioassays, we serendipitously discovered that adults of S. octoguttata trapped in two Brazilian biomes differed considerably in elytral markings, although males from both populations produced (Z)-7-hexadecene as an aggregation-sex pheromone. PMID- 30306315 TI - Tinnitus is multicausal and may not only be related to DNA variants. PMID- 30306312 TI - rHGF interacts with rIGF-1 to activate the satellite cells in the striated urethral sphincter in rats: a promising treatment for urinary incontinence? AB - PURPOSE: There are multitudes of factors contributing to urinary incontinence (UI). Dysfunction of the urethral sphincter is one of the common variables. Fortunately, satellite cells, which have the characteristics of stem cells, exist in the striated urethral sphincter. The purpose of the study was to seek whether rHGF combined with rIGF-1 owns the ability to promote the activation, proliferation, and differentiation of satellite cells to potentially improve urinary incontinence. METHODS: The SD rats were randomly divided into four groups and injected with 10 MUl rIGF-1, the concentration of which was 50 MUg/ml into the urethral wall of the urethral sphincter. Meanwhile, three groups were additionally treated with 10 MUl rHGF, the concentration of which was 20, 50, 100 MUg/ml. The group injected only with rIGF-1 was used as a control. 30 days later, the urethral tissues were harvested and serially sectioned. Immunofluorescent staining and HE staining were used to detect the activation, proliferation, and differentiation condition of satellite cells. The real-time RT-PCR analysis was applied to explore the potential signaling pathways. RESULT: Anti-c-Met antibody positive cells were discovered in the striated urethral sphincter. Positive expression of c-Met was relatively higher with the treatment of 100 MUg/ml rHGF compared to other concentration of rHGF. A similar result was found in additional immunofluorescent staining. The number of newborn myofibers with central nuclei increased as the concentration of rHGF becoming higher. The mRNA expression of ERK1, ERK2 and AKT was comparatively higher with the injection of 50 MUg/ml rHGF. CONCLUSION: There is supposed to be a synergistic effect between rHGF and rIGF-1 to promote satellite cell to activate, proliferate and differentiate into muscle cells. The urethral sphincter may be induced to renew by the injection of rHGF and rIGF-1 into the urethral wall. It can be used to develop a new therapy for UI. PMID- 30306316 TI - The protective effect of metformin against the noise-induced hearing loss. AB - OBJECTIVE: To test the protective effect of metformin against noise-induced hearing loss. METHODS: 24 rats were included in the study. The first group was exposed to noise only, the second group took metformin, the third group was exposed to noise and took metformin, and the fourth group was neither exposed to noise nor took metformin as control group. After measurement of baseline DPOAE and ABR of rats, the metformin group and the metformin + noise group received 300 mg/kg/day metformin via gavage for 10 days. On the 11th day, group 1 and group 3 were exposured to white noise at 105 dB SPL for 15 h. After noise exposure, DPOAE and ABR measurements of all rats were repeated on days 1st, 7th, and 21st. At the end of the study, all animals were sacrificed and cochlear tissues were separated for immunohistochemical assessments. RESULTS: ABR threshold values and DPAOE measurements of groups 1 and 3 were deteriorated on the 1st day after noise, while deterioration in group 1 continued on 7th and 21st days, but normalized on 7th day in group 3. After immune staining, a significant immunoreaction was observed in the noise group, while the reaction in the noise + metformin group was close to the control group. CONCLUSION: Metformin has a protective effect on noise-induced hearing loss in rats. As a conclusion, it is determined that metformin protects from permanent threshold shift in rats. It can be considered a good alternative for protecting noise-induced hearing loss. PMID- 30306317 TI - Clinical manifestations of hydropic ear disease (Meniere's). AB - INTRODUCTION: Hydropic ear disease, initially described by and named after Prosper Meniere, is one of the most frequent vertigo disorders and one of the most frequent inner ear disorders. It is the syndrome of endolymphatic hydrops which until 2007 could be diagnostically confirmed only by post-mortem histology. In the past, various attempts to formulate clinical diagnostic criteria have been undertaken but were hampered by the inability to ascertain the diagnosis in living patients. With the milestone achievement of endolymphatic hydrops imaging, today the pathology can be ascertained. In this study, we have performed a detailed analysis of the clinical features of hydropic ear disease for the first time by examining a large cohort of patients with morphologically confirmed endolymphatic hydrops using a detailed physician-administered neurotologic face to-face interview. RESULTS: During a hydropic vertigo attack, the patients report nausea, vomiting, sweating, urge to defecate, urge to urinate, phosphenes, headache, photophobia, phonophobia and even transient loss of consciousness. A third of the patients does not experience auditory symptoms during the vertigo attacks. Vertigo attacks last less than 20 min in more than one-fourth of the patients. Audiometric hearing loss has its greatest diagnostic value at the frequencies of 1 kHz and below. Cochleovestibular symptom onset simultaneity is associated with a high frequency of drop-attacks. Migraine and autoimmune disorders are not associated with hydropic ear disease. CONCLUSION: This study marks the beginning of the clinical characterization of hydropic ear disease. The findings have important implications for the future formulation of clinical diagnostic criteria. PMID- 30306318 TI - Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates. AB - PURPOSE: There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-D-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5 (4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([11C]HACH242). This paper reports the evaluation of [11C]HACH242 PET in non human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil. PROCEDURES: Eight 90-min dynamic [11C]HACH242 PET scans were acquired in three male anaesthetised rhesus monkeys, including a retest session of subject 1, at baseline and 10 min after intravenous 10 mg/kg radiprodil. Standardised uptake values (SUV) were calculated for 9 brain regions. Arterial blood samples were taken at six timepoints to characterise pharmacokinetics in blood and plasma. Reliable input functions for kinetic modelling could not be generated due to variability in the whole-blood radioactivity measurements. RESULTS: [11C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (+/- standard deviation, SD) Tmax was 17 +/- 7 min in baseline scans and 24 +/- 15 min in radiprodil scans. The rate of radioligand metabolism in plasma (primarily to polar metabolites) was high, with mean parent fractions of 26 +/- 10 % at 20 min and 8 +/- 5 % at 85 min. Radiprodil increased [11C]HACH242 whole-brain SUV in the last PET frame by 25 %, 1 %, 3 and 17 % for subjects 1, 2, 3 and retest of subject 1, respectively. The mean brain to plasma ratio was 5.4 +/- 2.6, and increased by 39 to 110 % in the radiprodil condition, partly due to lower parent plasma radioactivity of -11 to 56 %. CONCLUSIONS: The present results show that [11C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [11C]HACH242 brain uptake. These findings may be explained by variations in cerebral blood flow, a low fraction of specifically bound tracer, or interactions with endogenous NMDA receptor ligands at the binding site. Further experiments of ligand interactions are necessary to facilitate the development of radiotracers for in vivo imaging of the ionotropic NMDA receptor. PMID- 30306319 TI - Is calcitonin gene-related peptide a modulator of menopausal vasomotor symptoms? AB - PURPOSE: Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the central and peripheral nervous systems, which is known as a potent vasodilator. Postmenopausal women who experience hot flushes have high levels of plasma CGRP, suggesting its involvement in menopausal vasomotor symptoms. METHODS: In this review, we describe the biochemical aspects of CGRP and its effects associated with deficiencies of sexual hormones on skin temperature, vasodilatation, and sweating as well as the possible peripheral and central mechanisms involved in these events. RESULTS: Several studies have shown that the effects of CGRP on increasing skin temperature and inducing vasodilatation are potentiated by a deficiency of sex hormones, a common condition of postmenopausal women. Additionally, the medial preoptic area of the hypothalamus, involved in thermoregulation, contains over 25-fold more CGRP immunoreactive cells in female rodents compared with male rodents, reinforcing the role of female sex hormones on the action of CGRP. Some studies suggest that ovarian hormone deficiency decreases circulating endogenous CGRP, inducing an upregulation of CGRP receptors. Consequently, the high CGRP receptor density, especially in blood vessels, amplifies the stimulatory effects of this neuropeptide to raise skin temperature in postmenopausal women during hot flushes. CONCLUSIONS: The duration of the perception of each hot flush in a woman is brief, while local reddening after intradermal administration of alpha-CGRP persists for 1 to 6 h. This contrast remains unclear. PMID- 30306320 TI - Establishment, characterization, and toxicological application of a spontaneous immortalized cell line from the striped field mouse, Apodemus agrarius. AB - It is important to secure various biological resources in situations of diminishing wildlife genetic diversity. Cultured cells are useful bioresources because they can stably store genetic information for a long time and can be expanded efficiently. Here, we established fibroblast cell lines from Apodemus agrarius as a new living resource. A. agrarius is an important sub-predator species in ecosystem food chains and for the study of infection epidemiology. Established cell lines were characterized by chromosome and mitochondrial gene analysis, the observation of cell morphology, and their anchorage-dependent growth pattern. We also examined susceptibility to endocrine disruptors (EDCs), which threaten biodiversity, using these established cell lines. Nonylphenol (NP) is a well-known EDC that threatens wildlife; however, its impact is poorly understood. Sensitivity to NP was confirmed based on two cell viability assays, namely MTT and lactate dehydrogenase. Cells exposed to NP were analyzed for abnormalities in cell growth and mitochondrial function by evaluating the expression of genes (specifically, those encoding growth hormone receptor and cytochrome C oxidase). This newly established cell line represents a valuable tool for the evaluation of toxic substances such as EDCs and this cell was biobanked for study about relationship between various environmental pollution and decreasing biodiversity. PMID- 30306322 TI - Comparison of CHA2DS2-VASc and AHEAD scores for the prediction of incident dementia in patients hospitalized for heart failure: a nationwide cohort study. AB - This study explores the use of the CHA2DS2-VASc and the AHEAD scores to predict incident dementia in patients with heart failure (HF) who need hospitalization. We used a large national database to study 387,595 adult patients hospitalized for HF from Taiwan. This registration cohort was followed to document the cumulative incidence of dementia. The area under the curve of receiver operating characteristics (AUROC) was used to evaluate the discriminative ability of CHA2DS2-VASc and AHEAD scores in predicting dementia, whereas the DeLong test was used to examine the difference between the predictive capacity. A higher CHA2DS2 VASc and AHEAD scores appear to be more strongly associated with a higher incidence of dementia. The AUROC for CHA2DS2-VASc score in predicting dementia (0.61, 95% CI = 0.60-0.61) is significantly higher than the AHEAD score (0.55, 95% CI = 0.54-0.55) (DeLong test p < 0.001). A significantly higher ability, by AUROC, of CHA2DS2-VASc score to predict new-onset dementia in patients hospitalized for HF is found. PMID- 30306321 TI - Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study. AB - In our previous study, we have shown that number of synapses in the L5 segment of spinal dorsal horn increased significantly in a rat model of painful diabetic neuropathy (PDN) induced by high-dose of streptozotocin (an animal model of type 1 diabetes). The aims of this study were: (1) to determine whether high fat diet/low dose streptozotocin-diabetes, a rat model for type 2 diabetes, related PDN was also associated with this synaptic plasticity, (2) to reveal the range of this synaptic plasticity change occurred (in the whole length of spinal dorsal horn or only in the L5 lumbar segment of spinal dorsal horn) and (3) to discover whether treatment with metformin had effect on this synaptic plasticity. Male adult Sprague-Dawley rats were randomly allocated into the control group (n = 7), the PDN group (n = 6) and the PDN treated with metformin (PDN + M) group (n = 7), respectively. 28 days after medication, synaptic and neuronal numbers in the whole length of spinal dorsal horn or in 1 mm length of the L5 segment of spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group and the PDN + M group, number of synapses in the L5 segment of spinal dorsal horn increased significantly in the PDN group (P < 0.05). There was no significant change between the control group and the PDN + M group in terms of the parameters in the L5 segment of the spinal dorsal horn (P > 0.05). Parameters of the whole length of spinal dorsal horn showed no significant changes (P > 0.05). Our results suggest that high fat diet/low dose streptozotocin diabetes related PDN is also associated with a numerical increase of synapses in the L5 segment of spinal dorsal horn but not in the whole length of spinal dorsal horn. Furthermore, the analgesic effect of metformin against PDN is related to its inhibition of numerical increase of synaptic number in the rat spinal dorsal horn. PMID- 30306324 TI - ? PMID- 30306323 TI - Central venous oxygen saturation is not predictive of early complications in cancer patients presenting to the emergency department. AB - Central venous oxygen saturation (ScvO2) is easily observable in oncology patients with long-term central venous catheters (CVC), and has been studied as a prognostic factor in patients with sepsis. We sought to investigate the association between ScvO2 and early complications in cancer patients presenting to the ED. We prospectively enrolled adult cancer patients with pre-existing CVC who presented to the ED. ScvO2 was measured on their CVC. The outcome was admission to the intensive care unit (ICU) or mortality by day 7. ScvO2 was first studied as a continuous variable (%) with a ROC analysis and as a categorical variable (cut-off at < 70%) with a multivariate analysis. A total of 210 cancer patients were enrolled. At baseline, ScvO2 showed no significant difference between patients who were admitted to the ICU or died before day 7, and patients who did not (67%; IQR 62-68% vs. 71%; IQR 65-78% respectively, P = 0.3). The ROC analysis showed the absence of discrimination accuracy for ScvO2 to predict the outcome (AUC = 0.56). By multivariate analysis, ScvO2 < 70% was not associated with the outcome (OR 1.67; 95% CI 0.64-4.36). Variables that were associated with ICU admission or death by day 7 included a shock-index (heart rate/systolic blood pressure) > 1 and a performance status > 2 (OR 4.76; 95% CI 1.81-12.52 and OR 6.23, 95% CI 2.40-16.17, respectively). This study does not support the use of ScvO2 to risk stratify cancer patients presenting to the ED. PMID- 30306325 TI - The efficacy of oral piroxicam fast-dissolving tablets versus sublingual fentanyl in incident breakthrough pain due to bone metastases: a double-blinded randomized study. AB - PURPOSE: Breakthrough pain (BTP) is a transient exacerbation of pain occurring in a patient with chronic, persistent pain. The most common type is incident pain that is mostly related to bone metastases. The oral mucosa is an attractive route for drug delivery. Sublingual fentanyl preparations are a very attractive agent in controlling attacks of BTP due to its rapid absorption through the oral mucosa. Non-steroidal anti-inflammatory drugs (NSAIDs) play a key role as a first step in treatment of cancer pain; piroxicam sublingual formulations could be a useful alternative in controlling incident pain. Our study hypothesis is to evaluate the efficacy of sublingual fentanyl versus oral piroxicam fast dissolving tablets in patients with incident pain and its impact on functional status. PATIENTS AND METHODS: A cohort of 100 adults of both genders suffering from bone metastases. Patients were assigned to receive either sublingual fentanyl tablet (group 1) or oral piroxicam fast-dissolving tablets (group 2). The pain intensity reduction on a 0-10 visual analog scale (VAS), frequency of BTP attacks, and onset of pain relief. Secondary end points included the functional interference items of the Brief Pain Inventory (BPI). RESULTS: There is no significant difference between the two groups regarding the patients' demographics. Significant decline of the VAS in each group in comparison to the pretreatment values (p = 0.001). Non-significant changes of the VAS, duration of pain attacks, and number of rescue doses in comparing both groups were measured. There was significant reduction in group 2 BPI regarding the relation with others, sleep pattern and enjoyment of life parameters at 2 and 4 weeks (p = 0.001). CONCLUSION: Our study demonstrated that oral piroxicam fast-dissolving tablet is an analgesic alternative to sublingual fentanyl in patients with bone metastasis to control incidental BTP attacks with more favorable cost-benefit values. PMID- 30306326 TI - Joint pain and falls among women with breast cancer on aromatase inhibitors. AB - PURPOSE: Arthralgia is common among women with breast cancer on adjuvant aromatase inhibitor (AI) therapy. Pain is associated with falls in the general population; however, little is known about the relationship between arthralgia and falls among AI users. Our objective was to determine whether joint pain severity and interference predict future falls. METHODS: We conducted a prospective cohort study of postmenopausal women with stage I-III estrogen receptor-positive breast cancer who were prescribed a third-generation AI. Arthralgia symptoms were measured at baseline using a modified version of the Brief Pain Inventory. Fall occurrence was obtained at 24-month follow-up. RESULTS: Among 667 participants (median age 63 years, interquartile range 57-69 years), 232 (35%, 95% CI 31 to 39%) reported falls 12-24 months after baseline. Among women who fell, 65 (28%) reported seeking medical assistance. After controlling for multiple fall risk factors, we found significant non-linear associations between baseline joint pain severity and risk of falls (p = 0.001). Women with joint pain severity scores >= 4 had a more than twofold increase in fall risk compared to those without pain (41% vs. 20%). We observed a similar relationship for pain interference and fall risk (p < 0.001). Fewer than half of participants reported having been asked about falls in the past 12 months by their primary care physician (44%) or oncologist (36%). CONCLUSION: Joint pain increases the risk of falls among women with breast cancer on adjuvant AI therapy. Health care providers should evaluate and manage arthralgia symptoms and implement fall-prevention strategies for those who are at increased risk. PMID- 30306327 TI - Prospective study of a web-mediated management of febrile neutropenia related to chemotherapy (Bioconnect). AB - BACKGROUND: We aimed to investigate whether patient self-evaluated symptoms transmitted via Internet is feasible between planned visits to provide an early management of fever and neutropenia induced by chemotherapy, and if it can reduce hospitalizations for severe neutropenia. METHODS: Patients who received a chemotherapy regimen with an overall risk of febrile neutropenia >= 20% had to report daily temperature between physician planned visits using a web application. Fever and clinical signs of seriousness were reported to the physician (if some criteria were fulfilled in a specific algorithm) via automatic email notifications by the web application. Patients could be hospitalized quickly or could take over at home, make blood count, and take predefined oral antibiotics if indicated. Primary outcome was patient's compliance and satisfaction. The number and the cost of hospitalization were also assessed and compared with an historical cohort of patients with similar clinical conditions and treatment. RESULTS: Among the 41 patients included, 36 (87.8%) used the web application with 88% of daily compliance and 90% (28/33) of satisfaction. One patient (2.7%) had planned hospitalization after the web application alert. In the historical cohort, the rate of unplanned hospitalization for febrile neutropenia was 17% (6 patients) and 2.7% (1 patient) in users of the web application cohort. The cumulative cost of hospitalization for neutropenia was USD 28,827 in the historical cohort and USD 6563 in the web application cohort. CONCLUSION: Web-mediated follow-up of febrile neutropenia is feasible. It led to high patient satisfaction, high compliance, and a possible reduction of the number and the cost of hospitalizations. PMID- 30306328 TI - Accuracy of automated patient positioning in CT using a 3D camera for body contour detection. AB - OBJECTIVE: To assess the accuracy of a 3D camera for body contour detection and patient positioning in CT compared to routine manual positioning by radiographers. METHODS AND MATERIALS: Four hundred twenty-three patients that underwent CT of the head, thorax, and/or abdomen on a scanner with manual table height selection and 254 patients on a scanner with table height suggestion by a 3D camera were retrospectively included. Within the camera group, table height suggestion was based on infrared body contour detection and fitting of a scalable patient model to the 3D data. Proper positioning was defined as the ideal table height at which the scanner isocenter coincides with the patient's isocenter. Patient isocenter was computed by automatic skin contour extraction in each axial image and averaged over all images. Table heights suggested by the camera and selected by the radiographer were compared with the ideal height. RESULTS: Median (interquartile range) absolute table height deviation in millimeter was 12.0 (21.6) for abdomen, 12.2 (12.0) for head, 13.4 (17.6) for thorax-abdomen, and 14.7 (17.3) for thorax CT scans positioned by radiographers. The deviation was significantly less (p < 0.01) for the 3D camera at 6.3 (6.9) for abdomen, 9.5 (6.8) for head, 6.0 (6.1) for thorax-abdomen, and 5.4 (6.4) mm for thorax. CONCLUSION: A 3D camera for body contour detection allows for accurate patient positioning, thereby outperforming manual positioning done by radiographers, resulting in significantly smaller deviations from the ideal table height. However, radiographers remain indispensable when the system fails or in challenging cases. KEY POINTS: * A 3D camera for body contour detection allows for accurate patient positioning. * A 3D camera outperformed radiographers in patient positioning in CT. * Deviation from ideal table height was more extreme for patients positioned by radiographers for all body parts. PMID- 30306329 TI - Radiomics features on non-contrast-enhanced CT scan can precisely classify AVM related hematomas from other spontaneous intraparenchymal hematoma types. AB - OBJECTIVE: To investigate the classification ability of quantitative radiomics features extracted on non-contrast-enhanced CT (NECT) image for discrimination of AVM-related hematomas from those caused by other etiologies. METHODS: Two hundred sixty-one cases with intraparenchymal hematomas underwent baseline CT scan between 2012 and 2017 in our center. Cases were split into a training dataset (n = 180) and a test dataset (n = 81). Hematoma types were dichotomized into two classes, namely, AVM-related hematomas (AVM-H) and hematomas caused by other etiologies. A total of 576 radiomics features of 6 feature groups were extracted from NECT. We applied 11 feature selection methods to select informative features from each feature group. Selected radiomics features and the clinical feature age were then used to fit machine learning classifiers. In combination of the 11 feature selection methods and 8 classifiers, we constructed 88 predictive models. Predictive models were evaluated and the optimal one was selected and evaluated. RESULTS: The selected radiomics model was RELF_Ada, which was trained with Adaboost classifier and features selected by Relief method. Cross-validated area under the curve (AUC) on training dataset was 0.988 and the relative standard deviation (RSD%) was 0.062. AUC on the test dataset was 0.957. Accuracy (ACC), sensitivity, specificity, positive prediction value (PPV), and negative predictive value (NPV) were 0.926, 0.889, 0.937, 0.800, and 0.967, respectively. CONCLUSIONS: Machine learning models with radiomics features extracted from NECT scan accurately discriminated AVM-related intraparenchymal hematomas from those caused by other etiologies. This technique provided a fast, non-invasive approach without use of contrast to diagnose this disease. KEY POINTS: * Radiomics features from non-contrast-enhanced CT accurately discriminated AVM-related hematomas from those caused by other etiologies. * AVM-related hematomas tended to be larger in diameter, coarser in texture, and more heterogeneous in composition. * Adaboost classifier is an efficient approach for analyzing radiomics features. PMID- 30306330 TI - Answer to the Letter to the Editor of LJ Castro-Alves et al. concerning "Comparative study of the efficacy of transdermal buprenorphine patches and prolonged-release tramadol tablets for postoperative pain control after spinal fusion surgery: a prospective, randomized controlled non-inferiority trial" by HJ Kim et al. (2017) Eur Spine J;26:2961-2968. PMID- 30306331 TI - Endplate lesions in the lumbar spine: a novel MRI-based classification scheme and epidemiology in low back pain patients. AB - PURPOSE: The aims of the study were to introduce a classification scheme for endplate lesions based on T2-weighted magnetic resonance imaging and to detect possible associations between endplate lesions and other variables such as age, sex, disc degeneration and Modic changes in a large population. METHODS: MRI images of 996 low back pain patients were collected. All intervertebral spaces were classified as "normal", "wavy/irregular", "notched", "Schmorl's node" and "fracture". The associations between endplate lesions and age, sex, disc degeneration and Modic changes were determined in the considered population. RESULTS: The most common endplate lesions were "notched" and "Schmorl's nodes". The prevalence was higher among the male subjects. In most patients (62.8%), no endplate lesions were detected, with a significant difference between male (57.5%) and female subjects (67.9%) (p < 0.001). Lesions were found to be associated with intervertebral disc degeneration (relative risk 2.49) and signal alterations (relative risk 3.08). Fleiss kappas of 0.73 and 0.89 were, respectively, assessed for the inter- and intra-observer reliabilities of the new classification system. CONCLUSIONS: Endplate lesions were detected, classified with a novel scheme and analysed in a large population of patients suffering from low back pain based on MRI images. The reliability of the novel classification system was demonstrated. These slides can be retrieved under Electronic Supplementary Material. PMID- 30306332 TI - The use of CT Hounsfield unit values to identify the undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases. AB - PURPOSES: Our purpose was to use computed tomography (CT) Hounsfield unit (HU) values to identify the undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases. METHODS: A total of 334 patients with lumbar degenerative diseases were retrospectively reviewed and divided into two groups according to the degree of lumbar degenerative changes in preoperative lumbar CT images. Patients who had at least three vertebrae with severe degeneration at L1-L4 were placed in the degenerative group, and others were placed in the control group. HU value of trabecular bone in middle axial CT image of vertebral body, T-score and bone mineral density (BMD) at L1-L4 and hips were measured. CT HU thresholds for osteoporosis were obtained from control group and then applied to identify undiagnosed spinal osteoporosis. RESULTS: There were 182 patients in the degenerative group and 152 patients in the control group. CT HU value had a positive correlation with T-score and BMD of lumbar spine in both groups (P < 0.001), while the correlation coefficients at L1-L4 were higher in the control group (> 0.7) than in the degenerative group (< 0.7). T-score and BMD of lumbar spine were higher in the degenerative group (P < 0.05), while CT HU value, T score and BMD of hips had no significant difference between two groups. According to the linear regression equations of vertebral T-score and CT HU value in the control group, the thresholds matching T-score of - 2.5 were 110, 100, 85 and 80HU for L1, L2, L3 and L4, respectively. Defining CT osteoporosis as L1 <= 110HU or L2 <= 100HU or L3 <= 85HU or L4 <= 80HU was 88.5% (69/78) specific and 60.8% (45/74) sensitive for distinguishing DXA osteoporosis of lumbar spine in the control group. The rate of undiagnosed spinal osteoporosis was higher in the degenerative group than in the control group according to CT HU thresholds (38.7% vs. 11.5%, P < 0.05). CONCLUSIONS: Degenerative changes in the lumbar spine can increase BMD and T-score provided by lumbar DXA, leading to an underestimation of vertebral osteoporosis. Thresholds for osteoporosis based on CT HU values can be used as a complementary method to identify undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases. These slides can be retrieved under Electronic Supplementary Material. PMID- 30306334 TI - Bone-anchored maxillary protraction in patients with unilateral complete cleft lip and palate and Class III malocclusion. AB - OBJECTIVE: This prospective controlled study evaluated the effect of bone anchored maxillary protraction therapy in cleft children with Class III malocclusion using CBCT-derived 3D surface models. MATERIALS AND SUBJECTS: Eighteen cleft patients between 10 and 12 years old were included. Intermaxillary elastics were worn after the placement of four zygoma bone plates for 18 months. Uniquely, three age-matched untreated groups including both cleft subjects and non-cleft subjects with Class III malocclusion served as controls. Profile photos and CBCT scans for each patient were taken before (T0) and 18 months after the protraction (T1). 3D measurements were made on CBCT surface models from the treatment group using tomographic color mapping method. Cephalometric measurements were made on lateral cephalogram reconstructed from the CBCT scans and were compared with those obtained from the control groups. RESULTS: Two thirds of the treatment subjects showed improved lip projection towards more convex facial profile. The most significant skeletal changes on 3D surface models were observed at the zygomatic regions (mean 1.5-mm forward, downward, and outward displacement) and at the maxillary complex (mean 1.5-mm forward displacement). Compared with the control groups, the treatment subjects showed significant increase in the SNA and ANB angles, increased Wits appraisal, a more forward movement of point A and overjet improvement (p < 0.05). CONCLUSIONS: BAMP in cleft patients gives a significant forward displacement of the zygomaxillairy complex in favor of the Class III treatment. CLINICAL RELEVANCE: This treatment method shows clearly favorable outcome in cleft patients after 1.5 years of BAMP. PMID- 30306333 TI - Differences in the subgingival microbial population of chronic periodontitis in subjects with and without type 2 diabetes mellitus-a systematic review. AB - OBJECTIVES: The purpose of this systematic review was to evaluate the available evidence in the literature in regard to the subgingival microbial population of chronic periodontitis in subjects with type 2 diabetes mellitus (T2DM+PD) compared to non-diabetic subjects (NDM+PD). MATERIALS AND METHODS: A literature search was conducted at Ovid MEDLINE and EMBASE database from 1980 to 2016, supplemented by hand searching as needed. Studies presenting with at least one of the primary outcomes (presence of any subgingival microorganisms, proportion and/or the amount of any subgingival plaque bacteria in T2DM+PD versus NDM+PD) were included. Screening, data extraction and quality assessment were conducted independently and in duplicate. RESULTS: From 611 citations, 19 full-text papers were screened and 11 articles were included for critical appraisal by both reviewers. Some evidence of a difference in the microbial profile between chronic PD subjects with and without T2DM was identified. The strength of evidence is strongest in Tannerella forthysia (T .forsythia) which was reported to be less frequent in the diabetic (T2DM+PD) group in five of the studies, followed by a weaker strength of evidence for other periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), which were also found less frequent in the diabetic (T2DM+PD) group . CONCLUSION: Only few studies have compared T2DM+PD with NDM+PD. It is therefore strongly recommended that further studies which include four distinct groups of participants (NDM+PD, T2DM+PD, NDM+NPD, T2DM+NPD) instead of using intra-subject comparisons between healthy and diseased sites of the same subjects. CLINICAL RELEVANCE: Differences in bacterial populations of T2DM+PD in comparison to NDM+PD subjects may indicate the need of different protocols for the treatment of the diabetic patients with periodontal disease. PMID- 30306335 TI - Effect of NaF, AmF, KF gels and NaF toothpaste combined with a saliva substitute on dentin lesions in vitro. AB - OBJECTIVE: The aim of the present in vitro study was to evaluate the remineralizing effects of NaF, AmF, KF gels and NaF toothpaste in combination with a potentially demineralizing saliva substitute (Glandosane; pH = 5.1) being widely used in Germany. METHODS: In each of 120 dentin specimens, three artificial lesions were created. One lesion was covered for analysis of pre demineralization (DeltaZB). Treatments during pH cycling (3 * 1 h demineralization/day [pH = 5.0] and 3 * 3 h Glandosane/day; 12 h 100%humidity) were as follows: no treatment (NT), application (5 min,2*/day) of 12.500 ppm F- [pH = 6.04] (NaF-gel1), 12.500 ppm F- [pH = 7.34] (NaF-gel2), 12.500 ppm F- [pH = 5.82] (AmF-gel), 1450 ppm F- [pH = 7.35] (KF-gel), and 5000 ppm F- [pH = 8.14]; (NaF-TP) for 7 days (E1). Subsequently, from each specimen, one lesion was covered, while the remaining lesion was cycled for another 7 days (E2). Differences in integrated mineral loss (DeltaDeltaZE1/DeltaDeltaZE2) were calculated between values before and after pH cycling. RESULTS: Mean (95%CI) DeltaZB was 3851 (3762;3939) vol% * MUm. Except for NaF-gel2 and NaF-TP, specimens of all other groups further demineralized. Only NaF-gel2 induced a significant gain in mineral content (p <= 0.004; paired t test). Significant differences in the change of mineral loss were found between NT and all fluoride groups for both DeltaDeltaZE1 and for DeltaDeltaZE2 (p < 0.05, Bonferroni post hoc test). However, only NaF-gel2 and NaF-TP induced remineralization. CONCLUSION: Under the in vitro conditions chosen, all fluoride agents could significantly hamper the adverse effects of a demineralizing saliva substitute. CLINICAL SIGNIFICANCE: In combination with a demineralizing saliva substitute, slight mineral gain was only observed for neutral NaF-gel2 and 5000 ppm F- toothpaste. PMID- 30306336 TI - Overaugmentation to compensate for postextraction ridge atrophy using a putty type porcine bone substitute material with recombinant bone morphogenetic protein 2: 4 weeks of healing in a canine model. AB - OBJECTIVES: The aims of the present study were (i) to determine the short-term effects of putty-type porcine bone substitute material (PB) with recombinant bone morphogenetic protein-2 (rhBMP-2) for alveolar ridge preservation (ARP) and (ii) evaluate the early healing of labial overaugmentation. MATERIALS AND METHODS: Two groups were randomly assigned to the extraction sockets in mandibular incisors of eight dogs: labial overaugmentation with (i) PB (control) or (ii) rhBMP-2-loaded PB (BMP). Microcomputed tomography (micro-CT), and histologic and histomorphometric analyses were performed after 4 weeks. RESULTS: Micro-CT revealed that some of the overaugmented PB was dispersed in both groups. The new bone volume was significantly larger in the BMP group than in the control group (18.4 +/- 3.3 vs. 15.5 +/- 3.0 mm3, mean +/- SD, P < 0.05). Labial bone resorption was generally found histologically. No signs of mineralization were observed in the overaugmented area despite significantly increased ridge width, as compared to the adjacent tooth area. The area of new bone formation was larger in the BMP group than in the control group overall (23.7 +/- 18.8 vs. 18.3 +/- 21.2 mm2) and in three parts (apical, middle, and coronal), although the difference was statistically significant only in the coronal part (7.7 +/- 7.9 vs. 4.6 +/- 6.4 mm2, P < 0.05). CONCLUSIONS: The addition of rhBMP-2 enhanced ossification in the coronal part of the extraction socket relative to using PB alone. Overaugmentation increased the ridge dimension with no evidence of ossification in situ at 4 weeks. CLINICAL RELEVANCE: In early healing following ARP, rhBMP-2 enhances bone formation within the socket, but ossification in the overaugmented area needs to be studied further. PMID- 30306337 TI - Rehabilitation strategies for optimisation of functional recovery after major joint replacement. AB - Exercise-based interventions applied before and after total hip and knee arthroplasty (THA and TKA, respectively) have been investigated for a number of years, based on the assumption that they will enhance post-operative recovery. Although recent studies suggest that high-volume, pre-operative exercise may enhance post-operative recovery after TKA, studies of post-operative exercise based interventions, have not found superiority of one exercise regime over another. It seems, however, that post-operative, exercise-based, rehabilitation is superior to no or minimal rehabilitation after THA and TKA.The goal of this commentary is to summarize recent evidence for the efficacy of different peri operative exercise-based interventions to enhance recovery after THA and TKA, and to propose new strategies to further enhance post-operative recovery.There is a major need to improve functional recovery after THA and TKA. We propose a strategy of "enriched" trials where specific rehabilitation interventions are applied to different patients based on, for example, their expectations for post operative recovery, willingness to undertake exercise and physical activity, and pre-operative functional performance. PMID- 30306338 TI - Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia. AB - Sodium zirconium cyclosilicate (LokelmaTM) [hereafter referred to as SZC] is a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract (GIT), thereby increasing faecal potassium excretion and lowering serum potassium levels. It is available as a powder for oral suspension (in water) and is approved in the EU and the USA for the treatment of hyperkalaemia in adults. In two multinational, phase III studies in adults with hyperkalaemia, SZC 10 g three times daily lowered serum potassium levels to within the normal range (3.5-5.0 mmol/L) during the first 48 h of treatment, and SZC 5 and 10 g once daily maintained normokalaemia over <= 28 days' therapy. These beneficial effects were consistent across all patient subgroups (e.g. chronic kidney disease, diabetes, heart failure, concomitant use of RAAS inhibitor therapy), and appeared to be maintained over the longer term (<= 12 months). SZC was generally well tolerated in adults with hyperkalaemia. Its tolerability profile was generally similar to that seen with placebo over <= 28 day, and its safety profile appeared to remain consistent over the longer term (<= 12 months). Moreover, the incidence of hypokalemia was low. Current evidence indicates that SZC is a promising therapy for the management of hyperkalaemia in adults. PMID- 30306340 TI - The Association between Polypharmacy and Hip Fracture in Osteoporotic Women: A Nested Case-Control Study in South Korea. AB - BACKGROUND AND OBJECTIVE: Polypharmacy, regarded as an indicator of potentially inappropriate medications (PIMs), may lead to a higher risk of serious health consequences in elderly patients with osteoporosis. Thus, this study aimed to analyze the association between polypharmacy and hip fracture in patients with osteoporosis because only a limited number of studies have reported on this association, with inconsistent results to date. METHODS: In this nested case control study using a population-based sample cohort, the target cases were female patients with hip fracture diagnosed with osteoporosis and aged >= 50 years. Polypharmacy (prescription of an average of five or more daily drugs), PIMs for hip fracture (such as benzodiazepines and glucocorticoids), Charlson Comorbidity Index (CCI) score, and other comorbidities were analyzed during the year preceding the diagnosis of hip fracture. Adjusted odds ratios (ORs) for hip fracture for the variables were also analyzed. RESULTS: The cases (n = 1003) showed higher exposure rates to polypharmacy, glucocorticoids, and benzodiazepines, and had more severe comorbidity statuses compared with the controls. The ORs for hip fracture adjusted for confounders increased with polypharmacy level, with persistent statistical significance in most analyses. The ORs (95% confidence intervals), with reference to the 0 to < 1 drug group, were 1.65 (1.31-2.08) and 2.11 (1.12-3.96) for the 5 to < 10 and 10 + drug groups, respectively, with adjustment for PIMs, and 1.34 (1.04-1.72) and 1.45 (0.76-2.80) for the 5 to < 10 and 10 + drug groups, respectively, with adjustment for PIMs and CCI score. CONCLUSIONS: The results suggest that polypharmacy is associated with an increased risk of hip fracture after adjustment for confounders in patients with osteoporosis. These results highlight the importance of polypharmacy management in preventing hip fractures in patients with osteoporosis. PMID- 30306339 TI - Management of Post-Traumatic Nightmares: a Review of Pharmacologic and Nonpharmacologic Treatments Since 2013. AB - PURPOSE OF REVIEW: Post-traumatic nightmares (PTN) are a common and enduring problem for individuals with post-traumatic stress disorder (PTSD) and other clinical presentations. PTN cause significant distress, are associated with large costs, and are an independent risk factor for suicide. Pharmacological and non pharmacological treatment options for PTN exist. A previous review in this journal demonstrated that Prazosin, an alpha blocker, was a preferred pharmacological treatment for PTN and imagery rescripting therapy (IRT) was a preferred non-pharmacological treatment. Since that time, new and important research findings create the need for an updated review. RECENT FINDINGS: Based on the results of a recent study in the New England Journal of Medicine, Prazosin has been downgraded by both the American Academy of Sleep Medicine (AASM) and the Veterans Health Administration/Department of Defense (VA/DoD) for PTN. In Canada, Nabilone, a synthetic cannabinoid, appears to be promising. Few recent studies have been published on non-pharmacological interventions for PTN; however, recent data is available with regard to using IRT on an inpatient setting, with German combat veterans, and through the use of virtual technology. Recent evidence supports the use of exposure, relaxation, and rescripting therapy (ERRT) with children and individuals with comorbid bipolar disorder and PTN. Prazosin is no longer considered a first-line pharmacological intervention for PTN by AASM and VA/DoD. However, in the absence of a suitable alternative, it will likely remain the preferred option of prescribers. IRT and ERRT remain preferred non pharmacological treatments of PTN. Combining cognitive behavior therapy for insomnia (CBT-I) with IRT or ERRT may lead to improved outcomes. PMID- 30306341 TI - Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood-Brain Barrier. AB - Antibody, immuno- and gene therapies developed for neurological indications face a delivery challenge posed by various anatomical and physiological barriers within the central nervous system (CNS); most notably, the blood-brain barrier (BBB). Emerging delivery technologies for biotherapeutics have focused on trans cellular pathways across the BBB utilizing receptor-mediated transcytosis (RMT). 'Traditionally' targeted RMT receptors, transferrin receptor (TfR) and insulin receptor (IR), are ubiquitously expressed and pose numerous translational challenges during development, including species differences and safety risks. Recent advances in antibody engineering technologies and discoveries of RMT targets and BBB-crossing antibodies that are more BBB-selective have combined to create a new preclinical pipeline of BBB-crossing biotherapeutics with improved efficacy and safety. Novel BBB-selective RMT targets and carrier antibodies have exposed additional opportunities for re-targeting gene delivery vectors or nanocarriers for more efficient brain delivery. Emergence and refinement of core technologies of genetic engineering and editing as well as biomanufacturing of viral vectors and cell-derived products have de-risked the path to the development of systemic gene therapy approaches for the CNS. In particular, brain tropic viral vectors and extracellular vesicles have recently expanded the repertoire of brain delivery strategies for biotherapeutics. Whereas protein biotherapeutics and bispecific antibodies enabled for BBB transcytosis are rapidly heading towards clinical trials, systemic gene therapy approaches for CNS will likely remain in research phase for the foreseeable future. The promise and limitations of these emerging cross-BBB delivery technologies are further discussed in this article. PMID- 30306342 TI - Burden of gastrointestinal and liver diseases in India, 1990-2016. AB - There is no comprehensive report on the burden of gastrointestinal (GI) and liver diseases in India. In this study, we estimated the age-standardized prevalence, mortality, and disability adjusted life years (DALY) rates of GI and liver diseases in India from 1990 to 2016 using data from the Global Burden of Disease (GBD) Study, which systematically reviews literature and reports for international disease burden trends. Despite a decrease in the overall burden from GI infectious disorders since 1990, they still accounted for the majority of DALYs in 2016. Among noncommunicable disorders (NCDs), there were increases in the prevalence and mortality rates for pancreatitis, liver cancer, paralytic ileus and intestinal obstruction, gallbladder and biliary tract cancer, vascular intestinal disorders, colorectal cancer, and inflammatory bowel disease. Prevalence and mortality rates decreased for peptic ulcer disease, hernias, appendicitis, and stomach and esophageal cancer. For gastritis and duodenitis, cirrhosis and other chronic liver diseases, and gallbladder and biliary tract diseases, there was an increase in prevalence but a decrease in mortality while the opposite was true for pancreatic cancer (decreased prevalence, increased mortality). Indian gastroenterologists and hepatologists must continue to attend to the large majority of patients with infectious diseases while also managing the increasing number of GI and liver diseases, noncommunicable nonmalignant and malignant. PMID- 30306343 TI - Why starch is essential and dispensable. PMID- 30306345 TI - Prevention of low bone mass to achieve high bone density in Mexico: position of the Mexican Association for Bone and Mineral Metabolism. AB - : In Mexico, osteoporosis is a public health problem. In this document, the Mexican Association for Bone and Mineral Metabolism defines its position on calcium, vitamin D supplement use, and physical activity as an effective, safe, and cost-effective initiatives to prevent low bone mass. INTRODUCTION: In Mexico, osteoporosis is a public health problem that is expected to increase in the decades ahead. Generally, modifiable risk factors for bone health are related with lifestyles, especially nutrition and physical activity. METHODS: In this position paper, the Mexican Association for Bone and Mineral Metabolism (AMMOM, by its acronym in Spanish), which is a multidisciplinary group of researchers, dietitians, epidemiologists, nurses, and physicians who study bone and related tissues and communicate the best strategies for diagnosis, treatment, and prevention of bone problems, aims to analyze the association between nutrition and bone health, risk behaviors for low bone mass, and the economic impact that prevention of low bone mass represents for the health care system. RESULTS: Addressing therapeutic management with pharmacological and non-pharmacological approaches, we emphasize the important role the patient plays in the doctor patient relationship, both in the consulting room and in daily life. Furthermore, the AMMOM defines its position on calcium and vitamin D supplement use as an effective, safe, and cost-effective initiative to prevent low bone mass. CONCLUSIONS: In summary, most research and clinical practice related to osteoporosis have focused on diagnosis and treatment, but general measures for primary prevention based on addressing modifiable risk factors as a public health priority to delay the onset of loss of bone mass have not been considered by Mexican authorities. Consequently, the AMMOM task force also seeks to provide information on concrete actions to prevent low bone mass. PMID- 30306346 TI - Challenges in implementing best practice DVI guidelines in low resource settings: lessons learnt from the Meethotamulla garbage dump mass disaster. AB - The management of mass fatalities following disasters is a complex process which requires the involvement of multiple stakeholders and resources. A garbage dump at Meethotamulla in Sri Lanka suddenly collapsed, resulting in the death of 32 individuals. Efforts to implement best practice guidelines in Disaster Victim Identification (DVI) during this disaster revealed several important aspects that need to be considered by the forensic community. Delays in initiating the legal processes to investigate and manage the incident resulted in public dissatisfaction towards the post-disaster management process. Body recovery by Police and military personnel without the involvement of medical teams had numerous shortcomings including the lack of proper tagging and photography, commingling of body parts, and non-preservation of personal items. Public expectation and demand for early release of the bodies conflicted with the necessity to undergo a stringent DVI process according to best practice guidelines. Many adaptations and alternate strategies were necessary to ensure that DVI could be done scientifically. The use of primary identification markers including odontology and DNA had many limitations including non-availability of antemortem data, resource availability and cost. Identification was established using a combination of secondary identification markers including clothing, jewelry, scars, tattoos, morphological descriptions and circumstantial evidence. In two cases, odontological features further supported positive identification. Samples for DNA were obtained and preserved but were not utilized in establishing the identities. This paper highlights the need for better public awareness and multidisciplinary commitment in managing mass fatalities and also reflects on the challenges of implementing best practice DVI guidelines in low-resource settings with different legal and socio-cultural expectations. PMID- 30306344 TI - Histopathological classification of anti-neutrophil cytoplasmic antibody associated glomerulonephritis in a nationwide Japanese prospective 2-year follow up cohort study. AB - BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis. PMID- 30306347 TI - Analysis of particulate exposure during continuous drug infusion in critically ill adult patients: a preliminary proof-of-concept in vitro study. AB - BACKGROUND: In critically ill patients, drug incompatibilities frequently occur because of the number of drugs to be administered through a limited number of infusion lines. These are among the main causes of particulate contamination. However, little data is available to quantify particle exposure during simultaneous IV-drug infusion. The objective of this study was to evaluate the particulate matter potentially administered to critically ill patients. METHODS: The particulate matter (between 1 MUm and 30 mm) of infused therapies used in ICUs for patients suffering from either septic shock or acute respiratory distress syndrome was measured in vitro over 6 h using a dynamic image analysis device, so that both overall particulate contamination and particle sizes could be determined. Data is presented according to the recommendations of the European Pharmacopoeia (>= 10 and 25 MUm). RESULTS: For the six experimental procedures (continuous infusion of norepinephrine, midazolam, sufentanil, heparin, 5% glucose, binary parenteral nutrition and discontinuous administrations of omeprazole, piperacillin/tazobactam and fluconazole), the overall number of particles over the 6-h infusion period was 8256 [5013; 15,044]. The collected values for the number of particles >= 10 and 25 MUm were 281 [118; 526] and 19 [7; 96] respectively. Our results showed that discontinuous administrations of drugs led to disturbances in particulate contamination. CONCLUSIONS: This work indicates the amount of particulate matter potentially administered to critically ill adult patients. Particulate contamination appears lower than previous measurements performed during multidrug IV therapies in children. PMID- 30306349 TI - Evaluating parameters for ligand-based modeling with random forest on sparse data sets. AB - Ligand-based predictive modeling is widely used to generate predictive models aiding decision making in e.g. drug discovery projects. With growing data sets and requirements on low modeling time comes the necessity to analyze data sets efficiently to support rapid and robust modeling. In this study we analyzed four data sets and studied the efficiency of machine learning methods on sparse data structures, utilizing Morgan fingerprints of different radii and hash sizes, and compared with molecular signatures descriptor of different height. We specifically evaluated the effect these parameters had on modeling time, predictive performance, and memory requirements using two implementations of random forest; Scikit-learn as well as FEST. We also compared with a support vector machine implementation. Our results showed that unhashed fingerprints yield significantly better accuracy than hashed fingerprints ([Formula: see text]), with no pronounced deterioration in modeling time and memory usage. Furthermore, the fast execution and low memory usage of the FEST algorithm suggest that it is a good alternative for large, high dimensional sparse data. Both support vector machines and random forest performed equally well but results indicate that the support vector machine was better at using the extra information from larger values of the Morgan fingerprint's radius. PMID- 30306348 TI - Monitoring seasonal distribution of an endangered anadromous sturgeon in a large river using environmental DNA. AB - Monitoring dynamic distribution is crucial to conservation management of anadromous sturgeons, but traditional survey methods are less efficient for low density populations in a large river. Natural propagation of Chinese sturgeon has been monitored annually mainly at the spawning ground using netting for eggs and hydroacoustics for broodstock. However, absence of spawning was observed sporadically in recent years, indicating further crises for the declining population. We analyzed eDNA of water samples collected from 24 sites across 1360 km of the migratory route of anadromous Chinese sturgeon in the middle and lower reaches of the Yangtze River. Chinese sturgeon was detected at 9 sites during the spawning season and 14 sites after the spawning season. We found that positive eDNA detection rates remained constant in the middle reaches but dramatically changed in the lower reaches, reflecting seasonal migration pattern of Chinese sturgeon. Invasive sturgeons were detected in the river, indicating their possible escape from aquaculture facilities. This study established a protocol for the use of eDNA to monitor distribution of Chinese sturgeon and could be valuable in making better policies for the conservation of this endangered species. PMID- 30306350 TI - Headache disorder and the risk of dementia: a systematic review and meta-analysis of cohort studies. AB - BACKGROUND: Until now, headache disorders have not been established as a risk factor for dementia. The aim of this study was to determine whether headache was associated with an increased risk of dementia. METHODS: We systematically searched electronic databases, including PubMed, Embase, and Web of Science, for studies investigating the association between headache and dementia. We then conducted a meta-analysis to determine a pooled-effect estimate of the association. RESULTS: We identified 6 studies (covering 291,549 individuals) to investigate the association between headache and the risk of all-cause dementia or Alzheimer's disease (AD). Pooled analyses showed that any headache was associated with a 24% greater risk of all-cause dementia (relative risk [RR] = 1.24; 95% confidential interval [CI]: 1.09-1.41; P = 0.001), and that any headache was not statistically significantly associated with an increased risk of AD (RR = 1.47; 95% CI: 0.82-2.63; P = 0.192). CONCLUSIONS: Our results indicated that any headache was associated with an increased risk of all-cause dementia. However, additional studies are warranted to further confirm and understand the association. PMID- 30306353 TI - Filamentous gram-negative bacteria masquerading as actinomycetes in infectious endophthalmitis: a review of three cases. AB - BACKGROUND: To report microbiological diagnostic dilemma posed by observation of unusual morphology of bacteria in the vitreous sample of a series of three cases of bacterial endophthalmitis. RESULTS: A non-comparative, descriptive case series is described. All three cases presented to the retina-vitreous clinic with a clinical diagnosis of acute endophthalmitis between January and April 2018. Two patients had a past history of cataract surgery, and one had antecedent trauma within 1-2 days of presentation. As per the institutional protocol, patients underwent pars plana vitrectomy with intraocular antibiotics (vancomycin and ceftazidime) and microbiological investigation of the vitreous sample. Microscopic visualization of the stained vitreous fluid revealed the presence of filamentous organisms suggestive of Actinomycetales. However, the culture showed growth of gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella oxytoca, Morganella morganii) which were identified by ViTEK 2 compact system and biochemical tests. Though a combination antibiotic treatment of vancomycin and ceftazidime was given in all cases in view of the short history, the antibiotic susceptibility testing showed multi-drug resistance pattern in two out of three cases leading to unfavorable clinical outcome. CONCLUSIONS: Gram-negative bacilli can develop abnormal morphology due to stress or sub-inhibitory antibiotic exposure, and it is important for ocular microbiologists and pathologists to be aware of this phenomenon to avoid misinterpretation that may lead to inappropriate treatment. PMID- 30306352 TI - Estrogens, Aging, and Working Memory. AB - PURPOSE OF REVIEW: Working memory (WM) is a key process that is integral to many complex cognitive tasks, and it declines significantly with advancing age. This review will survey recent evidence supporting the idea that the functioning of the WM system in women is modulated by circulating estrogens. RECENT FINDINGS: In postmenopausal women, increased estrogen concentrations may be associated with improved WM function, which is evident on WM tasks that have a high cognitive load or significant manipulation demands. Experimental studies in rhesus monkeys and human neuroimaging studies support a prefrontal locus for these effects. Defining the basic neurochemical or cellular mechanisms that underlie the ability of estrogens to regulate WM is a topic of current research in both human and animal investigations. An emerging body of work suggests that frontal executive elements of the WM system are influenced by the circulating estrogen concentrations currently available to the CNS and that the effects are region specific within the frontal cortex. These findings have implications for women's brain health and cognitive aging. PMID- 30306354 TI - Acinetobacter Infections in Neonates. AB - PURPOSE OF REVIEW: MDR-Gram-negative bacteria are a great concern in the neonatal population, with a worldwide rise in the reported incidence and with very limited therapeutic options. Acinetobacter baumannii is responsible for many infections in neonates and outbreaks in neonatal intensive care unit (NICU); also, outbreaks caused by other Acinetobacter species have been reported. The aim of this review is to document the epidemiology of Acinetobacter spp. infections in neonates and risk factors for acquisition of Acinetobacter spp. in the NICU using data from published studies. RECENT FINDINGS: Acinetobacter spp. infections are increasing in neonates in NICU. Outbreak caused by multidrug resistant (MDR) or extensively drug resistant (XDR) A. baumannii but also outbreak caused by susceptible A. soli and A. septicus sp. nov., were reported in neonates. Acinetobacter spp. were responsible for bloodstream infections and respiratory tract infections in neonates. Risk factors for A. baumannii acquisition in neonates were low birthweight, length of NICU stay, umbilical catheterization, central-venous catheterization, assisted ventilation, and prior antibiotic use. This review highlights the importance of surveillance of risk factors for healthcare associated infections in NICU to control MDR and XDR A. baumannii infections in neonates. PMID- 30306351 TI - Gender-Affirming Hormone Use in Transgender Individuals: Impact on Behavioral Health and Cognition. AB - PURPOSE OF REVIEW: With increasing numbers of transgender and gender non-binary individuals presenting for care, knowing how to elucidate the mental health and cognitive outcomes of gender-affirming hormone therapy (GAHT) is necessary. This article reviews the present literature covering GAHT effects on mood, behavioral health, and cognition in these individuals and offers research priorities to address knowledge gaps. RECENT FINDINGS: Although there are some conflicting data, GAHT overwhelmingly seems to have positive psychological effects in both adolescents and adults. Research tends to support that GAHT reduces symptoms of anxiety and depression, lowers perceived and social distress, and improves quality of life and self-esteem in both male-to-female and female-to-male transgender individuals. Clinically, prescribing GAHT can help with gender dysphoria-related mental distress. Thus, timely hormonal intervention represents a crucial tool for improving behavioral wellness in transgender individuals, though effects on cognitive processes fundamental for daily living are unknown. Future research should prioritize better understanding of how GAHT may affect executive functioning. PMID- 30306355 TI - Mendelian randomization does not support serum calcium in prostate cancer risk. AB - PURPOSE: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer. METHODS: A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n <= 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls). RESULTS: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93). CONCLUSIONS: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer. PMID- 30306357 TI - Laboratory biomarkers of delayed cerebral ischemia after subarachnoid hemorrhage: a systematic review. AB - Delayed cerebral ischemia (DCI) is a severe complication of subarachnoid hemorrhage (SAH). Clinical and radiographic features of SAH may be helpful in identification of individuals prone to DCI. The aim of this systematic review was to analyze the present evidence on predictive value of blood and cerebrospinal fluid (CSF) biomarkers of DCI after SAH. We systematically searched in PubMed, Scopus, Web of Science, and Cochrane Library databases for publications before July 15, 2018, reporting correlations between blood/CSF biomarkers and occurrence of DCI and/or vasospasm in SAH patients. Included studies underwent quality assessment according to QUIPS and STARD guidelines. Level of evidence (I-IV) for each of tested biomarkers was assessed according to GRADE guidelines. Of 2181 unique records identified in four databases, 270 original articles and 5 meta analyses were included to this review. Of 257 blood and CSF parameters analyzed in 16.914 SAH patients, there was no biomarker with positive association with DCI/vasospasm showing level I evidence. Twenty-one biomarkers achieved level II evidence and could be confirmed as predictive biomarkers. In this review, six single nucleotide polymorphisms (for EET metabolic pathways, COMT, HMGB1, ACE, PAI-1 promoter, and Hp genes) and 15 non-genetic biomarkers (pNF-H, ADAMTS13, NPY, Copeptin, HMGB1, GFAP, periostin, Tau, BNP, NT pro-BNP, hs-TnT, PA-TEGMA, MPV:PLT, NLR, and PLR) were selected as predictive DCI biomarkers. We propose that a panel analysis of the selected genetic and protein biomarker candidates would be needed for further validation in a large SAH cohort. PMID- 30306358 TI - Foveal amplitudes of multifocal electroretinograms are larger following full field electroretinograms. AB - PURPOSE: The clinical standards for multifocal electroretinograms (mfERG) call for adaption to normal room lighting before the mfERG begins. They specify that any assessments where bright lights are used, should be done after the mfERG to prevent excess stimulation of retinal cells. However, full-field electroretinograms (FFERG) are performed prior to mfERGs in some clinical settings. It is unclear from the literature whether the FFERG has an impact on the mfERG. This study seeks to examine the effect of the FFERG on the mfERG when performed sequentially. METHODS: Thirty young healthy subjects (age 27.1 +/- 3.5 years) were included. Patients reported for two visits and were fully dilated at both visits. At visit one, a FFERG was recorded (VERIS 6.2) using our clinical protocol which includes an ISCEV standard flash sequence; each flash condition was repeated 4-6 times. Following the FFERG, an mfERG was recorded using a 4-min m-sequence at near 100% contrast. At visit two, only the mfERG was recorded. A Burian-Allen contact lens electrode filled with celluvisc was used for all recordings. The two mfERGs were compared for foveal, peripheral, and overall implicit time (IT) and amplitudes (amp). Paired t tests were used to evaluate the data. Coefficient of variation and Bland-Altman analysis was also reported for this patient group. RESULTS: There was a small but statistically significant difference in foveal amplitudes (amp) (p = 0.004) wherein the amp was larger following the FFERG stimuli. The mean difference was 11.1 nV/deg2 (100.9 nV vs 89.8 nV). There was no difference in foveal IT (p = 0.66). There was no difference in overall IT or amp when averaging the entire eye (p = 0.44 amp and p = 0.54 IT) or just evaluating the periphery (p = 0.87 amp and p = 0.051 IT). Bland-Altman analysis found a coefficient of repeatability overall was 1.57 ms (IT) and 10.7 nV/deg2 (amp). CONCLUSIONS: The difference in foveal amplitude is likely the result of a small long-term cone adaptation, but further studies are needed. While it is statistically significant, the small difference is unlikely to be clinically important. These results should help increase clinical confidence in mfERG results when recorded following a FFERG. PMID- 30306359 TI - Cyanoacetohydrazides in Synthesis of Heterocyclic Compounds. AB - Use of cyanoacetohydrazides as precursors in reactions leading to construction of heterocycles is reviewed. In addition to some common heterocyclic compounds, synthesis of other uncommon heterocycles such as thiadiazole, oxadiazole, fused heterocycles, and some seven- and eight-membered heterocycles such as benzodiazepine, oxazepine, and benzoxocine starting with cyanoacetohydrazides and their derivatives is also reported. The main aim of this review is to show the application of cyanoacetohydrazides in heterocyclic synthesis via different types of reaction, including cyclocondensation and cyclization. The results are arranged in terms of the type of heterocycle formed, from five-, six-, seven-, to eight-membered and fused rings. This review aims to cover literature up to 2018, showing the distribution of publications involving use of cyanoacetohydrazides for preparation of heterocycles. PMID- 30306356 TI - Electron microscopic study of Golgi-impregnated and gold-toned neurons and fibers in the claustrum of the cat. AB - The claustrum is a subcortical nucleus found in the telencephalon of all placental mammals. It is a symmetrical, thin and irregular sheet of grey matter which lies between the inner surface of the insular cortex and the outer surface of the putamen. The claustrum has extensive connections with the visual, auditory, somatosensory and motor regions of the cortex, as well as with subcortical and allocortical regions. The aim of this study was to provide a detailed description of the morphology of different types of Golgi-impregnated and gold-toned neurons and fibers in the dorsal claustrum of the cat employing the combined Golgi-electron microscope Fairen method. We were able to distinguish two major types of neurons: those with dendritic spines (spiny) and those without dendritic spines (aspiny). In both groups we observed large (21-40 um in diameter), medium-sized (16-21 um in diameter) and small cells (10-16 um in diameter), describing their ultrastructural organization and characteristic features, including the presence of terminal boutons. These ultrastructural findings allow us to conclude that large and medium-sized spiny claustral neurons are indeed efferent neurons, projecting to the cortex, while the small spiny and the different types of aspiny neurons are most likely inhibitory local circuit interneurons. The findings in the present study will hopefully contribute to a better understanding of the role of the claustrum. PMID- 30306361 TI - Endogenous endophthalmitis: a 9-year retrospective study at a tertiary referral hospital in Malaysia. AB - BACKGROUND: The objective of this study was to determine the clinical presentation, systemic risk factors, source of infective microorganism, treatment outcomes, and prognostic indicators of endogenous endophthalmitis at a main tertiary referral hospital for uveitis in Malaysia. A retrospective review of medical records of 120 patients (143 eyes) with endogenous endophthalmitis over a period of 9 years between January 2007 and December 2015 was undertaken. RESULTS: Identifiable systemic risk factors were present in 79.2%, with the majority related to diabetes mellitus (60.0%). The most common source of bacteremia was urinary tract infection (17.5%). A positive culture from ocular fluid or other body fluids was obtained in 82 patients (68.9%), and the blood was the highest source among all culture-positive results (42.0%). Gram-negative organisms accounted 42 cases (50.6%) of which Klebsiella pneumonia was the most common organism isolated (32.5%). Sixty-nine eyes (48.6%) were managed medically, and 73 eyes (51.4%) underwent vitrectomy. Final visual acuity of counting fingers (CF) or better was achieved in 100 eyes (73.0%). Presenting visual acuity of CF or better was significantly associated with a better final acuity of CF or better (p = 0.001). CONCLUSIONS: The visual prognosis of endogenous endophthalmitis is often poor, leading to blindness. As expected, gram-negative organisms specifically Klebsiella pneumonia were the most common organisms isolated. Urinary tract infection was the main source of infection. Poor presenting visual acuity was significantly associated with grave visual outcomes. A high index of suspicion, early diagnosis, and treatment are crucial to salvage useful vision. PMID- 30306362 TI - Cross-Dehydrogenative C-H/S-H Coupling Reactions. AB - Carbon-sulfur bond formation represents a key step in the synthesis of thioethers, which are a common structural motif in many pharmaceutically compounds. The direct cross-dehydrogenative coupling of C-H/S-H bonds has become a powerful tool for C-S bond formation. As these coupling reactions avoid pre functionalization of the starting materials, they are more atom-economical, practical, and environmentally friendly than traditional cross-coupling reactions. In this review, we will highlight the most important developments in this novel and interesting research arena with the emphasis on the mechanistic aspects of the reactions. The review is divided into three major sections: (1) C(sp3)-H/S-H bonds coupling reactions; (2) C(sp2)-H/S-H bonds coupling reactions; and (3) C(sp)-H/S-H bonds coupling reactions. PMID- 30306360 TI - Evidence-Based Management of Diabetes in Older Adults. AB - The number of older adults with diabetes is rapidly increasing worldwide. A variety of factors contribute to the age-related increase in the incidence of diabetes. The lack of empiric evidence in the field has limited the management guidelines to mostly expert opinion. Given uncertainty over the rate at which to lower blood glucose levels and the optimal method of doing so, the goals of diabetes control in older people must be individualized. If the patient requires insulin therapy, the newer insulins, with their improved pharmacodynamic consistency and reduced risk of hypoglycemia, should be preferred. Several oral agents are preferable for people with sufficient endogenous insulin because they do not cause hypoglycemia when used as monotherapy. Some of these oral agents have been found to have cardioprotective effects. Older people with diabetes also require management of the other risk factors for cardiovascular disease, with antihypertensive drugs, cholesterol-lowering agents and low-dose aspirin. However, the precise targets for blood pressure control and low-density lipoprotein (LDL) cholesterol levels continue to evolve as more data become available. Diabetes care in older adults should focus on enhancing the individual's quality of life rather than trying to normalize blood glucose levels or reach predetermined blood pressure and LDL cholesterol targets. PMID- 30306363 TI - Correction to: Allogeneic Hematopoietic Cell Transplantation in Patients with Primary Immunodeficiencies in Korea: Eleven-Year Experience in a Single Center. AB - The original version of this article unfortunately contained a mistake in the 7th author's given name. The correct version is presented above. PMID- 30306364 TI - Estimation of sodium and chloride storage in critically ill patients: a balance study. AB - BACKGROUND: Nonosmotic sodium storage has been reported in animals, healthy individuals and patients with hypertension, hyperaldosteronism and end-stage kidney disease. Sodium storage has not been studied in ICU patients, who frequently receive large amounts of sodium chloride-containing fluids. The objective of our study was to estimate sodium that cannot be accounted for by balance studies in critically ill patients. Chloride was also studied. We used multiple scenarios and assumptions for estimating sodium and chloride balances. METHODS: We retrospectively analyzed patients admitted to the ICU after cardiothoracic surgery with complete fluid, sodium and chloride balance data for the first 4 days of ICU treatment. Balances were obtained from meticulously recorded data on intake and output. Missing extracellular osmotically active sodium (MES) was calculated by subtracting the expected change in plasma sodium from the observed change in plasma sodium derived from balance data. The same method was used to calculate missing chloride (MEC). To address considerable uncertainties on the estimated extracellular volume (ECV) and perspiration rate, various scenarios were used in which the size of the ECV and perspiration were varied. RESULTS: A total of 38 patients with 152 consecutive ICU days were analyzed. In our default scenario, we could not account for 296 +/- 35 mmol of MES in the first four ICU days. The range of observed MES in the five scenarios varied from 111 +/- 27 to 566 +/- 41 mmol (P < 0.001). A cumulative value of 243 +/- 46 mmol was calculated for MEC in the default scenario. The range of cumulative MEC was between 62 +/- 27 and 471 +/- 56 mmol (P = 0.001 and P = 0.003). MES minus MEC varied from 1 +/- 51 to 123 +/- 33 mmol in the five scenarios. CONCLUSIONS: Our study suggests considerable disappearance of osmotically active sodium in critically ill patients and is the first to also suggest rather similar disappearance of chloride from the extracellular space. Various scenarios for insensible water loss and estimated size for the ECV resulted in considerable MES and MEC, although these estimates showed a large variation. The mechanisms and the tissue compartments responsible for this phenomenon require further investigation. PMID- 30306366 TI - Diacetyl control during brewery fermentation via adaptive laboratory engineering of the lager yeast Saccharomyces pastorianus. AB - Diacetyl contributes to the flavor profile of many fermented products. Its typical buttery flavor is considered as an off flavor in lager-style beers, and its removal has a major impact on time and energy expenditure in breweries. Here, we investigated the possibility of lowering beer diacetyl levels through evolutionary engineering of lager yeast for altered synthesis of alpha acetolactate, the precursor of diacetyl. Cells were exposed repeatedly to a sub lethal level of chlorsulfuron, which inhibits the acetohydroxy acid synthase responsible for alpha-acetolactate production. Initial screening of 7 adapted isolates showed a lower level of diacetyl during wort fermentation and no apparent negative influence on fermentation rate or alcohol yield. Pilot-scale fermentation was carried out with one isolate and results confirmed the positive effect of chlorsulfuron adaptation. Diacetyl levels were over 60% lower at the end of primary fermentation relative to the non-adapted lager yeast and no significant change in fermentation performance or volatile flavor profile was observed due to the adaptation. Whole-genome sequencing revealed a non-synonymous SNP in the ILV2 gene of the adapted isolate. This mutation is known to confer general tolerance to sulfonylurea compounds, and is the most likely cause of the improved tolerance. Adaptive laboratory evolution appears to be a natural, simple and cost-effective strategy for diacetyl control in brewing. PMID- 30306367 TI - Farewell from the Hernia Editorial Team. PMID- 30306368 TI - Smaller backward crosstalk effects for free choice tasks are not the result of immediate conflict adaptation. AB - In dual-task situations, mutual interference phenomena are often observed. One particularly interesting example of such phenomena is that even Task 1 performance is improved if Task 2 requires a compatible (e.g., both responses are given on the left side) instead of an incompatible response (e.g., one response is given on the right side, and the other on the left side). This is called the compatibility-based backward crosstalk effect (BCE). In a previous paper, we observed support for a critical role of stimulus-response (S-R) links in causing this effect: The BCE was smaller when one of the two tasks was a free choice task. However, an alternative explanation for this observation is that free choice tasks lead to immediate conflict adaptation, thereby reducing the interference from the other task. In the present two experiments, we tested this explanation by varying the amount of conflict assumed to be induced by a free choice task either sequentially (Exp. 1) or block-wise (Exp. 2). While we replicated a sequential modulation of the BCE with two forced choice tasks, we observed (1) no reduction of the BCE induced by (compatible) free choice trials nor (2) an effect of block-wise manipulations of the frequency of free choice trials on the size of the BCE. Thus, while the BCE is sensitive to sequential modulations induced by the (in)compatibility of two forced choice responses, which might point to conflict adaptation, the reduced BCE in dual-task situations involving a free choice task is likely due to its weaker S-R links. PMID- 30306369 TI - ASO Author Reflections: Parathyroid Carcinoma-Setting the Stage for Prognosis. PMID- 30306370 TI - ASO Author Reflections: Cytoreduction for Extrahepatic Metastatic Neuroendocrine Tumors. PMID- 30306371 TI - ASO Author Reflections: Prognostic Nutritional Index-Based Risk Stratification for Lung Cancer. PMID- 30306365 TI - Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics. AB - The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. In this review, we present the most recent advances in developing innovative NP-based delivery systems that efficiently deliver CRISPR/Cas9 constructs and maximize their effectiveness. PMID- 30306372 TI - ASO Author Reflections: Simplified Nomogram Predictive of Survival after R0 Resection for Gastric Cancer. PMID- 30306374 TI - ASO Author Reflections: Venous Thromboembolism After Esophagectomy-The Importance of an Optimal Strategy for Thromboprophylaxis. PMID- 30306373 TI - ASO Author Reflections: Tumor Markers in Gastric Cancer. PMID- 30306376 TI - ASO Author Reflections: Breast Cancer Local Recurrence Versus New Primary Clinical Predictors and Prognostic Implications. PMID- 30306375 TI - Medullary Thyroid Carcinoma: Do Ultrasonography and F-DOPA-PET-CT Influence the Initial Surgical Strategy? AB - BACKGROUND: At the time of diagnosis, one-third of medullary thyroid carcinoma (MTC) patients show lymph node (LN) or distant metastasis. A metastasized MTC requires different surgical strategies. OBJECTIVE: This study aimed to determine the value of ultrasound and [18F]fluoro-dihydroxyphenylalanine positron emission tomography with computed tomography (F-DOPA-PET-CT) in localizing MTC, as well as LN and distant metastasis. METHODS: The study included 50 patients (24 males/26 females) with preoperative ultrasound, F-DOPA-PET-CT, and histologically proven MTC. Imaging results were correlated with both preoperative basal calcitonin (bCt) levels and final histology. RESULTS: Tumors were classified as pT1a:17 (diameter, mean +/- standard deviation: 5.8 +/- 3.0 mm), pT1b:15 (15.0 +/- 3.2 mm), pT2:9 (27.3 +/- 7.0 mm), and pT3:9 (38.3 +/- 24.2 mm). The median bCt level was 202 pg/mL (lower/upper quartile: 82/1074 pg/mL). Ultrasound was positive for tumor in 45/50 (92%) patients (20.0 +/- 16.0 mm) and negative in 5 patients (3.2 +/- 2.2 mm). Overall, 43/50 (86%) patients had positive F-DOPA local scans (20.0 +/- 16.4 mm), while 7 (14%) patients were negative (7.7 +/- 8.1 mm). Lastly, 21/50 (42%) patients had LN metastasis; 8/21 (38%) patients had positive LNs suspected with ultrasound, and 12/21 (57%) patients had positive LNs suspected with F-DOPA. Tumor and LN sensitivity of ultrasound was 92% and 43%, respectively, and 86% and 57% of F-DOPA-PET-CT, respectively. In 3/50 (6%) patients and 3/50 (6%) patients, mediastinal LN metastasis and distant metastasis, respectively, were diagnosed only by F-DOPA-PET-CT. CONCLUSION: Ultrasound and F-DOPA-PET-CT are sensitive for the localization of MTC but not for the presence and location of LN metastasis (limitations: size/number). Only F DOPA ensures the diagnosis of distant metastasis and influences the extent of LN surgery. Surgical strategy cannot be predicted based on neither ultrasound nor F DOPA-PET-CT. PMID- 30306377 TI - ASO Author Reflections: Malnutrition After Gastrectomy and Its Impact on Survival. PMID- 30306378 TI - mTOR and ERK regulate VKORC1 expression in both hepatoma cells and hepatocytes which influence blood coagulation. AB - Deficiency of gamma-glutamyl carboxylation of coagulation factors, as evidenced by the elevated level of Des-gamma-carboxyl prothrombin (DCP), is a common feature in hepatocellular carcinoma patients. Additionally, treatment of cancer patients with mTOR inhibitors significantly increases hemorrhagic events. However, the underlying mechanisms remain unknown. In the present study, Vitamin K epoxide reductase complex subunit 1 (VKORC1) was found to be significantly down regulated in clinical hepatoma tissues and most tested hepatoma cell lines. In vitro investigations showed that VKORC1 expression was promoted by p-mTOR at the translational level and repressed by p-ERK at the transcriptional level. By exploring Hras12V transgenic mice, a hepatic tumor model, VKROC1 was significantly down-regulated in hepatic tumors and showed prolonged activated partial prothrombin time (APTT). In vivo investigations further showed that VKORC1 expression was promoted by p-mTOR and repressed by p-ERK in both hepatoma and hepatocytes. Consistently, APTT and prothrombin time were significantly prolonged under the mTOR inhibitor treatment and significantly shortened under the ERK inhibitor treatment. Conclusively, these findings indicate that mTOR and ERK play crucial roles in controlling VKORC1 expression in both hepatoma and hepatocytes, which provides a valuable molecular basis for preventing hemorrhage in clinical therapies. PMID- 30306379 TI - Schools Matter? Contextual Factors That May Affect Bias in Clinical Decision making. PMID- 30306380 TI - Correction to: Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature. AB - This paper was inadvertently published with open access; the authors have requested the copyright revert to the society. It has been re-published with appropriate licensing. PMID- 30306381 TI - Applications of Wireless Power Transfer in Medicine: State-of-the-Art Reviews. AB - Magnetic resonance within the field of wireless power transfer has seen an increase in popularity over the past decades. This rise can be attributed to the technological advances of electronics and the increased efficiency of popular battery technologies. The same principles of electromagnetic theory can be applied to the medical field. Several medical devices intended for use inside the body use batteries and electrical circuits that could be powered wirelessly. Other medical devices limit the mobility or make patients uncomfortable while in use. The fundamental theory of electromagnetics can improve the field by solving some of these problems. This survey paper summarizes the recent uses and discoveries of wireless power in the medical field. A comprehensive search for papers was conducted using engineering search engines and included papers from related conferences. During the initial search, 247 papers were found then non relevant papers were eliminated to leave only suitable material. Seventeen relevant journal papers and/or conference papers were found, then separated into defined categories: Implants, Pumps, Ultrasound Imaging, and Gastrointestinal (GI) Endoscopy. The approach and methods for each paper were analyzed and compared yielding a comprehensive review of these state of the art technologies. PMID- 30306382 TI - Bile acids and their effects on diabetes. AB - Diabetes is a widespread, rapidly increasing metabolic disease that is driven by hyperglycemia. Early glycemic control is of primary importance to avoid vascular complications including development of retinal disorders leading to blindness, end-stage renal disease, and accelerated atherosclerosis with a higher risk of myocardial infarction, stroke and limb amputations. Even after hyperglycemia has been brought under control, "metabolic memory," a cluster of irreversible metabolic changes that allow diabetes to progress, may persist depending on the duration of hyperglycemia. Manipulation of bile acid (BA) receptors and the BA pool have been shown to be useful in establishing glycemic control in diabetes due to their ability to regulate energy metabolism by binding and activating nuclear transcription factors such as farnesoid X receptor (FXR) in liver and intestine as well as the G-protein coupled receptor, TGR5, in enteroendocrine cells and pancreatic beta-cells. The downstream targets of BA activated FXR, FGF15/21, are also important for glucose/insulin homeostasis. In this review we will discuss the effect of BAs on glucose and lipid metabolism and explore recent research on establishing glycemic control in diabetes through the manipulation of BAs and their receptors in the liver, intestine and pancreas, alteration of the enterohepatic circulation, bariatric surgery and alignment of circadian rhythms. PMID- 30306383 TI - Aging results in iron accumulations in the non-human primate choroid of the eye without an associated increase in zinc, copper or sulphur. AB - We present further analyses of a previous experiment published in 2016 where the distribution, concentration and correlation of iron, zinc, copper and sulphur in the choroid of the eye in young and aged old world primates (Macaca fascicularis) was studied with synchrotron X-ray fluorescence with a 2 MUm resolution. The results indicate that iron accumulates in hotspots in the choroid with age with fluorescence intensity ranging from 2- to 7-fold (1002-3752 ppm) the mean level in the choroidal stroma (500 ppm) and maximum iron levels in blood vessel lumina. Iron hotspots with iron ppm > 1000 preferentially contained Fe3+ as demonstrated by Perls staining. There was a strong spatial co-localisation and correlation between copper and zinc (Pearson's correlation coefficient 0.97), and both elements with sulphur in the choroid of young animals. However, these are reduced in the choroid of aged animals and lost in the iron hotspots. The lack of proportional co-distribution suggests that iron accumulation does not induce a concomitant increase in zinc, copper or zinc-, copper-metalloproteins. It is possible that the iron hotspots are ferritin or hemosiderin molecules loaded with Fe3+ in stable, insoluble, non-toxic complexes without a significant oxidative environment. PMID- 30306384 TI - A numerical simulation of neural fields on curved geometries. AB - Despite the highly convoluted nature of the human brain, neural field models typically treat the cortex as a planar two-dimensional sheet of ne;urons. Here, we present an approach for solving neural field equations on surfaces more akin to the cortical geometries typically obtained from neuroimaging data. Our approach involves solving the integral form of the partial integro-differential equation directly using collocation techniques alongside efficient numerical procedures for determining geodesic distances between neural units. To illustrate our methods, we study localised activity patterns in a two-dimensional neural field equation posed on a periodic square domain, the curved surface of a torus, and the cortical surface of a rat brain, the latter of which is constructed using neuroimaging data. Our results are twofold: Firstly, we find that collocation techniques are able to replicate solutions obtained using more standard Fourier based methods on a flat, periodic domain, independent of the underlying mesh. This result is particularly significant given the highly irregular nature of the type of meshes derived from modern neuroimaging data. And secondly, by deploying efficient numerical schemes to compute geodesics, our approach is not only capable of modelling macroscopic pattern formation on realistic cortical geometries, but can also be extended to include cortical architectures of more physiological relevance. Importantly, such an approach provides a means by which to investigate the influence of cortical geometry upon the nucleation and propagation of spatially localised neural activity and beyond. It thus promises to provide model-based insights into disorders like epilepsy, or spreading depression, as well as healthy cognitive processes like working memory or attention. PMID- 30306385 TI - Longitudinal determinants of 12-month changes on bone health in adolescent male athletes. AB - : We identified the determinants of 12-month changes of areal bone mineral density (aBMD), hip geometry and trabecular bone score (TBS) in adolescent male athletes. Changes in region-specific lean mass and the type of sport are the most consistent determinants in this population. PURPOSE: This study aims to identify the determinants of 12-month changes of areal bone mineral density (aBMD), hip geometry and trabecular bone score (TBS) in adolescent male athletes. METHODS: The sample was 104 adolescent males aged 12-14 years at baseline that were followed over 12 months: 39 swimmers, 37 footballers (or soccer players) and 28 cyclists. Dual-energy X-ray absorptiometry measured aBMD at the whole body, lumbar spine and dual hip. Hip geometry estimates at the femoral neck were measured using hip structural analysis. Lumbar spine texture was measured by TBS. RESULTS: Multivariate regression models significantly explained 38-60% of the variance in the aBMD changes, 36-62% in the hip geometry estimates changes and 45% in the TBS changes. Deltaregion-specific lean mass was the most consistent predictor of changes in aBMD outcomes (beta = 0.591 to 0.696), followed by cycling participation (beta = - 0.233 to - 0.262), swimming participation (beta = - 0.315 to - 0.336) and DeltaMVPA (beta = 0.165). Cycling participation was the most consistent predictor of changes in hip geometry estimates (beta = - 0.174 to - 0.268), followed by Deltaregion-specific lean mass (beta = 0.587) and Deltacardiorespiratory fitness (beta = 0.253). Finally, cycling and swimming participation (beta = - 0.347 to - 0.453), Deltaregion-specific lean mass (beta = 0.848) and Deltastature (beta = 0.720) were predictors of change in TBS. CONCLUSIONS: Changes in region-specific lean mass and the type of sport are the most consistent determinants of 12-month changes in aBMD, hip geometry estimates and TBS in adolescent male athletes. TRIAL REGISTRATION: ISRCTN17982776. PMID- 30306387 TI - Traditional Plants Used by Remaining Healers from the Region of Grande Dourados, Mato Grosso do Sul, Brazil. AB - Although the traditional use of medicinal plants is a very widespread practice in Brazil, there are still few studies aimed at native prescribers, known as healers. The aim of this work was to catalog the medicinal species prescribed by remaining healers of the Grande Dourados region, Mato Grosso do Sul, Brazil. Semi structured interviews were conducted with support of a standardized questionnaire for remaining healers selected using the "snowball" technique. The medicinal species selected were collected, identified, and classified according to the British National Formulary. Remaining healers were identified in seven municipalities in the region of Grande Dourados. Family, divine revelation, and participation of the Catholic Church were the most important sources of knowledge. Seventy-one medicinal species, mainly herbaceous belonging to Asteraceae, Lamiaceae, Amaranthaceae, and Verbenaceae families, were the most prescribed. Most species are used in the treatment of digestive and cardiovascular diseases, in addition to immune and respiratory diseases. Healers from the region of Grande Dourados maintain considerable ethno-knowledge about the medicinal properties of different medicinal species. Sharing this information values their culture and preserves the knowledge for future generations. PMID- 30306386 TI - TERT Immunohistochemistry Is a Poor Predictor of TERT Promoter Mutations and Gene Expression in Follicular Thyroid Carcinoma. PMID- 30306388 TI - Medical Students' (Dis)comfort with Assessing Religious and Spiritual Needs in a Standardized Patient Encounter. AB - Most patients want to discuss their religious and spiritual concerns, yet few physicians discuss it. First-year medical students (n = 92) interviewed a standardized patient experiencing spiritual distress. There was a significant difference among the students' reasoning for their (dis)comfort and (mis)matching religion with their patient (X2 = 21.0831, p < .05). Most students whose religion matched their patient felt comfortable because of having this in common with their patient. Most students whose religion did not match that of their patient ascribed their comfort to their religious belief to be open and accepting. Discomfort may stem from more individual factors than a (mis)match in religion, as most of the students reported feeling comfortable. PMID- 30306390 TI - Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature. AB - Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominantly inherited cancer syndrome associated with a high risk for diffuse gastric and lobular breast cancer, caused by heterozygous CDH1 germline mutations. Of note, also cleft lip/palate (CLP) has been described in few HDGC families. Here we report on an extensive pedigree presenting with HDGC, CLP and a CDH1 splice site mutation (c.687 + 1G > A) and review the literature for families with CDH1 mutations, HDGC and CLP. Transcript analysis showed that the c.687 + 1G > A mutation leads to loss of the last 42 bp of exon 5 and is consequently predicted to cause loss of 14 amino acids in the first extracellular cadherin repeat (EC) domain. Five mutation carriers developed diffuse gastric cancer and four individuals presented with CLP. Wild type CDH1 expression levels did not differ between CDH1 mutation carriers with CLP compared to those without CLP. Beside this extensive pedigree, we outline another previously unreported HDGC/CLP family with a CDH1 (c.1711 + 1G > C) germline mutation in this study. Review of the literature revealed a significant enrichment of CDH1 mutations within the EC domains in CLP/HDGC families (Fisher's exact test, p = 0.007) in comparison to CDH1 mutations associated with HDGC only. Report of further CLP/HDGC associated mutations is necessary to confirm this observation. This study highlights that CLP represents an important phenotypic feature of CDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes in CDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies. PMID- 30306391 TI - Remapping versus short-term memory in visual stability across saccades. AB - Saccadic eye movements cause displacements of the image of the visual world projected on the retina. Despite the ubiquitous nature of saccades, subjective experience of the world is continuous and stable. In five experiments, we addressed the mechanisms that may support visual stability: matching of pre- and postsaccadic locations of the target by an internal copy of the saccade, or retention of the visual attributes of the target in short-term memory across the saccade. Healthy human adults were instructed to make a saccade to a peripheral Gabor patch. While the saccade was in midflight, the patch could change location, orientation, or both. The change occurred either immediately or following a 250 ms blank during which no visual stimuli were available. In separate experiments, subjects had to report either whether the patch stepped to the left or right or whether the orientation rotated clockwise or counterclockwise. Consistent with previous findings, we found that transsaccadic displacement discrimination was enhanced by the addition of the blank. However, contrary to previous findings reported in the literature, the feature change did not improve performance. Transsaccadic orientation change discrimination did not depend on either an irrelevant temporal blank or a simultaneous irrelevant target displacement. Taken together, these findings suggest that orientation is not a relevant visual feature for transsaccadic correspondence. PMID- 30306392 TI - Quasi-SMILES: quantitative structure-activity relationships to predict anticancer activity. AB - Reliable prediction of anticancer potential of different substances for different cells using unambiguous algorithms is attractive alternative of experimental investigation of impacts of various anticancer agents to various cells. Quasi SMILES is a sequence of symbols, which represents all available eclectic data, i.e. not only molecular structure, but also different conditions, which can have influence on examined endpoint (e.g. kinds of cells: human breast; human colon; human liver; human lung). In this work, quasi-SMILES have been used to establish predictive models for anticancer activity isoquinoline quinones related to different cells. Descriptor calculated with optimal correlation weights of different fragments of quasi-SMILES defined by the Monte Carlo technique is used to predict pIC50 as a mathematical function of molecular structure and kinds of cells. The using of the so-called index of ideality of correlation for optimization by the Monte Carlo method improves predictive potential of the model. The statistical quality of the models based on correlation weights of fragments of quasi-SMILES is good. The range of correlation coefficient between experimental and calculated pIC50 for external validation set is 0.76-0.89. The statistical stable promoters for increase and for decrease in pIC50 are established. These models can be used to improve quality of pharmaceutical agents. These computational experiments can be reproduced with available on the Internet software ( http://www.insilico.eu/coral ). PMID- 30306389 TI - Beyond DNA: the Role of Epigenetics in the Premalignant Progression of Breast Cancer. AB - Ductal Carcinoma in Situ (DCIS) is an early breast cancer lesion that is considered a nonobligate precursor to development of invasive ductal carcinoma (IDC). Although only a small subset of DCIS lesions are predicted to progress into a breast cancer, distinguishing innocuous from minacious DCIS lesions remains a clinical challenge. Thus, patients diagnosed with DCIS will undergo surgery with the potential for radiation and hormone therapy. This has led to a current state of overdiagnosis and overtreatment. Interrogating the transcriptome alone has yet to define clear functional determinants of progression from DCIS to IDC. Epigenetic changes, critical for imprinting and tissue specific development, in the incorrect context can lead to global signaling rewiring driving pathological phenotypes. Epigenetic signaling pathways, and the molecular players that interpret and sustain their signals, are critical to understanding the underlying pathology of breast cancer progression. The types of epigenetic changes, as well as the molecular players, are expanding. In addition to DNA methylation, histone modifications, and chromatin remodeling, we must also consider enhancers as well as the growing field of noncoding RNAs. Herein we will review the epigenetic interactions that have been uncovered in early stage lesions that impact breast cancer progression, and how these players may be utilized as biomarkers to mitigate overdiagnosis and overtreatment. PMID- 30306393 TI - Synthesis and antiphytoviral activity of alpha-aminophosphonates containing 3, 5 diphenyl-2-isoxazoline as potential papaya ringspot virus inhibitors. AB - alpha-Aminophosphonates compounds containing 3,5-diphenyl-2-isoxazoline were synthesized and evaluated for their bioactivity. Seventeen of them showed good bioactivity (protection effect > 50%) in vivo against papaya ringspot virus, while two of them (V29 and V45) exhibited excellent antiviral activity (both 77.8%). In the latter case, the antiviral activity was close to that of antiphytovirucides ningnanmycin and dufulin (both 83.3%) at 500 mg/L. The preliminary structure-activity relationships indicated that the bioactivity was strongly influenced by the substituents. PMID- 30306394 TI - Behaviour Change Strategies Endorsed by Gamblers Subtyped by Psychological Distress, Risky Alcohol Use, and Impulsivity. AB - Problem gambling is often accompanied by co-morbid psychiatric disorders and maladaptive personality traits. Subtyping gamblers based on these pervasive comorbidities has been attempted so as to aid understanding of the aetiology of problem gambling and inform treatment options. However, there has been less focus on subtyping gamblers with (past or current) or without a history of problem gambling, or on providing more specific treatment or self-help recommendations. The current study sought to subtype current-, past-, and non-problem gamblers using three common comorbidities; psychological distress, risky alcohol use, and impulsivity. Participants' endorsement of helpful behaviour change strategies was also examined by subtype membership. A total of 385 participants were recruited who had a current gambling problem (n = 128; 33%), a past gambling problem (n = 131, 34%) or never had a gambling problem (n = 126, 33%). Hierarchical cluster analysis identified distinct subtypes of current (i.e., low comorbidity, high psychological distress, risky alcohol use and high comorbidity), past (i.e., low comorbidity, high psychological distress and high comorbidity) and non-problem gamblers (i.e., low comorbidity, high psychological distress, risky alcohol use and moderate impulsivity). The most helpful change strategies for current and past gamblers were similar across subtypes (i.e., accept that gambling needs to change, remind yourself of the negative consequences). Non-problem gamblers reported the most helpful strategy as setting financial limits. This study indicated that treatment of psychological distress, risky alcohol use or impulsivity may be important for all gamblers regardless of their level of risk. PMID- 30306395 TI - The Comorbidity Burden of Hidradenitis Suppurativa in the United States: A Claims Data Analysis. AB - INTRODUCTION: Prior studies have reported that hidradenitis suppurativa (HS) is accompanied by a myriad of physical and mental conditions. However, given the small sample sizes and the limited number of pre-selected comorbidities, these studies do not provide a complete picture of the comorbidity burden of HS in the USA. Moreover, the relationship between HS severity and comorbidity burden has yet to be characterized. Using a large US claims database, we estimated the comorbidity burden associated with HS, stratified by disease severity. METHODS: A retrospective matched cohort design was used. Patients with HS were classified into two severity cohorts (milder and more severe) using an empirical algorithm based on treatments received. The comorbidity burden was compared between each HS cohort and their matched HS-free cohort, and between patients with milder vs. those with more severe forms of HS. RESULTS: Several physical and mental comorbidities were found to be more prevalent in both cohorts of patients with milder and more severe forms of HS than in their matched HS-free cohorts. The comorbidity burden also increased greatly as the disease progressed to more severe forms. CONCLUSIONS: The results of this study highlight the complexity of the comorbidity burden of HS patients and the need for a multidisciplinary approach to optimize the management of HS and its numerous associated comorbidities. FUNDING: AbbVie, Inc. PMID- 30306397 TI - Antimicrobial Activity of Essential Oils Against the Fungal Pathogens Ascosphaera apis and Pseudogymnoascus destructans. AB - Fungal pathogens are a growing worldwide concern. Declines in a number of economically and agriculturally important plant and animal species pose a significant threat to both biodiversity and food security. Although many effective antifungal agents have been identified, their toxicity often precludes their use with food products or sensitive animal species. This has prompted the exploration of natural products as effective treatment compounds. In the present study, several essential oils were tested for their capacity to limit the growth of the fungal pathogens Ascosphaera apis and Pseudogymnoascus destructans, the causative agents of chalkbrood disease among honey bee larvae and white-nose syndrome among bats, respectively. Essential oils of cinnamon bark, citronella, lemongrass, and orange were exposed to A. apis in contact-dependent oil-agar suspensions as well as in contact-independent shared airspaces. Essential oils of cinnamon bark, citronella, and lemongrass were exposed to P. destructans in contact-dependent oil-agar suspensions. All compounds were found to significantly inhibit mycelial growth at low concentrations, suggesting the potential for these natural products to be used for controlling these and other select fungal pathogens. PMID- 30306396 TI - CSF Abeta1-42, but not p-Tau181, Predicted Progression from Amnestic MCI to Alzheimer's Disease Dementia. AB - The purpose of the study was to determine whether Abeta1-42 and p-Tau181 cerebral spinal fluid (CSF) levels can predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease dementia (ADD) in a 3-year follow-up study. All participants were evaluated blindly by a behavioral neurologist and a neuropsychologist, and classified according to the Petersen criteria for aMCI and according to the Clinical Dementia Rating (CDR) scale. Individuals were also submitted to lumbar puncture at baseline. Levels of Abeta1-42 and p-Tau181 were measured by immunoenzymatic assay. Values were adjusted for age and sex. Thirty one of 33 (93.9%) participants completed follow-up. Approximately 39% of aMCI individuals progressed to ADD. The relative risk of developing ADD in those with Abeta1-42 CSF levels lower than 618.5 pg/mL was 17.4 times higher than in those whose levels were higher than 618.5 pg/mL (P = 0.003). p-Tau181 alone did not predict progression to ADD (P = 0.101). The relative risk in those with a p Tau181/Abeta1-42 ratio higher than 0.135 was 5.7 times greater (P < 0.001). Abeta1-42 and p-Tau181 explained 40.1% of the verbal memory test subscore of the Consortium to Establish a Registry for Alzheimer's Disease (DeltaCERADs) variance (P = 0.008). Abeta1-42 strongly predicted progression from aMCI to ADD. p-Tau181 alone, or its relation to Abeta1-42, was inferior than Abeta1-42 alone as a predictor of progression to ADD. PMID- 30306398 TI - Systematic literature review on the delays in the diagnosis and misdiagnosis of cluster headache. AB - INTRODUCTION: Patients with cluster headache (CH), the most common trigeminal autonomic cephalalgia, often face delayed diagnosis, misdiagnosis and mismanagement. OBJECTIVES: To identify, appraise and synthesise clinical studies on the delays in diagnosis and misdiagnosis of CH in order to determine its causes and help the management of this condition. METHODS: The systematic review was prepared, conducted and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis. It was registered with International Prospective Register of Systematic Reviews. A systematic search of different electronic databases (Medline, EMBASE, PsycINFO, PubMed, CINAHL, BNI, HMIC, AMED, HBE and Cochrane Library) was carried out in May 2017. Reference lists of relevant articles were hand searched. RESULTS: The search identified 201 unique studies. Fifteen studies met the inclusion criteria of which 13 case series studies and two survey studies. Nine studies assessed the delays in diagnosis and misdiagnosis of CH, five studies the delays in diagnosis and one study the misdiagnosis of CH. The studies included 4661 patients. Delays in diagnosis, misdiagnosis and mismanagement have been reported in many European countries, Japan and in the USA with well-developed health services. The patients with CH often visited many different clinicians, surgeons and dentists and received multiple diagnosis prior to being correctly diagnosed. CONCLUSION: This systematic review shows that the delays in the diagnosis of CH are a widespread problem, the time to diagnosis still vary from country to country and both patients and physicians are responsible for the delays in diagnosis. PMID- 30306399 TI - Rituals, Repetitiveness and Cognitive Load : A Competitive Test of Ritual Benefits for Stress. AB - A central hypothesis to account for the ubiquity of rituals across cultures is their supposed anxiolytic effects: rituals being maintained because they reduce existential anxiety and uncertainty. We aimed to test the anxiolytic effects of rituals by investigating two possible underlying mechanisms for it: cognitive load and repetitive movement. In our pre-registered experiment (osf.io/rsu9x), 180 undergraduates took part in either a stress or a control condition and were subsequently assigned to either control, cognitive load, undirected movement, a combination of undirected movement and cognitive load, or a ritualistic intervention. Using both repeated self-report measures and continuous physiological indicators of anxiety, we failed to find direct support for a cognitive suppression effect of anxiety through ritualistic behavior. Nevertheless, we found that induced stress increased participants' subsequent repetitive behavior, which in turn reduced physiological arousal. This study provides novel evidence for plausible underlying effects of the proposed anxiolytic effect of rituals: repetitive behavior but not cognitive load may decrease physiological stress responses during ritual. PMID- 30306400 TI - Transarterial chemoembolization with raltitrexed-based or floxuridine-based chemotherapy for unresectable colorectal cancer liver metastasis. AB - PURPOSE: To evaluate and compare the efficiency and safety of raltitrexed- or floxuridine (FUDR)-based transarterial chemoembolization (TACE) in patients with unresectable colorectal cancer liver metastasis (CRCLM). METHODS: We conducted a retrospective analysis of 81 patients with unresectable CRCLM who failed systemic chemotherapy and were treated with TACE in our department from Oct 2014 to Oct 2017. Of these, 61 patients received TACE using raltitrexed, oxaliplatin, and pirarubicin (raltitrexed group), and 20 received TACE using FUDR, oxaliplatin, and pirarubicin (FUDR group). The objective response rate (ORR), disease control rate (DCR), overall survival (OS, from the first TACE), progression-free survival (PFS, from the first TACE), and adverse reactions were evaluated and compared between the two groups, and prognostic factors for OS were analyzed. RESULTS: The ORRs of the raltitrexed group and FUDR group were 67.2 and 45.0%, respectively (P = 0.076), and the DCRs were 86.9 and 80.0%, respectively (P = 0.452). The median OS (from first TACE) was 14.0 months in the raltitrexed group and 13.0 months in the FUDR group (P = 0.556). The median PFS (from first TACE) was 2.1 months in the raltitrexed group and 2.4 months in the FUDR group (P = 0.878). Univariate and multivariate analyses showed that the primary tumor site, Child-Pugh class, and combination with local ablation (RFA or CRA) were independent significant factors affecting survival. There were no significant differences in adverse reactions between the two groups (P > 0.05), and no treatment-related death occurred in either group. CONCLUSION: TACE treatment based on raltitrexed or FUDR is an efficient and safe alternative choice for treating unresectable CRCLM. PMID- 30306401 TI - HER2 in stemness and epithelial-mesenchymal plasticity of breast cancer. AB - Breast cancer had been the first non-hematologic malignancy where sub-types based on molecular characterization had entered clinical practice. HER2 over expression, due to either gene amplification or protein up-regulation, defines one of these sub-types and is clinically exploited by addition of HER2-targeted treatments to the regimens of treatment. Nevertheless, in many occasions HER2 positive cancers are resistant or become refractory to these therapies. Several mechanisms, such as activation of alternative pathways or loss of expression of the receptor in cancer cells, have been proposed as the cause of these therapeutic failures. Cancer stem cells (CSCs, alternatively called tumor initiating cells) comprise a small percentage of the tumor cells, but are capable of reconstituting and propagating tumors due to their superior intrinsic capacity for regeneration, survival and resistance to therapies. CSCs possess circuits enabling epigenetic plasticity which endow them with the ability to alternate between epithelial and mesenchymal states. This paper will discuss the expression and regulation of HER2 in CSCs of the different sub-types of breast cancer and relationships of the receptor with both the circuits of stemness and epithelial mesenchymal plasticity. Therapeutic repercussions of the relationship of HER2 initiated signaling with stemness networks will also be proposed. PMID- 30306402 TI - Novel Random Triblock Copolymers for Sustained Delivery of Macromolecules for the Treatment of Ocular Diseases. AB - The objective of this study is to design, develop, and synthesize novel random triblock (RTB) copolymers for sustained delivery of macromolecules. RTB copolymers have not been utilized for the delivery of macromolecules for ocular diseases. RTB copolymers comprising of polyethylene glycol, glycolide, and E caprolactone blocks were synthesized and assessed for their molecular weights and purity using 1H-NMR spectroscopy, gel permeation chromatography, FTIR (functionality), and XRD (crystallinity). No toxicity was observed when ocular cell lines were treated with RTB copolymers. These materials were applied for encapsulation of peptides and proteins (catalase, IgG, BSA, IgG Fab fragment, lysozyme, insulin, and octreotide) in nanoparticles. Particle size ranged from 202.41 +/- 2.45 to 300.1 +/- 3.11 nm depending on the molecular size and geometry of proteins/peptides. Polydispersity indices were between 0.26 +/- 0.02 and 0.46 +/- 0.07 respectively. Percentage entrapment efficiency and drug loading ranged from 83.44 +/- 2.24 to 45.35 +/- 5.53 and 21.56 +/- 0.46 to 13.08 +/- 1.35 respectively depending on molecular weights of peptides or proteins. A sustained in vitro release of macromolecule was observed over 3-month period. These results suggest that RTB copolymers may be suitable for sustained delivery systems for various macromolecules for different diseases including ocular diseases. PMID- 30306403 TI - Avian Bioreactor Systems: A Review. AB - Animal bioreactors are genetically modified animal systems that have the potential to reduce production cost, and improve production efficiency, of pharmaceutically relevant recombinant proteins. Several species including goats, cattle, rabbits, and avians have been genetically modified to secrete target proteins into milk, egg whites, blood, or other bodily fluids. There are several advantages associated with the use of avians as bioreactor systems. Avians have a short generation time, leading to the quick establishment of a transgenic line and high egg production. Transgenic avian systems allow for appropriate post translational modification, as opposed to prokaryotic cell culture bioreactors, and have higher productivity than mammalian cell culture systems. Furthermore, recombinant proteins can be incorporated into egg whites and easily collected from the sterile environment of the egg. Magnum-specific expression of target genes has been achieved by use of the ovalbumin promoter, leading to a localization of the target protein into the avian egg. In this review, we discuss the current advancements, future potential, and limitations of avian bioreactor systems. PMID- 30306405 TI - Individual differences in tendencies to attention-deficit/hyperactivity disorder and emotionality: empirical evidence in young healthy adults from Germany and China. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is characterized by inattention, hyperactivity, and impulsivity but also by negative emotionality. The aim of the present study was to investigate whether subclinical ADHD tendencies are associated with negative emotionality in healthy adult samples. The present study is of special interest since it investigated negative emotionality with a questionnaire anchored in Neuroscience Theory-the Affective Neuroscience Personality Scales (ANPS). Furthermore, through the investigation of samples in two countries, namely Germany and China, the study aims to replicate the results across different cultures. German (n = 377; age: M = 23.25, SD = 8.47; 117 males) and Chinese (n = 389; age: M = 20.74, SD = 2.47; 279 males) subjects completed ANPS (primary emotional traits) and ASRS (ADHD tendencies) questionnaires in an online survey. Principal component analysis of the ANPS revealed one factor for negative emotionality and one factor for positive emotionality. Partial correlations between ANPS and ASRS (controlled for age) were conducted separately for nation and gender. The same correlation patterns between ADHD tendencies and negative emotionality could be found in male and female German/Chinese participants (range r = .189 to r = .352). Higher negative emotionality was always significantly associated with more inattentive, hyperactive/impulsive, or combined tendencies. However, significant negative correlations between ADHD tendencies and positive emotionality could only be observed in Chinese males (range r = - .264 to r = - .296). The results are in line with former findings in children and show that also in healthy adults, associations between negative emotionality and ADHD tendencies are robustly visible. The results were independent of the cultural background, indicating a general association between ADHD tendencies and negative emotionality, even in healthy adults. PMID- 30306404 TI - Pullulan-Based Nanoparticle-HSA Complex Formation and Drug Release Influenced by Surface Charge. AB - The nanomaterial composition of nanoparticles and their protein adsorption in the blood is of great significance in the design of drug-loaded nanoparticles. To explore the interaction between the different surface components of nanoparticles (NPs) and protein, we synthesized three kinds of pullulan NP polymers: cholesteric hydrophobically (CH) modified pullulan (CHP), CH-modified animated pullulan (CHAP), and CH-modified carboxylated pullulan (CHSP). Pullulan NPs were prepared by the dialysis method. Dynamic light scattering was used to determine the charge and size of the three NPs. The size of NPs was altered by the number of charge groups when polymers contain the same degree of cholesterol substitution. The zeta potentials were + 12.9, - 15.4, and - 0.698 mV for CHAP, CHSP, and CHP, respectively, and the dimensions were 116.9, 156.9, and 73.1 nm, respectively. Isothermal titration calorimetry was used to determine the thermodynamic changes of NPs with different surface charge, and the effect of human serum albumin (HSA) on the titration was investigated. The changes of enthalpy and entropy demonstrated an interaction between NPs and HSA; the binding constant (Kb) for CHSP, CHP, and CHAP was 1.41, 27.7, and 412 * 104 M-1, respectively, with the positive charge for CHAP-HSA, uncharged for CHP-HSA, and negative charge for CHSP-HSA complex. Fluorescence and circular dichroism spectroscopy were used to determine the protein structure change after the complexation between NPs and HSA. The NP and HSA complexation is a complicated process composed of protein alpha-helical content reduction and the peptide chain extension; CHP NPs had the largest reduction in HSA alpha-helical content. The drug release rates of all compounds of NP and HSA were significantly lower than those of free drug and drug-loaded NPs after 48 h. The highest and lowest rates were observed in CHSP-HSA and CHP-HSA, respectively. The drug release was significantly influenced by the adsorption of HSA on NPs, and the size and surface charge of NPs played an important role in this process. PMID- 30306406 TI - Patient preferences for treatment in type 2 diabetes: the Italian discrete-choice experiment analysis. AB - AIMS: Several drug classes are now available to achieve a satisfactory metabolic control in patients with type 2 diabetes (T2DM), but patients' preferences may differ. METHODS: In a discrete-choice experiment, we tested T2DM patients' preferences for recent antidiabetic drugs, in the event that their treatment might require intensification. The following attributes were considered: (a) route of administration; (b) type of delivery; (c) timing; (d) risk of adverse events; (e) effects on body weight. Twenty-two possible scenarios were built, transferred into 192 paired choices and proposed to 491 cases naive to injectable treatments and 171 treated by GLP-1 receptor agonists (GLP-1RAs). Analyses were performed by descriptive statistics and random effects logit regression model. RESULTS: Preferences according to dosing frequency, risk of nausea and urinary tract infections (UTls) were similar across groups, age, sex and BMI. Administration route and delivery type accounted for 1/3 of relative importance; the risk of UTIs, nausea and dosing frequency for ~ 20% each, and weight loss for only 6%. Two significant interactions emerged (p < 0.01): type of delivery * group, and weight change * BMI class. Irrespective of previous treatment, the three preferred choices were injectable, coupled with weekly dosing and a ready to-use device (first two choices). In a regression model, being naive or non naive changed the ranking of preferences (p < 0.001), and the order was systematically shifted towards injectable medications in non-naive subjects. CONCLUSION: Easy-to-deliver, injectable treatment is preferred in T2DM, independently of treatment history, and previous experience with GLP-1RAs strengthens patients' willingness to accept injectable drugs. PMID- 30306407 TI - High prevalence of humoral autoimmunity in first-degree relatives of Mexican type 1 diabetes patients. AB - AIMS: To assess the prevalence of autoantibodies (Aab) to insulin (IAA), glutamic acid decarboxylase 65 (GADA) and insulinoma antigen 2 (IA-2A), as well as human leukocyte antigen (HLA) class II alleles, in first degree relatives (FDR) of Mexican patients with type 1 diabetes (T1D), and to explore whether these parameters mirror the low incidence of T1D in the Mexican population. METHODS: Aab titers were determined by ELISA in 425 FDR, 234 siblings, 40 offspring and 151 parents of 197 patients with T1D. Typing of HLA-DR and -DQ alleles was performed in 41 Aab-positive FDR using polymerase chain reaction with allele specific oligotyping. RESULTS: Seventy FDR (16.47%) tested positive for Aab. The siblings (19.2%) and the offspring (25%) had significantly higher prevalence of Aab than the parents (9.9%). GADA was the most frequent Aab. Almost half of the Aab-positive FDR had two different Aab (45.7%), and none tested positive for three Aab. The highest prevalence of Aab was found among women in the 15-29 years age group. Moreover, the positivity for two Aab was significantly more frequent among females. A considerable number of FDR (48.8%) carried the susceptible HLA DR3, -DR4, -DQB1*0201 or -DQB1*0302 alleles, but almost none had the high risk genotype HLA-DR3/DR4. CONCLUSIONS: FDR of Mexican T1D patients have high prevalence of islet Aab, comparable to countries with the highest incidence of T1D. However, Aab positivity does not seem to be associated with HLA risk genotypes, which may have an impact on the low incidence of T1D in Mexico. PMID- 30306408 TI - The rippling dynamics of valenced messages in naturalistic youth chat. AB - Even though human behavior is largely driven by real-time feedback from others, this social complexity is underrepresented in psychological theory, largely because it is so difficult to isolate. In this work, we performed a quasi experimental analysis of hundreds of millions of chat room messages between young people. This allowed us to reconstruct how-and on what timeline-the valence of one message affects the valence of subsequent messages by others. For the highly emotionally valenced chat messages that we focused on, we found that these messages elicited a general increase of 0.1 to 0.4 messages per minute. This influence started 2 s after the original message and continued out to 60 s. Expanding our focus to include feedback loops-the way a speaker's chat comes back to affect him or her-we found that the stimulating effects of these same chat events started rippling back from others 8 s after the original message, to cause an increase in the speaker's chat that persisted for up to 8 min. This feedback accounted for at least 1% of the bulk of chat. Additionally, a message's valence affects its dynamics, with negative events feeding back more slowly and continuing to affect the speaker longer. By reconstructing the second-by-second dynamics of many psychosocial processes in aggregate, we captured the timescales at which they collectively ripple through a social system to drive system-level outcomes. PMID- 30306409 TI - Moderation analysis in two-instance repeated measures designs: Probing methods and multiple moderator models. AB - Moderation hypotheses appear in every area of psychological science, but the methods for testing and probing moderation in two-instance repeated measures designs are incomplete. This article begins with a short overview of testing and probing interactions in between-participant designs. Next I review the methods outlined in Judd, McClelland, and Smith (Psychological Methods 1; 366-378, 1996) and Judd, Kenny, and McClelland (Psychological Methods 6; 115-134, 2001) for estimating and conducting inference on an interaction between a repeated measures factor and a single between-participant moderator using linear regression. I extend these methods in two ways: First, the article shows how to probe interactions in a two-instance repeated measures design using both the pick-a point approach and the Johnson-Neyman procedure. Second, I extend the models described by Judd et al. (1996) to multiple-moderator models, including additive and multiplicative moderation. Worked examples with a published dataset are included, to demonstrate the methods described throughout the article. Additionally, I demonstrate how to use Mplus and MEMORE (Mediation and Moderation for Repeated Measures; available at http://akmontoya.com ), an easy-to-use tool available for SPSS and SAS, to estimate and probe interactions when the focal predictor is a within-participant factor, reducing the computational burden for researchers. I describe some alternative methods of analysis, including structural equation models and multilevel models. The conclusion touches on some extensions of the methods described in the article and potentially fruitful areas of further research. PMID- 30306410 TI - A short version of the MacArthur-Bates Communicative Development Inventories with high validity. AB - The MacArthur-Bates Communicative Development Inventories (CDIs) are among the most widely used evaluation tools for early language development. CDIs are filled in by the parents or caregivers of young children by indicating which of a prespecified list of words and/or sentences their child understands and/or produces. Despite the success of these instruments, their administration is time consuming and can be of limited use in clinical settings, multilingual environments, or when parents possess low literacy skills. We present a new method through which an estimation of the full-CDI score can be obtained, by combining parental responses on a limited set of words sampled randomly from the full CDI with vocabulary information extracted from the WordBank database, sampled from age-, gender-, and language-matched participants. Real-data simulations using versions of the CDI-WS for American English, German, and Norwegian as examples revealed the high validity and reliability of the instrument, even for tests having just 25 words, effectively cutting administration time to a couple of minutes. Empirical validations with new German speaking participants confirmed the robustness of the test. PMID- 30306411 TI - Callous-Unemotional Behaviors and Harsh Parenting: Reciprocal Associations across Early Childhood and Moderation by Inherited Risk. AB - Callous-unemotional (CU) behaviors increase children's risk for subsequent antisocial behavior. This risk process may begin in early childhood with reciprocal pathways between CU behaviors and harsh parenting. In a sample of 561 linked triads of biological mothers, adoptive parents, and adopted children, the present study examined bidirectional links between CU behaviors and harsh parenting across three time points from 18 to 54 months and investigated moderation by inherited risk for psychopathic traits. Child CU behaviors and harsh parenting were measured using adoptive mother and adoptive father reports, and biological mothers provided reports of their personality characteristics. Findings supported reciprocal associations between harsh parenting and CU behaviors during early childhood, especially during the transition from toddlerhood (27 months) to the preschool period (54 months). Moreover, multiple group analyses showed that level of inherited risk moderated associations between CU behaviors and harsh parenting. Specifically, there were statistically reliable associations between CU behaviors at 27 months and adoptive mothers' harsh parenting at 54 months, and between adoptive fathers' harsh parenting at 27 months and CU behaviors at 54 months among children at higher inherited risk, but not among those at lower inherited risk. The findings illustrate the dynamic interplay between parenting, CU behaviors, and heritable risk. PMID- 30306412 TI - Contrast-enhanced ultrasound patterns of hepatocellular adenoma: an Italian multicenter experience. AB - PURPOSE: Hepatocellular adenoma (HCA) is a rare benign monoclonal neoplasm, recently categorized on genetic and histopathological basis into four subtypes with different biological behaviors. Since contrast-enhanced ultrasonography (CEUS) is nowadays a well-established technique for liver nodule characterization, the aim of our study was to assess CEUS features of HCAs to identify criteria that correlate with different HCA subtypes as compared to histopathologic examination and other imaging modalities. METHODS: We retrospectively analyzed data of patients with histology-proven HCA who underwent CEUS, computed tomography or magnetic resonance imaging (MRI) in seven different Italian ultrasound units. RESULTS: The study enrolled 19 patients (16 females; 69% with concomitant/prior use of oral contraceptives): the mean size of all HCAs was 4.2 cm (range 1.6-7.1 cm); 14/19 had inflammatory HCAs (I-HCA), 1/19 beta catenin-activated HCA, and the others unclassified HCAs. On CEUS, during the arterial phase, all but one HCA displayed a rapid enhancement, with 89% of these showing centripetal and 11% centrifugal filling pattern, whereas during the portal and late venous phase 58% of HCA showed washout and the remaining 42% displayed persistent enhancement. In particular, among I-HCAs 7/14 showed no washout, 3/14 and 4/14 showed washout in the portal or late phase, respectively. CONCLUSIONS: This dataset represents one of the few published experiences on HCAs and CEUS in Italy and shows that HCAs are hypervascularized in the arterial phase usually with a centripetal flow pattern and have a heterogeneous behavior in portal and late phase. In particular, occurrence of delayed washout on CEUS but not on MRI is frequently observed in the subtype of I-HCA. PMID- 30306414 TI - Dopaminergic influences on risk preferences of Parkinson's disease patients. AB - Clinicians are increasingly recognizing impulse control disorders (ICDs) as a complication of dopaminergic treatment in Parkinson's disease (PD). Considering the pivotal role of dopamine in reward information processing, ICDs may originate from dysregulation of reward-oriented behavior, and the behavioral changes may be reflected in shifts of psychological risk preference during decision-making. We used a behavioral economics paradigm to evaluate quantitatively the risk preferences of PD patients in levodopa on and off states. We also examined age matched healthy controls. We found that levodopa increased the subjective value and prolonged the decision time in PD patients. These effects are apparently not explained by kinematic improvements but are attributed to psychological shifts of risk preferences and increased attention during risky decision-making. The risk preferences of healthy controls were similar to those of PD on levodopa treatment. The risk preferences of PD patients were not correlated with the scores of routine cognitive batteries, suggesting that dopamine-sensitive risk preferences are independent of cognitive capacities as measured by conventional batteries, including general intelligence, memory, and frontal functioning. By contrast, apathy and ICD partially predicted the risk attitude in PD patients, suggesting a common background of limbic origin behind these properties. The present results demonstrated that dopamine deficiency in off-state PD leads to risk-avoiding behavior and levodopa treatment increases the risk preferences. Behavioral economics framework is useful to evaluate short-term psychological changes in response to levodopa in PD patients. PMID- 30306413 TI - Enhanced near-infrared absorber: two-step fabricated structured black silicon and its device application. AB - Silicon is widely used in semiconductor industry but has poor performance in near infrared photoelectronic devices because of its high reflectance and band gap limit. In this study, two-step process, deep reactive ion etching (DRIE) method combined with plasma immersion ion implantation (PIII), are used to fabricate microstructured black silicon on the surface of C-Si. These improved surfaces doped with sulfur elements realize a narrower band gap and an enhancement of light absorptance, especially in the near-infrared range (800 to 2000 nm). Meanwhile, the maximum light absorptance increases significantly up to 83%. A Si PIN photoelectronic detector with microstructured black silicon at the back surface exhibits remarkable device performance, leading to a responsivity of 0.53 A/W at 1060 nm. This novel microstructured black silicon, combining narrow band gap characteristic, could have a potential application in near-infrared photoelectronic detection. PMID- 30306415 TI - Isavuconazole Kinetic Exploration for Clinical Practice. AB - BACKGROUND: Isavuconazole is a new antifungal prodrug for the treatment of invasive aspergillosis and mucormycosis. As no clear pharmacokinetic pharmacodynamic relationship has been established for patients, therapeutic drug monitoring is not currently required. However, as isavuconazole is a new drug, clinicians are sometimes sceptical about the exposure achieved in their patients and seek pharmacokinetic exploration. A minimal response consists of determining that the patient's pharmacokinetic profile agrees with profiles reported by Desai et al. using concentrations from the SECURE study. METHODS: Based on one concentration and Desai et al.'s population-pharmacokinetic model, it is possible to estimate a patient's most likely pharmacokinetic profile. If a patient's pharmacokinetic profile is close to the profiles reported by Desai et al., therapeutic drug monitoring is not required. In contrast, when the pharmacokinetic profile differs from the Desai et al. profiles, isavuconazole concentration monitoring and pharmacokinetic profile modeling are the only methods for obtaining information on a patient's exposure and the efficacy of isavuconazole. RESULTS: Four patients presented with surprising pharmacokinetic profiles, unexplained by drug interactions or cytochrome P450 3A4/5 polymorphisms. For two of them, a drug dosage adjustment was proposed and applied by clinicians, together with a check for a new pharmacokinetic profile a few days later. CONCLUSIONS: Collecting one blood sample just before the first maintenance dose to make an early estimation of the patient's most likely pharmacokinetic profile is one method of identifying patients with outlier pharmacokinetic behavior. PMID- 30306416 TI - A decade of thyroidology. AB - Significant scientific progress has been achieved in the past decade in thyroidology driven by scholarly enquiry, unmet patient needs, and investment by the pharmaceutical and diagnostics industry. In this review, nine publications have been selected for their impact in pushing the frontiers of knowledge and understanding. They include new perspectives in the diagnosis, pathophysiology, epidemiology and management of thyroid cancer, understanding of thyroid hormone physiology, and new treatments for Graves' orbitopathy. PMID- 30306418 TI - Applying Densely Connected Convolutional Neural Networks for Staging Osteoarthritis Severity from Plain Radiographs. AB - Osteoarthritis (OA) classification in the knee is most commonly done with radiographs using the 0-4 Kellgren Lawrence (KL) grading system where 0 is normal, 1 shows doubtful signs of OA, 2 is mild OA, 3 is moderate OA, and 4 is severe OA. KL grading is widely used for clinical assessment and diagnosis of OA, usually on a high volume of radiographs, making its automation highly relevant. We propose a fully automated algorithm for the detection of OA using KL gradings with a state-of-the-art neural network. Four thousand four hundred ninety bilateral PA fixed-flexion knee radiographs were collected from the Osteoarthritis Initiative dataset (age = 61.2 +/- 9.2 years, BMI = 32.8 +/- 15.9 kg/m2, 42/58 male/female split) for six different time points. The left and right knee joints were localized using a U-net model. These localized images were used to train an ensemble of DenseNet neural network architectures for the prediction of OA severity. This ensemble of DenseNets' testing sensitivity rates of no OA, mild, moderate, and severe OA were 83.7, 70.2, 68.9, and 86.0% respectively. The corresponding specificity rates were 86.1, 83.8, 97.1, and 99.1%. Using saliency maps, we confirmed that the neural networks producing these results were in fact selecting the correct osteoarthritic features used in detection. These results suggest the use of our automatic classifier to assist radiologists in making more accurate and precise diagnosis with the increasing volume of radiographic image being taken in clinic. PMID- 30306417 TI - Sex Differences in Personality Disorders. AB - PURPOSE OF REVIEW: This review aims to give an overview on the current literature on sex differences in personality disorders and to highlight the potential of dimensional approaches. RECENT FINDINGS: Empirical findings on sex differences in personality disorders are inconsistent and appear to be highly dependent on study settings. Current studies have mainly focused on borderline and antisocial personality disorder and the question whether these are sex-specific representations of a common substrate. In general, sexes differ in the manifestation of personality disorders as well as in comorbidities. Criticism of the established categorical model led to an additional dimensional model of personality disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Investigations on sex differences in personality disorders are sparse and mainly limited to antisocial and borderline personality disorder. The introduction of a dimensional model offers the chance to re-think the construct of "personality disorder" and thereby also opens the possibility for a better understanding of sex differences. PMID- 30306419 TI - Effect of Exogenous Zinc on MsrB1 Expression and Protein Oxidation in Human Lens Epithelial Cells. AB - Aging has been related to zinc deficiency, resulting in protein oxidation and age related decline of methionine sulfoxide reductase (Msr) activity. This study was designed to investigate the levels of methionine sulfoxide reductase B1 (MsrB1) mRNA and oxidized proteins in human lens epithelial (hLE) cells after treatment with exogenous zinc. The role of exogenous zinc in regulation of MsrB1 gene expression and protein oxidation in hLE cells was studied by MTT assay, oxidized protein measurement kit, and real-time PCR. The results showed that hLE cell viability was significantly decreased by MsrB1 gene knockdown or peroxynitrite (ONOO-) treatment, while it was significantly increased after treatment with exogenous zinc (P < 0.05). Protein carbonyl content in hLE cell by MsrB1 gene knockdown or ONOO- treatment was significantly decreased after treatment with ZnSO4 (P < 0.01). And exogenous zinc could increase the level of MsrB1 in hLE cell under normal (P < 0.001) and oxidative stress (P < 0.01) conditions. In conclusion, exogenous zinc could protect hLE cells against MsrB1 gene knockdown or ONOO--induced cell death by upregulation of MsrB1 involved in the elimination of reactive oxygen species (ROS) and oxidized proteins. PMID- 30306420 TI - Melatonin Ameliorates Neuropharmacological and Neurobiochemical Alterations Induced by Subchronic Exposure to Arsenic in Wistar Rats. AB - An experimental study was conducted in Wistar rats to characterize the arsenic ("As")-induced alterations in neurobiochemistry in brain and its impact on neuropharmacological activities with or without the melatonin (MLT) as an antioxidant given exogenously. Male Wistar rats were randomly divided in to four groups of six each. Group I served as untreated control, while group II received As [sodium (meta) arsenite; NaAsO2] at 10 mg/kg bw (p.o.) for a period of 56 days. Experimental rats in group III received treatment similar to group II but in addition received MLT at 10 mg/kg bw (p.o.) from day 32 onwards. Rats in group IV received MLT alone from day 32 onwards similar to group III. Sub-chronic exposure to As (group II) significantly reduced both voluntary locomotor and forced motor activities and melatonin supplementation (group III) showed a significant improvement in motor activities, when subjected to test on day 42 or 56. Rats exposed to As showed a significant increase in anxiety level and a marginal nonsignificant reduction in pain latency. Sub-chronic administration of As induced (group II) significant increase in the levels of thiobarbituric acid reactive substance (TBARS) called malondialdehyde (MDA) in the brain tissue (5.55 +/- 0.57 nmol g-1), and their levels were significantly reduced by MLT supplementation (group III 3.96 +/- 0.15 nmol g-1). The increase in 3 nitrotyrosine (3-NT) levels in As-exposed rats indicated nitrosative stress due to the formation of peroxynitrite (ONOO-). However, exogenously given MLT significantly reduced the 3-NT formation as well as prostaglandin (PGE2) levels in the brain. Similarly, MLT administration have suppressed the release of pro inflammatory cytokines (viz., IL-1beta, IL-6, and TNF-alpha) and amyloid-beta1-40 (Abeta) deposition in the brain tissues of experimental rats. To conclude, exogenous administration of melatonin can overcome the sub-chronic As-induced oxidative and nitrosative stress in the CNS, suppressed pro-inflammatory cytokines, and restored certain disturbed neuropharmacological activities in Wistar rats. PMID- 30306421 TI - Multivariate-based classification of predicting cooking quality ideotypes in rice (Oryza sativa L.) indica germplasm. AB - BACKGROUND: For predicting texture suited for South and South East Asia, most of the breeding programs tend to focus on developing rice varieties with intermediate to high amylose content in indica subspecies. However, varieties within the high amylose content class may still be distinguishable by consumers, who are able to distinguish texture that cannot be differentiated by proxy cooking quality indicators. RESULTS: This study explored a suite of assays to capture viscosity, rheometric, and mechanical texture parameters for characterising cooked rice texture in a set of 211 rice accessions from a diversity panel and employed multivariate approaches to classify rice varieties into distinct cooking quality classes. Results suggest that when the amylose content range is narrowed to the intermediate to high classes, parameters determined by rheometry and RVA become diagnostic. Modeled parameters distinguishing cooking quality ideotypes within the same range of amylose classes differ in textural parameters scored by a descriptive sensory panel. CONCLUSIONS: Our results reinforced the notion that it is important to define cooking quality classes in indica subtypes based on multidimensional parameters, by going beyond amylose predictions. These predictive cooking models will be handy in capturing cooking and eating quality properties that address consumer preferences in future breeding programs. Policy implications of such findings may lead to changes in criteria used in assessing grain quality in the intermediate to high amylose classes. PMID- 30306422 TI - Risk of various types of cataracts in a cohort of Mayak workers following chronic occupational exposure to ionizing radiation. AB - This study is the first to report cataract type specific risks in a cohort of Russian Mayak Production Association workers following chronic occupational exposure to ionizing radiation. In this retrospective cohort study, 22,377 workers (females 25.4%) first employed in 1948-1982 were followed up till the end of 2008. All cataract subtypes were significantly dependent on sex, attained age, diabetes mellitus, myopia and glaucoma. For each of posterior subcapsular (PSC), cortical and nuclear cataracts, the risk of cataract incidence significantly linearly increased with increasing radiation dose. Excess relative risk per unit effective dose (ERR/Sv) from external gamma-rays based on the linear model was 0.91 [95% confidence intervals (CIs) 0.67, 1.20] for PSC, 0.63 (95% CIs 0.49, 0.76) for cortical, and 0.47 (95% CIs 0.35, 0.60) for nuclear cataracts. For all three types of cataracts, exclusion of an adjustment for neutron dose as well as inclusion of additional adjustments for body mass index and smoking index decreased ERR/Sv of external gamma-rays. Inclusion of an additional adjustment for glaucoma, however, modestly increased incidence risks for cortical and nuclear cataracts, but not PSC cataracts. Inclusion of an adjustment for diabetes mellitus decreased ERR/Sv of external gamma-rays only for PSC incidence. Both males and females had increased risks for all three types of cataracts, but ERR/Sv was significantly higher in females than in males (p < 0.001), particularly for PSC cataracts. The results suggest that chronic occupational radiation exposure significantly increases risks of PSC, cortical and nuclear cataracts, and that such risks are higher in females than in males. PMID- 30306424 TI - Education modifies the relationship between height and cognitive function in a cross-sectional population-based study of older adults in Rural South Africa. AB - We aimed to estimate the relationship between height (a measure of early-life cumulative net nutrition) and later-life cognitive function among older rural South African adults, and whether education modified this relationship. Data were from baseline in-person interviews with 5059 adults >= 40 years in the population based "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) study in Agincourt sub-district, South Africa, in 2015. Linear regression was used to estimate the relationship between height quintile and latent cognitive function z-score (representing episodic memory, time orientation, and numeracy), with adjustment for life course covariates and a height-by-education interaction. Mean (SD) height was 162.7 (8.9) cm. Nearly half the sample had no formal education (46%; 2307/5059). Mean age- and sex-adjusted cognitive z-scores increased from - 0.68 (95% CI: - 0.76 to - 0.61) in those with no education in the shortest height quintile to 0.62 (95% CI: 0.52-0.71) in those with at least 8 years of education in the tallest height quintile. There was a linear height disparity in cognitive z-scores for those with no formal education (adjusted beta = 0.10; 95% CI: 0.08-0.13 per height quintile), but no height disparity in cognitive z-scores in those with any level of education. Short stature is associated with poor cognitive function and may be a risk factor for cognitive impairment among older adults living in rural South Africa. The height disparity in cognitive function was negated for older adults who had any level of education. PMID- 30306423 TI - Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion. AB - Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life. PMID- 30306425 TI - Hearing loss, cognitive ability, and dementia in men age 19-78 years. AB - Hearing loss in later life has been associated with risk of dementia. The impact of risk factors for dementia may change during life, and it is unknown whether hearing loss early in midlife represents a risk factor for dementia. We examined whether hearing loss diagnosed in midlife was associated with an increased risk of dementia. A cohort comprising 942,567 Danish men enrolled in the mandatory conscription board examination was followed from conscription (age 19). Cognitive ability was measured at conscription, while hearing loss was ascertained either by physicians diagnosis at conscription or by the Danish National Patient Registry from 1977 to 2016 (ICD-8:388; 389; ICD-10:H90; H91). Differences in cognitive ability in relation to hearing loss at conscription were calculated using t test, while the risk of dementia associated with hearing loss was estimated using Cox regression with adjustment for cognitive ability, education, depression, diabetes, hypertension, and cerebrovascular disease. Men with hearing loss at conscription had about 2 points (corresponding to 0.20 SD) lower mean cognitive score than those without hearing loss. During follow-up, 59,834 men had a hearing loss diagnosis, while 9114 were diagnosed with dementia. Midlife hearing loss was associated with an increased rate of dementia diagnosed before age 60 (adjusted Hazard Ratio (HR) = 1.90 [95% CI 1.59-2.76]) or at a later age (adjusted HR = 1.15 [95% CI 1.06-1.25]). Our study supports the evidence that early identification and correction of hearing loss holds promise for prevention of dementia later in life. PMID- 30306426 TI - Enhanced recovery after surgery (ERAS) pathways in breast reconstruction: systematic review and meta-analysis of the literature. AB - PURPOSE: Enhanced recovery after surgery (ERAS) pathways are increasingly promoted in post-mastectomy reconstruction, with several articles reporting their benefits and safety. This meta-analysis appraises the evidence for ERAS pathways in breast reconstruction. METHODS: A systematic search of Medline, EMBASE, and Cochrane databases was performed to identify reports of ERAS protocols in post mastectomy breast reconstruction. Two reviewers screened studies using predetermined inclusion criteria. Studies evaluated at least one of the following end-points of interest: length of stay (LOS), opioid use, or major complications. Risk of bias was assessed for each study. Meta-analysis was performed via a mixed effects model to compare outcomes for ERAS versus traditional standard of care. Surgical techniques were assessed through subgroup analysis. RESULTS: A total of 260 articles were identified; 9 (3.46%) met inclusion criteria with a total of 1191 patients. Most studies had "fair" methodological quality and incomplete implementation of ERAS society recommendations was noted. Autologous flaps comprised the majority of cases. In autologous breast reconstruction, ERAS significantly reduces opioid use [Mean difference (MD) = - 183.96, 95% CI - 340.27 to 27.64, p = 0.02) and LOS (MD) = - 1.58, 95% CI - 1.99 to 1.18, p < 0.00001] versus traditional care. There is no significant difference in the incidence of complications (major complications, readmission, hematoma, and infection). CONCLUSION: ERAS pathways significantly reduce opioid use and length of hospital stay following autologous breast reconstruction without increasing complication rates. This is salient given the current US healthcare climate of rising expenditures and an opioid crisis. PMID- 30306427 TI - Alternative splicing is an important mechanism behind KAI1 loss of function in breast cancer patients from Saudi Arabia. AB - PURPOSE: KAI1 (also called CD82) is a metastasis suppressor gene known to be downregulated in breast cancer and other solid tumors. The downregulation of KAI1 or loss of its function is usually associated with bad prognosis. The mechanism behind KAI1 loss of function is complex. In this study, we investigated "alternative splicing" as a possible mechanism that underlies KAI1 loss of function in breast cancer patients from a tertiary hospital in Saudi Arabia. METHODS: Expression of KAI1 was studied in FFPE breast cancer and control tissue sections by IHC using two different antibodies targeting different domains of the protein. The TS82B antibody targets the extracellular loop, which constitutes most of the protein, while the second EPR4112 antibody targets the C-terminal intracellular domain of the protein. RESULTS: Out of 90 breast cancer samples, 67% showed loss of KAI1 expression. The remaining 33% showed KAI1 expression with (TS82B) antibody; however, the protein was detected in only 11% of cancers when using the antibody (EPR4112) indicating a truncation of the protein at the C terminus (truncated-KAI1) in 22% of the studied cancer samples. A significant correlation was found between truncated-KAI1 expression and advanced cancer stage (association with lymph node metastasis, P value 0.008). CONCLUSION: Alternative splicing is an important mechanism underlying KAI1 loss of function in breast cancer, and it is associated with bad prognosis (advanced cancer stage). PMID- 30306428 TI - Kinesin family member-18A (KIF18A) is a predictive biomarker of poor benefit from endocrine therapy in early ER+ breast cancer. AB - PURPOSE: Identification of effective and reliable biomarkers that could be used to predict the efficacy of endocrine therapy is of crucial importance to the management of oestrogen receptor positive (ER+) breast cancer (BC). KIF18A, a key regulator of cell cycle, is overexpressed in many human cancers, including BC. In this study, we investigated the role of KIF18A as a biomarker to predict the benefit from endocrine treatment in early ER + BC patients. METHODS: KIF18A expression was assessed at the genomic level using the METABRIC dataset to explore its prognostic and predictive value in ER + BC patients (n = 1506). Predictive significance of KIF18A mRNA was validated using KM-Plot datasets (n = 2061). KIF18A protein expression was assessed using immunohistochemistry in a large annotated series of early-stage ER + BC (n = 1592) with long-term follow up. RESULTS: High mRNA and protein expression of KIF18A were associated with short recurrence-free survival (RFS), distant-metastasis free survival (DMFS) and BC specific survival (all P < 0.05) in ER + BC in patients who received no adjuvant treatment or adjuvant endocrine therapy. In multivariate analysis, high KIF18A expression was an independent prognostic biomarker for poor RFS (P = 0.027) and DMFS (P = 0.028) in patients treated with adjuvant endocrine therapy. CONCLUSION: KIF18A appears to be a candidate biomarker of a subgroup of ER + BC characterised by poor clinical outcome. High KIF18A expression has prognostic significance to predict poor benefit from endocrine treatment for patients with ER + BC. Therefore, measurement of KIF18A on ER + BC patients prior to treatment could guide clinician decision on benefit from endocrine therapy. PMID- 30306429 TI - The impact of gene expression profile testing on confidence in chemotherapy decisions and prognostic expectations. AB - PURPOSE: Little is known about whether gene expression profile (GEP) testing and specific recurrence scores (e.g., medium risk) improve women's confidence in their chemotherapy decision or perceived recurrence risk. We evaluate the relationship between these outcomes and GEP testing. METHODS: We surveyed women eligible for GEP testing (stage I or II, Gr1-2, ER+, HER2-) identified through the Surveillance, Epidemiology, and End Results (SEER) Registry of Washington or Kaiser Permanente Northern California from 2012 to 2016, approximately 0-4 years from diagnosis (N = 904, RR = 45.4%). Confidence in chemotherapy was measured as confident (Very, completely) versus Not Confident (Somewhat, A little, Not At All); perceived risk recurrence was recorded numerically (0-100%). Women reported their GEP test receipt (Yes, No, Unknown) and risk recurrence score (High, Intermediate, Low, Unknown). In our analytic sample (N = 833), we propensity score weighted the three test receipt cohorts and used propensity weighted multivariable regressions to examine associations between the outcomes and the three test receipt cohorts, with receipt stratified by score. RESULTS: 29.5% reported an unknown GEP test receipt; 86% being confident. Compared to no test receipt, an intermediate score (aOR 0.34; 95% CI 0.20-0.58), unknown score (aOR 0.09; 95% CI 0.05-0.18), and unknown test receipt (aOR 0.37; 95% CI 0.24-0.57) were less likely to report confidence. Most women greatly overestimated their recurrence risk regardless of their test receipt or score. CONCLUSIONS: GEP testing was not associated with greater confidence in chemotherapy decisions. Better communication about GEP testing and the implications for recurrence risk may improve women's decisional confidence. PMID- 30306430 TI - Impact of Topoisomerase IIalpha, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy. AB - PURPOSE: Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms. METHODS: We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIalpha (TopoIIalpha), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC. RESULTS: The status of vimentin and increasing labeling index (LI) of TopoIIalpha and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIalpha, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients. CONCLUSION: KI67, TopoIIalpha, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC. PMID- 30306431 TI - Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung. AB - In the original publication, the sixth author name was published incorrectly as Matthew Stein. The correct author name should read as Matthew K Stein. PMID- 30306432 TI - Correction to: Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer. AB - In the original publication, the sixth author name was published incorrectly as A. Wood. The correct author name should read as W. A. Wood. PMID- 30306433 TI - Determining the Roles that Club Drugs, Marijuana, and Heavy Drinking Play in PrEP Medication Adherence Among Gay and Bisexual Men: Implications for Treatment and Research. AB - Researchers have established that substance use interferes with anti-retroviral medication adherence among gay and bisexual men (GBM) living with HIV. There is limited parallel examination of pre-exposure prophylaxis (PrEP) adherence among HIV-negative GBM. We conducted retrospective 30-day timeline follow-back interviews and prospective semi-weekly diary data for 10 weeks with 104 PrEP using GBM, half of whom engaged in club drug use (ketamine, ecstasy, GHB, cocaine, or methamphetamine)-generating 9532 days of data. Participants reported their day-by-day PrEP, club drug, marijuana, and heavy alcohol use (5 + drinks in one sitting). On average, club drug users were no more likely to miss a dose of PrEP than non-club drug users (M = 1.6 doses, SD = 3.0, past 30 days). However, we found that club drug use (at the event level) increased the odds of missing a dose on the same day by 55% and the next day (e.g., a "carryover effect") by 60%. Further, missing a dose on one day increased the odds of missing a dose the following day by eightfold. We did not identify an event-level effect of marijuana use or heavy drinking on PrEP adherence. Our data suggest club drug users could have greater protective effects from daily oral or long-acting injectable PrEP compared to a time-driven PrEP regimen because of the concurrence of club drug use and PrEP non-adherence. PMID- 30306434 TI - A Review of Approaches Used to Increase Awareness of Pre-exposure Prophylaxis (PrEP) in the United States. AB - PrEP is an important and useful HIV prevention strategy, yet awareness remains low among at-risk populations in the United States and elsewhere in the world. As previous studies have shown PrEP awareness to be important to PrEP uptake, understanding approaches to increase PrEP awareness is imperative. The current systematic review provides an overview of published articles and on-going research on PrEP awareness. Using PRISMA guidelines, two published articles and seven on-going research studies were identified that use different approaches to increase PrEP awareness. Findings highlight the need for research to target other at-risk populations and geographic areas. Future research should consider the use of technology and network approaches to assess whether they lead to increased awareness, accurate knowledge, and uptake of PrEP, along with examining which messaging works best for specific targeted, at-risk population(s). PMID- 30306435 TI - Promoting 'Equitable Access' to PrEP in Australia: Taking Account of Stakeholder Perspectives. AB - As evidence of the safety and effectiveness of HIV pre-exposure prophylaxis (PrEP) has grown, so has attention to the views of prospective users and providers. However, far less attention has been paid to understanding the perspectives of other stakeholders in the rollout of PrEP access programs. We conducted 21 semi-structured qualitative interviews in 2017 with key stakeholders working across the policy, advocacy, research and/or clinical dimensions of the Australian HIV response, before federal support for a subsidised access scheme was achieved. Our analysis explored three areas of shared concern: who is a suitable candidate for PrEP; why are disparities in PrEP access important; and how can disparities be addressed? In examining how this diverse group of professionals grappled with the challenges of promoting 'equitable access' to PrEP in an increasingly resource rationed health system, we can see how the principles believed to underpin the Australian response to HIV were both reaffirmed and challenged through this period of significant change. PMID- 30306436 TI - Increases in Pre-exposure Prophylaxis Use and Decreases in Condom Use: Behavioral Patterns Among HIV-Negative San Francisco Men Who have Sex with Men, 2004-2017. AB - Using data from the National HIV Behavioral Surveillance of men who have sex with men (MSM), we estimated the prevalence of sexual behaviors among HIV-negative San Francisco MSM between 2004 and 2017. We estimate a recent increase in the 1-year prevalence of pre-exposure prophylaxis (PrEP) use, from 9.8% in 2014 to 44.9% in 2017. Over that same period, we estimate a decrease in the prevalence of consistent condom use, from 18.5 to 9.4%, and an increase in the percent of individuals with multiple condomless anal intercourse partners. We conclude that while risks for HIV infection may be decreasing among San Francisco MSM due, in part, to increases in PrEP use, the population faces increased risks for other sexually transmitted infections (STIs). Because PrEP alone does not protect against other STIs, we strongly recommend that PrEP users use condoms when possible, routinely screen for STIs, and disclose infections with sexual partners. PMID- 30306437 TI - Client and Provider Perspectives on Antiretroviral Treatment Uptake and Adherence Among People Who Inject Drugs in Indonesia, Ukraine and Vietnam: HPTN 074. AB - HIV-infected people who inject drugs (PWID) have low uptake of HIV services, increasing the risk of transmission to uninfected injection or sexual partners and the likelihood of AIDS-related deaths. HPTN 074 is a vanguard study assessing the feasibility of an integrated intervention to facilitate treatment as prevention to PWID in Indonesia, Ukraine, and Vietnam. We describe barriers to and facilitators of ART uptake and adherence among PWID. We conducted in-depth interviews with 62 participants, including 25 providers and 37 PWID at baseline across all sites. All interviews were recorded, transcribed, translated into English and coded in NVivo for analysis. Matrices were developed to identify emergent themes and patterns. Overall, differences between provider and PWID perspectives were greater than differences in cross-site perspectives. Providers and PWID recognized clinic access, financial barriers, side effects, and lack of information about HIV testing and ART enrollment as barriers to ART. However, providers tended to emphasize individual level barriers to ART, such as lack of motivation due to drug use, whereas PWID highlighted health systems barriers, such as clinic hours and financial burden, fears, and side effects. Providers did not mention stigma as a barrier though their language reflected stereotypes about drug users. The differences between provider and PWID perspectives suggest a gap in providers' understanding of PWID. This misunderstanding has implications for patient-provider interactions that may affect PWID willingness to access care or adhere to ART. Lessons learned from this study will be important as countries with a significant HIV burden among PWID design and implement programs to engage HIV-infected PWID in care and treatment. PMID- 30306438 TI - Cross-Cultural Validation of the Health Care Provider HIV/AIDS Stigma Scale (HPASS) in China. AB - The study aimed to validate the Health Care Provider HIV/AIDS Stigma Scale among medical staff in China. The validation was conducted in four steps from March to December 2017: translation and back-translation; content validity test with six experts; test-retest reliability testing with 63 medical staff with 2 weeks interval; and structural validation with 349 medical staff from 52 hospitals with a convenience sample,using exploratory factor analysis,including principal component analysis and varimax rotation. The scale content validity index average was 0.88, while for test-retest reliability, the ICC was 0.87. Three factors of "discrimination", "prejudice" and "stereotype" with 16 items were extracted and explained 59.61% variance. The Cronbach's alpha value for the total scale was of 0.88, and for the three factors, the values were 0.89, 0.86 and 0.74, respectively. The discrimination factor showed identical means between Canadian medical students and Chinese medical staff, while the prejudice and stereotype factors had higher mean scores in the Chinese sample. The three-factor structure of Health Care Provider HIV/AIDS Stigma Scale was confirmed in Chinese medical staff with a simpler solution. This could provide a basis for trans-cultural application and comparison. PMID- 30306439 TI - The Context of Sexual Risk Behaviour Among Men Who Have Sex with Men Seeking PrEP, and the Impact of PrEP on Sexual Behaviour. AB - There are still important gaps in our understanding of how people will incorporate PrEP into their existing HIV prevention strategies. In this paper, we explore how PrEP use impacted existing sexual risk behaviours and risk reduction strategies using qualitative data from the PROUD study. From February 2014 to January 2016, we conducted 41 in-depth interviews with gay, bisexual and other men who have sex with men (GBMSM) enrolled in the PROUD PrEP study at sexual health clinics in England. The interviews were conducted in English and were audio-recorded. The recordings were transcribed, coded and analysed using framework analysis. In the interviews, we explored participants' sexual behaviour before joining the study and among those using or who had used PrEP, changes to sexual behaviour after starting PrEP. Participants described the risk behaviour and management strategies before using PrEP, which included irregular condom use, sero-sorting, and strategic positioning. Participants described their sexual risk taking before initiating PrEP in the context of the sexualised use of drugs, geographical spaces linked with higher risk sexual norms, and digitised sexual networking, as well as problematic psychological factors that exacerbated risk taking. The findings highlight that in the main, individuals who were already having frequent condomless sex, added PrEP to the existing range of risk management strategies, influencing the boundaries of the 'rules' for some but not all. While approximately half the participants reduced other risk reduction strategies after starting PrEP, the other half did not alter their behaviours. PrEP provided an additional HIV prevention option to a cohort of GBMSM at high risk of HIV due to inconsistent use of other prevention options. In summary, PrEP provides a critical and necessary additional HIV prevention option that individuals can add to existing strategies in order to enhance protection, at least from HIV. As a daily pill, PrEP offers protection in the context of the sex cultures associated with sexualised drug use, digitised sexual applications and shifting social norms around sexual fulfilment and risk taking. PrEP can offer short or longer-term options for individuals as their sexual desires change over their life course offering protection from HIV during periods of heightened risk. PrEP should not be perceived or positioned in opposition to the existing HIV prevention toolkit, but rather as additive and as a tool that can and is having a substantial impact on HIV. PMID- 30306440 TI - Coil embolization of pseudoaneurysm as a complication of excimer laser coronary angioplasty: insights from intravascular ultrasound and optical coherence tomography findings. AB - The occurrence of pseudoaneurysm in the coronary artery is rare and can develop after percutaneous coronary interventions. To date, the optimal therapy, including conservative, surgical, and endovascular therapies, for pseudoaneurysm in the coronary artery remains unclear. Here, we report a case of pseudoaneurysm arising as a complication of excimer laser coronary angioplasty, which was successfully treated with stent-assisted coil embolization, after which optical coherence tomography revealed complete healing of the pseudoaneurysm. This report highlights the feasibility of stent-assisted coil embolization for coronary pseudoaneurysms involving bifurcation. PMID- 30306441 TI - Simulated reactive zone with emulsified vegetable oil for the long-term remediation of Cr(VI)-contaminated aquifer: dynamic evolution of geological parameters and groundwater microbial community. AB - Cr(VI), which is highly toxic and soluble, is one of the most challenging groundwater contaminants. Previous work has indicated that emulsified vegetable oil (EVO) is an effective in situ amendment for removing Cr(VI) from groundwater. However, the spatial and temporal changes in geological parameters and microbial community structures throughout the remediation period are poorly understood. In this study, a large laboratory-scale sand-packed chamber (reactive zone of 100 * 50 * 30 cm) was used to simulate the bioremediation of Cr(VI)-contaminated aquifer by EVO over a 512-day period. Various geological parameters and microbial communities were monitored during both the establishment and remediation stages. The results indicate that several biogeochemical reactions occurred in a specific sequence following the injection of EVO, creating an acidic and reducing environment. A shift in the community structure and a decrease in the community diversity were observed. The abundance of microbes involved in the degradation of EVO and reduction of electron acceptors significantly increased. Then, the EVO reactive zone was flushed with Cr(VI)-contaminated groundwater. Biogeochemical reactions were inhibited after the inflow of Cr(VI) and subsequently recovered a month later. The pH of the aquifer returned to the initial neutral condition (approximately 7.2). The EVO reactive zone could remediate Cr(VI)-contaminated groundwater at an efficiency exceeding 97% over 480 days. Biogeochemistry played a major role in the early period (0~75 days). In the later period (240~480 days), the remediation of Cr(VI) in the reactive zone depended mostly on bio-reduction by Cr(VI)-reducing bacteria. PMID- 30306443 TI - Transient dispersion of an initial point pollutant concentration in wetland flows. AB - Initial point pollutant transport in wetland flows acts as a typical form in various applications. Accurate determination of the basic characteristics for dispersion fundamentally supports the predication of pollutant transport especially in the transient stage. This work analytically studies the transient dispersion of an initial point pollutant concentration in wetland flows through the phase average technique and the method of concentration moments. The characteristics including the vertical mass distribution, longitudinal displacement, dispersivity, skewness, and kurtosis corresponding to the zeroth- to fourth-order concentration moments are accurately illustrated in their full time dependance for the first time. Present results show to be distinctive from those of initial uniform concentration in the transient dispersion process. The temporal evolutions of the five characteristics are all dependent of the initial point release position. The results further demonstrate that the timescale 3.0 as measured by the skewness, rather than 0.5 as measured by the dispersivity, should be characterized as the transient period for the dispersion of initial point concentration in comparison with that of initial uniform. Furthermore, the longitudinally distributed mean concentration is as well analyzed through the Hermite polynomials. The results imply that strict criteria for environmental and ecological implications should be established by further accounting for the five characteristics. PMID- 30306442 TI - Stage-specific testicular protein levels of the oestrogen receptors (ERalpha and ERbeta) and Cyp19 and association with oestrogenic contamination in the lambari Astyanax rivularis (Pisces: Characidae). AB - Oestrogens participate in various biological processes such as oogenesis, vitellogenesis and testicular development, but studies regarding the distribution and protein levels of oestrogen receptors (ERalpha and ERbeta) and aromatase (Cyp19) in testis are rarely investigated in fish species. The aim of the present study was to analyse the expression pattern of ERalpha, ERbeta and Cyp19 in testis of Astyanax rivularis and, in addition, to verify if oestrogenic contamination interferes in the expression levels of these proteins. Quarterly, field samplings were carried out during a reproductive cycle in a stream of the Upper Velhas River with a good conservation status (site S1). In the gonadal maturation peak (June), when ripe stage was most abundant, fish collection was made in three streams: S1, reference site, and S2 and S3, sites contaminated by untreated sewage. The results of immunohistochemistry demonstrated labelling of Cyp19 in Leydig cells and acidophilic granulocytes, but spermatogonia, Sertoli cells, spermatids and spermatozoa were also labelled. ERalpha was more widely distributed than ERbeta being found in all developmental germ cell phases. On the other hand, ERbeta was found only in spermatogonia and spermatocytes. During testicular maturation, ELISA levels for Cyp19, ERalpha and ERbeta followed the gonadosomatic index (GSI) with significant higher values in the ripe stage. Regarding to endocrine disruption, the males exposed to domestic sewage presented significant higher expression of Cyp19 and ERalpha when compared to the non exposed fish. Together, our results demonstrate expression patterns of Cyp19, ERalpha and ERbeta in the testis of A. rivularis. In addition, we indicate ERalpha and Cyp19 as sensitive biomarkers for monitoring of oestrogenic contamination in freshwater environments. PMID- 30306444 TI - Biocontrol, new questions for Ecotoxicology? PMID- 30306445 TI - Bed and suspended sediment-associated rare earth element concentrations and fluxes in a polluted Brazilian river system. AB - Rare earth elements (REEs) have been recently recognized as emergent pollutants in rivers. However, data regarding REE fluxes in association with either bed or suspended are scarce. To address this knowledge gap, we determined the concentrations and fluxes of La, Ce, Pr, Nd, Sm, Eu, Gd, Yb, Lu, Dy, Er, Ho, Tb, and Tm in bed and suspended sediment samples of a representative polluted Brazilian River. Sediment-associated data on REEs were placed in the context of corresponding background concentrations in soils under natural conditions along the Ipojuca watershed. Light rare earth elements (LREEs) comprised more than 94% of the total REEs associated with bed and suspended sediments. Suspended sediments accounted for more than 95% of the total REE flux. The Ce and Nd fluxes of about 7 t year-1 underscore the importance of including REEs in future estimations of global suspended sediment-associated element fluxes. In contrast, bedload often transported less than 0.0007 t year-1 of each REE. The main sources of pollution in the Ipojuca River are anthropogenic, likely due to domestic effluent and waste water from industrial and agricultural operations-major causes of sediment-associated Gd transport in polluted streams. PMID- 30306447 TI - Quantitative analysis of the coupling coefficients between energy flow, value flow, and material flow in a Chinese lead-acid battery system. AB - To reveal the historic characteristics of the material flow, energy flow and value flow in a lead-acid battery (LAB) system, a framework for the coupling relationship among the three flows was established based on material flow analysis and the characteristics of the energy and value flows. The coupling coefficients between energy and material (CCEM) and value and material (CCVM) were also defined. The investigation used by China as a case to study changes in stages and the historic evolution. The results show that the CCEM for lead in LABs was highest in the usage stage, approximately 5-16 times greater than in the other stages. The CCEM for production was almost twice as high for primary lead as for secondary lead, and the CCEM was lowest for the fabrication and product manufacture stage. The CCVM for lead in LABs was 2.5-6 times higher than for other types of lead. The CCVM was lower for scrap lead than for lead ore, and the CCVM was approximately 1.7 times higher for refined lead than for scrap and refined lead. For lead trade, CCVM was correlated with domestic and overseas markets. From 1990 to 2014, the CCEM for each stage was in decline, whereas the opposite was the case for CCVM. The influencing factors were analyzed in terms of resources, the environment, and markets. Increasing the circulation rate of scrap lead is an effective way to rapidly save resources, reduce lead pollution, and promote a circular economy. The limitations and potential value of the study are also highlighted, and future research is outlined. PMID- 30306446 TI - Self-assembled three-dimensional double network graphene oxide/polyacrylic acid hybrid aerogel for removal of Cu2+ from aqueous solution. AB - Three-dimensional (3D) double network graphene oxide/polyacrylic acid (GO/PAA) hybrid aerogels were fabricated under mild conditions from the mixture of GO and acrylic acid (AA) monomers using a one-pot in situ solution polymerization process which included the polymerization of AA and the self-assembly of functional GO sheets. The PAA chains served as not only binder to assemble GO sheets into 3D framework but also modifier to provide more active functional groups. The adsorbents based on such material exhibited superior adsorption performance towards Cu2+ ions in aqueous media due to rich mesopores, high specific surface area, and abundant active sites. This work brings a new vision for assembling 3D porous graphene-based nanomaterials as adsorbents in environmental protection. PMID- 30306448 TI - Factors Shaping Women's Pre-abortion Communication with Members of Their Social Network. AB - To understand women's pre-abortion conversations with members of their social network about their abortion decision. Semi-structured interviews were conducted with women presenting for first-trimester surgical abortion at a high volume, hospital-based abortion clinic. Women were asked their reasons for discussing or not discussing abortion and responses received after disclosing their abortion decision. Interviews were transcribed and computer-assisted content analysis was performed. Salient themes are presented. Thirty women who obtained an abortion were interviewed. All but three spoke to at least one member of their social network about their abortion decision making. However, women were very selective about whom they spoke to regarding this decision. Reasons not to discuss their abortion decision included: concerns about judgment, desiring to maintain privacy, and certainty about their decision. Reasons to discuss their abortion decision included: seeking information about the procedure, needing guidance about their decision, wanting support for their decision to proceed with abortion. While many were concerned about being judged, most women who spoke about their decision experienced a positive response. Though most women in this study had at least one person to turn to for assistance with abortion decision making, many participants avoided confiding in some or all members of their social network about their abortion decision due to concerns of judgment and stigma. PMID- 30306449 TI - A Workplace-Based Intervention to Improve Awareness, Knowledge, and Utilization of Breast, Cervical, and Colorectal Cancer Screenings Among Latino Service and Manual Labor Employees in Utah. AB - In the United States, Latinos are more likely to be uninsured and diagnosed with later stage cancer than non-Hispanic whites. Promotoras (lay health educators) help improve cancer knowledge and facilitate access to cancer screenings. We tested a promotora led workplace-based intervention to improve knowledge of and adherence to breast, cervical, and colorectal cancer screening among Latino employees in service or manual labor jobs. Latinos 18 and older from Salt Lake County, Utah were enrolled from January 2015 to February 2016. N = 265 completed pre- and post-intervention surveys that measured knowledge of and adherence to breast, cervical, and colorectal cancer screenings. Demographic, economic, and cancer factors of participants who completed the intervention were compared to those who were incomplete. Changes in knowledge and adherence were calculated using McNemar's tests. Logistic regression compared outcomes by select demographic, economic and cancer factors. More participants were older, spoke Non English languages, were single/widow(er)s, worked part-time, and had an immediate family member with cancer compared to those who did not complete the study (all p < 0.05). Knowledge of the age to begin cancer screenings increased significantly from baseline to follow-up for cervical (65.1-77.7%), breast (67.2-81.7%), and colorectal cancer (49.8-80.7%), all p <= 0.001. Knowledge of the frequency of cervical (34.0-46.5%) and colorectal (72.1-84.5%) screening increased from baseline to follow-up, both p < 0.001. Adherence to fecal immunochemical tests (FIT) for colorectal cancer increased from baseline to follow-up (13.8-56.9%, p < 0.001). Promotora led workplace-based interventions can strengthen community capacity for educating and supporting Latino employees in preventing breast, cervical, and colorectal cancer. PMID- 30306450 TI - VMAT2 Inhibitors in Neuropsychiatric Disorders. AB - The basal ganglia and dopaminergic pathways play a central role in hyperkinetic movement disorders. Vesicular monoamine transporter 2 (VMAT2) inhibitors, which deplete dopamine at presynaptic striatal nerve terminals, are a class of drugs that have long been used to treat hyperkinetic movement disorders, but have recently gained more attention following their development for specific indications in the United States. At present, there are three commercially available VMAT2 inhibitors: tetrabenazine, deutetrabenazine, and valbenazine. Pharmacokinetics, metabolism, and dosing vary significantly between the three drugs, and likely underlie the more favorable side effect profile of the newer agents (deutetrabenazine and valbenazine). Tetrabenazine and deutetrabenazine have demonstrated safety and efficacy in the treatment of chorea associated with Huntington's disease, including in randomized controlled trials, although direct comparison studies are limited. Both deutetrabenazine and valbenazine have demonstrated safety and efficacy in the treatment of tardive dyskinesia, with multiple double-blind, placebo-controlled trials, whereas tetrabenazine has been studied less rigorously. There have been no blinded, prospective trials with tetrabenazine in Tourette's syndrome (TS); however, double-blind, placebo controlled trials in TS are ongoing for both deutetrabenazine and valbenazine. Given the favored side effect profile of newer VMAT2 inhibitors, clinicians should be aware of the distinctions between agents and become familiar with differences in their use, especially as there is potential for their utilization to increase across the range of hyperkinetic movement disorders. PMID- 30306451 TI - Optimal Extent of Superior Mesenteric Artery Dissection during Pancreaticoduodenectomy for Pancreatic Cancer: Balancing Surgical and Oncological Safety. AB - BACKGROUND: We describe the short- and long-term outcomes for PDAC patients after tailored mesopancreas dissection using supracolic artery-first approach followed by adjuvant therapy. METHODS: This study analyzed 233 consecutive patients who underwent artery-first pancreaticoduodenectomy for PDAC. Dissection extent for the superior mesenteric artery (SMA) was categorized into three levels: level 2 (LV2) including regional lymph nodes, level 3 (LV3) with hemicircumferential nerve plexus dissection, and extended-level 3 (E-LV3) including borderline resectable cases for the SMA. All clinical, pathological, and survival outcomes were reviewed. RESULTS: LV2/3/E-LV3 dissection was performed in 77/115/41 patients. The short-term outcomes were similar among groups without mortality. Although postoperative diarrhea requiring opioids was significantly more frequent in the E-LV3 group (76%) than other groups (vs. LV2 (21%), P < .0001; vs. LV3 (34%), P < .0001; LV2 vs. LV3, P = 0.20), most cases of diarrhea were well controlled. Adjuvant chemotherapy was introduced similarly among groups (LV2, 76%; LV3, 81%; E-LV3, 88%, P = 0.29). The 3- and 5-year overall survival rates in the LV2/3/E-LV3 groups were 42/33/42% and 27/22/26%, respectively, showing no significant difference among groups. DISCUSSION: Our tailored dissection and preemptive use of opioid antidiarrheal effectively prevents intractable diarrhea, increasing the success of adjuvant chemotherapy. PMID- 30306452 TI - Importance of Resection Margins in the Treatment of Rectal Adenomas by Transanal Endoscopic Surgery. AB - BACKGROUND: Polypectomy is the gold standard for treating colorectal adenomas up to 2 cm in size. For larger lesions, various procedures ranging from endoscopy to transanal surgery can be performed and achieve varying results for en bloc resection and recurrence. There are no clear guidelines for dealing with involved resection margins. We assess the recurrence of rectal adenomas operated using TEM with full-thickness wall excision with or without free resection margins and define optimal endoscopic follow-up. METHOD: Observational study with prospective data collection, including patients undergoing TEM between 6/2004 and 11/2017, with definitive diagnosis of rectal adenoma. Data on epidemiological, preoperative, surgical, postoperative, pathological, and follow-up variables were recorded. Univariate analysis, follow-up risk function, and multivariate logistic regression analysis were performed to detect risk factors for recurrence. RESULTS: TEM was indicated in 736 patients; 481 adenomas were identified in the preoperative biopsy, of which 95 were infiltrating adenocarcinomas (19.8%) in the definitive pathology study. With a minimum follow-up of 1 year, 372 patients were included. Pathology study showed free margins in 324 (87%). Recurrences were recorded in 15 patients (4%), up to 18 months in the free margins group and up to 24 months in the involved margins group. Thirteen patients with recurrence (86.6%) were treated with TEM. No predictors of recurrence were found in the multivariate analysis. CONCLUSION: TEM is the technique of choice for treating rectal adenomas and recurrences, achieving a low relapse rate. Follow-up must be adapted to resection margins and should be extended to 24 months. PMID- 30306455 TI - Upregulation of HRD1 promotes cell migration and invasion in colon cancer. AB - 3-Hydroxy-3-methylglutaryl reductase degradation (HRD1) is an E3 ubiquitin ligase that functions by promoting degradation of misfolded proteins in processes such as embryogenesis and rheumatoid arthritis. However, little is known about the role of HRD1 in cancer. The aim of the present study was to investigate the expression pattern and functions of HRD1 in human colon cancer (CC). We found that HRD1 expression was increased significantly in human CC tissues, and its overexpression was associated with TNM stage, tumor differentiation, tumor invasive depth, and distant metastasis. Knockdown of HRD1 using small hairpin (sh) RNA plasmid significantly inhibited CC cell migration and invasion. Furthermore, the silencing of HRD1 decreased the expression of MMP-2 and MMP-9, which is critical for CC cell migration and invasion. Taken together, these results revealed that HRD1 is overexpressed in CC and promotes migration and invasion of CC cells. Inhibition of HRD1 may be considered as an effective anti CC strategy. PMID- 30306454 TI - Factors influencing the recruitment of lactating women in a clinical trial involving direct oral anticoagulants: a qualitative study. AB - Background Robust human data on medication use during lactation is scarce. With increasing medication use in postpartum women, it is important to conduct clinical lactation studies measuring the excretion of drugs in human milk and generate evidence. We plan to conduct a clinical lactation study, involving the direct oral anticoagulants (DOACs). Objective This study aimed to identify factors influencing lactating women's clinical trial participation and to improve the design of a proposed DOACs clinical lactation study. Setting Lactating women in London, UK. Methods Three focus groups were conducted in lactating women with differing experiences of being prescribed anticoagulants during puerperium. Main outcome measures Thematic framework approach was used to analyse and identify key themes, using NVivo version 11. Results Eight breastfeeding mothers participated. Women's decision-making on clinical trial participation was largely influenced by the lactation stage and previous breastfeeding experience. The concern of harm to their infant caused by the test medication or interruption of lactation were the predominant barriers to potential participation. Around 6 months following the birth of their infant and second-time mothers appeared to be more amenable to clinical trial participation. The provision of home visits for the execution of the study was highly recommended. Conclusion Our findings suggest that lactating women would participate in a clinical trial during the breastfeeding period, if the timing is right and if the woman is an experienced mother. Home visits will be provided in our proposed DOACs clinical lactation study. PMID- 30306456 TI - Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury. AB - Fatty infiltration and inflammation delay the healing responses and raise major concerns in the therapeutic management of rotator cuff tendon injuries (RCTI). Our evaluations showed the upregulation of 'metabolic check point' AMPK and inflammatory molecule, TREM-1 from shoulder biceps tendons collected from RCTI subjects. However, the epigenetic regulation of these biomolecules by miRNAs is largely unknown and it is likely that a deeper understanding of the mechanism of action can have therapeutic potential for RCTI. Based on this background, we have evaluated the miRNAs from RCTI patients with fatty infiltration and inflammation (FI group) and compared with RCTI patients without fatty infiltration and inflammation (No-FI group). NetworkAnalyst was employed to evaluate the genes interconnecting AMPK and TREM-1 pathway, using PRKAA1 (AMPK), TREM-1, HIF1alpha, HMGB1, and AGER as input genes. The most relevant miRNAs were screened by considering the fold change below - 7.5 and the number of target genes 10 and more which showed 13 miRNAs and 216 target genes. The exact role of these miRNAs in the fatty infiltration and inflammation associated with RCTI is still unknown and the understanding of biological activity of these miRNAs can pave ways to develop miRNA-based therapeutics in the management of RCTI. PMID- 30306457 TI - Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma. AB - Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components. PMID- 30306458 TI - A unified deep-learning network to accurately segment insulin granules of different animal models imaged under different electron microscopy methodologies. PMID- 30306459 TI - Rapid optimization of liposome characteristics using a combined microfluidics and design-of-experiment approach. AB - Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposome formulations, i.e., up to 30 liposome formulations in 1 day. Five representative liposome formulations based on clinically approved lipid compositions were formulated using systematic variations in microfluidics flow rate settings, i.e., flow rate ratio (FRR) and total flow rate (TFR). Interestingly, flow rate-dependent DoE models for the prediction of liposome characteristics could be grouped according to lipid-phase transition temperature and surface characteristics. For all formulations, the FRR had a significant impact (p < 0.001) on hydrodynamic diameter and size distribution of liposomes, while the TFR mainly affected the production rate. Liposome characteristics remained constant for TFRs above 8 mL/min. The stability study revealed an influence of lipid:cholesterol ratio (1:1 and 2:1 ratio) and presence of PEG on liposome characteristics during storage. To validate our DoE models, we formulated liposomes incorporating hydrophobic dodecanethiol-coated gold nanoparticles. This proof-of-concept step showed that flow rate settings predicted by DoE models successfully determined the size of resulting empty liposomes (109.3 +/- 15.3 nm) or nanocomposites (111 +/- 17.3 nm). This study indicates that a microfluidics-based formulation approach combined with DoE is suitable for the routine development of monodisperse and size-specific liposomes in a reproducible and rapid manner. PMID- 30306460 TI - Low Baseline Serum Sodium Concentration Is Associated with Poor Clinical Outcomes in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy. AB - BACKGROUND: A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO). OBJECTIVE: Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (<= 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO. PATIENTS AND METHODS: We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15-0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80-4.80; P < .001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70-3.90; P < .001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS. CONCLUSIONS: Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation. PMID- 30306461 TI - IgG4-related inflammatory pseudotumor of the brain parenchyma: a case report and literature review. AB - A 29-year-old male with a 4-month history of binocular temporal visual field defect, 1-month history of memory loss and 5-day history of headache was admitted to our hospital. Brain MRI showed progressive signal abnormalities in the brain parenchyma. His laboratory tests showed elevated serum IgG4 and liver dysfunction. Abdominal CT, ultrasound and liver biopsy showed chronic liver disease. According to the diagnostic criteria of IgG4-related disease, IgG4 related inflammatory pseudotumor of brain parenchyma was considered. After methylprednisolone treatment, his symptoms improved and brain lesion reduced. This is the second reported case of a tumefactive lesion of the brain with serum IgG4 elevation, which was responsive to steroid treatment. Coincidentally, his mother had similar medical history and imaging findings, and was subspecialty diagnosed with the same disease, but without pathological and immunohistochemical confirmation. This suggests that the disease may be hereditary. It is important to recognize IgG4-related inflammatory pseudotumors of the brain parenchyma so that patients do not undergo unnecessary surgical or other procedures. PMID- 30306462 TI - Response of the microbial community associated with sweet potato (Ipomoea batatas) to Bacillus safensis and Bacillus velezensis strains. AB - Sweet potato is a subsistence crop cultivated worldwide. Although it is generally considered tolerant to different diseases, it is quite susceptible to the fungus Plenodomus destruens that causes foot-rot disease. Plant growth-promoting bacteria associated with sweet potato remain poorly studied, but some Bacillus strains may have potential as biological control agents. Here, we evaluate the persistence of two bacterial strains-Bacillus safensis T052-76 and Bacillus velezensis T149-19-in pot experiments and assess their impact on indigenous bacterial and fungal communities associated with sweet potato. Numbers of cells of both strains introduced into pots remained stable in the rhizosphere of sweet potato over the 180-day experiment. Denaturing gradient gel electrophoresis based on the rrs gene encoding bacterial 16S rRNA and the fungal ribosomal internal transcribed spacer region showed that bands corresponding to the introduced strains were not detected in plant endosphere. PERMANOVA and non-metric multidimensional scaling statistical analyses showed that: (1) strain T052-76 altered the structure of the indigenous bacterial community (rhizosphere and soil) more than strain T149-19; (2) T052-76 slightly altered the structure of the indigenous fungal community (rhizosphere and soil) and (3) strain T149-19 did not disturb the fungal community. Our results demonstrate the stability of both Bacillus strains in the sweet potato rhizosphere and, apart from the influence of B. safensis T052-76 on the bacterial community, their limited impact on the microbial community associated with this important crop plant. PMID- 30306463 TI - Signalling in actinorhizal root nodule symbioses. AB - Plants able to establish a nitrogen-fixing root nodule symbiosis with the actinobacterium Frankia are called actinorhizal. These interactions lead to the formation of new root organs, called actinorhizal nodules, where the bacteria are hosted intracellularly and fix atmospheric nitrogen thus providing the plant with an almost unlimited source of nitrogen for its nutrition. Like other symbiotic interactions, actinorhizal nodulation involves elaborate signalling between both partners of the symbiosis, leading to specific recognition between the plant and its compatible microbial partner, its accommodation inside plant cells and the development of functional root nodules. Actinorhizal nodulation shares many features with rhizobial nodulation but our knowledge on the molecular mechanisms involved in actinorhizal nodulation remains very scarce. However recent technical achievements for several actinorhizal species are allowing major discoveries in this field. In this review, we provide an outline on signalling molecules involved at different stages of actinorhizal nodule formation and the corresponding signalling pathways and gene networks. PMID- 30306464 TI - Mucilaginibacter formosus sp. nov., a bacterium isolated from road-side soil. AB - A Gram-stain negative, aerobic, non-motile and rod-shaped novel bacterial strain, designated as MAH-5T, was isolated from a road-side soil sample and was characterised by using a polyphasic taxonomic approach. The colonies were observed to be yellowish orange in colour, smooth, circular and 0.3-0.7 mm in diameter when grown on nutrient agar for 2 days. Strain MAH-5T was found to be able to grow at 15-35 degrees C and at pH 4.0-8.0. The strain was observed to be positive for both the catalase and oxidase tests. Cells were found to be able to hydrolyse aesculin, gelatin and starch. By 16S rRNA gene sequence comparisons, the isolate was identified as a member of the genus Mucilaginibacter and to be closely related to Mucilaginibacter panaciglaebae BXN5-31T (98.35%), Mucilaginibacter soyangensis HME6664T (97.82%), Mucilaginibacter antarcticus S14 88T (97.49%) and Mucilaginibacter ximonensis XM-003T (97.06%). In DNA-DNA hybridization tests, the DNA relatedness values between strain MAH-5T and its close phylogenetic neighbors were below 45.0%. The genomic DNA G + C content of strain MAH-5T was determined to be 41.5 mol% and the predominant isoprenoid quinine was identified as MK-7. The major fatty acids were identified as C15:0 iso and summed feature 3 (comprising C16:1 omega7c and/or C16:1 omega6c). The genetic characteristics, in combination with chemotaxonomic and physiological data, demonstrated that the isolated strain MAH-5T represents a novel species within the genus Mucilaginibacter, for which the name Mucilaginibacter formosus sp. nov. is proposed, with MAH-5T as the type strain (= KACC 19291T = CGMCC1.16489T). PMID- 30306465 TI - Effectiveness of a novel real-time dosimeter in interventional radiology: a comparison of new and old radiation sensors. AB - Radiation dose management is important in interventional radiology (IR) procedures, such as percutaneous coronary intervention, to prevent radiation induced injuries. Therefore, radiation dose should be monitored in real time during IR. This study evaluated the fundamental characteristics of a novel real time skin dosimeter (RTSD) developed at our institution. In addition, we compared the performance of our new and old radiation sensors and that of a skin dose monitor (SDM), with ion chamber reference values. We evaluated the fundamental characteristics (e.g., energy dependence, dose dependence, and angular dependence) of the RTSD developed by us in the diagnostic X-ray energy range. The performance of our RTSD was similar to that of the SDM. In particular, the new radiation sensor of our RTSD demonstrated better dose rate dependence compared to the old sensor. In addition, the new sensor had the advantage of being small in size and thus minimally affecting the X-ray images compared to the old sensor. Therefore, the developed skin dosimeter and radiation sensor may be useful in real-time measurement of patients' exposure to and multi-channel monitoring of radiation in IR procedures. The new dosimeter system can be recommended for visualization and management of the radiation dose to which the patients' skin is exposed. PMID- 30306467 TI - Effects of Blood Flow Restriction Training on Muscular Strength and Hypertrophy in Older Individuals: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The combination of low-load resistance training with blood flow restriction (BFR) has recently been shown to promote muscular adaptations in various populations. To date, however, evidence is sparse on how this training regimen influences muscle mass and strength in older adults. PURPOSE: The purpose of this systematic review and meta-analysis was to quantitatively identify the effects of low-load BFR (LL-BFR) training on muscle mass and strength in older individuals in comparison with conventional resistance training programmes. Additionally, the effectiveness of walking with and without BFR was assessed. METHODS: A PRISMA-compliant systematic review and meta-analysis was conducted. The systematic literature research was performed in the following electronic databases from inception to 1 June 2018: PubMed, Web of Science, Scopus, CINAHL, SPORTDiscus and CENTRAL. Subsequently, a random-effects meta-analysis with inverse variance weighting was conducted. RESULTS: A total of 2658 articles were screened, and 11 studies with a total population of N = 238 were included in the meta-analysis. Our results revealed that during both low-load training and walking, the addition of BFR elicits significantly greater improvements in muscular strength with pooled effect sizes (ES) of 2.16 (95% CI 1.61 to 2.70) and 3.09 (95% CI 2.04 to 4.14), respectively. Muscle mass was also increased when comparing walking with and without BFR [ES 1.82 (95% CI 1.32 to 2.32)]. In comparison with high-load training, LL-BFR promotes similar muscle hypertrophy [ES 0.21 (95% CI - 0.14 to 0.56)] but lower strength gains [ES - 0.42 (95% CI - 0.70 to - 0.14)]. CONCLUSION: This systematic review and meta-analysis reveals that LL-BFR and walking with BFR is an effective interventional approach to stimulate muscle hypertrophy and strength gains in older populations. As BFR literature is still scarce with regard to potential moderator variables (e.g. sex, cuff pressure or training volume/frequency), further research is needed for strengthening the evidence for an effective application of LL-BFR training in older people. PMID- 30306468 TI - Computer-Aided Orthopaedic Surgery: State-of-the-Art and Future Perspectives. AB - Introduced more than two decades ago, computer-aided orthopaedic surgery (CAOS) has emerged as a new and independent area, due to the importance of treatment of musculoskeletal diseases in orthopaedics and traumatology, increasing availability of different imaging modalities and advances in analytics and navigation tools. The aim of this chapter is to present the basic elements of CAOS devices and to review state-of-the-art examples of different imaging modalities used to create the virtual representations, of different position tracking devices for navigation systems, of different surgical robots, of different methods for registration and referencing, and of CAOS modules that have been realized for different surgical procedures. Future perspectives will be outlined. It is expected that the recent advancement on smart instrumentation, medical robotics, artificial intelligence, machine learning, and deep learning techniques, in combination with big data analytics, may lead to smart CAOS systems and intelligent orthopaedics in the near future. PMID- 30306466 TI - Advances in diagnosis of chronic liver diseases in pediatric patients. AB - BACKGROUND: Chronic liver diseases (CLD) present important clinical problem in children with various age-dependent causes. Nonalcoholic fatty liver disease (NAFLD) with its increasing prevalence is a major problem with regard to its timely recognition and the need for long-term disease monitoring. At present, a perfect non-invasive method for the evaluation of liver fibrosis is not available. METHODS: A non-systematic literature search was performed to summarize the current knowledge about transient elastography (TE) with controlled attenuation parameter (CAP) in children with CLD. Ovid MEDLINE, Ovid EMBASE, Google scholar, and The Cochrane Library databases were searched for relevant articles evaluating TE in the pediatric population. RESULTS: Normal values of liver stiffness measurements (LSM) according to the age are given, as well as the advantages and disadvantages of the method. The utility of TE in specific liver disease in pediatric population is summarized. CONCLUSIONS: TE with CAP is a valuable non-invasive method for the liver-damage assessment. Clinical interpretation of TE results should be made in parallel with the assessment of the patient's demographics, disease etiology, and essential laboratory parameters. PMID- 30306469 TI - Computer-Aided Orthopedic Surgery: Incremental Shift or Paradigm Change? AB - Computer-aided orthopedic surgery (CAOS) is now about 25 years old. Unlike neurosurgery, computer-aided surgery has not become the standard of care in orthopedic surgery. In this paper, we provide the technical and clinical context raised by this observation in an attempt to elucidate the reasons for this state of affairs. We start with a brief outline of the history of CAOS, review the main CAOS technologies, and describe how they are evaluated. We then identify some of the current publications in the field and present the opposing views on their clinical impact and their acceptance by the orthopedic community worldwide. We focus on total knee replacement surgery as a case study and present current clinical results and contrasting opinions on CAOS technologies. We then discuss the challenges and opportunities for research in medical image analysis in CAOS and in musculoskeletal radiology. We conclude with a suggestion that while CAOS acceptance may be more moderate than that of other fields in surgery, it still has a place in the arsenal of useful tools available to orthopedic surgeons. PMID- 30306470 TI - CAMISS Concept and Its Clinical Application. AB - This chapter intends to provide an overview of computer-assisted minimally invasive spine surgery (CAMISS) and its clinical application. Since minimally invasive spine surgery was first brought out, the concept of decreasing the damage to patient was soon become popular. However, without the proper surgical field, the spine surgery can be very dangerous. The minimally invasive concept was restricted in promotion until the computer-assisted navigation system break down the obstacles. The CAMISS technique achieves better clinical outcomes with the advantages of smaller invasion, less injury, and better recovery and also became the gold standard for spine surgery. The spatial distribution concept and the respiration-induced motion concept help in promoting the accuracy and safety of the CAMISS concept. The CAMISS concept also facilitated the developing of robotic techniques, which was considered as the future of orthopedic surgery. PMID- 30306471 TI - Surgical Navigation in Orthopedics: Workflow and System Review. AB - Orthopedic surgery is a widely performed clinical procedure that deals with problems in relation to the bones, joints, and ligaments of the human body, such as musculoskeletal trauma, spine diseases, sports injuries, degenerative diseases, infections, tumors, and congenital disorders. Surgical navigation is generally recognized as the next generation technology of orthopedic surgery. The development of orthopedic navigation systems aims to analyze pre-, intra- and/or postoperative data in multiple modalities and provide an augmented reality 3-D visualization environment to improve clinical outcomes of surgical orthopedic procedures. This chapter investigates surgical navigation techniques and systems that are currently available in orthopedic procedures. In particular, optical tracking, electromagnetic localizers and stereoscopic vision, as well as commercialized orthopedic navigation systems are thoroughly discussed. Moreover, advances and development trends in orthopedic navigation are also discussed in this chapter. While current orthopedic navigation systems enable surgeons to make precise decisions in the operating room by integrating surgical planning, instrument tracking, and intraoperative imaging, it still remains an active research field which provides orthopedists with various technical disciplines, e.g., medical imaging, computer science, sensor technology, and robotics, to further develop current orthopedic navigation methods and systems. PMID- 30306472 TI - Multi-object Model-Based Multi-atlas Segmentation Constrained Grid Cut for Automatic Segmentation of Lumbar Vertebrae from CT Images. AB - In this chapter, we present a multi-object model-based multi-atlas segmentation constrained grid cut method for automatic segmentation of lumbar vertebrae from a given lumbar spinal CT image. More specifically, our automatic lumbar vertebrae segmentation method consists of two steps: affine atlas-target registration-based label fusion and bone-sheetness assisted multi-label grid cut which has the inherent advantage of automatic separation of the five lumbar vertebrae from each other. We evaluate our method on 21 clinical lumbar spinal CT images with the associated manual segmentation and conduct a leave-one-out study. Our method achieved an average Dice coefficient of 93.9 +/- 1.0% and an average symmetric surface distance of 0.41 +/- 0.08 mm. PMID- 30306473 TI - Deep Learning-Based Automatic Segmentation of the Proximal Femur from MR Images. AB - This chapter addresses the problem of segmentation of proximal femur in 3D MR images. We propose a deeply supervised 3D U-net-like fully convolutional network for segmentation of proximal femur in 3D MR images. After training, our network can directly map a whole volumetric data to its volume-wise labels. Inspired by previous work, multi-level deep supervision is designed to alleviate the potential gradient vanishing problem during training. It is also used together with partial transfer learning to boost the training efficiency when only small set of labeled training data are available. The present method was validated on 20 3D MR images of femoroacetabular impingement patients. The experimental results demonstrate the efficacy of the present method. PMID- 30306474 TI - Muscle Segmentation for Orthopedic Interventions. AB - Skeletal muscle segmentation techniques can help orthopedic interventions in various scenes. In this chapter, we describe two methods of skeletal muscle segmentation on 3D CT images. The first method is based on a computational anatomical model, and the second method is a deep learning-based method. The computational anatomy-based methods are modeling the muscle shape with its running and use it for segmentation. In the deep learning-based methods, the muscle regions are directly acquired automatically. Both approaches can obtain muscle regions including shape, area, volume, and some other image texture features. And it is desirable that the method be selected by the required orthopedic intervention. Here, we show each design philosophy and features of a representative method. We discuss the various examples of site-specific segmentation of skeletal muscle in non-contrast images using torso CT and whole body CT including in cervical, thoracoabdominal, surface and deep muscles. And we also mention the possibility of application to orthopedic intervention. PMID- 30306475 TI - 3X-Knee: A Novel Technology for 3D Preoperative Planning and Postoperative Evaluation of TKA Based on 2D X-Rays. AB - This chapter introduces a solution called "3X-knee" that can robustly derive 3D models of the lower extremity from 2D long leg standing X-ray radiographs for preoperative planning and postoperative treatment evaluation of total knee arthroplasty (TKA). There are three core components in 3X-knee technology: (1) a knee joint immobilization apparatus, (2) an X-ray image calibration phantom, and (3) a statistical shape model-based 2D-3D reconstruction algorithm. These three components are integrated in a systematic way in 3X-knee to derive 3D models of the complete lower extremity from 2D long leg standing X-ray radiographs acquired in weight-bearing position. More specifically, the knee joint immobilization apparatus will be used to rigidly fix the X-ray calibration phantom with respect to the underlying anatomy during the image acquisition. The calibration phantom then serves two purposes. For one side, the phantom will allow one to calibrate the projection parameters of any acquired X-ray image. For the other side, the phantom also allowsone to track positions of multiple X-ray images of the underlying anatomy without using any additional positional tracker, which is a prerequisite condition for the third component to compute patient-specific 3D models from 2D X-ray images and the associated statistical shape models. Validation studies conducted on both simulated X-ray images and on patients' X ray data demonstrate the efficacy of the present solution. PMID- 30306476 TI - Atlas-Based 3D Intensity Volume Reconstruction from 2D Long Leg Standing X-Rays: Application to Hard and Soft Tissues in Lower Extremity. AB - In this chapter, the reconstruction of 3D intensity volumes of femur, tibia, and three muscles around the thigh region from a pair of calibrated X-ray images is addressed. We present an atlas-based 2D-3D intensity volume reconstruction approach by combining a 2D-2D nonrigid registration-based 3D landmark reconstruction procedure with an adaptive regularization step. More specifically, an atlas derived from the CT acquisition of a healthy lower extremity, together with the input calibrated X-ray images, is used to reconstruct those musculoskeletal structures. To avoid the potential penetration of the reconstructed femoral and tibial volumes that might be caused by reconstruction error, we come up with an articulated 2D-3D reconstruction strategy, which can effectively preserve knee joint structure. Another contribution from our work is the application of the proposed 2D-3D reconstruction pipeline to derive the patient-specific volumes of three thigh muscles around the thigh region. PMID- 30306477 TI - 3D Ultrasound for Orthopedic Interventions. AB - Ultrasound is a real-time, non-radiation-based imaging modality with an ability to acquire two-dimensional (2D) and three-dimensional (3D) data. Due to these capabilities, research has been carried out in order to incorporate it as an intraoperative imaging modality for various orthopedic surgery procedures. However, high levels of noise, different imaging artifacts, and bone surfaces appearing blurred with several mm in thickness have prohibited the widespread use of ultrasound as a standard of care imaging modality in orthopedics. In this chapter, we provided a detailed overview of numerous applications of 3D ultrasound in the domain of orthopedic surgery. Specifically, we discuss the advantages and disadvantages of methods proposed for segmentation and enhancement of bone ultrasound data and the successful application of these methods in clinical domain. Finally, a number of challenges are identified which need to be overcome in order for ultrasound to become a preferred imaging modality in orthopedics. PMID- 30306478 TI - A Novel Ultrasound-Based Lower Extremity Motion Tracking System. AB - Tracking joint motion of the lower extremity is important for human motion analysis. In this study, we present a novel ultrasound-based motion tracking system for measuring three-dimensional (3D) position and orientation of the femur and tibia in 3D space and quantifying tibiofemoral kinematics under dynamic conditions. As ultrasound is capable of detecting underlying bone surface noninvasively through multiple layers of soft tissues, an integration of multiple A-mode ultrasound transducers with a conventional motion tracking system provides a new approach to track the motion of bone segments during dynamic conditions. To demonstrate the technical and clinical feasibilities of this concept, an in vivo experiment was conducted. For this purpose the kinematics of healthy individuals were determined in treadmill walking conditions and stair descending tasks. The results clearly demonstrated the potential of tracking skeletal motion of the lower extremity and measuring six-degrees-of-freedom (6-DOF) tibiofemoral kinematics and related kinematic alterations caused by a variety of gait parameters. It was concluded that this prototyping system has great potential to measure human kinematics in an ambulant, non-radiative, and noninvasive manner. PMID- 30306479 TI - Computer-Assisted Planning, Simulation, and Navigation System for Periacetabular Osteotomy. AB - Periacetabular osteotomy (PAO) is an effective approach for surgical treatment of hip dysplasia in young adults. However, achieving an optimal acetabular reorientation during PAO is the most critical and challenging step. Routinely, the correct positioning of the acetabular fragment largely depends on the surgeon's experience and is done under fluoroscopy to provide the surgeon with continuous live x-ray guidance. Our developed system starts with a fully automatic detection of the acetabular rim, which allows for quantifying the acetabular 3D morphology with parameters such as acetabular orientation, femoral head extrusion index (EI), lateral center-edge (LCE) angle, and total and regional femoral head coverage (FHC) ratio for computer-assisted diagnosis, planning, and simulation of PAO. Intraoperative navigation is conducted to implement the preoperative plan. Two validation studies were conducted on four sawbone models to evaluate the efficacy of the system intraoperatively and postoperatively. By comparing the preoperatively planned situation with the intraoperatively achieved situation, average errors of 0.6 degrees +/- 0.3 degrees , 0.3 degrees +/- 0.2 degrees , and 1.1 degrees +/- 1.1 degrees were found, respectively, along three motion directions (flexion/extension, abduction/adduction, and external rotation/internal rotation). In addition, by comparing the preoperatively planned situation with the postoperative results, average errors of 0.9 degrees +/- 0.3 degrees and 0.9 degrees +/- 0.7 degrees were found for inclination and anteversion, respectively. PMID- 30306480 TI - Biomechanical Optimization-Based Planning of Periacetabular Osteotomy. AB - Modern computerized planning tools for periacetabular osteotomy (PAO) use either morphology-based or biomechanics-based methods. The latter rely on estimation of peak contact pressures and contact areas using either patient-specific or constant thickness cartilage models. We performed a finite element analysis investigating the optimal reorientation of the acetabulum in PAO surgery based on simulated joint contact pressures and contact areas using patient-specific cartilage model. Furthermore we investigated the influences of using patient specific cartilage model or constant thickness cartilage model on the biomechanical simulation results. Ten specimens with hip dysplasia were used in this study. Image data were available from CT arthrography studies. Bone models were reconstructed. Mesh models for the patient-specific cartilage were defined and subsequently loaded under previously reported boundary and loading conditions. Peak contact pressures and contact areas were estimated in the original position. Afterward we used validated preoperative planning software to change the acetabular inclination by an increment of 5 degrees and measured the lateral center-edge angle (LCE) at each reorientation position. The position with the largest contact area and the lowest peak contact pressure was defined as the optimal position. In order to investigate the influence of using patient-specific cartilage model or constant thickness cartilage model on the biomechanical simulation results, the same procedure was repeated with the same bone models but with a cartilage mesh of constant thickness. Comparison of the peak contact pressures and the contact areas between these two different cartilage models showed that good correlation between these two cartilage models for peak contact pressures (r = 0.634 ?[0.6, 0.8], p < 0.001) and contact areas (r = 0.872 > 0.8, p < 0.001). For both cartilage models, the largest contact areas and the lowest peak pressures were found at the same position. Our study is the first study comparing peak contact pressures and contact areas between patient-specific and constant thickness cartilage models during PAO planning. Good correlation for these two models was detected. Computer-assisted planning with FE modeling using constant thickness cartilage models might be a promising PAO planning tool when a conventional CT is available. PMID- 30306481 TI - Biomechanical Guidance System for Periacetabular Osteotomy. AB - This chapter presents a biomechanical guidance navigation system for performing periacetabular osteotomy (PAO) to treat developmental dysplasia of the hip. The main motivation of the biomechanical guidance system (BGS) is to plan and track the osteotomized fragment in real time during PAO while simplifying this challenging procedure. The BGS computes the three-dimensional position of the osteotomized fragment in terms of conventional anatomical angles and simulates biomechanical states of the joint. This chapter describes the BGS structure and its application using two different navigation approaches including optical tracking of the fragment and x-ray-based navigation. Both cadaver studies and preliminary clinical studies showed that the biomechanical planning is consistent with traditional PAO planning techniques and that the additional information provided by accurate 3D positioning of the fragment does not adversely impact the surgery. PMID- 30306482 TI - Gravity-Assisted Navigation System for Total Hip Arthroplasty. AB - In this chapter we propose a new system that allows reliable acetabular cup placement in total hip arthroplasty (THA) when the surgery is operated in lateral approach. Conceptually it combines the accuracy of computer-generated patient specific morphology information with an easy-to-use mechanical guide, which effectively uses natural gravity as the angular reference. The former is achieved by using a statistical shape model-based 2D-3D reconstruction technique that can generate a scaled, patient-specific 3D shape model of the pelvis from a single conventional anteroposterior (AP) pelvic X-ray radiograph. The reconstructed 3D shape model facilitates a reliable and accurate co-registration of the mechanical guide with the patient's anatomy in the operating theater. We validated the accuracy of our system by conducting experiments on placing seven cups to four pelvises with different morphologies. Taking the measurements from an image-free navigation system as the ground truth, our system showed an average accuracy of 2. 1 +/- 0. 7? for inclination and an average accuracy of 1. 2 +/- 1. 4? for anteversion. PMID- 30306483 TI - 3D Visualization and Augmented Reality for Orthopedics. AB - Augmented reality (AR) techniques play an important role in the field of minimally invasive surgery for orthopedics. AR can improve the hand-eye coordination by providing surgeons with the merged surgical scene, which enables surgeons to perform surgical operations more easily. To display the navigation information in the AR scene, medical image processing and three-dimensional (3D) visualization of the important anatomical structures are required. As a promising 3D display technique, integral videography (IV) can produce an autostereoscopic image with full parallax and continuous viewing points. Moreover, IV-based 3D AR navigation technique is proposed to present intuitive scene and has been applied in orthopedics, including oral surgery and spine surgery. The accurate patient image registration, as well as the real-time target tracking for surgical tools and the patient, can be achieved. This paper overviews IV-based AR navigation and the applications in orthopedics, discusses the infrastructure required for successful implementation of IV-based approaches, and outlines the challenges that must be overcome for IV-based AR navigation to advance further development. PMID- 30306485 TI - Patient-Specific Surgical Guidance System for Intelligent Orthopaedics. AB - Clinical benefits for image-guided orthopaedic surgical systems are often measured in improved accuracy and precision of tool trajectories, prosthesis component positions and/or reduction of revision rate. However, with an ever increasing demand for orthopaedic procedures, especially joint replacements, the ability to increase the number of surgeries, as well as lowering the costs per surgery, is generating a similar interest in the evaluation of image-guided orthopaedic systems. Patient-specific instrument guidance has recently gained popularity in various orthopaedic applications. Studies have shown that these guides are comparable to traditional image-guided systems with respect to accuracy and precision of the navigation of tool trajectories and/or prosthesis component positioning. Additionally, reports have shown that these single-use instruments also improve operating room management and reduce surgical time and costs. In this chapter, we discuss how patient-specific instrument guidance provides benefits to patients as well as to the health-care community for various orthopaedic applications. PMID- 30306484 TI - Intelligent HMI in Orthopedic Navigation. AB - The human-machine interface (HMI) is an essential part of image-guided orthopedic navigation systems. HMI provides a primary platform to merge surgically relevant pre- and intraoperative images from different modalities and 3D models including anatomical structures and implants to support surgical planning and navigation. With the various input-output techniques of HMI, surgeons can intuitively manipulate anatomical models generated from medical images and/or implant models for surgical planning. Furthermore, HMI recreates sight, sound, and touch feedback for the guidance of surgery operations which helps surgeons to sense more relevant information, e.g., anatomical structures and surrounding tissue, the mechanical axis of limbs, and even the mechanical properties of tissue. Thus, with the help of interactive HMI, precision operations, such as cutting, drilling, and implantation, can be performed more easily and safely.Classic HMI is based on 2D displays and standard input devices of computers. In contrast, modern visual reality (VR) and augmented reality (AR) techniques allow the showing more information for surgical navigation. Various attempts have been applied to image-guided orthopedic therapy. In order to realize rapid image-based modeling and to create effective interaction and feedback, intelligent algorithms have been developed. Intelligent algorithms can realize fast registration of image to image and image to patients, and the algorithms to compensate the visual offset in AR display have been investigated. In order to accomplish more effective human-computer interaction, various input methods and force sensing/force reflecting methods have been developed. This chapter reviews related human-machine interface techniques for image-guided orthopedic navigation, analyzes several examples of clinical applications, and discusses the trend of intelligent HMI in orthopedic navigation. PMID- 30306486 TI - Intelligent Control for Human-Robot Cooperation in Orthopedics Surgery. AB - Cooperation between surgeon and robot is one of the key technologies that limit the robot to be widely used in orthopedic clinics. In this study, the evolution of human-robot cooperation methods and the control strategies for typical human robot cooperation in robot-assisted orthopedics surgery were reviewed at first. Then an intelligent admittance control method, which combines the fuzzy model reference learning control with the virtual constraint control, is proposed to solve the requirements of intuitive human-robot interaction during orthopedics surgery. That is, a variable damping parameter model of the admittance control based on fuzzy model learning control algorithm is introduced to make the robot move freely by using the reference model of surgeon's motion equation with the minimum jerk trajectory. And the virtual constraint control method based on the principle of virtual fixture is adopted to make the robot move within the pre defined area so as to perform more safe surgery. The basic principle and its realization of this intelligent control method are described in details. At last, a test platform is built based on our designed 6 DOF articulated robot. Experiments of safety and precision on acrylic model with this method show that the robot has the ability of better intuitive interaction and the high precision. And the pilot experiment of bone tumor resection on sawbone model shows the effectiveness of this method. PMID- 30306487 TI - Multilevel Fuzzy Control Based on Force Information in Robot-Assisted Decompressive Laminectomy. AB - The lumbar spinal stenosis (LSS) is a kind of orthopedic disease which causes a series of neurological symptom. Vertebral lamina grinding operation is a key procedure in decompressive laminectomy for LSS treatment. With the help of image guided navigation system, the robot-assisted technology is applied to reduce the burdens on surgeon and improve the accuracy of the operation. This paper proposes a multilevel fuzzy control based on force information in the robot-assisted decompressive laminectomy to improve the quality and the robotic dynamic performance in surgical operation. The controlled grinding path is planned in the medical images after 3D reconstruction, and the mapping between robot and images is realized by navigation registration. Multilevel fuzzy controller is used to adjust the feed rate to keep the grinding force stable. As the vertebral lamina contains different components according to the anatomy, it has different mechanical properties as the main reason causing the fluctuation of force. A feature extraction method for texture recognition of bone is introduced to improve the accuracy of component classification. When the inner cortical bone is reached, the feeding operation needs to stop to avoid penetration into spinal cord and damage to the spinal nerves. Experiments are conducted to evaluate the dynamic stabilities of the control system and state recognition. PMID- 30306488 TI - Potential Risk of Intelligent Technologies in Clinical Orthopedics. AB - Nowadays, the intelligent technologies are getting more and more attention, and the surgical robot is one of the most typical representatives. Orthopedic robots have revolutionized orthopedic surgery, but there are also risks. The risks can be categorized into those directly related to the use of the robotic system and the general risks of the operative procedure. This paper analyzes the potential risks of intelligent technologies in clinical orthopedics from three aspects, including surgical planning and strategies, spatial registration, and robotic guidance and navigation. Through these summaries, we hope to help clinical doctors better understand intelligent orthopedic techniques and promote a wide range of clinical applications of intelligent orthopedics. Besides, we also indicate the future research direction of intelligent orthopedic techniques, such as risk analysis, safety assessment, and risk management system. PMID- 30306489 TI - Clinical Application of Navigation in the Surgical Treatment of a Pelvic Ring Injury and Acetabular Fracture. AB - The purpose of this chapter is to review current evidence on indications, techniques, and outcomes of computer-navigated surgical treatment of pelvic ring injuries and acetabular fractures, particularly computer-navigated screw fixation.Iliosacral screw fixation of pelvic ring injury using navigation is attracting attention because the biomechanical stabilization of posterior pelvic ring disruption is of primary importance and is widely indicated because it does not require complete reduction of the fracture site. A cadaver study with a simulated zone II sacral fracture demonstrated a substantial compromise in the space available for iliosacral screws with displacements greater than 10 mm. It is possible to reduce the fracture fragment prior to intraoperative imaging in 2D or 3D fluoroscopic navigation. The use of 3D fluoroscopic navigation reportedly results in lower rates of iliosacral screw malpositioning than the use of the conventional technique or 2D fluoroscopic navigation. Moreover, compared with the conventional technique, it reduces radiation exposure and lowers revision rates. However, the malposition rate associated with 3D fluoroscopic navigation ranges from 0% to 31%, demonstrating that there is still room to improve the navigation performance.Conversely, complete articular surface reduction is required when treating a displaced acetabular fracture to prevent residual hip pain and subsequent osteoarthritic changes. Treating a severely displaced acetabular fracture by screw fixation is very challenging, even with the use of 3D fluoroscopic navigation, because of the difficulty in performing closed anatomical reduction. The indication for percutaneous screw fixation is limited to cases with a small articular displacement. Using 3D fluoroscopic navigation for open surgeries reportedly improves the quality of radiographic fracture reduction, limits the need for an extended approach, and lowers the complication rate.In conclusion, percutaneous screw fixation for pelvic ring injuries is widely indicated, and navigation makes these procedures safe and reliable. The indication for percutaneous screw fixation of acetabular fractures is limited to cases with a small articular displacement. Using 3D fluoroscopic navigation when performing open surgeries is reported to be useful in evaluating fracture reduction and screw position. PMID- 30306490 TI - Patient-Specific Surgical Guide for Total Hip Arthroplasty. AB - Three-dimensional printing technique has been adapted for orthopedic surgery, and a patient-specific surgical guide (PSG) has been introduced as a convenient surgical instrument and implicated in the ideal positioning of the components, including acetabular and femoral components in total hip arthroplasty (THA). PSG is designed and manufactured based on preoperative imaging data, mainly computed tomography (CT) data. PSGs for implantation in THA are classified into three types: PSG for guidewire insertion, PSG for bone cutting, and PSG for bone reaming and implant fixation. PSG positioning accuracy depends on the PSG design and surgical preparation in contact area on the bone surface. PSGs for the acetabular component, for the conventional femoral component, and for the resurfacing femoral component have been clinically used. To achieve precise implantation, precise PSG setting needs and careful surgical preparation of soft tissues are important. PMID- 30306491 TI - Computer Navigation in Orthopaedic Tumour Surgery. AB - In orthopaedic bone tumour surgery, surgeons perform malignant bone tumour resections with tumour-free margin. The bone defects following the resections have to be reconstructed to restore limb function. An inaccurate resection with positive surgical margin increased the risk of local recurrence and compromised patients' survival. Conventionally, orthopaedic tumour surgeons analyse two dimensional (2D) imaging information and mentally integrate to formulate a three dimensional (3D) surgical plan. It is difficult to translate the surgical plan to the operating room in complex cases.Computer-assisted tumour surgery (CATS) has been developed in orthopaedic oncology for the last decade. The technique may enable surgeons' 3D surgical planning and image-guided bone resection as planned. The technique may apply to difficult surgery in pelvic or sacral tumours, limited resection in joint-preserving tumour surgery or bone defect reconstruction using CAD prostheses or allograft.Early results suggested that the technique may help in safe tumour resection and improve surgical accuracy by replicating the preoperative planning. The improved surgical accuracy may offer clinical benefits.Surgeons have to be aware of the potential errors of the technique that may result in inaccurate bone resections with possible adverse clinical outcomes. Given that bone sarcoma is rare, the published reports from different tumour centres could only analyse relatively small patient population with the heterogeneous histological diagnosis. Multicentre comparative studies with long term follow-up are necessary to confirm its clinical efficacy.This chapter provides an overview of computer navigation in orthopaedic tumour surgery over the past decade. It (1) describes the current workflow, (2) reports the clinical indications and results and (3) discusses its limitations and future development. PMID- 30306492 TI - Sensor-Based Soft Tissue Balancing in Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) is a highly successful procedure with utilization expected to grow substantially over the coming decades. However, the revision burden has not concurrently improved, with over 30% of revisions related to technical imperfections (Mulhall KJ, Ghomrawi HM, Scully S, Callaghan JJ, Saleh KJ, Clin Orthop Relat Res 446:45, 2006; Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM, Clin Orthop Relat Res 404:7, 2002; Wylde V, Hewlett S, Learmonth ID, Dieppe P, Pain 152(3):566, 2011). Accurate alignment and soft tissue balancing have been identified as important factors in mitigating these risks. Historically, accuracy relating to soft tissue balance has relied upon surgeon experience and subjective tactile feel. This chapter will explore the utilization of intraoperative sensors related to soft tissue balancing in total knee arthroplasty. PMID- 30306493 TI - Implant Orientation Measurement After THA Using the EOS X-Ray Image Acquisition System. AB - We investigated the accuracy of measuring implant orientation after THA in standing position using EOS system (EOS Imaging Inc., Paris, France). Ninety patients who underwent THA were subjected to this study by comparing angles measured by EOS system and those measured from CT scans using 3D image analyzing software, ZedHip (LEXI, Tokyo, Japan). The radiographic cup inclination and anatomical cup anteversion were measured with respect to the anterior pelvic plane (APP) coordinate. The femoral stem antetorsion was analyzed by measuring the angles between the stem neck axis and the post-condylar axis in the femoral functional axis coordinate.The differences (mean +/- SD) (range of 95%CI) between angles measured by EOS system and those from CT scans in the cup inclination, cup anteversion, and stem antetorsion were - 2.3 degrees +/- 2.7 degrees (-2.8 degrees ~ - 1.7 degrees ), -0.1 degrees +/- 5.0 degrees (-1.2 degrees ~0.9 degrees ), and - 1.3 degrees +/- 6.5 degrees (-2.7 degrees ~0.1 degrees ), respectively. Cup inclination measured on 14 hips, cup anteversion measured on 28 hips, and stem antetorsion measured on 27 hips were classified as outliers whose differences were over 5 degrees . Difficulties in defining the reference points for APP correlated with the incidences of the outliers in cup orientation measurements.We could not set new reference points on the 3D bone surface models reconstructed by EOS system, so we have to use reference points defined on 2D images. In addition, the APP coordinate in EOS system was not the same as the standard definition. EOS system may not be used to measure the implant positions after THA until these problems will be improved. PMID- 30306494 TI - 3D Printing in Spine Surgery. AB - In the past 5 years, the application of 3D printing technology in the field of spine surgery had obtained enormous and substantial progress. Among which, vertebral skeleton model (including lesion model) printing has been widely used in clinical application due to its relatively simple technology and low cost. It shows practical value and becomes popular as the reference of clinical education, auxiliary diagnosis, communication between doctor and patient, and the planning of surgical approaches as well as the reference of more accurate operation in surgery. On the basis of vertebral skeleton model printing, it can be used to design and make navigation template to guide internal fixation screw, which also obtains some remarkable clinical effects. However, 3D printing technology has a more profound influence on spine surgery. The part with full expectation is undoubtedly the clinical application of 3D printing microporous metal implant and personalized implant as well as the clinical application of 3D printing biological materials in the future. PMID- 30306495 TI - Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV Infected Macrophages Exposed to Cocaine. AB - Pathogenesis of HIV-associated neurocognitive disorders (HAND) is mediated through the infiltration of perivascular macrophages into the brain with the secretion of viral, neurotoxic and inflammatory proteins. One of these proteins is cathepsin B (CATB), a lysosomal cysteine protease that induces neuronal apoptosis, and increases in plasma and cerebrospinal fluid from HIV-1 infected patients (Cantres-Rosario et al. AIDS 27(3):347-356, 2013). Cocaine further potentiates CATB neurotoxicity in vitro and in vivo (Zenon et al. J NeuroImmune Pharmacol 9(5):703-715, 2014). Modulation of sigma-1 (Sig1R) by cocaine increases oxidative species, cytokines and other factors that promote lysosomal disruption. However, the role of Sig1R in CATB secretion and HIV-1 replication in macrophages exposed to cocaine is unknown. We hypothesized that pharmacological modulation of Sig1R would alter CATB secretion from HIV-1 infected macrophages in vitro and in vivo. To test our hypothesis, monocyte derived-macrophages (MDM) from HIV-1 seronegative donors were isolated, infected with HIV-1ADA, and pretreated with Sig1R antagonist (BD1047) or Sig1R agonist (PRE-084) prior to cocaine exposure and followed for 3,6,9 and 11 days post-infection (dpi). Experiments in vivo were conducted using the HIV encephalitis mouse model (HIVE) with BD1047 treatments prior to cocaine for 14 days. Results demonstrate that in presence of cocaine, BD1047 decreases CATB secretion at 11 dpi, while PRE-084 did not have an effect. In the mouse model, BD1047 treatment prior to cocaine decreased CATB expression, cleaved caspase-3 an p24 antigen levels, reduced astrocytosis, but did not increase MAP-2 or synaptophysin. Results demonstrate that Sig1R plays a role in the modulation of CATB levels in HIV-1 infected MDM exposed to cocaine in vitro and in vivo. Graphical Abstract ?. PMID- 30306496 TI - Effect of 95% Ethanol Khat Extract and Cathinone on in vitro Human Recombinant Cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 Activity. AB - BACKGROUND AND OBJECTIVE: A significant number of people worldwide consume khat on daily basis. Long term of khat chewing has shown negative impact on several organ systems. It is likely that these people are co-administered khat preparations and conventional medication, which may lead to khat-drug interactions. This study aimed to reveal the inhibitory potencies of khat ethanol extract (KEE) and its major active ingredient (cathinone) on human cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 enzymes activities, which are collectively responsible for metabolizing 70-80% clinically used drugs. METHODS: In vitro fluorescence-based enzyme assays were developed and the CYP enzyme activities were quantified in the presence and absence of KEE and cathinone employing Vivid(r) CYP450 Screening Kits. RESULTS: KEE inhibited human CYP2C9, CYP2D6, and CYP3A4 enzyme activities with IC50 of 42, 62, and 18 MUg/ml. On the other hand, cathinone showed negligible inhibitory effect on these CYPs. Further experiments with KEE revealed that KEE inhibited CYP2C9 via non-competitive or mixed mode with Ki of 14.7 MUg/ml, CYP2D6 through competitive or mixed mode with Ki of 17.6 MUg/ml, CYP3A4 by mixed inhibition mode with Ki of 12.1 MUg/ml. CONCLUSION: Khat drug interactions are possible due to administration of clinical drugs metabolized by CYP2C9/CYP2D6/CYP3A4 together with khat chewing. Further in vivo studies are required to confirm our findings and identify the causative constituents of these inhibitory effects. PMID- 30306497 TI - It's raining men: descriptive results for engaging men with eating disorders in a specialized male assessment and treatment track (MATT). AB - PURPOSE: Men with eating disorders are not well understood and there is a need for innovative methods for engaging men in specialized outpatient assessment and treatment. We examined data collected over a 4-year period to explore whether the addition of a designated track for men at a hospital-based adult eating disorders program influenced the number of referrals or treatment engagement. METHODS: During assessment and treatment as usual (ATAU; September 2013-August 2015), 283 referrals were received (275 women, 8 men), with 3 men engaging in assessment and treatment (Mage = 36 years, SD = 14.18). After instatement of a male assessment and treatment track (MATT; September 2015-August 2017), 320 referrals were received (300 women, 20 men), with 14 men engaging in the specialized assessment and treatment (Mage = 28.21 years, SD = 8.04). Both groups of men completed measures of demographic characteristics, life satisfaction, depressive and anxiety symptoms, and eating disorder symptoms. RESULTS: Significantly more referrals for men, but not women, were received after the instatement of the MATT (i.e., a 250% increase). More men also engaged in specialized assessment and treatment after the instatement of the MATT (i.e., a 467% increase in engagement). CONCLUSIONS: The current study describes the number of referrals and the number of men who engaged in treatment before and after the instatement of a specialized treatment track for men. The results suggest that the addition of the MATT helped to increase the number of men referred and promoted their engagement in recommended care. LEVEL OF EVIDENCE: V retrospective descriptive study. PMID- 30306498 TI - Personalized group cognitive behavioural therapy for obesity: a longitudinal study in a real-world clinical setting. AB - PURPOSE: Severe obesity is difficult to treat, and non-surgical treatment is not supported by robust evidence. The aim of the present study was to establish the immediate and longer-term outcomes following "personalized" form of group cognitive behavioural therapy for obesity (CBT-OB)-a new treatment designed to address specific cognitive processes that have been associated with attrition, weight loss, and weight maintenance in previous studies. METHODS: Sixty-seven adult patients with obesity (body mass index (BMI) >= 30 kg/m2) were recruited from consecutive referrals to an Italian National Health Service obesity clinic. Each patient was offered 22 group sessions of CBT-OB (14 in the 6-month weight loss phase and 8 in the subsequent 12-month weight-maintenance phase). RESULTS: 76.2% patients completed the treatment, with an average weight loss of 11.5% after 6 months (10% in the intention-to-treat analysis) and 9.9% (7.5% in the intention-to-treat analysis) after 18 months. Weight loss was associated with a significant reduction in cardiovascular risk factors, anxiety, depression, and eating disorder psychopathology, and an improvement in obesity-related quality of life. CONCLUSIONS: These findings provide strong preliminary support for the use of CBT-OB for obesity in standard clinical settings, and justify its further evaluation in randomized controlled trials. LEVEL OF EVIDENCE: Level III, longitudinal cohort study. PMID- 30306499 TI - Bariatric/Metabolic Surgery in the Asia-Pacific Region: APMBSS 2018 Survey. AB - INTRODUCTION: The Asia-Pacific Metabolic and Bariatric Surgery Society (APMBSS) held its congress in Tokyo at the end of March, 2018, and representatives from Asia-Pacific countries presented the current status of bariatric/metabolic surgery in the "National Reports" session. The data are summarized here to show the current status and problems in the Asia-Pacific region in 2017. METHODS: A questionnaire including data of 2016 and 2017 and consisting of eight general questions was prepared and sent to representatives in 18 Asia-Pacific countries by e-mail before the congress. After the congress, the data were analyzed and summarized. RESULTS: Seventeen of 18 countries responded to the survey. The frequency of obesity (BMI >= 30) in the 4 Gulf countries was > 30%, much higher than that in the other countries. In total, 1640 surgeons and 869 institutions were engaging in bariatric/metabolic surgery. In many East and Southeast Asian countries, the indication for bariatric surgery was BMI >= 35 or >= 37, whereas in many Gulf countries and Australia, it was BMI >= 40 or >= 35 with obesity related disease. Ten of the 17 countries (58.8%) but only one of the 5 Southeast Asian countries (20.0%) had public health insurance coverage for bariatric surgery. In 2017, 95,125 patients underwent bariatric/metabolic surgery, with sleeve gastrectomy accounting for 68.0%, bypass surgery for 19.5%, and others for 12.5%. Current problems included public insurance coverage, training system, national registry, and lack of awareness and comprehension. CONCLUSION: This summary showed that bariatric/metabolic surgery is rapidly developing along with various problems in Asia-Pacific countries. PMID- 30306500 TI - Food Intolerance 1 Year After Banded Roux-En-Y Gastric Bypass. AB - : The purpose of this study is to evaluate the food intolerance after banded Roux en-Y gastric bypass (RYGB), correlating the data of food ingestion. METHODS: This is an observational prospective study, which evaluated the individuals before and 3, 6, and 12 months after banded RYGB. We performed an anthropometric evaluation and an assessment of the habitual food ingestion and applied a food tolerance questionnaire. RESULTS: The study group was comprised of 75 individuals, 89% of them female, with a percentual weight loss of 29.73 +/- 6.79%. The observed results were that food intolerance increased over time and 1 year after surgery, only 2.7% reported to ingest any type of food, while the greatest difficulty was related to red meat (80%). Regarding vomits, after surgery, this proportion significantly increased after 3, 6, and 12 months. Preoperatively, the mean protein ingestion was 98 g, which decreased to 50 g after 3 and 6 months and to 51 g after 12 months. As a conclusion, food intolerance significantly increased following banded RYGB, leading to a crescent dissatisfaction regarding food and an increase in the vomits frequency. PMID- 30306501 TI - Transcriptome profiling suggests roles of innate immunity and digestion metabolism in purplish Washington clam. AB - The purplish Washington clam (Saxidomus purpuratus) in the family Veneridae is distributed widely along the intertidal zones of northeast Asia and is increasingly being utilized as a commercially important food resource. Bivalves maintain homeostasis by regulating their food intake and digestion, innate immunity, and biotransformation in a mollusk-specific organ, the digestive gland. To understand digestive gland-specific pathways, we generated a high-quality de novo assembly of the digestive gland transcriptome of this clam using the Illumina Miseq platform. A total of 9.9 million raw reads were obtained and assembled using the Oases assembly platform, resulting in 27,358 contigs with an N50 of 433 bp. Functional gene annotations were performed using Gene Ontology, Eukaryotic Orthologous Groups, and Kyoto Encyclopedia of Genes and Genomes pathway analyses. In the transcriptome, many crucial genes involved in innate immunity and digestion metabolism were detected. A number of enzymes associated with drug metabolism were annotated, as much as that identified from the whole transcriptome of the Pacific oyster Crassostrea gigas. We provide valuable sequence information of S. purpuratus to predict functional understandings of the bivalve-specific digestive gland. This resource will be valuable for researchers comparing gene compositions and their expression levels in the digestive glands of bivalves. PMID- 30306503 TI - A comparison of the cuticular properties of the female ticks Ixodes pacificus and Amblyomma hebraeum (Acari: Ixodidae) throughout the feeding period. AB - The mechanical properties of the cuticle of Ixodes pacificus (Ip) are compared to those of Amblyomma hebraeum (Ah) from our earlier work. The 10-fold size difference between the species is expected to lead to significant differences in mechanical properties, because cuticular stretch depends on high internal hydrostatic pressure during the rapid phase of engorgement. We demonstrate here: (1) The cuticle of partially fed Ip is less stiff and viscous than that of Ah. (2) A stretch-recoil cycle in both ticks consists of recoverable deformation (ESv) and permanent deformation (ESp); ESp is higher in Ip, and increases sharply during the slow phase of engorgement, but not in Ah. (3) Injected dopamine (DA) increases ESp and reduces all measures of stiffness and viscosity, suggesting that a catecholaminergic neurotransmitter plays a fundamental role in modulating mechanical properties of the cuticle. However, unlike Ah, DA's effect was not different from that of the control (1.2% NaCl). Mere insertion of the needle may have punctured the gut, causing the release of perhaps a catecholamine that increases ESp, an hypothesis supported by the fact that inserting a needle without any injection also caused an increase in ESp. (4) Stretch reduces ESp, but subjecting loops to pH 6.5 in vitro restores it. (5) Despite the smaller size of Ip, later onset of the rapid phase of engorgement, a thinner cuticle and different mechanical properties all reduce the internal pressure needed for stretch. PMID- 30306504 TI - Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis. AB - Adrenomedullin (AM) exerts a potent anti-inflammatory effect. Intrarectal or consecutive intravenous administrations of AM reduce pathological manifestations in rodent colitis models. However, in clinical applications, a safer administration route that provides stronger alleviation of patient burden is preferred. We investigated whether subcutaneously administered AM is effective against dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were administered 1% DSS in drinking water and received AM at 8, 40 or 80 nmol/kg subcutaneously once a day for 7 consecutive days. Subcutaneously administered AM significantly and dose-dependently ameliorated body weight loss, diarrhea, and histological severity of colonic inflammation in DSS-treated mice. The AM therapeutic effect was associated with the upregulation of the production of autocrine AM, and expression of cAMP, c-fos, KLF4, and downregulation of STAT3 and NF-kappaB p65 phosphorylation, as well as a decrease in proinflammatory cytokine expression in the colon. Subcutaneous AM treatment potently attenuated DSS-induced colitis, which suggests that AM administered subcutaneously in ulcerative colitis (UC) patients may decrease diseases burden and improve quality of life. PMID- 30306502 TI - Molecular and morphological characterization of the predatory mite Amblyseius largoensis (Acari: Phytoseiidae): surprising similarity between an Asian and American populations. AB - The accurate characterization of biological control agents is a key step in control programs. Recently, Amblyseius largoensis from Thailand were introduced in Brazil to evaluate their efficiency for the control of the red palm mite, Raoiella indica. The aim of this study was to confirm their identification and to characterize the population from Thailand, comparing it to populations of the Americas and Indian Ocean islands. In addition, a population of A. largoensis from New Caledonia, Oceania, of which DNA sequences were available, was included in phylogenetic analyses. Morphometric data obtained for the population of A. largoensis from Thailand were compared to those of populations from Reunion Island and the Americas through univariate and multivariate analyses. Two DNA fragments were amplified and sequenced: the nuclear ribosomal region ITSS and the mitochondrial 12S rRNA. Haplotypes (12S rRNA) and genotypes (ITSS) were identified and phylogenetic analyses using both fragments were conducted separately and combined using maximum likelihood and the Bayesian information criterion. The integrative approach reveals morphometric and molecular variabilities among populations of A. largoensis and shows that the population identified as A. largoensis collected in Thailand, as well as that from New Caledonia, are conspecific to the populations of the Americas and Indian Ocean islands. Populations from the Americas and Asia are more related to each other than with that from the Indian Ocean islands. Hypotheses to explain this clustering are proposed. Data on the molecular intraspecific variability of this predatory mite from remote areas will be helpful for the development of molecular diagnosis. PMID- 30306505 TI - Ascorbic Acid Effectively Improved Lutein Extraction Yield from Australian Sweet Lupin Flour. AB - Lutein is a xanthophyll, a bioactive phytochemical that presents itself as colourful pigments in plants. Australian sweet lupin flour has been incorporated as a food ingredient in wheat bread and pasta to improve their sensory property and nutritional quality. However, the amount of lutein in lupin flour has not yet been determined. This is the first study to quantify naturally occurring lutein in Australian sweet lupin flour after the extraction efficiency was optimised. Several organic solvents (acetone, isopropyl alcohol, ethyl acetate and hexane), the use of an ultrasonic bath or a probe, the need for saponification and addition of ascorbic acid (served as antioxidant) were tested to compare the extraction yield. HPLC was employed to analyse lutein in flour. Lowest lutein (68 MUg/100 g) was determined in the hexane extract. Samples extracted using an ultrasonic bath (126-132 MUg/100 g) contained higher lutein than those extracted using a probe (84-109 MUg/100 g). Saponified samples showed significantly less lutein (30-64 MUg/100 g) than their respective non-saponified ones (122-134 MUg/100 g). Without added ascorbic acid, lutein that was extracted into isopropyl alcohol was 143 MUg/100 g and was higher than those released into acetone (92 MUg/100 g). When ascorbic acid was added, measured lutein in the extracts of isopropyl alcohol (155 MUg/100 g) and acetone (138 MUg/100 g) increased by 8 and 33%, respectively. Our results suggested that the choice of extraction solvents and addition of ascorbic acid was crucial for quantitative analysis of lutein, so that the lutein content in lupin flour can be accurately reported. PMID- 30306506 TI - Comparison of two different media for maturation rate of neural progenitor cells to neuronal and glial cells emphasizing on expression of neurotrophins and their respective receptors. AB - Neural cells derived from embryonic stem cells (ESCs) have potential usefulness for the treatment of neurodegenerative disorders. Modulation of intrinsic growth factors expression such as neurotrophins and their respective receptors by these cells is necessary to obtain functional neural cells for transplantation. In present study, we compared neural differentiation potential of two different media, NB + 5%ES-FBS + N2B27 and Ko-DMEM + 5%ES-FBS for conversion of mESC derived neural progenitors (NPs) into mature neural cells with emphasis on effect of the these two media on neurotrophins and their respective receptors expression. Immunofluorescence staining, RT-qPCR and western blot analysis showed that the expression of neuronal specific markers, MAP2 and Tuj-1, in NB + 5%ES FBS + N2B27 medium was significantly higher than the other medium. Western blot assay revealed that the expression of BDNF and NGF increased significantly in mature neural cells obtained from NB + 5%ES-FBS + N2B27 medium but decreased in neural cells from Ko-DMEM + 5%ES-FBS medium compared to mESCs. TrkB protein was not detectable in mESCs but its expression increased in neural cells obtained from both media although its expression in NB + 5%ES-FBS + N2B27 medium was significantly higher than the other medium. In contrast to TrkB, p75NTR protein was detectable in mESCs and is remained constant in neural cells cultured in NB + 5%ES-FBS + N2B27 medium but decreased significantly in the other medium. In conclusion, our results indicated that NB + 5%ES-FBS + N2B27 medium promoted neural differentiation process of mESCs and caused enhancement of neurotrophins protein expression in addition to their cognate receptors. PMID- 30306507 TI - beta2-AR regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway. AB - Psychological stress has been recognized as a well-documented risk factor associated with beta2-adrenergic receptor (beta2-AR) in the development of pancreatic cancer. Aldo-keto reductase 1 member B1 (AKR1B1) is a potential interacting partner of beta2-AR, but the effect of their interaction on pancreatic cancer cells is not known at present. We found a positive correlation between AKR1B1 and beta2-AR expression in pancreatic cancer tissue samples, and co-localization of these proteins in the human pancreatic cancer BXPC-3 cell line. Compared to the controls, the CFPAC-1 and PANC-1 pancreatic cancer cells overexpressing beta2-AR and AKR1B1 respectively showed significantly higher proliferation rates, which is attributed to higher proportion of cells in the S phase and decreased percentage of early apoptotic cells. Furthermore, overexpression of beta2-AR led to a significant increase in the expression of AKR1B1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2). Overexpression of AKR1B1 significantly decreased beta2-AR levels and increased that of p-ERK1/2. Taken together, beta2-AR directly interacted with and up regulated AKR1B1 in pancreatic cancer cells, and promoted their proliferation and inhibited apoptosis via the ERK1/2 pathway. Our findings also highlight the beta2 AR-AKR1B1 axis as a potential therapeutic target for pancreatic cancer. PMID- 30306508 TI - Antiproliferative, antioxidant and binding mechanism analysis of prodigiosin from newly isolated radio-resistant Streptomyces sp. strain WMA-LM31. AB - Streptomyces genus are filamentous Gram positive bacteria, of great intrest, producing biologically active compounds. Recent market and consumer curiosity in natural products have forced scientist and industry for the development of new products with therapeutic potential. This study focuses on evaluation of antioxidant and anticancerous properties of prodigiosin from radio-resistant Streptomyces sp. strain WMA-LM31. A molecular docking approach was adopted to understand theoretical binding mechanism and affinity for anticancer targets. A radio-resistant bacterium, labelled as strain WMA-LM31, was isolated from desert soil and screened for its radio-resistant potential and prodigiosin production. 16S rRNA gene sequencing showed that the bacterium clusters to genus Streptomyces and found resistant to ultraviolet radiation (dosage of 2 * 103 J/m2). Strain WMA LM31 produced a red color pigment in tryptone glucose yeast (TGY) medium.The LC MS analysis of the purified compound showed a molar mass of 324 [m/z]+ matched the chemical formula C20H25N3O, identified as prodigiosin. The compound showed strong antioxidant (62.51%) activities along with significant inhibitory action against oxidative damages to bovine serum albumin (BSA) and mice liver lipids in comparison to standard ascorbic acid. IC50 values of HepG2 and HeLa cell lines was found at 12.66 and 14.83 ug/mL of prodigiosin concentration, respectively. Furthermore, molecular docking was performed with two different cancers macromolecular targets: [2O2F (Bcl-2) and 1DI8 (CDK-2)], and BSA (PDB id: 3V03). The results indicated that the binding affinity of prodigiosin to its target molecules is due to the presence of terminal pyrrole rings. It is concluded from the results that prodigiosin from Streptomyces sp. strain WMA-LM31 has strong antioxidant, anticancer and apoptotic properties. The knowledge of binding mechanisms and interactions of prodigiosin could provide future directions in designing potent target specifc drugs. PMID- 30306510 TI - Molecular Mechanisms of the Sense of Touch: An Overview of Mechanical Transduction and Transmission in Merkel Discs of Whisker Hair Follicles and Some Clinical Perspectives. AB - The Merkel disc is a main type of tactile end organs for sensing gentle touch and is essential for sophisticated sensory tasks including social interaction, environmental exploration, and tactile discrimination. Recent studies have shown that Merkel cells are primary sites of mechanotransduction using Piezo2 channels as a molecular transducer in Merkel discs. Furthermore, tactile stimuli trigger serotonin release from Merkel cells to excite their associated whisker Abeta afferent endings and transmit tactile signals. The tactile transduction and transmission at Merkel discs may have important clinical implications in sensory dysfunctions such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes and inflammatory diseases and undergo chemotherapy. PMID- 30306509 TI - A comparative transcriptome approach for identification of molecular changes in Aphanomyces invadans infected Channa striatus. AB - Snakehead murrel, Channa striatus is an economically important aquatic species in Asia and are widely cultured and captured because of its nutritious and medicinal values. Their growth is predominantly affected by epizootic ulcerative syndrome (EUS) which is primarily caused by an oomycete fungus, Aphanomyces invadans. However, the molecular mechanism of immune response in murrel against this infection is still not clear. In this study, transcriptome technique was used to understand the molecular changes involved in C. striatus during A. invadans infection. RNA from the control (CF) and infected fish (IF) groups were sequenced using Illumina Hi-seq sequencing technology. For control group, 28,952,608 clean reads were generated and de novo assembly was performed to produce 60,753 contigs. For fungus infected group, 25,470,920 clean reads were obtained and assembled to produce 58,654 contigs. Differential gene expression analysis revealed that a total of 146 genes were up-regulated and 486 genes were down regulated. Most of the differentially expressed genes were involved in innate immune mechanism such as pathogen recognition, signalling and antimicrobial mechanisms. Interestingly, few adaptive immune genes, especially immunoglobulins were also significantly up regulated during fungal infection. Also, the results were validated by qRT-PCR analysis. These results indicated the involvement of various immune genes involved in both innate and adaptive immune mechanism during fungal infection in C. striatus which provide new insights into murrel immune mechanisms against A. invadans. PMID- 30306511 TI - TRP Channels in Nociception and Pathological Pain. AB - Thermal and noxious stimuli are detected by specialized nerve endings, which transform the stimuli into electrical signals and transmit the signals into central nervous system to facilitate the perception of temperature and pain. Several members within the transient receptor potential (TRP) channel family serve as the sensors for temperature and noxious stimuli and are involved in the development of pathological pain, especially inflammatory pain. Various inflammatory mediators can sensitize and modulate the activation threshold of TRP channels and result in the development of inflammatory pain behaviors. A brief review of the role of TRP channels in nociception and the modulatory mechanisms of TRP channels by inflammatory mediators, focusing on TRPV1, TRPA1, and TRPM2, will be presented. Recent advances in the development of therapeutic strategies targeting against TRP channels will also be reviewed. PMID- 30306512 TI - Involvement of TRPV1-ANO1 Interactions in Pain-Enhancing Mechanisms. AB - Primary sensory neurons detect potentially dangerous environmental situations via many "sensor" proteins located on the plasma membrane. Although receptor-type cation channels are thought to be the major sensors in sensory neurons, anion channels are also important players in the peripheral nervous system. Recently, we showed that transient receptor potential vanilloid 1 (TRPV1) interacts with anoctamin 1 (ANO1, also called TMEM16A) in primary sensory neurons and that this interaction enhanced TRPV1-mediated pain sensation. In that study, we induced ANO1 currents by application of capsaicin to small DRG neurons and showed that ANO1-dependent depolarization following TRPV1 activation could evoke more action potentials. Furthermore, capsaicin-evoked pain-related behaviors in mice were strongly inhibited by a selective ANO1 blocker. Together these findings indicate that selective ANO1 inhibition can reduce pain sensation. We also investigated non-specific inhibitory effects on ion channel activities to control ion dynamics via the TRPV1-ANO1 complex. We found that 4-isopropylcyclohexanol (4-iPr-CyH-OH) had an analgesic effect on burning pain sensations through its inhibition of TRPV1 and ANO1 together. Additionally, 4-iPr-CyH-OH did not have clear agonistic effects on TRPV1, TRPA1, and ANO1 activity individually. These results indicate that 4-iPr-CyH-OH could function globally to mediate TRP-ANO1 complex functions to reduce skin hypersensitivity and could form the basis for novel analgesic agents. PMID- 30306513 TI - Roles of ASICs in Nociception and Proprioception. AB - Acid-sensing ion channels (ASICs) are a group of proton-gated ion channels belonging to the degenerin/epithelial sodium channel (DED/ENaC) family. There are at least six ASIC subtypes - ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4 - all expressed in somatosensory neurons. ASIC3 is the most abundant in dorsal root ganglia (DRG) and the most sensitive to extracellular acidification. ASICs were found as the major player involved in acid-induced pain in humans. Accumulating evidence has further shown ASIC3 as the molecular determinant involved in pain associated tissue acidosis in rodent models. Besides having a role in nociception, members of the DEG/ENaC family have been demonstrated as essential mechanotransducers in the nematode Caenorhabditis elegans and fly Drosophila melanogaster. ASICs are mammalian homologues of DEG/ENaC and therefore may play a role in mechanotransduction. However, the role of ASICs in neurosensory mechanotransduction is disputed. Here we review recent studies to probe the roles of ASICs in acid nociception and neurosensory mechanotransduction. In reviewing genetic models and delicate electrophysiology approaches, we show ASIC3 as a dual function protein for both acid-sensing and mechano-sensing in somatosensory nerves and therefore involved in regulating both nociception and proprioception. PMID- 30306514 TI - Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors. AB - Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments. PMID- 30306515 TI - Advances in Experimental Medicine and Biology: Intrafascicular Local Anesthetic Injection Damages Peripheral Nerve-Induced Neuropathic Pain. AB - Peripheral nerve blockade (PNB) is advantageous for patients undergoing surgery to decrease the perioperative opioid consumptions and enhance recovery after surgery.Inadvertent local anesthetic (LA) administration into nerve fiber intrafascicularly easily results in unrecognized nerve injury. Using nerve block guidance either by ultrasound, electrical nerve stimulator, or using pressure devices does not prevent nerve damage, even though most of the nerve injury is transiently. The incidence of neurologic symptoms or neuropathy is in the range of 0.02-2.2%, and no significant difference of postoperative neurologic symptoms is found as compared with using ultrasound or guided nerve stimulator technique. However, intrafascicular lidocaine brought about macrophage migration into the damaged fascicle, Schwann cell proliferation, increased intensity of myelin basic protein, and shorten withdrawal time to mechanical stimuli. In dorsal root ganglion (DRG), intrafascicular LA injection increased the activated transcriptional factor 3 (ATF-3) and downregulated Nav1.8 (Nav1.8). In spinal dorsal horn (SDH), the microglia and astrocytes located in SDH were activated and proliferated after intrafascicular LA injection and returned to baseline gradually at the end of the month. This is a kind of neuropathic pain, so low injection pressure should be maintained, the correct needle bevel used, nerve stimulator or ultrasound guidance applied, and careful and deliberately slow injection employed as important parts of the injection technique to prevent intrafascicular LA administration-induced neuropathic pain. PMID- 30306516 TI - Microglia in the CNS and Neuropathic Pain. AB - Neuropathic pain occurring after peripheral nerve injury is not simply a consequence of temporal continuity of acute nociceptive signals, but rather of maladaptive nervous system function. Over the past decades, a body of literature has provided evidence for the necessity and sufficiency of microglia, the tissue resident macrophages of the central nervous system, for nerve injury-induced alterations in synaptic function. Recent studies have also revealed active roles for microglia in brain regions important for emotion and memory. In this chapter, I highlight recent advances in our understanding of the mechanisms that underlie the role of spinal and brain microglia in neuropathic pain, with a focus on how microglia are activated and alter synaptic function. I also discuss the therapeutic potential of microglia from recent advances in the development of new drugs targeting microglia, which may facilitate translation from the bench to bedside. PMID- 30306518 TI - Chronic Neuropathic Pain Protects the Heart from Ischemia-Reperfusion Injury. AB - The prevalence of chronic pain increases with age. The pain occurrence in the elderly ranges from 25% to 80% in different countries. Ischemic heart disease is also prevailing in the aged people. Restored blood flow quickly rescues myocardium but also causes ischemia-reperfusion (IR) injury. Brief episodes of ischemia at a distant organ could reduce the myocardial reperfusion injury. This is called remote ischemic preconditioning (RIPC) cardioprotection. Several circulating factors and neurogenic signals contribute to the cardioprotection by RIPC. Preinfarction angina, a form of chest pain, is associated with significant cardioprotection in myocardial infarction patients. Activation of peripheral nociception also induces cardioprotection against IR injury via neurogenic pathway. It is possible that angina also induces nociceptive signal pathway to provide cardioprotection. It is unclear whether pre-existing chronic pain will also have a cardioprotection effect. We recently reported chronic neuropathic pain attenuates cardiac IR injury in mice. ERK activation in anterior nucleus of paraventricular thalamus (PVA) is required for this remote cardioprotection. Direct activation of PVA neurons also provides cardioprotection against cardiac IR injury. Chronic neuropathic pain-induced cardioprotection requires activation of parasympathetic nerves. This review summarizes the potential interaction of chronic pain and cardiac IR injury. PMID- 30306517 TI - Descending Noradrenergic Inhibition: An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain. AB - Gabapentinoids are effective in a wide range of animal pain models and in patients with neuropathic pain and has become one of first-line treatments for neuropathic pain. Because spinal plasticity and sensitization have been intensely studied in neuropathic pain, most laboratory studies have focused on actions of gabapentinoids in the spinal cord, where they reduce primary afferent traffic and excitation of spinal nociceptive neurons, via interaction with alpha2delta subunits of voltage-gated Ca2+ channels. However, a recent clinical study questioned the relevance of this in vitro and in vivo rodent studies by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain. Curiously, preclinical studies continue to focus on spinal cord actions of gabapentinoids despite this lack of translation to humans.We and others demonstrated that gabapentin inhibits presynaptic GABA release and induces glutamate release from astrocytes in the locus coeruleus (LC), thereby increasing LC neuron activity and spinal noradrenaline release, and that gabapentin relies on this action in the LC for its analgesia. We also recently discovered that, with prolonged time after neuropathic injury, noradrenergic neurons in the LC become less responsive to gabapentin, leading to impaired gabapentin analgesia, and that astroglial glutamate dysregulation is critical to this impaired LC response. The clinically available drug valproate increases glutamate transporter-1 (GLT-1) expression in the LC to restore this impaired gabapentin analgesia. PMID- 30306519 TI - Knowing the Neuronal Mechanism of Spontaneous Pain to Treat Chronic Pain in the Future. AB - Spontaneous pain is the major complain for the patients to see a doctor. Human imaging studies presented that spontaneous pain is mainly associated with activity changes in medial pain pathway, while broader brain regions were activated by allodynia pain. On behavioral level, temporally disassociation between the evoked pain and spontaneous pain was observed; these data gave a hint that the spontaneous pain and evoked pain may be mediated by different neuronal mechanisms. And more attentions should be paid to the spontaneous pain to treat the chronic pain in the future. PMID- 30306520 TI - Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human to-Rodent Studies. AB - Opioid analgesics remain the most effective and widely used analgesics for the management of moderate to severe pain, including cancer pain and chronic non cancer pain. However, the efficacy of long-term opioid analgesics is attenuated by tolerance and/or hyperalgesia after long-term use, preventing adequate pain relief under stable opioid dosages for chronic pain patients. Classical neuron centered concepts about tolerance, such as internalization of opioid receptors, upregulation of N-methyl-D-aspartate receptor function, or downregulation of glutamate transporter activity, can only partially explain the phenomenon of tolerance. Recent evidence revealing glial activation and upregulation of inflammatory mediators in the rodent central nervous system has confirmed the pivotal role of neuroinflammation in neuropathic pain or opioid tolerance, or both. However, human evidence is still sparse.Based on our clinical practice, we conducted translational research by investigating the cerebrospinal fluid (CSF) cytokine and chemokine profiles of opioid-tolerant patients after research ethic committee approval. CSF samples from opioid-tolerant patients and opioid-naive subjects were compared. We found CXCL1, CXCL12, and leukemia inhibitory factor (LIF) were significantly upregulated among the opioid-tolerant patients and positively correlated with the opioid dosage.We translated these findings back to lab animal experiment; after induction of tolerance by morphine infusion, the spinal cord expression of CXCL1, CXCL12, and LIF were all upregulated. Although CXCL1 and CXCL12 infusion alone did not affect baseline tail-flick latency, morphine analgesic efficacy dropped significantly after intrathecal infusion of CXCL1 and CXCL12. After establishing tolerance by intrathecal continuous infusion of morphine, tolerance development was accelerated by co-administration of CXCL1 and CXCL12. In parallel, the effect was attenuated by co-administration of CXCL1- or CXCL12-neutralizing antibody or concordant receptor antagonists.On the contrary, although chronic morphine administration still induced LIF upregulation in rat spinal cords, intrathecal injection of LIF potentiated the analgesic action of morphine and delayed the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other pro-inflammatory cytokines.CXCL1, CXCL12, and LIF are upregulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance were affected by modulating the intrathecal CXCL1/CXCR2, CXCL12/CXCR4, and LIF signaling and could be novel drug targets for the treatment of opioid tolerance. PMID- 30306521 TI - Neural Mechanisms of Offset Analgesia. AB - One feels a disproportionately large decrease of pain sensation on a slight decrease of thermal pain stimulus. Such phenomenon is termed offset analgesia and considered mediated by endogenous analgesic mechanisms. Offset analgesia was found attenuated in patients with neuropathic pain. We further found that such attenuation occurred in a more heterogeneous population of patients with chronic pain. By functional magnetic resonance imaging, we also found negative blood oxygenation level-dependent signals at those areas concerned with descending pain modulatory and reward systems during offset analgesia in the same cohort of patients. We propose that dysfunction of those systems, as revealed by attenuation of offset analgesia, might well be part of neural mechanisms of pain chronification. PMID- 30306522 TI - Cortical LTP: A Synaptic Model for Chronic Pain. AB - Cumulative evidence indicates that cortical synapses not only play important roles in pain perception and related emotional functions but also undergo long term potentiation (LTP) and contribute to chronic pain. LTP is found at two key cortical regions such as the anterior cingulate cortex (ACC) and insular cortex (IC), and inhibition of cortical LTP produces analgesic effects as well as anxiolytic effects. In this chapter, I will summarize our work on ACC and IC and provide evidence for calcium-stimulated AC1 as a key molecule for cortical LTP and chronic pain. PMID- 30306523 TI - Pain-Associated Neural Plasticity in the Parabrachial to Central Amygdala Circuit : Pain Changes the Brain, and the Brain Changes the Pain. AB - In addition to the canonical spino-thalamo-cortical pathway, lines of recently accumulated anatomical and physiological evidence suggest that projections originating in nociception-specific neurons in lamina I of the dorsal horn or the spinal nucleus of the trigeminal nerve to the lateral parabrachial nucleus (LPB) and then to the central amygdala (CeA) play essential roles in the nociception emotion link and its tightening in chronic pain. With recent advances in the artificial manipulation of central neuronal activity, such as those with optogenetics, it is now possible to address many unanswered questions regarding the molecular and cellular mechanisms underlying the plastic changes in this pathway and their role in the pain chronification process. PMID- 30306524 TI - Electrophysiological Signature of Pain. AB - Pain is a complex neural function involving cognition, sensory, emotion, and memory. Imaging studies have shown that multiple brain regions are actively engaged in the processing of pain. However, roles of each brain regions and their contribution to pain are still largely unknown. Recent studies with electrophysiology especially high-density electroencephalogram (EEG) or multichannel recordings techniques have provided more insights into the dynamics of pain signature. The accumulations of the evidence could facilitate our understanding of pain and provide potential methods for objective pain evaluation and treatment of chronic pain. PMID- 30306525 TI - Neuroimaging Studies of Primary Dysmenorrhea. AB - Primary dysmenorrhea (PDM), cyclic menstrual pain in the absence of pelvic anomalies, is one of the most common gynecological disorders in reproductive females. Classified as chronic pelvic pain syndrome, PDM encompasses recurrent spontaneous painful ("on") and pain-free ("off") states and is thus a good clinical model to study state- and trait-related changes of pain in the brain. In this chapter, we summarize state-of-the-art neuroimaging studies of primary dysmenorrhea from phenotype and endophenotype to genotype facets. Structural and functional brain alterations associated with primary dysmenorrhea are discussed. PMID- 30306526 TI - Brain Reward Circuit and Pain. AB - Pain plays an important role in alerting the body to potential tissue injury and drives behavior that protects the body from further harm. In contrast, chronic pain does not serve this function and instead only provides a persistent sensation of pain and a negative experience. The mesolimbic dopaminergic system has been recognized to play a central role in motivated behaviors, including various types of reward and pleasure. Many dopaminergic neurons may release multiple neurotransmitters, and the physiological role of the co-release of these transmitters has been revealed incrementally. However, it was not yet clear whether the mesolimbic dopaminergic system and small molecules released in the nucleus accumbens (N.Acc.), the input region of mesolimbic dopaminergic neurons, are involved in pain modulation. Recently, we revealed that the mesolimbic dopaminergic system and small molecules released in the N.Acc. could contribute to pain modulation. In this review, we provide an overview of the relationship between pain and the brain reward circuit using a combination of optogenetics, electrophysiology, and in vivo microdialysis/mass spectrometry integrated system. PMID- 30306527 TI - Involvement of P2X7 Receptors and BDNF in the Pathogenesis of Central Poststroke Pain. AB - Central pain is commonly found in patients with neurological complications that are associated with central nervous system insult, such as stroke. It can result directly from central nervous system injury. Impairments in sensory discrimination can make it challenging to differentiate central neuropathic pain from other types of pain or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring the recognition of its association with past neurologic injury. This chapter focuses on the involvement of P2X7 receptor and brain-derived neurotrophic factor (BDNF) in central poststroke pain (CPSP). An experimental animal model is introduced that assesses the pathogenesis of central neuropathic pain, and pharmacological approaches and neuromodulatory treatments of this difficult-to-treat pain syndrome are discussed. PMID- 30306528 TI - Melatonin: A New-Generation Therapy for Reducing Chronic Pain and Improving Sleep Disorder-Related Pain. AB - Melatonin is an endogenous neurohormone that is produced in most living organisms, including unicellular and multicellular organisms, plants, vertebrates, and nonvertebrate animals. In diurnal animals, endogenous melatonin functions as a neurohormone and contributes to circadian rhythms. In nocturnal animals, endogenous melatonin no longer functions as a contributor to circadian rhythms. Circadian rhythms control the timing, quantity, and quality of hormones and neurotransmitters that the body produces and eventually secretes. An imbalance of these events creates disturbances in circadian rhythm. During disturbances of circadian rhythm, the body produces hormones, chemicals, and neurotransmitters in aberrant amounts or at the wrong time of day. The human circadian system is synchronized with physiological functions and metabolism. Many studies have reported that exogenous melatonin has analgesic and neuroprotective effects in chronic pain. Considering that chronotherapy may be beneficial for the treatment of chronic pain, the present review describes the properties, possible mechanisms, and function of melatonin in chronic pain. PMID- 30306529 TI - Central Poststroke Pain, Comorbidity, and Associated Symptoms in Animal and Human Models. AB - The objective of the present review paper was to comprehensively introduce the pain symptom and comorbidities of depression, anxiety, and learning and memory dysfunctions in the central poststroke pain (CPSP) of human and animal models. CPSP is a disease in which the lesion or dysfunction of the spinothalamocortical circuits is due to thalamic stroke hemorrhage. According to previous literature, CPSP patients experience impaired explicit and implicit learning and memory in addition to the pain symptom. Moreover, there are associated depression and anxiety comorbidities for CPSP. However, the data from some clinical studies were not supportive of the notion that CPSP patients also experienced induced comorbid depression and anxiety. On the other hand, the motor function test was likely to be inconsistent in terms of the results of human and animal models. The review paper provides some implications for further development of animal models for examinations of CPSP comorbidities of depression, anxiety, learning and memory dysfunction, and motor functions, aside from the central pain symptom. In human models, some conflicting data related to comorbid depression, anxiety, explicit and implicit learning memory, and motor dysfunctions should be re-elucidated in further studies. PMID- 30306531 TI - Low temperature induced modulation of photosynthetic induction in non-acclimated and cold-acclimated Arabidopsis thaliana: chlorophyll a fluorescence and gas exchange measurements. AB - Cold acclimation modifies the photosynthetic machinery and enables plants to survive at sub-zero temperatures, whereas in warm habitats, many species suffer even at non-freezing temperatures. We have measured chlorophyll a fluorescence (ChlF) and CO2 assimilation to investigate the effects of cold acclimation, and of low temperatures, on a cold-sensitive Arabidopsis thaliana accession C24. Upon excitation with low intensity (40 umol photons m- 2 s- 1) ~ 620 nm light, slow (minute range) ChlF transients, at ~ 22 degrees C, showed two waves in the SMT phase (S, semi steady-state; M, maximum; T, terminal steady-state), whereas CO2 assimilation showed a linear increase with time. Low-temperature treatment (down to - 1.5 degrees C) strongly modulated the SMT phase and stimulated a peak in the CO2 assimilation induction curve. We show that the SMT phase, at ~ 22 degrees C, was abolished when measured under high actinic irradiance, or when 3 (3, 4-dichlorophenyl)-1, 1- dimethylurea (DCMU, an inhibitor of electron flow) or methyl viologen (MV, a Photosystem I (PSI) electron acceptor) was added to the system. Our data suggest that stimulation of the SMT wave, at low temperatures, has multiple reasons, which may include changes in both photochemical and biochemical reactions leading to modulations in non-photochemical quenching (NPQ) of the excited state of Chl, "state transitions," as well as changes in the rate of cyclic electron flow through PSI. Further, we suggest that cold acclimation, in accession C24, promotes "state transition" and protects photosystems by preventing high excitation pressure during low-temperature exposure. PMID- 30306532 TI - The Possibility and Molecular Mechanisms of Cell Pyroptosis After Cerebral Ischemia. PMID- 30306530 TI - The role of small-angle scattering in structure-based screening applications. AB - In many biomolecular interactions, changes in the assembly states and structural conformations of participants can act as a complementary reporter of binding to functional and thermodynamic assays. This structural information is captured by a number of structural biology and biophysical techniques that are viable either as primary screens in small-scale applications or as secondary screens to complement higher throughput methods. In particular, small-angle X-ray scattering (SAXS) reports the average distance distribution between all atoms after orientational averaging. Such information is important when for example investigating conformational changes involved in inhibitory and regulatory mechanisms where binding events do not necessarily cause functional changes. Thus, we summarise here the current and prospective capabilities of SAXS-based screening in the context of other methods that yield structural information. Broad guidelines are also provided to assist readers in preparing screening protocols that are tailored to available X-ray sources. PMID- 30306533 TI - Making a picture worth a thousand numbers: recommendations for graphically displaying patient-reported outcomes data. AB - PURPOSE: Patient-reported outcomes (PROs) can promote patient-centered care in multiple ways: (1) using an individual patient's PRO data to inform his/her management, (2) providing PRO results from comparative research studies in patient educational materials/decision aids, and (3) reporting PRO results from comparative research studies in peer-reviewed publications. Patients and clinicians endorse the value of PRO data; however, variations in how PRO measures are scored and scaled, and in how the data are reported, make interpretation challenging and limit their use in clinical practice. We conducted a modified Delphi process to develop stakeholder-engaged, evidence-based recommendations for PRO data display for the three above applications to promote understanding and use. METHODS: The Consensus Panel included cancer survivors/caregivers, oncologists, PRO researchers, and application-specific end-users (e.g., electronic health record vendors, decision aid developers, journal editors). We reviewed the data display issues and their evidence base during pre-meeting webinars. We then surveyed participants' initial perspectives, which informed discussions during an in-person meeting to develop consensus statements. These statements were ratified via a post-meeting survey. RESULTS: Issues addressed by consensus statements relevant to both individual and research data applications were directionality (whether higher scores are better/worse) and conveying score meaning (e.g., none/mild/moderate/severe). Issues specific to individual patient data presentation included representation (bar charts vs. line graphs) and highlighting possibly concerning scores (absolute and change). Issues specific to research study results presentation included handling normed data, conveying statistically significant differences, illustrating clinically important differences, and displaying proportions improved/stable/worsened. CONCLUSIONS: The recommendations aim to optimize accurate and meaningful interpretation of PRO data. PMID- 30306535 TI - Magnetic-Based Cell Isolation Technique for the Selection of Stem Cells. AB - Magnetic-activated cell sorting (MACS) is the technology that is recently used as a magnetic-based cell isolation/purification technique. This technique enables the isolation and selection of germ, hematopoietic, and somatic stem cells including skin stem cells (SkSCs). Here, we have tried to describe the isolation of stem cells by MACS using CD34 antigen for SkSCs, again CD34 for hematopoietic stem cells (HSCs) and Thy-1 for spermatogonial stem cells (SpSCs). MACS allowed the isolation of CD34+, CD34+, and Thy-1+ human SkSCs, HSCs, and SpSCs with minimum 98% purity. PMID- 30306534 TI - Hearing loss and quality of life in survivors of paediatric CNS tumours and other cancers. AB - PURPOSE: Hearing loss, a complication of cancer treatment, may reduce health related quality of life (HRQoL), especially in childhood cancer survivors of central nervous system (CNS) tumours who often have multiple late effects. We examined the effect of hearing loss on HRQoL in young survivors of CNS and other childhood cancers. METHODS: Within the Swiss Childhood Cancer Survivor Study, we sent questionnaires about hearing loss and HRQoL (KIDSCREEN-27) to parents of survivors aged 8-15 years. We stratified the effect of hearing loss on HRQoL by cancer diagnosis, using multivariable logistic regression and adjusting for sociodemographic and clinical factors. RESULTS: Hearing loss was associated with impaired physical well-being [unadjusted estimated differences - 4.6 (CI - 9.2, - 0.1); adjusted - 4.0 (CI - 7.6, - 0.3)] and peers and social support [unadjusted 6.7 (CI - 13.0, - 0.3); adjusted - 5.0 (CI - 10.5, 0.9)] scores in survivors of CNS tumours (n = 123), but not in children diagnosed with other cancers (all p values > 0.20, n = 577). CONCLUSION: Clinicians should be alert to signs of reduced physical well-being and impaired relationships with peers. Especially survivors of CNS tumours may benefit most from strict audiological monitoring and timely intervention to mitigate secondary consequences of hearing loss on HRQoL. PMID- 30306537 TI - False-positive radioiodine whole body scan due to a renal cyst. AB - Patients affected by differentiated thyroid cancer are treated surgically and by ablative radioiodine therapy. Post-therapy whole body scan allows detecting thyroid remnants or local and distant metastases, although false-positive findings may be observed. We report a case of 75-year-old woman with follicular thyroid cancer, who underwent ablative radioiodine treatment. On post-therapy whole body scan, abnormal uptake in the left upper abdomen was found, although stimulated thyroglobulin level was not suggestive for distant metastases of differentiated thyroid carcinoma. Additional SPECT/CT acquisition revealed focal 131I uptake located at the posterolateral wall of the left kidney corresponding to a round lesion of 47 mm in maximal diameter. In order to verify this finding abdominal ultrasound and abdominal contrast-enhanced CT were performed, confirming multiple renal cysts in the left kidney, the biggest one was the site of abnormal radioiodine accumulation. Despite the high incidence of renal cysts, especially in the elderly, radioiodine uptake in renal cysts is extremely rare. Different hypotheses on the mechanism of radioiodine uptake in the cyst were proposed, among them active secretion by sodium-iodide symporter or other transporting proteins. We conclude that abnormal radioiodine uptake in renal cysts can be an exceptional finding mimicking a metastasis. PMID- 30306536 TI - Protective effect of alpha-mangostin on thioacetamide-induced liver fibrosis in rats as revealed by morpho-functional analysis. AB - Liver fibrosis is an excessive accumulation of scar tissue resulting from inflammation and cell death. Thioacetamide (TAA) is a well-known hepatotoxin that induces liver fibrosis. A marker of injured hepatocytes is transforming growth factor-beta 1 (TGF-beta1), while alpha-smooth muscle actin (alpha-SMA) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are markers of activated hepatic stellate cells. Alpha-mangostin, a major xanthone derivative from the mangosteen pericarp, has been shown to have anti-oxidant and anti-inflammatory activities. The objective of this study was to determine whether alpha-mangostin has a protective effect on TAA-induced liver fibrosis in rats. The rats were treated by intraperitoneal injection of compounds for eight weeks. For the control group a mixture of dimethyl sulfoxide and phosphate buffered saline was administered. Two hundred mg/kg BW of TAA was administered three times weekly. Alpha-mangostin was administered at 5 mg/kg BW and silymarin at 100 mg/kg BW, both twice weekly. TAA induced histologically recognizable liver damage and fibrosis, as anticipated. Furthermore, it increased immunohistochemically detectable TGF-beta1, alpha-SMA and TIMP-1. Co-administration of alpha-mangostin or silymarin with TAA prevented or ameliorated the effects of TAA administration alone. The anti-fibrotic effect of alpha-mangostin was stronger than that of silymarin. PMID- 30306538 TI - Implementing systematic reviews of prognosis studies in Cochrane. PMID- 30306539 TI - Clinically significant anxiety as a risk factor for dementia in the elderly community. AB - OBJECTIVE: To evaluate whether clinically significant anxiety is an independent risk factor for dementia, taking into account both depression among potentially confounding factors and the competing risk of death. METHOD: During the Zaragoza Dementia and Depression (ZARADEMP) study, a random sample of community dwellers aged 55 years or older was assessed (n = 4803), and a two-wave, 4.5-year follow up was completed. Geriatric Mental State (GMS)-AGECAT criteria were used to diagnose anxiety and DSM-IV criteria were applied to diagnose incident dementia. The multivariate Fine and Gray regression model was implemented to calculate dementia risk. RESULTS: Compared with non-cases (GMS-AGECAT criteria), the incidence rate of dementia was significantly higher in subcases of anxiety, and particularly significant in the cases of anxiety (incidence rate ratio (IRR): 2.77; P = 0.010). Cases of anxiety, but not subcases, at baseline were significantly associated with dementia risk (adjusted subdistribution hazard ratio (SHR): 2.7; P = 0.019). CONCLUSION: Clinically significant anxiety is associated with an almost threefold increase in the risk of dementia in the population, even when controlling for depression and considering mortality in the competing risks model. PMID- 30306540 TI - Senior PharmAssist: Less Hospital Use with Enrollment in an Innovative Community Based Program. AB - OBJECTIVES: To evaluate changes in acute health services use of Senior PharmAssist participants. DESIGN: Retrospective analysis. SETTING: Community based, nonprofit program in Durham County, North Carolina. PARTICIPANTS: Adults aged 60 and older with income of 200% of the federal poverty level or less who enrolled in the Senior PharmAssist program (N = 191) between August 1, 2011, and March 15, 2017. INTERVENTION: Medication therapy management (MTM), customized community referrals, Medicare insurance counseling, and medication copayment assistance provided by Senior PharmAssist. MEASUREMENTS: Primary outcomes were self-reported emergency department (ED) visits and hospital admissions in the previous year, assessed at baseline and every 6 months for up to 2 years. RESULTS: Mean number of ED visits declined over time (0.83 visits per year at baseline to 0.53 visits per year at 24 months, P = .002), as did the percentage of participants reporting an ED visit in the past year (49% at baseline to 31% at 24 months, P = .003). Mean hospital admissions also decreased (0.56 admissions per year at baseline to 0.4 admissions per year at 24 months, P = .02). There was no significant change in percentage of participants reporting a hospital admission in the past year (33% at baseline to 25% at 24 months, P = .23). CONCLUSION: Older adults who enrolled in a community-based program that helps them manage medications, connect with community resources, and overcome barriers to medication access experienced reductions in acute health services use. PMID- 30306541 TI - Central Nervous System Medication Burden and Risk of Recurrent Serious Falls and Hip Fractures in Veterans Affairs Nursing Home Residents. AB - OBJECTIVES: To examine the association between central nervous system (CNS) medication dosage burden and risk of serious falls, including hip fractures, in individuals with a history of a recent fall. DESIGN: Nested case-control study. SETTING: Veterans Health Administration (VHA) Community Living Centers (CLCs). PARTICIPANTS: CLC residents aged 65 and older with a history of a fall or hip fracture in the year before a CLC admission between July 1, 2005, and June 30, 2009. Each case (n = 316) was matched to four controls (n = 1264) on age, sex, and length of stay. MEASUREMENTS: Outcomes were serious falls identified using International Classification of Diseases, Ninth Revision (ACD-9) or Current Procedural Terminology (CPT) E codes, diagnosis codes, or procedure codes associated with a VHA emergency department visit or hospitalization during the CLC stay. Bar code medication administration data were used to calculate CNS standardized daily doses (SDDs) for opioid and benzodiazepine receptor agonists, some antidepressants, antiepileptics, and antipsychotics received in the 6 days before the outcome date by dividing residents' actual CNS daily doses by the minimum effective geriatric daily doses and adding the results. Multivariable conditional logistic regression models were used to evaluate the association between total CNS medication dosage burden, categorized as 0, 1 to 2, and 3 or more SDDs, and the outcome of recurrent serious falls. RESULTS: More cases (44.3%) than controls (35.8%) received 3.0 or more CNS SDDs (p = .02). Risk of serious falls was greater in residents with 3.0 or more SDDs than in those with 0 (adjusted odds ratio (aOR)=1.49, 95% confidence interval (CI)=1.03-2.14). Those with 1.0 to 2.9 SDDs had a risk similar to that of those with 0 SDDs (aOR=1.03, 95%CI=0.72-1.48). CONCLUSION: Nursing home residents with a history of a fall or hip fracture receiving 3.0 or more CNS SDDs were more likely to have a recurrent serious fall than those taking no CNS medications. Interventions targeting this vulnerable population may help reduce serious falls. PMID- 30306542 TI - A novel GABAergic dysfunction in human Dravet syndrome. AB - OBJECTIVE: Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation SCN1A, leading to a defective sodium channel that contributes to pathogenic brain excitability. A gamma-aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by GABAergic therapies. However, up to now the physiological mechanisms underlying the GABAergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here we studied, for the first time, human GABAA -evoked currents using cortical brain tissue from Dravet syndrome patients. METHODS: We transplanted in Xenopus oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age-matched controls. Additionally, experiments were performed on oocytes expressing human alpha1beta2gamma2 and alpha1beta2 GABAA receptors. GABAA currents were recorded using the two-microelectrodes voltage-clamp technique. Quantitative real-time polymerase chain reaction, immunohistochemistry, and double-labeling techniques were carried out on the same tissue samples. RESULTS: We found (1) a decrease in GABA sensitivity in Dravet syndrome compared to controls, which was related to an increase in alpha4- relative to alpha1-containing GABAA receptors; (2) a shift of the GABA reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters NKCC1/KCC2 expression ratio; (3) an increase of GABAA currents induced by low doses of cannabidiol both in Dravet syndrome and tuberous sclerosis complex comparable to that induced by a classical benzodiazepine, flunitrazepam, that still persists in gamma-less GABAA receptors. SIGNIFICANCE: Our study indicates that a dysfunction of the GABAergic system, considered as a feature of brain immaturity, together with defective sodium channels, can contribute to a general reduction of inhibitory efficacy in Dravet brain, suggesting that GABAA receptors could be a target for new therapies. PMID- 30306543 TI - The natural history of cutaneous sarcoidosis. Clinical spectrum and histological analysis of 40 cases. AB - BACKGROUND: Cutaneous lesions of sarcoidosis can allow physicians to establish the diagnosis of a systemic disease, but the need of monitoring patients presenting skin limited sarcoidosis in order to detect further extracutaneous involvement has rarely been evaluated. OBJECTIVES: To review clinical and histological features of patients with cutaneous sarcoidosis and the risk of progression to systemic disease. To characterize the phenotype of patients with isolated cutaneous sarcoidosis and to assess the temporal relationship between cutaneous and systemic disease. METHODS: Retrospective review of a series of patients with cutaneous sarcoidosis. Clinical, histopathological, and evolutive features were reviewed. RESULTS: Forty patients were included in the study. Systemic disease was present in 82.5% of patients. Previous or concurrent cutaneous involvement occurred in 81.8% of them. Seven out of 14 patients with cutaneous lesions evolved to a systemic sarcoidosis in a mean time of 6 years, with a range between 4 and 9 years. No clinical or histological differences were found between patients with systemic sarcoidosis and those who showed persistent isolated cutaneous lesions. CONCLUSIONS: Sarcoidosis may be manifested as an isolated cutaneous disorder. No clinical or histopathological features seem to be helpful to discriminate cases of a persistent isolated cutaneous disease from those that will develop systemic involvement. Since the development of systemic involvement in cases of isolated cutaneous sarcoidosis can occur many years afterward, careful monitoring seems advisable, and a long follow-up is recommended. PMID- 30306545 TI - Active mind-body movement therapies as an adjunct to or in comparison with pulmonary rehabilitation for people with chronic obstructive pulmonary disease. AB - BACKGROUND: Active mind-body movement therapies (AMBMTs), including but not limited to yoga, tai chi, and qigong, have been applied as exercise modalities for people with chronic obstructive pulmonary disease (COPD). AMBMT strategies have been found to be more effective than usual care; however, whether AMBMT is inferior, equivalent, or superior to pulmonary rehabilitation (PR) in people with COPD remains to be determined. OBJECTIVES: To assess the effects of AMBMTs compared with, or in addition to, PR in the management of COPD. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials and major Chinese databases, as well as trial registries from inception to July 2017. In addition, we searched references of primary studies and review articles. We updated this search in July 2018 but have not yet incorporated these results. SELECTION CRITERIA: We included (1) randomised controlled trials (RCTs) comparing AMBMT (i.e. controlled breathing and/or focused meditation/attention interventions for which patients must actively move their joints and muscles for at least four weeks with no minimum intervention frequency) versus PR (any inpatient or outpatient, community-based or home-based rehabilitation programme lasting at least four weeks, with no minimum intervention frequency, that included conventional exercise training with or without education or psychological support) and (2) RCTs comparing AMBMT + PR versus PR alone in people with COPD. Two independent review authors screened and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted outcome data, and assessed risk of bias. We contacted study authors if necessary to ask them to provide missing data. We calculated mean differences (MDs) using a random-effects model. MAIN RESULTS: We included in the meta-analysis 10 studies with 762 participants across one or more comparisons. The sample size of included studies ranged from 11 to 206 participants. Nine out of 10 studies involving all levels of COPD severity were conducted in China with adults from 55 to 88 years of age, a higher proportion of whom were male (78%). Nine out of 10 studies provided tai chi and/or qigong programmes as AMBMT, and one study provided yoga. Overall, the term 'PR' has been uncritically applied in the vast majority of studies, which limits comparison of AMBMT and PR. For example, eight out of 10 studies considered walking training as equal to PR and used this as conventional exercise training within PR. Overall study quality for main comparisons was moderate to very low mainly owing to imprecision, indirectness (exercise component inconsistent with recommendations), and risk of bias issues. The primary outcomes for our review were quality of life, dyspnoea, and serious adverse events.When researchers compared AMBMT versus PR alone (mainly unstructured walking training), statistically significant improvements in disease-specific quality of life (QoL) (St. George's Respiratory Questionnaire (SGRQ) total score) favoured AMBMT: mean difference (MD) -5.83, 95% confidence interval (CI) -8.75 to -2.92; three trials; 249 participants; low quality evidence. The common effect size, but not the 95% CI around the pooled treatment effect, exceeded the minimal clinically important difference (MCID) of minus four. The COPD Assessment Test (CAT) also revealed statistically significant improvements favouring AMBMT over PR, with scores exceeding the MCID of three, with an MD of 6.58 units (95% CI -9.16 to - 4.00 units; one trial; 74 participants; low-quality evidence). Results show no between-group differences with regard to dyspnoea measured by the modified Medical Research Council Scale (MD 0.00 units, 95% CI -0.37 to 0.37; two trials; 127 participants; low-quality evidence), the Borg Scale (MD 0.44 units, 95% CI -0.88 to 0.00; one trial; 139 participants; low-quality evidence), or the Chronic Respiratory Questionnaire (CRQ) Dyspnoea Scale (MD -0.21, 95% CI -2.81 to 2.38; one trial; 11 participants; low-quality evidence). Comparisons of AMBMT versus PR alone did not include assessments of generic quality of life, adverse events, limb muscle function, exacerbations, or adherence.Comparisons of AMBMT added to PR versus PR alone (mainly unstructured walking training) revealed significant improvements in generic QoL as measured by Short Form (SF)-36 for both the SF-36 general health summary score (MD 5.42, 95% CI 3.82 to 7.02; one trial; 80 participants; very low quality evidence) and the SF-36 mental health summary score (MD 3.29, 95% CI 1.45 to 4.95; one trial; 80 participants; very low-quality evidence). With regard to disease-specific QoL, investigators noted no significant improvement with addition of AMBMT to PR versus PR alone (SGRQ total score: MD -2.57, 95% CI -7.76 to 2.62 units; one trial; 192 participants; moderate-quality evidence; CRQ Dyspnoea Scale score: MD 0.04, 95% CI -2.18 to 2.26 units; one trial; 80 participants; very low-quality evidence). Comparisons of AMBMT + PR versus PR alone did not include assessments of dyspnoea, adverse events, limb muscle function, exacerbations, or adherence. AUTHORS' CONCLUSIONS: Given the quality of available evidence, the effects of AMBMT versus PR or of AMBMT added to PR versus PR alone in people with stable COPD remain inconclusive. Evidence of low quality suggests better disease-specific QoL with AMBMT versus PR in people with stable COPD, and evidence of very low quality suggests no differences in dyspnoea between AMBMT and PR. Evidence of moderate quality shows that AMBMT added to PR does not result in improved disease-specific QoL, and evidence of very low quality suggests that AMBMT added to PR may lead to better generic QoL versus PR alone. Future studies with adequate descriptions of conventional exercise training (i.e. information on duration, intensity, and progression) delivered by trained professionals with a comprehensive understanding of respiratory physiology, exercise science, and the pathology of COPD are needed before definitive conclusions can be drawn regarding treatment outcomes with AMBMT versus PR or AMBMT added to PR versus PR alone for patients with COPD. PMID- 30306544 TI - Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI 0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin. PMID- 30306547 TI - Treatment-as-Usual for Couples: Trajectories Before and After Beginning Couple Therapy. AB - Couple therapy has been shown to be a meaningful way to improve couples' relationships. However, less information is known about couples' functioning prior to entering treatment in community settings, as well as how their relationship functioning changes from initiating therapy onward. This study examined 87 couples who began community-based couple therapy during a longitudinal study of couples in the military. The couples were assessed six times over the course of 3 years, including time points before and after starting couple therapy. Using an interrupted-time series design, we examined trajectories across the start of couple therapy in relationship satisfaction, divorce proneness, and negative communication. The results demonstrated that couples' relationship satisfaction was declining and both divorce proneness and negative communication were increasing prior to entering couple therapy. After starting couple therapy, couples' functioning on all three variables leveled off but did not show further change, but previous experience in relationship education moderated these effects. Specifically, those who were assigned to the relationship education program (vs. control) demonstrated greater reductions in divorce proneness and greater increases marital satisfaction after starting therapy; however, they also started more distressed. PMID- 30306546 TI - Dietary modifications for infantile colic. AB - BACKGROUND: Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three weeks. This condition appears to be more frequent in the first six weeks of life (prevalence range of 17% to 25%), depending on the specific location reported and definitions used, and it usually resolves by three months of age. The aetiopathogenesis of infantile colic is unclear but most likely multifactorial. A number of psychological, behavioural and biological components (food hypersensitivity, allergy or both; gut microflora and dysmotility) are thought to contribute to its manifestation. The role of diet as a component in infantile colic remains controversial. OBJECTIVES: To assess the effects of dietary modifications for reducing colic in infants less than four months of age. SEARCH METHODS: In July 2018 we searched CENTRAL, MEDLINE, Embase , 17 other databases and 2 trials registers. We also searched Google, checked and handsearched references and contacted study authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of dietary modifications, alone or in combination, for colicky infants younger than four months of age versus another intervention or placebo. We used specific definitions for colic, age of onset and the methods for performing the intervention. We defined 'modified diet' as any diet altered to include or exclude certain components. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was duration of crying, and secondary outcomes were response to intervention, frequency of crying episodes, parental/family quality of life, infant sleep duration, parental satisfaction and adverse effects. MAIN RESULTS: We included 15 RCTs involving 1121 infants (balanced numbers of boys and girls) aged 2 to 16 weeks. All studies were small and at high risk of bias across multiple design factors (e.g. selection, attrition). The studies covered a wide range of dietary interventions, and there was limited scope for meta-analysis. Using the GRADE approach, we assessed the quality of the evidence as very low.Low-allergen maternal diet versus a diet containing known potential allergens: one study (90 infants) found that 35/47 (74%) of infants responded to a low-allergen maternal diet, compared with 16/43 (37%) of infants on a diet containing known potential allergens.Low-allergen diet or soy milk formula versus dicyclomine hydrochloride: one study (120 infants) found that 10/15 (66.6%) breastfed babies responded to dicyclomine hydrochloride, compared with 24/45 (53.3%) formula-fed babies. There was little difference in response between breastfed babies whose mother changed their diet (10/16; 62.5%) and babies who received soy milk formula (29/44; 65.9%).Hydrolysed formula versus standard formula: two studies (64 infants) found no difference in duration of crying, reported as a dichotomous outcome: risk ratio 2.03, 95% confidence interval (CI) 0.81 to 5.10; very low-quality evidence. The author of one study confirmed there were no adverse effects. One study (43 infants) reported a greater reduction in crying time postintervention with hydrolysed formula (104 min/d, 95% CI 55 to 155) than with standard formula (3 min/d, 95% CI -63 to 67).Hydrolysed formula versus another hydrolysed formula: one study (22 infants) found that two types of hydrolysed formula were equally effective in resolving symptoms for babies who commenced with standard formula (Alimentum reduced crying to 2.21 h/d (standard deviation (SD) 0.40) and Nutramigen to 2.93 h/d (SD 0.70)).Hydrolysed formula or dairy- and soy-free maternal diet versus addition of parental education or counselling: one study (21 infants) found that crying time decreased to 2.03 h/d (SD 1.03) in the hydrolysed or dairy- and soy-free group compared with 1.08 h/d (SD 0.7) in the parent education or counselling group, nine days into the intervention.Partially hydrolysed, lower lactose, whey-based formulae containing oligosaccharide versus standard formula with simethicone: one study (267 infants) found that both groups experienced a decrease in colic episodes (secondary outcome) after seven days (partially hydrolysed formula: from 5.99 episodes (SD 1.84) to 2.47 episodes (SD 1.94); standard formula: from 5.41 episodes (SD 1.88) to 3.72 episodes (SD 1.98)). After two weeks the difference between the two groups was significant (partially hydrolysed: 1.76 episodes (SD 1.60); standard formula: 3.32 episodes (SD 2.06)). The study author confirmed there were no adverse effects.Lactase enzyme supplementation versus placebo: three studies (138 infants) assessed this comparison, but none reported data amenable to analysis for any outcome. There were no adverse effects in any of the studies.Extract of Foeniculum vulgare, Matricariae recutita, and Melissa officinalis versus placebo: one study (93 infants) found that average daily crying time was lower for infants given the extract (76.9 min/d (SD 23.5), than infants given placebo (169.9 min/d (SD 23.1), at the end of the one-week study. There were no adverse effects.Soy protein-based formula versus standard cows' milk protein-based formula: one study (19 infants) reported a mean crying time of 12.7 h/week (SD 16.4) in the soy formula group versus 17.3 h/week (SD 6.9) in the standard cows' milk group, and that 5/10 (50%) responded in the soy formula group versus 0/9 (0%) in the standard cows' milk group.Soy protein formula with polysaccharide versus standard soy protein formula: one study (27 infants) assessed this comparison but did not provide disaggregated data for the number of responders in each group after treatment.No study reported on our secondary outcomes of parental or family quality of life, infant sleep duration per 24 h, or parental satisfaction. AUTHORS' CONCLUSIONS: Currently, evidence of the effectiveness of dietary modifications for the treatment of infantile colic is sparse and at significant risk of bias. The few available studies had small sample sizes, and most had serious limitations. There were insufficient studies, thus limiting the use of meta-analysis. Benefits reported for hydrolysed formulas were inconsistent.Based on available evidence, we are unable to recommend any intervention. Future studies of single interventions, using clinically significant outcome measures, and appropriate design and power are needed. PMID- 30306548 TI - Non-motor difficulties in children with idiopathic clubfoot: can this impact brace adherence? PMID- 30306549 TI - Concerns regarding the use of vaginal fractional CO2 laser. PMID- 30306551 TI - Re: Efficacy, feasibility and patient acceptability of ultrasound-guided manual vacuum aspiration for treating early pregnancy loss. PMID- 30306550 TI - Severe growth restriction undelivered at term and ultrasound examination: Some clarifications. PMID- 30306552 TI - Reply to: Severe growth restriction undelivered at term and ultrasound examination. Some clarifications. PMID- 30306553 TI - Reply to: 'Concerns regarding the use of vaginal fractional CO2 laser'. PMID- 30306554 TI - Reply to Re: 'Efficacy, feasibility and patient acceptability of ultrasound guided manual vacuum aspiration for treating early pregnancy loss'. PMID- 30306555 TI - A common medical schools curriculum in obstetrics and gynaecology. PMID- 30306556 TI - Awareness and use of iodine supplementation among Australian women attending a low-risk pregnancy clinic. PMID- 30306557 TI - Decreased allergy incidence in children supplemented with E. coli O83:K24:H31 and its possible modes of action. AB - The growing knowledge of the key role of microbiota in the maturation of neonatal immune system suggests that manipulation of microbiota could be exploited in hampering allergy development. In this study, Escherichia coli O83:K24:H31 (EcO83) was administered to newborns that were followed prospectively. Several immunological characteristics (cytokines, specific IgE, total T regulatory cells (Treg) and subpopulation of natural Treg (nTreg) and induced Treg (iTreg)) were tested in peripheral blood of 8-year-old children. Incidence of allergic disease was decreased in EcO83 supplemented children and significantly elevated levels of IL-10 and IFN-gamma were detected in serum of EcO83 supplemented children. Probiotic supplementation did not influence the numbers of the total Treg population but their functional capacity (intracellular expression of IL-10) was significantly increased in children supplemented with EcO83 in comparison to non supplemented children. Morover, decreased proportion of iTreg was present in peripheral blood of non-supplemented in comparison to EcO83 supplemented children. Finally, stimulation of cord blood cells with EcO83 promoted both gene expression and secretion of IL-10 and IFN-gamma suggesting that beneficial effect of EcO83 in prevention of allergy development could be mediated by promotion of regulatory responses (by IL-10) and Th1 immune response (by IFN-gamma). PMID- 30306558 TI - The patient-centered dental home: A standardized definition for quality assessment, improvement, and integration. AB - OBJECTIVE: To develop the first standardized definition of the patient-centered dental home (PCDH). DATA SOURCES/STUDY SETTING: Primary data from a 55-member national expert panel and public comments. STUDY DESIGN: We used a modified Delphi process with three rounds of surveys to collect panelists' ratings of PCDH characteristics and open-ended comments. The process was supplemented with a 1 month public comment period. DATA COLLECTION/EXTRACTION METHODS: We calculated median ratings, analyzed consensus using the interpercentile range adjusted for symmetry, and qualitatively evaluated comments. PRINCIPAL FINDINGS: Forty-nine experts (89%) completed three rounds and identified eight essential PCDH characteristics, resulting in the following definition: "The patient-centered dental home is a model of care that is accessible, comprehensive, continuous, coordinated, patient- and family-centered, and focused on quality and safety as an integrated part of a health home for people throughout the life span." CONCLUSIONS: This PCDH definition provides the foundation for developing measures for research, care improvement, and accreditation and is aligned with the patient centered medical home. Consensus among a broad national expert panel-including provider, payer, and accreditation stakeholder organizations and experts in medicine, dentistry, and quality measurement-supports the definition's usability and its potential to facilitate medical-dental primary care integration. PMID- 30306559 TI - A shifting balance: responses of mixotrophic marine algae to cooling and warming under UVR. AB - Mixotrophy is a dominant metabolic strategy in ecosystems worldwide. Shifts in temperature (T) and light (i.e. the ultraviolet portion of spectrum (UVR)) are key abiotic factors that modulate the conditions under which an organism is able to live. However, whether the interaction between both drivers alters mixotrophy in a global-change context remains unassessed. To determine the T * UVR effects on relative electron transport rates, nonphotochemical quenching, bacterivory, and bacterial production, we conducted an experiment with Isochrysis galbana populations grown mixotrophically, which were exposed to 5 degrees C of cooling and warming with respect to the control (19 degrees C) with (or without) UVR over light-dark cycles and different timescales. At the beginning of the experiment, cooling inhibited the relative electron transport and bacterivory rates, whereas warming depressed only bacterivory regardless of the radiation treatment. By the end of the experiment, warming and UVR conditions stimulated bacterivory. These reduced relative electron transport rates (c. 50% (warming) and > 70% (cooling)) were offset by increased (35%) cumulative bacterivory rates under warming and UVR conditions. We propose that mixotrophy constitutes an energy-saving and a compensatory mechanism to gain carbon (C) when photosynthesis is impaired, and highlight the need to consider the natural environmental changes affecting the populations when we test the impacts of interacting global-change drivers. PMID- 30306560 TI - Chemical profile, antioxidant, and enzyme inhibitory properties of two Scutellaria species: S. orientalis L. and S. salviifolia Benth. AB - OBJECTIVES: This study investigates into the biological effects of solvent extracts (ethyl acetate, methanol, and water) of Scutellaria orientalis L. and Scutellaria salviifolia Benth. based on its enzyme inhibitory activity and antioxidant ability together with the screening of bioactive compounds. METHODS: Total and individual bioactive components were determined using spectrophotometric and HPLC-ESI-MS methods. Six antioxidant assays were conducted and enzyme inhibition was tested against key enzymes linked to the pathology of common chronic disorders. KEY FINDINGS: Results revealed that the aqueous extracts of both plants exerted better 2,2'-azino-bis(3-ethylbenzothiazoline)-6 sulfonic acid scavenging, reducing power, metal chelating, and alpha-glucosidase inhibitory activities. The methanol extracts showed highest tyrosinase inhibition and antioxidant activity in phosphomolybdenum assay while the less polar ethyl acetate extracts showed better acetylcholinesterase, butyrylcholinesterase, and alpha-amylase inhibition. Phytochemical evaluation by HPLC-ESI-MS revealed the presence of high amounts of flavones. CONCLUSIONS: Scutellaria orientalis and S. salviifolia are important sources of bioactive agents that warrants further studies. PMID- 30306562 TI - Genetic variation and population structure among larval Lethenteron spp. within the Yukon River drainage, Alaska. AB - The absence of information on genetic variation and population structure of lampreys Lethenteron spp. in the eastern part of their distribution limits our understanding of the migration ecology and spatial population genetic structure of the species. We examined genetic variation within and among three aggregations of Lethenteron spp. larvae in the Yukon River drainage, Alaska, using microsatellite genotypes. A total of 120 larval lampreys were genotyped at eight microsatellite loci. Global FST was 0.053 (95% CI 0.021-0.086), while pairwise FST values ranged from 0.048-0.057. Model-based Bayesian clustering analyses with sample locality priors (LOCPRIOR) identified three distinct, but admixed, genetic clusters that corresponded with the three aggregations. Estimates of contemporary gene flow indicate substantial reciprocal migration among sites consistent with no or low-fidelity natal homing. These results are largely in agreement with previous reports of historic and contemporary gene flow among Lethenteron spp. in other parts of their geographic distribution. PMID- 30306561 TI - Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas. AB - Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes. In addition to CTNNB1-activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro-proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1alpha-regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 30306563 TI - Formation of intramuscular connective tissue network in fish: first insight from the rainbow trout (Oncorhynchus mykiss). AB - The formation of the intramuscular connective tissue was investigated in rainbow trout Oncorhynchus mykiss by combining histological and in situ gene-expression analysis. Laminin, a primary component of basement membranes, surrounded superficial slow and deep fast muscle fibres in O. mykiss as soon as the hatching stage (c. 30 days post fertilization (dpf)). In contrast, type I collagen, the primary fibrillar collagen in muscle of vertebrates, appeared at the surface of individual slow and fast muscle fibres only at c. 90 dpf and 110 dpf, respectively. The deposition of type I collagen in laminin-rich endomysium ensheathing individual muscle fibres correlated with the late appearance of collagen type 1 alpha 1 chain (col1alpha1) expressing fibroblasts inside slow and then fast-muscle masses. Double in situ hybridization indicated that coll1alpha1 expressing muscle resident fibroblasts also expressed collagen type 5 alpha 2 chain (col5alpha2) transcripts, showing that these cells are a major cellular source of fibrillar collagens within O. mykiss muscle. At c. 140 dpf, the formation of perimysium-like structure was manifested by the increase of type I collagen deposition around bundles of myofibres concomitantly with the alignment and elongation of some collagen-expressing fibroblasts. Overall, this study shows that the formation of O. mykiss intramuscular connective tissue network is completed only in aged fry when fibroblast-like cells expressing type I and V collagens arise inside of the growing myotome. PMID- 30306564 TI - Integrative approach reveals a new species of Nematocharax (Teleostei: Characidae). AB - An integrative approach based on morphological and multilocus genetic data was used to describe a new species of Nematocharax from the headwaters of the upper Contas River on the Diamantina Plateau, north-eastern Brazil and to infer the relationships among evolutionary lineages within this fish genus. Multispecies coalescent inference using three mitochondrial and five nuclear loci strongly supports a basal split between Nematocharax venustus and the new species, whose distinctive morphological characters include absence of filamentous rays on pelvic fins of maturing and mature males, reduced anal-fin lobe length and lower body depth. The unique morphological and genetic traits of the population from the upper Contas River were supported by previous reports based on cytogenetics, DNA barcode and geometric morphometrics, reinforcing the validation of the new species. The conservation status of this new species is discussed. PMID- 30306565 TI - iVI-TD-DFT: An iterative vector interaction method for exterior/interior roots of TD-DFT. AB - The recently proposed iterative vector interaction (iVI) method for large Hermitian eigenvalue problems (Huang et al., J. Comput. Chem. 2017, 38, 2481) is extended to generalized eigenvalue problems, HC = SCE, with the metric S being either positive definite or not. Although, it works with a fixed-dimensional search subspace, iVI can converge quickly and monotonically from above to the exact exterior/interior roots. The algorithms are further specialized to nonrelativistic and relativistic time-dependent density functional theories (TD DFT) by taking the orbital Hessian as the metric (i.e., the inverse TD-DFT eigenvalue problem) and incorporating explicitly the paired structure into the trial vectors. The efficacy of iVI-TD-DFT is demonstrated by various examples. (c) 2018 Wiley Periodicals, Inc. PMID- 30306566 TI - Resurgence when challenging alternative behavior with progressive ratios in children and pigeons. AB - Resurgence is defined as the recurrence of a previously reinforced and then extinguished target response when reducing or eliminating a more recently reinforced alternative response. In experiments with children and pigeons, we evaluated patterns of resurgence across and within sessions through decreases in reinforcer availability by challenging alternative responding with extinction and progressive-ratio schedules. In Phase 1, we reinforced only target responding. In Phase 2, we extinguished target responding while reinforcing an alternative response. Finally, Phase 3 assessed resurgence by (a) extinguishing alternative responding versus (b) introducing a progressive-ratio schedule of reinforcement for alternative responding. In both children and pigeons, resurgence of target responding occurred in both conditions but generally was greater when assessed during extinction than with progressive ratios. Importantly, within-session patterns of resurgence did not differ between testing with progressive ratios and extinction. Resurgence with progressive ratios tended to be greater with longer durations between reinforcers but we observed similar findings with only simulated reinforcers during extinction testing. Therefore, the present investigation reveals that the events contributing to instances of resurgence remain to be understood, and presents an approach from which to examine variables influencing within-session patterns of resurgence. PMID- 30306567 TI - Cellular polarity modulates drug resistance in primary colorectal cancers via orientation of the multidrug resistance protein ABCB1. AB - Colonic epithelial cells are highly polarised with a lumen-facing apical membrane, termed the brush border, and a basal membrane in contact with the underlying extracellular matrix (ECM). This polarity is often maintained in cancer tissue in the form of neoplastic glands and has prognostic value. We compared the cellular polarity of several ex vivo spheroid colonic cancer cultures with their parental tumours and found that those grown as non-attached colonies exhibited apical brush border proteins on their outer cellular membranes. Transfer of these cultures to an ECM such as collagen re-established the centralised apical polarity observed in vivo. The multidrug resistance protein ABCB1 also became aberrantly polarised to outer colony membranes in suspension cultures, unlike cultures grown in collagen where it was polarised to central lumens. This polarity switch was dependent on the presence of serum, or selected serum components including EGF, TGFB1 and IGF1. The apical/basal orientation of primary cancer colon cultures cultured in collagen/serum was modulated by alpha2beta1 integrin signalling. The polarisation of ABCB1 in colonies significantly altered drug uptake and sensitivity, as the outward polarisation of ABCB1 in suspension colonies effluxed substrates more effectively than ECM grown colonies with ABCB1 polarised to central lumens. Thus serum free suspension colonies were more resistant to a variety of anticancer drugs than ECM grown colonies. In conclusion the local stroma, or absence thereof, can have profound effects on the sensitivity of colorectal cultures to drugs that are ABCB1 substrates. PMID- 30306568 TI - Implementing dimer metadynamics using gromacs. AB - We develop a Gromacs implementation of dimer metadynamics (DM) (JCTC 13, 425 [2017]) for enhanced sampling through artificial delocalization effects. This implementation is based entirely on a Plumed collective variable developed for this purpose, the fine tuning of Gromacs input parameters, modified forcefields and custom nonbonded interactions. We demonstrate this implementation on alanine dipeptide in vacuum and in water, and on the 12-residue alanine polypeptide in water and compare the results with a standard multiple-replica technique such as parallel tempering. In all the considered cases, this comparison is consistent and the results with DM are smoother and require shorter simulations, thus proving the consistency and effectiveness of this Gromacs implementation. (c) 2018 Wiley Periodicals, Inc. PMID- 30306569 TI - Larval development of Brycon amazonicus (Teleostei, Bryconidae) with a focus on locomotory, respiratory and feeding structures. PMID- 30306570 TI - Evaluation of the use of portable ultrasonography to determine pregnancy status and fecundity in bonnethead shark Sphyrna tiburo. AB - This study examined the usefulness of portable ultrasonography in accurately predicting pregnancy and fecundity in the bonnethead shark Sphyrna tiburo by comparing ultrasound-obtained data with those obtained from animal dissection, the gold standard for elasmobranch reproduction studies. Mature female S. tiburo (n = 66) were collected throughout the period of reproduction and examined via portable ultrasonography using two different ultrasound transducers (8-5 MHz linear array transducer and a 5.0-2.5 MHz curvilinear array transducer) to determine pregnancy status and fecundity. Ultrasound-derived data were compared with validated assessments of pregnancy and litter size obtained using animal dissection to determine the level of agreement between the two approaches. Overall, there was strong agreement (90.9%) between pregnancy determinations obtained using ultrasonography and dissection. However, the effectiveness of portable ultrasonography in accurately determining specific stages of maturity and pregnancy differed slightly between transducer types (linear = 61.3%; curvilinear = 88.9%). Measurements of fecundity also agreed well between ultrasonography and dissection and there were no significant differences between mean fecundity estimates obtained using the two methods. In general, portable ultrasonography was found to be a good alternative to lethal sampling and animal dissection in obtaining reproductive data critical for the management and conservation of elasmobranchs. Special attention should be given to factors that can influence the reliability of ultrasound-derived data such as transducer type, embryo size and sound wave interference due to gut contents. PMID- 30306572 TI - Abstracts of the XXII FIGO World Congress of Gynecology & Obstetrics. PMID- 30306571 TI - Pytim: A python package for the interfacial analysis of molecular simulations. AB - Pytim is a versatile python framework for the analysis of interfacial properties in molecular simulations. The code implements several algorithms for the identification of instantaneous interfaces of arbitrary shape, and analysis tools written specifically for the study of interfacial properties, such as intrinsic profiles. The code is written in the python language, and makes use of the numpy and scipy packages to deliver high computational performances. Pytim relies on the MDAnalysis library to analyze the trajectory file formats of popular simulation packages such as gromacs, charmm, namd, lammps or Amber, and can be used to steer OpenMM simulations. Pytim can write information about surfaces and surface atomic layers to vtk, cube, and pdb files for easy visualization. The classes of Pytim can be easily customized and extended to include new interfacial algorithms or analysis tools. The code is available as open source and is free of charge. (c) 2018 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc. PMID- 30306573 TI - A new protein nucleic-acid coarse-grained force field based on the UNRES and NARES-2P force fields. AB - Based on the coarse-grained UNRES and NARES-2P models of proteins and nucleic acids, respectively, developed in our laboratory, in this work we have developed a coarse-grained model of systems containing proteins and nucleic acids. The UNRES and NARES-2P effective energy functions have been applied to the protein and nucleic-acid components of a system, respectively, while protein-nucleic-acid interactions have been described by the respective coarse-grained potentials developed in our recent work (Yin et al., J. Chem Theory Comput. 2015, 11, 1792). The Debye-Huckel screening has been applied to the electrostatic-interaction energy between the phosphate groups and charged amino-acid side chains. The model has been integrated into the UNRES package for coarse-grained molecular dynamics simulations of proteins and the implementation has been tested for energy conservation in microcanonical molecular dynamics runs and for temperature conservation in canonical molecular dynamics runs. Two case studies were performed: (i) the dynamics of the Ku protein heterodimer bound to DNA, for which it was found that the Ku70/Ku80 protein complex plays an active role in DNA repairing and (ii) conformational changes of the multiple antibiotic resistance (MarA) protein occurring during DNA binding, for which the functionally important motions occurring during this process were identified. (c) 2018 Wiley Periodicals, Inc. PMID- 30306574 TI - DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats. AB - BACKGROUND: DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. METHODS: Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. RESULTS: NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real-time quantitative polymerase chain reaction analysis revealed that plasticity-related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS related markers decreased. CONCLUSION: The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other. PMID- 30306576 TI - Targeted therapy for gynecologic cancers: Toward the era of precision medicine. AB - Recent advances in molecular biology of cancer have led to the development of targeted agents, mainly of monoclonal antibodies and small-molecule compounds. Unlike traditional drugs that inhibit DNA synthesis and mitosis, these agents target the signaling pathways of cancer cells, stroma, and vasculature in tumor tissues. For gynecologic cancers, drugs targeting angiogenesis such as anti-VEGF antibody have been used in the treatment of advanced or recurrent ovarian and cervical cancers, and the drugs targeting homologous recombination deficiency such as PARP inhibitors have been approved for maintenance after chemotherapy in platinum-sensitive ovarian cancer. In addition, novel immunotherapy using the immune checkpoint inhibitors such as anti-PD-1 antibody has received much attention for modulation of local immunity, resulting in the durable response of platinum-resistant ovarian cancer. In the precision medicine era, further understanding of cancer genomics and identification of predictive biomarkers are essential to ensure better health for women with gynecologic cancer. PMID- 30306575 TI - Modulating stability of functionalized fullerene cations [R-C60 ]+ with the nature of R-group. AB - In this study, the first comprehensive theoretical investigation of the stability of functionalized fullerene-based cations [R-C60 ]+ and its relationship with the nature of the attached R-group was performed. C60 -Fullerene core was functionalized with an alkyl group of different length (R = (CH2 )n CH3 , where n = 0-9). This set was further complemented by bulky isopropyl and tert-butyl and conjugated phenyl groups. A detailed study of the relative stability of target cationic species was accompanied by in-depth investigation of their electronic structure and aromaticity using a large set of descriptors of different nature. The stability of target species was considered with respect to two alternative and competing mechanisms of bond breaking, namely, heterolytic ([R-C60 ]+ -> R+ + C60 ) and homolytic ([R-C60 ]+ -> R* + C60 +* ) ones. The transformation of strained sp2 -carbon atom in unperturbed C60 -fullerene to nonconstrained tetrahedral sp3 -type in functionalized derivatives was found to be the driving force for the formation of its functionalized cations. In spite of the fact that all systems under consideration were found to be corresponding to local minima on corresponding potential energy surfaces, the functionalization of C60 -core with the smallest and simplest methyl group resulted in most stable compound, as evaluated by bonding energy between R+ and fullerene fragment (in the light of both mechanisms). Subsequent elongation of the alkyl chain or introducing bulky groups led to notable decrease of the bonding energy and, as consequence, of the stability within the framework of heterolytic bond cleavage, whereas homolytic pathway assumes opposite-slight increase of stability along with lengthening of the R-group. The orbital interaction (DeltaEorb ) was identified as the main driving force for these trends. In general, the homolytic path was found to be dominating for small-length R-groups such as those with n = 0 and 1. At n = 2, heterolytic and homolytic pathways are equally probable (the difference in corresponding bonding energies is about 1 kcal/mol). However, when the alkyl chain becomes longer (n = 3-9), the cationic bond cleavage appears as the most energetically favorable. (c) 2018 Wiley Periodicals, Inc. PMID- 30306577 TI - Uterine sarcomas. AB - Uterine sarcomas account for approximately 3%-7% of all uterine cancers. Since carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common subtype. Exclusion of several histologic variants of leiomyoma, as well as atypical smooth muscle tumors (so-called "smooth muscle tumors of uncertain malignant potential"), has highlighted that the vast majority of leiomyosarcomas are high-grade tumors associated with poor prognosis even when apparently confined to the uterus. Low-grade endometrial stromal sarcomas are indolent tumors associated with long-term survival. High grade endometrial stromal sarcomas and undifferentiated endometrial sarcomas behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. The prognosis for carcinosarcomas (which are considered here in a postscript fashion) is usually worse than that for grade 3 endometrial carcinomas. Tumor stage is the single most important prognostic factor for uterine sarcomas. PMID- 30306578 TI - Palliative care in women's cancer care: Global challenges and advances. AB - Women's cancer rates are increasing in low- and middle-income countries, with presentations that are often far advanced requiring intense symptom management, thus advancing the urgent need to address palliative care. Most resource settings have some options available to assist women with advanced gynecologic cancer, and a combination of leveraging these and expanding on emerging models for palliative care could lessen suffering and improve care for women with gynecologic cancers globally. Providing palliative care for women with cancer is constrained by resources (human and physical), lack of equipment, lack of access, and policy absence or barriers. There is important work to be done in advocating for appropriate infrastructure development and legislation to assure that these options are available to women and their families. Access to adequate opioid and other pain relief options for cancer-related pain is a particular concern given that availability, cost, and legislative prohibitions create barriers that cause suffering for patients and grief for their families who are unable to address their suffering. All of these require ongoing advocacy for continual advances to improve access and infrastructure for palliative care. PMID- 30306579 TI - Pathology of cancers of the female genital tract including molecular pathology. AB - To better understand pathology reports, gynecologic oncologists must be familiar with the terminology used in gynecologic pathology. This chapter of the FIGO Cancer Report 2018 summarizes the clinical and pathological features of the most common cancers of the female genital tract, as well as their main molecular genetic alterations. In selected cases, an approach for processing surgical specimens is also included. PMID- 30306580 TI - Cancer of the corpus uteri. AB - Endometrial cancer is the most common gynecological malignancy in high-income countries. Although the overall prognosis is relatively good, high-grade endometrial cancers have a tendency to recur. Recurrence needs to be prevented since the prognosis for recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal strategy to balance treatment efficacy against toxicity. Standard treatment consists of hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy (with ongoing studies of sentinel node biopsy) enables identification of lymph node positive patients who need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant radiotherapy is used for Stage I-II patients with high-risk factors and Stage III lymph node negative patients. In advanced disease, a combination of surgery to no residual disease and chemotherapy results in the best outcome. Surgery for recurrent disease is only advocated in patients with a good performance status with a relatively long disease-free interval. PMID- 30306581 TI - Psychosexual health in gynecologic cancer. AB - More people are living with the long-term effects of cancer owing to improvements in cancer treatments and an aging population. Many people diagnosed with cancer report a negative impact on sexual identity, sexual functioning, and their sexual relationship. Gynecologic cancer survivors are often the most severely affected. These cancers involve cancers of the ovaries, uterus, cervix, vagina, and vulva. The impact of these cancers on sexual health results not only from the disease process itself, but may also be due to the necessary treatments required. These can have a profound impact on psychological, physiological, and social well-being both in the short and long term, which may result in negative impact on the quality of life of the patient as well as her partner. Although most patients express that they would like to be more informed about sexual health and would like to have the opportunity to discuss these issues with their therapeutic team, sexual health is often not discussed with the patient. PMID- 30306582 TI - Surgical pelvic anatomy in gynecologic oncology. AB - Laparoscopy, with its many advantages, has revolutionized the field of pelvic surgery and enabled surgeons to gain a far greater understanding of pelvic anatomy. As technology evolves, our understanding is continuously improving. This article is a tribute to the anatomy of the pelvis, which itself has resisted evolutionary changes and remained the same, whereas our understanding of how to view and approach various organ structures has evolved. PMID- 30306583 TI - Cancer of the vulva. AB - Vulvar cancer is an uncommon gynecological malignancy primarily affecting postmenopausal women. There is no specific screening and the most effective strategy to reduce vulvar cancer incidence is the opportune treatment of predisposing and preneoplastic lesions associated with its development. While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion. Once established, the most common subtype is squamous cell carcinoma. Treatment of vulvar cancer depends primarily on histology and surgical staging. Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors. Management should be individualized, and carried out by a multidisciplinary team in a cancer center experienced in the treatment of these tumors. PMID- 30306584 TI - Cancer of the cervix uteri. AB - Since the publication of the last FIGO Cancer Report there have been giant strides in the global effort to reduce the burden of cervical cancer, with WHO announcing a call for elimination. In over 80 countries, including LMICs, HPV vaccination is now included in the national program. Screening has also seen major advances with implementation of HPV testing on a larger scale. However, these interventions will take a few years to show their impact. Meanwhile, over half a million new cases are added each year. Recent developments in imaging and increased use of minimally invasive surgery have changed the paradigm for management of these cases. The FIGO Gynecologic Oncology Committee has revised the staging system based on these advances. This chapter discusses the management of cervical cancer based on the stage of disease, including attention to palliation and quality of life issues. PMID- 30306585 TI - Enhanced recovery after surgery in gynecologic oncology. AB - Enhanced recovery protocols consist of a bundle of concepts including early feeding, opioid-sparing multimodal pain management, and euvolemia, with the overarching goal of hastening postoperative recovery. Enhanced recovery after surgery has been shown to reduce hospital length of stay, reduce costs, and decrease perioperative opioid requirements in benign and oncologic gynecologic surgery. Interventions without supporting evidence of benefit, such as the use of mechanical bowel preparation, routine use of nasogastric tubes and surgical drains, caloric restriction, routine use of intravenous opioid analgesics, and over-vigorous intravenous hydration should be discouraged to improve broader endpoints such as patient satisfaction and overall recovery. Successful implementation requires engagement from a multidisciplinary team including surgeons, anesthesiologists, nurses, and pharmacists. PMID- 30306586 TI - Update on the diagnosis and management of gestational trophoblastic disease. AB - Gestational trophoblastic disease (GTD) arises from abnormal placenta and is composed of a spectrum of premalignant to malignant disorders. Changes in epidemiology of GTD have been noted in various countries. In addition to histology, molecular genetic studies can help in the diagnostic pathway. Earlier detection of molar pregnancy by ultrasound has resulted in changes in clinical presentation and decreased morbidity from uterine evacuation. Follow-up with human chorionic gonadotropin (hCG) is essential for early diagnosis of gestational trophoblastic neoplasia (GTN). The duration of hCG monitoring varies depending on histology type and regression rate. Low-risk GTN (FIGO Stages I-III: score <7) is treated with single-agent chemotherapy but may require additional agents; although scores 5-6 are associated with more drug resistance, overall survival approaches 100%. High-risk GTN (FIGO Stages II-III: score >7 and Stage IV) is treated with multiple agent chemotherapy, with or without adjuvant surgery for excision of resistant foci of disease or radiotherapy for brain metastases, achieving a survival rate of approximately 90%. Gentle induction chemotherapy helps reduce early deaths in patients with extensive tumor burden, but late mortality still occurs from recurrent resistant tumors. PMID- 30306587 TI - FIGO Cancer Report 2018. PMID- 30306588 TI - Essential surgical skills for a gynecologic oncologist. AB - Gynecologic oncology has seen a tremendous growth as a surgical specialty over the past four decades. However, many regions of the world still lack structured training programs in this discipline. The aim of this article is to identify the essential skills for a gynecologic oncologist to be able to provide optimal care to women diagnosed with gynecologic cancer. Where the evidence exists in the literature we identify the learning curve necessary. Identifying essential skills required for the practice of gynecologic oncology should assist in standardizing care provision globally, and could be a starting point for health systems beginning structured training programs. Development of surgical skills requires adequate training, mentorship, and self-evaluation as an ongoing process beyond the years spent in training programs. PMID- 30306589 TI - Cancer of the vagina. AB - Diagnosis of a primary vaginal cancer is rare because most of these lesions will be metastatic from another primary site. Although cancer of the vagina is more common in postmenopausal women, an increase in young women being diagnosed with primary vaginal cancer has been reported, especially in countries with a high HIV prevalence. This will be associated with persistence of high-risk HPV infection. The emphasis should be on primary prevention with prophylactic HPV vaccination. Once there is a suspicion of a primary vaginal cancer, this should be confirmed histologically with biopsy. Staging has been done clinically, similar to cervical cancer; however, there is a role for imaging in assisting with staging as this is often a difficult assessment. Treatment should be individualized and depends on stage as well as histologic subtype. It is prudent to refer cases to centers of excellence with experience in dealing with this rare gynecological cancer. PMID- 30306590 TI - Cancer in pregnancy. AB - The incidence of cancer in pregnancy is increasing. The most frequent malignancies include breast and cervical cancers. Diagnosis may be complicated by late presentation. Imaging during pregnancy should consider risks to the fetus. Diagnostic work-up, including tumor markers, can be influenced by the physiology of pregnancy. Treatment of cancer can often be safely administered with good maternal and fetal outcomes. Chemotherapy, radiotherapy, and surgery must be adapted to the pregnancy state. Counselling and emotional support are an essential part of management. PMID- 30306591 TI - Cancer of the ovary, fallopian tube, and peritoneum. AB - The Gynecologic Oncology Committee of FIGO in 2014 revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis <=10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies. PMID- 30306592 TI - Preface. PMID- 30306593 TI - Role of imaging in the routine management of endometrial cancer. AB - Endometrial cancer is the most common gynecologic cancer in women today. It is surgically staged, and while surgery is the primary treatment modality, the identification of disease extent-in particular extrauterine spread-prior to surgery is important to optimize treatment decision making. Ultrasound and MRI are useful for evaluating the extent of local disease, while CT and PET are used for detecting lymph node or distant metastases. Diffusion-weighted MRI has also been used for detecting small metastatic deposits in lymph nodes and omentum. Extrauterine soft tissue involvement can be detected by ultrasound, CT, MRI, and PET. Recently, intraoperative visualization techniques, such as sentinel lymph node mapping, are increasingly used to avoid extensive surgical staging without compromising treatment. Imaging is also used for planning adjuvant treatment and detection of postoperative residual disease in high-risk patients, monitoring and detecting recurrent disease, and in post-treatment surveillance of asymptomatic patients with high risk of relapse. PMID- 30306594 TI - Molecular understanding of the adhesive interactions between silica surface and epoxy resin: Effects of interfacial water. AB - The molecular mechanism of the adhesion between silica surface and epoxy resin under atmospheric conditions is investigated by periodic density-functional theory (DFT) calculations. Slab models of the adhesion interface were built by integrating a fragment of epoxy resin and hydroxylated (0 0 1) surface of alpha cristobalite in the presence of adsorbed water molecules. Effects of adsorbed water on the adhesion interaction are evaluated on the basis of geometry optimized structures, adhesion energies, and forces. Calculated results demonstrate that adsorbed water molecules significantly reduce both the adhesion energies and forces of the silica surface-epoxy resin interface. The reduction of adhesion properties can be associated with structural deformation of water molecules confined in the tight space between the adhesive and adherend as well as structural flexibility of the hydrogen-bonding network in the interfacial region during detachment of the epoxy resin from the hydrophilic silica surface. (c) 2018 Wiley Periodicals, Inc. PMID- 30306595 TI - Keratin 17 in disease pathogenesis: from cancer to dermatoses. AB - Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue-specific diseases, represented by steatocystoma multiplex and pachyonychia congenita. In this review, we summarize our findings concerning the regulatory mechanisms of K17 overexpression in psoriasis and compare them to the literature relating to other diseases. We discuss data that pro-inflammatory cytokines including IL-17, IL-22, IFN-gamma, TGF-beta and transcription factors Gli1/2, Nrf2 and p53 can regulate K17 by transcriptional and translational control. Moreover, post-translational modification including phosphorylation and ubiquitination are involved in the regulation of K17 stability and biological functions. We therefore review the current understanding of K17 regulatory mechanism and its pathogenic role in diseases from dermatoses to cancer. Prospects for anti-K17 therapy in diagnosis, prognosis and disease treatment are also discussed. PMID- 30306596 TI - Investigating detailed mechanism of hydrogen molecules adsorbing on single-wall carbon nanotubes using fitted force field parameters containing carbon-carbon interactions. AB - The nonbonded and bonded force field parameters for carbon atoms in single-wall carbon nanotubes (SWNT) are fitted by means of quantum chemistry calculations with considering the periodic boundary conditions. The nonbonded parameters between carbon atoms and hydrogen atoms are fitted as well. All the fitted parameters are verified by comparing to quantum chemistry results and by calculating Young's modulus. Adsorption of Hydrogen molecules are then carried out on a bundle of self-assembled SWNTs. The adsorption isotherms are consistent to the Freundlich equation. Both hydrogen molecules adsorbed outside and inside the SWNTs are counted. According to our result, hydrogen molecules adsorbed inside the SWNTs are more stable at a relatively high temperature and are playing an important part in total amount of the adsorbed molecules. While C(10,10) have the highest adsorption capacities in most of the temperatures, hydrogen molecules inside C(5,5) are the most stable of all the four kinds of SWNTs. Thus, balancing adsorption capacities and strength of interaction can be important in choosing SWNT for gas adsorption. Besides, we deduct an equation that can describe the relation between hydrogen pressure and amount of SWNTs based on our simulation results. The hydrogen pressure may decrease by adding SWNTs in the system. The fitting method in our system is valid to SWNTs and can be tested in further studies of similar systems. (c) 2018 Wiley Periodicals, Inc. PMID- 30306597 TI - Fermi-Lowdin orbital self-interaction corrected density functional theory: Ionization potentials and enthalpies of formation. AB - The Fermi-Lowdin orbital self-interaction correction (FLO-SIC) methodology is applied to atoms and molecules from the standard G2-1 test set. For the first time FLO-SIC results for the GGA-type PBE functional are presented. In addition, examples where FLO-SIC like any proper SIC provides qualitative improvements compared to standard DFT functionals are discussed in detail: the dissociation limit for H2+ , the step-wise linearity behavior for fractional occupation, as well as the significant reduction of the error of static polarizabilities. Further, ionization potentials and enthalpies of formation obtained by means of the FLO-SIC DFT method are compared to other SIC variants and experimental values. The self-interaction correction gives significant improvements if used with the LDA functional but shows worse performance in case of enthalpies of formation if the PBE-GGA functional is used. The errors are analyzed and the importance of the overbinding of hydrogen is discussed. (c) 2018 Wiley Periodicals, Inc. PMID- 30306598 TI - Longitudinal pulsatility in arterial occlusion. AB - This pictorial essay aims to generate attention and inform sonographers and clinicians by remembering the "longitudinal pulsatility" as an evocative B-mode echographic sign of arterial occlusion, when the artery exhibits a systolic axial motion instead of its normal radial pulsatility. PMID- 30306599 TI - Implication of ultrasound contrast-enhancement of carotid plaques in prevalence of acute coronary syndrome and occurrence of cardiovascular outcomes. AB - PURPOSE: Ultrasonographic contrast enhancement of carotid plaque (CECP) has been used to detect neovascularization of vasa vasorum and plaque. However, it is uncertain whether CECP can provide risk stratification of coronary artery disease (CAD). This study aimed to evaluate the relationship between CECP and manifestations of acute coronary syndrome (ACS) in established CAD patients and to explore the prognostic implication of CECP for cardiovascular (CV) clinical outcomes. METHODS: A medical record review revealed that contrast-enhanced ultrasonography was performed to evaluate carotid atherosclerosis in 209 coronary artery-stented and 105 non-stented patients. The rate of ACS manifestations was compared depending on contrast uptake patterns: grade 0, absent; grade 1, dot; and grade 2, diffuse pattern. CV primary outcomes were assessed during a mean 7.6 months of follow-up. RESULTS: Male sex, smoking, history of old myocardial infarction, intensive medications, and a favorable lipid profile were common in the stented versus non-stented group. Patients with grade 2 CECP had a higher rate of ACS, greater plaque thickness, and class I-II of Gray-Weale plaque echogenicity. During follow-up, 10 coronary revascularizations (nine ACSs), six strokes, and four heart failures occurred. Grade 2 CECP was more closely related with CV primary outcomes and showed a tendency toward more acute CV outcomes. CONCLUSION: ACS manifestations were proportionate to CECP grade. Diffuse CECP uptake could be a risk factor for acute CV outcomes. PMID- 30306600 TI - Optimizing and evaluating biomarker combinations as trial-level general surrogates. AB - We extend the method proposed in a recent work by the Authors for trial-level general surrogate evaluation to allow combinations of biomarkers and provide a procedure for finding the "best" combination of biomarkers based on the absolute prediction error summary of surrogate quality. We use a nonparametric Bayesian model that allows us to select an optimal subset of biomarkers without having to consider a large number of explicit model specifications for that subset. This dramatically reduces the number of model comparisons needed. Given the model's flexibility, complex nonlinear relationships can be fit when enough data are available. We evaluate the operating characteristics of our proposed method in simulations designed to be similar to our motivating example. We use our method to compare and evaluate combinations of biomarkers as trial-level general surrogates for the pentavalent rotavirus vaccine RotaTeqTM (RV5) (Merck & Co, Inc, Kenilworth, New Jersey, USA), finding that the same single biomarker identified in our previously published analysis is likely the optimal subset. PMID- 30306601 TI - Maternal low-protein diet programmes low ovarian reserve in offspring AB - The ovarian reserve of primordial follicle oocytes is formed during in utero development and represents the entire supply of oocytes available to sustain female fertility. Maternal undernutrition during pregnancy and lactation diminishes offspring ovarian reserve in rats. In mice, maternal oocyte maturation is also susceptible to undernutrition, causing impaired offspring cardiovascular function. We aimed to determine whether programming of the ovarian reserve is impacted in offspring when maternal undernutrition extends from preconception oocyte development through to weaning. C57BL6/J female mice were fed normal protein (20%) or low-protein (8%) diet during preconception, pregnancy and lactation periods. Maternal ovaries were harvested at weaning and offspring ovaries were collected at postnatal day (PN)21 and 24 weeks of age. Total follicle estimates were obtained by histologically sampling one ovary per animal (n = 5/group). There was no impact of diet on maternal follicle numbers. However, in offspring, maternal protein restriction significantly depleted primordial follicles by 37% at PN21 and 51% at 24 weeks (P < 0.05). There were no effects of diet on other follicle classes. Histological analysis showed no differences in the proportion of proliferative follicles (pH3 positive), but increased atresia (cleaved caspase-3-positive, or TUNEL-positive) was detected in ovaries of protein-restricted offspring at both ages (P < 0.05). Our data show that maternal diet during the preconception period, in utero development and early life has significant impacts on follicle endowment and markers of follicle health later in life. This highlights the need for further investigation into the importance of maternal preconception diet for offspring reproductive development and health. PMID- 30306602 TI - Quantum dynamics of vibration-vibration energy transfer for vibrationally excited HF colliding with H2. AB - The rate constants for H2 -HF energy transfer processes, especially for those in vibrationally excited states, are very demanding in astrophysics and chemical laser engineering, especially for those in vibrationally excited states. Based on our recent potential energy surface, we used the coupled-states approximation including the nearest neighboring Coriolis couplings with energy-based local basis set to perform dynamics calculation for the H2 -HF energy transfer system. Rate constants for vibrational transitions (1; 3) -> (0; 4), (1; 3) -> (2; 2), and (0; 3) -> (1; 2) were obtained. For state-to-state rate constants, transitions that have no internal angular momentum gap dominate at high temperatures. The vibrational-resolved rate constant for (1; 3) -> (0; 4) initially decreases and then increases with the temperature, while those for (1; 3) -> (2; 2), and (0; 3) -> (1; 2) transitions monotonically increase. The calculated rate constants are in good agreement with the available experimental results. These dynamical data can be further applied to the numerical simulation of hydrogen fluoride chemical laser. (c) 2018 Wiley Periodicals, Inc. PMID- 30306603 TI - Randomised clinical trial: reducing the intake of dietary FODMAPs of breastfeeding mothers is associated with a greater improvement of the symptoms of infantile colic than for a typical diet. AB - BACKGROUND: Therapeutic diets for infantile colic lack evidence. In breastfed infants, avoiding "windy" foods by the breastfeeding mother is common. AIM: To examine the effects of a maternal low-FODMAP (Fermentable, Oligosaccharides, Disaccharides, Monosaccharides, And Polyols) diet compared to a typical Australian diet on infant crying-fussing durations of infants with colic in a randomised, double-blind, crossover feeding study. METHODS: Between 2014 and 2016 exclusively breastfed infants aged <=9 weeks meeting Wessel criteria for colic were recruited. Mothers were provided a 10-day low-FODMAP or typical-Australian diet, then alternated without washout. Infants without colic (controls) were observed prospectively and mothers remained on habitual diet. Infant crying fussing durations were captured using a Barr Diary. Measures of maternal psychological status and samples of breast milk and infant faeces were collected. RESULTS: Mean crying-fussing durations were 91 min/d in seven controls compared with 269 min/d in 13 colicky infants (P < 0.0001), which fell by median 32% during the low-FODMAP diet compared with 20% during the typical-Australian diet (P = 0.03), confirmed by a two-way mixed-model analyses-of-variance (np 2 = 0.719; P = 0.049) with no order effect. In breast milk, lactose concentrations remained stable and other known dietary FODMAPs were not detected. Changes in infant faecal calprotectin were similar between diets and groups, and faecal pH did not change. Median maternal anxiety and stress fell with the typical Australian diet (P < 0.01), but remained stable on the low-FODMAP diet. CONCLUSIONS: Maternal low-FODMAP diet was associated with enhanced reduction in crying-fussing durations of infants with colic. This was not related to changes in maternal psychological status, gross changes in breast milk or infant faeces. Mechanisms require elucidation. Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR): 12616000512426 - anzctr.org.au. PMID- 30306604 TI - l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial. AB - WHAT IS KNOWN AND OBJECTIVE: Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 MUg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS: Seventy-one (71) children and adolescents, with a mean age of 11.3 +/- 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] >=60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 MUg l selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION: At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Delta: -70.9 +/- 22.1 vs -6.7 +/- 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Delta: -116.2 +/- 68.4 vs +262.8 +/- 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION: In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT. PMID- 30306605 TI - Covariate selection strategies for causal inference: Classification and comparison. AB - When causal effects are to be estimated from observational data, we have to adjust for confounding. A central aim of covariate selection for causal inference is therefore to determine a set that is sufficient for confounding adjustment, but other aims such as efficiency or robustness can be important as well. In this paper, we review six general approaches to covariate selection that differ in the targeted type of adjustment set. We discuss and illustrate their advantages and disadvantages using causal diagrams. Moreover, the approaches and different ways of implementing them are compared empirically in an extensive simulation study. We conclude that there are considerable differences between the approaches but none of them is uniformly best, with performance depending on the chosen adjustment method as well as the true confounding structure. Any prior structural knowledge on the causal relations is helpful to choose the most appropriate method. PMID- 30306606 TI - Special Issue: Innovations in occupational therapy measurement. PMID- 30306607 TI - Multiple functional assessments used by occupational therapists with older adults exist but psychometric properties vary. PMID- 30306608 TI - Limited evidence exists for the psychometric properties of child-report measures that assess occupational performance in children ages 2-18 years. PMID- 30306610 TI - A systematic review of the psychometric properties of the Action Research Arm Test in neurorehabilitation. AB - BACKGROUND/AIM: The Action Research Arm Test (ARAT) measures upper limb activity limitations in people with acquired brain injuries. Evidence relating to the use of this test in neurorehabilitation is scattered. This review identifies, rates and synthesises evidence on the original 1981 ARAT use within neurorehabilitation. Psychometric properties are reviewed, including specific examination of participants with upper limb spasticity. METHODS: Systematic review of published articles describing psychometric properties and/or use of the original version of the ARAT in neurorehabilitation. COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) search strategy, reporting and methodological checklist with criterion-based appraisal of quality criteria for good measurement properties were applied. A best evidence synthesis for each psychometric property was completed. RESULTS: In 28 included studies, participants had suffered a stroke or traumatic brain injury, with 46% >6 months post-injury. Six studies identified participants with upper limb spasticity. Methodological quality of psychometric properties ranged from poor to excellent. Best evidence synthesis determined moderate positive evidence for using the ARAT with people without limb spasticity: intra-rater reliability (ICC 0.71 (95% CI 0.53-0.89) to 0.99 (95% CI 0.98, 0.99)); responsiveness (ROC curve 0.72-0.88, SRM 0.89); and regarding construct validity, it is a valid measure of activity limitation. Limited evidence for psychometric properties of the ARAT were found when used with people with upper limb spasticity for construct validity and responsiveness (ES 0.55-0.78). Gaps in evidence were found for inter and test retest reliability, measurement error, content validity, structural validity, floor and ceiling effects. CONCLUSIONS: The ARAT is an appropriate measure of activity limitation post-stroke and should be considered for use with people with TBI; evidence for people with upper limb spasticity is limited. Gaps and mixed limited to moderate evidence for psychometric properties in neurorehabilitation mean further research is required. PMID- 30306611 TI - Nonlinear association structures in flexible Bayesian additive joint models. AB - Joint models of longitudinal and survival data have become an important tool for modeling associations between longitudinal biomarkers and event processes. The association between marker and log hazard is assumed to be linear in existing shared random effects models, with this assumption usually remaining unchecked. We present an extended framework of flexible additive joint models that allows the estimation of nonlinear covariate specific associations by making use of Bayesian P-splines. Our joint models are estimated in a Bayesian framework using structured additive predictors for all model components, allowing for great flexibility in the specification of smooth nonlinear, time-varying, and random effects terms for longitudinal submodel, survival submodel, and their association. The ability to capture truly linear and nonlinear associations is assessed in simulations and illustrated on the widely studied biomedical data on the rare fatal liver disease primary biliary cirrhosis. All methods are implemented in the R package bamlss to facilitate the application of this flexible joint model in practice. PMID- 30306612 TI - Serum M2BPGi level and risk of hepatocellular carcinoma after oral anti-viral therapy in patients with chronic hepatitis B. AB - BACKGROUND: Mac-2 binding protein glycosylation isomer (M2BPGi) is an emerging biomarker for risk prediction of liver disease, but data remain sparse for patients with chronic hepatitis B (CHB) who are treated with nucleos(t)ide analogues (NA). AIM: To clarify serial changes in M2BPGi and its association with subsequent hepatocellular carcinoma (HCC) development in NA-treated CHB patients. METHODS: We enrolled 384 previously untreated CHB patients who received NAs. Among them, 195 had baseline cirrhosis (n = 142:48:5 for Child A:B:C). Sera were collected at NA initiation, and after 1 and 2 years. Serum M2BPGi levels were measured and expressed as cut-off index (COI) at different time points. The association between M2BPGi and HCC was evaluated by the Cox proportional hazard model. RESULTS: The median M2BPGi levels significantly decreased from 1.68 COI at baseline, to 1.0 at year 1, and 0.88 at year 2. During median follow-up of 72.7 months, HCC occurred in 37 patients, 36 of whom had cirrhosis. In patients with cirrhosis, baseline M2BPGi level was associated with HCC risk (adjusted hazard ratio, 1.07 per COI; 95% CI, 1.01-1.14) on the multivariable Cox analysis, whereas levels at year 1 or 2 were not independently predictive. A risk score for HCC was developed using baseline M2BPGi, age and body mass index with c statistics of 0.77, 0.79 and 0.87 at 3, 5 and 10 years, respectively. CONCLUSIONS: Serum M2BPGi level significantly decreases after NA treatment in CHB patients. Baseline level can be factored into the risk prediction of HCC in NA treated patients with cirrhosis. PMID- 30306613 TI - A comparative analysis of symmetric diketopyrrolopyrrole-cored small conjugated molecules with aromatic flanks: From geometry to charge transport. AB - Diketopyrrolopyrrole (DPP) derivatives are promising compounds for application in organic electronics. Here, we investigate several symmetrical N-unsubstituted and N-methyl substituted DPPs which differ in the heteroatom in the aromatic flanks. The conformational, electronic, and optical properties are characterized for single molecules in vacuum or a solvent. The intermolecular interactions are evaluated for interacting dimers. Here, a number of stacking geometries is tested, and dimers with mutual orientation of the molecules corresponding to the minimal binding energies are determined. The predicted charge carrier mobilities for stacks having minimal binding energies corroborate experimentally measured values. We conclude that DFT prediction of such stacks is a promising and computationally inexpensive approach to a rough estimation of transport properties. Additionally, the super-cell of the experimentally resolved crystal structure is used to study the dynamics and to compute the charge transport along the hopping pathways. We discuss obtained high mobilities and relate them to the symmetry of DPP core. (c) 2018 Wiley Periodicals, Inc. PMID- 30306614 TI - Impact of finite-temperature and condensed-phase effects on theoretical X-ray absorption spectra of transition metal complexes. AB - The impact of condensed-phase and finite-temperature effects on the theoretical X ray absorption spectra of transition metal complexes is assessed. The former are included in terms of the all-electron Gaussian and augmented plane-wave approach, whereas the latter are taken into account by extensive ensemble averaging along second-generation Car-Parrinello ab initio molecular dynamics trajectories. We find that employing the periodic boundary conditions and including finite temperature effects systematically improves the agreement between our simulated X ray absorption spectra and experimental measurements. (c) 2018 Wiley Periodicals, Inc. PMID- 30306615 TI - Ab initio molecular dynamics study of prebiotic production processes of organic compounds at meteorite impacts on ocean. AB - Recent experiments concerning prebiotic materials syntheses suggest that the iron bearing meteorite impacts on ocean during Late Heavy Bombardment provided abundant organic compounds associated with biomolecules such as amino acids and nucleobases. However, the molecular mechanism of a series of chemical reactions to produce such compounds is not well understood. In this study, we simulate the shock compression state of a meteorite impact for a model system composed of CO2 , H2 O, and metallic iron slab by ab initio molecular dynamics combined with multiscale shock technique, and clarify possible elementary reaction processes up to production of organic compounds. The reactions included not only pathways similar to the Fischer-Tropsch process known as an important hydrocarbon synthesis in many planetary processes but also those resulting in production of a carboxylic acid. It is also found that bicarbonate ions formed from CO2 and H2 O participated in some forms in most of these observed elementary reaction processes. These findings would deepen the understanding of the full range of chemical reactions that could occur in the meteorite impact events. (c) 2018 Wiley Periodicals, Inc. PMID- 30306617 TI - Automatic and voluntary motor inhibition: Intact processes for tic suppression? PMID- 30306616 TI - Thermodynamic integration network approach to ion transport through protein channels: Perspectives and limits. AB - We present a molecular dynamics simulation study of alkali metal cation transport through the double-helical and the head-to-head conformers of the gramicidin ion channel. Our approach is based on a thermodynamic integration network, which consists of a sequence of transport reactions, absolute free energies of solvation and cycles of alchemical transmutations of the ions. In this manner, we can reliably estimate free energies and their statistical errors via a least squares method without imposing external forces on the system. Within the double helical channel, we find a free energy surface typical for hopping transport between isoenergetic sites of ion localization, separated by comparatively large activation barriers. For fast transport through the head-to-head conformation, the thermodynamic network scheme starts to break down. (c) 2018 Wiley Periodicals, Inc. PMID- 30306619 TI - Giant circumflex coronary artery aneurysm presenting as an intra-pericardial mass. PMID- 30306620 TI - Treatment with incretins does not increase the risk of pancreatic diseases compared to older anti-hyperglycaemic drugs, when added to metformin: real world evidence in people with Type 2 diabetes. AB - AIMS: In people with metformin-treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second line anti-hyperglycaemic agent initiation. METHODS: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i, n = 50 095), glucagon-like peptide-1 receptor agonist (GLP 1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti hyperglycaemic drug groups for appropriate confounders. RESULTS: In the DPP-4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP-4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP-1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups. CONCLUSIONS: No significant differences in the risk of developing pancreatic diseases in those treated with various anti-hyperglycaemic drug classes were found. PMID- 30306618 TI - Validation of a performance-based assessment of cognitive functional ability in Parkinson's disease. AB - BACKGROUND: Outcome measures that capture functional abilities related to cognition offer the potential to demonstrate real-world effectiveness of cognitive-enhancing treatments. However, distinguishing functional disability related to cognition from that attributed to motor symptoms can be difficult in PD. A performance-based functional assessment allows for direct observation of activity of daily living skills and separation of cognitive from motoric disabilities. OBJECTIVES: Validate the University of California San Diego Performance-Based Skills Assessment in PD. METHODS: One hundred PD participants, ranging from normal cognition to dementia, completed the University of California San Diego Performance-Based Skills Assessment, a performance-based measure of cognitively demanding activities of daily living, as well as a neuropsychological battery and motor examination. Cognitive classification was determined by consensus conference, blinded to University of California San Diego Performance Based Skills Assessment scores. Psychometric properties of the University of California San Diego Performance-Based Skills Assessment, including internal consistency, test-retest and inter-rater reliability, and discriminant validity for dementia, were examined. RESULTS: The University of California San Diego Performance-Based Skills Assessment demonstrated strong internal consistency (Cronbach's alpha = 0.82) and test-retest reliability (r = 0.89) and correlated strongly with global cognition (Mattis Dementia Rating Scale: r = 0.80; P < 0.001). University of California San Diego Performance-Based Skills Assessment regression models indicated greater contribution from cognitive explanatory variables (marginal partial: R2 = 0.33) than motor variables (marginal partial: R2 = 0.05), controlling for age, education, disease duration, and l-dopa equivalent dose. Additionally, the University of California San Diego Performance Based Skills Assessment exhibited strong discriminant validity for dementia (area under the curve = 0.91). CONCLUSIONS: The University of California San Diego Performance-Based Skills Assessment is a valid measure of functional abilities related to cognition rather than motor symptoms in PD. Furthermore, it reliably distinguishes demented from nondemented participants. The University of California San Diego Performance-Based Skills Assessment may be considered as an outcome measure that combines cognitive and functional abilities in treatment trials for cognitive impairment in PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30306621 TI - Judicial appraisals of risk assessment in sentencing. AB - The assessment of an offender's risk of recidivism is emerging as a key consideration in sentencing policy in many US jurisdictions. However, little information is available on how actual sentencing judges view this development. This study surveys the views of a population sample of judges in Virginia, the state that has gone further than any other in legislatively mandating risk assessment for certain drug and property offenders. Results indicate that a strong majority of judges endorse the principle that sentencing eligible offenders should include a consideration of recidivism risk. However, a strong majority also report the availability of alternatives to imprisonment in their jurisdictions to be inadequate at best. Finally, most judges oppose the adoption of a policy requiring them to provide a written reason for declining to impose alternative interventions on "low-risk" offenders. PMID- 30306622 TI - A meta-analysis of >=5-year mortality in randomized controlled trials of off-pump versus on-pump coronary artery bypass grafting. AB - OBJECTIVES: We sought to determine whether off-pump coronary artery bypass grafting (CABG) increases long-term mortality, by performing a meta-analysis of randomized controlled trials (RCTs) of off-pump versus on-pump CABG with >=5-year follow-up. METHODS: MEDLINE and EMBASE, and the Cochrane Central Register of Controlled Trials were searched through July 2018. Hazard, risk, or odds ratios (HRs, RRs, or ORs) of long-term (>=5-year) mortality for off-pump versus on-pump CABG were extracted from each individual trial. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic HRs in the random-effects model. RESULTS: Our search identified eight medium- to large-size RCTs at low risk of bias with long-term follow-up of off-pump versus on-pump CABG enrolling a total of 8780 patients. Combining four RCTs reporting actual HRs generated a statistically significant result favoring on-pump CABG (HR, 1.21; P = 0.02). A pooled analysis of all eight RCTs demonstrated a statistically significant increase in mortality with off-pump CABG (HR/RR, 1.19; P = 0.01). There was no evidence of significant publication bias in the meta-analysis of all eight RCTs. In a sensitivity analysis, extracting RRs or ORs from all eight RCTs and pooling them demonstrated a statistically significant increase in mortality with off-pump CABG (RR, 1.17; P = 0.01; OR, 1.20; P = 0.007). Eliminating 2 RRs and combining six HRs still generated a statistically significant result favoring on-pump CABG (HR, 1.19; P = 0.05). CONCLUSIONS: Off-pump CABG increases long-term (>=5-year) mortality compared with on-pump CABG. PMID- 30306623 TI - A bridge from HeartMate XVE to HeartMate 3. AB - Cardiac recovery after left ventricular assist device (LVAD) implantation is rare. Recurrent heart failure after device explantation is also rare. We describe a patient who is the recipient of a third-generation LVAD due to recurrent heart failure nearly one decade after successfully being bridged to recovery after implantation of a first-generation LVAD. PMID- 30306624 TI - Harming animals and massacring humans: Characteristics of public mass and active shooters who abused animals. AB - Researchers have extensively studied the tendency of certain violent criminals to hurt or torture animals, primarily focusing on domestic abusers and serial killers. However, little is known about the extent or nature of prior animal abuse among active shooters and public mass shooters. Public mass and active shooters essentially represent a single offender type: they are people who commit rampage attacks in public places and attempt to harm multiple victims beyond a single target. The only difference is that "mass" shootings are traditionally defined as cases resulting in the death of four or more victims, while "active" shootings have no minimum threshold. This study aimed to identify all publicly reported cases of active and mass shooters who engaged in animal cruelty, describe the nature of their violence toward animals and humans, and examine how they differ from other perpetrators without this history. Overall, this study found 20 cases of offenders with a publicly reported history of animal abuse. Comparisons between offenders with and without this history indicated that animal abusing offenders were more likely to be young and White, less likely to die at the crime scene, and more likely to kill and wound a large number of victims. While this finding supports the idea that animal abuse might be a warning sign for a small but deadly minority of mostly youthful offenders, it is likely not a robust signal of future shooters in general because animal abuse is rarely reported in this population of offenders at large. PMID- 30306625 TI - On- versus off-pump coronary artery bypass-Another nail in the coffin? PMID- 30306627 TI - Quadricuspid aortic valve associated with two left main coronary ostia. PMID- 30306626 TI - SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response. AB - BACKGROUND: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. OBJECTIVES: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. METHODS: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. RESULTS: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. CONCLUSION: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated. PMID- 30306628 TI - Animal maltreatment: Implications for behavioral science professionals. AB - Despite the widespread belief among the public and an increasing number of law enforcement personnel that individuals who harm animals often harm other people, the subject of animal maltreatment has received little attention from behavioral scientists. Advances in comparative neuroanatomy have highlighted the ability of animals to feel physical and emotional pain, including complex psychological reactions to traumatic events. These advances, and recent studies (however sparse) that support the notion that perpetrators of crimes against animals often commit other crimes, have arguably created an ethical and practical imperative for behavioral scientists to undertake a serious examination of animal maltreatment and potential mechanisms for responding to it. In addition, the close and complex relationships many Americans have with animals and the advancements in animal protection law in the past two decades necessitate expertise on the part of forensic psychologists and psychiatrists, who will increasingly be called upon to evaluate animal maltreatment offenders and consult on related policy and legislation. PMID- 30306629 TI - Impaired step-length setting prior to turning in Parkinson's disease patients with freezing of gait. PMID- 30306630 TI - Bestiality: An introduction for legal and mental health professionals. AB - Bestiality, or human-animal intercourse, has been a concern of the legal and mental health communities for many years. Ancient legal codes delineated punishments for those who engaged in the behavior, denoting a moral and general societal concern surrounding bestiality dating to ancient times. Despite this longstanding interest in and legal efforts to punish humans for having sex with animals, there has been little research on the behavior. Current available research has largely been siloed based on the populations studied, making it difficult to render any firm conclusions about bestiality's prevalence, frequency, and the risk posed by those who have sex with animals. It is important for clinicians to know the legal status of the behavior in their jurisdictions, to understand possible medical and psychiatric complications and comorbidities, and to know how to evaluate and treat individuals who engage in bestiality or have the related diagnosis of zoophilic disorder. This article provides an overview of the terminology and research pertaining to bestiality, summarizes legal and ethical considerations, and describes clinically relevant information for the evaluation and management of individuals engaged in sex with animals. PMID- 30306631 TI - Left atrial myxoma and concomittant acute myocardial infarction due to coronary atherosclerosis. PMID- 30306632 TI - Penetrating atherosclerotic ulcer of the ascending aorta. PMID- 30306633 TI - Effects of law enforcement and community outreach on mammal diversity in a biodiversity hotspot. AB - Management activities such as law enforcement and community outreach are thought to affect conservation outcomes in protected areas, but their importance relative to intrinsic environmental characteristics of the parks and extrinsic human pressures surrounding the parks have not been explored. Furthermore, it is not clear which is more related to conservation outcomes - the management itself or local people's perceptions of the management. Here we measured how objective (park staff-reported) and subjective (local villager-reported) levels of community outreach and law enforcement related to mammal abundance and diversity in six protected areas in Xishuangbanna, southwest China, a biodiversity hotspot with high hunting and land conversion pressures. Local people's perception of law enforcement was positively related to the local abundance of two large, hunted species, wild boar (Sus scrofa; beta = 15.22) and muntjac (Muntiacus vaginalis; beta = 14.82), but not related to the abundance of smaller mammals or to objective levels of enforcement. The subjective frequency of outreach by park staff to local communities (beta = 3.42), and park size (beta = 3.28), were significantly related to mammal species richness while elevation, human population density, and subjective frequency of law enforcement were not. We cannot conclude that community outreach and law enforcement are directly causing increased mammal abundance and diversity. Nevertheless, the patterns that we detect are some of the first empirical evidence consistent with the idea that biodiversity in protected areas can be more strongly related to local perceptions of park management than to either intrinsic (e.g. elevation, park size) or extrinsic (e.g. human population density) environmental factors. Article impact statement: Law enforcement and community outreach may benefit mammal assemblage and conservation of large hunted species. This article is protected by copyright. All rights reserved. PMID- 30306634 TI - Mediterranean diet adherence is related to reduced probability of prodromal Parkinson's disease. AB - BACKGROUND: The International Parkinson and Movement Disorder Society recently introduced a methodology for probability score calculation for prodromal PD. OBJECTIVES: To assess the probability of prodromal PD in an older population and investigate its possible association with Mediterranean diet adherence. METHODS: Data from a population-based cohort study of older adults (HEllenic Longitudinal Investigation of Aging and Diet) in Greece were used. Probability of prodromal PD was calculated according to International Parkinson and Movement Disorder Society research criteria. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate Mediterranean diet adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. RESULTS: Median probability of prodromal PD was 1.9%, ranging from 0.2 to 96.7% in 1,731 PD-free individuals aged >= 65 (41% male). Lower probability for prodromal PD (P < 0.001) in the higher Mediterranean diet adherence groups was noted, driven mostly by nonmotor markers of prodromal PD, depression, constipation, urinary dysfunction, and daytime somnolence. Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal PD (P < 0.001). Compared to participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile were associated with a ~21% lower probability for prodromal PD. CONCLUSIONS: Adherence to the Mediterranean diet is associated with lower probability of prodromal PD in older people. Further studies are needed to elucidate the potential causality of this association, potential relation of the Mediterranean diet to delayed onset or lower incidence of PD, as well as the underlying neurobiological mechanisms. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30306635 TI - The importance of considering multiple interacting species for conservation of species at risk. AB - Species-at-risk conservation is complex and multi-faceted. However, mitigation strategies are typically narrow in scope, an artefact of conservation research that is often limited to a single species or stressor. The ability to research an entire community of strongly interacting species would greatly enhance our ability to forge more comprehensive and effective conservation decisions. We demonstrate how camera trapping and new statistical techniques can accomplish this using threatened boreal woodland caribou (Rangifer tarandus caribou; hereafter caribou) as a case study. Population declines in caribou are precipitous and well documented, but recovery strategies focus heavily on control of one predator (wolf, Canis lupus), with less attention on other known predators and apparent competitors. A multi-species conservation strategy is needed, but obtaining necessary data on multi-species densities has been prohibitively difficult. We used spatial count models, an extension of spatial-recapture models for unmarked populations, to concurrently estimate densities of caribou, their predators (wolf; black bear, Ursus americanus; and coyote, Canis latrans) and alternative prey (moose, Alces alces; and white-tailed deer, Odocoileus virginianus) from a camera trap array in a highly disturbed landscape within northern Alberta's Oil Sands Region. Median densities (individuals/100 km2 ) ranged from 0.22 caribou (95% BCI = 0.08-0.65), 0.77 wolves (95% BCI = 0.26 2.67), 2.39 moose (95% BCI = 0.56-7.00), 2.64 coyote (95% BCI = 0.45-6.68) to 3.63 black bear (95% BCI = 1.25-8.52; the white-tailed deer model did not converge). Though wolf densities were higher than densities recommended for caribou conservation, we suggest that the markedly higher black bear and coyote densities may be of greater concern, especially if government wolf control further releases these species. Caribou conservation with a singular focus on wolf control may leave caribou vulnerable to other important predators. We recommend a broader focus on the interacting species within a community when conserving species-at-risk. This article is protected by copyright. All rights reserved. PMID- 30306636 TI - Intravenous leiomyomatosis with extension to the pulmonary artery associated with syncope. PMID- 30306637 TI - Inflammation is a potential risk factor of voriconazole overdose in hematological patients. AB - Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin ) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin >= 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi-square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels <= 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved. PMID- 30306638 TI - Depression and excess mortality in the elderly living in low- and middle-income countries: Systematic review and meta-analysis. AB - OBJECTIVE: To investigate the association between depression and mortality in the elderly living in low- and middle-income countries. METHODS: A systematic review and meta-analysis was performed. We searched in five electronic databases for observational studies investigating the association between mortality and depression. Two reviewers worked independently to select articles, extract data, and assess study quality. RESULTS: A total of 10 studies including 13 828 participants (2402 depressed and 11 426 nondepressed) from six countries (Brazil, four articles; China, two articles; Botswana, India, South Africa, and South Korea, one article) were included. The overall unadjusted relative risk (RR) of mortality in depressed relative to nondepressed participants was 1.62 (95% CI, 1.39-1.88; P < 0.001), with high heterogeneity (I2 = 66%; 95% CI, 33-83; P < 0.005). After adjustment for publication bias, the overall RR decreased to 1.60 (95% CI, 1.37-1.86; P < 0.001). No significant differences were observed between subgroups except those defined by study quality. The high-quality studies had a pooled RR of 1.48 (95% CI, 1.32-1.67; P < 0.001), while the low-quality studies resulted had a pooled RR of 1.82 (95% CI, 1.25-2.65; P < 0.005). CONCLUSIONS: Depression is associated with excess mortality in the elderly living in low- and middle-income countries. In addition, this excess mortality does not differ substantially from that found in high-income countries. This suggests environmental factors occurring in low- and middle-income countries might not have a direct association with the excess mortality in the depressed elderly. PMID- 30306639 TI - Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury. AB - The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf, and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice with a Schwann cell-specific loss of EED showed the reversal of polycomb repression is required and a rate limiting step in the increased transcription of Neuregulin 1 (type I), which is required for efficient remyelination. However, mouse nerves with EED-deficient Schwann cells display slow axonal regeneration with significantly low expression of axon guidance genes, including Sema4f and Cntf. Finally, EED loss causes impaired Schwann cell proliferation after injury with significant induction of the Cdkn2a cell cycle inhibitor gene. Interestingly, PRC2 subunits and CDKN2A are commonly co-mutated in the transition from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST's). RNA-seq analysis of EED-deficient mice identified PRC2 regulated molecular pathways that may contribute to the transition to malignancy in neurofibromatosis. PMID- 30306640 TI - Inositol 1,4,5-trisphosphate receptor type 2-independent Ca2+ release from the endoplasmic reticulum in astrocytes. AB - Accumulating evidence indicates that astrocytes are actively involved in the physiological and pathophysiological functions of the brain. Intracellular Ca2+ signaling, especially Ca2+ release from the endoplasmic reticulum (ER), is considered to be crucial for the regulation of astrocytic functions. Mice with genetic deletion of inositol 1,4,5-trisphosphate receptor type 2 (IP3 R2) are reportedly devoid of astrocytic Ca2+ signaling, and thus widely used to explore the roles of Ca2+ signaling in astrocytic functions. While functional deficits in IP3 R2-knockout (KO) mice have been found in some reports, no functional deficit was observed in others. Thus, there remains a controversy regarding the functional significance of astrocytic Ca2+ signaling. To address this controversy, we re-evaluated the assumption that Ca2+ release from the ER is abolished in IP3 R2-KO astrocytes using a highly sensitive imaging technique. We expressed the ER luminal Ca2+ indicator G-CEPIA1er in cortical and hippocampal astrocytes to directly visualize spontaneous and stimulus-induced Ca2+ release from the ER. We found attenuated but significant Ca2+ release in response to application of norepinephrine to IP3 R2-KO astrocytes. This IP3 R2-independent Ca2+ release induced only minimal cytosolic Ca2+ transients but induced robust Ca2+ increases in mitochondria that are frequently in close contact with the ER. These results indicate that ER Ca2+ release is retained and is sufficient to increase the Ca2+ concentration in close proximity to the ER in IP3 R2-KO astrocytes. PMID- 30306641 TI - Tracking Molecular Diffusion in One-Dimensional Photonic Crystals. AB - The intuitive use, inexpensive fabrication, and easy readout of colorimetric sensors, including photonic crystal architectures and Fabry-Perot interference sensors, have made these devices a successful commercial case, and yet, understanding how the diffusion of analytes occurs throughout the structure is a key ingredient for designing the response of these platforms on demand. Herein, the diffusion of amines in a periodic multilayer system composed of two dimensional nanosheets and dielectric nanoparticles is tracked by a combination of spectroscopic measurements and theoretical modelling. It is demonstrated that diffusion is controlled by the molecular size, with larger molecules showing larger layer swelling and slower diffusion times, which translates into important sensor characteristics such as signal change and saturation time. Since the approach visualizes the analyte impregnation process in a time- and spatially resolved fashion, it directly relates the macroscopic color readout into microscopic processes occurring at the molecular level, thus opening the door to rational sensor design. PMID- 30306642 TI - Ceramic Robocasting: Recent Achievements, Potential, and Future Developments. AB - Additive manufacturing (AM) of ceramic materials has attracted tremendous attention in recent years, due to its potential to fabricate suitable advanced ceramic structures for various engineering applications. Robocasting, a subset of ceramic AM, is an ideal technique for constructing fine and dense ceramic structures with geometrically complex morphology. With the freedom and convenience to deposit various materials within any 3D spatial position, ceramic robocasting opens up unlimited opportunities, which are otherwise hardly attainable from other AM techniques. Here, a summary of the recent progress on the fabrication of single and multi-ceramic structures by robocasting is provided, as well as the prospects of achieving shapeable ceramic structures. The current challenges in ceramic robocasting and an outlook on its development, especially toward the fabrication of self-shaping ceramic structures, are also discussed. PMID- 30306643 TI - Amazonian deforestation and soil biodiversity. AB - Clearance and perturbation of Amazonian forests are one of the greatest threats to tropical biodiversity conservation of our times. A better understanding of how soil communities respond to Amazonian deforestation is crucially needed to inform policy interventions that effectively protect biodiversity and the essential ecosystem services it provides. Here we assessed the impact of deforestation and ecosystem conversion to arable land on Amazonian soil biodiversity using a meta analysis. We analysed 274 pairwise comparisons of soil biodiversity in Amazonian primary forests and sites under different stages of deforestation and land-use conversion - disturbed (wildfire and selective logging) and slash-and-burnt forests, pastures and cropping systems. Overall, 60% and 51% of responses of soil macrofauna and microbial community attributes (i.e. abundance, biomass, richness and diversity indexes) to deforestation were negative, respectively. We found few mesofauna (e.g. micro-arthropods) and microfauna (e.g. protozoa and nematodes) studies, and those groups could not be analyzed. Macrofauna abundance and biomass were more vulnerable to the displacement of forests by pastures than by agricultural fields, while microbes showed the opposite pattern. Effects of Amazonian deforestation on macrofauna were more detrimental at sites with mean annual precipitation higher than 1,900 mm, and higher losses of microbes occurred in highly acidic soils (pH < 4.5). Limited geographic coverage, omission of meso- and microfauna, and low taxonomic resolution were main factors impairing generalizations from the dataset. Furthermore, few studies have assessed the impacts of within-forest disturbance (wildfires and selective logging) on soil species in Amazonia, where logging operations rapidly expand across public lands and more frequent severe dry seasons are increasing the prevalence of wildfires. Future research is needed to tackle these knowledge gaps. This article is protected by copyright. All rights reserved. PMID- 30306644 TI - VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases. AB - V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 Delta/- mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC-sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies. PMID- 30306645 TI - Sedentary time, physical activity, and sleep quality in fibromyalgia: The al Andalus project. AB - PURPOSE: To get insight into the potential significance of objectively measured sedentary time (ST), and physical activity (PA) intensity levels on sleep quality (SQ) in women with fibromyalgia; and to assess whether those who meet moderate-to vigorous PA (MVPA) recommendations have better SQ than their counterparts. METHODS: Four-hundred and nine women with fibromyalgia (age range 30-65 years old) from Andalusia (southern Spain) were included in this cross-sectional study. Sedentary time, PA intensity levels (light, moderate, and MVPA), and total PA were assessed with accelerometers during seven consecutive days. Sleep quality was measured with the Pittsburgh Sleep Quality Index self-report questionnaire. RESULTS: Higher ST was associated with worse subjective SQ, sleep duration, sleep disturbances, daytime dysfunction, and SQ global score (all, P < 0.05). All PA levels were associated with better subjective SQ and sleep latency and with less sleep medication and daytime dysfunction (all, P < 0.05). In addition, light and total PA were associated with better sleep efficiency, SQ global score, and less sleep disturbances (all, P < 0.05). Finally, women meeting bouted PA recommendations displayed better SQ than patients not meeting the recommendations (bouted or non-bouted). CONCLUSION: Lower ST and greater PA levels are associated with better SQ in women with fibromyalgia. This result demonstrates that those patients with fibromyalgia who reduce periods of inactivity and perform PA could be better sleepers, which might contribute to a lower severity of the disease. It is noteworthy that meeting bouted PA recommendations is associated with better SQ. PMID- 30306646 TI - "Genetically Engineered" Biofunctional Triboelectric Nanogenerators Using Recombinant Spider Silk. AB - Self-powered electronics using triboelectric nanogenerators (TENGs) is drawing increasing efforts and rapid advancements in eco/biocompatible energy harvesting, intelligent sensing, and biomedical applications. Currently, the triboelectric performances are mainly determined by the pair materials' inherent electron affinity difference, and merely tuned by chemical or physical methods, which significantly limit the optional variety and output capability, especially for natural-biomaterial-based TENGs. Herein, a biocompatible triboelectric material with a programmable triboelectric property, multiple functionalization, large scale-fabrication capability, and transcendent output performance is designed, by genetically engineering recombinant spider silk proteins (RSSP). Featuring totally "green" large-scale manufacturing, the water lithography technique is introduced to the RSSP-TENG with facilely adjustable surface morphology, chemically modifiable surface properties, and controllable protein conformation. By virtue of the high electrical power, a proof-of-principle drug-free RSSP-patch is built, showing outstanding antibacterial performances both in vitro and in vivo. This work provides a novel high-performance biomaterial-based TENG and extends its potential for multifunctional applications. PMID- 30306647 TI - Antisolvent with an Ultrawide Processing Window for the One-Step Fabrication of Efficient and Large-Area Perovskite Solar Cells. AB - Photovoltaic technologies based on perovskite absorber materials have led this optoelectronic field into a brand-new horizon. However, the present antisolvents used in the one-step spin-coating method always encounter problems with the very narrow process window. Herein, anisole is introduced into the one-step spin coating method, and the technology is developed to fabricate perovskite thin films with ultrawide processing window with a dimethylformamide (DMF):dimethyl sulfoxide (DMSO) ratio varying from 6:4 to 9:1 in the precursor solution, anisole dripping time ranging from 5 to 25 s, and an antisolvent volume varying from 0.1 to 0.9 mL. Perovskite thin films as large as 100 cm2 are successfully fabricated using this method. Maximum photoelectric conversion efficiencies of 19.76% for small-area (0.14 cm2 ) and 17.39% for large-area (1.08 cm2 ) perovskite solar cell devices are obtained. It is also found that there are intermolecular hydrogen-bonding forces between anisole and DMF/DMSO that play critical roles in the wide process window. These results provide a deeper understanding of the crystallizing procedure of perovskite during the one-step spin-coating process. PMID- 30306648 TI - Simultaneous Strontium Doping and Chlorine Surface Passivation Improve Luminescence Intensity and Stability of CsPbI3 Nanocrystals Enabling Efficient Light-Emitting Devices. AB - A method is proposed to improve the photo/electroluminescence efficiency and stability of CsPbI3 perovskite nanocrystals (NCs) by using SrCl2 as a co precursor. The SrCl2 is chosen as the dopant to synthesize the CsPbI3 NCs. Because the ion radius of Sr2+ (1.18 A) is slightly smaller than that of Pb2+ (1.19 A) ions, divalent Sr2+ cations can partly replace the Pb2+ ions in the lattice structure of perovskite NCs and cause a slight lattice contraction. At the same time, Cl- anions from SrCl2 are able to efficiently passivate surface defect states of CsPbI3 nanocrystals, thus converting nonradiative trap states to radiative states. The simultaneous Sr2+ ion doping and surface Cl- ion passivation result in the enhanced photoluminescence quantum yield (up to 84%), elongated emission lifetime, and improved stability. Sr2+ -doped CsPbI3 NCs are employed to produce light-emitting devices with a high external quantum yield of 13.5%. PMID- 30306650 TI - Sandwich-Like Fibers/Sponge Composite Combining Chemotherapy and Hemostasis for Efficient Postoperative Prevention of Tumor Recurrence and Metastasis. AB - Intraoperative bleeding is an essential factor leading to the earliest recurrence and tumor metastasis frequently seen after resection of solid tumors. Local drug delivery implants show the unique advantages on postoperative cancer therapy. Herein, a sandwich-like cisplatin-loaded fibers/sponge composite (CFSC) combining chemotherapy and hemostasis is constructed. The obtained implantable CFSC is able to simultaneously stop bleeding and absorb disseminated tumor cells after tumor resection. More importantly, sustained released cisplatin can kill local residual tumor cells as well as those concentrated in the CFSC, which significantly inhibits local tumor recurrence and distant tumor metastasis on the subcutaneous postoperative recurrence model and metastasis models. This dual functional implant strategy with low toxicity to healthy organs may inspire new aspects for efficient postoperative cancer therapy. PMID- 30306649 TI - Honeycomb-Lantern-Inspired 3D Stretchable Supercapacitors with Enhanced Specific Areal Capacitance. AB - Traditional stretchable supercapacitors, possessing a thin electrode and a 2D shape, have limited areal specific areal capacitance and are incompatible with 3D wearables. To overcome the limitations of 2D stretchable supercapacitors, it is highly desirable to develop 3D stretchable supercapacitors with higher mass loading and customizable shapes. In this work, a new 3D stretchable supercapacitor inspired by a honeycomb lantern based on an expandable honeycomb composite electrode composed of polypyrrole/black-phosphorous oxide electrodeposited on carbon nanotube film is reported. The 3D stretchable supercapacitors possessing device-thickness-independent ion-transport path and stretchability can be crafted into customizable device thickness for enhancing the specific areal energy storage and integrability with wearables. Notably, a 1.0 cm thick rectangular-shaped supercapacitor shows enhanced specific areal capacitance of 7.34 F cm-2 , which is about 60 times higher than that of the original 2D supercapacitor (120 mF cm-2 ) at a similar discharge rate. The 3D supercapacitor can also maintain a capacitance ratio of 95% even under the reversible strain of 2000% after 10 000 stretch-and-release cycles, superior to state-of-the-art stretchable supercapacitors. The enhanced specific areal energy storage and the customizablility in shapes of the 3D stretchable supercapacitors show immense promise in a wide range of applications in stretchable and wearable electronics. PMID- 30306652 TI - Radix Salviae miltiorrhizae improves bone microstructure and strength through Wnt/beta-catenin and osteoprotegerin/receptor activator for nuclear factor-kappaB ligand/cathepsin K signaling in ovariectomized rats. AB - Although radix Salviae miltiorrhizae (RSM) is reported to exhibit the antiosteoporotic effect in preclinical study, the underlying mechanism is unclear. To this end, ovariectomized (OVX) rats were employed with administration of RSM (5 g/kg) for 14 weeks. The disturbed serum levels of alkaline phosphatase (ALP), osteoprotegerin (OPG), tartrate-resistant acid phosphatase, and receptor activator of nuclear factor-kappaB ligand (RANKL) in OVX rats were improved by RSM treatment. Furthermore, supplement of RSM to OVX rats resulted in an increase in femoral bone mineral density and bone strength as well as an improvement in bone microstructures. Moreover, the decreased expression of phosphor (p)-LRP6, insulin-like growth factor-1(IGF-1), ALP, and OPG, as well as increased expression of RANKL and cathepsin K in the tibias and femurs of OVX rats were shifted by RSM treatment. Additionally, RSM reversed the decreased ratio of p glycogen synthase kinase 3beta (GSK3beta) to GSK3beta and increased ratio of p beta-catenin to beta-catenin in OVX rats. Altogether, it is suggestive that RSM improves bone quantity and quality by favoring Wnt/beta-catenin and OPG/RANKL/cathepsin K signaling pathways in OVX rats thereby suggesting the potential of this herb to be a novel source of antiosteoporosis drugs. PMID- 30306653 TI - Organic-Inorganic Hybrid Passivation Enables Perovskite QLEDs with an EQE of 16.48. AB - Perovskite quantum dots (QDs) with high photoluminescence quantum yields (PLQYs) and narrow emission peak hold promise for next-generation flexible and high definition displays. However, perovskite QD films often suffer from low PLQYs due to the dynamic characteristics between the QD's surface and organic ligands and inefficient electrical transportation resulting from long hydrocarbon organic ligands as highly insulating barrier, which impair the ensuing device performance. Here, a general organic-inorganic hybrid ligand (OIHL) strategy is reported on to passivate perovskite QDs for highly efficient electroluminescent devices. Films based on QDs through OIHLs exhibit enhanced radiative recombination and effective electrical transportation properties compared to the primal QDs. After the OIHL passivation, QD-based light-emitting diodes (QLEDs) exhibit a maximum peak external quantum efficiency (EQE) of 16.48%, which is the most efficient electroluminescent device in the field of perovskite-based LEDs up to date. The proposed OIHL passivation strategy positions perovskite QDs as an extremely promising prospect in future applications of high-definition displays, high-quality lightings, as well as solar cells. PMID- 30306651 TI - The Atomic Circus: Small Electron Beams Spotlight Advanced Materials Down to the Atomic Scale. AB - Defects in crystalline materials have a tremendous impact on their functional behavior. Controlling and tuning of these imperfections can lead to marked improvements in their physical, electrical, magnetic, and optical properties. Thanks to the development of aberration-corrected (scanning) transmission electron microscopy (STEM/TEM), direct visualization of defects at multiple length scales has now become possible, including those critically important defects at the atomic scale. Thorough understanding of the nature and dynamics of these defects is the key to unraveling the fundamental origins of structure property relationships. Such insight can therefore allow the creation of new materials with desired properties through appropriate defect engineering. Herein, several examples of new insights obtained from representative functional materials are shown, including piezoelectrics/ferroelectrics, oxide interfaces, thermoelectrics, electrocatalysts, and 2D materials. PMID- 30306655 TI - Micro/Nanomotors for Water Purification. AB - Self-propelled micro/nanomotors are synthetic machines that can convert different sources of energy into motion; at the same time, they are able to serve innovative environmental applications, e.g., water purification. The self propelled autonomous micro and nanomachines can rapidly zoom through the solution, carrying catalytic surface or chemical to remove or degrade pollutants in much faster fashion than static systems which depend on diffusion and fluxes. This review highlights the recent progress of MNMs in water pollutant detection and removal applications. PMID- 30306654 TI - Infrared-Sensitive Memory Based on Direct-Grown MoS2 -Upconversion-Nanoparticle Heterostructure. AB - Photonic memories as an emerging optoelectronic technology have attracted tremendous attention in the past few years due to their great potential to overcome the von Neumann bottleneck and to improve the performance of serial computers. Nowadays, the decryption technology for visible light is mature in photonic memories. Nevertheless, near-infrared (NIR) photonic memristors are less progressed. Herein, an NIR photonic memristor based on MoS2 -NaYF4 :Yb3+ , Er3+ upconversion nanoparticles (UCNPs) nanocomposites is designed. Under excitation by 980 nm NIR light, the UCNPs show emissions well overlapping with the absorption band of the MoS2 nanosheets. The heterostructure between the MoS2 and the UCNPs acting as excitons generation/separation centers remarkably improves the NIR-light-controlled memristor performance. Furthermore, in situ conductive atomic force microscopy is employed to elucidate the photo-modulated memristor mechanism. This work provides novel opportunities for NIR photonic memory that holds promise in future multifunctional robotics and electronic eyes. PMID- 30306656 TI - Probing of Local Multifield Coupling Phenomena of Advanced Materials by Scanning Probe Microscopy Techniques. AB - The characterization of the local multifield coupling phenomenon (MCP) in various functional/structural materials by using scanning probe microscopy (SPM)-based techniques is comprehensively reviewed. Understanding MCP has great scientific and engineering significance in materials science and engineering, as in many practical applications, materials and devices are operated under a combination of multiple physical fields, such as electric, magnetic, optical, chemical and force fields, and working environments, such as different atmospheres, large temperature fluctuations, humidity, or acidic space. The materials' responses to the synergetic effects of the multifield (physical and environmental) determine the functionalities, performance, lifetime of the materials, and even the devices' manufacturing. SPM techniques are effective and powerful tools to characterize the local effects of MCP. Here, an introduction of the local MCP, the descriptions of several important SPM techniques, especially the electrical, mechanical, chemical, and optical related techniques, and the applications of SPM techniques to investigate the local phenomena and mechanisms in oxide materials, energy materials, biomaterials, and supramolecular materials are covered. Finally, an outlook of the MCP and SPM techniques in materials research is discussed. PMID- 30306657 TI - Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury. AB - Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system. In cultured Schwann cells, TNF-a not only enhances the synthesis of P2X4R protein but also promotes P2X4R trafficking to the surface of Schwann cells. TNF-a-induced BDNF secretion in Schwann cells is P2X4R dependent. in vivo experiments reveal that expression of P2X4R in Schwann cells of injured nerves is strikingly upregulated following nerve crush injury. Moreover, overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery and accelerates nerve remyelination via BDNF release following nerve injury. Our results suggest that enhancement of P2X4R expression in Schwann cells after nerve injury may be an effective approach to facilitate the regrowth and remyelination of injured nerves. PMID- 30306658 TI - Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus. AB - Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid-beta, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin-4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH. PMID- 30306659 TI - Anti-influenza activity of berberine improves prognosis by reducing viral replication in mice. AB - Berberine, a natural isoquinoline alkaloid isolated from the berberis species, has a wide array of biological properties such as anti-inflammatory, antibacterial, antifungal, and antihelminthic effects. We evaluated the antiviral effect of berberine against influenza A/FM1/1/47 (H1N1) in vivo and in vitro. The results showed that berberine strongly suppressed viral replication in A549 cells and in mouse lungs. Meanwhile, berberine relieved pulmonary inflammation and reduced necrosis, inflammatory cell infiltration, and pulmonary edema induced by viral infection in mice when compared with vehicle-treated mice. Berberine suppressed the viral infection-induced up-regulation of TLR7 signaling pathway, such as TLR7, MyD88, and NF-kappaB (p65), at both the mRNA and protein levels. Furthermore, berberine significantly inhibited the viral infection-induced increase in Th1/Th2 and Th17/Treg ratios as well as the production of inflammatory cytokines. Our data provide new insight into the potential of berberine as a therapeutic agent for viral infection via its antiviral activity. PMID- 30306660 TI - NG2 expression in NG2 glia is regulated by binding of SoxE and bHLH transcription factors to a Cspg4 intronic enhancer. AB - NG2 is a type 1 integral membrane glycoprotein encoded by the Cspg4 gene. It is expressed on glial progenitor cells known as NG2 glial cells or oligodendrocyte precursor cells that exist widely throughout the developing and mature central nervous system and vascular mural cells but not on mature oligodendrocytes, astrocytes, microglia, neurons, or neural stem cells. Hence NG2 is widely used as a marker for NG2 glia in the rodent and human. The regulatory elements of the mouse Cspg4 gene and its flanking sequences have been used successfully to target reporter and Cre recombinase to NG2 glia in transgenic mice when used in a large 200 kb bacterial artificial chromosome cassette containing the 38 kb Cspg4 gene in the center. Despite the tightly regulated cell type- and stage-specific expression of NG2 in the brain and spinal cord, the mechanisms that regulate its transcription have remained unknown. Here, we describe a 1.45 kb intronic enhancer of the mouse Cspg4 gene that directed transcription of EGFP reporter to NG2 glia but not to pericytes in vitro and in transgenic mice. The 1.45 kb enhancer contained binding sites for SoxE and basic helix-loop-helix transcription factors, and its enhancer activity was augmented cooperatively by these factors, whose respective binding elements were found in close proximity to each other. Mutations in these binding elements abrogated the enhancer activity when tested in the postnatal mouse brain. PMID- 30306661 TI - Endoscopic ultrasound-guided retrievable puncture anchor-assisted gastroenterostomy. PMID- 30306662 TI - Gas-Permeable, Multifunctional On-Skin Electronics Based on Laser-Induced Porous Graphene and Sugar-Templated Elastomer Sponges. AB - Soft on-skin electronics have broad applications in human healthcare, human machine interface, robotics, and others. However, most current on-skin electronic devices are made of materials with limited gas permeability, which constrain perspiration evaporation, resulting in adverse physiological and psychological effects, limiting their long-term feasibility. In addition, the device fabrication process usually involves e-beam or photolithography, thin-film deposition, etching, and/or other complicated procedures, which are costly and time-consuming, constraining their practical applications. Here, a simple, general, and effective approach for making multifunctional on-skin electronics using porous materials with high-gas permeability, consisting of laser-patterned porous graphene as the sensing components and sugar-templated silicone elastomer sponges as the substrates, is reported. The prototype device examples include electrophysiological sensors, hydration sensors, temperature sensors, and joule heating elements, showing signal qualities comparable to conventional, rigid, gas impermeable devices. Moreover, the devices exhibit high water-vapor permeability (~18 mg cm-2 h-1 ), ~18 times higher than that of the silicone elastomers without pores, and also show high water-wicking rates after polydopamine treatment, up to 1 cm per 30 s, which is comparable to that of cotton. The on-skin devices with such attributes could facilitate perspiration transport and evaporation, and minimize discomfort and inflammation risks, thereby improving their long-term feasiblity. PMID- 30306663 TI - Satisfaction of adolescent mothers with childbirth care at a public maternity hospital. AB - AIM: The aim was to assess adolescent satisfaction with childbirth and compare it with that of adult women. METHODS: An observational comparative study was conducted during the period of October 2016 and April 2017 in a public maternity hospital in Sao Paulo, Brazil. The population included 50 adolescents (14-19 years) and 51 adults (20-35 years) mothers in post-partum after a term live birth. Maternal satisfaction was assessed by the North Bristol modified Mackey Childbirth Satisfaction Rating Scale questionnaire with 18 items divided into five subscales (self, partner, baby, physician and overall) and two items on birth experience. Each item was rated on a 5-point Likert scale and a total score was calculated. The main outcome measure was a total score on questionnaire. RESULTS: The mean maternal age of adolescents was 18 years (95% confidence interval [CI] 11-25) and for adults, 28.3 years (95% CI 26.1-30.7). Primiparity was more common among adolescents than adults (92% vs 43.1%, P < 0.001). The median maternal satisfaction score of adolescents (88; 95% CI 83-90) was lower than that of adult women (90; 95% CI 87-93, P = 0.046). Adolescents also scored lower than adult women on the following subscales: satisfaction with baby (median 14 vs 15, P = 0.004) and satisfaction concerning care provided by doctors/midwives (median 33 vs 35, P = 0.006). CONCLUSION: Adolescents were statistically less satisfied with their childbirth experience. More dissatisfaction was seen among them specifically concerning their baby and the care provided by doctors/midwives. This shows that different strategies need to be developed for this specific group of women. PMID- 30306664 TI - The incidence of unexpected critical complications in monochorionic diamniotic twin pregnancies according to the interval period between ultrasonographic evaluations. AB - AIM: This study aimed to evaluate the incidence of unexpected critical complications (UCC) in monochorionic diamniotic (MCDA) twin pregnancies according to ultrasonographic scan interval. METHODS: This retrospective single-center cohort study, conducted between January 2005 and April 2015, investigated the incidence of UCC in patients with MCDA twin pregnancies undergoing weekly ultrasound (Group A) and those undergoing biweekly ultrasound (Group B). We also examined the incidence of predictable critical complications according to ultrasound interval. RESULTS: Of all 385 cases, the total incidence of UCC was 20 (5.2%), including 14 cases of twin-twin transfusion syndrome and 6 cases of intrauterine fetal death. The incidence of UCC was 3.9% in Group A and 9.0% in Group B (P = 0.046). In contrast, the incidence of predictable critical complications was 6.7% in Group A and 9.0% in Group B (P = 0.440). CONCLUSION: The incidence of UCC in patients with MCDA twin pregnancies was significantly lower in patients undergoing weekly ultrasound. Our results suggest that weekly ultrasound evaluation for patients with MCDA pregnancy is more effective for early detection of UCC such as intrauterine fetal death and twin-twin transfusion syndrome ; however, further investigations are needed to determine whether weekly ultrasound evaluation can improve clinical outcomes. PMID- 30306665 TI - Radiotherapy modality as a predictor of survival in hypopharyngeal cancer. AB - BACKGROUND: The impact of radiotherapy (RT) modality and dose on survival in hypopharyngeal cancer managed with definitive RT is unclear. METHODS: The National Cancer Database was queried for patients with hypopharyngeal squamous cell carcinoma (HPSCC) treated with definitive RT. Intensity-modulated radiotherapy (IMRT) was compared with other RT techniques. Clinicopathologic variables, RT modality, and dose impact on overall survival (OS) were assessed using log-rank test and Cox proportional hazard models. RESULTS: A total of 3928 patients with HPSCC were identified. Patients receiving IMRT (2098 patients) were more likely to be white, have higher income, have advanced classification, receive >=66 Gy, and receive chemoradiotherapy compared with those receiving non IMRT techniques (1830 patients). The 5-year OS was 41.9% (95% CI = 39.4%-44.4%) for the IMRT group and 36.8% for the non-IMRT group (95% CI = 34.3%-39.2%). After propensity score matching, IMRT had significantly better OS (P = .013). CONCLUSION: In HPSCC treated with definitive RT, IMRT may provide a significant survival benefit over non-IMRT modalities. PMID- 30306666 TI - Management of labor during registrarship: A prospective study during a two-year registrarship program. AB - AIM: Labor management is often considered to be stressful. Increases in cesarean section (CSD) and assisted vaginal (AVD) deliveries rates have been ascribed to inexperience. To address this issue, we observed the obstetric management activity of four obstetrics and gynecology registrars throughout their 2-year registrarship program. METHODS: We performed a prospective, observational study of urgent and semi-/nonurgent CSD and AVD in a tertiary maternity unit. The registrars' obstetric management was compared with that of a referral group. Changes over time in the registrars' practice were also monitored. RESULTS: A total of 4328 deliveries (including 670 CSD and 736 AVD) were analyzed. The registrars and the experienced obstetricians managed 2930 and 1398 deliveries, respectively, with similar neonatal outcomes. There were no intergroup differences in either total CSD percentage (455 [15.5%] and 215 [15.4%] for registrars and experienced practitioners, respectively, P = 0.90) or AVD percentage (478 [16.3%] and 258 [18.5%], respectively, P = 0.08), or according to degree of urgency. Rates did not change over the course of the registrarship program, regardless of degree of urgency. CONCLUSION: Lower degree of experience was not associated with elevated CSD or AVD rates. Skills required to appropriately manage an obstetric ward seemed to have been acquired at the end of residency. PMID- 30306668 TI - Insect midgut structures and molecules as targets of plant-derived protease inhibitors and lectins. AB - The midgut of insects is involved in digestion, osmoregulation and immunity. Although several defensive strategies are present in this organ, its organization and function may be disturbed by some insecticidal agents, including bioactive proteins like lectins and protease inhibitors (PIs) from plants. PIs interfere with digestion, leading to poor nutrient absorption and decreasing amino acid bioavailability. Intake of PIs can delay development, cause deformities and reduce fertility. Ingestion of PIs may lead to changes in the set of proteases secreted in the insect gut, but this response is often insufficient and results in aggravation of the malnutrition status. Lectins are proteins that are able to interact with glycoconjugates, including those linked to cell surfaces. Their effects on the midgut include disruption of the peritrophic matrix, brush border and secretory cell layer; induction of apoptosis and oxidative stress; interference with nutrient absorption and transport proteins; and damaging effects on symbionts. In addition, lectins can cross the intestinal barrier and reach the hemolymph. The establishment of resistant insect populations due to selective pressure resulting from massive use of a bioactive protein is an actual possibility, but this can be minimized by the multiple mode-of-action of these proteins, mainly the lectins. (c) 2018 Society of Chemical Industry. PMID- 30306667 TI - Lysosome: The metabolic signaling hub. AB - For the past five decades, the lysosome has been characterized as an unglamorous cellular recycling center. This notion has undergone a radical shift in the last 10 years, with new research revealing that this organelle serves as a major hub for metabolic signaling pathways. The discovery that master growth regulators, including the protein kinase mTOR (mechanistic target of rapamycin), make their home at the lysosomal surface has generated intense interest in the lysosome's key role in nutrient sensing and cellular homeostasis. The transcriptional networks required for lysosomal maintenance and function are just being unraveled and their connection to lysosome-based signaling pathways revealed. The catabolic and anabolic pathways that converge on the lysosome connect this organelle with multiple facets of cellular function; when these pathways are deregulated they underlie multiple human diseases, and promote cellular and organismal aging. Thus, understanding how lysosome-based signaling pathways function will not only illuminate the fascinating biology of this organelle but will also be critical in unlocking its therapeutic potentials. PMID- 30306669 TI - Pharmaceutical expenditure and gross domestic product: Evidence of simultaneous effects using a two-step instrumental variables strategy. AB - This paper estimates the income elasticity of government pharmaceutical spending and assesses the simultaneous effect of such spending on gross domestic product (GDP). Using a panel dataset for 136 countries from 1995 to 2006, we employ a two step instrumental variable procedure where we first estimate the effect of GDP on public pharmaceutical expenditure using tourist receipts as an instrument for GDP. In the second step, we construct an adjusted pharmaceutical expenditure series where the response of public pharmaceutical expenditure to GDP is partialled out and use this endogeneity adjusted series as an instrument for pharmaceutical expenditure. Our estimations show that GDP has a strong positive impact on pharmaceutical spending with elasticity in excess of unity in countries with low spending on pharmaceuticals and countries with large economic freedom. In the second step, we find that when the quantitatively large reverse effect of GDP is accounted for, public pharmaceutical spending has a negative effect on GDP per capita particularly in countries with limited economic freedom. PMID- 30306670 TI - Effects of a vestibular physiotherapy protocol on adults with intellectual disability in the prevention of falls: A multi-centre clinical trial. AB - BACKGROUND: Balance alterations are one of the main problems in people with intellectual disabilities (ID), increasing their risk of falls and impacting their life. AIMS: To describe a vestibular rehabilitation programme (VRP) and evaluate its effects on the ability to maintain balance and risk of suffering a fall. METHODS: Forty-seven adults with mild to moderate ID were randomly assigned to two groups: a control group (CG, N = 24), which performed a general physical exercise only, and an experimental group (EG, N = 23) which also completed a VRP. The variables, used pre- and post-training and 1 month after the intervention, were as follows: Center of Pressure Displacement, Berg Scale, Timed Up and Go Test, and the Modified Clinical Test of Sensory Interaction and Balance. RESULTS: The EG improved significantly in each variable. The CG did not show changes for any of the parameters. CONCLUSIONS: A programme based on VRP may improve balance and reduce the risk of falling. PMID- 30306671 TI - A proof-of-principle study of the effect of combined haloperidol and levodopa administration on working memory-related brain activation in humans. AB - OBJECTIVE: Cognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Dopamine D1 receptor modulated changes in prefrontal cortex function play a potentially important role in the pathology underlying such deficits. However, pharmacological interventions that selectively engage the D1 receptor are severely restricted for research in humans. The present study is a proof-of-principle for enhancing cognitive performance and associated brain activation via indirect D1 stimulation, operationalised by combining the nonselective dopamine agonist L-dopa with the D2-antagonist haloperidol. METHODS: Fourteen healthy volunteers received placebo or combined carbidopa (25 mg)/L-dopa (100 mg) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects crossover design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment. RESULTS: Drug treatment was associated with greater functional connectivity between the dorsolateral prefrontal cortex and areas within the salience network during all N-back trials. Drug treatment was also associated with reduced activation, most prominently in the occipital/temporal brain areas during 2-back performance. CONCLUSIONS: This preliminary study provides initial evidence for combined L-dopa/haloperidol modulation in cognition-related brain areas and networks, which is relevant for the treatment of cognitive impairments in mental illness. PMID- 30306672 TI - The practice of experimental studies in psychopharmacology: Top 10 tips from one centre's experience. AB - OBJECTIVE: Recent efforts to optimise translation of basic research findings to successful clinical trials have led to a sharper focus on experimental medicine translational studies. This is coupled with a movement towards greater methodological integrity and openness. Although this can be achieved through preregistration and detailed reporting of study methodology, the reality of study application can often be lost. METHODS: In practice, challenges in study application can often lead to diminished scientific robustness, even in well designed studies. A detailed description of experiences is essential for learning and subsequent improvement. To this end, the authors undertook a description of the experience of a specialised psychopharmacology experimental study centre. RESULTS: This centre's experiences reveal that even supposedly routine study elements, such as screening parameters, peri-drug administration, and peri discharge procedures, can pose significant practical obstacles to the achievement of minimal protocol deviation. Ultimately, these factors impact on academic standards such as enhanced data reliability; but they have additional implications for participant clinical safety and well-being, for instance in relation to adverse event and incidental finding recording. CONCLUSIONS: The facilitation of a scientific culture that is more transparent even at the operational level will hopefully augment translational process and probability of success. PMID- 30306673 TI - Strengthening Indigenous cultural competence in dentistry and oral health education: Academic perspectives. AB - INTRODUCTION: Indigenous Australians continue to experience significant oral health disparities, despite numerous closing-the-gap initiatives. Higher education institutions and accrediting bodies recognise the need to incorporate Indigenous culture more widely into dentistry curricula to address these inequalities. This study aimed to define and explore current Indigenous cultural competence curricula, identify enablers and barriers for integration of Indigenous cultural competence curricula and ascertain innovative strategies to aid students in becoming culturally competent upon graduation, from academics' perspectives. METHODS: Academics from the Doctor of Dental Medicine (DMD) and Bachelor of Oral Health (BOH) programmes at the University of Sydney, School of Dentistry participated in semi-structured interviews to define and explore current and future curricula practices to enable students to become competent in Indigenous culture. Thematic analysis was conducted to synthesise academics' responses. RESULTS: Thirteen School of Dentistry academics participated in interviews. Following analysis of the data, six key themes emerged: Theme One: Transfer of Indigenous cultural knowledge, Theme Two: Barriers to developing Indigenous cultural curriculum. Theme Three: Importance of cultural immersion, Theme Four: Resources required for Indigenous cultural education, Theme Five: Proposed Indigenous cultural content, Theme Six: Strategies to incorporate Indigenous culture into curricula. CONCLUSION: Improving Indigenous cultural competence amongst dentistry academics and students requires an educational and philosophical shift, incorporating the social determinants of health whilst maintaining the strengths of the biomedical foundations of dental care. It requires the inclusion of an informed history of Indigenous Australians, immersion within Indigenous communities and reflection upon these experiences, to facilitate culturally appropriate ways to improve the provision of dentistry and oral health for Indigenous peoples. PMID- 30306674 TI - Access to mental health services: The experiences of people with intellectual disabilities. AB - BACKGROUND: People with intellectual disability experience higher rates of mental health disorders than the rest of the population, and expert opinion holds that multiple barriers prevent people with intellectual disability from accessing appropriate services. METHODS: A qualitative study was designed to explore the lived experience of barriers and enablers to access to mental health services among people with intellectual disability. Interviews and focus groups were conducted with people with intellectual disability, carers and service providers. RESULTS: Barriers and enablers were identified across four key dimensions of access: utilization of services; service availability; relevance, effectiveness and access; and equity and access. These factors operated at both systemic and personal levels. CONCLUSIONS: The findings from this study provide empirical evidence of anecdotal experiences of access to mental health services and provide insight into the ways users, carers and service providers navigate an often hostile system and indicate further directions for research. PMID- 30306675 TI - Endocan expression in placenta of women with hypertension. AB - AIM: The aim of our study was to determine the endocan-1 expression in placenta of hypertensive women, and its association with maternal and fetal outcomes. METHODS: This was a cross-sectional study consisted of 21 pregnant women with hypertension and 23 without hypertension. The gestational age ranged from 28 to 39 weeks (hypertensive) and 32 to 40 weeks (normotensive). The paraffin embedded formalin fixed placenta tissue blocks were retrieved from the pathology archives. Endocan immunohistochemistry was performed on tissue sections of full thickness and maternal surface of the placenta. The endocan expression was determined in fetal endothelial cells, maternal endothelial cells, cytotrophoblasts, syncytiotrophoblasts and decidual cells. The differences in endocan expression in placenta between hypertensive and normotensive subjects were evaluated by Pearson chi-square test and t-test were used in the statistical analysis. RESULTS: The endocan expression was significantly higher in fetal endothelial cells (P < 0.001), maternal endothelial cells (P = 0.003) and decidual cells (P < 0.001) in the placenta of women with hypertension. When comparing positive and negative endocan expression in maternal outcomes, endocan was associated with the development of pre-eclampsia (P = 0.03). Also, a positive endocan expression was associated with low birthweight (P = 0.001) and prematurity (P = 0.005) in the fetal outcomes. CONCLUSION: This study showed endocan is highly expressed in fetal endothelial cells, maternal endothelial cells and decidual cells in placenta of hypertensive women. In addition, its expression was associated with poorer maternal and fetal outcomes. These findings suggest endocan may play an important role in the progression of hypertension in pregnancy. PMID- 30306676 TI - Introduction of integrated dental training jaw models and rubric criteria. AB - OBJECTIVE: The objective of the present study was to evaluate the effectiveness of introducing integrated jaw models, rubric criteria and homework tasks to a total clinical simulation training course to improve the clinical competence of preclinical dental students. METHODS: A total simulation training course, which involved six clinical dentistry departments, was held for 110 preclinical students in 2014 and 2015. We prepared integrated jaw models having several morbidities along with corresponding medical information and homework tasks. The students formulated diagnoses and devised treatment plans before performing dental treatment on the mannequin under the direction of instructors from the respective clinical departments. Their performance was assessed by both students and instructors using the rubric criteria. RESULTS: Based on quantitative evaluations, the introduction of integrated jaw models appeared to improve the students' ability to formulate diagnoses and devise dental treatment plans and to understand the respective clinical dentistry disciplines. The rubric criteria provided immediate feedback for the students. Based on a comparison of rubric scores, students tended to significantly underestimate their own performance compared with instructors. Moreover, the introduction of homework tasks improved student seriousness. CONCLUSION: Introducing integrated jaw models, rubric criteria and homework tasks to a total simulation training course may be a good approach for improving student performance in terms of dental diagnoses and treatment. PMID- 30306677 TI - Amide Effects in C-H Activation: Noncovalent Interactions with L-Shaped Ligand for meta Borylation of Aromatic Amides. AB - A new concept for the meta-selective borylation of aromatic amides is described. It has been demonstrated that while esters gave para borylations, amides lead to meta borylations. For achieving high meta selectivity, an L-shaped bifunctional ligand has been employed and engages in an O???K noncovalent interaction with the oxygen atom of the moderately distorted amide carbonyl group. This interaction provides exceptional control for meta C-H activation/borylation. PMID- 30306678 TI - Chronic mood instability: Bipolar, borderline, or both? PMID- 30306679 TI - Homo- and Heteroligand Poly-NHC Metal Assemblies: Synthesis by Narcissistic and Social Self-Sorting. AB - Homoleptic and heteroleptic cylinder-shaped poly-NHC metallosupramolecular assemblies [Ag3 (L)2 ](BF4 )3 have been prepared by control of the shape, size, and electronic properties of disk-shaped trisimidazolium salts of type H3 -L(BF4 )3 . Both imidazolium salts with an electron-deficient triazine backbone H3 A(BF4 )3 or an electron-rich benzene backbone H3 -D(BF4 )3 have been employed. Reaction of H3 -A(BF4 )3 or H3 -D(BF4 )3 with Ag2 O yield trinuclear homoligand complexes [Ag3 (L)2 ](BF4 )3 (L=A, D). However, equimolar mixtures of H3 -A(BF4 )3 and H3 -D(BF4 )3 react with Ag2 O under social self-sorting to give the heteroligand assembly [Ag3 (A)(D)](BF4 )3 . The same heteroligand assembly was obtained by transmetallation from mixtures of complexes [Ag3 (A)2 ](BF4 )3 and [Ag3 (D)2 ](BF4 )3 . The transmetallation from [Ag3 (A)(D)](BF4 )3 to [Au3 (A)(D)](BF4 )3 is also demonstrated. The study expands to concepts of narcissistic and social self-sorting from classical Werner-type ligands to organometallic NHC chemistry thereby opening new routes for the construction of poly-NHC metal assemblies with increasing complexity. PMID- 30306680 TI - Is the use of digital technologies for the fabrication of implant-supported reconstructions more efficient and/or more effective than conventional techniques: A systematic review. AB - OBJECTIVE: To identify clinical studies evaluating efficiency and/or effectiveness of digital technologies as compared to conventional manufacturing procedures for the fabrication of implant-supported reconstructions. MATERIALS AND METHODS: A systematic search from 1990 through July 2017 was performed using the online databases Medline, Embase, and Cochrane-Central-Register-of-Controlled Trials. Literature on efficiency and/or effectiveness during the impression session, the manufacturing process, and the delivery session were included. RESULTS: In total, 12 clinical studies were included. No meta-analysis was performed due to a large heterogeneity of the study protocols. Nine publications reported on posterior single implant crowns (SIC) and three on full-arch reconstructions. Mean impression time with intraoral scanners ranged between 6.7 and 19.8 min, whereas the range for conventional impressions was 8.8 and 18.4 min. In a fully digital workflow (FD-WF) for posterior SIC, mean fabrication time ranged between 46.8 and 54.5 min (prefabricated abutment) and 68.0 min (customized abutment). In a hybrid workflow (H-WF) including a digitally customized abutment and a manual veneering, mean fabrication time ranged between 132.5 and 158.1 min. For a conventional porcelain-fused-to-metal-crown, a mean time of 189.8 min was reported. The mean time for the delivery of posterior SIC ranged between 7.3 and 7.4 min (FD-WF), 10.5 and 12.5 min (H-WF), and 15.3 min (conventional workflow, C-WF). The FD-WF for posterior SIC was more effective than the H-/C-WF. CONCLUSIONS: The implementation of the studied digital technologies increased time efficiency for the laboratory fabrication of implant supported reconstructions. For posterior SIC, the model-free fabrication, the use of prefabricated abutments, and the monolithic design was most time efficient and most effective. PMID- 30306681 TI - Implant supported cantilevered fixed dental rehabilitations in partially edentulous patients: Systematic review of the literature. Part I. AB - OBJECTIVES: To investigate in which clinical situations a cantilever fixed implant supported restorations can be a treatment alternative and which complications are reported. MATERIALS AND METHODS: Two operators screened the literature (MEDLINE, EMBASE) and performed a hand search on the main journals dealing with implantology and prosthetics until 31 December 2017. Only articles that considered cantilever implant fixed restorations with at least 10 patients and with a mean follow-up of at least 5 year were selected. The outcome variables were survival of implants and prosthesis, mechanical, technical and biological complications, marginal bone loss. The review was performed according to the PRISMA statements. Risk of bias assessment was evaluated. Failure and complication rates were analysed using random effect Poisson regression models to obtain summary estimate of 5- and 10-year survival and complication rates. RESULTS: A total of nine papers were selected for partially edentulous patients and reported high survival rate of the prosthesis. The estimated survival rate for 5-10 years was calculated to be 98.4% for the implants and 99.2% for the rehabilitations. Mechanical, technical and biological complications were reported with a cumulative 5-10 years complication rate of 28.66% and 26.57% for the patients and for the prosthesis, respectively. Two papers for single implant supporting 2-unit cantilever were not sufficient to draw conclusions. CONCLUSIONS: There is evidence that cantilever can be successful treatment in partially edentulous patients. In two adjacent edentulous sites, data are not yet sufficient. PMID- 30306682 TI - A systematic review of the influence of the implant-abutment connection on the clinical outcomes of ceramic and metal implant abutments supporting fixed implant reconstructions. AB - OBJECTIVES: The objective of this systematic review was to assess the influence of implant-abutment connection and abutment material on the outcome of implant supported single crowns (SCs) and fixed dental prostheses (FDPs). METHODS: An electronic Medline search complemented by manual searching was conducted to identify randomized controlled clinical trials, prospective and retrospective studies with a mean follow-up time of at least 3 years. Patients had to have been examined clinically at the follow-up visit. Failure and complication rates were analyzed using robust Poisson regression, and comparisons were made with multivariable Poisson regression models. RESULTS: The search provided 1511 titles and 177 abstracts. Full-text analysis was performed for 147 articles resulting in 60 studies meeting the inclusion criteria. Meta-analysis of these studies indicated an estimated 5-year survival rate of 97.6% for SCs and 97.0% for FDPs supported by implants with internal implant-abutment connection and 95.7% for SCs and 95.8% for FDPs supported by implants with external connection. The 5-year abutment failure rate ranged from 0.7% to 2.8% for different connections with no differences between the types of connections. The total number of complications was similar between the two connections, yet, at external connections, abutment or occlusal screw loosening was more predominant. Ceramic abutments, both internally and externally connected, demonstrated a significantly higher incidence of abutment fractures compared with metal abutments. CONCLUSION: For implant-supported SCs, both metal and ceramic abutments with internal and external connections exhibited high survival rates. Moreover, implant-supported FDPs with metal abutments with internal and external connections for also showed high survival rates. PMID- 30306683 TI - Drugs and diseases: Summary and consensus statements of group 1. The 5th EAO Consensus Conference 2018. AB - OBJECTIVES: The task of this working group was to update the knowledge about the use of drugs and biologicals affecting healing of soft tissue and bone during implant treatment or procedures associated with it. Moreover, the impact of titanium particles and biocorrosion on complications and implant survival has been analysed. MATERIALS AND METHODS: The literature in the areas of interest (platelet concentrates, antiresorptive drugs as well as implant-host interaction) was screened using systematic reviews for the former two areas, whereas a narrative critical review was performed for the latter topic. Two manuscripts on platelet concentrates, one manuscript on antiresorptive drugs and one manuscript on the effects of biocorrosion, were presented for group analysis with subsequent discussion in the plenum and final consensus approval. RESULTS: Results and conclusions of the individual reviews of the three topics are presented in the respective papers. Conclusions of the group on strengths and weaknesses of available evidence as well as consensus statements and directions for further research are provided in this study. The following papers were subject to group discussions and formed the basis for the consensus statements: Stahli A, Strauss FJ, Gruber R. () The use of platelet-rich-plasma to enhance the outcomes of implant-related therapies: a systematic review Strauss FJ, Stahli A, Gruber R. (2018) The use of platelet-rich-fibrin to enhance the outcomes of implant-related therapies: a systematic review Mombelli A, Hashim D, Cionca N. () What is the impact of titanium particles and bio-corrosion on implant survival and complications? A critical review Stavropoulos A, Bertl K, Pietschmann P, Pandis N, Morten Schiodt, Klinge B. () The effect of antiresorptive drugs on implant therapy: a systematic review. PMID- 30306684 TI - The clinical performance of all-ceramic implant-supported single crowns: A systematic review and meta-analysis. AB - OBJECTIVE: This review aimed at evaluating the survival and technical complication rates of all-ceramic implant-supported single crowns (SC). MATERIAL AND METHODS: Three electronic databases were searched for clinical studies conducted at >= 15 patients examining implant-supported all-ceramic SCs over >= 12 months. Survival rates of implants and restorations plus technical complication rates of SCs were calculated and tested for statistical correlation with confounding variables. Statistical analysis was performed using a negative binomial distribution model to calculate 5- and 10-year survival and complication estimates. RESULTS: Forty-one included studies reported on implant-supported SCs made of veneered and monolithic high-strength oxide ceramics, monolithic, and veneered glass-based ceramics and of a monolithic resin-nano-ceramic (RNC). Survival estimates for SCs of 93% (95% CI: 86.6%-96.4%) after 5 years and 94.4% (95% CI: 91.1%-96.5%) after 10 years were calculated, corresponding values for implant survival were 95.3% (95% CI: 90.6%-97.7%) and 96.2% (95% CI: 95.1% 97.1%). Technical complication rates after 5/10 years were as follows: chipping 9.0% (95% CI: 5.4%-14.8%)/2.7% (95% CI: 2.1%-3.5%), framework fractures 1.9% (95% CI: 0.7%-4.9%)/1.2% (95% CI: 1%-1.5%), screw loosening 3.6% (95% CI: 1.6% 8.4%)/5.2% (95% CI: 3.6%-7.5%), and decementations with 1.1% (95% CI: 0.4%-2.8%) after 5 years. Some confounding variables influenced the above-mentioned estimates significantly. CONCLUSIONS: All-ceramic implant-supported SCs showed with the exception of a RNC material-high survival rates. However, failures and technical complications occurred which have to be considered when informing patients on the treatment with implant-supported all-ceramic SCs. PMID- 30306687 TI - Implant-supported cantilevered fixed dental rehabilitations in fully edentulous patients: Systematic review of the literature. Part II. AB - AIM: To investigate fully edentulous patients rehabilitated with cantilever-fixed implant-supported restorations and to analyse which complications are reported for this type of treatment. MATERIALS AND METHODS: Two operators screened the literature (MEDLINE, EMBASE) and performed a hand search on the main journals dealing with implantology and prosthetics until 31 December 2017. Only articles that considered cantilever implant-fixed restorations with at least 10 patients and with a mean follow-up of at least 5 years were selected. The outcome variables were survival of implants and prosthesis, mechanical, technical and biological complications, marginal bone loss. The review was performed according to the PRISMA statements. The risk of bias was evaluated for each article. Failure and complication rates were analysed using random effect Poisson regression models to obtain summary estimate of 5- and 10-year survival and complication rates. RESULTS: Fourteen papers for fully edentulous patients were selected. The estimated 5 to 10 years survival rate was calculated to be 99.00% and 96.7% for the implants and the prosthesis, respectively. A total of 299 complications (technical and biological) were reported with a cumulative 5-10 years complication rate of 44.41% and 39.46% for the patients and for the prosthesis, respectively. CONCLUSIONS: There is evidence that cantilever can be successful treatment in fully edentulous patients. PMID- 30306685 TI - Biological aspects: Summary and consensus statements of group 2. The 5th EAO Consensus Conference 2018. AB - OBJECTIVES: This publication reports the EAO Workshop group-2 discussions and consensus statements which provided the scientific evidence on the influence of biological parameters on implant-related clinical outcomes. MATERIAL AND METHODS: The first publication was a systematic review on the biological effects of abutment material on the stability of peri-implant marginal bone levels and the second, a critical narrative review on how peri-implant diagnostic parameters correspond with long-term implant survival and success. The group evaluated the content of both publications, made corrections and recommendations to the authors and agreed on the consensus statements, clinical recommendations and recommendations for future research, which are described in this consensus report. RESULTS: Tested abutment materials can be considered appropriate for clinical use according to the observation period studied (mean 3.5 years). Mean peri-implant bone loss and mean probing pocket depths are not adequate outcomes to study the prevalence of peri-implantitis, while the reporting of frequency distributions is considered more appropriate. CONCLUSIONS: Titanium is currently considered the standard of care as abutment material, although other materials may be more suitable for aesthetic locations. Peri-implantitis should be diagnosed through composite evaluations of peri-implant tissue inflammation and assessment of marginal bone loss with different thresholds. PMID- 30306686 TI - The use of platelet-rich plasma to enhance the outcomes of implant therapy: A systematic review. AB - OBJECTIVE: To assess the effect of platelet-rich plasma (PRP) on implant dentistry. The primary focused question was as follows: What are the clinical, histological, and radiographic outcomes of PRP administration for bone regeneration and implant therapy? METHODS: A literature search was conducted involving three databases: MEDLINE, EMBASE and Cochrane database followed by a hand search of relevant scientific journals. Human studies using PRP for bone regeneration and implant therapy were considered and articles published up to December 31, 2017 were included. Eligible studies were selected based on the inclusion criteria, and quality assessments were conducted. RESULTS: In total, out from the 9,497 titles meeting the original search criteria, 22 fulfilled the inclusion criteria and were chosen for data extraction. Among them were 15 randomized controlled trials (RCT) and seven controlled clinical trials (CCT). Overall, the risk of bias was moderate to high. A total of seven studies showed superior outcomes when PRP was added during sinus floor elevation and five showed no superior outcome. Three studies found a significant advantage of PRP for alveolar bone regeneration and another three studies for soft tissue healing. Three studies reported on beneficial effects of PRP directly during implant placement while another study failed to find significant differences. Due to the heterogeneity of study designs, no meta-analysis could be performed. SUMMARY AND CONCLUSIONS: Despite the lack of consistent evidence supporting the clinical benefit of PRP in healthy patients, PRP might have a positive effect on wound healing and bone regeneration in compromised patients. PMID- 30306689 TI - Frequency of infraposition and missing contact points in implant-supported restorations within natural dentitions over time: A systematic review with meta analysis. AB - OBJECTIVES: The aim of this systematic review was to assess clinical evidence on adverse effects of osseointegrated implants placed among natural teeth of a residual dentition. METHODS: Seven databases were searched without restrictions up to January 2018 for clinical studies on implant infraposition (IIP) or proximal contact point (PCP) loss to the adjacent teeth. After duplicate selection, data extraction, and risk of bias assessment according to the Cochrane guidelines, random-effects meta-analyses of odds ratios (OR) or mean differences (MD) and their 95% confidence intervals (CI) were performed, followed by meta regression and sensitivity analyses. RESULTS: A total of 27 nonrandomized studies with 1,572 patients (mean age 42.2 years/51.2% female) followed up to 18.5 years after implant placement were included. The pooled %prevalence of IIP was 50.5% (nine studies; 95% CI = 26.3-74.5%), and the pooled IIP extent was 0.58 mm (six studies; 95% CI = 0.33-0.83 mm), while IIP > 1 mm was seen for 20.8% of placed implants (five studies; 95% CI = 8.3-37.1%), and male patients were less prone to IIP than female patients (three studies; OR = 0.30; 95% CI = 0.10-0.88; p = 0.03). The pooled %prevalence of PCP loss was 46.3% (nine studies; 95% CI = 32.3 60.6%), with increase through observation time (two studies; OR = 1.09; 95% CI = 1.03-1.16; p = 0.004) and predilection for mesial PCPs (five studies; OR = 2.25; 95% CI = 1.06-4.77; p = 0.03). However, the quality of evidence was very low due to bias. CONCLUSIONS: Patients and doctors need to be aware that long-term adverse effects of dental implants among natural teeth can be observed in terms of IIP and PCP loss to the adjacent teeth. PMID- 30306690 TI - Biomechanical aspects: Summary and consensus statements of group 4. The 5th EAO Consensus Conference 2018. AB - OBJECTIVES: The aim of the present publication was to report on the EAO Workshop group-4 discussions and consensus statements on the five reviews previously prepared. These reviews provided the scientific evidence on the effect of crown to-implant ratio, on reconstructions with cantilevers in fully and partially edentulous patients, on biological and technical complications of tilted in comparison with straight implants, and on the effects of osseointegrated implants functioning in a residual dentition. MATERIAL AND METHODS: The group discussed, evaluated, corrected where deemed appropriate, and made recommendations to the authors regarding the following five reviews submitted: (a) Is there an effect of crown-to-implant ratio on implant treatment outcomes?; (b) Implant-supported cantilevered fixed dental rehabilitations in fully edentulous patients; (c) and in partially edentulous patients; (d) Biological and technical complications of tilted implants in comparison with straight implants supporting fixed dental prostheses; (e) What are the adverse effects of osseointegrated implants functioning among natural teeth of a residual dentition? Based on the five manuscripts and the discussion among the group as well as the plenum members, the major findings were summarized, consensus statements were formulated, clinical recommendations were proposed, and areas of future research were identified. RESULTS: Crown-to-implant ratios ranging from 0.9 to 2.2 did not influence the occurrence of biological or technical complications also in single-tooth restorations. Reconstructions with cantilevers for the rehabilitation of fully and partially edentulous jaws showed high implant and reconstruction survival rates. In contrast, the rate of complications-in particular associated with veneering material-was high during the observation period of 5-10 years. The data reported were primarily derived from studies with high risk of bias. The data for single-implant reconstructions were small. There was no evidence that distally tilted implants were associated with higher failure rates and increased amounts of marginal bone loss. The data supporting these findings, however, were at high risk of bias and frequently incompletely reported. Frequent positional changes occurred between the natural teeth and the implant-supported restorations. These changes were more pronounced in younger individuals, and even though they were reduced with age, they still occurred in adult patients. Even though these changes were frequent, potential implications for the patient are unclear. CONCLUSIONS: The use of single-tooth restorations with crown-to-implant ratio in between 0.9 and 2.2 may be considered a viable treatment option. Multiunit reconstructions with cantilevers are a viable treatment option in fully and partially edentulous patients. Clinicians and patients should be aware, however, that complications are frequent and primarily related to resin material used for veneering. There is some evidence that tilting an implant does affect stability of the implant and the surrounding bone. Treatment options to tilted implants should carefully be considered, as the effect on soft tissues and on prosthesis behavior is poorly reported for tilted implants. Positional changes in the dentition in relation to implant-supported restorations occur frequently. The patient should be informed about the possible need for a treatment related to these changes in the long term. PMID- 30306691 TI - Reconstructive aspects: Summary and consensus statements of group 3. The 5th EAO Consensus Conference 2018. AB - OBJECTIVES: The tasks of this working group were to evaluate the existing evidence on the efficiency and efficacy of the digital and conventional workflows for the fabrication of fixed implant reconstructions, to assess the performance of all-ceramic fixed implant reconstructions and, finally, to evaluate the outcomes of internally and externally connected implant abutments and reconstructions. METHODS: Four reviews were available analyzing the current literature on the respective topics. One review dealt with the efficiency and efficacy of digital and conventional fabrication workflows. Two reviews analyzed the outcomes of all-ceramic fixed implant reconstructions, one focusing on single implant reconstructions and the other evaluating multiple-unit implant fixed dental prostheses (FDPs). The fourth review evaluated the clinical outcome on external, respectively, internal implant-abutment connections. These reviews were the basis for the discussions within the group and at the plenary sessions. RESULTS: The present consensus report gives the consensus statements, the clinical recommendations, and the implications for future research as discussed and approved by the plenum of the consensus conference. The four manuscripts by Muhlemann et al., Rabel et al., Pieralli et al., and Pjetursson et al. are published as part of the journal supplement of the present EAO consensus conference. PMID- 30306692 TI - Dental implant register: Summary and consensus statements of group 2. The 5th EAO Consensus Conference 2018. AB - OBJECTIVES: This publication reports the EAO Workshop group-2 and consensus plenary discussions and statements on a narrative review providing the background and possible facilities and importance of a dental implant register, to allow for a systematic follow-up of the clinical outcome of dental implant treatment in various clinical settings. It should be observed that the format of the review and the subsequent consensus report consciously departs from conventional consensus publications and reports. MATERIAL AND METHODS: The publication was a narrative review on the presence and significance of quality registers regarding select medical conditions and procedures. The group discussed and evaluated the publication and made corrections and recommendations to the authors and agreed on the statements and recommendations described in this consensus report. RESULTS: Possible registrations to be included in an implant register were discussed and agreed as a preliminary basis for further development, meaning that additional parameters be included or some be deleted. CONCLUSIONS: It was agreed to bring the idea of an implant quality register, including the presented results of discussions and proposals by the group- and plenary sessions, to the EAO Board for further discussion and decision. PMID- 30306693 TI - What is the impact of titanium particles and biocorrosion on implant survival and complications? A critical review. AB - OBJECTIVES: To compile the current evidence regarding the association between the release of titanium particles and biologic complications of dental implants. MATERIAL AND METHODS: This is a critical review. We searched the literature using the terms "corrosion," "allergy," "hypersensitivity," or "particles" together with "titanium," "Ti," "TiO2. " The bibliographies of identified publications and previously published review articles were scanned to find additional related articles. We included clinical studies, in vivo and in vitro experiments. RESULTS: Titanium particles and degradation products of titanium have been detected in oral and nonoral tissues. Particles are released from surfaces of dental implants because of material degradation in a process called tribocorrosion. It involves mechanical wear and environmental factors, notably contact to chemical agents and interaction with substances produced by adherent biofilm and inflammatory cells. In vitro, titanium particles can interfere with cell function and promote inflammation. A temporal association between exposure to titanium and occurrence of tissue reactions suggested hypersensitivity in a limited number of cases. However, there is poor specificity as the observed reactions could be initiated by other factors associated with the placement of implants. Titanium particles are commonly detected in healthy and diseased peri implant mucosa alike, at low levels even in gingiva of individuals without titanium implants. Rather than being the trigger of disease, higher concentrations of titanium in peri-implantitis lesions could be the consequence of the presence of biofilms and inflammation. CONCLUSION: There is an association between biocorrosion, presence of titanium particles, and biological implant complications, but there is insufficient evidence to prove a unidirectional causal relationship. PMID- 30306694 TI - Clinical outcomes of partial and full-arch all-ceramic implant-supported fixed dental prostheses. A systematic review and meta-analysis. AB - OBJECTIVE: To assess the survival and technical complication rate of partial and full-arch all-ceramic implant-supported fixed dental prostheses (P-FDP/FA-FDP) and supporting implants. MATERIALS AND METHODS: An electronic search through three databases (MEDLINE/Pubmed, Cochrane Library, Embase) was conducted to identify relevant clinical studies with an observation period of at least 12 months, including >=15 patients. Reconstruction and implant survival rates, technical complications and confounding variables such as processed/installed materials, retention mode and location in the mouth were obtained. Failure and complication rates were analyzed using standard Poisson regression models to calculate 5-year survival and complication estimates. RESULTS: A total of five studies for the P-FDP group and seven studies for the FA-FDP group were included, throughout evaluating veneered zirconia reconstructions. In the P-FDP group, reconstructions were located in posterior regions. Meta-analysis indicated survival estimates on the reconstruction level of 98.3% and 97.7% for P- and FA FDPs after 5 years. However, chipping of the veneering ceramic was frequent, resulting in estimated 5-year complication rates of 22.8% (P-FDPs) and 34.8% (FA FDPs). Five-year survival estimates of implants supporting P-FDPs and FA-FDPs of 98.5% and 99.4% were calculated, respectively. Including a total of 540 FDPs, one screw-loosening and 11 de-cementations were reported. Confounding variables were not found to have a significant influence on survival and complication rates. CONCLUSIONS: All-ceramic implant-supported P- and FA-FDPs comprising veneered zirconia frameworks showed high survival but clinically inacceptable fracture rates of the veneering ceramic. Their suitability with regard to this indication and a successful long-term outcome needs to be further evaluated. PMID- 30306695 TI - The effect of antiresorptive drugs on implant therapy: Systematic review and meta analysis. AB - OBJECTIVES: A considerable portion of the adult population has received and/or is receiving treatment with antiresorptive drugs (ARDs). It is thus relevant to assess possible side effects of ARD intake in connection to various aspects of implant therapy. The aim of this study was to answer the focused question "In patients with systemic intake of ARDs, what is the outcome and complication rate of implant therapy including associated bone grafting procedures comparing to patients without systemic intake of ARDs?" MATERIALS AND METHODS: Original studies fulfilled predefined inclusion criteria (e.g., case series, cohort studies, case-control studies, and controlled and/or randomized controlled clinical trials; retro- or prospective design; and >=10 patients with systemic intake of ARDs). Various patient-, medication-, and intervention-related parameters [i.e., implant loss, grafting procedure complication/failure, peri implant marginal bone levels/loss, medication-related osteonecrosis of the jaws (MRONJ), and peri-implantitis] were extracted, and meta-analyses and quality assessment were performed. RESULTS: Twenty-four studies with bisphosphonate (BP) intake (mainly low dose for osteoporosis treatment) and seven studies on hormone replacement therapy (HRT), including >=10 patients, and controls not taking the medication were identified. Furthermore, seven studies on MRONJ associated with implants were included. Meta-analyses based on four studies reporting on patient level and eight studies reporting on implant level showed no significant differences in terms of implant loss between patients on BPs (mainly low dose for osteoporosis treatment) and controls. Furthermore, low-dose BP intake did not compromise peri-implant marginal bone levels. Based on two studies, no negative effect of HRT was observed on the implant level, while HRT appeared to exert a marginally significant negative effect regarding implant survival on the patient level and regarding peri-implant marginal bone levels. Based on six studies reporting single-patient data, MRONJ in patients on BP for osteoporosis appeared in 70% of the cases >36 months after start of drug intake, while in patients with cancer, MRONJ appeared in 64% of the cases <=36 months after first BP intake. CONCLUSION: Low-dose oral BP intake for osteoporosis treatment, in general, does not compromise implant therapy, that is, patients on ARDs do not lose more implants nor get more implant-related complications/failures comparing to implant patients without BP intake. There is almost no information available on the possible effect on implant therapy of high-dose BPs or other widely used ARDs (e.g., denosumab), or on the success or safety of bone grafting procedures. Patients with high-dose ARD intake for management of malignancies, patients on oral BP over a longer period of time, and patients with comorbidities should be considered as high-risk patients for MRONJ. PMID- 30306696 TI - Is there an effect of crown-to-implant ratio on implant treatment outcomes? A systematic review. AB - OBJECTIVES: High crown-to-implant ratios may lead to complications due to unfavorable occlusal forces, including nonaxial forces, on the bone surrounding the neck of the implant and within the connection of the crown and implant itself. The aim of this study was to perform a systematic review on the influence of crown-to-implant ratio of single-tooth, nonsplinted, implants on biological and technical complications. MATERIALS AND METHODS: MEDLINE (1950-January 2018), EMBASE (1966-January 2018), and Cochrane Central Register of Controlled Trials database (1800-January 2018) were searched to identify eligible studies. Inclusion criteria were as follows: crown-to-implant ratio of single-tooth, nonsplinted, implant-supported restorations in the posterior maxilla or mandible and follow-up of at least 1 year. Main outcome measures were as follows: implant survival rate, marginal bone level changes, biological complications, and technical complications. Two reviewers independently assessed the articles. A meta-analysis was carried out for implant survival rate and peri-implant bone changes. RESULTS: Of 154 primarily selected articles, eight studies fulfilled the inclusion criteria. Study groups presented a mean crown-to-implant ratio varying from 0.86 (with 10-mm implants) to 2.14 (with 6-mm implants). The meta-analysis showed an implant survival of more than 99% per year and mean peri-implant bone changes of <0.1 mm per year. Limited biological and technical complications were reported. CONCLUSION: Data reviewed in the current manuscript on crown-to-implant ratio, ranging from 0.86 to 2.14, of single-tooth, nonsplinted, implants did not demonstrate a high occurrence of biological or technical complications. PMID- 30306698 TI - The use of platelet-rich fibrin to enhance the outcomes of implant therapy: A systematic review. AB - OBJECTIVE: To assess the impact of platelet-rich fibrin (PRF) on implant dentistry. The primary focused question was as follows: What are the clinical, histological, and radiographic outcomes of PRF administration for bone regeneration and implant therapy? METHOD: A systematic literature search comprised three databases: MEDLINE, EMBASE, and Cochrane followed by a hand search of relevant scientific journals. Human studies using PRF for bone regeneration and implant therapy were considered and articles published up to December 31, 2017 were included. Eligible studies were selected based on the inclusion criteria. Randomized controlled trials (RCT) and controlled clinical trials (CCT) were included. RESULTS: In total, 5,963 titles were identified with the search terms and by hand search. A total of 12 randomized controlled trials (RCT) met the inclusion criteria and were chosen for data extraction. Included studies focused on alveolar ridge preservation after tooth extraction, osseointegration process, soft tissue management, bone augmentation, bone regeneration after sinus floor elevation and surgical peri-implantitis treatment. Overall, the risk of bias was moderate or unclear. Nine studies showed superior outcomes for PRF for any of the evaluated variables, such as ridge dimension, bone regeneration, osseointegration process, soft tissue healing. Three studies failed to show any beneficial effects of PRF. No meta-analysis could be performed due to the heterogeneity of study designs. CONCLUSIONS: There is moderate evidence supporting the clinical benefit of PRF on ridge preservation and in the early phase of osseointegration. It remains unclear whether PRF can reduce pain and improve soft tissue healing. More research support is necessary to comment on the role of PRF to improve other implant therapy outcomes. PMID- 30306699 TI - Dental Implant Quality Register-A possible tool to further improve implant treatment and outcome. AB - The Board of EAO (European Association for Osseointegration) has discussed an initiative to explore the conditions to establish a Dental Implant Register. It was suggested to bring this issue to the EAO Consensus Conference 2018 for a discussion and to possibly propose relevant and manageable parameters. This article presents some select examples from quality registers in the medical field. Based on the experience of established registers, essentially in the medical field, factors considered to be of importance, if and when establishing a Dental Implant Register are introduced and discussed. PMID- 30306700 TI - Biological and technical complications of tilted implants in comparison with straight implants supporting fixed dental prostheses. A systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the implant failure, marginal bone loss (MBL), and other biological or technical complications of restorations supported by tilted and straight implants after at least 3 years in function. METHODS: Electronic and manual searches were performed in MEDLINE, Embase, Web of Science, and OpenGrey to identify clinical studies published up to December 2017. After duplicate study selection and data extraction, the risk of bias was assessed with the ROBINS-I tool. Random-effects meta-analyses of relative risks (RRs) or mean differences (MD) and their 95% confidence intervals (CIs) were performed, followed by subgroup/sensitivity analyses and application of the GRADE approach. RESULTS: A total of 17 nonrandomized studies (eight prospective/nine retrospective) were included. The number of implants of the overall systematic review was 7,568 implants placed in 1,849 patients supporting either full-arch or partial implant prostheses. No difference in the failure of tilted and straight implants was seen (eight studies; 4,436 implants; RR = 0.95; 95% CI = 0.70 to 1.28; p = 0.74), with the quality of evidence being very low due to bias and imprecision. Likewise, no difference in MBL was seen between tilted and straight implants (16 studies; 5,293 implants; MD = 0.03 mm; 95% CI = -0.03 to 0.10 mm; p = 0.32), with the quality of evidence being very low due to bias and inconsistency. Contradictory results regarding implant survival were found from prospective and retrospective studies, which could indicate bias from the latter. CONCLUSIONS: Within the limitations of the present systematic review, no effect of implant inclination on implant survival or peri-implant bone loss was found. PMID- 30306697 TI - How do peri-implant biologic parameters correspond with implant survival and peri implantitis? A critical review. AB - OBJECTIVES: The aim of this critical review was to evaluate whether commonly used biologic diagnostic parameters correspond to implant survival and peri implantitis prevalence. MATERIALS AND METHODS: Publications from 2011 to 2017 were selected by an electronic search using the Pubmed database of the US National Library of Medicine. Prospective and retrospective studies with a mean follow-up time of at least 5 years and reporting prevalence of peri-implantitis as well as mean bone loss and standard deviation were selected. The correlation between reported prevalence of peri-implantitis and reported implant survival, mean follow-up time, mean bone loss, mean probing depth, and mean bleeding on probing was calculated. Mean bone loss and standard deviation were used for estimation of proportion of implants with bone loss exceeding 1, 2, and 3 mm. RESULTS: Full-text analysis was performed for 255 papers from 4,173 available ones, and 41 met all the inclusion criteria. The overall mean weighted survival rate was 96.9% (89.9%-100%) and the reported prevalence of peri-implantitis ranged between 0% and 39.7%, based on 15 different case definitions. The overall weighted bone loss was 1.1 mm based on 8,182 implants and an average mean loading time ranging from 5 to 20 years. No correlation was found between mean bone loss and the reported prevalence of peri-implantitis. The estimated prevalence of implants with bone loss above 2 mm was 23%. The overall weighted mean probing depth was 3.3 mm, and mean weighted bleeding was 52.2%. Only a weak correlation was found between survival and function time (r = -0.49). There was no relation between the probing depth or bleeding and the mean bone loss, mean follow-up time, and reported prevalence of peri-implantitis. CONCLUSION: Biologic parameters mean probing depth and mean bleeding on probing do not correlate with mean bone loss and this irrespective of follow-up. Case definition for peri implantitis varied significantly between studies indicating that an unambiguous definition based on a specified threshold for bone loss is not agreed upon in the literature. PMID- 30306701 TI - 3D convolutional neural networks for detection and severity staging of meniscus and PFJ cartilage morphological degenerative changes in osteoarthritis and anterior cruciate ligament subjects. AB - BACKGROUND: Semiquantitative assessment of MRI plays a central role in musculoskeletal research; however, in the clinical setting MRI reports often tend to be subjective and qualitative. Grading schemes utilized in research are not used because they are extraordinarily time-consuming and unfeasible in clinical practice. PURPOSE: To evaluate the ability of deep-learning models to detect and stage severity of meniscus and patellofemoral cartilage lesions in osteoarthritis and anterior cruciate ligament (ACL) subjects. STUDY TYPE: Retrospective study aimed to evaluate a technical development. POPULATION: In all, 1478 MRI studies, including subjects at various stages of osteoarthritis and after ACL injury and reconstruction. FIELD STRENGTH/SEQUENCE: 3T MRI, 3D FSE CUBE. ASSESSMENT: Automatic segmentation of cartilage and meniscus using 2D U-Net, automatic detection, and severity staging of meniscus and cartilage lesion with a 3D convolutional neural network (3D-CNN). STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, specificity and sensitivity, and class accuracy. RESULTS: Sensitivity of 89.81% and specificity of 81.98% for meniscus lesion detection and sensitivity of 80.0% and specificity of 80.27% for cartilage were achieved. The best performances for staging lesion severity were obtained by including demographics factors, achieving accuracies of 80.74%, 78.02%, and 75.00% for normal, small, and complex large lesions, respectively. DATA CONCLUSION: In this study we provide a proof of concept of a fully automated deep learning pipeline that can identify the presence of meniscal and patellar cartilage lesions. This pipeline has also shown potential in making more in-depth examinations of lesion subjects for multiclass prediction and severity staging. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30306702 TI - Clinical value of preoperative CA19-9 levels in evaluating resectability of gallbladder carcinoma. AB - BACKGROUND: This study evaluated the predictive ability of preoperative carbohydrate antigen 19-9 (CA19-9) level in assessing tumour resectability in patients with gallbladder carcinoma (GBC). METHODS: We retrospectively analysed preoperative serum levels of CA19-9 in 292 patients with potentially resectable GBC between January 2000 and March 2016 in our institution. All final diagnoses were confirmed by pathological examination. The optimal cut-off point of the CA19 9 for predicting resectability was determined by the receiver operating characteristic curve. The univariate analysis and multivariate Cox regression model were applied to assess the relationship between the parameters to resectability. RESULTS: A total of 292 patients with surgical treatment were included, of whom 195 were identified as curative resection (R0 resection), 69 were classified as R1/2 resection and the remaining 28 patients were operated on with palliative surgery. The receiver operating characteristic curve analysis calculated the best CA19-9 cut-off point of 98.91 U/mL in the prediction of resectability. Meanwhile, the sensitivity, specificity, positive predictive value and negative predictive value were 76.3%, 70.8%, 85.7% and 56.5%, respectively. In the multivariate logistic regression analysis, CA19-9 >98.91 U/mL (odds ratio (OR) 6.339, 95% confidence interval (CI) 3.562-11.284, P < 0.001), tumour located on hepatic side (OR 1.787, 95% CI 1.022-3.123, P = 0.042) and advanced American Joint Committee on Cancer stage (OR 2.156, 95% CI 1.180-3.940, P = 0.013) were independent determinants of resectability in patients diagnosed as GBC. CONCLUSION: Preoperative CA19-9 predicts resectability in patients with radiological resectable GBC. Increased preoperative CA19-9 is related to poor resectability rate. PMID- 30306704 TI - Catalytic Reductive N-Alkylations using CO2 and Carboxylic Acid Derivatives: Recent Progress and Developments. AB - N-Alkylamines are key intermediates in the synthesis of fine chemicals, dyes and natural products, hence being highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient protocols for their production continues to attract the interest of both academic and industrial chemists. So far, reductive protocols such as reductive amination or N alkylation through hydrogen autotransfer employing carbonyl compounds or alcohols as alkylating agents prevail for the synthesis of amines. In addition, in the last years, carboxylic/carbonic acid derivatives and carbon dioxide have been introduced as alternative convenient alkylating sources. The safety, easy accessibility and high stability of these reagents makes the development of new reductive transformations using them as N-alkylating agents a useful alternative to existing protocols. In this minireview, we will summarize all the reported examples up to date dealing with the one-pot reductive N-alkylation methods using carboxylic/carbonic acid derivatives or carbon dioxide as alkylating agents. PMID- 30306703 TI - Opioid prescribing in orthopaedic and neurosurgical specialties in a tertiary hospital: a retrospective audit of hospital discharge data. AB - BACKGROUND: To understand patterns of opioid prescribing on discharge in the orthopaedic and neurosurgical wards of a tertiary metropolitan hospital. METHODS: A retrospective audit of medical records and discharge summaries for all orthopaedic and neurosurgical patients admitted for at least 2 days on two surgical wards over a 6-month period between 1 January and 30 June 2017. RESULTS: A combined total of 355 patients (281 orthopaedic and 74 neurosurgical patients) were included in the audit. Approximately 82% were discharged on opioids. Of patients discharged on opioids, 71.4% of the orthopaedic group and 73.8% of the neurosurgical group were discharged on combinations of two or more opioids (immediate release together with slow release). Around 65% of the sample discharged on opioids was opioid naive on admission. About 32.5% of the orthopaedic patients and 68.9% of the neurosurgical patients were discharged on a combination of opioid and other pharmacotherapy that could potentiate the central nervous system depressant effect of the opioids. Only 6.9% of orthopaedic patients and 11.5% of the neurosurgical patients had discharge summaries that included any reference to opioid management after discharge. CONCLUSION: Orthopaedic and neurosurgical units had high opioid prescribing rates on discharge from hospital. This highlights the need for clear communication of the intended medication management plan post-discharge in order to minimize inappropriate and ongoing use of opioids post-surgery. PMID- 30306705 TI - Aviation-based teamwork skills work for surgeons: time for an 'aviation bundle'? AB - BACKGROUND: Aviation systems were developed to improve safety and have achieved remarkable results. Medicine has looked to replicate these systems; however, the gap in outcomes between the two industries remains vast. Bridging this chasm requires an in-depth analysis of the applicability of the aviation safety model in surgery. This study uses qualitative methods to explore how aviation-based practices may be adapted and applied more effectively in theatre. METHODS: Data were collected using multiprofessional focus groups in a single centre. The focus groups involved discussion around teamwork and aviation-based non-technical skills. With consent, audio recordings were anonymized and transcribed. Qualitative (thematic) analysis was used to identify themes. RESULTS: Five focus groups were conducted. Eight themes emerged, with a total of 18 sub-themes. Themes were: current practice, customization, applicability, team performance, human factors, analogy, incidents and integration of skills. Extent and limitations of the aviation surgery analogy also emerged. CONCLUSIONS: The new insights gained through this qualitative analysis highlight the need to tailor aviation-based practices to the operating theatre. To achieve this, we propose the 'aviation bundle' of non-technical skills. This blueprint aims to promote a culture of safety and efficiency in surgical practice and could be developed into a training programme for theatre staff. PMID- 30306707 TI - Gain-of-function variants in the melanocortin 4 receptor gene confer susceptibility to binge eating disorder in subjects with obesity: a systematic review and meta-analysis. AB - The association between coding variants in the melanocortin 4 receptor gene (MC4R) and binge eating disorder (BED) in patients with obesity is controversial. Two independent reviewers systematically searched MEDLINE, Embase, PsycINFO, BIOSIS Previews, Web of Science Core Collection and Google Scholar up to February 2018, using terms describing the MC4R gene and BED. Six of 103 identified references were included. Studies examined associations between at least one coding variant/mutation in MC4R and BED and screened for BED as per the Diagnostic and Statistical Manual of Mental Disorders. Risk of bias was assessed using a modified version of the Q-Genie tool, and overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation guidance. Meta-analysis was conducted via logistic regression models. A positive association between gain-of-function (GOF) variants in the MC4R and BED was observed (odds ratio [OR] = 3.05; 95% confidence interval [CI]: 1.82, 5.04; p = 1.7 * 10-5 ), while no association was detected between loss-of-function (LOF) mutations and BED (OR = 1.50; 95% CI: 0.73, 2.96; p = 0.25). Similar results were found after accounting for study quality (GOF variants: OR = 3.15; 95% CI: 1.76, 5.66; p = 1.1 * 10-4 ; LOF mutations: OR = 1.50; 95% CI: 0.73, 2.97; p = 0.25). Our systematic review and meta-analysis provides evidence that GOF variants as opposed to LOF mutations in MC4R are associated with BED in subjects with obesity. PMID- 30306706 TI - Aberrant MCT4 and GLUT1 expression is correlated with early recurrence and poor prognosis of hepatocellular carcinoma after hepatectomy. AB - The tumor microenvironment is a key determinant of cancer cell biology. The microenvironment is a complex mixture of tumor cells, stromal cells, and proteins, extracellular matrix, oxygen tension, and pH levels surrounding the cells that regulate the tumor progress. This study identified the prognostic factors associated with hepatocellular carcinoma (HCC) and MCT4 and GLUT1 expression levels in HCC specimens. In this study, we analyzed MCT4 and GLUT1 expression levels in tissue samples from 213 patients with HCC by immunohistochemical analyses and in HCC tumor tissues and matched adjacent nonneoplastic tissues by quantitative real-time PCR. We conducted a prognostic analysis of the overall survival (OS) and time to recurrence (TTR) using immunoreactivity and other common clinical and pathological parameters. All variables with prognostic impact were further analyzed by multivariate analysis. We found that MCT4 and GLUT1 expression levels were significantly higher in tumor tissues than in adjacent nontumor tissues, and they were positively correlated with tumor size. Survival analysis showed that patients with high expression levels of MCT4 or GLUT1 had a poor OS and TTR. In patients with HCC, MCT4 expression was an independent negative prognostic factor for OS (hazard ratio [HR] = 1.617; 95% confidence interval [CI] = 1.102-2.374; P = 0.014), and metabolic indicators were independent prognostic factors for OS (HR = 1.617, 95% CI = 1.102-2.374, P = 0.006) and TTR (HR = 1.348, 95% CI = 1.079-1.685, P = 0.009). Interestingly, patients with positive metabolic indicator expression in tumor cells had a significantly shorter OS and earlier TTR than those with negative metabolic indicator expression in tumor cells in the <=5 cm and >5 cm subgroups. In summary, using the expression of MCT4 and GLUT1 and their metabolic parameters to determine the metabolic status of tumors is promising for predicting the prognosis of patients with HCC. PMID- 30306708 TI - Topical haemostatic powder as a novel endoscopic therapy for severe colonic diverticular bleeding. AB - BACKGROUND: Although most diverticular bleeding resolve spontaneously, up to 30% can bleed torrentially, necessitating angioembolization, endoscopic or surgical intervention. Non-contact endoscopic therapies, such as topical haemostatic powders, do not require precise targeting and are attractive because identification of specific culprit diverticulum is difficult. While their use in non-variceal upper gastrointestinal bleeding is well established, its role in lower gastrointestinal bleeding remains unclear. We used topical Hemospray in a novel setting of severe diverticular bleeding, evaluating its efficacy in achieving haemostasis, reducing re-bleeding and the need for re-intervention. METHODS: Consecutive patients from a tertiary colorectal unit who underwent colonoscopy and Hemospray for severe diverticular bleeding from November 2016 to October 2017 were included. Hemospray was endoscopically applied to colonic segments with major stigmata of recent haemorrhage. RESULTS: Ten patients had a median time to colonoscopy of 22 h (range: 8-54) from admission. Median of 3.5 units (range: 0-10) of packed cells were transfused pre-endoscopy. All achieved immediate haemostasis without further haemodynamic instability or re-bleeding. No endoscopic, radiological or surgical re-intervention was required. Patients were fit for discharge within a median of 3 days (range: 2-7) following Hemospray. There were no morbidities, mortalities or readmissions for diverticular bleeding after a median follow-up of 9.5 months (range: 3-16). CONCLUSION: This feasibility study shows that topical haemostatic powders can offer a safe and effective therapeutic endoscopic option in severe diverticular bleeding with high haemostatic rate. Prospective controlled trials are required to establish its efficacy compared to conventional therapy. PMID- 30306709 TI - Secondary Acceptor Optimization for Full-Exciton Radiation: Toward Sky-Blue Thermally Activated Delayed Fluorescence Diodes with External Quantum Efficiency of ~30. AB - Efficient blue emitters are indispensable for organic light-emitting diodes (OLEDs) with respect to display and lighting applications. Because of their high energy excited states, both radiation enhancement and non-radiation suppression should be simultaneously optimized to realize 100% exciton utilization. Here, it is shown that the excited-state characteristics of blue thermally activated delayed fluorescence emitters can be precisely controlled by a secondary acceptor having moderate electronic effects on increasing the singlet charge-transfer component and preserving the triplet locally excited-state component. In addition of planar configuration between the donor and the primary acceptor, the radiative transition improvement and non-radiative transition suppression can be simultaneously achieved for "full-exciton radiation". A molecule using diphenylphosphine oxide as the secondary acceptor exhibits ~100% photoluminescence quantum yield on the basis of its tenfold increased singlet radiative rate constant, fivefold decreased singlet and triplet non-radiative rate constants, and ~100% reverse intersystem crossing efficiency, which further endows ~100% exciton utilization efficiency to its sky-blue OLEDs. PMID- 30306711 TI - Gender- and cholesterol-specific predictive value of body mass index in renal cell carcinoma: A multicenter study. AB - AIM: Recently, there have been some reports on preoperative body mass index (BMI) and total cholesterol (TC) as a prognostic predictor for patients with renal cell carcinoma (RCC) but the topic is controversial and still poorly understood. So we analyzed the effects of BMI and TC on the prognosis of RCC. METHODS: Retrospective data from 1988 to 2015 were collected from eight centers with a total of 7,271 patients surgically treated for nonmetastatic RCC. Receiver operating characteristic curve analysis was analyzed and the highest Youden index was shown at 163.5 mg/dL. According to the Asian BMI criteria, patients were divided into normal BMI < 25 kg/m2 and high BMI >= 25 kg/m2 . Kaplan-Meier analysis, multivariate Cox regression model were performed to identify the overall survival (OS) and the recurrence-free survival (RFS). RESULTS: Normal BMI and low TC group was associated with the shortest OS and RFS as compared to the other groups significantly. In the male patients, the results showed similar to the whole sample. But in the female, BMI had no effect on both OS and RFS. On multivariate Cox regression analysis, low TC was an independent predictor for OS in both genders. However, normal BMI was a significant prognostic factor in the males only. CONCLUSION: Preoperative BMI and TC are good predictive factors for both OS and RFS significantly in RCC patients. Also, TC was an independent predictor for OS in all RCC patients; however, BMI was a significant predictor in males only. PMID- 30306710 TI - A clinical 3D/4D CBCT-based treatment dose monitoring system. AB - To monitor delivered dose and trigger plan adaptation when deviation becomes unacceptable, a clinical treatment dose (Tx-Dose) reconstruction system based on three-dimensional (3D)/four-dimensional (4D)-cone beam computed tomograpy (CBCT) images was developed and evaluated on various treatment sites, particularly for lung cancer patient treated by stereotactic body radiation therapy (SBRT). This system integrates with our treatment planning system (TPS), Linacs recording and verification system (R&V), and CBCT imaging system, consisting of three modules: Treatment Schedule Monitoring module (TSM), pseudo-CT Generating module (PCG), and Treatment Dose Reconstruction/evaluation module (TDR). TSM watches the treatment progress in the R&V system and triggers the PCG module when new CBCT is available. PCG retrieves the CBCTs and performs planning CT to CBCT deformable registration (DIR) to generate pseudo-CT. The 4D-CBCT images are taken for target localization and correction in lung cancer patient before treatment. To take full advantage of the valuable information carried by 4D-CBCT, a novel phase-matching DIR scheme was developed to generate 4D pseudo-CT images for 4D dose reconstruction. Finally, TDR module creates TPS scripts to automate Tx-Dose calculation on the pseudo-CT images. Both initial quantitative commissioning and patient-specific qualitative quality assurance of the DIR tool were utilized to ensure the DIR quality. The treatment doses of ten patients (six SBRT-lung, two head and neck (HN), one breast and one prostate cancer patients) were retrospectively constructed and evaluated. The target registration error (mean +/ STD: 1.05 +/- 1.13 mm) of the DIR tool is comparable to the interobserver uncertainty (0.88 +/- 1.31 mm) evaluated by a publically available lung-landmarks dataset. For lung SBRT patients, the D99 of the final cumulative Tx-Dose of GTV is 93.8 +/- 5.5% (83.7-100.1%) of the originally planned D99 . CTV D99 decreases by 3% and mean ipsilateral parotid dose increases by 11.5% for one of the two HN patients. In conclusion, we have demonstrated the feasibility and effectiveness of a treatment dose verification system in our clinical setting. PMID- 30306713 TI - High Efficiency Removal of Cytokines and HMGB-1 by Continuous Hemofiltration With a Dual Layered Polyethersulfone Membrane: An Ex Vivo Study. AB - Cytokines and high mobility group box chromosomal protein-1 (HMGB-1) play key roles in inflammatory conditions. While hemofiltration has been shown to remove cytokines, removal of cytokines and HMGB-1 by hemofiltration using a polyethersulfone membrane has not been reported. This study aimed to test the hypothesis that the polyethersulfone membrane will achieve higher removal performance for substances including inflammatory cytokines compared to other hemofilters, while retaining low albumin removal capacity. Subjects were eight healthy volunteers. We collected 400 mL each of blood samples into containers with heparin and added 30 mg of lipopolysaccharide to spike cytokines and HMGB-1. After incubation at 39oC for 12 h, each blood sample was circulated through a hemofiltration circuit with a polyethersulfone hemofilter (2.1 m2 or 1.1 m2 ) at a filtration flow rate of 2 L/h. Measurement samples were collected from arterial, venous, and ultrafiltrate sampling points. Concentrations of cytokines (IL-1beta, IL-4, IL-6, IL-8, IL- 10, and tumor necrosis factor [TNF-a]), HMGB-1, and albumin were determined at each time point (1, 4, 8, 12, and 24h). High sieving coefficients (SCs) above 0.8 were obtained for all cytokines except for TNF-a as well as HMGB-1, whereas the SC for albumin was less than 0.04 with both hemofilters. The hemofilter with a larger membrane area achieved significantly higher clearances for TNF-a and HMGB-1, and slower decreases in SCs over time for IL-1beta, IL-6, IL-8, TNF-a, and albumin. Continuous hemofiltration with a polyethersulfone membrane achieved high efficiency removal of cytokines and HMGB 1, without excessive removal of albumin. PMID- 30306712 TI - Predicting post-operative pancreatic fistulae using preoperative pancreatic imaging: a systematic review. AB - BACKGROUND: Post-operative pancreatic fistulae (POPF) remain a major contributor to morbidity and mortality following pancreatic resection. Evidence for preoperative prediction of POPF based on cross-sectional imaging has not been systemically reviewed. This review aimed to determine whether preoperative imaging modalities can accurately predict the development of POPF. METHODS: A systematic review of major reference databases was undertaken, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, up to May 2018. RESULTS: There were 18 studies (2150 patients), seven used magnetic resonance imaging (MRI), five used computed tomography (CT) scans, four used transabdominal ultrasonography and one study each used MRI and CT and endoscopic ultrasonography elastography. All were retrospective, single-centre studies. Intensity of the pancreas signal relative to the spleen, liver or muscle was commonly used. Other studies compared signal intensity between unenhanced and post-contrast-enhanced pancreas, apparent diffusion coefficient values comparing normal parenchyma to fibrosis, perfusion fraction (f) of intravoxel incoherent motion diffusion-weighted imaging, or utilized a muscle-normalized signal intensity curve with signal intensity ratio or directly assessed pancreatic volume and duct width. Shear wave velocity measurement on transabdominal ultrasonography may reflect pancreas tissue fibrosis or stiffness and predict POPF. Most parameters used to predict the development of POPF were based on identifying imaging features of a fatty or fibrotic pancreas and main pancreatic duct diameter. CONCLUSION: A number of different and highly promising parameters have been used for preoperative prediction of POPF using ultrasound, MRI, CT or both. Large multicentre prospective studies are needed to determine which parameters most accurately predict POPF, using standardized definitions and methodology. PMID- 30306714 TI - E-cigarette use in England 2014-17 as a function of socio-economic profile. AB - BACKGROUND AND AIMS: E-cigarettes have the potential either to decrease or increase health inequalities, depending on socio-economic differences in their use and effectiveness. This paper estimated the associations between socio economic status (SES) and e-cigarette use and examined whether these associations changed between 2014 and 2017. DESIGN: A monthly repeat cross-sectional household survey of adults (16+) between January 2014 and December 2017. This time-period was chosen given that the prevalence of e-cigarette use stabilized in England in late 2013. SETTING: England. PARTICIPANTS: Participants in the Smoking Toolkit Study, a monthly household survey of smoking and smoking cessation among adults (n = 81 063; mean age = 48.4 years, 49% were women) in England. Subsets included past year smokers (n = 16 232; mean age = 42.8, 46% women), smokers during a quit attempt (n = 5305, mean age = 40.6, 49% women) and long-term ex-smokers (n = 13 562, mean age = 59.3, 44% women). MEASUREMENTS: The outcome measure for the analyses was current e-cigarette use. We also included smokers during a quit attempt where use of an e-cigarette during the most recent quit attempt was the outcome measure. Social grade based on occupation was the SES explanatory variable, using the National Readership Survey classification system of AB (higher and intermediate managerial, administrative and professional), C1 (supervisory, clerical and junior managerial, administrative and professional), C2 (skilled manual workers), D (semi-skilled and unskilled manual workers) and E (state pensioners, casual and lowest-grade workers, unemployed with state benefits only). The analyses were stratified by year to assess the changes in these associations over time. FINDINGS: Among past-year smokers, lower SES groups had lower overall odds of e-cigarette use compared with the highest SES group AB (D: odds ratio = 0.53, 95% confidence interval = 0.40-0.71; E: 0.67, 0.50-0.89). These differences in e-cigarette use reduced over time. The use of e-cigarettes during a quit attempt showed no clear temporal or socio-economic patterns. Among long-term ex-smokers, use of e-cigarettes increased from 2014 to 2017 among all groups and use was more likely in SES groups C2 (2.03, 1.08-3.96) and D (2.29, 1.13-4.70) compared with AB. CONCLUSIONS: From 2014 to 2017 in England, e cigarette use was greater among smokers from higher compared with lower socio economic status (SES) groups, but this difference attenuated over time. Use during a quit attempt was similar throughout SES groups. Use by long-term ex smokers increased over time among all groups and was consistently more common in lower SES groups. PMID- 30306715 TI - Characteristics of the essential pathogenicity factor Rv1828, a MerR family transcription regulator from Mycobacterium tuberculosis. AB - The gene Rv1828 in Mycobacterium tuberculosis is shown to be essential for the pathogen and encodes for an uncharacterized protein. In this study, we have carried out biochemical and structural characterization of Rv1828 at the molecular level to understand its mechanism of action. The Rv1828 is annotated as helix-turn-helix (HTH)-type MerR family transcription regulator based on its N terminal amino acid sequence similarity. The MerR family protein binds to a specific DNA sequence in the spacer region between -35 and -10 elements of a promoter through its N-terminal domain (NTD) and acts as transcriptional repressor or activator depending on the absence or presence of effector that binds to its C-terminal domain (CTD). A characteristic feature of MerR family protein is its ability to bind to 19 +/- 1 bp DNA sequence in the spacer region between -35 and -10 elements which is otherwise a suboptimal length for transcription initiation by RNA polymerase. Here, we show the Rv1828 through its NTD binds to a specific DNA sequence that exists on its own as well as in other promoter regions. Moreover, the crystal structure of CTD of Rv1828, determined by single-wavelength anomalous diffraction method, reveals a distinctive dimerization. The biochemical and structural analysis reveals that Rv1828 specifically binds to an everted repeat through its winged-HTH motif. Taken together, we demonstrate that the Rv1828 encodes for a MerR family transcription regulator. PMID- 30306716 TI - Monitoring excess unplanned return to theatre following colorectal cancer surgery. AB - BACKGROUND: To develop a risk-adjustment model for unplanned return to theatre (URTT) outcomes following colorectal surgeries in Australia and New Zealand hospitals and apply top-down and bottom-up statistical process control methods for fair comparison of hospitals and surgeons' URTT rates. METHODS: We analysed URTT outcomes from hospitals contributing data to the Bi-National Colorectal Cancer Audit clinical registry between 2007 and 2016. Preoperative and intraoperative covariates were considered for risk adjustment. A risk-adjusted rate funnel plot was prepared for between-hospital comparisons and identification of outlying hospitals with unusually high rates of URTT. Cumulative observed minus-expected charts with cumulative sum signals were then presented for surgeons within an outlying hospital. RESULTS: The study included 15 134 patients and 166 surgeons across 70 hospitals. The weighted average URTT rate was 5.2%. The risk-adjustment model identified 12 preoperative and intraoperative variables that significantly raise the risk of URTT: male sex, American Society of Anesthesiologists score, emergency admissions, conversion entry, left hemicolectomy, total colectomy, proctocolectomy, lower anterior resection, ultra low anterior resection, abdominoperineal resection, organ resection and excess lymph nodes harvested. Right hemicolectomy significantly reduced risk of URTT. URTT rates were not found to significantly vary across seniority of operator; however, comparisons were limited by lack of data on junior operators. The funnel plot identified five hospitals as 'possible outliers' and hospital T was identified as a 'definite outlier'. The cumulative observed-minus-expected charts with cumulative sum signals showed that within hospital T, one surgeon among three had a particularly bad run of URTTs. CONCLUSION: Feedback from aggregated URTT outcomes using a risk-adjusted rate funnel plot is enhanced when follow-up examination of outlying hospitals is conducted with concurrent application of cumulative observed-minus-expected charts with cumulative sum signals. PMID- 30306717 TI - Neighbourhood social capital and obesity: a systematic review of the literature. AB - Social capital, defined as the resources accessed by individuals and groups through social connections, has been posited to be a social determinant of obesity. However, empirical evidence for this association has been inconsistent - namely, some studies have found a protective association while others have reported no correlation. We sought to conduct a systematic review on the relation between neighbourhood social capital and obesity, considering potential differences on the results based on the measures used and the covariates and mediators included in the studies. PRISMA statement guidelines were followed. Our results indicate that an association between neighbourhood social capital and obesity exists, but that it depends on the measures and covariates used in the study design. Understanding the role of social capital in the development and/or maintenance of obesity will require the use of strong methodological designs and a thorough conceptualization of how this relationship may arise. PMID- 30306718 TI - Revisiting the methionine salvage pathway and its paralogues. AB - Methionine is essential for life. Its chemistry makes it fragile in the presence of oxygen. Aerobic living organisms have selected a salvage pathway (the MSP) that uses dioxygen to regenerate methionine, associated to a ratchet-like step that prevents methionine back degradation. Here, we describe the variation on this theme, developed across the tree of life. Oxygen appeared long after life had developed on Earth. The canonical MSP evolved from ancestors that used both predecessors of ribulose bisphosphate carboxylase oxygenase (RuBisCO) and methanethiol in intermediate steps. We document how these likely promiscuous pathways were also used to metabolize the omnipresent by-products of S adenosylmethionine radical enzymes as well as the aromatic and isoprene skeleton of quinone electron acceptors. PMID- 30306720 TI - Mitochondrial disease and amyloidosis in a patient with familial polyneuropathy. PMID- 30306719 TI - New era of robotic surgical systems. AB - INTRODUCTION: To provide an update on the current status of robotic systems for surgery and the companies that produce these systems. METHODS: A non-systematic literature review was performed by using the PubMED/MEDLINE electronic search engines. Existing patents for robotic companies and devices were researched by using the Google search engine. RESULTS: Since the da Vinci Surgical System's patent expired, we have been able to predict the future of robotic companies based on the various robotic systems being developed. Currently, various attempts are being made to create consoles, robotic arms, cameras, handles, and instruments and to implement specific functions (e.g. haptic feedback, eye tracking). Herein, the benefits and limitations of each technology are identified, and likely future developments are described. CONCLUSIONS: The robotic surgical systems are continually being developed by various companies around the world. New technologies have been increasingly implemented to improve on the capabilities of previously established systems and surgical ergonomics. Future studies may need to evaluate the strengths and weaknesses of each robotic surgical system. PMID- 30306721 TI - Association of self-reported and cotinine-verified smoking status with incidence of metabolic syndrome in 47 379 Korean adults. AB - BACKGROUND: The relationship of cotinine-verified vs self-reported smoking status with the incidence of metabolic syndrome (MetS) is not known. This study investigated the effect of urinary cotinine-verified vs self-reported smoking status on incident MetS. METHODS: In all, 47 379 participants without MetS enrolled in the Kangbuk Samsung Health Study and Kangbuk Samsung Cohort Study between 2011 and 2012 (baseline) were included in this study and followed-up in 2014; median follow-up duration was 25 months. Cotinine-verified current smoking was defined as urinary cotinine concentrations >50 ng/mL. According to cotinine verified smoking status at baseline and follow-up, individuals were divided into four groups: never, new, former, and sustained smokers. RESULTS: The incidence of MetS in the never, former, new, and sustained smoking groups was 9.9%, 19.4%, 21.4%, and 18.7%, respectively. Multivariate Cox hazard regression analyses revealed that the relative risk (RR) for incident MetS in cotinine-verified former smokers was significantly increased compared with that in cotinine verified never smokers (RR 1.27; 95% confidence interval [CI] 1.16-1.37), especially in individuals exhibiting weight gain (>=2 kg). These results were consistent with those of self-reported smoking status. Baseline cotinine-verified current smoking (RR 1.09; 95% CI 1.03-1.15) and self-reported former (RR 1.10; 95% CI 1.02-1.18) and current (RR 1.15; 95% CI 1.07-1.23) smoking were also significantly associated with incident MetS. CONCLUSIONS: This large observational study showed that cotinine-verified and self-reported former smoking during follow-up increased the risk for incident MetS, especially in individuals exhibiting weight gain (>=2 kg). This suggests that weight control in former smokers would be very important to reduce the development of MetS. PMID- 30306722 TI - Glycemic variability assessed by continuous glucose monitoring and the risk of diabetic retinopathy in latent autoimmune diabetes of the adult and type 2 diabetes. AB - AIMS/INTRODUCTION: The relationship between glycemic variability (GV) and diabetic complications has gained much interest and remains under debate. Furthermore, the association of GV with diabetic complications has not been examined in latent autoimmune diabetes of the adult (LADA). Therefore, we evaluated the relationships among several metrics of GV with diabetic retinopathy (DR) in patients with LADA and type 2 diabetes mellitus. MATERIALS AND METHODS: A total of 192 patients with LADA and 2,927 patients with type 2 diabetes mellitus were enrolled. After continuous glucose monitoring for 72 h, three metrics of GV including standard deviation, coefficient of variation and mean amplitude of glycemic excursions were calculated. DR was assessed by fundus photography performed with a digital non-mydriatic camera. RESULTS: The prevalence of DR was 20.3 and 26.4% in LADA and type 2 diabetes mellitus patients (P < 0.001), respectively. Generally, LADA patients had fewer cardiometabolic risk factors than type 2 diabetes mellitus patients, and all GV metrics were significantly higher in LADA than in type 2 diabetes mellitus. In the multivariate logistic regression analysis, no metrics for GV were identified as independent risk factors of DR (standard deviation: P = 0.175; coefficient of variation: P = 0.769; mean amplitude of glycemic excursions: P = 0.388) in LADA. However, the standard deviation was significantly associated with DR (OR 1.15, P = 0.017) in patients with type 2 diabetes mellitus after adjusting for confounders. The independent relationships of coefficient of variation and mean amplitude of glycemic excursions with DR (P = 0.194 and P = 0.251, respectively) did not reach statistical significance in type 2 diabetes mellitus. CONCLUSIONS: GV is more strongly associated with DR in type 2 diabetes than in LADA, suggesting that different glucose-lowering strategies should be used for these two types of diabetes. PMID- 30306724 TI - Compassion is a key quality for palliative care teams. PMID- 30306723 TI - ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase. AB - INTRODUCTION: MSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology. METHODS: Bone marrow derived MSCs were exposed to ATP for 4 days, in the presence of 100 ng IFNgamma/mL. Intracellular expression of IDO in MSCs was assessed by FACS. Conditioned media from thus stimulated MSCs was analyzed for kynurenine content and its suppressive effect on lymphocyte proliferation. Apyrase or P2 * 7-receptor antagonist (AZ 11645373) were applied in order to inhibit ATP induced effect on MSCs. RESULTS: We demonstrate, that ATP at concentrations between 0.062 and 0.5 mM increases dose dependently the expression of IDO in MSCs with subsequent increased kynurenine concentrations within the supernatant at about 60%. This effect could be abolished completely in the presence of ATP degrading enzyme (apyrase) or when MSCs were pretreated with a P2 * 7-receptor antagonist (AZ 11645373). Consistently, supernatants from MSCs stimulated with ATP, inhibited lymphocyte proliferation from 65% to 16%. CONCLUSIONS: We characterized ATP as a DAMP family member responsible for necrosis-induced immunomodulation. Given the increased concentration of DAMPs within tumor tissue and the fact that DAMPs can act as chemotattractants to MSCs, our results have implications for therapeutic strategies targeting the tumor microenvironment. PMID- 30306725 TI - Postoperative chemotherapy had no prognostic effect on early-staged young ovarian cancer with unilateral resection. AB - Postoperative chemotherapy has been widely used in the treatment of early-staged ovarian cancer patients underwent unilateral resection, but the clinical decision mainly depends on the doctor's experience without a well-defined guideline. This study used propensity score matching to analyze the effect of postoperative chemotherapy for early-staged ovarian cancer patients underwent unilateral resection on prognosis. Patients of age 50 or younger than 50 with early-staged ovarian cancer were explored from the Surveillance, Epidemiology, and End Results program database during 2000-2018. Propensity score matching was used to randomize the dataset and reduce the selection biases. Univariate and multivariate cox proportional hazards models were utilized to estimate the necessity of chemotherapy. In univariate analysis of matched population, both the overall survival and cancer-specific survival analysis showed that chemotherapy had no effect on the prognosis of early-staged young ovarian cancer patients (Overall survival, P = 0.477; Cancer-specific survival, P = 0.950). In propensity adjusted multivariate analysis, chemotherapy still had no effect on both the overall and cancer-specific survival probability after excluding the effect of all the confounding factors (HR = 0.863, CI = 0.587-1.269, P = 0.455; HR = 1.009, CI = 0.633-1.607, P = 0.970). Our study suggested that postoperative chemotherapy is not necessary for early-staged young ovarian cancer patients with unilateral resection, as indicated by both the overall survival and cancer-specific survival. PMID- 30306726 TI - Cranial Pair II: The Optic Nerves. AB - The optic nerves (ONs), one of the 12 pairs of cranial nerves (Pair II), together with the olfactory and the cochlear nerves, are devoted to transmit sensory inputs. In particular, ONs convey visual information from the retina to the brain. In mammals, the ONs are bilateral structures that extend from the optic disc to the optic chiasm containing glial cells and retinal ganglion cells (RGCs) axons. RGCs are the only retinal neurons able to collect visual information and transmit it to the visual centers in the brain for its processing and integration with the rest of sensory inputs. During embryonic development, RGCs born in the retina extend their axons to exit the eye and follow a stereotypic path outlined by the transient expression of a wide set of guidance molecules. As the rest of central nervous system structures, the ONs are covered with myelin produced by oligodendrocytes and wrapped by the meninges. ON injuries or RGCs degenerative conditions may provoke partial or complete blindness because they are incapable of spontaneous regeneration. Here, we first review major advances on the current knowledge about the mechanisms underlying the formation of the ONs in mammals. Then, we discuss some of the human disorders and pathologies affecting the development and function of the ONs and finally we comment on the existing view about ON regeneration possibilities. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30306727 TI - Reinfection with Streptococcus suis analysed by whole genome sequencing. AB - A butcher with chronic dermatitis presented with a second episode of Streptococcus suis meningitis, 8 years after the first episode. To distinguish between reinfection and persistent carriage, we compared the two S. suis isolates using whole genome sequencing. We investigated whole genome sequences of the S. suis isolates by means of substitution rates and population structure of closely related strains in addition to available clinical information. Genome-wide analyses revealed an inserted region consisting of 12 genes in the first isolate and the calculated substitution rate between the isolates suggested infections were caused by highly similar, but unrelated strains. Continuous occupational exposure likely resulted in reinfection with S. suis in a butcher. PMID- 30306728 TI - National Cancer Database Comparison of Radical Cystectomy vs Chemoradiotherapy for Muscle-Invasive Bladder Cancer: Implications of Using Clinical vs Pathologic Staging. AB - PURPOSE: To test the hypothesis that bladder preservation therapy consisting of definitive chemoradiotherapy (chemoRT) results in similar overall survival rates to radical cystectomy/chemotherapy when balancing baseline patient characteristics and initial (preoperative) clinical stage. MATERIALS/METHODS: A total of 7,322 patients with stage II-IV, M0 bladder cancer who were treated with cystectomy/chemo (N = 5,664) or definitive chemoRT (N = 1,658) were identified from the National Cancer Database. Baseline patient characteristics were compared using Pearson's chi-square, Fisher's exact test, and Wilcoxon's rank sum tests. Cox regressions were used to investigate for variables significantly correlated with overall survival (OS). OS was compared between cystectomy/chemo vs chemoRT before and after propensity score matched pair analyses using Kaplan-Meier curves and log-rank tests. RESULTS: Patients who underwent cystectomy/chemo were significantly younger than ones treated with definitive chemoRT (mean age 63.7 vs 75.2; P < 0.001). Age, race, Charlson/Deyo Comorbidity Score (CDCS), clinical stage, insurance status, and type of facility significantly correlated with OS (P < 0.05 for all covariates). Patients treated with cystectomy/chemo were younger, healthier with better CDCS, and more likely treated at academic facilities. Before matched pair analyses, OS was significantly better when treated with cystectomy/chemo (3 year 56.4%; 5 year 45.9%) compared to chemoRT (3 year 47.3%; 5 year 33.2%) (P < 0.001); 28.6% of patients undergoing cystectomy were upstaged at the time of surgery. After matched pair analyses matching age, race, sex, CDCS, clinical (presurgical) stage, insurance, and facility type (N = 1,750), OS was no longer significantly different between cystectomy/chemo (3 year 52.1% and 5 year 41.0%) vs chemoRT (3 year 53.3% and 5 year 40.1%) (P = 0.5). CONCLUSIONS: Patients treated with cystectomy/chemo were significantly younger and healthier compared to those treated with chemoRT. Once these factors were accounted for in propensity score matched pair analyses using clinical stage, overall survival was not significantly different between cystectomy/chemo and an organ-sparing approach with definitive chemoRT. PMID- 30306729 TI - Real-life effectiveness of MP-AzeFlu in Irish patients with persistent allergic rhinitis, assessed by visual analogue scale and endoscopy. AB - INTRODUCTION: Most allergic rhinitis (AR) patients have moderate-to-severe, persistent disease. Meda Pharma's AzeFlu (MP-AzeFlu) combines intranasal azelastine hydrochloride (AZE) and fluticasone propionate (FP) in a novel formulation in a single device to treat AR. This prospective, noninterventional study sought to assess the effectiveness of MP-AzeFlu (one spray/nostril twice daily; 548 ug AZE/200 ug FP daily dose) in relieving AR symptom severity. METHODS: A visual analogue scale (VAS) was used prior to MP-AzeFlu treatment on days 0, 1, 3, 7, 14, 21, 28, 35, and 42 by 53 persistent AR (PER) patients seen in routine clinical practice in Ireland. An endoscopy was performed on days 0 and 28, and symptoms of edema, discharge, and redness were scored on a three-point scale (for both nostrils). RESULTS: Patients using MP-AzeFlu experienced rapid VAS score reduction from 73.4 mm (standard deviation [SD], 20.3) at Day 0 to 31.5 mm (SD, 25.0) at day 28 (P < 0.0001) to 28.1 mm (SD, 24.1) at day 42 (P < 0.0001), a 45.3-mm reduction. On average, patients achieved a clinically relevant VAS score cutoff of 50 mm before Day 7. Total endoscopy score decreased from 7.5 mm (SD, 3.1) at baseline to 3.5 mm (SD, 2.5) at Day 28. The incidence of severe edema on endoscopy decreased from 53.1% at baseline to 3.8% at Day 28. A similar reduction in the incidence of thick/mucousy discharge (from 28.3% to 4.8%) and severe redness (from 34.9% to 0%) was also observed. CONCLUSIONS: MP-AzeFlu provided effective, rapid control of PER as assessed by VAS in a real-world clinical setting in Ireland. Symptom improvement was observed at Day 1, sustained for 42 days, and associated with improved mucosal appearance after 28 days. These results confirm the safety of MP-AzeFlu and exceed the efficacy demonstrated in phase 3 clinical studies for controlling AR in PER patients. PMID- 30306730 TI - Cytomegalovirus infection in day care centres: A systematic review and meta analysis of prevalence of infection in children. AB - Maternofetal transmission of cytomegalovirus (CMV) is the most common infectious cause of congenital malformation in developed countries. Maternal infection often results from close contact with infected children, and this may occur in day care centres (DCCs). A systematic review of observational studies was conducted to examine the prevalence of CMV infection among children attending DCCs. Meta analysis using the random effect model was performed for studies including controls. Sources included PubMed, EMBASE (until August 2018), and references from identified publications. Inclusion criteria were studies reporting CMV infection prevalence among childcare children aged less than 7 years of age. Controls were children without childcare exposure. CMV infection was defined as viral excretion detected by culture, polymerase chain reaction, or CMV seropositivity. Twenty-eight publications including 8347 participants met the eligibility criteria. The pooled prevalence of CMV infection among children in childcare from all studies was 32% (95% CI 23-41). Within case-controlled studies, prevalence among children attending DCCs was 34% (95% CI 25-44), whereas prevalence among those without childcare exposure was 22% (95% CI 15-30). Meta analysis showed a significant association between DCC attendance and CMV infection (odds ratio 2.69, 95% CI 1.68-4.30; heterogeneity chi2 /df = 8; I2 = 84%, P < 0.00001). Attendance at DCCs is significantly associated with increased risk of childhood CMV infection. Prevention strategies to reduce risk of CMV infection of pregnant women and children should involve review of DCC exposure and consideration of preventative hygiene strategies. PMID- 30306732 TI - Writing, Graphic Codes, and Asynchronous Communication. AB - We present a theoretical framework bearing on the evolution of written communication. We analyze writing as a special kind of graphic code. Like languages, graphic codes consist of stable, conventional mappings between symbols and meanings, but (unlike spoken or signed languages) their symbols consist of enduring images. This gives them the unique capacity to transmit information in one go across time and space. Yet this capacity usually remains quite unexploited, because most graphic codes are insufficiently informative. They may only be used for mnemonic purposes or as props for oral communication in real time encounters. Writing systems, unlike other graphic codes, work by encoding a natural language. This allows them to support asynchronous communication in a more powerful and versatile way than any other graphic code. Yet, writing systems will not automatically unlock the capacity to communicate asynchronously. We argue that this capacity is a rarity in non-literate societies, and not so frequent even in literate ones. Asynchronous communication is intrinsically inefficient because asynchrony constrains the amount of information that the interlocutors share and limits possibilities for repair. This would explain why synchronous, face-to-face communication always fosters the development of sophisticated codes (natural languages), but similar codes for asynchronous communication evolve with more difficulties. It also implies that writing cannot have evolved, at first, for supporting asynchronous communication. PMID- 30306731 TI - Identification of a six-gene signature with prognostic value for patients with endometrial carcinoma. AB - Uterine corpus endometrial carcinoma (UCEC) is frequently diagnosed among women worldwide. However, there are different prognostic outcomes because of heterogeneity. Thus, the aim of the current study was to identify a gene signature that can predict the prognosis of patients with UCEC. UCEC gene expression profiles were first downloaded from the The Cancer Genome Atlas (TCGA) database. After data processing and forward screening, 11 390 key genes were selected. The UCEC samples were randomly divided into training and testing sets. In total, 996 genes with prognostic value were then examined by univariate Cox survival analysis with a P-value <0.01 in the training set. Next, using robust likelihood-based survival modeling, we developed a six-gene signature (CTSW, PCSK4, LRRC8D, TNFRSF18, IHH, and CDKN2A) with a prognostic function in UCEC. A prognostic risk score system was developed by multivariate Cox proportional hazard regression based on this six-gene signature. According to the Kaplan-Meier curve, patients in the high-risk group had significantly poorer overall survival (OS) outcomes than those in the low-risk group (log-rank test P-value <0.0001). This signature was further validated in the testing dataset and the entire TCGA dataset. In conclusion, we conducted an integrated study to develop a six-gene signature for the prognostic prediction of patients with UCEC. Our findings may provide novel biomarkers for prognosis and have significant implications in the understanding of therapeutic targets for UCEC. PMID- 30306733 TI - Obturator nerve ganglion cyst: masquerading as groin hernia. PMID- 30306735 TI - Endothelial Cell Lineage Analysis Does Not Provide Evidence for EMT in Adult Valve Homeostasis and Disease. AB - Epithelial-to-mesenchymal transition (EMT) enables stationary epithelial cells to exhibit migratory behavior and is the key step that initiates heart valve development. Recent studies suggest that EMT is reactivated in the pathogenesis of myxomatous valve disease (MVD), a condition that involves the progressive degeneration and thickening of valve leaflets. These studies have been limited to in vitro experimentation and reliance on histologic costaining of epithelial and mesenchymal markers as evidence of EMT in mouse and sheep models of valve disease. However, longitudinal analysis of cell lineage origins and potential pathogenic or reparative contributions of newly generated mesenchymal cells have not been reported previously. In this study, a genetic lineage tracing strategy was pursued by irreversibly labeling valve endothelial cells in the Osteogenesis imperfecta and Marfan syndrome mouse models to determine whether they undergo EMT during valve disease. Tie2-CreER T2 and Cdh5(PAC)-CreER T2 mouse lines were used in combination with colorimetric and fluorescent reporters for longitudinal assessment of endothelial cells. These lineage tracing experiments showed no evidence of EMT during adult valve homeostasis or valve pathogenesis. Additionally, CD31 and smooth muscle alpha-actin (alphaSMA) double-positive cells, used as an indicator of EMT, were not detected, and levels of EMT transcription factors were not altered. Interestingly, contrary to the endothelial cell-specific Cdh5(PAC)-CreER T2 driver line, Tie2-CreER T2 lineage derived cells in diseased heart valves also included CD45+ leukocytes. Altogether, our data indicate that EMT is not a feature of valve homeostasis and disease but that increased immune cells may contribute to MVD. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30306736 TI - HNK-1 in Morphological Study of Development of the Cardiac Conduction System in Selected Groups of Sauropsida. AB - Human natural killer (HNK)-1 antibody is an established marker of developing cardiac conduction system (CCS) in birds and mammals. In our search for the evolutionary origin of the CCS, we tested this antibody in a variety of sauropsid species (Crocodylus niloticus, Varanus indicus, Pogona vitticeps, Pantherophis guttatus, Eublepharis macularius, Gallus gallus, and Coturnix japonica). Hearts of different species were collected at various stages of embryonic development and studied to map immunoreactivity in cardiac tissues. We performed detection on alternating serial paraffin sections using immunohistochemistry for smooth muscle actin or sarcomeric actin as myocardial markers, and HNK-1 to visualize overall staining pattern and then positivity in specific myocyte populations. We observed HNK-1 expression of various intensity distributed in the extracellular matrix and mesenchymal cell surface of cardiac cushions in most of the examined hearts. Strong staining was found in the cardiac nerve fibers and ganglia in all species. The myocardium of the sinus venosus and the atrioventricular canal exhibited transitory patterns of expression. In the Pogona and Crocodylus hearts, as well as in the Gallus and Coturnix ones, additional expression was detected in a subset of myocytes of the (inter)ventricular septum. These results support the use of HNK-1 as a conserved marker of the CCS and suggest that there is a rudimentary CCS present in developing reptilian hearts. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30306734 TI - Role of serum EBV-VCA IgG detection in assessing gastric cancer risk and prognosis in Northern Chinese population. AB - The study aimed to investigate the role of serum EBV-VCA IgG in assessing gastric cancer (GC) risk and prognosis. A total of 1790 Northern Chinese participants with pathologically confirmed disease underwent EBV-VCA IgG serologic testing using enzyme-linked immunosorbent assay (ELISA), including 821 controls, 410 atrophic gastritis (AG) patients, and 559 GC patients. We found that positive EBV VCA IgG was significantly associated with GC and its precursor, conferring a 1.55 and 1.36-fold increased risk of GC and AG, respectively (P = 0.001, 95% CI = 1.21-1.99; P = 0.011, 95% CI = 1.07-1.72, respectively). The risk effects were more remarkable in younger, female, and Helicobacter pylori-negative individuals than in older, male, and H. pylori-positive individuals. EBV-VCA IgG-positive subjects had a lower PGI/II ratio than EBV-VCA IgG-negative subjects (median 8.0 vs 8.8, P = 0.001), especially those in the H. pylori-positive (median 6.1 vs 6.8, P = 0.027) and GC subgroups (median 6.4 vs 7.9, P = 0.020). In the intestinal GC subgroup, the survival of EBV-VCA IgG-positive patients was worse than that of EBV-VCA IgG-negative patients (P = 0.041, HR = 2.45, 95% CI = 1.04 5.78). Our study suggests that EBV-VCA IgG seropositivity has potential in predicting the risk of GC and its precursor as well as the prognosis of histologically classified GC. PMID- 30306737 TI - Wireless vitals - proof of concept for wireless patient monitoring in an emergency department setting. AB - Vital sign assessment is a common task in emergency medicine, but resources for continuous monitoring are restricted, data is often recorded manually, and entangled wires cause frustration. Therefore, we designed a small, wireless photoplethysmographic device capable of continuously assessing pulse, respiratory frequency and oxygen saturation on the sternum and tested the performance and feasibility in an emergency department setting. Fifty (56.3 +/- 20.2 years), consenting emergency patients (29 male) were recruited. Heart rate, respiratory rate and oxygen saturation were recorded simultaneously using the device and standard monitoring equipment. Data was compared using Bland-Altman plotting (heart rate, respiratory rate) and mean difference (oxygen saturation). The bias for heart- and respiratory rate was 0.4 (limits of agreements -11.3, 12.2 and 6.1, 7.0). Mean difference for oxygen saturation was -0.21 +/- 2.35%. This may be the first wireless device to use photoplethysmography on the sternum for vital sign assessment. We noted good agreement with standard monitors, but lack of standardization in data processing between monitoring systems may limit the generalizability of these findings. Although further improvements are needed, the feasibility of this approach provides proof of concept for a new paradigm of large scale, wireless patient monitoring. This article is protected by copyright. All rights reserved. PMID- 30306739 TI - PhyMet2 : a database and toolkit for phylogenetic and metabolic analyses of methanogens. PMID- 30306740 TI - Microbial chemolithotrophy: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 30306738 TI - Strong impact of sulfotransferases on DNA adduct formation by 4-aminobiphenyl in bladder and liver in mice. AB - Bladder cancer risk is 3-4 times higher in men than women, but the reason is poorly understood. In mice, male bladder is also more susceptible than female bladder to 4-aminobiphenyl (ABP), a major human bladder carcinogen; however, female liver is more susceptible than male liver to ABP. We investigated the role of sulfotransferase (Sult) in gender-related bladder and liver susceptibility to ABP. Sulfation reactions of aromatic amine bladder carcinogens catalyzed by Sult may generate highly unstable and toxic metabolites. Therefore, liver Sult may decrease bladder exposure to carcinogens by promoting their toxic reactions in the liver. Notably, the expression of several liver Sults is suppressed by androgen in male mice. Here, we show that two Sults are critical for gender related bladder susceptibility to ABP in mice. We measured tissue level of N (deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP), a principal ABP-DNA adduct, as readout of tissue susceptibility to ABP. We identified Sutl1a1 and to a lesser extent Sult1d1 as Sults that promote dG-C8-ABP formation in hepatic cells. In mice, gender gap in bladder susceptibility to ABP was narrowed by knocking out Sult1a1 and was almost totally eliminated by knocking out both Sutl1a1 and Sult1d1. This was accompanied by dramatic decrease in ABP genotoxicity in the liver (>97%). These results show the strong impact of the Sults on bladder and liver susceptibility to a human carcinogen. Because liver expression of both Sult1a1 and Sutl1d1 is suppressed by androgen in male mice, our results suggest that androgen renders bladder more exposed to ABP in male mice by suppressing Sult-mediated ABP metabolism in liver, which increases bladder delivery of carcinogenic metabolites. PMID- 30306742 TI - Is a Longitudinal Trajectory Helpful in Identifying Phenotypes in Asthma? PMID- 30306741 TI - Modification of American Joint Committee on cancer prognostic groups for renal cell carcinoma. AB - BACKGROUND: To compare the predictive value of the current AJCC stage grouping for renal cell carcinoma (RCC) to our modifications. PATIENTS AND METHODS: A total of 2120 patients with RCC from Fudan University Shanghai Cancer Center (FUSCC) database and 74 506 counterparts from SEER database were included. Cox regression was used to calculate the relative impacts between prognostic groups. The predictive accuracy of overall survival (OS) was assessed using the concordance index (C-index), which was compared by likelihood ratio test. RESULTS: In FUSCC cohort, the 5-year-OS rate for T3N0M0 patients was higher than T1-3N1M0 (72.7% vs 38.1%). The 5-year-OS rate for T4N0M0 was 36.2%, which was close to T1-3N1M0 but not to T4N1M0 (0%) and TanyNanyM1 (12.6%). The elements of AJCC groups were regrouped according to the ranks of hazard ratios. The modified stages II (T3N0M0), III (T1-3N1M0, T4N0M0), and IV (T4N1M0, TanyNanyM1) exhibited greater survival stratification than AJCC groups. The modifications were validated in SEER cohort and yielded similar survival outcomes. The predictive accuracy of OS in modified prognostic groups was significantly higher than AJCC groups in stages II-IV subgroups in both FUSCC (C-index: 0.801 vs 0.779, P < 0.001) and SEER cohort (C-index: 0.770 vs 0.764, P < 0.001). CONCLUSIONS: The modified AJCC prognostic groups for RCC provided significantly improved survival prediction compared with the 8th AJCC edition. A precise risk stratification of modified stages II-IV disease provides an important basis for risk-equivalent treatment recommendation. PMID- 30306743 TI - Probiotics as a Potential Immunomodulating Pharmabiotics in Allergic Diseases: Current Status and Future Prospects. AB - The prevalence of allergic disorders has dramatically increased over the past decade, particularly in developed countries. Apart from gastrointestinal disorders, neoplasia, genital and dermatological diseases etc., dysregulation of gut microbiota (dysbiosis) has also been found to be associated with increased risk of allergies. Probiotics are increasingly being employed to correct dysbiosis and, in turn, to modulate allergic diseases. However, several factors like strain variations and effector metabolites or component of them in a bacterial species can affect the efficacy of those as probiotics. On the other hand, host variations like geographical locations, food habits etc. could also affect the expected results from probiotic usage. Thus, there is a glaring deficiency in our approach to establish probiotics as an irrefutable treatment avenue for suitable disorders. In this review, we explicate on the reported probiotics and their effects on certain allergic diseases like atopic dermatitis, food allergy and asthma to establish their utility. We propose possible measures like elucidation of effector molecules and functional mechanisms of probiotics towards establishing probiotics for therapeutic use. Certain probiotics studies have led to very alarming outcomes which could have been precluded, had effective guidelines been in place. Thus, we also propose ways to secure the safety of probiotics. Overall, our efforts tend to propose necessary discovery and quality assurance guidelines for developing probiotics as potential immunomodulatory 'Pharmabiotics.' PMID- 30306745 TI - Lung Function Trajectory Types in Never-Smoking Adults With Asthma: Clinical Features and Inflammatory Patterns. AB - PURPOSE: Asthma is a heterogeneous disease that responds to medications to varying degrees. Cluster analyses have identified several phenotypes and variables related to fixed airway obstruction; however, few longitudinal studies of lung function have been performed on adult asthmatics. We investigated clinical, demographic, and inflammatory factors related to persistent airflow limitation based on lung function trajectories over 1 year. METHODS: Serial post bronchodilator forced expiratory volume (FEV) 1% values were obtained from 1,679 asthmatics who were followed up every 3 months for 1 year. First, a hierarchical cluster analysis was performed using Ward's method to generate a dendrogram for the optimum number of clusters using the complete post-FEV1 sets from 448 subjects. Then, a trajectory cluster analysis of serial post-FEV1 sets was performed using the k-means clustering for the longitudinal data trajectory method. Next, trajectory clustering for the serial post-FEV1 sets of a total of 1,679 asthmatics was performed after imputation of missing post-FEV1 values using regression methods. RESULTS: Trajectories 1 and 2 were associated with normal lung function during the study period, and trajectory 3 was associated with a reversal to normal of the moderately decreased baseline FEV1 within 3 months. Trajectories 4 and 5 were associated with severe asthma with a marked reduction in baseline FEV1. However, the FEV1 associated with trajectory 4 was increased at 3 months, whereas the FEV1 associated with trajectory 5 was persistently disturbed over 1 year. Compared with trajectory 4, trajectory 5 was associated with older asthmatics with less atopy, a lower immunoglobulin E (IgE) level, sputum neutrophilia and higher dosages of oral steroids. In contrast, trajectory 4 was associated with higher sputum and blood eosinophil counts and more frequent exacerbations. CONCLUSIONS: Trajectory clustering analysis of FEV1 identified 5 distinct types, representing well-preserved to severely decreased FEV1. Persistent airflow obstruction may be related to non-atopy, a low IgE level, and older age accompanied by neutrophilic inflammation and low baseline FEV1 levels. PMID- 30306746 TI - Obesity-Associated Metabolic Signatures Correlate to Clinical and Inflammatory Profiles of Asthma: A Pilot Study. AB - PURPOSE: Obesity is associated with metabolic dysregulation, but the underlying metabolic signatures involving clinical and inflammatory profiles of obese asthma are largely unexplored. We aimed at identifying the metabolic signatures of obese asthma. METHODS: Eligible subjects with obese (n = 11) and lean (n = 22) asthma underwent body composition and clinical assessment, sputum induction, and blood sampling. Sputum supernatant was assessed for interleukin (IL)-1beta, -4, -5, -6, -13, and tumor necrosis factor (TNF)-alpha, and serum was detected for leptin, adiponectin and C-reactive protein. Untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolic profiles in sputum, serum and peripheral blood monocular cells (PBMCs) were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway topology enrichment analysis. The differential metabolites were further validated by correlation analysis with body composition, and clinical and inflammatory profiles. RESULTS: Body composition, asthma control, and the levels of IL-1beta, 4, -13, leptin and adiponectin in obese asthmatics were significantly different from those in lean asthmatics. OPLS-DA analysis revealed 28 differential metabolites that distinguished obese from lean asthmatic subjects. The validation analysis identified 18 potential metabolic signatures (11 in sputum, 4 in serum and 2 in PBMCs) of obese asthmatics. Pathway topology enrichment analysis revealed that cyanoamino acid metabolism, caffeine metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, pentose phosphate pathway in sputum, and glyoxylate and dicarboxylate metabolism, glycerolipid metabolism and pentose phosphate pathway in serum are suggested to be significant pathways related to obese asthma. CONCLUSIONS: GC-TOF-MS-based metabolomics indicates obese asthma is characterized by a metabolic profile different from lean asthma. The potential metabolic signatures indicated novel immune-metabolic mechanisms in obese asthma with providing more phenotypic and therapeutic implications, which needs further replication and validation. PMID- 30306744 TI - KAAACI Evidence-Based Clinical Practice Guidelines for Chronic Cough in Adults and Children in Korea. AB - Chronic cough is common in the community and causes significant morbidity. Several factors may underlie this problem, but comorbid conditions located at sensory nerve endings that regulate the cough reflex, including rhinitis, rhinosinusitis, asthma, eosinophilic bronchitis, and gastroesophageal reflux disease, are considered important. However, chronic cough is frequently non specific and accompanied by not easily identifiable causes during the initial evaluation. Therefore, there are unmet needs for developing empirical treatment and practical diagnostic approaches that can be applied in primary clinics. Meanwhile, in referral clinics, a considerable proportion of adult patients with chronic cough are unexplained or refractory to conventional treatment. The present clinical practice guidelines aim to address major clinical questions regarding empirical treatment, practical diagnostic tools for non-specific chronic cough, and available therapeutic options for chronic wet cough in children and unexplained chronic cough in adults in Korea. PMID- 30306747 TI - Pollen-Food Allergy Syndrome in Korean Pollinosis Patients: A Nationwide Survey. AB - PURPOSE: Pollen-food allergy syndrome (PFAS) is an immunoglobulin E (IgE) mediated allergy in pollinosis patients caused by raw fruits and vegetables and is the most common food allergy in adults. However, there has been no nationwide study on PFAS in Korea. In this study, we investigated the prevalence and clinical characteristics of PFAS in Korea. METHODS: Twenty-two investigators participated in this study, in which patients with allergic rhinoconjunctivitis and/or bronchial asthma with pollen allergy were enrolled. The questionnaires included demographic characteristics, a list of fruits and vegetables, and clinical manifestations of food allergy. Pollen allergy was diagnosed by skin prick test and/or measurement of the serum level of specific IgE. RESULTS: A total of 648 pollinosis patients were enrolled. The prevalence of PFAS was 41.7% (n = 270). PFAS patients exhibited cutaneous (43.0%), respiratory (20.0%), cardiovascular (3.7%) or neurologic symptoms (4.8%) in addition to oropharyngeal symptoms. Anaphylaxis was noted in 8.9% of the PFAS patients. Seventy types of foods were linked to PFAS; e.g., peach (48.5%), apple (46.7%), kiwi (30.4%), peanut (17.4%), plum (16.3%), chestnut (14.8%), pineapple (13.7%), walnut (14.1%), Korean melon (12.6%), tomato (11.9%), melon (11.5%) and apricot (10.7%). Korean foods such as taro/taro stem (8.9%), ginseong (8.2%), perilla leaf (4.4%), bellflower root (4.4%), crown daisy (3.0%), deodeok (3.3%), kudzu root (3.0%) and lotus root (2.6%) were also linked to PFAS. CONCLUSIONS: This was the first nationwide study of PFAS in Korea. The prevalence of PFAS was 41.7%, and 8.9% of the PFAS patients had anaphylaxis. These results will provide clinically useful information to physicians. PMID- 30306748 TI - Decreased CRTH2 Expression and Response to Allergen Re-stimulation on Innate Lymphoid Cells in Patients With Allergen-Specific Immunotherapy. AB - PURPOSE: Group 2 innate lymphoid cells (ILC2s) have been implicated in the pathogenesis of allergic disease. However, the effect of allergen-specific immunotherapy (AIT) on ILCs remains to be clarified. The aim of this study was to evaluate the levels of ILC subsets in allergic rhinitis (AR) patients in response to house dust mite (HDM)-specific immunotherapy. METHODS: We enrolled 37 AR patients undergoing AIT (16 responders and 11 non-responders) for 2 years, 35 HDM AR patients and 28 healthy subjects. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to identify ILC subsets. Stimulation of ILC2s with recombinant allergen-specific protein was used to determine ILC2's activation (CD69 expression). RESULTS: Responder AIT patients and healthy subjects had a decreased frequency of circulating ILC2s compared to non-responder AIT and AR patients. Conversely, ILC1s from responder AIT patients and healthy subjects showed increased frequency compared to non-responder AIT and AR patients. The frequency of ILC3s natural cytotoxicity receptor (NCR)+ and NCR- in responder AIT patients was significantly lower compared to AR patients and healthy subjects. The ILC1: ILC2 proportion in responder AIT patients was similar to that of healthy subjects. PBMCs from patients who were responders to AIT had a significantly lower expression of the activation marker CD69 on ILC2s in response to allergen re-stimulation compared to AR patients, but no difference compared to non-responder AIT patients and healthy subjects. CONCLUSIONS: We propose that AIT might affect ILC responses. The activation of ILC2s was reduced in AR patients treated with AIT. Our results indicate that a relative ILC1/ILC2 skewed response is a possible key to successful AIT. PMID- 30306749 TI - Efficacy and Safety of Sublingual Immunotherapy in Elderly Rhinitis Patients Sensitized to House Dust Mites. AB - PURPOSE: This study aims to determine the efficacy and safety of house dust mite (HDM)-sublingual immunotherapy (SLIT) in elderly patients with AR. METHODS: A total of 45 patients aged >= 60 years with HDM-induced AR who had >= 3 A/H ratio on skin prick test and/or >= 0.35 IU/L to both Dermatophagoides farinae and Dermatophagoides pteronyssinus by ImmunoCAP were enrolled in 4 university hospitals. To evaluate additional effects of HDM-SLIT, they were randomized to the SLIT-treated group (n = 30) or control group (n = 15). Rhinoconjunctivitis total symptom score (RTSS), rhinoscopy score, Korean rhinoconjunctivitis quality of life questionnaire, rhinitis control assessment test, asthma control test scores, and adverse reactions, were assessed at the first visit (V1) and after 1 year of treatment (V5); for immunological evaluation, serum levels of HDM specific immunoglobulin A/IgE/IgG1/IgG4 antibodies and basophil response to HDMs were compared between V1 and V5 in both groups. RESULTS: There were no significant differences in demographics, RTSS, skin reactivity to HDMs, or serum total/specific IgE levels to HDMs (P < 0.05, respectively) between the 2 groups. Nasal symptom score and RTSS decreased significantly at year 1 in the 2 groups (P < 0.05). There were no significant differences in percent decrease in nasal symptom score and RTSS at year 1 between the 2 groups (P < 0.05); however, rhinoscopic nasal symptom score decreased significantly in the SLIT-treated group (P < 0.05). Immunological studies showed that serum specific IgA levels (not specific IgE/IgG) and CD203c expression on basophils decreased significantly at V5 in the SLIT-treated group (P = 0.011 and P = 0.001, respectively), not in the control group. The control group required more medications compared to the treatment group, but there were no differences in adverse reactions. CONCLUSIONS: It is suggested that HDM-SLIT for 1 year could induce symptom improvement and may induce immunomodulation in elderly rhinitis patients. PMID- 30306750 TI - Montelukast Reduces Serum Levels of Eosinophil-Derived Neurotoxin in Preschool Asthma. AB - PURPOSE: Several markers for eosinophilic inflammation have been proposed to predict response to asthma treatment. However, definitive criteria for treatment decisions have not yet been established. We investigate a potentially useful relatively non-invasive biomarker, eosinophil-derived neurotoxin (EDN), to predict favorable responses to budesonide or montelukast, common treatment for children with asthma. METHODS: Young children (1 to 6 years old) were enrolled in this randomized, parallel, 2-group, open-label trial. Criteria for eligibility included: 1) being symptomatic during the run-in period; and 2) having a serum EDN (sEDN) level >= 53 ng/mL, with positive specific immunoglobulin E to house dust mite. Eligible patients were randomly placed into 2 groups: the BIS group received budesonide inhalation suspension (BIS) 0.5 mg once daily; the MONT group received montelukast 4 mg once daily. Ineligible patients were invited to receive montelukast 4 mg once daily (OBS group). Treatment period was 12 weeks. RESULTS: Asthma control days increased significantly in the BIS and MONT groups (P < 0.000) over the 12-week study period. There was no significant change in sEDN in the BIS group but there was a significant decrease in the MONT group (P < 0.000). Patients in the OBS group with high EDN levels (< 53 ng/mL) showed a significant decrease due to MONT treatment (P = 0.023). Rescue medication usage significantly decreased in the BIS and MONT groups (P < 0.000). CONCLUSIONS: EDN is a useful relatively non-invasive biomarker for predicting responses to montelukast and budesonide treatment of preschool children with beta2-agonist responsive recurrent wheeze and multiple-trigger wheeze (Trial registry at UMIN Clinical Trials Registry, UMIN000008335). PMID- 30306751 TI - Differential Hrd1 Expression and B-Cell Accumulation in Eosinophilic and Non eosinophilic Chronic Rhinosinusitis With Nasal Polyps. AB - PURPOSE: Hrd1 has recently emerged as a critical regulator of B-cells in autoimmune diseases. However, its role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remains largely unexplored. This study aimed to examine Hrd1 expression and B-cell accumulation and their possible roles in CRSwNP. METHODS: Quantitative real-time polymerase chain reaction, immunohistochemistry, enzyme-linked immunosorbent assay and Western blotting were used to assess gene and protein expression in nasal tissue extracts. Cells isolated from nasal tissues and peripheral blood mononuclear cells were characterized by flow cytometry. Local antibody production was measured in tissue extracts with a Bio-Plex assay. Additionally, changes in Hrd1 expression in response to specific inflammatory stimuli were measured in cultured dispersed polyp cells. RESULTS: Nasal polyps (NPs) from patients with eosinophilic CRSwNP (ECRS) had increased levels of Hrd1, B-cells and plasma cells compared with NPs from patients with non-eosinophilic CRSwNP (non-ECRS) or other control subjects (P < 0.05). The average Hrd1 levels in B-cells in NPs from ECRS patients were significantly higher than those from non-ECRS patients and control subjects (P < 0.05). NPs also contained significantly increased levels of several antibody isotypes compared with normal controls (P < 0.05). Interestingly, Hrd1 expression in cultured polyp cells from ECRS patients, but not non-ECRS patients, was significantly increased by interleukin-1beta, lipopolysaccharide and Poly(I:C) stimulation, and inhibited by dexamethasone treatment (P < 0.05). CONCLUSIONS: Differential Hrd1 expression and B-cell accumulation between the ECRS and non ECRS subsets suggests that they can exhibit distinct pathogenic mechanisms and play important roles in NP. PMID- 30306753 TI - Erratum: Seasonal Cycle and Relationship of Seasonal Rhino- and Influenza Virus Epidemics With Episodes of Asthma Exacerbation in Different Age Groups. AB - This corrects the article on p. 517 in vol. 9, PMID: 28913991. PMID- 30306752 TI - Serum Periostin Is Negatively Correlated With Exposure to Formaldehyde and Volatile Organic Compounds in Children. AB - Epidemiological studies have shown that exposure to tobacco smoke causing irritation and inflammation in the airways tends to reduce serum periostin concentrations in adults. We now investigate prospective cross-sectional study on 135 Korean students aged 7 years in the first grade who were participating in the Seongnam Atopy Project for Children's Happiness 2016 (SAP2016) cohort. To the best of our knowledge, this is the first study to show significant inverse correlations between serum periostin concentration and exposure to xylene and formaldehyde in children. Our findings suggested the need for caution in using the serum periostin level as a marker for allergic diseases, since exposure to volatile organic compounds and formaldehyde may confound the interpretation of these results. PMID- 30306755 TI - Parameterized level-set based pharmacokinetic fluorescence optical tomography using the regularized Gauss-Newton filter. AB - Pharmacokinetic tomography is emerging as an important methodology for detecting abnormalities in tissue based upon spatially varying estimation of the pharmacokinetic rates governing the leakage of an injected fluorophore between blood plasma and tissue. We present a shape-based reconstruction framework of a compartment-model based formulation of this dynamic fluorescent optical tomography problem to solve for the pharmacokinetic rates and concentrations of the fluorophore from time-varying log intensity measurements of the optical signal. The compartment-model based state variable model is set up in a radial basis function parameterized level set setting. The state (concentrations) and (pharmacokinetic) parameter estimation problem is solved with an iteratively regularized Gauss-Newton filter in a trust-region framework. Reconstructions obtained using this scheme for noisy data obtained from cancer mimicking numerical phantoms of near/sub-cm sizes show a good localization of the affected regions and reasonable estimates of the pharmacokinetic rates and concentration curves. PMID- 30306756 TI - [Vaccination refusal; the need for positive influence strategies]. AB - Although vaccinating seems self-evident, the immunization coverage in the Netherlands is decreasing. This decrease is often attributed to a lack of knowledge amongst the public. We argue, however, that it is rather a lack of trust that drives this reduction in uptake. In this article we discuss the role that trust, or rather a lack thereof, plays in vaccination refusal. We underpin our argument with a recent exploration of the way in which vaccination programmes are framed in newspaper articles and on internet forums. We show the importance of rumours and shared experiences (i.e. social influencing) in parents' decision making process when they consider whether or not to vaccinate their child. To conclude, we argue for the development of positive influence strategies to counteract negative influences from outside the medical profession. PMID- 30306754 TI - Erratum: Tolerogenic Dendritic Cells Reduce Airway Inflammation in a Model of Dust Mite Triggered Allergic Inflammation. AB - This corrects the article on p. 406 in vol. 10, PMID: 29949837. PMID- 30306757 TI - [Complete recovery from depression is the exception rather than the rule: prognosis of depression beyond diagnostic boundaries]. AB - OBJECTIVE: To investigate whether the course of depression changes when (a) follow-up duration is longer and (b) in addition to depression other mood and anxiety disorders are considered as outcome measures. DESIGN: Longitudinal observational cohort study. METHOD: We selected patients from the Netherlands Study of Depression and Anxiety (NESDA) who had active depression at baseline (n=903) and for whom data from the 2, 4 and/or 6 year measurements were available. Using DSM-IV diagnoses and data from the 'Life chart interview', we divided participants in one of the following four course categories: (1) recovered (no diagnosis at 2-year measurement or later), (2) recurring without chronic episodes, (3) recurring with chronic episodes or (4) consistent chronic depression since baseline. We looked at the distribution of patients over the course categories from a short, diagnostically narrow perspective (over 2 years, only looking at depression) to a long, diagnostically broad perspective (over 6 years, looking at depression, dysthymia, hypomania, mania and anxiety). RESULTS: In the short, diagnostically narrow perspective, 58% of participants had recovered and 21% met the criteria for a chronic episode. In the long, diagnostically broad perspective however, only 17% had recovered while 55% had chronic episodes. CONCLUSION: Monitoring patients with depression over a longer period and with broader outcome measures (depression and related psychiatric disorders belonging to the mood disorder spectrum) shows that the course of depression is unfavourable and chronic for the majority. Conceptualising depression as a defined episodic disorder underestimates the severity of the prognosis for many patients and, as a consequence, the type of care indicated. PMID- 30306758 TI - [Quantifying the impact of mass vaccination programmes on notified cases in the Netherlands]. AB - OBJECTIVE: To quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. DESIGN: Estimates based on model projections of historical morbidity data. METHOD: We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. RESULTS: In the first 13 years of mass vaccinations, case notifications declined rapidly with 18,900 (95%-CI: 12,000-28,600) notified cases of diphtheria averted, 5100 (95%-CI: 2200-13,500) cases of poliomyelitis, and 1800 (95%-CI: 1000-3200) cases of mumps. Vaccination of 11-year-old girls against rubella averted 13700 (95%-CI: 1400-38,300) cases, while universal rubella vaccination averted 700 (95% CI: 80-2300) cases. CONCLUSION: These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands. PMID- 30306759 TI - [A trial to study the effect of influenza vaccination in the elderly: ethical, feasible and badly needed]. AB - Based on current research, there are no valid reasons to assume that influenza vaccination of people aged 60 and over without any other medical indications, in the context of the national programme of influenza prevention, leads to significant, relevant and cost-effective health benefits. In view of the pressure on health care budgets and the decreasing social willingness to vaccinate, it is of great and urgent importance that the actual effect of influenza vaccination is quantified in a double-blind placebo-controlled randomized trial (RCT) with relevant outcome measures, which does not suffer from the methodological shortcomings of the few previous studies. In order to demonstrate a 10% reduction in hospitalisation for respiratory infections, this RCT should include approximately 100,000 subjects and follow these participants for three years. We consider such a trial feasible in the Dutch situation. PMID- 30306760 TI - [Risk of thrombosis in reactive thrombocytosis]. AB - Reactive thrombocytosis (RT; thrombocyte count: > 450 x 109/l) is a condition in which an increase in platelet production, stimulated by cytokines in the bone marrow, is secondary to some condition or circumstance. Although RT does often occur in children, the risk of thromboembolic complications is negligible in this group if they have no other risk factors for thrombosis. In the absence of additional risk factors for thrombosis it seems as though RT in adults does not predispose them to thromboembolic complications either. Patients with RT caused by a non-myeloproliferative malignancy do have an increased risk of thromboembolic complications; antithrombotic prophylaxis might be effective in this group, but there is no scientific evidence for this. We advise a watch-and wait approach in children and adults with RT who have no other risk factors for thromboembolism, even in patients with extreme thrombocytosis (thrombocyte count: > 1000 x 109/l). In patients who do have an increased risk of thromboembolic complications we advise tailoring prescription or non-prescription of antithrombotic prophylaxis to the individual patient. PMID- 30306761 TI - [Adherence to the 2015 Dutch dietary guidelines and risk of ten non-communicable diseases and mortality in the Rotterdam Study]. AB - OBJECTIVE: We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. DESIGN: We studied 9,701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45 years and over. METHOD: Dietary intake was assessed at baseline with a food frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (>=200g/d), fruit (>=200g/d), whole grains (>=90g/d), legumes (>=135g/wk), nuts (>=15g/d), dairy (>=350g/d), fish (>=100g/wk), tea (>=450mL/d), ratio whole-grains:total grains (>=50%), ratio unsaturated fats & oils:total fats (>=50%), red and processed meat (<300g/wk), sugar-containing beverages (<150mL/d), alcohol (<10 g/d) and salt (<=6g/d). Total adherence was calculated as sum-score of the adherence to the individual items (0 14). Information on disease incidence and all-cause mortality was collected during a median follow-up period of 13.5 years (range 0-27.0). RESULTS: Using Cox proportional-hazards models adjusted for confounders, we observed that every additional component adhered to was associated with a 3% lower mortality risk (HR=0.97,95% CI=0.95 - 0.98), lower risk of stroke (HR=0.95,95%CI 0.92;0.99), chronic obstructive pulmonary disease (HR=0.94,95%CI=0.91-0.98), colorectal cancer (HR=0.90,95%CI=0.84;0.96), and depression (HR=0.97,95%CI=0.95-0.999), but not with incidence of coronary heart disease, type 2 diabetes, heart failure, lung cancer, breast cancer, or dementia. CONCLUSION: Adherence to the Dutch dietary guidelines was associated with a lower mortality risk and a lower risk of developing some but not all of the chronic diseases on which the guidelines were based. PMID- 30306762 TI - [Neurotropic disease after vaccination against yellow fever]. AB - Millions of people are vaccinated each year to prevent morbidity and mortality by numerous bacterial and viral infections. Safety of vaccines is an important topic of discussion, especially because of the prophylactic nature of vaccination. Luckily, serious adverse events are rare. However, low incidence results in low awareness, and thus can make identification of these post-vaccination diseases difficult for healthcare workers. In the Netherlands, serious adverse events caused by travel vaccinations are especially rare, because of the low immunisation coverage compared to endemic countries. We present two Dutch cases that were diagnostically challenging. Both turned out to suffer from a serious adverse event of vaccination with live attenuated yellow fever virus, so-called yellow fever associated neurotropic disease (YEL-AND). With this article we hope to improve awareness of post-vaccination diseases, and YEL-AND in particular. PMID- 30306763 TI - [Influenza vaccination in the elderly: is a trial on mortality ethically acceptable?] AB - The effectiveness of influenza vaccination in the elderly has long been a topic of debate, fueled by the absence of direct evidence on its effect on mortality. It is argued that new placebo-controlled trials should be undertaken to resolve this uncertainty. However, such trials may be ethically questionable. We provide an overview of the ethical challenges of an influenza vaccine efficacy trial designed to evaluate mortality in the elderly. An important condition in the justification of a trial is the existence of genuine uncertainty regarding the answer to a research question. Therefore an extensive analysis of the existing levels of knowledge is needed to support the conclusion that an effect of vaccination on mortality is uncertain. Even if a so-called 'clinical equipoise' status applies, denying a control group vaccination would be problematic because vaccination is considered 'competent care' and withholding vaccination could substantially increase patients' risk for influenza and its complications. Given the high burden of disease and proven benefits of vaccination, the importance of a trial is unlikely to outweigh the risk patients are exposed to. While a placebo controlled trial in vaccine refusers may be considered, such a trial is unlikely to meet methodological standards regarding trial size and generalizability. We conclude that a new trial is unlikely to provide a direct answer, let alone change current policy. At the same time, given the lack of consensus on this topic, we invite researchers considering vaccine efficacy trials on mortality to address the ethical challenges as discussed. PMID- 30306764 TI - [The severe flu season of 2017-2018: making a case for the vaccination of healthcare professionals]. AB - The 2017/2018 influenza season was severe and lasted twice as long as usual. Hospitals struggled to meet the demand for care. In addition to a high number of patients with flu and its complications, other factors played a role. These included absenteeism of informal caretakers and professional home care staff due to having flu themselves, and added strain on hospital capacity due to flu related sick leave of hospital staff. A minority of the latter group is vaccinated annually against influenza. The authors of this article argue that all healthcare providers should take the yearly influenza vaccination. This will prove beneficial to the employer and employees, since non-attendance among employees will be reduced during peak demand and thus ensure continuity of care capacity. It will also have a positive impact in terms of patient safety and professionalism through improved protection of vulnerable patients against nosocomial influenza infection. PMID- 30306766 TI - The role of intragestational ghrelin on postnatal development and reproductive programming in mice AB - The purpose of this study was to evaluate the intragestational role of ghrelin in offspring development and reproductive programming in a mouse model of ghrelin imbalance during pregnancy. Female mice were injected with ghrelin (supraphysiological levels: 4 nmol/animal/day), antagonist (endogenous ghrelin inhibition with (D-Lys3)GHRP-6, 6 nmol/animal/day) or vehicle (control = normal ghrelin levels) throughout the pregnancy. Parameters evaluated in litters were growth, physical, neurobiological and sexual development and, at adulthood, reproductive function. Litter size and initial weight did not vary between treatments. Male pups from dams treated with ghrelin showed higher body weight increase until adulthood (31.7 +/- 0.8 vs control = 29.7 +/- 0.7, n = 11-14 litters/treatment; P < 0.05). Postnatal physical and neurobiological development was not modified by treatments. The antagonist accelerated male puberty onset, evidenced as earlier testis descent and increased relative testicular weight (antagonist = 0.5 +/- 0.0% vs ghrelin = 0.4 +/- 0.0% and control = 0.4 +/- 0.0%, n = 5-10 litters/treatment; P < 0.05). At adulthood, these males exhibited lower relative testicular weight and reduced sperm motility (63.9 +/- 3.6% vs control = 70.9 +/- 3.3 and ghrelin = 75.6 +/- 3.0, n = 13-15 animals; P < 0.05), without changes in plasma testosterone or fertility. Female pups intragestationally exposed to the antagonist showed earlier vaginal opening (statistically significant only at Day 25) and higher ovarian volume (antagonist = 1085.7 +/- 64.0 mm3 vs ghrelin = 663.3 +/- 102.8 mm3 and control = 512.3 +/- 116.4 mm3; n = 4-6 animals/treatment; P < 0.05), indicating earlier sexual maturation. At adulthood, these females and those exposed to ghrelin showed a tendency to higher percentages of embryo loss and/or foetal atrophy. In conclusion, ghrelin participates in reproductive foetal programming: alterations in ghrelin activity during pregnancy modified body weight increase and anticipated puberty onset, exerting (or tending to) negative effects on adult reproductive function. PMID- 30306767 TI - GATA4 is a negative regulator of contractility in mouse testicular peritubular myoid cells AB - Reduced contractility of the testicular peritubular myoid (PTM) cells may contribute to human male subfertility or infertility. Transcription factor GATA4 in Sertoli and Leydig cells is essential for murine spermatogenesis, but limited attention has been paid to the potential role of GATA4 in PTM cells. In primary cultures of mouse PTM cells, siRNA knockdown of GATA4 increased the contractile activity, while GATA4 overexpression significantly attenuated the contractility of PTM cells using a collagen gel contraction assay. Using RNA sequencing and qRT PCR, we identified a set of genes that exhibited opposite expressional alternation between Gata4 siRNA vs nontargeting siRNA-treated PTM cells and Gata4 adenovirus vs control adenovirus-treated PTM cells. Notably, ion channels, smooth muscle function, cytokines and chemokines, cytoskeleton, adhesion and extracellular matrix were the top four enriched pathways, as revealed by cluster analysis. Natriuretic peptide type B (NPPB) content was significantly upregulated by GATA4 overexpression in both PTM cells and their culture supernatant. More importantly, the addition of 100 MUM NPPB could abolish the promoting effect of Gata4 silencing on PTM cell contraction. Taken together, we suggest that the inhibitory action of GATA4 on PTM cell contraction is mediated at least partly by regulating genes belonging to smooth muscle contraction pathway (e.g. Nppb). PMID- 30306765 TI - Dynamic changes in gene expression and signalling during trophoblast development in the horse AB - Equine chorionic girdle trophoblast cells play important endocrine and immune functions critical in supporting pregnancy. Very little is known about the genes and pathways that regulate chorionic girdle trophoblast development. Our aim was to identify genes and signalling pathways active in vivo in equine chorionic girdle trophoblast within a critical 7-days window. We exploited the late implantation of the equine conceptus to obtain trophoblast tissue. An Agilent equine 44K microarray was performed using RNA extracted from chorionic girdle and chorion (control) from equine pregnancy days 27, 30, 31 and 34 (n = 5), corresponding to the initiation of chorionic girdle trophoblast proliferation, differentiation and migration. Data were analysed using R packages limma and maSigPro, Ingenuity Pathway Analysis and DAVID and verified using qRT-PCR, promoter analysis, western blotting and migration assays. Microarray analysis showed gene expression (absolute log FC >2, FDR-adjusted P < 0.05) was rapidly and specifically induced in the chorionic girdle between days 27 and 34 (compared to day 27, day 30 = 116, day 31 = 317, day 34 = 781 genes). Pathway analysis identified 35 pathways modulated during chorionic girdle development (e.g. FGF, integrin, Rho GTPases, MAPK) including pathways that have limited description in mammalian trophoblast (e.g. IL-9, CD40 and CD28 signalling). Rho A and ERK/MAPK activity was confirmed as was a role for transcription factor ELF5 in regulation of the CGB promoter. The purity and accessibility of chorionic girdle trophoblast proved to be a powerful resource to identify candidate genes and pathways involved in early equine placental development. PMID- 30306768 TI - Perforated vs nonperforated acute appendicitis: evaluation of short-term surgical outcomes in an elderly population. AB - BACKGROUND: Acute appendicitis is a common acute surgical abdominal condition and despite that most of cases are observed in children and young adults, its occurrence in the elderly seems to be increasing, with a higher risk of perforation. The aim of this study was to evaluate the surgical outcomes following appendectomy for acute appendicitis in the elderly, making a comparison between perforated and nonperforated groups regarding operative time, hospital stay and postoperative complications. METHODS: The medical records of 48 patients over the age of 60 years who had a pathologically confirmed diagnosis of acute appendicitis from January 2011 to December 2016 were retrospectively reviewed. Patients were grouped into those with perforated and those with non perforated appendicitis and a comparison was made between both groups regarding demography, operative time, lenght of hospital stay and postoperative complications. RESULTS: From 48 patients over 60 years diagnosed with acute appendicitis, a perforated appendicitis was removed from 10 patients (20.8%). The Perforated Appendicitis (PA) group consisted of 3 males and 7 females, and their mean age was 71.6 years ( range 6584). The Non Perforated Appendicitis (NPA) group included 22 males and 16 females, and their mean age was 76.5 years (range 6396). The mean operative time was 58 +/- 18.7 minutes and 43.3 +/- 9.9 minutes in the perforated and nonperforated groups respectively, with statistically significant difference (p= 0.0013). The mean length of hospital stay was similar in the PA group and in the NPA group, being 6.5 +/- 1.8 days and 5.4 +/- 1.8 days respectively, but theses differences were not statistically significant (p=0.093). The frequency of postoperative complications was similar in both groups as they were observed in 3 patients (30%) of the PA group and 10 patients (26%) of the NPA group (P = 0.2488). No postoperative intraabdominal abscess was observed in both groups and there was no death after the surgery. CONCLUSIONS: Perforated appendicitis, despite requiring a longer mean operative time, in our series is not producing a longer hospital stay or more postoperative complications compared to non perforated appendicitis. The non operative management of uncomplicated appendicitis is a reasonable option in frail patients in order to avoid the burden of morbidity related to operation, nevertheless surgery remains the standard of care in all age groups. PMID- 30306770 TI - Peripheral lymphadenopathy: role of excisional biopsy in differential diagnosis based on a five-year experience. AB - BACKGROUND: Peripheral lymphadenopathy can be caused by benign disease, or it could be a manifestation of underlying haematological disease or metastasis of a yet undiagnosed malignant condition. Fine-needle aspiration cytology (FNAC) and image- guided core biopsy usually make up the first line of investigation. There are several disadvantages to these techniques: FNAC is an acellular aspirate that may provide non- diagnostic specimens, while core biopsy may fail in the presence of composite lymphoma, nodal necrosis, and insufficiency or fragmentation of the specimens. Our aim was to evaluate the safety and effectiveness of excisional biopsy (EB) in a large case series. METHODS: 220 consecutive patients underwent lymph node EB under local anaesthesia. All patients underwent complete and systematic physical examination. Any palpable lymph node was evaluated for its location, size, consistency, fixation, and tenderness. All specimens were sent to the pathologist as fresh tissue. RESULTS: The EB materials demonstrated 89 (40.5%) benign lesions, 130 (59%) malignant diagnoses, and one (0.5%) unclear diagnosis. Mean operative time was 42.9 minutes (range 10-120 minutes). Harvested lymph nodes had a mean diameter of 3.3 x 2.3 cm. All patients were discharged within 8 hours. No major complications were reported, with a mean of 1.16 post operative outpatient visits. Temporary seroma and/or minor lymph leak at the site of the incision occurred in 14 cases (6.4%), haematoma in 7 (3.2%), and dehiscence of the surgical incision in 4 (1.8%), and in 3 cases (1.4%) pain was reported up to 7 days post-operatively. CONCLUSIONS: Excisional biopsy is a diagnostic method that can be applied safely with minimal morbidity and mortality. PMID- 30306769 TI - Surgical treatment of acute complicated diverticulitis in the elderly. AB - INTRODUCTION: Although the true prevalence is unknown, colonic diverticulosis is one of the most common disease of the digestive tract in Western countries. Based on administrative data of hospitalized patients, the incidence of diverticulitis has been increasing in last decades. In general, elderly patients undergo less frequently an elective colonic resection; but a substantial part of emergency surgeries is performed in elderly patients. In these older patients the choice of any clinical and surgical option is to be correlated not only to the severity of diverticulitis, but also to general status and the co-existing comorbidities. In this regard, it is mandatory that all patients undergo a multidimensional, comprehensive geriatric assessment to correctly identify those who are fit, vulnerable or frail. EVIDENCE ACQUISITION: The analysis of data currently available highlights three relevant elements: type and severity of peritoneal contamination, hemodynamic conditions (stable or unstable), and concomitant comorbidities (fit or frail status). EVIDENCE SYNTHESIS: There is no single ideal surgical treatment that can be considered as gold standard for all clinical presentations; the final clinical decision-making should always be based on patient's general health status, severity of peritonitis and of sepsis. CONCLUSIONS: In a septic elderly patient who is hemodynamically unstable, treatment should be as prompt as possible independent of the Hinchey's stage, and could include either a Mickulicz stoma or a DCS strategy. In an elderly patient who is fit and hemodynamically stable, the surgical options are similar to those in a younger patient. If a patient is frail but hemodynamically stable, he should be treated with a Hartmann's procedures. PMID- 30306771 TI - Maternal nutrition and reproductive functions of female and male offspring AB - This study aimed to investigate the effects of maternal unhealthy nutrition on the reproductive functions of female and male adult offspring. This was an animal study carried out with 24 virgin female Wistar rats (dams) and their male and female offspring. Rats were divided standard diet (SD) or cafeteria diet (CD) groups, after 10 weeks of feeding, all rats were paired with a Wistar stud male, and each group was again divided into CD and SD groups during the pregnancy and lactation periods. After birth, six female and six male pups in each group, were subjected to study. Following 3 weeks of lactation, the pups were fed with SD for 8 weeks and killed when they were considered adult at 11th week for analysis. Primordial and antral follicle counts, serum anti-Mullerian hormone (AMH) and phosphatase and tensin homolog (PTEN) in the oocyte cytoplasm were examined to evaluate ovarian function, and E-cadherin and integrin-beta1 levels were examined in endometrial tissues for the evaluation of endometrial receptivity in female offspring. Sperm analysis was performed in male offspring. In groups in which the dams were fed CD, primordial follicular pool, PTEN, and endometrial receptivity were reduced. In contrast, AMH and the number of antral follicles were not changed. In male offspring, the testicles were smaller, testosterone production decreased, AMH increased and the number and function of sperm were not changed. Sperm analysis results were not changed. All negative effects on reproductive functions were more apparent in groups fed with the CD during the pregestational period. PMID- 30306772 TI - PGRMC1/2 promotes luteal vascularization and maintains the primordial follicles of mice AB - To determine whether conditional depletion of progesterone receptor membrane component (PGRMC) 1 and PGRMC2 affected ovarian follicle development, follicle distribution was assessed in ovaries of young (~3-month-old) and middle-aged (~6 month-old) control (Pgrmc1/2fl/fl) and double conditional PGRMC1/2-knockout (Pgrmc1/2d/d) mice. This study revealed that the distribution of primary, preantral and antral follicles was not altered in Pgrmc1/2d/d mice, regardless of the age. Although the number of primordial follicles was similar at ~3 months of age, their numbers were reduced by ~80% in 6-month-old Pgrmc1/2d/d mice compared to age-matched Pgrmc1/2fl/fl mice. The Pgrmc1/2d/d mice were generated using Pgr cre mice, so ablation of Pgrmc1 and Pgrmc2 in the ovary was restricted to peri ovulatory follicles and subsequent corpora lutea (CL). In addition, the vascularization of CL was attenuated in Pgrmc1/2d/d mice, although mRNA levels of vascular endothelial growth factor A (Vegfa) were elevated. Moreover, depletion of Pgrmc1 and Pgrmc2 altered the gene expression profile in the non-luteal component of the ovary such that Vegfa expression, a stimulator of primordial follicle growth, was elevated; Kit Ligand expression, another stimulator of primordial follicle growth, was suppressed and anti-Mullerian hormone, an inhibitor of primordial follicle growth, was enhanced compared to Pgrmc1/2fl/fl mice. These data reveal that luteal cell depletion of Pgrmc1 and 2 alters the expression of growth factors within the non-luteal component of the ovary, which could account for the premature demise of the adult population of primordial follicles. In summary, the survival of adult primordial follicles is dependent in part on progesterone receptor membrane component 1 and 2. PMID- 30306773 TI - Myostatin is expressed in bovine ovarian follicles and modulates granulosal and thecal steroidogenesis AB - Myostatin plays a negative role in skeletal muscle growth regulation but its potential role in the ovary has received little attention. Here, we first examined relative expression of myostatin (MSTN), myostatin receptors (ACVR1B, ACVR2B and TGFBR1) and binding protein, follistatin (FST), in granulosa (GC) and theca (TC) cells of developing bovine follicles. Secondly, using primary GC and TC cultures, we investigated whether myostatin affects steroidogenesis and cell number. Thirdly, effects of gonadotropins and other intrafollicular factors on MSTN expression in GC and TC were examined. MSTN, ACVR1B, TGFBR1, ACVR2B and FST mRNA was detected in both GC and TC at all follicle stages. Immunohistochemistry confirmed follicular expression of myostatin protein. Interestingly, MSTN mRNA expression was lowest in GC of large oestrogen-active follicles whilst GC FST expression was maximal at this stage. In GC, myostatin increased basal CYP19A1 expression and oestradiol secretion whilst decreasing basal and FSH-induced HSD3B1 expression and progesterone secretion and increasing cell number. Myostatin also reduced IGF-induced progesterone secretion. FSH and dihydrotestosterone had no effect on granulosal MSTN expression whilst insulin like growth factor and tumour necrosis factor-alpha suppressed MSTN level. In TC, myostatin suppressed basal and LH-stimulated androgen secretion in a follistatin reversible manner and increased cell number, without affecting progesterone secretion. LH reduced thecal MSTN expression whilst BMP6 had no effect. Collectively, results indicate that, in addition to being potentially responsive to muscle-derived myostatin from the circulation, myostatin may have an intraovarian autocrine/paracrine role to modulate thecal and granulosal steroidogenesis and cell proliferation/survival. PMID- 30306774 TI - Emergence of a latent TSHoma pituitary macroadenoma on a background of primary autoimmune hypothyroidism AB - The coexistence of primary hypothyroidism and thyroid-stimulating hormone (TSH) stimulating pituitary macroadenomacan be a rare occurrence and can make diagnosis very challenging. We describe a case of a 44-year-old female witha history of fatigue, poor concentration, weight gain and amenorrhoea together with biochemical evidence ofprimary autoimmune hypothyroidism. Her initial TSH levels were elevated with low normal free thyroxine (T4) levels.Levothyroxine treatment was initiated and the dose was gradually titrated to supraphysiologic doses. This led to thenormalisation of her TSH levels but her free T4 and triiodothyronine (T3) levels remained persistently elevated. Thisprompted a serum prolactin check which returned elevated at 2495 MU/L, leading onto pituitary imaging. A MRI of thepituitary gland revealed a pituitary macroadenoma measuring 2.4 * 2 * 1.6 cm. Despite starting her on cabergoline therapywith a reduction in her prolactin levels, her TSH levels began to rise even further. Additional thyroid assays revealedthat she had an abnormally elevated alpha subunit at 3.95 (age-related reference range <3.00). This corresponded to athyroid-secreting hormone pituitary macroadenoma. She went on to have a transphenoidal hypophysectomy. Histologyrevealed tissues staining for TSH, confirming this to be a TSH-secreting pituitary macroadenoma. This case highlighted theimportance of further investigations with thyroid assay interferences, heterophile antibodies, alpha subunit testing andanterior pituitary profile in cases of resistant and non resolving primary hypothyroidism.Learning points:** Levothyroxine treatment in primary hypothyroidism can potentially unmask the presence of a latent TSH secretingpituitary macroadenoma, which can make diagnosis very challenging.** A high index of suspicion should prompt clinicians to further investigate cases of primary hypothyroidism whichdespite increasing doses of levothyroxine treatment with normalisation of TSH, the free T4 and T3 levels remainpersistently elevated.** Clinicians should consider investigating for adherence to levothyroxine, thyroid assay interference, heterophileantibodies, TSH dilution studies, alpha subunit and anterior pituitary profile testing to further clarity the diagnosisin these patients.** Although coexistent cases of TSHoma with primary hypothyroidism are rare, it should always be in the list ofdifferential diagnoses in cases of unresolving primary hypothyroidism. PMID- 30306775 TI - Detection of a novel, primate-specific 'kill switch' tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53 AB - The activation of TP53 is well known to exert tumor suppressive effects. We have detected a primate-specific adrenal androgen-mediated tumor suppression system in which circulating DHEAS is converted to DHEA specifically in cells in which TP53 has been inactivated. DHEA is an uncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD), an enzyme indispensable for maintaining reactive oxygen species within limits survivable by the cell. Uncompetitive inhibition is otherwise unknown in natural systems because it becomes irreversible in the presence of high concentrations of substrate and inhibitor. In addition to primate-specific circulating DHEAS, a unique, primate-specific sequence motif that disables an activating regulatory site in the glucose-6-phosphatase (G6PC) promoter was also required to enable function of this previously unrecognized tumor suppression system. In human somatic cells, loss of TP53 thus triggers activation of DHEAS transport proteins and steroid sulfatase, which converts circulating DHEAS into intracellular DHEA, and hexokinase which increases glucose 6-phosphate substrate concentration. The triggering of these enzymes in the TP53 affected cell combines with the primate-specific G6PC promoter sequence motif that enables G6P substrate accumulation, driving uncompetitive inhibition of G6PD to irreversibility and ROS-mediated cell death. By this catastrophic 'kill switch' mechanism, TP53 mutations are effectively prevented from initiating tumorigenesis in the somatic cells of humans, the primate with the highest peak levels of circulating DHEAS. TP53 mutations in human tumors therefore represent fossils of kill switch failure resulting from an age-related decline in circulating DHEAS, a potentially reversible artifact of hominid evolution. PMID- 30306777 TI - Role of the tumor microenvironment in digestive neuroendocrine tumors AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of heterogeneous tumors whose incidence increased over the past few years. Around half of patients already present with metastatic disease at the initial diagnosis. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with metastatic GEP-NETs, mainly due to the development of a certain state of resistance. One factor contributing to both the failure of systemic therapies and the emergence of an aggressive tumor phenotype may be the tumor microenvironment (TME), comprising dynamic and adaptative assortment of extracellular matrix components and non-neoplastic cells, which surround the tumor niche. Accumulating evidence shows that the TME can simultaneously support both tumor growth and metastasis and contribute to a certain state of resistance to treatment. In this review, we summarize the current knowledge of the TME of GEP-NETs and discuss the current therapeutic agents that target GEP-NETs and those that could be of interest in the (near) future. PMID- 30306776 TI - Mitochondrial disease: an uncommon but important cause of diabetes mellitus AB - Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism.Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the mostcommon endocrinopathy, and recognition of these patients is important due to its impact on management and screeningof family members. In particular, glycemic management differs in these patients: the use of metformin is avoided becauseof the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation ofhyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafnessand a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder.Learning points:** The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration ofa mitochondrial disorder.** Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetesand deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>Gin 80% of cases.** Metformin should be avoided due to the risk of lactic acidosis.** There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared totype 2 diabetes.** Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for futurecomplications.** Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in casesof significant weight loss, has been reported in MELAS patients. PMID- 30306779 TI - Resistance to thyroid hormone accompanied by atrial fibrillation AB - Resistance to thyroid hormone (RTH), which is primarily caused by mutations in the thyroid hormone (TH) receptorbeta (THRB) gene, is dominantly inherited syndrome of variable tissue hyposensitivity to TH. We herein describe a caseinvolving a 22-year-old Japanese man with RTH and atrial fibrillation (AF) complaining of palpitation and general fatigue.Electrocardiography results revealed AF. He exhibited elevated TH levels and an inappropriately normal level of thyroidstimulating hormone (TSH). Despite being negative for anti-TSH receptor antibody, thyroid-stimulating antibody andanti-thyroperoxidase antibody, the patient was positive for anti-thyroglobulin (Tg) antibody. Genetic analysis of the THRBgene identified a missense mutation, F269L, leading to the diagnosis of RTH. Normal sinus rhythm was achieved after1 week of oral bisoprolol fumarate (5 mg/day) administration. After 3 years on bisoprolol fumarate, the patient had beendoing well with normal sinus rhythm, syndrome of inappropriate secretion of TSH (SITSH) and positive titer of anti-Tgantibody.Learning points:** Atrial fibrillation can occur in patients with RTH.** Only a few cases have been reported on the coexistence of RTH and atrial fibrillation.** No consensus exists regarding the management of atrial fibrillation in patients with RTH.** Administration of bisoprolol fumarate, a beta-blocker, can ameliorate atrial fibrillation in RTH. PMID- 30306778 TI - Unusual high blood glucose in ketoacidosis as first presentation of type 1 diabetes mellitus AB - Diabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1diabetes where it is typically associated with only moderately increased blood glucose. Here, we report the case of a52 year-old female patient who was admitted to the emergency unit with severely altered mental status but stable vitalsigns. Laboratory results on admission revealed very high blood glucose (1687 mg/dL/93.6 mmol/L) and severe acidosis(pH <7) with proof of ketone bodies in serum and urine. Past history revealed a paranoid schizophrenia diagnosed10 years ago and for which the patient was treated with risperidone for many years. Acute treatment with intravenousfluids, intravenous insulin infusion and sodium bicarbonate improved the symptoms. Further laboratory investigationsconfirmed diagnosis of autoimmune type 1 diabetes. After normalization of blood glucose levels, the patient could soonbe discharged with a subcutaneous insulin therapy.Learning points:** Diabetic ketoacidosis as first manifestation of type 1 diabetes can occur with markedly elevated blood glucoseconcentrations in elder patients.** Atypical antipsychotics are associated with hyperglycemia and an increased risk of new-onset diabetes.** First report of risperidone-associated diabetic ketoacidosis in new-onset type 1 diabetes.** Patients treated with atypical antipsychotics require special care and regular laboratory examinations to detecthyperglycemia and diabetic ketoacidosis.** In cases when the diagnosis is in doubt, blood gas analysis as well as determination of C-peptide and isletautoantibodies can help to establish the definite diabetes type. PMID- 30306780 TI - Hyponatremia after anticoagulant treatment: a rare cause of adrenal failure AB - A 69-year-old male was admitted for severe hyponatremia disclosed after an accidental fall. He was anticoagulatedfrom 2 months after the implantation of a biologic aortic valve prosthesis. The work-up disclosed adrenal failure andMRI showed bilateral adrenal hemorrhage. Clinical picture and lab parameters normalized quickly after the appropriatereplacement treatment. Anticoagulation excess should be added to the list of drugs potentially causing hyponatremia.Learning points:** Hyponatremia requires a complete and timely workup in order to start an appropriate treatment for theimprovement of clinical conditions.** History is crucial: a detailed list of drugs potentially causing hyponatremia should be collected. Anticoagulantsshould be added to the list, mostly in the event of excessive anticoagulation.** Intra-adrenal hemorrhage is a rare cause of hyponatremia and adrenal failure.** The ACTH test is still the gold standard for the diagnosis of hypoadrenalism. PMID- 30306781 TI - Molecular underpinnings of enzalutamide resistance AB - Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure. This review will focus on the molecular underpinnings of enzalutamide resistance, bridging the gap between the preclinical and clinical research on novel therapeutic strategies for combating this lethal stage of prostate cancer. PMID- 30306782 TI - Aggressive and malignant pituitary tumours: state-of-the-art AB - Pituitary adenomas are unique in multiple ways. They are rarely malignant in terms of metastases; yet, they may be aggressive. Their cancerous potential is defined in a classic oncological way by the ability to metastasise, and therefore, it has been crucial to differentiate this process from aggressive behaviour, characterised as a particularly invasive and/or recurrent behaviour and resistance to common modalities of therapy. Recently, however, important changes have been introduced to the diagnosis and management of aggressive and malignant pituitary tumours including the 4th edition of the World Health Organization (WHO) classification for endocrine tumours (2017) as well as ESE Clinical Guidelines (2018), although an attempt to establish predictive and/or prognostic markers of clinical aggressiveness remains difficult. In this review, we focus on a group of pituitary tumours causing significant problems in clinical practice and requiring multidisciplinary input. We summarise updates in definitions of tumour invasiveness, aggressiveness and malignant transformation, as well as histological classification, and emphasise the new considerations regarding aggressive and malignant potential and its relationship to therapeutic strategies. PMID- 30306783 TI - A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1 AB - Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium andlow or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the setpoint for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASRcausing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individualsand required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affectedfamily members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow forproper management and screening of family members.Learning points:** ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familialhypocalciuric hypercalcaemia.** In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may bepresent in over a third of patients.** CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screeningand genetic counselling of affected family members.** Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due tothe risk of exacerbating hypercalciuria and its associated complications. PMID- 30306784 TI - Tumour growth and immune evasion as targets for a new strategy in advanced cancer AB - It has become clearer that advanced cancer, especially advanced breast cancer, is an entirely displayed pathological system that is much more complex than previously considered. However, the direct relationship between tumour growth and immune evasion can represent a general rule governing the pathological cancer system from the initial cancer cells to when the system is entirely displayed. Accordingly, a refined pathobiological model and a novel therapeutic strategy are proposed. The novel therapeutic strategy is based on therapeutically induced conditions (undetectable tumour burden and/or a prolonged tumour 'resting state'), which enable an efficacious immune response in advanced breast and other types of solid cancers. PMID- 30306785 TI - DICER1 mutation and pituitary prolactinoma AB - A young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when shebecame amenorrhoic. The mutation was identified as a result of family screening following the early death of thepatient's daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigationswere initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raisedprolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed. Diceris an RNase enzyme, which is essential for processing small non-coding RNAs. These molecules play pleiotropic roles inregulating gene expression, by targeting mRNA sequences for degradation. DICER1 plays different roles depending oncell context, but is thought to be a functional tumour suppressor gene. Accordingly, germline mutation in one DICER1allele is insufficient for oncogenesis, and a second hit on the other allele is required, as a result of postnatal somaticmutation. Loss of DICER1 is linked to multiple tumours, with prominent endocrine representation. Multinodular goitreis frequent, with increased risk of differentiated thyroid cancer. Rare, developmental pituitary tumours are reported,including pituitary blastoma, but not reports of functional pituitary adenomas. As DICER1 mutations are rare, case reportsare the only means to identify new manifestations and to inform appropriate screening protocols.Learning points:** DICER1 mutations lead to endocrine tumours.** DICER1 is required for small non-coding RNA expression.** DICER1 carriage and microprolactinoma are both rare, but here are reported in the same individual, suggestingassociation.** Endocrine follow-up of patients carrying DICER1 mutations should consider pituitary disease. PMID- 30306786 TI - Effective long-term temozolomide rechallenge in a macroprolactinoma AB - We describe the 20-year course of a 63-year-old male with a macroprolactinoma that acquired resistance to treatment andaggressive behavior after a 4-year successful treatment with cabergoline. He was submitted to multiple surgical resectionsby a skilled surgeon, fractionated radiotherapy and was eventually treated with temozolomide. After a first 6-monthstandard cycle, a relapse occurred and he was treated again successfully.Learning points:** Prolactinomas are the most frequent type of pituitary adenoma.** They usually have a benign course.** In most cases dopamine-agonist drugs, mainly cabergoline, are first line (and usually only) treatment.** Occasionally prolactinomas can have or acquire resistance to treatment and/or aggressive behavior.** Temozolomide (TMZ), an oral alkylating drug, can be effective in such aggressive tumors.** Multimodal treatment (surgery, radiation, cabergoline and TMZ) is warranted in aggressive pituitary tumors.** We describe here successful rechallenge with TMZ after relapse occurring 18 months after a first TMZ cycle. PMID- 30306787 TI - The inverse relationship between prostate specific antigen (PSA) and obesity AB - Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. The aim of this study was to determine the effect of obesity on PSA and the potential contributing mechanisms. A cohort of 1195 men aged 35 years and over at recruitment, with demographic, anthropometric (BMI, waist circumference (WC)) and serum hormone (serum testosterone, estradiol (E2)) PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. After adjusting for age, PSA levels were lower in men with greater WC (P = 0.001). In a multivariable model including WC, age, E2/testosterone and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC (P = 0.36) or PlasV (P = 0.49), while strong associations were observed with both E2/testosterone (P < 0.001) and age (P < 0.001). In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 20% of the total effect of WC on PSA (P = 0.31), while when E2/testosterone is a mediator, the ACME explained roughly 50% of the effect (P < 0.001). Our findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/testosterone ratio) and hemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway. PMID- 30306788 TI - Refractory spontaneous hypoglycaemia: a diagnostic conundrum AB - A frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodeswere diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism andhypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulinconcentrations, were inappropriately elevated at 4210 pmol/L (174-960) and >200 pmol/L (0-7) respectively with plasmainsulin suppressed at 12 pmol/L (0-180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified aheterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-isletcell tumour induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.Learning points:** Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulinsecretingtumours are potentially curable causes.** Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for thehypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.** Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, thediscrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the fasterrelative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorinliaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulinreference preparation.** Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imagingstudies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.** The concomitant renal mass identified radiologically proved to be a red herring.** In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established. PMID- 30306789 TI - A unique model for SDH-deficient GIST: an endocrine-related cancer AB - We describe a unique patient-derived xenograft (PDX) and cell culture model of succinate dehydrogenase-deficient gastrointestinal stromal tumor (SDH-deficient GIST), a rare mesenchymal tumor that can occur in association with paragangliomas in hereditary and non-hereditary syndromes. This model is potentially important for what it might reveal specifically pertinent to this rare tumor type and, more broadly, to other types of SDH-deficient tumors. The primary tumor and xenografts show a very high proliferative fraction, and distinctive morphology characterized by tiny cells with marked autophagic activity. It is likely that these characteristics resulted from the combination of the germline SDHB mutation and a somatic KRAS G12D mutation. The most broadly relevant findings to date concern oxygen and oxidative stress. In paragangliomas harboring SDHx mutations, both hypoxic signaling and oxidative stress are putative drivers of tumor growth. However, there are no models for SDH-deficient paragangliomas. This related model is the first from a SDHB-mutated human tumor that can be experimentally manipulated to study mechanisms of oxygen effects and novel treatment strategies. Our data suggest that tumor growth and survival require a balance between protective effects of hypoxic signaling vs deleterious effects of oxidative stress. While reduced oxygen concentration promotes tumor cell survival, a further survival benefit is achieved with antioxidants. This suggests potential use of drugs that increase oxidative stress as novel therapies. In addition, autophagy, which has not been reported as a major finding in any type of SDH deficient tumor, is a potential target of agents that might trigger autophagic cell death. PMID- 30306790 TI - Practice Patterns in Office-Based Rhinology: Survey of the American Rhinologic Society. AB - Background Recent years have witnessed significant expansion in office-based rhinology. This study assesses practice patterns of the American Rhinologic Society (ARS) membership regarding office-based rhinologic procedures. Methods A 24-item survey was disseminated to the ARS membership from March 15 to May 31, 2016. Results A total of 157 physicians (11.9%) completed the survey. Office based rhinologic procedures were performed by 99% of respondents, with sinonasal debridements (99%), polypectomy (77%), and balloon sinus ostial dilation (56%) being the most common. During a typical month, the number of sinonasal debridements was 0-10 in 23%, 11-20 in 34%, 21-30 in 26%, and >30 in 18%. For polypectomy, 57% of the respondents utilized a microdebrider (reusable electric 24%, disposable vacuum-powered-21%, and both-12%), 36% endoscopic forceps, and 7% a combination of both. With respect to balloon ostial dilation, the frontal sinuses were the most frequently addressed (53%) followed by the maxillary (46%) and sphenoid (39%) sinuses. In-office ethmoidectomies, antrostomies, sphenoidotomies, and frontal sinusotomies without the use of the balloon were performed by 35%, 31%, 24%, and 21% of the respondents, respectively. Thirty percent of respondents used steroid-eluting sinus implants and 10% used computer assisted surgical navigation in the office setting. Overall, 63% of respondents reported that the number of office-based rhinologic procedures they performed had increased over the last 5 years. Conclusions The present study illustrates the integration of office procedures into rhinologic clinical practice among ARS survey respondents. With ongoing technologic innovations, the scope of office based rhinology will likely continue to expand in the years to come. PMID- 30306791 TI - Dual Purpose Use of Flexor Hallucis Longus Tendon for Management of Chronic Achilles Tendon Ruptures. AB - BACKGROUND: Chronic Achilles tendon ruptures are uncommon and increase long-term morbidity when untreated. There is no standard treatment for this condition. METHODS: Chronic Achilles tendon rupture was repaired in 10 patients by harvesting the flexor hallucis longus tendon (FHL) using a minimally invasive technique. It was then transferred to the calcaneus and the remnant used to bridge the gap for reconstructing the Achilles tendon itself. The patients were assessed using the American Orthopaedic Foot and Ankle Score (AOFAS) Ankle Hindfoot Scale. RESULTS: Patients were evaluated postoperatively to assess pain, function, and alignment of the ankle and hindfoot. Average follow-up time was 30.9 months (range = 17-43 months). The average postoperative AOFAS score was 78.5 (range = 54-94). The average postoperative score for pain was 33.5 out of 40; for function, 38.7 out of 50; and for alignment, 6.3 out of 10. A single surgical site infection requiring Incision and Drainage (I&D) was the only operative complication noted. No patient developed a significant deformity of the hallux after transfer. CONCLUSIONS: FHL transfer using a minimally invasive harvest for the treatment of chronic Achilles tendon ruptures produces good to excellent outcome measures as judged by an AOFAS score of 75 or greater while minimizing risk to the medial neurovascular bundle. LEVELS OF EVIDENCE: Case series, Level IV: Retrospective. PMID- 30306792 TI - What am I thinking? Perspective-taking from the perspective of adolescents with autism. AB - Autistic people are often described as being impaired with regard to theory of mind, though more recent literature finds flaws in the theory of mind deficit paradigm. In addition, the predominant methods for examining theory of mind often rely on "observational" modes of assessment and do not adequately reflect the dynamic process of real-life perspective taking. Thus, it is imperative that researchers continue to test the autistic theory of mind deficit paradigm and explore theory of mind experiences through more naturalistic approaches. This study qualitatively examined theory of mind in 12 autistic adolescents through a series of semi-structured interviews. Interpretive phenomenological analysis of the data revealed four core themes in participants' theory of mind experiences and strategies, all of which highlighted how a more accurate representation of autistic theory of mind is one of difference rather than deficit. For instance, data showed that autistic heightened perceptual abilities may contribute to mentalizing strengths and that honesty in autism may be less dependent on systemizing rather than personal experience and choice. Such findings suggest that future research should reexamine autistic characteristics in light of their ability to enhance theory of mind processing. Understanding how an autistic theory of mind is uniquely functional is an imperative step toward both destigmatizing the condition and advocating for neurodiversity. PMID- 30306793 TI - Physical activity for brain health in older adults. AB - Physical activity is a promising strategy for dementia prevention and disease modification. Here, we provide a narrative review of the current evidence from epidemiological and intervention studies on the role of physical activity and exercise in promoting cognitive health in older adults both without and with cognitive impairment. We highlight some of the potential underlying mechanisms and discuss biological sex as a potential moderating factor. We conclude with limitations and future directions for this rapidly expanding line of research. PMID- 30306794 TI - Diagnostic reference levels and achievable doses for common computed tomography examinations: Results from the Japanese nationwide dose survey. AB - OBJECTIVE:: To propose a new set of Japanese diagnostic reference levels (DRLs) and achievable doses (ADs) for 2017 and to verify the usefulness of Japanese DRLs (DRLs 2015) for CT, by investigating changes in the volume CT dose index (CTDIvol) from 2014 to 2017. METHODS:: Detailed information on the CT scan parameters used throughout Japan were obtained by questionnaire survey. The CTDIvol and dose-length product for the 11 commonest adult and 6 commonest paediatric CT examinations were surveyed and compared with 2014 data and DRLs 2015. RESULTS:: Evaluations of adult head (helical), and abdomen and pelvis without contrast agent, paediatric chest without contrast agent, and abdomen and pelvis without contrast agent showed a slightly lower mean CTDIvol in 2017 than in 2014 (t-test, p < 0.05). The interquartile range of CTDIvol for all 2017 examinations was lower than in 2014. CONCLUSIONS:: This study verified the lower mean, 75th percentile, and interquartile range by investigating changes in the CTDIvol from 2014 to 2017. The DRLs 2015 contributed to CT radiation dose reduction. ADVANCES IN KNOWLEDGE:: The widespread implementation of iterative reconstruction algorithms and low-tube voltage in CT scanners is likely to facilitate further reduction in the CT radiation dose used in Japan. Although radiological technologists may require further education on appropriate CTDIvol and DLP usage, the DRLs 2015 greatly contributed to the reduction of the CT radiation dose used in Japan. PMID- 30306796 TI - An Occupational Health Education Program for Thai Farmers Exposed to Chlorpyrifos. AB - The majority of the farmers in this sample of Thai farmers did not use sufficient self-protective behaviors when using the organophosphate insecticide chlorpyrifos. Most were directly exposed to chlorpyrifos, potentially leading to illnesses. The aim of this study was to improve safety behaviors when using chlorpyrifos by an occupational health education program. A controlled trial (n = 70) of an occupational health education program was undertaken in rural Thailand prior to the occupational health education program. There were no differences in behavior between experimental and control groups. Completion of the program led to a significant improvement in safe working practices and in the amount of the metabolite. However, significant differences were noticed after participating in the occupational health education program on both safety behaviors and the amount of the metabolite 3,5,6-trichloro-2-pyridinol present in urine. PMID- 30306797 TI - Algorithm to Predict Which Children With Chronic Abdominal Pain Are Low Suspicion for Significant Endoscopic Findings. AB - Chronic abdominal pain (CAP) is a common and challenging problem in pediatric primary and specialty care. We developed a diagnostic algorithm to organize workup for gastrointestinal causes of CAP and improve identification of patients who are low suspicion (LS) or high suspicion (HS) to have significant intestinal pathology identified with endoscopy. We retrospectively used this algorithm to categorize 150 outpatients with CAP as LS (n = 99) or HS (n = 51) and examined subsequent endoscopic findings for all patients. There were 6% significant diagnoses in the LS group compared with 34% in the HS group ( P < .0001). The LS group had no patients with celiac or inflammatory bowel disease. These results can be used to help a clinician approach CAP, and discuss with families the likelihood of endoscopy finding a cause for CAP based on LS or HS designation. PMID- 30306795 TI - Race, psychosocial vulnerability and social support differences in inner-city women's symptoms of posttraumatic stress disorder. AB - BACKGROUND/OBJECTIVES: Inner-city Black women may be more susceptible to posttraumatic stress disorder (PTSD) than White women, although mechanisms underlying this association are unclear. Living in urban neighborhoods distinguished by higher chronic stress may contribute to racial differences in women's cognitive, affective, and social vulnerabilities, leading to greater trauma-related distress including PTSD. Yet social support could buffer the negative effects of psychosocial vulnerabilities on women's health. METHODS/DESIGN: Mediation and moderated mediation models were tested with 371 inner-city women, including psychosocial vulnerability (i.e., catastrophizing, anger, social undermining) mediating the pathway between race and PTSD, and social support moderating psychosocial vulnerability and PTSD. RESULTS: Despite comparable rates of trauma, Black women reported higher vulnerability and PTSD symptoms, and lower support compared to White Hispanic and non-Hispanic women. Psychosocial vulnerability mediated the pathway between race and PTSD, and social support moderated vulnerability, reducing negative effects on PTSD. When examining associations by race, the moderation effect remained significant for Black women only. CONCLUSIONS: Altogether these psychosocial vulnerabilities represent one potential mechanism explaining Black women's greater risk of PTSD, although cumulative psychosocial vulnerability may be buffered by social support. Despite higher support, inner-city White women's psychosocial vulnerability may actually outweigh support's benefits for reducing trauma-related distress. PMID- 30306798 TI - Giant Frontal Sinus Osteomas: Demographic, Clinical Presentation, and Management of 10 Cases. AB - Background Osteomas are rare benign and slow-growing osteogenic tumors mainly involving frontal and ethmoid sinuses. Objectives The primary objective of our study is to present the management of cases of giant frontal sinus osteomas. Secondarily, we describe our modified unilateral osteoplastic flap approach without obliteration to remove these osteomas. Methods Retrospective chart review at a tertiary academic center ("Hopital de l'Enfant-Jesus") from July 2006 to October 2016. Demographics characteristics, tumor characteristics, presenting symptoms, frontal sinus surgery technique (osteoplastic flap, endoscopic surgery, or a combination of both), and outcomes of giant frontal sinus osteomas (>=30 mm) were recorded. For laterally placed osteomas, tumors with posterior wall involvement, orbital roof involvement, or intracranial extension, the modified unilateral osteoplastic flap approach was used. A decision-making algorithm is proposed for the choice of surgical approach. Results Ten giant frontal osteomas were analyzed (7 men and 3 women). The mean age at diagnosis was 38 years old (range, 24-55 years; median, 39 years; standard deviation, 11 years). The most common presenting symptom was headache (43% of symptomatic patients). Five patients had complications preoperatively due to tumoral extension (sinusitis, cellulitis, mucocele, optic nerve compression, and convulsions). One patient was treated endoscopically, 3 patients had an open approach and 6 patients had a combined technique. One patient experienced a postoperative complication (local infection treated with oral antibiotics). Six patients had minimal residual tumor with one patient needing reoperation. Conclusion Osteomas are rare paranasal sinus tumors. Due to the proximity to noble structures, a giant frontal osteoma should be managed surgically. The modified unilateral osteoplastic flap without obliteration offers good long-term surgical and aesthetic results. Osteomas are not known for malignant transformation and recurrences are rare; thus, subtotal resection is warranted and safe when a cleavage plan is not found. PMID- 30306799 TI - Benzophenanthridine alkaloids from the roots of Thalictrum microgynum Lecoy.ex Oliv. AB - A new benzophenanthridine alkaloid, 2,3,9-trimethoxy-7,8-methylenedioxy-5 methylbenzo[c]-6(5H) phenanthridone (2) and a benzophenanthridine alkaloid first found from natural sources, 2,3-dimethoxy-7,8- methylenedioxy-5-methylbenzo[c] 6(5H)- phenanthridone (1) together with two known benzophenanthridine alkaloids, Dihydrosanguinarine (3) and Dihydrochelilutine (4) were isolated from the roots of Thalictrum microgynum Lecoy.ex Oliv. The structures of 1 and 2 were elucidated using various spectroscopic techniques including HRESIMS and 1 D and 2 D NMR. Antibacterial activity of these compounds were tested. Compound 1, 3 and 4 showed antibacterial activity against Staphylococcus aureus with MIC values of 50, 100, 25 MUg/mL, respectively. PMID- 30306800 TI - Digital panoramic radiography and cone-beam CT as ancillary tools to detect low bone mineral density in post-menopausal women. AB - OBJECTIVES: To evaluate the usefulness of the mandibular cortical index (MCI) obtained by digital panoramic radiography (DPR) and by panoramic reconstruction (PR) of cone-beam CT (CBCT) with three different slice thicknesses for the screening of low bone mineral density (BMD) in post-menopausal women. METHODS: Two trained oral and maxillofacial radiologists assessed the MCI based on the morphology of the mandibular bone cortex (classified as C1, C2 or C3). The DPR and PR of CBCT with slice thicknesses of 5, 15 or 25 mm were compared to the BMD obtained by dual-energy X-ray absorptiometry (DXA) in post-menopausal women. Measures related to accuracy were calculated with MedCalc software. The confidence interval was set at 95%. RESULTS: 54 women (mean age 58.70 +/- 7.35 years) participated in the study. The sensitivity and specificity values obtained for DPR were 52.6% and 56.2%, respectively, and values for PR of CBCT with 5, 15, and 25 mm slice thicknesses were 63.1% and 43.7%, 50.0% and 50.0%, and 52.6% and 62.5%, respectively. For the tools evaluated, the positive likelihood ratio ranged from 1.00 to 1.40 and negative likelihood ratio from 0.76 to 1.00. The positive predictive value (PPV) ranged from 70.4 to 76.9% and the negative predictive value (NPV) from 29.6 to 35.7%. Among the examinations, the highest value for area under the curve (AUC) was obtained for CBCT with 25 mm slice thickness (57.6%). CONCLUSIONS: The MCI calculated by DPR and CBCT differed with regard to accuracy. Within the limitations of this study, the PR of CBCT with 25 mm slice thicknesses seems to be the most accurate among the examinations evaluated. Should the dentist be attentive, DPR and CBCT may be useful tools for the screening of low BMD in post-menopausal women, facilitating their timely referral for further assessment. PMID- 30306801 TI - An epidemiologic and clinical description of e-cigarette toxicity. AB - INTRODUCTION: E-cigarettes are battery-powered electronic nicotine delivery systems that simulate smoking by vaporizing nicotine-containing solutions. Systematic published data on e-liquid toxicity and exposures are limited to case reports and retrospective studies. Prospectively-collected data on the type of exposure, symptomatology, duration of symptoms, and concentration/flavor of e fluids has not been published. METHODS: This was a prospective observational study over a 42-month period (07/01/2014-12/31/2017). For all calls to a single poison center that involved e-cigarette devices or refill fluid, a data collection instrument was filled out by the specialist in poison information (SPI). RESULTS: Two hundred sixty-five total cases were identified, including 193 children and 72 adults. The majority of both pediatric (72%; 139/193) and adult (61%; n = 44/72) exposures involved e-liquid refill containers or fluid. Fifty six percent (n = 108/193) of pediatric exposures involved ingestion of refill liquid. Though children who ingested e-liquid received only a small amount, initial symptoms were evident in 32% (n = 35/108) of cases. Children who did not ingest or inhale the products were less likely to develop toxicity. Only 2 children who were asymptomatic on initial call became symptomatic on follow-up. Most patients symptoms resolved within 4 hours. Seventy-one specific products/brands were identified with nicotine concentrations ranging from 0 mg/mL to 60 mg/mL with one product containing 3000 mg in a single bottle. A variety of flavors were identified, including several with names that may be attractive to toddlers or adolescents. DISCUSSION: E-cig exposures tend to produce irritant effects from topical exposures and nicotine toxicity from ingestions, as well as some dermal and "sucking" toddler exposures. CONCLUSION: Exposure to e-cig fluid or device frequently causes mild symptoms and rarely may produce systemic nicotine toxicity. PMID- 30306802 TI - Transdermal delivery system of nanostructured lipid carriers loaded with Celastrol and Indomethacin: optimization, characterization and efficacy evaluation for rheumatoid arthritis. AB - Co-encapsulation of drugs provides a convenient means for treating different symptoms of a disease. Celastrol (Cel) shows potent anti-arthritic activity and Indomethacin (Indo) is effective in relieving inflammatory pain. Nanostructured lipid carriers loaded with Celastrol and Indomethacin (Cel-Indo-NLCs) were prepared by emulsification evaporation-solidification method, optimized by the Box-Behnken design and characterized by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and powder X-ray diffraction analysis (PXRD). Visualization of transdermal translocation of Cel-Indo-NLCs was achieved by confocal laser scanning microscope (CLSM). Further, Cel-Indo-NLCs were incorporated into Carbopol 940 for transdermal delivery. The in vitro studies were evaluated by using the Franz diffusion cells. Cel-Indo-NLCs depicted small particle size (26.92 +/- 0.62 nm) and PDI (0.201 +/- 0.01), high entrapment efficiency (96.56 +/- 1.41%) and drug load (3.65 +/- 0.05%). Moreover, Cel-Indo NLCs showed prominent effect of decreasing paw oedema, inhibiting inflammation and pain by regulating the levels of IL-1beta, TNF-alpha, beta-endorphin and Substance P. After the administration of Cel-Indo-NLCs-gel, no skin irritation was observed in rats. There was no difference of gastrointestinal tract between different groups of rats when they were sacrificed. The histological analysis showed no renal and reproductive toxicity. Therefore, it can be concluded that co encapsulation strategy based NLCs have the potential to provide safe transdermal delivery and are promising in treatment of pain and inflammation associated with rheumatoid arthritis. PMID- 30306803 TI - Physiologically based pharmacokinetic modelling of acute digoxin toxicity and the effect of digoxin-specific antibody fragments. AB - CONTEXT: Recommended doses of digoxin-specific antibody fragments (digoxin-Fab) for treatment of acute digoxin poisoning are pharmacokinetically unsubstantiated and theoretically excessive. Physiologically based pharmacokinetic (PBPK) modelling creates clinical simulations which are closely related to physiological and pharmacokinetic behaviour. This paper details the formulation of a PBPK model of digoxin and explores its use as a simulation tool for acute digoxin toxicity and its management. MATERIALS AND METHODS: A PBPK model of digoxin was constructed and validated for acute digoxin poisoning management by comparing simulations with observed individual acute overdose patients. These simulations were compared with standard two-compartment PK model simulations. RESULTS: PBPK model simulations showed good agreement with post-absorption plasma concentrations of digoxin measured in 6 acute overdose patients. PBPK predictions were accurate to 1.5-fold or less of observed clinical values, proving to be more accurate than two-compartment simulations of the same patients which produced up to a 4.9-fold change. i Conclusions: Compared to conventional two-compartment modelling, PBPK modelling is superior in generating realistic simulations of acute digoxin toxicity and the response to digoxin-Fab. Simulation capacity provides realistic, continuous data which has the potential to substantiate alternative, less expensive, and safer digoxin-Fab dosing strategies for the treatment of acute digoxin toxicity. PMID- 30306804 TI - Salicylate toxicity after undetectable serum salicylate concentration: a retrospective cohort study. AB - BACKGROUND: Salicylates are usually rapidly absorbed and quickly measurable in serum. An undetectable serum salicylate concentration ([ASA]) may occur early after ingestion and may be interpreted as evidence of non-exposure and not repeated. Although cases of delayed salicylate detection are reported rarely, the risk factors associated with this phenomenon are not known. RESEARCH QUESTION: What factors are associated with an early undetectable [ASA] in salicylate poisoning? METHODS: Records from a single regional poison center were searched from 2002 to 2016 for cases of salicylate toxicity treated with bicarbonate and [ASA] > 30 mg/dL. Cases were excluded if initial [ASA] was obtained >4 h after presentation. Case information, serial [ASA], and outcomes were recorded and compared between groups. RESULTS: A total of 313 records met all criteria with 11 initially undetectable [ASA] (3.5%) and 302 detectable [ASA] (96.5%). Time of first [ASA] occurred sooner in the undetectable [ASA] group (89 vs. 137 min, p = 0.011) while time to peak [ASA] was longer (640 vs. 321 min, p < .001). The longest interval between ingestion and undetectable [ASA] was 225 min. Peak [ASA] and reported mean ingested dose were similar in both groups (45 vs. 50 mg/dL, p = NS; 19.7 g vs. 32.9 g, p = NS). Coingestion of agents that delay gastric emptying were similar in both groups (18% [2/11] vs. 25% [76/302], p = NS, chi-square). Hemodialysis was performed in 9% (1/11) of undetectable [ASA] patients and 5.6% (17/302) of detectable [ASA] patients (p = NS, chi-square). A single death occurred in the entire cohort in a patient with an initially detectable [ASA]. DISCUSSION: In this series, a small but significant proportion (3.5%) of patients who developed [ASA] > 30 mg/dL had an initially undetectable [ASA]. Those with an undetectable [ASA] were measured earlier after ingestion with a longer time to peak [ASA]. However, neither coingestion of agents prolonging gastric emptying nor reported dose ingested was different between groups. Formulation was infrequently recorded but one undetectable [ASA] did ingest a non-enteric coated product. Limitations include the small number of patients with undetectable [ASA], use of single poison center data and partial data on co-ingestants and aspirin formulation. CONCLUSIONS: [ASA] may be undetectable early after an overdose and need for serial [ASA] in the evaluation of salicylate ingestion should be further explored. Additional research is needed to determine any causative factors and the optimal timing of [ASA] measurements. PMID- 30306805 TI - Is manual therapy based on neurodynamic techniques effective in the treatment of carpal tunnel syndrome? A randomized controlled trial. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of manual therapy based on neurodynamic techniques in conservative treatment of carpal tunnel syndrome. DESIGN: Randomized controlled trial. SETTING: Several medical outpatient clinics in the south of Poland. PARTICIPANTS: The study included 103 patients with mild and moderate carpal tunnel syndrome (mean age = 53.95, SD = 9.5) years, who were randomly assigned to a neurodynamic techniques group (experimental group, n = 58) or a group without treatment (control group, n = 45). INTERVENTION: Neurodynamic techniques were used in the experimental group. Treatment was conducted twice weekly (20 sessions). Control group did not receive treatment. MAIN MEASURES: Nerve conduction study, pain, symptom severity and functional status of Boston Carpal Tunnel Questionnaire, and strength of cylindrical and pincer grips were assessed at baseline and immediately after treatment (nerve conduction study one month after treatment). RESULTS: Baseline assessment revealed no group differences in any assessed parameters ( P > 0.05). There were significant differences between groups after treatment, including nerve conduction (e.g. sensory conduction velocity: experimental group: 38.3 m/s, SD = 11.1 vs control group: 25.9 m/s, SD = 7.72, P < 0.01). Significant changes also occurred in pain (experimental group: 1.38, SD = 1.01 vs control group: 5.46, SD = 1.05, P < 0.01), symptom severity (experimental group: 1.08, SD = 0.46 vs control group: 2.87, SD = 0.68, P < 0.01), and functional status (experimental group: 1.96, SD = 0.64 vs control group: 2.87, SD = 1.12, P < 0.01). There were no group differences in strength ( P > 0.05). CONCLUSION: The use of neurodynamic techniques in conservative treatment for mild to moderate forms of carpal tunnel syndrome has significant therapeutic benefits. PMID- 30306806 TI - Effect of laterality, gender, age and body mass index on the fat fraction of salivary glands in healthy volunteers: assessed using iterative decomposition of water and fat with echo asymmetry and least-squares estimation method. AB - OBJECTIVES:: To evaluate the effect of laterality, gender, age and body mass index (BMI) on fat fraction (FF) measurements of both parotid glands (PGs) and submandibular glands (SMGs) by using: Iterative decomposition of water and fat with echo asymmetry and least-squares estimation method (IDEAL-IQ). METHODS:: A total of 87 healthy participants were enrolled in our study. IDEAL-IQ image was scanned using a 3.0 T scanner. Paired t test was performed to compare the difference on FF of both PGs and SMGs between left and right side. The FF of two glands between male and female healthy participants were compared using an unpaired t-test. The correlation between the FF of two glands and participant age or BMI were analyzed by Pearson's correlation. RESULTS:: Excellent inter- and intrareader agreements were obtained during the measurements of FF by IDEAL-IQ method (ICC, 0.952-0.981). FF values correlated positively with the age and BMI in both left and right PGs and SMGs (p < 0.05). No significant difference was found on FF between left and right PGs and SMGs (p > 0.05). There was also no difference on FF between male and female healthy participants (p > 0.05). CONCLUSIONS:: FFs of PGs and SMGs were age- and BMI- dependent, but not laterality- and gender-dependent. The effect of age and BMI need to be considered in further studies using Ideal-IQ technology to evaluate FFs of salivary gland diseases. PMID- 30306807 TI - Short-term glucose dysregulation following acute poisoning with organophosphorus insecticides but not herbicides, carbamate or pyrethroid insecticides in South Asia. AB - BACKGROUND: Ingestion of organophosphorus (OP) insecticides is associated with acute hyperglycaemia. We conducted a prospective study to determine whether glucose dysregulation on admission associated with ingestion of OP insecticides or other pesticides is sustained to hospital discharge or to 3-12 months later. METHODS: We recruited participants to two similar studies performed in parallel in Anuradhapura, Sri Lanka, and Chittagong, Bangladesh, following hospitalisation for OP insecticide, herbicide or other pesticide self-poisoning. Two-hour 75 g oral glucose tolerance testing (OGTT) was performed after recovery from the acute poisoning, at around the time of discharge. In Sri Lanka, a four time-point OGTT for area-under-the-curve (AUC), C-peptide and homeostatic modelling of insulin resistance (HOMA-IR) was undertaken, repeated after 1 year. In Bangladesh, a 2-h OGTT for glucose was undertaken and repeated after 3 months in participants with initial elevated 2-h glucose. We compared glucose homeostasis by poison group and adjusted findings for age, BMI and sex. FINDINGS: Seventy-three Sri Lankan and 151 Bangladeshi participants were recruited. We observed higher mean [SD] fasting (4.91 [0.74] vs. 4.66 [0.46] mmol/L, p = .003) and 2-h glucose (7.94 [2.54] vs. 6.71 [1.90] mmol/L, p < .0001) in OP-poisoned groups than pyrethroid, carbamate, herbicide or 'other poison' groups at discharge from hospital. In Sri Lanka, HOMA IR, glucose and C-peptide AUC were higher in OP than carbamate or herbicide groups. Adjusted analyses remained significant except for fasting glucose. Follow up analysis included 92 participants. There was no significant difference in OGTT results between OP-poisoned and other participants at follow-up (mean [SD] 2-h fasting glucose 4.67 [0.92] vs. 4.82 [0.62], p = .352; 2-h glucose 6.96 [2.31] mmol/L vs. 6.27 [1.86] mmol/L, p = .225). CONCLUSION: We found in this small prospective study that acute OP insecticide poisoning caused acute glucose dysregulation that was sustained to hospital discharge but had recovered by 3-12 months. Acute glucose dysregulation was related to defects in insulin action and secretion. This study did not address long-term risk of diabetes following acute OP insecticide poisoning, but could provide a power calculation for such a study. PMID- 30306808 TI - Comment on: Study habits and academic achievement among medical students: A comparison between male and female subjects. PMID- 30306809 TI - A tablet-based program to enable people with intellectual and other disabilities to access leisure activities and video calls. AB - PURPOSE: This study evaluated a tablet-based program to help eight participants with moderate intellectual disability, sensory and/or motor impairments, and lack of expressive or expressive and receptive verbal skills to select and access leisure activities and video calls independently. METHODS: The program relied on the use of a tablet (i.e., Samsung Galaxy Tab S2 LTE) with 8-inch screen, Android 6.0 Operating System, front camera, proximity sensor and multimedia player. The tablet was fitted with a SIM card and two specific applications, that is, WhatsApp Messenger for making video calls and MacroDroid for automating the tablet's functioning in accordance with the program conditions. The tablet presented pictures concerning leisure activities and preferred partners for video calls. The participant could select any activity or partner by touching (or nearing his or her hand to) the tablet's proximity sensor. RESULTS: During the baseline (i.e., without the program), the participants failed to access leisure activities or video calls. During the post-intervention phase (i.e., with the program), they selected and accessed those activities and calls independently and spent between about 75% and 90% of the session time engaging with them. CONCLUSION: The tablet-based program can be highly beneficial for people like the participants of this study. Implications for rehabilitation A technology-aided program may enable persons with intellectual and other disabilities to independently access leisure activities and communication with distant partners. The program may involve the use of video calls to allow communication to participants with limited or no verbal skills. The program may be realized using a tablet (a) including Android 6.0 Operating System, proximity sensor, and multimedia player, and (b) fitted with a SIM card and applications such as WhatsApp Messenger and MacroDroid. The program may be easily adapted to the participants' characteristics in terms of activities available and partners to reach. PMID- 30306810 TI - 'So many women suffer in silence': a thematic analysis of women's written accounts of coping with endometriosis. AB - OBJECTIVE: To understand women's experiences of coping with endometriosis, and impact on their lives. DESIGN: Women accessed an online questionnaire through a U.K.-based endometriosis charity website. METHODS: Thirty-four women, aged 22-56 years, with self-reported medically-diagnosed endometriosis, 30 of whom were White, responded to open-ended questions, analysed using inductive thematic analysis. RESULTS: Participants spoke about their lives being a constant struggle, where they tried to maintain their personal and working lives whilst dealing with long-term pain. Women had to 'battle' for an accurate diagnosis, and had limited faith in health professionals. Coping strategies included avoidance of social events to conserve energy (self-pacing), and avoiding taking painkillers to retain alertness. Women did not feel able to be honest with family and friends about their symptoms, and felt socially isolated and misunderstood. CONCLUSIONS: Implications for health professionals are discussed, including the need for earlier diagnosis and taking women's symptoms more seriously at referral; understanding the need to conserve energy in the context of long-term pain; that not taking pain medication may be an active choice to retain alertness; and that avoiding being honest with friends and family and subsequent feelings of isolation may be common experiences relevant to designing treatment programmes. PMID- 30306811 TI - Potential pharmacobezoar formation of large size extended-release tablets and their dissolution - an in vitro study. AB - OBJECTIVE: Extended release (ER) tablets/capsules in massive ingestion overdoses are prone to form pharmacobezoars potentially increasing the risk of late appearing toxic effects and prolonged symptoms. Oral activated charcoal is often sufficient to prevent drug absorption, but in a recent massive ingestion of highly toxic substances, prior orogastric lavage might be considered. The disintegration characteristics of ER preparations in overdose situations is valuable to understand if the time line and course of the intoxication might be prolonged, but information on these characteristics are unavailable. Slow disintegration and/or pharmacobezoar formation, and the large size makes ER preparation impossible to evacuate using a 30F orogastric lavage tube. This study evaluates the disintegration and pharmacobezoar formation of a simulated massive ER tablet ingestion in an in vitro model, using a selection of extended release tablets, with different disintegrating characteristics when present in therapeutic numbers. Furthermore, the sizes of the formed pharmacobezoars were compared with the dimensions of a 30F orogastric lavage tube. METHOD: A standardized model mimicking the physical effects on pharmaceutical preparations in simulated gastric fluid (SGF) was developed and tested on three mono-depot ER tablets (quetiapine/Seroquel(r)XR 50 mg, paracetamol/Pinex(r)Retard 500 mg, verapamil/Isoptin(r)Retard 240 mg), one poly-depot ER tablet (carbamazepine/Tegretol(r)Retard 200 mg), and one immediate-release tablet (paracetamol/Panodil(r) 500mg). Thirty tablets were placed in polyamide mesh bags, either together in one bag or in separate bags, immersed in 1 L SGF, and incubated at 37 degrees C for 48 h. Released drugs were quantified at 0.5-48 h. RESULTS: Visual inspection showed that Seroquel(r)XR, Pinex(r)Retard, and Isoptin(r)Retard tablets formed firm pharmacobezoars stable for more than 4 h and intact fractions remained for up to 24 h. Drug releases were reduced by 53%, 40%, and 31%, respectively, for up to 8 h compared to separated tablets. Light microscopy showed that contact with SGF transformed the coating of Seroquel(r)XR and Pinex(r)Retard to a diffusion-controlled swelled gel-layer, and the Isoptin(r)Retard tablets into a rigid and slow-releasing matrix. Tegretol(r)Retard disintegrated into microspheres within 30 min, and Panodil(r) disintegrated within minutes. DISCUSSION: The developed pharmacobezoars of mono depot ER tablets demonstrated prolonged drug release. Neither the formed pharmacobezoars, nor the single tablets of the tested mono-depot ER preparations, would pass through the lumen of a standard orogastric lavage tube, rendering this modality ineffective for tablet removal in gastrointestinal decontamination. PMID- 30306812 TI - Poison center exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products in the United States 2007-2016. AB - BACKGROUND: Overdoses due to therapeutic misuse result when the maximum dose of a drug is exceeded while using it for its intended purpose, due to either intentionally exceeding the label dose, misunderstanding the label or use of more than one product with the same ingredient. Nonprescription acetaminophen containing combination products have been hypothesized to be a risk for therapeutic misuse. This study assessed the contribution of nonprescription acetaminophen-containing products to Poison Center exposures and the time trend in these exposures since public attention was brought to their potential risks. METHODS: The National Poison Data System (NPDS) was used to identify exposures involving acetaminophen-containing products in individuals 12 years or older for the period 2007-2016. Exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products were identified and demographic and clinical features of these exposures tabulated. Product sale and US population data were used to normalize the exposures. RESULTS: Therapeutic misuse exposures involving nonprescription acetaminophen-containing combination products decreased from 8753 in 2007 to 6278 in 2016. The majority of exposures occurred in individuals 12-29 years of age. The rate of therapeutic misuse exposures was highest in the 12-19 years of age cohort with an estimated 638 exposures per million population per 10 years. More than one acetaminophen-containing product was involved in 24.8% of exposures. Individuals were hospitalized in 5.4% of exposures and 51 deaths occurred in the 10-year observation period in reported exposures. CONCLUSIONS: NPDS exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products are infrequent and the number of exposures decreased from 2007 to 2016. Nonetheless, these exposures impact poison centers, healthcare facilities and patients. Additional initiatives to educate consumers on the safe use of these products and innovative labeling efforts to prevent concurrent use of multiple acetaminophen-containing products should be continued and are encouraged. PMID- 30306813 TI - High intensity focused ultrasound treatment of adenomyosis: a comparative study. AB - OBJECTIVE: To compare the treatment efficacy and safety of high intensity focused ultrasound (HIFU) on its own, HIFU combined with levonorgestrel-releasing intrauterine system (LNG-IUS) and HIFU combined with gonadotropin-releasing hormone agonist (GnRHa). METHOD: Seventy-eight patients with adenomyosis who underwent HIFU treatment were retrospectively analyzed. Among them, 45 patients were treated only with HIFU, 15 patients were treated with HIFU combined with LNG IUS and 18 patients were treated with HIFU combined with GnRHa. Dysmenorrhea scores, menstrual blood volumes, uterine volumes and adenomyotic lesion volumes were evaluated 1, 6 and 12 months after HIFU. RESULT: After treatment, dysmenorrhea score, menstrual blood volume, uterine volume and adenomyotic lesion volume significantly decreased in all three groups (p < 0.05). No significant difference was observed among the HIFU group, HIFU with LNG-IUS group and HIFU with GnRHa group 1 month after HIFU. However, 6 and 12 months after HIFU, dysmenorrhea score, menstrual blood volume, uterine volume and adenomyotic lesion volume decreased significantly more in the HIFU with LNG-IUS group and HIFU with GnRH-a group than in the group treated with HIFU on its own (p < 0.05). CONCLUSION: HIFU can be effectively used in the management of adenomyosis. Based on the results of this study with a limited number of patients, our study suggested that combining HIFU with LNG-IUS or GnRHa may provide a superior clinical effect compared to HIFU treatment on its own. PMID- 30306814 TI - Letter to the editor: "safety of nonsteroidal anti-inflammatory drugs in copperhead snakebite patients" by Pham and Mullins, Clin Toxicol 2018 May 18. PMID- 30306815 TI - Epidemiology and outcome of acute kidney injury due to venomous animals from a subtropical region of India. AB - AIM: To study the epidemiology and outcome of acute kidney injury (AKI) caused by venomous animals. METHODS: A retrospective study of patients admitted at Indira Gandhi Medical College Hospital, Shimla, with AKI due to venomous animals over a period of 15 years (January 2003-December 2017). Medical records were evaluated for patient information on demographic factors, clinical characteristics, complications, and outcome. Outcomes of requirement for intensive care unit (ICU) support, treatment with dialysis, survival, and mortality were analyzed. The survival and non-survival groups were compared to see the difference in the demographic factors, laboratory results, clinical characteristics, and complications. RESULTS: One hundred and eighty-one patients were diagnosed with AKI caused by venomous creatures. Mean age was 44 +/- 15.4 years, and the majority (54.1%) was women. Snakebite (77.9%) and wasp stings (19.9%) were the leading causes of AKI. Clinical details were available in 148 patients. The median duration of arrival at hospital was two days. 81.8% had oliguria, and 54.7% had a history of hematuria or having passed red or brown colored urine. The hematological and biochemical laboratory abnormalities were as follows: anemia (75%), leukocytosis (75.7%), hyperkalemia (35.8%), severe metabolic acidosis (46.6%), hepatic dysfunction (54.7%), hemolysis (85.8%), and rhabdomyolysis (65.5%). Main complications were as follows: gastrointestinal bleed (9.5%), seizure/encephalopathy (10.8%), and pneumonia/acute respiratory distress syndrome (ARDS) (11.5%). 82.3% of the patients required dialysis. 154 (85.1%) patient survived, and 27 (14.9%) patients died. As compared to the survival group, the white blood cell count, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and lactate dehydrogenase were significantly higher, and serum albumin levels were significantly lower in patients who died. The proportion of patients with leukocytosis, hyperkalemia, metabolic acidosis, pneumonia/ARDS, seizure/encephalopathy, need for ICU support, and dialysis was significantly higher in patients who died. CONCLUSIONS: Snakebite and multiple Hymenoptera stings (bees and wasps) were the leading causes of AKI due to venomous animals. AKI was severe, a high proportion required dialysis, and the mortality was high. PMID- 30306816 TI - Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity. AB - BACKGROUND: Cyanide is a deadly compound used as a terrorist agent. Current FDA approved antidotes require intravenous administration, limiting their utility in a mass casualty scenario. Dimethyl trisulfide (DMTS), a sulfur-based molecule, binds cyanide converting it to the less toxic by-product thiocyanate. Studies evaluating efficacy in rodents have been performed, but a large, clinically relevant animal model has not been reported. OBJECTIVE: This study evaluates the efficacy of intramuscular DMTS on survival and clinical outcomes in a swine model of acute, severe cyanide toxicity. METHODS: Anesthetized swine were instrumented for continuous monitoring of hemodynamics. Prior to potassium cyanide infusion animals were acclimated and breathing spontaneously. At 5-minutes post-apnea animals were treated with DMTS or saline. Vital signs, hemodynamics, and laboratory values were evaluated at various time points. RESULTS: Baseline values and time to apnea were similar in both groups. Survival in the DMTS treated group was 83.3% and 0% in saline controls (p = .005). The DMTS group returned to breathing at a mean time of 19.3 +/- 10 min after antidote, control animals did not return to breathing (CI difference 8.8, 29.8). At the end of the experiment or time of death, mean lactate was 9.41 mmol/L vs. 4.35 mmol/L (CI difference 10.94,0.82) in the saline and DMTS groups, respectively and pH was 7.20 vs. 7.37 (CI difference -0.04, 0.38). No adverse effects were observed at the injection site. CONCLUSION: Intramuscular administration of DMTS improves survival and clinical outcomes in our large animal swine model of acute cyanide toxicity. PMID- 30306818 TI - Phonological false recognition produced by bottom-up automatic activation in young and older people. AB - Two experiments explored a new procedure to implicitly induce phonological false memories in young and older people. On the study tasks, half of the words were formed from half of the letters in the alphabet, whereas the remaining words were formed from all the letters in the alphabet. On the recognition tests, there were three types of non-studied new words: critical lures formed from the same half of the letters as the studied words; distractors formed from the other half of the letters not used, and distractors formed from all the letters in the alphabet. In both experiments, the results showed that, in both young and older people, critical lures produced more false recognitions than distractors composed of all the letters in the alphabet, which, in turn, produced more false alarms than distractors composed of the letters not used during the study. These results support the predictions of the activation/monitoring models, which assume that false memories are partly due to activation spreading from items (semantically or phonologically) related to the critical words. PMID- 30306817 TI - Automatic segmentation of cardiac substructures from noncontrast CT images: accurate enough for dosimetric analysis? AB - PURPOSE: We evaluated the feasibility of using an automatic segmentation tool to delineate cardiac substructures from noncontrast computed tomography (CT) images for cardiac dosimetry and toxicity analyses for patients with nonsmall cell lung cancer (NSCLC) after radiotherapy. MATERIAL AND METHODS: We used an in-house developed multi-atlas segmentation tool to delineate 11cardiac substructures, including the whole heart, four heart chambers, and six greater vessels, automatically from the averaged 4D-CT planning images of 49 patients with NSCLC. Two experienced radiation oncologists edited the auto-segmented contours. Times for automatic segmentation and modification were recorded. The modified contours were compared with the auto-segmented contours in terms of Dice similarity coefficient (DSC) and mean surface distance (MSD) to evaluate the extent of modification. Differences in dose-volume histogram (DVH) characteristics were also evaluated for the modified versus auto-segmented contours. RESULTS: The mean automatic segmentation time for all 11 structures was 7-9 min. For the 49 patients, the mean DSC values (+/-SD) ranged from .73 +/- .08 to .95 +/- .04, and the mean MSD values ranged from 1.3 +/- .6 mm to 2.9 +/- 5.1 mm. Overall, the modifications were small; the largest modifications were in the pulmonary vein and the inferior vena cava. The heart V30 (volume receiving dose >=30 Gy) and the mean dose to the whole heart and the four heart chambers were not different for the modified versus the auto-segmented contours based on the statistically significant condition of p < .05. Also, the maximum dose to the great vessels was no different except for the pulmonary vein. CONCLUSIONS: Automatic segmentation of cardiac substructures did not require substantial modifications. Dosimetric evaluation showed no significant difference between the auto-segmented and modified contours for most structures, which suggests that the auto-segmented contours can be used to study cardiac dose-responses in clinical practice. PMID- 30306819 TI - Anatomical variants of upper arm veins on preoperative mapping venography for hemodialysis access in Korean adults. AB - INTRODUCTION: The number of elderly patients requiring hemodialysis has increased, along with the need for multiple vascular access placements. Thus, the frequency of access creation using the upper arm veins, including transposed basilic arteriovenous fistula, has also increased. The purpose of this study was to identify the prevalence of anatomical variations in the upper arm veins on preoperative mapping venography and to investigate the implications of such variants on access creation. METHODS: A total of 494 venograms were performed on 251 patients for primary access creation from June 2014 to June 2017 in this single-center, retrospective study. The venograms were classified into eight subtypes, based on the anatomical relationship between the basilic and brachial veins. The presence of bifid cephalic arches and brachial-basilic ladders was also examined. RESULTS: The presence of bifid cephalic arches and brachial basilic ladders was identified in 8.7% and 14.0% of cases, respectively. Paired brachial veins joined separately with the basilic vein in 67.4% of venograms, whereas these veins merged into a common brachial vein before connecting to the basilic vein in 13.1% of cases. A single brachial vein was present in 19.3% of cases. 15.7% of cases were considered unsuitable for basilic vein transposition due to the early confluence of the brachial-basilic vein, posing a risk of obliterating the deep venous drainage if transposed. CONCLUSION: There are significant anatomical variations of upper arm veins, and the recognition of certain variants can affect surgical planning and outcomes of access placement. It is important to identify anatomical variants of the upper arm veins during preoperative vein mapping. PMID- 30306820 TI - The interaction between temporal grouping and phonotactic chunking in short-term serial order memory for novel verbal sequences. AB - The current study investigated the ways long-term memory contributes to short term serial order memory of novel verbal sequences, focusing on long-term knowledge of bi-element frequency, that is, co-occurrence frequency of two consecutive elements in a linguistic environment. Participants performed two types of immediate serial recall of nine-element (nine-mora) sequences: low bi mora frequency sequences where all eight associations between the nine morae were low frequency, and mixed bi-mora frequency sequences, with high-frequency associations for six of the eight bi-morae. Experiment 1 confirmed the bi directional bi-mora frequency effect, meaning better recall performance for morae having high-frequency association with either the preceding mora (forward association) or the following mora (backward association). In Experiment 2, two temporal pauses were inserted in each list to disrupt high-frequency associations with the preceding mora or the following mora. The results showed that the bi element frequency effect diminished when the high-frequency backward association was disrupted but the effect remained when the high-frequency forward association was disrupted. We discuss possible mechanisms underlying the asymmetric influence of temporal pauses on interactions between short-term memory and linguistic long term memory. PMID- 30306821 TI - Effects of sprint interval exercise dose and sex on circulating irisin and redox status markers in adolescent swimmers. AB - Irisin and redox status markers seem to share common pathways of exercise-induced upregulation. The aim of the present study was to assess the effects of sprint interval swimming exercise dose and sex on the circulating levels of irisin and redox status markers in adolescent swimmers. Sixteen male and 16 female adolescent swimmers completed two sets of 4 * 50 m maximal freestyle swimming with a send-off time of 90 s, separated by 10 min of passive recovery. Venous blood samples were obtained pre-exercise (Pre), after the first set (Post1) and after the second set (Post2). Males had higher irisin levels than females. Reduced glutathione (GSH, MUmol g Hb-1) increased from 8.6 (2.2) [pooled males and females, mean (SD) throughout] at Pre to 9.4 (2.1) at Post1 and Post2. Total antioxidant capacity (MUmol DPPH mL-1) increased from 0.89 (0.17) at Post1 to 0.94 (0.16) at Post2. 8-hydroxy-2'-deoxyguanosine (ng mL-1) increased from 20.9 (6.9) at Pre and 21.5 (7.1) at Post1 to 25.0 (10.9) at Post2. Overall, sprint interval swimming exercise induced small but potentially effective changes in the studied parameters. Exercise dose influenced the GSH and 8-OHdG responses, and sex affected irisin levels. PMID- 30306822 TI - Understanding the track and field sprint start through a functional analysis of the external force features which contribute to higher levels of block phase performance. AB - This study aimed to identify the continuous ground reaction force (GRF) features which contribute to higher levels of block phase performance. Twenty-three sprint trained athletes completed starts from their preferred settings during which GRFs were recorded separately under each block. Continuous features of the magnitude and direction of the resultant GRF signals which explained 90% of the variation between the sprinters were identified. Each sprinter's coefficient score for these continuous features was then input to a linear regression model to predict block phase performance (normalised external power). Four significant (p < 0.05) predictor features associated with GRF magnitude were identified; there were none associated with GRF direction. A feature associated with greater rear block GRF magnitudes from the onset of the push was the most important predictor (beta = 1.185), followed by greater front block GRF magnitudes for the final three quarters of the push (beta = 0.791). Features which included a later rear block exit (beta = 0.254) and greater front leg GRF magnitudes during the mid-push phase (beta = 0.224) were also significant predictors. Sprint practitioners are encouraged, where possible, to consider the continuous magnitude of the GRFs produced throughout the block phase in addition to selected discrete values. PMID- 30306823 TI - MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells. AB - Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss miR-216b mimics with and without a 5' phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells. PMID- 30306824 TI - Caution using data from triaxial accelerometers housed in player tracking units during running. AB - Usage of accelerometers within player tracking devices in sport to quantify load, vertical ground reaction force (vGRF) or energy expenditure is contrary to placement guidelines. This study aimed to determine whether trunk-mounted accelerometers were a valid and reliable method to estimate thoracic segment or centre of gravity (COG) acceleration or vGRF, and the whether the elasticised harness contributes to the overestimation of acceleration. Ten male amateur rugby players performed five linear running tasks per lower limb at three speeds, twice, each with a different player tracking unit. Three-dimensional data were recorded and triaxial accelerometers were attached lateral to the device on the harness and skin and both shanks. Accelerometers demonstrated poor reliability (ICC:0.0-0.67), high variability (CV%:14-33%) and change in mean (41-160%), and were not valid to estimate vertical acceleration of the COG and thoracic segment nor vGRF. Caution is advised when utilising trunk-mounted triaxial accelerometer data as it is not a valid or reliable means to estimate peak vertical acceleration for its thoracic location nor whole-body COG acceleration or vGRF during running. To improve player tracking instrument validity and reliability, a new attachment method and/or harness material(s), that reduce or eliminate extraneous acceleration during running, are urgently required. PMID- 30306825 TI - Anterior resection for rectal cancer in Sweden: validation of a registry-based method to determine long-term stoma outcome. AB - BACKGROUND: A permanent stoma after anterior resection for rectal cancer is common. Nationwide registries provide sufficient power to evaluate factors influencing this phenomenon, but validation is required to ensure the quality of registry-based stoma outcomes. METHODS: Patients who underwent anterior resection for rectal cancer in the Northern healthcare region of Sweden between 1 January 2007 and 31 December 2013 were reviewed by medical records and followed until 31 December 2014 with regard to stoma outcome. A registry-based method to determine nationwide long-term stoma outcomes, using data from the National Patient Registry and the Swedish Colorectal Cancer Registry, was developed and internally validated using the chart reviewed reference cohort. Accuracy was evaluated with positive and negative predictive values and Kappa values. Following validation, the stoma outcome in all patients treated with an anterior resection for rectal cancer in Sweden during the study period was estimated. Possible regional differences in determined stoma outcomes between the six Swedish healthcare regions were subsequently evaluated with the chi2 test. RESULTS: With 312 chart reviewed patients as reference, stoma outcome was accurately predicted through the registry-based method in 299 cases (95.8%), with a positive predictive value of 85.1% (95% CI 75.8%-91.8%), and a negative predictive value of 100.0% (95% CI 98.4%-100.0%), while the Kappa value was 0.89 (95% CI 0.82-0.95). In Sweden, 4768 patients underwent anterior resection during the study period, of which 942 (19.8%) were determined to have a permanent stoma. The stoma rate varied regionally between 17.8-29.2%, to a statistically significant degree (p = .001). CONCLUSION: Using data from two national registries to determine long-term stoma outcome after anterior resection for rectal cancer proved to be reliable in comparison to chart review. Permanent stoma prevalence after such surgery remains at a significant level, while stoma outcomes vary substantially between different healthcare regions in Sweden. PMID- 30306826 TI - Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? AB - Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer. Here, we discuss nutritional and other possible routes to counteract the age-mediated decline of spermidine levels. PMID- 30306827 TI - Large-Scale Preparation of Extracellular Vesicles Enriched with Specific microRNA. AB - IMPACT STATEMENT: This article describes a method for producing microRNA (miRNA) enriched extracellular vesicles in large quantities. It enables in vivo delivery of specific miRNA for therapeutic applications. PMID- 30306828 TI - Visuospatial working memory, auditory discrimination, and attention. AB - The present study examined the degree to which tests of visuospatial storage capacity tap into domain-general storage and attention processes. This was done by comparing performance of visuospatial memory tasks with performance on sound based sensory discrimination tasks. We found that memory task- and discrimination task performance both tapped into a cross-modality factor (visual and auditory). We further examined the degree to which this common variance could be explained by attention control and sustained attention. These attention factors accounted for roughly 60% of the variance in memory. This indicates that tests of visuospatial memory capacity reflect more than modality-specific memory. PMID- 30306829 TI - A new age-period-cohort model for cancer surveillance research. AB - We develop a new age-period-cohort model for cancer surveillance research; the theory and methods are broadly applicable. In the new model, cohort deviations are weighted to account for the variable number of periods that each cohort is observed. Weighting ensures that the fitted rates can be naturally expressed as a function of age * a function of period * a function of cohort. Furthermore, the age, period, and cohort deviations are split into orthogonal quadratic components plus higher-order terms. These decompositions enable powerful combination significance tests of first- and second-order age, period, and cohort effects. The regression parameters of the orthogonal quadratic polynomials (global curvatures) quantify how fast on average the trends in the rates are changing. Importantly, the global curvature for cohort determines the least squares slope of the expected annual percentage changes by age group versus age (local drifts), thereby providing a powerful one-degree-of-freedom test of age-period interactions. We introduce new estimable functions, including age gradients that quantify the rate of change of the longitudinal and cross-sectional age curves at each attained age, and gradient shifts that quantify how the cross-sectional age trend varies by period. We illustrate the new model using nationally representative multiple myeloma incidence. Comprehensive proofs are given in technical appendices. We provide an R package. PMID- 30306830 TI - Generation of Functional Human Adipose Tissue in Mice from Primed Progenitor Cells. AB - Adipose tissue is used extensively in reconstructive and regenerative therapies, but transplanted fat often undergoes cell death, leading to inflammation, calcification and requirement for further revision surgery. Previously we have found that mesenchymal progenitor cells within human adipose tissue can proliferate in 3-dimensional culture under pro-angiogenic conditions. These cells (Primed ADipose progenitor cells=PADS) robustly differentiate into adipocytes in vitro (ad-PADS). The goal of the present study is to determine whether ad-PADS can form structured adipose tissue in-vivo, with potential for use in surgical applications. Grafts formed from ad-PADS were compared to grafts formed from adipose tissue obtained by liposuction after implantation into nude mice. Graft volume was measured by micro-CT scanning, and the functionality of cells within the graft was assessed by quantifying circulating human adiponectin. The degree of graft vascularization by donor or host vessels, and the content of human or mouse adipocytes within the graft were measured using species-specific endothelial and adipocyte specific qRT-PCR probes, and histochemistry with mouse and human-specific lectins. Our results show that ad-PADS grafted subcutaneously into nude mice induce robust vascularization from the host, continue to increase in volume over time, express the human adipocyte marker PLIN1 at levels comparable to human adipose tissue, and secrete increasing amounts of human adiponectin into the mouse circulation. In contrast, grafts composed of adipose tissue fragments obtained by liposuction become less vascularized, develop regions of calcification and decreased content of PLIN1, and secrete lower amounts of adiponectin per unit volume. Enrichment of liposuction tissue with ad PADS improves vascularization, indicating that ad-PADS may be pro-angiogenic. Mechanistically, ad-PADS express an extracellular matrix gene signature that includes elements previously associated with small vessel development (COL4A1). Thus, through the formation of a pro-angiogenic environment ad-PADS can form functional adipose tissue with capacity for long-term survival, and can potentially be used to improve outcomes in reconstructive and regenerative medicine. PMID- 30306831 TI - Changes in cognitive distortions and affectivity levels in adolescent depression after acute phase fluoxetine treatment. AB - INTRODUCTION: It is supposed that both antidepressants and psychotherapies work in a manner consistent with cognitive theories of depression when changing negative affective and cognitive distortions. This study evaluated changes in cognitive distortions (i.e. systematic misinterpretations of new information) and affectivity in adolescent major depressive disorder (MDD) after acute phase treatment with fluoxetine. METHODS: Twenty-five adolescents (mean age 15.10 years (SD = 1.19); 17 (68%) females) with MDD receiving fluoxetine were followed for 8 weeks. Clinician rating scales of MDD and self-reports of cognitive distortions and affectivity were completed before and after the treatment. RESULTS: Seven (28%) adolescents showed significant improvement in cognitive distortions, 11 (44%) showed a significant decrease in negative affect, and 15 (60%) showed a significant increase in positive affect. The responders to fluoxetine had significantly decreased level of negative affect (62.5%) and an increased level in positive affect (81.2%) compared to non-responders, whereas there were no differences between the two regarding changes in cognitive distortions. CONCLUSIONS: Treatment with fluoxetine over 8 weeks led to reductions in cognitive distortions, with decreased negative and increased positive affect in adolescents with MDD. Improvements in affectivity levels closely corresponded to reductions in depressive symptoms and were greater than improvements in cognitive distortions. PMID- 30306832 TI - Acute intraocular pressure responses to high-intensity interval-training protocols in men and women. AB - We aimed (1) to test the acute impact of two high-intensity interval-training (HIIT) protocols differing in the level of effort on intraocular pressure (IOP) responses, and (2) to elucidate whether the IOP responses differ between men and women. Twenty-four physically active collegiate (12 men and 12 women) performed three protocols: low-fatigue HIIT (eight 30-m sprints with 60-s of rest), high fatigue HIIT (eight 30-m sprints with 30-s of rest), and control (walking). IOP was taken at baseline, after sprints and recovery by rebound tonometry. Our data revealed an acute IOP reduction during both HIIT protocols compared to the control condition (effect size [ES]:0.81-1.65). The differences between both HIIT protocols were generally negligible (ES<0.30), however, the reduction of IOP was moderately higher for the low-fatigue HIIT protocol after the 7th (ES: 0.67) and 8th (ES: 0.74) sprints. Women showed a more prominent lowering effect on IOP during the control condition (ES: 0.42-1.02), and during the two first sprints of both HIIT protocols (ES: 0.54-1.03). These findings highlight that a time efficient HIIT protocol may acutely reduce IOP levels, while low-fatigue HIIT protocol could be recommended since it induced a higher reduction on IOP than the high-fatigue HIIT protocol. PMID- 30306833 TI - Joint modeling of multiple repeated measures and survival data using multidimensional latent trait linear mixed model. AB - Impairment caused by Amyotrophic lateral sclerosis (ALS) is multidimensional (e.g. bulbar, fine motor, gross motor) and progressive. Its multidimensional nature precludes a single outcome to measure disease progression. Clinical trials of ALS use multiple longitudinal outcomes to assess the treatment effects on overall improvement. A terminal event such as death or dropout can stop the follow-up process. Moreover, the time to the terminal event may be dependent on the multivariate longitudinal measurements. In this article, we develop a joint model consisting of a multidimensional latent trait linear mixed model (MLTLMM) for the multiple longitudinal outcomes, and a proportional hazards model with piecewise constant baseline hazard for the event time data. Shared random effects are used to link together two models. The model inference is conducted using a Bayesian framework via Markov chain Monte Carlo simulation implemented in Stan language. Our proposed model is evaluated by simulation studies and is applied to the Ceftriaxone study, a motivating clinical trial assessing the effect of ceftriaxone on ALS patients. PMID- 30306834 TI - Patterns of Physical Activity Adherence by Adolescents With Diabetes or Obesity Enrolled in a Personalized Community-Based Intervention. AB - PURPOSE: The purpose of this study was to determine the feasibility of a personalized, 16-week community-based physical activity intervention for adolescents with diabetes or obesity and examine the weekly patterns of adherence to the intervention. METHODS: Physical activity adherence was evaluated throughout the intervention using accelerometers in 46 adolescents with type 1 diabetes (N = 22), type 2 diabetes (N = 12), or obesity (N = 12) (age, 14.4 +/- 1.5 years; 56.5% female; 61% Hispanic). Of these, 39 completed the intervention, and 7 did not. RESULTS: There were no differences in baseline anthropometric characteristics or fitness between the completers versus noncompleters. Completers began above 1060 metabolic equivalent (MET) min/wk-1and stayed above 900 MET min/wk-1 for ~4 weeks and declined 39 MET min/wk-1 until end of study. Noncompleters began at 924 MET min/wk-1 yet dropped below 800 MET min/wk-1 by end of week 1 and declined an average of 151 MET min/wk-1. Interestingly, self-report of barriers to activity were higher in completers versus noncompleters. CONCLUSIONS: Findings highlight that adolescents completing the intervention could sustain a prescribed level of personalized activity for at least 1 month but had steadfast declines in weekly activity. Even with individualized programs, factors other than barriers to activity need to be considered when designing approaches to physical activity adherence for adolescents with diabetes or obesity. PMID- 30306835 TI - Selection of recycling centre locations by using the interval type-2 fuzzy sets and two-objective genetic algorithm. AB - In the sense of contemporary industrial challenges, it may be said that many issues in the field of recycling may be analysed. In this paper, the model for choosing locations for construction of recycling centres equipped with new technology is proposed. The considered problem may be stated as a two-objective optimization problem, if the optimization criteria are presented as total distance and the overall suitability index sum. The relative importance and values of possible locations' attributes are described by pre-defined linguistic expressions, and modelled by interval triangular type-2 fuzzy numbers. Type-2 fuzzy numbers provide a possibility to incorporate the uncertainty of membership functions into the fuzzy set theory. The procedure for determination of the overall suitability index is proposed. Selection of the most appropriate locations is achieved by a two-objective genetic algorithm, since it is very suitable for the routing issues. The proposed model application is illustrated with the real-life data that come from a few regions in Serbia. PMID- 30306836 TI - Fibronectin and Collagen IV Microcontact Printing Improves Insulin Secretion by INS1E Cells. AB - IMPACT STATEMENT: This research deals with finding a proper bioengineering strategy for the creation of improved beta-cell replacement therapy in type 1 diabetes. It specifically deals with the microenvironment of beta-cells and its relationship to their endocrine function. PMID- 30306837 TI - Influence of mesophilic and thermophilic conditions on the anaerobic digestion of food waste: Focus on the microbial activity and removal of long chain fatty acids. AB - The mesophilic reactor (MR) exhibited advantages in biogas production and performance stability over thermophilic reactor (TR) during the long-term anaerobic digestion (AD) of food waste (FW) with stepwise organic loading rate elevating. It was interesting to explore the mechanism causing the divergences in performances between these two reactors. The microbial activity was compared on day 110 when TR began to deteriorate. The results show that MR had significantly higher specific acetoclastic methanogenic activities (SAMA) and specific propionate and butyrate oxidative activities (SPOA and SBOA) than TR. The SAMA, SPOA and SBOA in TR were only 50.3%, 18.6% and 46.4% of those values in MR, respectively. Remarkably, the specific hydrogenotrophic methanogenic activity of 15.5+/-2.1, 15.7+/-4.6 mmol CH4.L-1 original slurry.d-1 in MR and TR was comparative with insignificant difference, which indicates that the microbial activity in TR had been inhibited widely apart from the hydrogenotrophic methanogenesis. Additionally, many particles with the diameters of 1-2 mm were observed to form in MR and identified as complexes of calcium and long chain fatty acids (LCFAs). The formation of calcium crystallization might alleviate the inhibition of LCFAs during AD of FW, which further supports the better performance in MR than TR. PMID- 30306838 TI - Bi-level variable selection for case-cohort studies with group variables. AB - The case-cohort design is an economical approach to estimate the effect of risk factors on the survival outcome when collecting exposure information or covariates on all patients is expensive in a large cohort study. Variables often have group structure such as categorical variables and highly correlated continuous variables. The existing literature for case-cohort data is limited to identifying non-zero variables at individual level only. In this article, we propose a bi-level variable selection method to select non-zero group and within group variables for case-cohort data when variables have group structure. The proposed method allows the number of variables to diverge as the sample size increases. The asymptotic properties of the estimator including bi-level variable selection consistency and the asymptotic normality are shown. We also conduct simulations to compare our proposed method with some existing method and apply them to the Busselton Health data. PMID- 30306839 TI - Validity and reliability of a novel optoelectronic device to measure movement velocity, force and power during the back squat exercise. AB - This study analysed the validity and reliability of a new optoelectronic device (Velowin) for the measurement of vertical displacement and velocity as well as to estimate force and mechanical power. Eleven trained males with Mean (SD) age = 27.4 (4.8) years, completed an incremental squat exercise test with 5 different loads (<30-90% of their 1-repetition maximum) while displacement and vertical velocity of the barbell were simultaneously measured using an integrated 3D system (3D motion capture system + force platform) and Velowin. Substantial to almost perfect correlation (concordance correlation coefficient = 0.75-0.96), root mean square error as coefficient of variation +/-90% confidence interval <=10% and good to excellent intraclass correlation coefficient = 0.84-0.99 were determined for all the variables. Passing and Bablock regression methods revealed no differences for average velocity. However, significant but consistent bias were determined for average or peak force and power while systematic and not proportional bias was found for displacement. In conclusion, Velowin, in holds of some potential advantages over traditionally used accelerometer or linear transducers, represents a valid and reliable alternative to monitor vertical displacement and velocity as well as to estimate average force and mechanical power during the squat exercise. PMID- 30306841 TI - President's Message. PMID- 30306842 TI - Violence in the Workplace. PMID- 30306840 TI - Effects of pitch spatial references on players' positioning and physical performances during football small-sided games. AB - The aim of this study was to identify the effects of adding spatial references during football small-sided games in youth players' tactical and physical performance. Twelve under-15 players performed a Gk+ 6v6+ Gk game under two playing conditions: (i) without spatial references (CONTROL condition); (ii) with spatial references, by dividing equally the pitch into three corridors and three sectors (experimental situation, LINES). Players' positional data was used to compute time-motion and tactical-related variables. The results revealed that performance under LINES situation increased the regularity in the zones occupied (~14%, Cohen's d: 0.5; +/-0.3; p = 0.003) and in the distance between teammates' dyads (~19%, 0.9; +/-0.2; p < 0.001). Oppositely, LINES condition decreased the longitudinal synchronization of players' displacements (0.4; +/-0.2; p = 0.002), players' average speed (0.5; +/-0.3; p = 0.002) and distance covered at lower (0.9; +/-0.3; p < 0.001) and moderate speed (0.5; +/-0.3; p < 0.001). Adding spatial references seems to promote a more structured pattern of play and increase positional regularity. However, coaches should be aware that this constraint may decrease the synchronization between players. Overall, these findings may be generalized to most invasion team sports. PMID- 30306843 TI - The Power of Mentorship in Cultivating TCN Scholars. PMID- 30306849 TI - Stimuli-responsive drug delivery nanocarriers in the treatment of breast cancer. AB - Stimuli-responsive drug-delivery nanocarriers (DDNs) have been increasingly reported in the literature as an alternative for breast cancer therapy. Stimuli responsive DDNs are developed with materials that present a drastic change in response to intrinsic/chemical stimuli (pH, redox and enzyme) and extrinsic/physical stimuli (ultrasound, light, magnetic field and electric current). In addition, they can be developed using different strategies, such as functionalization with signaling molecules, leading to several advantages, such as (a) improved pharmaceutical properties of liposoluble drugs, (b) selectivity with the tumor tissue decreasing systemic toxic effects, (c) controlled release upon different stimuli, which are all fundamental to improving the therapeutic effectiveness of breast cancer treatment. Therefore, this review summarizes the use of stimuli-responsive DDNs in the treatment of breast cancer. We have divided the discussions into intrinsic and extrinsic stimuli and have separately detailed them regarding their definitions and applications. Finally, we aim to address the ability of these stimuli-responsive DDNs to control the drug release in vitro and the influence on breast cancer therapy, evaluated in vivo in breast cancer models. PMID- 30306845 TI - Kisspeptin and the control of emotions, mood and reproductive behaviour AB - Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/Kiss1 gene) is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin-releasing hormone (GnRH) at the apex of the hypothalamic-pituitary-gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin based therapies to treat related disorders of body and mind. PMID- 30306850 TI - Sam domains in multiple diseases. AB - BACKGROUND: The sterile alpha motif (Sam) domain is a small helical protein module able to undergo homo- and hetero-oligomerization as well as polymerization thus forming different types of protein architectures. A few Sam domains are involved in pathological processes and consequently, they represent valuable targets for the development of new potential therapeutic routes. This study intends to collect state-of-the-art knowledge on the different modes by which Sam domains can favor disease onset and progression. METHODS: This review was build up by looking throughout the literature for: a) the structural properties of Sam domains, b) interactions mediated by a Sam module, c) presence of a Sam domain in proteins relevant for a specific disease. RESULTS: Sam domains appear crucial in many diseases including but not limited to cataracts, cancer, renal disorders. Often pathologies are linked to mutations directly positioned in the Sam domains that alter its stability and/or affect interactions that are crucial for proper protein functions. In only a few diseases the Sam motif plays a kind of "side role" and cooperates to the pathological event by enhancing the action of a different protein domain. CONCLUSION: Considering the many roles of the Sam domain into a significant variety of diseases, more efforts and novel drug discovery campaigns need to be engaged to find out small molecules and/or peptides targeting Sam domains. Such compounds may represent the pillars on which to build novel therapeutic strategies to cure different pathologies. PMID- 30306851 TI - Recent Advances and Challenges of the Drugs Acting on Monoamine Transporters. AB - BACKGROUND: The human monoamine transporters (hMATs) primary including hSERT, hNET and hDAT are important targets for the treatment of depression and other behavioral disorders with more than availability of 30 approved drugs. OBJECTIVE: This paper is to review the recent progress in the binding mode and inhibitory mechanism of hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor design and discovery. The structure activity relationship (SAR) and the selectivity for hit/lead compounds to hMATs that evaluated by in vitro and in vivo experiments will be highlighted. METHODS: PubMed and Web of Science database were searched for protein-ligand interaction, novel inhibitors design and synthesis studies related to hMATs. RESULTS: Literature data indicate that since the first crystal structure determinations of the homologous bacterial leucine transporter (LeuT) complexed with clomipramine, a sizable database of over 100 experimental structures or computational models has been accumulated that now defines a substantial degree of structural variability hMATs-ligands recognition. In the meanwhile, a number of novel hMATs inhibitors have been discovered by medicinal chemistry with significant help from computational models. CONCLUSION: The reported new compounds act on hMATs as well as the structures of the transporters complexed with diverse ligands by either experiment or computational modeling have shed light on the poly-pharmacology, multimodal and allosteric regulation of the drugs to transporters. All of the studies will greatly promote the structure-based drug design (SBDD) of structurally novel scaffolds with high activity and selectivity for hMATs. PMID- 30306852 TI - The glycogen synthase kinase-3 in the regulation of ion channels and cellular carriers. AB - Glycogen synthase kinase-3 (GSK-3) is a highly evolutionarily conserved and ubiquitously expressed serine/threonine kinase, an enzyme protein profoundly specific for glycogen synthase (GS). GSK-3 is involved in various cellular functions and physiological processes, including cell proliferation, differentiation, motility, and survival as well as glycogen metabolism, protein synthesis, and apoptosis. There are two isoforms of human GSK-3 (named GSK-3alpha and GSK-3beta) encoded by two distinct genes. Recently, GSK-3beta has been reported to function as a powerful regulator of various transport processes across the cell membrane. This kinase, GSK-3beta, either directly or indirectly, may stimulate or inhibit many different types of transporter proteins, including ion channel and cellular carriers. More specifically, GSK-3beta-sensitive cellular transport regulation involves various calcium, chloride, sodium, and potassium ion channels, as well as a number of Na+-coupled cellular carriers including excitatory amino acid transporters EAAT2, 3 and 4, high-affinity Na+ coupled glucose carriers SGLT1, creatine transporter 1 CreaT1, and the type II sodium/phosphate cotransporter NaPi-IIa. The GSK-3beta-dependent cellular transport regulations are part of the kinase functions in numerous physiological and pathophysiological processes. Clearly, additional studies are required to examine the role of GSK-3beta in many other types of cellular transporters as well as further elucidating the underlying mechanisms of GSK-3beta-mediated cellular transport regulation. PMID- 30306853 TI - NADPH producing enzymes as promising drug targets for Chagas Disease. AB - Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a cofactor used in different anabolic reactions, such as lipid and nucleic acid synthesis, and for oxidative stress defense. NADPH is essential for parasite growth and viability. In trypanosomatid parasites, NADPH is supplied by the oxidative branch of the pentose phosphate pathway and by enzymes associated with the citric acid cycle. The present article will review recent achievements that suggest glucose-6 phosphate dehydrogenase and the cytosolic isoform of the malic enzyme as promising drug targets for the discovery of new drugs against Trypanosoma cruzi and T. brucei. Topics involving an alternative strategy in accelerating T. cruzi drug-target validation and the concept of drug-target classification will also be revisited. PMID- 30306855 TI - Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder among elderly population, and it is depicted by the degeneration of dopaminergic neurons in the midbrain which is progressive. Up to the present time, the precise cause remains ill-defined and the mechanism of neurons death indeterminate. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidences have been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokines in peripheral blood, as well as, the presence of auto antibodies. In addition, the infiltration of T cell in CNS has been reported. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process. In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients and trying to link them to the potential exacerbation of the neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD. PMID- 30306854 TI - Structural and molecular tear film changes in glaucoma. AB - The tear film (TF) is a trilaminar and dynamic fluid covering the entire ocular surface (OS), consisting of a mucus, aqueous, and lipid layer deeply interacting between them. Because of its structure and functions, TF plays a pivotal role in the preservation of the OS integrity and the quality of vision. Medical therapy for glaucoma is recognized to profoundly disturb the OS homeostasis by altering all components of the ocular surface unit, including TF. The presence of preservatives, the number of daily eye drops instillations, and the duration of therapy are the main contributors to TF changes. From the physio-pathological side, TF alterations are induced by toxic and allergic mechanisms, and result from goblet cell and Meibomian gland loss, dysfunction of accessory lacrimal glands, and epithelial disruption. In detail, TF changes are represented by mucus layer thinning, reduced mucin concentration, aqueous layer volume reduction, and lipid layer thinning with increased tear evaporation. Hyper-osmolarity and instability represent the main hallmarks of these changes and are expression of a iatrogenic form of dry eye. TF undergoes also molecular modifications that primarily reflect a therapy- or disease-induced inflammatory status of the OS. Over the last years, this field of research gained a progressively growing interest since molecular variations may be considered as potential candidate biomarkers of glaucoma. The aim of this review is to report the main TF changes occurring during glaucoma, exploring the relationship they may have with the glaucoma-related ocular surface disease and the patient quality of life, and their utility as potential biomarkers of disease. PMID- 30306856 TI - Goniothalamin-Related Styryl Lactones. Isolation, Synthesis, Biological Activity and Mode of Action. AB - This review covers the chemistry and biological aspects of goniothalamin-related styryl lactones isolated from natural sources. This family of secondary metabolites has been reported to display diverse uses in folk medicine, but only a limited number of these compounds have been throughly investigated regarding their biological profile. Herein, we cover the goniothalamin-related styryl lactones having a C6-C3-C4 framework which appeared in the literature for the first time in the period 2000-2017, and the reports on the synthesis, biological activity and mechanism of action which were published from 2007-2017. PMID- 30306857 TI - Role of Fatty Acid Binding Protein 4 (FABP4) in Kidney Disease. AB - Accumulating evidences indicated that obesity and metabolic syndrome were independent risk factors for the development and progression of kidney diseases. Apart from inflammation, lipotoxicity, and hemodynamic factors, adipokines have been proposed to play crucial roles in the relationship between kidney diseases and metabolic disorders. As one of key adipokines, fatty acid binding protein 4 (FABP4), which is mainly expressed in adipocytes and macrophages, has recently been shown to be associated with renal dysfunction and kidney damage. Both clinical and experimental studies have proposed circulating FABP4 as a novel predictor for renal injuries, and it might also be a predictor for cardiovascular events in patients with end stage renal disease (ESRD). FABP4 has also been detected in the glomerular cells and epithelial tubular cells in mouse and human kidneys, and the expression of FABP4 in these cells has been involved in the pathogenesis of kidney diseases. In addition, experimental studies suggested that inhibition of FABP4 had protective effects on renal damage. Here, we reviewed current knowledge regarding the role of FABP4 in pathophysiological insights as well as its potential function as a predictor and therapeutic target for kidney diseases. PMID- 30306858 TI - Multimodal treatment of homozygous familial hypercholesterolemia. AB - BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease, associated with premature atherosclerotic cardiovascular disease (CVD), especially in its homozygous type (HoFH). OBJECTIVE: The aim of this review is to discuss the safety and efficacy of combination treatments (procedures and drugs) for HoFH. RESULTS: Historically, liver transplantation was used first; however, it is currently considered only as a last resort for some patients. In the mid 70's, LDL aphaeresis was introduced and remains up today the treatment of choice for patients of any age, despite its significant cost. The use of Ezetimibe results in additive 15-20% reductions in LDL-C regardless of therapeutic approach, while statins are modestly effective in patients with class 4 or 5 mutations, in which LDL receptors (LDLR) are present. One of the novel drugs for HoFH is Lomitapide, which is a highly effective oral agent, but is also exceedingly expensive ($350,000/year). Mipomersen is administered every week subcutaneously, is also effective but has been approved only in US mainly due to injection site reactions up to 80%. Both Lomitapide (mainly) and Mipomersen have been found to promote fat accumulation in the liver, resulting in subsequent serum transaminases elevations. PCSK9 inhibitors are effective in those with partial LDLR presence and function by reducing frequency of LDL apheresis, improve cost effectiveness of treatment. CONCLUSION: Pediatric and adult HoFH treatment needs combination of procedures and drugs. The main treatment is LDL-C apheresis aided by ezetimibe and PCSK9 inhibitors. Lomitapide needs caution, and liver transplantation is an alternative as the last resort. PMID- 30306859 TI - Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from PCSK9 inhibition to ANGPTL3 inactivation. AB - BACKGROUND: Drugs mimicking natural beneficial mutations, including that for familial hypercholesterolemia (FH), might represent the future of hypolipidemic drug treatment. OBJECTIVE: The aim of this review is to review the properties and the effects of these drugs, which are either already commercially available or are in the process to be approved for the treatment of dyslipidemia. RESULTS: More than a decade ago, it was accidentally discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations resulted in marked lifelong reduction of LDL-C and the incidence of cardiovascular disease (CVD). This provided the idea for a human anti-PCSK9 antibody. Along with dozens of phase II and III studies demonstrating unprecedented reductions in LDL-C levels, two large clinical trials established the substantial benefits of evolocumab and alirocumab on cardiovascular morbidity and mortality, on top of standard treatment. Evolocumab and alirocumab are now approved and used in clinical practice for the treatment of FH, statin intolerance, and high risk patients not achieving LDL-C targets. Anti RNA, small molecules, peptides and also protein fragments against PCSK9 are in phase 1 trials. Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism increasing triglycerides (TGs), remnants, and LDL-C. In a huge study, ANGPTL3 deficiency due to gene(s) loss-of-function was associated with substantial reductions in circulating TGs, LDL-C, and CVD. Evinacumab, an ANGPTL3 antibody, caused a dose-dependent reduction in fasting TG levels of up to 76% and LDL-C of up to 23% and CVD risk by 41%. There is also antisense oligonucleotide and micro-RNA-27b (miR-27b) against ANGPTL3. Two naturally occurring mutations in apo3 gene, A23T and K58E, reduce TGs and CVD risk. A monoclonal antibody targeting apoC-III has the same effect. CONCLUSIONS: Mimicking the beneficial naturally happening mutations in lipid metabolism pathways with biological drugs is probably the future of hypolipidemic drug treatment. PMID- 30306860 TI - New horizons in the pathogenesis, pathophysiology and treatment of familial hypercholesterolaemia. AB - BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal-dominant genetic disease andrepresents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300,000 births. FH is characterized by high to very high low density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic cardiovascular disease (CVD) or aortic stenosis. OBJECTIVE: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH. RESULTS: The most common (60-80%) FH cause is mutations of the LDL receptor (LDLR) protein (6 classes with different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and gain-of function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its pathogenesis. An autosomal recessive hypercholesterolaemia (ARH) is another cause, very rare (1/2.500 births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis. CONCLUSION: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9, while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its accumulation and subsequent CVD earlier than in the general population. PMID- 30306861 TI - Prevalence, Identification, and Scouting for Familial Hypercholesterolaemia including Registries. AB - BACKGROUND: Familial hypercholesterolemia (FH) is the most common metabolic genetic disorder, with around 13 million people worldwide having the disease. However, FH is globally underdiagnosed and undertreated, while the vast majority of those treated do not achieve treatment goals. OBJECTIVE: This review aims to clarify how to identify patients with FH. METHODS: We performed a comprehensive search of the literature to identify available data. RESULTS: Patients with FH are at high risk for cardiovascular events and death at an early age. Therefore, prompt detection of individuals with FH is of pivotal importance in order to implement appropriate preventive measures at a young age. Patient registries are a powerful tool for recording and monitoring a disease and encouraging clinical practices, subsequently improving outcomes and reducing healthcare costs. National FH registries are successfully applied in several countries (e.g. Spain, Denmark, UK, USA and the Netherlands). Importantly, the last few years the European Atherosclerosis Society (EAS) launched a global FH network aiming to collect data from specialized FH centres from different countries and establish a worldwide, standardised registry of patients with FH. CONCLUSION: It appears that the establishment and proper function of such registries will improve FH diagnosis, as well as preventive measures and management of FH patients. PMID- 30306862 TI - Development of an Information System of Structures and Force Field Parameters of Chemical Compounds from Sri Lankan Flora. AB - BACKGROUND: Sri Lanka offers a huge diversity of flora with a large proportion of those being endemic to the island. Both the endemic and native plants species serve as a rich bank of phytochemicals. METHOD: In this study, "Sri Lankan Flora" an online web-based information system of phytochemical compounds isolated from the flora of Sri Lanka was proposed. RESULTS: The database contained 3D structures of those compounds, calculated quantitative-structure-activity relationship (QSAR) data and the GROMOS 54a7 force field parameters for each and every compound. The manually curated chemical structures, activities and force field parameters provide a possible direct avenue for computer aided drug discovery. The present study is a continuing project with a wider goal of building up a database, not only for assisting the computer aided drug designing process, but also for other chemical applications, as the database includes structural, physical, chemical and dynamic properties of chemical compounds of flora of Sri Lanka. The database is freely accessible at: http://science.cmb.ac.lk/tools/slflora. PMID- 30306863 TI - Recent Advances in Glyoxalase-I Inhibition. AB - Glyoxalase system is a ubiquitous system in human cells which has been examined thoroughly for its role in different disease conditions. It is composed of Glyoxalase-I (Glo-I) and Glyoxalase-II which perform an essential metabolic process inside the cell by detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic D-lactic acid. Tumor cells are well-known for their high metabolic rate which results in elevated levels of toxic metabolites. The over-expression of Glo-I in tumor cells makes this enzyme a pivotal target for anticancer drug development. Glo-I is metalloenzyme with two polypeptide chains and encompasses two active sites with an integral zinc atoms at their center. This review aims to highlight the important role of Glo-I in different pathogenic conditions, and more importantly, it provides a thorough discussion of all known human Glo-I inhibitors since its discovery, a hundred years ago, up to date. It embraces the different classes they belongs to, their design and chemical structures. We believe this review will help guide the design of novel and potent human Glo-I inhibitors by providing a handy reference for interested researchers in this target. PMID- 30306864 TI - Design, Synthesis and Biological Potential of 5-(2-Amino-6-(3/4 bromophenyl)pyrimidin-4-yl)benzene-1,3-diol Scaffolds as Promising Antimicrobial and Anticancer agents. AB - Pyrimidine derivatives attracted organic chemists very much due to their biological and chemotherapeutic importance. A series of pyrimidine scaffolds of 5 (2-amino-6-(3/4-bromophenyl)pyrimidin-4-yl)benzene-1,3-diol derivatives was synthesized by Claisen-Schmidt condensation and its chemical structures were confirmed by physicochemical properties and spectral data (NMR, IR, Mass and elemental analyses) study. The synthesized compounds were screened their in vitro antimicrobial activity against bacterial and fungal strains by tube dilution method and anticancer activity against HCT-116 cancer cell line by SRB assay method. The antimicrobial results demonstrated that compounds, k6, k12, k14 and k20 were found to be most potent ones. The anticancer results indicated that compounds, k8 and k14 displayed potent anticancer activity against HTC116 cell line. PMID- 30306865 TI - 2-Mercaptobenzimidazole Schiff Bases: Design, Synthesis, Antimicrobial Studies and Anticancer Activity on HCT-116 Cell Line. AB - BACKGROUND: Increased rate of mortality due to the development of resistance to currently available antimicrobial and anticancer agents initiated the need to develop new chemical entities for the treatment of microbial infections and cancer. OBJECTIVE: The present study was aimed to synthesize and evaluate antimicrobial and anticancer activities of Schiff bases of 2 mercaptobenzimidazole. METHOD: The Schiff bases of 2-mercaptobenzimidazole was synthesized from 4-(2-(1H-benzo[d]imidazol-2-ylthio)acetamido)benzohydrazide. The synthesized compounds were evaluated for antimicrobial and anticancer activities by tube dilution method and sulforhodamine-B (SRB) assay respectively. RESULTS: Compounds 8 (MICpa, an = 2.41, 1.20 uM/ml), 10 (MICse, sa = 2.50 uM/ml), 20 (MICec = 2.34 uM/ml) and 25 (MICca = 1.46 uM/ml) showed significant antimicrobial activity against tested bacterial and fungal strains and compounds 20 (IC50 = 8 ug/ml) and 23 (IC50 = 7 ug/ml) exhibited significant anticancer activity. CONCLUSION: In general, the synthesized derivatives exhibited moderate antimicrobial and anticancer activity. Compounds 8 and 25 having high antifungal potential among the synthesized compounds may be taken as lead compound for the development of novel antifungal agents. PMID- 30306866 TI - Identifying Keystone Species in the Microbial Community Based on Cross- Sectional Data. AB - BACKGROUND: In microbial communities, the keystone species have a greater impact on the performance and dynamics of ecosystem than that of other species, in which we can see from the results that losing gut microbiome causes some specific diseases. A number of ongoing studies aim at identifying links between microbial community structure and human diseases. METHOD: In this paper, we have introduced a valid keystone species identification method, in which a new Spread Intensity (SI) algorithm is used. Because the accuracies of current keystone species identification algorithms are difficult to evaluate for the high diversity and uncultivated status of microbial communities, we simulated cross-sectional data of microbial communities with known interactions and set up standard keystoneness rankings using Generalized Lotka-Volterra (GLV) model. Subsequently, we compared the SI algorithm with existing methods by using simulated data and obtained an obvious better performance of SI algorithm than other methods. Also, we applied this method to gut microbiota datasets and identified some microbes having the potential association with body weight. We first assembled three correlation metrics to calculate the interspecies correlation. Then we applied network deconvolution to remove indirect correlations. Finally, we used Molecular Ecological Network Analysis (MENA) to construct the co-occurrence network. According to experimental results, SI algorithm has an excellent performance in identifying highly correlated species in gut microbiome to body weight. RESULT: This result provides an effective indicator for modulating gut microbiota and thus enables the gene therapy and other gene-level treatments for losing-weight and other gut-associated diseases. PMID- 30306867 TI - Human Disease System Biology. PMID- 30306869 TI - Solid Lipid Nanoparticles and Chitosan-coated Solid Lipid Nanoparticles as Promising Tool for Silybin Delivery: Formulation, Characterization, and In Vitro Evaluation. AB - BACKGROUND: Silybin (Sb) is the major flavolignan of the extract of Silybum marianum. It is used for treatment of various acute and chronic liver toxicities, inflammation, fibrosis and oxidative stress. Many studies indicate that Sb is also active against different carcinomas and it has been very recently proposed to be beneficial in type 2 diabetes patients. However, Sb is a low water soluble and low permeable compound. OBJECTIVE: In this study, solid lipid nanoparticles (SLNs) were proposed to enhance the solubility and the intestinal absorption of Sb. METHODS: SLNs were made of stearic acid and brij 78 and subsequently coated with chitosan. Formulations were physically and chemically characterized. Stability studies were also assessed. Sb in vitro release was evaluated in different pH media. In vitro permeability test with artificial membranes and Caco 2 cells were performed. Cellular uptake and mucoadhesion studies were conducted. RESULTS: Both nanoparticles resulted stable. In vitro release indicated that SLNs may prevent burst release and gastric degradation of Sb. Higher extent of Sb permeation was observed for both nanoparticles in PAMPA and Caco-2 cell monolayer models. The results of the cellular uptake study suggested the involvement of active endocytic processes. Chitosan significantly improves mucoadhesion properties of nanoparticles. CONCLUSIONS: Together with the excellent stability, strong mucoadhesive property, and slow release, chitosan coated SLNs demonstrated promising potential to enhance absorption of hydrophobic Sb after oral administration. PMID- 30306868 TI - An Observation of the Role of Autophagy in Patients with Endometriosis of Different Stages during Secretory Phase and Proliferative Phase. AB - BACKGROUND: Autophagy exists widely in various physiological and pathological conditions. Lots of investigations have verified that the autophagic activity is always related to the occurrence and the development of cancer. Endometriosis (EMs) is a disease that endometrium-like tissues abnormally grow outside the uterus and also considered to possess the characters of tumor because of its malignant biological behavior. INTRODUCTION: Recently, several studies have already revealed that autophagy may play a potential role in proliferative-phase EMs. However, the function of autophagic activity in secretory-phase EMs is still unclear. METHODS: In our work, we explored autophagic activity between normal endometrium and EMs lesion endometrium during different menstrual phases and EMs stages. The clinical endometrium samples from 73 women were selected in this study, including 30 healthy individuals and 43 patients with EMs (endometrium samples include eutopic and its matched ectopic endometrium). All the participants were divided into two groups according to the menstrual cycle, namely proliferative-phase and secretive- phase group. Among the patients with EMs, 22 individuals in proliferative phase and the other 21 individuals in secretory phase were further classified into the groups of Stage I-II and Stage III-IV according to revised-American Fertility Society (r-AFS). Two autophagy related proteins microtubuleassociated protein 1 light chain 3 beta-II (LC3B-II) and sequestosome protein (P62), which are believed to be the indicators of autophagy activity, were chosen in the study. Immunohistochemical (IHC) staining, Western blot assay and Real-Time quantitative Polymerase Chain Reaction (RTqPCR) were used to examine the expression of LC3B-II and P62 in protein and mRNA level accordingly. RESULT: It showed that the expression of LC3B-II both in protein and mRNA level decreased and that of P62 increased in secretory phase of the healthy group (P<0.05), but showed no significant difference in ectopic and its eutopic endometrium group during proliferative and secretory phase (P>0.05). In addition, the expression of LC3B-II in ectopic endometrium group was significantly lower than that of its eutopic endometrium group (P<0.05), and the expression of P62 was significantly higher accordingly (P<0.05). At the same time, both LC3B-II and P62 levels remained same between eutopic endometrium group and control group (P>0.05). Furthermore, compared to Stage I-II EMs group, the expression of LC3B II was significantly lower (P<0.05) and P62 was significantly higher (P<0.05) in Stage III-IV EMs during secretory phase. CONCLUSION: Taken together, the periodicity-losing in EMs and the decreased autophagic activity in ectopic endometrium may exert a potential role in the pathogenesis of EMs. Down-regulated autophagy of ectopic endometrium in secretory phase may be related to the progression of EMs. PMID- 30306870 TI - Targeting Membrane Receptors of Ovarian Cancer Cells for Therapy. AB - Ovarian cancer is a leading cause of death worldwide from gynecological malignancies, mainly because there are few early symptoms and the disease is generally diagnosed at an advanced stage. In addition, despite the effectiveness of cytoreductive surgery for ovarian cancer and the high response rates to chemotherapy, survival has improved little over the last 20 years. The management of patients with ovarian cancer also remains similar despite studies showing striking differences and heterogeneity among different subtypes. It is therefore clear that novel targeted therapeutics are urgently needed to improve clinical outcomes for ovarian cancer. To that end, several membrane receptors associated with pivotal cellular processes and often aberrantly overexpressed in ovarian cancer cells have emerged as potential targets for receptor-mediated therapeutic strategies including specific agents and multifunctional delivery systems based on ligand-receptor binding. This review focuses on the profiles and potentials of such strategies proposed for ovarian cancer treatment and imaging. PMID- 30306871 TI - Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery. PMID- 30306872 TI - Combiphore (Structure and Ligand based Pharmacophore) Approach for Design of GPR40 Modulators in Management of Diabetes. AB - Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study. PMID- 30306873 TI - Aripiprazole: An FDA Approved Bioactive Compound to treat schizophrenia-A Mini Review. AB - OBJECTIVE: Aripiprazole,a synthetic compound, obtained by chemical modification of the structure of quinolinone is considered as an atypical antipsychotic drug. The present review is an attempt to summarize the updated information related to reported chemistry and pharmacology of Aripiprazole. DEVELOPMENT: Aripiprazole, under development by Otsuka Pharmaceutical, was approved by the U.S. Food and Drug Administration (USFDA) in the end months of 2002 to with an aim to treat patients with schizophrenia. This drug got approved by European Commission in February 2013 to treat the patients having severe manic episodes in bipolar I disorder Additionally, it got approval in Japan in January 2006 and in Canada in 2014. Pharmacology: Aripiprazole shows high specificity for dopamine receptor especially D2 and D3, serotonin 5-HT1A and serotonin 5-HT2A receptors, reasonable specificity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors. It also shows moderate specificity for the serotonin reuptake. The major side effects include headache, agitation, akithesia, anxiety, tachycardia, insomnia, postural hypotension, constipation, vomiting, dizziness, nervousness and somnolence. CONCLUSION: The present article embarks the available information on Aripiprazole with emphasis on its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism and clinical trials. PMID- 30306874 TI - Design, synthesis, characterization of novel linomide analogues and their evaluation for anticancer activity. AB - BACKGROUND: According to WHO, in 2017, about 90.5 million of people suffer from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background we thought of the following objective. OBJECTIVE: The objective of research work involves the synthesis of a series of N-(2-(4-hydroxy-2-oxo-1-phenyl-1,2 dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay. METHOD: The starting material 4 hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3). RESULTS: All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= -(CH2)2-CH3 ; R'= -H) and IV d-1 (R= -CH2-C6H5; R'= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 uM/ml and 0.455 uM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 uM/ml. CONCLUSION: The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series. PMID- 30306875 TI - Metabolic effects of metformin in humans. AB - BACKGROUND: both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and post-prandial hyperglycemia in patients with diabetes. INTRODUCTION: metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. RESULTS: patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagon-induced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves beta-cell function in patients with type 2 diabetes. CONCLUSION: several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown. PMID- 30306876 TI - Effects of Pulmonary Hypertension and Right Ventricular Function in Short and Long-Term Kidney Function. AB - Pulmonary hypertension is not uncommon in patients with renal disease and vice versa; therefore, influences treatments and outcomes. There is a large body of literature on pulmonary hypertension in patients with kidney disease, its prognostic implications, economic burden, and management strategies. However, the converse, namely the hemodynamic effects of pulmonary hypertension on kidney function (acute and chronic kidney injury) is less studied and described. There is also increasing interest in the effects of pulmonary hypertension on kidney transplant outcomes. The relationship is a complex phenomenon and multiple body systems and mechanisms are involved in its pathophysiology. Although the definition of pulmonary hypertension has evolved over time with the understanding of multiple interplays between the heart, lungs, kidneys, etc; there is limited evidence to provide a specific treatment strategy when kidneys and lungs are affected at the same time. Nevertheless, available evidence appears to support new therapeutics and highlights the importance of individualized approach. There is sufficient research showing that the morbidity and mortality from PH is driven by the influence of the pulmonary hemodynamic dysfunction on the kidneys. This concise review focuses on the effects of pulmonary hypertension on the kidneys, including, the patho-physiological effects of pulmonary hypertension on acute kidney injury, progression of CKD, effects on kidney transplant outcomes, progression of kidney disease in situations such as post LVAD implantation and novel diagnostic indices. We believe a review of this nature will fill in an important gap in understanding the prognostic implication of pulmonary hypertension on renal disease, and help highlight this important component of the cardio-reno-pulmonary axis. PMID- 30306877 TI - Synthesis and biological evaluation of 3-cyano-4H-chromene derivatives bearing carbamate functionality. AB - BACKGROUND: 2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities. OBJECTIVE: The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties. METHOD: A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation. RESULTS: These compounds were obtained by addition of various Grignard reagents to N-ethoxycarbonyl-3-cyanoiminocoumarinesin moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method. CONCLUSION: The antibacterial activity of the chromene derivatives was more pronounced on Gram positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed. PMID- 30306878 TI - In silico identification of novel Apolipoprotein E4 inhibitor for Alzheimer's disease therapy. AB - BACKGROUND: Apolipoprotein E4 (ApoE) is a major genetic risk factor due to its increase incidence of developing Alzheimer's disease (AD). ApoE plays a major role in the brain to maintain a constant supply of neuronal lipids for rapid and dynamic membrane synthesis. Aggregation of beta amyloid plaques (Abeta) and neurofibrillary tangles in the brain has responsible for onset of AD. Clearance of Abeta aggregation is required and any defect in this clearance may cause AD. APOE with epsilon4 allele is the major genetic risk factor for Alzheimer's disease (AD). OBJECTIVES: The study was designed to predict the compounds that may be helpful in drug designing to suppress the over activity of apoE4 protein. METHODS: The study was composed of docking of 22 natural compounds (marine, microorganism and plant derivative) which were used as inhibitors with target protein apoE4. Six Synthetic compounds that are in different phases of clinical trials were docked with target protein in order to compare and analyze the docking results with natural compounds. RESULTS: Natural Compounds S-Allyl-L Cysteine, Epicatechin Gallate and Fulvic Acid showed high binding affinity i.e. 7.1, - 7 and -7 respectively. Epicatechin Gallate showed hydrogen bonding with Gln156 and Asp35 while Fulvic Acid showed hydrogen bonding with Glu27. Among synthetic compound Tideglusib having high binding affinity with target protein but did not show hydrogen bonding with any amino acid residue. Same as of natural compound S-Allyl-L-Cysteine which showed high binding affinity but did not show hydrogen bonding with any amino acid residue. Protein-Protein interactions of apoE4 showed physical and functional interaction with related proteins while KEGG provided information about related networks for metabolism of this protein. CONCLUSION: Our study highlighted Epicatechin Gallate on the basis of binding affinity and hydrogen bonding with amino acid residue as a potential lead compound as an inhibitor of AD. PMID- 30306879 TI - In silico molecular modelling and binding features of estrogen receptor alpha selective natural ligands. AB - BACKGROUND: Breast cancer is one of the most common cancers diagnosed among women. It is now recognized that two receptors mediate estrogen action and the presence of estrogen receptor alpha (ERalpha) correlates with better prognosis and the likelihood of response to hormonal therapy. ERalpha is an attractive target for the treatment of breast cancer. Most of the drug currently used for the breast cancer treatment that has numerous side effects and often unsuccessfully to remove the tumour completely. Hence, we focused on natural compounds like flavonoids, polyphenols, etc. which do not exhibit any high toxic effects against normal cells. OBJECTIVES: To identify the potential natural inhibitors for BCa through an optimised in silico approach. METHODS: Structural modification and molecular docking-based screening approaches were imposed to identify the novel natural compounds by using Schrodinger (Maestro 9.5). The Qikprop v3.5 was used for the evaluation of important ADME parameters and its permissible ranges. Cytotoxicity of the compounds was evaluated by MTT assay against MCF-7 Cell lines. RESULTS: From the docking studies, we found that the compounds, Myricetin, Quercetin, Apigenin, Luteolin and Baicalein showed the highest Glide Scores -10.78, -9.48, -8.92, -8.87 and -8.82 kcal mol-1 respectively. Of these, Luteolin and Baicalein showed the significant IC50 values (25 +/- 4.0 and 58.3 +/- 4.4 MUM, respectively) against MCF-7 cell line. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. CONCLUSION: We mainly focused on in silico study to dock the compounds into the human estrogen receptor ligand binding domain (hERLBD) and compare their predicted binding affinity with known antiestrogens. Myricetin, Quercetin, Apigenin, Luteolin and Baicalein were identified as most promising among all. Of these, Luteolin and Baicalein showed the significant anticancer activities against MCF-7 cell line. These findings may provide basic information for the development of anti-breast cancer agents. PMID- 30306880 TI - Computational approaches towards kinases as attractive targets for anticancer drug discovery and development. AB - One of the major goals of computational chemists is to determine and develop the pathways for anticancer drug discovery and development. In recent past, high performance computing systems threw the light to elicit our desired results, with little or no side effects. Different approaches to facilitate anticancer drug discovery include determination of actual targets, multi-targeted drug discovery, ligand-protein inverse docking, virtual screening of drug like compounds, formation of di-nuclear analogs of drugs, drug specific nano-carrier design, kinetic and trapping studies in drug design, multi-target QSAR model, targeted co delivery of anticancer drug and siRNA, formation of stable inclusion complex, determination of mechanism of drug resistance, and designing drug like libraries for the prediction of drug-like compounds. Protein kinases have gained enough popularity as attractive targets for anticancer drugs. These kinases are responsible for uncontrolled and deregulated differentiation, proliferation, and cell signaling of malignant cells which result in cancer. In current review we have described an overview of researches carried out in the field of computational chemistry to target kinases for better anticancer therapy. PMID- 30306881 TI - Congenital cytomegalovirus prevention, awareness and policy recommendations - a scoping study. AB - Background Congenital cytomegalovirus (cCMV) is known to cause childhood deafness, neurodevelopmental disability and death. Simple hygiene precautions are effective in reducing maternal risk of CMV infection. Objective To review i) awareness of CMV infection and available primary prevention strategies both in the community and amongst health professionals ii) available cCMV information sources in the literature, grey literature and published professional guidelines. Method Scoping study to i) identify literature pertaining to cCMV awareness amongst parents and health professionals using MedLine and CINAHL databases via EBSCO ii) review one high income country's guidelines and recommendations regarding cCMV infection and pregnancy (example country Australia) iii) grey literature for parental information. Results Worldwide awareness of cCMV and of available prevention strategies amongst women and health professionals are poor. Findings internationally suggest at least half of maternity care health professionals do not routinely provide advice to women regarding simple hygiene precautions that can reduce their risk of infection during pregnancy. Though information resources regarding cCMV are available, they are frequently not included within general healthy pregnancy advice and require individuals to search for 'congenital cytomegalovirus'. Conclusion cCMV is a preventable cause of serious congenital disability and death. Prevention opportunities are being missed because most women are not aware of cCMV or how to reduce their risk of infection in pregnancy, in part due to poor health professional awareness. New strategies to disseminate cCMV information to the community and to support health professionals to embed cCMV advice within routine pregnancy counselling is required. PMID- 30306882 TI - Adipocytokines in Non-functional Adrenal Incidentalomas and Relation with Insulin Resistance Parameters. AB - OBJECTIVE: Adrenal incidentalomas are diagnosed incidentally during radiological screenings and requires endocrinological investigations for hormonal activity and malignancy. In certain studies, it has been reported that non-functional incidentalomas can be associated with high adipocytokines levels affecting the insulin resistance just like the adipose tissue with metabolic syndrome. Here, we studied serum adipocytokine levels including leptin, resistin, visfatin, omentin 1 and adiponectin in subjects with non-functional adrenal incidentaloma. METHODS: Seventy-seven (77) patients (Female 57; Male 20) with non-functional adrenal incidentaloma (NFAI) were assigned the study. All patients past medical history, physical examination including Body Mass Index (BMI) and waist circumference were performed. The patients' demographic, radiologic, hormonal and biochemical parameters were recorded. To compare the parameters, a control group (CG) (n=30) was formed from healthy volunteers. Both groups were matched for age, gender, waist circumference and BMI. Serum adipocytokines including leptin, resistin, visfatin, omentin 1 and adiponectin were measured quantitatively by ELISA. Fasting plasma glucose, insulin, sodium, potassium, cortisol, adrenocorticotropic hormone (ACTH), lipid profiles, and dehidroepiandrostenedion sulphate (DHEAS) were measured. RESULTS: Mean age the patients was 52.2+/-10.4 years. BMI and waist circumference of NFAI patients were 26.2+/-3.28 kg/m2 and 90.2 +/-7.5cm, respectively. The mean age of the control group was 48.0+/-8.16. BMI and waist circumference values for the control group were 25.3+/-3.5 kg/m2 and 88.3+/-9.6 cm, respectively. When compared both groups for age, gender, BMI and waist circumference were non-significant (p>0.05). Serum fasting insulin, total cholesterol, LDL, triglyceride levels of the NFAI group were significantly higher than the CG (p<0.05). The insulin resistance index (HOMA-IR) values of the NFAI subjects were found to be higher than the CG (2.5+/-1.37, 1.1+/-0.3 p=0.00). Resistin level of NFAI group was found higher than CG [286.6 ng/L vs 197 ng/L; (P=0,00)], respectively. Leptin levels of NFAI were significantly higher than CG [441.1 ng/mL vs 186.5 ng/mL; (P=0.00)] respectively. Adiponectin levels were significantly reduced in NFAI group than in the CG [10.7 mg/L vs 30.8 mg/L; (P=0.00)]. Comparing of visfatin and omentin levels were non-significant. CONCLUSION: In this study on subjects with non-functional adrenal incidentaloma, we found not only significantly decreased serum adiponectin levels but also increased leptin, resistin levels as well as dislipidemia, hypertension and high insulin resistance index. All of which could affect insulin resistance and cardiovascular risk factors. The underlying mechanisms of these findings are unknown, hence further studies needed. PMID- 30306883 TI - Effects of polyphenol administration to European farmed sea bass (Dicentrharcus labrax L): Special focus on hepatopancreas morphology. AB - BACKGROUND AND OBJECTIVE: Hepatopancreas is an accessory organ associated to the liver in some fish, even including sea bass (Dicentrharcus labrax L). Hepatopancreas contains an exocrine portion but until now its function has poorly been investigated. METHODS: Here, European farmed sea bass have been treated with a feed enriched in polyphenols extracted from seeds of red grape (Nero di Troia cultivar) at two different doses (100 and 200 mg/kg, respectively) from day 273 to day 323. In fish samples, hepatopancreas area sizes have been measured to evaluate the effects of this dietary regimen on its morphology. RESULTS: Quite interestingly, in treated fish area sizes of hepatopancreas were higher than those detected in untreated fish. Two hundred dose polyphenols was more effective than that of 100 mg/kg polyphenols. Finally, hepatic polyphenol concentration was diminished in fish receiving 100 mg dose polyphenols and normalized with 200 mg dose in comparison to untreated fish. This evidence suggests the utilization of polyphenols for liver function, even including hepatopancreas development. CONCLUSION: Our data suggest an expansion of hepatopancreas induced by polyphenol administration that is also associated to less mortality in farmed fish. PMID- 30306884 TI - Successful switching of patients with acute schizophrenia from another antipsychotic to brexpiprazole: comparison of clinicians' choice of cross titration schedules in a post hoc analysis of a randomized, double-blind, maintenance treatment study. AB - OBJECTIVE: To compare the tolerability and efficacy of different antipsychotic cross-titration schedules, using data from a brexpiprazole study (Equator; NCT01668797). METHODS: Patients with schizophrenia were cross-titrated from other antipsychotics to brexpiprazole monotherapy in a 1-4 week open-label conversion phase, then entered a single-blind brexpiprazole treatment phase. Patients were stratified into four "conversion groups," according to the amount of time spent in the conversion phase. Discontinuation rates, treatment-emergent adverse events (TEAEs), and efficacy (Positive and Negative Syndrome Scale [PANSS]) were compared between conversion groups. RESULTS: Of the 404 patients treated with brexpiprazole, the majority (72.0%) spent 22-33 days in the conversion phase. Discontinuation rates due to lack of efficacy or adverse events were low in all conversion groups. Of the 292 patients who successfully switched and completed 8 weeks of brexpiprazole treatment, most were converted to brexpiprazole over 22-33 days (80.1%), and fewer were converted over 1-7 days (2.4%), 8-14 days (6.5%), or 15-21 days (11.0%). The incidence of TEAEs over 8 weeks was lower among those converted over 22-33 days (44.4%) than in other conversion groups (62.5-84.2%), although low patient numbers with shorter conversion times limit the generalizability of this finding. Each conversion group showed comparable improvement in PANSS total score from baseline. CONCLUSION: The majority of patients were cross-titrated to brexpiprazole over a period of 22-33 days, by investigators' choice. Additional data on shorter conversions may help clinicians to choose a switching paradigm that best meets their patients' needs. PMID- 30306885 TI - Using quantile regression methodology to evaluate changes in the shape of growth curves in pigs selected for increased feed efficiency based on residual feed intake. AB - Growth rate is a major component of feed efficiency when estimating residual feed intake (RFI). Quantile regression (QR) methodology can be used to identify animals with different growth trajectories. The objective of this study was to evaluate the use of QR to identify phenotypic and genetic differences in pigs selected for low RFI. Using performance data on 750 Yorkshire pigs selected for low RFI, individual average daily gain (ADG), average daily feed intake (ADFI), RFI and Gompertz growth curve parameters (asymptotic weight (a), inflection point (b) and decay parameter (c)) were estimated for each pig. Using QR methodology, three Gompertz growth curves were estimated for the whole population for three quantiles (0.1, 0.5 and 0.9) of the BW data. Each animal was classified into one of the quantile regression groups (QRG) based on their overall Euclidian distance between each observed and estimated BW from the quantile growth curves. These three curves were also estimated using only part of the data (generations -1 to 3, and -1 to 4) in order to evaluate the agreement classification rate of animals from later generations into QRGs. We evaluated the effect of QRG on growth parameters and performance traits. Genetic parameters were estimated for these traits, as well as for QRG. In addition, genetic trends for each QRG were estimated. Three distinct growth curves were observed for animals classified into either quantiles 0.1 (QRG0.1), 0.5 (QRG0.5) or 0.9 (QRG0.9). When only part of the data was used to estimate quantile growth curves, all animals from QRG0.1 were correctly classified in their group. Animals in QRG0.1 had significantly lower ADFI, ADG and RFI, and greater a, b and c than animals in the other groups. Quantile regression groups analysed as a trait was highly heritable (0.41) and had high (0.8) and moderate (0.46) genetic correlations with ADG and RFI, respectively. Selection for reduced RFI increased the number of animals classified as QRG0.1 in the population. Overall, downward genetic trends were observed for all traits as a function of selection for reduced RFI. However, QRG0.1 was the only group that had a positive genetic trend for ADG. Altogether, these results indicate that selection for reduced RFI changes the shape of growth curves in Yorkshire in pigs, and that QR methodology was able to identify animals having different genetic potential for feed efficiency, bringing a new opportunity to improve selection for reduced RFI. PMID- 30306886 TI - Machine learning multivariate pattern analysis predicts classification of posttraumatic stress disorder and its dissociative subtype: a multimodal neuroimaging approach. AB - BACKGROUND: The field of psychiatry would benefit significantly from developing objective biomarkers that could facilitate the early identification of heterogeneous subtypes of illness. Critically, although machine learning pattern recognition methods have been applied recently to predict many psychiatric disorders, these techniques have not been utilized to predict subtypes of posttraumatic stress disorder (PTSD), including the dissociative subtype of PTSD (PTSD + DS). METHODS: Using Multiclass Gaussian Process Classification within PRoNTo, we examined the classification accuracy of: (i) the mean amplitude of low frequency fluctuations (mALFF; reflecting spontaneous neural activity during rest); and (ii) seed-based amygdala complex functional connectivity within 181 participants [PTSD (n = 81); PTSD + DS (n = 49); and age-matched healthy trauma unexposed controls (n = 51)]. We also computed mass-univariate analyses in order to observe regional group differences [false-discovery-rate (FDR)-cluster corrected p < 0.05, k = 20]. RESULTS: We found that extracted features could predict accurately the classification of PTSD, PTSD + DS, and healthy controls, using both resting-state mALFF (91.63% balanced accuracy, p < 0.001) and amygdala complex connectivity maps (85.00% balanced accuracy, p < 0.001). These results were replicated using independent machine learning algorithms/cross-validation procedures. Moreover, areas weighted as being most important for group classification also displayed significant group differences at the univariate level. Here, whereas the PTSD + DS group displayed increased activation within emotion regulation regions, the PTSD group showed increased activation within the amygdala, globus pallidus, and motor/somatosensory regions. CONCLUSION: The current study has significant implications for advancing machine learning applications within the field of psychiatry, as well as for developing objective biomarkers indicative of diagnostic heterogeneity. PMID- 30306887 TI - Life-course BMI and biomarkers in persons aged 60 years or older: a comparison of the USA and Costa Rica. AB - OBJECTIVE: There is a large literature linking current BMI to levels of cardiovascular risk biomarkers, but it is unknown whether measures of BMI earlier in the life course and maximum BMI are predictive of current levels of biomarkers. The objective of the current study was to determine how current, maximum and age-25 BMI among individuals over the age of 60 years are associated with their current levels of cardiovascular risk biomarkers. DESIGN: Cross sectional study with retrospective recall. SETTING: Costa Rica (n 821) and the USA (n 4110). SUBJECTS: Nationally representative samples of adults aged 60 years or over. RESULTS: We used regression models to examine the relationship between multiple meaures of BMI with four established cardiovascular risk biomarkers. The most consistent predictor of current levels of systolic blood pressure, TAG and HDL-cholesterol was current BMI. However, maximum BMI was the strongest predictor of glycosylated Hb (HbA1c) and was also related to HDL-cholesterol and TAG. HbA1c was independent of current BMI. We found that these relationships are consistent between Costa Rica and the USA for HbA1c and for HDL-cholesterol. CONCLUSIONS: Current levels of cardiovascular risk biomarkers are not only the product of current levels of BMI, but also of maximum lifetime BMI, particularly for levels of HbA1c and for HDL-cholesterol. Managing maximum obtained BMI over the life course may be most critical for maintaining the healthiest levels of cardiovascular risk. PMID- 30306888 TI - Insects and the Transmission of Bacterial Agents. AB - Arthropods are small invertebrate animals, among which some species are hematophagous. It is during their blood meal that they can transmit pathogenic microorganisms that they may be harboring to the vertebrate host that they parasitize, which in turn will potentially develop a vector-borne disease. The transmission may occur directly through their bite, but also through contaminated feces. Zoonotic diseases, diseases that can naturally be transmitted between humans and animals, are a considerable part of emerging diseases worldwide, and a major part of them are vector-borne. Research and public attention has long been focused on malaria and mosquito-borne arboviruses, and bacterial vector-borne diseases remains today a neglected field of medical entomology. Despite the emphasis on Lyme disease in recent decades, and despite the major outbreaks caused by bacteria in the last few centuries, this field has in fact been poorly explored and is therefore relatively poorly known, other than the most famous examples such as the plague and epidemic typhus outbreaks. Here we propose to review the state of knowledge of bacterial agents transmitted by arthropod vectors. PMID- 30306889 TI - Correction: Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties. PMID- 30306891 TI - The geometrical axis of the talocrural joint-Suggestions for a new measurement of the talocrural joint axis. AB - BACKGROUND: Despite intensive research there is no consensus about the talocrural joint axis. The aim of the present study is a new method to determinate the geometric rotational axis of the talocrural joint. METHODS: We analyzed 98 CT scans of full cadaver Caucasian legs. We generated three-dimensional reconstruction models of the talus. A best fitting cone was orientated to the talar articular surface. The geometric rotational axis was defined to be the axis of this cone. RESULTS: The geometric rotational axis of the talocrural joint is orientated from lateral-distal to medial-proximal (85.6 degrees +/-10 compared to anatomical tibial axis in torsional plane), from posterior-distal to anterior proximal (81.43 degrees +/-44.35 compared to anatomical tibial axis in sagittal plane) and from posterior-medial to anterior-lateral (169.2 degrees +/-5.91 compared to intermalleolar axis in axial plane). CONCLUSIONS: The consideration of our results might be helpful for better understanding of ankle biomechanics. PMID- 30306892 TI - Ankle morphometry based on computerized tomography. AB - BACKGROUND: Thorough understanding of the morphometry of the ankle joint is crucial to optimize conservative and operative therapy of ankle joint disorders. Despite recent improvements, basic anatomic and biomechanical correlations of the ankle joint including the orientation of the ankle joint axis and joint morphology as its key biomechanical features are not sufficiently recorded to date. The aim of this study was the evaluation of the ankle morphometry to gain information about the ankle joint axis. MATERIAL AND METHODS: In this study 98 high-resolution CT-scans of complete Caucasian cadaver legs were analysed. Using the software Mimics and 3-Matic (Materialize) 22 anatomic parameters of the talocrural joint were assessed, including the length, width and surface area of the tibial and talar articular areas. Additionally, the radii of the articular areas, the medial distal tibial angle and the height of the talar dome were determined. RESULTS: The radius of the central trochlea tali was 44.6+/-4.1mm (mean+/-SD). The central trochlea tali arc length was 40.8+/-3.0mm and its width was 27.4+/-2.5mm. Additionally we determined 47.0+/-4.4mm for the tibial sagittal radius, 27.6+/-3.0mm for the tibial arc length and 27.4+/-2.5mm for the central tibial width. CONCLUSION: The present study describes the three-dimensional morphometry of Caucasian ankle joints in detail. This dimensional analysis of the ankle joint will inform the development and placements of implants and prostheses. PMID- 30306893 TI - Cardio-respiratory values during recovery from exercise in soccer Spanish leagues. AB - OBJECTIVE: In this cross-sectional study, we compared Spanish division one (n = 114) and division two (n = 80) soccer players in terms of their cardio respiratory response during recovery following a maximum laboratory effort test. APPROACH: Following the maximum laboratory effort protocol, we measured oxygen consumption ([Formula: see text]), heart rate (HR), and ventilation ([Formula: see text]) during recovery. MAIN RESULTS: Over the first 60 s of recovery, no significant differences were seen in either [Formula: see text] (28.7 versus 28.3 ml/kg/m, in division one and two players, respectively), HR, or [Formula: see text] (p > 0.05). After 90 s, however, significant differences appeared between the players of the two divisions (p < 0.01), although not among playing positions. Significant differences in [Formula: see text] (21.1 versus 26.0 ml/kg/m, in division one and two players, respectively) and HR were still apparent at 180 s into the recovery period. The change in professional soccer players' cardio-respiratory values over the recovery period following maximum effort are independent of the position played, but are associated with the division in which a player competes. Second division players show significantly higher [Formula: see text] and HR values than first division players at 180 s into the recovery period. SIGNIFICANCE: These differences might influence performance in soccer and in other athletes whose sports require intermittent bouts of maximum effort and consequently times to repeat high-intensity efforts as short as possible. PMID- 30306890 TI - Effects of microcompartmentation on flux distribution and metabolic pools in Chlamydomonas reinhardtii chloroplasts. AB - Cells and organelles are not homogeneous but include microcompartments that alter the spatiotemporal characteristics of cellular processes. The effects of microcompartmentation on metabolic pathways are however difficult to study experimentally. The pyrenoid is a microcompartment that is essential for a carbon concentrating mechanism (CCM) that improves the photosynthetic performance of eukaryotic algae. Using Chlamydomonas reinhardtii, we obtained experimental data on photosynthesis, metabolites, and proteins in CCM-induced and CCM-suppressed cells. We then employed a computational strategy to estimate how fluxes through the Calvin-Benson cycle are compartmented between the pyrenoid and the stroma. Our model predicts that ribulose-1,5-bisphosphate (RuBP), the substrate of Rubisco, and 3-phosphoglycerate (3PGA), its product, diffuse in and out of the pyrenoid, respectively, with higher fluxes in CCM-induced cells. It also indicates that there is no major diffusional barrier to metabolic flux between the pyrenoid and stroma. Our computational approach represents a stepping stone to understanding microcompartmentalized CCM in other organisms. PMID- 30306896 TI - Twister: A Tool for Reducing Screening Time in Systematic Literature Reviews. AB - Systematic reviews are widely used as a tool for decision making to establish new clinical guidelines. Reviews can be time-consuming, potentially leaving authors with thousands of citations to screen. Software tools for assisting reviewers in this process are available, however, only few use text mining techniques to reduce screening time. In this work, we introduce Twister, a web-based tool for semi-automated literature reviews with broad research questions. We discuss how two text mining techniques can be used to (a) extract data elements from clinical abstracts and (b) how citations can be clustered based on a key phrase-extraction to help reviewers reduce screening time. We present the overall system architecture, design consideration and system implementation. PMID- 30306897 TI - Caveats for the Use of the Active Problem List as Ground Truth for Decision Support. AB - Diagnoses recorded on the problem list are increasingly being used for decision support applications. To obtain insight in the adequacy of the clinical user interface to capture what the clinician has in mind, and to reconstruct the clinical reality of the patient, we analyzed in the database of an EHR system the transactions that resulted from managing the problem list. Our findings indicate (1) that caution is required when using the evolution of the problem list for determining comorbidity or ongoing disease, and (2) that similarities or differences in problem list annotation sequences do not always correspond with similarities resp. differences in disease courses. It is to be investigated whether automatically identifiable subsets of problem list evolution patterns exist from which ground truth reliably can be inferred or whether clinicians need more education in how problem list user interfaces should be used to avoid erroneous interpretations by clinical decision support applications. PMID- 30306898 TI - Secondary Use of Healthcare Structured Data: The Challenge of Domain-Knowledge Based Extraction of Features. AB - : Secondary use of clinical structured data takes an important place in healthcare research. It was first described by Fayyad as "knowledge discovery in databases". Feature extraction is an important phase but received little attention. The objectives of this paper are: 1) to propose an updated representation of data reuse in healthcare, 2) to illustrate methods and objectives of feature extraction, and 3) to discuss the place of domain-specific knowledge. MATERIAL AND METHODS: an updated representation is proposed. Then, a case study consists of automatically identifying acute renal failure and discovering risk factors, by secondary use of structured data. Finally, a literature review published par Meystre et al. is analyzed. RESULTS: 1) we propose a description of data reuse in 5 phases. Phase 1 is data preprocessing (cleansing, linkage, terminological alignment, unit conversions, deidentification), it enables to construct a data warehouse. Phase 2 is feature extraction. Phase 3 is statistical and graphical mining. Phase 4 consists of expert filtering and reorganization of statistical results. Phase 5 is decision making. 2) The case study illustrates how time-dependent features can be extracted from laboratory results and drug administrations, using domain-specific knowledge. 3) Among the 200 papers cited by Meystre et al., the first and last authors were affiliated to health institutions in 74% (68% for methodological papers, and 79% for applied papers). DISCUSSION: features extraction has a major impact on success of data reuse. Specific knowledge-based reasoning takes an important place in feature extraction, which requires tight collaboration between computer scientists, statisticians, and health professionals. PMID- 30306899 TI - Terminology Coverage from Semantic Annotated Health Documents. AB - BACKGROUND: Unstructured health documents (e.g. discharge summaries) represent an important and unavoidable source of information. METHODS: A semantic annotator identified all the concepts present in the health documents from the clinical data warehouse of the Rouen University Hospital. RESULTS: 2,087,784,055 annotations were generated from a corpus of about 11.9 million documents with an average of 175 annotations per document. SNOMED CT, NCIt and MeSH were the top 3 terminologies that reported the most annotation. DISCUSSION: As expected, the most general terminologies with the most translated concepts were those with the most concepts identified. PMID- 30306900 TI - Enhancing Nationwide Medico-Administrative Databases Analysis with SAF4SUHAD: A Statistical Analysis Framework for Secondary Use of Healthcare Administrative Databases. AB - Many epidemiological studies now rely on the reuse of large healthcare administrative databases. In those studies, most of the time is consumed in managing data and performing basic statistical analyses and is not available anymore for complex statistical and medical analysis, therefore the potential of such databases is sometimes underexploited. The objective of this work is to build SAF4SUHAD, a statistical analysis framework for secondary use of healthcare administrative databases, using literature-based specifications. A literature review was performed on PubMed in four different medical domains: caesarian deliveries, cholecystectomies, hip replacement surgeries and bariatric surgeries. We identified 22 papers relating analyses of large databases. They reported epidemiological indicators (e.g. mean age), that were abstracted to features (e.g. univariate description of a quantitative variable), and then were implemented through 32 functions available for the user in R programming language. For instance, a function will draw a histogram, compute the mean with confidence interval, quantiles, etc. Those functions comprehend 4 functions for data management, 9 for univariate analysis, 8 for bivariate analysis, 11 for multivariate analysis, and many other intermediate functions. Those functions were successfully used to analyze a French database of 250 million discharge summaries. The set of R ready-to-use functions defined in this work could enable to secure repetitive tasks, and to refocus efforts on expert analysis. PMID- 30306901 TI - KITE: An Analytics Platform for Multimorbidity Management. AB - Managing multimorbidity entails processing distributed, dynamic and heterogeneous data using diverse analytics tools. We present KITE, a Cloud-based infrastructure allowing the aggregation and processing of health data using a dynamic set of analytical components. We showcase KITE in the context of the ProACT project, aiming at advancing home-based integrated care though IoT, analytics and a behavior change framework. We validate the viability of the infrastructure through an application of Bayesian networks to give a probabilistic representation of older individuals based on a variety of factors. PMID- 30306902 TI - Development of a Secure Cross-Institutional Data Collection System Based on Distributed Standardized EMR Storage. AB - This paper describes a secure data collection infrastructure involving standardized electronic medical record (EMR) storage and Private Set Intersection, a secure data collection technology based on Bloom filter. The objective of this infrastructure is to facilitate rapid secondary use of exported EMR data in cross-patient or cross-institutional analyses based on the Standardized Structured Medical Information eXchange (SS-MIX), Japan's domestic standard for EMR exporting. Design of the infrastructure and its underlying concepts are described herein. In an experimental test, an intersection operation involving approximately 1 million records was completed within a minute; this result is expected to be representative of the system in actual use. In forthcoming work, we plan to verify the system performance using larger data sets. PMID- 30306903 TI - Utilising Information of the Case Fee Catalogue to Enhance 30-Day Readmission Prediction in the German DRG System. AB - Unplanned hospital readmissions are a burden to the healthcare system and to the patients. To lower the readmission rates, machine learning approaches can be used to create predictive models, with the intention to provide actionable information for caregivers. According to the German Diagnosis Related Groups (G-DRG) system, for every stay in a German hospital, data are collected for the subsequent reimbursement calculations. After statistical evaluation, these data are summarised in the yearly updated Case Fee Catalogue, which not only contains the weights for the reimbursement calculations, but also the expected length of stay values. The aim of the present paper was to evaluate potential enhancements of the prediction accuracy of our 30-day readmission prediction model by utilising additional information from the Case Fee Catalogue. A bagged ensemble of 25 regression trees was applied to S21 datasets from five independent German hospitals from 2013 to 2017, resulting in 422,597 cases. The overall model showed an area under the receiver operating characteristics curve of 0.812. Three of the top five features ranked by out of bag feature importance emerged from the Case Fee Catalogue. We conclude, that additional information from the Case Fee Catalogue can enhance the accuracy of 30-day readmission prediction. PMID- 30306904 TI - Designing a Coding Data Warehouse to Support and Enhance Medical Act Coding. AB - Standards Data Warehouse has been implemented in many hospitals. It has enormous potential to improve performance measurement and health care quality. Accessing, organizing, and using these data to optimize clinical coding are evolving challenges for hospital systems. This paper describes development of a coding data warehouse based Entities-Attribute-Value (EAV) that we created by importing data from the clinical data warehouse (CDW) of public hospital. In particular, it focuses on design, implementation, and evaluation of the warehouse. Moreover, it defines the rules to convert a conceptual model of coding into an EAV logical model and his implementation using integrating biology and the bedside (i2b2). We evaluate it using data research mono and multi-criteria and then calculate the precision of our model. The result shows that, the coding data warehouse provides with good accuracy, an association of diagnostic code and medical act closer the patient's clinical landscape. Doctors without knowledge of coding rules could use this information to optimize and improve the diagnostic coding. PMID- 30306905 TI - Comparison of Changes in the Number of Included Patients Between Interventional Trials and Observational Studies Published from 1995 to 2014 in Three Leading Journals. AB - INTRODUCTION: Since the late 1990s, research and administrative institutions have been developing health data warehouses and increasingly reusing claims data. The impact of these changes is not yet completely quantified. Our objective was to compare the change in the number of patients included per study between observational and interventional studies over a 20-year period starting in 1995. MATERIALS AND METHODS: We extracted all abstracts from studies published in three leading medical journals over the period 1995-2014 (18,107 studies). Then, we divided our study into two steps. First, we constructed an SVM-based predictive model to categorize each abstract into "observational", "interventional" or "other" studies. In a second step, we built an algorithm based on regular expressions to automatically extract the number of included patients. RESULTS: During the investigated period, the median number of enrolled patients per study increased for interventional studies, from 282 in 1995-1999 to 629 in 2010-2014. In the same time, the median number of patients increased more for observational studies, from 368 in 1995-1999 to 2078 in 2010-2014. DISCUSSION: The routine storage of an increasing amount of data (from data warehouses or claims data) has had an impact in recent years on the number of patients included in observational studies. The recent development of "randomized registry trials" combining, on the one hand, an intervention and, on the other hand, the identification of the outcome through data reuse, may also have an impact, over the next decade, on the number of patients included in randomized clinical trials. PMID- 30306906 TI - Types of Data Clarify Senses of Data Processing Purpose in Health Care. AB - Data taxonomy facilitates data valuation. The origin-based data taxonomy contains four types of data (provided, observed, derived and inferred) and 10 subcategories. In this paper, we report the results of multivocal literature around the origin-based data taxonomy. The review results are used to refine the definitions of the types of data when to figure out data valuation within health care. Furthermore, we exemplify how the types of data can be recognized in health care (e.g., patient medication, alerting about risk patients, patient logistics, remote monitoring) to realize data valuation based on the proposed data taxonomy around the types of data. PMID- 30306907 TI - Common Data Models (CDMs) to Enhance International Big Data Analytics: A Diabetes Use Case to Compare Three CDMs. AB - Common data models (CDM) have enabled the simultaneous analysis of disparate and large data sources. A literature review identified three relevant CDMs: The Observational Medical Outcomes Partnership (OMOP) was the most cited; next the Sentinel; and then the Patient Centered Outcomes Research Institute (PCORI). We tested these three CDMs with fifteen pre-defined criteria for a diabetes cohort study use case, assessing the benefit (good diabetes control), risk (hypoglycaemia) and cost effectiveness of recently licenced medications. We found all three CDMs have a useful role in planning collaborative research and enhance analysis of data cross jurisdiction. However, the number of pre-defined criteria achieved by these three CDMs varied. OMOP met 14/15, Sentinel 13/15, and PCORI 10/15. None met the privacy level we specified, and most of the other gaps were clinical and cost outcome related data. PMID- 30306908 TI - Ontologies in Big Health Data Analytics: Application to Routine Clinical Data. AB - Ontologies are an important big-data analytics tool. Historically code lists were created by domain experts and mapped between different coding systems. Ontologies allow us to develop better representations of clinical concepts, data and facilitate better data extracts from routine clinical data. It also makes the process of case identification and key outcome measures transparent. We describe a process we have operationalised in our research. We use ontologies to resolve the semantics of complex health care data. The use of the method is demonstrated through a pregnancy case identification method. Pregnancy data are recorded in different coding systems and stored in different general practice systems; and pregnancy has its own complexities in that not all pregnancies proceed to term, they have different lengths and involve multiple providers of health care. PMID- 30306909 TI - Bridging Clinical and Social Determinants of Health Using Unstructured Data. AB - There is a growing interest in identifying, weighing and accounting for the impact of health determinants that lie outside of the traditional healthcare system, yet there is a remarkable paucity of data and sources to sustain these efforts. Decision support systems would greatly benefit from leveraging models which are able to extend and use such cross-domain knowledge. This paper describes an approach to identify and explore related social and clinical terms based on large corpora of unstructured data. Using word embedding techniques on relevant sources of knowledge, we have identified terms that appear close together in the high-dimensional space. In particular, having created a model with cross-domain knowledge on the social determinants of health, we have been able to demonstrate that it is possible to surface terms in this domain when querying for related clinical terms, thereby creating a bridge between the social and clinical determinants of health. This is a promising approach with significant applicability in decision support efforts in healthcare. PMID- 30306910 TI - Phenotyping Obstructive Sleep Apnea Patients: A First Approach to Cluster Visualization. AB - The varied phenotypes of obstructive sleep apnea (OSA) poses critical challenges, resulting in missed or delayed diagnosis. In this work, we applied k-modes, aiming to identify groups of OSA patients, based on demographic, physical examination, clinical history, and comorbidities characterization variables (n = 41) collected from 318 patients. Missing values were imputed with k-nearest neighbours (k-NN) and chi-square test was held. Thirteen variables were inserted in cluster analysis, resulting in three clusters. Cluster 1 were middle-aged men, while Cluster 3 were the oldest men and Cluster 2 mainly middle-aged women. Cluster 3 weighted the most, whereas Cluster 1 weighted the least. The same effect was described in increased neck circumference. The percentages of variables driving sleepiness, congestive heart failure, arrhythmias and pulmonary hypertension were very low (<20%) and OSA severity was more common in mild level. Our results suggest that it is possible to phenotype OSA patients in an objective way, as also, different (although not considered innovative) visualizations improve the recognition of this common sleep pathology. PMID- 30306911 TI - Disparities in Population-Level Socio-Economic Factors Are Associated with Disparities in Preoperative Clinical Risk Factors in Children. AB - African American children are more than twice as likely as white American children to die after surgery, and have increased risk for longer hospital stays, post-surgical complications, and higher hospital costs. Prior research into disparities in pediatric surgery outcomes has not considered interactions between patient-level Clinical Risk Factors (CRFs) and population-level Social, Economic, and Environmental Factors (SEEFs) primarily due to the lack of integrated data sets. In this study, we analyze correlations between SEEFs and CRFs and correlations between CRFs and surgery outcomes. We used a dataset from a cohort of 460 surgical cases who underwent surgery at a children's hospital in Memphis, Tennessee in the United States. The analysis was conducted on 23 CRFs, 9 surgery outcomes, and 10 SEEFs and demographic variables. Our results show that population-level SEEFs are significantly associated with both patient-level CRFs and surgery outcomes. These findings may be important in the improved understanding of health disparities in pediatric surgery outcomes. PMID- 30306913 TI - Process Analysis and Decision Support Tools in Parenteral Nutrition in Children. AB - Parenteral nutrition represents a well-established but highly sensitive process associated with several patient conditions. It typically involves assessments of many parameters and a wide range of observations in order to come up with the best possible parenteral solution for a patient. Different calculation tables are used to determine correct ratios of nutritional elements which would later be administered. This work focuses on providing a process map for parenteral nutrition in children using the combination of Petri nets and openEHR methodology to create an overview for the decision-making process. PMID- 30306914 TI - Integral Homeostasis Index in a Decision Support System for the Assessment and Prediction of the Clinical Condition of Children with Severe Mechanical Trauma. AB - OBJECTIVE: Daily assessment of the acid-base balance (ABB) in blood is one of the important elements of multi-parameter patient monitoring at intensive care units (ICUs). The present work aims to determine the effectiveness and validity of the integral homeostasis index IHx calculated from ABB blood test data for the assessment and prognosis of children with critical traumatic conditions. METHODS: 345 patients were studied. IHx was calculated and the data were subjected to statistical evaluation. An Arden-Syntax-based clinical decision support (CDS) platform was used. One purpose of the study was to incorporate the platform into the ICU IT landscape of the hospital, and the second purpose was to develop a CDS module for the calculation of IHx and present the results in real time to the attending physician. RESULTS: Integral homeostasis index IHx calculations as well as their prompt assessment permit better and more rapid treatment of children with severe traumatic injury. PMID- 30306915 TI - Harnessing Ontologies to Improve Prescription in Pediatric Medicine. AB - There are many drug databases, but sometimes the data quality may result in wrong medication for patients. Results that it is very important to provide a good quality drug information, supply structured information and build useful relations between the drugs related information and the patient status in terms of particularities. Children are the most sensitive to drug dosage or certain substances that is why pediatrics was our first choice for the research. To support this, we propose an ontology starting from on-line drug prospectuses. We start extracting the prospectuses information from the web pages, investigate the sections of the prospectuses structure (indications, contraindications, dosage, etc.) and use the information in an ontology that we integrate into a pediatric application. In the background of the application this solution provides the correct matching between the patient and the treatment, extracting for the physician only the best prescription options for the current case. The application allows the physician to select the appropriate drug and decide the best treatment in terms of correct substances and dosage for a certain child. We use the prospectuses solution because the application is in Romanian and other resources are not very well provided. For the future the solution will be adapted to other languages and other databases. This model can be generalized in different languages. The application is improved with the new ontology module and helps physicians to give a good treatment considering all relationships, constraints or antagonistic situations that may occur in providing a treatment. PMID- 30306916 TI - Data Reuse Through Anesthesia Data Warehouse: Searching for New Use Contexts. AB - INTRODUCTION: Due to high volumes of data routinely recorded through Hospital Information System, data reuse has become important in recent years. A data warehouse was developed in the Lille University Hospital to reuse anesthesia data. At the moment, it is mainly used for clinical research, by offering extraction of data tables to answer a clinical question. In this article, we try to identify other contexts of data reuse than the one currently provided by the data warehouse, in comparison with those in the literature. MATERIAL AND METHODS: A semi-structured interview grid was designed so that to tackle respondents' experience with clinical data reuse, the various contexts in which the data are reused along with the information systems they currently use to proceed and the difficulties they encounter. A semi-inductive thematic analysis process was performed to identify meaningful semantic units and grouped them into thematic categories. RESULTS: Ten anesthetists were interviewed; three main contexts emerge: research and knowledge discovery, evaluation of professional practices and organizational management. Data are accessed through complicated administrative procedures and clinicians have to perform tasks beyond their competencies. DISCUSSION: Difficulties encountered when searching for data express the need for easy and continuous access to data. PMID- 30306917 TI - Development of an Automatic Coding System for Digestive Endoscopies. AB - Digestive endoscopies, along with all medical procedures in France are coded with the CCAM. This task is done by the physicians, is time-consuming and requires a good knowledge of the terminology besides a medical knowledge. This method offers an automatic coding of endoscopic procedures from free-text reports. Thanks to a supervised learning method, the reports are coded with an average precision and recall of 0.92 on a 1639 texts corpus. PMID- 30306918 TI - Enhancing CDSS Alert Appropriateness in Clinical Workflow Using the Lean Method. AB - Despite the widespread use of clinical decision support systems with its alert function, there has been an increase in medical errors, adverse events as well as issues regarding patient safety, quality and efficiency. The appropriateness of CDSS must be properly evaluated by ensuring that CDSS provides clinicians with useful information at the point of care. Inefficient clinical workflow affects clinical processes; hence, it is necessary to identify processes in the healthcare system that affect provider's workflow. The Lean method was used to eliminate waste (non-value added) activities that affect the appropriate use of CDSS. Ohno's seven waste model was used to categorize waste in the context of healthcare and information technology. PMID- 30306919 TI - Design of InterFACE: A Tool to Improve Collaborative Work and Decision Making During Rescucitation. AB - Successful resuscitation requires good teamwork, communication and quick decision making. The complexity of the situation makes the communication often erratic. As a consequence, improper decisions can be taken and errors can occur, endangering patients. In order to support the resuscitation team in their work, we developed an innovative product named Interconnected and Focused Mobile Applications on Patients Care Environment (InterFACE), enhancing team situational awareness, and improving the team communication process. To develop our solution, we relied on a user-centred design process involving caregivers from both adult and paediatric emergency departments. The process started with interviews and observations, followed by an iterative development approach validated at each step by end users. The resulting intervention is composed of a tablet app interacting with a large screen, visible to each members of the resuscitation team, presenting real time information about the resuscitation. Resuscitations are very complex and challenging situations involving many actors. Designing a support tool for such situations requires a strong involvement of end users to understand how people work together and what information they share. PMID- 30306920 TI - Model of Decision Making Support for a Doctor in the Treatment of an Oncosurgical Patient in a Hospital. AB - At the present moment, there is no uniform approach to the decision to conduct a planned surgical intervention in case of oncosurgical pathology, with appropriate recommendations in different sources. Consequently, in modern medicine, there is a particular problem of an objective assessment of the patient's physical condition and a risk assessment of an upcoming surgical intervention for developing an individualized tactic of preparation for surgical treatment for each particular patient. The need for introduction of new approaches and technologies, as well as treatment regimens, that allow us to take a fresh look at the possibilities of solving the problems of predicting critical outcomes of planned operations, determined the purpose of our study. The result of our study was the design of a decision rule in the form of the Microsoft Access software, which allows to rank patients with oncological diseases by the probability of lethal outcome in surgery. PMID- 30306921 TI - The Impact of Telementoring. AB - Telementoring is a well-known practice in surgical training, and its impact is traditionally related to individual surgeons' performance and the quality of the procedure. The objective of this study was to explore telementoring in a wider organisational context. This paper reports on an ethnographic study carried out during 2014-2016 in Norway, combining observations, interviews, focus groups and field notes. We followed the surgical training of a specialist candidate at a medium-sized surgical ward. The training successfully took place through the use of telementoring, comprising updated standards for a surgical procedure that ensured minimum invasive surgery for a vulnerable patient group. We observed that telementoring was a necessary and important element in ongoing quality improvement processes at the ward, and its impact at the organisational level was important. In fact, a series of co-existing interwoven elements was necessary to normalise the new procedure in question. We conclude that the use of telementoring linking international expertise to local contexts is one of the factors that can facilitate and speed up quality improvement processes in small- to medium-sized surgical wards. PMID- 30306922 TI - Preference-Sensitive Apomediative Decision Support Is Key to Facilitating Self Produced Health. AB - In the health capital model, the main function of health services is not to produce health, but to support the person in their self-production investments. In the health context there are three types of decision support tools, depending on the role of the provider (e.g. clinician) and person. Non-mediative tools are designed to help the clinician decide what is best for the patient. Intermediative Patient Decision Aids are designed to help the clinician and patient decide together, in an encounter, what is best for the patient. Apomediative Personalised Decision Support Tools are designed to help the person decide what is best for themselves, including whether to seek a professional consultation and/or to prepare for, and engage in, an intermediative consultation. Only preference-sensitive apomediative support tools ensure that the key requirements of self-produced health are met, along with legally informed and preference-based consent to any subsequent provider action. The desirable form of apomediative support is a publicly accessible, direct-to-citizen, provider-independent, multi-criteria analysis-based decision support of the sort available in many other areas of self-production. Which (UK), Taenk (Denmark), Choice (Australia) and numerous other comparison magazines and websites provide independent multi-criterial support for decisions on, for example, which food and transport to buy to self-produce nutrition and movement. A personalised decision support tool for the statin decision is provided as illustration: Should I go to my general practitioner and ask for a statin prescription or go to discuss taking statins, in the light of the preliminary opinion of the tool? PMID- 30306923 TI - Knowledge Formalization to Support Decision-Making in Heart Failure Treatment. AB - This paper presents medical knowledge representation of data provided within Clinical Practice Guidelines for Heart Failure. The formalization is provided in order to support taking decisions on an appropriate treatment strategy for a specific patient. An intuitive and efficient mechanism of medical knowledge formalization, called extended Timed Transition Diagram (eTTD), is used to represent acquired medical knowledge. The presented models can be used to help students in their training as well as to support physicians with their decision making tasks. PMID- 30306924 TI - Intelligent Patient Flow Management System at a Primary Healthcare Center - The Effect on Service Use and Costs. AB - An intelligent patient flow management system (IPFM) was piloted at a large primary healthcare center in Finland in August 2017. The goals of the system are to help patients avoid unnecessary calls and visits to their health center and to enhance the use of professional resources through more streamlined patient pathways and the re-allocation of professionals from assessment tasks to actual patient care. These goals should be reflected in the decreased service costs through optimized contact forms. Using multiple regression analysis, we studied the associations between IPFM and patients' service utilization (17,943 patients; 73,038 service contacts) during the first five months of the pilot in 2017. The results indicated that the use of IPFM by the patient was associated with a decrease of EUR 31 in the total service costs of the patient in the study period. This decrease is 14% of patient's average total service cost. PMID- 30306925 TI - Computer Assisted Oswestry Disability Questionnaire Evaluation Using Fuzzy Inference Systems. AB - This paper proposes the evaluation of the Oswestry Disability Index (ODI) using a fuzzy inference system. The ODI is used to evaluate the impact of the low back pain on the patient's quality of life. The patient grades from 0 to 5 a number of 10 questions regarding usual daily activities. At the end a mathematical formula is used to calculate the degree of the impact/disability. It has been observed that this method easily can generate false positive results due to the fact that patients purposely try to score a higher degree so that they can benefit from advantages offered by the medical system. To eliminate the false positive results a fuzzy inference system was developed which can identify the contradictory input data and warn the medical staff about a possible erroneous result. PMID- 30306927 TI - GDPR and Health Personal Data; Tricks and Traps of Compliance. AB - The GDPR fixes general rules applying to any kind of personal data processing as well as specific rules applying to the processing of special categories of personal data such as health data taking place in the context of scientific research or clinical software development. A short overview of new rules about how to consider where scientific and professional projects include the processing of personal health data, genetic data or biometric data and other kinds of sensitive information whose use is strictly regulated by the GDPR is provided. Some key facts to researchers and developers to adapt their practices and ensure compliance to the EU laws are included. PMID- 30306928 TI - A Concept for Improving Cross-Sector Care by a Mobile Patient Navigator App. AB - Hip and knee joint prosthetic implants are common surgical interventions in Switzerland, as well as in other countries. Different care providers are involved in the care process which constitutes a potential risk of inefficiency and communication deficits. A patient can get lost on his cross-sectoral clinical pathway, miss appointments or underestimate the relevance of certain control visits or examinations. To address this, we introduce a concept for a mobile application that guides patients along the cross-sectoral clinical pathway. The information on appointments is consistently retrieved from information systems at the care provider's side. This facilitates the coordination of activities and appointments not only for the patient, but also for the care providers. The aim is to promote the patients' autonomy, to support their management of appointments, to increase the understanding for their clinical condition and to improve their adherence to the prescribed measures - all of which lead to an improved outcome. Another aim is to increase patient satisfaction in terms of adequate information and quality of treatment. The advantages and disadvantages of the concept will be discussed. goes here. PMID- 30306929 TI - Implementing CDS Hooks Communication in an Arden-Syntax-Based Clinical Decision Support Platform. AB - INTRODUCTION: Arden Syntax is a Health Level Seven International standard for the development of clinical decision support (CDS) solutions. CDS Hooks is a specification for an interface to call CDS services from an electronic health record. Implementing the CDS Hooks interface into ArdenSuite, an Arden-Syntax based CDS platform, will further enhance its interoperability with external systems. METHODS: The development of this interface consisted of three parts: (1) The RESTful interface defined by CDS Hooks had to be implemented; this included the support of specifically formatted data for the input and output of the CDS functions. (2) The existing FHIR connector had to be adjusted. In CDS Hooks, a FHIR server can be defined for each CDS service call individually. In the current version of the connector, a FHIR server has to be configured in advance to call the CDS service. (3) Additional data points that did not exist previously, such as a description or hook for each CDS service, had to be collected and saved. RESULTS: Basic support of the CDS Hooks API was established in the ArdenSuite and tested. The FHIR connector was adapted. DISCUSSION: The missing parts for full CDS Hooks support were implemented. As a use case, we employed Hepaxpert, an interpretive system for hepatitis serology tests. CDS Hooks defines FHIR as the only data source. ArdenSuite, in contrast, offers the option of various data sources with connectors and extensions. PMID- 30306930 TI - Anonymized Distributed PHR Using Blockchain for Openness and Non-Repudiation Guarantee. AB - We introduce our solution developed for data privacy, and specifically for cognitive security that can be enforced and guaranteed using blockchain technology in SAAL (Smart Ambient Assisted Living) environments. Personal clinical and demographic information segments to various levels that assures that it can only be rebuilt at the interested and authorized parties and no profiling can be extracted from the blockchain itself. Using our proposal the access to a patient's clinical process resists tampering and ransomware attacks that have recently plagued the HIS (Hospital Information Systems) in various countries. The core of the blockchain model assures non-repudiation possible by any of the involved information producers thus maintaining ledger fidelity of the enclosed historical process information. One important side effect of this data infrastructure is that it can be accessed in open form, for research purposes for instance, since no individual re-identification or group profiling is possible by any means. PMID- 30306931 TI - Towards an Evidence-Based Decision Support Tool for Management of Musculoskeletal Conditions. AB - Musculoskeletal (MSK) problems present an increasing burden for the healthcare sector, particularly in ageing populations. Advances in evidence are often slow to influence clinical decisions, suggesting decision support would be beneficial. We propose a Bayesian network (BN) for providing evidence-based decision support as it can explicitly represent domain knowledge as causal relations and allows both domain knowledge and clinical data to be combined to create a usable decision model. We make a preliminary evaluation of the model's performance. PMID- 30306932 TI - Assessment of Decision Models for Hybrid Approaches. AB - A wide range of Clinical Decision Support Systems (CDSS) have been developed. These CDSS are based on decision models, which normally have a knowledge- or data driven approach. In this work a structured development of potential hybrid approaches was realized by the assessment of decision models and identification of their advantages and disadvantages. For the assessment of different decision models, eight criteria were identified and three of them were chosen as main criteria for CDSS: transparency, learning aptitude and handling of uncertain and vague knowledge. The comparison of decision models in regard to the developed main criteria resulted in an identification of three groups of models with similar characteristics. Based on these groups hybrid approaches had been developed, so that different decision models could be combined in a beneficial way. Thereby this work provides an instrument for a structured development of hybrid decision models. PMID- 30306933 TI - A Speech Sound Disorder Screening System Database Structure. AB - This paper makes a brief review of several database structures of Computer-Based Speech Therapy (CBST) systems and solutions and describes the screening method, an experimental study conducted to validate the screening algorithm and a database structure for the Information Entropy-Based Sound Speech Disorder (SSD) Screening System aimed at by our research project. The final part briefly presents the essential design criteria and further development. PMID- 30306934 TI - Implementing Guideline-Based, Experience-Based, and Case-Based Approaches to Enrich Decision Support for the Management of Breast Cancer Patients in the DESIREE Project. AB - DESIREE is a European-funded project to improve the management of primary breast cancer. We have developed three decision support systems (DSSs), a guideline based, an experience-based, and a case-based DSSs, resp. GL-DSS, EXP-DSS, and CB DSS, that operate simultaneously to offer an enriched multi-modal decision support to clinicians. A breast cancer knowledge model has been built to describe within a common ontology the data model and the termino-ontological knowledge used for representing breast cancer patient cases. It allows for rule-based and subsumption-based reasoning in the GL-DSS to provide best patient-centered reconciled care plans. It also allows for using semantic similarity in the retrieval algorithm implemented in the CB-DSS. Rainbow boxes are used to display patient cases similar to a given query patient. This innovative visualization technique translates the question of deciding the most appropriate treatment into a question of deciding the colour dominance among boxes. PMID- 30306935 TI - Biomedical Informatics Investigator. AB - The BMI Investigator is a computer human interface built in .Net which allows simultaneous query of structured data such as demographics, administrative codes, medications (coded in RxNorm), laboratory test results (coded in LOINC) and formerly unstructured data in clinical notes (coded in SNOMED CT). The ontology terms identified using SNOMED are all coded as either positive, negative or uncertain assertions. They are then where applicable built into compositional expressions and stored in both a graph database and a triple store. The SNOMED CT codes are stored in a NOSQL database, Berkley DB, and the structured data is stored in SQL using the OMOP/OHDSI format. The BMI investigator also lets you develop models for cohort selection (data driven recruitment to clinical trials) and automated retrospective research using genomic criteria and we are adding image feature data currently to the system. We performed a usability experiment and the users identified some usability flaws which were used to improve the software. Overall, the BMI Investigator was felt to be usable by subject matter experts. Next steps for the software are to integrate genomic criteria and image features into the query engine. PMID- 30306936 TI - Modular Knowledge-Based Decision Support System Dedicated to a Cooperative Decision to Prevent Cardiovascular Diseases. AB - Despite the success of artificial intelligence solutions in the recent years, physicians are still reticent to use integrated functionalities to support their decision. Methods used to create these functionalities can be divided into two groups, each being associated to different questions. Data-based methods are seen as black boxes for which it is impossible to understand how the decision is taken; knowledge-based methods need to rely on formalized knowledge sources on the basis of evidence, which can be discussed and criticized by physicians for their use in real life. This paper presents a new modular decision support system for the prevention of cardiovascular diseases, based on knowledge and on cooperative decision between the patient and the physician. The decision support system is based on two layers: (i) the first layer is a knowledge-based module which generates automatically patient profile, and prevention strategies associated to the profile; (ii) the second layer is a dynamic collaborative graphic user interface which displayed information about the risks of treatment adherence failure, personalized motivation and follow-up strategies. In the future, we aim at assessing the platform in real life. PMID- 30306937 TI - Semantically Structured Web Form and Data Storage: A Generic Ontology-Driven Approach Applied to Breast Cancer. AB - Interoperability issues are common in biomedical informatics. Structured data acquisition modalities are of major importance since the data acquired need to be adequately structured and encoded to be automatically processed by dedicated systems. We have developed a web application that generates a semantically structured web form from an ontology. Beyond allowing for structured patient data acquisition, the application allows to save patient data in a triplestore storage solution, and to retrieve them. Thus, the application provides a solution for the user to edit, display, and delete patient data, when necessary. The method has been applied to generate a web form to acquire patient data from the breast cancer knowledge model structured as an OWL ontology of the guideline-based decision support system within the European-funded DESIREE project. PMID- 30306938 TI - Automatic Annotation Tool to Support Supervised Machine Learning for Scaphoid Fracture Detection. AB - The aim of this work is to develop and validate an automatic annotation tool for the detection and bone localization of scaphoid fractures in radiology reports. To achieve this goal, a rule-based method using a Natural Language Processing (NLP) tool was applied. Finite state automata were constructed to detect, classify and annotate reports. An evaluation of the method on a manually annotated dataset has shown 96,8% of total match. PMID- 30306940 TI - Educational Landscape of Biomedical Informatics in Croatia: Who Are the Teachers and What Are Their Attitudes. AB - Lack of experts with complementary competences in the field of information technology as well as medicine and health care has been recognised as an important obstacle to successful computerisation of the health care system. Using a questionnaire survey, we aimed to describe the current educational landscape of biomedical informatics in Croatia, focussing on teachers' profiles and attitudes about existing educational opportunities in the field. Our findings show that Croatian institutions of higher education should better recognise the need for education in biomedical informatics. Dedicated programs need to be established and teacher force strengthened. Joint efforts of existing teachers institutionalised through a working group focussing on education within the Croatian Society for Medical Informatics, for which strong support exists-might contribute to recognition of the field and improvement of educational opportunities. PMID- 30306941 TI - Similarity Detection Between Virtual Patients and Medical Curriculum Using R. AB - This paper presents the domain of information sciences, applied informatics and biomedical engineering, proposing to develop methods for an automated detection of similarities between two particular virtual learning environments - virtual patients at Akutne.cz and the OPTIMED curriculum management system - in order to provide support to clinically oriented stages of medical and healthcare studies. For this purpose, the authors used large amounts of text-based data collected by the system for mapping medical curricula and through the system for virtual patient authoring and delivery. The proposed text-mining algorithm for an automated detection of links between content entities of these systems has been successfully implemented by the means of a web-based toolbox. PMID- 30306942 TI - Curriculum Development of a Health Informatics Master Course in Understanding Technology. AB - Education in health informatics is an important contribution to the digital transformation in health care services, and there is a need to combine health and technology competencies. Traditional ways with separation of health sciences and computer science have shortcomings, and there is need for individuals with a holistic view and relevant education background for improving the technology supported clinical work processes. This paper presents how the curriculum was organised in a course in "Understanding Technology", which was a part of a Master's Programme in Health Informatics. The course targeted different aspects of technology for students with a diverse background, and it was organised with the aim to provide the students with theoretical technical insights and apply the knowledge through problem-solving and practical use. The course was decentralised and had a student-centred teaching approach over one semester. PMID- 30306943 TI - Physical and Sedentary Activity Among Facebook Users in Croatia. AB - : The aim of the research was to examine the level of physical activity of users of the social network in Croatia, the relation of the sociodemographic characteristics and the level of physical activity compared to the time spent on the following activity. The study involved 333 respondents who are active users of Facebook (FB). The short version of the IPAQ questionnaire and BMI Calculator were used to assess the physical activity of respondents. This research has determined that the BMI index (BMI) ranges from 16.04 to 42.25, average 24.00. The total level of physical activity of the participants, expressed through the Metabolic equivalent task (MET) is high, and according to the MET category the participants are in the high level of involvement category or HEPA active. There is a statistically significant correlation between the overall results obtained with the IPAQ compared to the MET category, BMI, quality of life and self assessment of health in FB users. Participants spend on average 5 hours per day sitting during a week, and there is statistically significant correlation between the overall results of the IPAQ compared to the MET category and the time spent sitting. IN CONCLUSION: that involvement in social networks for participants in this study does not disturb the level of physical activity. PMID- 30306944 TI - Specification and Description Language of Medical Activities. AB - Modern health care management takes place in organizations and institutions that are becoming more and more complex. The management of these institutions requires broad clinical and business administrative knowledge, but also excellent scientific skills. The scope of our study, presented in this paper, is to emphasis the management of medical activities. Based on set theory and scientific management of work, we developed a method called Specification and Description Language of Medical Activities (SDLMA) that can monitor performance, and can provide instructions to ensure the most efficient ways of working. PMID- 30306945 TI - Mixed Reality Supporting Modern Medical Education. AB - The paper presents new learning support for medical students exemplifying with several 3D applications for training on specific topics in medicine and investigates the impact on medical students. The applications were built using new concepts: Virtual Reality, Augmented Reality, as environments agreed by young people, and gamification to make learning easy and fun. Leap Motion and the VR headset are the devices to control the applications and provide a better human computer/mobile phone interaction as compared to the current ones. The concepts and the new technologies to display/visualize the applications are the core of the Mixed Reality concept resulting from combining the 4 applications implemented for medical education. PMID- 30306946 TI - ADHD Mobile App Feasibility Test for Adults. AB - Attention-deficit hyperactivity disorder (ADHD) is characterized by inattention and/or hyperactivity/impulsiveness. For many adults, ADHD remains undiagnosed and/or untreated impacting their quality of life. There is a growing interest to use mobile technology interventions as a complementary support for mental health issues. Mobile apps could be usefully personalized for helping adults in managing ADHD issues. The aim of this study is to examine perceived helpfulness, ergonomics and willingness to use of an ADHD mobile app based on the PAPM model. A sample of 6 ADHD patients tested the ADHD mobile app prototype and were interviewed about their satisfaction and the perceived helpfulness of the app. Data indicate that participants were very satisfied with ADHD app and perceived it as being moderately to very helpful regarding their ADHD symptoms. These findings suggest that the app has the potential to be an effective self management tool for ADHD. PMID- 30306947 TI - Team Competencies and Educational Threshold Concepts for Clinical Information Modelling. AB - Healthcare interoperability depends upon sound semantic models to support safe and reliable exchange of information. We argue that clinical information modelling requires a collaborative team of healthcare professionals, process and content analysts and terminologists and that 'separation of concerns' is unhelpful. We present six fundamental concepts that participants must understand to collaborate meaningfully in technology-agnostic information modelling. PMID- 30306948 TI - Dual Purpose, Dual Audience: MCDA-Based Tools Can Simultaneously Support Personal Health Decisions and Educate Persons and Clinicians. AB - In this vision paper we envisage paradigmatic change transforming the health professional from the empowered agent of a dependent patient into the final decision supporter of an empowered person; a person who comes equipped with the preliminary opinion of an apomediative personalised decision support tool and the enhanced health decision literacy it produces. The anomalies in the current paradigm that will produce this change arise from unworkable attempts to combine multicriterial personal preferences and the best available evidence in a medical reasoning model. Multi-Criteria Decision Analysis (MCDA)-based decision support tools provide one mechanism for achieving this synthesis in a transparent way in a specific case whilst, simultaneously, increasing the generic health decision literacy and competencies of both person and clinician. The educational task for both is less than might be expected because of their familiarity, as consumers, with the many comparison websites and magazines for products and services using an informal version of MCDA. The educational task, particularly for the clinician, is primarily one of acknowledging that MCDA is a decision competence that has the potential, not only to enhance decision quality, but also facilitate communication between person and professional, who will now be talking the same decisional language. Experience from developing the MyBoneHealth tool confirms both the feasibility and challenges of delivering a MCDA-based decision support and educational tool. PMID- 30306949 TI - HIN - Health Issue Network as Means to Improve Case-Based Learning in Health Sciences Education. AB - HIN (Health Issue Network) is introduced as a peculiar approach to enhance Case Based Learning (CBL) methodology for health sciences education, as well as innovative tool to query problem-oriented EHRs. In this paper HIN's Petri Nets based formalism is described, and a first example of its twofold (lower and upper) representation level is proposed. PMID- 30306950 TI - Healthcare Informatics Project-Based Learning: An Example of a Technology Management Graduation Project Focusing on Veterinary Medicine. AB - Teaching Healthcare Informatics using Project-Based Learning focuses students on active and inquiry-based learning and allows them to gain some knowledge and skills in the field. From the perspective of Technology Management, which is at the cross-road of Sciences, Engineering and Business Administration studies, Healthcare Informatics is an interesting application domain for developing both innovation and management capabilities. However, the specificities of Healthcare Informatics (standards, methodologies, human- or animal-focused information) require an additional involvement from the students to deliver projects that fit real-world needs and constraints. In this paper, we initially define the Technology Management field and describe how it is related to Healthcare Informatics, then we introduce Project-Based Learning and finally we present an example of a graduation project that focuses on Veterinary Medicine. PMID- 30306951 TI - Using the Behaviour Change Wheel for Designing an Online Platform for Healthy Weight Loss - "POEmaS". AB - INTRODUCTION: Behaviour change is a key point in weight management. Digital health interventions are attractive tools to deliver behaviour interventions for weight loss, due to the potential to reach a large number of people. We aimed to report how the Behaviour Change Wheel (BCW) was used to develop and implement a web platform to promote weight loss in Brazilian adults with overweight and obesity. Moreover, we aimed to describe the first 12 weeks of usage of the platform in a randomized controlled trial. METHODS: The BCW framework was used to define intake of fruit/vegetables, ultra-processed products and sweetened beverages, leisure physical activity and sitting time as target behaviours. The BCW components of behaviour-capability, opportunity and motivation were used to make a behaviour diagnosis of the population and BCW second layer oriented the selection of information, goal setting, self-monitoring, feedback, social support and incentives as behaviour techniques. Using these behaviour techniques, a 24 week behaviour intervention delivered by seven different platform functionalities was developed. The platform was tested in a three-arm parallel (basic platform versus enhanced platform versus minimal intervention control group) randomized controlled trial from September 2017 to April 2018. In the present analysis, we classified the platform functionalities according to the BCW behaviour component (capability, opportunity and behaviour) and used descriptive statistics and Spearman correlations to report functionalities usage according to the BCW behaviour component over the first 12 weeks of the trial. The study was approved by the Ethics Committee of the Federal University of Minas Gerais, Brazil and was registered under NCT 03435445. RESULTS: Over the first 12 weeks of the RCT, the 809 participants (619, 76.5% women; mean age 33.7 years, SD 10.3; mean BMI 29.9 kg/m2, SD 4.3) were enrolled for use of the basic and enhance versions of the platform. Capability-driven functionalities were accessed by 455 (56.2%) users with median access of 1 (IQR 1-6) times, whereas opportunity-driven platform functionalities were accessed by 592 participants with 8 (IQR 1-27) median access times and motivation-driven functionalities were accessed by 560 (69.2%) participants with 13 (IQR 1-30) median times of access. Spearman correlations between the use of capability and opportunity functionalities, capability and motivation functionalities and opportunity and motivation functionalities were 0.74 (95% CI 0.70-0.77), 0.74 (95% CI 0.70-0.78), 0.89 (95% CI 0.87-0.91), respectively. DISCUSSION: BCW provided a systematic approach to planning, designing and implementing a complex weight loss intervention based on behaviour change. Moreover, it promoted a clear understanding of the relation between platform functionalities and behaviour determinants. The low use of the capability-driven functionalities might have been related to lack of accuracy in the behaviour diagnosis, as well as to implementation issues. The high correlation between the functionalities use suggests that the BCW approach did not determine the platform usage profile. CONCLUSION: The BCW provided a framework for an evidence-based intervention on weight loss delivered by a web platform. Using the framework led to a clear understanding of the behaviour determinants and their relation to the platform features. PMID- 30306952 TI - Methodologies for Improving the Quality and Safety of Telehealth Systems. AB - A range of telehealth applications have been developed. In Canada, telehealth shows considerable promise given the country's large geographical area and need for support in rural areas. In this paper, the authors describe our method for ensuring the quality and safety of telehealth applications by applying clinical simulations. These simulations allow for testing and fine-tuning of telehealth applications before they are released on a large scale. Two applications are briefly described, one involving tele-triage and a second involving tele-nursing. The potential of the approach is discussed along with considerations in its application to ensure the quality and safety of telehealth technologies. PMID- 30306953 TI - Designing Telerehabilitation System for Multipronged Exercise in Patients with Multiple Sclerosis. AB - Patients with multiple sclerosis (PwMS) were shown to greatly benefit from multipronged exercise interventions comprising aerobic, resistance and corrective therapeutic components which result in endurance and strength improvement and reduction of fatigue and spasticity. However, telerehabilitation support of multipronged exercise programs in PwMS with significant mobility impairment has received limited attention. It is not clear whether severely disabled PwMS can successfully operate a telerehabilitation system at home independently. The goal of this study was to design a telerehabilitation system for individualized multipronged exercise programs and to assess the feasibility of the initial prototype in PwMS with significant mobility impairment. Usability assessment was based on the evaluation of patient ability to successfully carry out a standardized list of common tasks necessary to operate the system. For each task, time to completion, perceived difficulty and satisfaction were documented. Our results indicated a high level of acceptance of the system by these patients. On average, it took 83+/-41 seconds to complete all the major tasks necessary to operate the telerehabilitation system. After the initial introduction, all patients were able to successfully use the system and follow their individualized exercise prescription independently. A definitive systematic evaluation in a randomized clinical trial is warranted to demonstrate potential clinical impact of telerehabilitation in PwMS. PMID- 30306954 TI - Exploring Key Elements for Successful Telehealth Implementation Within Severely Under-Resourced Communities: A Case Study in the Pacific Islands. AB - The intent of this paper is to identify and provide insight on key enablers for successful implementation of telehealth services in severely under-resourced and rural populations. The case study presented is in the context of the U.S. Affiliated Pacific Islands that represent resilient and innovative communities who face many challenges of isolation, tiny populations, and developing economies. Long-standing telecommunication hindrances and lack of supporting resources are fundamental barriers to telehealth advancement. New undersea fiber optic developments present opportunities for reliable connectivity needed for telehealth applications. This paper reviews the emergence of telehealth champions in the region and reviews key elements that contribute to rapid and successful implementation of telehealth applications and services. PMID- 30306955 TI - Health Information Technology and Telehealth Challenges in the U.S. Affiliated Pacific Islands Region. AB - Small island developing states (SIDS) have much to gain from the use of Health Information Technology (HIT) and telehealth to improve care, improve population health, increase access to care, and lessen costs. At the same time, planning, implementing, and operationalizing HIT is costly and requires significant technical, human, financial and planning resource infrastructure to support implementation and operations. This paper provides a broad overview of how HIT and telehealth has evolved in the U.S. Affiliated Pacific Islands (USAPI) SIDS, the progress that has been achieved, the role of political affiliations and international assistance, and the many challenges that remain. The paper highlights the differences in treatment between the territories and the nations affiliated with the United States through the Compacts of Free Association (COFA), and the important roles of other donor countries, regional, and international organizations. The paper also raises questions of how advances in HIT and telehealth can be further achieved and sustained in the USAPIs. Finally, the paper identifies the need for the building of knowledge and skills to develop careful plans so pitfalls of silos, proprietary systems, and inadequate technical support can be lessened or avoided in the grand challenge of adoption and maturing of HIT and telehealth. PMID- 30306957 TI - Selfie Telemedicine - What Are the Legal and Regulatory Issues? AB - : Selfies, self-taken photographs using mobile phones or tablet computers, have become a way of life. People are now sending selfies to health professionals for medical advice or dermatology triage or postoperative wound assessment. These selfies may be unsolicited and sent to clinicians with whom the patient may or may not have a prior doctor-patient relationship or on the instruction of the attending doctor or even to social media groups. They may be sent by email, or by mobile phone and instant messaging applications, or sent to Websites, or telemedicine specific application sites. These photographs and accompanying information are legal documents, should form part of the patient's record, and should be securely transmitted and stored to maintain patient confidentiality and privacy. This paper reviews the legal, ethical and regulatory issues associated with the different forms of selfie telemedicine. METHOD: A scoping literature review was undertaken using PubMed, Scopus, Science Direct, Ebsco Host and Google Scholar which were searched for Selfie and any of medicine, telemedicine, telehealth, eHealth, or mHealth. Inclusion criteria were that the paper was in English and described the use of a selfie in relation to healthcare. These were then reviewed for reference to legal, ethical issues and regulatory issues. RESULTS: 68 papers met the inclusion criteria. Legal and ethical issues identified were consent, confidentiality, privacy, the doctor-patient relationship, data security, responsibility, record keeping, licensure, continuity of care, quality of care, image quality, concordance, phone stewardship and patient satisfaction. CONCLUSION: The literature provides little guidance on how legal and ethical issues and shortcomings of selfie telemedicine should be addressed especially the responsibilities of the patient and physician for unsolicited requests. Nor does it provide advice on how records are to be kept, or how images and information stored and sent to and from mobile phones or computers are to be managed. The new issues that arise need to be addressed. PMID- 30306956 TI - Comparative Study of Medical Reference and Information Mobile Apps for Healthcare Professionals and Students. AB - This paper presents a framework upon which medical applications can be evaluated both in terms of basic functionality, and their target area of users. The study was conducted on 40 mobile applications that were published within Google Play and Apple App store targeted for clinicians, medical practitioners and students. It was important to first classify the mobile apps selected because there are many generic applications, and some focus on special areas within the medical field. The classification process included determining the specialist areas of these applications such as educational and training, nursing, diagnosis and treatment, patient monitoring, testing and laboratories, and social networking. After the classification, a criterion to evaluate applications within individual categories, as well as in more general aspects such as their performance, security, user interface, and other software quality attributes, was developed. Test data was used to test the applications using the developed evaluation criteria, and the results were then used to determine the apps with surpassing features. As per the category-wise results, Medicine References and Education & Training categories had applications that had better scores than other categories. However, an equally important finding concluded that there are not enough applications to help with lab testing, and this gap needs to be filled. Most applications lacked the usability aspect and needed work in user interface (UI) and user experience (UX) areas. PMID- 30306958 TI - Citizens and Health Data - Untapped Resource for Telehealth? AB - In this paper I will engage with the discussion on Citizen and Health Data, and look specifically at challenges in citizen-centered digital health information management, if the goal is to stimulate self-management, support holistic trajectories of health and wellbeing, and implement new practice models with efficient use of health care services. A focus will be citizens' opportunities to engage in activities to a) collect, b) curate, c) control access to personal Health Data and relate these activities to telehealth locally and globally. PMID- 30306959 TI - Instant Messaging in Dermatology: A Literature Review. AB - : The use of smartphones and IM has the potential to transform the delivery of health services by providing an easy to use, cost-effective tool for remote doctor-to-doctor and patient-to-doctor consultation and diagnosis. Whilst the introduction of new technologies has improved access to healthcare, it has also created new challenges. The aim of this paper was to review the literature on the use of Instant Messaging (IM) and IM applications (apps) in dermatology. METHOD: PubMed, Scopus, and Science Direct were searched for multiple terms for 20 individual IM apps linked to the terms telehealth, telemedicine, ehealth, e health, mhealth, or m-health. After title and abstract review, 31 papers met the inclusion criteria of IM use in dermatology. RESULTS: Three papers, all from the developing world reported the benefits of using IM in a clinical dermatology service. Other uses included behavioural change, disease management, diagnosis, triage, screening, diagnoses, home monitoring, education, and administrative. Little mention was made of medico-legal issues such as consent, confidentiality, privacy and data security and storage. CONCLUSION: Currently there is little use of IM in clinical dermatology services, but its potential is great. There is need to address ethical and medico-legal concerns and develop guidelines for its use. IM is a simple, cheap and effective solution for the developing world. PMID- 30306960 TI - Security and Other Ethical Concerns of Instant Messaging in Healthcare. AB - : There is a growing body of evidence highlighting the benefits of mobile health in terms of cost effectiveness, efficiency and patient satisfaction. These benefits have been further enhanced through the development of Instant Messaging (IM) applications (apps) that enable the transmission of images and text messages. The aim of this paper is to review the use of IM in clinical services, and to understand the medico legal concerns with regard to the security and management of protected health information on doctors' phones. METHOD: PubMed was searched using the various IM apps as a search term. Inclusion criteria were that the paper was in English and described the use of IM in a clinical service. RESULTS: 39 papers met the inclusion criteria. Data are at risk at several levels, including during transmission, storage on servers en route, and on the sender's and receiver's phones. Consent is seldom obtained for instant messaging, and confidentiality, privacy, data security and record keeping remain areas of concern. CONCLUSION: The use of IM, and in particular WhatsApp, is now commonplace amongst clinicians and used extensively across different clinical services. Security concerns have created barriers preventing the global adoption of IM in healthcare. Guidelines in the management and use of IM need to be developed in order to prevent the unwanted consequences of non-compliance by uninformed clinicians. With improved security, IM has proven to be a viable option in the developing world. PMID- 30306961 TI - Clinician Perspectives of an Avatar-Directed Scheduling and Memory App. AB - BACKGROUND AND AIMS: Effective strategies are needed to address the need for scheduling support in the unique setting of a home rehabilitation service, providing home based therapy, as well as telerehabilitation. One approach is an electronic avatar-directed scheduling and memory aid in the form of an app. The aim of this study is to investigate clinician perspectives on the use of this type of technology. METHODS: In this mixed method study a total of sixteen clinicians from various disciplines based at a metropolitan hospital in Adelaide (SA, Australia) participated in 2 semi-structured focus groups aimed to explore experiences and attitudes towards scheduling support in the form of an avatar directed app, perceptions on the usefulness of the app, as well as acceptability. Thematic analysis was undertaken on focus groups' transcripts. Self-reported technology proficiency, perceived usefulness (PU), and perceived ease of use (PEOU) were assessed quantitatively. Summary statistics were used to analyse the quantitative data and Spearman's correlation was used to explore the relationship between participant characteristics and individual and mean scores for PU and PEOU. RESULTS: Four themes emerged from the focus groups: effectiveness versus efficiency, patient empowerment, practicality and ease of use, and likability of the avatar. Clinicians experienced time constraints, and welcomed technology that could assist with reliable scheduling of appointments and therapy sessions. They liked the concept of the avatar and found the app interesting, novel and fun. However, although the app was reasonably easy to use, the setting up was problematic and time consuming. Clinicians did not see the app as beneficial to their patients, and felt that the technology did not add value to the delivery of care. The older, more experienced, clinicians found the app more difficult to use, but neither the level of technological competency, nor gender, was found to be associated with PU or PEOU. DISCUSSION: Although clinicians appreciated the concept of an avatar-directed scheduling and memory app, they did not see it as a useful tool in the provision of scheduling assistance in this particular setting providing short-term rehabilitation services. Clinicians felt time-poor and emphasized the importance of a time-efficient solution. Perceived lack of usefulness in this context and poor likeability of the avatar highlight the need for clinician involvement in the design process before an app can be successfully implemented in a clinical setting. PMID- 30306962 TI - Habitual Personal Movement Patterns in a Structured Environment. AB - This paper presents an approach for describing personal movement patterns for typical daily activities undertaken by subjects within free living structured environments (e.g. home or office). Conventionally this requires specialized technology for personal movement monitoring involving measurement of location and motion, and results in the collection of large datasets in order to provide sufficient descriptive power. Here we advocate the preferential observation of sentinel activities based on the expectation of routine and repetitive personal movement episodes, which can be considered as 'habits'. These identified habitual patterns provide a useful context for understanding the dominant characteristics of typical daily activities, enabling purposeful design of behaviour change interventions to improve healthy living. This approach has been applied here to office stepcount data from consumer wearables. PMID- 30306963 TI - A Patient Agent to Manage Blockchains for Remote Patient Monitoring. AB - Continuous monitoring of patient's physiological signs has the potential to augment traditional medical practice, particularly in developing countries that have a shortage of healthcare professionals. However, continuously streamed data presents additional security, storage and retrieval challenges and further inhibits initiatives to integrate data to form electronic health record systems. Blockchain technologies enable data to be stored securely and inexpensively without recourse to a trusted authority. Blockchain technologies also promise to provide architectures for electronic health records that do not require huge government expenditure that challenge developing nations. However, Blockchain deployment, particularly with streamed data challenges existing Blockchain algorithms that take too long to place data in a block, and have no mechanism to determine whether every data point in every stream should be stored in such a secure way. This article presents an architecture that involves a Patient Agent, coordinating the insertion of continuous data streams into Blockchains to form an electronic health record. PMID- 30306964 TI - Characterising Routine Physical Activity in the Office. AB - Workplace health is of concern to management and employees alike. Managers are concerned about the impact of health and wellbeing on productivity, while employees are concerned about impacts on quality of life. In the past two decades, there has been growing concern about the impact of sedentary behaviour at work. Before any interventions can be made to encourage physical activity at work proactively, it is desirable to understand the baseline characteristics of office based physical activity at work. Consumer wearable technology has provided a new and convenient mechanism for using personal monitoring to achieve remote observation of lifestyle related health behaviours. This paper describes how this technology can potentially be used to characterize different levels of workplace physical activity. PMID- 30306965 TI - Tele-evidence comes to the rescue of overburdened medical doctors. PMID- 30306966 TI - Measles-Rubella vaccination campaign: A trust deficit? PMID- 30306967 TI - Proptosis with hemiplegia: Unusual presentation of multiple myeloma. PMID- 30306968 TI - Predatory journals: The rise of worthless biomedical science. AB - In today's world when biomedical science is experiencing continuous threats from various sources, publication of research articles in predatory journals has created a major havoc. These predatory journals are publishing worthless biomedical science which will haunt genuine researchers and keen readers of authentic biomedical journals for several decades. Hence, researchers of various disciplines and academic experience should be continuously made aware of these predatory publishers and potential ways to recognize them. The main aim of this article is to discuss the issues related to predatory publishing, techniques and strategies used by these publishers to prey young inexperienced researchers, and disadvantages of publishing in predatory journals. PMID- 30306969 TI - Iron Deficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Cross Sectional Survey from a Single Institution in China. AB - BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that often manifests with chronic intravascular hemolysis. Iron deficiency in patients with PNH is most often due to urinary losses of iron secondary to chronic intravascular hemolysis. MATERIAL AND METHODS This cross sectional survey assessed the prevalence of iron deficiency in a Chinese population of PNH patients who were enrolled between May 2012 and October 2014. RESULTS A total of 742 PNH cases were selected by FLARE and classified as classical PNH (15.36%), PNH in the setting of another specified bone marrow disorder (12.26%), and subclinical PNH (72.38%). The median age of all the patients was 32 years (range 5-77 years). The overall prevalence of iron deficiency was 17.9% among all the PNH patients enrolled in the survey, 76.3% (87/144) among those with classical PNH, 33.0% (30/91) among those with PNH in the setting of another specified bone marrow disorder, and 3.0% (16/537) among the subclinical PNH patients. The incidence of iron deficiency among classical PNH patients was higher than that in the other 2 subcategories (P-value=0.000). Multivariate analyses showed that age and disease duration were independent risk factors for iron deficiency in classical patients. CONCLUSIONS This survey shows that PNH patients were prone to iron deficiency, especially patients with classical PNH. PMID- 30306970 TI - Surface morphologies of spherical polyelectrolyte brushes induced by trivalent salt ions. AB - The surface morphologies of spherical polyelectrolyte brushes in salt solutions with opposite trivalent ions are studied using molecular dynamics (MD) simulations. The impact of salt concentration, grafting density, and charge fraction on brush morphologies is investigated systematically. A variety of surface patterns are predicted and the phase diagrams are presented. Both lateral and radial microphase separated structures in the brushes are observed upon varying the salt concentration. With low grafting density the spherical brush is separated into several patches, the number of which decreases with the addition of salt. At high grafting density, the polymer brush changes its morphology from an extended micelle to a 'carpet + brush' to the collapsed state upon increasing the salt concentration. Especially, the 'carpet + brush' structure consists of a core formed by partially collapsed brush chains and a corona formed by other stretched chains. The inter-chain 'bridging' interactions mediated by trivalent ions and the curvature effect play important roles in determining the chain conformations and brush structures. PMID- 30306972 TI - Nature of halogen bonding involving pi-systems, nitroxide radicals and carbenes: a highlight of the importance of charge transfer. AB - The recently developed adiabatic absolutely localized molecular orbital energy decomposition analysis (ALMO-EDA) has proven to be useful in determining the effects of different energy components on the geometries of complexes bound by intermolecular interactions. The authors have applied it to systems such as the water dimer, water-ion complexes, metallocenes and lone-pair type halogen-bonded (XB) dimers. In this study, we have extended the second-generation ALMO-EDA method to 40 different XB complexes by benchmarking against its classical counterpart and symmetry-adapted perturbation theory (SAPT). In addition, we have examined the nature of halogen bonding involving less studied XB acceptors, namely pi-systems, radicals and carbenes, using the adiabatic ALMO-EDA analyses, particularly to shed light on how each energy component affects the geometries of the XB complexes. Our results show that the second-generation ALMO-EDA predicts a higher electrostatic energy contribution in all XB complexes compared to SAPT and classical ALMO-EDA schemes. On the other hand, when comparing across different XB acceptors, all three partition schemes produced the same qualitative finding. The adiabatic ALMO-EDA analyses indicate that while the inclusion of a charge transfer contribution is important in achieving accurate XB bond lengths and interaction energies, as well as recovering the binding site specificity of XB involving benzene and naphthalene acceptors, it is sufficient to obtain the linearity of the XB complexes in the frozen approximation. PMID- 30306971 TI - Evaluation of the formation and carbon dioxide capture by Li4SiO4 using in situ synchrotron powder X-ray diffraction studies. AB - Carbon capture and storage using regenerable sorbents are an effective approach to reduce CO2 emissions from stationary sources. In this work, lithium orthosilicate (Li4SiO4) was studied as a carbon dioxide sorbent. For a deeper understanding of the synthesis and carbonation mechanism of Li4SiO4, an in situ synchrotron radiation powder X-ray diffraction technique was used. The Li4SiO4 powders were synthesized by a combination of ball milling of a Li2CO3 and SiO2 mixture followed by a thermal treatment process at low temperature. In situ studies showed that formation of Li4SiO4 from the as-milled 2Li2CO3-SiO2 mixture involves decomposition of Li2CO3 by reaction with SiO2via Li2SiO3 as an intermediate compound. No evidence of Li2Si2O5 formation was obtained, in spite of thermodynamic predictions. The CO2 capture by Li4SiO4 was evaluated dynamically over a wide temperature range, reaching a maximum weight increase of 34 wt% and good cyclability after about 10 cycles. By thermogravimetric and microstructural analyses in combination with ex situ and in situ measurements, a two step carbonation mechanism and its influence on the final CO2 capture was clearly elucidated. Under dynamical conditions up to 700 degrees C, the lower number of Li2CO3 nuclei initially formed retards the double shell formation and the nucleation and growth of the Li2CO3 particles remains the controlling step up to higher CO2 capture capacity. Isothermal carbonation at 700 degrees C favours the formation of a higher number of Li2CO3 nuclei that creates a thin carbonate shell. The CO2 diffusion through this shell is the limiting step from the beginning and further carbonation is hindered as the reaction progresses. PMID- 30306973 TI - Theoretical description of alkali metal closo-boranes - towards the crystal structure of MgB12H12. AB - Solid state closo-borane salts of alkali metals have very high ionic conductivity. This makes them interesting for practical applications as solid state electrolytes, and has triggered extensive research efforts. Improvement and understanding of their properties require accurate theoretical description of their static and dynamical properties. In this work, we report accuracy assessment of density functional theory in the description of solids with B12H122 anions. We show that these aromatic anions interact via weak dispersive forces. For that reason, non-local exchange-correlation functionals give better description of structural properties and phonons in Li2B12H12 and Na2B12H12. Numerically efficient semi-local methods provide satisfactory results when applied in structure volumes obtained in a non-local method. An extensive structural search for stable crystalline phases of MgB12H12 predicts a new denser lattice with C2/c symmetry that is stabilized by van der Waals interactions. These structures might be discovered as anhydrous MgB12H12 in high pressure experiments, avoiding the amorphous state at ambient pressures. PMID- 30306974 TI - Dy(iii) zig-zag chains assembled in a 3D framework with single-molecule magnet behaviour. AB - A new lanthanide-based framework, [Dy(STP)(1,2-bdc)]n (1), was constructed. It represents dysprosium(iii) 1D zigzag chains in a 3D framework and displays single molecule magnet (SMM) behaviour with an energy barrier of 55.76 K under zero dc field. PMID- 30306975 TI - Crystal structure prediction: reflections on present status and challenges. AB - Long thought to be impossible, crystal structure prediction (CSP) is a thriving field today, with many important discoveries in fields as diverse as computational materials discovery, drug design, high-pressure chemistry and mineralogy of the Earth's and planetary interiors. However, major challenges remain, warranting more research. In these Concluding Remarks, I try to summarize my personal view of the enormous progress made in the field of CSP and the open questions and challenges that keep this field more exciting than ever. PMID- 30306976 TI - What kind of neutral halogen bonds can be modulated by solvent effects? AB - The response of a series of neutral halogen bonds X'-XY (X'-X = BrF, ClF, I2, Br2 and Cl2; Y = pyridine, NH3, H2S, HCN, H2O and dimethyl ether) to solvent effects is investigated using quantum theory of atoms in molecules (AIM), molecular electrostatic potential (MESP) and generalized Kohn-Sham energy decomposition analysis (GKS-EDA). The physical origin of the halogen bonds in various environments is explored. It is shown that halogen bonds in the gas phase are indeed governed by electrostatic interactions. A linear correlation between the magnitude of the sigma hole and the electrostatic interaction is established. If the local softness of the donor or the acceptor is large, the polarization of the corresponding XB complex is large. Otherwise, the polarization is small. From gas phase to solvent environments, polarization is more sensitive to the solvent effects than the other interaction terms. For the strong XBs in a polar solvent environment, polarization is even larger than the electrostatic interaction. Our study shows that a halogen bond with a large portion of polarization can be modulated by solvent effects. If the contribution of polarization is small, the corresponding halogen bond is insensitive to solvent effects. PMID- 30306977 TI - Formation and characterization of nano- and microstructures of twinned cubic boron nitride. AB - Nano- and microstructures of phase-pure cubic boron nitride (c-BN) are synthesized by employing nanosecond pulsed-laser annealing techniques at room temperature and atmospheric pressure. In a highly non-equilibrium synthesis process, nanocrystalline h-BN is directly converted into phase-pure twinned c-BN from a highly undercooled melt state of BN. By changing nucleation and growth rates, we have synthesized a wide range of sizes (90 nm to 25 MUm) of c-BN. The electron diffraction patterns show the formation of twinned c-BN with [11[combining macron]1] as the twin axis. The twinning density in c-BN can be controlled by the degree of undercooling and quenching rates. The formation of twins predominantly occurs prior to the formation of amorphous quenched BN (Q BN). Therefore, the defect density in nano c-BN formed under higher undercooling conditions is considerably larger than that in micro c-BN, which is formed under lower undercooling conditions. The temperature-dependent Raman studies show a considerable blue-shift of ~6 cm-1 with a decrease in temperature from 300 to 78 K in nano c-BN as compared to micro c-BN. The size-effects of c-BN crystals in Raman spectra are modeled using spatial correlation theory, which can be used to calculate the correlation length and twin density in c-BN. It has also been found that the Raman blue-shift in nano c-BN is caused by anharmonic effects, and the decrease in Raman linewidth with decreasing temperature (300 to 78 K) is caused by three- and four-phonon decay processes. The bonding characteristics and crystalline nature of the synthesized c-BN are also demonstrated by using electron energy-loss spectroscopy and electron backscatter diffraction, respectively. We envisage that the controlled growth of phase-pure nano and microstructures of twinned c-BN and their temperature-dependent Raman-active vibrational mode studies will have a tremendous impact on low-temperature solid state electrical and mechanical devices. PMID- 30306978 TI - Temperature-dependent crystalline structure and phase transition of poly(butylene adipate) end-functionalized by multiple hydrogen-bonding groups. AB - Because of the different crystallization behaviors of semicrystalline supramolecular polymers (SMPs) from conventional polymers, investigation on the unique crystallization kinetics and crystalline structures of SMPs is of fundamental importance to tune their physical properties and functions in processing. Herein, we chose the multiple hydrogen-bonding 2-ureido-4[1H] pyrimidinone (UPy) group as the supramolecular unit and poly(butylene adipate) (PBA) as the polymorphic polymer block, and synthesized UPy-functionalized PBAs (i.e., UPy-bonded supramolecular PBAs). The crystallization kinetics, polymorphic crystalline structure, phase transition, and lamellar morphology of the UPy functionalized PBAs were investigated and compared with those of the pristine PBA. UPy end functionalization suppressed the crystallization rate and crystallinity of the linked PBA chains. Compared to the pristine PBA, the UPy functionalized PBAs preferred to form the thermally-stable alpha crystals at the same temperature; this was more obvious for the samples with a high content of the UPy end group. The facilitated formation of alpha crystals in the UPy functionalized PBAs was attributed to the decreased equilibrium melting temperature. UPy end functionalization also decreased the critical temperature and broadened the temperature range for the beta-to-alpha phase transition of PBA during heating. Due to the segregation of the UPy unit in the amorphous phase, the UPy-functionalized PBAs exhibited larger long periods than the pristine PBA, even though they had a lower degree of crystallinity. PMID- 30306979 TI - The structures and properties of anionic tryptophan complexes. AB - The physicochemical properties of [Trpn-H]- and [TrpnCl]- (n = 1, 2) have been investigated in a combined computational and experimental infrared multiple dissociation (IRMPD) study. IRMPD spectra within the 850-1900 cm-1 region indicate that deprotonation is localized on the carboxylic acid moiety in [Trpn H]- clusters. A combination of hydrogen bonding and higher order charge quadrupole interactions appear to influence cluster geometries for all investigated systems. Calculated global minimum and low energy geometries of [TrpCl]- and [Trp2Cl]- clusters favour coordination of the halide by the indole NH. [Trp2-H]- and [Trp2Cl]- exhibit additional pi-pi interactions between the heterocyclic side chains. PMID- 30306980 TI - Rationally designing mixed Cu-(MU-O)-M (M = Cu, Ag, Zn, Au) centers over zeolite materials with high catalytic activity towards methane activation. AB - The direct conversion of methane to methanol on [Cu(MU-O)M]2+ (M = Cu, Ag, Zn, Au) bimetal centers in ZSM-5 zeolite is investigated using periodic density functional theory for the first time. Some conclusions are drawn: (1) methane activation on [Cu(MU-O)M]2+ (M = Cu, Ag, Zn, Au) in the ZSM-5 zeolite proceeds through radical-like transition states, and the ability for CH4 activation decreases in the sequence [Cu(MU-O)Ag]2+ > [Cu(MU-O)Au]2+ > [Cu(MU-O)Cu]2+ > [Cu(MU-O)Zn]2+. (2) There are two factors that can dramatically enhance C-H bond activation: a greater spin density and a less negative charge of the MU-O atom. (3) The angles ?CuOM play a minor role in the reactivity difference among [CuOM]2+-ZSM-5 (M = Cu, Ag, Zn, Au). Our findings will provide insight into methane activation for designing highly effective catalysts applied in industrial processes. PMID- 30306981 TI - Unveiling anharmonic coupling by means of excited state ab initio dynamics: application to diarylethene photoreactivity. AB - In this work, excited state ab initio molecular dynamics together with a time resolved vibrational analysis is employed to shed light on the vibrational photoinduced dynamics of a well-known diarylethene molecule experiencing a ring opening reaction upon electronic excitation. The photoreactivity of diarylethenes is recognized to be controlled by a non-adiabatic intersection point between the ground and the first excited state surfaces. The computation of an energy scan, along a suitable reaction coordinate, allows us to identify the region of potential energy surfaces in which the ground (S0) and the first excited (S1) state are well separated. The adiabatic sampling of that region in S1 shows that in the first 3 picoseconds, the central CC bond, which is subject to break, oscillates in an antiphase with respect to the energy gap DeltaE(S1 - S0). A multiresolution analysis based on the wavelet transform was then applied to the structural parameters extracted from the excited state dynamics. The wavelet maps show characteristic oscillations of the frequencies, mainly CC stretching and CCC bending localized on the central 4-ring moiety. Moreover, we have identified the main frequency (methyl wagging motion) involved in the modulation of these oscillations. The anharmonic coupling within a group of vibrational modes was therefore highlighted, in good agreement with experimental evidence. For the first time, a quantitative analysis of time resolved signals from a wavelet transform/ab initio molecular dynamics approach was performed. PMID- 30306982 TI - Carbon nanodot aqueous binding phase-based diffusive gradients in thin films device for measurement of dissolved copper and lead species in the aquatic environment. AB - A reliable method for the determination of dissolved Cu2+ and Pb2+ species in water via a diffusive gradient in thin films (DGT) device using water-soluble carbon nanodots (CD) as the binding agent was developed (CD-DGT). The uptake of dissolved Cu2+ and Pb2+ species by CD-DGT increased linearly with a deployment time of over 120 h, while the uptake of Ca2+, Mg2+, Cd2+, Zn2+, Ni2+, and Co2+ by CD-DGT has no significant linear accumulation during the same deployment time. The concentrations of the dissolved Cu2+ and Pb2+ species measured using CD-DGT are in good agreement with the element concentrations spiked directly in a tested synthesis solution. The performance of CD-DGT for the determination of dissolved Cu2+ and Pb2+ species is found to be independent of ionic strength in the range of 0.001-0.05 mol L-1 and in the pH range from 5 to 8. The presence of fulvic acid and tannic acid has no significant influence on the uptake of dissolved Cu2+ and Pb2+ species by CD-DGT under the tested conditions. In different water samples, good agreement was observed between the dissolved Cu2+ and Pb2+ concentrations measured by CD-DGT, and diffusive equilibration in the thin film devices was found. Based on the results obtained, CD-DGT enables the selective and quantitative determination of dissolved Cu2+ and Pb2+ species in water. PMID- 30306983 TI - A nanoscale study of the negative strain rate dependency of the strength of metallic glasses by molecular dynamics simulations. AB - Compressive strength and deformation characteristics of a metallic glassy alloy related to strain rate are studied by molecular dynamics simulations. The negative strain rate dependency of strength is presented, i.e., compressive strength decreases with the increase of strain rate, which is well in line with the experimental results. The negative strain rate dependency of strength is explained from two aspects at the atomic scale of free volume and potential energy. Compressive strength is related to the free volume formation in a shear band, which is different from that in a metallic glass matrix. In addition, the relation of potential energy and temperature is also investigated, which indicates that thermal softening also plays an important role in the negative strain rate dependency of strength. The thermal-mechanical coupling mechanisms causing the negative strain rate dependency of the strength of the metallic glassy alloy are clarified. It is significant to explore the intrinsic deformation characteristics of the metallic glassy alloy under a high rate loading. PMID- 30306984 TI - Exploring the potential and design of zeolite nanosheets as pervaporation membranes for ethanol extraction. AB - Molecular dynamics simulations are employed to demonstrate the potential of zeolite nanosheets as pervaporation membranes for ethanol extraction. Our results show that zeolite nanosheets can provide orders of magnitude higher fluxes compared to currently available membranes and achieve outstanding separation factors. The dominant role of membrane surfaces in determining the separation performance is also identified and explored at an atomic level. Developing nanosheet membranes with hydrophobic surfaces and/or with a minimal surface silanol density represents the keys to enable highly selective separation processes. PMID- 30306985 TI - Titanium thiosalicylate complexes: functional metalloligands for the construction of redox-active heterometallic architectures. AB - The titanium complex [TiCp*(thiosal)(thiosalH)] (1) has been synthesised by reaction of [TiCp*Me3], Cp* = eta5-C5Me5, with thiosalicylic acid (H2thiosal). Complex 1 reacts with [M(MU-OH)(COD)]2 (M = Rh, Ir) to yield the corresponding early-late heterobimetallic complexes [TiCp*(thiosal)2M(COD)] (M = Rh (2); Ir (3)). Carbon monoxide replaces the COD ligand in 2 and 3 leading to the respective dicarbonyl complexes [TiCp*(thiosal)2M(CO)2] (M = Rh (4); Ir (5)). Compound 4 reacts with PPh3 to yield the monocarbonyl derivative [TiCp*(thiosal)2Rh(CO)(PPh3)] (6). The reaction of compound 1 with LinBu yields the tetrametallic complex [{TiCp*(thiosal)2Li}2(THF)3(H2O)] (7). Compound 7 reacts with [RuCp*Cl(COD)] yielding the heterometallic complex [TiCp*(thiosal)2RuCp*] (8). The molecular structures of compounds 4, 5 and 7 have been studied by X-ray diffraction. From cyclic voltammetric (CV) and square wave voltammetric (SWV) experiments, we observed that attachment of the titanium moiety of precursor 1 to a late transition metal moiety through the sulfur atoms has a significant influence on the reduction behaviour of the Ti(iv) metal centre. Thus, monometallic 1 exhibits an irreversible reduction process at -1.15 V vs. SCE, whereas the CVs of heterobimetallic compounds 2-6 are characterized by the reversible or quasi-reversible one-electron reduction of the Ti(iv)/Ti(iii) system, suggesting a significant stabilization of the Ti(iii) reduced species. Likewise, substitution of the M(COD) diolefin fragment in 2 and 3 by the M(CO)2 carbonyl-containing moiety (in compounds 4 and 5) leads to a significant anodic shift in the titanium E1/2 reduction redox potentials. PMID- 30306986 TI - Engineering more stable proteins. AB - Protein function requires the folded protein form, but this form is unstable mainly because it readily unfolds into a flexible, unstructured form. Protein folding is favored by burying of hydrophobic side chains and hydrogen bonding between the amino acids. Protein unfolding is favored by the increase in conformational freedom of the main chain of amino acids upon unfolding. Protein stability is usually measured by the reversible unfolding of the protein with either heat or chemical additives like urea. Engineering mores stable proteins involves making substitutions that shift the folding-unfolding balance toward the folded form. Stabilizing substitutions can either stabilize the folded conformation or destabilize the unfolded ensemble. This tutorial emphasizes web based tools to identify substitutions that stabilize proteins. Besides unfolding, other sources of protein instability are chemical modifications like oxidations or cleavage by proteases and aggregation of partly unfolded proteins into insoluble particles. PMID- 30306987 TI - Highly efficient surface hopping dynamics using a linear vibronic coupling model. AB - We report an implementation of the linear vibronic coupling (LVC) model within the surface hopping dynamics approach and present utilities for parameterizing this model in a blackbox fashion. This results in an extremely efficient method to obtain qualitative and even semi-quantitative information about the photodynamical behavior of a molecule, and provides a new route toward benchmarking the results of surface hopping computations. The merits and applicability of the method are demonstrated in a number of applications. First, the method is applied to the SO2 molecule showing that it is possible to compute its absorption spectrum beyond the Condon approximation, and that all the main features and timescales of previous on-the-fly dynamics simulations of intersystem crossing are reproduced while reducing the computational effort by three orders of magnitude. The dynamics results are benchmarked against exact wavepacket propagations on the same LVC potentials and against a variation of the electronic structure level. Four additional test cases are presented to exemplify the broader applicability of the model. The photodynamics of the isomeric adenine and 2-aminopurine molecules are studied and it is shown that the LVC model correctly predicts ultrafast decay in the former and an extended excited-state lifetime in the latter. Futhermore, the method correctly predicts ultrafast intersystem crossing in the modified nucleobase 2-thiocytosine and its absence in 5-azacytosine while it fails to describe the ultrafast internal conversion to the ground state in the latter. PMID- 30306988 TI - Tunable upconversion in a nanocrystal-organic molecule hybrid: reabsorption vs. resonant energy transfer. AB - Organic semiconductors, such as polycyclic aromatic hydrocarbons, are typically not responsive to near infrared (NIR) light due to their relatively large bandgaps. Here, we show that the NIR light at 980 nm can be efficiently converted to broadband visible upconversion (UC) emission by rubrene molecules in a solution dispersed with upconversion nanoparticles (UCNPs). Spectroscopic characterizations indicate that the sensitization of emission by rubrene molecules strongly depends on the location of the 4f levels of Er3+ ions and the interplay between reabsorption and Forster-type energy transfer. Even for the solution with the highest rubrene concentration (>1 mg mL-1), energy transfer by reabsorption of UC emission from the UCNPs is the dominant process, and the radiationless resonant energy transfer process is weak, as the separation between most rubrene molecules and NCs is far larger than the Forster distance. The results of this work could be of particular interest for the development of organic-inorganic hybrid systems for NIR light harvesting and detection. PMID- 30306989 TI - Correction: Penetrating probability and cross section of the Li+-C60 encapsulation process through an ab initio molecular dynamics investigation. AB - Correction for 'Penetrating probability and cross section of the Li+-C60 encapsulation process through an ab initio molecular dynamics investigation' by Thi H. Ho et al., Phys. Chem. Chem. Phys., 2018, 20, 7007-7013. PMID- 30306990 TI - Asymmetric abstraction of two chemically-equivalent methylene hydrogens: significant enantioselectivity of endoperoxide presented by fumitremorgin B endoperoxidase. AB - The combination of the inert C-H bond activation and asymmetric synthesis, especially the transformation of prochiral sp3 precursors to chiral sp3 centers, is a profound challenge. In the present DFT calculations, the unique enantioselectivity in verruculogen biosynthesis catalyzed by fumitremorgin B endoperoxidase (FtmOx1) has been mechanistically investigated, where a prochiral methylene in fumitremorgin B is dominantly converted to an R-chiral eight membered endoperoxy ring. FtmOx1 is the first-reported mononuclear alpha ketoglutarate-dependent non-heme iron enzyme responsible for chiral endoperoxide formation, which handles the substrate using a Tyr224 radical resulting from the hydrogen abstraction by an FeIV[double bond, length as m-dash]O species. It is demonstrated that the perfect enantioselectivity of the R-endoperoxy ring originates from the asymmetric abstraction of two chemically-equivalent methylene hydrogens from substrate chain A by the Tyr224 radical and the high conformation stability of the resultant chain A radical due to steric effects. The barrier difference in the abstraction of two hydrogens is 5.6 kcal mol-1. The hydrogen abstraction by the Tyr224 radical is rate-limiting in the FtmOx1 reaction with an overall barrier of 18.6 kcal mol-1. The results obtained here advance the understanding of the chemistry in enantioselectivity, providing a potentially general way for the transformation of prochiral sp3 precursors to chiral sp3 centers. PMID- 30306991 TI - Dissociative chemisorption of hydrogen molecules on defective graphene-supported aluminium clusters: a computational study. AB - Using periodic density functional theory-based calculations, in the present study, we address the chemical bonding between aluminium clusters (Aln, n = 4-8 and 13) and monovacant defective graphene. The adsorption strength of the above mentioned aluminium clusters is fivefold (~3 to 5 eV) higher on defective graphene as compared to the earlier reported values on non-defective graphene and BN-doped graphene. The Bader charge analysis and different charge densities reveal that this adsorption is driven by significant charge transfer from the Al clusters to defective graphene. Thus, chemisorbed Al clusters demonstrate high activity towards dissociative adsorption of molecular hydrogen. PMID- 30306992 TI - Explorative investigation of the anti-glycative effect of a rapeseed by-product extract. AB - The formation of advanced glycation end-products (AGEs) in biological systems is increased during hyperglycaemia due to higher levels of circulating glucose and carbonyl reactive species. AGEs are causative factors of common chronic diseases. Since synthetic AGE-inhibitors exert unwanted side effects and polyphenols act as potent antiglycative agents, vegetables (fruits, seeds and related by-products) are good candidates when searching for natural inhibitors. The aim of this research is to explore the suitability of a polyphenol-rich rapeseed cake extract (RCext) to decrease the formation of AGEs in an in vitro model. Different phenols, amino acids, carbohydrates, organic acids and fatty acids were identified in the RCext by GC-MS. The results confirm a high concentration of polyphenols (73.85 +/- 0.64 and 86.85 +/- 2.08 mg of gallic acid equivalents per g of RCext spray dried and freeze dried, respectively) which is correlated with the antioxidant capacity and anti-glycative activity in a dose dependent manner. Rapeseed cake extract (3.7 mg mL-1) significantly reduced the formation of free fluorescent AGEs and pentosidine up to 34.85%. The anti-glycative activity of the extract is likely to be due to the high concentration of sinapinic acid (0.108 +/ 0.0043 mg g-1) in its metabolic profile, and the mechanism of action is mediated by methylglyoxal trapping. The results show promising potential for using rapeseed cake extract as a food supplement to ameliorate the formation of AGEs. Rapeseed cake extract should therefore be considered a potential candidate for the prevention of glycation-associated complications of age-related pathologies. PMID- 30306993 TI - Non-innocent PNN ligand is important for CO oxidation by N2O catalyzed by a (PNN)Ru-H pincer complex: insights from DFT calculations. AB - Milstein et al. developed an efficient and mild method for CO oxidation by N2O to give CO2 and N2 catalyzed by a (PNN)Ru-H pincer complex. To gain mechanistic information on this catalytic transformation, the reaction mechanism has been studied using density functional theory (DFT) calculations. It was found that the catalytic cycle for CO oxidation by N2O proceeds in three stages: N2O activation to form a (PNN)Ru-OH intermediate, CO insertion into the Ru-OH bond to form a (PNN)Ru-COOH intermediate and CO2 release from (PNN)Ru-COOH. In the CO2 release stage, CO2 is not released via a beta-H elimination mechanism as proposed in experiments, instead it is released via a deprotonation mechanism. The calculations demonstrated that the Ru-H bond of the catalyst plays an important role in facilitating the activation of N2O, which is the rate-determining step for the whole catalytic cycle, and the non-innocent PNN ligand is very important for CO oxidation by N2O. Our theoretical results are consistent with the experimental observations and could help design highly efficient catalysts for N2O activation. PMID- 30306994 TI - Designed single-source precursors for iron germanide nanoparticles: colloidal synthesis and magnetic properties. AB - The synthesis of iron germanide nanoparticles at the nanoscale is a challenging task. Here, we describe the preparation of nanocrystals of the hexagonal Fe1.67Ge phase via the thermolysis of single source precursors [{iPrNC(tBu)NiPr}RGe]Fe(CO)4 (where R = Cl, N(SiMe3)2) under mild conditions (200 degrees C). These bimetallic precursors and the corresponding germylenes [{iPrNC(tBu)NiPr}RGe] were fully characterized by spectroscopic techniques as well as single crystal X-ray diffraction. While the structural features of the molecular species were shown to be almost identical, the results of the thermolysis were highly dependent on the nature of R. When R = Cl, multimodal size distributions and non-controlled phases were obtained. In contrast, the thermolysis of [{iPrNC(tBu)NiPr}{N(SiMe3)2}Ge]Fe(CO)4 yielded pure ferromagnetic Fe1.67Ge nanoparticles with a mean diameter close to 6 nm and a narrow size distribution (<12%). These results were rationalized in terms of Ge-substituent bond energy thanks to a computational study. PMID- 30306995 TI - Optical Kerr effect spectroscopy of CS2 in monocationic and dicationic ionic liquids: insights into the intermolecular interactions in ionic liquids. AB - A comparative study of the intermolecular dynamics of CS2 in monocationic and dicationic ionic liquids (ILs) was performed using optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES). The reduced spectral densities (RSDs) of mixtures of CS2 in 1-alkyl-3-methylimidazolium bis[(trifluoromethane)sulfonyl]amide ([CnC1im][NTf2] for n = 3-5) and 1,2n-bis(3 methylimidazolium-1-yl) alkane bis[(trifluoromethane)sulfonyl]amide ([(C1im)2C2n][NTf2]2 for n = 3-5) were investigated as a function of concentration at 295 K. An additivity model was used to obtain the CS2 contribution to the RSD of a mixture in the 0-200 cm-1 region. One of the aims of this study is to show how CS2 can be used as a probe of intermolecular/interionic interactions in ILs. The concentrations were chosen such that the CS2-to imidazolium ring mole fraction of a mixture with [(C1im)2C2n][NTf2]2 (DIL(2n)) is the same as that of a mixture with [CnC1im][NTf2] (MIL(n)). As found previously for CS2 in monocationic ILs, the intermolecular spectrum of CS2 in dicationic ILs is lower in frequency and narrower than that of neat CS2. The new result is that the intermolecular spectrum of CS2 is higher in frequency in DIL(2n) than in the corresponding MIL(n), indicating that CS2 molecules experience a stiffer potential in dicationic ILs than in monocationic ILs. The intermolecular dynamics of CS2 being higher in frequency in DIL(2n) than in MIL(n) is consistent with recent molecular dynamics simulations (Lynden-Bell and Quitevis, J. Chem. Phys., 2018, 148, 193844) that show the stiffer potential is the result of greater confinement of CS2 in DIL(2n) than in MIL(n). We also show in this study how effects due to dilution and the intermolecular potential seen by a solute molecule in solution are unraveled. PMID- 30306996 TI - A high pressure Raman study on confined individual iodine molecules as molecular probes of structural collapse in the AlPO4-5 framework. AB - The mechanical stability of porous zeolitic materials has long been an important issue due to their advanced applications in many fields. Here, we choose to study the pressure induced structural modifications on the AlPO4-5 (AFI) framework. We find that the Raman characteristics of the confined iodine molecules in the AFI channels, with a low filling density, show discontinuities at around 3 and 10 GPa, which can be attributed to the implications of framework changes. Subsequent theoretical simulations on the AFI framework demonstrate that both a tilting mechanism along the c axis and a rotating mechanism in the ab plane of the tetrahedrons contribute to the structural deformation, and the AFI framework is collapsible at 4 and 10 GPa, which confirms those values found in the Raman studies. In this nanoconfinement system of I@AFI, the host and guest depend on and interact with each other mutually. No supporting effect on the AFI framework is found for the confined individual iodine molecules with such a low filling density, but they can be regarded as molecular probes to reflect the structural collapse of AFI. Thus, we provide a novel way to detect the structural deformation of porous materials under high pressure. PMID- 30307002 TI - Suppressing the active site-blocking impact of ligands of Ni6(SR)12 clusters with the assistance of NH3 on catalytic hydrogenation of nitriles. AB - Atomically precise metal clusters stabilized by organic ligands have attracted extensive interest, and these monodisperse clusters have particular potential for providing insights into puzzling areas of heterogeneous catalysis such as inherent size polydispersity. In many traditional catalytic reactions, however, the reactivity of metal clusters is frequently found to be passivated, where the active sites on the surface metal atoms are blocked by the ligand molecules. Therefore, of particular interest are studies that involve triggering the catalytic ability of metal clusters, with no need to remove any ligands, via thermal treatments that usually destroy their atomically precise structures. Herein, with the determination of the structure of Ni6(SR)12 (where SR denotes thiolate), where Ni atoms are fully coordinated with the thiolate molecules, the catalytic activity of Ni6(SR)12 for nitriles hydrogenation toward primary amines could be significantly enhanced with the assistance of NH3 molecules that positively suppress the ligand-shielding effect. PMID- 30307003 TI - The formation of a functional pentacene/CH3NH3PbI3-xClx perovskite interface: optical gating and field-induced charge retention. AB - We fabricated a functional pentacene/CH3NH3PbI3-xClx perovskite interface where optical gating and field assisted charge retention occur. Using a pentacene/perovskite field effect transistor (FET) test platform, we investigated the interfacial charge transfer associated with optical gating through threshold voltage measurements under illumination. Importantly, bistable electrical conduction in pentacene/perovskite FET devices was achieved as a result of field induced charge retention at the interface and the origin is discussed to be associated with interfacial charging at the pentacene/perovskite interface. Interfacial contact modification associated with ion migration and other possible effects in the perovskite layer plays a crucial role in forming a functional interface involving organic semiconducting materials. PMID- 30307004 TI - The reaction of alkyl hydropersulfides (RSSH, R = CH3 and tBu) with H2S in the gas phase and in aqueous solution. AB - The RSSH + H2S -> RSH + HSSH reaction has been suggested by numerous labs to be important in H2S-mediated biological processes. Seven different mechanisms for this reaction (R = CH3, as a model) have been studied using the DFT methods (M06 2X and omegaB97X-D) with the Dunning aug-cc-pV(T+d)Z basis sets. The reaction of CH3SSH with gas phase H2S has a very high energy barrier (>45 kcal mol-1), consistent with the available experimental observations. A series of substitution reactions R1-S-S-H + -S-R2 (R1 = Me, tBu, Ad, R2 = H, S-Me, S-tBu, S-Ad) have been studied. The regioselectivity is largely affected by the steric bulkiness of R1, but is much less sensitive to R2. Thus, when R1 is Me, all -S-R2 favorably attack the internal S atom, leading to R1-S-S-R2. While for R1 = tBu, Ad, all -S R2 significantly prefer to attack the external S atom to form -S-S-R2. These results are in good agreement with the experimental observations. PMID- 30307005 TI - Ta-Doped porous TiO2 nanorod arrays by substrate-assisted synthesis: efficient photoelectrocatalysts for water oxidation. AB - Owing to its excellent chemical stability and low cost, titanium dioxide (TiO2) has been widely studied as a photoanode for photoelectrochemical (PEC) water splitting. However, TiO2's practical applications in solar energy-to-synthetic fuel conversion processes have been constrained by its inherently poor ability to transport photogenerated electrons and holes. In this paper, we report Ta-doped porous TiO2 nanorod arrays on Ta foil (Ta-PTNA) that do not possess this issue and that can thus efficiently photoelectrocatalyze water oxidation, helping the production of H2 (a clean fuel) from water at the expense of solar light. The materials are synthesized by a new, facile synthetic approach involving the hydrothermal treatment of a TiO2 precursor with Ta foil, without seeds and templates, and followed by calcination of the product. Besides serving as a source of Ta dopant atoms, Ta foil is found to play a vital role in the formation of nanopores in the materials. The material obtained with hydrothermal treatment at 180 degrees C for 10 h (Ta-PTNA-10), in particular, affords very large photocurrent density and very high photoconversion efficiency (0.32% at 0.79 V vs. RHE, which is better than those of many previously reported photocatalysts and ~4 times larger than that of undoped TiO2 nanorod arrays). Ta-PTNAs' remarkable PEC catalytic performance is found to be due to their nanoporous structure and high electronic conductivity. PMID- 30307006 TI - Emerging opportunities in exploring the nutritional/functional value of amaranth. AB - Amaranthus spp. is a highly nutritive pseudocereal, rich in macronutrients and micronutrients, including vitamins and minerals. Amaranth grain is rich in essential amino acids, particularly lysine, with high nutritional quality. In addition, recent research studies demonstrate that Amaranthus spp. essential nutrients, such as phytochemicals, have potential beneficial health effects. This review focuses on the amaranth grain's nutritional composition and antioxidant capacity. Also, limitations on its intake and strategies to improve its digestibility, bioaccessibility and bioavailability are summarized in this review. Finally, the most recent literature studies reporting food applications of amaranth (e.g., as encapsulating material) are discussed in order to deepen the understanding of potential health benefits and functionalities of this nutritious grain. PMID- 30307007 TI - A self-healing conductive and stretchable aligned carbon nanotube/hydrogel composite with a sandwich structure. AB - Self-healing conductive elastomers have emerged as a class of novel materials that are important for fabricating human-motion sensors, soft robots and healthcare monitoring systems. Herein, we report on a hydrogel of modified poly(gamma-glutamic) acid polymer chains crosslinked by coordination complexes, which exhibits good stretchability (1375%), long-term stability (more than 40 days), and self-healing ability (99.0 +/- 1.5% in 3 h). Furthermore, a "sandwich" structure composite was fabricated, which is composed of self-healing hydrogels and Au nanograin-decorated aligned multiwall carbon nanotube sheets. It possesses fast self-healing ability, a low stable electronic resistance of 10 +/- 1 Omega sq-1, in the temperature range of -40-90 degrees C, the humidity range of 10 90%, and a stretching range up to 200%. PMID- 30307008 TI - Anti-EGFR lipid micellar nanoparticles co-encapsulating quantum dots and paclitaxel for tumor-targeted theranosis. AB - Cancer theranosis is an emerging field of personalized medicine which enables individual anti-cancer treatment by monitoring the therapeutic responses of cancer patients. Based on a consideration of the nano-bio interactions related to the blood circulation of systemically administered nanoparticles in humans, as well as extravasation and active targeting, lipid micellar nanoparticles were co loaded with paclitaxel (PTX) and quantum dots (QDs) to generate a theranostic delivery vehicle. To provide with a tumor-targeting capability, either an antibody or an aptamer against the epidermal growth factor receptor (EGFR) was conjugated to the micelle surface. The QD-containing micelles (QDMs), antibody coupled QDMs (immuno-QDMs), and aptamer-coupled QDMs (aptamo-QDMs) were able to effectively circulate in blood for at least 8 h when administered intravenously into mice bearing EGFR-positive LS174T tumor xenografts. In vivo fluorescence imaging and a bio-distribution study showed that both the immuno-QDMs and aptamo QDMs were largely localized in the tumor tissue. The tumor targeting capability enhanced the therapeutic efficacy of PTX for the target cancer cells. Both the immuno-PTX-QDMs and the aptamo-PTX-QDMs caused a stronger inhibition of LS174T tumor growth in mice, compared to the non-targeted PTX-QDMs. These results suggest that the anti-EGFR immuno-PTX-QDMs and anti-EGFR aptamo-PTX-QDMs could be utilized as a tumor-targeted theranostic delivery system for cancer treatment in the clinic. PMID- 30307010 TI - Correction: Giant resistive switching in mixed phase BiFeO3via phase population control. AB - Correction for 'Giant resistive switching in mixed phase BiFeO3via phase population control' by David Edwards et al., Nanoscale, 2018, 10, 17629-17637. PMID- 30307011 TI - Facile scalable fabrication of ultra-thin freestanding SiO2-based hybrid nanosheets with multifunctional properties. AB - Two-dimensional (2D) nanomaterials with unique features like a large surface-to volume ratio and the quantum confinement effect have attracted great attention for applications in energy storage, catalysis, sensing, membranes, etc. Silica (SiO2)-based nanosheets, as members of the 2D material family, are extremely intriguing because of their unique electronic insulation, bio-compatibility and profound chemical and thermal stability. However, there is still a lack of available approaches for fabricating SiO2 nanosheets in a simple, large-scale and cost-effective fashion. In the present research, we have proposed a facile and mass fabrication method for ultra-thin freestanding SiO2-based hybrid nanosheets (SS) with a uniform thickness by crashing hollow microcapsules through ultrasonication treatment. The morphology, composition, and application of the hybrid nanosheets are investigated in detail. The experimental results demonstrate that SS nanosheets with an inorganic-organic hybrid structure display a Janus-type composition with double bonds residing on one side and hydroxyl groups on the other. Additionally, the SS nanosheets could be easily modified by introducing various functional components such as aluminium hydroxide (AH). The as-prepared SS nanosheets and AH modified nanosheets (SS-AH) could considerably enhance the thermal stability of silicone rubber with remarkably increased thermal decomposition temperatures and residues compared with the reference samples. SS and SS-AH sheets are highly superior in usage as polymer thermal stability fillers because of the following aspects: the hybrid nature of SS and SS-AH is advantageous to facilitate the filler-polymer interaction, so these particles could be readily dispersed into silicone without any hydrophobicity modification; these fillers could improve the thermal stability of elastomers at a much lower filler loading (<8%) than the previously reported filler system (e.g. >20 wt%). Furthermore, the nanosheets are also proved to be efficient in usage as emulsifiers for the immiscible oil-water system with a higher efficiency and emulsion stability than the commonly used emulsifiers. Consequently, the hybrid nanosheets fabricated in this work will not only enrich the family of ultra-thin 2D materials but also attract more interest in potential applications in functional nanocomposites and solid emulsifiers. PMID- 30307012 TI - A self-encapsulated porous Sb-C nanocomposite anode with excellent Na-ion storage performance. AB - In this study, a self-encapsulated Sb-C nanocomposite as an anode material for sodium-ion batteries (SIBs) was successfully synthesised using an SbCl3-citrate complex precursor, followed by a drying and calcination process under an inert N2 atmosphere. When the molar ratio of SbCl3 to citric acid was varied from 1 : 1 to 1 : 4, the Sb-C nanocomposite with a molar ratio of 1 : 3 (Sb-C3) exhibited the highest specific surface area (265.97 m2 g-1) and pore volume (0.158 cm3 g-1). Furthermore, the Sb-C3 electrode showed a high reversible capacity of 559 mA h g 1 at a rate of C/10 and maintained a high reversible capacity of 430 mA h g-1 even after 195 cycles at a rate of 1C. The Sb-C3 electrode exhibited an excellent rate capability of 603, 445, and 357 mA h g-1 at the rates of C/20, 5C, and 10C, respectively. Furthermore, a full cell composed of an Sb-C3 anode and a Na3V2(PO4)3 cathode exhibited good specific capacity and cyclability, making the Sb-C composite a promising anode material for high-performance SIBs. PMID- 30307014 TI - Viscous friction of squeezed bubbly liquid layers. AB - Shear viscosity of bubbly liquids is known to depend on both the gas volume fraction and the capillary number. Here, we study the impact of confinement on their behavior by investigating the viscosity of semi-dilute bubbly liquid layers confined between two plates and characterized by a ratio of the undeformed bubble diameter to the layer thickness equal to or larger than unity. For all the studied confinement ratios, viscosity is shown to be smaller than the viscosity of the suspending liquid for capillary numbers larger than 0.1. Measurements of bubble deformations show that this behavior is related to bubble stretching in the direction of shear induced flow. In the limit of high capillary numbers, viscosity reaches values predicted for unconfined bubbly liquids. On the other hand, our results for smaller capillary numbers, i.e. within the range 0.001-0.1, reveal a non-monotonic variation of the viscosity as a function of the confinement ratio, exhibiting a well-defined maximum value for the ratio close to 1.8. This behavior differs strongly from the reference case of unconfined bubbly liquid, and it is shown to result from both bulk and wall drag forces on the squeezed bubbles. PMID- 30307015 TI - Near interface ionic transport in oxygen vacancy stabilized cubic zirconium oxide thin films. AB - The cubic phase of pure zirconia (ZrO2) is stabilized in dense thin films through a controlled introduction of oxygen vacancies (O defects) by cold-plasma-based sputtering deposition. Here, we show that the cubic crystals present at the film/substrate interface near-region exhibit fast ionic transport, which is superior to what is obtained with similar yttrium-stabilized cubic zirconia thin films. PMID- 30307016 TI - Nuclear quantum effects in the direct ionization process of pure helium clusters: path-integral and ring-polymer molecular dynamics simulations on the diatomics-in molecule potential energy surfaces. AB - The direct photoionization of pure helium clusters, Hen (n = 100, 200 and 300), and its subsequent short-time process have been studied by path integral molecular dynamics (PIMD) and ring-polymer molecular dynamics (RPMD) simulations that can effectively describe the nuclear quantum effects in large systems. The modified diatomics-in-molecule (DIM) model [Calvo et al., J. Chem. Phys., 2011, 135, 124308] has been used to describe the electronic structures of Hen+ clusters. The PIMD simulations were able to reproduce the experimental ionization spectra having a broad and asymmetric nature, which can be ascribed to the inhomogeneity of the energy levels of He atoms in the inner and outer regions of the cluster. From the RPMD simulations, it is found that the ionized helium cluster in the higher excited state is followed by fast electronic state relaxation via nonadiabatic charge transfer including a small contribution of nuclear motions, and subsequently by slow relaxation of the cluster structure. PMID- 30307017 TI - Universal scaling behavior of polymer chains at the percolation threshold. AB - Two-dimensional macromolecular systems were studied by means of Monte Carlo simulations employing the Cooperative Motion Algorithm. The influence of chain length and internal architecture on the location of the percolation thresholds was shown. A universal behavior of chain size at these thresholds was presented. PMID- 30307018 TI - 3D self-assembled VS4 microspheres with high pseudocapacitance as highly efficient anodes for Na-ion batteries. AB - Surface structure plays a decisive role in the surface capacity and electrochemical kinetics of rechargeable batteries. Tuning the surface structure of building blocks has been considered to be a new effective strategy to promote the electrochemical performance of 3D self-assembled nanoarchitectures. Herein, VS4 microspheres assembled from the nano-units with different crystallinities are synthesized via a facile template-free hydrothermal method. The results show that the electrochemical performance of VS4 microspheres as anode materials for sodium ion batteries (SIBs) largely depends on their crystallinity, and a VS4 electrode with the lowest crystallinity delivers a high reversible capacity of 412 mA h g-1 at 0.2 A g-1 after 230 cycles and that of 345 and 293 mA h g-1 even at 1.0 and 2.0 A g-1, respectively. The insertion mechanism is revealed within the selected voltage window of 0.50-3.00 V. Further analysis suggests that decreasing the crystallinity of the nano-units can dramatically enhance the pseudocapacitive behavior of VS4 microspheres, which takes the main responsibility for the improvement of sodium storage properties. This work can provide a new insight for the exploration and design of high-performance anodes for SIBs. PMID- 30307019 TI - Synthesis of alpha-alkylated gamma-butyrolactones with concomitant anhydride kinetic resolution using a sulfamide-based catalyst. AB - The Kinetic Resolution (KR) of alpha-alkylated enolisable disubstituted anhydrides has been shown to be possible for the first time. In the presence of an ad hoc designed novel class of bifunctional sulfamide organocatalyst, a regio , diastereo- and enantioselective cycloaddition reaction between the enolisable anhydride and benzaldehydes provides densely functionalised gamma-butyrolactones in one pot (up to 19 : 1 dr, 94% ee) with control over three contiguous stereocentres. The concomitant resolution of the starting material anhydride, provides access to a range of chiral succinate derivatives with selectivity factors up to S* = 10.5. PMID- 30307023 TI - N-Carbamoylmaleimide-treated carbon dots: stabilizing the electrochemical intermediate and extending it for the ultrasensitive detection of organophosphate pesticides. AB - To date, numerous methods have been reported for the detection of organophosphorus pesticides (OP) due to their severe potential hazard to the environment, public health and national security. However, very few works have ever found that the signal loss of thiocholine (TCh) during electrochemical processing is a key factor leading to the low sensitivity of acetylcholinesterase (AChE)-based OP electrochemical sensing platforms. Herein, we propose an ultrasensitive detection method for multiple OPs including parathion-methyl, paraoxon, dimethoate and O,O-dimethyl-O-2,2-dichlorovinyl-phosphate using N carbamoylmaleimide-functionalized carbon dots (N-MAL-CDs) as a nano-stabilizer. For the first time, Michael addition is introduced into an AChE-based OP electrochemical sensing platform to enrich the electrochemical intermediate TCh. The Michael addition between TCh and N-MAL-CDs is demonstrated via XRD, FTIR, SEM and EDS elemental mapping experiments. Due to the stabilization and enhancement of TCh with N-MAL-CDs, the as prepared OP sensing platform achieves ultrahigh sensitivity by detecting the initial electrochemical signals of TCh without signal loss, showing a wide linear range of 3.8 * 10-15-3.8 * 10-10 M for parathion-methyl and 1.8 * 10-14-3.6 * 10-10 M for paraoxon, with a limit of detection of 1.4 * 10-15 M for parathion-methyl and 4.8 * 10-15 M for paraoxon. PMID- 30307024 TI - Measuring Patient Needs and Benefits in Dermatology using the Patient Benefit Index 2.0: A Validation Study. AB - This study investigated the validity and feasibility of the Patient Benefit Index 2.0 (PBI 2.0), a short instrument to assess patient-relevant treatment benefit. In a cross-sectional study, patients with skin diseases completed the PBI 2.0 alongside instruments on quality of life and disease-specific PBI long versions to assess convergent validity. Feasibility questions appraise comprehensibility, completeness, length, and readability. Data from a longitudinal study were used to explore responsiveness and test-retest reliability. Most patients rated the PBI 2.0 easy to understand, complete, legible, and not too long. The amount of missing values was overall low. In all groups, except for vitiligo, correlation analyses indicated good convergent validity of PBI 2.0. Responsiveness of the PBI 2.0 could not be clearly confirmed. Retest-reliability achieved satisfactory results. Thus, the PBI 2.0 may be a suitable instrument for its use in different skin diseases. Its broad applicability allows for comparisons across diagnosis groups. PMID- 30307025 TI - Spino-pelvic alignment, balance, and functional disability in patients with low grade degenerative lumbar spondylolisthesis. AB - OBJECTIVE: To evaluate the relationships among spino-pelvic parameters, trunk balance and functional disability in patients with degenerative lumbar spondylolisthesis. DESIGN: Cross-sectional study. SUBJECTS: Forty-five patients with degenerative lumbar spondylolisthesis and 32 patients without degenerative lumbar spondylolisthesis. METHODS: Spino-pelvic parameters (pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis) and pain severity were evaluated. Biodex balance tests (postural stability, limits of stability, modified clinical test of sensory interaction and balance, fall risk) and Quebec Back Pain Disability Scale (QBDS) scores were measured. RESULTS: Intergroup differences were found in age, low back pain, limits of stability, pelvic incidence, pelvic tilt and some subscales of QBDS. Correlations were found: (i) in the degenerative lumbar spondylolisthesis group: between pelvic incidence and sacral slope/pelvic tilt/lumbar lordosis/height/limits of stability; sacral slope and lumbar lordosis/height/limits of stability/modified clinical test of sensory interaction and balance (eyes closed on foam); lumbar lordosis and body mass index/QBDS/postural stability/modified clinical test of sensory interaction and balance (eyes open and eyes closed on foam); (ii) in the non-degenerative lumbar spondylolisthesis group: between pelvic incidence and pelvic tilt; pelvic tilt and sacral slope/lumbar lordosis; sacral slope and lumbar lordosis/fall risk. All spino-pelvic parameters in the degenerative lumbar spondylolisthesis group and pelvic tilt in the non-degenerative lumbar spondylolisthesis group correlated with QBDS. CONCLUSION: Pelvic tilt was the major compensating factor in both groups (patients with and without degenerative lumbar spondylolisthesis). Sacral slope and lumbar lordosis contributed to partial compensation in the degenerative lumbar spondylolisthesis group. Lumbar lordosis correlated with body mass index. Sacral slope could be an indicator of fall risk in the non-degenerative lumbar spondylolisthesis group. PMID- 30307026 TI - Pruritus in Chronic Liver Disease: A Questionnaire Survey on 216 Patients. PMID- 30307027 TI - Influence of Itch and Pain on Sleep Quality in Atopic Dermatitis and Psoriasis. AB - Subjective symptoms accompanying atopic dermatitis and psoriasis can negatively influence patients' well-being. This study assessed the impact of itch and pain on sleep quality among 100 patients with atopic dermatitis and 100 patients with psoriasis, compared with 50 controls. The Athens Insomnia Scale (AIS) and Pittsburgh Sleep Quality Index (PSQI) were used to evaluate a spectrum of sleep disturbances. Co-existence of insomnia was indicated in the majority of patients; atopic dermatitis (82%), psoriasis (62%). PSQI total scores for patients with atopic dermatitis (8.3 +/- 4.2 points) and those with psoriasis (8.1 +/- 4.8 points) qualified them, in 80% of cases, as poor sleepers and were significantly higher compared with controls (3.1 +/- 1.9 points). However, subjects with atopic dermatitis experienced more problems with insomnia and sleep quality than did those with psoriasis. Atopic dermatitis and psoriasis-related itch, but not pain, has a substantial association with insomnia and sleep quality in these patients, and is a crucial subjective symptom in these chronic, inflammatory skin diseases. PMID- 30307028 TI - Sexual function and depressive symptoms in men with overt hyperthyroidism. AB - INTRODUCTION: Although hyperthyroidism is characterized by female predominance, its presence may lead to the development of numerous complications in both sexes. This study was aimed at investigating sexual function and depressive symptoms in men with overt hyperthyroidism of autoimmune and non-autoimmune origin. MATERIAL AND METHODS: The study population consisted of three age-matched groups: men with overt hyperthyroidism and Graves' disease (group A; n=20), men with overt hyperthyroidism and toxic multinodular goiter or toxic adenoma (group B; n=21) and men with normal thyroid function (group C; n=23). Beyond measuring serum hormone levels, antibody titers and determining calculated parameters of thyroid homeostasis, all included patients filled in questionnaires evaluating sexual function (International Index of Erectile Function-15: IIEF-15) and assessing the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition - BDI-II). RESULTS: Compared with control subjects, men with overt hyperthyroidism obtained lower scores for erectile function, intercourse satisfaction, orgasmic function and overall satisfaction. Scores for erectile function, orgasmic function and sexual desire differed between both groups of men with thyroid hyperfunction and inversely correlated with thyrotropin receptor antibody titers. The BDI-II score was higher in patients with Graves' disease than in men with normal thyroid function. CONCLUSIONS: The obtained results indicate that overt hyperthyroidism in men causes multidimensional impairment of sexual function, which is particularly pronounced if excessive hormone production results from Graves' disease. PMID- 30307029 TI - The landscape of CAR T-cell therapy in the United States and China: a comparative analysis. AB - The clinical trials of CAR T-cell therapy are growing fast in recent years, and most of the trials are initiated by sponsors from the United States and China. Exhibiting the distinctions between the clinical trials in the two countries is of great value for understanding the panorama of CAR T-cell clinical trials and forecasting the future of this promising therapy. We analyzed the critical elements of 289 clinical trials posted on the clinicaltrials.gov website by sponsors from the two countries and evaluated the efficacy data in available 50 published CAR T-cell studies. Our analysis shows that China has become the country with the largest number of CAR-T cell clinical trials by the end of 2017, while overall subject sample size and study center numbers are still larger, and the design of the clinical trials is more cautious in the United States. There are obvious differences between the two countries in CAR-targeted antigens in solid tumors and genetic modifications besides CARs for enhancing the potency of CAR T-cells. Although the currently available response rates are promising in both countries, it is inexpedient to conclude that the clinical efficacy is comparable between the two countries considering the smaller patient sample sizes and discrete distribution of median cell doses in China. And finally, the flexible regulatory regime of cell therapy in China, which expedites the bursting of CAR T-cell therapy, is also firstly introduced in this study. This article is protected by copyright. All rights reserved. PMID- 30307030 TI - The roles of place-value understanding and non-symbolic ratio processing system in symbolic rational number processing. AB - BACKGROUND: While it has been widely demonstrated that children's and adolescents' understanding of rational number plays an important role in their mathematics achievement, we have limited knowledge about the cognitive correlates of this understanding. AIMS: The current study aimed at examining whether children's non-symbolic ratio processing and their understanding of place-value structure of whole numbers play a role in their understanding of fractions and decimals and whether their roles are different for fractions versus decimal understanding. SAMPLE: A sample of 124 fourth graders was tested. METHODS: Participants were tested on their symbolic rational number processing, non symbolic ratio processing, place-value understanding of whole numbers, mathematics achievement, as well as a series of domain-general and domain specific cognitive skills related to symbolic rational number processing. RESULTS: The findings suggest that, while the understanding of place value of whole numbers significantly predicted the understanding of both fractions and decimals, non-symbolic ratio processing specifically predicted the understanding of fractions, but not decimals. CONCLUSIONS: The findings highlight the roles of place-value understanding and non-symbolic ratio processing in the acquisition of symbolic rational numbers. PMID- 30307031 TI - Cognitive Outcomes After Heart Valve Surgery: A Systematic Review and Meta Analysis. AB - OBJECTIVES: To summarize evidence on cognitive outcomes after heart valve surgery; secondary aim, to examine whether aortic and mitral valve surgery are associated with different cognitive outcomes. DESIGN: Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review and meta-analysis. SETTING: Cardiac surgery. PARTICIPANTS: Individuals undergoing heart valve surgery. MEASUREMENTS: We searched MEDLINE, EMBASE, and PsycINFO for peer reviewed reports of individuals undergoing heart valve surgery who underwent pre- and postoperative cognitive assessment. Our initial search returned 1,475 articles, of which 12 were included. Postoperative cognitive results were divided into those from 1 week to 1 month (early outcomes, npooled = 450) and from 2 to 6 months (intermediate outcomes; npooled = 722). No studies with longer-term outcomes were identified. RESULTS: Subjects had moderate early cognitive decline from baseline (Becker mean gain effect size (ES)=-0.39 +/- 0.27) that improved slightly by 2 to 6 months (ES=-0.25 +/- 0.38). Individuals undergoing aortic valve surgery-who were older on average than those undergoing mitral valve surgery (68 vs 57)-had greater early cognitive decline than those undergoing mitral valve surgery (ES=-0.68 vs -0.12), but both cohorts had similar decline 2 to 6 months postoperatively (ES=-0.27 vs -0.20). CONCLUSIONS: Heart valve surgery is associated with cognitive decline over the 6 months after surgery, but outcomes beyond 6 months are unclear. These findings highlight the cognitive vulnerability of this population, especially older adults with aortic stenosis. (c) 2018 American Geriatrics Society and Wiley Periodicals, Inc. PMID- 30307032 TI - ELF18-INDUCED LONG NONCODING RNA 1 evicts fibrillarin from mediator subunit to enhance PATHOGENESIS-RELATED GENE 1 (PR1) expression. AB - Plant immune response is initiated upon the recognition of pathogen-associated molecular patterns such as elf18. Previously, we identified an Arabidopsis ELF18 INDUCED LONG NONCODING RNA 1 (ELENA1), as a positive transcriptional regulator of immune responsive genes. ELENA1 associated with Mediator subunit 19a (MED19a) to enhance enrichment of the complex on PATHOGENESIS-RELATED GENE 1 (PR1) promoter. In vitro and in vivo RNA-protein interaction experiments showed that ELENA1 can also interact with FIBRILLARIN 2 (FIB2). Co-immunoprecipitation and bimolecular fluorescence complementation assay showed that FIB2 directly interacts with MED19a in nucleoplasm and nucleolus. Analysis of fib2 mutant showed that FIB2 functions as a negative transcriptional regulator for immune responsive genes, including PR1. Genetic and biochemical analyses demonstrated that ELENA1 can dissociate the FIB2/MED19a complex and release FIB2 from PR1 promoter to enhance PR1 expression. ELENA1 increases PR1 expression by evicting the repressor (FIB2) from the activator (MED19a). Our findings uncover an additional layer of complexity in the transcriptional regulation of plant immune responsive genes by long noncoding RNA. PMID- 30307033 TI - Thrips as a supplementary pollinator in an orchid with granular pollinia: is this mutualism? PMID- 30307034 TI - miR-31 regulates energy metabolism and is suppressed in T cells from patients with Sjogren's syndrome. AB - Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNbeta and in patients with Sjogren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4+ T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN alpha also increased the basal levels of human CD4+ T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure. PMID- 30307036 TI - Systematic review of the safety and efficacy of osseointegration prosthesis after limb amputation. AB - BACKGROUND: Osseointegration, an approach for direct skeletal attachment of a prosthesis to an amputated limb, may address many of the problems associated with socket prostheses. The safety of osseointegration remains uncertain. The aim of this study was to summarize evidence on functional and clinical outcomes, as well as adverse effects of osseointegration for patients with a limb amputation. METHODS: MEDLINE, Embase, Web of Science and the Cochrane Library were searched to April 2018. Eligible studies were observational, case and qualitative studies, and RCTs conducted in patients with a limb amputation, who were managed with osseointegrated prostheses and had follow-up data. RESULTS: Twenty-two eligible articles comprising 13 unique studies were included. No RCT was identified. Apart from three case reports that comprised one to five patients, the sample size of studies ranged from 11 to 100 participants. All relevant studies reported improvement in functional outcomes (walking ability, prosthetic use and mobility), satisfaction and quality of life following osseointegration, compared with their preoperative status or when using a conventional socket prosthesis. Infection rates ranged from 1 (95 per cent c.i. 0 to 5) to 77 (59 to 88) per cent. The majority of infections were described as low-grade soft tissue or superficial infections related to the skin-implant interface, and were treated effectively with antibiotics. None of the studies reported additional amputation or death as a result of osseointegration. CONCLUSION: Osseointegration after limb amputation improves prosthetic use, comfort when sitting, walking ability, mobility, gait and quality of life. However, it is associated with an increased risk of soft tissue infection. PMID- 30307035 TI - Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor. AB - Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNalpha2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy. PMID- 30307037 TI - Whirly1 enhances tolerance to chilling stress in tomato via protection of photosystem II and regulation of starch degradation. AB - In plants, the chilling response involves decreased photosynthetic capacity and increased starch accumulation in chloroplasts. However, the mechanisms that modulate these processes remain unclear. We found that the SlWHY1 gene is significantly induced by chilling stress (4 degrees C) in tomato. Three SlWHY1 overexpression (OE) lines grew better than the wild type (WT) under chilling stress; the OE plants retained intact photosynthetic grana lamellae and showed enhanced hydrolysis of starch. By contrast, RNAi lines that inhibited SlWHY1 were more affected than the corresponding WT cultivar. Their grana lamellae were damaged and starch content increased. The psbA gene encodes the key photosystem II (PSII) protein D1. We show that SlWHY1 binds to the upstream region (A/GTTACCCT/A) of SlpsbA and enhances the de novo synthesis of D1 in chloroplasts. Additionally, SlWHY1 regulates the expression of the starch degrading enzyme alpha-amylase (SlAMY3-L) and the starch synthesis-related enzyme isoamylase gene (SlISA2) in the nucleus, thus modulating the starch content in chloroplasts. We demonstrate that SlWHY1 enhances the resistance of tomato to chilling stress by maintaining the function of PSII and degrading starch. Thus, overexpression of WHY1 may be an effective strategy for enhancing resistance to chilling stress of chilling-sensitive crops in agricultural production. PMID- 30307038 TI - Grass invasion and drought interact to alter the diversity and structure of native plant communities. AB - Understanding the interactive effects of species invasions and climate change is essential for predicting future shifts in biodiversity. Because multiple stressors can interact in synergistic or antagonistic ways, it is notoriously difficult to anticipate their combined effects on species assemblages. However, some hypotheses predict that plant invasions will become increasingly problematic as climate change improves conditions for invaders or lowers the biotic resistance of native communities. In a 4-yr field experiment, we quantified the individual and interactive effects of invasion by a globally problematic C4 grass, Imperata cylindrica, and chronic simulated drought imposed by rainout shelters on the whole plant communities of regenerating longleaf pine forest. Invasion both inhibited plant colonization and enhanced plot-level extinctions, resulting in a severe (60%) loss of plant diversity across all functional groups, including perennial grasses and forbs, annual forbs, and woody species and dramatic shifts in community composition. Experimental drought reduced diversity by 20%, and caused a shift in the dominant functional groups, but had no significant effect on cover of the invader. The invader partially ameliorated water stress in the drought treatment such that invaded plots had higher soil moisture than uninvaded plots. Consequently, the combined effects of invasion and drought were lower than expected from an additive model of multiple stressors. These findings, which may have broader implications for how other C4 grass invaders will interact with drought to shift native community dynamics, challenge the perception that climate change will exacerbate invasions. In revealing that invasive species pose a major threat to the diversity and structure of native communities despite their moderating effects on abiotic stress, this work also highlights that management of aggressive invaders may be critical to preserving biodiversity regardless of future climate. PMID- 30307039 TI - Evaluation of occupational exposure to static magnetic field in MRI sites based on body pose estimation and SMF analytical computation. AB - This paper tackles the problem of estimating exposure to static magnetic field (SMF) in magnetic resonance imaging (MRI) sites using a non-invasive approach. The proposed approach relies on a vision-based system to detect people's body parts and on a mathematical model to compute SMF exposure. A multi-view camera system was used to capture the MRI room, and a vision-based system was applied to detect body parts. The detected localization was then fed into a mathematical model to compute SMF exposure. In this study, we focused on exposure at the neck due to two main reasons. First, according to regulations, the limit of exposure at head and trunk for MR workers is higher than that for the general public. Second, it was easier to attach a dosimeter at the neck to perform measurements, which allowed a quantitative evaluation of our approach. This approach was applied to two scenarios simulating the daily movements of medical workers for which dosimeter measurements were also recorded. The results indicated that the proposed approach predicted occupational SMF exposure with reasonable accuracy compared with the dosimeter measurements. The proposed approach is a simple safe working procedure to estimate the exposure of MR workers at different parts of the body without wearing any marker detection. It can be applied to reduce occupational SMF exposure, without changes in workers' performances. For that reason, our non-invasive proposed method can be used as a simple safety tool to estimate occupational SMF exposure in MR sites. Bioelectromagnetics. 39:503-515, 2018.(c) 2018 Wiley Periodicals, Inc. PMID- 30307040 TI - Aquaporin regulation in roots controls plant hydraulic conductance, stomatal conductance, and leaf water potential in Pinus radiata under water stress. AB - Stomatal regulation is crucial for forest species performance and survival on drought-prone sites. We investigated the regulation of root and shoot hydraulics in three Pinus radiata clones exposed to drought stress and its coordination with stomatal conductance (gs ) and leaf water potential (Psileaf ). All clones experienced a substantial decrease in root-specific root hydraulic conductance (Kroot-r ) in response to the water stress, but leaf-specific shoot hydraulic conductance (Kshoot-l ) did not change in any of the clones. The reduction in Kroot-r caused a decrease in leaf-specific whole-plant hydraulic conductance (Kplant-l ). Among clones, the larger the decrease in Kplant-l , the more stomata closed in response to drought. Rewatering resulted in a quick recovery of Kroot-r and gs . Our results demonstrated that the reduction in Kplant-l , attributed to a down regulation of aquaporin activity in roots, was linked to the isohydric stomatal behaviour, resulting in a nearly constant Psileaf as water stress started. We concluded that higher Kplant-l is associated with water stress resistance by sustaining a less negative Psileaf and delaying stomatal closure. PMID- 30307041 TI - Type of endothelial cells affects HepaRG cell acetaminophen metabolism in both 2D and 3D porous scaffold cultures. AB - Recent advances in developing in vitro tissue models show that function of hepatocytes is altered in when cultured in 3D configuration and co-culturing with various non-parenchymal cells. However, tissue source for such non-parenchymal cells on viability and metabolic products of hepatocytes have not been explored. In this study, we evaluated the effect of 2D and 3D cultures either with HepaRG cells alone or in combination with liver sinusoidal endothelial cells (LSECs) and human umbilical vein ECs (HUVECs). For 3D cultures, we used chitosan-gelatin porous structures formed by freeze-drying. We cultured cells for 8 days before challenging with 1 mm acetaminophen (APAP) and assessed APAP, APAP-sulfate and APAP-glucuronide for 24 hours at 6-hour time intervals using high-performance liquid chromatography. We used multiple methods (phase contrast, confocal and scanning electron microscopy and histology via hematoxylin and eosin staining) to ensure cell distribution. We also measured total protein content and albumin secretion and viability. HUVEC 3D co-cultures showed the lowest HepaRG cell viability, while both 2D and 3D LSEC co-cultures had highest HepaRG cell viability. In addition, 3D cultures had significantly higher EC viability relative to 2D cultures. Further, HUVEC co-cultures showed reduced total protein content and albumin expression as early as day 4. However, urea production on a total protein content basis did not change. In addition, LSEC 3D co-cultures had the highest APAP conversion with reduced APAP-sulfate and APAP-glucuronide formation. CYP3A4 was higher in co-culture with HUVEC for 2D and 3D cultures. In conclusion, HepaRG cells with EC co-cultures demonstrated sensitivity to the EC line used. PMID- 30307042 TI - Assessment of a novel nanoparticle hyperthermia therapy in a murine model of osteosarcoma. AB - OBJECTIVE: To evaluate the effects of nanoparticle hyperthermia therapy on monocyte function and tumor-derived factors associated with macrophage polarization in a murine osteosarcoma model. STUDY DESIGN: Experimental study. ANIMALS: Female C3H mice. METHODS: Peripheral blood monocyte cell surface phenotype, monocyte chemotaxis, tumor messenger RNA expression, and survival were compared among osteosarcoma (OS)-bearing mice treated with nanoparticle hyperthermia therapy, OS-bearing mice with osteomyelitis, OS-bearing mice, vehicle control mice, and normal control mice. RESULTS: OS-bearing mice with osteomyelitis had a higher proportion of "nonclassical" monocytes (Ly6Clo ) compared with all other experimental groups. There were alterations in monocyte expression of multiple chemokine receptors among experimental groups including CXCR2, CCR2, and CXCR4. Monocytes from OS-bearing mice treated with hyperthermia therapy exhibited greater chemotaxis compared with monocytes from OS-bearing mice with osteomyelitis. CONCLUSION: OS likely induced alterations in monocyte phenotype and function. Nanoparticle hyperthermia therapy increased in vitro monocyte chemotaxis. CLINICAL IMPACT: Enhancing monocyte/macrophage function in dogs with OS may enhance antitumor immunity. PMID- 30307043 TI - A novel glycerophosphodiester phosphodiesterase improves phosphate deficiency tolerance in rice. AB - Soil phosphate (Pi) deficiency is major constraint for rice cultivation worldwide. Cellular membranes account for one third of cellular organic phosphorus (P) in the form of phospholipids. Therefore, remobilization of Pi from membrane phospholipids under Pi deficiency can be an important strategy to improve phosphorus use efficiency. Glycerophosphodiester phosphodiesterases (GDPDs) hydrolyse intermediate product of phospholipid catabolism, glycerophosphodiesters to glycerol-3-phosphate, a precursor for P and non P-lipid biosynthesis. Here, we show that OsGDPD2 is a Pi deficiency responsive gene, which is transcriptionally regulated by OsPHR2. In silico analysis of active site residues and enzymatic assays confirmed phosphodiesterase activity of OsGDPD2. All overexpression lines showed higher GDPD activity, Pi content, root growth, and biomass accumulation as compared with wild type. Conversely, silencing of OsGDPD2 led to decreased GDPD activity and Pi content. Notably, most of the P containing metabolites and fatty acids were elevated in transgenic lines. Further, quantitative analysis of polar lipids revealed higher accumulation of several classes of phospholipids and galactolipids in overexpression lines indicating a potential role of OsGDPD2 in de novo glycerolipid biosynthesis. Thus, present study provides insights into novel physiological roles of OsGDPD2 in low Pi acclimation in rice. PMID- 30307044 TI - Perineal repair of a full-thickness rectal prolapse in a wild Sumatran orangutan (Pongo abelii). AB - A Delorme's procedure perineal surgical repair was performed in a wild adult male Sumatran orangutan (Pongo abelii) with a chronic persistent rectal prolapse that had been unsuccessfully treated by 6 previous surgeries. The rectal prolapse did not recur, and the orangutan was successfully released to the wild, 6 weeks later. PMID- 30307045 TI - Automated thawing increases recovery of colony-forming units from banked cord blood unit grafts. AB - BACKGROUND: The cell dose infused for cord blood transplantation strongly correlates with outcomes following transplantation. Post thaw recoveries can be improved by washing cord blood units (CBUs) in dextran/albumin. Early methods used a labor-intensive manual process. We have recently developed and validated an automated washing method. We now report our results of a study comparing cellular recoveries achieved after manual and automated wash, as well as the impact on engraftment following allogeneic transplantation. STUDY DESIGN AND METHODS: CBUs distributed by the Carolinas Cord Blood Bank for clinical use at Duke University after manual or automated wash were included in this report. Precryopreservation total nucleated cell count, total CD34+, colony-forming units, recoveries, and sterility were analyzed by wash method. Patient age, cell dose/weight, diagnosis, conditioning regimen, immunosuppression, and time to neutrophil engraftment were also analyzed. RESULTS: Manual and automated washed CBUs yielded similar total nucleated cell count and total CD34+ recoveries. Significantly higher colony-forming units recoveries were achieved after automated washing. Patients who received CBUs washed via an automated method experienced earlier neutrophil engraftment. CONCLUSION: While manual and automated washing achieved similar post thaw cellular recoveries, automated washed CBUs demonstrated higher colony-forming unit recovery, which is an important predictor of potency and engraftment. Furthermore, we demonstrated that automated washing was associated with earlier neutrophil engraftment. Our findings favor the use of an automated wash method over a manual approach. PMID- 30307046 TI - Development and validation of a nomogram to predict recurrence and melanoma specific mortality in patients with negative sentinel lymph nodes. AB - BACKGROUND: Patients with melanoma and negative sentinel nodes (SNs) have varying outcomes, dependent on several prognostic factors. Considering all these factors in a prediction model might aid in identifying patients who could benefit from a personalized treatment strategy. The objective was to construct and validate a nomogram for recurrence and melanoma-specific mortality (MSM) in patients with melanoma and negative SNs. METHODS: A total of 3220 patients with negative SNs were identified from a cohort of 4124 patients from four EORTC Melanoma Group centres who underwent sentinel lymph node biopsy. Prognostic factors for recurrence and MSM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c index) and calibration in cross-validation across the four centres. A nomogram was developed for graphical presentation. RESULTS: There were 3180 eligible patients. The final prediction model for recurrence and the calibrated model for MSM included three independent prognostic factors: ulceration, anatomical location and Breslow thickness. The c-index was 0.74 for recurrence and 0.76 for the calibrated MSM model. Cross-validation across the four centres showed reasonable model performance. A nomogram was developed based on these models. One third of the patients had a 5-year recurrence probability of 8.2 per cent or less, and one-third had a recurrence probability of 23.0 per cent or more. CONCLUSION: A nomogram for predicting recurrence and MSM in patients with melanoma and negative SNs was constructed and validated. It could provide personalized estimates useful for tailoring surveillance strategies (reduce or increase intensity), and selection of patients for adjuvant therapy or clinical trials. PMID- 30307047 TI - The social life of DNA: racial reconciliation and institutional morality after the genome - a response. PMID- 30307048 TI - Race, Rome and the genome. PMID- 30307049 TI - Attitudes towards people with dementia: a cross-sectional study comparing dental hygiene students with registered dental hygienists. AB - OBJECTIVE: In order to adequately care for patients with dementia, it is necessary for dental hygienists to develop unprejudiced attitudes towards and obtain sufficient knowledge of dementia. The aim of this study was to assess attitudes towards and knowledge of dementia among Japanese dental hygiene students and identify related factors to the attitude and the knowledge. We compared the attitude and the knowledge between dental hygiene students and practising dental hygienists. BACKGROUND: Dental hygienists are required to care for patients with dementia by developing appropriate attitudes towards dementia and gaining knowledge of dementia. MATERIAL AND METHODS: Between May 2016 and July 2016, 191 third-grade dental hygiene students and 64 registered dental hygienists were surveyed. We modified questionnaires to assess attitudes towards and knowledge of dementia. Ageism was assessed using the Fraboni Ageism scale. To determine potential dementia awareness factors, information regarding participants' experiences with dementia was collected. RESULTS: Factor analysis revealed four factors in the attitude scale (Cronbach's alpha, 0.652-0.820). All item-total correlation coefficients for the knowledge scale were above 0.3, and Cronbach's alpha was 0.827. All awareness factors for dementia were significantly different between students and registered dental hygienists. Total scores of attitude and knowledge were higher among registered dental hygienists, indicating better attitude and knowledge, but total scores of ageism were lower among registered dental hygienists, indicating worse ageism. Multiple regression analysis revealed that the attitudes towards dementia correlated with years of experience, ageism, interest in dementia and desire to work with patients with dementia. CONCLUSION: Registered dental hygienists had more positive and more knowledge compared to dental hygiene students. Attitudes towards dementia, but not knowledge of dementia, were significantly positively correlated with ageism. PMID- 30307050 TI - Impact of maternal income on the risk of gestational diabetes mellitus in primiparous women. AB - AIMS: Findings concerning the impact of socio-economic status on the risk of gestational diabetes mellitus (GDM) are inconclusive and little is known about the simultaneous impact of income and educational attainment on the risk of GDM. This study aims to assess the impact of maternal prepregnancy income in combination with traditional GDM risk factors on the incidence of GDM in primiparous women. METHODS: This is an observational cohort study including 5962 Finnish women aged >= 20 years from the city of Vantaa, Finland, who delivered for the first time between 2009 and 2015, excluding women with pre-existing diabetes mellitus. The Finnish Medical Birth Register, Finnish Tax Administration, Statistics Finland, Social Insurance Institution of Finland and patient healthcare records provided data for the study. We divided the study population according to five maternal income levels and four educational attainment levels. RESULTS: Incidence of GDM decreased with increasing income level in primiparous women (P < 0.001 for linearity, adjusted for smoking, age, BMI and cohabiting status). In an adjusted two-way model, the relationship was significant for both income (P = 0.007) and education (P = 0.039), but there was no interaction between income and education (P = 0.52). CONCLUSIONS: There was an inverse relationship between both maternal prepregnancy taxable income and educational attainment, and the risk of GDM in primiparous Finnish women. This article is protected by copyright. All rights reserved. PMID- 30307051 TI - Nurses as role models in health promotion: Piloting the acceptability of a social marketing campaign. AB - AIM: To pilot the acceptability to practising nurses of the concept of being healthy role models as regards obesity and weight. BACKGROUND: Nursing standards expect nurses to act as role models of professionalism, including maintaining a healthy lifestyle. Many healthcare employers wish to instigate values and social norms about professional behaviour in staff. METHODS: A mixed methods study comprising two stages. In Stage One, an online survey was used to develop an intervention, which was then evaluated by a rapid intercept survey with open ended questions. Insights from 71 obese nurses, recruited at a 2016 nursing conference, were used to develop a social marketing campaign encouraging a social norm around professional behaviour as regards healthy lifestyles and obesity, with the message that "first impressions count" in staff-patient encounters. The campaign was tested with 79 nurses at three English hospitals. RESULTS: In Stage One, 58% agreed that nurses should be role models and 48% that being obese made the public less likely to trust their public health messages. In Stage Two, the campaign concept of "first impressions count" was widely understood and accepted, but nurses found the introduction of a professional expectation around personal behaviours unacceptable. CONCLUSION: Nurses accept an expectation that they are healthy role models but refute its value when confronted with real-life scenarios. Other aspects of identity were privileged to avoid engaging with the healthy role model message. Personal health behaviour was seen as part of a private domain and not part of their public presentation in professional life. PMID- 30307052 TI - Clinicopathological significance of RCAN2 production in gastric carcinoma. AB - AIMS: Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Genes expressed only in cancer tissue may be useful biomarkers for cancer diagnosis and therapeutics. The aim of the present study was to analyse the regulators of calcineurin 2 (RCAN2) in a large number of GCs and to investigate how these expression patterns correlate with clinicopathologic parameters and various markers. METHODS AND RESULTS: An immunohistochemical analysis of RCAN2 in 207 GC tissue samples showed that 110 (53%) GC cases were positive for RCAN2. RCAN2-positive GC cases were more advanced in terms of T, N, M classification and tumour stage than RCAN2-negative GC cases. Furthermore, the RCAN2 was an independent prognostic classifier for GC patients. The cell growth and invasiveness of RCAN2 siRNA-transfected GC cell lines was less than that of the negative control siRNA-transfected cell lines, while those of RCAN2 transfected cells significantly increased compared to those of empty vector transfected cells. RCAN2 siRNA inhibits the phosphorylation of AKT and p44/p42 (ERK1/2). RCAN2 protein was colocalised with EGFR, b-catenin nuclear localisation, MMP7, laminin-gamma2, VEGF-A and VEGF-C. CONCLUSION: These results suggest that RCAN2 is involved in tumour progression and is an independent prognostic classifier in patients with GC. This article is protected by copyright. All rights reserved. PMID- 30307053 TI - Including qualitative research in Randomized Controlled Trials: Opportunities for nursing researchers. PMID- 30307054 TI - Impulsivity, Painful and Provocative Events, and Suicide Intent: Testing the Interpersonal Theory of Suicide. AB - OBJECTIVE: The Interpersonal Theory of Suicide (IPTS; Joiner, 2005. Why People Die by Suicide. Cambridge, MA: Harvard University Press) hypothesizes that repeated exposure to painful and provocative events (PPE) increases capability for suicide (CS), therefore facilitating the development of suicidal intent, and that impulsive individuals are more likely to experience these painful and provocative events, creating an indirect relationship between impulsivity and CS. Research to date largely supports this hypothesis but has not translated this theory to actual suicidal intent. METHOD: The present study used data from the MacArthur Violence Risk Assessment Study to examine the relationship between PPE and intent, and the indirect relationship between impulsivity and intent among a sample of 245 recent suicide attempters, using the clinician-rated Suicide Intent Scale as an objective measure of intent. RESULTS: Results supported the hypothesized direct relationship between PPE and intent, and the indirect relationship between impulsivity and intent through PPE. There was no direct relationship between impulsivity and intent, suggesting that the relationship between impulsivity and intent occurs entirely through exposure to PPE. CONCLUSIONS: These findings suggest that assessing exposure to painful and provocative events is critical in evaluating risk of suicide, and that impulsivity itself does not confer an increased risk of lethal or nearly lethal attempts. PMID- 30307055 TI - Clinicopathological effect of PLAG1 fusion genes in pleomorphic adenoma and carcinoma ex pleomorphic adenoma with special emphasis on histological features. AB - AIMS: Pleomorphic adenoma gene 1 (PLAG1) rearrangement is well known in pleomorphic adenoma (PA), which is histologically characterised by admixed epithelial and mesenchymal components. Multiple fusion variants of PLAG1 and HMGA2 have been reported; currently, however, little is known regarding the clinicopathological impacts of these fusion types METHODS AND RESULTS: We examined the PLAG1- and HMGA2-related fusion status in 105 PAs and 11 cases of carcinoma ex PAs (CXPA) arising from salivary glands and lacrimal glands to elucidate their correlation to the clinicopathological factors. Forty cases harboured PLAG1 fusion genes: CTNNB1-PLAG1 in 22 cases, CHCHD7-PLAG1 in 14 cases and LIFR-PLAG1 in four cases. Only two cases possessed HMGA2 fusion genes. The mean age of LIFR-PLAG1-positive cases was significantly higher than that of CTNNB1-PLAG1- and CHCHD7-PLAG1-positive cases (P = 0.0358). PAs located in the submandibular gland demonstrated CTNNB1-PLAG1 fusion at a significantly higher rate than other fusions (P = 0.0109). Histologically, PLAG1 fusion-positive cases exhibited chondroid formation and plasmacytoid features more commonly (P = 0.043, P = 0.015, respectively) and myxoid abundant feature less frequently (P = 0.031) than PLAG1 fusion-negative cases. For CXPAs, four CTNNB1-PLAG1 fusions were detected in two salivary duct carcinomas and two myoepithelial carcinomas. Ductal formation was observed frequently (90.9%) in residual PA. CONCLUSIONS: The presence of PLAG1 fusion was associated with specific histological features in PA. Detecting the PLAG1 fusion gene and searching residual ductal formation in salivary gland malignant tumours with extensive hyalinisation could be useful for diagnosis. PMID- 30307056 TI - Impact of social deprivation, demographics and centre on HbA1c outcomes with continuous subcutaneous insulin infusion. AB - AIMS: To assess the impact of social deprivation, demographics and centre on HbA1c outcomes with continuous subcutaneous insulin infusion (CSII) in adults with Type 1 diabetes. METHODS: Demographic data, postcode-derived English Index of Multiple Deprivation data and 12-month average HbA1c (mmol/mol) pre- and post CSII were collated from three diabetes centres in the north west of England, University Hospital of South Manchester (UHSM), Salford Royal Foundation Hospital (SRFT) and Manchester Royal Infirmary (MRI). Univariable and multivariable regression models explored relationships between demographics, Index of Multiple Deprivation, centre and HbA1c outcomes. RESULTS: Data were available for 693 (78%) individuals (UHSM, n = 90; SRFT, n = 112; and MRI, n = 491) of whom 59% were women. Median age at CSII start was 39 (IQR 29.5-49.0) years and median diabetes duration was 20 (11-29) years. Median Index of Multiple Deprivation was 15 193 (6313-25 727). Overall median HbA1c improved from 69 to 64 mmol/mol (8.5% to 8.0%) within the first year of CSII. In multivariable analysis, higher pre CSII HbA1c was significantly associated with higher deprivation (P = 0.036), being female (P < 0.001), and centre (MRI; P = 0.005). Following pre-CSII HbA1c adjustment, post-CSII HbA1c or HbA1c change were not related to demographic factors and deprivation, but remained significantly related to the centre; UHSM and SRFT had larger reductions in HbA1c with CSII compared with MRI [median -7.0 (-0.6%) vs. -6.0 (-0.55%) vs. -4.5 (-0.45%) mmol/mol; P = 0.005]. CONCLUSIONS: Higher pre-CSII HbA1c levels were associated with higher deprivation and being female. CSII improves HbA1c irrespective of social deprivation and demographics. Significant differences in HbA1c improvements were observed between centres. Further work is warranted to explain these differences and minimize variation in clinical outcomes with CSII. PMID- 30307057 TI - Chronotype, nursing activity, and gender: A systematic review. AB - AIM: To synthesize evidence about the effect of individual circadian preference (chronotype) and gender in the development of sleep and mood problems in nursing professionals. BACKGROUND: Shift workers are more prone to having unhealthy habits and unfavourable clinical conditions than nonshift workers. These associations are mediated by chronotype and gender differences have also been detected. DESIGN: A quantitative systematic review. DATA SOURCES: Electronic searches were performed in MEDLINE, Scopus, ScienceDirect, and Web of Science from 1 July 2012 - 1 July 2017. REVIEW METHODS: A systematic review was conducted using the Cochrane Collaboration guidelines and two quality assessment tools: the National Heart, Lung and Blood Institute and GRADE. Inclusion criteria were quantitative studies where the sample consists entirely of nurses, analysing circadian rhythms or individual chronotype or gender and sleep/mood disturbances in nursing activity. The review was reported using the PRISMA statement. RESULTS: A total of 23 studies were included in the review (five cohort studies and 18 cross-sectional studies). Data on gender-specific attention were scarce (two studies) and showed a higher incidence of sleep problems. Female nurses with eveningness-oriented personality seem to be more prone to having sleep disorders, insomnia, fatigue, and anxiety than male and morningness ones. CONCLUSIONS: Evidence seems to show that female nurses with an evening-oriented preference suffer more problems of insomnia, sleepiness, fatigue, and anxiety. The impact of our results may affect nurses, patient safety and the quality of clinical practice. PMID- 30307058 TI - Increased IL-17-expressing gammadelta T cells in seborrhoeic dermatitis-like lesions of the Mpzl3 knockout mice. AB - Seborrhoeic Dermatitis (SD) is a common inflammatory skin disorder, but its molecular pathogenesis remains elusive. Previously, we have established the Mpzl3 knockout (-/-) mice as a model for SD. In this study, we focused on early phases of skin inflammation and determined the cytokine profiles and identified immune cell types in the lesional skin in the Mpzl3 -/- mice. Using flow cytometry, we detected a significant increase of CD45+ leucocytes, CD3+ T lymphocytes and especially gammadelta T cells but not alphabeta T cells in the lesional skin compared to control. We also detected high levels of IL-17 and determined that the gammadelta T cells were a major contributing source. CD3+ and gammadelta T cell localization in the skin was verified by indirect immunofluorescent staining. Since neither gammadelta T cells nor IL-17 had been implicated in SD, our study provides novel insights into the role of MPZL3 in the pathogenesis of SD-like skin inflammation. PMID- 30307059 TI - Targeted proteomics of hip articular cartilage in OA and fracture patients. AB - Osteoarthritis (OA) is a common chronic disease, causing joint pain and reduced physical function. OA progresses slowly over a period of several years; to avoid an exacerbation of symptoms, it is critical to able to diagnose the disease as early as possible. The identification of disease-specific biomarkers may enable such an early diagnosis. The aim of this study was to investigate potential biomarkers of cartilage metabolism in OA using a targeted multiplex approach by single reaction monitoring. Intact looking cartilage of femoral heads from patients with OA (n = 9) or femoral neck fractures (n = 12) was examined. Variations and relative quantifications of 35 selected extracellular matrix (ECM) proteins were analyzed using nano-LC coupled to tandem mass spectrometry. Our study showed statistically significantly increased levels of asporin (ASPN), mimecan (MIME), matrilin-3 (MATN3), cartilage intermediate layer protein 2 (CILP 2), collagen VI, collagen II and collagen III N-propeptide in OA cartilage compared with non-OA cartilage. The other proteins in the protein panel did not appear to be different between the two groups. In conclusion, we identified a number of cartilage matrix proteins which may represent early molecular changes in the OA process and may have potential to predict the development of OA. This article is protected by copyright. All rights reserved. PMID- 30307060 TI - Dermatologic findings of vitamin B12 deficiency in infants. AB - BACKGROUND/OBJECTIVES: Vitamin B12 deficiency in infants is uncommonly reported from developed countries and generally lacks dermatologic manifestations. On the contrary, infantile vitamin B12 deficiency is common in India and cutaneous manifestations are a constant feature, although often overshadowed by neurologic and hematological manifestations. The aim of this study was to describe the skin changes of vitamin B12 deficiency in infants. MATERIALS AND METHODS: A retrospective chart review of vitamin B12 deficient infants for clinical and laboratory parameters was performed and data analyzed. RESULTS: Forty-three infants, 30 boys and 13 girls, aged 4 to 27 months, with vitamin B12 deficiency were identified. Skin hyperpigmentation was present in 41 infants; it was localized to the dorsa of hands and feet in 26. Fifteen infants had generalized hyperpigmentation; 10 had a reticulate pattern, and 5 had a homogeneous pattern. Brown and sparse scalp hair were present in all. Glossitis was seen in 5 infants and cheilitis in 3. Of the 32 infants who underwent laboratory investigations, 28 had anemia and 21 macrocytosis. Serum vitamin B12 was measured in 30 infants; it was low in 19. Of the 11 with normal serum vitamin B12 , 9 had received vitamin B12 before referral but had macrocytosis and low maternal serum vitamin B12 . The infants were treated with vitamin B12 . Skin pigmentation and mucosal changes resolved completely by 3-4 weeks, but hair changes were slower to reverse. CONCLUSION: Cutaneous findings are a common feature of vitamin B12 deficiency in Indian infants and resolve with treatment. PMID- 30307061 TI - Regaining Agency & Autonomy: A Grounded Typology of Concealed Pregnancy. AB - AIM: To explore and understand the experience of concealed pregnancy and develop a framework for practitioners. BACKGROUND: Numerous cases of concealed pregnancy resulting in serious outcomes including maternal and perinatal death, newborn abandonment and neonaticide are reported internationally. Historically concealed pregnancy is associated with oppressive religious cultures where premarital pregnancy was shunned. Concealed pregnancy has traditionally been viewed through a biomedical lens and associated with mental illness but this assertion remains unsubstantiated by robust evidence. DESIGN: A Glaserian grounded theory study was undertaken. DATA SOURCES: Thirty women were interviewed, between 2014-2016, on up to three occasions (46 interviews) and 22 cases of public interest were included as data. METHODS: The constant comparative method and theoretical sampling which are the analytical strategies of grounded theory were used to analyse the data and generate the typology. RESULTS: Concealed pregnancy is a fearful, life altering and traumatic experience. Women with a history of controlling and oppressive relationships characterised by fear respond to a crisis pregnancy by keeping it secret. Many women's relationships were characterised by emotional, mental, sexual or physical violence. Fear for one's survival is common, may render women unable to access care or support and can be so extreme that a woman may end her own life or give birth alone. CONCLUSIONS: This typology of concealed pregnancy is intended to aid understanding the fear, trauma and complexities associated with concealed pregnancy which is vital if practitioners are to provide sensitive, responsive and non-judgemental care. This article is protected by copyright. All rights reserved. PMID- 30307062 TI - Sequential cyclic changes of hair roots revealed by dermoscopy demonstrate a progressive mechanism of diffuse alopecia areata over time. AB - BACKGROUND: Diffuse alopecia areata (DAA) often leads to a complete hair shedding within a few months. OBJECTIVE: To explore features and mechanisms underlying DAA. MATERIALS AND METHODS: Scalp and hair root dermoscopy were conducted on 23 DAA patients throughout the disease process, 20 patchy Alopecia areata patients, 23 acute telogen effluvium (ATE) patients and 10 normal controls. Histopathology was also evaluated. RESULTS: We found almost all hair roots were anagen in early stage DAA in 18 patients (18/23, 78.3%) within the first 4-8 weeks after hair loss onset. Anagen effluvium (~4 weeks) was followed by catagen (~4 weeks) and then telogen/exogen (~8 weeks) effluvium with overlap. Hair root and proximal hair shaft depigmentation was more prominent in later DAA disease stages. Black dots, exclamation mark hairs and inconsistent thickness of hair shafts were found more often in early than later DAA (Ps < 0.01). Early DAA histopathology revealed more prominent inflammation and hair follicle regression than that observed in the later stages. Patchy alopecia areata patients showed mixed anagen, catagen and telogen hair roots while ATE patients showed increased exogen and mildly decreased hair root pigmentation. CONCLUSION: Sequential cyclic staging of shed hairs in DAA indicates the insult may be hair-cycle specific. We suggest that DAA is initially an anagen effluvium disease involving an intense inflammatory insult, later progressing to a brief catagen effluvium, and then to telogen effluvium with premature exogen, in later stages of DAA. PMID- 30307063 TI - An evidence-based approach to learning clinical anatomy: A guide for medical students, educators, and administrators. AB - The amount of information that medical students learn is voluminous and those who do not use evidence-based learning strategies may struggle. Research from cognitive and educational psychology provides a blueprint on how best to learn science subjects, including clinical anatomy. Students should aim for high cognitive learning levels as defined in the SOLO taxonomy. Using a real-world example from a modern clinical anatomy textbook, we describe how to learn information using strategies that have been experimentally validated as effective. Students should avoid highlighting and rereading text because they do not result in robust learning as defined in the SOLO taxonomy. We recommend that students use (1) practice testing, (2) distributed practice, and (3) successive relearning. Practice testing refers to nonsummative assessments that contain questions used to facilitate retrieval (e.g., flashcards and practice questions). Practice questions can be fill-in, short-answer, and multiple-choice types, and students should receive explanatory feedback. Distributed practice, the technique of distributing learning of the same content within a single study session or across sessions, has been found to facilitate long-term retention. Finally, successive relearning combines both practice testing and distributed practice. For this strategy, students use practice questions to continue learning until they can answer all of the practice questions correctly. Students who continuously use practice testing, distributed practice, and successive relearning will become more efficient and effective learners. Our hope is that the real-world clinical anatomy example presented in this article makes it easier for students to implement these evidence-based strategies and ultimately improve their learning. Clin. Anat., 2018. (c) 2018 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists. PMID- 30307064 TI - Estrogen receptor-based multi-residue screening of bisphenol compounds in urine. AB - Human exposure to bisphenol compounds (BPs) has been implicated in the development of several chronic diseases. Instead of exploiting the traditional methods for determination of BPs, this work confirms that the human estrogen receptor alpha ligand binding domain (hERalpha-LBD) is a powerful recognition element that can be used to monitor multi-residue of BPs in urine samples by fluorescence polarization (FP) assay. Test parameters were optimized for the best performance. Under the optimal conditions, the IC50 values of BPs are in the range of 0.04 to 1.61 MUg mL-1 . Recovery experiments were then performed to assess the accuracy and precision of the established method. The results detected by FP assay show good agreements with that of liquid chromatography tandem-mass spectrometry method with a fit of R2 = 0.9372 and 0.9640 for BPE and BPAP, respectively. A computational methodology, ligand based pharmacophore model, was also employed to further explore the broad-specific of tested compounds. It was found that the two hydrogen bond acceptor features and one hydrophobic aliphatic feature were essential for the corresponding cross-reactivity results from the FP assay. All these results suggest that the established method can be successfully applied to monitor the occurrence of BPs in urine. This article is protected by copyright. All rights reserved. PMID- 30307065 TI - Gamma-H2AX immunofluorescence for the detection of tissue-specific genotoxicity in vivo. AB - The phosphorylation of histone H2AX in Serine 139 (gamma-H2AX) marks regions of DNA double strand breaks and contributes to the recruitment of DNA repair factors to the site of DNA damage. Gamma-H2AX is used widely as DNA damage marker in vitro, but its use for genotoxicity assessment in vivo has not been extensively investigated. Here, we developed an image analysis system for the precise quantification of the gamma-H2AX signal, which we used to monitor DNA damage in animals treated with known genotoxicants (EMS, ENU and doxorubicin). To compare this new assay to a validated standard procedure for DNA damage quantification, tissues from the same animals were also analyzed in the comet assay. An increase in the levels of gamma-H2AX was observed in most of the tissues from animals treated with doxorubicin and ENU. Interestingly, the lesions induced by doxorubicin were not easily detected by the standard comet assay, while they were clearly identified by gamma-H2AX staining. Conversely, EMS appeared strongly positive in the comet assay but only mildly in the gamma-H2AX immunofluorescence. These observations suggest that the two methods could complement each other for DNA damage analysis, where gamma-H2AX staining allows the detection of tissue specific effects in situ. Moreover, since gamma-H2AX staining can be performed on formalin-fixed and paraffin-embedded tissue sections generated during repeated dose toxicity studies, it does not require any further treatments or extra procedures during dissection, thus optimizing the use of resources and animals. 2018 Wiley Periodicals, Inc. PMID- 30307066 TI - Portal vein thrombosis prevalence and associated mortality in cirrhosis in a nationally representative inpatient cohort. AB - BACKGROUND AND AIM: Portal vein thrombosis (PVT) is increasingly common in cirrhotics, but its impact on mortality and outcomes is unclear. Studies evaluating PVT have been limited by small sample size. This study analyzes the trend of the prevalence of PVT and its associated mortality in hospitalized decompensated cirrhotics. METHODS: The Nationwide Inpatient Sample, the largest nationally representative database of hospital discharges, was queried from 1998 to 2014. Inpatients older than 18 years with decompensated cirrhosis were included, while those who received liver transplantation or had hepatocellular carcinoma were excluded. The primary outcomes were the trend in prevalence and associated mortality with PVT. Secondary outcomes included identifying risk factors of PVT and the effect of PVT on complications of portal hypertension. Multivariable logistic regression evaluated the outcomes. RESULTS: A total of 3 045 098 discharges were included, of which 1.5% had PVT. PVT prevalence increased from 0.7% to 2.4%, annual percent change of 9%. Mortality associated with PVT declined from 11.9% to 9.1%, annual percent change of -3.0%. In multivariable analysis controlling for factors associated with mortality in cirrhotics, PVT was associated with an increased risk of mortality (OR 1.12, P < 0.001). Multivariable logistic regression also demonstrated that PVT significantly increased the risk of acute kidney injury (OR 1.75, P < 0.001) and hepatorenal syndrome (OR 1.62, P < 0.001). CONCLUSIONS: The prevalence of PVT is increasing while its associated mortality is decreasing. However, PVT still is associated with risk of mortality and kidney injury, implying a significant impact on cirrhotic outcomes. PMID- 30307067 TI - Prevalence of low inflammatory tinea genitalis in southern China. AB - BACKGROUND: Emergence of highly inflammatory genital dermatophyte infections has been reported from Southeast Asia. In view of this, knowledge of the non-outbreak fungal flora of the genitals is required as a baseline study. OBJECTIVES: We present our 12-year experience in a tertiary clinic with the diagnosis of scrotal fungal infections. METHODS: A retrospective review was performed of patients with a diagnosis of scrotal fungal infections proven by direct microscopy and culture. Clinical, mycological and treatment data were collected. RESULTS: In total, 35 male patients were identified, of which 27 concerned dermatophyte infections and eight were yeasts. Nannizzia gypsea was the most common agent (48.6%), presenting as thick pseudomembraneous lesions limited to the scrotum. Trichophyton rubrum (22.9%) and Epidermophyton floccosum (5.7%) mainly presented erythematous, dry and scaly lesions and involving more sites besides the scrotum. Candida albicans (n = 3), C. glabrata (n = 2), C. guilliermondii (n = 1) and Trichosporon asteroides (n = 1), presented various lesions. Sports, sweating and concurrent tineas are hypothesised as predisposing factors. CONCLUSIONS: The prevalent causative agent of scrotum infections is N. gypsea, but wide species diversity is observed. All infections show mild skin inflammation. It is suggested that this genital fungal flora represents the current situation prior to clonal dermatophyte outbreaks. PMID- 30307068 TI - Engineering the Interface of Carbon Electrocatalysts at the Triple Point for Enhanced Oxygen Reduction Reaction. AB - The aqueous oxygen reduction reaction (ORR) has recently received increased attention due to its critical role in clean and sustainable energy-generation technologies, such as proton exchange membranes (PEM) fuel cells, alkaline fuel cells and Zn-air batteries. The sluggish kinetics associated with ORR result from multistep electron-transfer process. The slow kinetics are partially related to the O2 adsorption process onto the catalyst, which happens at the triple-phase boundary (TPB) of the electrocatalyst-electrolyte-oxygen interface. Hence, tremendous efforts have been devoted to improving the intrinsic properties of electrocatalysts such as active sites, electrical conductivity and porosity. Engineering the electrocatalyst's interfacial properties is another critical issue in ORR, however less described in the literature. The surface of the catalyst provides the microenvironment for the triple boundary interface reaction, which directly influences its electrocatalytic activity and the kinetics. This Minireview is a summary of the existing literature on manipulating the interfacial surface of non-precious metal catalysts at the triple point between the solid catalyst, the aqueous electrolyte and the O2 gas with the aim of improving the ORR efficiency. Various approaches towards improving the wettability and nanostructuring the catalyst surface to boost the activity of the surface-active sites and provide improved stability are discussed. PMID- 30307070 TI - Addressing substance misuse: a missed opportunity in suicide prevention. PMID- 30307069 TI - Polycomb repressive complex 2 attenuates ABA-induced senescence in Arabidopsis. AB - The phytohormone abscisic acid (ABA)-induced leaf senescence facilitates nutrient reuse and potentially contributes to enhancing plant stress tolerance. However, excessive senescence causes serious reductions in crop yield, and the mechanism by which senescence is finely tuned at different levels is still insufficiently understood. Here, we found that the double mutant of core enzymes of the polycomb repressive complex 2 (PRC2) is hypersensitive to ABA in Arabidopsis thaliana. To elucidate the interplay between ABA and PRC2 at the genome level, we extensively profiled the transcriptomic and epigenomic changes triggered by ABA. We observed that H3K27me3 preferentially targets ABA-induced senescence-associated genes (SAGs). In the double, but not single, mutant of PRC2 enzymes, these SAGs were derepressed and could be more highly induced by ABA compared with the wild-type, suggesting a redundant role for the PRC2 enzymes in negatively regulating ABA induced senescence. Contrary to the rapid transcriptomic changes triggered by ABA, the reduction of H3K27me3 at these SAGs falls far behind the induction of their expression, indicating that PRC2-mediated H3K27me3 contributed to long-term damping of ABA-induced senescence to prevent an oversensitive response. The findings of this study may serve as a paradigm for a global understanding of the interplay between the rapid effects of a phytohormone such as ABA and the long term effects of the epigenetic machinery in regulating plant senescence processes and environmental responses. PMID- 30307071 TI - Expected susceptibility contrast of the brain structures in normal conditions and in pathological models. PMID- 30307072 TI - Differential regulation and interaction of homoeologous WRKY18 and WRKY40 in Arabidopsis allotetraploids and biotic stress responses. AB - WRKY transcription factors (TFs) belong to a large family of regulatory proteins in plants that modulate many plant processes. Extensive studies have been conducted on WRKY-mediated defense response in Arabidopsis thaliana and several crop species. Here, we aimed to investigate the potential roles and contributions of WRKY TFs in improving the defense response in the resynthesized Arabidopsis allotetraploids (Arabidopsis suecica) derived from two related autotetraploid progenitors, Arabidopsis thaliana (At4) and Arabidopsis arenosa (Aa). Rapid and differential induction of WRKY18 and WRKY40 expression was evident in response to Pseudomonas syringae and salicylic acid (SA) treatments in the allotetraploids. Selected direct targets of the WRKYs and PR1 also showed altered induction kinetics in the allotetraploids. Cleaved amplified polymorphic sequence analysis further revealed the accumulation of preferential homoeologous alleles (AtWRKY18, AaWRKY40, and AtWRKY60) in the allotetraploids, suggesting the potential for altered protein-protein interaction networks in the hybrids. Indeed, results showed that the cis-interacting AtWRKY18/AtWRKY18 homodimer or trans-interacting AtWRKY18/AaWRKY40 heterodimer exists as the preferred dimer interaction. Moreover, differential affinities of WRKY18 and WRKY40 homo- and heterodimers toward the W-boxes in the WRKY60 promoter were observed. Transient and stable expression of the selected WRKYs in transgenic Arabidopsis further supported the idea that differential interactions lead to changes in PR1 induction and direct target expression under stress, respectively. Our data suggest that differential expression as well as differences in the strength of protein-protein and/or protein-DNA interactions among the WRKY homoeologs could lead to altered regulatory networks of defense genes, contributing to improved defense in allotetraploids. PMID- 30307073 TI - Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation. AB - BACKGROUND: Asthma is an allergic airway inflammation-driven disease that affects more than 300 million people world-wide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development cannot be prevented. Cdc42 GTPase has been shown to regulate actin cytoskeleton, cell proliferation and survival. OBJECTIVES: To investigate the role and targeting of Cdc42 in Th2 cell differentiation and Th2-mediated allergic airway inflammation. METHODS: Post-thymic Cdc42-deficient mice were generated by crossing Cdc42flox/flox mice with dLckicre transgenic mice in which Cre expression is driven by distal Lck promoter. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on Th2 cell differentiation were evaluated in vitro under Th2-polarized culture conditions. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on allergic airway inflammation were evaluated in ovalbumin- and/or house dust mite-induced mouse models of asthma. RESULTS: Post-thymic deletion of Cdc42 led to reduced peripheral CD8+ T cells and attenuated Th2 cell differentiation, with no effect on closely related Th1, Th17 and induced regulatory T (iTreg) cells. Post-thymic Cdc42 deficiency ameliorated allergic airway inflammation. The selective inhibition of Th2 cell differentiation by post-thymic deletion of Cdc42 was recapitulated by pharmacological targeting of Cdc42 with CASIN, a Cdc42 activity specific chemical inhibitor. CASIN also alleviated allergic airway inflammation. CASIN-treated Cdc42-deficient mice showed comparable allergic airway inflammation to vehicle-treated Cdc42-deficient mice, indicative of negligible off-target effect of CASIN. CASIN had no effect on established allergic airway inflammation. CONCLUSION AND CLINICAL RELEVANCE: Cdc42 is required for Th2 cell differentiation and allergic airway inflammation, and rational targeting Cdc42 may serve as a preventive but not therapeutic approach for asthma control. PMID- 30307074 TI - Signatures of genetic adaptation to extremely varied Australian environments in introduced European house sparrows. AB - Due to its history of multiple introductions to novel environments worldwide, the house sparrow has been used as a model species to study local adaption in invasive avian species. New genomic resources such as a custom 200K SNP array and a house sparrow reference genome provide great prospects for studying rapid local adaptation in this invasive species. Here, we analyse high-density genomewide genetic data collected across an extensive range of temperate, arid and tropical climates, in Australian populations that were introduced from Europe 150 years ago. We used two population differentiation (PD) and two ecological association (EA) methods to identify putative loci subject to selection across these varied climates. A majority of the outlier SNPs were identified through the use of the latent factor mixed models (LFMM) EA method, but the BayeScEnv EA method had the strongest overlap with the outliers from the two PD methods. Out of all the 971 outliers identified across the different methods, 38.3% were physically linked (within 20 kbps) to 575 known protein-coding regions in the house sparrow reference genome. Interestingly, some outlier genes had been previously identified in genome scan studies of broadly distributed species or had strong links to traits that are expected to be important to local adaptation, for example, heat-shock proteins, immune response and HOX genes. However, many outliers still have unknown relevance and some outliers can be false positives. Our results identify an opportunity to use the house sparrow model to further study local adaptation in an invasive species. PMID- 30307075 TI - Quantitative Gd-DOTA-based aerosol deposition mapping in the lungs of asthmatic rats using 3D UTE-MRI. AB - Asthma is a chronic respiratory disease, commonly treated with inhaled therapy. Better understanding of the mechanisms of aerosol deposition is required to improve inhaled drug delivery. Three-dimensional ultrashort echo time (UTE) MRI acquisitions at 1.5 T were combined with spontaneous nose-only inhalation of aerosolized gadolinium (Gd) to map the aerosol deposition and to characterize signal enhancement in asthmatic rat lungs. The rats were sensitized to ovalbumin (OVA) to develop asthmatic models and challenged before imaging by nebulization of OVA to trigger asthmatic symptoms. The negative controls were not sensitized or challenged by nebulization of saline. The animal lungs were imaged before and after administration of Gd-based aerosol in freely breathing rats, by using a T1 weighted 3D UTE sequence. A contrast-enhanced quantitative analysis was performed to assess regional concentration. OVA-sensitized rats had lower signal enhancement and lower deposited aerosol concentration. Their enhancement dynamics showed large inter-subject variability. The signal intensity was homogeneously enhanced for controls while OVA-sensitized rats showed heterogeneous enhancement. Contrast-enhanced 3D UTE was applied with aerosolized Gd to efficiently measure spatially resolved deposition in asthmatic lungs. The small administered dose (around 1 MUmol/kg body weight) and the use of standard clinical MRI suggest a potential application for the exploration of asthma. PMID- 30307076 TI - Genomic data recover previously undetectable fragmentation effects in an endangered amphibian. AB - A critical consideration when using molecular ecological methods to detect trends and parameterize models at very fine spatial and temporal scales has always been the technical limits of resolution. Key landscape features, including most anthropogenic modifications, can cause biologically important, but very recent changes in gene flow that require substantial statistical power to detect. The problem is one of temporal scale: Human change is rapid and recent, while genetic changes accumulate slowly. We generated SNPs from thousands of nuclear loci to characterize the population structure of New York-endangered eastern tiger salamanders (Ambystoma tigrinum) on Long Island and quantify the impacts of roads on population fragmentation. In stark contrast to a recent microsatellite study, we uncovered highly structured populations over an extremely small spatial scale (approximately 40 km2 ) in an increasingly human-modified landscape. Geographic distance and the presence of roads between ponds were both strong predictors of genetic divergence, suggesting that both natural and anthropogenic factors contribute to the observed patterns of genetic variation. All ponds supported small to modest effective breeding populations, and pond surface area showed a strong positive correlation with population size. None of these patterns emerged in an earlier study of the same system using microsatellite loci, and we determined that at least 300-400 SNPs were needed to recover the fine-scale population structure present in this system. Conservation assessments using earlier genetic techniques in other species may similarly lack the statistical power for small-scale inferences and benefit from reassessments using genomic tools. PMID- 30307077 TI - The arginine decarboxylase gene ADC1, associated to the putrescine pathway, plays an important role in potato cold-acclimated freezing tolerance as revealed by transcriptome and metabolome analyses. AB - Low temperature severely influences potato production as the cultivated potato (Solanum tuberosum) is frost sensitive, however the mechanism underlying the freezing tolerance of the potato is largely unknown. In the present research, we studied the transcriptome and metabolome of the freezing-tolerant wild species Solanum acaule (Aca) and freezing-sensitive cultivated S. tuberosum (Tub) to identify the main pathways and important factors related to freezing tolerance. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation indicated that polyamine and amino acid metabolic pathways were specifically upregulated in Aca under cold treatment. The transcriptome changes detected in Aca were accompanied by the specific accumulation of putrescine, saccharides, amino acids and other metabolites. The combination of transcriptome and metabolome analyses revealed that putrescine exhibited an accumulative pattern in accordance with the expression of the arginine decarboxylase gene ADC1. The primary role of putrescine was further confirmed by analyzing all three polyamines (putrescine, spermidine, and spermine) and the genes encoding the corresponding enzymes in two sets of potato genotypes with distinct freezing tolerance, implying that only putrescine and ADC1 were uniquely enhanced by cold in the freezing-tolerant genotypes. The function of putrescine was further analyzed by its exogenous application and the overexpression of SaADC1 in S. tuberosum cv. E3, indicating its important role(s) in cold-acclimated freezing tolerance, which was accompanied with the activation of C-repeat binding factor genes (CBFs). The present research has identified that the ADC1-associated putrescine pathway plays an important role in cold-acclimated freezing tolerance of potato, probably by enhancing the expression of CBF genes. PMID- 30307078 TI - Pediatric Telemedicine Use in United States Emergency Departments. AB - INTRODUCTION: The receipt of remote clinical care for children via telecommunications (pediatric telemedicine) appears to improve access to and quality of care in U.S. emergency departments (EDs), but the actual prevalence and characteristics of pediatric telemedicine receipt remain unclear. We determined the prevalence and current applications of pediatric telemedicine in U.S. EDs, focusing on EDs that received telemedicine from clinicians at other facilities. METHODS: We surveyed all 5,375 U.S. EDs to characterize emergency care in 2016. We then randomly surveyed 130 (39%) of the 337 EDs who reported receiving pediatric telemedicine. The second survey was administered by phone to ED directors primarily. It confirmed that the ED received pediatric telemedicine services in 2017 and asked about ED staffing and the nature, purpose, and concerns with pediatric telemedicine implementation. RESULTS: The first survey (4,507/5,375, 84% response) showed that 337 (8%) EDs reported receiving pediatric telemedicine. Among the randomly sampled EDs completing the second survey (107/130, 82% response), 96 (90%) confirmed 2016 use and 89 (83%) confirmed 2017 use. Reasons for discontinuation included technical and scheduling concerns. Almost all who confirmed their pediatric telemedicine use in 2017 also reported 24/7 availability (98%). The most widely reported use was for patient placement and transfer coordination (80%). Many EDs (39%) reported no challenges with implementing pediatric telemedicine and described its utility. However, the most frequently reported challenges were process concerns (30%), such as concerns about slowing or interrupting providers' work flow and technological concerns (14%). CONCLUSION: Few EDs receive telemedicine for the delivery of pediatric emergency care nationally. Among EDs that do use telemedicine for pediatric care, many report process concerns. Addressing these barriers through focused education or interventions may support EDs in further developing and optimizing this technological adjunct to pediatric emergency care. PMID- 30307079 TI - From organotypic culture to body-on-a-chip: A neuroendocrine perspective. AB - The methods used to study neuroendocrinology have been as diverse as the discoveries to come out of the field. Maintaining live neurones outside of a body in vitro was important from the beginning, building on methods that dated back to at least the first decade of the 20th Century. Neurosecretion defines an essential foundation of neuroendocrinology based on work that began in the 1920s and 1930s. Throughout the first half of the 20th Century, many paradigms arose for studying everything from single neurones to whole organs in vitro. Two of these survived as preeminent systems for use throughout the second half of the century: cell cultures and explant systems. Slice cultures and explants that emerged as organotypic technologies included such neuroendocrine organs such as the brain, pituitary, adrenals and intestine. The vast majority of these studies were carried out in static cultures for which media were changed over a time scale of days. Tissues were used for experimental techniques such as electrical recording of neuronal physiology in single cells and observation by live microscopy. When maintained in vitro, many of these systems only partially capture the in vivo physiology of the organ system of interest, often because of a lack of cellular diversity (eg, neuronal cultures lacking glia). Modern microfluidic methodologies show promise for organ systems, ranging from the reproductive to the gastrointestinal to the brain. Moving forward and striving to understand the mechanisms that drive neuroendocrine signalling centrally and peripherally, there will always be a need to consider the heterogeneous cellular compositions of organs in vivo. PMID- 30307080 TI - Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy. AB - White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi-automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: beta = .067; 95%CI[.024-0.111]; p < .01; EM: beta = .061; 95%CI[.025-.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, chi2 [1] = 9.3, p < .01) and for EM (likelihood ratio test, chi2 [1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (beta = -.170; p = .001) and hippocampal atrophy (beta = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD. PMID- 30307081 TI - HPA axis stress reactivity and hair cortisol concentrations in recently detoxified alcoholics and healthy controls with and without childhood maltreatment. AB - Childhood maltreatment (CM) is a strong risk factor for alcohol dependence (AD) and is associated with a more severe course of the disease. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in this relationship. The aim of the present study was to systematically investigate potential alterations in HPA functioning associated with AD diagnosis and CM. Four study groups were recruited: AD patients with (n = 29; 10?) and without (n = 33; 8?) CM and healthy controls with (n = 30; 20?) and without (n = 38; 15?) CM. Cumulative cortisol secretion was measured by hair cortisol concentration (HCC). To measure HPA axis response to the Trier social stress test (TSST), saliva and blood samples were analysed for adrenocorticotropic hormone (ACTH) and cortisol. In the AD groups, the period of hair growth covered acute alcohol consumption and withdrawal. The TSST was scheduled after completion of withdrawal. Irrespective of CM, higher HCCs and reduced ACTH and cortisol levels before and after TSST were observed in AD patients. The analyses did not reveal any differences between AD patients with and without CM. Healthy controls with CM had lower plasma cortisol levels compared with those without CM. The results suggest that AD is strongly related to HPA axis functioning, which may superimpose possible differences between AD patients with and without CM. Future studies should investigate whether biologically different subtypes of AD with and without CM can be identified in earlier stages or before the development of AD. PMID- 30307082 TI - Hot Off the Press: Comparison of Emergency Medicine Malpractice Cases Involving Residents to Nonresident Cases. PMID- 30307083 TI - Neural basis of smoking-induced relief of craving and negative affect: Contribution of nicotine. AB - Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal. PMID- 30307084 TI - Cannabidiol affects circadian clock core complex and its regulation in microglia cells. AB - Cannabis is often used by consumers for sleep disorders. Studies show that circadian rhythm could be affected by a misuse of cannabis. Recent research has connected the role of microglial cells with psychiatric disorders such as substance abuse. The aim was to show the effect of two major components of cannabis on circadian genes regulation in microglial cells. In BV-2 microglial cells, cannabidiol (CBD) induces a deregulation of circadian genes with (P-value = 0.039) or without (P-value = 0.0015) lipopolisaccharides stimulation. CBD up regulated Arntl (P = 9.72E-5) and down regulated Clock (P = 0.0034) in BV-2 cells. Temporal expression of Arntl (light and dark P = 0.0054) and Clock (light and dark P = 0.047) was confirmed to have 24 hours light and dark rhythmic regulation in dissected suprachiasmatic nucleus as well as of Cb1 cannabinoid receptor (light and dark P = 0.019). In BV-2 microglia cells, CBD also up regulated CRY2 (P = 0.0473) and PER1 (P = 0.0131). Other nuclear molecules show a deregulation of circadian rhythm in microglial cells by CBD, such as RORA, RevErbalpha, RORB, CREBBP, AFT4, AFT5 and NFIL3. Our study suggests that circadian rhythm in microglial cells is deregulated by CBD but not by THC. It is consistent with clinical observations of the use of therapeutic cannabis to treat insomnia. PMID- 30307085 TI - Digital Learning Resources for Prosthodontic Education: The Perspectives of a Long-Term Dental Educator Regarding 4 Key Factors. AB - Technological advances have led to the introduction of 3D education programs specifically designed for dentistry, leading to the author's use of these programs in the education of dental students. Based on this usage, this paper proposes there are 4 key factors that can enhance student education (spatial ability, interactivity, critical thinking, and clinical correlations with integration of multiple dental disciplines). These key factors can be incorporated into student learning through the use of 3D education programs in class. Lessons learned from using these programs include the importance of regular use in class as well as testing students both visually and textually on the content present in such programs. In this way, students will use the program and thereby enhance their 3D visualization skills while learning the required didactic information. Simply providing students with access to such programs without regular use in class and without testing the students on the content leads to these programs' lack of use. As a result, the students miss an opportunity to enhance their ability to visualize structures three dimensionally and manipulate them in their minds, a process known as spatial ability that is linked to success in the sciences. PMID- 30307086 TI - Early Implant Failures in Edentulous Patients: A Multivariable Regression Analysis of 4615 Consecutively Treated Jaws. A Retrospective Study. AB - PURPOSE: To study the incidence of early implant failures in edentulous jaws and to describe the effects of some patient- and implant-related factors on the risk for early implant failures. MATERIALS AND METHODS: The study retrospectively analyzed 4615 edentulous jaws (4067 patients), consecutively treated with dental implants at one referral clinic from 1986 to 2013. Implant failures that occurred from implant surgery up to the first recall examination 1 year after prosthesis insertion were recorded and defined as early implant failures. All removed implants were included as failures. Features of the study group and early implant failure rates were reported. A multivariable logistic regression model was used for analyzing possible associations between clinical factors, and the risk for early implant failures. Implant surfaces were categorized by means of roughness: turned (Sa 0.5-1.0 MUm) and moderately rough (Sa 1.0-2.0 MUm). RESULTS: Three hundred twenty-seven patients (344 jaws) were lost to follow-up. Early implant failures occurred in 8.6% of the jaws. In the maxilla there was a significantly higher incidence of early failures compared to the mandible both with turned implants, OR 5.93 (95% CI 4.21; 8.36), and moderately rough implants, OR 2.52 (95% CI 1.19; 5.34). The impact of implant surface roughness was significant in the maxilla with higher incidence of early failures with turned implants, OR 3.51 (95% CI 2.27; 5.42). There was a significant interaction between implant surface and jaw type on early failures (p = 0.034). Older age was associated with lower risk for early implant failures, OR 0.9 (95%CI 0.82; 0.99). In total, 63% of the jaws with failure could proceed with the prosthetic treatment without further implant insertions. Twenty-six percent of the early failures occurred after prosthesis insertion and 59% of those could maintain the same prosthesis after implant loss with or without adjustments. CONCLUSIONS: Changing the implant surface from turned to moderately rough decreased the incidence of early implant failures significantly in the maxilla, but not in the mandible. Older age at implant insertion was associated with lower risk for early implant failures in edentulous patients. PMID- 30307087 TI - Withaferin A, a novel compound of Indian ginseng (Withania somnifera), ameliorates Cerulein-induced acute pancreatitis: Possible role of oxidative stress and inflammation. AB - Acute pancreatitis is an inflammatory disorder of the pancreas that may precipitate due to various reasons such as chronic alcoholism, gall stone obstruction, and life style. Current treatment options offer limited efficacy, as they provide only symptomatic relief. This study is an attempt to study the effects of Withaferin A (WFA) against Cerulein-induced acute pancreatitis in mice. Animals were pretreated with WFA via intraperitoneal route, for 7 days. Plasma amylase and lipase, tissue malondialdehyde (MDA), and glutathione were evaluated for all groups. Western blot analysis; haematoxylin and eosin staining of the liver, lung, and pancreas; immunohistochemistry for nitrotyrosine; and myeloperoxidase activity were performed. Haematoxylin and eosin stained sections significantly revealed the altered architecture and thereby damage in the pancreas, lungs, and liver that has been low in treatment groups. Increased myeloperoxidase and nitrotyrosine have also been reduced upon treatment with WFA. Increased levels of MDA, NO, and expression of myeloperoxidase and nitrotyrosine in the parameters estimated add evidence to the role of oxidative stress and inflammation in acute pancreatitis. WFA evidently altered these conditions upon pretreatment. Our study shows that this novel steroidal compound has potent anti inflammatory property. Natural compounds can therefore be good remedies against many diseases if incorporated in routine diet as dietary supplement. PMID- 30307088 TI - Existential distress in cancer: Alleviating suffering from fundamental loss and change. AB - A severe life threatening illness can challenge fundamental expectations about security, interrelatedness with others, justness, controllability, certainty, and hope for a long and fruitful life. That distress and suffering but also growth and mastery may arise from confrontation with an existentially threatening stressor is a long-standing idea. But only recently have researchers studied existential distress more rigorously and begun to identify its distinct impact on health care outcomes. Operationalizations of existential distress have included fear of cancer recurrence, death anxiety, demoralization, hopelessness, dignity related distress, and the desire for hastened death. These focus in varying emphasis on fear of death, concern about autonomy, suffering, or being a burden to others; a sense of profound loneliness, pointlessness or hopelessness; grief, regret, or embitterment about what has been missed in life; and shame if dignity is lost or expectations about coping are not met. We provide an overview of conceptual issues, diagnostic approaches, and treatments to alleviate existential distress. Although the two meta-analyses featured in this special issue indicate the progress that has been made, many questions remain unresolved. We suggest how the field may move forward through defining a threshold for clinically significant existential distress, investigating its comorbidity with other psychiatric conditions, and inquiring into adjustment processes and mechanisms underlying change in existential interventions. We hope that this special issue may inspire progress in this promising area of research to improve recognition and management of a central psychological state in cancer care. PMID- 30307089 TI - Diastereoselective Cyclobutenol Synthesis: A Heterogeneous Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenols. AB - A highly selective and efficient oxidative carbocyclization/borylation of enallenols catalyzed by palladium immobilized on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was developed for diastereoselective cyclobutenol synthesis. The heterogeneous palladium catalyst can be recovered and recycled without any observed loss of activity or selectivity. The high diastereoselectivity of the reaction is proposed to originate from a directing effect of the enallenol hydroxyl group. Optically pure cyclobutenol synthesis was achieved by the heterogeneous strategy by using chiral enallenol obtained from kinetic resolution. PMID- 30307090 TI - Organic Dyes based on Tetraaryl-1,4-dihydropyrrolo-[3,2-b]pyrroles for Photovoltaic and Photocatalysis Applications with the Suppressed Electron Recombination. AB - A tetraaryl-1,4-dihydropyrrolo-[3,2-b]pyrroles (TAPP) moiety with the combination of two pyrrole rings and four phenyl moieties demonstrated strong electron donating ability and nonplanar configuration simultaneously. Once incorporated into the organic dyes as a novel electron donor, it was beneficial for the enhancement of light-harvesting ability and suppression of electron recombination in the photovoltaic and photocatalysis systems. With the linkage of tunable conjugated bridges and electron acceptor, the corresponding organic dyes exhibited improved photovoltaic performance in dye-sensitized solar cells and facilitated photocatalytic hydrogen generation with a highest turnover number (TON) of 4337. Through the detailed investigation of relationship between molecular structures and photovoltaic/photocatalysis property, the connection and difference in molecular design for these two systems are well explained, with the aim to promote the application of dye-sensitized technology in various fields. PMID- 30307091 TI - New Irreversible alpha-l-Iduronidase Inhibitors and Activity-Based Probes. AB - Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one mediated aziridination of l-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of alpha-l-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant alpha-l-iduronidase (rIDUA, Aldurazyme(r) ). The structures of IDUA when complexed with the inhibitors in a non-covalent transition state mimicking form and a covalent enzyme-bound form provide insights into its conformational itinerary. Inhibitors 1-3 adopt a half-chair conformation in solution (4 H3 and 3 H4 ), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1-3 may need to overcome an energy barrier in order to switch from the 4 H3 conformation to the transition state (2, 5 B) binding conformation before reacting and adopting a covalent 5 S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients. PMID- 30307092 TI - The In Situ Sulfidation of Cu2 O by Endogenous H2 S for Colon Cancer Theranostics. AB - Expression of a high concentration of H2 S is closely related to the formation of colon cancer tumors. However, only a few H2 S-triggered theranostics agents for colon cancer have been reported to date. Now, a turn-on theranostics agent was developed by utilizing the in situ reaction of Cu2 O and endogenous H2 S at colon tumor sites. Based on in vitro and in vivo experiments, excellent photoacoustic imaging and photothermal therapy were both confirmed by this in situ reaction activated colon cancer theranostics method. This work established a simple and efficient strategy for both diagnosis and treatment of colon cancer with a novel trigger mechanism, which provides a new route for colon cancer theranostics based on the in situ reactions at the tumor sites. PMID- 30307093 TI - The thermodynamics of insertion electrochemical electrodes - a team play of electrons and ions across two separate interfaces. AB - Insertion electrochemical electrodes exhibit simultaneous electron and ion transfer, where both transfers proceed across different interfaces. Here the thermodynamics of the overall electrochemical electrode reaction is discussed with respect to the thermodynamics of these two charge transfer equilibria. The review includes insertion electrochemical systems where the redox centers are in a solid phase and the ions are transferred between that phase and a solution, and also systems where the redox centers are in a liquid phase which is immiscible with another liquid phase and ions are transferred between these two liquid phases. The review is intended to spark similar studies, e.g., of battery materials, in order to improve their performance. PMID- 30307094 TI - A Long-Cycle-Life Self-Doped Polyaniline Cathode for Rechargeable Aqueous Zinc Batteries. AB - Rechargeable aqueous zinc batteries are promising energy-storage systems for grid applications. Highly conductive polyaniline (PANI) is a potential cathode, but it tends to deactivate in electrolytes with low acidity (i.e. pH >1) owing to deprotonation of the polymer. In this study, we synthesized a sulfo-self-doped PANI electrode by a facile electrochemical copolymerization process. The -SO3 - self-dopant functions as an internal proton reservoir to ensure a highly acidic local environment and facilitate the redox process in the weakly acidic ZnSO4 electrolyte. In a full zinc cell, the self-doped PANI cathode provided a high capacity of 180 mAh g-1 , excellent rate performance of 70 % capacity retention with a 50-fold current-density increase, and a long cycle life of over 2000 cycles with coulombic efficiency close to 100 %. Our study opens a door for the use of conducting polymers as cathode materials for high-performance rechargeable zinc batteries. PMID- 30307095 TI - Enzyme Encapsulation in Mesoporous Metal-Organic Frameworks for Selective Biodegradation of Harmful Dye Molecules. AB - Microperoxidase-8, a small, peroxidase-type enzyme was immobilized into nanoparticles of the mesoporous and ultra-stable metal-organic framework (MOF) MIL-101(Cr). The immobilized enzyme fully retained its catalytic activity and exhibited enhanced resistance to acidic conditions. The biocatalyst was reusable and showed a long-term stability. By exploiting the properties of the MOF's framework, we demonstrated, for the first time, that the MOF matrix could act in synergy with the enzyme (Microperoxidase-8) and enhance selectivity the oxidation reaction of dyes. The oxidation rate of the harmful negatively charged dye (methyl orange) was significantly increased after enzyme immobilization, probably as a result of the pre-concentration of the methyl orange reactant owing to a charge matching between this dye and the MOF. PMID- 30307096 TI - Peptide Ligations by Using Aryloxycarbonyl-o-methylaminoanilides: Chemical Synthesis of Palmitoylated Sonic Hedgehog. AB - A simple procedure for C-terminal activation of peptides in solution and its application in native chemical ligation and protein synthesis is described. This method involves a mild thioesterification based on the conversion of an aryloxy-o methylaminoanilide to thioester under aqueous conditions and in situ ligation with an N-terminal cysteine peptide. The versatility is shown in pH-controlled sequential ligations. To illustrate the usefulness of this methodology, we synthesized the palmitoylated N-terminal domain of human Sonic Hedgehog, a morphogen protein that binds the transmembrane receptor Patched and activates the Hedgehog signaling pathway, involved in embryonic development and in the proliferation of multiple tumors. This approach extends the chemical toolset of chemical protein synthesis based on o-aminoanilide and o-methylaminoanilide peptides. PMID- 30307097 TI - Enantiodivergent Desymmetrization in the Rhodium(III)-Catalyzed Annulation of Sulfoximines with Diazo Compounds. AB - RhIII - and IrIII -catalyzed asymmetric C-H functionalization reactions of arenes have relied on the employment of chiral RhIII /IrIII cyclopentadienyl catalysts, the introduction of chiral carboxylic acids to achiral Cp*RhX2 catalysts, and the integration of both strategies. Despite considerable progress, each reaction only provided a specific configuration of the enantioenriched product when using a particular chiral catalyst. Reported in this work is the enantiodivergent coupling of sulfoximines with various diazo compounds by RhIII -catalyzed desymmetrizing annulation. The enantiodivergence was enabled by a judicious choice of achiral carboxylic acids, and the enantioselectivity correlates with the steric bias of the carboxylic acid and the sulfoximine. PMID- 30307098 TI - A novel citrate synthase isoform contributes infection and stress resistance of the stripe rust fungus. AB - The early development of a rust fungus is dependent on the endogenous lipids stored in the urediniospores. After it establishes a parasitic relationship with the host, sugars absorbed from the host cells by haustoria become the primary nutrients. The tricarboxylic acid (TCA) cycle is essential to oxidize these nutrients. However, few studies have addressed the role of citrate synthase (CS), a rate-limiting enzyme of the TCA cycle, during the infection process of rust fungi. In this study, a CS gene from Puccinia striiformis f. sp. tritici (Pst), PsCS1, was cloned and characterized. Transcripts of PsCS1 and the enzyme activity of the CS were increased in the early Pst infection stage. Biochemical features and subcellular localization revealed that PsCS1 encoded a mitochondrial CS. Size exclusion chromatography, yeast two-hybrid and bimolecular fluorescence complementation experiments confirmed that PsCS1 could form a functional homo octamer. The overexpression of PsCS1 enhanced the resistance of Escherichia coli to salt stress. The knockdown of PsCS1 using a host-induced gene silencing (HIGS) system blocked Pst growth in wheat. These results indicate that PsCS1 is required for nutrient metabolism in Pst and contributes to Pst infection by regulating ATP production and the supply of carbon sources. PMID- 30307100 TI - European Young Chemist Award: A. Porchetta, M. Atzori, and S. Fabiano / EuChemS Award for Service: F. De Angelis, S. Facchetti, and R. Salzer. PMID- 30307099 TI - Where in the world do bacteria experience oxidative stress? AB - Reactive oxygen species - superoxide, hydrogen peroxide and hydroxyl radicals - have long been suspected of constraining bacterial growth in important microbial habitats and indeed of shaping microbial communities. Over recent decades, studies of paradigmatic organisms such as Escherichia coli, Salmonella typhimurium, Bacillus subtilis and Saccharomyces cerevisiae have pinpointed the biomolecules that oxidants can damage and the strategies by which microbes minimize their injuries. What is lacking is a good sense of the circumstances under which oxidative stress actually occurs. In this MiniReview several potential natural sources of oxidative stress are considered: endogenous ROS formation, chemical oxidation of reduced species at oxic-anoxic interfaces, H2 O2 production by lactic acid bacteria, the oxidative burst of phagocytes and the redox-cycling of secreted small molecules. While all of these phenomena can be reproduced and verified in the lab, the actual quantification of stress in natural habitats remains lacking - and, therefore, we have a fundamental hole in our understanding of the role that oxidative stress actually plays in the biosphere. PMID- 30307101 TI - Simultaneous determination of savaside A, acteoside, and isoacteoside in rat plasma by UHPLC-MS/MS: Comparative pharmacokinetic and bioavailability characteristics of Monochasma savatieri via different routes of administration. AB - Phenylethanoid glycosides are the bioactive components in Monochasma savatieri that primarily contains savaside A, acteoside, and isoacteoside. Pharmacological research has been comprehensive, but there have been few studies on pharmacokinetics, especially about savaside A. An ultra high performance liquid chromatography with tandem mass spectrometry with multiple reaction monitoring mode was developed and validated for the simultaneous determination of the three compounds from M. savatieri. Meanwhile, this method was fully validated and successfully applied to compare the pharmacokinetics and bioavailability following four different routes included intravenous injection, intraperitoneal injection, muscle injection, and oral administration. The results indicated that the three compounds could be rapidly absorbed within 1 h, and the main pharmacokinetic parameters showed significant differences (P < 0.05). The bioavailability of oral administration, intramuscular injection, and intraperitoneal injection did not exceed 0.2, 25, and 10%, respectively. Comparing the bioavailability, it exhibited that acteoside > isoacteoside > savaside A following the four administration routes. Notably, the isomerization position of acteoside and isoacteoside mainly occurred in the liver according to the pharmacokinetics profiles of intraperitoneal and intravenous injection, in addition, isoacteoside exhibited more structural selectivity than acteoside in vivo. It demonstrated that three compounds undergo different processes, mainly affected by the first-pass effect and their intestinal stability is extremely poor. PMID- 30307102 TI - NaCl promotes antibiotic resistance by reducing redox states in Vibrio alginolyticus. AB - The development of antibiotic resistance in Vibrio alginolyticus represents a threat to human health and fish farming. Environmental NaCl regulation of bacterial physiology is well documented, but whether the regulation contributes to antibiotic resistance remains unknown. To explore this, we compared minimum inhibitory concentration (MIC) of V. alginolyticus cultured in different media with 0.5%-10% NaCl, and found that the MIC increased as the NaCl concentration increased, especially for aminoglycoside antibiotics. Consistent with this finding, internal NaCl also increased, while intracellular gentamicin level decreased. GC-MS-based metabolomics showed different distributions of pyruvate cycle intermediates among 0.5%, 4% and 10% NaCl. Differential activity of enzymes in the pyruvate cycle and altered expression of Na(+)-NQR led to a reducing redox state, characterized by decreased levels of NADH, proton motive force (PMF) and ATP. Meanwhile, NaCl negatively regulated PMF as a consequence of the reducing redox state. These together are responsible for the decreased intracellular gentamicin level with the increased external level of NaCl. Our study reveals a previously unknown redox state-dependent mechanism regulated by NaCl in V. alginolyticus that impacts antibiotic resistance. PMID- 30307103 TI - Prolonged hospital stay and readmission rate in an enhanced recovery after surgery cohort undergoing colorectal cancer surgery. AB - AIM: The present database study aimed to identify patients with a longer postoperative length of stay (LOS) or patients readmitted and to characterize both groups based on perioperative factors. METHOD: A retrospective review of the Danish Colorectal Cancer Group database and a local database was performed of all patients undergoing elective resection for colorectal cancer in a 25-month period. The primary outcome was the number of patients with a prolonged hospital stay (LOS >= 10 days after the primary operation) and readmissions within 30 days after discharge. RESULTS: A total of 372 patients with colon resection and 215 patients with rectal resection were included. Patients undergoing colonic resection had a rate of prolonged hospital stay of 10.6% and a readmission rate of 13.7%; prolonged hospital stay was significantly associated with age >= 76 years and those who underwent a conversion from a laparoscopic procedure. Patients undergoing rectal cancer resection had a rate of prolonged hospital stay of 17.7% and a readmission rate of 14.0%; Charlson comorbidity score (CCS) >= 2, total mesorectal excision (TME) and laparoscopic conversion were significantly associated with prolonged hospital stay, and American Society of Anesthesiologists (ASA) score >= 3, TME and a duration of surgery >= 300 min were significantly associated with readmission. CONCLUSION: In patients with colon cancer, older age and conversion to open surgery were associated with prolonged hospital stay. In patients with rectal cancer, CCS >= 2, TME and conversion were associated with prolonged hospital stay, and a preoperative ASA score >= 3, TME and a duration of surgery >= 300 min were associated with readmission. PMID- 30307104 TI - Insight into the sulfur metabolism of Desulfurella amilsii by differential proteomics. AB - Many questions regarding proteins involved in microbial sulfur metabolism remain unsolved. For sulfur respiration at low pH, the terminal electron acceptor is still unclear. Desulfurella amilsii is a sulfur-reducing bacterium that respires elemental sulfur (S0 ) or thiosulfate, and grows by S0 disproportionation. Due to its versatility, comparative studies on D. amilsii may shed light on microbial sulfur metabolism. Requirement of physical contact between cells and S0 was analyzed. Sulfide production decreased by around 50% when S0 was trapped in dialysis membranes, suggesting that contact between cells and S0 is beneficial, but not strictly needed. Proteome analysis was performed under the aforementioned conditions. A Mo-oxidoreductase suggested from genome analysis to act as sulfur reductase was not detected in any growth condition. Thiosulfate and sulfite reductases showed increased abundance in thiosulfate-reducing cultures, while rhodanese-like sulfurtransferases were highly abundant in all conditions. DsrE and DsrL were abundantly detected during thiosulfate reduction, suggesting a modified mechanism of sulfite reduction. Proteogenomics suggest a different disproportionation pathway from what has been reported. This work points to an important role of rhodaneses in sulfur processes and these proteins should be considered in searches for sulfur metabolism in broader fields like meta-omics. PMID- 30307105 TI - Sexual specific functions of Tub1 beta-tubulins require stage-specific RNA processing and expression in Fusarium graminearum. AB - The wheat head blight fungus Fusarium graminearum has two highly similar beta tubulin genes with overlapping functions during vegetative growth but only TUB1 is important for sexual reproduction. To better understand their functional divergence during ascosporogenesis, in this study we characterized the sequence elements important for stage-specific functions of TUB1. Deletion of TUB1 blocked the late but not initial stages of perithecium formation. Perithecia formed by tub1 mutant had limited ascogenous hyphae and failed to develop asci. Silencing of TUB1 by MSUD also resulted in defects in ascospore formation. Interestingly, the 3'-UTR of TUB1 was dispensable for growth but essential for its function during sexual reproduction. RIP mutations that specifically affected Tub1 functions during sexual reproduction also were identified in two ascospore progeny. Furthermore, site-directed mutagenesis showed that whereas the non editable mutations at three A-to-I RNA editing sites had no effects, the N347D (not T362D or I368V) edited mutation affected ascospore development. In addition, the F167Y, but not E198K or F200Y, mutation in TUB1 conferred tolerance to carbendazim and caused a minor defect in sexual reproduction. Taken together, our data indicate TUB1 plays an essential role in ascosporogenesis and sexual specific functions of TUB1 require stage-specific RNA processing and Tub1 expression. PMID- 30307106 TI - Dehydrogenative Aromatization and Sulfonylation of Pyrrolidines: Orthogonal Reactivity in Photoredox Catalysis. AB - Oxidative dehydrogenative aromatization and selective sulfonylation reactions of N-heterocycles under visible-light photoredox catalysis were established. The mild reaction conditions make this approach an appealing and versatile strategy to functionalize/oxidize pyrrolidines whereby arylsulfonyl chlorides were identified to be both catalyst regeneration and sulfonylation reagents. PMID- 30307107 TI - First evidences that the ectomycorrhizal fungus Paxillus involutus mobilizes nitrogen and carbon from saprotrophic fungus necromass. AB - Fungal succession in rotting wood shows a surprising abundance of ectomycorrhizal (EM) fungi during the late decomposition stages. To better understand the links between EM fungi and saprotrophic fungi, we investigated the potential capacities of the EM fungus Paxillus involutus to mobilize nutrients from necromass of Postia placenta, a wood rot fungus, and to transfer these elements to its host tree. In this aim, we used pure cultures of P. involutus in the presence of labelled Postia necromass (15 N/13 C) as nutrient source, and a monoxenic mycorrhized pine experiment composed of labelled Postia necromass and P. involutus culture in interaction with pine seedlings. The isotopic labelling was measured in both experiments. In pure culture, P. involutus was able to mobilize N, but C as well, from the Postia necromass. In the symbiotic interaction experiment, we measured high 15 N enrichments in all plant and fungal compartments. Interestingly, 13 C remains mainly in the mycelium and mycorrhizas, demonstrating that the EM fungus transferred essentially N from the necromass to the tree. These observations reveal that fungal organic matter could represent a significant N source for EM fungi and trees, but also a C source for mycorrhizal fungi, including in symbiotic lifestyle. PMID- 30307108 TI - Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke. AB - Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3 . After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2018. PMID- 30307109 TI - Physiological and Proteomic Evidence for the Interactive Effects of Post-Anthesis Heat Stress and Elevated CO2 on Wheat. AB - Elevated CO2 promotes leaf photosynthesis and improves crop grain yield. However, as a major anthropogenic greenhouse gas, CO2 contributes to more frequent and severe heat stress, which threatens crop productivity. The combined effects of elevated CO2 and heat stress are complex, and the underlying mechanisms are poorly understood. In the present study, the effects of elevated CO2 and high temperature on foliar physiological traits and the proteome of spring wheat grown under two CO2 concentrations (380 and 550 umol mol-1 ) and two temperature conditions (ambient and post-anthesis heat stress) are examined. Elevated CO2 increases leaf photosynthetic traits, biomass, and grain yield, while heat stress depresses photosynthesis and yield. Temperature-induced impacts on chlorophyll content and grain yield are not significantly different under the two CO2 concentrations. Analysis of the leaf proteome reveals that proteins involved in photosynthesis as well as antioxidant and protein synthesis pathways are significantly downregulated due to the combination of elevated CO2 and heat stress. Correspondingly, plants treated with elevated CO2 and heat stress exhibit decreased green leaf area, photosynthetic rate, antioxidant enzyme activities, and 1000-kernel weight. The present study demonstrates that future post-anthesis heat episodes will diminish the positive effects of elevated CO2 and negatively impact wheat production. PMID- 30307110 TI - Renal manifestation of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. It commonly causes several types of cystic disease and benign tumors (angiomyolipomata) in the kidneys that can both lead to significant premature loss of glomerular filtration rate. The main risks of angiomyolipomata, severe bleeding, loss of renal function, and pulmonary lymphangioleiomyomatosis, can be ameliorated by active surveillance and preemptive therapy with mTOR inhibitors. The cystogenic mechanism may involve primary cilia, but also appears to also involve a majority of normal tubular cells and may be driven by a minority of cells with mutations inactivating both their TSC1 or TSC2 genes. Malignant tumors are rare. PMID- 30307111 TI - Enhanced enantioselectivity of native alpha-cyclodextrins by the synergy of chiral ionic liquids in capillary electrophoresis. AB - In the cyclodextrins family, the native alpha-cyclodextrin has almost been abandoned in capillary electrophoresis chiral separation due to its much weaker enantioselectivity compared with beta-cyclodextrin and their derivatives. In this work, several amino acid chiral ionic liquids were selected to establish synergistic enantioseparation systems with native alpha-cyclodextrin. Enhanced enantioselectivities were observed in the chiral ionic liquids/alpha-cyclodextrin synergistic systems compared with single alpha-cyclodextrin system. A series of comparison experiments were performed to demonstrate the superiority of the synergistic systems. Primary parameters affecting the enantioseparation were systematically optimized, including the type and concentration of chiral ionic liquids, alpha-cyclodextrin concentration, buffer pH, and applied voltage. Best separations of the model enantiomers were obtained in a 20 mM Tris/H3 PO4 buffer at pH 2.5 containing 3% (m/v) alpha-cyclodextrin and 30 mM tetramethylammonium-l arginine. The results show that the alpha-cyclodextrin is also worth our attention when selecting chiral selectors for capillary electrophoresis enantioseparation of specific racemic compound. PMID- 30307112 TI - Generation of MLC-2v-tdTomato knock-in reporter mouse line. AB - MLC-2v is a myosin light chain regulatory protein which is specifically expressed in ventricular cardiomyocytes and slow twitch skeletal muscle cells. MLC-2v plays critical roles in ventricular maturation during heart development. Mice lacking MLC-2v are embryonic lethal due to heart failure associated with abnormal myofibrillar organization of ventricular cardiomyocytes. To study the development of ventricular cardiac muscle and slow twitch skeletal muscle, we generated a new MLC-2v reporter mouse line by knocking-in a tdTomato reporter cassette into 3' UTR of the MLC-2v gene without disrupting the endogenous gene. Our results demonstrated specific MLC-2v-tdTomato knock-in reporter expression in ventricular cardiomyocytes and slow twitch muscle during myogenesis, precisely recapitulating the spatiotemporal expression pattern of endogenous MLC-2v. No tdTomato expression was observed in the atria, fast twitch muscle or other organs throughout development into adulthood. Isolated neonatal and adult ventricular cardiomyocytes uniformly express tdTomato. Taken together, MLC-2v-tdTomato knock in reporter mouse model described in this article will serve as a valuable tool to study cardiac chamber and skeletal muscle specification during development and regeneration by overcoming the pitfalls of transgenic strategies. PMID- 30307113 TI - Ratiometric fluorescence nanosensors based on core-shell structured carbon/CdTe quantum dots and surface molecularly imprinted polymers for the detection of sulfadiazine. AB - Sulfadiazine is an environmental pollutant derived from abuse of antibiotics. Its content in environmental water is closely related to human health. Thus, a novel dual-emission surface molecularly imprinted nanosensor is designed for the specific adsorption and detection of sulfadiazine. In the system, blue emissive carbon quantum dots wrapped with silica served as the internal reference signal for eliminating background interference, while red emissive thioglycolic acid modified CdTe quantum dots (CdTe QDs), which are low dimensional semiconductor materials by the combination of cadmium and tellurium with excellent optical properties, were encapsulated in the imprinted layer to offer recognition signal. The fluorescence of CdTe quantum dots was quenched and the fluorescence quenching degree of carbon quantum dots was inconspicuous with the increase of concentration of sulfadiazine, thereby reflecting the color change. The detection of sulfadiazine was successfully achieved in a concentration range of 0.25-20 MUmol/L with detection limit of 0.042 MUmol/L and nanosensors had specific recognition for sulfadiazine over its analogues. Compared to single-emission fluorescence sensors, ratiometric fluorescence nanosensors had wider linear range and higher detection accuracy. Furthermore, the nanosensors were also successfully applied for the determination of sulfadiazine in real water and milk samples with acceptable recoveries. The study provides a feasible method for the detection of sulfadiazine and a reference for the detection of sulfonamides. PMID- 30307114 TI - Validation of Peptide Identification Results in Proteomics Using Amino Acid Counting. AB - The efficiency of proteome analysis depends strongly on the configuration parameters of the search engine. One of the murkiest and nontrivial among them is the list of amino acid modifications included for the search. Here, an approach called AA_stat is presented for uncovering the unexpected modifications of amino acid residues in the protein sequences, as well as possible artifacts of data acquisition or processing, in the results of proteome analyses. The approach is based on comparing the amino acid frequencies of different mass shifts observed using the open search method introduced recently. In this work, the proposed approach is applied to publicly available proteomic data is applied and its feasibility for discovering unaccounted modifications or possible pitfalls of the identification workflow is demonstrated. The algorithm is implemented in Python as an open-source command-line tool available at https://bitbucket.org/J_Bale/aa_stat/. PMID- 30307115 TI - A Recombinant 12-His Tagged Pyrococcus furiosus Soluble [NiFe]-Hydrogenase I Overexpressed in Thermococcus kodakarensis KOD1 Facilitates Hydrogen-Powered in vitro NADH Regeneration. AB - Soluble hydrogenase I (SHI) from the hyperthermophilic archaeon Pyrococcus furiosus is a heterotetrameric [NiFe] hydrogenase that catalyzes the reversible reduction of protons by NADPH into hydrogen gas (H2 ). Here, the authors expressed the four alphabetagammadelta subunits of SHI encoded by one gene cluster in another hyperthermophilic archaeon, Thermococcus kodakarensis KOD1, which uses its hydrogenase maturation apparatus without the coexpression of native P. furiosus hydrogenase endopeptidases (maturation proteases). The SHI overexpression of T. kodakarensis resulted in more than 1200-fold enhancement in the hydrogenase activity of the cell lysate compared to that of the host strain with an empty vector. An active, purified 12-His tagged recombinant SHI (rSHI) is obtained by one-step affinity adsorption on nickel-charged resin. Size-exclusion chromatography show that purified rSHI is heterotetrameric and has a molecular mass of 150 kDa. The purified rSHI has a half-life of 70 h at 80 degrees C. This rSHI is used to design a novel in vitro synthetic enzymatic biosystem to convert pyruvate and H2 gas into lactate in a theoretical yield, whereas rSHI is used for NADPH regeneration; an FMN-containing diaphorase (DI) is used to match NADP preferred SHI and NAD-preferred lactate dehydrogenase (LDH). This study provides a cost-efficient method to obtain hyperthermostable hydrogenases, which can be used in in vitro synthetic enzymatic biosystems for cofactor regeneration and hydrogen production. PMID- 30307116 TI - Free fatty acid profiling in marine algae extract by LC-MS/MS and isolation as well as quantification of the omega-3 fatty acid hexadeca-4,7,10,13-tetraenoic acid. AB - Undaria pinnatifida (Wakame) alga contains high amounts of hexadeca-4Z,7Z,10Z,13Z tetraenoic acid which was reported to decrease the efficiency of cisplatin chemotherapeutics. To obtain a fatty acid enriched extract of this omega-3 poly unsaturated fatty acid as an analytical standard, Wakame was used as source material for its extraction. A two-step extraction protocol consisting of a liquid-liquid extraction followed by solid-phase extraction with 3-aminopropyl silica in accordance to a normal-phase elution mode was developed. An ultra high performance liquid chromatography with electrospray ionization tandem mass spectrometry method based on sequential windowed acquisition of all theoretical fragment ion mass spectra allowed a simultaneous comprehensive group selective fatty acids profiling in untargeted manner and quantitative analysis of the targeted fatty acid. Hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid was identified using high-resolution product ion spectra. The quantitative method was based on d5 deuterated hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid which was employed as surrogate calibrant. Preliminary method validation was performed by evaluating detection and quantification limits, linear range, intra-assay and inter-day precision. Finally, a concentration of 421.2 +/- 14.9 ng/mL (4% CV) of hexadeca 4Z,7Z,10Z,13Z-tetraenoic acid was determined in the extract which was further used as analytical standard. PMID- 30307118 TI - Lactotransferrin Gene (LTF) Polymorphisms and Dental Implant Loss: A Case-Control Association Study. PMID- 30307117 TI - Scaling up the manufacturing process of adoptive T cell immunotherapy. AB - Adoptive T cell immunotherapy, involving the reprogramming of immune cells to target specific cancer or virus-infected cells, has been recognized as a promising novel approach for the treatment of complex diseases. The impressive global momentum of this therapeutic approach has highlighted the urgent need for establishing it as an effective and standardized onco-therapeutic approach in a large manufacturing scale. However, given its heterogeneity and uncertainty in nature, adoptive T cell immunotherapy is associated with a high failure rate that restricts its manufacturing to a limited number of institutions worldwide. It is undoubted that quite a few major challenges must be met before engineered T cells can be considered as a reliable, safe and effective remedy for a broad range of diseases with global-wise patient benefits. Here we review the fundamental challenges that as yet remain unsolved in the manufacturing process before adoptive T cell therapy can be considered as a key element in the next generation of precision medicine. We propose that it is necessary to adopt a closed system, automation, cost-effective manufacturing model and quality-by-design strategy to enable scaled up manufacturing of adoptive T cell immunotherapy; and it is challenging to choose appropriate bioreactors, parameters and infrastructure in this process. PMID- 30307119 TI - Clinical Proteomics for Post-Hematopoeitic Stem Cell Transplantation Outcomes. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective form of tumor immunotherapy available to date. However, while HSCT can induce beneficial graft-versus-leukemia (GVL) effect, the adverse effect of graft-versus host disease (GVHD), which is closely linked to GVL, is the major source of morbidity and mortality following HSCT. Until recently, available diagnostic and staging tools frequently fail to identify those at higher risk of disease progression or death. Furthermore, there are shortcomings in the prediction of the need for therapeutic interventions or the response rates to different forms of therapy. The past decade has been characterized by an explosive evolution of proteomics technologies, largely due to important advances in high-throughput MS instruments and bioinformatics. Building on these opportunities, blood biomarkers have been identified and validated both as promising diagnostic tools, prognostic tools that risk-stratify patients before future occurrence of GVHD and as predictive tools for responsiveness to GVHD therapy and non-relapse mortality. These biomarkers might facilitate timely and selective therapeutic intervention. This review summarizes current information on clinical proteomics for GVHD as well as other complications following HSCT. Finally, it proposes future directions for the translation of clinical proteomics to discovery of new potential therapeutic targets to the development of drugs. PMID- 30307120 TI - Inhibition of miR-24 suppresses malignancy of human non-small cell lung cancer cells by targeting WWOX in vitro and in vivo. AB - BACKGROUND: We investigated the effect of micro-RNA 24 (miR-24) and WWOX on non small cell lung cancer (NSCLC) cell proliferation and migration in vitro and in vivo. METHODS: We performed bioinformatics analysis and 3' untranslated region luciferase assay to investigate the direct target of miR-24. Proliferation, apoptosis, and transwell invasion assays were employed to evaluate the effect of WWOX overexpression with pcDNA3-WWOX and knocking down miR-24 with miR-24 small interfering RNA. Quantitative real-time PCR, Western blot, and immunohistochemistry were also used to investigate miR-24 and c-Kit expression, and apoptosis and invasion-related proteins. Finally, we constructed a tumor xenograft model in nude mice to confirm the effect of miR-24 on NSCLC cell proliferation in vivo. RESULTS: According to our experimental data, miR-24 inhibition could induce apoptosis by activating caspase 3 and suppress the viability and proliferation of NSCLC cells in vitro and in vivo. MiR-24 downregulation could reduce the invasive ability of NSCLC cells by downregulating MMP9. WWOX was identified as a functional target of miR-24. WWOX overexpression generated the same effect with antagonizing miR-24, while blocking WWOX counteracted the tumor suppressive effect caused by miR-24 inhibition. MiR-24 may function as an oncogene and play an important role in the cell growth and migration of NSCLC. CONCLUSIONS: Our findings enhance understanding of the miR-24 regulatory network and the molecular mechanism that underlies the oncogenesis and development of NSCLC. Suppressing the effect of miR-24 on cancer cells using a miR-24 inhibitor may be an attractive therapeutic strategy against NSCLC. PMID- 30307121 TI - An atoxigenic L-strain of Aspergillus flavus (Eurotiales: Trichocomaceae) is pathogenic to the coffee twig borer, Xylosandrus compactus (Coleoptera: Curculionidea: Scolytinae). AB - This study isolated and evaluated virulence of fungal entomopathogens of Xylosandrus compactus - an important pest of Robusta coffee in Sub-Saharan Africa. A survey was conducted in five farming systems in Uganda to isolate entomopathogens associated with X. compactus. Four fungal isolates were screened for virulence against X. compactus in the laboratory at 1 * 107 conidia ml-1 where an atoxigenic L-strain of A. flavus killed 70%-100% of all stages of X. compactus compared with other unidentified isolates which caused 20%-70% mortalities. The time taken by A. flavus to kill 50% of X. compactus eggs, larvae, pupae and adults in the laboratory was 2-3 days; whereas the other unidentified fungal isolates took 4-7 days. The concentrations of A. flavus that killed 50% of different stages of X. compactus were 5 * 105 , 12 * 105 , 17 * 105 and 30 * 105 conidia ml-1 for larvae, eggs, pupae and adults respectively. A formulation of A. flavus in oil caused higher mortalities of X. compactus larvae, pupae and adults in the field (71%-79%) than its formulation in water (33%-47%). The atoxigenic strain of A. flavus could therefore be developed into a safe biopesticide against X. compactus. PMID- 30307122 TI - Optimizing first line 7-day standard triple therapy for Helicobacter pylori eradication: Prolonging treatment or adding bismuth: which is better? AB - OBJECTIVE: The 7-day standard triple therapy (STT) gives unacceptablly low eradication rates of Helicobacter pylori (H. pylori). We aimed to examine whether extending STT from 7 days to 14 days or adding a bismuth compound to a 7-day STT would result in better eradication rates. METHODS: H. pylori-positive patients were assigned to Group A (7-day STT; rabeprazole 20 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily, for 7 days), Group B (7-day STT with bismuth; rabeprazole 20 mg twice daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily and bismuth subcitrate 240 mg twice daily, for 7 days) and Group C (14-day STT; rabeprazole 20 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily for 14 days). Eradication was tested using 13 C-UBT at least 4 weeks after the completion of therapy. RESULTS: A total of 364 patients were recruited. In the intention-to-treat analysis, eradication rates were 79.3% (96/121; 95% confidence interval [CI] 71.3-85.6%) for 7-day STT, 81.7% (98/120; 95% CI 73.8-87.6%) for 7-day STT with bismuth, and 88.6% (109/123; 95% CI 81.8-93.1%) for 14-day STT, respectively. Statistical significance was achieved between the 7-day and the 14-day STT treatment (P = 0.048). CONCLUSIONS: Adding bismuth to the 7-day STT did not result in an increase in the eradication rate. Extending the STT to 14 days, however, achieved a significantly higher eradication rate. Nevertheless, this did not achieve the targeted 90% eradication rate on intention-to-treat analysis. PMID- 30307123 TI - mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. AB - Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed. PMID- 30307124 TI - The relationship of previous dental trauma with new cases of dental trauma. A systematic review and meta-analysis. AB - BACKGROUND/AIMS: Traumatic dental injuries (TDI) are a public health concern with high prevalence and recurrence rate. The aim of this study was to perform a systematic review and meta-analysis to determine whether previous dental trauma is a predictive factor for new episodes of TDI (recurrence or first episodes). MATERIALS AND METHODS: Electronic searches were performed with no language or date restrictions. According to the PECOS strategy, cohort studies that investigated subjects with and without previous TDI, and its association with new TDI episodes, as primary or secondary outcomes, were included. Quality assessment and bias control were carried out according to Fowkes and Fulton guidelines. A meta-analysis was performed by sub-grouping studies into deciduous and permanent dentition, and the risk ratio (RR) was also calculated (P <= 0.05). The evidence was quality-tested using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After titles and abstracts were examined, and full texts were read, five studies were included in this systematic review. Four studies had high methodological quality, and one presented a risk of bias on confounding factors. No association and a positive association were determined between previous history of TDI and new episodes of TDI in the primary (RR 1.26 [0.99, 1.62], P = 0.06) and in the permanent dentitions (RR 2.68 [1.20, 4.19], I2 = 37%, P < 0.00001), respectively. The pooled results demonstrated a positive association (P < 0.00001) between previous dental trauma and new episodes of TDI (RR 2.17 [1.20, 3.90], P = 0.01, I2 = 83%) with moderate evidence quality level. CONCLUSIONS: Individuals that have suffered previous TDI present a greater risk of suffering new episodes of TDI. PMID- 30307126 TI - Actual condition survey regarding mismatch of measurements between radioimmunoassay and enzyme-linked immunosorbent assay tests for anti-glutamic acid decarboxylase antibody in real-world clinical practice. AB - Anti-glutamic acid decarboxylase antibody (GADA) is an important islet cell associated autoantibody for the diagnosis of autoimmune type 1 diabetes mellitus. In Japan, the GADA assay kit was recently changed from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA). Thereafter, a mismatched measurement between the two tests became apparent in clinical situations. The present study aimed to clarify the actual extent of mismatch between the two measurements on a larger-scale real-world clinical practice. In this cross-sectional non-local/non hospital-based study, we collected anonymized data on GADA levels of 598 participants, who were simultaneously measured with GADA-RIA and GADA enzyme linked immunosorbent assay tests. We found that 34% of the GADA-RIA-positive participants showed negative results in the GADA enzyme-linked immunosorbent assay test; the mismatch was predominantly observed in participants with relatively low GADA-RIA levels (<32 U/mL). This considerable mismatch might lead to physicians' confusion in diagnosing type 1 diabetes mellitus. PMID- 30307127 TI - Diamond nanoparticles coating for in-tube solid-phase microextraction to detect polycyclic aromatic hydrocarbons. AB - Diamond nanoparticles were coated onto stainless steel wires as a extraction material, then it was filled into a poly(ether ether ketone) tube for in-tube solid-phase microextraction. Coupled with high-performance liquid chromatography, the extraction tube was evaluated with different types of analytes including polycyclic aromatic hydrocarbons, estrogens and plasticizers. As the coating, diamond nanoparticles exhibited greater extraction capacity for hydrophobic analytes. Several polycyclic aromatic hydrocarbons were used as model analytes, four main extraction and desorption factors were optimized, including sampling volume, sampling rate, methanol content in sample and desorption time. A sensitive analysis method was established with wide linear range (0.016-20 MUg/L), good correlation coefficients (0.9991-0.9997), low limits of detection (0.005-0.020 MUg/L), low limits of quantitation (0.016-0.070 MUg/L) and high enrichment factors (305-2396). Relative standard deviations for intra- and interday were less than 2.4% (n = 3) and 8.4% (n = 3), respectively. Durability and chemical stability were satisfactory with relative standard deviations less than 7.9% (n = 3). Finally, the method has been successfully applied to the detection of polycyclic aromatic hydrocarbons in real samples. PMID- 30307128 TI - Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes. AB - The present study evaluated the accuracy of interstitial glucose measurements by flash glucose monitoring (FGM) and continuous glucose monitoring (CGM). Five diabetes patients simultaneously underwent FGM (FreeStyle Libre Pro) and CGM (iProTM2), and their glucose levels were compared with venous blood and capillary blood glucose levels. The range of daily venous blood glucose levels (30 measurements) was 70-245 mg/dL, with a median of 138 mg/dL. There were good correlations of glucose levels measured by FGM (r2 = 0.90, mean absolute relative difference 8.2 +/- 5.6%), CGM (r2 = 0.86, mean absolute relative difference 9.2 +/- 9.1%) and capillary blood (r2 = 0.87, mean absolute relative difference 7.2 +/- 7.2%) with venous blood glucose levels. The accuracy of FGM measurements was also shown against CGM, with 99.9% of the FGM values (1,279 measurements) being within the Parkes error grid zones A and B. The results suggest that the accuracy of FGM is similar to that of CGM, and that FGM is a useful tool for determining daily glucose profile. PMID- 30307125 TI - The impact of volume loading-induced low pressure baroreflex activation on arterial baroreflex-controlled sympathetic arterial pressure regulation in normal rats. AB - Although low pressure baroreflex (LPB) has been shown to elicit various cardiovascular responses, its impact on sympathetic nerve activity (SNA) and arterial baroreflex (ABR) function has not been fully elucidated. The aim of this study was to clarify how volume loading-induced acute LPB activation impacts on SNA and ABR function in normal rats. In 20 anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses, controlled carotid sinus pressure (CSP), and measured central venous pressure (CVP), splanchnic SNA, and arterial pressure (AP). We infused blood stepwise (3 mL/kg/step) to activate volume loading-induced LPB. Under the ABR open-loop condition, stepwise volume loading markedly increased SNA by 76.8 +/- 21.6% at CVP of 3.6 +/- 0.2 mmHg. In contrast, further volume loading suppressed SNA toward the baseline condition. Bilateral vagotomy totally abolished the changes in SNA by volume loading. To assess the impact of LPB on ABR function, we changed CSP stepwise. Low volume loading (CVP = 3.6 +/- 0.4 mmHg) significantly shifted the sigmoidal CSP-SNA relationship (central arc) upward from baseline, whereas high volume loading (CVP = 5.4 +/- 0.4 mmHg) returned it to the baseline level. Volume loading shifted the linear SNA-AP relationship (peripheral arc) upward without significant changes in slope. In conclusions, volume loading-induced acute LPB activation evoked two-phase changes, an initial increase followed by decline from baseline value, in SNA via resetting of the ABR central arc. LPB may contribute greatly to stabilize AP in response to volume status. PMID- 30307129 TI - Comparing 4-mm dental implants to longer implants placed in augmented bones in the atrophic posterior mandibles: One-year results of a randomized controlled trial. AB - BACKGROUND: Short implants have been proposed as an alternative for the rehabilitation of atrophic edentulous areas. PURPOSE: To evaluate the efficacy of 4-mm implants vs longer implants in the atrophic posterior mandibles. MATERIALS AND METHODS: Eleven patients with bilateral atrophic mandibles were rehabilitated with two to four 4-mm implants and 10 or 8-mm long implants in augmented bone using Guided Bone Regeneration procedure. One side of the mandibles was randomly allocated to vertical augmentation with mixed autogenous bone and allograft. Implants were placed in both sides of the mandible after 6 months, and loaded after another 2 months. Subsequently, implant and prosthesis failures, marginal bone levels changes, and any complication were evaluated after 1-year follow-up. RESULTS: In this study, one patient dropped out and no failures occurred. However, 4-mm implants loss of 0.30 +/- 0.34 mm peri-implant marginal bone and long implants loss of 0.47 +/- 0.54 mm marginal bone were observed after 1-year of follow-up. The difference between the two groups was not statistically significant (difference = -0.16 +/- 0.68 mm; P = 0.46). Eight complications occurred in five augmented sites of the patients, and no complication was found to occur in the short implants sites. CONCLUSIONS: One-year after loading, 4-mm implants had similar outcomes as long implants in augmented bone. Therefore, short implants might be a feasible treatment in atrophic mandibles. PMID- 30307130 TI - Clinical outcomes of implants placed in ridge-preserved versus nonpreserved sites: A 4-year randomized clinical trial. AB - BACKGROUND: Consistent bone changes occur after tooth removal, often compromising the success of implants placed within the socket left to natural healing The long term effect of ridge preservation on implant outcomes is still unclear. PURPOSE: The aim of the study was to assess success and survival rates of implants placed in extraction sockets, with spontaneous healing, or grafted with cortical porcine bone, or collagenated corticocancellous porcine bone. MATERIALS AND METHODS: Ninety patients in need for a single premolar/molar tooth extraction and an implant treatment were selected for the present study. Patients were randomly distributed among 3 groups: sites that healed naturally (ctrl), or sites that received ridge preservation with either cortical (cort) or collagenated corticocancellous porcine bone (coll). Three months after, all the experimental sites were reentered to insert implants. Marginal bone levels were recorded; soft tissues were analyzed and summarized with the Pink Esthetic Score (PES). Forty two patients out of 90 (initial cohort study) completed the entire follow-up of 4 years. RESULTS: Cumulative survival and success rates for all implants were 100% at a 4-year evaluation. Mean marginal bone loss (MBL) was 1.14 +/- 0.23 mm in the cort group, 1.13 +/- 0.29 mm in the coll group, and 1.92 +/- 0.07 mm in the ctrl group. There were no significant differences between the 2 grafting materials but MBL was significantly greater in the nongrafted sites (P value < .001). The PES resulted significantly better (9.42 +/- 0.75) for the cort group than for the coll group (8.53 +/- 1.18) and ctrl group (6.07 +/- 1.89) at 4-year evaluation. CONCLUSIONS: Ridge preservation was more effective than natural healing in preserving marginal bone and in achieving better esthetic outcomes around implants 4 years after placement. The cortical porcine bone showed better clinical outcomes than collagenated corticocancellous porcine bone. PMID- 30307131 TI - Pain Susceptibility Phenotypes in Those Free of Knee Pain with or at Risk of Knee Osteoarthritis: The Multicenter Osteoarthritis Study. AB - OBJECTIVES: Why some individuals develop pain with knee osteoarthritis (OA) is not clear. We sought to identify pain susceptibility phenotypes (PSPs) and their relation to incident persistent knee pain (PKP) 2 years later. METHODS: We identified individuals free of PKP from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Latent class analysis was used to determine PSPs that may contribute to development of PKP apart from structural pathology: widespread pain, poor sleep, psychological factors and quantitative sensory tests (QST) (i.e., pressure pain threshold and temporal summation (TS)). We evaluated the association of sociodemographic factors with PSPs and the relation of PSPs to developing PKP over two years with logistic regression. RESULTS: 852 participants were included (mean age 67; BMI 29.5 kg/m2 , 55% women). Four PSPs were identified, primarily characterized by varying proportions (low/absent, moderate, or high) of the presence of pressure pain sensitivity and of facilitated TS, reflecting different measures of sensitization. The PSP with high proportion of pressure pain sensitivity + moderate proportion of facilitated TS was twice as likely to develop incident PKP over 2 years OR 2.11 (95% CI 1.06 4.22) compared with the PSP having low proportion of sensitization by both measures. CONCLUSIONS: Four PSPs were identified, of which three were predominated by QST evidence of sensitization, and one was associated with developing PKP 2 years later. Prevention or amelioration of sensitization may be a novel approach to preventing onset of persistent knee pain in OA. This article is protected by copyright. All rights reserved. PMID- 30307132 TI - PKC and PKA involved in the protection of rhGLP-1 on glomeruli and tubules in diabetic rats. AB - AIMS/INTRODUCTION: Blockade or reversal the progression of diabetic nephropathy is a clinical challenge. To study whether the recombinant human glucagon-like peptide-1 have an effect on alleviate urinary protein and urinary albumin levels in diabetic rats or not. MATERIALS AND METHODS: STZ induced Diabetes Rats were treated with rhGLP-1, Insulin, and Saline. Using Immunostaining, H&E, EM and PAS staining to study the pathology of DN, and we performed qRT-PCR, Western blot and IHC to identify the differentially expressed proteins. The mechanism was studied via AGEs-induced tubular epithelial cells. RESULTS: The recombinant human glucagon-like peptide-1 (rhGLP-1) inhibit PKC-beta but increase PKA, which reduce oxidative stress in glomeruli and in cultured glomerular microvascular endothelial cells. In tubules, rhGLP-1 increase the expression of two key proteins relate to re-absorption, megalin, and cubilin, which was accompanied by downregulation of PKC-beta and upregulation of PKA. On human proximal tubular epithelial cells, rhGLP-1 enhance the absorption of albumin, and this was blocked by a PKC activator or PKA inhibitor. CONCLUSIONS: These findings suggest that rhGLP-1 can reverse diabetic nephropathy by protecting both glomeruli and tubules via inhibiting PKC and activating PKA. This article is protected by copyright. All rights reserved. PMID- 30307133 TI - Response to "Underdocumentation of Obesity by Medical Residents Highlights Challenges to Effective Obesity Care". PMID- 30307134 TI - Structure-Based Discovery of Novel CK2alpha-Binding Cyclic Peptides with Anti Cancer Activity. AB - Protein kinase CK2 is considered as an emerging target in cancer therapy, and recent efforts have been made to develop its ATP-competitive inhibitors, but achieving selectivity with respect to related kinases remains challenging because of the highly conserved ATP-binding pocket of kinases. Non-ATP competitive inhibitors might solve this challenge; one such strategy is to identify compounds that target the CK2alpha/CK2beta interface as CK2 holoenzyme antagonists. Here we improved the binding affinity to CK2alpha and cell-based anti-cancer activity of a CK2beta-derived cyclic peptide (Pc) by combining structure-based computational design with experimental evaluation. By analyzing molecular dynamics simulations of Pc bound to CK2alpha, a series of Pc-derived peptides was rationally designed and synthesized to evaluate their binding affinity to CK2alpha, as well as anti proliferative and pro-apoptotic effects against HepG2 cancer cell line. One amino acid substitutions on Pc, I192F, exhibited over 10-fold improvement in the predicted binding affinity to CK2alpha when compared to Pc, and a cell-permeable version, I192F-Tat, also demonstrated more potent anti-proliferative and pro apoptotic effects against HepG2 compared to Pc. A second modification of Pc, H193W, also led to more potent cell-based activity, despite having weaker binding affinity (~5*) to CK2alpha. The discovery of the I192F and H193W peptides provides new insights for further optimization of CK2 antagonist candidates as anti-cancer leads. PMID- 30307135 TI - ? PMID- 30307136 TI - [Meningococcal infections in Switzerland : changes in epidemiology, clinical manifestations and prophylaxis]. AB - In the last decade, the epidemiology of meningococcal infections in Switzerland and Europe has changed. The prevalence of Y and W serogroups augmented, with more atypical clinical manifestations such as pharyngitis, pneumonia and arthritis. A hypervirulent clonal serogroup W strain of Neisseria meningitidis has emerged in Europe and Switzerland, with a noticeable potential for epidemics as evidenced by its clonality. In this context, vaccinal recommendations for risk groups have and will continue to evolve towards the use of novel conjugated vaccines. PMID- 30307137 TI - [Crimean-Congo hemorrhagic fever : an emerging viral hemorrhagic fever in Europe]. AB - Crimean-Congo hemorrhagic fever is transmitted by Hyalomma spp ticks or exposure to blood of infected persons or animals. It is present in European regions that are frequently visited by people living in Switzerland. It is suspected in case of fever with hemorrhagic signs and confirmed by PCR or serology. Because of its severity and potential for nosocomial transmission, it should be included of the differential diagnosis of fever in returning travelers in order to rapidly implement the adequate measures : hospitalisation with isolation precautions and treatment with ribavirin. In the absence of an effective vaccine, prevention consists of barriers precautions and postexposure prophylaxis with ribavirin in case of exposure to infected blood. PMID- 30307138 TI - [Management of acute diarrhea]. AB - Acute diarrhea is one of the most common pathologies in resource-limited, as well as in industrialized countries. For the clinician the major challenge is to know when to perform diagnostic tests, how to interpret them, and particularly to recognize the situations where an antibiotic treatment is recommended. This will also avoid unnecessary treatments, costs, side effects and selection of resistant strains. PMID- 30307139 TI - [Toxin-infections and toxin-related diseases due to Clostridia other than Clostridium difficile]. AB - Clostridia cause severe diseases. Tetanus is rare in Switzerland because of vaccine coverage and the application of guidelines for the management of contaminated wounds. Tetanus requires wound debridement and the administration of antibiotics and anti-tetanus immune. Besides gastroenteritis, infections due to C. perfringens most often require surgery, in addition to antibiotic treatment with penicillin and clindamycin. Botulism is a rare disease caused by a toxin produced by C. botulinum that causes flaccid paralysis. The clinical syndrome must be recognized early in order to administer the antitoxin and improve the prognosis. The other, rarer species of Clostridia require surgical and antibiotic management, but their prognosis remains poor. PMID- 30307140 TI - [Common causes of infectious mononucleosis]. AB - Most cases of infectious mononucleosis are caused by Epstein-Barr virus (EBV). However, other rare but potentially serious etiologies need to be considered. Cytomegalovirus (CMV) and Toxoplasma gondii infections, although generally benign, can cause severe congenital infections. An acute infection by the human immunodeficiency virus (HIV) can also mimic infectious mononucleosis. Laboratory diagnostic of those infections relies primarily on the detection of specific antibodies and antigens. The interpretation of laboratory results can be impeded by cross-reactions or persistence over several months of markers of acute infection. This article reviews the most common causes of infectious mononucleosis and their diagnosis. PMID- 30307141 TI - [Diagnosis of tuberculous arthritis : a sometimes long and winding road]. AB - Extraspinal tuberculous arthritis is a rare entity in developed countries, mostly found in populations of migrants. We describe a case of foot osteoarthritis in a young migrant, with an arduous diagnostic process. The sequence of the diagnostic studies (imaging, articular tap, bone biopsy together with cultures and molecular biology) must follow a logic based on clinical suspicion and on the knowledge of the diagnostic values of different tests. The diagnosis of tuberculous arthritis, a slowly progressing infection with a low bacteriologic burden, is difficult. The reported case emphases the need for perseverance. It shows the value of diagnostic procedures, their limits and the need for their integration to the clinical judgement. PMID- 30307142 TI - [Ambulatory emergencies and Tarmed on 2018]. AB - The practice of consulting with emergency medical centers without an appointment as an alternative to visiting one's doctor has been steadily increasing in Switzerland. Fully integrated in the Swiss health system and attending without appointment to late hours, these establishments can deal with a wide variety of medical and surgical emergencies. However, considered first recourse medical centers, they apply billing rates based on those of general practitioner offices. With the 2018 overhaul of the Tarmed, the billing of some services provided in an emergency center become intricate, particularly those involving time-consuming care or extended observation. PMID- 30307143 TI - ? PMID- 30307145 TI - ? PMID- 30307144 TI - ? PMID- 30307147 TI - ? PMID- 30307146 TI - ? PMID- 30307148 TI - ? PMID- 30307149 TI - How can a binary switch within the pars tuberalis control seasonal timing of reproduction? AB - Life in seasonally changing environments is challenging. Biological systems have to not only respond directly to the environment, but also schedule life history events in anticipation of seasonal changes. The cellular and molecular basis of how these events are scheduled is unknown. Cellular decision-making processes in response to signals above certain thresholds regularly occur i.e. cellular fate determination, apoptosis and firing of action potentials. Binary switches, the result of cellular decision-making processes, are defined as a change in phenotype between two stable states. A recent study presents evidence of a binary switch operating in the pars tuberalis (PT) of the pituitary, seemingly timing seasonal reproduction in sheep. Though, how a binary switch would allow for anticipation of seasonal environmental changes, not just direct responsiveness, is unclear. The purpose of this review is to assess the evidence for a binary switching mechanism timing seasonal reproduction and to hypothesize how a binary switch would allow biological processes to be timed over weeks to years. I draw parallels with mechanisms used in development, cell fate determination and seasonal timing in plants. I propose that the adult PT is a plastic tissue, showing a seasonal cycle of cellular differentiation, and that the underlying processes are likely to be epigenetic. Therefore, considering the mechanisms behind adult cellular plasticity offers a framework to hypothesize how a long term timer functions within the PT. PMID- 30307150 TI - miR-876-3p regulates glucose homeostasis and insulin sensitivity by targeting adiponectin AB - miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3'UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome. PMID- 30307151 TI - Hypothalamic gamma-melanocyte stimulating hormone gene delivery reduces fat mass in male mice AB - gamma-Melanocyte stimulating hormone (gamma-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of gamma-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition. Lentiviral gene delivery was used to induce a continuous expression of gamma-Msh only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The gamma-MSH treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (-15% vs -6%) and fat mass (-37% vs -12%) and reduced cumulative food intake were observed in gamma MSH-treated animals. Fasting-induced feeding was increased on chow diet only; however, voluntary running wheel activity on Western diet was increased. The gamma-MSH treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state-dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity. PMID- 30307153 TI - Thyroid hormones stimulate L-arginine transport in human endothelial cells AB - Thyroid hormone activity is associated with L-arginine metabolism and nitric oxide (NO) production, which participate in the cardiovascular manifestations of thyroid disorders. L-arginine transporters play an important role in activating L arginine uptake and NO production. However, the effects of thyroid hormones on L arginine transporters in endothelial cells have not yet been evaluated. The following methods were used. We measured L-arginine uptake, mRNA expression of L arginine transporters, endothelial nitric oxide synthase (eNOS) mRNA and NO generation after the administration of T3, T4 and the T3 analog, 3,3',5 triiodothyroacetic acid TRIAC in human umbilical vein endothelial cells (HUVECs). We also analyzed the role of alphavbeta3 integrin and of phosphatidyl-inositol-3 kinase (PI3K), mitogen-activated protein kinases (MAPKs: ERK1/2, p38 and SAPK JNK) and intracellular calcium signaling pathways as underlying mechanisms. To this end, alphavbeta3 integrin was pharmacologically inhibited by tetraiodothyroacetic acid (TETRAC) or genetically blocked by silencing alphav mRNA and PI3K, MAPKs and intracellular calcium by selective inhibitors. The following results were obtained. Thyroid hormones and the T3 analog TRIAC increased L-arginine uptake in HUVECs, the sodium-independent y+/CAT isoforms, except CAT2b, sodium-dependent y+L system and sodium-independent system b0,+L arginine transporters, eNOS mRNA and NO production. These effects were suppressed by alphavbeta3 integrin inhibition with TETRAC or alphav integrin downregulation or by PI3K, MAPK or intracellular Ca2+ signaling inhibitors. In conclusion, we report for the first time that activation of L-arginine uptake by thyroid hormones is related to an upregulation of L-arginine transporters. This effect seems to be mediated by activation of alphavbeta3 integrin receptor and subsequent PI3K, MAPK and intracellular Ca2+ signaling pathways. PMID- 30307152 TI - Maternal obesity impairs skeletal development in adult offspring AB - Intrauterine or early postnatal high-fat diet (HFD) has substantial influences on adult offspring health; however, studies of HFD-induced maternal obesity on regulation of adult offspring bone formation are sparse. Here, we investigated the effects of HFD-induced maternal obesity on both fetal and adult offspring skeletal development. We found that HFD-induced maternal obesity significantly decreased fetal skeletal development, but enhanced fetal osteoblastic cell senescence signaling and significantly increased the expression of inflammatory factors of the senescence-associated secretory phenotype (SASP) in osteo progenitors. It was found that p300/CBP activation led to H3K27 acetylation to increase the expression of senescence-related genes and PPARgamma in embryonic mouse osteogenic calvarial cells from HFD obese dams. These results were recapitulated in human umbilical cord mesenchymal stem cells (UC MSCs) isolated from offspring of pregnant obese and lean mothers following delivery. Regardless of postnatal HFD challenge, adult offspring from HFD obese dams showed significantly suppressed bone formation. Such early involution of bone formation of adult offspring from HFD obese dams may at least in part due to histone acetylation, i.e., epigenetic regulation of genes involved in cell senescence signaling in pre-osteoblasts from prenatal development. These findings indicate fetal pre-osteoblastic cell senescence signaling is epigenetically regulated by maternal obesity to repress bone formation in adult offspring in rodents and suggest that at least some of these effects may also manifest in humans. PMID- 30307154 TI - Impact of MR on mature adipocytes in high-fat/high-sucrose diet-induced obesity AB - Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice. PMID- 30307155 TI - Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects AB - Fibroblast growth factor 21 (FGF21) is a metabolic regulator of energy and lipid metabolism. FGF21 is highly expressed in liver while FGF21 receptors (beta-klotho (KLB) and FGFR1c) are highly expressed in white adipose tissues (WATs). Plasma FGF21 has been shown to be increased after 7-10 days of fasting but oppositely plasma FGF21 is also increased in obesity. The aim of this study was to measure the effect of 60 h of fasting on plasma FGF21 levels in obese and lean subjects and to determine the gene expression of KLB and FGFR1c in the subcutaneous WAT before, during and after 60 h of fasting. Eight obese (BMI >30 kg/m2) and seven lean subjects (BMI <25 kg/m2) were fasted for 60 h and blood samples were taken at time 0 and after 12, 36 and 60 h of fasting. A biopsy from the subcutaneous WAT was taken at time 0, 12 and 60 h of fasting. FGF21 was measured in plasma by an ELISA and mRNA expression of KLB and FGFR1c was measured in WAT by quantitative PCR (qPCR). The fast significantly decreased plasma FGF21 in obese subjects while no change in plasma FGF21 was observed in lean subjects. Interestingly, KLB was significantly decreased in WAT in response to fasting in both lean and obese subjects indicating a potential important adaptive regulation of KLB in response to fasting. PMID- 30307156 TI - Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats AB - RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague-Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP 3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype. PMID- 30307157 TI - Hypothalamic PDE3B deficiency alters body weight and glucose homeostasis in mouse AB - Pharmacological studies have suggested hypothalamic phosphodiesterase-3B to mediate leptin and insulin action in regulation of energy homeostasis. Whereas Pde3b-null mice show altered energy homeostasis, it is unknown whether this is due to ablation of Pde3b in the hypothalamus. Thus, to address the functional significance of hypothalamic phosphodiesterase-3B, we used Pde3bflox/flox and Nkx2.1-Cre mice to generate Pde3b Nkx2.1KD mice that showed 50% reduction of phosphodiesterase-3B in the hypothalamus. To determine the effect of partial ablation of phosphodiesterase-3B in the hypothalamus on energy and glucose homeostasis, males and females were subjected to either a low- or high-fat diet for 19-21 weeks. Only female but not male Pde3b Nkx2.1KD mice on the low-fat diet showed increased body weight from 13 weeks onward with increased food intake, decreased fat pad weights and hypoleptinemia. Glucose tolerance was improved in high-fat diet-fed male Pde3b Nkx2.1KD mice in association with decreased phosphoenolpyruvate carboxykinase-1 and glucose-6-phosphatase mRNA levels in the liver. Also, insulin sensitivity was increased in male Pde3b Nkx2.1KD mice on the low-fat diet. Changes in body weight or in glucose homeostasis were not associated with any alteration in hypothalamic proopiomelanocortin, neuropepide Y and agouti-related peptide mRNA levels. These results suggest that partial loss of phosphodiesterase-3B in the hypothalamus produces a sex-specific response in body weight and glucose homeostasis, and support a role, at least in part, for hypothalamic phosphodiesterase-3B in regulation of energy and glucose homeostasis in mice. PMID- 30307161 TI - NFATc3 deficiency reduces the classical activation of adipose tissue macrophages AB - Nuclear factors of activated T cells (NFAT) c3 have a prominent role in the regulation of proinflammatory factors in immune cells. The classically activated M1 macrophages are key players in the initiation and maintenance of adipose tissue (AT) inflammation. The role of NFATc3 in obesity and AT inflammation is unknown. We set out to determine how deficiency of NFATc3 effected macrophage polarization, inflammation and insulin resistance in visceral AT of high-fat diet (HFD)-fed mice. Nfatc3-/- and WT mice were fed a HFD for 8-17 weeks. Epididymal white AT (eWAT) F4/80(+) cells were characterized by fluorescence-activated cell sorting and quantitative RT-PCR. Results showed that Nfatc3-/- mice developed HFD induced obesity similar to WT mice, but insulin sensitivity and glucose tolerance were improved, and liver fat accumulation was reduced in Nfatc3-/- mice compared to WT control mice. Moreover, M1 macrophage content and proinflammatory factors were reduced, whereas the alternatively activated M2 macrophage content was increased in eWAT of HFD-fed Nfatc3-/- mice compared to that of WT mice. In addition, eWAT insulin signaling was improved in HFD-fed Nfatc3-/- mice. Importantly, after bone-marrow-derived macrophages had been isolated from Nfatc3 /- mice and cultured in vitro, treatment of these cells with interferon-gamma and lipopolysaccharide resulted in reduction of M1 inflammatory markers, suggesting that NFATc3 promoted M1 polarization by a cell-autonomous mechanism. The results demonstrated that NFATc3 played an important role in M1 macrophage polarization, AT inflammation and insulin resistance in response to obesity through transcriptional activation of proinflammatory genes. PMID- 30307160 TI - Recent insight into the correlation of SREBP-mediated lipid metabolism and innate immune response AB - Fatty acids are essential nutrients that contribute to several intracellular functions. Fatty acid synthesis and oxidation are known to be regulated by sterol regulatory element-binding proteins (SREBPs), which play a pivotal role in the regulation of cellular triglyceride synthesis and cholesterol biogenesis. Recent studies point to a multifunctional role of SREBPs in the pathogenesis of metabolic diseases, such as obesity, type II diabetes and cancer as well as in immune responses. Notably, fatty acid metabolic intermediates are involved in energy homeostasis and pathophysiological conditions. In particular, intracellular fatty acid metabolism affects an inflammatory response, thereby influencing metabolic diseases. The objective of this review is to summarize the recent advances in our understanding of the dual role of SREBPs in both lipid metabolism and inflammation-mediated metabolic diseases. PMID- 30307158 TI - The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases AB - Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPRmt) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPRmt has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPRmt and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance. PMID- 30307162 TI - Mechanisms of beneficial effects of metformin on fatty acid-treated human islets AB - Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2 day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2alpha and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2 day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p AMPK was reduced and p-EIF2alpha, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2alpha, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms. PMID- 30307159 TI - The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism AB - The concept of replenishing or elevating NAD+ availability to combat metabolic disease and ageing is an area of intense research. This has led to a need to define the endogenous regulatory pathways and mechanisms cells and tissues utilise to maximise NAD+ availability such that strategies to intervene in the clinical setting are able to be fully realised. This review discusses the importance of different salvage pathways involved in metabolising the vitamin B3 class of NAD+ precursor molecules, with a particular focus on the recently identified nicotinamide riboside kinase pathway at both a tissue-specific and systemic level. PMID- 30307164 TI - Lipocalin 2 regulates retinoic acid-induced activation of beige adipocytes AB - Lipocalin-2 (LCN2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for LCN2 in the recruitment and retinoic acid-induced activation of brown-like or 'beige' adipocytes. We found LCN2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2 -/- mice. Lcn2 -/ inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2 -/- inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both WT and Lcn2 -/- inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2 -/- adipocytes is able to recruit beige adipocytes at a normal level, however, further activation of beige adipocytes by insulin and RA is impaired in the absence of LCN2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1alpha expression is markedly reduced in Lcn2 -/- inguinal adipocytes. Most intriguingly, LCN2 and the retinoic acid receptor-alpha (RAR alpha) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-alpha translocation is absent in adipocytes deficient in LCN2. Our data suggest a novel LCN2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action. PMID- 30307163 TI - Knockdown of NLRP3 alleviates high glucose or TGFB1-induced EMT in human renal tubular cells AB - Tubular injury is one of the crucial determinants of progressive renal failure in diabetic nephropathy (DN), while epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the accumulation of matrix protein in the diabetic kidney. Activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leads to the maturation of interleukin (IL)-1B and is involved in the pathogenic mechanisms of diabetes. In this study, we explored the role of NLRP3 inflammasome on high glucose (HG) or transforming growth factor-B1 (TGFB1)-induced EMT in HK-2 cells. We evaluated EMT through the expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin as well as the induction of a myofibroblastic phenotype. Reactive oxygen species (ROS) was observed using the confocal microscopy. HG was shown to induce EMT at 48 h, which was blocked by NLRP3 silencing or antioxidant N-acetyl L-cysteine (NAC). We found that NLRP3 interference could inhibit HG-induced ROS. Knockdown of NLRP3 could prevent HG-induced EMT by inhibiting the phosphorylation of SMAD3, P38 MAPK and ERK1/2. In addition, P38 MAPK and ERK1/2 might be involved in HG-induced NLRP3 inflammasome activation. Besides, TGFB1 induced the activation of NLRP3 inflammasome and the generation of ROS, which were blocked by NLRP3 interference or NAC. Tubular cells exposed to TGFB1 also underwent EMT, and this could be inhibited by NLRP3 shRNA or NAC. These results indicated that knockdown of NLRP3 antagonized HG-induced EMT by inhibiting ROS production, phosphorylation of SMAD3, P38MAPK and ERK1/2, highlighting NLRP3 as a potential therapy target for diabetic nephropathy. PMID- 30307165 TI - The proneural bHLH genes Mash1, Math3 and NeuroD are required for pituitary development AB - Multiple signaling molecules and transcription factors are required for pituitary development. Activator-type bHLH genes Mash1, Math, NeuroD (Neurod) and Neurogenin (Neurog) are well known as key molecules in neural development. Although analyses of targeted mouse mutants have demonstrated involvement of these bHLH genes in pituitary development, studies with single-mutant mice could not elucidate their exact functions, because they cooperatively function and compensate each other. The aim of this study was to elucidate the roles of Mash1, Math3 and NeuroD in pituitary development. Mash1;Math3;NeuroD triple-mutant mice were analyzed by immunohistochemistry and quantitative real-time RT-PCR. Misexpression studies with retroviruses in pituisphere cultures were also performed. The triple-mutant adenohypophysis was morphologically normal, though the lumen of the neurohypophysis remained unclosed. However, in triple-mutant pituitaries, somatotropes, gonadotropes and corticotropes were severely decreased, whereas lactotropes were increased. Misexpression of Mash1 alone with retrovirus could not induce generation of hormonal cells, though Mash1 was involved in differentiation of pituitary progenitor cells. These data suggest that Mash1, Math3 and NeuroD cooperatively control the timing of pituitary progenitor cell differentiation and that they are also required for subtype specification of pituitary hormonal cells. Mash1 is necessary for corticotroph and gonadotroph differentiation, and compensated by Math3 and NeuroD. Math3 is necessary for somatotroph differentiation, and compensated by Mash1 and NeuroD. Neurog2 may compensate Mash1, Math3 and NeuroD during pituitary development. Furthermore, Mash1, Math3 and NeuroD are required for neurohypophysis development. Thus, Mash1, Math3 and NeuroD are required for pituitary development, and compensate each other. PMID- 30307167 TI - Give to MMPAC. PMID- 30307168 TI - Missouri State Medical Foundation 2014. PMID- 30307166 TI - Adiponectin regulates glycogen metabolism at the human fetal-maternal interface AB - Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal-maternal interface have not yet been characterized. Among the various factors acting at the fetal maternal interface, we focused on adiponectin - an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal-maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta. PMID- 30307170 TI - Credentials & Appointments. PMID- 30307169 TI - Awards: Legislative. PMID- 30307171 TI - Support Candidates Who Support Medicine. PMID- 30307172 TI - Nanoscale organization in the fluorinated room temperature ionic liquid: Tetraethyl ammonium (trifluoromethanesulfonyl)(nonafluorobutylsulfonyl)imide. AB - Fluorinated Room Temperature Ionic Liquids (FRTILs) are a branch of ionic liquids that is the object of growing interest for a wide range of potential applications, due to the synergic combination of specifically ionic features and those properties that stem from fluorous tails. So far limited experimental work exists on the micro- and mesoscopic structural organization in this class of compounds. Such a work is however necessary to fully understand morphological details at atomistic level that would have strong implications in terms of bulk properties. Here we use the synergy between X-ray and neutron scattering together with molecular dynamics simulations to access structural details of a technologically relevant FRTIL that is characterised by an anion bearing a long enough fluorinated tail to develop specific morphological features. In particular, we find the first experimental evidence that in FRTILs bearing an asymmetric bis(perfluoroalkyl)sulfonyl-imide anion, fluorous side chains tend to be spatially segregated into nm-scale spatial heterogeneities. This feature together with the well-established micro-segregation of side alkyl chains in conventional RTILs leads to the concept of triphilic ILs, whose technological applications are yet to be fully developed. PMID- 30307173 TI - Capillary evaporation of the ionic liquid [EMIM][BF4] in nanoscale solvophobic confinement. AB - Solvent density fluctuations play a crucial role in liquid-vapor transitions in solvophobic confinement and can also be important for understanding solvation of polar and apolar solutes. In the case of ionic liquids (ILs), density fluctuations can be used to understand important processes in the context of nanoscale aggregation and colloidal self-assemblies. In this article, we explore the nature of density fluctuations associated with capillary evaporation of the IL 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4]) in the confined region of model solvophobic nanoscale sheets by using molecular dynamics simulations combined with non-Boltzmann sampling techniques. We demonstrate that density fluctuations of the confined IL play an important role in capillary evaporation, suggesting analogies to dewetting transitions involving water. Significant changes in the interfacial structure of the IL are also detailed and suggested to underlie a non-classical (non-parabolic) dependence of the free energy barrier to evaporation on the degree of confinement. PMID- 30307174 TI - Cluster approach to the prediction of thermodynamic and transport properties of ionic liquids. AB - The prediction of physicochemical properties of ionic liquids such as conductivity and melting point would substantially aid the targeted design of ionic liquids for specific applications ranging from solvents for extraction of valuable chemicals to biowaste to electrolytes in alternative energy devices. The previously published study connecting the interaction energies of single ion pairs (1 IP) of ionic liquids to their thermodynamic and transport properties has been extended to larger systems consisting of two ion pairs (2 IPs), in which many-body and same-ion interactions are included. Routinely used cations, of the imidazolium and pyrrolidinium families, were selected in the study coupled with chloride, tetrafluoroborate, and dicyanamide. Their two ion pair clusters were subjected to extensive configuration screening to establish most stable structures. Interaction energies of these clusters were calculated at the spin ratio scaled MP2 (SRS-MP2) level for the correlation interaction energy, and a newly developed scaled Hartree-Fock method for the rest of energetic contributions to interaction energy. A full geometry screening for each cation anion combination resulted in 192 unique structures, whose stability was assessed using two criteria-widely used interaction energy and total electronic energy. Furthermore, the ratio of interaction energy to its dispersion component was correlated with experimentally observed melting points in 64 energetically favourable structures. These systems were also used to test the correlation of the dispersion contribution to interaction energy with measured conductivity. PMID- 30307175 TI - Solvent controlled intramolecular electron transfer in mixtures of 1-butyl-3 methylimidizolium tetrafluoroborate and acetonitrile. AB - Time-resolved emission techniques were used to study the excited-state intramolecular electron transfer of 9-(4-biphenyl)-10-methylacridinium (BPAc+) in mixtures of 1-butyl-3-methylimidizolium tetrafluoroborate ([Im41][BF4])+ acetonitrile (ACN), a mixture previously shown to be of nearly constant polarity and nearly ideal mixing behavior. Reaction times (tau rxn) track solvation times (tau solv) as a function of mixture composition over a range of more than 3 orders of magnitude in tau solv. This same correlation extends to a variety of neat dipolar solvents and ionic liquids. Reaction times are ~2-fold larger than tau solv over most of the range studied but appear to reach a limiting value of ~3 ps in the fastest solvents. PMID- 30307176 TI - Orientational dynamics in a room temperature ionic liquid: Are angular jumps predominant? AB - Reorientational dynamics of the constituent ions in a room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]), are explored via molecular dynamics simulations, and several features of orientation dynamics are summarized. The anion, [PF6]-, not only exhibits a higher propensity to orientation jumps than the cation, [BMIM]+ but also accesses a wider jump angle distribution and larger peak-angle. Jump and waiting time distributions for both the ions depict power-law dependences, suggesting temporally heterogeneous dynamics for the medium. This heterogeneity feature is further highlighted by the finding that the simulated first rank (l = 1) and second rank (l = 2) average reorientational correlation times reflect a severe break-down of Debye's l(l + 1) law for orientational diffusion in an isotropic homogeneous medium. Simulated average H-bond lifetime resides between the mean orientation jump and waiting times, while the structural H-bond relaxation suggests, as in normal liquids, a pronounced presence of translational motion of the partnering ions. Average simulated jump trajectories reveal a strong rotation-translation coupling and indicate relatively larger changes in spatial and angular arrangements for the anion during an orientation jump. In fact, a closer inspection of all these results points toward more heterogeneous dynamics for [PF6]- than [BMIM]+. This is a new observation and may simply be linked to the ion-size. However, such a generalization warrants further study. PMID- 30307177 TI - Change of hydrogen bonding structure in ionic liquid mixtures by anion type. AB - Ionic liquid mixtures have gained attention as a way of tuning material properties continuously with composition changes. For some mixture systems, physicochemical properties such as excess molar volume have been found to be significantly different from the value expected by linear interpolation, but the origin of this deviation is not well understood yet. The microstructure of the mixture, which can range from an ideal mixture of two initial consisting ionic liquids to a different structure from those of pure materials, has been suggested as the origin of the observed deviation. The structures of several different ionic liquid mixtures are studied by IR spectroscopy to confirm this suggestion, as a particular IR absorption band (nuC(2)-D) for the moiety participating in the hydrogen bonding changes sensitively with the change of the anion in the ionic liquid. The absorbance of nuC(2)-D changes proportionally with the composition, and a relatively small excess molar volume is observed for the mixtures containing an electronegative halide anion. By contrast, the absorbance changes nonlinearly, and the excess molar volumes are larger for the mixtures of which one of the anions has multiple interaction sites. PMID- 30307178 TI - NMR relaxometric probing of ionic liquid dynamics and diffusion under mesoscopic confinement within bacterial cellulose ionogels. AB - Bacterial cellulose ionogels (BCIGs) represent a new class of material comprising a significant content of entrapped ionic liquid (IL) within a porous network formed from crystalline cellulose microfibrils. BCIGs suggest unique opportunities in separations, optically active materials, solid electrolytes, and drug delivery due to the fact that they can contain as much as 99% of an IL phase by weight, coupled with an inherent flexibility, high optical transparency, and the ability to control ionogel cross-sectional shape and size. To allow for the tailoring of BCIGs for a multitude of applications, it is necessary to better understand the underlying principles of the mesoscopic confinement within these ionogels. Toward this, we present a study of the structural, relaxation, and diffusional properties of the ILs, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([emim][Tf2N]) and 1-butyl-1 methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([bmpy][Tf2N]), using 1H and 19F NMR T1 relaxation times, rotational correlation times, and diffusion ordered spectroscopy (DOSY) diffusion coefficients, accompanied by molecular dynamics (MD) simulations. We observed that the cation methyl groups in both ILs were primary points of interaction with the cellulose chains and, while the pore size in cellulose is rather large, [emim]+ diffusion was slowed by ~2-fold, whereas [Tf2N]- diffusion was unencumbered by incorporation in the ionogel. While MD simulations of [bmpy][Tf2N] confinement at the interface showed a diffusion coefficient decrease roughly 3-fold compared to the bulk liquid, DOSY measurements did not reveal any significant changes in diffusion. This suggests that the [bmpy][Tf2N] alkyl chains dominate diffusion through formation of apolar domains. This is in contrast to [emim][Tf2N] where delocalized charge appears to preclude apolar domain formation, allowing interfacial effects to be manifested at a longer range in [emim][Tf2N]. PMID- 30307180 TI - Simulating structure and dynamics in small droplets of 1-ethyl-3 methylimidazolium acetate. AB - To investigate the structure and dynamics of small ionic liquid droplets in gas phase, we performed a DFT-based ab initio molecular dynamics study of several 1 ethyl-3-methylimidazolium acetate clusters in vacuum as well as a bulk phase simulation. We introduce an unbiased criterion for average droplet diameter and density. By extrapolation of the droplet densities, we predict the experimental bulk phase density with a deviation of only a few percent. The hydrogen bond geometry between cations and anions is very similar in droplets and bulk, but the hydrogen bond dynamics is significantly slower in the droplets, becoming slower with increasing system size, with hydrogen bond lifetimes up to 2000 ps. From a normal mode analysis of the trajectories, we identify the modes of the ring proton C-H stretching, which are strongly affected by hydrogen bonding. From analyzing these, we find that the hydrogen bond becomes weaker with increasing system size. The cations possess an increased concentration inside the clusters, whereas the anions show an excess concentration on the outside. Almost all anions point towards the droplet center with their carboxylic groups. Ring stacking is found to be a very important structural motif in the droplets (as in the bulk), but side chain interactions are only of minor importance. By using Voronoi tessellation, we define the exposed droplet surface and find that it consists mainly of hydrogen atoms from the cation's and anion's methyl and ethyl groups. Polar atoms are rarely found on the surface, such that the droplets appear completely hydrophobic on the outside. PMID- 30307179 TI - Predicting structural properties of fluids by thermodynamic extrapolation. AB - We describe a methodology for extrapolating the structural properties of multicomponent fluids from one thermodynamic state to another. These properties generally include features of a system that may be computed from an individual configuration such as radial distribution functions, cluster size distributions, or a polymer's radius of gyration. This approach is based on the principle of using fluctuations in a system's extensive thermodynamic variables, such as energy, to construct an appropriate Taylor series expansion for these structural properties in terms of intensive conjugate variables, such as temperature. Thus, one may extrapolate these properties from one state to another when the series is truncated to some finite order. We demonstrate this extrapolation for simple and coarse-grained fluids in both the canonical and grand canonical ensembles, in terms of both temperatures and the chemical potentials of different components. The results show that this method is able to reasonably approximate structural properties of such fluids over a broad range of conditions. Consequently, this methodology may be employed to increase the computational efficiency of molecular simulations used to measure the structural properties of certain fluid systems, especially those used in high-throughput or data-driven investigations. PMID- 30307181 TI - A path integral methodology for obtaining thermodynamic properties of nonadiabatic systems using Gaussian mixture distributions. AB - We introduce a new path integral Monte Carlo method for investigating nonadiabatic systems in thermal equilibrium and demonstrate an approach to reducing stochastic error. We derive a general path integral expression for the partition function in a product basis of continuous nuclear and discrete electronic degrees of freedom without the use of any mapping schemes. We separate our Hamiltonian into a harmonic portion and a coupling portion; the partition function can then be calculated as the product of a Monte Carlo estimator (of the coupling contribution to the partition function) and a normalization factor (that is evaluated analytically). A Gaussian mixture model is used to evaluate the Monte Carlo estimator in a computationally efficient manner. Using two model systems, we demonstrate our approach to reduce the stochastic error associated with the Monte Carlo estimator. We show that the selection of the harmonic oscillators comprising the sampling distribution directly affects the efficiency of the method. Our results demonstrate that our path integral Monte Carlo method's deviation from exact Trotter calculations is dominated by the choice of the sampling distribution. By improving the sampling distribution, we can drastically reduce the stochastic error leading to lower computational cost. PMID- 30307182 TI - Stability and activity of lysozyme in stoichiometric and non-stoichiometric protic ionic liquid (PIL)-water systems. AB - There has been a substantial increase in enzyme applications within the biochemical and pharmaceutical industries, for example, as industrial biocatalysts. However, enzymes have narrow marginal stability which makes them prone to become inactive and/or denature with a slight change in the solvent environment. Typically industrial applications require harsher solvent environments than enzyme native environments, and hence there is a need to understand solvent-protein interactions in order to develop strategies to maintain, or enhance, the enzymatic activity under industrially relevant solvent conditions. Previously we have shown that protic ionic liquids (PILs) with water can have a stabilising effect on lysozyme, with a large variation dependent on which PIL ions are present, and the water concentration [E. C. Wijaya et al., Phys. Chem. Chem. Phys. 18(37), 25926-25936 (2016)]. Here we extend on this work using non-stoichiometric aqueous PIL solvents to investigate, and isolate, the role of pH and ionicity on enzymes. We have used the PILs ethylammonium nitrate (EAN) and ethanolammonium formate (EOAF) since our previous work has identified these as good solvents for lysozyme. Solvent libraries were made from these two PILs with an additional precursor acid or base to modify the acidity/basicity of the neutral stoichiometric PIL, and with water added, to have solutions with 4-17 mol. % of the PIL ions in water. Molar ratios of base:acid were varied between 1:1.05 and 2:1 for EAN and 1:1.25 and 2:1 for EOAF, which enabled from highly basic to highly acidic solutions to be obtained. This was to modify the acidity/basicity of the neutral stoichiometric PILs, without the addition of buffers. The structure and stability of hen egg white lysozyme (HEWL) were explored under these solvent conditions using synchrotron small angle X-ray scattering (SAXS), Fourier transform infrared (FTIR), and activity assays. The radius of gyration and Kratky plots obtained from the SAXS data showed little change with varying ionicity or acid:base ratio. FTIR showed that alpha-helix was maintained in all, except for the most acidic solvent conditions. The activity data show that HEWL was active between pH 0 and 11 for the EA:N-water system and pH 4.4 and 11 for the EOA:F-water system. This work indicates that ionic liquids have the potential to enable enzymes to maintain activity across a broader range of solvent conditions. PMID- 30307183 TI - Mechanical heterogeneity in ionic liquids. AB - Molecular dynamics (MD) simulations of five ionic liquids based on 1-alkyl-3 methylimidazolium cations, [C n C1im]+, have been performed in order to calculate high-frequency elastic moduli and to evaluate heterogeneity of local elastic moduli. The MD simulations of [C n C1im][NO3], n = 2, 4, 6, and 8, assessed the effect of domain segregation when the alkyl chain length increases, and [C8C1im][PF6] assessed the effect of strength of anion-cation interaction. Dispersion curves of excitation energies of longitudinal and transverse acoustic, LA and TA, modes were obtained from time correlation functions of mass currents at different wavevectors. High-frequency sound velocity of LA modes depends on the alkyl chain length, but sound velocity for TA modes does not. High-frequency bulk and shear moduli, K infinity and G infinity , depend on the alkyl chain length because of a density effect. Both K infinity and G infinity are strongly dependent on the anion. The calculation of local bulk and shear moduli was accomplished by performing bulk and shear deformations of the systems cooled to 0 K. The simulations showed a clear connection between structural and elastic modulus heterogeneities. The development of nano-heterogeneous structure with increasing length of the alkyl chain in [C n C1im][NO3] implies lower values for local bulk and shear moduli in the non-polar domains. The mean value and the standard deviations of distributions of local elastic moduli decrease when [NO3]- is replaced by the less coordinating [PF6]- anion. PMID- 30307184 TI - A molecular dynamics study of lithium-containing aprotic heterocyclic ionic liquid electrolytes. AB - Classical molecular dynamics simulations were performed on twelve different ionic liquids containing aprotic heterocyclic anions doped with Li+. These ionic liquids have been shown to be promising electrolytes for lithium ion batteries. Self-diffusivities, lithium transference numbers, densities, and free volumes were computed as a function of lithium concentration. The dynamics and free volume decreased with increasing lithium concentration, and the trends were rationalized by examining the changes to the liquid structure. Of those examined in the present work, it was found that (methyloxymethyl)triethylphosphonium triazolide ionic liquids have the overall best performance. PMID- 30307185 TI - New optimization scheme to obtain interaction potentials for oxide glasses. AB - We propose a new scheme to parameterize effective potentials that can be used to simulate atomic systems such as oxide glasses. As input data for the optimization, we use the radial distribution functions of the liquid and the vibrational density of state of the glass, both obtained from ab initio simulations, as well as experimental data on the pressure dependence of the density of the glass. For the case of silica, we find that this new scheme facilitates finding pair potentials that are significantly more accurate than the previous ones even if the functional form is the same, thus demonstrating that even simple two-body potentials can be superior to more complex three-body potentials. We have tested the new potential by calculating the pressure dependence of the elastic moduli and found a good agreement with the corresponding experimental data. PMID- 30307186 TI - Sum frequency generation spectroscopy of tetraalkylphosphonium ionic liquids at the air-liquid interface. AB - Sum frequency generation (SFG) spectroscopy is a nonlinear vibrational spectroscopic technique used in the study of interfaces, due to its unique ability to distinguish surface molecules that have preferential ordering compared to the isotropic bulk. Here, a series of alkyltrioctylphosphonium chloride ionic liquids, systematically varied by cation structure, were characterized at the air liquid interface by SFG. The effect on surface structure resulting from molecular variation (i.e., addition of cyano- and methoxy-functional groups) of the cation alkyl chain was investigated. SFG spectra in the C-H stretching region (2750-3100 cm-1) for [P8 8 8 n ][Cl], where n = 4, 5, 8, 10, 12, or 14, showed characteristic changes as the alkyl chain length was increased. Spectral profiles for n = 4, 5, 8, or 10 appeared similar; however, when the fourth alkyl chain was sufficiently long (as in the case of n = 12 or n = 14), abrupt changes occurred in the spectra. Molecular dynamics (MD) simulation of a slab of each ionic liquid (with n = 8, 10, or 12) confirmed gauche defects, with enhancement for the long alkyl chain and an abrupt increase of gauche occurrence from n = 8 to n = 10. A comparison of the tilt angle distribution from the simulation and the SFG analysis show a broad distribution of angles. Using experimental SFG spectra in conjunction with MD simulations, a comprehensive molecular picture at the surface of this unique class of liquids is presented. PMID- 30307187 TI - Spectroscopy and formation of lanthanum-hydrocarbon radicals formed by association and carbon-carbon bond cleavage of isoprene. AB - La atom reaction with isoprene is carried out in a laser-vaporization molecular beam source. The reaction yields an adduct as the major product and C-C cleaved and dehydrogenated species as the minor ones. La(C5H8), La(C2H2), and La(C3H4) are characterized with mass-analyzed threshold ionization (MATI) spectroscopy and quantum chemical computations. The MATI spectra of all three species exhibit a strong origin band and several weak vibronic bands corresponding to La-ligand stretch and ligand-based bend excitations. La(C5H8) is a five-membered metallacycle, whereas La(C2H2) and La(C3H4) are three-membered rings. All three metallacycles prefer a doublet ground state with a La 6s1-based valence electron configuration and a singlet ion. The five-membered metallacycle is formed through La addition and isoprene isomerization, whereas the two three-membered rings are produced by La addition and insertion, hydrogen migration, and carbon-carbon bond cleavage. PMID- 30307188 TI - Dynamics of an excess hole in the 1-methyl-1-butyl-pyrrolidinium dicyanamide ionic-liquid. AB - In a set of recent publications [C. J. Margulis et al., J. Am. Chem. Soc. 133, 20186 (2011); C. H. Xu et al., J. Am. Chem. Soc. 135, 17528 (2013); C. H. Xu and C. J. Margulis, J. Phys. Chem. B 119, 532 (2015); and K. B. Dhungana et al., J. Phys. Chem. B 121, 8809 (2017)], we explored for selected ionic liquids the early stages of excess charge localization and reactivity relevant both to electrochemical and radiation chemistry processes. In particular, Xu and Margulis [J. Phys. Chem. B 119, 532 (2015)] explored the dynamics of an excess electron in 1-methyl-1-butyl-pyrrolidinium dicyanamide. When electrons are produced from an ionic liquid, the more elusive hole species are also generated. Depending on the nature of cations and anions and the relative alignment of their electronic states in the condensed phase, the very early hole species can nominally be neutral radicals-if the electron is generated from anions-or doubly charged radical cations if their origin is from cations. However, in reality early excess charge localization is more complex and often involves more than one ion. The dynamics and the transient spectroscopy of the hole are the main objects of this study. We find that in the case of 1-methyl-1-butyl-pyrrolidinium dicyanamide, it is the anions that can most easily lose an electron becoming radical species, and that hole localization is mostly on anionic nitrogen. We also find that the driving force for localization of an excess hole appears to be smaller than that for an excess electron in 1-methyl-1-butyl-pyrrolidinium dicyanamide. The early transient hole species can absorb light in the visible, ultraviolet, and near infrared regions, and we are able to identify the type of states being connected by these transitions. PMID- 30307189 TI - Structure formation and surface chemistry of ionic liquids on model electrode surfaces-Model studies for the electrode | electrolyte interface in Li-ion batteries. AB - Ionic liquids (ILs) are considered as attractive electrolyte solvents in modern battery concepts such as Li-ion batteries. Here we present a comprehensive review of the results of previous model studies on the interaction of the battery relevant IL 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([BMP]+[TFSI]-) with a series of structurally and chemically well-defined model electrode surfaces, which are increasingly complex and relevant for battery applications [Ag(111), Au(111), Cu(111), pristine and lithiated highly oriented pyrolytic graphite (HOPG), and rutile TiO2(110)]. Combining surface science techniques such as high resolution scanning tunneling microscopy and X-ray photoelectron spectroscopy for characterizing surface structure and chemical composition in deposited (sub-)monolayer adlayers with dispersion corrected density functional theory based calculations, this work aims at a molecular scale understanding of the fundamental processes at the electrode | electrolyte interface, which are crucial for the development of the so-called solid electrolyte interphase (SEI) layer in batteries. Performed under idealized conditions, in an ultrahigh vacuum environment, these model studies provide detailed insights on the structure formation in the adlayer, the substrate adsorbate and adsorbate-adsorbate interactions responsible for this, and the tendency for chemically induced decomposition of the IL. To mimic the situation in an electrolyte, we also investigated the interaction of adsorbed IL (sub )monolayers with coadsorbed lithium. Even at 80 K, postdeposited Li is found to react with the IL, leading to decomposition products such as LiF, Li3N, Li2S, LixSOy, and Li2O. In the absence of a [BMP]+[TFSI]- adlayer, it tends to adsorb, dissolve, or intercalate into the substrate (metals, HOPG) or to react with the substrate (TiO2) above a critical temperature, forming LiOx and Ti3+ species in the latter case. Finally, the formation of stable decomposition products was found to sensitively change the equilibrium between surface Li and Li+ intercalated in the bulk, leading to a deintercalation from lithiated HOPG in the presence of an adsorbed IL adlayer at >230 K. Overall, these results provide detailed insights into the surface chemistry at the solid | electrolyte interface and the initial stages of SEI formation at electrode surfaces in the absence of an applied potential, which is essential for the further improvement of future Li ion batteries. PMID- 30307190 TI - Semiclassical initial value theory of rotationally inelastic scattering: Some remarks on the phase index in the interaction picture. AB - This paper deals with the treatment of quantum interferences in the semiclassical initial value theory of rotationally inelastic scattering in the interaction picture. Like many semiclassical methods, the previous approach involves a phase index related to sign changes of a Jacobian whose square root is involved in the calculations. It is shown that replacing the original phase index by a new one extends the range of applicability of the theory. The resulting predictions are in close agreement with exact quantum scattering results for a model of atom rigid diatom collision involving strong interferences. The developments are performed within the framework of the planar rotor model, but are readily applicable to three-dimensional collisions. PMID- 30307191 TI - Vapor-liquid equilibrium and equation of state of two-dimensional fluids from a discrete perturbation theory. AB - The interest in the description of the properties of fluids of restricted dimensionality is growing for theoretical and practical reasons. In this work, we have firstly developed an analytical expression for the Helmholtz free energy of the two-dimensional square-well fluid in the Barker-Henderson framework. This equation of state is based on an approximate analytical radial distribution function for d-dimensional hard-sphere fluids (1 <= d <= 3) and is validated against existing and new simulation results. The so-obtained equation of state is implemented in a discrete perturbation theory able to account for general potential shapes. The prototypical Lennard-Jones and Yukawa fluids are tested in its two-dimensional version against available and new simulation data with semiquantitative agreement. PMID- 30307192 TI - A simulation study of CS2 solutions in two related ionic liquids with dications and monocations. AB - Atomistic simulations of solutions of CS2 in an ionic liquid, [C8(C1im)2][NTf2]2 , with a divalent cation and in the corresponding ionic liquid with a monovalent cation, [C4C1im][NTf2], were carried out. The low-frequency librational density of states of the CS2 was of particular interest in view of recent optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES). Compared to the monocation ionic liquid, the maximum shifts to higher frequencies in the dication ionic liquid under ambient conditions, but was found to be significantly pressure-dependent. CS2 molecules lie above and below the plane of the imidazolium rings and found to be close to the butyl tails of the monocation. The diffusion rates and embedding energies of solvent ions and CS2 in the two ionic liquids were measured. PMID- 30307193 TI - Effect of the geometry of confining media on the stability and folding rate of alpha -helix proteins. AB - Protein folding in confined media has attracted wide attention over the past 15 years due to its importance to both in vivo and in vitro applications. It is generally believed that protein stability increases by decreasing the size of the confining medium, if the medium's walls are repulsive, and that the maximum folding temperature in confinement is in a pore whose size D 0 is only slightly larger than the smallest dimension of a protein's folded state. Until recently, the stability of proteins in pores with a size very close to that of the folded state has not received the attention it deserves. In a previous paper [L. Javidpour and M. Sahimi, J. Chem. Phys. 135, 125101 (2011)], we showed that, contrary to the current theoretical predictions, the maximum folding temperature occurs in larger pores for smaller alpha-helices. Moreover, in very tight pores, the free energy surface becomes rough, giving rise to a new barrier for protein folding close to the unfolded state. In contrast to unbounded domains, in small nanopores proteins with an alpha-helical native state that contain the beta structures are entropically stabilized implying that folding rates decrease notably and that the free energy surface becomes rougher. In view of the potential significance of such results to interpretation of many sets of experimental data that could not be explained by the current theories, particularly the reported anomalously low rates of folding and the importance of entropic effects on proteins' misfolded states in highly confined environments, we address the following question in the present paper: To what extent the geometry of a confined medium affects the stability and folding rates of proteins? Using millisecond-long molecular dynamics simulations, we study the problem in three types of confining media, namely, cylindrical and slit pores and spherical cavities. Most importantly, we find that the prediction of the previous theories that the dependence of the maximum folding temperature T f on the size D of a confined medium occurs in larger media for larger proteins is correct only in spherical geometry, whereas the opposite is true in the two other geometries that we study. Also studied is the effect of the strength of the interaction between the confined media's walls and the proteins. If the walls are only weakly or moderately attractive, a complex behavior emerges that depends on the size of the confining medium. PMID- 30307194 TI - Preface: Special Topic on Chemical Physics of Ionic Liquids. PMID- 30307195 TI - Revisiting imidazolium based ionic liquids: Effect of the conformation bias of the [NTf2] anion studied by molecular dynamics simulations. AB - We study ionic liquids composed of 1-alkyl-3-methylimidazolium cations and bis(trifluoromethyl-sulfonyl)imide anions ([C n MIm][NTf2]) with varying chain length n = 2, 4, 6, 8 by using molecular dynamics simulations. We show that a reparametrization of the dihedral potentials as well as charges of the [NTf2] anion leads to an improvement of the force field model introduced by Koddermann, Paschek, and Ludwig [ChemPhysChem 8, 2464 (2007)] (KPL-force field). A crucial advantage of the new parameter set is that the minimum energy conformations of the anion (trans and gauche), as deduced from ab initio calculations and Raman experiments, are now both well represented by our model. In addition, the results for [C n MIm][NTf2] show that this modification leads to an even better agreement between experiment and molecular dynamics simulation as demonstrated for densities, diffusion coefficients, vaporization enthalpies, reorientational correlation times, and viscosities. Even though we focused on a better representation of the anion conformation, also the alkyl chain-length dependence of the cation behaves closer to the experiment. We strongly encourage to use the new NGOLP (Neumann, Golub, Odebrecht, Ludwig, Paschek) force field for the [NTf2] anion instead of the earlier KPL parameter set for computer simulations aiming to describe the thermodynamics, dynamics, and also structure of imidazolium-based ionic liquids. PMID- 30307196 TI - CuS nanoplates from ionic liquid precursors-Application in organic photovoltaic cells. AB - Hexagonal p-type semiconductor CuS nanoplates were synthesized via a hot injection method from bis(trimethylsilyl)sulfide and the ionic liquid precursor bis(N-dodecylpyridinium) tetrachloridocuprate(ii). The particles have a broad size distribution with diameters between 30 and 680 nm and well-developed crystal habits. The nanoplates were successfully incorporated into organic photovoltaic (OPV) cells as hole conduction materials. The power conversion efficiency of OPV cells fabricated with the nanoplates is 16% higher than that of a control device fabricated without the nanoplates. PMID- 30307197 TI - Mixtures of glyme and aprotic-protic ionic liquids as electrolytes for energy storage devices. AB - Ionic liquids (ILs) have been proven to be promising electrolytes for electrochemical energy storage devices such as supercapacitors and lithium ion batteries. In the last years, due to deficiency in storage of lithium on earth, innovative systems, such as sodium-based devices, attracted considerable attention. IL-based electrolytes have been proposed also as electrolytes for these devices. Nevertheless, in the case of these systems, the advantages and limits of IL-based electrolytes need to be further investigated. In this work we report an investigation about the chemical-physical properties of mixtures containing bis(2-methoxyethyl)ether diglyme (2G), which is presently considered as one of the most interesting solvents for sodium-based devices, and the ionic liquids 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14TFSI) and 1-butylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PyrH4TFSI). The conductivities, viscosities, and densities of several mixtures of 2G and these ILs have been investigated. Furthermore, their impact on the electrochemical behaviour of activated carbon composite electrodes has been considered. The results of this investigation indicate that these mixtures are promising electrolytes for the realization of advanced sodium-based devices. PMID- 30307198 TI - Multi-resolution polymer Brownian dynamics with hydrodynamic interactions. AB - A polymer model given in terms of beads, interacting through Hookean springs and hydrodynamic forces, is studied. A Brownian dynamics description of this bead spring polymer model is extended to multiple resolutions. Using this multiscale approach, a modeller can efficiently look at different regions of the polymer in different spatial and temporal resolutions with scalings given for the number of beads, statistical segment length, and bead radius in order to maintain macro scale properties of the polymer filament. The Boltzmann distribution of a Gaussian chain for differing statistical segment lengths gives a diffusive displacement equation for the multi-resolution model with a mobility tensor for different bead sizes. Using the pre-averaging approximation, the translational diffusion coefficient is obtained as a function of the inverse of a matrix and then in closed form in the long-chain limit. This is then confirmed with numerical experiments. PMID- 30307199 TI - Electro-responsivity of ionic liquid boundary layers in a polar solvent revealed by neutron reflectance. AB - Using neutron reflectivity, the electro-responsive structuring of the non halogenated ionic liquid (IL) trihexyl(tetradecyl)phosphonium bis(mandelato)borate, [P6,6,6,14][BMB], has been studied at a gold electrode surface in a polar solvent. For a 20% w/w IL mixture, contrast matched to the gold surface, distinct Kiessig fringes were observed for all potentials studied, indicative of a boundary layer of different composition to that of the bulk IL solvent mixture. With applied potential, the amplitudes of the fringes from the gold-boundary layer interface varied systematically. These changes are attributable to the differing ratios of cations and anions in the boundary layer, leading to a greater or diminished contrast with the gold electrode, depending on the individual ion scattering length densities. Such electro-responsive changes were also evident in the reflectivities measured for the pure IL and a less concentrated (5% w/w) IL-solvent mixture at the same applied potentials, but gave rise to less pronounced changes. These measurements, therefore, demonstrate the enhanced sensitivity achieved by contrast matching the bulk solution and that the structure of the IL boundary layers formed in mixtures is strongly influenced by the bulk concentration. Together these results represent an important step in characterising IL boundary layers in IL-solvent mixtures and provide clear evidence of electro-responsive structuring of IL ions in their solutions with applied potential. PMID- 30307200 TI - Blurring out hydrogen: The dynamical structure of teflic acid. AB - The microwave spectra of 10 teflic acid isotopologues were recorded in the frequency range of 3-25 GHz using supersonic jet-expansion Fourier transform microwave spectroscopy. Despite being asymmetric in its equilibrium structure, the delocalization of the hydrogen atom leads to a symmetric top vibrational ground state structure. In this work, we present the zero point structure obtained from the experimental rotational constants and an approach to determine the semi-experimental equilibrium structure aided by ab initio data. The Te-O bond length determined in the equilibrium structure is accurate to the picometer and can be used as a benchmark for computational methods treating relativistic effects. PMID- 30307201 TI - Zooming in on vibronic structure by lowest-value projection reconstructed 4D coherent spectroscopy. AB - A fundamental goal of chemical physics is an understanding of microscopic interactions in liquids at and away from equilibrium. In principle, this microscopic information is accessible by high-order and high-dimensionality nonlinear optical measurements. Unfortunately, the time required to execute such experiments increases exponentially with the dimensionality, while the signal decreases exponentially with the order of the nonlinearity. Recently, we demonstrated a non-uniform acquisition method based on radial sampling of the time-domain signal [W. O. Hutson et al., J. Phys. Chem. Lett. 9, 1034 (2018)]. The four-dimensional spectrum was then reconstructed by filtered back-projection using an inverse Radon transform. Here, we demonstrate an alternative reconstruction method based on the statistical analysis of different back projected spectra which results in a dramatic increase in sensitivity and at least a 100-fold increase in dynamic range compared to conventional uniform sampling and Fourier reconstruction. These results demonstrate that alternative sampling and reconstruction methods enable applications of increasingly high order and high-dimensionality methods toward deeper insights into the vibronic structure of liquids. PMID- 30307202 TI - Water nucleation in helium, methane, and argon: A molecular dynamics study. AB - Nucleation of highly supersaturated water vapor in helium, methane, and argon carrier gases at 350 K was investigated using molecular dynamics simulations. Nucleation rates obtained from the mean first passage time (MFPT) method are typically one order of magnitude lower than those from the Yasuoka and Matsumoto method, which can be attributed to the overestimation of the critical cluster size in the MFPT method. It was found that faster nucleation will occur in carrier gases that have better thermalization properties such that latent heat is removed more efficiently. These thermalization properties are shown to be strongly dependent on the molecular mass and Lennard-Jones (LJ) parameters. By varying the molecular mass, for unaltered LJ parameters, it was found that a heavier carrier gas removes less heat although it has a higher collision rate with water than a lighter carrier. Thus, it was shown that a clear distinction between water vapor-carrier gas collisions and water cluster-carrier gas collisions is indispensable for understanding the effect of collision rates on thermalization. It was also found that higher concentration of carrier gas leads to higher nucleation rate. The nucleation rates increased by a factor of 1.3 for a doubled concentration and by almost a factor of two for a tripled concentration. PMID- 30307203 TI - Rotational and translational dynamics and their relation to hydrogen bond lifetimes in an ionic liquid by means of NMR relaxation time experiments and molecular dynamics simulation. AB - We report a concerted theoretical and experimental effort to determine the reorientational dynamics as well as hydrogen bond lifetimes for the doubly ionic hydrogen bond +OH?O- in the ionic liquid (2-hydroxyethyl)trimethylammonium bis(trifluoromethylsulfonyl)imide [Ch][NTf2] by using a combination of NMR relaxation time experiments, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. Due to fast proton exchange, the determination of rotational correlation times is challenging. For molecular liquids, 17O-enhanced proton relaxation time experiments have been used to determine the rotational correlation times for the OH vectors in water or alcohols. As an alternative to those expensive isotopic substitution experiments, we employed a recently introduced approach which is providing access to the rotational dynamics from a single NMR deuteron quadrupolar relaxation time experiment. Here, the deuteron quadrupole coupling constants (DQCCs) are obtained from a relation between the DQCC and the delta 1H proton chemical shifts determined from a set of DFT calculated clusters in combination with experimentally determined proton chemical shifts. The NMR-obtained rotational correlation times were compared to those obtained from MD simulations and then related to viscosities for testing the applicability of popular hydrodynamic models. In addition, hydrogen bond lifetimes were derived, using hydrogen bond population correlation functions computed from MD simulations. Here, two different time domains were observed: The short-time contributions to the hydrogen lifetimes and the reorientational correlation times have roughly the same size and are located in the picosecond range, whereas the long-time contributions decay with relaxation times in the nanosecond regime and are related to rather slow diffusion processes. The computed average hydrogen bond lifetime is dominated by the long-time process, highlighting the importance and longevity of hydrogen-bonded ion pairs in these ionic liquids. PMID- 30307204 TI - Focus Article: Oscillatory and long-range monotonic exponential decays of electrostatic interactions in ionic liquids and other electrolytes: The significance of dielectric permittivity and renormalized charges. AB - A unified treatment of oscillatory and monotonic exponential decays of interactions in electrolytes is displayed, which highlights the role of dielectric response of the fluid in terms of renormalized (effective) dielectric permittivity and charges. An exact, but physically transparent statistical mechanical formalism is thereby used, which is presented in a systematic, pedagogical manner. Both the oscillatory and monotonic behaviors are given by an equation for the decay length of screened electrostatic interactions that is very similar to the classical expression for the Debye length. The renormalized dielectric permittivities, which have similar roles for electrolytes as the dielectric constant has for pure polar fluids, consist in general of several entities with different physical meanings. They are connected to dielectric response of the fluid on the same length scale as the decay length of the screened interactions. Only in cases where the decay length is very long, these permittivities correspond approximately to a dielectric response in the long wavelength limit, like the dielectric constant for polar fluids. Experimentally observed long-range exponentially decaying surface forces are analyzed as well as the oscillatory forces observed for short to intermediate surface separations. Both occur in some ionic liquids and in concentrated as well as very dilute electrolyte solutions. The coexisting modes of decay are in general determined by the bulk properties of the fluid and not by the solvation of the surfaces; in the present cases, they are given by the behavior of the screened Coulomb interaction of the bulk fluid. The surface-fluid interactions influence the amplitudes and signs or phases of the different modes of the decay, but not their decay lengths and wavelengths. The similarities between some ionic liquids and very dilute electrolyte solutions as regards both the long-range monotonic and the oscillatory decays are analyzed. PMID- 30307205 TI - Nonequilibrium thermodynamics and boundary conditions for reaction and transport in heterogeneous media. AB - Nonequilibrium interfacial thermodynamics is formulated in the presence of surface reactions for the study of diffusiophoresis in isothermal systems. As a consequence of microreversibility and Onsager-Casimir reciprocal relations, diffusiophoresis, i.e., the coupling of the tangential components of the pressure tensor to the concentration gradients of solute species, has a reciprocal effect where the interfacial currents of solutes are coupled to the slip velocity. The presence of surface reactions is shown to modify the diffusiophoretic and reciprocal effects at the fluid-solid interface. The thin-layer approximation is used to describe the solution flowing near a reactive solid interface. Analytic formulas describing the diffusiophoretic and reciprocal effects are deduced in the thin-layer approximation and tested numerically for the Poiseuille flow of a solution between catalytic planar surfaces. PMID- 30307206 TI - Local free energies for the coarse-graining of adsorption phenomena: The interacting pair approximation. AB - We investigate the coarse-graining of host-guest systems under the perspective of the local distribution of pore occupancies, along with the physical meaning and actual computability of the coarse-interaction terms. We show that the widely accepted approach, in which the contributions to the free energy given by the molecules located in two neighboring pores are estimated through Monte Carlo simulations where the two pores are kept separated from the rest of the system, leads to inaccurate results at high sorbate densities. In the coarse-graining strategy that we propose, which is based on the Bethe-Peierls approximation, density-independent interaction terms are instead computed according to local effective potentials that take into account the correlations between the pore pair and its surroundings by means of mean-field correction terms without the need for simulating the pore pair separately. Use of the interaction parameters obtained this way allows the coarse-grained system to reproduce more closely the equilibrium properties of the original one. Results are shown for lattice-gases where the local free energy can be computed exactly and for a system of Lennard Jones particles under the effect of a static confining field. PMID- 30307207 TI - Ion-ion correlations across and between electrified graphene layers. AB - When an ionic liquid adsorbs onto a porous electrode, its ionic arrangement is deeply modified due to a screening of the Coulombic interactions by the metallic surface and by the confinement imposed upon it by the electrode's morphology. In particular, ions of the same charge can approach at close contact, leading to the formation of a superionic state. The impact of an electrified surface placed between two liquid phases is much less understood. Here we simulate a full supercapacitor made of the 1-butyl-3-methylimidazolium hexafluorophosphate and nanoporous graphene electrodes, with varying distances between the graphene sheets. The electrodes are held at constant potential by allowing the carbon charges to fluctuate. Under strong confinement conditions, we show that ions of the same charge tend to adsorb in front of each other across the graphene plane. These correlations are allowed by the formation of a highly localized image charge on the carbon atoms between the ions. They are suppressed in larger pores, when the liquid adopts a bilayer structure between the graphene sheets. These effects are qualitatively similar to the recent templating effects which have been reported during the growth of nanocrystals on a graphene substrate. PMID- 30307208 TI - Structure and dynamics of mica-confined films of [C10C1Pyrr][NTf2] ionic liquid. AB - The structure of the ionic liquid 1-decyl-1-methylpyrrolidinium bis[(trifluoromethane)sulfonyl]imide, [C10C1Pyrr][NTf2], has been probed using Molecular Dynamics (MD) simulations. The simulations endeavour to model the behaviour of the ionic liquid in bulk isotropic conditions and also at interfaces and in confinement. The MD results have been confronted and validated with scattering and surface force experiments reported in the literature. The calculated structure factors, distribution functions, and density profiles were able to provide molecular and mechanistic insights into the properties of these long chain ionic liquids under different conditions, in particular those that lead to the formation of multi-layered ionic liquid films in confinement. Other properties inaccessible to experiment such as in-plane structures and relaxation rates within the films have also been analysed. Overall the work contributes structural and dynamic information relevant to many applications of ionic liquids with long alkyl chains, ranging from nanoparticle synthesis to lubrication. PMID- 30307209 TI - Calculation of strained BaTiO3 with different exchange correlation functionals examined with criterion by Ginzburg-Landau theory, uncovering expressions by crystallographic parameters. AB - In the calculations of tetragonal BaTiO3, some exchange-correlation (XC) energy functionals such as local density approximation (LDA) have shown good agreement with experiments at room temperature (RT), e.g., spontaneous polarization (P S), and superiority compared with other XC functionals. This is due to the error compensation of the RT effect and, hence, will be ineffective in the heavily strained case such as domain boundaries. Here, ferroelectrics under large strain at RT are approximated as those at 0 K because the strain effect surpasses the RT effects. To find effective XC energy functionals for strained BaTiO3, we propose a new comparison, i.e., a criterion. This criterion is the properties at 0 K given by the Ginzburg-Landau (GL) theory because GL theory is a thermodynamic description of experiments working under the same symmetry-constraints as ab initio calculations. With this criterion, we examine LDA, generalized gradient approximations (GGA), meta-GGA, meta-GGA + local correlation potential (U), and hybrid functionals, which reveals the high accuracy of some XC functionals superior to XC functionals that have been regarded as accurate. This result is examined directly by the calculations of homogenously strained tetragonal BaTiO3, confirming the validity of the new criterion. In addition, the data points of theoretical P S vs. certain crystallographic parameters calculated with different XC functionals are found to lie on a single curve, despite their wide variations. Regarding these theoretical data points as corresponding to the experimental results, analytical expressions of the local P S using crystallographic parameters are uncovered. These expressions show the primary origin of BaTiO3 ferroelectricity as oxygen displacements. Elastic compliance and electrostrictive coefficients are estimated. For the comparison of strained results, we show that the effective critical temperature T C under strain <-0.01 is >1000 K from an approximate method combining ab initio results with GL theory. In addition, in a definite manner, the present results show much more enhanced ferroelectricity at large strain than the previous reports. PMID- 30307210 TI - Structural analysis of zwitterionic liquids vs. homologous ionic liquids. AB - Zwitterionic liquids (Zw-ILs) have been developed that are homologous to monovalent ionic liquids (ILs) and show great promise for controlled dissolution of cellulosic biomass. Using both high energy X-ray scattering and atomistic molecular simulations, this article compares the bulk liquid structural properties for novel Zw-ILs with their homologous ILs. It is shown that the significant localization of the charges on Zw-ILs leads to charge ordering similar to that observed for conventional ionic liquids with monovalent anions and cations. A low-intensity first sharp diffraction peak in the liquid structure factor S(q) is observed for both the Zw-IL and the IL. This is unexpected since both the Zw-IL and IL have a 2-(2-methoxyethoxy)ethyl (diether) functional group on the cationic imidazolium ring and ether functional groups are known to suppress this peak. Detailed analyses show that this intermediate range order in the liquid structure arises for slightly different reasons in the Zw-IL vs. the IL. For the Zw-IL, the ether tails in the liquid are shown to aggregate into nanoscale domains. PMID- 30307211 TI - Efficient Brownian Dynamics of rigid colloids in linear flow fields based on the grand mobility matrix. AB - We present an efficient general method to simulate in the Stokesian limit the coupled translational and rotational dynamics of arbitrarily shaped colloids subject to external potential forces and torques, linear flow fields, and Brownian motion. The colloid's surface is represented by a collection of spherical primary particles. The hydrodynamic interactions between these particles, here approximated at the Rotne-Prager-Yamakawa level, are evaluated only once to generate the body's (11 * 11) grand mobility matrix. The constancy of this matrix in the body frame, combined with the convenient properties of quaternions in rotational Brownian Dynamics, enables an efficient simulation of the body's motion. Simulations in quiescent fluids yield correct translational and rotational diffusion behaviour and sample Boltzmann's equilibrium distribution. Simulations of ellipsoids and spherical caps under shear, in the absence of thermal fluctuations, yield periodic orbits in excellent agreement with the theories by Jeffery and Dorrepaal. The time-varying stress tensors provide the Einstein coefficient and viscosity of dilute suspensions of these bodies. PMID- 30307212 TI - Cation effect on small phosphonium based ionic liquid electrolytes with high concentrations of lithium salt. AB - Ionic liquid electrolytes with high alkali salt concentrations have displayed some excellent electrochemical properties, thus opening up the field for further improvements to liquid electrolytes for lithium or sodium batteries. Fundamental computational investigations into these high concentration systems are required in order to gain a better understanding of these systems, yet they remain lacking. Small phosphonium-based ionic liquids with high concentrations of alkali metal ions have recently shown many promising results in experimental studies, thereby prompting us to conduct further theoretical exploration of these materials. Here, we conducted a molecular dynamics simulation on four small phosphonium-based ionic liquids with 50 mol. % LiFSI salt, focusing on the effect of cation structure on local structuring and ion diffusional and rotational dynamics-which are closely related to the electrochemical properties of these materials. PMID- 30307213 TI - Associative desorption of hydrogen isotopologues from copper surfaces: Characterization of two reaction mechanisms. AB - We report quantum-state resolved measurements of angular and velocity distributions of the associative desorption of H2, HD, and D2 from Cu(111) and Cu(211) surfaces. The desorbing molecules have bimodal velocity distributions comprising a "fast" channel and a "slow" channel on both facets. The "fast channel" is promoted by both hydrogen incidence translational and vibrational energy, while the "slow channel" is promoted by vibrational energy but inhibited by translational energy. Using detailed balance, we determine state-specific reaction probabilities for dissociative adsorption and compare these to theoretical calculations. The results for the activation barrier for the "fast channel" on Cu(111) are in agreement with theory within "chemical accuracy" (1 kcal/mole). Results on the Cu(211) facet provide direct information on the effect of increasing step density, which is commonly believed to increase reactivity. Differences in reactivity on the (111) and (211) facets are subtle - quantum state specific reactivity on the (211) surface is characterized by a broader distribution of barrier heights whose average values are higher than for reaction on (111). We fully characterize the "slow channel," which has not been found in theoretical calculations although it makes up a large fraction of the reactivity in these experiments. PMID- 30307214 TI - Ionic liquids at the surface of graphite: Wettability and structure. AB - The aim of this work is to provide a better understanding of the interface between graphite and different molecular and ionic liquids. Experimental measurements of the liquid surface tension and of the graphite-liquid contact angle for sixteen ionic liquids and three molecular liquids are reported. These experimental values allowed the calculation of the solid/liquid interfacial energy that varies, for the ionic liquids studied, between 14.5 mN m-1 for 1 ethyl-3-methylimidazolium dicyanamide and 37.8 mN m-1 for 3-dodecyl-1-(naphthalen 1-yl)-1H-imidazol-3-ium tetrafluoroborate. Imidazolium-based ionic liquids with large alkyl side-chains or functionalized with benzyl groups seem to interact more favourably with freshly peeled graphite surfaces. Even if the interfacial energy seems a good descriptor to assess the affinity of a liquid for a carbon based solid material, we conclude that both the surface tension of the liquid and the contact angle between the liquid and the solid can be significant. Molecular dynamics simulations were used to investigate the ordering of the ions near the graphite surface. We conclude that the presence of large alkyl side-chains in the cations increases the ordering of ions at the graphite surface. Benzyl functional groups in the cations lead to a large affinity towards the graphite surface. PMID- 30307215 TI - DAVIS: A direct algorithm for velocity-map imaging system. AB - In this work, we report a direct (non-iterative) algorithm to reconstruct the three-dimensional (3D) momentum-space picture of any charged particles collected with a velocity-map imaging system from the two-dimensional (2D) projected image captured by a position-sensitive detector. The method consists of fitting the measured image with the 2D projection of a model 3D velocity distribution defined by the physics of the light-matter interaction. The meaningful angle-correlated information is first extracted from the raw data by expanding the image with a complete set of Legendre polynomials. Both the particle's angular and energy distributions are then directly retrieved from the expansion coefficients. The algorithm is simple, easy to implement, fast, and explicitly takes into account the pixelization effect in the measurement. PMID- 30307216 TI - Zero-point energy conservation in classical trajectory simulations: Application to H2CO. AB - A new approach for preventing zero-point energy (ZPE) violation in quasi classical trajectory (QCT) simulations is presented and applied to H2CO "roaming" reactions. Zero-point energy may be problematic in roaming reactions because they occur at or near bond dissociation thresholds and these channels may be incorrectly open or closed depending on if, or how, ZPE has been treated. Here we run QCT simulations on a "ZPE-corrected" potential energy surface defined as the sum of the molecular potential energy surface (PES) and the global harmonic ZPE surface. Five different harmonic ZPE estimates are examined with four, on average, giving values within 4 kJ/mol-chemical accuracy-for H2CO. The local harmonic ZPE, at arbitrary molecular configurations, is subsequently defined in terms of "projected" Cartesian coordinates and a global ZPE "surface" is constructed using Shepard interpolation. This, combined with a second-order modified Shepard interpolated PES, V, allows us to construct a proof-of-concept ZPE-corrected PES for H2CO, V eff, at no additional computational cost to the PES itself. Both V and V eff are used to model product state distributions from the H + HCO -> H2 + CO abstraction reaction, which are shown to reproduce the literature roaming product state distributions. Our ZPE-corrected PES allows all trajectories to be analysed, whereas, in previous simulations, a significant proportion was discarded because of ZPE violation. We find ZPE has little effect on product rotational distributions, validating previous QCT simulations. Running trajectories on V, however, shifts the product kinetic energy release to higher energy than on V eff and classical simulations of kinetic energy release should therefore be viewed with caution. PMID- 30307217 TI - A classical density functional theory for the asymmetric restricted primitive model of ionic liquids. AB - A new three-parameter (valency, ion size, and charge asymmetry) model, the asymmetric restricted primitive model (ARPM) of ionic liquids, has recently been proposed. Given that ionic liquids generally are composed of monovalent species, the ARPM effectively reduces to a two-parameter model. Monte Carlo (MC) simulations have demonstrated that the ARPM is able to reproduce key properties of room temperature ionic liquids (RTILs) in bulk and at charged surfaces. The relatively modest complexity of the model raises the possibility, which is explored here, that a classical density functional theory (DFT) could resolve its properties. This is relevant because it might generate great improvements in terms of both numerical efficiency and understanding in the continued research of RTILs and their applications. In this report, a DFT for rod-like molecules is proposed as an approximate theoretical tool for an ARPM fluid. Borrowing data on the ion pair fraction from a single bulk simulation, the ARPM is modelled as a mixture of dissociated ions and connected ion pairs. We have specifically studied an ARPM where the hard-sphere diameter is 5 A, with the charge located 1 A from the hard-sphere centre. We focus on fluid structure and electrochemical behaviour of this ARPM fluid, into which a model electrode is immersed. The latter is modelled as a perfect conductor, and surface polarization is handled by the method of image charges. Approximate methods, which were developed in an earlier study, to take image interactions into account, are also incorporated in the DFT. We make direct numerical comparisons between DFT predictions and corresponding simulation data. The DFT theory is implemented both in the normal mean field form with respect to the electrostatic interactions and in a correlated form based on hole formation by both steric repulsions and ion-ion Coulomb interactions. The results clearly show that ion-ion correlations play a very important role in the screening of the charged surfaces by our ARPM ionic liquid. We have studied electrostatic potentials and ion density profiles as well the differential capacitance. The mean-field DFT fails to reproduce these properties, but the inclusion of ion-ion correlation by a simple approximate treatment yields quite reasonable agreement with the corresponding simulation results. An interesting finding is that there appears to be a surface phase transition at relatively low surface charge which is readily explored by DFT, but seen also in the MC simulations at somewhat higher asymmetry. PMID- 30307218 TI - A shell-resolved analysis of preferential solvation of coffee ingredients in aqueous mixtures of the ionic liquid 1-ethyl-3-methylimidazolium acetate. AB - Ionic liquids increase the solubility of various coffee ingredients in aqueous solution but little is known about the underlying mechanism. Kirkwood-Buff integrals as well as the potential of mean force indicate that the imidazolium cations are accumulated at the surface of the solutes, removing water molecules from the solute surface. Although hydrogen bonding of the anions to hydroxy groups of the solutes can be detected, their concentration at the surface is less enhanced compared to the cations. The decomposition into solvation shells by Voronoi tessellation reveals that structural features are only observed in the first solvation shell. Nevertheless, the depletion of water and the excess concentration of the ions and, in particular, of the cations are visible in the next solvation shells as well. Therefore, classical arguments of hydrotropic theory fail to explain this behavior. PMID- 30307219 TI - Ultrafast photodissociation dynamics of 1,4-diiodobenzene. AB - The photodissociation dynamics of 1,4-diiodobenzene is investigated using ultrafast time-resolved photoelectron spectroscopy. Following excitation by laser pulses at 271 nm, the excited-state dynamics is probed by resonance-enhanced multiphoton ionization with 405 nm probe pulses. A progression of Rydberg states, which come into resonance sequentially, provide a fingerprint of the dissociation dynamics of the molecule. The initial excitation decays with a lifetime of 33 +/- 4 fs, in good agreement with a previous study. The spectrum is interpreted by reference to ab initio calculations at the CASPT2(18,14) level, including spin orbit coupling. We propose that both the 5B1 and 6B1 states are excited initially, and based on the calculations, we identify diabatic spin-orbit coupled states corresponding to the main dissociation pathways. PMID- 30307220 TI - Linear response approach to active Brownian particles in time-varying activity fields. AB - In a theoretical and simulation study, active Brownian particles (ABPs) in three dimensional bulk systems are exposed to time-varying sinusoidal activity waves that are running through the system. A linear response (Green-Kubo) formalism is applied to derive fully analytical expressions for the torque-free polarization profiles of non-interacting particles. The activity waves induce fluxes that strongly depend on the particle size and may be employed to de-mix mixtures of ABPs or to drive the particles into selected areas of the system. Three dimensional Langevin dynamics simulations are carried out to verify the accuracy of the linear response formalism, which is shown to work best when the particles are small (i.e., highly Brownian) or operating at low activity levels. PMID- 30307221 TI - Nanostructure of propylammonium nitrate in the presence of poly(ethylene oxide) and halide salts. AB - Nanoscale structure of protic ionic liquids is critical to their utility as molecular electrochemical solvents since it determines the capacity to dissolve salts and polymers such as poly(ethylene oxide) (PEO). Here we use quantum chemical molecular dynamics simulations to investigate the impact of dissolved halide anions on the nanostructure of an archetypal nanostructured protic ionic liquid, propylammonium nitrate (PAN), and how this impacts the solvation of a model PEO polymer. At the molecular level, PAN is nanostructured, consisting of charged/polar and uncharged/nonpolar domains. The charged domain consists of the cation/anion charge groups, and is formed by their electrostatic interaction. This domain solvophobically excludes the propyl chains on the cation, which form a distinct, self-assembled nonpolar domain within the liquid. Our simulations demonstrate that the addition of Cl- and Br- anions to PAN disrupts the structure within the PAN charged domain due to competition between nitrate and halide anions for the ammonium charge centre. This disruption increases with halide concentration (up to 10 mol. %). However, at these concentrations, halide addition has little effect on the structure of the PAN nonpolar domain. Addition of PEO to pure PAN also disrupts the structure within the charged domain of the liquid due to hydrogen bonding between the charge groups and the terminal PEO hydroxyl groups. There is little other association between the PEO structure and the surrounding ionic liquid solvent, with strong PEO self-interaction yielding a compact, coiled polymer morphology. Halide addition results in greater association between the ionic liquid charge centres and the ethylene oxide components of the PEO structure, resulting in reduced conformational flexibility, compared to that observed in pure PAN. Similarly, PEO self-interactions increase in the presence of Cl- and Br- anions, compared to PAN, indicating that the addition of halide salts to PAN decreases its utility as a molecular solvent for polymers such as PEO. PMID- 30307222 TI - Communication: Diffusion constant in supercooled water as the Widom line is crossed in no man's land. AB - According to the liquid-liquid critical point (LLCP) hypothesis, there are two distinct phases of supercooled liquid water, namely, high-density liquid and low density liquid, separated by a coexistence line that terminates in an LLCP. If the LLCP is real, it is located within No Man's Land (NML), the region of the metastable phase diagram that is difficult to access using conventional experimental techniques due to rapid homogeneous nucleation to the crystal. However, a recent ingenious experiment has enabled measurement of the diffusion constant deep inside NML. In the current communication, these recent measurements are compared, with good agreement, to the diffusion constant of E3B3 water, a classical water model that explicitly includes three-body interactions. The behavior of the diffusion constant as the system crosses the Widom line (the extension of the liquid-liquid coexistence line into the one-phase region) is analyzed to derive information about the presence and location of the LLCP. Calculations over a wide range of temperatures and pressures show that the new experimental measurements are consistent with an LLCP having a critical pressure of over 0.6 kbar. PMID- 30307224 TI - Heterogeneous dynamics of ionic liquids: A four-point time correlation function approach. AB - Many ionic liquids show behavior similar to that of glassy systems, e.g., large and long-lasted deviations from Gaussian dynamics and clustering of "mobile" and "immobile" groups of ions. Herein a time-dependent four-point density correlation function-typically used to characterize glassy systems-is implemented for the ionic liquids, choline acetate, and 1-butyl-3-methylimidazolium acetate. Dynamic correlation beyond the first ionic solvation shell on the time scale of nanoseconds is found in the ionic liquids, revealing the cooperative nature of ion motions. The traditional solvent, acetonitrile, on the other hand, shows a much shorter length-scale that decays after a few picoseconds. PMID- 30307223 TI - Probing spatial locality in ionic liquids with the grand canonical adaptive resolution molecular dynamics technique. AB - We employ the Grand Canonical Adaptive Resolution Simulation (GC-AdResS) molecular dynamics technique to test the spatial locality of the 1-ethyl 3-methyl imidazolium chloride liquid. In GC-AdResS, atomistic details are kept only in an open sub-region of the system while the environment is treated at coarse-grained level; thus, if spatial quantities calculated in such a sub-region agree with the equivalent quantities calculated in a full atomistic simulation, then the atomistic degrees of freedom outside the sub-region play a negligible role. The size of the sub-region fixes the degree of spatial locality of a certain quantity. We show that even for sub-regions whose radius corresponds to the size of a few molecules, spatial properties are reasonably reproduced thus suggesting a higher degree of spatial locality, a hypothesis put forward also by other researchers and that seems to play an important role for the characterization of fundamental properties of a large class of ionic liquids. PMID- 30307225 TI - A theoretical investigation on Cu/Ag/Au bonding in XH2P?MY(X = H, CH3, F, CN, NO2; M = Cu, Ag, Au; Y = F, Cl, Br, I) complexes. AB - Intermolecular interaction of XH2P...MY (X = H, CH3, F, CN, NO2; M = Cu, Ag, Au; Y = F, Cl, Br, I) complexes was investigated by means of an ab initio method. The molecular interaction energies are in the order Ag < Cu < Au and increased with the decrease of RP...M. Interaction energies are strengthened when electron donating substituents X connected to XH2P, while electron-withdrawing substituents produce the opposite effect. The strongest P...M bond was found in CH3H2P...AuF with -70.95 kcal/mol, while the weakest one was found in NO2H2P...AgI with -20.45 kcal/mol. The three-center/four-electron (3c/4e) resonance-type of P:-M-:Y hyperbond was recognized by the natural resonance theory and the natural bond orbital analysis. The competition of P:M-Y <-> P-M:Y resonance structures mainly arises from hyperconjugation interactions; the bond order of bP-M and bM-Y is in line with the conservation of the idealized relationship bP-M + bM-Y ~ 1. In all MF-containing complexes, P-M:F resonance accounted for a larger proportion which leads to the covalent characters for partial ionicity of MF. The interaction energies of these Cu/Ag/Au complexes are basically above the characteristic values of the halogen-bond complexes and close to the observed strong hydrogen bonds in ionic hydrogen-bonded species. PMID- 30307226 TI - Experimental validation of calculated atomic charges in ionic liquids. AB - A combination of X-ray photoelectron spectroscopy and near edge X-ray absorption fine structure spectroscopy has been used to provide an experimental measure of nitrogen atomic charges in nine ionic liquids (ILs). These experimental results are used to validate charges calculated with three computational methods: charges from electrostatic potentials using a grid-based method (ChelpG), natural bond orbital population analysis, and the atoms in molecules approach. By combining these results with those from a previous study on sulfur, we find that ChelpG charges provide the best description of the charge distribution in ILs. However, we find that ChelpG charges can lead to significant conformational dependence and therefore advise that small differences in ChelpG charges (<0.3 e) should be interpreted with care. We use these validated charges to provide physical insight into nitrogen atomic charges for the ILs probed. PMID- 30307227 TI - Synthesis of the zeolitic imidazolate framework ZIF-4 from the ionic liquid 1 butyl-3-methylimidazolium imidazolate. AB - A new synthesis route for the zeolitic imidazolate framework ZIF-4 using imidazolium imidazolate is reported. Additionally, the ionic liquid-derived material is compared to conventional ZIF-4 with respect to the powder X-ray diffraction pattern pattern, nitrogen uptake, particle size, and separation potential for olefin/paraffin gas mixtures. Higher synthesis yields were obtained, and the different particle size affected the performance in the separation of ethane and ethylene. PMID- 30307228 TI - Thermodynamics and proton activities of protic ionic liquids with quantum cluster equilibrium theory. AB - We applied the binary Quantum Cluster Equilibrium (bQCE) method to a number of alkylammonium-based protic ionic liquids in order to predict boiling points, vaporization enthalpies, and proton activities. The theory combines statistical thermodynamics of van-der-Waals-type clusters with ab initio quantum chemistry and yields the partition functions (and associated thermodynamic potentials) of binary mixtures over a wide range of thermodynamic phase points. Unlike conventional cluster approaches that are limited to the prediction of thermodynamic properties, dissociation reactions can be effortlessly included into the bQCE formalism, giving access to ionicities, as well. The method is open to quantum chemical methods at any level of theory, but combination with low-cost composite density functional theory methods and the proposed systematic approach to generate cluster sets provides a computationally inexpensive and mostly parameter-free way to predict such properties at good-to-excellent accuracy. Boiling points can be predicted within an accuracy of 50 K, reaching excellent accuracy for ethylammonium nitrate. Vaporization enthalpies are predicted within an accuracy of 20 kJ mol-1 and can be systematically interpreted on a molecular level. We present the first theoretical approach to predict proton activities in protic ionic liquids, with results fitting well into the experimentally observed correlation. Furthermore, enthalpies of vaporization were measured experimentally for some alkylammonium nitrates and an excellent linear correlation with vaporization enthalpies of their respective parent amines is observed. PMID- 30307230 TI - A comparison of choline:urea and choline:oxalic acid deep eutectic solvents at 338 K. AB - 1:2 choline chloride:urea and 1:1 choline chloride:oxalic acid deep eutectic solvents are compared at 338 K using liquid-phase neutron diffraction with H/D isotopic substitution to obtain differential neutron scattering cross sections and fitting of models to the experimental data using Empirical Potential Structure Refinement. In comparison to the previously reported study of choline chloride:urea at 303 K, we observed significant weakening and lengthening of choline-OH?Cl- and choline-OH?hydrogen-bond acceptor correlations. PMID- 30307231 TI - Nanoprobe diffusion in entangled polymer solutions: Linear vs. unconcatenated ring chains. AB - We employ large-scale molecular dynamics computer simulations to study the problem of nanoprobe diffusion in entangled solutions of linear polymers and unknotted and unconcatenated circular (ring) polymers. By tuning both the diameter of the nanoprobe and the density of the solution, we show that nanoprobes of diameter smaller than the entanglement distance (tube diameter) of the solution display the same (Rouse-like) behavior in solutions of both polymer architectures. Instead, nanoprobes with larger diameters appear to diffuse markedly faster in solutions of rings than in solutions of linear chains. Finally, by analysing the distribution functions of spatial displacements, we find that nanoprobe motion in rings' solutions shows both Gaussian and ergodic behaviors, in all regimes considered, while, in solutions of linear chains, nanoprobes exceeding the size of the tube diameter show a transition to non Gaussian and non-ergodic motion. Our results emphasize the role of chain architecture in the motion of nanoprobes dispersed in polymer solutions. PMID- 30307232 TI - On the issue of closed versus open forms of gamma-aminobutyric acid (GABA) in water: Ab initio molecular dynamics and metadynamics studies. AB - Gamma-aminobutyric acid (GABA), a primary neurotransmitter, accomplishes its activities by binding to different receptor sites in different conformations. It is known to have two major conformers: the closed and open forms. Earlier studies on preferred conformation of GABA in water revealed differing results with some reporting the open form while others inferring the closed form to be more stable. We found the existence of many open forms and only one closed form of GABA in water through ab initio metadynamics simulation. Some of the open conformers are equally or more stable while others are less stable than the closed form. Free energy barriers reveal that different conformers are interconvertible at room temperature in typical experimental time scales. Ab initio molecular dynamics simulations are performed to further investigate the inter-conversion of various conformers of GABA in water and their dipole moments and also to make connections to experiments on the conformation of GABA in water. PMID- 30307229 TI - Explicit ions/implicit water generalized Born model for nucleic acids. AB - The ion atmosphere around highly charged nucleic acid molecules plays a significant role in their dynamics, structure, and interactions. Here we utilized the implicit solvent framework to develop a model for the explicit treatment of ions interacting with nucleic acid molecules. The proposed explicit ions/implicit water model is based on a significantly modified generalized Born (GB) model and utilizes a non-standard approach to define the solute/solvent dielectric boundary. Specifically, the model includes modifications to the GB interaction terms for the case of multiple interacting solutes-disconnected dielectric boundary around the solute-ion or ion-ion pairs. A fully analytical description of all energy components for charge-charge interactions is provided. The effectiveness of the approach is demonstrated by calculating the potential of mean force for Na+-Cl- ion pair and by carrying out a set of Monte Carlo (MC) simulations of mono- and trivalent ions interacting with DNA and RNA duplexes. The monovalent (Na+) and trivalent (CoHex3+) counterion distributions predicted by the model are in close quantitative agreement with all-atom explicit water molecular dynamics simulations used as reference. Expressed in the units of energy, the maximum deviations of local ion concentrations from the reference are within k B T. The proposed explicit ions/implicit water GB model is able to resolve subtle features and differences of CoHex distributions around DNA and RNA duplexes. These features include preferential CoHex binding inside the major groove of the RNA duplex, in contrast to CoHex biding at the "external" surface of the sugar-phosphate backbone of the DNA duplex; these differences in the counterion binding patters were earlier shown to be responsible for the observed drastic differences in condensation propensities between short DNA and RNA duplexes. MC simulations of CoHex ions interacting with the homopolymeric poly(dA.dT) DNA duplex with modified (de-methylated) and native thymine bases are used to explore the physics behind CoHex-thymine interactions. The simulations suggest that the ion desolvation penalty due to proximity to the low dielectric volume of the methyl group can contribute significantly to CoHex-thymine interactions. Compared to the steric repulsion between the ion and the methyl group, the desolvation penalty interaction has a longer range and may be important to consider in the context of methylation effects on DNA condensation. PMID- 30307233 TI - Lattice model of ionic liquid confined by metal electrodes. AB - We study, using Monte Carlo simulations, the density profiles and differential capacitance of ionic liquids confined by metal electrodes. To compute the electrostatic energy, we use the recently developed approach based on periodic Green's functions. The method also allows us to easily calculate the induced charge on the electrodes permitting an efficient implementation of simulations in a constant electrostatic potential ensemble. To speed up the simulations further, we model the ionic liquid as a lattice Coulomb gas and precalculate the interaction potential between the ions. We show that the lattice model captures the transition between camel-shaped and bell-shaped capacitance curves-the latter characteristic of ionic liquids (strong coupling limit) and the former of electrolytes (weak coupling). We observe the appearance of a second peak in the differential capacitance at ~0.5 V for 2:1 ionic liquids, as the packing fraction is increased. Finally, we show that ionic size asymmetry decreases substantially the capacitance maximum, when all other parameters are kept fixed. PMID- 30307234 TI - A comment on the position dependent diffusion coefficient representation of structural heterogeneity. AB - Experimental studies of the variation of the mean square displacement (MSD) of a particle in a confined colloid suspension that exhibits density variations on the scale length of the particle diameter are not in agreement with the prediction that the spatial variation in MSD should mimic the spatial variation in density. The predicted behavior is derived from the expectation that the MSD of a particle depends on the system density and the assumption that the force acting on a particle is a point function of position. The experimental data are obtained from studies of the MSDs of particles in narrow ribbon channels and between narrowly spaced parallel plates and from new data, reported herein, of the radial and azimuthal MSDs of a colloid particle in a dense colloid suspension confined to a small circular cavity. In each of these geometries, a dense colloid suspension exhibits pronounced density oscillations with spacing of a particle diameter. We remove the discrepancy between prediction and experiment using the Fisher Methfessel interpretation of how local equilibrium in an inhomogeneous system is maintained to argue that the force acting on a particle is delocalized over a volume with radius equal to a particle diameter. Our interpretation has relevance to the relationship between the scale of inhomogeneity and the utility of translation of the particle MSD into a position dependent diffusion coefficient and to the use of a spatially dependent diffusion coefficient to describe mass transport in a heterogeneous system. PMID- 30307235 TI - Communication: From close-packed to topologically close-packed: Formation of Laves phases in moderately polydisperse hard-sphere mixtures. AB - Particle size polydispersity can help to inhibit crystallization of the hard sphere fluid into close-packed structures at high packing fractions and thus is often employed to create model glass-forming systems. Nonetheless, it is known that hard-sphere mixtures with modest polydispersity still have ordered ground states. Here, we demonstrate by computer simulation that hard-sphere mixtures with increased polydispersity fractionate on the basis of particle size and a bimodal subpopulation favors the formation of topologically close-packed C14 and C15 Laves phases in coexistence with a disordered phase. The generality of this result is supported by simulations of hard-sphere mixtures with particle-size distributions of four different forms. PMID- 30307236 TI - Note: Maximum hardness and minimum electrophilicity principles. AB - We provide new arguments supporting the validity of the maximum hardness and the minimum electrophilicity principles, considering the overall change of these descriptors in a charge-transfer reaction. We analyze two cases: (a) how the reactivity is affected when we perturb one reagent, keeping the other constant; (b) how the hardness and electrophilicity change when we treat the interaction between the reagents as a perturbation. PMID- 30307237 TI - Finding the best density functional approximation to describe interaction energies and structures of ionic liquids in molecular dynamics studies. AB - Ionic liquids raise interesting but complicated questions for theoretical investigations due to the fact that a number of different inter-molecular interactions, e.g., hydrogen bonding, long-range Coulomb interactions, and dispersion interactions, need to be described properly. Here, we present a detailed study on the ionic liquids ethylammonium nitrate and 1-ethyl-3 methylimidazolium acetate, in which we compare different dispersion corrected density functional approximations to accurate local coupled cluster data in static calculations on ionic liquid clusters. The efficient new composite method B97-3c is tested and has been implemented in CP2K for future studies. Furthermore, tight-binding based approaches which may be used in large scale simulations are assessed. Subsequently, ab initio as well as classical molecular dynamics simulations are conducted and structural analyses are presented in order to shed light on the different short- and long-range structural patterns depending on the method and the system size considered in the simulation. Our results indicate the presence of strong hydrogen bonds in ionic liquids as well as the aggregation of alkyl side chains due to dispersion interactions. PMID- 30307238 TI - Quantum transition probabilities during a perturbing pulse: Differences between the nonadiabatic results and Fermi's golden rule forms. AB - For a perturbed quantum system initially in the ground state, the coefficient ck(t) of excited state k in the time-dependent wave function separates into adiabatic and nonadiabatic terms. The adiabatic term ak(t) accounts for the adjustment of the original ground state to form the new ground state of the instantaneous Hamiltonian H(t), by incorporating excited states of the unperturbed Hamiltonian H0 without transitions; ak(t) follows the adiabatic theorem of Born and Fock. The nonadiabatic term bk(t) describes excitation into another quantum state k; bk(t) is obtained as an integral containing the time derivative of the perturbation. The true transition probability is given by bk(t) 2, as first stated by Landau and Lifshitz. In this work, we contrast bk(t) 2 and ck(t) 2. The latter is the norm-square of the entire excited-state coefficient which is used for the transition probability within Fermi's golden rule. Calculations are performed for a perturbing pulse consisting of a cosine or sine wave in a Gaussian envelope. When the transition frequency omegak0 is on resonance with the frequency omega of the cosine wave, bk(t) 2 and ck(t) 2 rise almost monotonically to the same final value; the two are intertwined, but they are out of phase with each other. Off resonance (when omegak0 ? omega), bk(t) 2 and ck(t) 2 differ significantly during the pulse. They oscillate out of phase and reach different maxima but then fall off to equal final values after the pulse has ended, when ak(t) = 0. If omegak0 < omega, bk(t) 2 generally exceeds ck(t) 2, while the opposite is true when omegak0 > omega. While the transition probability is rising, the midpoints between successive maxima and minima fit Gaussian functions of the form a exp[-b(t - d)2]. To our knowledge, this is the first analysis of nonadiabatic transition probabilities during a perturbing pulse. PMID- 30307239 TI - Deriving uniform semiclassical approximations for one-dimensional fermionic systems. AB - A complete derivation is provided of the uniform semiclassical approximations to the particle and kinetic energy densities of N noninteracting bounded fermions in one dimension. The employed methodology allows the inclusion of non-perturbative quantum effects, including tunneling and quantum oscillations, via an infinite resummation of the Poisson summation formula. We explore the analytic behavior, physical meaning, and the relationship between the semiclassical uniform approximations for the fermionic kinetic energy and particle densities. PMID- 30307240 TI - Free energy of adhesion of lipid bilayers on silica surfaces. AB - The free energy of adhesion per unit area (hereafter referred to as the adhesion strength) of lipid arrays on surfaces is a key parameter that determines the nature of the interaction between materials and biological systems. Here we report classical molecular simulations of water and 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) lipid bilayers at model silica surfaces with a range of silanol densities and structures. We employ a novel technique that enables us to estimate the adhesion strength of supported lipid bilayers in the presence of water. We find that silanols on the silica surface form hydrogen bonds with water molecules and that the water immersion enthalpy for all surfaces varies linearly with the surface density of these hydrogen bonds. The adhesion strength of lipid bilayers is a linear function of the surface density of hydrogen bonds formed between silanols and the lipid molecules on crystalline surfaces. Approximately 20% of isolated silanols form such bonds but more than 99% of mutually interacting geminal silanols do not engage in hydrogen bonding with water. On amorphous silica, the bilayer displays much stronger adhesion than expected from the crystalline surface data. We discuss the implications of these results for nanoparticle toxicity. PMID- 30307241 TI - Generalized Breit-Wigner treatment of molecular transport: Charging effects in a single decanedithiol molecule. AB - We examine the relative contribution of ballistic and elastic cotunneling mechanisms to the charge transport through a single decanedithiol molecule linked to two terminal clusters of gold atoms. For this, we first introduced a conceptual model that permits a generalization of the Breit-Wigner scattering formalism where the cation, anion, and neutral forms of the molecule can participate with different probabilities of the charge transfer process, but in a simultaneous manner. We used a density functional theory treatment and considered the fixed geometry of each charge state to calculate the corresponding eigenvalues and eigenvectors of the extended system for different values of the external electric field. We have found that for the ballistic transport the HOMO and LUMO of the neutral species play a key role, while the charged states give a negligible contribution. On the other hand, an elastic cotunneling charge transfer can occur whenever a molecular orbital (MO) of the cation or anion species, even if localized in just one side of the molecule-gold clusters complex, has energy close to that of a delocalized MO of the neutral species. Under these conditions, a conduction channel is formed throughout the entire system, in a process that is controlled by the degree of resonance between the MOs involved. Our results indicate that while different charge transfer mechanisms contribute to the overall charge transport, quantum effects such as avoided-crossing situations between relevant frontier MOs can be of special importance. In these specific situations, the interchange of spatial localization of two MOs involved in the crossing can open a new channel of charge transfer that otherwise would not be available. PMID- 30307242 TI - Dielectric response and transport properties of alkylammonium formate ionic liquids. AB - Dielectric relaxation spectra of three members of the alkylammonium formate family of protic ionic liquids (PILs), namely, ethylammonium formate (EAF), n butylammonium formate (BuAF), and n-pentylammonium formate (PeAF), as well as the pseudo-PIL triethylamine + formic acid (molar ratio 1:2; TEAF) have been studied over a wide frequency (50 MHz to 89 GHz) and temperature range (5-65 degrees C), complemented by measurements of their density, viscosity, and conductivity. It turned out that the dominating relaxation of EAF, BuAF, and PeAF arises from both cation and anion reorientations which are synchronized in their dynamics due to hydrogen bonding. Amplitudes and relaxation times of this mode reflect the compared to nitrate-different nature of H bonding between the formate anion and ethylammonium cation, as well as increasing segregation of the PIL structure into polar and non-polar domains. The TEAF data suggest that its dominating relaxation is due to the rotation of the complex triethylamine?(formic acid)2 in which no significant proton transfer to an ion pair occurred. Weak dissociation of this complex into ions was postulated to account for the high conductivity of TEAF. PMID- 30307243 TI - Effects of aromaticity in cations and their functional groups on the temperature dependence of low-frequency spectrum. AB - In this study, we investigate the temperature dependence of low-frequency spectra in the frequency range of 0.3-200 cm-1 for ionic liquids (ILs) whose cations possess two systematically different cyclic groups, using femtosecond Raman induced Kerr effect spectroscopy. The target ILs are bis(trifluoromethylsulfonyl)amide [NTf2]- salts of 1-cyclohexylmethyl-1 methylpyrrolidinium [CHxmMPyrr]+, 1-cyclohexylmethyl-3-methylimidazolium [CHxmMIm]+, N-cyclohexylmethylpyridinium [CHxmPy]+, 1-benzyl-1 methylpyrrolidinium [BzMPyrr]+, 1-benzyl-3-methylimidazolium [BzMIm]+, and N benzylpyridinium [BzPy]+ cations. The aim of this study is to better understand the effects of aromaticity in the cations' constituent groups on the temperature dependent low-frequency spectral features of the ILs. The low-frequency spectra of these ILs are temperature dependent, but the temperature-dependent spectrum of [CHxmMPyrr][NTf2] is different from that of other ILs. While [CHxmMPyrr][NTf2] shows spectral changes with temperature in the low-frequency region below 50 cm 1, the other ILs also show spectral changes in the high-frequency region above 80 cm-1 (above 50 cm-1 in the case of [BzMPyrr][NTf2]). We conclude that the spectral change in the low-frequency region is due to both the cation and anion, while the change in the high-frequency region is attributed to the red shift of the aromatic ring librations. On the basis of the plots of the first moment of the spectra vs. temperature, we found that the first moment of the low-frequency spectrum of the IL whose cation does not have an aromatic ring is less temperature dependent than that of the other ILs. However, the intrinsic first moment, the first moment at 0 K, of the low-frequency spectrum is governed by the absence or presence of a charged aromatic group, while a neutral aromatic group does not have much influence on determining the intrinsic first moment. PMID- 30307244 TI - The 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)-imide ionic liquid nanodroplets on solid surfaces and in electric field: A molecular dynamics simulation study. AB - Atomistic molecular dynamics simulations were conducted to study the wetting states of 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)-imide ionic liquid (IL) nanodroplets on surfaces with different strengths of van der Waals (VDW) interactions and in the presence of an electric field. By adjusting the depth of Lennard-Jones potential, the van der Waals interaction between the solid surface and ionic liquid was systematically varied. The shape of the droplets was analyzed to extract the corresponding contact angle utilized to characterize wetting states of the nanodroplets. The explored range of surface-IL interactions allowed contact angles ranging from complete IL spreading on the surface to poor wettability. The effect of the external electrical field was explored by adding point charges to the surface atoms. Systems with two charge densities (+/-0.002 e/atom and +/-0.004 e/atom) that correspond to 1.36 V/nm and 2.72 V/nm electric fields were investigated. Asymmetrical wetting states were observed for both cases. At 1.36 V/nm electric field, contributions of IL-surface VDW interactions and Coulombic interactions to the wetting state were competitive. At 2.72 V/nm field, electrostatic interactions dominate the interaction between the nanodroplet and surface, leading to enhanced wettability on all surfaces. PMID- 30307245 TI - Incremental viscosity by non-equilibrium molecular dynamics and the Eyring model. AB - The viscoelastic behavior of sheared fluids is calculated by Non-Equilibrium Molecular Dynamics (NEMD) simulation, and complementary analytic solutions of a time-dependent extension of Eyring's model (EM) for shear thinning are derived. It is argued that an "incremental viscosity," eta i , or IV which is the derivative of the steady state stress with respect to the shear rate is a better measure of the physical state of the system than the conventional definition of the shear rate dependent viscosity (i.e., the shear stress divided by the strain rate). The stress relaxation function, C i (t), associated with eta i is consistent with Boltzmann's superposition principle and is computed by NEMD and the EM. The IV of the Eyring model is shown to be a special case of the Carreau formula for shear thinning. An analytic solution for the transient time correlation function for the EM is derived. An extension of the EM to allow for significant local shear stress fluctuations on a molecular level, represented by a gaussian distribution, is shown to have the same analytic form as the original EM but with the EM stress replaced by its time and spatial average. Even at high shear rates and on small scales, the probability distribution function is almost gaussian (apart from in the wings) with the peak shifted by the shear. The Eyring formula approximately satisfies the Fluctuation Theorem, which may in part explain its success in representing the shear thinning curves of a wide range of different types of chemical systems. PMID- 30307246 TI - Dynamical heterogeneities of rotational motion in room temperature ionic liquids evidenced by molecular dynamics simulations. AB - Room temperature ionic liquids (RTILs) have been shown to exhibit spatial heterogeneity or structural heterogeneity in the sense that they form hydrophobic and ionic domains. Yet studies of the relationship between this structural heterogeneity and the ~picosecond motion of the molecular constituents remain limited. In order to obtain insight into the time scales relevant to this structural heterogeneity, we perform molecular dynamics simulations of a series of RTILs. To investigate the relationship between the structures, i.e., the presence of hydrophobic and ionic domains, and the dynamics, we gradually increase the size of the hydrophobic part of the cation from ethylammonium nitrate (EAN), via propylammonium nitrate (PAN), to butylammonium nitrate (BAN). The two ends of the organic cation, namely, the charged Nhead-H group and the hydrophobic Ctail-H group, exhibit rotational dynamics on different time scales, evidencing dynamical heterogeneity. The dynamics of the Nhead-H group is slower because of the strong coulombic interaction with the nitrate counter-ionic anions, while the dynamics of the Ctail-H group is faster because of the weaker van der Waals interaction with the surrounding atoms. In particular, the rotation of the Nhead-H group slows down with increasing cationic chain length, while the rotation of the Ctail-H group shows little dependence on the cationic chain length, manifesting that the dynamical heterogeneity is enhanced with a longer cationic chain. The slowdown of the Nhead-H group with increasing cationic chain length is associated with a lower number of nitrate anions near the Nhead-H group, which presumably results in the increase of the energy barrier for the rotation. The sensitivity of the Nhead-H rotation to the number of surrounding nitrate anions, in conjunction with the varying number of nitrate anions, gives rise to a broad distribution of Nhead-H reorientation times. Our results suggest that the asymmetry of the cations and the larger excluded volume for longer cationic chain are important for both the structural heterogeneity and the dynamical heterogeneities. The observed dynamical heterogeneities may affect the rates of chemical reactions depending on where the reactants are solvated in ionic liquids and provide an additional guideline for the design of RTILs as solvents. PMID- 30307247 TI - Novel phases and superconductivity of tin sulfide compounds. AB - Tin sulfides, Sn x S y , are an important class of materials that are actively investigated as novel photovoltaic and water splitting materials. A first principles evolutionary crystal structure search is performed with the goal of constructing the complete phase diagram of Sn x S y and discovering new phases as well as new compounds of varying stoichiometry at ambient conditions and pressures up to 100 GPa. The ambient phase of SnS2 with P3-m1 symmetry remains stable up to 28 GPa. Another ambient phase, SnS, experiences a series of phase transformations including alpha-SnS to beta-SnS at 9 GPa, followed by beta-SnS to gamma-SnS at 40 GPa. gamma-SnS is a new high-pressure metallic phase with Pm3-m space group symmetry stable up to 100 GPa, which becomes a superconductor with a maximum T c = 9.74 K at 40 GPa. Another new metallic compound, Sn3S4 with I4-3d space group symmetry, is predicted to be stable at pressures above 15 GPa, which also becomes a superconductor with relatively high T c = 21.9 K at 30 GPa. PMID- 30307248 TI - Relaxation times measurement in single and multiply excited xenon clusters. AB - Direct measurement of the rates of nonradiative relaxation processes in electronically excited xenon clusters was carried out. The clusters were created in a pulsed supersonic beam and two-photon excited by femtosecond laser pulses with a wavelength of 263 nm. The measurements were performed using the pump-probe method and electron spectroscopy. It is shown that relaxation of light clusters XeN (N < 15) predominantly occurs by desorption of excited xenon atoms with a characteristic time constant of 3 ps. Heavier electronically excited clusters (N > 10) vibrationally relax to the lowest electronically excited state at a rate of about 0.075 eV/ps. Multiply excited clusters are deactivated via energy exchange between excited centers with the ionization of one of them. The production of electrons in this process occurs with a delay of ~4 ps from the pump pulse, and the process is completed in 10 ps. PMID- 30307249 TI - Dynamic and structural evidence of mesoscopic aggregation in phosphonium ionic liquids. AB - Mesoscopic aggregation in aprotic ionic liquids due to the microphase separation of polar and non-polar components is expected to correlate strongly with the physicochemical properties of ionic liquids and therefore their potential applications. The most commonly cited experimental evidence of such aggregation is the observation of a low-q pre-peak in the x-ray and neutron scattering profiles, attributed to the polarity alternation of polar and apolar phases. In this work, a homologous series of phosphonium ionic liquids with the bis(trifluoromethylsulfonyl)imide anion and systematically varying alkyl chain lengths on the phosphonium cation are investigated by small and wide-angle x-ray scattering, dynamic-mechanical spectroscopy, and broadband dielectric spectroscopy. A comparison of the real space correlation distance corresponding to the pre-peak and the presence or absence of the slow sub-alpha dielectric relaxation previously associated with the motion of mesoscale aggregates reveals a disruption of mesoscale aggregates with increasing symmetry of the quaternary phosphonium cation. These findings contribute to the broader understanding of the interplay of molecular structures, mesoscale aggregation, and physicochemical properties in aprotic ionic liquids. PMID- 30307250 TI - Extent of Fock-exchange mixing for a hybrid van der Waals density functional? AB - The vdW-DF-cx0 exchange-correlation hybrid design [K. Berland et al., J. Chem. Phys. 146, 234106 (2017)] has a truly nonlocal correlation component and aims to facilitate concurrent descriptions of both covalent and non-covalent molecular interactions. The vdW-DF-cx0 design mixes a fixed ratio, a, of the Fock exchange into the consistent-exchange van der Waals density functional, vdW-DF-cx [K. Berland and P. Hyldgaard, Phys. Rev. B 89, 035412 (2014)]. The mixing value a is sometimes taken as a semi-empirical parameter in hybrid formulations. Here, instead, we assert a plausible optimum average a value for the vdW-DF-cx0 design from a formal analysis; A new, independent determination of the mixing a is necessary since the Becke fit [A. D. Becke, J. Chem. Phys. 98, 5648 (1993)], yielding a' = 0.2, is restricted to semilocal correlation and does not reflect non-covalent interactions. To proceed, we adapt the so-called two-legged hybrid construction [K. Burke et al., Chem. Phys. Lett. 265, 115 (1997)] to a starting point in the vdW-DF-cx functional. For our approach, termed vdW-DF-tlh, we estimate the properties of the adiabatic-connection specification of the exact exchange-correlation functional, by combining calculations of the Fock exchange and of the coupling-constant variation in vdW-DF-cx. We find that such vdW-DF-tlh hybrid constructions yield accurate characterizations of molecular interactions (even if they lack self-consistency). The accuracy motivates trust in the vdW-DF tlh determination of system-specific values of the Fock-exchange mixing. We find that an average value a' = 0.2 best characterizes the vdW-DF-tlh description of covalent and non-covalent interactions, although there exists some scatter. This finding suggests that the original Becke value, a' = 0.2, also represents an optimal average Fock-exchange mixing for the new, truly nonlocal-correlation hybrids. To enable self-consistent calculations, we furthermore define and test a zero-parameter hybrid functional vdW-DF-cx0p (having fixed mixing a' = 0.2) and document that this truly nonlocal correlation hybrid works for general molecular interactions (at reference and at relaxed geometries). It is encouraging that the vdW-DF-cx0p functional remains useful also for descriptions of some extended systems. PMID- 30307251 TI - Molecular dynamics study of thermodynamic stability and dynamics of [Li(glyme)]+ complex in lithium-glyme solvate ionic liquids. AB - Equimolar mixtures of glymes and organic lithium salts are known to produce solvate ionic liquids, in which the stability of the [Li(glyme)]+ complex plays an important role in determining the ionic dynamics. Since these mixtures have attractive physicochemical properties for application as electrolytes, it is important to understand the dependence of the stability of the [Li(glyme)]+ complex on the ion dynamics. A series of microsecond molecular dynamics simulations has been conducted to investigate the dynamic properties of these solvate ionic liquids. Successful solvate ionic liquids with high stability of the [Li(glyme)]+ complex have been shown to have enhanced ion dynamics. Li-glyme pair exchange rarely occurs: its characteristic time is longer than that of ion diffusion by one or two orders of magnitude. Li-glyme pair exchange most likely occurs through cluster formation involving multiple [Li(glyme)]+ pairs. In this process, multiple exchanges likely take place in a concerted manner without the production of energetically unfavorable free glyme or free Li+ ions. PMID- 30307252 TI - Zombie states for description of structure and dynamics of multi-electron systems. AB - Canonical Coherent States (CSs) of Harmonic Oscillator have been extensively used as a basis in a number of computational methods of quantum dynamics. However, generalising such techniques for fermionic systems is difficult because Fermionic Coherent States (FCSs) require complicated algebra of Grassmann numbers not well suited for numerical calculations. This paper introduces a coherent antisymmetrised superposition of "dead" and "alive" electronic states called here Zombie State (ZS), which can be used in a manner of FCSs but without Grassmann algebra. Instead, for Zombie States, a very simple sign-changing rule is used in the definition of creation and annihilation operators. Then, calculation of electronic structure Hamiltonian matrix elements between two ZSs becomes very simple and a straightforward technique for time propagation of fermionic wave functions can be developed. By analogy with the existing methods based on Canonical Coherent States of Harmonic Oscillator, fermionic wave functions can be propagated using a set of randomly selected Zombie States as a basis. As a proof of principles, the proposed Coupled Zombie States approach is tested on a simple example showing that the technique is exact. PMID- 30307253 TI - Time-resolved photoelectron spectroscopy of adenosine and adenosine monophosphate photodeactivation dynamics in water microjets. AB - The excited state relaxation dynamics of adenosine and adenosine monophosphate were studied at multiple excitation energies using femtosecond time-resolved photoelectron spectroscopy in a liquid water microjet. At pump energies of 4.69 4.97 eV, the lowest pipi* excited state, S1, was accessed and its decay dynamics were probed via ionization at 6.20 eV. By reversing the role of the pump and probe lasers, a higher-lying pipi* state was excited at 6.20 eV and its time evolving photoelectron spectrum was monitored at probe energies of 4.69-4.97 eV. The S1 pipi* excited state was found to decay with a lifetime ranging from ~210 to 250 fs in adenosine and ~220 to 250 fs in adenosine monophosphate. This lifetime drops with increasing pump photon energy. Signal from the higher-lying pipi* excited state decayed on a time scale of ~320 fs and was measureable only in adenosine monophosphate. PMID- 30307254 TI - Thermally induced amorphous to amorphous transition in hot-compressed silica glass. AB - In situ Raman and Brillouin light scattering techniques were used to study thermally induced high-density amorphous (HDA) to low-density amorphous (LDA) transition in silica glass densified in hot compression (up to 8 GPa at 1100 degrees C). Hot-compressed silica samples are shown to retain structural and mechanical stability through 600 degrees C or greater, with reduced sensitivity in elastic response to temperature as compared with pristine silica glass. Given sufficient thermal energy to overcome the energy barrier, the compacted structure of the HDA silica reverts back to the LDA state. The onset temperature for the HDA to LDA transition depends on the degree of densification during hot compression, commencing at lower temperatures for samples with higher density, but all finishing within a temperature range of 250-300 degrees C. Our studies show that the HDA to LDA transition at high temperatures in hot-compressed samples is different from the gradual changes starting from room temperature in cold-compressed silica glass, indicating greater structural homogeneity achieved by hot compression. Furthermore, the structure and properties of hot-compressed silica glass change continuously during the thermally induced HDA to LDA transition, in contrast to the abrupt and first-order-like polyamorphic transitions in amorphous ice. Different HDA to LDA transition mechanisms in amorphous silica and amorphous ice are explained by their different energy landscapes. PMID- 30307255 TI - Quasi-variational coupled-cluster theory: Performance of perturbative treatments of connected triple excitations. AB - Quasi-variational coupled-cluster methods are applied to a selection of diatomic molecules. The potential energy curves, spectroscopic constants, and size consistency errors are calculated and compared to those obtained from both single and multi-reference methods. The effects of connected triple excitations are introduced with either the standard perturbative (T) formulation, or in the renormalised form, and its symmetrised approximation. It is found that the renormalised ansatz is significantly superior to the standard formulation when describing bond breaking and that in most circumstances, the computationally simpler symmetrisation gives nearly identical results. PMID- 30307256 TI - Microphase separation and the formation of ion conductivity channels in poly(ionic liquid)s: A coarse-grained molecular dynamics study. AB - We study generic properties of poly(ionic liquid)s (PILs) via coarse-grained molecular dynamics simulations in bulk solution and under confinement. The influence of different side chain lengths on the spatial properties of the PIL systems and on the ionic transport mechanism is investigated in detail. Our results reveal the formation of apolar and polar nanodomains with increasing side chain length in good agreement with previous results for molecular ionic liquids. The ion transport numbers are unaffected by the occurrence of these domains, and the corresponding values highlight the potential role of PILs as single-ion conductors in electrochemical devices. In contrast to bulk behavior, a pronounced formation of ion conductivity channels in confined systems is initiated in close vicinity to the boundaries. We observe higher ion conductivities in these channels for increasing PIL side chain lengths in comparison with bulk values and provide an explanation for this effect. The appearance of these domains points to an improved application of PILs in modern polymer electrolyte batteries. PMID- 30307257 TI - Time-resolved determination of the potential of zero charge at polycrystalline Au/ionic liquid interfaces. AB - The potential of zero charge (PZC) is a fundamental property that describes the electrode/electrolyte interface. The determination of the PZC at electrode/ionic liquid interfaces has been challenging due to the lack of models that fully describe these complex interfaces as well as the non-standardized approaches used to characterize them. In this work, we present a method that combines electrode immersion transient and impedance measurements for the determination of the PZC. This combined approach allows the distinction of the potential of zero free charge (pzfc), related to fast double layer charging on a millisecond timescale, from a potential of zero charge on a timescale of tens of seconds related to slower ion transport processes at the interface. Our method highlights the complementarity of these electrochemical techniques and the importance of selecting the correct timescale to execute experiments and interpret the results. PMID- 30307259 TI - An experimental test of the role of appearance-related safety behaviors in body dysmorphic disorder, social anxiety, and body dissatisfaction. AB - Individuals with appearance concerns engage in "safety behaviors" (SBs) aimed at checking, hiding, fixing, and reducing threat associated with their perceived flaw in appearance. Appearance-related SBs are important in contemporary accounts of body dysmorphic disorder (BDD), though they are also relevant to social anxiety (SAD) and eating disorders. The present study examined the extent to which appearance-related SBs contribute to the development of disorder-specific symptoms and maladaptive cognitions. Female undergraduates without clinically elevated appearance concerns (N = 99) were randomly assigned to 1 week of (a) increasing the frequency and duration of appearance-related SBs (SB+), (b) decreasing these behaviors (SB-), or (c) a control in which they increased their academic studying behaviors. Generally, SB+ participants demonstrated greater BDD symptoms, SAD symptoms, body dissatisfaction, disorder-relevant threat interpretations, beliefs about the importance of appearance, and reactivity to an in vivo appearance-related task following the manipulation, relative to the other groups, with some exceptions. The SB- and control conditions largely did not differ from one another in these outcomes. SB+ participants also reported greater anxiety and depressive symptoms postmanipulation relative to other conditions. Groups no longer differed from one another at a follow-up assessment. Overall, these findings suggest that engagement in appearance-related SBs may play an instrumental role in symptoms and maladaptive cognitions across a range of disorders. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307258 TI - Long-term changes in the effects of episode-specific drinking to cope motivation on daily well-being. AB - To further understand the role of drinking to cope (DTC) motivation in the development of drinking-related problems during young adulthood, we tested whether the association between episode-specific levels of nighttime DTC motivation and next-day negative affect and self-control depletion symptoms (SCDS) changed from college years to postcollege years (5 years later). We also examined whether these changes were moderated by recent life stress, adult social role attainment and gender, and whether mean levels of these variables were associated with changes in drinking-related problems from college to postcollege years. Participants (N = 927; 54% women) completed a 30-day daily diary during college and again 5 years later in which they reported their previous night's drinking level and motivation and their current negative affect and SCDS. We assessed drinking-related problems at both waves and recent life stress and adult social roles at Wave 2. DTC motivation was positively associated with next-day levels of negative affect and SCDS. The effect of DTC motivation on anxiety and SCDS became stronger over time. The effect of DTC motivation on depressive affect and anger (a) decreased across time among individuals who attained more adult roles and (b) was weaker among individuals who reported lower levels of postcollege life stress. Mean levels of postcollege DTC motivation was indirectly related to changes in drinking-related problems from college to postcollege through mean levels of negative affect and SCDS. Our findings indicate that DTC might exert its unique long-term effects on alcohol use disorders through disruption of daily emotion-regulation processes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307260 TI - Cross-language associative priming is influenced by language proficiency and executive control. AB - The present study investigated the impact of language proficiency and executive control (EC) ability on cross-language semantic activation using an English semantic priming lexical-decision task. Primes were either English-French homographs (i.e., words that share spelling but not meaning, e.g., pain means "bread" in French; related trial) or matched control words (e.g., pale; unrelated trial). Type of Priming was either translation (e.g., pain-BREAD) or cross language associative (e.g., pain-BUTTER). A living/nonliving judgment task and a colour Stroop task measured individual differences in language proficiency and EC, respectively. Reaction time (RT) data from 58 bilingual young adults were analysed using linear mixed-effects modelling. Experimental variables (Type of Priming, relatedness), and individual-differences variables (English language proficiency, EC ability) served as fixed variables. Unlike previous studies on cross-language semantic activation, the current study included EC ability as an individual difference variable and found that it interacted with language proficiency to impact associative priming performance. Linear mixed-effects models for associative priming revealed that participants with slow English access exhibited increased positive priming from homographs, whereas individuals with fast lexical access experienced negative priming. Furthermore, these effects were exaggerated for individuals with poor EC. No effects of individual difference variables were observed on translation priming. These results suggest that theories of bilingual word recognition need to incorporate individual difference variables beyond language proficiency. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307261 TI - Measurement invariance of language brokering extent and attitudes in linguistic minority adolescents: Item response theory analyses. AB - OBJECTIVE: Using item response theory, we sought to evaluate measurement invariance of language brokering extent and attitudes in 3 linguistic minority groups of adolescents. METHOD: The sample included 765 (302 Chinese American, 327 Korean American, and 136 Mexican American; 57% females) ninth graders from immigrant families. RESULTS: Differential item functioning was detected for several items, and we retained items with equivalent parameters across 3 groups. The final items showed adequate internal consistency reliability and criterion validity. CONCLUSION: The refined scale is cross-ethnically invariant and appropriate for use with Chinese-American, Korean-American, and Mexican-American adolescents to compare their language brokering experiences. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307262 TI - The effects of work-family experiences on health among older workers. AB - With the rapidly aging workforce worldwide, the need to retain healthy older workers is greater than ever. To promote health among older workers, a better understanding of the factors that contribute to their health is crucial. With this in mind, we investigated the impact of work-family conflict and work-family enrichment on older workers' health. Five waves of longitudinal data from the Health and Retirement Study were used. A total of 4,509 workers aged 55 years and older at baseline were included. Multilevel modeling was conducted to analyze the data. Our findings showed that greater work-to-family conflict was related to higher comorbidity and greater disability over time, controlling for other known predictors of health (employment status, total household income, living arrangement, marital status, depressive symptoms, and baseline demographic characteristics). No other work-family variables significantly predicted the health outcomes. Comorbidity and disability were also found to predict work-to family conflict. Using five waves of longitudinal data, our research showed that work that interferes with family negatively affects older workers' physical and functional health and that health relates to work-to-family conflict. Given the growing number of older workers and changing work and family situations, continued monitoring of work-family experiences among older workers is warranted. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307263 TI - Deceased-infant carrying in nonhuman anthropoids: Insights from systematic analysis and case studies of bonnet macaques (Macaca radiata) and lion-tailed macaques (Macaca silenus). AB - Existing models of attachment do not explain how death of offspring affects maternal behavior. Previous descriptions of maternal responsiveness to dead offspring in nonhuman anthropoids have not expounded the wide variation of deceased-infant carrying (DIC) behavior. Through the current study, we attempt to (a) identify determinants of DIC through a systematic survey across anthropoids, (b) quantitatively assess behavioral changes of mother during DIC, and (c) infer death perception of conspecifics. Firstly, we performed phylogenetic regression using duration of DIC as the dependent variable. Secondly, we undertook case studies of DIC in the bonnet monkey and the lion-tailed monkey through behavioral sampling. Results of phylogenetic Generalized Linear Mixed Model (Nspecies = 18; Ncases = 48) revealed a strong homology (H2 = 0.86). We also obtained a high intraspecific variation in DIC and found DIC to be affected by mother's age, context of death, habitat condition, and degree of arboreality. We found bonnet mothers to carry their deceased offspring for 3.56 +/- 4.03 SD days (N = 7) with diminished feeding, enhanced passivity, and social isolation during DIC and progressive decline in protection/attentiveness of corpse and attachment. Following Anderson (2016)'s framework of death perception, we interpreted repeated sensory investigation of corpses by mothers as comprehending causality of death, inanimate handling of corpse and its defense as comprehension of non functionality, and a progressive disinterest of mothers in them as perceiving irreversibility of death. Lastly, we integrated DIC with mother-infant attachment theories and proposed a conceptual model characterizing DIC with causal determinants. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307264 TI - Voluntary arousing negative experiences (VANE): Why we like to be scared. AB - This study examined survey data and neural reactivity associated with voluntarily engaging in high arousal negative experiences (VANE). Here we suggest how otherwise negative stimuli might be experienced as positive in the context of voluntary engagement. Participants were recruited from customers who had already purchased tickets to attend an "extreme" haunted attraction. Survey data measuring self-report affect, expectations, and experience was collected from 262 adults (139 women and 123 men; age M = 27.5 years, SD = 9.3 years) before and after their experience. Changes in electroencephalographic (EEG) indices of reactivity to cognitive and emotional tasks were further assessed from a subsample of 100 participants. Results suggested that participants' reported affect improved, particularly for those that reported feeling tired, bored, or stressed prior to the experience. Among those whose moods improved, neural reactivity decreased in response to multiple tasks. Together, these data suggest that VANE reduces neural reactivity following stress. This result could explain post-VANE euphoria and may be adaptive in that it could help individuals to cope with subsequent stressors. To the extent that this phenomenon replicates in clinical situations, it could inform clinical interventions by using VANE principles to reduce neural reactivity to subsequent stressors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307265 TI - A bifactor model of obsessive beliefs: Specificity in the prediction of obsessive compulsive disorder symptoms. AB - Although current cognitive-behavioral models suggest that maladaptive "obsessive beliefs" about threat, responsibility, uncertainty, perfectionism, importance, and control of thoughts contributes to the development of obsessive-compulsive disorder (OCD), the structure of such beliefs is unclear. The current study evaluated a bifactor model of obsessive beliefs, as assessed by the Obsessive Beliefs Questionnaire (OBQ-44), and its association with OCD symptoms in clinical (Study 1; N = 264) and nonclinical (Study 2; N = 437) samples. The goals were as follows: (a) to evaluate whether obsessive beliefs should be conceptualized as unidimensional or whether distinct dimensions should be interpreted, and (b) to use structural equation modeling to examine the extent to which distinct beliefs predict OCD symptoms above and beyond a general obsessive belief factor. Results revealed that in both clinical and nonclinical samples, a bifactor model fit the data well and significantly better than a standard three-factor model of the OBQ 44 that specified 3 separate, yet correlated factors (Responsibility/Threat Estimation, Perfectionism/Certainty, and Importance/Control of Thoughts). Despite evidence that the OBQ-44 consists of a general factor and the 3 specific factors, structural equation modeling showed that only the general factor uniquely predicted a broad OCD symptom latent factor in clinical and nonclinical samples. Although obsessive beliefs about Perfectionism/Certainty did predict symmetry and ordering symptoms of OCD when controlling for the general factor in both studies, the general factor was a more robust predictor of specific OCD symptoms than the 3 factors. These findings suggest that the general factor of the OBQ-44 may have more utility than its specific factors in predicting the heterogeneity of OCD symptoms. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307266 TI - Cross-validation of the demoralization construct in the Revised NEO Personality Inventory. AB - Demoralization is defined as a pervasive, generalized negative emotional construct present in psychiatric disorders and a variety of medical conditions. Demoralization is also conceptualized as a ubiquitous affective-laden factor common to most forms of psychopathology that increases the magnitude of intercorrelations among putatively distinct psychiatric symptom scales (Tellegen, 1985). Using exploratory structural equation modeling to identify common variance across the revised NEO Personality Inventory (NEO PI-R), a measure of the five factor model of personality, Noordhof, Sellbom, Eigenhuis, and Kamphuis (2015) constructed an 18-item Demoralization subscale in a Dutch-speaking sample of patients attending a clinic for personality disorders in the Netherlands. In the current study we sought to cross-validate these findings in an English-speaking and diagnostically heterogeneous sample of psychiatric patients (N = 1930) receiving consultation or treatment at a large mental health and addiction center in Canada. Our results support the construct validity of the Demoralization subscale and its capacity to account for demoralization-related variance in the NEO PI-R. We believe these findings support the general tenets of demoralization and the presence of this construct in the NEO PI-R item pool. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307267 TI - To go or not go: Patient preference in seeking specialty mental health versus behavioral consultation within the primary care behavioral health consultation model. AB - INTRODUCTION: Much of behavioral health care takes place within primary care settings rather than in specialty mental health settings. Access to specialty mental health care can be difficult due to limited access to mental health providers and wait times to receive mental health care. The purpose of this study is to determine patient satisfaction with behavioral health consultation visits that take place within the context of the primary care behavioral health consultation model. Patient likelihood to seek out specialty mental health care services if behavioral health consultation services were not provided was also examined. METHOD: Two primary care clinic systems were examined in this study. The first was a primary care clinic predominately serving low-income patients: 100 individuals participated. The second was primary care in the context of military treatment centers: 539 individuals participated. RESULTS: Results show that 61% of the patients in the low-income primary care clinic would not attend a specialty mental health appointment versus 30% in the military population. DISCUSSION: This study suggests that primary care behavioral health is a patient centered approach to care and reaches populations that otherwise may not receive behavioral health services. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307269 TI - Reentry interventions that address substance use: A systematic review. AB - Justice-involved individuals with substance use problems have heightened risk of relapse and recidivism after release from incarceration, making reentry a critical time to provide evidence-based treatments (EBTs) for substance use; however, the extent to which reentry interventions incorporate EBTs for substance use is unclear. This systematic review identified studies of reentry interventions in the past 10 years that address substance use, assessed whether EBTs were used, and explored which interventions were effective in reducing substance use and recidivism postrelease. Eligible studies included interventions that began during incarceration and continued postrelease or began within 3 months of release and addressed substance use in some capacity. One hundred twelve full text articles were reviewed and 38 met inclusion criteria, representing 34 unique interventions. Of the 34 interventions, 21 provided substance use treatment whereas 13 facilitated connections to treatment. Of the 21 interventions providing treatment, the primary modalities were cognitive behavioral therapy (n = 6), motivational interviewing (n = 2), medication assisted treatment (n = 2), therapeutic community (n = 2), psychoeducation or 12 step (n = 5), and four did not specify the modality. Of the 31 studies that assessed recidivism outcomes, 18 found reduced recidivism for the treatment group on at least one indicator (e.g., rearrest, reincarceration). Of the 13 studies that assessed substance use outcomes, 7 found reduced substance use for the treatment group on at least one indicator. Results were not consistent for any particular treatment approach or modality and highlight the need for consistent integration of EBTs for substance use into reentry interventions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307268 TI - Orthographic and phonological priming effects in the same-different task. AB - Masked priming tasks have been used widely to study early orthographic processes the coding of letter position and letter identity. Recently, using masked priming in the same-different task Lupker, Nakayama, and Perea (2015a) reported finding a phonological priming effect with primes presented in Japanese Katakana, and English target words presented in the Roman alphabet, and based on this finding, suggested that previously reported effects in the same-different task in the literature could be based on phonology rather than orthography. In this article, the authors explain why the design of Lupker et al.'s experiment does not address this question; they then report 2 new experiments that do. The results indicate that the priming produced by orthographically similar primes in the same different task for letter strings presented in the Roman alphabet is almost exclusively orthographic in origin, and phonology makes little contribution. The authors offer an explanation for why phonological priming was observed when the prime and target are presented in different scripts but not when they are presented in the same script. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307270 TI - Innovative study designs and methods for optimizing and implementing behavioral interventions to improve health. AB - OBJECTIVE: Improving diet, activity level, and medication adherence and controlling tobacco and other substance use have all been shown to produce measurable, cost-effective improvements in health outcomes. However, many individuals do not respond to available treatments, and efficacious interventions are often not brought to scale. Developing and implementing more potent behavioral treatments in diverse populations to ultimately improve public health involves a focus on behavioral intervention research across the translational spectrum. There has been little attention paid to designs, methods, and analytic techniques for early phase trials. METHOD: The National Institutes of Health sponsored a cross-institute, 2-day Workshop on Innovative Study Designs and Methods for Developing, Testing and Implementing Behavioral Interventions to Improve Health to review, evaluate, and disseminate a selection of innovative designs and analytic strategies for use in behavioral intervention studies. RESULTS: The workshop was organized to reflect methods appropriate for use across the translational spectrum. Because of the historical attention paid to the randomized clinical trial, the workshop placed particular emphasis on the designing and preliminary testing of behavioral interventions, the optimization of interventions, and the later effectiveness and implementation of trials. CONCLUSIONS: This article provides a summary of the methods discussed at the workshop, with recommendations for their use to improve the impact, reach, and cost-effectiveness of behavioral intervention research across the translational spectrum. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307271 TI - Anxiety, depression, and cardiac outcomes after a first diagnosis of acute coronary syndrome. AB - OBJECTIVE: Depression is an established risk factor for acute coronary syndrome (ACS), with an impact on cardiac prognosis; nonetheless, the literature disagrees on the role played by anxiety. No study has evaluated this relationship in a cardiac population with no history of depression and after their first diagnosis of ACS. The aim of this study is to explore these associations without the confounding role of long-lasting heart disease or psychiatric illnesses. METHOD: Two hundred sixty-six patients with no history of depression completed the Hospital Anxiety and Depression Scale and the Primary Care Evaluation of Mental Disorder at baseline and at 1, 2, 4, 6, 9, 12, and 24 months follow-up after their first diagnosis of ACS. During the follow-up period, we collected information regarding the major adverse cardiac events. RESULTS: Developing a first-ever depressive episode, in a proportional hazard model, was associated with almost 3 times the risk of a recurrent cardiac event (odds ratio = 2.590, 95% confidence interval [CI] [1.321, 5.078], p = .006). Furthermore, a moderation analysis revealed that increasing levels of baseline anxiety had opposing effects on cardiac outcomes, being protective only in those who did not develop incident depression (B = -0.0824, 95% CI [-0.164, -0.005], p = .048). No dose-response effect between depressive or anxious symptoms and cardiac outcomes emerged. CONCLUSION: Our results confirm the detrimental effect of depression on cardiac prognosis in a selected population and suggest that anxiety after the first diagnosis of ACS might have different roles depending on the illness' course. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307273 TI - Beliefs about the causes of hypertension and associations with pro-health behaviors. AB - OBJECTIVE: To describe behavioral and genetic beliefs about developing hypertension (HTN) by sociodemographic factors and self-reported HTN status, and among those with a history of HTN, evaluate associations between HTN-related causal beliefs and behavior change attempts. METHOD: Data from the 2014 Health Information National Trends Survey were evaluated. HTN causal beliefs questions included (a) "How much do you think health behaviors like diet, exercise, and smoking determine whether or not a person will develop high blood pressure/HTN?"; and (b) "How much do you think genetics, that is characteristics passed from one generation to the next, determine whether or not a person will develop high blood pressure/HTN?" Multivariate logistic regressions evaluated associations between HTN causal beliefs and behavior change attempts including diet, exercise, and weight management. RESULTS: Approximately 1,602 out of 3,555 respondents with nonmissing data (33% weighted) reported ever having HTN. In logistic regression models, results show that the more strongly people believed in the impact of behavior on developing HTN, the higher their odds for behavior change attempts. Beliefs about genetic causes of HTN were not associated with behavior change attempts. Women had higher odds of attempts to increase fruit and vegetable intake, reduce soda intake, and lose weight compared to men. Blacks and Hispanics were significantly more likely than Whites to report attempts to lose weight. CONCLUSIONS: Beliefs about behavioral causes of HTN, but not genetic, were associated with behavior change attempts. Health messages that incorporate behavioral beliefs and sociodemographic factors may enhance future prohealth behavior changes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307272 TI - Behavioral impact of return of genetic test results for complex disease: Systematic review and meta-analysis. AB - OBJECTIVE: Advances in genomewide association studies have made possible the return of genetic risk results for complex diseases. Two concerns about these results are (a) negative psychological consequences and (b) viewing probabilistic results as deterministic, leading to misinterpretation and inappropriate decisions. The present study evaluates these concerns through a meta-analytic review of existing literature. METHOD: Seventeen genetic testing studies of complex disease, including 1,171 participants and reporting 195 effects, 104 of which were unadjusted for covariates, were meta-analyzed under a random effects model. Diseases included Alzheimer's, cardiovascular and coronary heart disease, lung cancer, melanoma, thrombophilia, and type II diabetes. Six domains of behavioral-psychological reactions were examined. RESULTS: Carriers showed significantly increased self-reported behavior change compared to noncarriers when assessed 6 months or later after results return (Hedges's g = .36, p = .019). CONCLUSIONS: Return of genetic testing results for complex disease does not strongly impact self-reported negative behavior or psychological function of at-risk individuals. Return of results does appear to moderately increase self reported healthy behavior in carriers, although research on objectively observed behavior change is needed. This is a growing area of research, with preliminary results suggesting potential positive implications of genetic testing for complex disease on behavior change. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307275 TI - Sexually explicit media exposure as a sexual milestone among gay, bisexual, and other men who have sex with men. AB - OBJECTIVE: Gay, bisexual, and other men who have sex with men (GBMSM) remain at high risk of HIV infection via condomless anal sex. Sexually explicit media (SEM) likely influences GBMSM's sexual behavior and has been associated with condomless anal sex. SEM messages may be especially potent during formative developmental periods. METHOD: We examined the association between age of first SEM exposure and condomless anal sex in a sample of adult GBMSM (N = 1,114) recruited using the Internet. RESULTS: Every 1-year delay in age of first SEM exposure resulted in a 3% decrease in the odds of engaging in condomless anal sex as an adult (odds ratio = .97, 95% CI [.95, .99], p = .01). This association remained significant in 3 separate multivariable models that controlled for age of sexual debut, age of anal sex debut, and current age, respectively. This association was moderated by ethnicity such that the effect was stronger among Latino men. CONCLUSIONS: GBMSM who were exposed to SEM earlier in their lives report more sexual risk behavior as adults. SEM exposure in GBMSM is an important sexual development milestone deserving further research. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307276 TI - Nice guys finish last: When and why agreeableness is associated with economic hardship. AB - Recent research suggests that agreeable individuals experience greater financial hardship than their less agreeable peers. We explore the psychological mechanisms underlying this relationship and provide evidence that it is driven by agreeable individuals considering money to be less important, but not (as previously suggested) by agreeable individuals pursuing more cooperative negotiating styles. Taking an interactionist perspective, we further hypothesize that placing little importance on money-a risk factor for money mismanagement-is more detrimental to the financial health of those agreeable individuals who lack the economic means to compensate for their predisposition. Supporting this proposition, we show that agreeableness is more strongly (and sometimes exclusively) related to financial hardship among low-income individuals. We present evidence from diverse data sources, including 2 online panels (n1 = 636, n2 = 3,155), a nationally representative survey (n3 = 4,170), objective bank account data (n4 = 549), a longitudinal cohort study (n5 = 2,429), and geographically aggregated insolvency and personality measures (n6 = 332,951, n7 = 2,468,897). (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307274 TI - Racial discrimination, body mass index, and insulin resistance: A longitudinal analysis. AB - OBJECTIVE: To examine prospective relations of perceived racial discrimination at ages 16-18 with body mass index (BMI) at ages 19-21 and insulin resistance (IR) at ages 25 and 27 among Black youth in the rural South, and to determine whether BMI connected discrimination to IR as a mediator. METHOD: Participants were 315 African American adolescents in rural counties in Georgia who provided data on their perceptions of discrimination during adolescence. BMI was measured during a yearly home visit, and a certified phlebotomist drew a fasting blood sample from which IR was measured. RESULTS: The data analysis, with all confounding variables controlled, revealed that, over time, (a) discrimination was associated positively with both BMI and IR; (b) BMI was associated positively with IR; and (c) BMI acted as a mediator connecting discrimination with IR. CONCLUSIONS: The findings are consistent with the hypothesis that exposure to discrimination presages IR through its effects on BMI. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307277 TI - Is overconfidence a social liability? The effect of verbal versus nonverbal expressions of confidence. AB - What are the reputational consequences of being overconfident? We propose that the channel of confidence expression is one key moderator-that is, whether confidence is expressed verbally or nonverbally. In a series of experiments, participants assessed target individuals (potential collaborators or advisors) who were either overconfident or cautious. Targets expressed confidence, or a lack thereof, verbally or nonverbally. Participants then learned targets' actual performance. Across studies, overconfidence was advantageous initially-regardless of whether targets expressed confidence verbally or nonverbally. After performance was revealed, overconfident targets who had expressed confidence verbally were viewed more negatively than cautious targets; however, overconfident targets who had expressed confidence nonverbally were still viewed more positively than cautious ones. The one condition wherein nonverbal overconfidence was detrimental was when confidence was clearly tied to a falsifiable claim. Results suggest that, compared with verbal statements, nonverbal overconfidence reaps reputational benefits because of its plausible deniability. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30307278 TI - [Supplementary dairy products and bone health]. PMID- 30307279 TI - [Intracavitary electrocardiogram (IC-ECG) guidance for peripherally inserted central catheter (PICC) placement]. AB - INTRODUCTION: intracavitary electrocardiogram (IC-ECG) guidance has been recently proposed for peripherally inserted central catheter (PICC) placement since it may reduce the time of placement and avoid radiological control. OBJECTIVE: to evaluate IC-ECG compared to conventional radiological control. METHOS: prospective study of 532 consecutive patients. Those with arrhythmias or on antiarrhythmic drugs were excluded. In all cases, PICC tip placement was checked by IC-ECG guidance and by a chest X-ray, which was considered as the reference test. RESULTS: PICC placement with IC-ECG guidance was achieved in 96.8% of patients (applicability). PICC correct placement according to IC-ECG guidance was confirmed by chest X-ray in 94% of patients (accuracy). In 13 patients (2.7%) the catheter had to be repositioned after radiological control. The kappa concordance index was 0.356 (p < 0.001). The IC-ECG sensitivity was 0.98, with a PPV of 0.97 and a positive likelihood ratio of 1.5. However, the specificity was only 0.35 with a NPV of 0.41 and a negative likelihood ratio of 0.06. CONCLUSION: PICC placement by IC-ECG guidance is plausible, safe, presents adequate indexes of validity and reliability, and allows reducing the time of catheter placement. However, radiological verification is still necessary, especially in cases of negative or uncertain ECG. PMID- 30307280 TI - [Precipitation limits in pediatric parenteral nutritions with organic sources of calcium and phosphate]. AB - OBJECTIVE: to determine if precipitation processes occur in parenteral nutrition solutions (PNs) with calcium gluconate and sodium glycerophosphate in the precipitation threshold limits of the Spanish SENPE/SEGHNP/SEFH 2008 consensus document of PN preparation. METHODS: seven PNs with different composition were prepared in triplicate: five 100 ml PNs with different concentrations of amino acids, calcium and phosphorus similar to consensus document maximum concentrations for precipitation, and two control PNs: one without calcium and phosphorus and other with high calcium and phosphorus content and low concentration of amino acids. All PNs did not contain lipids to allow correct detection of precipitates. The no lipid PNs were stored at room temperature for 20 hours, and at 35 degrees C for four hours. Subsequently, they filtered through a 0.2 MUm filter, which was observed by electron microscopy. Because a large amount of not expected precipitates was observed, complementary studies were carried out. RESULTS: precipitates were observed in all PNs except in the control solution without calcium and phosphorus; many of them were greater than 10 MUm. However, according to our studies, these crystals were produced after filtration and calcium was found in their composition, but not phosphorus. Particles from the preparation of parenteral nutrition were also observed. CONCLUSIONS: in our study we did not find calcium phosphate precipitates in the limits included in the consensus document SENPE/SEGHNP/ SEFH. However, it is possible that micro precipitates with calcium are formed. It is important to filter PNs prior to their administration. PMID- 30307281 TI - Effects of intravenous fluid overload on caloric and protein deficit in critically ill patients. AB - INTRODUCTION: intravenous fluid overload may lead to dysmotility that may impair early enteral nutrition delivery in critically ill patients. OBJECTIVES: this study aimed to compare the volume of intravenous fluids (IF) with the occurrence of caloric and protein deficits in Intensive Care Unit (ICU) patients. METHODS: this cohort study included critically ill patients with mechanical ventilation and receiving early enteral nutrition (target: 25-30 kcal/kg/day and 1.25-2.0 g of protein/kg/day). Over the first five days the volume of IF infused and caloric/protein deficits were calculated. RESULTS: eighty-six critically ill patients (SAPS III score: 62 +/- 10) with a mean age of 68 (18-91) years were enrolled. Patients received a median of 2,969 (920-5,960) ml/day of IF, which corresponded to a median of 41.6 (17.0-88.2) ml/kg/day and 10.7 (3.31-21.45) g of sodium/day. All patients had a caloric deficit (mean: 1,812 +/- 850 kcal over five days) and in 23 (27%) this deficit exceeded 480 kcal/day. The mean protein deficit was 94.6 +/- 5.9 g over five days, and 34 patients (40%) had more than 20 g of deficit/day. Patients with caloric deficit greater than 480 kcal/day received approximately 1.5 l of IF and 10 g of NaCl more than the other patients. Similarly, patients with protein deficit greater than 20 g/day received approximately 3 l of IF and 25 g of NaCl more than the other patients. Mortality was greater in patients with critical protein deficit (69% vs 41.1%; p = 0.01). CONCLUSION: in critically ill patients receiving enteral nutrition, the volume of intravenous fluids infused affected nutrition delivery and increased caloric and protein deficits. PMID- 30307282 TI - [Maternal and infant characteristics associated with obesity in infants under one year of age in northern Mexico]. AB - INTRODUCTION: despite the fact that childhood obesity is a serious health problem, little is known about its related factors in early childhood. OBJECTIVE: to evaluate which maternal, cognitive and infant factors influence the infant's energy intake and if these influence their nutritional status before the year. METHODS: descriptive study of correlation. Two hundred and sixty-seven dyads (mother/child) participated. The questionnaires consisted of four instruments for the cognitive variables of the mother (maternal self-efficacy, attitude in the diet, perception of signs of hunger, satiety and weight of the child), energy intake through a 24-hour reminder and sociodemographic and anthropometric data of the mother and child, through which maternal body mass index (BMI) and Z-score of infant weight/height have been calculated. RESULTS: the model was significant for the intake of kcal/kg weight (F = 8.624, p < 0.001, R2 = 0.104), negatively correlating with the maternal perception of the weight of the child (B = -9.73, p = 0.002), hours of sleep (B = -2.19, p = 0.044) and age of the child (B = -2.26, p = 0.001). Also for the Z-score (weight/length) (F = 68.979, p < 0.001, R2 = 0.564) and explained positively with perception of the weight of the child (B = 1.133, p < 0.001) and age of the child (B = 0.054, p = 0.006) and negatively with hours of sleep of the mother (B = -0.07, p = 0.040) and caloric intake (B = 0.004, p = 0.027). CONCLUSION: mothers of nursing infants who underestimate their child's weight and sleep fewer hours provide more caloric intake and their children have a higher Z-score weight/length. PMID- 30307283 TI - Somatotypes of schoolchildren from Chile: higher endomorphic components among adolescent girls. AB - OBJECTIVE: this investigation describes the somatotype components and somatotype as a whole in Chilean children and adolescents. METHODS: a cross-sectional study was conducted in Valparaiso, Chile. The somatotypes of 1,409 schoolchildren (747 males) aged 6 to 18 yearswere assessed using the Heath-Carter anthropometric method. Comparative category analyses (endomorph, mesomorph, and ectomorph) were performed using t-tests. To analyze whole somatotypes along two and three dimensions, the somatotype dispersion mean (SDM) and somatotype attitudinal mean (SAM), respectively, were used in addition to a somatochart representation. RESULTS: the somatotype of the male sample showed a marked mesomorph-endomorph biotype (4.9-4.8-2.1), whereas that for the female sample showed a mesomorphic endomorph classification (5.8-4.3-1.8). The samples differed significantly by sex, with an increased endomorphic component observed in females aged 13 to 18 years old. These sex differences were primarily evident in adolescents with high somatotype values in two or three dimensions (SDM >= 3.0; SAM >= 1.2), indicating high between-group dispersion. The somatocharts showed displacement of the endomorphic components for both sexes, particularly females. CONCLUSIONS: the results provide strong evidence that biotype changes have increased, primarily in terms of relative adiposity (i.e., the endomorphiccomponent) and predominantly in adolescent girls. PMID- 30307284 TI - [Relationship between exclusive breastfeeding the first six months of life and development of insulin resistance in children and adolescents in Bucaramanga, Colombia]. AB - INTRODUCTION: exclusive breastfeeding (EB) is a protective factor against the development of insulin resistance (IR) as mainstay of the metabolic syndrome. OBJECTIVE: the objective of the study was to evaluate the relationship between EB during the first six months of life and the development of IR through the Homeostasis Model Assessment (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) indexes. MATERIAL AND METHODS: a population-based cohort study included 494 adolescent participants, from whom socio-demographic, anthropometric, and cardiometabolic variables were assessed using the HOMA-IR and QUICKI indexes to determine the degree of association between EB and the development IR. The results were expressed in medians. RESULTS: the prevalence of EB was 42%. The results suggest a protective effect of EB on IR, in such a way that for each extra month of EB, the HOMA-IR index decreases in 0.32 (p = 0.005) and the index QUICKI increases in 0.70 (p = 0.008). Regarding waist circumference, body mass index and waist size index, this relationship was not significant. CONCLUSION: the bivariate and multivariate analyses indicate an epidemiologically significant relationship that demonstrates a protective effect of EB on the HOMA-IR and QUICKI indexes. PMID- 30307285 TI - [Association between eating behavior and nutritional status in Chilean preschoolers]. AB - : INTRODUCCION: the eating behavior is associated with the nutritional status at early ages. However, in Chile there are still no studies that evaluate this relationship in the preschool stage. OBJECTIVE: to associate the nutritional status and eating behavior of Chilean preschoolers. METHODS: cross-sectional study in 247 preschoolers (2-4 years) from the region of Araucania, Chile. The nutritional status was evaluated through the anthropometric index weight/height and waist circumference/age. The Child Eating Behavior Questionnaire (CEBQ) survey was applied to mothers to assess their children's eating. RESULTS: one hundred and thirty were men and 117 were women with an overweight/obese percentage of 58.6% and 49.6%, respectively. Eating behavior scores pro-intake (food approach) have a positive and significant association with nutritional status) and in the food responsiveness sub-scale in the total sample. Regarding the anti-intake score (food avoidant), an inverse trend with nutritional status is shown; however, there is a negative and significant association in the satiety responsiveness scale and slowness in eating. CONCLUSION: the pro-intake eating behavior is directly associated with nutritional status, and anti-ingest score is inversely related only to certain sub-scales. PMID- 30307286 TI - Study on the nutritional status and feeding habits in school-children in Madrid City (Spain) during the economic crisis. AB - INTRODUCTION: the recent economic and financial crisis has affected most Western countries, especially families of low socioeconomic classes. We speculate that worsening of socioeconomic condition associated with the crisis would increase obesity, mainly in disadvantaged families. MATERIAL AND METHODS: cross-sectional study of the 290,111 children aged three to 12 years old attending public school during the term 2014-2015 in Madrid City, by means of a stratified weighted sample randomly chosen, taking into account age (grade), city district and schools. The questionnaire included weight and height (auto-reported), dietary report (weekly frequency of intake), as well as socioeconomic variables. RESULTS: 1,208 questionnaires were evaluated from 64 classes. Half of participants were boys; 42% were younger than five years old, 35% werebetween six and eight years old, and 23% older than eight. Undernutrition was present in 5.0%, and excess of weight (overweight + obesity) in 36.7%. Undernutrition was higher in children under the age of six (9.1%). No relationship was found between undernutrition and the characteristics of the families but was slightly higher in families where both parents were unemployed. Excess of weight was higher in children of non Spaniard parents (44% vs 32%, p < 0.0001), as well as in those families with economic problems (41% vs 31%, p = 0.0005). Only for meat, grains and dairy, the weekly intake was close to the recommendations. CONCLUSIONS: children from lower income households were at a higher risk of being overweight compared with their peers. Participation in a school-based food aid program may reduce food insecurity for children and their families. PMID- 30307287 TI - Association between adductor pollicis muscle thickness and nutritional parameters in hospitalized elderly patients. AB - INTRODUCTION: the measurement of the adductor pollicis muscle thickness (APMT) has been investigated as an anthropometric parameter; however, there are few studies related to hospitalized elderly patients. OBJECTIVE: to analyze the association between APMT and nutritional parameters in hospitalized elderly patients. METHOD: cross-sectional study made in 331 hospitalized elderly patients. The following variables have been assessed: APMT, Mini Nutritional Assessment(r) (MNA(r)), body mass index (BMI), arm circumference (AC), calf circumference (CC) and handgrip strength (HGS). RESULTS: the mean age was 78.4 +/ 9.7 years and 56.8% were women. The women had showed APMT mean values significantly lower than the men (12.67 +/- 4.13 mm vs 15.26 +/- 4.01 mm), as well as the elderly patients >= 80 years old showed APMT values lower than the younger patients (12.62 +/- 4.38 mm vs 14.83 +/- 3.90 mm). In relation to the APMT classification, the women were more frequently below P5 than the men (89.9% vs 37.1%). In the univariate analysis, the mean values of APMT were significantly lower in the malnourished elderly patients (MNA(r)), thinness (BMI), AC < 21 cm, CC < 31 and HGS < P5, regardless of gender. In the multivariate analysis, APMT remained as a factor independently associated with all nutritional indicators, even when adjusted to age and gender. CONCLUSION: APMT has associated with all the nutritional parameters investigated, regardless of gender and age, reinforcing its applicability in the nutritional assessment of elderly people. PMID- 30307288 TI - The association between obesity and vitamin D status among older adults in Ecuador: analysis of the SABE survey. AB - BACKGROUND: although it is well established that body fat mass is inversely associated with vitamin D (25[OH]D) concentrations, little is known whether obesity increases the risk of 25(OH)D insufficiency among older adults in Ecuador. METHODS: the present study used data from the National Survey of Health, Wellbeing, and Aging to describe the prevalence of obesity and 25(OH) D insufficiency (< 20 ng/ml) among Ecuadorians aged 60 years and older. Logistic regression models were used to examine the independent association between obesity and 25(OH)D insufficiency. RESULTS: a total of 2,270 participants with a mean age of 71.5 (SD 8.1) years comprised the sample size, representing an estimated 1.1 million older adults in Ecuador. Overall, the crude prevalence of obesity was 19.2% and 25(OH)D insufficiency was present in 14.0% of men and 34.6% of women. Moreover, the proportion of women with 25(OH)D insufficiency remained steady across BMI categories. In contrast, 25(OH) D insufficiency prevalence rates in men increased progressively as body mass index (BMI) categories also increase. Moreover, obese older men (OR 2.04; 95% CI: 1.99-2.09) were two times more likely to have 25(OH)D insufficiency compared with those defined as having an ideal weight, even after adjustment for potential confounders. In women, this association was attenuated. However, 25(OH)D insufficiency prevalence ratesremained 12% higher in obese women (OR 1.12; 95% CI: 1.11-1.14) than their normal weight counterparts. CONCLUSION: obesity is associated with increased risk of 25(OH)D insufficiency in Ecuador. Thus, obese older adults should be offered vitamin D supplementation and counseled regarding lifestyle modifications to improved their 25(OH)D status. PMID- 30307289 TI - Vitamin A deficiency is associated with body mass index and body adiposity in women with recommended intake of vitamin A. AB - INTRODUCTION: evidence indicates that vitamin A is involved in regulating fat mass. A low consumption of vitamin A has been reported in individuals with obesity, as have lower concentrations of this vitamin, than in eutrophic individuals when their dietary intake of vitamin A is not significantly different. OBJECTIVE: to investigate vitamin A nutritional status and its association with body mass index (BMI) and body fat in women who have the recommended dietary intake of vitamin A. METHODS: cross-sectional study with 200 women, paired by age and by the dietary intake of vitamin A recommended. Participants were divided into four groups, according to BMI. Anthropometric data were evaluated (weight, BMI and waist circumference [WC]), as well as the diagnosis of night blindness (NB). Lipid and glycemic profiles were measured. The cut-off points for deficiency of serum concentrations of retinol and beta carotene were < 1.05 MUmol/l and 40 MUg/dl, respectively. The recommended dietary intake of vitamin A was 700 MUg/day. RESULTS: there was a significant drop in retinol concentrations according to BMI (p < 0.001) and WC (p < 0.001). We found beta-carotene to behave similarly (p = 0.005; p < 0.001). We found NB in 7.5% of overweight (OW) cases and 20.0% of obesity class II (OII), and no functional alteration was found in the eutrophic group (EU). Inadequate levels of retinol and beta-carotene increased the odds ratio for the occurrence of OW, obesity class I (OI) and OII, as well as inadequate WC. CONCLUSION: even with recommended intake of vitamin A, we found a biochemical and functional inadequacy of vitamin A nutritional status,associated with overweight, obesity and body adiposity. PMID- 30307290 TI - [Causes and components of the metabolic syndrome in renal transplant recipients from a gender perspective]. AB - INTRODUCTION: the appearance of metabolic syndrome (MS) among renal recipients is one of the greatest post-transplant complications and is associated with an increased risk of graft failure and high rates of obesity and new onset diabetes. OBJECTIVE: the objective of this work is to identify the relationship between the glomerular filtration rate measured by two different methods and the components of the metabolic syndrome and their combinations in kidney transplant patients according to gender. MATERIAL AND METHOD: the samples consisted of 500 kidney transplant recipients, of whom 190 had MS, 121 men and 69 women. All subjects underwent clinical evaluation and blood sampling for laboratory measurements. The MS was determined according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III). Renal function was estimated using AMDRD equations and CrS determinations. RESULTS: the average age was 55.5 years. The prevalence of MS was significantly higher in men (23.1% < vs 9.8%). High blood pressure (HBP) was the most observed component of MS. Significant correlations (Pearson, p < 0.05) between TFG-AMDRD and TFG CrS and metabolic markers were observed more in men than in women. The body mass index (BMI) was significantly higher in women than in men. CONCLUSIONES: the decrease in renal function associated with the components of MS, HBP and obesity represent a high risk of adverse cardiovascular events and graft rejections. PMID- 30307291 TI - [Type 2 diabetes mellitus could predict a sub-optimal weight loss after bariatric surgery]. AB - INTRODUCTION: bariatric surgery does not benefit all patients. Identifying severely obese patients who will succeed after bariatric surgery remains a challenge for the transdiciplinary team. The objective of this retrospective study was to analyze preoperative dietary factors that could predict a successful weight loss after bariatric surgery. METHODS: the retrospective study included patients undergoing laparoscopic Roux-en-Y gastric bypass surgery as a procedure for severe obesity (n = 84). Patient demographics, comorbidities, dietary factors, and weight loss results were extracted from the electronic medical record. RESULTS: type 2 diabetes mellitus (DM2) was associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass surgery. CONCLUSIONS: although bariatric surgery continues being the most effective treatment for patients with severe obesity, developing strategies to improve and maintain weight loss, especially in patients with DM2, is fundamental. Assessing the dietary characteristics of candidates for bariatric surgery is crucial. PMID- 30307292 TI - [Qualitative study of the differences between men and women's perception of obesity, its causes, tackling and repercussions on health]. AB - INTRODUCTION: although obesity is a multidimensional health problem, few qualitative research studies have analyzed the discourse of obese individuals from the gender perspective in order to better understand the hard come by information gathered from quantitative research. AIM: to analyze the discourse of obese individuals in focus groups concerning factors underlying obesity, pathology risk perception, weight loss and other relevant factors. METHODS: two single-sex focus groups, with a total of 14 participants, were held in separate sessions. A moderator directed the session, addressing the different dimensions of the problem. The groups were recorded in audio and textually transcribed. The discourse was analyzed using qualitative methods. RESULTS: important differences were observed between male and female perspectives. The self-perceived causes of obesity for women were pregnancy and menopause. Men attributed obesity to eating habits and cultural customs. For men, the final aim of reducing weight was to improve their health, whereas women also included aesthetics. Both sexes believe that obesity can lead to greater problems. Women expressed their fear of putting on weight, but men did not. Differences were also observed in the strategies adopted for combating obesity. CONCLUSIONS: differences in the perception of the causes and how to tackle obesity between men and women show us the need to consider therapeutic and preventive measures that take gender into account, in addition to the environmental aspects surrounding the patient. PMID- 30307293 TI - Evaluation of factors that may influence in the insufficient weight loss in patients after two years of Roux-en-Y gastric bypass. AB - INTRODUCTION: bariatric surgery is a favorable option for the treatment of obesity, resulting in long-term weight loss. OBJECTIVES: to analyze whether feeding behavior, evaluated by caloric intake, dietary preferences and tolerance, can be considered as a determinant factor for weight loss in obese patients submitted to Roux-en-Y gastric bypass (RYGB). METHODS: cross-sectional study of 105 patients with at least two years post-RYGB surgery with a preoperative body mass index (BMI) of >= 35 kg/m2. Caloric intake was evaluated by 24-hour dietary recall and 3-day dietary intake record; dietary habits, by a qualitative dietary frequency questionnaire; and food tolerance, with a validated questionnaire. Multiple logistic regression was used for statistical analysis. RESULTS: the majority of the 105 participants were female (84%). The mean age was 43.3 +/- 11.4 years in the success group (n = 64) and 43.4 +/- 10.7 years in the failure group (n = 41). Preoperative BMI was not associated with the outcome. Mean caloric intake did not show significant differences between groups: 24 hours recall, p = 0.27; 3-day record, p = 0.95. The frequency of weekly consumption of desserts was twice as high in the success group. Only two patients in the success group presented daily vomiting. CONCLUSION: the factors that determine the failure of weight loss have not yet been fully elucidated. Caloric intake was not a determining factor of failure, and insufficient weight loss was more prevalent in patients who ceased to lose weight earlier. PMID- 30307294 TI - Serum vitamin D level and its relation to thyroid hormone, blood sugar and lipid profiles in Iranian sedentary work staff. AB - INTRODUCTION: the sedentary lifestyle is related to the incidence of various diseases and metabolic disorders. The aim of the current study was to understand the link between serum vitamin D levels, thyroid hormones and lipid profiles among Iranian sedentary staff. MATERIAL AND METHODS: in this cross-sectional study, 300 healthy subjects with normal body mass index (BMI) and age between 18 and 65 years, with sedentary lifestyles, were included. Serum levels of 25 hydroxyvitamin D, thyroid stimulating hormone (TSH), fasting blood sugar, plasma total cholesterol, and high-density lipoprotein (HDL) and triglycerides (TG) were measured with qualified laboratory methods. Low-density lipoprotein (LDL) concentration was calculated based on the Friedewald equation. A self-made questionnaire with different questions was used to assess physical activity. RESULTS: the means of BMI and age were 25.63 +/- 10.25 and 36.69 +/- 7.14 years, respectively. The prevalence of vitamin D deficiency was 65.7%. Results showed significant differences for TG, HDL, and thyroxine (T4) between subgroup categories. Serum levels of 25-hydroxyvitamin D had a negative significant correlation with triiodothyronine (T3) and T4, and a positive correlation with HDL. Linear regression analysis showed a significant association of 25 hydroxyvitamin D concentrations with HDL and T4 after adjustments based on the sex. CONCLUSION: finally, the results of this study show that with the improvement in vitamin D status, the decrease in the levels of TG, T3 and T4, with an increase in HDL can be expected. So, verification and detection of true causality through the interventional studies will be valuable, scientifically. PMID- 30307295 TI - Self-perception of weight and physical fitness, body image perception, control weight behaviors and eating behaviors in adolescents. AB - INTRODUCTION: self-perception of weight and physical fitness, aesthetic reasons to diet, self-weighing as a way to feel better and body image perception have been related to a constellation of risks to develop both body image dissatisfaction and eating behavior disturbances, especially among adolescents. OBJECTIVES: to analyze weight self-perception and self-reported physical fitness, to explore the links between these variables and weight control behaviors, to explore possible relations among weight self-perception, self-reported physical fitness, dieting, self-weighing frequency and body mass index (BMI)/body image and to analyze the relation between all these variables and different eating behaviors. METHODS: a total of 336 students (mean age of 12.46 +/- 2.14; 47.62% females) took part in this study. Different scales were administered (weight self perception and self-reported physical fitness, dieting, self-weighing frequency, body image perception, eating behaviors) and height and weight were measured in order to obtain the BMI. RESULTS: mean BMI was 20.18 +/- 3.58 and 41.14% of participants had overweight/obesity. Among those who perceived themselves as overweight,76.92% were girls. More than 70% of participants reported average or good physical fitness and more boys reported good or excellent physical fitness. Almost 60% of participants who planned to diet for aesthetic reasons were girls, and girls more than boys self-weighed to feel better. BMI was significantly correlated with body image dissatisfaction/restrictive eating. CONCLUSIONS: there are clear links between weight self-perception, body image, dieting, self weighing and eating behaviors at an age which might be considered as a starting point to eating behavior disturbances. PMID- 30307296 TI - Poor dietary intake and low nutritional knowledge in adolescent and adult competitive athletes: a warning to table tennis players. AB - INTRODUCTION: an evaluation of an athlete's dietary intake may help to understand the dietary inadequacies that are found in athletes and how other factors, such as nutritional knowledge and age, might also influence their food behavior. OBJECTIVE: to evaluate and compare the dietary intake and the nutrition knowledge between adult and adolescent table tennis players. METHOD: forty-two competitive athletes (25 adolescents and 17 adults) responded to two non-consecutive 24-hour recalls and a validated nutritionalknowledge questionnaire. Numerical and categorical variables were compared between groups by using independent-sample Student's t-tests and Pearson's Chi-square test, respectively. RESULTS: the adolescents showed lower intakes and higher inadequacies in the ingestion of micronutrients (p < 0.05). Most of the adolescents rated their dietary quality as excellent/good, while a higher prevalence of the adults rated their dietary quality as being poor/very poor (p < 0.05). The nutritional information sources that were most used by the adolescents and the adults were their parents and the internet, respectively. The between-group analyses showed that the adults had a higher nutrition knowledge than the adolescents (p < 0.05). CONCLUSIONS: the athletes showed poor dietary habits, low levels of nutritional knowledge, as well as the use of low quality nutritional information sources. The adolescents showed a higher prevalence of nutrient inadequacies, lower nutritional knowledge levels, as well as a worse self-perception of dietary quality than the adults. PMID- 30307297 TI - The influence of the aesthetic body shape model on adolescents with eating disorders. AB - INTRODUCTION: the relevance of sociocultural factors with respect to etiology, development and treatment of eating disorders has been supported by many studies. OBJECTIVES: the aims of this study were: a) to analyze the different effects of the aesthetic body shape model on adolescents with anorexia nervosa (AN) vs bulimia nervosa (BN); b) to analyze possible differences, regarding that body shape model, between patients with purging behaviors vs non purging types of patients; and c) to explore the relationship between the influence of the aesthetic body shape model and other clinically relevant variables such as body dissatisfaction, eating attitudes and personality traits. METHODS: the sample comprised 104 adolescents suffering from AN and BN. The Questionnaire of Influences on the Aesthetic Body Shape Model (CIMEC-40), the Body Shape Questionnaire (BSQ), the Eating Attitudes Test (EAT-40) and the Millon Adolescent Clinical Inventory (MACI) were applied. RESULTS: the aesthetic body shape model of thinness influenced 77.9% of this sample, this influence being higher in the case of BN patients. In addition, that influence was stronger in the purging-type patients than in the non-purging type. Moreover, there was a significant and positive correlation among the influence of the aesthetic body shape model, body dissatisfaction and severity of eating symptoms. Finally, there seems to exist some personality traits more vulnerable to be affected by sociocultural factors. CONCLUSIONS: in view of these results, it is necessary that psychotherapeutic approaches take into account the influence of sociocultural factors and body dissatisfaction mainly in the case of adolescents with BN. PMID- 30307298 TI - Agreement between Graz Malnutrition Screening (GMS) with subjective nutritional assessment instruments in hospitalized patients. AB - BACKGROUND: it is essential for an early nutritional intervention that utilizes effective and practical nutritional screening and evaluation tools to diagnose nutritional status, increasing the patient's survival. OBJECTIVE: to evaluate the agreement of the Graz Malnutrition Screening (GMS) with subjective methods of nutritional evaluation in hospitalized patients. METHODS: descriptive cross sectional study with adults and elderly of both sexes evaluated within 48 hours of hospital admission. Nutritional status in cancer patients was identified by the Patient-Generated Subjective Global Assessment (PG-SGA(r)) and in the elderly by the Mini Nutritional Assessment Short-Form (MNA-SF(r)). GMS was applied in both groups and its efficiency was compared with that of PG-SGA(r) and MNA-SF(r). The agreement between the methods was evaluated by the kappa test, followed by assessment of diagnostic performance and correlation test. RESULTS: of the 87 patients evaluated, 64.4% (56) presented nutritional risk according to GMS, while 49.4% (43) and 47.1% (41) indicated nutritional risk and malnutrition according to MNA-SF(r) and PG-SGA(r), respectively. GMS presented moderate agreement with PG-SGA(r)(p < 0.001) and MNA-SF(r) (p < 0.001), with high sensitivity, specificity, positive predictive value, and negative predictive value. Correlations wereobserved between the GMS score and both the PG-SGA(r) (p < 0.001) and MNA-SF(r) scores (p < 0.001). CONCLUSION: GMS was effective in detecting nutritional risk in hospitalized patients when compared to classic tools in the evaluation of nutritionalstatus in hospitalized patients. PMID- 30307299 TI - Parasitic infections, malnutrition and anemia among preschool children living in rural areas of Peshawar, Pakistan. AB - INTRODUCTION: it has previously been shown that parasitic infections (PI) have deleterious effects on the nutritional status of the host, particularly among young children. OBJECTIVE: the objective of this study was to estimate the severity of the problem of malnutrition and anemia in association with PI in preschool children and to identify the possible risk factors that contribute to these health problems. METHODS: four hundred and thirty-seven mother-child pairs were randomly selected from rural areas of Peshawar, Pakistan. Children with visible and invisible worms were identified. The nutritional status of the respondents was evaluated. Structured questionnaires were used to collect data on relevant parameters. Appropriate statistical tests were used to analyze the data. RESULTS: the average age of the children was 24 +/- 10 months. A total of 120 (27.5%) fecal samples of children tested positive for several parasites. Of the total, 267 (61%), 205 (47%), 109 (25%) and 140 (32%) children were anemic, stunted, wasted and underweight, respectively. The majority of wasted children (59% wasted versus 41% normal) and anemic (66% anemic versus 34% non-anemic) were infected with parasites (p < 0.05). Independent factors related to child anemia included child age, family size, mothers' awareness of overall child healthcare, and PIs. PIs were independent risk factors for malnutrition and general child wasting. Sociodemographic, parental and child-related risk factors for PIs included mothers' poor nutritional status and awareness level regarding overall child healthcare, fathers' formal education, child's pica habit, child's age, open sewage system in the houses and family size. CONCLUSION: in general, malnutrition and anemia were highly prevalent in children in association with PI. PMID- 30307300 TI - Prevalence and factors associated with fat-soluble vitamin deficiency in adolescents. AB - BACKGROUND: fat-soluble vitamin deficiency may be a health problem not recognized in children and adolescents. OBJECTIVE: to estimate the prevalence and factors associated with the deficiency of vitamins A, D and E among adolescent students from Northeastern Brazil. METHODS: transversal study with adolescents aged 12 to 19 of both genders. A questionnaire to collect socioeconomic and lifestyle data and food intake was applied to adolescents. Then, an anthropometric evaluation and a blood sampling were performed to analyze serum concentrations of retinol, beta-carotene, alpha-tocopherol and 25-hydroxy vitamin D (25[OH]D). RESULTS: the intake of vitamins A (50.3%), E (94.0%) and D (99.8%), as well as alpha tocopherol (88.1%), beta-carotene (74.1%), 25(OH)D (50.9%) and retinol (46.6%) serum levels were mostly deficient/insufficient. An increased risk of alpha tocopherol deficiency was observed in girls (PR = 1.11) and an increased risk of 25(OH)D deficiency was observed in boys (PR = 1.41). An increased likelihood of beta-carotene (PR = 1.14) and 25(OH) D (PR = 1.38) insufficiency was observed in overweight individuals. CONCLUSIONS: the adolescents had a deficit in the intake and in serum levels of fat-soluble vitamins. The greatest risk of inadequacy was associated with gender and weight excess. However, the behavior of fat-soluble vitamins in adolescents needs further research. PMID- 30307301 TI - [Development of a screening tool for a high sodium intake in an adult Mexican population]. AB - BACKGROUND: twenty-four-hour urinary sodium excretion is the reference method to assess sodium intake; however, tools that can be more easily applied in the clinical and population setting are needed. OBJECTIVES: to develop and evaluate a self-administered high-sodium food frequency questionnaire (abbreviated to CFCA-S in Spanish) as a screening tool for high sodium intake in an adult Mexico City population. METHODS: a CFCA-S including 28 sodium-rich food categories and a scoring system were developed. The 75 percentile for the total score was tested as cut-off point to classify high sodium consumers at two different levels (>= 2,000 and >= 3,000 mg/day) against 24-h urinary sodium excretion as reference method. RESULTS: ninety-five participants were included (median age: 39 [25th 75th percentiles: 26-46] years; men: 39 [41.1%]). A total score of 51.2 in the CFCA-S showed a sensitivity of 31.6% (95% confidence interval [CI]: 19.1-47.5), specificity of 78.9 (95% CI: 66.7-87.5), positive predictive value of 50% (95% CI: 31.4-68.6) and negative predictive value of 63.4% (95% CI: 51.8-73.6) to classify high-sodium consumers at a level of intake >= 3,000 mg/day. A total score >= 51.2 was significantly associated with a sodium intake >= 3,000 mg/day, observing an odds ratio of 3.12 (CI 95%: 1.03-9.44, p = 0.04), after adjusting by sex, age, and body mass index. CONCLUSIONS: the sodium CFCA-S developed in this study is a practical, feasible and useful tool to identify individuals at greater risk of having a high sodium intake. PMID- 30307302 TI - In vivo randomized trial of three marketed milk preparations enriched with calcium and vitamins (D and K) on bone mass and bone turnover markers from biological fluids in premenopausal Caucasian women. AB - INTRODUCTION: osteoporosis is a metabolic bone disease that leads to increased bone fragility and increased risk of fracture. OBJECTIVES: the aim of the present research was to determine the effectiveness of a diary intake of three different dairy products (250 ml) enriched with vitamins and calcium on decreasing bone mass. METHOS: the present study is a comparative trial of three dairy products fortified with calcium and vitamin D, parallel, randomized, double-blind andsingle-center. Bone mass content (BMC), bone mass density (BMD), T-score and Z score were measured in different locations, besides biochemical markers along 18 months in premenopausal women. Two hundred and ten volunteers from all the three groups were submitted to the same monitoring procedures, consisting on blood extraction, urine collection and energy X-ray absorptiometry (DEXA) done in the laboratory. The monitoring was carried on three times, first at month 0 (baseline), the second at month 9 (in the middle of the treatment) and, finally, at month 18 (the end of the treatment). RESULTS: the majority of anatomical locations showed both BMC and BMD decrease ranging between 0.5% and 1.5%. The T score and the Z-scoreincreased in lumbar spine after the treatment with the dairy products. Moreover, the most noteworthy change on the biomarkers of bone resorption was showed by plasmatic tartrate-resistant acid phosphatase (TRAP), with and increase between 20.7% and 29.5% after the intake of the different products. CONCLUSIONS: therefore, the intake of the three dairy products improves the bone mass in lumbar spine, leading to important changes in the concentration of biomarkers of bone resorption. Especially, tartrate-resistant acid phosphatase seems to be strongly influenced by the intake of every dairy product. However, no significant differences were found between the different dairy products used in the present study. Therefore, the intake of dairy product seems to be more determinant than micronutrients supplementation. PMID- 30307303 TI - Dietary intake and adequacy in Mexican preschool children: National Health and Nutrition Survey 2012. AB - OBJECTIVE: to estimate energy, nutrient intake and diet adequacy in preschool aged children based on data from the Mexican National Health and Nutrition Survey 2012. MATERIAL AND METHODS: dietary data in children < 5 years (n = 1,212) collected through a Semi-quantitative Food Frequency Questionnaire (SFFQ) were analyzed. Energy and daily nutrient intakes and adequacies were calculated comparing by sociodemographic characteristics. RESULTS: median daily energy intake was 1,252 kcal (adequacy 104%). Adequacies above 100% were observed for calcium, zinc, vitamin C, folate, vitamin B12, vitamin A and median of saturated fat. Low percent adequacies were observed for fiber, iron, polyunsaturated fat and vitamin D. Intakes were lower in the southern region compared to other regions. Most intakes and adequacies were higher in urban compared to rural areas, but fiber had the opposite trend. Indigenous children had low intakes and percent adequacies. CONCLUSIONS: risks of dietary deficiencies and excess are present in Mexican preschool-aged children, with marked differences across sociodemographicstrata. PMID- 30307304 TI - Effect of L-arginine intake on exercise-induced hypotension. AB - OBJECTIVE: to verify if one single dose of L-arginine improves post-exercise hypotension (PEH) in hypertensive. METHODS: double-blind, placebo, randomized with 20 hypertensive (51.47 +/- 1.24 years). Two sessions of aerobic exercise were performed proceeded for the ingestion of one dose of 7 g of L-arginine (EX LARG) or placebo (EX-PLA), plus one session only with L-arginine ingestion (L ARG). Blood pressure (BP) was measured at rest, and each ten minutes for a period of 60 minutes recovery after exercise. Blood samples were taken before and after exercise for analysis of plasma concentration of nitrite and malondialdehyde (MDA). One-way ANOVA tests were used to compare the baseline conditions and two way ANOVA, to evaluate possible differences in pressure responses between procedures. RESULTS: both sessions EX-LARG and EX-PLA showed similar peak reduction for the mean systolic blood pressure (-6.58 +/- 0.95 mmHg and -8.38 +/- 1.29 mmHg respectively, p = 0.28). On the other hand, for the diastolic component, only L-ARG was able to promote PEH (-1.85 +/- 0.44 mmHg), significantly better than EX-PLA (+2.13 +/- 0.62 mmHg; p < 0.01). L-ARG alone did not result in significant changes in BP. Nitrite and MDA behaved similarly between procedures. CONCLUSION: a single dose of L-arginine before exercise improves diastolic PEH. PMID- 30307305 TI - The risk of eating disorders and academic performance in adolescents: DADOS study. AB - INTRODUCTION: eating disorders (ED) are complex multifactorial chronic diseases with adverse consequences on cognition in adolescence. OBJECTIVES: the main aim of the present study was to analyze the association between the risk of ED and academic performance in adolescents, considering the key role of weight status. METHODS: a total of 261 adolescents (13.9 +/- 0.3 years) from the DADOS (Deporte, Adolescencia y Salud) Study were included in the analysis. The risk of ED was assessed using the Sick Control on Fast Food (SCOFF) questionnaire. Weight status was assessed by body mass index (BMI) (kg/m2). Academic performance was assessed through final grades and through the Spanish version of the SRA Test of Educational Ability (TEA). RESULTS: the risk of ED was negatively associated with academic grades, and with verbal and numeric abilities measured through TEA. Adolescents with non-eating disorder risk showed higher scores in academic grades (but not in the TEA components). Overweight and obese adolescents reported higher risk of ED. CONCLUSIONS: the risk of ED is negatively associated with academic performance, being higher in overweight and obese adolescents. Interventional programs aimed to improve academic performance should take into account weight status and the risk of ED. PMID- 30307306 TI - Health-related physical fitness of normal, stunted and overweight children aged 6 14 years in Macedonia. AB - OBJECTIVE: the objective of this study is to compare the growth and health related physical fitness of normal, overweight/obese and stunted Macedonian children aged 6-14 years. METHODS: this cross-sectional study included 9,241 children of Macedonian nationality, from 19 primary schools from the central and east part of the Republic, out of which eight are in a rural setting and eleven are in urban environment. In order to carry out the objectives of the research, four anthropometric measurements, two derived anthropometric measurements, two measurements for assessing body composition and seven fitness tests were applied. Normal-not stunted, not owt/ob; stunted-not owt/ob; and owt/ob-not stunted were compared with multivariate analysis of covariance controlling for socioeconomic status, residence status (urban or rural), sex, age and age squared. RESULTS: statistically significant differences were found in all anthropometric measurements, and measurements for assessing body composition among the groups of subjects classified as normal, stunted and overweight/obese (p < 0.000). Children who belong to the normal weight group achieve better results in all fitness tests (p < 0.001), except for the handgrip and bent arm hang tests. Overweight/obese children achieve better results in the handgrip fitness test compared to normal and stunted children. Stunted children achieve better results in the bent arm hang fitness test compared to normal and overweight/obese children. Intergroup differences were found in the sit and reach fitness test. CONCLUSION: when compared to normal weight children, both under- and over-nourished children performed poorer on some, but not all, health-related fitness tests. PMID- 30307307 TI - Vitamin A nutritional status in patients with coronary artery disease and its correlation with the severity of the disease. AB - INTRODUCTION: the purpose of this study was to assess the vitamin A (VA) nutritional status of patients with coronary artery disease (CAD) and its correlation with the severity of the disease, taking into consideration zinc concentration and oxidative stress. METHODS: the patients were preoperative inpatients awaiting myocardial revascularization surgery. The serum concentrations of retinol, beta-carotene, zinc, malondialdehyde (MDA) and C reactive protein (CRP) were quantified. CAD severity was assessed by cineangiography, observing the parameters of severity, extent and occlusion. An echocardiogram was performed to assess the ejection fraction. RESULTS: ninety individuals were studied (64.5 +/- 9.6 years). Zinc did not correlate with retinol (r = -0.009/p = 0.40), beta-carotene (r = -0.06/p = 0.73) or MDA (r = 0.03/p = 0.70), but zinc deficiency was more frequent amongst the patients with high MDA (quartiles 50 and 75). CRP was found to be associated with retinol (x2 = 3.95/p = 0.04). The individuals with retinol deficiency had more severe CAD, and beta-carotene diminished as the extent score rose, although this was not statistically significant (p = 0.12). The degree of severity was associated to extent (x2 = 67.9)/(p < 0.001), occlusion (x2 = 34.5/p < 0.001) and CRP (x2 = 5.9/p = 0.05), while extent was associated with MDA (x2 = 42.1)/(p < 0.001). There was a positive correlation between the ejection fraction and beta-carotene (r = 0.42/p = 0.02). CONCLUSION: findings from this study indicate that chronic inflammation resulting from atherosclerosis is related to disease severity and consequent influence on nutritional status of VA. PMID- 30307308 TI - [Nutritional screening in hospitalized pediatric patients: systematic review]. AB - INTRODUCTION: malnutrition in the pediatric population has been associated with a great number of physiological problems and complications, which lead to a longer period of hospitalization, a higher risk of infections, a rise in mortality rate, and hence, a rise in assistance expenses. OBJECTIVE: to collect available evidence on tools of nutritional screening frequently used in pediatrics that allow identifying, preventing and intervening hospital malnutrition, as well as providing guidelines regarding the appropriate application instant. MATERIALS AND METHODS: a systematic review of literature was carried out in accordance with the PRISMA Declaration (Preferred Reporting Items in Systematic Reviews and Meta Analyses) and in the main databases, search in ClinicalTrials and gray literature in Open Gray and TRIP Database. Then, the articles were selected and classified depending on the type of study. The quality assessment was done in accordance with the Scottish Intercollegiate Guidelines Network (SIGN) checklists. RESULTS: one hundred and ten articles were identified, following the parameters of the PRISMA declaration. Twenty-one articles were analyzed and evaluated through the SIGN methodology; 19 met the high quality criteria and were included in the present review. Six nutritional screening tools in pediatrics were identified, STRONGkids being the tool referred by 63% of the studies for the detection of malnutrition risk. CONCLUSIONS: the present systematic review allowed us to conclude that STRONGkids is the best screening tool for hospitalized children since it is practical, quick, easy to use and it reliably predicts the risk of malnutrition. However, further studies are required to validate the use of this in the Colombian context. PMID- 30307309 TI - [Palm oil and cardiovascular health: considerations to evaluate the literature critically]. AB - Palm oil is obtained from Elaeis guineensis, E. oleifera or the hybrid OxG palm fruits. When crude, it contains high carotenoid concentrations (responsible for the red color), tocopherols and tocotrienols, but most of them are eliminated during its refining. Palm oil main components are palmitic and oleic acids, both near 50%, but their proportion changes depending on the fraction used. Fatty acids absorption and the effect on blood lipid profile depend on the position in the triacylglycerol, especially in the sn-2 position. The location of the monounsaturated or saturated fatty acids varies depending on the type of palm oil or fraction used. We critically review the two main reviews published about palm oil, which analyze 67 publications, and several studies that are more recent. Most of the studies were performed in non-European countries where palm oil is the main culinary oil. The effect on cardiovascular risk factors depends on the fat used as counterpart. Palm oil improves lipid profile after a diet rich in trans and saturated fats, while it impairs lipid profile after a diet rich in monounsaturated and polyunsaturated fats. Relevant methodological errors have been identified, such as not differentiating between palm oil, palm kernel oil and their fractions, comparing single fatty acids with whole oils or fats, or not considering physical activity or other factors that can affect blood lipids. No studies considering palm oil as an ingredient in a Mediterranean diet context, where olive oil is the main culinary oil, were found, so extrapolation of data is currently very difficult. PMID- 30307310 TI - [Nutritional management of amyotrophic lateral sclerosis: summary of recommendations]. PMID- 30307311 TI - [In Memoriam: Pilar Marco Garde ( 1944-2018)]. PMID- 30307312 TI - Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac functions, and arterial remodeling. AB - Currently, dual or triple drug combinations comprising different vasodilators are the mainstay for the treatment of pulmonary arterial hypertension (PAH). But the patient outcome continues to be disappointing because the existing combination therapy cannot restrain progression of the disease. Previously, we have shown that when given as a monotherapy, long-acting inhaled formulations of sildenafil and rosiglitazone ameliorate PAH in rats. Here we prepared and characterized poly(lactic-co-glycolic acid (PLGA)-based long-acting inhalable particles of sildenafil and rosiglitazone. We have then assessed the efficacy of the combinations of sildenafil and rosiglitazone, given in plain forms or as PLGA particles, in reducing mean pulmonary arterial pressure (mPAP) and improving pulmonary arterial remodeling and right-ventricular hypertrophy (RVH) in SUGEN 5416 plus hypoxia induced PAH rats. After intratracheal (IT) administration of the formulations, we catheterized the rats and measured mPAP, cardiac output, total pulmonary resistance, and RVH. We also conducted morphometric studies using lung tissue samples and assessed the degree of muscularization, arterial medial wall thickening, and the extent of collagen deposition. Compared with the plain drugs, given via the pulmonary or oral route as a single or dual combination, PLGA particles of the drugs, although given at a longer dosing interval compared with the plain drugs, caused more pronounced reduction in mPAP without affecting mean systemic pressure (mSAP), improved cardiac function, slowed down right-heart remodeling, and reduced arterial muscularization. Overall, PLGA particles of sildenafil and rosiglitazone, given as an inhaled combination, could be a viable alternative to currently available vasodilator-based combination therapy for PAH. PMID- 30307313 TI - Consequences of Early Postnatal Lipopolysaccharide Exposure on Developing Lungs in Mice. AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants that is characterized by interrupted lung development. Postnatal sepsis causes BPD; yet, the contributory mechanisms are unclear. To address this gap, studies have used lipopolysaccharide (LPS) during the alveolar phase of lung development. However, the lungs of infants who develop BPD are still in the saccular phase of development, and the effects of LPS during this phase are poorly characterized. We hypothesized that chronic LPS exposure during the saccular phase disrupts lung development by mechanisms that promote inflammation and prevent optimal lung development and repair. Wild-type C57BL6J mice were intraperitoneally administered 3, 6, or 10 mg/kg of LPS or a vehicle once daily on postnatal days (PNDs) 3-5. The lungs were collected for proteomic and genomic analyses, and flow cytometric detection on PND6. The impact of LPS on lung development, cell proliferation and apoptosis was determined on PND7. Finally, we determined differences in the LPS effects between the saccular and alveolar lungs. LPS decreased the survival and growth rate, and lung development in a dose-dependent manner. These effects were associated with decreased expression of proteins regulating cell proliferation and differentiation, and increased expression of those mediating inflammation. While the lung macrophage population of LPS-treated mice increased, the T-regulatory cell population decreased. Further, LPS-induced inflammatory and apoptotic response, and interruption of cell proliferation and alveolarization was greater in alveolar than in saccular lungs. Collectively, the data support our hypothesis and reveal several potential therapeutic targets for sepsis-mediated BPD in infants. PMID- 30307314 TI - A Comparative Study of Fluorescence Assays in Screening for BRD4. AB - Fluorescence assay technologies are commonly used in high-throughput screening because of their sensitivity and ease of use. Different technologies have their characteristics and the rationale for choosing one over the other can differ between projects because of factors such as availability of reagents, assay performance, and cost. Another important factor to consider is the assay susceptibility to artifacts, which is almost as important as the ability of the assay to pick up active compounds. Spending time and money on false positives or missing the opportunity to build chemistry around false negatives is something that every drug project tries to avoid. We used a BET family Bromodomain, BRD4(1), to explore the outcome of a screening campaign using three fluorescent assay technologies as primary assays. A diverse 7,038 compound set was screened in fluorescence lifetime, fluorescence polarization, and homogeneous time resolved fluorescence to look at primary hit rates, compound overlap, and hit confirmation rates. The results show a difference between the fluorescence assay technologies with three separate hit lists and some overlap. The confirmed hits from each assay were further evaluated for translation into cells (NanoBRETTM). Most of the actives confirmed in cells originated from compounds that overlapped between the assays. In addition, a well-annotated set of compounds with undesirable mechanism of inhibition was screened against BRD4(1) to compare the ability to discriminate true hits from artifact compounds. The results indicate a difference between the assays in their ability to generate false positives and negatives. PMID- 30307315 TI - Retraction: Modulatory effects of rosemary leaves aqueous extraction against oxidative stress and related damages in experimental model of CCl4-induced cardiac toxicity in mice. PMID- 30307316 TI - Ex vivo evaluation of the effects of a white grape juice extract on lymphocytic mitochondrial functions. AB - The physio-pathological role of mitochondria in aging and age-related diseases has stimulated the search for compounds able to promote mitochondrial functionality. Our study was designed to evaluate the effect of a white grape juice extract (WGJe) on mitochondrial activity, in an ex vivo experimental model consisting of activated lymphocytes obtained from a younger age group and an older age group of subjects. WGJe steadily decreased the lymphocytic mitochondrial mass in the older subjects, without a relevant effect in their younger counterpart, and significantly enhanced Deltapsim in both groups investigated. Finally, WGJe reduced the endogenous mitochondrial production of H2O2 in all subjects. The results support the potential use of WGJe to improve mitochondrial functionality, thus maintaining human health and slowing down aging. PMID- 30307317 TI - Facile fabrication of a novel hybrid nanoparticles by self-assembling based on pectin-doxorubicin conjugates for hepatocellular carcinoma therapy. AB - Hepatocellular carcinoma (HCC) is one of the greatest public health problems worldwide, and chemotherapy remains the major approach for the HCC treatment. Doxorubicin (DOX) is one of the anthracycline antibiotics but its clinical use is limited due to its severe cardiotoxicity. In this study, novel hybrid nanoparticles by self-assembling based on pectin-doxorubicin conjugates (PDC-NPs) were fabricated for HCC treatment. The stabilized structure of the PDC-NPs was characterized by methylene blue absorption, the size, zeta potential and the morphology, which was investigated by Zetasizer nanoparticle analyzer and transmission electron microscope (TEM), of nanoparticles. The PDC-NPs achieved a sustained and prolonged release ability, which was illustrated with in vitro drug release profiles, anti-cell proliferation study, cellular uptake assay and in vivo pharmacokinetics analysis. Biocompatibility of the PDC-NPs was assessed with bovine serum albumin (BSA) adsorption test, hemolysis activity examination and viability evaluation of human umbilical vein endothelial cells. Importantly, in vivo studies of the PDC-NPs, which were performed in the athymic BALB/c nude mice, demonstrated that the PDC-NPs significantly reduced the lethal side effect of DOX. Additionally, the H&E staining and serum biochemistry study further confirmed the excellent biological security of the PDC-NPs. PMID- 30307318 TI - The importance of safe working legislation for neuroradiologists. PMID- 30307319 TI - Independent usefulness of flow phase 99mTc-red blood cell scintigraphy in predicting the results of angiography in acute gastrointestinal bleeding. AB - OBJECTIVE:: In acute gastrointestinal bleeding, despite positive dynamic phase 99mTc-red blood cell scintigraphy, invasive catheter angiography (CA) is frequently negative. In this study, we investigated the value of flow phase scintigraphy in predicting extravasation on CA. METHODS:: Institutional review board approval with a waiver of informed consent was obtained for this retrospective study. A total of 173 scintigraphy procedures performed in 145 patients with GIB between January 2013 and August 2014 were analysed. Scintigraphy had two phases: flow (1 image/s for 1 min) followed by dynamic (1 image/30 s for 1 h). Patients who underwent CA within 24 hours of positive scintigraphy were assessed. Each scintigraphy phase was randomly and independently reviewed by two nuclear medicine physicians blinded to the outcomes of the other phase and of CA. RESULTS:: A total of 42 patients (29%) had positive scintigraphy. Of these patients, 29 underwent CA, and extravasation was seen in 6 (21%). In all, dynamic phase scintigraphy was positive. 13 of the 29 patients also had positive flow phase scintigraphy. The sensitivity, specificity, positive predictive value, and negative-predictive value of flow phase scintigraphy for extravasation on CA were 100, 70, 46, and 100%, respectively. Specificity and positive predictive value were higher when CA was performed within 4 hours of positive flow phase scintigraphy. CONCLUSIONS:: Negative flow phase scintigraphy can identify patients who will not benefit from CA despite positive dynamic phase scintigraphy. The likelihood of extravasation on CA is higher when performed soon after positive flow phase scintigraphy. ADVANCES IN KNOWLEDGE:: Negative flow phase scintigraphy identifies patients who will not benefit from invasive catheter angiography despite positive results on subsequent dynamic phase scintigraphy. Increasing the delay between positive red blood cell scintigraphy and catheter angiography progressively reduces the likelihood of identifying extravasation, which is required to target embolization. PMID- 30307321 TI - Potential of dry powder inhalers for tuberculosis therapy: facts, fidelity and future. AB - Tuberculosis (TB) is a contagious and airborne infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). In spite of substantial research efforts, continuous multiple high-dose drug therapy regularly for 4-7 months can impede patient quality of life. The pathology of TB and biology of pulmonary airways permits for a variety of drug delivery strategies and natural route of infection denotes a more logical remedial approach for treatment of TB. Pulmonary delivery is non-invasive, allow easy transcytosis in alveolar region, avoids first-pass metabolism and extensive vascularization facilitates delivery of therapeutic agents to infection site. It also potentially reduces the frequency with dose requirement and linked side effects. Dry powder is a most preferred inhalation option due to their greater physiochemical stability over liquid or suspension based formulations. Dry powder inhalers (DPIs) are easy to handle and appropriate for high-dose formulations. Moreover, the progress of disciplines such as nanotechnology, particle engineering, material science and molecular biology permits further expansion of treatment capability and efficiency. Thus, this article will focus on the role of novel DPIs systems for treatment of TB. This article also contains a dedicated section discussing about technical limitations and clinical challenges with help of strengths, weaknesses, opportunities and threats (SWOT) analysis. Additionally, it will also offer some basic background information for drug repurposing, formulation development and drug delivery systems. PMID- 30307320 TI - Sources of Information and Support for Breastfeeding: Alignment with Centers for Disease Control and Prevention Strategies. AB - BACKGROUND AND OBJECTIVES: Research consistently supports health benefits of breastfeeding; however, rates in the United States remain below Healthy People 2020 goals. To increase breastfeeding, information and support are needed from multiple sources. Given differences in breastfeeding rates by demographic characteristics, sources of information and support may also differ. In addition, recent research suggests potential differences in health outcomes related to feeding method (direct breastfeeding only, feeding expressed human milk, combination-feeding with formula). This study examined (1) information and support received within Centers for Disease Control and Prevention (CDC)-defined strategies for supporting breastfeeding mothers, (2) differences in rates of information and support received by demographics, and (3) associations with feeding method at 6 weeks postpartum. MATERIALS AND METHODS: A sample of 447 women participating in the Synergistic Theory Research Obesity and Nutrition Group (STRONG) Kids 2 study completed surveys with questions from the CDC Survey on Infant Feeding Practices II related to sources of information and support for breastfeeding and breast pump use, and about demographics and feeding method at 6 weeks postpartum. RESULTS: Frequencies of supports received within each category indicate that professional supports were the most pervasive, followed by support from friends and relatives. However, women at greater risk for breastfeeding cessation (lower education, Women, Infants, and Children participants, single mothers) received information and support at lower rates. Education and information support was the only source significantly associated with feeding method. CONCLUSION: New approaches are needed to increase efficacy of information delivery, especially for at-risk populations, to better meet CDC recommendations. PMID- 30307323 TI - The International Commission on Radiological Protection at 90. PMID- 30307322 TI - Genetically Engineered Adipose Mesenchymal Stem Cells Using HIV-Based Lentiviral Vectors as Gene Therapy for Autoimmune Diseases. AB - The immunomodulatory and self-renewable features of human adipose-derived mesenchymal stem cells (hAD-MSCs) mark their importance in regenerative medicine. Interleukin (IL)-23 as a proinflammatory cytokine suppresses T regulatory cells and promotes the response of T helper 17 and T helper 1 cells. This pathway initiates inflammation and immunosuppression in several autoimmune diseases. The current study aimed at producing recombinant IL-23 decoy receptor (RIL-23R) using hAD-MSCs as a good candidate for ex vivo cell-based gene therapy purposes to reduce inflammation in autoimmune diseases. hAD-MSCs was isolated from lipoaspirate and then characterized by differentiation. RIL-23R was designed and cloned into a pCDH813A-1 lentiviral vector. The transduction of hAD-MSCs was performed at multiplicity of infection = 50 with pCDH-EFI alpha-RIL-23R-PGK copGFP. Expressions of RIL-23R and octamer-binding transcription factor 4 (OCT-4) were determined by real-time polymerase chain reaction. Self-renewing properties were assayed with OCT-4. Bioactivity of the designed RIL-23R was evaluated by IL 17 and IL-10 expression of mouse splenocytes. The results showed that the transducted hAD-MSCs/RIL-23R, expressing IL-23 decoy receptor, can provide a useful approach for a basic research on cell-based gene therapy for autoimmune disorders. PMID- 30307324 TI - Constitution of the International Commission on Radiological Protection 2016 March 21. PMID- 30307325 TI - Rules of the International Commission on Radiological Protection: Amended by the ICRP Main Commission on 2018 April 29. PMID- 30307326 TI - Self-control depletion and sleep duration: the mediating role of television viewing. AB - OBJECTIVE: Sleep insufficiency has been related to self-control failure: people fail to go to bed in time and end up sleep deprived. The role of state self control in predicting bedtime and sleep duration has not yet been investigated. Based on research claiming an overlap between depleted self-control resources and fatigue, self-control depletion may foster earlier bedtimes. Conversely, self control depletion also increases the propensity to procrastinate bedtime by giving in to the immediate gratification of late night entertainment. This study therefore looked at procrastinatory television viewing and its intermediary role in the association between state self-control and bedtime. The implications for sleep duration are examined. DESIGN: Firstyear students (N = 234) participated in an online survey. Using Day Reconstruction Method, they charted their activities and experiences during the preceding day and subsequent bedtime behavior. RESULTS: Self-control depletion was directly related to earlier bedtimes, which we explained by its similarity to fatigue. This was associated with longer sleep duration. Self-control depletion was indirectly related to later bedtimes because it increased the propensity to procrastinate by watching television. This was associated with shorter sleep duration. CONCLUSION: This study exposes a dual pathway between self-control depletion and sleep duration, whereby procrastinatory television viewing may reduce sleep duration. PMID- 30307327 TI - Characterization of Oxide Layers on Technical Copper Material Using Ultraviolet Visible (UV-Vis) Spectroscopy as a Rapid On-Line Analysis Tool. AB - An ultraviolet visible (UV-Vis) spectroscopy method was developed that can quantitatively characterize a technical copper surface to determine oxide layers and organic impurities. The oxide layers were produced by a heating step at 175 C for four different times (range = 1-10 min). Partial least squares (PLS) regression was used to establish a relation between the UV-Vis spectra and film thickness measurements using Auger electron spectroscopy depth profiles. The validation accuracy of the regression is in the range of approximately 2.3 nm. The prediction model allowed obtaining an estimation of the oxide layer thickness with an absolute error of 2.9 nm. Alternatively, already known methods cannot be used because of the high roughness of the technical copper surfaces. An integrating sphere is used to measure the diffuse reflectance of these surfaces, providing an average over all angles of illumination and observation. PMID- 30307328 TI - Chitosan-gold nanoparticles mediated gene delivery of c-myb facilitates osseointegration of dental implants in ovariectomized rat. AB - Osseointegration of dental implants is affected by osteoporosis. The purpose of this study was overcome the implant failure and facilitate the osseointegration of dental implants by c-myb in ovariectomized (OVX)-induced osteoporosis. c-myb is a transcription factor and supports bone formation. Plasmid DNA/c-myb conjugated with chitosan-gold nanoparticles (Ch-GNPs/c-myb) promoted osteogenesis and inhibited osteoclastogenesis in MC-3T3 E1 cells. Ch-GNPs/c-myb involved the reduction of the nuclear factor of activated T-cells 1, c-Fos, and tartrate resistant acid phosphatase-positive multinucleated osteoclasts in receptor activator of nuclear factor-kappaB ligand (RANKL) stimulated bone marrow macrophages. In vivo results of rat mandibles demonstrated Ch-GNP/c-myb-coated titanium (Ti) implants increased the volume and density of newly formed bone and the osseointegration of dental implant with bone by micro computed tomography examination after OVX-induced osteoporosis. Immunohistochemical analysis showed increased c-myb expression and upregulation of bone morphogenic proteins, osteoprotegerin and EphB4, as well as the downregulation of RANKL by Ch-GNP/c-myb coated Ti implants. Hematoxylin and Eosin staining expressed new bone formation by Ch-GNP/c-myb-coated Ti implants. Our findings indicated that c-myb delivered by Ch-GNPs supports osseointegration of dental implant even in osteoporotic condition. c-myb may be applicable to support dental implant integration and treatment in age-dependent bone destruction disease. PMID- 30307329 TI - Intracranial aneurysm distribution and characteristics according to gender. AB - OBJECTIVE: Female sex is associated with a greater prevalence of cerebral aneurysms. However, it also might be linked to the location and size of the aneurysm. The aim of this study was to find the link between female sex and aneurysm characteristics. METHODS: Our study group consisted of 357 patients admitted to the hospital with both unruptured and ruptured aneurysms confirmed by Digital Subtraction Angiography or Computed Tomography Angiography and aneurysmal subarachnoid haemorrhage confirmed by head CT. Patients' medical records were analyzed for necessary information including, but not limited to medical history, blood test results, and aneurysm prevalence, size and location. RESULTS: Women constituted 232 (64.98%) of all patients. In this group, compared to males, we observed a more common occurrence of multiple aneurysms (1.35 +/- 0.67 vs. 1.2 +/ 0.57; p = .046) and left internal carotid artery aneurysms (25.88% vs. 13.93%; p < .01). Anterior communicating artery aneurysms were less common (17.11% vs. 31.15%; p < .01). Women also had lower dome-to-neck ratios (2.16 +/- 0.82 vs. 2.82 +/- 1.92; p < .01), were less likely to be smokers (53.6% vs. 33.19%; p < .01) and smoked fewer cigarettes per day (15.09 +/- 6.62 vs. 21.09 +/- 11.08; p < 0.01). CONCLUSIONS: Female patients have a greater risk of multiple aneurysms and left internal carotid artery aneurysms, but a lower risk of anterior communicating artery aneurysms. PMID- 30307330 TI - Enhancement of radiotherapy efficacy by silver nanoparticles in hypoxic glioma cells. AB - Radiotherapy is one of the most widely used treatments for therapy of malignant tumors, but resistance to radiation of hypoxic cells in tumor tissues is still a serious concern. Previous studies have demonstrated that silver nanoparticles (AgNPs) enhance the radiosensitivity of human glioma cells in vitro, but the effect of AgNPs on hypoxic glioma cells has not been investigated in detail. The main purpose of this study is to evaluate the radiosensitizing efficacy of AgNPs on hypoxic glioma cells. The half maximal inhibitory concentration (IC50) values of AgNPs for the hypoxic U251 cells and C6 cells were 30.32 MUg/mL and 27.53 MUg/mL, respectively. The sensitization enhancement ratio (SER) demonstrated that AgNPs exhibit higher capacity in radiosensitization in hypoxic cells (U251: 1.78; C6: 1.84) than that in normoxic cells (U251: 1.34; C6: 1.45). The underlying mechanism of AgNPs' radiosensitization in hypoxic cells is through the promotion of apoptosis and enhanced destructive autophagy. There is evidence of crosstalk between apoptosis and autophagy in AgNPs-radiosensitized hypoxic cells where inhibition of autophagy results in decreased apoptosis. These findings suggest that AgNPs can be used as a highly effective nano-radiosensitizer for the treatment of hypoxic glioma. PMID- 30307331 TI - A perfect stimuli-responsive magnetic nanocomposite for intracellular delivery of doxorubicin. AB - Iron oxide nanoparticles (IONs) have been extensively applied in cancer therapy and theranostics due to their admissible magnetic properties, excellent chemical stability and biocompatibility. Herein, a novel stimuli-responsive magnetic nanocomposite was synthesized for cancer therapy; thereby, the triblock copolymer of poly[(2-succinyloxyethylmethacrylate)-b-(N-isopropylacrylamide)-b dimethylaminoethylmethacrylate) [poly(SEMA-b-NIPAM-b-DMAEMA)] was prepared by reversible addition of fragmentation chain transfer (RAFT) polymerization. This triblock copolymer with carboxylic groups of succinyloxyethylmethacrylate was adsorbed onto the surface of Fe3O4 nanoparticles. The morphology, nanocomposite properties and stimuli-responsive behaviours were investigated by field emission scanning electron microscopy, X-ray diffraction, dynamic light scattering, vibrating sample magnetometer (VSM) and thermogravimetric analysis. Doxorubicin (DOX) encapsulation efficacy was 94.3%. Release behaviours of DOX from the magnetic nanocomposite exhibited that the rate of DOX release could be efficiently controlled through temperature and pH. The cytotoxicity of the drug was investigated in vitro against breast cancer cell line (MCF7) using (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assays, 4',6 diamidino-2-phenylindole (DAPI) staining and cellular uptake. In conclusion, the synthesized DOX@nanocomposite can be applied in theranostic applications and anticancer drug delivery owing to admissible properties. PMID- 30307332 TI - Combined adjuvant-delivery system for new generation vaccine antigens: alliance has its own advantage. AB - Vaccines are a significant historical accomplishment in medical science due to its significance in saving millions of lives around the world with a manifold decline in disease burden and health expenditure. Since last decade, extensive efforts in vaccine design based on rational and experimental set up prompts the acknowledgement of several protective antigens; however, the utilization of those antigens as intense safe vaccines is still far beyond their discovery. The advancement of accomplished vaccines will need the combination of numerous strategies. In this way, the vaccine can be capable of provoking an abundant and effective immunization to compete against antigens with minimal/no adverse effects on recipients. First, stable and striking enough on the pharmaceutical point of view. Second, application of rational and realistic approaches to select an appropriate combination of adjuvant, antigen and delivery vehicle in the suitable formulation. Different vaccine adjuvants-delivery system combinations were discussed here elaborately, which are approved/licensed for human vaccines and are in various phases of clinical trials and pre-clinical trials. Challenges/limitations associated with vaccine designing and parameters to be considered, approaches to be applied, using available adjuvants are also detailed. PMID- 30307333 TI - Extracorporeal treatment in salicylate poisoning. PMID- 30307334 TI - The combined administration of parthenolide and ginsenoside CK in long circulation liposomes with targeted tLyp-1 ligand induce mitochondria-mediated lung cancer apoptosis. AB - BACKGROUND: Combinations of natural products with low toxicities using tumor targeting carriers may improve cancer treatment. The combined parthenolide and ginsenoside compound K (CK) within tLyp-1 liposomes, with the aim of improving the efficacy of lung cancer treatment. RESULTS: In vitro studies in A549 human pulmonary adenocarcinoma cells demonstrated that parthenolide/CK tLyp-1 liposomes increased reactive oxygen species levels and induced mitochondrial apoptosis. It enters into cells via receptor-mediated uptake and micropinocytosis, followed by endosomal/lysosomal escape. In vivo studies illustrated that it produced a greater antitumor effect than combined administration of these compounds, with minimal toxicity. CONCLUSION: The findings of this study indicated that combined application of natural products in nanocarriers could offer attractive therapeutic options. PMID- 30307335 TI - Ingestion of bar soap may produce serious injury: clinical effects and risk factors. AB - INTRODUCTION: Most household and body soaps have an alkaline pH (9-12). In addition to their foaming effect, they irritate the skin. This study aims to review soap exposure reported to the Angers Poison Control Centre. METHOD: A retrospective study of accidental or deliberate oral exposure to solid soaps reported to the Angers Poison Control Centre between 1 January 2000 and 1 April 2015. Poisoning severity was reassessed for each case according to the Poisoning Severity Score (PSS). RESULTS: 553 cases of exposure were recorded. In more than 40% of cases (n = 226), exposure occurred in community settings (retirement homes, nursing homes). Patients had a history of dementia in 220 cases (40%). The most common symptoms were labial oedema (28%, n = 153), oropharyngeal irritation (10%, n = 56), salivation (10%, n = 53), vomiting (9%, n = 48) and cough (8%, n = 45). Among symptomatic patients (n = 276), one patient died from aspiration pneumonia and one patient died from a cardiogenic shock following oropharyngeal oedema, vomiting, cough and bronchial obstruction. Patients with dementia were more often symptomatic (75% vs 34%, p < .001) and more frequently hospitalised (22% vs 0.8%, p < .001). They experienced more moderate to severe symptoms (8% vs 0%, p < .001). Mildly severe (PSS2, n = 14), highly severe (PSS3, n = 1) and fatal (PSS4, n = 2) poisoning were observed only in patients with dementia. CONCLUSION: Ingestion of soap bars is potentially serious, especially in patients with dementia. This type of soap should not be available to them in community settings and close monitoring should be considered in the event of oral exposure. PMID- 30307337 TI - Gastroduodenal injury induced by orally administered sodium polystyrene sulfonate. PMID- 30307336 TI - Interpreting gamma-hydroxybutyrate concentrations for clinical and forensic purposes. AB - INTRODUCTION: gamma-Hydroxybutyric acid is an endogenous substance, a therapeutic agent, and a recreational drug of abuse. This psychoactive substance acts as a depressant of the central nervous system and is commonly encountered in clinical and forensic practice, including impaired drivers, poisoned patients, and drug related intoxication deaths. OBJECTIVE: The aim of this review is to assist clinical and forensic practitioners with the interpretation of gamma hydroxybutyric acid concentrations in blood, urine, and alternative biological specimens from living and deceased persons. METHODS: The information sources used to prepare this review were PubMed, Scopus, and Web-of-Science. These databases were searched using keywords gamma-hydroxybutyrate (GHB), blood, urine, alternative specimens, non-conventional biological matrices, saliva, oral fluid, sweat, hair, vitreous humor (VH), brain, cerebrospinal fluid (CSF), dried blood spots (DBS), breast milk, and various combinations thereof. The resulting 4228 references were screened to exclude duplicates, which left 1980 articles for further consideration. These publications were carefully evaluated by taking into account the main aims of the review and 143 scientific papers were considered relevant. Analytical methods: The analytical methods used to determine gamma hydroxybutyric acid in blood and other biological specimens make use of gas- or liquid-chromatography coupled to mass spectrometry. These hyphenated techniques are accurate, precise, and specific for their intended purposes and the lower limit of quantitation in blood and other specimens is 0.5 mg/L or less. Human pharmacokinetics: GHB is rapidly absorbed from the gut and distributes into the total body water compartment. Only a small fraction of the dose (1-2%) is excreted unchanged in the urine. The plasma elimination half-life of gamma hydroxybutyric acid is short, being only about 0.5-0.9 h, which requires timely sampling of blood and other biological specimens for clinical and forensic analysis. Endogenous concentrations of GHB in blood: GHB is both an endogenous metabolite and a drug of abuse, which complicates interpretation of the laboratory results of analysis. Moreover, the concentrations of GHB in blood and other specimens tend to increase after sampling, especially in autopsy cases. This requires the use of practical "cut-off" concentrations to avoid reporting false positive results. These cut-offs are different for different biological specimen types. Concentrations of GHB in clinical and forensic practice: As a recreational drug GHB is predominantly used by young males (94%) with a mean age of 27.1 years. The mean (median) and range of concentrations in blood from apprehended drivers was 90 mg/L (82 mg/L) and 8-600 mg/L, respectively. The concentration distributions in blood taken from living and deceased persons overlapped, although the mean (median) and range of concentrations were higher in intoxication deaths; 640 mg/L (280 mg/L) and 30-9200 mg/L, respectively. Analysis of GHB in alternative specimens: All biological fluids and tissue containing water are suitable for the analysis of GHB. Examples of alternative specimens discussed in this review are CSF, saliva, hair strands, breast milk, DBS, VH, and brain tissue. CONCLUSIONS: Body fluids for the analysis of GHB must be obtained as quickly as possible after a poisoned patient is admitted to hospital or after a person is arrested for a drug-related crime to enhance chances of detecting the drug. The sampling of urine lengthens the window of detection by 3-4 h compared with blood samples, but with longer delays between last intake of GHB and obtaining specimens, hair strands, and/or nails might be the only option. In postmortem toxicology, the concentrations of drugs tend to be more stable in bladder urine, VH, and CSF compared with blood, because these sampling sites are protected from the spread of bacteria from the gut. Accordingly, the relationship between blood and urine concentrations of GHB furnishes useful information when drug intoxication deaths are investigated. PMID- 30307338 TI - Engineering stability in NADPH oxidases: a common strategy for enzyme production. AB - NADPH oxidases (NOXs) are membrane enzymes whose sole function is the generation of reactive oxygen species. Humans have seven NOX isoenzymes that feature distinct functions in immune response and cell-signaling but share the same catalytic core comprising a FAD-binding dehydrogenase domain and a heme-binding transmembrane domain. We previously described a mutation that stabilizes the dehydrogenase domain of a prokaryotic homolog of human NOX5. The thermostable mutant exhibited a large 19 degrees C increase in the melting temperature (Tm) and a much tighter binding of the FAD cofactor, which allowed the crystallization and structure determination of the domain holo-form. Here, we analyze the transferability of this mutation onto prokaryotic and eukaryotic full-length NOX enzymes. We found that the mutation exerts a significative stabilizing effect on the full-length NOX5s from both Cylindrospermum stagnale (Tm increase of 8 degrees C) and Homo sapiens (DeltaTm of 2 degrees C). Enhanced thermal stability resulted in more homogeneous preparations of the bacterial NOX5 with less aggregation problems. Moreover, we also found that the mutation increases the overall expression of recombinant human NOX4 and NOX5 in mammalian cells. Such a 2-5 fold increase is mainly due to the lowered cell toxicity, which leads to higher biomasses. Because of the high sequence identity of the catalytic core within this family of enzymes, this strategy can be a general tool to boost the production of all NOXs. PMID- 30307339 TI - Simultaneous determination of methocarbamol and aspirin in presence of their pharmacopeial-related substances in combined tablets using novel HPLC-DAD method. AB - Objective and Significance: Methocarbamol (MET) and aspirin (ASP) are widely used as a muscle relaxant combination. The USP reports guaifenesin (GUA) and salicylic acid (SAL) as related substances and hydrolytic products of MET and ASP, respectively. This work aimed at developing and validating a simple and sensitive RP-HPLC method for the determination of both drugs as well as their related substances (at their pharmacopeial limits) in their bulk powders, laboratory prepared mixtures, and MET-ASP combined tablets. Methods and Results: Chromatographic separation was achieved in less than 9 min with the required resolution, peak symmetry, and accuracy on C18 column using isocratic elution system of diluted acetic acid (pH 3.2): acetonitrile at the ratio of 79: 21, v/v, at a flow rate of 1 mL/min. Detection was achieved with photodiode array at 233 nm for MET, GUA, and SAL and at 273 nm for ASP. The developed method has been validated as per ICH guidelines and the calibration plots were linear over the concentration ranges of 2-150, 0.4-30, 25-450, and 0.2-27 MUg/mL for MET, GUA, ASP, and SAL, respectively. Conclusion: The optimized method proved to be specific, robust and precise for the quality control of the studied drugs in pharmaceutical preparations to ascertain that their related substances are not exceeding the permitted pharmacopeial limits. PMID- 30307340 TI - Magnetic resonance imaging features influencing high-intensity focused ultrasound ablation of adenomyosis with a nonperfused volume ratio of >=90% as a measure of clinical treatment success: retrospective multivariate analysis. AB - OBJECTIVE: This retrospective study aimed (1) to investigate the magnetic resonance imaging (MRI) features influencing a nonperfused volume ratio (NPVr) >= 90% after high-intensity focussed ultrasound (HIFU) ablation of adenomyosis, and (2) to assess the safety, which was defined in terms of adverse events (AEs) and changes in anti-Mullerian hormone (AMH) concentrations, and clinical efficacy, which was defined in terms of adenomyosis volume reduction and symptom improvement at 6 months' follow-up. METHODS: Sixty-six women who underwent HIFU treatment were divided into groups A (NPVr >=90%; n = 26) and B (NPVr <90%, n = 40). Multivariate logistic regression analyses of MRI features were conducted to identify the potential predictors of an NPVr >=90%. RESULTS: Generalized estimating equation (GEE) analysis was used to model the prediction of an NPVr >=90% with four significant predictors from multivariate analyses: the thickness of the subcutaneous fat layer, adenomyosis volume, T2 signal intensity (SI) ratio of adenomyosis to myometrium, and the Ktrans ratio of adenomyosis to myometrium. Clinical efficacy was significantly greater in group A than in group B. The findings showed no serious AEs and no significant differences between AMH concentrations before and 6 months after treatment. CONCLUSIONS: The present retrospective study demonstrated that achievement of NPVr >=90% as a measure of clinical treatment success in MRI-guided HIFU treatment of adenomyosis using multivariate analyses and a prediction model is clinically possible without compromising the safety of patients. PMID- 30307341 TI - Effect of cholinergic crisis on the potency of different emergency anaesthesia protocols in soman-poisoned rats. AB - BACKGROUND: In a military or terrorist scenario, combination of organophosphorus compounds (OP) poisoning with physical trauma requiring surgical treatment and thus general anaesthesia are possible. Previous in vitro studies showed an altered potency of relevant anaesthetics during cholinergic crisis. Hence, it is not clear, which anaesthetics are suitable to achieve the necessary stage of surgical anaesthesia in OP poisoning. METHODS: In the present study, different anaesthetic regimens (ketamine-midazolam, propofol-fentanyl, thiopental fentanyl), relevant in military emergency medicine, were examined in soman poisoned rats. Clinical signs and cardiovascular variables were recorded continuously. Blood samples for acetylcholinesterase (AChE) activity were drawn. After euthanasia or death of the animals, brain and diaphragm were collected for cholinesterase assays. RESULTS: Propofol-fentanyl and thiopental-fentanyl resulted in surgical anaesthesia throughout the experiments. With ketamine midazolam, surgical anaesthesia without respiratory impairment could not be achieved in pilot experiments (no soman challenge) and was therefore not included in the study. Soman-poisoned and control animals required a comparable amount of propofol-fentanyl or thiopental-fentanyl. In combination with atropine, significantly less propofol was needed. Survival rate was higher with thiopental compared to propofol. Atropine improved survival in both groups. Blood and tissue AChE activities were strongly inhibited after soman administration with and without atropine treatment. DISCUSSION: The current in vivo study did not confirm concerns of altered potency of existing anaesthetic protocols for the application of propofol or thiopental with fentanyl due to soman poisoning. Despite severe cholinergic crisis, sufficient anaesthetic depth could be achieved in all animals. CONCLUSION: Further experiments in in vivo models closer to human pharmaco- and toxicokinetics (e.g., swine) are required for confirmation of the initial findings and for improving extrapolation to humans. PMID- 30307342 TI - Minimally invasive surgical clip closure of anorectal fistulas: current status of OTSC Proctology. AB - OTSC Proctology is a minimally invasive sphincter-preserving technique for the surgical treatment of anorectal fistulas. It is based on a super-elastic Nitinol clip which closes the internal fistula opening to allow healing of the fistula tract. A systematic search of the literature was undertaken to identify publications about OTSC Proctology. All studies and reports identified were reviewed and evaluated to determine the feasibility, efficacy and safety of clip surgery. The assessment of all available studies with a total of more than 200 surgical cases strongly suggests that the clip procedure is safe and effective with a low rate of complications. The technique rendered convincing short and long term results with an overall healing rate of approximately 63%. Best results were achieved when OTSC Proctology was used as first-line treatment (healing rate 74%) and for cryptoglandular fistulas (healing rate 64%). However, its future clinical role for IBD-associated recurrent and anorecto-vaginal fistulas remains to be determined, due to a relatively low number of these patients in the evaluated studies. OTSC Proctology is part of the novel armamentarium for the treatment for anorectal fistulas, which is based on high-technology devices. They can be repeatedly used and even combined without causing irreversible sphincter damage. PMID- 30307343 TI - Real-world experience of calcipotriene and betamethasone dipropionate foam 0.005%/0.064% in the treatment of adults with psoriasis in the United States. AB - BACKGROUND: Clinical trials have established calcipotriene 0.005%/betamethasone dipropionate 0.064% (Cal/BD) foam as a well-tolerated and efficacious topical therapy for psoriasis. METHODS: A chart review of 24 US healthcare providers gathered real-world information (clinical characteristics and outcomes, safety, and resource utilization) for patients (>=18 years old) prescribed Cal/BD foam between January 1 and October 31, 2016, along with healthcare provider characteristics and perceptions of Cal/BD foam. RESULTS: Data were reported from 105 patients and 177 active psoriatic lesions. Cal/BD foam was applied once daily; the prescription was 4 weeks for 69/177 (39%) lesions (median 4, range 1 26 weeks). Knees (n = 41; 23%) and elbows (n = 37; 20%) were the most frequently treated areas. Among 114 lesions, severity improved from "mild"/"moderate"/"severe" to "clear"/"almost clear" in 71%, and 54% had a clinically significant improvement (two-step/greater improvement) in lesion severity from baseline. Of 128 lesions with baseline itch, 90% were not itchy at the best treatment response. Most healthcare providers reported prescribing Cal/BD foam due to its overall efficacy (n = 20/23; 87%). Adverse events were reported in 1/105 patients (1%). CONCLUSION: Data from real clinical practice demonstrate that Cal/BD foam improves psoriasis disease severity and associated itch in patients and further extend results of clinical trials. PMID- 30307345 TI - Numerical analysis of thermal response of tissues subjected to high intensity focused ultrasound. AB - The present work is concerned with the numerical investigation of the thermal response of tissue-mimicking biological phantom(s) subjected to high intensity focused ultrasound (HIFU). Simulations have been performed on the 3-dimensional physical domain for two-layered as well as multi-layered medium consisting of water and liver tissue. Local pressure distribution within the body of the phantom has been calculated by solving the complete full-wave nonlinear form of Westervelt equation. The solution of the pressure wave equation has been coupled with Pennes bioheat transfer equation to determine the full field temperature distribution. Results in the form of pressure fields, temperature distributions and the corresponding thermal dosage in the targeted region of the tissue domain have been presented. Magnitudes of the maximum pressure (and hence the resultant temperature levels) in the focal region as obtained using the nonlinear form of Westervelt equation are found to be significantly higher than that determined based on the linear form of the equation. Compared to water, wherein the acoustic intensity is maximum, the addition of sub-layers of skin, fat, and muscle into water resulted in the reduction of the peak intensity and also shifted the intensity profiles along the direction of propagation of the acoustic waves. However, addition of liver tissue into water led to the shifting of intensity profile in the opposite direction i.e., towards the transducer. The results further reveal that due to the dependence of attenuation coefficient on the source frequency, the temperature at the focal region increases with an increase in the transducer frequency. The work is further extended from single lesion to multiple lesion generation through controlled movement of the transducer and the resultant transient full field temperature distribution has been presented. The concerned observations highlight the need of optimizing the thermal energy for each lesion, the inter spatial distance between different lesions and the delay time so as to ensure minimal thermal damage to the surrounding healthy cells as well as to reduce the total treatment duration. PMID- 30307344 TI - Safety and effectiveness of conventional systemic therapy and biological drugs in patients with moderate to severe psoriasis and HIV infection: a retrospective multicenter study. AB - BACKGROUND: The management of HIV-positive patients with psoriasis is controversial and limited to individual cases or short series of patients. OBJECTIVES: To evaluate the safety and effectiveness of conventional and biologic immunosuppressive drugs in the treatment of patients with psoriasis and concomitant HIV infection. METHODS: A retrospective multicenter study was conducted. The study included data from 2008 to 2016. Inclusion criteria were: HIV adult patients with moderate-to-severe psoriasis, HIV viral load determinations at baseline and at least after 6 months of treatment, and systemic immunosuppressive treatment for at least 6 months. A descriptive analysis was performed. RESULTS: Twenty-three patients with plaque-type psoriasis and HIV infection (five with AIDS) were included. Median follow-up time was 3.2 years. The main drugs used were etanercept, methotrexate, and ustekinumab. In most cases, viral load and CD4 cell count not only remained stable but also improved throughout the follow-up. Six patients presented severe adverse events during the follow-up, four of them in the AIDS stage. At the end of the follow-up period, 76.5% of the patients had achieved a PASI 75. CONCLUSION: Biologic drugs, both anti-TNF alpha agents and ustekinumab, seem to have an acceptable safety profile and high effectiveness in HIV-positive patients. PMID- 30307346 TI - Percutaneous image-guided ablation of bone metastases: local tumor control in oligometastatic patients. AB - INTRODUCTION: Percutaneous image-guided cryo- (CA) and radiofrequency- (RFA) ablations have been widely used in the treatment of painful bone metastases (BM). However, paucity of data is available for the performance of these treatments when used with a curative intent. The aim of this study is to investigate the local progression free-survival (LPFS) after radical percutaneous image-guided ablation of BM in oligometastatic patients, and to identify predictive factors associated with local tumor progression. MATERIALS AND METHODS: This is a retrospective review of all patients who underwent percutaneous image-guided CA or RFA of BM with a radical intent between 2007 and 2018. RESULTS: Forty-six patients with a total of forty-nine BM underwent percutaneous image-guided CA (N = 37; 75,5%) or RFA (N = 12; 24,5%). Primary malignancies included thyroid (N = 11, 22.5%), breast (N = 21; 42.9%), lung (N = 8; 16.3%) and other (N = 9; 18,3%) cancers. Additional consolidation was performed after ablation in 20.4% cases (N = 10). Mean follow-up was 34.1 +/- 22 months. Local progression at the treated site was observed in 28.5% cases (N = 14); 1- and 2-year LPFS was 76.8% and 71.7%, respectively. Size of BM (>2 cm) predicted local tumor progression (p = .002). CONCLUSIONS: Percutaneous image-guided locoregional therapies used in the radical treatment of BM in oligometastatic patients demonstrate significant rates of LPFS providing the size of BM <=2 cm. PMID- 30307347 TI - Impact of scenario based training on asthma first aid knowledge and skills in school staff: an open label, three-arm, parallel-group repeated measures study. AB - OBJECTIVE: To test the hypothesis that scenario-based skills training is more effective than knowledge training alone in improving the asthma first aid skills of school personnel. Education developed specifically for non-primary caregivers such as school staff is vital to minimize the risk of mortality associated with asthma. METHODS: Schools were allocated to one of three arms to compare AFA knowledge and AFA skills. Arm 1 underwent conventional asthma training, arm 2 underwent scenario-based training and arm 3 had a combination of the two. Conventional asthma training involved a didactic oral presentation. The scenario based skills training required the participant to describe and demonstrate how they would manage a child having a severe exacerbation of asthma using equipment provided. Follow-up occurred at 3 weeks post baseline and again between 3-7 months after the first training/education visit. RESULTS: Nineteen primary schools (204 participants) were recruited. One-way ANOVA and Bonferroni Post-Hoc Tests showed there was a significant difference in AFA skills scores between the study arms who underwent scenario-based training; arms 2 and 3 (91.5% and 91.1%) and arm 1 who underwent conventional asthma training (77.3%) (p < 0.001). AFA knowledge improved significantly in all study arms with no differences between study arms. Improvements seen in both AFA knowledge and AFA skills were maintained over time. CONCLUSIONS: Scenario-based training was superior to conventional didactic asthma training for AFA skills acquisition and overall competency in the administration of AFA and should be included in future asthma training programs. PMID- 30307348 TI - Programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocytes in advanced non-small cell lung cancer treated with microwave ablation and chemotherapy. AB - BACKGROUND: Programmed death-ligand 1 (PD-L1) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with non-small cell lung cancer (NSCLC). We conducted this study to evaluate the correlation between PD-L1 or CD8+ TILs expression and MWA or survival in advanced NSCLC patients treated with microwave ablation (MWA) plus chemotherapy. METHODS: Previously untreated, pathologically verified advanced NSCLC patients with adequate tissues for the analysis of PD-L1 expression and the presence of CD8+ TILs were retrospectively enrolled. None of the patients had sensitive mutations, and therefore, they were treated with MWA of the primary tumors followed by chemotherapy. RESULTS: A total of 51 patients were enrolled. PD-L1 expression and the presence of CD8+ TILs were identified in 31 (60.8%) and 9 (17.6%) patients, respectively. PD-L1 expression and CD8+ TILs had no correlation with baseline characteristics, the response to chemotherapy or MWA. Patients with PD-L1 expression had similar progression-free survival (PFS: 7.9 months for PD-L1-positive vs. 5.8 months for PD-L1-negative; p = .660) and overall survival (OS: 18.7 months for PD-L1-positive vs. 15.2 months for PD-L1 negative; p = .901). Patients with CD8+ TIL expression did not show superior PFS (CD8+ TIL vs. CD8- TIL, 8.0 vs. 6.2 months, p = .435) or OS (CD8+ TIL vs. CD8- TIL, 20.5 vs. 16.9 months, p = .653). CONCLUSION: PD-L1 expression and the presence of CD8+ TILs could predict neither the patients' response to chemotherapy or MWA nor survival in advanced NSCLC patients treated with MWA plus chemotherapy. PMID- 30307349 TI - Laparoscopic near-total splenectomy: a single-center experience of a standardized procedure. AB - BACKGROUND: Near-total splenectomy (NTS) represents an innovative and effective surgery technique for spleen disease, reducing the risk of severe infections and thromboembolic events after total splenectomy. The authors reported a laparoscopic near-total splenectomy (LNTS) surgical experience following the optimal results of the open approach, describing a standardized and effective minimally invasive technique with the purpose of preserving a minimal residual spleen. MATERIAL AND METHODS: From November 2006 to September 2016, 15 patients with splenic and hematologic disease underwent LNTS, according to a laparoscopic procedure developed by the authors. The end criterion was to conserve a remanent spleen of 10-15 cm3 in size. RESULTS: Patient age ranged between 18 and 59 years. Mean operative time was 70 +/- 20 min. Mean hospital stay was 3.46 (range 3-7) days. One complication occurred during the surgery for a lesion of the inferior polar artery with need of a total splenectomy. No conversion to open surgery was necessary. CONCLUSIONS: LNTS is a safe and effective technique for the management of splenic and hematologic disease with a low intra- and post-operative complication rate, and it can minimize the late sequelae of secondary splenectomy. However, it requires further studies with more cases to evaluate its role. PMID- 30307350 TI - Lipid emulsion for acute organophosphate insecticide poisoning - a pilot observational safety study. AB - INTRODUCTION: Organophosphate (OP) poisoning is an important public health concern in South-Asia especially in the farming population. Treatment of OP poisoning has remained unchanged since decades and case fatality is 10-40% despite best supportive care, anticholinergic agents and oximes. A new antidote is the need of the hour. Lipid emulsion being inexpensive, easily available and effective in management of other lipid soluble toxins may be a novel option. However, safety has not been established and efficacy is limited to animal studies and case reports in humans with OP poisoning. METHODS: An open-label pilot study was undertaken to establish the safety of lipid emulsion in OP poisoning. Patients with symptomatic OP poisoning, meeting the inclusion and exclusion criteria were treated with 100 mL of 20% intravenous lipid emulsion (after consent) in addition to standard of care. They were monitored for change in hemodynamic parameters, change in hematology and biochemical parameters at various intervals of time after initiation of therapy. Morbidity, mortality, and occurrence of adverse effects were compared with historical control group. RESULTS: Forty patients with symptomatic OP poisoning were enrolled in the study group. No significant change in hemodynamic parameters (pulse rate, systolic, diastolic blood pressure, and mean arterial pressure) or in hematology and biochemical parameters were seen. No adverse effects were noted. Compared to historical controls, no change in mortality was noted, although there was reduced duration of mechanical ventilation, hospital stay, and early resolution of hypernatremia. CONCLUSIONS: This study evaluates the safety of lipid emulsion in OP poisoning. Absence of change in hemodynamic parameters and adverse effects suggests lipid emulsion may be safe for this indication. Large randomized controlled trials are now required to assess clinical efficacy. ClinicalTrials.gov number: NCT03564574. PMID- 30307351 TI - Association between second hand smoke (SHS) exposure and caregiver stress in children with poorly controlled asthma. AB - OBJECTIVE: Urban children with asthma experience high rates of second hand smoke (SHS) exposure. The objective was to examine whether SHS exposure is associated with symptom frequency in children with poorly controlled asthma. METHODS: Children were enrolled in a RCT to test the efficacy of an environmental control behavioral intervention versus an attention control group and followed over 12 months. SHS exposure assessed using salivary cotinine measurement. Frequency of child asthma symptoms, healthcare utilization, household smoking and caregiver daily life stress were obtained via caregiver report. Time of enrollment was recorded to assess seasonal factors. Symptom days and nights were the primary outcomes. Multivariable models and odds ratios examined factors that best predicted increased frequency of daytime/nighttime symptoms. RESULTS: Children (n = 222) with a mean age of 6.3 (SD 2.7) years, were primarily male (65%), African American (94%), Medicaid insured (94%), and had poorly controlled asthma (54%). The final multivariable model indicated symptoms in the fall (OR 2.78; 95% CI 1.16, 6.52) and increased caregiver daily life stress (OR 1.13, 95% CI 1.02, 1.25) were significantly associated with increased symptom days when controlling for cotinine level, intervention status, child age and home and car smoking restrictions. CONCLUSIONS: There was no impact of SHS exposure on increased symptom frequency. High caregiver daily life stress and symptoms in fall season may place children with asthma at risk for increased day/nighttime symptoms. Close monitoring of symptoms and medication use during the fall season and intervening on caregiver life stress may decrease asthma morbidity in children with poorly controlled asthma. PMID- 30307352 TI - Empirically Supported Treatments for Students with Autism: General Education Teacher Knowledge, Use, and Social Validity Ratings. AB - OBJECTIVE: To examine teachers' knowledge and use of empirically supported treatments (ESTs) for children with autism spectrum disorder (ASD), and the extent to which they deem them socially valid in general education settings. METHOD: Totally, 155 general education teachers completed an online survey examining knowledge, use, and perceived social validity of ESTs targeting school readiness skills. Sources of information accessed and the relationship of knowledge, use, and social validity with demographic variables were investigated. RESULTS: Teachers reported knowledge of, and were using, all ESTs. ESTs were used more frequently than non-ESTs. Knowledge, use, and social validity of ESTs were strongly associated. Teachers reported accessing a range of sources of information, with varying degrees of trust placed in these sources. CONCLUSION: Teachers' knowledge of available ESTs for children with ASD is linked to their use. Increasing awareness of social validity of ESTs, and how they can be successfully translated into classroom settings will influence uptake. PMID- 30307354 TI - Afatinib treatment for her-2 amplified metastatic colorectal cancer based on patient-derived xenograft models and next generation sequencing. AB - BACKGROUND: Substantial progress has been made in metastatic colorectal cancer (mCRC) treatment, but there is still a fraction of patients cannot find any effective therapeutic strategy after guideline-recommended standard chemotherapy and molecular targeted therapy. CASE PRESENTATION: Here we present a KRAS/NRAS/BRAF wild-type mCRC patient who has been previously treated with FOLFIRI (fluorouracil, leucovorin, and irinotecan), XELOX (capecitabine and oxaliplatin), cetuximab and bevacizumab, and then received the next generation sequencing (NGS) and whose metastatic subcutaneous nodule was resected to generate patient-derived xenograft (PDX) models. The NGS revealed HER-2 amplification as well as an activating mutation S310F and PDX models tested several drugs finding that afatinib was the optimal agent with notable efficacy and well tolerance among 6 regimens. Therefore, this patient started to take afatinib orally and achieved 3 months progression-free survival (PFS) and relief of clinical symptoms without severe adverse effects. CONCLUSIONS: NGS and PDX models have great significance for precision and individualized medicine in the mCRC treatment, especially for patients whose diseases have been progressed after multiline standard therapies. PMID- 30307353 TI - Trichostatin A, an epigenetic modifier, mitigates radiation-induced androphysiological anomalies and metabolite changes in mice as evident from NMR based metabolomics. AB - PURPOSE: Ionizing radiation is known to damage male reproductive system. Current study aims to study the mitigative effects of trichostatin A on male reproductive system and accompanying metabolite changes in testicular tissue of mice. MATERIALS AND METHODS: Eight-week-old male C57 Bl/6J mice were exposed to 2 Gy gamma-radiation with or without trichostatin A administration. The animals were sacrificed at various time intervals for organ body weight index, sperm head abnormality assay, sperm mobility assay, and study of various metabolites in testicular tissue using NMR spectroscopy. RESULTS: Ionizing radiation induced no significant change in organ body weight index at any time points studied, however a significant increase in sperm head abnormality and significant decrease in sperm mobility was evident on fifth postirradiation week. trichostatin A administration, 1 and 24 h postirradiation, could efficiently mitigate radiation induced changes studied. NMR metabolome profile also showed prominent changes associated with energy metabolism, osmolytes and membrane metabolism at 24 h postirradiation and some of these changes (choline, glycerolphosphoethanol amine, and glycine) were persistent till fifth postirradiation week. Trichostatin A administration resulted in reverting metabolic profile of the irradiated animals to normal level suggesting its mitigative role. CONCLUSION: Results obtained suggest that trichostatin A could restore normal metabolic profile of testicular tissue of irradiated male mice and also restored certain morphological and functional properties of sperms. Trichostatin A thus could further be exploited for its radio-mitigative properties. PMID- 30307355 TI - Deperitoneum biological mesh repair for abdominal wall hernia: a novel wound healing promotion idea. AB - PURPOSE: Nowadays, biological matrix has become more widely applied than synthetic mesh for the surgical management of ventral hernia. Conventionally, such biodegradable matrix is commonly placed in an intraperitoneal or extraperitoneal position to reinforce the abdominal wall during surgery. Herein, we introduce our novel idea to deliver such biological material. MATERIAL AND METHODS: After contrast-enhanced CT-scan via lateral decubitus confirmed the position of ventral hernias, 11 patients underwent deperitoneum biological mesh repair by open or laparoscopic approach. During surgery, biological material was placed in preperitoneal position with elimination of matrix-covered peritoneum meanwhile. No bridge repair was allowed for this technique. Postoperative complications were prospectively documented. RESULTS: Laparoscopic and open repair were performed in six and five patients, respectively. The mean operative time was 115 min, with no significant difference between the two procedures. All patients had quick recovery and returned to their normal life, with median five days (range, 3-12 days) of hospital stay after surgery. Although wound dehiscence and chronic pain occurred in three (27.3%) patients, no additional surgery was required. No recurrence case was observed within the one-year follow-up period. CONCLUSION: This novel approach could be safely performed in ventral hernia patients. Early evaluation of this surgical technique demonstrates quick recovery and minimal complications. PMID- 30307356 TI - Long-term clinical experience with laparoscopic ventral hernia repair using a ParietexTM composite mesh in severely obese and non-severe obese patients: a single center cohort study. AB - BACKGROUND: The treatment of incisional and ventral hernias is associated with significant complications and recurrences, especially in severely obese patients. Recent studies have shown a reduced rate of surgical site infections and length of hospital stay in severely obese patients undergoing a laparoscopic ventral hernia repair. AIM: This study aims to describe the clinical experience in terms of efficacy and safety with laparoscopic ventral hernia repair using the ParietexTM Composite mesh (Covidien Sofradim Production, Trevoux, France) in severely obese patients (body mass index >=35) compared with non-severe obese patients in a seven-year single-center cohort. MATERIAL AND METHODS: All patients with a primary ventral or incisional hernia admitted to our hospital from 2006 until December 2012 who underwent a laparoscopic repair with the Parietex Composite mesh were included in this study. Pain scores using a numeric rating were collected prospectively 24-48 hours postoperatively. Patient data were retrospectively collected. RESULTS: A total number of 210 patients were included; 173 with a BMI <35 and 37 with a BMI >=35. Mean follow-up was 31 months. No statistically significant differences were found with regard to operation time, hospital stay, use of analgesics and postoperative complications. The long-term follow up recurrence rate in non-severely obese patients was 13% compared to 16% in severely obese patients (p = .60). CONCLUSION: Laparoscopic ventral and incisional hernia repair using the Parietex Composite mesh is feasible and safe in severely obese patients compared to non-severely obese patients. PMID- 30307359 TI - Documentation of Late-Effects Risks and Screening Recommendations for Adolescent and Young Adult Central Nervous System, Soft Tissue, or Bone Tumor Survivors Treated with Radiotherapy in British Columbia, Canada. AB - PURPOSE: To assess the documentation of late-effects (LE) risks and screening recommendations in medical records of adolescent and young adult central nervous system (CNS), soft tissue, and bone tumor survivors. METHODS: The medical records of all patients diagnosed with a CNS neoplasm, an arteriovenous malformation, a soft tissue, and bone tumor, at ages 15-39 years, treated between 1985 and 2010 with radiation therapy in the province of British Columbia, Canada, surviving >5 years, alive, and discharged to the community were assessed. The documentation of LE risks and screening recommendations were analyzed descriptively. RESULTS: In the medical records of 132 CNS tumor survivors and 94 soft tissue or bone tumor survivors, 15% and 13% included no documentation of LE risks, 21% and 22% included only nonspecific documentation, and 64% and 65% minimal documentation, respectively. Documentation of at least one specific LE risk increased significantly among CNS tumor patient charts (from 29% in 1980-1989, to 67% in 1990-1999, to 88% in 2000-2010, chi2 [2, N = 132] = 32.257, p < 0.000) and soft tissue or bone tumor patient charts (from 47% [1980-1989] to 56% [1990-1999] to 78% [2000-2010], chi2 [2, N = 94] = 6.702, p = 0.035). There was no documentation of a screening recommendation in 75% of CNS tumor patient charts and 91% of soft tissue and bone tumor charts. CONCLUSION: The documentation of LE risks and screening recommendations has been limited, highlighting the need to improve written communication with primary care providers. PMID- 30307357 TI - Coupling of oxidative stress responses to tricarboxylic acid cycle and prostaglandin E2 alterations in Caenorhabditis elegans under extremely low frequency electromagnetic field. AB - PURPOSE: With all-pervasive presence of extremely low-frequency electromagnetic field (ELF-EMF) in modern life, ELF-EMF has been regarded as an essential factor which may induce changes in many organisms. The objective of the present study was to investigate the physiological responses of Caenorhabditis elegans (C. elegans) to 50 Hz, 3 mT ELF-EMF exposure. MATERIALS AND METHODS: Worms were exposed to ELF-EMF from the egg stage until reaching the fourth larva (L4) stage. After exposure, expressions of the tricarboxylic acid (TCA) cycle enzymes were examined by qRT-PCR and western blot analysis. Two lipid metabolites were detected by GC-MS. Reactive oxygen species (ROS) level was detected by dichlorofluorescein staining and worm antioxidant system was investigated by enzymatic activity analysis, including detection of the superoxide dismutase and catalase (CAT) activity and the total antioxidant capacity (T-AOC). RESULTS: The TCA cycle enzyme, fumarase was found with decreased expression under ELF-EMF exposure. And arachidonic acid (ArA) and prostaglandin E2(PGE2) showed elevated concentrations, with increased expression of prostaglandin E2 synthase (PGES-2) in ELF-EMF exposed worms. Significant elevation of ROS level was identified accompanied with the significant depression of T-AOC in response to ELF-EMF. CONCLUSIONS: Our results suggested that exposure to 50 Hz, 3 mT ELF-EMF in C. elegans can elicit disruptions of the TCA cycle metabolism and PGE2 formation, coupling ELF-EMF-induced oxidative stress responses. Our study probably will attract increasing attentions to the controllable application of ELF-EMF associated with health and disease. PMID- 30307361 TI - Sarcoidosis following alemtuzumab treatment: Autoimmunity mediated by T cells and interferon-gamma. PMID- 30307360 TI - The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21Cip1 and p27Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21Cip1 and p27Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects . Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS. PMID- 30307362 TI - Machine and deep learning for sport-specific movement recognition: a systematic review of model development and performance. AB - Objective assessment of an athlete's performance is of importance in elite sports to facilitate detailed analysis. The implementation of automated detection and recognition of sport-specific movements overcomes the limitations associated with manual performance analysis methods. The object of this study was to systematically review the literature on machine and deep learning for sport specific movement recognition using inertial measurement unit (IMU) and, or computer vision data inputs. A search of multiple databases was undertaken. Included studies must have investigated a sport-specific movement and analysed via machine or deep learning methods for model development. A total of 52 studies met the inclusion and exclusion criteria. Data pre-processing, processing, model development and evaluation methods varied across the studies. Model development for movement recognition were predominantly undertaken using supervised classification approaches. A kernel form of the Support Vector Machine algorithm was used in 53% of IMU and 50% of vision-based studies. Twelve studies used a deep learning method as a form of Convolutional Neural Network algorithm and one study also adopted a Long Short Term Memory architecture in their model. The adaptation of experimental set-up, data pre-processing, and model development methods are best considered in relation to the characteristics of the targeted sports movement(s). PMID- 30307363 TI - Successful implementation of genomically based treatment of chemotherapy refractory peripheral T-cell lymphoma (PTCL). AB - BACKGROUND: The treatment of peripheral T-cell lymphoma (PTCL) after failure of standard therapy represents a significant clinical challenge as the best approach has not been defined. The outcomes of patients with peripheral T-cell lymphoma (PTCL) after relapse, in the absence of hematopoietic stem-cell transplantation, are poor with median overall survival is less than six months. Thus, relapsed/refractory PTCL presents an area of unmet medical need. CASE PRESENTATION: Herein, we report an 84-year old woman with stage IV PTCL with extensive involvement of the bowel and abdominal pain. She was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy which was complicated by prolonged pancytopenia, without response. Disease progression was manifested by small bowel obstruction, for which she received palliative radiation therapy, further complicated by cardiac arrhythmia and sepsis. In the meantime, clinical-grade next generation sequencing of a lymph node (406 gene panel) showed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19-21, along with an intermediate tumor mutational burden. Tissue PD-L1 staining was low positive by immunohistochemistry. The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months. Side effects at five months included only low-grade rash and peripheral edema. CONCLUSIONS: Our observations suggest that matching patients with hematologic malignancies with customized combinations based on genomic sequencing warrants further study as a way to achieve and/or deepen responses, including in patients who are elderly and/or have refractory disease and significant disease-related complications. PMID- 30307364 TI - Sarcoidosis following alemtuzumab treatment for multiple sclerosis. AB - Despite proven efficacy of alemtuzumab in multiple sclerosis (MS), approximately 50% of individuals will develop a new autoimmune disease following treatment. To date, these have largely been antibody mediated and organ specific (primarily affecting the thyroid gland). In a retrospective case series of 187 patients from two UK specialist centres (Cardiff and Cambridge) followed up for a median of 10 years, we report three (1.6%) cases of sarcoidosis following alemtuzumab treatment of MS. This report increases the spectrum of auto-inflammatory disease following alemtuzumab and should be considered by clinicians when using this therapeutic agent for MS. PMID- 30307365 TI - Robot-Assisted Partial Nephrectomy for Totally Endophytic Renal Tumors: Step by Step Standardized Surgical Technique and Long-Term Outcomes with a Median 59 Month Follow-Up. AB - BACKGROUND: Treatment of totally endophytic renal tumors is a technically demanding surgery. While few studies show promising perioperative and short-term outcomes of robot-assisted partial nephrectomy (RAPN), its long-term outcomes remain undetermined. MATERIALS AND METHODS: A retrospective analysis of 89 patients with totally endophytic renal tumors undergoing either RAPN (n = 52) or open partial nephrectomy (OPN; n = 37) in a tertiary-care institution between 2005 and 2015 was performed. Primary endpoint was to describe our transperitoneal RAPN surgical technique, while secondary endpoint was to compare the 5-year chronic kidney disease (CKD)-free survival, cancer-specific survival (CSS), and metastasis-free survival (MFS) rates between RAPN and OPN. RESULTS: The median follow-up was 59 and 53 months for RAPN and OPN, respectively. Apart from increased prevalence of high complex tumors among RAPN cases (RAPN, 38.5% versus OPN, 16.2%; P = .037), and lower median eGFR (RAPN, 86 versus OPN 96 mL/minute/1.73 m2; P = .032), the remaining demographic characteristics were similar between the groups. At latest follow-up, the rates of local recurrence (P = .577), distant metastasis (P = .854), and cancer death (P = .187), and CKD upstaging >=stage 3 (P = .728) did not differ between groups. The 5-year CKD upstaging-free survival was 96.2% versus 94.6% (log-rank, P = .746), MFS was 95.8% versus 97.1% (P = .876), and CSS was 100% versus 93.8% (log-rank, P = .102) when stratified by RAPN and OPN, respectively. CONCLUSION: RAPN is a safe and feasible option for treatment of totally endophytic renal tumors. Despite the increased prevalence of high tumor complexity and lower baseline renal function in the RAPN group, it achieved equivalent long-term oncologic control and functional outcome compared to OPN. PMID- 30307366 TI - Laparoscopic Repair for Groin Hernias in Female Patients: A Single-Center Experience in 15 Years. AB - BACKGROUND: Our objective was to investigate the clinical characteristics of laparoscopic repair for groin hernias in female patients. STUDY DESIGN: The clinical data of 316 female patients (341 hernias) who underwent laparoscopic inguinal hernia repair at Shanghai Minimally Invasive Surgery Center between January 2001 and December 2015 was analyzed retrospectively. The operation related data were to provide an overview of female groin hernias, preferred surgical approach, and the management of round ligament of uterus. RESULTS: There were 274 transabdominal preperitoneal patch plastic repairs and 67 total extraperitoneal repairs performed on 257 and 59 patients, respectively. The median follow-up period was 48 months. Fifty-eight femoral hernias were noted in 52 patients, of which 18 femoral hernias were incarcerated. Cysts on the round ligament of uterus were found in 39 patients, and most of them underwent laparoscopic resection. Round ligaments of uterus were preserved in 152 patients and transected in 162 patients. The preservation group requires longer operation time and trickier surgical technique. None of the cases was converted to laparotomy. All patients returned to normal activity soon and no recurrence was noted during follow-up. CONCLUSIONS: Laparoscopic inguinal hernia repair is well adopted around the world. Meanwhile, there still remain questions to be discussed in female patients. Based on this study, the round ligament cyst could be resected while the operation. Either "open and suture" or keyhole technique will be available to preserve the round ligament of uterus. PMID- 30307367 TI - Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer. AB - Blood vessel epicardial substance (BVES) is a tight-junction associated protein that was originally discovered from a cDNA screen of the developing heart. Research over the last decade has shown that not only is BVES is expressed in cardiac and skeletal tissue, but BVES is also is expressed throughout the gastrointestinal epithelium. Mice lacking BVES sustain worse intestinal injury and inflammation. Furthermore, BVES is suppressed in gastrointestinal cancers, and mouse modeling has shown that loss of BVES promotes tumor formation. Recent work from multiple laboratories has revealed that BVES can regulate several molecular pathways, including cAMP, WNT, and promoting the degradation of the oncogene, c-Myc. This review will summarize our current understanding of how BVES regulates the intestinal epithelium and discuss how BVES functions at the molecular level to preserve epithelial phenotypes and suppress tumorigenesis. PMID- 30307368 TI - High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies. AB - As an immune evasion strategy, MICA and MICB, the major histocompatibility complex class I homologs, are proteolytically cleaved from the surface of cancer cells leading to impairment of CD8 + T cell- and natural killer cell-mediated immune responses. Antibodies that inhibit MICA/B shedding from tumors have therapeutic potential, but the optimal epitopes are unknown. Therefore, we developed a high-resolution, high-throughput glycosylation-engineered epitope mapping (GEM) method, which utilizes site-specific insertion of N-linked glycans onto the antigen surface to mask local regions. We apply GEM to the discovery of epitopes important for shedding inhibition of MICA/B and validate the epitopes at the residue level by alanine scanning and X-ray crystallography (Protein Data Bank accession numbers 6DDM (1D5 Fab-MICA*008), 6DDR (13A9 Fab-MICA*008), 6DDV (6E1 Fab-MICA*008). Furthermore, we show that potent inhibition of MICA shedding can be achieved by antibodies that bind GEM epitopes adjacent to previously reported cleavage sites, and that these anti-MICA/B antibodies can prevent tumor growth in vivo. PMID- 30307370 TI - Brain Lesions as a Predictor of Therapeutic Outcomes of Hand Function in Infants With Unilateral Cerebral Palsy. AB - AIM:: The present study aimed to investigate whether the response variability of infants to modified constraint-induced movement therapy and bimanual therapy are associated with different types of brain lesions. METHOD:: Infants with unilateral cerebral palsy (N = 22) ages 8-15 months (mean = 10.95, standard deviation = 2.15 months) were grouped according to having either a periventricular brain lesion or a middle cerebral artery infarct lesion. Improvement in hand function was analyzed based on the mini-Assistive Hand Assessment results. RESULTS:: Infants with periventricular brain lesion displayed greater positive response to upper limb treatment compared to those with middle cerebral artery infarct ( P = .02). A significant difference in improvement according to type of treatment was found in the middle cerebral artery infarct group but not in the periventricular brain lesion. CONCLUSION:: The present study showed an association between the type of brain lesion and the efficacy of upper limb treatment in infants. Infants with periventricular brain lesions displayed greater positive responses than those with middle cerebral artery infarct. PMID- 30307369 TI - An interconnection between tip-focused Ca2+ and anion homeostasis controls pollen tube growth. AB - Plant reproduction is the basis for economically relevant food production. It relies on pollen tube (PTs) growth into the female flower organs for successful fertilization. The high cytosolic Ca2+ concentration ([Ca2+]cyt) at the PT tip is sensed by Ca2+-dependent protein kinases (CPKs) that in turn activate R- and S type anion channels to control polar growth. Lanthanum, a blocker for plant Ca2+ permeable channels was used here to demonstrate a strict dependency for anion channel activation through high PT tip [Ca2+]cyt. We visualized this relationship by live-cell anion imaging and concurrent triggering of Ca2+-elevations with the two-electrode voltage-clamp (TEVC) technique. The anion efflux provoked by a TEVC triggered [Ca2+]cyt increase was abolished by Lanthanum and was followed by an overall rise in the cytosolic anion concentration. An interrelation between Ca2+ and anion homeostasis occurred also on the transcript level of CPKs and anion channels. qRT-PCR analysis demonstrated a co-regulation of anion channels and CPKs in media with different Cl- and NO3- compositions. Our data provides strong evidence for the importance of a Ca2+-dependent anion channel regulation and point to a synchronized adjustment of CPK and anion channel transcript levels to fine-tune anion efflux at the PT tip. PMID- 30307371 TI - Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment. AB - BACKGROUND:: Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial. OBJECTIVE:: To report a case of acute sarcoidosis (Lofgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment. CASE REPORT:: Sarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased). CONCLUSION:: Our case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications. PMID- 30307372 TI - LET dependence on killing effect and mutagenicity in the model filamentous fungus Neurospora crassa. AB - PURPOSE: To assess the unique biological effects of different forms of ionizing radiation causing DNA double-strand breaks (DSBs), we compared the killing effect, mutagenesis frequency, and mutation type spectrum using the model filamentous fungus Neurospora. MATERIALS AND METHODS: Asexual spores of wild-type Neurospora and two DSB repair-deficient strains [one homologous recombination- and the other non-homologous end-joining (NHEJ) pathway-deficient] were irradiated with argon (Ar)-ion beams, ferrous (Fe)-ion beams, or X-rays. Relative biological effectiveness (RBE), forward mutation frequencies at the ad-3 loci, and mutation spectra at the ad-3B gene were determined. RESULTS: The canonical NHEJ (cNHEJ)-deficient strain showed resistance to higher X-ray doses, while other strains showed dose-dependent sensitivity. In contrast, the killing effects of Ar-ion and Fe-ion beam irradiation were dose-dependent in all strains tested. The rank order of RBE was Ar-ion > Fe-ion > C-ion. Deletion mutations were the most common, but deletion size incremented with the increasing value of linear energy transfer (LET). CONCLUSIONS: We found marked differences in killing effect of a cNHEJ-deficient mutant between X-ray and high-LET ion beam irradiations (Ar and Fe). The mutation spectra also differed between irradiation types. These differences may be due to the physical properties of each radiation and the repair mechanism of induced damage in Neurospora crassa. These results may guide the choice of irradiation beam to kill or mutagenize fungi for agricultural applications or further research. PMID- 30307373 TI - Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment. AB - The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs. In this review we concentrate on these developments toward the treatment of the neuromuscular diseases Duchenne muscular dystrophy and spinal muscular atrophy toward a platform technology for the enhancement of cellular and in vivo delivery suitable for widespread use as neuromuscular and neurodegenerative ON drugs. PMID- 30307374 TI - Thinking about your running movement makes you less efficient: attentional focus effects on running economy and kinematics. AB - A number of studies have shown that attentional focus instructions can effect running economy. This study assessed spiroergometry, as well as running kinematics as a possible mechanism to explain these effects. Twelve runners had to focus their attention on either their running movement, their breathing or on a video while running on a treadmill at a set, submaximum speed. Spiroergometry and running kinematics were measured. Results revealed worse running economy in both internal focus conditions (breathing and movement) compared to the external focus condition (video), replicating previous findings. In addition, vertical oscillation during the running movement was elevated in the movement compared to the video condition, indicating a less efficient running style. No changes in kinematics were found for the breathing compared to the video condition. Therefore, consciously focusing on the running movement moves runners away from their optimised running pattern and leads to detriments in economy. The decreases in running economy in the breathing condition can be better explained by changes in breathing patterns. PMID- 30307375 TI - Diagnosis of NUT carcinoma of lung origin by next-generation sequencing: case report and review of the literature. AB - NUT carcinoma (NC) is an aggressive squamous tumor characterized by NUT gene rearrangement, and the most common fusion form is BRD4-NUT. However, NC diagnosis is difficult for its rareness and often being confused with a variety of poorly differentiated tumors. A 21-year-old Chinese woman was referred to our hospital for cough and intermittent fever. Chest computed tomography (CT) imaging revealed a left lobe hilar mass. Fiberoptic bronchoscopy results showed that tumor cells were poorly differentiated. In combination with immunohistochemistry staining, she was misdiagnosed with Ewing's sarcoma/primitive neuroectodermal tumor. Next generation sequencing (NGS) revealing BRD4-NUT fusion, and NUT immunohistochemistry confirmed the diagnosis of NC. Subsequently, left pneumonectomy and lymph node dissection were performed, and the patient received pemetrexed and lobaplatin treatment. NGS technology played an important role in NC diagnosis in this case, and it may have clinical use for rare cancer diagnosis and guidance of potential targeted therapies. PMID- 30307376 TI - Simvastatin delivery on PEEK for bioactivity and osteogenesis enhancements. AB - The strategy of a functional biomimetic system built to obtain the positive cellular response remains a field of topical interest. In this study, a hydrogel covered simvastatin-loaded polyetheretherketone (PEEK) bio-composites was constructed with the purpose of bone tissue regeneration therapy. Briefly, a three-dimensional (3D) porous structure was fabricated on PEEK surface; then the substrate was functionalized with the poly(L-lactic acid)/simvastatin porous film and hyaluronic acid hydrogel subsequently. In vitro cell attachment, proliferation, and cytoskeletal observation experiments reveal that our scaffolds show better bio-affinity due to the layer of hyaluronic acid hydrogel compared with control. Furthermore, the alkaline phosphatase activity, calcium mineral deposition evaluation, and gene expression for osteogenic potential all exhibit that the superior osteogenic differentiation of MC3T3-E1 pre-osteoblasts on our scaffolds. Therefore, our PEEK samples loaded with simvastatin and covered with hyaluronic acid hydrogel hold great potential in clinical applications for bone repair. PMID- 30307377 TI - Meta-analysis of the effects of third-wave behavioural interventions on disordered eating and body image concerns: implications for eating disorder prevention. AB - Third-wave behavioural interventions are increasingly popular for treating and preventing mental health conditions. Recently, researchers have begun testing whether these interventions can effectively targeting eating disorder risk factors (disordered eating, body image concerns). This meta-analysis examined whether third-wave behavioural interventions (acceptance and commitment therapy; dialectical behaviour therapy; mindfulness-based interventions; compassion focused therapy) show potential for being effective eating disorder prevention programs, by testing their effects on eating disorder risk factors in samples without an eating disorder. Twenty-four studies (13 randomized trials) were included. Most studies delivered selective prevention programs (i.e. participants who reported elevated risk factor). Third-wave interventions led to significant pre-post (g = 0.59; 95% CI = 0.43, 0.75) and follow-up (g = 0.83; 95% CI = 0.38, 1.28) improvements in disordered eating, and significant pre-post improvements in body image (g = 0.35; 95% CI = 0.13, 0.56). DBT-based interventions were associated with the largest effects. Third-wave interventions were also significantly more efficacious than wait-lists (g = 0.39; 95% CI = 0.09, 0.69) in reducing disordered eating, but did not differ to other interventions (g = 0.25; 95% CI = -0.06, 0.57). Preliminary evidence suggests that third-wave interventions may have a beneficial effect in ameliorating eating disorder risk. PMID- 30307378 TI - Evaluation of the Seegene AllplexTM Respiratory Panel for diagnosis of acute respiratory tract infections. AB - OBJECTIVES: The Seegene AllplexTM Respiratory panel was retrospectively challenged using a collection of quality control samples (QCMD) and clinical samples previously analysed with validated routine methods. METHODS: A collection of 111 samples [43 QCMD samples, 13 bronchoalveolar lavage fluids and 55 nasopharyngeal aspirates/swabs] was tested with Seegene AllplexTM. The clinical samples were tested previously using either FTD(r) Respiratory Pathogens 21 qPCR assay (Fast Track Diagnostics), an in-house multiplex PCR for Bordetella, or BioGX Sample-ReadyTM Atypical pneumo panel (Becton Dickinson). Samples were stored at -80 degrees C prior to analysis with Seegene AllplexTM, nucleic acids were automatically extracted with NucliSENS Easymag (bioMerieux). Samples returning discordant results were subjected to repeat testing and/or additional testing by reference laboratories. RESULTS: Seegene correctly identified 41/43 QCMD samples (95.4%); two samples positive for respiratory syncytial virus (RSV) and human metapneumovirus, respectively, were only correctly identified following repeat testing. In the 56 clinical samples, overall, 97 pathogens were identified: 65 pathogens (67.0%) were detected both by routine methods and Seegene, 24 pathogens (24.7%) only by routine methods, and 8 pathogens (8.2%) only by Seegene. The majority of discordant results was detected in samples with low pathogen load (22/32, 68.8%) and in samples containing multiple pathogens (25/32, 78.1%). Full agreement between methods was observed for influenza, RSV, adenovirus, Bordetella (para)pertussis and Chlamydia pneumoniae. Discordance was observed for human metapneumovirus, coronavirus OC43, bocavirus and parainfluenza virus, mainly type 4. CONCLUSION: Overall, the Seegene AllplexTM assay performed well for routine detection of important respiratory targets. Acceptable agreement was observed between Seegene and other routine assays. PMID- 30307379 TI - Functional Near-Infrared Spectroscopy in the Evaluation of Urban Rail Transit Drivers' Mental Workload under Simulated Driving Conditions. AB - The objective of this study is to investigate the potential of functional near infrared spectroscopy (fNIRS) combined with heart rate variability indices, for the evaluation of the mental workload of urban rail transit drivers under simulated driving conditions, particularly during task engagement and disengagement. Experienced metro drivers wearing fNIRS monitoring systems were asked to drive for 90 min in a professional metro driving simulator. Workload stimulus tasks were added and an n-back task (n = 3) was implemented to induce workload in the simulated driving experiment. Experimental results indicate that fNIRS is sensitive to mental workload and reliable for discriminating the degree of mental workload. Research findings demonstrate the feasibility and reliability of fNIRS as a tool for real-time evaluating and monitoring driver mental workload along with task factors from a perspective of brain activations during simulated or actual driving. Practitioner Summary: This study provides evidence for the potential of functional near-infrared spectroscopy (fNIRS) for the evaluation of the mental workload of urban rail transit drivers under simulated driving conditions. The first fNIRS application to mental workload evaluation in the field of urban rail transportation helps companies develop reasonable shiftwork schedule and ensure operation safety. PMID- 30307382 TI - Examining risk factors for overweight and obesity in children with disabilities: a commentary on Bronfenbrenner's ecological systems framework. AB - Globally, overweight and obesity (OW/OB) levels are high among children, with rates surpassing the adult population. With such high pediatric OW/OB rates, it is imperative that risk factors are identified and explored. Thus, Davison and Birch developed an adapted framework, based on Bronfenbrenner's Ecological Systems Theory, which identifies and categorizes the factors in a child's life that put them at risk for OW/OB. While a socioecological perspective has been a useful tool for examining risk factors in typically developing pediatric populations, this holistic approach has not yet been applied to populations of children with disabilities, who are at an even higher risk of OW/OB than their typically developing peers. This commentary, therefore, explores Bronfenbrenner's Ecological Framework as applied to OW/OB by Davison and Birch, and critically examines its application to children with disabilities. PMID- 30307383 TI - Low-dose CT screening for lung cancer reduced lung cancer mortality in Hitachi City. AB - PURPOSE: To detect early, curable lung cancer, screening using low-dose CT (CT screening) was initiated in Japan and Western countries around the early 1990s. MATERIAL AND METHODS: In 2013, the National Lung Screening Trial (NLST) reported that annual CT screening for high-risk participants leads to a 16% reduction in lung cancer death. In Hitachi City, CT screening for citizens 50 years of age or older was started in 1998, and 30% of the citizens had received a CT examination at least once by 2006. RESULTS: We reported excellent survival (5-year survival of 90%) of 210 patients with lung cancer detected by CT screening. Based on a time trend analysis, a significant reduction (24%) in lung cancer mortality was observed 4 to 8 years after the introduction of CT screening among Hitachi residents. CT images can detect numerous smoking-related factors represented by pulmonary emphysematous change (CT emphysema). If we can evaluate the risk of respiratory disease according to these images, the benefits of screening are expected to increase further. CONCLUSION: To establish the effectiveness of CT screening for the general population, an optimum screening schedule is desired based on the risk of individuals. In addition, long-term follow-up is necessary to evaluate the effects of radiation exposure. PMID- 30307384 TI - Indioceanicola profundi gen. nov., sp. nov., isolated from Indian Ocean sediment. AB - A novel basophilic bacterial strain, designated as SCSIO 08040T, was recovered from a deep-sea sediment sample collected from the Indian Ocean. The strain was Gram-stain-negative, vibrioid or spiral, light pink, 0.6-1.0 um wide and 1.0-2.5 um long. Growth occurred at 20-45 degrees C, pH 7-11 and <5 % (w/v) NaCl, with optimum growth at 28-37 degrees C, pH 7 and 0-3 % (w/v) NaCl. Catalase-, oxidase and urease-positive, nitrate reduction-negative. Analysis of 16S rRNA gene sequencing revealed that strain SCSIO 08040T had the highest similarity of 95.3 % to Rhodocista pekingensis 3-pT. Phylogenetic analysis based on nearly complete 16S rRNA gene sequences showed that the novel isolate formed a distinct phylogenetic lineage in the family Rhodospirillaceae. The whole-cell hydrolysate contained meso-diaminopimelic acid, galactose, mannose and xylose. The total cellular fatty acid profile was dominated by C18:1omega7c and C19:0cycloomega8c. Q-10 was the predominant ubiquinone. The major phospholipids were diphosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine. The DNA G+C content of strain SCSIO 08040T was 66.82 mol%. Based on these polyphasic data, a new genus, Indioceanicola gen. nov., is proposed in the family Rhodospirillaceae with the type species Indioceanicola profundi sp. nov. and the type strain SCSIO 08040T (=DSM 105146T=CGMCC 1.15812T). PMID- 30307385 TI - Proposal to modify Rules 27 and 30(3)(b) of the International Code of Nomenclature of Prokaryotes. AB - We propose to modify Rules 27 and 30(3)(b) of the International Code of Nomenclature of Prokaryotes so that the formal description of new taxa (the 'protologue') will include a statement about the nomenclatural type, so that this information will be linked to the name of the taxon, the derivation (etymology) of the name, and the properties of the taxon. PMID- 30307386 TI - Alcanivorax indicus sp. nov., isolated from seawater. AB - A Gram-stain-negative, motile, rod-shaped bacterium, designated SW127T, was isolated from a seawater sample collected from the Indian Ocean. Strain SW127T was aerobic, catalase- and oxidase-positive, and grew at 8-42 degrees C (optimum, 30 degrees C), at pH 5.5-9.0 (optimum, pH 7.5) and in the presence of 0.5-11.0 % (w/v) NaCl (optimum, 3.0-4.0 %). Comparative analysis of 16S rRNA gene sequences indicated that strain SW127T belonged to the genus Alcanivorax, and closely related to Alcanivorax pacificus MCCC 1A00474T (96.7 % sequence similarity). The predominant cellular fatty acids of strain SW127T were C16 : 0 and summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c). Strain SW127T contained phosphatidylethanolamine and phosphatidylglycerol as the major polar lipids. The genomic DNA G+C content of strain SW127T was 62.8 mol%. On the basis of its phenotypic characteristics and phylogenetic data, strain SW127T represents a novel species of the genus Alcanivorax, for which the name Alcanivorax indicus sp. nov. is proposed. The type strain is SW127T (=CGMCC 1.16233T=KCTC 62652T). PMID- 30307387 TI - Rickettsia fournieri sp. nov., a novel spotted fever group rickettsia from Argas lagenoplastis ticks in Australia. AB - Strain AUS118T was isolated from an Argas lagenoplastis tick collected from the nest of a Petrochelidon ariel (fairy martin) in Australia in 2013. Microscopic observation of infected cell cultures indicated this strain had a morphology and intracellular location typical of Rickettsiaspecies. Phylogenetic analysis of this strain based firstly on multi-locus sequence analysis and subsequently on whole genome analysis demonstrated that AUS118T was most closely related to, but divergent from Rickettsia japonica and Rickettsia heilongjiangensis. We therefore propose the creation of a novel species, Rickettsia fournieri sp. nov, with the type strain AUS118T (DSM 28985 and CSUR R501). PMID- 30307388 TI - Paenibacillus montanisoli sp. nov., isolated from mountain area soil. AB - A Gram-stain-negative, aerobic, motile, endospore-forming and rod-shaped bacterium, designated RA17T, was isolated from Dafan, Hubei Province, China. Based on 16S rRNA gene sequence similarity comparisons, strain RA17T was most closely related to Paenibacillus taihuensis THMBG22T (97.4 %), Paenibacillus rhizoryzae ACCC 1ZS3-5T (97.4 %) and Paenibacillus sacheonensis DSM SY01T (96.5 %). Analysis of the rpoB gene also indicated that RA17T had the highest similarity to P. rhizoryzae ACCC 1ZS3-5T (92.3 %), P. taihuensis THMBG22T (88.4 %) and P. sacheonensis DSM SY01T (85.5 %). The DNA-DNA hybridization values between strain RA17T and the two type strains, P. taihuensis THMBG22T and P. rhizoryzae ACCC 1ZS3-5T, were 36.8 and 22.9 %, respectively. Its genome size was 6.17 Mb, comprising 5677 predicted genes with a DNA G+C content of 52.82 mol %. The major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0 and iso-C16 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphoglycolipid, four aminophospholipids, an unidentified phospholipid and an unidentified polar lipid. The major quinone was menaquinone 7. The diagnostic diamino acid of the cell wall was meso-diaminopimelic acid. The low DNA-DNA hybridization values, physiological and biochemical differences, such as growth at 4 degrees C, acid production from inositol, lack of alpha chymotrypsin activity, no casein hydrolysis, and negative for acid production from d-fructose, melibiose and sucrose, could distinguish strain RA17T from its closely related species. Consequently, strain RA17T represents a novel species of the genus Paenibacillus, for which the name Paenibacillusmontanisoli sp. nov. is proposed, with RA17T (=KCTC 33894T=CCTCC AB 2017053T) as the type strain. PMID- 30307389 TI - Pedobacter chitinilyticus sp. nov., a chitin-degrading bacterium isolated from wheat leaf tissue. AB - A bacterium, designated strain CM134L-2T, was isolated from a chitin-enriched wheat leaf microbiome in Chengdu, Sichuan province, China. It was Gram-stain negative, strictly aerobic, non-spore-forming, motile, rod-shaped, and bright yellow in colour. Strain CM134L-2T grew at 4-35 degrees C, at pH 6.0-9.0 and could use chitin as the only carbon resource. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CM134L-2T was most closely related to Pedobacter nanyangensis Q-4T (97.7 %) and Pedobacter zeaxanthinifaciens TDMA-5T (97.4 %). Digital DNA-DNA hybridization (dDDH) values between strain CM134L-2T with these two type strains were 26.8 and 20.8 %, respectively, and average nucleotide identity (ANI) values were 83.2 and 76.2 %; these values are lower than the proposed and generally accepted species boundaries of 70 % for dDDH and 95-96 % for ANI, which suggests strain CM134L-2T represents a novel species. The genomic DNA G+C content of strain CM134L-2T was 39.3 mol%, menaquinone-7 was the major respiratory quinone, phosphatidylethanolamine was the major polar lipid and the major components of the cellular fatty acids were iso-C15 : 0, and C16 : 1omega7c/C16 : 1omega6c (summed feature 3); these features supported the affiliation of strain CM134L-2T to the genus Pedobacter. Overall, strain CM134L 2T belongs to the genus Pedobacter, but can be classified as a novel species, for which the name Pedobacter chitinilyticus sp. nov. is proposed. The type strain is CM134L-2T (=CGMCC 1.16520T=KCTC 62643T). PMID- 30307390 TI - Pleomorphochaeta naphthae sp. nov., a new anaerobic fermentative bacterium isolated from an oil field. AB - A novel anaerobic fermentative bacterium, strain SEBR 4209T, was isolated from a water sample of a Congolese oil field. Strain SEBR 4209T is phylogenetically related to the genus Pleomorphochaeta, in the family Spirochaetaceae. Its closest relatives are Pleomorphochaeta caudata SEBR 4223T (94.5 % 16S rRNA gene sequence similarity) and Pleomorphochaeta multiformis MO-SPC2T (94.3 % similarity). Like the other members of this genus, cells have a pleomorphic morphology, in particular an annular shape and long stalks. Optimal growth was observed at 37 degrees C, at pH between 6.8 and 7.0, and with 40 g l-1 NaCl. This strain was only able to grow by fermentation of carbohydrates. The fermentation products from glucose utilization were acetate, ethanol, CO2 and H2. Predominant fatty acids were C14 : 0, C14 : 0 DMA, C16 : 0 and C16 : 1omega7c. The major polar lipids were phosphoglycolipids, phospholipids and glycolipids. The G+C content of the DNA was 29.6 mol%. Based on phenotypic characteristics and phylogenetic traits, strain SEBR 4209T is considered to represent a novel species of the genus Pleomorphochaeta, for which the name Pleomorphochaetanaphthae sp. nov. is proposed. The type strain is SEBR 4209T (=DSM 104684T=JCM 31871T). PMID- 30307391 TI - The apolipoprotein N-acyl transferase Lnt is dispensable for growth in Acinetobacter species. AB - Directing the flow of protein traffic is a critical task faced by all cellular organisms. In Gram-negative bacteria, this traffic includes lipoproteins. Lipoproteins are synthesized as precursors in the cytoplasm and receive their acyl modifications upon export across the inner membrane. The third and final acyl chain is added by Lnt, which until recently was thought to be essential in all Gram-negatives. In this report, we show that Acinetobacter species can also tolerate a complete loss-of-function mutation in lnt. Absence of a fully functional Lnt impairs modification of lipoproteins, increases outer membrane permeability and susceptibility to antibiotics, and alters normal cellular morphology. In addition, we show that loss of lnt triggers a global transcriptional response to this added cellular stress. Taken together, our findings provide new insights on and support the growing revisions to the Gram negative lipoprotein biogenesis paradigm. PMID- 30307392 TI - Cysteine biosynthesis in Neisseria species. AB - The principal mechanism of reducing sulfur into organic compounds is via the synthesis of l-cysteine. Cysteine is used for protein and glutathione synthesis, as well as being the primary sulfur source for a variety of other molecules, such as biotin, coenzyme A, lipoic acid and more. Glutathione and other cysteine derivatives are important for protection against the oxidative stress that pathogenic bacteria such as Neisseria gonorrhoeae and Neisseria meningitidis encounter during infection. With the alarming rise of antibiotic-resistant strains of N. gonorrhoeae, the development of inhibitors for the future treatment of this disease is critical, and targeting cysteine biosynthesis enzymes could be a promising approach for this. Little is known about the transport of sulfate and thiosulfate and subsequent sulfate reduction and incorporation into cysteine in Neisseria species. In this review we investigate cysteine biosynthesis within Neisseria species and examine the differences between species and with other bacteria. Neisseria species exhibit different arrangements of cysteine biosynthesis genes and have slight differences in how they assimilate sulfate and synthesize cysteine, while, most interestingly, N. gonorrhoeae by virtue of a genome deletion, lacks the ability to reduce sulfate to bisulfide for incorporation into cysteine, and as such uses the thiosulfate uptake pathway for the synthesis of cysteine. PMID- 30307394 TI - Twitterature. PMID- 30307395 TI - Twitterature: will social media have an impact on scientific journals? PMID- 30307393 TI - A complex peripheral code for salt taste in Drosophila. AB - Each taste modality is generally encoded by a single, molecularly defined, population of sensory cells. However, salt stimulates multiple taste pathways in mammals and insects, suggesting a more complex code for salt taste. Here, we examine salt coding in Drosophila. After creating a comprehensive molecular map comprised of five discrete sensory neuron classes across the fly labellum, we find that four are activated by salt: two exhibiting characteristics of 'low salt' cells, and two 'high salt' classes. Behaviorally, low salt attraction depends primarily on 'sweet' neurons, with additional input from neurons expressing the ionotropic receptor IR94e. High salt avoidance is mediated by 'bitter' neurons and a population of glutamatergic neurons expressing Ppk23. Interestingly, the impact of these glutamatergic neurons depends on prior salt consumption. These results support a complex model for salt coding in flies that combinatorially integrates inputs from across cell types to afford robust and flexible salt behaviors. PMID- 30307396 TI - Current status and future perspectives for transcatheter and surgical aortic valve replacement: the role of aortic valve surgery in the era of transcatheter based therapies. PMID- 30307397 TI - What should interventional cardiologists do for patients with prediabetes? PMID- 30307398 TI - A tune of triumph. PMID- 30307399 TI - The use of covered stents in the field of interventional procedures for congenital heart defects. PMID- 30307400 TI - The future of vascular restoration therapy. PMID- 30307401 TI - miRNAs as biofluid markers for diagnostics of Alzheimer's disease: recent status and perspectives. AB - After many decades of research in the field of neurodegeneration, we have no effective cure for Alzheimer's disease (AD), a major form of dementia. It is mainly due to the lack of early, reliable and sensitive biomarkers and incomplete understanding of disease mechanisms at molecular level. Several recently employed biomarkers, especially their combinations, can discriminate advanced stages of AD from other forms of dementia or neuropathy. They do not provide much information on molecular mechanisms of disease rather they reflect the amount of key histopathological markers in the diseased brain. This review is focussed on novel class of potentially very promising AD biomarkers: extracellular miRNAs in body liquids, such as cerebrospinal fluid and blood. They have a great potential not only to indicate the presence of AD, but more importantly, to reflect the molecular mechanisms playing a role early at the beginning of the pathogenic pathways consequently leading to AD. We believe this comprehensive review on deregulated miRNAs in AD can be a good source of information for thorough in silico analyses aiming to identification, development and validation of miRNAs as "diseases mechanism engaged" candidate biomarkers. Having such molecules could bring us closer to the goal - successful treatment of AD. PMID- 30307402 TI - The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters. AB - The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect. PMID- 30307403 TI - Rat liver intoxication with CCl4: biochemistry, histology, and mass spectrometry. AB - This work provides complex characterisation of cirrhotic rat liver tissue induced by carbon tetrachloride using biochemical and histopathological analyses, and also presents a novel approach, secondary ion mass spectrometry (SIMS). According to our knowledge, this is the first report that compares these three different approaches in study of liver damage. We observed increased levels of triacylglycerols and total cholesterol in the liver and decreased levels of those parameters in the plasma. Histopathological observations include fat accumulation in the cells and changes in internal configuration of cells such as shift of position of organelles from the centre to the edge. The damage to the rat tissue is additionally determined by SIMS analysis, which characterizes, among other substances, diacylglycerols, cholesterol and fatty acids, such as linoleic and oleic acids. Interestingly, unlike other observed particles, a marked difference in SIMS intensity for diacylglycerol C37H69O4 positive fragment at 575.5 m/u was observed. In fact, there was one order of magnitude difference between intoxicated liver samples and controls and this molecular signal seems to be a potential chemical indicator of the damage. The SIMS images are consistent with histopathological results and they additionally provide information about distribution of chemical compound which is a new potential tool for the liver disease characterisation on molecular level. PMID- 30307404 TI - Role of protein kinase C, PI3 kinase, tyrosine kinases, NO-synthase, KATP channels and MPT pore in the signaling pathway of the cardioprotective effect of chronic continuous hypoxia. AB - It was established that adaptation to chronic continuous normobaric hypoxia (CCNH) increases cardiac tolerance to ischemia and reperfusion. It was performed coronary artery occlusion (20 min) and reperfusion (3 h) in Wistar rats. CCNH promoted a decrease in the infarct size/area at risk ratio in 2-fold. CCNH promoted an increase in the nitrite/nitrate levels in blood serum and myocardium. Pretreatment with protein kinase C (PKC) inhibitor chelerythrine, NO-synthase (NOS) inhibitor L-NAME, iNOS inhibitor S-methylisothiourea, KATP channel blocker glibenclamide, mitoKATP channel blocker 5-hydroxydecanoic acid abolished the infarct-reducing effect of CCNH. The non-selective tyrosine kinase inhibitor genistein attenuated but not eliminated infarct-sparing effect of CCNH. The nNOS inhibitor 7-nitroindazole, sarcKATP channel blocker HMR 1098, MPT pore inhibitor atractyloside, PI3 kinase inhibitor wortmannin did not reverse infarct-limiting effect of CCNH. It was concluded that infarct-reducing effect of CCNH is mediated via PKC, iNOS activation and mitoKATP channel opening. While nNOS, PI3 kinase, sarcKATP channel, MPT pore are not involved in the development of CCNH-induced cardiac tolerance to impact of ischemia-reperfusion. PMID- 30307405 TI - Effects of selected triorganotin compounds on transcriptional activity of vitamin D3 receptor and peroxisome proliferator-activated receptor gamma. AB - Both, the vitamin D3 receptor (VDR) and the peroxisome proliferator-activated receptor gamma (PPARgamma), are ligand-inducible transcription factors that control expressions of various genes involved in essential biological processes. Structurally diverse chemical substances are capable to bind to VDR and PPARgamma, consequently acting in agonistic or antagonistic mode. Ubiquitous triorganotin compounds, key components of antifouling, disinfectant and biocidal agents were found to act as cognate ligands of several nuclear receptors. Triorganotins affect endocrine systems in disruptive manner recruiting proliferative, differentiation and apoptotic pathways. In this study, we have investigated agonistic as well as antagonistic effects of selected triorganotin compounds on VDR and PPARgamma in transgenic gene reporter IZ-VDRE and PAZ PPARgamma human cell lines, allowing rapid and sensitive assessment of receptor transcriptional activity. We demonstrated that most of investigated triorganotins at nanomolar concentration exerted significant agonistic effects on VDR with fold activation ranging from 2.0 to 3.0-fold as well as some significant changes ranging from 127 to 199% of the maximal 1,25-dihydroxyvitamin D3 (calcitriol) induction, in antagonistic mode. In agonistic mode, PPARgamma transcriptional activity was not affected by studied triorganotins significantly, but studied tributyltin compounds in antagonistic mode, revealed significant values ranging from 147 to 171% of the maximal 15-deoxy-delta12,14-prostaglandin J2 induction. PMID- 30307406 TI - Thermodynamic properties of DNA-dendrimer complexes and features of their applications. AB - The commercial solution of fourth generation (G4) of poly-amidoamine (PAMAM) dendrimers contains methanol, which is toxic for human body. Our differential scanning calorimetry (DSC) study of dendrimers confirmed the existence of this threat. The recommendation is done on how to prepare dendrimer solutions for practical and safely use in gene delivery. DSC have been also used to study the thermodynamic properties of DNA/dendrimer complexes (dendriplexes). We showed that up to DNA/dendrimer ratio 43 +/- 3 (w/w) the solution was homogeneous, but stable aggregates were formed at higher PAMAM content. DSC experiments performed with homogeneous solution of dendriplexes revealed existence of the pH-dependent melting curves that contain several endothermic peaks associated with melting of GC-rich regions. PMID- 30307407 TI - Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. AB - Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin alphavbeta5 (ITGalphavbeta5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target. PMID- 30307408 TI - CDCA7 and HELLS mutations undermine nonhomologous end joining in centromeric instability syndrome. AB - Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of gammaH2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis. PMID- 30307409 TI - Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis. AB - GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13 negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2 IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL. PMID- 30307410 TI - Tacrolimus and Single Intraoperative High-dose of Anti-T-lymphocyte Globulins Versus Tacrolimus Monotherapy in Adult Liver Transplantation: One-year Results of an Investigator-driven Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study is to evaluate whether intra-operative induction with anti-lymphocytic serum (ALS) is superior to no induction in adult liver transplantation (LT). BACKGROUND: The efficacy of ALS induction remains inconclusive in LT, because of poorly designed trials. METHODS: A randomized controlled trial was conducted, including 206 adults (>15 years) and comparing tacrolimus monotherapy (TAC, n = 109) and tacrolimus plus a single, intraoperative, high-dose (9 mg/kg), rabbit anti-T-lymphocyte globulins (ATLG; n = 97). All patients had similar follow-up, including Banff-scored biopsies. Rejection was considered clinically relevant and treated if pathologic and biochemical changes were concordant. The primary endpoint was immunosuppression minimization to monotherapy; secondary endpoints were biopsy-proven rejection, clinical rejection, patient (PS) and graft (GS) survival. RESULTS: At 1 year, 79/81 (96.3%) ATLG and 101/102 (99.0%) TAC patients were steroid-free (P = 0.585); 28 (34.6%) ATLG, and 31 (30.4%) TAC patients were on double-drug immunosuppression (P = 0.633). One-year PS and GS of ATLG and TAC patients were 84% and 92% (P = 0.260) and 76% and 90% (P = 0.054).Despite significantly a fewer day-7 moderate-to-severe acute cellular rejections (ACR) in ATLG group (10.0% vs 24.0% in TAC group, P = 0.019), cumulative proportion of patients experiencing steroid-sensitive (11.3% ATLG vs 14.7% TAC, P = 0.539), steroid-resistant (2.1% ATLG vs 3.7% TAC, P = 0.686) and chronic rejection (1.0% ATLG vs 0.9% TAC, P = 1.000) were similar. ATLG administration brought about greater hemodynamic instability and blood products use (P = 0.001). CONCLUSIONS: At 1 year from LT, ATLG induction did not significantly affect immunosuppressive load, treated rejection, patient, and graft survival. The observed adverse events justify a modification of dosing and timing of ATLG infusion. Long-term results are required to judge the ATLG possible benefits on immunosuppressive load and tolerance induction. PMID- 30307411 TI - Stomach and duodenum. PMID- 30307412 TI - Coronary artery calcification: recent developments in our understanding of its pathologic and clinical significance. AB - PURPOSE OF REVIEW: Prior investigations have shown the close association between coronary artery calcification (CAC) and total atherosclerotic plaque burden as well as the risk of cardiovascular and all-cause mortality. However, recent pathologic and imaging-based studies suggested that massive dense calcifications are usually associated with stable plaque; whereas, micro calcifications, especially in the thin fibrous cap, are related to vulnerable characteristics. Further, the molecular mechanisms for initiation/progression of vascular calcification are highly complex and still need to be elucidated. In this manuscript, we discuss recent advancement in our understanding of CAC from the basic, pathologic, and clinical perspectives. RECENT FINDINGS: Research on the relationship between genetic polymorphisms and CAC has been growing and may potentially lead to future precision-based medicine. In basic research field, more attention has been focused on the relationship between inflammation and vascular calcification. Large-scale imaging based studies support the association between statin and calcification progression, maybe one of the ways by which statins prevent cardiovascular events. Nevertheless, the mechanism responsible for this effect is still not fully understood. Optical coherence tomography has improved resolution to detect CAC over traditional CT and may be especially promising for the detection of calcified nodules. SUMMARY: A better understanding of CAC in all of its forms will advance our understanding of its natural history of atherosclerosis. More work is needed to understand the basic molecular mechanisms responsible for the initiation/progression of CAC, which may eventually lead to the development of effective treatments for atherosclerosis. PMID- 30307413 TI - New-onset atrial fibrillation after PCI and CABG for left main disease: insights from the EXCEL trial and additional studies. AB - PURPOSE OF REVIEW: To provide an up-to-date review of recent trials examining the incidence and prognostic impact of new-onset atrial fibrillation (NOAF) following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD) and the impact of postprocedural NOAF compared to nonsurgical atrial fibrillation. RECENT FINDINGS: A recent analysis from the Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial demonstrated that NOAF is much more frequent following surgical compared with percutaneous revascularization for LMCAD, and is strongly associated with an increased 3-year risk of mortality and stroke. In a recent Danish registry-based, propensity score-matched analysis, postsurgical NOAF conferred a lower risk of adverse outcomes compared with nonsurgical nonvalvular atrial fibrillation. SUMMARY: These new studies confirm that although postsurgical NOAF after left main revascularization may be of less clinical significance than nonvalvular atrial fibrillation, its occurrence still is strongly associated with subsequent stroke and mortality. Future efforts are warranted to prevent postsurgical NOAF and determine strategies for its optimal management should it occur. PMID- 30307414 TI - Allogeneic hematopoietic stem-cell transplantation from haploidentical donors using 'ex-vivo' T-cell depletion in pediatric patients with hematological malignancies: state of the art review. AB - PURPOSE OF REVIEW: Nowadays, T-cell-depleted haploidentical transplantation is considered a valid approach for children lacking a human leukocyte antigen (HLA) identical donor for allogeneic transplantation. This kind of allogeneic transplant is now widely used especially for pediatric patients with high-risk hematological malignancies. However, relapsing disease and life-threatening viral infections are still relevant clinical problems as a consequence of delayed immune reconstitution. Adoptive cell therapies have been proposed to overcome this problem. RECENT FINDINGS: After initial clinical approach using CD34+ selection as method for T-cell depletion (TCD), it was observed that immune reconstitution was delayed and it resulted on high incidence of opportunistic infections and nonrelapse mortality. It is now evident that development over time of graft manipulation techniques for TCD, have provide clinicians a useful tool for overcoming transplant complication such as graft failure, severe graft-vs. host disease and opportunistic infections. As such, several procedures of almost total or partial TCD have been developed including CD3/CD19 depletion, T cell receptor alphabeta/CD19 depletion and more recently CD45RA+ depletion. Recent studies showed that immune reconstitution is associated with transplant outcomes. Based on this, haploidentical transplantation is now been explored as platform for cellular therapy to prevent disease recurrence or to treat clinical complications. SUMMARY: Allogeneic transplantation still remains a standard of care for pediatric patients with high-risk hematological malignancies. In absence of an HLA identical donor, T-cell-depleted haploidentical transplant is now considered a valid option and provide a platform for cellular therapy to prevent relapse disease or to treat opportunistic infections. PMID- 30307415 TI - [Current issues in pancreatic surgery]. AB - AIM: To present own experience of pancreatic surgery and to analyze literature data for this issue. MATERIAL AND METHODS: We have analyzed work of abdominal surgery department over the last 5 years. Moreover, MEDLINE and RSCI databases regarding surgical treatment of pancreatic diseases were assessed. RESULTS: There were 456 pancreatectomies. Postoperative complications arose in 176 (38.6%) patients, 11 patients died (2.4%). According to world data, mortality after pancreatectomy reaches 10%. Only creation of specialized centers is proven way to improve the outcomes. CONCLUSION: Current medical assistance for pancreatic disease may be only achieved in specialized centers with large number of various pancreatic procedures. The organization of such centers is required throughout the country and certain accreditation criteria should be developed for this purpose. Targeted routing of patients to specialized pancreatology centers will be able to reduce incidence of diagnostic, tactical and technical errors. PMID- 30307416 TI - [Comparison of standard and fast track rehabilitation in patients with acute appendicitis. Intermediate results of multicenter prospective randomized trial]. AB - AIM: To analyze outcomes of fast track rehabilitation in patients with acute appendicitis. MATERIAL AND METHODS: Prospective, randomized multi-center trial including 86 patients was conducted. There were 38 patients in the main group and 48 in the control group. All patients underwent laparoscopic appendectomy under endotracheal anesthesia. Protocol included informing, no premedication, glucose infusion prior to surgery, antibiotics administration, mesoappendix excision, limited deployment of drainage tubes, intraabdominal prolonged anesthesia, minimal pneumoperitoneum, limited irrigation, minimum power monopolar electrocautery, antiemetics, early activation and eating (2 and 6 hours after surgery). Pain was evaluated by visual-analogue scale. Auscultative peristalsis was considered every 2 hours after surgery. Cortisol level was assessed preoperatively, in 6 and 12-24 hours after surgery in 11 (29%) and 15 (31%) patients of the main and control groups respectively. Discharge criteria: no leukocytosis, fever and pain syndrome requiring anesthesia, no signs of complications and patient's consent. RESULTS: Terms of disease, gender, age and comorbidities were similar in all patients. Duration of surgery under minimal pneumoperitoneum and standard pressure was also similar: 69.2+/-3.98 and 70.9+/ 3.89 min (p=0.762). Pain syndrome grade and need for analgesics were significantly lower in the main group within entire follow-up. Pain syndrome was absent at the 1st postoperative day in 16 (42%) and 2 (4.1%) patients of both groups, respectively (score 0-1). Phrenic nerve syndrome was observed in 36.8% of the main group and 60.4% of the control group (p=0.05). Incidence of dyspepsia and terms of peristalsis onset were similar. Length of hospital-stay was 1.45 days in the main group and 3.15 days in the control group (p=0.002). In the main group 18 (47%) patients were discharged on the first day after surgery. There were only 4 (8.3%) patients with similar hospital-stay in the control group (p<0.001). There were no repeated hospitalizations. Postoperative cortisol concentration was similar in both groups as well as in complicated and uneventful postoperative period. In the main group postoperative intestinal paresis (Clavien Dindo grade 2) occurred in 1 patient. In the control group 7 patients had postoperative infiltrate and 1 patient - intestinal paresis (Clavien-Dindo grade 2). Postoperative drainage tube was deployed in 3 out of 7 patients with postoperative infiltrates and 6 of them received antibiotic therapy. Medication was successfully applied in all patients with complications. CONCLUSION: There are some advantages of FTR for AA including reduced pain syndrome, morbidity and less length of hospital-stay. Issue of cortisol concentration requires further trials. PMID- 30307417 TI - [Early outcomes of open, laparoscopic and robot-assisted pancreatoduodenectomy]. AB - AIM: To study immediate results of open, laparoscopic and robot-assisted pancreatoduodenectomy for malignancies. MATERIAL AND METHODS: There were 158 patients with cancer of biliopancreatoduodenal area. Open procedures were performed in 118 cases, laparoscopic in 17, robot-assisted pancreatoduodenectomy in 23. RESULTS: After 'standard' pancreatoduodenectomy 31 (62.0%) complications were registered, after laparoscopic - 12 (24.0%) and aWfter robot-assisted surgery - 7 (14.0%) complications. Relationship between probability of complications was absent (correlation coefficient 0.10491), however, significant differences in incidence of complications after various surgical approaches were observed (c2=6.8832; df=0.9679; p<0.05). CONCLUSION: Laparoscopic and robot assisted pancreatoduodenectomy was not followed by advanced early postoperative morbidity. Moreover, minimally invasive approach was associated with improved outcomes. PMID- 30307418 TI - [Technique of invaginative pancreatojejunostomy in pancreatectomy]. AB - Pancreatoenterostomy is one of the key moments in pancreatic surgery. It was proposed invaginative pancreatojejunostomy in end-to-side fashion by using of two continuous single-row purse-string sutures. This technique may be used in pancreatoduodenectomy and Beger's procedure. This method will be useful in cases of edematous and erupting pancreatic parenchyma and hard-to-differentiate lumen of pancreatic duct. It is followed by reduced trauma of tissue and bleeding, allows to avoid sutures failure and to achieve sealed anastomosis. PMID- 30307419 TI - [Preventive anterior abdominal wall repair in recipients of renal allograft]. AB - AIM: Retrospective analysis of safety and efficacy of preventive anterior abdominal wall repair in recipients of renal allograft. MATERIAL AND METHODS: Kidney transplantation was performed in 396 patients with terminal renal failure within January 2015 - May 2017. Preventive endoprosthetics (PE) was applied in 28 (7.1%) patients. There were 7 women (26.9%) and 19 men (73.1%) aged 25-69 years (mean 44.5 (35, 56) years). Median of body mass index (BMI) was 27.5 (23.9, 29.9) kg/m2. RESULTS: Postoperative morbidity was 42.3%. Complications were mild (type I and II) and did not require invasive treatment. Postoperative morbidity was similar regardless protocol of immunosuppressive therapy (IST). CONCLUSION: Preventive abdominal wall repair after kidney transplantation is effective and safe to prevent postoperative hernia. PMID- 30307421 TI - [Ectopic ACTH-syndrome caused by neuroendocrine tumor of lung]. AB - Ectopic ACTH-syndrome is a relatively rare neuroendocrine disease. It is characterized by hypercortisolemia-associated severe complications that justifies need for timely diagnosis and radical therapy. Case report of young patient with ACTH-producing lung tumor is presented. There was 1-year diagnostic search on background of endogenous hypercorticism. Treatment resulted severe postoperative adrenal insufficiency that demonstrates current difficulties in management of these patients. PMID- 30307420 TI - [Why should we refuse simple suturing of duodenal ulcer complicated by perforation?] AB - AIM: To determine the role of simple suturing of perforated duodenal ulcer. MATERIAL AND METHODS: There were 170 patients with perforated duodenal ulcer. Patients were divided into 2 groups: group 1 - 40 patients who underwent simple closure of the ulcer; group 2 - 130 patients who underwent Judd pyloroplasty with ulcerative defect excision. Abdominal effusion nature and severity of peritonitis were comparable in both groups. RESULTS: Mortality was significantly higher in group of simple suturing of ulcerative defect. CONCLUSION: Simple closure of perforated duodenal ulcers should be discarded. PMID- 30307422 TI - [Contrast-enhanced ultrasonography as the most perspective diagnostic method for unstable atherosclerotic plaque of carotid artery]. AB - Problem of internal carotid artery disease diagnosis appears to be crucial today. Complications of this pathology are strokes and transient ischemic attacks. There is no technology for their prediction or at least stratifying risks. Some recent researches are devoted to a new diagnostic method. This new technology is called Contrast Enhanced Ultrasonography (CEUS) and followed by outstanding results in studying the morphological peculiarities of internal carotid artery plaques and predicting the probability of complications. CEUS is a new way for atherosclerotic process analysis because it is able to detect intraplaque neovascularization and vascular wall inflammation. PMID- 30307423 TI - [Current directions in professional training of surgeon]. AB - AIM: To develop 'Cadaveric Course' of operative surgery for severe combined trauma for students, surgical residents, postgraduate students of medical universities and to compare its effectiveness with other approaches. MATERIAL AND METHODS: 'Cadaveric course' program of operative surgery for severe combined trauma consisted of four stages. The first stage is theoretical course (2 weeks), the second stage - students' work in cadaveric operating theatre with instructors (5 weeks), the third stage - their independent work in 'cadaveric operating theatre (10 weeks), the fourth stage - analysis of the results and their comparison with those of 5 2-year residents (control group). RESULTS: There were significant differences in practical skills between students. Mean time of surgery and expert assessment score were 32.0+/-9.5 min and 4.6+/-0.5 in the main group, respectively, in the control group - 46.0+/-7.5 min and 3.6+/-0.5 scores, respectively (p=0.03 and p=0.02). Theoretical background was similar in both groups (p>0.05). CONCLUSION: Research has opened new opportunities to introduce 'cadaveric course' into educational process, to analyze its outcomes and further improvement. PMID- 30307424 TI - [Classification of surgical complications]. AB - AIM: To develop classification of surgical complications. MATERIAL AND METHODS: The most common and recently proposed classifications of surgical complications (Clavien-Dindo, Occordion, R. Satava, et al., A. Kazaryan, et al.) were analyzed. Postoperative complications in 25 556 patients were retrospectively assessed. Incidence and severity of complications, methods of their correction, effect of complications on length of hospital-stay were analyzed. RESULTS: As a result of comprehensive analysis, new classification of surgical complications was proposed. 5 grades of complications were identified. Classification is based on anatomical features, type of complications (within surgical access, organ or cavity), correction depending on this type, severity of complications. Causal relationship of complication with type of repair and increased length of hospital stay was considered. CONCLUSION: Classification proposed is anatomically justified, considers causal relationship of complications and their repair, as well as length of hospital-stay. PMID- 30307425 TI - [Efficiency of structural antigipoxants in perioperative period of patients with lower limbs fractures]. AB - The aim of the study was to study the effectiveness of pathogenetic correction of the metabolism with the inclusion of reamberin (1.5% sodium meglumine succinate solution) in patients with lesions of large segments of the lower limbs. In connection with the task, the efficiency pathogenetic correction of metabolism in 211 patients with diaphyseal hip and shin bones fractures had been analyzed. Patients were divided into the main and control groups. In the main group (86 patients), intravenous infusions of reamberin were administered intravenously at a rate of 1 ml/min at a rate of 10 ml/kg of body weight 1 time per day, a course of 10 days. Patients in the comparison group (125 patients) received an infusion therapy with isotonic solution. The parameters of functional activity and peripheral blood dates had been analyzed. The analysis showed that the use of antihypoxants in the perioperative period provides an earlier recovery of the physical component of quality of life in patients with lesions of large segments of the lower limbs that have undergone stably - functional osteosynthesis according to the principles of Damage control. PMID- 30307426 TI - [Wirsungorrhagia in cystic mucinous pancreasic tumor]. AB - A rare case of virsungorrhagia in a 65 y/o patient with a mucinous tumor of the tail of the pancreas is presented. Recurrent gastrointestinal bleeding was associated with an arrosis of the splenic artery adjacent to the tumor, which required a two-step treatment - endovascular occlusion of the splenic artery and distal resection of the pancreas. PMID- 30307427 TI - [Ileocecal intussusceptions]. AB - AIM: To present treatment of patients with ileocecal intussusception. MATERIAL AND METHODS: There were 3 patients with ileocecal intussusception for the period from June 2016 to August 2017. CONCLUSION: Abdominal sonography is main diagnostic method for intestinal intussusception. X-ray examination including contrast-enhanced irrigography gives more complete information about suspected intussusception. It is necessary to differentiate intestinal intussusception from other diseases accompanied by abdominal pain, vomiting, bloody discharge from rectum, abdominal neoplasm. Minimally invasive laparoscopic approach is advisable for diagnosis and treatment of intestinal intussusception. PMID- 30307429 TI - [Operational management of the state forensic medical expert activity in Russia as a scientific problem: brief history analyzed and prospects for further studies]. AB - The authors consider and systematize the methods currently in use for the purpose of operational management of the state forensic medical expert activity (FMA) in Russia throughout the entire historical period since the establishment and development of the forensic medical expertise service in this country as well as the prospects for its further improvement. The importance of the problem arises from the fact that the legal status of the forensic medical expertise in the Russian Federation remains a matter of scientific discussions. On the one hand, some experts consider it necessary to set up on a broader basis forensic medical facilities of a new type as an alternative to the existing governmental bodies. On the other hand, such structures are being de facto established by the state law-enforcement agencies. The organizational restructuring keeps abreast with the better understanding of the its theoretical principles, forms of and approaches to the operational management of the state forensic medical expert activity. Under these conditions, the historical analysis of the current forensic medical activities at different stages of their development and their operational management as well as prospects for their further improvement appears to be both highly justified and useful. PMID- 30307428 TI - [Prevention of venous thromboembolic complications in firearm injury]. AB - Prevention of venous thromboembolic complications in wounded is a complex problem which has not yet been fully resolved throughout the world. Current state of venous thrombosis prevention in wounded in different countries and certain ways of its improvement are analyzed in the article. PMID- 30307431 TI - [The analysis of the commission forensic medical expertises concerning charges against healthcare providers]. AB - This article as designed to present the results of the many-year analysis of the results and procedures of commission medical expertises concerning charges against healthcare providers as exemplified by the activities in these fields carried out by the Saint-Petersburg Bureau of Forensic Medical Expertise. The analysis has demonstrated the well apparent tendency toward the growth in the number of expertises necessitated by the constantly increasing frequency of private claims and complaints in connection with the inadequacy and/or poor quality of medical assistance provided for the population. This growth may be attributable either to the enhanced activities of the judicial and investigation governmental bodies (including the increased frequency and periodicity of the planned inspections of the cases of lethal outcomes) or to the more active behavior of the patients themselves exhibiting a greater than during the preceding period concern about their health status (or both). PMID- 30307430 TI - [Organization of the quality control service for the forensic medical expert activity at the Saint-Petersburg state budgetary healthcare facility 'Bureau of Forensic Medical Expertise']. AB - The Saint-Petersburg Bureau of Forensic Medical Expertise has created the universal system of the internal quality control oriented toward the more rational exploitation of the available resources, material and technical facilities, and systemic management of the quality of forensic medical activities. The system serves as a basis for the timely identification of undesirable problematic situations, efficiently predict and/or prevent them and the resulting deterioration of the quality of expert work leading to the inadequate provision of finance and resources. Moreover, the system makes it possible to optimize and correct the operational management of the Bureau activities and develop programs for successful carrying them out in the future. The results of the evaluation of all forms of control are used to work out the modern technologies for the management of forensic medical expertise activities together with the final concluding reports and analytical reviews of the positive experience and of the typical imperfections in forensic medical expertise operations are distributed among the structural departments of the Bureau. These materials are used as a basis for the development of the measures and recommendations for the improvement of forensic medical expert activities of the Bureau, compilation of analytical reviews, specification of the criteria for the effectiveness of the forensic medical expertise, improvement of the procedures for the specialist screening studies (in conformity with the internal standards adopted by the Bureau), the subject matter and the schedule of advanced expert training, contents and procedures of instructions, the systems of delegation of authorities and empowerment with responsibilities, provision of economic incentives for the staff members, etc. PMID- 30307432 TI - [Organization of quality control of the forensic medical investigations]. AB - The article describes the system of quality control at all stages of forensic chemical investigations (including pre-analytical, analytical, and post analytical ones) carried out by the Saint-Petersburg Bureau of Forensic Medical Expertise It is shown that standardization and control taken together make up a solid foundation for obtaining the reliable and reproducible results of forensic chemical investigations. Responsibility for the quality control at all stages of forensic chemical investigations lies on the heads of the respective departments. Special staff members are appointed to supervise performing each concrete form of control and keeping the relevant documentation. PMID- 30307433 TI - [The chemical toxicological investigation of gamma-hydroxybutyric acid in biological objects and the interpretation of the results of the analysis]. AB - The authors propose a method for the quantitative determination of gamma hydroxybutyric acid (GHBA) in biological objects including biological fluids (blood, urine) and tissues with the use of gas chromatography with mass-selective detector. The samples for the analysis were prepared by liquid-liquid extraction by butyl acetate with subsequent derivatization using a N,O Bis(trimethylsilyl)trifluoroacetamide/Trimethylchlorosilane mixture (BSTFA + 1%TMCS). The graded graphs were linear in the range of GHBA concentrations from 26.4 to 1321.6 mg/l. Coefficients of correlation for all the graphs were higher than 0.999. The threshold of detectability for GHBA in blood, urine, and internal organs was 10 mg/l, the quantification limit concentration 26 mg/l. PMID- 30307434 TI - [The influence of the packaging on the storage qualities of the volatile substances]. AB - The objective of the present study was to evaluate the storage qualities of the acetone and ethanol aqueous solutions kept in the polyethylene flasks, polypropylene and glass tubes that were stored under different environmental temperature. It was shown that the acetone aqueous solution better retained its properties when stored in glass vials at room temperature as well as at 0 degrees C and 4 degrees C. The most pronounced decrease of acetone concentrations (from 70 up to 95%) was documented after its storage in the polyethylene flasks. The ethanol concentration fell down by 40% when stored in polyethylene flasks at room temperature. PMID- 30307435 TI - [The blunt open injury to the lower extremities resulting from the overextension of the knee joint]. AB - This article reports a case of the blunt open injury to the lower extremities resulting from the overextension of the knee joint that, despite it severity, turned out to be a mere accompanying event of a more serious condition. This case is of great interest in the context of forensic medical expertise by virtue of the apparent discrepancy between the extent of the injury and the circumstances of the accident. Clearly, such discrepancy may influence the reliability of the expert conclusion as regards the evaluation of such injury. PMID- 30307436 TI - [About some peculiar features of gunshot wounds inflicted by shot-gun cartridges for the short-barreled weapons of the limited injurious power]. AB - The cases of application of 'non-standard' ammunition constitute a serious challenge for the forensic medical expertise. Bearing in mind the importance of this issue, the authors report a case encountered in their practical work, namely a gunshot wound inflicted by the 'non-standard' shot-gun cartridges for the short barreled weapons of the limited injurious power that required the expert evaluation. The case under consideration illustrates the peculiar features of the gunshot wound inflicted by 'non-standard' shot-gun cartridges for the short barreled weapons of the limited injurious power. Moreover, the forensic medical expertise of this case exemplifies the effectiveness of the cooperation between various department of the Saint-Petersburg Bureau of Forensic Medical Expertise during investigation of the case being considered. PMID- 30307437 TI - [A rare case of suicide carried out by firearm]. AB - This article reports the rare case of suicide carried out with the use of the firearm. Subject K. suffered three mortal wounds he inflicted to himself by shooting from the 9.0 mm 'Viking' pistol when performing training exercises at a shooting range of DOSAAF (Russian abbreviation for the Volunteer Society for Cooperation with the Army, Aviation, and Navy). The case is of special interest in the context of forensic medical expertise because it clearly shows the occurrence of the suicidal events in the practical work of the forensic medical experts in which the victim himself makes damages that are at first sight impossible to make of one's own free will. PMID- 30307438 TI - [About the estimation of the possibility of carrying out of several self inflicted fatal injuries by the victim]. AB - Forensic medical experts are not infrequently faced in their practical work with the question of the possibility of inflicting body injuries by the victim to himself (herself). In such cases, the law-enforcement authorities are in the first place interested not in the possibility of such self-inflicted injuries but rather in the correspondence between the character of the injuries and the circumstances of the event that needs to be objectively established in the course of the forensic medical expertise. The cases of multiple severe self-inflicted injuries in which all the witnesses were one way or another involved in the accident as the participants of the fight with the victim, attract especially close attention and require careful examination. The authors present a case that evolved into a massive public outcry in which a car driver, supposedly under the influence of narcotic drugs, provoked a road traffic accident and the conflict with other road users after which he inflicted severe stab and slash wounds to himself by five knife hits to the left half of the chest. PMID- 30307439 TI - [On the necessity of the development of modern algorithms for the evaluation of the injuries inflicted with scissors]. AB - At present, a steady growth in the frequency of wounds inflicted by sharp injurious objects (e.g. scissors) is being observed. It necessitates an enhanced attention to the investigation of the causes underlying such events and the circumstances accompanying them. This article presents an example of one of the injuries inflicted with scissors that required the most careful and comprehensive criminalistic study despite the seemingly self-evident circumstances of the event. This case illustrates the necessity of development of the modern algorithms for the evaluation of the injuries inflicted with the scissors. PMID- 30307440 TI - [Forensic medical expertise in Saint-Petersburg in the period from the XVIII and the early XX centuries: the sources and organization of the forensic medical expert activity]. AB - This article contains information about the organization of the forensic medical expert investigation in the city of Saint-Petersburg since the time of its foundation. The sources of origin of the first Russian service of forensic medical expertise as a component of the state-supported healthcare system, as exemplified by the Saint-Petersburg state healthcare institution 'Bureau of Forensic Medical Expertise', are described. PMID- 30307442 TI - [The historical examples of 'self-bumping' by inadvertency]. AB - The stories of 'self-bumping up' against a sharp object by inadvertency appeared in the historical chronicles with a periodicity of once per each 1000 years. The victims of such accidents include, inter alia, the Persian tsar Kambik II (522 b.c), Russian tsarevich Dimitry (1591), etc. The forensic medical analysis of the self-bumping by inadvertency episodes involving the historical characters made it possible to evaluate the circumstances, specific features and mechanism of the resulting injuries, the specific features of the inflicted wounds and their outcomes. PMID- 30307441 TI - [Forensic medical expertise in Petrograd - Leningrad - Saint-Petersburg in the XX XXI centuries: the past and the present]. AB - The Saint-Petersburg state healthcare institution 'Bureau of Forensic Medical Expertise' (SPb SBHCI 'Bureau of Forensic Medical Expertise') celebrated its 100th anniversary on April 9, 2018. This article provides information concerning the organization and management of the forensic medical expertise system in Petrograd, Leningrad, and Saint-Petersburg in the XX-XXI centuries. The data on the staff composition of the Bureau and character of its activities are presented together with the outline of its main directions and practical achievements. PMID- 30307443 TI - LIPID DISORDERS: ADVANCES IN RESEARCH AND CHALLENGES IN CLINICAL PRACTICE. PMID- 30307444 TI - DYSLIPIDEMIA IN MEXICO, A CALL FOR ACTION. AB - The purpose of this manuscript is to highlight the peculiarities of the Mexican population regarding the clinical expression, genetics, and treatment of lipid disorders. Furthermore, it is a call for action to address the existing gaps in care and research of dyslipidemias. The Mexican Mestizos are highly susceptible to metabolic disorders (i.e., low high-density lipoprotein cholesterol concentrations, hypertriglyceridemia, abdominal obesity, and type 2 diabetes); these conditions are associated with ethnic-specific genetic variants. On the other hand, despite the high prevalence of dyslipidemia in Mexican adults, there is a lack of awareness of these conditions. The public is not informed about the need for screening and the potential benefit of the lipid-lowering treatments. Underdiagnosis and undertreatment are two of the main challenges to be solved. Dyslipidemias are not among the priorities of the health systems for the prevention of cardiovascular disease; access to laboratory resources and medications is insufficient in primary care units despite the proven cost-benefit of the treatment of lipid disorders. Evidence-based public policies are needed to change the practice and allocation of assets to be capable of preventing cardiovascular diseases. Treatment of dyslipidemia should have a prominent role in any effort to decrease the number of preventable deaths caused by non communicable diseases. PMID- 30307445 TI - CONTROVERSIAL ISSUES IN THE TREATMENT OF DYSLIPIDEMIAS IN PATIENTS WITH DIABETES MELLITUS. AB - Patients with diabetes mellitus have an elevated cardiovascular risk. Lipid lowering therapy is a successful strategy to prevent atherosclerotic events in these patients. Therefore, almost all professional societies recommend statin therapy for patients with diabetes under certain conditions. Despite this broad consensus, a number of controversial issues remain. Thus, it remains unclear in which patients the lipid parameters should be determined in the fasting state and in which postprandial values are sufficient. It is also an open issue whether all patients with diabetes should receive statin therapy and which goals should be achieved. While the benefit of statin-ezetimibe and statin-PCSK9-inhibition combinations has been shown in large outcome trials, results of outcome trials involving statins with triglyceride lowering drugs have been ambiguous. Thus, it is currently unclear which patients benefit from such combinations. Finally, the best strategy to address severe hypertriglyceridemia in patients with diabetes is unclear. This article discusses these issues and aims to provide help and information to practicing physicians taking care of patients with diabetes mellitus. (REV INVEST CLIN. 2018;70:237-43). PMID- 30307446 TI - FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES. AB - Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36). PMID- 30307447 TI - NEW BIOTECHNOLOGICAL TREATMENTS FOR LIPID DISORDERS. AB - Disorders of lipid and lipoprotein metabolism play a central role in the pathogenesis of atherosclerotic cardiovascular diseases (CVDs). Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high. The purpose of this manuscript is to review the application of new technologies in the treatment of lipid disorders. New therapies work mostly at the gene expression level and are, therefore, different from traditional small-molecule drugs that work mainly by inhibiting already synthesized proteins. We will briefly lay out the function of the gene products targeted by the new agents. Then, we will organize our review of new biotechnological treatments by the molecular approach, namely: monoclonal antibodies, antisense oligonucleotides, small-interfering RNAs, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9)-based genome editing. The paper concludes with the description of the current clinical studies and the perspectives for the use of these agents. (REV INVEST CLIN. 2018;70:244-54). PMID- 30307448 TI - GENOMICS AND SYSTEMS BIOLOGY APPROACHES IN THE STUDY OF LIPID DISORDERS. AB - Cardiovascular disease (CVD) is a broad definition for diseases of the heart and blood vessels with high mortality and morbidity worldwide. Atherosclerosis and hypertension are the most common causes of CVD, and multiple factors confer the susceptibility. Some of the predisposing factors are modifiable such as diet, smoking, and exercise, whereas others, including age, sex, and individual's genetic variations contributing to the CVD composition traits, are non modifiable. This latter group includes serum lipid traits. High serum lipid levels, specifically high levels of serum low-density lipoprotein cholesterol and triglycerides, are well-established key risk factors of atherosclerosis. This review will discuss genomics and systems biology approaches in the study of common dyslipidemias. The non-Mendelian forms of dyslipidemias are highly complex, and the molecular mechanisms underlying these polygenic lipid disorders are estimated to involve hundreds of genes. Interactions between the different genes and environmental factors also contribute to the clinical outcomes; however, very little is known about these interactions and their molecular mechanisms. To better address the complex genetic architecture and multiple properties leading to high serum lipid levels, networks and systems approach combining information at genomic, transcriptomics, methylomics, proteomics, metabolomics, and phenome level are being developed, with the ultimate goal to elucidate the cascade of dynamic changes leading to CVD in humans. (REV INVEST CLIN. 2018;70:217-23). PMID- 30307449 TI - Coordination structure conversion of protonated bisporphyrinato terbium(iii) double-decker complexes and creation of a Kondo assembly by electron injection on the Au(111) surface. AB - The first step towards the synthesis of single-molecule magnet (SMM)-based spintronics devices is the organization and manipulation of magnetic molecules on surfaces. Our previous studies on bulk crystals demonstrated that protonated porphyrinato double-decker complexes [Tb(Hoep)(oep)] (oep = 2,3,7,8,12,13,17,18 octaethylporphyrinato) are not SMMs; however, once a hydrogen is removed to produce their neutral radical forms, [Tb(oep)2], they convert to SMMs. These intriguing properties encouraged us to examine the electronic/spin properties of these complexes and their chemical conversion ability after their transfer onto a metal substrate, similar to the environment required for the practical application of SMMs. Herein, we conducted a single-molecule-scale conversion of the protonated bis(porphyrinato)terbium(iii) double-decker complex [Tb(Hoep)(oep)], whose hepta-coordinated terbium ion changes into octa coordinated [Tb(oep)2] on detaching a hydrogen atom by scanning tunnelling microscopy. This conversion can be caused by the injection of tunnelling electrons of energy 1.5-2.5 eV. We confirmed the conversion by analysing the topographic image and the spin state of the molecule. The latter was achieved by examining the Kondo resonance, which originated from the screening of the molecular spin by the conduction electrons of the metal. The Kondo resonance was not observed for [Tb(Hoep)(oep)] but was observed for the converted species, which agrees well with a model containing the [Tb(oep)2] molecule and Kondo resonance originating from the pi-electron spin of the porphyrin ligand. Even though it is not possible to provide complete evidence of the SMM properties of the transferred molecule, we have demonstrated a possible path to realize the switch-on SMM properties of a single molecule. PMID- 30307450 TI - Magnetothermal heating facilitates the cryogenic recovery of stem cell-laden alginate-Fe3O4 nanocomposite hydrogels. AB - Constructs of magnetic nanocomposite hydrogels microencapsulated with stem cells are of great interest as smart materials for tissue engineering and regenerative medicine. Due to the short shelf life of such biocomposites at an ambient temperature, their long-term storage and banking at cryogenic temperatures are essential for the "off-the-shelf" availability of such biocomposites for widespread clinical applications. However, high-quality cryogenic recovery of stem cell-nanocomposite hydrogel constructs has not yet been achieved due to the damage to cells and/or microstructures of hydrogel constructs caused by ice formation, particularly during warming from cryogenic temperatures. Herein, stem cell-magnetic nanocomposite hydrogel constructs, which have an inherent magnetothermal property provided by embedded magnetic nanoparticles, are explored to achieve ultra-rapid cryogenic warming. The binding of water molecules by the hydrogel combined with the magnetothermal heating greatly suppressed ice formation during both cryogenic cooling and warming. Thus, the cryogenic recovery of nanocomposite hydrogel constructs with intact microstructures and fully functional stem cells from ultra-low temperatures was successfully achieved. We further demonstrated that magnetic nanocomposite hydrogels microencapsulated with stem cells could be conveniently manipulated for a self-assembled 3D culture. Together, we have developed a highly efficient and easy-to-perform approach for the cryogenic recovery of stem cell-encapsulated magnetic nanocomposite hydrogel constructs. Our results will facilitate the applications of such stem cell magnetic nanocomposite hydrogels in regenerative medicine and tissue engineering. PMID- 30307452 TI - Infrared spectroscopy of gas phase alpha hydroxy carboxylic acid homo and hetero dimers. AB - New gas phase infrared spectroscopy is reported for an aromatic alpha hydroxy carboxylic acid homo dimer of 9-hydroxy-9-fluorene carboxylic acid (9HFCA)2, and the hetero dimer of 9HFCA with glycolic acid. In terms of the 9-hydroxy stretching frequency, the 16 cm-1 blue-shift in the homo dimer and the 17 cm-1 blue-shift in the hetero dimer, relative to that in 9HFCA monomer, are attributed to collective effects with anti-cooperativity stronger than cooperativity. Furthermore, for the hetero dimer, the two alpha hydroxy groups' stretching frequencies are clearly resolved, and differ by 30 cm-1. This difference represents a modest, quantitative enhancement of the intramolecular H-bond by the fluorene moiety in 9HFCA monomer, as opposed to that in glycolic acid. Accurate vibrational frequencies of the alpha OH, 3568 cm-1 in the bare glycolic acid, and 3584 cm-1 in the glycolic acid homo dimer are determined for the first time by comparison to 9HFCA monomer, homo and hetero dimers. The quantitative studies by infrared spectroscopy reveal subtle interactions among intra- and intermolecular H-bonds in the alpha hydroxyl acid dimers, which are also uniquely extended to probe each monomer's subtle intramolecular interactions. PMID- 30307451 TI - Unravelling the 2D self-assembly of Fmoc-dipeptides at fluid interfaces. AB - Dipeptides self-assemble into supramolecular structures showing plenty of applications in the nanotechnology and biomedical fields. A set of Fmoc dipeptides with different aminoacid sequences has been synthesized and their self assembly at fluid interfaces has been assessed. The relevant molecular parameters for achieving an efficient 2D self-assembly process have been established. The self-assembled nanostructures of Fmoc-dipeptides displayed significant chirality and retained the chemical functionality of the aminoacids. The impact of the sequence on the final supramolecular structure has been evaluated in detail using in situ characterization techniques at air/water interfaces. This study provides a general route for the 2D self-assembly of Fmoc-dipeptides. PMID- 30307453 TI - An unprecedented {CuTe} core incorporated in a 36-tungsto-4-silicate polyoxometalate with visible light-driven catalytic hydrogen evolution activity. AB - We report an unprecedented {CuII14TeIV10} core containing the novel MU,MU-/MU6 TeIVO32- mode and TeIVO44- embedded within a 36-tungsto-4-silicate POT shell, which constitutes the first example of a tellurous copper cluster in POMs. The structure-stabilizing and templating effects of tellurite anions are crucial for this assembly. Moreover, its visible light-driven catalytic H2 evolution activity and related quenching mechanism are demonstrated, and extensive stability studies are presented. PMID- 30307454 TI - Topology-dependent hydrocarbon transformations in the methanol-to-hydrocarbons reaction studied by operando UV-Raman spectroscopy. AB - The methanol-to-hydrocarbons (MTH) reaction represents a versatile, industrially viable alternative to crude-oil based processes for the production of chemicals and fuels. In the MTH reaction, the shape selectivity of acidic zeolites is exploited to direct the synthesis towards the desired product. However, due to unavoidable side reactions occurring under processing conditions, all MTH catalysts suffer deactivation due to coke formation. Though it is likely that some common characteristics for carbon formation exist for all zeolite topologies, it has been proposed that the differences in shape selectivity among the different catalysts will also influence the individual deactivation mechanisms. As deactivating species are mostly aromatic compounds, highly methylated benzenes and/or polycyclic aromatic hydrocarbons (PAHs) have been discussed. In some cases, these can further grow to extended carbon structures. Here, we have investigated the hydrocarbon reactivities and carbon formation for five topologically different zeolite catalysts through an operando UV-Raman approach, taking advantage of the high sensitivity of this technique towards aromatic and other carbonaceous species. The combination of the spectroscopic tool with activity measurements allowed us to obtain valuable details and some general trends on the deactivation paths during MTH. This approach made accessible unique insight on the complex chemistry of MTH by allowing the real time observation of hydrocarbon transformations typical for the peculiar topology of each catalyst, usually inaccessible by ex situ techniques. PMID- 30307455 TI - One-step facile synthesis and high H2-evolution activity of suspensible CdxZn1-xS nanocrystal photocatalysts in a S2-/SO32- system. AB - For a CdS-based photocatalyst, both the photocorrosion resistance and the rapid H2-production reaction are highly required for improving its photocatalytic H2 production performance. In this study, a facile strategy was reported to simultaneously realize an improved photocorrosion resistance and rapid interfacial H2-evolution reaction of CdxZn1-xS solid-solution photocatalysts in a sulfur-rich S2-/SO32- solution. Here, the suspensible CdxZn1-xS nanocrystal photocatalysts are prepared by a one-step co-precipitation route through the direct introduction of Zn2+/Cd2+ mixing ions in a sulfur-rich Na2S-Na2SO3 solution, and the resultant CdxZn1-xS nanocrystals (ca. 5 nm) display a suspensible structure owing to the numerous and selective adsorption of S2-/SO32- on the surface of these CdxZn1-xS nanocrystals. It is found that the bandgap structure of CdxZn1-xS (from 2.25 to 3.52 eV) nanocrystals can be easily controlled by adjusting the Cd2+/Zn2+ molar ratio. The photocatalytic experimental results suggested that the suspensible CdxZn1-xS nanocrystal photocatalysts clearly displayed an excellent photocatalytic H2-production performance, and the suspensible Cd0.6Zn0.4S nanocrystals exhibit the highest photocatalytic H2-generation performance of 717.19 MUmol h-1, a value higher than that of the sole CdS (320.99 MUmol h-1) and ZnS (5.89 MUmol h-1) by a factor of 2.2 and 121.8 times, respectively. Based on the experimental results, a possible S2- active site-mediated mechanism accounted for the high H2-production activity of the suspensible CdxZn1-xS nanocrystals, namely the numerous adsorbed S2- ions not only function as efficient hole scavengers to rapidly consume the photogenerated holes, resulting in an improved photocorrosion resistance of suspensible CdxZn1-xS nanocrystals, but also serve as effective H+-capturing active sites to accelerate the interfacial H2-production reaction. Meanwhile, an optimum bandgap structure of suspensible CdxZn1-xS nanocrystals is also extremely required for promoting the photocatalytic H2-production activity. This research may provide advanced insights for developing stable and high-activity photocatalytic materials. PMID- 30307456 TI - Novel fully reduced phosphomolybdates for highly efficient removal of inorganic hexavalent chromium and the organic dye methylene blue. AB - New Na-bridged phosphomolybdates (H2en)12[{Na0.8K0.2(H2O)}2{Na[Mo6O12(OH)3(HPO4)2(PO4)2]2}2].7H2O (1), (H2bpp)2[{Sr2(H2O)4}{Na3(H2O)10}{Na[Mo6O12(OH)3(HPO4)3(PO4)]2}].2H2O (2), and (H2bpp)6 [{Ca2(H2O)4}{Na2(H2O)4}{Na[Mo6O12(OH)3(HPO4)3(PO4)]2}2] (3) (en = ethylenediamine, bpp = 1,3-bi(4-pyridyl)propane), were synthesized by a hydrothermal method and characterized. Single-crystal X-ray diffraction analysis revealed that the three hybrids were composed of fully reduced 'hourglass-shaped' {Na[PV4MoV6X31]2}n- (X = O/OH) clusters and N-containing organic cations. The electrochemical measurements showed that this kind of highly negatively charged metal-oxygen cluster in crystals 1-3 has the ideal behaviour of reversible electron gain or loss, which is related to the function of electron transfer catalysts in oxidation reduction reactions. Experimental results indicated that they were active as heterogeneous crystal catalysts in the catalytic reduction of inorganic hexavalent chromium with formic acid as reductant, and also had a significant catalytic effect on the photodegradation of the organic dye methylene blue under mild conditions. PMID- 30307457 TI - Structure searching methods: general discussion. PMID- 30307458 TI - Fluorogenic "photoclick" labelling of DNA using a Cy3 dye. AB - Two 2'-deoxyuridines as new building blocks for automated DNA synthesis carry a small aryltetrazole as "photoclickable" group at their 5-positions. The postsynthetic "photoclick" labeling of such presynthesized DNA using a maleimide modified Cy3 dye shows an up to 17-fold fluorogenicity due to an energy transfer between the pyrazoline moiety and the Cy3 fluorophore in the DNA products. This concept is also applicable to other maleimide-modified dyes. PMID- 30307459 TI - From 1D ordered linear polymers to discrete macrocycles: surface adsorption and pH take control. AB - In this work we demonstrate that the surface adsorption and pH play a determining role in controlling the final product of a Schiff base reaction. Either 1D linear polymers or discrete macrocycles can be obtained by tuning the pH and surface confinement. PMID- 30307460 TI - One pot ligand exchange method for a highly stable Au-SBA-15 catalyst and its room temperature CO oxidation. AB - A modified deposition precipitation (DP) method has been developed to address a fundamental issue of supporting well dispersed Au nanoparticles on silica. Ammonium chloride (NH4Cl) plays an important role in in situ modifying the gold precursor (HAuCl4.3H2O) solution allowing facile deposition of gold NPs in the channels of SBA-15. The Au-SBA-15 catalyst (2.8 wt%) synthesized by this procedure showed 100% conversion for CO oxidation at room temperature with excellent stability at room temperature and high temperature. PMID- 30307461 TI - Spectral signatures of proton delocalization in H+(H2O)n=1-4 ions. AB - Couplings involving large amplitude vibrations in H+(H2O)n (n = 1-4) are explored using several theoretical approaches. These include harmonic treatments, analysis of harmonically coupled anharmonic oscillator (HCAO) models of the OH stretching vibrations, vibrational perturbation theory (VPT2) in internal coordinates, and diffusion Monte Carlo (DMC). It is found that couplings between shared proton stretches and HOH bends can lead to normal modes that are significantly mixed in character. Couplings between the various OH stretching vibrations are much weaker, and the OH stretches are well-described by harmonically coupled anharmonic oscillator models. Anharmonic couplings and the role of these large amplitude vibrations are further explored using DMC and VPT2. Based on the results of these calculations, it is found that all of the H+(H2O)n ions considered in this study display several different types of large amplitude vibrational motions even in their ground states. In the case of H7O3+, degenerate VPT2 calculations indicate that there are large couplings between the shared proton stretch and various lower frequency vibrations that correspond to motions that break the ionic hydrogen bonds. This leads to vibrational eigenstates that have contributions from several zero-order states. PMID- 30307462 TI - Performance Evaluation and Measurement Uncertainty Determination of the New Version of the Abbott ARCHITECT 25-OH Vitamin D 5P02 Assay. AB - Objectives: We evaluated performance and measurement uncertainty of the newly released ARCHITECT 25-OH vitamin D 5P02 assay (Abbott Diagnostics, Abbott Park, IL). Methods: In total, 300 samples were used to compare the results from ELECSYS Vitamin D Total (Roche Diagnostics, Mannheim, Germany) and ADVIA Centaur Vitamin D Total (Siemens, Tarrytown, NY). To quantify the measurement uncertainty, 25 samples and four levels of standard reference material (SRM) were measured using isotope dilution-liquid chromatography-tandem mass spectrometry according to international guidelines. Results: The results of the ARCHITECT assay were equivalent to other immunoassays, but correlation coefficients were lower than the recommended criterion. SRM level 2 was considered adequate for uncertainty estimation, and the expanded measurement uncertainty of the ARCHITECT assay was 4.2%, which was superior to the other two assays. Conclusions: The restandardized ARCHITECT assay has acceptable performance in a clinical setting. However, there is still a need for further standardization of total vitamin D measurement among the automated immunoassays. PMID- 30307463 TI - Diagnostic Accuracy of beta-d-Glucan (Fungitell) Testing Among Patients With Hematologic Malignancies or Solid Organ Tumors: A Systematic Review and Meta Analysis. AB - Objectives: To determine the accuracy of Fungitell, a beta-d-glucan (BDG) test, for the diagnosis of invasive fungal infection (IFI) among cancer patients. Methods: For this meta-analysis, MEDLINE and EMBASE were searched for references related to BDG testing. Study quality was evaluated using QUADAS-2. Statistical analysis was performed using Stata 14. Results: We screened 12,426 references and identified 189 studies for full-text review. Nineteen studies were included in the final meta-analysis. There was moderate heterogeneity between studies. Nine studies had a high risk of bias, which significantly elevated the overall specificity estimate. Restricting to only low-bias studies, the sensitivity and specificity were 80% and 63%, respectively. Conclusions: The overall sensitivity and specificity of Fungitell as a diagnostic test for IFI is moderate, and there is substantial heterogeneity between studies. Limiting studies to only low-bias risk reduced heterogeneity but also lowered the overall specificity estimate. PMID- 30307464 TI - Vitamin K1 cream significantly reduces incidence and severity of cetuximab related acneiform skin rash in women: A post hoc analysis of the EVITA trial. PMID- 30307465 TI - "Personalized biomarker-based treatment strategy for patients with squamous cell carcinoma of the head and neck: EORTC position and approach." AB - The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology.Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059).In this paper, we review the different trial designs for biomarker driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials. PMID- 30307466 TI - Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. AB - Background: Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and Methods: NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna(r)-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) x3 21-day courses followed by docetaxel 100 mg/m2 x3 21-day courses. Primary endpoint was residual cancer burden (RCB 0-1 rate). Secondary endpoints included clinical response, proliferation-based markers, and safety. Results: Overall, 106 patients were randomised (median Prosigna(r) ROR Score 71 (22-93)). RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7 25.7)] arms, respectively. pCR rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with two versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion: LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna(r)-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number: NCT02400567. PMID- 30307468 TI - Identification and characterization of novel fusion genes in prostate cancer by targeted RNA capture and next-generation sequencing. AB - Gene fusions play critical roles in the development and progression of prostate cancer, and have been used as molecular biomarkers for diagnosis of the malignant disease. To further explore the novel fusions in prostate cancer, we performed targeted RNA capture and next-generation sequencing in a cohort of 52 prostate cancer patients, identified and validated 14 fusion events (7 types of fusion genes) in 12 cases, including three novel fusion genes. We characterized a chromosome rearrangement-induced trigenic KLK2-DGKB-ETV1 fusion, which may function as a non-coding RNA to upregulate the expression of the wild-type ETV1 protein in the tumor tissue. Additionally, we detected two novel fusion forms of HNRNPA2B1-ETV1 and SLC45A2-AMACR fusions, respectively. Interestingly, fusion events participated by kinase genes, which frequently occurred in other human cancers, were not present in these prostate cancer cases, suggesting discrepant gene fusion patterns in different cancers. These findings expand the genetic spectrum of prostate cancer and provide insight into diagnosis of this prevalent disease. PMID- 30307469 TI - Reply to the Letter to the Editor "A Centralised multidisciplinary clinic approach for germ cell tumours" by Crawford SM. PMID- 30307467 TI - n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. AB - Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (Tnf-alpha)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues. PMID- 30307470 TI - Frequency, intensity and localization of pain as risk factors for frailty in older adults. AB - Background: the association between pain characteristics and frailty risk is uncertain. Objective: to investigate the separate impact of the frequency, intensity and location of pain on frailty risk and its possible mechanisms. Methods: prospective cohort of 1505 individuals >=63 years followed between 2012 and 2015 in Spain. In 2012, pain was classified into: lowest pain (Score 0), middle pain (Score 1-4) and highest pain (Score 5-6). Incident frailty was assessed in 2015 as having >=3 Fried criteria or a Frailty Index (FI) >=0.30. Results: in multivariate analyses, the risk of frailty (measured with the Fried criteria or the FI) increased progressively with the frequency of pain, its intensity and the number of pain locations. Compared with those having the lowest pain score, the odds ratio (95% confidence interval) of Fried-based frailty was 1.24 (0.56-2.75) in the middle score and 2.39 (1.34-4.27; P-trend <0.01) in the highest score. Corresponding values for frailty as FI >=0.30 were 1.39 (0.80 2.42) and 2.77 (1.81-4.24; P-trend <0.01). Odds ratios did not change after adjustment for alcohol intake, Mediterranean diet adherence or sedentary time, but were reduced with adjustment for pain-associated chronic diseases (cardiovascular disease, diabetes, chronic lung disease, osteomuscular disease and depression). A higher pain score was linked to higher risk of exhaustion and low physical activity (two out of five Fried criteria) and to a worse score in all FI domains. Conclusion: frequency, intensity and location of pain were associated with higher risk of frailty. Study associations were partly explained by pain-associated morbidity. PMID- 30307471 TI - Association Between Executive Functioning and Functional Impairment Among Pediatric Cancer Survivors and Controls. AB - Objective: To examine the impact of cancer treatment upon neurocognitive and functional impairment; and to explore the relationship between these constructs in pediatric cancer survivors compared to controls. Method: A cross-sectional cohort of survivors (n = 26) and controls (n = 53) was included. Survivors were off treatment an average of 6.35 years (SD = 5.38; range 1-15 years) and demonstrated an average "medium" Central Nervous System (CNS) treatment intensity score. Participants completed measures of neurocognitive functions including intellectual assessment (RIST) and executive functions (NIH Examiner), while parents reported on children's functional impairment (BIS). Results: Survivors were similar to controls in neurocognitive ability, including intellectual and executive functions, and functional impairment. Regardless of group membership, NIH Examiner performance and functional impairment increased with age. Increased impairment was associated with different neurocognitive variables for survivors versus controls. Conclusions: Research regarding functional impairment of cancer survivors and the association between neurocognitive deficits and functional impairment has been limited. Our results demonstrate that, while low treatment intensity may confer relative sparing of neurocognitive and executive functioning among survivors, functional impairment continues to be a potential risk. In conclusion, pediatric cancer survivors should be screened for functional difficulties, particularly in the areas of interpersonal relations and self-care. PMID- 30307472 TI - Relation of cigarette smoking and alcohol drinking in midlife with risk of cognitive impairment in late life: the Singapore Chinese Health Study. AB - Background: the relations of cigarette smoking and alcohol drinking with risk of cognitive impairment remain inconsistent. Methods: to examine the independent and joint relations of smoking and alcohol drinking with cognitive impairment, we used data from 16,948 men and women, who had been followed-up for 16-23 (mean of 20) years as participants of the Singapore Chinese Health Study, a population based prospective cohort. Data on smoking and alcohol drinking were collected at baseline (1993-98), when participants were aged 45-74 (mean 53) years. Cognition was assessed using a 30-item Mini-Mental State Examination during follow-up three visits (2014-16), when participants were aged 61-96 (mean 73) years. Multivariable logistic regression models were used to estimate the odd ratios (ORs) and 95% confidence intervals (CIs). Results: cognitive impairment was present in 2,443 (14.4%) participants. Compared with non-current smokers, current smokers had 20% increased risk (OR = 1.20, 95% CI = 1.04-1.39). Compared with those who drank less than weekly, regular alcohol drinking (at least weekly) had 17% increased risk (OR = 1.17, 95% CI = 1.01-1.36). Compared with those who were neither smokers nor drinkers, those who were either current smokers or regular drinkers alone had no significantly increased risk, while the risk was highest in those who were both current smokers and regular drinkers (OR = 1.77, 95% CI = 1.39-2.26, Pinteraction = 0.003). Conclusions: co-existence of smoking and regular alcohol drinking at midlife had a much stronger impact than the individual factors on risk of cognitive impairment in late life. PMID- 30307474 TI - Education and Training in Clinical Neuropsychology: Recent Developments and Documents From the Clinical Neuropsychology Synarchy. AB - The Clinical Neuropsychology Synarchy (CNS) interfaces with the American Psychological Association and affiliated organizations to address issues and advances in specialty training. The past several years have seen the development and dissemination of several initiatives pertinent to specialty training. Among these initiatives was the creation of a taxonomy for education and training in clinical neuropsychology. In additional there has been a movement towards competency-based education that has become codified in the APA's new Standards for Accreditation. Calls for competency-based education have also influenced the expectations of the APA's Committee on Recognition of Specialties and Proficiencies in Professional Psychology. As the convener of national clinical neuropsychology organizations the CNS has overseen the development of relevant documents for our specialty. This paper presents three documents critical to training in our field that were developed through the CNS and approved by its member organizations. The first is the Taxonomy for Education and Training in Clinical Neuropsychology. The second is Entry Level Competencies for Clinical Neuropsychology and the third is a distillation of the entry-level competency document for the purpose of identifying competencies to be addressed at the post doctoral residency level. PMID- 30307473 TI - SNX6 predicts poor prognosis and contributes to the metastasis of pancreatic cancer cells via activating epithelial-mesenchymal transition. AB - Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate around 6%. Though significant progress has been made in the availability of diagnostic techniques and treatment strategies, pancreatic cancer remains a disease of high mortality rate. Therefore, there is an urgent need for a better understanding of the molecular mechanisms that governs the oncogenesis and metastasis process of pancreatic cancer. In the present study, by using the Cancer Genome Atlas (TCGA) dataset analysis, we demonstrated that sorting nexin 6 (SNX6) serves as a biomarker for predicting prognosis of pancreatic cancer. In vitro studies demonstrated that silencing of SNX6 expression reduced cell proliferation, colony formation, invasion, and metastasis. Higher level of SNX6 helps maintain the mesenchymal properties, which renders migration and invasive capacities to pancreatic cancer cells. Moreover, in the process of TGF-beta induced epithelial to mesenchymal transition (EMT), the expression level of SNX6 was increased, and silencing of SNX6 expression could inhibit the TGF-beta induced EMT program. These results collectively uncovered a novel predictive marker for pancreatic cancer and provided the possible underlying molecular mechanism. PMID- 30307475 TI - Accessory navicular syndrome as a cause of foot pain during stroke rehabilitation. AB - Although usually asymptomatic, an accessory navicular bone can lead to medial foot pain, especially in younger people engaged in high impact sports. In many such cases, the tendon of posterior tibialis (which inverts and plantarflexes the foot) inserts onto the accessory bone resulting in greater strain on the tendon. In the present case, pain due to an accessory navicular bone first developed during stroke rehabilitation in a 69-year-old man. The relative overactivity of posterior tibialis in strokes involving the leg and overuse due to active rehabilitation were likely contributors. An accessory navicular syndrome should be considered as a cause of medial foot pain in patients following a stroke. As in our case, conservative management with rest, ice and elevation is usually successful. PMID- 30307476 TI - Comparing Self to Peers in Percentile Equivalents during Cognitive Testing: More Accurate Self-Appraisal Estimates are Associated with Greater Ability and Less Reliance on the Representativeness Heuristic. AB - Objective: For individuals with neurologic disorders, self-awareness of cognitive impairment is associated with indicators of better treatment course and clinical outcomes. Lower self-appraisal accuracy has been found to be associated with impairments in neuropsychological test performance, but individuals who perform unusually well may be equally vulnerable to inaccurate self-ratings. The mixed pattern of cognitive strengths and deficits in individuals with neurologic disorders complicates development of formal metrics for assessment of self awareness. It remains unclear to what extent distortions in self-appraisal represent a deficit associated with impaired cognitive functioning, or a normal reliance on the "representativeness-heuristic" that results in greater bias in self-ratings in both strong and poor performers. Method: The present study investigated these hypotheses using a common-metric approach (Rothlind, Dukarm, and Kraybill, 2016). Participants included 199 adults, recruited from community sources, including healthy adult volunteers and individuals at-risk for neuropsychological impairment secondary to human immunodeficiency virus (HIV) positive status or active heavy alcohol consumption or both. Immediately following completion of standardized neuropsychological tests, participants estimated their own performance percentile ranking. Results: Both high and low scoring examinees displayed a conservative bias in ranking their own neuropsychological performance. However, lower scores were associated with least accurate self-appraisals overall. Conclusion: Findings suggest that cognitive impairments are associated with lower accuracy in self-rating of cognitive ability, but also that normal biases complicate interpretation of self-appraisal ratings across the spectrum of neuropsychological functioning. The importance of recognizing these biases in clinical research and practice is emphasized, and directions for future research are discussed. PMID- 30307477 TI - Hypoxia induces hypomethylation of the HMGB1 promoter via the MAPK/DNMT1/HMGB1 pathway in cardiac progenitor cells. AB - Apoptosis is involved in the death of cardiac progenitor cells (CPCs) after myocardial infarction (MI) in the heart. The loss of CPCs results in infarct scar and further deterioration of the heart function. Though stem cell-based therapy provides an effective approach for heart function recovery after MI, the retention of CPCs in the infarcted area of the heart is the main barrier that limits its promising therapy. Therefore, the underlying mechanisms of CPC apoptosis in hypoxia are important for the development of new therapeutic targets for MI patients. In this work, we found that the expression of high-mobility group box 1(HMGB1) was upregulated in CPCs under hypoxia conditions. Further study demonstrated that HMGB1 was regulated by DNA methyltransferases 1 (DNMT1) via changing the methylation state of CpGs in the promoter of HMGB1 in CPCs during hypoxia process. Additionally, mitogen-activated protein kinase (MAPK) signaling pathway was found to be involved in regulating DNMT1/HMGB1-mediated CPC apoptosis in hypoxia process. In conclusion, our findings demonstrate a novel regulatory mechanism for CPC apoptosis and proliferation under hypoxia conditions, which may provide a new therapeutic approach for MI patients. PMID- 30307478 TI - Bone Marrow Biopsy Needle Type Affects Core Biopsy Specimen Length and Quality and Aspirate Hemodilution. AB - Objectives: Bone marrow biopsies are essential for evaluating patients with suspected or confirmed hematopoietic disorders or malignancies, but little is known about how biopsy needle type affects biopsy length and/or quality. We sought to compare bone marrow biopsy quality in specimens obtained with two different needles. Methods: A retrospective analysis was performed on bone marrow specimens obtained with manual single-bevel (n = 114) or triple-bevel (n = 166) needles. The lengths of evaluable marrow, core quality, and aspirate quality were assessed by blinded hematopathologists. Results: The triple-bevel needle produced 1.33-mm shorter lengths of evaluable marrow than the single-bevel needle and was five times less likely to produce a specimen rated as "adequate" and 4.2 times more likely to produce crush artifact. The triple-bevel needle was also 2.4 times more likely to produce hemodilute aspirates. Conclusions: Bone marrow biopsy needle type affects the length of evaluable marrow and quality of core and aspirate specimens. PMID- 30307481 TI - Influenza Vaccination During Pregnancy Can Protect Women Against Hospitalization Across Continents. PMID- 30307479 TI - Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex. AB - SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada-/- and Sadb-/- double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada-/- mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada-/- mice. Time lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada-/- mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD A in neuronal migration and differentiation. PMID- 30307482 TI - Interspecies interaction of Serratia plymuthica 4Rx13 and Bacillus subtilis B2g alters the emission of sodorifen. AB - Sodorifen is the major volatile of Serratia plymuthica 4Rx13. It is assumed to be a long-distance communication signal. However, so far the emission patterns of sodorifen had been studied using mono-cultures of S. plymuthica 4Rx13 neglecting that in natura bacteria live in communities. Here, we show that the structured co cultivation of S. plymuthica 4Rx13 and Bacillus subtilis B2g in a low-diversity model community grown under nutrient-rich conditions led to quantitative changes in sodorifen emission compared to self-paired mono-cultivations. Co-culturing revealed a decreased emission of sodorifen (50%) during exponential growth phase, whereas in the late stationary stage of growth, the amount of headspace sodorifen was increased compared to self-paired mono-cultivation (217% at 500 h of cultivation). Six other compounds that are most probably related to sodorifen or are isomers showed similar emission patterns. These data indicated that S. plymuthica 4Rx13 enhances its communication signal sodorifen as a consequence of interaction with B. subtilis B2g. PMID- 30307483 TI - False-Positive Light Chain Clonal Restriction by Flow Cytometry in Patients Treated With Alemtuzumab: Potential Pitfalls for the Misdiagnosis of B-Cell Neoplasms. AB - Objectives: To increase awareness of potential diagnostic test interference associated with alemtuzumab, which is a therapeutic immunoglobulin G1 kappa monoclonal antibody used in hematologic malignancies, autoimmune diseases, and transplant-related disorders. Methods: Bone marrow and blood from patients with T cell prolymphocytic leukemia treated with alemtuzumab were evaluated by flow cytometry. Healthy donor blood was analyzed with or without in vitro treatment with alemtuzumab for comparison. Results: Immunophenotypic analysis of bone marrow collected 4 weeks after alemtuzumab treatment demonstrated artifactual surface kappa light chain restriction in CD19+ B cells and CD3+ T cells. Similar findings were observed in blood from another patient in a specimen collected 3 days after alemtuzumab treatment. These findings were recapitulated in healthy donor blood incubated with alemtuzumab. Conclusions: Alemtuzumab can produce direct interference during flow cytometry analysis, resulting in false-positive evidence of light chain clonality. Clinicians and laboratorians should be cognizant of this risk to avoid misdiagnosis of B-cell neoplasms. PMID- 30307480 TI - Functional Parcellation of the Cerebral Cortex Across the Human Adult Lifespan. AB - Adult aging is associated with differences in structure, function, and connectivity of brain areas. Age-based brain comparisons have typically rested on the assumption that brain areas exhibit a similar spatial organization across age; we evaluate this hypothesis directly. Area parcellation methods that identify locations where resting-state functional correlations (RSFC) exhibit abrupt transitions (boundary-mapping) are used to define cortical areas in cohorts of individuals sampled across a large range of the human adult lifespan (20-93 years). Most of the strongest areal boundaries are spatially consistent across age. Differences in parcellation boundaries are largely explained by differences in cortical thickness and anatomical alignment in older relative to younger adults. Despite the parcellation similarities, age-specific parcellations exhibit better internal validity relative to a young-adult parcellation applied to older adults' data, and age-specific parcels are better able to capture variability in task-evoked functional activity. Incorporating age-specific parcels as nodes in RSFC network analysis reveals that the spatial topography of the brain's large-scale system organization is comparable throughout aging, but confirms that the segregation of systems declines with increasing age. These observations demonstrate that many features of areal organization are consistent across adulthood, and reveal sources of age-related brain variation that contribute to the differences. PMID- 30307484 TI - The Pace of Neurogenesis Is Regulated by the Transient Retention of the Apical Endfeet of Differentiating Cells. AB - The development of the mammalian cerebral cortex involves a variety of temporally organized events such as successive waves of neuronal production and the transition of progenitor competence for each neuronal subtype generated. The number of neurons generated in a certain time period, that is, the rate of neuron production, varies across the regions of the brain and the specific developmental stage; however, the underlying mechanism of this process is poorly understood. We have recently found that nascent neurons communicate with undifferentiated progenitors and thereby regulate neurogenesis, through a transiently retained apical endfoot that signals via the Notch pathway. Here, we report that the retention time length of the neuronal apical endfoot correlates with the rate of neuronal production in the developing mouse cerebral cortex. We further demonstrate that a forced reduction or extension of the retention period through the disruption or stabilization of adherens junction, respectively, resulted in the acceleration or deceleration of neurogenesis, respectively. Our results suggest that the apical endfeet of differentiating cells serve as a pace controller for neurogenesis, thereby assuring the well-proportioned laminar organization of the neocortex. PMID- 30307485 TI - Blockade of NKG2D/NKG2D Ligand Interaction Attenuated Cardiac Remodeling after Myocardial Infarction. AB - Aims: Accumulating evidence demonstrates that cardiomyocyte death contributes to the onset and progression of heart failure (HF) after myocardial injury. Recent studies revealed that immune/inflammatory reactions play important roles in cardiovascular diseases. However, it remains unclear whether immunosurveillance system, which eliminates cytopathic cells, including infected or malignant cancer cells, is involved in cardiomyocyte death, though cardiomyocytes are exposed to pathological stresses during post-infarct remodeling. The aim of this study is to clarify the pathophysiological significance of Natural Killer Group 2 member D (NKG2D)/NKG2D ligand (NKG2DL)-mediated cell death in HF after myocardial infarction (MI). Methods and Results: MI was generated by ligating left anterior descending artery in mice. The expression of NKG2D, NKG2DLs, especially Retinoic acid early induced transcript-1epsilon (Rae-1epsilon), perforin and granzyme B was concomitantly upregulated after MI. Immunohistological analysis revealed that Rae-1 was expressed on the membranes of injured cardiomyocytes in the infarct and border area. The MI-induced increase of Rae-1 expression was suppressed in p53-/- mice and Rae-1 was induced by the overexpression of p53. We identified p53 binding sites in Rae-1epsilon gene promoter, by chromatin immunoprecipitation assay, indicating that Rae-1 expression was mediated partially through p53. Flow cytometric analysis indicated that NKG2D-expressing immune cells in the post infarct myocardium were mainly gammadeltaT cells. The co-culture with gammadeltaT cells increased the frequency of apoptotic cells in the cultured cardiomyocytes. The blockade of NKG2D/NKG2DL interaction by intraperitoneal injection of anti-Rae 1epsilon antibody after MI reduced the frequency of apoptotic cardiomyocytes, accompanied by suppression of cardiac fibrosis, attenuating cardiac dysfunction. Finally, tamoxifen-inducible cardiomyocyte-specific Rae-1epsilon overexpressing mice exhibited the susceptibility to post-infarct remodeling with increased cardiomyocyte apoptosis and severer cardiac dysfunction. Conclusion: The interaction between immune cells and cardiomyocytes via NKG2D/NKG2DL induces cardiomyocyte death, exacerbating cardiac remodeling after MI. The blockade of NKG2D/NKG2DL interaction could be a promising therapeutic strategy against HF. PMID- 30307487 TI - Clinical usefulness of proteomics in inflammatory bowel disease: A comprehensive review. AB - The protein domain is likely the most ubiquitously affected in disease, response and recovery, and therefore proteomics holds special promise for biomarker discovery in general, and particularly in inflammatory bowel disease (IBD), i.e., ulcerative colitis and Crohn's disease. Tremendous progress has been made over the past decade in the development and refinement of proteomic technologies. These advances provide opportunities for a long-anticipated personalized medicine approach to the treatment of IBD. The present review examines the current state of IBD proteomics research and its real usefulness in clinical practice. We have performed a systematic bibliographic search to identify studies investigating the use of proteomics in patients with IBD, and then we have summarized the current "state of the art" in the applications of proteomic technologies in the study of IBD. In particular, as it has been summarized in Figure 1, we have included in the present review: 1) a brief introduction on proteomics in health and disease; 2) a review of the different stages from biomarker discovery to clinical application; and 3) a comprehensive review on the clinical usefulness and application of proteomics in IBD, including: a) screening to differentiate IBD from healthy controls; b) differentiating Crohn's disease from ulcerative colitis; c) prediction of the behavior or the IBD course; d) prediction of IBD response to biologic treatment; and e) monitoring response to treatment. We have also reviewed the importance of the type of sample -blood vs intestinal tissue- for the proteomic study in IBD patients. Finally, we have emphasized the current limitations of proteomic studies in IBD. PMID- 30307488 TI - Heritability of Gray Matter Structural Covariation and Tool Use Skills in Chimpanzees (Pan troglodytes): A Source-Based Morphometry and Quantitative Genetic Analysis. AB - Nonhuman primates, and great apes in particular, possess a variety of cognitive abilities thought to underlie human brain and cognitive evolution, most notably, the manufacture and use of tools. In a relatively large sample (N = 226) of captive chimpanzees (Pan troglodytes) for whom pedigrees are well known, the overarching aim of the current study was to investigate the source of heritable variation in brain structure underlying tool use skills. Specifically, using source-based morphometry (SBM), a multivariate analysis of naturally occurring patterns of covariation in gray matter across the brain, we investigated (1) the genetic contributions to variation in SBM components, (2) sex and age effects for each component, and (3) phenotypic and genetic associations between SBM components and tool use skill. Results revealed important sex- and age-related differences across largely heritable SBM components and associations between structural covariation and tool use skill. Further, shared genetic mechanisms appear to account for a heritable link between variation in both the capacity to use tools and variation in morphology of the superior limb of the superior temporal sulcus and adjacent parietal cortex. Findings represent the first evidence of heritability of structural covariation in gray matter among nonhuman primates. PMID- 30307486 TI - Direct Diagnostic Tests for Lyme Disease. AB - Borrelia burgdorferi was discovered to be the cause of Lyme disease in 1983, leading to seroassays. The 1994 serodiagnostic testing guidelines predated a full understanding of key B. burgdorferi antigens and have a number of shortcomings. These serologic tests cannot distinguish active infection, past infection, or reinfection. Reliable direct-detection methods for active B. burgdorferi infection have been lacking in the past but are needed and appear achievable. New approaches have effectively been applied to other emerging infections and show promise in direct detection of B. burgdorferi infections. PMID- 30307489 TI - Sequence Alterations of Cortical Genes Linked to Individual Connectivity of the Human Brain. AB - Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans.Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual's brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans. PMID- 30307490 TI - Influenza Vaccine Effectiveness in Preventing Influenza-associated Hospitalizations During Pregnancy: A Multi-country Retrospective Test Negative Design Study, 2010-2016. AB - Background: To date, no study has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy. Methods: The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) consisted of public health or healthcare systems with integrated laboratory, medical, and vaccination records in Australia, Canada (Alberta and Ontario), Israel, and the United States (California, Oregon, and Washington). Sites identified pregnant women aged 18 through 50 years whose pregnancies overlapped with local influenza seasons from 2010 through 2016. Administrative data were used to identify hospitalizations with acute respiratory or febrile illness (ARFI) and clinician-ordered real-time reverse transcription polymerase chain reaction (rRT-PCR) testing for influenza viruses. Overall IVE was estimated using the test-negative design and adjusting for site, season, season timing, and high-risk medical conditions. Results: Among 19450 hospitalizations with an ARFI discharge diagnosis (across 25 site-specific study seasons), only 1030 (6%) of the pregnant women were tested for influenza viruses by rRT-PCR. Approximately half of these women had pneumonia or influenza discharge diagnoses (54%). Influenza A or B virus infections were detected in 598/1030 (58%) of the ARFI hospitalizations with influenza testing. Across sites and seasons, 13% of rRT-PCR confirmed influenza-positive pregnant women were vaccinated compared with 22% of influenza-negative pregnant women; the adjusted overall IVE was 40% (95% confidence interval = 12%-59%) against influenza-associated hospitalization during pregnancy. Conclusion: Between 2010 and 2016, influenza vaccines offered moderate protection against laboratory-confirmed influenza-associated hospitalizations during pregnancy, which may further inform the benefits of maternal influenza vaccination programs. PMID- 30307492 TI - Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study. AB - Background: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillusfumigatus, but a direct comparison with triazole-susceptible IA is lacking. Methods: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients at 3 university medical centers were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. Results: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038), corresponding with a hazard ratio of 1.4 (day 42 95% confidence interval, 0.8 to 2.5; P = .272). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days. Conclusions: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality. PMID- 30307493 TI - Sparse Representation in Awake Auditory Cortex: Cell-type Dependence, Synaptic Mechanisms, Developmental Emergence, and Modulation. AB - Sparse representation is considered an important coding strategy for cortical processing in various sensory modalities. It remains unclear how cortical sparseness arises and is being regulated. Here, unbiased recordings from primary auditory cortex of awake adult mice revealed salient sparseness in layer (L)2/3, with a majority of excitatory neurons exhibiting no increased spiking in response to each of sound types tested. Sparse representation was not observed in parvalbumin (PV) inhibitory neurons. The nonresponding neurons did receive auditory-evoked synaptic inputs, marked by weaker excitation and lower excitation/inhibition (E/I) ratios than responding cells. Sparse representation arises during development in an experience-dependent manner, accompanied by differential changes of excitatory input strength and a transition from unimodal to bimodal distribution of E/I ratios. Sparseness level could be reduced by suppressing PV or L1 inhibitory neurons. Thus, sparse representation may be dynamically regulated via modulating E/I balance, optimizing cortical representation of the external sensory world. PMID- 30307491 TI - Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. AB - Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior. PMID- 30307495 TI - Morphological and Physiological Characteristics of Ebf2-EGFP-Expressing Cajal Retzius Cells in Developing Mouse Neocortex. AB - Cajal-Retzius (CR) cells are one of the earliest populations of neurons in the cerebral cortex of rodents and primates, and they play a critical role in corticogenesis and cortical lamination during neocortical development. However, a comprehensive morphological and physiological profile of CR cells in the mouse neocortex has not yet been established. Here, we systematically investigated the dynamic development of CR cells in Tg(Ebf2-EGFP)58Gsat/Mmcd mice. The morphological complexity, membrane activities and presynaptic inputs of CR cells coordinately increase and reach a plateau at P5-P9 before regressing. Using 3D reconstruction, we delineated a parallel-stratification pattern of the axonal extension of CR cells. Furthermore, we found that the morphological structure and presynaptic inputs of CR cells were disturbed in Reelin-deficient mice. These findings confirm that CR cells undergo a transient maturation process in layer 1 before disappearing. Importantly, Reelin deficiency impairs the formation of synaptic connections onto CR cells. In conclusion, our results provide insights into the rapid maturation and axonal stratification of CR cells in layer 1. These findings suggest that both the electrophysiological activities and the morphology of CR cells provide vital guidance for the modulation of early circuits, in a Reelin-dependent manner. PMID- 30307494 TI - Trajectories and Milestones of Cortical and Subcortical Development of the Marmoset Brain From Infancy to Adulthood. AB - With increasing attention on the developmental causes of neuropsychiatric disorders, appropriate animal models are crucial to identifying causes and assessing potential interventions. The common marmoset is an ideal model as it has sophisticated social/emotional behavior, reaching adulthood within 2 years of birth. Magnetic resonance imaging was used in an accelerated longitudinal cohort (n = 41; aged 3-27 months; scanned 2-7 times over 2 years). Splines were used to model nonlinear trajectories of grey matter volume development in 53 cortical areas and 16 subcortical nuclei. Generally, volumes increased before puberty, peaked, and declined into adulthood. We identified 3 milestones of grey matter development: I) age at peak volume; II) age at onset of volume decline; and III) age at maximum rate of volume decline. These milestones differentiated growth trajectories of primary sensory/motor cortical areas from those of association cortex but also revealed distinct trajectories between association cortices. Cluster analysis of trajectories showed that prefrontal cortex was the most heterogenous of association regions, comprising areas with distinct milestones and developmental trajectories. These results highlight the potential of high field structural MRI to define the dynamics of primate brain development and importantly to identify when specific prefrontal circuits may be most vulnerable to environmental impact. PMID- 30307496 TI - Factors influencing patient uptake of an exercise referral scheme: a qualitative study. AB - Exercise referral schemes aim to increase physical activity amongst inactive individuals with or at risk of long-term health conditions. Yet many patients referred to these schemes (by health professionals) fail to take up the exercise opportunities on offer. Understanding factors influencing uptake to exercise referral schemes may help improve future attendance. Using the Socio-Ecological Model as a framework, this qualitative study aimed to explore factors influencing uptake to an exercise referral scheme based in the North West of England. Semi structured interviews were conducted with referred patients (n = 38) about their reasons for referral, interactions with referring health professionals, events following referral and ideas to improve future uptake. Data were analysed thematically and mapped onto the constructs of the Socio-Ecological Model. Factors reported to influence uptake included intrapersonal (past PA experiences, motivation, competing priorities), interpersonal (scheme explanations, support) and organizational influences (scheme promotion, communication between service, cost). Whilst several intrapersonal-level factors influenced patient decisions to uptake the exercise referral scheme, modifiable interpersonal and organizational factors were identified as potential targets for intervention. Recommendations are made for improving awareness of exercise referral schemes and for enhancing communication between referring practitioners, patients and referral scheme staff. PMID- 30307498 TI - Food-grade gene transformation system constructed in Lactobacillus plantarum using a GlmS-encoding selection marker. AB - Food-grade gene expression systems in lactic acid bacteria enable production of functional proteins or product testing without antibiotic requirement. Here, we expanded the available selection markers by developing a novel food-grade genetic transformation system for Lactobacillus plantarum WCFS1 using the glucosamine-6 phosphate synthase gene (glmS1). A glmS-vector pSIPH497 was constructed by replacing the erythromycin resistance gene (erm) with L. plantarum glmS1 under control of the PldhL promoter from WCFS1. The selection efficiency and stability of the glmS-vector were shown to be comparable to those of the erm-based plasmid. Moreover, using mCherry expression as a reporter gene, we showed the feasibility of the system for producing foreign proteins. This food-grade host/vector system will provide an effective and safe technique for the application of lactic acid bacteria in the food and medical industries. Furthermore, this study provides a useful strategy for developing food-grade selection markers in other host/vector systems. PMID- 30307497 TI - Preoperative thoracic muscle area on computed tomography predicts long-term survival following pneumonectomy for lung cancer. AB - OBJECTIVES: To assess the prognostic role of thoracic muscle as quantified on preoperative computed tomography (CT) for the estimation of overall survival (OS) following pneumonectomy. METHODS: Muscle cross-sectional area (CSA) at the level of the fifth (T5) and eighth (T8) thoracic vertebra was measured on CT scans of consecutive patients with lung cancer prior to pneumonectomy. We stratified patients into high and low muscle groups using the gender-specific median of muscle CSA as separator and estimated associations of muscle CSA and OS using the Kaplan-Meier analysis. Multivariable logistic regression adjusted for body mass index, Charlson comorbidity index (includes age), forced expiratory volume in the first second as a % of predicted, sex, race, smoking status, tumour stage and prior lung cancer treatment was performed. RESULTS: A total of 128 patients were included (61.0 +/- 10.6 years of age, mean body mass index of 26.9 kg/m2, 55.5% men). The T8 level showed fewer artefacts and strong correlation with the T5 level (Pearson's rho = 0.904). T8 CSA was therefore used for subsequent analyses. Mean T8 CSA was 118.5 cm2 (median 115.3 cm2) in men and 75.2 cm2 (median 74.0 cm2) in women. During a median follow-up of 23.6 months (interquartile range 39.3), 65 patients (50.8%) died, of whom 41 were in the low muscle group. The Kaplan-Meier analysis showed significantly longer OS in the high muscle group (log-rank P = 0.02). Multivariable analysis showed an independent association of muscle CSA and OS (P = 0.02) with a hazard ratio of 0.80 (confidence interval 0.67-0.98) per 10-cm2 increment. CONCLUSIONS: Thoracic muscle is independently associated with long-term overall survival following pneumonectomy for lung cancer and may contribute to refined survival estimates in this population. IRB Protocol: Protocol #2017P000650, approved 21 April 2017. PMID- 30307500 TI - CAPON Is a Critical Protein in Synaptic Molecular Networks in the Prefrontal Cortex of Mood Disorder Patients and Contributes to Depression-Like Behavior in a Mouse Model. AB - Aberrant regulation and activity of synaptic proteins may cause synaptic pathology in the prefrontal cortex (PFC) of mood disorder patients. Carboxy terminal PDZ ligand of NOS1 (CAPON) is a critical scaffold protein linked to synaptic proteins like nitric oxide synthase 1, synapsins. We hypothesized that CAPON is altered together with its interacting synaptic proteins in the PFC in mood disorder patients and may contribute to depression-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). Here, we found that CAPON immunoreactivity (ir) was significantly increased in the dorsolateral PFC (DLPFC) and anterior cingulate cortex in major depressive disorder (MDD), which was accompanied by an upregulation of spinophilin-ir and a downregulation of synapsin ir. The increases in CAPON and spinophilin and the decrease in synapsin in the DLPFC of MDD patients were also seen in the PFC of CUMS mice. CAPON-ir positively correlated with spinophilin-ir (but not with synapsin-ir) in mood disorder patients. CAPON colocalized with spinophilin in the DLPFC of MDD patients and interacted with spinophilin in human brain. Viral-mediated CAPON downregulation in the medial PFC notably reversed the depression-like behaviors in the CUMS mice. These data suggest that CAPON may contribute to aspects of depressive behavior, possibly as an interacting protein for spinophilin in the PFC. PMID- 30307499 TI - Whole genome sequence association with E-selectin levels reveals Loss-of-function variant in African Americans. AB - E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p.Glu274Lys, p=9.02 x 10 24) with higher soluble E-selectin levels. This variant is considerably more common in populations of African-ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women's Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an EMR-based phenome-wide association scan of over 9,000 African Americans. PMID- 30307501 TI - Society for Glycobiology Awards - 2018. PMID- 30307502 TI - Prph2 initiates outer segment morphogenesis but maturation requires Prph2/Rom1 oligomerization. AB - The retinal disease gene peripherin 2 (PRPH2) is essential for the formation of photoreceptor outer segments (OS), where it functions in oligomers with and without its homologue ROM1. However, the precise role of these proteins in OS morphogenesis is not understood. By utilizing a knockin mouse expressing a chimeric protein comprised of the body of Rom1 and the C-terminus of Prph2 (termed RRCT), we find that the Prph2 C-terminus is necessary and sufficient for the initiation of OSs, while OS maturation requires the body of Prph2 and associated large oligomers. Importantly, dominant-negative physiological and biochemical defects in RRCT heterozygous rods are rescued by removing Rom1, suggesting Rom1 is a regulator for OS formation. Our experiments evaluating Prph2 trafficking show that Rom1 is a key determinant of whether Prph2 complexes utilize conventional vs. unconventional (Golgi-bypass) secretory pathways to reach the OS. These findings significantly advance our understanding of the molecular underpinnings of OS morphogenesis, and particularly the role of Rom1. PMID- 30307503 TI - Clinical Impact of Tumor Mutational Burden in Neuroblastoma. AB - Background: Neuroblastoma is the most common pediatric extracranial solid tumor. Within conventional risk groups, there is considerable heterogeneity in outcomes, indicating the need for improved risk stratification. Methods: In this study we analyzed the somatic mutational burden of 515 primary, untreated neuroblastoma tumors from three independent cohorts. Mutations in coding regions were determined by whole-exome/genome sequencing of tumor samples compared to matched blood leukocytes. Survival data for 459 patients were available for analysis of 5 year overall survival using the Kaplan-Meier method and log-rank test. All statistical tests were two-sided. Results: Despite a low overall somatic mutational burden (mean = 3, range = 0-56), 107 patients were considered to have high mutational burden (>3 mutations). Unfavorable histology and age 18 months and older were associated with high mutational burden. Patients with high mutational burden had inferior 5-year overall survival (29.0%, 95% confidence interval [CI] = 17.2 to 41.8%) vs those with three or fewer somatic mutations (76.2%, 95% CI = 71.5 to 80.3%) (log-rank P < .001) and this association persisted when limiting the analysis to genes included on a 447-gene panel commonly used in clinical practice. On multivariable analysis, mutational burden remained prognostic independent of age, stage, histology and MYCN status. Conclusions: This study demonstrates that mutational burden of primary neuroblastoma may be useful in combination with conventional risk factors to optimize risk stratification and guide treatment decisions, pending prospective validation. PMID- 30307505 TI - Characterization of Bromethalin and its Degradation Products in Veterinary Toxicology Samples by GC-MS-MS. AB - Bromethalin is a neurotoxicant with unusual instability and chromatographic behavior that make it difficult to analyze by gas chromatography (GC) in forensic examination of non-target animal deaths. Physicochemical breakdown of bromethalin produced multiple unique products with discernible mass spectra. This paper describes an investigation of the GC electron impact-mass spectrometric properties of bromethalin and its capacity to generate up to twenty heat- or light-induced breakdown products. Two principal breakdown products are isomeric with one another and involve release of both fluorine and methyl groups to develop dehydrofluorodesmethylbromethalin products. These compounds have proven to be excellent surrogate markers in screening forensic samples for bromethalin exposure, particularly in veterinary samples in which the active metabolite desmethylbromethalin has not yet accumulated to any appreciable extent, such as baits and animal stomach contents. The compounds as well as their parent bromethalin were easily monitored by GC interfaced with a tandem-quadrupole mass spectrometer using multiple-reaction monitoring (MRM) modes. Unusual gas chromatographic properties of bromethalin included: (i) specific requirements for a maximum oven temperature; (ii) non-linear increases in detector response on increased injection volumes, hypothesized to result from variable diffusion coefficients. We report here the development of GC strategies that facilitate detection of bromethalin and its breakdown products, as well as their MRM analysis by tandem-quadrupole mass spectrometry. The developed approaches are applicable to feed, baits and stomach contents as well as extracted tissue samples such as liver and kidney. PMID- 30307504 TI - Spot urine samples compared with 24-h urine samples for estimating changes in urinary sodium and potassium excretion in the China Salt Substitute and Stroke Study. AB - Background: The capacity of spot urine samples for detecting changes in population sodium and potassium excretion is unclear. Methods: Changes in urinary sodium and potassium excretion, over a 6-month to 2-year interval, were measured from 24-h urine samples and estimated from spot urine samples using several published methods in 3270 Chinese. Additional estimates were made by multiplying individual spot sodium and potassium concentrations by a single estimated 24-h urine volume derived from external data. Results: The measured difference in 24-h urinary excretion between intervention and control groups was -0.35 g (95% CI: 0.68 to -0.02; P = 0.039) for sodium and 0.66 g (95% CI: 0.52 to 0.80; P < 0.001) for potassium, based upon 24-h urine samples. The corresponding estimates of sodium differences for the Tanaka (-0.06 g), Kawasaki (-0.09 g), Intersalt without potassium (-0.09 g) and Intersalt with potassium (-0.14 g) equations were all smaller and identified no reduction in sodium excretion (all P > 0.10). The estimates were -0.65 g for sodium and 1.11 g for potassium using individual spot urine concentrations and an externally derived standard urine volume (both P < 0.01). Conclusions: The published equations were unable to detect the differences in sodium excretion measured by 24-h urine samples. A method based upon spot urine electrolyte concentrations and a standard urine volume may offer an alternative approach to measuring differences in sodium and potassium excretion between population groups without requiring 24-h urine, but will need further investigation. PMID- 30307506 TI - Towards diaspora-driven research capacity strengthening in low- and middle-income countries: results from India and Nepal. AB - Background: Biomedical research from high-income countries often informs practice and policy in low- and middle-income countries (LMICs) with vastly different socioeconomic and health systems. Engagement of LMIC-based researchers is integral to setting research priorities in the local context. Methods: A program, comprising a research seminar and workshop, and utilizing diaspora health professionals to understand research needs and build research capacity in LMICs, was created and pilot-tested at two institutions in India (65 participants) and Nepal (30 participants). Pre- and post-program surveys were instituted to assess participants' attitudes towards research. Results: In the pre-program survey, most participants (India: 76%, Nepal: 100%) perceived research as 'very/extremely important' in their careers. However, a majority felt that finding time (India: 75%, Nepal: 81%) and funding (India: 82%, Nepal: 100%) for research was 'difficult/very difficult'. After the program, 86-91% and 86-100% of participants from India and Nepal, respectively, felt that the various courses were very useful/useful for their research careers. Conclusions: Research is seen as an integral part of educational training and career advancement in LMICs. However, inadequate training, funding and mentorship remain a challenge. Engagement of diaspora health workers may serve as an important avenue for collaborative biomedical research capacity strengthening in LMICs. PMID- 30307507 TI - Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: a systematic appraisal. AB - Protein synthesis inhibitor antibiotics inhibit synthesis of new proteins, including exotoxins and other important virulence determinants in Staphylococcus aureus. A summary of the literature regarding the use of adjunctive protein synthesis inhibitors for toxin suppression in the setting of S. aureus infections is presented. PMID- 30307508 TI - Transgenic zebrafish model of DUX4 misexpression reveals a developmental role in FSHD pathogenesis. AB - Facioscapulohumeral dystrophy Type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of approximately 1 in 8,000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germline, primate specific transcription factor DUX4-fl (double homeo-box 4, full-length isoform) linked to the chromosome 4q35. In vitro and in vivo studies have demonstrated that very low levels of DUX4-fl expression are sufficient to induce an apoptotic and/or lethal phenotype, and therefore modeling of the disease has proved challenging. In this study, we expand upon our previously established injection model of DUX4 misexpression in zebrafish and describe a DUX4 inducible transgenic zebrafish model that better recapitulates the expression pattern and late onset phenotype characteristic of FSHD patients. We show that an induced burst of DUX4 expression during early development results in the onset of FSHD-like phenotypes in adulthood, even when DUX4 is no longer detectable. We also utilize our injection model to study long-term consequences of DUX4 expression in those that fail to show a developmental phenotype. Herein we introduce a hypothesis that DUX4 expression during developmental stages, is sufficient to induce FSHD-like phenotypes in later adulthood. Our findings point to a developmental role of DUX4 misexpression in the pathogenesis of FSHD and should be factored into the design of future therapies. PMID- 30307509 TI - Exposure to non-persistent chemicals in consumer products and fecundability: a systematic review. AB - BACKGROUND: Exposure to non-persistent chemicals in consumer products is ubiquitous and associated with endocrine-disrupting effects. These effects have been linked to infertility and adverse pregnancy outcomes in some studies and could affect couple fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). OBJECTIVE AND RATIONALE: Few epidemiologic studies have examined the impact of non-persistent chemicals specifically on TTP, and the results of these studies have not been synthesized. We undertook a systematic review to summarize the strength of evidence for associations of common non-persistent chemicals with couple fecundability and to identify gaps and limitations in the literature, with the aim of informing policy decisions and future research. SEARCH METHODS: We performed an electronic search of English language literature published between 1 January 2007 and 25 August 2017 in MEDLINE, EMBASE.com, Global Health, DART/TOXLINE, POPLINE and DESTAF. We included human retrospective and prospective cohort, cross-sectional and case-control studies that examined phthalates, bisphenol A, triclosan, triclocarban, benzophenones, parabens and glycol ethers in consumer products, and considered TTP or fecundability as an outcome among women, men and couples conceiving without medical assistance. We excluded editorials, opinion pieces, introductions to special sections, articles that described only lifestyle (e.g. caffeine, stress) or clinical factors (e.g. semen parameters, IVF success). Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. OUTCOMES: The search returned 3456 articles. There were 15 papers from 12 studies which met inclusion criteria, of which eight included biomarkers of chemical exposure. Studies varied widely in terms of exposure characterization, precluding a meta-analytic approach. Among the studies that measured exposure using biospecimens, results were equivocal for associations between either male or female phthalate exposure and TTP. There was preliminary support for associations of female exposure to some parabens and glycol ethers and of male exposure to benzophenone with longer TTP, but further research and replication of these results are needed. The results provided little to no indication that bisphenol A, triclocarban or triclosan exposure was associated with TTP. WIDER IMPLICATIONS: Despite a growing literature on couple exposure to non-persistent endocrine-disrupting chemicals and fecundability, evidence for associations between biologically measured exposures and TTP is limited. Equivocal results with different non-persistent chemical compounds and metabolites complicate the interpretation of our findings with respect to TTP, but do not preclude action, given the documented endocrine disrupting effects on other reproductive outcomes as well as fetal development. We therefore advocate for common-sense lifestyle changes in which both females and males seeking to conceive minimize their exposure to non-persistent chemicals. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018084304. PMID- 30307511 TI - The importance of clinical registries. PMID- 30307510 TI - TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice. AB - Congenital vertebral malformations (CVM) are associated with human TBX6 compound inheritance which combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. < 50%) as a potential mechanism of TBX6-associated CVM. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found ten (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVM, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6. PMID- 30307512 TI - Prediction and identification of novel sRNAs involved in Agrobacterium strains by integrated genome-wide and transcriptome-based methods. AB - Small RNAs (sRNAs) are a class of gene regulators in bacteria, playing a central role in their response to environmental changes. Bioinformatic prediction facilitates the identification of sRNAs expressed under different conditions. We propose a novel method of prediction of sRNAs from the genome of Agrobacterium based on a positional weight matrix of conditional sigma factors. sRNAs predicted from the genome are integrated with the virulence-specific transcriptome data to identify putative sRNAs that are overexpressed during Agrobacterial virulence induction. A total of 384 sRNAs are predicted from transcriptome data analysis of Agrobacterium fabrum and 100-500 sRNAs from the genome of different Agrobacterial strains. In order to refine our study, a final set of 10 novel sRNAs with best features across different replicons targeting virulence genes were experimentally identified using semi-quantitative polymerase chain reaction. Since Ti plasmid plays a major role in virulence, out of 10 sRNAs across the replicons, 4 novel sRNAs differentially expressed under virulence induced and non-induced conditions are predicted to be present in the Ti plasmid T-DNA region flanking virulence related genes like agrocinopine synthase, indole 3-lactate synthase, mannopine synthase and tryptophan monooxygenase. Further validation of the function of these sRNAs in conferring virulence would be relevant to explore their role in Agrobacterium-mediated plant transformation. PMID- 30307513 TI - Commentary: Factors Predicting the Need for Surgery of the Opposite Side After Unilateral Evacuation of Bilateral Chronic Subdural Hematomas. PMID- 30307514 TI - Intradialytic kinetics of middle molecules during hemodialysis and hemodiafiltration. AB - Background: The kinetics of beta2-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than beta2 microglobulin have not been extensively studied. Methods: Intradialytic plasma concentrations and overall dialyzer clearances of beta2-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate. Results: In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for beta2 microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083). Conclusions: A two compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than beta2-microglobulin if the central compartment is small and dependent on overall dialyzer clearance. PMID- 30307515 TI - Defining renal phenotype in Alstrom syndrome. AB - Background: Alstrom syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. Method: Prospective observational cohort study. Setting and Participants: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. Outcomes: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. Analytical approach: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. Results: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of 16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo interstitial and glomerular disease. Conclusions: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases. PMID- 30307517 TI - Gender dynamics in digital health: overcoming blind spots and biases to seize opportunities and responsibilities for transformative health systems. AB - Much remains to ensure that digital health affirms rather than retrenches inequality, including for gender. Drawing from literature and from the SEARCH projects in this supplement, this commentary highlights key gender dynamics in digital health, including blind spots and biases, as well as transformative opportunities and responsibilities. Women face structural and social barriers that inhibit their participation in digital health, but are also frequently positioned as beneficiaries without opportunities to shape such projects to better fit their needs. Furthermore, overlooking gender relations and focussing on women in isolation can reinforce, rather than address, women's exclusions in digital health, and worsen negative unanticipated consequences. While digital health provides opportunities to transform gender relations, gender is an intimate and deeply structural form of social inequality that rarely changes due to a single initiative or short-term project. Sustained support over time, across health system stakeholders and levels is required to ensure that transformative change with one set of actors is replicated and reinforced elsewhere in the health system. There is no one size prescriptive formula or checklist. Incremental learning and reflection is required to nurture ownership and respond to unanticipated reactions over time when transforming gender and its multiple intersections with inequality. PMID- 30307516 TI - mHealth use for non-communicable diseases care in primary health: patients' perspective from rural settings and refugee camps. AB - Background: Non-communicable diseases (NCDs) account for 85% of deaths in Lebanon and contribute to remarkable morbidity and mortality among refugees and underserved populations. This study assesses the perspectives of individuals with hypertension and/or diabetes in rural areas and Palestinian refugee camps towards a population based mHealth intervention called 'eSahha'. Methods: The study employs a mixed-methods design to evaluate the effectiveness of SMSs on self reported perceptions of lifestyle modifications. Quantitative data was collected through phone surveys, and qualitative data through focus group discussions. Descriptive statistics and bivariate analysis were performed. Results: About 93.9% (n = 1000) of respondents perceived the SMSs as useful and easy to read and understand. About 76.9% reported compliance with SMSs through daily behavioral modifications. Women (P = 0.007), people aged >=76 years (P < 0.001), unemployed individuals (P < 0.001), individuals who only read and write (P < 0.001) or those who are illiterate (P < 0.001) were significantly more likely to receive and not read the SMSs. Behavior change across settings was statistically significant (P < 0.001). Conclusion: While SMS-based interventions targeting individuals with hypertension and/or diabetes were generally satisfactory among those living in rural areas and Palestinian refugee camps in Lebanon, a more tailored approach for older, illiterate and unemployed individuals is needed. Keywords: e-health, refugees. PMID- 30307518 TI - Growing plants in fluctuating environments: why bother? PMID- 30307519 TI - Commentary: Long-Term Hearing Outcomes Following Stereotactic Radiosurgery in Vestibular Schwannoma Patients-A Retrospective Cohort Study. PMID- 30307520 TI - "If The Problem Persists, Come Back to See Me ... ."-An Empirical Study of Clinical Negligence Cases Against General Practitioners. AB - The law of negligence, as it applies to General Practitioners (GPs), is underexplored in the literature. There has been no substantial research undertaken that has penetrated deeper into claims that have actually reached court in order to analyse judicial reasoning pertaining to both breach of duty and causation. Given the increased pressures that GPs now face, these are important questions to consider. It is against this backdrop that this article seeks to present the findings of an empirical investigation into a number of reported clinical negligence claims brought against GPs. This analysis provides an original contribution to the developing academic discussion surrounding the changing nature of the doctor-patient relationship, and how it has come to be viewed in the eyes of the law. It also assesses the extent to which judges have become more receptive to protecting patient rights through the law of negligence, engaging in the expanding discourse concerning judicial deference to medical decision-making. It is argued that judges should sometimes show a greater propensity to question expert medical testimony in support of GPs, because some of the issues GPs typically face are less complex than in other clinical negligence cases involving technical areas of medicine, and that causation does not appear to be such a key factor in defeating patient claims. The work also provides useful guidance for GPs and their advisers in respect of where liability is most likely to be founded and how behaviour can be modified accordingly to reduce the chances of being sued. PMID- 30307521 TI - Screening Tools to Predict the Development of Chronic Low Back Pain: An Integrative Review of the Literature. AB - Objective: To identify and describe available instruments that can be used to screen patients with acute or subacute low back pain for a chronic low back pain trajectory. Design: Integrative literature review. Methods: An electronic search of PubMed/MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, and PsychINFO databases took place from May through July of 2014 using systematic search strategies to identify screening instruments developed to identify people at risk of chronic low back pain. After screening for inclusion and exclusion criteria as well as quality indicators, the identified studies were categorized based on whether the instrument measured psychological, clinical, or functional measures to predict chronic low back pain. Results: Initial searches identified 2,274 potential articles. After assessing for duplicates, title, and abstract content, there were 129 remaining articles. Articles were further excluded after analysis of the text, for a total of 42 studies reviewed. Most instruments reviewed were unable to provide evidence of predictive power for developing chronic low back pain. Conclusions: This review identified numerous instruments developed to assess the likelihood of chronic low back pain in acute and subacute low back pain populations. Of the instruments reviewed, the STarT Back Screening Tool and the Orebro Musculoskeletal Pain Questionnaire demonstrated superior predictive power compared with other instruments. Both screening tools offer evidence of validation, translation into different languages and international application, and usage in various health care settings and provide data on predictive power. PMID- 30307522 TI - Effects of Climate and Latitude on Age at Maturity and Longevity of Lizards Studied by Skeletochronology. AB - Longevity and age at maturity are key life-history traits, directly linked to fitness attributes such as survival and reproductive output. It has been proposed that these traits are strongly influenced by environmental factors, such as temperature, seasonality, and precipitations, which determine the existence of a continuum of life-histories that goes from the "slow" life histories characterized by late maturity and high longevity of cold and highly seasonal climates to the "fast" life histories characterized by early maturity and low longevity, typical of the tropical climates. However, large-scale studies that address these topics in lizards are scarce and most of them are based on heterogeneous data, which may overlook the real patterns. Using skeletochronology, we studied age at maturity and longevity of two species of Phymaturus lizards, Phymaturus aguanegra from the Andes and P. zapalensis from the Patagonian steppe (Argentina). Then, we confronted longevity and age at maturity in these species with published skeletochronology-based data on 46 other lizard species to examine possible association of these life-history traits with latitude and mean annual temperature, thermal amplitude and precipitations. Both Phymaturus species showed late sexual maturity (7 years and 8-9 years, respectively) and high longevity (16 years and 14-15 years, respectively) in coincidence with the other species of the genus studied up to date. The phylogenetic comparative analysis revealed that the most important variable in the determination of longevity patterns in the species studied was latitude: at higher latitudes lizards tend to live longer. In contrast, age at sexual maturity was dependent on mean annual temperature most, especially in males, as lizards from hotter climates mature earlier than lizards from cold sites. PMID- 30307523 TI - PVsiRNAdb: a database for plant exclusive virus-derived small interfering RNAs. AB - Ribonucleic acids (RNA) interference mechanism has been proved to be an important regulator of both transcriptional and post-transcription controls of gene expression during biotic and abiotic stresses in plants. Virus-derived small interfering RNAs (vsiRNAs) are established components of the RNA silencing mechanism for incurring anti-viral resistance in plants. Some databases like siRNAdb, HIVsirDB and VIRsiRNAdb are available online pertaining to siRNAs as well as vsiRNAs generated during viral infection in humans; however, currently there is a lack of repository for plant exclusive vsiRNAs. We have developed 'PVsiRNAdb (http://www.nipgr.res.in/PVsiRNAdb)', a manually curated plant exclusive database harboring information related to vsiRNAs found in different virus-infected plants collected by exhaustive data mining of published literature so far. This database contains a total of 322 214 entries and 282 549 unique sequences of vsiRNAs. In PVsiRNAdb, detailed and comprehensive information is available for each vsiRNA sequence. Apart from the core information consisting of plant, tissue, virus name and vsiRNA sequence, additional information of each vsiRNAs (map position, length, coordinates, strand information and predicted structure) may be of high utility to the user. Different types of search and browse modules with three different tools namely BLAST, Smith-Waterman Align and Mapping are provided at PVsiRNAdb. Thus, this database being one of its kind will surely be of much use to molecular biologists for exploring the complex viral genetics and genomics, viral-host interactions and beneficial to the scientific community and can prove to be very advantageous in the field of agriculture for producing viral resistance transgenic crops. PMID- 30307525 TI - Developing prognostic models for advanced prostate cancer when the goal line keeps changing. PMID- 30307524 TI - Impact of Pharmacy-Initiated Interventions on Influenza Vaccination Rates in Pediatric Solid Organ Transplant Recipients. AB - Background: In solid organ transplant (SOT) recipients, influenza infection can lead to subsequent graft dysfunction and death. Vaccination is the most effective approach to preventing influenza infection; however, vaccination rates are low, and interventions to optimize vaccine coverage are needed. The purpose of this study was to evaluate if pharmacy-initiated screening and recommendations for influenza immunization improve the rate of vaccination in pediatric SOT recipients. Methods: We performed a retrospective pre-post chart review of all kidney, liver, and heart transplant recipients followed by Children's Healthcare of Atlanta/Emory University transplant services between September 1, 2011, and February 16, 2017. Influenza vaccination coverage and influenza rates before (2011-2013) and after (2014-2016) the implementation of pharmacy-driven vaccination in SOT recipients were assessed. Results: A total of 822 patients were included; 101 (13%) of these patients were diagnosed with influenza, and 40 (5%) were hospitalized secondarily during the study period. Vaccination coverage increased over time (144 [36%] patients vaccinated in 2011 vs 430 [74%] in 2016; P < .001). Influenza diagnosis rates decreased between the 2 eras (P = .006). The median time in which 50% of the population was vaccinated decreased over time from 163 days in 2012 to 94 days in 2016 (P < .001). Conclusion: Within the constraints of the pre-post study design, we observed a significant increase in influenza vaccination rates after implementation of a transplant pharmacy initiated screening and vaccination program. The number of patients diagnosed with influenza and the time to vaccination decreased after our pharmacy intervention. All efforts should be made to increase compliance with influenza vaccination; pharmacy-initiated interventions can improve protection against influenza infection in pediatric SOT recipients. PMID- 30307526 TI - Commentary on: A Different Perspective on Breast Implant Surface Texturization and Anaplastic Large Cell Lymphoma (ALCL). PMID- 30307527 TI - Commentary on: Pathophysiology Study of Filler-Induced Blindness. PMID- 30307528 TI - A global transcriptomic pipeline decoding core network of genes involved in stages leading to acquisition of drug-resistance to cisplatin in osteosarcoma cells. AB - Motivation: Traditional cancer therapy is focused on eradicating fast proliferating population of tumor cells. However, existing evidences suggest survival of sub-population of cancer cells that can resist chemotherapy by entering a 'persister' state of minimal growth. These cells eventually survive to produce cells resistant to drugs. The identifying of appropriate targets that can eliminate the drug-tolerant "persisters" remains a challenge. Hence, a deeper understanding of the distinctive genetic signatures that lead to resistance is of utmost importance to design an appropriate therapy. Results: In this study, deep sequencing of mRNA was performed in osteosarcoma (OS) cells, exposed to the widely used drug, cisplatin which is an integral part of current treatment regime for OS. Transcriptomic analysis was performed in (i) untreated OS; (ii) persister sub-population of cells post drug-shock; (iii) cells which evade growth bottleneck; and (iv) drug-resistant cells obtained after several rounds of drug shock and revival. The transcriptomic signatures and pathways regulated in each group were compared; the transcriptomic pipeline to the acquisition of resistance was analyzed and the core network of genes altered during the process was delineated. Additionally, our transcriptomic data was compared with OS patient data obtained from Gene Ontology Omnibus. We observed a sub-set of genes to be commonly expressed in both data sets with a high correlation (0.81) in expression pattern. To the best of our knowledge, this study is uniquely designed to understand the series of genetic changes leading to the emergence of drug resistant cells, and implications from this study have a potential therapeutic impact. Availability: All raw data can be accessed from GEO database (https://www.ncbi.nlm.nih.gov/geo/) under the GEO accession number GSE86053. Supplementary information: Supplementary data is available at Bioinformatics online. PMID- 30307530 TI - Impact of antibiotic use on survival in patients with advanced cancers treated on immune checkpoint inhibitor phase I clinical trials. PMID- 30307531 TI - A comparison of matched interim analysis publications and final analysis publications oncology clinical trials. AB - Background: Progression-free survival is an increasingly popular surrogate endpoint for overall survival. The strength of correlation between the two endpoints varies, raising questions about the correlation between results of interim analyses that report mature progression-free survival data with the subsequent final publication that report overall survival. Methods: We searched PubMed from 2005 to 2015 for randomized controlled trials that measured both progression-free survival and overall survival. We matched interim publications that reported mature progression-free survival data with their final analyses that reported overall survival. We included 25 matched pairs and 8 unmatched interim analyses whose final analyses are not published. Our primary objectives are to compare interim publications with matched final publications in terms of journal prominence and Altmetric score and to compare progression-free survival and overall survival effect sizes. Results: All interim analyses (n = 33) were prespecified and there was a statistically significant progression-free survival benefit in 31 (93.9%). Only 8 matched final analyses had statistically significant overall survival data. Interim analyses were more often published in top-5 general medicine journals (p < .01) but not in top-5 oncology journals (p = .26). Altmetric scores were higher in interim analyses (p < .01). Progression free survival effect sizes from interim analyses were a median of 31% larger than overall survival effect sizes from final analyses. Conclusion: Interim analyses with progression-free survival data may generate hype in oncology, as evidenced by journal impact factors and Altmetric scores. The cause of this hype may be due, in part, to large progression-free survival effect sizes. Regardless, in trials that investigate progression-free and overall survival, publishing interim analyses with mature progression-free survival data apart from the final analyses with mature overall survival should be cautioned. PMID- 30307529 TI - Dissection of DLBCL Microenvironment Provides a Gene Expression-Based Predictor of Survival Applicable to Formalin-Fixed Paraffin-Embedded Tissue. AB - Background: Gene-expression-profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1,028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we performed a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. 45 genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MF), dendritic cells, and CD4+ T-cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel, Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME. PMID- 30307532 TI - Colocalization analyses of genomic elements: approaches, recommendations and challenges. AB - Motivation: Many high-throughput methods produce sets of genomic regions as one of their main outputs. Scientists often use genomic colocalization analysis to interpret such region sets, for example to identify interesting enrichments and to understand the interplay between the underlying biological processes. Although widely used, there is little standardization in how these analyses are performed. Different practices can substantially affect the conclusions of colocalization analyses. Results: Here, we describe the different approaches and provide recommendations for performing genomic colocalization analysis, while also discussing common methodological challenges that may influence the conclusions. As illustrated by concrete example cases, careful attention to analysis details is needed in order to meet these challenges and to obtain a robust and biologically meaningful interpretation of genomic region set data. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30307533 TI - The Burden of Frailty Among U.S. Veterans and Its Association With Mortality, 2002-2012. AB - Background: Frailty is a key determinant of clinical outcomes. We sought to describe frailty among U.S. Veterans and its association with mortality. Methods: Nationwide retrospective cohort study of regular Veterans Affairs (VA) users, aged at least 65 years in 2002-2012, followed through 2014, using national VA administrative and Medicare/Medicaid data. A frailty index (FI) for VA (VA-FI) was calculated using the cumulative deficit method. Thirty-one age-related deficits in health from diagnostic and procedure codes were included and were updated biennially. Survival analysis assessed associations between VA-FI and mortality. Results: A VA-FI was calculated for 2,837,152 Veterans over 10 years. In 2002, 36.7% were non-frail (FI = 0-0.10), 33.3% were pre-frail (FI = 0.11 0.20), 18.6% were mildly frail (FI = 0.21-0.30), 8.0% were moderately frail (FI = 0.31-0.40), and 3.4% were severely frail (FI > 0.40). From 2002 to 2012, the prevalence of moderate frailty increased to 12.6%and severe frailty to 12.3%. Frailty was strongly associated with survival and was independent of age, sex, race, and smoking; the VA-FI better predicted mortality than age alone. Although prevalence of frailty rose over time, compared to non-frail Veterans, 2 years' hazard ratios (95% confidence intervals) for mortality declined from a peak in 2004 of 2.05 (2.02-2.09), 3.72 (3.67, 3.78), 6.43 (6.33-6.53), and 11.11 (10.93 11.29) for pre-frail, mildly, moderately, and severely frail, respectively, to 1.53 (1.51, 1.55), 2.48 (2.44-2.51), 3.96 (3.90-4.01), 6.98 (6.89-7.07) in 2014. At every frailty level, risk of mortality was lower for women versus men and higher for blacks versus whites. Conclusions: Frailty affects 3 of every 10 U.S. Veterans aged at least 65 years, and is strongly associated with mortality. The VA-FI could be used to more accurately estimate life expectancy and individualize care for Veterans. PMID- 30307535 TI - Counting the cost of critical antibiotic shortages. PMID- 30307534 TI - Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity. AB - Retroviruses package two complete RNA genomes into a viral particle but generate only one provirus after each infection. This pseudodiploid replication strategy facilitates frequent recombination, which occurs during DNA synthesis when reverse transcriptase switches templates between two copackaged RNA genomes, generating chimeric DNA. Recombination has played an important role in shaping the current HIV-1 pandemic; however, whether recombination is required for HIV-1 replication is currently unknown. In this report, we examined viral replication when recombination was blocked in defined regions of the HIV-1 genome. We found that blocking recombination reduced viral titers. Furthermore, a significant proportion of the resulting proviruses contained large deletions. Analyses of the deletion junctions indicated that these deletions were the direct consequence of blocking recombination. Thus, our findings illustrate that recombination is a major mechanism to maintain HIV-1 genome integrity. Our study also shows that both obligatory and nonobligatory crossovers occur during reverse transcription, thereby supporting both the forced and dynamic copy-choice models of retroviral recombination. Taken together, our results demonstrate that, in most viruses, both packaged RNA genomes contribute to the genetic information in the DNA form. Furthermore, recombination allows generation of the intact HIV-1 DNA genome and is required for efficient viral replication. PMID- 30307536 TI - Cross-type Biomedical Named Entity Recognition with Deep Multi-Task Learning. AB - Motivation: State-of-the-art biomedical named entity recognition (BioNER) systems often require handcrafted features specific to each entity type, such as genes, chemicals and diseases. Although recent studies explored using neural network models for BioNER to free experts from manual feature engineering, the performance remains limited by the available training data for each entity type. Results: We propose a multi-task learning framework for BioNER to collectively use the training data of different types of entities and improve the performance on each of them. In experiments on 15 benchmark BioNER datasets, our multi-task model achieves substantially better performance compared with state-of-the-art BioNER systems and baseline neural sequence labeling models. Further analysis shows that the large performance gains come from sharing character- and word level information among relevant biomedical entities across differently labeled corpora. Availability: Our source code is available at https://github.com/yuzhimanhua/lm-lstm-crf. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30307537 TI - Information = equity? How increased access to information can enhance equity and improve health outcomes for pregnant women in Peru. AB - Background: The Peruvian health system provides care through numerous, disconnected health establishments and information systems. Our objective was to explore information use and needs of pregnant women to improve quality of care. Methods: We carried out a mixed methods study in the Lima capital metropolitan area in 15 health centers. This included four focus groups with 34 pregnant women and surveys with 403 pregnant women. Results: Pregnant women's information needs depend on their age, number of pregnancies and environment. Women relied on their social networks for pregnancy-related advice and valued high-quality, timely and targeted information from the health system. Participants' information needs include access to reliable information and responses to their questions in a warm, caring and safe environment. These needs can be met during prenatal check ups and in group settings through informational talks and visual displays in waiting areas, as well as through appropriate digital technologies such as SMS messages and electronic health records. Conclusions: Pregnant women need individualized health information in an understandable, secure and friendly manner to maximize their understanding of their pregnancy, follow recommendations and optimize health outcomes. Customizing e-Health programs that reach many pregnant women has greater potential for more equitable health outcomes. Keywords: electronic health records, health information systems, healthcare disparities, maternal health services, pregnant women, text messaging. PMID- 30307538 TI - Alpine species in dynamic insular ecosystems through time: conservation genetics and niche shift estimates of the endemic and vulnerable Viola cheiranthifolia. AB - Background and Aims: Alpine oceanic ecosystems are considered amongst the most ephemeral and restricted habitats, with a biota highly vulnerable to climate changes and disturbances. As an example of an alpine insular endemic, the past and future population genetic structure and diversity, and the future distribution of Viola cheiranthifolia (Violaceae), endemic to Tenerife (Canary Islands), were estimated. The main goals were to predict distribution changes of this alpine oceanic plant under climate change, and to assist in actions for its conservation. Methods: To perform population genetic analysis, 14 specific microsatellite markers and algorithms which considered the polyploid condition of V. cheiranthifolia were employed. The niche modelling approach incorporated temperature gradients, topography and snow cover maps. Models were projected into climate change scenarios to assess the extent of the altitudinal shifts of environmental suitability. Finally, simulations were performed to predict whether the environmental suitability loss will affect the genetic diversity of populations. Key Results: Viola cheiranthifolia presents short dispersal capacity, moderate levels of genetic diversity and a clear population genetic structure divided into two main groups (Teide and Las Canadas Wall), showing signs of recolonization dynamics after volcanic eruptions. Future estimates of the distribution of the study populations also showed that, despite being extremely vulnerable to climate change, the species will not lose all its potential area in the next decades. The simulations to estimate genetic diversity loss show that it is correlated to suitability loss, especially in Las Canadas Wall. Conclusions: The low dispersal capacity of V. cheiranthifolia, coupled with herbivory pressure, mainly from rabbits, will make its adaptation to future climate conditions in this fragile alpine ecosystem difficult. Conservation actions should be focused on herbivore control, population reinforcement and surveillance of niche shifts, especially in Guajara, which represents the oldest isolated population and a genetic reservoir for the species. PMID- 30307539 TI - How do immune checkpoint targeted antibodies work? The need for improved pharmacokinetic evaluation in early phase studies. PMID- 30307540 TI - Joint Analysis of Individual-level and Summary-level GWAS Data by Leveraging Pleiotropy. AB - Motivation: A large number of recent genome-wide association studies (GWASs) for complex phenotypes confirm the early conjecture for polygenicity, suggesting the presence of large number of variants with only tiny or moderate effects. However, due to the limited sample size of a single GWAS, many associated genetic variants are too weak to achieve the genome-wide significance. These undiscovered variants further limit the prediction capability of GWAS. Restricted access to the individual-level data and the increasing availability of the published GWAS results motivate the development of methods integrating both the individual-level and summary-level data. How to build the connection between the individual-level and summary-level data determines the efficiency of using the existing abundant summary-level resources with limited individual-level data, and this issue inspires more efforts in the existing area. Results: In this study, we propose a novel statistical approach, LEP, which provides a novel way of modeling the connection between the individual-level data and summary-level data. LEP integrates both types of data by LEveraing Pleiotropy to increase the statistical power of risk variants identification and the accuracy of risk prediction. The algorithm for parameter estimation is developed to handle genome-wide-scale data. Through comprehensive simulation studies, we demonstrated the advantages of LEP over the existing methods. We further applied LEP to perform integrative analysis of Crohn's disease from WTCCC and summary statistics from GWAS of some other diseases, such as Type 1 diabetes, Ulcerative colitis and Primary biliary cirrhosis. LEP was able to significantly increase the statistical power of identifying risk variants and improve the risk prediction accuracy from 63.39% (+/- 0.58%) to 68.33% (+/- 0.32%) using about 195,000 variants. Availability: The LEP software is available at https://github.com/daviddaigithub/LEP. PMID- 30307541 TI - Erratum: Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. PMID- 30307543 TI - Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes. AB - The autoimmune response that characterizes type 1 diabetes (T1D) has no clear cause. Extracellular vesicles (EVs) play an important role in triggering the immune response in other contexts. Here, we propose a model by which EVs isolated from human islets stimulate proinflammatory immune responses and lead to peripheral blood mononuclear cell (PBMC) activation. We show that human islet EVs are internalized by monocytes and B cells and lead to an increase in T-helper 1, 2, and 17 cytokine expression, as well as T and B cell proliferation. Importantly, we demonstrate memory T and B cell activation by EVs selectively in PBMCs of patients with T1D. Additionally, human islet EVs induce an increase in antibodies against glutamic acid decarboxylase 65 (GAD65) in T1D PBMCs. Furthermore, pretreatment of T1D PBMCs with ibrutinib, an inhibitor of Bruton tyrosine kinase, dampens EV-induced memory B cell activation and GAD65 antibody production. Collectively, our findings indicate a role for human islet EVs in mediating activation of B and T cells and GAD65 autoantibody production. PMID- 30307544 TI - Clinical workflow and applicability of electrophysiological cardiovascular magnetic resonance-guided radiofrequency ablation of isthmus-dependent atrial flutter. AB - Aims: To determine safety and efficacy of electrophysiological cardiovascular magnetic resonance (EP-CMR)-guided radiofrequency (RF) ablation in patients with typical right atrial flutter in a routine clinical setting. Methods and results: Thirty patients with typical right atrial flutter underwent clinically indicated EP-CMR-guided cavotricuspid isthmus ablation. EP-CMR protocols included pre- and post-ablation CMR imaging (whole heart, T2-weighted, and early-/late-gadolinium enhancement) together with electroanatomic mapping of the right atrium. Coronary sinus cannulation time and total ablation procedure duration were used as performance measures to determine the learning experience of the EP-CMR interventionalist and for comparison with conventional, fluoroscopy-guided atrial flutter ablation. Procedural safety and success rates were evaluated at 1 week and 3 months follow-up. Safety and success rates of EP-CMR were similar to conventional flutter ablations (primary success rate, 93% vs. 100%; recurrence rate, 0% vs. 3%, respectively). EP-CMR procedure duration indicated a learning experience (first vs. last six patients, 54.2 +/- 23.1 vs. 29.7 +/- 20.0 min) and the minimum number of procedures needed to achieve a level of competency was n = 12. An isthmus angle <110 degrees and the presence of pouch-like isthmus anatomy were indicative of significantly prolonged EP-CMR procedure duration. CMR-defined ablation lesion size was not associated with total RF-ablation time or RF-induced maximum temperature. Conclusion: In a routine clinical setting, EP-CMR demonstrated its safety and high efficacy for the treatment of typical right atrial flutter with performance and outcome measures similar to conventional, fluoroscopy-guided flutter ablation. Hence, EP-CMR represents a valid alternative to conventional right atrial flutter ablation. PMID- 30307542 TI - Deciphering Steroid Receptor Crosstalk in Hormone-Driven Cancers. AB - Steroid hormone receptors (SRs) have a multitude of functions in human biology and disease progression. The SR family of related ligand-activated transcription factors includes androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone receptors. Antiestrogen or estrogen receptor (ER)-targeted therapies to block ER action remain the primary treatment of luminal breast cancers. Although this strategy is successful, ~40% of patients eventually relapse due to endocrine resistance. The majority of hormone-independent tumors retain some level of SR expression, but sidestep hormone ablation treatments. SRs are known to crosstalk extensively with kinase signaling pathways, and this interplay has been shown to bypass ER-targeted therapies in part by providing alternative proliferation and survival signals that enable hormone independence. Modified receptors adopt alternate conformations that resist antagonism or promote agonism. SR-regulated transcription and SR-binding events have been classically studied as single receptor events using single hormones. However, it is becoming increasingly evident that individual steroids and SRs rarely act alone. Emerging evidence shows that coexpressed SRs crosstalk with each other in hormone-driven cancers, such as breast and prostate. Crosstalk between related SRs allows them to modulate signaling and transcriptional responses to noncognate ligands. This flexibility can lead to altered genomic binding and subsequent changes in SR target gene expression. This review will discuss recent mechanistic advances in elucidating SR crosstalk and the implications for treating hormone-driven cancers. Understanding this crosstalk (i.e., both opposing and collaborative) is a critical step toward expanding and modernizing endocrine therapies and will ultimately improve patient outcomes. PMID- 30307545 TI - Increased myocardial sodium signal intensity in Conn's syndrome detected by 23Na magnetic resonance imaging. AB - Aims: Sodium intake has been linked to left ventricular hypertrophy independently of blood pressure, but the underlying mechanisms remain unclear. Primary hyperaldosteronism (PHA), a condition characterized by tissue sodium overload due to aldosterone excess, causes accelerated left ventricular hypertrophy compared to blood pressure matched patients with essential hypertension. We therefore hypothesized that the myocardium constitutes a novel site capable of sodium storage explaining the missing link between sodium and left ventricular hypertrophy. Methods and results: Using 23Na magnetic resonance imaging, we investigated relative sodium signal intensities (rSSI) in the heart, calf muscle, and skin in 8 PHA patients (6 male, median age 55 years) and 12 normotensive healthy controls (HC) (8 male, median age 61 years). PHA patients had a higher mean systolic 24 h ambulatory blood pressure [152 (140; 163) vs. 125 (122; 130) mmHg, P < 0.001] and higher left ventricular mass index [71.0 (63.5; 106.8) vs. 55.0 (50.3; 66.8) g/m2, P = 0.037] than HC. Compared to HC, PHA patients exhibited significantly higher rSSI in the myocardium [0.31 (0.26; 0.34) vs. 0.24 (0.20; 0.27); P = 0.007], calf muscle [0.19 (0.16; 0.22) vs. 0.14 (0.13; 0.15); P = 0.001] and skin [0.28 (0.25; 0.33) vs. 0.19 (0.17; 0.26); P = 0.014], reflecting a difference of +27%, +38%, and +39%, respectively. Treatment of PHA resulted in significant reductions of the rSSI in the myocardium, calf muscle and skin by -13%, -27%, and -29%, respectively. Conclusion: Myocardial tissue rSSI is increased in PHA patients and treatment of aldosterone excess effectively reduces rSSI, thus establishing the myocardium as a novel site of sodium storage in addition to skeletal muscle and skin. PMID- 30307546 TI - Endocrinology of Transgender Medicine. AB - Gender affirming treatment for transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treatment of this population and its effect on physical, psychological and mental health. The Endocrine Society guidelines for transgender women include estrogens in combination with androgen lowering medications. Feminizing treatment with estrogens and anti-androgens has desired physical changes, such as enhanced breast growth, reduction of facial and body hair growth and fat redistribution in a female pattern. Possible side effects should be discussed with patients, particularly those at risk of venous thromboembolism. The Endocrine Society guidelines for transgender men include testosterone therapy for virilization with deepening of the voice, cessation of menses plus increase of muscle mass, facial and body hair. Due to the lack of evidence, treatment for gender non-binary people should be individualized. Young people may receive pubertal suspension, consisting of gonadotrophin-releasing hormone analogs, later followed by sex steroids. Options for fertility preservation should be discussed before any hormonal intervention. Morbidity and cardiovascular risk with cross-sex hormones is unchanged among transgender men and unclear among transgender women. Sex steroid-related malignancies can occur, but are rare. Mental health problems such as depression and anxiety have been found to reduce considerably following hormonal treatment. Future studies should aim to explore the long-term outcome of hormonal treatment in transgender people and provide evidence as to effect of gender affirming treatment in the non-binary population. PMID- 30307547 TI - Colostrum feeding shapes the hindgut microbiota of dairy calves during the first 12 h of life. AB - This study evaluated the effect of feeding non-heated and heated colostrum on the mucosa- and digesta-associated microbiota in the colon of dairy calves during the first 12 h of life. Thirty-two neonatal Holstein male calves were fed: no colostrum (NC, n = 8), non-heated colostrum (FC, n = 12) and heated colostrum (HC (60 degrees C, 60 min), n = 12) immediately after birth. The abundances of mucosa- and digesta-associated total bacteria were higher in the colon of FC fed calves compared to those fed no colostrum (NC) at 12 h of life. Compare to NC calves, a higher proportion of mucosa- and digesta-associated Clostridium cluster XIVa and Bifidobacterium, and a lower abundance of mucosa and digesta-associated E. coli were detected in the colon of FC and HC fed calves, as well as a tentatively lower relative abundance of Escherichia-Shigella genus in colon mucosa of HC fed calves. In addition, HC calves had lower abundances of E. coli and higher abundances of Bifidobacterium in mucosa-associated microbiota than FC fed calves. Our results suggest that feeding non-heated colostrum immediately after birth benefit neonatal calves with increased Bifidobacterium and decreased opportunistic pathogenic E. coli and Escherichia-Shigella genus in the colon, and feeding heated colostrum can fortify such effects. PMID- 30307548 TI - Impact of modelled PM2.5, NO2 and O3 annual air concentrations on some causes of mortality in Tuscany municipalities. AB - Background: In 2014, the European Environment Agency estimated 59 630 premature deaths in Italy attributable to long-term exposure to PM2.5, 17 290 to NO2 and 2900 to O3. The aim of this study was to test an approach for assessing health impact of the above pollutants analyzing possible associations between annual municipal concentrations, estimated by the national dispersion model developed by ENEA, and mortality rates for trachea, bronchus and lung (TBL) cancer, total respiratory diseases (RD) and chronic obstructive pulmonary diseases (COPD). Tuscany was selected as test case. Methods: For the 287 municipalities, 2009-13 standardized mortality rates (SMRates) for each cause of death were calculated by the ENEA epidemiological database. The SMRates of municipalities, aggregated on the basis of the 2003 or 2010 estimated pollutant concentration tertiles, were also computed. Results: TBL cancer SMRate in municipalities with 2003 PM2.5 levels >15.2 MUg/m3 was significantly higher than the SMRates of the two lowest tertiles and COPD SMRates in the two highest O3 tertiles were significantly higher than that of the lower tertile. No association between PM2.5 or NO2 concentrations and RD and COPD was detected. Approximately 625 TBL cancer deaths attributable to PM2.5 levels above 10 MUg/m3 in 2003 were estimated in the region. Smoking habits and deprivation index were homogeneously distributed among municipalities. Conclusions: This methodological approach allowed detecting associations between mortality and specific air pollutants even at levels below the Italian normative limits and could be employed to evaluate the potential health impact of air pollution in areas where direct measures of concentration are unavailable. PMID- 30307549 TI - Echocardiography should be mandatory in ECMO venous cannula placement. PMID- 30307550 TI - Fatty acids as biomarkers of total dairy and dairy fat intakes: a systematic review and meta-analysis. AB - Context: Dairy intake in humans is commonly assessed using questionnaires, but the data collected are often biased. As a result, there is increasing interest in biomarkers of dairy fat. To date, there has been no overview of the fatty acids suitable for use as biomarkers of dairy fat intake. Objective: This systematic review and meta-analysis of observational studies was performed to identify circulating fatty acids as biomarkers of total dairy and dairy fat intakes in the general population. Data Sources: MEDLINE, Embase, and Web of Knowledge databases were searched for eligible studies published until June 2017. Study Selection: Articles were included when a correlation between circulating dairy fatty acids and intakes of total dairy and dairy fat was found, as measured by dietary assessment tools. Data Extraction: Two authors extracted data independently and assessed the risk of bias. An adapted form of the Newcastle-Ottawa Scale was used for quality assessment. Results: Data were pooled using the random-effects model. Meta-analysis revealed that the fatty acids in plasma/serum were significantly correlated with intakes of total dairy (C14:0 [r = 0.15; 95%CI, 0.11 - 0.18], C15:0 [r = 0.20; 95%CI, 0.13 - 0.27], and C17:0 [r = 0.10; 95%CI, 0.03 - 0.16] and dairy fat (C14:0 [r = 0.16; 95%CI, 0.10 - 0.22], C15:0 [r = 0.33; 95%CI, 0.27 - 0.39], C17:0 [r = 0.19; 95%CI, 0.14 - 0.25], and trans-C16:1n-7 [r = 0.21; 95%CI, 0.14 - 0.29). Conclusions: C14:0, C15:0, C17:0, and trans-C16:1n-7 were identified as biomarkers of total dairy and dairy fat intakes in the general population. In light of the suboptimal measurement techniques used in some studies, correlations with trans-C18:1n-7 and conjugated linoleic acid require further investigation. PMID- 30307551 TI - The Kruppel-Like Factors and Control of Energy Homeostasis. AB - Nutrient handling by higher organisms is a complex process that is regulated in a significant manner at the transcriptional level. Studies over the past 15 years highlight the critical importance of a family of transcriptional regulators termed the Kruppel-like factors (KLFs) in metabolism. Within an organ, distinct KLFs direct networks of metabolic gene targets to achieve specialized functions. This regulation is often orchestrated in concert with recruitment of tissue specific transcriptional regulators, particularly members of the nuclear receptor family. Upon nutrient entry into the intestine, gut and liver KLFs control a range of functions from bile synthesis to intestinal stem cell maintenance to affect nutrient acquisition. Subsequently, coordinated KLF activity across multiple organs distributes nutrients to sites of storage or liberates them for use, in response to changes in nutrient status. Finally, in energy consuming organs like cardiac and skeletal muscle, KLFs tune local metabolic programs to precisely match substrate uptake, flux and utilization, particularly via mitochondrial function, with energetic demand; this is achieved in part through circulating mediators including glucocorticoids and insulin. In this Review, we summarize current understanding of KLFs in regulation of nutrient absorption, inter-organ circulation, and tissue-specific utilization. PMID- 30307552 TI - Impact of the duration of antibiotic therapy on relapse and survival following surgery for active infective endocarditis. AB - OBJECTIVES: Surgery is often required for acute infective endocarditis (IE) to repair or replace damaged heart valves. Traditionally, long courses of antibiotic treatment have been prescribed after surgery for active IE for fear of infecting newly implanted/repaired valves, but the need for this, in the present era of enhanced antimicrobial stewardship, has been questioned. In our institution, the choice and duration of antimicrobial therapy is tailored to individual patients by a multidisciplinary team with an interest in IE. The influence of the duration of postoperative antibiotic therapy on outcomes was studied in patients requiring surgery prior to the completion of a planned course of antibiotic therapy. METHODS: This was a retrospective observational study on patients with acute IE requiring surgery between January 2004 and December 2015. The primary outcome was relapse. Secondary outcomes were early reoperation and 1-year mortality. RESULTS: In total, 182 IE episodes were included in the final analysis. The median duration of postoperative antibiotic therapy was 23.5 days (interquartile range 12-40 days) and decreased significantly during the period of study (P < 0.001). There were 2 relapses (1.1%) and 18 (9.9%) postoperative deaths within 1 year. Nine (5%) patients underwent early reoperation. The duration of postoperative antibiotic therapy did not affect either the primary or the secondary outcomes. CONCLUSIONS: This work supports previous findings that selected patients who require surgery during active IE can be safely given shorter courses of postoperative antibiotics without an impact on relapse of infection or survival. PMID- 30307553 TI - Retraction. PMID- 30307554 TI - Socioeconomic differences in healthy and disease-free life expectancy between ages 50 and 75: a multi-cohort study. AB - Background: There are striking socioeconomic differences in life expectancy, but less is known about inequalities in healthy life expectancy and disease-free life expectancy. We estimated socioeconomic differences in health expectancies in four studies in England, Finland, France and Sweden. Methods: We estimated socioeconomic differences in health expectancies using data drawn from repeated waves of the four cohorts for two indicators: (i) self-rated health and (ii) chronic diseases (cardiovascular, cancer, respiratory and diabetes). Socioeconomic position was measured by occupational position. Multistate life table models were used to estimate healthy and chronic disease-free life expectancy from ages 50 to 75. Results: In all cohorts, we found inequalities in healthy life expectancy according to socioeconomic position. In England, both women and men in the higher positions could expect 82-83% of their life between ages 50 and 75 to be in good health compared to 68% for those in lower positions. The figures were 75% compared to 47-50% for Finland; 85-87% compared to 77-79% for France and 80-83% compared to 72-75% for Sweden. Those in higher occupational positions could expect more years in good health (2.1-6.8 years) and without chronic diseases (0.5-2.3 years) from ages 50 to 75. Conclusion: There are inequalities in healthy life expectancy between ages 50 and 75 according to occupational position. These results suggest that reducing socioeconomic inequalities would make an important contribution to extending healthy life expectancy and disease-free life expectancy. PMID- 30307555 TI - A combined treatment with erythrocyte lysis solution and Sudan Black B reduces tissue autofluorescence in double-labeling immunofluorescence. AB - The autofluorescence of animal tissues complicates the results obtained using fluorescence microscopy. Many techniques have been used to reduce autofluorescence; however, all these techniques have the disadvantage of reducing the intensity of immunofluorescence staining. We observed the features of autofluorescence in formalin-fixed paraffin-embedded (FFPE) vascularized liver and kidney sections and assessed the effects of an intravascular treatment with erythrocyte lysis solution (ELS) before a routine perfusion with normal saline (NS) and Sudan Black B (SBB) treatment after antigen retrieval on reducing autofluorescence reduction and the visualization of antigens to establish an optimal method for reducing autofluorescence. Erythrocytes exhibited bright autofluorescence in FFPE liver and kidney sections, which altered the results of actin and destrin immunofluorescence staining. The SBB treatment significantly reduced background autofluorescence and exerted a moderate effect on reducing the autofluorescence of erythrocytes, and the intravascular ELS treatment eliminated erythrocyte autofluorescence in FFPE liver and kidney sections. A combined treatment with ELS and SBB further reduced autofluorescence but did not decrease actin and destrin immunofluorescence staining in double-labeled FFPE liver and kidney sections. In conclusion, the application of an intravascular ELS treatment before the NS perfusion combined with an SBB treatment after antigen retrieval is a simple and efficient strategy for reducing autofluorescence in FFPE vascularized tissues and can be broadly used in fluorescence microscopy analyses. PMID- 30307556 TI - Hard X-ray imaging microscopy with self-imaging phenomenon. AB - The self-imaging phenomenon referred to as the Talbot effect in the field of optics was discovered by H.F. Talbot in the 1830s, and is now widely used for imaging using not only visible light but also X-rays, electrons, neutrons, and matter waves. In this review, the author introduces the current progress being made in hard-X-ray imaging microscopy based on the self-imaging phenomenon. Hard X-ray imaging microscopy is a promising technique for non-destructively visualizing internal structures in specimens with a spatial resolution up to a few tens of nanometers. The use of the self-imaging phenomenon makes it possible to realize highly sensitive phase-contrast X-ray imaging microscopes. These approaches have several advantages over conventional X-ray imaging microscopes, including the widely used Zernike X-ray phase-contrast microscopes, and can provide a powerful way of quantitative visualization with a high spatial resolution and a high sensitivity even for thick specimens. PMID- 30307557 TI - Response to DeSantis and Jemal. PMID- 30307558 TI - Observation of wet specimens sensitive to evaporation using scanning electron microscopy. AB - Wet specimens are notoriously difficult to image in scanning electron microscopes (SEM) owing to evaporation from the required vacuum of the specimen chamber. Traditionally, this issue has been addressed by increasing the specimen chamber pressure. Unfortunately, observation under high specimen chamber pressure cannot prevent the initial evaporation effects. The wet cover method, where the original surface water is retained (and, therefore, considered wet), provides a way to introduce and subsequently image specimens that are sensitive to evaporation within a SEM, while preventing evaporation-related damage, and to observe interesting specimen-water interactions. PMID- 30307559 TI - Association Between Environmental Factors and Oral Epstein-Barr Virus DNA Loads: A Multicenter Cross-sectional Study in China. AB - Background: Oral Epstein-Barr virus (EBV) status reflects host EBV activity and potentially links to EBV-associated diseases, however, factors influencing oral EBV loads or reactivation, such as environmental exposures or host factors, are not fully understood. Methods: A 2-stage, multicenter, cross-sectional study of 6558 subjects from 21 administrative cities of southern China and 3 populations from representative geographical areas in China (referred to as the south, north, and northeastern populations) was performed. The relationships between demographical factors and environmental exposures to EBV loads were analyzed by logistic regression models. Results: Current smoking, with a dose-response effect, was found to be strongly associated with higher oral EBV loads in the pooled data, with an odds ratio of 1.58 (95% confidence interval, 1.39-1.79), as well as in each of the separate populations. The odds ratio increased to 3.06 when current smokers in southern China were compared to never smokers in northern China. Additionally, higher oral EBV loads tended to be detected in older participants, male participants, and participants in southern China. Conclusions: This study provided evidence linking the effect of host-environmental factors, particularly smoking, to oral EBV activity. It could strengthen our understanding of the possible causal roles of EBV-related diseases, which may help to prevent or mitigate EBV-associated diseases. PMID- 30307560 TI - Impact of Hepatitis B Virus Coinfection on Human T-Lymphotropic Virus Type 1 Clonality in an Indigenous Population of Central Australia. AB - The prevalence of human T-cell lymphotropic virus type 1 (HTLV-1) and hepatitis B virus (HBV) coinfection is high in certain Indigenous Australian populations, but its impact on HTLV-1 has not been described. We compared 2 groups of Indigenous adults infected with HTLV-1, either alone or coinfected with HBV. The 2 groups had a similar HTLV-1 proviral load, but there was a significant increase in clonal expansion of HTLV-1-infected lymphocytes in coinfected asymptomatic individuals. The degree of clonal expansion was correlated with the titer of HBV surface antigen. We conclude that HTLV-1/HBV coinfection may predispose to HTLV-1 associated malignant disease. PMID- 30307561 TI - Inhibiting Adenosine Receptor Signaling Promotes Accumulation of Effector CD4+ T Cells in the Lung Parenchyma During Severe Tuberculosis. AB - Background: Tuberculous pneumonia, necrotic granulomatous lesions, and bacterial dissemination characterize severe forms of mycobacterial infection. Methods: To evaluate the pulmonary CD4+ T-cell response during severe tuberculosis, C57BL/6 mice were infected with approximately 100 bacilli of 3 hypervirulent mycobacterial isolates (Mycobacterium tuberculosis strain Beijing 1471 and Mycobacterium bovis strains B2 and MP287/03) or the H37Rv M tuberculosis strain as reference for mycobacterial virulence. Because high expression of both CD39 and CD73 ectonucleotidases was detected on parenchymal CD4+ T cells, we investigated whether CD4+ T-cell suppression in the context of severe disease was due to the extracellular adenosine accumulation that resulted from tissue damage. Results: Lowest expression of CD69, which is an activation marker implicated in maintaining cells in tissues, was observed in lungs from mice displaying the most severe pulmonary pathology. Reduced interferon (IFN)gamma-producing CD4+ T cells were also found in the lung of these mice. Intranasal administration of the adenosine receptor antagonist caffeine substantially enhanced the frequency and number of parenchymal CD4+ T cells as well as both CD69 expression and IFNgamma production. Conclusions: These results indicate that adenosine, which may be generated by extracellular adenosine triphosphate degradation, impairs the parenchymal CD4+ T-cell response and contributes to the development of severe tuberculosis. PMID- 30307562 TI - Reply to Suthar et al. PMID- 30307563 TI - The Relationship Between Blood Sample Volume and Diagnostic Sensitivity of Blood Culture for Typhoid and Paratyphoid Fever: A Systematic Review and Meta-Analysis. AB - Background: Blood culture is the standard diagnostic method for typhoid and paratyphoid (enteric) fever in surveillance studies and clinical trials, but sensitivity is widely acknowledged to be suboptimal. We conducted a systematic review and meta-analysis to examine sources of heterogeneity across studies and quantified the effect of blood volume. Methods: We searched the literature to identify all studies that performed blood culture alongside bone marrow culture (a gold standard) to detect cases of enteric fever. We performed a meta regression analysis to quantify the relationship between blood sample volume and diagnostic sensitivity. Furthermore, we evaluated the impact of patient age, antimicrobial use, and symptom duration on sensitivity. Results: We estimated blood culture diagnostic sensitivity was 0.59 (95% confidence interval [CI], 0.54 0.64) with significant between-study heterogeneity (I2, 76% [95% CI, 68%-82%]; P < .01). Sensitivity ranged from 0.51 (95% CI, 0.44-0.57) for a 2-mL blood specimen to 0.65 (95% CI, 0.58-0.70) for a 10-mL blood specimen, indicative of a relationship between specimen volume and sensitivity. Subgroup analysis showed significant heterogeneity by patient age and a weak trend towards higher sensitivity among more recent studies. Sensitivity was 34% lower (95% CI, 4%-54%) among patients with prior antimicrobial use and 31% lower after the first week of symptoms (95% CI, 19%-41%). There was no evidence of confounding by patient age, antimicrobial use, symptom duration, or study date on the relationship between specimen volume and sensitivity. Conclusions: The relationship between the blood sample volume and culture sensitivity should be accounted for in incidence and next-generation diagnostic studies. PMID- 30307564 TI - Evaluation of Protein Bait Manufactured From Brewery Yeast Waste for Controlling Drosophila suzukii (Diptera: Drosophilidae). AB - We evaluated a protein bait based on an enzymatically hydrolyzed beer yeast and two widely used baits including a sugar + vinegar + wine mixture and apple cider vinegar for their ability to trap Drosophila suzukii (Matsumura) in the laboratory and outdoors. The protein bait was a more attractive lure than the other tested baits, with the protein bait capturing significantly more female and male adults at different developmental stages than the other baits. Furthermore, the protein bait with 20% vinegar attracted significantly more adult flies than the other baits, and the protein bait without dilution attracted the most adults. Except for the addition of 0.05% spinosad, increased insecticide content in protein bait reduced its attractiveness to adult flies. Moreover, we found that D. suzukii has a bimodal activity pattern in visiting protein bait, where maximum activity occurs during 8:00-10:00 a.m. and 14:00-16:00 p.m. The antennae and maxillary palpi played an important role in detecting the chemicals emitted from the protein bait, as the number of intact flies that responded to new protein bait was significantly higher than the number of flies without antennae that responded, but almost 15% of defective flies still responded to the protein bait. Our results suggested that the protein bait based on spent brewery yeast could be a promising alternative for D. suzukii population monitoring and for managing this pest when combined with bioinsecticides, providing guidance for using this protein bait as a component of integrated pest management. PMID- 30307565 TI - Antimicrobial Resistance and Substandard and Falsified Medicines: The Case of HIV/AIDS. PMID- 30307566 TI - A Retrospective Review of Hospital-Based Data on Enteric Fever in India, 2014 2015. AB - Background: Enteric fever remains a threat to many countries with minimal access to clean water and poor sanitation infrastructure. As part of a multisite surveillance study, we conducted a retrospective review of records in 5 hospitals across India to gather evidence on the burden of enteric fever. Methods: We examined hospital records (laboratory and surgical registers) from 5 hospitals across India for laboratory-confirmed Salmonella Typhi or Salmonella Paratyphi cases and intestinal perforations from 2014-2015. Clinical data were obtained where available. For laboratory-confirmed infections, we compared differences in disease burden, age, sex, clinical presentation, and antimicrobial resistance. Results: Of 267536 blood cultures, 1418 (0.53%) were positive for S. Typhi or S. Paratyphi. Clinical data were available for 429 cases (72%); a higher proportion of participants with S. Typhi infection were hospitalized, compared with those with S. Paratyphi infection (44% vs 35%). We observed resistance to quinolones among 82% of isolates, with cases of cephalosporin resistance (1%) and macrolide resistance (9%) detected. Of 94 participants with intestinal perforations, 16 (17%) had a provisional, final, or laboratory-confirmed diagnosis of enteric fever. Discussion: Data show a moderate burden of enteric fever in India. Enteric fever data should be systematically collected to facilitate evidence-based decision-making by countries for typhoid conjugate vaccines. PMID- 30307567 TI - Transmission and age impact the risk of developing febrile malaria in children with asymptomatic Plasmodium falciparum parasitaemia. AB - Background: Plasmodium falciparum infections lead to febrile illness unless the host has sufficient immunity, in which case infection may cause no immediate symptoms (i.e. "asymptomatic parasitaemia"). Previous studies are conflicting on the role of asymptomatic parasitemia in determining the risk of developing febrile malaria. Methods: We monitored 2,513 children living in Kilifi (Kenyan Coast) with blood smears in 17 cross-sectional surveys to identify asymptomatic parasitemia and used active surveillance over 11,325 child-years of follow up to detect febrile malaria. We evaluated the interaction between transmission intensity, age and asymptomatic parasitaemia in determining the risk of developing febrile malaria. Results: In the moderate and high transmission intensity settings, asymptomatic parasitaemia was associated with a reduced risk of febrile malaria in older children (> 3 years), while in the lower transmission setting, asymptomatic parasitaemia was associated with an increased risk of febrile malaria in children of all ages. Additionally, the risk associated with asymptomatic parasitaemia was limited to the first 90 days of follow up. Conclusions: Asymptomatic parasitaemia is modified by transmission intensity and age, altering the risk of developing febrile episodes and suggesting that host immunity plays a prominent role in mediating this process. PMID- 30307569 TI - ELEVATION OF GAMMA DOSE RATE BY CONSTRUCTION OF THE ASIAN HIGHWAY 3 (AH3) BETWEEN ULAANBAATAR AND SAINSHAND, MONGOLIA. AB - The present study aimed at examining changes of gamma radiation level associated with road construction in Mongolia. A car-borne survey of gamma dose rate was made for a paved, ~450-km long part of the Asian Highway 3 between Ulaanbaatar and Sainshand. The gamma dose rates ranged from 48 to 173 nGy/h. Elevation of the gamma dose rates was observed only on a 86-km long segment of the survey route which was newly constructed from 2011 to 2013. The gamma dose rates over the newer paved segment were twice as high as those over the bare dirt surface alongside it. Outdoor measurements of gamma-ray pulse height distributions also indicated an abundance of natural radionuclides, especially 232Th-series elements in road materials. These findings suggest that the gamma dose rates were elevated by introduction of road materials containing large amounts of natural radionuclides. PMID- 30307570 TI - Enzymes and/or combination of organic acid and essential oils supplementation in pasture-fed free-range laying hens increased the digestibility of nutrients and non-starch polysaccharides. AB - Pasture intake can be a major challenge for free-ranging hens. This study was conducted to examine pasture digestion and to manage its negative effects. A total of 300 ISA Brown laying hens were used to investigate the effect of time on range (T) in short-term (6 wk) and long-term (12 wk) of 2 range types (R) (gravel vs. pasture) and dietary supplements (F) (T1 = xylanase; T2 = xylanase/beta glucanase/pectinase/protease; T3 = xylanase/benzoic acid/essential oils) on crude protein, crude fiber, acid detergent fiber, neutral detergent fiber, non-starch polysaccharides (NSP), calcium and phosphorus digestibility, pH of the crop, and ileum digesta viscosity and morphology. Hens exposed to the range for 12 wk had lower (P < 0.05) digestibility of crude protein, insoluble rhamnose, ribose, and lower ileal pH compared to hens that ranged for 6 wk. Hens ranging on pasture had lower digestibility (P < 0.05) of crude protein, acid detergent fiber, neutral detergent fiber, insoluble arabinose, and insoluble xylose, but higher digestibility (P < 0.05) of insoluble mannose and glucose compared to hens that ranged on gravel. Hens fed T2 and T3 had higher digestibility (P < 0.05) of CP, acid detergent fiber, and neutral detergent fiber compared to hens fed T1. Hens fed T2 had higher digestibility (P < 0.05) of free oligosaccharide arabinose and xylose than those fed T1 or T3 diets. A significant interaction between T * R was detected for crude fiber digestibility and villus height. Digestibility of crude fiber was reduced and villus height was increased in hens ranged on pasture for 12 wk compared to 6 wk. An interaction between R * F was observed on phosphorus and soluble NSP digestibility (P < 0.05). Hens fed T2 and T3 diets had lower digestibility of phosphorus and NSP on gravel than on pasture.In conclusion, pasture consumption impaired the digestibility of nutrients. Supplementing free range diets with a multi-enzyme or xylanase/benzoic acid/essential oil product reduced these negative effects and increased the ileal nutrient digestibility. PMID- 30307568 TI - Past-year relational victimization is associated with a blunted neural response to rewards in emerging adults. AB - Anhedonia is associated with multiple forms of psychopathology, yet relatively, little is known about how anhedonia develops. Emerging evidence suggests that anhedonia is the result of interactions between life stress and the brain's reward systems, and that social stress, in particular, may drive these processes. One potent form of social stress is peer victimization, but very little research has focused on peer victimization beyond adolescence, and even less has examined the associations between peer victimization and neural response to rewards. The present study sought to identify associations between past-year history of peer victimization and neural response to rewards in emerging adults (N = 61). Relational and physical forms of victimization were assessed separately since these distinct types of social stress have different trajectories across development and different associations with psychopathology. Reward sensitivity was indexed with the event-related potential component known as the reward positivity, which was elicited using a forced-choice monetary reward guessing task. Results demonstrated that past-year relational, but not physical, victimization was associated with a blunted neural response to rewards. These findings provide insight into one potential mechanism in the etiology of anhedonia, which may, in turn, help us to better identify pathways to multiple psychopathologies. PMID- 30307571 TI - The potential of Mid-Infrared spectroscopy for prediction of wood density and vulnerability to embolism in woody angiosperms. AB - Xylem resistance to embolism formation determines the species-specific drought tolerance and the survival prospects of plants under extreme climatic conditions. Fourier Transform-Infrared (FTIR) spectroscopy is a cost-effective and rapid analytical tool with potential beyond its current use in plant physiology. We tested the use of FTIR spectroscopy as a method for estimating wood density (WD) and xylem resistance to embolism formation (P50) in 24 angiosperm species. Higher WD was associated with more negative P50 (r2 = 0.41). Partial least squares regression was applied to establish models of FTIR spectra and the reference data. They showed a high predictive quality for WD (r2 = 0.73), whereas the prediction of P50 was weaker (r2 = 0.49). By including WD in the model as an additional factor influencing P50, its predictive power significantly increased (r2 = 0.59). The spectral range in the model elaboration has been also narrowed (bands of lignin, cellulose, hemicellulose), but this did not influence the model descriptors, suggesting that for P50 prediction broad spectral range is more informative than narrow band regions reflecting main wood constituents. In conclusion, FTIR spectroscopy associated with WD measurements has proven to be a promising alternative to traditional methods for screening of individual- or species-specific resistance to embolism in angiosperms. PMID- 30307572 TI - Growth-regulating factor 15 is required for leaf size control in Populus. AB - Growth-regulating factors (GRFs) are involved in various developmental events, particularly leaf development. However, the functions of GRFs in woody plants remain elusive. In this study, functional characterization of GRF15 in Populus was performed. Most GRFs are preferentially expressed in young leaves. As GRF15 was expressed at the highest level and with highest ratio in Populus species with large leaves, this gene was investigated through transgenic analyses. Promotor beta-glucuronidase analysis revealed expression of GRF15 at the leaf expansion zone. Additionally, GRF15 was found to be localized in the nucleus and regulated by miR396. Leaf size and palisade cell size were significantly increased and decreased in GRF15-overexpressing and dominant repression lines, respectively. Consistently, expression of EXPA11a, a homolog of cell-expansion marker EXPA11 in Arabidopsis, was strongly upregulated and downregulated in the GRF15 overexpressing and dominant repression lines, respectively, which was further manifested by activation of EXPA11a by GRF15 in transactivation assays. Therefore, GRF15 is required for leaf size control and primarily modulates cell expansion during leaf development in Populus. PMID- 30307573 TI - No Association of Polymorphisms in Nav1.7 or Nerve Growth Factor Receptor Genes with Trigeminal Neuralgia. AB - Objective: Trigeminal neuralgia is defined as a sudden severe shock-like pain within the distribution of the trigeminal nerve. Pain is a subjective experience that is influenced by gender, culture, environment, psychological traits, and genes. Sodium channels and nerve growth factor play important roles in the transmission of nociceptive signals and pain. The aim of this study was to investigate the occurrence of Nav1.7 sodium channel and nerve growth factor receptor TrkA gene polymorphisms (SCN9A/rs6746030 and NTRK1/rs633, respectively) in trigeminal neuralgia patients. Methods: Ninety-six subjects from pain specialty centers in the southeastern region of Brazil were divided into 2 groups: 48 with classical trigeminal neuralgia diagnosis and 48 controls. Pain was evaluated using the visual analog scale and multidimensional McGill Pain Questionnaire. Genomic DNA was obtained from oral swabs in all individuals and was analyzed by real-time polymerase chain reaction. Results: No association was observed between evaluated polymorphisms and trigeminal neuralgia. For allele analyses, patients and controls had similar frequencies for both genes. Genotype distribution or allele frequencies of polymorphisms analyzed here did not correlate to pain scores. Conclusions: Although no association of evaluated polymorphisms and trigeminal neuralgia diagnosis or pain severity was observed, our data do not exclude the possibility that other genotypes affecting the expression of Nav1.7 or TrkA are associated with the disease. Further studies should investigate distinct genetic polymorphisms and epigenetic factors that may be important in expression of these molecules. PMID- 30307574 TI - Evolution of lipid classes and fatty acid digestibility along the gastrointestinal tract of broiler chickens fed different fat sources at different ages. AB - The aim of the present study is to evaluate the effect of the dietary fat saturation degree and age on the lipid class (TAG, DAG, MAG, and FFA) composition and fatty acid digestibility along the gastrointestinal tract (GIT) and excreta in broiler chickens. A total of 120 one-day-old female broiler chickens were randomly distributed in 2 dietary treatments (6 cages/treatment), which resulted from the supplementation of a basal diet with 6% of soybean oil or palm oil. Two digestibility balances were carried out at 14 and 35 d and fatty acid digestibility and lipid class composition were determined in the gizzard, duodenum, jejunum, ileum, and excreta. Along de GIT, both fatty acid digestibility and lipid class composition were influenced by the dietary fat source and the age of the chickens. The absorption of the unsaturated fat was more efficient and faster than it was for the saturated fat. The ability of adult chickens to absorb fat was higher than for young chickens. The results show that the duodenum is the main place of fat digestion (hydrolysis), and the jejunum the main place of fat absorption. The role of the ileum on fat absorption is very important, as it is the last segment of the GIT where the absorption of fatty acids has been described. Thus, it was the contribution of the ileum that was responsible for the higher fat utilization observed for animals fed the unsaturated diet than for those fed the saturated diet at 14 d, and it was also responsible for the improvement on the utilization of the saturated diet between 14 and 35 d. All the results suggest that the absorption of fatty acids is more limiting than is hydrolysis, because the main differences were observed in the jejunum and ileum, where the absorption of fatty acids takes place. PMID- 30307575 TI - The Simplified Epiduralysis After Laminectomy/Fusion (SEAL) Procedure for Postsurgical Radicular Low Back Pain. PMID- 30307576 TI - Effect of light intensity adjusted for species-specific spectral sensitivity on blood physiological variables of male broiler chickens. AB - Replacing outdated incandescent light sources provides the opportunity to modify lighting systems according to the needs of different species and according to their spectral sensitivity. Providing a lighting environment geared towards poultry vision may improve bird welfare and blood physiological homeostasis. The influence of two LED light sources (red-supplemented vs. un-supplemented) adjusted to either human spectral sensitivity (lux) or poultry spectral sensitivity (CLUX) was investigated on selected blood physiological variables of male broilers. A total of 960 1-d-old male chicks were randomly distributed into 16 environmentally controlled rooms (60 chicks/room). Birds were provided a diet formulated to meet NRC recommendations with feed and water provided ad libitum. The treatments consisted of two LED light sources (red-supplemented (RS) vs. un supplemented (WL)) adjusted to either human spectral sensitivity (CIE) or poultry spectral sensitivity (CLUX) arranged in a 2 * 2 factorial. Blood samples were collected from the brachial wing vein of six birds per room on d 21, 28, 42, and 56, which were then analyzed immediately for whole blood physiological variables. Blood plasma samples were analyzed for corticosterone. In comparison to broilers reared under RS, broilers reared under WL had lower levels of pO2, SaO2, angap, and Osmo, which were within physiological ranges. Also, birds reared under CIE had lower levels of Na+, which were also within the physiological range. In addition, blood glucose and plasma corticosterone concentrations were not affected by treatments, suggesting an absence of physiological stress. In conclusion, it is suggested that minor differences in lighting programs such as lighting source should not be expected to compromise broilers welfare, but rather is primarily an economic decision driven by capital and operation costs. PMID- 30307577 TI - Expression and secretion of albumin in male turkey (Meleagris gallopavo) reproductive tract in relation to yellow semen syndrome. AB - Yellow semen syndrome (YSS) is the most widely recognized problem among male turkeys. Yellow semen is of low quality and, when used for insemination, results in reduction of fertility and hatchability. Elevated level of serum albumin-like protein accession no. XP_003205725 is a characteristic feature of yellow seminal plasma suggesting albumin role in YSS pathology. However, knowledge regarding the expression of albumin in the reproductive tract in relation to YSS is very limited. The aim of this study was to identify albumin secretion and localization sites in the turkey reproductive tract in relation to YSS. Reproductive tract tissues and liver originating from turkeys producing white semen (WS) and YSS were used for analysis of albumin mRNA expression and its localization using immunohistochemistry. Moreover, albumin abundance in tissues, blood and seminal plasma was analyzed using two dimensional electrophoresis and western blot analysis. Albumin mRNA expression was found in all parts of the reproductive tract. Apart from the liver, the highest expression of albumin was found in the ductus deferens in YSS turkeys. The testicular spermatids, Leydig, and myoid cells and the epithelium of the epididymis and ductus deferens were the main secretion sites of albumin in the reproductive tract in turkeys. Higher albumin abundance was found in the reproductive tract and seminal plasma of YSS toms compared to WS toms. Our results demonstrated that germ cells from spermatocytes to spermatids, Leydig cells, and myoid cells synthesized and secreted albumin in turkey testis, and epithelial cells are the main secretion sites in epididymis and ductus deferens. Ductus deferens secretion of albumin seems to be mostly responsible for YSS. Over-secretion by the ductus deferens may be the main origin of albumin abundance in YSS semen. Knowledge regarding disturbances of albumin secretion in relation to YSS may be useful for future work on studies related to better understanding the molecular basis of YSS. PMID- 30307578 TI - Storage of defense metabolites in the leaves of Myrtaceae: news of the eggs in different baskets. PMID- 30307579 TI - Metaproteomic characterization of theVitis vinifera rhizosphere. AB - The rhizosphere is a hotspot of microbial activity where the release of root exudates stimulates bacterial density and diversity. The majority of the bacterial cells in soil are viable, unculturable, but active. Proteomic tools could be useful in gaining information about microbial community activity and to better understand the real interactions between roots and soil. The aim of this work was to characterize the bacterial community associated with Vitis vinifera cv. Pinot Noir roots using a metaproteome approach. Our results confirmed the large potential of proteomics in describing the environmental microbial communities and their activities: in particular, we showed that bacteria belonging to Streptomyces, Bacillus, Bradyrhizobium, Burkholderia and Pseudomonas genera are the most active in protein expression. Concerning the biological activity of these genera in the rhizosphere, we observed the exclusive presence of the phosphorus metabolic process and the regulation of primary metabolic processes. To our knowledge, this is the first study reporting the rhizosphere proteome of V. vinifera, describing the bacterial community structure and activity of an important ecosystem for the Italian landscape, agriculture and economy. PMID- 30307580 TI - Re: Black-White Breast Cancer Incidence Trends: Effects of Ethnicity. PMID- 30307581 TI - Times Are Changing. PMID- 30307582 TI - Family Medicine's Task in Population Health: Defining It and Owning It. PMID- 30307583 TI - Supporting Family Physician Maternity Care Providers. AB - Maternity care access in the United States is in crisis. The American Congress of Obstetrics and Gynecology projects that by 2030 there will be a nationwide shortage of 9,000 obstetrician-gynecologists (OB/GYNs). Midwives and OB/GYNs have been called upon to address this crisis, yet in underserved areas, family physicians are often providing a majority of this care. Family medicine maternity care, a natural fit for the discipline, has been on sharp decline in recent years for many reasons including difficulties cultivating interdisciplinary relationships, navigating privileging, developing and maintaining adequate volume/competency, and preventing burnout. In 2016 and 2017, workshops were held among family medicine educators with resultant recommendations for essential strategies to support family physician maternity care providers. This article summarizes these strategies, provides guidance, and highlights the role family physicians have in addressing maternity care access for the underserved as well as presenting innovative ideas to train and retain rural family physician maternity care providers. PMID- 30307584 TI - Validation and Comparison of a Brief Instrument vs a Single-Item Screen to Predict Entry to Family Medicine at Matriculation to Medical School. AB - BACKGROUND AND OBJECTIVES: A strong US primary care workforce is necessary to meet health care needs, yet fewer than 9% of allopathic medical students choose family medicine each year. No validated instrument exists to identify students likely to enter family medicine upon medical school matriculation. METHODS: A subset of a larger survey at the University of Washington School of Medicine (UWSOM) was used to create the Family Medicine Interest Survey (FMIS), a 15-item instrument to predict eventual practice in family medicine for a 2003-2007 matriculating cohort. A single-item screen asking about top specialty choice was administered at UWSOM for the same cohort and for a 2006-2012 matriculating cohort of students at Oregon Health & Science University (OHSU). Test performance measures including D (discrimination) and Cronbach alpha were calculated. Logistic regression determined whether FMIS score or reporting family medicine as the top specialty choice predicted family medicine practice for 601 UWSOM graduates or family medicine residency match for 744 OHSU graduates. RESULTS: The FMIS is reliable (Cronbach alpha=0.76). Both tests significantly predicted the probability of entering family medicine. Listing family medicine as the preferred specialty choice yielded a 47% predicted probability for UWSOM graduates entering family medicine. OHSU graduates listing family medicine first had an eightfold odds of matching to family medicine residencies. Combining the two instruments for UWSOM graduates showed a dose-response curve for predicted probability of entering family medicine with increasing levels of interest. CONCLUSION: Each screening tool can predict students more likely to enter family medicine upon matriculation. PMID- 30307585 TI - Burnout and Job Satisfaction Among Family Medicine Residency Coordinators: Results From a National Survey. AB - BACKGROUND AND OBJECTIVES: Research into rates of burnout and job satisfaction among family medicine residency coordinators is nonexistent. Coordinators play a pivotal role in medical education, sometimes have multiple roles and titles, and often work in stressful environments. The goals of this study were to explore the prevalence of, and relationship between, burnout and job satisfaction among family medicine residency coordinators. METHODS: This national wellness study involved 307 family medicine residency coordinators. Modified questions of the Professional Quality of Life Scale, Version 5 were used to measure participants' burnout and job satisfaction rates. The authors used chi-square tests, Pearson's r correlations, and multiple linear regression to analyze the data. RESULTS: The response rate was 72% (307/429), with 24% of family medicine residency coordinators reporting high, 51% reporting moderate, and 26% reporting low rates of work-related burnout. Twenty-eight percent of the family medicine residency coordinators reported high, 46% moderate, and 26% low job satisfaction. There was a significantly negative relationship between job satisfaction and work-related burnout, r (306)=-.638, P<0.001. Regression explained 42% of variance in job satisfaction, and showed that burnout (beta=-.62) and years on the job (beta=.15) were significant predictors of job satisfaction (R=0.64; F [5, 277]=40.28, P<.001). CONCLUSIONS: The results demonstrate that family medicine residency coordinators are generally satisfied with their work and reported moderate to high degree of burnout rates. PMID- 30307586 TI - Cultivating Country Doctors: Preparing Learners for Rural Life and Community Leadership. AB - BACKGROUND AND OBJECTIVES: Rural health disparities are growing, and medical schools and residency programs need new approaches to encourage learners to enter and stay in rural practice. Top correlates of rural practice are rural upbringing and rurally located training, yet preparation for rural practice plays a role. The authors sought to explore how selected programs develop learners' competencies associated with rural placement and retention: rural life, community engagement, and community leadership. METHODS: Qualitative, semistructured phone interviews (n=20) were conducted with faculty of medical schools or family medicine residencies across the United States, Canada, Australia, and South Africa in which success in training rural practitioners was identified in the literature or by leaders of the National Rural Health Association's Rural Medical Educators Group. Participants included 18 physician program directors, one nonphysician program administrator, and one PhD researcher who had studied rural preparation. Interview transcripts were read twice using an inductive process: first to identify themes, and then to identify specific strategies and quotes to exemplify each theme. RESULTS: Participants' recommendations for rural preparation were: (1) Be intentional about strategies to prepare learners for rural practice; (2) Identify and cultivate rural interest; (3) Develop confidence and competence to meet rural community needs; (4) Teach skills in negotiating dual relationships, leading, and improving community health; and (5) Fully engage rural host communities throughout the training process. CONCLUSIONS: Medical schools and residencies may increase the likelihood of producing rural physicians by implementing these experts' strategies. Educators may select strategies that mesh with the structure and location of their training program. PMID- 30307587 TI - An "Invaluable Skill": Reflections on Abortion Training and Postresidency Practice. AB - BACKGROUND AND OBJECTIVES: The goal of this study was to explore family medicine residents' experiences with abortion training and identify positive and negative influences, and facilitators and barriers to providing abortion care. METHODS: We conducted a qualitative study of recent graduates of an urban family medicine residency in the Northeast United States with an opt-out abortion curriculum. Individual recorded interviews were conducted with two classes of graduated residents until data saturation was reached. Data were coded and interpreted by both authors using the template analysis method. RESULTS: Twenty residents completed interviews. Most trainees had limited or no abortion exposure prior to residency but were open to learning abortion care. By graduation, residents reported confidence in providing options counseling for unintended pregnancy. Overall, residents felt more comfortable providing medication abortion than aspiration abortion. Many reported feeling less emotional reaction to medication abortion and noted more technical and logistical barriers to learning aspiration abortion. Logistical barriers impede integration of medication abortion into practice for many, but were perceived to be less difficult to overcome than barriers to aspiration abortion integration. All participants agreed abortion care fits into the scope of primary care. Due to a variety of barriers, few of those who had not previously planned to become abortion providers after graduation incorporated it in their practice. CONCLUSIONS: Abortion training prepared residents to counsel women with unintended pregnancy, but numerous barriers inhibit integration of abortion care into practice. Given limited abortion training resources and fewer perceived barriers to medication abortion provision, family medicine residencies may consider focusing training on medication abortion. PMID- 30307588 TI - Competencies to Guide a Leadership Curriculum for Family Medicine Chief Residents. AB - BACKGROUND AND OBJECTIVES: Chief resident leadership competencies are neither clear nor standardized. The goal of this project was to identify specific leadership skills for chief residents and to develop a self-assessment tool. METHODS: Chief residents from 10 family medicine residencies participated in focus groups to identify leadership skills required to be an effective chief resident. The ideas generated by participants were grouped into 10 competencies and a self-assessment tool was developed. The tool has been used to help chief residents self-assess their leadership strengths and weaknesses, and to identify teaching priorities for biannual leadership workshops. RESULTS: The self assessment instrument was completed by 83 chief residents over 5 years. Mean ratings range from 3.19 to 3.57 on a 5-point scale (low to high competency). The self-ratings of residents starting their chief year compared to residents at the end of their chief year showed an increase in 9 of the 10 competencies. CONCLUSIONS: The leadership competencies are a useful tool to identify training priorities and to help chief residents or other leaders within a residency program identify skills for further development. PMID- 30307590 TI - Identifying Opportunities to Improve Intimate Partner Violence Screening in a Primary Care System. AB - BACKGROUND AND OBJECTIVES: Intimate partner violence (IPV) is a silent epidemic affecting one in three women. The US Preventive Services Task Force recommends routine IPV screening for women of childbearing age, but actual rates of screening in primary care settings are low. Our objectives were to determine how often IPV screening was being done in our system and whether screening initiated by medical assistants or physicians resulted in more screens. METHODS: We conducted a retrospective chart review to investigate IPV screening practices in five primary care clinics within a university-based network in Northern California. We reviewed 100 charts from each clinic for a total of 500 charts. Each chart was reviewed to determine if an IPV screen was documented, and if so, whether it was done by the medical assistant or the physician. RESULTS: The overall frequency of IPV screening was 22% (111/500). We found a wide variation in screening practices among the clinics. Screening initiated by medical assistants resulted in significantly more documented screens than screening delivered by physicians (74% vs 9%, P<0.001). CONCLUSIONS: IPV screening is an important, but underdelivered service. Using medical assistants to deliver IPV screening may be more effective than relying on physicians alone. PMID- 30307589 TI - Opioid Overdose Prevention in Family Medicine Clerkships: A CERA Study. AB - BACKGROUND AND OBJECTIVES: The national opioid crisis requires medical education to develop a proactive response centering on prevention and treatment. Primary care providers (PCPs)-many of whom are family medicine physicians-commonly treat patients on opiates, and write nearly 50% of opioid prescriptions. Despite linkages between PCP opioid prescribing patterns and the associated potential for overdose, little is known about how family medicine clerkship students are trained to prevent opioid overdose, including training on the use of naloxone. This study describes the presence of opioid overdose education at the national level and barriers to inclusion. It also discusses implementation strategies along with instructional methodology and learner evaluation. METHODS: Data were collected as part of a cross-sectional survey administered electronically by the Council of Academic Family Medicine Educational Research Alliance to 139 family medicine clerkship directors. RESULTS: A total of 99 clerkship directors (71.2% response rate) responded to the survey. A large majority (86.4%) agreed that it is important to offer opioid overdose prevention education in the clerkship, yet only 25.8% include this topic. Of these, only 50.0% address naloxone use. The most common barriers to including opioid overdose prevention education were prioritization of educational topics (82.1%) followed by lack of available faculty with sufficient experience/expertise (67.7%). CONCLUSIONS: Findings point to a disparity between perceived importance of opioid overdose prevention education and inclusion of this topic in family medicine clerkship-level medical education. Innovative use of online education and partnering with community resources may address barriers related to curricular prioritization while supporting interprofessional education principles. PMID- 30307591 TI - "How's the New Job Working Out for You, Doc?" PMID- 30307592 TI - Exile. PMID- 30307593 TI - The Confession. PMID- 30307594 TI - Valediction. PMID- 30307595 TI - Racism Education is Needed at All Levels of Training. PMID- 30307596 TI - Authors' Reply "Racism Education is Needed at All Levels of Training". PMID- 30307597 TI - Collaborative Skills Essential to Leadership. PMID- 30307598 TI - Letter to the Editor in Response to "Residents' Perspectives on Careers in Academic Medicine: Obstacles and Opportunities". PMID- 30307599 TI - If I Understood You, Would I Have This Look on My Face? My Adventures in the Art and Science of Relating and Communicating. PMID- 30307600 TI - Healthcare Choices: 5 Steps to Getting the Medical Care You Want and Need. PMID- 30307601 TI - We Can Become Stronger Through Diversity of Thought. PMID- 30307602 TI - Support surfaces for treating pressure ulcers. AB - BACKGROUND: Pressure ulcers are treated by reducing pressure on the areas of damaged skin. Special support surfaces (including beds, mattresses and cushions) designed to redistribute pressure, are widely used as treatments. The relative effects of different support surfaces are unclear. This is an update of an existing review. OBJECTIVES: To assess the effects of pressure-relieving support surfaces in the treatment of pressure ulcers. SEARCH METHODS: In September 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We included published or unpublished randomised controlled trials (RCTs), that assessed the effects of support surfaces for treating pressure ulcers, in any participant group or setting. DATA COLLECTION AND ANALYSIS: Data extraction, assessment of 'Risk of bias' and GRADE assessments were performed independently by two review authors. Trials with similar participants, comparisons and outcomes were considered for meta-analysis. Where meta-analysis was inappropriate, we reported the results of the trials narratively. Where possible, we planned to report data as either risk ratio or mean difference as appropriate. MAIN RESULTS: For this update we identified one new trial of support surfaces for pressure ulcer treatment, bringing the total to 19 trials involving 3241 participants. Most trials were small, with sample sizes ranging from 20 to 1971, and were generally at high or unclear risk of bias. PRIMARY OUTCOME: healing of existing pressure ulcersLow-tech constant pressure support surfacesIt is uncertain whether profiling beds increase the proportion of pressure ulcer which heal compared with standard hospital beds as the evidence is of very low certainty: (RR 3.96, 95% CI 1.28 to 12.24), downgraded for serious risk of bias, serious imprecision and indirectness (1 study; 70 participants).There is currently no clear difference in ulcer healing between water-filled support surfaces and foam replacement mattresses: (RR 0.93, 95% CI 0.63 to 1.37); low-certainty evidence downgraded for serious risk of bias and serious imprecision (1 study; 120 participants).Further analysis could not be performed for polyester overlays versus gel overlays (1 study; 72 participants), non-powered mattresses versus low-air-loss mattresses (1 study; 20 participants) or standard hospital mattresses with sheepskin overlays versus standard hospital mattresses (1 study; 36 participants).High-tech pressure support surfacesIt is currently unclear whether high-tech pressure support surfaces (such as low-air loss beds, air suspension beds, and alternating pressure surfaces) improve the healing of pressure ulcers (14 studies; 2923 participants) or which intervention may be more effective. The certainty of the evidence is generally low, downgraded mostly for risk of bias, indirectness and imprecision.Secondary outcomesNo analyses were undertaken with respect to secondary outcomes including participant comfort and surface reliability and acceptability as reporting of these within the included trials was very limited.Overall, the evidence is of low to very low certainty and was primarily downgraded due to risk of bias and imprecision with some indirectness. AUTHORS' CONCLUSIONS: Based on the current evidence, it is unclear whether any particular type of low- or high-tech support surface is more effective at healing pressure ulcers than standard support surfaces. PMID- 30307603 TI - Clinical trials involving carbon-ion radiation therapy and the path forward. AB - To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing. PMID- 30307604 TI - IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10. AB - The objective of this study was to test the capacity of a newly developed fusion protein of interleukin 4 (IL-4) and IL-10 [IL4-10 fusion protein (FP)] to shift multiple pro-inflammatory pathways towards immune regulation, and to inhibit pro inflammatory activity in arthritis models. The effects of IL4-10 FP in comparison with IL-4, IL-10 and IL-4 plus IL-10 on pro- and anti-inflammatory mediators, T cells and immunoglobulin (Ig) receptors in favour of immunoregulatory activity were studied. In addition, the capacity of IL4-10 FP to inhibit pro-inflammatory activity in ex-vivo and in-vivo arthritis models was investigated. IL4-10 FP robustly inhibited pro-inflammatory cytokine [IL-1beta, tumour necrosis factor (TNF)-alpha, IL-6 and IL-8] production in whole blood cultures, mediated by both the IL-10 and the IL-4 moiety. IL4-10 fusion protein induced IL-1 receptor antagonist (IL-1RA) production and preserved soluble TNF receptor (sTNFR) levels, strongly increasing IL-1RA/IL-1beta and sTNFR/TNF-alpha ratios. In addition, IL4 10 FP strongly inhibited T helper (Th) type 1 and 17 cytokine secretion, while maintaining FoxP3 expression and up-regulating Th2 activity. In addition, while largely leaving expression of activating Fc gamma receptor (FcgammaR)I, III and Fc epsilon receptor (FcepsilonR) unaffected, it significantly shifted the FcgammaRIIa/FcgammaRIIb ratio in favour of the inhibitory FcgammaRIIb. Moreover, IL4-10 FP robustly inhibited secretion of pro-inflammatory cytokines by rheumatoid arthritis synovial tissue and suppressed experimental arthritis in mice, without inducing B cell hyperactivity. IL4-10 fusion protein is a novel drug, signalling cells to induce immunoregulatory activity that overcomes limitations of IL-4 and IL-10 stand-alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis. PMID- 30307605 TI - Enterovirus infection and type 1 diabetes: unraveling the crime scene. AB - Enteroviruses (EV) have been historically associated to type 1 diabetes. Definitive proof for their implication in disease development is lacking, but growing evidence suggests that they could be involved in beta cell destruction either directly by killing beta cells or indirectly by creating an exacerbated inflammatory response in the islets, capable of attracting autoreactive T cells to the 'scene of the crime'. Epidemiological and serological studies have been associated with the appearance of islet autoimmunity and EV RNA has been detected in prospective studies. In addition, the EV capsid protein has been detected in the islets of recent-onset type 1 diabetic donors, suggesting the existence of a low-grade EV infection that could become persistent. Increasing evidence in the field shows that a 'viral signature' exists in type 1 diabetes and involves interferon responses that could be sustained during prolonged periods. These include the up-regulation of markers such as protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), retinoic acid inducible gene I (RIG I), myxovirus resistance protein (MxA) and human leukocyte antigen-I (HLA-I) and the release of chemokines able to attract immune cells to the islets leading to insulitis. In this scenario, the hyperexpression of HLA-I molecules would promote antigen presentation to autoreactive T cells, favoring beta cell recognition and, ultimately, destruction. In this review, an overview of the standing evidence that implicates EVs in beta cell 'murder' is provided, the time-line of events from EV entry in the cell to beta cell death is investigated and possible accomplices that might be involved in beta cell demise are highlighted. PMID- 30307607 TI - More than one angle to target aplastic anemia? PMID- 30307606 TI - Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia. AB - BACKGROUND: The immune-mediated destruction of hematopoietic stem cells is implicated in the pathophysiology of aplastic anemia (AA). Immunosuppressive therapy (IST) using antithymocyte globulin and cyclosporine is successful in this setting. Eltrombopag is active in patients with refractory AA, presumably by increasing the bone marrow progenitors. METHODS: This phase 2 trial initially was designed to evaluate standard IST in newly diagnosed patients with severe AA and later was amended to add eltrombopag to simultaneously address immune destruction and stem cell depletion. The primary outcome was the overall response rate (ORR) at 3 months and 6 months. RESULTS: A total of 38 patients were enrolled: 17 (45%) received IST alone and 21 (55%) received additional eltrombopag. The ORR was 74%. Patients receiving IST plus eltrombopag had a similar ORR (76% vs 71%; P = .72), complete remission rate (38% vs 29%; P = .73), and median time to response (84 days vs 57 days; P = .30) compared with those receiving IST alone. The 2-year overall survival rate in the IST group was 91% compared with 82% for those patients treated with IST plus eltrombopag (P = .82). No cumulative toxicities were noted after the addition of eltrombopag. CONCLUSIONS: The addition of eltrombopag to standard IST was well tolerated and resulted in similar responses. PMID- 30307608 TI - Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population. AB - Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T- B- severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T- B- SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T- B- SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T- B+ CID. PMID- 30307609 TI - Effect of locally tailored clinical guidelines on intrapartum management of severe hypertensive disorders at Zanzibar's tertiary hospital (the PartoMa study). AB - OBJECTIVE: To estimate the effect of locally tailored clinical guidelines on intrapartum care and perinatal outcomes among women with severe hypertensive disorders in pregnancy (sHDP). METHODS: A pre-post study at Zanzibar's low resource Mnazi Mmoja Hospital was conducted. All labouring women with sHDP were included at baseline (October 2014 to January 2015) and at 9-12 months after implementation of the ongoing intervention (October 2015 to January 2016). Background characteristics, clinical practice, and delivery outcomes were assessed by criterion-based case file reviews. RESULTS: Overall, 188 of 2761 (6.8%) women had sHDP at baseline, and 196 of 2398 (8.2%) did so during the intervention months. The median time between last blood pressure recording and delivery decreased during the intervention compared with baseline (P=0.015). Among women with severe hypertension, antihypertensive treatment increased during the intervention compared with baseline (relative risk [RR] 1.37, 95% confidence interval [CI] 1.14-1.66). Among the neonates delivered (birthweight >=1000 g), stillbirths decreased (RR 0.56, 95% CI 0.35-0.90) and Apgar scores of seven or more increased during the intervention compared with baseline (RR 1.17, 95% CI 1.03-1.33). CONCLUSION: Although health system strengthening remains crucial, locally tailored clinical guidelines seemed to help work-overloaded birth attendants at a low-resource hospital to improve care for women with sHDP. CLINICALTRIALS.ORG: NCT02318420. PMID- 30307610 TI - Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. AB - BACKGROUND: To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class. METHODS: A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with >=1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors. RESULTS: A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047). CONCLUSIONS: The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate risk, and poor-risk groups for OS. PMID- 30307612 TI - Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation. AB - Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17 have been reported as a cause of PC. Herein we present a female patient with an amino acid substitution mutation in KRT6A (c.1381G>A, p.Glu461Lys in exon 7) and classic features of PC associated with oral leucokeratosis and follicular hyperkeratosis. We also demonstrate successful treatment of the patient with rosuvastatin. A 3.6-mm reduction in plantar callosity thickness was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC. PMID- 30307611 TI - Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage. AB - BACKGROUND: The outcomes of patients with relapsed or refractory (R-R) acute lymphoblastic leukemia (ALL) are poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their addition to low-intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse. METHODS: The chemotherapy was lower in intensity than conventional hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone and was called mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (or mini-HCVD). Inotuzumab was given on day 3 of each of the first 4 cycles at 1.8 to 1.3 mg/m2 for cycle 1, and this was followed by 1.3 to 1.0 mg/m2 for subsequent cycles. From patient 39 onward, the inotuzumab dose was reduced and fractionated into weekly doses (0.6 and 0.3 mg/m2 during cycle 1 and 0.3 and 0.3 mg/m2 during subsequent cycles), and blinatumomab was administered for up to 4 cycles after inotuzumab therapy. RESULTS: Forty-eight patients with Philadelphia chromosome-negative ALL with a median age of 39 years were treated during their first relapse. Overall, 44 patients (92%) responded, with 35 of them (73%) achieving a complete response. The overall minimal residual disease negativity rate among the responders was 93%. Twenty-four patients (50%) underwent allogeneic stem cell transplantation (ASCT). Veno-occlusive disease of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median progression-free survival (PFS) and the median overall survival (OS) were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients were alive at the last follow-up (13 [54%] in remission). Of the remaining 20 responding patients who did not undergo subsequent ASCT, 6 (30%) remained in remission at the last follow-up. According to propensity score matching, the combination of mini-HCVD and inotuzumab with or without blinatumomab conferred better outcomes than intensive salvage chemotherapy or inotuzumab alone. CONCLUSIONS: The combination of inotuzumab and low-intensity mini-HCVD chemotherapy with or without blinatumomab shows encouraging results in patients with ALL in first salvage. PMID- 30307613 TI - Countering Youth's Negative Stereotypes of Teens Fosters Constructive Behavior. AB - Adolescence can be a time of unconstructive behavior for many youth. This research examined if an intervention countering youth's stereotypes of teens as irresponsible fosters their constructive behavior. In two experimental intervention studies (Ns = 124 and 319) with seventh graders, stereotypes of teens as irresponsible were described as inaccurate portrayals; youth then provided their own observations of teens acting responsibly. Youth in this counterstereotyping intervention (vs. the control) held higher intentions for academic engagement and performed better on an academic task (i.e., a word-search puzzle). Over the 3 days following the intervention, their academic engagement was higher. Youth's risk taking was also reduced. Redirecting youth to see teens as responsible has the potential to provide a foundation for flourishing. PMID- 30307614 TI - Sunscreen applied at >= 2 mg cm-2 during a sunny holiday prevents erythema, a biomarker of ultraviolet radiation-induced DNA damage and suppression of acquired immunity. AB - BACKGROUND: Sun protection factor (SPF) is assessed with sunscreen applied at 2 mg cm-2 . People typically apply around 0.8 mg cm-2 and use sunscreen daily for holidays. Such use results in erythema, which is a risk factor for skin cancer. OBJECTIVES: To determine (i) whether typical sunscreen use resulted in erythema, epidermal DNA damage and photoimmunosuppression during a sunny holiday, (ii) whether optimal sunscreen use inhibited erythema and (iii) whether erythema is a biomarker for photoimmunosuppression in a laboratory study. METHODS: Holidaymakers (n = 22) spent a week in Tenerife (very high ultraviolet index) using their own sunscreens without instruction (typical sunscreen use). Others (n = 40) were given SPF 15 sunscreens with instructions on how to achieve the labelled SPF (sunscreen intervention). Personal ultraviolet radiation (UVR) exposure was monitored electronically as the standard erythemal dose (SED) and erythema was quantified. Epidermal cyclobutane pyrimidine dimers (CPDs) were determined by immunostaining, and immunosuppression was assessed by contact hypersensitivity (CHS) response. RESULTS: There was no difference between personal UVR exposure in the typical sunscreen use and sunscreen intervention groups (P = 0.08). The former had daily erythema on five UVR-exposed body sites, increased CPDs (P < 0.001) and complete CHS suppression (20 of 22). In comparison, erythema was virtually absent (P < 0.001) when sunscreens were used at >= 2 mg cm-2 . A laboratory study showed that 3 SED from three very different spectra suppressed CHS by around ~50%. CONCLUSIONS: Optimal sunscreen use prevents erythema during a sunny holiday. Erythema predicts suppression of CHS (implying a shared action spectrum). Given that erythema and CPDs share action spectra, the data strongly suggest that optimal sunscreen use will also reduce CPD formation and UVR-induced immunosuppression. PMID- 30307615 TI - Neurocardiac regulation: from cardiac mechanisms to novel therapeutic approaches. AB - Cardiac sympathetic overactivity is a well-established contributor to the progression of neurogenic hypertension and heart failure, yet the underlying pathophysiology remains unclear. Recent studies have highlighted the importance of acutely regulated cyclic nucleotides and their effectors in the control of intracellular calcium and exocytosis. Emerging evidence now suggests that a significant component of sympathetic overactivity and enhanced transmission may arise from impaired cyclic nucleotide signalling, resulting from compromised phosphodiesterase activity, as well as alterations in receptor-coupled G-protein activation. In this review, we address some of the key cellular and molecular pathways that contribute to sympathetic overactivity in hypertension and discuss their potential for therapeutic targeting. PMID- 30307616 TI - Does nonmetastatic inflammatory breast cancer have a worse prognosis than other nonmetastatic T4 cancers? AB - BACKGROUND: Both patients with inflammatory breast cancer (IFLBC) and patients with noninflammatory T4 breast cancer (non-IFLBC) have a heavy disease burden in the breast; whether the unique biology of IFLBC conveys a higher locoregional recurrence (LRR) risk and worse outcomes in comparison with other T4 lesions is uncertain. Here the outcomes of patients with IFLBC and patients with non-IFLBC treated with modern multimodality therapy are compared. METHODS: Patients with nonmetastatic T4 breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiation therapy between 2006 and 2016 were identified. Recurrences and survival were compared between patients with IFLBC and patients with non-IFLBC overall and stratified by receptor subtype. RESULTS: For 199 T4 patients, the median age was 52 years, and the median clinical tumor size was 7 cm. One hundred seventeen (59%) had IFLBC. With a median follow-up of 41 months, 4 patients had isolated LRR; all cases occurred in patients with IFLBC. The 5-year isolated LRR rate for patients with IFLBC was 4.8%. Overall, 14 patients had both LRR and distant recurrence (DR); 47 had DR only. The 5-year distant recurrence-free survival (DRFS) rates were similar for patients with IFLBC and patients with non IFLBC (63% vs 71%; log-rank P = .14). The 5-year DRFS rate was lowest among triple-negative (TN) patients (43%) and was significantly lower for patients with TN IFLBC versus patients with non-IFLBC (28% vs 62%; log-rank P = .02). The 5 year overall survival rates (71% vs 74%; log-rank P = .4) and cancer-specific survival rates (74% vs 79%; log-rank P = .23) did not differ between IFLBC and non-IFLBC. CONCLUSIONS: Although IFLBC is often considered a unique biologic subtype, patients with IFLBC and patients with non-IFLBC had similar outcomes with modern multimodality therapy; isolated LRR was uncommon. The TN subtype in patients with IFLBC is associated with poor outcomes, and this indicates the need for new treatment approaches in this group. PMID- 30307617 TI - Risk of cardiovascular disease among Nordic childhood cancer survivors with diabetes mellitus: A report from adult life after childhood cancer in Scandinavia. AB - BACKGROUND: Childhood cancer survivors have an increased risk of cardiovascular disease (CVD) and diabetes mellitus. Because diabetes is a potentially modifiable risk factor for CVD in the general population, it is important to understand how diabetes affects the risk of CVD among childhood cancer survivors. METHODS: This study examined the risk of CVD among survivors with diabetes and 142,742 population comparison subjects. From the national cancer registries of the 5 Nordic countries, 29,324 one-year survivors of cancer diagnosed before the age of 20 years between 1968 and 2008 were identified. Study subjects were linked to the national hospital registers. The cumulative incidence of CVD was determined with competing risk methods. A Cox proportional hazards model was used to estimate the effects of diabetes and cancer on the hazard of CVD. The interaction between diabetes and cancer was analyzed. RESULTS: Diabetes was diagnosed in 324 of the 29,324 one-year survivors, and CVD was diagnosed in 2108. The hazard of diabetes was 1.7 times higher among survivors than comparison subjects (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-1.9), whereas the HR of CVD was 3.6 (95% CI, 3.3-3.8) 1 to 15 years after the cancer diagnosis and 1.9 (95% CI, 1.8-2.0) after more than 15 years. Individuals with diabetes had a 2.4 times higher hazard of CVD (95% CI, 2.1-2.8) among both survivors and comparison subjects in comparison with individuals without diabetes. CONCLUSIONS: Childhood cancer survivors with diabetes have a markedly increased risk of CVD in comparison with survivors without diabetes. However, diabetes does not increase the risk of CVD more in survivors than the general population. PMID- 30307618 TI - Atopic diseases and type I sensitization from adolescence to adulthood in an unselected population (TOACS) with focus on predictors for allergic rhinitis. AB - BACKGROUND: While much is known on childhood atopic diseases, knowledge about persistence of atopic diseases from childhood to adulthood is limited. We therefore aimed to study the clinical course of atopic diseases and type I sensitization prospectively in an unselected cohort of adolescents followed into adulthood. METHODS: A cohort of unselected 8th-grade school children (mean age 14 years) established in 1995 and followed up in 2010 were evaluated with questionnaire, clinical examination, skin prick tests and measurements of specific IgE. RESULTS: The lifetime prevalence of atopic diseases was high and increased significantly from adolescence (31%) to adulthood (57%); particularly allergic rhinitis increased with an incidence rate of 17.5/1000 person-years. Childhood predictors for adult allergic rhinitis were atopic dermatitis, asthma and asymptomatic sensitization to pollen and house dust mite. Among those with asymptomatic sensitization in adolescence, 53%-78% developed allergic rhinitis in adulthood. Furthermore, type I sensitization increased significantly from adolescence to adulthood mostly due to increased sensitization to pollen. Type I sensitization was found mainly in those with allergic rhinitis. A high number of adults had oral allergy symptoms due to the high number of birch pollen allergic individuals. CONCLUSION: Persistence of atopic diseases in adulthood is common, and a high proportion of the adult population is sensitized giving a high prevalence of allergic rhinitis. Many with asymptomatic sensitization in adolescence will develop allergic rhinitis in adult life. The focus should be on prevention of atopic diseases and sensitization already in childhood. PMID- 30307619 TI - Retrospectively seroprevalence study on anti-HEV-IgG antibody in patients with chronic hepatitis or liver cirrhosis in a Chinese teaching hospital. AB - BACKGROUND AND OBJECTIVE: To investigate the serum anti-hepatitis E virus (HEV) antibody positive rate in patients with different types of chronic hepatitis (CH) or cirrhosis. METHODS: A total of 1751 hospitalized patients were chart reviewed, who were diagnosed with mono-CH or cirrhosis between 2011 and 2016. RESULTS: The total anti-HEV-IgG positive rate was 1.33% (13/981) in CH patients, which was significantly lower than that (6.49%; 50/770) in cirrhosis patients (odds ratio [OR], 4.78 [2.51-9.10]; P = 0.00). The comparison of positive rate of anti-HEV IgG between the same etiology CH and cirrhosis groups was as follows: chronic hepatitis B 1.27% (10/790) versus hepatitis B virus (HBV)-related cirrhosis 4.21% (22/522) (OR, 3.04 [1.36-6.77]; P = 0.00); chronic alcoholic hepatitis 1.41% (1/71) versus alcoholic cirrhosis 9.40% (11/117) (OR, 8.00 [1.00-64.25]; P = 0.03); chronic autoimmune hepatitis 1.69% (1/59) versus autoimmune cirrhosis 13.33% (12/90) (OR, 13.11 [1.49-115.27]; P = 0.01); the differences above were statistically significant. And chronic hepatitis C 3.23% (1/31) versus hepatitis C virus-related cirrhosis 10.81% (4/37) (OR, 4.40 [0.45-43.53]; P > 0.05); chronic NASH 0.00% (0/30) versus NASH-related cirrhosis 25.00% (1/4) (P > 0.05), the differences were not statistically significant. Anti-HEV-IgG positive rates were also compared among different types of CH groups and no significant difference was found. Likewise, anti-HEV-IgG positive rate was compared among different types of cirrhosis groups, showing that the positive rates of both alcoholic cirrhosis (9.40%) and autoimmune cirrhosis (13.33%) were significantly higher than that of HBV-related cirrhosis (4.21%) (P < 0.05). CONCLUSION: We observed that the cirrhosis patients had a significantly higher anti-HEV-IgG positive rate comparing with the CH patients, especially in those with HBV related, alcohol-related, and autoimmune-related cirrhosis (after adjusted for age). Additionally, it seems that the conditions of alcoholic cirrhosis and autoimmune cirrhosis are more susceptible to HEV infection due to the significantly higher positive anti-HEV-IgG rate in these patients. PMID- 30307620 TI - Timing of puberty in boys and girls: A population-based study. AB - BACKGROUND: A secular trend towards earlier puberty has been observed in girls, while a similar trend has been more uncertain in boys. We estimated current ages at pubertal development in both boys and girls. METHODS: In this population-based cohort study, 14 759 of 22 439 invited boys and girls born from 2000 to 2003 in the Danish National Birth Cohort gave half-yearly self-reported information on puberty from the age of 11.5 years and throughout puberty. This late start of follow-up limits the estimation of age at onset of puberty but not later pubertal milestones. We estimated mean age at attaining the following pubertal milestones in years with 95% confidence intervals (CI): age at menarche, voice break, first ejaculation of semen and Tanner stages for pubic hair development and breast development or genital development. Further, the difference in mean age at menarche between mothers and daughters was estimated. RESULTS: In boys, voice break occurred at 13.1 (95% CI 13.0, 13.1) years, first ejaculation of semen occurred at 13.4 (95% CI 13.3, 13.4) years, and Tanner Genital Stage 5 occurred at 15.6 (95% CI 15.5, 15.6) years. In girls, age at menarche occurred at 13.0 (95% CI 13.0, 13.1) years and Tanner Breast Stage 5 occurred at 15.8 (95% CI 15.7, 15.9) years. Daughters had menarche 3.6 (95% CI 3.1, 4.2) months earlier than their mothers had. CONCLUSION: These data indicate that age at menarche has declined and to some extent support a decline in age at attaining other markers of pubertal development among boys. PMID- 30307621 TI - Recent structural advances in constrained helical peptides. AB - Given the ubiquity of the ?-helix in the proteome, there has been much research in developing mimics of ?-helices, and most of this study has been toward developing protein-protein interaction inhibitors. A common strategy for mimicking ?-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling." Beyond those strategies, there have been many recent advances in developing constrained peptides. The purpose of this review is to highlight recent advances in the development of new helix-stabilizing technologies, constraint diversification strategies, tether diversification strategies, and combination strategies that create new bicyclic helical peptides. PMID- 30307622 TI - Pharmacokinetics of ceftriaxone in Green sea turtles (Chelonia mydas) following intravenous and intramuscular administration at two dosages. AB - Green sea turtles are widely distributed in tropical and subtropical waters. Adult green sea turtles face many threats, primarily from humans, including injuries from boat propellers, being caught in fishing nets, pollution, poaching, and infectious diseases. To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for green sea turtles. Therefore, the present study aimed to describe the pharmacokinetic characteristics of ceftriaxone (CEF) in green sea turtles, Chelonia mydas, following single intravenous and intramuscular administrations at two dosages of 10 and 25 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 96 hr. The plasma concentrations of CEF were measured by liquid chromatography tandem mass spectrometry. The concentrations of CEF in the plasma were quantified up to 24 and 48 hr after i.v. and i.m. administrations at dosages of 10 and 25 mg/kg b.w., respectively. The Cmax values of CEF were 15.43 +/- 3.71 MUg/ml and 43.48 +/- 4.29 MUg/ml at dosages of 10 and 25 mg/kg, respectively. The AUClast values increased in a dose-dependent fashion. The half-life values were 2.89 +/- 0.41 hr and 5.96 +/- 0.26 hr at dosages of 10 and 25 mg/kg b.w, respectively. The absolute i.m. bioavailability was 67% and 108%, and the binding percentage of CEF to plasma protein was ranged from 20% to 29% with an average of 24.6%. Based on the pharmacokinetic data, susceptibility break-point and PK-PD index (T > MIC, 0.2 MUg/ml), i.m. administration of CEF at a dosage of 10 mg/kg b.w. might be appropriate for initiating treatment of susceptible bacterial infections in green sea turtles. PMID- 30307623 TI - Development of an attenuation correction method for direct x-ray fluorescence (XRF) imaging utilizing gold L-shell XRF photons. AB - PURPOSE: This work proposes a semiempirical correction method for attenuation of x-ray fluorescence (XRF) photons and/or an excitation beam during direct XRF imaging (i.e., mapping) of gold nanoparticle (GNP) distribution utilizing gold L shell XRF photons. METHODS: The current method was first devised by finding the two following relationships: (a) ratio of gold XRF peak intensity (Lalpha at ~9.7 keV and Lbeta at ~11.4 keV) vs pathlength of XRF photons; (b) XRF photon counts produced (Nxrf ) vs scattered photon counts produced (Nscat ). Monte Carlo simulations were performed using the Geant4 tool kit to characterize the aforementioned relationships for different tissue-like media. The applicability of the method was tested experimentally by acquiring 2D L-shell XRF images of custom-made phantoms using an experimental benchtop x-ray fluorescence computed tomography setup. RESULTS: The results show that the ratio of gold L-shell XRF peak intensities allowed an estimation of the pathlength of XRF photons, thus can be utilized to correct for attenuation of XRF photons after emission. The results also demonstrate that Nscat , through a proportionality CONCLUSIONS: The current results suggest that the developed attenuation correction method plays an essential role for the detection of GNPs on the order of parts-per-million, and also for the determination of GNP concentration/location within the imaging object made of tissue-like media, without any prior knowledge of the imaging object shape, under the conditions deemed relevant to biomedical applications of gold L-shell XRF-based imaging. PMID- 30307624 TI - Technical Note: Clustering-based motion compensation scheme for multishot diffusion tensor imaging. AB - PURPOSE: To extend image reconstruction using image-space sampling function (IRIS) to address large-scale motion in multishot diffusion-weighted imaging (DWI). METHODS: A clustered IRIS (CIRIS) algorithm that would extend IRIS was proposed to correct for large-scale motion. For DWI, CIRIS initially groups the shots into clusters without intracluster large-scale motion and reconstructs each cluster by using IRIS. Then, CIRIS registers these cluster images and combines the registered images by using a weighted average to correct for voxel mismatch caused by intercluster large-scale motion. For diffusion tensor imaging (DTI), CIRIS further reduces the effect of motion on diffusion directions by treating motion-induced direction changes as additional diffusion directions. CIRIS also introduces the detection and rejection of motion-corrupted data to avoid corresponding image degradation. The proposed method was evaluated by simulation and in vivo diffusion datasets. RESULTS: Experiments demonstrated that CIRIS can reduce motion-induced blurring and artifacts in DWI and provide more accurate DTI estimations in the presence of large-scale motion, compared with IRIS. CONCLUSION: The proposed method presents a novel approach to correct for large scale in-plane motion for multishot DWI and is expected to benefit the practical application of high-resolution diffusion imaging. PMID- 30307625 TI - Principal component analysis modeling of Head-and-Neck anatomy using daily Cone Beam-CT images. AB - PURPOSE: To model Head-and-Neck anatomy from daily Cone Beam-CT (CBCT) images over the course of fractionated radiotherapy using principal component analysis (PCA). METHODS AND MATERIALS: Eighteen oropharyngeal Head-and-Neck cancer patients, treated with volumetric modulated arc therapy (VMAT), were included in this retrospective study. Normal organs, including the parotid and submandibular glands, mandible, pharyngeal constrictor muscles (PCMs), and spinal cord were contoured using daily CBCT image datasets. PCA models for each organ were developed for individual patients (IP) and the entire patient cohort/population (PP). The first 10 principal components (PCs) were extracted for all models. Analysis included cumulative and individual PCs for each organ and patient, as well as the aggregate organ/patient population; comparisons were made using the root-mean-square (RMS) of the percentage predicted spatial displacement for each PC. RESULTS: Overall, spatial displacement prediction was achieved at the 95% confidence level (CL) for the first three to four PCs for all organs, based on IP models. For PP models, the first four PCs predicted spatial displacement at the 80%-89% CL. Differences in percentage predicted spatial displacement between mean IP models for each organ ranged from 2.8% +/- 1.8% (1st PC) to 0.6% +/- 0.4% (4th PC). Differences in percentage predicted spatial displacement between IP models vs the mean IP model for each organ based on the 1st PC were <12.9% +/- 6.9% for all organs. Differences in percentage predicted spatial displacement between IP and PP models based on all organs and patients for the 1st and 2nd PC were <11.7% +/- 2.2%. CONCLUSION: Tissue changes during fractionated radiotherapy observed on daily CBCT in patients with Head-and-Neck cancers, were modeled using PCA. In general, spatial displacement for organs-at-risk was predicted for the first 4 principal components at the 95% confidence levels (CL), for individual patient (IP) models, and at the 80%-89% CL for population-based patient (PP) models. The IP and PP models were most predictive of changes in glandular organs and pharyngeal constrictor muscles, respectively. PMID- 30307627 TI - Courses and Conferences. PMID- 30307626 TI - Epstein-Barr virus, but not human cytomegalovirus, is associated with a high grade human papillomavirus-associated cervical lesions among women in North Carolina. AB - STATEMENT OF THE PROBLEM: Human papillomavirus (HPV) infection is known to contribute to cervical carcinogenesis, yet other cofactors that may contribute to oncogenesis are poorly understood. Herein, we examine whether the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV), two oncomodulatory viruses, are associated with HPV-mediated cervical neoplastic progression. METHODS: Sixty patient cervical brush samples from a study of North Carolina women were obtained. HPV RNA positivity was determined by Aptima testing (Hologic Corporation, Marlborough, MA). The level of viral transcripts for EBV and CMV was quantified (reverse transcription polymerase chain reaction analysis), and the coinfection status with HPV was then compared with the patient's cervical cytology grade. RESULTS: Over one-third (38.3%) of the study population was CMV positive, whereas 43.3% was EBV positive. When sample data were stratified by the cytology grade, 36.5% (19/52) of normal patients, 75% (3/4) of low-grade squamous intraepithelial lesions (LSIL), and 100% (4/4) of patients with high-grade SIL (HSIL) were EBV positive. Conversely, 35.2% (18/52) of normal patients, 25% (1/4) of patients with LSIL, and 50% (2/4) of patients with HSIL were CMV positive. When examining only HPV positive-associated HSIL, 100% (4/4) were positive for both HPV and EBV detection. This suggests that co-viral detection with HPV and EBV is associated with more advanced HSIL cervical lesions, while CMV displayed no clear association with a higher grade of cervical cytology. CONCLUSIONS: Co viral detection with EBV may increase the oncogenicity and/or serve as a viral marker of progression to HPV-associated high-grade cervical dysplasia. PMID- 30307628 TI - Modifiable life style factors and risk for incident endometriosis. AB - BACKGROUND: Caffeine, alcohol, smoking and physical activity are known to alter sex steroid synthesis, which may affect hormone-dependent gynaecologic disease risk, such as endometriosis; however, few studies have assessed life style factors prior to endometriosis diagnosis. METHODS: Four hundred and seventy three women, ages 18-44 years, underwent laparoscopy or laparotomy, regardless of clinical indication, at 14 clinic sites, 2007-2009. Women with prior surgically confirmed endometriosis were excluded. Life style factors were assessed prior to surgery. Adjusted risk ratios (RR) of endometriosis by caffeine, alcohol, smoking (serum cotinine), and physical activity were estimated, adjusting for age, marital status, education, race/ethnicity, age at menarche, gravidity, BMI, study site, and other life style factors. RESULTS: There were no associations between women with endometriosis and alcohol consumption (RR 0.9, 95% CI 0.7, 1.3), caffeine consumption (RR 1.1, 95% CI 0.8, 1.5), or smoking (serum cotinine <10 vs >=10 ng/mL; RR 1.0, 95% CI 0.7, 1.6). Similar null findings were found between endometriosis and weekly occurrences of physical activity and total walking, moderate, and vigorous activity; a modest trend was found between total daily sitting time and increased endometriosis risk. CONCLUSIONS: This study, which is unique in its capture of life style exposures prior to incident endometriosis diagnosis, largely found no association between alcohol, caffeine, smoking, and physical activity and risk of endometriosis. PMID- 30307630 TI - Bariatric surgery and birth defects: A systematic literature review. AB - BACKGROUND: Bariatric procedures are on the rise. The risk of birth defects in pregnancies following such procedures may be increased (eg, due to nutrient deficiencies) or decreased (eg, due to decreased maternal body mass index, BMI). METHODS: We conducted a systematic literature review of the association between bariatric surgery and birth defects using Ovid MEDLINE and PubMed (1946-2017). Information was abstracted on study design, exposures, outcomes, covariates and estimates of association. RESULTS: Fifteen studies met our inclusion criteria: 14 evaluated the outcome of any birth defect, and one evaluated neural tube defects. Estimates of association between bariatric surgery and birth defects were available for nine studies and ranged from 0.6 to 1.9 (all 95% confidence intervals included 1.0). When studies were stratified by surgery type, there was no obvious pattern of association. When stratified by the approach used to account for BMI, positive associations were observed in studies that did not account for maternal prepregnancy BMI or used women with normal BMI as the reference group (range: 1.3-1.9). Estimates from studies that either matched or adjusted for prepregnancy BMI were closer to the null (range: 1.1-1.2) and studies that compared to morbidly obese women reported protective associations (range: 0.6-0.7). CONCLUSIONS: Studies of the association between bariatric surgery and birth defects vary with respect to the surgical procedures included, birth defects ascertainment methods and approaches used to account for maternal BMI. Consequently, it is not possible to draw a conclusion regarding the association between bariatric surgery and birth defects. Additional studies are warranted. PMID- 30307632 TI - Erratum: "Technical Note: Penumbral Width Trimming in Solid Lung Dose Profiles for 0.9 T and 1.5 T MRI-Linac Prototypes" [Med. Phys. 45(1), 479-487 (2018)]. PMID- 30307633 TI - Community science and reaching the promise of big data in health care. PMID- 30307631 TI - Seasonal changes in social cohesion among males in a same-sex primate group. AB - Male-male interactions in mixed-sex groups of social mammals are typically characterized by a mix of hostility and affiliation, as a result of inherent conflicts over mating opportunities, and the costs and benefits of social alliances, co-operative behaviors, and coalitionary defense. In species of nonhuman primates that form all-male groups, it is still unclear how the tradeoffs between the benefits of forming an all-male group and the cost of male male competition in seeking mating opportunities with females in bisexual groups influence social cohesion in different seasons. Here, we used social network analysis to quantify the impact of reproductive seasonality on social cohesion and clique size of bachelor males residing in an all-male unit (AMU) in wild black-and-white snub-nosed monkeys (Rhinopithecus bieti). These primates are strict seasonal breeders and live in a modular social system composed of a number of one-male units (OMUs) and an associated peripheral AMU. We found that the AMU social network had a significantly lower density, centralization, clustering coefficient, and smaller clique size during the mating season compared to the non mating period. However, aggression among AMU males during both mating and non mating periods was low. Our results suggest that network structure topology in male same-sex social units is modulated by seasonal changes. Bachelor males engage in two types of competition to gain reproductive success: first, which is analogous to contest competition, in which bachelor males act aggressively and challenge OMU leader males in an attempt to take over an OMU; and second, which is more analogous to scramble competition, in which bachelor males avoid aggressive interactions and instead engage in sneaky copulations with fertile females. Our work adds to an understanding of the maintenance of all-male groups in species that form a multilevel society. PMID- 30307629 TI - Treatable traits in the European U-BIOPRED adult asthma cohorts. PMID- 30307634 TI - Foraging strategies underlying bird egg predation by macaques: A study using artificial nests. AB - Bird egg predation is widespread in non-human primates. Although nest predation is often described as opportunistic, little is known about foraging strategies and nest detection in primates. Since it is the prevalent cause of nest failure in the tropics, birds select nest sites within specific microhabitats and use different nest types to increase nesting success. Identifying the nests targeted by the northern pigtailed macaques (Macaca leonina), an omnivorous cercopithecine species, and known nest predator, will shine light on nest foraging strategies in primates. The aim of this research was to reveal if nest predation is a selective or opportunistic feeding behavior. We studied, using artificial nests and camera traps, the influence of nest type (open-cup vs. cavity), microhabitat (i.e., understory density, canopy cover, canopy height, ground cover, and presence vs. absence of thorns and lianas), and nest height, on nest predation by a troop of northern pigtailed macaques in the Sakaerat Biosphere Reserve (Thailand), a degraded environment. In our study, macaque predation on artificial nests was high; out of the 200 nests that were set up, 112 were plundered by macaques. Although predation rates decreased with nest height, nest type, and microhabitat had no significant effect on predation by macaques. Nest detectability and accessibility did not affect predation rates. Macaques actively searched for nests in different microhabitats, suggesting that nest predation by this primate might be considered a selective feeding behavior in this degraded habitat. Consequently, nest predation by this primate might have important conservation implications on the population dynamics of forest-dwelling bird species. Behavior observation methods, such as instantaneous scan sampling, may underestimate nest predation by primates, a furtive and cryptic behavior. PMID- 30307635 TI - Orofacial pain assessment and management for patients with dementia: A meta ethnography. AB - Delivering dental treatment for patients with dementia can be challenging, and the complexity of treatment provision can increase as dementia progresses. Treatment at the later stages of dementia can be associated with ethical challenges and procedural risk meaning that a comprehensive patient assessment is crucial; the presence of orofacial pain is a key indication for active intervention from dental teams. To explore the process of oro-facial pain assessment and management, a comprehensive review of qualitative literature was undertaken by searching six electronic databases. No literature specific to orofacial pain assessment was identified. The inclusion criteria were widened to explore assessment and management of pain in general for patients with dementia. Meta-ethnography with reciprocal translation was used to identify key concepts and themes and synthesise information applicable to the dental setting. Three major themes arose as follows: challenges with pain assessment, challenges with pain management and logistics and education. Healthcare teams struggle with pain identification in patients with dementia though many signs were identified which may suggest a patient is experiencing pain. The long-term knowledge of individual patients held by family members and care teams can allow identification of deviation from patients' normal states; this knowledge can assist healthcare professionals in determining whether to provide specific treatments or interventions. Pain assessment tools were found to be problematic and are unlikely to be a practical solution to use for complex patients in dental settings. Education for dental and wider care teams on orofacial pain would be highly valuable; yet, this needs to be based on suitable evidence. PMID- 30307636 TI - Effectiveness of mobilisation of the upper cervical region and craniocervical flexor training on orofacial pain, mandibular function and headache in women with TMD. A randomised, controlled trial. AB - BACKGROUND: Studies exploring interventions targeting the cervical spine to improve symptoms in patients with temporomandibular disorders (TMD) are limited. OBJECTIVES: To determine whether mobilisation of the upper cervical region and craniocervical flexor training decreased orofacial pain, increased mandibular function and pressure pain thresholds (PPTs) of the masticatory muscles and decreased headache impact in women with TMD when compared to no intervention. METHODS: In a single-blind randomised controlled trial, 61 women with TMD were randomised into an intervention group (IG) and a control group (CG). The IG received upper cervical mobilisations and neck motor control and stabilisation exercises for 5 weeks. The CG received no treatment. Outcomes were collected by a blind rater at baseline and 5-week follow-up. Orofacial pain intensity was collected once a week. A mixed ANOVA and Cohen's d were used to determine differences within/between groups and effect sizes. RESULTS: Pain intensity showed significant time-by-group interaction (P < 0.05), with significant between group differences at four and five weeks (P < 0.05), with large effect sizes (d > 0.8). The decrease in orofacial pain over time was clinically relevant only in the IG. Change in headache impact was significantly different between groups, and the IG showed a clinically relevant decrease after the treatment. No effects were found for PPT or mandibular function. CONCLUSION: Women with TMD reported a significant decrease in orofacial pain and headache impact after 5 weeks of treatment aimed at the upper cervical spine compared to a CG. PMID- 30307637 TI - In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease. AB - BACKGROUND: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats. HYPOTHESIS/OBJECTIVES: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats. ANIMALS: Eleven LD and 11 age-matched control cats. METHODS: Case-control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half-life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD. RESULTS: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1-4] hours versus 1 [1-4] hours; P = .03). The calculated half-life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9-61.4] hours versus 7.4 [6.7-9.1] hours; P < .002). Mirtazapine half-life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (-0.0022 min-1 , CI: -0.0050 to 0.00054 min-1 ) and cats without LD (0.01849 min-1 , CI: 0.025 to -0.012 min-1 ; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with LD might require less frequent administration of mirtazapine than normal cats. PMID- 30307638 TI - Babesia conradae infection in coyote hunting dogs infected with multiple blood borne pathogens. AB - BACKGROUND: Babesia conradae is an intraerythrocytic piroplasm infecting dogs in the southern United States. Ticks have been suspected, but unproven, as vectors. We identified B. conradae and other blood-borne pathogens in 2 kennels of sighthounds with a history of coyote fighting. OBJECTIVES: To examine clinicopathologic abnormalities associated with B. conradae infection, risk factors for infection, and the prevalence of coinfections with other blood-borne pathogens. ANIMALS: Fifty-five Greyhounds and Greyhound mixes METHODS: Blood samples were collected from each dog for CBC, serum biochemistry panel, conventional and real-time PCR assays (Babesia spp., hemoplasmas, Ehrlichia canis, Bartonella spp., Anaplasma spp., and Rickettsia spp.), vector-borne pathogen ELISA, and immunofluorescent serology and culture for Bartonella spp and Francisella tularensis sero-agglutination test. Associations between B. conradae infection and coyote fighting, age and laboratory abnormalities were investigated. RESULTS: Twenty-nine dogs were PCR-positive for B. conradae. Of these, 16 were PCR-positive for other vector-borne organisms including Mycoplasma haemocanis, "Candidatus Mycoplasma haematoparvum," E. canis, and a Hepatozoon felis-like organism. Twelve of the 20 dogs tested for seroreactivity to Bartonella spp. antigens were positive, but none were seropositive for tularemia. Infection with B. conradae was associated with a history of aggressive interactions with coyotes; lower hematocrit, leukocyte count, MCHC, platelet count and serum albumin concentration; and higher MCV, MPV, and serum globulin concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Babesia conradae infection should be considered in dogs with anemia, leukopenia, thrombocytopenia, hypoalbuminemia and hyperglobulinemia. As with B. gibsoni, aggressive interactions with other canids may play a role in B. conradae transmission. PMID- 30307639 TI - Influence of lower complete denture use on masseter muscles and masticatory function: A longitudinal study. AB - BACKGROUND: Edentulism can reduce mastication, leading to changes in food pattern, with possible consequences to masticatory muscle thickness. OBJECTIVES: This study verified masticatory function and oral perception in subjects who did not use lower CDs, and whether the insertion of new upper and lower CDs would improve such variables. METHODS: Fifteen edentulous elderly who wore only the upper CD were selected and received new upper and lower CD. Volunteers were evaluated at baseline and after 1, 3 and 6 months of new prosthesis use. Masticatory performance (MP) was assessed by the sieving method (X50 values). Masseter thickness (MT) was evaluated by ultrasonography. Oral sensorial ability (OSA) was assessed by oral stereognosis test and maximum tongue pressure (MTP) was verified by pressure sensors. Data were submitted to repeated measures ANOVA and Tukey-Kramer posthoc tests (alpha = 0.05). Correlation between OSA and MTP was verified by Person's correlation. RESULTS: X50 and MTP decreased (P < 0.05) after 1 month and remained stable (P > 0.05) for next assessments. After 3 months, MT in rest position was increased (P < 0.05), while during maximum voluntary contraction 1 month was enough to increase MT (P < 0.05). There were no differences for OSA (P > 0.05) and no correlation between OSA and MTP. CONCLUSION: Masticatory performance and masseter thickness of elderly who did not use the lower dentures were improved after 2 months using new upper and lower CDs. However, new CDs in both dental arch decreased MTP. Brazilian Registry of Clinical Trials (ReBEC #RBR-37gdst). PMID- 30307640 TI - Alleviation of acute dental pain from localised apical periodontitis: A prospective randomised study comparing two emergency treatment procedures. AB - OBJECTIVE: To compare the outcomes of two emergency treatment procedures to alleviate pain from localised symptomatic apical periodontitis: complete chemo mechanical disinfection (CMD) of the root canal system, or removal of necrotic tissue from the pulp chamber (RNT), that is without instrumentation of the root canals. METHODS: Fifty-seven consecutive patients from the emergency clinic at Malmo University met the inclusion criteria: spontaneous pain and/or pain on percussion and palpation, non-bleeding pulp in the canal orifice, pain >=4 on a Numeric Rating Scale and >=18 years of age. The diagnosis was symptomatic apical periodontitis, in the absence of swelling and/or fever. Pre-operative pain levels and intake of analgesics were registered. The patients were randomised to one of the two treatment groups. Three to five days post-operatively, the patients were contacted by telephone and asked to grade their current pain level and report any post-operative intake of analgesics and antibiotics. RESULTS: Of the patients treated with CMD of the root canal system, 26/30 (87%) reported satisfactory pain relief, compared with 22/27 (81%) of those treated by RNT. There was no mean difference in pain relief between the two groups (P = 0.879). Post-operatively, 37% in each group reported using analgesics and one in each group reported using antibiotics. CONCLUSION: Three to five days after treatment, a majority (>80%) in both groups reported adequate pain relief, in some cases in combination with analgesics. Removal of necrotic and infected tissue from the pulp chamber might therefore be a cost-effective emergency treatment alternative to complete chemo mechanical disinfection. PMID- 30307641 TI - Long-term stability of intrabony defects treated with minimally invasive non surgical therapy. AB - AIM: The aim of this study was to assess the stability over time of periodontal intrabony defects treated with minimally invasive non-surgical therapy (MINST) and supportive periodontal therapy (SPT). METHODS: Clinical and radiographic analysis was carried out in 21 intrabony defects treated with MINST in 14 consecutive patients included in a prospective study and reassessed after 5 years of SPT. Baseline, 1- and 5-year radiographs were analysed, and bone levels were compared by multilevel linear regression adjusted by latent variable method. RESULTS: None of the 21 teeth with intrabony defects was lost at 5 years. Average probing pocket depth, clinical attachment level and radiographic intrabony vertical defect depth reductions were 3.6, 3.5 and 2.6 mm, respectively, 5 years after treatment (p < 0.001 compared with baseline). Further non-statistically significant reductions were seen in clinical and radiographic measures between 1 and 5 years. Deeper initial defects and narrower angles were predictive of a bigger reduction in defect depth (p < 0.001 and p = 0.017, respectively). CONCLUSIONS: Clinical and radiographic improvements in intrabony defects after MINST seen at 1 year are stable up to 5 years, bringing evidence to support its long-term efficacy for the treatment of intrabony defects in non-smokers. PMID- 30307642 TI - MiR-182 enhances radioresistance in non-small cell lung cancer cells by regulating FOXO3. AB - Upregulated in lung cancer, miRNA-182 was found to be related to cancer proliferation and chemoresistance. However, there is no report on the role of miR 182 in radioresistance, which is a main obstacle of radiotherapy. In this study, we aimed to depict the effect of miR-182 inhibition on cellular sensitivity to ionizing radiation. Our data confirmed that miR-182 was upregulated in lung cancers and tissues and that miR-182 was responsive to irradiation. We also showed that miR-182 knockdown suppressed cell proliferation and increased cell apoptosis after irradiation. DNA damage remains unrepaired in miR-182 knockdown cells, which results in cell cycle arrest. Finally, we found that FOXO3 is a direct target of miR-182 and that overexpression of FOXO3 enhances radiation resistance in miR-182 knockdown cells. In conclusion, our data suggested that miR 182 might account for radioresistance in lung cancer and that miR-182-FOXO3 provides a novel radiosensitizing target. This article is protected by copyright. All rights reserved. PMID- 30307643 TI - Evaluation of cell culture-grown Bartonella antigens in immunofluorescent antibody assays for the serological diagnosis of bartonellosis in dogs. AB - BACKGROUND: Because of poor sensitivity and questionable specificity of immunofluorescent antibody assays (IFAs), serological diagnosis of Bartonella species infections in dogs remains challenging. Despite limitations, IFA testing is the historical "gold standard" for Bartonella serodiagnosis in animals and humans. Because most diagnostic laboratories test against only 1 or 2 Bartonella spp., testing against a broader panel of Bartonella antigens may enhance diagnostic sensitivity and specificity. OBJECTIVE: To evaluate the sensitivity and specificity of Bartonella IFA using 8 cell culture-grown Bartonella spp. isolates. ANIMALS: Archived serum samples from 34 Bartonella spp. naturally exposed, polymerase chain reaction (PCR)-positive dogs and from 26 PCR-negative and IFA-negative dogs. METHODS: Bartonella IFA sensitivity and specificity were assessed using cell culture-grown whole cell antigens derived from 3 Bartonella henselae (Bh) strains (Bh Houston 1, Bh San Antonio Type 2, Bh California 1), 3 Bartonella vinsonii subsp. berkhoffii genotypes (Bvb I, II, and III), Bartonella koehlerae (Bk), and Bartonella quintana (Bq). RESULTS: Only 62% of 34 Bartonella spp. PCR-positive dogs were seroreactive to any of the 8 Bartonella IFA antigens, indicating low IFA sensitivity. PCR-positive dogs were most often IFA seroreactive to Bq (n = 15), to Bvb II (n = 13), or to both (n = 9) antigens. Of the 26 previously IFA-negative/PCR-negative dogs, 4 (15%) were seroreactive using the expanded antigen panel. CONCLUSION AND CLINICAL IMPORTANCE: Despite IFA testing of dogs against 8 different Bartonella isolates, IFA sensitivity remained poor, and specificity was only 85%. Development of a reliable serological assay is needed to facilitate the diagnosis of Bartonella infection in dogs. PMID- 30307644 TI - Babesia gibsoni cytochrome b mutations in canine blood samples submitted to a US veterinary diagnostic laboratory. AB - BACKGROUND: Babesiosis caused by Babesia gibsoni is recognized throughout the world and can be difficult to treat. Resistance to atovaquone is associated with mutations in the B. gibsoni mitochondrial genome, specifically the M128 position of cytochrome b (cytb). The prevalence of cytb mutations in North America has not been reported. HYPOTHESIS/OBJECTIVES: The objective of our study was to describe the prevalence of cytb M128 mutations in B. gibsoni in canine blood samples submitted to a US veterinary diagnostic laboratory. A secondary objective was to determine whether or not some dogs had wild-type cytb in our initial samples then had M128 mutations detected in follow-up samples. ANIMALS: One-Hundred seventy four dogs that tested positive for the presence of B. gibsoni between 2012 and 2017. METHODS: Case series of consecutive samples submitted to a veterinary diagnostic laboratory. Partial B. gibsoni cytb genes were amplified by polymerase chain reaction and screened for the presence of mutations at the M128 position. RESULTS: The overall prevalence of M128 mutants was 3.5% (6/173 dogs) in the initial samples. The incidence of new cytb mutants in dogs that tested positive for B. gibsoni, which then had follow-up testing, was 12.1% (5/41). Conclusions and Clinic Importance: Our study reaffirms that B. gibsoni infection is widespread and most commonly detected in American Staffordshire Terrier/American Pit Bull Terrier dogs (128/174, 74% of the infected dogs in our study). The prevalence of cytb mutations does not warrant pretreatment genotyping. PMID- 30307646 TI - Medial thalamus in the territory of oculomotor basal ganglia represents stable object value. AB - Many visual objects are attached with values which were created by our long rewarding history. Such stable object values attract gaze. We previously found that the output pathway of basal ganglia from caudal-dorsal-lateral portion of substantia nigra pars reticulata (cdlSNr) to superior colliculus (SC) carries robust stable value signal to execute the automatic choice of valuable objects. An important question here is whether stable value signal in basal ganglia can influence on other inner processing such as perception, attention, emotion, or arousal than motor execution. The key brain circuit is another output path of basal ganglia: the pathway from SNr to temporal and frontal lobes through thalamus. To examine the existence of stable value signal in this pathway, we explored thalamus in a wide range. We found that many neurons in the medial thalamus represented stable value. Histological examination showed that the recorded sites of those neurons included ventral anterior nucleus, pars magnocellularis (VAmc) which is the main target of nigrothalamic projection. Consistent with the SNr GABArgic projection, the latency of value signal in the medial thalamus was later than cdlSNr, and the sign of value coding in the medial thalamus was opposite to cdlSNr. As is the case with cdlSNr neurons, the medial thalamus neurons showed no sensitivity to frequently updated value (flexible value). These results suggest that the pathway from cdlSNr to the medial thalamus influences on various aspects of cognitive processing by propagating stable value signal to the wide cortical area. PMID- 30307647 TI - National surveys of UK and Italian neonatal units highlighted significant differences in the use of non-invasive respiratory support. AB - AIM: This study compared how non-invasive respiratory support (NRS) was provided in neonatal units in Italy and the UK. METHODS: An NRS questionnaire was sent to tertiary neonatal centres, identified by national societies, from November 2015 to May 2016. RESULTS: Responses were received from 49/57 (86%) UK units and 103/115 (90%) Italian units. NRS was started in the delivery room by 61% of UK units and 85% of Italian units. In neonatal intensive care units, 33% of UK units used nasal high-flow therapy (HFT) as primary support, compared to 3% in Italy. Nasal continuous positive airway pressure (CPAP) was used in 57% of UK units and 90% of Italian units. The commonest starting flow rate on nasal HFT for term and preterm infants was 6 L/min in the UK, while Italian units mainly used this flow for term infants. In the UK, 67% of units decreased nasal HFT by 1 L/min per day. In Italy, infants on nasal CPAP were weaned by 1 cm H2 O per day in 39% of units. CONCLUSION: The way that NRS was managed for very preterm infants differed between the UK and Italy, reflecting a lack of evidence on optimal NRS and the use of local protocols. PMID- 30307645 TI - Investigation of sensory thresholds in Cavalier King Charles Spaniels with and without Chiari-like malformations and syringomyelia. AB - BACKGROUND: Cavalier King Charles Spaniels (CKCS) suffer pain associated with Chiari-like malformation and syringomyelia (CMSM). People suffer from a similar condition and describe numerous sensory abnormalities. Sensory changes have not been quantified in affected CKCS. OBJECTIVES: To use quantitative sensory testing (QST) to quantify thermal and mechanical thresholds in CKCS and to compare QST in dogs with and without syringomyelia (SM). ANIMALS: Forty-four CKCS. METHODS: Prospective study. Dogs underwent neurological examinations and craniocervical magnetic resonance imaging (MRI). Thermal testing was performed over the humerus and thorax (n = 32); mechanical testing was performed on the paw and neck (n = 44). Latencies, thresholds, and response rates were compared with presence and severity of SM on MRI, presence of pain reported by the owner and pain identified on examination. RESULTS: Thirty dogs had SM, 30 were painful on examination, 29 were owner-reported symptomatic. Thermal and mechanical variables were not significantly different based on presence or severity of SM. Dogs with pain on examination had decreased mechanical thresholds on the paw (0.38 kg, SD = 0.18) and neck (2.05 kg, SD = 0.74) compared to thresholds of dogs without pain on examination on the paw (0.60 kg, SD = 0.30) and neck (2.72 kg, SD = 0.57; P = .021). CONCLUSIONS AND CLINICAL IMPORTANCE: Mechanical and thermal sensitivity does not appear to be related to the presence of SM, but mechanical sensitivity appears to be related to the presence of pain and clinical signs. Mechanical testing may be useful for assessing sensory abnormalities during clinical trials. PMID- 30307648 TI - Prevalence of naturally occurring non-AB blood type incompatibilities in cats and influence of crossmatch on transfusion outcomes. AB - BACKGROUND: Recognition of the feline red blood cell (RBC) antigen Mik and the presence of naturally occurring anti-Mik antibodies resulting in acute hemolytic transfusion reactions prompted the recommendation to perform a crossmatch before a cat's first RBC transfusion, but this guideline has not yet become a standard practice. OBJECTIVE: To determine the prevalence of naturally occurring non-AB alloantibodies detectable by tube crossmatch, and to compare transfusion outcomes in cats with and without a crossmatch performed. ANIMALS: Three hundred cats that received an RBC transfusion, with or without a major crossmatch performed. METHODS: Retrospective study. RESULTS: Major crossmatch incompatibilities were documented in 23 of 154 transfusion-naive cats (14.9%) and in 15 of 55 previously transfused cats (27%; P = 0.042). Type-specific packed RBCs (pRBCs) were administered to 167 and 82 cats with and without a crossmatch, respectively. Median volume of pRBCs administered during the first transfusion was 5.3 mL/kg (range, 2.4-18 mL/kg). Median change in PCV scaled to dose of pRBCs was +0.8%/mL/kg; administration of crossmatch-compatible pRBCs was not associated with a greater increase in PCV. Febrile transfusion reactions occurred more often in cats that received non-crossmatched (10.1%) compared to crossmatched (2.5%) pRBCs (P = 0.022). Seventy-six percent of cats that received pRBC transfusions survived to hospital discharge. A crossmatch was not associated with improved survival to discharge or at 30 or 60 days posttransfusion. CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of naturally occurring non-AB incompatibilities is sufficiently high to justify the recommendation to perform a crossmatch before all (including the first) RBC transfusions in cats. PMID- 30307649 TI - Variables of initial examination and clinical management associated with survival in small ruminants with obstructive urolithiasis. AB - BACKGROUND: Obstructive urolithiasis is a common disease associated with a guarded prognosis in small ruminants. HYPOTHESIS/OBJECTIVE: The results of physical examination, laboratory analyses, and clinical management of male small ruminants presented to 2 referral clinics were investigated to identify variables significantly associated with disease outcome, so as to provide better recommendations to animal owners regarding the management of these patients. ANIMALS: Two-hundred ten small ruminants (130 sheep and 80 goats) with confirmed diagnosis of obstructive urolithiasis. METHODS: Clinical findings (including diagnostic imaging) and laboratory results of the 210 animals were reviewed, and relevant information regarding clinical and laboratory variables recorded upon admission and clinical management was retrieved. The association of the different variables with nonsurvival was investigated by univariable and multivariable logistic regression models. RESULTS: Only 39% of all patients considered for treatment and 52% of those undergoing tube cystostomy survived to be released from the clinic. Nonsurvival was strongly associated with a very poor clinical condition upon presentation, obesity, castration, and evidence of uroperitoneum. Among blood variables, abnormal PCV, severely increased serum creatinine concentrations, and increased activity of the creatine kinase were associated with increased risk of nonsurvival. Presence of signs of colic or macroscopic appearance of urine was not significantly associated with outcome. CONCLUSIONS AND CLINICAL IMPORTANCE: The prognosis of obstructive urolithiasis was guarded with survival rates of 39% (overall) to 52% (after tube cystostomy). Intact young males with normal body condition presented early in the course of disease had the best chances of survival. PMID- 30307650 TI - Disturbance of approach-avoidance behaviors in non-human primates by stimulation of the limbic territories of basal ganglia and anterior insula. AB - The basal ganglia (BG) are involved in motivation and goal-directed behavior. Recent studies suggest that limbic territories of BG not only support reward seeking (appetitive approach) but also the encoding of aversive conditioned stimuli (CS) and the production of aversive-related behaviors (avoidance or escape). This study aimed to identify inside two BG nuclei, the striatum and pallidum, the territories involved in aversive behaviors and to compare the effects of stimulating these territories to those resulting from stimulation of the anterior Insula (aIns), a region that is well-known to be involved in aversive encoding and associated behaviors. Two monkeys performed an approach/avoidance task in which they had to choose a behavior (approach or avoidance) in an appetitive (reward) or aversive (air-puff) context. During this task, either one (single-cue) or two (dual-cue) CS provided essential information about which context-adapted behavior should be selected. Microstimulation was applied during the CS presentation. Stimulation generally reduced approaches in the appetitive contexts and increased escape behaviors (premature responses) and/or passive avoidance (noninitiated action) in aversive context. These effects were more pronounced in ventral parts of all examined structures, with significant differences observed between stimulated structures. Thresholds to induce effects were lowest in the pallidum. Striatal stimulation led to the largest diversity of effects, with a subregion even leading to enhanced active avoidance. Finally, aIns stimulations produced stronger effects in the dual-cue context. These results provide causal evidence that limbic territories of BG, like aIns, play crucial roles in the selection of context-motivated behaviors. PMID- 30307651 TI - International standardisation of the test of masticating and swallowing solids in children. AB - The Test of Masticating and Swallowing Solids (TOMASS) is a validated assessment tool measuring the efficiency of solid bolus intake by four quantitative parameters: discrete bites, masticatory cycles, swallows and time to ingest a single cracker. A normative database for adults (20-80+ years) has previously been established. The objective of this study was to investigate the applicability and reliability of the TOMASS in children and adolescents (TOMASS C) and to establish the normative database for this younger population. We collected data from 638 participants (male: 311, female: 327) in five age groups (4-18 years) with five different but very similar test crackers in four countries. Significant effects of bolus type (cracker), age group and gender on the TOMASS parameters were identified, requiring stratification of the TOMASS-C database by these variables. Intra-rater reliability was excellent (ICC > 0.94) for all parameters; inter-rater reliability was moderate for "number of swallows" (ICC = 0.54), good for "bites" (ICC = 0.78) and "time" (ICC = 0.82), and excellent for "masticatory cycles" (ICC = 0.96). The "Test of Masticating and Swallowing Solids in Children (TOMASS-C)" was identified to be a reliable diagnostic tool for the comprehensive measurement of discrete oral stage components of solid bolus ingestion, standardised by a large normative database that covers age groups from preschoolers to young adults. While differences between gender groups were less pronounced than in the adult population, previous results relating to changes in masticatory and swallowing as a function of age are confirmed by our data. PMID- 30307652 TI - The pharmacokinetics of gabapentin in cats. AB - BACKGROUND: Gabapentin is the most commonly prescribed medication for the treatment of chronic musculoskeletal pain in cats. Despite this common and chronic usage, clinically relevant pharmacokinetic data is lacking. OBJECTIVES: To evaluate the pharmacokinetics of clinically relevant dosing regimens of gabapentin in cats. ANIMALS: Eight research-purpose mixed-breed cats. METHODS: Cats were enrolled in a serial order, non-randomized pharmacokinetic study. Gabapentin was administered as an IV bolus (5 mg/kg), orally (10 mg/kg) as a single dose or twice daily for 2 weeks, or as a transdermal gel (10 mg/kg) in serial order. Serial blood samples were collected up to 48 hours. Plasma concentrations were determined using Ultra Performance Liquid Chromatography-Mass Spectrometry. Compartmental analysis was used to generate gabapentin time concentration models. RESULTS: After IV administration CL (median (range)) and terminal half-life were 160.67 mL/kg*hr (119.63-199.11) and 3.78 hours (3.12 4.47), respectively. The oral terminal half-life was 3.63 hours (2.96-4.77), and 3.72 hours (3.12-4.51) for single and repeated dosing. TMAX and CMAX , as predicted by the model were 1.05 hours (0.74-2.11), and 12.42 MUg/mL (8.31-18.35) after single oral dosing, and 0.77 hours (0.58-1.64), and 14.78 MUg/mL (9.70 18.41) after repeated oral dosing. Bioavailability after a single oral dose was 94.77% (82.46-122.83). IMPORTANCE: Repeated oral dosing of gabapentin did not alter the drug's pharmacokinetics, making dose adjustments unnecessary with long term treatment. As prepared, the transdermal route is an inappropriate choice for drug administration. These relevant data are important for future studies evaluating potential efficacy of the medication for treating chronic pain states in cats. PMID- 30307653 TI - Intestinal polycyclic aromatic hydrocarbon-DNA adducts in a population of beluga whales with high levels of gastrointestinal cancers. AB - Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926-1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19-year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH-DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH-DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin-embedded intestine from 51 SLE beluga (0-63 years), 4 Cook Inlet (CI) Alaska beluga (0-26 years), and 20 beluga (0-46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light-to-dark pink color indicating the presence of PAH-DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H-scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH-DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH-DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. PMID- 30307654 TI - Two mixed breed dogs with sensory neuropathy are homozygous for an inversion disrupting FAM134B previously identified in Border Collies. AB - Two unrelated 8-month-old male mixed breed dogs were presented for evaluation of progressive ataxia, knuckling, and lack of pain perception in the distal limbs. Because of the similarity in age of onset, progression, and clinical findings with previously described sensory neuropathy in Border Collies, the affected dogs were screened for an FAM134B mutation and were determined to be homozygous for the mutation. Despite few phenotypic similarities with other breeds, genetic testing for specific diseases should be considered in mixed breed dogs with compatible clinical signs, especially if ancestry is unknown. PMID- 30307655 TI - Probing the Physical Origin of Anisotropic Thermal Transport in Black Phosphorus Nanoribbons. AB - Black phosphorus (BP) has emerged as a promising candidate for next-generation electronics and optoelectronics among the 2D family materials due to its extraordinary electrical/optical/optoelectronic properties. Interestingly, BP shows strong anisotropic transport behavior because of its puckered honeycomb structure. Previous studies have demonstrated the thermal transport anisotropy of BP and theoretically attribute this to the anisotropy in both the phonon dispersion relation and the phonon relaxation time. However, the exact origin of such strong anisotropy lacks clarity and has yet to be proven experimentally. Here, the thermal transport anisotropy of BP nanoribbons is probed by an electron beam technique. Direct evidence is provided that the origin of this anisotropy is dominated by the anisotropic phonon group velocity, verified by Young's modulus measurements along different directions. It turns out that the ratio of the thermal conductivity between zigzag (ZZ) and armchair (AC) ribbons is almost same as that of the corresponding Young modulus values. The results from first principles calculation are consistent with this experimental observation, where the anisotropic phonon group velocity between ZZ and AC is shown. These results provide fundamental insight into the anisotropic thermal transport in low symmetry crystals. PMID- 30307657 TI - Serum cytokine measurements and biological therapy of psoriasis - Prospects for personalized treatment? AB - Psoriasis is an immune-mediated disease where the IL-23/Th17 axis as well as TNF comprise main targets of biological therapy. Immune profiling has so far not been embraced as a clinical tool. We aimed to investigate relationships between individual serum cytokine levels in 40 psoriasis patients before and after receiving biological therapy and Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI). Serum concentration of 25 cytokines was determined by Luminex technology. Mean PASI and DLQI decreased by 71% and 65%, respectively. Increase of IL-2 positively correlated with improvement of PASI and DLQI. Moreover, increase of IL-5, IL-10, IL-12, IL-22 and GM-CSF correlated with treatment effect. Notably, logistic regression revealed four times higher risk of having severe psoriasis when IL-17A increased by 1 pg/mL (OR: 4.06, P < 0.05). Selected serum cytokines might constitute useful biomarkers for monitoring disease activity and optimizing therapeutic strategies in psoriasis patients. PMID- 30307656 TI - Retrospective evaluation of toceranib phosphate (Palladia(r)) use in the treatment of gastrointestinal stromal tumors of dogs. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are uncommon intestinal neoplasms in the dog. Literature regarding adjunctive therapy for GISTs in dogs is sparse. High-risk GISTs in humans respond to tyrosine kinase inhibition in the adjuvant setting. OBJECTIVES: To review cases of toceranib phosphate use in dogs with GISTs and provide initial assessment of possible biological activity. A secondary aim was to evaluate patient and tumor characteristics for possible prognostic value. ANIMALS: Twenty-seven dogs with confirmed GISTs based on histopathology and immunohistochemistry treated with toceranib. METHODS: Retrospective study in which cases of toceranib use in dogs with GIST were solicited using the American College of Veterinary Internal Medicine Oncology and Small Animal Internal Medicine listservs. RESULTS: Five of 7 dogs with gross disease experienced clinical benefit (71%; 3 complete responses, 1 partial response, 1 stable disease). These included 2 dogs with durable responses after toceranib discontinuation. Median progression-free interval (PFI) in dogs with gross disease was 110 weeks (range, 36-155 weeks). Median PFI in dogs with microscopic disease was 67 weeks (range, 9-257 weeks). Metastasis at diagnosis (P = 0.04) and high mitotic index (P < 0.001) were associated with shorter PFI in toceranib-treated dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Biological activity of toceranib is evident in dogs with gross disease. Metastasis of GIST at diagnosis, as well as high tumor mitotic index, was associated with shorter PFI in toceranib-treated dogs. Larger studies are needed to define postsurgical risk and refine the use of toceranib in dogs with gross and microscopic GIST. PMID- 30307658 TI - Geospatial variation in co-occurrence networks of nitrifying microbial guilds. AB - Microbial communities transform nitrogen (N) compounds, thereby regulating the availability of N in soil. The N cycle is defined by interacting microbial functional groups, as inorganic N-products formed in one process are the substrate in one or several other processes. The nitrification pathway is often a two-step process in which bacterial or archaeal communities oxidize ammonia to nitrite, and bacterial communities further oxidize nitrite to nitrate. Little is known about the significance of interactions between ammonia-oxidizing bacteria (AOB) and archaea (AOA) and nitrite-oxidizing bacterial communities (NOB) in determining the spatial variation of overall nitrifier community structure. We hypothesize that nonrandom associations exist between different AO and NOB lineages that, along with edaphic factors, shape field-scale spatial patterns of nitrifying communities. To address this, we sequenced and quantified the abundance of AOA, AOB, and Nitrospira and Nitrobacter NOB communities across a 44 hectare site with agricultural fields. The abundance of Nitrobacter communities was significantly associated only with AOB abundance, while that of Nitrospira was correlated to AOA. Network analysis and geostatistical modelling revealed distinct modules of co-occurring AO and NOB groups occupying disparate areas, with each module dominated by different lineages and associated with different edaphic factors. Local communities were characterized by a high proportion of module-connecting versus module-hub nodes, indicating that nitrifier assemblages in these soils are shaped by fluctuating conditions. Overall, our results demonstrate the utility of network analysis in accounting for potential biotic interactions that define the niche space of nitrifying communities at scales compatible to soil management. PMID- 30307659 TI - Demographic risk factors for lymphoma in Australian dogs: 6201 cases. AB - BACKGROUND: Lymphoma is common in the dog. Studies of population risk factors primarily have been derived from referral institution or insurance data. OBJECTIVE: To identify and quantify the host risk factors for lymphoma in a broad population of Australian dogs. ANIMALS: Data on 6201 client owned dogs were retrieved from a commercial veterinary laboratory, a general practice group and 2 referral hospitals. METHODS: Data collected included breed, sex, and neuter status. A reference population of 640 105 dogs was generated from the referral hospitals and from council registration data. The risk of lymphoma by sex and neuter status was calculated as odds ratios (OR). RESULTS: The study identified 30 breeds at increased risk of lymphoma, 15 that have not been reported previously, and 26 breeds at decreased risk, 18 that have not been reported previously. Males were over represented compared to females with an OR of 1.1 (95% CI, 1.1-1.2; P < .001). Neutered animals were at higher risk compared to intact animals with an OR of 3.2 (95% CI, 2.9-3.5) which was found in both males (OR, 2.8; 95% CI; 2.5-3.2) and females (OR, 4.4; 95% CI, 3.5-5.1). CONCLUSIONS AND CLINICAL IMPORTANCE: Breed, sex, and neuter status alter the risk of lymphoma in dogs. These 3 factors must be considered when evaluating lymphoma risk as potential markers of underlying differences in disease etiology. Comparison of breeds at increased and decreased risk could be advantageous when evaluating specific etiological factors. PMID- 30307660 TI - Distributed representation of vocalization pitch in marmoset primary auditory cortex. AB - The pitch of vocalizations is a key communication feature aiding recognition of individuals and separating sound sources in complex acoustic environments. The neural representation of the pitch of periodic sounds is well defined. However, many natural sounds, like complex vocalizations, contain rich, aperiodic or not strictly periodic frequency content and/or include high-frequency components, but still evoke a strong sense of pitch. Indeed, such sounds are the rule, not the exception but the cortical mechanisms for encoding pitch of such sounds are unknown. We investigated how neurons in the high-frequency representation of primary auditory cortex (A1) of marmosets encoded changes in pitch of four natural vocalizations, two centred around a dominant frequency similar to the neuron's best sensitivity and two around a much lower dominant frequency. Pitch was varied over a fine range that can be used by marmosets to differentiate individuals. The responses of most high-frequency A1 neurons were sensitive to pitch changes in all four vocalizations, with a smaller proportion of the neurons showing pitch-insensitive responses. Classically defined excitatory drive, from the neuron's monaural frequency response area, predicted responses to changes in vocalization pitch in <30% of neurons suggesting most pitch tuning observed is not simple frequency-level response. Moreover, 39% of A1 neurons showed call invariant tuning of pitch. These results suggest that distributed activity across A1 can represent the pitch of natural sounds over a fine, functionally relevant range, and exhibits pitch tuning for vocalizations within and outside the classical neural tuning area. PMID- 30307661 TI - Factors associated with complications in total laryngectomy without microvascular reconstruction. AB - BACKGROUND: There is little population-level data evaluating risk factors for postoperative complications after total laryngectomy. METHODS: We conducted a retrospective review of the American College of Surgeons National Quality Improvement Program identifying patients who underwent total laryngectomy as a primary procedure from 2005 to 2014. Multivariate analysis was performed to identify variables that were independently associated with overall and major complications. RESULTS: Eight hundred seventy-one cases met inclusion criteria. Three hundred twenty-eight patients (37.7%) had complications, with operative time (hours; P < .0001), class III (P < .001) wound status, and patient age (decade; P = .003) associated with overall complications. Two hundred one patients had major complications that were associated with steroid use (P = .01) and class III (P = .0083) wound classification. Preoperative hematocrit was correlated with a reduction of all and major complications on multivariate analysis (P < .0001 and P = .036). CONCLUSION: Identifying and optimizing risk factors may improve outcomes in total laryngectomy. PMID- 30307662 TI - Biodiversity-function relationships in methanogenic communities. AB - Methanogenic communities play a crucial role in carbon cycling and biotechnology (anaerobic digestion), but our understanding of how their diversity, or composition in general, determines the rate of methane production is very limited. Studies to date have been correlational because of the difficulty in cultivating their constituent species in pure culture. Here, we investigate the causal link between methanogenesis and diversity in laboratory anaerobic digesters by experimentally manipulating the diversity of cultures by dilution and subsequent equilibration of biomass. This process necessarily leads to the loss of the rarer species from communities. We find a positive relationship between methane production and the number of taxa, with little evidence of functional saturation, suggesting that rare species play an important role in methane-producing communities. No correlations were found between the initial composition and methane production across natural communities, but a positive relationship between species richness and methane production emerged following ecological selection imposed by the laboratory conditions. Our data suggest methanogenic communities show little functional redundancy, and hence, any loss of diversity-both natural and resulting from changes in propagation conditions during anaerobic digestion-is likely to reduce methane production. PMID- 30307663 TI - Propofol pharmacokinetic and pharmacodynamic profile and its electroencephalographic interaction with remifentanil in children. AB - BACKGROUND: Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect-site target-controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined. AIMS: We designed this study to derive an integrated propofol pharmacokinetic-pharmacodynamic model in children and to describe the pharmacodynamic interaction between propofol and remifentanil on the electroencephalographic bispectral index effect. METHODS: Thirty children (mean age: 5.45 years, range 1.3-11.9; mean weight: 23.5 kg, range 8.5-61) scheduled for elective surgery with general anesthesia were studied. After sevoflurane induction, maintenance of anesthesia was based on propofol and remifentanil. Blood samples to measure propofol concentration were collected during anesthesia maintenance and up to 6 hours in the postoperative period. Bispectral index data were continuously recorded throughout the study. A pharmacokinetic pharmacodynamic model was developed using population modeling. The Greco model was used to examine the pharmacokinetic-pharmacodynamic interaction between propofol and remifentanil for BIS response RESULTS: Propofol pharmacokinetic data from a previous study in 53 children were pooled with current data and simultaneously analyzed. Propofol pharmacokinetics were adequately described by a three-compartment distribution model with first-order elimination. Theory-based allometric relationships based on TBW improved the model fit. The Greco model supported an additive interaction between propofol and remifentanil. Remifentanil showed only a minor effect in BIS response. CONCLUSION: We have developed an integrated propofol pharmacokinetic-pharmacodynamic model that can describe the pharmacodynamic interaction between propofol and remifentanil for BIS response. An additive interaction was supported by our modeling analysis. PMID- 30307664 TI - Illness perceptions as predictors of psychological distress among head and neck cancer survivors: a longitudinal study. AB - BACKGROUND: Leventhal's commonsense model implies illness perceptions influence illness outcomes. This study examined illness perceptions among head and neck cancer survivors, and whether these predicted subsequent psychological distress. METHODS: A total of 124 survivors of head and neck cancer (87% nasopharyngeal carcinoma; NPC) completed measures of psychological distress (Hospital Anxiety and Depression Scale; HADS), illness perceptions (Brief Illness Perception Questionnaire; B-IPQ), dispositional optimism (revised Chinese version of the Life Orientation Test; C-LOT-R), and clinical and demographic data approximately12.9 months after diagnosis (T1). Six months later (T2) psychological distress (HADS) was again measured. Adjusted multivariate analyses tested whether illness perceptions predicted T2 HADS scores. RESULTS: Illness perception dimensions were significantly intercorrelated (0.01-0.68), explaining 8.0% of anxiety and 4.8% of depression symptom variability at T2. After adjustment for T1 distress, illness identity (beta = 0.270, P < .01) and sex identification as a woman (beta = 0.275, P < .01) predicted T2 anxiety symptoms while illness identity (beta = 0.195, P < .05), unemployment (beta = 0.195, P < .05), and pessimism (beta = -0.227, P < .01) predicted T2 depression symptoms. CONCLUSION: Perceived illness identity predicted psychological distress, accounting for modest levels of distress variance. Unresolved symptoms may exacerbate distress. PMID- 30307665 TI - Prognostic role of extracapsular spread in planned neck dissection after chemoradiotherapy. AB - BACKGROUND: The purpose of this study is to evaluate the prognostic significance of nodes with extracapsular spread (ECS) in patients treated with a planned neck dissection after chemoradiotherapy. METHODS: We carried out a retrospective study of 109 cN+ patients who achieved a complete response in the primary location after chemoradiotherapy and treated with a planned neck dissection. RESULTS: The 5-year disease-specific survival for patients without residual metastatic nodes in the neck dissection (pN0, n = 69) was 75.7% (95% CI: 64.4%-87.0%). For patients with metastatic nodes without ECS (pN+/ECS-negative, n = 17), the corresponding figure was 74.0% (95% CI: 48.2%-99.8%), and for patients with metastatic neck nodes with ECS (pN+/ECS-positive, n = 23) it was 8.7% (95% CI: 0.0%-24.3%) (P = .0001). CONCLUSION: The presence of ECS in the pathologic study of the planned neck dissections carried out after chemoradiotherapy in patients with human papillomavirus-negative (HPV-negative) head and neck squamous cell carcinoma (SCC) allows identification of a group of patients with a high risk of failure. PMID- 30307666 TI - Structural modeling and mRNA expression of epididymal beta-defensins in GnRH immunized boars: A model for secondary hypogonadism in man. AB - Human secondary hypogonadism is associated with impaired testicular function, however, little is known about its impact on sperm epididymal maturation. Endocrine disruption in the epididymis could impair the secretion of key proteins, such as beta-defensins, responsible for spermatozoa maturation during epididymal transit. This study evaluated the sequence and structural similarities between porcine epididymal beta-defensins porcine beta-defensins (pBD3), pBD4, pBD125, and pEP2C and their human homologs using bioinformatics integrated with information derived from protein databanks. We then verified whether the expression of pBD3, pBD4, pBD125, and pEP2C genes in the testis and epididymis are influenced by disruption of the hypothalamic-pituitary-testicular (HPT) axis in a pig model for male human secondary hypogonadism. Upon modeling porcine beta defensins, structural and functional analysis confirmed the presence of motifs associated with beta-defensin function, validating the models generated in silico. pBD3 and pBD4 showed acceptable structural alignments with human beta defensins BDEF103 and BDEF110, respectively. In addition, evaluation of hormonal regulation of beta-defensins was assessed by analyzing the expression of these four beta-defensins in adult boars immunized against gonadotropin-releasing hormone (GnRH). Our results indicate that HPT axis disruption modifies the expression of pBD3, pBD4, pBD125, and pEP2C in boar testis and epididymis, suggesting an endocrine-dependent regulation of beta-defensins in swine epididymis. In conclusion, sequence and structural homology between pBD3 and pBD4 and their human homologs provide a basis for using the pig as a model for the study of human secondary hypogonadism. Further investigation of the human homologs in hypogonadal men could elucidate the connections between fertility and epididymal expression of beta-defensins. PMID- 30307667 TI - Prelimbic cortex is a common brain area activated during cue-induced reinstatement of cocaine and heroin seeking in a polydrug self-administration rat model. AB - Many preclinical studies examined cue-induced relapse to heroin and cocaine seeking in animal models, but most of these studies examined only one drug at a time. In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self-administration relapse model in rats to determine similarities and differences in brain areas activated during cue-induced reinstatement of heroin and cocaine seeking. We trained rats to lever press for cocaine (1.0 mg/kg per infusion, 3-hr/day, 18 day) or heroin (0.03 mg/kg per infusion) on alternating days (9 day for each drug); drug infusions were paired with either intermittent or continuous light cue. Next, the rats underwent extinction training followed by tests for cue-induced reinstatement where they were exposed to either heroin- or cocaine-associated cues. We observed cue selective reinstatement of drug seeking: the heroin cue selectively reinstated heroin seeking and the cocaine cue selectively reinstated cocaine seeking. We used Fos immunohistochemistry to assess cue-induced neuronal activation in different subregions of the medial prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala. Fos expression results indicated that only the prelimbic cortex (PL) was activated by both heroin and cocaine cues; in contrast, no significant cue-induced neuronal activation was observed in other brain areas. RNA in situ hybridization indicated that the proportion of glutamatergic and GABAergic markers in PL Fos-expressing cells was similar for the heroin and cocaine cue-activated neurons. Overall, the results indicate that PL may be a common brain area involved in both heroin and cocaine seeking during polydrug use. PMID- 30307668 TI - Reduced oxygen concentration during in vitro oocyte maturation alters global DNA methylation in the maternal pronucleus of subsequent zygotes in cattle. AB - Preimplantation epigenetic reprogramming is sensitive to the environment of the gametes and the embryo. In vitro maturation (IVM) of bovine oocytes is a critical step of embryo in vitro production procedures and several factors influence its efficiency, including atmospheric oxygen tension. The possibility that the IVM environment can alter this process is tested by determining whether the global DNA methylation pattern (measured via immunofluorescent labeling of 5 methylcytosine [5meC]) in the parental pronuclei of bovine zygotes produced from cumulus-oocyte complexes matured under low (5%) and atmospheric (~20%) oxygen tension. Normalized 5meC signals differed significantly between maternal and paternal pronuclei of oocytes matured in vitro at 5% oxygen (p <= 0.05). There was a significant difference of 5meC between maternal pronuclei of oocytes matured at 5% oxygen and 20% oxygen ( p <= 0.05). The relative methylation level (normalized fluorescence intensity of paternal pronucleus divided by the normalized fluorescence intensity of maternal pronucleus) subsequent to maturation in vitro at 5% and 20% oxygen was also significantly altered ( p <= 0.05). Our results show that the pattern of global DNA methylation in the maternal pronucleus of bovine zygotes is affected by maturing the oocytes under low oxygen tension which may have an impact on early embryonic development. These data may contribute to the understanding of possible effects of IVM conditions on pronucleus reprogramming. PMID- 30307669 TI - Does informal care impact utilisation of home-based formal care services among end-of-life patients? A decade of evidence from Ontario, Canada. AB - Understanding how informal care impacts formal care utilisation for home-based end-of-life patients is an important policy- and practice-relevant question. This paper aims to assess the relationship between informal and formal home care among home-based end-of-life patients and how this relationship has changed over the last decade and over the end-of-life trajectory. We focus on informal care provided by family members or friends, and three types of home-based formal care services: care by personal support workers, physician visits, and nurse visits. Using survey data collected in a home-based end-of-life care programme in Ontario, Canada from 2005 to 2016, we build a two-part utilisation model analysing both the propensity to use each type of formal care and the amount of formal care received by patients. The results suggest that informal care is a substitute for care by personal support workers, but a complement to physician visits and nurse visits. In the case of nurse visits, an increased complementary effect is observed in more recent years. For home-based physician and nurse visits, the complementary effect grows with patient's proximity to death. These results highlight the complexity of the relationship between informal and formal care among home-based end-of-life patients. Decision-makers need to take into account the relationship between informal care and different types of formal services when introducing future policies. PMID- 30307670 TI - Risk analysis for tracheostomy dependency in curatively treated laryngeal cancer with organ preservation. AB - BACKGROUND: A tracheostomy has an enormous negative impact on the patient's quality of life. The purpose of this study is to describe risk factors for permanent tracheostomies in patients undergoing curative organ-preserving treatment of laryngeal cancer. METHODS: The charts of all patients with laryngeal cancer diagnosed at our tertiary referral center were reviewed. Cases receiving a tracheostomy before, during, or after primary organ-preserving treatment were eligible. RESULTS: A total of 87 patients who underwent tracheostomies were enrolled in the present study. During follow-up, 48 patients (55%) required a permanent tracheostomy, whereas 39 patients (45%) were decannulated. Multivariate analysis revealed primary radiotherapy (RT; odds ratio [OR] 12.857; P < .001) and recurrence (OR 25.84; P < .001) as independent factors of permanent tracheostomy. CONCLUSION: This study identifies primary curative RT and tumor relapse as independent risk factors of permanent tracheostomy dependency in patients with laryngeal cancer undergoing a tracheostomy during or after primary curative organ preserving treatment. PMID- 30307671 TI - Linear gadolinium-based contrast agent (gadodiamide and gadopentetate dimeglumine)-induced high signal intensity on unenhanced T1 -weighted images in pediatric patients. AB - BACKGROUND: Recent studies of adults have found an association between hyperintensity of the dentate nucleus (DN) and globus pallidus (GP) on T1 weighted images (T1 WI) and a history of linear gadolinium-based contrast agent (GBCA) administration. Several reports have also focused on this phenomenon in pediatric patients; however, data in the current literature remains limited. PURPOSE/HYPOTHESIS: To evaluate the associations between DN and GP T1 -signal increase and previous administration of linear GBCAs in pediatric patients. STUDY TYPE: Single-center, retrospective, cross-sectional study. POPULATION: We included pediatric patients with histories of >=5 linear GBCA (gadodiamide and gadopentetate dimeglumine) administrations (the ">=5 Linear GBCA administrations" group), 1-4 administrations (the "1-4 Linear GBCA administrations" group), and no history of GBCA administration (the "No GBCA administration" group). Each group included 42 patients. Therefore, 126 patients (male:female, 72:54; median age, 16 [range, 4-18] years) were included in this study. FIELD STRENGTH/SEQUENCE: 1.5T/ Spin-echo unenhanced T1 -weighted imaging. ASSESSMENT: Unenhanced T1 -weighted images were quantitatively analyzed by two radiologists. The DN-to-pons and GP-to thalamus signal intensity ratios (DN-to-pons and GP-to-thalamus ratios, respectively) were compared. STATISTICAL TESTS: Wilcoxon test with the Bonferroni correction and intraclass correlation coefficients. RESULTS: The DN-to-pons ratio increased as the number of GBCA administrations increased (P < 0.0063). The GP-to thalamus ratio of the ">=5 Linear GBCA administrations" group was significantly higher than those of the other two groups (P < 0.0001). The GP-to-thalamus ratio of the "1-4 Linear GBCA administrations" group did not differ significantly from that of the "No GBCA administration" group (P = 1.000). The DN-to-pons and GP-to thalamus ratios' interobserver intraclass correlation coefficients were excellent (0.8236) and good (0.6738), respectively. DATA CONCLUSION: High signal intensities in the DN and GP on T1 WI were associated with previous linear GBCA administration in pediatric patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30307672 TI - Photoredox/Nickel-Catalyzed Single-Electron Tsuji-Trost Reaction: Development and Mechanistic Insights. AB - A regioselective, nickel-catalyzed photoredox allylation of secondary, benzyl, and alpha-alkoxy radical precursors is disclosed. Through this manifold, a variety of linear allylic alcohols and allylated monosaccharides are accessible in high yields under mild reaction conditions. Quantum mechanical calculations [DFT and DLPNO-CCSD(T)] support the mechanistic hypothesis of a Ni0 to NiII oxidative addition pathway followed by radical addition and inner-sphere allylation. PMID- 30307676 TI - Development of a loop-mediated isothermal amplification assay for specific detection of all known subspecies of Clavibacter michiganensis. AB - AIMS: Clavibacter michiganensis is an important bacterial plant pathogen that causes vast destruction to agriculturally important crops worldwide. Early detection is critical to evaluate disease progression and to implement efficient control measures to avoid serious epidemics. In this study, we developed a sensitive, specific and robust loop-mediated isothermal amplification (LAMP) assay for detection of all known subspecies of C. michiganensis. METHODS AND RESULTS: Whole genome comparative genomics approach was taken to identify a unique and conserved region within all known subspecies of C. michiganensis. Primers specificity was evaluated in silico and with 64 bacterial strains included in inclusivity and exclusivity panels; no false positives or false negatives were detected. Both the sensitivity and spiked assay of the developed LAMP assay was 1 fg of the pathogen DNA per reaction. A 100% accuracy was observed when tested with infected plant samples. CONCLUSIONS: The developed LAMP assay is simple, sensitive, robust and easy to perform using different detection platforms and chemistries. SIGNIFICANCE AND IMPACT OF THE STUDY: The developed LAMP assay can detect all known subspecies of C. michiganensis. The LAMP process can be performed isothermally at 65 degrees C and results can be visually assessed, which makes this technology a promising tool for monitoring the disease progression and for accurate pathogen detection at point-of-care. This article is protected by copyright. All rights reserved. PMID- 30307675 TI - Antifungal activity of immunosuppressants used alone or in combination with fluconazole. AB - Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals. PMID- 30307673 TI - Quantifying user preferences for sanitation construction and use: Application of discrete choice experiments in Amhara, Ethiopia. AB - OBJECTIVE: To quantify stated preferences for latrine use and construction in Amhara, Ethiopia, using Discrete Choice Experiments (DCEs). METHODS: We conducted image-based DCEs to assess preferences for latrine use (stratified by gender) and construction (among men only) in Amhara, Ethiopia. Preference was quantified using a conditional logistic model to estimate utilities and corresponding odds ratios associated with a set of latrine attributes. RESULTS: For latrine use, tin roof, handwashing stations and clean latrines had the highest relative utility coefficients. Tin roof was preferred to no roof for use (Women: OR: 3.68, 95% CI: 3.18-4.25; Men: OR: 3.75, 95% CI: 3.21-4.39) and new latrine construction (5.92, 5.04-6.95). Concrete slabs, a critical aspect of improved sanitation, was not preferred to dirt floors for use (Women: 0.87, 0.75-1.00; Men: 1.03, 0.88-1.20), but was preferred for new construction (1.52, 1.30-1.78). We did not observe any trends in preference for direct (monetary) or indirect cost (labour days), so we were not able to elicit trade-offs between latrine attributes and these costs for the construction of new latrines. CONCLUSION: Our findings suggest similar latrine use preferences between men and women. We found that tin roofs are the most strongly preferred latrine characteristic, but concrete slabs, commonly promoted in sanitation programmes, were not preferred for use. We demonstrate the utility of DCEs to elicit stated preferences for latrine use and construction among community members who have myriad motivations for using and making improvements to their sanitation facilities, including the ease of cleaning and hygiene, durability, or privacy and comfort. PMID- 30307674 TI - Spatio-temporal distribution of vertically transmitted dengue viruses by Aedes aegypti (Diptera: Culicidae) from Arroyo Naranjo, Havana, Cuba. AB - OBJECTIVE: To study the distribution of vertical transmission of dengue viruses in field-collected Aedes aegypti larvae in the municipality of Arroyo Naranjo in Havana, Cuba. METHODS: Aedes aegypti larvae and pupae were collected monthly between September 2013 and July 2014 in the seven Municipal Health Areas of Arroyo Naranjo. Pools formed of 30-55 larvae were examined through PCR and sequencing to detect the presence of each serotype. RESULTS: We analysed 111 pools of larvae and pupae (4102 individuals) of which 37 tested positive for at least one DENV. More than one DENV type was observed in 10 of the 37 positive pools. Infected pools were detected every month, except in January, suggesting a sustained circulation of DENV in the vector populations. DENV-1 and DENV-3 were the most frequent and dispersed, though all four DENV types were detected. Nucleotide sequencing from positive pools confirmed RT-PCR results for DENV-1 (genotype V), DENV-3 (genotype III) and DENV-4 (genotype II). DENV-2 was detected by RT-PCR but could not be confirmed by nucleotide sequencing. CONCLUSION: Our study of the distribution of natural vertical transmission of dengue virus types highlights extrinsic virus activity patterns in the area and could be used as a new surveillance tool. PMID- 30307677 TI - Array-based CGH of primary cutaneous CD8+ aggressive EPIDERMO-tropic cytotoxic T cell lymphoma. AB - Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised. PMID- 30307678 TI - On monoxenous trypanosomatids from lesions of immunocompetent patients with suspected cutaneous leishmaniasis in Iran. PMID- 30307680 TI - Sustaining an intervention for physical health promotion in community mental health services: A multisite case study. AB - There is a growing body of literature on sustainability, but its definition and the factors that affect it are not well understood. This paper focuses on the sustainment of health promotion interventions in community mental health organisations, where the institutional context has been found to play an important role. Normalisation Process Theory (NPT) was used to characterise the extent of sustainment of health promotion interventions and to identify important factors that influence it. The study builds on a previously reported qualitative multiple case design focusing on four Danish community mental health organisations. We aimed to include cases (provider organisations) with varied political-administrative contexts that were expected to impact sustainment. Data included 27 semistructured interviews with managers and frontline staff. The analysis adopted a thematic approach combining within-case and cross-case analysis. One important factor contributing to sustainment was the high degree of coherence generated during and after implementation. Perceptions of meaningfulness and formal tools for external accountability such as municipal activity plans also stimulated the cognitive participation of management and staff in sustaining the intervention. On the practical level of collective action, working with health promotion in a continuous way was particularly supported by two formal tools: internal health policies and municipal activity plans. Sustainment was further aided by reflexive monitoring based on ongoing informal assessments, supplemented by information required for status reports to the municipality on individual users and information from the annual individual user health checks. Future studies should adapt NPT to a broader range of cases to assess more thoroughly its contribution to the literature on sustainment. Future interventions need to pay closer attention to securing continuous and active local management support as well as to political-administrative contexts as potential external drivers of sustainment. PMID- 30307679 TI - Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast. AB - Cationic amphiphiles are a large and diverse class of antimicrobial agents. Although their mode of action is not fully resolved, it is generally accepted that these antimicrobials perturb the structural integrity of the plasma membrane leading to the microbial cell disruption. Here we report on the development of inherently fluorescent antifungal cationic amphiphiles and on the study of their effects on cells of Candida, one of the most common fungal pathogens in humans. Fluorescent images of Candida yeast cells that express a fluorescent reporter protein revealed that the cationic amphiphiles rapidly accumulated in the cytosol and led to structural changes in proteins and DNA. Using fluorescent organelle specific dyes, we showed that these antifungal agents also caused organelle disassembly in Candida cells. The results of this study indicate that, in designing antifungal cationic amphiphiles for clinical use, the intracellular activities of these molecules must be addressed to avoid undesired side effects to mammalian cells. PMID- 30307681 TI - Prices, availability and affordability of insulin products: a cross-sectional survey in Shaanxi Province, western China. AB - OBJECTIVE: To evaluate price, availability and affordability of insulin products in Shaanxi Province, western China. METHODS: We used a simplified and adapted WHO/Health Action International method to obtain the availability and prices of insulin products and five oral anti-diabetic medicines as comparators in public general hospitals and private retail outlets. In addition, we investigated the price components of eight selected insulin products by tracing the supply chain. RESULTS: All three kinds of insulin products, prandial, basal and premixed insulin, are 100% available in public hospitals, and have fairly high availability in the private sector (62.5-68.8%). The prices of most insulin products were higher than international reference prices in both sectors (ranging from 0.95 times to 2.33 times). All insulin products were unaffordable as they would cost 3.5-17.1 days' wage of the lowest-paid government workers in Shaanxi. The manufacturer's markup (selling price), which comprised more than 60% of the final price of all insulin products surveyed, was the largest price component. CONCLUSIONS: Although availability of insulin products was high in public general hospitals and private retail pharmacies, their high price made them unaffordable to diabetes patients, especially low-income patients. The government should increase insurance compensation for those who need these life-saving medicines or decrease the cost of insulin products through negotiation with suppliers. PMID- 30307682 TI - Efficacy of direct-acting antiviral treatment in patients with compensated liver cirrhosis: A multicenter study. AB - AIM: Although the development of new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. METHODS: This large-scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety-two patients (4.3%) previously received DAA-based treatment. Seven hundred and forty-five patients (34.9%) had cirrhosis. RESULTS: Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 * 10-7 ). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 * 10-3 ), no previous DAA-based treatment (P = 2.54 * 10-14 ), low HCV-RNA levels (P = 1.64 * 10-6 ), wild-type non structural protein 5A L31/Y93 (P = 7.33 * 10-13 ), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 * 10-14 ) were independent factors contributing to SVR. Except for patients with DAA-based treatment history, absence of cirrhosis (P = 2.15 * 10-3 ; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA-naive patients. CONCLUSION: This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment. PMID- 30307683 TI - Hydrogen Evolution from Aqueous Solutions Mediated by a Heterogenized [NiFe] Hydrogenase Model: Low pH Enables Catalysis through an Enzyme-Relevant Mechanism. AB - [NiFe]-hydrogenase enzymes are efficient catalysts for H2 evolution but their synthetic models have not been reported to be active under aqueous conditions so far. Here we show that a close model of the [NiFe]-hydrogenase active site can work as a very active and stable heterogeneous H2 evolution catalyst under mildly acidic aqueous conditions. Entry in catalysis is a NiI FeII complex, with electronic structure analogous to the Ni-L state of the enzyme, corroborating the mechanism modification recently proposed for [NiFe]-hydrogenases. PMID- 30307684 TI - Multilocus sequence typing of Carnobacterium maltaromaticum strains associated with fish disease and dairy products. AB - AIMS: Carnobacterium maltaromaticum is a lactic acid bacterium of technological interest in the field of dairy ripening and food bioprotection and is generally recognized as safe in the United States. As it is associated with fish infections, the European Food Safety Agency did not include this species in the qualified presumption safety list of micro-organisms. This implies that the risk assessment for the species has to be performed at the strain level. METHODS AND RESULTS: Multilocus sequence typing (MLST) is a tool that (i) potentially allows to discriminate strains isolated from diseased fish from apathogenic strains and (ii) to assess the genetic relatedness between both groups of strains. In this study, we characterized by MLST 21 C. maltaromaticum strains including 16 strains isolated from diseased fish and 5 apathogenic dairy strains isolated from cheese. The resulting population structure was investigated by integrating these new data to the previously published population structure (available at http://pubmlst.org), which represents an overall of 71 strains. CONCLUSIONS: This analysis revealed that none of the strains isolated from diseased fish is assigned to a clonal complex containing cheese isolates, and that 11 strains exhibit singleton genotypes suggesting that the population of diseased fish isolates is not clonal. SIGNIFICANCE AND IMPACT OF THE STUDY: This study thus provides a population structure of C. maltaromaticum that could serve in the future as a reference that could contribute to the risk assessment of C. maltaromaticum strains intended to be used in the food chain. PMID- 30307685 TI - An integrative review on family caregivers' involvement in care of home-dwelling elderly. AB - Often family members provide care-giving, which allows older adults to remain in their homes. With declining health and increasing frailty, care-giving of elderly people becomes a task of family caregivers (FC) in conjunction with home care nurses. It has been shown in both acute care settings and long-term care facilities that family members prefer to be involved in decision-making and care planning for their next of kin. Therefore, an integrative review was conducted to explore the body of knowledge of FCs' involvement in home-care settings from the FCs' perspective. CINAHL, PubMed, and Cochrane databases was searched with the terms family caregiver, involvement, home care, and community dwelling. Studies written in German or English between 1996 and 2017 focusing on FCs' caring for home-dwelling older adults together with home care nurses were included and critically appraised. The extracted findings were analysed with concept analysis method. Twenty-six studies were included and five themes were identified. Four themes formed the basis of assistance towards family caregivers by nurses and included "relationship building with professionals," "negotiating with professional care," "being professionally supported," and "managing role expectations and knowledge sharing". The fifth theme, "working together" described the mutual care for the care recipient. Although the first four themes were consistent with a pre-existing conceptual model by Sims-Gould and Marin Matthews (2010), the fifth required an expansion of the model with an additional contribution "collaborative practice". The findings illustrate that involvement in care is an interactional process, which provides the basis for collaborative practices with the home care nurses for family caregivers. Family members often want to be part of the healthcare team, and nurses need contextual factors that allow providing their full range of skills and knowledge to involve family caregivers accordingly. PMID- 30307686 TI - Environmental temperature and case fatality of patients with Ebola virus disease in Sierra Leone and Liberia, 2014-2015: a retrospective cohort study. AB - OBJECTIVE: Fluid loss during Ebola virus disease (EVD) infections from gastrointestinal dysfunction leads to volume depletion. It is possible that high environmental temperatures may exacerbate volume depletion or interfere with the provision of medical care by providers in full personal protective equipment. We investigated the effect of environmental temperature on case fatality. METHODS: The International Medical Corps (IMC) operated five Ebola Treatment Units (ETUs) in Liberia and Sierra Leone during the 2014-2016 epidemic. Demographic and outcomes variables for 465 patients with EVD were sourced from a de-identified, quality-checked clinical database collected by IMC. Daily environmental temperature data for Liberia and Sierra Leone were collected from a publicly available database (Weather Underground). Mean daily environmental temperatures were averaged across each patient's ETU stay and environmental temperature thresholds were determined. Multiple logistic regression was utilised, with forward variable selection and threshold for entry of P < 0.1. Statistical significance was defined as P < 0.05. The following variables were analysed as potential confounders: age, sex, ETU, length of ETU operation and date of treatment. RESULTS: Case fatality was 57.6% among patients diagnosed with EVD. Analysis of case fatality across environmental temperature quintiles indicated a threshold effect; the optimal threshold for average environmental temperature during a patient's ETU stay was determined empirically to be 27.4 degrees C (81.3 degrees F). Case fatality was significantly greater for patients with average environmental temperatures above the threshold (70.4%) vs. below (52.0%) (P < 0.001). In multiple regression, patients with average environmental temperature above the threshold during their ETU stay were significantly more likely to die than patients below the threshold (aOR = 2.5, 95% CI 1.6-3.8, P < 0.001). This trend was observed only among patients treated in white tent ETUs, and not in ETUs with aluminium roofs. DISCUSSION: These findings suggest that an average environmental temperature above 27.4 degrees C (81.3 degrees F) during patients' ETU stay is associated with greater risk of death among patients with EVD. Further studies should investigate this effect. These results have potential implications for reducing case fatality through improved ETU construction or other temperature control methods within ETUs during future outbreaks. PMID- 30307687 TI - Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder. AB - Social anxiety is a common disorder that has negative impacts across multiple domains of function. Several clinical groups are at elevated risk for social anxiety, including those with fragile X syndrome and those with autism spectrum disorder. Measuring social anxiety in these clinical subgroups is fraught with challenge, however, given the complexity of social anxiety and measurement limitations that are particularly acute in persons with neurodevelopmental disorders. The over-arching aim of this study was to contribute to our understanding of the nature of social anxiety in fragile X syndrome and its association with autism spectrum disorder. To address this aim, we created a multi-faceted composite representing behavioral and biological aspects of social anxiety and examined differences in two adolescent and young adult-aged groups: 59 males with fragile X syndrome and 18 males with autism spectrum disorder. Results indicated a lower score on the multivariate composite for the males with fragile X syndrome relative to autism spectrum disorder but with evidence that traits of autism and social anxiety overlap. We conclude that measuring anxiety and autism traits in fragile X syndrome and autism spectrum disorder is complex with features that overlap and interact in a dynamic manner. PMID- 30307688 TI - Age at diagnosis and the surgical management of small renal carcinomas: findings from a cross-sectional population-based study. AB - OBJECTIVES: To describe the use of partial nephrectomy (PN) for patients with stage T1a renal cell carcinoma (RCC) by age group (<65 and >=65 years) in two Australian states. MATERIALS AND METHODS: All adults diagnosed with RCC in 2012 and 2013 were identified through population-based cancer registries in the Australian states of Queensland and Victoria. For each patient, research assistants extracted patient, tumour and treatment data from medical records. Percentages of patients treated by PN were determined for the two age groups. Multivariable logistic regression analyses examined factors associated with PN. Clinicians treating RCC were sent surveys to assess attitudes towards PN. RESULTS: Data were collected on 956 patients (Victoria: n = 548; Queensland: n = 404) with stage T1a RCC. Of those undergoing surgery (n = 865), PN was more common for those aged <65 years (61%) than for those aged >=65 years (44%), with this difference significant after adjusting for patient, tumour (odds ratio 0.50, 95% confidence interval 0.36-0.70). There were significant interactions between age and treatment centre volume (P < 0.05) and residential state (P < 0.05). PN was less likely for younger patients treated at lower-volume hospitals (<24 patients a year) but hospital volume was not associated with PN for older patients. PN was less likely for older patients in Queensland than Victoria. In multivariable analyses, age was not related to laparoscopic surgery. Queensland clinicians were less likely than those from Victoria to agree that PN was the treatment of choice for most T1aN0M0 tumours (P < 0.001). CONCLUSIONS: In Australia, patients aged > 65 years with small renal cancers were less likely to be treated by PN than younger patients. The variation in the surgical procedure used to treat older T1a RCC patients by state and hospital volume indicates that better evidence is needed to direct practice in this area. PMID- 30307689 TI - Spectroscopic Characterization of the Product Ions Formed by Electron Ionization of Adamantane. AB - A structural characterization of the products formed in the dissociative electron ionization of adamantane (C10 H16 ) is presented. Molecular structures of product ions are suggested based on multiple-photon dissociation spectroscopy using the Free Electron Laser for Infrared eXperiments (FELIX) in combination with quantum chemical calculations. Product ions are individually isolated in an ion trap tandem mass spectrometer and their action IR spectra are recorded. Atomic hydrogen loss from adamantane yields the 1-adamantyl isomer. The IR spectrum of the C8 H11 + product ion is best reproduced by computed spectra of 2- and 4 protonated meta-xylene and ortho- and para-protonated ethylbenzenes. The spectrum of the product ion at m/z 93 suggests that it is composed of a mixture of ortho protonated toluene, para-protonated toluene and 1,2-dihydrotropylium, while the spectrum of the m/z 79 ion is consistent with the benzenium ion. This study thus suggests that adamantane is efficiently converted into aromatic species and astrophysical implications for the interstellar medium are highlighted. PMID- 30307690 TI - Histone Tail Sequences Balance Their Role in Genetic Regulation and the Need To Protect DNA against Destruction in Nucleosome Core Particles Containing Abasic Sites. AB - Abasic sites (AP) are produced 10 000 times per day in a single cell. Strand cleavage at AP is accelerated ~100-fold within a nucleosome core particle (NCP) compared to free DNA. The lysine-rich N-terminal tails of histone proteins catalyze single-strand breaks through a mechanism used by base-excision-repair enzymes, despite the general dearth of glutamic acid, aspartic acid, and histidine-the amino acids that are typically responsible for deprotonation of Schiff base intermediates. Incorporating glutamic acid, aspartic acid, or histidine proximal to lysine residues in histone N-terminal tails increases AP reactivity as much as sixfold. The rate acceleration is due to more facile DNA cleavage of Schiff-base intermediates. These observations raise the possibility that histone proteins could have evolved to minimize the presence of histidine, glutamic acid, and aspartic acid in their lysine-rich N-terminal tails to guard against enhancing the toxic effects of DNA damage. PMID- 30307691 TI - In Situ Fabrication of Heterostructure on Nickel Foam with Tuned Composition for Enhancing Water-Splitting Performance. AB - Exploiting economical and high-performance bifunctional electrocatalysts toward hydrogen and oxygen evolution reactions (HER/OER) is at the heart of overall water splitting in large-scale application. Herein, an in situ and stepwise strategy for synthesizing core-shell Ni3 (S1- x Sex )2 @NiOOH (0 <= x <= 1) nanoarray heterostructures on nickel foam with tailored compositions for enhancing water-splitting performance is reported. A series of Ni3 (S1- x Sex )2 nanostructures is firstly grown on nickel foam via an in situ reaction in a heated polyol solution system. Ni3 (S1- x Sex )2 @NiOOH nanocomposites are subsequently prepared via electrochemical oxidation and the oxidation degree is systematically investigated by varying the oxidation time. Benefitting from the vertical standing architecture, abundant exposed active sites, and synergetically interfacial enhancement, Ni3 (S0.25 Se0.75 )2 @NiOOH heterojunctions with electrochemical polarization for 8 h exhibit superior HER and OER behaviors, achieving a water-splitting current density of 10 mA cm-2 at a small overpotential of 320 mV as well as boosted reaction kinetics and long-term stability. This work should shed light on the controllable synthesis of metal based hybrid materials and provide a promising direction for developing the highest-performing electrocatalysts based on interfacial and heterostructural regulation for advanced electrochemical energy conversion technologies. PMID- 30307692 TI - Effectiveness of Two Different Methods for Pain Reduction During Insulin Injection in Children With Type 1 Diabetes: Buzzy and ShotBlocker. AB - BACKGROUND: Repeated injections may prevent children from performing insulin administration (skip dosing) and may cause anxiety. AIMS: To compare the effect of ShotBlocker and the combination of vibration and cold application (Buzzy) in reducing pain during insulin administration in children. METHODS: This research was designed as a randomized controlled experimental study. The study sample consisted of 60 children aged between 6 and 12 years who were diagnosed as having type 1 diabetes and received insulin from the Child Endocrinology Department of the medical faculty in Eskisehir Osmangazi University between May 2015 and June 2017. The children were randomized into the Buzzy (n = 20), ShotBlocker (n = 20), and control (n = 20) groups. Three instruments were used to obtain the research data: Interview and Observation Form, Children's Anxiety and Pain Scale (CAPS), and Faces Pain Scale-Revised (FPS-R). RESULTS: The mean age of the children was 9.43 +/- 2.18 years (range 6-12 years). There were no significant differences among preprocedural anxiety levels of the study groups in terms of self-, parent , and observer-reported levels (p = .935, p = .374, and p = .680, respectively). Children in the control group had higher levels of pain than children in the Buzzy and ShotBlocker groups (p = .008, p = .007, and p > .001, respectively). There was a significant difference between the groups with procedural anxiety levels reported by the family and observer (p = .006 and p = .002, respectively), favoring the intervention groups. LINKING EVIDENCE TO ACTION: Nurses should be aware of pain during insulin injection and use methods for pain relief accordingly. ShotBlocker is recommended as a helpful option in cases where a pain control method is required. PMID- 30307693 TI - Copy number variation and neuropsychiatric problems in females and males in the general population. AB - Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex-specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100-500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex-specific effects. Medium deletions (OR[CI] = 1.18[1.05-1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19 1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14-3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45-9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects. PMID- 30307694 TI - Metabolic syndrome is associated with decreased heart rate variability in a sex dependent manner: a comparison between 252 men and 249 women. AB - Impaired heart rate variability (HRV) is associated with increased risk of cardiovascular disease, but evidence regarding alterations of HRV in metabolic syndrome (MetS) remains elusive. In order to examine HRV in MetS, we subjected 501 volunteers without atherosclerosis, diabetes or antihypertensive medication, mean age 48 years, to passive head-up tilt. The subjects were divided to control men (n = 131), men with MetS (n = 121), control women (n = 191) and women with MetS (n = 58) according to the criteria by Alberti et al. (Circulation, 2009, 120, 1640). In unadjusted analyses (i) men and women with MetS had lower total power and high-frequency (HF) power of HRV than controls whether supine or upright (P<0.05 for all). (ii) Supine low-frequency (LF) power of HRV was lower in men (P = 0.012) but not in women (P = 0.064) with MetS than in controls, while men and women with MetS had lower upright LF power of HRV than controls (P <0.01 for both). (iii) The LF:HF ratio did not differ between subjects with and without MetS. After adjustment for age, smoking habits, alcohol intake, height, heart rate and breathing frequency, only the differences in upright total power and HF power of HRV between women with MetS and control women remained significant (P<0.05). In conclusion, reduced total and HF power of HRV in the upright position may partially explain why the relative increase in cardiovascular risk associated with MetS is greater in women than in men. Additionally, the present results emphasize that the confounding factors must be carefully taken into consideration when evaluating HRV. PMID- 30307695 TI - Remodeling Tumor-Associated Macrophages and Neovascularization Overcomes EGFRT790M -Associated Drug Resistance by PD-L1 Nanobody-Mediated Codelivery. AB - Precision medicine has made a significant breakthrough in the past decade. The most representative success is the molecular targeting therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) with oncogenic drivers, approved by the US Food and Drug Administration (FDA) as first-line therapeutics for substituting chemotherapy. However, the rapidly developed TKI resistance invariably leads to unsustainable treatment. For example, gefitinib is the first choice for advanced NSCLC with EGFR mutation, but most patients would soon develop secondary EGFRT790M mutation and acquire gefitinib resistance. TKI resistance is a severe emergency issue to be solved in NSCLC, but there are a few investigations of nanomedicine reported to address this pressing problem. To overcome EGFRT790M -associated drug resistance, a novel delivery and therapeutic strategy is developed. A PD-L1 nanobody is identified, and first used as a targeting ligand for liposomal codelivery. It is found that simvastatin/gefitinib combination nanomedicine can remodel the tumor microenvironment (e.g., neovascularization regulation, M2 macrophage repolarization, and innate immunity), and display the effectiveness of reversing the gefitinib resistance and enhancing the EGFRT790M -mutated NSCLC treatment outcomes. The novel simvastatin-based nanomedicine provides a clinically translatable strategy for tackling the major problem in NSCLC treatment and demonstrates the promise of an old drug for new application. PMID- 30307696 TI - Perfluorocarbon Nanoparticles Mediated Platelet Blocking Disrupt Vascular Barriers to Improve the Efficacy of Oxygen-Sensitive Antitumor Drugs. AB - Currently, limited tumor drug permeation and poor oxygen perfusion are two major bottlenecks that significantly impair the efficacy of existing antitumor drugs, especially oxygen-sensitive antitumor drugs. One vital cause of these major bottlenecks is the abnormal tumor vessel barrier. To the best knowledge of the authors, platelets play a vital role in the maintenance of an abnormal tumor blood barrier through platelet-tumor interaction. Thus, platelet inhibition may present a new way to enhance drug delivery. In this study, it is originally discovered that perfluorotributylamine-based albumin nanoparticles (PFTBA@HSA) possess excellent platelet inhibiting abilities, which then selectively disrupt the tumor vessel barrier, resulting in a remarkably enhanced intratumoral drug accumulation. Interestingly enough, the tumor hypoxia is also obviously relieved by enhanced oxygen carrier red blood cell distribution and PFTBA@HSA infiltration in the tumors. Finally, the efficacy of oxygen-sensitive antitumor drugs is significantly amplified by PFTBA@HSA owing to enhanced drug permeation and relieved tumor hypoxia. Therefore, for the first time, it is demonstrated that PFTBA@HSA could be used as an effective way to improve the efficacy of existing tumor therapies by disrupting tumor vessel barriers through targeted platelet inhibition. PMID- 30307697 TI - Manipulating Depletion Region of Aqueous-Processed Nanocrystals Solar Cells with Widened Fermi Level Offset. AB - Water soluble nanocrystals (NCs) are promising materials in aqueous-processed solar cells because of their high extinction coefficient, low-cost, and favorable photoelectric characteristics. However, the power conversion efficiency (PCE) of the present aqueous-processed NC solar cells is restricted by the short depletion region of the active layer and limited Fermi level offset between NCs and the electron transport layer. Herein, these issues are effectively addressed by preparing Cdx Zn1- x Te NCs capped with 2-aminoethanethiol hydrochloride. The introduction of Zn2+ into CdTe NCs widens the Fermi level offset from 0.68 to 0.74 eV, lengthens the depletion region from 130 to 137 nm, and hence brings obvious improvement in the open circuit voltage (Voc ) and fill factor. Especially, the depletion region is successfully tuned from 137 to 171 nm, and even lengthened to a record thickness of 200 nm based on aqueous-processed solar cells. As a result, a champion thickness ratio (74%) of depletion region to active layer (200/270 nm) is achieved. A champion PCE of 5.96% and short-circuit current (Jsc ) of 21.2 mA cm-2 are achieved among aqueous-processed NC solar cells. This work provides a simple way to prepare polynary NCs and highlights a prospective method to develop more efficient and cost-effective solution processed environment friendly solar cells. PMID- 30307698 TI - Vessel-on-a-chip with Hydrogel-based Microfluidics. AB - Hydrogel structures equipped with internal microchannels offer more in vivo relevant models for construction of tissues and organs in vitro. However, currently used microfabrication methods of constructing microfluidic devices are not suitable for the handling of hydrogel. This study presents a novel method of fabricating hydrogel-based microfluidic chips by combining the casting and bonding processes. A twice cross-linking strategy is designed to obtain a bonding interface that has the same strength with the hydrogel bulk, which can be applied to arbitrary combinations of hydrogels. It is convenient to achieve the construction of hydrogel structures with channels in branched, spiral, serpentine, and multilayer forms. The experimental results show that the combination of gelatin and gelatin methacrylate (GelMA) owns the best biocompatibility and can promote cell functionalization. Based on these, a vessel on-a-chip system with vascular function in both physiological and pathological situations is established, providing a promising model for further investigations such as vascularization, vascular inflammation, tissue engineering, and drug development. Taken together, a facile and cytocompatible approach is developed for engineering a user-defined hydrogel-based chip that can be potentially useful in developing vascularized tissue or organ models. PMID- 30307699 TI - Rhoptry neck protein 2 expressed in Plasmodium sporozoites plays a crucial role during invasion of mosquito salivary glands. AB - Malaria parasite transmission to humans is initiated by the inoculation of Plasmodium sporozoites into the skin by mosquitoes. Sporozoites develop within mosquito midgut oocysts, first invade the salivary glands of mosquitoes, and finally infect hepatocytes in mammals. The apical structure of sporozoites is conserved with the infective forms of other apicomplexan parasites that have secretory organelles, such as rhoptries and micronemes. Because some rhoptry proteins are crucial for Plasmodium merozoite infection of erythrocytes, we examined the roles of rhoptry proteins in sporozoites. Here, we demonstrate that rhoptry neck protein 2 (RON2) is also localized to rhoptries in sporozoites. To elucidate RON2 function in sporozoites, we applied a promoter swapping strategy to restrict ron2 transcription to the intraerythrocytic stage in the rodent malaria parasite, Plasmodium berghei. Ron2 knockdown sporozoites were severely impaired in their ability to invade salivary glands, via decreasing the attachment capacity to the substrate. This is the first rhoptry protein demonstrated to be involved in salivary gland invasion. In addition, ron2 knockdown sporozoites showed less infectivity to hepatocytes, possibly due to decreased attachment/gliding ability, indicating that parts of the parasite invasion machinery are conserved, but their contribution might differ among infective forms. Our sporozoite stage-specific knockdown system will help to facilitate understanding the comprehensive molecular mechanisms of parasite invasion of target cells. PMID- 30307700 TI - Graphene Nanoribbons with Atomically Sharp Edges Produced by AFM Induced Self Folding. AB - The ability to create graphene nanoribbons with atomically sharp edges is important for various graphene applications because these edges significantly influence the overall electronic properties and support unique magnetic edge states. The discovery of graphene self-folding induced by traveling wave excitation through atomic force microscope scanning under a normal force of less than 15 nN is reported. Most remarkably, the crystallographic direction of self folding may be either along a chosen direction defined by the scan line or along the zigzag or armchair direction in the presence of a pre-existing crack in the vicinity. The crystalline direction of the atomically sharp edge is confirmed via careful lateral force microscopy measurements. Multilayer nanoribbons with lateral dimensions of a few tens of nanometers are realized on the same graphene sheet with different folding types (e.g., z-type or double parallel). Molecular dynamics simulations reveal the folding dynamics and suggest a monotonic increase of the folded area with the applied normal force. This method may be extended to other 2D van der Waals materials and lead to nanostructures that exhibit novel edge properties without the chemical instability that typically hinders applications of etched or patterned graphene nanostructures. PMID- 30307701 TI - Tumor-pH-Responsive Dissociable Albumin-Tamoxifen Nanocomplexes Enabling Efficient Tumor Penetration and Hypoxia Relief for Enhanced Cancer Photodynamic Therapy. AB - Despite the promises of applying nano-photosensitizers (nano-PSs) for photodynamic therapy (PDT) against cancer, severe tumor hypoxia and limited tumor penetration of nano-PSs would lead to nonoptimized therapeutic outcomes of PDT. Therefore, herein a biocompatible nano-PS is prepared by using tamoxifen (TAM), an anti-estrogen compound, to induce self-assembly of chlorin e6 (Ce6) modified human serum albumin (HSA). The formed HSA-Ce6/TAM nanocomplexes, which are stable under neutral pH with a diameter of ~130 nm, would be dissociated into individual HSA-Ce6 and TAM molecules under the acidic tumor microenvironment, owing to the pH responsive transition of TAM from hydrophobic to hydrophilic. Upon systemic administration, such HSA-Ce6/TAM nanoparticles exhibit prolonged blood circulation and high accumulation in the tumor, where it would undergo rapid pH responsive dissociation to enable obviously enhanced intratumoral penetration of HSA-Ce6. Furthermore, utilizing the ability of TAM in reducing the oxygen consumption of cancer cells, it is found that HSA-Ce6/TAM after systemic administration could efficiently attenuate the tumor hypoxia status. Those effects acting together lead to remarkably enhanced PDT treatment. This work presents a rather simple approach to fabricate smart nano-PSs with multiple functions integrated into a single system via self-assembly of all-biocompatible components, promising for the next generation cancer PDT. PMID- 30307702 TI - Highly Fluorescent and Stable Black Phosphorus Quantum Dots in Water. AB - Although 2D black phosphorus (BP) shows excellent optical and electronic properties, there are few reports on the photoluminescence (PL) properties of BP nanostructures because of the low yield of mechanical exfoliation, instability in water, and relatively weak emission. Herein, liquid exfoliation is combined with surface passivation to produce fluorescent BP quantum dots (BPQDs) with a high yield. The BPQDs exhibit strong PL in both ethanol and water and the absolute fluorescent quantum yield in water reaches 70%. Moreover, the BPQD solution exhibits stable PL for 150 d under ambient conditions and better photostability than conventional organic dyes and heavy-metal semiconducting nanostructures with intense fluorescence. The experiments and theoretical calculation reveal that the intense and stable PL originates from the intrinsic band-to-band excitation states and two surface states related to the P?OH and P?O?CH2 CH3 bonding structures introduced by passivation. The polar water molecules remove many nonradiative centers and simultaneously increase the P-related fluorescent groups on the surface of BPQDs. Therefore, PL from the BPQDs in water is enhanced largely. The excellent fluorescent properties of BPQDs in an aqueous solution bode well for bioimaging and the negligible biotoxicity and distinct cell images suggest large potential in the biomedical and display fields. PMID- 30307703 TI - Functionalized MoS2 Nanovehicle with Near-Infrared Laser-Mediated Nitric Oxide Release and Photothermal Activities for Advanced Bacteria-Infected Wound Therapy. AB - The rising dangers of bacterial infections have created an urgent need for the development of a new generation of antibacterial nanoagents and therapeutics. A new near-infrared 808 nm laser-mediated nitric oxide (NO)-releasing nanovehicle (MoS2 -BNN6) is reported through the simple assembly of alpha-cyclodextrin modified MoS2 nanosheets with a heat-sensitive NO donor N,N'-di-sec-butyl-N,N' dinitroso-1,4-phenylenediamine (BNN6) for the rapid and effective treatment of three typical Gram-negative and Gram-positive bacteria (ampicillin-resistant Escherichia coli, heat-resistant Escherichia faecalis, and pathogen Staphylococcus aureus). This MoS2 -BNN6 nanovehicle has good biocompatibility and can be captured by bacteria to increase opportunities of NO diffusion to the bacterial surface. Once stimulated by 808 nm laser irradiation, the MoS2 -BNN6 nanovehicle not only exhibits photothermal therapy (PTT) efficacy but also can precisely control NO release, generating oxidative/nitrosative stress. The temperature-enhanced catalytic function of MoS2 induced by 808 nm laser irradiation simultaneously accelerates the oxidation of glutathione. This acceleration disrupts the balance of antioxidants, ultimately resulting in significant DNA damage to the bacteria. Within 10 min, the MoS2 -BNN6 with enhanced PTT/NO synergetic antibacterial function achieves >97.2% inactivation of bacteria. The safe synergetic therapy strategy can also effectively repair wounds through the formation of collagen fibers and elimination of inflammation during tissue reconstruction. PMID- 30307705 TI - Epigenetic soluble epoxide hydrolase regulation causes endothelial dysfunction. PMID- 30307704 TI - Self-Adaptive Electrode with SWCNT Bundles as Elastic Substrate for High-Rate and Long-Cycle-Life Lithium/Sodium Ion Batteries. AB - Massive volume change of active materials in lithium/sodium ion batteries (LIB/SIB) causes severe structural collapse of electrodes and fast capacity decay of batteries. Here, a coaxial composite of single-wall carbon nanotube bundle (SWCNTB/SnO2 ) nanoparticles (NPs)/N-doped carbon shell (SWCNTB@SnO2 @C) is constructed, where SWCNTBs with exceptional elasticity are explored as a self adaptive substrate to supply a highly resilient conductive network. Within the confinement of hard carbon shells, SWCNTB can produce radially elastic deformation to accommodate the volume change of SnO2 during Li+ /Na+ insertion/extraction. This overcomes the problem of strain fracturing of the outer carbon shell, as well as maintains close electrical contact between SnO2 and the conductive network. The LIB/SIB with the self-adaptive SWCNTB@SnO2 @C electrode presents a series of superior battery performances, for example, a high specific capacity of 608 mAh g-1 at 10 A g-1 and 600 cycles in LIB without capacity decay. PMID- 30307706 TI - Partially Reversible Thermal-Induced Oxidation During a Dehydration Process in an H-bonded Supramolecular System. AB - The thermal behaviour of an H-bonded molecular network A based on [FeII (CN)6 ]4- anions and organic bisamidium cations 12+ was investigated. Heating was found to induce the partial oxidation of [FeII (CN)6 ]4- into [FeIII (CN)6 ]3- , together with a thermochromic effect and also a loss of crystallinity was evidenced from mid and far FT-IR spectroscopic data, XRPD and DSC/TGA analysis. Rehydration also partially reversed the redox reaction and its colour, and after that, a mixture of A with an amorphous phases was observed. FT-IR spectroscopy revealed that the oxidation of Fe(II) was accompanied by a deprotonation of the cation. PMID- 30307707 TI - Potential influence of p16 immunohistochemical staining on the diagnosis of squamous cell lesions in cervical biopsy specimens: Observation from cytologic histologic correlation. AB - BACKGROUND: The p16 immunohistochemical (IHC) marker has been used increasingly as an adjunct to morphologic assessment of cervical biopsies in which the differential diagnoses include high-grade squamous intraepithelial lesion (HSIL) and its mimics. The objective of this study was to assess the potential influence of p16 IHC staining on the evaluation of cervical biopsy as observed through cytologic-histologic correlation (CHC). METHODS: Cervical biopsy samples that had cytologic diagnoses of either low-grade squamous intraepithelial lesion (LSIL) or HSIL and also had histologic follow-up were retrieved from the department database. CHC and the use of p16 IHC from 2 periods (group 1, 2008; group 2, 2014 2016) were compared and analyzed. RESULTS: Histology on 452 samples from patients who had prior LSIL cytology in group 1 yielded 126 benign (27.9%), 272 LSIL (60.2%), and 54 HSIL (11.9%) diagnoses. By comparison, 491 samples from the patients in group 2 yielded 106 benign (21.6%), 277 LSIL (56.4%), and 108 HSIL (22.0%) diagnoses. The difference in CHC discrepancies between the 2 groups was significant (P = .0001), mainly because of the increased diagnosis of HSIL in group 2. Although p16 IHC was not applied to any sample from group 1, it was performed on 141 of 491 samples (28.7%) from group 2. Further follow-up of patients who had histologic HSIL revealed that residual HSIL was identified significantly more often in those who did not have p16 IHC applied in the preceding cervical biopsy than in those did (P = .0004). A similar comparison was performed between 113 patients from group 1 and 152 patients from group 2 who had a prior diagnosis of HSIL cytology, and the difference was statistically insignificant. CONCLUSIONS: The use of p16 IHC on cervical biopsies in patients who had a prior cytologic diagnosis of LSIL may lead to greater detection and upgrading of HSIL, thereby compounding the discrepancy in CHC. PMID- 30307708 TI - Right heart failure as a risk factor for severe exacerbation in patients with chronic obstructive pulmonary disease: Prospective cohort study. AB - BACKGROUND: The prognosis in patients with Chronic Obstructive Pulmonary Disease (COPD) depends, in large part, on the frequency of exacerbations. Cardiovascular diseases, including heart failure (HF), are the risk factors for exacerbations. However, the importance of HF type over the exacerbations in COPD patients is unknown. OBJECTIVE: To determine whether right heart failure (RHF) is an independent risk factor for severe exacerbations in patients with COPD. METHODS: A prospective cohort study of 133 patients diagnosed with COPD with a follow-up period from 2010 to 2016. Patients with bronchial hyperreactivity, asthma, or pulmonary embolism were excluded. RESULTS: The mean age was 74.7 +/- 8.2 years and 43.6% were men, 69.9% had severe exacerbations during follow-up. Subjects with RHF had lower FEV1 (50.2 +/- 19.9 vs 57.4 +/- 16.9, P = .006) and greater incidence of stroke (15.4% vs 1.8%, P = .009) compared to those without RHF. Subjects with RHF were at higher risk of severe exacerbations (HR, 2.46; CI 95%, 1.32-4.58, P = .005) compared to those without RHF after adjusting for confounding variables. CONCLUSION: In patients with COPD, RHF is an independent risk factor for suffering severe exacerbations. PMID- 30307709 TI - 3D 3C-SiC/Graphene Hybrid Nanolaminate Films for High-Performance Supercapacitors. AB - High-performance supercapacitors feature big and stable capacitances and high power and energy densities. To fabricate high-performance supercapacitors, 3D 3C SiC/graphene hybrid nanolaminate films are grown via a microwave plasma-assisted chemical vapor deposition technique. Such films consist of 3D alternating structures of vertically aligned 3C-SiC and graphene layers, leading to high surface areas and excellent conductivity. They are further applied as the capacitor electrodes to construct electrical double layer capacitors (EDLCs) and pseudocapacitors (PCs) in both aqueous and organic solutions. The capacitance for an EDLC in aqueous solutions is up to 549.9 uF cm-2 , more than 100 times higher than that of an epitaxial 3C-SiC film. In organic solutions, it is 297.3 uF cm-2 . The pseudocapacitance in redox-active species (0.05 Fe(CN)6 3-/4- ) contained aqueous solutions is as high as 62.2 mF cm-2 . The capacitance remains at 98% of the initial value after 2500 charging/discharging cycles, indicating excellent cyclic stability. In redox-active species (0.01 m ferrocene) contained organic solutions, it is 16.6 mF cm-2 . Energy and power densities of a PC in aqueous solution are 11.6 W h kg-1 and 5.1 kW kg-1 , respectively. These vertically aligned 3C-SiC/graphene hybrid nanolaminate films are thus promising electrode materials for energy storage applications. PMID- 30307710 TI - Genetic diversity of porcine circovirus type 2 in China between 1999-2017. AB - Porcine circovirus type 2 (PCV-2), is linked to PCV-2 associated disease, which has caused considerable economic loss in the swine industry. Here, we report the genetic diversity of PCV-2 in China. A total of 74 Chinese PCV-2 strains sequenced between 1999 and 2017 were studied. Based on the ORF2 and complete genomes, we found that apart from the PCV-2a, PCV-2b, and PCV-2d genotypes, two unstable recombination genotypes also exist, referred to as IM1 and IM2 genotypes. We found that the patterns of PCV-2 genetic shift in China are similar to the patterns at the global level. Additionally, for the PCV-2 ORF2 gene of Chinese isolates, we found a similar time to the most recent common ancestor and evolutionary rate to the global values. This indicates that PCV2 genetic diversity in China is driven by genetic drift/recombination of local strains and by the sporadic introduction of foreign genotypes from other countries. Overall, our study illustrates the genetic diversity and evolution dynamics of PCV-2 in China. PMID- 30307713 TI - Detection of Homologue and Isomer Vapors through Dynamic Reflection Spectra of Hollow Mesoporous Silica Sphere Photonic Crystals. AB - Vapors of homologues and isomers with very similar refractive indices can be easily distinguished by using dynamic reflection spectra (DRS) of hollow mesoporous silica sphere (HMSS) photonic crystals (PCs). Different diffusion behaviors render the HMSS PCs with a distinct response to different chemicals vapors, leading to diversity in the evolution of the reflection spectra and their DRS patterns. Therefore, by studying the geometric characteristics and color changes of color-filled contour maps, as well as the reflection peak shift speeds at different stages, even isomers such as n-butanol and iso-butanol, with a refractive index difference of only 0.001, can be recognized. The reflection peak shift speed depends on both the refractive index and the diffusion speed of chemicals. The proposed strategy provides a convenient, accurate, and low-cost method to detect vapors of homologues and isomers. PMID- 30307712 TI - Aerosol exposure enhanced infection of low pathogenic avian influenza viruses in chickens. AB - To assess the impact of different routes of inoculation on experimental infection of avian influenza (AI) viruses in chickens, this study compared virus replication and cytokine gene expression in respiratory and gastrointestinal organ tissues of chickens, which were inoculated with four low pathogenic subtypes, H6N1, H10N7, H10N8, and H13N6 AI viruses via the aerosol, intranasal, and oral routes respectively. Aerosol inoculation with the H6N1, H10N7, and H10N8 viruses significantly increased viral titres and upregulated the interferon (IFN) gamma, interleukin (IL)-6, and IL-1beta genes in the trachea and lung tissues compared to intranasal or oral inoculation. Furthermore, one or two out of six chickens died following exposure to aerosolized H6N1 or H10N8 virus respectively. The H13N6 virus reached the lung via aerosol inoculation although failed to establish infection. Collectively, chickens were more susceptible to aerosolized AI viruses compared to intranasal or oral inoculation, and virus aerosols might post a significant threat to poultry health. PMID- 30307714 TI - Synthesis of Nucleoside-5'-O-Tetraphosphates from Activated Trimetaphosphate and Nucleoside-5'-O-Monophosphates. AB - This article describes a straight-forward chemical method for the synthesis of nucleoside-5'-O-tetraphosphates, such as cytosine-, guanosine-, adenosine-, and uridine-5'-O-tetraphosphates, starting from the corresponding nucleoside monophosphates and trimetaphosphate, a readily available and inexpensive starting material. The procedure involves reacting the tri(tetrabutylammonium) salt of trimetaphosphate with mesitylenesulfonyl chloride and N-methylimidazole. The resulting activated cyclic trimetaphosphate is reacted with the tetrabutylammonium salts of nucleoside monophosphates. After quenching the reaction with buffer and high-performance liquid chromatography purification, the desired nucleoside-5'-O-tetraphosphates were obtained in yields of 84% to 86%. (c) 2018 by John Wiley & Sons, Inc. PMID- 30307711 TI - Quantitative proteomic analysis of intracerebral hemorrhage in rats with a focus on brain energy metabolism. AB - INTRODUCTION: Intracerebral hemorrhage (ICH) is a lethal cerebrovascular disorder with a high mortality and morbidity. The pathophysiological mechanisms underlying ICH-induced secondary injury remain unclear. METHODS: To examine one of the gaps in the knowledge about ICH pathological mechanisms, isobaric tag for relative and absolute quantification (iTRAQ)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used in collagenase-induced ICH rats on the 2nd day. RESULTS: A total of 6,456 proteins were identified with a 1% false discovery rate (FDR). Of these proteins, 126 and 75 differentially expressed proteins (DEPs) were substantially increased and decreased, respectively. Based on Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING analyses, the protein changes in cerebral hemorrhage were comprehensively evaluated, and the energy metabolism in ICH was anchored. The core position of the nitrogen metabolism pathway in brain metabolism in ICH was found for the first time. Carbonic anhydrase 1 (Ca1), carbonic anhydrase 2 (Ca2), and glutamine synthetase (Glul) participated in this pathway. We constructed the protein-protein interaction (PPI) networks for the energy metabolism of ICH, including the Atp6v1a-Atp6v0c-Atp6v0d1-Ppa2-Atp6ap2 network. CONCLUSIONS: It seems that dysregulation of energy metabolism, especially nitrogen metabolism, may be a major cause in secondary ICH injury. This information provides novel insights into secondary events following ICH. PMID- 30307715 TI - Imaging the Solvation of a One-Dimensional Solid on the Molecular Scale. AB - We have observed the inversion of the solvation environment of a one-dimensional solid by low-temperature scanning tunneling microscopy. Adsorption of 3-methoxy-9 diazofluorene on Ag(111) yields highly oriented supramolecular chains, which are then exposed to water molecules. The annealing of dry and water-decorated chains results in diametrically opposed outcomes. While the former simply leads to an increase in chain length and number, the latter results in a complete loss of order and produces water clusters decorated with the organic molecule. PMID- 30307716 TI - Marginal soft tissue stability around conical abutments inserted with the one abutment-one time protocol after 5 years of prosthetic loading. AB - BACKGROUND: Soft tissue stability is crucial to obtain and maintain optimal esthetic results. PURPOSE: This study aimed to investigate, over 5 years, the soft tissue response using a conical abutment together with the "one-abutment one time" (OA-OT) protocol in the restoration of implants inserted in the anterior esthetic area. MATERIAL AND METHODS: From January 2011 to January 2012, all consecutive patients requiring an implant n the maxillary area between canines were enrolled. After submerged healing and osseointegration, a definitive abutment with a provisional crown was inserted. After 1 month, the definitive crown was delivered (Tdef). Analog impressions were taken before tooth extraction (T0), at implant insertion Timpl, and Tdef, and at 12 months (T1) and 60 months (T5). Casts were scanned and superimposed using a dedicated software. Differences in vertical height of soft tissue margins between the digitized model casts were calculated and paired sample t test was conducted to compare results. To detect the potential role of biotype, groups (thick vs. thin) were compared by analysis of variance with general linear model. RESULTS: Twenty-five patients were enrolled. Three patients dropped out. At the 60-month, 22 patients (12 men and 10 women with mean age of 68.3 +/- 11 years) concluded the study follow-up. Horizontal changes demonstrated gain of 1.06 mm at Timpl, 0.94 mm at Tdef, 0.92 mm at T1 and 0.97 mm at T5 compared to T0. Vertical changes demonstrated gain of 0.84 mm at Timpl, 0.11 mm at Tdef, 0.29 mm at T1 and 0.59 mm at T5 compared to T0. The analysis of variance showed a significant better performance of thick biotype in soft tissue horizontal width (P = .022). No statistical differences were noticed for vertical width (P = .111). CONCLUSIONS: The use of a conical abutment together with the OA-OT approach allowed longitudinal stable soft tissue dimensions. PMID- 30307717 TI - 16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability. AB - INTRODUCTION: Mutations of the PRRT2 gene are the most common cause for paroxysmal kinesigenic dyskinesia. However, patients with negative PRRT2 mutations are not rare. The aim of this study is to determine whether copy number variant of PRRT2 gene is another potential pathogenic mechanism in the patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. METHODS: We screened PRRT2 copy number variants using the AccuCopyTM method in 29 patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. Next-generation sequencing was used to determine the chromosomal deletion sites in patients with PRRT2 copy number variants, and to exclude mutations in other known causative genes for paroxysmal kinesigenic dyskinesia. RESULTS: Two sporadic patients with negative PRRT2 point and frameshift mutations (6.9%) were identified to have de novo PRRT2 copy number deletions (591 and 832 Kb deletions located in 16p11.2). The two patients presented with pure paroxysmal kinesigenic dyskinesia and paroxysmal kinesigenic dyskinesia and benign infantile convulsions, respectively. They had normal intelligence and neuropsychiatric development, in contrast to those previously reported with 16p11.2 deletions complicated with neuropsychiatric disorders. No correlation between the deletion ranges and phenotypic variations was found. CONCLUSION: 16p11.2 deletions play causative roles in paroxysmal kinesigenic dyskinesia, especially for sporadic cases. Our findings extend the phenotype of 16p11.2 deletions to pure paroxysmal kinesigenic dyskinesia. Screening for 16p11.2 deletions should thus be included in genetic evaluations for patients with paroxysmal kinesigenic dyskinesia. PMID- 30307719 TI - Metformin synergistically enhances the antitumor activity of the third-generation EGFR-TKI CO-1686 in lung cancer cells through suppressing NF-kappaB signaling. AB - PURPOSE: Third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), rociletinib (CO-1686), is great efficacy against EGFR-mutated patients bearing the T790M resistance mutation. However, acquired resistance may emerge. There is a need to characterize acquired resistance mechanism(s) and to devise ways to overcome CO-1686 resistance. EXPERIMENTAL DESIGN: MTT assay, ki67 incorporation assay, transwell assay and TUNEL assay were employed to analyze the effects of metformin to reverse CO-1686 resistance in vitro. The NF-kappaB activity was measured by the antibody of p50, p65, p IKBalpha, and p-IKKalpha/beta. Western blotting was used to analyze the proteins in cells. RESULTS: We have established CO-1686-resistant cell lines of PC-9GRCOR and H1975COR from two parental cell lines of PC-9GR and H1975 by long-term exposure to increasing doses of CO-1686. Compared with the parental cells, PC 9GRCOR cells and H1975COR cells showed 90-folds and 20-folds higher resistance to CO-1686, respectively. Critically, we showed that the nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB) signaling molecular proteins subunits of p50, p65 and its inhibitor proteins of IKBalpha, IKKalpha/beta in phosphorylation levels in resistant cells were higher than parental cells. Accordingly, inhibition of NF-kappaB activity used TPCA-1 effective in decreasing viability and inducing apoptosis of resistant cells. Moreover, metformin overcame the acquired resistance to CO-1686 by reducing cell proliferation and invasion. Metformin combined with CO-1686 synergistically inhibited the p-IKBalpha, p IKKalpha/beta, p50, and p65. CONCLUSIONS: NF-kappaB signaling activation induced acquired resistance to CO-1686. Metformin sensitized resistant cells to CO-1686 via inhibiting NF-kappaB signaling. PMID- 30307718 TI - Patterned Optoelectronic Tweezers: A New Scheme for Selecting, Moving, and Storing Dielectric Particles and Cells. AB - Optical micromanipulation has become popular for a wide range of applications. In this work, a new type of optical micromanipulation platform, patterned optoelectronic tweezers (p-OET), is introduced. In p-OET devices, the photoconductive layer (that is continuous in a conventional OET device) is patterned, forming regions in which the electrode layer is locally exposed. It is demonstrated that micropatterns in the photoconductive layer are useful for repelling unwanted particles/cells, and also for keeping selected particles/cells in place after turning off the light source, minimizing light-induced heating. To clarify the physical mechanism behind these effects, systematic simulations are carried out, which indicate the existence of strong nonuniform electric fields at the boundary of micropatterns. The simulations are consistent with experimental observations, which are explored for a wide variety of geometries and conditions. It is proposed that the new technique may be useful for myriad applications in the rapidly growing area of optical micromanipulation. PMID- 30307720 TI - Mini Dental Implants in the Management of The Atrophic Maxilla and Mandible: A New Implant Design and Preliminary Results. AB - Although the edentulous population in the UK is falling, those that are rendered edentulous are becoming edentate later in life and with significantly resorbed ridges. This creates a challenge because the management of such patients and their ability to adapt to new dentures is impaired later in life. Despite widespread endorsement of two implants to retain lower complete dentures, the inability to comply has resulted in elderly patients with compromised ability to function and unable to eat a healthy diet. Mini dental implants may offer an ideal solution for the elderly edentulous population who may not be keen on invasive surgery for the placement of conventional dental implants. Further work is required to show the longevity of these restorations, however, existing research and clinical experience show that they potentially offer a simple solution to this group of patients. This paper presents the development of a new design of mini implant, based on clinical problems encountered during a pilot randomised controlled trial. The design of the new implant specifically aims to overcome problems in managing severely atrophic ridges. A preliminary survival study shows survival rates to be equivalent to other mini dental implants and highly satisfactory in the short to medium term. PMID- 30307721 TI - Importance of proximal or distal location of deep vein thrombosis: They are truly different. PMID- 30307734 TI - Data Linkage Strategies to Advance Youth Suicide Prevention. AB - OBJECTIVES: Linking national, State, and community data systems, such as those used for medical service billing, to existing data from suicide prevention efforts could facilitate the assessment of longer term outcomes. Our objective was to identify and describe data systems that can be linked to data from studies of youth suicide prevention interventions and to identify analytic approaches to advance youth suicide prevention research. DATA SOURCES: We conducted a systematic review to identify studies of suicide prevention interventions and three types of searches to identify data systems providing suicide-related outcomes: (1) a literature search, (2) an environmental scan of gray literature, and (3) a targeted search, through contact with relevant individuals, in six States, two cities, and one tribal community. REVIEW METHODS: Two independent reviewers screened all results. Studies and data systems had to be based in the United States; include individuals between 0 and 25 years of age; and include suicide, suicide attempt, or suicide ideation as an outcome. RESULTS: Of the 47 studies (described in 59 articles) of suicide prevention interventions identified in our systematic review, only 6 studied outcomes by linking to external data systems and only 12 explored treatment heterogeneity through the effects of moderators such as gender or race/ethnicity. We identified 153 unique and potentially linkable external data systems, 66 of which we classified as "fairly accessible" with data dictionaries available. CONCLUSIONS: There is potential for linking existing data systems with suicide prevention efforts to assess the broader and extended impact of suicide prevention interventions. However, sparse availability of data dictionaries and lack of adherence to standard data elements limit the potential utility of linking prevention efforts with data systems. PMID- 30307735 TI - Omega-3 Fatty Acids and Maternal and Child Health: An Updated Systematic Review. AB - OBJECTIVES: To update a prior systematic review on the effects of omega-3 fatty acids (n-3 FA) on maternal and child health and to assess the evidence for their effects on, and associations with, additional outcomes. DATA SOURCES: MEDLINE(r), Embase(r), the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Centre for Agriculture and Biosciences (CAB) Abstracts from 2000 to August 2015; eligible studies from the original report; and relevant systematic reviews. REVIEW METHODS: We included randomized controlled trials (RCTs) of any defined dose of n-3 FA (or combination) compared to placebo, any other n-3 FA, or alternative dose with an outcome of interest conducted in pregnant or breastfeeding women or neonates (preterm or term). We also included prospective observational studies that analyzed the association between baseline n-3 FA intake or biomarker level and followup outcomes. Postnatal interventions began within a week of birth for term infants and within a week of beginning enteral or oral feeding for preterm infants. Standard methods were used for data abstraction and analysis, according to the Evidence-based Practice Center Methods Guide. RESULTS: We identified 4,275 potentially relevant titles from our searches, of which 95 RCTs and 48 observational studies met the inclusion criteria. Risk of bias was a concern with both RCTs and observational studies. Outcomes for which evidence was sufficient to draw a conclusion are summarized here with the Strength of Evidence (SoE). (Outcomes for which the evidence was insufficient to draw a conclusion are summarized in Appendix G of the report.). : Maternal Exposures and Outcomes: Gestational length and risk for preterm birth: Prenatal algal docosahexaenoic acid (DHA) or DHA-enriched fish oil supplementation had a small positive effect on length of gestation (moderate SoE), but no effect on risk for preterm birth (low SoE). Prenatal EPA (eicosapentaenoic acid) plus DHA-containing fish oil supplementation has no effect on length of gestation (low SoE). Supplementation with DHA, or EPA plus DHA-, or DHA-enriched fish oil does not decreaserisk for preterm birth (low SoE). : Birth weight and risk for low birth weight: Changes in maternal n-3 FA biomarkers were significantly associated with birth weight. Prenatal algal DHA or DHA-enriched fish oil supplementation had a positive effect on birth weight among healthy term infants (moderate SoE), but prenatal DHA supplementation had no effect on risk for low birth weight (low SoE). Prenatal EPA plus DHA or alpha linolenic acid (ALA) supplementation had no effect on birth weight (low SoE). : Risk for peripartum depression: Maternal n-3 FA biomarkers had no association with risk for peripartum depression. Maternal DHA, EPA, or DHA-enriched fish oil supplementation had no effect on risk for peripartum depression (low SoE). : Risk for gestational hypertension/preeclampsia: Prenatal DHA supplementation among high-risk pregnant women had no effect on the risk for gestational hypertension or preeclampsia (moderate SoE). Prenatal supplementation of any n-3 FA in normal risk women also had no significant effect on risk for gestational hypertension or preeclampsia (low SoE). : Fetal, Infant, and Child Exposures and Outcomes: Postnatal growth patterns: Maternal fish oil or DHA plus EPA supplementation had no effect on postnatal growth patterns (attainment of weight, length, and head circumference) when administered prenatally (moderate SoE) or both pre- and postnatally (low SoE). Fortification of infant formulas with DHA plus arachidonic acid (AA, an n-6 FA) had no effect on growth patterns of preterm or term infants (low SoE). : Visual acuity: Prenatal supplementation with DHA had no effect on development of visual acuity (low SoE). Supplementing or fortifying preterm infant formula with any n-3 FA had no significant effect on visual acuity assessed by visual evoked potentials (VEP) at 4 or 6 months corrected age (low SoE). Data conflicted on the effectiveness of supplementing infant formula for term infants with n-3 FA depending on when and how visual acuity was assessed (i.e. by VEP or by behavioral methods) and the type of essential FA provided (low SoE). : Neurological development: Prenatal or postnatal n-3 FA supplementation had no consistent effect on neurological development (low SoE). : Cognitive development: Prenatal DHA supplementation with AA or EPA had no effect on cognitive development (moderate SoE). Supplementing breastfeeding women with DHA plus EPA also had no effect on cognitive development in infants and children (low SoE). Supplementing or fortifying preterm infants' formula with DHA plus AA had a positive effect on infant cognition at some short-term followup times (moderate SoE). Supplementing or fortifying infant formula for term infants with any n-3 FA had no effect on cognitive development (low SoE). Evidence is insufficient to support any effect of n-3 FA infant supplementation on long-term cognitive outcomes. : Autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disorders: Maternal or infant n-3 FA supplementation had no effect on risk for autism spectrum disorders or ADHD (low SoE). No studies on other learning disorders were identified. : Atopic dermatitis (AD), allergies, and respiratory disorders: Pre- and postnatal (maternal and infant) n-3 FA supplementation had no consistent effect on the risk for AD/eczema, allergies, asthma, and other respiratory illnesses (moderate SoE). Biomarkers and intakes had no consistent association with the risk for AD, allergies, and respiratory disorders (low SoE). : Adverse events: Prenatal and infant supplementation with n 3 FA or fortification of foods with n-3 FA did not result in any serious or nonserious adverse events (moderate SoE); with the exception of an increased risk for mild gastrointestinal symptoms. CONCLUSIONS: Most studies in this report examined the effects of fish oil (or other combinations of DHA and EPA) supplements on pregnant or breastfeeding women or the effects of infant formula fortified with DHA plus AA. As with the original report, with the exception of small increases in birth weight and length of gestation,n-3 FA supplementation or fortification has no consistent evidence of effects on peripartum maternal or infant health outcomes. No effects of n-3 FA were seen on gestational hypertension, peripartum depression, or postnatal growth. Apparent effects of n-3 FA supplementation were inconsistent across assessment methods and followup times for outcomes related to infant visual acuity, cognitive development and prevention of allergy and asthma. Future RCTs need to assess standardized preparations of n-3 and n-6 FA, using a select group of clinically important outcomes, on populations with baseline n-3 FA intakes typical of those of most western populations. PMID- 30307736 TI - Health Information Exchange. AB - OBJECTIVES: This review sought to systematically review the available literature on health information exchange (HIE), the electronic sharing of clinical information across the boundaries of health care organizations. HIE has been promoted as an important application of technology in medicine that can improve the efficiency, cost-effectiveness, quality, and safety of health care delivery. However, HIE also requires considerable investment by sponsors, which have included governments as well as health care organizations. This review aims to synthesize the currently available research addressing HIE effectiveness, use, usability, barriers and facilitators to actual use, implementation, and sustainability, and to present this information as a foundation on which future implementation, expansion, and research can be based. DATA SOURCES: A research librarian designed and conducted searches of electronic databases, including MEDLINE(r) (1990 to February 2015), PsycINFO(r) (1990 to February 2015), CINAHL(r) (1990 through February 2015), the Cochrane Central Register of Controlled Trials (through January 2015), the Cochrane Database of Systematic Reviews (through January 2015), the Database of Abstracts of Reviews of Effects (through the first quarter of 2015), and the National Health Sciences Economic Evaluation Database (through the first quarter of 2015). The searches were supplemented by reviewing reference lists and the table of contents of journals not indexed in the databases we searched. REVIEW METHODS: Two investigators reviewed abstracts and the selected full-text articles for inclusion based on predefined criteria. Discrepancies were resolved through discussion and consensus, with a third investigator making the final decision as needed. Data were abstracted from each included article by one person and verified by another. All analyses were qualitative, and they were customized according to the topic. RESULTS: We included 136 studies overall, with 34 on effectiveness, 26 of which reported intermediate clinical, economic, or patient outcomes, and 8 that reported on clinical perceptions of HIE. We also found 58 studies on the use of HIE, 22 on usability and other facilitators and barriers to actual use of HIE, 45 on facilitators or barriers to HIE implementation, and 17 on factors related to sustainability of HIE. : No studies of HIE effectiveness reported impact on primary clinical outcomes (e.g., mortality and morbidity) or identified harms. Low-quality evidence somewhat supports the value of HIE for reducing duplicative laboratory and radiology test ordering, lowering emergency department costs, reducing hospital admissions (less so for readmissions), improving public health reporting, increasing ambulatory quality of care, and improving disability claims processing. In studies of clinician perceptions of HIE, most respondents attributed positive changes to HIE, such as improvements in coordination, communication, and knowledge about the patient. However in one study clinicians reported that the HIE did not save time and may not be worth the cost. : Studies of HIE use found that HIE adoption has increased over time, with 76 percent of U.S. hospitals exchanging information in 2014, an 85-percent increase since 2008 and a 23-percent increase since 2013. HIE systems were used by 38 percent of office-based physicians in 2012, while use remains low, less than 1 percent, among long-term care providers. : Within organizations with HIE, the number of users or the number of visits in which the HIE was used was generally very low. The degree of usability of an HIE was associated with increased rates of use but was not associated with effectiveness outcomes. The most commonly cited barriers to HIE use were lack of critical mass electronically exchanging data, inefficient workflow, and poorly designed interface and update features. Information was insufficient to allow us to assess usability by HIE function or architecture. : Studies provided information on both external environmental and internal organizational characteristics that affect implementation and sustainability. General characteristics of the HIE organization (e.g., strong leadership) or specific characteristics of the HIE system were the most frequently cited facilitators, while disincentives such as competition or lack of a business case for HIE were the most frequently identified barriers. LIMITATIONS: The scope of studies identified was limited compared with the actual uses and capabilities of HIE. The outcomes measured and methods of measurement and analysis, for example, were limited and narrowly defined; the issue of potential confounders was not addressed in most studies of effectiveness, and harms were not adequately studied. There was a high degree of heterogeneity in study designs, outcomes, HIE types, and settings across the studies, limiting the ability to synthesize the evidence; no quantitative analyses were possible. The applicability of this evidence base is uncertain because the HIE systems studied were so diverse, and many in existence have not contributed to research in this field. CONCLUSIONS: The full impact of HIE on clinical outcomes and potential harms is inadequately studied, although evidence provides some support for benefit in reducing use of some specific resources and achieving improvements in quality-of-care measures. Use of HIE has risen over time, and is highest in hospitals and lowest in long term care settings. However, use of HIE within organizations that offer it is still low. Barriers to HIE use include lack of critical mass participating in the exchange, inefficient workflow, and poorly designed interface and update features. Studies have identified numerous facilitators and barriers to implementation and sustainability, but the studies have not ranked or compared their impact. To advance our understanding of HIE, future studies need to address comprehensive questions, use more rigorous designs, use a standard for describing types of HIE, and be part of a coordinated systematic approach to studying HIE. PMID- 30307737 TI - Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review. AB - BACKGROUND: The effect and association of omega-3 fatty acids (n-3 FA) intake and biomarker levels with cardiovascular (CV) clinical and intermediate outcomes remains controversial. We update prior Evidence Reports of n-3 FA and clinical and intermediate CV disease (CVD) outcomes. OBJECTIVES: Evaluate the effect of n 3 FA on clinical and selected intermediate CV outcomes and the association of n-3 FA intake and biomarkers with CV outcomes. The n-3 FA under review include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), stearidonic acid (SDA), and alphalinolenic acid (ALA). DATA SOURCES: MEDLINE(r), Embase(r), the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CAB Abstracts from 2000 or 2002 to June 8, 2015, and eligible studies from the original reports and relevant existing systematic reviews. REVIEW METHODS: We included randomized controlled trials (RCTs) of any n-3 FA intake compared to no, lower, or other n-3 FA intake with an outcome of interest conducted in healthy adults, those at risk for CVD, or those with CVD. We also included prospective observational studies of the association between baseline n-3 FA intake or biomarker level and followup outcomes. We required 1 year or more of followup for clinical outcomes and 4 weeks for intermediate outcomes (blood pressure [BP] and lipids). RESULTS: From 11,440 citations (from electronic literature searches and existing systematic reviews), 829 abstracts met basic eligibility criteria; 61 RCTs and 37 longitudinal observational studies (in 147 articles) were included. Most RCTs and observational studies had few risk-of-bias concerns. : Total n-3 FA: There is low strength of evidence (SoE) of no association between total n-3 FA intake and stroke death or myocardial infarction. There is insufficient evidence for other outcomes. : Marine oils, total: There is moderate to high SoE that higher marine oil intake lowers triglycerides (Tg), raises high density lipoprotein cholesterol (HDL-c), and lowers the ratio of total cholesterol to HDL-c but raises low density lipoprotein cholesterol (LDL-c); also that higher marine oil intake does not affect major adverse CV events, all-cause death, total stroke, sudden cardiac death, coronary revascularization, atrial fibrillation, or BP. There is low SoE of associations between higher marine oil intake and decreased risk of CVD death, coronary heart disease (CHD), myocardial infarction, ischemic stroke, and congestive heart failure (CHF). There is low SoE of no association with CHD death or hemorrhagic stroke. There is insufficient evidence for other outcomes. : Marine oil FA individually: There is low SoE of no associations between EPA or DHA intake (separately) and CHD, and between EPA or DPA and atrial fibrillation. There is low SoE of no association between EPA biomarkers and atrial fibrillation, but moderate SoE of no effect of purified DHA supplementation on BP or LDL-c. There is insufficient evidence for other specific marine oil FA and outcomes. : ALA: There is moderate SoE of no effect of ALA intake on BP, LDL-c, HDL-c, or Tg. There is low SoE of no association between ALA intake or biomarker level and CHD, CHD death, atrial fibrillation, and CHF. There is insufficient evidence for other outcomes. : Other n-3 FA analyses: There is insufficient evidence comparing n-3 FA with each other or for SDA. : Subgroup analyses: Nineteen of 22 studies found no interaction of sex on any effect of n-3 FA. Likewise, 19 of 20 studies found no differential effect by statin co-use. Within 16 studies evaluating diabetes subgroups, 2 found statistically significant beneficial effects of n-3 FA in those with diabetes but not in those without diabetes, but no test of interaction was reported. CONCLUSIONS: The 61 RCTs mostly compared marine oil supplements with placebo on CVD outcomes in populations at risk for CVD or with CVD, while the 37 observational studies mostly examined associations between various individual n-3 FA and long-term CVD events in generally healthy populations. Compared with the prior report on n-3 FA and CVD, there is more robust RCT evidence on ALA and on clinical CV outcomes; also, by design there are newly added data on associations between n-3 FA biomarkers and CV outcomes. However, conclusions regarding the effect of n-3 FA intake on CV outcomes or associations with outcomes remain substantially unchanged. Marine oils statistically significantly raise HDL-c and LDL-c by similar amounts (<=2 mg/dL), while lowering Tg in a dose-dependent manner, particularly in individuals with elevated Tg; they have no significant effect on BP. ALA has no significant effect on intermediate outcomes. Limited data were available from RCTs on the effect of n-3 FA on clinical CVD outcomes. Observational studies suggest that higher marine oil intake (including from dietary fish) is associated with lower risk of several CVD outcomes. No clear differences in effects or associations were evident based on population, demographic features, or cointerventions. Future RCTs would be needed to establish adequate evidence of the effect of n-3 FA on CVD outcomes or to clarify differential effects in different groups of people. However, future trials are unlikely to alter conclusions about the effects of n-3 FA supplementation on intermediate cardiovascular outcomes (BP, LDL-c, HDL-c, or Tg). PMID- 30307738 TI - Vertical Extension of the T-Capsulotomy Incision in Hip Arthroscopic Surgery Does Not Affect the Force Required for Hip Distraction: Effect of Capsulotomy Size, Type, and Subsequent Repair. AB - BACKGROUND:: Interportal and T-capsulotomies are popular techniques for exposing femoroacetabular impingement deformities. The difference between techniques with regard to the force required to distract the hip is currently unknown. PURPOSE:: To quantify how increasing interportal capsulotomy size, conversion to T capsulotomy, and subsequent repair affect the force required to distract the hip. STUDY DESIGN:: Controlled laboratory study. METHODS:: Eight fresh-frozen cadaveric hip specimens were dissected and fixed in a materials testing system, such that pure axial distraction of the iliofemoral ligament could be achieved. The primary outcome measure was the load required to distract the hip to a distance of 6 mm at a rate of 0.5 mm/s. Each hip was tested in the intact state and then sequentially under varying capsulotomy conditions: 2-cm interportal, 4 cm interportal, half-T (4-cm interportal and 2-cm T-capsulotomy), and full-T (4 cm interportal and 4-cm T-capsulotomy). After serial testing, isolated T-limb repair and then subsequent complete repair were performed. Repaired specimens underwent distraction testing as previously stated to assess the ability to restore hip stability to the native profile. Distraction force as well as the relative distraction force (percentage normalized to the intact capsule) were compared between all capsulotomy and repair conditions. RESULTS:: Increasing interportal capsulotomy size from 2 to 4 cm resulted in significantly less force required to distract the hip ( P < .001). The largest relative decrease in force was seen between the intact state (274.6 +/- 71.2 N; 100%) and 2-cm interportal (209.7 +/- 73.2 N; 76.4% +/- 15.6%; P = .0008). There was no significant mean difference in distraction force when 4-cm interportal (160.4 +/- 79.8 N) was converted to half-T (140.7 +/- 73.5 N; P = .270) and then full-T (112.0 +/- 70.2 N; P = .204). When compared with the intact state, isolated T-limb repair partially restored stability (177.3 +/- 86.3 N; 63.5% +/- 19.8%; P < .0001), while complete repair exceeded native values (331.7 +/- 103.7 N; 122.7% +/- 15.1%; P = .0008). CONCLUSION:: The conversion of interportal capsulotomy to T capsulotomy did not significantly affect the force required to distract the hip in a cadaveric model. However, larger interportal capsulotomies resulted in significant stepwise decreases in distraction force. When performing interportal or T-capsulotomy, the iliofemoral ligament strength is significantly decreased, but complete capsular repair demonstrated the ability to restore joint stability to the native, intact hip. CLINICAL RELEVANCE:: Increasing interportal capsulotomy size decreases the force required to distract the hip. In an effort to maximize visualization and minimize the magnitude of iliofemoral ligament fibers cut, many surgeons have moved from extended interportal capsulotomy to T capsulotomy. Interportal and T-capsulotomies result in equivalent hip distraction, partial capsular repair marginally improves hip stability, and only complete repair has the ability to restore the hip to its native biomechanical profile. PMID- 30307739 TI - IL-23 mediates murine liver transplantation ischemia reperfusion injury via IFN gamma /IRF-1 pathway. AB - : Interleukin-23 (IL-23) is a pro-inflammatory cytokine initially studied in autoimmune disease which has been more recently linked to innate immunity. We observed that the expression of IL-23 is upregulated during hypoxia in hepatocyte and non-parenchymal cell (NPC) co-culture system, as well as during ischemia reperfusion (I/R) injury in the liver. Interferon regulatory factor-1 (IRF-1) is a transcription factor that induces expression of multiple inflammatory cytokines and has been shown to play a critical role in liver I/R injury. We observed that IL-23 signaling induces not only the IL-17/CXCL2 pathway, but also the IFN gamma/IRF-1 pathway. Quantification of cytokine genes revealed increased liver expression of IL-17a, CXCL2, and IRF-1 messenger RNA (mRNA) during liver transplantation. Recombinant IL-23 treated hepatocytes and NPC co-culture led to IL-17, CXCL2, IFN-gamma, and IRF-1 expression. With anti-IL17 and anti-Ly6G antibody neutralization, neutrophil recruitment and IFN-gamma production was decreased during warm I/R injury. Overexpression of IL-23 in vivo through use of an adenovirus vector also led to expression of IL-17, CXCL2, IFN-gamma, and IRF 1. The increased expression of IL-23 also led to increased apoptosis in the liver. By neutralization of IL-23 through use of an anti-IL-23p19 antibody, we were able to attenuate liver damage in wildtype mouse but not NKT deficient mouse. This suggests that IL-23 signaling shares a common pathway with NKT cells. CONCLUSION: IL-23 is induced early by I/R in the liver. Its signaling leads to activation of the IL-17/CXCL2 and IFN-gamma/IRF-1 pathways resulting in increased apoptosis and necrosis. PMID- 30307740 TI - Epidemiological Evaluation of Meniscal Ramp Lesions in 3214 Anterior Cruciate Ligament-Injured Knees From the SANTI Study Group Database: A Risk Factor Analysis and Study of Secondary Meniscectomy Rates Following 769 Ramp Repairs. AB - BACKGROUND:: Ramp lesions are characterized by disruption of the peripheral meniscocapsular attachments of the posterior horn of the medial meniscus. Ramp repair performed at the time of anterior cruciate ligament reconstruction (ACLR) has been shown to improve knee biomechanics. PURPOSE:: The primary objectives of this study were to evaluate the incidence of and risk factors for ramp lesions among a large series of patients undergoing ACLR. Secondary objectives were to determine the reoperation rate for failure of ramp repair, defined by subsequent reoperations for partial medial meniscectomy. STUDY DESIGN:: Case-control study; Level of evidence, 3. Case series; Level of evidence, 4. METHODS:: All patients underwent transnotch posteromedial compartment evaluation of the knee during ACLR. Ramp repair was performed if a lesion was detected. Potentially important risk factors were analyzed for their association with ramp lesions. A secondary analysis of all patients who underwent ramp repair and had a minimum follow-up of 2 years was undertaken to determine the secondary partial meniscectomy rate for failed ramp repair. RESULTS:: The overall incidence of ramp lesions in the study population was 23.9% (769 ramp lesions among 3214 patients). Multivariate analysis demonstrated that the presence of ramp lesions was significantly associated with the following risk factors: male sex, patients aged <30 years, revision ACLR, chronic injuries, preoperative side-to-side laxity >6 mm, and concomitant lateral meniscal tears. The secondary meniscectomy rate was 10.8% at a mean follow-up of 45.6 months (range, 24.2-66.2 months). Patients who underwent ACLR + anterolateral ligament reconstruction had a >2-fold reduction in the risk of reoperation for failure of ramp repair as compared with patients who underwent isolated ACLR (hazard ratio, 0.457; 95% CI, 0.226-0.864; P = .021). CONCLUSION:: There is a high incidence of ramp lesions among patients undergoing ACLR. The identification of important risk factors for ramp lesions should help raise an appropriate index of suspicion and prompt posteromedial compartment evaluation. The overall secondary partial meniscectomy rate after ramp repair is 10.8%. Anterolateral ligament reconstruction appears to confer a protective effect on the ramp repair performed at the time of ACLR and results in a significant reduction in secondary meniscectomy rates. PMID- 30307741 TI - Consultations with Naturopaths and Western Herbalists: Prevalence of Use and Characteristics of Users in Australia. AB - OBJECTIVES: To report the prevalence of naturopathic and Western herbal medicine service utilization in Australia, and describe the characteristics of individuals who use these services. DESIGN: This is a national cross-sectional study. SETTINGS: Online survey platform. SUBJECTS: Purposive convenience sampling was used to recruit 2025 adults who were matched to Australian population demographics by gender, age, and state of residence. INTERVENTIONS: A survey instrument consisting of 50 items covering demographics, health service utilization, health status, health literacy, and medicine disclosure to complementary healthcare providers. OUTCOME MEASURES: The prevalence, frequency, and cost of naturopathy and Western herbal medicine consultations and sociodemographic characteristics of users of naturopathic and Western herbalist services and associations between these factors. RESULTS: The final data set included 2019 participants: 6.2% (n = 126) consulted a naturopath and 3.8% (n = 76) a Western herbalist. These health services were most commonly used to improve well-being. An average of AUD$102.67 and AUD$49.64 was spent per user on consultations with naturopaths and Western herbalists, respectively, in the previous year. The most prevalent users were those between 18 and 29 years of age (39.3%), in a relationship (51%), employed (70%), and held a bachelor degree or higher (40.5%). Some degree of financial difficulty was reported by 65.4% of users. Having a chronic illness (p < 0.01) and using both conventional and complementary medicines (p = 0.05) were both associated with using naturopathic or Western herbal medicine services. Less than 40% of participants disclosed their use of conventional medicines to Western herbalists. CONCLUSIONS: Naturopathy and Western herbal medicine services are used by a substantial number of Australian adults who also use conventional health services. Accordingly, research is needed to determine how these health professions can be better integrated into mainstream healthcare settings to improve patient-practitioner communication and safety related to the use of these health services. PMID- 30307743 TI - Evaluating the Outcomes of Rotator Cuff Repairs With Polytetrafluoroethylene Patches for Massive and Irreparable Rotator Cuff Tears With a Minimum 2-Year Follow-up. AB - BACKGROUND:: Massive and irreparable rotator cuff tears are difficult to manage surgically. One technique is to use a synthetic polytetrafluoroethylene (PTFE) patch to bridge the tear. However, there is little information regarding the outcomes of this procedure. PURPOSE:: To determine the >=2-year outcomes of patients for whom synthetic patches were used as tendon substitutes to bridge irreparable rotator cuff defects. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: This retrospective cohort study used prospectively collected data. Patients included those with a synthetic patch inserted as an interposition graft for large and/or irreparable rotator cuff tears with a minimum 2-year follow-up. Standardized assessment of shoulder pain, function, range of motion, and strength was performed preoperatively, at 6 and 12 weeks, and at 6 months and >=2 years. Radiograph and ultrasound were performed preoperatively, at 6 months, and >=2 years. RESULTS:: At a mean of 36 months, 58 of 68 eligible patients were followed up, and 53 of 58 (90%) patches remained in situ. Three patches failed at the patch-tendon interface, while 1 patient (2 shoulders/patches) went on to have reverse total shoulder replacements. Patient-ranked shoulder stiffness ( P < .001), frequency of pain with activity and sleep ( P < .0001), level of pain at rest and overhead ( P < .0001), and overall shoulder function improved from bad to very good ( P < .0001) by 6 months. Supraspinatus (mean +/- SEM: 29 +/- 16 N to 42 +/- 13 N) and external rotation (39 +/- 13 N to 59 +/- 15 N) strength were the most notable increases at the >=2-year follow-up ( P < .0001). Passive range of motion also improved by 49% to 67%; forward flexion, from 131 degrees to 171 degrees ; abduction, from 117 degrees to 161 degrees ; external rotation, from 38 degrees to 55 degrees ; and internal rotation, from L3 to T10 ( P < .0001) preoperatively to >=2 years. The most improvement in passive range of motion occurred between 12 months and >=2 years. The mean (SD) Constant-Murley score was 90 (12), while the American Shoulder and Elbow Surgeons score was 95 (8). CONCLUSION:: At 36 months postoperatively, patients who had synthetic patches used as tendon substitutes to bridge irreparable rotator cuff defects reported less pain and greater overall shoulder function as compared with preoperative assessments. They demonstrated improved range of passive motion and improved strength. The data support the hypothesis that the technique of using a synthetic PTFE patch to bridge a large and/or irreparable tear has good construct integrity and improves patient and clinical outcomes. PMID- 30307742 TI - Autologous Chondrocyte Implantation and Tibial Tubercle Osteotomy for Patellofemoral Chondral Defects: Improved Pain Relief and Occupational Outcomes Among US Army Servicemembers. AB - BACKGROUND:: The occupational and functional results of patellofemoral autologous chondrocyte implantation (ACI) are underreported. This investigation sought to establish clinical outcomes and rates for return to work in a predominantly high demand military cohort undergoing this procedure. PURPOSE:: To determine the return-to-work, pain relief, and perioperative complication rates in a high demand athletic cohort undergoing patellofemoral ACI. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: All military servicemembers from 2 military medical centers undergoing ACI for high-grade patellofemoral chondral defects between 2006 and 2014 were identified, and data were abstracted from their medical records and clinical databases. Demographic and surgical variables were obtained for patients with at least 2 years of postoperative follow-up, and perioperative complications, rates of return to work, and survivorship from revision were quantified. RESULTS:: Seventy-two patients (72%) had >2-year follow up and had patellofemoral ACI for high-grade chondral defects, with 66 knees (91%) undergoing a concomitant offloading tibial tubercle osteotomy. Mean follow up was 4.3 years (range, 2.0-9.9 years). The mean +/- SD age was 34.4 +/- 6.1 years; 86% were male; and 57% were involved in military occupational specialties of heavy or very heavy demand. Second-generation patellofemoral ACI with a type I/III collagen membrane was used for 85% of knees. Most defects were isolated to the patella (n = 40, 55%). The mean total defect surface area was 4.5 +/- 2.9 cm2 (range, 2.7-13.5 cm2). Fifty-six servicemembers (78%) returned to their occupational specialties. Three patients (4.1%) were classified as having surgical failures, requiring subsequent knee arthroplasty (n = 2) or a revision chondral procedure (n = 1). Mean visual analog scores improved significantly from 6.5 +/- 1.5 to 3.2 +/- 2.1 ( P < .0001). Multivariate analysis identified use of a periosteal patch as the only significant independent predictor for surgical ( P = .013) and overall ( P = .033) failures. Age <30 years ( P = .019), female sex ( P = .019), and regular tobacco use ( P = .011) were independent predictors of overall failure. CONCLUSION:: For patellofemoral chondral defects without a failed primary procedure, second-generation ACI successfully returned to work 78% of patients of moderate to very heavy occupational demand with significantly decreased patient-reported knee pain. Risk factors after ACI for patellofemoral articular lesions for overall failure were age <30 years, female sex, and tobacco use, while surgical and overall failures were associated with periosteal patch use. PMID- 30307744 TI - Videourology Abstracts. PMID- 30307745 TI - Enhanced Gastrointestinal Passive Paracellular Permeability Contributes to the Obesity-associated Hyperoxaluria. AB - Most kidney stones (KS) are composed of calcium oxalate and small increases in urine oxalate enhance the stone risk. Obesity is a risk factor for KS and urinary oxalate excretion increases with increased body size. We previously established the obese ob/ob ( ob) mice as a model (3.3-fold higher urine oxalate) to define the pathogenesis of obesity-associated hyperoxaluria (OAH). The purpose of this study was to test the hypothesis that the obesity-associated enhanced intestinal paracellular permeability contributes to OAH by increasing passive paracellular intestinal oxalate absorption. ob mice have significantly higher jejunal (1.6 fold) and ileal (1.4-fold) paracellular oxalate absorption ex vivo, and significantly higher (5-fold) urine 13C-oxalate following oral gavage with 13C oxalate, indicating increased intestinal oxalate absorption in vivo. Observing higher oxalate absorption in vivo compared to ex vivo suggest the possibility of increased paracellular permeability along the entire gut. Indeed, ob mice have significantly higher fractions of the administered sucrose (1.7-fold), lactulose (4.4-fold), and sucralose (3.1-fold) excreted in the urine, reflecting increased gastric, small intestinal, and colonic paracellular permeability, respectively. The ob mice have significantly reduced gastrointestinal occludin, ZO-1, and claudins-1 & 3 mRNA and total protein expression. Proinflammatory cytokines and oxidative stress, which are elevated in obesity, significantly enhanced paracellular intestinal oxalate absorption in vitro & ex vivo. We conclude that obese mice have significantly higher intestinal oxalate absorption and enhanced gastrointestinal paracellular permeability in vivo, which would likely contribute to the pathogenesis of OAH, since there is a transepithelial oxalate concentration gradient to drive paracellular intestinal oxalate absorption. PMID- 30307746 TI - A Practical Guide to Whole Slide Imaging: A White Paper From the Digital Pathology Association. AB - CONTEXT.-: Whole slide imaging (WSI) represents a paradigm shift in pathology, serving as a necessary first step for a wide array of digital tools to enter the field. Its basic function is to digitize glass slides, but its impact on pathology workflows, reproducibility, dissemination of educational material, expansion of service to underprivileged areas, and intrainstitutional and interinstitutional collaboration exemplifies a significant innovative movement with far-reaching effects. Although the benefits of WSI to pathology practices, academic centers, and research institutions are many, the complexities of implementation remain an obstacle to widespread adoption. In the wake of the first regulatory clearance in the United States of WSI for primary diagnosis, some barriers to adoption have fallen. Nevertheless, implementation of WSI remains a difficult prospect for many institutions, especially those with stakeholders unfamiliar with the technologies necessary to implement a system or who cannot effectively communicate to executive leadership and sponsors the benefits of a technology that may lack clear and immediate reimbursement opportunity. OBJECTIVES.-: To present an overview of WSI technology-present and future-and to demonstrate several immediate applications of WSI that support pathology practice, medical education, research, and collaboration. DATA SOURCES. : Peer-reviewed literature was reviewed by pathologists, scientists, and technologists who have practical knowledge of and experience with WSI. CONCLUSIONS.-: Implementation of WSI is a multifaceted and inherently multidisciplinary endeavor requiring contributions from pathologists, technologists, and executive leadership. Improved understanding of the current challenges to implementation, as well as the benefits and successes of the technology, can help prospective users identify the best path for success. PMID- 30307747 TI - How to Validate Predictive Immunohistochemistry Testing in Pathology?: A Practical Approach Exploiting the Heterogeneity of Programmed Death Ligand-1 Present in Non-Small Cell Lung Cancer. PMID- 30307748 TI - Commentary: Campylobacter and Hemolytic Uremic Syndrome. AB - There are reports in the literature stating that Campylobacter infections can cause hemolytic uremic syndrome (HUS); however, a mechanism for how Campylobacter induces HUS has not been proposed by investigators. The most common bacterial inducer of HUS is the Shiga toxin-producing Escherichia coli (STEC), and a few cases of HUS are induced by an invasive Shigella dysenteriae or Streptococcus pneumoniae infection. Campylobacter spp. have not been shown to produce Shiga toxin (Stx) nor do they possess genetic elements capable of producing a Stx-like toxin. The neuraminidase associated with pneumococcal HUS has not been observed in Campylobacter. Therefore, in the absence of a well-defined toxic mechanism, it not clear that Campylobacter actually causes HUS. PMID- 30307750 TI - Factor Invariance of the Trait Meta-Mood Scale-24 in a Sample of Chilean Adolescents. AB - The purpose of this study is to adapt the Trait Meta-Mood Scale-24 (TMMS-24; Fernandez-Berrocal, Extremera, & Ramos, 2004 , Spanish short version of the TMMS, Salovey, Mayer, Goldman, Turvey, & Palfai, 1995 ) to the Chilean adolescent population (13-17 years), analyzing the psychometric properties of the instrument through confirmatory factor analyses, factor invariance analysis, and latent mean differences. For this purpose, a sample of 3,255 secondary and high school students, between 12 and 18 years old (M = 15.28, SD = 1.24), were recruited. The results confirm the measurement invariance and structure of TMMS-24 scores by sex and age. The results of the latent mean analysis show the existence of significant differences associated with sex and age in the TMMS-24 attention to feelings factor. The adequate psychometric properties of the TMMS-24 show that it is valid for the Chilean adolescent population, thus covering the existing gap in this context. PMID- 30307751 TI - Early Childhood Psychopathology Prospectively Predicts Social Functioning in Early Adolescence. AB - Psychopathology in school-age children predicts impairment later in development. However, the long-term psychosocial consequences of early childhood psychopathology are less well known. The current study is the first to prospectively examine how a range of diagnoses and symptoms in early childhood predict psychosocial functioning across specific domains during early adolescence 6-9 years later. A community sample (N = 595; 44.9% female; 88.7% White, 12.6% Hispanic) was assessed for psychopathology at ages 3 and 6 using the Preschool Age Psychiatric Assessment. Diagnoses and dimensional scores for depressive, anxiety, attention-deficit/hyperactivity (ADHD), and oppositional defiant disorders (ODD) were examined. When children were 12 years old, children and parents completed the UCLA Life Stress Interview for Children, a semistructured interview assessing functioning in multiple domains (academic, behavior, close friends, broader peers, maternal relationship, paternal relationship). Having a diagnosis in early childhood predicted greater impairment in all domains in early adolescence, except paternal relationship. Externalizing disorders predicted impairment in more domains than internalizing disorders. Most of the associations between early childhood psychopathology and poorer functioning in adolescence persisted after taking into account adolescent psychopathology. Moreover, the majority of bivariate associations with depressive, ODD, and ADHD symptoms, but not anxiety symptoms, persisted in a subsample of children who did not meet criteria for a diagnosis in early childhood. Early childhood psychopathology has long-lasting deleterious effects on several domains of psychosocial functioning, often beyond the effects of continuing or recurring adolescent psychopathology. Findings thereby highlight the validity and clinical significance of early psychopathology. PMID- 30307752 TI - Sexual Attitudes, Erotophobia, and Sociosexual Orientation Differ Based on Relationship Orientation. AB - Consensual nonmonogamy (CNM) is an overarching term for relationship orientations that differ based on the degree to which consensual sexual and emotional needs are fulfilled outside of a dyad. Despite the diversity of CNM relationship orientations and growing research examining CNM, it is unclear whether the sexual attitudes, inclination to approach/avoid sexual stimuli (i.e., erotophobia erotophilia), and sociosexuality differ among individuals who identify with distinct CNM relationships. Further, as the agreements made in CNM relationships permit extradyadic relationships, important differences might emerge for CNM and monogamous individuals. A convenience sample (N = 641) of individuals who self identified as monogamous (n = 447), open (n = 80), polyamorous (n = 62), or swinger (n = 52) provided ratings of their sexual attitudes, erotophobia erotophilia, and sociosexuality. Results indicated that swingers had the most permissive and instrumental attitudes, were the most erotophilic, and were the most unrestricted sexually. Conversely, monogamists scored the lowest on these traits. No differences emerged between relationship orientations for attitudes toward communion and birth control. These findings have important implications for sexuality research because they reinforce the view that some underlying differences and similarities exist between monogamous and CNM individuals. PMID- 30307753 TI - Not Just Asking Questions: Effects of Implicit and Explicit Conspiracy Information About Vaccines and Genetic Modification. AB - While conspiracy ideation has attracted overdue attention from social scientists in recent years, little work focuses on how different pro-conspiracy messages affect the take-up of conspiracy beliefs. In this study, we compare the effect of explicit and implicit conspiracy cues on the adoption of conspiracy beliefs. We also examine whether corrective information can undo conspiracy cues, and whether there are differences in the effectiveness of corrective information based on whether a respondent received an explicit or implicit conspiracy cue. We examine these questions using a real-world but low-salience conspiracy theory concerning Zika, GM mosquitoes, and vaccines. Using a preregistered experiment (N = 1018: https://osf.io/hj2pw/ ), we find that both explicit and implicit conspiracy cues increase conspiracy beliefs, but in both cases corrections are generally effective. We also find reception of an explicit conspiracy cue and its correction is conditional on feelings toward the media and pharmaceutical companies. Finally, we find that examining open-ended conspiracy belief items reveals similar patterns, but with a few key differences. These findings have implications for how news media cover controversial public health issues going forward. PMID- 30307754 TI - Molecular Characterization of Enterotoxigenic Staphylococcus aureus Isolated from Raw Cow Milk in Poland. AB - The aim of this study was to characterize enterotoxigenic Staphylococcus aureus recovered from raw cow milk from two geographical regions of Poland using pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Among 610 samples tested, 229 (37.5%) were positive for S. aureus and 30 (13.1%) of them possessed at least one gene encoding enterotoxins. The sec marker was the most commonly identified (12; 40.0% isolates), followed by the sed (9; 30.0%), sea (6; 20.0%), and seb (1; 3.3%) genes. Some S. aureus possessed a combination of the sea and sec or sea and seb toxin markers. Only two (6.7%) of the enterotoxin gene positive isolates were not able to produce enterotoxins in vitro. Genotypic analysis with the PFGE method of a total of 50 toxigenic S. aureus isolates from the present and previous studies identified 16 clonal groups. Furthermore, MLST revealed the presence of 15 sequence types with the most common being ST45 and ST1. The results of this study indicate that raw cow milk may be a source of S. aureus with classical enterotoxin genes, which may pose a potential threat for the consumers' safety. PMID- 30307755 TI - Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy. AB - BACKGROUND: Renin-angiotensin system (RAS) is a complex network of enzymes and peptides with the essential role in blood pressure control. The relationships between RAS components, RAS-related genetic polymorphisms and therapy response in essential hypertension (EH) were widely explored but the results were inconclusive. AIM: The aim of this study was to explore the functional role of ACE insertion/deletion (I/D) polymorphism on the systemic quantity of angiotensin converting enzyme (ACE), its homolog - ACE2, chymase and angiotensin II in EH patients with respect to achieved therapeutic blood pressure control. RESULTS: Genotyping of ACE I/D polymorphism was performed among 140 patients with EH from Bulgaria. The serological analyses reveal the significant elevation of the serum quantity of all investigated enzymes in EH than normotensive controls. In addition, serum ACE2 (183.57 pg/ml; vs. 151.78 pg/ml; p = 0.02) and chymase (68.5 pg/ml; vs. 23.66 pg/ml; p = 0.034) were significantly higher in patients with uncontrolled EH than controlled EH in response to ACE-inhibitory therapy. Also, ACE I/D polymorphism showed a significant impact on the serum ACE and chymase levels. ACE quantity was the highest among carriers of DD-genotype, followed by ID and II-genotype. Contrary, chymase was in the highest quantity in II-genotype compared to ID-genotype (p = 0.025) and DD-genotype (p = 0.044). CONCLUSIONS: Our results suggest that insufficient blood pressure control by ACE-inhibitory therapy could be associated with elevation of serum ACE2 and chymase levels. Also, it appears that ACE I/D polymorphism may influence the circulating quantity of chymase in addition to ACE. PMID- 30307756 TI - Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema. AB - INTRODUCTION: The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available. Areas covered: Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018. Expert opinion: Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema. PMID- 30307758 TI - A systematic review and meta-analysis of return to work after mild Traumatic brain injury. AB - OBJECTIVE: To perform a systematic review and meta-analysis of return to work (RTW) times for adult patients with mild traumatic brain injury (mTBI). METHODS: Six databases and six trials registries were searched. Inclusion: studies reporting RTW, > 30 patients, adults, with mTBI. Exclusion: final measurement RTW < 30 days after injury, first measurement > 1 year. RESULTS: Of 978 records, 14 eligible studies were identified. Two included patients exclusively in paid employment pre-injury; four included paid employment, students, homemakers or other activities; seven included pre-injury occupational status described but unclear; one included patients whose pre-injury occupational status not described. Three reported average RTW, 12 reported proportions of patients RTW at pre-specified time-points (1 both). Average RTW times varied from 13 to 93 days. At 1 month the proportion of patients RTW (three pooled studies) was 0.56 (95% CI 0.30-0.79), at 6 months (six studies) 0.83 (0.74-0.89), at 12 months (seven studies) 0.89 (0.83-0.93). CONCLUSION: More than half of patients with mTBI have returned to work by 1 month after injury, and more than 80% by 6 months. Most studies had poor internal validity. Reporting of outcomes in mTBI is variable, and this accounted for some of the heterogeneity found in this review. PMID- 30307757 TI - Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5. AB - : The incidence of hypertension and diabetes is increasing, it is reported that adipocytokines might be involved in the pathogenesis of diabetes and hypertension. We aimed to investigate the features of adipocytokines, included of Leptin, Irisin, LGR4, and Sfrp5 in type 2 diabetes mellitus (T2DM) patients with hypertension, simultaneously analyzed the connection of the alteration of adipocytokines with blood pressure and glucose. 424 patients with T2DM and 90 healthy subjects were included in the study. The patients with T2DM were divided into 4 groups based on the blood pressure. The levels of adipocytokines (Leptin, Irisin, LGR4, and Sfrp5) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly higher levels of Leptin and lower levels of Irisin, LGR4 and Sfrp5 were seen in patients with diabetes compared with non-diabetes (P < 0.05), the mean values of Leptin level was ascending and Irisin, LGR4, and Sfrp5 levels were declining with promoting of blood pressure in hypertension as compared to the non-hypertension with diabetic patients. Multiple stepwise linear regression analysis showed that the concentrations of Leptin, Irisin, Sfrp5, and LGR4 were found to be closely associated with the control of blood pressure and glucose. CONCLUSION: Four adipocytokines might play different roles and closely relate to the occurrence and development of diabetes and hypertension. PMID- 30307759 TI - Efficacy of Propidium Monoazide on Quantitative Real-Time PCR-Based Enumeration of Staphylococcus aureus Live Cells Treated with Various Sanitizers. AB - Propidium monoazide (PMA) has been used together with quantitative real-time PCR (qPCR) to enumerate live bacteria, while discriminating against the residual DNA of dead bacterial cells. Although the effectiveness of PMA at increasing the accuracy of enumeration of live bacteria treated with heat has been investigated in a number of studies, few studies have involved bacteria treated with sanitizers. In this study, dead Staphylococcus aureus cells were prepared by treatment with six kinds of sanitizers (ethanol, isopropyl alcohol, benzalkonium chloride, sodium hypochlorite, hydrogen peroxide, and nisin) and were mixed with a culture of live bacteria in different ratios. PMA-qPCR was able to accurately enumerate live bacteria with a <0.5 CFU/500 MUL difference with that of plate counts for cultures treated with ethanol, isopropyl alcohol, and nisin. For ethanol and isopropyl alcohol treatments, live cells were accurately enumerated for live/dead cell ratios of 10/1 to 0.01/1, while live cells for the nisin treatment were accurately enumerated for live/dead cell ratios of 10/1 to 0.1/1. In contrast, PMA-qPCR was not able to accurately enumerate live cells in bacterial cultures treated with benzalkonium chloride and hydrogen peroxide. In addition, qPCR without PMA was able to enumerate live cells as consistently as plate counts with a bacterial culture treated with sodium hypochlorite. The results of this study show that the use of PMA for qPCR-based enumeration of live cells is not always recommended, and its effectiveness depends on the treatment used on the cells. PMID- 30307760 TI - Driver Vigilance in Automated Vehicles: Effects of Demands on Hazard Detection Performance. AB - OBJECTIVE: The current study investigated driver vigilance in partially automated vehicles to determine whether increased task demands reduce a driver's ability to monitor for automation failures and whether the vigilance decrement associated with hazard detections is due to driver overload. BACKGROUND: Drivers of partially automated vehicles are expected to monitor for signs of automation failure. Previous research has shown that a driver's ability to perform this duty declines over time. One possible explanation for this vigilance decrement is that the extreme demands of vigilance causes overload and leads to depletion of limited attentional resources required for vigilance. METHOD: Participants completed a 40-min drive in a simulated partially automated vehicle and were tasked with monitoring for hazards that represented potential automation failures. Two factors were manipulated to test the impact of monitoring demands on performance: Spatial uncertainty and event rate. RESULTS: As predicted, hazard detection performance was poorer when monitoring demands were increased, and performance declined as a function of time on task. Subjective reports also indicated high workload and task-induced stress. CONCLUSION: Drivers of partially automated vehicles are impaired by the vigilance decrement and elevated task demands, meaning that safe operation becomes less likely when the demands associated with monitoring automation increase and as a drive extends in duration. This study also supports the notion that vigilance performance in partially automated vehicles is likely due to driver overload. APPLICATION: Developers of automation technologies should consider countermeasures that attenuate a driver's cognitive load when tasked with monitoring automation. PMID- 30307761 TI - From the Editor-in-Chief's Desk. PMID- 30307762 TI - Guanfacine as a Facilitator of Recovery from Conversion Disorder in a Young Girl. PMID- 30307763 TI - Accuracy assessment of a novel image-free handheld robot for Total Knee Arthroplasty in a cadaveric study. AB - Surgical navigation has been shown to improve the accuracy of bone preparation and limb alignment in total knee arthroplasty (TKA). Previous work has shown the effectiveness of various types of navigation systems. Here, for the first time, we assessed the accuracy of a novel imageless semiautonomous handheld robotic sculpting system in performing bone resection and preparation in TKA using cadaveric specimens. In this study, we compared the planned and final implant placement in 18 cadaveric specimens undergoing TKA using the new tool. Eight surgeons carried out the procedures using three types of implant designs. A quantitative analysis was performed to determine the translational, angular, and rotational differences between the planned and achieved positions of the implants. The mean femoral flexion, varus/valgus, and rotational error was -2.0 degrees , -0.1 degrees , and -0.5 degrees , respectively. The mean tibial posterior slope, and varus/valgus error was -0.2 degrees , and -0.2 degrees , respectively. We obtained higher flexion errors for the femoral implant when using cut-guides as compared to using a bur for cutting the bones. The image-free robotic sculpting tool achieved accurate implementation of the surgical plan with small errors in implant placement. Future studies will focus on determining how well the accurate implant placement translates into a clinical and functional benefit for the patient. PMID- 30307764 TI - Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-kappaB pathway. AB - Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low-toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN-induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross-sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF-kappaB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF-kappaB pathway. Our study furthers the understanding of the mechanism of FEN-induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.-Qiu, L.-L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang S.-L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-kappaB pathway. PMID- 30307765 TI - N-acetylglucosaminyltransferase-I as a novel regulator of epithelial-mesenchymal transition. AB - N-Glycans are involved in numerous biologic processes, such as cell adhesion, migration, and invasion. To distinguish the functions of complex high-mannose types of N-glycans, we used the clustered, regularly interspaced, short palindromic repeats/Cas9 system to establish N-acetylglucosaminyltransferase (GnT)-I-knockout (KO) cells. Loss of GnT-I greatly induced cell-cell adhesion and decreased cell migration. In addition, the expression levels of epithelial mesenchymal transition (EMT) markers such as alpha-SMA, vimentin, and N-cadherin were suppressed, whereas the expression of claudin-1 was promoted, suggesting a mesenchymal-epithelial transition-like phenotype, an opposite process to the EMT, was occurred in the KO cells. The phosphorylation levels of Smad-2, epidermal growth factor receptor, and integrin-mediated focal adhesion kinase (FAK) were consistently suppressed. Furthermore, the restoration of GnT-I in the KO cells suppressed the cell-cell adhesion and augmented the expression of EMT markers as well as that of FAK activation. The expression levels of integrins were upregulated in the KO cells, although their functions were decreased, whereas their expression levels were downregulated in the rescued cells, which suggests a negative feedback loop between function and expression. Finally, we also found that the expression of GnT-I was important for cell survival, resistance to cancer drugs, and increased colony formation. The results of the present study demonstrate that GnT-I works as a switch to turn on/off EMT, which further supports the notion that on most surface receptors, the N-glycans differentially play essential roles in biologic functions.-Zhang, G., Isaji, T., Xu, Z., Lu, X., Fukuda, T., Gu, J. N-acetylglucosaminyltransferase-I as a novel regulator of epithelial-mesenchymal transition. PMID- 30307766 TI - circDiaph3 regulates rat vascular smooth muscle cell differentiation, proliferation, and migration. AB - Intimal hyperplasia is a reaction to vascular injury, which is the primary reason for vascular restenosis caused by the diagnostic or therapeutic procedure for cardiovascular diseases. Circular RNAs (circRNAs) are known to be associated with several cardiovascular conditions, but the expression of circRNAs in the neointima has not been reported in detail. In this study, we established the balloon-injured rat carotid artery model and detected the expression of circRNAs in the carotid arteries with a microarray. We found that the circRNA expression profile of the healthy carotid arteries and the injured arteries were significantly different. We investigated the role of rno-circ_005717 ( circDiaph3) in the differentiation of rat vascular smooth muscle cells (VSMCs). We found that knockdown of circDiaph3 up-regulated the level of diaphanous related formin-3 and promoted the differentiation of VSMCs to contractile type. In addition, circDiaph3 up-regulated the transcription of Igf1r and supported the proliferation and migration of VSMCs. circDiaph3 could be a molecular target to combat intimal hyperplasia.-Xu, J.-Y., Chang, N.-B., Rong, Z.-H., Li, T., Xiao, L., Yao, Q.-P., Jiang, R., Jiang, J. circDiaph3 regulates rat vascular smooth muscle cell differentiation, proliferation and migration. PMID- 30307767 TI - Effect of Klotho on autophagy clearance in tacrolimus-induced renal injury. AB - Recently, we showed that tacrolimus-induced renal injury was closely associated with impairment of autophagy clearance, and Klotho deficiency aggravated tacrolimus-induced renal injury. In this study, we evaluated the effect of Klotho treatment on autophagy clearance in tacrolimus-induced renal injury. We evaluated the effect of Klotho on tacrolimus-induced renal injury in an experimental mouse model and in vitro by treatment with tacrolimus and/or recombinant mouse Klotho. In vivo and in vitro studies showed that tacrolimus treatment impaired lysosomal acidification and decreased cathepsin B activity, expression of lysosome associated membrane protein 2, and expression of transcription factor EB (TFEB), a master regulator for lysosomal biogenesis. These results were improved by Klotho treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effect of Klotho, indicating that the protective effect of Klotho was closely associated with lysosome function. Klotho induced nuclear translocation of TFEB through inhibition of phosphorylation of glycogen synthase kinase 3beta (GSK3beta) by confirming using CHIR99021, a GSK3beta inhibitor. Collectively, our data suggest that Klotho improves autophagy clearance via activation of lysosomal function in tacrolimus-induced nephrotoxicity.-Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Effect of Klotho on autophagy clearance in tacrolimus-induced renal injury. PMID- 30307768 TI - Involvement of thapsigargin and cyclopiazonic acid-sensitive pumps in the rescue of TMEM165-associated glycosylation defects by Mn2. AB - Congenital disorders of glycosylation are severe inherited diseases in which aberrant protein glycosylation is a hallmark. Transmembrane protein 165 (TMEM165) is a novel Golgi transmembrane protein involved in type II congenital disorders of glycosylation. Although its biologic function is still a controversial issue, we have demonstrated that the Golgi glycosylation defect due to TMEM165 deficiency resulted from a Golgi Mn2+ homeostasis defect. The goal of this study was to delineate the cellular pathway by which extracellular Mn2+ rescues N glycosylation in TMEM165 knockout (KO) cells. We first demonstrated that after extracellular exposure, Mn2+ uptake by HEK293 cells at the plasma membrane did not rely on endocytosis but was likely done by plasma membrane transporters. Second, we showed that the secretory pathway Ca2+-ATPase 1, also known to mediate the influx of cytosolic Mn2+ into the lumen of the Golgi apparatus, is not crucial for the Mn2+-induced rescue glycosylation of lysosomal-associated membrane protein 2 (LAMP2). In contrast, our results demonstrate the involvement of cyclopiazonic acid- and thapsigargin (Tg)-sensitive pumps in the rescue of TMEM165-associated glycosylation defects by Mn2+. Interestingly, overexpression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2b isoform in TMEM165 KO cells partially rescues the observed LAMP2 glycosylation defect. Overall, this study indicates that the rescue of Golgi N-glycosylation defects in TMEM165 KO cells by extracellular Mn2+ involves the activity of Tg and cyclopiazonic acid-sensitive pumps, probably the SERCA pumps.-Houdou, M., Lebredonchel, E., Garat, A., Duvet, S., Legrand, D., Decool, V., Klein, A., Ouzzine, M., Gasnier, B., Potelle, S., Foulquier, F. Involvement of thapsigargin and cyclopiazonic acid-sensitive pumps in the rescue of TMEM165-associated glycosylation defects by Mn2+. PMID- 30307769 TI - Farnesoid X receptor-alpha is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. AB - Hepatitis B virus (HBV) infection and bile acid (BA) metabolism are interdependent: infection modifies the expression of the BA nuclear receptor farnesoid X receptor (FXR)-alpha, and modulation of FXRalpha activity by ligands alters HBV replication. Mechanisms of HBV control by FXRalpha remain to be unveiled. FXRalpha silencing in HBV-infected HepaRG cells decreased the viral covalently closed circular (ccc)DNA pool size and transcriptional activity. Treatment with the FXRalpha agonist GW4064 inhibited FXRalpha proviral effect on cccDNA similarly for wild-type and hepatitis B viral X protein (HBx)-deficient virus, whereas agonist-induced inhibition of pregenomic and precore RNA transcription and viral DNA secretion was HBx dependent. These data indicated that FXRalpha acts as a proviral factor by 2 different mechanisms, which are abolished by FXRalpha stimulation. Finally, infection of C3H/HeN mice by a recombinant adeno-associated virus-2/8-HBV vector induced a sustained HBV replication in young mice in contrast with the transient decline in adult mice. Four-week GW4064 treatment of infected C3H/HeN mice decreased secretion of HBV DNA and HB surface antigen in adult mice only. These results suggest that the physiologic balance of FXRalpha expression and activation by bile acid is a key host metabolic pathway in the regulation of HBV infection and that FXRalpha can be envisioned as a target for HBV treatment.-Mouzannar, K., Fusil, F., Lacombe, B., Ollivier, A., Menard, C., Lotteau, V., Cosset, F.-L., Ramiere, C., Andre, P. Farnesoid X receptor alpha is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. PMID- 30307770 TI - Prominin-like, a homolog of mammalian CD133, suppresses di lp6 and TOR signaling to maintain body size and weight in Drosophila. AB - CD133 (AC133/prominin-1) has been identified as a stem cell marker and a putative cancer stem cell marker in many solid tumors. Its biologic function and molecular mechanisms remain largely elusive. Here, we show that a fly mutant for prominin like, a homolog of mammalian CD133, shows a larger body size and excess weight accompanied with higher fat deposits as compared with the wild type. The expression levels of prominin-like are mediated by ecdysone signaling where its protein levels increase dramatically in the fat body during metamorphosis. Prominin-like mutants exhibit higher Drosophila insulin-like peptide 6 (di lp6) levels during nonfeeding stages and increased Akt/ Drosophila target of rapamycin (dTOR) signaling. On an amino acid-restricted diet, prominin-like mutants exhibit a significantly larger body size than the wild type does, similar to that which occurs upon the activation of the dTOR pathway in the fat body. Our data suggest that prominin-like functions by suppressing TOR and dilp6 signaling to control body size and weight. The identification of the physiologic function of prominin like in Drosophila may provide valuable insight into the understanding of the metabolic function of CD133 in mammals.-Zheng, H., Zhang, Y., Chen, Y., Guo, P., Wang, X., Yuan, X., Ge, W., Yang, R., Yan, Q., Yang, X., Xi, Y. Prominin-like, a homolog of mammalian CD133, suppresses di lp6 and TOR signaling to maintain body size and weight in Drosophila. PMID- 30307771 TI - Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration. AB - Preeclampsia (PE) is a common cause of maternal morbidity, characterized by impaired trophoblast invasion and spiral artery transformation resulting in progressive uteroplacental hypoxia. Given the primary role of LIN28A and LIN28B in modulating cell metabolism, differentiation, and invasion, we hypothesized that LIN28A and/or LIN28B regulates trophoblast differentiation and invasion, and that its dysregulation may contribute to PE. Here we show that LIN28B is expressed ~1300-fold higher than LIN28A in human term placenta and is the predominant paralog expressed in primary human trophoblast cultures. The expression of LIN28B mRNA and protein levels are significantly reduced in gestational age-matched preeclamptic vs. normal placentas, whereas LIN28A expression is not different. First trimester human placental sections displayed stronger LIN28B immunoreactivity in extravillous (invasive) cytotrophoblasts and syncytial sprouts vs. villous trophoblasts. LIN28B overexpression increased HTR8 cell proliferation, migration, and invasion, whereas LIN28B knockdown in JEG3 cells reduced cell proliferation. Moreover, LIN28B knockdown in JEG3 cells suppressed syncytin 1 (SYN-1), apelin receptor early endogenous ligand (ELABELA), and the chromosome 19 microRNA cluster, and increased mRNA expression of ITGbeta4 and TNF-alpha. Incubation of BeWo and JEG3 cells under hypoxia significantly decreased expression of LIN28B and LIN28A, SYN-1, and ELABELA, whereas TNF-alpha is increased. These results provide the first evidence that LIN28B is the predominant paralog in human placenta and that decreased LIN28B may play a role in PE by reducing trophoblast invasion and syncytialization, and by promoting inflammation.-Canfield, J., Arlier, S., Mong, E. F., Lockhart, J., VanWye, J., Guzeloglu-Kayisli, O., Schatz, F., Magness, R. R., Lockwood, C. J., Tsibris, J. C. M., Kayisli, U. A., Totary-Jain, H. Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration. PMID- 30307772 TI - HSF1 mediated TNF-alpha production during proteotoxic stress response pioneers proinflammatory signal in human cells. AB - The proteotoxic stress response that safeguards the cellular proteome from various stressors was shown to activate NF-kappaB signaling pathways (NkappaBS) with an underlying mechanism that is poorly understood. We show here that the TNF alpha gene, a pleiotropic NkappaBS inducer, is a direct target of heat shock factor 1 (HSF1). Human HSF1 drives this process by assembling a multiprotein activation complex at a heat shock element (HSE) located at the 3'-UTR of the TNF alpha gene (HSE5). HSF1 associated with the HSE5 at the TNF-alpha 3'-UTR communicates with the promoter through chromatin looping by recruiting lymphoid enhancer-binding factor 1 at an adjacent Wnt-responsive element through its transactivation domain. TNF-alpha thus produced guides the activation of NkappaBS by acting through TNF-alpha receptor 1 (TNFR1). Notably, cells with TNFR1-/- background or masked HSE5 through Clustered Regularly Interspaced Short Palindromic Repeats/dead CRISPR-associated protein 9 were defective in NkappaBS and exhibited marked alteration in cellular biology, which includes loss of ability of cancer cells to migrate, to clear the protein aggregates, and associated toxicity upon heat shock. For the first time, our results suggest that TNF-alpha thus produced pioneers the proinflammatory signal during proteotoxic stress response with an important implication for inflammation and cancer.-Ali, A., Biswas, A., Pal, M. HSF1 mediated TNF-alpha production during proteotoxic stress response pioneers proinflammatory signal in human cells. PMID- 30307774 TI - Correction to: Steiner et al., Small for gestational age as an independent risk factor for long-term pediatric gastrointestinal morbidity of the offspring. PMID- 30307773 TI - Predictive value of long noncoding RNA ZFAS1 in patients with ischemic stroke. AB - BACKGROUND: LncRNAs play an essential role in a variety of diseases. Zinc finger antisense 1 (ZFAS1), a newly identified lncRNA, is a transcript antisense to the 5' end of the gene Znfx1. The purpose of this study was to aim to compare the levels of ZFAS1 between ischemic stroke (IS) and healthy control subjects and explore its potential role as a noninvasive biomarker in the diagnosis of IS. METHODS: A total of 176 patients and 111 healthy controls were included in the study. RT-qPCR was performed to detect the expression of ZFAS1. RESULTS: The results showed that level of ZFAS1 in IS patients was significantly lower than controls (P = 0.0002). Furthermore, we found that the ZFAS1 levels in large artery atherosclerosis (LAA) strokes were significantly downregulated than those in non-LAA strokes and controls. Meanwhile, ZFAS1 levels in the small vessel occlusion (SVO) group were lower than those in cardioembolism (CE) (P = 0.0197) and controls (P = 0.0041). Multinomial logistic regression analyses showed that the expression of ZFAS1 was not associated with the CE (P = 0.185) and SVO (P = 0.268) stroke groups, while lower ZFAS1 levels (P < 0.003, adjusted OR = 0.218, 95% CI: 0.079-0.597) showed significant associations with increased probability of having LAA strokes, compared to control subjects. The receiver operating characteristic curve analyses indicated that the sensitive of ZFAS1 was 89.39% in differentiating LAA strokes from controls. CONCLUSION: These results suggest that ZFAS1 might be used as a potential noninvasive biomarker for the diagnosis of LAA stroke. PMID- 30307775 TI - Manual therapy and early return to sport in football players with adductor related groin pain: A prospective case series. AB - OBJECTIVES: To study the clinical course including return to sport success rates of football players with adductor-related groin pain (ARGP) after manual therapy of the adductor muscles. DESIGN: Prospective case series. METHODS: Thirty-four football players with ARGP with median pre-injury Tegner scores of 9 (IQR 25-75: 9-9) were treated with manual therapy of the adductor muscles. Main outcome measures were numeric pain rating scale (NPRS), Hip and Groin Outcome Score (HAGOS) and global perceived effect (GPE) for treatment and patient satisfaction at 2, 6 and 12 weeks. Return to sport was documented. RESULTS: Pain during (NPRS 7 (6-8) and after (NPRS 8 (6-8) sports decreased to NPRS 1 (0.2-3) and 1 (0.8-3), respectively (p < 0.001). Within 2 weeks 82% of the players returned to pre injury playing levels with improved (p < 0.001) HAGOS subscale scores. Eighty five percent reported clinically relevant improvement, 82% reported to be satisfied. At 12 weeks, 88% had returned to pre-injury playing levels. HAGOS showed symptoms were still present. CONCLUSION: Early return to sport seems possible and safe after manual therapy of the adductor muscles in football players with ARGP in the short term. While the majority of injured football players return to sport within two weeks, caution is advised regarding effectiveness as hip and groin symptoms were still present and no control groups were available. PMID- 30307777 TI - Immune Response and Mechanisms of IFN-gamma in Administration for Keratomycosis. AB - PURPOSE: To investigate the immune response and mechanisms of interferon-gamma (IFN-gamma) in the fungal keratitis in mice. METHODS: Mice were divided into two groups: group A, topical PBS four times daily post-infection; group B: topical IFN-gamma four times daily post-infection. At1, 3, 5, and 7 days, the corneal lesions and inflammatory responses were observed by slit lamp, and immunofluorescence staining was performed to evaluate F4/80+ and CD4+ cells. Using ELISA, and RT-PCR to detect the expression levels of macrophage migration inhibitory factor (MIF), macrophage inflammatory protein-2 (MIP-2), IL-4, IL-10, IL-12, and IFN-gamma. RESULTS: The treatment with IFN-gamma decreased clinical scores and expression levels of IL-4, increased expression of F4/80+ and CD4+ cells, whereas IL-12, MIF, and MIP-2 were expressed highly, and the peaks of IL 10 and IFN-gamma move forward. CONCLUSION: This experiment showed that IFN-gamma eye drops increase the accumulation of macrophages and shorten the duration of fungal keratitis. PMID- 30307778 TI - Oral Medication Adherence Among Adolescents and Young Adults with Cancer Before and Following Use of a Smartphone-Based Medication Reminder App. AB - PURPOSE: This study evaluated oral medication adherence among adolescents and young adults (AYAs) with cancer during a trial of a smartphone-based medication reminder application (app). METHODS: Twenty-three AYAs receiving at least one prescribed, scheduled oral medication related to their outpatient cancer treatment participated in this 12-week single-group interrupted time series longitudinal design study. Baseline oral medication adherence was monitored using electronic monitoring caps for 4 weeks. Participants then used a medication reminder app and continued to have their oral medication adherence monitored for 8 weeks. Participants completed an electronically administered weekly survey addressing perceived adherence and reasons for nonadherence. RESULTS: Four adherence phenotypes were identified using visual graphical analysis of individual participants' weekly adherence: (1) high adherence during the preintervention and intervention periods (n = 13), (2) low preintervention adherence and improved adherence during the intervention period (n = 3), (3) low adherence during both periods (n = 6), and (4) high preintervention adherence and low adherence during the intervention period (n = 1). Growth curve models did not show significant changes in adherence by preintervention versus intervention trajectories (p > 0.05); however, the variance in adherence during the intervention narrowed for more highly adherent AYAs. "Forgetfulness" was the most frequently reported reason for nonadherence. CONCLUSION: Although overall adherence did not improve following use of the app, the variance decreased for more highly adherent participants. Additional or alternative interventions are needed for AYAs with persistently poor adherence. Assessment of adherence patterns may support individualized recommendation of tailored interventions. PMID- 30307779 TI - Positive Emotions During Infant Feeding and Postpartum Mental Health. AB - BACKGROUND: Research shows that individuals can improve mental health by increasing experiences of positive emotions. However, the role of positive emotions in perinatal mental health has not been investigated. This study explored the extent to which positive emotions during infant feeding are associated with maternal depression and anxiety during the first year postpartum. MATERIALS AND METHODS: One hundred and sixty-four women drawn from a longitudinal cohort of mother-infant dyads were followed from the third trimester through 12 months postpartum. We measured positive emotions during infant feeding at 2 months using the mean subscale score of the modified Differential Emotions Scale. Depression and anxiety symptoms were assessed with the Beck Depression Inventory II and State Trait Anxiety Inventory-State subscale at months 2, 6, and 12. Generalized linear mixed models were used to estimate crude and multivariable associations. RESULTS: Among women with no clinical depression during pregnancy, higher positive emotions during infant feeding at 2 months were associated with significantly fewer depression symptoms at 2, 6, and 12 months and with lower odds of clinically significant depression symptoms at 2 and 6 months. In contrast to depression outcomes, women with clinical anxiety during pregnancy who experienced higher positive emotions had significantly fewer anxiety symptoms at 2, 6, and 12 months and lower odds of clinically significant anxiety at 2 and 6 months. CONCLUSIONS: Positive emotions during infant feeding are associated with depression and anxiety outcomes during the first year postpartum and may be a modifiable protective factor for maternal mental health. PMID- 30307780 TI - Pregnancy-Associated Cancer: A U.S. Population-Based Study. AB - BACKGROUND: The incidence of pregnancy-associated cancer (PAC) is expected to increase as more women delay childbearing until later ages. However, information on frequency and incidence of PAC is scarce in the United States. METHODS: We identified pregnancies among women aged 10-54 years during 2001-2013 from five U.S. health plans participating in the Cancer Research Network (CRN) and the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). We extracted information from the health plans' administrative claims and electronic health record databases, tumor registries, and infants' birth certificate files to estimate the frequency and incidence of PAC, defined as cancer diagnosed during pregnancy and up to 1 year postpartum. RESULTS: We identified 846 PAC events among 775,709 pregnancies from 2001 to 2013. The overall incidence estimate was 109.1 (95% confidence interval [CI] = 101.8-116.7) per 100,000 pregnancies. There was an increase in the incidence between 2002 and 2012 (the period during which complete data were available), from 75.0 (95% CI = 54.9-100.0) per 100,000 pregnancies in 2002 to 138.5 (95% CI = 109.1-173.3) per 100,000 pregnancies in 2012. The most common invasive cancers diagnosed were breast (n = 208, 24.6%), thyroid (n = 168, 19.9%), melanoma (n = 93, 11.0%), hematologic (n = 87, 10.3%), and cervix/uterus (n = 74, 8.7%). CONCLUSIONS: Our study provides contemporary incidence estimates of PAC from a population-based cohort of U.S. women. These estimates provide the data needed to help develop clinical and public health policies aimed at diagnosing PAC at an early stage and initiating appropriate therapeutic interventions in a timely manner. PMID- 30307781 TI - Biological Characterization of an Edible Species from Brazilian Biodiversity: From Pharmacognostic Data to Ethnopharmacological Investigation. AB - Talisia esculenta (A. St.-Hil.) Radlk. is a large tree belonging to family Sapindaceae and popularly known as "pitombeira" or "pitomba." Although species have relevant economic and medicinal uses in Brazil, no study has investigated its effectiveness as a diuretic, hypotensive, and antihypertensive agent. The aim of this study was to present a detailed anatomical and histochemical study for T. esculenta and provide important safety and efficacy parameters. After morpho anatomical and microchemical study, a purified aqueous extract (ethanol soluble fraction obtained from T. esculenta [ESTE]) was obtained, and detailed phytochemical investigation was performed. Subsequently, acute oral toxicity test was performed in male and female rats. Moreover, diuretic, hypotensive, and antihypertensive effects on normotensive and spontaneously hypertensive rats (SHR) were investigated. Finally, the effects of prolonged treatment with ESTE on serum levels of nitrite, thiobarbituric acid reactive species, and nitrotyrosine were also measured in SHR. Oral treatment with ESTE did not induce acute toxic effects and did not affect urine production, blood pressure, or heart rate of normotensive and SHR. Prolonged treatment with ESTE was able to increase serum nitrite levels and significantly reduce oxidative and nitrosative stress markers in SHR. Data obtained showed that ESTE has a significant antioxidant activity without showing any clinical signs of acute toxicity. The use of this species as a diuretic, hypotensive, or antihypertensive agent should be carried out with caution, since administration in rodents did not produce renal and/or hemodynamic responses that justify this indication. PMID- 30307776 TI - Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline. PMID- 30307782 TI - Individual, Social, and Societal Correlates of Health-Related Quality of Life Among African American Survivors of Ovarian Cancer: Results from the African American Cancer Epidemiology Study. AB - OBJECTIVE: While the incidence of epithelial ovarian cancer (EOC) is lower among African American (AA) women compared with European American (EA) women, AA women have markedly worse outcomes. In this study, we describe individual, social, and societal factors in health-related quality of life (HRQL) in AA women diagnosed with EOC in the African American Cancer Epidemiology Study (AACES) that we hypothesize may influence a patient's capacity to psychosocially adjust to a diagnosis of cancer. METHODS: There were 215 invasive EOC cases included in the analysis. HRQL was measured using the SF-8 component scores for physical (PCS) and mental (MCS) health. We used least squares regression to test the effects of individual dispositional factors (optimism and trait anxiety); social level (perceived social support); and societal-level factors (SES defined as low family income and low educational attainment, and perceived discrimination) on HRQL, while adjusting for patient age, tumor stage, body mass index, and comorbidity. Mediation analysis was applied to test whether social support and physical activity buffer impacts of EOC on HRQL. RESULTS: Optimism, trait anxiety, social support, poverty, and past perceived discrimination were significantly associated with HRQL following diagnosis of EOC. Specifically, higher family income, lower phobic anxiety, and higher social support were associated with better wellbeing on the MCS and PCS (p < 0.01). Higher perceived discrimination was associated with both lower MCS and PCS, whereas higher optimism was associated with higher MCS. Physical activity (MET-min/week) and social support displayed significant overall mediation for effects of SES on MCS and PCS, but not for trait anxiety. CONCLUSIONS: Both pre- and postdiagnosis characteristics of AA women with EOC are important predictors of HRQL after cancer diagnosis. Individual, social, and societal-level factors each contribute to HRQL status with EOC and should be assessed. PMID- 30307783 TI - "It's the Symptom of the Problem, Not the Problem itself": A Qualitative Exploration of the Role of Pro-anorexia Websites in User's Disordered Eating. AB - The growing trend in the use of the Internet and social media as a method of self managing illness presents a critical opportunity to better understand the role of pro-anorexia (pro-ana) websites for eating disorders. Therefore, 155 pro-ana website messages regarding criticism that the site was responsible for developing anorexia were inductively thematically analysed. The analysis revealed five main themes: eating disorders are mental illnesses and websites do not cause mental illness, pro-ana websites and eating disorders are more than wanting to be thin (with sub-theme residents and visitors), eating disorders develop regardless of pro-ana websites, pro-ana sites do not cause eating disorders but they may trigger or encourage them (with sub-theme the problem is the user, not the site) and pro-ana sites provide support. Pro-ana websites and online communities present clinicians with complex treatment challenges. Collaborative, therapeutic consultations about pro-ana website use may help to establish how and when accessing them may hinder the treatment process. PMID- 30307784 TI - An Interrupted Time Series Evaluation of the Testing Makes Us Stronger HIV Campaign for Black Gay and Bisexual Men in the United States. AB - Black gay, bisexual, and other men who have sex with men (BMSM) are the subpopulation most disproportionately affected by HIV in the United States. Testing Makes Us Stronger (TMUS), a communication campaign designed to increase HIV testing rates among BMSM ages 18 to 44, was implemented in the United States from December 2011 through September 2015. We used interrupted time series analysis (ITSA) to compare pre- and post-campaign trends in monthly HIV testing events among the priority audience in six of the implementation cities from January 2011 through December 2014. In the 11 months prior to the launch of TMUS, HIV testing events among BMSM in the six campaign implementation cities decreased by nearly 35 tests per month (p = .021). After the introduction of TMUS, the number of HIV testing events among BMSM in the same cities increased by more than 6 tests per month (p = .002). ITSA represents a quasi-experimental technique for investigating campaign effects beyond underlying time trends when serial outcome data are available. Future evaluations can be further strengthened by incorporating a comparison group to account for the effects of history and maturation on pre- and post-campaign trends. PMID- 30307785 TI - Endurance Exercise Training Attenuates Natriuretic Peptide Release During Maximal Effort Exercise: Biochemical Correlates of the "Athlete's Heart". AB - Endurance exercise training (ET) stimulates eccentric left ventricular hypertrophy (LVH) with left atrial dilation. To date, the biochemical correlates of exercise-induced cardiac remodelling (EICR) remain incompletely understood. Collegiate male rowers (n = 9) were studied with echocardiography and maximal effort cardiopulmonary exercise testing (MECPET) before and after 90 days of ET intensification. Mid-regional pro-atrial natriuretic peptide (MR-proANP), N terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hscTn) were measured at rest, peak MECPET, and 60 minutes post-MECPET at both study time points. ET resulted in eccentric LVH (LV mass = 102 +/- 8 vs. 110 +/- 11 g/m2, p=0.001; relative wall thickness = 0.36 +/- 0.04 vs. 0.37 +/- 0.04, p=0.103), left atrial dilation (74 +/- 18 vs. 84 +/- 15 mL, p<0.001), and increased exercise capacity (peak VO2 = 53.0 +/- 5.9 vs. 67.3 +/- 8.2 ml/kg/min, p<0.001). LV remodelling was characterized by an approximate 7% increase in LV wall thickness but only a 3% increase in LV chamber radius. The magnitude of natriuretic peptide release, examined as percent change from rest to peak exercise, was significantly lower for both MR-proANP (115 [95, 127]% vs. 78 [59, 87]%, p=0.04) and NT-proBNP (46 [31, 70]% vs. 27 [25, 37]%, p=0.02) after ET. Rowing-based ET and corollary EICR appear to result in an attenuated natriuretic peptide response to maximal effort exercise. This may occur as a function of decreased cardiac wall stress after ET as seen by disproportionally higher ventricular wall thickening compared to chamber dilation. PMID- 30307786 TI - Prognostic utility of circulating nucleic acids in acute brain injuries. AB - INTRODUCTION: Acute brain injuries represent major causes of morbidity and mortality worldwide. Nevertheless, therapeutic options are centered mainly on supportive care, and accurate prognosis prediction following traumatic brain injury (TBI) or stroke remains a challenge in clinical settings. Areas covered: Circulating DNA and RNA have shown potential as predictive molecules in acute brain injuries. In particular, plasma cell-free DNA (cfDNA) levels have been correlated to severity, mortality, and outcome after TBI and stroke. The real time quantitative polymerase chain reaction (qPCR) is the most widely used technique for determination of cfDNA in brain injuries; however, to consider the use of cfDNA in emergency settings, a quicker and easier methodology for detection should be established. A recent study proposed detection of cfDNA applying a rapid fluorescent test that showed compatible results with qPCR. Expert commentary: As a promising perspective, detection of cfDNA levels using simple, rapid, and cheap methodology has potential to translate to clinic as a point-of-care marker, supporting the clinical decision-making in emergency care settings. Conversely, miRNA profiles may be used as signatures to determine the type and severity of injuries. Additionally, in the future, some miRNAs may constitute innovative neurorestorative therapies without the common hurdles associated with cell therapy. PMID- 30307787 TI - Environmental Exposure History and Vulvodynia Risk: A Population-Based Study. AB - BACKGROUND: Risk factors for vulvodynia continue to be elusive. We evaluated the association between past environmental exposures and the presence of vulvodynia. MATERIALS AND METHODS: The history of 28 lifetime environmental exposures was queried in the longitudinal population-based Woman-to-Woman Health Study on the 24-month follow-up survey. Relationships between these and vulvodynia case status were assessed using multinomial logistic regression. RESULTS: Overall, 1585 women completed the 24-month survey, the required covariate responses, and questions required for case status assessment. Screening positive as a vulvodynia case was associated with history of exposures to home-sprayed chemicals (insecticides, fungicides, herbicides-odds ratio [OR] 2.47, 95% confidence interval [CI] 1.71 3.58, p < 0.0001), home rodent poison and mothballs (OR 1.62, 95% CI 1.25-2.09, p < 0.001), working with solvents and paints (OR 2.49, 95% CI 1.68-3.70, p < 0.0001), working as a housekeeper/maid (OR 2.07, 95% CI 1.42-3.00, p < 0.0001), working as a manicurist/hairdresser (OR 2.00, 95% CI 1.14-3.53, p < 0.05), and working at a dry cleaning facility (OR 2.13, 95% CI 1.08-4.19, p < 0.05). When classified into nine individual environmental exposure categories and all included in the same model, significant associations remained for four categories (home-sprayed chemicals, home rodent poison or mothballs, paints and solvents, and working as a housekeeper). CONCLUSIONS: This preliminary evaluation suggests a positive association between vulvodynia and the reported history of exposures to a number of household and work-related environmental toxins. Further investigation of timing and dose of environmental exposures, relationship to clinical course, and treatment outcomes is warranted. PMID- 30307788 TI - We have the technology, but should we build the test? PMID- 30307789 TI - Sex Bias in Interventional Clinical Trials. AB - INTRODUCTION: Prior studies have shown that sex bias exists with subject enrollment in clinical trials, with more men being enrolled than women. The objective of this study was to identify if sex bias continues to exist in present day clinical trials entered into ClinicalTrials.gov . We hypothesize that males and females are not equally represented in recent clinical trials. MATERIALS AND METHODS: Data were abstracted from all interventional Phase I, II, and III clinical trials with adult subjects entered into ClinicalTrials.gov from January 1, 2011 to December 31, 2013 and completed by November 30, 2015. Number and sex of subjects, funding source, allocation, end point classification, interventional model, and purpose were recorded. Studies pertaining to diseases that were sex specific were excluded. RESULTS: Of 1,668 studies included in the initial search, 167 were excluded due to sex-specific study topic. Of the remaining 1,501 studies, 177,656 (51.1%) male and 170,331 (49.0%) female subjects were included. There was a significant difference in the sex of the subjects included in Phase I (64.1% male/35.9% female), Phase II (48.4% male/51.6% female), and Phase III (51.0% male/49.1% female) clinical trials (p < 0.05). Similarly, there was a significant difference in the sex of the subjects included in industry (50.7% male/49.3% female), National Institutes of Health (NIH) (56.6% male/43.4% female), "Other US Federal" (62.5% male/37.5% female), and "Other" funded (53.4% male/46.6% female) clinical trials (p < 0.0001), as well as between randomized (50.5% male/49.6% female) and nonrandomized (54.8% male/45.2% female) clinical trials (p < 0.0001). Upon evaluating if the sex of the subjects included in the individual clinical trials was equally matched, we found that only 4.1% of clinical trials had 100% sex matching, 22.2% had 80% sex matching, and 56.5% had 50% sex matching. Using a liberal 50% sex-matching criteria, Phase III and II clinical trials matched the sex of the subjects more frequently compared to Phase I trials (60.8%, 57.8%, and 45.5%, respectively, p = 0.003). CONCLUSION: These data reveal that sex bias is present in current day clinical trials. Despite legislation requiring NIH-funded clinical trials to include women, NIH-funded trials were not better than industry-funded trials at matching the inclusion of both sexes. PMID- 30307790 TI - Facets of Innate Immunity to Viral Infection. PMID- 30307791 TI - Does Gender Have Prognostic Value Among Patients with Myocardial Infarction? Analysis of the Data from the Hungarian Myocardial Infarction Registry. AB - BACKGROUND: The authors analyzed data from the Hungarian Myocardial Infarction Registry (HUMIR) to examine the potential impact of gender on the treatment and 30-day and 1-year mortality of patients with myocardial infarction (MI). MATERIALS AND METHODS: The National Registry of Myocardial Infarction included 42,953 patients between January 1, 2013 and December 31, 2016; 19,875 of whom were diagnosed with ST-elevation myocardial infarction (STEMI) and 23,078 with non-ST-elevation myocardial infarction (NSTEMI). The proportion of women was 39% and 41.9% in the two groups, respectively. Logistic regression analysis was performed adjusting for age, the year and month of hospital admission, smoking, as well as for five concomitant diseases and anamnestic data. We found that the odds ratio (OR) of performing percutaneous coronary intervention (PCI) was influenced by age, the year of treatment, prior stroke, and peripheral artery disease (PAD) in both patient groups. RESULTS: Gender had an impact on treatment in both cases; women had significantly fewer PCIs (OR = 0.86 confidence interval [95% CI: 0.77-0.95] in the STEMI group, OR = 0.75 [95% CI: 0.70-0.82] in the NSTEMI group). Age and PCI, PAD, and diabetes mellitus proved to be prognostic factors for 30-day and 1-year mortality in both groups. In the STEMI group, hypertension proved to be of prognostic value for both 30-day and 1-year mortality, whereas prior MI, stroke, and smoking only affected 1-year mortality. Similarly, in the NSTEMI group, prior stroke was also of prognostic value for 30 day and 1-year mortality, whereas prior MI, hypertension and smoking were only associated with 1-year mortality. CONCLUSIONS: The independent prognostic value of gender could not be proven for any of the MI types or follow-up periods. In conclusion, gender influenced the treatment of patients with MI but had no significant impact on prognosis in itself. PMID- 30307792 TI - The Effects of Probiotic Formulation Pretreatment (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on a Lipopolysaccharide Rat Model. AB - OBJECTIVE: The role of gut microbiota in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), via the gut brain axis has recently been demonstrated; hence, modification of the intestinal microbiota composition by probiotic biotherapy could be a therapeutic target for these conditions. The aim of this study was to assess the effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on inflammatory and memory processes in lipopolysaccharide (LPS)-induced rats, one of the animal models used in peripherally induced neuroinflammation and neurodegeneration. METHODS: Rats were randomly divided into four groups (Control, LPS, Probiotic + LPS, and Probiotic). All experimental groups were orally administrated maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 14 consecutive days and then were injected with saline or LPS (1 mg/kg, intraperitoneally [i.p.], single dose) 20 hours later. Memory retention ability and systemic and neuroinflammatory markers were assessed 4 hours after the injections. RESULTS: Systemic exposure to LPS resulted in significant elevation of both the circulating and hippocampal levels of proinflammatory cytokines, which decreased remarkably following probiotic pretreatment. Oral bacteriotherapy with a combination of L. helveticus R0052 and B. longum R0175 also attenuated the decremental effect of LPS on memory through brain-derived neurotrophic factor (BDNF) expression at the molecular level; however, this effect was not significant in the passive avoidance test at the behavioral level. CONCLUSIONS: These results suggest that the management of gut microbiota with this probiotic formulation could be a promising intervention to improve neuroinflammation associated disorders such as AD. PMID- 30307793 TI - Soft Poly-Limbs: Toward a New Paradigm of Mobile Manipulation for Daily Living Tasks. AB - We present the design and development of the fluid-driven, wearable, Soft Poly Limb (SPL), from the Greek word polys, meaning many. The SPL utilizes the numerous traits of soft robotics to enable a novel approach in providing safe and compliant mobile manipulation assistance to healthy and impaired users. This wearable system equips the user with a controllable additional limb that is capable of complex three-dimensional motion in space. Similar to an elephant trunk, the SPL is able to manipulate objects using a variety of end effectors, such as suction adhesion or a soft grasper, as well as its entire soft body to conform around an object, able to lift 2.35 times its own weight. To develop these highly articulated soft robotic limbs, we provide a novel set of systematic design rules, obtained through varying geometrical parameters of the SPL through experimentally verified finite element method models. We investigate performance of the limb by testing the lifetime of the new SPL actuators, evaluating its payload capacity, operational workspace, and capability of interacting close to a user through a spatial mobility test. Furthermore, we are able to demonstrate limb controllability through multiple user-intent detection modalities. Finally, we explore the limb's ability to assist in multitasking and pick and place scenarios with varying mounting locations of the SPL around the user's body. Our results highlight the SPL's ability to safely interact with the user while demonstrating promising performance in assisting with a wide variety of tasks, in both work and general living settings. PMID- 30307794 TI - Dietary Patterns and Attention Deficit Hyperactivity Disorder Among Iranian Children: A Case-Control Study. AB - OBJECTIVE: Associations between nutritional/dietary factors and mental disorders have been suggested. This study was conducted to assess the relation of major dietary patterns determined by factor analysis with attention deficit/hyperactivity disorder (ADHD) in a group of Iranian preschool- and school aged children. METHODS: This case-control study was conducted with 500 preschool- and school-aged children (4-12 years old) matched by age and sex, in Isfahan, Iran. Dietary intake was identified by a 168-item questionnaire, and major dietary patterns were identified by factor analysis. The multivariable logistic regression is used for the association of dietary patterns with the diagnosis of ADHD. ADHD diagnosis was carried out with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. RESULTS: Two major dietary patterns were identified: healthy and Western. The healthy dietary pattern was rich in fruits, vegetables, vegetable oils, whole grains, legumes, and dairy products. The Western pattern was rich in processed meat, red meat, pizza, eggs, snacks, animal fat, hydrogenated fat, and salt. After controlling for potential confounders, children in the top quintile of the Western dietary pattern score had greater odds having ADHD, compared with those in the lowest quintile (odds ratio [OR] = 3.45; 95% confidence interval [CI], 1.17-18.3; ptrend = 0.03). The healthy pattern was inversely associated with ADHD (OR = 0.46; 95% CI, 0.38-0.91; ptrend = 0.01). CONCLUSIONS: A significant independent association was found between the Western dietary pattern and the odds of ADHD. The healthy dietary pattern was associated with lower odds of having ADHD. Prospective studies are needed to confirm these findings. PMID- 30307795 TI - Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival. AB - Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling. However, it has been challenging to dissect the contribution of the virus and specific inflammatory mediators during an infection. In addition to initiating an antiviral program in infected NSPCs, cytokines/chemokines can induce multiple changes in NSPC behavior that can perturb NSPC numbers, differentiation into other neural cells, and migration to sites of injury, and ultimately brain development and repair. The focus of this review was to dissect the effects of common antiviral cytokines and chemokines on NSPC activity, and to consider the subsequent pathological consequences for the host from changes in NSPC function. PMID- 30307797 TI - "Still Raped Over Here": Gay Male Femininity and the Rewards of Camp Ambivalence in Richard Day's Girls Will Be Girls. AB - Girls Will Be Girls (GWBG) delivers a substantive queer-feminist critique of heteronormative animus toward women and gay men through jokes that weaponize that animus for insurgent purposes. The film's rape and abortion jokes showcase the provocative notion that negative representations of femininity might be wielded strategically and, in fact, more resonantly because they resist recuperation by marginalizing normative hierarchies. GBWG's enactment of gay male femininity deploys queer dissidence by ameliorating pain through mockery while emphasizing the costs of heteronormative and patriarchal inflictions. This essay offers a test case for a queer feminist politics-one that, without discarding the imperatives for and rewards of more materially grounded political work, mines the critical as well as affective affordances of rage, mockery, and indignity against heteronormativity's arbitrary but still formidable injunctions. A queer feminist reading of camp denaturalizes heteronormativity with a potency that queer theory and feminist theory might harness yet more effectually in less divided collaboration. PMID- 30307796 TI - Pluralistic Ignorance of Physical Attractiveness in the Gay Male Community. AB - Researchers have found that a disproportionate percentage of men diagnosed with eating disorders identify as gay, and there is extensive evidence that gay men have significantly more body image concerns than heterosexual men (Bosley, 2011). The current studies investigated whether pluralistic ignorance exists about what is considered attractive in the gay community. It was hypothesized that gay males would privately reject the notion that only a mesomorphic (thin and muscular) body type is attractive, yet incorrectly assume that their peers are attracted primarily to a mesomorphic body type. The studies found evidence for the existence of pluralistic ignorance about what is considered attractive in the gay community. Further, there was evidence for a significant association between pluralistic ignorance and body image concerns, particularly among men who were not in committed romantic relationships. PMID- 30307798 TI - "It's My Responsibility, But..." A Qualitative Study of Perpetrators' Understanding of Child Sexual Abuse. AB - The present study looked at child sexual abuse (CSA) from the perpetrator's perspective, focusing on precursors to, sustaining mechanisms, and inhibitors of CSA. Individuals serving sentences for sexual abuse of children under the age of 16 were interviewed (N = 8). A qualitative design using interpretative phenomenological analysis was employed. Negative childhood events such as poly victimization, poor social skills, loneliness, and insecure sexual identity were reported as predisposing elements. Abuse was sustained due to a strong conviction of not being responsible for doing anything wrong. Respondents conveyed few salient inhibitors for the abuse, though not wanting to physically harm the child was often cited as important. Implications for the prevention of CSA in risk groups suggest the need to increase the understanding of children from a child's perspective, changing conceptions leading to disavowal of adult responsibility toward children, strengthening social competency, integration into a social context, and increasing knowledge about the harmful consequences of CSA. PMID- 30307799 TI - Feminism Is Queer: The Intimate Connection Between Queer and Feminist Theory. PMID- 30307800 TI - Spirituality and Social Media: The Search for Support Among Black Men Who Have Sex With Men in Tennessee. AB - Young Black Men Who Have Sex With Men (BMSM) have been the subject of much research focused on health disparities in HIV occurrence, stigma, and mental health. Although such research is important, fewer studies focus on other equally salient areas of their lives such as spirituality, religious practices, and social support. Informed by literature on social support, this research endeavors to better understand these dynamics for a group of young BMSM who reside in a metropolitan city in Tennessee. Focus group results and content analysis uncover themes related to religion and resilience; queering Christianity; and virtual spirituality. Participants expressed an overarching need for support, safe spaces, genuine relationships, and godly instruction, conveyed through traditional Black Church involvement and nontraditional Internet usage. Findings are important for strategic, proactive, cross-generational collaboration with young BMSM to holistically meet their varied needs. PMID- 30307801 TI - Factors Influencing Rust (Melampsora apocyni) Intensity on Cultivated and Wild Apocynum venetum in Altay Prefecture, China. AB - Rust (Melampsora apocyni) on Apocynum venetum is the major constraint to the commercial development of this medicinal herb. To determine the factors influencing rust intensity (Maximum disease index, DImax), rust was investigated from 2011 to 2015 in both cultivated and wild A. venetum plants. Partial Least Squares Path Modeling (PLS-PM) was used to analyze the paths and extent of the factors related to pathogen, environment, and host that affect rust intensity. DImax exhibited considerable variations across years and study sites with variations linked to various factors fostering disease development. PLS-PM explained 80.0% and 70.1% of variations in DImax in cultivated and wild plants, respectively. Precipitation was the key factor determining DImax in both cultivated and wild plants (Path Coefficient, PC = 0.313 and 0.544, respectively). In addition, the topsoil water content in cultivated plants and the total vegetation coverage in wild plants were also critical determinants of DImax via their effects on the micro-climatic factor (Contribution Coefficients, CC = 0.681 and 0.989, respectively; PC = 0.831 and 0.231, respectively). In both cultivated and wild plants, host factors were mainly dominated by A. venetum density (CC = 0.989 and 0.894, respectively) and their effect on DImax via the micro-climatic factor (PC = 0.841 and 0.862, respectively) exceeded that via the inoculum factor (PC = 0.705 and 0.130, respectively). However, the indirect effects led to DImax variation, while the dilution effect on host (CC = -0.154) from weed in wild plants led to the indirect effect size in wild plants of 0.200, which was lower than 0.699 in cultivated plants. PMID- 30307802 TI - Resistance and acceptance: Ambivalent attitudes toward the aging body and antiaging practices among older Korean migrants living in New Zealand. AB - Using intersectionality as a conceptual framework, this study investigated how older Korean women living in New Zealand perceived their aging bodies, antiaging practices and/or products, and how they used such products. Thematic analysis identified three themes: tension between acceptance of the aging body as an inevitable process and transformation of the aging body into a healthy body, juggling between abstinence and use of antiaging products and practices, and redefining natural aging. The findings challenge binary interpretations between "acceptance" of and "resistance" to the experiences of the aging process and the use of antiaging practices. PMID- 30307803 TI - "You Have to Keep Yourself Hidden": Perspectives From Malaysian Malay-Muslim Men Who Have Sex With Men on Policy, Network, Community, and Individual Influences on HIV Risk. AB - Malay-Muslim men who have sex with men (MSM) are marginalized and hidden in Malaysia, a predominantly Muslim country in southeast Asia. We explored the policy, network, community, and individual factors related to HIV infection among Malay-Muslim MSM through 26 in-depth interviews and one focus group discussion (n = 5) conducted in Kuala Lumpur and Kota Bharu between October 2013 and January 2014. As religion plays an important role in their lives, participants viewed homosexuality as a sin. Low risk perception and misconceptions about HIV/AIDS were common, and most participants expressed reluctance to consult a doctor unless they had symptoms. Additionally, buying condoms was embarrassing and anxiety-producing. Fear of discrimination by health care providers and community hindered participants from disclosing sexual behaviors and accessing health services. Homophobic comments and policies by the government and religious leaders were concerns of participants. A safe and enabling environment is needed to reduce HIV risks among Malay-Muslim MSM. PMID- 30307804 TI - Androgen Receptor and ALDH1 Expression Among Internationally Diverse Patient Populations. AB - PURPOSE: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2/ neu (triple-negative breast cancer [TNBC]) are higher among African American (AA) compared with white American (WA) women, and TNBC prevalence is elevated among selected populations of African patients. The extent to which TNBC risk is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers, is uncertain. METHODS: We used immunohistochemistry to evaluate estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2/ neu, androgen receptor and aldehyde dehydrogenase 1 (ALDH1) expression among WA (n = 153), AA (n = 76), Ethiopian (Eth)/East African (n = 90), and Ghanaian (Gh)/West African (n = 286) patients with breast cancer through an institutional review board-approved international research program. RESULTS: Mean age at diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. TNBC frequency was higher for AA and Gh patients (41% and 54%, respectively) compared with WA and Eth patients (23% and 15%, respectively; P < .001) Frequency of ALDH1 positivity was higher for AA and Gh patients (32% and 36%, respectively) compared with WA and Eth patients (23% and 17%, respectively; P = .007). Significant differences were observed for distribution of androgen receptor positivity: 71%, 55%, 42%, and 50% for the WA, AA, Gh, and Eth patients, respectively ( P = .008). CONCLUSION: Extent of African ancestry seems to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1. PMID- 30307805 TI - Survey to Assess Knowledge and Reported Practices Regarding Blood Transfusion Among Cancer Physicians in Uganda. AB - PURPOSE: Optimal decision making regarding blood transfusion for patients with cancer requires appropriate knowledge of transfusion medicine among physicians. We assessed blood transfusion knowledge, attitudes, and reported practices among physicians working at Uganda Cancer Institute (UCI). MATERIALS AND METHODS: A cross-sectional self-administered survey of UCI physicians on their knowledge, attitudes, and practices regarding blood transfusion was conducted from June to September 2014. In consultation with transfusion medicine experts, 30 questions were developed, including 10 questions for each of the following three domains: knowledge, attitudes, and practices. For the knowledge domain, we created a knowledge score equal to the number of questions correctly answered out of 10. RESULTS: Of 31 physicians approached, 90% participated. The mean knowledge score was 5.3 (median, 5.5), and 32% correctly answered at least seven of 10 questions. Almost all (96%) understood the importance of proper patient identification before transfusion and indicated identification error as the most common cause of fatal transfusion reactions. More than 60% of physicians acknowledged they lacked knowledge and needed training in transfusion medicine. Most physicians reported sometimes changing their mind about whether to provide a patient with a transfusion on the basis of opinion of colleagues and sometimes administering unnecessary transfusions because of influence from others. CONCLUSION: Although UCI physicians have some basic knowledge in transfusion, most reported gaps in their knowledge, and all expressed a need for additional education in the basics of blood transfusion. Transfusion training and evidence-based guidelines are needed to reduce inappropriate transfusions and improve patient care. Greater understanding of peer influence in transfusion decision making is required. PMID- 30307806 TI - Burden of Cancer Among Syrian Refugees in Jordan. AB - The Syrian crisis, which started in 2011, has had a profound impact on the entire region. Jordan, with its limited resources, now has the second highest ratio of refugees to inhabitants in the world (89 to 1,000). The actual number of Syrians in Jordan is hotly contested: more than 630,776 refugees registered in November 2015 compared with 1,265,514 reported by the national census conducted at the same time. Although the numbers are slowly but steadily increasing, the number of patients with cancer who were registered by the Jordan Cancer Registry peaked in 2013 at 510 patients reported and subsequently slumped downward, which coincided with changes in funding as a result of the increasing strains on the Ministry of Health. Older individuals, women, and patients with advanced diseases were less likely to be registered. These findings overlap with data obtained from the authors' own center registry. Using age- and sex-specific population-based incidence rates, we estimated that 869 Syrians are diagnosed with cancer in Jordan annually. Using diagnosis-specific cost records of the King Hussein Cancer Foundation, we estimated that the cost of their treatments is 15.6 million Jordan dinars (US$22.1 million). PMID- 30307807 TI - Fluoroquinolone Resistance Mechanisms in Shigella Isolates in Shanghai, China Between 2010 and 2015. AB - OBJECTIVES: This study aimed to investigate the antimicrobial susceptibility of Shigella isolated in Shanghai, China and to determine the genetic basis of its resistance to fluoroquinolones. MATERIALS AND METHODS: A total of 402 strains of Shigella, including 145 Shigella flexneri and 257 Shigella sonnei isolates, were analyzed. The Kirby-Bauer disk diffusion method was used to determine the susceptibility of the strains to 13 antimicrobials. Minimum inhibitory concentration of ciprofloxacin was determined by E-test. Mutations within the quinolone resistance-determining regions (QRDRs) of gyrA and parC and in the plasmid-mediated quinolone resistance (PMQR) genes, including qnrA, qnrB, qnrS, and aac (6')-Ib-cr, were detected by polymerase chain reaction. All the products were then sequenced. RESULTS: Most of the Shigella isolates were found to be resistant to nalidixic acid (96.4%), streptomycin (96.4%), ampicillin (86.2%), tetracycline (79.8%), and sulfamethoxazole/trimethoprim (80.6%). S. flexneri isolates showed a significantly higher resistance to cefepime (33.6%), ciprofloxacin (54.2%), norfloxacin (34.1%), and levofloxacin (12.1%) compared with that observed for the S. sonnei strains (chi2 analysis, p < 0.05). Three mutations (Ser83, Asp87, and His211) in gyrA and one mutation (Ser80) in parC were detected. Of 257 S. sonnei isolates, 11.7% possessed gyrA mutations and 2% had parC mutations. Of 145 S. flexneri isolates, 98.6% possessed gyrA mutations and 97.9% had parC mutations. The plasmid-mediated resistance genes of qnrS and aac (6')-Ib-cr were detected among 17 strains (4.2%). CONCLUSIONS: The mutation percentage within the QRDR of S. flexneri was as high as 98.6 in gyrA and 97.9 in parC. The significant abundance of mutations within QRDRs conferred high levels of fluoroquinolone resistance. Moreover, the PMQR genes, particularly qnrS, played an important role in the decreased susceptibility of Shigella to fluoroquinolones. PMID- 30307808 TI - Body Image, Attractiveness, and Sexual Satisfaction Among Midlife Women: A Qualitative Study. AB - BACKGROUND: Women often undergo physical changes during the menopause transition, but the relationship between body image and sexual function in midlife is unclear. We used a qualitative approach to explore how body image relates to sexual function and satisfaction in midlife women. MATERIALS AND METHODS: We conducted 19 individual interviews and 3 focus groups (total N = 39) among sexually active women 45-60 years of age using a semistructured guide. Sessions were audiorecorded and transcribed. Two investigators developed a codebook using an iterative process; the primary investigator then coded all data. Codes relating to body image were examined to identify key themes. RESULTS: The mean age was 58 (range 46-59); 54% were White, 36% Black, and 10% were of another race. Most (72%) were peri- or postmenopausal. All but two women identified as heterosexual. Feeling attractive was an important reason for sexual activity. Changes in appearance, especially weight gain and breast changes, were common among these women. Women's body image impacted their sexual satisfaction; women who felt self-conscious about their bodies reported that these concerns had a negative impact on their sexual satisfaction, whereas women who felt confident discussed better sexual satisfaction, even in the face of bodily changes. Black women were more likely to discuss feeling confident than White women. CONCLUSIONS: Feeling attractive is important to sexual satisfaction in midlife women. Bodily changes, especially weight gain, are common during midlife. While many women are self-conscious about their appearance, some women develop increased self-acceptance. Supporting positive body image may help midlife women maintain sexual satisfaction with aging. PMID- 30307809 TI - Comparative Study Between Laparoscopic and Open Techniques for Insertion of Ventriculperitoneal Shunt for Treatment of Congenital Hydrocephalus. AB - INTRODUCTION: Different methods and devices have been developed to regulate cerebrospinal fluid flow for the treatment of congenital hydrocephalus (HC). In addition, progress in shape and materials of catheters and also valves has been achieved. Although many studies in literature have evaluated the benefits of a laparoscopic approach, few researches have compared the two techniques used for the insertion of the ventriculoperitoneal shunt (VPS). AIM: The aim of this study was to compare laparoscopically assisted VPS (LVPS) with open VPS and to evaluate the benefits of LVPS. PATIENTS AND METHODS: This cross-sectional analytic study was conducted on 192 children undergoing either laparoscopic or open placement of VPSs for congenital HC over 1-year period. Insertion of the proximal tube and reservoir were performed and the distal tube was then passed into the peritoneal cavity, either conventionally or laparoscopically assisted. RESULTS: Mean operative time was 50.1 minutes (28.0-121.8 minutes) in the laparoscopic group versus 74.0 minutes (39.0-162.0 minutes) in the open group (P < .05). Duration of hospital stay was the same (P = .938). The percentage of shunt failure during the follow-up period was 10% in the laparoscopic group and 17% in the open group (P = .623). Shunts were working in 85% at 6 months and 78.5% at 1 year. CONCLUSION: The laparoscopically assisted placement of VPS in children is safe, effective, associated with lower rates of abdominal malposition of the distal catheter, and a technically easy approach. It is an alternative method that may improve and simplify the safety of VPS surgery. PMID- 30307810 TI - How happiness expectations relate to the Dark Triad traits. AB - In samples of Americans (N = 273) and Indians (N = 194) paid through Mechanical Turk (Study 1) and British (N = 132) volunteers contacted through Reddit (Study 2), we examined how the Dark Triad traits (i.e., psychopathy, narcissism, and Machiavellianism) were associated with happiness expectations when participants imagined solving adaptive tasks. In Study 1, the traits were linked to forecasted happiness in achieving status and power and mate-seeking, with psychopathy demonstrating less happiness when pursuing slow life history tasks (e.g., avoiding diseases), whereas the other two traits led to expectations of happiness when forming social bonds, retaining mates, and avoiding pathogens. In Study 2, the traits were associated with choosing to pursue mating opportunities to induce happiness. Women expected more happiness in response to ensuring their safety over pursuing mating opportunities. We suggest happiness might be an affective feedback system that rewards people for pursuing their life history goals. PMID- 30307811 TI - Skin injury prevalence and incidence in China: a multicentre investigation. AB - OBJECTIVE:: To quantify the prevalence and incidence of different skin injuries, pressure ulcers (PU), skin tears (ST) and incontinence-associated dermatitis (IAD) in China, and to identify their causes to aid prevention and control. METHOD:: A cross-sectional observational study was conducted across nine tertiary hospitals. Registered nurses were trained on a standard approach to injury assessment and examination. The study was carried out at the same time on the same day across the participating centres. Participating patients were examined for PU, ST or IAD. RESULTS:: A total of 13,176 inpatients were assessed and 233 PU were identified, of which 126 occurred in hospitals, 99 cases at home and eight cases within community hospitals. In addition, there were 141 skin tears and 97 IADs. CONCLUSION:: This study involved the largest number of hospitals, to date (in China). Therefore, the prevalence and rate of incidence of skin injury obtained in this study may represent a regional baseline in China. PMID- 30307812 TI - Enhancing daily practice through knowledge sharing. PMID- 30307813 TI - The effect of different types of honey on healing infected wounds. AB - OBJECTIVE:: To investigate the effects of treatments of 'mad honey', blossom honey and nitrofurazone on infected wound healing. METHOD:: Male albino Wistar rats were randomly divided into four groups: 'mad honey' (MH), blossom honey (BH), nitrofurazone (N) and control (C). All rats were anaesthetised intraperitoneally. A circular skin incision was made to the back regions. Grafts containing slime-producing Staphylococcus epidermidis were placed on the incision area and then sutured to the skin. Infection in the wound area was confirmed after 48 hours. Wounds were dressed twice daily with the various treatment materials. Rats were randomly euthanised on days 7 or 14, and tissue samples taken. Tissue samples were assessed for hydroxyproline (HP), tensile strength (TS) and macroscopic measurement (area and intensity). RESULTS:: HP levels were higher in the treatment groups (MH, BH, N) at days 7 and 14 compared with the control group. 'Group x day' interaction was found in the HP levels (p=0.015). Increases in HP levels in the MH and N groups between days 7 and 14 were significantly higher than those in the other groups (p<0.05). Intensity was significantly lower in the control group and significantly higher in group MH compared with the other groups. Significant 'group x day' interaction was observed in intensity (p=0.006). TS was significantly lower on day 7 than on day 14 (p=0.022). No marked difference was observed between the groups, nor any 'group x day' interaction, in terms of TS. CONCLUSION:: Honey administration successfully healed infected wounds. However, there was no significant difference between the effect of MH and that of N in terms of wound healing. PMID- 30307814 TI - WUWHS news column. PMID- 30307815 TI - Baseline characteristics of infected foot ulcers in patients with diabetes at a tertiary care hospital in Pakistan. AB - OBJECTIVE:: Studies on diabetic foot ulcers (DFU) involving a representative sample of patients in Pakistan are scarce. This study aimed to determine baseline characteristics of infected DFUs in patients hospitalised at the Pakistan Institute of Medical Sciences Islamabad. METHOD:: In this cross-sectional study, carried out during May 2015 and June 2016, foot ulcer characteristics of patients with DFUs were investigated and documented. From infected DFUs, aerobic bacterial pathogens were isolated, identified and evaluated for antimicrobial susceptibility. RESULTS:: A total of 214 patients were recruited to the study, 62.6% of which were male, 90.2% were aged >=40 years, 76.2% had type 1 diabetes and 78.5% had poor glycaemic control at time of presentation to hospital. Most patients had grade 3/moderate ulceration (based on the Wagner and International Working Group on the Diabetic Foot/Infectious Diseases Society of America criteria). Over half of the DFUs (57.9%) were of <=3 months' duration and 70.1% were >=3 cm2. Of the patients with deep infection grade ulcers, 26.6% underwent amputation, accounting for their prolonged hospital stay (>=20 days). Significant differences were observed between patients with type 1 and type 2 diabetes with DFUs in relation to gender (p<=0.0001), ulcer size (p=0.0421) and duration of hospital stay (p=0.0253). The most significant predictors for lower extremity amputation were osteomyelitis (p=0.0114), retinopathy (p=0.0001) and neuropathy (p=0.0001. Piperacillin/tazobactam was found to be an effective antibiotic against the most commonly isolated Staphylococcus non-aureus (35.48%), Pseudomonas aeruginosa (22.26%), and Staphylococcus aureus (20.96%) species indentified in the DFU infections. CONCLUSION:: The findings of this study may be helpful in the optimal management and appropriate treatment of patients with infected DFUs. PMID- 30307816 TI - Use of wet-to-moist cleansing with different irrigation solutions to reduce bacterial bioburden in chronic wounds. AB - OBJECTIVE:: The influence of different irrigation solutions, in conjunction with wet-to-moist cleansing, on the reduction of sessile, non-planktonic bacteria which colonise wounds, has not been investigated. In this study, the antibacterial effect of different irrigation solutions, during a 20-minute wet-to moist cleansing, has been evaluated in chronic wounds. METHODS:: This study was designed as a prospective cohort study with 12 study arms and was conducted between June 2011 and April 2016. Patients with chronic wounds present for more than three months, irrespective of previous treatments, were recruited into this study. Quantitative wound swabs were obtained before and after a 20-minute, wet to-moist cleansing, using different wound irrigation solutions. Sterile 0.9% saline served as a control. RESULTS:: We recruited 308 patients, of which 260 patients with 299 chronic wounds were eligible for analysis. Staphylococcus aureus was the most common recovered (25.5%) microorganism, of which 8% were meticillin-resistant Staphylococcus aureus (MRSA) strains. Although 0.9% saline supported cleansing of the wound bed, it did not significantly reduce the bacterial burden. The highest reduction of bacterial burden was achieved with an aqueous solution containing betaine, zinc and polyhexamethylene biguanide (polihexanide; ln RF=3.72), followed by a 3% saline solution containing 0.2% sodium hypochlorite (ln RF=3.40). The most statistically significant reduction of bacterial burden, although not the highest, was achieved with povidone-iodine (ln RF=2.98; p=0.001) and an irrigation solution containing sea salt 1.2% and NaOCl 0.4% (ln RF=2.51; p=0.002). CONCLUSION:: If a reduction of bacterial burden is warranted, wound irrigation solutions containing a combination of hypochlorite/hypochlorous acid, or antiseptics such as polihexanide, octenidine or povidone-iodine, ought to be considered. PMID- 30307817 TI - Preventing and treating trench foot: validation of an educational manual for military personnel. AB - OBJECTIVE:: To develop and validate an educational manual on the prevention and treatment of trench foot for military personnel. METHOD:: This is a prospective, descriptive, observational study. A manual was developed based on a literature review of books, theses and articles published in the last 10 years. The manual was evaluated by an expert committee of the Brazilian Army, and tested and validated by military students from an Army Sargent School in Brazil. Students evaluated the following parameters: definition of trench foot, risk of trench foot development among the military, risk factors, identification of trench foot, preventive measures, treatment of trench foot, and final considerations. RESULTS:: A total of 99 military students participated in the testing. Some parameters were exclusively evaluated by the experts, 12 physicians and 11 nurses, and rated as 'good or very good' as follows: thematic content (100%), graphic display (100%), topic sequence (100%), clarity of language and comprehension of information (91.3%) and illustrations (95.6%). Other parameters were rated as 'good or very good' by both the experts and military students, as follows: definition of trench foot (100% and 85.8%), risk of trench foot among the military (95.6% and 86.8%), risk factors (100% and 82.8%), identification of trench foot (100% and 86.8%), preventive measures (100% and 81.8%), treatment (95.6% and 84.8%) and final considerations (95.6% and 81.82 %), respectively. Cronbach's alpha was 0.891 for consistency and 0.854 for reliability. CONCLUSION:: The educational manual was validated by health professionals, tested by military students, and showed to be a consistent, reliable and valid educational instrument for the prevention and treatment of trench foot. PMID- 30307818 TI - Effect of diaphragm fatigue on subsequent exercise tolerance in healthy men and women. AB - Women are more resistant to diaphragmatic fatigue (DF) and experience an attenuated inspiratory muscle metaboreflex relative to men. The effects of such sex-based differences on whole-body endurance exercise tolerance are yet to be examined. Healthy men (n = 9, age = 24 +/- 3 years) and women (n = 9, age = 24 +/ 3 years) completed a maximal incremental cycle test on day 1. On day 2, subjects performed isocapnic inspiratory pressure-threshold loading (PTL) to task failure followed by a constant load submaximal time-to-exhaustion (TTE) exercise test at 85% of the predetermined peak work rate. On day 3, subjects performed the same exercise test without prior-induced DF. Days 2 and 3 were randomized and counterbalanced. Magnetic stimulation of the phrenic nerve roots was used to non volitionally assess DF by measurement of transdiaphragmatic twitch pressure (Pdi,tw). A similar degree of DF was induced in both sexes following PTL (Pdi,tw [% change from baseline]: M = -24.6 +/- 7.8% , W = -23.1 +/- 5.4%; p = 0.54). There was a significant reduction in TTE with prior-induced DF compared to the control condition in both men (10.9 +/- 3.5 min vs. 13.0 +/- 3.2 min; p = 0.05) and women (10.1 +/- 2.4 min vs. 12.2 +/- 3.3 min; p = 0.03) that did not differ in magnitude between the sexes (M = -15.8 +/- 19.5%, W = -14.5 +/- 19.2%; p = 0.89). In conclusion, DF negatively and equally impairs exercise tolerance independent of sex. PMID- 30307819 TI - EXPERIMENTAL MYOFASCIAL TRIGGER POINT CREATION IN RODENTS. AB - Myofascial pain syndrome is one of the most common forms of muscle pain. In this syndrome pain is originated by the so-called trigger points, which consists of a set of palpable contraction knots in the muscle. It has been proposed that a high spontaneous neurotransmission may be involved in the generation of these contraction knots. To confirm this hypothesis, we exposed mouse muscles to an anticholinesterasic agent to increase the neurotransmision in the synaptic cleft in two different conditions, in vivo and ex vivo experiments. Using intracellular recordings a sharp increase in the spontaneous neurotransmission in the levator auris longus muscle and a lower increase in the diaphragm muscle could be seen. Likewise electromyography recordings reveal an elevated endplate noise in gastrocnemius muscle of treated animals. These changes are associated with structural changes such as abundant neuromuscular contracted zones observed by rhodaminated alpha-bungarotoxin and the presence of abundant glycosaminoglycan's around the contraction knots evidenced by Alcian PAS staining. In a second set of experiments we aimed at demonstrating that the increases in the neurotransmission reproduced most of the clinical signs associated to a trigger point. We exposed rats to the anticholinesterase agent neostigmine and 30 min. after we observed the presence of palpable taut bands, the echocardiographic presence of contraction knots and local twitch responses upon needle stimulation. In summary, we demonstrated that increased neurotransmission induced trigger points in both rats and mice and we evidenced glycosaminoglycan's around the contraction zones as a novel hallmark of this pathology. PMID- 30307820 TI - CT-Measured Lung Air-Trapping is Associated with Higher Carotid Artery Stiffness in Individuals with Chronic Obstructive Pulmonary Disease. AB - Early stages of chronic obstructive pulmonary disease (COPD) are characterized by the loss and narrowing of terminal bronchioles in the lung resulting in 'air trapping,' often occurring before overt emphysema manifests. Individuals with an airway-predominant phenotype of COPD display extensive lung air-trapping and are at greater cardiovascular disease (CVD) risk than COPD patients with an emphysema predominant phenotype. We hypothesized that the degree of computed tomography (CT)-quantified lung air-trapping would be associated with greater aortic and carotid artery stiffness and lower endothelial function, known biomarkers of CVD risk. Lung air-trapping was associated with greater aortic stiffness (carotid femoral pulse wave velocity, CFPWV) (r=0.60, p=0.007) and carotid beta-stiffness (r=0.75, p=0.0001) among adults with (n=10) and without (n=9) a clinical diagnosis of COPD and remained significant after adjusting for blood pressure (BP) and smoking history (pack-years) (carotid beta-stiffness r=0.68, p<0.01; CFPWV r=0.53, p=0.03). The association between lung air-trapping and carotid beta stiffness remained significant after additionally adjusting for age and FEV1 (r=0.64, p=0.01). In the COPD group only (n=10), lung air-trapping remained associated with carotid beta-stiffness (r=0.82, p=0.05) after adjustment for age, pack-years and FEV1. In contrast, no association was observed between CFPWV and lung air-trapping after adjustment for BP, pack-years, age and FEV1 (r=0.12, p=0.83). Lung air-trapping was not associated with endothelial function (brachial artery flow mediated dilation) in the entire cohort (p=0.80) or in patients with COPD only (p=0.71). These data suggest that carotid artery stiffness may be a mechanism explaining the link between airway- predominant phenotypes of COPD and high CVD risk. PMID- 30307821 TI - Impact of Short-Term Exercise Training Intensity on beta-cell Function in Older Obese Adults with Prediabetes. AB - The effect of work-matched exercise intensity on beta-cell function is unknown in people with prediabetes prior to clinical weight loss. We determined if short term moderate continuous (CONT) versus high intensity interval (INT) exercise increased beta-cell function. Thirty-one subjects (Age: 61.4+/-2.5 yr; BMI: 32.1+/-1.0 kg/m2) with prediabetes (ADA criteria, 75g OGTT) were randomized to work-matched CONT (70% HRpeak) or INT (3 min 90% HRpeak and 3 min 50% HRpeak) exercise for 60min/d over 2-weeks. A 75g 2 hr OGTT was conducted after an overnight fast, and plasma glucose, insulin, C-peptide and FFA were determined for calculations of skeletal muscle (Oral Minimal Model; OMM), hepatic (HOMA-IR), and adipose (Adipose-IR) insulin sensitivity. beta-cell function was defined from glucose-stimulated insulin secretion (GSIS, deconvolution modeling) and the disposition index (DI). GLP-1(active) and GIP were also measured during the OGTT, along with VO2peak and body composition. CONT and INT increased skeletal muscle, but not hepatic or adipose, derived DI ( P<0.05). Although both treatments tended to reduce fasting GLP-1(active) ( P=0.08), early phase GLP-1(active) increased post-CONT and INT training ( P<0.001). Interestingly, CONT exercise increased fasting GIP compared with decreases in INT ( P=0.02). Early and total phase skeletal muscle DI correlated with decreased total glucose area under the curve (r=-0.52, P=0.002 and r=-0.50, P=0.003, respectively). Independent of intensity, short-term training increased pancreatic function adjusted to skeletal muscle in relation to improved glucose tolerance in adults with prediabetes. Exercise also uniquely affected GIP and GLP-1(active). Further work is needed to elucidate the dose-dependent mechanism(s) by which exercise impacts glycemia. PMID- 30307823 TI - Cross-Domain Assessment of Distress Intolerance: Associations With Borderline Personality Disorder Features. AB - Distress tolerance (DT) is central to major etiological theories of, and popular treatments for, borderline personality disorder (PD), but empirical evidence for the connection between DT and borderline PD is inconclusive. Such inconsistency is partly due to limited concordance across DT indices from different measurement domains (e.g., behavioral, physiological). In a student sample (N = 267), we assessed subjective perceptions of DT capabilities, task performance on a distressing laboratory challenge, and borderline pathology. Subjective and behavioral indices of DT were largely unrelated. Further, borderline PD features were moderately associated with self-perceived DT (r = -.53); in contrast, they were weakly related to performance on the DT task (r = -.09). We conclude that there is mixed evidence for an association between borderline pathology and DT. Further, we propose a systematic approach to examining the construct validity of DT in multimethod, multimeasure research that might resolve the equivocal results from prior work. PMID- 30307822 TI - TESTING THE VAGAL WITHDRAWAL HYPOTHESIS DURING LIGHT EXERCISE UNDER AUTONOMIC BLOCKADE: A HEART RATE VARIABILITY STUDY. AB - INTRODUCTION: We performed the first analysis of heart rate variability (HRV) at rest and exercise under full autonomic blockade on the same subjects, to test the conjecture that vagal tone withdrawal occurs at exercise onset. We hypothesized that, between rest and exercise: i) no differences in total power (PTOT) under parasympathetic blockade; ii) a PTOT fall under beta1-sympathetic blockade; iii) no differences in Ptot under blockade of both ANS branches. METHODS: 7 males (24+/-3 years) performed 5-min cycling (80W) supine, preceded by 5-min rest during control and with administration of atropine, metoprolol and atropine+metoprolol (double blockade). Heart rate and arterial blood pressure were continuously recorded. HRV and blood pressure variability were determined by power spectral analysis, and baroreflex sensitivity (BRS) by the sequence method. RESULTS: At rest, PTOT and the powers of low (LF) and high (HF) frequency components of HRV were dramatically decreased in atropine and double blockade compared to control and metoprolol, with no effects on LF/HF ratio and on the normalised LF (LFnu) and HF (HFnu). At exercise, patterns were the same as at rest. Comparing exercise to rest, PTOT varied as hypothesized. For SAP and DAP, resting PTOT was the same in all conditions. At exercise, in all conditions, PTOT was lower than in control. BRS decreased under atropine and double blockade at rest, under control and metoprolol during exercise. CONCLUSIONS: The results support the hypothesis that vagal suppression determined disappearance of HRV during exercise. PMID- 30307824 TI - All-Cause Mortality of Hospital-Treated Borderline Personality Disorder: A Nationwide Cohort Study. AB - Patients with borderline personality disorder (BPD) are known to present frequently in emergency rooms, and they have a high rate of suicide. The mortality rate of patients with BPD is still unclear. The Danish Psychiatric Central Research Register and The Danish Register for Causes of Death were used to identify patients with a first-ever diagnosis of BPD (ICD-10: F60.31) from 1995 through 2011 together with time and cause of death. A total of 10,545 patients with a BPD diagnosis were followed for a mean time of 7.98 years. A total of 547 deaths were registered. The standardized mortality ratio of patients with BPD compared to the general population was 8.3 (95% CI [7.6, 9.1]). More than three inpatient admissions per year or a comorbid diagnosis of substance use disorder correlated with a higher mortality rate. The increased mortality rate in patients with BPD treated in secondary care emphasizes that it is a severe mental disorder. PMID- 30307825 TI - Respiratory Sinus Arrhythmia Mediates Links Between Borderline Personality Disorder Symptoms and Both Aggressive and Violent Behavior. AB - Although emotion dysregulation (ED) is a core symptom of borderline personality disorder (BPD), tests of associations between ED and aggression and violence which are common to BPD-are sparse. The authors evaluated mediating effects of an autonomic vulnerability to ED on links between BPD symptoms and (a) reactive aggression, (b) proactive aggression, and (c) histories of interpersonal violence in a sample of young adults (N = 104), ages 18-22 years. Low baseline respiratory sinus arrhythmia (RSA) mediated the association between BPD symptoms and reactive aggression. In contrast, although BPD symptoms were correlated with proactive aggression, no mediational effect was found. In addition, low RSA mediated the association between BPD symptoms and histories of interpersonal violence. Collectively, these findings add evidence that neurobiological vulnerability to ED contributes to aggressive and violent behavior among those with BPD. PMID- 30307826 TI - Multisite Implementation and Evaluation of 12-Month Standard Dialectical Behavior Therapy in a Public Community Setting. AB - Dialectical behavior therapy (DBT) is an effective intervention for treating adults with emotional and behavioral dysregulation. The National DBT Project, Ireland was established in 2013 to coordinate the implementation of DBT across public community mental health settings at a national level. This study describes the implementation and evaluation of DBT across multiple independent sites in adult mental health services (AMHS). The Consolidated Framework for Implementation Research was used to guide this national implementation where barriers and facilitators to DBT implementation were considered. Nine AMHS teams completed DBT training and delivered the standard 12-month program. One hundred and ninety-six adults with borderline personality disorder participated in the program, and outcome measures were recorded at four time points. Significant reductions on outcome measures, including frequency of self-harm and suicidal ideation, were observed. This study highlights that DBT can be successfully implemented in community mental health settings as part of a coordinated implementation. PMID- 30307827 TI - Borderline Personality Disorder and Violence Toward Self and Others: A National Study. AB - Borderline personality disorder (BPD) is associated with violence toward self and others. This study aims to further identify which DSM-5 BPD criteria are independently related to violence, using data from National Epidemiologic Survey on Alcohol and Related Conditions-III, which included a total of 36,309 U.S. respondents ages 18 and older (n = 4,301 for BPD; n = 19,404 for subthreshold BPD). Multinomial logistic regression examined the associations between BPD criteria and violence categories, including suicide attempt (self-directed), violence toward others (other-directed), combined (self-/other-directed) violence, and no violence. In the total population, identity disturbance, impulsivity, and intense anger significantly characterized violence toward others, while avoidance of abandonment, self-mutilating behavior, feelings of emptiness, and intense anger significantly characterized violence toward self. These criteria (except identity disturbance) also significantly characterized combined self- and other-directed violence. Differential associations of the BPD criteria with violence among BPD and subthreshold BPD populations also are discussed. PMID- 30307828 TI - Stigma, Emotion Appraisal, and the Family Environment as Predictors of Carer Burden for Relatives of Individuals Who Meet the Diagnostic Criteria for Borderline Personality Disorder. AB - There is some research exploring carers' experiences within the National Health Service in the UK, but only one has focused on carers of individuals with borderline personality disorder (BPD). Ninety-eight carers completed a questionnaire-based study; 57 carers of individuals who meet the diagnostic criteria for BPD were compared to 41 carers of individuals with other mental health problems. The study aimed to investigate whether perceived stigma, perceived threat of strong emotions, and expressed emotion (EE) within the family environment predicted carer burden. The results showed that carers of those who met the diagnosis for BPD experienced higher levels of carer burden, stigma, EE, emotional over involvement (EOI), criticism (CC), and perceived threat of strong emotions than carers of individuals with other mental health difficulties. EOI, CC, carer group (BPD and mental health), and gender of participant were predictors of carer burden, with EOI explaining the most variance of burden. PMID- 30307829 TI - A Comparison of the Youth Psychopathic Traits Inventory (YPI)-Triarchic Scales and the YPI in a Sample of Justice-Involved Youth. AB - The Triarchic model (Patrick, Fowles, & Krueger, 2009) posits that psychopathy consists of three elements: Boldness, Meanness, and Disinhibition. Drislane et al. (2015) recently derived scales from the Youth Psychopathic Traits Inventory (YPI; Andershed, Kerr, Stattin, & Levander, 2002) to assess these traits. The initial validation efforts appeared promising, but researchers have yet to evaluate these scales among justice-involved youth. The current study examines the validity of the YPI-Triarchic scales in an archival sample of 928 male adolescent offenders and tests whether the new scales provide information incremental to the original YPI. The YPI-Triarchic scales were strongly correlated with original YPI scales (rs = .56-.96), and some associations were contrary to predictions and previous findings about the Triarchic model (e.g., YPI-Boldness was not inversely related to symptomatology). Thus, caution is warranted when attempting to study the Triarchic model with the YPI-Triarchic scales. PMID- 30307830 TI - The Higher-Order Structure of Schema Modes. AB - In schema therapy, modes are proposed as a key concept and main target for treatment of personality disorders. The present study aimed to assess a comprehensive set of 20 modes, to explore their higher-order structure, and to link the mode factors to the generic schema factor and basic personality traits. The sample consisted of N = 533 inpatients. Earlier versions of the Schema Mode Inventory (SMI, SMI-2) were merged into the German Extended SMI (GE-SMI). Item level confirmatory factor analyses indicated that the structure of 16 out of 20 GE-SMI scales might be unidimensional. Scale-level exploratory factor analysis revealed three hierarchically structured mode factors: internalization, externalization, and compulsivity. Regressing mode factor scores on the Big Five factors and the generic schema factor supported the validity of the mode factors. The hierarchical structure of modes will be linked to the Hierarchical Taxonomy of Psychopathology, and implications for case conceptualization and treatment will be discussed. PMID- 30307831 TI - The General Criteria for Personality Disorders Assessed by Interview: Do They Still Have a Role to Play? AB - On the path to developing dimensional models of personality disorder (PD), we are at risk of leaving key diagnostic aspects behind. The general criteria for PD may be important ones because they reflect the defining aspects of personality pathology: long duration, independence from psychopathological states, and harmfulness. We assessed these criteria by interview in a sample of 362 psychiatric outpatients after administering the Personality Diagnostic Questionnaire-4+. The result was a 42.5% fall in self-reported endorsements, due to misinterpretations (11.5%), short duration of traits or contamination by state psychopathology (9.8%), and traits being non-harmful (21.2%). However, not all personality traits and disorders underwent correction to the same extent, and ultimately, the interview did not improve the prediction of clinical variables. These findings raise doubts about the practical relevance of the general criteria for PD and support the role of self-report questionnaires for diagnostic purposes. PMID- 30307832 TI - A Systematic Review and Meta-Analysis of Personality Disorder Prevalence and Patient Outcomes in Emergency Departments. AB - The objectives of this study were to perform a systematic review and meta analysis of studies reporting prevalence of personality disorders (PDs) in emergency departments (EDs) and evaluate the effect of comorbid PDs on clinical outcomes. A systematic search of five databases along with manual searching and expert consultation was performed. A quality appraisal was conducted. A total of 29 articles were included. Prevalence of PDs in ED attendees varied depending on presenting complaint, Q(4) = 577.5, p < .01, with meta-analytic prevalence rates of suicide and self-harm at 35% and 22%, respectively. The assessment method had a significant effect on prevalence rates, Q(3) = 17.36, p < .01. Comorbid PD was a risk factor for repeating presenting complaint, subsequent ED return, and hospitalization. Better identification of PDs using screening tools in EDs could improve patient management and clinical outcomes. Future research should focus on PD prevalence in unselected ED populations using validated diagnostic interviews. PMID- 30307834 TI - Resistance of Sclerotinia homoeocarpa Field Isolates to Succinate Dehydrogenase Inhibitor Fungicides. AB - Sclerotinia homoeocarpa isolates were collected from golf courses in Japan and the United States (2016-2017). Japan isolates were collected during a monitoring study and the U.S. isolates were collected due to field failure. Five succinate dehydrogenase inhibitor (SDHI) active ingredients (boscalid, fluopyram, fluxapyroxad, isofetamid, and penthiopyrad) were examined using in vitro sensitivity assays to determine cross-resistance. Sequence analysis revealed a point mutation leading to an amino acid substitution (H267Y) and a silent mutation (CTT to CTC) at codon 181 in the SdhB subunit gene. Isolates with the B H267Y (n = 10) mutation were resistant to boscalid and penthiopyrad and had increased sensitivity to fluopyram. SdhB silent mutation 181C>T isolates (n = 2) were resistant to boscalid, isofetamid, and penthiopyrad. Sequence analysis revealed 3 mutations leading to an amino acid substitution (G91R, n = 5; G150R, n = 1; G159W, n = 1) in the SdhC subunit gene. Isolates harboring the SdhC (G91R or G150R) mutations were resistant to boscalid, fluxapyroxad, isofetamid, and penthiopyrad. A genetic transformation system was used to generate mutants from a SDHI sensitive isolate to confirm the B-H267Y and C-G91R mutations were direct determinants of SDHI resistance and associated with in vitro sensitivity assay results. PMID- 30307833 TI - Role of particle size in assessment of physico-chemical properties and trace elements of Indian fly ash. AB - In this paper, the effect of particle size on the physico-chemical, mineralogical, and leaching behavior of Indian fly ash was studied. Experiments were carried out to study the leaching of different elements such as Mg, Cr, Zn, Pb, Mn, Fe, Cu, Co, Mo, and Ni from Indian fly ash. During the experiments, the liquid-to-solid (L/S) ratio of the fly ash was taken as 9/1, 8/2, 7/3, 3/2, 1/1, and 2/3. The effect of four different particle size ranges (below 53, 53-75, 75 106, and 106-150 MUm) of fly ash was analyzed. The ASTMD-3987 method was used to analyze the presence of trace elements from fly ash. In the ASTM D-3987 method, distilled water was used for extraction of leachate. Fly ash slurry samples were agitated in a lubricating type temperature-controlled Remi orbital shaker for a time duration of 18 hours with speed of 100 revolutions per minute (rpm) at a temperature of 25oC. Distilled water does not save cost as well as being easily available. The leaching test of trace elements from fly ash was investigated at different pH conditions in order to predict the environmental effect from the ash disposal on the groundwater quality. Results revealed that pH of slurry suspension increases with increase in particle size. The pH value of fly ash slurries was negligibly affected by the decrease in L/S ratio for all particle sizes. Fine particles of fly ash produce a more harmful effect as compared to the coarser range of fly ash particles. PMID- 30307835 TI - Evaluation of Quinoxyfen Resistance of Erysiphe necator (Grape Powdery Mildew) in a Single Virginia Vineyard. AB - The protectant fungicide quinoxyfen has been used against grape powdery mildew (Erysiphe necator) in the United States since 2003. In 2013, isolates of grape powdery mildew with reduced quinoxyfen sensitivity (here designated as quinoxyfen lab resistance or QLR) were detected in a single vineyard in western Virginia, USA. Field trials were conducted in 2014, 2015, and 2016 at the affected vineyard to determine to what extent quinoxyfen might still contribute to disease control. Powdery mildew control by quinoxyfen was similar to, or only slightly less than, that provided by myclobutanil and boscalid in all three years. In 2016, early- versus late-season applications of quinoxyfen were compared to test the hypothesis that early-season applications were more effective, but differences were small. A treatment with two early quinoxyfen applications, at bloom and 2 weeks later, followed by a myclobutanil-boscalid plus a low dose of sulfur rotation provided slightly better control of foliar disease incidence than treatments containing four quinoxyfen applications or two midseason or two late quinoxyfen applications supplemented by myclobutanil and boscalid applications; severity differences were small and nonsignificant. Metrafenone and benzovindiflupyr generally provided excellent powdery mildew control. The frequency of QLR in vines not treated with quinoxyfen slowly declined from 65% in 2014 to 46% in 2016. Further research is needed to explain how, despite this QLR frequency, quinoxyfen applied to grapes in the field was still able to effectively control powdery mildew. PMID- 30307836 TI - Prevalence and Incidence of Yellow Dwarf Viruses Across a Climatic Gradient: A Four-Year Field Study in Southeastern Australia. AB - Yellow dwarf viruses (YDVs) form a complex of economically important pathogens that affect cereal production worldwide, reducing yield and quality. The prevalence and incidence of YDVs including barley yellow dwarf viruses (BYDV-PAV and BYDV-MAV) and cereal yellow dwarf virus (CYDV-RPV) in cereal fields in Victoria, Australia were measured. As temperature decreases and rainfall increases from north to south in Victoria, fields in three geographical regions were evaluated to determine potential differences in virus prevalence and incidence across the weather gradient. Cereal samples randomly collected from each field during spring for four consecutive years (2014-2017) were tested for BYDV-PAV, BYDV-MAV, and CYDV-RPV using tissue blot immunoassay. BYDV-PAV was the most prevalent YDV species overall and had the highest overall mean incidence. Higher temperature and lower rainfall were associated with reduced prevalence and incidence of YDVs as the northern region, which is hotter and drier, had a 17 fold decrease in virus incidence compared with the cooler and wetter regions. Considerable year-to-year variation in virus prevalence and incidence was observed. This study improves our understanding of virus epidemiology, which will aid the development of more targeted control measures and predictive models. It also highlights the need to monitor for YDVs and their vectors over multiple years to assess the level of risk and to make more informed and appropriate disease management decisions. PMID- 30307837 TI - The relation of early positive emotional memories to women's social safeness: The role of shame and fear of receiving compassion. AB - Early affiliative experiences play an important role in social and emotional development. Several authors have suggested that early positive experiences may be recorded as memories of warmth and soothing. However, the relationship between such memories and current feelings of social safeness and connectedness remains scarcely studied. The current study examined the association between recall of early positive affiliative experiences (with family and peers) and women's social safeness. External shame and fear of others' compassion were hypothesized to be mediators in these associations. The sample was recruited from October 2016 to February 2016 and included 400 women from the Portuguese population, aged between 18 and 55 years. The path model explained 52% of the variance of social safeness. Early positive affiliative memories (with family and peers) were associated with a lower tendency to fear receiving others' compassion and to feel ashamed, which seemed to be associated with an increased sense of social safeness. These findings offer pertinent insights for future studies in and interventions for women's well-being and mental health by highlighting the importance of addressing shame and fears of compassion when working with women who tend to perceive their social world as unsafe and others' compassion as threatening. PMID- 30307838 TI - Development of a Participatory Health Communication Intervention: An Ecological Approach to Reducing Rural Information Inequality and Health Disparities. AB - A strong and diverse communication infrastructure is essential for communication to improve health. When that infrastructure is weak, health information fails to reach appropriate audiences; this is a component of information inequality that contributes to health disparities. Approaches to addressing information inequality have either focused on individual-level barriers or exclusively on changing the information environment. Largely missing from information inequality interventions is a multilevel, ecological approach consistent with the ways in which information inequality affects health. This study addresses that gap by describing a participatory intervention in a rural, majority-Latino community. Previous work identified a weak information infrastructure as a major barrier to health: Residents struggled to find timely, relevant information, while stakeholders faced challenges knowing how to reach diverse audiences with critical health-related information. We employed participatory health communication asset mapping to identify health communication resources - safe, trusted spaces, and places - that served three distinct communication functions: informational (i.e., where health information can be provided), conversational (i.e., where residents feel comfortable discussing health issues), and connection (i.e., where a relationship exists). Through a six-step process, community leaders and residents identified communication resources and collaborated to create a communication resource map. We discuss how this study advances the theoretical understanding of integration of culture-centered and ecological approaches for communication to reduce health disparities. PMID- 30307839 TI - Gay Porn's Bareback Momentum. AB - A profound shift has occurred in the last decade in mainstream commercial gay pornography from condoms to "bareback" (condomless) depictions of anal sex between men. This article explores gay porn's "bareback momentum" as demonstrated by the displacement of condoms in the 10 most visited gay porn Web sites (that have operated for 10 years or more). While all 10 began by releasing condom pornography, the study finds all except one (Falcon) have since gone bareback represented visually as a timeline. The sites analyzed are, in order of popularity: Sean Cody, Helix Studios, Lucas Entertainment, Corbin Fisher, Bel Ami, Next Door Studios, Randy Blue, Falcon Studios, Cocky Boys, and Chaos Men. Textual analysis reads each site's transition individually, yet connections between the sites are the article's central concern, from which an emphasis on couples and break-up narratives is revealed. Falcon's commitment to retain the condom is attributed to its brand identity. PMID- 30307840 TI - Sexistential Crisis: An Intersectional Analysis of Gender Expression and Sexual Orientation in Masculine Overcompensation. AB - Masculine overcompensation-a phenomenon where men react to masculinity threats by endorsing hypermasculine ideals-has been demonstrated among straight men but has yet to be examined among gay men. The current study therefore proposed to examine whether gay men overcompensate similarly to their straight counterparts by providing participants with randomized feedback that threatened their masculinity. Overcompensation was measured in 867 online respondents by administering a series of questionnaires regarding views of pornography, rape, sex roles, and political orientation. Although our hypothesis was not confirmed, results revealed the intersectionality of both sexual orientation and self reported gender expression regarding the formation of different views and beliefs. Specifically, masculinity was differentially related to homophobic attitudes, more callous views toward victims of sexual assault, and various components of attitudes toward pornography in gay and straight men. Masculine gay males held stereotypically masculine views less strongly than their masculine straight counterparts, providing evidence that gay males adopt a different type of masculinity than straight males-something of a "masculinity lite." Such findings point to the converging influence of sexual orientation and gender expression as contributors relevant to the attitudes of gay and straight men. This information adds to a growing body of literature on differences between gay and straight men and can be used to inform theory, education, and clinical practice, particularly in settings where men grapple with the implications of their masculinity. PMID- 30307841 TI - EOV-C2 Editorial Board page. PMID- 30307842 TI - Sub-lethal doses of surotomycin and vancomycin have similar effects on Clostridium difficile virulence factor production in vitro. AB - PURPOSE: Clostridium difficile is an anaerobic spore-forming bacterial pathogen that causes a spectrum of illness severity ranging from mild diarrhoea to severe life-threatening pseudomembranous colitis. C. difficile infection (CDI) is antibiotic-associated and primarily mediated by two exotoxins, Toxins A and B. We and others have shown that some antibiotics stimulate Toxin A and B production by C. difficile in a strain-specific manner. Still, the effects of newer anti-C. difficile antibiotics on this process and spore formation remain to be investigated. METHODOLOGY: Surotomycin (formally CB-183,315) is a novel, minimally absorbed, narrow-spectrum antibiotic. We determined the effects of surotomycin on C. difficile growth, toxin production and sporulation in historical and BI/NAP1/027 epidemic strains of C. difficile.Results/Key findings. While antibiotic free controls showed toxin production during the stationary phase growth, all strains exposed to sub-inhibitory concentrations of surotomycin and vancomycin demonstrated increased TcdA and TcdB production during early (log phase) growth by all strains. However, this effect was not observed at 24 or 48 h post-treatment by any of the C. difficile strains exposed to either antibiotic. Additionally, all doses of surotomycin and vancomycin suppressed spore formation in all tested strains. CONCLUSION: In summary, these findings demonstrate that surotomycin and vancomycin have similar effects on exotoxin production and sporulation by C. difficile in vitro. Furthermore, since spores contribute to recurrent infection, the ability of surotomycin to suppress spore formation may explain its ability to disrupt the reinfection cycle in the clinical setting. PMID- 30307843 TI - Genomic epidemiology of clinical Campylobacter spp. at a single health trust site. AB - Campylobacter is the leading cause of bacterial enteritis in the developed world, and infections with the organism are largely sporadic in nature. Links between sporadic cases have not been established, with the majority of infections thought to be caused by genetically distinct isolates. Using a read-mapping approach, 158 clinical isolates collected during 2014 from the greater Nottinghamshire area were analysed to assess the local population structure and investigate potential case linkages between sporadic cases of campylobacteriosis. Four instances (2.5 %) of case linkage were observed across the dataset. This study demonstrates that case linkage does occur between sporadic Campylobacter infections, and provides evidence that a dual multi-locus sequence typing/within-lineage single nucleotide polymorphism typing approach to Campylobacter genomic epidemiology provides a benefit to public-health investigations. PMID- 30307844 TI - Are bacterial culture quantifications reliable? Comparative performance of the WASP automated inoculation instrument in the era of ISO 15189 accreditation. AB - PURPOSE: Isolating colonies and obtaining accurate colony counts from bacterial cultures are critical steps for the optimal management of infected patients. The uncertainties in the colony count results from the bacterial cultures were evaluated by verifying the performance of the WASP inoculation system according to the International Organization for Standardization (ISO) 15189 standard. METHODOLOGY: We first (i) evaluated the cross-contamination and precision of the WASP instrument (Copan Diagnostics, Italy) and (ii) established enumeration reading grids for urine, swab, bronchopulmonary specimens (BPSs) and catheter tip cultures. Subsequently, 72 clinical samples were tested to compare the results of the WASP, PREVI Isola (bioMerieux, France) and manual inoculation methods. RESULTS: The WASP method did not show cross-contamination. The coefficient of variation for the colony counts in the repeatability experiment was evaluated for 10 ul and 30 ul loop protocols and determined to be 29 and 14 %, respectively. The agreement between the automated and manual methods and between the automated methods for the colony counts was high (94.4 and 100 %, respectively). The WASP method yielded better isolation quality compared to the manual method (P=0.020) and to the PREVI Isola only when polymicrobial specimens were considered (P=0.014). For quantification evaluation, the measurement uncertainty was evaluated to 1.8*103 c.f.u. ml-1 for a suspension of Escherichia coli at 104 c.f.u. ml-1. CONCLUSION: We report the verification of the performance of the WASP instrument and describe a rapid procedure for achieving semi-quantitative cultures from BPSs and catheter tips. Quantitative interpretation of the bacterial cultures should be performed with caution. PMID- 30307846 TI - Erratum: Silicosis in Turkey: Is It an Endless Nightmare? PMID- 30307847 TI - Erratum: Assessing the Prevalence and Incidence of Asthma and Chronic Obstructive Pulmonary Disease in the Eastern Mediterranean Region. PMID- 30307845 TI - Survey of Ebola Viruses in Frugivorous and Insectivorous Bats in Guinea, Cameroon, and the Democratic Republic of the Congo, 2015-2017. AB - To clarify the role of bats in the ecology of Ebola viruses, we assessed the prevalence of Ebola virus antibodies in a large-scale sample of bats collected during 2015-2017 from countries in Africa that have had previous Ebola outbreaks (Guinea, the Democratic Republic of the Congo) or are at high risk for outbreaks (Cameroon). We analyzed 4,022 blood samples of bats from >12 frugivorous and 27 insectivorous species; 2-37 (0.05%-0.92%) bats were seropositive for Zaire and 0 30 (0%-0.75%) bats for Sudan Ebola viruses. We observed Ebola virus antibodies in 1 insectivorous bat genus and 6 frugivorous bat species. Certain bat species widespread across Africa had serologic evidence of Zaire and Sudan Ebola viruses. No viral RNA was detected in the subset of samples tested (n = 665). Ongoing surveillance of bats and other potential animal reservoirs are required to predict and prepare for future outbreaks. PMID- 30307848 TI - Dry Electrode-based Fully Isolated EEG/fNIRS Hybrid Brain-monitoring System. AB - A portable hybrid brain monitoring (HBM) system is proposed to perform simultaneous 16-channel electroencephalogram (EEG) and 8-channel functional near infrared spectroscopy (fNIRS) measurements. An EEG of sufficient resolution and latency-less reliable bio-optical measurements were simultaneously obtained by basing the architecture-optimized frontend on ADS1299 and ADS8688A-analog frontend (AFE) integrated circuits (ICs). Suppression of the noise and crosstalk generated by the digital circuit components and flashing NIR light sources was maximized through linear regulator-based fully isolated circuit design. Gel-less EEG measurements were enabled by using spring-loaded dry electrodes. Several evaluations were carried out by conducting an EEG phantom test and an arterial occlusion experiment. An alpha rhythm detection test and an experiment to measure mental arithmetic operation were conducted to determine whether the system is applicable to human subject studies. The evaluation results show that the proposed system is sufficiently capable of detecting micro-voltage EEG signals and hemodynamic responses. The results of the studies on human subjects enabled us to verify that the proposed system is able to detect task-related EEG spectral features such as eye-closed event-related synchronization (ERS) and mental arithmetic event-related desynchronization (ERD) in the alpha and beta rhythm ranges. An analysis of the fNIRS measurements with an arithmetic operation task also revealed a decreasing trend in oxyhemoglobin concentration. PMID- 30307849 TI - A unified framework for plasma data modelling in dynamic Positron Emission Tomography studies. AB - OBJECTIVE: Full quantification of dynamic PET data requires the knowledge of tracer concentration in the arterial plasma. However, its accurate measurement is challenging due to the presence of radiolabeled metabolites and measurement noise. Mathematical models are fitted to the plasma data for both radiometabolite correction and data denoising. However, the models used are generally not physiologically informed and not consistently applied across studies even when quantifying the kinetics of the same radiotracer, introducing methodological variability affecting the results interpretation. The aim of this study was to develop and validate a unified framework for the arterial data modelling to achieve an accurate and fully-automated description of the plasma tracer kinetics. METHODS: The proposed pipeline employs basis pursuit techniques for estimating both radiometabolites and parent concentration models from the raw plasma measurements, allowing the resulting algorithm to be both robust and flexible to the different quality of data available. The pipeline was tested on four PET tracers ([11C]PBR28, [11C]MePPEP, [11C]WAY-100635 and [11C]PIB) with continuous and discrete blood sampling. RESULTS: Compared to the standard procedure, the pipeline provided similar fit of the parent fraction but yielded a better description of the total plasma radioactivity, which in turn allowed a more accurate fit of the tissue PET data. CONCLUSION: The new method showed superior fits compared to the standard pipeline, for both continuous and discrete arterial sampling protocol, yielding to better description of PET data. SIGNIFICANCE: The proposed pipeline has the potential to standardize the blood data modeling in dynamic PET studies given its robustness, flexibility and easiness of use. PMID- 30307850 TI - A Wearable Pulse Oximeter with Wireless Communication and Motion Artifact Tailoring for Continuous Use. AB - Advances in several engineering fields have led to a trend towards miniaturization and portability of wearable biosensing devices, which used to be confined to large tools and clinical settings. Various systems to continuously measure electrophysiological activity through electrical and optical methods are one category of such devices. Being wearable and intended for prolonged use, the amount of noise introduced on sensors by movement remains a challenge and requires further optimization. User movement causes motion artifacts that alter the overall quality of the signals obtained, hence corrupting the resulting measurements. This paper introduces a fully wearable optical biosensing system to continuously measure pulse oximetry and heart rate, utilizing a reflectance-based probe. Furthermore, a novel data-dependent motion artifact tailoring algorithm is implemented to eliminate noisy data due to the motion artifact and measure oxygenation level with high accuracy in real-time. By taking advantages of current wireless transmission and signal processing technologies, the developed wearable photoplethysmography device successfully captures the measured signals and sends them wirelessly to a mobile device for signal processing in real-time. After applying motion artifact tailoring, evaluating accuracy with a continuous clinical device, the blood oxygenation measurements obtained from our system yielded an accuracy of at least 98%, when compared to a range of 93.6-96.7% observed before from the same initial data. Additionally, heart rate accuracy above 97% was achieved. Motion artifact tailoring and removal in real-time, continuous systems will allow wearable devices to be truly wearable and a reliable electrophysiological monitoring and diagnostics tool for everyday use. PMID- 30307851 TI - Multi-wavelength Photoplethysmography Enabling Continuous Blood Pressure Measurement with Compact Wearable Electronics. AB - OBJECTIVE: To fight the "silent killer" hypertension, continuous blood pressure (BP) monitoring has been one of the most desired functions in wearable electronics. However, current BP measuring principles and protocols either involve a vessel occlusion process with a cuff or require multiple sensing nodes on the body, which makes it difficult to implement them in compact wearable electronics like smartwatches and wristbands with long-term wearability. METHODS: In this work, we proposed a highly-compact multi-wavelength photoplethysmography (MWPPG) module and a depth-resolved MWPPG approach for continuous monitoring of BP and systemic vascular resistance (SVR). By associating the wavelength dependent light penetration depth in the skin with skin vasculatures, our method exploited the pulse transit time (PTT) on skin arterioles for tracking SVR (n=20). Then we developed an arteriolar PTT-based method for beat-to-beat BP measurement. The BP estimation accuracy of the proposed arteriolar PTT method was validated against Finometer (n=20) and the arterial line (n=4). RESULTS: The correlation between arteriolar PTT and SVR was theoretically deduced and experimentally validated on twenty human subjects performing various maneuvers. The proposed arteriolar PTT-based method outperformed the traditional arterial PTT-based method with better BP estimation accuracy and simpler measurement setup, i.e., with a single sensing node. CONCLUSION: The proposed depth-resolved MWPPG method can provide accurate measurements of SVR and BP, which are traditionally difficult to measure in a noninvasive or continuous fashion. SIGNIFICANCE: This MWPPG work provides the wearable healthcare electronics of compact size with a low-cost and physiology-based solution for continuous measurement of BP and SVR. PMID- 30307852 TI - Magnetic Resonance Fingerprinting using A Fast Dictionary Searching Algorithm: MRF-ZOOM. AB - OBJECTIVE: Magnetic resonance fingerprinting (MRF) is a new technique for simultaneously quantifying multiple MR parameters using one temporally resolved MR scan. In MRF, MR signal is manipulated to have distinct temporal behavior with regard to different combinations of the underlying MR parameters and across spatial regions. The temporal behavior of acquired MR signal is then used as a key to find its unique counterpart in a MR signal dictionary. The dictionary generation and searching (DGS) process represents the most important part of MRF, which however can be intractable because of the disk space requirement and the computational demand exponentially increases with the number of MR parameters, spatial coverage, and spatial resolution. The goal of this paper was to develop a fast and space efficient MRF DGS algorithm. METHODS: The optimal DGS algorithm: MRF ZOOM was designed based on the properties of the parameter matching objective function characterized with full dictionary simulations. Both synthetic data and in-vivo data were used to validate the method. CONCLUSION: MRF ZOOM can dramatically save MRF DGS time without sacrificing matching accuracy. SIGNIFICANCE: MRF ZOOM can facilitate a wide range of MRF applications. PMID- 30307853 TI - Improving Performance of Devanagari Script Input-Based P300 Speller Using Deep Learning. AB - The performance of an existing Devanagari Script (DS) input based P300 speller with conventional machine learning techniques suffers from low information transfer rate (ITR). This occurs due to its required large size of display i.e. 8 x 8 row-column (RC) paradigm which exhibits issues like crowding effect, adjacency, fatigue, task difficulty and required large number of trials for character recognition. For P300 detection, deep learning algorithms have shown the state of art performance compared to the conventional machine learning algorithms in the recent past. Therefore, authors have motivated to develop a deep learning architecture for DS based P300 speller which can detect the target characters more accurately and in less number of trials. For this, two proven deep learning algorithms, stacked autoencoder (SAE) and deep convolution neural network (DCNN) have been adopted. For further bettering their performances, batch normalization and innovative double batch training included here to achieve accelerated training and alleviate the problem of overfitting. Additionally, a leaky ReLU activation function has also been used in DCNN to overcome dying ReLU problem. The experiments have been performed on self-generated dataset of 20 Devanagari words with 79 characters acquired from 10 subjects using 16 channel actiCAP Xpress EEG recorder. The experimental results illustrated that the proposed DCNN is able to detect 88.22 % correct targets in just 3 trials. Moreover, it also provides ITR of 20.58 bits per minutes which is significantly higher than existing techniques. PMID- 30307854 TI - Highly efficient isolation of circulating tumor cells using a simple wedge-shaped microfluicdic device. AB - OBJECTIVE: We have developed a novel simple wedge-shaped microfluidic device for high efficiently isolation of circulating tumor cells (CTCs) from cancer patient blood samples. METHODS: We used wet chemical etching and thermal bonding technologies to fabricate the wedge-shaped microdevice and performed optimization assays to obtain optimal capture parameters. Cancer cells spiked samples were used to evaluate the capture performance. Clinic assays were performed to isolate and identify CTCs from whole blood samples of patients with liver, breast, lung and gastric cancer. RESULTS: Outlet height of 5.5 MUm and flow rate of 200 MUL/min were chosen as the optimal CTC-capture conditions. This method exhibited excellent isolation performance (more than 85% capture efficiency) for four cancer cell lines (HepG2, SKBR3, A549, and BGC823). In clinic assay, the platform identified CTCs 5 in 6 liver (83.3%), 8 in 10 breast (80%), 5 in 8 lung (62.5%), 5 in 9 gastric (55.6%) patients and only 1 in 25 healthy blood samples (4%). CONCLUSION: Our wedge-shaped microfluidic device had several advantages, including relatively simple fabrication, high capture efficiency, simple sample processing steps and easy observation. SIGNIFICANCE: This method had successfully demonstrated the clinic feasibility of CTC isolation and shown a great potential of clinically usefulness in monitoring tumor prognosis and guiding individualized treatment in the future. PMID- 30307855 TI - On the Bending and Stretching of Liquid Metal Receive Coils for Magnetic Resonance Imaging. AB - The eGaIn coil on neoprene demonstrated in this paper presents a stretchable radio frequency receive coil for MRI. The coil with dimensions 86mm * 70mm is tuned to resonate at 128MHz for 3T MRI. We investigate the effect of stretching (up to 40% strain) and bending (50mm radius of curvature) of the coil on the coil's resistance and resonance frequency. Measurements and simulations show a decrease in resonance frequency of 2.5MHz per 10% strain. The higher resistivity of liquid metal compared to copper reduces the SNR of MRI scans by 2.1dB; therefore a trade-off between flexibility and performance remains. Nevertheless, we have successfully performed MRI scans with the liquid metal coil. PMID- 30307856 TI - Scalable and Robust Tensor Decomposition of Spontaneous Stereotactic EEG Data. AB - OBJECTIVE: Identification of networks from resting brain signals is an important step in understanding the dynamics of spontaneous brain activity. We approach this problem using a tensor-based model. METHODS: We develop a rank-recursive Scalable and Robust Sequential Canonical Polyadic Decomposition (SRSCPD) framework to decompose a tensor into several rank-1 components. Robustness and scalability are achieved using a warm start for each rank based on the results from the previous rank. RESULTS: In simulations we show that SRSCPD consistently outperforms the multi-start alternating least square (ALS) algorithm over a range of ranks and signal-to-noise ratios (SNRs), with lower computation cost. When applying SRSCPD to resting in-vivo stereotactic EEG (SEEG) data from two subjects with epilepsy, we found components corresponding to default mode and motor networks in both subjects. These components were also highly consistent within subject between two sessions recorded several hours apart. Similar components were not obtained using the conventional ALS algorithm. CONCLUSION: Consistent brain networks and their dynamic behaviors were identified from resting SEEG data using SRSCPD. SIGNIFICANCE: SRSCPD is scalable to large datasets and therefore a promising tool for identification of brain networks in long recordings from single subjects. PMID- 30307857 TI - A Maximum Likelihood Approach for Depth Field Estimation Based on Epipolar Plane Images. AB - In this paper, a multi-resolution method for depth estimation from dense image arrays is presented. Recent progress in consumer electronics has enabled the development of low cost hand-held plenoptic cameras. In these systems, multiple views of a scene are captured in a single shot by means of a micro-lens array placed on the focal point of the first camera lens, in front of the imaging sensor. These views can be processed jointly to obtain accurate depth maps. In this contribution, to reduce the computational complexity associated to global optimization schemes based on match cost functions, we make a local estimate based on the maximization of the total log-likelihood spatial density aggregated along the epipolar lines corresponding to each view pair. This method includes the local maximum likelihood estimation of the depth field based on epipolar plane images. To face the potential accuracy losses associated to the ambiguity problem that arises in flat surface regions while preserving bandwidth in correspondence of the edges, we adopt a multi-resolution scheme. In practice, the depth map resolution is reduced in regions where maximizing the higher resolution functional is ill-conditioned. The main benefits of the proposed system are in a reduced computational complexity and a high accuracy of the estimated depth. Experimental results show that the proposed scheme represents a good tradeoff among accuracy, robustness, and discontinuities handling. PMID- 30307858 TI - Detecting Coherent Groups in Crowd Scenes by Multiview Clustering. AB - Detecting coherent groups is fundamentally important for crowd behavior analysis. In the past few decades, plenty of works have been conducted on this topic, but most of them have limitations due to the insufficient utilization of crowd properties and the arbitrary processing of individuals. In this study, a Multiview-based Parameter Free framework (MPF) is proposed. Based on the L1-norm and L2-norm, we design two versions of the multiview clustering method, which is the main part of the proposed framework. This paper presents the contributions on three aspects: (1) a new structural context descriptor is designed to characterize the structural properties of individuals in crowd scenes; (2) an self-weighted multiview clustering method is proposed to cluster feature points by incorporating their motion and context similarities; (3) a novel framework is introduced for group detection, which is able to determine the group number automatically without any parameter or threshold to be tuned. The effectiveness of the proposed framework is evaluated on real-world crowd videos, and the experimental results show its promising performance on group detection. In addition, the proposed multiview clustering method is also evaluated on a synthetic dataset and several standard benchmarks, and its superiority over the state-of-the-art competitors is demonstrated. PMID- 30307859 TI - Infant Brain Development Prediction with Latent Partial Multi-View Representation Learning. AB - The early postnatal period witnesses rapid and dynamic brain development. However, the relationship between brain anatomical structure and cognitive ability is still unknown. Currently, there is no explicit model to characterize this relationship in the literature. In this paper, we explore this relationship by investigating the mapping between morphological features of the cerebral cortex and cognitive scores. To this end, we introduce a multi-view multi-task learning approach to intuitively explore complementary information from different time-points and handle the missing data issue in longitudinal studies simultaneously. Accordingly, we establish a novel model, Latent Partial Multi View Representation Learning. Our approach regards data from different time points as different views and constructs a latent representation to capture the complementary information from incomplete time-points. The latent representation explores the complementarity across different time-points and improves the accuracy of prediction. The minimization problem is solved by the Alternating Direction Method of Multipliers (ADMM). Experimental results on both synthetic and real data validate the effectiveness of our proposed algorithm. PMID- 30307860 TI - In-phase and Quadrature Analysis for Amplitude and Frequency Modulation Due to Vibrations on a Surface Acoustic Wave Resonator. AB - Surface acoustic wave resonators (SAWR) have found widespread usage in various modern consumer radiofrequency (RF) communications electronics, such as cellular phones, wireless devices, GPS devices, frequency control, and sensing applications. External mechanical vibrations modify a SAWR relative dimensions and the substrate's elastic properties, which alter the device's acoustic wave propagation velocity, and ultimately causes the SAWR RF response to change. Detecting vibrations is desirable for dynamic strain, or vibration sensing applications. Whereas, external mechanical excitations can result in spurious signals which compromise SAW based filters and oscillators used in RF communication, frequency control, and sensors targeting measurands such as temperature and pressure. Therefore, understanding and characterizing the SAWR's response to external vibration is relevant for establishing device operation, and assisting in device design and packaging to either mitigate the impact of vibrations for RF communications and frequency control, or enhance the SAWR response for sensor applications. This paper presents an in-phase and quadrature demodulation technique (I-Q technique) to detect, quantify, and analyze the effect of externally induced mechanical vibrations on a SAWR. The I-Q technique disclosed reveals that the mechanical vibrations cause both frequency and amplitude modulation of the SAWR RF response, which can be separated by this technique. Furthermore, the procedure also allows the direct measurement of vibration frequencies and vibration magnitude. The technique, measured results, and analysis established here provide a better understanding of the impact of external mechanical vibrations on a SAWR response, which is important in contemporary communications, frequency control, and sensing applications. PMID- 30307861 TI - Graph-Based Blind Image Deblurring From a Single Photograph. AB - Blind image deblurring, i.e., deblurring without knowledge of the blur kernel, is a highly ill-posed problem. The problem can be solved in two parts: i) estimate a blur kernel from the blurry image, and ii) given an estimated blur kernel, de convolve the blurry input to restore the target image. In this paper, we propose a graph-based blind image deblurring algorithm by interpreting an image patch as a signal on a weighted graph. Specifically, we first argue that a skeleton image a proxy that retains the strong gradients of the target but smooths out the details-can be used to accurately estimate the blur kernel and has a unique bi modal edge weight distribution. Then, we design a reweighted graph total variation (RGTV) prior that can efficiently promote a bi-modal edge weight distribution given a blurry patch. Further, to analyze RGTV in the graph frequency domain, we introduce a new weight function to represent RGTV as a graph l1-Laplacian regularizer. This leads to a graph spectral filtering interpretation of the prior with desirable properties, including robustness to noise and blur, strong piecewise smooth (PWS) filtering and sharpness promotion. Minimizing a blind image deblurring objective with RGTV results in a non-convex non differentiable optimization problem. Leveraging the new graph spectral interpretation for RGTV, we design an efficient algorithm that solves for the skeleton image and the blur kernel alternately. Specifically for Gaussian blur, we propose a further speedup strategy for blind Gaussian deblurring using accelerated graph spectral filtering. Finally, with the computed blur kernel, recent non-blind image deblurring algorithms can be applied to restore the target image. Experimental results demonstrate that our algorithm successfully restores latent sharp images and outperforms state-of-the-art methods quantitatively and qualitatively. PMID- 30307862 TI - Discrete Spectral Hashing for Efficient Similarity Retrieval. AB - To meet the required huge data analysis, organization, and storage demand, the hashing technique has got a lot of attention as it aims to learn an efficient binary representation from the original high-dimensional data. In this paper, we focus on the unsupervised spectral hashing due to its effective manifold embedding. Existing spectral hashing methods mainly suffer from two problems, i.e., the inefficient spectral candidate and intractable binary constraint for spectral analysis. To overcome these two problems, we propose to employ spectral rotation to seek a better spectral solution and adopt the alternating projection algorithm to settle the complex code constraints, which are therefore named as Spectral Hashing with Spectral Rotation and Alternating Discrete Spectral Hashing, respectively. To enjoy the merits of both methods, the spectral rotation technique is finally combined with the original spectral objective, which aims to simultaneously learn better spectral solution and more efficient discrete codes and is called as Discrete Spectral Hashing. Furthermore, the efficient optimization algorithms are also provided, which just take comparable time complexity to existing hashing methods. To evaluate the proposed three methods, extensive comparison experiments and studies are conducted on four large-scale data sets for the image retrieval task, and the noticeable performance beats several state-of-the-art spectral hashing methods on different evaluation metrics. PMID- 30307863 TI - Context-Aware Mouse Behavior Recognition Using Hidden Markov Models. AB - Automated recognition of mouse behaviors is crucial in studying psychiatric and neurologic diseases. To achieve this objective, it is very important to analyze the temporal dynamics of mouse behaviors. In particular, the change between mouse neighboring actions is swift in a short period. In this paper, we develop and implement a novel hidden Markov model (HMM) algorithm to describe the temporal characteristics of mouse behaviors. In particular, we here propose a hybrid deep learning architecture, where the first unsupervised layer relies on an advanced spatial-temporal segment Fisher vector encoding both visual and contextual features. Subsequent supervised layers based on our segment aggregate network are trained to estimate the state-dependent observation probabilities of the HMM. The proposed architecture shows the ability to discriminate between visually similar behaviors and results in high recognition rates with the strength of processing imbalanced mouse behavior datasets. Finally, we evaluate our approach using JHuang's and our own datasets, and the results show that our method outperforms other state-of-the-art approaches. PMID- 30307864 TI - Effective Content-Aware Chroma Reconstruction Method for Screen Content Images. AB - In this paper, we propose an effective novel content-aware chroma reconstruction (CACR) method for screen content images (SCIs). After receiving the decoded downsampled YUV image on the client side, our fast chroma-copy approach reconstructs the missing chroma pixels in the flat regions of SCI. Then, for non flat regions, a non-flat region-based winner-first voting (NRWV) strategy is proposed to identify the chroma subsampling scheme used on the server side prior to compression. Further, an effective adaptive hybrid approach is proposed to reconstruct each missing chroma pixel in the non-flat region by fusing the two reconstructed results, one from our modified NRWV-based chroma subsampling binding and luma-guided chroma reconstruction scheme, which favors the sharp edges in SCI, as well as the other from the bicubic interpolation scheme, which favors blurred and continuous-tone textures. Further, based on the identified chroma subsampling scheme, a geometry alignment-based error compensation approach is proposed to enhance the reconstructed chroma image. Based on typical test SCIs and JCT-VC screen content videos, comprehensive experiments are carried out in HEVC-16.17 to demonstrate that in terms of quality, visual effect, and quality bitrate tradeoff of the reconstructed SCIs, our CACR method significantly outperforms the existing state-of-the-art methods. PMID- 30307865 TI - Weighted Graph Embedding-Based Metric Learning for Kinship Verification. AB - Given a group photograph, it is interesting and useful to judge whether the characters in it share specific kinship relation, such as father-daughter, father son, mother-daughter, or mother-son. Recently, facial image-based kinship verification has attracted wide attention in computer vision. Some metric learning algorithms have been developed for improving kinship verification. However, most of the existing algorithms ignore fusing multiple feature representations and utilizing kernel techniques. In this paper, we develop a novel weighted graph embedding-based metric learning (WGEML) framework for kinship verification. Inspired by the fact that family members usually show high similarity in facial features like eyes, noses, and mouths, despite their diversity, we jointly learn multiple metrics by constructing an intrinsic graph and two penalty graphs to characterize the intraclass compactness and interclass separability for each feature representation, respectively, so that both the consistency and complementarity among multiple features can be fully exploited. Meanwhile, combination weights are determined through a weighted graph embedding framework. Furthermore, we present a kernelized version of WGEML to tackle nonlinear problems. Experimental results demonstrate both the effectiveness and efficiency of our proposed methods. PMID- 30307866 TI - MPTV: Matching Pursuit Based Total Variation Minimization for Image Deconvolution. AB - Total variation (TV) regularization has proven effective for a range of computer vision tasks through its preferential weighting of sharp image edges. Existing TV based methods, however, often suffer from the over-smoothing issue and solution bias caused by the homogeneous penalization. In this paper, we consider addressing these issues by applying inhomogeneous regularization on different image components. We formulate the inhomogeneous TV minimization problem as a convex quadratic constrained linear programming problem. Relying on this new model, we propose a matching pursuit based total variation minimization method (MPTV), specifically for image deconvolution. The proposed MPTV method is essentially a cuttingplane method, which iteratively activates a subset of nonzero image gradients, and then solves a subproblem focusing on those activated gradients only. Compared to existing methods, MPTV is less sensitive to the choice of the trade-off parameter between data fitting and regularization. Moreover, the inhomogeneity of MPTV alleviates the over-smoothing and ringing artifacts, and improves the robustness to errors in blur kernel. Extensive experiments on different tasks demonstrate the superiority of the proposed method over the current state-of-the-art. PMID- 30307867 TI - Divide and Count: Generic Object Counting by Image Divisions. AB - We propose a general object counting method that does not use any prior category information. We learn from local image divisions to predict global image-level counts without using any form of local annotations. Our method separates the input image into a sets of image divisions - each fully covering the image. Each image division is composed of a set of region proposals or uniform grid cells. Our approach learns in an endto- end deep learning architecture to predict global image-level counts from local image divisions. The method incorporates a counting layer which predicts object counts in the complete image, by enforcing consistency in counts when dealing with overlapping image regions. Our counting layer is based on the inclusion-exclusion principle from set theory. We analyze the individual building blocks of our proposed approach on Pascal- VOC2007 and evaluate our method on the MS-COCO large scale generic object dataset as well as on three class-specific counting datasets: UCSD pedestrian dataset, and CARPK and PUCPR+ car datasets. PMID- 30307868 TI - Online Data Organizer: Micro-Video Categorization by Structure-Guided Multimodal Dictionary Learning. AB - Micro-videos have rapidly become one of the most dominant trends in the era of social media. Accordingly, how to organize them draws our attention. Distinct from the traditional long videos that would have multi-site scenes and tolerate the hysteresis, a micro-video: 1) usually records contents at one specific venue within a few seconds. The venues are structured hierarchically regarding their category granularity. This motivates us to organize the micro-videos via their venue structure. 2) timely circulates over social networks. Thus, the timeliness of micro-videos desires effective online processing. However, only 1.22% of micro videos are labeled with venue information when uploaded at the mobile end. To address this problem, we present a framework to organize the micro-videos online. In particular, we first build a structure-guided multi-modal dictionary learning model to learn the concept-level micro-video representation by jointly considering their venue structure and modality relatedness. We then develop an online learning algorithm to incrementally and efficiently strengthen our model, as well as categorize the micro-videos into a tree structure. Extensive experiments on a real-world data set validate our model well. In addition, we have released the codes to facilitate the research in the community. PMID- 30307869 TI - Revisiting Outlier Rejection Approach for Non-Lambertian Photometric Stereo. AB - Photometric stereo offers a single camera based approach to recover 3D information and has attracted wide range of applications in computer vision. Presence of non-Lambertian reflections in almost all the real-world objects limits the usage of the Lambertian model for surface normal vector estimation. Previous methods proposed to address such non-Lambertian phenomena employ an outlier rejection approach while more recent methods introduce BRDF models which can generate more accurate results. However, results with comparable accuracy can also be achieved by simply filtering the observed intensity values. This paper presents two novel outlier rejection techniques which attempt to identify the data which are more reliable and likely to be Lambertian. In the first technique, observed intensity values with less reliability are automatically eliminated. This reliability is determined by the responses from a newly introduced inter relationship function. In the second technique, those photometric ratio equations which are less likely to be Lambertian are identified by observing the residue of the equations. By eliminating the data which is unreliable and likely to be non Lambertian, surface normal vectors are more accurately estimated. Our comparative and reproducible experimental results using both real and synthetic datasets illustrate superior performance over the state-of-the-art methods, which validates our theoretical arguments presented in this paper. PMID- 30307870 TI - Image Restoration by Iterative Denoising and Backward Projections. AB - Inverse problems appear in many applications, such as image deblurring and inpainting. The common approach to address them is to design a specific algorithm for each problem. The Plug-and-Play (P&P) framework, which has been recently introduced, allows solving general inverse problems by leveraging the impressive capabilities of existing denoising algorithms. While this fresh strategy has found many applications, a burdensome parameter tuning is often required in order to obtain high-quality results. In this paper, we propose an alternative method for solving inverse problems using off-the-shelf denoisers, which requires less parameter tuning. First, we transform a typical cost function, composed of fidelity and prior terms, into a closely related, novel optimization problem. Then, we propose an efficient minimization scheme with a P&P property, i.e., the prior term is handled solely by a denoising operation. Finally, we present an automatic tuning mechanism to set the method's parameters. We provide a theoretical analysis of the method and empirically demonstrate its competitiveness with task-specific techniques and the P&P approach for image inpainting and deblurring. PMID- 30307871 TI - An Adaptive SSVEP-Based Brain-Computer Interface to Compensate Fatigue-Induced Decline of Performance in Practical Application. AB - Brain-computer interfaces based on steady-state visual evoked potentials are promising communication systems for people with speech and motor disabilities. However, reliable SSVEP response requires user's attention, which degrades over time due to significant eye-fatigue when low-frequency visual stimuli (5-15 Hz) are used. Previous studies have shown that eye-fatigue can be reduced using high frequency flickering stimuli (>25 Hz). Here, it is quantitatively demonstrated that the performance of a high-frequency SSVEP BCI decreases over time, but this amount of decrease can be compensated effectively by using two proposed adaptive algorithms. This leaded to a robust alternative communication system for practical applications. The asynchronous spelling system implemented in this study uses a threshold-based version of LASSO algorithm for frequency recognition. In long online experiments, when participants typed a sentence with the BCI system for 16 times, accuracy of the system was close to its maximum along the experiment. However, regression analysis on typing speed of each sentence demonstrated a significant decrease in all 7 subjects ( ) when thresholds obtained from a calibration test were kept fixed over the experiment. In comparison, no significant change in typing speed was observed when the proposed adaptive algorithms were used. The analysis of variances revealed that the average typing speed of the last four sentences when using adaptive relational algorithm (8.7 char/min) was significantly higher than the tolerance based algorithm (8.1 char/min) and significantly above 6 char/min when the fixed thresholds were used. Therefore, the relational algorithm proposed in this paper could successfully compensate for the effect of fatigue on performance of the SSVEP BCI system. PMID- 30307872 TI - A Neuromechanical Model of Reduced Dorsiflexor Torque During the Anticipatory Postural Adjustments of Gait Initiation. AB - Anticipatory postural adjustments (APAs) precede gait initiation and function to accelerate the center of mass forward and towards the initial stance leg. Impairments in APA generation, such as those seen in people with Parkinson's disease (PD), can impact the quality of the first step. An initial burst of activity in the dorsiflexor muscle (tibialis anterior) of the stepping leg is an important contributor to the posterior excursion of the center of pressure that accelerates the center of mass forward during an APA. Tibialis anterior activation can be diminished or absent in people with PD; however, the neuromechanical consequence of this diminished dorsiflexor torque on APA generation is not fully understood. Computational models of gait initiation that include components of the neuromuscular system may provide additional insight. In this paper, an inverted pendulum model of the body generated from healthy young adult data was used to simulate reduced dorsiflexor torque during an APA for gait initiation. Forward body lean angle and center of pressure were assessed over various settings of decreased dorsiflexor torque and compared to experimental data from a person with PD. Results from the model demonstrate that reducing the peak dorsiflexor torque by as little as 8-Nm may alter forward body lean and the center of pressure excursion from their nominal trajectories. These results can help inform how much torque is needed from an external device to effectively modulate APAs for gait initiation, as well as provide insight into compensation strategies for reduced dorsiflexor torque in pathology. PMID- 30307873 TI - Cryopreserved Cells Regeneration Monitored by Atomic Force Microscopy and Correlated With State of Cytoskeleton and Nuclear Membrane. AB - Atomic force microscopy (AFM) helps to describe and explain the mechanobiological properties of living cells on the nanoscale level under physiological conditions. The stiffness of cells is an important parameter reflecting cell physiology. Here, we have provided the first study of the stiffness of cryopreserved cells during post-thawing regeneration using AFM combined with confocal fluorescence microscopy. We demonstrated that the nonfrozen cell stiffness decreased proportionally to the cryoprotectant concentration in the medium. AFM allowed us to map cell surface reconstitution in real time after a freeze/thaw cycle and to monitor the regeneration processes at different depths of the cell and even different parts of the cell surface (nucleus and edge). Fluorescence microscopy showed that the cytoskeleton in fibroblasts, though damaged by the freeze/thaw cycle, is reconstructed after long-term plating. Confocal microscopy confirmed that structural changes affect the nuclear envelopes in cryopreserved cells. AFM nanoindentation analysis could be used as a noninvasive method to identify cells that have regenerated their surface mechanical properties with the proper dynamics and to a sufficient degree. This identification can be important particularly in the field of in vitro fertilization and in future cell-based regeneration strategies. PMID- 30307874 TI - Fast Short Read De-novo Assembly Using Overlap-Layout-Consensus Approach. AB - The de-novo genome assembly is a challenging computational problem for which several pipelines have been developed. The advent of long-read sequencing technology has resulted in a new set of algorithmic approaches for the assembly process. In this work, we identify that one of these new and fast long-read assembly techniques (using Minimap2 and Miniasm) can be modified for the short read assembly process. This possibility motivated us to customize a long-read assembly approach for applications in a short-read assembly scenario. Here, we compare and contrast our proposed de-novo assembly pipeline (MiniSR) with three other recently developed programs for the assembly of bacterial and small eukaryotic genomes. We have documented two trade-offs: one between speed and accuracy and the other between contiguity and base-calling errors. Our proposed assembly pipeline shows a good balance in these trade-offs. The resulting pipeline is 6 and 2.2 times faster than the short-read assemblers Spades and SGA, respectively. MiniSR generates assemblies of superior N50 and NGA50 to SGA, although assemblies are less complete and accurate than those from Spades. A third tool, SOAPdenovo2, is as fast as our proposed pipeline but had poorer assembly quality. PMID- 30307875 TI - Advances in Acoustic Signal Processing Techniques for Enhanced Bowel Sound Analysis. AB - With the invention of the electronic stethoscope and other similar recording and data logging devices, acoustic signal processing concepts and methods can now be applied to bowel sounds. In this paper, the literature pertaining to acoustic signal processing for bowel sound analysis is reviewed and discussed. The article outlines some of the fundamental approaches and machine learning principles that may be used in bowel sound analysis. The advances in signal processing techniques that have allowed useful information to be obtained from bowel sounds from an historical perspective is provided. The document specifically address the progress in bowel sound analysis, such as improved noise reduction, segmentation, signal enhancement, feature extraction, localisation of sounds, and machine learning techniques. We have found that advanced acoustic signal processing incorporating novel machine learning methods and artificial intelligence can lead to better interpretation of acoustic information emanating from the bowel. PMID- 30307876 TI - A Novel FES Strategy for Post-Stroke Rehabilitation Based on the Natural Organization of Neuromuscular Control. AB - The past decades have witnessed remarkable progresses in neural technologies such as functional electrical stimulation (FES) and their applications in neuro rehabilitation and neuromodulation. These advances are powered by new neuroscientific understandings of the organization and compositionality of neuromuscular control illuminating how muscle groups may be activated together as discrete units known as muscle synergies. These parallel developments have promoted novel approaches to clinical rehabilitation for neurological disorders that are insurmountable to current treatments. One such breakthrough is the evolution of FES as a therapeutic tool in post-stroke rehabilitation with an interventional strategy particularly inspired by the concept that muscles in humans may be purposefully coordinated through neuromotor modules known as muscle synergies. This article will review recent advances in multi-channel FES technology, its potential applications in post-stroke rehabilitation, new findings that support the neurological basis of the muscle synergies for generating natural motor tasks, and the application of the muscle-synergy concept in post-stroke assessment and rehabilitation of motor impairment. Finally, we will recommend future directions of development in relation to assistive FES and synergy-driven adaptive training for post-stroke rehabilitation. PMID- 30307877 TI - Spatio-Temporal Interpolated Echo State Network for Meteorological Series Prediction. AB - Spatio-temporal series prediction has attracted increasing attention in the field of meteorology in recent years. The spatial and temporal joint effect makes predictions challenging. Most of the existing spatio-temporal prediction models are computationally complicated. To develop an accurate but easy-to-implement spatio-temporal prediction model, this paper designs a novel spatio-temporal prediction model based on echo state networks. For real-world observed meteorological data with randomness and large changes, we use a cubic spline method to bridge the gaps between the neighboring points, which results in a pleasingly smooth series. The interpolated series is later input into the spatio temporal echo state networks, in which the spatial coefficients are computed by the elastic-net algorithm. This approach offers automatic selection and continuous shrinkage of the spatial variables. The proposed model provides an intuitive but effective approach to address the interaction of spatial and temporal effects. To demonstrate the practicality of the proposed model, we apply it to predict two real-world datasets: monthly precipitation series and daily air quality index series. Experimental results demonstrate that the proposed model achieves a normalized root-mean-square error of approximately 0.250 on both datasets. Similar results are achieved on the long short-term memory model, but the computation time of our proposed model is considerably shorter. It can be inferred that our proposed neural network model has advantages on predicting meteorological series over other models. PMID- 30307878 TI - Exploiting Generalization in the Subspaces for Faster Model-Based Reinforcement Learning. AB - Due to the lack of enough generalization in the state space, common methods of reinforcement learning suffer from slow learning speed, especially in the early learning trials. This paper introduces a model-based method in discrete state spaces for increasing the learning speed in terms of required experiences (but not required computation time) by exploiting generalization in the experiences of the subspaces. A subspace is formed by choosing a subset of features in the original state representation. Generalization and faster learning in a subspace are due to many-to-one mapping of experiences from the state space to each state in the subspace. Nevertheless, due to inherent perceptual aliasing (PA) in the subspaces, the policy suggested by each subspace does not generally converge to the optimal policy. Our approach, called model-based learning with subspaces (MoBLeSs), calculates the confidence intervals of the estimated $Q$-values in the state space and in the subspaces. These confidence intervals are used in the decision-making, such that the agent benefits the most from the possible generalization while avoiding from the detriment of the PA in the subspaces. The convergence of MoBLeS to the optimal policy is theoretically investigated. In addition, we show through several experiments that MoBLeS improves the learning speed in the early trials. PMID- 30307879 TI - STRAINet: Spatially Varying sTochastic Residual AdversarIal Networks for MRI Pelvic Organ Segmentation. AB - Accurate segmentation of pelvic organs is important for prostate radiation therapy. Modern radiation therapy starts to use a magnetic resonance image (MRI) as an alternative to computed tomography image because of its superior soft tissue contrast and also free of risk from radiation exposure. However, segmentation of pelvic organs from MRI is a challenging problem due to inconsistent organ appearance across patients and also large intrapatient anatomical variations across treatment days. To address such challenges, we propose a novel deep network architecture, called ''Spatially varying sTochastic Residual AdversarIal Network'' (STRAINet), to delineate pelvic organs from MRI in an end-to-end fashion. Compared to the traditional fully convolutional networks (FCN), the proposed architecture has two main contributions: 1) inspired by the recent success of residual learning, we propose an evolutionary version of the residual unit, i.e., stochastic residual unit, and use it to the plain convolutional layers in the FCN. We further propose long-range stochastic residual connections to pass features from shallow layers to deep layers; and 2) we propose to integrate three previously proposed network strategies to form a new network for better medical image segmentation: a) we apply dilated convolution in the smallest resolution feature maps, so that we can gain a larger receptive field without overly losing spatial information; b) we propose a spatially varying convolutional layer that adapts convolutional filters to different regions of interest; and c) an adversarial network is proposed to further correct the segmented organ structures. Finally, STRAINet is used to iteratively refine the segmentation probability maps in an autocontext manner. Experimental results show that our STRAINet achieved the state-of-the-art segmentation accuracy. Further analysis also indicates that our proposed network components contribute most to the performance. PMID- 30307880 TI - A Deep Learning Approach to Competing Risks Representation in Peer-to-Peer Lending. AB - Online peer-to-peer (P2P) lending is expected to benefit both investors and borrowers due to their low transaction cost and the elimination of expensive intermediaries. From the lenders' perspective, maximizing their return on investment is an ultimate goal during their decision-making procedure. In this paper, we explore and address a fundamental problem underlying such a goal: how to represent the two competing risks, charge-off and prepayment, in funded loans. We propose to model both potential risks simultaneously, which remains largely unexplored until now. We first develop a hierarchical grading framework to integrate two risks of loans both qualitatively and quantitatively. Afterward, we introduce an end-to-end deep learning approach to solve this problem by breaking it down into multiple binary classification subproblems that are amenable to both feature representation and risks learning. Particularly, we leverage deep neural networks to jointly solve these subtasks, which leads to the in-depth exploration of the interaction involved in these tasks. To the best of our knowledge, this is the first attempt to characterize competing risks for loans in P2P lending via deep neural networks. The comprehensive experiments on real-world loan data show that our methodology is able to achieve an appealing investment performance by modeling the competition within and between risks explicitly and properly. The feature analysis based on saliency maps provides useful insights into payment dynamics of loans for potential investors intuitively. PMID- 30307881 TI - A Robust AUC Maximization Framework With Simultaneous Outlier Detection and Feature Selection for Positive-Unlabeled Classification. AB - The positive-unlabeled (PU) classification is a common scenario in real-world applications such as healthcare, text classification, and bioinformatics, in which we only observe a few samples labeled as ''positive'' together with a large volume of ''unlabeled'' samples that may contain both positive and negative samples. Building robust classifiers for the PU problem is very challenging, especially for complex data where the negative samples overwhelm and mislabeled samples or corrupted features exist. To address these three issues, we propose a robust learning framework that unifies area under the curve maximization (a robust metric for biased labels), outlier detection (for excluding wrong labels), and feature selection (for excluding corrupted features). The generalization error bounds are provided for the proposed model that give valuable insight into the theoretical performance of the method and lead to useful practical guidance, e.g., to train a model, we find that the included unlabeled samples are sufficient as long as the sample size is comparable to the number of positive samples in the training process. Empirical comparisons and two real-world applications on surgical site infection (SSI) and EEG seizure detection are also conducted to show the effectiveness of the proposed model. PMID- 30307882 TI - Dynamic Graph Theoretical Analysis of Functional Connectivity in Parkinson's Disease: The Importance of Fiedler Value. AB - Graph theoretical analysis is a powerful tool for quantitatively understanding the topological properties of complex networks, such as system-level descriptions of brain connectivity. In conventional functional connectivity analysis, brain connectivity is assumed to be temporally stationary, while increasing evidence suggests that functional connectivity exhibits temporal variations during dynamic brain activity. Although a number of methods have been developed to estimate time dependent brain connectivity, there is a paucity of studies examining the utility of brain dynamics for assessing brain disease states. Therefore, this paper aims to assess brain connectivity dynamics in Parkinson's disease (PD) and determine the utility of such dynamic graph measures as potential components to an imaging biomarker. Resting-state fMRI data were collected from 29 healthy controls (HCs) and 69 PD subjects. Time-varying functional connectivity was first estimated using a sliding windowed sparse inverse covariance matrix. Then, a collection of graph measures, including the Fiedler value - an indicator of how well connected a network is - were computed and the dynamics of the graph measures were investigated. The results demonstrated that PD subjects had a lower variability in the Fiedler value, modularity, and global efficiency, suggesting both abnormal dynamic global integration and local segregation of brain networks in PD. Autoregressive models fitted to the dynamic graph measures suggested that Fiedler value, characteristic path length, global efficiency and modularity were all less deterministic in PD. With canonical correlation analysis (CCA), the altered dynamics of functional connectivity networks, and particularly dynamic Fiedler value, were shown to be related with disease severity and other clinical variables including age. Similarly, Fiedler value was the most important feature for classification. Collectively, our findings demonstrate altered dynamic graph properties, and in particular the Fiedler value, provide an additional dimension upon which to non-invasively and quantitatively assess PD. PMID- 30307883 TI - Fusion of Multiple Person Re-id Methods With Model and Data-Aware Abilities. AB - Person re-identification (person re-id) has attracted rapidly increasing attention in computer vision and pattern recognition research community in recent years. With the goal of providing match ranking results between each query person image and the gallery ones, the person re-id technique has been widely explored and a large number of person re-id methods have been developed. As these algorithms leverage different kinds of prior assumptions, image features, distance matching functions, et al., each of them has its own strengths and weaknesses. Inspired by these facts, this paper proposes a novel person re-id method based on the idea of inferring superior fusion results from a variety of previous base person re-id algorithms using different methodologies or features. To achieve this goal, we propose a novel framework which mainly consists of two steps: 1) a number of existing person re-id methods are implemented, and the ranking results are obtained in the test datasets. and 2) the robust fusion strategy is applied to obtain better re-ranked matching results by simultaneously considering the recognition abilities of various base re-id methods and the difficulties of different gallery person images to be correctly recognized under the generative model of labels, abilities, and difficulties framework. Comprehensive experiments show the effectiveness of our proposed method, and we have received state-of-the-art results on recent popular person re-id datasets. PMID- 30307884 TI - Matsuoka's CPG With Desired Rhythmic Signals for Adaptive Walking of Humanoid Robots. AB - The desired rhythmic signals for adaptive walking of humanoid robots should have proper frequencies, phases, and shapes. Matsuoka's central pattern generator (CPG) is able to generate rhythmic signals with reasonable frequencies and phases, and thus has been widely applied to control the movements of legged robots, such as walking of humanoid robots. However, it is difficult for this kind of CPG to generate rhythmic signals with desired shapes, which limits the adaptability of walking of humanoid robots in various environments. To address this issue, a new framework that can generate desired rhythmic signals for Matsuoka's CPG is presented. The proposed framework includes three main parts. First, feature processing is conducted to transform the Matsuoka's CPG outputs into a normalized limit cycle. Second, by combining the normalized limit cycle with robot feedback as the feature inputs and setting the required learning objective, the neural network (NN) learns to generate desired rhythmic signals. Finally, in order to ensure the continuity of the desired rhythmic signals, signal filtering is applied to the outputs of NN, with the aim of smoothing the discontinuous parts. Numerical experiments on the proposed framework suggest that it can not only generate a variety of rhythmic signals with desired shapes but also preserve the frequency and phase properties of Matsuoka's CPG. In addition, the proposed framework is embedded into a control system for adaptive omnidirectional walking of humanoid robot NAO. Extensive simulation and real experiments on this control system demonstrate that the proposed framework is able to generate desired rhythmic signals for adaptive walking of NAO on fixed and changing inclined surfaces. Furthermore, the comparison studies verify that the proposed framework can significantly improve the adaptability of NAO's walking compared with the other methods. PMID- 30307885 TI - Deep Network Embedding for Graph Representation Learning in Signed Networks. AB - Network embedding has attracted an increasing attention over the past few years. As an effective approach to solve graph mining problems, network embedding aims to learn a low-dimensional feature vector representation for each node of a given network. The vast majority of existing network embedding algorithms, however, are only designed for unsigned networks, and the signed networks containing both positive and negative links, have pretty distinct properties from the unsigned counterpart. In this paper, we propose a deep network embedding model to learn the low-dimensional node vector representations with structural balance preservation for the signed networks. The model employs a semisupervised stacked auto-encoder to reconstruct the adjacency connections of a given signed network. As the adjacency connections are overwhelmingly positive in the real-world signed networks, we impose a larger penalty to make the auto-encoder focus more on reconstructing the scarce negative links than the abundant positive links. In addition, to preserve the structural balance property of signed networks, we design the pairwise constraints to make the positively connected nodes much closer than the negatively connected nodes in the embedding space. Based on the network representations learned by the proposed model, we conduct link sign prediction and community detection in signed networks. Extensive experimental results in real-world datasets demonstrate the superiority of the proposed model over the state-of-the-art network embedding algorithms for graph representation learning in signed networks. PMID- 30307886 TI - A Network Reduction-Based Multiobjective Evolutionary Algorithm for Community Detection in Large-Scale Complex Networks. AB - Evolutionary algorithms have been demonstrated to be very competitive in the community detection for complex networks. They, however, show poor scalability to large-scale networks due to the exponential increase of search space. In this paper, we suggest a network reduction-based multiobjective evolutionary algorithm for community detection in large-scale networks, where the size of the networks is recursively reduced as the evolution proceeds. In each reduction of the network, the local communities found by the elite individuals in the population are identified as nodes of the reduced network for further evolution, thereby considerably reducing the search space. A local community repairing strategy is also suggested to correct the misidentified nodes after each network reduction during the evolution. Experimental results on synthetic and real-world networks demonstrate the superiority of the proposed algorithm over several state-of-the art community detection algorithms for large-scale networks, in terms of both computational efficiency and detection performance. PMID- 30307887 TI - Identifying Key Opinion Leaders in Social Media via Modality-Consistent Harmonized Discriminant Embedding. AB - The digital age has empowered brands with new and more effective targeted marketing tools in the form of key opinion leaders (KOLs). Because of the KOLs' unique capability to draw specific types of audience and cultivate long-term relationship with them, correctly identifying the most suitable KOLs within a social network is of great importance, and sometimes could govern the success or failure of a brand's online marketing campaigns. However, given the high dimensionality of social media data, conducting effective KOL identification by means of data mining is especially challenging. Owing to the generally multiple modalities of the user profiles and user-generated content (UGC) over the social networks, we can approach the KOL identification process as a multimodal learning task, with KOLs as a rare yet far more important class over non-KOLs in our consideration. In this regard, learning the compact and informative representation from the high-dimensional multimodal space is crucial in KOL identification. To address this challenging problem, in this paper, we propose a novel subspace learning algorithm dubbed modality-consistent harmonized discriminant embedding (MCHDE) to uncover the low-dimensional discriminative representation from the social media data for identifying KOLs. Specifically, MCHDE aims to find a common subspace for multiple modalities, in which the local geometric structure, the harmonized discriminant information, and the modality consistency of the dataset could be preserved simultaneously. The above objective is then formulated as a generalized eigendecomposition problem and the closed form solution is obtained. Experiments on both synthetic example and a real-world KOL dataset validate the effectiveness of the proposed method. PMID- 30307889 TI - 9th International Conference on Early Psychosis: Poster Session A PMID- 30307888 TI - False Data Injection Attack for Cyber-Physical Systems With Resource Constraint. AB - Cyber-security is of the fundamental importance for cyber-physical systems (CPSs), since CPSs are vulnerable to cyber attack. In order to make the defensive measures better, one needs to understand the behavior from the view of an attacker. In this paper, the problem of false data injection attack on remote state estimation with resource constraints is studied in two cases, where the first case is that the attacker adds a Gaussian noise to the innovation, while the other is that the attacker employs a Gaussian noise to replace the innovation. In addition, the attacker is assumed to has a resource constraint, i.e., he/she cannot attack all the sensors, at the same time should decide which sensors to attack. By using the matrix theory, the optimal attack strategy problem, which aims to maximize the trace of the remote estimation error covariance, is converted into a convex optimization problem that can be solved. Thus, an optimal attack strategy is given to illustrate which sensors should be attacked. An example is given to show the effectiveness of the theoretical results. PMID- 30307890 TI - A New Composite Index to Measure National-Level Quality of Family Planning Programs. AB - CONTEXT: Despite efforts to use facility surveys to measure the quality of family planning programs, routine, reliable measurement and monitoring of national-level quality has not been possible. METHODS: A new composite index to measure national level quality, the National Quality Composite Index (NQCI), is proposed and used to compare program quality in 30 developing countries. Index scores represent the unweighted average of scores from indicators of three different dimensions of quality-structure, process and outcome. The structural indicator, the Method Availability Index, used data from the 2014 Family Planning Effort survey, while the process indicator (the Method Information Index) and outcome indicator (the Method Success Index) used data from the most recent Demographic Health Surveys conducted in the included countries. Correlations between these and other indicators were examined. RESULTS: The unweighted average NQCI score for the 30 countries was 60; scores ranged from 50 in Pakistan to 72 in Cambodia. The average scores for the three NQCI components were 52 for Method Availability (range, 40-73), 41 for Method Information (range, 13-71) and 86 for Method Success (range, 70-99). Scores for these components were not correlated with each other, suggesting that they measure distinct dimensions of program quality. Overall NQCI scores were correlated with existing measures of national-level quality, but not with total fertility rate and modern contraceptive prevalence rate. CONCLUSIONS: The NQCI and its three components use data routinely collected through national surveys, and can be used to measure and monitor national-level quality of family planning programs. PMID- 30307892 TI - What is happening to laboratory medicine in Denmark? AB - A number of current trends will affect and probably change laboratory medicine, as we know it. Scientific and technological developments, digital health with big data and artificial intelligence, and centralization will change the interfaces among the specialties of laboratory medicine. They might even challenge the identity of some specialties. Other trends such as demographic changes, increased complexity of health care, digital health with electronic health records, and more demanding and well-informed patients will change the way laboratory medicine specialties deliver their services. This paper discusses the possible changes of laboratory medicine in Denmark - a Scandinavian country where almost all hospitals are public. If Danish laboratories grasp the new possibilities instead of trying to avoid them, laboratory medicine is likely to prosper. Such a positive development will call upon good leadership and a genuine willingness among laboratory specialist to adapt to a future where their own specialty might be very different from today. PMID- 30307891 TI - Large platelet size is associated with poor outcome in patients with metastatic pancreatic cancer. AB - Background Platelets are a major cellular component of blood and their interaction with cancer cells is well-established to influence cancer progression and metastases. The physical size of platelets may have a critical impact on the interaction with cancer cells. In this study, we explored the potential prognostic role of platelet size measured by the determination of the mean platetlet volume (MPV) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Data from 527 patients with PDAC diagnosed and treated between 2004 and 2015 at a single center were evaluated retrospectively. Associations between MPV and baseline covariates were assessed with Wilcoxon's rank-sum tests, chi2-tests, and Fisher's exact tests. Median follow-up was estimated with a reverse Kaplan Meier estimator according to Schemper and Smith. Analysis of time-to-death was performed with Kaplan-Meier estimators, log-rank tests and uni- and multivariable Cox proportional hazards models. Results The median MPV was 10.5 femto liter (fL) [9.8-11.3], ranged from 5.9 to 17.7 fL. A large platelet volume was associated with high-grade G3/4 tumors (p=0.004) and worse overall survival (OS) in patients with metastatic disease in univariable analysis (hazard ratio [HR] per fL increase in MPV=1.13 [95% CI: 1.04-1.23, p=0.005]). In multivariable analysis of metatatic PDAC patients, the adverse association between large platelets and a higher risk-of-death prevailed (adjusted HR per doubling of MPV=2.00; 95% CI: 1.10-3.62, p=0.02). Conclusions Large platelets represent a negative prognostic factor and add an independent prognostic information to well-established factors in PDAC patients. MPV should be considered for future individual risk assessment in patients with stage IV PDAC. PMID- 30307893 TI - Should phosphatidylethanol be currently analysed using whole blood, dried blood spots or both? AB - Phosphatidylethanol (PEth) are phospholipids produced through non-oxidative ethanol metabolism. They accumulate in red blood cells and have been traditionally analysed in whole blood as potential biomarkers for moderate to long-term alcohol consumption. More recently, their analysis in dried blood spots has been gaining favour, namely, due to the ease in sampling, transport and storage conditions required. This paper aims at providing a short comparative review between analysing PEth in whole blood and dried blood spots and the potential pitfalls that researchers may face when setting up PEth testing for clinical use. PMID- 30307894 TI - Moving average quality control: principles, practical application and future perspectives. AB - Moving average quality control (MA QC) was described decades ago as an analytical quality control instrument. Although a potentially valuable tool, it is struggling to meet expectations due to its complexity and need for evidence-based guidance. For this review, relevant literature and the world wide web were examined in order to (i) explain the basic concepts and current understanding of MA QC, (ii) discuss moving average (MA) optimization methods, (iii) gain insight into practical aspects related to applying MA in daily practice and (iv) describe future prospects to enable more widespread acceptance and application of MA QC. Each of the MA QC optimization methods currently available has their own advantages and disadvantages. Recently developed simulation methods provide realistic error detecting properties for MA QC and are available for laboratories. Operational MA management issues have been identified that allow developers of MA software to upgrade their packages to support optimal MA QC application and guide laboratories on MA management issues, such as MA alarm workup. The new insights into MA QC characteristics and operational issues, together with supporting online tools, may promote more widespread acceptance and application of MA QC. PMID- 30307895 TI - Diagnostic test accuracy: a valuable tool for promoting quality and patient safety. PMID- 30307896 TI - Prevalence of overweight and obesity and anthropometric reference centiles for Albanian children and adolescents living in four Balkan nation-states. AB - Background The extent of the obesity epidemic among youth is an important public health statistic which provides an indication of the future burden of non communicable diseases. Many developing countries, including Albania, do not have systematic and repeated monitoring systems in operation. Methods The Balkan Survey of Inactivity in Children study is a population-based cross-sectional survey including Albanian children living in the four Balkan nation-states of Albania, Kosovo, FYR Macedonia and Montenegro. In total, 19,850 children from 49 schools were approached. The LMS method was used to provide body mass index (BMI), height, weight and waist circumference reference centiles for boys and girls. The World Health Organisation (WHO) and International Obesity Task Force (IOTF) age- and sex-specific BMI cut-points were applied to evaluate adiposity levels. Results A sample of 18,460 participants aged 6-16 years old was available for creation of the BMI for age and sex reference centiles. The prevalence of overweight (including obesity) in the full sample was 21% (95% CI: 20%-21%) according to IOTF cut-off points and 28% (95% CI: 28%-29%) at WHO cut-off points. Overweight/obesity levels where higher in boys than in girls irrespective of the cut-off points applied (p<0.001). Noticeable between-country differences were observed with a prevalence of overweight/obesity of 40% (95% CI: 38%-42%) in Montenegro but only 20% (95% CI: 19%-21%) in Kosovo (WHO cut-off points). Conclusions Overweight/obesity is highly prevalent in Albanian children and adolescents. The apparent sex and country differences may inform public health actions. PMID- 30307897 TI - Severe hyperchylomicronemia in two infants with novel APOC2 gene mutation. AB - Background Familial apo C-II deficiency is a rare hereditary disorder frequently caused by lipoprotein lipase (LPL) and APOC2 gene mutations. To date, less than 30 patients with familial apo C-II deficiency with 24 different mutations have been identified in the literature. Here, we describe two familial chylomicronemia syndrome cases in infants with two novel mutations of the APOC2 gene. Case presentation Case 1, a 46-day-old female, was admitted to our hospital for evaluation due to the lipemic appearance of the blood sample. A clinical examination revealed hepatomegaly and lipemia retinalis. Triglyceride level of 6295 mg/dL was decreased with a strict low-fat diet, medium-chain triglycerides (MCT) oil-rich formula and omega-3 fatty acid supplementation. Due to low adherence to the diet, TG elevation was detected and fresh frozen plasma (10 mL/kg/day) was administered for 2 days. A novel homozygous p.Q25X (c.73C>T) mutation in the APOC2 gene was detected. Case 2, a 10-month-old female patient, referred to our center for the differential diagnosis of hyperlipidemia as her blood sample could not be assessed due to its lipemic appearance. Laboratory examinations showed a TG level of 4520 mg/dL which was reduced with a low-fat diet, MCT oil-rich formula and omega-3 fatty acid supplementation. Hepatosteatosis and splenomegaly were determined using abdominal sonography. A novel homozygous IVS2+6T>G (c.55+6T>G) mutation in the APOC2 gene was identified. Conclusions We describe two novel homozygous mutations (p.Q25X [c.73C>T] and IVS2+6T>G [c.55+6T>G]) in the APOC2 gene in infants with hyperchylomicronemia. To the best of our knowledge, Case 1 is the youngest patient with familial apo C-II deficiency in the literature to date. PMID- 30307899 TI - Letter to the Editor concerning the paper "A novel database of bio-effects from non-ionizing radiation". PMID- 30307898 TI - Application of lactic acid derived from food waste on pathogen inactivation in fecal sludge: a review on the alternative use of food waste. AB - Food waste generation and disposal have led to several environmental problems, especially in developing countries. This phenomenon is partly because most cities rapidly urbanize, which results in population increase, urban settlement and waste generation. Improper management of waste has continued to create environmental problems. These problems have indeed interfered with the inadequate measures in managing other organic waste such as food waste. Food waste can be fermented and used for pathogen inactivation in fecal sludge (FS). The continual decrease in global crop production due to soil erosion, nutrient runoff and loss of organic matter has generated interest in using FS for soil amendment. However, due to the high number of pathogens in FS that are harmful to humans, FS must be treated before being used in agriculture. Thus, given the high amounts of food waste generated globally and the lactic acid potential of fermented food waste, several researchers have recently proposed the use of fermented food waste to suppress pathogens in FS. This review presents the various approaches in pathogen inactivation in FS using different types of food waste. On the basis of the literature review, the major problems associated with the generation, collection and application of food waste in pathogen inactivation in FS are discussed. Moreover, the trends and challenges that concern the applicability of each method are critically reviewed. PMID- 30307900 TI - Correlations between the active straight leg raise, sleep and somatosensory sensitivity during pregnancy with post-partum lumbopelvic pain: an initial exploration. AB - Background and aims For some women, lumbopelvic pain (LPP) developed during pregnancy becomes a continuing post-partum problem. Increased understanding of potential prognostic factors is required. This study investigated whether active straight leg raise (ASLR), sleep dysfunction and pressure pain sensitivity during pregnancy are correlated with LPP intensity and quality, disability, and physical health-related quality of life (HRQoL) post-partum. Methods An exploratory, prospective cohort study design was used. Baseline factors of interest were: (1) ASLR, (2) Pittsburgh Sleep Quality Index, and (3) pressure pain thresholds (PPTs) collected from pregnant women from sites local and distal to the lumbopelvic area. Follow-up data collected 11-18 months post-partum (n=29) were: (1) pain intensity score (numerical rating scale), (2) pain quality (McGill Pain Questionnaire), (3) disability (Pelvic Girdle Questionnaire), and (4) HRQoL (36 item Short Form Health Survey). Correlation analysis was performed. Results Greater difficulty with an ASLR during pregnancy correlated with lower post partum physical HRQoL scores (r=-0.563, p=0.002). Likewise, reduced PPTs at the sacrum during pregnancy was correlated with a higher post-partum pain quality score (r=-0.384, p=0.040). Conclusions In this cohort, findings indicate that poor ASLR performance and localised pressure pain hypersensitivity at the pelvis during pregnancy are correlated with post-partum physical HRQoL and pain quality, respectively. Implications Pain sensitivity may contribute to the prognosis of women with LPP during pregnancy. These explorative findings may be important for designing larger prognostic studies and may assist in directing potential pain management in post-partum LPP. PMID- 30307901 TI - Offset analgesia is not affected by cold pressor induced analgesia. AB - Background and aims Offset analgesia (OA) is a pain modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a minor decrease in stimulus intensity. Precise mechanisms of OA are still not elucidated and studies are needed to evaluate factors modulating OA. The aim of this study was to investigate OA before and during tonic cold pain (thought to induce descending inhibition), in a group of healthy volunteers. Methods A randomized, crossover study was performed in 17 healthy participants (8 males and 9 females). The OA paradigm lasted 35 s and was induced by the traditional method using thermal stimulation applied to the forearm. A constant control heat stimulus (CTL) paradigm was used as control to assess adaptation. Pain intensity was assessed continuously. For induction of tonic cold pain, the participants immersed their hand into 2 degrees C water for 2 min. After 1 min and 25 s, the heat stimulation (OA or CTL paradigm) was repeated to assess the modulatory effect of the cold pressor test. Results It was possible to induce OA both before and during the cold pressor test. Tonic cold pain modulated the peak pain reported during both the OA (p=0.015) and CTL paradigms (p=0.001) reflecting endogenous pain modulation. However, the magnitude of OA was not modulated by tonic cold pain (p>0.05). Conclusions The offset analgesia magnitude was not modulated by simultaneously tonic cold pain, thought to reflect another endogenous pain modulation mechanism. Implications Neither offset analgesia magnitude nor adaptation were modulated by cold pressor induced endogenous analgesia. This could be explained by the fact, that offset analgesia was already at maximum in healthy participants. Hence, offset analgesia may not be a suitable assessment tool to investigate modulation induced by experimental methods or pharmacology in healthy participants. PMID- 30307902 TI - Intravenous Immunoglobulin Gamma (IVIG) versus IVIG Plus Infliximab in Young Children with Kawasaki Disease. AB - BACKGROUND Kawasaki disease (KD) is a serious disease characterized by systemic lesions of the skin and mucous membranes, as well as lymphomas and vascular inflammation. KD threatens the health and lives of children, especially young ones. Here, we compared the therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. a combination of IVIG and infliximab in young children with Kawasaki disease (KD). MATERIAL AND METHODS A total of 154 children with KD, younger than 5 years old, were enrolled in the study from January 2013 to January 2017. The patients were randomly divided into an IVIG group and a combination of IVIG and infliximab treatment group. After systematic treatments, the therapeutic indicators of the 2 groups were compared. During the treatment process, body temperature and other important inflammatory indicators, including C-reactive protein (CRP), white blood cell count (WBC), and tumor necrosis factor alpha (TNF-alpha), were monitored in the first 4 days. RESULTS There were fewer refractory KD patients in the combined treatment group than in the IVIG group (4 vs. 14, p<0.001). KD patients in the combined treatment group had better outcomes with shorter fever durations and hospital stays, as well as less coronary artery dilation. However, there was no obvious differences in the incidence rate of coronary artery aneurysms between the 2 groups (p>0.05). Costs of administration were similar between groups (p>0.05). Body temperature, CRP, WBC, and TNF-alpha in the combined therapy group all showed an earlier drop than in the IVIG group, indicating a more effective anti-inflammation effect. CONCLUSIONS The introduction of IVIG combined with infliximab in the treatment of young children with KD has more advantages than single IVIG therapy and can be considered as a preferred treatment for KD. However, it would be necessary to further investigate whether there is a significant difference in aneurysm frequency and long-term outcome between these 2 strategies among a larger number of patients. PMID- 30307903 TI - Notes from the Field: Rubella Infection in an Unvaccinated Pregnant Woman - Johnson County, Kansas, December 2017. PMID- 30307904 TI - Vaccination Coverage for Selected Vaccines and Exemption Rates Among Children in Kindergarten - United States, 2017-18 School Year. AB - State and local school vaccination requirements exist to ensure that students are protected from vaccine-preventable diseases (1). This report summarizes vaccination coverage and exemption estimates collected by state and local immunization programs* for children in kindergarten (kindergartners) in 49 states and the District of Columbia (DC) and kindergartners provisionally enrolled (attending school without complete vaccination or exemption while completing a catch-up vaccination schedule) or in a grace period (a set interval during which a student may be enrolled and attend school without proof of complete vaccination or exemption) for 28 states. Median vaccination coverage? was 95.1% for the state required number of doses of diphtheria and tetanus toxoids, and acellular pertussis vaccine (DTaP); 94.3% for 2 doses of measles, mumps, and rubella vaccine (MMR); and 93.8% for 2 doses of varicella vaccine. The median percentage of kindergartners with an exemption from at least one vaccineS was 2.2%, and the median percentage provisionally enrolled or attending school during a grace period was 1.8%. Vaccination coverage among kindergartners remained high; however, schools can improve coverage by following up with students who are provisionally enrolled, in a grace period, or lacking complete documentation of required vaccinations. PMID- 30307906 TI - Notes from the Field: Exported Case of Sin Nombre Hantavirus Pulmonary Syndrome - Israel, 2017. PMID- 30307905 TI - Differences in Characteristics and Clinical Outcomes Among Hispanic/Latino Men and Women Receiving HIV Medical Care - United States, 2013-2014. AB - The prevalence of diagnosed human immunodeficiency virus (HIV) infection among Hispanics/Latinos in the United States is approximately twice that of non Hispanic whites (1). Barriers to, and experiences with, medical care have been found to vary by sex (2). Describing characteristics of Hispanics/Latinos in care by sex can help identify disparities and inform delivery of tailored services to this underserved population. Data from the 2013 and 2014 cycles of the Medical Monitoring Project (MMP) were analyzed to describe demographic, behavioral, and clinical characteristics among Hispanics/Latinos by sex. MMP is an annual cross sectional, nationally representative surveillance system that, during 2013-2014, collected information about behaviors, medical care, and clinical outcomes among adults receiving outpatient HIV care. Hispanic/Latina women were significantly more likely than were men to live in poverty (78% versus 54%), report not speaking English well (38% versus 21%), and receive interpreter (27% versus 16%), transportation (35% versus 21%), and meal (44% versus 26%) services. There were no significant differences between Hispanic/Latino women and men in prescription of antiretroviral therapy (ART) (95% versus 96%) or sustained viral suppression (68% versus 73%). Although women faced greater socioeconomic and language-related challenges, the clinical outcomes among Hispanic/Latina women were similar to those among men, perhaps reflecting their higher use of ancillary services. Levels of viral suppression for Hispanics/Latinos are lower than those found among non-Hispanic whites (3) and lower than the national prevention goal of at least 80% of persons with diagnosed HIV infection. Providers should be cognizant of the challenges faced by Hispanics/Latinos with HIV infection in care and provide referrals to needed ancillary services. PMID- 30307907 TI - Vaccination Coverage Among Children Aged 19-35 Months - United States, 2017. AB - The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination by age 24 months against 14 potentially serious illnesses (1). CDC used data from the 2017 National Immunization Survey-Child (NIS-Child) to assess vaccination coverage at national, state, territorial, and selected local levels among children aged 19-35 months in the United States. Coverage remained high and stable overall, exceeding 90% for >=3 doses of poliovirus vaccine, >=1 dose of measles, mumps, and rubella vaccine (MMR), >=3 doses of hepatitis B vaccine (HepB), and >=1 dose of varicella vaccine. Although the proportion of children who received no vaccine doses by age 24 months was low, this proportion increased gradually from 0.9% for children born in 2011 to 1.3% for children born in 2015. Coverage was lower for most vaccines among uninsured children and those insured by Medicaid, compared with those having private health insurance, and for children living outside of metropolitan statistical areas* (MSAs), compared with those living in MSA principal cities. These disparities could be reduced with greater awareness and use of the Vaccines for Children? (VFC) program, eliminating missed opportunities to vaccinate children during visits to health care providers, and minimizing interruptions in health insurance coverage. PMID- 30307908 TI - Notes from the Field: Large Cluster of Verona Integron-Encoded Metallo-Beta Lactamase-Producing Carbapenem-Resistant Pseudomonas aeruginosa Isolates Colonizing Residents at a Skilled Nursing Facility - Chicago, Illinois, November 2016-March 2018. PMID- 30307909 TI - QuickStats: Percentage* of Youths Aged 2-19 Years Consuming Any Fast Food? on a Given Day, by Race and Hispanic OriginS - National Health and Nutrition Examination Survey, 2013-2016. PMID- 30307910 TI - Gender disparities among independent fellows in biomedical research. PMID- 30307911 TI - Decoding mood. PMID- 30307912 TI - FDA approves Galafold, a triumph for Amicus. PMID- 30307913 TI - The virome hunters. PMID- 30307915 TI - Akcea's antisense drug rejection worries analysts. PMID- 30307916 TI - Around the world in a month. PMID- 30307917 TI - Correction. AB - This corrects the article DOI: 10.1038/nbt0818-671. PMID- 30307919 TI - Author Correction: Precision medicine in the clouds. AB - This corrects the article DOI: 10.1038/nbt.4210. PMID- 30307920 TI - Smart insulin: redesign could end hypoglycemia risk. PMID- 30307921 TI - In defense of the press... and more. PMID- 30307922 TI - Setbacks shadow microRNA therapies in the clinic. PMID- 30307914 TI - Biotech leaders call for free press. PMID- 30307924 TI - Regeneron buys into CAR-Ts with Bluebird Bio deal. PMID- 30307923 TI - Designing efficient translation. PMID- 30307925 TI - Barcodes galore for developmental biology. PMID- 30307926 TI - Publisher Correction: Guided self-organization and cortical plate formation in human brain organoids. AB - This corrects the article DOI: 10.1038/nbt.3906. PMID- 30307928 TI - Recent patents in antimicrobials. PMID- 30307929 TI - Sangamo's landmark genome editing trial gets mixed reception. PMID- 30307931 TI - US law threatens flow of foreign capital to biotech sector. PMID- 30307930 TI - Opening options for material transfer. PMID- 30307932 TI - Are the new clinical trial transparency rules incompatible with the patentability requirements in Europe? PMID- 30307934 TI - Ten quick tips for getting the most scientific value out of numerical data. AB - Most studies in the life sciences and other disciplines involve generating and analyzing numerical data of some type as the foundation for scientific findings. Working with numerical data involves multiple challenges. These include reproducible data acquisition, appropriate data storage, computationally correct data analysis, appropriate reporting and presentation of the results, and suitable data interpretation. Finding and correcting mistakes when analyzing and interpreting data can be frustrating and time-consuming. Presenting or publishing incorrect results is embarrassing but not uncommon. Particular sources of errors are inappropriate use of statistical methods and incorrect interpretation of data by software. To detect mistakes as early as possible, one should frequently check intermediate and final results for plausibility. Clearly documenting how quantities and results were obtained facilitates correcting mistakes. Properly understanding data is indispensable for reaching well-founded conclusions from experimental results. Units are needed to make sense of numbers, and uncertainty should be estimated to know how meaningful results are. Descriptive statistics and significance testing are useful tools for interpreting numerical results if applied correctly. However, blindly trusting in computed numbers can also be misleading, so it is worth thinking about how data should be summarized quantitatively to properly answer the question at hand. Finally, a suitable form of presentation is needed so that the data can properly support the interpretation and findings. By additionally sharing the relevant data, others can access, understand, and ultimately make use of the results. These quick tips are intended to provide guidelines for correctly interpreting, efficiently analyzing, and presenting numerical data in a useful way. PMID- 30307933 TI - Partial homologies between sleep states in lizards, mammals, and birds suggest a complex evolution of sleep states in amniotes. AB - It is crucial to determine whether rapid eye movement (REM) sleep and slow-wave sleep (SWS) (or non-REM sleep), identified in most mammals and birds, also exist in lizards, as they share a common ancestor with these groups. Recently, a study in the bearded dragon (P. vitticeps) reported states analogous to REM and SWS alternating in a surprisingly regular 80-s period, suggesting a common origin of the two sleep states across amniotes. We first confirmed these results in the bearded dragon with deep brain recordings and electro-oculogram (EOG) recordings. Then, to confirm a common origin and more finely characterize sleep in lizards, we developed a multiparametric approach in the tegu lizard, a species never recorded to date. We recorded EOG, electromyogram (EMG), heart rate, and local field potentials (LFPs) and included data on arousal thresholds, sleep deprivation, and pharmacological treatments with fluoxetine, a serotonin reuptake blocker that suppresses REM sleep in mammals. As in the bearded dragon, we demonstrate the existence of two sleep states in tegu lizards. However, no clear periodicity is apparent. The first sleep state (S1 sleep) showed high-amplitude isolated sharp waves, and the second sleep state (S2 sleep) displayed 15-Hz oscillations, isolated ocular movements, and a decrease in heart rate variability and muscle tone compared to S1. Fluoxetine treatment induced a significant decrease in S2 quantities and in the number of sharp waves in S1. Because S2 sleep is characterized by the presence of ocular movements and is inhibited by a serotonin reuptake inhibitor, as is REM sleep in birds and mammals, it might be analogous to this state. However, S2 displays a type of oscillation never previously reported and does not display a desynchronized electroencephalogram (EEG) as is observed in the bearded dragons, mammals, and birds. This suggests that the phenotype of sleep states and possibly their role can differ even between closely related species. Finally, our results suggest a common origin of two sleep states in amniotes. Yet, they also highlight a diversity of sleep phenotypes across lizards, demonstrating that the evolution of sleep states is more complex than previously thought. PMID- 30307935 TI - A systematic review of antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid. AB - BACKGROUND: The temporal and spatial change in trends of antimicrobial resistance (AMR) in typhoid have not been systematically studied, and such information will be critical for defining intervention, as well as planning sustainable prevention strategies. METHODOLOGY AND FINDINGS: To identify the phenotypic trends in AMR, 13,833 individual S. Typhi isolates, reported from 1973 to 2018 in 62 publications, were analysed to determine the AMR preponderance over time. Separate analyses of molecular resistance determinants present in over 4,000 isolates reported in 61 publications were also conducted. Multi-drug resistant (MDR) typhoid is in decline in Asia in a setting of high fluoroquinolone resistance while it is on the increase in Africa. Mutations in QRDRs in gyrA (S83F, D87N) and parC (S80I) are the most common mechanisms responsible for fluoroquinolone resistance. Cephalosporin resistant S. Typhi, dubbed extensively drug-resistant (XDR) is a real threat and underscores the urgency in deploying the Vi-conjugate vaccines. CONCLUSION: From these observations, it appears that AMR in S. Typhi will continue to emerge leading to treatment failure, changes in antimicrobial policy and further resistance developing in S. Typhi isolates and other Gram-negative bacteria in endemic regions. The deployment of typhoid conjugate vaccines to control the disease in endemic regions may be the best defence. PMID- 30307936 TI - Predictive risk mapping of an environmentally-driven infectious disease using spatial Bayesian networks: A case study of leptospirosis in Fiji. AB - INTRODUCTION: Leptospirosis is a zoonotic disease responsible for over 1 million severe cases and 60,000 deaths annually. The wide range of animal hosts and complex environmental drivers of transmission make targeted interventions challenging, particularly when restricted to regression-based analyses which have limited ability to deal with complexity. In Fiji, important environmental and socio-demographic factors include living in rural areas, poverty, and livestock exposure. This study aims to examine drivers of transmission under different scenarios of environmental and livestock exposures. METHODS: Spatial Bayesian networks (SBN) were used to analyse the influence of livestock and poverty on the risk of leptospirosis infection in urban compared to rural areas. The SBN models used a combination of spatially-explicit field data from previous work and publically available census information. Predictive risk maps were produced for overall risk, and for scenarios related to poverty, livestock, and urban/rural setting. RESULTS: While high, rather than low, commercial dairy farm density similarly increased the risk of infection in both urban (12% to 18%) and rural areas (70% to 79%), the presence of pigs in a village had different impact in rural (43% to 84%) compared with urban areas (4% to 24%). Areas with high poverty rates were predicted to have 26.6% and 18.0% higher probability of above average seroprevalence in rural and urban areas, respectively. In urban areas, this represents >300% difference between areas of low and high poverty, compared to 43% difference in rural areas. CONCLUSIONS: Our study demonstrates the use of SBN to provide valuable insights into the drivers of leptospirosis transmission under complex scenarios. By estimating the risk of leptospirosis infection under different scenarios, such as urban versus rural areas, these subgroups or areas can be targeted with more precise interventions that focus on the most relevant key drivers of infection. PMID- 30307938 TI - Can sequential aerosol technique be used against riverine tsetse? PMID- 30307937 TI - Seizure pathways: A model-based investigation. AB - We present the results of a model inversion algorithm for electrocorticography (ECoG) data recorded during epileptic seizures. The states and parameters of neural mass models were tracked during a total of over 3000 seizures from twelve patients with focal epilepsy. These models provide an estimate of the effective connectivity within intracortical circuits over the time course of seizures. Observing the dynamics of effective connectivity provides insight into mechanisms of seizures. Estimation of patients seizure dynamics revealed: 1) a highly stereotyped pattern of evolution for each patient, 2) distinct sub-groups of onset mechanisms amongst patients, and 3) different offset mechanisms for long and short seizures. Stereotypical dynamics suggest that, once initiated, seizures follow a deterministic path through the parameter space of a neural model. Furthermore, distinct sub-populations of patients were identified based on characteristic motifs in the dynamics at seizure onset. There were also distinct patterns between long and short duration seizures that were related to seizure offset. Understanding how these different patterns of seizure evolution arise may provide new insights into brain function and guide treatment for epilepsy, since specific therapies may have preferential effects on the various parameters that could potentially be individualized. Methods that unite computational models with data provide a powerful means to generate testable hypotheses for further experimental research. This work provides a demonstration that the hidden connectivity parameters of a neural mass model can be dynamically inferred from data. Our results underscore the power of theoretical models to inform epilepsy management. It is our hope that this work guides further efforts to apply computational models to clinical data. PMID- 30307939 TI - Optimising sampling regimes and data collection to inform surveillance for trachoma control. AB - It is estimated that 190 million individuals are at risk of blindness from trachoma, and that control by mass drug administration (MDA) is reducing this risk in many populations. Programs are monitored using prevalence of follicular trachoma disease (TF) in children. However, as programs progress to low prevalence there are challenges interpreting this indirect measure of infection. PCR and sero-surveillance are being considered as complementary tools to monitor low-level transmission, but there are questions on how they can be most effectively used. We use a previously-published, mathematical model to explore the dynamic relationship between TF and PCR throughout a control program and a sero-catalytic model to evaluate the utility of two cross-sectional sero-surveys for estimating sero-conversion rates. The simulations show that whilst PCR is more sensitive than TF at detecting infection, the probability of detecting at least one positive individual declines during an MDA program more quickly for PCR than for TF (for the same sample size). Towards the end of a program there is a moderate chance of a random sample showing both low PCR prevalence and higher TF prevalence, which may contribute to the lack of correlation observed in epidemiological studies. We also show that conducting two cross-sectional sero surveys 10 years apart can provide more precise and accurate estimation of epidemiological parameters than a single survey, supporting previous findings that whilst serology holds great promise, multiple cross-sections from the same community are needed to generate the most valuable information about transmission. These results highlight that the quantitative dynamics of infection and disease should be included alongside the many logistical and practical factors to be considered in designing a monitoring and evaluation strategy at the operational research level, in order to help subsequently inform data collection for individual country programs. Whilst our simulations provide some insight, they also highlight that some level of longitudinal, individual-level data on reinfection and disease may be needed to monitor elimination progress. PMID- 30307941 TI - Ten simple rules for developing good reading habits during graduate school and beyond. PMID- 30307940 TI - Rutin (quercetin-3-rutinoside) modulates the hemostatic disturbances and redox imbalance induced by Bothrops jararaca snake venom in mice. AB - Snakebites are a major Collective Health problem worldwide. In Brazil, Bothrops jararaca snake venom (BjV) evokes hemostatic disturbances, bleeding manifestations, and redox status imbalance. Specific antivenom therapy, although efficacious to revert most snakebite-induced manifestations, is incapable of treating secondary manifestations, such as oxidative/nitrosative stress. Searching for new complementary therapies that could attenuate physiological derangements triggered by envenomation, we elected to test quercetin-3-rutinoside (rutin) by its potential as both a potent antioxidant and a hemostasis modulatory compound. The activity of rutin was evaluated both on the biological activities of crude BjV in vitro, and in vivo by the ability of rutin (14.4 mg/kg b.w.) to modulate hematological, hemostatic and redox status markers altered by BjV injection (1.6 mg/kg b.w., s.c.) in mice. In vitro, rutin failed to inhibit BjV induced platelet aggregation and biological activities of major BjV enzymes (metalloproteinases, phospholipases A2, serine proteases, and L-amino acid oxidases). On the other hand, rutin attenuated local hemorrhage, and the increase in reactive species, prevented the fall in RBC counts and fibrinogen levels, diminished tail bleeding and shortened prothrombin time (PT) evoked by envenomation. Furthermore, rutin reduced tissue factor (TF) activity and altered the protein expression of TF in liver, lungs, heart and skin. In conclusion, the disturbances in redox status and hemostatic system induced by B. jararaca envenomation were modulated by rutin, suggesting it has a great potential to be used as an ancillary therapeutic agent for snakebites. PMID- 30307942 TI - Self-organized traffic via priority rules in leaf-cutting ants. AB - Ants, termites and humans often form well-organized and highly efficient trails between different locations. Yet the microscopic traffic rules responsible for this organization and efficiency are not fully understood. In previous experimental studies with leaf-cutting ants (Atta colombica), a set of local priority rules were isolated and it was proposed that these rules govern the temporal and spatial organization of the traffic on the trails. Here we introduce a model based on these priority rules to investigate whether they are sufficient to produce traffic similar to that observed in the experiments on both a narrow and a wider trail. We establish that the model is able to reproduce key characteristics of the traffic on the trails. In particular, we show that the proposed priority rules induce de-synchronization into clusters of inbound and outbound ants on a narrow trail, and that priority-type dependent segregated traffic emerges on a wider trail. Due to the generic nature of the proposed priority rules we speculate that they may be used to model traffic organization in a variety of other ant species. PMID- 30307944 TI - The shape language in application to the diagnosis of cervical vertebrae pathology. AB - In this paper the possibility of classification of X-ray images of the cervical vertebrae is studied. The images should be classified into one of the following classes-the images of healthy vertebrae and the images of vertebrae with syndesmophytes. The vertebra contours, described unambiguously by using the generalized shape language, are the basis of the analysis. As a result, the contour is represented as a chain of sinquads that determine switches. The found switches are the characteristic points of the analyzed contour. In these points additional features of the contour are determined. On the basis of these features two aforementioned classes of images are defined as fuzzy sets. Such an approach allows us to create a hierarchical algorithm of classification based on the syntactic and fuzzy description of the contour. PMID- 30307943 TI - A gene expression comparison of Trypanosoma brucei and Trypanosoma congolense in the bloodstream of the mammalian host reveals species-specific adaptations to density-dependent development. AB - In the bloodstream of mammalian hosts Trypanosoma brucei undergoes well characterised density-dependent growth control and developmental adaptation for transmission. This involves the differentiation from proliferative, morphologically 'slender' forms to quiescent 'stumpy' forms that preferentially infect the tsetse fly vector. Another important livestock trypanosome, Trypanosoma congolense, also undergoes density-dependent cell-cycle arrest although this is not linked to obvious morphological transformation. Here we have compared the gene expression profile of T. brucei and T. congolense during the ascending phase of the parasitaemia and at peak parasitaemia in mice, analysing species and developmental differences between proliferating and cell-cycle arrested forms. Despite underlying conservation of their quorum sensing signalling pathway, each species exhibits distinct profiles of gene regulation when analysed by orthogroup and cell surface phylome profiling. This analysis of peak parasitaemia T. congolense provides the first molecular signatures of potential developmental competence, assisting life cycle developmental studies in these important livestock parasites. Furthermore, comparison with T. brucei identifies candidate molecules from each species that may be important for their survival in the mammalian host, transmission or distinct tropism in the tsetse vector. PMID- 30307945 TI - Pre- and post-natal macronutrient supplementation for HIV-positive women in Tanzania: Effects on infant birth weight and HIV transmission. AB - OBJECTIVE: To determine if a protein-calorie supplement (PCS) plus a micronutrient supplement (MNS) improves outcomes for HIV-infected lactating women and their infants. DESIGN: Randomized, controlled trial. SETTING: Dar es Salaam, Tanzania. SUBJECTS, PARTICIPANTS: Pregnant HIV-infected women enrolled in PMTCT programs who intended to breastfeed for 6 months. INTERVENTION: Randomization 1:1 to administration of a PCS plus MNS versus MNS alone among 96 eligible women beginning in the third trimester and continuing for 6 months of breast-feeding. MAIN OUTCOME MEASURE(S): Primary: infant weight at 3 months. Secondary: maternal BMI at 6 months. RESULTS: PCS resulted in significant increases in daily energy intake compared to MNS at all time points (range of differences: +388-719 Kcal); and increases in daily protein intake (range of differences: +22-33 gm). Infant birth weight (excluding twins) was higher in the PCS than MNS groups: 3.30 kg vs 3.04 kg (p = 0.04). Infant weight at 3 months did not differ between PCS and MNS groups: 5.63 kg vs 5.99 kg (p = 0.07). Maternal BMI at 6 months did not differ between PCS and MNS groups: 24.3 vs 23.8 kg/m2 (p = 0.68). HIV transmission occurred in 0 infants in the PCS group vs 4 in the MNS group (p = 0.03). CONCLUSIONS: In comparison to MNS the PCS + MNS intervention was well tolerated, increased maternal energy and protein intake, and increased infant birth weight, but not weight at 3 months or maternal BMI at 6 months. Reduced infant HIV transmission in the PCS + MNS group was observed. TRIAL REGISTRATION: Clinical Trials.Gov NCT01461863. PMID- 30307946 TI - Thermodynamic and computational analyses reveal the functional roles of the galloyl group of tea catechins in molecular recognition. AB - Catechins, biologically active polyphenols in green tea, exhibit various biological activities, such as anticancer and antiviral activities, arising from interactions with functional proteins. However, the molecular details of these interactions remain unclear. In this study, we investigated the interactions between human serum albumin (HSA) and various catechins, including some with a galloyl group, by means of isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and docking simulations. Our results indicate that the galloyl group was important for recognition by HSA and was responsible for enthalpic gains derived from a larger buried surface area and more van der Waals contacts. Thus, our thermodynamic and computational analyses suggest that the galloyl group plays important functional roles in the specific binding of catechins to proteins, implying that the biological activities of these compounds may be due in part to the physicochemical characteristics of the galloyl group. PMID- 30307947 TI - Estimating the economic impact of canine rabies to Viet Nam 2005-2014. AB - The global economic impact of canine rabies has been estimated by several studies. Asia bears a disproportionate burden of this zoonosis due to high levels of human deaths and rates of post-exposure prophylaxis (PEP), but low investment in preventative dog vaccination. The same factors that cause rabies to burden much of Asia are also present in Viet Nam. This study estimated the economic burden of canine rabies in a societal perspective including direct and indirect cost of rabies in dogs, livestock, and humans. Using data collected from personal interviews, published literature, published and supplementary reports, and primary data collection, we estimated the economic impact of canine rabies in Viet Nam over a ten year period (2005-2014). We incorporated the direct and indirect costs for PEP, dog vaccination efforts, livestock losses, and disability adjusted life years (DALYs) into the analysis. General findings from this analysis indicated that over the 10 year study period, the total economic impact of canine rabies was over $719 million USD. The largest portion of impacts (92%) were made up of PEP-related costs. Canine rabies created between 36,560 and 45,700 DALYs, measured in years of life lost (YLL). A total of 914 human deaths were reported over the study period. Deaths/100,000 people were 0.11, which is lower than the reported level for Asian countries. The cost per dog vaccinated was $1.75 USD. Our results indicate that canine rabies impacts in Viet Nam are consistent with the burden elsewhere reported in Asia, with large expenditures on PEP and very small investments in dog vaccination. PMID- 30307948 TI - Transcription factor programming of human ES cells generates functional neurons expressing both upper and deep layer cortical markers. AB - Human neurodegenerative disorders affect specific types of cortical neurons. Efficient protocols for the generation of such neurons for cell replacement, disease modeling and drug screening are highly warranted. Current methods for the production of cortical neurons from human embryonic stem (ES) cells are often time-consuming and inefficient, and the functional properties of the generated cells have been incompletely characterized. Here we have used transcription factor (TF) programming with the aim to induce rapid differentiation of human ES cells to layer-specific cortical neurons (hES-iNs). Three different combinations of TFs, NEUROGENIN 2 (NGN2) only, NGN2 plus Forebrain Embryonic Zinc Finger-Like Protein 2 (FEZF2), and NGN2 plus Special AT-Rich Sequence-Binding Protein 2 (SATB2), were delivered to human ES cells by lentiviral vectors. We observed only subtle differences between the TF combinations, which all gave rise to the formation of pyramidal-shaped cells, morphologically resembling adult human cortical neurons expressing cortical projection neuron (PN) markers and with mature electrophysiological properties. Using ex vivo transplantation to human organotypic cultures, we found that the hES-iNs could integrate into adult human cortical networks. We obtained no evidence that the hES-iNs had acquired a distinct cortical layer phenotype. Instead, our single-cell data showed that the hES-iNs, similar to fetal human cortical neurons, expressed both upper and deep layer cortical neuronal markers. Taken together, our findings provide evidence that TF programming can direct human ES cells towards cortical neurons but that the generated cells are transcriptionally profiled to generate both upper and deep layer cortical neurons. Therefore, most likely additional cues will be needed if these cells should adopt a specific cortical layer and area identity. PMID- 30307949 TI - The BH3 only Bcl-2 family member BNIP3 regulates cellular proliferation. AB - The BH3-only family member BNIP3 has been described as either promoting cell survival or cell death. This depends upon the level of BNIP3 expression and its cellular localization. Increased BNIP3 expression under hypoxia contributes to cell death through increased mitochondrial dysfunction. Furthermore, mice lacking BNIP3 show inhibition of ischemic cardiomyocyte apoptosis. In contrast, nuclear localization of BNIP3 contributes to blockage of apoptosis in glioma cells through repression of pro-apoptotic genes. We have discovered that mouse embryonic fibroblasts (MEFs) lacking BNIP3 expression show increased proliferation and cell number compared to wild-type cells. Furthermore, the cells lacking BNIP3 showed increased MAPK activation. Increased proliferation was not due to decreased cell death as oxidative stress induced cell death in BNIP3 null MEFs. In addition, we isolated astrocytes from wild-type or embryonic mice lacking expression of BNIP3. There was increased density and cell number in the astrocytes lacking BNIP3 expression. To confirm these results in human cells, we inducibly expressed BNIP3 in human embryonic kidney (HEK293) cells and found that induced BNIP3 reduced cell proliferation and failed to change background cell death levels. Transient over-expression of BNIP3 in the nucleus of HEK293 cells also reduced DNA synthesis. Finally, to determine whether this increased proliferation occurs in mice lacking BNIP3, we isolated brains from wild-type mice or those lacking BNIP3 expression. The mice lacking BNIP3 had increased cellularity in the brain of embryonic and adult mice. Taken together, our study describes a new function for BNIP3 in the regulation of cellular proliferation. PMID- 30307950 TI - Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS. AB - The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgDelta65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgDelta65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions. PMID- 30307951 TI - High density genetic mapping of Fusarium head blight resistance QTL in tetraploid wheat. AB - Breeding for Fusarium head blight (FHB) resistance in durum wheat is complicated by the quantitative trait expression and narrow genetic diversity of available resources. High-density mapping of the FHB resistance quantitative trait loci (QTL), evaluation of their co-localization with plant height and maturity QTL and the interaction among the identified QTL are the objectives of this study. Two doubled haploid (DH) populations, one developed from crosses between Triticum turgidum ssp. durum lines DT707 and DT696 and the other between T. turgidum ssp. durum cv. Strongfield and T. turgidum ssp. carthlicum cv. Blackbird were genotyped using the 90K Infinium iSelect chip and evaluated phenotypically at multiple field FHB nurseries over years. A moderate broad-sense heritability indicated a genotype-by-environment interaction for the expression of FHB resistance in both populations. Resistance QTL were identified for the DT707 * DT696 population on chromosomes 1B, 2B, 5A (two loci) and 7A and for the Strongfield * Blackbird population on chromosomes 1A, 2A, 2B, 3A, 6A, 6B and 7B with the QTL on chromosome 1A and those on chromosome 5A being more consistently expressed over environments. FHB resistance co-located with plant height and maturity QTL on chromosome 5A and with a maturity QTL on chromosome 7A for the DT707 * DT696 population. Resistance also co-located with plant height QTL on chromosomes 2A and 3A and with maturity QTL on chromosomes 1A and 7B for the Strongfield * Blackbird population. Additive * additive interactions were identified, for example between the two FHB resistance QTL on chromosome 5A for the DT707 * DT696 population and the FHB resistance QTL on chromosomes 1A and 7B for the Strongfield * Blackbird population. Application of the Single Nucleotide Polymorphic (SNP) markers associated with FHB resistance QTL identified in this study will accelerate combining genes from the two populations. PMID- 30307952 TI - Taking common ground into account: Specifying the role of the mentalizing network in communicative language production. AB - Several studies have shown that communicative language production as compared to non-communicative language production recruits parts of the mentalizing or theory of mind network, yet the exact role of this network in communication remains underspecified. In this study, we therefore aimed to test under what conditions the mentalizing network contributes to communicative language production. We were especially interested in distinguishing between situations in which speakers have to consider which information they do or do not share with their addressee (common vs. privileged ground information). We therefore manipulated whether speakers had to distinguish between common and privileged ground in order to communicate efficiently with the listener, in addition to comparing language production in a communicative and a non-communicative context. Participants performed a referential communicative game in the MRI-scanner as well as a similar, non-communicative task. We found that the medial prefrontal cortex, a core region of the mentalizing network, is especially sensitive to communicative contexts in which speakers have to take their addressee's needs into account in order to communicate efficiently. In addition, we found neural differences between the communicative and the non-communicative settings before speakers started to plan their utterances, suggesting that they continuously update common ground in a communicative context. PMID- 30307954 TI - Proof of concept study: Testing human volatile organic compounds as tools for age classification of films. AB - Humans emit numerous volatile organic compounds (VOCs) through breath and skin. The nature and rate of these emissions are affected by various factors including emotional state. Previous measurements of VOCs and CO2 in a cinema have shown that certain chemicals are reproducibly emitted by audiences reacting to events in a particular film. Using data from films with various age classifications, we have studied the relationship between the emission of multiple VOCs and CO2 and the age classifier (0, 6, 12, and 16) with a view to developing a new chemically based and objective film classification method. We apply a random forest model built with time independent features extracted from the time series of every measured compound, and test predictive capability on subsets of all data. It was found that most compounds were not able to predict all age classifiers reliably, likely reflecting the fact that current classification is based on perceived sensibilities to many factors (e.g. incidences of violence, sex, antisocial behaviour, drug use, and bad language) rather than the visceral biological responses expressed in the data. However, promising results were found for isoprene which reliably predicted 0, 6 and 12 age classifiers for a variety of film genres and audience age groups. Therefore, isoprene emission per person might in future be a valuable aid to national classification boards, or even offer an alternative, objective, metric for rating films based on the reactions of large groups of people. PMID- 30307953 TI - Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis. AB - BACKGROUND: Pulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies. OBJECTIVES: To assess the effects of PH-targeted therapy on exercise capacity in HF patients. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate. RESULTS: 22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08-0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: 14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment. CONCLUSIONS: In conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies. PMID- 30307955 TI - Therapeutic potential of tranilast for the treatment of chronic graft-versus-host disease in mice. AB - Chronic graft-versus-host disease (cGVHD) is a marked complication of hematopoietic stem cell transplantation, and multiple organs can be affected by cGVHD-induced inflammation and fibrosis. In clinical settings, immunosuppressive agents have been the last resort to treat cGVHD. However, it has been only partially effective for cGVHD. Hence, efficacious treatment of cGVHD is eagerly awaited. Our previous work suggested that oxidative stress was elevated in cGVHD disordered lacrimal glands and that epithelial-to-mesenchymal transition (EMT) was implicated in fibrosis caused by ocular cGVHD. In addition, our recent article demonstrated that thioredoxin interaction protein (TXNIP) and transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-??B) were associated with the development of cGVHD. After our search for effective drugs, we chose tranilast to combat systemic cGVHD. Tranilast is known to (1) act as an inhibitor of the inflammatory molecules TXNIP and NF kappaB and (2) exert anti-fibrotic, anti-EMT and anti-oxidative effects. To investigate the effectiveness of tranilast for cGVHD, we used an MHC-compatible, multiple minor histocompatibility antigen-mismatched murine model of cGVHD. Tranilast or a solvent-vehicle were orally given to the allogeneic bone marrow transplantation (allo-BMT) recipients from the day before allo-BMT (Day-1) to Day 27 after allo-BMT. Their cGVHD-vulnerable organs were collected Day 28 after allo BMT and analyzed by using various methods such as histology, immunohistochemistry and immunoblotting. As indicated by our results, tranilast alleviated cGVHD elicited inflammation and fibrosis by suppressing the expression and/or activation of TXNIP and NF-kappaB and preventing EMT. Taken together, although this strategy may not be a complete cure for cGVHD, tranilast could be a promising medication to ameliorate cGVHD-triggered disabling symptoms. PMID- 30307956 TI - Learning and generalizing non-adjacent dependencies in 18-month-olds: A mechanism for language acquisition? AB - The ability to track non-adjacent dependencies (the relationship between ai and bi in an aiXbi string) has been hypothesized to support detection of morpho syntactic dependencies in natural languages ('The princess is reluctantly kissing the frog'). But tracking such dependencies in natural languages entails being able to generalize dependencies to novel contexts ('The general is angrily berating his troops'), and also tracking co-occurrence patterns between functional morphemes like is and ing (a class of elements that often lack perceptual salience). We use the Headturn Preference Procedure to investigate (i) whether infants are capable of generalizing dependencies to novel contexts, and (ii) whether they can track dependencies between perceptually non-salient elements in an artificial grammar aXb. Results suggest that 18-month-olds extract abstract knowledge of a_b dependencies between non-salient a and b elements and use this knowledge to subsequently re-familiarize themselves with specific ai_bi combinations. However, they show no evidence of generalizing ai_bi dependencies to novel aiYbi strings. PMID- 30307957 TI - Effects of customer self-audit on the quality of maternity care in Tabriz: A cluster-randomized controlled trial. AB - OBJECTIVE: To study the effects of customer self-audit on the service quality (SQ) and customer quality (CQ) of maternity care. DESIGN: A community-based cluster-randomized controlled trial. SETTING: Twenty-one health centres and health posts in Tabriz, Iran. PARTICIPANTS: Of 21 health centres/health posts, 10 were randomly assigned to the intervention group and 11 randomly assigned to the control group. Participants were 185 pregnant women selected from health centre/post registration lists (intervention group: n = 92; control group: n = 93). INTERVENTIONS: The intervention was a customer self-audit based on the CenteringPregnancy(r) model of prenatal group care. The intervention group attended group support sessions focused on participants' opinions, questions, and self-management concerns. They also received sessions on experiential learning, coping, problem-solving, and goal-setting by a family health expert, a midwife, and a doctor. Control group participants continued to receive individual care. PRIMARY OUTCOME MEASURES: SQ and CQ were assessed using questionnaires. Patients rated the importance and performance of non-health quality dimensions. SQ was calculated as: SQ = 10 - (Importance * Performance). RESULTS: Total mean SQ scores were 7.63 (0.91) and 8.91 (0.76) for the control and intervention groups, respectively, a statistically significant difference (p<0.001). Compared with the control group, the intervention group scored higher on the SQ aspects confidentiality, communication, autonomy, availability of support group, dignity, safety, prevention, and accessibility. Total mean CQ scores for the control and intervention groups were 82.63(7.21) and 87.47 (6.75), respectively, a statistically significant difference (p<0.001). After intervention, 82.6% of intervention group participants and 50.5% of control group participants reached the highest stage of self-management, showing an ability to take care of themselves under stress and financial constraints. CONCLUSIONS: The group prenatal care customer self-audit improved the SQ and CQ of maternity care by increased involvement of participants and giving them active roles in the care process. PMID- 30307958 TI - Testing a novel multicomponent intervention to reduce meat consumption in young men. AB - Both epidemiological studies and randomised controlled trials have shown that meat-eating can be harmful to human health. Meat-eating is also considered to be a moral issue, impacting negatively on the environment and the welfare of animals. To date, very little scientific research has aimed to reduce this dietary behavior. Therefore, the current research tests the effectiveness of a 4 week multicomponent intervention designed to reduce meat-eating. Using a randomised controlled trial procedure, thirty-two young men (mean age: 23.5 +/- 3.1 years old) were randomly assigned into two equal groups, the intervention vs control group. Based on research in social and health psychology, the intervention was composed of five components expected to reduce meat consumption: a social norm component; an informational/educational component; an appeal to fear; a mind attribution induction; and a goal setting/self-monitoring component. Measures of different types of meat intake (using dietary journals) were taken at baseline (Time 1) as well as 2 (Time 2) and 4 weeks later (Time 3). Emotions and attitudes toward meat-eating and animals were also assessed at Time 3. Significant reductions in total and weekend red meat consumption as well as cold cuts consumed on the weekend were observed in the intervention condition from Time 1 to Time 3. Moreover, reduced positive emotions toward eating meat mediated the reduction in red meat consumption. The component of the intervention that participants most often perceived as having led to a reduction in their meat consumption was the informational component. In conclusion, results provide support for the effectiveness of the multicomponent intervention and for the mediating role of positive emotions when predicting behavioral changes in meat consumption. PMID- 30307959 TI - Inferring causal pathways among three or more variables from steady-state correlations in a homeostatic system. AB - Cross-sectional correlations between two variables have limited implications for causality. We examine here whether it is possible to make causal inferences from steady-state data in a homeostatic system with three or more inter-correlated variables. Every putative pathway between three variables makes a set of differential predictions that can be tested with steady state data. For example, among 3 variables, A, B and C, the coefficient of determination, [Formula: see text] is predicted by the product of [Formula: see text] and [Formula: see text] for some pathways, but not for others. Residuals from a regression line are independent of residuals from another regression for some pathways, but positively or negatively correlated for certain other pathways. Different pathways therefore have different prediction signatures, which can be used to accept or reject plausible pathways using appropriate null hypotheses. The type 2 error reduces with sample size but the nature of this relationship is different for different predictions. We apply these principles to test the classical pathway leading to a hyperinsulinemic normoglycemic insulin-resistant, or pre diabetic, state using four different sets of epidemiological data. Currently, a set of indices called HOMA-IR and HOMA-beta are used to represent insulin resistance and glucose-stimulated insulin response by beta cells respectively. Our analysis shows that if we assume the HOMA indices to be faithful indicators, the classical pathway must in turn be rejected. In effect, among the populations sampled, the classical pathway and faithfulness of the HOMA indices cannot be simultaneously true. The principles and example shows that it is possible to infer causal pathways from cross sectional correlational data on three or more correlated variables. PMID- 30307960 TI - Cataract surgery and age-related cognitive decline: A 13-year follow-up of the English Longitudinal Study of Ageing. AB - BACKGROUND: Visual impairment has been associated with lower cognitive ability among older adults, yet little is known about whether improving visual function with cataract surgery would be associated with slower cognitive decline. This study aimed to assess whether trajectories of cognitive decline differed before and after cataract surgery and compare those trajectories between older adults with cataract surgery and without cataract. METHODS AND FINDINGS: Data were drawn from the English Longitudinal Study of Ageing (ELSA) Wave 1 (2002/03) until Wave 7 (2014/15). The study population consisted of 2,068 individuals who underwent cataract surgery between Wave 2 and Wave 6 as the treatment group and 3,636 individuals with no cataract as the control group. We included only respondents who took part in a minimum three waves. Propensity score matching method was used to match the individuals in the treatment group with those in the control group. After we put an "artificial" intervention point for the individuals in the control group at the point that the matched person has cataract surgery, spline method was used to identify differences in cognitive trajectories pre- and post cataract surgery. In the treatment group, we found that cataract surgery was positively associated with episodic memory scores after controlling for the potential covariates (beta = 4.23, p<0.001). Episodic memory scores declined with older age, but the decline in episodic memory scores was slower after cataract surgery (beta = -0.05, p<0.001) than before cataract surgery (beta = -0.1, p<0.001). Although the episodic memory among respondents in the control group before intervention (beta = -0.08, p<0.001) declined slower than those in the intervention group (beta = -0.1, p<0.001), the declines in episodic memory scores were similar in both groups after the intervention (control: beta = -0.05, p<0.001; intervention: beta = -0.05, p<0.001). CONCLUSIONS: Cataract surgery may have a positive impact on trajectories of cognitive decline in later life. Further research is required to identify the mechanism to explain the association between cataract surgery and cognitive ageing, and whether early intervention towards vision correction results in a reduction in dementia risk. PMID- 30307961 TI - Accuracy of training recommendations based on a treadmill multistage incremental exercise test. AB - Competitive runners will occasionally undergo exercise in a laboratory setting to obtain predictive and prescriptive information regarding their performance. The present research aimed to assess whether the physiological demands of lab-based treadmill running (TM) can simulate that of over-ground (OG) running using a commonly used protocol. Fifteen healthy volunteers with a weekly mileage of >= 20 km over the past 6 months and treadmill experience participated in this cross sectional study. Two stepwise incremental tests until volitional exhaustion was performed in a fixed order within one week in an Outpatient Clinic research laboratory and outdoor athletic track. Running velocity (IATspeed), heart rate (IATHR) and lactate concentration at the individual anaerobic threshold (IATbLa) were primary endpoints. Additionally, distance covered (DIST), maximal heart rate (HRmax), maximal blood lactate concentration (bLamax) and rate of perceived exertion (RPE) at IATspeed were analyzed. IATspeed, DIST and HRmax were not statistically significantly different between conditions, whereas bLamax and RPE at IATspeed showed statistical significance (p < 0.05). Apart from RPE at IATspeed, IATspeed, DIST, HRmax and bLamax strongly correlate between conditions (r = 0.815-0.988). High reliability between conditions provides strong evidence to suggest that running on a treadmill are physiologically comparable to that of OG and that training recommendations and be made with assurance. PMID- 30307963 TI - Political cycles: Beyond rational expectations. AB - MOTIVATION AND METHOD: Existing rational expectations models cannot satisfactorily explain why political budget manipulations systematically raise re election chances and only occur in "specific contexts". This paper offers a theoretical explanation by including unsophisticated voters into an opportunistic political cycle model; unsophisticated voters are unable to take the optimal behaviour of other agents (fully) into account, but may, nonetheless, vaguely suspect government deception. RESULTS: First, rationally expected manipulations are, on average, fruitless in equilibrium. By including unsophisticated voters we can, however, corroborate empirically found electoral effects of political budget manipulations. Second, unsophisticated voters become anxious and suspicious in an intransparent or uncertain world, but the government tries to "outperform" their scepticism by increasing budget manipulations in order to appear more competent and, ultimately, increase re-election chances. It is, therefore, not surprising that political budget cycles are observed in countries suffering from intransparencies such as developing countries or new democracies. Third and in addition, the model presented here predicts that political opportunism produces, unintentionally, a countercyclical policy effect in election years, thereby, for instance, alleviating the typical problem of policy procyclicality in developing countries. ADDITIONAL CONTRIBUTION: The paper also offers a theoretical explanation for political distortions found in forecasts by US states. Based on overly optimistic revenue forecasts the incumbent state government can conduct expansionary fiscal policies in order to appear more competent prior to an upcoming election. Since the resulting deficit can only be observed afterwards, the government can effectively circumvent a constitutional balanced budget constraint. As a result, there are political forecast and budget cycles in the state. More generally, however, these findings may also apply to European countries where balanced budget constraints are or will be in place (for instance the debt brakes in Switzerland and Germany); similarly, they apply to the supra national European Fiscal Compact of the European Union. PMID- 30307964 TI - Wide-eyed glare scares raptors: From laboratory evidence to applied management. AB - Raptors are one of the most important causes of fatalities due to their collisions with aircrafts as well as being the main victims of collisions with constructions. They are difficult to deter because they are not influenced by other airspace users or ground predators. Because vision is the primary sensory mode of many diurnal raptors, we evaluated the reactions of captive raptors to a "superstimulus" (a "paradoxical effect whereby animals show greater responsiveness to an exaggerated stimulus than to the natural stimulus") that combined an "eye shape" stimulus (as many species have an aversion for this type of stimulus) and a looming movement (LE). This looming stimulus mimics an impending collision and induces avoidance in a wide range of species. In captivity, raptors showed a clear aversion for this LE stimulus. We then tested it in a real life setting: at an airport where raptors are abundant. This study is the first to show the efficiency of a visual non-invasive repellent system developed on the basis of both captive and field studies. This system deterred birds of prey and corvids through aversion, and did not induce habituation. These findings suggest applications for human security as well as bird conservation, and further research on avian visual perception and sensitivity to signals. PMID- 30307962 TI - Screening of herbal extracts for TLR2- and TLR4-dependent anti-inflammatory effects. AB - Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory diseases. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptors (TLRs), TLR2 and TLR4. Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways. The 28 identified anti-inflammatory extracts were tested in comparative assays of stimulated HEK-TLR2 and HEK-TLR4 transfected reporter cells to differentiate between direct TLR4 antagonistic effects and interference with downstream signaling cascades. Furthermore, the ten most effective anti-inflammatory extracts were tested on their ability to inhibit nuclear factor-kappaB (NF kappaB) translocation in HeLa-TLR4 transfected reporter cell lines and for their ability to repolarize M1-type macrophages. Ethanolic extracts which showed the highest anti-inflammatory potential, up to a complete inhibition of pro inflammatory cytokine production were Castanea sativa leaves, Cinchona pubescens bark, Cinnamomum verum bark, Salix alba bark, Rheum palmatum root, Alchemilla vulgaris plant, Humulus lupulus cones, Vaccinium myrtillus berries, Curcuma longa root and Arctostaphylos uva-ursi leaves. Moreover, all tested extracts mitigated not only TLR4, but also TLR2 signaling pathways. Seven of them additionally inhibited translocation of NF-kappaB into the nucleus. Two of the extracts showed impact on repolarization of pro-inflammatory M1-type to anti-inflammatory M2-type macrophages. Several promising anti-inflammatory herbal extracts were identified in this study, including extracts with previously unknown influence on key TLR signaling pathways and macrophage repolarization, serving as a basis for novel lead compound identification. PMID- 30307965 TI - Validity of bioelectrical impedance analysis in predicting total body water and adiposity among Senegalese school-aged children. AB - INTRODUCTION: Childhood obesity is currently a serious public health challenge in developing countries. Therefore, an accurate assessment of adiposity is required. The objective of this study was to validate BIA prediction equations for the assessment of total body water and adiposity or percentage of body fat for the first time in Senegalese school-aged children. METHODS: One-hundred-fifty-one (151) pupils who were 8-11 years old were randomly selected from four public schools in Dakar. The body composition measured by deuterium dilution method (DDM) was used as the reference method and compared to that predicted by BIA using a multi-frequency analyser. Stepwise backward multiple linear regression was performed to calculate TBW and %BF in a subsample, which were then validated in the rest of the sample. The Bland and Altman approach was used to assess the agreement between the two methods (bias and limits of agreement). RESULTS: FFM was higher in boys (24.6+/-6.9 kg) compared to girls (21.2+/-3.3 kg; P<0.001), and FM was lower in boys: 3.7 kg [0.9-26.4] compared to girls: 4.5 kg [1.7-22.7]. Overall, 11.3% of children presented excess adiposity (%BF >25% in boys, and >30% in girls) and 2.0% were obese according to WHO cut points for obesity (BMI z score >+2.0). The equations developed were as follows: TBW = 0.376(Height2/Z50) 0.470 (sex) +0.076(weight) +0.065(height)-2.28. %BF = -1.10(height2/Z50) +3.14(sex)+1.57(weight)-4.347. These specific equations showed good precision and a low and non-significant mean bias (0.11 kg, P = 0.279; and 0.19 kg, P = 0.764) for TBW and %BF, respectively. CONCLUSION: The newly developed equations can be used as an accurate and alternative screening tool for the assessment of obesity among children in various settings. PMID- 30307966 TI - Impact of oral rehabilitation on the quality of life of partially dentate elders in a randomised controlled clinical trial: 2 year follow-up. AB - OBJECTIVE: This randomised clinical trial aimed to compare the impact of two different tooth replacement strategies for partially dentate older patients namely; removable partial dentures (RPDs) and functionally orientated treatment based on the shortened dental arch (SDA) concept, on Oral Health-related Quality of Life (OHrQOL). METHODS: 89 patients completed a randomised clinical trial. Patients were recruited in two centres: Cork University Dental Hospital (CUDH) and a Geriatric Day Hospital (SFDH). 44 patients were randomly allocated to the RPD group and 45 to the SDA group where adhesive bridgework was used to provide 10 pairs of occluding contacts. The impact of treatment on OHrQOL was used as the primary outcome measure. Each patient completed the Oral Health Impact Profile (OHIP-14) at baseline, 1, 6, 12 and 24 months after treatment. RESULTS: Both treatment groups reported improvements in OHIP-14 scores at 24 months (p<0.05). For the SDA group OHIP-14 scores improved by 8.0 scale points at 12 months (p<0.001) and 5.9 scale points at 24 months (p<0.05). For the RPD group OHIP-14 scores improved by 5.7 scale points at 12 months (p<0.05) and 4.2 scale points at 24 months (p<0.05). Analysis using ANCOVA showed that there were significant between group differences recorded in both treatment centres. 24 months after intervention the SDA group recorded better OHIP-14 scores by an average of 2.9 points in CUDH (p<0.0001) and by an average of 7.9 points in SFDH (p<0.0001) compared to the RPD group. CONCLUSIONS: Patients in the SDA group maintained their improvements in OHrQOL scores throughout the 24 month study period. For the RPD group the initial improvement in OHrQOL score began to diminish after 6 months, particularly for those treated in SFDH. Thus, the benefits of functionally orientated treatment increased over time, particularly for the older, more systemically unwell cohort in SFDH. PMID- 30307968 TI - Towards the colonization of Mars by in-situ resource utilization: Slip cast ceramics from Martian soil simulant. AB - Here we demonstrate that by applying exclusively Martian resources a processing route involving suspensions of mineral particles called slurries or slips can be established for manufacturing ceramics on Mars. We developed water-based slurries without the use of additives that had a 51 wt. % solid load resembling commercial porcelain slurries in respect to the particle size distribution and rheological properties. These slurries were used to slip cast discs, rings and vases that were sintered at temperatures between 1000 and 1130 degrees C using different sintering schedules, the latter were set-up according the results of hot-stage microscopic characterization. The microstructure, porosity and the mechanical properties were characterized by SEM, X-ray computer tomography and Weibull analysis. Our wet processing of minerals yields ceramics with complex shapes that show similar mechanical properties to porcelain and could serve as a technology for future Mars colonization. The best quality parts with completely vitrificated matrix supporting a few idiomorphic crystals are obtained at 1130 degrees C with 10 h dwell time with volume and linear shrinkage as much as ~62% and ~17% and a characteristic compressive strength of 51 MPa. PMID- 30307967 TI - Investigation of mRNA expression changes associated with field exposure to DDTs in chickens from KwaZulu-Natal, South Africa. AB - The objective of this study was to identify potential mRNA expression changes in chicken livers associated with environmental exposure to dichloro-diphenyl trichloroethane (DDT) and its metabolites (DDTs). In particular, we focused on genes relating to the immune system and metabolism. We analyzed liver samples from free-ranging chickens in KwaZulu-Natal, South Africa, for contamination by DDTs. This area predominantly uses DDT in its malaria control program, and homes are sprayed annually with the pesticide. Genes relating to the immune system and metabolism were selected as potential genetic biomarkers that could be linked to higher contamination with DDTs. RT-qPCR analysis on 39 samples showed strong correlations between DDTs contamination and mRNA expression for the following genes: AvBD1, AvBD2, AvBD6 and AvBD7 (down-regulated), and CYP17, ELOVL2 and SQLE (up-regulated). This study shows for the first time interesting and significant correlations between genetic material collected from environmentally-exposed chickens and mRNA expression of several genes involved in immunity and metabolism. These findings show the usefulness of analysis on field samples from a region with high levels of environmental contamination in detecting potential biomarkers of exposure. In particular, we observed clear effects from DDT contamination on mRNA expression of genes involved in immune suppression, endocrine-disrupting effects, and lipid dysregulation. These results are of interest in guiding future studies to further elucidate the pathways involved in and clinical importance of toxicity associated with DDT exposure from contaminated environments, to ascertain the health risk to livestock and any subsequent risks to food security for people. PMID- 30307969 TI - Learning what to approach. AB - Most decisions share a common goal: maximize reward and minimize punishment. Achieving this goal requires learning which choices are likely to lead to favorable outcomes. Dopamine is essential for this process, enabling learning by signaling the difference between what we expect to get and what we actually get. Although all animals appear to use this dopamine prediction error circuit, some do so more than others, and this neural heterogeneity correlates with individual variability in behavior. In this issue of PLOS Biology, Lee and colleagues show that manipulating a simple task parameter can bias the animals' behavioral strategy and modulate dopamine release, implying that how we learn is just as flexible as what we learn. PMID- 30307972 TI - Analysis of the conflicts of interest disclosed by the program reviewers of the scoliosis research society (SRS) congresses, 2010-2014. AB - BACKGROUND: Conflicts of interest (COI) between industry and surgeons frequently introduce biases into surgical research. The abstracts submitted for presentation in scientific congresses are usually vetted for any indication of commercial bias. Members of review program committees regularly have recognized qualifications, and therefore certain COI are unavoidable. This study aims to determine the prevalence and magnitude of possible COI among those responsible for the selection of presentations at two important international conferences on spine surgery during a five-year period. METHODOLOGY: COI declarations by those responsible for the final programs of the annual SRS (Scoliosis Research Society) and IMAST (International Meeting of Advanced Spine Technologies) conferences from 2010 to 2014 were collected and analyzed from data published by the corresponding scientific programs. The SRS's disclosure index did not contain financial amounts; therefore, this aspect could not be analyzed. RESULTS: Five scientific committees and 117 members (76 individuals) were studied. Of these 76, 41 (53.9%) participated in more than one conflict of interest (>1 COI). Scientific committee members were from 11 countries across 4 continents, but most were from the Unites States (76.9%). Of the 117 program reviewers, 65.8% declared >1 COI and 34.2% reported no COI. The 77 program reviewers who disclosed a potential COI declared a total of 273 COI (mean = 3.54 COI/member). Overall, 36.0%, 26.1%, 10.7%, and 10.7% of the COI corresponded to consultancies, research funds, bureau participation, and advisory board panel participation, respectively. Stockholder reimbursement corresponded to 8.8% of the disclosed COI, and financial or material support were mentioned in 7.4% of COI. Among the COI disclosures, 55 companies were mentioned, and 5 of the top 10 companies involved in spinal device markets were responsible for 65.2% of the COI. CONCLUSIONS: More than two thirds of the members of the SRS and IMAST scientific committees reported COI. Consultancies and research grants account for two thirds of these. Most of the grants and major COI are related to the five companies leading the spinal implant market. PMID- 30307970 TI - Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk. AB - Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFbeta pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk. PMID- 30307971 TI - Anti-cancer effects of 3,5-dimethylaminophenol in A549 lung cancer cells. AB - Exposure to 3,5-dimethylaminophenol (3,5-DMAP), the metabolite of the 3-5 dimethylaniline, was shown to cause high levels of oxidative stress in different cells. The aim of the present work was to observe whether this metabolite can lead to cytotoxicity, oxidative stress, DNA damage and cell cycle changes in non small cell lung cancer A549 cells. 3,5-DMAP caused a dose-dependent increase in cytotoxicity, generation of superoxide (O2-.), inductions in the enzyme activities orchestrating cellular antioxidant balance, increases in lipid peroxidation as well as DNA damage. However, 3,5-DMAP showed significantly lower cytotoxicity towards human lung fibroblast (HLF) cells. 3,5-DMAP also led to molecular events, like inducing apoptotic markers (ie. p53, Bad, Bax and cytochrome c); decreasing anti-apoptotic proteins (Bcl-2) and alterations in cell cycle. Our findings indicate that the cytotoxicity caused by this particular alkylaniline metabolite led to initiation of caspase 3-mediated apoptosis. Furthermore, 3,5-DMAP attenuated carcinogenic properties like migration capacity of A549 cells and eventually inhibited growth of A549 cells in an in vivo mouse model. Tumor sections showed that 3,5-DMAP down-regulated c-Myc expression but up regulated p53 and cytochrome c, all of which might result in tumor growth arrest. Co-treatment with N-acetylcysteine provided reductions in cytotoxicity and positively modulated genetic events induced by 3,5-DMAP in A549 cells. In conclusion, our findings demonstrate 3,5-DMAP may be a potential anti-cancer drug in cancer, due to its self redox cycling properties. PMID- 30307973 TI - Integrated information as a metric for group interaction. AB - Researchers in many disciplines have previously used a variety of mathematical techniques for analyzing group interactions. Here we use a new metric for this purpose, called "integrated information" or "phi." Phi was originally developed by neuroscientists as a measure of consciousness in brains, but it captures, in a single mathematical quantity, two properties that are important in many other kinds of groups as well: differentiated information and integration. Here we apply this metric to the activity of three types of groups that involve people and computers. First, we find that 4-person work groups with higher measured phi perform a wide range of tasks more effectively, as measured by their collective intelligence. Next, we find that groups of Wikipedia editors with higher measured phi create higher quality articles. Last, we find that the measured phi of the collection of people and computers communicating on the Internet increased over a recent six-year period. Together, these results suggest that integrated information can be a useful way of characterizing a certain kind of interactional complexity that, at least sometimes, predicts group performance. In this sense, phi can be viewed as a potential metric of effective group collaboration. PMID- 30307974 TI - Older adult fall prevention practices among primary care providers at accountable care organizations: A pilot study. AB - BACKGROUND: Falls are a serious and common problem among older adults. Low-tech, inexpensive, community-based fall prevention programs have been shown to be both effective and cost effective, however, these programs are not well-integrated into clinical practice. RESEARCH DESIGN: We surveyed primary care providers at a convenience sample of two accountable care organizations in Massachusetts to assess their beliefs, attitudes, knowledge, and practices relative to fall risk assessment and intervention for their older patients. RESULTS: Response rate was 71%. Providers' beliefs about the efficacy of fall risk assessment and intervention were mixed. Eighty-seven percent believed that they could be effective in reducing fall risk among their older adult patients. Ninety-six percent believed that all older adults should be assessed for fall risk; and, 85% believed that this assessment would identify fall risk factors that could be modified. Nonetheless, only 52% believed that they had the expertise to conduct fall risk assessment and only 68% believed that assessing older adult patients for fall risk was the prevailing standard of practice among their peer providers. Although most providers believed it likely that an evidence-based program could reduce fall risk among their patients, only 14% were aware of the Centers for Disease Control and Prevention's fall risk assessment algorithm (STEADI Toolkit), and only 15% were familiar with Matter of Balance, the most widely disseminated community fall risk prevention program in Massachusetts. DISCUSSION: New strategies that more directly target providers are needed to accelerate integration of fall risk assessment and intervention into primary care practice. PMID- 30307975 TI - Kernel-based geographically and temporally weighted autoregressive model for house price estimation. AB - Spatiotemporal nonstationarity and autocorrelation are two crucial points in modeling geographical data. Previous studies have demonstrated that geographically and temporally weighted autoregressive (GTWAR) model accounts for both spatiotemporal nonstationarity and autocorrelation simultaneously to estimate house prices. Therefore, this paper proposes a kernel-based GTWAR (KBGTWAR) model by incorporating the basic principle of support vector machine regression into spatially and temporally varying coefficients model. The efficacy of KBGTWAR model is demonstrated through a case study on housing prices in the city of Shenzhen, China, from year 2004 to 2008. Comparing the existing models, KBGTWAR model obtains the lowest value for the residual sum of squares (RSS) and the highest value for the coefficient of determination R2. Moreover, KBGTWAR model improves the goodness of fit of the existing GTWAR model from 12.0 to 4.5 in terms of RSS, from 0.914 to 0.968 in terms of R2 and from 3.84 to 4.45 in terms of F-statistic. The results show that KBGTWAR model provides a comparatively high goodness of fit and sufficient explanatory power for both spatiotemporal nonstationarity and autocorrelation. The results of this study demonstrate that the proposed KBGTWAR model can be used to effectively formulate polices for real estate management. PMID- 30307976 TI - Ups and downs in catch-up saccades following single-pulse TMS-methodological considerations. AB - Transcranial magnetic stimulation (TMS) can interfere with smooth pursuit or with saccades initiated from a fixed position toward a fixed target, but little is known about the effect of TMS on catch-up saccade made to assist smooth pursuit. Here we explored the effect of TMS on catch-up saccades by means of a situation in which the moving target was driven by an external agent, or moved by the participants' hand, a condition known to decrease the occurrence of catch-up saccade. Two sites of stimulation were tested, the vertex and M1 hand area. Compared to conditions with no TMS, we found a consistent modulation of saccadic activity after TMS such that it decreased at 40-100ms, strongly resumed at 100 160ms, and then decreased at 200-300ms. Despite this modulatory effect, the accuracy of catch-up saccade was maintained, and the mean saccadic activity over the 0-300ms period remained unchanged. Those findings are discussed in the context of studies showing that single-pulse TMS can induce widespread effects on neural oscillations as well as perturbations in the latency of saccades during reaction time protocols. At a more general level, despite challenges and interpretational limitations making uncertain the origin of this modulatory effect, our study provides direct evidence that TMS over presumably non oculomotor regions interferes with the initiation of catch-up saccades, and thus offers methodological considerations for future studies that wish to investigate the underlying neural circuitry of catch-up saccades using TMS. PMID- 30307977 TI - People making deontological judgments in the Trapdoor dilemma are perceived to be more prosocial in economic games than they actually are. AB - Why do people make deontological decisions, although they often lead to overall unfavorable outcomes? One account is receiving considerable attention: deontological judgments may signal commitment to prosociality and thus may increase people's chances of being selected as social partners-which carries obvious long-term benefits. Here we test this framework by experimentally exploring whether people making deontological judgments are expected to be more prosocial than those making consequentialist judgments and whether they are actually so. In line with previous studies, we identified deontological choices using the Trapdoor dilemma. Using economic games, we take two measures of general prosociality towards strangers: trustworthiness and altruism. Our results procure converging evidence for a perception gap according to which Trapdoor deontologists are believed to be more trustworthy and more altruistic towards strangers than Trapdoor-consequentialists, but actually they are not so. These results show that deontological judgments are not universal, reliable signals of prosociality. PMID- 30307978 TI - Mice lacking RAP1 show early onset and higher rates of DEN-induced hepatocellular carcinomas in female mice. AB - RAP1, a component of the telomere-protective shelterin complex, has been shown to have both telomeric and non-telomeric roles. In the liver, RAP1 is involved in the regulation of metabolic transcriptional programs. RAP1-deficient mice develop obesity and hepatic steatosis, these phenotypes being more severe in females than in males. As hepatic steatosis and obesity have been related to increased liver cancer in mice and humans, we set out to address whether RAP1 deficiency resulted in increased liver cancer upon chemical liver carcinogenesis. We found that Rap1 /- females were more susceptible to DEN-induced liver damage and hepatocellular carcinoma (HCC). DEN-treated Rap1-/- female livers showed an earlier onset of both premalignant and malignant liver lesions, which were characterized by increased abundance of gammaH2AX-positive cells, increased proliferation and shorter telomeres. These findings highlight an important role for RAP1 in protection from liver damage and liver cancer. PMID- 30307979 TI - Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population. AB - Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis). FEV1 values were referenced to both a normal population (FEV1% predicted) and CF population (CF-specific FEV1 percentile). We utilized a linear mixed model with repeated measures to assess changes in lung function (before and after diagnosis of CFLD), relative to both the normal and CF populations. At diagnosis of CFLD, the mean FEV1 was 81% predicted, or at the 53rd percentile referenced to CF patients without CFLD. There was a significant difference in post-CFLD slope compared to pre-CFLD slope (post-pre) using FEV1% predicted ( 1.94, p-value < 0.0001). However, there was insignificant evidence of this difference using the CF-specific FEV1 percentile measure (-0.99, p-value = 0.1268). Although FEV1% predicted values declined in patients following CFLD diagnosis, there was not significant evidence of lung function decline in CF specific FEV1 percentiles. Thus, the observed study cohort indicates diagnosis of severe CFLD was not associated with worsened CF lung disease when compared to a large CF reference population. PMID- 30307980 TI - Measuring caregiver activation to identify coaching and support needs: Extending MYLOH to advanced chronic illness. AB - INTRODUCTION: Family and friends of seriously ill patients are key partners in providing support and health care at home, managing relationships with clinicians, and navigating complex health care systems. Becoming a knowledgeable, confident, and effective caregiver is a developmental process we term 'caregiver activation' and could be facilitated by clinicians equipped with suitable tools. Managing Your Loved One's Health (MYLOH) is a new tool to identify gaps in caregivers' knowledge, skills, and access to clinical and personal support. Created in partnership with caregivers and clinicians, MYLOH items reflect the essential dimensions of caregiving and can be used to tailor caregiver coaching to domains of greatest need. In this study, we extend MYLOH's initial focus on dementia care to caregivers of patients with other chronic life-limiting illnesses. METHODS: MYLOH was completed by primary caregivers (n = 190) of people with a range of advanced chronic illnesses enrolled in the LifeCourse study, an innovative, whole-person approach to health management. Item relevance and responses were compared by group across MYLOH items and domains using z-tests for equality of proportions. RESULTS: All MYLOH items were relevant to caregiving for all types of chronic illness; only 13% of caregivers answered "not my responsibility" to any question. MYLOH identified caregiving struggles across patient diagnosis groups with a few, disease-specific 'hotspots'. Overall, 64% of caregivers scored low in activation on at least one healthcare management task, especially getting enough help with caregiving, managing everyday caregiving tasks, understanding/managing medications, and knowing how to respond to rapid changes in care recipients' health status. No difficulty was unique to a specific type of care recipient illness. CONCLUSIONS: MYLOH has potential as a tool for identifying caregiver coaching and support needs in managing a range of serious chronic illnesses. Caregiving difficulties endorsed by over 20% of caregivers should be core components of chronic illness management programs regardless of disease focus, with disease-specific tailoring as required. MYLOH may be useful in evaluating caregiver interventions and health systems' performance in integrating caregivers into the care management of patients with complex life limiting illness. PMID- 30307981 TI - Transforming growth factor beta 1 mediates the low-frequency vertical vibration enhanced production of tenomodulin and type I collagen in rat Achilles tendon. AB - Vertical vibration (VV) is a whole-body vibration with mechanical loading that commonly used in rehabilitation and sports training to increase athlete muscle strength. Our previous study showed that low-magnitude, low-frequency VV at 8 Hz and 10 Hz increased myoblast myogenesis. Herein, we investigated whether a VV frequency at low-frequency 5-10 Hz has anabolic effects on tenocytes and improves tendon stiffness. In primary tenocytes, 10 Hz VV treatment increased the tenogenic marker gene expression of tenomodulin and extracellular matrix type I collagen but decreased decorin expression. qPCR and Enzyme-Linked Immunosorbent Assay (ELISA) results showed that TGF-beta1 expression was increased in tenocytes after 3 days of 10 Hz VV treatment in vitro and in Achilles tendons after 3 weeks in vivo. Tenomodulin expression and Achilles tendon stiffness were significantly increased in Achilles tendons after 3 weeks in vivo. We also showed that the TGF beta1 receptor inhibitor SB431542 (10 MUM) decreased the expression of tenomodulin and type I collagen but increased the decorin expression in tenocytes. These results indicated that the 10 Hz VV stimulated anabolic effects in tenocytes by increasing TGF-beta1 expression that subsequently increases the expression of tenomodulin and type I collagen, and increased the Achilles tendon stiffness. This study provides insight into the low-frequency 10 Hz VV treatment improves tendon properties and can minimizes the risk of ligament/tendon reinjure during rehabilitation. PMID- 30307982 TI - Evaluation of compost, vegetable and food waste as amendments to improve the composting of NaOH/NaClO-contaminated poultry manure. AB - Regular usage of NaOH/NaClO disinfectants results in high sodium salt and alkalinity of poultry manure. This study compared three amendments: vegetable waste (V), food waste (F) and mature compost (C) for their ability to improve the composting of NaOH/NaClO-contaminated poultry manure. C compost resulted in the highest compost temperatures (p<0.001) and greatest reduction in OM, TC, TN and NH4-N (p<0.05). C and V composts were more efficient at lowering extractable-Na (ext-Na) and electrical conductivity (EC) than F (p<0.05). Maturity was primarily indicated by NH4-N, EC and ext-Na. Bacterial dynamics was profoundly influenced by NH4-N, EC and TC, with the decrease leading to discriminate genera shift from Sinibacillus and Thiopseudomonas to Brevbacterium, Brachybacterium, and Microbacterium. These findings suggest that mature compost was more desirable amendment than vegetable and food waste in the composting of NaOH/NaClO contaminated poultry manure, and the decrease of ext-Na indicated compost maturity but did not influence bacterial dynamics. PMID- 30307983 TI - Topical anti-inflammatory activity of palmitoleic acid improves wound healing. AB - This study investigated the effects of palmitoleic acid on different phases of the healing process. Macroscopic analyses were performed on wounds in rats with or without palmitoleic acid treatment, and the results showed that palmitoleic acid directly hastened wound closure. The topical treatment of wounds with palmitoleic acid resulted in smaller wounds than those observed in the control group. The anti-inflammatory activity of palmitoleic acid may be responsible for healing, especially in the stages of granulation tissue formation and remodelling. Palmitoleic acid modified TNF-alpha, IL-1beta, IL-6, CINC 2alpha/beta, MIP-3alpha and VEGF-alpha profiles at the wound site 24, 48, 120, 216 and 288 hours post-wounding. Assays assessing neutrophil migration and exudate formation in sterile inflammatory air pouches revealed that palmitoleic acid had potent anti-inflammatory activity, inhibiting the LPS-induced release of TNF-alpha (73.14%, p<=0.05), IL-1beta (66.19%, p<=0.001), IL-6 (75.19%, p<=0.001), MIP-3alpha (70.38%, p<=0.05), and l-selectin (16%, p<=0.05). Palmitoleic acid also inhibited LPS-stimulated neutrophil migration. We concluded that palmitoleic acid accelerates wound healing via an anti-inflammatory effect. PMID- 30307985 TI - Diachronic Atlas of Comparative Linguistics (DiACL)-A database for ancient language typology. AB - Feature stability, time and tempo of change, and the role of genealogy versus areality in creating linguistic diversity are important issues in current computational research on linguistic typology. This paper presents a database initiative, DiACL Typology, which aims to provide a resource for addressing these questions with specific of the extended Indo-European language area of Eurasia, the region with the best documented linguistic history. The database is pre prepared for statistical and phylogenetic analyses and contains both linguistic typological data from languages spanning over four millennia, and linguistic metadata concerning geographic location, time period, and reliability of sources. The typological data has been organized according to a hierarchical model of increasing granularity in order to create datasets that are complete and representative. PMID- 30307986 TI - An economic analysis of patient controlled remifentanil and epidural analgesia as pain relief in labour (RAVEL trial); a randomised controlled trial. AB - OBJECTIVE: To compare the costs of a strategy of patient controlled remifentanil versus epidural analgesia for pain relief in labour. DESIGN: We performed a multicentre randomised controlled trial in 15 hospitals in the Netherlands, the RAVEL trial. Costs were analysed from a health care perspective alongside the RAVEL trial. POPULATION: Pregnant women of intermediate to high risk beyond 32 weeks gestation who planned vaginal delivery. METHODS: Women were randomised before the onset of labour, to receive either patient controlled remifentanil or epidural analgesia when pain relief was requested during labour. MAIN OUTCOME MEASURES: Primary outcome for effectiveness was satisfaction with pain relief, expressed as the area under the curve (AUC). A higher AUC represents higher satisfaction with pain relief. Here, we present an economic analysis from a health care perspective including costs from the start of labour to ten days postpartum. Health-care utilization was documented in the Case Report Forms and by administering an additional questionnaire. RESULTS: The costs in the patient controlled remifentanil group (n = 687) and in the epidural group (n = 671) were ?2900 versus ?3185 respectively (mean difference of -?282 (95% CI -?611 to ?47)). The (non-significant) higher costs in the epidural analgesia group could be mainly attributed to higher costs of neonatal admission. CONCLUSION: From an economic perspective, there is no preferential pain treatment in labouring intermediate to high risk women. Since patient controlled remifentanil is not equivalent to epidural analgesia with respect to AUC for satisfaction with pain relief we recommend epidural analgesia as the method of choice. However, if appropriately counselled on effect and side effects there is, from an economic perspective, no reason to deny women patient controlled remifentanil. PMID- 30307984 TI - Precision in a rush: Trade-offs between reproducibility and steepness of the hunchback expression pattern. AB - Fly development amazes us by the precision and reproducibility of gene expression, especially since the initial expression patterns are established during very short nuclear cycles. Recent live imaging of hunchback promoter dynamics shows a stable steep binary expression pattern established within the three minute interphase of nuclear cycle 11. Considering expression models of different complexity, we explore the trade-off between the ability of a regulatory system to produce a steep boundary and minimize expression variability between different nuclei. We show how a limited readout time imposed by short developmental cycles affects the gene's ability to read positional information along the embryo's anterior posterior axis and express reliably. Comparing our theoretical results to real-time monitoring of the hunchback transcription dynamics in live flies, we discuss possible regulatory strategies, suggesting an important role for additional binding sites, gradients or non-equilibrium binding and modified transcription factor search strategies. PMID- 30307987 TI - Quantitative computed tomography phenotypes, spirometric parameters, and episodes of exacerbation in heavy smokers: An analysis from South America. AB - OBJECTIVE: To evaluate the quantitative computed tomography (QCT) phenotypes, airflow limitations, and exacerbation-like episodes in heavy smokers in Southern Brazil. METHODS: We enrolled 172 smokers with a smoking history >=30 pack-years who underwent pulmonary function tests (PFTs) and CT scan for lung cancer screening. Patients were classified regarding airflow limitation (FEV1/FVC <0.7 forced expiratory volume in 1 second/forced vital capacity) and the presence of emphysema on the QCT. The QCT were analyzed in specialized software and patients were classified in two disease-predominant phenotypes: emphysema-predominant (EP) and non-emphysema-predominant (NEP). EP was determined as >=6% of percent low attenuation areas (LAA%) with less than -950 Hounsfield units. NEP was defined as having a total LAA% of less than 6%. RESULTS: Most of our patients were classified in the EP phenotype. The EP group had significantly worse predicted FEV1 (60.6 +/-22.9 vs. 89.7 +/-15.9, p <0.001), higher rates of airflow limitation (85.7% vs. 15%; p <0.001), and had more exacerbation-like episodes (25.8% vs. 8.3%, p <0.001) compared to the NEP group. Smoking history, ethnicity, and BMI did not differ between the groups. The total LAA% was the QCT parameter with the strongest correlation to FEV1 (r = -0.669) and FEV1/FVC (r = -0.787). CONCLUSIONS: Heavy smokers with the EP phenotype on QCT were more likely to have airflow limitation, worse predicted FEV1, and a higher rate of exacerbation-like episodes than those with the NEP phenotype. Approximately 23% of patients with no airflow limitation on PFTs were classified in EP phenotype. PMID- 30307988 TI - Domain architecture of BAF250a reveals the ARID and ARM-repeat domains with implication in function and assembly of the BAF remodeling complex. AB - BAF250a and BAF250b are subunits of the SWI/SNF chromatin-remodeling complex that recruit the complex to chromatin allowing transcriptional activation of several genes. Despite being the central subunits of the SWI/SNF complex, the structural and functional annotation of BAF250a/b remains poorly understood. BAF250a (nearly 2200 residues protein) harbors an N-terminal DNA binding ARID (~110 residues) and a C-terminal folded region (~250 residues) of unknown structure and function, recently annotated as BAF250_C. Using hydrophobic core analysis, fold prediction and comparative modeling, here we have defined a domain boundary and associate a beta-catenin like ARM-repeat fold to the C-terminus of BAF250a that encompass BAF250_C. The N-terminal DNA-binding ARID is found in diverse domain combinations in proteins imparting unique functions. We used a comparative sequence analysis based approach to study the ARIDs from diverse domain contexts and identified conserved residue positions that are important to preserve its core structure. Supporting this, mutation of one such conserved residue valine, at position 1067, to glycine, resulted in destabilization, loss of structural integrity and DNA binding affinity of ARID. Additionally, we identified a set of conserved and surface-exposed residues unique to the ARID when it co-occurs with the ARM repeat containing BAF250_C in BAF250a. Several of these residues are found mutated in somatic cancers. We predict that these residues in BAF250a may play important roles in mediating protein-DNA and protein-protein interactions in the BAF complex. PMID- 30307989 TI - The arginase inhibitor Nomega-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target. AB - Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist in hosts and evade therapy. Accordingly, there is significant interest in drugging cancer-specific hypoxic responses. However, a major challenge in leukemia is identifying differential and druggable hypoxic responses between leukemic and normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of the urea cycle, is overexpressed in CML but not normal progenitors. ARG2 is a target of the hypoxia inducible factors (HIF1-alpha and HIF2-alpha), and is required for the generation of polyamines which are required for cell growth. We therefore explored if the clinically-tested arginase inhibitor Nomega hydroxy-nor-arginine (nor-NOHA) would be effective against leukemic cells under hypoxic conditions. Remarkably, nor-NOHA effectively induced apoptosis in ARG2 expressing cells under hypoxia but not normoxia. Co-treatment with nor-NOHA overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. While nor-NOHA itself is promising in targeting the leukemia hypoxic response, we unexpectedly found that its anti-leukemic activity was independent of ARG2 inhibition. Genetic ablation of ARG2 using CRISPR/Cas9 had no effect on the viability of leukemic cells and their sensitivity towards nor-NOHA. This discrepancy was further evidenced by the distinct effects of ARG2 knockouts and nor-NOHA on cellular respiration. In conclusion, we show that nor-NOHA has significant but off-target anti-leukemic activity among ARG2-expressing hypoxic cells. Since nor-NOHA has been employed in clinical trials, and is widely used in studies on endothelial dysfunction, immunosuppression and metabolism, the diverse biological effects of nor-NOHA must be cautiously evaluated before attributing its activity to ARG inhibition. PMID- 30307992 TI - Working memory span tasks: Group administration and omitting accuracy criterion do not change metric characteristics. AB - The study examined the psychometric characteristics of three automated working memory span tasks: operational, reading, and symmetry span task, administered in groups of participants. For each task, the metric characteristics of six scoring procedures were evaluated: partial, absolute, partial non-weighted, absolute non weighted, partial weighted, and absolute weighted scoring. Metric characteristics of all measures were compared across two parallel analyses: with and without application of a typical 85% accuracy criterion on the processing component of the tasks. The study demonstrates that the group administration of span tasks does not compromise their psychometric characteristics. All the tasks had an adequate internal consistency with Cronbach's alphas equal to or above .70; the exception being all types of the symmetry span task absolute scores with alpha values close to .60. Furthermore, all tasks have satisfactory convergent construct validity as well as criterion validity estimated in relation to measures of fluid intelligence. Omitting the 85% accuracy criterion on the processing component of the span tasks did not impair their psychometric properties. Thus, it is recommended that researchers discard this accuracy criterion as a criterion for filtering the results for further statistical analyses. PMID- 30307991 TI - Effects of 4 weeks of beta-alanine supplementation on aerobic fitness in water polo players. AB - The purpose of the present study was to investigate the ergogenic effects of 4 weeks of beta-alanine supplementation on peak oxygen uptake ([Formula: see text]) and force associated with [Formula: see text] ([Formula: see text]) during a tethered swimming graded exercise test, and a three-minute all-out effort (3minALL-OUT) in water polo players. Twenty-two male national competitive level water polo players were randomly assigned to receive either 4 weeks of beta alanine (n = 11) or a placebo (n = 11) (i.e., 4.8 g.day-1 for 10 days, then6.4 g.day-1 for 18 days, resulting in 163.2 g over 28 days). The participants performed the TSGET and 3minALL-OUT before and after the supplementation period. There were no significant interaction effects between-groups for any variable, however, the magnitude-based inferences analyses showed a possibly beneficial effect (74%) of beta-alanine supplementation on [Formula: see text] compared to placebo treatment (Delta% [post-pre] for Placebo group = -5.2%; Delta% [post-pre] for beta-alanine group = +0.7%). Only the beta-alanine group presented a significant reduction in [Formula: see text] expressed in absolute values (PRE = 3.3+/-0.6L.min-1; POST = 3.0+/-0.4L.min-1; p = .021). Similarly, only the beta alanine group presented a significant increase in critical force (PRE = 51.2+/ 10.4N; POST = 56.5+/-13.1N; p = .044) and a reduction in the curvature constant parameter (W'; PRE = 2998.0+/-1103.7N.s; POST = 2224.6+/-1058.9N.s; p = .049). Thus, we can conclude that 4 weeks of beta-alanine supplementation presented mixed results in water polo players, indicating that this nutritional strategy may not be effective in improving parameters of the TSGET and 3minALL-OUT . PMID- 30307993 TI - A case study of well child care visits at general practices in a region of disadvantage in Sydney. AB - INTRODUCTION: Well-Child Care (WCC) is the provision of preventive health care services for children and their families. Prior research has highlighted that several barriers exist for the provision of WCC services. OBJECTIVES: To study "real life" visits of parents and children with health professionals in order to enhance the theoretical understanding of factors affecting WCC. METHODS: Participant observations of a cross-sectional sample of 71 visits at three general practices were analysed using a mixed-methods approach. RESULTS: The median age of the children was 18 months (IQR, 6-36 months), and the duration of visits was 13 mins (IQR, 9-18 mins). The reasons for the visits were immunisation in 13 (18.5%), general check-up in 10 (13.8%), viral illness in 33 (49.2%) and miscellaneous reasons in 15 (18.5%). Two clusters with low and high WCC emerged; WCC was associated with higher GP patient-centeredness scores, younger age of the child, fewer previous visits, immunisation and general check-up visits, and the solo general practitioner setting. Mothers born overseas received less WCC advice, while longer duration of visit increased WCC. GPs often made observations on physical growth and development and negotiated mothers concerns to provide reassurance to them. The working style of the GP which encouraged informal conversations with the parents enhanced WCC. There was a lack of systematic use of developmental screening measures. CONCLUSIONS: GPs and practice nurses are providing parent/child centered WCC in many visits, particularly when parents present for immunisation and general check-ups. Providing funding and practice nurse support to GPs, and aligning WCC activities with all immunisation visits, rather than just a one-off screening approach, appears to be the best way forward. A cluster randomised trial for doing structured WCC activities with immunisation visits would provide further evidence for cost-effectiveness studies to inform policy change. PMID- 30307994 TI - Understanding the cryptic introgression and mixed ancestry of Red Junglefowl in India. AB - Red Junglefowls (RJFs), the wild progenitor of modern day chickens (DCs), are believed to be in genetic endangerment due to introgression of domestic genes through opportunistic matings with domestic or feral chickens. Previous studies from India reported rare hybridization of RJFs in the wild. However, RJF population genetic structure, pattern of gene flow and their admixture with DC populations are poorly understood at the landscape level. We conducted this study with a large sample size, covering the predicted natural distribution range of RJFs in India. We documented strong evidence of directional gene flow from DCs to free-ranging wild RJFs, with the Northeastern RJF population exhibiting the most genetic variants in their nuclear and mitochondrial genomes, indicating it to be the ancestral population from which early radiation may have occurred. The results provide evidence that landscape features do not act as a barrier to gene flow and the distribution pattern could not be explored due to physical sharing or exchange of wild birds in the past when forests were continuous across RJF range in India. PMID- 30307990 TI - Polynucleotide phosphorylase: Not merely an RNase but a pivotal post transcriptional regulator. AB - Almost 60 years ago, Severo Ochoa was awarded the Nobel Prize in Physiology or Medicine for his discovery of the enzymatic synthesis of RNA by polynucleotide phosphorylase (PNPase). Although this discovery provided an important tool for deciphering the genetic code, subsequent work revealed that the predominant function of PNPase in bacteria and eukaryotes is catalyzing the reverse reaction, i.e., the release of ribonucleotides from RNA. PNPase has a crucial role in RNA metabolism in bacteria and eukaryotes mainly through its roles in processing and degrading RNAs, but additional functions in RNA metabolism have recently been reported for this enzyme. Here, we discuss these established and noncanonical functions for PNPase and the possibility that the major impact of PNPase on cell physiology is through its unorthodox roles. PMID- 30307995 TI - Downscaling of national crop area statistics using drivers of cropland productivity measured at fine resolutions. AB - Despite substantial research and policy interest in pixel level cropland allocation data, few sources are available that span a large geographic area. The data used for much of this research are derived from complex modeling techniques that may include model simulation and other data processing. We develop a transparent econometric framework that uses pixel level biophysical measurements and aggregate cropland statistics to develop pixel level cropland allocation predictions. Such pixel level land use data can be used to investigate the impact of human activities on the environment. Validation exercises show that our approach is effective at downscaling cropland allocation to multiple levels of resolution. PMID- 30307996 TI - Development of novel aptamers for low-density lipoprotein particle quantification. AB - Cardiovascular disease (CVD) remains the leading cause of death worldwide. Low density lipoprotein cholesterol (LDL-C) is commonly used for CVD risk assessment; however, recent research has shown LDL particle (LDL-P) number to be a more sensitive indicator of CVD risk than both LDL-C and non-high-density lipoprotein cholesterol (HDL-C). Described herein are five single stranded DNA aptamers with dissociation constants in the low picomolar range specific to LDL-P and its subfractions. Furthermore, a set of antisense sequences have been developed and characterized that are capable of binding to the best aptamers and undergoing displacement by LDL-P for use in a simple, affordable diagnostic assay. PMID- 30307997 TI - Ecological risk assessment for land contaminated by petrochemical industry. AB - Contamination with harmful chemical substances, including organic compounds of the BTEX and PAH groups, constitutes one of the major threats to the functioning of soil habitat. Excessive contents of the above substances can exert adverse effects on soil organisms, reduce biodiversity, and thus deteriorate soil quality. The threat to soil ecosystems within areas particularly exposed to contamination with accumulating chemical compounds was assessed using the Ecological Risk Assessment (ERA) with a multi-stage Triad (triage rapid initial assessment) procedure (taking into account the different lines of evidence). The article presents the results of chemical and ecotoxicological study of soils sampled at sites affected by contamination from petrochemical industry. The study results provided foundations for developing the site specific ERA framework for the area examined. PMID- 30307999 TI - Accurate real time localization tracking in a clinical environment using Bluetooth Low Energy and deep learning. AB - Deep learning has started to revolutionize several different industries, and the applications of these methods in medicine are now becoming more commonplace. This study focuses on investigating the feasibility of tracking patients and clinical staff wearing Bluetooth Low Energy (BLE) tags in a radiation oncology clinic using artificial neural networks (ANNs) and convolutional neural networks (CNNs). The performance of these networks was compared to relative received signal strength indicator (RSSI) thresholding and triangulation. By utilizing temporal information, a combined CNN+ANN network was capable of correctly identifying the location of the BLE tag with an accuracy of 99.9%. It outperformed a CNN model (accuracy = 94%), a thresholding model employing majority voting (accuracy = 95%), and a triangulation classifier utilizing majority voting (accuracy = 95%). Future studies will seek to deploy this affordable real time location system in hospitals to improve clinical workflow, efficiency, and patient safety. PMID- 30308000 TI - Receding horizon control strategy for an electric vehicle with dual-motor coupling system in consideration of stochastic vehicle mass. AB - Additional degrees of freedom existed in dual-motor coupling system bring considerable challenge to the optimal control of electric vehicles. Moreover, the stochastic characteristic of vehicle mass can further increase this challenge. A receding horizon control (RHC) strategy in consideration of stochastic vehicle mass is proposed in this study to respond to this challenge. Aiming at an electric vehicle with dual-motor coupling, a Markov chain is firstly deployed to predict future driving conditions by a formulated state transition probability matrix, based on historical driving cycles in real-world. Then, future required power is predicted by the predicted driving conditions, stochastic vehicle mass and road gradient, where the stochastic vehicle mass is formulated as stochastic variables in different bus stops. Finally, dynamic programming is employed to calculate the optimal vector of the vehicle within the defined prediction horizon, and only the first control values extracted from the optimal control vector are used to execute real-time power distribution control. The simulation results show that the proposed strategy is reasonable and can at least reduce electric consumption by 4.64%, compared with rule-based strategy. PMID- 30307998 TI - The relationship between birth season and early childhood development: Evidence from northwest rural China. AB - OBJECTIVE: To examine the correlation between birth season and early childhood development. BACKGROUND: Almost all previous studies that examine the effect of birth season on early childhood development were conducted in developed countries with a limited sample size. The present study was conducted in poor, rural areas of western China, a developing region with a continental monsoon climate. METHOD: We administered a hemoglobin test to 650 infants (52% boys), aged 8-10 months, using a Hemocue Hb 201+ finger prick system, and assessed the cognitive and psychomotor development of sample infants using Bayley Scales of Infant Development. RESULTS: Infants born in winter have higher Hb concentrations (t = 3.63, p < 0.001) compared to infants born in summer. Similarly, cognitive development scores (t = 5.17, p < 0.001) and psychomotor development scores (t = 10.60, p < 0.001) were significantly higher among winter-born infants. CONCLUSION: The findings point to the involvement of birth season in early childhood development and suggest that aspects of the environment shape the experiences that contribute to early childhood development. Policy suggestions such as providing infants with ample opportunities for movement and stimulation during the cold season are discussed. PMID- 30308001 TI - Prognostic value of pre-procedural left ventricular strain for clinical events after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative therapy for surgically high-risk patients with severe aortic stenosis (AS). Although TAVI improves survival of patients with severe AS, the mechanism of this effect remains to be clarified. We investigated the effects of TAVI on left ventricular (LV) function and identified the predictive parameters for cardiac events after TAVI. METHODS AND RESULTS: We studied 128 patients with severe symptomatic AS who underwent TAVI. Echocardiographic assessments were performed before and after TAVI. In addition to the conventional echocardiographic parameters such as LV ejection fraction (LVEF) and LV mass index (LVMI), the LV global longitudinal strain (GLS) and early diastolic peak strain rate (SR_E) using two-dimensional speckle tracking echocardiography were also evaluated. All patients were assessed for clinical events including major adverse cardiac events and stroke according to Valve Academic Research Consortium-2 criteria. GLS, early diastolic peak velocity (e'), aortic regurgitation (AR) severity, and SR_E were significantly improved after TAVI. Thirteen patients had an event during the observational period of 591 days (median). Patients with events had higher LVMI, more severe AR, and worse GLS compared to those without events. Furthermore, receiver-operating curve analysis revealed that GLS was the strongest predictor for clinical events (p = 0.009; area under the curve, 0.73). CONCLUSION: Preoperative LV geometric deformation and dysfunction, as a consequence of the cumulative burden of pressure overload, improved after TAVI and could predict cardiac events after TAVI. PMID- 30308002 TI - Grape polyphenols reduce gut-localized reactive oxygen species associated with the development of metabolic syndrome in mice. AB - High-fat diet (HFD)-induced leaky gut syndrome combined with low-grade inflammation increase reactive oxygen species (ROS) in the intestine and may contribute to dysbiosis and metabolic syndrome (MetS). Poorly bioavailable and only partially metabolizable dietary polyphenols, such as proanthocyanidins (PACs), may exert their beneficial effects on metabolic health by scavenging intestinal ROS. To test this hypothesis, we developed and validated a novel, noninvasive, in situ method for visualizing intestinal ROS using orally administered ROS-sensitive indocyanine green (ICG) dye. C57BL/6J mice fed HFD for 10 weeks accumulated high levels of intestinal ROS compared to mice fed low-fat diet (LFD). Oral administration of poorly bioavailable grape polyphenol extract (GPE) and beta-carotene decreased HFD-induced ROS in the gut to levels comparable to LFD-fed mice, while administration of more bioavailable dietary antioxidants (alpha-lipoic acid, vitamin C, vitamin E) did not. Forty percent of administered GPE antioxidant activity was measured in feces collected over 24 h, confirming poor bioavailability and persistence in the gut. The bloom of beneficial anaerobic gut bacteria, such as Akkermansia muciniphila, associated with improved metabolic status in rodents and humans may be directly linked to protective antioxidant activity of some dietary components. These findings suggest a possible mechanistic explanation for the beneficial effects of poorly bioavailable polyphenols on metabolic health. PMID- 30308003 TI - The effects of kinase modulation on in vitro maturation according to different cumulus-oocyte complex morphologies. AB - Successful production of transgenic pigs requires oocytes with a high developmental competence. However, cumulus-oocyte complexes (COCs) obtained from antral follicles have a heterogeneous morphology. COCs can be classified into one of two classes: class I, with five or more layers of cumulus cells; and class II, with one or two layers of cumulus cells. Activator [e.g., epidermal growth factor (EGF)] or inhibitors (e.g., wortmannin and U0126) are added to modulate kinases in oocytes during meiosis. In the present study, we investigated the effects of kinase modulation on nuclear and cytoplasmic maturation in COCs. Class I COCs showed a significantly higher developmental competence than class II COCs. Moreover, the expression of two kinases, AKT and ERK, differed between class I and class II COCs during in vitro maturation (IVM). Initially, inhibition of the PI3K/AKT signaling pathway in class I COCs during early IVM (0-22 h) decreased developmental parameters, such as blastocyst formation rate, blastomere number, and cell survival. Conversely, EGF-mediated AKT activation in class II COCs enhanced developmental capacity. Regarding the MAPK signaling pathway, inhibition of ERK by U0126 in class II COCs during early IVM impaired developmental competence. However, transient treatment with U0126 in class II COCs increased oocyte maturation and AKT activity, improving embryonic development. Additionally, western blotting showed that inhibition of ERK activity negatively regulated the AKT signaling pathway, indicative of a relationship between AKT and MAPK signaling in the process underlying meiotic progression in pigs. These findings may help increase the developmental competence and utilization rate of pig COCs with regard to the production of transgenic pigs and improve our understanding of kinase-associated meiosis events. PMID- 30308005 TI - Examining the contribution of smoking and HPV towards the etiology of oral cavity squamous cell carcinoma using high-throughput sequencing: A prospective observational study. AB - Oral cavity Squamous Cell Carcinoma (OCSCC) is a common form of head and neck cancer throughout the developed and developing world. However, the etiology of OCSCC is still unclear. Here, we explored the extent to which tobacco use, Human Papillomavirus (HPV) infection and genetic and transcriptomic changes contributed to the oncogenesis of OCSCC. In a prospective observational study, we analysed fresh tissue biopsies from 45 OCSCC collected from 51 subjects presenting with OCSCC to the Brisbane Head and Neck Clinics between 2013 and 2015. Exploration of the genetic and transcriptomic landscape of the biopsies were performed using RNA sequencing (RNA-seq) and whole exome sequencing. HPV associated tumours were determined using p16 staining of histological sections and RNA sequencing. Patient demographics including tumor location within the oral cavity, and history of tobacco and alcohol use were correlated with genomic and transcriptomics analyses. About 4.5% of OCSCC were HPV associated. The most frequent mutations in the OCSCC samples were in the TP53 and CDKN2A genes, but no association of specific mutations with HPV or tobacco use was observed. Using weighted gene co expression network analysis to explore the RNA-seq data, tumors from participants with a history of tobacco use showed a significant trend towards increased mammalian target of Rapamycin (mTOR) signaling and decreased mitochondrial respiration. In conclusion, HPV was shown to be an uncommon association with OCSCC and changes in TP53 transcriptional regulation, mTOR signaling and mitochondrial function were associated with a history of tobacco use. Larger data sets will be required to enable detection of differences which may help with development of personalized therapeutics in the future. PMID- 30308004 TI - Exercise effects on bed rest-induced brain changes. AB - PURPOSE: Spaceflight negatively affects sensorimotor behavior; exercise mitigates some of these effects. Head down tilt bed rest (HDBR) induces body unloading and fluid shifts, and is often used to investigate spaceflight effects. Here, we examined whether exercise mitigates effects of 70 days HDBR on the brain and if fitness and brain changes with HDBR are related. METHODS: HDBR subjects were randomized to no-exercise (n = 5) or traditional aerobic and resistance exercise (n = 5). Additionally, a flywheel exercise group was included (n = 8). Exercise protocols for exercise groups were similar in intensity, therefore these groups were pooled in statistical analyses. Pre and post-HDBR MRI (structure and structural/functional connectivity) and physical fitness measures (lower body strength, muscle cross sectional area, VO2 max, body composition) were collected. Voxel-wise permutation analyses were used to test group differences in brain changes, and their associations with fitness changes. RESULTS: Comparisons of exercisers to controls revealed that exercise led to smaller fitness deterioration with HDBR but did not affect brain volume or connectivity. Group comparisons showed that exercise modulated post-HDBR recovery of brain connectivity in somatosensory regions. Posthoc analysis showed that this was related to functional connectivity decrease with HDBR in non-exercisers but not in exercisers. Correlational analyses between fitness and brain changes showed that fitness decreases were associated with functional connectivity and volumetric increases (all r >.74), potentially reflecting compensation. Modest brain changes or even decreases in connectivity and volume were observed in subjects who maintained or showed small fitness gains. These results did not survive Bonferroni correction, but can be considered meaningful because of the large effect sizes. CONCLUSION: Exercise performed during HDBR mitigates declines in fitness and strength. Associations between fitness and brain connectivity and volume changes, although unadjusted for multiple comparisons in this small sample, suggest that supine exercise reduces compensatory HDBR-induced brain changes. PMID- 30308007 TI - Thy1 transgenic mice expressing the red fluorescent calcium indicator jRGECO1a for neuronal population imaging in vivo. AB - Calcium imaging is commonly used to measure the neural activity of large groups of neurons in mice. Genetically encoded calcium indicators (GECIs) can be delivered for this purpose using non-invasive genetic methods. Compared to viral gene transfer, transgenic targeting of GECIs provides stable long-term expression and obviates the need for invasive viral injections. Transgenic mice expressing the green GECI GCaMP6 are already widely used. Here we present the generation and characterization of transgenic mice expressing the sensitive red GECI jRGECO1a, driven by the Thy1 promoter. Four transgenic lines with different expression patterns showed sufficiently high expression for cellular in vivo imaging. We used two-photon microscopy to characterize visual responses of individual neurons in the visual cortex in vivo. The signal-to-noise ratio in transgenic mice was comparable to, or better than, mice transduced with adeno-associated virus. In addition, we show that Thy1-jRGECO1a transgenic mice are useful for transcranial population imaging and functional mapping using widefield fluorescence microscopy. We also demonstrate imaging of visual responses in retinal ganglion cells in vitro. Thy1-jRGECO1a transgenic mice are therefore a useful addition to the toolbox for imaging activity in intact neural networks. PMID- 30308006 TI - Characterization of genetic diversity in Turkish common bean gene pool using phenotypic and whole-genome DArTseq-generated silicoDArT marker information. AB - Turkey presents a great diversity of common bean landraces in farmers' fields. We collected 183 common bean accessions from 19 different Turkish geographic regions and 5 scarlet runner bean accessions to investigate their genetic diversity and population structure using phenotypic information (growth habit, and seed weight, flower color, bracteole shape and size, pod shape and leaf shape and color), geographic provenance and 12,557 silicoDArT markers. A total of 24.14% markers were found novel. For the entire population (188 accessions), the expected heterozygosity was 0.078 and overall gene diversity, Fst and Fis were 0.14, 0.55 and 1, respectively. Using marker information, model-based structure, principal coordinate analysis (PCoA) and unweighted pair-group method with arithmetic means (UPGMA) algorithms clustered the 188 accessions into two main populations A (predominant) and B, and 5 unclassified genotypes, representing 3 meaningful heterotic groups for breeding purposes. Phenotypic information clearly distinguished these populations; population A and B, respectively, were bigger (>40g/100 seeds) and smaller (<40g/100 seeds) seed-sized. The unclassified population was pure and only contained climbing genotypes with 100 seed weight 2 3 times greater than populations A and B. Clustering was mainly based on A: seed weight, B: growth habit, C: geographical provinces and D: flower color. Mean kinship was generally low, but population B was more diverse than population A. Overall, a useful level of gene and genotypic diversity was observed in this work and can be used by the scientific community in breeding efforts to develop superior common bean strains. PMID- 30308009 TI - Nest sites as a key resource for population persistence: A case study modelling nest occupancy under forestry practices. AB - Natural nest sites are important breeding resource in terms of population dynamics, especially in forest systems where nest trees limit populations or timber harvesting destroys nests. Nest structures usually have a long life and can be reused by breeding pairs across multiple breeding seasons, so studying their dynamics is of relevance for biodiversity conservation. In this study, we develop a dynamic model to evaluate nest site availability and its influence on the breeding settlement of a forest raptor community composed of booted eagle (Hieraaetus pennatus), common buzzard (Buteo buteo) and northern goshawk (Accipiter gentilis) in a Mediterranean forest ecosystem in southeast Spain. This model approach is also applied to analyse the influence of forestry practices on the dynamics of occupied nests for a simulated period (2010-2050). The simulated scenarios include unmanaged forest and timber harvesting practices of clearcuttings every ten years considering two factors: the age class of trees for clearcutting (40, 50, 60 and 70 years old) and the type of forest management (with or without nest protection). Our simulated results show that the number of breeding pairs is constant during the period without timber harvest, whereas breeding pairs gradually decrease in the scenario of clearcutting trees aged from 70 to 50-years without nest protection, and populations become extinct with the clearcutting of 40-year old trees. Considering the practice of clearcutting and nest protection, nest occupancy can reach the maximum number of occupied nests for the scenarios of cutting 70 and 60-year old trees, and maintain populations without extinction for the scenarios of cutting 40-year old trees. We conclude that nest sites (whether occupied or not) are key resources for increasing the occupancy of the forest raptor community and that nest protection measures buffer the effects of clearcuttings, thus preventing population extinction. PMID- 30308008 TI - Marker-trait associations in two-rowed spring barley accessions from Kazakhstan and the USA. AB - In this study, phenotyping and single nucleotide polymorphism (SNP) genotyping data of 272 accessions of two-rowed spring barley from the USA along with 94 accessions from Kazakhstan were assessed in field trials at six breeding organizations in Kazakhstan to evaluate the performance of the USA samples over three years (2009-2011). The average grain yield over the six locations was not significantly higher in Kazakh accessions in comparison to the USA samples. Twenty four samples from Montana, Washington, the USDA station in Aberdeen Idaho, and the Anheuser-Busch breeding programs showed heavier average yield than the local standard cultivar "Ubagan". Principal Coordinate analysis based on two sets of SNP data suggested that Kazakh accessions were closest to the USA accessions among eight groups of samples from different parts of the World, and within five US barley origin groups the samples from Montana and Washington perfectly matched six groups of Kazakh breeding origins. A genome-wide association study (GWAS) using data from eighteen field trials allowed the identification of ninety one marker-trait associations (MTA) in two or more environments for nine traits, including key characters such as heading time (HT), number of kernels per spike (NKS), and thousand grain weight (TGW). Our GWAS allowed the identification of eight MTA for HT and NKS, and sixteen MTA for TGW, when those MTA were linked to mapped SNPs. Based on comparisons of chromosomal positions of MTA identified in this study, and positions of known genes and quantitative trait loci for HT, NKS and TGW, it was suggested that MTA for HT on chromosome 2H (at 158.2 cM, 11_21414), MTA for NKS on 5H (at 118.6 cM, 11_20298), and two MTA for TGW on chromosome 4H (at 94.7 cM, 12_30718, and at 129.3 cM, 11_20013) were potentially new associations in barley. GWAS suggested that six MTA for HT, including two on chromosome 1H, two on chromosome 3H, and one each on chromosomes 4H and 6H, had useful pleiotropic effects for improving barley spike traits. PMID- 30308010 TI - A benthic bioindicator reveals distinct land and ocean-Based influences in an urbanized coastal embayment. AB - Biogeochemical maps of coastal regions can be used to identify important influences and inputs that define nearshore environments and biota. Biogeochemical tracers can also track animal movement and their diet, monitor human coastal development, and evaluate the condition of habitats and species. However, the beneficial applications of spatial biogeochemical analysis are hindered by a limited understanding of how tracer distribution is affected by different land and ocean-based influences. To help address these knowledge gaps, we determined the spatial trends of three stable isotopes (delta13C-carbon, delta15N-nitrogen, delta34S-sulfur) and 13 major and trace elements in an urbanized coastal embayment (Moreton Bay, Australia), as incorporated into the muscle tissue of a marine consumer, the eastern king prawn Melicertus plebejus. Results were used to identify unique biochemical regions within the bay and to discuss how spatial patterns in tracers could be used to indicate the relative importance of catchment, urban and offshore drivers in coastal bays. Discriminant analysis identified seven biogeochemical regions that were likely distinguished by variation in catchment, urban, and offshore input, and habitat type. delta13C and delta15N patterns suggested nearshore areas could be distinguished by increased sediment resuspension and higher wastewater inputs from catchments. High inshore lead (Pb) and copper (Cu) concentrations were likely the result of urban input. Arsenic (As) and cadmium (Cd) increased further from shore. This trend implied oceanic influences were a significant control over As and Cd bioavailability. Cobalt (Co) and rare earths were also used to differentiate some nearshore areas, but incongruent distribution patterns in Co suggested it may be less reliable. Overall, results indicated that delta15N, delta13C, Cd, Cu, Pb and rare earth elements were the most reliable tracers to differentiate nearshore and offshore environments, and catchment-based effects. We encourage future studies to consider using a similar multivariate approach in coastal spatial analysis, and to include unrelated tracers that reflect distinct coastal influences. PMID- 30308011 TI - Clinical outcomes of patients with residual medial osteophytes following mobile bearing unicompartmental knee arthroplasty. AB - INTRODUCTION: The surgical technique used in unicompartmental knee arthroplasty (UKA) is crucial for achieving good short and long term clinical outcomes. The medial mobile bearing UKA has shown excellent clinical outcomes and survivorship. But release of the medial collateral ligament during entering joint is cause of mobile bearing dislocation in short term outcomes and lateral compartment osteoarthritis may occur in the mid to long term outcomes. Removing all osteophytes at the time of UKA is sometime impossible due to their large size and extend to the inferior part of medial tibial plateau and removing them completely my result in release of the MCL. But no data exist on clinical outcomes in such patients. METHODS: We conducted a prospective study from 2010 to 2015 of patients undergoing mobile bearing UKA and classified them in to two groups: those with (Gp1) and without (Gp2) residual osteophytes. Osteophyte size was measured using Hernborg's technique. The primary outcomes were pain score, functional score, and knee scores and the presence of reported medial knee pain. RESULTS: 176 patients who underwent 199 mobile bearing UKAs were recruited: Gp1 = 42 patients (46 knees) and Gp2 = 134 patients (153 knees). Residual osteophyte sizes ranged from 2.13-9.42 mm (mean 4.12). The mean Gp1 Gp2 pain score (49.04, 48.92, p = 0.84), functional score (83.75, 84.04, p = 0.83) and knee score (89.86, 98.7, p = 0.0.78) scores were almost identical and no one complained of medial joint pain. Followed up ranged from 2 - 7 years (mean 4.23). No patients were lost to follow up. CONCLUSION: The patients with residual osteophytes of length less than 9 mm had good and similar clinical outcomes as patients without residual osteophytes following mobile bearing UKA. LEVEL OF EVIDENCE: Level II-2, evidence obtained from well-designed cohort studies or case-control studies, preferably from more than one center or research group. PMID- 30308013 TI - Lamivudine monotherapy as a holding regimen for HIV-positive children. AB - BACKGROUND: In resource-limited settings holding regimens, such as lamivudine monotherapy (LM), are used to manage HIV-positive children failing combination antiretroviral therapy (cART) to mitigate the risk of drug resistance developing, whilst adherence barriers are addressed or when access to second- or third-line regimens is restricted. We aimed to investigate characteristics of children placed on LM and their outcomes. METHODS: We describe the characteristics of children (age <16 years at cART start) from 5 IeDEA-SA cohorts with a record of LM during their treatment history. Among those on LM for >90 days we describe their immunologic outcomes on LM and their immunologic and virologic outcomes after resuming cART. FINDINGS: We included 228 children in our study. At LM start their median age was 12.0 years (IQR 7.3-14.6), duration on cART was 3.6 years (IQR 2.0-5.9) and median CD4 count was 605.5 cells/MUL (IQR 427-901). Whilst 110 (48%) had no prior protease inhibitor (PI)-exposure, of the 69 with recorded PI exposure, 9 (13%) patients had documented resistance to all PIs. After 6 months on LM, 70% (94/135) experienced a drop in CD4, with a predicted average CD4 decline of 46.5 cells/MUL (95% CI 37.7-55.4). Whilst on LM, 46% experienced a drop in CD4 to <500 cells/MUL, 18 (8%) experienced WHO stage 3 or 4 events, and 3 children died. On resumption of cART the average gain in CD4 was 15.65 cells/uL per month and 66.6% (95% CI 59.3-73.7) achieved viral suppression (viral load <1000) at 6 months after resuming cART. INTERPRETATION: Most patients experienced immune decline on LM. Its use should be avoided in those with low CD4 counts, but restricted use may be necessary when treatment options are limited. Managing children with virologic failure will continue to be challenging until more treatment options and better adherence strategies are available. PMID- 30308014 TI - Costs and cost-effectiveness of LEEP versus cryotherapy for treating cervical dysplasia among HIV-positive women in Johannesburg, South Africa. AB - BACKGROUND: Cervical cancer incidence is significant in countries, such as South Africa, with high burdens of both HIV and human papillomavirus (HPV). Cervical cancer is largely preventable if dysplasia is diagnosed and treated early, but there is debate regarding the best approaches for screening and treatment, especially for low-resource settings. Currently South Africa provides Pap smears followed by colposcopic biopsy and LEEP if needed in its public health facilities. We estimated the costs and cost-effectiveness of two approaches for treating cervical intraepithelial neoplasia grade 2 or higher (CIN2+) among HIV infected women, most of whom were taking antiretroviral treatment, at a public HIV treatment facility in Johannesburg, South Africa. METHODS: Method effectiveness was derived from an intention-to-treat analysis of data gathered in a clinical trial completed previously at the study facility. In the trial, women who were diagnosed with CIN2+ and eligible for cryotherapy were randomized to cryotherapy or LEEP. If women were CIN2+ at six months as determined via Pap smear and colposcopic biopsy, all women-regardless of their original treatment assignment-received LEEP. "Cure" was then defined as the absence of disease at 12 months based on Pap smear and colposcopic biopsy. Health service costs were estimated using micro-costing between June 2013 and April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered, and results from an as-treated analysis were considered in sensitivity analysis. RESULTS: In total, 166 women with CIN2+ were enrolled (86 had LEEP; 80 had cryotherapy). At 12 months, cumulative loss to follow-up was 12.8% (11/86) for the LEEP group and 13.8% (11/80) for cryotherapy. Based on the unadjusted intention-to-treat analysis conducted for this economic evaluation, there was no significant difference in efficacy. At 12 months, 83.8% (95% CI 73.8-91.1) of women with CIN2+ at baseline and randomized to cryotherapy were free of CIN2+ disease. In contrast, 76.7% (95% CI 66.4-85.2) of women assigned to LEEP were free from disease. On average, women initially treated with cryotherapy were less costly per patient randomized at US$ 118.00 (113.91 122.10), and per case "cured" at US$ 140.90 (136.01-145.79). Women in the LEEP group cost US$ 162.56 (157.90-167.22) per patient randomized and US$ 205.59 (199.70-211.49) per case cured. In the as-treated analysis, which was based on trial data, LEEP was more efficacious than cryotherapy; however, the difference was not significant. Cryotherapy remained more cost-effective than LEEP in all sensitivity and scenario analyses. CONCLUSIONS: For this cost-effectiveness analysis, using an intention-to-treat approach and taking into consideration uncertainty in the clinical and cost outcomes, a strategy involving cryotherapy plus LEEP if needed at six months was dominant to LEEP plus LEEP again at six months if needed for retreatment. However, compared to other studies comparing LEEP and cryotherapy, the efficacy results were low in both treatment groups possibly due to the HIV-positivity of the participants. Further research is needed, but at present choosing the "right" treatment option may be less important than ensuring access to treatment and providing careful monitoring of treatment outcomes. PMID- 30308012 TI - MicroRNA and mRNA expression associated with ectopic germinal centers in thymus of myasthenia gravis. AB - BACKGROUND: A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases. We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance. METHODS: MG thymus samples were assessed by histology and grouped based upon the appearance of GC; GC positive and GC negative. A systems biology approach was used to study the differences between the groups. Our study included miRNA and mRNA profiling, quantitative real-time PCR validation, miRNA target identification, pathway analysis, miRNA-mRNA reciprocal expression pairing and interaction. RESULTS: Thirty-eight mature miRNAs and forty six annotated mRNA transcripts were differentially expressed between the two groups (>1.5 fold change, ANOVA p<0.05). The miRNAs were found to be involved in immune response pathways and identified in other autoimmune diseases. The cellular and molecular functions of the mRNAs showed involvement in cell death and cell survival, cellular proliferation, cytokine signaling and extra-cellular matrix reorganization. Eleven miRNA and mRNA pairs were reciprocally regulated. The Regulator of G protein Signalling 13 (RGS13), known to be involved in GC regulation, was identified in specimens with GC and was paired with downregulation of miR-452-5p and miR-139-5p. MiRNA target sites were validated by dual luciferase assay. Transfection of miRNA mimics led to down regulation of RGS13 expression in Raji cells. CONCLUSION: Our study indicates a distinct miRNA and mRNA expression pattern in ectopic GC in MG thymus. These miRNAs and mRNAs are involved in regulatory pathways common to inflammation and immune response, cell cycle regulation and anti-apoptotic pathways suggesting their involvement in support of GC formation in the thymus. We demonstrate for the first time that miR 139-5p and miR-452-5p negatively regulate RGS13 expression. PMID- 30308015 TI - Recombinant AfusinC, an anionic fungal CSalphabeta defensin from Aspergillus fumigatus, exhibits antimicrobial activity against gram-positive bacteria. AB - Antimicrobial peptides (AMPs) are short and generally positively charged peptides found in a wide variety of organisms. CSalphabeta defensins are a group of AMPs. These defensins are composed of an alpha-helix and a beta-sheet linked by three or four disulphide bridges. In this study, we describe the antimicrobial activity of an anionic CSalphabeta fungal defensin from Aspergillus fumigatus, AfusinC. AfusinC was recombinantly produced as a fusion protein in Escherichia coli. The tag was removed by proteolytic cleavage, and AfusinC was purified by size exclusion chromatography. About 0.8 mg of recombinant AfusinC was obtained from 1 L of culture. Recombinant AfusinC was active against mainly gram-positive bacteria including human pathogens and a multiresistant-strain of A. aureus. Additionally, AfusinC showed bactericidal effect against Micrococcus luteus. PMID- 30308016 TI - Identification of water use efficiency related genes in 'Garnem' almond-peach rootstock using time-course transcriptome analysis. AB - Drought is one of the main abiotic stresses with far-reaching ecological and socioeconomic impacts, especially in perennial food crops such as Prunus. There is an urgent need to identify drought resilient rootstocks that can adapt to changes in water availability. In this study, we tested the hypothesis that PEG induced water limitation stress will simulate drought conditions and drought related genes, including transcription factors (TFs), will be differentially expressed in response to this stress. 'Garnem' genotype, an almond * peach hybrid [P. amygdalus Batsch, syn P. dulcis (Mill.) x P. persica (L.) Batsch] was exposed to PEG-6000 solution, and a time-course transcriptome analysis of drought stressed roots was performed at 0, 2 and 24 h time points post-stress. Transcriptome analysis resulted in the identification of 12,693 unique differentially expressed contigs (DECs) at the 2 h time point, and 7,705 unique DECs at the 24 h time point after initiation of the drought treatment. Interestingly, three drought-induced genes, directly related to water use efficiency (WUE) namely, ERF023 TF; LRR receptor-like serine/threonine-kinase ERECTA; and NF-YB3 TF, were found induced under stress. The RNAseq results were validated with quantitative RT-PCR analysis of eighteen randomly selected differentially expressed contigs (DECs). Pathway analysis in the present study provides valuable information regarding metabolic events that occur during stress induced signalling in 'Garnem' roots. This information is expected to be useful in understanding the potential mechanisms underlying drought stress responses and drought adaptation strategies in Prunus species. PMID- 30308017 TI - Particulate matter containing environmentally persistent free radicals induces AhR-dependent cytokine and reactive oxygen species production in human bronchial epithelial cells. AB - Particulate matter (PM) is emitted during the combustion of fuels and wastes. PM exposure exacerbates pulmonary diseases, and the mechanism may involve oxidative stress. At lower combustion temperatures such as occurs in the cool zone of a flame, aromatic compounds chemisorb to the surface of metal-oxide-containing PM, resulting in the formation of surface-stabilized environmentally persistent free radicals (EPFR). Prior studies showed that PM-containing EPFR redox cycle to produce reactive oxygen species (ROS), and after inhalation, EPFR induce pulmonary inflammation and oxidative stress. Our objective was to elucidate mechanisms linking EPFR-induced oxidant injury with increased cytokine production by pulmonary epithelial cells. We thus treated human bronchial epithelial cells with EPFR at sub-toxic doses and measured ROS and cytokine production. To assess aryl hydrocarbon receptor (AhR) activity, cells were transfected with a luciferase reporter for xenobiotic response element activation. To test whether cytokine production was dependent upon AhR activation or oxidative stress, some cells were co-treated with an antioxidant or an AhR antagonist. EPFR increased IL 6 release in an ROS and AhR- and oxidant-dependent manner. Moreover, EPFR induced an AhR activation that was dependent upon oxidant production, since antioxidant co-treatment blocked AhR activation. On the other hand, EPFR treatment increased a cellular ROS production that was at least partially attenuated by AhR knockdown using siRNA. While AhR activation was correlated with an increased expression of oxidant-producing enzymes like cytochrome P450 CYP1A1, it is possible that AhR activation is both a cause and effect of EPFR-induced ROS. Finally, lipid oxidation products also induced AhR activation. ROS-dependent AhR activation may be a mechanism for altered epithelial cell responses after EPFR exposure, potentially via formation of bioactive lipid or protein oxidation products. PMID- 30308019 TI - Urinary steroid profiling in women hints at a diagnostic signature of the polycystic ovary syndrome: A pilot study considering neglected steroid metabolites. AB - BACKGROUND: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS. METHODS: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites. RESULTS: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20betaDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2). CONCLUSION: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability. PMID- 30308018 TI - Location-dependent effects of trauma on oxidative stress in humans. AB - Though circulating antioxidant capacity in plasma is homeostatically regulated, it is not known whether acute stressors (i.e. trauma) affecting different anatomical locations could have quantitatively different impacts. For this reason, we evaluated the relationship between the anatomical location of trauma and plasma total antioxidant capacity (TAC) in a prospective study, where the anatomical locations of trauma in polytraumatic patients (n = 66) were categorized as primary affecting the brain -traumatic brain injury (TBI)-, thorax, abdomen and pelvis or extremities. We measured the following: plasma TAC by 2 independent methods, the contribution of selected antioxidant molecules (uric acid, bilirubin and albumin) to these values and changes after 1 week of progression. Surprisingly, TBI lowered TAC (919 +/- 335 MUM Trolox equivalents (TE)) in comparison with other groups (thoracic trauma 1187 +/- 270 MUM TE; extremities 1025 +/- 276 MUM TE; p = 0.004). The latter 2 presented higher hypoxia (PaO2/FiO2 272 +/- 87 mmHg) and hemodynamic instability (inotrope use required in 54.5%) as well. Temporal changes in TAC are also dependent on anatomical location, as thoracic and extremity trauma patients' TAC values decreased (1187 +/- 270 to 1045 +/- 263 MUM TE; 1025 +/- 276 to 918 +/- 331 MUM TE) after 1 week (p < 0.01), while in TBI these values increased (919 +/- 335 to 961 +/- 465 MUM TE). Our results show that the response of plasma antioxidant capacity in trauma patients is strongly dependent on time after trauma and location, with TBI failing to induce such a response. PMID- 30308020 TI - Semantic and psychometric validation of the Brazilian Portuguese version (PASE-P) of the Psoriatic Arthritis Screening and Evaluation questionnaire. AB - : PASE (Psoriatic Arthritis Screening and Evaluation) was developed in the English language to screen for inflammatory arthritis among patients with psoriasis. It is 15 item self administered questionnaire with a score from 15 to 75. A higher score indicates a greater risk for inflammatory joint disease. The purpose of this study was to translate, adapt and validate this questionnaire into Brazilian Portuguese (PASE-P). METHODS: 465 patients diagnosed with psoriasis (158 with psoriatic arthritis confirmed by a rheumatologist according to the CASPAR criteria and 307 without) were evaluated in dermatology clinics. We performed the analysis of semantic equivalence in eight steps. For psychometric equivalence, we evaluated the data quality, reliability, construct validity, well known groups and discriminant characteristics of the items, as well as a ROC curve to determine optimal PASE-P cutoff points in case identification and their sensitivity / specificity. The final version presented excellent reproducibility (CCI = 0.97) and reliability (Cronbach's alpha> 0.9). A cut-off point of 25 distinguished between patients with and without psoriatic arthritis, with sensitivity of 69.5 and specificity of 86.8. PASE-P proved to be culturally valid and reliable to screen for psoriatic arthritis in Brazilian patients with psoriasis. PMID- 30308021 TI - The development of indicator measure for monitoring the quality of patient centered care in China's tertiary hospitals. AB - OBJECTIVE: To develop a set of structure and process indicators to evaluate tertiary hospitals' performance in the Healthcare Improvement Initiative, a national program with a goal to improve quality of patient-centered care. METHODS: A modified Delphi technique, including literature review, multidisciplinary panel meeting and anonymous rating, was used to generate a set of indicators. A practice test involving both general and special hospitals was conducted to ensure the feasibility of data collection for these indicators. RESULTS: 62 indicators were generated by literature review. The panel review procedure involving 39 panelists with diverse backgrounds resulted in a total of 59 indicators, which included 40 qualitative indicators and 19 quantitative indicators. In the practice test, six quantitative indicators were found unfeasible. According to the suggestion of the experts in the hospital evaluation committee, three of those indicators were kept by adjusting their data collection methods, while other three ones were discarded. DISCUSSION: A set of 56 structure and process indicators was developed to evaluate hospitals' performance in the implementation of the Healthcare Improvement Initiative, which could be used in both general and special tertiary hospitals. Results of the indicator measurement could present a panorama of the quality of patient-centered care in tertiary hospitals nation-wide, and inform health administrators of the ways to attain the goal of the Initiative. PMID- 30308022 TI - Dissolved organic carbon in glaciers of the southeastern Tibetan Plateau: Insights into concentrations and possible sources. AB - Dissolved organic carbon (DOC) released from glaciers has an important role in the biogeochemistry of glacial ecosystems. This study focuses on DOC from glaciers of the southeastern Tibetan Plateau, where glaciers are experiencing rapid shrinkage. We found that concentrations of DOC in snowpits (0.16+/-0.054 MUg g-1), aged snow (0.16+/-0.048 MUg g-1), and bare ice (0.18+/-0.082 MUg g-1) were similar across the southeastern Tibetan Plateau, but were slightly lower than those in other glaciers on the Tibetan Plateau. Vertical variations of DOC, particulate organic carbon, black carbon, and total nitrate in snowpit showed no systematic variations in the studied glaciers, with high values of DOC occurring in the ice or dusty layers. We estimated the export of DOC and particulate organic carbon from glaciers to be 1.96+/-0.66 Gg yr-1 and 5.88+/-2.15 Gg yr-1 in this region, respectively, indicating that organic carbon released from glacier meltwater may be affecting downstream ecosystems. Potential sources of the air masses arriving at the southeastern Tibetan glaciers include South Asia, Central Asia, Middle East, and northwest China. Emissions from biomass burning of South Asia played an important role in the deposition of DOC to the glacier, which can be evidenced by backward trajectories and fire spot distributions from MODIS and CALIPSO images. Our findings suggest that anthropogenic aerosols contribute abundant DOC to glaciers on the southeastern Tibetan Plateau. The pronounced rate of glacial melting in the region may be delivering increased quantities of relic DOC to downstream rivers. PMID- 30308023 TI - Comparison of echocardiographic linear dimensions for male and female child and adolescent athletes with published pediatric normative data. AB - BACKGROUND: Application of normative data for echocardiographic measurements to children practicing sports may lead to false positive findings. The aim of the study was to define the normative data of basic echocardiographic measurements for this group and to compare them to the previously published normative data for the pediatric population. METHODS: Parasternal long-axis 2D-guided echocardiographic measurements were obtained from a group of 791 child athletes (ages 5-18 years). According to the methodology presented previously by Pettersen et al. (2008), the regression equations for basic cardiac dimensions against body surface area were derived and individual Z-scores values were computed, using both Pettersen's equations and newly derived ones. RESULTS: Z-scores computed based on Pettersen's equations were found to differ significantly from those based on the new equations, for all the analyzed parameters (p<0.001). In agreement analysis, the most pronounced differences were found for the left atrium, interventricular septum and the left ventricular posterior wall. However, in most cases, the indications of abnormality were concordant (91.8%-97.6%); except for the left atrium, where there were 30.8% discordant results. CONCLUSION: The study presents normative data for basic echocardiographic cardiac measurements for children of both sexes practicing varying sporting disciplines and compares them with general pediatric population. Mean values of cardiac dimensions are higher in young athletes, particularly in relation to the left atrium and left ventricular muscle thickness. In most cases, the upper limit of normality observed in the young athletes is confined within the upper limit of the general pediatric population. PMID- 30308024 TI - A comparison of the effectiveness of three LED phototherapy machines, single- and double-sided, for treating neonatal jaundice in a low resource setting. AB - INTRODUCTION: Neonatal jaundice is one of the most common reasons for hospital admission in low resource settings. Treatment is frequently inadequate as conventional phototherapy requires frequent bulb changes. LED phototherapy has comparable efficacy to conventional phototherapy, and the bulbs last over 40,000 hours. This observational study compares the effectiveness of three LED machines, two single-sided and one double-sided in routine use in Vietnam. METHODS: We included all infants weighting >=1500g and with jaundice diagnosed visually or by Total Serum Bilirubin (TSB) measurement at The Da Nang Hospital for Women and Children (Da Nang, Vietnam). The primary endpoint was the average hourly change in TSB over the first six hours of treatment. The secondary endpoints were duration of treatment; average hourly change in TSB over treatment, and length of stay in the neonatal unit. Multivariable analysis and bootstrap methods was performed to compare outcomes, adjusting for potential confounders. RESULTS: All outcomes were comparable in the two single-sided machines. The double-sided machine showed 54% increase in the hourly speed of TSB reduction (1.3 MUmol/L/hr, 95% CI 0.3-2.3), with a 45% increase in the speed of TSB reduction over the duration of treatment (0.9 MUmol/L/hr, 95% CI 0.6-1.3). In addition, the double sided machine was associated with 21% reduction in the duration of treatment (14 hours, 95% CI 5-22) and 16% reduction of length of stay (14 hours, 95% CI 3-25). CONCLUSION: The results confirm and quantify the benefits of increasing surface area exposure during phototherapy. Adjusted for multiple potential confounders, use of double-sided phototherapy can substantially increase the speed of TSB reduction, and substantially decrease the duration of treatment and length of stay in the NCU. PMID- 30308025 TI - Performances of five risk algorithms in predicting cardiovascular events in patients with Psoriatic Arthritis: An Italian bicentric study. AB - INTRODUCTION: In patients with psoriatic arthritis (PsA) an increased cardiovascular (CV) risk has been observed. Recently, a EULAR taskforce suggested to use a multiplication by the factor of 1.5 of CV risk algorithms in patients with inflammatory arthritis. This study aims to evaluate the performance of five original and adapted according to EULAR recommendations CV risk algorithms in PsA: SCORE, CUORE, Framingham Risk Score (FRS), QRISK2, and Reynold's Risk Score (RRS). METHODS: Prospectively collected data from two Italian cohorts were used. Discriminatory ability for CV risk prediction was evaluated by the area under the ROC curves. Calibration between predicted and observed events was assessed by Hosmer-Lemeshow (HL) tests. Sensibility and specificity were calculated for low to-intermediate and intermediate-to-high risk cut-offs. RESULTS: One hundred fifty-five patients were enrolled with an observation of 1550 patient/years. Area under the ROC were 0.7679 (95% CI 0.64768 to 0.88812), 0.864 (95% CI 0.79675 to 0.93278), 0.7575 (95% CI 0.65784 to 0.85708), 0.8660 (95% CI 0.79428 to 0.93772), and 0.7183 (95% CI 0.57795 to 0.85862) for SCORE, CUORE, FRS, QRSIK2, and RRS, respectively. HL tests demonstrated poor model fit (p<0.05) for SCORE, CUORE, and RRS. Discriminative ability and calibration were not improved by adaption of the algorithms according to EULAR recommendations. Up to 80% of CV events occurred in patients at "low risk" and up to 93% of CV events in patients at "low intermediate risk". CONCLUSIONS: Adaption of the CV risk algorithms according to EULAR indications did not provide improvement in discriminative ability and calibration in patients with PsA. PMID- 30308026 TI - MR-compatible, 3.8 inch dual organic light-emitting diode (OLED) in-bore display for functional MRI. AB - PURPOSE: Functional MRI (fMRI) is a well-established method used to investigate localised brain activation by virtue of the blood oxygen level dependent (BOLD) effect. It often relies on visual presentations using beam projectors, liquid crystal display (LCD) screens, and goggle systems. In this study, we designed an MR compatible, low-cost display unit based on organic light-emitting diodes (OLED) and demonstrated its performance. METHODS: A 3.8" dual OLED module and an MIPI-to-HDMI converter board were used. The OLED module was enclosed using a shielded box to prevent noise emission from the display module and the potentially destructive absorption of high power RF from the MRI transmit pulses. The front of the OLED module was covered by a conductive, transparent mesh. Power was supplied from a non-magnetic battery. The shielding of the display was evaluated by directly measuring the electromagnetic emission with the aid of a pickup loop and a low noise amplifier, as well as by examining the signal-to noise ratio (SNR) of phantom MRI data. The visual angle of the display was calculated and compared to standard solutions. As a proof of concept of the OLED display for fMRI, a healthy volunteer was presented with a visual block paradigm. RESULTS: The OLED unit was successfully installed inside a 3 T MRI scanner bore. Operation of the OLED unit did not degrade the SNR of the phantom images. The fMRI data suggest that visual stimulation can be effectively delivered to subjects with the proposed OLED unit without any significant interference between the MRI acquisitions and the display module itself. DISCUSSION: We have constructed and evaluated the MR compatible, dual OLED display for fMRI studies. The proposed OLED display provides the benefits of high resolution, wide visual angle, and high contrast video images during fMRI exams. PMID- 30308027 TI - Diversity of spined loaches from Asia Minor in a phylogenetic context (Teleostei: Cobitidae). AB - Accurate determination of species diversity in areas of high endemicity, particularly those lacking comprehensive systematic knowledge, represents a challenge for both taxonomists and conservationists. This need is particularly evident in areas greatly affected by anthropogenic disturbances such as the Eastern Mediterranean and its freshwater environments. To improve our knowledge of Eastern Mediterranean freshwater fishes, we phylogenetically studied Western Palearctic Cobitis species, focusing on those found in Turkey. Overall, our results provide a robust framework to assess the number of species of Cobitis. Phylogenetic reconstructions based on mitochondrial (cyt b) and nuclear (RAG1) sequences show seven major clades (Clades 1-7) grouping all Western Palearctic Cobitis species, except C. melanoleuca. In general, each major clade comprises Cobitis species that inhabit geographically close areas and have similar secondary sexual characters. Multiple divergent lineages were identified in our analyses, some of which were highly divergent such as the ones inhabiting Turkish freshwaters. Moreover, in some analyses, several of the identified lineages were incongruent with a priori defined species. Furthermore, our analyses identified eight potentially new candidate species, six that had been suggested in previous studies and two that are reported here for the first time. Our results reveal Turkey as the area with the greatest diversity of spined loaches in the Mediterranean. PMID- 30308029 TI - Retraction: Identification of Autoantibodies against Transthyretin for the Screening and Diagnosis of Rheumatoid Arthritis. PMID- 30308028 TI - Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vaso-occlusion, inflammation and anemia. AB - Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/MUL in vehicle-treated SS mice to 2.89 x 106/MUL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002 treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/MUL in vehicle-treated versus 20.3 x 103/MUL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-kappaB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration dependent manner. Collectively, these findings support HBI-002 as a useful anti inflammatory agent to treat SCD and warrants further development as a therapeutic. PMID- 30308030 TI - Effective detection of biocatalysts with specified activity by using a hydrogel based colourimetric assay - beta-galactosidase case study. AB - The main aim of this study was to prepare gelatine-based hydrogels containing entrapped substrate and to examine the applicability of these matrices for detection of enzymes with a specified catalytic activity. The general research concept assumed the use of a substrate that, in the presence of a particular enzyme, will quickly undergo conversion to a coloured product. ortho-Nitrophenyl beta-D-galactopyranoside (ONPG) was used as the immobilized substrate and beta galactosidase from Kluyveromyces lactis as the biocatalyst to be determined. Among other factors, the range of detectable concentrations of galactosidase, the operational pH range, the time necessary to achieve a visible response and the preferred storage conditions for the test were determined. As a result, an effective colourimetric test for beta-galactosidase detection was obtained. Its main advantages include (i) the effective detection of the enzyme at concentrations greater than or equal to 0.6 mg.L-1, (ii) the ability to perform initial quantification of the enzyme on the basis of the intensity of the obtained colour (iii) applicability in a wide pH range (from 4.0 to 9.0), (iv) a relatively short response time (from 1 to a maximum of 30 minutes) and (v) stability in long-term storage at 4 degrees C (90 days without loss of specific properties). PMID- 30308031 TI - Considerations for ethics review of big data health research: A scoping review. AB - Big data trends in biomedical and health research enable large-scale and multi dimensional aggregation and analysis of heterogeneous data sources, which could ultimately result in preventive, diagnostic and therapeutic benefit. The methodological novelty and computational complexity of big data health research raises novel challenges for ethics review. In this study, we conducted a scoping review of the literature using five databases to identify and map the major challenges of health-related big data for Ethics Review Committees (ERCs) or analogous institutional review boards. A total of 1093 publications were initially identified, 263 of which were included in the final synthesis after abstract and full-text screening performed independently by two researchers. Both a descriptive numerical summary and a thematic analysis were performed on the full-texts of all articles included in the synthesis. Our findings suggest that while big data trends in biomedicine hold the potential for advancing clinical research, improving prevention and optimizing healthcare delivery, yet several epistemic, scientific and normative challenges need careful consideration. These challenges have relevance for both the composition of ERCs and the evaluation criteria that should be employed by ERC members when assessing the methodological and ethical viability of health-related big data studies. Based on this analysis, we provide some preliminary recommendations on how ERCs could adaptively respond to those challenges. This exploration is designed to synthesize useful information for researchers, ERCs and relevant institutional bodies involved in the conduction and/or assessment of health-related big data research. PMID- 30308032 TI - Impact of the duration of the evidence-based medicine use in acute heart failure: A nationwide cohort study. AB - BACKGROUND: Several randomized control trials have established that drugs can decrease the heart failure (HF) rehospitalization in patients with HF. However, limited studies have investigated the duration of medicine use to decrease the rehospitalization period in the real world. Hence, this study aims to investigate whether the evidence-based medicine decreases the HF rehospitalization in different treatment intervals in the clinical practice. METHOD: We examined patients admitted with acute HF from the National Health Insurance Research Database in Taiwan. In addition, the major adverse cardiovascular events (MACE) were the composite endpoints of the in-hospital mortality and rehospitalization after 1 year. Furthermore, we analyzed the medicine use to decrease 14 days and 1, 6, and 12 months' HF rehospitalization. RESULTS: Overall, we examined 11,012 patients. The use of the renin-angiotensin system (RAS) blockers [hazard ratio (HR), 0.58; P < 0.01], beta-blocker (HR, 0.67; P < 0.01), spironolactone (HR, 0.63; P < 0.01), and digitalis (HR, 0.67; P < 0.01) associated with the lower in hospital mortality rate. The Cox regression analysis revealed that RAS blocker (HR, 0.86; P < 0.01) and beta-blocker (HR, 0.71; P < 0.01) were independent predictors for MACE. Although RAS blockers declined rehospitalization to 6 months, beta-blocker decreased the rehospitalization rate after 1 month use and the benefit persisted till 12 months. Furthermore, digitalis only lowered rehospitalization to 14 days. CONCLUSION: This study suggests that the use of evidence-based medicine is associated with lower MACE for patients with HF, and these drugs could play vital roles in different periods to decrease the rehospitalization in the clinical setting. PMID- 30308033 TI - Presence of lymphocytic infiltrate cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy. AB - Tumor-Infiltrating Lymphocytes (TILs) has been shown to be essential to predict disease outcome in several types of cancers. Moreover, the distribution of cytotoxic T lymphocytes (CD8+) and T cells in general (CD3+) have been used to establish an Immunoscore, as a new cancer prognosticator for survival in colon and lung cancer. In bladder cancer, immune activation has been shown to be associated with genomic subtypes of muscle invasive bladder cancer (MIBC). We sought to evaluate the prognostic impact of these immune cell types in MIBC patients treated with radical cystectomy. For this purpose, cystectomy sections (n = 67) with identifiable invasive margin were selected and stained for CD8+ and CD3+ tumour infiltrating lymphocytes (TILs); both tumor core (CT) and invasive margin (IM) were assessed. Immunoscore was calculated based on previously defined criteria and used to illustrate differences in survival. High density of CD8IM TILs was associated with better disease-free (DFS) (P = 0.01) and overall survival (OS) (P = 0.02) whereas CD3IM TILs were associated with better OS (P = 0.05). Immunoscore was associated with improved DFS (P = 0.02) and OS (P = 0.05). The expression of cytotoxic T cells (CD8+ T cells) in TCGA bladder cancer was also investigated from RNA-Seq profiles of 344 cases. T cell cytotoxicity associated genes (n = 113) were derived from MSig GSEA database. Luminal (n = 121) and basal (n = 68) samples were used to evaluate expression differences. Differential expression (P<0.05) of cytotoxic T cell genes was noted across different molecular subsets of bladder cancer within TCGA analysis. Our data suggests host immune system appears to play a valuable prognostic role in MIBC. PMID- 30308034 TI - Desiccation tolerance in Acinetobacter baumannii is mediated by the two-component response regulator BfmR. AB - For the opportunistic pathogen Acinetobacter baumannii, desiccation tolerance is thought to contribute significantly to the persistence of these bacteria in the healthcare environment. We investigated the ability of A. baumannii to survive rapid drying, and found that some strains exhibited a profoundly desiccation resistant phenotype, characterized by the ability of a large proportion of cells to survive on a dry surface for an extended period of time. However, this phenotype was only displayed during the stationary phase of growth. Most interestingly, we found that drying resistance could be lost after extended cultivation in liquid medium. Genome sequencing of isolates that became drying sensitive identified mutations in bfmR, which encodes a two-component response regulator that is important for A. baumannii virulence. Additionally, BfmR was necessary for the expression of stress-related proteins during stationary phase, and one of these, KatE, was important for long-term drying survival. These results suggested that BfmR may control stress responses, and we demonstrated that the DeltabfmR mutant was more sensitive to hydrogen peroxide, nutrient starvation, and increased osmolarity. We also found that cross-protection against drying could be stimulated by either starvation, which required BfmR, or increased osmolarity. These results imply that BfmR plays a role in controlling stress responses in A. baumannii which help protect cells during desiccation, and they provide a regulatory link between this organism's ability to persist in the environment and pathogenicity. PMID- 30308035 TI - Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells. AB - Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial-mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial-mesenchymal transition is an antitumor mechanism of metformin. PMID- 30308036 TI - ALDH1A1 expression is associated with poor differentiation, 'right-sidedness' and poor survival in human colorectal cancer. AB - BACKGROUND: Aldehyde dehydrogenase 1A1 (ALDH1A1) encodes an enzyme that oxidizes aldehydes to their corresponding carboxylic acids. In colorectal cancer ALDH1A1 marks cancer stem cells and plays putative roles in tumor progression and drug resistance. However, the potential value of ALDH1A1 as a diagnostic marker or target for therapy remains unclear. Here, we have analyzed ALDH1A1 mRNA and protein levels in relation to clinical, histopathological and molecular tumor features in large series of human colorectal cancer. METHODS: ALDH1A1 protein levels were determined by immunohistochemistry in a series of primary colorectal tumors and their corresponding liver metastases (n = 158). ALDH1A1 mRNA levels were analyzed in several large patient cohorts of colorectal cancer. ALDH1A1 mRNA and protein levels were then related to overall survival and to clinical, histopathological and molecular tumor features. RESULTS: High levels of ALDH1A1 were associated with a poorly differentiated histology and a right-sided tumor location, but not to a mesenchymal-like molecular subtype. Liver metastases contained significantly higher levels of ALDH1A1 compared to the corresponding primary tumors. Radio- and/or chemotherapy prior to tumor resection was associated with increased ALDH1A1 levels regardless of the molecular subtype. Finally, ALDH1A1 protein expression in primary tumors and metastases correlated with shorter overall survival. CONCLUSIONS: ALDH1A1 expression is associated with features of poor prognosis, including a poorly differentiated histology and 'right-sidedness' of the primary tumor, and with shorter overall survival. ALDH1A1 is also highly expressed in therapy-surviving tumors and in liver metastases. These results warrant further research into the potential value of targeting ALDH1A1 in order to improve the efficacy of standard treatment and thereby preventing tumor recurrence. PMID- 30308038 TI - Microbial community and functions associated with digestion of algal polysaccharides in the visceral tract of Haliotis discus hannai: Insights from metagenome and metatranscriptome analysis. AB - Haliotis discus hannai, a species of Pacific abalone, is a highly valuable food source throughout Northeast Asia. As H. discus hannai primarily feed on brown algae and largely extract their energy from algal polysaccharides, understanding the mechanisms by which they digest algal polysaccharides is essential for elucidating their energy metabolism. Gut microbes, as well as the host animal, are involved in the process of polysaccharide degradation. To identify algal polysaccharide-digestion mechanisms and their origin, we analyzed the metagenome and metatranscriptome of abalone visceral extracts. Microbial communities were characterized using the 16S rRNA gene sequences in the metagenome and our results differed significantly from those of previous studies using traditional microbiological methods such as bacterial cultivation and cloning. A greater diversity of bacterial taxa was identified here than was previously identified using cultivation methods. Furthermore, the most abundant bacterial taxa also differed from previous studies, which is not common when comparing the results of bacterial culturing with those of molecular methodologies. Based on the metatranscriptome, overall functions were identified and additional analyses were performed on the coding sequences of algal polysaccharide-digestive enzymes, including alginate lyase. Results of the transcriptomic analyses suggest that alginate lyase in the visceral extracts of H. discus hannai was produced by the host itself, not by visceral bacteria. This is the first next-generation sequencing study performed on abalone to characterize the visceral microbiota and the source of the ability to digest algal polysaccharides by analyzing the metagenome and metatranscriptome together. PMID- 30308037 TI - Effects of the nitric oxide releasing biomimetic nanomatrix gel on pulp-dentin regeneration: Pilot study. AB - Successful disinfection alongside complete endodontic tissue regeneration and revascularization are the most desired clinical outcomes of regenerative endodontics. Despite reported clinical successes, significant limitations to the current regenerative endodontic procedure (REP) have been elucidated. To improve the current REP, an antibiotics and nitric oxide (NO) releasing biomimetic nanomatrix gel was developed. The study evaluates antibacterial effects of an antibiotics and NO releasing biomimetic nanomatrix gel on multispecies endodontic bacteria. Antibiotics, ciprofloxacin (CF) and metronidazole (MN) were mixed and encapsulated within the NO releasing biomimetic nanomatrix gel. The gel was synthesized and self-assembled from peptide amphiphiles containing various functional groups. Antibacterial effects of the antibiotics and NO releasing biomimetic nanomatrix gel were evaluated using bacterial viability assays involving endodontic microorganisms including clinical samples. Pulp-dentin regeneration was evaluated via animal-model experiments. The antibiotics and NO releasing biomimetic nanomatrix gel demonstrated a concentration dependent antibacterial effect. In addition, NO alone demonstrated a concentration dependent antibacterial effect on endodontic microorganism. An in vivo analysis demonstrated the antibiotics and NO releasing biomimetic nanomatrix gel promoted tooth revascularization with maturation of root canals. An optimal concentration of and NO releasing nanomatrix gel is suggested for its potential as a root treatment material for REP and an appropriate protocol for human trials. Further investigation is required to obtain a larger sample size and decide upon ideal growth factor incorporation. PMID- 30308039 TI - Simplified inducible system for Trypanosoma brucei. AB - Nowadays, most reverse genetics approaches in Trypanosoma brucei, a protozoan parasite of medical and veterinary importance, rely on pre-established cell lines. Consequently, inducible experimentation is reduced to a few laboratory strains. Here we described a new transgene expression system based exclusively on endogenous transcription activities and a minimum set of regulatory components that can easily been adapted to different strains. The pTbFIX vectors are designed to contain the sequence of interest under the control of an inducible rRNA promoter along with a constitutive dicistronic unit encoding a nucleus targeted tetracycline repressor and puromycin resistance genes in a tandem "head to-tail" configuration. Upon doxycycline induction, the system supports regulatable GFP expression (170 to 400 fold) in both bloodstream and procyclic T. brucei forms. Furthermore we have adapted the pTbFIX plasmid to perform RNAi experimentation. Lethal phenotypes, including alpha-tubulin and those corresponding to the enolase and clathrin heavy chain genes, were successfully recapitulated in procyclic and bloodstream parasites thus showing the versatility of this new tool. PMID- 30308040 TI - Implementation of a novel continuous fetal Doppler (Moyo) improves quality of intrapartum fetal heart rate monitoring in a resource-limited tertiary hospital in Tanzania: An observational study. AB - BACKGROUND: Intrapartum Fetal Heart Rate (FHR) monitoring is crucial for the early detection of abnormal FHR, facilitating timely obstetric interventions and thus the potential reduction of adverse perinatal outcomes. We explored midwifery practices of intrapartum FHR monitoring pre and post implementation of a novel continuous automatic Doppler device (the Moyo). METHODOLOGY: A pre/post observational study among low-risk pregnancies at a tertiary hospital was conducted from March to December 2016. In the pre-implementation period, intermittent monitoring was conducted with a Pinard stethoscope (March to June 2016, n = 1640 women). In the post-implementation period, Moyo was used for continuous FHR monitoring (July-December 2016, n = 2442 women). The primary outcome was detection of abnormal FHR defined as absent, FHR<120or FHR>160bpm. The secondary outcomes were rates of assessment/documentation of FHR, obstetric time intervals and intrauterine resuscitations. Chi-square test, Fishers exact test, t-test and Mann-Whitney U test were used in bivariate analysis whereas binary and multinomial logistic regression were used for multivariate. RESULTS: Moyo use was associated with greater detection of abnormal FHR (8.0%) compared with Pinard (1.6%) (p<0.001). There were higher rates of non assessment/documentation of FHR pre- (45.7%) compared to post-implementation (2.2%) (p<0.001). At pre-implementation, 8% of deliveries had FHR documented as often as <= 60 minutes, compared to 51% post-implementation (p<0.001). Implementation of continuous FHR monitoring was associated with a shorter time interval from the last FHR assessment to delivery i.e. median (IQR) of 60 (30,100) to 45 (21,85) minutes (p<0.001); and shorter time interval between each FHR assessment i.e. from 150 (86,299) minutes to 60 (41,86) minutes (p<0.001). Caesarean section rates increased from 2.6 to 5.4%, and vacuum deliveries from 2.2 to 5.8% (both p<0.001). Perinatal outcomes i.e. fresh stillbirths and early neonatal deaths were similar between time periods. The study was limited by both lack of randomization and involvement of low-risk pregnant women with fewer adverse perinatal outcomes than would be expected in a high-risk population. CONCLUSION: Implementation of the Moyo device, which continuously measures FHR, was associated with improved quality in FHR monitoring practices and the detection of abnormal FHR. These improvements led to more frequent and timely obstetric responses. Follow-up studies in a high-risk population focused on a more targeted description of the FHR abnormalities and the impact of intrauterine resuscitation is a critical next step in determining the effect on reducing perinatal mortality. PMID- 30308041 TI - NKL homeobox gene activities in B-cell development and lymphomas. AB - Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naive B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation. PMID- 30308042 TI - Genome-wide association studies and meta-analysis uncovers new candidate genes for growth and carcass traits in pigs. AB - Genome-wide association studies (GWAS) have been widely used in the genetic dissection of complex traits. As more genomic data is being generated within different commercial or resource pig populations, the challenge which arises is how to collectively investigate the data with the purpose to increase sample size and implicitly the statistical power. This study performs an individual population GWAS, a joint population GWAS and a meta-analysis in three pig F2 populations. D1 is derived from European type breeds (Pietrain, Large White and Landrace), D2 is obtained from an Asian breed (Meishan) and Pietrain, and D3 stems from a European Wild Boar and Pietrain, which is the common founder breed. The traits investigated are average daily gain, backfat thickness, meat to fat ratio and carcass length. The joint and the meta-analysis did not identify additional genomic clusters besides the ones discovered via the individual population GWAS. However, the benefit was an increased mapping resolution which pinpointed to narrower clusters harboring causative variants. The joint analysis identified a higher number of clusters as compared to the meta-analysis; nevertheless, the significance levels and the number of significant variants in the meta-analysis were generally higher. Both types of analysis had similar outputs suggesting that the two strategies can complement each other and that the meta-analysis approach can be a valuable tool whenever access to raw datasets is limited. Overall, a total of 20 genomic clusters that predominantly overlapped at various extents, were identified on chromosomes 2, 7 and 17, many confirming previously identified quantitative trait loci. Several new candidate genes are being proposed and, among them, a strong candidate gene to be taken into account for subsequent analysis is BMP2 (bone morphogenetic protein 2). PMID- 30308044 TI - Correction: Bacterial diversity of bat guano from Cabalyorisa Cave, Mabini, Pangasinan, Philippines: A first report on the metagenome of Philippine bat guano. AB - [This corrects the article DOI: 10.1371/journal.pone.0200095.]. PMID- 30308043 TI - Preclinical cardiovascular changes in children with obesity: A real-time 3 dimensional speckle tracking imaging study. AB - The aims of this study were (1) to quantify changes in 3-dimensional (3D) strain in obese children using real-time 3D echocardiography (RT3DE) and 3D speckle tracking echocardiography (3DSTE), and (2) to investigate the utility of left ventricular (LV) strain variables in measuring early cardiovascular changes in children with obesity. A total of 181 obese children (study group) aged 4-18 years old were prospectively enrolled and compared with 229 healthy subjects (control group). We acquired demographic, clinical, biochemical, and 2D echocardiography/Doppler data. Also, RT3DE and 3DSTE were performed to measure LV volume, left ventricular ejection fraction (LVEF), LV mass (LVM), LV peak systolic global longitudinal strain (GLS), radial strain (GRS), circumferential strain (GCS), and global strain (GS). There were significant differences in anthropometric measurements, blood pressures, Cholesterol, C-reactive protein (CRP), Intima-media thickness (IMT), left atrium end-systolic dimension (LASD), interventricular septal end-diastolic dimension (IVSD), LV posterior wall end diastolic dimension (LVPWD), LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), LV end-diastolic volumes (LVEDV), and LV end-systolic volumes (LVESV), E and A velocities, E/A,e', e'/a', E/e', LVM, LV mass index (LVMI), GLS, GRS, GCS, and GS between the study and control groups. The receiver operating characteristic curves (ROC) for the statistically significant echocardiographic variables showed that the range of areas of ROC curves varied from 0.76 (GLS), 0.74 (GRS), 0.72 (LASD), to 0.58 (LVESD), respectively. In conclusion, LV 3D strain variables by RT3DE and 3DSTE decrease in obese children. LV 3D strain is more sensitive than other echocardiographic and vascular ultrasound variables in detecting cardiovascular changes in children with obesity. PMID- 30308046 TI - Retraction: Transcriptome and Multivariable Data Analysis of Corynebacterium glutamicum under Different Dissolved Oxygen Conditions in Bioreactors. PMID- 30308045 TI - Oral iron exacerbates colitis and influences the intestinal microbiome. AB - Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44 fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS. PMID- 30308047 TI - Prevalence of hypothyroidism in patients with hyponatremia: A retrospective cross sectional study. AB - OBJECTIVE: Hypothyroidism has been suggested to be an uncommon cause of hyponatremia. However, little is known about the prevalence of hypothyroidism in patients with different levels of hyponatremia. The objective of this study was to investigate the prevalence of hypothyroidism among patients with hyponatremia of varying severity while taking into consideration potential confounders associated with thyroid function. METHODS: All data on thyrotropin (TSH), free thyroxine (T4), and serum sodium (Na) levels were retrospectively collected from medical records at two Japanese tertiary hospitals. The main outcome measure was overt hypothyroidism, defined as TSH > 10.0 MUIU/mL and free T4 < 1.01 ng/dL. RESULTS: Of 71,817 patients, 964 patients (1.3%) had overt hypothyroidism. The prevalence of overt hypothyroidism in each category of hyponatremia (Na >=136, 130-135, and <=129 mEq/L) was 1.2% (787/65,051), 2.4% (124/5,254) and 3.5% (53/1,512), respectively. A significant increase in prevalence was observed as the severity of hyponatremia increased (P < 0.001 for trend). Multivariate logistic regression with adjustment for age, sex, kidney function, and serum albumin level showed that the odds ratios for overt hypothyroidism increased with increasing severity of hyponatremia when compared with Na >= 136 mEq/L (130-135 mEq/L: 1.43, 95% confidence interval [CI], 1.15 to 1.78, P = 0.001; <=129 mEq/L: 1.87, 95% CI, 1.32 to 2.63, P < 0.001; P< 0.001 for trend). CONCLUSION: The prevalence of overt hypothyroidism was significantly higher as the severity of hyponatremia progressed, even after adjusting for potential confounders. Hypothyroidism should be differentiated in patients with hyponatremia. PMID- 30308048 TI - Comparative analysis of different preservation techniques for the storage of Staphylococcus phages aimed for the industrial development of phage-based antimicrobial products. AB - Bacteriophages have been proven as effective antimicrobial agents in the treatment of infectious diseases and in other biocontrol applications including food preservation and disinfection. The extensive use of bacteriophages requires improved methodologies for medium- and long-term storage as well as for easy shipping. To this aim, we have determined the stability of four Staphylococcus phages (phiIPLA88, phiIPLA35, phiIPLA-RODI and phiIPLA-C1C) with antimicrobial potential at different temperatures (20 degrees C/25 degrees C, 4 degrees C, -20 degrees C, -80 degrees C, -196 degrees C) and during lyophilization (freeze drying) using several stabilizing additives (disaccharides, glycerol, sorbitol and skim milk). Differences between phages were observed at different temperatures (20 degrees C/25 degrees C, 4 degrees C and -20 degrees C), where phages were less stable. At lower temperatures (-80 degrees C and -196 degrees C), all phages showed good viability after 24 months regardless of the stabilizer. Differences between phages were also observed after lyophilization although the addition of skim milk yielded a dry powder with a stable titer after 24 months. As an alternative to facilitate storage and transportation, phage encapsulation has been also explored. Phage phiIPLA-RODI encapsulated in alginate capsules retained high viability when stored at 4 degrees C for 6 months and at 20 degrees C for 1 month. Moreover, the spray-dryer technique allowed obtaining dry powders containing viable encapsulated phages (phiIPLA-RODI and phiIPLA88) in both skim milk and trehalose for 12 months at 4 degrees C. Storage of phages at 20 degrees C was less effective; in fact, phiIPLA88 was stable for at least 12 months in trehalose but not in skim milk, while phiIPLA-RODI was stable only for 6 months in either stabilizer. These results suggest that encapsulated phages might be a suitable way for shipping phages. PMID- 30308049 TI - The TRKB rs2289656 genetic polymorphism is associated with acute suicide attempts in depressed patients: A transversal case control study. AB - INTRODUCTION: Suicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE) and are difficult to predict. Suicide is associated with the expression of Receptor Tyrosin-Kinase B (TRKB), the receptor of the Brain Derived Neurotrophic Factor (BDNF) involved in MDE. However, the impact of its genetic polymorphisms as predictive factors of SA should be clarified. Our main aim is to assess the association of 8 TRKB genetic polymorphisms and SA in depressed patients. MATERIAL AND METHODS: In 624 patients currently experiencing an MDE in the context of Major Depressive Disorder (MDD) (METADAP study), we assessed the association between 8 TRKB genetic polymorphisms (rs1778933, rs1187352, rs2289658, rs2289657, rs2289656, rs3824519, rs56142442 and rs1439050) and acute (previous month) or past (older than one month) SA. Bonferroni corrections and multivariate analysis adjusted for age, sex, level of education, marital status, Hamilton Depression Rating Scale score and previous MDE were used. RESULTS: The rs2289656 was associated with acute SA (CC = 28.5%, CT = 15.0% and TT = 11.5%, p = 0.0008). However, the other SNPs were not. Patients with the CC genotype had a higher rate of acute SA (28.5%) as compared to T carriers (14.6%) (adjusted OR = 2.2, CI95% [1.4; 3.5], p<0.0001). CONCLUSION: The TRKB rs2289656 CC genotype is associated with a 2.2 fold higher risk of acute SA in depressed patients. If this result could be confirmed, this TRKB SNP may be assessed to contribute to the prediction of SA in depressed patients. PMID- 30308050 TI - Does the severity or cause of preoperative stiffness affect the clinical results and range of motion after total knee arthroplasty? AB - The purpose of this study was to assess the overall clinical results and range of motion (ROM) after total knee arthroplasty (TKA) in patients with preoperative stiffness. We also aimed to determine whether the severity or cause of the stiffness can affect the clinical outcome after surgery. This retrospective study included 122 knees (117 patients) with follow-up of more than 2 years (mean age, 64.3 years). TKA was performed using posterior-stabilized, varus-valgus constrained (VVC), and hinged prostheses. To determine the effect of the severity of stiffness on the clinical outcome, the subjects were divided into two groups: the severe group (preoperative ROM <= 50 degrees ; 18 knees) and the moderate group (preoperative ROM, 50 degrees -90 degrees ; 104 knees). Then, clinical results and ROM were compared according to the severity or cause of preoperative stiffness. After surgery, preoperative ROM (mean, 78 degrees ; range, 25 degrees 90 degrees ) was improved (mean, 107 degrees ; range, 70 degrees - 130 degrees ). The severe group more frequently used the VVC or hinged prostheses (72% vs. 18%). Furthermore, the severe group had worse knee and function scores as well as more complications (33% vs. 13%), even though the severe group had a greater ROM increment (47 degrees vs. 27 degrees ) after surgery. Patients with osteoarthritis and rheumatoid arthritis showed better ROM and clinical results compared to patients with infectious or traumatic arthritis. Although TKA in stiff knees can be successful, the results are inferior in knees with severe stiffness and knees with infectious or traumatic arthritis. PMID- 30308052 TI - Impact of chemical and physical treatments on the mechanical properties of poly(epsilon-caprolactone) fibers bundles for the anterior cruciate ligament reconstruction. AB - The anterior cruciate ligament rupture is one of the most common sport injuries. Due to ligaments' poor healing capacity, surgical intervention is often required. Nowadays, these injuries are managed using replacement autografts or to a lesser extent using artificial ligaments. With the expansion of tissue engineering, more recent researches focus on the development of biodegradable structures that could allow graft functioning while enhancing host integration. The main challenge is to develop a structure that gradually loses its mechanical properties when at the same time the neo-ligament gains in solidity. Mechanical behavior and reconstruction of natural tissue are the two key points for such a successful device. This article evaluates the mechanical consistency of poly(epsilon caprolactone) fibers bundles grafted with sodium polystyrene sulfonate, as a candidate for ligament prosthesis. In order to be medically used, PCL fibers need to cope with multiple steps before implantation including extensive washings, knitting, grafting and sterilization processes. The evolution of mechanical properties at each step of the elaboration process has been investigated. The results show that PCL bundles have the same visco-elastic behavior than the native ACL. Nevertheless, when undergoing physical treatments such as ionizing radiations, like UV or beta-rays, the material endures a hardening, increasing its stiffness but also its fragility. At this opposite, the thermal radical grafting acts like an annealing step, increasing significantly the elasticity of the PCL fibers. With this chemical treatment, the stiffness is decreasing, leading to higher energy dissipation. Added to the observation of the structure of the material, this demonstrates the possibility of the PCL to modulate it microstructure. In case of orthopedic prosthesis, the need of such a construct is strongly required to avoid distension of the future prosthesis and to restore good knee stabilization, showing the promising future of PCL ligament prosthesis. PMID- 30308051 TI - Phosphatidylcholine and phosphatidylethanolamine plasmalogens in lipid loaded human macrophages. AB - BACKGROUND: Plasmalogens are either phosphatidylcholine (PC P) or phosphatidylethanolamine (PE P) glycerophospholipids containing a vinyl ether moiety in sn-1-position and an esterified fatty acid in sn-2 position. Multiple functions have been proposed, including reservoir of precursors for inflammatory mediators, modulation of membrane fluidity, and anti-oxidative properties. They could therefore play a role under conditions of metabolic stress. Especially enzymatically modified LDL (eLDL) and oxidatively modified LDL (oxLDL) represent modifications of LDL that are taken up by macrophages in atherosclerotic plaques. The aim of this study was to analyze plasmalogen related effects of eLDL and oxLDL in human monocyte derived macrophages, as well as the effects of HDL3 mediated deloading. METHODS: Elutriated monocytes from nine healthy donors were differentiated in vitro for four days. Macrophages were then loaded with native LDL, eLDL and oxLDL for 24h and subsequently deloaded with HDL3 for another 24h. Lipidomic and transcriptomic profiles were obtained. RESULTS: Loading of macrophages with eLDL and oxLDL led to a transient but strong elevation of lysophosphatidylcholine (LPC) most likely through direct uptake. Only eLDL induced increased levels of total PC, presumably through an induction of PC synthesis. On the other hand treatment with oxLDL led to a significant increase in PC P. Analysis of individual lipid species showed lipoprotein and saturation specific effects for LPC, PC P and PE P species. Membrane fluidity was decreased by the large amount of FC contained in the lipoproteins, as indicated by a lower PC to FC ratio after lipoprotein loading. In contrast the observed changes in the saturated to mono-unsaturated fatty acid (SFA to MUFA) and saturated to poly unsaturated fatty acid (SFA to PUFA) ratios in PE P could represent a cellular reaction to counteract this effect by producing more fluid membranes. Transcriptomic analysis showed considerable differences between eLDL and oxLDL treated macrophages. As a common feature of both lipoproteins we detected a strong downregulation of pathways for endogenous lipid synthesis as well as for exogenous lipid uptake. Deloading with HDL3 had only minor effects on total lipid class as well as on individual lipid species levels, most of the time not reaching significance. Interestingly treatment with HDL3 had no effect on membrane fluidity under these conditions, although incubation with HDL3 was partially able to counteract the oxLDL induced transcriptomic effects. To investigate the functional effect of lipoprotein treatment on macrophage polarization we performed surface marker flow cytometry. Under our experimental conditions oxLDL was able to partially shift the surface marker pattern towards a pro-inflammatory M1-like phenotype. This is consistent with the consumption of arachidonic acid containing PE P species in oxLDL treated cells, presumably for the synthesis of inflammatory mediators. SUMMARY: Our findings provide novel data on the lipoprotein induced, lipidomic and transcriptomic changes in macrophages. This can help us better understand the development of metabolic, inflammatory diseases as well as improve our background knowledge on lipid biomarkers in serum. PMID- 30308054 TI - Optimizing shelf life conditions for anthocyanin-rich tomatoes. AB - Shelf life is the time a product can be stored without losing its qualitative characteristics. It represents one of the most critical quality traits for food products, particularly for fleshy fruits, including tomatoes. Tomatoes' shelf life is usually shortened due to fast over-ripening caused by several different factors, among which changes in temperature, respiration and pathogen exposure. Although tomatoes usually do not contain anthocyanins, varieties enriched in these antioxidant compounds have been recently developed. The anthocyanin-rich tomatoes have been shown to possess a significantly extended shelf life by delayed over-ripening and reduction of the susceptibility to certain pathogens. In the present work, we compared different conditions of postharvest storage of anthocyanin-rich tomato fruits with the aim to understand if the added value represented by the presence of the anthocyanins in the fruit peel can be affected in postharvest. For this purpose we used an anthocyanin-enriched tomato line derived from conventional breeding and took into consideration different light and temperature conditions, known to affect fruit physiology during postharvest as well as anthocyanin production. Several quality traits related to the fruit ripening were measured, including anthocyanin and carotenoid content, pH, titratable acidity and total soluble solids. In this way we identified that the most suitable fruit storage and postharvest anthocyanin accumulation were obtained through exposure to cool temperature (12 degrees C), particularly in the presence of light. Under these parameters, tomato fruits showed increased anthocyanin content and unchanged flavour-related features up to three weeks after harvesting. PMID- 30308053 TI - Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy. AB - AIMS: Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs. METHODS: Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy. RESULT: Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011-1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations. CONCLUSION: High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy. PMID- 30308055 TI - Identification of genes which regulate stroma-dependent in vitro hematopoiesis. AB - Cultured splenic stroma has been shown to support in vitro hematopoiesis in overlaid bone marrow and spleen progenitors. These co-cultures support longterm production of a novel dendritic-like cell type along with transient production of myeloid cells. They also maintain a progenitor cell population. The splenic stromal lines 5G3 and 3B5 have been identified as a supporter and a non-supporter of hematopoiesis. Based on their gene expression profile, both 5G3 and 3B5 express genes related to hematopoiesis, while 5G3 cells express several unique genes, and show upregulation of some genes over 3B5. Based on gene expression studies, specific inhibitors were tested for capacity to inhibit hematopoiesis in co-cultures. Addition of specific antibodies and small molecule inhibitors identified VCAM1, CXCL12, CSF1 and SPP1 as potential regulators of hematopoiesis, although both are expressed by 5G3 and 3B5. Through inhibition of function, SVEP1 and ALDH1 are also shown here to be deterministic of 5G3 hematopoietic support capacity, since these are uniquely expressed by 5G3 and not 3B5. The achievement of inhibition is notable given the dynamic, longterm nature of co-cultures which involve only small numbers of cells. The alternate plan, to add recombinant soluble factors produced by 5G3 back into 3B5 co-cultures in order to recover in vitro hematopoiesis, proved ineffective. Out of 6 different factors added to 3B5, only IGF2 showed any effect on cell production. The identification of differentially expressed or upregulated genes in 5G3 has provided an insight into potential pathways involved in in vitro hematopoiesis leading to production of dendritic-like cells. PMID- 30308056 TI - Comparative study on the modulation of incretin and insulin homeostasis by butyrate in chicken and rabbit. AB - The pancreatic secretion of insulin, a key endocrine regulator of metabolism and growth, can be greatly influenced by the gut-derived incretin hormones, namely by GIP (Glucose-dependent Insulinotropic Peptide) and GLP-1 (Glucagon-like Peptide 1). As insulin is a major stimulator of growth, affecting its producion may be of special importance in food-producing livestock. The aim of the present study was to investigate novel ways of modulating incretin and insulin homeostasis in chickens and rabbits by nutrition, e.g. by oral butyrate application, also studying the mechanisms of incretin action in both species as a comparative approach. Acute oral butyrate challenge significantly decreased plasma GIP levels by approx. 40% in both species: significant interactions of butyrate exposure and incubation time were found in both chickens (P = 0.038 and P = 0.034 at 30 and 60 min following butyrate ingestion [1.25 g/kg BW], respectively) and rabbits (P = 0.036 and P = 0.039 at 30 and 60 min after butyrate ingestion [0.25 g/kg BW], respectively), while plasma GLP-1, insulin and glucose concentrations remained unaffected by butyrate in both species over time. These results are in contrast to butyrate's stimulating effect on both incretin and insulin secretion in mice, indicating specific, species-dependent differences even among mammalian species. Further, based on the analyzed correlations between the measured endocrine parameters (regardless of the butyrate exposure), it can be assumed that incretins may regulate pancreatic insulin release in rabbits on a partly different way compared to mice, humans and chickens. PMID- 30308057 TI - Serum periostin as a biomarker in eosinophilic granulomatosis with polyangiitis. AB - OBJECTIVE: Identification of a biomarker for disease activity in eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) remains an unmet need. This study examined the value of serum periostin, a marker of type 2 inflammation, as a measure of disease activity in patients with EGPA. METHODS: Participants enrolled in a multicenter, prospective cohort of patients with EGPA were included in this study if they had disease activity (defined as Birmingham Vasculitis Activity Score [BVAS] > 0) during follow-up. Serum levels of periostin were measured at flare visit as well as two pre- and two post-flare visits, if available. The outcome of disease activity was assessed either with BVAS or Physician Global Assessment (PGA). Mixed-effect models were used to examine the association between periostin levels and disease activity. Comparisons were made with a historical cohort of healthy individuals and patients with asthma. RESULTS: In the 49 patients included in the study, the median periostin level was 60 ng/ml (IQR 50 to 73) in all visits and did not significantly change across visits. Multivariate analyses found no association between periostin level and presence or absence of flare according to the BVAS (adjusted OR 1.00 [95% CI 0.98 to 1.02], p = 0.98) but an increase in periostin level was significantly associated with greater disease severity during a flare according to the PGA (adjusted beta-coefficient 0.02 [95% CI 0.004 to 0.03], p = 0.01). Periostin levels in EGPA were significantly higher than previously studied healthy controls and patients with asthma. CONCLUSION: In EGPA serum periostin level is modestly associated with greater disease severity during a flare but does not discriminate active from inactive disease. Periostin levels in EGPA are higher than in other previously studied cohorts, including healthy populations and patients with asthma, and are relatively stable over time. PMID- 30308058 TI - Ultrastructure of antennal sensilla of three fruit borers (Lepidoptera: Crambidae or Tortricidae). AB - Three fruit borers Conogethes punctiferalis (Guenee) (Crambidae), Grapholita molesta Busck (Tortricidae), and Spilonota albicana Motschulsky (Tortricidae) are serious pests of fruit trees. In this study, their antennal morphology, types of sensilla, and distributions were observed by using SEM (Scanning Electron Microscope). Nine types of sensilla were found on the antennae of C. punctiferalis, while eight types of sensilla were presented on each of G. molesta and S. albicana. The sensilla trichodea with two subtypes were the most abundant sensilla among three fruit borers. Two subtypes of sensillum coeloconica (type I with spines and type II without spines) were observed on the antennae of C. punctiferalis and G. molesta. However, sensilla coeloconica (type I) were only found in S. albicana. Although the sensilla campaniformia were only found on the antennae of C. punctiferalis, our observations confirm sensilla campaniformia presence in the moths. In addition, the functions of these sensilla were discussed based on previously reported lepidopteran insects. As a result, our study may provide useful information for advanced electrophysiological and behavioral experiments to better understand the mechanisms related to pests control. PMID- 30308059 TI - Slip of fluid molecules on solid surfaces by surface diffusion. AB - The mechanism of fluid slip on a solid surface has been linked to surface diffusion, by which mobile adsorbed fluid molecules perform hops between adsorption sites. However, slip velocity arising from this surface hopping mechanism has been estimated to be significantly lower than that observed experimentally. In this paper, we propose a re-adsorption mechanism for fluid slip. Slip velocity predictions via this mechanism show the improved agreement with experimental measurements. PMID- 30308060 TI - Anemia and associated factors among adolescent girls living in Aw-Barre refugee camp, Somali regional state, Southeast Ethiopia. AB - BACKGROUND: Adolescent girls have a higher risk of anemia due to an increased requirement, low intake of hematopoietic nutrients and low intake of a nutrient that enhance absorption of these hematopoietic nutrients. Adolescent girls living in refugee camps are more vulnerable to anemia. The study aimed to determine the prevalence of anemia and associated factors among adolescent girls aged 10-19 years in Aw-Barre refugee camp, Somalia regional state, Southeast Ethiopia. METHODS: A cross-sectional study design was employed. Study participants were recruited using a simple random sampling technique. A structured questionnaire was used to collect the data. Hemoglobin level was tested using HemoCueHb 301 from 10MUl finger prick blood samples. Adolescents with a hemoglobin level of <12.5gm/dl after altitude adjustment were classified as anemic. Data were entered using Epi Info version 7.0 and analyzed using SPSS version 20.0. Binary logistic regression was used to explore the association of independent variables with anemia. Variables having P-value <= 0.05 was considered to be statistically significant. RESULTS: Four hundred thirty-seven adolescent girls participated in the study with a response rate of 95.83%. The prevalence of anemia was 22% (95% CI (17.6, 26.1)). Late adolescents were 2 times more likely to have anemia as compared to early adolescents (AOR: 1.95, 95% CI (1.09, 3.47). Those who stayed >=8 years in the camp were 3 times more likely to develop anemia (AOR: 2.92, 95% CI (1.14, 7.50)). Those who ate heme iron food sources less than one time per month were 11 times more likely to develop anemia compared to those who ate more than twice within a week (AOR: 11.42, 95% CI (3.42, 38.18)). CONCLUSIONS: The prevalence of anemia among adolescent girls was a moderate public health problem. Education and awareness on adolescent nutrition with special attention of late adolescents and duration in the refugee camps is warranted. Moreover, promoting the intake of foods rich in heme iron is suggested. PMID- 30308061 TI - Correction: Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006902.]. PMID- 30308063 TI - Activation of adiponectin receptors has negative impact on muscle mass in C2C12 myotubes and fast-type mouse skeletal muscle. AB - This study investigated the effects of AdipoRon, which is an agonist for adiponectin receptor 1 (AdipoR1) and AdipoR2, on the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells and skeletal muscle mass in C57BL/6J mice. AdipoRon suppressed the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells of C2C12 myotubes in a dose dependent manner. Adiponectin-associated decline of protein content, diameter, and number of nuclei per myotube in C2C12 myotubes was partially rescued by knockdown of AdipoR1 and/or AdipoR2. Phosphorylation level of AMPK showed a trend to be increased by AdipoRon. A significant increase in phosphorylation level of AMPK was observed at 20 MUM AdipoRon. Knockdown of AdipoR1 and/or AdipoR2 rescued AdipoRon-associated decrease in protein content of C2C12 myotubes. AdipoRon associated increase in phosphorylation level of AMPK in C2C12 myotubes was suppressed by knockdown of AdipoR1 and/or AdipoR2. Successive intravenous injections of AdipoRon into mice caused a decrease in the wet weight of plantaris muscle (PLA), but not in soleus muscle (SOL). Mean fiber cross-sectional area of PLA, but not of SOL, was significantly decreased by AdipoRon administration. On the one hand, the expression level of phosphorylated AMPK and ubiquitinated protein in SOL and PLA muscles was upregulated by AdipoRon administration. On the other hand, AdipoRon administration induced no changes in the expression level of puromycin-labeled proteins in both SOL and PLA muscles. Expression level of adiponectin in extensor digitorum longus (EDL) muscle was increased by aging, but not in SOL muscle. Aging had no effect on the expression level of AdipoR1 and AdipoR2 in both muscles. Phosphorylation level of AMPK in EDL was increased by aging, but not SOL muscle. Results from this study suggest that high level of circulating adiponectin may induce skeletal muscle atrophy, especially fast-type muscle. PMID- 30308062 TI - Function of BriC peptide in the pneumococcal competence and virulence portfolio. AB - Streptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that causes otitis media, sinusitis, pneumonia, meningitis and sepsis. The progression to this pathogenic lifestyle is preceded by asymptomatic colonization of the nasopharynx. This colonization is associated with biofilm formation; the competence pathway influences the structure and stability of biofilms. However, the molecules that link the competence pathway to biofilm formation are unknown. Here, we describe a new competence-induced gene, called briC, and demonstrate that its product promotes biofilm development and stimulates colonization in a murine model. We show that expression of briC is induced by the master regulator of competence, ComE. Whereas briC does not substantially influence early biofilm development on abiotic surfaces, it significantly impacts later stages of biofilm development. Specifically, briC expression leads to increases in biofilm biomass and thickness at 72h. Consistent with the role of biofilms in colonization, briC promotes nasopharyngeal colonization in the murine model. The function of BriC appears to be conserved across pneumococci, as comparative genomics reveal that briC is widespread across isolates. Surprisingly, many isolates, including strains from clinically important PMEN1 and PMEN14 lineages, which are widely associated with colonization, encode a long briC promoter. This long form captures an instance of genomic plasticity and functions as a competence independent expression enhancer that may serve as a precocious point of entry into this otherwise competence-regulated pathway. Moreover, overexpression of briC by the long promoter fully rescues the comE-deletion induced biofilm defect in vitro, and partially in vivo. These findings indicate that BriC may bypass the influence of competence in biofilm development and that such a pathway may be active in a subset of pneumococcal lineages. In conclusion, BriC is a part of the complex molecular network that connects signaling of the competence pathway to biofilm development and colonization. PMID- 30308064 TI - Human and entomologic investigations of chikungunya outbreak in Mandera, Northeastern Kenya, 2016. AB - Chikungunya is a reemerging vector borne pathogen associated with severe morbidity in affected populations. Lamu, along the Kenyan coast was affected by a major chikungunya outbreak in 2004. Twelve years later, we report on entomologic investigations and laboratory confirmed chikungunya cases in northeastern Kenya. Patient blood samples were received at the Kenya Medical Research Institute (KEMRI) viral hemorrhagic fever laboratory and the immunoglobulin M enzyme linked immunosorbent assay (IgM ELISA) was used to test for the presence of IgM antibodies against chikungunya and dengue. Reverse transcription polymerase chain reaction (RT-PCR) utilizing flavivirus, alphavirus and chikungunya specific primers were used to detect acute infections and representative PCR positive samples sequenced to confirm the circulating strain. Immature mosquitoes were collected from water-holding containers indoors and outdoors in the affected areas in northeastern Kenya. A total of 189 human samples were tested; 126 from Kenya and 63 from Somalia. 52.9% (100/189) tested positive for Chikungunya virus (CHIKV) by either IgM ELISA or RT-PCR. Sequence analysis of selected samples revealed that the virus was closely related to that from China (2010). 29% (55/189) of the samples, almost all from northeastern Kenya or with a history of travel to northern Kenya, tested positive for dengue IgM antibodies. Entomologic risk assessment revealed high house, container and Breteau indices of, 14.5, 41.9 and 17.1% respectively. Underground water storage tanks were the most abundant, 30.1%, of which 77.4% were infested with Aedes aegypti mosquitoes. These findings confirm the presence of active chikungunya infections in the northeastern parts of Kenya. The detection of dengue IgM antibodies concurrently with chikungunya virus circulation emphasizes on the need for improved surveillance systems and diagnostic algorithms with the capacity to capture multiple causes of arbovirus infections as these two viruses share common vectors and eco-systems. In addition sustained entomological surveillance and vector control programs targeting most productive containers are needed to monitor changes in vector densities, for early detection of the viruses and initiate vector control efforts to prevent possible outbreaks. PMID- 30308065 TI - Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass. AB - Cardiopulmonary bypass (CPB) with moderate hypothermic cardiac arrest (MHCA) is essential for prolonged complex procedures in cardiac surgery and is associated with postoperative complications. Although cytokine release provoked through MHCA under CPB plays a pivotal role in postoperative organ damage, the pathomechanisms are unclear. Here, we investigated the cytokine release pattern and histological organ damage after MHCA using a recently described mouse CPB model. Eight BALB/c mice underwent 60 minutes of circulatory arrest under CPB, were successively rewarmed and reperfused. Blood cytokine concentrations and liver and kidney function parameters were measured and histological changes to these organs were compared to control animals. Our results showed a marked increase in proinflammatory cytokines and histological changes in the kidney, lung, and liver after CPB. Furthermore, clinical chemistry showed signs of hemolysis and acute kidney injury. These results suggest early onset of solid organ injury which correlates with increased leukocyte infiltration. A better understanding of the interplay between pro-inflammatory cytokine activation and solid organ injury in this model of CBP with MHCA will inform strategies to reduce organ damage during cardiac surgeries in the clinic. PMID- 30308066 TI - Escherichia coli mediated resistance of Entamoeba histolytica to oxidative stress is triggered by oxaloacetate. AB - Amebiasis, a global intestinal parasitic disease, is due to Entamoeba histolytica. This parasite, which feeds on bacteria in the large intestine of its human host, can trigger a strong inflammatory response upon invasion of the colonic mucosa. Whereas information about the mechanisms which are used by the parasite to cope with oxidative and nitrosative stresses during infection is available, knowledge about the contribution of bacteria to these mechanisms is lacking. In a recent study, we demonstrated that enteropathogenic Escherichia coli O55 protects E. histolytica against oxidative stress. Resin-assisted capture (RAC) of oxidized (OX) proteins coupled to mass spectrometry (OX-RAC) was used to investigate the oxidation status of cysteine residues in proteins present in E. histolytica trophozoites incubated with live or heat-killed E. coli O55 and then exposed to H2O2-mediated oxidative stress. We found that the redox proteome of E. histolytica exposed to heat-killed E. coli O55 is enriched with proteins involved in redox homeostasis, lipid metabolism, small molecule metabolism, carbohydrate derivative metabolism, and organonitrogen compound biosynthesis. In contrast, we found that proteins associated with redox homeostasis were the only OX-proteins that were enriched in E. histolytica trophozoites which were incubated with live E. coli O55. These data indicate that E. coli has a profound impact on the redox proteome of E. histolytica. Unexpectedly, some E. coli proteins were also co identified with E. histolytica proteins by OX-RAC. We demonstrated that one of these proteins, E. coli malate dehydrogenase (EcMDH) and its product, oxaloacetate, are key elements of E. coli-mediated resistance of E. histolytica to oxidative stress and that oxaloacetate helps the parasite survive in the large intestine. We also provide evidence that the protective effect of oxaloacetate against oxidative stress extends to Caenorhabditis elegans. PMID- 30308068 TI - CD8+ lymphocyte control of SIV infection during antiretroviral therapy. AB - CD8+ lymphocytes play an important role in suppressing in vivo viral replication in HIV infection. However, both the extent to which and the mechanisms by which CD8+ lymphocytes contribute to viral control are not completely understood. A recent experiment depleted CD8+ lymphocytes in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) on antiretroviral treatment (ART) to study the role of CD8+ lymphocytes. CD8+ lymphocytes depletion resulted in temporary plasma viremia in all studied RMs. Viral control was restored when CD8+ lymphocytes repopulated. We developed a viral dynamic model to fit the viral load (VL) data from the CD8 depletion experiment. We explicitly modeled the dynamics of the latent reservoir and the SIV-specific effector cell population including their exhaustion and their potential cytolytic and noncytolytic functions. We found that the latent reservoir significantly contributes to the size of the peak VL after CD8 depletion, while drug efficacy plays a lesser role. Our model suggests that the overall CD8+ lymphocyte cytolytic killing rate is dynamically changing depending on the levels of antigen-induced effector cell activation and exhaustion. Based on estimated parameters, our model suggests that before ART or without ART the overall CD8 cytolytic killing rate is small due to exhaustion. However, after the start of ART, the overall CD8 cytolytic killing rate increases due to an expansion of SIV-specific CD8 effector cells. Further, we estimate that the cytolytic killing rate can be significantly larger than the cytopathic death rate in some animals during the second phase of ART-induced viral decay. Lastly, our model provides a new explanation for the puzzling findings by Klatt et al. and Wong et al. that CD8 depletion done immediately before ART has no noticeable effect on the first phase viral decay slope seen after ART initiation Overall, by incorporating effector cells and their exhaustion, our model can explain the effects of CD8 depletion on VL during ART, reveals a detailed dynamic role of CD8+ lymphocytes in controlling viral infection, and provides a unified explanation for CD8 depletion experimental data. PMID- 30308067 TI - Incidence, causes, and consequences of preventable adverse drug reactions occurring in inpatients: A systematic review of systematic reviews. AB - BACKGROUND: Preventable adverse drug reactions (PADRs) in inpatients are associated with harm, including increased length of stay and potential loss of life, and result in elevated costs of care. We conducted an overview of reviews (i.e., a systematic review of systematic reviews) to determine the incidence of PADRs experienced by inpatients. Secondary review objectives were related to assessment of the effects of patient age, setting, and clinical specialty on PADR incidence. METHODS: The protocol was registered in PROSPERO (CRD42016043220). We performed a search of Medline, Embase, and the Cochrane Library, limiting languages of publication to English and French. We included published systematic reviews that reported quantitative data on the incidence of PADRs in patients receiving acute or ambulatory care in a hospital setting. The full texts of all primary studies for which PADR data were reported in the included reviews were obtained and data relevant to review objectives were extracted. Quality of the included reviews was assessed using the AMSTAR-2 tool. Both narrative summaries of findings and meta-analyses of primary study data were undertaken. RESULTS: Thirteen systematic reviews encompassing 37 unique primary studies were included. Across primary studies, the PADR incidence was highly varied, ranging from 0.006 to 13.3 PADRs per 100 patients, with a pooled incidence estimate of 0.59 PADRs per 100 patients. Substantial heterogeneity was present across both reviews and primary studies with respect to review/study objectives, patient age, hospital setting, medical discipline, definitions and assessment tools used, event detection methods, endpoints of interest, and units of measure. Thirteen primary studies used prospective event detection methods and had a pooled PADR incidence of 3.13 (2.87-3.38) PADRs per 100 patients; however, extreme statistical heterogeneity (I2 = 97%) indicated this finding should be considered with caution. Subgroup meta-analyses demonstrated that PADR incidence varied significantly with event detection method (prospective > retrospective > voluntary reporting methods), hospital setting (ICU > wards), and medical discipline (medical > surgical). High statistical heterogeneity (I2 > 80%) was present across all analyses, indicating results should be interpreted with caution. Effects of patient age could not be assessed due to poor reporting of age groups used in primary studies. DISCUSSION: The method of event detection appeared to significantly influence PADR incidence, with prospective methods having the highest reported PADR rate. This finding is in agreement with the background literature. High methodological and statistical heterogeneity across primary studies evaluating adverse drug events reduces the validity of the overall PADR incidence derived from the meta-analyses of the pooled data. Data pooled from studies using only prospective methods of event detection should provide an overall estimate closest to the true PADR incidence; however, our estimate should be considered with caution due to the statistical heterogeneity found in this group of studies. Future studies should employ prospective methods of detection. This review demonstrates that the true overall incidence of PADRs is likely much greater than the overall pooled incidence estimate of 0.59 PADRs per 100 patients obtained when event detection method was not taken into consideration. PMID- 30308070 TI - Association of dysfunctional breathing with health-related quality of life: A cross-sectional study in a young population. AB - Symptomatic hyperventilation (SH) is a pathological condition that manifests with breathlessness, dyspnea, light-headedness, anxiety, and paresthesia. However, little is known about the prevalence of SH and its association with health related quality of life (HRQoL) in a young population. The Nijmegen questionnaire (NQ), which measures severity of SH, had not previously been cross-culturally translated into Korean. In this study, the NQ was cross-culturally translated into Korean (KNQ), using translation and back-translation methods. To examine the reliability and validity levels of the KNQ, as well as its association with HRQoL, 237 college students (21.38 +/- 2.45 years) were asked to complete the KNQ, the Korean version of the general health questionnaire (K-GHQ-30) and the short form-36 (K-SF-36). The KNQ showed satisfactory reliability (Cronbach's alpha = 0.878). In the construct validity test, four factors (neuropsychological, respiratory, neurogastrointestinal, and neuromuscular) were extracted (% of total variance = 59.8). Using a KNQ cut-off score of 23 points, the prevalence of SH was 22.8%. Physical and mental HRQoL levels estimated by the K-GHQ-30 score and the 8 subscale scores of the K-SF-36 were lower in the SH group than in those of the non-SH group. It is concluded that the cross-culturally translated KNQ is reliable and valid, and management of SH may prevent a reduction in physical and mental HRQoL in a young population. PMID- 30308069 TI - Region-specific susceptibility change in cognitively impaired patients with diabetes mellitus. AB - Emerging evidence suggests that diabetes mellitus (DM) is associated with iron and calcium metabolism. However, few studies have investigated the presence of DM in cognitively impaired patients and its effect on brain iron and calcium accumulation. Therefore, we assessed the effects of DM on cognitively impaired patients using quantitative susceptibility mapping (QSM). From June 2012 to Feb 2014, 92 eligible cognitively impaired patients underwent 3T magnetic resonance imaging (MRI). There were 46 patients with DM (DM+) and 46 aged matched patients without DM (DM-). QSM was obtained from gradient echo data and analyzed by drawing regions of interest around relevant anatomical structures. Clinical factors and vascular pathology were also evaluated. Measurement differences between DM+ and DM- patients were assessed by t tests. A multiple regression analysis was performed to identify independent predictors of magnetic susceptibility. DM+ patients showed lower susceptibility values, indicative of lower brain iron content, than DM- patients, which was significant in the hippocampus (4.80 +/- 8.31 ppb versus 0.22 +/- 10.60 ppb, p = 0.024) and pulvinar of the thalamus (36.30 +/- 19.88 ppb versus 45.90 +/- 20.02 ppb, p = 0.023). On multiple regression analysis, microbleed number was a predictor of susceptibility change in the hippocampus (F = 4.291, beta = 0.236, p = 0.042) and DM was a predictor of susceptibility change in the pulvinar of the thalamus (F = 4.900, beta = - 0.251, p = 0.030). In cognitively impaired patients, presence of DM was associated with lower susceptibility change in the pulvinar of the thalamus and hippocampus. This suggests that there may be region-specific alterations of calcium deposition in cognitively impaired subjects with DM. PMID- 30308072 TI - Rapid antibiotic susceptibility testing on blood cultures using MALDI-TOF MS. AB - Antibiotic resistance is a major public health problem requiring the early optimization of antibiotic prescriptions. Matrix-Assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS) has been shown to accurately identify bacteria from positive blood culture. Here, we developed a rapid detection of Escherichia coli resistance to amoxicillin (AMX) and cefotaxime (CTX) from positive blood culture based on MALDI-TOF MS. Potential sparing of broad-spectrum antibiotics was also evaluated. We tested 103 E. coli positive blood cultures. Blood cultures were subculture 1-hour in antibiotic-free rich liquid media before further incubation with and without AMX for 2.5 h or CTX for 2 h. Protein extracts associated with an internal control were spotted on a MALDI-TOF target and spectra were analyzed with the MBT-ASTRA prototype software (Bruker Daltonik GmbH, Bremen, Germany). Bacterial growth ratio was calculated from the AUC spectra obtained in the presence and absence of the antibiotic and compared to a threshold which classified E. coli as susceptible or resistant. Results were interpreted with MICs determined using agar dilution method as reference technique. MBT-ASTRA recognized 95% and 84% of the AMX- and CTX susceptible isolates, respectively. Overall, quantitative analysis of mass spectra allows susceptibility testing within 4 hours after the positivity of blood culture with E. coli. At the first report of positive blood culture, MALDI TOF MS would then provide the prescribers with the bacterial identification and the susceptibility to AMX and CTX, thus limiting the use of broad-spectrum compounds. PMID- 30308071 TI - Case conferences for infective endocarditis: A quality improvement initiative. AB - BACKGROUND: A multidisciplinary approach has been recommended for the management of patients with infective endocarditis. We evaluated the impact of multidisciplinary case conferences on morbidity, mortality, and quality of care for these patients. METHODS: We conducted a quasi-experimental study of consecutive patients admitted for infective endocarditis before (2013/10/1 2015/10/12, n = 97) and after (2015/10/13-2017/11/30, n = 80) implementation of case conferences to discuss medical and surgical management. These occurred as face-to-face discussions or electronically (for non-complex patients), and included physicians from cardiac surgery, cardiology, critical care, infectious diseases and neurology. We assessed process-of-care and clinical outcomes, with the primary outcome being complications up to 90 days after hospital discharge. RESULTS: A case conference was held for 80/80 (100%) of patients in the post intervention group. After the intervention, more patients received inpatient cardiology assessment (81.3% [post-intervention] vs. 63.9% [pre-intervention], p = 0.01), and more patients with definite infective endocarditis underwent cardiac surgery treatment (44.6% vs. 21.7%, p = 0.007). All pre-intervention and post intervention patients received guideline-concordant antimicrobial therapy. There was no difference in rates of complications (40.0% vs. 51.5%, p = 0.13) or mortality up to 90 days after hospital discharge (26.3% vs. 17.5%, p = 0.20). In multivariable analyses, the intervention was not associated with differences in mortality (odds ratio 1.87, 95% confidence interval 0.88-3.99) or a composite measure of complications and mortality (odds ratio 0.86, 95% confidence interval 0.46-1.58). CONCLUSION: We successfully implemented a standardized multidisciplinary case conference protocol for patients with infective endocarditis. This intervention had no detectable effect on complications or mortality. PMID- 30308074 TI - Stress in native grasses under ecologically relevant heat waves. AB - Future increases in the intensity of heat waves (high heat and low water availability) are predicted to be one of the most significant impacts on organisms. Using six native grasses from Eastern Australia, we assessed their capacity to tolerate heat waves with low water availability. We were interested in understanding differential response between native grasses of differing photosynthetic pathways in terms of physiological and some molecular parameters to ecologically relevant summer heat waves that are associated with low rainfall. We used a simulation heatwave event in controlled temperature cabinets and investigated effects of the different treatments on four stress indicators: leaf senescence, leaf water content, photosynthetic efficiency and the relative expression of two heat shock proteins, Hsp70 and smHsp17.6. Leaf senescence was significantly greater under the combined stress treatment, while declines in leaf water content and photosynthetic efficiency were much larger for C3 than C4 plants, particularly under the combined stress treatment. Species showed an increase in expression of Hsp70 associated with heat treatment, rather than drought stress. In contrast Hsp17.6 was only detected in two species, responding to heat rather than drought, although species' responses were variable. Overall, the C3 species were less tolerant than C4 species. Variation in individual plants within species was evident, especially under multiple stresses, and indicates that losses of individual plants may occur during a heat wave associated with this variability in tolerance. Heat waves will impose significant stress on plant communities that would not otherwise occur when heat and drought stress are experienced singly. Using ecologically relevant heat stress is likely to yield better predictability of how native plants will cope under a hotter, drier future. PMID- 30308073 TI - High-resolution plasma metabolomics analysis to detect Mycobacterium tuberculosis associated metabolites that distinguish active pulmonary tuberculosis in humans. AB - INTRODUCTION: Pulmonary tuberculosis (TB) is a major worldwide health problem that lacks robust blood-based biomarkers for detection of active disease. High resolution metabolomics (HRM) is an innovative method to discover low-abundance metabolites as putative blood biomarkers to detect TB disease, including those known to be produced by the causative organism, Mycobacterium tuberculosis (Mtb). METHODS: We used HRM profiling to measure the plasma metabolome for 17 adults with active pulmonary TB disease and 16 of their household contacts without active TB. We used a suspect screening approach to identify metabolites previously described in cell culture studies of Mtb based on retention time and accurate mass matches. RESULTS: The association of relative metabolite abundance in active TB disease subjects compared to their household contacts predicted three Mtb-associated metabolites that were significantly increased in the active TB patients based on accurate mass matches: phosphatidylglycerol (PG) (16:0_18:1), lysophosphatidylinositol (Lyso-PI) (18:0) and acylphosphatidylinositol mannoside (Ac1PIM1) (56:1) (p<0.001 for all). These three metabolites provided excellent classification accuracy for active TB disease (AUC = 0.97). Ion dissociation spectra (tandem MS/MS) supported the identification of PG (16:0_18:1) and Lyso-PI (18:0) in the plasma of patients with active TB disease, though the identity of Ac1PIM1 could not be definitively confirmed. CONCLUSIONS: Presence of the Mtb-associated lipid metabolites PG (16:0_18:1) and Lyso-PI (18:0) in plasma accurately identified patients with active TB disease. Consistency of in vitro and in vivo data suggests suitability for exploring these in future studies for possible development as TB disease biomarkers. PMID- 30308075 TI - Schadenfreude is higher in real-life situations compared to hypothetical scenarios. AB - Schadenfreude (i.e., the pleasure derived from another's misfortune) has been widely studied by having participants imagine how they would feel in hypothetical scenarios describing another person's pain or misfortune. However, research on affective forecasting shows that self-judgments of emotions are inaccurate in hypothetical situations. Here we show a study in which we first presented a hypothetical schadenfreude situation and few months later, due to an exceptional circumstance, the situation turned out to happen in reality. This fortuitous circumstance allowed us to compare people's imagined emotional reactions with their actual feelings. Results showed that schadenfreude was higher in the real situation than in the hypothetical one. More importantly, participants used different proxies to predict their emotional reaction: while out-group dislike served as a proxy of schadenfreude in both types of scenario, the degree of in group identification also increased schadenfreude in those who had experienced the real event, arguably a mechanism to promote positive self-evaluation. These results highlight the importance of assessing schadenfreude in the heat of the moment. PMID- 30308077 TI - Actions required to implement integrated care for older people in the community using the World Health Organization's ICOPE approach: A global Delphi consensus study. AB - BACKGROUND: Integrated care is recognised as an important enabler to healthy ageing, yet few countries have managed to sustainably deliver integrated care for older people. We aimed to gather global consensus on the key actions required to realign health and long-term systems and integrate services to implement the World Health Organization (WHO) Integrated Care for Older People (ICOPE) approach. METHODS: A two-round eDelphi study, including a global consultation meeting, was undertaken to identify, refine and generate consensus on the actions required across high-, middle- and low-income countries to implement the WHO ICOPE approach. In round 1, a framework of 31 actions, empirically derived from previous WHO evidence reviews was presented to panellists to judge the relative importance of each action (numeric rating scale; range:1-9) and provide free-text comments concerning the scope of the actions. These outcomes were discussed and debated at the global consultation meeting. In round 2, a revised framework of 19 actions was presented to panellists to measure their extent of agreement and identify 'essential' actions (five-point Likert scale; range: strongly agree to strongly disagree). A threshold of >=80% for agree/strongly agree was set a priori for consensus. RESULTS: After round 1 (n = 80 panellists), median scores across 31 actions ranged from 6 to 9. Based on pre-defined category thresholds for median scores, panellists considered 28 actions (90.3%) as 'important' and three (9.7%) as 'uncertain'. Fifteen additional actions were suggested for inclusion based on free-text comments, creating 46 for consideration at the global consultation meeting. In round 2 (n = 84 panellists), agreement (agree or strongly agree) ranged from 84.6-97.6%, suggesting consensus. Fourteen (73.7%) actions were rated as essential. CONCLUSION: Fourteen essential actions and five important actions are necessary at system (macro; n = 10) and service (meso; n = 9) levels to implement community-based integrated care for older people. PMID- 30308076 TI - A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages. AB - As antimicrobial signalling molecules, type III or lambda interferons (IFNlambdas) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNlambda4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNlambda4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNlambda4 function, we screened a panel of all known extant coding variants of human IFNlambda4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest 'Pygmy' hunter-gatherers. K154E greatly enhanced in vitro activity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNlambda4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genus Homo, including Neanderthals. Compared to chimpanzee IFNlambda4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNlambda4 correlates with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNlambda4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNlambda4 is conserved among humans and postulate that differences in IFNlambda4 activity between species contribute to distinct host-specific responses to-and outcomes of-infection, such as HCV infection. The driver of reduced IFNlambda4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa. PMID- 30308078 TI - Who were the miners of Allumiere? A multidisciplinary approach to reconstruct the osteobiography of an Italian worker community. AB - This research presents an in-depth study of the skeletal remains collected from the archaeological site of Allumiere (15th-16th centuries CE; Rome, Italy). A multidisciplinary approach was used, combining skeletal biology, molecular anthropology and archaeobotany with the aim of reconstructing the osteobiography of the alum miners buried at the site. Since 1460, the area of the Tolfa Mountains was significant for the exploitation of alum which was used for a wide range of purposes in the Middle Ages, ranging from woven production to medical practice. A total of 70 individuals (63 adults and 7 juveniles) were studied. The sex ratio of the community indicated a higher prevalence of males with respect to females. Morphological examination indicated occupational musculoskeletal stress markers, which might reflect the specific phase of alum production that each individual was occupied in. Dietary reconstruction was primarily performed through carbon and nitrogen stable isotope analysis with integration of the results obtained by microscopic, genetic and GC-MS investigations on dental calculus. The diet was omnivorous, indicating a reliance on C3-terrestrial protein and evidence for limited C4 consumption by some individuals. Herbivores, such as sheep and cattle, appear to have contributed to the diet more than pigs and chickens. Consumption of Fagaceae and Poaceae species was predominant; moreover, indicators of Brassicaceae and milk and its derivatives were abundantly recurrent in the population, followed by plant oils and theophylline. Furthermore, the detection of pharmacological alkaloids indicated the knowledge and application of medicinal plants by the community. The novel use of multiple techniques based on cutting-edge technologies has provided a unique window on the lifestyles of individuals from one of the first Italian settlements of alum workers. PMID- 30308079 TI - Amino acid substitutions in CPC-LIKE MYB reveal residues important for protein stability in Arabidopsis roots. AB - TRYPTICHON (TRY) and ENHANCER OF TRY AND CPC2 (ETC2) encode R3-type MYB transcription factors that are involved in epidermal cell differentiation in Arabidopsis thaliana. TRY and ETC2 belong to the CPC-like MYB gene family, which includes seven homolog genes. Previously, we showed that among the CPC family members, TRY and ETC2 are characterized by rapid proteolysis compared with that of other members, and we demonstrated that this proteolysis is mediated by the proteasome-dependent pathway. In this study, we compared the functions of the wild-type TRY and ETC2 proteins and their amino acid-substituted versions. Our results showed that the substitution of amino acids in the C-terminal of TRY and ETC2 conferred them the ability to induce root hair formation. Furthermore, we confirmed that these mutations enhanced the stability of the TRY and ETC2 proteins. These results revealed that the amino acids, which are important for the functions of TRY and ETC2, mediate morphological pattern formation and can be useful in understanding the pathway determining the fate of root hair cells. PMID- 30308081 TI - Recent advances in medical management of hepatocellular carcinoma. AB - Transcatheter arterial therapies for hepatocellular carcinoma (HCC) have developed during the last decade. A fine powder formulation of cisplatin and the new platinum agent miriplatin became standard medicines in addition to anthracyclines in transcatheter arterial chemoembolization (TACE) in Japan. Recent prospective and retrospective studies supported the usefulness of platinum agents as a chemotherapeutic at the time of varied TACE therapy. Although balloon occluded TACE is an effective therapy for localized HCC and drug-eluting microspheres seemed to show a higher response rate in certain HCCs, the definite advantages of those procedures still remain uncertain. Intermediate stage HCC, or Barcelona Clinic Liver Cancer stage B, is regarded as a heterogeneous category with a wide spectrum of tumors and patients, and several subclassifications of the stage have been proposed to show different prognoses; there are also different recommended therapies in each subgroup. Authors have subclassified patients based on combinations of tumor size, tumor number, and liver function, with or without performance status. Because of differences of available medical resources and techniques in treatment procedures between countries, the most ideal and useful subgrouping remains inconclusive at present. Recently, a few systemic chemotherapies proved to be effective for advanced stage HCC in phase III studies: lenvatinib as the first line of therapy, and regorafenib, cabozantinib, and ramucirumab as second-line therapy. Other molecular-targeted and immune-oncological medicines are expected to follow in the near future. Some studies have suggested an advantage of early introduction of molecular-targeted therapy for TACE-resistant HCC in the intermediate stage. PMID- 30308080 TI - Detection of fungal and bacterial carbohydrates: Do the similar structures of chitin and peptidoglycan play a role in immune dysfunction? PMID- 30308082 TI - A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease. PMID- 30308083 TI - Thyroiditis and immune check point inhibitors: the post-marketing experience using the French National Pharmacovigilance database. AB - Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation. PMID- 30308084 TI - AIUM-ACR-SPR-SRU Practice Parameter for the Performance of an Ultrasound Examination for Detection and Assessment of Developmental Dysplasia of the Hip. PMID- 30308085 TI - Highly Efficient Synthesis and Assay of Protein-Imprinted Nanogels by Using Magnetic Templates. AB - We report an approach integrating the synthesis of protein-imprinted nanogels ("plastic antibodies") with a highly sensitive assay employing templates attached to magnetic carriers. The enzymes trypsin and pepsin were immobilized on amino functionalized solgel-coated magnetic nanoparticles (magNPs). Lightly crosslinked fluorescently doped polyacrylamide nanogels were subsequently produced by high dilution polymerization of monomers in the presence of the magNPs. The nanogels were characterised by a novel competitive fluorescence assay employing identical protein-conjugated nanoparticles as ligands to reversibly immobilize the corresponding nanogels. Both nanogels exhibited Kd <10 pM for their respective target protein and low cross-reactivity with five reference proteins. This agrees with affinities reported for solid-phase-synthesized nanogels prepared using low surface-area glass-bead supports. This approach simplifies the development and production of plastic antibodies and offers direct access to a practical bioassay. PMID- 30308087 TI - AIUM-ACR-SPR-SRU Practice Parameter for the Performance and Interpretation of a Diagnostic Ultrasound Examination of the Extracranial Head and Neck. PMID- 30308088 TI - Chapter 20: Update on Pharmacologically-Relevant Vitamin D Analogs. AB - Ever since the metabolism of vitamin D was elucidated in the early 1970s, organic chemists and pharmacologists have sought to design and synthesize vitamin D analogs that would mimic some, if not all, of the biological actions of the parent vitamin. Thousands of molecules have been prepared and tested but only a few of these have been successfully translated into marketed drug forms that can be used to treat bone disease or in other areas of clinical medicine. These synthetic vitamin D analogs have been reviewed extensively in recent years [1-5] and this chapter will not attempt to duplicate those reviews. Furthermore, this review will not spend much time exploring the precise biochemical mechanism by which the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] is able to modulate gene expression of target genes involved in the physiological effects of vitamin D on calcium/phosphate homeostasis or its effects on cell proliferation and differentiation covered in recent summaries of this subject [6 8]. Rather this short treatise will focus on the pharmacologically important vitamin D agents recently introduced or are under active development that might be employed ultimately in the treatment of bone disease or related conditions. We start by reviewing new work on two early metabolites of vitamin D3: 25 hydroxyvitamin D3 [25-OH-D3] and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], then move on to review newer analogs of 1,25-(OH)2D3 that are modified chemically to be more selective in their actions, especially in bone. PMID- 30308086 TI - Comparative evaluation of a novel, moderately hypofractionated radiation protocol in 56 dogs with symptomatic intracranial neoplasia. AB - BACKGROUND: Use of strongly hypofractionated radiation treatments in dogs with intracranial neoplasia did not improve outcomes and yielded increased rates of toxicosis. OBJECTIVES: To evaluate safety and efficacy of a new, moderately hypofractionated radiation protocol of 10 * 4 Gy compared to a standard protocol. ANIMALS: Convenience sample of 56 client-owned dogs with primary symptomatic brain tumors. METHODS: Retrospective observational study. Twenty-six dogs were assigned to the control standard protocol of 20 * 2.5 Gy (group A) and 30 dogs to the new protocol of 10 * 4 Gy (group B), assigned on owners' informed consent. Statistical analysis was conducted under the "as treated" regime, using Kaplan Meier and Cox-regression analysis. Treatment was delivered with technically advanced image-guided radiation therapy. The 2 treatment groups were compared in terms of outcome and signs of toxicosis. RESULTS: Overall progression-free interval (PFI) and overall survival (OS) time were favorable, with 663 (95%CI: 497;828) and 637 (95%CI: 403;870) days, respectively. We found no significant difference between the two groups: PFI for dogs in group A vs B was 608 (95%CI: 437;779) days and mean (median not reached) 863 (95%CI: 644;1083) days, respectively (P = .89), and OS for dogs in group A vs B 610 (95%CI: 404;816) and mean (median not reached) 796 (95%CI: 586;1007) days (P = .83). CONCLUSION AND CLINICAL IMPORTANCE: In conclusion, 10 * 4 Gy is a safe and efficient protocol for treatment of primary intracranial neoplasia and future dose escalation can be considered. PMID- 30308089 TI - Variability in Phelan-McDermid syndrome: The impact of the PNPLA3 p.I148M polymorphism. AB - The PNPLA3 gene maps in the 22q13 region and can have modifying effects on the phenotype of patients with Phelan-McDermid syndrome (PMS). The PNPLA3 p.I148M variant was detected in two PMS patients presenting with refractory seizures, gastrointestinal issues, and liver dysfunction. The p.I148M variant leads to macrovescicular steaosis and predisposes to liver disorders from steatohepatitis to fibrosis. Accumulation of lipid macrovescicles in the hepatocytes affects several pathways, including the metabolismof anti-epileptics, possibly leading to the lack of response to anti-epileptic treatments reported in the two cases. Screening for the p.I148M variant can identify PMS patients at higher risk for liver dyfunction and help designing personalized therapeutic protocols. PMID- 30308092 TI - CGRP Antagonists: Physiologic Effects and Serious Side Effects. PMID- 30308091 TI - AIUM-ACR-ACOG-SMFM-SRU Practice Parameter for the Performance of Standard Diagnostic Obstetric Ultrasound Examinations. PMID- 30308090 TI - Hypoxia-mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus. AB - Brain-derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF-mediated pro-death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague-Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro-BDNF and alteration in N-linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose-regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase beta (Trkbeta) in non-raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkbeta from non-raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkbeta from non-raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation-induced alteration in raft dynamics which is promotes p75 receptor-mediated death signalling in hippocampal neurons during chronic hypoxia. PMID- 30308095 TI - A simple statement about the concept of archetypes stimulated by Warren Colman's paper 'Are archetypes essential?' PMID- 30308094 TI - Vitamin E intestinal absorption: Regulation of membrane transport across the enterocyte. AB - Vitamin E is an essential molecule for our development and health. It has long been thought that it was absorbed and transported through cellular membranes by a passive diffusion process. However, data obtained during the past 15 years showed that its absorption is actually mediated, at least in part, by cholesterol membrane transporters including the scavenger receptor class B type I (SR-BI), CD36 molecule (CD36), NPC1-like transporter 1 (NPC1L1), and ATP-binding cassettes A1 and G1 (ABCA1 and ABCG1). This review focuses on the absorption process of vitamin E across the enterocyte. A special attention is given to the regulation of this process, including the possible competition with other fat-soluble micronutrients, and the modulation of transporter expressions. Overall, recent results noticeably increased the comprehension of vitamin E intestinal transport, but additional investigations are still required to fully appreciate the mechanisms governing vitamin E bioavailability. (c) 2018 IUBMB Life, 2018. PMID- 30308096 TI - Editorial. PMID- 30308097 TI - Giacometti's Gaze. PMID- 30308099 TI - Response to Roger Brooke's critique of 'On matters of mind and body: regarding Descartes'. PMID- 30308098 TI - An unhealable wound: left by suicide. AB - This article is about the author's experience of being left by suicide and the effect the experience had on her work as an analyst in the consulting room and as a member of psychological organizations. The effects are generalized to others who have been left by suicide based on the writings of those left, and on writings of authors who have researched the subject. Shame and the effects the judgments of society now and in the past have on the person who suffers this experience are central, as well as the positive and negative ways groups are used by a person left by suicide to find solace and to emerge from the darkness of such abandonment. There is a constant longing (often unconscious) for replacement of the lost one. The article seeks to help analysts and those who have been left by suicide understand the suffering and the indelible mark that is experienced when there is a suicide of someone close. Understanding by the analyst is important in order to modulate the shame of this experience. PMID- 30308100 TI - The Artist and The Model. PMID- 30308101 TI - 'Just black sometimes': analytic tools applied at the frontlines of social upheaval, part 1. AB - Analysts are increasingly grappling with making space for the discussion of turbulent and disturbing current events in their practices. This social disorder raises questions about the role of social activism and advocacy for groups suffering discrimination, persecution, violence, and displacement. Jung too commented on the immediacy of political happenings that show up in our practices with 'violence'. The author discusses an organizational consultation he did in Berlin in 2017 to consult for an NGO that handles placements for unaccompanied minors who are refugees. Such consultation can employ analytic ideas and concepts to the benefit of the organization and its staff. This process, though, requires some translation of these ideas so as not to burden consultees with theoretical terminology with which they may have little or no familiarity. The role of vicarious trauma is discussed, including how it is passed along, and its implications for frontline helpers are considered. Developmental aspects of adolescence figured prominently in the consultation. This is the first of two papers addressing this topic; the second will focus on interactions that the author had with young refugees. PMID- 30308103 TI - Descartes' dualism and the phenomenological tradition: a response to Elizabeth Urban's 'On matters of mind and body: regarding Descartes'. PMID- 30308104 TI - Human Flow/Sweet Country/No Law. PMID- 30308107 TI - THE JOURNAL OF ANALYTICAL PSYCHOLOGY: INDEX FOR VOLUME 63, 2018. PMID- 30308105 TI - Wiki-analysis: speed, adaptation and subjectivity in a liquid world. AB - The paper is a reflection on the conflictual relationship between adaptation and subjectivity, persona and individuation, starting from Jung's seminal writings, and their developing features in contemporary society. With reference to sociologist Zygmunt Bauman's speculations on so called liquid society and retrotopia, concepts like nostalgia are examined in the article. A case of a manic and violent nine-year-old child, a millennial-to-be boy treated in the mid nineties, is presented to describe issues like shame, object promiscuity, consumerism and overexcitement, and suggests questions on whether and how these patterns would be different for patients belonging to the Generations Z (born between 1996 and 2010) and Alpha (born after 2010). The case material shows how the construction of a suitable persona was the only aim of the child's family, in terms of a merely quantitative regulation, their model being that of being adequately capable of consuming and being consumed, using each other for utilitarian purposes, and essentially avoiding the sense of self-and-other as live objects. Psychoanalysis is theoretically and clinically challenged and confronted with the conflict between the new features of adaptation and a dimension of subjectivity whose traits are more and more difficult to detect. PMID- 30308108 TI - Response to Hugh Gee's 'A simple statement about the concept of archetypes'. PMID- 30308109 TI - 'Routine is a blind alley' (C. G. Jung): on the similarities between artistic creative and psychoanalytic work. AB - The transformation processes in artistic-creative work and those of the analytic process can be considered to be comparable. To illustrate the relatedness of the two, the author describes three self-states that characterized the artist Alberto Giacometti's creative process. With reference to Jungian concepts, the author subsequently illustrates how these states of mind can be found in the analyst during the analytic encounter. By comparing both processes, he explores the temptations and denials that accompany the analyst's struggle for an analytic attitude. PMID- 30308110 TI - Art and Psyche. PMID- 30308111 TI - Acceleration of 3D DOSY NMR by Spatial Encoding of the Chemical Shift. AB - Diffusion-ordered NMR spectroscopy (DOSY) is a powerful method for the analysis of solution mixtures. With 3D DOSY, the 2D NMR spectra of a mixture's components can be separated according to the translational diffusion coefficient of each component. The acquisition of 3D DOSY data is, however, very time-consuming because of the need to consecutively acquire scans for both the diffusion and the indirect spectral dimensions. We show that spatial encoding of the indirect spectral dimension, of the kind used in ultrafast 2D NMR, can accelerate 3D DOSY experiments by an order of magnitude or more. This is illustrated with homonuclear single-quantum (COSY) and double-quantum (DQS) correlation spectra. Implementations with concatenated and incorporated (iDOSY) diffusion blocks are compared and in both cases, 2D spectra are separated with less than 6 min of experiment time. PMID- 30308112 TI - Anticancer activity of thymol: A literature-based review and docking study emphasized on its anticancer mechanisms. AB - This review aims to summarize the anticancer effects of the natural monoterpene phenol derivative of cymenethymol and its derivatives as well as further molecular docking study to correlate the interaction of thymol and biomacromolecules that involved in cancer cell growth. For this, an up-to-date (till July 2018) literature study were made through using PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society, Clinicaltrials.gov, and Google Scholar databases. Literature study demonstrated that thymol, melasolv (3,4,5-Trimethoxycinnamate thymol ester), and Mannich bases of thymol have potential anticancer effects in various test systems, including mice, rats and cultured cancer cells through various anticancer pathways such as antioxidant/oxidative stress induction, apoptosis, anti inflammatory/immunomodulatory, anti-genotoxicity, chemo-, and radiopreventive ways. A few earlier scientific evidences showed that thymol is less toxic to mammalian systems. In silico study of thymol and its derivatives against 17 essential proteins revealed that 6BVH (PARP-1) and 5LIH (protein kinase C) are the most efficient receptor protein for interaction and binding of thymol and melaslov for the cancer prevention and initiation. On the basis of the summary of this review and docking study, it is evident that thymol may be one of promising plant-derived cancer chemotherapeutic agents. (c) 2018 IUBMB Life, 2018. PMID- 30308113 TI - Porous and nonporous silk fibroin (SF) membranes wrapping for Achilles tendon (AT) repair: Which one is a better choice? AB - Two types of silk fibroin (SF) membranes were developed for tendon repair: porous and nonporous SF membranes. The objective of this study was to compare the efficiency of these two films according to the ability of tendon regeneration using a rat Achilles tendon (AT) rupture suture wrapping model. The in vitro tests were conducted, and theSF membranes were proved to be with ultimate biodegradability, good-biocompatibility and without toxicity. In vivo, 12 Sprague Dawley rats were used to create a rat AT rupture suture model wrapped by SF membranes. They were randomly divided into six groups. The results revealed that the nonporous SF membrane wrapping group was shown to reduce the inflammatory effect and induce the proliferation of fibroblast-like cells at one week and four weeks post-operatively. After four weeks, the nonporous SF membrane wrapping group exhibited more organized collagen structures and had increased expression of tendon repair proteins. Hence, our nonporous SF membrane improved the efficacy of tendon regeneration by decreasing inflammatory cells, growing fibroblast-like cells, and promoting extracellular matrix production. Nonporous SF membrane can, therefore, be regarded as a better functional membrane for tendon repair. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 000-000, 2018. PMID- 30308114 TI - Gold(III)-Catalyzed Site-Selective and Divergent Synthesis of 2-Aminopyrroles and Quinoline-Based Polyazaheterocycles. AB - A facile, site-selective, and divergent approach to construct 2-aminopyrroles and quinoline-fused polyazaheterocycles enabled by a simple gold(III) catalyst from ynamides and anthranils under mild reaction conditions is described. This one-pot strategy uses readily available starting materials, proceeds in a highly step- and atom-economical manner, with broad substrate scope and scale-up potential. The key element for success in this tandem reaction is a catalyst-directed preferred quenching of the in situ generated gold carbene intermediates by a nucleophilic benzyl/2-furylmethyl moiety on the ynamides as an alternative to the known C-H annulation leading to indoles. PMID- 30308115 TI - Color Engineering of Silicon Nitride Surfaces to Characterize the Polydopamine Refractive Index. AB - A simple methodology to generate polydopamine (PDA) surfaces featured with color due to thin-film interference phenomena is presented. It is based on depositing ultra-thin films of polydopamine on a Si/Si3 N4 wafer that exhibits an interferential reflectance maximum right at the visible/UV boundary (~400 nm). Therefore, a small deposit of PDA modifies the optical path, in such manner that the wavelength of the maximum of reflectance red shifts. Because the human eye is very sensitive to any change of the light spectral distribution at the visible region, very small film thickness changes (~30 nm) are enough to notably modify the perceived color. Consequently, a controlled deposit of PDA, tune the color along the whole visible spectrum. Additionally, good quality of PDA deposits allowed us to determine the refractive index of polydopamine by ellipsometry spectroscopy. This data can be crucial in confocal skin microscopic techniques, presently used in diagnosis of skin tumors. PMID- 30308116 TI - Interventions for replacing missing teeth: attachment systems for implant overdentures in edentulous jaws. AB - BACKGROUND: Implant overdentures are one of the most common treatment options used to rehabilitate edentulous patients. Attachment systems are used to anchor the overdentures to implants. The plethora of attachment systems available dictates a need for clinicians to understand their prosthodontic and patient related outcomes. OBJECTIVES: To compare different attachment systems for maxillary and mandibular implant overdentures by assessing prosthodontic success, prosthodontic maintenance, patient preference, patient satisfaction/quality of life and costs. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 24 January 2018); Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (searched 24 January 2018); MEDLINE Ovid (1946 to 24 January 2018); and Embase Ovid (1980 to 24 January 2018). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials on 24 January 2018. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: All randomised controlled trials (RCTs), including cross-over trials on maxillary or mandibular implant overdentures with different attachment systems with at least 1 year follow-up. DATA COLLECTION AND ANALYSIS: Four review authors extracted data independently and assessed risk of bias for each included trial. Several corresponding authors were subsequently contacted to obtain missing information. Fixed-effect meta-analysis was used to combine the outcomes with risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (95% CI). We used the GRADE approach to assess the quality of evidence and create 'Summary of findings' tables. MAIN RESULTS: We identified six RCTs with a total of 294 mandibular overdentures (including one cross-over trial). No trials on maxillary overdentures were eligible. Due to the poor reporting of the outcomes across the included trials, only limited analyses between mandibular overdenture attachment systems were possible.Comparing ball and bar attachments, upon pooling the data regarding short-term prosthodontic success, we identified substantial heterogeneity (I2 = 97%) with inconsistency in the direction of effect, which was unexplained by clinical or methodological differences between the studies, and accordingly we did not perform meta-analyses for this outcome. Short-term re treatment (repair of attachment system) was higher with ball attachments (RR 3.11, 95% CI 1.68 to 5.75; 130 participants; 2 studies; very low-quality evidence), and there was no difference between both attachment systems in short term re-treatment (replacement of attachment system) (RR 1.18, 95% CI 0.38 to 3.71; 130 participants; 2 studies; very low-quality evidence). It is uncertain whether there is a difference in short-term prosthodontic success when ball attachments are compared with bar attachments.Comparing ball and magnet attachments, there was no difference between them in medium-term prosthodontic success (RR 0.84, 95% CI 0.64 to 1.10; 69 participants; 1 study; very low-quality evidence), or in medium-term re-treatment (repair of attachment system) (RR 1.75, 95% CI 0.65 to 4.72; 69 participants; 1 study; very low-quality evidence). However, after 5 years, prosthodontic maintenance costs were higher when magnet attachments were used (MD -247.37 EUR, 95% CI -346.32 to -148.42; 69 participants; 1 study; very low-quality evidence). It is uncertain whether there is a difference in medium-term prosthodontic success when ball attachments are compared with magnet attachments.One trial provided data for ball versus telescopic attachments and reported no difference in prosthodontic maintenance between the two systems in short-term patrix replacement (RR 6.00, 95% CI 0.86 to 41.96; 22 participants; 1 study; very low-quality evidence), matrix activation (RR 11.00, 95% CI 0.68 to 177.72; 22 participants; 1 study; very low-quality evidence), matrix replacement (RR 1.75, 95% CI 0.71 to 4.31; 22 participants; 1 study; very low-quality evidence), or in relining of the implant overdenture (RR 2.33, 95% CI 0.81 to 6.76; 22 participants; 1 study; very low-quality evidence). It is uncertain whether there is a difference in short-term prosthodontic maintenance when ball attachments are compared with telescopic attachments.In the only cross-over trial included, patient preference between different attachment systems was assessed after only 3 months and not for the entire trial period of 10 years. AUTHORS' CONCLUSIONS: For mandibular overdentures, there is insufficient evidence to determine the relative effectiveness of different attachment systems on prosthodontic success, prosthodontic maintenance, patient satisfaction, patient preference or costs. In the short term, there is some evidence that is insufficient to show a difference and where there was no evidence was reported. It was not possible to determine any preferred attachment system for mandibular overdentures.For maxillary overdentures, there is no evidence (with no trials identified) to determine the relative effectiveness of different attachment systems on prosthodontic success, prosthodontic maintenance, patient satisfaction, patient preference or costs.Further RCTs on edentulous cohorts must pay attention to trial design specifically using the same number of implants of the same implant system, but with different attachment systems clearly identified in control and test groups. Trials should also determine the longevity of different attachment systems and patient preferences. Trials on the current array of computer-aided designed/computer-assisted manufactured (CAD/CAM) bar attachment systems are encouraged. PMID- 30308117 TI - MicroRNA-107 regulates anesthesia-induced neural injury in embryonic stem cell derived neurons. AB - Ketamine, though widely used in pediatric anesthesia, may induce cortical neurotoxicity in young patients. This study focused on an in vitro model of rat brain embryonic stem cell (ESC)-derived neurons to investigate the effects of microRNA-107 (miR-107) on ketamine-induced neural injury. Rat brain ESCs were proliferated in vitro and differentiated toward neuronal fate. Ketamine induced neural injury in ESC-derived neurons was inspected by TUNEL and neurite growth assays. Ketamine-induce aberrant miR-107 expression was examined by qRT-PCR. MiR 107 was downregulated in ESCs through lentiviral transduction. Its effect on ketamine-induced neural injury in ESC-derived neurons was then examined. Potential downstream target of miR-107, brain derived neurotrophin factor (BDNF), was inspected by dual-luciferase reporter assay and qRT-PCR. BDNF was knocked down, through siRNA transfection, in NSCs to investigate its functional involvement in miR-107 mediated neural protection in ketamine-injured NSC-derived neurons. Ketamine induced apoptosis, neurite degeneration, and upregulated miR 107 in NSC-derived neurons. Lentivirus-mediated miR-107 downregulation attenuated ketamine-induced neural injury. BDNF was proven to be directly and inversely regulated by miR-107 in NSC-derived neurons. SiRNA-mediated BDNF inhibition reversed the protective effect of miR-107 downregulation on ketamine injury in NSC-derived neurons. MiR-107 / BDNF was demonstrated to be an important epigenetic signaling pathway in regulating ketamine-induced neural injury in cortical neurons. (c) 2018 IUBMB Life, 2018. PMID- 30308119 TI - 2018 Scholar's Research Symposium Abstracts. PMID- 30308120 TI - Santayana's Axiom: The South Dakota State Medical Association and Medical Practice Legislation in 1929 and 2017. AB - In 1928 members of the South Dakota State Medical Association (SDSMA or the Association) held a special meeting in Huron to consider a basic science bill that conformed "...in its entirety to the conditions existing in our state." Their draft bill proposed a standardized examination for all practitioners of the healing arts. A legislative committee, with its attorney, "...was in Pierre during the early part of the 1929 legislative session to make sure the bill was properly launched and in effective channels." Shortly after its introduction, the bill was withdrawn due to opposition from one SDSMA district whose legislative representatives were among the most influential in the legislature. A similar bill promoted by the SDSMA in 1933 also failed. It would be another six years before a basic science bill was enacted by the legislature. Eighty-nine years later, a bill governing the practice of certified nurse practitioners (NP) and certified nurse midwives (NM), including a board independent of the South Dakota Board of Medical and Osteopathic Examiners, was considered (Senate Bill 61). Introduced by a senator who characterized herself as representing the "House of Nursing," the bill challenged "...the overarching role that medicine thinks and perceives that they may have regarding advanced practice nursing practice." SB 61 passed in the senate and house and was signed by the governor. For this legislation in the 1930s and in 2017, the SDSMA's interest was defining and maintaining control of medical practice under the twin rubrics of quality and patient welfare. In both circumstances, legislators and other health care professional organizations contested not only the SDSMA's motivations, but also the evidence supporting their efforts. Our research explored (1) whether the collective viewpoints and conduct of the legislature, the SDSMA, and non physician medical professionals are comparable in the two circumstances; and (2) if the circumstances are comparable, can we derive a useful concept or theme that could help guide the SDSMA in the future? PMID- 30308118 TI - Colloidal Molecules from Valence-Endowed Nanoparticles by Covalent Chemistry. AB - We demonstrate a simple method to create a variety of silica-based colloidal molecules through the covalent assembly of site-specifically functionalized patchy nanoparticles with complementary nanospheres. Colloidal analogues of BeBr2 , BBr3 and CBr4 are obtained from sp-, sp2 - and sp3 -like particles, while Br2 O and NBr3 analogues can be fabricated by varying the relative amounts of both colloidal precursors. We also show that it is possible to attach covalently silica nanospheres of various sizes to one central patchy nanoparticle, which leads to the formation of more complex colloidal molecules, including chiral ones. The possibility to easily extend the strategy to other colloidal precursors which can serve as satellites, for example, ellipsoidal polymer particles or metallic nanoparticles, opens the way to a rich variety of new colloidal analogues of atoms which could serve as building blocks of next generation materials. PMID- 30308121 TI - Role of Bedside Preparation in Reducing "Door-to-Needle" Tissue-Type Plasminogen Activator (Alteplase) Administration Times and Association with Patient Outcomes. AB - INTRODUCTION: The purpose of this study is to assess the benefit of bedside alteplase preparation as a component of the acute stroke process. METHODS: A retrospective, single center study, designed to evaluate the impact of a bedside alteplase preparation protocol. Stroke patients receiving intravenous (IV) alteplase prepared at bedside were compared to pre-bedside alteplase preparation patients. The primary outcome was to compare door-to-needle (DTN) times between the groups. The secondary outcomes included comparison of pre-bedside alteplase preparation to post-bedside alteplase preparation on the following variables: imaging-to-drug times, order entry to drug administration times, percentage of patients achieving the 60 minute DTN goal, rate of intracranial hemorrhage (ICH), and patient discharge disposition. RESULTS: Patients in the pre-bedside preparation group included those who received IV alteplase between Jan. 1, 2012 and Jan. 31, 2015 and post-bedside preparation patients between Feb. 1, 2015 and March 31, 2016. Thirty-one patients were enrolled in the study, 16 in the pre bedside preparation group and 15 in the post-beside preparation group. The mean DTN time in the post-bedside alteplase preparation group was significantly reduced, as compared to the pre-bedside preparation group (66.6 minutes vs. 95.9 minutes, p=0.024). Percent of patients meeting the 60 minute DTN time goal was significantly improved when alteplase was prepared at bedside (53.3 percent vs. 18.8 percent) (p=0.044). Rates of ICH were not significantly different between the two populations. CONCLUSIONS: Bedside alteplase preparation significantly reduced DTN times in an academic hospital emergency department. PMID- 30308122 TI - Caring for the Bariatric Surgery Patient. PMID- 30308123 TI - Quality Focus: Increasing Community Awareness and Involvement in Sepsis. PMID- 30308125 TI - Modulatory effects of Viola odorata flower and leaf extracts upon oxidative stress related damage in an experimental model of ethanol-induced hepatotoxicity. AB - Ethanol is the most widely abused drug in the world in which long term use of ethanol induces oxidative stress in the liver tissue. The aim of this study was to evaluate protective effect of V. odorata against ethanol-induced hepatotoxicity in wistar rat. Animals were divided into nine groups as follows: control (normal saline), ethanol (10 mg/kg, ip), ethanol with three doses (125, 250 and 500 mg/kg) of ethyl acetate flower and leaf extracts and positive control (vitamin E 80mg/kg) were gavaged 30 min before ethanol injection for 28 days. Then, animals were killed and the liver were separated. Oxidative stress parameters including reactive oxygen species, lipid peroxidation, and protein carbonyl as well as glutathione content were evaluated. Also, histopathological examination and assessment of blood ALT, AST, ALP, total antioxidant capacity were done. Ethanol significantly increased oxidative stress markers in liver. Interestingly, administration of both extracts significantly decreased oxidative stress markers in liver tissue and biochemical parameters in the plasma. In addition, abnormal pathological features was improved after treatment with flower and leaf extracts. These results suggested that viola odorata can be considered as a candidate for improving conditions due to ethanol-induced tissue oxidative damage because of its antioxidant activity. PMID- 30308124 TI - Lessons for health program monitoring and evaluation in a low resource setting. AB - Numerous guidelines outline best practices for health program monitoring and evaluation (M&E). However, health programs are often implemented in less than ideal circumstances where these best practices may not be resourced or feasible. This article describes how M&E has been conducted for a health service delivery improvement program in remote Papua New Guinea and outlines lessons learned. The lessons learned were to integrate M&E into every aspect of the program, strengthen existing health information data, link primary data collection with existing program activities, conduct regular monitoring and feedback for early identification of implementation issues, involve the program team in evaluation, and communicate M&E data through multiple mediums to stakeholders. These lessons could be applied to other health programs implemented in low resource settings. PMID- 30308126 TI - Changes in arterial stiffness after eccentric versus concentric cycling. AB - This study compared changes in brachial-ankle pulse wave velocity (baPWV) after concentric (CON) versus eccentric cycling (ECC). It was hypothesized that baPWV would increase after the first ECC bout (ECC1) because of muscle damage, but not after the second ECC bout (ECC2), and would decrease after CON. Fifteen young (20 30 y) men performed two bouts of 30-min ECC (ECC1 and ECC2) at 60% of maximal CON power output and two bouts of 30-min CON at the same intensity as that of ECC (CON1), and at the same oxygen consumption as that of ECC (CON2) every two weeks. Oxygen uptake during the cycling was recorded, and baPWV was measured before and 0.5, 1, 24 and 48 h after each cycling. Maximal voluntary contraction (MVC) torque and muscle soreness of the knee extensors were assessed before, 24 and 48 h after each cycling. Changes in these variables over time were compared among the four cycling bouts by two-way repeated measured ANOVA. baPWV decreased (P<0.05) 8% from the baseline (1119 +/- 116 cm/s) at 0.5 h after CON1 (1028 +/- 126 cm/s), but no significant changes were evident after ECC1, ECC2 and CON2. MVC torque decreased 10% from the baseline at 24 h after ECC1, but no significant changes were evident after CON1, CON2 and ECC2. These results did not support the hypothesis, and suggest that minor muscle damage induced by eccentric cycling does not affect arterial stiffness. PMID- 30308127 TI - The Effects of Dietary Flaxseed on Cardiac Arrhythmias and Claudication in Patients with Peripheral Arterial Disease. AB - Patients with peripheral artery disease (PAD) are at increased risk for cardiovascular events and higher susceptibility for cardiac arrhythmias may be involved. The objectives of this double blinded, randomized controlled FLAX-PAD trial were to determine whether daily consumption of a diet supplemented with 30g of milled flaxseed (or placebo) over one year by PAD patients has effects on the prevalence of cardiac arrhythmias and exercise capacity. Cardiac arrhythmias were assessed on a cardiac stress test and at rest. At baseline, the PAD patients had a high incidence of cardiac arrhythmias (48% in the flaxseed group and 32% in the placebo group). After 1 year, the presence of cardiac arrhythmias in the flaxseed group decreased by 2% and increased by 12% in the placebo group (P>0.05). Electrocardiographic variables (P, PR, QRS, QT, QTc) did not change in either group during the trial. Patients from both groups improved initial and absolute claudication distances but the intergroup difference was also not statistically significant. In summary, the prevalence of cardiac arrhythmias and physical capacity trended in a positive direction for patients ingesting flaxseed but either a larger sample size or a longer intervention with flaxseed may be required to show statistically significant differences. PMID- 30308128 TI - Structure and function of the Fgd family of divergent FYVE domain proteins. AB - FYVE domains are highly conserved protein modules that typically bind phosphatidylinositol 3-phosphate (PI3P) on the surface of early endosomes. Along with pleckstrin homology (PH) and phox homology (PX) domains, FYVE domains are the principal readers of the phosphoinositide (PI) code that mediate specific recognition of eukaryotic organelles. Of all the human FYVE domain containing proteins, those within the faciogenital dysplasia (Fgd) subfamily are particularly divergent and couple with GTPases to exert unique cellular functions. The subcellular distributions and functions of these evolutionarily conserved signal transducers, which also include Dbl homology (DH) and two PH domains, are discussed here to better understand the biological range of processes that such multidomain proteins engage in. Determinants of their various functions include specific multidomain architectures, posttranslational modifications including PIP stops that have been discovered in sorting nexins, PI recognition motifs, and phospholipid-binding surfaces as defined by the Membrane Optimal Docking Area (MODA) program. How these orchestrate Fgd function remains unclear but has implications for developmental diseases including Aarskog-Scott syndrome, which is also known as faciogenital dysplasia, and forms of cancer that are associated with mutations and amplifications of Fgd genes. PMID- 30308129 TI - Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes. AB - Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, alpha-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 MUM) prevented doxorubicin induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. alpha-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins alpha-actinin and troponin I are, however, not targeted by MMP-2 under these conditions. PMID- 30308130 TI - Effects of Metformin on Apoptosis and Alpha Synuclein in Rat Model of Pentylenetetrazole-induced Epilepsy. AB - OBJECTIVES: To examine the possible neuroprotective and antiepileptic effects of metformin in a rat model of PTZ-induced epilepsy and its possible underlying mechanisms. METHODS: forty male albino rats were allocated into 4 equal groups; 1) normal control (NC) group, 2) Metf group: metformin (200 mg/kg i.p. daily) for 2 weeks, 3) PTZ-group: received PTZ (50 mg/Kg, i.p. every other day) for 2 weeks and 4) Metf group: received PTZ and metformin (200 mg/kg i.p. daily) for 2 weeks. RESULTS: administration of PTZ caused significant increase in seizure score and duration with a state of oxidative stress (high MDA, low GSH and CAT) and upregulation of beta-catenin, caspase-3 and its splitted products, Hsp70 and alpha-synuclein in hippocampal regions and significant reduction in seizure latency. While, Metf treatment ameliorated significantly PTZ-induced seizures, attenuated the oxidative stress and the upregulated alpha-synuclein and beta catenin expression, inhibited caspase-3 activation and the release of splitting product and caused more upregulation in Hsp70 expression in hippocampal regions (p< 0.05). CONCLUSION: Metf has antiepileptic and neuroprotective effects in PTZ induced epilepsy which might be due to inhibition of apoptosis, attenuation of oxidative stress and alpha-synuclein expression and upregulation of Hsp70. PMID- 30308131 TI - The Effects of Esophageal Acidification on Esophageal Reflexes Controlling the Upper Esophageal Sphincter. AB - The aim of this study was to determine the effects of esophageal acid exposure on esophago-UES relaxation (EURR) and contractile (EUCR) reflexes. Cats, decerebrate (N=27) or chronic (N=4), were implanted with EMG electrodes on pharynx, larynx and esophagus. The esophagus was infused with either NaCl (0.9%) or HCl (0.1 N). The EUCR was activated by balloon distension in acute cats and slow air injection in chronic cats, and the EURR was activated by rapid air injection in both sets of cats. We found that NaCl infused for 15 or 30 minutes had no effect on EUCR or EURR in acute cats. HCl infused for 15, 30 or 45 minutes significantly (P<0.05) decreased the sensitivity to activate EUCR. HCl infused for 15 minutes significantly (P<0.05) increased and for 45 minutes significantly (P<0.05) decreased sensitivity to activate EURR. In chronic cats, HCl infused for 15 minutes/day increased sensitivity to activate EURR and decreased (P<0.05) sensitivity to activate EUCR after 4 days of infusion. EURR occurred spontaneously during HCl infusions on the third and fourth (P < 0.05) days of HCl infusion. We conclude that esophageal acid exposure initially sensitizes the esophagus to activation of EURR and desensitizes to activation of EUCR, but with longer exposure desensitizes to both. The alteration in sensitivity to activate EURR and EUCR caused by gastro-esophageal reflux may play a role in the generation of supra-esophageal reflux. PMID- 30308133 TI - Update on the clinical management of juvenile dermatomyositis. AB - INTRODUCTION: Juvenile dermatomyositis (JDM) is a rare, chronic autoimmune illness with primary features of symmetric, proximal muscle weakness and involvement of the skin with a number of identifiable rashes. Evidence to support treatment decisions is limited, given the paucity of clinical trials. Consensus based methods, informed by available data, play an important role in treatment recommendations. Areas covered: This review focuses on evidence and consensus opinion regarding therapeutic options in JDM and identifies gaps where future research is needed. Expert commentary: The combination of trial evidence (as limited as it is) and consensus opinion support standard initial management for children with JDM to consist of high-dose corticosteroids, either intravenous or oral, and methotrexate. Several other agents have preliminary support, either through clinical trials or case series for their use in patients who either fail to respond adequately, have severe disease or have contraindications to standard initial therapy. One of the important goals of management in JDM will be to reduce the corticosteroid exposure experienced by patients. To meet this goal, progress in a number of key areas is needed: increased international collaboration, advances in study design and increased translational research. PMID- 30308132 TI - Current anti-biofilm strategies and potential of antioxidants in biofilm control. AB - INTRODUCTION: Biofilm formation is a strategy for microorganisms to adapt and survive in hostile environments. Microorganisms that are able to produce biofilms are currently recognized as a threat to human health. Areas covered: Many strategies have been employed to eradicate biofilms, but several drawbacks from these methods had subsequently raised concerns on the need for alternative approaches to effectively prevent biofilm formation. One of the main mechanisms that drives a microorganism to transit from a planktonic to a biofilm-sessile state, is oxidative stress. Chemical agents that could target oxidative stress regulators, for instance antioxidants, could therefore be used to treat biofilm associated infections. Expert commentary: The focus of this review is to summarize the function and limitation of the current anti-biofilm strategies and will propose the use of antioxidants as an alternative method to treat, prevent and eradicate biofilms. Studies have shown that water-soluble and lipid-soluble antioxidants can reduce and prevent biofilm formation, by influencing the expression of genes associated with oxidative stress. Further in vivo work should be conducted to ensure the efficacy of these antioxidants in a biological environment. Nevertheless, antioxidants are promising anti-biofilm agents, and thus is a potential solution for biofilm-associated infections in the future. PMID- 30308135 TI - Impact of Family History of Diabetes on Diabetes Control and Complications. AB - OBJECTIVE: Our aim was to assess the impact of parental and sibling history of type 2 diabetes (T2D) on patient characteristics, glycemic control, and T2D complications. METHODS: This cross-sectional study included adults with T2D. Type 1 diabetes and gestational diabetes patients were excluded. The laboratory data were retrieved from the patients' electronic files, and baseline measurements were obtained by the researchers. RESULTS: The study included a total of 511 T2D patients, with a mean age of 60.1 +/- 10.9 years and mean hemoglobin A1c of 8.94 +/- 2.1% (74.2 +/- 22.9 mmol/mol). Of these patients, 54% were male and 49.7% had a parental history of T2D. The patients with parental history of T2D were diagnosed at a younger age and had a higher body mass index (BMI) ( P = .035) and higher waist circumference (WC) ( P = .013) than those T2D patients with no parental history. Approximately 60% of the participants had siblings with a history of T2D, and in comparison with those with no sibling history, they had higher prevalence of cerebrovascular accidents ( P = .02). CONCLUSION: Having a parental history of T2D is significantly associated with diagnosis at a younger age and a higher BMI and WC. Having a sibling history of T2D is significantly associated with worse cerebrovascular outcome. ABBREVIATIONS: ACR = albumin to creatinine ratio; BMI = body mass index; DBP = diastolic blood pressure; DM = diabetes mellitus; FBG = fasting blood glucose; GFR = glomerular filtration rate; HbA1c = hemoglobin A1c; LDL = low-density lipoprotein; SBP = systolic blood pressure; T2D = type 2 diabetes; TG = triglyceride; WC = waist circumference. PMID- 30308134 TI - Ideglira is Associated With Improved Short-Term Clinical Outcomes and Cost Savings Compared with Insulin Glargine U100 Plus Insulin Aspart in the U.S. AB - OBJECTIVE: In the DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes) VII trial, IDegLira (a combination of insulin degludec and liraglutide) was compared with insulin glargine U100 plus insulin aspart. Both treatment approaches achieved similar glycemic control, but there were differences in hypoglycemia, changes in body weight, and injection frequency. The aim of the present analysis was to assess the short-term cost effectiveness of IDegLira versus insulin glargine U100 plus insulin aspart for treatment of patients with type 2 diabetes mellitus not meeting glycemic targets on basal insulin in the U.S. SETTING: METHODS: A cost-utility model was developed to evaluate the clinical and economic outcomes associated with the 2 treatments over a 1-year time horizon, capturing the impact on quality of life of hypoglycemic events, body mass index, and injection frequency. Costs were captured from a healthcare payer perspective in 2017 U.S. dollars ($). RESULTS: IDegLira was associated with improved quality of life by 0.12 quality-adjusted life years compared with insulin glargine U100 plus insulin aspart. The key drivers of this difference were reduced injection frequency and hypoglycemic events avoided. IDegLira was associated with increased annual drug costs, but this was entirely offset by reduced needle costs and reduced costs of self-monitoring of blood glucose testing. IDegLira was associated with total annual cost savings of $743 per patient. CONCLUSION: IDegLira was found to improve quality-adjusted life expectancy and reduce costs when compared with insulin glargine U100 plus insulin aspart for treatment of patients with type 2 diabetes not achieving glycemic control on basal insulin in the U.S. SETTING: ABBREVIATIONS: ADA = American Diabetes Association; BMI = body mass index; CI = confidence interval; DUAL = Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; ICER = incremental cost effectiveness ratio; IU = international units; QALY = quality-adjusted life year; SMBG = self-monitoring of blood glucose. PMID- 30308136 TI - Implementing Key Changes in the American Thyroid Association 2015 Thyroid Nodules/Differentiated Thyroid Cancer Guidelines Across Practice Types. AB - OBJECTIVE: This article provides suggestions to help clinicians implement important changes in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma ("ATA 2015") across diverse settings. METHODS: Key ATA 2015 changes are summarized regarding: ( 1) thyroid nodule management; ( 2) lobectomy versus thyroidectomy for differentiated thyroid carcinoma (DTC); and ( 3) surveillance following primary treatment of DTC. Advice to facilitate implementation is based on clinical experience and selected literature. RESULTS: Strategies are described to enhance acquisition of high-quality information that helps identify patients who may possibly avoid fine-needle aspiration (FNA) of thyroid nodules or total thyroidectomy for DTC, or undergo less intense postoperative surveillance. Sonographic imaging of nodules may improve if sonograms are obtained by clinicians ordering or performing FNA or trusted high-volume sonographers. Cytopathologic assessment and reporting can be improved by working with regional or national experts. Pre-operative evaluation by endocrinologists is important so that patients are referred to experienced, proficient surgeons and assisted with well-informed decision-making regarding surgical radicality. Endocrinologists and surgeons should ensure performance of pre-operative neck ultrasonography, voice/laryngeal evaluation, and contrast-enhanced cross-sectional imaging when appropriate. Findings should be disseminated to all healthcare team members, ideally through a comprehensive medical record accessible to the entire team. CONCLUSION: Optimization of the sequence of specialist visits and assembly of interactive multidisciplinary teams coupled with intensified interdisciplinary and patient communication may enable clinicians to more effectively implement ATA 2015, which calls for more individualized, and often, less "invasive" management of thyroid nodules and DTC. ABBREVIATIONS: ATA 2009 = 2009 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; ATA 2015 = 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; DTC = differentiated thyroid carcinoma; FNA = fine-needle aspiration; PET/CT = positron emission tomography/computed tomography. PMID- 30308137 TI - Association of soluble TREM-like transcript-1 with clinical features and patient reported outcomes in systemic lupus erythematosus. AB - OBJECTIVE: The soluble triggering receptor expressed on myeloid cells (TREM-1) like transcript 1 (sTLT-1) has a modulatory effect on the activation of TREM-1. We compared plasma sTLT-1 levels between patients with systemic lupus erythematosus (SLE) and healthy individuals and determined the association between sTLT-1 levels and clinical features and patient-reported outcomes (PROs) among patients with lupus. METHODS: An unmatched case-control study was conducted in 46 patients with SLE and 28 healthy subjects. sTLT-1 plasma levels were determined using enzyme-linked immunosorbent assay. Demographic factors, SLE manifestations, comorbidities, pharmacologic profile, disease activity (per SLAM R), damage accrual, and PROs (as per Lupus Patient-Reported Outcome [LupusPRO]) were studied. RESULTS: Patients with SLE were found to have lower sTLT-1 levels compared with healthy individuals (9.0+/-7.2 vs. 18.6+/-22.3 pg/mL, p=0.008). Among patients with SLE, higher sTLT-1 levels were found in those taking corticosteroids (11.1+/-8.8 vs. 6.9+/-4.6 pg/mL, p=0.014). Significant correlations were found for the cognition (r=-0.442, p=0.027) and desires/goals (r=0.435, p=0.030) domains of LupusPRO. A tendency was observed between sTLT-1 levels and the SLAM-R (r=-0.278, p=0.064) and the lupus symptoms (r=-0.388, p=0.055) and physical health (r=-0.382, p=0.060) domains of LupusPRO. CONCLUSION: Compared with healthy individuals, sTLT-1 levels were significantly lower in patients with SLE. Among patients with SLE, correlations were observed for some domains of LupusPRO. Given that sTLT-1 has anti-inflammatory properties, the deficiency of this protein could play an important role in the pathogenesis of SLE. PMID- 30308138 TI - Chronic large nasal bloody crusting and recurrent episcleritis: Limited granulomatosis with polyangiitis. PMID- 30308140 TI - Transient osteoporosis of the hip. PMID- 30308139 TI - Clinical characteristics and prognosis of Neuro-Behcet's disease. AB - OBJECTIVE: Neuro-Behcet's disease (NBD) is a rare manifestation of Behcet's disease (BD) and may cause severe disability. The aim of this study was to evaluate the treatment response in patients with NBD and to investigate the parameters that may influence the prognosis of the disease in patients with severe to mild-moderate disability. METHODS: The files of 60 patients admitted to our outpatient clinic for NBD between January 2007 and June 2014 were retrospectively reviewed. We compared the BD duration, time to NBD, NBD type and course, clinical findings of BD, functional neurological system involvement, localization of lesions on brain MRI, and all the medications between the severe and mild-moderate disability groups. RESULTS: The mean time to the onset of NBD was significantly longer (17.8+/-4.6 years) and the mean age was significantly higher (50.25+/-9.1 years) in patients with severe disability than in those with mild-moderate disability (7.5+/-8.0 years and 37.5+/-10.9 years; p=0.01 and p=0.03, respectively). Moreover, hemispheric involvement was significantly associated with severe disability (p=0.006). No difference was found with regard toother investigated parameters between the groups. CONCLUSION: We believe that severe neurological disability may be associated with older age at the onset of NBD or longer time to NBD and hemispheric lesions on brain MRI. However, our results should be cautiously evaluated with further research. PMID- 30308142 TI - Disseminated hollow and solid lung nodules as a unique pulmonary manifestation of rheumatoid arthritis. PMID- 30308141 TI - Relationship between interstitial CD34 positive cells and active phase of lupus nephritis. AB - OBJECTIVE: Lupus nephritis is one of the most serious and common complications of systemic lupus erythematosus. It has an unpredictable course, and the type, severity, and activity of renal lesions cannot be assessed only by clinical and laboratory findings. The aim of the present study was to determine the relationship between the expression of CD34 and the histopathological findings of lupus nephritis. METHODS: A total of 73 renal biopsy samples of patients with a diagnosis of lupus nephritis were examined for CD34 expression by immunohistochemistry. Samples without staining were considered as 0, mild staining as 1+, moderate as 2+, and strong staining as 3+. The relationship between CD34 expression and histopathological and clinical data (including activity index, chronicity index, lupus nephritis class, age, sex, blood pressure, complete blood count, renal function tests, and serological findings) was analyzed. RESULTS: The mean age of the patients was 29.3+/-11.3 years. CD34 was expressed in all of the cases but with different intensities. There was a significant relationship between the expression of CD34 and the activity index, as a strong expression was seen in lower activity indices (p<0.001). CD34 expression was correlated with patients' white blood cell (WBC) count and systolic blood pressure (SBP). Patients with strong (score 3) CD34 expression had higher SBPs and lower WBC counts (p=0.03 and 0.04, respectively). CONCLUSION: A strong interstitial expression of CD34 was observed in lower activity indices. It seems that CD34 expression could play a protective role in lupus nephritis and could reduce renal activity. PMID- 30308143 TI - Unilateral shortening of third metacarpal bone in a patient with tuberous sclerosis. PMID- 30308144 TI - Acro-osteolysis. PMID- 30308145 TI - The time has come to invest more in the prevention of day care-associated infection in children. PMID- 30308146 TI - Relationship Between Nasal Fracture and Blowout Fracture: Can Nasal Fracture Be a Predictor of Blowout Fracture? AB - PURPOSE: Nasal and blowout fractures are the most common injuries from craniomaxillofacial trauma. Nasal fractures are easily diagnosed by clinical signs, such as pain and crepitus. However, blowout fractures are frequently asymptomatic and are easy to miss without computed tomographic (CT) scanning. This study analyzed the relation between the 2 fracture types to determine whether nasal fracture could be used as a predictor of blowout fracture. MATERIALS AND METHODS: CT scans of 1,368 patients who underwent reduction surgery for nasal fracture were retrospectively reviewed. The pattern of nasal fractures (n = 1,368) was classified as frontal or lateral according to the direction of impact. Blowout fractures (n = 297) were classified into 3 types according to the position of the fracture: medial, inferior, or inferomedial wall. After calculating the number of patients in each group, the relation between nasal and blowout fracture types was statistically analyzed. RESULTS: Of 305 patients with frontal-type nasal fractures, the incidence of medial, inferior, and inferomedial wall fracture was 26, 7, and 9, respectively. Of 1,063 patients with lateral-type nasal fractures, the incidence of medial, inferior, and inferomedial wall fracture was 118, 75, and 62, respectively. Medial wall fracture was most common in the 2 nasal fracture groups and showed a higher frequency in the lateral-type group. CONCLUSIONS: This study showed a strong relation between nasal fractures and medial wall blowout fractures. If nasal fracture is suspected, especially the lateral type, then thorough examination for medial wall blowout fracture, with a high index of suspicion, should be performed. PMID- 30308147 TI - Integrative Review of Pregnancy Health Risks and Outcomes Associated With Adverse Childhood Experiences. AB - OBJECTIVE: To identify pregnancy risk factors and outcomes associated with a woman's history of adverse childhood experiences (ACEs) and summarize what is known about routine screening for ACEs as part of prenatal care. DATA SOURCES: The Academic Search Premier, Academic Search Complete, CINAHL, Health Source: Nursing Academic Edition, MEDLINE, PsychINFO, and PubMed databases were searched. The terms adverse childhood experiences or ACEs, trauma informed care, and childhood trauma were each paired individually with the terms pregnancy or pregnant or prenatal or antenatal or perinatal or maternal; obstetrics; and maternal-child health. STUDY SELECTION: Database and reference list searches resulted in 1,626 articles with 230 retained for full review and 17 included in the final sample. Studies were included if results were reported specific to pregnancy and ACEs as operationally defined in the ACE Study. DATA EXTRACTION: Studies were evaluated for methodologic quality using Joanna Briggs Institute appraisal tools. Data were extracted with the matrix method. Tabular synthesis was used to cluster and compare findings and identify themes. DATA SYNTHESIS: Five categories of pregnancy health risks and outcomes related to ACEs were identified: physiologic risk, psychologic risk, social risk, behavioral risk, and negative pregnancy outcomes. Limited research was found on routine screening for ACEs as part of prenatal care, but findings indicated women's support for ACE screening during prenatal appointments. CONCLUSION: Routine prenatal ACE screening may be accepted by women and may help identify significant pregnancy health risks. This could provide opportunities for interventions that improve pregnancy outcomes. More research is needed to determine the most effective and efficient methods to screen pregnant women for ACEs and intervene for those with high screening scores. To optimally advance science in this area, conceptual and operational clarity in ACE research is important. Nurses should be at the forefront of these research and practice translation efforts. PMID- 30308148 TI - A Sugar Rush for Innate Immunity. AB - Early detection of microbial patterns is a hallmark of innate immunity and essential for clearance of invading pathogens. A recent Nature publication by Zhou et al. (2018) has uncovered ALPK1 as a pattern recognition receptor for Gram negative bacteria triggering NF-kappaB activation and identified the bacterial sugar ADP-Hep as its ligand. PMID- 30308149 TI - Open Sesame: New Keys to Unlocking the Gate to Norovirus Infection. AB - Three recent papers highlight the impact of an entry receptor on murine norovirus pathogenesis. CD300lf was shown to be the first proteinaceous entry receptor for a norovirus, specialized intestinal epithelial cells constitute the reservoir for persistence, and a new link between the receptor and a lipid biosynthetic enzyme was revealed. PMID- 30308151 TI - Better Safe than Sorry: A Dual-Function Viral Protein Inhibiting Host Defense. AB - Viruses employ intricate means to evade host innate immune systems. In this issue of Cell Host & Microbe, Nayak et al. (2018) demonstrate that the cricket paralysis virus (CrPV) protein CrPV-1A blocks host defense through a dual mechanism: directly inhibiting Argonaute2 (Ago2) and simultaneously targeting Ago2 for proteasomal degradation. PMID- 30308150 TI - Hijacking Host Angiogenesis to Drive Mycobacterial Growth. AB - In this issue of Cell Host & Microbe, Walton et al. (2018) uncover the mycobacterial factors that activate VEGF signaling and promote aberrant angiogenesis in the tuberculous granuloma. Preventing abnormal angiogenesis in the granuloma represents a potential therapeutic approach for tuberculosis. PMID- 30308152 TI - Gutting TMA to Save the Heart. AB - Microbial activities of gut commensals have been linked to several host diseases. In recent work, Roberts et al. (2018) develop therapeutics targeting microbial production of the metabolite trimethylamine (TMA), which has been linked to cardiovascular disease. This microbiota-based approach holds promise for efficacious therapies that may also reduce host side effects. PMID- 30308153 TI - Microbiomes through the Looking Glass: What Do UC? AB - Pediatric ulcerative colitis incidence is rapidly rising, yet improved prognostic and therapeutic strategies are needed. In this issue of Cell Host & Microbe, Schirmer et al. (2018) reveal the dynamism of pediatric patient microbiomes through initial diagnosis and treatments, providing insights into microbial targets that predict therapeutic response and disease outcomes. PMID- 30308154 TI - Elucidating Bacterial Gene Functions in the Plant Microbiome. AB - There is a growing appreciation for the important roles microorganisms play in association with plants. Microorganisms are drawn to distinct plant surfaces by the nutrient-rich microenvironment, and in turn some of these colonizing microbes provide mutualistic benefits to their host. The development of plant probiotics to increase crop yield and provide plant resistance against biotic and abiotic stresses, while minimizing chemical inputs, would benefit from a deeper mechanistic understanding of plant-microbe interaction. Technological advances in molecular biology and high-throughput -omics provide stepping stones to the elucidation of critical microbiome gene functions that aid in improving plant performance. Here, we review -omics-based approaches that are propelling forward the current understanding of plant-associated bacterial gene functions, and describe how these technologies have helped unravel key bacterial genes and pathways that mediate pathogenic, beneficial, and commensal host interactions. PMID- 30308155 TI - A Single-Dose Live-Attenuated Zika Virus Vaccine with Controlled Infection Rounds that Protects against Vertical Transmission. AB - Zika virus (ZIKV) infection of the mother during pregnancy causes devastating Zika congenital syndrome in the offspring. A ZIKV vaccine with optimal safety and immunogenicity for use in pregnant women is critically needed. Toward this goal, we have developed a single-dose live-attenuated vaccine candidate that infects cells with controlled, limited infection rounds. The vaccine contains a 9-amino acid deletion in the viral capsid protein and replicates to titers of > 106 focus forming units (FFU)/mL in cells expressing the full-length capsid protein. Immunization of A129 mice with one dose (105 FFU) did not produce viremia, but elicited protective immunity that completely prevented viremia, morbidity, and mortality after challenge with an epidemic ZIKV strain (106 PFU). A single-dose vaccination also fully prevented infection of pregnant mice and maternal-to-fetal transmission. Intracranial injection of the vaccine (104 FFU) to 1-day-old mice did not cause any disease or death, underscoring the safety of this vaccine candidate. PMID- 30308156 TI - Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis. AB - Sepsis is a life-threatening inflammatory syndrome accompanying a bloodstream infection. Frequently secondary to pathogenic bacterial infections, sepsis remains difficult to treat as a singular disease mechanism. We compared the pathogenesis of murine sepsis experimentally elicited by five bacterial pathogens and report similarities among host responses to Gram-negative Salmonella and E. coli. We observed that a host protective mechanism involving de-toxification of lipopolysaccharide by circulating alkaline phosphatase (AP) isozymes was incapacitated during sepsis caused by Salmonella or E. coli through activation of host Toll-like receptor 4, which triggered Neu1 and Neu3 neuraminidase induction. Elevated neuraminidase activity accelerated the molecular aging and clearance of AP isozymes, thereby intensifying disease. Mice deficient in the sialyltransferase ST3Gal6 displayed increased disease severity, while deficiency of the endocytic lectin hepatic Ashwell-Morell receptor was protective. AP augmentation or neuraminidase inhibition diminished inflammation and promoted host survival. This study illuminates distinct routes of sepsis pathogenesis, which may inform therapeutic development. PMID- 30308158 TI - A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability. AB - The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2 binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity. PMID- 30308157 TI - Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling. AB - Mycobacterial infection leads to the formation of characteristic immune aggregates called granulomas, a process accompanied by dramatic remodeling of the host vasculature. As granuloma angiogenesis favors the infecting mycobacteria, it may be actively promoted by bacterial determinants during infection. Using Mycobacterium marinum-infected zebrafish as a model, we identify the enzyme proximal cyclopropane synthase of alpha-mycolates (PcaA) as an important bacterial determinant of granuloma-associated angiogenesis. cis-Cyclopropanation of mycobacterial mycolic acids by pcaA drives the activation of host Vegf signaling within granuloma macrophages. Cyclopropanation of the mycobacterial cell wall glycolipid trehalose dimycolate is both required and sufficient to induce robust host angiogenesis. Inducible genetic inhibition of angiogenesis and Vegf signaling during granuloma formation results in bacterial growth deficits. Together, these data reveal a mechanism by which PcaA-mediated cis cyclopropanation of mycolic acids promotes bacterial growth and dissemination in vivo by eliciting granuloma vascularization and suggest potential approaches for host-directed therapies. PMID- 30308159 TI - Recurring and Adaptable Binding Motifs in Broadly Neutralizing Antibodies to Influenza Virus Are Encoded on the D3-9 Segment of the Ig Gene. AB - Discovery and characterization of broadly neutralizing antibodies (bnAbs) to the influenza hemagglutinin (HA) stem have provided insights for the development of a universal flu vaccine. Identification of signature features common to bnAbs from different individuals will be key to guiding immunogen design. S9-3-37 is a bnAb isolated from a healthy H5N1 vaccinee. Here, structural characterization reveals that the D3-9 gene segment of S9-3-37 contributes most of the interaction surface with the highly conserved stem epitope on HA. Comparison with other influenza bnAb crystal structures indicates that the D3-9 segment provides a general mechanism for targeting HA stem. Interestingly, such bnAbs can approach the HA stem with vastly different angles and orientations. Moreover, D3-9 can be translated in different reading frames in different bnAbs yet still target the same HA stem pocket. Thus, the D3-9 gene segment in the human immune repertoire can provide a robust defense against influenza virus. PMID- 30308160 TI - Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. AB - HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 A and 4.06 A cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4 induced rearrangements that result in V1V2 displacement and formation of a 4 stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor induced Env changes and inform design of therapeutics disrupting viral entry. PMID- 30308162 TI - Correction. PMID- 30308163 TI - The Blind Men and the Elephant: The Quest for Open Data Repositories. AB - Nonhuman primate imaging is maturing into a solid subfield within basic and translational neurosciences. In the present issue of Neuron, Milham et al. (2018) present a data repository to openly share anatomical, functional, and diffusion based neuroimaging data from monkeys. PMID- 30308164 TI - Pericytes: The Brain's Very First Responders? AB - Infection can negatively impact brain functions. Here, Duan et al. (2018) show that specific PDGFRbeta-expressing cell subtypes of the neurovascular unit release the chemokine CCL2 rapidly after systemic infection, leading to increased neural excitability. PMID- 30308165 TI - CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. AB - Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPalpha, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPalpha signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs. PMID- 30308161 TI - Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course. AB - Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care. PMID- 30308167 TI - Progress and Future Goals for Neuroscience. AB - Scientists reflect on how neuroscience has quickly progressed and continues to open new avenues for great discovery with improvements in imaging, interrogating, and interfacing with the nervous system of experimental model systems and humans. PMID- 30308166 TI - Subtype Diversification and Synaptic Specificity of Stem Cell-Derived Spinal Interneurons. AB - Neuronal diversification is a fundamental step in the construction of functional neural circuits, but how neurons generated from single progenitor domains acquire diverse subtype identities remains poorly understood. Here we developed an embryonic stem cell (ESC)-based system to model subtype diversification of V1 interneurons, a class of spinal neurons comprising four clades collectively containing dozens of molecularly distinct neuronal subtypes. We demonstrate that V1 subtype diversity can be modified by extrinsic signals. Inhibition of Notch and activation of retinoid signaling results in a switch to MafA clade identity and enriches differentiation of Renshaw cells, a specialized MafA subtype that mediates recurrent inhibition of spinal motor neurons. We show that Renshaw cells are intrinsically programmed to migrate to species-specific laminae upon transplantation and to form subtype-specific synapses with motor neurons. Our results demonstrate that stem cell-derived neuronal subtypes can be used to investigate mechanisms underlying neuronal subtype specification and circuit assembly. PMID- 30308168 TI - The STATe of the Neuron Leads to Synaptic Stripping. AB - In a recent issue of Cell, Di Liberto et al. (2018) elucidate the mechanisms involved in synaptic stripping during viral infection. Infected neurons orchestrate their own synaptic loss downstream of IFNgamma signaling, ultimately attracting phagocytic monocytes into the CNS through CCL2 production. PMID- 30308170 TI - Spinal Interneurons "a La Carte". AB - The study of interneuron diversity in the spinal cord is complex and needs new models that can accelerate discovery. In this issue, Hoang et al. (2018) use ESC derived neurons to create simplified microcircuits to study spinal interneuron diversification, connectivity, and function. PMID- 30308169 TI - Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives. AB - Increasingly, national governments across the globe are prioritizing investments in neuroscience. Currently, seven active or in-development national-level brain research initiatives exist, spanning four continents. Engaging with the underlying values and ethical concerns that drive brain research across cultural and continental divides is critical to future research. Culture influences what kinds of science are supported and where science can be conducted through ethical frameworks and evaluations of risk. Neuroscientists and philosophers alike have found themselves together encountering perennial questions; these questions are engaged by the field of neuroethics, related to the nature of understanding the self and identity, the existence and meaning of free will, defining the role of reason in human behavior, and more. With this Perspective article, we aim to prioritize and advance to the foreground a list of neuroethics questions for neuroscientists operating in the context of these international brain initiatives. PMID- 30308172 TI - The Long and Short of It: A Dwarf Neurexin Suffices for Synapse Assembly. AB - Neurexins have been established as a major coordinator of synapse assembly, functioning through interactions with postsynaptic cell adhesion molecules. Kurshan et al. (2018) now show that a C. elegans "dwarf neurexin" lacking its extracellular interaction domains can conduct synapse formation independent of postsynaptic partners. PMID- 30308171 TI - A Head-Mounted Camera System Integrates Detailed Behavioral Monitoring with Multichannel Electrophysiology in Freely Moving Mice. AB - Breakthroughs in understanding the neural basis of natural behavior require neural recording and intervention to be paired with high-fidelity multimodal behavioral monitoring. An extensive genetic toolkit for neural circuit dissection, and well-developed neural recording technology, make the mouse a powerful model organism for systems neuroscience. However, most methods for high bandwidth acquisition of behavioral data in mice rely upon fixed-position cameras and other off-animal devices, complicating the monitoring of animals freely engaged in natural behaviors. Here, we report the development of a lightweight head-mounted camera system combined with head-movement sensors to simultaneously monitor eye position, pupil dilation, whisking, and pinna movements along with head motion in unrestrained, freely behaving mice. The power of the combined technology is demonstrated by observations linking eye position to head orientation; whisking to non-tactile stimulation; and, in electrophysiological experiments, visual cortical activity to volitional head movements. PMID- 30308174 TI - The Fountain of Youth: It's All in Our Veins. AB - Cardiovascular dysfunction becomes recognized as a risk for dementia. In this issue of Neuron, Park et al. (2018) report the age-related, brain endothelial specific upregulation of acid sphingomyelinase (ASM), leading to blood-brain barrier malfunction, neurodegeneration, and memory deficits that were mitigated by ASM inhibition in mice. PMID- 30308175 TI - Bridging the translational divide: Emerging strategies in pharmacological approaches to traumatic brain injury. PMID- 30308176 TI - Nonlinear harmonic generation in the corticothalamic system. AB - Neural field theory of the corticothalamic system is applied to quantitatively analyze harmonic generation in normal sleep and wake states. The linear power spectrum is derived analytically via the transfer function and is then convolved with itself and other factors to calculate the nonlinear power spectrum analytically via a recent perturbation expansion. Analysis shows that strong spectral peaks generate a harmonic at twice the original frequency with peak power proportional to the square of that of the original peak. Fits to the data enable absolute normalization to be determined, with the conclusion that the experimentally observed spindle harmonic peak is nonlinear. Using this normalization, the same analysis is applied to the wake state and nonlinear contributions to the alpha and beta peaks are quantified. PMID- 30308173 TI - Abrogating Native alpha-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease. AB - alpha-Synuclein (alphaS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of alphaS, alpha-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E->K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. alphaS monomers accumulate at membranes and form vesicle-rich inclusions. alphaS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal alphaS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications. PMID- 30308177 TI - Dropwise Additive Manufacturing of Pharmaceutical Products Using Particle Suspensions. AB - The principal method of drug delivery is by oral solid doses, the production of which often necessitates multiple post-crystallization unit operations to ensure content uniformity or enhance bioavailability. As an alternative to conventional dose production methods, applications of additive manufacturing technologies based on solvent- or melt-based formulations have demonstrated the potential for improvements to process efficiency, flexibility, and dosing precision. Here we explore the use of particulate suspensions in a dropwise additive manufacturing process as a method for dosing active ingredients in crystalline form, which may be difficult to achieve via powder processing due to poor flow properties. By employing a fluid-based method, powder flow issues are alleviated and adaptation of the process to new particles/crystals is facilitated by dimensional analysis. In this work, a feasibility study was conducted using 4 active ingredient powders, each with non-ideal particle properties, and 2 carrier fluids, in which the active ingredient does not dissolve, to formulate suspensions for dose manufacturing; drug products were analyzed to show reproducibility of dosing and to assess preservation of particle size through the process. Performance across particle types is affected by particle size and shape, and is related through effects on the rheological properties of the formulation. PMID- 30308178 TI - The Wright-Fisher site frequency spectrum as a perturbation of the coalescent's. AB - The first terms of the Wright-Fisher (WF) site frequency spectrum that follow the coalescent approximation are determined precisely, with a view to understanding the accuracy of the coalescent approximation for large samples. The perturbing terms show that the probability of a single mutant in the sample (singleton probability) is elevated in WF but the rest of the frequency spectrum is lowered. A part of the perturbation can be attributed to a mismatch in rates of merger between WF and the coalescent. The rest of it can be attributed to the difference in the way WF and the coalescent partition children between parents. In particular, the number of children of a parent is approximately Poisson under WF and approximately geometric under the coalescent. Whereas the mismatch in rates raises the probability of singletons under WF, its offspring distribution being approximately Poisson lowers it. The two effects are of opposite sense everywhere except at the tail of the frequency spectrum. The WF frequency spectrum begins to depart from that of the coalescent only for sample sizes that are comparable to the population size. These conclusions are confirmed by a separate analysis that assumes the sample size n to be equal to the population size N. Partly thanks to the canceling effects, the total variation distance of WF minus coalescent is 0.12/logN for a population sized sample with n=N, which is only 1% for N=2*104. The coalescent remains a good approximation for the site frequency spectrum of large samples. PMID- 30308179 TI - Stationary distribution of a 2-island 2-allele Wright-Fisher diffusion model with slow mutation and migration rates. AB - The stationary distribution of the diffusion limit of the 2-island, 2-allele Wright-Fisher with small but otherwise arbitrary mutation and migration rates is investigated. Following a method developed by Burden and Tang (2016, 2017) for approximating the forward Kolmogorov equation, the stationary distribution is obtained to leading order as a set of line densities on the edges of the sample space, corresponding to states for which one island is bi-allelic and the other island is non-segregating, and a set of point masses at the corners of the sample space, corresponding to states for which both islands are simultaneously non segregating. Analytic results for the corner probabilities and line densities are verified independently using the backward generator and for the corner probabilities using the coalescent. PMID- 30308180 TI - Sexually active bucks are a critical social cue that activates the gonadotrope axis and early puberty onset in does. AB - In rodents, early exposure to adult male is well known to induce an early puberty in females (Vandenbergh effect). This phenomenon has been less studied in other mammals. In goats, despite our extensive knowledge about the "male-effect" phenomenon in adults (i.e. ovulation induced by the introduction of the male during the anestrous), there are few data on the consequences of an early exposure of females to males. Here, we evaluated the puberty onset of young alpine goats when raised since weaning with intact bucks (INT), with castrated bucks (CAS) or isolated from bucks (ISOL). The INT group had the first ovulation 1.5 month before the two other groups. Despite the earlier puberty the INT group of females had normal and regular ovarian cycles. Morphological study of the genital tract showed that at 6 months, uterus of INT goats was 40% heavier than CAS and ISOL goats. Moreover, INT females had a myometrium significantly thicker and INT was the only group having corpora lutea. In our study, INT females were pubescent in the month following the entry of bucks into the breeding season, suggesting that only sexually active bucks provide the signal responsible for puberty acceleration. By removing direct contact with the bucks, we showed that somatosensory interactions were dispensable for an early puberty induction. Finally, no difference in the GnRH network (fiber density and number of synaptic appositions) can be detected between pubescent and non-pubescent females, suggesting that the male stimulations triggering puberty onset act probably on upstream neuronal networks, potentially on kisspeptin neurons. PMID- 30308181 TI - Intracellular calcium and NF-kB regulate hypoxia-induced leptin, VEGF, IL-6 and adiponectin secretion in human adipocytes. AB - AIMS: Hypoxia-induced adipokine release has been attributed mainly to HIF-1alpha. Here we investigate the role of intracellular calcium and NF-kB in the hypoxia dependent release of leptin, VEGF, IL-6 and the hypoxia-induced inhibition of adiponectin release in human adipocytes. MAIN METHODS: We used intracellular calcium imaging to compare calcium status in preadipocytes and in adipocytes. We subjected both cell types to hypoxic conditions and measured the release of adipokines induced by hypoxia in the presence and absence of HIF-1alpha inhibitor YC-1, NF-kappaB inhibitor SN50 and intracellular calcium chelator BAPTA-AM. KEY FINDINGS: We demonstrate reduced intracellular calcium oscillations and increased oxidative stress as the cells transitioned from preadipocytes to adipocytes. We show that differentiation of preadipocytes to adipocytes is associated with distinct morphological changes in the mitochondria. We also show that hypoxia induced secretion of leptin, VEGF, IL-6 and hypoxia-induced inhibition of adiponectin secretion are independent of HIF-1alpha expression. The hypoxia induced leptin, VEGF and IL-6 release are [Ca++]i dependent whereas adiponectin is NF-kB dependent. SIGNIFICANCE: Our work suggests a major role for [Ca++]i in preadipocyte differentiation to adipocytes and that changes in mitochondrial morphology in the adipocytes might underlie the reduced calcium oscillations observed in the adipocytes. It also demonstrates that multiple signaling pathways are associated with the hypoxia-induced adipokine secretion. PMID- 30308182 TI - Stem cell factor and NSC87877 synergism enhances c-Kit mediated proliferation of human erythroid cells. AB - The biological mechanisms underlying the effects of stem cell factor (SCF) and an inhibitor, NSC87877 (N) of the c-Kit negative regulator (SHP-1 and SHP-2) on cell proliferation are different. Therefore, we compared the cell's response to these two either alone or in combination in K562 cells. Binding of SCF (S) to c-Kit induces dimerization that activates its kinase activity. The activated c-Kit undergoes autophosphorylation at tyrosine residues that serve as a docking site for signal transduction molecules containing SH2 domains. Predominantly, the phosphotyrosine 568 (pY568) in Juxtamembrane (JM) region of c-Kit interacts with adaptor protein APS, Src family kinase, and SHP-2, while phosphotyrosine 570 (pY570) interacts with the SHP-1 and the adaptor protein Shc. The dephosphorylation of phosphotyrosine residues by SHP-1/SHP-2 leads to inhibition of c-Kit proliferative signaling. A chemical molecule, N is reported to inhibit the enzymatic activity of SHP-1/SHP-2, but its effect on c-Kit-mediated proliferation has not been studied yet. Thus, this work aims at examining the effect of the combination of S and N on cells growth as compared to individual treatment. The present study is performed with erythroleukemic K562 cells, chosen for its mRNA expression concerning the c-Kit, and SHP-1/SHP-2. Interestingly, proliferation assay showed that combination significantly increased proliferation when G1 sorted K562 cells were used. These changes were significantly higher when K562 cells were initially treated with N followed by S treatment. Collectively, these results give mechanistic insight into the proliferation enhancement of bone marrow transplantation through the synergistic effect of S and N by inhibiting SHP-1/SHP-2. The study gives solid evidence that S and N combination can be used to enhance cell proliferation/growth. PMID- 30308184 TI - Silibinin to improve cancer therapeutic, as an apoptotic inducer, autophagy modulator, cell cycle inhibitor, and microRNAs regulator. AB - Silibinin is a natural plant polyphenol with high antioxidant and anticancer properties, which causes broad-spectrum efficacy against cancer, including cell cycle arrest and apoptosis in most cancer cell types. Silibinin, by modulating the apoptosis, cell cycle progression and autophagic pathways in various cellular and molecular routs might be used to design more effective anticancer strategies. Silibinin also regulates aberrant miRNAs expression linked to many aspects of cell biology in cancer. Maybe the most interesting aspect of silibinin is its ability to trigger multiple cellular signaling pathways to induce a particular biologic effect in various cell types. This review discusses investigations supporting the ability of silibinin to be as a natural modulator of involved cellular biological events in cancer progression. In this review, we introduce the salient features of silibinin therapy to optimize clinical outcomes for oncology patients. The goal of the treatments is to make it possible to eliminate the tumor with the minimum side effects and cure the patient in the early stage cancer. Therefore, plant extracts such as silibinin can be included in the treatments. PMID- 30308183 TI - MiR-185-5p suppresses HBV gene expression by targeting ELK1 in hepatoma carcinoma cells. AB - AIMS: To investigate the role and underlying mechanism of miR-185-5p in hepatitis B virus (HBV) expression and replication. MAIN METHODS: The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme linked immunosorbent assay (ELISA). The HBV DNA copies in the cultures medium were measured by RT-qPCR. The HBV large surface antigen promoter (S1p) activity was analyzed by luciferase reporter assay. The target relationship between miR 185-5p and ELK1 was identified by bioinformatics analysis and EGFP fluorescent reporter assay. The ELK1 expression was determined by RT-qPCR and Western blot. KEY FINDINGS: miR-185-5p significantly decreased HBV large surface antigen promoter activity and subsequently the production of HBV proteins and HBV DNA copies in vitro. Further, we identified the ETS transcription factor ELK1 is a target of miR-185-5p. Overexpression and knockdown experiments showed overexpression of ELK1 stimulated HBV large surface antigen promoter activity and promoted the production of HBV proteins and HBV DNA copies, whereas knockdown of ELK1 has the opposite effects. Moreover, the rescue of ELK1 expression reversed the suppression of miR-185-5p on HBV replication and gene expression. Further mechanistic study showed that the ETS binding sites within the HBV large surface antigen promoter are required for the repression effect of miR-185-5p on HBV. SIGNIFICANCE: There are few reports about the interaction between miRNAs and the transcription from HBV S1p, we found that miR-185-5p decreases HBV S1p activity by targeting ELK1, which may provide a promising therapeutic strategy for HBV infection. PMID- 30308185 TI - MicroRNA-148b-3p is involved in regulating hypoxia/reoxygenation-induced injury of cardiomyocytes in vitro through modulating SIRT7/p53 signaling. AB - Accumulating evidence has suggested that microRNAs (miRNAs) are emerging as critical regulators in myocardial ischemia/reperfusion injury. miR-148b-3p has been reported to regulate cell apoptosis of various cell types. However, whether miR-148b-3p is involved in regulating cardiomyocyte apoptosis in myocardial ischemia/reperfusion injury remains unknown. In this study, we aimed to investigate the potential role and molecular mechanism of miR-148b-3p in regulating cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) injury in vitro, a cellular model of myocardial ischemia/reperfusion injury. We found that miR-148b-3p expression was significantly up-regulated in response to H/R treatment in cardiomyocytes. Functional experiments showed that miR-148b-3p overexpression significantly decreased the viability, increased LDH release and promoted the apoptosis of H/R-treated cardiomyocytes. In contrast, miR-148b-3p inhibition improved the viability, decreased LDH release and reduced the apoptosis of H/R-treated cardiomyocytes, showing a protective effect against H/R induced injury. Bioinformatics analysis predicted that Sirtuin7 (SIRT7), a critical stress survival gene of cardiomyocytes, was a potential target gene of miR-148b-3p, which was then validated by dual-luciferase reporter assay, real time quantitative polymerase chain reaction and Western blot analysis. Moreover, our results showed that miR-148b-3p regulated the acetylation of the p53 protein and modulated p53-mediated pro-apoptotic signaling through targeting SIRT7. Notably, the silencing of SIRT7 significantly abrogated miR-148b-3p inhibition mediated cardio-protective effects, while SIRT7 overexpression rescued miR-148b 3p-induced cell apoptosis in cardiomyocytes with H/R treatment. Overall, our results indicate that miR-148b-3p contributes to the regulation of H/R-induced cardiomyocyte apoptosis in vitro through targeting SIRT7 and modulating p53 mediated pro-apoptotic signaling. PMID- 30308186 TI - Autonomic Disorders. AB - Autonomic complaints are frequently encountered in clinical practice. They can be due to primary autonomic disorders or secondary to other medical conditions. Primary autonomic disorders can be categorized as orthostatic intolerance syndromes and small fiber neuropathies; the latter are associated with autonomic failure, pain, or their combinations. The review outlines orthostatic intolerance syndromes (neurally mediated syncope, orthostatic hypotension, postural tachycardia syndrome, inappropriate sinus tachycardia, orthostatic cerebral hypoperfusion syndrome, and hypocapnic cerebral hypoperfusion) and small fiber neuropathies (sensory/autonomic/mixed, acute/subacute/chronic, idiopathic/secondary, inflammatory and noninflammatory). Several specific autonomic syndromes (diabetic neuropathy, primary hyperhidrosis, paroxysmal sympathetic hyperactivity, autonomic dysreflexia), neurogenic bladder, and gastrointestinal motility disorders are discussed as well. PMID- 30308187 TI - A rare STAP1 mutation incompletely associated with familial hypercholesterolemia. AB - Autosomal dominant hypercholesterolemia, being referred to as familial hypercholesterolemia (FH), is mainly due to defective LDL receptor (LDLR) function, but is also associated with variants in genes encoding APOB (LDLR ligand) and PCSK9, the catabolic regulator of LDLR. The signal-transducing adaptor family member 1 (STAP1) gene has been recently linked to FH. We describe the case of a 56-year-old male patient found to have hypercholesterolemia at age 34, but who did not continue follow-up nor received treatment with lipid-lowering drugs. At age 55 he suffered a myocardial infarction. A systematic NGS analysis did not show point mutations in the LDLR, APOB, LDLRAP1, or PCSK9 genes, nor large rearrangements of the LDLR gene, but revealed the heterozygous missense variant rs199787258 of STAP1 (c.526C > T; p.Pro176Ser). This variant was also found in heterozygosis in the two siblings of the index case, who also had hypercholesterolemia, but did not cosegregate in his progeny. A bioinformatics analysis and available structural information predicts p.Pro176Ser as the most damaging of all STAP1 missense variants associated with familial hypercholesterolemia. Our findings confirm and extend the linkage between STAP1 variants and FH, and point to an important role of this adaptor protein within a signaling pathway that affects cholesterol homeostasis. PMID- 30308188 TI - Pavlovian-instrumental interactions in active avoidance: The bark of neutral trials. AB - In active avoidance tasks, subjects have to learn to execute particular actions in order to avoid an aversive stimulus, such as a shock. Such paradigms pose a number of psychological and neural enigmas, and so have attracted substantial computational interest. However, the ratio of conjecture to confirmation remains high. Here, we perform a theoretical inquiry into a recent experiment by Gentry, Lee, and Roesch ('Phasic dopamine release in the rat nucleus accumbens predicts approach and avoidance performance', Nat. Commun., 7:13154) who measured phasic dopamine concentrations in the nucleus accumbens core of rats whilst they avoided shocks, acquired food, or acted to gain no programmed outcome. These last, neutral, trials turned out to be a perfect probe for the workings of avoidance, partly because of the substantial differences between subjects and sessions revealed in the experiment. We suggest a way to interpret this probe, gaining support for opponency-, safety-, and Pavlovian-influenced treatments of avoidance. PMID- 30308189 TI - Human cytochrome P450 expression in bacteria: Whole-cell high-throughput activity assay for CYP1A2, 2A6 and 3A4. AB - Cytochrome P450s (CYPs) are key enzymes involved in drug and xenobiotic metabolism. A wide array of in vitro methodologies, including recombinant sources, are currently been used to assess CYP catalysis, to identify the metabolic profile of compounds, potential drug-drug interactions, protein-protein interactions in the CYP enzyme complex and the role of polymorphic enzymes. We report here on a bacterial whole-cells high-throughput method for the activity evaluation of human CYP1A2, 2A6, and 3A4, when sustained by NADPH cytochrome P450 oxidoreductase (CPR), in the absence or presence of cytochrome b5 (CYB5). This new assay consists of a microplate real-time fluorometric method, with direct measurement of metabolite formation, in a suspension of Escherichia coli BTC-CYP bacteria, a human CYP competent tester strain when incubated with specific fluorogenic substrates. Overall, the maximum turnover (kcat) velocities of the three human CYPs resulting from the whole-BTC cells assays were similar to those obtained when applying the corresponding standard reference membrane fractions assays. CYP activity screening with co-expression of CYB5 suggests an enhancing effect of CYB5 on the kcat of specific isoforms, when using the whole-BTC cells assay. Our results demonstrate that this new approach can offer an efficient high throughput method for screening of CYP1A2, 2A6 and 3A4 activity and can be potentially applicable for other human CYPs. This can be of particular use for timely and efficient screening of chemical libraries or mutant libraries of CYP enzyme complex proteins, without the necessity for labor intensive isolation of subcellular fractions. PMID- 30308190 TI - Antibiotic Resistance Is the Key Element in Treatment of Helicobacter pylori Infection. PMID- 30308191 TI - Acetyl-Coenzyme A carboxylase inhibition Delivers, as Anticipated, for Patients With Nonalcoholic Steatohepatitis. PMID- 30308192 TI - Evidence-Based Guidelines for Screening Individuals With a Family History of Colorectal Cancer- More Questions Than Answers. PMID- 30308193 TI - Intraepithelial Lymphocytes Are the First Line of Defense Against Enteric Infection. PMID- 30308194 TI - Eosinophilic Esophagitis and Epithelial Inflammation: Just the Tip of the Iceberg? PMID- 30308195 TI - Inhibition of microRNA-182-5p contributes to attenuation of lupus nephritis via Foxo1 signaling. AB - MiR-182-5p suppresses expression of Foxo1 that is a protective factor in renal disorders and is up-regulated in systemic lupus erythematosus patients. Thus, we hypothesized that dys-function of miR-182-5p/Foxo1 axis contributed to development of lupus nephritis (LN). Firstly, we investigated the expressions of miR-182-5p and Foxo1 in LN patients and during growth of LN MRL/lpr mice. Then we subjected MRL/lpr mice to the injection of miR-182-5p antagomirs and assessed the effect of miR-182-5p inhibition on renal structure and function. In vitro, we administrated renal cell lines with TGF-beta1 to explore the relation between renal fibrosis and miR-182-5p. The level of miR-182-5p was up-regulated in high Chronicity Index patients while the level of Foxo1 was suppressed. The progression of LN in mice was associated with the increased level of miR-182-5p and the decreased level of Foxo1. The inhibition of miR-182-5p ameliorated renal structure and function impairments associated with LN, along with the increased expression of Foxo1. The administration of TGF-beta1 in vitro increased the expression of miR-182-5p in renal cells in an overall dose-dependent manner. The current study demonstrated that the expression of miR-182-5p was increased in LN patients, contributing to the suppression of Foxo1 and development of LN. PMID- 30308196 TI - Insights into hepatic and renal FXR/DDAH-1/eNOS pathway and its role in the potential benefit of rosuvastatin and silymarin in hepatic nephropathy. AB - OBJECTIVES: The repression of renal Farnesoid X Receptor (FXR) had been shown to result from lack of bile acid production from cirrhotic liver. We hypothesized that silymarin and rosuvastatin (Rvs) could have a hepatorenal therapeutic effects in hepatic nephropathy through induction of FXR. METHODS: Forty two male Wistar rats were used; naive (n = 12); six of them were sacrificed after 4 weeks and six continued till the end of the experiment. Thirty rats were treated as follows: Rvs, silymarin, thioacetamide (TAA), TAA + Rvs and TAA + silymarin. Liver and kidney function tests as well as the renal and hepatic expression of transforming growth factor beta1 (TGFbeta1), FXR, dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and eNOS were performed. Histological and immuno-histochemical studies of liver and kidney were also done. RESULTS: TAA inducted liver cirrhosis was associated with significant deterioration of liver and renal functions together with increasing expression of hepatic and renal TGFbeta1 and decreasing expression of hepatic and renal FXR, DDAH-1 and eNOS. Giving silymarin or Rvs induced hepatic and renal improvement which was evidenced biochemically and histologically. Significant positive correlation was detected between all the investigated biomarkers except for the correlation between FXR and TGFbeta1 which was negative. CONCLUSIONS: In conclusion, liver cirrhosis is associated with deterioration of renal functions. Silymarin and Rvs have a potential hepatorenal therapeutic benefit through simultaneous enhancement of FXR/DDAH-1/eNOS pathway in both organs. PMID- 30308197 TI - Cardioprotection of benzolamide in a regional ischemia model: Role of eNOS/NO. AB - BACKGROUND: Recent studies from our laboratory show the cardioprotective action of benzolamide (BZ, carbonic anhydrase inhibitor) against ischemia-reperfusion injury. However, the mechanisms involved have not been fully elucidated. OBJECTIVE: To examine the participation of the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) in the effects of BZ in a model of regional ischemia. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of coronary artery occlusion followed by 60 min of reperfusion (IC). Other hearts received BZ during the first 10 min of reperfusion in absence or presence of L-NAME, NOS inhibitor. The infarct size (IS) and the post-ischemic recovery of myocardial function were measured. Oxidative/nitrosative damage were assessed by reduced glutathione (GSH) content, thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine levels. The expression of phosphorylated forms of Akt, p38MAPK and eNOS, and the concentration of inducible nitric oxide synthase (iNOS) were also determined. RESULTS: BZ significantly decreased IS (6.2 +/- 0.5% vs. 34 +/- 4%), improved post-ischemic contractility, preserved GSH levels and diminished TBARS and 3-nitrotyrosine. In IC hearts, P-Akt, P-p38MAPK and P-eNOS decreased and iNOS increased. After BZ addition the levels of P-kinases and P eNOS increased and iNOS decreased. Except for P-Akt, P-p38MAPK and iNOS, the effects of BZ were abolished by L-NAME. CONCLUSIONS: Our data demonstrate that the treatment with BZ at the onset of reperfusion was effective to reduce cell death, contractile dysfunction and oxidative/nitrosative damage produced by coronary artery occlusion. These BZ-mediated beneficial actions appear mediated by eNOS/NO-dependent pathways. PMID- 30308198 TI - Disruptive effect of tocopherol oxalate on DPPC liposome structure: DSC, SAXS, and fluorescence anisotropy studies. AB - alpha-Tocopherol oxalate (TO), a tocopherol ester derivative, was investigated for its effect on the structural changes of fully hydrated 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC) liposomes, as a function of concentration and temperature, by applying differential scanning calorimetry (DSC), small angle X ray scattering (SAXS), and DPH fluorescence anisotropy methods. The DSC and DPH anisotropy data indicated that TO embedded into DPPC membrane lowered the enthalpy (DeltaHm) and temperature (Tm) of the main phase transition as well its cooperativity. Fluidization of the membrane at a lowered temperature was accompanied by formation of mixed structures of tocopherol-enriched domains. SAXS studies showed the formation of various ordered structures in DPPC gel-phase during incorporation of TO into the bilayer, as evidenced by the existence of lamellar phases with repeat distances (d) of 6.13 and 6.87 nm, assigned to TO enriched domains and a lamellar, liquid-ordered DPPC phase with d = 8.45 nm at increasing TO concentrations with lowering and broadening of the Bragg peaks, and diffuse scattering, characteristic of a fluid Lalpha phase, were observed. In DPPC fluid-phase, the increasing presence of TO at low concentrations resulted in the appearance of a liquid-ordered phase with repeat d = 6.9 nm coexistent with a lamellar structure with d = 9.2 nm, assigned to liquid-disordered structures. An increasing repeat distance observed with raising the TO amount in the DPPC bilayer evolved from an increasing interlamellar water layer of increasing thickness. Presence of TO facilitated penetration of water molecules into the acyl chain region which decreased van der Waals interactions in the bilayer. The DSC, SAXS, and fluorescence anisotropy data established that TO exhibited pronounced disruptive activity in DPPC membranes compared to alpha-tocopherol. The driving force of the observed action was attributed to electrostatic and dipole interactions of the acidic moiety with the polar head group of phospholipids in the interface region of the bilayer. PMID- 30308199 TI - Preparation of gene drug delivery systems of cationic peptide lipid with 0G-PAMAM as hydrophilic end and its biological properties evaluation. AB - As an efficient gene delivery, non-viral vectors should have high transfection efficiency, excellent endosomal escape, low cytotoxicity, and the ability to rapidly release the gene into the cytoplasm.Cationic liposome have been widely used as efficient gene carriers, but the cytotoxicity, rapid degradation and low cellular uptake are major drawback impeding its further appolication. Herein, with double lauric acid as hydrophobic chains, tartaric acid as skeleton, 0 generation PAMAM modified with lysine as hydrophilic head, a new type cationic peptide lipid was synthetised. The alkyl chain promote lipid across cell membranes and with membrane fusion, 0 generation PAMAM modified with lysine hydrophilic end amino can contain a large number of protons which can change into ammonium and combine with the DNA negatively charge phosphate groups. It is expected that this carrier has low toxicity, high transfection efficiency and targeting property. By adjusting the cationic liposome/gene weight ratio, the transfection system was optimized to improved gene transfection efficiency, reduce cytotoxicity, and increase property and stability, etc. PMID- 30308201 TI - Progression of diabetic microaneurysms according to the internal reflectivity on structural OCT and visibility on OCT angiography. AB - PURPOSE: To investigate the progression of diabetic microaneurysms (MAs) according to the SD-OCT and OCT Angiography (OCTA) characteristics and to evaluate their influence on the retinal extracellular fluid accumulation at 1 year follow-up in patients with non proliferative diabetic retinopathy (NPDR). DESIGN: Prospective, observational case series. METHODS: Fourteen patients with NPDR underwent SD-OCT and OCTA at the baseline and at 1 year follow-up. For all the selected MAs the visibility, the changes of internal reflectivity, graded as hypo-, moderate, or hyper-reflective, and the extracellular fluid accumulation surrounding each MA on SD-OCT at one year were evaluated. The changes in term of visualization at the level either of superficial (SCP) and deep (DCP) capillary plexus and the presence of flow on the corresponding OCTA scan at 1 year were evaluated. RESULTS: Of 127 MAs selected at the baseline 89 (70%) were still visible on SD-OCT at 1 year. The reflectivity pattern at baseline was strongly associated with extracellular fluid accumulation at 1 year with 18% of hyporeflective vs. 66% of hyperreflective MAs developing extracellular fluid (p=0.004). Among OCTA findings, the presence of flow (p=0.001) the visibility (p<0.001) and the deep location (DCP or both DCP and SCP, p=0.007) were strongly associated with the development of extracellular fluid at 12 months. CONCLUSIONS: This study suggests an association between the SD-OCT and OCTA characteristics of diabetic MAs and the retinal extracellular fluid accumulation at 1 year. A better interpretation of MAs characteristics could improve the timing and the management of diabetic maculopathy. PMID- 30308202 TI - Predictive Factors of Response to Mineralocorticoid Receptor Antagonists in non resolving Central Serous Chorioretinopathy. AB - PURPOSE: To assess the efficacy and safety of mineralocorticoid receptor antagonists (MRA) in the treatment of non-resolving central serous chorioretinopathy (CSC) and identify predictive factors of treatment response. DESIGN: Retrospective, multicenter, non-comparative, interventional case series. METHODS: Clinical and imaging data from consecutive patients with non-resolving CSC treated with eplerenone or spironolactone for 3-6 months between 2012 and 2016 were reviewed. Outcome measurements were: the resolution of foveal subretinal detachment (SRD), changes in SRD height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA) and the occurrence of adverse events assessed at 3 and 6 months. The response to treatment was defined by a decrease by more than 50% in SRD height under treatment. Comparisons between responder and non-responder groups were performed using univariate and multivariate regression analyzes to identify predictive factors of treatment response. RESULTS: Fifty-nine patients (64 eyes) were included. The mean SRD height and CMT significantly decreased while the mean BCVA significantly improved at 3 and 6 months. The mean SFCT significantly decreased at 3 months. Among the 64 eyes included, 67.2% responded to treatment among which 38.3% and 40.5% had a complete resolution of the foveal SRD at 3 and 6 months, respectively. The baseline SFCT was the only factor associated with a treatment response in the multivariate analysis. CONCLUSION: Our study suggests that MRA could be a safe and effective treatment in non-resolving CSC patients. MRA treatment is more effective in cases with a thicker baseline choroid. PMID- 30308200 TI - Factors Associated With Graft Rejection in the Cornea Preservation Time Study. AB - PURPOSE: To identify factors related to graft rejection following Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter randomized clinical trial. METHODS: A total of 1330 eyes of 1090 subjects undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0-7 days (n = 675) or 8-14 days (n = 655) and followed for 3 years. Central endothelial cell density (ECD) was determined by a central image analysis reading center. Multivariable Cox models adjusted for PT, recipient diagnosis, and surgeon effect were used to identify factors associated with rejection. RESULTS: Cumulative probability of definite graft rejection was 3.6% (99% confidence interval 2.5% 5.3%). Younger recipient age was associated with graft rejection (P < .001; hazard ratio: 0.53 [0.33, 0.83] per decade). PT, donor-recipient sex mismatch, recipient diagnosis, recipient race, graft size, discontinuation of topical corticosteroids and immune-modulators, prior immunizations within 3 months, and prior glaucoma surgery were not associated with rejection (P > .01). Among clear grafts with an ECD measurement at baseline and 3 years (n = 913), endothelial cell loss (ECL) was greater in eyes that experienced a rejection episode (n = 27) than in those that did not (n = 886) (48% vs 38%, P = .03). Twelve of 44 eyes (27%) with definite graft rejection subsequently failed, comprising 15% of the 79 failures in the CPTS. CONCLUSIONS: Graft rejection is uncommon after DSAEK and more likely with younger age, in a study cohort mostly > 50 years old. Rejection increases ECL, but it is not a leading cause of DSAEK failure. PMID- 30308203 TI - Diabetes alone does not impair recovery from uneventful cataract surgery. AB - PURPOSE: To study the outcomes of uneventful cataract surgery in diabetic patients without retinal complications. SETTING: Conducted at Kymenlaakso Central Hospital, Kotka, Finland. DESIGN: A post-hoc treatment analysis using data from 2 double-blind RCTs. METHODS: A total of 276 eyes of 266 patients undergoing routine cataract surgery were included in the study. Patients with type I or II diabetes (N=56 eyes) were compared to non-diabetic patients (N=220 eyes). Clinical evaluation was conducted by the operating physician, and outcome measures taken before surgery and day 28 were recorded by a research technician. RESULTS: Patient age, gender distribution and all baseline ophthalmic and surgical parameters were comparable for the non-diabetic and diabetic patient groups. Increase in aqueous flare 6.3+/-16.4pu/msec vs. 3.7+/-8.9pu/msec (mean+/ SD; P=0.282), CRT 12.0+/-38.2MUm vs. 5.9+/-15.8MUm (P=0.256), corrected distance visual acuity 0.57+/-0.31decimals vs. 0.53+/-0.35decimals (P=0.259), and patient satisfaction 9.3+/-0.9 vs. 9.2+/-1.1 (P=0.644) were comparable for non-diabetic and diabetic patients. In eyes with steroid monotherapy (N=64), CRT increased 38.1+/-72.8MUm in non-diabetic patients compared to 7.8+/-6.6MUm in diabetic ones (P=0.010). In eyes with nonsteroidal anti-inflammatory drug (NSAID) monotherapy (N=157), CRT increased 5.7+/-18.4MUm in non-diabetic patients compared to 6.2+/ 20.5MUm in diabetic ones (P=0.897). Among eyes with steroid and NSAID combination therapy (N=55), CRT increased 3.6+/-4.1MUm in non-diabetic patients compared to 2.9+/-3.2MUm in diabetic ones (P=0.606). At 28 days, pseudophakic cystoid macular edema (PCME) was reported in eight eyes, of which seven in non-diabetic patients (P=1.000). CONCLUSIONS: Diabetic patients showed less changes in CRT when compared to controls in steroid monotherapy. Other outcome measurement shows no statistical differences. PMID- 30308204 TI - Histoplasmosis following Systemic Immunomodulatory Therapy for Ocular Inflammation. AB - PURPOSE: Histoplasmosis is a known complication of systemic immunosuppressive therapy, particularly among patients receiving tumor necrosis factor alpha (TNFalpha) inhibitors. There is limited data on the development of disseminated or pulmonary histoplasmosis among patients receiving systemic immunosuppressive medication for non-infectious ocular inflammation. DESIGN: Retrospective case series. METHODS: We reviewed all patients with uveitis or scleritis who subsequently developed pulmonary or disseminated histoplasmosis at the Mayo Clinic in Rochester, MN from September 1994 through July 1st, 2017 with a 3:1 age and sex-matched control cohort who did not develop histoplasmosis. This was a single institutional study examining patients that developed histoplasmosis after the initiation of systemic immunomodulatory therapy (IMT). Patients had to develop either disseminated or pulmonary histoplasmosis while receiving systemic immunosuppressive therapy and have an ophthalmic examination at Mayo Clinic Rochester. The controls were comprised of patients who received systemic IMT for ocular inflammation but did not develop histoplasmosis. RESULTS: Nine cases of histoplasmosis were identified: 2 disseminated and 7 pulmonary. Both of the patients with disseminated histoplasmosis were on TNFalpha inhibitors. Seven of the nine patients received systemic anti-fungal medication, including both disseminated cases. Over a median follow up of 4.4 years, none of the patients died, and there were no recurrences of histoplasmosis. When compared to the control cohort, there was no correlation between length of time on IMT and the risk of histoplasmosis. CONCLUSIONS: Ocular inflammation patients on systemic immunomodulatory therapy may develop pulmonary or disseminated histoplasmosis. Most cases require treatment with systemic anti-fungal medication, but it might not be necessary to stop systemic immunomodulatory medication for ocular inflammation. Ophthalmologists should be aware that patients receiving systemic immunomodulatory therapy have a higher risk of developing Histoplasma infections. Prompt diagnosis and treatment utilizing the expertise of an infectious diseases specialist may ensure low mortality for these patients. PMID- 30308205 TI - Dual augmented transposition of vertical recti in chronic abducens palsy. AB - PURPOSE: to report the results of dual augmentation of vertical rectus muscle transposition (VRT) in the treatment of chronic sixth nerve palsy. DESIGN: retrospective case series. METHODS: this is a retrospective review of medical records of patients with chronic sixth nerve palsy who underwent dual augmented VRT with or without medial rectus (MR) recession from 2013 to 2016. Data collection included gender, age, laterality and duration of post operative follow up. Pre and postoperative limitation of abduction and adduction were recorded using a 6 point scale. Improvement of esotropia in prism diopter (PD), head turn in degrees ( degrees ) and limitation of abduction and adduction were reported and analyzed. REULTS: 14 cases were identified. Mean patients' age at the time of surgery was 22.5 year. Postoperatively, esotropia and head turn were corrected by a mean of 31.3PD and 18.2o respectively. Limited abduction was improved from -4.3 to -1.6 while in cases which underwent MR recession, adduction declined from 0.4 to -0.3. Postoperative induced small amplitude hypertropia was reported in 3 cases. CONCLUSION: Dual augmented VRT was effective in controlling esotropia, head turn and limited abduction associated with chronic six nerve palsy with low rate of induced vertical deviation. Combined MR recession carries a risk of induced limitation of adduction. PMID- 30308206 TI - Laboratory Results, Epidemiological Features, and Outcome Analyses of Microbial Keratitis: A 15-Year Review from Saint Louis. AB - PURPOSE: To evaluate the laboratory results and prognostic factors of poor clinical outcomes in microbial keratitis cases over 15 years at Saint Louis University. DESIGN: Retrospective cohort and trend study. METHODS: Microbiological and clinical information from culture-positive cases seen at Saint Louis University from 1999-2013 were reviewed retrospectively. Statistical analyses were used to determine microbiological and antibiotic susceptibility trends. Prognostic factors of poor clinical outcome from the literature were used to create multivariate regression models to describe our cohort. RESULTS: Gram positive organisms predominated (48%), followed by Gram-negative organisms (34%) and fungi (16%). The most commonly isolated organism was Pseudomonas aeruginosa (21%). Oxacillin-resistant rates of Staphylococcus aureus and Coagulase-negative Staphylococci were 45% and 43%, respectively. Only the proportion of Pseudomonas changed significantly over time (p=0.02). The only antibiotic found to lose efficacy over time was gentamicin for Gram-positive organisms (p=0.005). Multivariate logistic regression analyses revealed that major complications were associated with large ulcers (p<0.006), fungal cases (p<0.001), and co-morbid ophthalmic conditions (p<0.001). Poor healing was associated with large ulcers (p<0.001) and fungal cases (p<0.001). Lastly, poor visual outcome was associated with large ulcers (p<0.01) and age >= 60 years (p<0.02). CONCLUSIONS: In the Saint Louis area, oxacillin-resistant organisms, Pseudomonas aeruginosa, and fungi are commonly recovered from microbial keratitis cases with a disproportionally high incidence. Hence, empiric antibiotic choice should reflect these trends. Special care needs to be taken for patients with large ulcers and fungal infections as well as elderly patients with co-morbid ophthalmic conditions, as these patients have worse clinical outcomes. PMID- 30308207 TI - Brucellosis seroprevalence in dairy cattle in China during 2008-2018: A systematic review and meta-analysis. AB - Brucellosis remains one of the most common zoonotic diseases globally with more than a half million human cases reported annually. The Brucella reservoir associated with livestock brucellosis poses a significant threat to public health, and awareness of the seroprevalence and spatial distribution of livestock brucellosis is valuable for the prevention and control of diseases caused by Brucella, especially human brucellosis. Therefore, we conducted a systematic review and meta-analysis to evaluate the seroprevalence of brucellosis in dairy cattle in China. We retrieved 88 studies related to the seroprevalence of brucellosis in dairy cattle in China in which samples were harvested between 2008 and 2018. The results of our systematic review and meta-analysis reveal that the overall seroprevalence of brucellosis in dairy cattle herds in China was 1.9% during the selected period, rising from 1.6% in 2008-2012 to 2.6% in 2013-2018. In Northern China, where the traditional agropastoral areas with more developed animal breeding industry are located, the brucellosis seroprevalence was >10%. In contrast, the seroprevalence of brucellosis in Southern China reached only 5.5%. At the provincial level, the highest brucellosis seroprevalence in dairy cattle was estimated at >30% in Jilin province, followed by Shanxi, Ningxia, Inner Mongolia, and Guizhou, each with a prevalence of 10-20%. Additionally, the seroprevalence of brucellosis in some local areas was >30% or even >50%, indicating that Brucella infection was highly endemic in dairy herds in China. Our data may facilitate the prevention and control of brucellosis in domestic animals in China. Further epidemiological surveillance and the administration of a comprehensive monitoring program to determine the risk factors associated with brucellosis incidence in humans and domestic animals are recommended to refine brucellosis control strategies. PMID- 30308208 TI - In silico modeling of Plasmodium falciparum chloroquine resistance transporter protein and biochemical studies suggest its key contribution to chloroquine resistance. AB - Chloroquine (CQ) has been used for decades as the primary chemotherapeutic drug for the treatment of malaria. The emergence of drug resistance in Plasmodium falciparum has been considered to be because of the excessive use of antimalarial drugs worldwide. Moreover, the intense distribution and prevalence of chloroquine resistant strains in endemic regions has aided the incidence of more complications to malaria treatment and control. Due to the lack of literature that portrays evident molecular mechanisms of drug resistance, it has been difficult to understand the drug resistance conferred by Plasmodium species. Intensive research on CQ drug resistance has identified the association of P. falciparum chloroquine resistance transporter protein (PfCRT), which belongs to the drug/metabolite transporter and EamA-like superfamily. Additionally, it has shown that K76 T mutation in PfCRT protein has mainly attributed to CQ resistance than other mutations. This study deals with the development of an in silico model of the PfCRT protein and its interaction with the CQ ligand molecule as well as the biochemical and biophysical characterization of the transmembrane domain 1 (TMD 1) peptide of the PfCRT protein. The physiochemical analysis of the PfCRT protein identified basic differences between the wild and mutant forms of the protein, as well as identifying the high hydrophobic nature of the mutant-type protein. The tertiary structure of the PfCRT protein was predicted and interaction with CQ revealed different active pocket binding regions in both the wild and mutant form of PfCRT proteins. The CQ2+ molecule interacts with TMD 10 of the wild-type PfCRT protein, whereas it interacts with TMD 1 of the mutant type protein. Studies on the TMD 1 peptide revealed the insertion of the peptide in the micelles adopting stable alpha-helical structure. Binding studies with the CQ molecule detected high binding affinity toward the mutant-type TMD 1 peptide rather than the wild-type, thus confirming that the TMD 1 peptide is involved in substrate selectivity. Our findings help to characterize the structure of the PfCRT protein and the role played by the TMD 1 region in CQ resistance using in silico and biochemical approaches. Molecular docking and ligand binding studies confirm that TMD 1 is involved in substrate selectivity and aids in CQ efflux, thereby contributing to the parasite's CQ drug resistance mechanism. PMID- 30308209 TI - The role of alphabeta T-cells in spontaneous regression of melanoma tumors in swine. AB - Using a porcine model, we describe Melanoma-Associated CD4+CD8hi T-lymphocytes (MATL) in peripheral blood that increase during melanoma regression. These MATL possess the CD4+CD8hi phenotype and they have their direct counterparts in Tumor Infiltrating Lymphocytes (TIL) isolated from melanoma loci. Both MATL and CD4+CD8hi TIL have a similar expression of selected markers indicating that they represent effector/memory alphabeta T-cell subset. Moreover, although TIL also contain CD4-CD8+ T-cells, only CD4+CD8hi TIL expand during melanoma regression. Importantly, TIL isolated from different pigs and different melanoma loci among the same pig have similar composition of CD4/CD8 subsets, indicating that the composition of the MATL and TIL compartment is identical. Analysis of sorted cells from regressing pigs revealed a unique MATL subpopulation with mono specific T-cell receptor that was further analyzed by sequencing. These results indicate that pigs regressing melanomas possess a characteristic population of recirculating T-cells playing a role in tumor control and regression. PMID- 30308211 TI - A low-cost open-architecture taste delivery system for gustatory fMRI and BCI experiments. AB - BACKGROUND: Tasting is a complex process involving chemosensory perception and cognitive evaluation. Different experimental designs and solution delivery approaches may in part explain the variability reported in literature. These technical aspects certainly limit the development of taste-related brain computer interface devices. NEW METHOD: We propose a novel modular, scalable and low-cost device for rapid injection of small volumes of taste solutions during fMRI experiments that gathers the possibility to flexibly increase the number of channels, allowing complex multi-dimensional taste experiments. We provide the full description of the hardware and software architecture and illustrate the application of the working prototype in single-subject event-related fMRI experiments by showing the BOLD responses to basic taste qualities and to five intensities of tastes during the course of perception. RESULTS: The device is shown to be effective in activating multiple clusters within the gustatory pathway and a precise time-resolved event-related analysis is shown to be possible by the impulsive nature of the induced perception. COMPARISON WITH EXISTING METHOD(S): This gustometer represents the first implementation of a low cost, easily replicable and portable device that is suitable for all kinds of fMRI taste experiments. Its scalability will boost the experimental design of more complex multi-dimensional fMRI studies of the human taste pathway. CONCLUSIONS: The gustometer represents a valid open-architecture alternative to other available devices and its spread and development may contribute to an increased standardization of experimental designs in human fMRI studies of taste perception and pave the way to the development of novel taste-related BCIs. PMID- 30308212 TI - Sonchus yellow net virus core particles form on ring-like nuclear structure enriched in viral phosphoprotein. AB - The phosphoprotein (P) of the nucleorhabdovirus sonchus yellow net virus has been shown to accumulate in ring-shaped structures in virus-infected nuclei. Further examination by live-cell imaging, in combination with structural examination by transmission electron microscopy and immunolocalization demonstrated that P-rings do not form in association with nucleoli. Furthermore, viral cores were shown to condense on the nucleoplasm-contacting surface of the rings. The data presented here offer evidence for the site of nucleocapsid assembly in SYNV-infected nuclei. PMID- 30308210 TI - Electrokinetic infusions into hydrogels and brain tissue: Control of direction and magnitude of solute delivery. AB - BACKGROUND: Delivering solutes to a particular region of the brain is currently achieved by iontophoresis for very small volumes and by diffusion from a microdialysis probe for larger volumes. There is a need to deliver solutes to particular areas with more control than is possible with existing methods. NEW METHOD: Electrokinetic infusions of solutes were performed into hydrogels and organotypic hippocampal slice cultures. Application of an electrical current creates electroosmotic flow and electrophoresis of a dicationic fluorescent solute through organotypic hippocampal tissue cultures or larger hydrogels. Transport was recorded with fluorescence microscopy imaging in real-time. RESULTS: Electrokinetic transport in brain tissue slice cultures and hydrogels occurs along an electrical current path and allows for anisotropic delivery over distances from several hundred micrometers to millimeters. Directional transport may be controlled by altering the current path. The applied electrical current linearly affects the measured solute fluorescence in our model system following infusions. COMPARISON WITH EXISTING METHODS: Localized drug delivery involves iontophoresis, with diffusion primarily occurring beyond infusion capillaries under current protocols. Pressure-driven infusions for intraparenchymal targets have also been conducted. Superfusion across a tissue surface provides modest penetration, however is unable to impact deeper targets. In general, control over intraparenchymal drug delivery has been difficult to achieve. Electrokinetic transport provides an alternative to deliver solutes along an electrical current path in tissue. CONCLUSIONS: Electrokinetic transport may be applied to living systems for molecular transport. It may be used to improve upon the control of solute delivery over that of pressure-driven transport. PMID- 30308213 TI - Development of a high throughput optical density assay to determine fungicide sensitivity of oomycetes. AB - A high-throughput assay was developed to screen Phytophthora species for fungicide sensitivity using optical density measurements for unbiased, automated measurement of mycelial growth. The efficacy of the optical density assay (OD) to measure phosphite sensitivity in Phytophthora species was compared to two widely used methods, radial growth (RG) and dry weight (DW) assays. Three isolates of each of Phytophthora cinnamomi, P. multivora and P. pluvialis, with known phosphite exposure and three isolates of each species with no prior phosphite exposure, were screened for phosphite sensitivity using the three assays. Mycelial growth measurements were taken after culturing for 6, 14 and 15 days for the OD, DW and RG assays respectively. Mycelial growth inhibition at 15, 80, 200 and 500 MUg/mL phosphite relative to growth on control media was used to determine effective concentration values for 50% growth reduction (EC50). The species varied in their tolerance to phosphite with P. cinnamomi being the least sensitive followed by P. multivora and P. pluvialis. No significant differences in tolerance were found between isolates within the same species using any method. The OD assay produced comparable EC50 values to the RG and DW assays. The growth of the three species was more sensitive to phosphite in the DW than the RG and OD assays, however limited sample throughput and greater variation in measuring small amounts of mycelia in the dry weight assessment increase variability and limits throughput. The OD assay offers a fast method to enable an inventory of chemical resistance and is particularly advantageous for slow growing species as it requires less time and offers greater throughput than existing RG and DW methods. PMID- 30308214 TI - Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors. AB - AIMS: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3 134 as a potential anti-cocaine therapeutic. METHODS: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. RESULTS: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. CONCLUSIONS: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs. PMID- 30308215 TI - Microbiological and clinical characteristics of Acinetobacter baumannii bacteremia: Implications of sequence type for prognosis. AB - OBJECTIVES: Acinetobacter baumannii (Ab) is an important cause of healthcare associated infections. Multilocus sequence typing (MLST) provides a highly discriminative typing method. We aimed to determine the clinical impact of Ab sequence types (ST) in patients with bloodstream infection (BSI). METHODS: Patients with Ab-BSI were followed prospectively from 2009 to 2014. We randomly selected one-third of non-duplicate bacteremic isolates for MLST and correlated the Ab ST with the clinical course. The primary outcome was all-cause in-hospital mortality. RESULTS: We enrolled 148 patients. Seventy-seven (52.0%) of the isolates were ST2. Patients with ST2-BSI were less likely to be treated with appropriate empirical antimicrobial agents (31.1% vs. 60.6%; P < 0.001). They had greater mortality (66.2% vs. 40.8%; P = 0.003) than patients with non-ST2-BSI. In the multivariable analysis, ST2 independently predicted greater severity of infection (Pitt bacteremia score) (adjusted odds ratio (aOR), 3.38; 95% confidence interval (CI), 1.75-6.54; P < 0.001). Mediated by a higher Pitt bacteremia score (Sobel test P < 0.001), ST2 is an independent prognostic factor that predict mortality (aOR, 2.34; 95% CI, 1.07-5.11; P = 0.03). CONCLUSIONS: ST2 was associated with high rates of inappropriate antimicrobial therapy, severe infection and mortality. Further studies are needed to confirm our findings and explore the potential of role of the virulence. PMID- 30308217 TI - Antigen-presenting cells and T-lymphocytes homing to the thymus shape T cell development. AB - Hematopoietic precursors entering the thymus undergo a maturation process leading to the generation of a variety of T cell subsets that migrate to the periphery to perform their effector functions. This maturation process is strictly regulated by multiple interactions of developing T cells with thymic stroma cells. Signals received via the T cell receptor for antigen, co-stimulatory molecules and cytokines will determine, through thymic selection and lineage choice, thymocyte fate. Recently, different populations of peripheral antigen presenting cells and T cells have been reported to enter the thymus. Here we review how these cells migrating from the periphery to the thymus modulate T cell development. PMID- 30308216 TI - Development and validation of a TaqMan RT-qPCR for the detection of convert mortality nodavirus (CMNV). AB - Covert mortality nodavirus (CMNV), an emerging RNA virus, is the pathogen of viral covert mortality disease (VCMD), which has emerged as a cause of serious losses in shrimp aquaculture in China. To improve VCMD diagnosis, a one-step, real-time TaqMan probe-based reverse transcription quantitative PCR (RT-qPCR) was developed in this study. The TaqMan RT-qPCR was optimized firstly, whereby the best results were obtained with 0.2 MUM of each primer, 0.2 MUM probe, and 0.5 MUL Enzyme Mix II. The optimal reaction program was determined as 15 min at 51oC for reverse transcription and 5 min at 95 oC, followed by 40 cycles of denaturation at 94 oC for 10 s, and annealing and extension at 52.7 oC for 30 s. The optimized assay detected as little as 9.6 pg total RNA from CMNV-infected shrimp and 5.7 copies of the target plasmid. The RT-qPCR assay for CMNV with a high correlation coefficient (r2 = 0.996) was developed basing on the standard curve generated by plotting the threshold cycle values (y) against the common logarithmic copies (log10nc as x; nc is copy number) of pMD20-CMNV. The diagnostic sensitivity and specificity of this assay versus the previously reported RT-qPCR was 96.2% and 98.0%, respectively. This method is highly specific to CMNV, as it showed no cross-reactivity with other common shrimp viruses. It is anticipated that the newly developed and optimized RT-qPCR assay will be instrumental for the rapid diagnosis and quantitation of CMNV. PMID- 30308218 TI - Impact of alterations in X-linked IRAK1gene and miR-146a on susceptibility and clinical manifestations in patients with systemic sclerosis. AB - Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease with unknown etiology. Numerous studies have indicated that the disease heterogeneity implies various genetic abnormalities. Considering that SSc is characterized by a strong sex bias and that the position of IRAK1 gene is on the X chromosome, we assume that variations in IRAK1 gene could explain female predominance of SSc. It was previously described that miR-146a has a role in 'fine-tuning' regulation of the TLR/NF-kB signaling pathway through down-regulation of IRAK1 gene. The aim of the present study was to analyze both variants and expression level of IRAK1 and miR-146a genes in terms of susceptibility to SSc and clinical presentation of SSc patients. We analyzed variants IRAK1 rs3027898 C > A and miR-146a rs2910164 C > G in 102 SSc patients and 66 healthy subjects. Genotyping was performed by Sanger sequencing. Expression level of IRAK1 mRNA and miR-146a in PBMCs was performed in subset of 50 patients and 13 healthy controls by RT-qPCR. Our results showed that there was no association between IRAK1 rs3027898 and the risk of SSc in women. However, the analysis of genotype distribution of the mir-146a rs2910164 C > G variant indicated that CC genotype shows strong association with lung fibrosis and active form of the disease. When expression level of IRAK1 gene was analyzed, we detected significant downregulation of IRAK1 mRNA in SSc patients compared to controls, as well as in male compared to female patients, in patients with ACAs autoantibodies and in patients with severe skin involvement. Regarding the expression level of miR-146a, we have found significantly reduced expression in SSc patients, in patients with skin involvement and in male SSc patients. The results from this study indicate that expression of IRAK1 gene could explain phenotypic heterogeneity of SSc and may be involved in the pathogenesis of SSc due to its differential expression in certain subgroups. Our results also suggested that miR-146a rs2910164 CC genotype may be predisposing factor for development lung fibrosis and more progressive form of SSc. Results from relative expression analysis of miR-146a demonstrated that changes in the level of this miRNA may have an impact on development and clinical course of SSc. PMID- 30308219 TI - Optic Disc Edema after 30 Days of Strict Head-down Tilt Bed Rest. PMID- 30308220 TI - Deinococcus radiodurans' SRA-HNH domain containing protein Shp (Dr1533) is involved in faithful genome inheritance maintenance following DNA damage. AB - BACKGROUND: Deinococcus radiodurans R1 (DR) survives conditions of extreme desiccation, irradiation and exposure to genotoxic chemicals, due to efficient DNA breaks repair, also through Mn2+ protection of DNA repair enzymes. METHODS: Possible annotated domains of the DR1533 locus protein (Shp) were searched by bioinformatic analysis. The gene was cloned and expressed as fusion protein. Band shift assays of Shp or the SRA and HNH domains were performed on oligonucleotides, genomic DNA from E. coli and DR. shp knock-out mutant was generated by homologous recombination with a kanamycin resistance cassette. RESULTS: DR1533 contains an N-terminal SRA domain and a C-terminal HNH motif (SRA HNH Protein, Shp). Through its SRA domain, Shp binds double-strand oligonucleotides containing 5mC and 5hmC, but also unmethylated and mismatched cytosines in presence of Mn2+. Shp also binds to Escherichia coli dcm+ genomic DNA, and to cytosine unmethylated DR and E. coli dcm- genomic DNAs, but only in presence of Mn2+. Under these binding conditions, Shp displays DNAse activity through its HNH domain. Shp KO enhanced >100 fold the number of spontaneous mutants, whilst the treatment with DNA double strand break inducing agents enhanced up to 3-log the number of survivors. CONCLUSIONS: The SRA-HNH containing protein Shp binds to and cuts 5mC DNA, and unmethylated DNA in a Mn2+ dependent manner, and might be involved in faithful genome inheritance maintenance following DNA damage. GENERAL SIGNIFICANCE: Our results provide evidence for a potential role of DR Shp protein for genome integrity maintenance, following DNA double strand breaks induced by genotoxic agents. PMID- 30308221 TI - Methylation of selenocysteine catalysed by thiopurine S-methyltransferase. AB - BACKGROUND: Methylation driven by thiopurine S-methylatransferase (TPMT) is crucial for deactivation of cytostatic and immunosuppressant thiopurines. Despite its remarkable integration into clinical practice, the endogenous function of TPMT is unknown. METHODS: To address the role of TPMT in methylation of selenium compounds, we established the research on saturation transfer difference (STD) and 77Se NMR spectroscopy, fluorescence measurements, as well as computational molecular docking simulations. RESULTS: Using STD NMR spectroscopy and fluorescence measurements of tryptophan residues in TPMT, we determined the binding of selenocysteine (Sec) to human recombinant TPMT. By comparing binding characteristics of Sec in the absence and in the presence of methyl donor, we confirmed S-adenosylmethionine (SAM)-induced conformational changes in TPMT. Molecular docking analysis positioned Sec into the active site of TPMT with orientation relevant for methylation reaction. Se-methylselenocysteine (MeSec), produced in the enzymatic reaction, was detected by 77Se NMR spectroscopy. A direct interaction between Sec and SAM in the active site of rTPMT and the formation of both products, MeSec and S-adenosylhomocysteine, was demonstrated using NMR spectroscopy. CONCLUSIONS: The present study provides evidence on in vitro methylation of Sec by rTPMT in a SAM-dependant manner. GENERAL SIGNIFICANCE: Our results suggest novel role of TPMT and demonstrate new insights into enzymatic modifications of the 21st amino acid. PMID- 30308222 TI - Fate of degraded pollutants in waste gas biofiltration: An overview of carbon end points. AB - The fate of the carbon from degraded pollutants in biofiltration is not well understood. The issue of missing carbon needs to be addressed quantitatively to better understand and model biofilter performance. Elucidating the various carbon end-points in various phases should contribute to the fundamental understanding of the degradation kinetics and metabolic pathways as a function of various environmental parameters. This article reviews the implications of key environmental parameters on the carbon end-points. Various studies are evaluated reporting carbon recovery over a multitude of parameters and operational conditions with respect to the analytical measurements and reported distribution of the carbon end-points. PMID- 30308223 TI - SNP markers for the genetic characterization of Mexican shrimp broodstocks. AB - Selective breeding of shrimp has major potential to enhance production traits, including growth and disease resistance. Genetic characterization of broodstock populations is a key element of breeding programs, as it enables decisions on inbreeding restrictions, family structure, and the potential use of genomic selection. Single Nucleotide Polymorphisms (SNPs) are suitable genetic markers for this purpose. A set of SNPs was developed to characterize commercial breeding stocks in Mexico. Individuals from local and imported lines were selected for sequencing using the nextRAD technique, resulting in the identification of 2619 SNPs. Genetic structure analysis showed three to five genetic groups of Ecuadorian and Mexican origins. A subset of 1231 SNPs has potential for stock identification and management. Further, three SNPs were identified as candidate sex-linked markers. The role of SNPs possibly associated with genes related to traits of importance to shrimp farming, such as growth and immune response, should be further investigated. PMID- 30308224 TI - Early maternal feeding practices: Associations with overweight later in childhood. AB - BACKGROUND: Current understanding of the impact of maternal feeding practices on weight outcomes in young children remains unclear given equivocal longitudinal study outcomes. OBJECTIVES: To determine whether feeding practices used by mothers when their child was less than 2 years of age were related to overweight status at ages 3.5 and 5 years in a large cross-country sample; and investigate whether these associations were moderated by weight status in early life. DESIGN: Data from mother-child dyads participating in four childhood obesity prevention trials across Australia and New Zealand were pooled (n = 723). Each trial administered items from the Comprehensive Feeding Practices Questionnaire (CFPQ) to mothers when infants were approximately 20 months of age, measuring food as a reward, modelling, restriction for health, pressure to eat, and emotion regulation. Poisson regression was used to determine risk ratios (RR) for overweight (BMI z-score >=85th percentile) at 3.5 and 5 years by CFPQ scores. RESULTS: Greater use of emotion regulation at 20 months of age predicted higher risk for overweight at 3.5 and 5 years (RR = 1.19 and 1.28, respectively), while restriction for health predicted lower risk for overweight at 5 years (RR = 0.88). Child's weight status at 20 months moderated the association between pressure to eat and overweight risk at 5 years, such that those who were not overweight at 20 months of age had reduced risk of overweight associated with the use of pressure to eat (RR = 0.68) but those who were overweight had an increased risk (RR = 1.09). CONCLUSION: Early maternal feeding practices are related to a child's later risk of overweight. PMID- 30308225 TI - Toxicological evaluation of Microbacterium foliorum SYG27B-MF. AB - Microbacterium foliorum is a naturally occurring bacteria in cruciferous vegetables and ripened cheese. The safety of M. foliorum SYG27B-MF has been assessed in both acute and subchronic studies and a battery of mutagenicity and clastogenicity tests. In a single dose acute study, the LD50 of M. foliorum SYG27B-MF was greater than 3 g/kg bw or 5.1 * 1016 colony forming unit (CFU)/kg bw, the highest dose tested. In a 90-day subchronic toxicity study in 80 Sprague Dawley rats, no animals died and there were no treatment-related abnormalities at doses of 0, 500, 1000, or 2000 mg/kg bw. In a 90-day repeated toxicity test, the no-observed-adverse-effect level (NOAEL) M. foliorum SYG27B-MF was 2000 mg/kg/day or 3.4 * 1016 CFU/kg bw/day, the highest level tested. A mutagenicity study using reverse bacterial mutation tests and a genotoxicity study employing cultured hamster ovarian fibroblasts (CHO-K1) cell showed that M. foliorum SYG27B-MF was not mutagenic or clastogenic in the presence or absence metabolic activation. In an in vivo mouse micronucleus assay, M. foliorum SYG27B-MF did not induce did not induce micronuclei formation in the bone marrow cells of mice, indicating that it is non-clastogenic. The results from these studies support the safety of M. foliorum SYG27B-MF for use as a production organism for human food ingredients. PMID- 30308226 TI - The potential for remodelling the tumour vasculature in glioblastoma. AB - Despite significant improvements in the clinical management of glioblastoma, poor delivery of systemic therapies to the entire population of tumour cells remains one of the biggest challenges in the achievement of more effective treatments. On the one hand, the abnormal and dysfunctional tumour vascular network largely limits blood perfusion, resulting in an inhomogeneous delivery of drugs to the tumour. On the other hand, the presence of an intact blood-brain barrier (BBB) in certain regions of the tumour prevents chemotherapeutic drugs from permeating through the tumour vessels and reaching the diseased cells. In this review we analyse in detail the implications of the presence of a dysfunctional vascular network and the impenetrable BBB on drug transport. We discuss advantages and limitations of the currently available strategies for remodelling the tumour vasculature aiming to ameliorate the above mentioned limitations. Finally we review research methods for visualising vascular dysfunction and highlight the power of DCE- and DSC-MRI imaging to assess changes in blood perfusion and BBB permeability. PMID- 30308227 TI - Nitrogen mustard exposure perturbs oocyte mitochondrial physiology and alters reproductive outcomes. AB - Nitrogen mustard (NM) is an alkylating chemical warfare agent, and its derivatives are used in chemotherapy. Alkylating agents can cause mitochondrial damage, so exposed females may transmit damaged genomes to their children, since mitochondria are maternally inherited and oocytes are not thought to undergo mitophagy (Boudoures et al. [1]). The objective of this study is to investigate NM's effects on oocyte mitochondria to understand risks facing female soldiers, cancer patients, and their children. Mice were injected intraperitoneally with NM, monitored for reproductive outcomes, and ovaries and oocytes were isolated for analysis. Escalating doses of NM increased oxidative stress in parental and F1 generation oocytes, suggesting that mitochondrial damage by NM is enhanced by mitochondrial superoxide. NM-treated ovaries in vitro exhibited smaller mitochondrial volume, more electron-dense and multivesicular structures, and lower birth weight litters. These results demonstrate that females must be protected from alkylating agents for their health, and the health of their offspring. PMID- 30308229 TI - 'Cough CPR': Misinformation perpetuated by social media. PMID- 30308228 TI - The food additive BHA modifies energy metabolism in the perfused rat liver. AB - A study of the effects of butylated hydroxyanisole (BHA) on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism and mitochondrial reactive oxygen species production. The experimental systems were the isolated perfused rat liver and isolated mitochondria. It was found that BHA inhibits biosynthetic pathways (gluconeogenesis) and ammonia detoxification, which are dependent on ATP generated within the mitochondria. Conversely, the compound stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, BHA diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Inhibition of gluconeogenesis started at the concentration of 50 MUM and was generally pronounced at concentrations under 200 MUM. Several effects, however, were prominent only at the concentrations of 500 and 750 MUM. BHA can be considered, thus, a mild metabolic agent that becomes toxic only at high doses. An aggravating factor could be the observation that BHA exerts a net stimulating action on reactive oxygen species (ROS) production in isolated mitochondria, an observation that contradicts the general notion that the compound acts primarily as an antioxidant. Considerable time was required for the reversion of most effects after removal of the compound from the circulation. In toxicological terms, besides the lack of circulating glucose, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis and possible excessive ROS production. PMID- 30308230 TI - Meroterpenoids from Ganoderma sinense protect hepatocytes and cardiomyocytes from oxidative stress induced injuries. AB - Four meroterpenoids, applanatumols F (1), H (3), I (2), and lingzhiol (4) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense. Their structures were established on the basis of NMR spectroscopic analyses, optical rotatory dispersion data, ECD spectra, and X-ray crystallography. Compounds 1, 2, 4 existed as racemic mixtures ((+) 1a, 2a, 4a; (-) 1b, 2b, 4b), while 3 as a single enantiomer. Base on the seperated enantiomers, we sought to explicit possible effects of compounds 1-4 on hydrogen peroxide (H2O2)-induced cell death and to determine their underlying molecular mechanisms in human normal liver LO2 cells. Among them, compound 2a treatment effectively protected LO2 cells against H2O2-induced cell damage and apoptosis. H2O2 exposure increased ROS, which was inhibited by 2a treatment. Mitochondrial membrane potential decrease, nuclear fragments, caspase-3 activation and PARP cleavage were also arrested by 2a. Further, increased levels of Nrf2, HO-1, phosphorylation Akt and up-regulation of antioxidant enzymes were detected in 2a treated cells, indicating that the anti-oxidative effects of 2a might protect LO2 cells against oxidative damage via PI3K/Akt-mediated activation of Nrf2/HO-1 pathway. In addition, compound 2a showed potential protective role of cardiomyocyte from ischemia/reperfusion injury, and pretreatment with 2a could decrease CK and LDH levels and increase GSH level. PMID- 30308231 TI - Asperimides A-D, anti-inflammatory aromatic butenolides from a tropical endophytic fungus Aspergillus terreus. AB - Four new aromatic butenolides, asperimides A-D (1-4), together with a known analogue, butyrolactone I (5), were isolated from solid cultures of a tropical endophytic fungus Aspergillus terreus. The structures of these compounds were elucidated on the basis of spectroscopic methods and electronic circular dichroism calculations. Compounds 1-4 represent the first examples of butenolides with a maleimide core isolated from Aspergillus sp. Inhibitory effects of the isolated compounds on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells. Compounds 3 and 4 exhibited potent anti-inflammatory with IC50 values of 0.78 +/- 0.06 and 1.26 +/- 0.11 MUM, respectively. PMID- 30308232 TI - On the significance of sodium ionic channels in analysis of the breast cancer metastaticity. AB - Using the results from previous modeling of the ball and chain inactivation of the potassium channels we try to model the inactivation of the NaV 1.5 sodium channels in adult and neonatal form. The (fast) inactivation of sodium channels differs from the inactivation of the potassium channels by the use of a inactivating hinge rather than a ball on a chain. The adult and neonatal variants of the channel differ mostly in a charged amino acid residue located on the extracellular side. We show that a drift caused by this residue is sufficient to describe the differences in inactivation between the two forms of the NaV 1.5. We use the survival probability, the patch-clamp measurable parameter, to discriminate between the cells of different metastaticity. PMID- 30308233 TI - The host defense peptide LL-37 triggers release of nucleic acids from human mast cells. AB - The human host defense peptide LL-37 possesses antimicrobial activity but also affects host cell function and viability. Mast cells are involved in innate immunity but no data have been presented on effects of LL-37 on human mast cell viability and export of nucleic acids. Here, we demonstrated by immunofluorescence microscopy that synthesized LL-37 was internalized by human LAD2 mast cells and detected both in cytoplasm and nucleus. Treatment with high (4 and 10 MUM) but not low (1 MUM) concentrations of LL-37 for 4 h reduced cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Stimulation with 10 MUM LL-37 for 4 h enhanced export of nucleic acids, total protein and lactate dehydrogenase (LDH), suggesting that both nuclear and plasma membranes are permeabilized by LL-37. Although LL-37 triggered release of nucleic acids, no extracellular trap-like structures were observed by laser scanning confocal microscopy of cells incubated with the plasma membrane impermeable nucleic acid fluorophore SYTOX-Green, indicating that LL-37 promotes export of nucleic acids but not formation of extracellular traps. On the other hand, phorbol-12-myristate-13-acetate (PMA), which is a well-known inducer of extracellular traps, stimulated export of nucleic acids and also formation of extracellular trap-like structures. However, PMA had no effect on export of either total protein or LDH. Hence, LL-37 and PMA seem to stimulate export of nucleic acids from LAD2 mast cells through different pathways. In conclusion, we demonstrate that LL-37 triggers release of nucleic acids from human mast cells but not the formation of extracellular trap-like structures. PMID- 30308234 TI - Burrowing owls eavesdrop on southern lapwings' alarm calls to enhance their antipredatory behaviour. AB - Eavesdropping is a widespread behaviour among animals, providing the receiver with valuable information to assess the habitat, resources or threats. This kind of behaviour has been reported for the burrowing owl (Athene cunicularia), which in its northern range lives in close association with fossorial mammals and eavesdrops on their alarm calls as indicators of risk. In their southernmost range, burrowing owls do not associate with mammals, but they are often found sharing foraging and nesting patches with the southern lapwing (Vanellus chilensis), a noisy, territorial and aggressive plover species. We designed a field experimental study aimed at determining if burrowing owls are able to use lapwing calls as indicator of potential risk. We exposed focal owls to a sequence of sounds including lapwing alarm calls, and biological and non-biological controls, and registered their response as alert or relax behaviours. Linear mixed modeling showed that owls increased their alert behaviour in response to lapwing alarm calls but not in response to control treatments. In addition, owls' response was consistent between habitats (rural and urban) and seasons (breeding and non-breeding). Our results suggest that eavesdropping is a generalized strategy of burrowing owls to acquire environmental information throughout its distribution range. PMID- 30308235 TI - Introduction to the special issue on functional neuroimaging of the emotional brain. PMID- 30308236 TI - CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor. AB - INTRODUCTION: CHRFAM7A is a uniquely-human gene that encodes a human-specific variant of the alpha-7 nicotinic acetylcholine receptor (alpha7nAchR). While the homopentameric alpha7nAChR consists of 5 equal subunits, previous studies demonstrated that CHRFAM7A expression disrupts the formation of alpha7nAChR homopentamers. Here we use a rat neuronal cell line expressing CHRFAM7A and a transgenic mouse expressing CHRFAM7A to define the alpha-bungarotoxin (alpha-BTX) binding in vitro and in vivo. METHODS: Rat PC12 cells were stably transfected with human CHRFAM7A. alpha-BTX, a protein that irreversibly binds the alpha7nAchR, was utilized to assess the capacity for CHRFAM7A to interfere with alpha 7AchR subunits using immunohistochemistry and flow cytometry. To evaluate the effects of CHRFAM7A on alpha7nAchR at the neuromuscular junction in vivo, transgenic mice were engineered to express the uniquely human gene CHRFAM7A under the control of the EF1-alpha promoter. Using this model, muscle was harvested and CHRFAM7A and CHRNA7 gene expression evaluated by PCR. Binding of alpha-BTX to the alpha7nAchR in muscle was compared in sibling-matched wild-type C57 mice by immunostaining the neuromuscular junction using alpha-BTX and neurofilament antibodies. RESULTS: Expression of CHRFAM7A in transfected, but not vector cells, was confirmed by PCR and by immunoblotting using an antibody we raised to a peptide sequence unique to CHRFAM7A. CHRFAM7A decreased alpha-BTX binding as detected by immunohistochemistry and flow cytometry. In vivo, alpha-BTX co stained with neurofilament at the neuromuscular junction in wild-type mice, however, alpha-BTX staining was decreased at the neuromuscular junction of CHRFAM7A transgenic mice. CONCLUSION: CHRFAM7A expression interferes with the binding of alpha7nAchR to alpha-BTX. Understanding the contribution of this uniquely human gene to human disease will be important in the identification of potential therapeutic targets. PMID- 30308237 TI - Primary sensory neurons expressing tropomyosin receptor kinase A in the rat trigeminal ganglion. AB - Tropomyosin receptor kinase A (trkA), a high affinity receptor for nerve growth factor (NGF), has been implicated in neuronal survival, neurite outgrowth and inflammatory pain. So far, the characterization of the primary sensory neurons that express trkA, and are thus potentially affected by NGF, has remained incomplete. The goal of this study was to investigate the trkA-expressing neurons and fibers in the rat trigeminal ganglion and its sensory root using light- and electron-microscopic immunohistochemistry and quantitative analysis. TrkA immunopositive (+) trigeminal neurons varied from small to large. Double immunofluorescent staining showed that about 28%, 33% and 3% of the trkA(+) neurons coexpressed SP, CGRP and IB4, respectively. About 11% of the trkA(+) neurons also coexpressed parvalbumin. Electron microscopy revealed that trkA was expressed in all types of fibers: While the large majority of the trkA(+) fibers were unmyelinated (35.3%) and small myelinated (<20 MUm2 in cross-sectional area; 45.5%), a still considerable fraction (19.2%) was large myelinated. These findings indicate that all types of trigeminal neurons (ones with unmyelinated, small myelinated or large myelinated fibers) may be regulated by NGF/trkA signaling. PMID- 30308238 TI - alpha-Lipoic acid and amlodipine/perindopril combination potentiate the therapeutic effect of mesenchymal stem cells on isoproterenol induced cardiac injury in rats. AB - Cardiac injury is a dangerous disease and become a greater issue in the forthcoming decades. The ultimate goal is to prevent the progression of heart failure and apoptotic processes. Cardiac tissue may regenerate itself but to certain extent depending on the number of resident stem cells that is limited. Thus, research had been focused on bone marrow derived stem cells (BM-MSCs) as a promising therapy in different types of tissues, including the heart. This study is designed not only to assess the therapeutic effect of BM-MSCs but also to improve their therapeutic effect in combination with antioxidant alpha-lipoic acid (ALA) and antihypertensive therapeutic drug form (AP) against isoproterenol induced cardiac injury and compared with that of BM-MSCs alone. Cardiac injury was induced in 70 male rats by Isoproterenol (ISO was injected s.c. for four consecutive days). Experimental animals were divided into six ISO-treated groups beside a control non treated one. The six ISO-treated groups were divided into: ISO group, ISO+BM-MSCs group, ISO+ALA group, ISO+AP group, ISO+ALA+AP group and ISO+ALA+AP+BM-MSCs group, the last five groups were treated with the examined materials after one week of ISO injection. Isoproterenol significantly increased serum CK-MB, LDH activities, Troponin1 and TNF-alpha. Oxidative stress is evidenced by the increased MDA, NO and Caspase-3 activity associated with significant reduction of GSH content and SOD activity in cardiac tissue. Furthermore, mRNA expression of NFkappaB and iNOS were significantly up regulated and eNOS mRNA expression was down regulated. Administration of BM-MSCs, ALA and AP alone significantly mitigated the induced cardiac injury. Concomitant administration of ALA and AP after BM-MSCs induced a more pronounced improving effect on cardiac functions. In conclusion, the concomitant administration of ALA and AP after BM-MSCs infusion increases the cellular antioxidant levels of cardiac tissue that improves the repairing function of BM-MSCs. PMID- 30308239 TI - Rethinking the impact of the protonable amine density on cationic polymers for gene delivery: A comparative study of partially hydrolyzed poly(2-ethyl-2 oxazoline)s and linear poly(ethylene imine)s. AB - To gain a more profound insight into the impact of the number and the density of protonable amines on the performance of polycations as non-viral vectors, a series of linear poly(ethylene imine)s (LPEIs) with different numbers of ethylene imine (EI) units was compared to partially hydrolyzed (21 to 86%, 20 kDa) poly(2 ethyl-2-oxazoline)s (PHPEtOxs) with a corresponding number of EI units but with varying densities. PHPEtOx polyplexes demonstrated lower transfection efficiencies than the corresponding LPEIs although having the same number of EI units as LPEI, exhibiting smaller or comparable polyplex diameters, similar zeta potentials, and similar or even preferred cyto- and hemocompatibility profiles. The lower efficiency was found to be related to a lower DNA binding capacity and less efficient protection of plasmid DNA against enzymatic degradation. The direct comparison of both types of polymers revealed that the density of charges within the polymer backbone seems to be more important than the total number of EI units. In conclusion, the reduction of the EI density to produce more biocompatible polyplexes must be critically examined, since the presence of high numbers of EI next to each other seems to have a dramatically higher impact on the transfection efficiency than on the in vitro toxicity. PMID- 30308240 TI - Adequate Evidence, Inadequate Incentives for Disease Management Programs. PMID- 30308241 TI - A Novel Simple Diagnostic Algorithm for Rapid and Accurate Detection of Anemia Etiology in Patients With Advanced Heart Failure. PMID- 30308242 TI - Remote Monitoring of Patients With Heart Failure: A White Paper From the Heart Failure Society of America Scientific Statements Committee. AB - BACKGROUND: After several neutral telehealth trials, the positive findings and subsequent Food and Drug Administration approval of an implantable pulmonary arterial pressure monitor (PAPM) led to renewed interest in remote patient monitoring (RPM). Here we seek to provide contemporary guidance on the appropriate use of RPM technology. RESULTS: Although early trials of external RPM devices suggested benefit, subsequent multicenter trials failed to demonstrate improved outcomes. Monitoring features of cardiac implantable electronic devices (CIEDs) also did not deliver improved HF outcomes, newer, multisensor algorithms may be better. Earlier technologies using direct pressure measurement via implanted devices failed to show benefit owing to complications or failure. Recently, 1 PAPM showed benefit in a randomized controlled trial. Although not showing cost reduction, cost-benefit analysis of that device suggests that it may meet acceptable standards. Additional research is warranted and is in progress. Consumer-owned electronic devices are becoming more pervasive and hold hope for future benefit in HF management. Practical aspects around RPM technology include targeting of risk populations, having mechanisms to ensure patient adherence to monitoring, and health care team structures that act on the data. CONCLUSIONS: Based on available evidence, routine use of external RPM devices is not recommended. Implanted devices that monitor pulmonary arterial pressure and/or other parameters may be beneficial in selected patients or when used in structured programs, but the value of these devices in routine care requires further study. Future research is also warranted to better understand the cost effectiveness of these devices. PMID- 30308243 TI - Process and organisation of in-hospital emergencies in France. PMID- 30308244 TI - Endothelial cells promote excitatory synaptogenesis and improve ischemia-induced motor deficits in neonatal mice. AB - Brain microvascular endothelial cells (BMEC) are highly complex regulatory cells that communicate with other cells in the neurovascular unit. Cerebral ischemic injury is known to produce detectable synaptic dysfunction. This study aims to investigate whether endothelial cells in the brain regulate postnatal synaptic development and to elucidate their role in functional recovery after ischemia. Here, we found that in vivo engraftment of endothelial cells increased synaptic puncta and excitatory postsynaptic currents in layers 2/3 of the motor cortex. This pro-synaptogenic effect was blocked by the depletion of VEGF in the grafted BMEC. The in vitro results showed that BMEC conditioned medium enhanced spine and synapse formation but conditioned medium without VEGF had no such effects. Moreover, under pathological conditions, transplanted endothelial cells were capable of enhancing angiogenesis and synaptogenesis and improved motor function in the ischemic injury model. Collectively, our findings suggest that endothelial cells promote excitatory synaptogenesis via the paracrine factor VEGF during postnatal development and exert repair functions in hypoxia-ischemic neonatal mice. This study highlights the importance of the endothelium-neuron interaction not only in regulating neuronal development but also in maintaining healthy brain function. PMID- 30308245 TI - High-fat diet increases respiratory frequency and abdominal expiratory motor activity during hypercapnia. AB - Breathing disorders are commonly observed in association with obesity. Here we tested whether high-fat diet (HFD) impairs the chemoreflex ventilatory response. Male Holtzman rats (300-320 g) were fed with standard chow diet (SD) or HFD for 12 weeks. Then, tidal volume (VT), respiratory frequency (fR) and pulmonary ventilation (VE) were determined in conscious rats during basal condition, hypercapnia (7% or 10% CO2) or hypoxia (7% O2). The mean arterial pressure (MAP), heart rate (HR) and baroreflex sensitivity were also evaluated in conscious rats. A group of anesthetized rats was used for the measurements of the activity of inspiratory (diaphragm) and expiratory (abdominal) muscles under the same gas conditions. Baseline fR, VT and VE were similar between SD and HFD rats. During hypercapnia, the increase of fR was exacerbated in conscious HFD rats (60 +/- 3, vs. SD: 47 +/- 3 Delta breaths.min-1, P < 0.05). In anesthetized rats, hypercapnia strongly increased abdominal muscle activity in HFD group (238 +/- 27, vs. basal condition: 100 +/- 0.3%; P < 0.05), without significant change in SD group (129 +/- 2.1, vs. basal condition: 100 +/- 0.8%; P = 0.34). The ventilatory responses to hypoxia were similar between groups. In conscious HFD rats, MAP and HR were elevated and the baroreflex function was impaired (P < 0.05). These data demonstrated that 12 weeks of HFD exaggerate the ventilatory response activated by hypercapnia. The mechanisms involved in these responses need more investigation in future studies. PMID- 30308246 TI - Aberrant memory system connectivity and working memory performance in subjective cognitive decline. AB - Subjective cognitive decline, a perceived worsening of cognitive functioning without objective deficit on assessment, could indicate incipient dementia. However, the neural correlates of subjective cognitive decline as assessed by magnetic resonance imaging remain somewhat unclear. Here, we evaluated differences in functional connectivity across memory regions, and cognitive performance, between healthy older adults aged 50 to 85 with (n = 35, Age = 68.5 +/- 7.7, 22 female), and without (n = 48, Age = 67.0 +/- 8.8, 29 female) subjective cognitive decline. We also evaluated neurite density, fractional anisotropy, and mean diffusivity of the parahippocampal cingulum, cingulate gyrus cingulum, and uncinate fiber bundles in a subsample of participants (n = 37). Participants with subjective cognitive decline displayed lower average functional connectivity across regions of a putative posterior memory system, and lower retrosplenial-precuneus functional connectivity specifically, than those without memory complaints. Furthermore, participants with subjective cognitive decline performed poorer than controls on visual working memory. However, groups did not differ in cingulum or uncinate diffusion measures. Our results show differences in functional connectivity and visual working memory in participants with subjective cognitive decline that could indicate potential incipient dementia. PMID- 30308247 TI - The effect of artichoke on lipid profile: A review of possible mechanisms of action. AB - Cardiovascular disease is a highly prevalent issue worldwide, and one of its main manifestations, dyslipidaemia, needs more attention. Cooked artichoke (Cynara scolymus) hearts or artichoke leaf extract (ALE) are believed to be helpful in the treatment of dyslipidaemia. In this narrative review, we provide a brief overview of the potential impact of artichoke consumption on lipid profile. We appraised the Cochrane, MEDLINE and Web of Science databases, and included articles published between 2000 and June 2018 on intervention in humans only. The main potential of ALE administration observed on lipid profile relates to decreased serum LDL, total cholesterol and triglyceride concentrations, although no strong evidence for increasing HDL appears to exist. Evidence suggests that decreases of 8-49 mg/dL for LDL concentration, 12-55 mg/dL for total cholesterol, and 11-51 mg/dL for triglycerides, can be attributed to 2 to 3 g/d of ALE, in which its components luteolin and chlorogenic acid may play a key role. On the other hand, the effects of cooked artichoke hearts can be attributed mainly to its soluble fibres, particularly inulin. Despite the convincing evidence on its health benefits, additional long-term clinical trials are pivotal to fully elucidate the potential effects of ALE administration on positive cardiovascular outcomes. PMID- 30308248 TI - Stratification of microbial communities throughout a biological sulphate reducing up-flow anaerobic packed bed reactor, revealed through 16S metagenomics. AB - Biological sulphate reduction (BSR) is a promising low-cost treatment of acid rock drainage effluents. In this paper, the system performance and microbial ecology of a lactate supplemented BSR up-flow anaerobic packed bed reactor (UAPBR) are evaluated across reactor height and compared to a continuous stirred tank reactor (CSTR). The biomass concentrations of planktonic and biofilm communities were quantified and subsequently characterised by 16S rRNA gene amplicon sequencing. The defined microbial communities were shown to correlate with differing availability of lactate, volatile fatty acids produced from lactate degradation and sulphate concentration. The UAPBR was able to achieve near complete sulphate conversion at a 4-day hydraulic residence time (HRT) at a sulphate feed concentration of 10.41 mM (1 g/L). The high volumetric sulphate reduction rate of 0.184 mM/L.h achieved in the first third of the reactor was attributed to OTUs present in the planktonic and biofilm communities. While the scavenging of sulphate within the final third of the UAPBR was attributed to an acetate oxidising genus of SRB which was not detected in the lactate-fed CSTR. The detailed analyses of the microbial communities throughout the UAPBR and CSTR contribute to the growing understanding of the impact of the microbial communities of BSR reactors on system performance. PMID- 30308250 TI - Division of rare cancer research. PMID- 30308251 TI - Safety and accuracy of the Rhythmia mapping system in pediatric patients. AB - BACKGROUND: A new mapping system (Rhythmia) using a 64 mini-electrode small basket array (Orion) was developed that enables rapid high-density mapping in a short time. However, there are few reports about the usefulness of this system in pediatric cases. OBJECTIVE: The purpose of this study was to investigate the safety and accuracy of the Rhythmia system and Orion catheter in children. METHODS: Catheter ablation was performed using the Rhythmia system and Orion catheter in 23 patients younger than 20 years (body weight >20 kg) without a past medical history of cardiac disease. Mapping time, number of mapping beats, and number of mapping electrodes were compared for left atrium, right atrium and right ventricular outflow tract. RESULTS: Twenty-three maps of the right atrium were acquired in 12.6 minutes (range 8.9-15.1), consisting of 709 beats (range 492-1163) and 7132 electrograms (range 4618-10,533). Twelve maps of the left atrium were acquired in 12.1 minutes (range 9.8-14.6), consisting of 565 beats (range 446-881) and 6412 electrograms (range 4912-11,402). There were no significant difference in mapping time, accepted beats, and electrograms between the 2 chambers. Manual annotation was needed in 53 of 293,185 electrograms (0.01%) due to far-field ventricular electrogram sensing and artifact. No adverse events occurred in any of the cases. CONCLUSION: The Orion catheter and Rhythmia mapping system were safe and accurate for mapping various arrhythmias in pediatric patients. Detailed geometry and high-resolution activation mapping were acquired without the need for manual reannotation. PMID- 30308249 TI - Better With Time: An Economic Assessment of Long-Term Mechanical Circulatory Support in a Population Surviving at Least 1 Year with a Left Ventricular Assist Device. AB - This study aims to identify the major components of left ventricular assist device (LVAD)-related costs in a population on long-term mechanical circulatory support to gain insight into opportunities for improvements in quality, safety, and efficiency of care for end-stage heart failure patients. This was a single institution, retrospective cost analysis of patients who received a Heartmate II or HeartWare LVAD between November 2005 and October 2015. Payments for hospitalization for device implantation and subsequent readmissions were represented as the institution's 2015 Medicare reimbursement rate. The incidence, average Medicare reimbursement, and length of stay of readmissions were analyzed for the first year postimplant. A full year of LVAD-related hospitalizations in patients surviving >=12 months, has a median Medicare reimbursement of $247,208. The most common complications related to ventricular assist devices were gastrointestinal bleeding, driveline infection, stroke, and pump thrombosis. Over 90% of total costs were incurred during the initial hospitalization. Seventy-five percent of first-time readmissions occurred within the first 4 months post discharge. Intensive care unit costs accounted for the single largest cost category during readmissions for all of the 4 most common complications. The trends demonstrated suggest that longer lengths of LVAD support in appropriately selected patients results in progressively decreasing cost-per-month up to 12 months, given the large upfront cost of device implantation and relatively modest additional costs of readmissions. This analysis emphasizes the importance of devices with improved complication profiles and clinical protocols to reduce unnecessary intensive care unit stays to increase the cost effectiveness of long term ventricular assist device therapy. PMID- 30308252 TI - Bioengineering a novel 3D in vitro model of gastric mucosa for stomach permeability studies. AB - The field of stomach-directed therapeutics and diagnosis is still hampered by the lack of reliable in vitro models that closely mimic the gastric mucosa where gastric cancer cells are generally confined. Here we propose a rapid, complex, and innovative 3D in vitro model of the gastric mucosa, by extending a conventional gastric monolayer model to an inner stratum of the mucosa - the lamina propria. The developed model comprises normal stomach fibroblasts embedded in a 3D RGD-modified alginate hydrogel prepared on the basolateral side of a Transwell(r) insert, mimicking the extracellular matrix and cellular component of the lamina propria, onto which a moderately differentiated adenocarcinoma stomach cell line (MKN74) was seeded, reproducing the physiological conditions of the gastric barrier. The integrity and functionality of the in vitro model was evaluated through permeability studies of FITC-dextran and 200 nm fluorescent polystyrene nanoparticles at gastric conditions. Nanoparticle transport was pH dependent and strongly impacted by the biomimetic lamina propria, highlighting that a gastric extracellular matrix (ECM)-like microenvironment should be integrated in an in vitro permeability model to be adopted as a reliable evaluation tool of innovative therapeutics and diagnosis of gastric diseases. STATEMENT OF SIGNIFICANCE: Current in vitro models of the gastric mucosa are limited to simplistic 2D cell culture systems, which ignore the dimensionality of the stomach wall and make it difficult to reliably test new therapeutic approaches to gastric pathologies. By combining stomach fibroblasts embedded within a 3D RGD-modified alginate hydrogel and epithelial gastric cancer cells in a Transwell(r) system, we established a new biomimetic model of the stomach mucosa. Epithelial cells recreate the gastric epithelium, while the cell-laden 3D hydrogel recapitulates both the cellular composition and dimensionality of the extracellular matrix of gastric lamina propria. This cellularized 3D model stands as a promising evaluation platform to assist the development of new strategies for the treatment and diagnosis of gastric diseases. PMID- 30308253 TI - A surveillance system for lymphatic filariasis after its elimination in Sri Lanka. AB - Lymphatic filariasis (LF) has been declared eliminated in Sri Lanka in September 2016. To maintain elimination status, a surveillance system to detect hidden endemic foci or LF resurgence is of highest priority. In this paper, we have reported an investigation of LF transmission in Trincomalee district where a surveillance program was not carried out due to 30 years of civil unrest. Proposed surveillance system included, measurement of anti-filarial IgG4 in urine of schoolchildren in areas where LF transmission could exist and assessment of circulating filarial antigen (CFA) and microfilaria (mf) in all urine antibody positive schoolchildren, their family members and 10-15 neighbours of each urine antibody positive household. Spatial distribution of the anti-filarial antibody titers in urine in a high antibody suspected area was analyzed using GPS logger data. Among 2301 school children from 11 schools studied, 41 (1.8%) urine antibody positives were found. The antibody positive rates of the schools ranged between 0 and 4.0%. Nine of the 630 (1.4%) examined became positive for CFA but were negative for mf. Although there were no mf positives, positive CFA and antibody results indicated the existence of Wuchereria bancrofti in Trincomalee. Highest antibody titres in an area correlated with the prevalences of urine antibodies and CFA. Spatial analysis showed LF transmission foci. Therefore, a combination of the non-invasive methods, urine ELISA and GPS mapping, will be a new effective surveillance system to identify hidden LF transmission foci. PMID- 30308254 TI - The use of STarT back screening tool to predict functional disability outcomes in patients receiving physical therapy for low back pain. AB - BACKGROUND CONTEXT: The STarT Back Screening Tool (SBST) categorizes risk of future disability in patients with low back pain (LBP). Previous studies evaluating the use of SBST in physical therapy (PT) populations do not reflect the ethnic and socioeconomic diversity occurring in clinical practice and lack statistical power to evaluate factors associated with outcomes within each SBST risk category. PURPOSE: The purpose of this study is to further refine SBST risk categorization for predicting improvements in functional disability with attention toward patient level factors that might guide SBST use in routine outpatient physical therapy practice. STUDY DESIGN/SETTING: This was a retrospective cohort study that took place within a large academic, tertiary-care health system. PATIENT SAMPLE: The study cohort consisted of 1,169 patients with LBP who completed a course of outpatient physical therapy from June 1, 2014 to May 31, 2015 and who completed the patient-reported SBST and modified low back pain disability questionnaire (MDQ) questionnaires as part of standard of care. OUTCOME MEASURES: Improvement in functional disability defined as decrease in 10 or more points in the MDQ. METHODS: Multivariable logistic regression was performed to evaluate independent predictors of improvement after PT, which included SBST risk category, baseline MDQ, a two-way interaction term between SBST category and baseline MDQ, prior level of function (independent vs. required assistance), demographic characteristics, number of completed PT visits, and duration of PT episode of care. In exploratory analyses, additional two-way interaction terms between SBST category and the significant predictors were added to the regression model. RESULTS: Mean age of patients in the study cohort was 55.1 years (SD 16.1); 657 (56.2%) were female, 117 (10.0%) were black race, 127 (10.9%) had Medicaid insurance, and 353 (30.2%) had previously received PT for back pain. In all, 35.8% (n=419) patients categorized as low risk SBST category, 40.7% (n=476) medium risk SBST category, and 23.4% (n=274) high risk SBST category. There was an interaction between baseline MDQ and SBST risk category and improvement with PT. For all three SBST categories, higher baseline MDQ was associated with higher probability of improvement, but the effect was less pronounced as SBST risk category increased. Additional factors independently associated with reduced odds of improvement after PT included black race (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.28-0.72), Medicaid insurance (OR=0.58, 95% CI 0.36-0.95), and prior PT (OR=0.48, 95% CI 0.34-0.67). In exploratory analyses, there was a significant interaction between insurance type and SBST risk category in predicting functional improvement after PT. Patients with Medicare and Medicaid insurance had similar rates of improvement in low and high risk SBST categories but different rates of improvement in the medium risk categories. CONCLUSIONS: The SBST tool predicts outcomes of PT in a cohort of patients receiving outpatient PT for LBP. The odds of improvement varied according to baseline disability and SBST risk status. Race, insurance type, and history of previous PT influenced prediction independent of SBST risk status. Incorporating these variables and the interaction between SBST and baseline disability in outcome models has the potential to refine prediction of outcomes after PT. PMID- 30308255 TI - PAMAM dendrimers: blood-brain barrier transport and neuronal uptake after focal brain ischemia. AB - Drug delivery to the central nervous system is restricted by the blood-brain barrier (BBB). However, with the onset of stroke, the BBB becomes leaky, providing a window of opportunity to passively target the brain. Here, cationic poly(amido amine) (PAMAM) dendrimers of different generations were functionalized with poly(ethylene glycol) (PEG) to reduce cytotoxicity and prolong blood circulation half-life, aiming for a safe in vivo drug delivery system in a stroke scenario. Rhodamine B isothiocyanate (RITC) was covalently tethered to the dendrimer backbone and used as a small surrogate drug as well as for tracking purposes. The biocompatibility of PAMAM was markedly increased by PEGylation as a function of dendrimer generation and degree of functionalization. The PEGylated RITC-modified dendrimers did not affect the integrity of an in vitro BBB model. Additionally, the functionalized dendrimers remained safe when in contact with the bEnd.3 cells and rat primary astrocytes composing the in vitro BBB model after hypoxia induced by oxygen-glucose deprivation. Modification with PEG also decreased the interaction and uptake by endothelial cells of PAMAM, indicating that the transport across a leaky BBB due to focal brain ischemia would be facilitated. Next, the functionalized dendrimers were tested in contact with red blood cells showing no haemolysis for the PEGylated PAMAM, in contrast to the unmodified dendrimer. Interestingly, the PEG-modified dendrimers reduced blood clotting, which may be an added beneficial function in the context of stroke. The optimized PAMAM formulation was intravenously administered in mice after inducing permanent focal brain ischemia. Twenty-four hours after administration, dendrimers could be detected in the brain, including in neurons of the ischemic cortex. Our results suggest that the proposed formulation has the potential for becoming a successful delivery vector for therapeutic application to the injured brain after stroke reaching the ischemic neurons. PMID- 30308256 TI - Recent progress of drug nanoformulations targeting to brain. AB - Most of the potential therapeutic agents capable to modulate the pathophysiology or treat the neurological disorders and brain tumors are useless in the current modern and advanced era of neuroscience due to the impeding action of biological barriers. Among various therapeutic strategies applied for translocation of drug delivery across the blood-brain barrier (BBB), nanoformulations set an excellent platform for brain targeting by overcoming the biological and chemical barriers and protecting drug from efflux to promote the optimum therapeutic drug concentration in brain parenchyma tissues. Nanocarriers are the most widely studied delivery vehicles for BBB translocation with the efficiency of selectively targeting or exploiting inherent biological molecules, receptors, carriers or mechanisms of the brain. Nearly all of the available drug delivery nanocarriers explored in recent years for brain therapeutics and theranostics are based on lipid or polymeric materials. Polymeric nanoparticles (NPs) and lipid based nanocarriers including liposomes, solid lipid NPs (SLNs) and micelles, etc. are under the direct focus of neuroscientists due to the promising attributes and vast applications in neurological disorders. Surface modification of nanovehicles with proper targeting moiety or coating with surfactants promotes the interaction with endothelial cells and passage of nanocarriers to the brain. This review comprehensively depicts challenges to the brain targeted drug delivery, mechanisms of drug transportation across the BBB, and potential contributions of endogenous cells as NPs delivery cells and novel targeting ligands decorated nanoformulations in imaging, treating and controlling neurological disorders. PMID- 30308257 TI - Translating nanomedicines: Thinking beyond materials? A young investigator's reply to 'The Novelty Bubble'. PMID- 30308258 TI - Crosslinked self-assembled nanoparticles for chemo-sonodynamic combination therapy favoring antitumor, antimetastasis management and immune responses. AB - Sonodynamic therapy (SDT) has been proposed as a new modality for cancer management through low-intensity ultrasound induced activation of sonosensitizers. Here, we designed a novel redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatform loading docetaxel, combining SDT and chemotherapy, for antiproliferation and antimetastasis of melanoma. The reversibly crosslinked and self-assembled nanoparticles possessed monodispersive size distribution, stability in physical conditions, while showing increased uptake with rapid drug release in simulated tumor microenvironment (reductive potentials and degradative hyaluronidase-1). With synthesized ultrasound sensitive polymer backbones, SDT induced the generation of cellular reactive oxygen species and mitochondrial damage, exerting the apoptotic effect through the release of cytochrome C, the expression of cleaved caspase-9 followed by the functional cleaved caspase-3. Chemo-sonodynamic therapy not only inhibited tumor growth and metastasis with reduced metastatic protein expression, but also caused immune response via the release of tumor-associated antigens. It was initially demonstrated that SDT could induce the tumor cell death, therefore having potentials to recruit cytotoxic lymphocytes into tumor sites. Notably, the nanoplatforms exhibited good in vivo stability and blood compatibility, indicating the safety and efficiency in drug delivery. Our work thus presents a convenient approach to fabricate intelligent multifunctional nanoparticles and paves a path for effective cancer therapies. PMID- 30308259 TI - Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection. AB - A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy 3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160 nm and negative zeta potential (-30 to -25 mV) were stable for a period of 10 months at 4 degrees C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8 * LD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time dependent additivity and increased reactivation up to 35% were observed. PMID- 30308260 TI - Post-prostatectomy Lymphocoele Presenting With Renal Failure. AB - Since its advent in 2001, robotic-assisted laparoscopic prostatectomy has become the gold standard treatment for the management of localized prostate cancer. Pelvic lymphocoele is most commonly found after gynecological or renal transplant surgery or following extensive pelvic lymphadenectomy. Its formation following prostatectomy is not uncommon1 but it seldom causes major complications or morbidity.2 We present a case of a 66-year-old man who presented with left-sided abdominal pain, a palpable infra-umbilical mass, and renal failure. He was initially presumed to have high pressure chronic retention however catheterization did not result in any improvement in his renal function. Further investigations revealed a large lymphocoele causing bilateral ureteric obstruction with resultant hydronephrosis. PMID- 30308261 TI - Recovery of Voiding Efficiency and Bladder Function in Male Patients With Non neurogenic Detrusor Underactivity After Transurethral Bladder Outlet Surgery. AB - OBJECTIVE: The aim of this study is to investigate the treatment outcome in men with detrusor underactivity (DU) and voiding dysfunction who underwent transurethral resection or incision of the prostate (TURP or TUIP). DU usually affects decision making whether bladder outlet surgery is necessary. MATERIALS AND METHODS: A total of 60 men with urodynamic DU and voiding dysfunction who underwent TURP or TUIP from 1998 to 2015 were retrospectively analyzed for their treatment outcome after follow-up for more than 1 year. DU was defined as urodynamic evidence of low detrusor pressure (<40 cm H2O), low flow rate (<10 mL/s), a postvoid residual urine volume >300 mL, and a voiding efficiency (VE) of <33%. Satisfactory outcome was defined as improved quality of life and having a VE of >50% after treatment. Predictive factor for a successful outcome was also analyzed. RESULTS: At a mean follow-up of 31 months, 49 (81.7%) patients had achieved a satisfactory treatment outcome. Among the patients who received TURP and TUIP, 38/44 (86.4%) and 11/16 (68.8%) had satisfactory outcome, respectively. The satisfactory group had significantly higher detrusor pressure and greater bladder compliance at baseline than the unsatisfactory group. There was significant improvement in the urodynamic parameters after treatment in the satisfactory group. Among the patients with satisfactory outcome, 34 (69.4%) patients had recovery of detrusor function within 3 months. CONCLUSION: Active surgical treatment such as TURP or TUIP results in recovery of VE and detrusor function within 3 months after treatment in the majority of patients with DU. PMID- 30308262 TI - Herniated Kidney. AB - Postoperative incisional hernia is a relatively common complication following abdominal surgery. Herniation of the kidney is a less common entity and typically occurs as a congenital or acquired diaphragmatic defect, and rare case reports have demonstrated partial flank or lumbar herniation of the kidney. Herein we present a unique case of a postoperative incisional hernia containing the entire right kidney. PMID- 30308263 TI - A Large Urinary Bladder Hemangioma Mimicking Urachal Cancer: A Case Report and Literature Review. AB - Urinary bladder hemangiomas are rare, especially in children and adolescents. We present a case of a 17-year-old young man with persistent gross hematuria for 1 month. Computed tomography revealed a 3.6 cm mass on the superior anterior wall of the urinary bladder, which was highly suspected as an urachal tumor. We carried out an en bloc resection of the urachus and bladder tumor. The pathologic report indicated a cavernous hemangioma of the urinary bladder. No tumor recurrence or bleeding was found during the 2-year follow-up. Urinary bladder hemangioma is an important differential diagnosis in young patients with hematuria. PMID- 30308264 TI - Live Surgery for Laparoscopic Radical Prostatectomy-Does it Worsen the Outcomes? A Single-center Experience. AB - OBJECTIVE: To compare outcomes of laparoscopic radical prostatectomy (LRP) performed in live surgery versus daily routine LRP. METHODS: From January 2014 to June 2017, data from LRP performed at our Institution in live broadcasting by 3 experienced laparoscopic surgeons during educational events were collected. A 1:2 matching (according to BMI, comorbidities, NCCN risk groups, and operating surgeon) was performed with the routine LRP patients collected in our prospectively-maintained database. Chosen procedures were performed within the same time span by the same surgeons. Data of interest were compared. RESULTS: Twenty-three live surgery LRPs were analyzed (Group A). Forty-six matched patients were the controls (Group B). Groups were comparable at baseline. No differences were found in perioperative data (operative time, blood loss, and intraoperative complications, 4.3% in both Groups) and postoperative complications. Particularly, 10 (43.5%) and 22 patients (47.8%) did not report complications (Group A vs B, respectively, P = .54). The majority of complications were Clavien 1-2, with 2 patients per Group requiring blood transfusion. Overall positive surgical margins rate was 26.1%. It was significantly higher in Group A (43.5% vs 17.4%; P = .02), but no differences were found in the number of patients who relapsed, who needed radiotherapy or androgen deprivation therapy within a median follow-up of 25 months in both Groups. No differences were found regarding functional data. Limitations include a low sample size and limited follow-up. CONCLUSION: LRP has similar perioperative outcomes when performed in either live surgery or daily routine setting. We underline the higher positive surgical margins rate after live surgeries that should increase the awareness before embarking on it. PMID- 30308265 TI - A short periconceptional exposure to maternal type-1 diabetes is sufficient to disrupt the feto-placental phenotype in a rabbit model. AB - Tight metabolic control of type-1 diabetes is essential during gestation, but it could be crucial during the periconception period. Feto-placental consequences of maternal type-1 diabetes around the time of conception need to be explored. Using a rabbit model, type-1 diabetes was induced by alloxan 7 days before mating. Glycemia was maintained at 15-20 mmol/L with exogenous insulin injections to prevent ketoacidosis. At 4 days post-conception (dpc), embryos were collected from diabetic (D) or normoglycemic control (C) dams, respectively, and transferred into non-diabetic recipients. At 28dpc, D- and C-feto-placental units were collected for biometry, placental analyses and lipid profiles. D-fetuses were growth-retarded, hyperglycemic and dyslipidemic compared to C-fetuses. The efficiency of D-placentas was associated with an increased gene expression related to nutrient supply and lipid metabolism whereas volume density of fetal vessels decreased. Fetal plasma, placental and fetal liver membranes had specific fatty acid signatures depending on embryonic origin. Tissues from D-fetuses contained more omega-6 polyunsaturated fatty acids. The concentrations of docosahexaenoic acid decreased while linoleic acid increased in the heart of D fetuses. This study demonstrates that a short exposure to maternal type-1 diabetes in the periconception window, until the blastocyst stage, is able to irreversibly malprogram the feto-placental phenotype, through precocious and persistent structural and molecular adaptations of placenta. PMID- 30308266 TI - Human versus non-human sex steroid use in hormone replacement therapies part 1: Preclinical data. AB - Prior to 2002, hormone replacement therapy (HRT) was considered to be an important component of postmenopausal healthcare. This was based on a plethora of basic, epidemiological and clinical studies demonstrating the health benefits of supplementation with human sex steroids. However, adverse findings from the Women's Health Initiative (WHI) studies that examined the 2 major forms of HRT in use in the US at that time - Premarin (conjugated equine estrogens; CEE) and Prempro (CEE + medroxyprogesterone acetate; MPA), cast a shadow over the use of any form of HRT. Here we review the biochemical and physiological differences between the non-human WHI study hormones - CEE and MPA, and their respective human counterparts 17beta-estradiol (E2) and progesterone (P4). Preclinical data from the last 30 years demonstrate clear differences between human and non-human sex steroids on numerous molecular, physiological and functional parameters in brain, heart and reproductive tissue. In contrast to CEE supplementation, which is not always detrimental although certainly not as optimal as E2 supplementation, MPA is clearly not equivalent to P4, having detrimental effects on cognitive, cardiac and reproductive function. Moreover, unlike P4, MPA is clearly antagonistic of the positive effects of E2 and CEE on tissue function. These data indicate that minor chemical changes to human sex steroids result in physiologically distinct actions that are not optimal for tissue health and functioning. PMID- 30308267 TI - The androgen receptor is required for maintenance of bone mass in adult male mice. AB - Previous studies evaluating the role of the androgen receptor (AR) for bone mass have used mouse models with global or tissue-specific lifelong inactivation of the AR. However, these mouse models have the AR inactivated already early in life and the relative roles of the AR during development, sexual maturation and in adult mice cannot be evaluated separately. The aim of the present study was to determine the specific roles of the AR in bone during sexual maturation and in adult mice. The AR was conditionally ablated at four (pre-pubertal) or ten (post pubertal) weeks of age in male mice using tamoxifen-inducible Cre-mediated recombination. Both the pre-pubertal and the post-pubertal AR inactivation were efficient demonstrated by substantially lower AR mRNA levels in seminal vesicle, bone and white adipose tissue as well as markedly reduced weights of reproductive tissues when comparing inducible ARKO mice and control mice at 14 weeks of age. Total body BMD, as analyzed by DXA, as well as tibia diaphyseal cortical bone thickness and proximal metaphyseal trabecular bone volume fraction, as analyzed by MUCT, were significantly reduced by both pre-pubertal and post-pubertal AR inactivation. These bone effects were associated with an increased bone turnover, indicating a high bone turnover osteoporosis. Pre-pubertal but not post-pubertal AR inactivation resulted in substantially increased fat mass. In conclusion, the AR is required for maintenance of both trabecular and cortical bone in adult male mice while AR expression during puberty is crucial for normal fat mass homeostasis in adult male mice. PMID- 30308268 TI - Simultaneous penetration monitoring of oil component and active drug from fluorinated nanoemulsions. AB - In the field of dermal drug delivery, determining the penetration depth of actives is a standard procedure for the development of novel formulations. Regarding the vehicle components, respective penetration studies are rather scarce due to their often challenging analytics. However, an understanding of the interactions between drugs and additives during skin penetrating could help to develop promising drug delivery systems. Thus, the objective of the present study was to simultaneously monitor the skin penetration of the incorporated model drug diclofenac sodium and the semifluorinated oil perfluorohexyloctane (F6H8) from newly developed nanoemulsions. In vitro tape stripping studies were conducted and the tapes were analysed for their content of drug and additive in parallel by HPLC and 19F NMR. The penetration depth and total recovered amount of both substances of interest were successfully determined on each tape strip. The vehicle oil compound F6H8 itself showed a very small skin penetration, while the penetration of diclofenac sodium was consistently about 9- to 10-fold higher. Higher amounts of the oil content led to higher skin penetration of diclofenac sodium and slightly increased oil penetration; this effect might be explained by the increasing occlusion effect caused by increasing amounts of fluorinated oil. PMID- 30308269 TI - Enhanced uptake and improved anti-tumor efficacy of doxorubicin loaded fibrin gel with liposomal apatinib in colorectal cancer. AB - Colorectal cancer (CRC) exhibited high incidence rate worldwide and the advanced CRC had a poor prognosis. Thereupon, seeking efficient treatment for CRC is critical. Apatinib is a novel vascular epithelial growth factor receptor (VEGFR) inhibitor with inspiring therapeutic effect in some malignant cancers. In our study, doxorubicin was mixed in fibrin gel and apatinib was encapsulated with self-synthesized liposome. The results showed liposomal apatinib (Lipo-Apatinib) could enhance the intracellular uptake of doxorubicin in vitro. Moreover, compared with doxorubicin loaded fibrin gel (DOX-FG) alone, the combination of DOX-FG and Lipo-Apatinib significantly improved the anti-tumor effect in mice CRC subcutaneous model and abdominal metastasis model Drug combination successfully inhibited tumor angiogenesis and tumor proliferation, and also promoted tumor apoptosis. Our data suggested that combined therapy of DOX-FG and Lipo-Apatinib would be a promising treatment approach for CRC. PMID- 30308270 TI - The impact of protein corona on the behavior and targeting capability of nanoparticle-based delivery system. AB - Once introduced into physiological environment, nanoparticles (NPs) are immediately coated with proteins, resulting in formation of what is known as protein corona. The formation of protein corona can be affected by many factors. Likewise, the addition of protein corona can alter the physicochemical properties and biodistribution of NPs. NPs with the coating protein corona can be considered as a biological identity that recognized by cells in biological system. Thus, to understand and regulate the effect of protein corona on targeting capability of NPs in vivo, it is necessary to elucidate the interaction between the NPs and the biological fluid. In this review, we first elucidate the factors influencing the formation of protein corona, including NPs physicochemical factors, such as NPs composition, size, shape, surface chemistry, etc., and environmental factors, such as environmental temperature, protein origins, etc. Then, we focus on the effect of protein corona on the passive targeting and active targeting, and discuss the probable reasons that causing the discrepant results. Finally, we review the strategies for tuning the protein corona to promote targeting, including reducing protein adsorption and recruiting specific proteins. PMID- 30308271 TI - Pollen grains as a novel microcarrier for oral delivery of proteins. AB - Oral delivery of proteins and peptides is a challenge due to their degradation in the stomach. To overcome this challenge, ragweed (Ambrosia elatior) pollen grains were engineered to serve as protective microcapsules. A matrix comprising of Eudragit L100-55, an enteric polymer was deposited on the inner surfaces of ragweed pollens to protect the encapsulated protein from gastric degradation and to achieve pH-dependent release in the intestine. The Eudragit L100-55 matrix was formed without use of organic solvents so that solvent-induced damage to protein molecules could be prevented. To demonstrate the concept, bovine serum albumin (BSA) a model protein was used. A matrix of Eudragit L100-55 embedded with BSA was prepared in ragweed pollens by optimizing their respective concentrations for maximizing BSA loading in the matrix. The ability of this optimized formulation to protect BSA in simulated gastric acid fluid was evaluated. Release studies in simulated gastric fluid (pH 1.2) showed minimal BSA release from the ragweed Eudragit L100-55 formulation. Analysis of BSA retained in the formulation after its exposure to gastric fluid confirmed that the residual BSA had not denatured. Release studies in the simulated intestinal fluid (pH 6.8) showed that ragweed pollen offered additional controlled release mechanism within the first few hours of release by virtue of their solid wall. In conclusion, upon use of a protein friendly solvent for Eudragit L100-55, proteins could be encapsulated in ragweed pollen without denaturing them, and the resulting formulation exhibited selective release of the proteins at intestinal pH suggesting that the ragweed pollen grain based formulation could be promising for oral delivery of proteins. PMID- 30308272 TI - Injectable long-acting human immunodeficiency virus antiretroviral prodrugs with improved pharmacokinetic profiles. AB - While highly active antiretroviral therapy (HAART) has significantly reduced mortality rates in patients with human immunodeficiency virus type 1 (HIV-1), its efficacy may be impeded by emergence of drug resistance caused by lack of patient adherence. A therapeutic strategy that requires infrequent drug administration as a result of sustained release of antiretroviral drugs would put less burden on the patient. Long-acting antiretroviral prodrugs for HIV therapy were synthesized through modification of the active drugs, emtricitabine (FTC) and elvitegravir (EVG), with docosahexaenoic acid (DHA) in one-step, one-pot, high-yielding reactions. The in vitro drug release profiles of these synthetic conjugates demonstrated sustained and controlled release of the active drug over a period of 3-4 weeks attributable to the hydrolysis of the chemical linker in conjunction with the hydrophilicity of the parent drug. Both conjugates exhibited superior antiviral activities in tissue culture models of HIV replication as compared to those of the free drugs, strengthening their role as potent prodrugs for HIV therapy. Pharmacokinetic analysis in CD1 mice further confirmed the long-acting aspect of these conjugates with released drug concentrations in plasma detected at their respective IC90/IC95 values over a period of 2 weeks and discernable amounts of active drug even at 6 weeks. Our findings suggest that the injectable small molecule conjugates could be used as long-acting controlled release of FTC and EVG in attempts to mitigate adherence-related HIV resistance. PMID- 30308273 TI - The physiochemical, mechanical, and adhesive properties of solvent-cast vitamin E/Soluplus(r) films. AB - Soluplus(r) is an amphiphilic graft copolymer used in hot melt extrusion applications and electrospinning. Very little information is available on the use of Soluplus(r) as a film former and in the development of film-based formulations. The overall aim of this work was to study the mechanical and adhesive properties of Soluplus(r) films prepared by the solvent casting technique. More specifically, we discovered that vitamin E can serve as a plasticizer for the Soluplus(r) polymer and to significantly modulate its mechanical and adhesive properties. Vitamin E (0-75% w/w) and Soluplus(r) were dissolved in ethanol and cast on liners to produce transparent films. Cast films were tested for their physiochemical properties by IR, XRD, and MDSC, and for their adhesive and mechanical properties by texture analysis. Vitamin E was found to be miscible with Soluplus(r) and to reduce the crystallinity of the films. Vitamin E also decreased the films' tensile strength and Young's modulus while significantly increasing their percent elongation. The most notable effect was the observed increase in the adhesiveness (tackiness) and hydrophobicity of the films, which was evidenced by a significant increase in their water contact angle and a decrease in their swelling capacity and disintegration. These observations indicated that vitamin E/Soluplus(r) blends might be used for the preparation of highly pliable films, especially when made with 30-50% vitamin E, and in the development of a new type of pressure sensitive adhesive films when prepared with >=65% vitamin E load. PMID- 30308274 TI - Self-assembly of biotinylated poly(ethylene glycol)-poly(curcumin) for paclitaxel delivery. AB - Paclitaxel (PTX), one of the most potent anticancer agents, has showed a remarkable activity against varieties of tumors. However, the bioavailability of PTX is quite low due to its poor aqueous solubility. Moreover, the emerging multidrug resistance (MDR) in cancer to PTX remains a major obstacle for successful chemotherapy. In order to address these problems, we developed self assembly of biotinylated poly(ethylene glycol)-poly(curcumin) (Biotin-PEG-PCDA) for PTX delivery (termed as PTX-BPC NPs) with the application of mPEG2K-P(CL-co LLA) as an emulsifier. The loading content and encapsulation efficiency of PTX were 13.2% and 92.0%, respectively. In vitro drug release study showed that PTX BPC NPs could degrade rapidly and then release the PTX payload in a 10 mM glutathione (GSH) environment. Compared with free PTX, PTX-BPC NPs exhibited enhanced anticancer efficacy (IC50(MCF-7/ADR cells), 17.28 ug/mL vs. 1.15 ug/mL). In addition, these biotin-modified nanoparticles could also significantly reverse PTX resistance by suppressing the over-expression of P-gp, thus resulting in increased intracellular drug accumulation and reduced drug efflux in MCF-7/ADR cells, which showed a great anticancer effect. PMID- 30308275 TI - Methodology to estimate the break force of pharmaceutical tablets with curved faces under diametrical compression. AB - This paper develops a methodology to estimate the break force of curved faced tablets under diametrical compression. Common excipients used in pharmaceutical tablet formulations, including microcrystalline cellulose, calcium phosphate and mannitol as well as their mixtures were characterised. Compacts of different densities were manufactured and their compressive and tensile strength was measured. The break force of curved face tablets having a comprehensive range of face curvatures and thickness was measured using the diametrical compression method ("hardness" test). Equation sigmad=FpiD2atD+bWD-1 introduced by Shang et al. (2013) was used to relate the break force (F) to tablet geometry (D, t, W) and material tensile strength (sigmad). Here, we propose a method to estimate the parameters a and b using data for curved faced tablets made from three pure excipients. The method was validated for four mixtures. The errors were analysed and compared with the USP29 method sigmad=10FpiD2(2.84(t/D) 0.126t/W+3.15(W/D)+0.01)-1. The proposed method has better accuracy, however, requires additional characterisation of the compressive strength of the material. PMID- 30308276 TI - Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co glycolic acid) nanofiber for theranostic purposes. AB - Local delivery of viruses via nanomaterials has been demonstrated in the treatment of colon cancer. A cancer-favoring oncolytic vaccinia virus (CVV), which is an evolutionary cancer-favoring engineered vaccinia virus carrying the green fluorescent protein (GFP) gene, has antitumor efficacy in drug-resistant colon cancer and metastatic liver cells. Here, we present the antitumor efficacy of a CVV coated a poly lactic-co-glycolic acid (PLGA) nanofiber for local drug delivery in theranostic approaches. In vitro- and in vivo-based analyses using mouse colon carcinoma models confirmed the therapeutic efficacy of CVV-PLGA nanofibers through diagnostic localization of the tumors and reduced tumor burden as a result of enhanced apoptosis. We propose that the CVV-PLGA nanofiber may be used for theranostic purposes in cancer therapy. PMID- 30308277 TI - SPF enhancement provided by rutin in a multifunctional sunscreen. AB - Unprotected chronic exposure to solar radiation can contribute to premature skin cancer and sunscreens are a key factor to avoid those detrimental effects. Currently, there is a growing interest in the photoprotector and antioxidant potential of bioactive substances, such as rutin, that could increase the sun protection factor (SPF) value and, also, donate multifunctional characteristics to sunscreens. Recent in vitro findings indicated that rutin, when incorporated into sunscreens, can provide antioxidant activity and SPF improvement. However, clinical studies are fundamental to determine this activity, due to the lack of repeatability of in vitro methodology and low correlation with the in vivo data. We aimed at evaluating the clinical safety and in vivo SPF of rutin by comparing sunscreen formulations containing 0.1% (w/w) rutin, 3.0% (w/w) butyl methoxydibenzoylmethane and 8.0% (w/w) octyl dimethyl PABA (2-ethylhexyl 4 (dimethylamino)benzoato) with a similar bioactive-free preparation. Additionally, skin hydration, in vitro SPF and in vitro antioxidant activity of rutin, in association with the ultraviolet (UV) filters, were investigated. The safety profile of the formulations under sun-exposed skin conditions qualified the formulas for clinical efficacy assays. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) test confirmed the antioxidant properties of rutin, revealing around 40% increase in radical scavenging potential when the bioactive compound was present. Rutin in combination with the UV filters robustly elevated the clinical SPF around 70%, when compared with the bioactive-free formulation. To date, this is the first report in the specialized literature of an in vivo SPF measurement of a rutin containing photoprotective preparation, supporting the claim that rutin is an effective and safe bioactive compound to be used in multifunctional sunscreens. PMID- 30308278 TI - Towards a global phylogeny of freshwater mussels (Bivalvia: Unionida): Species delimitation of Chinese taxa, mitochondrial phylogenomics, and diversification patterns. AB - The Yangtze River Basin in China is one of the global hotspots of freshwater mussel (order Unionida) diversity with 68 nominal species. Few studies have tested the validity of these nominal species. Some taxa from the Yangtze unionid fauna have not been adequately examined using molecular data and well-positioned phylogenetically with respect to the global Unionida. We evaluated species boundaries of Chinese freshwater mussels, and disentangled their phylogenetic relationships within the context of the global freshwater mussels based on the multi-locus data and complete mitochondrial genomes. Moreover, we produced the time-calibrated phylogeny of Unionida and explored patterns of diversification. COI barcode data suggested the existence of 41 phylogenetic distinct species from our sampled 40 nominal taxa inhabiting the middle and lower reaches of the Yangtze River. Maximum likelihood and Bayesian inference analyses on three loci (COI, 16S, and 28S) and complete mitochondrial genomes showed that the subfamily Unioninae sensu stricto was paraphyletic, and the subfamily Anodontinae should be subsumed under Unioninae. In addition, we described two new tribes (Aculamprotulini tribe nov. and Lepidodesmini tribe nov.) in the subfamily Unioninae and one new genus (Parvasolenaiagen. nov.) in the subfamily Gonideinae. Molecular dating analysis suggested freshwater mussels diversified at 346.1 Mya (HPD = 286.6-409.9). The global diversification rate for Unionida was estimated to be 0.025 species/Myr. Our study found only a single well-supported rate shift in Unionida diversification, occurring at the base of the subfamily Ambleminae. The evolution of active host-attraction may have triggered the burst of speciation in Ambleminae, and the environment and geography of the Mississippi River Basin likely sustained this radiation. PMID- 30308279 TI - Unraveling the intricate biodiversity of the benthic harpacticoid genus Nannopus (Copepoda, Harpacticoida, Nannopodidae) in Korean waters. AB - Nannopus (Harpacticoida, Nannopodidae) species are abundant and widely distributed throughout the world across a variety of habitats. Nannopus is well known for high frequencies of misidentifications and thus may comprise several cryptic complexes and morphologically distinct species. Cryptic taxa are common in meiofauna communities. In this study, we aimed to identify Nannopus species using an integrative approach including molecular taxonomy. We adopted a non destructive DNA extraction method so that morphological and molecular data could be obtained from the same specimen. We analyzed the molecular diversity and distributions of Nannopus using a total of 190 individuals. We sequenced the 190 mtCOI, 53 mtCYTB, 25 18SrDNA, and 43 28SrDNA genes from 190 individuals. Several species delimitation approaches were applied, including uncorrected p-distances for mtCOI, mtCYTB, 18SrDNA, and 28SrDNA, and Automatic Barcode Gap Discovery and Bayesian implemented Poisson tree processes for mtCOI and mtCYTB data. The maximum likelihood and Bayesian approaches were used to examine the phylogenetic relationships among individuals using the combined set of all four genes. Our species delimitation and phylogenetic analyses indicated the presence of three cryptic and six morphologically distinct species. All species are sympatric and widely distributed across mudflats ranging from the Yellow Sea to the South Sea in Korea. The divergence patterns of the four genes were not congruent. A phylogenetic tree based on the concatenated dataset was the most robust, was congruent with morphology, and suggested two major clades. We considered the validity of reinstating the genus Ilyophilus (Lilljeborg, 1902) and ultimately concluded that including all congeners in Nannopus until the type species (N. palustris Brady, 1880) is re-described was the most prudent approach. PMID- 30308280 TI - Phylogenomics, life history and morphological evolution of ophiocomid brittlestars. AB - Brittlestars in the family Ophiocomidae are large and colourful inhabitants of tropical shallow water habitats across the globe. Here we use targeted capture and next-generation sequencing to generate robust phylogenomic trees for 39 of the 43 species in order to test the monophyly of existing genera. The large genus Ophiocoma, as currently constituted, is paraphyletic on our trees and required revision. Four genera are recognised herein: an expanded Ophiomastix (now including Ophiocoma wendtii, O. occidentalis, O. endeani, O. macroplaca, and Ophiarthrum spp), Ophiocomella (now including the non-fissiparous Ophiocoma pumila, aethiops and valenciae) and Breviturma (now including Ophiocoma pica, O. pusilla, O. paucigranulata and O. longispina) and a restricted Ophiocoma. The resulting junior homonym Ophiomastix elegans is renamed O. brocki. The genus Ophiomastix exhibits relatively high rates of morphological disparity compared to other lineages. Ophiomastix flaccida and O. (formerly Ophiarthrum) pictum have divergent mitochondrial genomes, characterised by gene-order rearrangements, strand recoding, enriched GT base composition, and a corresponding divergence of nuclear mitochondrial protein genes. The new phylogeny indicates that larval and developmental transitions occurred rarely. Larval culture trials show that species with abbreviated lecithotrophic larval development occur only within Ophiomastix, although the possible monophyly of these species is obscured by the rapid early radiation within this genus. Asexual reproduction by fission is limited to one species-complex within Ophiocomella, also characterised by elevated levels of allelic heterozygosity, and which has achieved a relatively rapid global distribution. The crown ages of the new genera considerably predate the closure of the Tethyan seaway and all four are distributed in both the Atlantic and Indo-Pacific Oceans. Two species pairs appear to reflect the closure of the Panama Seaway, although their fossil-calibrated node ages (12-14 +/- 6 my), derived from both concatenated sequence and multispecies coalescent analyses, considerably predate the terminal closure event. Ophiocoma erinaceus has crossed the East Pacific barrier and is recorded from Clipperton Island, SW of Mexico. PMID- 30308281 TI - A collagen film with micro-rough surface can promote the corneal epithelization process for corneal repair. AB - Corneal disease is a major cause of blindness and keratoplasty is an effective treatment method. A freeze-dried collagen film (FD-Col) with micro-rough surface structure for corneal epithelial repair was reported in our previous studies. In this research, we conducted a more comprehensive study on the FD-Col film. Besides with excellent mechanical property and optical transparency, the FD-Col film also has good penetrating ability in nutrient solutions. The permeability coefficient of the FD-Col in NaCl and tryptophan solution is (2.58 +/- 0.47) * 10 6 cm2/s and (2.67 +/- 0.13) * 10-7 cm2/s, respectively. In addition, the morphology change of the FD-Col film before and after water absorption is relatively stable suggesting that this film can be fabricated with various dimensions easily. Moreover, corneal lamellar keratoplasty shows that the FD-Col film can be sutured in rabbit's ocular surface and the re-epithelization process in vivo is complete in about 12 days, and the transparency is restored quickly in the first month. Corneal rejection reaction, neovascularization and keratoconus are not observed within 2 months. This FD-Col film, which can be prepared in large quantities and at low cost, should have potential application in corneal repair in the future. PMID- 30308282 TI - Characterization and comparative analysis of six complete mitochondrial genomes from ectomycorrhizal fungi of the Lactarius genus and phylogenetic analysis of the Agaricomycetes. AB - Lactarius is one of the most prominent genera of mushroom-forming fungi in the world. In the present study, complete mitochondrial genomes (mitogenomes) from six Lactarius species were sequenced and assembled. The six mitogenomes were all composed of circular DNA molecules, with total lengths ranging from 38,445 bp to 60,843 bp. The GC contents, GC skews, and AT skews of the mitogenomes varied among the six species. Mitogenomic synteny analysis revealed the presence of gene rearrangements among the mitogenomes. Among the 15 core protein coding genes (PCGs) within the mitogenomes, nad4L exhibited the least genetic distance among species, indicating a high degree of conservation. In addition, the Ka/Ks values for all 15 core PCGs were <1, suggesting that they were subject to purifying selection. Comparative analyses indicated that the increase of intron numbers and sizes contributed to the expansion of mitogenomes in Lactarius. Phylogenetic analyses based on three combined gene datasets yielded identical and well supported (BPP >= 0.83) topologies, dividing the six Lactarius species into two groups. This study provides the first report of mitogenomes from Lactarius and promotes further understanding of the genetics, evolution, and phylogenetic relationships of this important ectomycorrhizal fungal genus. PMID- 30308284 TI - Conformational deviation of Thrombin binding G-quadruplex aptamer (TBA) in presence of divalent cation Sr2+: A classical molecular dynamics simulation study. AB - Thrombin binding TBA-G-quadruplex aptamer (TBA) plays a major role in blood coagulation cascade. The 15-mer TBA sequence tends to form four-stranded TBA-G quadruplex structure. In this research work, a series of explicit solvent classical MD simulations of the TBA is carried out using different salt (SrCl2) concentrations (0, 50, 100 and 200 mM). Here we have also testified the effect of salt concentration of divalent cation Sr2+ on the conformational change of quadruplex DNA. The structural deviations, fluctuations, torsional angles and the affinity of the ion are explored at different salt concentrations. It is found that the conformation of TBA-G-quadruplex at 0 mM and 50 mM salt concentrations, is very much different than the other salt concentrations (100 mM and 200 mM). Also observed are as follows: (i) no exchange of Sr2+ ion between inside and outside of the channel, (ii) an enhancement in the Sr2+ ion density around the phosphate region of the loop residues as salt concentration increases and (iii) the stacking of T3 and T4 residues of loop-1 that appears up to 50 mM concentration, vanishes as the salt concentration is increased further. PMID- 30308283 TI - Multiple site-directed mutagenesis of a Phaseolus vulgaris epoxide hydrolase to improve its catalytic performance towards p-chlorostyrene oxide based on the computer-aided re-design. AB - To improve the activity and regioselectivity of a Phaseolus vulgaris epoxide hydrolase (PvEH3) towards p-chlorostyrene oxide (pCSO), the site-directed mutagenesis was conducted based on the computer-aided re-design. Firstly, seven single-site variants of a PvEH3-encoding gene (pveh3) were constructed as designed theoretically and expressed in E. coli BL21(DE3), respectively. One transformant, E. coli/pveh3G170E, had the higher EH activity towards racemic pCSO, while both E. coli/pveh3F187L and /pveh3P237L with enhanced regioselectivity coefficient alphaS values. Secondly, to combine their respective merits, the double- and triple-site variants, pveh3G170E/F187L, pveh3G170E/P237L and pveh3G170E/F187L/P237L, were also constructed. Among all E. coli transformants, E. coli/pveh3G170E/F187L/P237L simultaneously had the highest EH activity of 20.3 U/g wet cell and alphaS value of 95.2%, by which the hydrolysis of rac-pCSO enantioconvergently produced (R)-p-chlorophenylethane-1,2-diol with an enantiomeric excess of 93.2%. Furthermore, PvEH3G170E/F187L/P237L expressed in E. coli/pveh3G170E/F187L/P237L was purified. Its specific activity and catalytic efficiency towards rac-pCSO were 4.1 U/mg protein and 1.81 mM-1 s-1, which were 3.0- and 3.1-fold those of PvEH3. Finally, the molecular docking simulation analysis indicated that PvEH3G170E/F187L/P237L preferentially attacks the more hindered benzylic carbon of (S)-pCSO over PvEH3, which was consistent with their alphaS values measured experimentally. PMID- 30308285 TI - Molecular dynamics studies of polysaccharide carrier based on starch in dental cavities. AB - Health is an important element that influences the level of development in a community. Studies show that tooth decay has been prevalent recently. Starch incorporating curcumin can serve as an alternative approach in preventing the activity of Streptococcus mutans attributed to biofilm and plaque formation on teeth. In this research, the performance of starch nanoparticle as a carrier for curcumin, a natural anti-inflammatory and a strong antioxidant agent, in decreasing dental caries was simulated. In the first stage, the conformational rearrangements of molecules and their interactions with other molecular species in a range of environments were examined via computational techniques and molecular dynamics (MD) simulation. The charts of energy, temperature, density, cell size and the radial distribution function (RDF) derived from the simulation, confirmed that during 5 initial steps there was a stable binding between the curcumin and starch in the presence of bacteria. The energy released in the starch formed nanosphere is very high, and this indicates a full reaction in the system. However, the density-decreasing trend of nanosystem suggests that it can effectively inhibit the activity of microorganism. PMID- 30308286 TI - Monitoring Alcohol Use in Heavy Drinking Soup Kitchen Attendees. AB - Rates of heavy alcohol use in soup kitchen attendees range from 30% to 38%, but these data are based entirely on self-reported drinking. Little is known about the intensity or frequency of drinking in this population. We assessed alcohol use transdermally every 30 minutes over a 3-week period among heavy drinkers who attended local soup kitchens. In addition to transdermal alcohol monitoring, participants were randomly assigned to daily breath alcohol monitoring with or without reinforcement for alcohol-negative breath samples (BrAC). Analyses assessed feasibility of transdermal monitoring and examined alcohol use based on BrAC, transdermal, and self-report data, as well as effect sizes for these metrics based on group assignment. Nineteen participants completed the 21-day monitoring period in full; three persons removed the anklet 3-16 days early due to hospitalization, impending hospitalization, or incarceration. Participants reported minimal impacts of the monitors and severity ratings of side effects were mild. When using BrAC, transdermal, and self-report data, the percentage of non-drinking days was 93%, 58%, and 57% and the longest duration of consecutive non-drinking days averaged 10.3, 7.2, and 5.7 days, respectively. About half of drinking days involved heavy drinking (5+ drinks). Self-report and transdermal drinking days correlated significantly, p < .001, but neither index was associated with BrAC. Group comparisons indicate small-to-moderate sized effects of reinforcement compared to no reinforcement for increasing the proportion of alcohol negative breath samples and durations of consecutive non-drinking samples during the study when BrAC was the metric. Transdermal data and self-report data indicated a more complex pattern. Reinforcement participants drank more often but at lower quantities than monitoring (control) participants per both transdermal and self-report data. These data suggest that transdermal monitors are well tolerated and documented substantial heavy drinking in this population. Soup kitchens users are in need of alcohol interventions, and soup kitchens may represent a novel opportunistic setting for intervention delivery for an important and growing health disparities population. PMID- 30308287 TI - Daily Factors Driving Daily Substance Use and Chronic Pain among Older Adults with HIV: An Exploratory Study Using Ecological Momentary Assessment. AB - BACKGROUND: Adults 50 and older make up approximately 50% of persons living with HIV. Multiple co-morbidities are common among this group, including chronic pain and substance abuse, yet little is known about the daily factors that either enhance or inhibit these experiences or behaviors. This study explored daily drivers of substance use, pain, and relief from pain among older adults living with HIV utilizing ecological momentary assessment (EMA). METHOD: Participants (N=55), ages 49-71, completed seven consecutive days of daily EMA online surveys prior to treatment initiation within a randomized controlled trial. Multilevel modeling tested predictors of pain, substance use, and relief from pain by examining within- and between-person relationships. RESULTS: Results revealed an associational, reciprocal relationship between daily worst pain and daily drinking, where greater worst pain ratings predicted heavier drinking and heavier drinking predicted greater daily and overall pain. Greater happiness and poorer quality of sleep predicted greater daily worst pain. Exercising and overall confidence to cope with pain without medication were associated with lower levels of daily worst pain. Finally, spending less time with a loved one over time and reporting any coping behavior were associated with relief from pain. CONCLUSION: Investigation of daily factors that drive pain and substance use behaviors among this unique population help inform which daily factors are most risky to their health and well-being. Alcohol use emerged as the only substance associated with both driving pain and responding to pain. Findings suggest key points for prevention and intervention. PMID- 30308288 TI - Beneficial alterations in body composition, physical performance, oxidative stress, inflammatory markers, and adipocytokines induced by long-term high intensity interval training in an aged rat model. AB - Sarcopenia is associated with loss of muscle mass and function as well as oxidative stress, chronic low-grade inflammatory status, and adipocytokine dysfunction. It has been reported that sarcopenia can be attenuated by exercise training. The purpose of this study was to evaluate whether long-term high intensity interval training (HIIT) and moderate-intensity continuous training (MICT) protocols could differentially modulate changes in body composition, physical performance, inflammatory parameters, and adipocytokines in fat tissues and serum, as well as oxidative parameters and insulin-like growth factor 1 (IGF 1) levels in skeletal muscle tissue of aged rats. Middle-aged (18-month-old) female Sprague Dawley rats (n = 36) were subjected to 8 months of MICT (26-m MICT) or HIIT (26-m HIIT) treadmill training (45 min, 5 times per week), and the results were compared with those of age-matched sedentary controls (26-m SED); 8 month-old (8-m SED) and 18-month-old (18-m SED) rats served as aging sedentary controls. Body composition parameters; physical performance; serum and skeletal muscle oxidative stress parameters; levels of IGF-1, a serum and fat tissue inflammatory marker; adipocytokine (leptin, adiponectin) levels; and plasma glucose and lipid metabolism-related parameters were analyzed among the five groups. The percent fat and body fat to lean mass ratio increased as a main effect with age, whereas 26-m HIIT but not 26-m MICT attenuated these alterations. The 26-m HIIT group showed a larger improvement in grip strength compared to that of 26-m MICT, with a similar increase in inclined plane performance, maximum running speed, and exhaustion over time as compared with the 26-m SED group. Notably, the 26-m HIIT group showed lower high-sensitivity C reactive protein levels and higher IL-10 in serum compared with those of the 26-m SED and 26-m MICT groups. Both exercise protocols promoted increased skeletal muscle IGF-1 and decreased serum IGF-1 and adiponectin relative to those in the 26-m SED group, whereas only 26-m HIIT dampened the age-related decrease in plasma free fatty acids and increased serum leptin, along with providing lower fat tissue leptin as compared with that in the 26-m SED group. Moreover, the 26-m HIIT group showed lower serum and skeletal muscle malonylaldehyde and skeletal muscle 8-hydroxydeoxyguanosine (8-OHdG) levels than those in the 26-m MICT group, albeit similar decreases in serum and skeletal muscle 4-hydroxynonenal and serum 8-OHdG and increases in skeletal muscle superoxide dismutase 2 activity. In conclusion, HIIT initiated late in life exhibited greater beneficial effects in ameliorating aged-related elevations in oxidative stress and inflammation, as well as dysfunction of circulating adipocytokine levels, than a volume-matched MICT program. HIIT may therefore contribute to improvements in body composition and physical performance changes associated with aging. PMID- 30308289 TI - Association between plasma CCL11 (eotaxin-1) and cognitive status in older adults: Differences between rural and urban dwellers. AB - The chemokine CCL11 has been implicated in age-related cognitive deterioration in mice, yet evidence on the relationship between CCL11 and cognitive function in humans is limited. This study explored associations between CCL11 and cognition in rural and urban community-dwelling older adults. Participants were 515 urban dwellers from the 3C-Bordeaux cohort and 318 rural dwellers from the AMI cohort. Plasma CCL11 was measured using an enzyme-linked immunoassay. Mini Mental State Examination (MMSE) test scores were used as the main measure of cognitive performance. Multivariate regression analysis was used to evaluate the cross sectional association between CCL11 and cognitive performance. CCL11 was significantly higher in rural dwellers compared to city dwellers (median [IQR]: 145 [115-201] pg/mL vs. 103 [85-129] pg/mL; p < 0.001). After adjustment for confounders, CCL11 was found to be negatively associated with cognitive performance in rural dwellers but not in city dwellers. These results suggest that CCL11 may be an independent determinant of cognitive function in older rural dwellers and that the residential environment modifies this association. PMID- 30308290 TI - A novel interleukin-1 receptor-associated kinase-4 from thick shell mussel Mytilus coruscus is involved in inflammatory response. AB - Interleukin-1 receptor-associated kinase-4 (IRAK4) is considered as the most upstream kinase of IRAKs and plays a vital role in Toll-like receptor/Interleukin 1 receptor (TLR/IL-1R) signal transduction. In the present study, IRAK4 from thick shell mussel Mytilus coruscus (McIRAK4) was identified and characterized. McIRAK4 showed the most similarity to its counterparts in bivalves. The conserved death domain (DD) and catalytic domain of serine/threonine kinases (STKc) were predicted in all examined IRAK4s. McIRAK4 transcripts were constitutively expressed in all examined tissues with the higher expression level in immune related tissues, and were significantly induced in haemocytes upon lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly I:C) challenge. Further, the expression of McIRAK4 was obviously repressed by dsRNA mediated RNA interference (RNAi), meanwhile the proinflammatory cytokines TNF alpha and IL17 were down-regulated while the antiinflammatory cytokine TGF-beta was up-regulated. Additionally, McIRAK4 showed a global cytoplasmic localization in HEK293T cells through fluorescence microscopy. These results collectively indicated that McIRAK4 is one member of IRAK4 subfamily and might play the potential signal transducer role in inflammatory response. The present study provides supplement for TLR-mediated signaling pathway triggered by pathogenic invasions in thick shell mussel, and contributes to the clarification of the innate immune response in molluscs. PMID- 30308291 TI - Identification and characterization of two novel vascular endothelial growth factor genes in Litopenaeus vannamei. AB - Vascular endothelial growth factor (VEGF) signaling pathway induces endothelial cell proliferation, promotes cell migration, and inhibits apoptosis. Although three VEGF and two VEGF receptor genes have been identified in Litopenaeus vannamei and demonstrated their roles in WSSV infection, another two novel VEGF genes (LvVEGF4, LvVEGF5) were isolated and their involvements in the WSSV infection of shrimp were studied in the present study. The deduced amino acid sequences of both LvVEGF4 and LvVEGF5 contained a signal peptide, a typical PDGF/VEGF domain and a cysteine knot motif (CXCXCX). Tissue distribution analysis showed that LvVEGF4 was predominantly expressed in gill and hemocytes, while LvVEGF5 was mainly detected in hemocytes and intestine. WSSV infection could cause up-regulation of the transcriptional levels of LvVEGF4 and LvVEGF5. Their functions were studied by double-strand RNA interference. The results showed that knock-down of LvVEGF4 and LvVEGF5 led to a decrease of the viral copy number in WSSV infected shrimp. Yeast two-hybrid analysis showed that both LvVEGF4 and LvVEGF5 could interact with LvVEGFR1 rather than LvVEGFR2. In addition, knock down of LvVEGF4 and LvVEGF5 could reduce the expressional levels of downstream genes FAK and PI3K. The present study provides new clues in demonstrating that the VEGF signaling pathway is involved in the process of WSSV infection in shrimp. PMID- 30308292 TI - MiR-214 inhibits snakehead vesiculovirus (SHVV) replication by targeting host GS. AB - MicroRNAs (miRNAs) are small noncoding RNAs that have been reported to play important roles in virus replication. Snakehead vesiculovirus (SHVV) is a new rhabdovirus isolated from diseased hybrid snakehead and has caused heavy economical losses in cultured snakehead fish in China. Our previous study has revealed that miR-214 inhibited SHVV replication, but the underline mechanism was not completely understood. In this study, glycogen synthase (GS) gene was identified as a target gene of miR-214. Overexpression of miR-214 reduced cellular GS gene expression. Knockdown of GS by siRNA, similar to the overexpression of miR-214, inhibited SHVV replication. Moreover, we found that siGS-mediated inhibition of SHVV replication could be restored by reducing cellular miR-214 level via using miR-214 inhibitor, indicating that miR-214 inhibited SHVV replication at least partially via targeting GS. This study provided information for understanding the molecular mechanism of SHVV pathogenicity and a potential antiviral strategy against SHVV infection. PMID- 30308293 TI - Molecular isolation and characterization of a spatzle gene from Macrobrachium rosenbergii. AB - Spatzle protein is an extracellular ligand of Toll receptor in Toll signaling pathway involved in the embryonic dorsoventral patterning and in the innate immunity. In this study, a spatzle gene of freshwater prawn, Macrobrachium rosenbergii (MrSpz) was isolated and characterized. The open reading frame of MrSpz consisted of 747 nucleotides encoding 248 amino acid residues containing a signal peptide and C-terminal spatzle activated domain. MrSpz shared high similarity to spatzle of Fenneropenaeus chinensis (FcSpz) at 92% identity and Marsupenaeus japonicus (MjSpz) at 83% identity. Phylogenetic analysis was performed and the results revealed that MrSpz was a member of the clade containing LvSpz3 of Litopenaeus vannamei, FcSpz and Penaeus monodon spatzle protein. The expression distribution at transcriptional level in various tissues of normal prawn revealed that the MrSpz was detected in gills, heart and hepatopancreas while no expression was observed in hemocyte, muscle and stomach. In the Aeromonas caviae challenged prawn, the expression level of MrSpz in hemocyte was increased gradually at 6, 12 and 24 h post-injection. Furthermore, in MrSpz knocked down prawn injected with Aeromonas caviae, the mortality rate were higher than that of non-related dsRNA group and control group. These results suggest that MrSpz protein may play a key role in the innate immunity of M. rosenbergii, especially in response to Gram-negative bacteria A. caviae invasion. PMID- 30308294 TI - The influence of three antibiotics on the growth, intestinal enzyme activities, and immune response of the juvenile sea cucumber Apostichopus japonicus selenka. AB - The global abuse and misuse of antibiotics in the treatment and prevention of bacterial infections has resulted in the ubiquitous existence of these drugs in aquatic environments, which causes frequent antimicrobial resistance and pollution in ecosystems. However, the chronic effects of antimicrobial agents on aquatic animal growth and health have not been fully evaluated. In the present study, three typical antibiotics (tetracycline, erythromycin, and norfloxacin) were administered orally to juvenile sea cucumbers Apostichopus japonicus for 45 days, to mimic the long-term use of antibiotics. As a result, tetracycline and erythromycin promoted the growth and digestive activity of lipase, pepsin, and trypsin, but norfloxacin did not show significant prompting effect on digestive activity and even retarded the weight gain of the sea cucumbers. The mortality was higher in antibiotic treated groups between the 2nd and 4th days after challenge with Vibrio splendidus. At the same time, lower immune-related parameters were found in antibiotic feeding juveniles, suggesting that the use of antibiotics might weaken the immune defense system of sea cucumbers. This study revealed that antibiotic administration could facilitate the growth of sea cucumbers to varying degrees yet coupled with high risks of impaired immune function and compromised disease resistance. PMID- 30308295 TI - Involvement of inducible nitric oxide synthase (iNOS) in immune-functioning of Paphia malabarica (Chemnitz, 1782). AB - In recent years, the role of inducible nitric oxide synthase (iNOS) isoform has been widely studied because of its immunological relevance in higher organisms as well as invertebrates including bivalves. However, little is known about the immunological role of iNOS in Paphia malabarica defense mechanism. In this study, we immunodetected the presence of iNOS in P. malabarica hemocytes using antibody N9657 monoclonal anti-nitric oxide synthase. In addition, increased iNOS activity was evident in response to a higher bacterial dosage (Vibrio parahaemolyticus and V. cholerae), highlighting the dose-dependent iNOS activity induction. Also, higher bacterial survivability was observed in the presence of iNOS inhibitor, i.e., S-methylisothiourea hemisulphate (SMIS) thus, validating the bactericidal role of iNOS. These findings implicate the involvement of iNOS in immune functioning of P. malabarica. Future work should focus on elucidating the expression and regulation of pathogenesis in P. malabarica, involving iNOS. PMID- 30308296 TI - GroEL, a novel vaccine candidate of piscine Streptococcus agalactiae identified by immunoproteome. AB - Streptococcus agalactiae is the major etiological agent of streptococcosis, which is responsible for huge economic losses in fishery, particularly in tilapia (Oreochromis niloticus) aquaculture. A research priority to control streptococcosis is to develop vaccines, so we sought to figure out the immunogenic proteins of S. agalactiae and screen the vaccine candidates for streptococcosis in the present study. Immunoproteomics, a technique involving two dimensional gel electrophoresis (2-DE) followed by immunoblotting and mass spectrometry (MS), was employed to investigate the immunogenic proteins of S. agalactiae THN0901. Whole-cell soluble proteins were separated using 2-DE, and the immunogenic proteins were detected by western blotting using rabbit anti-S. agalactiae sera. A total of 17 immunoreactive spots on the soluble protein profile, corresponding to 15 different proteins, were identified by MALDI-TOF/TOF MS. Among the immunogenic proteins, GroEL attracted our attention as it was demonstrated to be immunogenic and protective against other streptococci. Nevertheless, to date, there have been no published reports on the immunogenicity and protective efficacy of GroEL against piscine S. agalactiae. Therefore, recombinant GroEL (rGroEL) was expressed in Escherichia coli BL21 (DE3) and purified by affinity chromatography. Immunization of tilapia with rGroEL resulted in an increase in antibody titers and conferred protection against S. agalactiae, with the relative percentage survival of 68.61 +/- 7.39%. The immunoproteome in the present study narrows the scope of vaccine candidates, and the evaluation of GroEL immunogenicity and protective efficacy shows that GroEL forms an ideal candidate molecule in subunit vaccine against S. agalactiae. PMID- 30308297 TI - Characterization of cathepsin C from orange-spotted grouper, Epinephelus coioides involved in SGIV infection. AB - The lysosomal cysteine protease cathepsin C plays a pivotal role in regulation of inflammatory and immune responses. However, the function of fish cathepsin C in virus replication remains largely unknown. In this study, cathepsin C gene (Ec CC) was cloned and characterized from orange-spotted grouper, Epinephelus coioides. The full-length Ec-CC cDNA was composed of 2077 bp. It contained an open reading frame (ORF) of 1374 bp and encoded a 458-amino acid protein which shared 89% identity to cathepsin C from bicolor damselfish (Stegastes partitus). Amino acid alignment analysis showed that Ec-CC contained an N-terminal signal peptide, the propeptide region and the mature peptide. RT-PCR analysis showed that Ec-CC transcript was expressed in all the examined tissues which abundant in spleen and head kidney. After challenged with Singapore grouper iridovirus (SGIV) stimulation, the relative expression of EC-CC was significantly increased at 24 h post-infection. Subcellular localization analysis revealed that Ec-CC was distributed mainly in the cytoplasm. Further studies showed that overexpression of Ec-CC in vitro significantly delayed the cytopathic effect (CPE) progression evoked by SGIV and inhibited the viral genes transcription. Moreover, overexpression of Ec-CC significantly increased the expression of proinflammatory cytokines during SGIV infection. Taken together, our results demonstrated that Ec CC might play a functional role in SGIV infection by regulating the inflammation response. PMID- 30308298 TI - Atrazine exposure triggers common carp neutrophil apoptosis via the CYP450s/ROS pathway. AB - Due to the excessive pursuit of crop yields and the abuse of herbicides, water pollution caused by atrazine (ATR) has become one of the most severe environmental issues threatening the health of fish and aquatic animals. However, no detailed report has been conducted on the mechanisms of ATR immunotoxicity in fish neutrophils. To investigate these mechanism, we exposed peripheral blood neutrophils to 25 MUg/ml atrazine for 1, 2, and 3 h. The results showed that ATR induced the mRNA expression of CYPs enzymes (CYP1A1, CYP1B1, CYP1C and CYP3A138), which increased the ROS levels, and inhibited the SOD and CAT activities, GSH content and spurred the accumulation of MDA. Additionally, a significant decline in the OXPHOS, Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities of mitochondria was observed after ATR exposure. Concurrently, ATR activated Caspase3 and induced apoptosis by changing the expression of mitochondrial pathway factors (Bcl-2, BAX, Caspase9) and death receptor pathway major genes (TNF-alpha, TNFR, Fas, FasL, and Caspase8). The results reported here indicate that the oxidative stress and mitochondrial damage caused by ATR metabolism may play a crucial role in the apoptosis of carp neutrophils, and enrich the immunotoxicological mechanisms of ATR observed in fish. PMID- 30308299 TI - A conveniently synthesized Pt (IV) conjugated alginate nanoparticle with ligand self-shielded property for targeting treatment of hepatic carcinoma. AB - The clinical translation remains a major challenge for platinum drug loaded nanoparticle due to the complexity of composition and preparation. Here we employed only three ingredients to prepare Pt (IV) prodrug-loaded ligand-induced self-assembled nanoparticles (GA-ALG@Pt NPs) via facile one-pot route for liver tumor treatment. GA-ALG@Pt NPs were found equipped with intelligently ligand self shielded property in which the internal GA could be induced to expose by initial cellular recognition, resulting in strengthened cellular uptake (20%-30%) and prolonged blood circulation time (3.43 times). Appreciable tumor targeting ability (2 times) and especially tumor selectivity (2.5 times) were obtained. Glutathione-triggered release of therapeutic agent generated satisfactory antitumor effect. Bio-safety is also a distinguishing feature of GA-ALG@Pt NPs that greatly relief the nephrotoxicity and systematic toxicity of cisplatin. This conveniently synthesized nanoparticle processes superior targeting capacity and biosecurity, supplying an effective approach to translational cancer therapy in the future. PMID- 30308300 TI - Targeted codelivery of doxorubicin and IL-36gamma expression plasmid for an optimal chemo-gene combination therapy against cancer lung metastasis. AB - Cancer metastasis is the main cause for the high mortality in breast cancer patients. In this work we developed a polymer POEG-st-Pmor for targeted co delivery of IL-36gamma expression plasmid and doxorubicin (Dox) to lung metastasis of breast cancer. The polymer readily formed micelles that were effective in loading Dox and simultaneously forming complexes with IL-36gamma plasmid. Interestingly, particles co-loaded with Dox and plasmid was significantly smaller and more stable than the particles loaded with Dox only. Gene transfection in both lungs and s.c. tumors was significantly higher with our polymer compared to PEI. In addition, the Dox + IL-36gamma/POEG-st-Pmor not only could bring improved anti-metastatic effect but synergistically enhance the type I immune response by increasing the IFN-gamma positive CD4+ and CD8+ T cells and simultaneously decreasing the immunosuppressive myeloid-derived suppressor cells in the lung. POEG-st-Pmor may represent a simple and effective delivery system for an optimal chemo-gene combination therapy. PMID- 30308301 TI - Setting up and exploitation of a nano/technological platform for the evaluation of HMGA1b protein in peripheral blood of cancer patients. AB - Even if cancer specific biomarkers are present in peripheral blood of cancer patients, it is very difficult to detect them with conventional technology because of their low concentration. A potential cancer biomarker is the HMGA1b protein, whose overexpression is a feature of several human malignant neoplasias. By taking advantage of the surface plasmon resonance (SPR) phenomenon, we realized a specific nano/technology-based assay for cancer detection. More in details, anti-HMGA1b monoclonal antibodies, whose affinity was previously defined by ELISA, were immobilized onto metallic surfaces to develop a direct SPR-based assay. After having analyzed blood samples from colorectal cancer patients and healthy people for the presence of HMGA1b, we observed a 2-fold increase of the HMGA1b levels in the blood of cancer patients with respect to the healthy control people. We conclude that the set-up technology might allow to detect a tumoral mass through the evaluation of HMGA1b protein blood levels. PMID- 30308302 TI - Enhanced salt tolerance of euryhaline tadpoles depends on increased Na+, K+ ATPase expression after salinity acclimation. AB - Understanding physiological responses and osmoregulatory mechanisms for dealing with salinity stress is essential to clarify how amphibians living in coastal areas adapt to fluctuating salinity levels. Euryhaline species are rare among reported tadpole species inhabiting saline habitats, and few studies addressed the osmoregulatory mechanisms. We quantified the effects of salinity acclimation on survival, osmolality, water content, ion concentration, and gill Na+, K+ ATPase (NKA) expression of euryhaline tadpoles of Fejervarya cancrivora, to examine time-course changes of osmoregulatory responses of tadpoles subjected to salinity stress and how osmoregulatory mechanisms were involved in the process. Acclimation to 10 ppt for 24 h increased tadpole survival of F. cancrivora in 15 ppt, and it activated osmoregulatory mechanisms such as increase in NKA expression, which enabled them to maintain a stable osmolality below that of the surrounding media, to reach lower sodium and chloride concentrations of body fluid, and to modulate dehydration at higher salinities. The minimum required acclimation period is shorter than that reported previously on this species and non-euryhaline tadpoles. This study highlights that these physiological mechanisms are ecologically relevant and critical for tadpoles living in coastal brackish waters, improving their survival in coastal microhabitats with highly variable salinity levels. PMID- 30308303 TI - Influence of seasonality on the natural modulation of oxidative stress biomarkers in mangrove crab Ucides cordatus (Brachyura, Ucididae). AB - The estuaries are characterized by the formation of salinity gradients and are frequently associated with anthropic activities. Studies that show the condition of organisms against the natural environmental variations are fundamental for future evaluation of environmental change due to anthropic impacts. Biomarkers are useful tools defined as biological changes in low levels of organization induced by stressors and considered as predictive responses of more severe effects. The aim of this study was to characterize the modulation of biochemical biomarkers in Ucides cordatus against the natural variation a pristine mangrove forest in an Amazonic estuary (Japerica Bay). The samplings were carried out throughout one year at rainy-dry transitional period (June/2013), dry period (September/ 2013), dry-rainy transitional period (November/ 2013) and rainy period (February/ 2014) in the lower, middle and upper estuary. The biochemical biomarkers evaluated were glutathione-S-transferase (GST), glutamate cysteine ligase (GCL), total antioxidant capacity (ACAP), reduced glutathione (GSH) concentration and the lipid peroxidation (LPO). There was a decrease in the activity of both enzymes, GSH concentration and lower LPO in the rainy-dry transitional period for the organisms of all sites, pointing to this period as a season of greater metabolic stability. The organisms, especially those of the middle estuary, presented physiological plasticity against the variations of the environment which they are submitted. Seasonality, more than salinity influence due to position in estuary, is the main modulator of biomarkers. Also, our results indicate that the species presents high viability for biomonitoring studies. PMID- 30308304 TI - Effect of molting on the concentration of plasma 25-hydroxyvitamin D in captive African penguins (Spheniscus demersus). AB - Feed intake and body weight are drastically altered in penguins during peri molting period, and molting is known to affect the nutritional status of vitamin A and E. Although vitamin D status is not known in penguins during peri-molting period, vitamin D intake is supposed to be remarkably altered. The objective of the present study was to clarify the alterations in plasma 25-hydroxyvitamin D (25(OH)D) concentration, the most reliable biomarker for assessing vitamin D status, and vitamin D intake during peri-molting period. Blood samples were collected from seven adult male African penguins (Spheniscus demersus) in the control period, pre-molting period, early-molting period, and late-molting period. The dietary content of vitamin D and calcium (Ca) were higher than that of the estimated requirements. Feed intake increased in the pre-molting period and drastically decreased during the molting periods. Body weight increased in the pre-molting period, followed by the loss of weight towards the end of the experiment. Although vitamin D and Ca intakes decreased during the molting periods, plasma 25(OH)D concentration increased during the molting periods and the increase in plasma Ca concentration was also observed in the late-molting period. These results suggest that the reduction in body fat induced by reducing feed intake stimulated the release of vitamin D from body fat, which increased plasma 25(OH)D and Ca concentrations in molting penguins. Penguins are unlikely to suffer from typical hypervitaminosis D even during molting and vitamin D toxicity is not a realistic problem in penguins because of the short duration of molting. PMID- 30308305 TI - Hysteroscopic Endometrial Polypectomy with Manual Vacuum Aspiration Compared to Mechanical Morcellation. AB - STUDY OBJECTIVE: To examine the effectiveness of hysteroscopy plus manual vacuum aspiration (MVA) for endometrial polypectomy compared with hysteroscopic morcellation. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Duke University Medical Center database. PATIENTS: Women who underwent hysteroscopic removal of endometrial polyps performed by Duke Fertility Center faculty physicians between January 1, 2015, and January 29, 2018, using either hysteroscopy plus MVA or hysteroscopic morcellation. INTERVENTIONS: The 2 groups were compared using the chi2 or Fisher's exact test, Student's t test, and multivariable regression analysis. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the duration of the procedure. Secondary outcomes were fluid deficit, rate of complete polyp resection, estimated blood loss, and operative complications. A total of 102 women undergoing endometrial polypectomy were identified. Patients in whom polyps were removed using only a hysteroscopic grasper and/or scissors (n = 31); patients who underwent an additional simultaneous procedure, such as laparoscopy (n = 12); and patients in whom the duration of the procedure was not recorded (n = 2) were excluded. Among the remaining 57 patients, 28 underwent hysteroscopy plus MVA and 29 underwent hysteroscopic morcellation. The mean duration of procedure was longer for hysteroscopic morcellation compared with hysteroscopy plus MVA (32 +/- 10 minutes vs 20 +/- 6 minutes; p = .04), and this difference remained significant after adjusting for age, body mass index, surgeon, and number and size of polyps. Mean fluid deficit was greater for morcellation than for hysteroscopy plus MVA (277 +/ 204 mL vs 51 +/- 97 mL; p < .001). Complete polyp resection was possible in all patients; however, the use of a hysteroscopic scissors and grasper was required for 1 patient in the MVA group. Estimated blood loss was minimal in all cases, and there were no operative complications. CONCLUSION: Hysteroscopy plus MVA is an effective method for removing large or multiple endometrial polyps, with outcomes comparable to hysteroscopic morcellation. PMID- 30308306 TI - Successful pregnancies in women with diffuse uterine leiomyomatosis after hysteroscopic management using the Hysteroscopy Endo Operative system. AB - STUDY OBJECTIVE: To evaluate the feasibility, effectiveness, and reproductive outcome of hysteroscopic management using the Hysteroscopy Endo Operative system (HEOS) in patients with diffuse uterine leiomyomatosis (DUL). DESIGN: Retrospective study (Canadian Task Force Classification III). SETTING: Beijing Tiantan Hospital, Capital Medical University, Beijing, China. PATIENTS: Eight women of reproductive age suffering from menorrhagia and anemia or infertility were diagnosed with DUL by ultrasonography and hysteroscopy. INTERVENTIONS: Hysteroscopic surgery using cold graspers combined with electric loop by the HEOS was performed to excise submucous myomas (including type 0, type I, and II), leaving other intramural myomas in place. The fenestration method is used in electrical hysteroscopic myomectomy. Postoperative endometrial repair and synechiae, menstrual improvement, conception, and pregnancy were recorded. MEASUREMENTS AND MAIN RESULTS: Two patients underwent a single hysteroscopic myomectomy, while six patients underwent 2-3 myomectomies. No complications were observed. The mean follow-up period was 39.13 +/- 17.01(range, 21-67) months. The endometrium recovered 2-3 months after the initial surgery, and 100% improvement in menstruation was observed. Two patients had mild synechia after the first hysteroscopic surgery. Seven patients conceived spontaneously (postoperative pregnancy rate, 87.5%), six of whom had a full-term pregnancy. One patient suffered a miscarriage in the second trimester (live birth rate, 75%). CONCLUSION: Hysteroscopic surgery using cold graspers combined with electric loop by the HEOS is feasible and effective for treatment of DUL as it preserves the uterus and yields favorable reproductive outcomes. The cold surgery and fenestration method minimize electrical and thermal damage to the endometrium surrounding the myoma, consequently reducing surgical risks. PMID- 30308307 TI - Laparoscopic Oophorectomy to Treat Pelvic Pain FollowingOvary-Sparing Hysterectomy: Factors Associated with Surgical Complications and Pain Persistence. AB - STUDY OBJECTIVE: To examine the surgical management and outcomes of patients treated laparoscopically for pelvic pain following ovary-sparing hysterectomy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: General gynecology unit at a tertiary university hospital. PATIENTS: A total of 99 patients treated with laparoscopic oophorectomy for pelvic pain following ovary-sparing hysterectomy between January 2008 and December 2016. INTERVENTIONS: Laparoscopic oophorectomy was performed in all patients. MEASUREMENTS AND MAIN RESULTS: The patients undergoing surgery had a mean age of 48.9 years and a mean body mass index (BMI) of 28.1. They reported a mean of 3.0 previous abdominal surgeries. Sixty percent of patients reported previous abdominal hysterectomy, 21% had previous laparoscopic hysterectomy, and 19% had previous vaginal hysterectomy. At a 6-week follow-up, 59.5% of patients reported resolution of symptoms, 10.7% reported persistent symptoms, and 29.8% reported improved but not resolved symptoms. Younger patients and those reporting a previous history of gastrointestinal disease were more likely to report persistent pain at follow-up. Thirteen percent of patients had intraoperative (6%) or postoperative complications (7%), and there was a 2% rate of conversion to laparotomy. Patients at greater risk of intraoperative complications were those with a higher BMI, a greater number of previous open abdominal surgeries, or severe adhesions noted at the time of procedure. CONCLUSIONS: Laparoscopic oophorectomy to treat pelvic pain following ovary-sparing hysterectomy is a feasible yet challenging procedure. Despite a significant rate of complications and a small proportion of patients reporting persistent symptoms, most experience symptom resolution or improvement after such surgery. Further studies are needed to assess long-term outcomes. Careful patient selection and counseling are critical before this procedure. PMID- 30308308 TI - Design and implementation of novel hyperspectral imaging for dental carious early detection using laser induced fluorescence. AB - Early detection of carious is vital for demineralization reversal, offering less pain, as well as precise carious removal. In this study, the difference in optical properties of normal tissue and human carious lesion has been used for early diagnosis, using laser induced fluorescence spectroscopy. The optical system consists of light source in visible band and hyperspectral camera, associated with designed digital image processing algorithm. The human tooth sample was illuminated with visible band sources at 488, and 514 nm with energy of 5 m watt. The reflected and emitted light from the tested sample was captured using hyperspectral camera in an attempt to generate multispectral images (cubic image). The variation of reflected and emitted energy as function of wavelength was employed to generate characteristic spectrum of each tooth tissue. Human teeth carious tissue lesion releases its excess energy by emitting fluorescence light producing chemical footprint signature; this signature is dependent on the elemental composition of tooth elements and carious state. This non-invasive, non contact and non-ionizing imaging system with associated novel pattern recognition algorithm was employed to diagnose and classify different carious types and stages. It was reported that the perceived fluorescence emission is function of the illuminating wavelength. While enamel and dentin carious were distinguished and characterized at 514 nm illuminating wavelength; white spot lesion were contoured and recognized at 488 nm. Therefore, full recognition could be achieved through generated cubic image after sample irradiation at 488 nm and 514 nm. In conclusion, this study reports on a customized optical image system that can offer high sensitivity, high resolution, and early carious detection with optimum performance at 514 nm and 488 nm. PMID- 30308309 TI - Comparison of final disinfection protocols using antimicrobial photodynamic therapy and different irrigants after single-file reciprocating instrumentation against intracanal bacterial biofilm - An in vitro study. AB - BACKGROUND: The aim of the study was to compare the efficacy of antimicrobial photodynamic therapy (aPDT) with irrigation protocols that include sodium hypochlorite (NaOCl), ethylenediaminotetraacetic acid (EDTA) or QMiX (combined irrigant: EDTA, chlorhexidine, detergent) solution after single-file reciprocating root canal instrumentation. METHODS: The study sample included 68 extracted mandibular human single canal teeth. The canals were inoculated with bacterial suspension made of wild strain of Enterococcus faecalis. After 17 days of incubation, the samples were assigned to experimental groups according to the final disinfection protocol and a control group. The root canals in all groups were, firstly, instrumented with Wave One Gold reciprocating system. Then the canals were disinfected as follows: Group 1. 2.5% NaOCl and EDTA followed by the application of the aPDT; Group 2. 2.5% NaOCl, EDTA and 2.5% NaOCl; Group 3. 2.5% NaOCl and QMIX solution; Group 4. 2.5% NaOCl and EDTA. In the control group, the canals were irrigated with saline solution. Microbiological samples were collected at baseline, after single-file instrumentation and after the final disinfection protocols. The samples were plated onto Mitis Salivarius agar plates for incubation. The colony forming units (CFUs) were counted, and the final number was determined based on the dilution factor. RESULTS: Reciprocating single file instrumentation reduced CFUs significantly in all groups (p<0.05). No significant difference between Group 1 and Group 2 was observed (p=0.178). Irrigation with the QMiX was more efficient than the aPDT (p=0.02). CONCLUSIONS: The aPDT used after irrigation with NaOCl and EDTA demonstrated similar antimicrobial efficacy as conventional irrigation with NaOCl. PMID- 30308310 TI - Effect of Chloroaluminium phthalocyanine in cationic nanoemulsion on photoinactivation of multispecies biofilm. AB - BACKGROUND: Photosensitizers in nanocarriers have been investigated for antimicrobial Photodynamic Therapy (aPDT). However, most studies are focused against microorganisms in planktonic or monospecies biofilm. Thus, this in vitro study evaluated the effect of aPDT using Chloroaluminium phthalocyanine (ClAlPc) in cationic nanoemulsion (NE) against Candida albicans, Candida glabrata and Streptococcus mutans grown as multispecies biofilm. METHODS: Standard suspensions of each microorganism were added into wells of a microtiter plate for biofilm growth for 48 h in a candle jar. The biofilms were incubated with ClAlPc in cationic NE at 31.8 MUM for 30 min and illuminated with red light fluence of 39.3 J/cm2 (P+L+ group). Additional samples were treated only with photosensitizer (P+L-) or red light (P-L+) or neither (P-L-, control group). aPDT efficacy was assessed by colony quantification, biofilm's metabolic activity, total biomass, and confocal microscopy. Data were analyzed by ANOVA/Welch and post-hoc Tukey/Games-Howell tests (alpha = 0.05). RESULTS: aPDT (P+L+) reduced the colony count in 1.30 to 2.24 lg10 and the metabolic activity in 53.7% compared with the control group (P-L-). The total biomass showed no statistical difference among the groups. The confocal microscopy analyzes showed uptake of the PS in the biofilm, and dead cells were observed in the biofilm treated with aPDT. CONCLUSION: aPDT mediated by ClAlPc in cationic NE promoted photoinactivation of the multispecies biofilm, which was confirmed by colony quantification, metabolic activity, and confocal microscopy. However, the total biomass of the biofilm was not affected by the treatment. PMID- 30308311 TI - Cytotoxicity of ultraviolet-C radiation on a heterogeneous population of human glioblastoma multiforme cells: Meta-analysis. AB - INTRODUCTION: Current treatment strategies for glioblastoma multiforme are limited due to early recurrence and heterogeneity of the cell population that causes a varied response to treatment. Ultraviolet-C (UVC) radiation may be a potential adjuvant treatment that could theoretically be delivered locally by implantable micro-electromechanical systems that sense and kill early recurrence and/or minimally residual cancer. in vitro irradiation experiments are limited because they commonly use a single cell line. Therefore other methods are required to investigate cytotoxicity across a heterogeneous population of GBM. METHODS: A meta-analysis was conducted to assess the cytotoxic effects of UVC radiation on human GBM cell lines, with or without genetic modification, in monolayer to simulate a heterogeneous model. 16 publications were included using 14 different cell lines and 19 gene vectors. Effect sizes were calculated for cell survival, viability, apoptosis and proliferation. Univariate meta-regression was used to investigate the effects of radiant exposure (J/m2) and timing on cytotoxicity. RESULTS: UVC resulted in a 70.9% (CI: 63.6%-78.2%) reduction in survival, 16.6% (CI: 10.8%-22.4%) increase in apoptosis, 32.0% (CI: 9.95%-54.2%) reduction in viability, and 413.8% (CI: 95.7%-731.9%) reduction in proliferation of GBM cell lines compared to controls. Radiant exposure was significantly associated with survival (R2 = 0.486, p < 0.0001) but not with apoptosis or viability. CONCLUSIONS: This study provides more data on the therapeutic translational potential of UVC to a more clinically-realistic context. Overall, UVC is cytotoxic to GBM cell lines in aggregate and may be clinically useful when combined with genetic modification or other adjuvant treatments. PMID- 30308312 TI - Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies. PMID- 30308313 TI - Catalytic crosslinking-based methods for enzyme-specified profiling of RNA ribonucleotide modifications. AB - Well over a hundred types of naturally occurring covalent modifications can be made to ribonucleotides in RNA molecules. Moreover, several types of such modifications are each known to be catalysed by multiple enzymes which largely appear to modify distinct sites within the cellular RNA. In order to aid functional investigations of such multi-enzyme RNA modification types in particular, it is important to determine which enzyme is responsible for catalysing modification at each site. Two methods, Aza-IP and methylation-iCLIP, were developed and used to map genome-wide locations of methyl-5-cytosine (m5C) RNA modifications inherently in an enzyme specific context. Though the methods are quite distinct, both rely on capturing catalytic intermediates of RNA m5C methyltransferases in a state where the cytosine undergoing methylation is covalently crosslinked to the enzyme. More recently the fundamental methylation iCLIP principle has also been applied to map methyl-2-adenosine sites catalysed by the E. coli RlmN methylsynthase. Here I describe the ideas on which the two basic methods hinge, and summarise what has been achieved by them thus far. I also discuss whether and how such principles may be further exploited for profiling of other RNA modification types, such as methyl-5-uridine and pseudouridine. PMID- 30308314 TI - Naturally split intein Npu DnaE mediated rapid generation of bispecific IgG antibodies. AB - High product purity, preserving natural IgG architecture, and excellent production efficiency are highly desirable in bispecific antibody manufacturing. We have reported a platform called Bispecific Antibody by Protein Trans-Splicing (BAPTS) to synthesize BsAbs with natural human IgG structure and no chain mispairing. In the method, two antibody fragments carrying different target specificities are separately expressed in mammalian cells and subsequently fused to form BsAbs by utilizing the trans-splicing property of the split intein Npu DnaE. The hinge region of antibody, a region with less functional impact, is selected for conjugating the two fragments. The method involves the following steps: (i) constructing five plasmids coding antibody components; (ii) separately expressing and purifying two antibody fragments A and B. Fragment A contains one Fab, "Knobs-into-Holes" mutations in the CH3 domain and NPU DnaEC. Fragment B contains another Fab and NPU DnaEN; (iii) mixing of fragments A and B under permissive reducing conditions in vitro to enable trans-splicing reaction; (iv) removing the reductant to allow re-oxidation of disulfide bonds; (v) isolating BsAb product from unreacted precursors by affinity chromatography. The method allows correct assembly of two heavy and two light chains to form bispecific IgG antibodies in natural structure with no synthetic linkers. No chain mispairing was observed in the product by UPLC-MASS. In addition, the observed kinetics and low reaction activation energy confirmed that the trans-splicing is thermodynamically favored reaction. The BAPTS technology is feasible for industrial applications. PMID- 30308315 TI - META RNA profiling: Multiplexed quantitation of targeted RNAs across large numbers of samples. AB - META RNA profiling is a simple and inexpensive method to measure the expression of multiple targeted RNAs across many samples. By assigning sample-specific tags up-front during reverse-transcription, cDNAs from multiple samples can be pooled prior to amplification and deep sequencing. Such early parallelization of samples simplifies the workflow, minimizes cross-sample experimental variability, and reduces reagent and sequencing costs. Herein we describe the theoretical framework of the method and provide a detailed protocol to facilitate its implementation. PMID- 30308317 TI - Improved patient adherence to subcutaneous allergen immunotherapy using a modified rush immunotherapy protocol. PMID- 30308316 TI - Draft genome sequence of a multidrug-resistant CTX-M-15 beta-lactamase-producing uropathogenic Escherichia coli isolate (ST131-O25b-H30) from Pakistan exhibiting high potential virulence. AB - OBJECTIVES: Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs). The pandemic sequence type 131 (ST131) clonal group is associated with multidrug resistance and virulence. Here we report the first draft genome of a ST131-O25b-H30 strain from Pakistan, isolated from a patient with community-acquired UTI. METHODS: Next-generation sequencing was performed using MiSeq and HiSeq 2500 platforms. De novo assembly of the reads was performed using SPAdes v.3.11. Genomic features were determined with PATRIC and RAST tool kits. RESULTS: The 5327975-bp draft genome sequence has 5433 coding sequences and 82 tRNAs, an array of antimicrobial resistance genes [blaCTX-M-15, blaOXA-1, blaCMY-2, sul2, catB, dfrA17, mph(A)], a class 1 integron, 77 insertion sequence (IS) elements, a Tn3-like transposon, multiple virulence markers and 7 intact prophage loci. CONCLUSION: In conclusion, the genome sequence of this new UPEC isolate from Pakistan provides a novel insight into the genetic attributes of an epidemic clone associated with a high level of resistance and virulence. PMID- 30308318 TI - Anaphylaxis After Anal Intercourse With Tolerance By Vaginal Route. PMID- 30308319 TI - H. pylori and Parkinson's disease: Meta-analyses including clinical severity. AB - The exact etiology of Parkinson's disease (PD) remains unclear. Some evidence supports Helicobacter pylori infection as a trigger or driving event, but detection and eradication of H. pylori are not part of PD management. The aims of this case-control study and meta-analysis were to determine (i) the prevalence of H. pylori infection in PD patients, (ii) associations between H. pylori infection and clinical status, and (iii) differences in motor status in PD patients before and after H. pylori eradication. A literature search was performed using the PubMed database. The prevalence of H. pylori infection in PD, its association with the unified Parkinson's disease rating scale (UPDRS), and the association of H. pylori eradication therapy with the UPDRS-III score were determined by calculating the odds ratios (OR) and the standardized mean differences (SMD) with 95% confidence intervals (CI). Fixed- and random-effects models were applied. Ten studies were included in the first meta-analysis (5043 PD patients, 23,449 HCs); H. pylori infection prevalence was higher in PD patients than in HCs [OR (95% CI): 1.47 (1.27, 1.70), Pz<0.00001]. In seven studies reporting UPDRS scores (150 H. pylori infected, 228 non-infected PD patients), there was a significant association between H. pylori infection and mean UPDRS scores [SMD (95% CI): 0.33 (0.12, 0.54), Pz = 0.003]. Regarding H. pylori eradication, in five studies (90 PD patients), there was a significant reduction in UPDRS-III scores after treatment [SMD (95% CI): 6.83 (2.29, 11.38), Pz = 0.003]. In conclusion, the present meta-analysis revealed a higher prevalence of H. pylori infection in PD patients suggesting that H. pylori may contribute to PD pathophysiology. In addition, the significantly lower UPDRS scores in non-infected PD patients and in patients after H. pylori eradication therapy demonstrate that the infection may deteriorate the clinical severity of the disease. PMID- 30308320 TI - Avoiding maternal vitamin D deficiency may lower blood glucose in pregnancy. AB - BACKGROUND: Vitamin D status is hypothesised to play a role in gestational glucose control. No studies to date have examined vitamin D in relation to changes in blood glucose in pregnancy. Thus, the aim was to examine if vitamin D in early pregnancy and vitamin D trajectory associate with blood glucose trajectory over pregnancy in a Swedish cohort. We also investigated the relation between maternal vitamin D status and excessive fetal growth. METHODS: In 2013 2014, pregnant women were recruited to the GraviD cohort study when registering at the antenatal clinics in south-west Sweden. In the present analysis, 1928 women were included. Women with preexisting diabetes and multifetal pregnancy were excluded. Random blood glucose was assessed according to routine practice, in first trimester (T1, gestational week 4-16), second trimester (T2, gestational week 17-27), early (T3a, gestational week 28-35) and late third trimester (T3b, gestational week 36-41). In T1 and T3a, serum 25-hydroxyvitamim D (25OHD) was analyzed by liquid chromatography tandem mass spectrometry. Large for gestational age (LGA), as a proxy of excessive fetal growth, was defined as body weight at birth above 2 standard deviations of the gender specific population mean. Adjusted linear regression, linear mixed models analysis and logistic regression analysis were used to study 25OHD in relation to T1 blood glucose, glucose trajectory and LGA, respectively. RESULTS: Mean blood glucose increased during pregnancy (5.21 mmol/L in T1, 5.27 mmol/L in T2, 5.31 mmol/L in T3a and 5.34 mmol/L in T3b; p = 0.003). In T1, 25OHD was negatively associated with blood glucose, i.e. 25OHD >= 30 nmol/L was associated with 0.25-0.35 mmol/L lower glucose. T1 25OHD was also negatively associated with blood glucose trajectory. Higher T3 25OHD was associated with higher odds of LGA (p = 0.032). CONCLUSION: Avoiding maternal vitamin D deficiency in early pregnancy is associated with lower blood glucose in early pregnancy and throughout pregnancy. Higher 25OHD in late pregnancy was associated with higher odds of LGA at birth. PMID- 30308321 TI - Antineoplastic effect of 1alpha,25(OH)2D3 in spheroids from endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein coupled receptor. AB - The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor (KSHV/vGPCR) is a key molecule in the pathogenesis of Kaposi's sarcoma. In endothelial cells, tumor maintenance and NF-kappaB activation depends on vGPCR constitutive expression and activity. We have previously demonstrated that 1alpha,25(OH)2D3 induces apoptosis in a VDR dependent manner, inhibits vGPCR cell growth and NF-kappaB activity. In this study, we developed a method to obtain multicellular spheroids (MCS) from endothelial cells expressing vGPCR in order to test whether MCS have a similar response to 2D-cultures after 1alpha,25(OH)2D3 treatment. Firstly, we found that vGPCR MCS started to form at 2nd day-growth, reaching a diameter up to 300 MUm at 7th day-growth, whereas cells without vGPCR expression (SVEC) developed spheroids earlier and remained smaller throughout the period monitored. Secondly, vGPCR MCS size and architecture were analyzed during 1alpha,25(OH)2D3 (0.1-100 nM, 48 h) treatment. We found that once treated with 10 nM of 1alpha,25(OH)2D3 the initials MCS began a slight disaggregation with no changes in size; whereas at the higher dose (100 nM) the architecture of MCS was found completely broken. Furthermore, VDR mRNA expression increased significantly and this change was accompanied by a reduction of HIF-1alpha, an increase of VEGF, p21 and Bim mRNA expression. Finally, results from Western blot analysis showed that 1alpha,25(OH)2D3 decreased Akt and ERK1/2 protein phosphorylation. In conclusion, these data have revealed that 1alpha,25(OH)2D3 inhibits vGPCR MCS proliferation and induces apoptosis similar to vGPCR cells growing in 2D cultures. PMID- 30308322 TI - Effects of anticoagulants and storage conditions on clinical oxylipid levels in human plasma. AB - Metabolomics and lipidomics are of fundamental importance to personalized healthcare. Particularly the analysis of bioactive lipids is of relevance to a better understanding of various diseases. Within clinical routines, blood derived samples are widely used for diagnostic and research purposes. Hence, standardized and validated procedures for blood collection and storage are mandatory, in order to guarantee sample integrity and relevant study outcomes. We here investigated different plasma storage conditions and their effect on plasma fatty acid and oxylipid levels. Our data clearly indicate the importance of storage conditions for plasma lipidomic analysis. Storage at very low temperature (-80 degrees C) and the addition of methanol directly after sampling are the most important measures to avoid ex vivo synthesis of oxylipids. Furthermore, we identified critical analytes being affected under certain storage conditions. Finally, we carried out chiral analysis and found possible residual enzymatic activity to be one of the contributors to the ex vivo formation of oxylipids even at -20 degrees C. PMID- 30308323 TI - Enhancement of lipid accumulation in microalgae by metabolic engineering. AB - Microalgal lipids have drawn great attention as a promising sustainable resource for biodiesel or food supplement production. The development of high-performance strains of microalgae by metabolic engineering is invaluable for increasing the quantity or quality of desired lipids. The synthesis routes of lipids used as biodiesel in microalgae are based on fatty acid synthase (FAS) and triacylglycerols (TAG) biosynthesis pathway. Polyunsaturated fatty acids (PUFAs), including omega-6 and omega-3 fatty acids, are essential nutrients for humans. Notably, microalgae possess two distinct pathways for polyunsaturated fatty acids (PUFAs) biosynthesis, including the desaturase/elongase pathway and the polyketide synthase (PKS) pathway. Thus, it is necessary to identify which biosynthetic pathways are responsible for PUFA synthesis in particular microalgae species. In recent years, various key enzymes and functional domains involved in fatty acid and TAG biosynthesis pathway were identified and potentially regulated by genetic engineering approaches to elevate specific lipids content. In addition, other studies have reported the implementation of strategies to increase lipid accumulation based on increasing acetyl-CoA/NADPH supply, enhancing photosynthetic efficiency, or blocking competing pathways. Furthermore, other efforts have used transcription factor engineering to simultaneously regulate multiple genes related to lipid accumulation. This review summarizes recent research about a variety of microalgae lipid biosynthesis pathways, and discusses multiple gene manipulation strategies that have been employed for specific lipid overproduction in industrial microalgae. PMID- 30308324 TI - Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions. AB - Group V Phospholipase A2 (Pla2g5) is a member of the PLA2 family of lipid generating enzymes. It is expressed in immune and non-immune cell types and is inducible during several pathologic conditions serving context-specific functions. In this review, we recapitulate the protective and detrimental functions of Pla2g5 investigated through preclinical and translational approaches. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau. PMID- 30308325 TI - Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia. AB - The outcome of persons > 65 years with acute myeloid leukemia (AML) is poor. A transplant from an HLA-identical sibling or an HLA-matched unrelated donor can cure some of these patients but is associated with a substantial transplant related mortality and a high relapse risk. We analyzed 185 subjects > 65 years with high-risk AML receiving conventional (n = 42) or reduced-intensity (n = 143) pretransplant conditioning and a transplant from an HLA-identical sibling (n = 66) or a 10/10 loci HLA-matched unrelated donor (n = 119). Two-year survival was 37%. Subjects with serious adverse events during before chemotherapy for their leukemia had a poor outcome after stem cell transplantation. Patients who had active leukemia or measurable residual disease (MRD) before transplantation had a worse outcome. Delayed hematologic recovery after induction or consolidation chemotherapy, high-risk AML genetics, donor-recipient HLA-DRbeta3/4/5-DP mismatches, and history of cardiovascular disease were also correlated with survival in multivariate analyses. The 57 MRD-negative patients with few other adverse prognostic factors had an excellent outcome (2-year overall survival, 76%), whereas the 58 patients with detectable leukemia and more than 1 other additional factor fared poorly (2-year overall survival, 8%). These data indicate it is possible to identify persons > 65 years with high-risk AML likely to benefit from an allotransplant. Validation of this prediction is needed. PMID- 30308326 TI - Comparison of HLA Allele Mismatch and Antigen Mismatch in Unrelated Bone Marrow Transplantation in Patients with Leukemia. AB - We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1 antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P = .006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P = .025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P = .046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P < .001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P = .001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P = .002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P = .02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4 years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell-replete UBMT. PMID- 30308327 TI - Positive Psychological Constructs and Health Outcomes in Hematopoietic Stem Cell Transplantation Patients: A Systematic Review. AB - Positive psychological constructs (eg, optimism, positive affect) have been independently associated with superior health outcomes across many medical populations. However, there has been little synthesis of the literature examining these associations among patients with hematologic malignancies receiving hematopoietic stem cell transplantation (HSCT). To address this gap we completed a systematic review, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of studies examining relationships between positive psychological constructs and health-related outcomes (eg, psychiatric symptoms, function, health-related quality of life [HRQoL], or treatment compliance) after HSCT. Eighteen eligible studies (N = 4201; 47% women; mean age, 47.1) were identified. Optimism (n = 12 studies) was the most frequently studied positive construct and HRQoL (examined in n = 11 studies) the most common outcome. All 17 studies with quantitative analyses found a significant (P < .05) association between a positive psychological construct and a health outcome; most but not all controlled for 1 or more relevant covariates. Among patients with hematologic malignancies who receive HSCT, positive psychological constructs appear to be associated with improved HRQoL and other health outcomes. Further work is warranted to more comprehensively understand the independent effects of positive psychological constructs on a variety of health outcomes and to develop interventions to promote well-being that are adapted to the needs of this population. PMID- 30308328 TI - Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease. AB - The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of beta-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder. PMID- 30308329 TI - Exploring patterns of child pedestrian behaviors at urban intersections. AB - Children are more vulnerable as pedestrians due to their cognitive, physical and behavioral traits. However, walking is one of the main forms of travel for children, particularly during leisure hours. Child pedestrian injury primarily occurs in urban areas, with a significant share at crosswalks. This study observed child pedestrian behaviors at crosswalks of urban intersections aiming to characterize their behavior patterns and identify risk factors that may lead to injury. Crossing behaviors of children and adolescents up to age 18, during leisure hours, were video-recorded at 29 crosswalks, on signalized and un signalized intersections situated on collector roads. Some children used pedestrian crosswalks while riding a bicycle or other non-motorized means; they were also included in the sample. Behaviors of 2930 young road users were encoded and compared by age groups. Multivariate logistic regression models were adjusted to identify factors associated with crossing on red and with non-checking vehicle traffic at un-signalized crosswalks. The findings pointed to different behavior patterns for the various child age groups. Risk-taking behaviors are higher for older children; adolescents aged 14-17 cross more on red, without checking traffic, outside crosswalk boundaries and while distracted. At all types of sites, a fifth of children over the age of 9 crossed by riding, the probability of crossing on red and of non-checking traffic prior to crossing at an un signalized crosswalk was higher for children riding an electric bicycle or kick scooter. The non-checking of traffic was also higher when a child is distracted by a mobile phone or other electronic gadget, or carries a big object. Children under age 9 were usually accompanied by adults but still exhibited risk-taking behaviors that apparently mirrored those of the adults. Risk-taking behaviors of young road users should be taken into account in the development of injury prevention programs focusing on child and parent education and training, and by adapting the urban environment to better meet their needs. PMID- 30308330 TI - Situational influences on response time and maneuver choice: Development of time critical scenarios. AB - Findings concerning drivers' response times to sudden events vary considerably across studies due to different experimental setups and situational characteristics, such as expectancy of an event and urgency to react. While response times are widely reported in the literature, understanding of drivers' choice of maneuvers in time-critical situations is limited. Standardized test scenarios could enhance the comparability of studies and help in attaining a better understanding of driver behavior in these situations. In an effort to achieve these improvements, three driving simulator studies (N = 131) were conducted to investigate drivers' response time and maneuver choice under a range of situational conditions. Each study took place in a specific environmental setting (urban, rural, and highway) and incorporated one unexpected and 12 subsequent events (increased expectancy). Four different time-critical scenarios were used to evoke different driver responses. In three scenarios, obstacles suddenly entered the roadway (braking, steering, or both possible). A fourth scenario comprised the sudden braking of a leading vehicle (only braking possible). Half of the drivers performed a cognitive secondary task. To validate the findings, results from an additional field test (N = 14) were compared to the results from the simulated urban environment. As expected, response choice was influenced by scenario characteristics (available braking distance and room for evasive maneuvers). Braking maneuvers were more frequent in settings with lower speed limits (urban) while steering maneuvers were found at higher speed limits (highway). Responses to suddenly appearing obstacles were fastest in the urban setting at 540-680 ms; these responses were 200-300 ms slower in the rural and highway settings. Response times increased by 100-200 ms when drivers responded to braking leading vehicles rather than obstacles. Braking responses were 200-350 ms slower and steering responses were 90-200 ms slower when drivers responded to an unexpected event rather than subsequent events. The cognitive secondary task had no significant effect. The simulated environment and the field test produced comparable response behavior. The current study provides reference numbers that help to establish a set of standardized test scenarios for future studies. On basis of this study, nine scenarios are recommended for the context of time critical crash avoidance maneuvers. Such standardized test scenarios could improve the comparability of future studies on response time and maneuver choice. PMID- 30308331 TI - Cancer associated fibroblasts: is the force the path to the dark side? AB - The most abundant cell type in the tumor microenvironment are cancer-associated fibroblasts (CAFs). CAFs play an important role in tumor growth and progression. Besides direct communication with cancer cells via secreted molecules or cell cell adhesions, CAFs also indirectly affect cancer cell behavior by remodeling the extracellular matrix (ECM). Here, we summarize recent findings on the distinct mechanisms that CAFs use to modify ECM, specifically, their proteolytic versus force-dependent activity. We then review the consequences of CAF force transmission on the physico-chemical properties of the matrix, focusing on the deposition of new matrix components, and the alteration of the organization and stiffness of the ECM. CAFs promote tumor invasion by creating the roads cancer cells use to escape the tumor mass. However, there is also evidence that CAFs can prevent invasion, possibly by forming a physical barrier around the tumor edge. We discuss the controversial role of CAFs in tumor progression. PMID- 30308332 TI - Effects of carvacrol on oocyte development in semi-engorged Rhipicephalus sanguineus sensu lato females ticks (Acari: Ixodidae). AB - Currently, the most commonly used method to control ticks is the use of synthetic acaricides. However, these compounds are potentially harmful to hosts and the environment, in addition to causing the selection of resistant individuals. Therefore, several studies have been conducted to find sustainable methods to control ticks, such as Rhipicephalus sanguineus sensu lato, the most important vectors of pathogens for dogs. There has been increasing research on natural products with acaricidal action, especially with regard to plant-derived compounds as carvacrol, an aromatic monoterpene with several biological properties, including repellent and acaricidal activities, besides exerting cytotoxic effects on the exposed ticks. The objective of the present study was to evaluate the action of different carvacrol concentrations on the ovaries morphophysiology in semi-engorged R. sanguineus s.l. females to determine its effect on oocyte development. The results showed the occurrence of significant morphological alterations in the shape of oocytes (from round-shaped to irregular) and in the germinal vesicles, in addition to extensive cytoplasmic vacuolation.These effects were observed after the application of carvacrol at a concentration of 20 MUL/mL. The most significant alterations were observed at the highest concentration (100 MUL/mL), at which the oocytes could not develop further than stage II (total absence of oocytes III, IV and V). These data showed that even though carvacrol was unable to kill all ticks at these concentrations, surviving females could have had an altered reproduction, which would hinder the generation of new individuals, resulting in a long-term control. Data regarding the inhibition of oocyte development are unprecedented and indicate the use of carvacrol as a natural product with the potential to control R. sanguineus s.l. ticks. PMID- 30308333 TI - Cooked color of precooked ground beef patties manufactured with mature bull trimmings. AB - Lean (80%) ground beef was formulated with 0, 25, 50, 75, or 100% mature bull trimmings, formed into patties, cooked to 71 degrees C in an air-impingement oven, and stored at -20 degrees C until reheating to 71 degrees C either in a microwave oven or on a gas-fired chargrill. Instrumental color of raw patties was not (P >= .080) affected by levels of bull trim. After initial cooking, internal cooked redness values were not affected (P >= .202) by the proportion of bull trim; however, the internal reheated patty redness increased (greater a* values and lesser HA; P <= .001) with increasing proportions of bull trimmings. Formulating ground beef with high levels (>50%) of mature, bull trimmings had minimal effects on raw ground beef color, but patties formulated with the highest proportions of bull trimmings appeared undercooked even after cooking twice to 71 degrees C. PMID- 30308334 TI - Comparison of simultaneous static standing balance data on a pressure mat and force plate in typical children and in children with cerebral palsy. AB - BACKGROUND: Balance testing is an important component in treatment planning and outcome assessment for children with Cerebral Palsy (CP). Objective measurement for static standing balance is typically conducted in motion labs utilizing force plates; however, a plantar pressure mat may prove to be a viable alternative for this type of balance assessment. METHODS: This study examined static standing balance simultaneously on a force plate and a plantar pressure mat in 30 typically developing (TD) and 30 children with CP to determine if valid measures of static standing balance could be obtained in children with CP using a pressure mat. RESULTS: Examination of the data provided evidence that reliable and valid measures of static standing balance can be produced with a plantar pressure mat for both groups. Five variables out of the 21 variables examined were found to be reliable and valid on both devices (pressure mat and force plate) for both subgroups (TD and CP). The variables medial/lateral (ML) average radial displacement, range moved-ML, anterior/posterior average velocity, ellipse area, and area per second were found to have high test-retest reliability (ICC > .6) and possess discriminant validity between the subgroups (TD vs. CP). Additionally, the ellipse area and area per second variables also had the ability to discriminate between GMFCS levels. A normative center of pressure (CoP) balance data set using all 21 variables was also established for typically developing children for both devices (pressure mat and force plate) within this study. SIGNIFICANCE: The ability to utilize a portable plantar pressure mat for quick and reliable standing balance measurement allows for expanded ability to capture objective data in a variety of settings thereby increasing opportunity for outcomes analysis. PMID- 30308335 TI - Early-warning of ARDS using novelty detection and data fusion. AB - Acute respiratory distress syndrome (ARDS) is a critical condition that disturbs the respiratory system and may lead to death. Early identification of this syndrome is crucial for the implementation of preventive measures. The present paper focuses on the prediction of the onset of this syndrome using physiological records of patients. Heart rate, respiratory rate, peripheral arterial oxygen saturation and mean airway blood pressure were considered. The method proposed in this paper uses first distance-based novelty detection that allows detecting deviations from normal states for each signal. Then, linear and nonlinear kernel based data fusion algorithms are introduced to combine the individual signal decisions. The proposed method is evaluated using the MIMIC II physiological database. As a result, ARDS is detected in the early phases of occurrence with sensitivity and specificity of 65% and 100% respectively for the combination of all the signals in study. Moreover, the proposed method outperforms current state of-the-art methods in real-time surveillance of ARDS using only physiological data with an average prediction before 39 h of onset. PMID- 30308336 TI - Retinal image analysis for disease screening through local tetra patterns. AB - Age-related Macular Degeneration (AMD) and Diabetic Retinopathy (DR) are the most prevalent diseases responsible for visual impairment in the world. This work investigates discrimination potential in the texture of color fundus images to distinguish between diseased and healthy cases by avoiding the prior lesion segmentation step. It presents a retinal background characterization approach and explores the potential of Local Tetra Patterns (LTrP) for texture classification of AMD, DR and Normal images. Five different experiments distinguishing between DR - normal, AMD - normal, DR - AMD, pathological - normal and AMD - DR - normal cases were conducted and validated using the proposed approach, and promising results were obtained. For all five experiments, different classifiers namely, AdaBoost, c4.5, logistic regression, naive Bayes, neural network, random forest and support vector machine were tested. We experimented with three public datasets, ARIA, STARE and E-Optha. Further, the performance of LTrP is compared with other texture descriptors, such as local phase quantization, local binary pattern and local derivative pattern. In all cases, the proposed method obtained the area under the receiver operating characteristic curve and f-score values higher than 0.78 and 0.746 respectively. It was found that both performance measures achieve over 0.995 for DR and AMD detection using a random forest classifier. The obtained results suggest that the proposed technique can discriminate retinal disease using texture information and has potential to be an important component for an automated screening solution for retinal images. PMID- 30308337 TI - Effort or outcome? Children's meritorious decisions. AB - How individuals determine what is fair and just when allocating resources is a fundamental aspect of moral development. Decisions about fairness involve considerations such as merit, which includes effort (one's own exertion to achieve a goal) and outcome (one's product). Previous research has described merit in terms of both effort and outcome (e.g., a meritorious individual is both hard-working and productive). Crucially, no research has documented whether children give priority to being hard-working (high effort) or to being productive (high outcome or product) when allocating resources. This gap in the literature obfuscates two constructs that reflect how individuals allocate resources. The current study examined this process by which children (3- to 10-year-olds, N = 100; Mage = 7.27 years, SD = 2.39) weighed these two different aspects of merit in their fairness decisions in several situations where levels of effort and outcome were varied. When there was a discrepancy between effort and outcome, children increasingly prioritized effort over outcome with age and allocated more resources to hard-working peers than to productive peers. Effort and outcome were also examined. In situations where only effort varied (i.e., outcome was controlled), with age children were more likely to incorporate effort into their fairness decisions; however, in situations where only outcome varied (i.e., effort was controlled), with age children were less likely to incorporate effort into their fairness decisions. Taken together, the findings suggest that as children get older, they increasingly focus on effort of individuals rather than on their productivity when distributing resources. PMID- 30308338 TI - Comparing the Risk of Shunt-Dependent Hydrocephalus in Patients with Ruptured Intracranial Aneurysms Treated by Endovascular Coiling or Surgical Clipping: An Updated Meta-Analysis. AB - BACKGROUND: This meta-analysis aimed to evaluate the risk of shunt-dependent hydrocephalus among patients with ruptured intracranial aneurysms treated with either coil placement or clipping. METHODS: A systematic literature search of Embase, PubMed, Web of Science, and the Cochrane Library was performed to confirm relevant studies. The scientific literature was screened in accordance with the predetermined inclusion and exclusion criteria. After quality assessment and data extraction from the eligible studies, a meta-analysis was conducted using the STATA 12.0 software (Stata corporation, College Station, Texas, USA). RESULTS: Thirteen studies met all inclusion criteria and were included in the analysis. In total, these studies included 13,751 patients. Of the patients, 8444 of them underwent neurosurgical clipping, and 5307 underwent endovascular coiling. The overall result of a pooled estimate revealed there was no statistically significant risk of shunt dependency difference between the clipping and coiling groups (11.4% vs. 12.0%, respectively; relative risk [RR], 0.92; 95% confidence interval [CI], 0.84-1.01). Six prospective studies (n = 1373) reported shunt dependent hydrocephalus revealed no significant difference between clipping and coiling (23.3% vs. 20.1%, respectively; RR, 1.12; 95% CI, 0.91-1.38). Seven retrospective studies (n = 12,378) reported shunt-dependent hydrocephalus found statistical significance between the surgical and endovascular treatment groups (10.0% vs. 11.1%, respectively; RR, 0.88; 95% CI, 0.79-0.98). CONCLUSIONS: Microsurgical clipping and endovascular coiling of ruptured cerebral aneurysms are associated with similar incidences of ventricular shunt placement for hydrocephalus. The risk of shunt-dependent hydrocephalus is not higher after coiling than after clipping of ruptured intracranial aneurysms. PMID- 30308339 TI - Transforaminal Interbody Debridement and Fusion to Manage Postdiscectomy Discitis in Lumbar Spine. AB - BACKGROUND: Traditionally, nonoperative management with long-term antibiotics and bed rest has been recommended as first-line treatment for most patients with postoperative discitis. A recent trend in treatment under a limited range of indications has been to perform surgical debridement followed by long-term administration of antibiotics. This descriptive study investigated whether transforaminal lumbar interbody debridement and fusion (TLIDF) combined with intravenous antibiotics is appropriate to manage postdiscectomy discitis. METHODS: This study retrospectively analyzed demographic data, laboratory data, and radiography and magnetic resonance imaging of 10 patients with postoperative discitis who underwent surgical TLIDF followed by antibiotic treatment. Preoperative and postoperative spine sagittal alignment, visual analog scale scores, and Kirkaldy-Willis criteria for functional outcomes were evaluated. RESULTS: An infection clearance rate of 100% was ultimately achieved for the patients who underwent TLIDF with short posterior instrumentation. TLIDF yielded better outcomes than traditional conservative treatment in terms of spine alignment correction, functional outcomes, and quality of life. CONCLUSIONS: Based on previously reported data and the findings of this study, we suggest that surgical intervention should be used in certain cases, as it can achieve better outcomes than conservative treatment. We recommend a novel single posterior approach with TLIDF and posterior pedicle screw instrumentation for management of postdiscectomy discitis. PMID- 30308340 TI - Quantitative Endoscopic Comparison of Contralateral Interhemispheric Transprecuneus and Supracerebellar Transtentorial Transcollateral Sulcus Approaches to the Atrium. AB - OBJECTIVE: The contralateral interhemispheric transprecuneus approach (CITP) and the supracerebellar transtentorial transcollateral sulcus approach (STTC) are 2 novel approaches to access the atrium of the lateral ventricle. We quantitatively compared the 2 approaches. METHODS: Both approaches were performed in 6 sides of fixed and color-injected cadaver heads. We predefined the 6 targets in the atrium for measurement and standardization of the approaches. Using a navigation system, we quantitatively measured the working distance, cortical transgression, angle of attack, area of exposure, and surgical freedom. RESULTS: The distances from the craniotomy edge to the posterior pole of the choroid plexus of the CITP (mean +/- standard deviation, 67 +/- 5.3 mm) and STTC (mean, 57 +/- 4.0 mm) differed significantly (P < 0.01). Cortical transgression with the CITP (mean, 27 +/- 2.8 mm) was significantly greater than that with the STTC (mean, 21 +/- 6.7 mm; P = 0.03). The CITP showed a significantly wider rostrocaudal angle of attack than that with the STTC (P = 0.01). The STTC showed a significantly wider mediolateral angle (P < 0.01). No significant difference was found for surgical freedom of any target except for point E, for which the CITP was larger. The exposure area did not differ significantly between the 2 approaches (P = 0.07). CONCLUSIONS: Both approaches were feasible for accessing the atrium. The STTC provided a shorter working distance and wider mediolateral angle, CITP provided a wider rostrocaudal angle of attack and better exposure and maneuverability to the anterior and superior atrium. In contrast, the STTC was more favorable for the inferior and posterior regions. PMID- 30308341 TI - Meckel's Cave Epidermoid Cyst Presenting as Multiple Cranial Nerve Deficits Due to Indirect Tumoral Compression of the Cavernous Sinus: A Case Report and Literature Review. AB - BACKGROUND: Epidermoid cysts in Meckel's cave are exceedingly rare. Since 1971, only 17 cases have been reported in the literature with the majority of patients presenting with trigeminal hypesthesia. However, outgrowth of these lesions from Meckel's cave can rarely lead to compression of the proximate cavernous sinus and the neurovascular structures contained within. To date, two cases have reported a Meckel's cave epidermoid cyst presenting clinically as an intracavernous cranial nerve palsy, presumably a clinical manifestation of cavernous sinus compression from the lesion. CASE DESCRIPTION: We describe a case involving a 51-year-old female presenting with unilateral refractory trigeminal neuralgia, facial hypesthesia, abducens palsy, plus new onset partial ptosis. Magnetic resonance imaging revealed a mass in the left Meckel's cave that was T1 hypointense, T2 hyperintense, peripherally enhancing, and restricting diffusion. A stereotactic left subtemporal extradural approach was used to resect the lesion, which alleviated most of the patient's symptomatology except for minimal intermittent left-sided facial hypesthesia that remained at her one-year postoperative visit. CONCLUSIONS: This is a unique report depicting an epidermoid cyst in the Meckel's cave causing numerous cranial nerve deficits due to indirect tumoral compression of cranial nerves within the cavernous sinus. PMID- 30308342 TI - A Novel Height-Adjustable Nano-Hydroxyapatite/Polyamide-66 Vertebral Body for Reconstruction of Thoracolumbar Structural Stability After Spinal Tumor Resection. AB - BACKGROUND: Reconstruction of thoracolumbar structural stability is a formidable challenge for spine surgeons after vertebral body tumor resection. Various disadvantages of the currently used expandable or nonexpandable cages have limited their clinical applications. We sought to develop a novel prosthesis for clinical use and assess its preliminary clinical outcome in reconstruction of thoracolumbar structural stability after spinal tumor resection. METHODS: Using data obtained from a retrospective analysis of the morphological characteristics of the thoracolumbar vertebrae and endplates in previously reported studies, we modified the nano-hydroxyapatite/polyamide-66 (n-HA/PA66) strut into a novel height-adjustable vertebral body. A retrospective study was performed of 7 patients who had undergone reconstruction of thoracolumbar structural stability with this novel prosthesis from August 2016 to January 2017. RESULTS: A novel height-adjustable vertebral body (AHVB) composed of n-HA/PA66 with 2 separate components with a 163 degrees contact surface at each end was manufactured. The height-adjustable range was 28-37 mm. No significant implant-related complications were observed in the process of operation. All patients experienced a significant reduction in pain, with the visual analog scale score decreasing from 7.9 to 4.0. Neurological improvement was assessed using the Frankel grading system after surgery. Postoperative radiographic and computed tomography/magnetic resonance imaging findings indicated that the operated segment was stable, the outcome of kyphosis correction was good, and no prosthesis subsidence or dislocation was observed. CONCLUSION: This novel prosthesis has many advantages in the reconstruction of height, lordosis, and alignment after thoracolumbar spinal tumor resection and has a favorable prospect for clinical application. PMID- 30308343 TI - Prognostic Importance of Cumulative Intracranial Tumor Volume in Patients with Gastrointestinal Brain Metastasis Treated with Stereotactic Radiosurgery. AB - BACKGROUND: The disease-specific Graded Prognostic Assessment (ds-GPA) for patients with gastrointestinal (GI) tract cancer brain metastases (BM) suggests Karnofsky Performance Status (KPS) as the only pertinent prognostic factor. We evaluated the prognostic importance of cumulative intracranial tumor volume (CITV). METHODS: KPS, CITV, and overall survival were collected from consecutive patients with stereotactic radiosurgery-treated GI BM. Patients were grouped into 2 independent cohorts for development and validation of the model (termed "exploratory" and "validation" cohorts). Analyses were performed using logistic regression, Cox proportional hazards models, Net Reclassification Index (NRI >0), integrated discrimination improvement (IDI >0), and Akaike information criterion. RESULTS: In univariable logistic regression models, both CITV and KPS were independently associated with patient survival. The association between CITV and overall survival remained robust after controlling for KPS (P < 0.001) in a multivariable Cox proportional hazards model. Based on NRI analysis of the exploratory cohort, we found that a CITV cutoff of 12 cm3 best augments the prognostic accuracy of GI-ds-GPA. In this analysis, incorporation of CITV (as < or >=12 cm3) improved prognostication of the GI-specific GPA model by NRI >0 of 0.397 (95% confidence interval [CI], 0.165-0.630; P < 0.001) and IDI of 0.019 (95% CI, 0.004-0.033; P = 0.013). We confirmed the prognostic usefulness of the CITV-incorporated GI-ds-GPA in an independent validation cohort, in which CITV incorporation improved prognostic usefulness with an NRI >0 of 0.478 (95% CI, 0.257-0.699; P < 0.001) and IDI of 0.028 (95% CI, 0.014-0.043; P < 0.001). CONCLUSIONS: CITV is an important prognostic variable in patients with stereotactic radiosurgery-treated GI BM and augments the prognostic accuracy of the GI-ds-GPA index. PMID- 30308344 TI - CD34 Expression in Low-Grade Epilepsy-Associated Tumors: Relationships with Clinicopathologic Features. AB - OBJECTIVE: To analyze relationships between CD34 expression and several demographic, clinical, and pathologic features in patients with histopathologic evidence of low-grade epilepsy-associated tumors who underwent epilepsy surgery. METHODS: A retrospective study enrolling 187 patients with low-grade epilepsy associated tumors who underwent surgery between January 2009 and June 2015 at 8 Italian epilepsy surgery centers was conducted. All cases were histologically diagnosed according to the World Health Organization classification of central nervous system tumors. Univariate and multivariate analyses were performed to identify variables associated with CD34 expression. RESULTS: Of 187 patients, 95 (50.8%) were CD34 positive. Tumor type and duration of epilepsy were independently associated with CD34 expression on multivariate analysis. Ganglioglioma and pleomorphic xanthoastrocytoma were the histologic types with the strongest association with CD34 positivity with an odds ratio of 9.2 and 10.4, respectively, compared with dysembryoplastic neuroepithelial tumors. Patients with a duration of epilepsy >10 years had a significantly greater likelihood to show CD34 expression, with an odds ratio of 2.8 compared with patients with a duration of epilepsy <2 years. On univariate analysis, CD34 expression appeared to be significantly related to older age at surgery, higher antiepileptic drug intake, and female sex. CONCLUSIONS: CD34 expression holds promise as a useful biomolecular marker for patients with low-grade epilepsy associated tumors with evidence of a link with clinicopathologic features. This study confirmed the association between CD34 expression and tumor type and demonstrated a significantly higher probability of CD34 expression in patients with longer duration of epilepsy, independent of histology. PMID- 30308345 TI - Stereotactic Body Radiation Therapy in Non-Surgical Patients with Metastatic Spinal Disease and Epidural Compression: A Retrospective Review. AB - In the setting of spinal metastases with epidural cord compression, radiosurgery is often only considered when there is sufficient separation between the epidural disease and the spinal cord. However, in patients who are non-surgical candidates or those who prefer non-operative management, there may be a benefit from stereotactic body radiation therapy (SBRT) even when the epidural target is closer than the traditionally referenced 3 mm distance from the spinal cord. The purpose of this retrospective study is to evaluate our institution's experience in treating twenty such patients. Local control was obtained in 55% of patients meeting these criteria without a single case of radiation myelitis. The majority of patients with disease progression were able to undergo additional local treatment. Though local control was less than expected when compared to spine radiosurgery with adequate separation between target and spinal cord, this treatment appears to be a viable option in the non-surgical candidate. PMID- 30308346 TI - Repetitive Computed Tomography Perfusion for Detection of Cerebral Vasospasm Related Hypoperfusion in Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Delayed cerebral infarction after aneurysmal subarachnoid hemorrhage (aSAH) still remains the leading cause of disability in patients that survive the initial ictus. It has been shown that computed tomography perfusion (CTP) imaging can detect hypoperfused brain areas. The aim of this study was to evaluate if a single acute CTP examination at time of neurologic deterioration is sufficient or if an additional baseline CTP increases diagnostic accuracy. METHODS: Retrospective analysis of acute and baseline (within 24 hours after aneurysm treatment) CTP examinations of patients with neurologic deterioration because of vasospasm-related hypoperfusion. Patients without clinical deterioration during the vasospasm period served as control subjects. The following CTP parameters were analyzed for predefined brain regions: time to drain (TTD), mean transit time, time to peak, cerebral blood flow, and volume. RESULTS: Thirty-three patients with and 23 without neurologic deterioration were included. Baseline CTP examination did not ameliorate diagnostic accuracy of the acute CTP examination in symptomatic patients. The same was true for interhemispheric comparison of perfusion parameters of the acute examination. The CTP parameter with the highest diagnostic yield was TTD of the symptomatic brain region (threshold value, 4.7 seconds; sensitivity, 97%; specificity, 96%). CONCLUSIONS: Acute CTP examination in case of suspected vasospasm-induced neurologic deterioration after aSAH has the highest diagnostic accuracy to detect misery perfusion. Additional baseline CTP is not needed. The most sensitive parameter to detect critically perfused brain areas is TTD. PMID- 30308347 TI - Characteristics of child physical and sexual abuse as predictors of psychopathology. AB - Childhood physical and sexual abuse victims are at increased risk for developing depression, anxiety, and post-traumatic stress disorder (PTSD) in adulthood. Prior findings suggest abuse onset, duration, and severity moderate relationships between victimization and psychopathology. However, because these abuse characteristics are highly intercorrelated, their unique, individual effects on mental health outcomes remain unclear. To address this gap, the present study examined relationships between physical and sexual abuse characteristics and mental health outcomes and whether these relationships differed by sex. A diverse community sample of late adolescents and emerging adults (N = 1270; mean age = 19.68; 51% female) self-reported the onset, duration, and severity of physical and sexual abuse, as well as their depressive, anxiety, and PTSD symptoms. Results of a multivariate regression model (simultaneously evaluating all physical and sexual abuse characteristics) indicated that physical abuse onset in middle childhood and sexual abuse onset in middle childhood or adolescence were associated with all forms of psychopathology; and physical abuse onset at any time was uniquely linked with PTSD. Duration and severity of physical or sexual abuse did not predict psychopathology after accounting for time of onset. Multigroup analyses indicated that adolescence-onset and duration of sexual abuse respectively predicted anxiety and PTSD in females but not males, whereas sexual abuse severity predicted fewer PTSD symptoms in males but not females. Overall, results suggested that abuse occurring after age 5 may have the most deleterious impact on mental health. PMID- 30308348 TI - The economic burden of child maltreatment in the United States, 2015. AB - Child maltreatment incurs a high lifetime cost per victim and creates a substantial US population economic burden. This study aimed to use the most recent data and recommended methods to update previous (2008) estimates of 1) the per-victim lifetime cost, and 2) the annual US population economic burden of child maltreatment. Three ways to update the previous estimates were identified: 1) apply value per statistical life methodology to value child maltreatment mortality, 2) apply monetized quality-adjusted life years methodology to value child maltreatment morbidity, and 3) apply updated estimates of the exposed population. As with the previous estimates, the updated estimates used the societal cost perspective and lifetime horizon, but also accounted for victim and community intangible costs. Updated methods increased the estimated nonfatal child maltreatment per-victim lifetime cost from $210,012 (2010 USD) to $830,928 (2015 USD) and increased the fatal per-victim cost from $1.3 to $16.6 million. The estimated US population economic burden of child maltreatment based on 2015 substantiated incident cases (482,000 nonfatal and 1670 fatal victims) was $428 billion, representing lifetime costs incurred annually. Using estimated incidence of investigated annual incident cases (2,368,000 nonfatal and 1670 fatal victims), the estimated economic burden was $2 trillion. Accounting for victim and community intangible costs increased the estimated cost of child maltreatment considerably compared to previous estimates. The economic burden of child maltreatment is substantial and might off-set the cost of evidence-based interventions that reduce child maltreatment incidence. PMID- 30308349 TI - Synthesis and characterization of La-doped Zn(O,S) photocatalyst for green chemical detoxification of 4-nitrophenol. AB - La-doped Zn(O,S) nanoparticles (NPs) with different contents of lanthanum have been synthesized with a simple sol-gel method at low temperature (90 C) for 4 nitrophenol (4-NP) detoxification. The as-prepared catalysts were characterized with X-ray diffraction (XRD), scanning electron microscope (SEM), high resolution transmission electron microscope (HRTEM), photoluminescence (PL) and UV-vis absorbance spectroscopy, X-ray photoelectron spectroscopy (XPS), electrochemical impedance spectroscopy (EIS), and photoresponsivity. In this work, it is considered that the detoxification of 4-NP to 4-aminophenol (4-AP) without NaBH4 by using photocatalytic method is a green chemical conversion. The experimental data showed 30 ppm toxic 4-NP had been totally converted to useful 4-aminophenol (4-AP) with lower toxicity in 2 h, which was confirmed with a specific peak shift as indicated with UV-vis absorbance spectra and high performance liquid chromatography (HPLC) measurement. The lower amount of evolved hydrogen from photocatalytic process on La-doped Zn(O,S) NPs in the presence of 4-NP confirmed the produced hydrogen was consumed as a reducing agent during the 4-NP-to-4-AP conversion. The photocatalytic detoxification of 4-NP to 4-AP had been demonstrated and an appropriate mechanism based on the experimental data had been proposed and elucidated in this work. PMID- 30308350 TI - Mechanism and optimization of electrochemical system for simultaneous removal of nitrate and ammonia. AB - In this study, an electrochemical system was established for simultaneous harmless removal of nitrate and ammonia multiple contamination in an undivided single cell. Cyclic voltammetry was used to investigate the electrochemical cathode and anode coupling redox mechanism and concurring evolution of nitrate and ammonia. The cyclic voltammograms showed the cathodic reduction of nitrate to ammonia and nitrite, the chloride ion conversion to hypochlorite and hypochlorous acid, and the oxidation of ammonia to nitrogen gas and nitrate. A circular transformation process was formed in the electrochemical system and the final product was harmless nitrogen gas. The multiple nitrogen pollutants in the original contaminated system were gradually removed with the reaction predominantly produced harmless nitrogen gas. Response surface methodology was used to build mathematical models for optimizing the operating conditions. The optimum time, NaCl concentration, and current density were 85.38 min, 0.24 g/L, and 45.13 mA/cm2, respectively. Under the optimum conditions, the nitrate and ammonia concentrations in the treated solution were 9.17 and 0.00 mg/L, respectively. PMID- 30308351 TI - Heart developmental toxicity by carbon black waste generated from oil refinery on zebrafish embryos (Danio rerio): Combined toxicity on heart function by nickel and vanadium. AB - This study assessed the developmental toxicities of water-soluble carbon black wastes (CBW) extract (1:5, w/v) in zebrafish embryos (Danio rerio). Acute embryonic toxicity was performed following OECD guideline 236. Analysis using ICP OES revealed that nickel (Ni) and vanadium (V) were predominant in CBW. Embryos exposed to CBW exhibited developmental delay, along with pericardial and yolk sac edemas. Malformed heart chambers were found in the CBW-exposed embryos and heart rates were significantly reduced since 48 h post fertilization (hpf). After RT qPCR analysis, two cardiac forming-related genes, amhc and nppa responsible for atrial cardiac myofibril assembly and cardiac muscle cell proliferation, were up regulated after 96 hpf. The increased mortality and delayed yolk-sac development appeared related to CBW-induced decrease in pH to about 5.5. Individual treatments of Ni and V did not cause identical toxic effects as CBW showed. At 100 ppm, V had a pH of approximately 5.5, causing developmental delay and pericardial edema in zebrafish embryos. At the same pH, combined Ni and V induced morphological anomalies and reduced heart rates similar to CBW-exposed embryos. Conclusively, this study demonstrates that environmental runoff is a serious concern, and thus, CBW incineration bottom ash should be treated carefully before disposal in landfills. PMID- 30308352 TI - Functionalized graphene with Co-ZIF adsorbed borate ions as an effective flame retardant and smoke suppression agent for epoxy resin. AB - In order to reduce the fire risk of epoxy resin (EP), functionalized reduced graphene oxide (RGO) with Co-ZIF (zeolitic imidazolate frameworks-67) adsorbed borate ions (ZIF-67/RGO-B) was prepared. The results of transmission electron microscopy (TEM) showed that ZIF-67 was grown on the surface of RGO triumphantly. In addition, the structure of ZIF-67/RGO-B was not significantly changed compared with ZIF-67/RGO. Subsequently, ZIF-67/RGO-B was added into EP by a simple blending method. The combustion results showed that the heat and smoke production of EP composites were obviously reduced. In particular, compared with pure EP, the peak heat release rate (pHRR), the total heat release (THR) and the maximum value of smoke density (Ds,max) of the composite with 2 wt% ZIF-67/RGO-B were reduced by 65.1%, 41.1% and 66.0%, respectively. The main mechanism of ZIF-67/RGO B for reducing the fire risk of EP was analyzed according to the results of the char analysis. This work provided a new type of modified RGO for reducing the fire hazard of EP. PMID- 30308353 TI - Research on the influence of driving gas types in compound jet on extinguishing the pool fire. AB - Compound jet fire extinguishing technology is an efficient technology for oil fires. The hydrophobic ultrafine dry powder is used for the solid phase in the compound jet, but it can't be supplied continuously due to the insufficient supply of compressed nitrogen. Thus, the feasibility of using the compressed air to replace the compressed nitrogen in the compound jet was explored. The key factor for the replacement, which influences the fire extinguishing efficiency, is the oxygen content in the contact point between the jet and the flame. Firstly, the oxygen content of the ultrafine powder jet driven by air or nitrogen were investigated by gas analyzer; Secondly, 150 L (liter) gas oil and 50 L water were put in a oil pan, the compared fire extinguishing experiments were conducted, the fire extinction time and the temperature drop range were investigated. In order to reveal the effect of ultrafine dry powder on oxygen content in gas jet, the experiment that spray the compressed nitrogen were conducted. The results show that there are not much differences for the two gases in extinguishing the pool fire, indicating that compressed air as the driving gas of the compound jet is feasible during fire extinguishing process. PMID- 30308354 TI - Fabrication of terminal amino hyperbranched polymer modified graphene oxide and its prominent adsorption performance towards Cr(VI). AB - In order to increase the density and quantity of functional groups on adsorbent, three terminal amino hyperbranched polymer modified graphene oxide adsorbents including GO-HBP-NH2-DETA, GO-HBP-NH2-TETA and GO-HBP-NH2-TEPA with N-containing functional group density of 7.21 wt%, 10.20 wt% and 12.43 wt%, respectively, were prepared and used for the adsorption and reduction of toxic hexavalent chromium Cr(VI) to less toxic Cr(III). The morphology and structure of obtained adsorbents were characterized by FT-IR, SEM, XRD, Raman, BET, XPS and zeta potential. The density of receptor sites (Nm) of the three adsorbents calculated from statistical physics model with one energy site were found to be 456.62, 604.54 and 636.03, respectively. Adsorption experiments demonstrated that the high adsorption capacities of the three adsorbents obtained from Langmuir isotherm model towards Cr(VI) were 245.01, 257.26 and 300.88 mg/g, respectively, suggesting that GO-HBP-NH2-TEPA had better adsorption ability. The density functional theory calculation (DFT) indicated that GO-HBP-NH2-TEPA was more likely to adsorb HCrO4- rather than Cr2O72- at lower pH conditions. A possible adsorption mechanism was also proposed where electrostatic interaction between Cr(VI) (HCrO4- or Cr2O72-) and the N functional group (+) on GO-HBP-NH2-TEPA dominated the adsorption of Cr(VI) and reduction mechanism dominated the reduction of Cr(VI)-Cr(III). PMID- 30308355 TI - Plant-microbial synergism: An effective approach for the remediation of shale-gas fracturing flowback and produced water. AB - Effective and affordable treatment of hydraulic fracturing flowback and produced water (FPW) is a major challenge for the sustainability of unconventional shale gas exploration and development. We investigated the effectiveness of different combinations of activated sludge (AS), three microbial preparations, and ten plants (ryegrass, water dropwort, typha, reed, iris, canna, water caltrop, rape, water spinach, and Alternanthera philoxeroides) on the treatment performance of FPW. Water quality parameters (NH4-N, NO3-N, NO2-N, CODcr, and BOD) and the algal toxicity of the treated FPW were used as metrics to assess the treatment efficiency. The results showed that AS had higher treatment efficiency than the prepared microorganisms, and water dropwort was the best plant candidate for boosting performance of AS treatment of FPW. The treated FPW showed improved water quality and microbial diversity. The Shannon-Wiener index increased from 4.76 to 7.98 with FPW treatment. The relative abundance of microbes with a greater resistance to high salt conditions, such as Bacteroidetes, Firmicutes, Chloroflexi, increased substantially in the treated FPW. The combination of water dropwort and AS showed the greatest improvement in water quality, the highest algal density and microbial diversity, thus indicating good potential for this candidate in the treatment of FPW. PMID- 30308356 TI - Selective recovery of mercury from high mercury-containing smelting wastes using an iodide solution system. AB - The mercury resources recovery and safe disposal of mercury-containing waste is an urgent problem. In this study, a new method using an iodide solution system was proposed to selectively recover mercury from high mercury-containing smelting wastes. The mercury leaching efficiency, yields, leaching kinetics and thermodynamics were researched. The major factors which affect mercury leaching efficiency including iodide concentration, oxidant, pH and temperature were evaluated. Over 97% and 93% of mercury can be efficiently leached from wastewater treatment sludge (W-S) and acid sludge (A-S). After leaching, the mercury concentration during leaching toxicity test is under the limits set for hazardous waste. Additionally, the electrolytic technology can efficiently recover mercury from leachate in the form of elemental mercury, and the leachate after electrolytic can be reused for mercury leaching. The mercury leaching kinetics follows the shrinking core diffusion model and is controlled by solid product diffusion. The mechanism research shows the leaching efficiency was strongly dependent on the distribution of mercury species in smelting waste. The consequence on mercury leaching and recovery could provide nonferrous smelters with a practical and yet easy-to-adopt perspective to reduce the risk of mercury contamination and selectively recover mercury resources from mercury-containing smelting wastes. PMID- 30308357 TI - The characteristics of flame propagation in ammonia/oxygen mixtures. AB - As a carbon free fuel and a hydrogen-energy carrier, ammonia is expected to be one of the promising energy carriers and to be widely used in industries. In this study, the parameters of ammonia/oxygen flame, such as laminar flame speed, the Markstein length, laminar flame thickness, and critical radius of flame instability onset have been investigated experimentally and numerically. A spherical ammonia /oxygen flame propagated in a constant volume chamber and a high speed digital Schilieren photograph system were used in the study. The influences of initial pressure and equivalence ratio on flame propagation have been investigated. It was found that the maximum laminar flame speed in ammonia/oxygen mixture is 1.09 m/s. The flame thickness decreases with the initial pressure increase. Generally, Markstein length increases with the increasing of equivalence ratio while it decreases with the increasing of initial pressure. The minimum critical radius in ammonia/oxygen is 1.8 cm. And the critical radius decreases with the increase of initial pressure. The mechanisms of flame instability in ammonia/oxygen mixture were analyzed, and the stabilize effect of flame stretch in ammonia/oxygen have been observed. PMID- 30308358 TI - Haloalkaliphilic microorganisms assist sulfide removal in a microbial electrolysis cell. AB - Several industrial processes produce toxic sulfide containing streams that are often scrubbed using caustic solutions. An alternative, cost effective sulfide treatment method is bioelectrochemical sulfide removal. For the first time, a haloalkaliphilic sulfide-oxidizing microbial consortium was introduced to the anodic chamber of a microbial electrolysis cell operated at alkaline pH and with 1.0 M sodium ions. Under anode potential control, the highest sulfide removal rate was 2.16 mM/day and chemical analysis supported that the electrical current generation was from the sulfide oxidation. Biotic operation produced a maximum current density of 3625 mA/m2 compared to 210 mA/m2 while under abiotic operation. Furthermore, biotic electrical production was maintained for a longer period than for abiotic operation, potentially due to the passivation of the electrode by elemental sulfur during abiotic operation. The use of microorganisms reduced the energy input in this study compared to published electrochemical sulfide removal technologies. Sulfide-oxidizing populations dominated both the planktonic and electrode-attached communities with 16S rRNA gene sequences aligning within the genera Thioalkalivibrio, Thioalkalimicrobium, and Desulfurivibrio. The dominance of the Desulfurivibrio-like population on the anode surface offered evidence for the first haloalkaliphilic bacterium able to couple electrons from sulfide oxidation to extracellular electron transfer to the anode. PMID- 30308359 TI - Removal of acetylsalicylate and methyl-theobromine from aqueous environment using nano-photocatalyst WO3-TiO2 @g-C3N4 composite. AB - Highly efficient, visible light-driven and a novel ternary hybrid photocatalyst WO3-TiO2-g-C3N4 with robust stabilities and versatile properties has been synthesized through facile hydrothermal method. This study considers the photo degradation of aspirin (acetylsalicylate) and caffeine (methyl-theobromine) via photocatalysts (WO3, WO3/TiO2, and WO3/TiO2/g-C3N4 (WTCN) composite) under visible-light irradiation. The SEM and TEM images show the formation of WO3 nanoparticles with orthorhombic structure and average particle size of 65 nm. The photocatalyst WTCN composite possesses higher-catalytic activity when compared to that of WO3 and WO3/TiO2 for degradation of aspirin and caffeine. The incorporation of g-C3N4 in WO3/TiO2 composite exhibited significant influence on the photocatalytic performance for both pollutants. Excellent photocatalytic performance of WTCN composite was observed owing to hydroxyl radical (OH) and superoxide radical (O2-) as main active species. The enhanced photocatalytic activity of WTCN composite can be attributed to following three reasons: (1) extended visible-light absorption; (2) extended surface area; (3) efficient charge-separation due to synergistic effects between g- and WO3/TiO2 composite. The removal efficiency of aspirin and caffeine (Methyl theobromine) could be achieved as much as 98% and 97% for acetylsalicylate and methyl-theobromine using WTCN composite material, respectively. This study could provide new insights into the synthesis of novel WO3-based materials for environmental and energy applications. PMID- 30308360 TI - Highly enhanced soot oxidation activity over 3DOM Co3O4-CeO2 catalysts by synergistic promoting effect. AB - Three-dimensionally ordered macroporous (3DOM) Co3O4-CeO2 catalysts with controllable Co/Ce molar ratios synthesized by colloidal crystal template method were developed to catalyze the NOx-assisted soot oxidation for the first time, and the obtained 3DOM Co3O4-CeO2 catalysts exhibited highly enhanced soot oxidation activity. Detailed characterizations of 3DOM Co3O4-CeO2 catalysts revealed that the highly enhanced soot oxidation activity was originated from the synergistic promoting effect by combining the macroporous effect resulted from the unique 3DOM framework, the chemical nature associated with more Co3+ reactive sites, the surface enrichment of Ce species and the improved redox properties. Meanwhile, the high NOx storage and oxidation capacity resulted from the integrated respective merits of Co3O4 and CeO2 also accounted for the enhanced soot oxidation activity via NOx-assisted mechanism. Furthermore, the 3DOM Co3O4 CeO2 catalysts demonstrated strong stability because of the surface enrichment of Ce species improving the thermal stability and the robust 3DOM framework inhibiting the structural collapse, showing their potential applications under practical conditions. PMID- 30308361 TI - Biodegradation of the aromatic fraction from petroleum diesel fuel by Oerskovia sp. followed by comprehensive GC*GC-TOF MS. AB - Polycyclic aromatic hydrocarbons (PAHs) from petroleum and fossil fuels are one of the most dominant pollutants in the environment. Since aromatic fraction from petroleum diesel fuel is mainly composed of PAHs, it is important to discover new microorganisms that can biodegrade these compounds. This article describes the biodegradation of the aromatic fraction separated from petroleum diesel fuel using the strain Oerskovia sp. CHP-ZH25 isolated from petroleum oil-contaminated soil. The biodegradation was monitored by gravimetry and GC * GC-TOF MS. An innovative method was applied to visualize degraded compounds in the data provided by a GC * GC-TOF MS. It was shown that Oerskovia sp. CHP-ZH25 degraded 77.4% based on gravimetric analysis within 30 days. Average rate of degradation was 14.4 mg/L/day, 10.5 mg/l/day and 4.0 mg/l/day from 0 to 10 day, 10-20 and 20 30 day, respectively. The order of PAH degradation based on decrease in peak volume after 30 days of incubation was as follows: dibenzothiophene derivatives > benzo[b]thiophene derivatives > naphthalene derivatives > acenaphthene derivatives > acenaphthylene/biphenyl derivatives > fluorene derivatives > phenanthrene/anthracene derivatives. Here we demonstrated that Oerskovia sp. CHP ZH25 could potentially be a suitable candidate for use in bioremediation of environments polluted with different PAHs. PMID- 30308362 TI - Quantum chemistry and experimental studies of hydrothermal destruction of Co-EDTA complexes. AB - Hydrothermal oxidation, a promising method for removal of cobalt radionuclides from EDTA-containing liquid radioactive waste streams, is in the focus of the present study. It has been demonstrated that Co(III)-EDTA complexes, which are very stable under normal conditions, undergo oxidation as a result of the electron transfer from the EDTA carboxyl group to Co(III) ions under elevated temperature. The electron transfer reaction follows the first-order rate law with an activation energy of 91.8 kJ/mol at rH 12 and time of Co(III) ions half conversion of 0.2 s at 200 degrees C. The rate of EDTA oxidation is proportional to the concentration of Co(III) ions and solution pH. Based on quantum chemistry simulations, possible intermediate structures formed upon the electron transfer from EDTA to Co(III) ions have been suggested. It has been shown that the introduction of hydrogen peroxide provides a continuous generation of Co(III) ions and a sequential decarboxylation of the EDTA until complete degradation of the chelate structure. The pathways of cobalt immobilization have been clarified. PMID- 30308363 TI - Preparation of a bioflocculant by using acetonitrile as sole nitrogen source and its application in heavy metals removal. AB - A novel bioflocculant, A-GS408, produced by Klebsiella oxytoca GS-4-08 cultured in acetonitrile (ACN) as sole nitrogen source was investigated in this study. A complete degradation of 1 g l-1 of ACN was achieved in 350 h, and 4.6 g of crude A-GS408 can be obtained in one litter of synthetic medium. The as-prepared bioflocculant exhibits good flocculation efficiency (over 90%) toward Kaolin solution with the aid of Fe3+. Chemical analysis showed that the bioflocculant was mainly composed of polysaccharides (46.3%) and proteins (20.6%). FTIR and XPS results indicated the abundant carboxyl, amine and hydroxyl groups in A-GS408 s, which play an important role on Pd2+ and Cu2+ adsorption. The adsorption of heavy metals can be well stimulated by Freundlich isotherm equation, and the Kf was up to 439.2 mg1-1/n l1/n g-1 and 112.2 mg1-1/n l1/n g-1 for Pb2+ and Cu2+, respectively. The kinetic fitting results proved that the adsorption of heavy metals by A-GS408 was chemisorption. This study may provide a new method for preparation of bioflocculant, which can not only degrade toxic compound i.e., acetonitrile, but also can reuse considerable nitrogen source from nitrile containing wastewater. PMID- 30308364 TI - Highly efficient immobilization of uranium(VI) from aqueous solution by phosphonate-functionalized dendritic fibrous nanosilica (DFNS). AB - A novel phosphonate assisted fabrication dendritic fibrous nanosilica (DFNS) based adsorbing material was successfully synthesis via organic modification with 3-aminopropyltriethoxysilane (KH550), epichlorohydrin (ECH) and phytic acid (PA) on the grounds of hard-soft-acid-base theory, in which organic phosphorous can be applied for efficient chelating uranium(VI) (U(VI)). The adsorption properties can be evaluated by setting a series parameters (pH, adsorbent dose, contact time, initial U(VI) concentration). It is clear that uranium as a "hard" lewis acid can easily form chelating bond with "hard" donor-ligands so that as-papered PA-DFNS has an excellent adsorption capacity (qm = 1106 mg g-1, 298.15 K), which exhibits a 163% increment compared with that of original DNFS under the same condition. In the meantime, the adsorption equilibrium time of PA-DNFS (t = 60 min) was shortened by 33% compared with that of pristine DNFS. Besides, the PA DFNS exhibited good removal efficiency and stability under the 0.1 M HNO3 after 6 cycles, extending the application of PA-DFNS in the field of adsorption. PMID- 30308365 TI - Characterization of the role of phosphogypsum foam in the transport of metals and radionuclides in the Southern Mediterranean Sea. AB - The Gabes Gulf had received huge quantities of phosphogypsum discharged from fertilizer plants. Dumping phosphogypsum in coastal waters leads to the formation of foam layers which can float on the surface and be passively transported to distant areas. This is the first attempt at geochemical and mineralogical characterization of these industrial foams in order to understand their role in the dynamic and behavior of contaminants in marine environment. Chemically, phosphogypsum foams (PGFs) are heavily loaded with radiochemical contaminants. Their mineralogical composition showed a prevalence of synthetic gypsum followed by other secondary minerals including halite, quartz, dolomite, sphalerite-Cd and fluorapatite. PGFs are rich in organic matter (OM), precursor of their formation. Once released in gypseous water, the OM in solution undergoes agglomeration, cementing and flotation steps leading to the formation of floating foams. The foams' OM was found to control the mobility of industrial contaminants contributing then to the marine environment pollution. Consequently, PGFs are the main accumulating, transporting and dispersion agent of phosphogypsum radiochemical contaminants. Thus, PGFs removal has the potential to reduce enormously the dynamics of contaminants transferred from the fertilizer plants to the aquatic environment, reducing thus their impacts on the marine environment and health status in Gabes. PMID- 30308366 TI - Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units. AB - The present study aimed to identify plasticizers present in indwelling plastic medical devices commonly used in the pediatric intensive care unit (PICU). We have analyzed a wide range of medical devices (n = 97) daily used in the PICUs of two academic hospitals in Belgium and the Netherlands. Identified compounds varied between the samples. Most of the indwelling medical devices and essential accessories were found to actively leach phthalates and alternative plasticizers. Results indicated that DEHP was predominantly present as plasticizer (60 of 97 samples), followed by bis(2-ethylhexyl) adipate (DEHA, 32 of 97), bis(2 ethylhexyl) terephthalate (DEHT, 24 of 97), tris(2-ethylhexyl) trimellitate (TOTM, 20 of 97), and tributyl-O-acetyl citrate (ATBC, 10 of 97). Other plasticizers, such as di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH, 2 of 97), di-isononyl phthalate (DiNP, 4 of 97), di(2-propylheptyl) phthalate (DPHP, 4 of 97) and di-isodecyl phthalate (DiDP, 2 of 97) were detected in < 5% of the investigated samples. Several devices contained multiple plasticizers, e.g. devices containing TOTM contained also DEHP and DEHT. Our data indicate that PICU patients are exposed to a wide range of plasticizers, including the controversial DEHP. Future studies should investigate the exposure to APs in children staying in the PICU and the possible health effects thereof. PMID- 30308367 TI - Simultaneous removal of heavy metals and cyanate in a wastewater sample using immobilized cyanate hydratase on magnetic-multiwall carbon nanotubes. AB - Global environmental problems allied with waste management require novel approaches for the simultaneous removal of heavy metals and other associated compounds including cyanate. In this study, iron-oxide filled multi-walled carbon nanotubes (m-MWCNTs) were successfully synthesized and characterized by field emission gun scanning electron microscopy (FEGSEM), high-resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD). The m-MWCNTs were amino functionalized for the covalent immobilization of a recombinant cyanate hydratase (rTl-Cyn), and were characterized by fourier transform infrared (FTIR) spectroscopy. The immobilized rTl-Cyn on the m-MWCNTs (m-MWCNT-rTl-Cyn) had long term storage stability and showed great potential towards cyanate biodegradability. We found that m-MWCNT-rTl-Cyn retained >94% of the initial activity even after 10 repeated cycles of bio-catalysis. Strikingly, the m-MWCNT rTl-Cyn simultaneously reduced the concentration of chromium (Cr), iron (Fe), lead (Pb) and copper (Cu) by 39.31, 35.53, 34.48 and 29.63%, respectively as well as the concentration of cyanate by >=84%, in a synthetic wastewater sample. PMID- 30308368 TI - Novel nanofibers mat as an efficient, fast and reusable adsorbent for solid phase extraction of non-steroidal anti-inflammatory drugs in environmental water. AB - Core-shell polyaniline/polyacrylonitrile nanofibers mat (PANI/Pan NFsM) was prepared for extraction of hydrophilic non-steroidal anti-inflammatory drugs (NSAIDs) in environmental water. Superior adsorption and desorption performance of PANI/Pan NFsM was confirmed by both static and dynamic adsorption/desorption experiments. These properties proved PANI/Pan NFsM was a potentially efficient and fast solid phase extraction (SPE) adsorbent for NSAIDs. Under the optimized conditions, only 3 mg of PANI/Pan NFsM could easily extract eight target analytes in 10 mL of water sample without any pre-treatment, and the analytes retained on NFsM could be easily eluted by 500 MUL of 1% acetic acid methanol for direct UPLC MS/MS analysis. In addition, each piece of PANI/Pan NFsM could be reused for at least 20 times without performance decline. Possible adsorption mechanisms were also proposed. Practical feasibility was validated through the actual sample analysis. PMID- 30308369 TI - Catalytic oxidation of chlorobenzene over noble metals (Pd, Pt, Ru, Rh) and the distributions of polychlorinated by-products. AB - Catalytic oxidation of chlorobenzene over noble metal catalysts Pd/TiO2, Pt/TiO2, Ru/TiO2, and Rh/TiO2 was evaluated, and Ru/TiO2 contributed the highest catalytic activity and CO2 selectivity. During the oxidation, polychlorinated benzenes PhClx (x >= 2) were observed, and Ru/TiO2 showed apparently lower PhClx concentrations than other three samples. With the improvement of temperature, the maximum concentration appeared in the sequence of dichlorobenzene (PhCl2), trichlorobenzene (PhCl3), tetrachlorobenzene (PhCl4), and pentchlorobenzene (PhCl5), whereas the concentration of hexachlorobenzene (PhCl6) was always low and showed no apparent regularity. Besides, the dioxin-like PCBs (dl-PCBs) were collected and analyzed for Pd/TiO2 and Ru/TiO2. The ?dl-PCBs produced by Pd/TiO2 (0.0055 ng WHO-TEQ/Nm3) was about 1.5 times that of Ru/TiO2 (0.0027 ng WHO TEQ/Nm3). XPS analyses revealed that Ru/TiO2-used and Rh/TiO2-used gave the lowest and the highest Cl content of 0.61% and 1.87%. Ru/TiO2-used afforded the lowest (Clad+Clor)/Cl value (22.1%) and the highest Clbr/Cl value (77.9%), which might be an important reason for its strongest chlorine removal ability and the lowest yields of polychlorinated by-products, whereas other three catalysts showed similarity in the Cl distributions. Additionally, systematic in-situ FTIR studies were conducted, and a reaction mechanism for the catalytic oxidation of chlorobenzene was proposed. PMID- 30308370 TI - Simultaneous p-nitrophenol and nitrogen removal in PNP wastewater treatment: Comparison of two integrated membrane-aerated bioreactor systems. AB - The chemical p-nitrophenol (PNP) is a priority pollutant, and PNP wastewater is highly toxic and resistant to biodegradation. The traditional physical and chemical methods (adsorption, extraction, and oxidation) for treating PNP wastewater have the disadvantages of complicated processes, high costs and secondary pollution generation. In this study, two integrated membrane-aerated bioreactor systems (RA and RB) with anoxic and aerated zones were constructed to enhance PNP biodegradation. The results showed that a helical silicone rubber membrane module displayed a high oxygen supply rate under a low membrane aeration pressure, and the hydraulic flow state of the reactor approached ideal mixing. At an influent PNP concentration of 500 mg/L, the average removal rates of PNP, chemical oxygen demand (COD) and total nitrogen (TN) reached 95.86%, 89.77%, and 94.81%, respectively, for RA and 89.48%, 74.26% and 64.78%, respectively, for RB, indicating efficient simultaneous PNP and nitrogen removal. Compared with that of RB, the pre-anoxic zone in RA not only performed detoxification pretreatment but also enhanced PNP degradation and denitrification effects, which relieved the biological treatment burden of the subsequent aerated zone. Based on these comprehensive analyses of reactor performance, the hydroquinone pathway might be the main route in the aerobic degradation of PNP. PMID- 30308371 TI - Prioritization of unregulated disinfection by-products in drinking water distribution systems for human health risk mitigation: A critical review. AB - Water disinfection involves the use of different types of disinfectants, which are oxidizing agents that react with natural organic matter (NOM) to form disinfection by-products (DBPs). The United States Environmental Protection Agency (USEPA) has established threshold limits on some DBPs, which are known as regulated DBPs (R-DBPs). The human health risks associated with R-DBPs in drinking water distribution systems (DWDSs) and application of stricter regulations have led water utilities to switch from conventional disinfectant (i.e., chlorination) to alternative disinfectants. However, the use of alternative disinfectants causes formation of a new suit of DBPs known as unregulated DBPs (UR-DBPs), which in many cases can be more toxic. There is a growing concern of UR-DBPs formation in drinking water. This review prioritizes some commonly occurring UR-DBP groups and species in DWDSs based on their concentration level, reported frequency, and toxicity using an indexing method. There are nine UR-DBPs group and 36 species that have been identified based on recent published peer-reviewed articles. Haloacetonitriles (HANs) and haloacetaldehydes (HALs) are identified as important UR-DBP groups. Dichloroacetonitrile (DCAN) and trichloroacetaldehye (TCAL) are identified as critical UR-DBPs species. The outcomes of this review can help water regulators to identify the most critical UR-DBPs species in the context of drinking water safety and provide them with useful information to develop guidelines or threshold limits for UR-DBPs. The outcomes can also help water utilities in selecting water treatment processes for the mitigation of human health risk posed by UR-DBPs through drinking water. PMID- 30308372 TI - Development of a novel chem-bio hybrid process using biochar supported nanoscale iron sulfide composite and Corynebacterium variabile HRJ4 for enhanced trichloroethylene dechlorination. AB - A sequential chem-bio hybrid process was developed using a novel biochar supported carboxymethyl cellulose-stabilized nanoscale iron sulfide (CMC FeS@biochar) as a chemical remover and Corynebacterium variabile HRJ4 as a biological agent for trichloroethylene (TCE) degradation. Compared with CMC-FeS, FeS@biochar600, bare FeS and biochar600, the CMC-FeS@biochar600 composite displayed better physiochemical properties (smaller hydrodynamic diameter and higher stability) and demonstrated excellent removal capacity for TCE from aqueous phase. A facultative bacterial strain, Corynebacterium variabile HRJ4, growing well in the presence of CMC-FeS@biochar (added up to 0.25 g L-1), further enhanced TCE removal after chemical treatment. The dechlorination pathway proposed based on the gas chromatography-mass spectrometry (GC-MS) analysis revealed that TCE was dechlorinated to cis-1,2-dichloroethene (cis-DCE) and acetylene via hydrogenolysis and beta-elimination, respectively within 12 h by CMC-FeS@biochar. Addition of HRJ4 strain into the reaction system effectively enhanced the degradation of the residual TCE, cis-DCE and acetylene to ethylene. Acetylene was the main product in chemical process, whereas ethylene was the main product in biological process as strain HRJ4 could reduce acetylene to ethylene effectively. The results of this study signify the potential application of CMC FeS@biochar600/HRJ4 chem-bio hybrid system for complete degradation of TCE in the anaerobic environment. PMID- 30308373 TI - The potential of osmolytes and their precursors to alleviate osmotic stress of anaerobic granular sludge. AB - Increasing amounts of saline (waste)water with high concentrations of organic pollutants are generated globally. In the anaerobic (waste)water treatment domain, high salt concentrations are repeatedly reported to inhibit methanogenic activity and strategies to overcome this toxicity are needed. Current research focuses on the use of potential osmolyte precursor compounds for osmotic stress alleviation in granular anaerobic sludges upon exposure to hypersalinity shocks. Glutamic acid, aspartic acid, lysine, potassium, gelatine, and tryptone were tested for their potential to alleviate osmotic stress in laboratory grown and full - scale granular sludge. The laboratory grown granular sludge was adapted to 5 (R5) and 20 (R20) g Na+/L. Full-scale granular sludge was obtained from internal circulation reactors treating tannery (waste)water with influent conductivity of 29.2 (Do) and 14.1 (Li) mS/cm. In batch experiments which focused on specific methanogenic activity (SMA), R5 granular sludge was exposed to a hypersalinity shock of 20 g Na+/L. The granular sludge of Do and Li was exposed to a hypersalinity shock of 10 g Na+/L with sodium acetate as the sole carbon source. The effects on R20 granular sludge were studied at the salinity level to which the sludge was already adapted, namely 20 g Na+/L. Dosing of glutamic acid, aspartic acid, gelatine, and tryptone resulted in increased SMA compared to only acetate fed batches. In batches with added glutamic acid, the SMA increased by 115% (Li), 35% (Do) and 9% (R20). With added aspartic acid, SMA increased by 72% (Li), 26% (Do), 12% (R5) and 7% (R20). The addition of tryptone resulted in SMA increases of 36% (R5), 17% (R20), 179% (Li), and 48% (Do), whereas added gelatine increased the SMA by 30% (R5), 14% (R20), 23% (Li), and 13% (Do). The addition of lysine, meanwhile, gave negative effects on SMA of all tested granular sludges. Potassium at sea water Na/K ratio (27.8 w/w) had a slight positive effect on SMA of Do (7.3%) and Li (10.1%), whereas at double the sea water ratio (13.9% w/w) had no pronounced positive effect. R20 granular sludge was also exposed to hyposalinity shock from 20 down to 5 g Na+/L. Glutamate and N-acetyl-beta-lysine were excreted by microbial consortium in anaerobic granular sludge adapted to 20 g Na+/L upon this exposure to hyposalinity. A potential consequence when applying these results is that saline streams containing specific and hydrolysable proteins can be anaerobically treated without additional dosing of osmolytes. PMID- 30308374 TI - Occurrence of emerging pollutants in estuaries of the Basque Country: Analysis of sources and distribution, and assessment of the environmental risk. AB - In this study, the spatial and temporal-distribution of 41-multiclass organic compounds were assessed in three estuaries of the Basque Country, from winter 2016 to winter 2017 by grab (active) sampling methods and an extra campaign combining both, grab and passive sampling methods. Wastewater treatment plant (WWTP) effluents were also evaluated to assess their impact on the estuaries. Moreover, the physicochemical features (phosphate and nitrate concentrations, pH, etc.) of each site were measured and included in the statistical analysis. Anti inflammatory drugs (diclofenac and acetaminophen), hypertensive drugs (irbesartan and valsartan), a stimulant (caffeine), an artificial sweetener (acesulfame) and a corrosion inhibitor (2-hydroxybenzothiazole) were the most ubiquitous compounds. Due to the stratification of the waters in the estuary of Bilbao two independent sources were identified: WWTP and harbour activities. In the case of Gernika and Plentzia, both are estuaries with a high tidal dilution, and the main sources were localized in the effluents of the WWTPs. In addition to this, the use of POCIS provides an efficient way to monitor emerging pollutants over a relatively long sampling period. Finally, risk quotient (RQ) values of each contaminant were estimated from the maximum values determined at each estuary and WWTP effluent for acute and chronic effects. In the case of acute toxicity the highest RQ values ("1) were obtained for the angiotensin II receptor blockers (telmisartan, eprosartan, etc.), diuron and diclofenac. In the case of the chronic toxicity the highest RQ values ("1) were estimated for caffeine, diclofenac, bezafibrate and sulfadiazine. PMID- 30308375 TI - New insight into the applicability of spectroscopic indices for dissolved organic matter (DOM) source discrimination in aquatic systems affected by biogeochemical processes. AB - Despite numerous studies on changes to optical proxies of dissolved organic matter (DOM) by biogeochemical processing, the applicability of commonly-used spectroscopic indices has not been explored as DOM source tracking tools under conditions where biogeochemical processes may alter them. For this study, two contrasting DOM end members, Suwannee River fulvic acid (SRFA) and algogenic DOM (ADOM), and their mixtures, were used to examine the potential changes in the conservative mixing behaviors of several well-known optical indices via end member mixing analysis under the influence of biodegradation, UV irradiation, and clay mineral (kaolin) adsorption. Most of the source tracking indices exhibited large deviations from conservative mixing behavior between the two end-members. Biodegradation tended to lower the portions of labile and ADOM in the mixtures, while the allochthonous end member (SRFA) was reduced by a greater extent after the process of UV irradiation or adsorption. The extent of the variations in biological index (BIX) and fluorescence index (FI) was smaller for more allochthonous DOM mixtures under the processes of biodegradation and UV irradiation. Overall, the process-driven variations in ratios of humic-like: protein-like fluorescence (as modeled by parallel factor analysis, PARAFAC) were greater for the SRFA versus ADOM. Evaluation criteria used in this study suggested that BIX, specific UV absorbance (SUVA), and FI each could be the reliable discrimination parameter least affected by biodegradation, UV irradiation, and adsorption, respectively. This study provided criterion information for the choice and the interpretation of the optical indices for DOM source discrimination in aquatic environments after substantial biogeochemical processing. PMID- 30308376 TI - Controlling aerobic biological floc size using Couette-Taylor Bioreactors. AB - Biological floc size is an important reactor microenvironment parameter that is often not experimentally controlled due to a lack of suitable methods. Here, we introduce the Couette-Taylor bioreactor (CTB) as an improved tool for controlling biological floc size, specifically as compared with bubble-column sequencing batch reactors (SBRs). A CTB consists of two concentric walls, either of which may be rotated to induce fluid motion. The induced flow produces hydrodynamic shear which is more uniform than that produced through aeration in SBRs. Because hydrodynamic shear is a major parameter controlling floc size, we hypothesized the ability to better control shear rates within a CTB would enable better controlled floc sizes. To test this hypothesis, we measured the particle size distributions of activated sludge flocs from CTBs with either inner (iCTB) or outer (oCTB) rotating walls as well as SBRs with varying height to diameter ratios (0.5, 1.1, and 9.4). The rotation speed of the CTBs and aeration rate of the SBRs were varied to produce predicted mean shear rates from 25 to 250 s-1. Further, the shear rate distributions for each experiment were estimated using computational fluid dynamics (CFD). In all SBR experiments, the floc distributions did not significantly vary with shear rate or geometry, likely because shear rates (estimated by CFD) differed much less than originally predicted by theory. In the CTB experiments, the mean particle size decreased proportionally with increased hydrodynamic shear, and iCTBs produced particle size distributions with smaller coefficients of variation than oCTBs (0.3 vs. 0.5 0.7, respectively). PMID- 30308378 TI - Effect of GHB-use and GHB-induced comas on dorsolateral prefrontal cortex functioning in humans. AB - BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a recreational drug associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced comas. Working memory (WM) deficits have been reported in association with GHB use, and animal studies have shown that GHB induces oxidative stress in vulnerable WM-related brain areas such as the dorsolateral prefrontal cortex (DLPFC). However, the effects of chronic GHB use and multiple GHB-induced comas on WM-related brain function in humans remains unknown. METHODS: We recruited 27 GHB users with >=4 GHB-induced comas (GHB-Coma), 27 GHB users who never experienced GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants performed an n-back WM task during functional magnetic resonance imaging (fMRI) to probe DLPFC functioning. RESULTS: The GHB-Coma group had lower premorbid IQ (p = .006) than the GHB-NoComa group despite comparable age and education level. There were also group differences in the use of other drugs than GHB. Therefore, all group comparisons were adjusted for IQ and drug use other than GHB. Compared with the GHB-NoComa and the No-GHB groups, the GHB-Coma group showed increased activity in the right DLPFC (pSVC = 0.028) and increased functional connectivity of the right DLPFC with a cluster comprising the left anterior cingulate and medial frontal gyrus (pFWE = 0.003). No significant fMRI differences were observed between the GHB-NoComa and No-GHB groups. Due to technical problems, no behavioural data were collected. DISCUSSION: These results suggest that multiple GHB-induced comas, but not GHB use per se, are associated with alterations in WM-related brain function. Public awareness campaigns are required to minimize the potential adverse effects induced by GHB recreational use, and especially GHB-induced comas, even if no immediate side effects are experienced. PMID- 30308377 TI - Prenatal to postnatal trajectory of brain growth in complex congenital heart disease. AB - Altered brain development is a common feature of the neurological sequelae of complex congenital heart disease (CHD). These alterations include abnormalities in brain size and growth that begin prenatally and persist postnatally. However, the longitudinal trajectory of changes in brain volume from the prenatal to postnatal environment have not been investigated. We aimed to evaluate the trajectory of brain growth in a cohort of patients with complex CHD (n = 16) and healthy controls (n = 15) to test the hypothesis that patients with complex CHD would have smaller total brain volume (TBV) prenatally, which would become increasingly prominent by three months of age. Participants underwent fetal magnetic resonance imaging (MRI) at a mean of 32 weeks gestation, a preoperative/neonatal MRI shortly after birth, a postoperative MRI (CHD only), and a 3-month MRI to evaluate the trajectory of brain growth. Three-dimensional volumetric analysis was applied to the MRI data to measure TBV, as well as tissue specific volumes of the cortical gray matter (CGM), white matter (WM), subcortical (deep nuclear) gray matter (SCGM), cerebellum, and cerebrospinal fluid (CSF). A random coefficients model was used to investigate longitudinal changes in TBV and demonstrated an altered trajectory of brain growth in the CHD population. The estimated slope for TBV from fetal to 3-month MRI was 11.5 cm3 per week for CHD infants compared to 16.7 cm3 per week for controls (p = 0.0002). Brain growth followed a similar trajectory for the CGM (p < 0.0001), SCGM (p = 0.002), and cerebellum (p = 0.005). There was no difference in growth of the WM (p = 0.30) or CSF (p = 0.085). Brain injury was associated with reduced TBV at 3 month MRI (p = 0.02). After removing infants with brain injury from the model, an altered trajectory of brain growth persisted in CHD infants (p = 0.006). These findings extend the existing literature by demonstrating longitudinal impairments in brain development in the CHD population and emphasize the global nature of disrupted brain growth from the prenatal environment through early infancy. PMID- 30308379 TI - Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7. AB - Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that selectively affect vulnerable neuronal populations in the cerebellum and other subcortical regions. While previous studies have reported subtype differences in the absolute amount of degeneration in specific regions of interest, they failed to account for two important factors. First, they did not control for overall differences in the severity of the degeneration pattern, and second, they did not fully characterize the spatial pattern of degeneration for each SCA subtype. Here, we provide a systematic characterization of the spatial degeneration patterns for three polyQ SCAs (55 patients, either SCA2, SCA3, or SCA7) while controlling for the severity of the degeneration pattern. After this correction, the cerebellar degeneration pattern can successfully classify between the three different SCA subtypes with high cross-validated accuracy. Specifically, degeneration in SCA3 disproportionally affects motor regions of the cerebellar cortex, which explains the relatively severe motor symptoms observed in this subtype. Our results demonstrate that each of the three studied SCA subtypes has a unique cerebellar degeneration signature, hinting at differences in the disease process. Clinically, these differentiable patterns of cerebellar degeneration can be used to reliably discern subtypes, even at relatively early stages of the disease. PMID- 30308380 TI - Physical activity is associated with left corticospinal tract microstructure in bipolar depression. AB - Psychomotor retardation and reduced daily activities are core features of the depressive syndrome including bipolar disorder (BD). It was the aim of this study to investigate white matter microstructure of the motor system in BD during depression and its association with motor activity. We hypothesized reduced physical activity, microstructural alterations of motor tracts and different associations between activity levels and motor tract microstructure in BD. Nineteen bipolar patients with a current depressive episode (BD) and 19 healthy controls (HC) underwent diffusion weighted magnetic resonance imaging (DW-MRI) scans. Quantitative motor activity was assessed with 24 h actigraphy recordings. Bilateral corticospinal tracts (CST), interhemispheric connections between the primary motor cortices (M1) and between the pre-supplementary motor areas (pre SMA) were reconstructed individually based on anatomical landmarks using Diffusion Tensor Imaging (DTI) based tractography. Mean fractional anisotropy (FA) was sampled along the tracts. To enhance specificity of putative findings a segment of the optic radiation was reconstructed as comparison tract. Analyses were complemented with Tract Based Spatial Statistics (TBSS) analyses. BD had lower activity levels (AL). There was a sole increase of fractional anisotropy (FA) in BD in the left CST. Further, there was a significant group x AL interaction for FA of the left CST pointing to a selective positive association between FA and AL in BD. The comparison tract and TBSS analyses did not detect significant group differences. Our results point to white matter microstructure alterations of the left CST in BD. The positive association between motor activity and white matter microstructure suggests a compensatory role of the left CST for psychomotor retardation in BD. PMID- 30308382 TI - Astaxanthin exerts anti-inflammatory and antioxidant effects in macrophages in NRF2-dependent and independent manners. AB - Although anti-inflammatory effects of astaxanthin (ASTX) have been suggested, the underlying mechanisms have not been fully understood. Particularly, the modulatory action of ASTX in the interplay between nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappaB (NFkappaB) to exert its anti inflammatory effect in macrophages is unknown. The effect of ASTX on mRNA and protein expression of pro-inflammatory and antioxidant genes and/or cellular reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages, bone marrow-derived macrophages (BMDM) from wild-type (WT) and Nrf2 deficient mice, and/or splenocytes and peritoneal macrophages of obese mice fed ASTX. The effect of ASTX on M1 and M2 macrophage polarization was evaluated in BMDM. ASTX significantly decreased LPS-induced mRNA expression of interleukin 6 (Il-6) and Il-1beta by inhibiting nuclear translocation of NFkappaB p65; and attenuated LPS-induced ROS with an increase in NRF2 nuclear translocation, concomitantly decreasing NADPH oxidase 2 expression in RAW 264.7 macrophages. In BMDM of WT and Nrf2-deficient mice, ASTX decreased basal and LPS-induced ROS accumulation. The induction of Il-6 mRNA by LPS was repressed by ASTX in both types of BMDM while Il-1beta mRNA was decreased only in WT BMDM. Furthermore, ASTX consumption lowered LPS sensitivity of splenocytes in obese mice. ASTX decreased M1 polarization of BMDM while increasing M2 polarization. ASTX exerts its anti-inflammatory effect by inhibiting nuclear translocation of NFkappaB p65 and by preventing ROS accumulation in NRF2-dependent and -independent mechanisms. Thus, ASTX is an agent with anti-inflammatory and antioxidant properties that may be used for the prevention of inflammatory conditions. PMID- 30308381 TI - High-fat diet affects pregestational adiposity and glucose tolerance perturbing gestational placental macronutrient transporters culminating in an obese offspring in wild-type and glucose transporter isoform 3 heterozygous null mice. AB - We examined the effect of a high-fat diet (HFD) vs. control diet (CD) upon pregestational and gestational wild-type (wt) and glucose transporter (glut)3 heterozygous (glut3+/-) female mice and observed an increase in pregestational body weights, white adiposity (wt > glut3+/-), circulating cholesterol, and high density lipoproteins, with glucose intolerance in both genotypes. The HFD-exposed offspring displayed reduced birth weight with catch up to CD-fed in wt vs. an increased birth weight persisting as such at weaning by day 21 in glut3+/- mice. To decipher the mechanism behind this genotype-specific difference in the HFD offspring's phenotype, we first examined placental macronutrient transporters and noted HFD-induced increase in CD36 in wt with no change in other FATPs, sodium coupled neutral amino acid transporters and system L amino acid transporter in both genotypes. In contrast, while placental Glut1 increased in both the genotypes, only Glut3 increased in the glut3+/- genotype in response to HFD. Hence, we next assessed glut3+/- embryonic (ES) cells under differing stressors of low glucose, hypoxia and inhibition of oxidative phosphorylation. Reduced Glut3-mediated glucose uptake in glut3+/- vs. wt ES cells culminated in deficient growth. We conclude that maternal HFD affects the in utero growth potential of the offspring by altering placental CD36 and Glut1 concentrations. In contrast, a differential effect on placental Glut3 concentrations between glut3+/- and wt genotypes is evident, with an increase occurring in the glut3+/- genotype alone. Deficient Glut3 in ES cells interferes with glucose uptake, cell survival and growth being further exaggerated with low glucose, hypoxia and inhibition of oxidative phosphorylation. PMID- 30308383 TI - Brasilane sesquiterpenoids and dihydrobenzofuran derivatives from Aspergillus terreus [CFCC 81836]. AB - Brasilanones A-F and asperterreusines A-C, undescribed brasilane sesquiterpenoids and dihydrobenzofuran derivatives, were isolated from the marine-derived fungus Aspergillus terreus [CFCC 81836]. Their structures with absolute configurations were elucidated on the basis of spectroscopic data, X-ray crystallographic analyses, and electronic circular dichroism (ECD) calculations. Brasilanones A-F are unusual brasilane sesquiterpenoids with an alpha,beta-unsaturated ketone unit, interestingly, brasilanones B-D are stereo isomers. All of the isolates were evaluated for their inhibitory activities against NO production and cytotoxic activities against five human cancer cell lines (HL-60, SW-480, A-549, MCF-7, and SMMC-7721). Brasilanones A and E showed moderate inhibitory effect with NO inhibition rates of 47.7% (p < 0.001) and 37.3% (p < 0.001) at the concentration of 40 MUM. Asperterreusines A showed cytotoxicity against HL-60 and SW-480 cell lines with IC50 values of 15.3 and 25.7 MUM, respectively. PMID- 30308384 TI - Predictors of resistant alcohol withdrawal (RAW): A retrospective case-control study. AB - BACKGROUND: Benzodiazepine-resistant alcohol withdrawal (RAW), defined by a requirement of >= 40 mg of diazepam in 1 h, represents a severe form of withdrawal without predictive parameters. This study was designed to identify risk factors associated with RAW versus withdrawal without benzodiazepine resistance (nRAW). METHODS: A retrospective cohort of adults with severe alcohol withdrawal were screened. Demographic and clinical variables, collected through chart review, underwent logistic regression to select the subset that predicst RAW. RESULTS: 736 patients (515 nRAW, 221 RAW) were analyzed. RAW patients were younger (P < 0.001), male (P = 0.008) Caucasians (P = 0.037) with histories of psychiatric illness (P < 0.001), higher serum ethanol concentrations (P < 0.007), and abnormal liver enzymes (P = 0.01). RAW patients had significantly lower platelets (P < 0.001), chloride (P = 0.02), and potassium (P = 0.01) levels; severity of illness (SAPSII) (P < 0.001) and comorbidity scores (P < 0.001). Caucasian race and male gender were found to be 3.6 and 2.6 times more likely to be RAW. For every 1-unit increase in comorbidity and severity of illness scores, patients were 22% [OR(95% CI) 0.78 (0.66-0.90)] and 4% [0.96 (0.93-0.98)] less likely to be RAW. Patients with a psychiatric history or thrombocytopenia were 2 times more likely [2.02 (1.24-3.30); 2.13 (1.31-3.50), respectively] to be RAW. CONCLUSION: These data demonstrate the predictive ability of a history of psychiatric illness, thrombocytopenia, gender, race, baseline severity of illness and comorbidity scores for developing RAW. Considering these characteristics in early withdrawal management may prevent progression to RAW outcomes. PMID- 30308386 TI - Activation against absenteeism - Evidence from a sickness insurance reform in Norway. AB - I evaluate a program aimed at strictly enforcing a requirement that people on long-term sick leave be partly back at work unless explicitly defined as an exception. Employing the synthetic control method, I find that the reform reduced work-hours lost due to sickness absenteeism by 12% in the reform region compared to a comparison unit created by a weighted average of similar regions. The effect is driven by both increased part-time presence of temporary disabled workers and accelerated recovery. Musculoskeletal disorders was the diagnosis group declining the most. The findings imply large savings in social security expenditures. PMID- 30308385 TI - Oxytocin receptor gene methylation and substance use problems among young African American men. AB - BACKGROUND: Stressful or supportive social environments promote biological changes with regulatory implications for future relationships and substance abuse. Recent research suggests links between adverse social environments, prosocial relationships, methylation at the oxytocin receptor gene (OXTR), and substance abuse. The potential for OXTR methylation to act as the mechanism linking social environments to substance abuse has yet to be investigated. We hypothesized that, for young African American men, childhood adversity increases, and supportive, prosocial bonds with parents, peers, partners, and community mentors decrease OXTR methylation levels, which in turn predict increases in substance-related symptoms. METHODS: A sample of 358 rural African American men (age 19 at baseline) provided self-report data at three time points separated by 18 months and a genetic specimen at Time 2. RESULTS: Early adversity was associated with OXTR methylation indirectly via contemporary prosocial relationships. OXTR methylation was a proximal predictor of changes in substance related symptoms. We found no evidence for a direct association of self-reported childhood trauma with OXTR methylation status. CONCLUSIONS: Findings suggest that OXTR methylation is linked to substance use symptomatology, ostensibly resulting in increased expression of oxytocin (OT) in peripheral and central nervous systems. OXTR may act as a mechanism to explain how prosocial ties deter substance abuse and related problems. Despite conjectures in the literature that early adversity may become physiologically embedded via methylation in the OT system, direct effects were not evident. Rather, early adversity may affect OXTR methylation via influence on contemporary prosocial relationships. PMID- 30308387 TI - Biotransformation of trace organic chemicals in the presence of highly refractory dissolved organic carbon. AB - Previous studies demonstrated that the transformation of trace organic chemicals (TOrCs) in managed aquifer recharge (MAR) systems is favored under carbon-limited and oxic redox conditions especially, if the dissolved organic carbon (DOC) serving as primary substrate has a refractory character. Since co-metabolism is suggested to be the dominant removal mechanism, it is hypothesized that TOrCs transformation is controlled by the concentration of the refractory carbon under oxic redox conditions. A laboratory-scale soil column experiment mimicking MAR was established to investigate the influence of two different concentrations of highly refractory carbon sources on TOrCs transformation, namely drinking water (DW) and drinking water augmented with humic acid (DW + HA). Oxic redox conditions and carbon-limitation were present in both systems (DeltaDOCDW+HA ~ 0.6-0.7 mg/L; DeltaDOCDW ~ 0.1 mg/L). Of the 12 TOrCs investigated seven exhibited moderate to efficient transformation in both systems with only one compound (diclofenac) showing significantly enhanced (co-metabolic) biotransformation by adding humic acids as primary growth substrate. It is postulated that transformation of some TOrCs is characterized by metabolic degradation under starving conditions (DeltaDOC <= 0.1 mg/L). By comparing the transformation efficiency of selected TOrCs with previous studies operated under carbon-limited and oxic conditions, an inconsistent behavior of some compounds was observed. These results demonstrate that key factors triggering the transformation of TOrCs are still poorly understood and thus, further investigations regarding the biodegradation pathways of TOrCs, upregulation of key enzymes by the microbial community but also more detailed analysis of the composition of the biodegradable DOC are needed. PMID- 30308388 TI - Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. AB - BACKGROUND: The addition of palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. METHODS: Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative MBC were randomised 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/d; 3/1 schedule; n = 347) or placebo (n = 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration >=18 months). RESULTS: By August 2016, 100 patients (29%) on palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated <18 months, such as having one disease site (40% vs 29% on palbociclib-fulvestrant and 69% vs 29% on placebo-fulvestrant), bone-only disease (32% vs 22% and 46% vs 17%) and were less heavily pretreated (69% vs 56% and 73% vs 60% had <=2 prior therapies). Baseline tumour ESR1 and PIK3CA mutation rates were lower among long-term responders in both arms; median oestrogen receptor H scores were similar, whereas progesterone receptor H-scores were higher among long-term responders. CONCLUSIONS: This exploratory analysis demonstrates that some patients with endocrine-resistant MBC derive significant and prolonged benefit when treated with palbociclib-fulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with palbociclib-fulvestrant (ClinicalTrials.gov, NCT01942135). PMID- 30308389 TI - Cortisol, progesterone, 17alphaOHprogesterone, and pregnenolone in foals born from mare's hormone-treated for experimentally induced ascending placentitis. AB - This study aimed to evaluate steroid hormones in foals born from mares treated for ascending placentitis with different combinations of trimethoprim sulfamethoxazole (TMS), flunixin meglumine (FM), long-acting altrenogest (ALT) and estradiol cypionate (ECP) for ten consecutive days, starting two days after experimental induction of placentitis with Streptococcus zooepidemicus. Fourty six pregnant mares and respective foals were assigned as healthy group (Control, n = 8) or treated groups as follows: TMS+FM (n = 8), TMS+FM+ALT (n = 8), TMS+FM+ALT+ECP (n = 6), TMS+FM+ECP (n = 6) and no treatment (NO TREAT n = 10). At delivery, foals were classified as high-risk or low-risk based on clinical and hematologic findings, and survival rates were recorded during the first week of life for comparisons across groups. Cortisol, progesterone, 17alphaOHprogesterone, and pregnenolone concentrations were determined via immunoassays in 31 of the 46 foals immediately after foaling (0 h), at 12, 24, 48 h, and seven days post-partum (168h). At birth, serum cortisol concentrations were higher in Control and TMS+FM+ECP foals than in remaining groups (p < 0.05). Foals in TMS+FM+ALT and TMS+FM groups had higher 17alphaOHprogesterone concentrations at 24 h and 48 h, respectively (p < 0.05). Pregnenolone concentrations were higher in TMS+FM than TMS+FM+ALT+ECP foals at 7 days (p < 0.05). High-risk and non-surviving foals had decreased concentrations of cortisol at parturition, but increased concentrations of progesterone from 0 h to 48 h. Pregnenolone and 17alphaOHprogesterone concentrations were increased and pregnenolone after 12 h in high-risk and non-surviving foals (p < 0.05). In conclusion, adding ECP to the treatment of experimentally-induced placentitis appears to improve foal viability and endocrine response. Cortisol and progestogen profiles were abnormal in high-risk and non-surviving foals, and those treated with ALT or TMS+FM only. PMID- 30308390 TI - Artificial insemination of African catfish (Clarias gariepinus) using cryopreserved sperm. AB - In this study, we aimed to develop a practical protocol for using cryopreserved sperm for induced/wild/tank spawning of fish species with external fertilization. Experiments were carried out on African catfish (Clarias gariepinus) as a model species. Sperm was collected for cryopreservation and diluted with the cryomedium (266 mM fructose, 20% methanol) at a ratio of 1:1 with a final methanol concentration of 2.47 M pH7.73. Diluted sperm was loaded into 0.5-ml straws and cryopreserved by conventional protocol. Samples were prepared for insemination 24 h later, by thawing for 13 s in a 40 degrees C water bath, and centrifuged at 500 * g for 10 min at 20 degrees C. The seminal plasma, extender and external cryoprotectant were removed from the concentrated spermatozoa. The pellet was then resuspended in common carp (Cyprinus carpio) seminal plasma to reconstitute the lost volume. Sperm samples were then injected by a catheter into the ovarian cavity through the oviduct of the experimental females by the so-called ovarian lavage method in parallel with the intramuscular hormonal administration (5 mg carp pituitary/kg bw). Inseminated females (n = 9) were monitored for 10 h and ovulated eggs and spermatozoa stored in in the ovary were stripped. Stripped gamete samples were divided into two batches: (1) the first batch contained only the previously injected spermatozoa and was activated by aerated water (WA) immediately after stripping; (2) in case of the second batch additional, freshly stripped sperm was added as positive control to the stripped eggs before water activation (PC). Furthermore, five females were propagated by using the dry fertilization method (in vitro fertilization) as negative control (NC). All sperm and hormone injected females produced fertilised eggs with a hatching rate of 17.7 +/- 13.2%, 12.5 +/- 9.3%, and 61 +/- 11.5% for WA, PC and NC respectively. These results indicate that artificial insemination based on using cryopreserved sperm with ovarian lavage can be a viable alternative to in vitro fertilization in a catfish species. Thus, we describe a proof of principle for a practical protocol for the induced/wild/tank spawning of an externally fertilising fish species with economical importance and propose that the protocol could be also applied to endangered marine or fresh fish species. PMID- 30308391 TI - Boar sperm protein tyrosine phosphorylation in the presence of egg yolk soluble and low density lipoprotein fractions during cooling. AB - Increased protein tyrosine phosphorylation and the appearance of a phosphorylated protein of 32 kD (p32) are reported among the capacitation-like changes in cryopreserved boar sperm. Egg yolk freezing extenders are composed by two fractions: insoluble granules and soluble plasma, which contains the low density lipoproteins (LDL) proposed as responsible for the egg yolk cryoprotective action. The aim of this work was to analyze the effects of complete egg yolk and its insoluble, soluble and LDL fractions on boar sperm quality and protein tyrosine phosphorylation after the first stage of a standard cryopreservation protocol. Semen samples in Androstar(r) Plus diluent were centrifuged and resuspended in the different egg yolk extenders. Temperature was decreased from 17 degrees C to 5 degrees C and sperm quality, protein tyrosine phosphorylation and protein pattern were analyzed. Results showed that complete egg yolk as well as soluble and LDL egg yolk fractions maintained sperm quality after temperature decrease. Cooling without any lipid component or in the presence of the insoluble fraction, significantly reduced sperm motility. About sperm protein tyrosine phosphorylation analysis, the p32 band appeared before treatments or after cooling in Androstar(r) Plus diluent. Complete egg yolk and its insoluble fraction interfered with sperm tyrosine phosphorylation even after cells were extensively washed. Analysis of extenders revealed a high amount of tyrosine phosphorylated proteins in the insoluble fraction, which may have co-precipitate with sperm in experiments. Samples submitted to temperature decrease from 17 degrees C to 5 degrees C in the presence of soluble and LDL egg yolk fractions in Androstar(r) Plus diluent did not show any change in the p32 band associated with sperm capacitation. However, a tyrosine-phosphorylated protein of 33 kD present in clarified egg yolk was also observed in sperm treated with this extender. Protein transference from plasma and LDL egg yolk extenders was also observed in sperm protein profile. Results suggested that soluble and LDL fractions might have a protective action preventing sperm protein tyrosine phosphorylation during cooling from 17 degrees C to 5 degrees C. Further studies are needed to expand the knowledge of the LDL protection mechanism as well as to determine the possible benefits of clarified egg yolk in freezing protocols. PMID- 30308392 TI - Effect of bST administration on plasma concentrations of IGF-I and follicular dynamics and ovulation during the interovulatory cycle of sheep and goats. AB - This study used a comparative approach to gather clinical information to assess the effect of bovine somatotropin (bST) on follicular dynamics and ovulation in sheep and goats during an interovulatory cycle. The performance of general markers of ovarian function and specific features of follicular dynamics obtained by daily ultrasonography (US) were used to assess the hypothesis that bST, associated with supraphysiological levels of IGF-I, was able to disrupt the follicular dynamics and ovulation in Highlander ewes and Saanen goats. In Exp 1, 15 ewes and 14 goats were estrous-synchronized (P4-6 days + PGFalpha d-6) and then allocated to a bST-treated group (50 and 100 mg, Lactotropin(r); n = 5 females each) and to an untreated control group (5 ewes and 4 goats) to assess the activity of bST through plasma IGF-I (RIA). In Exp 2, 12 animals from each species were synchronized. At day 6, they were divided into a bST-group (100 mg in sheep and 50 mg in goats, n = 6 each) and an untreated control group (n = 6 each). Starting at day 6 and up to 22 days after ovulation in sheep and 25 days in goats, each female was subjected to daily US (10 mHz probe) to assess follicular and luteal (CL) dynamics and ovulation. This included assessments of both general ovarian features and specific follicular wave features. Our results showed that bST increased plasma IGF-I by day 3 (p < 0.01) when compared to the control group. Moreover, these concentrations were maintained for at least 10 days in sheep and 10 days in goats before returning to pre-treatment concentrations. Increases in IGF-I after bST doses were similar in terms of a daily and total amount (P > 0.10). Results from Exp.2 indicate that in sheep, bST administration had a subtle inhibitory effect on follicular function. However, bST in goats had a stronger influence, extending the interovulatory cycle (P = 0,034), increasing the number of follicular waves during the period (P = 0.003), and reducing the functional potential of large follicles as measured by their lower follicular diameter (P = 0.02), duration of the follicle waves (P = 0.02), and persistence of follicles after reaching their maximum diameters (P = 0.04). In addition, untreated sheep and goats shared common patterns of terminal follicular development and ovulations characterized by overlapping between follicular waves and ovulations of follicles from different waves, features not seen in cattle. PMID- 30308393 TI - Endocrine and molecular regulation mechanisms of the reproductive system of Hungarian White geese investigated under two artificial photoperiodic programs. AB - Hungarian White geese are regarded as good producers of meat, eggs, and feathers, but specific lighting schedules are required to improve their egg-laying performance. This study reveals the neuroendocrine regulatory mechanisms that govern the reproductive activities and egg-laying performances of Hungarian White geese. The results indicated that increasing the daily photoperiod from a short 8 h period to either 11 h or 14 h initiated reproduction. Egg-laying rates increased faster in the 14 h group, peaking (48.2%) on day 33 as compared to the peak (52.67%) reached on day 53 in the 11 h group. Changes to the plasma estradiol and progesterone concentrations produced similar patterns in the two groups. In the hypothalamus, OPN5, Dio2, c-Fos, and GnRH-I expression levels showed similar sequential increases and decreases. Changes in GnIH and VIP expression levels were the opposite to those of GnRH-I, but the levels peaked earlier under the 14 h photoperiod conditions. Pituitary LH beta and FSH beta expression levels increased at slower rates but remained significantly higher in the 11 h group than in the 14 h group. However, pituitary PRL expression increased considerably earlier and was higher in 14 h geese than in 11 h geese, which was opposite to the observed egg-laying rate patterns. An increase from a short to a relatively long photoperiod (11 h) regulated the neuroendocrine system and led to reproductive activities being sustained for a longer period, which resulted in high egg-laying performances. PMID- 30308394 TI - Comparison of Th1 and Th2 cytokines production in ovine lymph nodes during early pregnancy. AB - As a fetal allograft to the mother, early conceptus regulates the intrauterine immune and systemic immune responses during early pregnancy in sheep. However, expression of T helper 1 (Th1) and Th2 cytokines in maternal lymph nodes is unclear during early pregnancy in sheep. In this study, inguinal lymph nodes were obtained on day 16 of the estrous cycle and on days 13, 16 and 25 of pregnancy (n = 4 for each group) in ewes, and qRT-PCR, western blot and immunohistochemistry were used to compare the expression of Th1 and Th2 cytokines in the lymph nodes. Our results showed that there were the highest levels of Th1 cytokines (IFN gamma, TNF-beta and IL-2) and Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) in the lymph nodes on day 13 or 16 of pregnancy. Furthermore, there were a downregulation of TNF-beta and IL-2 and an upregulation of IL-5 and IL-10 on day 25 of pregnancy compared with that in nonpregnancy, with no significant difference in the expression of IFN-gamma, IL-4, and IL-6 between the ewes on day 25 of pregnancy and nonpregnancy. The immunohistochemistry results showed that the IL-2 and IL-10 proteins were limited to the subcapsular sinus and trabeculae in the cortex, lymph sinus. In conclusion, early pregnancy exerted its effects on the lymph node and induced a Th2-biased response, which was essential for a normal pregnancy in sheep. PMID- 30308395 TI - Distal limb pathologic conditions in horses treated with sleeve-style digital cryotherapy (285 cases). AB - Digital cryotherapy (DC) is frequently used as laminitis prophylaxis for horses. While DC with ice-water slurries is reported to be safe for up to 48 h, the safety of sleeve-style digital cryotherapy (SSDC) with ice in direct contact with the distal limb has not been evaluated. Our objective was to determine the incidence of distal limb pathologic conditions (DLPC) among horses treated with SSDC. A retrospective study of cases from 2011 to 2015 identified 285 horses treated with SSDC for a minimum of 12 h. Data collected from medical records included demographic, treatment, diagnostic, and SSDC treatment parameters. Bivariate statistics and a generalized linear regression model were created to evaluate risk factors associated with increased incidence of DLPC. Among horses treated with SSDC, 7% had tissue injury of the distal limb. Increasing duration of SSDC was associated with increased incidence of DLPC. Lesions observed included dermatitis, cellulitis, alopecia, coronitis, tissue necrosis, and distal limb edema. These lesions were similar to frostbite, non-freezing cold injury, and prolonged water immersion injuries seen in other species. While the incidence of DLPC was low, the authors recommend that horses undergoing SSDC with ice in direct contact with the skin should be monitored closely for injury when prolonged cryotherapy is clinically indicated. Further studies to improve safety, efficacy, and convenience of alternative methods of DC for horses are warranted. PMID- 30308396 TI - Theoretical investigation on the low-lying electronic states of beryllium antimonide. AB - The Lambda-S electronic states with respect to the lowest four dissociation limits of BeSb are investigated theoretically on the icMRCI + Q level employing basis set of quintuple-zeta quality. The geometrical parameters, potential energy curves, vibrational energy levels, spectroscopic constants for the twelve Lambda S states are obtained, analyzed and compared with those of the Beryllium-VA group diatomic family species where data are available. The permanent dipole moments, transition dipole moments, Einstein emission coefficients, radiative lifetimes and Franck-Condon factors for interested Lambda - S states are also derived. Further assessments of the spin-orbit coupling effect are performed for states associated with the first two dissociation asymptotes of BeSb. Four Lambda - S states split into seven Omega states, and some of the PECs are distorted significantly through the spin-orbit coupling effect, which is similar to its isovalent diatomics BeAs. In consideration of potential risks of manipulating beryllium-containing species directly, the information associated with molecular structures, spectroscopic parameters as well as transition properties that provide in this paper is anticipated to serve as guidelines for further researches of BeSb. PMID- 30308397 TI - A phenolphthalein-based fluorescent probe for the sequential sensing of Al3+ and F- ions in aqueous medium and live cells. AB - A novel fluorescent probe, phenolphthalein-dialdehyde-(2-pyridyl) hydrazone (L), for sequentially detecting Al3+ and F- in almost 100% aqueous medium was successfully designed and synthesized. The probe offers two binding pockets for Al3+ to form a 1: 2 ligand/metal complex, leading to a significant fluorescence enhancement at 465 nm. Further, the in-situ formed L-Al complex acts as a secondary fluorescent chemosensor for F- by quenching the fluorescence of the complex with high selectivity. The detection limit for Al3+ and F- sensing is 2.28 nM and 0.13 MUM, respectively, which are far below the World Health Organization (WHO) acceptable limits (7.41 MUM for Al3+ ion and 79 MUM for F-) in drinking water. The probe L was successfully applied to the detection of Al3+ and F- in cells using fluorescence microscopy. PMID- 30308398 TI - Highly selective and sensitive detection of Zn(II) and Cu(II) ions using a novel peptide fluorescent probe by two different mechanisms and its application in live cell imaging. AB - Metalloproteins are often a useful template for the design and development of peptide fluorescent probes. Herein, we report a novel and simple fluorescent probe L comprised of tetrapeptide and dansyl groups by the solid phase peptide synthesis (SPPS). As a multifunctional analytical probe, L exhibited a highly selective "turn-on" fluorescent response to zinc ions, and a selective "turn-off" fluorescent response to copper ions at an excitation wavelength of 330 nm. The high sensitivity of L was made possible photo-induced electron transfer (PET), and L exhibited very low detection limits for Zn2+ and Cu2+ of 4.9 nM and 15 nM in 100% aqueous solutions, respectively. Furthermore, L displayed very low biotoxicity and excellent cell permeability, and was successfully used for detection of Zn2+ and Cu2+ in living HeLa cells based on two different mechanisms. We believe that the probe L may have many potential applications in environmental and biological research. PMID- 30308399 TI - Light induced DNA-functionalized TiO2 nanocrystalline interface: Theoretical and experimental insights towards DNA damage detection. AB - Owing to the emerging applications of DNA-functionalized TiO2 nanocrystals towards DNA damage detection, it is inevitable to understand the better chemistry as well as in-depth molecular interaction phenomena. Fundamentally, energy difference underlies the layer-by-layer construction, resulted in the increase of the interaction energy and thus, altering the electrochemical behavior. Herein, Density functional theory (DFT) calculations were performed using DMol3 and DFTB+ codes successfully to elucidate the structural, electronics, and vibrational properties of the layer-by-layer components composing ss-DNA/dopamine/TiO2/FTO. The obtained results are in good agreement with the experimental findings. The band gaps of FTO and TiO2 were computationally obtained at 3.335 and 3.136 eV which are comparable with the experimental data (3.500 eV; FTO and 3.200 eV; TiO2). Frontier orbital analysis is also considered to elucidate their electron transfer phenomena. Further, a 100 ns MD simulations are carried out using canonical ensemble embedded with COMPASS-Universal Forcefields generating useful thermodynamics parameters. Binding energies indicate increasing interaction energies for the layer-by-layer nanosystem, in agreement with the increasing diameter of electrochemical impedance spectroscopy (EIS) semicircle. Our results reveal the fundamental understanding of the DNA-functionalized TiO2 nanocrystals down to molecular and electronic level and further, paving a way of its application towards nanoelectrochemical DNA biosensors. PMID- 30308400 TI - The role of bladder volume in the success of external cephalic version. AB - OBJECTIVE: Numerous studies have evaluated the factors associated with ECV success. Yet, bladder volume has never been examined. We hypothesize that maternal bladder volume may affect ECV success rate. We aim to evaluate the role of maternal bladder volume during external cephalic version (ECV) on the procedure success rates. STUDY DESIGN: We reviewed prospective collected data of all patients who underwent ECV at our center during 2001-2012. The study group included 100 patients that underwent ECV with bladder volume below 400 ml. These patients were matched to 400 patients that underwent ECV with bladder volume equal or above 400 ml which composed the control group. Maternal and fetal characteristics and outcomes were compared. RESULTS: ECV was successfully performed in 80/100 (80.0%) of patients in the study group as compared to 257/400 (64.3%) in the control group (P = 0.002). Factors associated with ECV success were older age (P = 0.003), having prior delivery (P < 0.0001), higher amniotic fluid index (AFI) (P = 0.001) and placenta located in the posterior wall (P = 0.001). In a logistic regression analysis, bladder volume was found to be an independent predictor of ECV success Odds radio (OR) for ECV success 2.5 (CI 1.42 4.34). Posterior placenta and higher AFI were found to be an independent predictors of ECV success as well; OR 2.7 (CI 1.74-4.34) and OR 1.07 (CI 1.02 1.13) respectively. CONCLUSION: ECV is more successful in patient with bladder volume below 400 ml. Amniotic fluid volume and placental location were found as independent predictors of ECV outcome as well. PMID- 30308401 TI - Potential benefits of pregnancy on endometriosis symptoms. AB - OBJECTIVE: To explore the potential benefits of pregnancy on endometriosis symptoms. This is a retrospective study that has been conducted at Academic department and referral center for endometriosis. STUDY DESIGN: We included all conservative women who had a live birth after at least one surgery for endometriosis and who reported pre-pregnancy moderate to severe pelvic pain symptoms (at least one among dysmenorrhea, deep dyspareunia, non menstrual pelvic pain and dyschezia). Data were collected before pregnancy and two years after delivery. The main aim of the study was comparing endometriosis-related pain symptoms before and after pregnancy. Mental health and quality of life were also assessed to investigate the possible psychological benefits of pregnancy. RESULTS: One-hundred thirty- one women were identified. Forty- nine women (37%, 95% CI: 29-47%) had a clinically relevant recurrence of symptoms requiring medical or surgical treatment. Two years after delivery, 84% of women (95% CI 77 90%) reported at least one moderate-severe pain symptom. A statistically significant improvement was observed for HADS and SF-12 scores but not for FSFI. CONCLUSION: Women with endometriosis experiencesymptoms relief during and immediately after pregnancy. However, as for hormonal medical therapy, symptoms rapidly recur in the vast majority of cases. PMID- 30308402 TI - Sexual function after Bartholin gland abscess treatment: A randomized trial of the marsupialization and excision methods. AB - OBJECTIVE: To compare sexual function scores in patients who had marsupialization and gland excision procedures for the treatment of Bartholin gland abscesses. STUDY DESIGN: Patients who had bartholin abscess for the first time were randomized into marsupialization or gland excision methods. The primary outcome was to compare post surgical Female Sexual Function Index (FSFI) scores between the marsupialization group and the excision group. Secondary outcomes were to calculate the recurrence rates and other postoperative complications after the surgery. RESULTS: 195 women were evaluated for the treatment of Bartholin abscess and 154 of them were included in our study. The final analysis was carried out on 134 participants. There was no statistically significant difference among the study groups in terms of age, BMI, gravidity, parity, site of the abscess, and diameter of the abscess. The mean diameter of the abscess was not significantly different among patients who had dyspareunia (4 +/- 1.34 cm) and did not have dyspareunia (3.39 +/- 0.99 cm). No recurrence was observed in the gland excision group while 5 patients had a recurrence of the abscess in the marsupialization group. Dyspareunia after the procedure was more common in patients who underwent marsupialization (2.9% vs 15.1%, p = 0.01). The FSFI scores were <26.5 in both treatment groups. The total score was 24.76 +/- 4.32 in the excision group and was 22.33 +/- 5.15 in the marsupialization group. CONCLUSION: The excision of the gland for treating the Bartholin abscess resulted in less dyspareunia and recurrence when compared to the marsupialization procedure. Lower FSFI scores were reported in both groups, however, FSFI scores in the excision group were higher than in the marsupialization group. The excision of the Bartholin gland did not hamper sexual function. PMID- 30308403 TI - Assessment of trace metal contamination and ecological risk in the forest ecosystem of dexing mining area in northeast Jiangxi Province, China. AB - Samples of soil, earthworms, and tree roots from the forest ecosystem in the Dexing Pb/Zn mining area of Jiangxi Province were collected and the status of trace metal pollution analyzed to assess potential ecological risks. Chemometric and geographic information system methods were used to identify and describe the spatial distributions and the main contamination sources of trace metals. The order of potential ecological risks of trace metals in this area are as follows: cadmium (Cd) > arsenic (As) > copper (Cu) > nickel (Ni) > lead (Pb) > chromium (Cr) > zinc (Zn). Elemental spatial distribution maps showed the existence of zones heavily polluted by trace metals around the mining area. Earthworms and roots of three tree species were also heavily contaminated, with concentrations of trace metals in earthworms much higher than in previous studies. The potential ecological risk index and other soil quality indices indicated that soil had moderate to severe contamination and there were high ecological risks, with Cd making the greatest contribution. Multivariate statistical analyses showed that Cd, As, Cu, Pb, and Zn in soil came from a mining activity source, whereas Ni and Cr primarily originated from a natural source. PMID- 30308404 TI - Efficient saccharification of agave biomass using Aspergillus niger produced low cost enzyme cocktail with hyperactive pectinase activity. AB - To develop a cost-effective, time-saving and efficient saccharification system for converting biomass into mono-/oligo-saccharides for production of bioethanol or other biochemicals, a relatively low recalcitrant and widely available biomass Agave americana was selected as feedstock. During the investigation of efficient enzyme cocktail, pectinase, which usually is neglect for biomass saccharification, was confirmed that it dramatically improves the saccharification of agave biomass. A production-friendly fungal strain of Aspergillus niger Gyx086 was employed for low-cost enzyme cocktails production using wheat straw as substance. The enzyme cocktail which was with hyperactive pectinase activity of 6.29 +/- 0.42 U/ml could efficiently saccharify un pretreated agave biomasses. As a result, under a mild condition at 35 degrees C in less than 72 h, most of the polysaccharides were completely converted into reducing sugar. The low-cost, process-simplified, and efficient biotechnology should stimulate the development of agave as feedstock for green energy and bio based products production. PMID- 30308405 TI - Bioflocculation formation of microalgae-bacteria in enhancing microalgae harvesting and nutrient removal from wastewater effluent. AB - Microalgal bacterial flocs can be a promising approach for microalgae harvesting and wastewater treatment. The present study provides an insight on the bioflocs formation to enhance harvesting of Chlorella vulgaris and the removal of nutrients from seafood wastewater effluent. The results showed that the untreated seafood wastewater was the optimal culture medium for the cultivation and bioflocculation of C. vulgaris, with the flocculating activity of 92.0 +/- 6.0%, total suspended solids removal of 93.0 +/- 5.5%, and nutrient removal of 88.0 +/- 2.2%. The bioflocs collected under this optimal condition contained dry matter of 107.2 +/- 5.6 g.L-1 and chlorophyll content of 25.5 +/- 0.2 mg.L-1. The results were promising when compared to those obtained from the auto-flocculation process that induced by the addition of calcium chloride and pH adjustment. Additionally, bacteria present in the wastewater aided to promote the formation of bioflocculation process. PMID- 30308406 TI - Comparison of sulphide and nitrate removal from synthetic wastewater by pure and mixed cultures of nitrate-reducing, sulphide-oxidizing bacteria. AB - In this study, the activities of hydrogen sulphide (H2S) oxidation and nitrate (N NO3-) reduction by three pure and mixed strains of nitrate-reducing, sulphide oxidizing bacteria (NR-SOB) were determined. Batch experiments were performed at 35 degrees C and pH 7.0-8.0 with initial H2S concentrations of 650-900 ppmv and N-NO3- concentrations of ~120 mg/L. The strains MAL 1HM19, TPN 1HM1 and TPN 3HM1 were capable of removing 100% gas-phase H2S. The co-cultures showed better performance for H2S and N-NO3- removal. The mixed NR-SOB strains showed a higher H2S oxidation rate (143 +/- 18 ppmv/h), while the highest N-NO3- removal rate (5.5 +/- 0 and 5.1 +/- 0.6 N-NO3- mg/L.h) was obtained by a mixture of two NR-SOB strains. The 16S rDNA sequence analysis revealed that all strains belonged to the sub-class Alphaproteobacteria and are closely related to Paracoccus sp. (>99%). PMID- 30308407 TI - Investigation into role of CO2 in two-stage pyrolysis of spent coffee grounds. AB - As a way of improving process efficiency of pyrolysis of waste biomass, the effect of carbon dioxide (CO2) on pyrolysis of spent coffee grounds (SCGs) was examined using a two-stage pyrolysis reactor consisting of a region with increasing temperature and an isothermal region. It was experimentally validated that CO2 accelerates thermal cracking of organic compounds formed during the pyrolysis of SCGs. The expedited thermal cracking attributed to employing CO2 in pyrolysis of SCGs led to changing pyrolytic products in gas, liquid, and solid phases. The production of gaseous carbon monoxide was increased when using CO2 as the pyrolysis medium. In liquid pyrolytic products, the formation of phenolic compounds was hindered in the CO2-assited pyrolysis. Biochar morphology (solid pyrolytic product) was also changed with different pyrolysis environments. This study shows that CO2 can help improve applicability of pyrolysis of waste biomass by modifying three phase pyrolytic products in a two-stage pyrolyzer. PMID- 30308408 TI - 16s rRNA gene sequencing and radioisotopic analysis reveal the composition of ammonia acclimatized methanogenic consortia. AB - Different mesophilic and thermophilic methanogenic consortia were acclimatised and enriched to extreme total ammonia (9.0 and 5.0 g NH4+-N L-1, respectively) and free ammonia (1.0 and 1.4 g NH3-N L-1, respectively) levels in this study. [2 14C] acetate radioisotopic analyses showed the dominance of aceticlastic methanogenesis in all enriched consortia. According to 16S rRNA gene sequencing result, in mesophilic consortia, methylotrophic Methanomassiliicoccus luminyensis was predominant, followed by aceticlastic Methanosarcina soligelidi. A possible scenario explaining the dominance of M. luminyensis includes the use of methylamine produced by Tissierella spp. and biomass build-up by metabolizing acetate. Nevertheless, further studies are needed to pinpoint the exact metabolic pathway of M. luminyensis. In thermophilic consortia, aceticlastic Methanosarcina thermophila was the sole dominant methanogen. Overall, results derived from this study demonstrated the efficient biomethanation ability of these ammonia-tolerant methanogenic consortia, indicating a potential application of these consortia to solve ammonia toxicity problems in future full-scale reactors. PMID- 30308409 TI - Synthesis, toxicities and bio-activities of manganese complexes with CO and H2S dual donors. AB - A series of H2SCO dual-donors [Mn(CO)4CS2NR1R2] was synthesized, and evaluated from toxicity and bioactivity. The COH2S measuring test showed all the complexes not only released CO, but released H2S. The resulting data of cytotoxicity showed all the complexes had activities against the cell proliferation; among them, complexes 1, 2 and 7 displayed higher activities than the others, and their potencies were close to cis-platinum (DDP); whereas the precursors A1-A22 had almost no activities against all five tumor cell lines and W138 cell line proliferation. It is worth noting that complex 1 displayed the highest activity to MCF-7, complex 2 displayed the highest activity to HePG2, and complex 7 showed selectivity inhibition to both A549 and HeLa. The developmental toxicities of the complex were assessed using zebrafish embryos. The results showed complexes 1 and 2 had effect on the mortality and hatching rate of zebrafish embryos in dose dependent manner. They caused zebrafish malformations when they were over 10 MUM. Meanwhile, they displayed dose-dependent toxicities to larval zebrafish. In the test of bio-activities, complexes 1 and 2 had strong anti-inflammatory activities; they not only down-regulated the expression levels of iNOS and TNF alpha, up-regulated the expression of HO-1 and IL-10, but also up-regulated COX-2 levels. In contrast, the precursor compound (A1 or A2) displayed lower anti inflammatory activity than the corresponding complex, which suggests both the CO and H2S from the complex took synergistic effects in the process of anti inflammation. In addition, the complex showed antihypertensive effect and myocardial protection. This effect also possibly resulted from this synergistic effect. All these suggest the complexes have potential to be candidate medicines. PMID- 30308411 TI - Discovery of traditional Chinese medicine monomers and their synthetic intermediates, analogs or derivatives for battling P-gp-mediated multi-drug resistance. AB - P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) is a well-documented and predominant phenotype hampering patients' response to cancer chemotherapy. Although the past several decades have witnessed the development of three generations of P-gp inhibitors, they have not lived up to the high expectations owing to their drawbacks, as exemplified by limited efficacy, drug-drug interactions (DDIs) and severe untoward reactions. The discovery of artemisinin is a testimony of the importance of traditional Chinese medicine (TCM) in innovative drug discovery. In search for a new generation of chemo-sensitizers, P gp modulators originated from TCM have attracted increasing concern in the research community. In addition to identify TCM monomers or their synthetic intermediates as P-gp modulators, massive medicinal chemistry efforts have been made in discovering promising structural analogs and derivatives of them. Among these, compounds with dual role both as P-gp inhibitor and cytotoxic agent have continuously emerged. Hence, in this article, we will mainly enumerate the representative work conducted in the discovery of TCM monomers and their synthetic intermediates, analogs or derivatives as reversers of P-gp-mediated MDR. PMID- 30308412 TI - Algal toxicity of binary mixtures of zinc oxide nanoparticles and tetrabromobisphenol A: Roles of dissolved organic matters. AB - The present study investigated the impacts of dissolved organic matters (DOM) on joint toxicity involved in zinc oxide nanoparticles (ZnO NPs) and tetrabromobisphenol A (TBBPA) at relevant low-exposure concentrations (<1 mg/L). It was found that ZnO NPs in single and combined systems exhibited severe inhibition effects on a freshwater microalgae Scenedesmus obliquus. However, the presence of DOM slightly alleviated the growth inhibition toxicity induced by the binary mixtures of ZnO NPs and TBBPA. Ultrastructure analysis revealed that ZnO NPs caused structural damage to cells, including plasmolysis, membrane destruction, and the disruption of thylakoid in the chloroplast, regardless of the presence of coexisting substances. Oxidative stress biomarker quantitative analysis and in situ observations indicated that the massive accumulation of reactive oxygen species in the binary mixtures of ZnO NPs and TBBPA caused severe oxidative damage, but the presence of DOM significantly mitigated the damage. PMID- 30308410 TI - Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode. AB - Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl 2/Bcl-xL pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyridoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-xL targeting strategies. PMID- 30308413 TI - Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population. AB - Schizophrenia (SCZ) is a devastating mental disorder affecting approximately 1% of the worldwide population. Early studies have indicated that genetics plays an important role in the onset and development of SCZ. Accumulating evidence supports that SCZ is linked to abnormalities of synapse transmission and synaptic plasticity. Voltage-gated calcium channel (VGCC) subunits are critical for mediating intracellular Ca2 + influx and therefore are responsible for changing neuronal excitability and synaptic plasticity. To systematically investigate the role of calcium signaling genes in SCZ susceptibility, we conducted a case control study that included 2518 SCZ patients and 7521 healthy controls with Chinese Han ancestry. Thirty-seven VGCC genes, including 363 tag single nucleotide polymorphisms (SNPs), were examined. Our study replicated the following previously identified susceptible loci: CACNA1C, CACNB2, OPRM1, GRM7 and PDE4B. In addition, several novel loci including CACNA2D1, PDE4D, NALCN, and CACNA2D3 were also identified to be associated with SCZ in our Han Chinese sample. Combined with GTEx eQTL data, we have shown that CASQ2, ITGAV, and TMC2 can be also added into the prioritization list of SCZ susceptible genes. Two-way interaction analyses identified widespread gene-by-gene interactions among VGCC activity and complex-related genes for the susceptibility of SCZ. Further sequencing based studies are still needed to unravel potential contributions of schizophrenia risk from rare or low frequency variants of these candidate genes. PMID- 30308415 TI - High fat diet activates adult mouse lung stem cells and accelerates several aging induced effects. AB - High fat diet (HFD) decreases the lifespan of mice, and is a risk factor for several human diseases. Here, we investigated the effects of a HFD on lung epithelial and stem cells and its interaction with aging. Young and old mice were fed with either a standard diet (SD) or a HFD then their trachea and lung were examined for histological changes, inflammation, and mitochondrial function. Their stem cell function was examined using the in vitro organoid/colony forming efficiency (CFE) assay. Aging reduced the number of tracheal basal and alveolar type-2 (AT2) cells. HFD significantly increased the number of AT2 cells. Aging also caused a significant increase in lung inflammation, and HFD caused a similar increase, in young mice. Aging reduced mitochondrial mass and function, and increased reactive oxygen species. In young mice, HFD caused mitochondrial changes similar to the aging-induced changes. Organoid culture of tracheal and lung epithelial cells collected from both young and old HFD-fed mice showed higher CFE compared to SD-fed mice. Switching the HFD to low calorie/fat diet (LCD) efficiently reversed several of the HFD-induced effects. Thus, HFD induces several histological, inflammatory, and functional changes in the lung, and exacerbates the aging-induced lung inflammation and mitochondrial deterioration. LCD can reverse many of the HFD-induced effects. PMID- 30308416 TI - Use of dietary interventions for functional gastrointestinal disorders. AB - The role of food in the development of symptoms experienced within functional gastrointestinal disorders (FGIDs) is well recognised. This review aims to describe the evidence base for dietary interventions in the different functional esophageal, duodenal and bowel disorders. Randomised controlled trials are lacking for many of the FGIDs, with the exception of irritable bowel syndrome (IBS). Restricting rapidly fermentable, short-chain carbohydrates (FODMAPs) provides an evidence based dietary approach for the management of symptoms of IBS. Recent evidence shows the upper GI motility response varies between carbohydrates, which gives promise for the potential application of the low FODMAP diet in upper GI disorders. In addition to fine-tuning our FODMAP understanding, other observational data and smaller sized studies create an exciting and optimistic future for dietary management of all FGIDs. PMID- 30308414 TI - Safety and efficacy of switching from branded to generic imatinib in chronic phase chronic myeloid leukemia patients treated in Italy. AB - The use of generic drugs after patent expiration of their originators is a relative novelty in the treatment of chronic cancer patients in Western countries. In this observational study we analyzed a cohort of 294 Italian chronic phase chronic myeloid leukemia patients treated frontline with branded imatinib (Glivec(r)) for at least 6 months and then uniformly switched to generic imatinib upon requirement of health authorities in early 2017. Median age at diagnosis was 57 years (range 19-87). Sokal risk was low/intermediate/high in 55%, 32% and 8% of cases, respectively. Median duration of branded imatinib treatment was 7.4 years (range 0.5-16.7). At a median follow-up of 7.5 months after switch to generic imatinib, 17% of patients reported new or worsening side effects, but grade 3-4 non-hematological adverse events were rare. Six patients switched back to branded imatinib, with improvement in the side effect profile, and 4 pts moved to bosutinib or nilotinib for resistance/intolerance. The majority of patients were in major (26%) or deep molecular response (66%) at the time of switch. Molecular responses remained stable, improved or worsened in 61%, 25% and 14% of patients, respectively. We conclude that switch to generic imatinib for patients who have been receiving branded imatinib appears to be effective and safe. Molecular responses may continue to improve over time. Some patients experienced new or worsened side effects but less than 5% of the whole cohort needed to switch back to branded imatinib or move to other treatments. Savings were around 3 million Euros. PMID- 30308417 TI - Clinical metabolomics analysis of therapeutic mechanism of Tongmai Yangxin Pill on stable angina. AB - Tongmai Yangxin Pill (TMYX) is a traditional Chinese medicine for the treatment of angina and arrhythmia. Although its clinical application is extensive, and the curative effect is significant, little information is available on the molecular biological basis and therapeutic mechanism of TMYX for the treatment of stable angina. In this study, we analyzed serum samples of clinical patients collected from seven different clinical units in China after oral administration of TMYX using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Multiple statistical analysis including principal component analysis (PCA) and partial least square discrimination analysis (PLS DA), were used to examine metabolite profile changes in serum samples. After TMYX treatment, 10 biomarkers were reversed to the normal conditions. The above biomarkers were mainly involved in energy metabolism, amino acid metabolism, oxidative stress and inflammation. These results suggested that TMYX exerted therapeutic effects by improving myocardial energy supply disorder and amino acid dysfunction, and attenuating oxidative stress and inflammation. The present study, as the first multicenter clinical study which reveals the molecular biological basis and therapeutic mechanism of TMYX on stable angina, can provide objective indicators for efficacy evaluation of TMYX on stable angina. And it also lays a foundation for the use of TMYX clinically. PMID- 30308419 TI - Development of an aptamer-based field effect transistor biosensor for quantitative detection of Plasmodium falciparum glutamate dehydrogenase in serum samples. AB - There has been a continuous strive to develop portable, stable, sensitive and low cost detection system for malaria to meet the demand of effective screening actions in developing countries where the disease is most endemic. Herein, we report an aptamer-based field effect transistor (aptaFET) biosensor, developed by using an extended gate field effect transistor with inter-digitated gold microelectrodes (IDuE) for the detection of the malaria biomarker Plasmodium falciparum glutamate dehydrogenase (PfGDH) in serum samples. A 90 mer long ssDNA aptamer (NG3) selective to PfGDH was used in the aptaFET to capture the target protein. The intrinsic surface net charge of the captured protein led to change in gate potential of the aptaFET device, which could be correlated to the concentration of the protein. This biosensor exhibited a sensitive response in broad dynamic range of 100 fM -10 nM with limits of detection of 16.7 pM and 48.6 pM in spiked buffer and serum samples, respectively. The high selectivity of the biosensor for PfGDH was verified by testing relevant analogous human and parasitic proteins on the device. Overall, the results validated the application potential of the developed aptaFET for diagnosis of both symptomatic and asymptomatic malaria. PMID- 30308418 TI - Preparation of magnetic molecularly imprinted polymers with double functional monomers for the extraction and detection of chloramphenicol in food. AB - In this study, an efficient, selective, and simple analytical method for the extraction of chloramphenicol (CAP) from food using magnetic molecularly imprinted polymers (MMIPs) as the solid-phase extraction (SPE) sorbent was successfully developed. MMIPs with varying ratios of methacrylic acid to acrylamide were prepared by suspension polymerization on the surface of double bond-modified Fe3O4 magnetic nanoparticles. Further, these MMIPs were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy, as well as using a vibrating sample magnetometer. Furthermore, the adsorption capacities of MMIPs and MNIPs were investigated by binding experiments. Methodology evaluation for the detection of CAP from food was carried out using MMIPs as the SPE sorbent. By using an external magnetic field, MMIPs were separated by a simple and rapid method. The diameter of the so obtained MMIPs, exhibiting good monodispersity, was 400-700 nm. The MMIPs exhibited the maximum apparent adsorption capacity of up to 42.60 mg g-1 with good selectivity. For the detection of food samples, the linear response range was 0.02-10.00 mg L-1, with a detection limit of 10 MUg L-1, and intra- and inter day stabilities ranged from 1.34% to 1.89% and from 1.76% to 2.77%, respectively, with good recoveries (95.31%-106.89%) and satisfactory relative standard deviations (1.21%-2.60%). PMID- 30308420 TI - Determination of urea with special emphasis on biosensors: A review. AB - Urea is the major end product of nitrogen metabolism in humans, which is eliminated from the body mainly by the kidneys through urine but is also secreted in body fluids such as blood and saliva. Its level in urine ranges from 7 to 20 mg/dL, which drastically rises under patho-physiological conditions thus providing key information of renal function and diagnosis of various kidney and liver disorders. Increase in urea levels in blood, also referred to as azotemia or uremia. The chronic kidney disease (CKD) or end stage renal disease (ESRD) is generally caused due to the progressive loss of kidney function. Hence, there is an urgent need of determination of urea in biological fluids to diagnose these diseases at their early stage. Among the various methods available for detection of urea, most are complicated and require time-consuming sample pre-treatment, expensive instrumental set-up and trained persons to operate, specifically for chromatographic methods. The biosensing methods overcome these drawbacks, as these are simple, fast, specific and highly sensitive and can also be applied for detection of urea in vivo. This review presents the principles of various analytical methods for determination of urea with special emphasis on biosensors. The use of various nanostructures and electrochemical microfluidic paper based analytical device (EMUPAD) are suggested for further development of urea biosensors. PMID- 30308421 TI - Two-dimensional oriented growth of Zn-MOF-on-Zr-MOF architecture: A highly sensitive and selective platform for detecting cancer markers. AB - Fabricating novel bimetallic metal organic framework (MOF) architectures and exploiting them as aptasensor scaffolds for detecting diverse analytes, especially cancer markers, have aroused widespread research attention. Herein, we report a novel strategy for obtaining ZnZr bimetallic MOFs via the MOF-on-MOF method and exploit them as an aptasensor platform for detecting the cancer marker protein tyrosine kinase-7 (PTK7). Basic characterizations reveal that the chemical structure, crystalline properties, and surface functionality of bimetallic ZnZr-MOFs can be modulated by changing the order of addition of metal precursors and organic ligands. The Zn-MOF-on-Zr-MOF hybrid exhibits a hierarchically decussated foliace, whereas Zr-MOF-on-Zn-MOF demonstrates a multilayered nanosheet structure. The electrochemical results reveal that Zr-MOF facilitates aptamer strand immobilization, whereas the Zn-MOF stabilizes the G quadruplex formed by aptamer strands and PTK7. The Zn-MOF-on-Zr-MOF-based aptasensor outperforms the Zr-MOF-on-Zn-MOF-based one, providing ultralow detection limits of 0.84 and 0.66 pg mL-1, as obtained by electrochemical impedance spectroscopy and differential pulse voltammetry, respectively, within the PTK7 concentration range of 1.0 pg mL-1 to 1.0 ng mL-1. The proposed Zn-MOF on-Zr-MOF-based aptasensor exhibits high selectivity in the presence of various interferences, good stability, reproducibility, and acceptability in human serum. The proposed strategy provides a new approach for fabricating ultrasensitive and selective bimetallic MOFs-based aptasensors and contributes to efforts to broaden their applications in early cancer diagnosis. PMID- 30308423 TI - Stone in the distal jejunum presenting as small bowel obstruction: A case report. AB - INTRODUCTION: Gallstone ileus is a rare presentation of cholelithiasis accounting for around 4% of cases of small bowel obstruction under 65 years of age but rises to 25% in those more than 65 years of age. Most gall stones, if impact in the bowel, are seen to lodge at the ileocecal valve as this is the most narrow part of the bowel. PRESENTATION OF CASE: We present a case of small intestinal obstruction because of a gallstone stuck in the distal jejunum. Patient was explored and one-stage surgery was done i.e. cholecystectomy, enterotomy and stone retrieval, and fistula repair. Our patient had uneventful postoperative recovery and was discharged after a week. DISCUSSION: Gallstone ileus is a rare entity presenting a significant diagnostic challenge to surgeons due to lack of specific findings. Moreover, the surgical management options to be adopted are diverse and depend upon the condition of the patient. Stable patients can be managed with two-stage procedures i.e. enterotomy and stone retrieval earlier with cholecystectomy in an elective setting. Our patient was managed with one stage procedure i.e. cholecystectomy was done in the same setting and our patient did well. CONCLUSION: Gallstone ileus needs to be kept in the differential diagnosis list of intestinal obstruction in middle aged patients even in the absence of history of gallstones as this may be the first presentation of gallstone disease. PMID- 30308422 TI - A novel ejection protein from bacteriophage 80alpha that promotes lytic growth. AB - Many staphylococcal bacteriophages encode a minor capsid protein between the genes for the portal and scaffolding proteins. In Staphylococcus aureus bacteriophage 80alpha, this protein, called gp44, is essential for the production of viable phage, but dispensable for the phage-mediated mobilization of S. aureus pathogenicity islands. We show here that gp44 is not required for capsid assembly, DNA packaging or ejection of the DNA, nor for generalized transduction of plasmids. An 80alpha Delta44 mutant could be complemented in trans by gp44 expressed from a plasmid, indicating that gp44 plays a post-injection role in the host. Our results show that gp44 is an ejection (pilot) protein that is involved in deciding the fate of the phage DNA after injection. Our data are consistent with a model in which gp44 acts as a regulatory protein that promotes progression to the lytic cycle. PMID- 30308424 TI - Successful treatment for severe pancreatitis with colonic perforation using video assisted retroperitoneal debridement: A case report. AB - INTRODUCTION: Colorectal complications including penetration and perforation in acute pancreatitis often become severe and fatal. Effective drainage is pivotal for successful treatment. We present a case of large retroperitoneal abscess with colonic necrotizing perforation due to severe acute pancreatitis treated with video-assisted retroperitoneal debridement (VARD) in a step-up approach. PRESENTATION OF CASE: A 31-year-old man was admitted to a general hospital with a diagnosis of severe acute pancreatitis. Ten days after onset, he was referred to our hospital for more intensive treatment. On day 16, he experienced melena and shock, and embolization of the three straight arteries of the descending colon was performed. On day 30, percutaneous drainage was performed for large retroperitoneal abscess. On day 36, ileostomy was performed because the drained pus from the retroperitoneal abscess became feces-like. On day 58, VARD was performed to treat the refractory retroperitoneal abscesses causing high systemic inflammation due to insufficient drainage. On day 85, fluoroscopic examination showed disappearance of the abscess cavity. He was transferred to the previous hospital on day 89. DISCUSSION: Colonic perforation due to severe acute pancreatitis often causes sepsis and fatal condition of patients, and drainage of the retroperitoneal abscesses via laparotomy is thought to be highly invasive and risky. VARD enables radical necrosectomy and drainage less invasively. CONCLUSIONS: VARD enabled less invasive treatment for patients with large retroperitoneal abscess due to colonic necrotizing perforation in severe pancreatitis. PMID- 30308425 TI - A case of obstructive jaundice due to early carcinoma of the cystic duct protruding into the common bile duct. AB - INTRODUCTION: Cystic duct carcinoma is a rare disease, and only 33 cases reported worldwide have completely fulfilled the criteria first established by Farrar in 1951. Here we describe an extremely rare case of early cystic duct carcinoma that fulfilled the Farrar criteria, the papillary tumour protruding into the common bile duct, leading to obstructive jaundice. CASE PRESENTATION: A 76-year-old man visited a clinic with icteric conjunctivae, and was referred to our hospital for investigation of suspected obstructive jaundice. He was initially diagnosed as having a distal bile duct carcinoma on the basis of ultrasonography (US), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiography (MRC), and underwent pancreatoduodenectomy with regional lymphadenectomy. Macroscopic examination showed that the stalk of the papillary tumour originated from the cystic duct, and that the protruding lesion was 50 mm in size. Histopathological examination revealed the tumour to be a papillary adenocarcinoma confined within the fibromuscular layer, with no evidence of lymph node metastasis. Therefore, the final diagnosis was early cystic duct carcinoma. CONCLUSION: To our knowledge, this is the first case report of obstructive jaundice due to early carcinoma of the cystic duct protruding into the bile duct, with characteristics fulfilling the Farrar criteria. PMID- 30308426 TI - Long-term seizure outcomes in patients with drug resistant epilepsy. AB - PURPOSE: Despite the availability of a broad range of treatments for epilepsy, a significant proportion of patients have ongoing seizures. This study aims to characterize the drug resistant population and to report long-term outcomes of patients undergoing different types of pharmacological and surgical treatment. METHODS: Adult patients with drug resistant epilepsy (DRE) were identified from a largely retrospective database of 900 consecutive patients with epilepsy, recruited from two reference centers for DRE in Belgium. We report treatment trajectories and long-term seizure outcomes in the different treatment groups. RESULTS: 640 patients had DRE. 249 (38.9%) underwent presurgical assessment, followed by surgical treatment in 197 (30.8%), resulting in seizure freedom in 86 (13.4%). 443 patients (69.2%) were treated only with further AED trials, of which 163 (25.5%) became seizure free. In the 391 patients with ongoing seizures (61.1%), mean age was 43.2 years, mean disease duration 23 years and mean number of AED trials 6.9. 291 (74.4%) had tonic-clonic seizures, and 43 (11.0%) had one or more episodes of status epilepticus. Patients with hippocampal sclerosis were significantly more likely to be seizure free, while patients with malformation of cortical development and those with temporal lobe epilepsy of unknown etiology were more likely to have ongoing seizures. CONCLUSION: Our findings demonstrate that - even with adequate access to surgical treatment and further AED trials - 61.1% of patients with DRE had ongoing seizures. This illustrates that there is a scope for ongoing development of novel treatments for DRE. PMID- 30308427 TI - Efficacy of levetiracetam for reducing rolandic discharges in comparison with carbamazepine and valproate sodium in rolandic epilepsy. AB - PURPOSE: The main purpose of this study was to compare the efficacy of levetiracetam (LEV) with the older antiepileptic drugs (AEDs) for preventing atypical evolution in children with Rolandic epilepsy (RE). Accordingly, the present study compared the efficacy of older AEDs (carbamazepine (CBZ) and valproate sodium (VPA)) with LEV in reducing rolandic discharges (RDs) on interictal electroencephalogram (EEG) in children with RE. METHODS: Patients in this heterogenous study were subdivided into CBZ, VPA and LEV groups in accordance with the initial monotherapy. The CBZ and VPA groups were studied retrospectively, but the LEV group was studied prospectively. Appearances of discharges were counted and these rates were computed. In comparison with the baseline RD frequency, EEG response to AED treatment was classified such as complete disappearance and response (>=50% reduction in RD frequency). The time taken to attain complete disappearance or response in EEG responders was assessed for each AED treatment group. RESULTS: Responders comprised 10 (11.2%) of the 89 patients treated with CBZ, 41 (56.2%) of the 73 patients with VPA, and 25 (71.4%) of the 35 patients with LEV. Mean interval to achievement of EEG response in the CBZ, VPA, and LEV groups were 36.3, 23.1, and 14.7 months, respectively. EEG response was achieved significantly more rapidly with LEV than with CBZ (p < 0.001) or VPA (p < 0.005). Seizure control was not significantly different in all 3 investigated drugs. CONCLUSIONS: LEV seems to be superior to CBZ and VPA in its ability to suppress RDs in children with RE. PMID- 30308428 TI - A randomized, double-blind, double-dummy, multicenter trial comparing the efficacy and safety of extended- and immediate-release levetiracetam in people with partial epilepsy. AB - PURPOSE: The aim of this trial was to compare the efficacy and safety of two formulations of levetiracetam in people with partial epilepsy over a 12-week treatment period. METHODS: We performed a randomized, paralleled, and multicenter trial that consisted of a 4-week single-blind placebo run-in, followed by a 12 week double-blind, double-dummy treatment phase to compare the efficacy and safety of levetiracetam extended-release (LEV-ER) and immediate-release (LEV-IR) tablets as an adjunctive treatment in adult patients with uncontrolled epilepsy. RESULTS: The median partial-onset seizure (POS) frequency per week (min-max) was 0.3 (0.0, 17.4; 95% confidence interval [95% CI] 1.3, 4.8) in the LEV-ER group and 0.3 (0.0, 31.4; 95% CI - 0.1, 4.3) in the LEV-IR group. No serious adverse events occurred during the trial period. Both groups had the same responder rate (58.6%), while a higher rate of seizure freedom over the treatment period was noted in the LEV-ER group compared with the LEV-IR group (27.6% vs. 13.8%, respectively). The European Quality of Life-5 Dimensions scores significantly increased in the LEV-ER-treated group, in contrast to the scores in the LEV-IR group, which decreased (7.2 vs. - 1.5, p = 0.03). CONCLUSION: These results suggest that LEV-ER is equivalent to LEV-IR in reducing the frequency of POS and has a similar tolerability as LEV-IR as an add-on therapy. In addition, LEV-ER treatment improved the health-related quality of life of people with uncontrolled partial epilepsy. PMID- 30308429 TI - Pretreatment quantitative 18F-FDG PET/CT parameters as a predictor of survival in adenoid cystic carcinoma of the salivary glands. AB - PURPOSE: The aim of this study was to determine the unique prognostic value of quantitative 18F-FDG PET/CT parameters to assess progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with salivary gland adenoid cystic carcinoma (ACC). METHODS: We performed a retrospective study including 23 patients (15 men, 8 women; median age, 58 years; range, 21-91 years) with salivary gland ACC between January 2009 and October 2017 who underwent 18F-FDG PET/CT scan prior to treatment. Maximum, mean, peak, tumor to-mediastinal blood pool and tumor-to-liver standardized uptake values (SUVmax, SUVmean, SUVpeak, SUVratio[med] and SUVratio[liver]), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from 18F-FDG PET/CT. The prognostic value of quantitative 18F-FDG PET/CT parameters and other clinicopathological variables were evaluated utilizing the Cox proportional regression analysis. RESULTS: The 3-year and 5-year OS for all the patients were 90.9%, and 62.3%, respectively. Log rank test determined that the SUVratio[med], SUVratio[liver], MTV and TLG were predictive factors of DMFS, PFS, and OS (p < 0.05), furthermore, SUVmax, minor salivary gland tumors and DM at initial diagnosis (M1 stage) were predictor for PFS; M1 stage and overall stage 3-4 predicted DMFS (all p < 0.05). Cox regression analyses confirmed that the higher SUVratio[med], SUVratio[liver], MTV, and TLG values predicted DMFS, PFS and OS independently, whereas SUVmax was an independent predictor of only PFS (p < 0.05). CONCLUSIONS: The pretreatment metabolic 18F-FDG PET/CT parameters may reflect tumor aggressiveness in patients with salivary gland ACC and may potentially be utilized as a prognostic biomarker. PMID- 30308430 TI - Diagnostic performance of quantitative diffusion tensor imaging for the differentiation of breast lesions at 3 T MRI. AB - BACKGROUND: Conventional breast magnetic resonance imaging (MRI), including dynamic contrast-enhanced MR mammography, may lead to ambiguous diagnosis and unnecessary biopsies. PURPOSE: To investigate the contribution of quantitative diffusion tensor imaging (DTI) in the discrimination between benign and malignant breast lesions at 3 T MRI. MATERIAL AND METHODS: The study included a total of 86 lesions (44 benign and 42 malignant) in 58 women (34 with malignant lesions, 23 with benign lesions and 1 with both types of lesions). All patients were examined on a 3 T MRI scanner. Fractional Anisotropy (FA), Mean Diffusivity (MD), Apparent Diffusion Coefficient (ADC), as well as eigenvalues (lambda1, lambda2, lambda3) were calculated and compared between benign and malignant lesions using two different software packages (GE Functool and ExploreDTI). RESULTS: Malignant lesions exhibited significantly lower ADC values compared to benign ones (ADCmal = 1.06 * 10-3 mm2/s, ADCben = 1.54 * 10-3 mm2/s, p-value < 0.0001). FA measurements in carcinomas indicated slightly higher values than those in benign lesions (FAmal = 0.20 +/- 0.07, FAben = 0.15 +/- 0.05, p-value = 0.0003). Eigenvalues lambda1, lambda2, lambda3, showed significantly lower values in malignant tumors compared to benign lesions and normal breast tissue. ROC curve analysis of ADC and DTI metrics demonstrated that ADC provides high diagnostic performance (AUC = 0.944) while, MD and lambda1 showed best discriminative results (AUC = 0.906) for the differentiation of malignant and benign lesions in contrast to other DTI parameters. CONCLUSION: The addition of eigenvalue analysis improves DTI's ability to differentiate between benign and malignant breast lesions. PMID- 30308431 TI - Avulsion fracture of the medial collateral ligament association with Segond fracture. AB - The Segond fracture is a tibial avulsion injury of the insertion of the middle third of the lateral capsular ligament that is typically associated with anterior cruciate ligament and meniscal tears. The classically assigned mechanism of injury is a combination of internal rotation and varus stress. We report two cases of Segond fractures that presented with a variant pattern including osseous avulsion injuries of the medial collateral ligament at the femoral origin, anterior cruciate ligament tear, and pivot shift-type osseous contusion pattern, suggesting an alternative mechanism of injury that includes dominant valgus stress and external rotation components. Awareness of this pattern may aid radiologists, surgeons, and sport medicine physicians in the accurate diagnosis of this injury complex and initiation of appropriate treatment in a timely fashion. PMID- 30308432 TI - Ultrasound elastography in neuromuscular and movement disorders. AB - The purpose of this review is to summarize main pathophysiology of neuromuscular and movement disorders, present published evidence of ultrasound elastography in the assessment of common neuromuscular and movement disorders, and discuss what role ultrasound elastography modality can play in respect to neuromuscular and movement disorders. PMID- 30308433 TI - Potential advantages of CD1-restricted T cell immunotherapy in cancer. AB - Adoptive cell therapy (ACT) using tumor-specific "conventional" MHC-restricted T cells obtained from tumor-infiltrating lymphocytes, or derived ex vivo by either antigen-specific expansion or genetic engineering of polyclonal T cell populations, shows great promise for cancer treatment. However, the wide applicability of this therapy finds limits in the high polymorphism of MHC molecules that restricts the use in the autologous context. CD1 antigen presenting molecules are nonpolymorphic and specialized for lipid antigen presentation to T cells. They are often expressed on malignant cells and, therefore, may represent an attractive target for ACT. We provide a brief overview of the CD1-resticted T cell response in tumor immunity and we discuss the pros and cons of ACT approaches based on unconventional CD1-restricted T cells. PMID- 30308435 TI - Establishing the waist as the better location for attaching a single accelerometer to estimate center of pressure trajectories. AB - BACKGROUND: In this study, we seek to replace conventional force platforms with a single accelerometer for measuring Center of Pressure trajectories, in order to achieve portability and convenience without sacrificing accuracy. METHODS: We measure the actual Anterior/Posterior and Medial/Lateral Center of Pressure trajectories of ten healthy young subjects using a force platform, and compare them with estimated measurements derived from accelerometer signals collected from three body locations (upper trunk, waist, and lower thigh) using three machine learning algorithms (Neural Network, Genetic Algorithm, and Adaptive Network-based Fuzzy Inference System). Error ratios and correlation coefficients corresponding to body locations were compared via one-way repeated-measures ANOVA. The ratios and coefficients corresponding to the three algorithms were also compared using the same approach. FINDINGS: Estimated Anterior/Posterior trajectories indicated that measurements collected from the waist provided the lowest margins of error (8.1-8.4% v. 12.1-13.4%, P <= .001) and the highest correlation (.95 v. .82-.86, P <= .032). Estimated Medial/Lateral trajectories indicated that measurements collected from both the waist and thigh, as compared to the upper trunk, provided lower margins of error (7.0-7.3% v. 8.5-10.8%). In general, the waist is the better accelerometer attachment location. INTERPRETATION: The results of our study corroborate our deduction that the high correlation between Center of Pressure and body's Center of Mass provides the rationale to place the single accelerometer close to the waist for Center of Pressure estimations. This study also supports the feasibility of using one single accelerometer programmed with algorithms for similar clinical applications. PMID- 30308434 TI - Modeling a rotator cuff tear: Individualized shoulder muscle forces influence glenohumeral joint contact force predictions. AB - BACKGROUND: Rotator cuff tears in older individuals may result in decreased muscle forces and changes to force distribution across the glenohumeral joint. Reduced muscle forces may impact functional task performance, altering glenohumeral joint contact forces, potentially contributing to instability or joint damage risk. Our objective was to evaluate the influence of rotator cuff muscle force distribution on glenohumeral joint contact force during functional pull and axilla wash tasks using individualized computational models. METHODS: Fourteen older individuals (age 63.4 yrs. (SD 1.8)) were studied; 7 with rotator cuff tear, 7 matched controls. Muscle volume measurements were used to scale a nominal upper limb model's muscle forces to develop individualized models and perform dynamic simulations of movement tracking participant-derived kinematics. Peak resultant glenohumeral joint contact force, and direction and magnitude of force components were compared between groups using ANCOVA. FINDINGS: Results show individualized muscle force distributions for rotator cuff tear participants had reduced peak resultant joint contact force for pull and axilla wash (P <= 0.0456), with smaller compressive components of peak resultant force for pull (P = 0.0248). Peak forces for pull were within the glenoid. For axilla wash, peak joint contact was directed near/outside the glenoid rim for three participants; predictions required individualized muscle forces since nominal muscle forces did not affect joint force location. INTERPRETATION: Older adults with rotator cuff tear had smaller peak resultant and compressive forces, possibly indicating increased instability or secondary joint damage risk. Outcomes suggest predicted joint contact force following rotator cuff tear is sensitive to including individualized muscle forces. PMID- 30308436 TI - Role of rare earth elements in methanol oxidation. AB - For decades rare earth elements (or lanthanides) were considered not to be involved in biological processes, until their discovery in the active site of the XoxF-type methanol dehydrogenase of the methanotrophic bacterium Methylacidiphilum fumariolicum SolV. Follow-up studies revealed the presence of lanthanides in other pyrroloquinoline quinone-containing enzymes involved in alcohol metabolism. This review discusses the biochemistry of the lanthanide dependent enzymes and the ability of these metals of influencing the gene expression and the type of methanol dehydrogenase used by microorganisms. Furthermore, it highlights novel insights on the uptake mechanism of rare earth elements into bacterial cells. PMID- 30308437 TI - Trending topics and open questions in anaerobic ammonium oxidation. AB - Anaerobic ammonium-oxidizing (anammox) bacteria are major players in the biological nitrogen cycle and can be applied in wastewater treatment for the removal of nitrogen compounds. Anammox bacteria anaerobically convert the substrates ammonium and nitrite into dinitrogen gas in a specialized intracellular compartment called the anammoxosome. The anammox cell biology, physiology and biochemistry is of exceptional interest but also difficult to study because of the lack of a pure culture, standard cultivation techniques and genetic tools. Here we review the most important recent developments regarding the cell structure - anammoxosome and cell envelope - and anammox energy metabolism - nitrite reductase, hydrazine synthase and energy conversion - including the trending topics electro-anammox, extracellular polymeric substances and ladderane lipids. PMID- 30308438 TI - Diagnostically relevant updates to the 2017 WHO classification of lymphoid neoplasms. AB - The recent 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues contains a number of updates under the category of lymphoid neoplasms. These changes include introduction of new entities, amended classification or terminology, and addition of newly discovered diagnostic and molecular features. In this review, we perform a focused, concise summary of selected lymphoid neoplasms and discuss changes in their classification. Rather than a comprehensive overview, we place specific emphasis on important and diagnostically relevant aspects of each entity that are novel or different from the previous WHO iteration and bring the practicing pathologist quickly up to speed with the updated classification. PMID- 30308439 TI - Comparing the optical and mechanical properties of PEKK polymer when CAD/CAM milled and pressed using a ceramic pressing furnace. AB - The aim was to optimise the hot pressing parameters for processing PEKK polymer using a standard ceramic pressing furnace and compare the optical and mechanical properties of pressed samples to PEKK samples produced via CAD/CAM milling. The samples were compared using a spectrophotometer to determine the CIE L*a*b* colour values and DeltaE colour difference. A universal testing machine was used for biaxial flexural strength testing and Vickers Hardness machine for measuring the hardness. It was concluded that hot pressed and milled PEKK samples showed no significant difference in the colour values, biaxial flexural strength or hardness. PMID- 30308440 TI - Berberine alleviates endothelial glycocalyx degradation and promotes glycocalyx restoration in LPS-induced ARDS. AB - In the pathogenesis of acute respiratory distress syndrome (ARDS), an increase in vascular endothelial permeability may trigger pulmonary edema and ultimately lead to respiratory failure. Endothelial glycocalyx damage is an important factor that causes an increase in vascular endothelial permeability. Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis, a plant used in traditional Chinese medicine that exerts multiple pharmacological effects. In this study, pretreatment with BBR inhibited the increase in vascular endothelial permeability in mice with lipopolysaccharide (LPS)-induced ARDS. BBR pretreatment inhibited the shedding of syndecan-1 (SDC-1) and heparan sulfate (HS), which are important components of the endothelial glycocalyx that lessen endothelial glycocalyx damage. BBR further significantly inhibited increases in important endothelial glycocalyx damage factors, including reactive oxygen species (ROS), heparanase (HPA), and matrix metalloproteinase 9 (MMP9) in LPS-induced ARDS mice and in LPS-stimulated human umbilical vein endothelial cells. BBR pretreatment also decreased the production of pro-inflammatory cytokines TNF-alpha, IL-1beta, IL-6, and inhibited NF-kappaB signaling pathway activation in LPS-induced ARDS. In addition, BBR promoted the recovery of SDC-1 and HS content in injured endothelial glycocalyx after LPS treatment and accelerated its restoration. This is the first report of BBR maintaining the integrity of endothelial glycocalyx. These results provide a new theoretical basis for the use of BBR in the treatment of ARDS and other diseases related to endothelial glycocalyx damage. PMID- 30308441 TI - Coping related variables, cardiac vagal activity and working memory performance under pressure. AB - The aim of this study was to assess the predictive role of coping related variables (trait emotional intelligence and reinvestment, challenge and threat appraisals and cardiac vagal activity) on cardiac vagal activity and working memory under low pressure (LP) and high pressure (HP) conditions. Participants (n = 49) completed trait questionnaires, the Decision Specific Reinvestment Scale, the Movement Specific Reinvestment Scale and Trait Emotional Intelligence Questionnaire. They realized the automated span task, which tests working memory, under counterbalanced LP and HP conditions. Cardiac vagal activity measurements were taken at rest, task and post task for 5 min, along with self-reported ratings of stress. Upon completion of the task, self-report measures of motivation, stress appraisal, attention and perceived pressure were completed. Current findings suggest cardiac vagal activity at rest can predict cardiac vagal activity under pressure, decision reinvestment influences cardiac vagal activity in cognitive tasks under LP and working memory performance is predicted by task cardiac vagal activity in HP only. These results show the importance of combining both subjective and objective psychophysiological variables in performance prediction and strengthen the need for this approach to be adopted across samples. PMID- 30308442 TI - The influence of visual cues on temporal anticipation and movement synchronization with musical sequences. AB - Music presents a complex case of movement timing, as one to several dozen musicians coordinate their actions at short time-scales. This process is often directed by a conductor who provides a visual beat and guides the ensemble through tempo changes. The current experiment tested the ways in which audio motor coordination is influenced by visual cues from a conductor's gestures, and how this influence might manifest in two ways: movements used to produce sound related to the music, and movements of the upper-body that do not directly affect sound output. We designed a virtual conductor that was derived from morphed motion capture recordings of human conductors. Two groups of participants (29 musicians and 28 nonmusicians, to test the generalizability of visuo-motor synchronization to non-experts) were shown the virtual conductor, a simple visual metronome, or a stationary circle while completing a drumming task that required synchronization with tempo-changing musical sequences. We measured asynchronies and temporal anticipation in the drumming task, as well as participants' upper body movement using motion capture. Drumming results suggest the conductor generally improves synchronization by facilitating anticipation of tempo changes in the music. Motion capture results showed that the conductor visual cue elicited more structured head movements than the other two visual cues for nonmusicians only. Multiple regression analysis showed that the nonmusicians with less rigid movement and high anticipation had lower asynchronies. Thus, the visual cues provided by a conductor might serve to facilitate temporal anticipation and more synchronous movement in the general population, but might also cause rigid ancillary movements in some non-experts. PMID- 30308443 TI - Solar photocatalytic reclamation of agro-waste water polluted with twelve pesticides for agricultural reuse. AB - This study aims to demonstrate a technically feasible alternative to remove pesticide residues from agro-waste water produced in farms from remnants in containers and treatment tanks, rinse in tanks after treatments, and cleaning of machines and equipment. For this, the photocatalyzed degradation of 12 pesticides commonly used on vegetables, vines, citrus and fruit crops was investigated in aqueous suspensions of TiO2 in tandem with Na2S2O8 at pilot plant scale under natural sunlight in Murcia (SE of Spain) during summer and winter seasons. Previously, preliminary experiments were carried out at laboratory scale using a photoreactor to optimize the photocatalyst (200 mg L-1) and oxidant (250 mg L-1) concentrations on the rate constants of the studied pesticides. The photodegradation of all pesticides can be modelled assuming a pseudo-first-order kinetics. The time needed for disappearance of 90% (DT90) of the studied pesticides, was lower than 4 h in summer in all cases with the exception of cyproconazole (4.9 h), while, cyproconazole (8.9 h), metalaxil (6.1 h) and propyzamide (7.9 h) showed DT90 higher than 6 h in winter. The reaction rate was enhanced 3-fold in summer season, which is directly correlated to the higher accumulated fluence per time received during this season (about a factor of 2.9 higher than in winter). In both cases, the higher and lower degradation rates were obtained for cyprodinil and cyproconazole, respectively. The total fluence to get a 90% reduction (H90) ranged from 4.6 to 5.2 J cm-2 (cyprodinil) to 71.5 76 J cm-2 (cyproconazole). PMID- 30308445 TI - Crossed cerebellar diaschisis in Creutzfeldt-Jakob disease evaluated through single photon emission computed tomography. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease; it is characterized as a transmissible spongiform encephalopathy. Previously, only two case reports have discussed crossed cerebellar diaschisis (CCD) and sCJD. Herein, we detected CCD in five patients with sCJD and four patients with genetic CJD through SPECT. The combined data of the nine patients further supported CCD when analyzed by 3D-SSP. CCD can occur in several disorders, including, stroke, epilepsy, and encephalitis. Hence, CCD possibly could help in making earlier CJD diagnoses. Further studies with more patients are necessary to confirm the strong relationship here suggested between CJD and CCD. PMID- 30308444 TI - Long-term effects of prolonged-release fampridine in cognitive function, fatigue, mood and quality of life of MS patients: The IGNITE study. AB - BACKGROUND: Studies have reported conflicting results regarding the potential benefit of prolonged release (PR) fampridine in other domains besides walking. Moreover, only a small number of studies have explored long- term effects of PR fampridine. The aim of this study was to assess cognitive function, quality of life, mood and fatigue in MS patients treated with fampridine after 6 and 12 months of treatment. METHODS: IGNITE was an observational, open label study. Subjects were examined with the timed 25-ft walk (T25FW) and the BICAMS battery and were asked to complete the Multiple Sclerosis Impact Scale (MSIS-29), Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory-II (BDI-II) and MS International Quality-of-Life questionnaire (MUSIQOL) at baseline and at weeks 24 and 48. Patients were sub-grouped into responders (n:40) and non-responders (n:20) according to T25FW performance after 2 weeks on treatment. RESULTS: After 6 months, statistically significant improvement was observed on T25FW (p < .001), SDMT (p < .001) and MSIS29 (p < .001), for responders. After 1 year on treatment, statistically significant improvement was observed in T25FW (p < .001), MSIS29 (p = .004), SDMT (p < .001) and MUSIQOL (p = .03) for responders. There were no statistically significant improvements for the non-responders. CONCLUSIONS: PR Fampridine may have a beneficial effect on information processing speed though not on memory. Study data provide some evidence that fampridine treatment may reduce the impact of MS on daily activities and improve quality of life but has no effect on subjective fatigue and mood. PMID- 30308446 TI - Clot length does not impact outcome following thrombectomy. AB - BACKGROUND AND AIMS: Clot length was associated with outcome after treatment with intravenous tissue plasminogen activator (tPA) in patients with stroke secondary to emergent large vessel occlusions (ELVO) but data regarding the influence of clot length on outcome after thrombectomy is lacking. PATIENTS AND METHODS: Prospectively accrued data on consecutive patients with ELVO treated with thrombectomy was analyzed. Data on demographics, risk factors, stroke severity, survival and occurrence of symptomatic intracranial hemorrhage (sICH) was collected. Procedural details including clot length measured on the pre thrombectomy digital subtraction angiograms in multiple projections were collected. Functional outcome was determined with the modified Rankin Scale (mRS) 90 days post stroke and mRS <= 2 was considered as favorable outcome. RESULTS: Data was collected for 94 patients that fulfilled entry criteria. On univariate analysis clot length did not differ between patients with favorable or unfavorable outcomes. Clot length also did not influence the rates of sICH or mortality. On multivariate logistic regression age and stroke severity remained significant modifiers for favorable outcome. In a second regression model age, poor collaterals, the number of passes needed for recanalization and the magnitude of change in neurological deficits between presentation and discharge remained significant modifiers of outcomes. However, clot length had no effect on outcome in both models. CONCLUSIONS: In patients undergoing thrombectomy for ELVO, clot length has no effect on functional outcomes, mortality or sICH. Therefore, patients with ELVO should not be excluded from thrombectomy based on lot length. PMID- 30308447 TI - Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. AB - Neurofibromatosis Type 1 (NF1) is caused by mutations of the NF1 gene. The aim of this study was to identify the genetic causes underlying the disease, attempt possible phenotype/genotype correlations and add to the NF1 mutation spectrum. A screening protocol based on genomic DNA was established in 168 patients, encompassing sequencing of all coding exons and adjoining introns using a custom targeted next generation sequencing protocol and subsequent confirmation of findings with Sanger sequencing. MLPA was used to detect deletions/duplications and positive findings were confirmed by RNA analysis. All novel findings were evaluated according to ACMG Standards and guidelines for the interpretation of sequence variants with the aid of in-silico bioinformatic tools and family segregation analysis. A germline variant was identified in 145 patients (86%). In total 49 known and 70 novel variants in coding and non-coding regions were identified. Seven patients carried whole or partial gene deletions. NF1 patients, present with high phenotypic variability even in cases where the same germline disease causing variant has been identified. Our findings will contribute to a better knowledge of the genetic causes and the phenotypic expression related to the disease. PMID- 30308449 TI - Trends of self-reported sleep duration in Korean Adults: results from the Korea National Health and Nutrition Examination Survey 2007-2015. AB - OBJECTIVE/BACKGROUND: Sleep plays a vital role in maintaining homeostasis and promoting individual health. This study aimed to investigate the trends of sleep duration in Korean adults. PATIENTS/METHODS: We collected data from individuals who were adults (>=18 years) and participated in three cycles (2007-2009, 2010 2012, and 2013-2015) of the Korea National Health and Nutrition Examination Survey (KNHANES) for the analysis of self-reported sleep duration pattern. A total of 51,545 adults (21,937 men and 29,608 women) were included. RESULTS: Sleep duration decreased among both men and women from 2007 to 2009 KNHANES to 2013-2015 KNHANES. Sleep duration differed by age group and sex. Moreover, sleep duration declined among middle-aged (30-49 years old) and older (50-64 years old) men and young (18-29 years old) and middle-aged (30-49 years old) women, although not among older and elderly women. CONCLUSIONS: The young and middle-aged adult groups (18-49 years old) showed a significant decline in sleep duration in the KNHANES 2007-2015. PMID- 30308448 TI - Microgreens-A review of food safety considerations along the farm to fork continuum. AB - The food safety implications of microgreens, an emerging salad crop, have been studied only minimally. The farm to fork continuum of microgreens and sprouts has some overlap in terms of production, physical characteristics, and consumption. This review describes the food safety risk of microgreens as compared to sprouts, potential control points for microgreen production, what is known to date about pathogen transfer in the microgreen production environment, and where microgreens differ from sprouts and their mature vegetable counterparts. The synthesis of published research to date may help to inform Good Agricultural Practices (GAPs) and Good Handling Practices (GHPs) for the emerging microgreen industry. PMID- 30308450 TI - Early nighttime parental interventions and infant sleep regulation across the first year. AB - BACKGROUND: Sleep quality in early life has implications for individual and family well-being [19]. Parenting in the early months may be highly influential on infant sleep patterns and trajectories. METHOD: This study used observational and survey data to investigate how sleeping arrangement and two types of nighttime interventions at one and three months (non-distress-initiated and distress-initiated) are associated with infants' sleep development across the first nine months. Distress-initiated interventions were identified as parents' responses to infants' distress signals whereas non-distress initiated interventions were identified as parents' behaviors in response to non-distressed vocalizations or while infants were asleep. RESULTS: Analysis from 107 families revealed that infant night wakings decreased over time as expected. The link between early non-distress initiated interventions and rate of change in infant night wakings was significantly moderated by sleep arrangement such that solitary sleeping infants who experienced higher levels of non-distress-initiated interventions showed a less steep decline across time in infant night wakings compared to solitary infants who experienced low levels of non-distress-initiated interventions. Results also showed that higher levels of distress-initiated interventions at one and three months were associated with a steeper decrease in infant night wakings for both solitary and cosleeping infants. Notably, these findings were not replicated when parental interventions as predictors of infant sleep were examined at later points in the first year. CONCLUSIONS: Results inform conceptualizations of parenting competence in infant sleep contexts during the first few months of life and how best to promote infant sleep regulation across the first year. PMID- 30308451 TI - Nocturnal motor behaviors with unexpected EEG and brain MRI findings. PMID- 30308452 TI - Cellular basis of growth in plants: geometry matters. AB - The growth of individual cells underlies the development of biological forms. In plants, cells are interconnected by rigid walls, fixing their position with respect to one another and generating mechanical feedbacks between cells. Current research is shedding new light on how plant growth is controlled by physical inputs at the level of individual cells and growing tissues. In this review, we discuss recent progress in our understanding of the cellular basis of growth from a biomechanical perspective. We describe the role of the cell wall and turgor pressure in growth and highlight the often-overlooked role of cell geometry in this process. It is becoming apparent that a combination of experimental and theoretical approaches is required to answer new emerging questions in the biomechanics of plant morphogenesis. We summarise how this multidisciplinary approach brings us closer to a unified understanding of the generation of biological forms in plants. PMID- 30308453 TI - Quantitative detection of acyclovir by surface enhanced Raman spectroscopy using a portable Raman spectrometer coupled with multivariate data analysis. AB - Acyclovir (ACV) is a synthetic antiviral agent with serious side effect, particularly its nephrotoxicity, so this study was to explore the ultrasensitive detection of ACV by surface-enhanced Raman scattering (SERS). The enhancement capability of nanoparticles prepared by different chemical reduction were compared, and Ag nanoparticles reduced by citrate are the most propriate enhanced substrate for acyclovir. In addition, comparison between prominent SERS-enhanced bands and the precise mode descriptions predicted through density functional theory (DFT) simulations is used to understand the mechanisms between ACV and metallic surface. 130 different levels of ACV concentrations in a range from 10 1~10-7 were used to build quantitative prediction models by two different modeling methods, partial least-squares (PLS) regression and artificial neural network (ANN). Under the optimal conditions, the performance of the PLS model was much better than ANN. The results demonstrated that SERS imaging with multivariate analysis holds great potential for the sensitive and cost effective clinic test of ACV and its metabolites in biological fluids. PMID- 30308454 TI - Interaction of surfactant and protein at the O/W interface and its effect on colloidal and biological properties of polymeric nanocarriers. AB - HYPOTHESIS: The use of polymer-based surfactants in the double-emulsion (water/oil/water, W/O/W) solvent-evaporation technique is becoming a widespread strategy for preparing biocompatible and biodegradable polymeric nanoparticles (NPs) loaded with biomolecules of interest in biomedicine, or biotechnology. This approach enhances the stability of the NPs, reduces their size and recognition by the mononuclear phagocytic system, and protects the encapsulated biomolecule against losing biological activity. Different protocols to add the surfactant during the synthesis lead to different NP colloidal properties and biological activity. EXPERIMENTS: We develop an in vitro model to mimic the first step of the W/O/W NP synthesis method, which enables us to analyze the surfactant biomolecule interaction at the O/W interface. We compare the interfacial properties when the surfactant is added from the aqueous or the organic phase, and the effect of pH of the biomolecule solution. We work with a widely used biocompatible surfactant (Pluronic F68), and lysozyme, reported as a protein model. FINDINGS: The surfactant, when added from the water phase, displaces the protein from the interface, hence protecting the biomolecule. This could explain the improved colloidal stability of NPs, and the higher biological activity of the lysozyme released from nanoparticles found with the counterpart preparation. PMID- 30308455 TI - The effects of blood conditioning films on the antimicrobial and retention properties of zirconium-nitride silver surfaces. AB - External bone fixation devices provide support and rehabilitation for severely damaged/broken bones, however, this invasive procedure is prone to infection. Zirconium nitride/silver (Ti-ZrN/Ag) coatings were characterised for surface topography, chemical composition, physicochemistry and antimicrobial efficacy (against Staphylococcus aureus and Staphylococcus epidermidis), in the presence of a blood conditioning film. The conditioning film altered the width of the microtopography of the surfaces however, the depth of the features remained relatively constant. The conditioning film also altered the coatings from hydrophobic to hydrophilic/partially hydrophilic surfaces. Following the MATH assay, the presence of a conditioning film reduced affinity towards the hydrocarbons for both microorganisms. The addition of a blood conditioning film reduced the antimicrobial efficacy of the Ti-ZrN/Ag coatings but also reduced the number of retained bacteria. This study suggests that the presence of a pre defined blood conditioning film may result in surfaces with anti-adhesive properties, potentially leading to a reduction in bacterial retention. This, combined with the antimicrobial efficacy of the coatings, could reduce the risk of infection on biomaterial surfaces. PMID- 30308456 TI - On the role of epigallocatechin-3-gallate in protecting phospholipid molecules against UV irradiation. AB - Catechin molecules such as epigallocatechin-3-gallate (EGCG) are capable of attenuating the biomolecular damage induced by UV radiation, possibly through molecular mechanisms involving the cell membranes. In this study, we confirmed the protective role of EGCG against UV of 1,2-dipalmitoyl-sn-glycero-3-[phospho rac-(1-glycerol) (sodium salt) (DPPG) in liposomes and cast films. The incorporation of EGCG increased the stability of DPPG liposomes as indicated by UV-vis absorption spectra. Using 2D correlation spectroscopy to analyse the spectra, we found that DPPG and EGCG are co-helpers and complement each other against degradation induced by UV. At the molecular level, UV irradiation affects the phosphate and carbonyl groups of DPPG, in addition to triggering the oxidation and opening of the pyrogallol ring of EGCG. Since EGCG can be incorporated into liposomes and is a strong shield against UV radiation, one may envisage its use in anti-ageing and sunscreen creams, and in dermal drug delivery. PMID- 30308457 TI - Computational roles of plastic probabilistic synapses. AB - The probabilistic nature of synaptic transmission has remained enigmatic. However, recent developments have started to shed light on why the brain may rely on probabilistic synapses. Here, we start out by reviewing experimental evidence on the specificity and plasticity of synaptic response statistics. Next, we overview different computational perspectives on the function of plastic probabilistic synapses for constrained, statistical and deep learning. We highlight that all of these views require some form of optimisation of probabilistic synapses, which has recently gained support from theoretical analysis of long-term synaptic plasticity experiments. Finally, we contrast these different computational views and propose avenues for future research. Overall, we argue that the time is ripe for a better understanding of the computational functions of probabilistic synapses. PMID- 30308459 TI - Fate and distribution of kynurenic acid administered as beverage. AB - BACKGROUND: Kynurenic acid (KYNA) is a biologically active metabolite of tryptophan exerting action on several receptors located in the brain and periphery. KYNA can be synthesized endogenously or supplied in the diet. It was documented that KYNA is present in various types of food. However, its presence in beverages was not yet investigated. Here, we measured content of KYNA in tea and coffee as well as analyzed distribution and fate of intragastrically administered labelled KYNA in mice. METHODS: 16 and 13 studied samples of tea and coffee, respectively were of commercial origin. Tea and coffee infusions were prepared according to the producers' guidelines. KYNA content in beverages was measured by means of HPLC detection. Adult male mice were used for analysis of fate of intragastrically administered labelled KYNA and collected samples were analyzed using liquid scintillation counter. RESULTS: KYNA was identified in all studied beverages. Amounts of KYNA found in various types of beverages differed significantly. The highest content of KYNA in tea and coffee was 8.7 MUg/100 ml and 0.63 MUg/100 ml, respectively. It was found that KYNA administered intragastrically as a liquid is absorbed from the digestive system and readily excreted in urine. The atypical kinetics of KYNA distribution were found in intestinal content of cecum, where it appeared later and persisted longer than in other tissues. CONCLUSIONS: Our data show that tea and coffee intake may contribute to KYNA content in the human organism. The distribution pattern of KYNA delivered as a liquid suggests that it either directly affects digestive system's functioning and intestinal microbiome composition, or participates in the whole body pool of KYNA. PMID- 30308458 TI - Melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (afmk) enhance chemosensitivity to gemcitabine in pancreatic carcinoma cells (PANC-1). AB - BACKGROUND: Gemcitabine is a standard chemotherapeutic agent for patients suffering from pancreatic cancer. However, the applied therapy is not effective due to the resistance of tumor cells to cytostatics, caused by inefficiency of the apoptotic mechanisms. Herein, we present the hypothesis that melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) modify the effect of gemcitabine on PANC-1 cells and that this phenomenon is dependent on the modulation of apoptosis. METHODS: PANC-1 cells have been incubated with melatonin, AFMK or gemcitabine alone or in combination to determine the cytotoxity and proliferative effects. In subsequent part of the study, cells were harvested, the proteins were isolated and analyzed employing immunoprecipitation/immunoblotting. RESULTS: Incubation of PANC-1 cells with gemcitabine resulted in upregulation of pro-apoptotic bax and caspases proteins expression, downregulation of anti-apoptotic Bcl-2, heat shock proteins (HSPs) and modulation of cellular inhibitors of apoptosis (IAPs). Both melatonin and AFMK administered to PANC-1 in combination with gemcitabine inhibited the production of HSP70 and cIAP-2 as compared to the results obtained with gemcitabine alone. These changes were accompanied by upregulation of Bax/Bcl-2 ratio and reduction of procaspases-9 and -3 abundance, followed by an increase in the formation of active caspase of PANC-1 cells with combination of gemcitabine plus low doses of melatonin or AFMK led to enhanced cytotoxicity and resulted in the inhibition of PANC-1 cells growth as compared to effects of gemcitabine alone. CONCLUSION: Melatonin and AFMK could improve the anti-tumor effect of gemcitabine in PANC-1 cells presumably through the modulation of apoptotic pathway. PMID- 30308460 TI - Potential pro-oxidative effects of single dose of mephedrone in vital organs of mice. AB - BACKGROUND: Mephedrone is a recreationally used synthetic cathinone, relatively new abusive substances with molecular structure similar to amphetamine. As there is still lack of scientific data regarding mechanisms of action as well as metabolism of mephedrone, especially in aspects other than neurotoxicity, addiction or behavioral changes, therefore we aimed, for the first time, to investigate potential pro-oxidative actions of a single dose of mephedrone in organs other than brain and its structures, i.e. in liver, kidneys, heart and spleen of Swiss mice. METHODS: The following biomarkers of oxidative stress were measured: concentration of ascorbic acid (AA) and malondialdehyde (MDA) as well as total antioxidant capacity (TAC) of the tissues homogenates. RESULTS: Our study revealed that mephedrone intoxication induces oxidative stress by reducing concentration of AA and TAC and increasing concentration of MDA in these organs. CONCLUSIONS: Such occurred state of antioxidant-oxidant imbalance may be etiopathological factor of a number of severe diseases within cardiovascular, digestive as well as immunological systems. PMID- 30308461 TI - Preliminary diversity assessment of an undervalued tropical bean (Lablab purpureus (L.) Sweet) through fatty acid profiling. AB - Several large-scale metabolic profiling studies have been directed to prospect crops with a major focus on yield-related traits and, ultimately, with the definition of specific markers for plant selection in breeding programs. However, some of these technologies are expensive, time-consuming and not easily feasible for a quick approach. Fatty acid profiling was described as reliable biomarkers and as a chemotaxonomic tool allowing to study not only the diversity in germplasm collections but also to discriminate their geographic origin. We have used fatty acids profiling for a preliminary assessment of Lablab purpureus (L.) Sweet (hyacinth bean) diversity and landraces discrimination. Hyacinth bean displays an enormous variability of agro-morphological traits, probably linked to the multi-purpose uses in different regions, i.e. as pulse, or as food with nutraceutical potential (Africa and Asia), forage (Africa and Australia) and ornamental (Europe and USA). Only two forage cultivars are widely marketed, cv. Rongai and cv. Highworth, with several landraces remaining to be addressed in terms of diversity. We show that fatty acids profiling was able to distinguish landraces, which display shared fatty acids with cultivars from the center of hyacinth bean diversity origin (East Africa). We propose that fatty acid profiling is a tool that may be used not only for nutritional value assessment but also as a chemodiversity tool in crop research. PMID- 30308462 TI - Validation of the Barratt Impulsiveness Scale- short form among Indian adolescents. AB - BACKGROUND: Impulsivity is widely assessed with a 30 item self-report measure known as the Barrratt Impulsiveness Scale (BIS-11). Further development involved creation of an abbreviated version, called Barratt Impulsiveness Scale- short form (BIS-15; Spinella, 2007) from the original BIS-11. Unlike the original BIS 11, BIS-15 has not undergone sufficient cross cultural validation especially among the adolescent population. AIM: To evaluate the factor structure and psychometric properties of BIS-15 among school and college attending Indian adolescents. METHOD: A total of 1806 adolescents (females = 48%, mean age = 17.14 years) completed BIS-15 questionnaire, strengths and difficulties questionnaire (SDQ) and a risk taking questionnaire that assessed adolescents level of involvement in two protypical risky behaviours- substance use and unsafe sexual behaviours. RESULTS: The results of the principal component analysis of BIS-15 items revealed a three factor structure: attentional, motor and non-planning impulsivity. The internal consistency of BIS-15 was 0.79. The total score on BIS 15 was significantly associated with the externalizing, internalizing and total difficulty score on SDQ. Significant associations were observed between BIS-15 total impulsivity score and the level of risk taking among adolescents. Further, the results also revealed gender variance in impulsivity scores where male adolescents scored higher on attentional and non-planning impulsivity as compared to female adolescents. CONCLUSION: BIS-15 is a reliable measure of impulsivity that can be used with Indian adolescent population. It would be particularly more suitable for use in settings that require comprehensive assessment of trait impulsivity in shorter time duration and without burdening the participants. PMID- 30308463 TI - 'It's now or never'-nulliparous women's experiences of pregnancy at advanced maternal age: A grounded theory study. AB - BACKGROUND: Delayed pregnancy is increasingly common in many countries including the UK. There has been international interest in providing maternity care which aims to improve outcomes for mothers and babies when pregnancy occurs after the age of 35. Despite this, there is a lack of understanding of the experience of pregnancy at advanced maternal age from the woman's perspective. OBJECTIVES: To explore the experience of uncomplicated pregnancy for nulliparous women aged 35 and over and determine key processes involved in their pregnancy journey. DESIGN: A two phase constructivist grounded theory study. SETTING: South West of England, United Kingdom. PARTICIPANTS: 15 nulliparous women aged 35 and over, in their third trimester of pregnancy. METHODS: Data were collected through semi structured, in depth interviews which were transcribed and analysed using coding, constant comparison and memo-writing. RESULTS: The core category 'It's now or never' reflects how women may experience their pregnancy. This appears to influence feelings of readiness to become a mother, anxieties about the pregnancy and their care choices. This was felt more acutely as maternal age advances towards 40 years and beyond. CONCLUSIONS: Women's understanding that their future chances to have a baby may be limited can impact upon the way pregnancy is experienced. Despite having an uncomplicated pregnancy, older pregnant women may experience considerable worry throughout their pregnancy. Further research is required on how health care providers can better support women in early pregnancy and in making decisions regarding childbirth choices which are related to age. PMID- 30308464 TI - Intimate partner violence moderates the association between oxytocin and reactivity to dyadic conflict among couples. AB - Emerging literature indicates individual and contextual differences impact response to oxytocin (OT). Intimate partner violence (IPV) is one chronic stressor that may moderate OT response. To test the hypothesis that IPV moderates the association between OT and reactivity to a dyadic conflict task, data from a larger randomized controlled study was collected from heterosexual couples (N = 60 individuals; 30 couples) at high risk for IPV due to substance misuse. Partners within each dyad completed a 10-minute dyadic conflict task in the laboratory, and then self-administered a single dose of OT (40 IU) or placebo. Forty-five minutes later, participants completed another 10-minute dyadic conflict task. Stress reactivity was measured before and after the second conflict task using neuroendocrine (i.e., salivary cortisol), physiological (i.e., skin conductance), and subjective responses. Couple conflict behaviors were observed during the conflict tasks and assessed using a validated coding system. Among women, physical IPV modulated skin conductance in those administered OT, and OT interacted with physical and psychological IPV to yield less positive subjective and behavioral responses. No main or moderating effects were found for men. Findings support emerging literature on sex differences in response to OT. Future research is needed to effectively translate OT into therapeutic intervention. PMID- 30308465 TI - Caregiver correlates of patient-initiated violence in early psychosis. AB - Patient-initiated violence may pose a significant risk to the strength and longevity of informal caregiving relationships in psychosis. We aimed to assess caregiver reports of patient-initiated violence in early psychosis and to examine the relationship between violent incidents and appraisals of caregiving, perceived mental wellbeing in caregivers and Expressed Emotion (EE) in the caregiving relationship. Eighty psychosis caregivers were recruited via Early Intervention (EI) psychosis services in London, United Kingdom. Caregivers were questioned about their experiences of patient-initiated violence during the semi structured Camberwell Family Interview, and completed the Experience of Caregiving Inventory and the RAND SF-36 health survey in a cross-sectional experimental design. One third of the sample reported at least one incident of patient-initiated violence. Reports of violence were associated with poorer mental wellbeing scores amongst caregivers and more negative appraisals of caregiving. Patient-initiated violence also correlated with greater criticism and hostility expressed towards patients, and a rating of high EE in caregiver reports. The results underscore the need to ask explicitly and routinely about the physical safety of caregivers looking after someone with psychosis. Families should be directed towards appropriate interventions to help manage any risk of violence and the likely negative impact on the caregiving relationship. PMID- 30308466 TI - Molecular imaging to enlighten cancer immunotherapies and underlying involved processes. AB - Cancer immunotherapy has led to impressive antitumor effects. However, not all patients respond to immunotherapy, serious toxicity can occur and combination therapy may be warranted. Strategies for rational early treatment choices are urgently required. In the absence of ideal accompanying biomarkers it remains challenging to capture the dynamic, heterogeneous and complex tumor behavior. Tumor immune response involves next to tumor cells, numerous other cells and molecules in the tumor microenvironment. We review research to identify potential novel imaging biomarkers by non-invasive whole body molecular imaging with positron emission tomography and single-photon emission computed tomography for cancer immunotherapy. Firstly, imaging with radiolabeled immune checkpoint targeting molecules. Secondly, imaging of immune cells with ex vivo or in vivo radiolabeled tracers and thirdly, imaging extracellular matrix components, including adhesion molecules, growth factors and cytokines. These molecular imaging strategies - used alone, in combination or serially - could potentially contribute to patient selection upfront or early during immunotherapy. PMID- 30308467 TI - Understanding molecular mechanisms of disease through spatial proteomics. AB - Mammalian cells are organized into different compartments that separate and facilitate physiological processes by providing specialized local environments and allowing different, otherwise incompatible biological processes to be carried out simultaneously. Proteins are targeted to these subcellular locations where they fulfill specialized, compartment-specific functions. Spatial proteomics aims to localize and quantify proteins within subcellular structures. PMID- 30308468 TI - Surfaceome nanoscale organization and extracellular interaction networks. AB - The reductionist view of 'one target-one drug' has fueled the development of therapeutic agents to treat human disease. However, many compounds that have efficacy in vitro are inactive in complex in vivo systems. It has become clear that a molecular understanding of signaling networks is needed to address disease phenotypes in the human body. Protein signaling networks function at the molecular level through information transfer via protein-protein interactions. Cell surface exposed proteins, termed the surfaceome, are the gatekeepers between the intra- and extracellular signaling networks, translating extracellular cues into intracellular responses and vice versa. As 66% of drugs in the DrugBank target the surfaceome, these proteins are a key source for potential diagnostic and therapeutic agents. In this review article, we will discuss current knowledge about the spatial organization and molecular interactions of the surfaceome and provide a perspective on the technologies available for studying the extracellular surfaceome interaction network. PMID- 30308469 TI - C-reactive protein and procalcitonin profile in ventilator-associated lower respiratory infections. AB - PURPOSE: Ventilator-associated tracheobronchitis (VAT) has been suggested as an intermediate process between tracheobronchial colonization and ventilator associated pneumonia (VAP) in patients receiving mechanical ventilation. The aim of this study was to evaluate the ability of C-reactive protein (CRP) and procalcitonin (PCT) to differentiate between VAT and VAP. METHODS: Pre-planned analysis of the prospective multinational TAVeM database, performed on 2960 patients receiving mechanical ventilation for >48 h, including 689 patients with VA-LRTI. Patients with the diagnosis of VAT or VAP microbiologically documented and with one measurement of CRP and/or PCT on the day of diagnosis were included. RESULTS: Four hundred and four patients (mean age 63 years, 298 men, ICU mortality 40%) were studied, 207 with VAT and 197 with VAP. On the day of infection diagnosis, the median CRP was elevated in both groups but significantly higher in VAP (18 mg/dL vs. 14 mg/dL, p = .001). Median PCT was also significantly higher in VAP (2.1 ng/dL vs. 0.64 ng/d L, p < .001). Both biomarkers could not help distinguish between VAT and VAP. CONCLUSION: Although PCT and CRP presented lower values in VAT as compared to VAP, there was a marked overlap of both biomarkers values in both VA-LRTI not allowing adequate discrimination. PMID- 30308470 TI - Longitudinal trends of per- and polyfluoroalkyl substances in children's serum. AB - Studies suggest negative health impacts from early life exposure to per- and polyfluoroalkyl substances (PFASs). However, information on longitudinal exposure to PFASs during childhood is scarce for background-exposed individuals. This study sought to fill this gap by investigating children's longitudinal exposure trends through measurement of PFAS serum concentrations and calculation of body burdens (MUg, total in body). Blood of 54 Finnish children was sampled 2005-2015 and analyzed for 20 PFASs at 1, 6 and 10.5 years of age. The body burden was calculated by multiplying the serum concentration by the volume of distribution and the bodyweight for each individual. Associations between serum concentrations or body burdens and parameters, such as sex, breastfeeding duration, body mass index as well as indoor dust and air PFAS concentrations, were evaluated. Serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) decreased significantly (p < 0.001) with age. In contrast to serum concentrations, body burdens stayed unchanged or even increased significantly (p < 0.05), except for PFOA in female children. Breastfeeding duration was positively correlated (p < 0.001) with serum concentrations of PFHxS, PFOS, PFOA and PFNA at 1 year of age. Some associations were found at 10.5 years with sex and indoor PFAS concentrations. Observations of longitudinal decreasing trends of serum concentrations can be misleading for understanding exposure levels from external media during childhood, as the serum concentration is influenced by parallel temporal changes and growth dilution. Body burdens account for growth dilution and thus better reflect differences in early-life to adolescence exposure than serum concentrations. PMID- 30308471 TI - Air quality management policy and reduced mortality rates in Seoul Metropolitan Area: A quasi-experimental study. AB - BACKGROUND: The air quality management policy was introduced in Seoul and Incheon metropolitan cities in the Republic of Korea, from 2005 to 2014. Despite particulate matter concentrations decreasing after policy implementation, the consequent health benefits have not been evaluated. Therefore, we evaluated the effects of the air quality management policy on cause-specific mortality rates in Seoul and Incheon. METHODS: Using interrupted time series analysis with a generalized Poisson regression model, we compared daily average mortality rates before (baseline, 2004-2005) and after (2006-2007, 2008-2009, 2010-2011, 2012 2013) the policy implementation. To account for the long term mortality trends, we weighted daily mortality rate of Seoul and Incheon with daily mortality rate of Daejeon (another metropolitan city with no air quality management policy implemented during the same period). RESULTS: Decline in the particulate matter concentration was greater in Seoul and Incheon than in Daejeon. After adjusting for potential confounders, there were 8% decrease in cardiovascular disease mortality rates and 10% decrease in cerebrovascular disease mortality rates in Seoul in 2012-2013 compared to the baseline period. In Incheon, an 8% reduction in cerebrovascular disease mortality rates in 2012-2013 was calculated. There was no change in mortality rates due to external causes or respiratory disease after policy implementation. CONCLUSIONS: Our study suggests that the air quality management policy was effective in reducing cardiovascular and cerebrovascular mortality rates in Seoul and cerebrovascular mortality rates in Incheon. PMID- 30308472 TI - Stroke-mimics: An acute brainstem syndrome after intravenous contrast medium application as a rare cause of contrast-induced neurotoxicity. PMID- 30308473 TI - Microbiological changes of the ageing oral cavity. AB - OBJECTIVE: Ageing is a physiological process that affects virtually all systems of the human body. Age-associated changes in the oral cavity reflect changes in the composition of its microbial inhabitants, which can be compatible with health or form dysbiotic communities that favor the establishment of disease. This paper focuses on discussing such age-driven changes of the oral microbiome, as well as their association with common oral infectious diseases, including dental caries, periodontitis, peri-implantitis and oral candidiasis. DESIGN: This is a comprehensive narrative review of the literature. RESULTS: The oropharyngeal microbiome of elderly individuals may foster a number of microorganisms such as enterobacteria, pseudomonads, staphylococci and yeasts that can become opportunistic pathogens in elderly individuals with weakened immunity or deteriorated general health. No considerable microbiological variations are noted with regards to common oral diseases, such as dental caries and periodontitis, between younger and elderly populations, whereas an increase in the prevalence of oral actinomycetes is noted by ageing. CONCLUSIONS: Whether naturally occurring or driven by underlying disease, the ecology of oral cavity is dynamically modified over time, eliciting changes in the composition of the resident oral microbiome. PMID- 30308474 TI - The effects of psychosocial interventions on death anxiety: A meta-analysis and systematic review of randomised controlled trials. AB - Death anxiety has been proposed as a transdiagnostic construct, underlying numerous mental disorders. Although it has been argued that treatments, which reduce death anxiety, are needed, research investigating the impact of interventions on death fears has produced mixed results. As such, the current meta-analysis aimed to examine the effect of psychosocial interventions on death anxiety. Overall, results from 15 randomised controlled trials suggested that psychosocial treatments produced significant reductions in death anxiety, with a small to medium effect size (g = .45). Intervention type (death education vs. therapy) did not significantly moderate the effect of intervention on death anxiety (g = -.47). However, therapy type was a significant moderator of treatment efficacy (g = -1.39). Cognitive Behaviour Therapy was found to be particularly efficacious, producing significant reductions in death anxiety relative to control (g = 1.7), whereas other therapies did not (g = .20). The number of treatment sessions and baseline death anxiety significantly moderated intervention efficacy, whereas the duration of the intervention, training of the interventionist, and clinical nature of the sample did not. Given the small number and generally low quality of the included studies, future research using more rigorous methodology, as well as clinical samples, is needed. PMID- 30308475 TI - Diphenyl diselenide protects neuronal cells against oxidative stress and mitochondrial dysfunction: Involvement of the glutathione-dependent antioxidant system. AB - Oxidative stress and mitochondrial dysfunction are critical events in neurodegenerative diseases; therefore, molecules that increase cellular antioxidant defenses represent a future pharmacologic strategy to counteract such conditions. The aim of this study was to investigate the potential protective effect of (PhSe)2 on mouse hippocampal cell line (HT22) exposed to tert-BuOOH (in vitro model of oxidative stress), as well as to elucidate potential mechanisms underlying this protection. Our results showed that tert-BuOOH caused time- and concentration-dependent cytotoxicity, which was preceded by increased oxidants production and mitochondrial dysfunction. (PhSe)2 pre-incubation significantly prevented these cytotoxic events and the observed protective effects were paralleled by the upregulation of the cellular glutathione-dependent antioxidant system: (PhSe)2 increased GSH levels (> 60%), GPx activity (6.9-fold) and the mRNA expression of antioxidant enzymes Gpx1 (3.9-fold) and Gclc (2.3-fold). Of note, the cytoprotective effect of (PhSe)2 was significantly decreased when cells were treated with mercaptosuccinic acid, an inhibitor of GPx, indicating the involvement of GPx modulation in the observed protective effect. In summary, the present findings bring out a new action mechanism concerning the antioxidant properties of (PhSe)2. The observed upregulation of the glutathione-dependent antioxidant system represents a future pharmacologic possibility that goes beyond the well-known thiol-peroxidase activity of this compound. PMID- 30308477 TI - A validation strategy for in silico generated aptamers. AB - The selection of high-affinity aptamers is of paramount interest for clinical and technological applications. A novel strategy is proposed to validate the reliability of the 3D structures of a group of anti- Angiopoietin-2 aptamers, produced in silico by using free software. In a previous literature these aptamers were processed both in vitro and in silico, by using an approach different from that here presented, and finally tested with a SPS experiment. Computational expectations and experimental outcomes did not agree. The procedure here proposed consists of three steps: a. the production of a large set of conformations for each candidate aptamer; b. the rigid docking upon the receptor; c. the topological and electrical characterization of the products. Steps a. and b. allow a global binding score of the ligand-receptor complexes based on the distribution of the "effective affinity", i.e. the sum of the conformational and the docking energies. Step c. employs a complex network approach (Proteotronics) to characterize the electrical properties of the aptamers and the ligand-receptor complexes. Finally, the results are discussed and compared with the literature on the same aptamers. The computational predictions are in good agreement with the known experimental measurements. PMID- 30308478 TI - Beyond RGD; nanoclusters of syndecan- and integrin-binding ligands synergistically enhance cell/material interactions. AB - Biomaterials are a powerful platform for directing cellular behaviour. Herein, we employed a biomimetic strategy to synthesize a low-fouling polymer functionalized with nano-scale clusters of ligands that bind both integrin and syndecan-4 receptors, as both receptor types are critical in focal adhesion signalling and mechanotransduction. Our results demonstrate that the presence of both ligand types synergistically increases the adhesion of human umbilical vein endothelial cells (more than a two fold increase after 4 h) and increases the rate of surface endothelialization compared to surfaces functionalized with only one ligand type. Additionally, we observe that the mixed population of ligands regulates endothelial cell migration, likely due to improved focal adhesion formation as observed through confocal microscopy. Furthermore, we illustrate that only endothelial cells cultured on these mixed ligand surfaces exhibit the appropriate morphological changes - elongation and alignment in the direction of flow - when exposed to laminar shear flow, and neither of the individual ligands alone is sufficient. These results illustrate that both receptor types must be engaged for optimum cell-material interactions and are mandatory for appropriate mechanotransduction. The results presented in this manuscript will be critical for the development of next generation biomedical devices and tissue engineering scaffolds. PMID- 30308476 TI - Redox regulation by reversible protein S-thiolation in Gram-positive bacteria. AB - Low molecular weight (LMW) thiols play an important role as thiol-cofactors for many enzymes and are crucial to maintain the reduced state of the cytoplasm. Most Gram-negative bacteria utilize glutathione (GSH) as major LMW thiol. However, in Gram-positive Actinomycetes and Firmicutes alternative LMW thiols, such as mycothiol (MSH) and bacillithiol (BSH) play related roles as GSH surrogates, respectively. Under conditions of hypochlorite stress, MSH and BSH are known to form mixed disulfides with protein thiols, termed as S-mycothiolation or S bacillithiolation that function in thiol-protection and redox regulation. Protein S-thiolations are widespread redox-modifications discovered in different Gram positive bacteria, such as Bacillus and Staphylococcus species, Mycobacterium smegmatis, Corynebacterium glutamicum and Corynebacterium diphtheriae. S thiolated proteins are mainly involved in cellular metabolism, protein translation, redox regulation and antioxidant functions with some conserved targets across bacteria. The reduction of protein S-mycothiolations and S bacillithiolations requires glutaredoxin-related mycoredoxin and bacilliredoxin pathways to regenerate protein functions. In this review, we present an overview of the functions of mycothiol and bacillithiol and their physiological roles in protein S-bacillithiolations and S-mycothiolations in Gram-positive bacteria. Significant progress has been made to characterize the role of protein S thiolation in redox-regulation and thiol protection of main metabolic and antioxidant enzymes. However, the physiological roles of the pathways for regeneration are only beginning to emerge as well as their interactions with other cellular redox systems. Future studies should be also directed to explore the roles of protein S-thiolations and their redox pathways in pathogenic bacteria under infection conditions to discover new drug targets and treatment options against multiple antibiotic resistant bacteria. PMID- 30308479 TI - Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs/mRNAs and miRNAs with Associated ceRNA Networks in Triple-Negative Breast Cancer. AB - BACKGROUND/AIMS: Triple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. Growing evidence indicates that Long noncoding RNAs (lncRNAs) play important regulatory roles in the development and progression of a variety of cancers including breast cancer. However, the underlying mechanisms remain largely unknown. METHODS: Here, we compared the expression profiles of mRNAs, lncRNAs and miRNAs between 111 TNBC tissues and 104 non-cancerous tissues utilizing RNA-Seq Data from The Cancer Genome Atlas (TCGA). Gene Ontology and KEGG pathway enrichment analyses were executed to investigate the principal functions of the significantly dysregulated mRNAs. Moreover, Kaplan Meier survival analyses were performed to determine the effects of differentially expressed lncRNAs/mRNAs/miRNAs on overall survival. Subsequently, we constructed a competing endogenous RNA (ceRNA) network, which included 66 dysregulated lncRNAs, 24 miRNAs and 55 mRNAs. The four dysregulated lncRNAs, three aberrantly expressed miRNAs and four mRNAs were confirmed in the ceRNA network by qRT-PCR in 30 pairs of samples, respectively. RESULTS: A total of 1441 lncRNAs, 114 miRNA and 2501 mRNAs were found to be differentially expressed in TNBC tissues compared with controls. 109 lncRNAs and 124 mRNAs might serve as prognostic signature for patients with TNBC according to the survival analysis. Functional analysis revealed that 19 mRNAs in the ceRNA network were enriched in 17 cancer-related pathways. CONCLUSION: Taken together, we identified novel lncRNAs/miRNAs which may serve as potential biomarkers to predict the survival and therapeutic targets for TNBC patients based on a large-scale sample. More importantly, we constructed the ceRNA network of TNBC, which provides valuable information to further explore the molecular mechanism underlying tumorigenesis and development of TNBC. PMID- 30308480 TI - Effect of Baicalein on GLUT4 Translocation in Adipocytes of Diet-Induced Obese Mice. AB - BACKGROUND/AIMS: Although baicalein has been shown to increase insulin sensitivity in liver of mice, there is no literature available about the effect of baicalein on glucose transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of diet-induced obese mice. METHODS: In the present study, the obese model was induced in mice fed a high fat diet (20% carbohydrates, 21% protein and 59% fat) for 16 weeks. The diet-induced obese mice were given 20mg/kg baicalein intraperitoneally (i.p.) once a day for 21 days. The plasma insulin was measured by enzyme-linked immunosorbent assay. Fasting blood glucose and insulin resistance indexes were measured by glucose tolerance test (GTT). The expression levels of PGC-1alpha, UCP1, GLUT4, PPARgamma, pP38MAPK, pERK and pAKT in adipocytes were determined by quantitative real-time polymerase chain reaction and western blotting. RESULTS: The present findings showed that administration of baicalein decreased pP38MAPK, pERK and PPARgamma levels, but enhanced pAKT, PGC-1alpha and UCP1 contents as well as GLUT4 expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalein treatment increased GLUT4 concentration in plasma membranes of adipocytes, i.e. baicalein may prevent insulin resistance through the GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. CONCLUSION: These results suggest that baicalein is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/GLUT4 pathway. PMID- 30308482 TI - The Relationship between Macular Pigment and Vessel Density in Patients with Type 1 Diabetes Mellitus. AB - AIM: Macular pigment density and microvascular density on optical coherence tomography angiography (OCTA) were measured in a cohort of type 1 diabetes mellitus (T1DM) patients with retinopathy in the attempt to shed light on the pathophysiology of this condition. METHODS: Eighty-two consecutive eyes of 59 patients with diabetic retinopathy examined at the Eye Clinic of the University of Naples Federico II from November 2016 to April 2017 were enrolled in this prospective study. Eighty normal eyes of 40 age-matched subjects without diabetes mellitus, without a history of glaucoma or evidence of intraocular surgery, and without retinal pathologic features constituted the control group. All patients and controls underwent a complete ophthalmic examination, best corrected visual acuity evaluation according to the ETDRS visual logMAR scale, measurement of intraocular pressure, OCTA, and evaluation of macular pigment. RESULTS: There were no significant age differences between patients and controls. Both macular pigment measurements and vessel density measured by OCTA were significantly lower in patients than in controls. A moderate correlation was found between vessel density in all ETDRS sectors and macular pigment parameters. CONCLUSIONS: There was a reduction in macular pigment and in OCTA vessel density in T1DM patients with retinopathy, which may have prognostic value in determining disease progression. PMID- 30308481 TI - Synthesis of Biotin-Modified Galactosylated Chitosan Nanoparticles and Their Characteristics in Vitro and in Vivo. AB - BACKGROUND/AIMS: Our previous study found that a nanoparticle drug delivery system that operates as a drug carrier and controlled release system not only improves the efficacy of the drugs but also reduces their side effects. However, this system could not efficiently target hepatoma cells. The aim of this study was to synthesize biotin-modified galactosylated chitosan nanoparticles (Bio-GC) and evaluate their characteristics in vitro and in vivo. METHODS: Bio-GC nanomaterials were synthesized, and confirmed by fourier transform infrared spectroscopy (FT-IR) and hydrogen-1 nuclear magnetic resonance (1H-NMR). The liver position and cancer target property of Bio-GC nanoparticles in vitro and in vivo was tested by confocal laser and small animal imaging system. The characteristics of Bio-GC/5-fluorouracil (5-FU) nanoparticles in vitro and in vivo were explored by cell proliferation, migration and cytotoxicity test, or by animal experiment. RESULTS: Bio-GC nanoparticles were synthesized with biodegradable chitosan as the nanomaterial skeleton with biotin and galactose grafts. Bio-GC was confirmed by FT-IR and 1H-NMR. Bio-GC/5-FU nanoparticles were synthesized according to the optimal mass ratio for Bio-GC/5-FU (1: 4) and had a mean particle size of 81.1 nm, zeta potential of +39.2 mV, and drug loading capacity of 8.98%. Bio-GC/5-FU nanoparticles had sustained release properties (rapid, steady, and slow release phases). Bio-GC nanoparticles targeted liver and liver cancer cell in vitro and in vivo, and this was confirmed by confocal laser scanning and small animal imaging system. Compared with GC/5-FU nanoparticles, Bio-GC/5-FU nanoparticles showed more specific cytotoxic activity in a dose- and time-dependent manner and a more obvious inhibitory effect on the migration of liver cancer cells. In addition, Bio-GC/5-FU nanoparticles significantly prolonged the survival time of mice in orthotopic liver cancer transplantation model compared with other 5-FU nanoparticles or 5-FU alone. Bio-GC (0.64%) nanomaterial had no obvious cytotoxic effects on cells; thus, the concentration of Bio-GC/5-FU nanoparticles used was only 0.04% and showed no toxic effects on the cells. CONCLUSION: Bio-GC is a liver- and cancer-targeting nanomaterial. Bio GC/5-FU nanoparticles as drug carriers have stronger inhibitory effects on the proliferation and migration of liver cancer cells compared with 5-FU in vitro and in vivo. PMID- 30308483 TI - Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy. AB - BACKGROUND/AIMS: The phenotype switching of vascular smooth muscle cells (VSMCs) was associated with the onset or progression of the atherogenic process in type 2 diabetes mellitus (T2DM). Alprostadil (Prostaglandin E1, PGE1) as a bioactive drug had a protective effect on vascular function. However, it is unknown whether PGE1 inhibited the phenotype switching in VSMCs via autophagy, which played a protective role in the vascular complications of diabetes. METHODS: The phenotype switching was induced by high glucose (HG, 25mM) in VSMCs, the protein expression was measured by western blot analysis and immunofluorescent staining. In vivo study, vascular lesion and dysfunction were produced in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. RESULTS: The decrease of alpha-SMA and the increase of vimentin, collagen I and proliferating cell nuclear antigen (PCNA) were found in HG-treated VSMCs. Along with more abundance of p62, autophagy markers LC3B and Beclin-1 significantly decreased in VSMCs exposed to HG. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy activator rapamycin and was dramatically counteracted by 3-methyladenine, an autophagy inhibitor. Furthermore, PGE1 suppressed the phosphorylation of AKT and mTOR, which negatively regulated autophagy level in VSMCs. In vivo study, PGE1 remarkably improved the endothelium-independent contraction of thoracic aorta and restored the expression of alpha-SMA, osteopontin, LC3B, phosphorylated mTOR in the artery media of T2DM rats. CONCLUSION: These results demonstrated that PGE1 maintained the phenotype of VSMCs via the AKT/mTOR-dependent autophagy, which prevented diabetes-induced vascular complications. PMID- 30308484 TI - Joining Parents' Bed at Night and Overweight among 2- to 6-Year-Old Children - Results from the 'Healthy Start' Randomized Intervention. AB - OBJECTIVE: Parental and child co-sleeping has been suggested as a risk factor for short sleep duration and poor sleep quality that may lead to overweight. We examined if joining parent's bed during night was associated with child overweight. METHODS: Cross-sectional data from the 'Healthy Start' study including 635 2- to 6-year-old Danish children, who were all considered obesity prone. Of these, 496 children had complete information on BMI and whether the child joined parents' bed during night and if so, how frequently. International cut-offs for overweight according to age and gender were applied, and logistic regression was used to estimate odds ratio (OR) and 95% Confidence Intervals (CI). Analyses were adjusted for the child's age and gender, overall family stress, parental educational level, and parental BMI. RESULTS: Children who did not join their parent's bed were more likely to be overweight compared to children who did (OR 1.75 (95% CI 0.99-3.10)). Children who rarely joined their parents' bed had OR 2.74 of being overweight (95% CI 1.01-7.44) compared to children who joined every night. CONCLUSION: Children who rarely joined parents' bed during night were almost three times more likely to be overweight than those who joined every night. PMID- 30308485 TI - AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo. AB - BACKGROUNDS/AIMS: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. METHODS: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153's activity in vivo. RESULTS: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. CONCLUSION: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells. PMID- 30308486 TI - Generation of a Urine-Derived Ips Cell Line from a Patient with a Ventricular Septal Defect and Heart Failure and the Robust Differentiation of These Cells to Cardiomyocytes via Small Molecules. AB - BACKGROUND/AIMS: Ventricular septal defects (VSDs) are one of the most common types of congenital heart malformations. Volume overload resulting from large VSDs can lead to heart failure (HF) and constitutes a major cause of pediatric HF with a series of often-fatal consequences. The etiology of VSD with HF is complex, and increasing evidence points toward a genetic basis. Indeed, we identified an L2483R mutation in the ryanodine receptor type 2 (RyR2) in a 2 month-old male patient with VSD with HF. METHODS: We generated integration-free induced pluripotent stem cells from urine samples (UiPSCs) of this patient using Sendai virus containing the Yamanaka factors and characterized these cells based on alkaline phosphatase activity, pluripotency marker expression, and teratoma formation. Then, we induced the derived UiPSCs to rapidly and efficiently differentiate into functional cardiomyocytes through temporal modulation of canonical Wnt signaling with small molecules. Real-time PCR and immunofluorescence were used to verify the expression of myocardium-specific markers in the differentiated cardiomyocytes. The ultrastructure of the derived myocardial cells was further analyzed by using transmission electron microscopy. RESULTS: The established UiPSC lines were positive for alkaline phosphatase activity, retained the RyR2 mutation, expressed pluripotency markers, and displayed differentiation potential to three germ layers in vivo. The UiPSC derived cells showed hallmarks of cardiomyocytes, including spontaneous contraction and strong expression of cardiac-specific proteins and genes. However, compared with cardiomyocytes derived from H9 cells, they had a higher level of autophagy, implying that autophagy may play an important role in the development of VSD with HF. CONCLUSION: The protocol described here yields abundant myocardial cells and provides a solid platform for further investigation of the pathogenesis, pharmacotherapy, and gene therapy of VSD with HF. PMID- 30308487 TI - Hypermethylation of miR-338-3p and Impact of its Suppression on Cell Metastasis Through N-Cadherin Accumulation at the Cell -Cell Junction and Degradation of MMP in Gastric Cancer. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) have been well studied in human carcinogenesis and cancer progression. Our previous study showed the down regulation of miR-338-3p expression in human gastric cancer (GC). However, the reasons of this dysregulation remain largely unclear. METHODS: Bisulfite sequence analysis was performed to explore the methylation status of the promoter region of miR-338-3p. Cell wound-healing and transwell assays were performed to examine the capacity of cell migration and cell interaction. A dual-luciferase reporter was used to validate the bioinformatics-predicted target gene of miR-338-3p. Western blotting, RNA interference, and immunofluorescence (IF) were used to evaluate the expression of MMPs and the location of N-cadherin to determine the mechanism underlying miR-338-3p-induced anti-tumor effects. RESULTS: miR-338-3p was epigenetically silenced, and this loss of expression was significantly correlated with the Borrmann Stage in GC. Restoring miR-338-3p expression in BGC 823 cells inhibited cell migration and invasion. Moreover, Ras-related protein (Rab-14) and Hedgehog acyltransferase (Hhat) were identified as direct targets of miR-338-3p. Both enforced expression of miR-338-3p and small interfering RNA induced Rab14-mediated accumulation of N-cadherin in the cell -cell junctions or Hhat-associated matrix metalloproteinase (MMP) degradation, which may underline the metastasis defects caused by loss of miR-338-3p in GC. CONCLUSION: These data indicate that miR-338-3p functions as a tumor suppressor in GC, and that the hypermethylation status of its CpG island might be a novel potential strategy for treating GC. PMID- 30308488 TI - Factors Associated with High Weight Gain and Obesity Duration: The Norwegian Women and Cancer (NOWAC) Study. AB - AIM: To identify factors associated with high weight gain and obesity duration in a representative sample of Norwegian women. METHODS: 66,618 Norwegian women aged 34-70 years at baseline were included in the analysis. Baseline and follow-up questionnaires completed in 1991-2011 provided information on height, weight as well as sociodemographic, lifestyle and reproductive factors. We assessed the association with multivariable logistic regression. RESULTS: Women gained on average 0.5 kg/year (95% CI 0.5-0.5 kg/year) during 6 years of follow-up, and 3.5% maintained in obesity during 13 years of follow-up. The factors with strongest association with high weight gain (>=10 kg) were smoking cessation (cessation vs. no change, OR = 4.39, 95% CI 3.91-4.94) and decreased physical activity level (decrease vs. no change, OR = 2.40, 95% CI 2.21-2.61). Low physical activity level (high vs. low, OR = 0.17, 95% CI 0.14-0.20), higher than median age at menarche (over median vs. median or under median, OR = 0.36, 95% CI 0.31-0.41), and less than 10 years of education (>12 years vs. <10 years, OR = 0.44, 95% CI 0.37-0.51) were strongly associated with obesity duration. CONCLUSION: The modifiable factor with the strongest association with adverse weight development and potential for prevention was low or decreased physical activity level. PMID- 30308489 TI - miR-136-5p Regulates the Inflammatory Response by Targeting the IKKbeta/NF kappaB/A20 Pathway After Spinal Cord Injury. AB - BACKGROUND/AIMS: miR-136-5p participates in recovery after spinal cord injury (SCI) via an unknown mechanism. We investigated the mechanism underlying the involvement of miR-136-5p in the inflammatory response in a rat model of SCI. METHODS: Sprague-Dawley rat astrocytes were cultured in vitro to construct a reporter plasmid. Luciferase assays were used to detect the ability of miR-136-5p to target the IKKbeta and A20 genes. Next, recombinant lentiviral vectors were constructed, which either overexpressed miR-136-5p or inhibited its expression. The influence of miR-136-5p overexpression and miR-136-5p silencing on inflammation was observed in vivo in an SCI rat model. The expression of IL 1beta, IL-6, TNF-alpha, IFN-alpha, and related proteins (A20, IKKbeta, and NF kappaB) was detected. RESULTS: In vitro studies showed that luciferase activity was significantly activated in the presence of the 3' untranslated region (UTR) region of the IKKbeta gene after stimulation of cells with miR-136-5p. However, luciferase activity was significantly inhibited in the presence of the 3'UTR region of the A20 gene. Thus, miR-136-5p may act directly on the 3'UTR regions of the IKKbeta and A20 genes to regulate their expression. miR-136-5p overexpression promoted the production of related cytokines and NF-kappaB in SCI rats and inhibited the expression of A20 protein. CONCLUSION: Overexpression of miR-136-5p promotes the generation of IL-1beta, IL-6, TNF-alpha, IFN-alpha, IKKbeta, and NF kappaB in SCI rats but inhibits the expression of A20. Under these conditions, inflammatory cell infiltration into the rat spinal cord increases and injury is significantly aggravated. Silencing of miR-136-5p significantly reduces the protein expression results described after miR-136-5p overexpression and ameliorates the inflammatory cell infiltration and damage to the spinal cord. Therefore, miR-136-5p might be a new target for the treatment of SCI. PMID- 30308490 TI - Activation Levels, Cardiovascular Risk, and Functional Impairment in Remitted Bipolar Patients: Clinical Relevance of a Dimensional Approach. PMID- 30308491 TI - An Analysis of Relationship Between RAS Mutations and Prognosis of Primary Tumour Resection for Metastatic Colorectal Cancer Patients. AB - BACKGROUND/AIMS: Non-radical primary tumour resection (PTR) of asymptomatic metastatic colorectal cancer (mCRC) can prolong survival time of some patients. Patients with mutated RAS gene have worse survival outcome. This study aimed to investigate the impact of RAS gene mutations on the prognosis of asymptomatic unresectable mCRC patients who underwent PTR. METHODS: A retrospective observational cohort study was deduced among mCRC patients who experienced PTR or had intact primary tumour (IPT). All of them had the primary tumour tissue genotyping tested for RAS (KRAS and NRAS) gene mutations. The tumour-related overall survival (OS) time and progression-free survival (PFS) time was estimated. From January 2011 to June 2014, 421 mCRC patients with asymptomatic, unresectable, metastatic disease were enrolled in this study. Among them, 282 patients underwent PTR and 139 patients had IPT. RESULTS: The mutation rate of RAS was 53.8% (221/411). With a median followed-up time of 46.5 months, the overall survival time of mCRC patients harboring wtRAS or mtRAS was 28.0 versus 22.0 months (p = 0.043) in PTR group and was 21.6 versus 17.8 months (p=0.071) in IPT groups. A Multivariate regression analysis suggested that RAS gene (p=0.039, HR=1.288,95%CI [1.072~2.911]), metastatic organ number (p=0.033, HR=3.091,95%CI [1.090~5.755]) and systemic therapy response (p=0.019, HR=0.622,95%CI [0.525~0.811]) were independent prognostic factors in PTR population. CONCLUSION: We found that wild-type RAS gene was a favorable factor for the asymptomatic unresectable mCRC patients experiencing PTR. PMID- 30308492 TI - Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Gamma/AMPK/ACC Signaling Pathway. AB - BACKGROUND/AIMS: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- gamma/AMPK/ACC signaling pathway. METHODS: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- gamma/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT qPCR) and Westernblot. Besides, PPAR-gamma antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-gamma and AMPK. RESULTS: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-gamma mediated the activation of AMPK and subsequent inhibition of ACC expression. CONCLUSION: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-gamma/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN. PMID- 30308493 TI - High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion. AB - BACKGROUND/AIMS: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. METHODS: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. RESULTS: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor alpha (ERalpha) and beta (ERbeta) in UECC, blocking ERalpha or ERbeta resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. CONCLUSION: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER. PMID- 30308494 TI - Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT. AB - BACKGROUND/AIMS: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. METHODS: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan-Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. RESULTS: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. CONCLUSION: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA. PMID- 30308495 TI - Combination of Fluoride and SO2 Induce DNA Damage and Morphological Alterations in Male Rat Kidney. AB - BACKGROUND/AIMS: We investigated the combined toxic effect of sodium fluoride (NaF) and sulfur dioxide (SO2) on kidney morphological changes and DNA damage in male Wistar rats. METHODS: In this study we selected totally 96 male Wistar rats (12-week-old) then randomly group-housed them into four cages, treated with deionized water, NaF, SO2 and co-treatment of NaF and SO2 respectively. Morphological changes of kidney were detected by hematoxylin and eosin (H&E) staining at 2, 4, 6 and 8 weeks. Correspondingly, tailing ratio and comet length were measured by BAB Bs Comet Assay System, including DNA damage special unit were calculated to evaluate the grades of kidney DNA damage at the same time. RESULTS: Treated groups showed a body weight decrease when compared to control group. However, no significant difference in the relative weight of kidney was found in all four groups. It is noteworthy that at 2, 4, 6 and 8 weeks after exposure, the morphological alteration of renal tubules were observed in all treated groups, especially in group-IV. Also, at 4 and 6 weeks, notable DNA damage was found in all treated groups, as assessed by significantly increasing trend of comet length tailing ratio. CONCLUSION: The study manifests that presence of NaF and SO2 will not only induce renal tissue lesions but also impact DNA integrity. In addition, this combined exposure exhibits a synergistic effect, characterizing a dose-dependence and time correlation. These findings may provide novel insights regarding perturbations of DNA damage and its functions as a potential new mechanism, by which cautious interpretation of NaF and SO2 co exposure evolved in both animals and human beings is necessary. PMID- 30308496 TI - SMARCAD1 in Breast Cancer Progression. AB - BACKGROUND/AIMS: Breast cancer is the most common cancer in women worldwide, and within this cancer type, triple-negative breast cancers have the worst prognosis. The identification of new genes associated with triple-negative breast cancer progression is crucial for developing more specific anti-cancer targeted therapies, which could lead to a better management of these patients. In this context, we have recently demonstrated that SMARCAD1, a DEAD/H box-containing helicase, is involved in breast cancer cell migration, invasion, and metastasis. The aim of this study was to investigate the impact of the stable knockdown of SMARCAD1 on human breast cancer cell progression. METHODS: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of the stable knockdown of SMARCAD1 on human breast cancer cell proliferation and colony growth in vitro and on tumour growth in chick embryo and nude mouse xenograft models in vivo using MDA-MB-231 (ER-/PR-/ HER2-) and T47D (ER+/PR+/-/HER2-) human breast cancer cell lines. RESULTS: We found that SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKbeta expression. CONCLUSION: These results indicate that SMARCAD1 is involved in breast cancer progression and can be a promising target for breast cancer therapy. PMID- 30308497 TI - Nasal Symptom Questionnaire: Our Proposed Scoring System and Prognostic Factors in Chronic Rhinosinusitis. AB - OBJECTIVES: We aimed to verify the usefulness of our proposed nasal symptom questionnaire (NSQ) scoring system and to determine predictors linked to the improvement in nasal symptoms in chronic rhinosinusitis (CRS) patients undergoing endoscopic sinus surgery (ESS). PATIENTS AND METHODS: Ninety-one CRS patients undergoing ESS and 144 volunteers with results of NSQ available were enrolled. The NSQ consists of 10 items. Receiver-operating-characteristic (ROC) curve, area under the ROC curve (AUC), internal consistency, and test-retest reproducibility of the NSQ were analyzed. The relationship of the NSQ score with the visual analogue scale (VAS) was examined. After classifying into two groups, i.e., (i) "improvement group" and (ii) "no-improvement group," factors linked to the improvement in NSQ after ESS were investigated. RESULTS: ROC-AUC (0.9318), the Cronbach alpha coefficient (0.8696), and the test-retest coefficient (0.8131) showed high reliability. NSQ score significantly correlated with VAS in both pre- (p < 0.0001, rs = 0.6007) and postoperative stages (p < 0.0001, rs = 0.5975). The postoperative NSQ scores significantly decreased compared with baseline levels (p < 0.0001). In multivariate analysis, the computed tomography (CT) score by the Lund-Mackay scoring system revealed to be significant (p = 0.0481). CONCLUSION: Our proposed NSQ scoring system was well verified. The CT score can be helpful for predicting the improvement in nasal symptoms after ESS in CRS patients. PMID- 30308498 TI - CDC27 Facilitates Gastric Cancer Cell Proliferation, Invasion and Metastasis via Twist-Induced Epithelial-Mesenchymal Transition. AB - BACKGROUND/AIMS: Lymph node metastasis is the primary cause of cancer-related death among patients with gastric cancer (GC), and cell division cycle 27 (CDC27) promotes the metastasis and epithelial-mesenchymal transition in many cancers. Till now, the mechanisms underlying CDC27-induced the epithelial-mesenchymal transition (EMT) of GC are still unclear. METHODS: We analyzed the expression levels of CDC27 and EMT-related biomarkers using immunohistochemistry and Western blot in 60 cases of GC tissues, and then GC cells with CDC27 shRNAs or plasmids were subjected to in vitro and in vivo assays, including CCK-8, wound healing and transwell assays. RESULTS: The CDC27 expression was obviously increased in GC tissues, and significantly correlates with EMT-related biomarkers, lymph node metastasis and poor 5-year overall survival. Additionally, in vitro and in vivo assays demonstrated that silencing of CDC27 expression effectively inhibited GC cell proliferation, invasion and metastasis. Conversely, CDC27 overexpression led to the opposite results. Finally, we demonstrated that Twist shRNA inhibited CDC27-meditated invasion and EMT of GC cells. CONCLUSION: CDC27 facilitates gastric cancer cell proliferation, invasion and metastasis via Twist-induced EMT; thus, this study offered a new therapy method for GC patients. PMID- 30308499 TI - Riligustilide Attenuated Renal Injury by the Blockade of Renin. AB - BACKGROUND/AIMS: Nephropathy related with renin can be alleviated with ACE inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. METHODS: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. RESULTS: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. CONCLUSION: C20 plays importantly reno protective roles most likely through the relocation of CREB-CBP complex. PMID- 30308500 TI - Breast Tumours Resembling the Tall Cell Variant of Thyroid Papillary Carcinoma: Are They Part of the Papillary Carcinoma Spectrum or a Distinct Entity? AB - BACKGROUND: Papillary tumours of the breast are diagnostically challenging lesions and represent a wide spectrum of diseases from papilloma to invasive papillary carcinoma. A rare subtype of breast papillary tumour resembling the tall cell variant of thyroid papillary carcinoma (BTRTPC) has been described. The nomenclature of this entity, its relationship to other papillary tumours, and its nature, whether in situ or invasive, remain unclear. METHODS: Seventy-five papillary carcinomas (PCs) of the breast previously diagnosed in routine practice were reviewed and the presence of features (n = 10) characteristic of BTRTPC were assessed to determine whether BTRTPC comprises a distinct entity or is part of the spectrum of the previously defined PC variants. RESULTS: Nuclear overlapping and eosinophilic granular cytoplasm were seen in 81 and 75% of the cases, whereas nuclear grooves, nuclear clearing, and tall cells were noticed in 51, 42, and 38% of the cases, respectively; 27% of the cases showed macro- and micro-follicular architecture filled with colloid-like material. Five cases (7%) lacked oestrogen receptor (ER) expression. Co-existing invasive carcinoma was seen in 25 cases (33%). Two cases displayed several features characteristic of BTRTPC, and both were ER-negative. CONCLUSION: Features characteristic of BTRTPC overlap with other PCs of the breast. Molecular and immunohistochemical biomarkers are needed to provide objective diagnostic criteria for the characterisation of such lesions in routine practice. PMID- 30308501 TI - Cervical and Amniotic Fluid Matrix Metalloproteinase-8 and Interleukin-6 Concentrations in Preterm Pregnancies with or without Preterm Premature Rupture of Membranes. AB - INTRODUCTION: Intra-amniotic inflammation is defined by elevated inflammatory biomarkers in the amniotic fluid (AF), either due to microbial invasion of the amniotic cavity (MIAC) or sterile inflammation. Amniocentesis being an invasive procedure, we wanted to investigate whether elevated matrix metalloproteinase-8 (MMP-8) or interleukin-6 (IL-6) concentrations could be detected from cervical fluid samples. MATERIALS AND METHODS: This prospective study included 67 women with singleton nondiabetic pregnancies with or without preterm premature rupture of membranes (PPROM) between 22+0 and 37+0 weeks of gestation. Simultaneous AF and cervical samples were obtained. RESULTS: In women without PPROM, cervical MMP 8 concentrations correlated with AF MMP-8 concentrations (rS = 0.466, p = 0.002), but cervical IL-6 did not correlate with AF IL-6 (rS = 0.277, p = 0.076). In PPROM cases no correlations were found. Women with MIAC had higher concentrations of AF MMP-8 and AF IL-6 compared to women without MIAC regardless of membrane status. However, only women without PPROM had higher concentrations of cervical MMP-8 in proven MIAC. CONCLUSION: In women without PPROM, cervical MMP-8 concentration reflects the magnitude of AF MMP-8, thus potentially guiding the selection of patients benefitting from amniocentesis. PMID- 30308502 TI - Characterization of New Wheat-Dasypyrum breviaristatum Introgression Lines with Superior Gene(s) for Spike Length and Stripe Rust Resistance. AB - Dasypyrum breviaristatum (genome VbVb) contains potentially important traits for commercial wheat production. Chromosome 2Vb of D. breviaristatum carries several desirable agronomic characters, including long spike length as well as enhanced resistance to stripe rust, which are expressed in a common wheat background. In this study, wheat-D. breviaristatum 2Vb deletion lines were produced and identified by fluorescence in situ hybridization (FISH), and 74 molecular markers specific to D. breviaristatum chromosome 2Vb were physically localized in 4 distinct chromosomal regions. New wheat-D. breviaristatum 2Vb translocation lines were also characterized by FISH. The breakpoint of the translocation T3AS.3AL 2VbS was determined by physically mapped molecular markers. Field evaluation revealed that genes affecting plant height and spike length are located on fraction length (FL) 0.65-1.00 of 2VbS, while the stripe rust resistance gene(s) are located on FL 0.40-1.00 of D. breviaristatum chromosome 2VbL. The newly characterized wheat-Dasypyrum chromosomal introgressions are of potential value for the improvement of the yield and disease resistance of wheat. PMID- 30308503 TI - Comparative Transcriptomic Analysis of Embryo Implantation in Mice and Rats. AB - BACKGROUND/AIMS: Embryo implantation is an essential process for eutherian pregnancy, but this process varies across eutherians. The genomic mechanisms that led to the emergence and diversification of embryo implantation are largely unknown. METHODS: In this study, we analyzed transcriptomic changes during embryo implantation in mice and rats by using RNA-seq. Bioinformatics and evolutionary analyses were performed to characterize implantation-associated genes in these two species. RESULTS: We identified a total of 518 differentially expressed genes in mouse uterus during implantation, of which 253 genes were up-regulated and 265 genes were down-regulated at the implantation sites compared with the inter implantation sites. In rat uterus, there were 374 differentially expressed genes, of which 284 genes were up-regulated and 90 genes were down-regulated. A cross species comparison revealed that 92 up-regulated genes and 20 down-regulated genes were shared. The differences and similarities between mice and rats were investigated further at the gene ontology, pathway, network, and causal transcription factor levels. Additionally, we found that embryo implantation might have evolved through the recruitment of ancient genes into uterine expression. The evolutionary rates of the differentially expressed genes in mouse and rat uterus were significantly lower than those of the non-changed genes, indicating that implantation-related genes are evolutionary conserved due to high selection pressure. CONCLUSION: Our study provides insights into the molecular mechanisms involved in the evolution of embryo implantation. PMID- 30308505 TI - Bladder Explosion During Transurethral Resection of the Prostate Repaired Laparoscopically: A Case Report and Review of Literature. AB - OBJECTIVE: To report on a case of intravesical explosion during transurethral resection of prostate (TURP) which was managed laparoscopically and to review the relevant literature. CLINICAL PRESENTATION AND INTERVENTION: During TURP, a loud explosion was heard and a jolt was felt in abdomen. A bladder tear was seen endoscopically. Systematic laparoscopic exploration showed no injury to abdominal organs apart from the irregular large bladder tear which was repaired laparoscopically. The patient had an uneventful recovery. CONCLUSION: Bladder explosion during TURP is an extremely rare and serious complication. It should be considered as a blast injury and systematic exploration of abdominal organs and vessels should be performed. The severity and urgency of the condition should not preclude the use of laparoscopy for exploration and repair. PMID- 30308504 TI - Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model. AB - BACKGROUND/AIMS: Epithelial Na+ channels (ENaCs) play crucial roles in control of blood pressure by determining the total amount of renal Na+ reabsorption, which is regulated by various factors such as aldosterone, vasopressin, insulin and osmolality. The intracellular trafficking process of ENaCs regulates the amount of the ENaC-mediated Na+ reabsorption in the collecting duct of the kidney mainly by determining the number of ENaC expressed at the apical membrane of epithelial cells. Although we previously reported protein tyrosine kinases (PTKs) contributed to the ENaC-mediated epithelial Na+ reabsorption, we have no information on the role of PTKs in the intracellular ENaC trafficking. METHODS: Using the mathematical model recently established in our laboratory, we studied the effect of PTKs inhibitors (PTKIs), AG1296 (10 uM: an inhibitor of the PDGF receptor (PDGFR)) and AG1478 (10 uM: an inhibitor of the EGF receptor (EGFR)) on the rates of the intracellular ENaC trafficking in renal epithelial A6 cells endogenously expressing ENaCs. RESULTS: We found that application of PTKIs significantly reduced the insertion rate of ENaC to the apical membrane by 56%, the recycling rate of ENaC by 83%, the cumulative time of an individual ENaC staying in the apical membrane by 27%, the whole life-time after the first insertion of ENaC by 47%, and the cumulative Na+ absorption by 61%, while the degradation rate was increased to 3.8-fold by application of PTKIs. These observations indicate that PTKs contribute to the processes of insertion, recycling and degradation of ENaC in the intracellular trafficking process under a hypotonic condition. CONCLUSION: The present study indicates that application of EGFR and PDGFR-inhibitable PTKIs reduced the insertion rate (kI), and the recycling rate (kR) of ENaCs, but increased degradation rate (kD) in renal A6 epithelial cells under a hypotonic condition. These observations indicate that hypotonicity increases the surface expression of ENaCs by increasing the insertion rate (kI) and the recycling rate (kR) of ENaCs associated with a decrease in the degradation rate but without any significant effects on the endocytotic rate (kE) in EGFR and PDGFR-related PTKs-mediated pathways. PMID- 30308506 TI - Circulating miRNA Expression Profiling and Target Prediction in Patients Receiving Dexmedetomidine. AB - BACKGROUND/AIMS: Circulating miRNAs could serve as biomarkers for diagnosis or prognosis of heart diseases and cerebrovascular diseases. Dexmedetomidine has protective effects in various organs. The effects of dexmedetomidine on circulating miRNAs remain unknown. Here, we investigated differentially expressed miRNA and to predict the target genes of the miRNA in patients receiving dexmedetomidine. METHODS: The expression levels of circulating miRNAs of 3 patients were determined through high through-put miRNA sequencing technology. Target genes of the identified differentially expressed miRNAs were predicted using TargetScan 7.1 and miRDB v.5. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to conduct functional annotation and pathway enrichment analysis of target genes respectively. RESULTS: Twelve differentially expressed miRNAs were identified. Five miRNAs were upregulated (hsa-miR-4508, hsa-miR-novel-chr8_87373, hsa-miR-30a-3p, hsa-miR-novel chr16_26099, hsa-miR-4306) and seven miRNAs (hsa-miR-744-5p, hsa-miR-320a, hsa miR-novel-chr9_90035, hsa-miR-101-3p, hsa-miR-150-5p, hsa-miR-342-3p, and hsa-miR 140-3p) were downregulated after administration of dexmedetomidine in the subjects. The target genes and pathways related to the differentially expressed miRNAs were predicted and analyzed. CONCLUSION: The differentially expressed miRNAs may be involved in the mechanisms of action of dexmedetomidine. Specific miRNAs, such as hsa-miR-101-3p, hsa-miR-150-5p and hsa-miR-140-3p, are new potential targets for further functional studies of dexmedetomidine. PMID- 30308507 TI - Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis. AB - BACKGROUND/AIMS: Atherosclerosis is a serious disease that increases the risk of myocardial infarction and ischemic stroke. Previous studies have demonstrated that microRNA (miR)-29c could play significant roles in atherosclerosis via regulating inflammatory processes. However, the relationship between miR-29c and carotid intima-media thickness (CIMT) remains unknown. This study investigated associations between miR-29c and atherosclerosis and tested whether plasma miR 29c levels could be used to detect atherosclerosis. METHODS: Plasma miR-29c levels were estimated by quantitative real-time PCR, and CIMT was measured by carotid ultrasound. Associations between miR-29c and CIMT were assessed by Spearman's correlation coefficient and multiple linear regression analyses. RESULTS: In total, 170 participants were divided into the study (CIMT >=0.9 mm) and control (CIMT < 0.9 mm) groups. The study group showed higher C-reactive protein (CRP) and miR-29c relative expression levels compared with the control group. CIMT was positively correlated with miR-29c (r=0.659, p< 0.001) and CRP (r=0.447, p< 0.001), and miR-29c levels were also correlated with CRP (r=0.512, p< 0.001). Furthermore, multiple linear regression analysis showed that CIMT was significantly correlated with miR-29c (beta=0.573, 95% confidence interval [CI]: 0.315-0.839; p< 0.001) and CRP (beta=0.439, 95%CI: 0.186-0.825; p< 0.001). After age, body mass index, systolic blood pressure, total cholesterol and fasting blood-glucose were adjusted for, CIMT was still closely associated with miR-29c (beta=0.529, 95%CI: 0.354-0.812; p< 0.001) and CRP (beta=0.417, 95%CI: 0.198 0.724; p< 0.001). Evaluating CRP and miR-29c together (AUC=0.900, p< 0.001) achieved a better prognostic value for atherosclerosis than miR-29c (AUC=0.870, p< 0.001) or CRP (AUC=0.722, p< 0.001) alone. CONCLUSION: Increased miR-29c was closely associated with CIMT and may serve as a biomarker for identifying atherosclerotic patients. PMID- 30308508 TI - TGFbeta1-Smad Signaling Pathway Participates in Interleukin-33 Induced Epithelial to-Mesenchymal Transition of A549 Cells. AB - BACKGROUNDS/AIMS: Epithelial-to-mesenchymal transition (EMT) has been proven to be involved in development and progression of pulmonary fibrosis. This study aims to investigate the role of transforming growth factor beta1 (TGFbeta1)-smad signaling pathway in the interleukin-33 (IL-33) induced EMT. METHODS: The human type II alveolar epithelial cell line, A549, and small airway epithelial cells (SAEC) were cultured and divided into 4 groups including Control, LY-2109761 (TGFbeta receptor inhibitor), IL-33 and IL-33+LY-2109761 group. Expression of TGFbeta1, E-cadherin (E-cad) and alpha-smooth muscle actin (alpha-SMA) were examined by using real-time PCR (RT-PCR) and western blot assay, respectively. The smad3 signaling pathway factors, including smad3 and phosphorylated smad3 (p smad3), were also detected by using western blot assay. RESULTS: IL-33 significantly activated T1/ST2 expression in A549 cells (P< 0.05). TGFbeta1 receptor inhibitor significantly suppressed the IL-33 caused down-expression of E cad compared to IL-33 alone (P< 0.05). IL-33 significantly increased the alpha SMA levels compared to Control group (P< 0.05) and TGFbeta1 receptor inhibitor inhibited the other effects of IL-33. IL-33 significantly enhanced the levels of TGFbeta1 compared to Control group (P< 0.05). TGFbeta1 receptor inhibitor suppressed the IL-33 induced up-expression of p-smad3. CONCLUSION: The TGFbeta1 smad signaling pathway participates in the IL-33 induced epithelial-to mesenchymal transition of A549 cells. PMID- 30308509 TI - Forecasting Future Trends in Obesity across Europe: The Value of Improving Surveillance. AB - OBJECTIVE: To project the prevalence of obesity across the WHO European region and examine whether the WHO target of halting obesity at 2010 levels by 2025 is achievable. METHODS: BMI data were collected from online databases and the literature. Past and present BMI trends were extrapolated to 2025 using a non linear categorical regression model fitted to nationally representative survey data. Where only 1 year of data was available, a flat trend was assumed. Where no data were available, proxy country data was used adjusted for demographics. RESULTS: By 2025, obesity is projected to increase in 44 countries. If present trends continue, 33 of the 53 countries are projected to have an obesity prevalence of 20% or more. The highest prevalence is projected for Ireland (43%, 95% confidence interval (CI): 28-58%). Lithuania, Finland, and the Netherlands were each estimated to have an absolute increase of 2 percentage points in the prevalence of obesity between 2015 and 2025. DISCUSSION: The quality of BMI data across Europe is highly variable, with fewer than 50% of the 53 countries having measured nationally representative data and often not enough data to interpret projections meaningfully. Nevertheless, the prevalence of obesity in the European Region appears to be increasing in most countries and, with it, the health and economic burden of its associated diseases. This paints a concerning picture of the future burden of obesity-related noncommunicable diseases across the region. Greater and continued effort for the implementation of effective preventive policies and interventions is required from governments. PMID- 30308511 TI - Surgical Outcome after Lamellar Macular Hole Associated with Epiretinal Membrane. AB - PURPOSE: To evaluate functional and anatomical outcomes after pars plana vitrectomy (PPV) in patients with epiretinal membrane associated with lamellar hole (LH). PATIENTS AND METHODS: All patients who underwent PPV with epiretinal membrane peeling associated with an LH from January 2016 to December 2017 were included. Each patient received a complete ophthalmological examination including best-corrected visual acuity using Snellen charts (in decimal form; converted to logMAR) and spectral domain optical coherence tomography (SD-OCT) before surgery as well as 3 months after surgery. In all patients, the contour of the LH was postoperatively graded using SD-OCT images. RESULTS: A total of 36 consecutive patients (36 eyes) with LH associated with epiretinal membrane were reviewed. Most of the patients had normalization or at least an improvement of the LH contour postoperatively (p < 0.001). Median logMAR improved significantly after surgery from 0.3 to 0.2 (p < 0.001). CONCLUSIONS: PPV with epiretinal membrane peeling in symptomatic patients with LH caused by epiretinal membrane is a safe treatment with favorable functional and anatomical short-term outcomes. PMID- 30308510 TI - Lycium Barbarum Polysaccharides Alleviates Oxidative Damage Induced by H2O2 Through Down-Regulating MicroRNA-194 in PC-12 and SH-SY5Y Cells. AB - BACKGROUND/AIMS: Currently, scientists attempt to improve outcome of spinal cord injury (SCI) via reducing secondary injury during SCI. Oxidative stress is critical for pathophysiology of secondary damage, thus we mainly focused on the anti-oxidant effects of Lycium barbarum polysaccharides (LBPs) on PC-12 and SH SY5Y cells as well as the underlying mechanisms. METHODS: Oxidative stress was induced by H2O2 stimulation. Effects of LBPs on cell viability, apoptosis, and expression of proteins associated with apoptosis and autophagy in H2O2-induced cells were assessed by CCK-8 assay, flow cytometry assay and Western blot analysis, respectively. Then, expression of miR-194 was determined by qRT-PCR. Expression of miR-194 was dysregulated, and whether LBPs affected H2O2-treated cells through modulating miR-194 was verified. The expression of key kinases in the PI3K/AKT pathway and the intracellular levels of ROS and NO were testified by Western blot analysis and flow cytometry with fluorescent probes. RESULTS: H2O2 induced decrease of cell viability and increases of apoptosis and autophagy in PC 12 cells were mitigated by LBPs treatment. Next, we found that miR-194 expression was both down-regulated by LBPs treatment in PC-12 and SH-SY5Y cells. More experiments consolidated that influence of LBPs on H2O2-treated cells was reversed by miR-194 overexpression while was augmented by miR-194 inhibition. LBPs elevated the phosphorylated levels of PI3K and AKT and reduced levels of ROS and NO through miR-194. CONCLUSION: LBPs alleviated H2O2-induced decrease of cell viability, and increase of apoptosis and autophagy through down-regulating miR 194. Moreover, LBPs activated the PI3K/AKT pathway and reduced oxidative stress through miR-194. PMID- 30308512 TI - Reduced Serum Levels of Brain-Derived Neurotrophic Factor Are Related to Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is involved in obesity, type 2 diabetes mellitus (T2DM), and cognitive dysfunction. The present study sought to assess the role of serum levels of BDNF in the pathophysiological process of mild cognitive impairment (MCI), a preclinical phase of dementia in 715 Chinese patients with T2DM. METHODS: Cross-sectional data were obtained from 715 patients with T2DM recruited from a Chinese diabetes center. Serum levels of BDNF were measured with sandwich enzyme-linked immunosorbent assay. The influence of BDNF on MCI was examined using univariate and multivariate binary logistic regression analyses. RESULTS: In univariate and multivariate logistic regression analyses, for each one-unit increase of BDNF, the unadjusted and adjusted risk of MCI decreased by 9% (OR 0.91; 95% CI 0.88-0.93, p < 0.001) and 6% (0.94; 0.87-0.98, p < 0.001) respectively. In multivariate models comparing the first (Q1), second and third quartiles against the fourth quartile of BDNF, BDNF in Q1 and Q2 were associated with MCI, and increased risk of MCI by 275% (OR 3.75; 95% CI 2.38 6.03) and 155% (2.55; 1.32-4.02). These results suggested that for each 1 ng/mL increase of serum level of BDNF, the association became stronger among obese diabetic patients (OR 0.91, 95% CI 0.85-0.96; p < 0.001) versus nonobese diabetic patients (OR 0.95, 95% CI 0.86-0.98; p = 0.001). CONCLUSION: The present data demonstrated that reduced serum levels of BDNF were associated with increased risk of MCI and might be useful for identifying diabetic patients at risk of dementia for early prevention strategies. PMID- 30308513 TI - Radiation Enhances the Epithelial- Mesenchymal Transition of A549 Cells via miR3591-5p/USP33/PPM1A. AB - BACKGROUND/AIMS: Radiotherapy plays a critical role in lung cancer treatment. Radiation can activate transforming growth factor-beta (TGF-beta) signaling and induce the epithelial-mesenchymal transition (EMT), which may lead to distant metastases. MicroRNAs (miRNAs) have been suggested to affect radiotherapy in lung cancer. METHODS: miRNA Next-Generation Sequencing was performed to investigate the effects of irradiation on the miRNA profile of lung cancer A549 cells. The functions of identified miRNA on the radiation induced EMT and TGF-beta activation in A549 cells were then explored. Protein expression was evaluated by western blotting. Immunofluorescence staining was performed to detect the localization of Snail. Luciferase Assay was used to determine the target gene regulated by the identified miRNA. RESULTS: Radiation time-dependently induced EMT in A549 lung cancer cells as indicated by the changes of morphology, the expression of EMT marker proteins (E-cadherin, alpha-SMA and Vimentin) and the nuclear localization of Snail. Moreover, miR-3591-5p was identified as the most significant increased miRNA in response to radiation, and further experiments indicated that miR-3591-5p was required for radiation induced EMT and TGF-beta/ Smad2/3 activation. Ubiquitin Specific Peptidase 33 (USP33) was a downstream target of miR-3591-5p as predicted by TargetScan and validated by 3' untranslated regions (UTRs) Luciferase Assay. USP33 could deubiquitinate PPM1A (protein phosphatase, Mg2+/Mn2 + dependent 1A), a phosphatase for Smad2/3. Ectopic expression of USP33 or PPM1A partially abolished the effects of miR-3591-5p on EMT and TGF-beta/ Smad2/3 activation. CONCLUSION: The present study revealed the critical role of miR-3591-5p/USP33/PPM1A in radiation-induced EMT via TGF-beta signaling and may suggest novel radiation sensitise strategies for lung cancer. PMID- 30308514 TI - Psoriasis Treatment Changes the Expression Profile of Selected Caspases and their Regulatory MicroRNAs. AB - BACKGROUND/AIMS: Psoriasis, an autoimmune diseases of the skin, characterized by patches of abnormal/inflammed skin, although not usually life-threatening, it causes severe discomfort, esthetic impairments, and may lead to impaired social functions and social withdrawal. Besides UV-phototherapy, various anti inflammatory treatments are applied, depending on the severity of symptoms. In 2008, adalimumab (fully humanized human anti-TNF antibody) was launched for the treatment of psoriasis. In the quest to better understand the pathomechanism of adalimumab's therapeutic effects, and the acquired resistance to the drug, we have investigated how its administration affect the regulation of the expression of selected caspases, including those activated by inflammosome. METHODS: The research was initially carried out on normal human dermal fibroblasts (NHDF) treated with adalimumab for 2, 8 and 24 hours in vitro. Then, expression profile of genes encoding caspases and their regulatory micro-RNAs was determined with the use of oligonucleotide microarray. The validation of the microarray results was carried out by qRT-PCR. The in vitro study was followed by ex-vivo investigation of adalimumab's effects on the expression of caspase-6 in blood of the psoriatic patients. The samples were collected before, and 2 hours after adalimumab's administration and the analysis was determined by qRT-PCR. RESULTS: The result of the analysis indicated that introduction of adalimumab to the NHDF culture resulted in the change of the transcription activity of genes encoding caspases and genes encoding miRNAs. The analysis revealed 5 different miRNA molecules regulating the expression of: CASP2, CASP3 and CASP6. There were no statistically significant differences in the expression of gene encoding caspase 6 in the patients' blood before and 2 hours after the anti-TNF drug administration. CONCLUSION: We have found that adalimumab administration affects caspases expression, thus they may be used as molecular markers for monitoring the therapy with the use of an anti-TNF drugs, including adalimumab. It is likely that the mechanisms responsible for changed expression profiles of genes encoding caspase-2,-3, and -6, may be caused by the upregulation of the respective microRNA molecules. Increased expression of genes encoding specific caspases may induce inflammatory processes, as well as trigger apoptosis. Furthermore, the proapoptotic activity of caspases may be enhanced by miRNA molecules, which exhibit proapoptotic function. The overexpression of such miRNAs was observed in our study. PMID- 30308515 TI - Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Uncertainties and Controversies. AB - The mechanisms of idiopathic pulmonary fibrosis (IPF), a rare, devastating disease with a median survival of 3-5 years, are not fully understood. Gastroesophageal reflux disease (GERD) is a frequent comorbidity encountered in IPF. Hypothetically, GERD-associated microaspiration may lead to persistent inflammation impairing lung infrastructure, thereby possibly accelerating the progression of IPF. IPF may increase intrathoracic pressure, which can aggravate GERD and vice versa. On the basis of the possible beneficial effects of antireflux or antacid therapy on lung function, acute exacerbation, and survival, the recent international IPF guideline recommends antacid therapies for patients with IPF, regardless of symptomatic GERD. However, due to newer conflicting data, several national guidelines do not support this recommendation. Elucidation of these questions by further clinical and bench-to-bedside research may provide us with rational clinical diagnostic and therapeutic approaches concerning GERD in IPF. The present review aims to discuss the latest data on the controversial association of IPF and GERD. PMID- 30308516 TI - Downregulation of NGAL is Required for the Inhibition of Proliferation and the Promotion of Apoptosis of Human Gastric Cancer MGC-803 Cells. AB - BACKGROUND/AIMS: Gastric cancer is considered as a common malignancy with a poor prognosis as well as unsatisfactory treatment. Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to affect multiple aspects of human tumor, including gastric cancer. This study aims to explore the effects of NGAL gene silencing on the proliferation as well as apoptosis of human gastric cancer MGC 803 cells. METHODS: This study included 87 patients with gastric cancer. MGC-803 cells were collected and mainly treated with siRNA against NGAL and recombinant NGAL plasmid. The expression of NGAL mRNA and the expressions of NGAL protein and apoptosis-related proteins were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. Cell cycle and apoptosis were tested by flow cytometry, and cell proliferation was detected by water soluble tetrazolium-1 (WST-1) assay. The effect of NGAL gene silencing on tumorigenicity of MGC-803 cells in vivo was detected through establishment of xenograft in nude mice. RESULTS: NGAL was highly expressed in gastric cancer tissues. The protein and mRNA expressions of NGAL gene in MGC-803 cells treated with NGAL-siRNA were obviously reduced, and the amount of cells in G0/G1 phase was increased. Moreover, MGC-803 cells treated with NGAL-siRNA exhibited inhibited proliferation, enhanced apoptosis, decreased expressions of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) as well as B-cell lymphoma-2 (Bcl-2) and increased expressions of cysteine-aspartic acid specific protease-9 (caspase-9) and Bcl2-associated X (Bax), as well as repressed tumorigenicity in vivo. CONCLUSION: NGAL gene silencing inhibits proliferation and promotes apoptosis of MGC-803 cells, which can provide a novel theory for treatment of gastric cancer. PMID- 30308517 TI - Shufeng Jiedu Capsules Alleviate Lipopolysaccharide-Induced Acute Lung Inflammatory Injury via Activation of GPR18 by Verbenalin. AB - BACKGROUND/AIMS: Acute respiratory tract infection (ARTI) is the most common reason for outpatient physician office visits. Although powerful and significant in the treatment of infections, antibiotics used for ARTI inappropriately have been an important contributor to antibiotic resistance. We previously reported that Shufeng Jiedu Capsule (SJC) can effectively amplify anti-inflammatory signaling during infection. In this study, we aimed to systematically explore its composition and the mechanism of its effects in ARTI. METHODS: Pseudomonas aeruginosa (PAK) strain was used to generate a mouse model of ARTI, which were then treated with different drugs or compounds to determine the corresponding anti-inflammatory roles. High-performance liquid chromatography-quadrupole time of flight-tandem mass spectrometry. was conducted to detect the chemical compounds in SJC. RNAs from the lung tissues of mice were prepared for microarray analysis to reveal globally altered genes and the pathways involved after SJC treatment. RESULTS: SJC significantly inhibited the expression and secretion of inflammatory factors from PAK-induced mouse lung tissues or lipopolysaccharide induced peritoneal macrophages. Verbenalin, one of the bioactive compounds identified in SJC, also showed notable anti-inflammatory effects. Microarray data revealed numerous differentially expressed genes among the different treatment groups; here, we focused on studying the role of GPR18. We found that the anti inflammatory role of verbenalin was attenuated in GPR18 knockout mice compared with wild-type mice, although no statistically significant difference was observed in the untreated PAK-induced mice types. CONCLUSION: Our data not only showed the chemical composition of SJC, but also demonstrated that verbenalin was a significant anti-inflammatory compound, which may function through GPR18. PMID- 30308518 TI - Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo. AB - BACKGROUND/AIMS: Mammalian target of rapamycin (mTOR) is a valuable treatment target of renal cell carcinoma (RCC). Palomid 529 is a novel mTORC1/2 dual inhibitor. METHODS: RCC cells were treated with different concentrations of Palomid 529. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by BrdU ELISA assay. Cell apoptosis was tested by the Hoechst-33342 nuclei staining assay and Histone DNA ELISA assay. mTOR signaling was tested by Western blotting assay and co-immunoprecipitation (IP) assay. The SCID mouse 786-O xenograft model was established to test RCC cell growth in vivo. RESULTS: Palomid 529 exerted cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O RCC cells. Palomid 529 disassembled mTORC1/2, causing de phosphorylation of mTORC1/2 substrates. Bromodomain-containing protein 4 (BRD4) is a primary resistant factor of Palomid 529. Palomid 529-induced 786-O cell apoptosis was sensitized by BRD4 inhibitors or BRD4 silencing, but inhibited with BRD4 over-expression. Palomid 529-induced cytotoxicity in the primary human RCC cells was negatively correlated with BRD4 expression level. In vivo, Palomid 529 i.p. administration inhibited 786-O xenograft tumor growth in SCID mice. Its anti tumor activity was further sensitized by co-administration of the BRD4 inhibitor JQ1. Cconclusion: Palomid 529 inhibits RCC cell growth in vitro and in vivo. BRD4 inhibition could further sensitize Palomid 529 against RCC cells. PMID- 30308519 TI - A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway. AB - BACKGROUND/AIMS: The roles and related mechanisms of RNA binding protein FUS (fused in sarcoma/translocated in liposarcoma) are unclear in numerous cancers, including hepatocellular carcinoma (HCC). METHODS: Quantitative reverse transcription PCR (qRT-PCR), western blot, cell viability, transwell migration and invasion, tumor spheres formation and in vivo tumor formation assays were used to examine the effects of FUS on HCC progression in HuH7 and MHCC97 cells. Additionally, transcriptome analysis based on RNA-sequencing data, qRT-PCR, western blots, luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays were used to explore the LATS1/2 (large tumor suppressor kinases 1/2)-related mechanisms contributing to FUS functions. Finally, qRT-PCR and western blot analysis were used to detect the levels of FUS and LATS1/2 in HCC and adjacent normal tissues, and the correlation between them in HCC tissues. RESULTS: Overexpression of FUS decreased cell viability, migration, invasion and stemness. Moreover, FUS interacted and stabilized LATS1/2 stability, and thus promoted LATS1/2 expression and activated Hippo pathway. Finally, FUS and LAST1/2 levels were positively correlated and significantly down-regulated in HCC tissues. CONCLUSION: We demonstrate that FUS/LATS1/2 axis inhibits HCC progression via activating Hippo pathway. PMID- 30308520 TI - Overnutrition and Scholastic Achievement: Is There a Relationship? An 8-Year Follow-Up Study. AB - OBJECTIVE: The aim of this study was to assess the association between overnutrition and scholastic achievement (SA). METHODS: A representative and proportional sample of 477 children of the 5th elementary school grade of both genders was randomly chosen during 2010, in the Metropolitan Region of Chile. SA was measured through the 2009 Education Quality Measurement System (SIMCE) tests of language (LSA), mathematics (MSA) and understanding of the natural environment (UNESA). Current nutritional status was assessed through the body mass index Z score (Z-BMI). Nutritional quality of diet, schedule exercise, socioeconomic status, family, and educational variables were also recorded. Four and 8 years later, SA was assessed through the 2013 SIMCE and the University Selection Test (2017 PSU), respectively. RESULTS: Socioeconomic status, the number of repeated school years, and maternal schooling were strong predictors of 2009 SIMCE and the independent variables with the greatest explanatory power for LSA (Model R2 = 0.178; p < 0.00001) variances, besides of gender for MSA (Model R2 = 0.205; p< 0.00001) and UNESA (Model R2 = 0.272; p < 0.00001). Overnourished children did not have significantly lower 2009 and 2013 SIMCE and 2017 PSU outcomes. CONCLUSIONS: These results confirm that overnourished children did not achieve significantly lower SA. PMID- 30308522 TI - Modified ROTEM for the detection of rivaroxaban and apixaban anticoagulant activity in whole blood. AB - BACKGROUND: Rapid detection of the anticoagulant effect of oral factor Xa (FXa) inhibitors may be essential in several emergency clinical situations. Specific assays quantifying the drugs are performed in plasma and require a turnaround time that is too long to be useful in emergency situations. Rotational thromboelastometry (ROTEM) is a whole blood coagulation assay of blood viscoelasticity and could be of interest for FXa inhibitor detection in emergency. However, conventional ROTEM reagents only detect high amounts of inhibitors. OBJECTIVE: The aim of this study was first to assess the effect of whole blood components on the viscoelastic measurement of the effects of FXa inhibitors, an second to evaluate whether a modified ROTEM, triggered with a low amount of tissue factor and a saturating amount of phospholipid vesicles, can reliably detect low levels of FXa inhibitor activity in whole blood. DESIGN: Diagnostic test study. SETTINGS: A university research laboratory. From November 2014 to April 2016. PATIENTS: Sixty-six patients: 30 treated with rivaroxaban, 17 with apixaban and 19 without treatment. INTERVENTION: ROTEM was triggered with 2.5 pmol l of tissue factor and 10 MUmol l of phospholipid vesicles. MAIN OUTCOME MEASURES: Modified ROTEM parameters were measured in different experimental conditions: platelet-poor plasma (PPP), platelet-rich plasma, PPP supplemented with fibrinogen and reconstituted whole blood with various haematocrit levels adjusted between 30 and 60%. Modified ROTEM was further validated using whole blood from patients who were either treated or not treated with FXa inhibitors. RESULTS: Modified ROTEM allowed detection of as little as 25 ng ml FXa inhibitors in PPP, with at least a 1.4-fold increase of the clotting time (P <= 0.02). Neither changes of fibrinogen concentration nor variations of platelet count or haematocrit precluded FXa inhibitor detection. A lengthened modified ROTEM clotting time of more than 197 s allowed detection of FXa inhibitor concentrations above 30 ng ml in whole blood with 90% sensitivity and 85% specificity. CONCLUSION: Modified ROTEM may be applicable in emergency situations for the detection of FXa inhibitors in whole blood. PMID- 30308521 TI - Glucagon-Like Peptide-1 Modulates Cholesterol Homeostasis by Suppressing the miR 19b-Induced Downregulation of ABCA1. AB - BACKGROUND/AIMS: Abnormal regulation of cholesterol homeostasis is associated with type 2 diabetes mellitus (T2DM) and multiple other diseases. Glucagon-like peptide-1 (GLP-1) has unique effects on modulating hepatic lipid metabolism. However, the mechanism behind these is largely unknown. The aim of this study was to investigate the effects of GLP-1 on cholesterol-induced lipotoxicity in hepatocytes and examine the underlying mechanisms. METHODS: Cell viability was determined by CCK-8. Caspase-3 detection was used to assess the effects of GLP-1 on cholesterol-induced apoptosis. TNF-alpha and IL-6 as the inflammatory markers were measured by ELISA. The alterations of miR-19b and ATP-binding cassette transporter A1 (ABCA1) resulting from high-fat diet/cholesterol incubation or GLP 1 were detected by real-time PCR and western blot. RESULTS: GLP-1 markedly up regulated the expression of ABCA1 protein, but didn't affect peroxisome proliferator-activated receptor alpha (PPAR-alpha) protein. The miR-19b levels were significantly down-regulated in GLP-1-treated groups. The inhibition and overexpression of miR-19b were established to explore the effects of a GLP-1 mediated alteration in miR-19b. Cholesterol transport assays revealed that treatment with GLP-1 alone or together with miR-19b inhibitor significantly enhanced ABCA1-dependent cholesterol efflux, resulting in reduced total cholesterol. Further, histological examination was used to detect lipid accumulation. Cholesterol significantly attenuated cell viability, promoted hepatic cell apoptosis, and facilitated lipid accumulation, and these effects could be reversed by GLP-1. CONCLUSION: GLP-1 may affect cholesterol homeostasis by regulating the expression of miR-19b and ABCA1. PMID- 30308523 TI - Bilateral suprazygomatic maxillary nerve blocks vs. infraorbital and palatine nerve blocks in cleft lip and palate repair: A double-blind, randomised study. AB - BACKGROUND: Cleft defects are common craniofacial malformations which require early surgical repair. These patients are at high risk of postoperative airway obstruction and respiratory failure. Cleft surgery may require high doses of opioids which may contribute to these complications. OBJECTIVES: To compare the effectiveness of proximal and distal approaches to blocking the maxillary nerve in patients undergoing cleft lip or cleft palate surgery. DESIGN: Randomised, controlled and double-blind study. SETTING: The current study was carried out in Guwahati (Assam, India) between April 2014 and June 2014. PATIENTS: A total of 114 patients older than 6 months who underwent cleft lip or cleft palate surgery were included. Exclusion criteria included coagulation disorders, peripheral neuropathy or chronic pain syndrome, infection in the puncture site, allergy to local anaesthetics, lack of consent and language problems or other barriers that could impede the assessment of postoperative pain. INTERVENTIONS: Patients were randomly assigned to one of two groups: proximal group (bilateral suprazygomatic maxillary nerve blocks) and distal group (bilateral infraorbital nerve blocks for cleft lip repair and bilateral greater and lesser palatine nerve blocks and nasopalatine nerve block for cleft palate surgery). MAIN OUTCOME MEASURE: The primary endpoint was the percentage of patients requiring extra doses of opioids. Secondary endpoints included pain scores, respiratory and nerve block-related complications during the first 24 h. RESULTS: In the intra-operative period, there was a significant reduction of nalbuphine consumption in the proximal group (9.1 vs. 25.4%, P = 0.02). The percentage of patients requiring intra-operative fentanyl was lower in the proximal group (16.4 vs. 30.5%, P = 0.07). There were no differences in either postoperative pain scores or in postoperative complications. No technical failure or block-related complications were reported. CONCLUSION: Bilateral suprazygomatic maxillary nerve block is an effective and safe alternative to the traditional peripheral nerve blocks for cleft lip and cleft palate surgery, in a mixed paediatric and adult population. PMID- 30308524 TI - Measurement of forces applied using a Macintosh direct laryngoscope compared with a Glidescope video laryngoscope in patients with predictors of difficult laryngoscopy: A randomised controlled trial. AB - BACKGROUND: In patients with predictive features associated with easy direct laryngoscopy, videolaryngoscoy with the GlideScope has been shown to require less force when compared with Macintosh direct laryngoscopy. OBJECTIVE: The aim of this study was to compare forces applied with Glidescope vs. Macintosh laryngoscopes in patients with predictive features associated with difficult direct laryngoscopy. DESIGN: A prospective randomised study. SETTING: Toronto General Hospital, a university tertiary centre in Canada. PATIENTS: Forty-four patients aged over 18 years, with one or more features of difficult intubation, undergoing elective surgery requiring single-lumen tracheal intubation. INTERVENTION: We measured the force applied to oropharyngeal tissues by attaching three FlexiForce Sensors (A201-25) to the concave surface of Macintosh and GlideScope laryngoscope blades.Anaesthetists or experienced anaesthesia residents performed laryngoscopies with both devices in a randomised sequence. MAIN OUTCOME MEASURES: The primary outcome was peak force. The secondary outcomes were average force and impulse force. The latter is the integral of the force over the time during which the force acted. RESULTS: Complete data were available for 40 individuals. Peak and average forces decreased with GlideScope (17 vs. 21 N, P = 0.03, and 6 vs. 11 N, P < 0.001, respectively). Laryngoscopy time increased with the GlideScope (30 vs. 18 s, P < 0.001), resulting in similar median impulse forces (206 vs. 175 N, P = 0.92). CONCLUSION: GlideScope laryngoscopy resulted in reduced peak and average forces, but as the laryngoscopy duration increased, the product of force and time (impulse force) was similar with both devices. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01814176. PMID- 30308526 TI - Testing for Human Papillomavirus Strains 16 and 18 Helps Predict the Presence of Anal High-Grade Squamous Intraepithelial Lesions. AB - BACKGROUND: More than 90% of anal cancers are caused by human papillomavirus, and human papillomavirus strains 16 and 18 are the most oncogenic. Anal high-grade squamous intraepithelial lesions are cancer precursors. Treating these high-grade intraepithelial lesions likely reduces the risk of cancer, but cytology is an imperfect screening test. OBJECTIVE: The purpose of this study was to determine whether human papillomavirus 16 and/or 18 testing better predicts the presence of high-grade squamous intraepithelial lesions. DESIGN: In this retrospective study, 894 consecutive patients underwent anal dysplasia screening with digital anorectal examination, anal cytology, high-risk human papillomavirus testing, and high-resolution anoscopy with biopsy. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of each test and for a novel screening protocol. The absolute and relative risk of high-grade squamous intraepithelial lesions for all of the cytology/human papillomavirus combinations were also calculated. SETTINGS: The study was conducted at a single practice specializing in anal dysplasia. PATIENTS: Ninety-two percent of participants were men who have sex with men. Forty-four percent were HIV-positive individuals who were well controlled on antiretroviral therapy. The median age was 50 years. MAIN OUTCOME MEASURES: The presence of high-grade squamous intraepithelial lesions as a function of human papillomavirus and the cytology results were measured. RESULTS: High-risk human papillomavirus testing alone demonstrated better sensitivity (96% vs 89%; p = 0.03) and negative predictive value (99% vs 96%; p = 0.008) over cytology. Human papillomavirus 16/18 testing increased specificity (48% to 71%; p < 0.0001) and positive predictive value (24% to 37%; p = 0.003) over testing for all of the high-risk strains. For each cytology category, high grade squamous intraepithelial lesions were more prevalent when human papillomavirus 16/18 was detected. Benign cytology with 16/18 had a 31-fold increased risk of high-grade squamous intraepithelial lesions. LIMITATIONS: This study was conducted in a single private practice specializing in anal dysplasia screening with a mostly male population, and results might not be generalizable. CONCLUSIONS: Testing of high-risk human papillomavirus strains 16/18 improves specificity and positive predictive value over cytology for anal dysplasia screening. Patients testing positive for strains 16/18 are at a high risk for high-grade squamous intraepithelial lesions and should undergo high-resolution anoscopy regardless of the cytology result. See Video Abstract at http://links.lww.com/DCR/A654. PMID- 30308525 TI - Thoracic Epidural Analgesia: Does It Enhance Recovery? AB - BACKGROUND: Thoracic epidural analgesia has been shown to be an effective method of pain control. The utility of epidural analgesia as part of an enhanced recovery after surgery protocol is debatable. OBJECTIVE: This study aimed to determine if the use of thoracic epidural analgesia in an enhanced recovery after surgery protocol decreases hospital length of stay or inpatient opioid consumption after elective colorectal resection. DESIGN: This is a single institution retrospective cohort study. SETTINGS: The study was performed at a high-volume, tertiary care center in the Midwest. An institutional database was used to identify patients. PATIENTS: All patients undergoing elective transabdominal colon or rectal resection by board-certified colon and rectal surgeons from 2013 to 2017 were included. MAIN OUTCOME MEASURES: The main outcome was length of stay. The secondary outcome was oral morphine milligram equivalents consumed during the first 48 hours. RESULTS: There were 1006 patients (n = 815 epidural, 191 no epidural) included. All patients received multimodal analgesia with opioid-sparing agents. Univariate analysis demonstrated no difference in length of stay between those who received thoracic epidural analgesia and those who did not (median, 4 vs 5 days; p = 0.16), which was substantiated by multivariable linear regression. Subgroup analysis showed that the addition of epidural analgesia resulted in no difference in length of stay regardless of an open (n = 362; p = 0.66) or minimally invasive (n = 644; p = 0.46) approach. Opioid consumption data were available after 2015 (n = 497 patients). Univariate analysis demonstrated no difference in morphine milligram equivalents consumed in the first 48 hours between patients who received epidural analgesia and those who did not (median, 135 vs 110 oral morphine milligram equivalents; p = 0.35). This was also confirmed by multivariable linear regression. LIMITATIONS: The retrospective observational design was a limitation of this study. CONCLUSION: The use of thoracic epidural analgesia within an enhanced recovery after surgery protocol was not found to be associated with a reduction in length of stay or morphine milligram equivalents consumed within the first 48 hours. We cannot recommend routine use of thoracic epidural analgesia within enhanced recovery after surgery protocols. See Video Abstract at http://links.lww.com/DCR/A765. PMID- 30308527 TI - IDIOPATHIC FULL-THICKNESS MACULAR HOLE IN AN 8-YEAR-OLD BOY. AB - PURPOSE: To report a case of idiopathic full-thickness macular hole in a young boy, which was managed surgically with good visual and anatomical outcomes. METHOD: Single case report. RESULTS: An 8-year-old boy presented for defective vision in the left eye noticed for the past 2 weeks with best-corrected visual acuity of 6/24. A large full-thickness macular hole was diagnosed clinically and was confirmed on optical coherence tomography. There was no clinical or tomographic findings suggestive of trauma or retinal degeneration. After observation for 8 weeks, the patient underwent macular hole surgery in the left eye including internal limiting membrane peeling and C3F8 gas tamponade. Intraoperatively abnormally tight vitreoretinal adherence was noted during the induction of posterior vitreous detachment. Optical coherence tomography at 1 month after surgery showed decrease in the size of macular hole suggestive of incomplete closure. Repeat optical coherence tomography at 3 months showed closed macular hole with mild foveal thinning and ellipsoid zone discontinuity with best corrected visual acuity improving to 6/18. The tomographic features and best corrected visual acuity remained stable at 6-month follow-up. CONCLUSION: We hereby report the first case, to the best of our knowledge, of a truly idiopathic full-thickness macular hole in an 8-year-old boy. Surgical treatment offers the best outcomes in these cases and should be considered at the earliest without waiting for spontaneous closure unlike in the case of traumatic full-thickness macular hole. PMID- 30308529 TI - Sideline Management of Nonmusculoskeletal Injuries by the Orthopaedic Team Physician. AB - Although recognized as the most well-trained providers to address musculoskeletal injuries, many orthopaedic surgeons do not routinely treat patients with nonmusculoskeletal issues in their clinical practice. Nonetheless, when serving as a team physician, an orthopaedic surgeon may need to initiate management of or manage many nonmusculoskeletal issues. Knowing how to accurately diagnose and initiate management of sports-related medical and surgical conditions is an important facet of being an orthopaedic team physician. Common systems that may be involved include the cerebral/neurologic, ocular, dental, respiratory/pulmonary, cardiac, abdominal, and genitourinary systems. Each of these systems has specific pathologic processes and risks related to athletic or sporting participation. Orthopaedic team physicians must have a baseline familiarity with the most common nonmusculoskeletal issues to provide comprehensive quality care to athletes and patients. PMID- 30308528 TI - Female Reproductive, Adrenal, and Metabolic Changes during an Antarctic Traverse. AB - PURPOSE: To explore the effects of the first all-female transantarctic expedition on hormonal axes pertinent to reproductive and metabolic function. METHODS: Six females (aged 28-36, BMI 24.2 +/-0.97 kgm) hauled 80kg sledges 1700km in 61 days. Estimated average energy intake was 20.8 +/- 0.103 MJ/day (4970 +/-25 kcal/day). Whole and regional body composition was measured by DXA one and two months before and 15 days after, the expedition. Body fat was also estimated by skinfold and bioimpedance immediately before and after the expedition. Basal metabolic and endocrine blood markers and, after 0.25 mg dexamethasone suppression, 1-hour 10 MUg Gonadorelin and 1.0 MUg ACTH-(1-24) tests were completed, 39-38 days pre- and 4-5 and 15-16 days post-expedition. Cortisol was assessed in hair (monthly average concentrations) and saliva (5-point day curves and two-point diurnal sampling). RESULTS: Average body mass loss was 9.37 +/-2.31 kg (p<0.0001), comprising fat mass only; total lean mass was maintained. Basal sex steroids, corticosteroids and metabolic markers were largely unaffected by the expedition except leptin, which decreased during the expedition and recovered after 15 days, a proportionately greater change than body fat. LH reactivity was suppressed prior to and during the expedition, but recovered after 15 days, while FSH did not change during or after the expedition. Cortisol reactivity did not change during or after the expedition. Basal (suppressed) cortisol was 73.25 +/-45.23 mmol/L before, 61.66 +/- 33.11 mmol/L 5 days post- and 54.43 +/-28.60 mmol/L 16 days post-expedition (p=0.67). Hair cortisol was elevated during the expedition.Maintenance of reproductive and HPA axis function in women following an extreme physical endeavor, despite energy deficiency, suggests high female biological capacity for extreme endurance exercise. PMID- 30308530 TI - Pregnancy, Penile-anal Sex and Other Sexual Behaviors in the United States, 2011 2015. AB - We used US national survey data to examine sexual behavior by pregnancy status and found that, overall, pregnant women did not differ from non-pregnant women in penile-anal sex and associated condom use. Compared to non-pregnant women, pregnant women had lower or similar reports of other sexual behaviors. PMID- 30308531 TI - Risk of Gonococcal Infection During Vaginal Exposure is Associated with high Vaginal pH and Active Menstruation. AB - BACKGROUND: An understanding of the biological reasons why 25%-35% of women resist infection during vaginal intercourse with a man infected with N. gonorrhoeae could lead to novel control measures. We sought modifiable biological bases for infection resistance by comparing women in the same core-mixing group who did or did not become infected after sexual exposure. METHODS: We enrolled 61 female contacts of index men with gonorrhoea seen at Baltimore City Health Department clinics from January 2008 through May 2012. Exposure and sexual practices and histories, co-infections, physical signs on exam, patient symptom report, and menstrual history were collected. RESULTS: Thirty-eight of the exposed women developed cervical infections (62.3%). Multiple logistic regression found that a vaginal pH >=4.5 at presentation to clinic was significantly associated with gonococcal infection (adjusted odds ratio 5.5; p = 0.037) in women who presented within one menstrual cycle, 35 days. In this group of women, there was a significant association between acquiring an N. gonorrhoeae cervical infection and sexual exposure during menstruation (adjusted odds ratio 12.5; p = 0.05). CONCLUSIONS: Modification of vaginal pH could be explored as novel strategy for reducing the risk of Neisseria gonorrhoeae infections in women. PMID- 30308532 TI - Integrating cervical cancer screening into safer conception services to improve women's health outcomes: a pilot study at a primary care clinic in South Africa. AB - BACKGROUND: Sub-optimal cervical cancer screening in low- and middle-income countries contributes to preventable cervical cancer deaths, particularly amongst HIV-positive women. We assessed feasibility and outcomes of integrating cervical cancer screening into safer conception services for HIV-affected women. METHODS: At a safer conception service in Johannesburg, South Africa, HIV-affected women desiring pregnancy received a standard package of care designed to minimise HIV transmission risks, whilst optimising pre-pregnancy health. All eligible women were offered Papanicolaou smear and those with significant pathology were referred for colposcopy before attempting pregnancy. Multivariable analyses identified associations between patient characteristics and abnormal pathology. RESULTS: In total, 454 women were enrolled between June 2015 and April 2017. At enrolment, 91% were HIV-positive, 92% were on antiretroviral treatment (ART) and 82% virally suppressed. Eighty-three percent (376/454) of clients were eligible for cervical cancer screening and 85% (321/376) of these completed screening. More than half had abnormal cervical pathology (185/321) and 20% required colposcopy for possible high-grade or persistently atypical lesions (64/321). Compared to HIV-negative women, abnormal pathology was more likely amongst HIV positive women, both those on ART <2 years [aPR 2.5: 95%CI 1.2, 5.0] and those on ART >=2 years [aPR 2.1: 95% CI 1.0, 4.2]. CONCLUSION: Integrating cervical cancer screening into safer conception care was feasible with high coverage, including for HIV-positive women. Significant pathology, requiring colposcopy, was common, even amongst healthy women on ART. Safer conception services present an opportunity for integration of cervical cancer screening to avert preventable cancer-related deaths amongst HIV-affected women planning pregnancy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30308533 TI - Causative Agents of Drug-Induced Pancreatitis: A Nationwide Assessment. AB - OBJECTIVES: The aim of this study was to analyze causes of drug-induced acute pancreatitis (DIAP) in Korea and factors associated with serious DIAP. METHODS: Case records of DIAP voluntarily reported to the Korea Adverse Event Reporting System from 2004 to 2013 were reviewed. When a patient took 2 or more drugs, each drug was identified as a potential cause. The seriousness of each case was determined based on the International Conference on Harmonization E2D Guideline. Logistic regression was performed to identify factors associated with the seriousness of DIAP. RESULTS: During the study period, 210 (0.05%) of 442,523 adverse event reports were (0.05%) DIAP. The most common causative medication of the DIAP cases with certain, probable/likely, and possible causality (n = 74) was L-asparaginase (n = 18), followed by azathioprine (n = 6), methylprednisolone (n = 6), and fenofibrate (n = 5). Serious events occurred in 43 cases (58%) with certain, probable/likely, and possible causality. They were significantly associated with the year of report (odds ratio, 0.572; P = 0.025) and the number of concurrently used medications (odds ratio, 2.659; P = 0.006). CONCLUSIONS: L Asparaginase is the most common cause of DIAP in Korea. Serious DIAP is more likely to occur in patients taking multiple medications. PMID- 30308534 TI - The Levels of Tumor Markers in Pancreatic Neuroendocrine Carcinoma and Their Values in Differentiation Between Pancreatic Neuroendocrine Carcinoma and Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: The levels of tumor markers in pancreatic neuroendocrine carcinoma (PNEC) are unknown, and imaging findings of PNEC and pancreatic ductal adenocarcinoma (PDAC) have overlaps. In this study, we show the tumor markers in PNEC and evaluate their values for distinguishing PNEC from PDAC. METHODS: Thirty three cases of PDAC and 21 cases of PNEC were retrospectively evaluated. The demographic information and clinical data were reviewed. RESULTS: Pancreatic neuroendocrine carcinoma was usually misdiagnosed (57.1%) as PDAC based on imaging findings. Abnormal carbohydrate antigen (CA) 19-9, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP) were observed in 19.0% to 28.6% of PNECs. Abnormal CA 19-9 and CA 125 levels were more common in PDAC than in PNEC (P < 0.05). Higher level of AFP was more common in PNEC than in PDAC (33.3% vs 3.0%, P < 0.05). The cutoff value of CA 19-9 for detecting PNEC was calculated as 38.5 U/mL or less with 0.788 sensitivity and 0.800 specificity. Carbohydrate antigen 19-9 (odds ratio [OR], 22.9; 95% confidence interval [CI], 2.94-179.3), AFP (OR, 0.08; 95% CI, 0.012-0.564), and CA 125 (OR, 17.4; 95% CI, 1.13-267.3) were predictors in differentiating PDAC from PNEC. CONCLUSIONS: Carbohydrate antigen 19-9, AFP, and CA 125 have potential for distinguishing hypovascularized PNEC from PDAC. PMID- 30308536 TI - Clinical Characteristics and Genetic Causes of Infantile Exocrine Pancreatic Insufficiency in Chinese Patients: Study From a Tertiary Care Center. AB - OBJECTIVE: Infantile exocrine pancreatic insufficiency is a rare disease. We examined phenotypes and performed genetic sequencing in children with this disorder. METHODS: We enrolled 4 infants with exocrine pancreatic insufficiency. Patients were characterized by phenotypes and radiologic findings. Genetic sequencing was performed. RESULTS: Average age of disease onset was 2 months. Average (standard deviation [SD]) age at diagnosis was 11.9 (7.0) months. Patients presented with chronic steatorrhea and failure to thrive. Two had mild zinc deficiency. Imaging showed pancreatic lipomatosis and metaphyseal dysplasia among all patients. For these patients with similar phenotypes, genetic sequencing revealed that 2 patients had novel UBR1 mutations (c.[3043_3046delAAAG; c.3848 + 6T > C] and c.[1850-2A > T;c.4290T > G], reference sequence NM_174916), and another 2 patients had homozygous SBDS c.258 + 2T > C mutation and SBDS c.[258 + 2T > C;c.428C > T] mutations (reference sequence NM_016038.2). All patients received pancreatic enzyme replacement therapy. CONCLUSIONS: Here we described 4 patients with infantile exocrine pancreatic insufficiency confirmed by laboratory tests and imaging. Whole-exome sequencing and Sanger sequencing showed that 2 patients had Johanson-Blizzard syndrome and 2 patients had Shwachman-Diamond syndrome. Genetic sequencing should be applied for definite diagnosis among these patients. PMID- 30308535 TI - Imaging and Cytopathological Criteria Indicating Malignancy in Mucin-Producing Pancreatic Neoplasms: A Series of 68 Histopathologically Confirmed Cases. AB - OBJECTIVES: This study aims to evaluate the performance of clinical, imaging, and cytopathological criteria in the identification of high-grade dysplasia/carcinoma (HGD/Ca) in pancreatic mucin-producing cystic neoplasms. METHODS: Sixty-eight consecutive, histopathologically confirmed mucin-producing cystic neoplasms, evaluated by endoscopic ultrasound-guided fine-needle aspiration, were enrolled; specifically, 39 branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), 21 main duct IPMNs, and 8 mucinous cystic neoplasms. The associations between HGD/Ca in histopathology and findings of endoscopic ultrasound and cytology, demographic, lifestyle, and clinical parameters were evaluated, separately in IPMNs and mucinous cystic neoplasms. RESULTS: Age 65 years or more was associated with HGD/Ca in IPMNs. In BD-IPMNs, cyst diameter 3 cm or greater (sensitivity, 68.8%; specificity, 65.2%), a mural nodule (sensitivity, 56.3%; specificity, 78.3%), main pancreatic duct diameter 5 to 9 mm (sensitivity, 50.0%; specificity, 87.0%), and suspicious cytology (sensitivity, 81.3%; specificity, 100%) signaled the presence of HGD/Ca. Similarly, in main duct IPMNs, suspicious cytology predicted HGD/Ca with high sensitivity (88.9%) and excellent specificity (100%). Regarding cytopathological criteria, in BD-IPMNs, HGD/Ca was associated with a high nuclear/cytoplasmic ratio, background necrosis, presence of papillary structures, hypochromatic nuclei, hyperchromatic nuclei, and major nuclear membrane irregularities (thickening and/or indentations). CONCLUSIONS: Clinical, imaging, and cytopathological criteria are useful in the identification of HGD/Ca in IPMNs. PMID- 30308537 TI - Natural History of Small Pancreatic Lesions Suspected to Be Nonfunctioning Pancreatic Neuroendocrine Tumors. AB - OBJECTIVES: Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are a rare disease but have been diagnosed more frequently than before. The aim of this study was to evaluate the natural course of small NF-PNETs. METHODS: We performed a retrospective analysis of patients with incidentally found small NF-PNETs (<20 mm) from 1999 to 2015. The patients who were recommended surveillance were included. RESULTS: There were 69 patients with small NF-PNETs with a mean size of 10.9 (standard deviation [SD], 3.1) mm. The average follow-up period was 52.2 (SD, 38.7) months. The changes in tumor size were as follows: increased (13.0%), sustained (84.1%), and decreased (2.9%). Eighteen were evaluated with grade 1 NF PNETs and 1 with grade 2 among the obtained tissues. Thirteen patients underwent surgery after an average 32.9 (SD, 42.6) months later. There were 7 patients of Ia, 1 of Ib, 2 of IIa, and 1 of IIb according to the pathologic stages. Two patients received reoperation for recurrent tumors, and 2 patients showed distant metastasis after surgery, but no disease-related death occurred. CONCLUSIONS: Most of the small NF-PNETs did not increase in size and seldom showed metastasis. The wait-and-see strategy can be used for NF-PNETs less than 2 cm. PMID- 30308538 TI - Twenty-four hour versus Extended Antibiotic Administration After Surgery in Complicated Appendicitis: A Randomized Controlled Trial. AB - BACKGROUND: Recent investigations noted noninferiority in short-course antimicrobial treatments following source control in abdominal infections. We set out to investigate noninferiority of a short and fixed (24-hour) antibiotic administration compared to extended treatment after source control in complicated appendicitis in a prospective single-center open-label randomized controlled trial. METHODS: After IRB approval, all consecutive adult patients (age >=18 years) with complicated appendicitis including gangrenous appendicitis, perforated appendicitis, and appendicitis with periappendicular abscess between 5/2016 and 2/2018 were randomly allocated to antibacterial therapy limited to 24 hours (short) vs. >24 hours (extended) administration after appendectomy. Primary outcomes included composite postoperative complications and Comprehensive Complication Index (CCI). Secondary outcome was hospital length of stay (HLOS). Follow-up analysis at 1 month was conducted per intention and per protocol. RESULTS: A total of 80 patients were enrolled with 39 and 41 cases allocated to the short and the extended therapy group, respectively. Demographic profile and disease severity was similar between the study groups. Overall rate of complications was 17.9% and 29.3% in the short and extended group, respectively (p=0.23). Mean CCI did not differ between the study groups (p=0.29). HLOS was significantly reduced in the short therapy group (61 +/- 34 vs. 81 +/- 40 hours, p=0.005). CONCLUSIONS: In the current prospective randomized investigation, the short (24-hours) antibiotic administration following appendectomy did not result in a worse primary outcome in complicated appendicitis. The short interval administration resulted in a significant reduction in HLOS with a major cost saving and antibacterial stewardship perspective. LEVEL OF EVIDENCE: Level II, Randomized Controlled Trial. PMID- 30308539 TI - Simultaneous damage control surgery and endovascular procedures for patients with blunt trauma in the Hybrid Emergency Room System (HERS): New multidisciplinary trauma team building. PMID- 30308541 TI - Optimizing continuous renal replacement therapy in the ICU: a team strategy. AB - PURPOSE OF REVIEW: The consideration of acute kidney injury, its incidence and its impact on the outcome of patients has grown continuously in recent years, leading to an increase in the use of renal replacement therapy (RRT) techniques. However, the successful conduct of RRT depends on the effectiveness of the entire team, doctors and nurses. It is therefore important to know the essential elements to be implemented in the ICU to ensure optimal RRT. RECENT FINDINGS: Recent studies show that the successful conduct of a RRT session requires a good knowledge of the principles of the technique, regular basic training, identification of experts, drafting clear and well followed protocols and good communication between the various stakeholders. In addition, the use of the latest advances, such as regional citrate anticoagulation, allows further optimization of therapy, only if, again, both physicians and nurses are properly trained and highly involved. SUMMARY: We now have a better understanding of the measures to be deployed to optimize RRT. Organization, training, evaluation and protocols are the key points of the team's efficiency for a safe and effective implementation of RRT. PMID- 30308540 TI - Perioperative renal protection. AB - PURPOSE OF REVIEW: The present article reviews the recent literature on the main aspects of perioperative acute kidney injury (AKI). RECENT FINDINGS: AKI occurs in 1 in every 10 surgical patients, with cardiac, orthopedic, and major abdominal surgeries being the procedures associated with the highest risk. Overall, complex operations, bleeding, and hemodynamic instability are the most consistent procedure-related risk factors for AKI. AKI increases hospital stay, mortality, and chronic kidney disease, gradually with severity. Furthermore, delayed renal recovery negatively impacts on patients' outcomes. Cell cycle arrest biomarkers seem promising to identify high-risk patients who may benefit from the bundles recommended by the Kidney Disease: Improving Global Outcomes guidelines. Hemodynamic management using protocol-based administration of fluids and vasopressors helps reducing AKI. Recent studies have highlighted the benefit of personalizing the blood pressure target according to the patient's resting reference, and avoiding both hypovolemia and fluid overload. Preliminary research has reported encouraging renoprotective effects of angiotensin II and nitric oxide, which need to be confirmed. Moreover, urinary oxygenation monitoring appears feasible and a fair predictor of postoperative AKI. SUMMARY: AKI remains a frequent and severe postoperative complication. A personalizedmulticomponent approach might help reducing the risk of AKI and improving patients' outcomes. PMID- 30308542 TI - Who is a high-risk surgical patient? AB - PURPOSE OF REVIEW: Timely identification of high-risk surgical candidates facilitate surgical decision-making and allows appropriate tailoring of perioperative management strategies. This review aims to summarize the recent advances in perioperative risk stratification. RECENT FINDINGS: Use of indices which include various combinations of preoperative and postoperative variables remain the most commonly used risk-stratification strategy. Incorporation of biomarkers (troponin and natriuretic peptides), comprehensive objective assessment of functional capacity, and frailty into the current framework enhance perioperative risk estimation. Intraoperative hemodynamic parameters can provide further signals towards identifying patients at risk of adverse postoperative outcomes. Implementation of machine-learning algorithms is showing promising results in real-time forecasting of perioperative outcomes. SUMMARY: Perioperative risk estimation is multidimensional including validated indices, biomarkers, functional capacity estimation, and intraoperative hemodynamics. Identification and implementation of targeted strategies which mitigate predicted risk remains a greater challenge. PMID- 30308543 TI - Decreased T-Cell Programmed Death Receptor-1 Expression in Pregnancy-Associated Melanoma. AB - INTRODUCTION: Pregnancy depends on tolerance of an immunologically foreign fetus through type 1 T-cell suppression. Worse melanoma outcomes have been described within 1 year of childbirth. We assessed immunopathologic factors that may account for the observed negative impact of pregnancy on outcome. MATERIALS AND METHODS: Women of child-bearing age with >=24 months follow-up were identified from our Institutional Melanoma Registry. Women with available primary tumor blocks were compared [history of childbirth within 1 year of diagnosis (CB1Y) (n = 18) vs. nonpregnant age-matched controls (n = 13)]. Immunohistochemical staining with quantification of immune infiltrates: CD68 tumor-associated macrophages, CD3 tumor-infiltrating T cells, and PD-1 activated/exhausted T cells; and hematolymphangiogenesis: CD31/D2-40 blood vessels and D2-40 lymphatics was performed by 2 blinded dermatopathologists. RESULTS: CB1Y tumors showed decreased CD3 tumor-infiltrating T cells (P < 0.05) with significantly reduced PD1 expression (P <= 0.05). The CD3:PD1 ratio was higher in CB1Y (P < 0.05). Other tested parameters did not significantly differ between the 2 groups. DISCUSSION: As PD1 expression is induced during type 1 T-cell activation, these data suggest that immune ignorance or suppression may predominate in CB1Y. Further studies are required to identify interventions that may promote tumor associated T-cell inflammation in such patients. PMID- 30308544 TI - A Blue-Gray Macule on the Back: Challenge. PMID- 30308545 TI - Primary Localized Cutaneous Amyloidosis Affecting Female Individuals of a Pakistani Pedigree. AB - Primary localized cutaneous amyloidosis is a group of rare conditions where amyloid deposition is limited to the skin without systemic manifestations. Most cases are sporadic; however, mutations in the oncostatin M receptor (OSMR) and interleukin-31 receptor A (IL31RA) genes can cause a familial form of the condition in up to 10% of cases. Here, we describe a family in which 8 female individuals are affected by either macular amyloidosis or amyloidosis cutis dyschromica. To the best of our knowledge, a sex-specific expression or the coexistence of 2 different phenotypes of primary localized cutaneous amyloidosis in 1 pedigree has not yet been reported. PMID- 30308546 TI - Comparison Between an Oral Sulfate Solution and a 2 L of Polyethylene Glycol+Ascorbic Acid as a Split Dose Bowel Preparation for Colonoscopy. AB - BACKGROUND/AIMS: This study aimed to compare the efficacy and tolerability of an oral sulfate solution (OSS) versus 2 L of polyethylene glycol/ascorbic acid (2L PEG/Asc) for bowel cleansing before colonoscopy. METHODS: A prospective, single center, single-blinded, noninferiority, randomized, controlled trial was performed. The primary outcome was the rate of successful bowel cleansing, evaluated using the Boston Bowel Preparation Scale (BBPS). Secondary outcomes were examination time, polyp, and adenoma detection rate (PDR and ADR), tolerability, and safety. Ease of use, palatability, intention to reuse, and satisfaction were evaluated using a questionnaire. RESULTS: A total of 187 participants were randomized to receive either OSS (n=93) or 2L-PEG/Asc (n=94). Successful bowel cleansing was achieved in 86.0% (80/93) of the OSS group, which was noninferior to the 2L-PEG/Asc group (88.3%, 83/94), with a difference of 2.3% by ITT analysis [95% confidence interval (CI) -12.0 to +7.4]. The withdrawal time of the OSS group was significantly shorter than that of the 2L-PEG/Asc group (11.8+/-5.2 vs. 14.3+/-8.5; P=0.016). Ease of use, palatability, intention to reuse, and satisfaction were similar between the 2 groups. Adverse events were also similar between the 2 groups. Mucosal erythema (4.3%) and aphthous lesions (2.1%) were found only in the 2L-PEG/Asc group. CONCLUSIONS: OSS was as effective as 2L-PEG/Asc for successful bowel cleansing and had acceptable tolerability. OSS is a promising and safe low-volume preparation alternative for colonoscopy. (Clinical trial registration number: NCT02761213.). PMID- 30308547 TI - Systematic Review of Drug Packaging Methods in Body Packing and Pushing: A Need for a New Classification. AB - A systematic review of the literature regarding drug packaging methods in body packing and materials used is presented, with the aim (a) to summarize data regarding the packaging methods adopted by drug trafficking organizations, (b) to support forensic pathologists and police forces to classify and describe drug packages, (c) to propose a new classification for drug packaging techniques, and (d) to better clarify the impact of packaging methods on radiological detectability.Packaging methods have been described in 2981 cases, permitting us to summarize the different materials used and to propose a new classification for packaging method based on the materials used. Information concerning the affiliation of body packers and pushers with major (or not) drug trafficking organizations and techniques used to reduce the radiological detectability of the concealed drugs have also been collected.Besides the packaging methods described over the years, our study suggests a standardized approach for the description of drug packages based on the use of different materials and packaging procedures, which provide a possible insight to the type of drug trafficking organization involved. PMID- 30308548 TI - Postarrest Steroid Use May Improve Outcomes of Cardiac Arrest Survivors. AB - OBJECTIVES: To evaluate the ramifications of steroid use during postarrest care. DESIGN: Retrospective observational population-based study enrolled patients during years 2004-2011 with 1-year follow-up. SETTING: Taiwan National Health Insurance Research Database. PATIENTS: Adult nontraumatic cardiac arrest patients in the emergency department, who survived to admission. INTERVENTIONS: These patients were classified into the steroid and nonsteroid groups based on whether steroid was used or not during hospitalization. A propensity score was used to match patient underlying characteristics, steroid use prior to cardiac arrest, the vasopressors, and shockable rhythm during cardiopulmonary resuscitation, hospital level, and socioeconomic status. MEASUREMENTS AND MAIN RESULTS: There were 5,445 patients in each group after propensity score matching. A total of 4,119 patients (75.65%) in the steroid group died during hospitalization, as compared with 4,403 patients (80.86%) in the nonsteroid group (adjusted hazard ratio, 0.74; 95% CI, 0.70-0.77; p < 0.0001). The mortality rate at 1 year was significantly lower in the steroid group than in the nonsteroid group (83.54% vs 87.77%; adjusted hazard ratio, 0.73; 95% CI, 0.70-0.76; p < 0.0001). Steroid use during hospitalization was associated with survival to discharge, regardless of age, gender, underlying diseases (diabetes mellitus, chronic obstructive pulmonary disease, asthma), shockable rhythm, and steroid use prior to cardiac arrest. CONCLUSIONS: In this retrospective observational study, postarrest steroid use was associated with better survival to hospital discharge and 1-year survival. PMID- 30308549 TI - Evaluating Delivery of Low Tidal Volume Ventilation in Six ICUs Using Electronic Health Record Data. AB - OBJECTIVES: Mechanical ventilation with low tidal volumes is recommended for all patients with acute respiratory distress syndrome and may be beneficial to other intubated patients, yet consistent implementation remains difficult to obtain. Using detailed electronic health record data, we examined patterns of tidal volume administration, the effect on clinical outcomes, and alternate metrics for evaluating low tidal volume compliance in clinical practice. DESIGN: Observational cohort study. SETTING: Six ICUs in a single hospital system. PATIENTS: Adult patients who received invasive mechanical ventilation more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tidal volumes were analyzed across 1,905 hospitalizations. Although mean tidal volume was 6.8 mL/kg predicted body weight, 40% of patients were exposed to tidal volumes greater than 8 mL/kg predicted body weight, with 11% for more than 24 hours. At a patient level, exposure to 24 total hours of tidal volumes greater than 8 mL/kg predicted body weight was associated with increased mortality (odds ratio, 1.82; 95% CI, 1.20-2.78), whereas mean tidal volume exposure was not (odds ratio, 0.87/1 mL/kg increase; 95% CI, 0.74-1.02). Initial tidal volume settings strongly predicted exposure to volumes greater than 8 mL/kg for 24 hours; the adjusted rate was 21.5% when initial volumes were greater than 8 mL/kg predicted body weight and 7.1% when initial volumes were less than 8 mL/kg predicted body weight. Across ICUs, correlation of mean tidal volume with alternative measures of low tidal volume delivery ranged from 0.38 to 0.66. CONCLUSIONS: Despite low mean tidal volume in the cohort, a significant percentage of patients were exposed to a prolonged duration of high tidal volumes which was correlated with higher mortality. Detailed ventilator records in the electronic health record provide a unique window for evaluating low tidal volume delivery and targets for improvement. PMID- 30308550 TI - Electrophysiological Assessment and Classification of Motor Pathway Function in Patients With Spinal Dural Arteriovenous Fistula. AB - PURPOSE: The diagnosis of spinal dural arteriovenous fistula (SDAVF) is difficult and often delayed because clinical features are often nonspecific. We assessed the motor function electrophysiologically in patients with SDAVF. METHODS: Motor evoked potentials after transcranial magnetic stimulation and compound muscle action potentials and F-waves after electrical stimulation in the ulnar and tibial nerves were measured from the abductor hallucis (AH) muscles in 14 patients with SDAVF (SDAVF group), 12 patients with compressive thoracic myelopathy (CTM group), and 16 normal subjects (control group). The peripheral conduction time determined from abductor hallucis muscles (PCT-AH) and the central motor conduction time determined from abductor hallucis muscles (CMCT-AH) were calculated. According to the neurological findings, patients in the SDAVF group were classified to upper motor neuron (UMN) sign and lower motor neuron (LMN) sign categories. RESULTS: CMCT-AH in the SDAVF and CMT groups were significantly longer than those in the control group. PCT-AH in the SDAVF group was significantly longer than that in the control and CMT groups. Twelve patients in the SDAVF group showed abnormal CMCT-AH and/or PCT-AH. Abnormal CMCT-AH and PCT-AH were detected in five cases that exhibited UMN sign and/or LMN sign. Three cases with abnormal CMCT-AH and normal PCT-AH exhibited UMN sign. LMN sign without UMN sign was observed in four cases with abnormal PCT-AH and normal CMCT AH. CONCLUSIONS: Our study revealed abnormalities in the corticospinal tract and/or lower motor neurons, and classified the patients with SDAVF into three types: the UMN type, LMN type, and mixed type. PMID- 30308551 TI - Total Disc Replacement Surgery in a Professional Australian Rugby League Player-A Case Report. AB - Chronic persistent lower back pain due to degenerative disc disease (DDD) of the lumbar spine is a common condition in the athletic population, which does not always improve with nonoperative treatment. We present a case report of a professional Australian rugby league player with DDD of the lumbar spine presenting with persistent lower back pain, which was not responding to conventional nonsurgical treatment. He then underwent a surgical total disc replacement of the lumbar spine and was subsequently able to return to playing professional rugby league at his previous level of competition. This is the only known documented case of a professional athlete in any form of contact sport successfully returning to his previous level of function and competition after undergoing a total disc replacement of the lumbar spine. PMID- 30308552 TI - Simultaneous bilateral neck of femur fractures in an adolescent secondary to hypocalcaemic seizure. AB - We present a rare case of a previously healthy 16-year-old boy who sustained simultaneous bilateral femoral neck fractures after a single first-time seizure episode. He was diagnosed to have severe vitamin D deficiency and secondary hyperparathyroidism. Symptomatic hypocalcemia was the cause of seizures. Both fractures were treated surgically and united at 3 months. Bilateral femoral neck fractures after seizures are very rare, especially in children. Severe vitamin D deficiency may cause seizures and also weakening of bone, predisposing to fractures without significant trauma. We recommend that paediatric cases of femoral neck fractures after seizures should be investigated for underlying metabolic disease. PMID- 30308553 TI - Agreement of radiographic measurements and patient-reported outcome in 61 patients with Legg-Calve-Perthes disease at mean follow-up of 28 years. AB - It is unclear how patient-reported outcome in patients with Legg-Calve-Perthes disease (LCPD) is correlated with radiographic outcome. It was therefore the aim of our long-term follow-up to evaluate the agreement of patient-reported outcome measures (PROM) with radiographic outcome in patients with a history of unilateral LCPD and a femoral head involvement of more than 50%. We further investigated to what extent the functional outcome (range of motion and Trendelenburg sign) correlates with PROM and radiographic outcome. At a mean follow-up of 28 years (15-42), 61 patients were investigated clinically and by plain radiography to evaluate the sphericity deviation score, femoral head enlargement and femoral neck growth inhibition. The patients also completed questionnaires for generic measures of health-related quality-of-life (ED-5D, EQ visual analogue scale), the joint-specific Harris hip score and the nonarthritic hip score questionnaire. The radiographic measures sphericity deviation score, femoral head enlargement and femoral neck growth inhibition were strongly correlated with the joint-specific PROMs (Harris hip score and nonarthritic hip score) but not with EQ-5D and EQ-visual analogue scale. Inferior range of flexion and abduction and a positive Trendelenburg sign were associated with an inferior patient-reported outcome. Our findings highlight the importance of supporting femoral head re-modelling and containment and balancing trochanteric and femoral neck growth in patients with LCPD. To capture the whole picture of the outcome after LCPD, future studies should include a combination of radiographic measurements and joint-specific and generic outcome scores. Level of Evidence: Level III. PMID- 30308554 TI - Posterior hemivertebral resection for upper thoracic congenital scoliosis: be aware of high risk of complications. AB - The treatment of congenital hemivertebrae in the upper thoracic region is challenging. The objective of this study was to investigate the outcomes of posterior hemivertebral resection for the upper thoracic region. Twenty-one patients diagnosed with upper thoracic congenital scoliosis were included. All of them received hemivertebral resection surgery via the posterior-only approach with at least 2 years of follow-up. The radiographic parameters and Scoliosis Research Society-22 score were analyzed. All the intraoperative and postoperative complications were recorded retrospectively. The segmental main curve was 35.9 degrees before surgery and 7.0 degrees at the last follow-up, with an average correction rate of 80.2%. The total main curve was 44.1 degrees before surgery and 11.6 degrees at the last follow-up, with an average correction rate of 73.9%. The caudal compensatory curve was corrected from 20.2 degrees to 7.1 degrees , with an average correction rate of 64.9%. The segmental kyphosis was corrected from 30.9 degrees to 8.9 degrees , with an average correction rate of 65.5%. The total Scoliosis Research Society-22 score significantly improved in all patients at the last follow-up, mainly resulting from the improvement of the self-image, mental health, and satisfaction domains. The following complications were found: one pedicle fracture, two malpositioned screws, one transient neurologic deficit, one implant failure, and four postoperative curve progressions. Although good radiographic deformity correction and clinical results were achieved after surgery, the incidence rate of complications was high at 42.9%; great care should be taken to prevent them, especially for postoperative curve progression (19.0%). PMID- 30308555 TI - Influence of Gestational Age and Working Memory on Math Skills in Children Aged 8 to 9 Years. AB - OBJECTIVE: Prematurity affects children's functioning in domains such as cognitive skills and math skills. However, there is limited research examining math skills as gestational age (GA) increases weekly. We aimed at determining, in a population-based cohort of children aged 8 to 9 years, the association between the GA spectrum and math skills and working memory's (WM's) role in this relationship. METHODS: Children aged 8 to 9 years in 2014 (n = 1761), from 44 primary schools in a metropolitan city, were recruited through the Memory Maestros study in 2012. GA was measured using the parent report. Math skills were measured using the Wide Range Achievement Test 4 math computation subtest (mean, 100; SD, 15), and WM was measured using 2 subtests of the Automated Working Memory Assessment. The method of analysis was multivariate linear regression, with adjustment for both WM measures and social risk indicators as potential confounders. RESULTS: A total of 1168 children (66%) had analyzable data. Compared with children of <=34-week gestation, there was a mean difference increase of 0.48 in math standard scores per weekly increase in GA (95% confidence interval, 0.11-0.85%; p = 0.01). This equates to a difference of 6.29 (0.42 SD) standard math scores between the <=34- and >=42-week group. The relationship was independent of WM. CONCLUSION: Weekly increases in GA beyond 34 weeks are associated with higher mathematics achievement scores for children aged 8 to 9 years, independent of the child's WM. This assists with identification of individuals at risk of poorer math skills. PMID- 30308556 TI - Pilot of an International Collaboration to Build Capacity to Provide Gynecologic Oncology Surgery in Botswana. AB - OBJECTIVES: Gynecologic malignancies are the leading cause of cancer death among women in Botswana. Twenty-five percent of cervical cancers present at a stage that could be surgically cured; however, there are no gynecologic oncologists to provide radical surgeries. A sustainable model for delivery of advanced surgery is essential to advance treatment for gynecologic malignancies. METHODS/MATERIALS: A model was developed to provide gynecologic oncology surgery in Botswana, delivered by US-based gynecologic oncologists in four 2-week blocks per year. A pilot gynecologic oncology campaign was planned at a district hospital. Eligible patients were identified through the gynecologic oncology multidisciplinary clinic at the regional referral hospital, where gynecologic oncology treatment planning is provided. Local providers were invited to participate to build local surgical capacity. RESULTS: One US-based gynecologic oncologist, 2 gynecologists, and 2 surgeons working in Botswana participated in the pilot campaign. Sixteen operations were performed over 7 days. Indications included cervical cancer (4), ovarian cancer (3), vulvar cancer (1), complex atypical hyperplasia (1), pre-invasive cervical disease (2), and benign disease (3), as well as 2 obstetric emergencies. The only gynecologic oncology complication was a case of bleeding requiring transfusion and postoperative intensive care unit admission. Follow-up care was coordinated through the gynecologic oncology multidisciplinary clinic. CONCLUSIONS: Periodic gynecologic oncology campaigns in settings otherwise lacking local capacity to perform advanced surgery are a feasible model to create access and build local capacity. Strong local collaboration is essential. Future strategies to increase impact include recruitment of more gynecologic oncologists to increase service and training availability. PMID- 30308557 TI - The reliability and validity of a newly developed self-rating functional scale compared with Personal and Social Performance Scale and World Health Organization Disability Assessment Schedule II. AB - A new self-rating functional scale (SRFS) was developed to assess the functionality of patients with schizophrenia, referred to the structure of Personal and Social Performance Scale (PSP). The main aim of this study was to evaluate the reliability and validity of the SRFS. A total of 210 patients with schizophrenia were recruited from outpatient clinics in six sites in China. Demographic information, SRFS, PSP, World Health Organization Disability Assessment Schedule II, and Positive and Negative Syndrome Scale were assessed. Spearman's correlation coefficient and path analysis were used to assess the reliability and validity of the SRFS. Cronbach's alpha coefficient was used to assess the internal consistency reliability. Cronbach's alpha was 0.83, and ranged from 0.80 to 0.82 stably, indicating that the scale was reliable in internal consistency. Spearman's correlation coefficient between split two parts was 0.68 (P<0.01), suggesting a moderate to strong split-half reliability. The standardized regression coefficients ranged from 0.48 to 0.79, indicating moderate construct validity. Spearman's correlation coefficients between SRFS and PSP, World Health Organization Disability Assessment Schedule II, and Positive and Negative Syndrome Scale are 0.59, 0.65, and 0.47 (all P<0.01), respectively, indicating moderate criteria validities. The SRFS is a reliable and valid instrument for assessing personal and social functionality in patients with schizophrenia. PMID- 30308558 TI - ASSESSMENT OF ANATOMICAL AND FUNCTIONAL OUTCOMES WITH OCRIPLASMIN TREATMENT IN PATIENTS WITH VITREOMACULAR TRACTION WITH OR WITHOUT MACULAR HOLES: Results of OVIID-1 Trial. AB - PURPOSE: To evaluate the anatomical and functional outcomes with ocriplasmin in patients with vitreomacular traction (VMT) with or without macular hole (MH). METHODS: In a Phase 4, multicenter, single-arm, open-label study, eligible patients (VMT with focal adhesion, without epiretinal membrane, and with MH <=400 um [if present]) received a single intravitreal injection of ocriplasmin. Nonsurgical resolution of VMT (Day 28 [primary endpoint]), best-corrected visual acuity, MH closure, vitrectomy rate, and safety were assessed through Day 180. RESULTS: Overall, 466 patients were included in the full analysis set, of whom 47.4% had VMT resolution by Day 28; resolution rates in patients with VMT without MH, VMT with MH <=250 um, and VMT with MH >250 to <=400 um were 43.4%, 68.6%, and 62.7%, respectively. Macular hole closure was higher in eyes with VMT and MH <=250 um (57.1%) than in eyes with VMT and MH >250 to <=400 um (27.5%) at Day 28. Overall, 30.8% of patients with VMT resolution gained >=10 letters in best corrected visual acuity at Day 180. Adverse events were consistent with the known safety profile of ocriplasmin. CONCLUSION: Ocriplasmin is effective for resolution of VMT without or with MH (<=400 MUm); treatment outcomes can be optimized with patient selection.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30308559 TI - CHARACTERISTICS AND CLASSIFICATION OF TYPE 3 NEOVASCULARIZATION WITH B-SCAN FLOW OVERLAY AND EN FACE FLOW IMAGES OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To study B-scan flow overlay and en face flow optical coherence tomography angiography (OCT-A) images of Type 3 neovascularization (NV) and to characterize a staging system for Type 3 NV based on the OCT-A findings. METHODS: We retrospectively collected data on consecutive treatment-naive eyes with Type 3 NV. All eyes underwent fluorescein angiography, indocyanine green angiography, structural spectral domain OCT, and OCT-A (AngioPlex). Localization and extension of abnormal flows detected by B-scan flow overlay and en face OCT-A images were assessed. RESULTS: Of 24 eyes of 22 patients with Type 3 NV, B-scan flow overlay images showed that 4.2% had telangiectatic flow in the deep retinal layer without outer plexiform layer disruption (Stage 1), 8.3% had downward intraretinal flow and subretinal flow without retinal pigment epithelium disruption (Stage 2), and 87.5% had downward flow and retinal pigment epithelium disruption (Stage 3). Of the Stage 3 eyes, 95.2% showed flow signal penetrating at the site of the retinal pigment epithelium disruption on the B-scan flow overlay images. CONCLUSION: We showed the characteristics of Type 3 NV using B-scan flow overlay and en face OCT A images. B-scan flow overlay OCT-A images seem useful to improve the detection and accurate diagnosis of Type 3 NV. PMID- 30308560 TI - CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA. AB - PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2 REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 10 genome particles during vitrectomy. Twelve-month data are reported. RESULTS: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (-4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of -2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (-36.1 [66.9] deg) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure. CONCLUSION: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained. PMID- 30308561 TI - OCULAR HYPERTENSION AFTER INTRAVITREAL INJECTION OF 2-MG TRIAMCINOLONE. AB - PURPOSE: To report the incidence and course of ocular hypertension after intravitreal injection of 2-mg triamcinolone acetonide (IVT). METHODS: In a retrospective, consecutive series, all patients receiving 2-mg IVT at a single institution between March 1, 2012, and March 1, 2017, with a minimum of 3-month follow-up were reviewed. Ocular hypertension was defined as an intraocular pressure (IOP) measurement over 24 mmHg at any follow-up visit after IVT. Patients receiving topical, periocular, or intravitreal corticosteroid other than 2-mg IVT were excluded. RESULTS: A total of 106 eyes in 100 patients receiving at least one injection of 2-mg IVT were included. Eyes received an average of 2.9 injections (range 1-17), and average patient follow-up was 15.1 months (range 3.0 52.5 months). A total of 14 eyes (13.2%) in 14 patients developed ocular hypertension after a median of 1.5 injections (range 1-9) with an average peak IOP of 29 mmHg (range 25-38 mmHg). Overall, a total of 11 eyes (10.4%) had an IOP elevation >=10 mmHg above baseline at any point after first IVT. In all cases of ocular hypertension, IOP was successfully managed with observation or topical IOP lowering medication alone; no patients required surgical intervention. CONCLUSION: Ocular hypertension developed in 13.2% of eyes receiving intravitreal injection of 2-mg triamcinolone acetonide. Incidence of ocular hypertension after 2-mg IVT compares favorably with other intravitreally administered corticosteroids. PMID- 30308562 TI - EVOLUTION AND PATTERNS OF CHOROIDAL THICKNESS CHANGES IN RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To evaluate the changes in choroidal thickness (CT) before and after a successful pars plana vitrectomy for rhegmatogenous retinal detachment (RD), and to compare the evolution of CT with respect to the extent of RD. METHODS: Fifty four patients were divided into three groups: peripheral macula-on RD (>3 mm from the fovea; 14 eyes); paracentral macula-on RD (fovea-sparing; <=3 mm from the fovea; 14 eyes); and macula-off RD (involving the fovea; 26 eyes). Choroidal thickness was measured at 1 month (M1) and 3 months (M3) postoperatively, preoperatively in macula-on RDs, with enhanced depth imaging optical coherence tomography, from the nasal side (+2.5 mm) to the temporal side (-2.5 mm) of the fovea. RESULTS: In peripheral macula-on RD, the intereye difference in CTs showed thickening throughout follow-up (subfoveally: preoperatively = 19.6% +/- 43.9%, M1 = 22.9% +/- 27.5%, M3 = 18.2% +/- 35.6%). In paracentral macula-on RD, the intereye difference in CTs showed a thinning throughout follow-up (subfoveally: preoperatively = -7.8% +/- 21.9%, M1 =-5.5% +/- 26.1%, M3 = -9.3% +/- 19.4%), as well as in the macula-off RD (subfoveally: M1 = -14.1% +/- 18.7%, M3 = -9.9% +/- 15%). CONCLUSION: The extent of RD was related to the evolution of the CT before and after surgery. Further studies are necessary to clarify the relationship between the changes in CT and the effects of circulatory alterations, vitrectomy, and RD.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30308563 TI - INCIDENCE AND RISK FACTORS FOR HYPOTONY AFTER 25-GAUGE PARS PLANA VITRECTOMY WITH NONEXPANSILE ENDOTAMPONADE. AB - PURPOSE: The purpose of this study was to assess the incidence and risk factors for early postoperative hypotony after 25-gauge pars plana vitrectomy with nonexpansile endotamponade. METHODS: A retrospective study of consecutive patients who underwent 25-G pars plana vitrectomy. Hypotony was defined as an intraocular pressure of 5 mmHg or less after surgery and ocular hypertension as an intraocular pressure greater than 21 mmHg. RESULTS: Overall, 307 eyes of 307 patients with a mean age of 61.7 +/- 14.3 of which 56.7% were males were included. Hypotony was identified in 5.2% of cases (n = 16) at Day 1 and 0.7% (n = 2) at Week 1 with no hypotony-related complications. The hypotony group had a higher number of previous vitreoretinal surgeries (1.5 +/- 1.1 vs. 0.4 +/- 0.7, P < 0.001) and a higher prevalence of preoperative ocular hypertension (22.2% vs. 4.8%, P = 0.02), pseudophakia (77.8% vs. 48.4%, P = 0.01), silicone oil removal (61.1% vs. 8.3%, P < 0.001), and external diathermy performed (55.6% vs. 20.1%, P = 0.001). In stepwise multivariate analysis, significant parameters were silicone oil removal (R = 16.34%, odds ratio 13.45, P < 0.001), pseudophakia (R = 5.69%, odds ratio 3.65, P = 0.03), and younger age (R = 2.68%, odds ratio 0.96, P = 0.04). CONCLUSION: Silicone oil removal is a significant risk factor for early postoperative hypotony after 25-G pars plana vitrectomy. PMID- 30308564 TI - Correspondence. PMID- 30308565 TI - CHANGES OF CONE PHOTORECEPTOR MOSAIC IN AUTOSOMAL RECESSIVE BESTROPHINOPATHY. AB - PURPOSE: To assess the morphological changes of cone photoreceptors in eyes with autosomal recessive bestrophinopathy. METHODS: Both eyes of five patients with autosomal recessive bestrophinopathyunderwent spectral domain optical coherence tomography and adaptive optics fundus imaging. The cone photoreceptor densities were measured at intervals of 100 MUm between 500 MUm nasal and temporal eccentricities from the foveal center. RESULTS: The median age of the patients was 30 years (range, 23-45 years), and the best-corrected visual acuity ranged from 20/20 to 20/80. Adaptive optics fundus images showed reduced cone photoreceptor densities corresponding to the damages of the photoreceptor layer in the spectral domain optical coherence tomography images in four patients with relatively good best-corrected visual acuity. The cone photoreceptor densities at the center of the fovea were less than one-third of the normal cone densities (range 11,600-30,400 cells/mm). Cone photoreceptor mosaics were visible over the lesions with serous retinal detachment and retinal edema, although they were partially hyporeflective. CONCLUSION: There is a significant cone photoreceptor loss in the macular region of patients with autosomal recessive bestrophinopathy, although they had relatively good visual acuity. Monitoring cone photoreceptors by adaptive optics fundus imaging should provide accurate assessments of the disease status and indications for future therapeutic interventions. PMID- 30308566 TI - Prelicensure Nursing Students' Attitudes and Perceptions of End-of-Life Care. AB - BACKGROUND: It is important that education on palliative care begin early in prelicensure nursing education because of the complex care needs of patients requiring end-of-life care. PROBLEM: Nursing students often lack confidence and skills in providing quality care for these patients. APPROACH: Nursing students' attitudes on end-of-life care were assessed using the Frommelt Attitudes Toward Care of the Dying scale. Students were tested as sophomores, then again as seniors, in a nursing program where the End-of-Life Nursing Education Consortium (ELNEC) curriculum had previously been integrated. OUTCOMES: Seniors reported improved comfort levels providing end-of-life care. CONCLUSION: Assessing for improved comfort levels among nursing students who receive ELNEC training could help support ongoing efforts to integrate this education in all nursing programs. Students who had formal education in end-of-life care were more comfortable caring for patients at end of life and had a better understanding of their role. PMID- 30308567 TI - Horizontal Integration of Concepts: An Innovative Teaching Strategy. AB - BACKGROUND: Horizontal integration of a prelicensure nursing curriculum is an innovative discipline-specific teaching-learning strategy for facilitating interactive learning and achievement of quality student learning outcomes. PURPOSE: The purpose of this article is to describe the impact of the horizontal integration of an nursing curriculum on students' attendance, collaboration for interactive learning, course grades, and satisfaction with the course learning outcomes. METHODS: An intervention of horizontal integration of 2 courses, one on nursing research and evidence-based practice and the other on mental health nursing, in an undergraduate nursing curriculum was used. RESULTS: Class attendance and student collaboration improved by 60% to 65%, and final examination scores improved by 14% to 16% for students in the intervention group. CONCLUSION: Horizontal integration of a nursing curriculum is a strategy that can improve class attendance, student collaboration, course grades, and student satisfaction with the course learning outcomes. PMID- 30308568 TI - Factors Influencing Staff's Attitude Toward Electroconvulsive Therapy: A Comparison of New Versus Experienced Electroconvulsive Therapy Clinics. AB - OBJECTIVES: Despite being a highly effective treatment, electroconvulsive therapy (ECT) is still stigmatized even among professionals. The aim of this study was to identify factors associated with a positive attitude toward ECT among health care workers. METHODS: We investigated staff's attitude and their self-assessment of knowledge while introducing ECT in 3 German psychiatric clinics. Furthermore, we compared this data to that of a clinic where ECT has been applied with a long tradition. An anonymous questionnaire was answered by n = 182 employees in the ECT-introducing clinics (novices) and n = 68 employees in the clinic with a long history of ECT (experts). RESULTS: Irrespective of the clinical history, the majority of participants approved the application of ECT in their clinic. Factors associated with a positive attitude were (a) profession (physicians presented a more positive mindset about ECT than nursing staff), (b) subjective feeling of being adequately informed, and (c) having had contact to patients undergoing ECT. Interestingly, the general attitude toward ECT did not differ between subjects who reported to have seen an ECT and those who had not. CONCLUSIONS: When introducing ECT as a new treatment into a clinic, formal information should be adapted to the needs of each profession with a special emphasis on nurses. To further increase acceptance, contact to ECT-experienced patients (professionals taught by patients) might result in a more positive attitude toward ECT than participation in an ECT treatment itself. PMID- 30308569 TI - Clozapine-Associated Aspiration During Electroconvulsive Therapy. AB - Clozapine-induced gastric hypomotility (CIGH) is an underreported, underrecognized effect from high-dose clozapine. In this report, we present a patient with treatment refractory schizophrenia receiving high-dose clozapine who aspirated during general anesthesia for electroconvulsive therapy. To our knowledge, this is the first report of aspiration under general anesthesia as a result of CIGH and highlights the potential dangers high-dose clozapine can pose on patients undergoing electroconvulsive therapy with unrecognized CIGH. PMID- 30308571 TI - Completeness of Descriptions of Repetitive Transcranial Magnetic Stimulation Intervention: A Systematic Review of Randomized Controlled Trials of rTMS in Depression. AB - OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is an innovative therapeutic option in major depressive disorder (MDD). A complete description of the procedure in reports of randomized controlled trials (RCTs) is a prerequisite for implementation of rTMS in clinical practice. The aim of this study was to evaluate the completeness of descriptions of the intervention in RCTs assessing rTMS in MDD. METHODS: We performed a systematic review of RCTs evaluating rTMS in MDD and published until August 2016. We searched PubMed, the Cochrane library, and PsycINFO to identify eligible trials. The completeness of the intervention description was evaluated by the use of an adapted-to-rTMS version of the Template for Intervention Description and Replication (TIDieR) checklist. We defined core items that are the most essential to be reported. Missing information was then sought from additional sources and by e-mailing authors. RESULTS: We identified 98 trials reporting 134 interventions. None of the interventions were completely described in the full text of the articles, even after searching additional sources. After contacting the authors, 14 (10.4%) of 134 interventions were completely described. The core items were completely described in 74 (55.2%) of 134 interventions after contacting the authors. CONCLUSIONS: We found that rTMS interventions delivered in RCTs are incompletely reported, which prevents their adequate implementation in clinical practice and accurate interpretation of their efficacy. We encourage authors, editors, and reviewers to use the existing reporting guidelines and specifically the TIDieR checklist when describing the intervention. We provide an adapted-to-rTMS TIDieR checklist that could help in the reporting of future trials.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30308570 TI - On the Concurrent Use of Self-System Therapy and Functional Magnetic Resonance Imaging-Guided Transcranial Magnetic Stimulation as Treatment for Depression. AB - OBJECTIVES: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar depression, its typical effect sizes have been modest, and methodological and conceptual challenges remain regarding how to optimize its efficacy. Linking rTMS to a model of the neurocircuitry underlying depression and applying such a model to personalize the site of stimulation may improve the efficacy of rTMS. Recent developments in the psychology and neurobiology of self-regulation offer a conceptual framework for identifying mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. We applied this framework to develop a multimodal treatment for depression by pairing self-system therapy (SST) with simultaneously administered rTMS delivered to an individually targeted region of dorsolateral prefrontal cortex identified via functional magnetic resonance imaging (fMRI). METHODS: In this proof-of-concept study, we examined the acceptability, feasibility, and preliminary efficacy of combining individually fMRI-targeted rTMS with SST. Using the format of a cognitive paired associative stimulation paradigm, the treatment was administered to 5 adults with unipolar depression in an open-label trial. RESULTS: The rTMS/SST combination was well tolerated, feasible, and acceptable. Preliminary evidence of efficacy also was promising. We hypothesized that both treatment modalities were targeting the same neural circuitry through cognitive paired associative stimulation, and observed changes in task-based fMRI were consistent with our model. These neural changes were directly related to improvements in depression severity. CONCLUSIONS: The new combination treatment represents a promising exemplar for theory-based, individually targeted, multimodal intervention in mood disorders. PMID- 30308572 TI - Obesity and stones. AB - PURPOSE OF REVIEW: The incidence of urolithiasis has shown a prominent increase in the last two to three decades and evidence-based data have clearly indicated the certain role of obesity and overweight in both children and adults. As a certain component of metabolic syndrome, 'obesity' has been found to have a significant impact on the urinary metabolic risk factors which may be important in stone formation. In this present review article, we aimed to evaluate the possible association between obesity and urolithiasis and related risk factors. The epidemiology, pathophysiology, and management of stone disease in obese cases will be discussed in detail. RECENT FINDINGS: The possible influence of overweight/obesity on the metabolic stone-forming risk factors has been subjected to several studies which in turn well demonstrated the increased risk of stone formation in this population. Although the exact underlying mechanisms are still to be outlined, some certain pathogenetic factors, namely, changes in urinary pH and increased excretion of some urinary stone components have been well demonstrated. Given this increased risk status, these cases require a more comprehensive workup for urolithiasis. Appropriate metabolic evaluation-based medical therapy alongside dietary recommendations will be effective in preventing stone formation. SUMMARY: Patients suffering from obesity problem have particular risk factors for urolithiasis when compared with their normal-weight counterparts. All efforts should be taken to increase the awareness of this problem and necessary precautions with well-planned treatment plan are the main tasks for urologists. PMID- 30308573 TI - Can ablation win against partial nephrectomy and become first line therapy in cT1a renal tumours? AB - PURPOSE OF REVIEW: Currently, small renal masses account for the largest proportion of renal tumour and small renal cell carcinomas (RCC). Although partial nephrectomy, whenever possible, is recognized as the gold standard for treatment, thermal ablation has gained increasing attention as optional treatment in a population sector harbouring small renal masses/small RCCs. The purpose of this review is to update comparative outcomes between these two options of treatment. RECENT FINDINGS: Recent observational case-control and population based cohorts applying propensity score or inverse probability treatment weighted methodology adjusting for baseline patient and tumour characteristics, compare outcomes between partial nephrectomy and thermal ablation (both cryotherapy and radiofrequency), radical nephrectomy and thermal ablation and between thermal ablation and nonsurgical management. Most of them focus on T1aRCC. SUMMARY: Comparative outcomes' evidence is limited to population-based or institutional series adjusted for baseline differences and systematic reviews. With exception of special clinical situations, thermal ablation provides similar estimated 5 year cancer and overall survival with a clear benefit in postoperative outcomes when compared to partial nephrectomy in cT1a older patients. The trade-off is more evident when thermal ablation is compared to radical nephrectomy. The advantages in terms of adverse events persist up to 1 year after treatment. Benefits are less apparent in solitary kidneys and when synchronous bilateral approaches are performed. PMID- 30308574 TI - Evaluation of the discriminative performance of the prehospital National Advisory Committee for Aeronautics score regarding 48-h mortality. AB - OBJECTIVE: The National Advisory Committee for Aeronautics (NACA) score is used by many emergency medical services to assess the severity of prehospital patients. Little is known about its discriminative performance regarding short term mortality. PARTICIPANTS AND METHODS: We retrospectively included adult missions between 2008 and 2014 in a Swiss ground and air-based emergency medical services. We excluded uninjured or dead-on-scene patients. Primary outcome was assessment of the discriminative performance of the NACA score to classify the 48 h vital status of patients. Overall discrimination was quantified using the area under receiver operating characteristic curve (AUC). We also explored the influence of epidemiological characteristics (age and sex), mechanism (trauma or nontrauma) and clinical parameters (respiratory rate, oxygen saturation, heart rate, systolic blood pressure, capillary refill time, and Glasgow Coma Scale) on its discriminative performance. We then assessed the incremental value of these variables in the classification accuracy of a rule based on these variables in addition to the NACA score. RESULTS: We included 11 567 patients out of 11 639 (72 exclusions for missing data). Overall AUC was 0.86. The score was more discriminant for trauma (AUC=0.95 vs. 0.83), and for younger patients (AUC=0.91 for 16-59 vs. 0.78 for 84-104 years). Adding age, sex, mechanism, and clinical parameters resulted in a classification rule with higher discriminative performance than NACA score alone (AUC of 0.92 vs. 0.86; P<0.001). CONCLUSION: The NACA score is an efficient way to discriminate victims regarding short-term mortality. Its performance can be enhanced by also integrating epidemiological and clinical parameters into an extended classification rule. PMID- 30308575 TI - A worldwide survey of Live liver donor selection policies at 24 centers with a combined experience of 19 009 adult living donor liver transplants. AB - BACKGROUND: While surgical technique in LDLT has evolved with a focus on donor safety and recipient challenges, the donor selection criteria remain considerably disparate. METHODS: A questionnaire on donor selection was sent to 41 centers worldwide. 24 centers with a combined experience of 19009 LDLTs responded. RESULTS: Centers were categorized into predominantly LDLT (18) or DDLT (6), and high (10) or low volume (14) centers.At the majority of centers, the minimum acceptable GRWR was < 0.7 (67%), and remnant 30% (75%). The median upper limit of donor age was 60 years and BMI 33 kg/m. At 63% centers, age influenced the upper limit of BMI inversely. Majority preferred AST and ALT <50 IU/ml. Most accepted donors with nondebilitating mild mental or physical disability and rejected donors with treated coronary artery disease, CVA and nonbrain, nonskin primary malignancies. Opinions were divided about previous psychiatric illness, substance abuse and abdominal surgery. Most performed selective liver biopsy, commonly for steatosis, raised transaminases and > 1 features of metabolic syndrome. On biopsy, all considered macrovesicular and 50% considered microvesicular steatosis important. Nearly all (92%) rejected donors for early fibrosis, and minority for nonspecific granuloma or mild inflammation. Most anatomical anomalies except portal vein type D/E were acceptable at high volume centers. There was no standard policy for pre or peroperative cholangiogram. CONCLUSIONS: This first large live liver donor survey provides insight into donor selection practices that may aid standardization between centers, with potential expansion of the donor pool without compromising safety. PMID- 30308576 TI - Donor-specific Cell-Free DNA as a Biomarker in Solid Organ Transplantation. A Systematic Review. AB - BACKGROUND: There is increasing interest in the use of noninvasive biomarkers to reduce the risks posed by invasive biopsy for monitoring of solid organ transplants (SOT). One such promising marker is the presence of donor-derived cell-free DNA (dd-cfDNA) in the urine or blood of transplant recipients. METHODS: We systematically reviewed the published literature investigating the use of cfDNA in monitoring of graft health following SOT. Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy (DTA) were extracted. Narrative analysis was performed. RESULTS: 95 manuscripts from 47 studies met the inclusion criteria (18 kidney, 7 liver, 11 heart, 1 kidney-pancreas, 5 lung, and 5 multiorgan). The majority were retrospective and prospective cohort studies, with 19 reporting DTA data. Multiple techniques for measuring dd-cfDNA were reported, including many not requiring a donor sample. dd-cfDNA falls rapidly within 2 weeks, with baseline levels varying by organ type. Levels are elevated in the presence of allograft injury, including acute rejection (AR) and infection, and return to baseline following successful treatment. Elevation of cfDNA levels are seen in advance of clinically apparent organ injury. Discriminatory power was greatest for higher grades of T cell mediated and antibody-mediated AR, with high negative predictive values. CONCLUSIONS: cfDNA is a promising biomarker for monitoring the health of solid-organ transplants. Future studies will need to define how it can be used in routine clinical practice and determine clinical benefit with routine prospective monitoring. PMID- 30308577 TI - Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis. AB - Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6-1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53-2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62-0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55-0.72; P<0.0001). In advanced MM treated with IT or BRAFi+/ MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS. PMID- 30308579 TI - Marriage and Gut (Microbiome) Feelings: Tracing Novel Dyadic Pathways to Accelerated Aging. AB - Couples influence each other's mental and physical health. This review focuses on how couples' relationships, the partners' individual and joint vulnerabilities, and their health behaviors influence health through changes in the gut microbiota, metabolism, and immune function. Couples' shared stressors and emotions and their intertwined lifestyles and routines serve to promote common disease risks in part through parallel changes in their gut microbiotas. Marital discord, stress, and depression have strong bidirectional links, fueling one another. Chronic marital stress and depression can elevate the risk for obesity, metabolic syndrome, and cardiovascular disease by altering resting energy expenditure, insulin production, and triglyceride responses following unhealthy meals. During stressful times, health behaviors typically suffer-and sleep disturbances, poor diets, and sedentary behavior all influence these metabolic pathways while also promoting gut dysbiosis. Dysbiosis increases intestinal permeability (gut leakiness), providing a mechanistic pathway from marital distress and depression to heightened inflammation and accelerated aging. Age related changes in the gut microbiota's composition and gut leakiness foster immunosenescence, as well as the progression of inflamm-aging; these age-related risks may be altered by stress and depression, diet, sleep, exercise habits, and developmental shifts in emotion regulation strategies. Consideration of the strong mutual influences that partners have on each other's mood and health behaviors, as well as the biological pathways that underlie these influences, provides a new way to view marriage's health implications. PMID- 30308578 TI - Disease progression of nonalcoholic steatohepatitis in Taiwanese patients: a longitudinal study of paired liver biopsies. AB - OBJECTIVES: Nonalcoholic steatohepatitis (NASH) might progress to fibrosis, cirrhosis, and hepatocellular carcinoma. However, the natural history of NASH has not been fully clarified. This study aimed to investigate the disease progression in NASH patients receiving paired liver biopsies. We also aimed to examine the factors associated with NASH progression. PATIENTS AND METHODS: Ten NASH patients who had received liver biopsies during June 2001 and February 2010 were consecutively enrolled. The histopathological changes were examined retrospectively, including nonalcoholic fatty liver disease activity score (NAS) and fibrosis stage. The associated clinical profiles were also analyzed. RESULTS: The median duration between paired biopsies was 20.5 months (range: 12-106 months). According to NAS and fibrosis stage, disease progression, stable disease, and disease regression were observed in seven patients, two patients, and one patient, respectively. Six (60%) patients had increased NAS on second biopsy, and two were lean NASH patients. The only patient with an improvement in NAS had achieved body weight reduction (13.3%) between paired biopsies. None of the 10 patients experienced an improvement in fibrosis. Five (50%) patients showed progression of fibrosis on second biopsy and the annual fibrosis progression rate was 0.32/year. Two of the five patients who showed progression of fibrosis were of the nonobese phenotype, whereas three patients were nondiabetic. CONCLUSION: NASH is a progressive disease in Taiwanese patients. The disease progression should be further clarified in lean and nondiabetic NASH patients. PMID- 30308580 TI - Influence of Incision Size on Dry Eye Symptoms in the Small Incision Lenticule Extraction Procedure. AB - PURPOSE: To evaluate the influence of incision size on dry eye symptoms in the small incision lenticule extraction (SMILE) procedure. METHODS: Ninety-four eyes of 47 patients with myopia and/or myopic astigmatism who had undergone the SMILE procedure were enrolled in this study. The patients were divided into 3 groups according to the incision size (2, 3, and 4 mm) applied during the SMILE procedure. RESULTS: There were no significant differences among the groups in respect to age and sex (P values 0.251 and 0.974, respectively) and in respect to preoperative, postoperative first day, first week, first month, third month, and sixth month values of the Ocular Surface Disease Index score, tear break-up time, ST1, and staining grades. CONCLUSIONS: There was no difference in dry eye symptoms with 2-, 3-, and 4-mm incisions. In the learning period of SMILE surgery, larger incision sites can be used to make the procedure easier. PMID- 30308581 TI - Descemet's Membrane Biomimetic Microtopography Differentiates Human Mesenchymal Stem Cells Into Corneal Endothelial-Like Cells. AB - PURPOSE: Loss of corneal endothelial cells (CECs) bears disastrous consequences for the patient, including corneal clouding and blindness. Corneal transplantation is currently the only therapy for severe corneal disorders. However, the worldwide shortages of corneal donor material generate a strong demand for personalized stem cell-based alternative therapies. Because human mesenchymal stem cells are known to be sensitive to their mechanical environments, we investigated the mechanotransductive potential of Descemet membrane-like microtopography (DLT) to differentiate human mesenchymal stem cells into CEC-like cells. METHODS: Master molds with inverted DLT were produced by 2 photon lithography (2-PL). To measure the mechanotransductive potential of DLT, mesenchymal stem cells were cultivated on silicone or collagen imprints with DLT. Changes in morphology were imaged, and changes in gene expression of CEC typical genes such as zonula occludens (ZO-1), sodium/potassium (Na/K)-ATPase, paired like homeodomain 2 (PITX2), and collagen 8 (COL-8) were measured with real-time polymerase chain reaction. At least immunofluorescence analysis has been conducted to confirm gene data on the protein level. RESULTS: Adhesion of MSCs to DLT molded in silicone and particularly in collagen initiates polygonal morphology and monolayer formation and enhances not only transcription of CEC typical genes such as ZO-1, Na/K-ATPase, PITX2, and COL-8 but also expression of the corresponding proteins. CONCLUSIONS: Artificial reproduction of Descemet membrane with respect to topography and similar stiffness offers a potential innovative way to bioengineer a functional CEC monolayer from autologous stem cells. PMID- 30308582 TI - Long-Term Results of Femtosecond Laser-Enabled Keratoplasty With Zig-Zag Trephination. AB - PURPOSE: To report long-term visual and astigmatism outcomes in cases of zig-zag femtosecond laser-enabled penetrating keratoplasty (FLEK). METHODS: Retrospective review. Three hundred thirty-five eyes of 287 patients underwent (FLEK) with a zig-zag incision pattern. Patients were assessed preoperatively and underwent postoperative comprehensive examinations at standard intervals of 1, 3, 6, 9, and 12 months, and 6 months thereafter. Postoperative uncorrected distance visual acuity and spectacle-corrected distance visual acuity and manifest and topographical (Mrx cyl and Topo cyl) astigmatism were compared with preoperative values. RESULTS: Three hundred thirty-five eyes received FLEK with zig-zag configuration. Data are presented for the last recorded visit before any refractive procedure. Sutures were removed in 202 of 335 eyes at an average time to removal of 1.3 +/- 1.1 years, and a mean follow-up period of 2.9 +/- 2.1 years (range 0-10 years). After full suture removal, mean uncorrected distance visual acuity and spectacle-corrected distance visual acuity were logarithm of the minimum angle of resolution 0.84 (Snellen 20/138) +/- 0.55 and 0.33 (Snellen 20/42) +/- 0.33, respectively. Mean Mrx cyl and Topo cyl of these groups were 3.38 +/- 2.22 and 4.77 +/- 3.15, respectively. Of the total number of grafts, the rate of graft rejections was 14.0%, and the failure rate was 5.6%. CONCLUSIONS: The femtosecond laser-generated zig-zag-shaped incision results in lower manifest and topographical astigmatism than the reported average for conventional penetrating keratoplasty. Graft rejection and failure rates are similar to published data for conventional penetrating keratoplasty. PMID- 30308584 TI - Celebrating NP success. PMID- 30308583 TI - Two Femtosecond Laser LASIK Platforms: Comparison of Evolution of Visual Acuity, Flap Thickness, and Stromal Optical Density. AB - PURPOSE: To compare postoperative evolution of visual acuity, flap thickness, and stromal optical density during the first 3 months after femtosecond (FS) laser in situ keratomileusis surgery for correction of myopia using the iFS 150-kHz FS laser and LenSx FS laser platforms. METHODS: This was a prospective case series. Thirty-nine eyes treated with the iFS 150-kHz FS laser versus 38 refraction matched eyes treated with the LenSx FS laser platform were included. Visual outcomes, flap morphology, and optical density of the stroma (in both flap and residual stromal bed) were compared at 4 visits during a three-month follow-up period. RESULTS: No significant differences were found in uncorrected distance visual acuity in any of the follow-up visits (1 day -0.02 vs. -0.03; 1 week -0.04 vs. -0.03; 1 month -0.04 vs. -0.04; 3 months -0.03 vs. -0.05 logarithm of the minimum angle of resolution). Flaps created with the iFS 150-kHz FS laser were closer to the intended thickness (110 MUm) in every postoperative comparison (1 day 108.6 vs. 124.3; 1 week 107.6 vs. 123.6; 1 month 110.4 vs. 126.8; 3 months 116.2 vs. 126.5 MUm; P < 0.0001). Dispersion of values, standard deviation, intraflap range, and differences in symmetric points were lower in the iFS 150 kHz FS laser group. Flap stromal optical density was significantly higher in the LenSx FS laser group at day 1 and week 1 (134.5 vs. 158.9 gray scale unit [GSU]; P < 0.0001 and 144.8 vs. 160.1 GSU; P = 0.011, respectively). Residual stromal bed optical density was higher in the LenSx FS laser group at all postoperative visits, and the differences reached significance at 1 week postoperatively (121.9 vs. 135.4 GSU; P = 0.03). CONCLUSIONS: Although both devices provided satisfactory visual outcomes, significant differences were detected in flap parameters. Flaps made with the iFS 150-kHz FS laser were thinner, more uniform, transparent, and accurate compared with those obtained with the LenSx FS laser. PMID- 30308585 TI - Resistant functioning and/or progressive symptomatic metastatic gastroenteropancreatic neuroendocrine tumors: efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy in this setting. AB - BACKGROUND AND AIMS: Functioning and symptomatic disease resistant to conventional therapies constitutes a subset amongst neuroendocrine tumors (NETs) that are commonly considered for peptide receptor radionuclide therapy (PRRT). The aim of this study was to evaluate the efficacy of Lu-DOTATATE PRRT in this group with objective assessment criteria. MATERIALS AND METHODS: A total of 46 patients with refractory or progressive symptomatic GEP-NETs (previously treated at various stages with long-acting octreotide, chemotherapy, multikinase inhibitors, etc.) who had undergone treatment with PRRT were retrospectively analyzed. These patients were evaluated for response on three scales: clinical, biochemical parameters (tumor marker levels), and imaging (functional molecular and contrast enhanced anatomic). They were classified as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) on each scale. Furthermore, the patients were classified as (a) those who gained benefit from PRRT and (b) those who were nonresponders using predefined criteria. RESULTS: Ninety-one percent of the patient population had liver metastases, with a mean serum chromograninA level of 3307 U/ml, consistent with high volume tumor burden and refractory symptoms. Clinical symptomatic response on an analogue scale showed 54% CR, 35% PR, and 6% SD, whereas 4% showed worsening of symptoms. Biochemically, 17% CR, 28% PR, and 28% SD were observed, whereas 12% showed PD. On evaluation by imaging (PERCIST and RECIST 1.1 criteria), we observed 4% CR, 39% PR, and 36% SD, whereas 19% showed PD. The clinical scale showed the highest overall benefit of 95.6% in the population studied. CONCLUSION: The data support the evidence that PRRT could be potentially beneficial in resistant, refractory, and progressive symptomatic groups of GEP-NETs with functional disease burden. The use of a multidimensional response evaluation should be adopted (rather than only anatomical-functional imaging) and needs to be considered while managing this subset of patients. PMID- 30308586 TI - Prasugrel versus clopidogrel for residual thrombus burden in patients with ST segment elevation myocardial infarction: an optical coherence tomography study. AB - BACKGROUND: Prasugrel was shown to inhibit platelet activity more rapidly and consistently than clopidogrel. We compared the effects of prasugrel and clopidogrel on residual thrombus burden assessed by optical coherence tomography after stent implantation in patients with ST-segment elevation myocardial infarction (STEMI). PATIENTS AND METHODS: A total of 76 patients with STEMI undergoing percutaneous coronary intervention (PCI) within 12 h after the onset were retrospectively enrolled. Of them, 34 patients were treated with prasugrel (loading dose, 20 mg) and the remaining 42 with clopidogrel (loading dose, 300 mg). Stent volume and in-stent thrombus volume were assessed by post-PCI optical coherence tomography. RESULTS: Baseline clinical characteristics, angiographic findings, and PCI procedure did not differ between the two groups. There was no difference in in-stent volume between patients with prasugrel and clopidogrel [169 (134-214) versus 166 (128-210) mm, P=0.83]. Patients with prasugrel had a significantly reduced in-stent thrombus volume compared with those with clopidogrel [0.59 (0.16-1.09) vs. 1.08 (0.32-2.30) mm, P=0.03]. The mean area and maximum area of in-stent thrombus were also significantly smaller in prasugrel than in clopidogrel group [0.03 (0.01-0.05) vs. 0.05 (0.01-0.10) mm, P=0.04, and 0.45 (0.27-0.75) vs. 0.77 (0.34-1.23) mm, P=0.03, respectively]. CONCLUSION: Prasugrel more effectively reduced residual thrombus burden after stent implantation in patients with STEMI, indicating a faster and more potent platelet inhibitory effect of prasugrel compared with clopidogrel. PMID- 30308587 TI - Family history of coronary artery disease and adverse clinical outcomes in patients suffering from acute ST-segment elevation myocardial infarction. AB - BACKGROUND: A positive family history (FHx+) of coronary artery disease (CAD) is a well-known risk factor for the development of coronary pathology in first degree relatives. We sought to evaluate the association between FHx+ of CAD and clinical outcomes in patients presenting with a first ST-elevation myocardial infarction (STEMI). PATIENTS AND METHODS: A historical cohort study of all patients with a first STEMI, who were admitted to cardiac ICU between 2007 and 2016, was carried out. Univariate and multivariate analyses were carried out to compare patients with or without a FHx+ of CAD. In further analysis, propensity score matching was used to reduce differences in baseline characteristics. RESULTS: The study included 1785 patients, 365 (20%) of whom had FHx+ of CAD. FHx+ was associated with decreased in-hospital major adverse events and long-term mortality rates (hazard ratio=0.208, 95% confidence interval: 0.051-0.857; P=0.03). After propensity score matching, patients with FHx+ had decreased long term mortality rates (hazard ratio=0.105, 95% confidence interval: 0.033-0.33; P<0.001). CONCLUSION: In this large cohort of patients with STEMI, FHx+ was associated with better short-term and long-term outcomes. Understanding the rule of FHx in patients with STEMI is important to evaluate the prognosis and may help to construct a prediction model for patients admitted to cardiac ICU. PMID- 30308588 TI - Safety and efficacy of dedicated guidewire and microcatheter technology for chronic total coronary occlusion revascularization: principal results of the Asahi Intecc Chronic Total Occlusion Study. AB - BACKGROUND: Limited study has detailed the procedural outcomes and utilization of contemporary coronary guidewires and microcatheters designed for chronic total occlusion (CTO) percutaneous revascularization and with application of modern techniques. PATIENTS AND METHODS: A prospective, multicenter, single-arm trial was conducted to evaluate procedural and in-hospital outcomes among 163 patients undergoing attempted CTO revascularization with specialized guidewires and microcatheters. The primary endpoint was defined as successful guidewire recanalization and absence of in-hospital cardiac death, myocardial infarction, or repeat target vessel revascularization (major adverse cardiac events). RESULTS: The prevalence of diabetes was 42.9%; prior myocardial infarction, 41.1%; and previous bypass surgery, 36.8%. Average (mean+/-SD) CTO length was 41+/-29 mm, and mean Japanese CTO score was 2.6+/-1.3. A guidewire support catheter was used in 91.7% of cases, and the mean number of CTO-specific guidewires per procedure was 3.1+/-2.9. Overall, procedural success was observed in 73.0% of patients. The rate of successful guidewire recanalization was 89.0%, and absence of in-hospital major adverse cardiac event was 81.0%. Methods included antegrade (45.4%), retrograde (5.5%) and combined antegrade/retrograde techniques (49.1%). Total mean procedure time was 119+/-68 min; mean radiation dose, 2613+/-1881 mGy; and contrast utilization, 287+/-142 ml. Clinically significant perforation resulting in hemodynamic instability and/or requiring intervention occurred in 13 (8.0%) patients. CONCLUSION: In this multicenter, prospective registration trial representing contemporary technique, favorable procedural success and early clinical outcomes inform technique and strategy using dedicated CTO guidewires and microcatheters in a high lesion complexity patient population. PMID- 30308589 TI - Quality Improvement Program Outcomes for Endotracheal Intubation in the Emergency Department. AB - OBJECTIVES: We describe our 3-year experience with endotracheal intubation (ETI) outcomes during a multidisciplinary emergency department (ED)-based quality improvement (QI) program. METHODS: This was a single-center, observational study taking place during a QI program. We used a registry for airway management performed in the ED from April 2014 to February 2017. The QI program focused on procedural standardization, airway management education, and comprehensive preparation of airway equipment. The primary outcome was first-pass success (FPS) rate. The secondary outcomes were multiple-attempts rate and overall rate of complications. RESULTS: A total of 1087 emergent ETIs were included. The FPS rate significantly increased from 68% in the first year to 74% in the second year and 79% in the third year (P for trend <0.01). The multiple-attempts rate in the first year was 12%, followed by 7% and 6% in the second and third years, respectively (P for trend <0.01). The overall complication rate was 16% in the first year, 8% in the second year, and 8% in the third year (P for trend <0.01). CONCLUSIONS: We observed improved ETI outcomes in the ED, including increased FPS rate and decrease in multiple-attempt rate and overall complication rate during the multidisciplinary QI program to enhance patient safety. PMID- 30308591 TI - Infrastructure Design: A Critical Element in the Care of the Patient With Obesity. AB - The worldwide rate of obesity continues to rise, causing healthcare systems to morph to meet the demands posed by the concomitant increase in comorbidities associated with this condition. Increasing patient weight imposes its own constraints on the safety of patients and providers; therefore, a sound healthcare facility infrastructure is required to properly address the medical needs of patients with obesity. Currently, most healthcare systems-in their attitudes, equipment, and facility design-are ill equipped to meet the needs of this epidemic. In this article, we discuss the facilities and equipment design considerations in providing medical care to patients with obesity. Extending beyond the physical plant, we also touch on organizational elements that enable the healthcare provider to safely care for this challenging patient population. The rising prevalence and disease burden of excess adiposity highlight the obligation to recognize that the design needs common to all of our patients must include the particular needs of the patient with obesity. PMID- 30308590 TI - An Analysis of the FDA MAUDE Database and the Search for Cobalt Toxicity in Class 3 Johnson & Johnson/DePuy Metal-on-Metal Hip Implants. AB - INTRODUCTION: This study was designed to determine whether systemic cobalt toxicity as an adverse event could be documented using the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for cobalt-chromium containing hip implant recipients. Class 3 Johnson & Johnson (J&J)/DePuy devices were chosen for analysis because of the large number of adverse event reports related to their Pinnacle and ASR XL Acetabular hip replacement systems. A secondary goal was to characterize the reporters who are populating the information in the MAUDE database and to evaluate the quality of the data and information submitted. METHODS: Using FDA MAUDE downloadable data files, 83,528 adverse event medical device narrative reports were identified with the product code of KWA (Prosthesis, Hip, Semiconstrained [Metal Uncemented Acetabular Component]) for J&J/DePuy (KWA Text File). These are class 3 devices and devices with known high failure rates. The ASR XL Acetabular hip replacement Systems and Pinnacle fall into this category. This group of implants was chosen because implant failure is associated with elevated cobalt levels. Two additional subfiles were created from Free Text records in the narrative reports containing key words that indicated a chromium or cobalt (CrCo) device and another for key words indicating elevated levels of cobalt or toxicity. These files were then searched for symptoms of systemic cobalt toxicity with Microsoft Excel using key words pertaining to symptom categories of: cognitive/memory loss, tremor, neuropathy, depression, auditory symptoms, visual symptoms, cardiac, and thyroid disease. Reports are submitted to the FDA at the device component level. It was common for multiple reports to be submitted for a single device. RESULTS: It was not possible to differentiate systemic versus local symptoms for adverse event reports in the neuropathy category. This category was not analyzed. The number of adverse event reports in the other categories ranged from 119 to 16 for the J&J/DePuy KWA Text File and 59 to 4 in the file of records having key words indicating potential elevation of CrCo or toxicity. Cardiac, visual, and auditory conditions were most frequently reported. With the possible exception of cardiomyopathy, the numbers of these reports are far below the prevalence expected in the general population of comparable age. The content of the MAUDE database records often contained little objective data. We found less than 4% of 14,714 records, which indicated cobalt elevation or toxicity contained units for quantitative measurement. There was also frequent use of nondescript, all encompassing words and phrases such as "mental anguish," found in 321 KWA Text File records. Manufacturers submitted more than 99% of the reports and the most common reporter occupation was attorney, found in 42.24% of the 83,550 J&J/DePuy KWA Reporter File records. Physician was the reporter's occupation in 20.48% of reports but seldom reported directly to the FDA. CONCLUSIONS: We were not able find in the FDA MAUDE database meaningful warning signs to support the contention that chromium-cobalt-containing Class 3 J&J and DePuy hip implants caused systemic neurological or thyroid symptoms in patients. The incidence of reported cardiomyopathy was rare but frequent enough to be cause of concern. The redaction of most patient data along with the nonstructured nature of data entry would be expected to hinder the identification of warning signs. Even identification of the type of device could not be consistently carried out. In addition, the FDA needs to implement a methodology to identify and group all reports from a single device implanted into a patient, so duplication of event counting would not occur. Of 83,550 J&J/DePuy KWA Reporter File records, we found only two physician reports sent directly to the FDA. Almost all reports are submitted by manufacturers and are most commonly authored by attorneys. A standard of care needs to be set for physicians to report medical device adverse events to the FDA. PMID- 30308592 TI - Examining Medical Office Owners and Clinicians Perceptions on Patient Safety Climate. AB - OBJECTIVE: An essential element of effective medical practice management is having a shared set of beliefs among members regarding patient safety climate. Recognizing the need for improving patient safety, the Agency for Healthcare Research and Quality began a series of surveys to assess medical practice members' attitudes and beliefs on patient safety climate. The aim of the study was to examine owners and clinicians perceptions of their medical practice's patient safety climate. METHODS: We used the 2010-2011 Medical Office Survey on Patient Safety Culture collected by the Agency for Healthcare Research and Quality. We used hierarchical linear modeling to examine owners' and clinicians' perceptions of practice's patient safety climate while controlling for the nested nature of individuals within practices. RESULTS: Managers with ownership responsibility, clinicians with ownership responsibility, and staff clinicians have different perceptions of the practice's patient safety climate. In particular, managers with ownership responsibility have more positive perceptions of the patient safety climate, as compared with non-owners. Clinicians with ownership responsibility had less favorable views than managers in a similar role. Finally, staff clinicians have the most negative perceptions of patient safety climate as compared with individuals in the ownership positions. CONCLUSIONS: There is a statistically significant lack of agreement among medical office team members depending on their backgrounds and roles. Increasing the communication among organizational members about their practice's patient safety climate is a principal aim whether improvements in care quality are to be achieved. PMID- 30308593 TI - Interaction between low-density lipoprotein-cholesterolaemia, serum uric level and incident hypertension: data from the Brisighella Heart Study. AB - OBJECTIVE: Previous evidence suggest that high low-density lipoprotein cholesterol (LDL-C) and serum uric acid (SUA) levels are risk factors for endothelial dysfunction and vascular ageing. The aim of our study was to evaluate the short-term interaction between SUA, LDL-C and incident hypertension in a sample of overall healthy individuals. METHODS: In January 2018, we selected from the general database of the Brisighella Heart Study four groups of age and sex matched nonhypertensive individuals with different levels of LDL-C and SUA level and examined during the 2008 population survey. Incident hypertension has been defined as the increase of SBP values over 140 mmHg and/or of DBP over 90 mmHg and or the beginning of an antihypertensive treatment. RESULTS: In a model adjusted for age, sex, baseline blood pressure, family history of hypertension, smoking status, BMI and physical activity intensity, hazard rations for hypertension development compared with individuals with baseline normal LDL-C and SUA levels are 1.14 [95% confidence interval (95% CI) 0.87-1.55] for individuals with isolated high LDL-C level, 1.55 (95% CI 0.96-2.48) for individuals with isolated high SUA level and 1.57 (95% CI 1.20-2.15) for individuals with both high SUA and LDL-C levels. CONCLUSION: In an overall healthy population sample, the contemporary presence of suboptimal LDL-C and SUA values is associated with an increased risk to develop hypertension. PMID- 30308594 TI - Recurrent vertigo is a predictor of stroke in a large cohort of hypertensive patients. AB - OBJECTIVE: Dizziness is associated with hypertension but there are numerous other causes. The aims of the present study were to describe the characteristics and the clinical correlates of dizziness in a large cohort of hypertensive patients, and to test its prognostic value for all-cause, cardiovascular, and stroke mortality. METHODS: A total of 1716 individuals from the OLD-HTA Lyon's cohort of hypertensive patients recruited in the 1970s were categorized according to the absence or the presence of dizziness. The dizziness group was subdivided into vertigo and other dizziness excluding vertigo. RESULTS: Multiple regression analysis demonstrated that presence of dizziness was predicted by age, female sex, coronary artery disease, and the absence of microalbuminuria. During 30 years of follow-up, we observed 956 deaths, 508 of which with a cardiovascular cause, and 114 fatal acute strokes. In the multivariate Cox regression model, the presence of dizziness had no impact on the risk for all-cause mortality [hazard ratio 0.91; 95% CI (0.78-1.06)], cardiovascular mortality [hazard ratio 0.86; 95% CI (0.70-1.05)], or stroke mortality [hazard ratio 1.27; 95% CI (0.85-1.90)]. In an analysis of the different subgroups of dizziness, only vertigo had a prognostic impact. The increased risk was particularly marked on stroke death with a hazard ratio of 2.43 (95% CI 1.33-4.46) vs. patients without dizziness and 2.22 (95% CI 1.21-4.06) vs. patients with dizziness excluding vertigo. CONCLUSION: Hypertensive patients with dizziness did not have a high-risk profile at baseline, but those with vertigo must be carefully followed over years because of the higher stroke mortality. PMID- 30308595 TI - Transgenic overexpression of glutathione S-transferase MU-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat. AB - BACKGROUND: Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase MU-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. METHOD: Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF 1alpha promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1 and SHRSP-Tg(Gstm1)2]. RESULTS: Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2 +/- 3.7 mmHg vs. SHRSP-Tg(Gstm1)1 175.5 +/- 1.6 mmHg and SHRSP-Tg(Gstm1)2 172 +/- 3.2 mmHg, P < 0.001; pulse pressure: SHRSP 58.4 +/- 0.73 mmHg vs. SHRSP-Tg(Gstm1)1 52.7 +/- 0.19 mmHg and SHRSP-Tg(Gstm1)2 40.75 +/- 0.53 mmHg, P < 0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification (RQ): SHRSP-Tg(Gstm1)1 1.95 vs. SHRSP 1.0, P < 0.01; aorta RQ: SHRSP-Tg(Gstm1)1 2.8 vs. SHRSP 1.0, P < 0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidized : reduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04 +/- 0.009 MUmol/l vs. SHRSP-Tg(Gstm1)1 0.024 +/- 0.002 MUmol/l and SHRSP-Tg(Gstm1)2 0.021 +/- 0.002 MUmol/l; (oxidized : reduced glutathione ratio): SHRSP 5.19 +/- 2.26 MUmol/l vs. SHRSP-Tg(Gstm1)1 0.17 +/- 0.111 MUmol/l and SHRSP-Tg(Gstm1)2 0.471 +/- 0.223 MUmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. CONCLUSION: These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0. PMID- 30308596 TI - Arterial stiffness in normal pregnancy at 11-13 weeks of gestation and risk of late-onset hypertensive disorders of pregnancy. AB - OBJECTIVE: We evaluated the possible correlation between pulse wave analysis (PWA) parameters measured during the first trimester of pregnancy in normotensive, low-risk women, and the development of hypertensive disorders later in pregnancy. Our hypothesis was that a still asymptomatic increase in arterial stiffness may potentially precede the onset of overt hypertension in pregnancy and that PWA could detect it. METHODS: The study population (n = 1648) was recruited at the time of prenatal screening for chromosomal abnormalities (11-12 weeks of gestation). The radial pressure waveform was obtained with an applanation tonometer (Sphygmocor, Atcor Medical, West Ryde, Australia) on pregnant women in recumbent position. Arterial stiffness was evaluated using arterial PWA. The aortic systolic pressure (aSp), aortic diastolic pressure, and aortic mean pressure, the aortic pulse pressure, the augmentation pressure, and the augmentation index were calculated. The main outcome measure was the development of hypertensive disorders later in pregnancy. RESULTS: The values of aSp (P < 0.0001), aortic diastolic pressure (P < 0.0001), aortic mean pressure (P < 0.0001), aortic pulse pressure (P = 0.0140), and augmentation index-75 (P < 0.0001) measured in the first trimester of pregnancy were significantly higher in the women who later developed hypertensive disorders of pregnancy than in those who remained normotensive. The aSp (sensitivity 72.6%; specificity 59.6%) was found to be the best predictor for the later development of hypertension. CONCLUSION: In normotensive, low-risk pregnant women, PWA may be useful for the early detection of risk for the development of hypertensive disorders of pregnancy. PMID- 30308597 TI - Performance of simplified tables for high blood pressure screening in a European pediatric population. AB - OBJECTIVE: We assessed the performance of the simplified American Academy Pediatrics (AAP) 2017 guideline table and a simplified table based on the Fourth Report blood pressure (BP) reference tables for high BP screening compared with the European Society Hypertension 2016 guideline diagnostic thresholds. METHODS: We obtained data from a cross-sectional, school-based screening study in north Greece during 2013-2016. BP was measured by mercury sphygmomanometer. The simple tables' performance for high BP was assessed by receiver operator characteristic curve analysis, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The study population included 1846 children aged 6-12 years and 986 adolescents aged 13-18 years. Compared with the European Society Hypertension 2016 classification, the AAP 2017 simple table showed AUC 0.93, sensitivity 95.5%, specificity 91.6%, PPV 35.9%, and NPV 99.7%, whereas the Fourth Report one showed AUC 0.96, sensitivity 99.2%, specificity 93.2%, PPV 42.1%, and NPV 99.9%. Comparing the prevalence of high BP by the two tables, we found agreement in 96.9% of the participants, and disagreement in 3.1% (kappa coefficient = 0.85, P < 0.001). 20.8% of the adolescents classified for further screening by the Fourth Report, but not by the AAP 2017 simple table, had BP levels at the high-normal category. CONCLUSION: Simple tables for BP screening based on age present good performance to identify children and adolescents with high BP levels. However, they may provide high rate of false positive results, and the simple table by the AAP 2017 guideline may fail to classify some adolescents eligible for further BP evaluation. PMID- 30308598 TI - Hypertension prevalence and risk factors among residents of four slum communities: population-representative findings from Port-au-Prince, Haiti. AB - OBJECTIVES: The aim of this study was to estimate the prevalence of hypertension and its risk factors among adults in four slum communities in Port-au-Prince. METHODS: Cluster area random sampling was used to select adults for a health and demographic survey, including anthropometric measurements. Hypertension was defined as SBP at least 140 mmHg and/or DBP at least 90 mmHg, or current hypertension treatment, and was age-standardized to WHO world population. Correlates of hypertension were tested using sex-stratified logistic regression. RESULTS: Overall, 20.3% of adults had hypertension (28.5% age-standardized), including 22.3% of men and 18.9% of women. Three percent of participants reported current hypertension treatment, and 49.5% of them had their hypertension controlled. Overweight/obesity (BMI >=25) was the most common risk factor (20.6% among men, 48.5% among women), while smoking was less common (11.8 and 3.9%, respectively). Increasing age and hypertension prevalence in immediate surroundings were associated with greater odds of hypertension. Among men, having in-migrated in the 3 years prior (versus >=3 years) was also associated with hypertension [adjusted odds ratio (aOR)=3.32, 95% confidence interval (95% CI): 1.79-6.17], as was overweight and obesity (aOR = 1.90, 95% CI: 1.09-3.33, and aOR = 5.73, 95% CI: 2.49-13.19, respectively) and nonreceipt of needed medical care in the preceding 6 months (aOR = 2.82, 95% CI: 1.35-5.88) among women. CONCLUSION: Hypertension prevalence was high across the age spectrum, in addition to substantial levels of overweight/obesity and unmet healthcare needs. It is important to better understand the possible effects of intraurban migration and environmental risk factors on hypertension and ensure that the benefits of increasingly cost-effective prevention and treatment programmes extend to slum residents. PMID- 30308600 TI - Denouement. PMID- 30308599 TI - Safety Follow-up of a Dengue Vaccine When Administered Concomitantly with a Yellow Fever Vaccine in Healthy Toddlers in Colombia. AB - This was a safety follow-up study conducted in 382 toddlers in Colombia who had last received dengue vaccine (CYD-TDV) 2 years before. A review of local municipal epidemiologic reports for dengue cases was also conducted for ~28 months postimmunization. One case of clinical dengue was reported; it was neither considered as severe nor related to the study vaccine. PMID- 30308601 TI - A Phase 3 Study of Micafungin Versus Amphotericin B Deoxycholate in Infants With Invasive Candidiasis: ERRATUM. PMID- 30308602 TI - Potential Transmission of Herpes Simplex Virus Via Vaginal Seeding. PMID- 30308603 TI - Shanghai Fever in a Healthy Infant: First Report in South America. PMID- 30308604 TI - Predictors of Intravenous Immunoglobulin Nonresponse and Racial Disparities in Kawasaki Disease. PMID- 30308605 TI - Utility of Point-of-care Ultrasound in Children With Pulmonary Tuberculosis. PMID- 30308606 TI - Cardiorespiratory Events After Monoclonal Antibody Prophylaxis With Palivizumab. PMID- 30308607 TI - Development and Implications of an Evidence-based and Public Health-relevant Definition of Complicated Appendicitis in Children. AB - OBJECTIVE: To characterize the influence of intraoperative findings on complications and resource utilization as a means to establish an evidence-based and public health-relevant definition for complicated appendicitis. SUMMARY OF BACKGROUND DATA: Consensus is lacking surrounding the definition of complicated appendicitis in children. Establishment of a consensus definition may have implications for standardizing the reporting of clinical research data and for refining reimbursement guidelines. METHODS: This was a retrospective cohort study of patients ages 3 to 18 years who underwent appendectomy from January 1, 2013 to December 31, 2014 across 22 children's hospitals (n = 5002). Intraoperative findings and clinical data from the National Surgical Quality Improvement Program Pediatric Appendectomy Pilot Database were merged with cost data from the Pediatric Health Information System Database. Multivariable regression was used to examine the influence of 4 intraoperative findings [visible hole (VH), diffuse fibrinopurulent exudate (DFE) extending outside the right lower quadrant (RLQ)/pelvis, abscess, and extra-luminal fecalith] on complication rates and resource utilization after controlling for patient and hospital-level characteristics. RESULTS: At least 1 of the 4 intraoperative findings was reported in 26.6% (1333/5002) of all cases. Following adjustment, each of the 4 findings was independently associated with higher rates of adverse events compared with cases where the findings were absent (VH: OR 5.57 [95% CI 3.48 8.93], DFE: OR 4.65[95% CI 2.91-7.42], abscess: OR 8.96[95% CI 5.33-15.08], P < 0.0001, fecalith: OR 5.01[95% CI 2.02-12.43], P = 0.001), and higher rates of revisits (VH: OR 2.02 [95% CI 1.34-3.04], P = 0.001, DFE: OR 1.59[95% CI 1.07 2.37], P = 0.02, abscess: OR 2.04[95% CI 1.2-3.49], P = 0.01, fecalith: OR 2.31[95% CI 1.06-5.02], P = 0.04). Each of the 4 findings was also independently associated with increased resource utilization, including longer cumulative length of stay (VH: Rate ratio [RR] 3.15[95% CI 2.86-3.46], DFE: RR 3.06 [95% CI 2.83-3.13], abscess: RR 3.94 [95% CI 3.55-4.37], fecalith: RR 2.35 [95% CI 1.87 2.96], P = < 0.0001) and higher cumulative hospital cost (VH: RR 1.97[95% CI 1.64-2.37], P < 0.0001, DFE: RR 1.8[95% CI 1.55-2.08], P = < 0.0001, abscess: RR 2.02[95% CI 1.61-2.53], P < 0.0001, fecalith: RR 1.49[95% CI 0.98-2.28], P = 0.06) compared with cases where the findings were absent. CONCLUSION AND RELEVANCE: The presence of a visible hole, diffuse fibrinopurulent exudate, intra abdominal abscess, and extraluminal fecalith were independently associated with markedly worse outcomes and higher cost in children with appendicitis. The results of this study provide an evidence-based and public health-relevant framework for defining complicated appendicitis in children. PMID- 30308609 TI - Staged Breast Operations: The Nipple Delay as an Old and New Idea. PMID- 30308608 TI - Concomitant Intraductal Papillary Mucinous Neoplasm in Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas. AB - OBJECTIVE: To determine the factors predicting the subsequent development of pancreatic ductal adenocarcinoma in remnant pancreas (PDAC-RP) after partial pancreatectomy for PDAC. SUMMARY BACKGROUND DATA: PDAC-RP after partial pancreatectomy for PDAC is currently not so rare because of improved prognosis of PDAC patients due to recent advances in surgical techniques and adjuvant therapy. However, the predictive factors related to PDAC-RP remain unknown. METHODS: We retrospectively reviewed the clinicopathological data of a consecutive series of 379 patients with PDAC treated by partial pancreatectomy between 1992 and 2015; 14 patients (3.69%) had PDAC-RP. Clinicopathological variables were compared between PDAC-RP and non-PDAC-RP. RESULTS: In univariate analysis, concomitant intraductal papillary mucinous neoplasm (IPMN) (P = 0.0005), cancer location (body/tail) (P = 0.0060), and lower T factor in UICC (P = 0.0039) were correlated with PDAC-RP development. Multivariate analysis revealed concomitant IPMN (P = 0.0135) to be an independent predictive factor for PDAC-RP. PDAC concomitant with IPMN had higher cumulative incidence of PDAC-RP (47.5%/10 yrs) than PDAC without IPMN (9.96%/10 yrs) (P = 0.0071). Moreover, the density of pancreatic intraepithelial neoplasia lesions in the background pancreas of cases of PDAC concomitant with IPMN (1.86/cm) was higher than that of cases of PDAC without IPMN (0.91/cm) (P = 0.0007). CONCLUSIONS: Concomitant IPMN in PDAC is an independent predictive factor for the development of new PDAC in remnant pancreas. Cancer susceptibility of remnant pancreas after resection for PDAC concomitant with IPMN is probably due to an increased density of pancreatic intraepithelial neoplasia lesions. PMID- 30308611 TI - Toward Long-term Livers. PMID- 30308610 TI - Smaller Inguinal Hernias are Independent Risk Factors for Developing Chronic Postoperative Inguinal Pain (CPIP): A Registry-based Multivariable Analysis of 57, 999 Patients. AB - OBJECTIVE: Impact of inguinal hernia defect size as stratified by the European Hernia Society (EHS) classification I to III on the rate of chronic postoperative inguinal pain (CPIP). BACKGROUND: CPIP is the most important complication after inguinal hernia repair. The impact of hernia defect size according to the EHS classification on CPIP is unknown. METHODS: In total, 57,999 male patients from the Herniamed registry undergoing primary unilateral inguinal hernia repair including a 1-year follow-up were selected between September 1, 2009 and November 30, 2016. Using multivariable analysis, the impact of EHS inguinal hernia classification (EHS I vs EHS II vs EHS III and/or scrotal) on developing CPIP was investigated. RESULTS: Multivariable analysis revealed for smaller inguinal hernias a significant higher rate of pain at rest [EHS I vs EHS II: odds ratio, OR = 1.350 (1.180-1.543), P < 0.001; EHS I vs EHS III and/or scrotal: OR = 1.839 (1.504-2.249), P < 0.001; EHS II vs EHS III and/or scrotal: OR = 1.363 (1.125 1.650), P = 0.002], pain on exertion [EHS I vs EHS II: OR = 1.342 (1.223-1.473), P < 0.001; EHS I vs EHS III and/or scrotal: OR = 2.002 (1.727-2.321), P < 0.001; EHS II vs EHS III and/or scrotal: OR = 1.492 (1.296; 1.717), P < 0.001], and pain requiring treatment [EHS I vs EHS II: OR = 1.594 (1.357-1.874), P < 0.001; EHS I vs EHS III and/or scrotal: OR = 2.254 (1.774-2.865), P < 0.001; EHS II vs EHS III and/or scrotal: OR = 1.414 (1.121-1.783), P = 0.003] at 1-year follow-up. Younger patients (<55 y) revealed higher rates of pain at rest, pain on exertion, and pain requiring treatment (each P < 0.001) with a significantly trend toward higher rates of pain in smaller hernias. CONCLUSIONS: Smaller inguinal hernias have been identified as an independent patient-related risk factor for developing CPIP. PMID- 30308612 TI - Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer: A Randomized Controlled Trial. AB - BACKGROUND: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) may reduce complications. METHODS: A single-center randomized controlled trial was conducted, assigning 112 patients with resectable intrathoracic esophageal cancer to either RAMIE or OTE. The primary endpoint was the occurrence of overall surgery-related postoperative complications (modified Clavien-Dindo classification grade 2-5). RESULTS: Overall surgery-related postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) [risk ratio with RAMIE (RR) 0.74; 95% confidence interval (CI), 0.57-0.96; P = 0.02]. RAMIE resulted in less median blood loss (400 vs 568 mL, P <0.001), a lower percentage of pulmonary complications (RR 0.54; 95% CI, 0.34-0.85; P = 0.005) and cardiac complications (RR 0.47; 95% CI, 0.27-0.83; P = 0.006) and lower mean postoperative pain (visual analog scale, 1.86 vs 2.62; P < 0.001) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group [RR 1.48 (95% CI, 1.03-2.13; P = 0.038)] with better quality of life score at discharge [mean difference quality of life score 13.4 (2.0-24.7, p = 0.02)] and 6 weeks postdischarge [mean difference 11.1 quality of life score (1.0-21.1; P = 0.03)]. Short- and long-term oncological outcomes were comparable at a medium follow-up of 40 months. CONCLUSIONS: RAMIE resulted in a lower percentage of overall surgery-related and cardiopulmonary complications with lower postoperative pain, better short-term quality of life, and a better short-term postoperative functional recovery compared to OTE. Oncological outcomes were comparable and in concordance with the highest standards nowadays. PMID- 30308613 TI - Is Pfannenstiel Incision the "One-Size-Fits-All" Solution for Specimen Retrieval in Colorectal Surgery? PMID- 30308614 TI - Prognostic Nutritional Index, Tumor-infiltrating Lymphocytes, and Prognosis in Patients with Esophageal Cancer. AB - OBJECTIVE: To determine whether prognostic nutritional index (PNI) affects clinical outcome through local immunity in esophageal cancers. BACKGROUND: PNI is an indicator of nutritional status and systemic immune competence, and has attracted attention as a prognostic biomarker. Tumor-infiltrating lymphocytes (TILs) are a specific histological feature of human cancers, reflecting an individual's immunological tumor response. METHODS: Using a nonbiased database of 337 curatively resected esophageal cancers, we evaluated the relationship between PNI, TILs status, CD8 expression by immunohistochemical staining, and clinical outcome. RESULTS: Compared with PNI-high cases (n = 220), PNI-low cases (n = 117) showed significantly worse overall survival (log-rank P < 0.001; hazard ratio: 2.23; 95% confidence interval: 1.56-3.18; P < 0.001; multivariate hazard ratio: 1.67; 95% confidence interval: 1.14-2.44; P = 0.008). The TILs status was also significantly correlated with overall survival (P < 0.001). In addition, PNI was significantly associated with TILs status (P < 0.001) and the CD8-positive cell count (P = 0.041). A significant relationship between the peripheral blood lymphocyte count and TILs status was also observed (P < 0.001). CONCLUSIONS: PNI and TILs score expression were associated with clinical outcome in esophageal cancer, supporting their roles as prognostic biomarkers. Considering the relationship between PNI and TILs, nutritional status and systemic immune competence may influence patient prognosis through local immune response. PMID- 30308615 TI - Implant Based Breast Reconstruction With Acellular Dermal Matrix: Safety Data From an Open-label, Multicenter, Randomized, Controlled Trial in the Setting of Breast Cancer Treatment. AB - OBJECTIVE: To evaluate clinical outcomes of using acellular dermal matrix (ADM) with implant based breast reconstructions (IBBRs) in a randomized controlled trial. SUMMARY BACKGROUND DATA: The use of ADMs in IBBRs is widespread, but link between ADM and complications remain a controversial topic. In view of reports concerning harm, we present 6-months safety data of ADM-assisted IBBR in the setting of breast cancer treatment. METHODS: An open-label, randomized, controlled trial recruiting patients from 4 centers in Sweden and 1 in UK. Eligible were women with breast cancer planned for mastectomy with immediate IBBR. Participants were randomly allocated to IBBR with or without ADM (Strattice, Branchburg, NJ), with stratification by center in blocks of 6. Main primary endpoint was number of unplanned reoperations at 24 months, and safety expressed as the incidence of adverse events with a 6-month follow-up time for all participants. Analysis were done per protocol using Fisher exact test for complications and reoperations. RESULTS: From start of enrolment on April 24, 2014, to close of trial on May 10, 2017, 135 women were enrolled, of whom 64 with ADM and 65 without ADM were included in the final analysis. Four patients (6%) in each group had reconstructive failure with implant loss, but IBBR with ADM exhibited a trend of more overall complications and reoperations (difference 0.16, 95% CI, -0.01 to 0.32, P = 0.070), and with higher risk of wound healing problems (P = 0.013). CONCLUSIONS: With 6-months follow-up for all participants, immediate IBBR with ADM carried a risk of implant loss equal to conventional IBBR without ADM, but was associated with more adverse outcomes requiring surgical intervention. Further investigation of risk factors and patient selection in a long-term follow-up is warranted.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30308616 TI - Negative Pressure Wound Therapy for Surgical-site Infections: A Randomized Trial. AB - OBJECTIVE: This study seeks to evaluate the efficacy of negative pressure wound therapy for surgical-site infection (SSI) after open pancreaticoduodenectomy. BACKGROUND: Despite improvement in infection control, SSIs remain a common cause of morbidity after abdominal surgery. SSI has been associated with an increased risk of reoperation, prolonged hospitalization, readmission, and higher costs. Recent retrospective studies have suggested that the use of negative pressure wound therapy can potentially prevent this complication. METHODS: We conducted a single-center randomized, controlled trial evaluating surgical incision closure during pancreaticoduodenectomy using negative pressure wound therapy in patients at high risk for SSI. We randomly assigned patients to receive negative pressure wound therapy or a standard wound closure. The primary end point of the study was the occurrence of a postoperative SSI. We evaluated the economic impact of the intervention. RESULTS: From January 2017 through February 2018, we randomized 123 patients at the time of closure of the surgical incision. SSI occurred in 9.7% (6/62) of patients in the negative pressure wound therapy group and in 31.1% (19/61) of patients in the standard closure group (relative risk = 0.31; 95% confidence interval, 0.13-0.73; P = 0.003). This corresponded to a relative risk reduction of 68.8%. SSIs were found to independently increase the cost of hospitalization by 23.8%. CONCLUSIONS: The use of negative pressure wound therapy resulted in a significantly lower risk of SSIs. Incorporating this intervention in surgical practice can help reduce a complication that significantly increases patient harm and healthcare costs. PMID- 30308617 TI - Relationship between Nicotine Dependency and Occupational Injury in a Japanese Large-scale Manufacturing Enterprise: A Single-Center Study. AB - OBJECTIVES: Although several studies have shown the association between smoking and occupational injury, the exact mechanism by which smoking contributes to occupational injury remains unclear. We conducted a five-year case-control study in a population of Japanese large-scale enterprise workers aimed to verify the hypothesis that nicotine dependency is positively associated with occupational injury. METHODS: A total of 3179 to 3574 male workers annually participated in this study conducted from 2008 to 2012. Employees who had an occupational injury as detailed in the company records were included in the case group, while employees who did not have any occupational injury were included in the control group. Information on smoking status, nicotine dependency (assessed according to time to first cigarette (TTF) and cigarette per day (CPD)), and potential confounders were obtained via questionnaires administered during periodic health checkups. Odds ratios (ORs) were estimated via multiple logistic regression analysis and integrated using the general variance-based fixed effects model. RESULTS: The overall adjusted OR of occupational injury in smokers was 1.71 (95% CI: 1.10-2.66). The OR for low and high nicotine dependency according to TTF was 1.52 (95% CI: 0.92-2.51) and 1.98 (95% CI: 1.15-3.41), respectively. CONCLUSIONS: Nicotine dependency was related to increased risk of occupational injury. These findings support the hypothesis that smoking is associated with occupational injury. PMID- 30308618 TI - Job-Related Determinants of Unhealthy Lifestyles. AB - OBJECTIVE: We investigate whether job-related characteristics are related to unhealthy lifestyles. We consider two components of unhealthy lifestyles, namely smoking behavior and overweight. METHODS: For our study, we use data from the German Socio-Economic Panel (SOEP). Depending on our dependent variables, we apply tobit and ordered probit estimations. We further run fixed-effects estimations since the panel structure of the SOEP allows us to follow individuals over time. Furthermore, we include interaction terms into our analysis and examine whether there are age differences concerning the relation between job related characteristics and unhealthy lifestyles. RESULTS: We find evidence that time pressure and overtime, in particular, are associated to unhealthy lifestyles. Furthermore, we find that the relationship between overtime, fixed term contracts, commuting, and unhealthy lifestyles is particularly pronounced for the elderly. CONCLUSIONS: Employees who experience high time pressure or who work more hours than defined in their employment contract are more at risk of practicing unhealthy lifestyles. The relations between overtime, fixed-term contracts, commuting, and unhealthy lifestyles are getting stronger with age. PMID- 30308619 TI - Chronic Exposure to Solvents Among Construction Painters: Reductions in Exposure and Neurobehavioral Health Effects. AB - OBJECTIVE: To assess the neurobehavioral effects of lifetime solvent exposure by comparing the performance of painters and demographically comparable controls. METHODS: Performance of exposed painters (N = 133) was compared to unexposed tapers, glaziers, or carpenters (N = 78) on the following domains: motor/perceptual speed, visual contrast, attention, working memory/planning, and visual and verbal memory. Lifetime exposure was estimated with questionnaires, field measurements, and paint composition. RESULTS: After controlling for confounders, lifetime solvent exposure did not predict reduction in performance for overall domains of function. Lifetime solvent exposures predicted subtle alterations for individual tests of verbal learning, motor coordination, and visuospatial accuracy. CONCLUSIONS: Concentrations of solvents in paints have steadily declined during the working lifetime of subjects in this study. Although reduced performance was observed on individual tests, these alterations were not consistent across tests and unlikely to be of clinical significance. PMID- 30308620 TI - Steady State Hydration Levels of Career Firefighters in a Large, Population-Based Sample. AB - OBJECTIVES: To establish the extent of steady state hypohydration among firefighters and examine factors associated with their hydration status. METHODS: Data on 450 career firefighters from 11 randomly selected fire departments had their body composition, total body water (TBW), and hypohydration status assessed using bioelectrical impedance. Measured height and weight were used to determine body mass index (BMI) and weight classification. RESULTS: The hypohydration rate was 17% and 94% of hypohydrated firefighters were obese. A one-unit increase in BMI was associated with an 83% greater likelihood of being hypohydrated. CONCLUSIONS: This study indicates that steady state hypohydration is a significant issue among obese firefighters. Current hydration policies based on previous reports that most (>90%) firefighters are hypohydrated in the steady state should be revisited and additional, confirmatory research in this area should be conducted. PMID- 30308621 TI - Occupation and Risk of Kidney Cancer in Nordic Countries. AB - OBJECTIVE: The aim of this study was to describe the occupational variation in the incidence of kidney cancer in the Nordic population. METHODS: The population comprised of 14.9 million individuals included in censuses between 1960-1990. Standardized incidence ratios (SIRs) were calculated for each occupational group. RESULTS: Significantly increased SIRs were observed in welders (1.24, 95% CI 1.14 1.35), public safety workers (1.16, 95% CI 1.08-1.25), and seamen (1.16, 95% CI 1.07-1.26). Significantly decreased SIRs were found in laboratory assistants (0.76, 95% CI 0.60-0.94) and forestry workers (0.77, 95% CI 0.72-0.83). CONCLUSIONS: A relatively small variation in the incidence of malignancies of the kidney between occupational groups was found in the cohort. There is abundant room for further progress in determining the effect of smoking in particular occupational groups. PMID- 30308622 TI - Device Measured Sedentary Behaviour Patterns in Office Based University Employees. AB - OBJECTIVE: The aim of this study was to describe device-measured patterns of sedentary behavior in self-identified sedentary university employees. METHODS: Participants (n = 78) wore the ActiGraph GT3X+ and the activPAL3 for 7 days. Data from the ActiGraph were used to identify time in sedentary behavior, light intensity, and moderate-to-vigorous physical activity. Data from the activPAL identified time sitting/lying, standing, and stepping. Breaks in sedentary time and prolonged sedentary bouts were described. RESULTS: During workdays, participants spent 65% to 79% of time sedentary, 16% in light-intensity physical activity, and 4% in moderate-to-vigorous physical activity, 76% of time was spent sitting/lying, 16% standing, and 8% stepping. Between 10 and 12 breaks in sedentary time were accumulated. CONCLUSION: Office-based university employees spend a high proportion of their time sedentary, but accumulate a high number of breaks. Whether these breaks are appropriate in timing, duration, and intensity to elicit health benefits seen in laboratory studies requires further investigation. PMID- 30308623 TI - Occupational Safety and Health of Foreign-Born, Latinx Dairy Workers in Colorado. AB - OBJECTIVE: The US dairy industry, which employs foreign-born, primarily Latinx workers, has a two-fold higher injury rate compared to the national average. Little research has been conducted to understand the factors associated with the occupational safety and health (OSH) among foreign-born, Latinx dairy workers. METHODS: Structured interviews were conducted with 55 workers to assess a variety of OSH variables, including training experiences, health outcomes, and the psychosocial environment of the dairy. RESULTS: Participants reported a high number of work-related injuries, limited awareness of the risks inherent in dairy work, and the perception that work-related injuries are unpreventable. The psychosocial environment of the dairy was found to have a significant influence on OSH outcomes. CONCLUSIONS: In addition to implementing culturally congruent OSH training for all workers, it is imperative to promote strong leadership and communication skills among dairy managers. PMID- 30308624 TI - Extracellular histones promote pulmonary fibrosis in patients with coal workers' pneumoconiosis. AB - OBJECTIVE: This investigation assessed the pro-fibrotic role that extracellular histones play in the pathogenesis of coal workers' pneumoconiosis (CWP). METHODS: The correlation of extracellular histones with small opacity profusion (SOP) and transforming growth factor-beta (TGF-beta) was analyzed. The stimulating effect of extracellular histones on pulmonary fibroblast was assessed in vitro. RESULTS: The levels of extracellular histones in plasma were positively correlated with SOP and TGF-beta in the coal miners investigated. Plasma collected from patients with CWP caused apparent lung fibroblast proliferation, while anti-H4 antibody antagonized the stimulating effect of the patient plasma by blocking histone H4. In vitro experiments showed that extracellular histones directly stimulated fibroblast proliferation. CONCLUSION: Consistent with our hypothesis, the concentrations of extracellular histones were indices of the severity of pulmonary fibrosis in simple CWP, and extracellular histones-targeted intervention could inhibit the proliferation of lung fibroblast. PMID- 30308625 TI - 60 Years of JOEM and Counting. PMID- 30308626 TI - Description of four new species of Burrowing Frogs in the Fejervarya rufescens complex (Dicroglossidae) with notes on morphological affinities of Fejervarya species in the Western Ghats. AB - The Rufescent Burrowing Frog, Fejervarya rufescens, is thought to have a wide distribution across the Western Ghats in Peninsular India. This locally abundant but secretive species has a short breeding period, making it a challenging subject for field studies. We sampled 16 populations of frogs morphologically similar to F. rufescens in order to understand the variation among populations found across the Western Ghats. Our study shows significant morphological and genetic differences among the sampled populations, suggesting that F. 'rufescens' is a complex of several undescribed species. Using evidence from morphology and genetics, we confirm the presence of five distinct species in this group and formally describe four as new. The new species were delineated using a phylogeny based on three mitochondrial genes (16S, COI and Cytb) and a haplotype network of a nuclear gene (Rag1). Hereafter, the distribution of F. rufescens is restricted to the state of Karnataka and adjoining regions of northern Kerala. Three new species (Fejervarya kadar sp. nov., Fejervarya manoharani sp. nov. and Fejervarya neilcoxi sp. nov.) are from regions south of Palghat gap in the state of Kerala, and one (Fejervarya cepfi sp. nov.) from the northern Western Ghats state of Maharashtra. These findings indicate that Fejervarya frogs of the Western Ghats are more diverse than currently known. Our results will also have implications on the conservation status of F. rufescens, which was previously categorized as Least Concern based on its presumed wide geographical distribution. Furthermore, in order to facilitate a better taxonomic understanding of this region's fejervaryan frogs, we divide all the known Fejarvarya species of the Western Ghats into four major groups-Fejervarya nilagirica group, Fejervarya rufescens group, Fejervarya sahyadris group and Fejervarya syhadrensis group, based on their morphological affinities. PMID- 30308627 TI - An additional record of Fejervarya manoharani Garg and Biju from the Western Ghats with a description of its complete mitochondrial genome. AB - An additional sighting of newly described frog species, Fejervarya manoharani Garg and Biju, outside of the type locality along with their morphological data is reported herewith. We are also providing the whole DNA sequence of the mitochondrial genome with its gene organization as additional data to distinguish this species from its congeners. The mitogenome of F. manoharani was 17,654 bp in length. It contains 38 genes including two rRNAs, 23 tRNAs, 13 protein-coding genes and a control region. Similar to other dicroglossid frogs, a tandem duplication of tRNAMet was found. The ND5 gene was located at the 3' end of the control region like in three other Fejervarya species for which mitogenomic data are available. A rearrangement of four tRNA genes, namely Leucine, Threonine, Proline, and Phenylalanine, between ND5 and 12S rRNA, differing from other Fejervarya species, was also observed. PMID- 30308628 TI - Taxonomic revision of the Dichotomius sericeus (Harold, 1867) species group (Coleoptera: Scarabaeidae: Scarabaeinae). AB - The Dichotomius sericeus species group of the subgenus Luederwaldtinia is reviewed. This group comprises eight species endemic to the South American Atlantic forests, Caatinga and associated areas of Brazil, Paraguay and Argentina: Dichotomius sericeus (Harold, 1867); Dichotomius irinus (Harold, 1867); Dichotomius laevicollis (Felsche, 1901); Dichotomius schiffleri Vaz-de Mello, Gavino Louzada, 2001; Dichotomius guaribensis sp. nov.; Dichotomius gilletti sp. nov; Dichotomius iannuzziae sp. nov; and Dichotomius catimbau sp. nov. Lectotypes are designated for D. sericeus (Harold, 1867), D. irinus (Harold, 1867), D. laevicollis (Felsche, 1901) and D.sericeus var. aterrimus (Luederwaldt, 1929) [here synonymized with D. sericeus]. In this revision each species is analyzed as follows: a detailed literature review, a diagnosis, description, illustrations of key morphological characters, list of material examined and a geographic distribution. PMID- 30308629 TI - Review of East Palaearctic species of Sympycnus Loew, 1857, with a key to species. AB - Four new species of Sympycnus Loew, 1857, S. ferganicus sp. nov., S. leleji sp. nov., S. stackelbergi sp. nov. and S. yakutensis sp. nov. from Russia (Yakutia), Kazakhstan, Kyrgyzstan, Tajikistan and Uzbekistan are described. Sympycnus convergens Negrobov, 1973 and S. urgaicus Negrobov, 1973 are placed in synonymy with S. changaicus Negrobov (syn. nov.). Lectotype and paralectotypes are designated for Sympycnus simplicipes Becker, 1908. A checklist of the East Palaearctic species of the genus is compiled and a key to males of the 14 species is provided. Five species groups are defined. New data on the distribution of known species are presented. The known distribution of East Palaearctic Sympycnus species is briefly discussed. PMID- 30308630 TI - Neotype designation for Rhinogobius carpenteri Seale 1910, and its placement in Tukugobius Herre 1927 (Teleostei: Gobiidae). AB - In order to unravel the synonymy of Rhinogobius Gill 1859, a neotype for Rhinogobius carpenteri Seale 1910, type species of its oldest synonym, Tukugobius Herre 1927, is designated and described based on topotypic material. The genus Tukugobius is removed from the synonymy of Rhinogobius from which it is distinct in having a longitudinal cephalic lateralis system, a naked pectoral-fin base, the first dorsal fin supported by 7 pterygiophores, and the first pterygiophore of the second dorsal fin inserted in interneural space 9. Its type species further differs from other species of Philippine Tukugobius by the presence of a median naked strip along the belly. PMID- 30308631 TI - The larvae of the European Helicopsyche species (Trichoptera: Helicopsychidae). AB - This synoptic paper gives descriptions of the hitherto unknown or poorly known larvae of Helicopsyche megalochari Malicky 1974 and H. revelieri McLachlan 1884 (Trichoptera: Helicopsychidae). We present information on the morphology of the larvae and illustrate the most important diagnostic features. This information is used for the construction of a comprehensive larval key to the five European species of family Helicopsychidae. In the context of this key, larvae can be easily diagnosed by setation patterns of the dorsal head capsule, submentum shape, and propleuron morphology. With respect to distribution, Helicopsyche megalochari has been reported from the Greek Islands of Andros, Euboea, Ikaria, and Naxos whereas H. revelieri is known from the islands of Capraia, Corsica, and Sardinia. In addition, ecological characteristics and distributions of the European species are briefly discussed. PMID- 30308632 TI - A new species of Isthmura (Caudata: Plethodontidae) from the montane cloud forest of central Veracruz, Mexico. AB - We describe a new plethodontid salamander species of the genus Isthmura, known only from one locality in the mountainous region of central Veracruz, Mexico. Like its congeners, Isthmura corrugata sp. nov. has a large and robust body, but it is easily distinguished from the other species in the genus by the absence of any spot or mark on the dorsum (except by dull reddish brown coloration on eyelids) and by extremely well-marked costal grooves separated by very pronounced costal folds. Based on an mtDNA phylogeny, the new species is most closely related to the geographically distant I. boneti and I. maxima but occurs very near I. naucampatepetl and I. gigantea on the eastern slope of Cofre de Perote, Veracruz. The region where I. corrugata occurs contains a high number of plethodontid salamander species and is threatened by human activity. PMID- 30308633 TI - Tapantiomyia enigmatica, new genus and species proposed for a stilt-legged and otherwise bizarre coenosiine fly (Diptera: Muscidae) from Costa Rica. AB - A new monotypic genus, Tapantiomyia gen. nov., is proposed for a new species of muscid fly, T. enigmatica sp. nov., found in the Tapanti National Park, Costa Rica. It is only known by a single male specimen taken in a Malaise trap in tropical cloud forest, but deserves immediate attention because of its bizarre, stilt-legged appearance in combination with several other unique apomorphies that preclude placement in any known genus of Muscidae. Tapantiomyia enigmatica is so strange that it tend to run out to Scathophagidae rather than Muscidae in keys to families of Diptera. However, the morphology of the male genitalia provides decisive evidence for a placement in Coenosiinae, a large and diverse group of predatory Muscidae. Two tribes, Limnophorini and Coenosiini, are currently recognized within Coenosiinae, but the monophyly of Limnophorini remains uncertain. Tapantiomyia is tentatively assigned to the Limnophorini. PMID- 30308634 TI - Stethorus spp. (Coleoptera: Coccinellidae) predatory on Schizotetranychus hindustanicus (Hirst) (Acari: Tetranychidae) from South India, including a new species and a new synonymy in Indian Stethorus. AB - Stethorus forficatus sp. nov. and Stethorus tetranychi Kapur (Coccinellidae: Stethorini) are reported as predators of the citrus hindu mite, Schizotetranychus hindustanicus (Hirst), from the southern Indian state of Tamil Nadu. Stethorus forficatus sp. nov. is described and illustrated with diagnostic notes on S. tetranychi and S. vietnamicus Hoang, morphologically its closest relatives. In a remarkable case of larval mimicry in Stethorus, the larva of this species mimics the larvae of S. tetranychi and S. pauperculus Weise. Stethorus curvus Hoang, 1985 is reduced to a new junior synonym of Stethorus keralicus Kapur, 1961 (syn. nov.). PMID- 30308635 TI - Erratum: XINGYUE LIU, XIUMEI LU, FANGYUAN XIA BO WANG (2017) First description of female of Haplosialodes liui Huang et al., 2016 (Megaloptera: Sialidae) from Cretaceous Burmese amber. Zootaxa, 4258 (2): 172-178. PMID- 30308636 TI - Key to the world species of Holoparasitus Oudemans, 1936 (Acari: Parasitiformes: Parasitidae). AB - Keys to the world species of the mite genus Holoparasitus (Parasitidae family) are provided separately for males and females. The genus includes 55 species, 42 of which are allocated to eight species groups. The Holoparasitus inornatus species group is newly defined. PMID- 30308637 TI - Description of a new and two known species of Cephaloboides Rahm, 1928 (Nematoda: Rhabditidae) from India, with discussion on the taxonomy of the genus. AB - A new species of Rhabditidae, collected from manure, is described and illustrated. Cephaloboides anisospiculus sp. n., an amphimictic species with a 1:1 sex ratio, is characterized by a small to medium-sized body (female: L = 0.5 0.7 mm, a = 13.6-20.0, b = 2.7-3.6, c = 15.4-22.7, c' = 1.0-1.8, V = 51.2-60.9), finely striated, punctated cuticle; slightly raised labial papillae; stoma with slightly anisomorphic metastegostom; presence of epiptygma; eggs measuring 37-42 x 20-24 um; slightly protruded vulval lips with cuticular flaps; rectum 16-19 um long; males with small, stout, slightly arcuate spicules with hood-like capitula and genital papillae in 1/2/(1+3)+2+P configuration; bursa leptoderan, greatly reduced and not enveloping the caudal spike. C. curvicaudatus (Schneider, 1866) Zullini, 1982 is also redescribed, with an emended diagnosis. The present population of C. curvicaudatus shows a few minor differences viz., relatively smaller 'b' value, presence of elongate capitula of spicules and strong copulatory muscle bands. Another species, C. parapapillosus (Schuurmans Stekhoven, 1951) comb. n. has been reinstated. PMID- 30308639 TI - Evidence of hybrid origin for Tachyphonus nattereri Pelzeln, 1870 (Aves: Thraupidae). AB - Tachyphonus nattereri is one of the three "mystery birds" collected almost 200 years ago by J. Natterer in Brazil whose validity has been disputed in many publications over the last century. Known only from the male holotype and perhaps a female specimen without type status, it is currently treated as either a valid species, a subspecies or a doubtful taxon (an extreme of variation or an aberrant colored individual). We reviewed the taxonomy of T. nattereri based on fieldwork near the type locality and a careful examination of the holotype and related museum specimens. Our extensive fieldwork revealed that no natural population found in the type locality matches the phenotype of T. nattereri. We found that the holotype is intermediate in plumage, morphometry and body shape between Tachyphonus cristatus and T. luctuosus, two sympatric species locally scarce and at their distributional edge around the type locality. We, therefore, suggest that T. nattereri is a hybrid. On the other hand, the purported female falls within the variation found in Tachyphonus c. madeirae, of which it probably represents an extreme phenotype. PMID- 30308638 TI - Molecular operational taxonomic units of mosquitoes (Diptera: Culicidae) collected in high Andean mountain ecosystems of Antioquia, Colombia. AB - Accurate taxonomic identification of highland mosquito species may be complicated because of the lack of comprehensive regional morphological keys and taxonomic specialists, particularly for mosquitoes of medical or ecological importance. We applied a multi-locus approach to explore the diversity of genera/species collected, to define the Molecular Operational Taxonomic Units (MOTUs) and to perform phylogenetic clustering. Twenty MOTUs and three single sequences were revealed from 78 concatenated cox1 + ITS2 sequences, and the species name was allocated for five of these. This study provides molecular taxonomic information of culicid fauna present in high Andean mountain ecosystems in Antioquia, Colombia. However, future morphological and integrative taxonomic studies should be conducted to achieve the specific identity of all detected MOTUs. PMID- 30308640 TI - Small range distributions in the high Andes: two new species of Liaghinella (Hemiptera: Heteroptera: Reduviidae: Emesinae) from Colombia. AB - Liaghinella Wygodzinsky, 1966 (Hemiptera: Heteroptera: Reduviidae: Emesinae: Metapterini), is an endemic Neotropical genus with two described species, one from Jamaica and one from Colombia. In this paper we describe two additional new species from the high Andes in Colombia, Liaghinella heldamariae sp. nov from Monserrate and Villa de Leyva, and L. tuberculata sp. nov. from Chicaque Natural Park, both in the Eastern Cordillera. The new species were collected very close to the type locality of the previously known Colombian species, L. andina Forero, 2007. These two new species differ from L. andina by having both a pair of conspicuous tubercles on the posterior margin of the pronotum, and by the structure of the male and female genitalia. Species diagnosis and descriptions, digital macrophotographies, and a key to separate the species of Liaghinella are presented. A discussion on the small range distributions exhibited by the high Andean species of Liaghinella is provided. PMID- 30308641 TI - Review of the genus Eopompilus Gussakovskij, 1932 (Hymenoptera: Pompilidae) with the description of new species from China. AB - The genus Eopompilus Gussakovskij, 1932 is reviewed. A new species, Eopompilus pseudominor Loktionov, Lelej Xu, sp. nov. is described and illustrated from China, Yunnan. A new synonymy is proposed for E. minor Gussakovskij, 1932 =E. minor itoi Ishikawa, 1965, syn. nov. A lectotype of E. orientalis Gussakovskij, 1932 is designated. The distribution of E. minor Gussakovskij and E. luteus Lelej is enlarged to include China. Araneus ventricosus (L. Koch) (Araneae, Araneidae) is a newly recorded host for E. luteus. An updated diagnosis of the genus Eopompilus, and key to females and males are given. PMID- 30308642 TI - Revision of Continental African Germalus (Heteroptera: Lygaeoidea: Geocoridae). AB - Germalus species of Continental Africa are now revised including redescription of Germalus ghesquierei Schouteden 1957 and Germalus conradsi Schouteden 1957. Two new species, Germalus oroszi sp. nov. and Germalus telekii sp. nov. are described. PMID- 30308643 TI - A century in synonymy: molecular and morphological evidence for the revalidation of Glyptosternon osshanini (Herzenstein, 1889) (Actinopterygii: Sisoridae). AB - Exostoma oschanini, presently treated as a junior synonym of Glyptosternon reticulatum, is revalidated within Glyptosternon based on a phylogenetic analysis of the CO1 gene and morphological characters. Glyptosternon oschanini is known to occur in tributaries of the Syr Darya River in Uzbekistan and Kyrgyzstan and may also occur in the Amu Darya River drainage. A morphological diagnosis and description are provided for G. oschanini. Exostoma gracile is a junior synonym of G. oschanini rather than of G. reticulatum. PMID- 30308644 TI - Caledomus gen. nov., a new cillaeine genus (Coleoptera, Nitidulidae) from New Caledonia and taxonomic notes. AB - Caledomus extraordinarius gen. et sp. nov. of the subfamily Cillaeinae is described from New Caledonia (Tinchialit). This new genus is a member of the Adocimus-complex of genera. The new name Brittonoma nom. nov. is proposed for the junior homonym Brittonema Kirejtshuk, 2011, non Thorne, 1967. PMID- 30308645 TI - Descriptions of four new sponge-inhabiting barnacles (Thoracica: Archaeobalanidae: Acastinae). AB - Within the family Archaeobalanidae, the sponge-inhabiting barnacles include species from the subfamilies Acastinae and Bryozobiinae as well as from the genus Membranobalanus in the subfamily Archaeobalaninae. Members of these groups are obligatory symbionts of poriferans, but the Acastinae can also be found in association with alcyonaceans and antipatharians. Acasta sulcata Lamarck, 1818, is one of the most widely reported sponge-inhabiting barnacle species, with numerous records across the Indo-West Pacific region revealing significant morphological variation. A combined morphological and molecular approach has revealed high diversity in recent collections of sponge-inhabiting barnacles in Taiwan and Australia, and four new species, namely Acasta aspera sp. nov., Acasta huangi sp. nov., Acasta radenta sp. nov., and Acasta undulaterga sp. nov., have been described here. All four species are morphologically close to A. sulcata, and the morphological similarity between these proposed species has led to the proposal of a "sulcata species complex." PMID- 30308646 TI - Strongly carinate species of Alpheopsis Coutiere, 1897 of the tropical Atlantic and eastern Pacific, with redescription of A. trigona (Rathbun, 1901) and description of three new species (Malacostraca: Decapoda: Alpheidae). AB - The present study deals with four species of the alpheid shrimp genus Alpheopsis Coutiere, 1897 characterised by the presence of at least one strong carina on the dorsal surface of the carapace. Alpheopsis trigona (Rathbun, 1901) is redescribed based on the holotype from Puerto Rico and additional material from US Virgin Islands and Florida. Two new species closely related to A. trigona, viz. A. paratrigona sp. nov. and A. gotrina sp. nov., are described, the first based on material from several localities in the tropical western Atlantic, and the second from the Pacific coast of Panama and Colombia. The three species together form a distinctive transisthmian clade within Alpheopsis, the A. trigona species complex, characterised by the presence of several strong longitudinal carinae on the carapace and very distinctive colour pattern. A more distantly related species, A. aristoteles sp. nov., characterised by the presence of only one strong mid-dorsal carina in the anterior region of the carapace, is described based on material from Sao Tome Island in the tropical eastern Atlantic. PMID- 30308647 TI - DNA barcode for identification of immature stages of sand flies (Diptera: Psychodidae) collected from natural breeding sites. AB - Although phlebotomine sand flies breeding sites have been identified and recorded by several studies, the microhabitats exploited by these insects remain little known and hard to find. In this context, the difficulty of finding immature stages, and the limited number of taxonomic studies to identify immature stages of phlebotomine sand flies, are considered the major obstacles when attempting a complete inventory of Lutzomyia species. The objective of this study is to validate Cytochrome Oxidase I (Barcode region) as a marker for the identification of immature stages of Lutzomyia species recovered from natural breeding sites in Colombia. Among 142 collected sand flies, 18 immature individuals that did not complete their life cycle were identified to species level through sequencing of the COI gene. Values of K2P genetic distance between 0.002-0.031 allowed the identification of larvae at species level. The bootstrap support values (96%) in the Neighbor-Joining dendrogram were consistent for the majority of the established MOTUS of Lutzomyia atroclavata, Lutzomyia micropyga, Lutzomyia serrana, Lutzomyia cayennensis, Lutzomyia rangeliana, Lutzomyia shannoni and some species of the genus Brumptomyia. The COI gene is validated as a marker for the identification of immature stages of the genus Lutzomyia. PMID- 30308648 TI - Molecular analysis reveals a new cryptic species in a limpet Lottia kogamogai (Patellogastropoda: Lottiidae) from Japan. AB - A group of small lottiid species in Japan, the Lottia kogamogai complex, was phylogenetically analyzed based on the mitochondrial COI gene. As a result, L. kogamogai is subdivided into two geographic clades. Lottia kogamogai s.s. is limited to southern temperate Japan. The northern population formerly considered an intraspecific variation of the species is shown to be a distinct new species, here described as Lottia goshimai n. sp. The new species is distinguishable from L. kogamogai not only genetically, but in radular morphology and shell sculpture. PMID- 30308649 TI - A new species of Rheumatobates Bergroth (Hemiptera: Heteroptera: Gerridae) from mangroves of the Colombian Caribbean region, new records, and a key to species recorded from the country. AB - Rheumatobates urabaensis sp. nov. (Gerridae: Rhagadotarsinae) is described from a mangrove of the Colombian Caribbean region. R. urabaensis sp. nov. is differentiated from other species of the genus by features of the male antennae, fore legs, and genitalia. New distribution records are presented for R. bergrothi Meinert, R. crassifemur esakii Schroeder, and R. spinosus Hungerford. A key to the species of Rheumatobates from Colombia is also provided. PMID- 30308650 TI - Lacrimacandona n. gen. (Crustacea: Ostracoda: Candonidae) from the Edwards Aquifer, Texas (USA). AB - Lacrimacandona n. gen. with its type species Lacrimacandona wisei n. sp. from the San Marcos artesian well on the Texas State University campus (Hays County, Texas, USA) is proposed as a new genus of the subfamily Candoninae. The new species is sexually dimorphic, and so far no congeneric species have been found. The new genus has the following distinguishing characters: subtriangular carapace tapering posteriorly, uropod with a claw-like anterior seta and two short claws, one long "a" setae on male maxilliped, very large asymmetric clasping organs in males, unique shape and size of hemipenis, and unique occurrence of setae on segments. PMID- 30308652 TI - Mexican biogeographic provinces: Map and shapefiles. AB - We provide a map of the 14 biogeographic provinces of Mexico based on the ecoregions recognized for the country, which combine climatic, geological and biotic criteria. These provinces belong to the Nearctic region (Californian, Baja Californian, Sonoran, Chihuahuan Desert and Tamaulipas provinces), Neotropical region (Pacific Lowlands, Balsas Basin, Veracruzan and Yucatan Peninsula provinces) and the Mexican transition zone (Sierra Madre Occidental, Sierra Madre Oriental, Transmexican Volcanic Belt, Sierra Madre del Sur and Chiapas Highlands provinces). In order to facilitate future biogeographic analyses, we provide a file of the biogeographical regionalisation of Mexico by converting the map into a polygon shapefile and a raster file with all provinces. We also separately provide each of the provinces in vector and raster format. All the maps are in geographical and Lambert Conformal Conic projections. PMID- 30308651 TI - Eudendrium tayronensis sp. nov. (Cnidaria, Hydrozoa) from coastal lagoons on the Caribbean Coast of Colombia. AB - The purpose of this note is to describe a new species of the hydrozoan Eudendrium found during an ecological study at the coastal lagoon Bahia de Chengue, near the city of Santa Marta, Colombia (Alvarez-Leon et al., 1995). Colonies of 6-16 cm height were collected between September 1982 and March 1983, up to 0.6 m deep. As of February 2016, this species was still present in the region. They grow on stilt roots of the red mangrove, Rhizophora mangle, in the lagoon channel, and near the opening of Cienaga Grande de Santa Marta estuary. This species is similar to the more common Caribbean Eudendrium carneum Clarke, 1882, but differs in the morphology of female and male gonophores. Voucher material is deposited in the Senckenberg Museum in Frankfurt, Germany (SMF) and in the Makuriwa-Museo de Historia Natural Marina de Colombia at Instituito de Investigaciones Marinas y Costeras-INVEMAR, Santa Marta (INV-CNI). PMID- 30308653 TI - The tadpole of Physalaemus nanus (Boulenger, 1888) (Anura, Leptodactylidae) from Southern Brazil. AB - The genus Physalaemus Fitzinger, 1826 currently comprises 47 described species distributed from Central America (Guianas) to Uruguay (Frost 2016). The genus has been recently organized in two main clades based on molecular data, Physalaemus signifer Clade and Physalaemus cuvieri Clade (Lourenco et al. 2015). The P. signifer Clade, with 15 species, is composed by the P. deimaticus and P. signifier groups, plus P. nattereri (Steindachner, 1863) and P. maculiventris (Lutz, 1925) (Nascimento et al. 2005; Lourenco et al. 2015). PMID- 30308654 TI - First record and range extension of the Galapagos slipper lobster, Scyllarides astori (Decapoda, Scyllaridae) in the central Pacific coast of Mexico mainland. AB - The Galapagos slipper lobster Scyllarides astori was found for the first time off western Mexico mainland. A male and two female specimens were collected in south Jalisco and north Colima. This represents a new record from central Pacific coast of Mexico and a range extension of 700 km southwards, as the species was previously reported from the Gulf of California, 780 km eastwards from Revillagigedo Archipelago and 2400 km northwestwards from Isla del Coco and Galapagos Archipelago. PMID- 30308655 TI - A new species of Sphelodon Townes (Hymenoptera: Ichneumonidae: Banchinae) from Colombia. AB - The genus Sphelodon Townes has 13 described species, nine species from the Neotropical region, three species from the Nearctic region and one (Sphelodon phoxopteridis) that occurs in both regions. A new species, Sphelodon antioquensis sp. n. is described here. This is the first record of Sphelodon for Colombia. A key to Sphelodon species occurring in the Neotropical Region is provided. PMID- 30308656 TI - African Spilogona Schnabl: morphology of the male terminalia and description of a new species (Diptera: Muscidae). AB - Spilogona breviaristata sp. nov. from South Africa is described and the morphology of the male terminalia of seven African Spilogona Schnabl (Diptera, Muscidae) species are described and illustrated: Spilogona biguttata Emden, Spilogona fuscotriangulata Emden, Spilogona natalensis Zielke, Spilogona pertinisetodes Emden, Spilogona quasifasciata Emden, Spilogona semifasciata Emden and Spilogona spinipes (Bigot). The material studied is deposited in the Natural History Museum (BMNH), London, United Kingdom, and paratypes of the new species are also in the Museu Nacional, Universidade Federal do Rio de Janeiro (MNRJ), Rio de Janeiro, Brazil, and the Oxford University Museum of Natural History (OUMNH), Oxford, United Kingdom. PMID- 30308657 TI - A new species of extinct Late Quaternary giant tortoise from Hispaniola. AB - Insular giant tortoise diversity has been depleted by Late Quaternary extinctions, but the taxonomic status of many extinct populations remains poorly understood due to limited available fossil or subfossil material, hindering our ability to reconstruct Quaternary island biotas and environments. Giant tortoises are absent from current-day insular Caribbean ecosystems, but tortoise remains from Quaternary deposits indicate the former widespread occurrence of these animals across the northern Caribbean. We report new Quaternary giant tortoise material from several cave sites in Pedernales Province, southern Dominican Republic, Hispaniola, representing at least seven individuals, which we describe as Chelonoidis marcanoi sp. nov. Although giant tortoise material was first reported from the Quaternary record of Hispaniola almost 35 years ago, tortoises are absent from most Quaternary deposits on the island, which has been studied extensively over the past century. The surprising abundance of giant tortoise remains in both vertical and horizontal caves in Hispaniola's semi-arid ecoregion may indicate that this species was adapted to open dry habitats and became restricted to a habitat refugium in southeastern Hispaniola following climatic driven environmental change at the Pleistocene-Holocene boundary. Hispaniola's dry forest ecosystem may therefore have been shaped by giant tortoises for much of its evolutionary history. PMID- 30308658 TI - On the systematics of the water mites Hygrobates nigromaculatus Lebert, 1879 and H. setosus Besseling, 1942 (Acari, Hydrachnidia, Hygrobatidae). AB - The first description of the deutonymph of the water mite Hygrobates setosus and a redescription of larvae, females and males of H. nigromaculatus and H. setosus are presented, with a comparative analysis of some morphological structures in all active stages of both species. PMID- 30308659 TI - Luciobarbus chelifensis and L. mascarensis, two new species from Algeria (Teleostei: Cyprinidae). AB - Cyprinids of the genus Luciobarbus are the most abundant and widespread fishes in most freshwater ecosystems in the Maghreb. In the Mediterranean basin of Morocco, Algeria and Tunisia, all species of Luciobarbus-with exception of L. guercifensis are superficially very similar and are distinguished mostly by minor morphometric characters. Molecular characters distinguish all species well and nine species are recognised from the area, two of them described here. Luciobarbus chelifensis, from the Chelif River drainage in Algeria, is distinguished by having 41-43+1-2 lateral line scales and a very short anal fin (18-19% SL). Luciobarbus mascarensis, from the Macta River drainage in Algeria, is distinguished by having usually 41+1-2 lateral line scales, a long anal-fin (19 22%) and a short caudal peduncle (15-17% SL). An identification key is given for all African Mediterranean Luciobarbus species except for L. callensis and L. rifensis, which could not be distinguished. PMID- 30308660 TI - A new genus and species of the family Symphysanodontidae, Cymatognathus aureolateralis (Actinopterygii: Perciformes) from Indonesia. AB - A new genus and species of the percoid family Symphysanodontidae, Cymatognathus aureolateralis are described based on three specimens collected from North Sulawesi, Indonesia. The new species shares with the confamilial genus Sym physanodon the unique supraneural and spinous dorsal-fin pterygiophore insertion pattern usually of 0/0/0+2+1/1/, T-shaped first supraneural, foreshortened base of the penultimate ventral procurrent caudal-fin ray, well-developed outer tooth patches at anterior tips of both jaws as well as along the medial surface of most of the length of the coronoid process of the dentary. The new species, however, is distinguishable from members of Symphysanodon by the following diagnostic characters: posterior tip of coronoid process of dentary abruptly depressed, so that teeth on anterior portion appear as an elevated patch, anterior tip of upper jaw not notched, and posterior nostril horizontally slit-like. Although the new species superficially resembles the members of the genus Giganthias (Giganthiidae) and some members of the subfamily Anthiadinae (Serranidae) in the unique characters it shares with Symphysanodon, it differs from Giganthias in having the above-mentioned unique pterygiophore insertion pattern and tips of all dorsal- and pelvic-fin spines smooth (vs. pterygiophore insertion pattern 0/0/2/1+1/1/, and tips of second, third and/or fourth dorsal- and pelvic-fin spines serrated), and from the members of Anthiadinae in having two flat opercular spines (vs. three) and 10 + 15 = 25 vertebrae (vs. 10 + 16-18 = 26-28). A revised diagnosis of the Symphysanodontidae is presented. PMID- 30308661 TI - Review of Australian genera Tessaromma Newman and Phlyctaenodes Newman with description of a new genus and species (Coleoptera: Cerambycidae: Cerambycinae: Phlyctaenodini). AB - Two Australian genera, Tessaromma Newman and Phlyctaenodes Newman of the tribe Phlyctaenodini Lacordaire, 1868 (=Tessarommatini Lacordaire, 1868) syn. nov. are revised. All known species are redescribed and illustrated. Keys to the genera of Australian Phlyctaenodini and species of Tessaromma Newman and Phlyctaenodes are provided. One new genus Escalonia gen. nov. (type species: Tessaromma loxleyae McKeown, 1942) and three new species Phlyctaenodes queenslandicus sp. nov., Escalonia carolinae sp. nov. and Escalonia surprise sp. nov. are described. Tessaromma truncatispina McKeown, 1940 is regarded as a junior synonym of Tessaromma sordida McKeown, 1940; Tessaromma nigroapicale Aurivillius, 1917 is synonymized with Tessaromma nanum Blackburn, 1899; and Tessaromma sericans (Erichson, 1842) is synonymized with Tessaromma triste (Hope, 1841). Tessaromma setosa McKeown, 1942 is moved to Ectinope Pascoe, and Zoedia intricata Gressitt, 1959 is moved to Escalonia gen. nov. PMID- 30308662 TI - List of leaf beetles (Coleoptera: Chrysomelidae) from Lagodekhi reserve with new records for Transcaucasia and Georgia. AB - Leaf beetles of Lagodekhi National Park have been studied for the first time. Thirty two species were recorded from the area of which 14 are new for Georgia, 1 genus and 8 species are new to Transcaucasus. Together with the additional 16 species that were already known from literature, a total of 48 chrysomelid species for Lagodekhi reserve is listed here with notes on the specimens examined and general distributions. Some insights into the elevational pattern of leaf beetle diversity in Lagodekhi National Park are also provided. PMID- 30308663 TI - Trachelus stipa (Hymenoptera: Cephidae), a new stem sawfly from Central Anatolia associated with feather grass (Stipa holosericea, Poaceae). AB - Trachelus stipa is described from Central Anatolia, Turkey. It is morphologically close to T. flavicornis and T. troglodyta regarding the structure of the preapical sterna of the male. It is unique among Trachelus species regarding the shape of the claw of the posterior leg, the size of the denticles of the ovipositor and the short valvula 3 of the ovipositor sheath in the female, and the distally notched hypopygium in the male. The genetic distance found in two mitochondrial (COI and cyt b) and one nuclear (EF-1alpha) gene regions support the recognition of this species and its placement within Trachelus, although the shape of the ovipositor sheath disagrees with this concept. Stipa holosericea, the host of T. stipa according to field observations, represents the first record of a feather grass as the host of a sawfly species. PMID- 30308664 TI - On the taxonomy of the genus Thysanoptyx Hampson, 1894, with description of two new species from Indochina (Lepidoptera, Erebidae, Arctiinae). AB - The taxonomic structure of the genus Thysanoptyx Hampson, 1894 is discussed, and the genus is subdivided into five species-groups. Two new species, T. indosinica Volynkin Dubatolov, sp. nov. from Thailand, Cambodia and Vietnam, and T. mirifica Volynkin Dubatolov, sp. nov. from Vietnam are described. Adults, male and female genitalia of the new species and their congeners are illustrated. The checklist of the genus Thysanoptyx is presented. PMID- 30308665 TI - Redescription of the Philippine leafhopper genus Iposcopus Baker (Hemiptera: Cicadellidae: Idiocerinae). AB - The Philippine leafhopper genus Iposcopus Baker is redescribed. The male and female genitalia of I. breviceps and I. distanti are described and illustrated for the first time. Baker (1915) established the genus Iposcopus and included two new species, I. breviceps and I. distanti (the type species) from the Philippines. Previously, only the external morphology and color have been described, not the genitalia. Here we first give a more complete description of the species, including male and female genitalia. PMID- 30308666 TI - Alburnoides recepi, a junior synonym of Alburnus caeruleus (Teleostei: Cyprinidae). AB - Alburnoides recepi was described from the stream Merzimen, a tributary of the Euphrates in Turkey. Morphometric, meristic and molecular (Cyt b) characters of A. recepi are largely overlapping or even identical with those of Alburnus caeruleus, a species known from the Qweik, Euphrates and Tigris River drainages. Alburnoides recepi is treated as a synonym of A. caeruleus. PMID- 30308667 TI - Two new species of Apteroscelio Kieffer (Hymenoptera: Scelionidae) from India. AB - Two new species of Apteroscelio Kieffer, a previously monotypic genus, are here described, illustrated and keyed. Affinities between Apteroscelio and other scelionine genera are discussed. The male of this genus is imaged and described for the first time. PMID- 30308668 TI - A new Schistura from the Pearl River in Guangxi, China (Teleostei: Nemacheilidae). AB - Schistura paraxena, new species, is described from the Pearl River drainage in Laibin, Guangxi Province, China. The new species is easily distinguished from its congeners in having conspicuous peduncular crests along its dorsal and ventral extremities and a plain beige body coloration with crests brownish gray and a pale spot medially at caudal-fin base. Further characters useful to diagnose the species, but not unique to it, are: 81/2 branched dorsal-fin rays; 11-12 pectoral fin and 9 pelvic-fin rays; modally 38 vertebrae; predorsal length 50-52% SL; caudal-peduncle length 17-18% SL (88-92% HL; 5.6-5.8 times SL); lateral line complete; breast naked; predorsal area scaled; and upper lip not notched. PMID- 30308670 TI - The Magnitude of the Opioid Epidemic and What We Can Doto Help. PMID- 30308669 TI - Value of Diffusion-Weighted Magnetic Resonance Imaging Combined with miR-18a Level in Predicting Radiosensitivity of Cervical Cancer. AB - BACKGROUND Radioresistance during radiotherapy of cervical cancer often leads to treatment failure; therefore, there is an urgent need to develop effective predictive indicators of radiosensitivity for cervical cancer patients. MATERIAL AND METHODS Cervical cancer cells were collected from 40 patients who received surgical resections. The relationships between apparent diffusion coefficient (ADC) values of masses before surgery and different micro-RNAs (miRNA) levels (miR-18a, miR-132, and miR-145) of these cells were investigated. Cervical cancer cells were divided into 4 groups according to the ADC values of original tumor tissues and expression level of miR-18a. Then, these cells were exposed with irradiation both in vitro and in vivo. RESULTS Advanced cervical cancer showed lower ADC values in magnetic resonance imaging. miR-18a, miR-132, and miR-145 all were increased in the cervical cancer tissues, while miR-18a showed a more marked negative correlation with ADC values. The results of in vitro and in vivo assays showed that higher expression of miR-18a in cervical cancer cells leads to more radiosensitivity, especially in cells from cancer tissues with lower ADC values. CONCLUSIONS The combination of ADC values with expression level of miR-18a may be a new and reliable predictor for radiosensitivity of cervical cancer, helping cervical cancer patients with low ADC values and high expressions of miR-18a to achieve better outcomes in radiotherapy. PMID- 30308671 TI - Vitamin K Administration. PMID- 30308672 TI - Trampolines: What's the Harm? AB - Trampolines hold the promise of fun and enjoyment for many children, but they are associated with a significant number of orthopedic and other injuries. Injuries vary from minor to severe, and the most common are extremity injuries. Although most injuries are associated with residential (ie, backyard) trampolines, a growing number of injuries now occur in trampoline parks. Adult supervision has not been effective for prevention. Emerging data on trampoline park-related injuries indicate that caution should be exercised in these settings as well. [Pediatr Ann. 2018;47(10):e385-e387.]. PMID- 30308673 TI - Common Problems in General Pediatrics. PMID- 30308674 TI - Enuresis Management in the Primary Care Pediatrics Clinic. AB - Enuresis is a frequent complaint not always volunteered by parents or patients. The pediatric clinician has to inquire about enuresis to break the secrecy surrounding this symptom that could be related to a more serious underlying renal, endocrine, or psychosocial disease. Determining the type of enuresis is crucial to offer optimal treatment. We present a review for the pediatric clinician to optimize their care of the child with monosymptomatic enuresis. [Pediatr Ann. 2018;47(10):e390-e395.]. PMID- 30308675 TI - Sinusitis in Children. AB - Acute bacterial sinusitis (ABS) mostly occurs as a complication of acute viral upper respiratory tract infection (URI), which is a common condition encountered in an outpatient setting. ABS manifests with three different presentations, most commonly as persistent symptoms of viral URI (nasal drainage and or cough) for more than 10 days. ABS is also diagnosed when the patient presents with severe symptoms of a URI accompanied by fever >102.2 degrees F and purulent nasal drainage for at least 3 days. Lastly, ABS can complicate viral URI around day 6 or 7 of illness after initial improvement in the symptoms of URI. Imaging studies are not recommended for diagnosing ABS, unless intracranial or orbital complications are suspected. Signs of proptosis, restriction of eye movements, ophthalmoplegia, and visual impairment are very specific for orbital involvement. Treatment of ABS with antibiotics is recommended based on the clinical scenario and has been shown to have higher cure rates as compared to placebo. [Pediatr Ann. 2018;47(10):e396-e401.]. PMID- 30308676 TI - Approach to Children with Aggressive Behavior for General Pediatricians and Hospitalists: Part 1-Epidemiology and Etiology. AB - Children and adolescents are increasingly presenting to the hospital and emergency department with aggressive behavior and psychiatric emergencies. The rise in pediatric mental health problems, coupled with a lack of much needed resources, necessitates that pediatricians safely diagnose and treat patients presenting with aggressive behavior. In this article, we discuss the broad differential diagnosis that should be considered when initially evaluating a patient presenting with aggression or altered mental status; underlying causes include predisposing factors, comorbid conditions, and acute organic causes involving almost every organ system. Emergency and hospital physicians should tailor their examination and testing individually based on the patient's history and presentation. [Pediatr Ann. 2018;47(10):e402-e407.]. PMID- 30308677 TI - Approach to Children with Aggressive Behavior for General Pediatricians and Hospitalists: Part 2-Evaluation, Tests, and Treatment. AB - After reviewing the various etiologies that can contribute to a presentation of aggressive behavior in a child (see part 1), a physician should conduct a thorough history and physical examination. The history should be obtained from the patient and caregivers, both together and separately in adolescents. A good physical examination starts with assessment and interpretation of vital signs, followed by a head-to-toe examination focusing on the skin, eyes, and thyroid, and then a neurologic examination. The testing and observation should be tailored to the individual patient, including laboratory results, imaging, and specialist consultation. Management of aggressive behavior can often be achieved through a combination of environmental modifications and verbal techniques, with special consideration given to children with neurodevelopmental problems such as autism. Pharmacologic agents are a good next step, and physical restraints can be used as a last resort. Evaluation of suicidality with thorough and complete questioning as well as assessment of a safety plan can aid in determining patient disposition such as need for admission to a psychiatric facility. [Pediatr Ann. 2018;47(10):e408-e412.]. PMID- 30308678 TI - Advocating for Automatic Eligibility for Early Intervention Services for Children Exposed to Lead. AB - Lead poisoning remains one of the most prevalent and preventable environmental health hazards affecting children. Low-level lead exposure has been shown to significantly increase the risk of learning disabilities, behavioral problems, and developmental delay. It also has substantial social implications as lead toxicity disproportionately affects children from low-income, ethnic minority households. Early Intervention (EI) is a state-based federal program (Part C of the Federal Individuals with Disabilities Education Act) created to support the development of children from birth to age 3 years who are experiencing or who are at risk for developmental delay. In 2016, an Illinois EI and Lead Workgroup was established to address the best practice of offering EI services to children who have been exposed to lead. This work serves as a template for advocates and health providers in other states to establish automatic eligibility for EI services at low levels of lead exposure, while also demonstrating the capacity to serve these children without overwhelming the state's EI system. [Pediatr Ann. 2018;47(10):e413-e418.]. PMID- 30308680 TI - Two Titles for the Family Medicine Board Review. PMID- 30308679 TI - Drug Allergy. AB - Drug allergy is commonly encountered in clinical practice. It is an immunological response to a pharmaceutical agent. The clinical presentation can vary from mild cutaneous reactions to life-threatening conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Diagnosis is most often clinical, but investigations such as measurement of immunoglobulin E, patch testing, and skin biopsy may be required. In patients with a known drug allergy, the offending drug should be avoided. [Pediatr Ann. 2018;47(10):e419-e425.]. PMID- 30308681 TI - Oophoropexy to the Round Ligament after Recurrent Adnexal Torsion. AB - Recurrent adnexal torsion is a rare gynecological emergency. We report a case of recurrent ipsilateral adnexal torsion in a woman with polycystic ovaries, previously submitted to a laparoscopic plication of the utero-ovarian ligament. Due to the recurrence after the plication of the utero-ovarian ligament, the authors performed a laparoscopic oophoropexy to the round ligament, which is an underreported procedure. The patient was asymptomatic for 1 year, after which she had a new recurrence and needed a unilateral laparoscopic adnexectomy. Since then, she regained the quality of life without any gynecological symptoms.Oophoropexy to the round ligament may be considered when other techniques fail or, perhaps, as a first option in selected cases of adnexal torsion, as it may allow the prevention of recurrence without increasing morbidity while preserving the adnexa. PMID- 30308682 TI - Radiation-Induced Uterine Carcinosarcoma after Concurrent Chemoradiotherapy for Cervical Squamous Cell Carcinoma. AB - OBJECTIVE: To describe a case of radiation-induced uterine carcinosarcoma 6 years after a cervical squamous cell carcinoma treatment, which imposed some diagnostic and management challenges. CASE REPORT: A 57-year-old woman with a history of pelvic chemoradiotherapy ~ 6.5 years before the event described in this study, following an International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer, presented with a cervical mass, involving the uterine cavity, the cervical canal and the upper two thirds of the vagina. The biopsy showed a poorly differentiated carcinoma, and a positron emission tomography (PET) scan excluded distant metastasis, although it was unable to define the origin of the tumor as either a new primary malignancy of the endometrium/cervix or as a cervical recurrence. Surgical staging procedure was performed, and the diagnosis was endometrial carcinosarcoma, FIGO stage IIB. The patient was not able to complete the adjuvant therapy, and the progression of the disease was remarkable. CONCLUSION: The present case highlights one of the less common but more serious consequences of radiotherapy for cervical cancer, which has an increasing incidence in younger women, raising concerns about the long term consequences of its management. PMID- 30308683 TI - Fetal Noncompaction Cardiomyopathy and Histologic Diagnosis of Spongy Myocardium: Case Report and Review of the Literature. AB - Noncompaction cardiomyopathy (NCCM) and left ventricular noncompaction (LVNC), in their isolated form, are rare cardiomyopathies. They are characterized by a thickened myocardium due to the presence of deep trabeculae recesses, and to thick trabeculae. This condition is associated with a variable clinical phenotype including heart failure, thromboembolism, and sudden death. We report a case of LVNC at 26 weeks and 4 days of gestation revised on the basis of what is currently reported in the literature. A review of the literature was performed to better describe this rare condition. Left ventricular noncompaction is a rare fetal condition and it should be suspected in case of cardiomyopathy. PMID- 30308684 TI - Personality Traits of Postmenopausal Women with Sexual Dysfunction. AB - OBJECTIVE: The aim of the present study is to identify the association between personality traits of postmenopausal women and the occurrence of sexual dysfunction. METHODS: A total of 43 postmenopausal women were evaluated according to their self-perception of the quality of their sexual life. They answered the following questionnaires: Sociodemographic Profile Questionnaire, Female Sexual Function Index (FSFI), Beck Depression Inventory (BDI) and Factorial Personality Inventory (FPI-II). RESULTS: Women with poorer sexual self perception showed low affective need (p < 0.01) and low need for organization (p < 0.01). Based on the need for control and opposition, there was no difference between the groups. Groups separated by the scores obtained on the FSFI showed no significant differences. CONCLUSION: Postmenopausal women with lower schooling and personality characteristics that demonstrate low affective and organizational needs are more likely to present sexual dysfunction. PMID- 30308685 TI - Obstetric Outcomes among Syrian Refugees: A Comparative Study at a Tertiary Care Maternity Hospital in Turkey. AB - OBJECTIVE: The aim of this study was to analyze and compare obstetric and neonatal outcomes between Syrian refugees and ethnic Turkish women. METHODS: Retrospective, observational study. A total of 576 Syrian refugees and 576 ethnic Turkish women were included in this study, which was conducted between January 2015 and December 2015 at a tertiary maternity training hospital in Ankara, Turkey. The demographic characteristics, obstetric and neonatal outcomes were compared. The primary outcomes were pregnancy outcomes and cesarean rates between the groups RESULTS: The mean age was significantly lower in the refugee group (p < 0.001). Mean gravidity, proportion of adolescent pregnancies, proportion of pregnant women aged 12 to 19 years, and number of pregnancies at < 18 years were significantly higher among the refugee women (p < 0.001). Rates of antenatal follow-up, double testing, triple testing, gestational diabetes mellitus (GDM) screening, and iron replacement therapy were significantly lower in the refugee group (p < 0.001). The primary Cesarean section rate was significantly lower in the refugee group (p = 0.034). Pregnancies in the refugee group were more complicated, with higher rates of preterm delivery (< 37 weeks), preterm premature rupture of membranes (PPROM), and low birth weight (< 2,500 g) when compared with the control group (4.2% versus 0.7%, p < 0.001; 1.6% versus 0.2%, p = 0.011; and 12% versus 5.8%, p < 0.001, respectively). Low education level (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 0.5-0.1), and weight gain during pregnancy (OR = 1.7, 95% CI = 0.5-0.1) were found to be significant indicators for preterm birth/PPROM and low birthweight. CONCLUSION: Syrian refugees had increased risks of certain adverse obstetric outcomes, including preterm delivery, PPROM, lower birth weight, and anemia. Several factors may influence these findings; thus, refugee women would benefit from more targeted care during pregnancy and childbirth. PMID- 30308686 TI - Hyperdense Middle Cerebral Artery in a Boy with Road Traffic Accident. PMID- 30308687 TI - Neuromuscular Involvement in Glycogen Storage Disease Type III in Fifty Tunisian Patients: Phenotype and Natural History in Young Patients. AB - BACKGROUND: Our aim was to describe the natural history of neuromuscular involvement (NMI) in glycogen storage disease type III (GSDIII). METHODS: We conducted a longitudinal study of 50 Tunisian patients, 9.87 years old in average. RESULTS: NMI was diagnosed at an average age of 2.66 years and was clinically overt in 85% of patients. Patients with clinical features were older (p = 0.001). Complaints were dominated by exercise intolerance (80%), noticed at 5.33 years in average. Physical signs, observed at 6.75 years in average, were dominated by muscle weakness (62%). Functional impairment was observed in 64% of patients, without any link with age (p = 0.255). Among 33 patients, 7 improved. Creatine kinase (CK) and aspartate aminotransferase (AST) levels were higher with age.Electrophysiological abnormalities, diagnosed in average at 6.5 years, were more frequent after the first decade (p = 0.0005). Myogenic pattern was predominant (42%). Nerve conduction velocities were slow in two patients. Lower caloric intake was associated with more frequent clinical and electrophysiological features. Higher protein intake was related to fewer complaints and physical anomalies. CONCLUSION: Neuromuscular investigation is warranted even in asymptomatic patients, as early as the diagnosis of GSDIII is suspected. Muscle involvement can be disabling even in children. Favorable evolution is possible in case of optimal diet. PMID- 30308688 TI - Selecting Patients for Lobar Lung Volume Reduction Therapy: What Quantitative Computed Tomography Parameters Matter? AB - PURPOSE: Evaluation of emphysema distribution with quantitative computed tomography (qCT) prior to endoscopic lung volume reduction (ELVR) is recommended. The aim of this study was to determine which of the commonly assessed qCT parameters prior to endoscopic lung volume reduction (ELVR) best predicts outcome of treatment. MATERIALS AND METHODS: 50 patients who underwent technically successful ELVR at our institution were retrospectively analyzed. We performed quantitative analysis of the CT scans obtained prior to ELVR and carried out Mann Whitney U-tests and a logistic regression analysis to identify the qCT parameters that predict successful outcome of ELVR in terms of improved forced expiratory volume in 1 second (FEV1). RESULTS: In the Mann-Whitney U-test, the interlobar emphysema heterogeneity index (p = 0.008) and the pulmonary emphysema score (p = 0.022) showed a statistically significant difference between responders and non responders. In multiple logistic regression analysis only the interlobar emphysema heterogeneity index (p = 0.008) showed a statistically significant impact on the outcome of ELVR, while targeted lobe volume, total lung volume, targeted lobe emphysema score and total lung emphysema score did not. CONCLUSION: Of all commonly assessed quantitative CT parameters, only the heterogeneity index definitely allows prediction of ELVR outcome in patients with advanced chronic obstructive pulmonary disease (COPD). KEY POINTS: . Quantitative CT is recommended prior to ELVR.. . The relevance of the obtained parameters from quantitative CT remains controversial.. . This study confirms that only the emphysema heterogeneity index has a definite impact.. CITATION FORMAT: . Theilig DC, Huebner R, Neumann K et al. Selecting Patients for Lobar Lung Volume Reduction Therapy: What Quantitative Computed Tomography Parameters Matter?. Fortschr Rontgenstr 2018; DOI: 10.1055/a-0638-0058. PMID- 30308689 TI - Evaluation of the static magnetic field interactions for a newly developed magnetic ophthalmic implant at 3 Tesla MRI. AB - PURPOSE: The purpose of this study is to analyze the static magnetic field interactions for an ophthalmic-magnetic shunt implant with a ferromagnetic steel plate in a thin silicon layer. The plate is used for opening of a valve flap. Ten different sizes of this steel plate were investigated to characterize the relationship between the size of the metal and the magnetic forces of the static magnetic field of a 3.0 T MRI. MATERIALS AND METHODS: The magnetic translation force Fz was quantified by determining the deflection angle using the deflection angle test (ASTM F 2052). The torque was qualitatively estimated by using a 5 point grading scale (0: no torque; + 4: very strong torque) according to Sommer et al. 11. For the visual investigation of the function of the metal plate both prototypes were positioned at the magnetic field's spatial gradient and at the magnet's isocenter. The stitches were exposed to the thousandfold of the translational force by a dynamometer. RESULTS: The translational force was found to be 10 times greater than the weight of a single plate. The plates were exposed to a high torque (grade 3 to 4). The seams and the tissue withstood more than a thousandfold of the determined translational force. No spontaneous, uncontrolled opening of the valve flap was visible in the MRI, as a result of which the intraocular pressure could decrease considerably. CONCLUSION: Due to the small size of the plates the translational force and the torque will be compensated by the silicon layer and also by the fixation in the eye. KEY POINTS: . Magnetic forces will be compensated by silicon layer and fixation in the eye.. . The magnetic-ophthalmological implant is not restricted in its function by the MRI magnetic field.. . The ophthalmic magnetic shunt implant can be considered conditionally MRI-safe.. CITATION FORMAT: . Bodenstein A, Lupke M, Seiler C et al. Evaluation of the static magnetic field interactions for a newly developed magnetic ophthalmic implant at 3 Tesla MRI. Fortschr Rontgenstr 2018; DOI: 10.1055/a-0690-9050. PMID- 30308690 TI - Ultrasound-assisted catheter placement in CT-guided HDR brachytherapy for the local ablation of abdominal malignancies: Initial experience. AB - PURPOSE: To evaluate the safety and feasibility of sonographically-assisted catheter placement in interstitial high-dose-rate brachytherapy of abdominal malignancies. MATERIALS AND METHODS: In an initial cohort of 12 patients and 16 abdominal tumors (colorectal liver metastases n = 9; renal cell cancer n = 3; hepatocellular carcinoma n = 2; cholangiocellular carcinoma n = 2), initial puncture and catheter placement for CT-guided brachytherapy were performed under sonographic assistance when possible. The interventional procedure was prospectively recorded and in-patient data were collected. All data underwent descriptive statistics and comparative analysis by the Mann-Whitney test. RESULTS: In 12 out of 16 lesions (diameter 1.5 - 12.9 cm), initial puncture was successfully achieved under ultrasound guidance without utilization of CT fluoroscopy, yielding a significantly shorter mean total fluoroscopy time (14.5 vs. 105.5 s; p = 0.006). In 8 lesions visibility was rated better in ultrasound than in CT fluoroscopy (p = 0.2). No major or minor complications occurred within 30 days after treatment. CONCLUSION: Ultrasound-assisted catheter placement during interstitial CT-guided brachytherapy of abdominal tumors could improve catheter positioning and reduce radiation exposure for medical staff. KEY POINTS: Ultrasound-assisted catheter placement in CT-guided brachytherapy is safe and feasible. Ultrasound puncture may improve catheter positioning. Reduced CT fluoroscopy time can significantly help to minimize radiation exposure for medical staff. CITATION FORMAT: Damm R, El-Sanosy S, Omari J et al. Ultrasound assisted catheter placement in CT-guided HDR brachytherapy for the local ablation of abdominal malignancies: Initial experience. Fortschr Rontgenstr 2018; DOI: 10.1055/a-0636-4055. PMID- 30308691 TI - Radiation Dose Optimization in Pediatric Chest CT: Major Indicators of Dose Exposure in 1695 CT Scans over Seven Years. AB - PURPOSE: To analyze possible influencing factors on radiation exposure in pediatric chest CT using different approaches for radiation dose optimization and to determine major indicators for dose development. MATERIALS AND METHODS: In this retrospective study at a clinic with maximum care facilities including pediatric radiology, 1695 chest CT examinations in 768 patients (median age: 10 years; range: 2 days to 17.9 years) were analyzed. Volume CT dose indices, effective dose, size-specific dose estimate, automatic dose modulation (AEC), and high-pitch protocols (pitch >= 3.0) were evaluated by univariate analysis. The image quality of low-dose examinations was compared to higher dose protocols by non-inferiority testing. RESULTS: Median dose-specific values annually decreased by an average of 12 %. High-pitch mode (n = 414) resulted in lower dose parameters (p < 0.001). In unenhanced CT, AEC delivered higher dose values compared to scans with fixed parameters (p < 0.001). In contrast-enhanced CT, the use of AEC yielded a significantly lower radiation dose only in patients older than 16 years (p = 0.04). In the age group 6 to 15 years, the values were higher (p < 0.001). The diagnostic image quality of low-dose scans was non-inferior to high-dose scans (2.18 vs. 2.14). CONCLUSION: Radiation dose of chest CT was reduced without loss of image quality in the last decade. High-pitch scanning was an independent factor in this context. Dose reduction by AEC was limited and only relevant for patients over 16 years. KEY POINTS: . The radiation dose of pediatric chest CT was reduced in the last decade.. . High-pitch scanning is an independent factor of dose optimization.. . Dose reduction by AEC is limited and only relevant for older children.. CITATION FORMAT: . Esser M, Hess S, Teufel M et al. Radiation Dose Optimization in Pediatric Chest CT: Major Indicators of Dose Exposure in 1695 CT Scans over Seven Years. Fortschr Rontgenstr 2018; 190: 1131 - 1140. PMID- 30308692 TI - ? PMID- 30308693 TI - [Waiting List Management and Organ Allocation for Lung Transplantation 2018]. AB - In 2017 an amendment to the German transplant law concerning organ allocation and waiting list management became effective. This implies important consequences on lung transplant centers. Crucial innovations concern the transplant conference, indications for lung transplantation and waiting list management. Certain medical conditions now imply a restriction of waiting list enrollment for patients and there are new options for size-matching of donor lung and recipient. Moreover, the new amendment describes in detail how the clinical parameters, on which the lung allocation score (LAS) is based, are defined and how the essential physical examinations have to be performed. Furthermore, the current article provides a summary of the process of organ allocation by the organ exchange organization. PMID- 30308694 TI - Pharmacological Properties of Geraniol - A Review. AB - Geraniol is an acyclic isoprenoid monoterpene isolated from the essential oils of aromatic plants including Cinnamomum tenuipilum, Valeriana officinalis, and several other plants. The limited source of geraniol from plant isolation cannot fulfill the great demand from the flavor and fragrance industries, which require maximizing geraniol production through biotechnology processes. The diverse activities of geraniol suggested that geraniol could treat various diseases as a promising drug candidate. In order to evaluate the potential of geraniol applied in a clinical trial, this review aims at providing a comprehensive summary of the pharmacological effects of geraniol. The publications retrieved from PubMed, ScienceDirect, Springer, and Wiley databases were collected and summarized for the last 6 years. Then, the potential application of geraniol as a drug is discussed based on its pharmacological properties, including antitumor, anti inflammatory, antioxidative, and antimicrobial activities, and hepatoprotective, cardioprotective, and neuroprotective effects. Hence, this review aims at providing evidence of the pharmacological activities of geraniol in the context of further development as a drug candidate in clinical application. PMID- 30308695 TI - Contribution of psychiatric diagnoses to extent of opioid prescription in the first year post-head and neck cancer diagnosis: A longitudinal study. AB - PURPOSE: The purpose of this study was to determine, within the first-year post head and neck cancer (HNC) diagnosis, the contribution of past and upon HNC psychiatric diagnoses (ie, substance use disorder, major depressive disorder, and anxiety disorder) to the extent (ie, cumulated dose) of opioid prescription. METHODS: Prospective longitudinal study of 223 consecutive adults (on 313 approached; 72% participation) newly diagnosed (<2 weeks) with a first occurrence of primary HNC, including Structured Clinical Interviews for DSM-IV disorders, validated psychometric measures, and medical chart reviews. Opioid doses were translated into standardized morphine milligram equivalents (MME) using CDC guidelines. A model of variables was tested using multiple linear regression. RESULTS: Fifty-five percent (123/223) of patients received opioids at some point during the first 12 months post-HNC diagnosis, 37.7% (84/223) upon HNC diagnosis (pre-treatment), 40.8% (91/223) during treatments, and 31.4% (70/223) post treatment. The multiple linear regression indicated that an AD (P = 0.04) upon HNC diagnosis in early stage contributes to cumulated MME dose in the first year post-HNC diagnosis. CONCLUSION: This study underlines how anxiety has important repercussions on the management of pain and illustrates the importance of screening for AD upon HNC diagnosis to allow for early prophylactic treatment and support. PMID- 30308697 TI - Predictive factors of improvement for voiding symptoms after holmium laser enucleation of the prostate. PMID- 30308696 TI - Early thrombosis prophylaxis with enoxaparin is not associated with hematoma expansion in patients with spontaneous intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Early pharmacological deep vein thrombosis (DVT) prophylaxis is recommended by guidelines, but rarely started within 48 h. We aimed to analyze the effect of early (within 48 h) versus late (>48 h) DVT prophylaxis on hematoma expansion (HE) and outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We analyzed 134 consecutive patients admitted to a tertiary neurointensive care unit with diagnosed spontaneous ICH, without previous anticoagulation, severe coagulopathy, hematoma evacuation, early withdrawal of therapy or ineligibility for DVT prophylaxis according to our institutional protocol. Significant late HE was defined as >=6 mL increase of hematoma volume between neuroimaging within 48 h and day 3-6. Multivariate analysis was performed to identify risk factors for late HE, poor 3-month outcome (modified Rankin Scale score >= 4) and mortality. RESULTS: Patients had a median Glasgow Coma Scale score of 14 [interquartile range (IQR), 10-15], ICH volume of 11 (IQR, 5-24) mL and were 71 (IQR, 61-76) years old. A total of 56% (n = 76) received early DVT prophylaxis, 37% (n = 50) received late DVT prophylaxis and 8 (6%) had unknown bleeding onset. Patients with early DVT prophylaxis had smaller ICH volume [9.5 (IQR, 4-18.5) vs. 17.5 (IQR, 8-29) mL, P = 0.038] and were more often comatose (26% vs. 10%, P = 0.025). Significant late HE [n = 5/134 (3.7%)] was associated with larger initial ICH volume (P = 0.02) and lower thrombocyte count (P = 0.03) but not with early DVT prophylaxis (P = 0.36). Early DVT prophylaxis was not associated with worse outcome. CONCLUSION: Significant late HE is uncommon and DVT prophylaxis within 48 h of symptom onset may be safe in selected patients with ICH. PMID- 30308698 TI - Editorial Comment to Occurrence and characterization of carbapenem-resistant Gram negative bacilli: A collaborative study of antibiotic-resistant bacteria between Indonesia and Japan. PMID- 30308699 TI - A randomized controlled trial of a walking training with simultaneous cognitive demand (dual-task) in chronic stroke. AB - BACKGROUND AND PURPOSE: The aim was to evaluate the tolerability of, adherence to and efficacy of a community walking training programme with simultaneous cognitive demand (dual-task) compared to a control walking training programme without cognitive distraction. METHODS: Adult stroke survivors at least 6 months after stroke with a visibly obvious gait abnormality or reduced 2-min walk distance were included in a two-arm parallel randomized controlled trial of complex intervention with blinded assessments. Participants received a 10 week, bi-weekly, 30 min treadmill programme at an aerobic training intensity (55%-85% heart rate maximum), either with or without simultaneous cognitive demands. Outcome was measured at 0, 11 and 22 weeks. The primary assessment involved 2-min walk tests with and without cognitive distraction to investigate the dual-task effect on walking and cognition; secondary results were the Short Form Health Survey 36, EuroQol-5D-5L, the Physical Activity Scale for the Elderly (PASE) and step activity. RESULTS: Fifty stroke patients were included; 43 received allocated training and 45 completed all assessments. The experimental group (n = 26) increased their mean (SD) 2-min walking distance from 90.7 (8.2) to 103.5 (8.2) m, compared with 86.7 (8.5) to 92.8 (8.6) m in the control group, and their PASE score from 74.3 (9.1) to 89.9 (9.4), compared with 94.7 (9.4) to 77.3 (9.9) in the control group. Statistically, only the change in the PASE differed between the groups (P = 0.029), with the dual-task group improving more. There were no differences in other measures. CONCLUSIONS: Walking with specific additional cognitive distraction (dual-task training) might increase activity more over 12 weeks, but the data are not conclusive. PMID- 30308700 TI - Role of the general practitioner in the care of BRCA1 and BRCA2 mutation carriers: General practitioner and patient perspectives. AB - BACKGROUND: General practitioners (GPs) have an increasing role in referring patients with putative mutation in BRCA1/2 genes for genetics consultation and for long-term follow-up of mutation carriers. METHODS: We compared the expectations of the GPs' role according to BRCA1/2 mutation carriers and to GPs themselves. RESULTS: Overall, 38% (58/152) of eligible GPs and 70% (176/252) of eligible patients were surveyed. Although 81% of GPs collected the family history, only 24% considered that they know criteria indicating genetics consultation and 39% sufficient knowledge of BRCA1/2 guidelines to answer patients' questions. Twelve% of GPs were aware of the French national guidelines. Among unsatisfied patients, 40% felt that their GP was able to answer (moderately, sufficiently, or completely) specific questions about BRCA1/2 care as compared with 81% in satisfied patients. Only 33% of GPs reported being informed directly by the geneticist about the patients' results. GPs' main expectations for their role in BRCA1/2 carrier care were psychological support and informing relatives about screening (72% and 71%, respectively), which contrasts with the perceptions of patients, who mainly requested medical advice for BRCA1/2-related care (51%). CONCLUSION: There is an important need for GP training and enhancing interactions between GPs and geneticists to improve the GP's role in BRCA1/2 screening and management. PMID- 30308701 TI - Molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa isolated from urine in Hyogo, Japan. AB - OBJECTIVES: To investigate the molecular characteristics and epidemiology of metallo-beta-lactamase-producing Pseudomonas aeruginosa from urine of urinary tract infection patients in Hyogo Prefecture, Japan. METHODS: Carbapenem resistant P. aeruginosa isolated from the urine of 21 urinary tract infection patients in three general hospitals in Hyogo Prefecture (Japan) were collected between 2007 and 2014. Their antibiotic susceptibilities, metallo-beta-lactamase screening test, metallo-beta-lactamase gene sequencing, multilocus sequence typing and repetitive-sequence-based polymerase chain reaction were determined for epidemiological analyses to investigate the genetic characteristics. RESULTS: Out of 21 isolates, 13 (61.9%) were positive for metallo-beta-lactamase. There were 11 (52.4%) isolates with IMP-1 in them, one (4.5%) isolate with IMP-7 and one (4.5%) isolate with VIM-1. Metallo-beta-lactamase-positive isolates were mainly identified as ST235, and metallo-beta-lactamase-negative isolates were STs 357, 277, 234, 439 and 639. Repetitive-sequence-based polymerase chain reaction showed metallo-beta-lactamase-positive isolates were grouped in eight clusters, and ST235 isolates with IMP-1 from three hospitals belonging to the identical group I, the other ST235 isolates with IMP-7 and VIM-1 were from two hospitals belonging to group II. CONCLUSIONS: Metallo-beta-lactamase-positive P. aeruginosa of ST235 isolates with IPM-1 were mainly identified from the urine of urinary tract infection patients in Hyogo, Japan. A ST235 isolate with VIM-1 was found for the first time. Further investigation is necessary to follow the spread of metallo-beta-lactamase-positive isolates. PMID- 30308702 TI - Comparative population genomics reveals key barriers to dispersal in Southern Ocean penguins. AB - The mechanisms that determine patterns of species dispersal are important factors in the production and maintenance of biodiversity. Understanding these mechanisms helps to forecast the responses of species to environmental change. Here, we used a comparative framework and genomewide data obtained through RAD-Seq to compare the patterns of connectivity among breeding colonies for five penguin species with shared ancestry, overlapping distributions and differing ecological niches, allowing an examination of the intrinsic and extrinsic barriers governing dispersal patterns. Our findings show that at-sea range and oceanography underlie patterns of dispersal in these penguins. The pelagic niche of emperor (Aptenodytes forsteri), king (A. patagonicus), Adelie (Pygoscelis adeliae) and chinstrap (P. antarctica) penguins facilitates gene flow over thousands of kilometres. In contrast, the coastal niche of gentoo penguins (P. papua) limits dispersal, resulting in population divergences. Oceanographic fronts also act as dispersal barriers to some extent. We recommend that forecasts of extinction risk incorporate dispersal and that management units are defined by at-sea range and oceanography in species lacking genetic data. PMID- 30308703 TI - Terrestrial species adapted to sea dispersal: Differences in propagule dispersal of two Caribbean mangroves. AB - A central goal of comparative phylogeography is to understand how species specific traits interact with geomorphological history to govern the geographic distribution of genetic variation within species. One key biotic trait with an immense impact on the spatial patterns of intraspecific genetic differentiation is dispersal. Here, we quantify how species-specific traits directly related to dispersal affect genetic variation in terrestrial organisms with adaptations for dispersal by sea, not land-the mangroves of the Caribbean. We investigate the phylogeography of white mangroves (Laguncularia racemosa, Combretaceae) and red mangroves (Rhizophora mangle, Rhizophoraceae) using chloroplast genomes and nuclear markers (thousands of RAD-Seq loci) from individuals throughout the Caribbean. Both coastal tree species have viviparous propagules that can float in salt water for months, meaning they are capable of dispersing long distances. Spatially explicit tests of the role of ocean currents on patterning genetic diversity revealed that ocean currents act as a mechanism for facilitating dispersal, but other means of moving genetic material are also important. We measured pollen- vs. propagule-mediated gene flow and discovered that in white mangroves, seeds were more important for promoting genetic connectivity between populations, but in red mangroves, the opposite was true: pollen contributed more. This result challenges our concept of the importance of both proximity to ocean currents for moving mangrove seeds and the extent of long-distance pollen dispersal. This study also highlights the importance of spatially explicit quantification of both abiotic (ocean currents) and biotic (dispersal) factors contributing to gene flow to understand fully the phylogeographic histories of species. PMID- 30308704 TI - Linagliptin inhibits high glucose-induced transdifferentiation of hypertrophic scar-derived fibroblasts to myofibroblasts via IGF/Akt/mTOR signalling pathway. AB - Hypertrophic scar (HS) is a fibroproliferative disease after serious burns; the underlying mechanism remains unknown. The study was performed to clarify the effect of high glucose (HG) on HS. The expression of Col1, Col3 and alpha-SMA was upregulated in HS-derived fibroblasts (HSF) exposed to HG (20 and 30 mmol/L), and HG activated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway in HSF. Dpp4, a marker targeted the treatment of diabetes mellitus, was overexpressed in HG-induced HSF. Linagliptin, a Dpp4 inhibitor, played the antifibrotic role in HSF exposed to HG, the levels of Col1, Col3 and alpha-SMA were significantly downregulated, and the cell proliferation and migration were also inhibited. Furthermore, linagliptin alleviated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway. Moreover, the mTOR inhibitor (rapamycin) mimicked the effect of linagliptin on the collagen and alpha-SMA that means linagliptin may inhibit HG-induced transdifferentiation of HSF to myofibroblasts via IGF/Akt/mTOR signalling pathway. PMID- 30308705 TI - Chronological changes in epidemiological characteristics of lower urinary tract urolithiasis in Japan. AB - OBJECTIVES: To determine changes and trends in the annual incidence and epidemiological aspects of lower urinary tract stones in Japan. METHODS: Data about patients who had been diagnosed by urologists in 2015 with first and recurrent lower urinary tract stones were collected from 301 hospitals approved by the Japanese Board of Urology. The estimated annual incidence according to sex, age and stone composition was compared with previous nationwide surveys between 1965 and 2005. RESULTS: The incidence of lower urinary tract stones in Japan has steadily increased from 4.7 per 100 000 in 1965 to 12.0 per 100 000 in 2015. However, the age standardized annual incidence of lower urinary tract stones has remained relatively stable over the same period at 5.5 per 100 000 and 6.0 per 100 000 in 1965 and 2015, respectively. The increase in incidence was most evident among individuals aged >=80 years. The incidence of calcium oxalate stones has steadily increased among males and females, whereas that of infection related stones has significantly decreased from 26.2% to 14.3% among men over the past 50 years. CONCLUSIONS: Nationwide surveys suggest a steady increase in the incidence of lower urinary tract stones over a 50-year period in Japan. This trend might reflect changes in the aging population and improved Japanese medical standards. PMID- 30308706 TI - Disease progression in blepharospasm: a 5-year longitudinal study. AB - BACKGROUND AND PURPOSE: The clinical manifestation of dystonic spasms in blepharospasm (BSP) patients may be heterogeneous. Whether the varying phenomenology of eyelid spasms becomes manifest sequentially during the course of the disease or aggregates in separate clusters according to different disease courses is still unclear. For this purpose, the clinical features in BSP patients were evaluated longitudinally over a 5-year period and also the blink reflex recovery cycle was tested in a subgroup of BSP patients. METHODS: Sixty BSP patients were videotaped at time 0 and after approximately 5 years of follow-up. Two experts in movement disorders, who were blinded to the video order, reviewed the videotapes and scored the severity of BSP using the Blepharospasm Severity Rating Scale. Changes in the R2 recovery index were also evaluated in 18 patients twice, i.e. upon enrolment and at the follow-up. RESULTS: The severity of BSP worsened significantly over the 5-year follow-up period owing to the appearance or the increased duration and frequency of prolonged spasms. It was also found that the blink reflex recovery cycle worsened at follow-up in comparison with the baseline. CONCLUSIONS: This study shows that the disease progression of BSP is characterized by the appearance or worsening of prolonged spasms. Prolonged spasms are accompanied by changes in the excitability of brainstem interneurons. Aging-related effects may exacerbate the pathophysiological mechanisms underlying spasms. PMID- 30308707 TI - Preclinical orthotopic xenograft model of renal pelvis cancer in which cancer growth could be traced by an in vivo imaging system. PMID- 30308708 TI - General practice in Ireland: are we equipped to manage mental health? PMID- 30308709 TI - Patient-controlled benzodiazepine dose reduction in a community mental health service. AB - : Abstact Objectives: We report a patient-controlled benzodiazepine discontinuation programme in a generic multidisciplinary community mental health service. METHOD: A prescribing audit identified suboptimal benzodiazepine use which stimulated a discontinuation programme [prescribing policy, psychoeducation, anxiety management] to encourage benzodiazepine cessation. Benzodiazepine status was re-assessed at 12 and 24 month follow-ups. RESULTS: 158 patients were receiving benzodiazepines at study onset. At 12 month follow-up, 68 of these were still receiving benodiazepines. This was due to discontinuation (n = 32), dose reduction (n = 26) and service dropout (n = 71). Benzodiazepine status at follow-up was predicted by attendance at anxiety management sessions (p = 0.01) and shorter duration of benzodiazepine use (p = 0.005). Patients attending anxiety management sessions were 2.5 times more likely to reduce use. Discontinuation followed four patterns: (a) rapid and complete discontinuation (n = 19); (b) total discontinuation in a gradual manner (n = 13); (c) partial dose reduction without total discontinuation (n = 18) and (d) almost total discontinuation with continued low-dose use (n = 8). The patients that achieved total discontinuation were younger (p = 0.01) and in receipt of benzodiazepine agents for a shorter duration (p = 0.009). At 24 month follow-up only three patients had relapsed into benzodiazepine use and a further 13 had achieved total discontinuation. CONCLUSIONS: Many chronic benzodiazepine users can achieve lasting discontinuation with patient-controlled dose tapering. Patient refusal and service dropout are common during discontinuation programmes. Anxiety management is a valuable adjunct to discontinuation. PMID- 30308711 TI - Schizophrenia: update on genetics, cognitive behavioural therapy and early intervention. AB - There have been considerable advances in the understanding of schizophrenia in recent years. This educational review paper focuses on three areas of interest and relevance to trainees preparing for the membership examination of the Royal College of Psychiatrists (MRCPsych): (a) recent advances in the genetics of schizophrenia; (b) advances in cognitive behavioural therapy in schizophrenia; and (c) advances in early intervention strategies for schizophrenia. Relevant papers and systematic reviews are discussed, and recommendations for further reading are provided. PMID- 30308710 TI - Contributions of social influences and psychopathological factors to cannabis use and dependence in high-school students. AB - OBJECTIVES: To evaluate the relative contributions of peers cannabis use or non use, parental approval of such use, adolescents' own beliefs about use, self esteem, and depressive and symptoms of borderline personality disorder, in the prediction of cannabis use and dependence. METHOD: Participants were 257 high school students who completed questionnaires assessing cannabis use frequency, cannabis dependence, the number of peers using cannabis, the number of peers opposed to cannabis use, parental attitude toward cannabis use, participants' attitude toward use, self-esteem, depressive and borderline symptomatology. Logistic regression analyses were conducted to predict cannabis use, daily use and dependence. RESULTS: The number of peers using cannabis, participants' approval of cannabis use, and the intensity of symptoms of borderline personality disorder were risk factors for use whereas the number of peers opposed to cannabis use was a protective factor. Parental attitudes toward use and participants' depressive symptomatology were not significant independent predictors of use. There were no significant predictors of probable cannabis dependence. CONCLUSION: To inform adolescents that a significant proportion of them disapprove of cannabis use may be an effective component of prevention of use. Symptoms of borderline personality disorder may account for the association between depression and cannabis use. The social influences and psychopathological factors evaluated in this study did not appear to play a major role in the development of cannabis dependence. PMID- 30308712 TI - Physical sciences and psychological medicine: the legacy of Prof John Dunne. AB - Fifty years ago, on July 13, 1955, Professor John Dunne delivered his presidential address to the annual meeting of the Royal Medico-Psychological Association in Dublin, focussing on the contributions of 'the physical sciences to psychological medicine.' In his address, Professor Dunne discussed (a) the principle of conditioning, and the work of Hans Selye, especially in relation to 'General Adaptation Syndrome' and the role of stress in producing psychosomatic symptoms; (b) cybernetics and the generation of partial models of cerebral functioning, such as Grey Walter's Conditioned Reflex Analogue and the Electronic Delayed Storage Automatic Computer of Cambridge and (c) the development of integrated, holistic models of cerebral functioning, that took account of advances in both physical medicine and psychoanalytic thought. Professor Dunne placed particular emphasis on the importance of basic scientific research and the development of broadly based models of psychiatric care, both of which were to play critical roles in the development of more scientifically-based, bio-psycho social models of service provision in the decades to follow. PMID- 30308713 TI - A case of clarithromycin psychosis. AB - A 19 year old girl developed an immediate psychotic reaction following IV clarithromycin (Klacid). She responded to atypical antipsychotics but needed psychiatric hospitalisation. She recovered after a year and is now symptom free without any medication. This is a rare side-effect but needs to be recognised. PMID- 30308714 TI - Psychology and psychiatry training. PMID- 30308715 TI - ADHD. PMID- 30308716 TI - Eight Item Short Form. PMID- 30308717 TI - Alcohol use in Ireland - can we hold our drink? PMID- 30308718 TI - Postnatal depression: a study of the predictive effects of postnatal anxiety. AB - OBJECTIVES: The aim of this study was to evaluate the predictive effects of anxiety, experienced on the third day after delivery, on postnatal depression, evaluated around the sixth week postpartum. METHOD: The subjects were 291 postpartum mothers who responded to a certain number of inclusion criteria. The EPDS (Edinburgh Postnatal Depression Scale) and the STAI (State-Trait Anxiety Inventory) were used to evaluate the anxious and depressive symptomatology on the third day postpartum and around the sixth week postpartum. The mothers who obtained scores indicating a probable risk of postnatal depression also completed the Beck Depression Inventory. RESULTS: We observed that 31% of the mothers showed postpartum blues symptomatology on the third day postpartum. Around the sixth week postpartum 13% of the mothers showed postnatal depression. The results suggest that the level of trait anxiety (beta = 0.39; t = 3.64 p < 0.05) and more particularly the intensity of the postpartum blues symptomatology (beta = 0.50; t = 6.88 p < 0.001) can predict the risk of postpartum depression. Furthermore, 17.9% of the mothers with postnatal depression around the sixth week postpartum were not detected by the EPDS on the third day after delivery. However, all these mothers were detected by the State-Trait anxiety inventory. CONCLUSION: A high level of anxiety during the first few days after delivery may contribute to the mothers' risk of developing postnatal depression. The early detection of high anxiety levels may enable the early screening of mothers at risk of developing postnatal depression. PMID- 30308719 TI - Predictors of discontinuation on clozapine: a population study. AB - OBJECTIVES: A quarter of people with schizophrenia may be classed as 'treatment resistant'. Clozapine is an antipsychotic that holds significant potential benefit for this patient group and has recently been recommended by the National Institute for Clinical Excellence. Early discontinuation is common. This study explores the factors that predict such discontinuation. METHOD: This retrospective cohort design was carried out on two hundred and one people with treatment resistant schizophrenia who had commenced clozapine between 1990 and 1997 identified from the Clozaril Patient Monitoring Service (CPMS) in Northern Ireland. Clinical and socio-demographic data was collected for three years before and after commencement on clozapine. Kaplan Meier survival analyses were conducted to identify differences in discontinuation rates according to a range of variables. RESULTS: Forty-five per cent of patients had discontinued before three years. No difference in rates were found between men and women, nor whether side-effects were reported or not Patients who had commenced clozapine at an older age had significantly higher cessation rates. People who had started clozapine at age 50+ were four times more likely to stop taking clozapine within three years than people aged between 17-29 years. CONCLUSIONS: Differences in continuation rates may be due to a number of factors. Treatment resistance may increase with age, side-effects may worsen or patient willingness to tolerate such effects may reduce. Alternatively, clinicians may be more anxious about prescribing clozapine as levels of co-morbidity increase. Further research is required to identify precise reasons and develop interventions to reduce discontinuation rates among older patients. PMID- 30308720 TI - Long-stay forensic psychiatric inpatients in the Republic of Ireland: aggregated needs assessment. AB - OBJECTIVES: To profile the current cohort of forensic psychiatric inpatients in the Republic of Ireland, comparing psychiatric healthcare and placement needs of long-stay patients with those more recently admitted. METHOD: All forensic psychiatric inpatients in the Central Mental Hospital, Dundrum on a census date were included in the study. Patients and key worker were interviewed using a standardised schedule and validated research instruments. Static and dynamic risk factors for violence including demographic, diagnostic and legal characteristics were supplemented by detailed chart review. Standardised anonymised case vignettes were presented to panels of forensic and community psychiatric multidisciplinary teams who assessed current and future treatment and placement requirements for the cohort. RESULTS: There were 88 forensic psychiatric inpatients on the census date. Forty-three had lengths of stay over two years (17 over 20 years). Both patient groups were predominantly males with severe mental illness and histories of violent offending. The majority of the long-stay group were receiving regular parole and this group had lower levels of positive symptoms and comorbid substance misuse disorders. Significant gaps in existing rehabilitation inputs were identified. Almost half the long-stay patients were inappropriately placed. Thirty per cent of long-stay patients could be safely transferred to lower levels of security within six months and 63% within three years. CONCLUSIONS: Holding patients in conditions of excessive security impedes rehabilitation and has considerable human rights implications. Almost half of long-stay forensic psychiatric patients in Ireland are inappropriately placed. Barriers to discharge include legislative inadequacies, lack of local low-secure facilities and under-resourcing of community psychiatric services. Such barriers lead to inappropriate utilisation of limited resources and limit access to secure facilities for higher-risk mentally disordered offenders. These findings are of particular relevance in the context of proposed new insanity legislation. PMID- 30308721 TI - The timing of deliberate self harm behaviour. AB - OBJECTIVES: To critically review the scientific literature relating to the timing of deliberate self harm behaviour and completed suicide. METHOD: A literature search of the Medline and CINAHL databases from 1970-2002 was performed, using deliberate self harm, overdose, self poisoning, suicide, parasuicide, and time, timing, day, week, month and season as key words. Relevant secondary references were retrieved and hand searching of important journals was done. RESULTS: The time of day of non-fatal self harm shows a marked diurnal variation, with an evening peak that is related to non-violent episodes, concomitant alcohol use, and a younger age. It is not conclusively linked to the degree of suicidal intent or particular psychiatric diagnoses. Completed suicides more commonly occur earlier in the day, at the beginning of the week and during springtime, but show no overall increase during many national events and holidays. CONCLUSIONS: Circadian biological mechanisms involving the serotonin-melatonin axis, Cortisol secretion and sleep abnormalities appear to be implicated. Psychosocial explanations for these epidemiological findings include alcohol use, a sense of personal isolation and the 'broken promise' effect. PMID- 30308722 TI - Pseudophaeochromocytoma associated with clozapine treatment. AB - We describe a 44 year old man with treatment resistant schizophrenia who developed pseudophaeochromocytoma on clozapine with high blood pressure, tachycardia and elevated 24 hour urinary catecholamines. All resolved on discontinuing clozapine. We reviewed the literature and found five other cases. We suggest that this is a common side effect, transient in some patients. Elevated plasma noradrenaline does not appear to be relevant to the unique benefits of clozapine. PMID- 30308723 TI - The imperative in PTSD: integrating biology and clinical practice. PMID- 30308724 TI - Problems experienced by young men and attitudes to help-seeking in a rural Irish community. AB - OBJECTIVES: Suicide is now the commonest cause of death among young Irish males. The literature identifies a wide range of contributory risk factors in suicide. However, a number of realities have frustrated clinicians' efforts in the area, including the reluctance of young males to engage in mental health services. In this study, we sought to explore the problems experienced by young men in a rural setting and their attitudes towards seeking help. METHODS: Focus groups were employed to generate themes for a qualitative and quantitative questionnaire which was administered to a community sample of 71 young men (22.4% of the total number of males aged 16-30 years in the area) and 79 key informants. The questionnaires contained demographic items and examined available social outlets, types and extent of difficulties experienced by young men and perceptions of and access to potential sources of support. RESULTS: Both young men and key informants reported that peer pressure and alcohol misuse are areas of most difficulty, that friends and family are the preferred sources of support and that young men view much existing professional help as unacceptable. CONCLUSIONS: This study provides a basis for the next stage in the research cycle and also supports the viability of building a partnership between the health services and the local community in developing future suicide prevention strategies for young men. PMID- 30308725 TI - Persistence of psychological problems in adolescence: a one year follow-up study. AB - OBJECTIVES: To examine the prevalence and persistence of psychological problems in older adolescents. METHODS: This study is a one year follow-up of 110 adolescents, 64 girls and 46 boys attending three secondary schools in Ireland. All were 16 at initial testing. The Youth Self Report (YSR) was the measure used. RESULTS: Over a fifth of adolescents have problems in the clinical range. These problems persisted from 16 to 17. Females reported more problems than males at both ages. Some females showed a slight reduction in internalising problems at 17. Both males and females showed an increase in externalising problems at 17. Odds ratios indicate that those in the clinical ranges of the YSR at 16, had increased risk of being in the clinical range at 17 compared to those in the no problem range at 16. In comparison to those with no suicidal feeling, those with suicidal feelings at 16 were at an increased risk of still feeling suicidal at 17. More males remained psychologically healthy than girls. CONCLUSIONS: A large proportion of adolescents in this sample have psychological problems and these appear to persist over a one year period. These problems impact substantially on the adolescents themselves, their families and society. Given the increasing suicide rate in young people and the persistence of suicidal feelings in this cohort, the inadequacy of mental health services in Ireland for adolescents, particularly those ages 16-18 is highlighted. The challenge of developing and providing adolescent friendly services is addressed. PMID- 30308726 TI - Social function, clinical symptoms and personality disturbance. AB - OBJECTIVES: To investigate the relationship between psychiatric symptoms, personality disturbance, and social function. METHOD: Longitudinal study of 100 psychiatric patients presenting as emergencies originally entered to a randomised trial of community and hospital-based treatment strategies. Ratings of social function using the Social Functioning Questionnaire, personality status using the Personality Assessment Schedule, and clinical symptomatology using the Comprehensive Psycho-pathological Rating Scale were recorded at baseline with assessment of social function repeated at two, four and 12 weeks. Correlation, regression, and path analysis were performed to test the hypothesis that personality status had more influence than clinical symptoms on social function. RESULTS: Path and regression analysis showed, that at baseline both psychopathology and personality pathology contributed to social dysfunction equally, but from two weeks onwards personality abnormality contributed to a greater degree than clinical psychopathology. Of the 100, 35 patients had a personality disorder and in these there was a strong correlation between social function scores at baseline and 12 weeks (48% of variation explained) whereas in those with no personality disorder the correlation was much weaker (14%); regression analyses confirmed this conclusion. CONCLUSIONS: Psychopathology and personality status contribute to social dysfunction in patients presenting as emergencies but persistent social dysfunction is more likely to reflect personality pathology than other forms of mental disorder. PMID- 30308727 TI - Risk factors for violence: an audit on the effect of a tutorial on risk assessment. AB - OBJECTIVES: To evaluate the effect of a risk assessment tutorial on the adequacy of case note documentation in a general adult psychiatry setting. METHODS: A comparison of case note documentation of risk factors for violence prior to and subsequent to a risk assessment tutorial. RESULTS: Prior to the tutorial there were very low rates of documentation of risk of violence. Subsequent to the tutorial, statistically significant improvements in documentation occurred in approximately one third of the items being assessed. Significant improvements occurred in the following; recording a collateral history (from 18%-36%) and previous history of deliberate self harm (from 24%-50%), noting emotions related to violence in the mental state examination (from 2%-24%) and documenting a risk management plan (from 2%-28%). However, levels of documentation remained overall sub-optimal. CONCLUSIONS: Some improvement in case note documentation can result from providing tutorials in risk assessment. However, the ideal format for teaching risk assessment needs to ascertained. PMID- 30308728 TI - Paroxetine induced mania in pre-adolescence. AB - Selective serotonin reuptake inhibitor induced mania has been described in adults, and more recently in adolescents. To the authors' knowledge a case in pre adolescents has not yet been published in the literature. The authors would like to report two cases of SSRI-induced mania. Both cases were pre-adolescent girls, A and B, who had a DSM-IV diagnosis of panic disorder, and were treated with paroxetine. PMID- 30308729 TI - Luis Simarro and his friends Cajal and Sorolla: three men, one passion. AB - Luis Simarro, Santiago Ramon y Cajal and Joaquin Sorolla were friends who cultivated art and science in an unhappy Spain. Simarro was the country's leading psychiatrist at the turn of the 20th century, Ramon y Cajal, or simply Cajal as he came to be known in the wider world won the Nobel Prize for his work on the nervous system, and Sorolla is remembered as 'the Velazquez of light'. All three felt a deep love of Spain and strove to bring freedom, science and the light of truth to their countrymen, each in his own unique way. PMID- 30308730 TI - Electroconvulsive therapy: do the figures add up? PMID- 30308731 TI - Flying solo: single/unmarried mothers and stigma in Ireland. PMID- 30308732 TI - Evolutionary theory in psychiatry and psychology. PMID- 30308733 TI - Cannabis abuse and psychiatric disorder. PMID- 30308734 TI - Adolescents with suicidal behaviour: attendance at A&E and six month follow-up. AB - OBJECTIVES: To review the clinical presentation, and Accident and Emergency Department clinical response to 14-20 year olds in suicidal crisis in inner city Dublin and to carry out a six month follow up of these young people. METHOD: A retrospective review of the case notes of all 14-20 year olds who had attended the Mater Hospital A&E department between June 2001 and May 2002 with suicidal behaviour or ideation was carried out in order to establish socio-demographic information, type of suicidal or self-harming behaviour, intervention in the A&E department, and discharge plan. Active outreach attempts were made to trace, contact and interview these young peoples at least six months after the initial presentation. Quantitative measures of psychological functioning at follow-up included the General Health Questionnaire, The Beck Depression Inventory and The Scale for Suicidal Ideation. A qualitative interview covered their recall of the reasons for their deliberate self harm, their view of their current psychological functioning and personal relationships, reported repetition of deliberate self harm, and their views of what type of services would be useful for young people with suicidal ideation or behaviour. RESULTS: A total of 89 young people aged 14 20 years (male: female ratio = 2:3) presented to the Mater A&E department between June 2001 and May 2002 with deliberate self-harm, deliberate self-poisoning and/or suicidal ideation, and accounted for 108 presentations. They showed high levels of psychosocial disadvantage. Almost half had a history of previous contact with mental health services, while the same proportion had a history of previous deliberate self-harm. Drug overdose using paracetamol was the most common method used. Psychiatric assessment was documented in 66% of cases, and documented follow up recommendations were made in 60% of cases. Two thirds of the 89 young people who formed the study population were traced. Half of those contacted agreed to be interviewed and half refused. The majority of those interviewed described themselves as functioning better psychologically than at the time of the index attendance at the A&E department The quantitative measures supported this. One third of those interviewed reported repeated deliberate self harm since their index attendance, for which most did not seek medical intervention. Many of the young people had clear views about the importance of talking to someone when in crisis. They described a service, which was informal, accessible on a 24-hour basis, and staffed by people with experience of mental health, alcohol and drug related disorders. CONCLUSIONS: This is a particularly vulnerable group of patients from a socio-demographic and mental health perspective. Their attendance at the A&E department provides a unique opportunity for an in-depth psychosocial assessment, which should be recorded in a systematic way to assist clinical audit, facilitate strategic mental health planning and may confer some therapeutic clinical benefit to at risk young people. An easily accessible, active DSH team specifically tailored for young people in the A&E department could provide assessment and short-term follow-up. This is the approach recommended by young people in suicidal crisis, whose views need to be heard. PMID- 30308735 TI - Withdrawal of antipsychotic drugs from adults with intellectual disabilities. AB - OBJECTIVES: There is a view that antipsychotic drugs can be successfully withdrawn from people with intellectual disabilities with resultant health gain. This study critically examines whether antipsychotic drug withdrawal is beneficial. METHODS: 119 adults with intellectual disabilities were included in a programme of antipsychotic drug withdrawal. RESULTS: The clinical outcomes of this programme are poor. Only 7.6% completely withdrew from antipsychotic drugs, and 48.7% experienced onset/deterioration in problem behaviours or mental ill health. Significant drug side effects with the introduction of new drugs were experienced by 23.3%. Resultant mean antipsychotic drug doses were higher compared with those at the start of the programme. The cost to the intellectual disabilities psychiatric service (over and above that of routine psychiatric care) was L258,050 (?391,693), and the human cost was considered high. Primary care, social care and family costs were not calculated. The only specific factors found to be associated with poor outcome were increased severity of intellectual disabilities and female gender. CONCLUSIONS: The successful role of antipsychotic drugs in the management of problem behaviours in people who do not have verbal communication skills may relate to the pathoplastic effect of intellectual disabilities on clinical presentation, with problem behaviours being markers of eg. psychosis and anxiety disorders. Our original findings challenge the view that routine withdrawal of antipsychotic drugs is good practice; we reinterpret the existing literature, and recommend caution and vigilance in pharmacotherapy. PMID- 30308736 TI - Evidence for use of depot neuroleptic medication. AB - OBJECTIVE: To review the evidence guiding conventional and atypical depot neuroleptic usage. METHOD: A search of biomedical electronic databases including Medline, Embase, PsychInfo and Cochrane was performed. Hand searching of journals was also carried out. RESULTS: Depot neuroleptics are safe and effective in the maintenance treatment of patients with schizophrenia. There is some evidence to support the use of depot neuroleptics in illnesses other than schizophrenia. The evidence base guiding depot usage is sparse. CONCLUSIONS: Although guidelines are emerging there is a pressing need for rigorous well designed trials of depot antipsychotic usage. The advent of atypical depot antipsychotic preparations should stimulate research in this important area of clinical practice. PMID- 30308737 TI - Sertraline as a treatment for PTSD: a systematic review and meta-analysis. AB - OBJECTIVE: Post-traumatic stress disorder (PTSD) is one of the most prevalent psychological disorders. Methods to alleviate its symptoms range from 'talking therapies' to pharmaceutical interventions. Our objective was to carry out a systematic review of the effectiveness of sertraline, an SSRI, as a treatment for PTSD. METHOD: Databases were searched to identify relevant research on sertraline as a treatment for PTSD. RESULTS: Five randomised control trials were identified, along with seven open trials and case series studies. CONCLUSIONS: The review and meta-analysis supported the use of sertraline for PTSD though further research on sub-group differences (eg. gender) is required. PMID- 30308738 TI - Interpersonal disturbance in OCD and its place in the professional consultation. AB - People with obsessive-compulsive disorder (OCD) typically experience their relationships with others with a high level of trepidation and bring their anxieties into their work with professionals. We have written this paper to describe experiences of working with people with diagnoses of OCD and the impression that we have formed about the kinds of relationship that builds up in the early stages of this work. We believe that it is important to consider the quality of these professional relationships because of their impact on the patient's ability to benefit from whatever intervention we propose. Here, we place particular attention on the roles of magical thinking, disturbed relationships and the fear of rejection. The perspective presented here is designed to complement those of other approaches to OCD - including the neurological, behavioural and cognitive-behavioural. The following themes relating to the social and interpersonal experiences of people with OCD are examined here: (a) their general tentativeness and uncertainty in social interactions, (b) their fear of being damaged by others in social interactions, (c) their magical thinking relating to damaging others. PMID- 30308739 TI - Investing in the future. PMID- 30308740 TI - The relationship between bullying, depression and suicidal thoughts/behaviour in Irish adolescents. AB - OBJECTIVES: This study examined the prevalence of depressive symptoms, including suicidal ideation/behaviour, among bullied and non-bullied young people. METHODS: Participants were 209 students, 97 male and 112 female, attending eight urban post-primary schools and aged between 12 and 15 years. Participants were interviewed using the Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version, the Hopelessness Scale for Children, the Scale for Suicide Ideation, and the Suicide Intent Scale. RESULTS: Data were analysed using a series of non-parametric comparison tests. Being a victim of bullying was found to be significantly associated with depression (chi2 = 10.986; df = 1; p = 0.001) and suicidal ideation (chi2 = 5.811; df = 1; p = 0.022). Results also indicated that victims were more likely to have reported a suicide attempt (chi2 = 5.995; df = 1; p = 0.022). Finally, those bullied were significantly more likely to have been referred to psychiatric services (chi2 = 6.661; df = 1;p = 0.011). CONCLUSIONS: These findings suggest that the issue of bullying needs to be re-addressed within Irish schools, with particular emphasis placed on further investigation into the psychological consequences thereof. PMID- 30308741 TI - Prevalence and detection of postnatal depression in an Irish community sample. AB - OBJECTIVES: To establish the prevalence of postnatal depression using standardised methods of diagnosis and to evaluate early detection of postnatal depression. METHODS: Prospective cohort study. Prevalence established using two step screening with EPDS and semi-structured clinical interview for ICD-10 diagnosis. EPDS recorded at day three-five postnatal evaluated as predictor of depression at week six postnatal. RESULTS: Prevalence established at 14.4%. EPDS recorded at day three-five postnatal when combined with past history of depression was a predictor of depression occurring at week six postnatal. CONCLUSIONS: We found a similar prevalence of postnatal depression in this Irish sample to other international prevalence studies. There are implications for hospital based screening to identify those at risk of developing a postnatal depression. PMID- 30308742 TI - Self-rated prospective memory and central executive deficits in excessive alcohol users. AB - OBJECTIVES: This study assessed self-reported prospective memory and related central executive processes in a group of excessive alcohol users and non-users. The aim was to assess whether excessive alcohol use is associated with impairments in these two sets of memory processes. METHODS: Eighty participants from the North-East of England were tested. Of these, 40 were excessive alcohol users (using above the recommended weekly 'safe' dose of alcohol) and 40 were low dose/non-users. Each participant was assessed using self-reports of prospective memory (PM) - measured using the Prospective Memory Questionnaire (PMQ) and central executive (CE) processes - measured using the Dysexecutive Questionnaire (DEX). Other drug use, age and strategy use were incorporated into the study as controls. RESULTS: After controlling for other drug use, age, and strategy use, excessive alcohol users reported global impairments in everyday prospective memory and in their central executive processes, when compared to a low-dose/no alcohol control group. CONCLUSIONS: These findings suggest that excessive alcohol use has a detrimental impact upon everyday memory - a relatively unexplored area of research. PM and CE deficits should be added to the growing list of neuropsychological sequelae associated with chronic excessive alcohol use. PMID- 30308743 TI - A retrospective analysis of the sentence writing component of Folstein's MMSE. AB - OBJECTIVES: Agraphia is the loss or impairment of the ability to produce written language as a consequence of brain damage and is a well recognised feature of dementia. However there is no generally accepted classification of agraphic disorders. Our aim was to determine the influence of writing style, lettercase and sentence polarity of the writing component of Folstein's MMSE on the overall test score. METHODS: We retrospectively reviewed the 'write a sentence' request of Folstein's MMSE of 280 randomly selected patients attending a geriatric day hospital. We analysed four sentence characteristics: 1 Number of words, 2 Writing legibility, 3 Sentence polarity, 4 Letter case. RESULTS: 280 MMSE forms were examined, 165 were from female patients. Mean age was 81.7(+/- 6.6) years. Mean MMSE score was 21.6 (males: 21.9, females: 21.4). Significant correlation was detected between the overall MMSE score and both legibility and number of words. Legibility scores were significantly higher for females than for males (7.2 vs. 6.6, p < 0.03). The mean MMSE of females writing in lowercase was significantly higher than for those writing in uppercase (21.5 vs. 18.6, p < 0.05). The mean MMSE score of subjects writing sentences with a positive tone was significantly higher than that of those writing a neutral or negative sentence (22.6 vs. 21.0 p < 0.03). CONCLUSIONS: We have demonstrated a relationship between the content and structure of the writing assessment aspect of the MMSE and the overall test score. PMID- 30308744 TI - A one-year audit of specialist psycho-oncology services in an Irish tertiary referral centre. AB - OBJECTIVES: Psychological services to patients with cancer are very limited in Ireland. A dedicated psycho-oncology service was established at our Institution 18 months ago. The aim of this study was to examine referral rates, psychiatric diagnoses and treatment interventions in this patient group. METHODS: The clinical and psychiatric characteristics of consecutive patients (n = 63) referred to a recently established specialist psycho-oncology service in an Irish university teaching hospital over a one-year period were examined prospectively. International diagnostic criteria were applied. Forms of treatment instituted and clinical response to same were also audited. RESULTS: Over half (54%) of patients presented with affective disorder spectrum illnesses. The remaining referrals represented a diverse group of psychiatric diagnoses, but included a large proportion of patients with delirium. Approximately 20% of patients did not meet criteria for a psychiatric diagnosis. There was an over-representation of breast cancer and lymphoma. Thirty-eight per cent of patients were on prescribed corticosteroids at the time of referral. Eighty-two per cent of patients required some form of psychiatric intervention, and 86% of these benefited clinically from our intervention. CONCLUSIONS: The data suggest that even in oncology services with good existing support networks, such as this one, the role of an additional input from liaison psychiatry is considerable. PMID- 30308745 TI - Nearly lethal suicide attempt - implications for research and prevention. PMID- 30308746 TI - Doctor Foster 'went' to Gloucester: the origin and aims of The Royal College of Psychiatrists. AB - In 1841 Dr Samuel Hitch organised a meeting at Gloucester Lunatic Asylum during which a decision was taken to establish the Association of Medical Officers of Asylums and Hospitals for the Insane with a view to "improvement in the management of such institutions and the treatment of the insane, and the acquirement of a more extensive and more correct knowledge of insanity". From the six medical officers present at this historic meeting the membership of The Royal College of Psychiatrists has grown to more than 11,000, of whom over 1,500 practise overseas. Dr Mike Shooter (President) believes that the College's most important, and painful, transformation has been from a largely educational to a political organisation. PMID- 30308748 TI - Consultants' experiences during their first year in post. PMID- 30308747 TI - The case of Robert Walser (1878-1956). AB - Robert Walser (1878-1956), one of the great literary geniuses of 20th century German literature, was also one of the most mysterious writers of his time. Born in Switzerland in 1878 he was diagnosed with schizophrenia at the age of 50 and spent the remaining two and a half decades of his life in Swiss psychiatric hospitals until his death in 1956. His literary legacy consists of four novels, numerous pieces of short prose (essays and stories) as well as 526 pages of pencil notes written in minuscule script, the famous 'micro-gramms'. Although highly unsuccessful during his lifetime and leading the life of an artist on the margins of society, his writings have been linked to Kleist, Kafka, Joyce and Beckett. The silencing of Walser's unique voice by mental illness and his disappearance behind the walls of psychiatric hospitals has been considered a tragedy and over the years doubts were raised about the true nature of his illness. PMID- 30308749 TI - Stimulant medication in ADHD: what do children and their parents say? AB - OBJECTIVES: The prescription of stimulant medication to children with attention deficit hyperactivity disorder remains topical. Few reports target children's views about taking long-term medication. The aim was to assess child and parent views of stimulant medication. To compare attitudes to medication between two groups of children, those with attention deficit hyperactivity disorder taking stimulant medication and those with epilepsy taking anti-epileptic medication. METHOD: Forty children (n = 40) with attention deficit hyperactivity disorder on stimulant medication, and 40 children (n = 40) with epilepsy on anti-epileptic medication formed the study population. A semi-structured interview was carried out with each child and parent. Each parent completed the Dosage and Side-effects Questionnaire and the Attitude to Medication Questionnaire. Each child completed the Attitude to Medication Questionnaire. RESULTS: Sixty per cent of children (n = 24) with attention deficit hyperactivity disorder and 62.5% (n = 25) of those with epilepsy knew the name and purpose of their medication. Forty per cent (n = 16) of children in the stimulant group and 32.5% (n = 13) in the anti-epileptic group reported themselves as being non-compliant with medication. In both groups children reported positive aspects to taking medication. More children with epilepsy reported negative aspects. Only 32.5% (n = 13) of children with attention deficit hyperactivity disorder said that they would tell a friend about their medication, while 55% (n = 22) of the children with epilepsy indicated that they would do so. In both groups parents were better informed than their children were about the purpose of the medication. Parents of children with attention deficit hyperactivity disorder tended to be more positive about medication than their children and than the parents in the comparison group. CONCLUSIONS: The majority of children and their parents express positive views about the stimulant medication. Children's views about medication compliance and side-effects should be sought, as they may differ significantly from those of their parents. Where parents have noticed positive changes, but children have not, this information can be used therapeutically to help children feel more in control of their behaviour. PMID- 30308750 TI - Social inclusion of people with intellectual disabilities: the impact of place of residence. AB - OBJECTIVES: People with intellectual disabilities are increasingly living in more domestic style accommodation, either in housing provided within a specialised campus setting or in ordinary houses in community settings. The main objective of the study was to determine if the extent of residents' involvement with their families and with the local community varied when they resided in campus settings (n = 55) or community housing (n = 51) and to investigate the main predictors of this involvement. METHOD: With the resident's permission, their key-workers - mainly nurses - completed standard questionnaires that covered resident characteristics, contact with families and a range of life experiences. RESULTS: Although the type of accommodation did have a significant effect on residents' social inclusion in families and communities, the best predictor of this was the individual's level of dependency in personal self-care. Those who were more dependent tended to be more excluded. CONCLUSIONS: Staff working with more dependent residents need to proactively promote their social inclusion although this could be harder to achieve for those living in campus style settings. PMID- 30308751 TI - Service response to benzodiazepine use in opiate addicts: a national postal survey. AB - OBJECTIVES: The study reports on benzodiazepine use among opiate dependent patients attending National Health Service community prescribing services and examines current practice in the clinical management of benzodiazepine dependence. METHOD: A postal questionnaire survey of 174 NHS substance misuse services in England and Wales. RESULTS: A 71% response rate was achieved. Services estimated the prevalence of benzodiazepine use to be 40% and the prevalence of benzodiazepine dependence to be less than 25% among opiate dependent patients in treatment. Illicit supplies (street) and general practitioners were regarded as the most common source of benzodiazepines. The most commonly reported reasons for benzodiazepine use were for the direct intoxicating effects and for the treatment of anxiety/insomnia. The majority of services (93,75%) reported prescribing benzodiazepines to patients for benzodiazepine detoxification while 43 (35%) reported prescribing for benzodiazepine maintenance treatment. The variations in benzodiazepine prescribing practices across services are described. CONCLUSIONS: Benzodiazepine use remains common among opiate addicts in contact with treatment services. The majority of services surveyed reported prescribing benzodiazepines but there was much variation in clinical practice nationally. There is need for further research to identify effective treatment approaches for comorbid benzodiazepine dependence in opiate misusers. PMID- 30308752 TI - Neuropsychiatric complications of corticosteroids in older people. AB - The neuropsychiatric effects of corticosteroids are well described in the literature but relatively little is known specifically about their effects among older people. As the population ages, and increasing numbers of older people receive assertive medical treatment for physical conditions, more patients are likely to present to psychiatric services suffering from adverse neuropsychiatric effects associated with corticosteroid use. A review of the effects of corticosteroids among older people was carried out through Medline and PubMed searches and a review of article references. Very little has been specifically written about steroid use and the effects on older people. This paper briefly outlines the current level of knowledge of neuropsychiatric effects of steroids, and relates this to general treatment considerations for older subjects. Recommendations for further research and early identification of complications are made. PMID- 30308753 TI - A paranoid migrant family - folie a famille. AB - This report describes a case of folie a famille in which an African man (Mr X), his wife and three daughters travelled around the world as Mr X transmitted his persecutory delusions to his family members. Mr X who had previously had two brief admissions in the UK and in Ireland, received an adequate trial of antipsychotic treatment in his third admission with us in Dublin. During informal contact with his daughter B, it became apparent that the whole family shared his delusions. On her advice, the other family members voluntarily consented for assessment and psychological interventions, they were interviewed separately. All the family members recovered following separation and psychological interventions without antipsychotic treatment. This case illustrates folie imposee, one of the four subgroups summarised by Gralnick1 from the 20th century literature. This family undertook an extreme measure of travelling around the world because of their induced delusions. PMID- 30308754 TI - Of the Right and Left Hand (1646): Sir Thomas Browne's historical survey of 'handedness". AB - 'Handedness' as an expression of cerebral lateralisation is valuable in analysis of hemispheric asymmetries, carrying implications for implementation (as well as interpretation) of complex cognitive functions. In recent decades it has become possible to categorise handedness in a reproducible manner and, independently, to estimate accurately the degree of language lateralisation of the brain. These advances have re-focussed attention on cerebral organisation and hemispheric asymmetries, and there is now considerable interest in the neuropsychology of left-handedness. Because of procedural and ethical constraints there are relatively few large scale studies on language dominance, whereas handedness has been studied extensively in recent decades. Language is represented in the left hemisphere in all but 1% of right-handers, and in 60% of left-handers; in 15% of right-handers speech representation was bilateral. Precise determination of handedness or lateralisation does not appear to have been assessed in major studies of electroconvulsive therapy (ECT). Results in 29 reports, when the electrodes were placed over either the non-dominant or both hemispheres, were tabulated and briefly discussed by d'Elia and Raotma, but the criterion of lateral dominance assignment was not clearly specified; the unilateral and bilateral placements were equally efficacious in their antidepressant effect. d'Elia, who introduced unilateral therapy in 1970, accepted the assumption that the left hemisphere was 'dominant', but later workers were more circumspect. PMID- 30308755 TI - Implementing the Mental Health Act 2001: What should be done? What can be done? PMID- 30308756 TI - Mental health in general practice: assessment of current state and future needs. AB - OBJECTIVES: To determine the extent of mental health services provided in the community in one Irish health board area. To examine the influence of postgraduate mental health training of GPs on provision of mental health services. METHOD: Questionnaire and focus group methods were employed to determine views on mental health service provision. Data analysis was with parametric and non-parametric tests of association including student's t and chi squared tests. Thematic analysis of the focus groups was carried out. RESULTS: Twenty-five per cent of patients attending general practice have mental health problems and over 95% of these problems are dealt with in primary care. Only 32% of GPs had received postgraduate training in psychological therapies. GPs with postgraduate training in psychological therapies were more likely to estimate a higher proportion of their patient population with mental health problems and less likely to refer to psychiatric services. A need for support from other health care professionals in primary care was also identified. CONCLUSION: The majority of patients with mental health problems are treated in primary care. Further training of GPs and increased resources would improve mental health care in primary care and lead to fewer referrals to psychiatric services. PMID- 30308757 TI - A longitudinal study of depression in old age I: outcome and relationship to social networks. AB - OBJECTIVES: To ascertain the relationship between social network type and depression over time. METHOD: A longitudinal outcome study of depressed elderly patients attending an old age psychiatric service was carried out. Subjects were seen at baseline and regular intervals over two years. RESULTS: Depression severity at baseline and at follow-up times differed according to subjects' social network. Those with more socially integrated networks had the best outcome and those who had more dependent networks had a poorer outcome. There was a lot of movement between networks over time for subjects, with many moving towards more dependent networks. CONCLUSIONS: When treating depression in the elderly it is important to consider the social network and milieu in which the patient resides. Treatments should include strategies encouraging the maintenance and formation of social integration. PMID- 30308758 TI - A longitudinal study of depression in old age II: depression and physical disability. AB - OBJECTIVES: As part of an outcome study of depression in older people, the relationship between physical disability and depression was explored at baseline and longitudinally. The aims were to identify whether illness in specific body systems or physical disability was associated with a poorer outcome of depression. METHOD: Subjects over 65 with depression referred to an old age psychiatry service were recruited. Depression was diagnosed according to ICD-10 criteria. An in-depth initial assessment obtained data concerning depression severity and illness in specific body systems as well as disability levels. Objective and subjective ratings of health status were also made. Subjects were followed up at three, six, 12, 18, and 24 months. Ongoing assessments were made of depressive symptomatology and of physical status. RESULTS: Subjects with higher disability levels had more severe depression at baseline. There was no relationship between illness in specific body systems and depression severity. At follow up assessments, those with higher disability scores had poorer outcomes as recorded by depression rating scales and by reviewing the longitudinal course of depression in terms of proportions remaining well, suffering relapses or remaining depressed. CONCLUSIONS: There is an ongoing relationship between depression and disability. Older people with greater physical disability have a poorer outcome of depression. Service providers should be aware of this relationship and respond rapidly and assertively to depression in older people with disability. There should be a lower threshold for initiating treatment in this population. PMID- 30308759 TI - Atypical antipsychotic monitoring in the Kilkenny Mental Health Services. AB - OBJECTIVES: To examine baseline testing and ongoing monitoring of cardiovascular and other risk factors in individuals prescribed atypical antipsychotic medications. METHODS: We derived a list of baseline and ongoing monitoring tests from the literature (Weight, BMI, blood pressure, U&E, LFTs, glucose, HbA1C, FBC, TFTs, prolactin, lipids & ECG) and then reviewed a random sample of 80 records of patients prescribed atypical antipsychotics and currently attending an Irish public catchment area service, for evidence of testing. RESULTS: Levels of testing for baseline tests ranged from 45% for blood pressure to 0% for BMI. Levels of ongoing monitoring tests ranged from 42.5% for U&E to 0% for BMI. Patients admitted to hospital were much more likely to have had testing. CONCLUSIONS: The need for baseline and ongoing monitoring of certain tests in patients prescribed atypical antipsychotics is increasingly accepted. Levels of such testing are currently quite low and need to increase. PMID- 30308760 TI - Topical issues in old age psychiatry. AB - With advancements in medical science over past decades, our aging population has increased substantially. Census studies in 2001 showed that 429,100 of the population of the Republic of Ireland were aged 65yrs and older, making up 11.2% of the overall population. While the overall population of the Republic is expected to remain stable over the next ten years, the demographic projections for the elderly population is for significant growth: numbers of over 65yrs are expected to increase by nearly 108,000 people between 1996 - 2011, comprising over 14.1% of the overall population. In particular, our communities will contain a much higher proportion of octogenarians and nonagenarians: at present 21% of our over 65's are 80 yrs or older; by 2011, it is projected that this number will increase to 25%. In tandem, the prevalence of dementia will increase. In 2000, it was estimated that 31,000 people suffered with dementia in the Republic of Ireland, and this figure is expected to increase by 5000 cases per year between 2001-2011. The ultimate outcome of this demographic shift, will be higher demands on medical services for older people, especially geriatric medicine and old age psychiatry. This paper will focus on two particular aspects of management which will increasingly impact on the work of old age psychiatrists - medicolegal issues and management issues in dementia. PMID- 30308761 TI - Recognising, assessing and managing offending behaviour in persons with intellectual disability. AB - The association between intellectual disability and offending is complex. Recent evidence would suggest that the received wisdom of intellectually disabled persons being more prone to offending is either incorrect or only tells part of the story. Those within the 'borderline' intellectual disability range may be more prone to committing sexual and criminal damage offences but those with an IQ less than 50 rarely offend. The offender with intellectual disability shares characteristics with his counterpart from the general population. As with the general population as a whole, offending in this group is often unreported and its recognition is complicated by issues of competence. The lack of validated forensic assessment schedules for this population poses a further challenge. Some general approaches to assessment in this population are discussed. This case report illustrates the difficulties of assessing and managing offending behaviour in an individual with moderate intellectual disability. The challenge of treating offenders with an intellectual disability is immense and requires specialist expertise. Managing such cases in a generic setting is inappropriate and the need for a forensic learning disability service in Ireland is highlighted. PMID- 30308762 TI - Erotomania secondary to cerebrovascular accident in frontotemporal impairment. AB - We report a case of erotomania with onset coinciding with a cerebrovascular accident in a 65-year-old woman. She believed Dick Haymes, a famous singer and actor who died in 1980 was in love with her, visited her and wanted to have sex with her. It is argued that the erotomania stemmed from an interaction between the frontotemporal impairment due to the cerebrovascular accident and personality factors. PMID- 30308763 TI - SSRIs, aggression and suicide - a cause for concern or the result of media hype? PMID- 30308764 TI - Attitudes to visits by children to parents hospitalised with acute psychiatric illness. AB - BACKGROUND: There is no published research on attitudes of psychiatrists towards children visiting parents who are acutely-unwell and inpatients in psychiatric hospitals. Nor is there information on facilities available for such visits. OBJECTIVES: (I) To assess the attitudes of Irish psychiatrists towards children visiting. (II) To determine the availability of child-friendly facilities within admission units. METHOD: A questionnaire was posted to every consultant psychiatrist accepting acute adult admissions in the Republic of Ireland and Northern Ireland. RESULTS: The response rate was 69%. Ninty-seven per cent were in favour of children visiting. Almost half felt that decisions on visits should depend on the particular situation, considering the child, parent, ward, etc. However, only 11% of units had a room/area designated for children visiting. 90% had no facilities they considered child-friendly on their unit. A majority felt that arrangements for children visiting were inadequate. CONCLUSIONS: This topic is of interest to psychiatrists, and can be contentious, particularly when considering supervision of, and legal responsibility for, children visiting. Guidance on these issues would aid psychiatrists and hospital management. Poor facilities and infrequent visits may be a factor in the early development of stigma towards mental illness. Further research, improvements in facilities and staff training in liaison with children are needed. PMID- 30308766 TI - Mania in elderly people. PMID- 30308765 TI - A tariff system for nervous shock: introducing the total impact score. AB - OBJECTIVES: This study was designed to test a proposed relationship between the total impact score (devised by the authors) and the quantum of damages in compensation received by victims of criminal and political violence. In so doing, the authors sought to develop a mathematical formula which could be used to quantify damages in a simple and expeditious manner. METHOD: Data on 2,191 victims of violence was collated forming three databases of information, on the incident, on the victim and on the outcomes. A tool of measurement of the psychosocial impact of the traumatic event was designed (the Total Impact Score). Information on a subsample of the 208 survivors of attempted assassination was then selected and the TIS for each individual was calculated and examined for correlations with other variables including the quantum damages awarded. RESULTS: The TIS was shown to have validity as a measure of the psychosocial impact of a traumatic event upon an individual. The analysis showed a significant relationship between the TIS and quantum awarded. This relationship was used to generate a mathematical formula which could be used to calculate quantum damages in any case. Compensation = L500 * (10(0037t+0.059y) -1), where t is the TIS and y is the number of years after 1985. CONCLUSIONS: The TIS can be taken as a valid tool for quantifying the psychosocial impact of a traumatic event or violent act. The tool consists of a checklist of readily ascertainable outcome variables each of which can be scored and a TIS calculated. From this score the amount of damages can be ascertained. The authors believe that this measurement tool represents a fair and equitable method of calculating a case's worth. PMID- 30308767 TI - Mental Health Policy in Ireland 1984-2004: theory, overview and future directions. AB - Recent years have seen renewed emphasis on the importance of mental health policy as a key component of health and social policy at both national and international levels. In 2001 the European Commission produced a public health framework for mental health in the EU. In the same year, the World Health Organisation devoted its annual health report to mental health and called on countries to formulate, update and implement mental health policies. The EU and WHO initiatives both recognised that the challenges facing mental health policy makers are increasingly transnational in scope, related to issues such as rapid demographic change, increased transnational migration, the protection of human rights and the implementation of a growing number of international laws, directives and protocols in relation to mental health care. Significant progress has been made in the development of Irish mental health services over the past 40 years. Nevertheless, many challenges remain. The aims of this paper are to outline: * Prevailing theoretical perspectives on mental health policy * Mental health policy in Ireland since the last major policy revision in 1984 * Relevant economic and demographic changes in Ireland since 1984 * Relevant clinical, legislative and policy developments in relation to mental health * Future directions for mental health policy. Electronic literature searches were performed using Psyclit (American Psychological Association, 1887-2003), Medline (United States National Library of Medicine, 1985 - 2003), with broad search terms related to mental health policy. Additional books and papers were identified by tracking back through references and consulting with colleagues. Policy documents and selected literature on Irish psychiatric services were reviewed and related to recent literature on mental health policy. PMID- 30308768 TI - A psychoanalytic psychotherapist working within psychiatry: covert and overt functions. AB - Within psychiatric practice, psychotherapy occupies a unique role. Not only is it a mode of treatment for some patients, it is also an explanatory model; not only is the psychotherapist called upon to fulfil numerous overt functions within the institution, there are also all sorts of other functions which a psychotherapist may be called upon or expected to fulfil, some more welcome and appropriate than others. Within medicine the choice of becoming a psychiatrist is often seen as feminine, unscientific, perhaps unsafe and slightly illicit. The same applies within psychiatry, to the choice of psychotherapy, and the decision to leave behind dopamine and clozapine for immeasurable, bizarre, unconscious objects. This paper will describe some of the overt and covert roles in the life of a consultant psychotherapist within the National Health Service (NHS) and then in more detail elucidate these roles with two examples from clinical practice. PMID- 30308769 TI - Withdrawal delirium with dance drug 'liquid ecstasy' (GHB). AB - We wish to describe a case of gamma hydroxyl butyrate (GHB) withdrawal, including seizure activity in a 34 year old male, who had been taking the substance over a two year period. The syndrome has many aspects in common with alcohol withdrawal (delirium tremens) and benzodiazepine withdrawal (long duration of symptoms), however detoxification presents many challenges for clinicians. PMID- 30308770 TI - Spectrum disorders survive by creativity. PMID- 30308771 TI - ECT: a controversial but effective treatment. PMID- 30308772 TI - Self-reported alcohol consumption in the Irish community dwelling elderly. AB - OBJECTIVES: To examine the associations of self-reported alcohol consumption in a community based sample of elderly subjects. METHODS: A total of 518 non institutionalised community dwelling elderly identified from general practice registers were interviewed in their own homes using the Geriatric Mental State (GMS-AGECAT), the Mini-Mental State Examination and the sociodemographic questionnaire. Physical health was rated on a six-point scale. Self reported alcohol consumption was recorded in units per week. The group was then divided according to the presence or absence of excessive alcohol consumption (ie. consumption of over 14 units per week for females and 21 units per week for males). Results were analysed using multivariate regression analysis with excessive alcohol consumption as the dependent variable. RESULTS: The mean age of the sample was 73 (range 65-95), 63% (n = 329) were female. Thirty-six per cent of the population were abstinent and 7% reported excessive alcohol consumption. Analysis of the data revealed no association between excessive alcohol consumption and diagnosis, age, cognitive function or poor physical health. Excess consumption was found to be significantly associated with gender (male) and widowed status (p < 0.001, p = 0.013 respectively). CONCLUSIONS: As alcohol misuse is commonly missed in the elderly identifying high risk groups is important for the development of intervention strategies. Our results suggest that elderly widowers may be more at risk than their peers of alcohol misuse. PMID- 30308773 TI - Psychiatric consultation to elderly medical inpatients in a general hospital. AB - OBJECTIVES: To determine the reasons for referral of elderly medical inpatients for psychiatric consultation and the appropriateness of such referrals. To determine whether the provision of a consultation service is associated with increases in referral rates over time. METHOD: One hundred consecutive referrals seen over an 18-week period were included in the study and data on reason for referral, ICD-10 diagnosis and recommended interventions gathered prospectively. Rates of referral were calculated and compared with a similar study performed in the same location five years previously. RESULTS: In this location the most frequent reason for referral was for assessment of depressive symptoms (47%). Referrals were generally appropriate and there was a high degree of concordance between reason for referral and psychiatric diagnosis, particularly for depressive symptoms. There was a moderate (22%) increase in referral rates in the five years since the previous study. Concordance rates between reason for referral and psychiatric diagnosis had improved considerably during this period, particularly for depressive symptoms. CONCLUSIONS: Referral rates for psychogeriatric consultation increase over time. Referrals are generally appropriate, and recognition of depressive illness improves. Psychiatric illness may still be under-recognised and increasing workload may indicate a need for more refined models of service delivery. PMID- 30308774 TI - Computer-assisted learning in undergraduate psychiatry (CAL-PSYCH): evaluation of a pilot programme. AB - OBJECTIVES: To introduce and evaluate a computer assisted learning programme in undergraduate psychiatry (CAL-PSYCH). METHODS: An interactive e-learning environment was created within the University College Dublin portal to assist students in acquiring the necessary skills in undergraduate psychiatry. The pilot phase consisted of providing their lectures on-line on the interactive site. Data were gathered from the last group of students in 2001 (pre-CAL-PSYCH) and the first group of students using CAL-PSYCH in 2002. We included assessment of percentage of students accessing the site, attendance rates at face-to-face lectures and tutorials, and also a feedback questionnaire from students who accessed the site. RESULTS: All responders had used CAL-PSYCH. Students gave higher ratings for quality and interactivity of lectures compared with the pre CAL-PSYCH curriculum. Students also expressed enthusiasm about CAL-PSYCH and encouraged us to develop it further. CONCLUSIONS: Computer-assisted learning environments such as CAL-PSYCH provide the opportunity to bring modern e-learning techniques to medical education, and may provide a new model for life-long learning in medicine. PMID- 30308776 TI - Combining psychiatric and psychological approaches in the inpatient assessment of aggression in a client with moderate intellectual disability. AB - The literature on challenging behaviour is large, with heavy emphasis on behavioural approaches. In recent years more attention has been given to the effect of psychiatric illness on the behaviour of people with intellectual disability. However, theoretical differences between disciplines can lead to one or other approach dominating the assessment process. Increasingly, functional assessment is receiving attention as an assessment approach by both psychiatrists and psychologists. When used properly it can give a holistic overview of the individual and their behaviour, allowing a team approach to assessment and treatment that ensures the consideration of all possible psychiatric/medical/behavioural/environmental possibilities (a bio-behavioural model) in the aetiology and maintenance of challenging behaviour. This case study illustrates the effectiveness of teamwork in this area using functional assessment as a tool. The case also illustrates the possible futility of such comprehensive assessments of challenging behaviour in the absence of appropriate resources to implement the recommendations of such an assessment. PMID- 30308775 TI - Obstructive asphyxia: a cause of excess mortality in psychiatric patients. AB - The purpose of this study was to determine the number of deaths which were caused by choking in a 10 year period in the Irish psychiatric in-patient population and the factors associated with such deaths. PMID- 30308777 TI - Porphyria and dementia: a case report. AB - The porphyrias are a group of rare hereditary metabolic disorders where there is an excess formation and excretion of porphyrins or their precursors. Type IIA, acute intermittent porphyria (AIP), has an estimated prevalence of one to eight per 100,000 in the general population but is thought to have a higher prevalence in psychiatric patients. AIP can present with a variety of psychiatric symptoms, often misdiagnosed. Associated neuropathological changes including focal cerebral ischaemic lesions have been found. However, to our knowledge, no case of dementia and AIP has been described. We present the case of a 56 year old man with a five year history of progressive cognitive decline, diagnosed with AIP at an advanced stage of dementia. Whether AIP contributed to the dementia or is a coincidental finding is unknown. However treatment of AIP in this case resulted in some improvement in the patient's cognitive state. PMID- 30308778 TI - ECT and etomidate-induced seizure-like activity. AB - Following the withdrawal of methohexitone from the market place psychiatrists and anaesthetists have been forced to seek out alternative anaesthetic agents for ECT. We report a case of etomidate-induced seizure-like activity. We review the literature on ECT and anaesthetic agents and discuss the alternatives available in accordance with a statement by The Royal College of Psychiatrists. PMID- 30308779 TI - The prevalence of neuroleptic malignant syndrome in learning disability. AB - OBJECTIVES: No information has been published on the incidence of neuroleptic malignant syndrome in learning disability. However, some studies of individuals who have developed neuroleptic malignant syndrome have suggested that individuals with learning disabilities may be over represented. This study aims to identify the association between learning disability and neuroleptic malignant syndrome. METHOD: A retrospective case-note analysis was performed with psychiatric case notes for clients with learning disability, in two geographical catchment areas. It was recorded whether clients had been exposed to neuroleptics, and whether any neurological symptoms had subsequently developed which could have been suggestive of neuroleptic malignant syndrome. RESULTS: It was found that 301 individuals had been exposed to neuroleptics, out of 570 case notes examined. Only one case of neuroleptic malignant syndrome was identified, giving a lifetime prevalence rate of 0.3%. CONCLUSION: This study failed to demonstrate a higher than expected prevalence of neuroleptic malignant syndrome in clients with learning disability exposed to neuroleptics. PMID- 30308780 TI - Documentation of alcohol, cigarette and cannabis use by psychiatric and general practice trainees. PMID- 30308781 TI - The multidisciplinary team in child psychiatry. PMID- 30308782 TI - Suicidal ideation among Irish adolescents: the CDI suicide question (item 9). PMID- 30308783 TI - Irish addiction services - past, present and future. PMID- 30308784 TI - Psychiatric problems of children exposed to opiates in utero - a descriptive study. AB - OBJECTIVES: To describe the psychosocial and clinical characteristics of children referred to a community-based child and adolescent mental health service, whose mothers reported that they took opiates during the pregnancy. METHODS: In a retrospective study, the case notes of all children whose mothers reported that they had been exposed to opiates in utero, and who were referred to the Department of Child and Family Psychiatry, Mater Hospital, between 2001-2003, were identified by maternal reports. Information was obtained on age, gender, referral source, socio-economic group, family type, number of siblings, involvement of community care services, nature of presenting problems, diagnosis, interventions offered, and treatment difficulties. Information was recorded anonymously. RESULTS: 15 children were identified, of whom nine were male. Most were found to be living with their mother alone or with their mother and a partner, and to be socially and financially disadvantaged. Their presenting complaints usually involved combinations of aggressive, hyperactive, and oppositional behaviour. Diagnoses included ADHD, a speech and language disorder, and an axis II disorder. Interventions were frequently unsuccessful because of parents' difficulties with attending appointments, and because of instability in the families' living arrangements. CONCLUSIONS: These children, due to a complex interplay of biological and psychosocial adversity, are at serious risk of ongoing psychiatric disorders in childhood and adolescence, and for adverse outcomes in adult life. A prospective cohort study of all children born to opiatedependent mothers is necessary to quantify the level of risk and identify resilience factors. PMID- 30308785 TI - Old age medical patients screening positive for depression. AB - OBJECTIVE: The aim was to observe whether medical inpatients screening positive for depression using the Geriatric Depression Scale (GDS) continue to screen positive following hospital discharge. METHOD: Participants aged 65 or over, were recruited from consecutive admissions to a city teaching hospital. Subjects had an Abbreviated Mental Test Score (AMTS) of seven or above and a GDS-15 score of five or above. Information was collected on past psychiatric history and living arrangements. Subjects were followed-up three months later and the GDS repeated. RESULTS: Thirty subjects were recruited and 26 (87%) followed-up. Ten (38%) no longer scored positive on the GDS, and overall the mean GDS score decreased by two points (Z = 2.235 p < 0.05). Patients with a past psychiatric history or living alone were more likely to be depressed at follow-up. No participants were referred to the psychiatric service or started on antidepressant medication during the course of the study. CONCLUSION: Depressive symptoms are likely to persist following hospital discharge, especially in those patients with a past psychiatric history. An understanding of the risk factors associated with persistent depressive symptoms is necessary if the patients appropriate for treatment are to be identified. PMID- 30308786 TI - Delirium in the hospitalised elderly: An audit of NCHD prescribing practice. AB - OBJECTIVES: This study was carried out to determine the prescribing of psychotropic medication of non-consultant hospital doctors in the management of delirium and to compare this with best practice guidelines. METHOD: A structured questionnaire was forwarded to all non-consultant hospital doctors (n = 95) working at St Vincent's University Hospital and data was collected over a six month period. The questionnaire addressed type, dose and route of psychotropic medication use in delirium as well as adjunctive measures used to manage delirium. RESULTS: There was a 55% response rate (n = 52). Haloperidol and lorazepam were the two most frequently prescribed psychotropic agents used and over one third of respondents (n = 20) reported the use of risperidone. There was wide variation in doses used and a substantial proportion of NCHDs used higher than recommended starting doses for elderly patients with delirium. In addition, the intramuscular route was reported as the commonest route of administration with a majority of respondents reporting infrequent intravenous route of administration. CONCLUSIONS: The drug choice reported by respondents followed best practice guidelines. However, the wide variation in drug doses used and frequency of parenteral route of administration (particularly intramuscular) indicate the need for increasing awareness of best practice international guidelines. Guidance and clarification regarding the use of atypical antipsychotic medication is required following concerns about their use in dementia. PMID- 30308787 TI - Autistic spectrum disorders. AB - Autistic spectrum disorders (ASD), are a group of disorders characterised by qualitative abnormalities in social and emotional behaviour and are associated with restricted, stereotyped and repetitive interests and activities. There has been considerable understanding of ASD in recent years. This educational review paper focuses on four areas of interest and relevance to trainees preparing for the membership examination of the Royal College of Psychiatrists (MRCPsych): (a) diagnosing ASD; (b) epidemiology of ASD; (c) aetiology, including genetic, cognitive and neurochemical/neuropathological theories in ASD; and (d) treatment of ASD. Relevant papers are discussed and recommendations for further reading are provided. PMID- 30308789 TI - 'Split personality' and the stigma of schizophrenia. PMID- 30308788 TI - The Victorian genius of Earlswood - a review of the case of James Henry Pullen. AB - London born James Henry Pullen (1836-1915) was admitted to Essex Hall in Colchester, an institution catering for learning disability, at the age of 13. Here his artistic talent was spotted before he moved two years later to Earlswood Asylum for Idiots, where he was apprenticed to woodworking. Such was his manual skill he was eventually employed making furniture for the asylum. His artistic propensity was similarly encouraged and although he never mastered coherent speech he has left a pictorial autobiography of some distinction. At observation he underwent detailed examination by Frederich Sano (1871-1946), particular attention being paid to tokens of arrested development. The clinical and pathological evidence of a pervasive developmental disorder points to a retrospective diagnosis of autism. PMID- 30308790 TI - Flows, stocks, and emissions of DEHP products in Japan. AB - The usage of products containing Bis (2-ethylhexyl) Phthalate (DEHP) is widespread, mainly through the great variety of PVC products. However, DEHP has become a worldwide concern, due to the potential health and environmental risks it presents. In this study, material flow analysis and emission estimations for DEHP products in Japan, from 1948 to 2030, were performed. Moreover, an evaluation of the potentially damaging impacts on human health and the environment was completed through a lifecycle impact assessment approach. The analysis focused on three representative lifecycle phases - Production, Use and Treatment and Disposal. The peak flows of DEHP from Production to the Use phase were in 1996 with 285,300 tons for shipment and the stocks peaked in 2001 with 1,981,908 tons. Accordingly, in 2006 the peak of DEHP waste to the Treatment and disposal phase was 190,792 tons. The primary emissions were observed in the Use phase, due to the large stocks, with DEHP mostly being released to the pedosphere. The total emissions from the Use phase reached the maximum of 48,960 tons in 2000, whereas in the Production and Treatment and disposal phase it was 248 tons and 15 tons, respectively. Subsequently, concerning the evaluation of impacts, the damage to the human health was the most widespread impact, totaling 13,782 disability-adjusted life years (DALYs), compared with the damage to the ecosystems, with 0.12 species.year. Furthermore, the risk-risk tradeoffs between the lifecycle phases were clarified throughout the years. PMID- 30308791 TI - Biofilm and temperature controls on greenhouse gas (CO2 and CH4) emissions from a Rhizophora mangrove soil (New Caledonia). AB - Seasonal variations of CO2 and CH4 fluxes were investigated in a Rhizophora mangrove forest that develops under a semi-arid climate, in New Caledonia. Fluxes were measured using closed incubation chambers connected to a CRDS analyzer. They were performed during low tide at light, in the dark, and in the dark after having removed the top 1-2 mm of soil, which may contain biofilm. CO2 and CH4 fluxes ranged from 31.34 to 187.48 mmol m-2 day-1 and from 39.36 to 428.09 MUmol m-2 day-1, respectively. Both CO2 and CH4 emissions showed a strong seasonal variability with higher fluxes measured during the warm season, due to an enhanced production of these two gases within the soil. Furthermore, CO2 fluxes were higher in the dark than at light, evidencing photosynthetic processes at the soil surface and thus the role of biofilm in the regulation of greenhouse gas emissions from mangrove soils. The mean delta13C-CO2 value of the CO2 fluxes measured was -19.76 +/- 1.190/00, which was depleted compared to the one emitted by root respiration (-22.32 +/- 1.060/00), leaf litter decomposition (-21.43 +/- 1.890/00) and organic matter degradation (-22.33 +/- 1.820/00). This result confirmed the use of the CO2 produced within the soil by the biofilm developing at its surface. After removing the top 1-2 mm of soil, both CO2 and CH4 fluxes increased. Enhancement of CH4 fluxes suggests that biofilm may act as a physical barrier to the transfer of GHG from the soil to the atmosphere. However, the delta13C-CO2 became more enriched, evidencing that the biofilm was not integrally removed, and that its partial removal resulted in physical disturbance that stimulated CO2 production. Therefore, this study provides useful information to understand the global implication of mangroves in climate change mitigation. PMID- 30308792 TI - Quantifying the spatio-temporal drivers of planned vegetation restoration on ecosystem services at a regional scale. AB - Vegetation restoration often has a significant effect on the supply of an ecosystem service (ES). Assessment of this effect is crucial for informed decision-making in sustainable ecosystem management. In this respect, this study analyses three regulating, two provisioning, and a single cultural ES over a 30 year period (1985 to 2015, with 15 years pre-restoration and 15 years post restoration) in the Loess Plateau, China, using data from a combination of modelling and statistical yearbooks. On applying a suite of standard statistical tools, results indicate: (1) regional scale restoration promotes the increase of vegetation cover as the coverage increased faster between 2000 and 2015 than between 1985 and 2000; (2) vegetation restoration changes the temporal trend of regulating ESs, and enhances the supply of provisioning and cultural ESs; (3) the 40 municipalities of the Loess Plateau can be divided into four ES categories where areas with poor ES delivery account for about 30% of the Loess Plateau; (4) vegetation restoration changes the interaction among ESs, resulting in synergistic relationships between provisioning and regulating ESs; (5) precipitation has a significant impact on regulating ESs, while population density is critical for provisioning and cultural ESs. This study demonstrates that ESs, their interactions and their groupings can change across both time and space following the implementation of a vegetation restoration programme, which makes understanding ES dynamics complicated. Recommendations are provided for improved and coherent ecosystem management. PMID- 30308793 TI - Chlorinated paraffins in the indoor and outdoor atmospheric particles from the Pearl River Delta: Characteristics, sources, and human exposure risks. AB - Chlorinated paraffins (CPs) are ubiquitously present in the environment due to their abundant production and consumption. Information on CPs as part of indoor particles is very limited although a significant amount of time is spent in indoor environments. Seventy-two indoor and 66 outdoor TSP/PM10/PM2.5 samples (particulate matters with aerodynamic diameter <100, 10, and 2.5MUm) from 24 homes of the Pearl River Delta (PRD), China, were analyzed for CPs. PM2.5 were found to be the dominant particles both indoors and outdoors. CPs were mainly distributed in PM2.5 that accounted for 89.1% and 93.0% of the total particles indoors and outdoors, respectively. The geometric mean (GM) concentrations of medium-chain CPs (MCCPs) exceeded those of short-chain CPs (SCCPs) (22.0 vs. 9.2ng/m3) in all particle samples. Both SCCPs and MCCPs in the indoor particles (GM: 13.4 and 30.9ng/m3) were approximately twice as high as in the outdoor environment (GM: 6.1 and 15.2ng/m3). C11 and C14 carbon chains as well as six and seven chlorine homologues were found to be predominant in all samples with average percentages of 43.0% and 55.4%, respectively. The estimated daily CP intakes via PM2.5 inhalation were 8.1-24.6 and 25.1-76.0ng/kg.bw/day for all age subgroups based on both mean and 95th percentile concentrations of CPs. However, the estimated daily uptakes decreased to 4.4-16.4 and 13.5-50.6ng/kg.bw/day, respectively, when the deposition fractions of PM2.5 in the human lung were considered. Indoor PM2.5 attributed to 93.8% exposure of CPs based on both total estimated daily intakes (EDIs) and estimated daily uptakes (EDUs), indicating that the indoor PM2.5 exposure was very important. Infants and toddlers suffered higher exposure risks of CPs compared to other subgroups, indicating higher potential health risks; however, based on the margin of the exposure analysis these risks could be ignored. PMID- 30308794 TI - China's low-carbon economic transition: Provincial analysis from 2002 to 2012. AB - As the largest energy consumer and CO2-emitting country, China is committed to achieving a low-carbon economy (LCE). This study seeks to understand the spatial evolution of China's LCE provinces and determine which sectors could promote the formation of LCE provinces. Multiregional input-output (MRIO) analysis is applied to filter the LCE provinces and the sectoral structure changes behind the LCE in China from 2002 to 2012. The result shows that approximately 30% of the provinces (i.e., Tianjin, Zhejiang, Jiangsu and Chongqing) become LCE provinces faster than other provinces from 2002 to 2012, and the location of the LCE provinces gradually shifts from coastal to inland regions after 2007. Some sectors (i.e., nonmetal mining, chemical industry and nonmetal manufacturing) gradually become LCE sectors from 2002 to 2012, and these sectors promote the formation and development of LCE provinces. On this basis, this study proposes policy implications regarding the benchmarking of sectors and a sectoral structure that can promote the formation of LCE provinces. PMID- 30308795 TI - Use it or not: An agro-ecological perspective to flooded riparian land along the Three Gorges Reservoir. AB - The extensive flooded land associated with the Three Gorges Reservoir, poses a great social and environmental challenge, yet it is a potential valuable land and sociological resource for resolving human-land conflicts in the surrounding communities. Controversies arose over use or non-use of such land among local communities and authorities; and different management strategies were adopted. We compared two representative ecosystems, Wuyang Bay in small-scale agricultural use through opportunistic farming, and Baijiaxi Bay in a state of natural succession, and learned the challenges-cum-opportunities regarding sustainability through an agro-ecological perspective. We integrated the plant diversity, water quality improvement, market production services and people's attitudes to obtain a holistic evaluation of the socio-ecological and economic benefits delivered by two bays. Significant differences were found: Wuyang Bay performed much better than Baijiaxi Bay in terms of plant diversity maintenance and people's acceptance. Regarding the concerns about impacts on reservoir water, Wuyang Bay has lower TN, and NH4-N concentrations than Baijiaxi Bay. This may be because of the decomposition of a large amount of naturally grown-drowned vegetation in Baijiaxi Bay. Emergy analysis showed that the economic efficiency of Wuyang Bay is better than other similar systems given its limited growing season. However, this is at the expense of the environment through chemical fertilisers and pesticides seeping into the reservoir waters. Strictly speaking, Wuyang Bay cannot be counted as a sustainable agro-ecosystem although it hints at many practical merits, such as integrating natural landscape elements in fields, and employing multiple crops in spatial and temporal patterns. Our study offers new insights into the impacts of world's largest reservoir construction on the livelihoods of nearby communities on a small scale and the possible solutions. With the use-or-not contradiction, the government should offer appropriate policies and technical support to incentivise farmers to a more sustainable, multi-functional living landscape. PMID- 30308797 TI - The implications of weather, nutrient prices, and other factors on nutrient concentrations in agricultural watersheds. AB - This paper examines how nutrient prices, weather, and other factors influenced P outputs in agricultural watersheds using a detailed daily dataset of water quality observations over a 40-year period. Because policies have focused differentially on soluble P through federal permitting programs for point sources and sediments through federal subsidies for conservation, we examine sediment, particulate P and soluble P separately. A novel element of this study is the inclusion of farm fertilizer and output (i.e., corn) prices, which affect agricultural sources of P in these watersheds. We do not find that sediment concentrations are influenced by P prices, but sediment has trended downward, and is seasonally lower in all months except February and March in the Maumee. In contrast, we find that soluble P concentrations are heavily influenced by P prices. They trended downward through 1995, but upwards since. While concerns about fall and winter P application have emerged, we do not find evidence that the distribution of soluble P concentrations shifted towards winter over time. Weather accounts for about 50% of the higher soluble P loadings in 1996-2011, but higher P prices in 2005-2011 lowered P concentrations relative to what they would have been. Other factors account for the remaining 50% of the increase in soluble P concentrations in 1996-2011. PMID- 30308796 TI - Drivers and barriers of adaptation initiatives - How societal transformation affects natural hazard management and risk mitigation in Europe. AB - A key challenge of hazard risk management is finding novel ways to respond to future extremes amid increasing vulnerability. Societal transformation in the context of multi-functional protection schemes offers potential in this regard. However, the drivers and barriers of societal transformation in hazard management are poorly understood. Here we interrogate drivers and barriers of societal transformation in natural hazard management through case studies in Austria, France and Ireland focusing on attempts to integrate multi-functional protection schemes in the context of flood and avalanche hazards. We conducted qualitative semi-structured interviews with key stakeholders connected to proposed transformative strategies in the selected case studies. We find that transformative approaches have been mainly supported by local initiatives instigated by local governments, residents, or NGOs with the aim of complementing conventional hazard management policies. Our analysis shows that local actors and stakeholders often pursue initiatives to address local problems or to seize local opportunities rather than to contribute to a broader societal transformation. According to our findings, key drivers of community-based initiatives with multiple functionality and use include: (i) lack of funding, (ii) lack of legal protection or (iii) lack of space, where classical risk management measures can no longer respond to new circumstances. In contrast, key barriers relate to: (i) lack of local capacities, (ii) lack of local political support and (iii) technological challenges in the implementation phase. These insights support European regions currently working on the implementation of climate change adaptation strategies arising from natural hazards. PMID- 30308798 TI - Exploring the changes and driving forces of water footprints in China from 2002 to 2012: A perspective of final demand. AB - Due to economic development and population growth, the water shortage in China has gradually become increasingly severe. In this paper, by developing an environmentally expanded input-output (IO) model, water footprint in China during 2002-2012 is calculated from the perspective of final demand. Furthermore, a structural decomposition analysis (SDA) model is used to study the driving factors of the water footprint of rural and urban household consumption, gross fixed capital formation and exports. The findings indicate that: 1) the water footprint driven by final demand in China increased by 18.3% during 2002-2012, reaching 617.68 billion m3 in 2012, of which urban household consumption accounts for the highest proportion. 2) Of the different sectors, agricultural commodities have the highest water footprint, accounting for 35% of national water footprint in 2012. 3) In terms of the driving factors, water efficiency inhibits the increase of water footprint regardless of final demand types, while GDP per capita makes a great contribution to its rise. 4) As for rural household consumption, the most important driving factor is the inhibition effects of consumption pattern in water footprint. For urban household consumption, the water footprint is inhibited by consumption pattern but promoted by production structure during 2002-2010. However, it is no longer the case during 2010-2012 that consumption pattern becomes a promoting factor, with production structure being inhibiting one. 5) Regarding gross fixed capital formation, its water footprint increase driven by consumption pattern is only 12.4 billion m3 during 2007-2010. As for exports, consumption pattern causes the decline of water footprint after 2005 and the overall water footprint of exports declines during 2007-2012. Finally, this paper provides policy implications with respect to the promotion of China's water footprint conservation. PMID- 30308800 TI - Occurrence and enantiomer profiles of beta-blockers in wastewater and a receiving water body and adjacent soil in Tianjin, China. AB - A total of 58 samples were collected from hospitals, municipal wastewater treatment plants (WWTPs), a receiving water body (Dagu Drainage Canal, DDC), and adjacent farmland in Tianjin City, China, in May and November 2013 and were analyzed for five common beta-blockers (atenolol, sotalol, metoprolol, propranolol, and nadolol) to elucidate their source, occurrence and fate in a typical city in China. The profiles of the enantiomers of the beta-blockers in some samples were examined. Sotalol, metoprolol and propranolol were frequently detected, atenolol was less frequently detected, and nadolol was mostly not detected. Generally, the concentrations in hospital wastewaters occurred from 100/cm3 was influenced by air masses originating from the Indian Ocean and Indochina regions. Receptor models extracted five potential sources of PNCs: industrial emissions, transportation, aged traffic emissions, miscellaneous sources, and a source of secondary origin coupled with meteorological factors. A respiratory deposition model for male and female receptors predicted that the deposition flux of PM1 (particle mass <=1 MUm) into the alveolar (AL) region was higher (0.30 and 0.25 MUg/h, respectively) than the upper airway (UA) (0.29 and 0.24 MUg/h, respectively) and tracheobronchial (TB) regions (0.02 MUg/h for each). However, the PM2.5 deposition flux was higher in the UA (2.02 and 1.68 MUg/h, respectively) than in the TB (0.18 and 0.15 MUg/h, respectively) and the AL regions (1.09 and 0.91 MUg/h, respectively); a similar pattern was also observed for PM10. PMID- 30308809 TI - Oral acute toxicity of imidacloprid, thiamethoxam and clothianidin in eared doves: A contribution for the risk assessment of neonicotinoids in birds. AB - Neonicotinoids have recently been demonstrated to cause direct negative impacts on birds from North America and Europe. To further understand the impact of these compounds on bird species and to improve risk assessment capacities, the current study determined the acute toxicities of imidacloprid, clothianidin, and thiamethoxam formulations on South American eared doves (Zenaida auriculata). Insecticides were administered by gavage to adult doves to determine median lethal doses (LD50) according to a standardized sequential procedure. The acute toxicity of formulated imidacloprid (LD50=59mg active ingredient, a.i./kg body weight, b.w.) was much higher than that of the tested formulations of clothianidin (LD50=4248mga.i./kg b.w.) and thiamethoxam (LD50=4366mga.i./kg b.w.). Imidacloprid also differed from the other two neonicotinoids in terms of the onset and intensity of intoxication signs and the times of death and recovery. All three insecticides induced a reduction in food consumption that led to body weight loss. An average weight dove of 127g would obtain a dose equivalent to the LD50 of imidacloprid by consuming 1.7g of treated sorghum seeds. As eared doves offered non-treated sorghum seeds 5h per day consumed on average 6.4+/-1.8g (mean+/-S.D.), it is concluded that these doves could feasibly be exposed to lethal doses in the field. This work is the first to describe intoxication signs and report oral neonicotinoid LD50s in a wild South-American bird species. PMID- 30308810 TI - Strontium in fin whale baleen: A potential tracer of mysticete movements across the oceans? AB - Strontium is a metal broadly distributed in oceanic waters, where its concentrations follow gradients mainly driven by oceanographic and biological factors. Studies on terrestrial vertebrates show that Sr can accumulate in mammalian hair in amounts mainly related to the external environment, a property that has been scarcely investigated in aquatic mammals. Cetaceans are marine mammals whose skin is generally hairless, but the species belonging to the mysticete group feed through a filtering apparatus made of keratinous baleen plates that, like hair, grow continuously. During their annual latitudinal migrations, mysticetes cross water masses with variable chemo-physical characteristics that may be reflected in these tissues. In the present study, baleen plates were sampled from 10 fin whales obtained from NW Spain (N = 5) and SW Iceland (N = 5) to investigate Sr concentrations along the plates growth axis. Samples were taken longitudinally at regular 1 cm-intervals on each plate. Sr concentrations, determined through mass spectrometry, ranged from 5 to 40 mg kg-1 and increased from proximal to distal positions along plates. These results suggest a progressive adsorption of Sr on the plate surface, a process that also occurs in mammalian hair. Increasing trends were similar in the two regions but overall concentrations were significantly higher in NW Spain, reflecting different Sr baseline concentrations in the two areas and indicating isolation between the two whale populations. Some oscillations in Sr longitudinal trends were also detected, likely indicating that whales migrate across water masses with different Sr baselines. These results suggest that Sr concentrations in keratinous tissues of marine mammals can be used as ecological tracers of their migrations and habitat use. PMID- 30308811 TI - Exposure of Candida parapsilosis complex to agricultural azoles: An overview of the role of environmental determinants for the development of resistance. AB - This work investigated the phenotypic behavior of Candida parapsilosis species complex in response to exposure to agricultural azoles and fluconazole. Three fluconazole-susceptible strains of C. parapsilosis sensu stricto, C. orthopsilosis and C. metapsilosis were used. Initial minimum inhibitory concentrations (iMICs) for agricultural and clinical azoles were determined by broth microdilution. Then, the strains were exposed to tebuconazole, tetraconazole and fluconazole for 15 days, at concentrations that were two-folded daily, starting at one-eighth the iMIC (iMIC/8) up to 64 times iMIC (64xiMIC). After 15-day-exposure, antifungal susceptibility, biofilm formation, CDR, MDR and ERG expression were evaluated. The three cryptic species developed tolerance to the antifungals they were exposed and presented reduction (P < 0.05) in fluconazole susceptibility. In addition, C. parapsilosis sensu stricto and C. metapsilosis also presented reduced susceptibility to voriconazole, after fluconazole exposure. Azole exposure decreased (P < 0.05) biofilm production by C. parapsilosis sensu stricto and C. orthopsilosis and increased (P < 0.05) the expression of ERG11 in all tested strains. The results show that exposure to agricultural azoles and fluconazole induces changes in the phenotypic behavior and gene expression by the three cryptic species of C. parapsilosis complex, highlighting the importance of environmental determinants for the development of antifungal resistance. PMID- 30308812 TI - Uptake and toxic effects of triphenyl phosphate on freshwater microalgae Chlorella vulgaris and Scenedesmus obliquus: Insights from untargeted metabolomics. AB - The flame retardant triphenyl phosphate (TPhP) has been widely detected in surface waters. Yet, little information is known regarding its impact on microalgae. We investigated the uptake and toxicity of TPhP on two freshwater microalgae Chlorella vulgaris (CV) and Scenedesmus obliquus (SO) after exposure to 10 MUg/l-10 mg/l for 5 days. The presence of microalgae significantly enhanced TPhP degradation, with the final concentrations dropped to 5.5-35.1% of the original concentrations. Most of the medium TPhP were sorbed and transformed by microalgae in just one day. Growth of CV was inhibited in a concentration dependent manner, whereas growth of SO were only inhibited significantly at 10 mg/l TPhP exposure. Mass spectrometry-based untargeted metabolomics revealed concentration- and species-dependent metabolic responses. Exposure to TPhP in CV resulted in enhanced respiration (increase of fumarate and malate) and osmoregulation (increase of sucrose and myo-inositol), synthesis of membrane lipids (accumulation of monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), decrease of lysoglycerolipids, fatty acids, and glyceryl-glucoside). Exposure to TPhP in SO resulted in enhanced osmoregulation (increase of valine, proline, and raffinose) and lipolysis (decrease of MGDG, accumulation of fatty acids, lysophospholipids, and glycerol phosphate). Although chlorophyll a and b contents did not change significantly, decrease of chlorophyll derivatives was observed in both CV and SO at high exposure concentrations. Further bioassays confirmed that CV exhibited enhanced membrane integrity and decreased cellular reactive oxygen species (ROS) possibly as a defense strategy, whereas SO showed disruption of membrane integrity and induction of ROS at 10 mg/l exposure. This study demonstrated the potential of microalgae to remove TPhP in water, and offered new insights for the risk assessment of TPhP on freshwater microalgae using metabolomics. PMID- 30308813 TI - Exposure to pollen-bound pesticide mixtures induces longer-lived but less efficient honey bees. AB - Due to the widespread use of pesticides and their persistence in the environment, non-target organisms are chronically exposed to mixtures of toxic residues. Fungicides, herbicides and insecticides are all found at low doses in the diet of pollinators such as honey bees, but due to the lack of data on the toxicological effects of these mixtures, determining their risk is difficult to assess. We therefore developed a study combining the identification of common pollen-bound pesticide mixtures associated with poor colony development and tested their effects on bee behavior and physiology. We exposed bees to the identified pesticide mixtures during the first days of their adult life, a crucial period for physiological development. Using optic bee counters we recorded the behavior of bees throughout their lives and identified two pesticide mixtures that delay the onset of foraging and slow-down foraging activity. Furthermore, one of these mixtures hampers pollen foraging. As bee longevity is strongly influenced by the time spent foraging, bees exposed to these pesticide mixtures outlived control bees. Physiological analysis revealed that perturbations of the energetic metabolism preceded the altered behavior. In conclusion, we found that early-life exposure to low doses of pesticide mixtures can have long-term effects that translate into longer-lived but slower and less efficient bees. These surprising findings contrast with the commonly reported increase in bee mortality upon pesticide exposure, and demonstrate that exposure that may seem harmless (e.g., very low doses, pesticides not intended to kill insects) can have undesirable effects on non-target organisms. PMID- 30308814 TI - Effects of 21st century climate change on seasonal flow regimes and hydrologic extremes over the Midwest and Great Lakes region of the US. AB - Analyzing future changes in hydrologic extremes such as floods, low flows, and soil moisture extremes is important because many impacts on ecosystems and human systems occur during extreme events. To quantify changes in hydrologic extremes, this study conducts hydrologic modeling experiments over 20 Midwestern watersheds using the Variable Infiltration Capacity (VIC) model forced by historical observed datasets and future projections from statistically downscaled Global Climate Model (GCMs) simulations. Our results show that peak daily streamflow at the 100-yr reoccurrence interval will increase (+10-30%) in most watersheds by 2080s due to significant increases in precipitation (P) and increasing P as rainfall during winter and spring seasons. The simulations also show strong shifts towards earlier peak flow timing (up to a month), especially in strongly snowmelt-dominated watersheds. These effects are linked to strong decreasing trends in maximum Snow Water Equivalent (SWE) with warming, which are simulated over essentially the entire domain. Projected changes in 7-day extreme low flows are smaller in magnitude (-10-+10%) with somewhat larger decreases simulated at the end of century; however, the timing of extreme low flows is projected to shift from winter/spring to summer and fall in strongly snowmelt-dominated watersheds in the northernmost parts of the domain. Extreme low soil moisture increases over most of the domain in the future projections up to the 2050s, but by the 2080s there are more widespread decreases in extreme low soil moisture, especially in the northernmost parts of the domain. PMID- 30308815 TI - Spatial trends in congenital malformations and stream water chemistry in Southern Brazil. AB - The incidence of variable congenital malformation (CM) among 399 municipalities in the state of Parana, southern Brazil, suggests the etiological role of environmental factors. This study examined a) environmental concentrations of chlorine anions (Cl-) associated with organochlorines (OCs) and b) associations between these chemicals and agricultural output with CMs using a geographical information system. In one of the three years during the sampling period (2008, 2009 or 2010) Cl-, dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethylene (p,p'-DDE), dichlorodiphenyldichloroethane (p,p' DDD), and endosulfan levels were measured in 465 (465/736, 63%) catchment basins. Agricultural outputs for crops during 2006-2010 were also evaluated (t/km2). Further, CM kernel density for the 399 municipalities in Parana during 2007-2014 was investigated. Cl- levels increased significantly in one of the three years (2008, 2009 or 2010) in western catchment basins, compared to 1996 (p < 0.0001). The municipalities were divided according to the obtained Cl- levels, where sub region C2 (central-southern) < 1.8 mg/L <= sub-regions C1 (northern-western) and C3 (eastern-southern). We identified 8756 cases of CMs among 1,221,287 newborns (NB) in all sub-regions. C1 had higher DDT-DDE-DDD (p,p'-DDT + p,p'-DDE + p,p' DDD) concentrations, agricultural output, and CM kernel density. C2 and C3 had minor agricultural outputs (per square kilometer) and CM densities. A 2.96 mg/L increase in Cl- between sub-regions C1 and C2 was co-localized with a 45% increase in CM density (spatial relative risk = 1.45, CI 95%: 1.36-1.55). C1 had the highest log likelihood ratios (p = 0.001) identified via SaTScan clustering analyses. Organochlorines and other toxic chlorinated chemicals may contribute to CMs in humans, and these chemicals are ultimately transformed and release Cl- in rivers. Higher Cl- levels were correlated significantly with higher agricultural productivity, DDT-DDE-DDD levels, and CMs in some parts of the northern and western sub-regions (C1). PMID- 30308816 TI - Extended persistence of general and cattle-associated fecal indicators in marine and freshwater environment. AB - Fecal contamination of recreational waters with cattle manure can pose a risk to public health due to the potential presence of various zoonotic pathogens. Fecal indicator bacteria (FIB) have a long history of use in the assessment of recreational water quality, but FIB quantification provides no information about pollution sources. Microbial source tracking (MST) markers have been developed in response to a need to identify pollution sources, yet factors that influence their decay in ambient waters are often poorly understood. We investigated the influence of water type (freshwater versus marine) and select environmental parameters (indigenous microbiota, ambient sunlight) on the decay of FIB and MST markers originating from cattle manure. Experiments were conducted in situ using a submersible aquatic mesocosm containing dialysis bags filled with a mixture of cattle manure and ambient water. Culturable FIB (E. coli, enterococci) were enumerated by membrane filtration and general fecal indicator bacteria (GenBac3, Entero1a, EC23S857) and MST markers (Rum2Bac, CowM2, CowM3) were estimated by qPCR. Water type was the most significant factor influencing decay (three-way ANOVA, p: 0.006 to <0.001), although the magnitude of the effect differed among microbial targets and over time. The presence of indigenous microbiota and exposure to sunlight were significantly correlated (three-way ANOVA, p: 0.044 to <0.001) with decay of enterococci and CowM2, while E. coli, EC23S857, Rum2Bac, and CowM3 (three-way ANOVA, p: 0.044 < 0.001) were significantly impacted by sunlight or indigenous microbiota. Results indicate extended persistence of both cultivated FIB and genetic markers in marine and freshwater water types. Findings suggest that multiple environmental stressors are important determinants of FIB and MST marker persistence, but their magnitude can vary across indicators. Selective exclusion of natural aquatic microbiota and/or sunlight typically resulted in extended survival, but the effect was minor and limited to select microbial targets. PMID- 30308817 TI - Resource depletion potentials from bottom-up models: Population dynamics and the Hubbert peak theory. AB - Life cycle impact assessment uses so-called characterization factors to address different types of environmental impact (e.g. climate change, particulate matter, land use...). For the topic of resource depletion, a series of proposals was based on heuristic and formal arguments, but without the use of expert-based models from relevant research areas. A recent study in using fish population models has confirmed the original proposal for characterization factors for biotic resources of the nineties. Here we trace the milestones of the arguments and the designs of resource depletion, delivering an ecological-based foundation for the biotic case, and extend it by a novel analysis of the Hubbert peak theory for the abiotic case. We show that the original abiotic depletion potential, used for two decades in life cycle assessment, estimates accurately a marginal depletion characterization factor obtained from a dynamic model of the available reserve. This is illustrated for 29 metal resources using published data. PMID- 30308818 TI - An insight into nanocellulose as soft condensed matter: Challenge and future prospective toward environmental sustainability. AB - Nanocellulose, a structural polysaccharide that has caught tremendous interests nowadays due to its renewability, inherent biocompatibility and biodegradability, abundance in resource, and environmental friendly nature. They are promising green nanomaterials derived from cellulosic biomass that can be disintegrated into cellulose nanofibrils (CNF) or cellulose nanocrystals (CNC), relying on their sensitivity to hydrolysis at the axial spacing of disordered domains. Owing to their unique mesoscopic characteristics at nanoscale, nanocellulose has been widely researched and incorporated as a reinforcement material in composite materials. The world has been consuming the natural resources at a much higher speed than the environment could regenerate. Today, as an uprising candidate in soft condensed matter physics, a growing interest was received owing to its unique self-assembly behaviour and quantum size effect in the formation of three dimensional nanostructured material, could be utilised to address an increasing concern over global warming and environmental conservation. In spite of an emerging pool of knowledge on the nanocellulose downstream application, that was lacking of cross-disciplinary study of its role as a soft condensed matter for food, water and energy applications toward environmental sustainability. Here we aim to provide an insight for the latest development of cellulose nanotechnology arises from its fascinating physical and chemical characteristic for the interest of different technology holders. PMID- 30308819 TI - Ambient mercury source identification at a New York State urban site: Rochester, NY. AB - Gaseous elemental mercury (GEM), gaseous oxidized mercury (GOM), and particle bound mercury (PBM) were measured continuously in Rochester, NY (NY43) from January 2012 to December 2014. Continuous measurements of ozone (O3), sulfur dioxide (SO2), carbon monoxide (CO), nitrogen oxide (NO), nitrogen dioxide (NO2), particulate matter (PM2.5), and meteorological data were also made at this site. A principal component analysis (PCA) of the resulting 15 variables showed that the ambient mercury in Rochester was primarily produced by non-local sources in contrast to earlier studies that showed that local sources were present. Positive matrix factorization (PMF) analysis of the atmospheric mercury and other pollutant species concentrations showed that transport and atmospheric processes have become the major source of mercury in Rochester. Conditional bivariate probability function (CBPF) and potential source contribution function (PSCF) were used to identify local and distant mercury sources. The results in this study showed that the closure of a coal-fired power plant and promulgation of several fuel quality policies reduced local mercury emissions making long distance transport the major source of mercury in Rochester. PMID- 30308821 TI - Antibiotics in a typical karst river system in China: Spatiotemporal variation and environmental risks. AB - Karst aquifers are highly susceptible to contamination because compounds in water from the land surface are able to enter aquifers directly through sinkholes and travel rapidly through conduits. To investigate the occurrence and profiles of antibiotics in the typical karst river system in Kaiyang, southwest China, 34 aqueous samples were collected periodically to delineate seasonal trends in antibiotic levels. Thirty-five antibiotics, including nine sulfonamides, four tetracyclines, five macrolides, 16 quinolones and chloramphenicol, were analysed via solid phase extraction combined with ultra-performance liquid chromatography tandem mass spectrometry. A total of 25 antibiotics were detected with the highest detection frequency reaching 94.1%, indicating the ubiquity of antibiotics in the study area. The total concentration of antibiotics ranged from 0.37 to 508.6 ng/L, with the dominating proportion including macrolides and quinolones based on the distribution profiles and seasonal variation. Due to the natural attenuation, the total concentration of antibiotics gradually decreased with the flow direction in the southern part of the river. The total concentrations of antibiotics in the mainstream were significantly higher in the dry season than in the rainy seasons. However, the distribution profiles were susceptible to anthropogenic activities, such as the leakage of septic tank wastewater. The dendrogram and heatmap revealed that three clusters of sample sites represented tributaries and the upstream areas, the downstream areas, and the potential pollutant source, and three clusters of antibiotics represented different concentration patterns. The high ecological risks of tetracycline, erythromycin and ciprofloxacin for algae and ofloxacin for plants were determined. These findings contributed to the establishment of a database for future monitoring and control of antibiotics in karst areas. PMID- 30308820 TI - Environmental factors driving the occurrence of the invasive cyanobacterium Sphaerospermopsis aphanizomenoides (Nostocales) in temperate lakes. AB - Cyanobacterial blooms are an increasing threat worldwide. Invasions of certain cyanobacterial species, mainly towards higher latitudes, add to this concern as they enrich the pool of potential bloom-formers in the invaded region. Among the numerous causes of this escalating process, climate warming is commonly considered the most crucial factor, but empirical studies of this issue are lacking. The aim of our study was to identify physical, chemical and biological factors related to the occurrence of an invasive cyanobacterium at the northern border of its putative current range, and thus enabling its expansion. This study focuses on the relatively little studied species Sphaerospermopsis aphanizomenoides (Nostocales, Cyanobacteria; synonyms: Aphanizomenon aphanizomenoides, Anabaena aphanizomenoides), which is predicted to become one of the main nuisance species of the future. Forty-nine freshwater lakes located between latitudes 51 degrees and 55 degrees N were examined for the presence of S. aphanizomenoides, and environmental factors that could drive its occurrence were studied simultaneously. To identify factors correlated with the presence of the species, principal component analysis (PCA) and Mann-Whitney U test were performed. Water temperature did not differentiate lakes with or without S. aphanizomenoides, however the study was conducted in a particularly hot summer. Total phosphorus concentration was identified as the primary driving factor of the occurrence of S. aphanizomenoides. The species grew in poor light conditions and high phytoplankton biomass, mainly in shallow lakes. As shown by detrended correspondence analysis (DCA), the species accompanied shade tolerant, eutrophic species of native and invasive cyanobacteria as well as eukaryotic algae. Our results indicate that eutrophication may be the primary factor enabling the increasing occurrence of S. aphanizomenoides in temperate environments, and suggest that this process may stimulate expansion of cyanobacterial species towards high latitudes. PMID- 30308822 TI - Bioaccumulation of tetrabromobisphenol A in a laboratory-based fish-water system based on selective magnetic molecularly imprinted solid-phase extraction. AB - Recently, magnetic solid-phase extraction (MSPE) using magnetic molecularly imprinted polymers (MMIPs), which is a simple process with excellent selectivity, has attracted much attention for the determination of environmental pollutants. In this study, MMIPs were used as an adsorbent to establish a selective MSPE method coupled with high-performance liquid chromatography using ultraviolet detection (HPLC-UV) for the determination of tetrabromobisphenol A (TBBPA) levels in water and fish samples. The samples were collected from a laboratory-based fish-water system after 0, 2, 5, 8, 11, 20, 30, and 50 days. We found that the concentrations of TBBPA in the sample group spiked with TBBPA decreased in the water samples over time and increased in the fish samples from 2 to 30 days, then finally decreased. The calculated bioconcentration factor (BCF) increased over time, reaching 33.98 L/kg after 50 days exposure to TBBPA. Linear and exponential kinetic models were applied to fit the correlation between BCF and exposure time, and the constant of the time-dependent BCF (Ku) ranged from 0.0364 to 1.5250 L/kg per day with a corresponding R2 of 0.6786 to 0.9985. Simplified mathematical models to evaluate the transfer characteristics of TBBPA in a laboratory-based fish-water system have been developed. PMID- 30308823 TI - Fate of veterinary antibiotics during animal manure composting. AB - Antibiotics are widely used in animals for disease treatment and prevention. After use, these antibiotics end up in manure. Here we investigated the fate of veterinary antibiotics in animal manure during composting and their residues in manure-applied soils. The results showed that 64.7% of the detected veterinary antibiotics were removed after composting for 171 days, which mainly occurred at the thermophilic phase in the second week, followed by a long stable stage with limited variations. The removal rates for lincomycin, trimethoprim and the macrolides during the composting were >89.7%, while those for the sulfonamides, tetracyclines and fluoroquinolones were less than <63.7%. The dissipation of antibiotics during the composting was related to the change of compost physicochemical properties, especially moisture and C/N ratio. The application of compost products with antibiotic residues could still lead to soil contamination, which may pose risks of resistance selection to the soil ecosystem. PMID- 30308824 TI - Climate, forest growing season, and evapotranspiration changes in the central Appalachian Mountains, USA. AB - We analyzed trends in climatologic, hydrologic, and growing season length variables, identified the important variables effecting growing season length changes, and evaluated the influence of a lengthened growing season on increasing evapotranspiration trends for the central Appalachian Mountains region of the United States. We generated three growing season length variables using remotely sensed GIMMS NDVI3g data, two variables from measured streamflow, and 13 climate parameters from gridded datasets. We included various climate, hydrology, and phenology explanatory variables in two applications of Principle Components Analysis to reduce dimensionality, then utilized the final variables in two Linear Mixed Effects models to evaluate the role of climate on growing season length and evapotranspiration. The results showed that growing season length has increased, on average, by ~22 days and evapotranspiration has increased up to ~12 mm throughout the region. The results also suggest that a suite of climatic variables including temperature, vapor pressure deficit, wind, and humidity are important in growing season length change. The climatic variables work synergistically to produce greater evaporative demand and atmospheric humidity, which is theoretically consistent with intensification of the water cycle and the Clausius-Clapeyron relation, which states that humidity increases nonlinearly by 7%/K. Optimization of the evapotranspiration model was increased by the inclusion of growing season length, suggesting that growing season length is partially responsible for variations in evapotranspiration over time. The results of this research imply that a longer growing season has the potential to increase forest water cycling and evaporative loss in temperate forests, which may lead to decreased freshwater provisioning from forests to downstream population centers. Additionally, results from this study provide important information for runoff and evapotranspiration modelling and forest water management under changing climate. PMID- 30308825 TI - Domestic waste disposal sites secure food availability but diminish plasma antioxidants in Egyptian vulture. AB - Some domestic waste disposal sites (DWDS) accumulate enormous amounts of food that humans discard. This food resource is exploited by different species whose population dynamics have as a result been altered. The effects of feeding on human waste on individual health parameters such as body condition are still unknown. Traditionally, body condition in wildlife has been assessed using morphological indices based on size and weight. Expanding the range of indices to include the analysis of indicators at the physiological level can provide a more comprehensive picture of the animals' health status. In this work, we studied how different amounts of waste consumption (assessed using stable isotope analysis) affect nestling health and body condition in an expanding population of the endangered Egyptian Vulture (Neophron percnopterus). We used morphometric and physiological approaches, including plasma biochemistry, antioxidant defences and oxidative stress biomarkers. The results of the multivariate redundancy analysis and variance partitioning showed that the proportion of diet originating from DWDS is the main factor explaining physiological indicators in the studied vulture population. Nestlings that were fed on food from DWDS had lower levels of vitamins (e.g. alpha-tocopherol) and carotenoids (zeaxanthin and lutein), which have important functions as antioxidant defences, immunostimulant properties and ornamental purposes. Nevertheless, nestlings that were fed on food from DWDS were better nourished and experienced fewer food shortages than individuals not fed using this resource, which had lower levels of cholesterol. Possibly due to the easy access to food, breeding pairs using DWDS could have fewer difficulties in feeding their nestlings and thus could engender more regular brood sizes than those not exploiting this type of resource. Our integrative approach using diverse components was crucial for a reliable assessment of health and body condition in Egyptian Vulture nestlings and its relationship to the consumption of food derived from human-altered environments. PMID- 30308826 TI - Assessment of eutrophication and water quality in the estuarine area of Lake Wuli, Lake Taihu, China. AB - Our study assessed the actual water situation in the estuarine area of Lake Wuli, Meiliang Bay, Lake Taihu, China, based on eutrophication levels and status of water quality using the trophic level index (TLI) and water quality index (WQI) methods. In the wet (August 2017) and dry (March 2018) seasons, 22 estuarine areas were tested at 69 sampling sites, which included lake and rivers. Five parameters-chlorophyll a (Chl-a), total phosphorus (TP), total nitrogen (TN), Secchi disk (SD) and permanganate index (CODMn)-were measured to calculate the TLI, and 15 parameters-temperature (T), pH, electrical conductivity (EC), dissolved oxygen (DO), total dissolved solids (TDS), TN, TP, ammonium (NH4-N), nitrate (NO3-N), nitrite (NO2-N), CODMn, calcium (Ca2+), magnesium (Mg2+), chloride (Cl-) and phosphate (PO4-P)-were measured to calculate the WQI. The average TLI and WQI values in the wet season were 61.69 and 60.70, respectively, and the eutrophication level and water quality status were worse than that in the dry season (TLI: 57.40, WQI: 65.74). Significant differences were observed between three parts of Lake Wuli (West, Middle and East). Regardless of wet or dry season, East Wuli had worse eutrophication levels and water quality status than the other parts, whereas West Wuli showed less severe levels. DO, TN and CODMn used in the minimum WQI (WQImin) were the most effective parameters in our study. WQImin had stricter standards than WQI when analyzing water quality in the estuarine area of Wulihu. Factor analysis from principal component analysis (PCA) indicated that N might be the main factor affecting water quality of the most eastern sites in the wet season, and P may be the main factor in the dry season. Our results provide a valuable contribution to inform decision-making for the management of water environments by providing the actual water situation of the estuarine area of Lake Wuli. PMID- 30308827 TI - Application of macroalgae analysis to assess the natural variability in selected pollution concentrations (N and Hg), and to detect sources of it in coastal environments. AB - Here we present a new method in which algae are used to detect sources of heavy metal and organic pollution in coastal areas. The procedure involves characterization of the natural range of concentrations of the elements in areas not affected by local sources of pollution and subsequent comparison of concentrations in the study site to these natural range levels. To develop the method, the concentrations of various elements were determined in specimens of the macroalgae Fucus vesiculosus collected at >150 sampling sites along the shoreline. The natural variability in the element concentrations in these zones was established by determining the differences in the tissue concentrations of the elements between pairs of samples separated by different distances. The method was then tested in the surroundings of possible sources of nitrogen and was found to be a tool for detecting sources of small scale nitrogen contamination and for monitoring and evaluating water quality. PMID- 30308828 TI - Influences of isolated fractions of natural organic matter on adsorption of Cu(II) by titanate nanotubes. AB - With different functional groups and hydrophobic/hydrophilic properties, natural organic matters (NOMs) displayed different combining capacities with metal ions. By using XAD-4 and DAX-8 resins, NOMs in natural lake were isolated into three fractions, i.e., HoB (hydrophobic base), HoA (hydrophobic acid) and HiM (hydrophilic matter). Afterwards, influences on Cu(II) adsorption onto titanate nanotubes (TNTs) were compared with varying NOMs and initial pH. As results, HoB can significantly control Cu(II) adsorption at pH 5, with the adsorption capacity increased 15% for 0.5 mg L-1 of HoB (ca. 120 mg g-1), which could be attributed to the formation of HoB-Cu complexation and electrostatic bridge effect of HoB with optimal concentration. Due to the easier ionization and complexation with Cu(II) at lower pH, HoA showed more obvious impaction on Cu(II) adsorption at pH 2. While HiM can influence Cu(II) adsorption at all pH ranges due to its hydrophilic groups and weak affinity to both TNTs and Cu(II). Furthermore, HoB dramatically changed the Langmuir model, with sharp increase of adsorption capacity as equilibrium Cu(II) increased, suggesting its significant involvement in Cu(II) adsorption. X-ray photoelectron spectroscopy (XPS) analysis revealed the absorbed Cu(II) existed in the form of TNTs-OCu, TNTs-COOCu and Cu(OH)2, proving Cu(II) adsorption mechanism including both direct adsorption by TNTs and bridging connection with NOMs. Moreover, the CO and OCO groups content ranked as HiM > HoB > HoA, while TNTs-COOCu content ranked as HoA > HoB > HiM, suggesting HoB had the moderate connection with both TNTs and Cu(II), thus the impact on Cu(II) adsorption was remarkable. PMID- 30308829 TI - Changes of the denitrifying communities in a multi-stage free water surface constructed wetland. AB - Microorganisms play crucial roles in the nitrogen removal processes of wetlands. However, the key functional genes and microbes related to the nitrogen removal remain largely unknown in the free water surface constructed wetland (FWS CW). Here we studied the abundances of denitrifiers by targeting the key functional genes (nirS, nirK and nosZ) and investigated the community compositions of denitrifiers and their correlations with the abiotic variables in a FWS CW. The increase of nosZ/(nirS + nirK) and nirS/nirK ratios in the outlet indicated a shift of denitrifiers' communities which tended to release less nitrous oxide at the genetic potential level. The denitrifiers dominated the bacterial community which also remarkably changed from the inlet to the outlet. PICRUSt analysis revealed that the denitrifiers contributed to 39.1% of the nitrogen metabolism, 38.9% of the amino acid metabolism and 25.6% of the amino acid related enzymes. Four bacterial genera including Hydrogenophaga, Hylemonella, Aquabacterium and Cellvibrio were detected as the putative keystone denitrifiers. The abundance (nirS, nirK and nosZ) and the relative abundance of putative keystone denitrifiers were significantly correlated with total organic carbon, oxidation reduction potential and C/N ratio, which could be regarded as the determinants for the denitrification process in the free water. PMID- 30308830 TI - Quantifying ecosystem services supply and demand shortfalls and mismatches for management optimisation. AB - Research on ecosystem services (ESs) has increased substantially in recent decades, but the findings have been slow to affect actual management, perhaps because most studies to date have neglected ESs supply and demand coupling mechanisms. Human reliance on ESs is due to the capacity of the landscape to supply services, but also to a societal need for these services. Sustainable land management requires supply and demand mismatches to be reconciled and the needs of different stakeholders to be balanced. Explicit spatial mapping of ESs supply and demand associated with land use changes can provide relevant insights for enhancing land management in urban areas. The emphasis is now shifting to enhancing sustainable land use, to ensure that supply meets or exceeds demand. In this study, a comprehensive framework comprising four core steps for quantifying ESs supply and demand changes associated with land use changes was developed and applied in a case study on Shanghai municipality, on the basis of environmental quality standards and policy goals. The balance thresholds of ESs supply and demand were derived by regression analysis between ESs and land use/land cover types. The results revealed large spatial heterogeneity in supply and demand for four key ESs tested: carbon sequestration, water retention, particulate (PM10) removal and recreation. Carbon sequestration, water retention and recreation services all showed major shortfalls in supply that changed dramatically with urban land use change. This is valuable empirical evidence and has timely policy implications for management in a rapid urbanising world. PMID- 30308831 TI - Bioenergetic responses of freshwater mussels Unio tumidus to the combined effects of nano-ZnO and temperature regime. AB - Bivalves from the cooling reservoirs of electrical power plants (PP) are exposed to the chronic heating and chemical pollution making them a suitable model to study the combined effects of these stressors. We investigated the effect of in situ exposures to chemical and thermal pollution in the PP cooling ponds on the metabolic responses of unionid bivalves (Unio tumidus) to a novel widespread pollutant, ZnO nanoparticles (nZnO). Male U. tumidus from the reservoirs of Dobrotvir and Burshtyn PPs (DPP and BPP) were maintained in clean water at 18 degrees C, or exposed for 14 days to one of the following conditions: nZnO (3.1 MUM) or Zn2+ (3.1 MUM, a positive control for Zn impacts) at 18 degrees C, elevated temperature (T, 25 degrees C), or nZnO at 25 degrees C (nZnO + T). Baseline levels of glycogen, lipids and ATP were similar in the two studied populations, whereas the levels of proteins, lactate/pyruvate ratio (L/P) and extralysosomal cathepsin D level were higher in the tissues of BPP mussels. The levels of glycogen and glucose declined in most experimental exposures indicating elevated energy demand except for a slight increase in the digestive gland of warming-exposed BPP mussels and in the gills of the nZnO + T-exposed DPP-mussels. Experimental exposures stimulated cathepsin D activity likely reflecting onset of autophagic processes to compensate for stress-induced energy demand. No depletion of ATP in Zn-containing exposures was observed indicating that the cellular metabolic adjustments were sufficient for such compensation. Unexpectedly, experimental warming mitigated most metabolic responses to nZnO in co-exposures. Our data thus indicate that metabolic effects of nZnO strongly depend on the environmental context of the mussels (such as temperature and acclimation history) which must be taken into account for the molecular and cellular biomarker-based assessment of the nanoparticle effects in the field. PMID- 30308832 TI - Projections of water, carbon, and nitrogen dynamics under future climate change in an alpine tundra ecosystem in the southern Rocky Mountains using a biogeochemical model. AB - Using statistically downscaled future climate scenarios and a version of the biogeochemical model (PnET-BGC) that was modified for use in the alpine tundra, we investigated changes in water, carbon, and nitrogen dynamics under the Representative Concentration Pathways at Niwot Ridge in Colorado, USA. Our simulations indicate that future hydrology will become more water-limited over the short-term due to the temperature-induced increases in leaf conductance, but remains energy-limited over the longer term because of anticipated future decreases in leaf area and increases in annual precipitation. The seasonal distribution of the water supply will become decoupled from energy inputs due to advanced snowmelt, causing soil moisture stress to plants during the growing season. Decreases in summer soil moisture are projected to not only affect leaf production, but also reduce decomposition of soil organic matter in summer despite increasing temperature. Advanced future snowmelt in spring and increasing rain to snow ratio in fall are projected to increase soil moisture and decomposition of soil organic matter. The extended growing season is projected to increase carbon sequestration by 2% under the high radiative forcing scenario, despite a 31% reduction in leaf display due to the soil moisture stress. Our analyses demonstrate that future nitrogen uptake by alpine plants is regulated by nitrogen supply from mineralization, but plant nitrogen demand may also affect plant uptake under the warmer scenario. PnET-BGC simulations also suggest that potential CO2 effects on alpine plants are projected to cause larger increases in plant carbon storage than leaf and root production. PMID- 30308833 TI - Robust eco-efficiency assessment of hydrogen from biomass gasification as an alternative to conventional hydrogen: A life-cycle study with and without external costs. AB - Hydrogen is a key product for the decarbonisation of the energy sector. Nevertheless, because of the high number of technical options available for hydrogen production, their suitability needs to be thoroughly evaluated from a life-cycle perspective. The standardised concept of eco-efficiency is suitable for this purpose since it relates, with a life-cycle perspective, the environmental performance of a product system to its value. Hence, this work benchmarks the eco-efficiency performance of renewable hydrogen produced through biomass gasification against conventional hydrogen from the steam reforming of natural gas. For the eco-efficiency assessment, the harmonised environmental indicators of global warming, acidification and cumulative non-renewable energy demand were individually used, while the product system value was based on the levelised cost of hydrogen with/without internalisation of the external socio environmental costs associated with climate change and human health. On the one hand, when the environmental and economic performances are separately considered, hydrogen from biomass gasification performs significantly better than hydrogen from steam methane reforming under environmental aspects (e.g., greenhouse gas emissions saving of 98%), whereas the opposite conclusion was found from an economic standpoint (levelised cost of 3.59 ? and 2.17 ? per kilogramme of renewable and fossil hydrogen, respectively). On the other hand, when combining life-cycle environmental and economic indicators under the umbrella of the eco efficiency assessment, it is concluded that the renewable hydrogen option outperforms the conventional one, which is further remarked when implementing socio-environmental externalities. In this regard, a relative eco-efficiency score above 14 was estimated for the renewable hydrogen option when benchmarked against conventional hydrogen. PMID- 30308834 TI - Strategies to mitigate the nitrous oxide emissions from nitrogen fertilizer applied with organic fertilizers in sugarcane. AB - Vinasse is a major byproduct of the sugarcane biofuel industry, recycled in the fields. However, there is evidence that the application of vinasse with mineral nitrogen (N) fertilizers in sugarcane enhances the emission of greenhouse gases (GHGs). Therefore, strategies are needed to decrease the environmental impacts caused by both inputs. We carried out three sugarcane field experiments by applying N fertilizer (ammonium nitrate) with types of vinasses (concentrated-CV and standard-V) in different combinations (vinasses with N fertilizer and vinasses one month before or after mineral N fertilization). The gases nitrous oxide (N2O), carbon dioxide (CO2), and methane (CH4) were measured in one experiment fertilized in the beginning (fall/winter = dry season) and two experiments fertilized in the end (spring = rainy season) of the harvest season. Sugarcane fields were sinks rather than sources of CH4, while total carbon emitted as CO2 was similar between seasons and treatments. The effect of mineral fertilization and vinasses (CV and V) on N2O emissions was highly dependent on soil moisture (rain events). The N2O-N fertilizer emission factor (EF) varied from 0.07% to 0.51%, whereas the average EF of V and CV were 0.66% and 0.34%, respectively. On average across the three experiments, the combination of vinasse (CV or V) with N fertilizer increased the N2O emissions 2.9-fold compared to that of N fertilizer alone. For CV + N, the EF was 0.94% of the applied N and 0.23% of the ammonium nitrate-N, and for V + N (EF = 0.47%), increased emissions were observed in two out of three experiments. The strategy of anticipating or postponing vinasse application by one month with respect to mineral N reduced the N2O emissions by 51% for CV, but not for V. Therefore, to avoid boosting N2O emissions, we suggest applying vinasses (CV and V) before or after mineral N fertilization. PMID- 30308835 TI - Spatial mismatch in fish and coral loss following 2016 mass coral bleaching. AB - Record-breaking temperatures between 2015 and 2016 led to unprecedented pan tropical bleaching of scleractinian corals. On the Great Barrier Reef (GBR), the effects were most pronounced in the remote, northern region, where over 90% of reefs exhibited bleaching. Mass bleaching that results in widespread coral mortality represents a major disturbance event for reef organisms, including reef fishes. Using 133 replicate 1 m2 quadrats, we quantified short-term changes in coral communities and spatially associated reef fish assemblages, at Lizard Island, Australia, in response to the 2016 mass bleaching event. Quadrats were spatially matched, permitting repeated sampling of fish and corals in the same areas: before, during and 6 months after mass bleaching. As expected, we documented a significant decrease in live coral cover. Subsequent decreases in fish abundance were primarily driven by coral-associated damselfishes. However, these losses, were relatively minor (37% decrease), especially compared to the magnitude of Acropora loss (>95% relative decrease). Furthermore, at a local, 1 m2 scale, we documented a strong spatial mismatch between fish and coral loss. Post-bleaching fish losses were not highest in quadrats that experienced the greatest loss of live coral. Nor were fish losses associated with a proliferation of cyanobacteria. Several sites did, however, exhibit increases in fish abundance suggesting substantial spatial movements. These results challenge common assumptions and emphasize the need for caution when ascribing causality to observed patterns of fish loss at larger spatial scales. Our results highlight the potential for short-term resilience to climate change, in fishes, through local migration and habitat plasticity. PMID- 30308836 TI - High-resolution climate projections for South Asia to inform climate impacts and adaptation studies in the Ganges-Brahmaputra-Meghna and Mahanadi deltas. AB - Climate impacts and adaptation studies often use output from impact models that require data representing future climates at a resolution greater than can be provided by Global Climate Models (GCMs). This paper describes the use of Regional Climate Model (RCM) simulations to generate high-resolution future climate information for assessing climate impacts in the Ganges-Brahmaputra Meghna (GBM) and Mahanadi deltas as part of the DECCMA project. In this study, three different GCMs (HadGEM2-ES, CNRM-CM5 and GFDL-CM3), all using a single scenario for future greenhouse forcing of the atmosphere (RCP 8.5), were downscaled to a horizontal resolution of 25 km over south Asia using the HadRM3P RCM. These three GCMs were selected based on ability to represent key climate processes over south Asia and ability to sample a range of regional climate change responses to greenhouse gas forcing. RCM simulations of temperature, precipitation, and lower level (850 hPa) atmospheric circulation in the monsoon season (June, July, August, September - JJAS) were compared with observational datasets and their respective driving GCMs to ensure large-scale consistency. Although there are some biases in the RCM simulations, these comparisons indicate that the RCMs are able to simulate realistically aspects of the observed climate of South Asia, such as the monsoon circulation and associated precipitation that are key for informing downstream impacts and adaptation studies. Simulated future temperature and precipitation changes on seasonal and daily timescales suggest increases in both temperature and precipitation across all three models during the monsoon season, with an increase in the amount of extremely heavy precipitation over the GBM and Mahanadi basins. Despite different driving conditions, these results are consistent across all three RCM simulations, providing a level of confidence in the magnitudes and spatial characteristics of temperature and precipitation projections for South Asia. PMID- 30308837 TI - First assessment of persistent organic pollutant contamination in blubber of Chilean blue whales from Isla de Chiloe, southern Chile. AB - Persistent organic pollutants (POPs) were assessed for the first time in blue whales from the South Pacific Ocean. Concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane and its main metabolites (DDTs), were determined in 40 blubber samples from 36 free-ranging individuals and one stranded, dead animal along the coast of southern Chile between 2011 and 2013. PCBs were the most abundant pollutants (2.97-975 ng/g l.w.), followed by DDTs (3.50-537 ng/g l.w.), HCB (nd-77.5 ng/g l.w.) and PBDEs (nd-33.4 ng/g l.w). There was evidence of differences between sexes, with lower loads in females potentially due to pollutants passing to calves. POP concentrations were higher in specimens sampled in 2013; yet, between-year differences were only statistically significant for HCB and PBDEs. Lower chlorinated (penta > tetra > tri) and brominated (tetra > tri) congeners were the most prevalent among PCBs and PBDEs, respectively, mostly in agreement with findings previously reported in blue and other baleen whales. The present study provides evidence of lower levels of contamination by POPs in eastern South Pacific blue whales in comparison to those reported for the Northern Hemisphere. PMID- 30308838 TI - The effects of litter quality and living plants on the home-field advantage of aquatic macrophyte decomposition in a eutrophic urban lake, China. AB - The 'home-field advantage' (HFA) hypothesis states that litter decomposes faster in its 'home' habitat, i.e., in the same habitat as the plant species from which it was derived than it does 'away' from its home, i.e., in the habitat of a different plant species. However, studies pertaining to HFA in aquatic ecosystems are relatively few. One area not well-studied is whether the presence of living plants has an effect on the HFA of aquatic macrophyte decomposition in a eutrophic lake. Here, we conducted reciprocal litter transplanting experiments, coupled with removal of living plants, between a dominant submerged macrophyte (Myriophyllum spicatum) and a floating-leaved macrophyte (Trapa natans) in a eutrophic urban lake in China, for 50 days. Test plots were created at sites by removing the dominant macrophytes from their 'home' habitats to test the effect of living plants on decomposition rates and HFA effect. The water chemistry of the two sites was not significantly different. The initial litter qualities were significantly higher in M. spicatum than in T. natans. The decomposition rates of T. natans were significantly greater in both the control and test plots in its 'home' habitat, indicating a positive HFA effect, while the decomposition rates of M. spicatum were significantly greater in the 'away' habitat compared to its 'home' habitat in all treatments, indicating a home-field disadvantage effect. The removal of living plants had a noticeable effect on the abundance of associated-macroinvertebrates, but had an inconsistent effect on decomposition rates providing conflicting evidence for HFA. In total, 10 macroinvertebrate taxa from four functional feeding groups (FFGs) were collected during the experiment. Compared to macroinvertebrate communities, microbial activities showed less correlation with decomposition rates. Our results provide evidence to suggest that decomposition-based HFA is dependent upon litter quality, habitat, and their interactions in a eutrophic urban lake. PMID- 30308839 TI - Lost forever? Ecosystem functional changes occurring after agricultural abandonment and forest recovery in the semiarid Chaco forests. AB - Semiarid forests are worldwide threatened by land use changes, particularly agriculture. However, in some cases, due to particular economic or social processes, agriculture ends and forests may or may not recover to their original state. Using different databases and satellite images integrated into a geographical information system, we located in the central region of the semiarid Chaco forests of Argentina adjacent land use patches of secondary forest (SF), remnant forest (RF) and crops (CP). Using a chronosequence approach, we evaluated changes in the fraction of the photosynthetic active radiation absorbed by the vegetation (FAPAR) between SF and RF and CP, using the enhanced vegetation index (EVI). We evaluated both intra and inter-annual changes in EVI mean (EVImean), EVI maximum (EVImax), EVI minimum (EVImin), and EVI relative range (EVIrr) as descriptors of FAPAR dynamics and analyzed their changes through time (2000 to 2010) and their relation to rainfall. Secondary forests showed higher seasonality and higher EVImean values than RF, but differences disappeared as time since agricultural abandonment increased, suggesting that SF recover their functioning (when compared to RF) after 10 to 15 years. Our results suggest that Chaco's SF have intermediate seasonal patterns in-between RF and CP, as expected by successional theory, and that FAPAR interception by RF appears to be dependent on previous year's precipitation. We found that, although all land uses showed similar precipitation use efficiency (PUE), SF and cropland's productivity were less stable across the years and showed faster increases or decreases compared to RF, depending on precipitation (higher precipitation marginal response- PMR). Our results suggest that at least some aspects of ecosystem functioning can be restored after agricultural abandonment. Future research that combines floristic and structural changes is necessary to fully understand secondary forests regrowth process after agricultural abandonment in the Chaco region. PMID- 30308840 TI - Hatching failure and accumulation of organic pollutants through the terrestrial food web of a declining songbird in Western Europe. AB - Population growth in passerine birds is largely driven by fecundity. If fecundity is affected, for instance by hatching failure, populations may decline. We noted high hatching failure of up to 27% per year in relict populations of the Northern wheatear (Oenanthe oenanthe) in The Netherlands, a strongly declining, migratory passerine in Europe. This hatching failure itself can cause population decline, irrespective of other adverse factors. Additionally, we investigated the cause of hatching failure. Unhatched eggs showed egg yolk infections or embryonic malformations, part of which is associated with the actions of dioxin-like compounds (DLCs). Indeed, DLCs appear to bioaccumulate in the local foodweb, where the soil contained only background concentrations, similar to those found at many other locations. DLC concentrations in Dutch eggs were six-fold higher than those in a reference population in Sweden, where egg failure was only 6%. However, Northern wheatears appear to be only moderately sensitive to the actions of DLCs, because of their specific Ah-receptor type which may moderate the receptor mediated effects of DLCs. This indicates that the concentrations of DLCs, although elevated, may not have caused the embryo malformations or the low hatching rates. We discuss whether other toxins may be important or imbalances in the nutrition and if inbreeding may play a larger role than expected. PMID- 30308841 TI - Spatial distribution of sediment nitrogen and phosphorus in Lake Taihu from a hydrodynamics-induced transport perspective. AB - Hydrodynamics play an important role in sediment nutrient dynamics in large shallow eutrophic lakes. In this study, the spatial patterns of sediment nitrogen and phosphorus in Lake Taihu were compared from a hydrodynamics-induced transport perspective based on high-resolution investigation of sediment, field observations, numerical simulations and long-term ecological data analysis. The results showed that sediments were primarily distributed in the west and southeast portions of the lake. Additionally, the total nitrogen (TN) and phosphorus (TP) stored in the active sediments was 166,329 t and 67,112.4 t, respectively. The sediment TN content was 319.4-3123.8 mg kg-1, with high content areas being primarily located in the Zhushan, Meiliang and East Taihu bays. The external nitrogen-containing nutrients in the overlying water, which is mostly dissolved nitrogen, can be horizontally transported by lake currents to the water areas with high biomass levels and weak vertical hydrodynamic disturbance where sediment nitrogen enrichment primarily occurs via bio-deposition. The sediment TP content ranged between 382.6 and 1314.1 mg kg-1, and the high content areas were primarily distributed near the inflowing river mouths. Sediment phosphorus enrichment primarily occurred via physical and chemical deposition. Surface waves caused vertical phosphorus transport from sediments to the overlying water but had a limited effect on its spatial distribution. Although the horizontal transport of phosphorus was found to be weaker than that of nitrogen, short distance vertical transport of sediment phosphorus may relieve nutrient limitations, leading to maintenance of cyanobacterial blooms found in Lake Taihu. PMID- 30308842 TI - Complexity versus simplicity in water energy food nexus (WEF) assessment tools. AB - Approaching water, energy, and food, as interconnected system of systems, as an alternative to traditional silo-based resources planning and management approaches continues to fall short of expectations of its research-backed benefits. The lack of nexus applications in policy and decision making can be related to numerous factors, with the main barrier being the complex nature of "nexus" systems combined with the disarray of tools attempting to model its interconnections. The paper aims to provide a method for comparing the perceived complexity of nexus tools identified by international organizations as well as primary literature sources. Eight separate criteria are introduced and discussed as measures of a tool "complexity index" and used to score the relative simplicity, or complexity, of a given tool. The result of this process is used to identify trends within existing nexus-assessment tools while guiding potential users towards appropriate tool(s) best-suited for their case study needs and objectives. The main objectives of this paper are to: 1) categorize nexus assessment tools according to a criteria-set which allows for suitable tool selection; 2) identify a method for rapid evaluation of the trade-offs for choosing different tools (simple-complex spectrum). The results of the comparative analysis of the selected nexus assessment tools concur with literature citing a growing gap between nexus research and applications in actual policy and decision-making settings. Furthermore, results suggest that tools receiving higher complexity scores, while being able to capture details to specific resource interactions, are unable to cover a larger number of interactions and system components simultaneously, as compared to lower complexity score tools. Lastly, the outcome of the analysis point towards the need for integrating more preliminary assessment capabilities, i.e. diagnostics, guidelines, and capacity building, into existing tools that improve the communication and translation of model outputs into policy and decision-making. PMID- 30308843 TI - Uncertainty and variability of extension rate, density and calcification rate of a hermatypic coral (Orbicella faveolata). AB - Skeleton growth variables of hermatypic corals, such as extension rate, density and calcification rate, are widely used to study coral response to environmental stressors, establish chronological age models and reconstruct the evolution of key climate variables. In this work, we addressed methodological aspects of the measurement of coral growth variables and the implications of their variability. A core of Orbicella faveolata was collected from the Puerto Morelos coral reef, in the Mexican Caribbean, and we measured and analysed 10 parallel transects of a core slab, covering 30 years. Density calibration was performed by measuring a high-quality and well-characterised wedge of Tridacna maxima, and the interval of interest was adjusted to the measured coral optical densities. The measurement uncertainties of extension rate, density and calcification rate were 0.011%, 1.1% and 1.6%, respectively. However, for density and calcification rate, overall variability was 29% and 33%, respectively, of which about half was attributed to intra-band growth variability. The intra-band variability of extension rate was only 0.68%, indicating the suitability of extension rate as a precise environmental proxy. These results likely differ by coral species, environments and experimental conditions, such as the exact location of the core within the colony and the method used to determine density. Uncertainties of coral growth variables should be carefully considered when reconstructing past environmental conditions. PMID- 30308844 TI - Effectiveness of commercial face masks to reduce personal PM exposure. AB - Cycling and walking are promoted as means of transportation which can contribute to the reduction of traffic pollution in urban areas. However, cyclists and pedestrians may be exposed to high concentrations of air pollutants due to their proximity to vehicle emissions. Commercial face mask respirators are widely used, in both developing and developed countries, as an individual protective measure against particle pollution. However scientific data on the efficacy of face mask respirators in reducing airborne particle exposure is limited. In this study, a custom experimental set-up was developed in order to measure the effectiveness of nine different respirators under real environmental conditions in terms of particle mass concentration below 2.5 MUm (PM2.5), particle number concentration (PNC), Lung Deposited Surface Area (LDSA) and Black Carbon concentration (BC). Face mask performances were assessed in a typical traffic affected urban background environment in the city of Barcelona under three different simulated breathing rates to investigate the influence of flow rate. Results showed a median face mask effectiveness for PM2.5 equal to 48% in a range of 14-96%, 19% in a range of 6%-61% for BC concentration, 19% in a range of 4%-63% for PNC and 22% in a range of 5%-65% for LDSA. For each pollutant under investigation, the best performance was found always with the same mask (N7) although it is not the most expensive (in a range of price of 1 to 44, its cost was 20 euros), which has a filter on the entire surface except for the 2 exhalation valves where air cannot enter but just exit and shows a good fit on the dummy head. PMID- 30308845 TI - Field evaluation of the fertilizing potential of biologically treated sanitation products. AB - Among different approaches of treating source-separated urine and feces for agronomic utilization, the treatment by addition of nitrifying bio-seeds seems to be useful in increasing the fertilizing potential of these sanitation products by modifying and stabilizing the nitrogen profile. In this study, biological treatment was applied to an onsite resource-oriented sanitation system by adding nitrifying microorganism bio-seeds. Further, the potential of the sanitation products to be utilized as fertilizer for white radish (Raphanus sativus var. longipinnatus) cultivation was examined and compared with that of a commercial fertilizer. This was done through the measurement of nutrients released in soil samples as well as measurements of root mass, root length, and the measurement of accumulated nitrogen, sugar, and water content in plant tissues. Our results show that soil fertilized with a mixture of biologically treated urine and feces exhibits a statistically similar nutrient release trend to soil fertilized using a commercial fertilizer. Moreover, soil fertilized with a mixture of biologically treated urine and feces yielded larger white radishes with a higher sugar and water content, as well as a higher accumulation of nutrients in the plant tissues, than soil fertilized with a commercial fertilizer. PMID- 30308846 TI - Analytical and bioanalytical assessments of organic micropollutants in the Bosna River using a combination of passive sampling, bioassays and multi-residue analysis. AB - Complex mixtures of contaminants from multiple sources, including agriculture, industry or wastewater enter aquatic environments and might pose hazards or risks to humans or wildlife. Targeted analyses of a few priority substances provide limited information about water quality. In this study, a combined chemical and effect screening of water quality in the River Bosna, in Bosnia and Herzegovina was carried out, with focus on occurrence and effects of contaminants of emerging concern. Chemicals in water were sampled at 10 sites along the Bosna River by use of passive sampling. The combination of semipermeable membrane devices (SPMDs) and polar organic chemical integrative samplers (POCIS) enabled sampling of a broad range of contaminants from hydrophobic (PAHs, PCBs, OCPs) to hydrophilic compounds (pesticides, pharmaceuticals and hormones), which were determined by use of GC-MS and LC-MS (MS). In vitro, cell-based bioassays were applied to assess (anti)androgenic, estrogenic and dioxin-like potencies of extracts of the samplers. Of a total of 168 targeted compounds, 107 were detected at least once. Cumulative pollutant concentrations decreased downstream from the city of Sarajevo, which was identified as the major source of organic pollutants in the area. Responses in all bioassays were observed for samples from all sites. In general, estrogenicity could be well explained by analysis of target estrogens, while the drivers of the other observed effects remained largely unknown. Profiling of hazard quotients identified two sites downstream of Sarajevo as hotspots of biological potency. Risk assessment of detected compounds revealed, that 7 compounds (diazinon, diclofenac, 17beta-estradiol, estrone, benzo[k]fluoranthene, fluoranthene and benzo[k]fluoranthene) might pose risks to aquatic biota in the Bosna River. The study brings unique results of a complex water quality assessment in a region with an insufficient water treatment infrastructure. PMID- 30308847 TI - Ecological assessment of river networks: From reach to catchment scale. AB - Freshwater ecosystems are increasingly under threat as they are confronted with multiple anthropogenic impairments. This calls for comprehensive management strategies to counteract, or even prevent, long-term impacts on habitats and their biodiversity, as well as on their ecological functions and services. The basis for the efficient management and effective conservation of any ecosystem is sufficient knowledge on the state of the system and its response to external influence factors. In freshwater ecosystems, state information is currently drawn from ecological assessments at the reach or site scale. While these assessments are essential, they are not sufficient to assess the expected outcome of different river restoration strategies, because they do not account for important characteristics of the whole river network, such as habitat connectivity or headwater reachability. This is of particular importance for the spatial prioritization of restoration measures. River restoration could be supported best by integrative catchment-scale ecological assessments that are sensitive to the spatial arrangement of river reaches and barriers. Assessments at this scale are of increasing interest to environmental managers and conservation practitioners to prioritize restoration measures or to locate areas worth protecting. We present an approach based on decision support methods that integrates abiotic and biotic ecological assessments at the reach-scale and aggregates them spatially to describe the ecological state of entire catchments. This aggregation is based on spatial criteria that represent important ecological catchment properties, such as fish migration potential, resilience, fragmentation and habitat diversity in a spatially explicit way. We identify the most promising assessment criteria from different alternatives based on theoretical considerations and a comparison with biological indicators. Potential applications are discussed, particularly for supporting the strategic, long-term planning and spatial prioritization of restoration measures. PMID- 30308848 TI - Redox potential as a method to evaluate the performance of retention soil filters treating combined sewer overflows. AB - Retention soil filters (RSFs) protect water bodies from pollutant loads originating from combined sewer overflows (CSOs) by filtering the wastewater through a filter layer having a depth of 0.75 to 1 m. The microbiological processes in the filter material are influenced by the redox potential (Eh). This potential is a strong indicator of the prevailing environmental conditions and the possible type of microbial activity. Previous investigations of filter bodies have been confined to constructed wetlands (CWs) with regular intermittent wastewater inflow. Compared to CWs, RSFs are characterized by higher oxygen availability due to alternating operating and dry periods. This study aimed to determine the Eh in RSFs and investigate its influence on the removal efficiency for different substances. We established a conceptual model for the standard Eh curve following a loading event, and the variations to this standard in two depths and between treatments. Correlations were determined with a canonical correlation analysis between the pollutant removal of COD, ammonium, phosphorous, E. coli, somatic coliphages and diclofenac and the Eh. Although the removal efficiency is influenced by several additional operating factors such as the preceding dry period, filter age and the respective inflow concentrations, our results show that the Eh is an adequate approach to assess the removal efficiency of RSFs for these substances. PMID- 30308849 TI - Gibberellic acid surface complexation on ferrihydrite at different pH values: Outer-sphere complexes versus inner-sphere complexes. AB - Gibberellic acid (GA3) is a widely used plant growth regulator and environmental toxin especially in China, but no study has focused on the mechanism of the interactions between GA3 and minerals/soils. In this study, the GA3 surface complexation mechanism on ferrihydrite (Fh) was investigated by combining sorption-desorption batch experiments with Fourier transform infrared (FTIR) spectroscopy and moving-window two-dimensional (MW2D) correlation spectroscopy. The results showed that the Fh-GA3 surface complexes and retention after desorption depended strongly on the pH. For pH > 2.9, electrostatic interactions played an important role in GA3 sorption on Fh in two ways. One was directly forming an outer-sphere complex by electrostatic attraction to a minor extent. The other was acting as a driving force to facilitate the formations of surface hydration-shared ion pair (mainly formed at pH < 5.7) and solvent-surface hydration-separated ion pair (mainly formed at pH > 5.7). Those three outer sphere complexes were partially reversible according to the high total desorption percentage of GA3 (69-80%). For pH <= 2.9, the generated monodentate complex was observed and increased with decreasing pH, which showed more retention on Fh after desorption than the outer-sphere complexes according to the lower total desorption percentage of GA3 (37%). At the typical soil and groundwater pH values (4.5-9), the outer-sphere complexes predominate, where GA3 could be out-competed by nitrate and other anions and then easily desorbed from Fh. This increases the risk of groundwater contamination. PMID- 30308850 TI - Nutrient, metal contents and microbiological properties of litter and soil along a tree age gradient in Mediterranean forest ecosystems. AB - The link among the age of aboveground tree species, litter, soil quality and status in Mediterranean forests is not entirely comprehended (especially in Mediterranean forest sites). This study evaluates whether and by what extent tree stand composition and forest structure modify nutrient depository or alter physical, chemical and microbiological properties of soil and litter in a 120 years old pine forest chronosequence. In general, the enzymatic activity related to the phosphorous, carbon and nitrogen cycles were more developed in litter than in soil surface, while the sulphur enzymatic activity was not significantly different between the two analyzed systems. The higher dehydrogenase content measured in the litter may be an index of a higher extracellular microbial activity, compared to soil. A noticeable effect of forest age and structure on the majority of analyzed elements was detected, with nutrients and metals tending to accumulate in soil rather in the litter. Moreover, the contents of P and some metals and sulphur enzymatic activity in the litter are influenced by forest age and associated forest structure. Finally, since nutrient, metals and enzyme contents in the litter increase with forest age, forest management strategies targeted to increase the stand structure may be advisable in order to achieve higher soil functionality. PMID- 30308851 TI - Significantly depleted 15N in suspended particulate organic matter indicating a strong influence of sewage loading in Daya Bay, China. AB - The influence of anthropogenic nutrient loading on the stable isotopic signatures (delta13C and delta15N) in the suspended particulate organic matter (SPOM) is still not fully understood. Water quality and the values of delta13C and delta15N in the SPOM were investigated in the surface water of Daya Bay during the spring of 2016 and 2017. The results indicated that the Dan'ao River is the main point source of nutrient pollution in Daya Bay. The delta15NPOM was very low in the Dan'ao River. The distribution pattern for this parameter in Daya Bay was determined chiefly by Dan'ao River discharge. Variations in delta15NPOM were ascribed mostly to the input of 15N-depleted DIN assimilated by the estuarine phytoplankton in Daya Bay. Extremely high NH4+ level in the river discharge should be responsible for the low delta15NPOM in the river water. The distribution of delta13CPOM in Daya Bay was regulated mainly by the input of 13C depleted riverine SPOM. In the present study, the influence of phytoplankton growth on the delta13CPOM was not significant. Moreover, episodic rain events significantly influenced the temporal and spatial variations in water quality and isotopic signature in Daya Bay. The relatively depleted SPOM 15N in 2016 may have been correlated with the strong El Nino events of 2015-2016. Increases in the frequency and volume of rainfall associated with El Nino may have enhanced nutrient loading and the risk of algal red tide in the Daya Bay. In general, significant 15N depletion in SPOM could be the characteristic of hypereutrophic riverine waters. This study suggested that delta15NPOM may be an effective indicator of the strength of riverine nutrient loading in Daya Bay. PMID- 30308852 TI - Influence of filtration during sample pretreatment on the detection of antibiotics and non-steroidal anti-inflammatory drugs in natural surface waters. AB - Owing to the ease and effectiveness of removing suspended substances (SSs), filtration has become a universal pretreatment step during water sample preparation. However, it can lead to the underestimation of contaminants if the targets easily associate with the SSs or filters. For the first time, this study comprehensively assessed issues related to filtration for the accurate quantification of 35 typical pharmaceuticals, including 28 antibiotics and seven non-steroidal anti-inflammatory drugs (NSAIDs), in water samples by comparing the effects of different filter materials, preservatives, and water matrices on the recoveries. The results showed that some sulfonamides and NSAIDs had an affinity for nylon filters, whereas trimethoprim and macrolides were easily retained on mixed cellulose ester filters. The use of glass fiber filter (0.7 MUm) resulted in improved recovery of all the targets. Acidification promoted the adsorption of fluoroquinolones, tylosin, and roxithromycin on SSs, whereas 5% methanol resulted in desorption of macrolides from the SSs and other pharmaceuticals (sulfadiazine, trimethoprim, etc.) from the solid-phase extraction cartridges. Without additional detection of targets adsorbed on the SSs and filters, the addition of appropriate surrogates prior to filtration can help correct the loss. PMID- 30308853 TI - Polychlorinated biphenyls in apple snails from an abandoned e-waste recycling site, 2010-2016: A temporal snapshot after the regulatory efforts and the bioaccumulation characteristics. AB - The rudimentary recycling of electronic waste (e-waste) has been banned in China since the late 2000s, leaving many abandoned e-waste sites. However, knowledge is limited on the concentrations and fates of the e-waste derived contaminants such as polychlorinated biphenyls (PCBs) in these abandoned sites. In this work, we assessed the temporal trend of PCB concentrations in the year 2010, 2012, and 2016 at an abandoned e-waste site in South China, using apple snail as a bioindicator. The mean ?PCBs concentrations in apple snails sampled in 2016 (53.2 ng/g dry weight) was approximately 11-fold higher than that (4.68 ng/g dry weight) in apple snails from a reference site. The result suggested that the abandoned e-waste recycling site was still heavily polluted by PCBs, despite of the fact that crude e-waste recycling processes have been prohibited for nearly 10 years. The concentrations of ?PCBs were significantly decreased in 2016 compared to those in 2010 (mean: 115 ng/g dry weight) and 2012 (mean: 92.3 ng/g dry weight), but there were no significant differences in the concentrations between 2010 and 2012. Regarding the congener profiles, the contributions of lower chlorinated congeners (tri- and tetra-PCBs) in the snails tended to be higher over the years. The ?PCBs in snails were significantly correlated with those in soils. Additionally, PCB profiles in snails resembled those in soils. These results suggested that apple snails can be used as an ideal bioindicator for PCBs in the paddy soils. Field determined biota-soil accumulation factors (BSAFs) for PCBs ranged from 0.31 to 1.9, with most of the values being 1-2; indicating that theoretical BSAFs can be used to predict the bioaccumulation of PCBs in the snails with a reasonable degree of certainty. PMID- 30308854 TI - The potential human exposure to antibiotic resistant-Escherichia coli through recreational water. AB - It is important that bathing water sites are free as possible from antibiotic resistant bacteria (ARB) to prevent the spread of difficult to treat infections throughout the population. This study examines the possible human exposure to antibiotic resistant Escherichia coli (AR-E. coli) through recreational activities at two different bathing water sites located near wastewater treatment plants (WWTPs). A quantitative risk assessment model was created to model the pathway of the AR-E. coli from the WWTPs effluent water through to the bathing water sites. Both sampling data and data from scientific literature were used. The main steps considered for the model were: the dilution and decay of the AR-E. coli from the WWTPs effluent water into the river; the dilution of the river into the bathing water sites and the human exposure to AR-E. coli through recreational activities at the bathing water sites (as a result of water ingestion). The results show the mean predicted human exposure levels ranged between 0.45 and 345.09 cfu/100 ml. A back calculation method determined that in accordance with the European Bathing Water Directive (2006/7/EC) (BWD) to be considered "poor" water quality, the concentration of AR-E. coli in WWTP effluent water would need to exceed 2.45 log cfu/ml at site 1 and exceed 2.71 log cfu/ml at site 2. This study provides valuable information for regulatory bodies and policy makers on the possible human exposure levels to AR-E. coli and the maximum permissible concentrations in WWTP effluent water to ensure compliance with relevant bathing water legislation. PMID- 30308855 TI - Characterizing the atmospheric conditions during the 2010 heatwave in Rio de Janeiro marked by excessive mortality rates. AB - Global temperatures have increased considerably over the last decades, directly impacting the number, intensity and duration of extreme events such as heat waves. Climate model projections accounting for anthropogenic factors indicate that deadly mega-heat waves are likely to become more frequent in the future. Although the atmospheric features and social-economic related impacts of heat waves have already been documented in various regions around the world, for other highly populated regions, such as the Metropolitan Region of Rio de Janeiro (MRRJ), a similar objective assessment is still needed. Heat waves directly impact the public health sector and particularly the less wealthy and elderly population groups. During February 2010, an elevated mortality peak occurred during a 8-day period (from 2 to 9 Feb 2010) characterized as a heat wave episode in MRRJ. A total excess of 737 deaths was recorded with the elderly group registering the highest mortality incidence. During this heat wave period, a quasi-stationary anticyclonic anomaly forced in altitude by a Rossby wave train was established over the south Brazilian coast. At the surface, the meteorological scenario from January 2010 to the heat wave period was marked by clear sky conditions, large precipitation deficits, and enhanced diabatic heating. During the heat wave period, warm and dry air masses were advected from interior regions towards the MRRJ, exacerbating temperature conditions by pronounced subsidence and adiabatic heating mechanisms. All these conditions contributed to pronounced positive temperature anomalies, reinforced by land atmosphere feedbacks. PMID- 30308856 TI - Wildfires as a major challenge for natural regeneration in Atlantic Forest. AB - The natural regeneration management is a good strategy of ecological restoration of the Atlantic Forest, one of the most devastated biomes on the planet. However, the frequent occurrence of wildfires is one of the challenges to the success of this method. The objective of this study was to evaluate the effects of wildfires on forest dynamics in Atlantic Forest. The studied area was explored during the coffee cycle when plantations replaced primary forests. We used remote sensing data to analyze the forest dynamics over a period of 50 years (1966-2016). We used the INPE burn database to find the occurrence of hot spots from 1998 to 2016. During this period, we selected the years most affected by the fires for the identification of fire scars using the Normalized Burn Ratio spectral index. From this set of information, we used the methodology of weights of evidence to relate forest dynamics and wildfire events with biophysical and anthropic variables. The results showed that in 1966 the forest area accounted for 8.01% of the land cover, and in 2016 this number rose to 18.55% due to the spontaneous natural regeneration process. The regenerating areas were mainly related to the proximity of the remaining fragments and the portions of the landscape receiving the least amount of global solar radiation. The proximity to urban areas, roads and highways, damaged regeneration and favored both deforestation and wildfire events. Fire scars preferentially occur where there is greater sun exposure. It is possible to observe a negative correlation between the natural regeneration process and the fire scars. We concluded that fire severity is one of the factors that shape the landscape of the region while slowing the regeneration process in preferential areas. PMID- 30308857 TI - Do commercial building sector-derived carbon emissions decouple from the economic growth in Tertiary Industry? A case study of four municipalities in China. AB - Decoupling economic development from carbon emissions generated from China's commercial buildings (CECCB) is regarded as an important indicator for evaluating the energy efficiency of the commercial building sector in China. Our study is the first to propose a decoupling method based on a Logarithmic Mean Divisia Index (LMDI) decomposition analysis with the Kaya identity to analyze the relationship between economic development in China's Tertiary Industry and the CECCB growth at both national and municipal levels. The following three main results are found. (1) At the national level, commercial building sector decoupling from 2001 to 2015 is limited. Only four decoupling stages are observed at the municipal level with the ordering of municipal decoupling measured as follows: Tianjin > Beijing > Shanghai > Chongqing (2001-2010), Chongqing > Beijing > Tianjin > Shanghai (2011-2015). (2) Two extended versions of Environmental Kuznets Curves further show what drives different decoupling levels in the four municipalities. (3) More significant decoupling effects observed in recent years can be attributed to significant improvements made in the energy efficiency work of China's commercial building sector. Overall, our approach successfully covers a research gap relevant to the decoupling of the relationship between CECCB growth and the economic development of China's Tertiary Industry. Furthermore, we believe our results can be used to guide the evaluation of energy efficiency work in China's commercial building sector, and such efforts can also enrich diverse research conducted on China's low carbon economic systems. PMID- 30308858 TI - Composition and spatial distribution of elements and isotopes of a giant human bladder stone and environmental implications. AB - The composition and spatial distribution of minerals, trace elements, as well as carbon and nitrogen isotopes from the outer crust to inner nucleus of a 20-year old giant human bladder stone comprising thirteen layers were intensively investigated. Calcium oxalate monohydrate (COM) was found to concentrate in the inner and middle layers, struvite was concentrated in middle and outer layers, and fluorapatite occurred in almost all layers. The spatial distribution of minerals has the potential to provide preliminary knowledge regarding the long term urine composition, or even the physiological condition of the patient. The stable carbon isotope ratio (delta13C) and stable nitrogen isotope ratio (delta15N) were measured in each layer and significant correlation was found between delta13C with calcium oxalate monohydrate content and between delta15N and struvite content. Nearly constant values of -23.20/00 and 7.10/00 for delta13C and delta15N, respectively, were found in the organic components of the stone. Both isotope ratios indicate a long-term fixed diet consisting mainly of C3 plants, such as rice and wheat, for the 20-year time period of the stone formation. In addition, eighteen elements (Ca, P, Mg, K, Na, Al, Fe, Zn, Pb, Cu, Sr, Ba, Ti, V, Cr, Ni, Mn and Co) were measured in all the layers. The trace elements Al, Fe, Cu, Zn, Pb, Sr, Ba and Ti showed a similar spatial distribution pattern from the outer crust to the inner core. Although there were complex correlations between elements and minerals, Factor Analysis suggests that the occurrence of these elements in stones may be mainly the result of environmental exposure to metals during the formation of the stone, indicating that urinary stones may serve as potential long-term biomonitors. In particular, Ni and Cr showed a distinct distribution pattern in the stone, which may relate to human metabolic activities. PMID- 30308859 TI - Chinese cropland losses due to urban expansion in the past four decades. AB - Since 1970s, China has experienced the large-scale losses of croplands during urban expansion process, which has drawn great attentions to Chinese government. Although in-depth studies about cropland losses have been executed widely, relatively little attention has been paid to describe long term and high frequency influences of urban expansion on it and reveal its differences systematically. Based on remote sensing and GIS technology, we quantified, analyzed, and mapped cropland losses in China due to urban expansion from the national, administrative-level, population-size, and city scales. Results indicated that (1) Since the 1970s, croplands were the primary contributor to urban expansion in China, and their losses due to urban expansion underwent five obvious stages. The consciousness of cropland protection is being strengthened continuously and has developed from the initial to the deep execution stages. (2) Cropland losses were unbalanced in China, with the loss magnitude, rate, and influences on urban expansion positively related to the administrative-level and large population-size. That is, obvious losses always emerged in cities with high administrative-level and large population-size. (3) Seven basic trends of cropland losses were quantitatively recognized, which was conducive to the formulation of different policies or strategies for cropland protection for different cities. PMID- 30308860 TI - Convergent evolution in bacteria from multiple origins under antibiotic and heavy metal stress, and endophytic conditions of host plant. AB - The focus of this work is to study the convergent evolution in bacteria from multiple origins under antibiotic and heavy metal stress, and endophytic conditions of host plant cultivated on the Yamuna river bank. Forty-one endophytic bacteria (EB) were isolated from green leafy vegetables (GLV's) and were found to be resistant to a wide range of antibiotics (AB) and heavy metals (HM) tested. Further, they showed susceptibility to Quinolones group of antibiotics, and the HM, Cadmium, Chromium, and Mercury. Twenty-seven percent of these bacteria endowed with Class I integron. The probability of co-existence of HM resistance with beta-lactams was higher, whereas quinolones group of AB recorded lesser values. These EB owned a wide array of beneficial traits, through which they improved the plant health under HM and salt stress conditions. Bacterial identity revealed the association of both plant beneficial and human pathogenic bacteria as an endophyte with GLV's. Principal component analysis showed a pattern of convergent evolution irrespective of their origin. In conclusion, under the selection pressure of AB and HM, the susceptible EB population may reduce with time and the resistant native/introduced bacteria might survive. The vertical and horizontal gene transfer between introduced and native bacteria is the crucial factor in enhancing their fitness along with the host plant to survive under abiotic stress conditions. PMID- 30308861 TI - Evaluation of volatile organic compounds coupled to seasonality effects in indoor air from a commercial office in Madrid (Spain) applying chemometric techniques. AB - Volatile organic compounds (VOCs) concentrations depend on several sources and factors, such as temperature, ventilation, and humidity. Sources can be external atmospheric pollution or indoor release from furniture, coatings or occupants. In this context, this study focused on quantification of VOCs present in a confined atmosphere in a commercial office in downtown Madrid, Spain. The influence of seasonal changes in VOCs concentrations was evaluated using chemometric approaches. Indoor air was systematically monitored for one year using stainless steel tubes filled with Tenax(r) TA. Sampling was conducted one week a month, for three days during that week (Monday, Wednesday and Friday) for 60 min, every 2 h, totaling 24 h, using an autosampler carousel. The analyses were performed using thermal desorption, and compounds were analyzed by a gas chromatograph coupled with a mass spectrometer. The correlation between these compounds and their concentrations, climatic variations, seasons, among others, were explained by multivariate statistics. Considering the current legislation in Spain, only benzene was present above the maximum permissible concentration (threshold value < 1 MUg/m3) from all analyzed compounds. The results indicate that concentrations are related to significant environmental changes, such as ventilation, the number of occupants in the office and types of activity undertaken in the environment. The chemometric analyses allowed the identification of structure analyses correlations between multiple variables for the one-year study. These results underscore the importance of indoor atmosphere studies and chronic exposure to these contaminants. PMID- 30308862 TI - Lithium and its isotopes as tracers of groundwater salinization: A study in the southern coastal plain of Laizhou Bay, China. AB - In the southern coastal plain of Laizhou Bay, due to intensive exploitation of groundwater since the early 1970s, the shallow aquifer has been severely influenced by saltwater intrusion, which causes the extraction to shift from shallow to deeper aquifer changing the hydrogeological condition greatly. This study was conducted to investigate the groundwater salinization using hydrochemistry and H, O and Li isotope data. Dissolved Li shows a linear correlation with Cl and Br in seawater, brine and saline groundwater indicating the marine Li source, whereas the enrichment of Li in surface water, brackish and fresh groundwater is impacted by dissolution of silicate minerals. The analyses of hydrochemistry and isotopes (H, O and Li) indicate that brine originated from seawater evaporation, followed by mixing processes and some water-rock interactions; shallow saline groundwater originated from brine diluted with seawater and fresh groundwater; deep saline groundwater originated from seawater intrusion. The negative correlation of delta7Li and Li/Na in surface water, brackish and fresh groundwater is contrary to the general conclusion, indicating the slow weathering of silicate minerals and hydraulic interaction between surface water and shallow groundwater in this area. The analyses of hydrochemistry and isotopes (Li, H and O) can well identify the salinity sources and isotope fractionation in groundwater flow and mixing, especially groundwater with high TDS. As both mixing with saltwater and isotope fractionation can explain the combination of high delta7Li and low TDS in brackish groundwater, isotope fractionation may limit their use in recognizing salinity sources of groundwater with low TDS. PMID- 30308863 TI - Monthly blue water footprint caps in a river basin to achieve sustainable water consumption: The role of reservoirs. AB - The blue water footprint (WF) measures the consumption of runoff in a river basin. In order to ensure sustainable water consumption, setting a monthly blue WF cap, that is an upper-limit to the blue WF in a river basin each month, can be a suitable policy instrument. The blue WF cap in a river basin depends on the precipitation that becomes runoff and the need to maintain a minimum flow for sustaining ecosystems and livelihoods. Reservoirs along the river generally smooth runoff variability and thus raise the WF cap and reduce blue water scarcity during the dry season. Previous water scarcity studies, considering the ratio of actual blue WF to the blue WF cap under natural background conditions, have not studied this effect of reservoir storages. Here we assess how water reservoirs influence blue WF caps over time and how they affect the variability of blue water scarcity in a river basin. We take the Yellow River Basin over the period January 2002-July 2006 as case study and consider data on observed storage changes in five large reservoirs along the main stream. Results indicate that reservoirs redistribute the blue WF cap and blue water scarcity levels over time. Monthly blue WF caps were generally lowered by reservoir storage during the flood season (July-October) and raised by reservoir releases over the period of highest crop demand (March-June). However, with water storage exceeding 20% of natural runoff in most rainy months, reservoirs contribute to "scarcity in the wet months", which is to be understood as a situation in which environmental flow requirements related to the occurrence of natural peak flows are no longer met. PMID- 30308865 TI - PM2.5-induced alteration of DNA methylation and RNA-transcription are associated with inflammatory response and lung injury. AB - The mechanisms of systemic pulmonary inflammation and toxicity of fine particulate matter (PM2.5) exposure remains unclear. The current study investigated the inflammatory response and lung toxicity of PM2.5 in rats following intratracheal instillation of PM2.5. After repeated (treated every 3 days for 30 days) PM2.5 exposure, total protein (TP), lactate dehydrogenase (LDH) activity and inflammatory cytokines including interleukin 6 (IL-6), interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) levels in bronchoalveolar lavage fluid (BALF) were markedly elevated. The expression levels of IL-6, IL-1beta, TNF-alpha and NF-kappaB in rat lung tissue and BEAS-2B cells were significantly upregulated after PM2.5 exposure. Histopathological evaluation suggested that the major pathological changes were alveolar wall thickening and inflammatory cell infiltration of the lungs. Genome wide DNA methylation and RNA transcription analysis was performed on human bronchial epithelial cells (BEAS 2B) to explore the potential mechanisms in vitro. PM2.5 induced genome wide DNA methylation and transcription changes. Differentially methylated CpGs were located in gene promoter region linked with CpG islands. Integrated analysis with DNA methylation and transcription data indicated a clear bias toward transcriptional alteration by differential methylation. Disease ontology of differentially methylated and expressed genes addressed their prominent role in respiratory disease. Functional enrichment revealed their involvement in inflammation or immune response, cellular community, cellular motility, cell growth, development and differentiation, signal transduction and responses to exogenous stimuli. Gene expression validation of ACTN4, CXCL1, MARK2, ABR, PSEN1, PSMA3, PSMD1 verified their functional participation in critical biological processes and supported the microarray bioinformatics analysis. Collectively, our data shows that PM2.5 induced genome wide methylome and transcriptome alterations that could be involved in pulmonary toxicity and pathological process of respiratory disease, providing new insight into the toxicity mechanisms of PM2.5. PMID- 30308864 TI - Assessment of bisphenol-A in the urban water cycle. AB - The plasticizer bisphenol-A (BPA) is common to municipal wastewaters and can exert toxicity to exposed organisms in the environment. Here BPA concentration at 5 sewage treatment works (STW) and distribution throughout a river catchment in South West UK were investigated. Sampling sites included influent and effluent wastewater (n = 5), river water (n = 7) and digested sludge (n = 2) which were monitored for 7 consecutive days. Findings revealed average BPA loads in influent wastewater at two STWs were 10-37 times greater than the other wastewaters monitored. Concentrations up to ~100 MUg L-1 were measured considerably higher than previously reported for municipal wastewaters. Temporal variability throughout the week (i.e., highest concentrations during weekdays) suggests these high concentrations are linked with industrial activity. Despite >=90% removal during wastewater treatment, notable concentrations remained in tested effluent (62-892 ng L-1). However, minimal impact on BPA concentrations in river water was observed for any of the effluents. The maximum BPA concentration found in river water was 117 ng L-1 which is considerably lower than the current predicted no effect concentration of 1.6 MUg L-1. Nevertheless, analysis of digested sludge from sites which received these elevated BPA levels revealed average concentrations of 4.6 +/- 0.3 and 38.7 +/- 5.4 MUg g-1. These sludge BPA concentrations are considerably greater than previously reported and are attributed to the high BPA loading in influent wastewater. A typical sludge application regime to agricultural land would result in a predicted BPA concentration of 297 ng g-1 in soil. Further studies are needed on the toxicological thresholds of exposed terrestrial organisms in amended soils to better assess the environmental risk here. PMID- 30308866 TI - Predicting soil microplastic concentration using vis-NIR spectroscopy. AB - Microplastic accumulation in soil may have a detrimental impact on soil biota. The lack of standardized methods to identify and quantify microplastics in soils is an obstacle to research. Existing techniques are time-consuming and field data are seldom collected. To tackle the problem, we explored the possibilities of using a portable spectroradiometer working in the near infrared range (350-2500 nm) to rapidly assess microplastic concentrations in soils without extraction. Four sets of artificially polluted soil samples were prepared. Three sets had only one polymer polluting the soil (low-density polyethylene (LDPE), polyethylene terephthalate (PET), or polyvinyl chloride (PVC)). The fourth set contained random amounts of the three polymers (Mix). The concentrations of microplastics were regressed on the reflectance observed for each of the 2150 wavelengths registered by the instrument, using a Bayesian approach. For a measurement range between 1 and 100 g kg-1, results showed a root-mean-squared deviation (RMSD) of 8, 18, and 10 g kg-1 for LDPE, PET, and PVC. The Mix treatment presented an RMSD of 8, 10, and 5 g kg-1 for LDPE, PET, and PVC. The repeatability of the proposed method was 0.2-8.4, 0.1-5.1, and 0.1-9.0 g kg-1 for LDPE, PET, and PVC, respectively. Overall, our results suggest that vis-NIR techniques are suitable to identify and quantify LDPE, PET, and PVC microplastics in soil samples, with a 10 g kg-1 accuracy and a detection limit ~ 15 g kg-1. The method proposed is different than other approaches since it is faster because it avoids extraction steps and can directly quantify the amount of plastic in a sample. Nevertheless, it seems to be useful only for pollution hotspots. PMID- 30308867 TI - Residual pollution and vegetation distribution in amended soils 20 years after a pyrite mine tailings spill (Aznalcollar, Spain). AB - The present work assesses the residual pollution in the Guadiamar Green Corridor (SW, Spain) after a long-term aging process (18 years) since the accident of the Aznalcollar pyrite mine. We have focused on the study of trace elements (Cu, Zn, Cd, As and Pb) in soils, their fractionation and the transference to the surrounding vegetation. The residual polluted areas are characterized by scattered plots with absence of vegetation, presenting high concentrations of trace elements, acidic pH and low organic carbon content. Surrounding these polluted plots, two vegetation gradient belts are clearly identified by changes in plant cover and richness. The inhibition of plant growth in the bare soils is related to the highest mobility of soluble and exchangeable Cu, Zn and Cd forms, which significantly decrease with the distance to the polluted plots. Plant richness and cover show differences between belts; bioaccumulation of trace elements in plants also differs, with a preferential accumulation in roots. Despite the low bioavailability of As and Pb in soils, bioaccumulation factors in plants for these elements are significantly higher in belt 1 in relation to belt 2. High Cu and Cd potential toxic concentrations in aerial parts of vegetation are found, posing a risk for livestock and a potential entrance to the food chain. On the other hand, Lamarckia aurea (L.) Moench (in belt1) and Trifolium campestre Schreb. (in belt2) were the most dominant species in severely polluted soils. Elevated concentrations of trace elements in the vegetation growing in the area indicate plant adaptation mechanisms to live in these severely polluted soils, which can be used as a good bioindicator of pollution in similar polluted areas. PMID- 30308868 TI - Synergistic strengthening mechanism of hydraulic selection pressure and poly aluminum chloride (PAC) regulation on the aerobic sludge granulation. AB - This study aimed to enhance aerobic granulation by the integration of hydraulic selection pressure (HSP) and poly aluminum chloride (PAC) regulation. Based on an investigation of sludge characteristics, microbial aggregation and extracellular polymeric substances (EPS) secretion, the synergistic mechanisms of HSP and PAC regulation were revealed. For granule formation, HSP primarily improved the cell hydrophobicity and extracellular protein production, while PAC regulation markedly neutralized the surface charge of cells and reduced the interaction energy between them. In addition, biomass retention was also facilitated by the PAC dosing. Notably, the results of total interaction energy and flocculating ability imply that prior HSP screening could significantly promote PAC regulation on microbial aggregation. To optimize the balance between granule formation and reactor performances, five kinds of integrated strategies for HSP and PAC regulation were conducted in batch test. According to the results, 4.3 g/L initial mixed liquor volatile suspended solids (MLVSS) was preferred before the addition of PAC. PMID- 30308869 TI - The influence of OH concentration on SOA formation from isoprene photooxidation. AB - The formation of secondary organic aerosol (SOA) from isoprene photooxidation was investigated to reveal the influence of OH concentration on SOA formation through varying the concentrations of isoprene and H2O2 in a smog chamber. The results indicated that the higher the OH concentration was, the less the isoprene consumed for the detectable SOA mass concentration, for example, the lowest isoprene consumption for the detectable SOA was about 14.4 ppb under the OH concentration of about 1.65 * 107 molecules cm-3, whereas tens ppb of isoprene consumption were needed under the OH concentrations <1.0 * 107 molecules cm-3, and even no detectable SOA was observed with isoprene consumption of 75.1 ppb under OH concentration of 7.2 * 105 molecules cm-3. SOA yield was also found to increase with increasing OH concentration for a given aerosol loading (M0) at atmospherically relevant conditions, confirming that OH concentration played important role in SOA formation from isoprene photooxidation. The maximal SOA yields (5.8-42.8%) obtained by this study were a factor of 1.5-3.1 greater than those reported by previous study for the almost the same initial reactant concentrations of isoprene and H2O2, and the difference was mainly ascribed to the higher OH concentrations in the reaction systems of this study than those of previous study. The OH concentrations adopted in this study closed to those in the real atmosphere around noontime, and hence the SOA yield obtained from the isoprene photooxidation might be representative. PMID- 30308870 TI - Potentially toxic elements in muscle tissue of different fish species from the Sava River and risk assessment for consumers. AB - Fish from the Sava River are consumed daily by the local people: therefore, concern has been raised about the health implications of eating contaminated fish. In the present study, potentially toxic elements (PTE), such as Zn, Cu, Cr, Ni, Cd, Pb, As, Hg, and methylmercury (MeHg), were determined in ichthyofauna that are commonly consumed. PTE were determined in the fish muscle tissue. Fish were sampled at 12 locations from the source of the Sava River to its confluence with the Danube River during two sampling campaigns, namely; in 2014 under high water conditions and in 2015 under normal water conditions. Due to the different water regimes, different fish species were collected for chemical analysis. We observed that the concentrations of elements analysed in the fish muscle tissue were generally very low, except for those of Hg. Moreover, more than 90% of Hg present in the fish was in its most toxic form, namely MeHg. Especially in fish from the 2015 sampling campaign, Hg and MeHg concentrations increased with fish size, trophic level, and in the downstream direction. In addition, for Pb and As, and to some extent for Cd and Cr, spatial differences were detected in both years. The highest concentrations of PTE were detected in fish from sites with intensive industrial and agricultural activities. The consumption of fish in general does not pose a health risk for the PTE studied, except for Hg/MeHg at selected contaminated sites. PMID- 30308871 TI - Explaining variation in elevated blood lead levels among children in Minnesota using neighborhood socioeconomic variables. AB - BACKGROUND: Childhood lead exposure is linked to numerous adverse health effects and exposure in the United States is highest among people living in substandard housing, which is disproportionately inhabited by socioeconomically disadvantaged individuals. In this paper, we compared the Vox lead exposure risk score and concentrated disadvantage based on principal component analysis (PCA) to weighted quantile sum (WQS) regression to determine which method was best able to explain variation in elevated blood lead levels (EBLLs). METHODS: We constructed indices for census tracts in Minnesota and used them in Poisson regression models to identify the best socioeconomic measure for explaining EBLL risk. RESULTS: All indices had a significant association with EBLL in separate models. The WQS index had the best goodness-of-fit, followed next by the Vox index, and then the concentrated disadvantage index. Among the most important variables in the WQS index were percent of houses built before 1940, percent renter occupied housing, percent unemployed, and percent African American population. CONCLUSIONS: The WQS approach was best able to explain variation in EBLL risk and identify census tracts where targeted interventions should be focused to reduce lead exposure. PMID- 30308872 TI - Exposure to road traffic noise: Annoyance, perception and associated factors among Brazil's adult population. AB - BACKGROUND: One of the major environmental problems of the modern world is noise. A health-related marker of environmental noise exposure that can be considered a predictor of annoyance is noise sensitivity. The aim of this study was to ascertain the correlation between levels of exposure to road traffic noise in residential areas and the resulting annoyance based on the perception and sensitivity reported. METHODS: The study involved noise assessment, with the creation of noise maps of the neighborhood in the city of Sao Paulo, Brazil, and application of a questionnaire to ascertain the perception of the residents of the neighborhood, regarding the effects of this exposure. RESULTS: The noise levels at all the measured points were found to exceed the critical level for the area, 55 dB(A). A total of 225 interviews were conducted. Noise-related annoyance was reported by 48.4% of the respondents. Associations were observed between living in areas exposed to traffic noise and feeling annoyed with this noise (p < 0.001). CONCLUSIONS: These findings suggest the importance of reviewing and updating Brazilian public policies regarding environmental noise. We found a high prevalence of annoyance reports, as well as aspects indicative of sensitivity to noise exposure. PMID- 30308873 TI - Evidences of metabolic alterations and cellular damage in mussels after short pulses of Ti contamination. AB - Mytilus galloprovincialis mussels were exposed to seawater contaminated with Ti. Initial concentrations were 4.1, 32, and 66 MUg L-1 that declined during the first 24 h of the experiments, and after 48 h values were <2 MUg L-1. Experiments were run in triplicate, under constant salinity and temperature. Mussels were fed every two days, and water renewed every seven days and Ti concentrations re stabilized. During the first 28 days of experimental period, mussels were exposed to four short pulses of contamination, followed by few days of low Ti concentration between weekly contamination renewals. Then mussels were exposed to additional 14-day exposure to Ti uncontaminated seawater. Only residual Ti concentrations were measured in mussels' whole soft tissue after the four pulses of Ti contamination, indicating low Ti accumulation by the organisms. Nevertheless, the biomarkers related to mussels' metabolic capacity (electron transport system activity, ETS), oxidative damage (lipid peroxidation, LPO and reduced glutathione content, GSH), and defense mechanisms (antioxidant and biotransformation enzymes) evidenced the impact of Ti during the 28 days of experimental period. The biomarkers that better indicated the recovery of mussels' biochemical performance were the ETS, LPO, GSH, and the antioxidant enzyme glutathione peroxidase (GPx). LPO was the prime indicator among the analyzed biochemical responses. Organisms appear to hold coping mechanisms to lower the damage induced by Ti, and to recover, albeit the 14 days period of exposure to uncontaminated seawater following the four Ti pulses were not enough for full recovery, as evidenced by results on LPO levels and GSH concentrations. Despite the low solubility of Ti in seawater, the toxicity of this element to a model marine organism was demonstrated. PMID- 30308874 TI - Observations of particulate matter, NO2, SO2, O3, H2S and selected VOCs at a semi urban environment in the Amazon region. AB - This research aims to assess air quality in a transitional location between city and forest in the Amazon region. Located downwind of the Manaus metropolitan region, this study is part of the large-scale experiment GoAmazon2014/5. Based on their pollutant potential, inhalable particulate matter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), hydrogen sulfide (H2S), benzene, toluene, ethylbenzene and meta-, orto-, para-xylene (BTEX) were selected for analysis. Sampling took place during the wet season (March-April 2014) and dry season (August-October 2014). The number of forest fires in the surroundings was higher during the dry wet season. Results show significant increase during the dry season in mass concentration (wet: <0.01-10 MUg m-3; dry: 9.8-69 MUg m-3), NH4+ soluble content (wet: 13-125 MUg m-3; dry: 86-323 MUg m-3) and K+ soluble content (wet: 11-168 MUg m-3; dry 60-356 MUg m-3) of the PM2.5, and O3 levels (wet: 1.4-14 MUg m-3; dry: 1.0-40 MUg m-3), indicating influence of biomass burning emissions. BTEX concentrations were low in both periods, but also increased during the dry season. A weak correlation in the time series of the organic and inorganic gaseous pollutants indicates a combination of different sources in both seasons and NO2 results suggest a spatial heterogeneity in gaseous pollutants levels beyond initial expectations. PMID- 30308875 TI - Spatial variation of heavy metal contamination in the riparian sediments after two-year flow regulation in the Three Gorges Reservoir, China. AB - Regular impoundment of the Three Gorges Reservoir (TGR) with intensified human activities in the watershed imparts a significant effect on the environmental changes in the riparian zone. In this study, six heavy metals (Cd, Cr, Cu, Ni, Pb and Zn) in the riparian sediments of the entire TGR mainstream were investigated in 2014 and 2016 to identify their contamination and risk characteristics and decipher the main factors for the variation of the metal contamination. The results showed that the concentrations of the heavy metals in the sediments did not vary significantly between 2014 and 2016, and their contamination degrees decreased in the order of Cd> > Cu ~ Zn > Pb > Cr ~ Ni in 2014 and Cd> > Zn > Cu ~ Pb > Cr ~ Ni in 2016. The potential eco-risk of Cd was extremely high in the two years, while the eco-risk of other metals was very low. The sediments showed a moderate to high contamination level, a high potential eco-risk but a low toxic risk to aquatic biota in the two years. Spatially, the contamination and risk levels of heavy metals were relatively higher in the downstream TGR region in 2014 except for the sites close to the urban areas but in the upper-middle TGR region in 2016. Increasing anthropogenic influence contributed to the high contamination and risk levels of Cd, Cu, Pb and Zn in the upper-middle region in 2016. The results indicated that the Cd contamination in the riparian sediments of the TGR was still a vital environmental issue, and the decreased sediment inputs from the upstream major tributaries, the periodic and anti-seasonal flow regulation, local geomorphological characteristics and anthropogenic activities determined the contamination distribution of heavy metals in the riparian sediments. PMID- 30308876 TI - Pharmaceuticals, illicit drugs and their metabolites in fish from Argentina: Implications for protected areas influenced by urbanization. AB - Because an understanding of aquatic bioaccumulation of human pharmaceuticals in Latin America is limited, this area was recently identified as a priority environmental quality research need. We examined bioaccumulation of twenty-seven pharmaceuticals, illicit drugs and their metabolites in muscle, liver and gills of multiple fish species (Rhamdia quelen, Hypostomus commersoni, Hoplias lacerdae, Prochilodus lineatus) from an urban river receiving wastewater discharges (Parana) and a lotic system (Acaragua) without direct wastewater sources, which runs through a protected area. All samples were analyzed using isotope-dilution liquid chromatography-tandem mass spectrometry. Caffeine, which was detected up to 13 MUg/kg, and antibiotics were consistently detected in all fish. Among antibiotics, erythromycin was ubiquitous (0.7-5.6 MUg/kg) but its tissue concentrations were lower than levels of sulfamethoxazole, sulfathiazole and trimethoprim (0.9-5.5 MUg/kg), which are used in human medicine, aquaculture and livestock. Erythromycin bioaccumulation in fish is reported here from Argentina for the first time, though levels of antibiotics in edible muscles of these species were lower than the maximum residue limits for human consumption. We observed norfluoxetine, the primary active metabolite of the antidepressant fluoxetine, ranging from 1.1-9.1 MUg/kg in fish. We further identified benzoylecgonine, a primary metabolite of cocaine, in fish from both study systems, representing the first observation an illicit drug or associated metabolites bioaccumulation in aquatic life from Argentina. Interestingly, high pharmaceutical levels were observed in fish from the Acaragua river suggesting their transport into the protected area, from the surrounding lands. Though fish from the Parana river were sampled near WWTP discharges, pharmaceutical concentrations may have been reduced by hydrological and other environmental conditions, and biological differences among species. These findings, which observed bioaccumulation of select pharmaceuticals, their metabolites and illicit drugs in wild fish sampled inside a protected area, highlight the importance of developing an advanced understanding of urban influences on inland protected watersheds. PMID- 30308877 TI - The costs of delaying remediation on human, ecological, and eco-cultural resources: Considerations for the Department of Energy: A methodological framework. AB - Remediation and restoration of the Nation's nuclear legacy of radiological and chemical contaminated areas is an ongoing and costly challenge for the U.S. Department of Energy (DOE). For large sites, such as the Hanford and Savannah River Sites, successful remediation involves complex decisions related to remedies, end-states, timing, and sequencing of cleanup of separate and related contaminated units within a site. Hanford Site cannot clean up every unit simultaneously due to limits in funding, personnel, and technology. This paper addresses one of the major considerations - the consequences of delaying remediation of a unit on different receptors (e.g. people, ecological, and eco cultural resources), using the DOE Hanford Site as a case study. We develop a list of attributes that managers should consider for successful remediation, examine how delaying remediation could affect workers, the public and ecological resources (including water resources), and use some examples to illustrate potential effects of delays. The factors to consider when deciding whether and how long to delay remediation of a unit include personnel, information and data, funding, equipment, structural integrity, contaminant source, and resource vulnerability. Each of these factors affects receptors differently. Any remediation task may be dependent on other remediation projects, on the availability of transport, containers, interim storage and ultimate disposition decisions, or the availability of trained personnel. Delaying remediation may have consequences for people (e.g. workers, site neighbors), plants, animals, ecosystems, and eco-cultural resources (i.e. those cultural values that depend upon ecological resources). The risks, benefits, and uncertainties for evaluating the consequences of delaying remediation are described and discussed. Assessing the advantages and disadvantages of delaying remediation is important for health professionals, ecologists, resource trustees, regulators, Tribal members, recreationists, fishermen, hunters, conservationists, and a wide range of other stakeholders. PMID- 30308878 TI - Shade trees have higher impact on soil nutrient availability and food web in organic than conventional coffee agroforestry. AB - Conventional, intensively managed coffee plantations are currently facing environmental challenges. The use of shade trees and the organic management of coffee crops are welcome alternatives, aiming to reduce synthetic inputs and restore soil biological balance. However, little is known about the impacts of the different types of shade tree species on soil functioning and fauna. In this paper, we assess soil nutrient availability and food web structure on a 17-year old experimental coffee plantation in Turrialba in Costa Rica. Three shade types (unshaded coffee, shaded with Terminalia amazonia, and shaded with Erythrina poepiggiana) combined with two management practices (organic and conventional) were evaluated. Total C and N, inorganic N and Olsen P content, soil pH, global soil fertility, and nematode and microarthropod communities were measured in the top 10 cm soil layer, with the objective of determining how shade tree species impact the soil food web and soil C, N and P cycling under different types of management. We noted a decrease in soil inorganic N content and nematode density under conventional management (respectively -47% and -91% compared to organic management), which suggested an important biological imbalance, possibly caused by the lack of organic amendment. Under conventional management, soil nutrient availability and fauna densities were higher under shade, regardless of the shade tree species. Under organic management, only soils under E. poeppigiana, a heavily pruned, N2-fixing species, had increased nutrient availability and fauna density, while T. amazonia shade had a null or negative impact. The effects of coffee management and shade type on soil nutrient availability were mirrored by changes in soil food web structure. Higher fertility was recorded in soil with balanced food webs. These results emphasize the importance of the choice of shade tree species for soil functions in low input systems, more so than in fertilized systems. PMID- 30308879 TI - The biodegradative effect of Tenebrio molitor Linnaeus larvae on vulcanized SBR and tire crumb. AB - The overall world consumption rate of rubber tends to increase by an average of 2.8% per year in the period between 2017 and 2025. Rubber residues represent a severe problem to both health and environment due to their cross-linked structure that offers a prolonged degradation rate. A good solution to eliminate this problem is recycling and recovery, aiming at the production of new materials. The tire crumb can be recycled by chemical/biological recovery, where the elastomer is devulcanized, or by physical recovery, where the three-dimensional network is transformed into small fragments. In this study, we investigated the bio degradation effect caused by Mealworms (the larvae of Tenebrio molitor Linnaeus) on vulcanized SBR-rubber and tire crumb as a desulphurization method. The surface modifications of both rubbers were studied by instrumental techniques: FTIR-ATR, TGA, XRD, and SEM. The cross-linking degree of the rubber was determined via circular condensation method. The obtained results show that the Tenebrio molitor could survive after three weeks of direct contact with SBR-rubber and tire crumb as the only alimentation. There was a declining effect of cross-linking degree by increasing the contact time between the rubbers and larvae. The FTIR results indicate surface/chemical modifications of the rubbers and the SEM results show the free sulfur after it was released in the form of sulfur flower-like. Also, the TGA results highlight a difference in the degrading behavior and residues of the treated and non-treated rubbers. Therefore, the reported results were promising, demonstrating the biodegradation effect caused by the Tenebrio molitor mealworms, highlighting an alternative and natural mean of degrading vulcanized rubber residues. PMID- 30308880 TI - Monitoring of the 17 EU Watch List contaminants of emerging concern in the Ave and the Sousa Rivers. AB - The occurrence of micropollutants in the environment is a matter of high concern. Some regulations have been published in the last years and a Watch List of contaminants of emerging concern (CECs) for European Union monitoring of surface water was launched in the Decision 2015/495, including three estrogens (estrone, E1; 17-beta-estradiol, E2; and 17-alpha-ethinylestradiol, EE2), four pharmaceuticals (diclofenac and the macrolide antibiotics azithromycin, clarithromycin and erythromycin), an anti-oxidant (2,6-ditert-butyl-4 methylphenol, BHT), an UV filter (2-ethylhexyl 4-methoxycinnamate, EHMC), some pesticides (methiocarb and the neonicotinoids imidacloprid, thiacloprid, thiamethoxam, clothianidin and acetamiprid) and two herbicides (oxadiazon and triallate). This study provides the first spatial and seasonal monitoring campaign in the Ave and the Sousa Rivers for the all set of the 17 Watch List CECs (not reported yet for any country), in order to assess their occurrence, distribution, frequency and risk assessment. It also highlights the need of extend the study to other regions and environmental matrices to investigate the occurrence and possible sources of contamination of CECs, aiming to give insights for decision makers to define mitigation strategies for a more sustainable water policy. PMID- 30308881 TI - Time, geography and weather provide insights into the ecological strategy of a migrant species. AB - Farmland and migratory bird populations are in decline. The Common quail (Coturnix coturnix) provides an exception to this trend and its populations have remained stable over the last two decades. However, some basic facts regarding quail biology and ecology, such as the geographic distribution of age and sex classes during the summer, remain poorly understood. We analyzed 43,194 Spanish quail ringing records from 1961 to 2014 to assess the effects of geography and weather conditions on the probability that individuals will be ringed during the various stages of their annual cycle (arrival -spring migration-, stationary breeding period, departure -autumn migration- and winter) for the different quail age-sex classes over time. We found that spatial distribution of the age and sex classes can be explained by date, latitude, longitude, altitude, rainfall, and temperature. Our results suggest that date accounts for most of the variation in the distribution of quail age classes, followed by the weather variables, and then latitude, and altitude. Similarly, date also accounts for most of the variation in the distribution of the two sexes. These results could partially explain why this species has avoided population decline, since its ecological strategy is based on its temporal and spatial distribution combined with the segregation of age and sex groups. We hypothesize that the distribution of quail age and sex classes follows variations in weather and habitat suitability to exploit seasonal and geographic variations in resource availability. The migratory and nomadic movements of quail, combined with the occurrence of multiple breeding attempts within a single season, may also allow these birds to overcome the impacts of predators and anthropogenic environmental change. Conservation and management efforts should therefore take account of these age and sex related temporal and spatial patterns. PMID- 30308882 TI - Recent rising temperatures drive younger and southern Korean pine growth decline. AB - The Earth has experienced an unequivocal warming, with the warmest period of the past 150 years occurring in the last three decades. Korean pine (Pinus koraiensis), a key tree species in northeast Asia, is predicted to be particularly vulnerable to climate change. Here, we use dendrochronological methods to test whether the observed growth decline of Korean pine in northeast China is related to climate warming and whether climate-growth responses varied with age. A total of 628 cores from 401 trees across 16 sites were sampled over the entire distribution area of Korean pine in China. Samples were divided into three age classes: younger (50-130 years), middle (131-210 years), and older trees (>210 years), and measured by the ring-width index and basal area increment (BAI). Results showed a significant decline in BAI in most sites coinciding with an increase of temperature in the growing season and a decrease in precipitation since the 1980s. Meanwhile, we found that temperature-induced growth decline was significantly related to tree age. The BAI of younger trees decreased significantly and sharply (0.44 cm2 year-1, P < 0.0001), while old trees either decreased slightly or stabilized (0.04 cm2 year-1, P = 0.33). Tree growth in the southernmost locations was more likely to decline, what was most likely a result of forest-stand age. The age-related growth decline induced by climate warming might be explained by tree species traits, differences in growth rates between age classes and their relation to stress, changes in root system, competition/stand structure or physiological mechanisms. Our results might also predict that early stand process-thinning is exacerbated by warming and drying. This research informs that the age effect of growth response to rising temperature should be considered in forest management under climate change, and particularly models of future carbon cycle patterns and forest dynamics. PMID- 30308883 TI - Effect of full-scale ozonation and pilot-scale granular activated carbon on the removal of biocides, antimycotics and antibiotics in a sewage treatment plant. AB - Several micropollutants show low removal efficiencies in conventional sewage treatment plants, and therefore enter the aquatic environment. To reduce the levels of micropollutants in sewage effluent, and thereby the effects on biota, a number of extra treatment steps are currently being evaluated. Two such techniques are ozonation and adsorption onto activated carbon. In this study, we investigated the efficiency of Sweden's first full-scale ozonation treatment plant at removing a number of antibiotics, antimycotics and biocides. The effect of adding granular activated carbon (GAC) on a pilot scale and pilot-scale ozonation were also evaluated. The conventional treatment (13,000 PE) with the add-on of full-scale ozonation (0.55 g O3/g Total organic carbon (TOC)) was able to remove most of the studied compounds (>90%), except for benzotriazoles and fluconazole (<50%). Adsorption on GAC on a pilot scale showed a higher removal efficiency than ozonation (>80% for all studied compounds). Three types of GAC were evaluated and shown to have different removal efficiencies. In particular, the GAC with the smallest particle sizes exhibited the highest removal efficiency. The results demonstrate that it is important to select an appropriate type of carbon to achieve the removal goal for specific target compounds. PMID- 30308884 TI - Effects of pharmaceuticals used to treat salmon lice on non-target species: Evidence from a systematic review. AB - Aquaculture is currently one of the best prospects to help meet the growing need for protein in the human diet. However, aquaculture development and production result in consequences for the environment and also impact other productive activities. Salmon and trout cage culture has required the use of large quantities of pharmaceuticals in order to control outbreaks and the persistence of different pathogens, including sea lice (parasitic copepods), which cause economic losses of around 0.39 ? Kg-1 of salmon produced. The pharmaceuticals currently used for the control of sea lice (cypermethrin, deltamethrin, azamethiphos, hydrogen peroxide) are applied by in situ immersion treatments, enclosing net pens using tarpaulin and then bathing fish with the pharmaceutical. After treatment the pharmaceuticals are released into the surrounding environment, exposing non-target species. Although the effects of such pharmaceutical exposure has been studied in some species, to date a systematic and exhaustive review of these potential effects has not yet been performed. In this study, an exhaustive review of the literature evaluating lethal and sub lethal effects of anti-sea lice pharmaceuticals on non-target crustaceans and bivalves was performed, in order to assess the extent of the effects, toxicity, variables affecting such toxicity and identify potential synergistic effects previously unexplored. Our results show clear negative effects at concentrations lower than those used in treatments against sea lice in all of the species studied. Likewise, this study demonstrates knowledge gaps that need to be addressed in order to improve our understanding of the effects of these pharmaceuticals on non-target species, ecosystems in general and other productive activities. PMID- 30308885 TI - Contamination of the guttation liquid of two common weeds with neonicotinoids from coated maize seeds planted in close proximity. AB - Neonicotinoid uptake by maize plants emerged from coated seeds and by two common weeds grown in close proximity to coated seeds has been studied. Uptake of thiamethoxam (TMX) and clothianidin (CLO) have been characterized via guttation liquid measurements. The creeping thistle (Cirsium arvense), a well-known maize weed, as well as red poppy or Flanders poppy (Papaver rhoeas) were chosen as model species. The results confirmed that cross-contamination may occur by uptake of the neonicotinoid AIs through soil from neighbouring plants that emerged from coated seeds. Although the levels of these neonicotinoids were substantially lower in the guttation liquid of the weeds than in that of maize plants emerged from coated seeds, the compounds were detected up to 36th day after planting of the maize seeds. The highest peak concentrations of TMX were around 150 and 21 mg L-1, while similar data for CLO were around 70 and 21 mg L-1 for maize and creeping thistle, respectively. Mostly due to its higher guttation intensity significantly lower values were determined for red poppy (0.740 mg L-1). PMID- 30308886 TI - Dynamics of emerging organic contaminant removal in conventional and intensified subsurface flow treatment wetlands. AB - Six pilot-scale treatment wetlands treating municipal wastewater were monitored for classical wastewater parameters and selected Emerging Organic Compounds (EOCs): caffeine (CAF), ibuprofen (IBU), naproxen (NPX), benzotriazole (BTZ), diclofenac (DCL), acesulfame (ACE) and carbamazepine (CBZ) on a weekly basis over the course of one year. Treatment efficacy of the wetland systems was compared to that of a municipal wastewater treatment plant adjacent to the research site (activated sludge technology). The aerated wetlands VAp and HAp, and the two stage vertical flow system VGp + VSp showed the highest treatment efficacy (>70% removal on a mass basis) and comparable treatment efficacy to the conventional WWTP for removal of CAF, IBU, NPX, BTZ, and DCL. Annual mass removal of ACE in the WWTP was 50% and varied in the wetlands (depending on system design) from zero to 62%. On a mean monthly basis, ACE removal in the treatment wetlands VGp + VSp, VAp, HAp, R was high (> 90%) for six months of the year. Monthly mean mass removal of CBZ was negligible for the WWTP and all treatment wetland systems except H50p, which showed up to 49% mass removal in June. Monthly mean mass removals of classical wastewater parameters and readily biodegradable EOCs (represented by CAF, IBU, NPX) were most stable in the intensified wetland designs VAp, HAp, and R. A statistical analysis confirms that system complexity, aerobic conditions, and temperature have the highest correlation to overall pollutant removal in the treatment wetland systems, including EOCs of high to moderate biodegradability. First-order removal rate coefficents and temperature correction factors for EOCs are reported for the first time in the treatment wetland literature. Limitations on the use of these values in engineering design are discussed. PMID- 30308887 TI - eDNA as a tool for identifying freshwater species in sustainable forestry: A critical review and potential future applications. AB - Environmental DNA (eDNA) is an emerging biological monitoring tool that can aid in assessing the effects of forestry and forest manufacturing activities on biota. Monitoring taxa across broad spatial and temporal scales is necessary to ensure forest management and forest manufacturing activities meet their environmental goals of maintaining biodiversity. Our objectives are to describe potential applications of eDNA across the wood products supply chain extending from regenerating forests, harvesting, and wood transport, to manufacturing facilities, and to review the current state of the science in this context. To meet our second objective, we summarize the taxa examined with targeted (PCR, qPCR or ddPCR) or metagenomic eDNA methods (eDNA metabarcoding), evaluate how estimated species richness compares between traditional field sampling and eDNA metabarcoding approaches, and compare the geographical representation of prior eDNA studies in freshwater ecosystems to global wood baskets. Potential applications of eDNA include evaluating the effects of forestry and forest manufacturing activities on aquatic biota, delineating fish-bearing versus non fish-bearing reaches, evaluating effectiveness of constructed road crossings for freshwater organism passage, and determining the presence of at-risk species. Studies using targeted eDNA approaches focused on fish, amphibians, and invertebrates, while metagenomic studies focused on fish, invertebrates, and microorganisms. Rare, threatened, or endangered species received the least attention in targeted eDNA research, but are arguably of greatest interest to sustainable forestry and forest manufacturing that seek to preserve freshwater biodiversity. Ultimately, using eDNA methods will enable forestry and forest manufacturing managers to have data-driven prioritization for conservation actions for all freshwater species. PMID- 30308888 TI - Impact of the particulate matter from wastewater discharge on the abundance of antibiotic resistance genes and facultative pathogenic bacteria in downstream river sediments. AB - Wastewater treatment plants (WWTPs) are point sources for both, the release of antibiotic resistance genes (ARGs) and the discharge of antibiotics (ABs) into the environment. While it is well established that ARGs emission by WWTPs leads to an ARGs increase in receiving rivers, also the role of sub-inhibitory AB concentrations in this context is being discussed. However, the results obtained in this study suggest that, at environmental concentrations, ABs do not have an effect on resistance selection. Instead, we emphasize the significance of ARG transport and, in that respect, highlight the relevance of wastewater particles and associated microorganisms. We can show that ARGs (ermB, blaTEM,tetM, qnrS) as well as facultative pathogenic bacteria (FPB) (enterococci, Pseudomonas aeruginosa, Acinetobacter baumannii) inside the particulate fraction of WWTP effluent are very likely to remain in the riverbed of the receiving water due to sedimentation. Moreover, ARG and FPB abundances measured in the particulate fraction strongly correlated with the delta ARG and FPB abundances measured in the receiving river sediment (downstream compared to upstream) (R2 = 0.93, p < 0.05). Apparently, the sheer amount of settleable ARGs and FPB from WWTP effluent is sufficient, to increase abundances in the receiving riverbed by 0.5 to 2 log units. PMID- 30308889 TI - Hydrological system behaviour of an alluvial aquifer under climate change. AB - In this paper, we present an assessment of the sensitivity of groundwater-surface water interactions to climate change in an alluvial aquifer, located in the Ljubljansko polje, Slovenia. The investigation is motivated by a recent assessment of climate change pressures on the water balance in the Sava River Basin (Gampe et al., 2016). The assessment was performed using a comprehensive hydrological modelling approach, which is based on the direct/indirect communication between FEFLOW and WaSiM/MIKE 11. This modelling framework provides a precise simulation of the critical processes in the study domain, which are the main drivers influencing the interactions between precipitation, river water and groundwater under different future climate scenarios. Climate projections were based on the results of the three regional climate models SMHI-RCA4, KNMI RACMO22E and CLMcom-CCLM4. The results show that there will be higher levels of local precipitation during 2036-2065, the projected river discharge will be larger in the future compared to 2000-2014, and it is unlikely that the Ljubljansko polje will suffer from water scarcity. In addition, amongst the various sections of the Sava River the section between Crnuce and Sentjakob is the one most sensitive to climate change. By running the models under different climate scenarios a deeper insight into aquifer system functioning was obtained. Investigating impacts of climate change on groundwater and interactions between surface water and groundwater on the local scale is a basis for applying such a study on the global scale, which was still not very well investigated. PMID- 30308890 TI - Effectiveness of zinc oxide-assisted photocatalysis for concerned constituents in reclaimed wastewater: 1,4-Dioxane, trihalomethanes, antibiotics, antibiotic resistant bacteria (ARB), and antibiotic resistance genes (ARGs). AB - Microbial and emerging chemical contaminants are unwanted constituents in reclaimed wastewater, due to the health concerns of using the water for agricultural irrigation, aquifer recharges, and potable water. Removal of these contaminants is required but it is currently challenging, given that there is no simple treatment technology to effectively remove the mixture of these contaminants. This study examined the effectiveness of ZnO-assisted photocatalytic degradation of several constituents, including 1,4-dioxane, trihalomethanes (THMs), triclosan (TCS), triclocarban (TCC), antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARGs), under low intensity of UV exposure. E. coli with an ARGs-carrying circular plasmid (pUC19) was used as a model antibiotic resistant bacterium. Our results show that commercial zinc oxide (C-ZnO) assisted photodegradation of 1,4-dioxane, and dehalogenation of THMs, TCS, and TCC, while tetrapodal zinc oxide (T-ZnO) enhanced the dehalogenation of TCS and TCC. Additionally, T-ZnO assisted the photocatalytic inactivation of the E. coli within 6 h and caused structural changes in the plasmid DNA (pUC19) with additional UV exposure, resulting in non-functional AGR-containing plasmids. These results also suggest that higher UV dose is required not only to inactivate ARB but also to damage ARGs in the ARB in order to decrease risks in promoting ARB population in the environment. Overall, our results implicated that, under low UV intensity, ZnO-assisted photocatalysis is a promising alternative to simultaneously remove biological and emerging chemical contaminants in treated wastewater for safe reuse. PMID- 30308891 TI - Monitoring hydrological drought using long-term satellite-based precipitation data. AB - Long-term (over 30a) satellite-based quantitative rainfall estimate (SRE) products provide an ideal data source for hydrological drought monitoring. This study mainly explores the suitability of the two long-term SREs, the Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks-Climate Data Record (PERSIANN-CDR) and the Climate Hazards Group (CHG) Infrared Precipitation with Stations (CHIRPS), for hydrological drought monitoring. A hydrological drought index called the standardized streamflow index (SSI) was used as an example and the Grid-based Xinanjiang (GXAJ) hydrological model was used for streamflow generation of the SREs. A middle size basin in the humid region of south China was selected as case study. The obtained results show that both SREs present acceptable performances for hydrological modeling, and CHIRPS outperformed PERSIANN-CDR. SSIs calculated by the SRE simulations generally fit well with the trend of observation-based on SSI but apparent deviations in drought intensity were also found. In contrast to hydrological modeling, performance of the SRE-based SSI showed almost no change after model recalibration. Both SREs generally present acceptable classification accuracy but tended to underestimate the levels of drought types. Both SREs accurately captured the beginning, end, and duration of this drought event; however, several deviations were found in severity and intensity estimation of the drought event. In general, both SREs are suitable for hydrological drought monitoring. Although the CHIRPS generally presented better performance, the PERSIANN-CDR is still adequate for hydrological drought monitoring. PMID- 30308892 TI - Cadmium accumulation capacity and resistance strategies of a cadmium hypertolerant fern - Microsorum fortunei. AB - Microsorum fortunei (M. fortunei), a close relative to the cadmium (Cd) hyperaccumulator Microsorum pteropus, is an epiphytic Polypodiaceae fern with strong antioxidant activity. The Cd-accumulation capacities and Cd-resistance mechanisms of M. fortunei were analyzed in this study by measuring metal contents (Cd, Fe, Mg, Ca, Zn, Mn, K and Na) and chlorophyll fluorescence parameters (Fv/Fm, qN, qP, Y(II), Y(NPQ) and Y(NO)) and by performing an RNA-sequencing analysis. M. fortunei could accumulate up to 2249.10 MUg/g DW Cd in roots under a 15-day 1000 MUmol/L Cd treatment, with little Cd translocated into the leaves (maximum 138.26 MUg/g DW). The M. fortunei leaves could maintain their normal physiological functions with no phytosynthesis damage and few changes in metal contents or differentially expressed genes. M. fortunei roots showed a decrease in Zn concentration, with potential Cd-tolerance mechanisms such as heavy metal transporters, vesicle trafficking and fusion proteins, antioxidant systems, and primary metabolites like plant hormones, revealed by differentially expressed functional genes. In conclusion, M. fortunei may serve as a potential cadmium hypertolerant fern that sequesters and detoxifies most cadmium in the roots, with a minimum root-to-shoot Cd translocation to guarantee the physiological functions in the more vulnerable leaves. PMID- 30308893 TI - Reflectance and imaging spectroscopy applied to detection of petroleum hydrocarbon pollution in bare soils. AB - Accidental releases of hazardous waste related to the extraction, refining, and transport of oil and gas are inevitable. Petroleum facilities and intrinsic pipelines present environmental pollution risks, threatening both human health and ecosystems. Research has been undertaken to enhance the conventional methods for monitoring hazardous waste problems and to improve time-consuming and cost effective ways for leak detection and remediation process. In this study, both diffuse and imaging (hyperspectral) reflectance spectroscopy are used for detection and characterization of petroleum hydrocarbon (PHC) contamination in latosols. Laboratory and field measurements of PHC-contaminated and PHC-free soils were collected from an oil facility using an ASD FieldSpec-3 high resolution portable spectrometer (2150 channels) covering visible, near infrared and shortwave infrared wavelengths (VNIR-SWIR: 350-2500 nm). The hyperspectral image dataset was acquired with the ProSpecTIR-VS airborne sensor using 357 channels in the VNIR-SWIR range at 1 m of spatial resolution. Narrow intervals of reflectance spectra were analyzed to identify the primary mineral and PHC absorption bands in soil samples and to investigate the spectral match with airborne hyperspectral data. The Multiple Endmember Spectral Mixture Analysis (MESMA) method was employed in three hierarchical levels to classify the hyperspectral imagery. The classification product yielded from MESMA model at the fourth level was 98% accurate in discriminating contaminated soils. The results demonstrated the applicability of both diffuse reflectance and imaging (hyperspectral) spectroscopy to identify bare soils contaminated by PHC leaks and spills. These technologies can also provide useful information for remediation initiatives, thereby avoiding further problems with hazardous waste. PMID- 30308894 TI - Potentially toxic elements in saltmarsh sediments and common reed (Phragmites australis) of Burullus coastal lagoon at North Nile Delta, Egypt: A survey and risk assessment. AB - Burullus lagoon is the second largest lake in Egypt. However, there has never been a comprehensive survey which studied nineteen potentially toxic elements in sediments and plants and evaluated the associated potential risk. Thus, we aimed to study the total and potentially available content of As, Al, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Sb, Se, Sn, Tl, V, and Zn in the sediments and common reed (Phragmites australis) at thirty two sites along the entire lagoon and connected drains. Contamination Factor (CF), Pollution Load Index (PLI), Geo-accumulation Index (Igeo), and Enrichment Factor (EF) were calculated to assess the grade of contamination. Element accumulation factor (AF) and bio-concentration ratio (BCR) were also calculated. Aluminum showed the highest median (mg kg-1) total content (41,200), followed by Fe (30,300), Mn (704.7), V (82.0), Zn (75.5), Cr (51.2), Cu (47.8), Ni (44.3), As (31.9), Tl (24.6), Co (21.4), Se (20.3), Sb (17.6), Sn (15.6), Mo (11.3), and Hg (16.6 MUg kg-1). Values of the EF, CF, and Igeo showed that the sediments were heavily contaminated with As, Sb, Se, Tl, Mo, Sn, Co, Ni, and Cu. The drained sediment had significantly higher values of total and potentially available element content than the lagoon sediments. Sediments of the middle and western area showed significantly higher contents of total and available elements than the eastern section. The BCR and AF values indicate that the studied plant is efficient in taking up high amounts of Zn, Fe, As, Sn, Tl, Ni, Mo, Mn; then Co, Cu, and V. The results exhibit a dramatic contamination at certain sites of the lagoon, and the studied PTEs have a predominant role in contamination-related ecological risk. Further investigations concerning redox induced mobilization of PTEs in sediments, the risk of fish contamination and the potential health hazards are highly recommended. PMID- 30308895 TI - Karst rocky desertification progress: Soil calcium as a possible driving force. AB - Karst rocky desertification is a severe irreversible ecosystem failure. The karst ecosystem is so fragile that it is vulnerable to environmental changes, degrading into rocky desertification. Prior studies revealed the potential connections between the soil bacterial community, the edaphic properties and the aboveground vegetation cover in the karst ecosystem. However, how these three elements affect each other and work together in propelling in the karst rocky desertification progress largely remains unexplored. To answer this question, we monitored the bacterial community variations in soils sampled from multiple sites at a successional karst rocky desertification region by sequencing the 16S rRNA V3-V4 regions. Overall, we detected 34 bacterial phyla in the karst soils, of which Proteobacteria, Actinobacteria, and Acidobacteria are the most abundant. Network analysis of the bacterial community- vegetation-edaphic property-vegetation interactions identified 6 bacterial herds that had significant correlation with soil Ca2+ and available phosphorus change during vegetation degradation. Further functional simulation of these bacterial herds unveiled the change of Ca2+ and available phosphorus might disturb the soil carbon and nitrogen metabolism, and thus weakened soil quality. In summary, we hypothesized a calcium-driven bacterial response mechanism in the karst rocky desertification progress. PMID- 30308896 TI - Spectroscopic insights into photochemical transformation of effluent organic matter from biological wastewater treatment plants. AB - The photodegradation of discharged effluent organic matter (EfOM) changes its composition and shifts its impacts on pollutant migration and transformation in receiving waters. However, to date, EfOM photodegradation processes are not well understood due to the complexity and heterogeneity of EfOM. Herein, the spectroscopic analysis including ultra violet-visible (UV-Vis), fluorescence and FTIR spectroscopies coupled with two-dimensional correlation analysis (2D-COS) were used to draw a comprehensive view of EfOM photodegradation and involving mechanisms. Results revealed that the photolability of each component in EfOM followed the order: tannin-like > humic-like > protein-like > carbohydrate-like and aliphatic compounds. The photolability of different components of EfOM were found to be related to the photolability of their functional groups. Specifically, the aromatic, carboxylic, phenolic and quinonoid groups associated with humic or tannin-like compounds were more prone to be photodegraded than amides in proteins or C-OH and C-O-C in carbohydrates. Furthermore, the humic like components, dominating the light absorption of EfOM, were found to be degraded by direct photolysis. Nevertheless, the photodegradation of tannin-like and protein-like components were mainly due to the indirect photodegradation by ROS and 3OM*. Furthermore, results indicated that UV light, rather than visible light, was responsible for the photodegradation of EfOM. The spectroscopic techniques integrated with 2D-COS analysis could serve as a powerful tool with which to clarify complex EfOM photodegradation process as well as to improve our understanding of the fate of discharged EfOM and related environmental processes. PMID- 30308897 TI - Mass balance-based inventory of heavy metals inputs to and outputs from agricultural soils in Zhejiang Province, China. AB - It is important to understand the status and extent of soil contamination with heavy metals to make sustainable management strategies for agricultural soils. Input and output inventory of heavy metals in agricultural soil of Zhejiang Province was systematically studied. The results showed that atmospheric deposition was responsible for 47.88% and 76.87% of the total Cr and Pb inputs, respectively. Livestock manures accounted for approximately 54-85% of the total As, Cu, and Zn inputs. Livestock manure and irrigation were the main sources of Hg, contributed 50.25% and 38.63% of the total inputs, respectively. Ni was derived mainly from atmospheric deposition (57.86%), followed by irrigation (22.69%). As for Cd, the relative contributions of atmospheric deposition, irrigation, and livestock manure were similar. Crop harvesting and leaching were found to be the dominant output pathways of the soil elements Cd, Cu, Hg, and Zn, being responsible for 74.43-83.62% of the total outputs. Surface runoff was the dominant output pathway for As, Cr, Ni, and Pb, accounting for approximately 73.36%, 46.32%, 54.16%, and 48.11% of the total outputs, respectively. According to prediction and early warning, Cd is the priority control pollutant in agricultural soil. This work will assist in developing strategies for reducing heavy metal inputs to agricultural soil and effectively targeting policies to protect soil environment from long-term heavy metal accumulation. PMID- 30308899 TI - A global meta-analysis of the economic values of provisioning and cultural ecosystem services. AB - Despite a growing demand to integrate ecosystem services into sustainability decision-making, our understanding of the global distribution of the economic value of ES is scarce. We extracted information from provisioning and cultural ecosystem services (PCES) from The Economics of Ecosystems and Biodiversity (TEEB) database using a meta-analytical approach. We then employed geostatistical methods to analyze the relationship between economic values and environmental and socio-economic predictors. Here we show that anthropogenic related factors such as accessibility, spatially explicit gross domestic product and ecosystem services scarcity explain global trends of PCES economic values. We observe higher PCES values in agricultural areas of strong human presence such as the British Isles, Southwest of Brazil and India and lower values in less disturbed natural areas. These findings highlight the decisive role that human systems play in the economic realization of PCES and caution that single-criterion sustainability and conservation policies aimed at maximizing the economic returns of PCES may not overlap with wild nature. PMID- 30308898 TI - Hydrochemical properties and chemocline of the Sansha Yongle Blue Hole in the South China Sea. AB - Blue holes can provide valuable information regarding paleoclimate, climate change, karst processes, marine ecology, and carbonate geochemistry. The Sansha Yongle Blue Hole, located on Yongle Atoll in the Paracel Islands in the South China Sea, is the deepest blue hole in the world. A comprehensive investigation of the blue hole was conducted to determine the hydrochemical properties and associated redox processes active in the water column. Results indicate the presence of two thermoclines, one at 13-20 m and a second at 70-150 m, dividing the water column into five stratified water layers. Based on redox state, the water column can be divided into three layers: an oxic layer in the top 70 m, a chemocline at 70-100 m, which acts as a redox boundary, and an anoxic deep layer. In the oxic layer, photosynthesis in the oxic layer above the seasonal thermocline, results in nutrient uptake, transformation of inorganic carbon to organic carbon in the top mixed layer above the seasonal thermocline; Below the seasonal thermocline, organic matter degradation and nitrification, which are the main biological process at depths around 30 m and 50-70 m, lead to the accumulation of nitrate and a decrease in dissolved oxygen and pH; whereas photosynthesis is dominant at depths of 30-50 m, leading to increase in dissolved oxygen and pH. Within the chemocline, organic matter decays via a variety of reactions (e.g. aerobic mineralization, denitrification and anammox), leading to sharp decreases in the oxidizing chemical species (e.g., dissolved oxygen and nitrate) and corresponding increases in the reduced species (e.g., ammonium and sulfide). Within this layer, about 60% of the nitrogen is lost and chemoautotrophic/photoautotrophic production may contribute significantly to particulate organic carbon. Within the deep anoxic layer, sulfate reduction and degradation of organic matter result in accumulations of sulfide, dissolved inorganic carbon, and nutrients. PMID- 30308900 TI - Management-induced greenhouse gases emission mitigation in global rice production. AB - Mitigating greenhouse gases (GHGs) emissions from rice paddy (Oryza sativa L.) and balancing the trade-offs between reducing emission and sustaining food security have raised global concerns. A global meta-analysis of rice experimental data was conducted to assess changes in emissions of GHGs (CH4 and N2O) and global warming potential (GWP) in response to improvements through 12 field management practices. The results indicated that changes in GWP were mainly attributed to CH4 emission even though N2O emission was significantly affected by conversion of field management practices. Specifically, GWP per unit rice plant area (area-scaled) was significantly increased by 20.1%, 66.2%, and 84.5% with nitrogen (N) fertilizer input, manuring, and residue retention (P < 0.05), along with significant increments in area-scaled CH4 emission under the above management practices by 8.9%, 60.4%, and 91.8%, respectively (P < 0.05). Due to the significant increase in rice yield, a decreasing trend for GWP per unit rice yield (yield-scaled) was observed with N fertilizer input. In addition, CH4 and GWP decreased significantly at both area- and yield-scale under non-flooding irrigation but with a reduction in rice yield by 3.3% (P < 0.05). Improvement in rice variety significantly enhanced crop yield by 15.3% while reducing area scaled GWP by 27.7% (P < 0.05). Furthermore, other management practices, such as application of herbicides, biochar, and amendments (non-fertilizer materials) reduced yield-scaled GWP while increasing rice yield. Thus, changes in field management practices have the potential to balance the trade-offs between high yield and low emission of GHGs. However, in-depth studies are needed to determine the interactions between field management practices and site-specific soil/climate conditions. PMID- 30308901 TI - pH dependent of the waste activated sludge reduction by short-time aerobic digestion (STAD) process. AB - The short-time aerobic digestion (STAD) process has been found to be a unique and significant technique for the stabilization of waste activated sludge (WAS), but the influences of the system pH on the STAD process was unclear. This study systematically disclosed the influences of the system pH on the STAD process of WAS. Under neutral or weak alkaline conditions, although the biodegradation rates of VSS (~0.0085 h-1) were low, high biodegradation rates of TCOD (kTCOD) (~0.0096 h-1) were achieved. Less releases of the biopolymers from the WAS led to low concentrations of STOC, UV254, the low MW organic matters, NH4+ - N and PO43- - P in the supernatant. However, the appropriate pH for the microorganisms improved SOUR, indicating that the released substances were further reused or biodegraded by the microorganisms. Under acidic or alkaline conditions, the biodegradation rates of VSS (0.009-0.019 h-1) and TCOD (kTCOD) (0.005-0.009 h-1) were opposite with those under neutral or weak alkaline conditions. The releases of the biopolymers were increased, leading to high concentrations of STOC, UV254, the low MW organic matters, PO43- - P and NH4+ - N in the supernatant. However, the extreme pH inhibited the microbial activity. The SOURs were only 0.0097 h-1 and 0.0053 h-1 for system pH of 8.0 and 4.0, respectively. Accordingly, neutral and weak alkaline conditions should be more suitable for the STAD process of WAS. This work lays the foundation for optimizing system pH for the reduction of WAS in STAD system. PMID- 30308902 TI - Vehicular contribution of PAHs in size dependent road dust: A source apportionment by PCA-MLR, PMF, and Unmix receptor models. AB - This study focuses on the source apportionments of polycyclic aromatic hydrocarbons (PAHs) in road dust (RD) with four size fractions through three receptor models of principal component analysis with multiple linear regression (PCA-MLR), positive matrix factorization (PMF) and Unmix. The concentrations of total PAHs range from 0.45 to 2.03MUgg-1. Results show that the concentrations of PAHs increased with a decreasing size fraction. Similar potential sources to PAHs in RD were extracted by three models with a little difference in numbers and percent load contributions of each identified sources. The overall proportion of the identified sources were ranked as vehicular emission>coke oven>surface pavement>others in each size fractions. In terms of risk assessment, the mean values of incremental lifetime cancer risk (ILCR) of the total cancer risk of PAHs in RD were lower than the baseline value of an acceptable risk. However, PAHs in smaller size fraction prone to have a higher adverse effect on children via ingestion. Furthermore, the ecological risk assessment of hazard quotients and mean hazard quotients indicated that PAHs in RD had a 9% probability of being toxic to the benthic organisms and aquatic environment. PMID- 30308903 TI - Surface movement and cascade processes on debris cones in temperate high mountain (Picos de Europa, northern Spain). AB - Debris talus is a very common landform in the temperate high mountain, so much so that it is the most representative of the periglacial and nival processes. This work studies debris cones in the Picos de Europa, an Atlantic mountain range in the north of the Iberian Peninsula. A detailed geomorphological map was prepared, fieldwork was carried out on the debris cone surface, the ground and air thermal regime was analyzed, and a five-year Terrestrial Laser Scan survey carried out. Annual volume changes on the surface of the debris cones were detected and related to active processes and sediment transfer. Two different behaviors were observed in each cone. Cone A is linear, with equilibrium between accumulation and sediment transfer, while Cone B is concave-convex denoting accumulation processes in the upper part deriving from the greater frequency of snow avalanches. Changes in morphology surpass 50 cm/year with most of the activity taking place in the highest and lowest areas. The presence and action of the ice on the debris slope are moderate or non-existent and freeze-thaw processes are only active on the walls at over 2000 m a.s.l. The main processes on debris cones are debris flow and creep related to snowcover, but sediment transfer on the slopes involves high intensity-low frequency (debris flow, avalanches) and high frequency-low intensity processes (creep, shift, solifluction and wasting). PMID- 30308904 TI - Spatiotemporal impact of soil moisture on air temperature across the Tibet Plateau. AB - The Himalayan Tibet Plateau (HTP) is regarded as the third pole of the globe and is highly sensitive to global climate change. The hydrothermal properties of HTP greatly impacts the water cycle of the HTP and climate change in its surrounding regions. Using the NCEP-CFSR dataset, this study investigated the spatiotemporal pattern of soil moisture (SM) during different seasons considering vegetation types. The response of the evaporation fraction (EF) to SM and the impact of SM on air temperature through evapotranspiration were analyzed. Results showed that the spatial distribution of SM across the HTP was persistent during different seasons. A decreasing SM trend was observed from southeastern to northwestern HTP. Further, results of this study indicated a wetting tendency in past thirty years, espcially in desert region. In addition, the majority of the HTP regions were dominated by persistent transitional SM conditions which could be identified in the Himalayas and the southeastern HTP, whereas a persistent SM deficit in the Qaidam basin. The sensitivity of temperature response to EF was the strongest during spring and summer. Moreover, the spatial distribution of sensitivity was highly consistent with the vegetation regionalization, indicating the remarkable impact of vegetation type on the sensitivity of temperature to EF changes in summer. PMID- 30308905 TI - Microbial recycling cells (MRCs): A new platform of microbial electrochemical technologies based on biocompatible materials, aimed at cycling carbon and nutrients in agro-food systems. AB - This article reviews the mechanisms that drive nutrients and carbon sequestration from wastewaters by microbial electrochemical technologies (METs). In this framework, a new generation of METs is also presented (to be called microbial recycling cells, MRCs), based on 100%-recyclable materials (biomass-derived char coal, clay, terracotta, paper, ligno-cellulosic plant materials, etc.), which can act as bio-electrodes, separators and structural frames. In traditional METs architectures (based on technological materials such as carbon cloths, plastic panels, membranes, binders), inorganic salts precipitation and adsorption, as well as biofouling due to organic-matter deposition, are considered as main drawbacks that clog and hinder the systems over relatively short periods. In MRCs, these mechanisms should be maximized, instead of being avoided. In this perspective, both inorganic and organic forms of the main nutrients are sequestered from wastewater and deposited on METs modules. Once the systems become saturated, they can entirely be recycled as agricultural soil conditioners or as base for organic-mineral fertilizers. PMID- 30308906 TI - CFD modelling of air quality in Pamplona City (Spain): Assessment, stations spatial representativeness and health impacts valuation. AB - A methodology based on CFD-RANS simulations (WA CFD-RANS, Weighted Averaged Computational Fluid Dynamic-Reynolds-Averaged Navier-Stokes simulations) which includes appropriate modifications, has been applied to compute the annual, seasonal, and hourly average concentration of NO2 and NOX throughout the city of Pamplona (Spain) at pedestrian level during 2016. The results have been evaluated using measurements provided both by the city's network of air quality monitoring stations and by a network of mobile microsensors carried around by cyclists during their daily commutes, obtaining a maximum relative error lower than 30% when computing NO2 annual average concentrations. The model has taken into account the actual city layout in three dimensions, as well as the traffic emissions. The resulting air pollution maps provided information critical for studying the traffic-related health effects of NO2 and their associated external costs in the city of Pamplona and the spatial representativeness of the current network of air quality monitoring stations (it has not been carried out for an entire city to date). The developed methodology can be applied to similar cities, providing useful information for the decision-makers. PMID- 30308907 TI - Seagrass soil archives reveal centennial-scale metal smelter contamination while acting as natural filters. AB - The upper Spencer Gulf in South Australia hosts the world's largest single stream Pb-Zn smelter, which has caused environmental and health issues related to elevated metal concentrations in the surrounding environment. The area also has extensive seagrass meadows, occupying >4000 km2. We reconstructed the fluxes of heavy metals over the last ~3000 years through a multi-parameter study of the soil archives formed by the seagrass Posidonia australis. Pb, Zn and Cd concentrations increased up to 9-fold following the onset of smelter operations in the 1880s, and the stable Pb isotopic signatures confirmed the smelter has been the main source of lead pollution in the seagrass soils until present. Preliminary estimates suggest that over the past 15 years seagrass meadows within 70 km2 of the smelter accumulated ~7-15% of the smelter emissions in their soils. Here we demonstrate that seagrass meadows act as pollution filters and sinks while their soils provide a record of environmental conditions, allowing baseline conditions to be identified and revealing the time-course of environmental change. PMID- 30308908 TI - Impact of adsorbed nitrate on the heterogeneous conversion of SO2 on alpha-Fe2O3 in the absence and presence of simulated solar irradiation. AB - Adsorbed nitrate is ubiquitous in the atmosphere, and it can undergo photolysis to produce oxidizing active radicals. Nitrate photolysis may be coupled with the oxidation conversions of atmospheric gaseous pollutants. However, the processes involved remain poorly understood. In this study, the impact of adsorbed nitrate on the heterogeneous oxidation of SO2 on alpha-Fe2O3 was investigated in the absence and presence of simulated solar irradiation by using in situ Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS). The results indicate that for alpha-Fe2O3 particles with no adsorbed nitrate, the formation of adsorbed sulfate on humid particles is stronger than that on dry particles. Meanwhile, light can also promote the heterogeneous conversion of SO2 and the formation of sulfate on dry particles because alpha-Fe2O3 is a typical photocatalyst. However, the heterogeneous conversion of SO2 on humid alpha-Fe2O3 particles is somewhat suppressed under light, suggesting the occurrence of photoinduced reductive dissolution. For the heterogeneous conversion of SO2 on alpha-Fe2O3 particles with adsorbed nitrate, the formation of sulfate on humid particles is still higher than that on dry particles. For the dry alpha-Fe2O3 particles with adsorbed nitrate, light promotes the formation of adsorbed sulfate. For the humid alpha-Fe2O3 particles with adsorbed nitrate, the heterogeneous conversion of SO2 under light is stronger than that under no light, indicating that the photolysis of adsorbed nitrate is coupled with the oxidation of SO2 and the formation of sulfate. The consumption of adsorbed nitrate and the formation of adsorbed N2O4 are observed during the introduction of SO2. A possible mechanism for the impact of adsorbed nitrate on the heterogeneous conversion of SO2 on alpha-Fe2O3 particles is proposed, and atmospheric implications based on these results are discussed. PMID- 30308909 TI - Impacts of biochar application rates and particle sizes on runoff and soil loss in small cultivated loess plots under simulated rainfall. AB - Increasing literature suggests that biochar can be used to improve soil fertility and subsequently benefit crop yield. However, the effects of biochar application rates and particle sizes on soil erosion processes have yet to be fully identified. The objective of the present study was to evaluate the influence of biochar with different application rates and particle sizes on soil erosion. Addition of biochar to loess generally increased the mean time to runoff by 19.47% relative to the control. The time to runoff decreased with an increase in the biochar application rates and fluctuated with a decrease in biochar particle sizes. The combined 1% and <0.25 mm biochar treatment yielded the longest time to runoff (2.97 min) and the lowest runoff (36.23 kg m-2 h-1) and soil loss (1.33 kg m-2 min-1). Biochar addition decreased the total runoff volume by 12.21% and generally inhibited soil loss under lower application rates (1% and 3%) while promoting soil loss under higher application rates (5% and 7%). With a decrease in biochar particle size, total runoff volume increased under the 5% and 7% biochar, but no uniform trend was observed under the 1% and 3% biochar treatments. The total soil loss increased with increasing biochar application rates, whereas a negative trend was observed with decreasing biochar particle sizes. The contribution of biochar application rates to runoff and soil loss rates was distinctly greater than the biochar particle sizes. Additionally, biochar addition could increase >2 mm water-stable soil aggregates and saturated hydraulic conductivity (Ksat) in this study. We inferred that the positive effects on soil and water loss were potentially due to the improvement in >2 mm water-stable soil aggregates and Ksat. The results implied that soil-biochar additions could be a potential measure for conserving soil and water in the Loess Plateau. PMID- 30308910 TI - Macrolides induce severe cardiotoxicity and developmental toxicity in zebrafish embryos. AB - Macrolide antibiotics (MALs) are widely used for both human and animal health. Most MALs and their metabolites transfer into aquatic organisms and environment resulting in violent consequences. Previous studies show that MALs cause cardiotoxicity in humans and mammals. However, the potential risk of these chemicals in aquatic organisms remains unclear. Here, we used zebrafish embryos as a model to evaluate the toxicity of MALs. Zebrafish embryos were exposed to four typical MALs including azithromycin (AZM), clarithromycin (CLR), tilmicosin (TMS) and tylosin (TYL) to study their cardiotoxicity. The heart rate of zebrafish embryos showed similar biphasic distribution in the presence of four MALs at 2 days post-fertilization (dpf). The heart rate increased significantly at low levels of MALs while decreased obviously at high levels. Subsequently, TMS was chose to study its acute toxicity and developmental toxicity, which caused pericardial edema and spinal curvature in zebrafish embryos at 4 dpf. Furthermore, we found that TMS triggered oxidative stress, with decreased SOD activities and increased MDA contents. Lastly, apoptosis was observed in zebrafish embryos under TMS treatment, with up-regulation of apoptosis associated genes such as p53, bcl 2, bax, caspase 3 and caspase 9, confirmed by increased protein expression based on Western blot analysis. Taken together, these data indicate that MALs can cause serious toxicity in the development of zebrafish. Great caution should be taken due to the huge consumption of MALs for food animal production and treatments with TMS for infections in aquaculture. PMID- 30308911 TI - In vitro lung toxicity of indoor PM10 from a stove fueled with different biomasses. AB - Biomass combustion significantly contributes to indoor and outdoor air pollution and to the adverse health effects observed in the exposed populations. Besides, the contribution to toxicity of the particles derived from combustion of different biomass sources (pellet, wood, charcoal), as well as their biological mode of action, are still poorly understood. In the present study, we investigate the toxicological properties of PM10 particles emitted indoor from a stove fueled with different biomasses. PM10 was sampled by gravimetric methods and particles were chemically analyzed for Polycyclic Aromatic Hydrocarbons (PAHs) and elemental content. Human lung A549 cells were exposed for 24 h to 1-10 MUg/cm2 PM and different biological endpoints were evaluated to comparatively estimate the cytotoxic, genotoxic and pro-inflammatory effects of the different PMs. Pellet PM decreased cell viability, inducing necrosis, while charcoal and wood ones mainly induced apoptosis. Oxidative stress-related response and cytochrome P450 enzymes activation were observed after exposure to all the biomasses tested. Furthermore, after pellet exposure, DNA lesions and cell cycle arrest were also observed. The severe genotoxic and pro-necrotic effects observed after pellet exposure were likely the consequence of the high metal content. By administering the chelating agent TPEN, the genotoxic effects were indeed rescued. The higher content in PAHs measured in wood and charcoal PMs was likely the reason of the enhanced expression of metabolizing and oxidative stress-related enzymes, like CYP1B1 and HO-1, and the consequent increase in apoptotic cell death. These data suggest that combustion particles from different biomass sources may impact on lung cells according to different pathways, finally producing different toxicities. This is strictly related to the PM chemical composition, which reflects the quality of the combustion and the fuel in particular. Further studies are needed to clarify the role of particle dimension and the molecular mechanisms behind the harmful effects observed. PMID- 30308912 TI - Kinetic study of colored species formation during paracetamol removal from water in a semicontinuous ozonation contactor. AB - Paracetamol aqueous solutions, when ozonized, acquired a strong red coloration depending on the applied ozone dose and the initial pH of the aqueous solution. Then, this color loses intensity and turns to yellow. Color formation is favored when operating at initial pH0 = 12.0 and ozone flow-rate 4.2 mg/min. A mechanism describing color formation was proposed, being the main pathway involved an initial paracetamol hydroxylation to yield 3-hydroxyacetaminophen followed by the formation of 2-amino-5-hydroxyacetofenone. Then, these compounds are degraded to colored oxidation by-products. A model describing color evolution was also proposed, considering first-order kinetics for both color formation and degradation. The corresponding kinetic constant values were determined to be kf = 0.01 (1/min) and kd = 0.03 pH -0.055 (1/min), respectively. A relationship between aromaticity loss and color changes during the reaction has been estimated considering the parameter alpha=kA/kf, being alpha = 1.62 pH + 3.5 and the first order rate constant for aromaticity loss given by kA = 0.0162 pH + 0.035 (1/min). PMID- 30308913 TI - Effect of oil spill stress on fatty acid stable carbon isotope composition of Ulva pertusa. AB - Petroleum is one of the most important pollutants in the marine ecosystem, and oil spills have a long-term effect on the marine environment. After an oil spill, petroleum continues to diffuse, flowing to the intertidal zone where it accumulates. Ulva pertusa is the main macroalgae species in the intertidal zone of the ocean, and petroleum is toxic to marine macroalgae. Fatty acids, which are involved in various physiological activities, including metabolism, are indispensable substances in organisms. Thus, an organism's fatty acid composition reflects its physiological state. Because fatty acids are carbon-rich compounds, their stable carbon isotope composition can be measured to assess the state of the organism. In this study, the effects of the water accommodated fraction (WAF) of different concentrations of 180# fuel oil and 0# diesel oil on the chlorophyll a and fatty acid carbon stable isotope composition (delta13CFAs) of U. pertusa were assessed. The fatty acid carbon stable isotope value varied among the different petroleum treatments, and high WAF concentrations significantly inhibited the synthesis of unsaturated fatty acids. Thus, exposure to petroleum products affected the synthesis of fatty acids in U. pertusa and also caused carbon stable isotope fractionation during the fatty acid synthesis process. The results indicate that the saturated fatty acid delta13C16:0 and the unsaturated fatty acid delta13C18:1 can be used as biomarkers to evaluate the degree of petroleum-induced stress in U. pertusa and that carbon stable isotope analysis of U. pertusa can be used as an environmental risk assessment tool in the intertidal zone. PMID- 30308914 TI - A simple spatial typology for assessment of complex coastal ecosystem services across multiple scales. AB - This paper aims to present and demonstrate the applicability of a methodology to characterise supply and demand for ecosystem services (ES) on the basis of spatial properties and interdependence, and economic properties of ES. The typology is demonstrated to support inclusion of ES flow in social-ecological systems management. Ria de Aveiro coastal lagoon, Portugal, is used as a showcase for the proposed spatial typology for ecosystem services assessment across multiple scales. To address the proposed objective a four-step methodology was developed: i) choice of the management area and definition of the boundaries of the system to be governed; ii) assessment and classification of ES produced or consumed within the management area, where supply or demand of an ES may be endogenous, exogenous or partially exogenous/endogenous; iii) mapping of production and consumption areas covering the major categories of ES (biotic and abiotic provisioning services, regulating and maintenance services, and cultural services) and major types of spatial relationships, which may be independent; interdependent, dependent or controlling; and iv) spatial characterisation of the ES production and benefits based on excludability and rivalness of ES. In Ria de Aveiro from the variety of ES and their spatial relationships we highlight interdependencies between the Lagoon and other locations outside the management area. This approach shows that the proposed methodology can support the understanding of these interrelationships and improve these connections by, identifying inherent transactions and key-actors. PMID- 30308915 TI - The crucial factors of soil fertility and rapeseed yield - A five year field trial with biochar addition in upland red soil, China. AB - Biochar has been used as an amendment to improve soil fertility and increase crop yield. However, the effects of biochar on soil properties and rapeseed yield in upland red soil have not been thoroughly investigated, and the factors crucial for rapeseed yield are not yet clear. A five-year field trial was conducted to investigate the effects the of biochar (biochar application rates of 0, 2.5, 5, 10, 20, 30, and 40 t ha-1, respectively) on soil physicochemical and microbial properties as well as rapeseed yield in upland red soil in Jiangxi Province, China. Results showed that biochar can significantly increase soil pH, available phosphorus, organic carbon, Ks, and water retention, however, the influences of biochar on these indexes declined over time. Soil total nitrogen increased significantly when the dose of biochar exceeded 5 t ha-1, and the content of total nitrogen in the 40 t ha-1 biochar treatment increased each year. While the application of biochar gradually increased the contents of NH4+-N, NO3--N and enhanced the soil microorganism and enzymatic activities during the first three years, they had returned nearly to their starting values by the end of this study. Rapeseed yield and yield components were significantly improved relative to the control for all biochar amendments in the first year, but the rapeseed yield in all biochar treatments decreased steadily after 2012. According to the principal components analysis and path analysis, the most responsive parameters in the upland red soil were soil acidity and hydraulic properties, meanwhile, soil acidity and hydraulic properties had greater impacts on rapeseed yield than did other indexes. Taken together, these results suggest that biochar can significantly improve soil fertility and rapeseed yield, but the improvements are not permanent. Soil acidity and hydraulic properties were the crucial factors that determined soil fertility and rapeseed yield in upland red soil. PMID- 30308916 TI - Ecosystem damage from anthropogenic seabed disturbance: A life cycle impact assessment characterisation model. AB - Despite the high amount of pressure placed on benthic habitats by anthropogenic activities, particularly in coastal shelf areas, as yet, the impact of seabed damaging activities on ecosystem quality has not been included in Life Cycle Assessment (LCA). We present a globally applicable impact characterisation approach, parameterized within 17 marine ecoregions in Europe. Our modelling approach includes two perspectives: the single-impact perspective and the repeated-impact perspective. The approach for the single-impact perspective is a function of the spatio-temporal scale and intensity of the anthropogenic disturbance, the initial benthic response, and an estimated ecological recovery period. The approach for the repeated-impact perspective additionally accounts for the industry-specific interval between disturbance events, allowing for consideration of potentially incomplete ecological recovery between disturbance events and therefore the potential for both recoverable and non-recoverable potential impacts. We exemplify the repeated-impact perspective for the benthic trawl fishing industry in Europe. Analogous to current approaches for characterizing land use impacts in LCA, we quantify characterisation factors (CFs) for both occupation and transformation impacts. CFs for occupation impacts are ecoregion-specific. CFs for transformation impacts are spatially differentiated at the resolution of seabed substrate type, categories of hydrodynamic energy, i.e. water movement due to the influence of waves and currents, fisheries management zone (repeated-impact perspective only) and marine ecoregion. We estimate ecological recovery times with consideration of the influence of seabed substrate type, hydrodynamic energy at the seabed and the stock of potential recolonizers. The characterisation factors allow for quantifying indicators of ecosystem damage from seabed disturbance in terms of a time-integrated relative species loss. With a single-impact perspective, the largest impact intensities are found in areas with the longest estimated ecological recovery time. In the repeated-impact perspective, the largest intensity of time-integrated non-recoverable impact occurs when the disturbance interval is equal to half the ecological recovery time. PMID- 30308917 TI - The microbiome and antibiotic resistance in integrated fishfarm water: Implications of environmental public health. AB - Aquaculture, the production of farm-raised fish, is a major industry that employs and feeds millions of individuals across the globe, but which may also be a nexus of emerging public health threats. This study examined potential health risks associated with integrated aquaculture operations by with One Health approach using a suite of tools to study water contamination sources, pathogens, antibiotic resistant bacteria, and bacterial community in the water from fishponds. Water samples from 27 fishponds across 9 villages were collected in Jiangmen City, China. Microbial source tracking, pathogens (including Salmonella and Arcobacter), toxin-producing Microcystis, and antibiotic resistant bacteria (ARB) resistant to tetracycline, sulfonamide, and carbapenem were quantified with qPCR. Bacterial community was determined with next-generation sequencing. All ponds exceeded E. coli single-day maximum criteria of US, and 67% ponds exceeded World Health Organization (WHO) waste-fed aquaculture guidelines for protecting consumers and pond workers, representing a high degree of fecal contamination and potential pathogen risks in these ponds. The majority of the ponds were positive for human- (84%) and pig- (41%) associated fecal contamination. Salmonella and microcystin-producing Microcystis were detected in 37% and 15% of the ponds, respectively, while Arcobacter was not detected in any ponds. ARB were highly prevalent. Among the measured factors, canonical correspondence analysis and network analysis demonstrated that secchi depth, temperature and conductivity were the major environmental elements impacting the bacterial community structure, while Proteobacteria and Actinobacteria were the major biological factor. This study demonstrated the presence of intersecting health risk factors in aquaculture facilities and can lay the foundation for addressing these risks in aquaculture management in rural China, with potential applicability in other developing regions dependent on aquaculture. PMID- 30308918 TI - Reforestation of agricultural land in the tropics: The relative contribution of soil, living biomass and debris pools to carbon sequestration. AB - Tropical regions of the world experience high rates of land-use change and this has a major influence on terrestrial carbon (C) pools and the global C cycle. We assessed land-use change from agriculture to reforested plantings (with endemic species), up to 33 years of age, using 10 paired sites in the wet tropics, Australia. We determined the impacts on 0-50 cm below-ground C (soil organic C (SOC), charcoal C, humic organic C, particulate organic C, resistant organic C), C stored in roots (fine and coarse), C stored in living above-ground biomass and debris C pools. Reforested areas accumulated ecosystem C at a rate of 7.4 Mg ha-1 yr-1. Reforestation plantings contained, on average, 2.3 times more ecosystem C than agricultural areas (102 Mg ha-1 and 233 Mg ha-1, respectively). Most of the C accumulation was in living above-ground and below-ground biomass (60 and 30%, respectively) with a smaller amount in debris pools (16%). Apart from C in roots, soil C accumulation was not obvious across sites ranging from 8 to 33 years since reforestation, relative to the agricultural baseline. Differences in SOC (and associated SOC pools) to a depth of 50 cm, did exist between reforested areas and adjacent agriculture at some sites, however there was not a consistent trend in SOC associated with reforestation. Local site-based factors (e.g. soil texture and mineralogy, land-use history and microbial activity) appear to have a strong influence on the direction of the change in SOC. While reforestation in the tropics has great potential to accumulate C in biomass in living vegetation, and debris pools, it is likely to take approximately 50 years before C stocks of reforested areas resemble natural ecosystems. Accumulation of SOC through reforestation is difficult to achieve, highlighting the need to conserve carbon pools in remnant forests in the tropics. PMID- 30308919 TI - Detection of coliphages and human adenoviruses in a subtropical estuarine lake. AB - Fecal indicator bacteria (FIB) have been used to assess fecal contamination in recreational water. However, enteric viruses have been shown to be more persistent in the environment and resistant to wastewater treatment than bacteria. Recently, U.S Environmental Protection Agency has proposed the use of coliphages as viral indicators to better protect against viral waterborne outbreaks. This study aimed to detect and determine correlation between coliphages (F-specific and somatic), fecal indicator bacteria (enterococci and fecal coliforms), and human enteric viruses (human adenovirus) in a subtropical brackish estuarine lake. Water samples were collected from 9 estuarine recreation sites on Lake Pontchartrain in southeast Louisiana. Water samples (n = 222, collected weekly) were analyzed for coliphages and fecal indicator bacteria using culture-based methods and large volume water samples (n = 54, collected monthly) were analyzed for human adenovirus using quantitative PCR. Somatic coliphage and F-specific coliphage were found in 93.7 and 65.2% of samples with geometric mean concentrations of 30 and 3 plaque forming units (PFU) per 100 mL, respectively. Enterococci, fecal coliforms, and adenovirus were found in all samples with geometric mean concentrations of 27 most probable number (MPN), 77 MPN, and 3.0 * 104 gene copies per 100 mL, respectively. Watersheds in suburban areas exhibited significantly higher concentrations of coliphages and fecal indicator bacteria, indicating potential fecal contamination from septic systems. There was no significant correlation (p > 0.05) observed between the presence of adenoviruses and fecal indicator bacteria and coliphages. The presence of human adenovirus in Lake Pontchartrain poses a significant public health problem for both recreational use and seafood harvesting as it increases exposure risks. This study demonstrated the lack of relationship between fecal indicators and human viral pathogen in Lake Pontchartrain supporting an alternative microbial surveillance system such as direct pathogen detection. PMID- 30308920 TI - Profiling of individual naphthenic acids at a composite tailings reclamation fen by comprehensive two-dimensional gas chromatography-mass spectrometry. AB - Naphthenic acids (NAs) are naturally occurring in the Athabasca oil sands region (AOSR) and accumulate in tailings as a result of water-based extraction processes. NAs exist as a complex mixture, so the development of an analytical technique to characterize them has been an on-going challenge. The aim of this study was to use comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry to monitor individual NAs within a wetland reclamation site in the AOSR. Samples were collected from four monitoring wells at the site and the extracts were found to contain numerous resolved isomers of classical (monocyclic , bicyclic-, adamantane-, indane-, and tetralin-type carboxylic acids) and sulfur containing NAs (thiamonocyclic- and thiophene-type carboxylic acids). The absolute abundances of the monitored NAs were compared between four monitoring wells and unique profiles were observed at each well. Few significant changes in absolute abundances were observed over the sampling period, with the exception of one well (Well 6A). In addition, isomeric percent compositions were calculated for each set of structural isomers, and one-way analysis of variance (ANOVA) and two-dimensional hierarchical cluster analysis revealed high spatial variation at the site. However, consistent distributions were observed at each of the monitoring wells for some sets of NA isomers (such as: adamantane NAs), which may be useful for forensic applications, such as identifying sources of contamination or demonstrating biodegradation. The methods and results presented in this study demonstrate the utility of monitoring individual NAs, since both changes in absolute abundances of individual NAs and the distribution of NA isomers have the ability to provide insight into their sources and the processes controlling their concentrations that are not only of relevance to the Alberta Oil Sands, but also to other petroleum deposits and environmental systems. PMID- 30308921 TI - Nine phthalate metabolites in human urine for the comparison of health risk between population groups with different water consumptions. AB - Phthalates are a group of high production volume chemicals widely detected in environment matrix and human specimens. Potential health risks due to the prevalence of their exposure through water consumption and the endocrine disrupting activities have become an important issue. This work aims to compare the distributions of phthalate levels and potential health risks caused by phthalate exposure among three groups of participants ingesting different types of water. Here, a method with good performance was applied for the analysis of nine common phthalate metabolites in 125 human urine samples collected from Wuhan women. Seven analytes (mono-ethyl, mono-benzyl, mono-n-butyl, mono-(2 ethylhexyl), mono-(2-ethyl-5-oxohexyl), mono-(2-ethyl-5-hydroxyhexyl), and mono (2-ethyl-5-carboxypentyl) phthalate) were detected in over 80% of the samples. By measuring urinary concentrations of phthalate monoesters, the exposure levels of respective parent phthalates, exposure patterns, the estimated daily intakes and accumulative risk assessments were investigated in three groups of participants consuming water from different sources (bottled water, filtered water and boiled tap water). The results showed that the exposure patterns of phthalates varied among the population groups with different water intakes, and the health risk was higher for people ingesting the boiled tap water than that of the groups consuming bottled water (purified water) and filtered water with filter cartridge containing activated carbon. PMID- 30308922 TI - Particle-phase concentrations and sources of legacy and novel flame retardants in outdoor and indoor environments across Spain. AB - Levels of particle-phase legacy polybrominated diphenyl ethers (PBDEs), and novel brominated and chlorinated flame retardants, such as decabromodiphenyl ethane (DBDPE) and Dechlorane Plus (DP), were measured in ambient outdoor air, indoor workplace air and indoor dust, in different locations across Spain. PBDE concentrations were generally higher in outdoor ambient air samples than in indoor air, ranging between 1.18 and 28.6 pg m-3, while DP was the main flame retardant (FR) in indoor air (2.90-42.6 pg m-3). A different behavior of legacy versus novel FRs was observed in all the environments and matrices considered, which seemed to indicate a progressive replacement of the former. Although the emission sources could not be fully identified, certain evidences suggested that high outdoor PBDE concentrations could be associated with old goods in landfills and recycling centers, while high indoor DP concentrations were linked to the presence of new electronic devices. A direct impact of land use on outdoor atmospheric DP concentrations was observed, with DP concentrations correlating with high density of buildings within a city. In addition, DP concentrations outdoors correlated with inorganic species with FR properties (e.g., Cr, Cu). Significant differences in the fraction of anti-DP to the total DP (Fanti ratio) were observed between indoor air (PM2.5) and dust (PM10), which could be related with: a) a dependence on particle size, suggesting a higher relative abundance of the anti-isomer in PM10 than in PM2.5, while similar concentrations were recorded for the syn-isomer; b) a higher deposition rate of the anti-isomer compared to the syn-isomer; and/or c) a more accentuated preferential degradation of the anti isomer linked to artificial light or other agents coexisting in the air. The detectable presence of all the FR families analyzed in indoor air and dust points to the importance of monitoring these compounds in order to minimize human exposure. PMID- 30308924 TI - Effect of PM2.5 on daily outpatient visits for respiratory diseases in Lanzhou, China. AB - The present study assessed the effect of short-term exposure to PM2.5 of daily outpatient visits for respiratory diseases. Electronic records of daily outpatient visits were collected from two large general hospitals in Lanzhou, China from 01 January 2007 to 31 December 2016. Daily air pollution data from the Lanzhou Environmental Monitoring Station and daily meteorological data from the Lanzhou Meteorological Bureau were collected in the same period. A distributed lag non-linear model, based on a gender and age groups, was applied to analyse the exposure-response relationship between the air pollutants, and the daily outpatient visits for respiratory diseases. From 2007 to 2016, the PM2.5 concentrations were associated with an increase in the daily outpatient visits for respiratory diseases in Lanzhou. In addition, a lag effect was observed and this effect was the strongest on day 1. For every 10 MUg/m3 increase in the PM2.5 concentration, the daily outpatient visits for respiratory diseases increased by 0.53% (95% CI: 0.22%-0.84%). People aged 18 years or younger were most sensitive to PM2.5, and the influence of PM2.5 was more significant for females than for males. The cumulative effect of the PM2.5 concentration for the number of outpatient visits was greater than its daily effect, and the cumulative effect peaked on day 12. From day 0 to day 14, every 10-MUg/m3 increase in the PM2.5 concentration had a statistically significant cumulative effect on the outpatient visits for respiratory diseases among individuals aged 18 years or younger (p < 0.05), reaching a maximum value on day 14 (PM2.5: RR = 1.0213, 95% CI: 1.0128 1.0299). PMID- 30308923 TI - Succession and interaction of surface and subsurface cyanobacterial blooms in oligotrophic/mesotrophic reservoirs: A case study in Miyun Reservoir. AB - Subsurface cyanobacterial blooms, are a significant source of odor problems in source water and have been recorded in many oligotrophic/mesotrophic drinking water reservoirs. In this study, we explored the key driving forces responsible for the succession between surface and subsurface cyanobacteria using ecological niche modelling based upon a case study in Miyun Reservoir, China. The results suggest a negative effect of water depth and surface light irradiance (I0) on subsurface Planktothrix sp. growth (p-values < 0.001), and a unimodal effect of surface water temperature (T0) with the optimum at 23 degrees C (p-value < 0.001). While the surface Microcystis spp. shows a strong positive relationship with temperature (T0; p-value < 0.001), and significant effects for the interaction between T0 and I0 (p- value < 0.01). In addition, we identified the extent and type of interaction between subsurface and surface cyanobacteria and conclude that the high irradiance surface water combined with sufficient nutrients at the pre-bloom stage are key factors responsible for the preferential growth of surface cyanobacteria, while the gradual decline of the surface cyanobacteria in post-bloom stage is associated with nutrient reduction. This decline and loss of surface populations enhanced underwater irradiance and thus promoted the growth and allowed for succession of subsurface cyanobacteria in deeper layers where the nutrient supply was still adequate. Based upon this, the growth potentials for the subsurface and surface cyanobacteria are different under different environmental conditions: the subsurface cyanobacteria have greater growth potential than surface cyanobacteria in shallow oligotrophic and deep eutrophic reservoirs during median light irrigation seasons. PMID- 30308925 TI - Associations of root-inhabiting fungi with herbaceous plant species of temperate forests in relation to soil chemical properties. AB - The overwhelming majority of research on fungal interactions with plants in the forest ecosystems of the temperate climate zone focuses on ectomycorrhizal associations and no studies so far have compared the occurrence of root inhabiting fungi in herbaceous plant species. We thus studied arbuscular mycorrhizal fungi (AMF) and fungal root endophyte colonization rates as well as AMF species richness and composition under 19 herbaceous plant species in temperate forests (southeast Poland) in relation to soil chemical properties. Seventeen species formed arbuscular mycorrhiza (AM), while 2 were non mycorrhizal. The intensity of AMF colonization varied between species. Relative mycorrhizal root length (MAMF%) ranged from 0% to 100%. AMF spore abundance ranged from 0 to 11.4 in 1 g of soils. Sixteen AMF species were recorded, both widespread (e.g. Funneliformis constrictum, Claroideoglomus claroideum) and rare (Acaulospora cavernata, Entrophospora infrequens). The composition of AMF species related to the plants differed. Fungal root endophytes were recorded only in some plants; dark septate endophytes (DSE) in 13 species, while Olpidium spp. in 6 species. Moreover, DSE mycelia and Olpidium spp. sporangia were observed with low abundance, and their occurrence differed between particular plant species. Among soil chemical properties, only the concentration of available phosphorus was significantly negatively correlated with the MAMF% parameter. In conclusion, several groups of root-inhabiting fungi were related to herbaceous plants; however, they occurred with varied frequency. AMF spore abundance and species richness differed as well; however, they persisted at a low level compared to other ecosystems. Nonetheless, we detected significant negative correlation between available P contents in soils and the intensity of mycorrhizal colonization, which suggests the importance of AM for the plants in sites with low P concentration. PMID- 30308926 TI - Mapping ammonia risk on sensitive habitats in Ireland. AB - The aim of this study was to provide a simple, cost-effective, risk-based map of terrestrial areas in Ireland where environmental quality may be at risk from atmospheric ammonia. This risk-based approach identifies Natura 2000 sites in Ireland at risk from agricultural atmospheric ammonia, collating best available data using Geographical Information Systems (GIS). In mapping ammonia risk on sensitive habitats (MARSH), the method identifies sources of ammonia, classifying them on a scale of risk from 0 to 5. These sources are subsequently summed based on a weighting determined by their contribution to national emissions divided by their potentially impacted area. A Pearson's correlation coefficient of 0.72 allows for concentrations from United Kingdom's FRAME modelling to be applied to the MARSH model, which are corrected based on recent monitoring. Applying Designation Weighted Indicators (DWI), the MARSH model predicts that 80.7, 34.3 and 5.9% of Natura 2000 sites in Ireland may exceed ambient concentrations of 1, 2, and 3 MUg/m3, respectively. A Nitroindex map of Ireland based on available lichen records was also developed and is presented as part of this study. This Nitroindex was used to identify areas where impacts have already been recorded, thus informing the classification of sites "at-risk". The combination of both the MARSH and Nitroindex models ascertains which Natura 2000 sites are most at risk, thereby providing valuable data to relevant authorities. The MARSH model acts as a first step towards screening and assessing Natura 2000 sites most at risk from atmospheric ammonia, providing a tool to demonstrate compliance with the National Emissions Ceilings Directive. PMID- 30308927 TI - Bioconcentration, metabolism and the effects of tetracycline on multiple biomarkers in Chironomus riparius larvae. AB - The antibiotic tetracycline (TC) is widespread in surface waters, but few data are available regarding its adverse effects on aquatic insects. In this study, we investigated the bioconcentration, metabolism, and effects of TC on Chironomus riparius larvae exposed to different concentrations of TC (1.83, 18.5 and 174 MUg L-1) for 48 h. The bioconcentration factors were 3.65, 0.74 and 0.23 in larvae with exposure to 1.83, 18.5 and 174 MUg L-1 TC, respectively. High concentration ratios of the metabolites anhydrotetracycline (0.56-0.60), 4-epitetracycline (0.43-0.69), and 4-epianhydrotetracycline (0.50-0.55) to the unmetabolized compound were found. Additionally, the activities of superoxide dismutase and glutathione S-transferase were markedly inhibited with a significant increase in malondialdehyde contents at high exposure concentrations of TC (18.5 and 174 MUg L-1). Moreover, significant up-regulation of heat shock genes (hsp70 and hsp27), the ecdysone receptor gene, and the E74 early ecdysone responsive gene was observed at all exposure concentrations except for hsp70 at 1.83 MUg L-1. Collectively, these results suggested that TC was quickly absorbed and metabolized by C. riparius and resulted in molecular and biochemical disturbances. PMID- 30308928 TI - Comparative analysis of methods and models for predicting biochemical methane potential of various organic substrates. AB - Biochemical methane potential (BMP) corresponds to the maximum methane production at anaerobic digestion infinite time and is a key parameter to evaluate the suitability of substrates to obtain biogas. The main objective of this work is to explore the data available in the literature for ten categories of substrates to compare and develop new methods and mathematical models able to predict BMP. Indeed, experimental procedure is time-consuming, laborious and costly, and the development of methods or models based on properties easily assessed may be very helpful at industrial scale. In this study, three substrates (banana waste, tomato waste and winery wastewater) were tested and compared with >150 results from the literature. The analysis involved four methods (Met_I to Met_IV) and five models developed by multivariate regression (Mod_I to Mod_V). Met_I is related to elemental analysis; Met_II with the organic fraction composition; Met_III is associated with chemical oxygen demand (COD); Met_IV is based on NIR spectra. Regression models are combinations by grouping single variables: C, H, O, N (Mod_I); hemicellulose, lignin (LG), acid detergent fibre (ADF) (Mod_II); volatile solids (VS), COD (Mod_III); proteins (PT), carbohydrates (CRB), lipids (LP) (Mod_IV); and CRB, LP, PT, LG, ADF (Mod_V). The results showed that no significant correlation can be found between BMP and single common properties (e.g. VS or C/N ratio). However, good results may be achieved with models developed by multivariate regression (R2 from 0.93 to 0.98, and R2adj from 0.91 to 0.96). The prediction of BMP based on Met_IV, which is based on NIR spectroscopy combined with a multivariate regression model, revealed to be a promising method for both data from literature as well as for substrates analyzed in the present work. PMID- 30308929 TI - The impact of ship emissions on PM2.5 and the deposition of nitrogen and sulfur in Yangtze River Delta, China. AB - Ship emissions contribute significantly to the deterioration of air quality, while their impacts on ambient PM2.5 and depositions have not been comprehensively evaluated. This is especially true for China because it has a long coastline, busy shipping routes and many large ports. To fill this gap, this study applied the SMOKE/WRF/CMAQ modeling system to quantifying the impacts of ships on PM2.5 compositions, annual and seasonal contribution to PM2.5 as well as the wet and dry deposition of nitrogen and sulfur compounds over the land areas in YRD region for 2014. The results showed that 4.0% of annual PM2.5 concentrations over the land areas could be explained by ship emissions and the largest contribution could reach up to 35.0% in port areas. Temporally, the contribution to PM2.5 exhibited an obviously seasonal variation. The highest contribution was predicted in autumn (6.2%), followed by summer (5.4%), spring (3.6%) and winter (1.2%) for the land areas. Spatially, the contribution reached up to 13.6% along the coastline and dropped to 2.1% 300 km inland. As for the impacts on PM2.5 components, the primary components were relatively small and increased mainly along the shipping routes and the Yangtze River, whereas the secondary components played a more important role in both water and land areas. The sulfur deposition due to ship emissions was occurred generally along the shipping routes and was dominated by the dry SO2 deposition. The nitrogen depositions, on the contrary, was observed not only along the shipping routes but also extend to wide land areas. Further investigation revealed that ship emissions have caused an evident increase of dry nitrogen deposition in NO2 and HNO3, while a slight decrease in NH3 over YRD region. These results indicated that comprehensive regulations of ship emissions are required considering their adverse effects on the ambient concentration of PM2.5 and the deposition of sulfur and nitrogen. PMID- 30308930 TI - Aquatic organic matter: Classification and interaction with organic microcontaminants. AB - Organic matter (OM) in aquatic system is originated from autochthonous and allochthonous natural sources as well as anthropogenic inputs, and can be found in dissolved, particulate or colloidal form. According to the type/composition, OM can be divided in non-humic substances (NHS) or humic substances (HS). The present review focuses on the main groups that constitute the NHS (carbohydrates, proteins, lipids, and lignin) and their role as chemical biomarkers, as well as the main characteristics of HS are presented. HS functions, properties and mechanisms are discussed, in addition to their association to the fate, bioavailability, and toxicity of organic microcontaminants in the aquatic systems. Despite the growing diversity and potential impacts of organic microcontaminants to the aquatic environment, limited information is available about their association with OM. A protective effect is, however, normally seen since the presence of OM (HS mainly) may reduce bioavailability and, consequently, the concentration of organic microcontaminants within the organism. It may also affect the toxicity by either absorbing ultraviolet radiation incidence and, then, reducing the formation of phototoxic compounds, or by increasing the oxygen reactive species and, thus, affecting the decomposition of natural and anthropogenic organic compounds. In addition, the outcome data is hard to compare since each study follows unique experimental protocols. The often use of commercial humic acid (Aldrich) as a generic source of OM in studies can also hinder comparisons since differences in composition makes this type of OM not representative of any aquatic environment. Thus, the current challenge is find out how this clear fragmentation can be overcome. PMID- 30308931 TI - Systemic Administration of Polyelectrolyte Microcapsules: Where Do They Accumulate and When? In Vivo and Ex Vivo Study. AB - Multilayer capsules of 4 microns in size made of biodegradable polymers and iron oxide magnetite nanoparticles have been injected intravenously into rats. The time-dependent microcapsule distribution in organs was investigated in vivo by magnetic resonance imaging (MRI) and ex vivo by histological examination (HE), atomic absorption spectroscopy (AAS) and electron spin resonance (ESR), as these methods provide information at different stages of microcapsule degradation. The following organs were collected: Kidney, liver, lung, and spleen through 15 min, 1 h, 4 h, 24 h, 14 days, and 30 days after intravenous injections (IVIs) of microcapsules in a saline buffer at a dosage of 2.5 * 108 capsule per kg. The IVI of microcapsules resulted in reversible morphological changes in most of the examined inner organs (kidney, heart, liver, and spleen). The capsules lost their integrity due to degradation over 24 h, and some traces of iron oxide nanoparticles were seen at 7 days in spleen and liver structure. The morphological structure of the tissues was completely restored one month after IVI of microcapsules. Comprehensive analysis of the biodistribution and degradation of entire capsules and magnetite nanoparticles as their components gave us grounds to recommend these composite microcapsules as useful and safe tools for drug delivery applications. PMID- 30308932 TI - A Novel Approach for Assessing the Fatigue Behavior of PEEK in a Physiologically Relevant Environment. AB - In recent years, the need of surgical procedures has continuously increased and, therefore, researchers and clinicians are broadly focusing on the development of new biocompatible materials. Among them, polyetheretherketone (PEEK) has gained wide interest in load-bearing applications due to its yielding behaviour and its superior corrosion resistance. To assure its reliability in these applications where notches and other stress concentrators weaken implants resistance, a design tool for assessing its tensile and fatigue behaviour in the presence of geometrical discontinuities is highly claimed. Herein, a new fatigue design method based on a local approach is proposed for PEEK implant, and the results are compared with those obtained using the two main biomaterial design approaches available in literature, i.e., the theory of critical distances (TCD) and the notch stress intensity factor (NSIF) approach. To this aim, previously published datasets of PEEK-notched specimens are used, and the proposed method is reported to provide more accurate results and to be robust for different notch geometries. PMID- 30308934 TI - Tailoring Perpendicular Exchange Bias Coupling in Au/Co/NiO Systems by Ion Bombardment. AB - Here, we systematically investigated the influence of ion bombardment with different fluences on the strength and direction of the exchange bias coupling in Au/Co/NiO systems with perpendicular magnetic anisotropy of the Co layer. We found that the direction of the exchange bias coupling can be reversed as a result of ion bombardment performed in an external magnetic field which is in the opposite direction to the magnetic field applied during film deposition. Moreover, the strength of the exchange bias coupling can be tailored by varying the ion fluence. These results show behaviors similar to the results found for systems of ferromagnetic layers with in-plane anisotropy. Our experimental work, supported by a two-energy-level model, demonstrates that exchange bias coupling can be tuned in a layered system with perpendicular magnetic anisotropy using ion bombardment. PMID- 30308933 TI - Potential Application of Bacteriophages in Enrichment Culture for Improved Prenatal Streptococcus agalactiae Screening. AB - Vertical transmission of Streptococcus agalactiae can cause neonatal infections. A culture test in the late stage of pregnancy is used to screen for the presence of maternal S. agalactiae for intrapartum antibiotic prophylaxis. For the test, a vaginal-rectal sample is recommended to be enriched, followed by bacterial identification. In some cases, Enterococcus faecalis overgrows in the enrichment culture. Consequently, the identification test yields false-negative results. Bacteriophages (phages) can be used as antimicrobial materials. Here, we explored the feasibility of using phages to minimize false-negative results in an experimental setting. Phage mixture was prepared using three phages that specifically infect E. faecalis: phiEF24C, phiEF17H, and phiM1EF22. The mixture inhibited the growth of 86.7% (26/30) of vaginal E. faecalis strains. The simple coculture of E. faecalis and S. agalactiae was used as an experimental enrichment model. Phage mixture treatment led to suppression of E. faecalis growth and facilitation of S. agalactiae growth. In addition, testing several sets of S. agalactiae and E. faecalis strains, the treatment with phage mixture in the enrichment improved S. agalactiae detection on chromogenic agar. Our results suggest that the phage mixture can be usefully employed in the S. agalactiae culture test to increase test accuracy. PMID- 30308935 TI - Investigations of Alkaline and Enzymatic Membrane Cleaning of Ultrafiltration Membranes Fouled by Thermomechanical Pulping Process Water. AB - The pulp and paper industry is one of the most important industrial sectors worldwide, and has considerable potential for the sustainable fractionation of lignocellulosic biomass to provide valuable compounds. Ultrafiltration (UF) is a suitable separation technique for the profitable production of hemicelluloses from process water from thermomechanical pulping (ThMP), but is limited by membrane fouling. Improvements in cleaning protocols and new alternative cleaning agents are required to ensure a long membrane lifetime, and thus a sustainable process. This study, therefore, focuses on the cleaning of polymeric UF membranes after the filtration of ThMP process water, comparing alkaline with enzymatic cleaning agents. The aim was to develop a cleaning procedure that is efficient under mild conditions, resulting in a lower environmental impact. It was not possible to restore the initial permeability of the membrane when cleaning the membrane with enzymes alone, but the permeability was restored when using a two step cleaning process with enzymes in the first step and an alkaline cleaning agent in the second step. Scanning electron microscopy gave a deeper inside into the cleaning efficiency. Attenuated total reflectance Fourier-transform infrared spectroscopy analysis confirmed that not only polysaccharides, but also extractives are adsorbed onto the membrane surface. PMID- 30308936 TI - Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress. AB - BACKGROUND: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. METHODS: Forty-eight mice were divided into four groups (n = 12 per group): Group 1: Wild-type (WT) mice, Group 2: RasGRF1 deficiency (RasGRF1-/-) mice. Group 3: Streptozotocin (STZ)-induced diabetic WT mice, Group 4: STZ-induced diabetic RasGRF1-/- mice. Myocardial functions were assessed by cardiac echography. Heart tissues from all of the mice were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. RESULTS: Worse impaired diastolic function with elevation serum interleukin (IL) 6 was found in the diabetic group compared with the non-diabetic groups. Serum IL 6 levels were found to be elevated in the diabetic compared with the non-diabetic groups. However, the diabetic RasGRF1-/- mice exhibited lower serum IL-6 levels and better diastolic function than the diabetic WT mice. The diabetic RasGRF1-/- mice were associated with reduced cardiac inflammation, which was shown by lower invading inflammation cells, lower expression of matrix metalloproteinase 9, and less chemokines compared to the diabetic WT mice. Furthermore, less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was also found in the diabetic RasGRF1-/- mice compared with the diabetic WT mice. CONCLUSION: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress. PMID- 30308937 TI - Miniature Spectroscopes with Two-Dimensional Guided-Mode Resonant Metal Grating Filters Integrated on a Photodiode Array. AB - A small spectroscope with 25 color sensors was fabricated by combining metamaterial color filters and Si photodiodes. The metamaterial color filters consisted of guided-mode resonant metal gratings with subwavelength two dimensional periodic structures. Transmittance characteristics of the color filters were designed to obtain peak wavelengths proportional to grating periods. For each color sensor, a peak wavelength of the spectral sensitivity could be tuned in the range of visible wavelengths by adjusting each grating period. By performing spectrum reconstruction using Tikhonov regularization, the spectrum of an incident light was obtained from the signal of photodiodes. Several monochromatic lights were made incident on the fabricated device and the spectral characteristics of the incident light were reconstructed from the output signals obtained from the respective color sensors. The peak wavelengths of the reconstructed spectra were in good agreement with the center wavelengths of the monochromatic lights. PMID- 30308938 TI - Evolution and Function of the Chloroplast. Current Investigations and Perspectives. AB - Chloroplasts are the place for the major conversion of the sun's radiation energy to chemical energythat is usable by organisms[...]. PMID- 30308940 TI - Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment. AB - To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment. PMID- 30308939 TI - Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target. AB - Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients. As compared with paired normal tissues and healthy individuals, CCND2 promoter hypermethylation was detected in 40.9% of breast tumors and 44.4% of plasma circulating cell-free DNA of patients. The western cohort of The Cancer Genome Atlas also demonstrated CCND2 promoter hypermethylation in female lung cancer, lung adenocarcinoma, and breast cancer patients and that CCND2 promoter hypermethylation is an independent poor prognostic factor. The cell model assay indicated that CCND2 expression inhibited cancer cell growth and migration ability. The demethylating agent antroquinonol D upregulated CCND2 expression, caused cell cycle arrest, and inhibited cancer cell growth and migration ability. In conclusion, hypermethylation of CCND2 is a potential diagnostic, prognostic marker and drug target, and it is induced by antroquinonol D. PMID- 30308941 TI - Identification of Alkaloids from Corydalis yanhusuo W. T. Wang as Dopamine D1 Receptor Antagonists by Using CRE-Luciferase Reporter Gene Assay. AB - Corydalis yanhusuo W. T. Wang (C. yanhusuo) has been traditionally used for drug addiction and pain relief in China. In our previous study, we showed that the extract of C. yanhusuo blocks dopamine receptors, demonstrating that its pharmacological activities are mostly due to the antagonistic effects of some of its components at dopamine receptors. As part of our ongoing project on C. yanhusuo, the aim of the present study is to establish a high-throughput and low cost screening assay system and test the abilities of the isolated alkaloids from C. yanhusuo to inhibit dopamine-induced dopamine D1 receptor activity. By using our established cyclic adenosine monophosphate (cAMP)-response element (CRE) luciferase reporter gene assay system, we identified eight alkaloids from C. yanhusuo with D1 receptor antagonistic activities. We next validated the activities of these compounds using fluorometric imaging plate reader (FLIPR) assay by measuring the intracellular Ca2+ change. Six out of eight compounds, including tetrahydropalmatine, corydaline, 13-methyldehydrocorydalmine, dehydrocorybubine, dehydrocorydaline, and columbamine, can be confirmed for their inhibitory activities. The dopamine-receptor-antagonistic effects of four compounds, including 13-methyldehydrocorydalmine, dehydrocorydaline, columbamine, and corydaline, are reported for the first time. The present study provides an important pharmacological basis to support the traditional use of C. yanhusuo in China. PMID- 30308942 TI - Federation of Internet of Things Testbeds for the Realization of a Semantically Enabled Multi-Domain Data Marketplace. AB - The Internet of Things (IoT) concept has attracted a lot of attention from the research and innovation community for a number of years already. One of the key drivers for this hype towards the IoT is its applicability to a plethora of different application domains. However, infrastructures enabling experimental assessment of IoT solutions are scarce. Being able to test and assess the behavior and the performance of any piece of technology (i.e., protocol, algorithm, application, service, etc.) under real-world circumstances is of utmost importance to increase the acceptance and reduce the time to market of these innovative developments. This paper describes the federation of eleven IoT deployments from heterogeneous application domains (e.g., smart cities, maritime, smart building, crowd-sensing, smart grid, etc.) with over 10,000 IoT devices overall which produce hundreds of thousands of observations per day. The paper summarizes the resources that are made available through a cloud-based platform. The main contributions from this paper are twofold. In the one hand, the insightful summary of the federated data resources are relevant to the experimenters that might be seeking for an experimental infrastructure to assess their innovations. On the other hand, the identification of the challenges met during the testbed integration process, as well as the mitigation strategies that have been implemented to face them, are of interest for testbed providers that can be considering to join the federation. PMID- 30308943 TI - Diphlorethohydroxycarmalol Isolated from Ishige okamurae Represses High Glucose Induced Angiogenesis In Vitro and In Vivo. AB - Diabetes mellitus causes abnormalities of angiogenesis leading to vascular dysfunction and serious pathologies. Diphlorethohydroxycarmalol (DPHC), which is isolated from Ishige okamurae, is well known for its bioactivities, including antihyperglycemic and protective functions against diabetes-related pathologies. In the present study, the inhibitory effect of DPHC on high glucose-induced angiogenesis was investigated on the human vascular endothelial cell line EA.hy926. DPHC inhibited the cell proliferation, cell migration, and tube formation in cells exposed to 30 mM of glucose to induce angiogenesis. Furthermore, the effect of DPHC against high glucose-induced angiogenesis was evaluated in zebrafish embryos. The treatment of embryos with DPHC suppressed high glucose-induced dilation in the retinal vessel diameter and vessel formation. Moreover, DPHC could inhibit high glucose-induced vascular endothelial growth factor receptor 2 (VEGFR-2) expression and its downstream signaling cascade. Overall, these findings suggest that DPHC is actively involved in the suppression of high glucose-induced angiogenesis. Hence, DPHC is a potential agent for the development of therapeutics against angiogenesis induced by diabetes. PMID- 30308944 TI - In Vitro Fermentation of Selected Prebiotics and Their Effects on the Composition and Activity of the Adult Gut Microbiota. AB - Recently, the concept of prebiotics has been revisited to expand beyond non digestible oligosaccharides, and the requirements for selective stimulation were extended to include microbial groups other than, and additional to, bifidobacteria and lactobacilli. Here, the gut microbiota-modulating effects of well-known and novel prebiotics were studied. An in vitro fermentation screening platform (i-screen) was inoculated with adult fecal microbiota, exposed to different dietary fibers that had a range of concentrations (inulin, alpha-linked galacto-oligosaccharides (alpha-GOS), beta-linked GOS, xylo-oligosaccharides (XOS) from corn cobs and high-fiber sugar cane, and beta-glucan from oats), and compared to a positive fructo-oligosaccharide (FOS) control and a negative control (no fiber addition). All dietary fibers displayed prebiotic activity, with beta-glucan showing more distinct effects on the microbial composition and metabolism compared to the other fibers. Beta-glucan induced the growth of Prevotella and Roseburia with a concomitant increase in propionate production. Inulin and both forms of GOS and XOS had a strong bifidogenic effect on the microbial composition. A dose-response effect was observed for butyrate when exposed to beta-glucan and inulin. The findings of this study support the potential for alpha-GOS, XOS, and oat beta-glucan to serve as novel prebiotics, due to their association with the positive shifts in microbiome composition and short-chain fatty acid production that point to potential health benefits. PMID- 30308946 TI - Basketball Game-Related Statistics that Discriminate among Continental Championships for Under-18 Women. AB - The purposes of this study were (a) to evaluate differences in basketball game related statistics among continental championships for under-18 (U18) women, and (b) to identify game-related statistics that discriminate among the continents. The analysis was performed on all matches (n = 136) in the four continental championships (Africa, America, Asia, Europe) of 2016. Differences in game related statistics among the continents were analyzed by an analysis of variance (ANOVA) with effect size statistics. Game-related statistics that discriminate among the continents were assessed by discriminant analysis. The ANOVA yielded significant F-values for 13 of 16 variables and large effect size differences for 10 of 16 variables. The discriminant analysis yielded three significant functions. The Asian championship was discriminated from the other continental championships by ball possessions, defensive rebounds, assists, and fouls. The African championship was discriminated from the European championship by ball possessions, successful 3-point field goals, unsuccessful free throws, and turnovers, and from the American championship by ball possessions, unsuccessful 2 point field goals, successful 3-point field goals, successful free throws, and assists. The results of this study suggest that U18 women's basketball games are played differently in each continent. PMID- 30308945 TI - Optimization of Fermentation Condition for Echinacoside Yield Improvement with Penicillium sp. H1, an Endophytic Fungus Isolated from Ligustrum lucidum Ait Using Response Surface Methodology. AB - (1) Background: Application of echinacoside has become increasingly important for its significant biological activities. However, there are many disadvantages in existing synthesis methods such as contaminating the environment, harsh reaction conditions and so on. Therefore, it is urgent to invent a novel alternative method that can increase the yield of echinacoside. (2) Methods: In this study, we isolated and purified an endophyte from the leaves of Ligustrum lucidum Ait. Then, we improved the yield of echinacoside by optimizing the fermentation condition with an endophytic fungus. Penicillium sp. H1 was isolated from Ligustrum lucidum Ait. In addition, response surface methodology was used to optimize the fermentation condition. (3) Results: The results indicate that the maximal yield of echinacoside (37.16 mg/L) was obtained when inoculation rate, temperature and days were 13.98%, 27.85 degrees C and 26.06 days, respectively. The yield of echinacoside was 150.47 times higher under the optimal conditions than under the control conditions. The results indicate that the yield of echinacoside could be improved with endophytic fermentation by optimizing the fermentation condition. We provide an alternative method for echinacoside production by endophytic fermentation in this paper. It may have a profound effect on the application of echinacoside. PMID- 30308947 TI - The Extremely High Adsorption Capacity of Fluoride by Chicken Bone Char (CBC) in Defluoridation of Drinking Water in Relation to Its Finer Particle Size for Better Human Health. AB - The ingestion of fluoride-contaminated water causes serious health issues in people all over the world. In the current study, the adsorption of fluoride onto chicken bone char (CBC) was investigated as a defluoridation technique. Finer sized CBC with a diameter of 106-212 um was used to investigate the fluoride adsorption capacity onto CBC. Results revealed that finer-sized CBC yielded an unusually high fluoride adsorption capacity of 11.2 mg/g at the equilibrium fluoride concentration of 10 mg/L. The study shows that CBC can be utilized in the defluoridation of drinking water and that finer-sized CBC enhances ion exchange to perform a higher adsorption capacity. PMID- 30308948 TI - Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery. AB - There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment. PMID- 30308950 TI - Apulo-Calabrese and Crossbreed Pigs Show Different Physiological Response and Meat Quality Traits after Short Distance Transport. AB - Despite the increasing interest in the welfare of animals during transport, very little is known on the response of local pig breeds to the transport procedures. This study aims to compare the effect of short journey on behaviour, blood parameters, and meat quality traits in 51 Apulo-Calabrese and 52 crossbreed [Duroc * (Landrace * Large White)] pigs. All the animals were blood sampled five days before delivery (basal condition) and at exsanguination for the analysis of creatine kinase, cortisol, glucose, lactate, albumin, albumin/globulin, total protein, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphate, sodium, and potassium. Post mortem pH, color, drip loss, cooking loss, and Warner-Bratzler shear force were measured at different times in longissimus thoracis samples. Univariate and multivariate analyses showed that glucose, albumin/globulin, urea, and AST at exsanguination were influenced by the genetic type. Apulo-Calabrese showed the highest increase in blood values of lactate, creatinine, sodium and potassium after the short distance transport. Behavioural occurrences were similar in both genetic types during unloading and lairage. Small differences were observed for meat quality although significantly higher a* and lower L* were found in Apulo-Calabrese pigs, showing meat with a deeper red colour than crossbreeds. PMID- 30308949 TI - Induction of ATP Release, PPIX Transport, and Cholesterol Uptake by Human Red Blood Cells Using a New Family of TSPO Ligands. AB - Two main isoforms of the Translocator Protein (TSPO) have been identified. TSPO1 is ubiquitous and is mainly present at the outer mitochondrial membrane of most eukaryotic cells, whereas, TSPO2 is specific to the erythroid lineage, located at the plasma membrane, the nucleus, and the endoplasmic reticulum. The design of specific tools is necessary to determine the molecular associations and functions of TSPO, which remain controversial nowadays. We recently demonstrated that TSPO2 is involved in a supramolecular complex of the erythrocyte membrane, where micromolar doses of the classical TSPO ligands induce ATP release and zinc protoporphyrin (ZnPPIX) transport. In this work, three newly-designed ligands (NCS1016, NCS1018, and NCS1026) were assessed for their ability to modulate the functions of various erythrocyte's and compare them to the TSPO classical ligands. The three new ligands were effective in reducing intraerythrocytic Plasmodium growth, without compromising erythrocyte survival. While NCS1016 and NCS1018 were the most effective ligands in delaying sorbitol-induced hemolysis, NCS1016 induced the highest uptake of ZnPPIX and NCS1026 was the only ligand inhibiting the cholesterol uptake. Differential effects of ligands are probably due, not only, to ligand features, but also to the dynamic interaction of TSPO with various partners at the cell membrane. Further studies are necessary to fully understand the mechanisms of the TSPO's complex activation. PMID- 30308951 TI - Acylphloroglucinol Derivatives from Garcinia multiflora with Anti-Inflammatory Effect in LPS-Induced RAW264.7 Macrophages. AB - Two new acylphloroglucinol derivatives, 13,14-didehydroxygarcicowin C (1) and 13,14-didehydroxyisoxanthochymol (2), have been isolated from the stems of Garcinia multiflora, together with seven known compounds (3-9). The structures of new compounds 1 and 2 were elucidated by MS and extensive 1D/2D NMR spectroscopic analyses. Among the isolates, 13,14-didehydroxy-isoxanthochymol (2) and sampsonione B (3) exhibited inhibition against lipopolysaccharide (LPS)-induced NF-kappaB activation in macrophages at 30 MUM with relative luciferase activity values (inhibitory %) of 0.75 +/- 0.03 (24 +/- 4%) and 0.12 +/- 0.03 (88 +/- 4%), respectively. Additionally, sampsonione B (3) reduced LPS-induced nitric oxide (NO) production in murine RAW264.7 macrophages and did not induce cytotoxicity against RAW 264.7 cells after 24 h treatment. Compound 3 is worth further investigation and may be expectantly developed as an anti-inflammatory drug candidate. PMID- 30308952 TI - Use of Psychotropic Drugs among Children and Adolescents with Autism Spectrum Disorders in Denmark: A Nationwide Drug Utilization Study. AB - Children with autism spectrum disorder (ASD) have a considerable use of psychotropics. Leveraging nationwide registry data, we aimed to describe the use of psychotropics among children and adolescents with ASD in Denmark. Use of melatonin and attention-deficit/hyperactivity disorder (ADHD) medication increased from 2010 to 2017, while there were limited changes in use of antidepressants and antipsychotics. Thirty percent of the identified children used psychotropics in 2017 most commonly ADHD medication (17%) and melatonin (13%). Methylphenidate, sertraline and risperidone were most often prescribed. Most children filled more than one prescription and, across drug classes, at least 38% received treatment two years after treatment initiation. Use of psychotropics followed psychiatric comorbidities. Comorbidities did not affect age at treatment initiation. Use of psychotropics varied according to age and sex with limited use in the youngest children. In summary, psychotropic drug use has increased in children with ASD mainly due to an increase in the use of ADHD medication and melatonin. In accordance with previous studies, use seems to follow comorbidities. The long treatment duration underlines the need to investigate long-term effects of psychotropic drug use in children with ASD. PMID- 30308954 TI - Crystalline Defects Induced during MPCVD Lateral Homoepitaxial Diamond Growth. AB - The development of new power devices taking full advantage of the potential of diamond has prompted the design of innovative 3D structures. This implies the overgrowth towards various crystallographic orientations. To understand the consequences of such growth geometries on the defects generation, a Transmission Electron Microscopy (TEM) study of overgrown, mesa-patterned, homoepitaxial, microwave-plasma-enhanced, chemical vapor deposition (MPCVD) diamond is presented. Samples have been grown under quite different conditions of doping and methane concentration in order to identify and distinguish the factors involved in the defects generation. TEM is used to reveal threading dislocations and planar defects. Sources of dislocation generation have been evidenced: (i) doping level versus growth plane, and (ii) methane concentration. The first source of dislocations was shown to generate <110> Burgers vector dislocations above a critical boron concentration, while the second induces <112> type Burgers vector above a critical methane/hydrogen molar ratio. The latter is attributed to partial dislocations whose origin is related to the dissociation of perfect ones by a Shockley process. This dissociation generated stacking faults that likely resulted in penetration twins, which were also observed on these samples. Lateral growth performed at low methane and boron content did not exhibit any dislocation. PMID- 30308953 TI - Unraveling the Roles of Regulatory Genes during Domestication of Cultivated Camellia: Evidence and Insights from Comparative and Evolutionary Genomics. AB - With the increasing power of DNA sequencing, the genomics-based approach is becoming a promising resolution to dissect the molecular mechanism of domestication of complex traits in trees. Genus Camellia possesses rich resources with a substantial value for producing beverage, ornaments, edible oil and more. Currently, a vast number of genetic and genomic research studies in Camellia plants have emerged and provided an unprecedented opportunity to expedite the molecular breeding program. In this paper, we summarize the recent advances of gene expression and genomic resources in Camellia species and focus on identifying genes related to key economic traits such as flower and fruit development and stress tolerances. We investigate the genetic alterations and genomic impacts under different selection programs in closely related species. We discuss future directions of integrating large-scale population and quantitative genetics and multiple omics to identify key candidates to accelerate the breeding process. We propose that future work of exploiting the genomic data can provide insights related to the targets of domestication during breeding and the evolution of natural trait adaptations in genus Camellia. PMID- 30308955 TI - Geographical Accessibility of the Referral Networks in France. Intermediate Results from the IGeAS Research Program. AB - Rare cancer patients face lower survival and experience delays in diagnosis and therapeutic mismanagement. Considering the specificities of rare cancers, referral networks have been implemented in France to improve the management and survival of patients. The IGeAS research program aims to assess the networks' ability to reduce inequalities. Data analysis of the IGeAS cohort (n = 20,590, sarcoma diagnosed between 2011 and 2014) by gathering medical data and geographical index will identify risk factors associated with the belated access to expertise or with no access to expertise. Intermediate results show that referral networks give sarcoma patients access to sarcoma expertise despite the remoteness of some of them. Regional expert centers mostly receive requests from within their area while national referral centers receive requests from the whole country. Delays in the access to expertise may be reduced by making outside practitioners more sensitive to the issues of rare cancers. The perception and involvement of outside practitioners in this device will be assessed using a qualitative survey. All the results are discussed and will contribute to design guidelines to improve early access to expertise and reduce inequalities. Results of the IGeAS research program may contribute to the assessment of referral sarcoma networks and provide some useful lessons to improve cancer care management. PMID- 30308956 TI - Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia. AB - The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase. PMID- 30308957 TI - Translation and Test-Retest of the Spanish Podiatry Health Questionnaire (PHQ-S). AB - Background: The Podiatric Health Questionnaire (PHQ) is a health-related questionnaire consisting of six questions designed for measuring foot health status. To date, the PHQ has only been validated in the English-language version. Thus, this study aimed to perform the Spanish translation and test-retest procedures of the PHQ (PHQ-S). Method: The forward/backward translation and test retest reliability methods were applied from English to Spanish languages. Regarding the total score for each domain, internal consistency and reliability were determined by the Cronbach alpha and intraclass correlation coefficient (ICC) with a confidence interval (CI) of 95%. Results: High internal consistency was shown for the six domains: (1) walking with a Cronbach alpha of 0.97; (2) hygiene and nail care with 0.93 and 093, respectively; (3) foot pain with 0.91; (4) worry and concern domain with 0.904; (5) quality of life with 0.87; and (6) the self-perception of how their feet are feeling measured by a visual analogic scale with 0.92. Excellent test-retest reliability (ICC = 0.99 (95% CI = 0.96 0.98)) was shown for the total score. Conclusions: The PHQ-S was shown to be a valid and reliable tool for an acceptable use in the Spanish population. PMID- 30308958 TI - Molecular Markers of Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Literature Review. AB - This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet another challenge-that of preserving oral functions, which involves the use of multidisciplinary therapies, such as multiple chemotherapies (CT) and radiotherapy (RT). Designing personalized therapeutic options requires the study of genes involved in drug resistance. This review provides an overview of the molecules that have been linked to resistance to chemotherapy in HNSCC, including the family of ATP binding cassette transporters (ABCs), nucleotide excision repair/base excision repair (NER/BER) enzymatic complexes (which act on nonspecific DNA lesions generated by gamma and ultraviolet radiation by cross-linking and forming intra/interchain chemical adducts), cisplatin (a chemotherapeutic agent that causes DNA damage and induces apoptosis, which is a paradox because its effectiveness is based on the integrity of the genes involved in apoptotic signaling pathways), and cetuximab, including a discussion of the genes involved in the cell cycle and the proliferation of possible markers that confer resistance to cetuximab. PMID- 30308960 TI - A New Protocol for the Synthesis of New Thioaryl-Porphyrins Derived from 5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin: Photophysical Evaluation and DNA Binding Interactive Studies. AB - A new protocol for the preparation of thioaryl-porphyrins is described. The compounds were prepared from different disulfides employing NaBH4 as a reducing agent. The methodology allowed the preparation of four different thioaryl porphyrins in very-good to excellent yields under soft conditions, such as short reaction times and smooth heating. Additionally, the photophysical properties of new compounds were determined and experimental and theoretical DNA interactions were assessed. PMID- 30308961 TI - Light Trapping Effect in Perovskite Solar Cells by the Addition of Ag Nanoparticles, Using Textured Substrates. AB - In this contribution, the efficiencies of perovskite solar cells have been further enhanced, based on optical optimization studies. The photovoltaic devices with textured perovskite film can be obtained and a power conversion efficiency (PCE) of the textured fluorine-doped tin oxide (FTO)/Ag nanoparticles (NPs) embedded in c-TiO2/m-TiO2/CH3NH3PbI3/Spiro-OMeTAD/Au showed 33.7% enhancement, and a maximum of up to 14.01% was achieved. The efficiency enhancement can be attributed to the light trapping effect caused by the textured FTO and the incorporated Ag NPs, which can enhance scattering to extend the optical pathway in the photoactive layer of the solar cell. Interestingly, aside from enhanced light absorption, the charge transport characteristics of the devices can be improved by optimizing Ag NPs loading levels, which is due to the localized surface plasmon resonance (LSPR) from the incorporated Ag NPs. This light trapping strategy helps to provide an appropriated management for optical optimization of perovskite solar cells. PMID- 30308962 TI - Every Day's a New Day: A Captain's Reflection on a Losing Season. AB - Being captain of any team is a significant and prestigious position. In elite sport, the captain plays a vital role in both team and organisational leadership. To date there has been minimal research investigating captaincy, and none assessing the impact of regularly losing performances. A captain of a women's national basketball league team participated in an in-depth, semi-structured interview reflecting on her experience during a losing season. Following Schutz's (1967) framework, a social phenomenological analysis approach was taken, with seven higher-order themes emerging: being captain; relationship with coaching staff; relationship with teammates; team development; stressors; stress management; and self. Results suggest that while poor results affect all team members, there are increased levels of stress for the captain. The captain is expected to lead by example and avoid external expression of negativity. Further strains are placed on the captain, as they are the conduit between coaching and playing groups. As a result, the captain needs to have good support networks, from a variety of sources, to cope and minimise the impact on personal performance. PMID- 30308959 TI - The Comparative Associations of Ultrasound and Computed Tomography Estimates of Muscle Quality with Physical Performance and Metabolic Parameters in Older Men. AB - Estimates of muscle tissue composition may have greater prognostic value than lean body mass levels regarding health-related outcomes. Ultrasound provides a relatively low cost, safe, and accessible mode of imaging to assess muscle morphology. The purpose of this study was to determine the construct validity of muscle echogenicity as a surrogate measure of muscle quality in a sample of older, predominantly African American (AA) participants. We examined the association of rectus femoris echogenicity with mid-thigh computed tomography (CT) scan estimates of intra- and intermuscular adipose tissue (IMAT), basic metabolic parameters via blood sample analysis, muscle strength, and mobility status. This observational study was conducted at a federal medical center and included 30 community-dwelling men (age, 62.5 +/- 9.2; AA, n = 24; Caucasian, n = 6). IMAT estimates were significantly associated with echogenicity (r = 0.73, p < 0.001). Echogenicity and IMAT exhibited similar associations with the two-hour postprandial glucose values and high-density lipoproteins values (p < 0.04), as well as grip and isokinetic (180 degrees /s) knee extension strength adjusted for body size (p < 0.03). The significant relationship between ultrasound and CT muscle composition estimates, and their comparative association with key health related outcomes, suggests that echogenicity should be further considered as a surrogate measure of muscle quality. PMID- 30308963 TI - A Novel Natural Influenza A H1N1 Virus Neuraminidase Inhibitory Peptide Derived from Cod Skin Hydrolysates and Its Antiviral Mechanism. AB - In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration membrane (5000 Da), sephadex G-15 gel column and reverse-phase high-performance liquid chromatography (RP-HPLC). The amino acid sequence of the pure peptide was determined by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) was PGEKGPSGEAGTAGPPGTPGPQGL, with a molecular weight of 2163 Da. The analysis of the Lineweacer-Burk model indicated that the peptide was a competitive NA inhibitor with Ki of 0.29 mM and could directly bind free enzymes. In addition, docking studies suggested that hydrogen binding might be the driving force for the binding affinity of PGEKGPSGEAGTAGPPGTPGPQGL to NA. The cytopathic effect reduction assay showed that the peptide PGEKGPSGEAGTAGPPGTPGPQGL protected Madin Darby canine kidney (MDCK) cells from viral infection and reduced the viral production in a dose-dependent manner. The EC50 value was 471 +/- 12 MUg/mL against H1N1. Time-course analysis showed that PGEKGPSGEAGTAGPPGTPGPQGL inhibited influenza virus in the early stage of the infectious cycle. The virus titers assay indicated that the NA-inhibitory peptide PGEKGPSGEAGTAGPPGTPGPQGL could directly affect the virus toxicity and adsorption by host cells, further proving that the peptide had an anti-viral effect with multiple target sites. The activity of NA-inhibitory peptide was almost inactivated during the simulated in vitro gastrointestinal digestion, suggesting that oral administration is not recommended. The peptide PGEKGPSGEAGTAGPPGTPGPQGL acts as a neuraminidase blocker to inhibit influenza A virus in MDCK cells. Thus, the peptide PGEKGPSGEAGTAGPPGTPGPQGL has potential utility in the treatment of the influenza virus infection. PMID- 30308964 TI - Deep Learning Scene Recognition Method Based on Localization Enhancement. AB - With the rapid development of indoor localization in recent years; signals of opportunity have become a reliable and convenient source for indoor localization. The mobile device cannot only capture images of the indoor environment in real time, but can also obtain one or more different types of signals of opportunity as well. Based on this, we design a convolutional neural network (CNN) model that concatenates features of image data and signals of opportunity for localization by using indoor scene datasets and simulating the situation of indoor location probability. Using the method of transfer learning on the Inception V3 network model feature information is added to assist in scene recognition. The experimental result shows that, for two different experiment sceneries, the accuracies of the prediction results are 97.0% and 96.6% using the proposed model, compared to 69.0% and 81.2% by the method of overlapping positioning information and the base map, and compared to 73.3% and 77.7% by using the fine tuned Inception V3 model. The accuracy of indoor scene recognition is improved; in particular, the error rate at the spatial connection of different scenes is decreased, and the recognition rate of similar scenes is increased. PMID- 30308965 TI - Carotenoid-Chlorophyll Interactions in a Photosynthetic Antenna Protein: A Supramolecular QM/MM Approach. AB - Multichromophoric interactions control the initial events of energy capture and transfer in the light harvesting peridinin-chlorophyll a protein (PCP) from marine algae dinoflagellates. Due to the van der Waals association of the carotenoid peridinin (Per) with chlorophyll a in a unique 4:1 stoichiometric ratio, supramolecular quantum mechanical/molecular mechanical (QM/MM) calculations are essential to accurately describe structure, spectroscopy, and electronic coupling. We show that, by enabling inter-chromophore electronic coupling, substantial effects arise in the nature of the transition dipole moment and the absorption spectrum. We further hypothesize that inter-protein domain Per Per interactions are not negligible, and are needed to explain the experimental reconstruction features of the spectrum in wild-type PCP. PMID- 30308967 TI - Chemical Diversity of Metal Sulfide Minerals and Its Implications for the Origin of Life. AB - Prebiotic organic synthesis catalyzed by Earth-abundant metal sulfides is a key process for understanding the evolution of biochemistry from inorganic molecules, yet the catalytic functions of sulfides have remained poorly explored in the context of the origin of life. Past studies on prebiotic chemistry have mostly focused on a few types of metal sulfide catalysts, such as FeS or NiS, which form limited types of products with inferior activity and selectivity. To explore the potential of metal sulfides on catalyzing prebiotic chemical reactions, here, the chemical diversity (variations in chemical composition and phase structure) of 304 natural metal sulfide minerals in a mineralogy database was surveyed. Approaches to rationally predict the catalytic functions of metal sulfides are discussed based on advanced theories and analytical tools of electrocatalysis such as proton-coupled electron transfer, structural comparisons between enzymes and minerals, and in situ spectroscopy. To this end, we introduce a model of geoelectrochemistry driven prebiotic synthesis for chemical evolution, as it helps us to predict kinetics and selectivity of targeted prebiotic chemistry under "chemically messy conditions". We expect that combining the data-mining of mineral databases with experimental methods, theories, and machine-learning approaches developed in the field of electrocatalysis will facilitate the prediction and verification of catalytic performance under a wide range of pH and Eh conditions, and will aid in the rational screening of mineral catalysts involved in the origin of life. PMID- 30308968 TI - Walking the Food Security Tightrope-Exploring the Experiences of Low-to-Middle Income Melbourne Households. AB - There is limited evidence of how Australian low-to-middle income (AUD $40,000 $80,000) households maintain food security. Using a sequential explanatory mixed methods methodology, this study explored and compared the food security (FS) and insecurity (FIS) experiences of these households. An initial quantitative survey categorised participants according to food security status (the 18-item United States Department of Agriculture Household Food Security Survey Module) and income level to identify and purposefully select participants to qualitatively explore food insecurity and security experiences. Of the total number of survey participants (n = 134), 42 were categorised as low-to-middle income. Of these, a subset of 16 participants (8 FIS and 8 FS) was selected, and each participant completed an in-depth interview. The interviews explored precursors, strategies to prevent or address food insecurity, and the implications of the experience. Interview data were analysed using a thematic analysis approach. Five themes emerged from the analysis: (i) food decision experiences, (ii) assets, (iii) triggers, (iv) activation of assets, and (v) consequences and emotion related to walking the food security tightrope. The leverage points across all themes were more volatile for FIS participants. Low-to-middle income Australians are facing the challenges of trying to maintain or improve their food security status, with similarities to those described in lower income groups, and should be included in approaches to prevent or address food insecurity. PMID- 30308966 TI - An Apoptotic and Endosymbiotic Explanation of the Warburg and the Inverse Warburg Hypotheses. AB - Otto Warburg, a Nobel prize winner, observed that cancer cells typically "switch" from aerobic to anaerobic respiration. He hypothesized that mitochondrial damage induces neoplastic transformation. In contrast, pathological aging is observed mainly in neuron cells in neurodegenerative diseases. Oxidative respiration is particularly active in neurons. There is inverse comorbidity between cancer and neurodegenerative diseases. This led to the creation of the "inverse Warburg hypothesis", according to which excessive mitochondrial activity induces pathological aging. The findings of our studies suggest that both the Warburg effect and the "inverse Warburg hypothesis" can be elucidated by the activation or suppression of apoptosis through oxidative respiration. The key outcome of our phylogenetic studies was the discovery that apoptosis and apoptosis-like cell death evolved due to an evolutionary "arms race" conducted between "prey" protomitochondrion and "predator" primitive eukaryotes. The ancestral protomitochondrial machinery produces and releases toxic mitochondrial proteins. Extant apoptotic factors evolved from these toxins. Our experiments indicate that the mitochondrial machinery is directly involved in adaptation to aerobic conditions. Additionally, our hypothesis is supported by the fact that different apoptotic factors are directly involved in respiration. PMID- 30308969 TI - Meliacarpinin-Type Limonoids from the Bark of Melia toosendan. AB - Three new meliacarpinin-type limonoids, toosendanes A-C (1-3), along with three, known meliacarpinins (4-6) were isolated from the bark of Melia toosendan. Their structures, along with their absolute configurations, were elucidated, based on detailed analyses. These included HRESIMS and 1D/2D-NMR, modified Mosher's method, and electronic circular dichroism (ECD). Limonoids 2 and 3 showed moderate inhibitory activity on LPS-activated, RAW 264.7 macrophages. PMID- 30308971 TI - A Protein Intrinsic Disorder Approach for Characterising Differentially Expressed Genes in Transcriptome Data: Analysis of Cell-Adhesion Regulated Gene Expression in Lymphoma Cells. AB - Conformational protein properties are coupled to protein functionality and could provide a useful parameter for functional annotation of differentially expressed genes in transcriptome studies. The aim was to determine whether predicted intrinsic protein disorder was differentially associated with proteins encoded by genes that are differentially regulated in lymphoma cells upon interaction with stromal cells, an interaction that occurs in microenvironments, such as lymph nodes that are protective for lymphoma cells during chemotherapy. Intrinsic disorder protein properties were extracted from the Database of Disordered Protein Prediction (D2P2), which contains data from nine intrinsic disorder predictors. Proteins encoded by differentially regulated cell-adhesion regulated genes were enriched in intrinsically disordered regions (IDRs) compared to other genes both with regard to IDR number and length. The enrichment was further ascribed to down-regulated genes. Consistently, a higher proportion of proteins encoded by down-regulated genes contained at least one IDR or were completely disordered. We conclude that down-regulated genes in stromal cell-adherent lymphoma cells encode proteins that are characterized by elevated levels of intrinsically disordered conformation, indicating the importance of down regulating functional mechanisms associated with intrinsically disordered proteins in these cells. Further, the approach provides a generally applicable and complementary alternative to classification of differentially regulated genes using gene ontology or pathway enrichment analysis. PMID- 30308972 TI - Mental Health and Environmental Exposures: An Editorial. PMID- 30308973 TI - Stress-Reducing Function of Matcha Green Tea in Animal Experiments and Clinical Trials. AB - Theanine, a major amino acid in green tea, exhibits a stress-reducing effect in mice and humans. Matcha, which is essentially theanine-rich powdered green tea, is abundant in caffeine. Caffeine has a strong antagonistic effect against theanine. The stress-reducing effect of matcha was examined with an animal experiment and a clinical trial. The stress-reducing effect of matcha marketed in Japan and abroad was assessed based on its composition. The stress-reducing effect of matcha in mice was evaluated as suppressed adrenal hypertrophy using territorially-based loaded stress. High contents of theanine and arginine in matcha exhibited a high stress-reducing effect. However, an effective stress reducing outcome was only possible when the molar ratio of caffeine and epigallocatechin gallate (EGCG) to theanine and arginine was less than two. Participants (n = 39) consumed test-matcha, which was expected to have a stress reducing effect, or placebo-matcha, where no effect was expected. Anxiety, a reaction to stress, was significantly lower in the test-matcha group than in the placebo group. To predict mental function of each matcha, both the quantity of theanine and the ratios of caffeine, EGCG, and arginine against theanine need to be verified. PMID- 30308970 TI - Genes Contributing to Domestication of Rice Seed Traits and Its Global Expansion. AB - Asian rice (Oryza sativa) and African rice (Oryza glaberrima) are separately domesticated from their wild ancestors Oryza rufipogon and Oryza barthii, which are very sensitive to daylength. In the process of domestication, some traits that are favorable for the natural survival of wild rice such as seed dormancy and shattering have become favorable ones for human consumption due to the loss of-function mutations in the genes that are underlying these traits. As a consequence, many genes that are related to these kinds of traits have been fixed with favorable alleles in modern cultivars by artificial selection. After domestication, Oryza sativa cultivars gradually spread to temperate and cool regions from the tropics and subtropics due to the loss of their photoperiod sensitivity. In this paper, we review the characteristics of domestication related seed traits and heading dates in rice, including the key genes controlling these traits, the differences in allelic diversity between wild rice and cultivars, the geographic distribution of alleles, and the regulatory pathways of these traits. A comprehensive comparison shows that these genes contributed to rice domestication and its global expansion. In addition, these traits have also experienced parallel evolution by artificial selection on the homologues of key genes in other cereals. PMID- 30308974 TI - Comparison of a Bioelectrical Impedance Device against the Reference Method Dual Energy X-Ray Absorptiometry and Anthropometry for the Evaluation of Body Composition in Adults. AB - This study aimed to compare the use of the bioelectrical impedance device (BIA) seca(r) mBCA 515 using dual X-ray absorptiometry (DXA) as a reference method, for body composition assessment in adults across the spectrum of body mass indices. It explores the utility of simple anthropometric measures (the waist height ratio (WHtR) and waist circumference (WC)) for the assessment of obesity. In the morning after an overnight fast (10 h), 30 participants underwent a body composition DXA (GE iDXA) scan, BIA (seca 515), and anthropometric measures. Compared to the DXA reference measure, the BIA underestimated fat mass (FM) by 0.32 kg (limits of agreement -3.8 kg, 4.4 kg); overestimated fat free mass (FFM) by 0.43 kg (limits of agreement -8.2 kg, 4.3 kg). Some of the variation was explained by body mass index (BMI), as for FM, the mean difference of the normal range BMI group was smaller than for the overweight/obese group (0.25 kg and 0.35 kg, respectively) with wider limits of agreement (-4.30 kg, 4.81 kg, and -3.61 kg, 4.30 kg, respectively). There were significant differences in visceral adipose tissue (VAT) volume measurements between methods with BIA systematically overestimating VAT compared to DXA. WC was more strongly correlated with DXA FM (rho = 0.90, p < 0.001) than WHtR (rho = 0.83, p < 0.001). BIA had some agreement with DXA; however, they are not equivalent measures for the range of BMIs explored, with DXA remaining the more informative tool. WC is a useful and simple assessment tool for obesity. PMID- 30308975 TI - Significance of a Non-Thermal Plasma Treatment on LDPE Biodegradation with Pseudomonas Aeruginosa. AB - The use of plastics has spanned across almost all aspects of day to day life. Although their uses are invaluable, they contribute to the generation of a lot of waste products that end up in the environment and end up polluting natural habitats such as forests and the ocean. By treating low-density polyethylene (LDPE) samples with non-thermal plasma in ambient air and with an addition of ~4% CO2, the biodegradation of the samples can be increased due to an increase in oxidative species causing better cell adhesion and acceptance on the polymer sample surface. It was, however, found that the use of this slight addition of CO2 aided in the biodegradation of the LDPE samples more than with solely ambient air as the carbon bonds measured from Raman spectroscopy were seen to decrease even more with this change in gas composition and chemistry. The results show that the largest increase of polymer degradation occurs when a voltage of 32 kV is applied over 300 s and with a mixture of ambient air and CO2 in the ratio 25:1. PMID- 30308977 TI - Classification of Cells in CTC-Enriched Samples by Advanced Image Analysis. AB - In the CellSearch(r) system, blood is immunomagnetically enriched for epithelial cell adhesion molecule (EpCAM) expression and cells are stained with the nucleic acid dye 4'6-diamidino-2-phenylindole (DAPI), Cytokeratin-PE (CK), and CD45-APC. Only DAPI+/CK+ objects are presented to the operator to identify circulating tumor cells (CTC) and the identity of all other cells and potential undetected CTC remains unrevealed. Here, we used the open source imaging program Automatic CTC Classification, Enumeration and PhenoTyping (ACCEPT) to analyze all DAPI+ nuclei in EpCAM-enriched blood samples obtained from 192 metastatic non-small cell lung cancer (NSCLC) patients and 162 controls. Significantly larger numbers of nuclei were detected in 300 patient samples with an average and standard deviation of 73,570 +/- 74,948, as compared to 359 control samples with an average and standard deviation of 4191 +/- 4463 (p < 0.001). In patients, only 18% +/- 21% and in controls 23% +/- 15% of the nuclei were identified as leukocytes or CTC. Adding CD16-PerCP for granulocyte staining, the use of an LED as the light source for CD45-APC excitation and plasma membrane staining obtained with wheat germ agglutinin significantly improved the classification of EpCAM enriched cells, resulting in the identification of 94% +/- 5% of the cells. However, especially in patients, the origin of the unidentified cells remains unknown. Further studies are needed to determine if undetected EpCAM+/DAPI+/CK /CD45- CTC is present among these cells. PMID- 30308978 TI - Purification and Characterization of JZTx-14, a Potent Antagonist of Mammalian and Prokaryotic Voltage-Gated Sodium Channels. AB - Exploring the interaction of ligands with voltage-gated sodium channels (NaVs) has advanced our understanding of their pharmacology. Herein, we report the purification and characterization of a novel non-selective mammalian and bacterial NaVs toxin, JZTx-14, from the venom of the spider Chilobrachys jingzhao. This toxin potently inhibited the peak currents of mammalian NaV1.2-1.8 channels and the bacterial NaChBac channel with low IC50 values (<1 uM), and it mainly inhibited the fast inactivation of the NaV1.9 channel. Analysis of NaV1.5/NaV1.9 chimeric channel showed that the NaV1.5 domain II S3-4 loop is involved in toxin association. Kinetics data obtained from studying toxin-NaV1.2 channel interaction showed that JZTx-14 was a gating modifier that possibly trapped the channel in resting state; however, it differed from site 4 toxin HNTx III by irreversibly blocking NaV currents and showing state-independent binding with the channel. JZTx-14 might stably bind to a conserved toxin pocket deep within the NaV1.2-1.8 domain II voltage sensor regardless of channel conformation change, and its effect on NaVs requires the toxin to trap the S3-4 loop in its resting state. For the NaChBac channel, JZTx-14 positively shifted its conductance-voltage (G-V) and steady-state inactivation relationships. An alanine scan analysis of the NaChBac S3-4 loop revealed that the 108th phenylalanine (F108) was the key residue determining the JZTx-14-NaChBac interaction. In summary, this study provided JZTx-14 with potent but promiscuous inhibitory activity on both the ancestor bacterial NaVs and the highly evolved descendant mammalian NaVs, and it is a useful probe to understand the pharmacology of NaVs. PMID- 30308979 TI - Sub-Nanomolar Methylmercury Exposure Promotes Premature Differentiation of Murine Embryonic Neural Precursor at the Expense of Their Proliferation. AB - Methylmercury (MeHg) is a ubiquitous environmental pollutant that is known to be neurotoxic, particularly during fetal development. However, the mechanisms responsible for MeHg-induced changes in adult neuronal function, when their exposure occurred primarily during fetal development, are not yet understood. We hypothesized that fetal MeHg exposure could affect neural precursor development leading to long-term neurotoxic effects. Primary cortical precursor cultures obtained from embryonic day 12 were exposed to 0 nM, 0.25 nM, 0.5 nM, 2.5 nM, and 5 nM MeHg for 48 or 72 h. Total Hg accumulated in the harvested cells in a dose dependent manner. Not all of the concentrations tested in the study affected cell viability. Intriguingly, we observed that cortical precursor exposed to 0.25 nM MeHg showed increased neuronal differentiation, while its proliferation was inhibited. Reduced neuronal differentiation, however, was observed in the higher dose groups. Our results suggest that sub-nanomolar MeHg exposure may deplete the pool of neural precursors by increasing premature neuronal differentiation, which can lead to long-term neurological effects in adulthood as opposed to the higher MeHg doses that cause more immediate toxicity during infant development. PMID- 30308976 TI - Role of Functional Beverages on Sport Performance and Recovery. AB - Functional beverages represent a palatable and efficient way to hydrate and reintegrate electrolytes, carbohydrates, and other nutrients employed and/or lost during physical training and/or competitions. Bodily hydration during sporting activity is one of the best indicators of health in athletes and can be a limiting factor for sport performance. Indeed, dehydration strongly decreases athletic performance until it is a risk to health. As for other nutrients, each of them is reported to support athletes' needs both during the physical activity and/or in the post-workout. In this study, we review the current knowledge of macronutrient-enriched functional beverages in sport taking into account the athletes' health, sports performance, and recovery. PMID- 30308980 TI - Fucoxanthin-Containing Cream Prevents Epidermal Hyperplasia and UVB-Induced Skin Erythema in Mice. AB - Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1 macrophages and TNF-alpha-stimulated HaCaT keratinocytes, and its antioxidant activity in UVB irradiated HaCaT cells. Next, in vitro and ex vivo permeation studies were developed to determine the most suitable formulation for in vivo FX topical application. Then, we evaluated the effects of a FX-containing cream on TPA induced epidermal hyperplasia in mice, as well as on UVB-induced acute erythema in hairless mice. Our results confirmed the in vitro reduction of TNF-alpha, IL 6, ROS and LDH production. Since the permeation results showed that cream was the most favourable vehicle, FX-cream was elaborated. This formulation effectively ameliorated TPA-induced hyperplasia, by reducing skin edema, epidermal thickness, MPO activity and COX-2 expression. Moreover, FX-cream reduced UVB-induced erythema through down-regulation of COX-2 and iNOS as well as up-regulation of HO 1 protein via Nrf-2 pathway. In conclusion, FX, administered in a topical formulation, could be a novel natural adjuvant for preventing exacerbations associated with skin inflammatory pathologies as well as protecting skin against UV radiation. PMID- 30308981 TI - Multiwalled Carbon Nanotube for One-Step Cleanup of 21 Mycotoxins in Corn and Wheat Prior to Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry Analysis. AB - One-step solid-phase extraction (SPE) using a multiwalled carbon nanotube (MWCNT) for simultaneous analysis of 21 mycotoxins, including nine trichothecenes, zearalenone (ZEN) and its derivatives, four aflatoxins, and two ochratoxins, in corn and wheat was developed. Several key parameters affecting the performance of the one-step SPE procedure-types of MWCNT, combinations with five sorbents (octadecylsilyl (C18), hydrophilic-lipophilic balance (HLB), mixed-mode cationic exchange (MCX), silica gel, and amino-propyl (NH2)), and filling amounts of the MWCNTs-were thoroughly investigated. The combination of 20 mg carboxylic MWCNT and 200 mg C18 was proven to be the most effective, allowing the quantification of all analyzed mycotoxins in corn and wheat. Under the optimized cleanup procedure prior to ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, the method was validated by analyzing samples spiked at the limit of quantification (LOQ), two-times LOQ, and 10-times LOQ. Satisfactory linearity (r2 >= 0.9910), high sensitivity (LOQ in different ranges of 0.5-25 MUg L-1), good recovery (75.6-110.3%), and acceptable precision (relative standard deviation (RSD), 0.3-10.7%) were obtained. The applicability of the method was further confirmed using raw samples of corn and wheat. In conclusion, the established method was rapid, simple and reliable for simultaneous analysis of 21 mycotoxins in corn and wheat. PMID- 30308982 TI - Hydrophobic Amino Acid Tryptophan Shows Promise as a Potential Absorption Enhancer for Oral Delivery of Biopharmaceuticals. AB - Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase the oral delivery of insulin in its single amino acid form. Therefore, in the present study, we evaluated the ability of another key amino acid, tryptophan, to enhance the intestinal absorption of biopharmaceuticals. We demonstrated that co-administration with l-tryptophan significantly facilitated the oral and intestinal absorption of the peptide drug insulin administered to rats. Furthermore, l-tryptophan exhibited the ability to greatly enhance the intestinal absorption of other peptide drugs such as glucagon-like peptide-1 (GLP 1), its analog Exendin-4 and macromolecular hydrophilic dextrans with molecular weights ranging from 4000 to 70,000 g/mol. However, no intermolecular interaction between insulin and l-tryptophan was observed and no toxic alterations to epithelial cellular integrity-such as changes to cell membranes, cell viability, or paracellular tight junctions-were found. This suggests that yet to be discovered inherent biological mechanisms are involved in the stimulation of insulin absorption by co-administration with l-tryptophan. These results are the first to demonstrate the significant potential of using the single amino acid l tryptophan as an effective and versatile bioavailability enhancer for the oral delivery of biopharmaceuticals. PMID- 30308984 TI - Effects of Probiotic (Bifidobacterium longum 35624) Supplementation on Exercise Performance, Immune Modulation, and Cognitive Outlook in Division I Female Swimmers. AB - Our aim was to determine the effects of probiotic supplementation (Bifidobacterium longum 35624; 1 billion CFU.d-1) on exercise performance, immune modulation, and cognitive outlook in collegiate female athletes during six weeks of offseason training. Seventeen National Collegiate Athletic Association (NCAA) Division 1 collegiate female swimmers participated in this two-group matched, double-blind, placebo controlled design. Via stratified randomization, participants were assigned to probiotic (B. longum 35624; n = 8) or placebo (n = 9) groups. Pre, mid, and post-training, all participants completed exercise performance testing (aerobic/anaerobic swim time trials and force plate vertical jump) as well as provided serum (cytokine and gastrointestinal inflammatory markers) and salivary immunoglobulin A samples. Recovery-stress questionnaire for athletes (RESTQ-Sport) was administered at baseline and conclusion of each week. Data were analyzed by analysis of covariance (ANCOVA) by time point with the respective baseline values of each dependent variable being the covariate. No significant differences in exercise performance and biochemical markers were observed between groups following offseason training. Recovery-Stress Questionnaire for Athletes (RESTQ-sport) values in B. longum 35624 group had significantly higher (i.e., more desired; p < 0.05) values in sport recovery (weeks five and six) than placebo. Probiotic supplementation in collegiate female swimmers did not affect exercise performance or immune function throughout offseason training, but did indicate alterations in cognitive outlook. PMID- 30308983 TI - Molecular Cloning and Expression of MnGST-1 and MnGST-2 from Oriental River Prawn, Macrobrachium nipponense, in Response to Hypoxia and Reoxygenation. AB - The glutathione-S-transferase (GST) superfamily includes seven classes, and different classes have different functions. GST superfamily members function in various processes including detoxification of xenobiotics, protection against oxidative damage, and intracellular transport of hormones, endogenous metabolites, and exogenous chemicals. Herein, to elucidate the tissue-specific expression pattern of GSTs in response to hypoxia stress, which induces cell death, we investigated the expression of GSTs in response to hypoxia and reoxygenation in oriental river prawn, Macrobrachium nipponense. Full-length cDNAs of two delta class GSTs were cloned from the hepatopancreas, and named MnGST-1 and MnGST-2 based on the established GST nomenclature system. Expression profiles of both GSTs in various tissues were different under acute and chronic experimental hypoxia stress conditions, suggesting that both respond strongly to hypoxia-induced oxidative stress. However, the intensity of responses to hypoxia and reoxygenation were different in different tissues. During acute hypoxia stress, MnGST-1 responds earlier than MnGST-2 in the hepatopancreas and gill, but more slowly in muscle. By contrast, during chronic hypoxia stress, MnGST-2 plays a more important role in the hepatopancreas and gill than MnGST-1. PMID- 30308985 TI - Synergistic Effect of Laccase and Sugar Beet Pectin on the Properties of Concentrated Protein Emulsions and Its Application in Concentrated Coconut Milk. AB - Concentrated coconut milk (CCM), a raw material from coconut products, is extremely unstable because of its high oil content (>30%). In this study, three model emulsions-primary emulsions stabilized by coconut proteins only, secondary emulsions stabilized by the conjugation of sugar beet pectin (SBP) and coconut protein, and laccase-treated secondary emulsions-were prepared to investigate the effects of different factors (coconut proteins, coconut proteins + SBP, laccase treated emulsions) on the stability of model emulsions and the application of this method to real CCM. The stability of the emulsions was evaluated based on their interfacial tension, zeta potential, particle size distribution, rheological properties, and the assembly formation of SBP and coconut protein at the oil-water interface. Results showed that addition of SBP or laccase can increase the viscosity and reduce the interfacial tension of the emulsion, and the effect was concentration dependent. Zeta potential of the emulsion decreased with the increase of protein (from -16 to -32 mV) and addition of SBP (from -32 to -46 mV), and it was reduced when laccase was added (from -9.5 to -6.0 mV). The secondary emulsion exhibited the narrowest particle size distribution (from 0.1 to 20 MUm); however, laccase-catalyzed secondary emulsions showed the best storage stability and no layering when the laccase content reached 10 U/100 g. Confocal laser scanning microscopy (CLSM) revealed that protein was adsorbed on the oil-water interface and SBP distributed in the continuous phase could undergo oxidative crosslinking by laccase. These results show that the stability of the concentrated emulsion can be effectively improved by adding SBP and laccase. PMID- 30308986 TI - Concentric Ring Probe for Bioimpedance Spectroscopic Measurements: Design and Ex Vivo Feasibility Testing on Pork Oral Tissues. AB - Many oral diseases, such as oral leukoplakia and erythroplakia, which have a high potential for malignant transformations, cause abnormal structural changes in the oral mucosa. These changes are clinically assessed by visual inspection and palpation despite their poor accuracy and subjective nature. We hypothesized that non-invasive bioimpedance spectroscopy (BIS) might be a viable option to improve the diagnostics of potentially malignant lesions. In this study, we aimed to design and optimize the measurement setup and to conduct feasibility testing on pork oral tissues. The contact pressure between a custom-made concentric ring probe and tissue was experimentally optimized. The effects of loading time and inter-electrode spacing on BIS spectra were also clarified. Tissue differentiation testing was performed for ex vivo pork oral tissues including palatinum, buccal mucosa, fat, and muscle tissue samples. We observed that the most reproducible results were obtained by using a loading weight of 200 g and a fixed time period under press, which was necessary to allow meaningful quantitative comparison. All studied tissues showed their own unique spectra, accompanied by significant differences in both impedance magnitude and phase (p <= 0.014, Kruskal-Wallis test). BIS shows promise, and further studies are warranted to clarify its potential to detect specific pathological tissue alterations. PMID- 30308988 TI - Development of a Screening Method for Health Hazard Ranking and Scoring of Chemicals Using the Mahalanobis-Taguchi System. AB - For efficient management of chemicals, it is necessary to preferentially select hazardous chemicals as being high-priority through a screening method. Over the past 20 years, chemical ranking and scoring (CRS) methods have been applied in many countries; however, these CRS methods have a few limitations. Most of the existing methods only use some of the variables to calculate the hazard of chemicals or use the most conservative score without consideration of the correlation between chemical toxicities. This evaluation could underestimate or overestimate the real health hazard of the chemicals. To overcome the limitations of these methods, we developed a new CRS method using the Mahalanobis-Taguchi System (MTS). The MTS, which conducts multivariate analysis, produced chemical rankings that took into accounts the correlation between variables related to chemical health hazards. Also, the proportion of chemicals managed by the Korea Chemicals Control Act that were given a high rating appeared to be higher when the MTS was used, compared to the existing methods. These results indicated that the new method evaluated the health hazards of chemicals more accurately, and we expect that the MTS method could be applied to a greater range of chemicals than the existing CRS methods. PMID- 30308987 TI - Dietary Protein Sources and Muscle Mass over the Life Course: The Lifelines Cohort Study. AB - The influence of dietary protein intake on muscle mass in adults remains unclear. Our objective was to investigate the association between protein intake and muscle mass in 31,278 men and 45,355 women from the Lifelines Cohort. Protein intake was estimated by food frequency questionnaire and muscle mass was estimated from 24 h urinary creatinine excretion. The age range was 18-91 years and mean total protein intake was 1.0 +/- 0.3 g/kg/day. Across increasing quartiles of total protein intake, animal protein intake, and fish/meat/egg protein intake, creatinine excretion significantly increased in both men (+4% for total and +6% for fish/meat/egg protein intake, p < 0.001) and women (+3% for total and +6% for fish/meat/egg protein intake, p < 0.001). The associations were not systematically stronger or weaker with increasing age, but associations were strongest for young men (26-45 years) and older women (>75 years). The association between total protein intake and muscle mass was dependent on physical activity in women (p interaction < 0.001). This study suggests that total protein intake, animal protein intake, and in particular fish/meat/egg protein intake may be important for building and preserving muscle mass. Dietary protein sources should be further studied for their potential to build and preserve muscle mass. PMID- 30308989 TI - Fabrication of an Optical Waveguide-Mode-Field Compressor in Glass Using a Femtosecond Laser. AB - We report on fabrication of an optical waveguide-mode-field compressor in glass using a femtosecond laser. Our approach is based on building up a stress field within the waveguiding area which is realized by sandwiching the waveguide between a pair of laser-induced-modification-tracks. To induce an adiabatic conversion of the optical mode in the waveguide, the tracks are intentionally designed to be tapered along the waveguide. We show that our technique can allow for reducing the mode field size in a single mode waveguide from more than 10 MUm to around 7 MUm. PMID- 30308991 TI - Study of PtOx/TiO2 Photocatalysts in the Photocatalytic Reforming of Glycerol: The Role of Co-Catalyst Formation. AB - In this study, relationships between preparation conditions, structure, and activity of Pt-containing TiO2 photocatalysts in photoinduced reforming of glycerol for H2 production were explored. Commercial Aerolyst(r) TiO2 (P25) and homemade TiO2 prepared by precipitation-aging method were used as semiconductors. Pt co-catalysts were prepared by incipient wetness impregnation from aqueous solution of Pt(NH3)4(NO3)2 and activated by calcination, high temperature hydrogen, or nitrogen treatments. The chemico-physical and structural properties were evaluated by XRD, 1H MAS NMR, ESR, XPS, TG-MS and TEM. The highest H2 evolution rate was observed over P25 based samples and the H2 treatment resulted in more active samples than the other co-catalyst formation methods. In all calcined samples, reduction of Pt occurred during the photocatalytic reaction. Platinum was more easily reducible in all of the P25 supported samples compared to those obtained from the more water-retentive homemade TiO2. This result was related to the negative effect of the adsorbed water content of the homemade TiO2 on Pt reduction and on particle growth during co-catalyst formation. PMID- 30308993 TI - Synthetic Aperture Radar Processing Approach for Simultaneous Target Detection and Image Formation. AB - Finding out interested targets from synthetic aperture radar (SAR) imagery is an attractive but challenging problem in SAR application. Traditional target detection is independent on SAR imaging process, which is purposeless and unnecessary. Hence, a new SAR processing approach for simultaneous target detection and image formation is proposed in this paper. This approach is based on SAR imagery formation in time domain and human visual saliency detection. First, a series of sub-aperture SAR images with resolutions from low to high are generated by the time domain SAR imaging method. Then, those multiresolution SAR images are detected by the visual saliency processing, and the corresponding intermediate saliency maps are obtained. The saliency maps are accumulated until the result with a sufficient confidence level. After some screening operations, the target regions on the imaging scene are located, and only these regions are focused with full aperture integration. Finally, we can get the SAR imagery with high-resolution detected target regions but low-resolution clutter background. Experimental results have shown the superiority of the proposed approach for simultaneous target detection and image formation. PMID- 30308992 TI - Wnt/beta-Catenin Signaling as a Potential Target for the Treatment of Liver Cirrhosis Using Antifibrotic Drugs. AB - Cirrhosis is a form of liver fibrosis resulting from chronic hepatitis and caused by various liver diseases, including viral hepatitis, alcoholic liver damage, nonalcoholic steatohepatitis, and autoimmune liver disease. Cirrhosis leads to various complications, resulting in poor prognoses; therefore, it is important to develop novel antifibrotic therapies to counter liver cirrhosis. Wnt/beta-catenin signaling is associated with the development of tissue fibrosis, making it a major therapeutic target for treating liver fibrosis. In this review, we present recent insights into the correlation between Wnt/beta-catenin signaling and liver fibrosis and discuss the antifibrotic effects of the cAMP-response element binding protein/beta-catenin inhibitor PRI-724. PMID- 30308994 TI - Medial Collateral Ligament Deficiency of the Elbow Joint: A Computational Approach. AB - Computational elbow joint models, capable of simulating medial collateral ligament deficiency, can be extremely valuable tools for surgical planning and refinement of therapeutic strategies. The objective of this study was to investigate the effects of varying levels of medial collateral ligament deficiency on elbow joint stability using subject-specific computational models. Two elbow joint models were placed at the pronated forearm position and passively flexed by applying a vertical downward motion on humeral head. The models included three-dimensional bone geometries, multiple ligament bundles wrapped around the joint, and the discretized cartilage representation. Four different ligament conditions were simulated: All intact ligaments, isolated medial collateral ligament (MCL) anterior bundle deficiency, isolated MCL posterior bundle deficiency, and complete MCL deficiency. Minimal kinematic differences were observed for isolated anterior and posterior bundle deficient elbows. However, sectioning the entire MCL resulted in significant kinematic differences and induced substantial elbow instability. Joint contact areas were nearly similar for the intact and isolated posterior bundle deficiency. Minor differences were observed for the isolated anterior bundle deficiency, and major differences were observed for the entire MCL deficiency. Complete elbow dislocations were not observed for any ligament deficiency level. As expected, during isolated anterior bundle deficiency, the remaining posterior bundle experiences higher load and vice versa. Overall, the results indicate that either MCL anterior or posterior bundle can provide anterior elbow stability, but the anterior bundle has a somewhat bigger influence on joint kinematics and contact characteristics than posterior one. A study with a larger sample size could help to strengthen the conclusion and statistical significant. PMID- 30308990 TI - Chronic Infections: A Possible Scenario for Autophagy and Senescence Cross-Talk. AB - Multiple tissues and systems in the organism undergo modifications during aging due to an accumulation of damaged proteins, lipids, and genetic material. To counteract this process, the cells are equipped with specific mechanisms, such as autophagy and senescence. Particularly, the immune system undergoes a process called immunosenescence, giving rise to a chronic inflammatory status of the organism, with a decreased ability to counteract antigens. The obvious result of this process is a reduced defence capacity. Currently, there is evidence that some pathogens are able to accelerate the immunosenescence process for their own benefit. Although to date numerous reports show the autophagy-senescence relationship, or the connection between pathogens with autophagy or senescence, the link between the three actors remains unexplored. In this review, we have summarized current knowledge about important issues related to aging, senescence, and autophagy. PMID- 30308995 TI - Development of Cracking Patterns in Modified Cement Matrix with Microsilica. AB - The paper evaluates the cracking patterns created on the surface of a microsilica modified cement matrix, which has been subjected to exposure at elevated temperatures. To do this, image analysis techniques were used, and the structure of the cracks was described by the stereological parameters. Four series of specimens were tested and in two of them, microsilica was used as a 10% replacement for the cement content. Using the theory of dispersion systems, the factors affecting the cracks' characteristics were identified. Additionally, the development process of cracking patterns due to the thermal interaction was schematically modeled. In addition, the analysis of the local microstructure of the cement matrix was performed by means of a scanning electron microscope and energy dispersive x-ray spectroscopy. PMID- 30308996 TI - Multi-Target Intense Human Motion Analysis and Detection Using Channel State Information. AB - Intense human motion, such as hitting, kicking, and falling, in some particular scenes indicates the occurrence of abnormal events like violence and school bullying. Camera-based human motion detection is an effective way to analyze human behavior and detect intense human motion. However, even if the camera is properly deployed, it will still generate blind spots. Moreover, camera-based methods cannot be used in places such as restrooms and dressing rooms due to privacy issues. In this paper, we propose a multi-target intense human motion detection scheme using commercial Wi-Fi infrastructures. Compared with human daily activities, intense human motion usually has the characteristics of intensity, rapid change, irregularity, large amplitude, and continuity. We studied the changing pattern of Channel State Information (CSI) influenced by intense human motion, and extracted features in the pattern by conducting a large number of experiments. Considering occlusion exists in some complex scenarios, we distinguished the Line-of-Sight (LOS) and Non-Line-of-Sight (NLOS) conditions in the case of obstacles appearing between the transmitter and the receiver, which further improves the overall performance. We implemented the intense human motion detection system using single commercial Wi-Fi devices, and evaluated it in real indoor environments. The experimental results show that our system can achieve intense human motion detection rate of 90%. PMID- 30308997 TI - Self-Calibration of an Industrial Robot Using a Novel Affordable 3D Measuring Device. AB - This work shows the feasibility of calibrating an industrial robot arm through an automated procedure using a new, low-cost, wireless measuring device mounted on the robot's flange. The device consists of three digital indicators that are fixed orthogonally to each other on an aluminum support. Each indicator has a measuring accuracy of 3 um. The measuring instrument uses a kinematic coupling platform which allows for the definition of an accurate and repeatable tool center point (TCP). The idea behind the calibration method is for the robot to bring automatically this TCP to three precisely-known positions (the centers of three precision balls fixed with respect to the robot's base) and with different orientations of the robot's end-effector. The self-calibration method was tested on a small six-axis industrial robot, the ABB IRB 120 (Vasteras, Sweden). The robot was modeled by including all its geometrical parameters and the compliance of its joints. The parameters of the model were identified using linear regression with the least-square method. Finally, the performance of the calibration was validated with a laser tracker. This validation showed that the mean and the maximum absolute position errors were reduced from 2.628 mm and 6.282 mm to 0.208 mm and 0.482 mm, respectively. PMID- 30308998 TI - Sleep and Delirium in Pediatric Critical Illness: What Is the Relationship? AB - With growing recognition of pediatric delirium in pediatric critical illness there has also been increased investigation into improving recognition and determining potential risk factors. Disturbed sleep has been assumed to be one of the key risk factors leading to delirium and is commonplace in the pediatric critical care setting as the nature of intensive care requires frequent and invasive monitoring and interventions. However, this relationship between sleep and delirium in pediatric critical illness has not been definitively established and may, instead, reflect significant overlap in risk factors and consequences of underlying neurologic dysfunction. We aim to review the existing tools for evaluation of sleep and delirium in the pediatric critical care setting and review findings from recent investigations with application of these measures in the pediatric intensive care unit. PMID- 30308999 TI - Filling the Gaps: Current Research Directions for a Rational Use of Probiotics in Preterm Infants. AB - The use of probiotics among very low-birth-weight infants is constantly increasing, as probiotics are believed to reduce the incidence of severe diseases such as necrotizing enterocolitis and late-onset sepsis and to improve feeding tolerance. However, despite the enthusiasm towards these products in neonatal medicine, theoretical knowledge and clinical applications still need to be improved. The purpose of this review is to give an overview of the most important gaps in the current literature about potential uses of probiotics in preterm infants, highlighting promising directions for future research. Specifically, further well-designed studies should aim at clarifying the impact of the type of feeding (mother's milk, donor milk, and formula) on the relationship between probiotic supplementation and clinical outcome. Moreover, future research is needed to provide solid evidence about the potential greater efficacy of multi strain probiotics compared to single-strain products. Safety issues should also be addressed properly, by exploring the potential of paraprobiotics and risks connected to antibiotic resistance in preterm infants. Last, in light of increasing commercial and public interests, the long-term effect of routine consumption of probiotics in such a vulnerable population should be also evaluated. PMID- 30309000 TI - Fatty Acid Composition and Fatty Acid Associated Gene-Expression in Gilthead Sea Bream (Sparus aurata) are Affected by Low-Fish Oil Diets, Dietary Resveratrol, and Holding Temperature. AB - To sustainably produce marine fish with a high lipid quality rich in omega-3 fatty acids, alternative sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are being identified. Moreover, the use of bioactive compounds that would stimulate the in vivo fatty acid synthesis, such as resveratrol (RV), would reduce the dependence on fish oil in aquafeeds. Gilthead sea bream (Sparus aurata) were fed four experimental diets combining two fish oil levels (6% dry matter (DM); 2% DM) with or without 0.15% DM resveratrol supplementation (F6, F2, F6 + RV, F2 + RV) for two months. Additionally, the fish were challenged either at 19 degrees C or 23 degrees C. A higher water temperature promoted their feed intake and growth, resulting in an increased crude lipid content irrespective of dietary treatment. The fatty acid composition of different tissues was significantly affected by the holding temperature and dietary fish oil level. The dietary RV significantly affected the hepatic EPA and DHA content of fish held at 19 degrees C. The observed effect of RV may be partly explained by alterations of the mRNA steady-state levels of ?6-desaturase and beta-oxidation-related genes. Besides the relevant results concerning RV mediated regulation of fatty acid synthesis in marine fish, further studies need to be conducted to clarify the potential value of RV to enhance fillet lipid quality. PMID- 30309002 TI - Diffusion Logarithm-Correntropy Algorithm for Parameter Estimation in Non Stationary Environments over Sensor Networks. AB - This paper considers the parameter estimation problem under non-stationary environments in sensor networks. The unknown parameter vector is considered to be a time-varying sequence. To further promote estimation performance, this paper suggests a novel diffusion logarithm-correntropy algorithm for each node in the network. Such an algorithm can adopt both the logarithm operation and correntropy criterion to the estimation error. Moreover, if the error gets larger due to the non-stationary environments, the algorithm can respond immediately by taking relatively steeper steps. Thus, the proposed algorithm achieves smaller error in time. The tracking performance of the proposed logarithm-correntropy algorithm is analyzed. Finally, experiments verify the validity of the proposed algorithmic schemes, which are compared to other recent algorithms that have been proposed for parameter estimation. PMID- 30309001 TI - Tumor Location Influences Oncologic Outcomes of Hepatocellular Carcinoma Patients Undergoing Radiofrequency Ablation. AB - : Radiofrequency ablation (RFA) is recommended as a first-line therapy for small hepatocellular carcinoma (HCC). Tumor location is a potential factor influencing the procedure of RFA. To compare oncologic outcomes of RFA for different tumor locations, this retrospective study enrolled 194 patients with small HCC who had undertaken RFA. The HCC nodules were classified as peri-hepatic-vein (pHV) or non pHV, peri-portal-vein (pPV) or non-pPV, and subcapsular or non-subcapsular HCC. The regional recurrence-free survival (rRFS), overall survival (OS), recurrence free survival (recurrence in any location, RFS) and distant recurrence-free survival (dRFS) were compared. Operation failures were recorded in five pPV HCC patients, which was more frequent than in non-pPV HCC patients (p = 0.041). The 1 , 3-, and 5-year rRFS was 68.7%, 53.7%, and 53.7% for pHV patients and 85.1%, 76.1%, and 71.9% for non-pHV patients, respectively (p = 0.012). After propensity score matching, the 1-, 3-, and 5-year rRFS was still worse than that of non-pHV patients (p = 0.013). The OS, RFS, and dRFS were not significantly different between groups. CONCLUSIONS: A pHV location was a risk factor for the regional recurrence after RFA in small HCC patients. The tumor location may not influence OS, RFS, and dRFS. Additionally, a pPV location was a potential high-risk factor for incomplete ablation. PMID- 30309004 TI - Selectable Markers and Reporter Genes for Engineering the Chloroplast of Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii is a model alga of increasing interest as a cell factory for the production of valuable compounds, including therapeutic proteins and bioactive metabolites. Expression of foreign genes in the chloroplast is particularly advantageous as: (i) accumulation of product in this sub-cellular compartment minimises potential toxicity to the rest of the cell; (ii) genes can integrate at specific loci of the chloroplast genome (plastome) by homologous recombination; (iii) the high ploidy of the plastome and the high-level expression of chloroplast genes can be exploited to achieve levels of recombinant protein as high as 5% total cell protein; (iv) the lack of any gene silencing mechanisms in the chloroplast ensures stable expression of transgenes. However, the generation of C. reinhardtii chloroplast transformants requires efficient methods of selection, and ideally methods for subsequent marker removal. Additionally, the use of reporter genes is critical to achieving a comprehensive understanding of gene expression, thereby informing experimental design for recombinant applications. This review discusses currently available selection and reporter systems for chloroplast engineering in C. reinhardtii, as well as those used for chloroplast engineering in higher plants and other microalgae, and looks to the future in terms of possible new markers and reporters that will further advance the C. reinhardtii chloroplast as an expression platform. PMID- 30309003 TI - Kaempferol Attenuates ROS-Induced Hemolysis and the Molecular Mechanism of Its Induction of Apoptosis on Bladder Cancer. AB - Bladder cancer has become the most common malignant urinary carcinoma. Studies have shown that significant antioxidant and bladder cancer-fighting properties of several plant-based diets like Psidium guajava, ginger and amomum, are associated with their high kaempferol content. In this paper, we evaluated the antioxidant and anticancer activities of kaempferol and its mechanism of induction to apoptosis on bladder cancer cells. Our findings demonstrated that kaempferol showed an obvious radical scavenging activity in erythrocytes damaged by oxygen. Kaempferol promoted antioxidant enzymes, inhibited ROS generation and lipid peroxidation and finally prevented the occurrence of hemolysis. Additionally, kaempferol exhibited a strong inhibitory effect on bladder cancer cells and high safety on normal bladder cells. At the molecular level, kaempferol suppressed EJ bladder cancer cell proliferation by inhibiting the function of phosphorylated AKT (p-AKT), CyclinD1, CDK4, Bid, Mcl-1 and Bcl-xL, and promoting p-BRCA1, p-ATM, p53, p21, p38, Bax and Bid expression, and finally triggering apoptosis and S phase arrest. We found that Kaempferol exhibited strong anti-oxidant activity on erythrocyte and inhibitory effects on the growth of cancerous bladder cells through inducing apoptosis and S phase arrest. These findings suggested that kaempferol might be regarded as a bioactive food ingredient to prevent oxidative damage and treat bladder cancer. PMID- 30309005 TI - A High-Performance Optoelectronic Sensor Device for Nitrate Nitrogen in Recirculating Aquaculture Systems. AB - The determination of nitrate nitrogen (NO3-N) in recirculating aquaculture systems is of great significance for the health assessment of the living environment of aquatic animals. Unfortunately, the commonly used spectrophotometric methods often yield unstable results, especially when the ambient temperature varies greatly in the field measurement. Here, we have developed a novel handheld absorbance measurement sensor based on the thymol-NO3 N chromogenic rearrangement reaction. In terms of hardware, the sensor adopts a dual channel/dual wavelength colorimeter structure that features a modulated light source transmitter and a synchronous detector receiver. The circuit measures the ratio of light absorbed by the sample and reference containers at two LEDs with peak wavelengths at 420 nm and 450 nm. Using the modulated source and synchronous detector rather than a constant (DC) source eliminates measurement errors due to ambient light and low frequency noise and provides higher accuracy. In terms of software, we design a new quantitative analysis algorithm for absorbance by studying colloid absorbing behavior. The application of a buffer operator embedded in the algorithm makes the sensor get the environmental correction function. The results have shown that the sensitivity, repeatability, precision and environmental stability are higher than that by ordinary spectrophotometry. Lastly, we have a brief overview of future work. PMID- 30309006 TI - Functionalization of Silk with In-Situ Synthesized Platinum Nanoparticles. AB - After platinum nanoparticles (PtNPs) were in-situ synthesized on silk fabrics through heat treatment, it was determined that the treatment of the silk fabrics with PtNPs imparted multiple functions, including coloring, catalysis, and antibacterial activity. The formation of PtNPs on fabrics was affected by the Pt ion concentration, pH value of solution, and reaction temperature. Acidic condition and high temperature were found to facilitate the formation of PtNPs on silk. The color strength of silk fabrics increased with the concentration of Pt ions. The PtNP treated silk fabrics exhibited reasonably good washing color fastness and excellent rubbing color fastness. The morphologies and chemical components of the treated silk fabrics were analyzed using scanning electron microscopy and X-ray photoelectron spectroscopy. The PtNP treated silk fabric exhibited significant catalytic function and a notable antibacterial effect against Escherichia coli (E. coli). PMID- 30309007 TI - Sequence Composition and Evolution of Mammalian B Chromosomes. AB - B chromosomes (Bs) revealed more than a hundred years ago remain to be some of the most mysterious elements of the eukaryotic genome. Their origin and evolution, DNA composition, transcriptional activity, impact on adaptiveness, behavior in meiosis, and transfer to the next generation require intensive investigations using modern methods. Over the past years, new experimental techniques have been applied and helped us gain a deeper insight into the nature of Bs. Here, we consider mammalian Bs, taking into account data on their DNA sequencing, transcriptional activity, positions in nuclei of somatic and meiotic cells, and impact on genome functioning. Comparative cytogenetics of Bs suggests the existence of different mechanisms of their formation and evolution. Due to the long and complicated evolvement of Bs, the similarity of their morphology could be explained by the similar mechanisms involved in their development while the difference between Bs even of the same origin could appear due to their positioning at different stages of their evolution. A complex analysis of their DNA composition and other features is required to clarify the origin and evolutionary history of Bs in the species studied. The intraspecific diversity of Bs makes this analysis a very important element of B chromosome studies. PMID- 30309009 TI - Large Depth-of-Field Integral Microscopy by Use of a Liquid Lens. AB - Integral microscopy is a 3D imaging technique that permits the recording of spatial and angular information of microscopic samples. From this information it is possible to calculate a collection of orthographic views with full parallax and to refocus computationally, at will, through the 3D specimen. An important drawback of integral microscopy, especially when dealing with thick samples, is the limited depth of field (DOF) of the perspective views. This imposes a significant limitation on the depth range of computationally refocused images. To overcome this problem, we propose here a new method that is based on the insertion, at the pupil plane of the microscope objective, of an electrically controlled liquid lens (LL) whose optical power can be changed by simply tuning the voltage. This new apparatus has the advantage of controlling the axial position of the objective focal plane while keeping constant the essential parameters of the integral microscope, that is, the magnification, the numerical aperture and the amount of parallax. Thus, given a 3D sample, the new microscope can provide a stack of integral images with complementary depth ranges. The fusion of the set of refocused images permits to enlarge the reconstruction range, obtaining images in focus over the whole region. PMID- 30309010 TI - The Epidemiological Influence of Climatic Factors on Shigellosis Incidence Rates in Korea. AB - Research has shown the effects of climatic factors on shigellosis; however, no previous study has evaluated climatic effects in regions with a winter seasonality of shigellosis incidence. We examined the effects of temperature and precipitation on shigellosis incidence in Korea from 2002-2010. The incidence of shigellosis was calculated based on data from the Korean Center for Disease Control and Prevention (KCDC, Cheongju, Korea), and a generalized additive model (GAM) was used to analyze the associations between the incidence and climatic factors. The annual incidence rate of shigellosis was 7.9 cases/million persons from 2002-2010. During 2007-2010, high incidence rates and winter seasonality were observed among those aged >=65 years, but not among lower age groups. Based on the GAM model, the incidence of shigellosis is expected to increase by 13.6% and 2.9% with a temperature increase of 1 degrees C and a lag of two weeks and with a mean precipitation increase of 1 mm and a lag of five weeks after adjustment for seasonality, respectively. This study suggests that the incidence of shigellosis will increase with global climate change despite the winter seasonality of shigellosis in Korea. Public health action is needed to prevent the increase of shigellosis incidence associated with climate variations. PMID- 30309008 TI - The Effectiveness of a Smartphone Application on Modifying the Intakes of Macro and Micronutrients in Primary Care: A Randomized Controlled Trial. The EVIDENT II Study. AB - BACKGROUND: This study evaluates the effectiveness of adding a diet smartphone application to standard counseling to modify dietary composition over the long term (12 months). METHODS: A randomized, controlled, multicenter clinical trial was conducted involving the participation of 833 subjects from primary care clinics (415 to the intervention (counseling + application) group (IG) and 418 to the control (counseling) group (CG)). Both groups were counseled about a healthy diet and physical activity. For the 3-month intervention period, the IG was also trained to use a diet smartphone application that involved dietary self monitoring and tailored feedback. Nutritional composition was estimated using a self-reported food frequency questionnaire. RESULTS: An analysis of repeated measures revealed an interaction between the group and the percentages of carbohydrates (p = 0.031), fats (p = 0.015) and saturated fats (p = 0.035) consumed. Both groups decreased their energy intake (Kcal) at 12 months (IG: -114 (95% CI: -191 to -36); CG: -108 (95% CI: -184 to -31)). The IG reported a higher percentage intake of carbohydrates (1.1%; 95% CI: 0.1 to 2.0), and lower percentage intakes of fats (-1.0%; 95% CI: -1.9 to -0.1) and saturated fats ( 0.4%; 95%CI: -0.8 to -0.1) when compared to the CG. CONCLUSIONS: Better results were achieved in terms of modifying usual diet composition from counseling and the diet smartphone application compared to counseling alone. This was evaluated by a self-reported questionnaire, which indicated an increased percentage intake of carbohydrates, and decreased percentage intakes of fats and saturated fats. PMID- 30309011 TI - Phytochemical Profiling of Fruit Powders of Twenty Sorbus L. Cultivars. AB - Rowanberries have been traditionally used in various processed foods. Scientific research demonstrates the pharmacological effects of Sorbus L. fruits are determined by their unique composition of biologically active compounds. The aim of this study was to determine the composition of flavonoids, phenolic acids, anthocyanins, carotenoids, organic acids and sugars as well as the total antioxidant activity in fruit powders of 20 Sorbus cultivars. Chemical profiles of rowanberry fruit powders vary significantly. Cultivars 'Burka', 'Likernaja', 'Dodong', and 'Fructo Lutea' distinguish themselves with exclusive phytochemical composition and high antioxidant activity. Fruit powders from 'Burka', 'Likernaja' contain the highest contents of anthocyanins while fruit powder samples from 'Fructo Lutea' and 'Dodong' contain the highest levels of phenolic acids, ascorbic acid and the lowest levels of fructose. Fruit powder samples from 'Dodong' also contain the highest levels of beta-carotene and sorbitol and the lowest levels of malic acid. Cultivars 'Burka', 'Likernaja', 'Dodong', and 'Fructo Lutea' could be selected as eligible raw materials for the preparation of rowanberry fruit powders. PMID- 30309012 TI - Estimation of Starch and Sugar Intake in a Japanese Population Based on a Newly Developed Food Composition Database. AB - Due to a lack of a food composition database on starch and sugars, we developed a comprehensive database on starch and seven types of sugars in commonly consumed foods (n = 2222) in Japan. Dietary record data of 368 toddlers (aged 18-35 months), 376 preschool children (aged 3-6 years), 915 schoolchildren (aged 8-14 years) and 392 adults (aged 20-69 years) were used. The mean starch intake ranged from 55.6 g/day (female toddlers) to 206.0 g/day (male schoolchildren). Irrespective of age and sex, >50% of starch was provided by rice and grains. The mean total sugar intake ranged from 46.1 g/day (female toddlers) to 68.7 g/day (male schoolchildren). In all age and sex groups, the major contributors of total sugar included sucrose (mean: 18.2-34.0 g/day), glucose (7.8-13.1 g/day), lactose (5.3-13.1 g/day) and fructose (7.6-11.1 g/day). The top food sources were dairy products (toddlers) and confectionaries (other age groups) for total sugar, confectionaries for sucrose, fruits (toddlers) and vegetables (other age groups) for glucose, dairy products for lactose and fruits (toddlers and preschool children) and vegetables (schoolchildren and adults) for fructose. In conclusion, this study clarified the starch and sugar intake in Japan and provides a foundation for future research. PMID- 30309013 TI - A Metagenomic Approach to Evaluating Surface Water Quality in Haiti. AB - The cholera epidemic that occurred in Haiti post-earthquake in 2010 has resulted in over 9000 deaths during the past eight years. Currently, morbidity and mortality rates for cholera have declined, but cholera cases still occur on a daily basis. One continuing issue is an inability to accurately predict and identify when cholera outbreaks might occur. To explore this surveillance gap, a metagenomic approach employing environmental samples was taken. In this study, surface water samples were collected at two time points from several sites near the original epicenter of the cholera outbreak in the Central Plateau of Haiti. These samples underwent whole genome sequencing and subsequent metagenomic analysis to characterize the microbial community of bacteria, fungi, protists, and viruses, and to identify antibiotic resistance and virulence associated genes. Replicates from sites were analyzed by principle components analysis, and distinct genomic profiles were obtained for each site. Cholera toxin converting phage was detected at one site, and Shiga toxin converting phages at several sites. Members of the Acinetobacter family were frequently detected in samples, including members implicated in waterborne diseases. These results indicate a metagenomic approach to evaluating water samples can be useful for source tracking and the surveillance of pathogens such as Vibrio cholerae over time, as well as for monitoring virulence factors such as cholera toxin. PMID- 30309014 TI - Prevalence and Risk Factors of Human Papillomavirus in Male Patients: A Systematic Review and Meta-Analysis. AB - Human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections. Although the research focus has been on women, men are also affected. Thus, the aim was to estimate the prevalence of HPV in men and to analyse its risk factors. A systematic review with meta-analysis was performed. The main health science databases were consulted. The search terms were was: "papilloma virus AND (prevalence OR risk factors) AND men". The final sample of studies was n = 16 and the men sample for the meta-analysis was n = 18,106. The meta-analysis revealed a prevalence of 49% (95% Confidence Interval (CI): 35-64%) of any type of human papillomavirus in men and 35% (95% CI: 26-45%) of high-risk human papillomavirus in men. The included studies showed that stable sexual habits, circumcision and condom use are protective factors against HPV. In addition, there is a certain positive association with tobacco use and the early initiation of sexual intercourse. In conclusion, the prevalence of HPV in men is high. The risk factors for HPV infection are sexual promiscuity, early sexual debut, absence of circumcision, lack of condom use and smoking. Further study in this field about the effectiveness of the vaccine and health education should be conducted. PMID- 30309016 TI - The Safety Properties of a Potential Kind of Novel Green Primary Explosive: Al/Fe2O3/RDX Nanocomposite. AB - Green primary explosives have gained wide attention for environmental protection. A potential novel lead-free primary explosive, Al/Fe2O3/RDX hybrid nanocomposite was prepared by ultrasonic mixing, and its safety properties are discussed in detail. Results showed that their sensitivity and safety properties were a function of the specific surface area and proportions of their ingredients. Their impact sensitivity fell and their static discharge, flame, and hot bridge wire sensitivities rose as the specific surface area of nano-Fe2O3 increased. As the amount of Al/Fe2O3 nanothermite was increased, its impact sensitivity fell and its flame sensitivity rose; their static discharge and hot bridge wire sensitivities, however, followed an inverted "U" type change trend and were determined by both the particle size of the ingredients and the resistance of the nanocomposite. Their firing properties in an electric detonator depended on the proportion of the constituents. Thus, green nanoscale primary explosives are appropriate for a range of initiatory applications and can be created by adjusting their specific surface area and the amount of their constituents. PMID- 30309015 TI - The Epidemiology of Transition into Adulthood of Rare Diseases Patients: Results from a Population-Based Registry. AB - Background: Despite the fact that a considerable number of patients diagnosed with childhood-onset rare diseases (RD) survive into adulthood, limited information is available on the epidemiology of this phenomenon, which has a considerable impact both on patients' care and on the health services. This study describes the epidemiology of transition in a population of RD patients, using data from the Veneto Region Rare Diseases Registry (VRRDR), a web-based registry monitoring since 2002 a consistent number of RD in a defined area (4.9 million inhabitants). Methods: Longitudinal cohorts of patients born in the years 1988 to 1998 and enrolled in the VRRDR in their paediatric age were identified. Data referred to this group of patients, experiencing transition from paediatric to adult age during the years 2006-2016, are presented. Results: 2153 RD patients (44.1% females and 55.9% males) passed from childhood to adulthood in the study period, corresponding to a 3-fold increase from 2006 to 2016. The majority of these patients was affected by congenital anomalies (32.0%), by hematologic diseases (15.9%), eye disorders (12.1%) and neoplasms (7.9%). RD patients who experienced transition from paediatric age to adulthood represent the 9.2% of adult patients enrolled in the Registry at 31 December 2016. Conclusions: We described a subset of RD young adults experiencing transition into adulthood. The data reported can be considered as minimum values for estimating the size of this increasing population presenting specific transition needs. These figures are valuable for clinicians, patients and health planners. Public policy interventions are needed in order to promote dedicated care transition pathways in the broader framework of health policies devoted to RD. PMID- 30309017 TI - Study on Fabrication of ZnO Waveguide Layer for Love Wave Humidity Sensor Based on Magnetron Sputtering. AB - The ZnO waveguide layer for the Love wave humidity sensor was fabricated by radio frequency (RF) magnetron sputtering technique using ZnO as the target material. To investigate the effect of RF magnetron sputtering temperature on the ZnO waveguide layer and Love wave device, a series of Love wave devices with ZnO waveguide layer were fabricated at different sputtering temperatures. The crystal orientation and microstructure of ZnO waveguide was characterized and analyzed, and the response characteristics of the Love wave device were analyzed by network analyzer. Furthermore, a humidity measurement system is designed, and the performance of the Love wave humidity sensor was measured and analyzed. The research results illustrate that the performance of the ZnO waveguide layer is improved when the sputtering temperature changes from 25 degrees C to 150 degrees C. However, when the sputtering temperature increases from 150 degrees C to 200 degrees C, the performance of the ZnO waveguide layer is degraded. Compared with the other sputtering temperatures, the ZnO waveguide layer fabricated at 150 degrees C has the best c-axis orientation and the largest average grain size (53.36 nm). The Love wave device has the lowest insertion loss at 150 degrees C. In addition, when the temperature of the measurement chamber is 25 degrees C and the relative humidity is in the range of 10% to 80%, the fabricated Love wave humidity sensor with ZnO waveguide layer has good reproducibility and long-term stability. Moreover, the Love wave humidity sensor has high sensitivity of 6.43 kHz/RH and the largest hysteresis error of the sensor is 6%. PMID- 30309018 TI - Surface Area Evaluation of Electrically Conductive Polymer-Based Textiles. AB - In this paper, the surface area of coated polymer-based textiles, i.e., copper and nickel plated woven polyester fabric, copper and acrylic coated woven polyester fabric, and copper and acrylic coated non-woven polyamide fabric, is investigated. In order to evaluate the surface area of the woven fabrics, Peirce's geometrical model of the interlacing point and measurement using an electron microscope are used. Non-woven fabrics are evaluated using an optical method, handmade method, and MATLAB functions. An electrochemical method, based on the measurement of the resistance between two electrodes, is used for relative comparison of the effective surface area of the coated woven and non-woven fabrics. The experimental results show that the measured and calculated warp lengths do not differ within the standard deviation. The model for the surface area evaluation of the Pierce's geometrical model for monofilament (non-fibrous) yarns is extended to multifilament yarns and to a uniform sample size. The experimental results show the increasing trend of surface area evaluation using both modeling and electrochemical methods, i.e., the surface area of the copper and acrylic coated woven Polyester fabric (PES) is the smallest surface area of investigated samples, followed by the surface area of the copper and acrylic coated non-woven fabric, and by copper and nickel plated woven PES fabric. These methods can be used for surface area evaluation of coated polymer-based textiles in the development of supercapacitors, electrochemical cells, or electrochemical catalysts. PMID- 30309019 TI - Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II. AB - Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism. PMID- 30309021 TI - Multi-Frequency Based Direction-of-Arrival Estimation for 2q-Level Nested Radar & Sonar Arrays. AB - Direction finding is a hot research area in radar and sonar systems. In the case of q >= 2, the 2qth-order cumulant based direction of arrival (DOA) estimation algorithm for the 2q-level nested array can achieve high resolution performance. A virtual 2qth-order difference co-array, which contains O(N2q) virtual sensors in the form of a uniform linear array (ULA), is yielded and the Gaussian noise is eliminated. However, some virtual elements are separated by the holes among the 2qth-order difference co-array and cannot be fully used. Even though the application of the multi-frequency method for minimum frequency separation (MFMFS) can fill the holes with low computation complexity, it requires that the number of frequencies must increase with the number of holes. In addition, the signal spectra have to be proportional for all frequencies, which is hard to satisfy when the number of holes is large. Aiming at this, we further propose a multi-frequency method for a minimum number of frequencies (MFMNF) and discuss the best frequency choice under two specific situations. Simulation results verify that, compared with the MFMFS method, the proposed MFMNF method can use only one frequency to fill all the holes while achieving a longer virtual array and the DOA estimation performance is, therefore, improved. PMID- 30309020 TI - Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver. AB - Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release-passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells-and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets. PMID- 30309022 TI - Selective Synthesis of 3-O-Palmitoyl-Silybin, a New-to-Nature Flavonolignan with Increased Protective Action against Oxidative Damages in Lipophilic Media. AB - A selective acylation protocol using cerium chloride (CeCl3) as catalyst was applied to functionalize silybinin (1), a natural antioxidant flavonolignan from milk thistle fruit, in order to increase its solubility in lipophilic media while retaining its strong antioxidant activity. The selective esterification of 1 at the position 3-OH with a palmitate acyl chain leading to the formation of the 3-O palmitoyl-silybin (2) was confirmed by both mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. The antioxidant activity of 1 was at least retained and even increased with the CUPRAC assay designed to estimate the antioxidant activity of both hydrophilic and lipophilic compounds. Finally, the 3 O-palmitoylation of 1, resulting in the formation of 2, also increased its anti lipoperoxidant activity (i.e., inhibition of conjugated diene production) in two different lipophilic media (bulk oil and o/w emulsion) subjected to accelerated storage test. PMID- 30309024 TI - New Insight to the Effects of Heat Treatment in Air on the Permeation Properties of Thin Pd77%Ag23% Membranes. AB - Sputtered Pd77%Ag23% membranes of thickness 2.2-8.5 um were subjected to a three step heat treatment in air (HTA) to investigate the relation between thickness and the reported beneficial effects of HTA on hydrogen transport. The permeability experiments were complimented by volumetric hydrogen sorption measurements and atomic force microscopy (AFM) imaging in order to relate the observed effects to changes in hydrogen solubility and/or structure. The results show that the HTA-essentially an oxidation-reduction cycle-mainly affects the thinner membranes, with the hydrogen flux increasing stepwise upon HTA of each membrane side. The hydrogen solubility is found to remain constant upon HTA, and the change must therefore be attributed to improved transport kinetics. The HTA procedure appears to shift the transition from the surface to bulk-limited transport to lower thickness, roughly from ~5 to <=2.2 um under the conditions applied here. Although the surface topography results indicate that HTA influences the surface roughness and increases the effective membrane surface area, this cannot be the sole explanation for the observed hydrogen flux increase. This is because considerable surface roughening occurs during hydrogen permeation (no HTA) as well, but not accompanied by the same hydrogen flux enhancement. The latter effect is particularly pronounced for thinner membranes, implying that the structural changes may be dependent on the magnitude of the hydrogen flux. PMID- 30309023 TI - The Impact of the Hazard Correlation between Risk Factors and Diabetes. AB - This study examined the occurrence of diabetes and sustainable risk factors in residents aged 30 and above of a community in Taoyuan County, Taiwan. The main purpose of this research was to explore the correlations between related variables and the occurrence of diabetes. The demographic variables, health exam variables, healthy behavior variables, and environmental variables had obvious impacts on the risk of diabetes. As age increased, the risk of developing the disease also increased; higher educational levels lowered risk, while unemployment raised it. Also, analysis of the health exam variables showed that abnormal BMIs, waist-hip ratios, and body fat percentages had significant impacts on individuals' risk of diabetes. Moreover, it was found that smoking affected the risk of having diabetes: smokers, particularly male smokers, had a relatively higher risk of developing the disease. Lastly, the results showed that exposure to second-hand smoke did not have a significant effect on the diabetes proportion in the male population. However, a significantly higher proportion of females who had been exposed to second-hand smoke had diabetes. PMID- 30309026 TI - Multi-Target Detection Method Based on Variable Carrier Frequency Chirp Sequence. AB - Continuous waveform (CW) radar is widely used in intelligent transportation systems, vehicle assisted driving, and other fields because of its simple structure, low cost and high integration. There are several waveforms which have been developed in the last years. The chirp sequence waveform has the ability to extract the range and velocity parameters of multiple targets. However, conventional chirp sequence waveforms suffer from the Doppler ambiguity problem. This paper proposes a new waveform that follows the practical application requirements, high precision requirements, and low system complexity requirements. The new waveform consists of two chirp sequences, which are intertwined to each other. Each chirp signal has the same frequency modulation, the same bandwidth and the same chirp duration. The carrier frequencies are different and there is a frequency shift which is large enough to ensure that the Doppler frequencies for the same moving target are different. According to the sign and numerical relationship of the Doppler frequencies (possibly frequency aliasing), the Doppler frequency ambiguity problem is solved in eight cases. Theoretical analysis and simulation results verify that the new radar waveform is capable of measuring range and radial velocity simultaneously and unambiguously, with high accuracy and resolution even in multi-target situations. PMID- 30309025 TI - Alleviation of Irritable Bowel Syndrome-Like Symptoms and Control of Gut and Brain Responses with Oral Administration of Dolichos lablab L. in a Mouse Model. AB - Irritable bowel syndrome (IBS) is a common gastrointestinal disorder manifesting as unexplained abdominal pain and bowel habit changes. The pathogenesis of post infectious IBS is associated with gut-brain axis dysfunction, including low-grade colonic inflammation and anxiety-related long-term brain changes. This study analyzed the efficacy of a standardized extract of Dolichos lablab L. extract (DL), a bean species, in an IBS mouse model resembling post-infectious, diarrhea dominant IBS. Using a zymosan-induced animal IBS model, we found that oral administration of DL significantly attenuated zymosan-induced increases in colonic macroscopic scores and minimized weight loss without affecting food intake. In the DL-treated mice, the mast cell count and tumor necrosis factor alpha level in the colon markedly decreased, similar to results in sulfasalazine treated mice and in mice with lipopolysaccharide-stimulated bone marrow-derived mast cells. The number of visceral pain-related behaviors was much lower in the DL-treated mice. Anxiety-like behaviors significantly improved, comparable to that after treatment with amitriptyline. The c-Fos expression level in the prefrontal cortex was significantly reduced. Our data suggest that DL could be beneficial for treating IBS by acting on the gut and brain. PMID- 30309027 TI - On the Improvement of Thermal Protection for Temperature-Responsive Protective Clothing Incorporated with Shape Memory Alloy. AB - This study explored the application of shape memory alloy (SMA) springs in a multilayer protective fabric assembly for intelligent insulation that responded to thermal environment changes. Once the SMA spring was actuated, clothing layers were separated, creating an adjustable air gap between the adjacent fabric layers. The impacts of six different SMA arrangement modes and two different spring sizes on thermal protection against either a radiant heat exposure (12 kW/m2) or a hot surface exposure (400 degrees C) were investigated. The findings showed that the incorporation of SMA springs into the fabric assembly improved the thermal protection, but the extent to which the springs provided thermal protection was dependent on the arrangement mode and spring size. The effectiveness of reinforcing the protective performance using SMA springs depended on the ability of clothing layers to expand an air layer. The regression models were established to quantitatively assess the relationship between the air gap formed by SMA spring and the thermal protective performance of clothing. This study demonstrated the potential of SMA spring as a suitable material for the development of intelligent garments to provide additional thermal protection and thus reduce the number of clothing layers for transitional thermal protective clothing. PMID- 30309029 TI - Odor Fingerprint Analysis Using Feature Mining Method Based on Olfactory Sensory Evaluation. AB - In this paper, we aim to use odor fingerprint analysis to identify and detect various odors. We obtained the olfactory sensory evaluation of eight different brands of Chinese liquor by a lab-developed intelligent nose. From the respective combination of the time domain and frequency domain, we extract features to reflect the samples comprehensively. However, the extracted feature combined time domain and frequency domain will bring redundant information that affects performance. Therefore, we proposed data by Principal Component Analysis (PCA) and Variable Importance Projection (VIP) to delete redundant information to construct a more precise odor fingerprint. Then, Random Forest (RF) and Probabilistic Neural Network (PNN) were built based on the above. Results showed that the VIP-based models achieved better classification performance than PCA based models. In addition, the peak performance (92.5%) of the VIP-RF model had a higher classification rate than the VIP-PNN model (90%). In conclusion, odor fingerprint analysis using a feature mining method based on the olfactory sensory evaluation can be applied to monitor product quality in the actual process of industrialization. PMID- 30309030 TI - Melamine Sponge Functionalized with Urea-Formaldehyde Co-Oligomers as a Sorbent for the Solid-Phase Extraction of Hydrophobic Analytes. AB - A new procedure for the functionalization of melamine sponge (MeS) with urea formaldehyde (UF) co-oligomers is put forward. The procedure differs from the typical synthesis of the UF co-polymer, as it employs a base-catalyzed condensation step at certain concentrations of urea and formaldehyde. The produced melamine-urea-formaldehyde (MUF) sponge cubes are hydrophobic, despite the presence of hydrophilic groups in the oligomers. The MUF sponge developed herein is used as a sorbent for the solid-phase extraction of 10 analytes, from 6 different classes (i.e., non-steroidal anti-inflammatory drugs, benzophenones, parabens, phenols, pesticides and musks) and an analytical method is developed for their liquid chromatographic separation and detection. Low limits of quantification (0.03 and 1.0 MUg L-1), wide linear ranges and excellent recoveries (92-100%) are some of the benefits of the proposed procedure. The study of the synthesis conditions of MUF cubes reveals that by altering them the hydrophilic/lipophilic balance of the MUF cubes can be tuned, hinting towards a strong potential for many other applications. PMID- 30309028 TI - Curcumin Inhibits Age-Related Vascular Changes in Aged Mice Fed a High-Fat Diet. AB - Inhibiting the onset of arteriosclerotic disease, which has been increasing due to the westernized diet and aging, is a significant social challenge. Curcumin, a type of polyphenol, has anti-oxidative effects and anti-inflammatory action and is expected to treat and to have prophylactic effects on different diseases. In this study, we examined the effects of long-term administration of curcumin on vascular aging and chronic inflammation-the causes of arteriosclerotic disease. Eight-week-old C57BL/6J mice were fed with high fat diet (HFD) or 0.1% curcumin mixed HFD (HFD + Cu) until 80 weeks old (n = 20 for each group). After the breeding, we examined the expression of antioxidant enzymes, heme oxygenase-1 (HO 1), oxidative stress, vascular aging, and inflammatory changes in the aorta. In the HFD group, oxidative stress increased with decreased sirt1 expression in the aorta followed by increased senescent cells and enhanced inflammation. Whereas in the HFD + Cu group, HO-1 was induced in the aorta with the suppression of oxidative stress. Additionally, it was shown that sirt1 expression in the aorta in the HFD + Cu group remained at a level comparable to that of the 8-week-old mice with suppression of increased senescent cells and enhanced inflammation. Consequently, disorders associated with HFD were resolved. These results suggest that curcumin might be a food with a prophylactic function against arteriosclerotic disease. PMID- 30309031 TI - A Joint Space-Time Array for Communication Signals-Based on a Moving Platform and Performance Analysis. AB - A joint space-time array for communication signals is constructed in this paper to settle the contradiction between the performance of angle estimation and the array aperture. It introduces Doppler information caused by platform motion into the signal processing to obtain favorable performance with limited array aperture. We analyze the theoretical performance in the aspects of distinguishable source number, spatial resolution and Cramer-Rao bound (CRB), respectively. Both theoretical analysis and simulation results demonstrate that the proposed space-time array can give rise to a significant enhancement in achievable array performance. PMID- 30309032 TI - User-Information-Aware D2D Multicast File Distribution Mechanism. AB - There are a large number of redundant transmissions in current D2D multicast content delivery systems, which seriously reduces the utilization efficiency of resources. This paper designs a novel user-information-aware D2D video distribution mechanism. More specifically, by predicting users' video requests, the video can be pushed to potential service requesters while distributing video for service requesters. Firstly, the willingness of potential requesters to accept the pushed video is estimated based on the users' interests, the popularity of the videos and the residual-energy of the users' devices, and the user-demand-aware clustering algorithm is proposed. Secondly, considering social and interference information, the utility metric of D2D multicast is proposed to measure the value of content distribution service. Finally, this paper proposes a D2D video distribution mechanism to optimize the utility value. Simulation results show that the proposed mechanism significantly improves throughput, energy and spectrum efficiency compared to the traditional distribution mechanism. PMID- 30309033 TI - Real-Time Recursive Fingerprint Radio Map Creation Algorithm Combining Wi-Fi and Geomagnetism. AB - Fingerprint is a typical indoor-positioning algorithm, which measures the strength of wireless signals and creates a radio map. Using this radio map, the position is estimated through comparisons with the received signal strength measured in real-time. The radio map has a direct effect on the positioning performance; therefore, it should be designed accurately and managed efficiently, according to the type of wireless signal, amount of space, and wireless-signal density. This paper proposes a real-time recursive radio map creation algorithm that combines Wi-Fi and geomagnetism. The proposed method automatically recreates the radio map using geomagnetic radio-map dual processing (GRDP), which reduces the time required to create it. It also reduces the size of the radio map by actively optimizing its dimensions using an entropy-based minimum description length principle (MDLP) method. Experimental results in an actual building show that the proposed system exhibits similar map creation time as a system using a Wi-Fi-based radio map. Geomagnetic radio maps exhibiting over 80% positioning accuracy were created, and the dimensions of the radio map that combined the two signals were found to be reduced by 23.81%, compared to the initially prepared radio map. The dimensions vary according to the wireless signal state, and are automatically reduced in different environments. PMID- 30309034 TI - Characterization and Prebiotic Potential of Longan Juice Obtained by Enzymatic Conversion of Constituent Sucrose into Fructo-Oligosaccharides. AB - The prebiotic potential of longan juice obtained by a commercial Viscozyme L for conversion of constituent sucrose to fructo-oligosaccharide was investigated. The physicochemical properties and carbohydrate composition of the longan juice was evaluated before and after enzymatic treatment. The stimulation effects of the treated longan juice on probiotic bacteria growth were also studied in vitro. The results showed that total soluble solids, yield and clarity of longan juice were all significantly improved after enzyme treatment. The water-soluble polysaccharide content, including pectin, was significantly increased. Compared with the natural longan pulp, the enzyme treated juice showed a significant decrease in sucrose content. Substantial fructo-oligosaccharides including 1 kestose and nystose were synthesized after enzyme treatment. The molecular weight distribution and the monosaccharide composition of the water-soluble polysaccharide were significantly changed by enzyme treatment. The treated longan juice and its ethanol-soluble sugar fraction promoted the growth of Streptococus thermophiles, Lactobacillus acidophilus and Lactobacillus delbrueckii, showing a good potential of the treated longan juice for producing functional foods and nutraceuticals. PMID- 30309035 TI - A Vision-Based Approach to UAV Detection and Tracking in Cooperative Applications. AB - This paper presents a visual-based approach that allows an Unmanned Aerial Vehicle (UAV) to detect and track a cooperative flying vehicle autonomously using a monocular camera. The algorithms are based on template matching and morphological filtering, thus being able to operate within a wide range of relative distances (i.e., from a few meters up to several tens of meters), while ensuring robustness against variations of illumination conditions, target scale and background. Furthermore, the image processing chain takes full advantage of navigation hints (i.e., relative positioning and own-ship attitude estimates) to improve the computational efficiency and optimize the trade-off between correct detections, false alarms and missed detections. Clearly, the required exchange of information is enabled by the cooperative nature of the formation through a reliable inter-vehicle data-link. Performance assessment is carried out by exploiting flight data collected during an ad hoc experimental campaign. The proposed approach is a key building block of cooperative architectures designed to improve UAV navigation performance either under nominal GNSS coverage or in GNSS-challenging environments. PMID- 30309038 TI - Determination of Trace Nickel in Water Samples by Graphite Furnace Atomic Absorption Spectrometry after Mixed Micelle-Mediated Cloud Point Extraction. AB - A simple and sensitive cloud point extraction method for the preconcentration of ultra-trace amounts of nickel as a prior step to its determination by graphite furnace atomic absorption spectrometry was proposed. It is based on the reaction of nickel with 2-(5-bromo-2-pyridylazo)-5-dimethylaminoaniline (5-Br-PADMA) in HAc-NaAc buffer media and mixed micelle-mediated extraction of the complex using the anionic surfactant sodium dodecyl sulfate sodium (SDS) and non-ionic surfactant (1,1,3,3-Tetramethylbutyl)phenyl-polyethylene (Triton X-114). The optimal reaction and extraction conditions such as pH, concentration of 5-Br PADMA, SDS and Triton X-114, equilibrium temperature, incubation, and centrifuge time were evaluated and optimized. Under the optimal conditions, the calibration graph was linear over the range 0.1-5.5 ng/mL of nickel with a correlation coefficient of 0.9942. The detection limit obtained was 0.031 ng/mL, and the relative standard deviation was 2.1% for nickel (c = 2 ng/mL, n = 6). The proposed method was successfully applied to the determination of nickel in water samples. PMID- 30309039 TI - Engaging with and Shaping Nature: A Nature-Based Intervention for Those with Mental Health and Behavioural Problems at the Westonbirt Arboretum in England. AB - Mental health problems have become one of the leading causes of disease burden worldwide. This study used qualitative mixed methods including in-situ 'being and doing' activities with participants, interviews, and participant observations to explore participant's experiences of a multi-visit nature-based intervention at Westonbirt Arboretum in England. The research found that three engagement types: (1) social, (2) woodland craft, and (3) creative and sensory, provided a meaningful programme to engage those with mental health, addiction, autism and behavioural problems. These types of engagement conferred a wide range of well being benefits on participants. The study highlights key elements of the programme that were effective including the importance of repeat visits to nature to enable familiarity, using creative, sensory and craft activities, creating a supportive environment, involving the volunteers, and understanding the needs of participants and the organisations that work with them. The research suggests that nature-based programmes can be designed to be flexible and adaptable to meet the needs of participants with mental health and behavioural problems. Small numbers of participants can be involved in an intensive and immersive way that encourages an emotional affinity with nature. Inclusive and supportive programmes are particularly important for those who are vulnerable, as they are less likely to engage with nature than the wider population. PMID- 30309040 TI - Estimation of Driver's Danger Level when Accessing the Center Console for Safe Driving. AB - This paper proposes a system for estimating the level of danger when a driver accesses the center console of a vehicle while driving. The proposed system uses a driver monitoring platform to measure the distance between the driver's hand and the center console during driving, as well as the time taken for the driver to access the center console. Three infrared sensors on the center console are used to detect the movement of the driver's hand. These sensors are installed in three locations: the air conditioner or heater (temperature control) button, wind direction control button, and wind intensity control button. A driver's danger level is estimated to be based on a linear regression analysis of the distance and time of movement between the driver's hand and the center console, as measured in the proposed scenarios. In the experimental results of the proposed scenarios, the root mean square error of driver H using distance and time of movement between the driver's hand and the center console is 0.0043, which indicates the best estimation of a driver's danger level. PMID- 30309037 TI - Multi-Target Approach for Drug Discovery against Schizophrenia. AB - Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D2 receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of alpha7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds. PMID- 30309041 TI - Chromosome Painting in Neotropical Long- and Short-Tailed Parrots (Aves, Psittaciformes): Phylogeny and Proposal for a Putative Ancestral Karyotype for Tribe Arini. AB - : Most Neotropical Psittacidae have a diploid number of 2n = 70, and a dichotomy in chromosome patterns. Long-tailed species have biarmed macrochromosomes, while short-tailed species have telo/acrocentric macrochromosomes. However, the use of chromosome painting has demonstrated that karyotype evolution in Psittacidae includes a high number of inter/intrachromosomal rearrangements. To determine the phylogeny of long- and short-tailed species, and to propose a putative ancestral karyotype for this group, we constructed homology maps of Pyrrhura frontalis (PFR) and Amazona aestiva (AAE), belonging to the long- and short-tailed groups, respectively. Chromosomes were analyzed by conventional staining and fluorescent in situ hybridization using whole chromosome paints of Gallus gallus and Leucopternis albicollis. Conventional staining showed a karyotype with 2n = 70 in both species, with biarmed macrochromosomes in PFR and telo/acrocentric chromosomes in AAE. Comparison of the results with the putative avian ancestral karyotype (PAK) showed fusions in PFR of PAK1p/PAK4q (PFR1) and PAK6/PAK7 (PFR6) with a paracentric inversion in PFR6. However, in AAE, there was only the fusion between PAK6/7 (AAE7) with a paracentric inversion. Our results indicate that PFR retained a more basal karyotype than long-tailed species previously studied, and AAE a more basal karyotype for Neotropical Psittacidae analyzed so far. PMID- 30309042 TI - Fabry-Perot Cavity Sensing Probe with High Thermal Stability for an Acoustic Sensor by Structure Compensation. AB - Fiber Fabry-Perot cavity sensing probes with high thermal stability for dynamic signal detection which are based on a new method of structure compensation by a proposed thermal expansion model, are presented here. The model reveals that the change of static cavity length with temperature only depends on the thermal expansion coefficient of the materials and the structure parameters. So, fiber Fabry-Perot cavity sensing probes with inherent temperature insensitivity can be obtained by structure compensation. To verify the method, detailed experiments were carried out. The experimental results reveal that the static cavity length of the fiber Fabry-Perot cavity sensing probe with structure compensation hardly changes in the temperature range of -20 to 60 degrees C and that the method is highly reproducible. Such a method provides a simple approach that allows the as fabricated fiber Fabry-Perot cavity acoustic sensor to be used for practical applications, exhibiting the great advantages of its simple architecture and high reliability. PMID- 30309043 TI - The Theory of Planned Behavior to Predict Protective Behavioral Intentions against PM2.5 in Parents of Young Children from Urban and Rural Beijing, China. AB - Smog and air pollution have fast become significant environmental problems and are attributed to rapid global industrialization and urbanization. Emissions of fine particulate matter with an aerodynamic diameter of <=2.5 MUm (PM2.5) increase smog and air pollution, with strong impacts on human health. Children are particularly vulnerable. While increasing studies are being conducted on the behaviors leading to PM2.5 toxicity from the perspective of environmental toxicants, there is a lack of research on factors influencing anti-PM2.5 behavioral intentions. Thus, this study aims to narrow this gap by adapting the theory of planned behavior framework to investigate the effects of attitude, subjective norms, and perceived behavioral control on protective behavioral intentions against PM2.5. In total, 1277 online questionnaires were collected from parents of young children living in urban and rural areas of Beijing, and the data was analyzed using correlation, regression, and path analyses. Results revealed that there were significant differences between parents from urban and rural areas in terms of attitude (t = 4.727 > 1.96, p < 0.001), subjective norms (t = 5.529 > 1.96, p < 0.001), perceived behavioral control (t = 6.155 > 1.96, p < 0.001), and anti-PM2.5 behavioral intentions (t = 6.838 > 1.96, p < 0.001). Path analysis revealed that parents from urban and rural areas had different behavioral intention paths. For urban parents, the findings indicated that subjective norms (beta = 0.73, t = 21.84 > 3.29) and perceived behavioral control (gamma = 0.22, t = 6.12 > 3.29) had direct impacts on anti-PM2.5 behavioral intentions. In contrast, the attitudes (gamma = 0.39, t = 3.74 > 3.29) and subjective norms (beta = 0.60, t = 8.55 > 3.29) of rural parents were found to directly influence anti-PM2.5 behavioral intentions. PMID- 30309044 TI - Differences in Hypotensive vs. Non-Hypotensive Sepsis Management in the Emergency Department: Door-to-Antibiotic Time Impact on Sepsis Survival. AB - BACKGROUND: Sepsis diagnosis can be incorrectly associated with the presence of hypotension during an infection, so the detection and management of non hypotensive sepsis can be delayed. We aimed to evaluate how the presence or absence of hypotension, on admission at the emergency department, affects the initial management and outcomes of patients with community-onset severe sepsis. METHODS: Demographic, clinical, laboratory, process of care, and outcome variables were recorded for all patients, at the emergency department of our university hospital, who presented with community-onset severe sepsis, between 1 March and 31 August in three consecutive years. Patient management consisted of standardized bundled care with five measures: Detection, blood cultures and empirical antibiotics, oxygen supplementation and fluid resuscitation (if needed), clinical monitoring, and noradrenalin administration (if needed). We compared all variables between patients who had hypotension (mean arterial pressure <65 mmHg), on admission to the emergency department, and those who did not. RESULTS: We identified 153 episodes (84 (54.5%) men; mean age 73.6 +/- 1.2; mean Sequential Organ Failure Assessment (SOFA) score 4.9 +/- 2.7, and 41.2% hospital mortality). Hypotension was present on admission to the emergency department in 57 patients (37.2%). Hemodynamic treatment was applied earlier in patients who presented hypotension initially. Antibiotics were administered 48 min later in non-hypotensive sepsis (p = 0.08). A higher proportion of patients without initial hypotension required admission to the intensive care unit (ICU) (43.1% for patients initially hypotensive vs. 56.9% in those initially non hypotensive, p < 0.05). Initial hypotension was not associated with mortality. A delay in door-to-antibiotic administration time was associated with mortality [OR 1.150, 95%CI: 1.043-1.268). CONCLUSIONS: Initial management of patients with community-onset severe sepsis differed according to their clinical presentation. Initial hypotension was associated with early hemodynamic management and less ICU requirement. A non-significant delay was observed in the administration of antibiotics to initially non-hypotensive patients. The time of door-to-antibiotic administration was related to mortality. PMID- 30309045 TI - A Volume Measurement Method for Lunar Soil Collection Based on a Single Monitoring Camera. AB - In the task of lunar soil collection, estimating the volume of the collected soil is an important part of the sampling control of the lander. Due to the design constraints of the lander, there is no additional installation position for volume measurement equipment. To fully use the sensors already installed, a collected soil volume measurement method is designed in this paper based only on a single monitoring camera. This method uses a sequence of images of the collection area captured by the camera mounted on the acquisition arm to accurately reconstruct the terrain of the collection area surface before and after soil acquisition. Additionally, bi-temporal dense point clouds are reconstructed. Based on the area of change associated with soil collection, the constructed dense point clouds are compared according to the topographic characteristics of the area to estimate the volume of soil collected. Experiments show that the method is stable and reliable and can meet the requirements of actual measurement tasks. PMID- 30309036 TI - Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism. AB - Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed. PMID- 30309047 TI - A Solvothermal Synthesis of TiO2 Nanoparticles in a Non-Polar Medium to Prepare Highly Stable Nanofluids with Improved Thermal Properties. AB - Nanofluids are systems with several interesting heat transfer applications, but it can be a challenge to obtain highly stable suspensions. One way to overcome this challenge is to create the appropriate conditions to disperse the nanomaterial in the fluid. However, when the heat transfer fluid used is a non polar organic oil, there are complications due to the low polarity of this solvent. Therefore, this study introduces a method to synthesize TiO2 nanoparticles inside a non-polar fluid typically used in heat transfer applications. Nanoparticles produced were characterized for their structural and chemical properties using techniques such as X-ray Diffraction (XRD), Raman spectroscopy, Transmission Electron Microscopy (TEM), Fourier Transform Infrared (FTIR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The nanofluid showed a high stability, which was analyzed by means of UV-vis spectroscopy and by measuring its particle size and zeta potential. So, this nanofluid will have many possible applications. In this work, the use as heat transfer fluid was tested. In this sense, nanofluid also presented enhanced isobaric specific heat and thermal conductivity values with regard to the base fluid, which led to the heat transfer coefficient increasing by 14.4%. Thus, the nanofluid prepared could be a promising alternative to typical HTFs thanks to its improved thermal properties and high stability resulting from the synthesis procedure. PMID- 30309048 TI - Effects of Initial Water Content on Microstructure and Mechanical Properties of Lean Clay Soil Stabilized by Compound Calcium-Based Stabilizer. AB - Initial water content significantly affects the efficiency of soil stabilization. In this study, the effects of initial water content on the compressibility, strength, microstructure, and composition of a lean clay soil stabilized by compound calcium-based stabilizer were investigated by static compaction test, unconfined compression test, optical microscope observations, environment scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction. The results indicate that as the initial water content increases in the range studied, both the compaction energy and the maximum compaction force decrease linearly and there are less soil aggregates or agglomerations, and a smaller proportion of large pores in the compacted mixture structure. In addition, for specimens cured with or without external water supply and under different compaction degrees, the variation law of the unconfined compressive strength with initial water content is different and the highest strength value is obtained at various initial water contents. With the increase of initial water content, the percentage of the oxygen element tends to increase in the reaction products of the calcium-based stabilizer, whereas the primary mineral composition of the soil-stabilizer mixture did not change notably. PMID- 30309046 TI - Examining Associations between Body Mass Index in 18-25 Year-Olds and Energy Intake from Alcohol: Findings from the Health Survey for England and the Scottish Health Survey. AB - Evidence on the relationship between alcohol consumption and body mass index (BMI) is mixed, particularly for young adults. This study explored the relationship between energy obtained from alcoholic beverages and BMI using data for 18-25 year-olds (n = 7691) from pooled cross-sections of the 2008-2014 Health Survey for England and the Scottish Health Survey. Energy obtained from alcoholic beverages (excluding mixers) on the heaviest drinking day in the past week was expressed as percentage of total recommended dietary allowance (RDA) of energy (% RDA Energy). Linear regressions were estimated of BMI on alcohol intake categories controlling for intake frequency, physical activity, longstanding illness and other covariates, with separate analyses for men and women, and by beverage type. Significant associations with BMI were observed with the 'Very High' category of alcohol intake (>75% RDA Energy) for men (p < 0.001, 1.74, 95% confidence interval (CI) 0.98, 2.49) and with the "High" (>50% to 75% RDA Energy) (p < 0.001, 1.67, 95% CI 0.26, 2.58) and above category for women, when compared with the Low (>0-25% RDA Energy) category. Young adults drinking the highest levels of alcohol on a single occasion were more likely to be obese than those with the lowest intake. Interventions to address internationally rising youth obesity rates should also consider reducing alcohol consumption by increasing alcohol prices, and reducing availability and marketing exposure. PMID- 30309050 TI - Ultrastructure of the posterior half of the intestine of the channel catfish, Ictalurus punctatus. AB - The posterior half of the channel catfish intestine has a similar histological organization to that of other teleost fishes. This region is organized into a muscosa, a submucosa, a double layered muscularis and a serosa. A "stratum compactum" of dense connective tissue was confirmed for the submucosa. In its histology and cytology, the midgut resembles the hindgut, except that in the hindgut the muscularis is thicker, the microvilli are shorter, there are fewer absorptive inclusions in the columnar cells and there are more goblet cells. With the exception of the serosa, the tissue layers of the intestine of the 6 cm juvenile catfish are fully developed. The most notable difference between the intestines of the juvenile and adult catfish occurs in the columnar epithelial cells. The mucosal cells of the juvenile catfish contain an abundance of large clear vacuoles while the mucosal cells of the mature catfish contain smaller dense granules. With few exceptions, the ultrastructural details of the cells in the catfish intestine are identical to those of the same cell types of the mammalian intestine. PMID- 30309049 TI - The integument of the paddlefish, Polyodon spathula. AB - The integument of the paddlefish (Polyodon spathula) is unusual as a relatively small amount of mucus is produced by epithelial cells that are not modified into regular mucous gland cells. A thick compact epidermis and dermis compensate for the slight amount of mucus secreted. Paddlefish have a variety of scales formed of concentric bony lamellae containing osteocytes. There are five kinds of scales: dorsal and ventral fulcra on the caudal fin, rhomboidal scales on the caudal lobe, horny denticles over the pectoral girdle, calcareous denticles on the trunk, and anchor-shaped plates on the rostrum. Except for the fulcra, the scales are undoubtedly vestigial. The numerous surface pits on the rostrum, head, operculum, and throat are epithelial invaginations which are not connected to lateral line canals. No nerves lead to the pits. The spherical to cuboidal and often ciliated cells at the base of the pits are considered to be aplasic cells of unformed neuromasts. PMID- 30309051 TI - The interstitial origin of germinal cells in the testis of the stickleback. AB - The brook stickleback, Culaea inconstans (Kirtland), in common with other bony fishes, lacks a germinal epithelium in the tubules of the testis, and the tubule wall is composed of a thin, discontinuous layer of myoid cells and collagenous fibers. Labelling of germ cells with tritiated thymidine has shown that the germ cells are derived from clumps of spermatogonia in the interstitial area. Large companion cells within the lumina of the tubules extend their processes to engulf spermatogonia from the interstitium which then enter the lumen of the tubule. Subsequent development of the germ cells takes place within individual compartments formed by folds of the plasma membrane of a companion cell. The companion cell, together with its complement of germ cells, constitutes a cyst. A companion cell may surround spermatogonia in the interstitium and at the same time encompass residual sperm of the previous season within the lumen. The plasma membranes of the germ cells and the companion cells remain discrete. Mature sperm are released into the lumen of the tubule and the companion cell again extends its processes into the interstitium and engulfs more spermatogonia for the following year. Companion cells may be homologous to the Sertoli cells of higher vertebrates although their processes penetrate the interstitium during the initial stages of spermatogenesis and they do not contain a permanent stock of spermatogonia. PMID- 30309052 TI - The ecdysial gland of the spider crab, Libinia emarginata (L). I. Ultrastructure of the gland in the male. AB - The ecdysial glands of mature male Libinia emarginata are pale, yellowish organs composed of lobes of epithelial cells having oval nuclei which are often eccentric and which have one or two nucleoli containing amorphous granular material and coarse strands. The plasma membrane bordering the basal lamina consists of invaginations containing microtubules which may serve to increase the surface area for metabolic exchange. Masses of smooth endoplasmic reticulum and associated vesicles are scattered throughout the cytoplasm. Two or more vacuoles may coalesce. Larger vesicles lie close to the cell surface. Numerous mitochondria with tubular cristae surround the nucleus and frequently are associated with SER. A few Golgi complexes consisting of flattened sacs, cisternae or vesicles, lipid droplets and free ribosomes were seen. Adjacent plasma membranes may be in close apposition or separated by a space filled with vesicles, granules, or blood or supporting cells. This type of ultrastructure is associated with steroid-secreting cells. PMID- 30309053 TI - The aquiferous systems of three marine demospongiae. AB - The aquiferous systems of three common, coastal, marine Demospongiae, Halichondria panicea (Pallas), Haliclona permollis (Bowerbank) and Microciona Prolifera (Ellis and Solander), are analyzed by measurements of cross-sectional areas of conducting elements. The patterns in demosponges of extremely different organizational morphologies are found to be quantitatively similar. The porocyte nature of the ostia is established for all three species. Choanocyte chamber densities range from 1 to 1.8 * 107 chambers ml-1 with 57 to 95 choanocytes per chamber (means). Cross-sectional area of the intervillar space of the choanocyte collars is calculated to be 12 to 56 times the lateral surface area of the specimen. Velocities of water movement through specific elements of the aquiferous system are calculated from cross-sectional area data and measured oscular flow of Haliclona permollis. The calculated Reynolds numbers lie below the critical value and fluid flow is thus considered laminar throughout the aquiferous systems of these sponges. PMID- 30309054 TI - The fine structure of the lateral ocellus of the dobsonfly larva. AB - The lateral ocelli of the dobsonfly (Protohermes grandis, Neuroptera) larva have been examined with light and electron microscopy. The larva has six ocelli on both sides of the head, each containing a single corneal lens. A conical crystalline body, of some 10-20 cells is situated immediately posterior to the lens. From 100 to 300 elongated retinular cells are arranged perpendicular to the crystalline body except at the innermost surface of the lens, where they are absent. The distal process of each retinular cell is enclosed by a tube-like rhabdom formed by the close association of microvilli from the same and adjacent distal processes. The distal process contains many mitochondria, multivesicular bodies, microtubles and pigment granules. In the dark-adapted ocellus the pigment granules are concentrated near the nucleus which lies under the rhabdomic layer. The granules diffuse toward the rhabdomic microvilli during light adaptation. Each retinular cell has a single axon, which extends from the ocellus as an ocellar nerve fiber into the optic lobe, where it frequently synapses upon second order neurons. In addition to these afferent synapses, there are two other synaptic combinations: (1) a feedback synapse from a second order neuron to a retinular axon, and (2) a synapse between second order neurons. These results suggest that photic signals reach the more proximal part of the brain via second order neurons after some degree of integration in the optic lobe. PMID- 30309055 TI - The long-term organ culture of tissues from adult Necturus maculosus, the mud puppy. AB - Fragments of Necturus maculosus liver, spleen and kidney were cultured at 25 degrees C in 50% Minimal Essential Medium (MEM) or 50% Leibovitz L-15 Medium (L 15) for up to 49 days. The integrity of tissue structure was evaluated, hepatocyte cell and nuclear volumes were measured, the respiration rates of freshly-isolated and cultured liver fragments were determined, and the mitotic incidences in cultured liver, spleen and kidney were estimated. The addition of adrenalin caused a reduction in the glycogen content of liver cultures, and the subsequent addition of insulin resulted in a net increase in glycogen synthesis. Glycogen levels fell in fragments cultured in L-15, but rose in cultures in MEM. Arginase and ornithine transcarbamylase levels fell gradually throughout a 49-day culture period in L-15. Evidence presented supports the position that the survival of tissues in vitro is related to cell size and respiration rate. These experiments show that N. maculosus is a suitable donor of tissues for long-term organ culture studies on the maintenance and control of tissue-type specific structure and function. PMID- 30309056 TI - The suspensorium of Ctenopoma acutirostre: A comparative functional analysis with Anabas testudineus. AB - The functional and structural aspects of the suspensorium of Ctenopoma acutirostre have been correlated with those of Anabas testudineus. The different parts of the suspensorium are described, as are the muscles that are functionally connected with the suspensorium. Functions were analyzed by observations on living specimens, and by measurements recorded from the movie films. The role played by various bones and muscles to carry out the functions (the respiration, the gulping, and the feeding) has been explained. The different bones and muscles have been considered as functional units which often are connected to form couplings. During the respiration in Ctenopoma the depression of the lower jaw is conducted by the levator operculiopercular apparatus-mandible coupling. The presence of this coupling is indicated by the presence of dorso-ventral movement of the operculum. A remarkable ventro-dorsal and antero-caudal movement in the urhyal during feeding shows in Ctenopoma the presence of the sternohyoideus-hyoid apparatus-interopercular-mandible coupling, which depresses the lower jaw. In Ctenopoma, the suspensorium takes part in respiration, gulping, and feeding, whereas in Anabas it is only involved in gulping and feeding. To carry out its functions, the suspensorium implies three articulations: palatocranial, craniohyomandibular, and quadratomandibular with the cranium and the lower jaw, respectively. Finally, the suspensorium has been analyzed as a part of the architectonic structure of the entire head by using a diagrammatic model (fig. 13) based on mutual influence, integration, and couplings. PMID- 30309057 TI - The epithelium of the gastro-intestinal tract of Polypterus senegalus (Pisces:Brachiopterygii). AB - Light and electron microscopic studies revealed ciliation of the epithelium of the entire gastro-intestinal tract of Polypterus. Acidophil cells were found in the different regions of the alimentary canal, including its derivatives (the lungs and hepato-pancreatic ducts). Compared to other primitive forms and modern teleosts, the extreme fusion of the intestinal caeca in Polypterus, the ciliation and the overall dispersion of acidophil cells may represent a special organization inherited from a palaeoniscoid ancestor. Attention is also drawn to a possible channel of early evolution and function of the stomach diverticulum. PMID- 30309058 TI - The maxillary palp organs of a wood-boring beetle, Melittomma sericeum (coleoptera, lymexylonidae). AB - The complex and conspicuous basket-like structure attached to the third segment of each maxillary palp of Melittomma sericeum males is densely covered with tactile hairs on its outer or convex surface and with thinwalled chemoreceptors on its inner or concave surface. In a living male the structure is highly mobile and is extended laterally and ventrally. It evidently serves to detect odors produced by the female. PMID- 30309059 TI - The hyoid, laryngeal and pharyngeal regions of bathyergid and other selected rodents. AB - The morphology of the hyoid, laryngeal and pharyngeal regions of the following rodent genera was studied: Cryptomys, Bathyergus, Georychus, Heliophobius, Heterocephalus, Ctenomys, Petromus, Thryonomys, Geomys, Cannomys, and Tachyoryctes. A number of morphological conditions unique to bathyergids, and associated with the use of the head and lower incisors in burrowing are described. The conditions include the formation of functional complexes of MM. sterno-geniohyoideus and omo-mylohyoideus, the presence of a unique deep oblique part of M. transversus mandibulae and a strong separate slip of M. platysma myoides pars mentalis. The hyoid skeleton is modified to allow the muscle complexes to act independently of the basihyal bone, and to allow the unusually protrusible tongue to be withdrawn. The nerves of the jugular foramen do not form a true pharyngeal plexus, and their configuration is influenced by the absence of a well developed internal carotid artery in hystricognaths. The morphology of the regions studied indicates a natural grouping of bathyergids, but one in which Heterocephalus is somewhat separate from the remaining bathyergid genera. The grouping of bathyergids and New and Old World hystricognath rodents into a suborder Hystricognatha is supported. PMID- 30309060 TI - The feeding system of terrestrial tiger salamanders (Ambystoma tigrinum melanostictum baird). AB - High speed cinematography was used to record the feeding activities of terrestrial Ambystoma tigrinum melanostictum. A description of these activities based on films of more than 50 feeding sequences is presented, and the mechanical units involved are defined, described, and functionally analyzed. Evolutionary implications of the feeding system are discussed. In a typical feeding sequence, A. t. melanostictum stations and maintains its lower jaw 3-5 mm from the prey. The mouth is then opened to form a gape of ~60 degrees by raising the anterior end of the flexed skull and by elevating and advancing the trunk while the mental symphysis of the lower jaw remains stationary. As the mouth opens the bulging tongue is recontoured so that the posterior glandular region becomes the tip of the fully protruded tongue, which may extend 3 to 7 mm beyond the symphysis. Dorsally the protruded tongue has a deep central depression and pronounced anterolateral rims. The anterior rim collapses on contact, thereby engulfing the prey in a sticky trough that retains it during tongue withdrawal. The cervical region is then flexed and the skull snaps downward. If the prey resists the tongue and is captured by marginal teeth, A. t. melanostictum relies on repeated tongue protraction and retraction, in some cases accompanied by inertial feeding. Swallowing involves gular expansion and contraction, and is accompanied by eye depression. When the mouth is opened during ingestive activities, the lower jaw remains in place. Apparently, A. t. melanostictum uses the dorsal trunk, the cucullaris major and the robust heads of the depressor mandibulae muscles to open the mouth. During skull elevation the lower jaw is partially immobilized by the geniohyoideus, and rectus cervicis superficialis muscles. The subarcualis rectus I muscles are prime movers in tongue projection. Hebosteoypsiloideus muscles assist in tongue protrusion by slackening the rectus cervicis profundus muscles that would otherwise restrict anterior displacement of the otoglossal cartilage and copula. Tongue contouring is performed by the complex genioglossus musculature. Sublingual and anterolingual sinuses facilitate protrusion and contouring by providing space and lubrication. Rectus cervicis muscles (profundus and superficialis) are responsible for tongue withdrawal. Closure of the mouth is accomplished by the four levator mandibulae muscles, and again the lower jaw is immobilized, mostly by ventral longitudinal muscles. Skull-trunk elevation during prey capture and ingestion was also observed and filmed in several other species of Ambystoma, in Dicamptodon ensatus, and in two salamandrid species. Apparently raising and straightening the craniovertebral axis, while the mental symphysis retains contact with the substratum, is a common feature of urodele feeding systems, and does not require peculiar morphological adaptations. PMID- 30309061 TI - Trophotaeniae, embryonic adaptations, in the viviparous ophidioid fish, Oligopus Longhursti: A study of museum specimens. AB - Prepartum embryos obtained from old museum specimens of the ovo-viviparous fish, Oligopus longhursti, possess external intestinal appendages. They are structurally identical to the trophotaeniae described by Turner ('37) and Mendoza ('37) in goodeid fishes. This is the first report of trophotaeniae in the viviparous ophidioids. Two developmental Stages, A and B, were observed. A is a tailbud stage, 2.0-2.25 mm in length, and B is a finfold embryo, 3.0-3.25 mm in length (Wourms and Bayne, '73). Trophotaeniae occur in the form of a single median anterior process and a pair of median posterior processes. They originate from a conspicuous peduncle formed around the anus. The processes of stage A are 1.5-2.0 mm long, 0.05 mm in diameter at their base and 0.04 mm at their tip. The stage B processes are 2.75-3.00 mm long, 0.075 mm in diameter at their base and 0.050 mm at their tip. Serial sections show that the surface epithelium of the trophotaeniae is continuous with and identical to the surface epithelium of the trophotaeniae is continuous with and identical to the surface epithelium of the embryonic gut. Examination both by transmission and scanning electron microscopy confirms that the apical surface of the trophotaenial epithelium and intestinal epithelium are covered with microvilli. Trophotaeniae are considered to function in the uptake of nutrients since they are structurally identical to intestinal epithelial cells. We suggest that maternal nutrients absorbed by trophotaeniae rather than yolk reserves are the principal source of embryonic metabolites. Trophotaeniae may afford a selective advantage since their existence in O. longhursti maximizes the number of large size embryos which a female can produce at one time. Occurrence of trophotaeniae in ophidioid, goodeid and zoarcid embryos is a remarkable example of convergent evolution. PMID- 30309062 TI - Staghorn calculus. PMID- 30309063 TI - Atoll sign: High resolution CT. PMID- 30309064 TI - Cobra head sign: Ureterocele. PMID- 30309065 TI - Coracoid and coronoid: Normal anatomy. PMID- 30309066 TI - Horseshoe lung. PMID- 30309068 TI - Horseshoe abscess: Perianal and giant abdominal abscess. PMID- 30309067 TI - Parrot beak and fish mouth signs: Meniscal tear. PMID- 30309069 TI - Scimitar sign: Anomalous pulmonary venous drainage. PMID- 30309070 TI - Oesophageal web. PMID- 30309071 TI - Avian appendix: Anatomic variant. PMID- 30309072 TI - Talar beak sign: Tarsal coalition. PMID- 30309073 TI - Tadpole adrenal and seagull adrenal: Normal anatomic appearance. PMID- 30309074 TI - Bat wing or butterfly sign: Pulmonary oedema. PMID- 30309075 TI - Cocoon sign: Sclerosing encapsulating peritonitis. PMID- 30309076 TI - Pectus carinatum: Chest deformity. PMID- 30309077 TI - Seagull sign: Respiratory motion artefact. PMID- 30309078 TI - Perirenal cobwebs: Perinephric stranding. PMID- 30309079 TI - Beaking of bowel: Bowel obstruction. PMID- 30309080 TI - Wasp waist sign: Congenital vertebral fusion. PMID- 30309081 TI - Tail sign: Phlebolith. PMID- 30309082 TI - Bird's beak configuration: Thoracic aortic graft. PMID- 30309083 TI - Crocodile jaw sign: Annular pancreas. PMID- 30309084 TI - Pes anserinus: Normal anatomy. PMID- 30309085 TI - Snoopy sign: Congenital absence of the left pericardium. PMID- 30309086 TI - Pica: Eating disorder. PMID- 30309087 TI - Bear paw sign: Xanthogranulomatous pyelonephritis. PMID- 30309088 TI - Winking owl sign: Unilateral absent pedicle. PMID- 30309089 TI - Turtle Shell: Appearance of liver in schistosomiasis. PMID- 30309090 TI - Bovine aortic arch. PMID- 30309091 TI - Elephants of Rogers: Normal anatomy. PMID- 30309092 TI - Crow's feet appearance: Fissured gallstones. PMID- 30309093 TI - Jellyfish sign: Pleural effusion. PMID- 30309095 TI - Porcupine appearance: Gout. PMID- 30309094 TI - Horseshoe adrenal: Anatomical variant. PMID- 30309097 TI - Playboy bunny and moose head sign: Hepatic veins in congestive heart failure. PMID- 30309096 TI - Tadpole appearance: Azygous fissure. PMID- 30309098 TI - Beaver tail liver: Anatomic variant. PMID- 30309100 TI - Uterus didelphys: Anatomic variant. PMID- 30309099 TI - Zebra stripe sign: Transverse sclerotic lines in the long bones. PMID- 30309101 TI - Bunny waveform: Early feature of subclavian steal syndrome. PMID- 30309103 TI - Dog ears appearance: Ascites. PMID- 30309102 TI - Endosteal scalloping: Pattern of bone erosion. PMID- 30309104 TI - Pig bronchus. PMID- 30309105 TI - Horseshoe appendix: Anatomical variant. PMID- 30309106 TI - Rat bite erosion: Gout. PMID- 30309107 TI - Tail sign: Pulmonary sclerosing pneumocytoma. PMID- 30309108 TI - Ram's Horn Sign: Gastric antrum in Crohn's disease. PMID- 30309109 TI - Bird's beak sign: Achalasia. PMID- 30309111 TI - Feather pattern: Muscle disease. PMID- 30309110 TI - Vermiform appendix: Normal anatomy. PMID- 30309112 TI - Plankton sign: Pleural effusion. PMID- 30309113 TI - Liver atoll sign: Nodular regenerative hyperplasia. PMID- 30309114 TI - Scotty dog: Normal anatomy - pars interarticularis. PMID- 30309115 TI - Takotsubo syndrome. PMID- 30309116 TI - Rat tail appearance: Gastrointestinal strictures. PMID- 30309118 TI - Fish vertebrae: Osteoporosis. PMID- 30309117 TI - Bullfrog swallow: Bilateral pharyngocoeles. PMID- 30309119 TI - Pleural mouse: fibrin bodies. PMID- 30309120 TI - Horseshoe sign: Sigmoid volvulus. PMID- 30309121 TI - Serpentine lines: Osteonecrosis. PMID- 30309122 TI - Tracheal and bronchial stenosis: Rat tails and Webs. PMID- 30309123 TI - Scalloping of the liver: Pseudomyxoma peritonei. PMID- 30309124 TI - Bull's-eye sign: Various manifestations in the gastrointestinal tract. PMID- 30309125 TI - Chicken on a fence sign: Pericardial effusion. PMID- 30309126 TI - Dromedary hump: Anatomic variant. PMID- 30309127 TI - Frog leg: Radiographic view. PMID- 30309128 TI - Pleural tail sign: pleural tags. PMID- 30309129 TI - Leaping dolphin sign: Pneumoperitoneum. PMID- 30309130 TI - Serpentine varices. PMID- 30309131 TI - Seagull appearance: Vascular anatomy on ultrasound. PMID- 30309132 TI - Anteater nose and reverse anteater signs: Calcaneo-navicular coalition. PMID- 30309133 TI - Canine tooth: Mature cystic teratoma. PMID- 30309134 TI - Zebra spleen and liver. PMID- 30309135 TI - Chicken wing configuration: Left atrial appendage. PMID- 30309136 TI - Feline oesophagus. PMID- 30309137 TI - Gorilla rib: Anatomic variant. PMID- 30309138 TI - Pulmonary artery webs: Chronic pulmonary thromboembolism. PMID- 30309139 TI - Liver atoll sign: Nodular regenerative hyperplasia. PMID- 30309140 TI - Shark's fin sign: Unilateral facet joint dislocation. PMID- 30309141 TI - Seagull sign: Peritoneal line on rectal MRI. PMID- 30309142 TI - Beak-type Pellegrini Stieda lesion. PMID- 30309143 TI - Cor bovinum: Large heart. PMID- 30309144 TI - Fish hook coeliac: Median arcuate ligament syndrome. PMID- 30309145 TI - Gull-wing deformity: Osteoarthritis. PMID- 30309147 TI - Liver atoll sign: Inflammatory hepatocellular adenoma. PMID- 30309146 TI - Rabbit's ears: Pulmonary arteriovenous malformations. PMID- 30309148 TI - Butterfly vertebra: Congenital variant. PMID- 30309149 TI - Coral reef aorta. PMID- 30309150 TI - Animal signs in Radiology: method of creating a compendium. PMID- 30309151 TI - Fish hook ureter: 2 types of variant course. PMID- 30309152 TI - Gull-wing sign: Acetabular fracture. PMID- 30309153 TI - Rabbit's ears sign: Mucoid impaction in bronchi. PMID- 30309154 TI - Lobster claw sign: Renal papillary necrosis. PMID- 30309155 TI - Chicken intestine: Intestinal tuberculosis. PMID- 30309156 TI - Cauda equina: Normal anatomy. PMID- 30309157 TI - Crow's feet: Asbestos related lung changes. PMID- 30309158 TI - Fish tail pancreas: Anatomic variant. PMID- 30309159 TI - Horseshoe abscess: Hand. PMID- 30309160 TI - Rat tail sign: Breast implants. PMID- 30309162 TI - Marsupial cava: Anatomic variant. PMID- 30309161 TI - Staghorn sign: Extra-abdominal desmoid fibromatosis. PMID- 30309163 TI - Snail shell sign: Testicular/ovarian torsion. PMID- 30309164 TI - Anemone appearance: Papillary fibroelastoma. PMID- 30309165 TI - Chinese dragon sign: Ulcerative colitis. PMID- 30309167 TI - Fish mouth appearance: Mitral valve. PMID- 30309166 TI - Claw osteophyte: Spine. PMID- 30309168 TI - Fishnet/cobweb ovary: Haemorrhagic ovarian cyst. PMID- 30309169 TI - Moth eaten: Infiltrative destruction of bone. PMID- 30309170 TI - Saddle embolism: Pulmonary thromboembolism. PMID- 30309171 TI - Swan neck deformity. PMID- 30309172 TI - Mickey mouse signs. PMID- 30309173 TI - Snake or serpent sign: Hydatid. PMID- 30309174 TI - Antler sign: Pulmonary venous hypertension. PMID- 30309175 TI - Chinese dragon: Splenic artery. PMID- 30309176 TI - Claw sign: MRI of degenerative disc disease. PMID- 30309177 TI - Fish mouth sign: Bicuspid aortic valve. PMID- 30309178 TI - Goose head: Pelvic floor spasm. PMID- 30309179 TI - CPD questions. PMID- 30309180 TI - Tadpole sign: Ganglion. PMID- 30309181 TI - Snakeskin sign: Oesophageal candidiasis. PMID- 30309182 TI - Aortic beak sign: Aortic dissection. PMID- 30309183 TI - Chipmunk swallow: Piecemeal deglutition. PMID- 30309184 TI - The use of animal signs in Radiology: Lessons in image interpretation from art theory, patternicity and analogy. PMID- 30309185 TI - Claw toe. PMID- 30309186 TI - Giant dog ear: Left atrial appendage aneurysm. PMID- 30309187 TI - Goose neck: Intestinal tuberculosis. PMID- 30309188 TI - Tadpole sign: Stener lesion. PMID- 30309189 TI - Spider's web sign: Budd-Chiari syndrome. PMID- 30309190 TI - Aortic webs and cobwebs: Aortic dissection and arteriopathies. PMID- 30309191 TI - Claw sign: Origin of a mass. PMID- 30309192 TI - Cockscomb appearance: Retrocalcaneal bursitis. PMID- 30309193 TI - Goose neck appearance: Endocardial cushion defect. PMID- 30309194 TI - Mouse ear erosions: Psoriatic arthritis. PMID- 30309195 TI - Hidebound sign: Small bowel in systemic sclerosis. PMID- 30309196 TI - Scalloping: Various signs in the chest. PMID- 30309197 TI - Medullary sponge kidney. PMID- 30309198 TI - Araneid limb-like sign: Eosinophilic enteritis. PMID- 30309199 TI - Tail sign: Soft tissue tumour. PMID- 30309201 TI - Editor's Introduction to This Issue (G&I 16:3, 2018). PMID- 30309200 TI - The Presence of Neural Stem Cells and Changes in Stem Cell-Like Activity With Age in Mouse Spiral Ganglion Cells In Vivo and In Vitro. AB - OBJECTIVES: Spiral ganglion neurons (SGNs) include potential endogenous progenitor populations for the regeneration of the peripheral auditory system. However, whether these populations are present in adult mice is largely unknown. We examined the presence and characteristics of SGN-neural stem cells (NSCs) in mice as a function of age. METHODS: The expression of Nestin and Ki67 was examined in sequentially dissected cochlear modiolar tissues from mice of different ages (from postnatal day to 24 weeks) and the sphere-forming populations from the SGNs were isolated and differentiated into different cell types. RESULTS: There were significant decreases in Nestin and Ki67 double positive mitotic progenitor cells in vivo with increasing mouse age. The SGNs formed spheres exhibiting self-renewing activity and multipotent capacity, which were seen in NSCs and were capable of differentiating into neuron and glial cell types. The SGN spheres derived from mice at an early age (postnatal day or 2 weeks) contained more mitotic stem cells than those from mice at a late age. CONCLUSION: Our findings showed the presence of self-renewing and proliferative subtypes of SGN-NSCs which might serve as a promising source for the regeneration of auditory neurons even in adult mice. PMID- 30309202 TI - Antibacterial and Pharmacological Evaluation of Fluoroquinolones: A Chemoinformatics Approach. AB - Fluoroquinolone (FQ) antibiotics are an important class of synthetic antibacterial agents. These are the most extensively used drugs for treating bacterial infections in the field of both human and veterinary medicine. Herein, the antibacterial and pharmacological properties of four fluoroquinolones: lomefloxacin, norfloxacin, ciprofloxacin, and ofloxacin have been studied. The objective of this study was to analyze the antibacterial characteristics of the different fluoroquinolones. Also, the pharmacological properties of the compounds including the Lipinski rule of five, absorption, distribution, metabolism, and excretion, LD50, drug likeliness, and toxicity were evaluated. We found that among all four FQ molecules, ofloxacin showed the highest antibacterial activity through in silico assays with a strong interaction (-38.52 kJ/mol) with the antibacterial target protein (topoisomerase-II DNA gyrase enzyme). The pharmacological and pharmacokinetic analysis also showed that the compounds ciprofloxacin, ofloxacin, lomefloxacin and norfloxacin have good pharmacological properties. Notably, ofloxacin was found to possess an IGC50 (concentration needed to inhibit 50% growth) value of 0.286 MUg/L against the Tetrahymena pyriformis protozoa. It also tested negative for the Ames toxicity test, showing its non-carcinogenic character. PMID- 30309203 TI - Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity. AB - In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials. PMID- 30309204 TI - Genome-Wide Association Studies Associated with Backfat Thickness in Landrace and Yorkshire Pigs. AB - Although pork quality traits are important commercially, genome-wide association studies (GWASs) have not well considered Landrace and Yorkshire pigs worldwide. Landrace and Yorkshire pigs are important pork-providing breeds. Although quantitative trait loci of pigs are well-developed, significant genes in GWASs of pigs in Korea must be studied. Through a GWAS using the PLINK program, study of the significant genes in Korean pigs was performed. We conducted a GWAS and surveyed the gene ontology (GO) terms associated with the backfat thickness (BF) trait of these pigs. We included the breed information (Yorkshire and Landrace pigs) as a covariate. The significant genes after false discovery rate (<0.01) correction were AFG1L, SCAI, RIMS1, and SPDEF. The major GO terms for the top 5% of genes were related to neuronal genes, cell morphogenesis and actin cytoskeleton organization. The neuronal genes were previously reported as being associated with backfat thickness. However, the genes in our results were novel, and they included ZNF280D, BAIAP2, LRTM2, GABRA5, PCDH15, HERC1, DTNBP1, SLIT2, TRAPPC9, NGFR, APBB2, RBPJ, and ABL2. These novel genes might have roles in important cellular and physiological functions related to BF accumulation. The genes related to cell morphogenesis were NOX4, MKLN1, ZNF280D, BAIAP2, DNAAF1, LRTM2, PCDH15, NGFR, RBPJ, MYH9, APBB2, DTNBP1, TRIM62, and SLIT2. The genes that belonged to actin cytoskeleton organization were MKLN1, BAIAP2, PCDH15, BCAS3, MYH9, DTNBP1, ABL2, ADD2, and SLIT2. PMID- 30309205 TI - A Short Report on the Markov Property of DNA Sequences on 200-bp Genomic Units of ENCODE/Broad ChromHMM Annotations: A Computational Perspective. AB - The non-coding DNA in eukaryotic genomes encodes a language which programs chromatin accessibility, transcription factor binding, and various other activities. The objective of this short report was to determine the impact of primary DNA sequence on the epigenomic landscape across 200-base pair genomic units by integrating nine publicly available ChromHMM Browser Extensible Data files of the Encyclopedia of DNA Elements (ENCODE) project. The nucleotide frequency profiles of nine chromatin annotations with the units of 200 bp were analyzed and integrative Markov chains were built to detect the Markov properties of the DNA sequences in some of the active chromatin states of different ChromHMM regions. Our aim was to identify the possible relationship between DNA sequences and the newly built chromatin states based on the integrated ChromHMM datasets of different cells and tissue types. PMID- 30309206 TI - Generation of Whole-Genome Sequencing Data for Comparing Primary and Castration Resistant Prostate Cancer. AB - Because castration-resistant prostate cancer (CRPC) does not respond to androgen deprivation therapy and has a very poor prognosis, it is critical to identify a prognostic indicator for predicting high-risk patients who will develop CRPC. Here, we report a dataset of whole genomes from four pairs of primary prostate cancer (PC) and CRPC samples. The analysis of the paired PC and CRPC samples in the whole-genome data showed that the average number of somatic mutations per patients was 7,927 in CRPC tissues compared with primary PC tissues (range, 1,691 to 21,705). Our whole-genome sequencing data of primary PC and CRPC may be useful for understanding the genomic changes and molecular mechanisms that occur during the progression from PC to CRPC. PMID- 30309207 TI - GNI Corpus Version 1.0: Annotated Full-Text Corpus of Genomics & Informatics to Support Biomedical Information Extraction. AB - Genomics & Informatics (NLM title abbreviation: Genomics Inform) is the official journal of the Korea Genome Organization. Text corpus for this journal annotated with various levels of linguistic information would be a valuable resource as the process of information extraction requires syntactic, semantic, and higher levels of natural language processing. In this study, we publish our new corpus called GNI Corpus version 1.0, extracted and annotated from full texts of Genomics & Informatics, with NLTK (Natural Language ToolKit)-based text mining script. The preliminary version of the corpus could be used as a training and testing set of a system that serves a variety of functions for future biomedical text mining. PMID- 30309208 TI - Novel biological strategies to enhance the radiation therapeutic ratio. AB - Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio. PMID- 30309209 TI - Clinical outcome of proton therapy for patients with chordomas. AB - PURPOSE: To investigate the clinical outcome of proton therapy (PT) in patients with chordoma. Materials and METHODS: Fifty-eight patients with chordoma treated with PT between June 2007 and December 2015 at the National Cancer Center, Korea, were retrospectively analyzed. The median total dose was 69.6 cobalt gray equivalent (CGE; range, 64.8 to 79.2 CGE). Local progression-free survival (LPFS), distant metastasis-free survival (DMFS), overall survival (OS), and diseasespecific survival (DSS) rates were calculated by the Kaplan-Meier method. RESULTS: With the median follow-up of 42.8 months (range, 4 to 174 months), the 5 year LPFS, DMFS, OS, and DSS rates were 87.9%, 86.7%, 88.3%, and 92.9%, respectively. The tumor location was associated with the patterns of failure: the LPFS rates were lower for cervical tumors (57.1%) than for non-cervical tumors (93.1%) (p = 0.02), and the DMFS rates were lower for sacral tumors (53.5%) than for non-sacral tumors (100%) (p = 0.001). The total dose was associated with both the LPFS rate and DMFS rate. The initial tumor size was associated with the DMFS rate, but was not associated with the LPFS rate. Three patients had grade 3 late toxicity with none >=grade 4. CONCLUSION: PT is an effective and safe treatment in patients with chordomas. The tumor location was associated with the patterns of failure: local failure was common in cervical tumors, and distant failure was common in sacral tumors. Further refinement of PT, such as the utilization of intensity modulated PT for cervical tumors, is warranted to improve the outcome. PMID- 30309210 TI - Optimal timing for salvage surgery after definitive radiotherapy in hypopharyngeal cancer. AB - PURPOSE: Use of radiotherapy combined with chemotherapy is increasing in hypopharyngeal cancer. However, many show residual tumor after radiotherapy. Timing for treatment evaluation and salvage therapy is essential. However, optimal timing for salvage surgery has not been suggested. In this study, we tried to evaluate optimal timing for salvage surgery. Methods and Materials: Patients who were diagnosed with hypopharyngeal squamous cell carcinoma between 2006 and 2015 were retrospectively analyzed. All patients received definitive radiotherapy with or without chemotherapy. Response of all treated patients were analyzed at 1, 3, and 6 months after radiotherapy. Any patients with progression before 6 months were excluded. RESULTS: A total of 54 patients were analyzed. Complete remission (CR) rates at 1 month (CR1), 3 months (CR3) and 6 months (CR6) were 66.7%, 81.5%, and 90.7%, respectively. Non-CR at 1 month (NCR1), 3 months (NCR3), and 6 months (NCR6) showed poor locoregional recurrence-free survival rates (1-year rates of 63.7%, 66.7%, and 0.0%, respectively) compared to CR1, CR3, and CR6 (1-year rates 94.3%, 88.0%, and 91.5%, respectively). Particularly significant differences were seen between CR6 and NCR6 (p < 0.001). Of 10 patients with NCR3, 5 showed CR at 6 months (NCR3/CR6). There was no statistical difference in locoregional recurrence-free survival between CR3 and NCR3/CR6 group (p = 0.990). CONCLUSION: Our data suggest half of patients who did not show CR at 3 months eventually achieved CR at 6 months. Waiting until 6 months after radiotherapy may be appropriate for avoiding additional salvage therapy. PMID- 30309212 TI - Use of radiotherapy in patients with palliative double bypass for locally advanced pancreatic adenocarcinoma. AB - PURPOSE: Pancreatic cancer (PC) has not changed overall survival in recent years despite therapeutic efforts. Surgery with curative intent has shown the best long term oncological results. However, 80%-85% of patients with these tumors are unresectable at the time of diagnosis. In those patients, first therapeutic attempts are minimally invasive or surgical procedures to alleviate symptoms. The addition of radiotherapy (RT) to standard chemotherapy, ergo chemoradiation, in patients with locally advanced pancreatic cancer (LAPC) is still controversial. The study aims to compare outcomes in patients with a double bypass surgery due to LAPC treated or not with RT. Materials and METHODS: A retrospective cohort study of patients with double bypass for LAPC were registered and divided into two groups: treated or not with postoperative RT. Baseline characteristics, postoperative complications, those related to RT and their relation to the main event (mortality) were compared. RESULTS: Seventy-four patients were included. Surgical complications between the groups did not offer significant differences. Complications related to RT were mostly mild, and 86% of patients completed the treatment. Overall survival at 1 and 2 years for patients in the exposed group was 64% and 35% vs. 50% and 28% in the non-exposed group, respectively (p = 0.11; power 72%; hazard ratio = 0.53; 95% confidence interval, 0.24-1.18). CONCLUSION: We observed a tendency for survival improvement in patients with postoperative RT. However, we've not had enough power to demonstrate this difference, possibly due to the small sample size. It is indispensable to develop randomized and prospective trials to guide more specific treatment lines in this patients. PMID- 30309211 TI - Effectiveness and feasibility of concurrent chemoradiotherapy using simultaneous integrated boost-intensity modulated radiotherapy with and without induction chemotherapy for locally advanced pancreatic cancer. AB - PURPOSE: To evaluate the effectiveness and feasibility of chemoradiotherapy (CRT) using simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) in locally advanced pancreatic cancer (LAPC) patients. Materials and METHODS: Between January 2011 and May 2015, 47 LAPC patients received CRT using SIB-IMRT. Prior to SIBIMRT, 37 patients (78.7%) received induction chemotherapy (IC-CRT group) and remaining 10 patients (21.3%) did not received induction chemotherapy (CRT group). During SIB-IMRT, all patients received concomitant chemotherapy, with gemcitabine (n = 37) and capecitabine (n = 10). RESULTS: At the time of analysis, 45 patients had died and 2 patients remained alive and the median follow-up time was 14.2 months (range, 3.3 to 51.4 months). For all patients, the median times of local progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were 18.1, 10.3, and 14.2 months, respectively. The median time of LPFS between IC-CRT and CRT groups was similar (18.1 months vs. 18.3 months, p = 0.711). IC-CRT group had a higher trend in PFS (10.9 months vs. 4.1 months, p = 0.054) and had significantly higher OS (15.4 months vs. 9.5 months, p = 0.007) than CRT group. In multivariate analysis, the use of induction chemotherapy and tumor response were significant factors associated with OS (p < 0.05, each). During SIBIMRT, toxicity of grade >=3 was observed in 7 patients (14.9%) in all patients. CONCLUSION: CRT using SIB-IMRT is feasible and promising in LAPC patients. PMID- 30309213 TI - Single nucleotide polymorphism of GSTP1 and pathological complete response in locally advanced rectal cancer patients treated with neoadjuvant concomitant radiochemotherapy. AB - PURPOSE: Standard treatment for locally advanced rectal cancer consists of neoadjuvant radiochemotherapy with concomitant fluoropyrimidine or oxaliplatin and surgery with curative intent. Pathological complete response has shown to be predictive for better outcome and survival; nevertheless there are no biological or genetic factors predictive for response to treatment. We explored the correlation between the single nucleotide polymorphisms (SNPs) GSTP1 (A313G) and XRCC1 (G28152A), and the pathological complete response and survival after neoadjuvant radiochemotherapy in locally advanced rectal cancer patients. Materials and METHODS: Genotypes GSTP1 (A313G) and XRCC1 (G28152A) were determined by pyrosequencing technology in 80 patients affected by locally advanced rectal cancer. RESULTS: The overall rate of pathological complete response in our study population was 18.75%. Patients homozygous AA for GSTP1 (A313G) presented a rate of pathological complete response of 26.6% as compared to 8.5% of the AG+GG population (p = 0.04). The heterozygous comparison (AA vs. AG) showed a significant difference in the rate of pathological complete response (26.6% vs. 6.8%; p = 0.034). GSTP1 AA+AG patients presented a 5- and 8-year cancer-specific survival longer than GSTP1 GG patients (87.7% and 83.3% vs. 44.4% and 44.4%, respectively) (p = 0.014). Overall survival showed only a trend toward significance in favor of the haplotypes GSTP1 AA+AG. No significant correlations were found for XRCC1 (G28152A). CONCLUSION: Our results suggest that GSTP1 (A313G) may predict a higher rate of pathological complete response after neoadjuvant radiochemotherapy and a better outcome, and should be considered in a more extensive analysis with the aim of personalization of radiation treatment. PMID- 30309214 TI - Dose comparison between prescription methods according to anatomical variations in intracavitary brachytherapy for cervical cancer. AB - PURPOSE: We compared how doses delivered via two-dimensional (2D) intracavitary brachytherapy (ICBT) and three-dimensional (3D) ICBT varied anatomically. Materials and METHODS: A total of 50 patients who received 30 Gy of 3D ICBT after external radiotherapy (RT) were enrolled. We compared the doses of the actual 3D and 2D ICBT plans among patients grouped according to six anatomical variations: differences in a small-bowel V2Gy, small bowel circumference, the direction of bladder distension, bladder volume, sigmoid V3.5Gy, and sigmoid circumference. Seven dose parameters were measured in line with the EMBRACE recommendations. RESULTS: In terms of bladder volume, the bladder and small-bowel D2cc values were lower in the 150-250 mL bladder volume subgroup; and the rectum, sigmoid, and bladder D2mL values were all lower in the >250 mL subgroup, for 3D vs. 2D ICBT. In the sigmoid V3.5Gy >2 mL subgroup, the sigmoid and bladder D2mL values were significantly lower for 3D than 2D ICBT. The bladder D2mL value was also significantly lower for 3D ICBT, as reflected by the sigmoid circumference. In patients with a small bowel V2.0Gy >10 mL or small bowel circumference >15%, most dose parameters were significantly lower for 3D than 2D ICBT. The bladder distension direction did not significantly affect the doses. CONCLUSION: Compared to 2D ICBT, a greater bladder volume can reduce the internal 3D ICBT organ dose without affecting the target dose. PMID- 30309215 TI - Assessment of inter- and intra-fractional volume of bladder and body contour by mega-voltage computed tomography in helical tomotherapy for pelvic malignancy. AB - PURPOSE: We describe the daily bladder volume change observed by mega-voltage computed tomography (MVCT) during pelvic radiotherapy with potential predictors of increased bladder volume variations. Materials and METHODS: For 41 patients who received pelvic area irradiation, the volumes of bladder and pelvic body contour were measured twice a day with pre- and post-irradiation MVCT from the 1st to the 10th fraction. The median prescription dose was 20 Gy (range, 18 to 30 Gy) up to a 10th fraction. The upper and lower margin of MVCT scanning was consistent during the daily treatments. The median age was 69 years (range, 33 to 86 years) and 10 patients (24.4%) were treated postoperatively. RESULTS: Overall bladder volume on planning computed tomography was 139.7 +/- 92.8 mL. Generally, post-irradiation bladder volume (POSTBV) was larger than pre-irradiation bladder volume (PREBV) (p < 0.001). The mean PREBV and POSTBV was reduced after 10 fraction treatments by 21.3% (p = 0.028) and 25.4% (p = 0.007), respectively. The MVCT-scanned body contour volumes had a tendency to decrease as the treatment sessions progressed (p = 0.043 at the 8th fraction and p = 0.044 at the 10th fraction). There was a statistically significant correlation between bladder filling time and PREBV (p = 0.001). CONCLUSION: Daily MVCT-based bladder volume assessment was feasible both intra- and inter-fractionally. PMID- 30309217 TI - Impact of testicular shielding in liposarcoma to scrotum by using radio photoluminescence glass dosimeter (RPLGD): a case report. AB - Radiation protection in the scrotum to reduce the risk of genetic effect in the future is very important. This study aimed to measure the scrotal dose outside the treatment fields by using the radio-photoluminescence glass dosimeter (RPLGD). The characteristics of RPLGD model GD-302M were studied. Scattered dose to scrotum was measured in one liposarcoma case with the prescribed dose of 60 Gy. RPLGDs were placed in three different locations: one RPLGD was positioned at the posterior area which closer to the scrotum, and the other two RPLGDs were placed between the penis and the scrotum. Three RPLGDs were employed in each location. The scattered doses were measured in every fraction during the whole course of treatment. The entire number of 100 RPLGDs showed the uniformity within +/-2%. The signal from RPLGD demonstrated linear proportion to the radiation dose (r = 0.999). The relative energy response correction factor was 1.05. The average scrotal dose was 4.1 +/- 0.9 cGy per fraction. The results presented a wide range since there was a high uncertainty during RPLGD placement. The total scrotal dose for the whole course of treatment was 101.9 cGy (1.7% of the prescribed dose). The RPLGD model GD-302M could be used to measure scattered dose after applying the relative energy correction factor. PMID- 30309216 TI - Evaluation of the hybrid-dynamic conformal arc therapy technique for radiotherapy of lung cancer. AB - PURPOSE: A hybrid-dynamic conformal arc therapy (HDCAT) technique consisting of a single half-rotated dynamic conformal arc beam and static field-in-field beams in two directions was designed and evaluated in terms of dosimetric benefits for radiotherapy of lung cancer. Materials and METHODS: This planning study was performed in 20 lung cancer cases treated with the VERO system (BrainLAB AG, Feldkirchen, Germany). Dosimetric parameters of HDCAT plans were compared with those of three-dimensional conformal radiotherapy (3D-CRT) plans in terms of target volume coverage, dose conformity, and sparing of organs at risk. RESULTS: HDCAT showed better dose conformity compared with 3D-CRT (conformity index: 0.74 +/- 0.06 vs. 0.62 +/- 0.06, p < 0.001). HDCAT significantly reduced the lung volume receiving more than 20 Gy (V20: 21.4% +/- 8.2% vs. 24.5% +/- 8.8%, p < 0.001; V30: 14.2% +/- 6.1% vs. 15.1% +/- 6.4%, p = 0.02; V40: 8.8% +/- 3.9% vs. 10.3% +/- 4.5%, p < 0.001; and V50: 5.7% +/- 2.7% vs. 7.1% +/- 3.2%, p < 0.001), V40 and V50 of the heart (V40: 5.2 +/- 3.9 Gy vs. 7.6 +/- 5.5 Gy, p < 0.001; V50: 1.8 +/- 1.6 Gy vs. 3.1 +/- 2.8 Gy, p = 0.001), and the maximum spinal cord dose (34.8 +/- 9.4 Gy vs. 42.5 +/- 7.8 Gy, p < 0.001) compared with 3D-CRT. CONCLUSION: HDCAT could achieve highly conformal target coverage and reduce the doses to critical organs such as the lung, heart, and spinal cord compared to 3D CRT for the treatment of lung cancer patients. PMID- 30309218 TI - Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan. AB - Purpose: Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan. Materials and Methods: PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations. Results: A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127; 0.8%). Besides, four in silico predicted potentially functional mutations including three missense mutations and one 5' untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (<30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated. Conclusion: Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan. PMID- 30309219 TI - Risk Assessment of Secondary Primary Malignancies in Nasopharyngeal Carcinoma: A Big-Data Intelligence Platform-Based Analysis of 6,377 Long-Term Survivors from an Endemic Area Treated with Intensity-Modulated Radiation Therapy during 2003 2013. AB - Purpose: The incidence, risk factors and survival impact of secondary primary malignancies (SPMs) among survivors of nasopharyngeal carcinoma (NPC) treated with definitive intensity-modulated radiation therapy (IMRT) with or without chemotherapy are poorly characterized. Methods and Materials: Consecutive patients (n=6,377) from the big-data intelligence platform at Sun Yat-Sen University Cancer Center, China (in a high-incidence area) with newly diagnosed non-metastatic pathologically proven non-keratinizing undifferentiated NPC treated with IMRT+/-chemotherapy between January 2003 and June 2013 were retrospectively analyzed. Cumulative incidence of SPMs was calculated using the Kaplan-Meier method. Cox proportional hazards model was used to identify potential risk factors for SPMs and assess whether SPMs affect overall survival. Results: Of the 6,377 patients, 189 (3.0%) suffered SPMs (median follow-up, 62 months). One-, 2-, 3-, 4-, and 5- cumulative risks of SPMs were 0.4%, 0.9%, 1.6%, 2.2%, and 2.6%, respectively. Latency from start of IMRT to SPMs diagnosis was 37 months (range, 6 to 102 months). In patients with SPMs, 14.3% suffered SPMs within 1 year post-IMRT: 1-3 years, 38.1%; 3-5 years, 33.9%; and >5 years, 13.7%. Lung cancer was the most common SPM (50/6,377, 0.78%). Multivariate analysis demonstrated sex (male, 64% increase), age (>=50 years, 68% increase), and smoking history (41% increase) were significant risk factors for SPMs, and SPMs were associated with poorer overall survival. Conclusion: This large cohort study confirms SPMs a dreadful complication for long-term survivors of NPC treated with IMRT. SPMs negatively impact overall survival in NPC. Close follow-up is recommended for older male survivors with a smoking history. PMID- 30309220 TI - Improved Survival of Cancer Patients Admitted to the Intensive Care Unit between 2002 and 2011 at a U.S. Teaching Hospital. AB - Purpose: Cancer patients are at increased risk of treatment- or disease-related admission to the intensive care unit [1]. Over the past decades, both critical care and cancer care have improved substantially. Due to increased cancer specific survival [2], we hypothesized that the number of cancer patients admitted to the intensive care unit (ICU) and survival have increased. Materials and Methods: MIMIC-III [3] was used to study trends and outcomes of cancer patients admitted to the ICU between 2002 and 2011. Multiple logistic regression analysis was performed to adjust for confounders of mortality. Results: Among 41,468 patients analyzed, 1,083 were hemato-oncologic, 4,330 were oncologic and 66 patients had both a hematological and solid malignancy. Admission numbers more than doubled and the proportion of cancer patients in the ICU increased steadily from 2002 to 2011. In both the univariate and multivariate analyses, solid cancers and hematologic cancers were strongly associated with 28-day mortality. This association was even stronger for 1-year mortality, with odds ratios of 4.02 (95% confidence interval [CI], 3.69 to 4.38) and 2.25 (95% CI, 1.93 to 2.62), respectively. Over the 10-year study period, both 28-day and 1-year mortality decreased, with hematologic patients showing the strongest annual adjusted decrease in the odds of death. There was considerable heterogeneity among solid cancer types. Conclusion: Between 2002 and 2011, the number of cancer patients admitted to the ICU more than doubled, while clinical severity scores remained overall unchanged, suggesting improved treatment. Although cancer patients had higher mortality rates, both 28-day and 1-year mortality of hematologic patients decreased faster than that of non-cancer patients, while mortality rates of cancer patients strongly depended on cancer type. PMID- 30309221 TI - Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib. AB - Purpose: Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1. Materials and Methods: We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3' mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines. Results: We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR) dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit alpha (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase alpha (PI3Kalpha) inhibitor. Conclusion: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kalpha inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients. PMID- 30309222 TI - Clinical and Genetic Characteristics of BRCA1/2 Mutation in Korean Ovarian Cancer Patients: A Multicenter Study and Literature Review. AB - Purpose: We investigated the clinical relevance and spectrum of BRCA1/2 mutations in Korean ovarian cancer (KoOC) patients. Materials and Methods: Two hundred seventy-nine KoOC patients were enrolled from three university hospitals between 2012 and 2017. Their peripheral blood samples were obtained for BRCA1/2 mutation analysis by direct sequencing. Clinicopathological characteristics were retrospectively reviewed, and spectrum analyses of BRCA1/2 mutation were assessed by systematic literature review. Results: Frequency of BRCA1/2 mutations was 16.5% in KoOC patients. BRCA1/2 mutations were significantly associated with family history of breast/ovarian cancer (p<0.001), serous histology (p=0.044) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (III/IV, p=0.018) but not with early age-of-onset (age < 50, p=0.729). Literature review of BRCA1/2 mutations in KoOC patients found 111 (55 distinct) mutations with high proportion of Korean-specific mutations (24/55, 43.6%). Comparing the spectrum of BRCA1/2 mutation between KoOC and Korean breast cancer (KoBC) patients, the ratio of BRCA1-to-BRCA2 mutations was different, with BRCA1 (78.4%) being predominant in KoOC and BRCA2 in KoBC (59.2%). The most common mutation also differed between the two (c.3627insA of BRCA1 in KoOC and c.7480C>T of BRCA2 in KoBC). Conclusion: The clinical relevance of BRCA1/2 mutations in KoOC patients was confirmed but that of early age-of-onset was not. Possible inconsistency in the ratio of BRCA1-to-BRCA2 mutations and the most common mutation between KoOC and KoBC may probably suggest presence of mutation sequence associated penetrance tendency in hereditary Korean breast and ovarian cancer (KoBOC). These data may provide insights for optimal genetic counseling and prophylactic treatment for at-risk relatives of KoOC patients. PMID- 30309223 TI - Dynamics of Soluble Programmed Death-Ligand 1 (sPDL1) during Chemotherapy and its Prognostic Implications in Cancer Patients: Biomarker Development in Immuno Oncology. AB - Purpose: The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre-and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients. Materials and Methods: From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre-and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed. Results: The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (>=1.30 ng/mL) showed worse OS than patients with low pre-chemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR 1.82, 95% CI; 1.1-3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs 0.72 ng/mL, p=0.003). Conclusions: The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value. PMID- 30309224 TI - Percutaneous Left Atrial Appendage Occlusion for the Prevention of Stroke in Patients with Atrial Fibrillation: Review and Critical Appraisal. AB - The authors review the current status of percutaneous left atrial appendage (LAA) occlusion therapy in patients with atrial fibrillation with the goal to prevent ischemic stroke and systemic embolism and to reduce oral anticoagulation associated bleeding. While we cover the historical and also surgical background, and all tested devices, the main focus rests on the single currently U.S. Food and Drug Administration (FDA) approved LAA occluder, the WATCHMAN device, and its approval process. The authors also give a critical appraisal beyond the review of mere facts, trying to put the current data into perspective. PMID- 30309225 TI - Non-Vitamin K Oral Anticoagulants Associated Bleeding and Its Antidotes. AB - Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban. PMID- 30309228 TI - Cognitive Functions in Children and Adults with Moyamoya Vasculopathy: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Patients with moyamoya vasculopathy (MMV) may experience cognitive impairment, but its reported frequency, severity, and nature vary. In a systematic review and metaanalysis, we aimed to assess the presence, severity, and nature of cognitive impairments in children and adults with MMV. METHODS: We followed the MOOSE guidelines for meta-analysis and systematic reviews of observational studies. We searched Ovid Medline and Embase for studies published between January 1, 1969 and October 4, 2016. Independent reviewers extracted data for mean intelligence quotient (IQ) and standardized z-scores for cognitive tests, and determined percentages of children and adults with cognitive deficits, before and after conservative or surgical treatment. We explored associations between summary measures of study characteristics and cognitive impairments by linear regression analysis. RESULTS: We included 17 studies (11 studies reporting on 281 children, six on 153 adults). In children, the median percentage with impaired cognition was 30% (range, 13% to 67%); median IQ was 98 (range, 71 to 107). Median z-score was -0.39 for memory, and -0.43 for processing speed. In adults, the median percentage with impaired cognition was 31% (range, 0% to 69%); median IQ was 95 (range, 94 to 99). Median z-scores of cognitive domains were between -0.9 and -0.4, with multiple domains being affected. We could not identify determinants of cognitive impairment. CONCLUSION: s A large proportion of children and adults with MMV have cognitive impairment, with modest to large deficits across various cognitive domains. Further studies should investigate determinants of cognitive deficits and deterioration, and the influence of revascularization treatment on cognitive functioning. PMID- 30309227 TI - Consensus Guides on Stroke Thrombolysis for Anticoagulated Patients from Japan: Application to Other Populations. AB - Development of direct oral anticoagulants and their antidotes has led to the need to reconsider the eligibility of acute stroke patients who have been taking oral anticoagulants for intravenous thrombolysis. Officially authorized Japanese guidelines on this issue were revised twice at the time of approval for clinical use of direct oral anticoagulants and idarucizumab, a specific reversal agent for dabigatran. A unique recommendation in the latest Japanese clinical guides was that thrombolysis can be recommended if the time of the last dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal, i.e., international normalized ratio of prothrombin time <1.7 and activated partial thromboplastin time <1.5 times the baseline value (<=40 seconds only as a guide). These criteria are partly supported by the findings of domestic multicenter and single-center surveys that symptomatic or asymptomatic intracranial hemorrhage following thrombolysis was rare under the conditions of the criteria. Even for dabigatran users, stroke thrombolysis can be considered without pretreatment by idarucizumab if patients meet the above criteria. If not, direct mechanical thrombectomy can be considered without pretreatment by idarucizumab or thrombolysis, and use of idarucizumab, followed immediately by thrombolysis, can be considered only when thrombectomy cannot be quickly performed. These clinical guides are practical and to some extent economical, but they have some limitations, including lack of corroborating information from sufficient numbers of relevant cases. The guides will be further modified based on the results of future research. PMID- 30309229 TI - Correlation of Adventitial Vasa Vasorum with Intracranial Atherosclerosis: A Postmortem Study. AB - BACKGROUND AND PURPOSE: Vasa vasorum (VV) have been believed to be rare or non existent in small-caliber intracranial arteries. In a series of human cerebral artery specimens, we identified and examined the distribution of VV in association with co-existing intracranial atherosclerosis. METHODS: We obtained cerebral artery specimens from 32 consecutive autopsies of subjects aged 45 years or above. We scrutinized middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) for the presence of adventitial VV. We described the distribution of VV, and the characteristics of co-existing atherosclerotic lesions. RESULTS: Among 157 intracranial arteries, adventitial VV were present in 74 of the 157 specimens (47%), involving MCA (n=13, 18%), BA (n=14, 19%), and VA (n=47, 64%). Although qualitatively these 74 adventitial VV distributed similarly in arteries with or without atherosclerotic lesions (disease-free arteries n=4/8; arteries of pre-atherosclerosis n=17/42; and arteries of progressive atherosclerosis n=53/107), the presence of adventitial VV in intracranial VA was associated with a heavier plaque load (1.72+/-1.66 mm2 vs. 0.40+/-0.32 mm2, P<0.001), severer luminal stenosis (25%+/-21% vs. 12%+/-9%, P=0.002), higher rate of concentric lesions (79% vs. 36%, P=0.002), and denser intraplaque calcification (44% vs. 0%, P=0.003). Histologically, intracranial VA with VV had a larger diameter (3.40+/-0.79 mm vs. 2.34+/-0.58 mm, P<0.001), thicker arterial wall (0.31+/-0.13 mm vs. 0.23+/-0.06 mm, P=0.002), and a larger intima-media (0.19+/-0.09 mm vs. 0.13+/- 0.04 mm, P=0.003) than VA without VV. CONCLUSION: s Our study demonstrated the distribution of adventitial VV within brain vasculature and association between vertebral VV and progressive atherosclerotic lesions with a heavier plaque load and denser intraplaque calcification. PMID- 30309226 TI - Cerebral Small Vessel Disease: A Review Focusing on Pathophysiology, Biomarkers, and Machine Learning Strategies. AB - Cerebral small vessel disease (cSVD) has a crucial role in lacunar stroke and brain hemorrhages and is a leading cause of cognitive decline and functional loss in elderly patients. Based on underlying pathophysiology, cSVD can be subdivided into amyloidal and non-amyloidal subtypes. Genetic factors of cSVD play a pivotal role in terms of unraveling molecular mechanism. An important pathophysiological mechanism of cSVD is blood-brain barrier leakage and endothelium dysfunction which gives a clue in identification of the disease through circulating biological markers. Detection of cSVD is routinely carried out by key neuroimaging markers including white matter hyperintensities, lacunes, small subcortical infarcts, perivascular spaces, cerebral microbleeds, and brain atrophy. Application of neural networking, machine learning and deep learning in image processing have increased significantly for correct severity of cSVD. A linkage between cSVD and other neurological disorder, such as Alzheimer's and Parkinson's disease and non-cerebral disease, has also been investigated recently. This review draws a broad picture of cSVD, aiming to inculcate new insights into its pathogenesis and biomarkers. It also focuses on the role of deep machine strategies and other dimensions of cSVD by linking it with several cerebral and non-cerebral diseases as well as recent advances in the field to achieve sensitive detection, effective prevention and disease management. PMID- 30309230 TI - Aberrant Promoter Hypomethylation of Sortilin 1: A Moyamoya Disease Biomarker. AB - BACKGROUND AND PURPOSE: The pathogenesis of moyamoya disease (MMD) remains poorly understood, and no reliable molecular biomarkers for MMD have been identified to date. The present study aimed to identify epigenetic biomarkers for use in the diagnosis of MMD. METHODS: We performed integrated analyses of gene expression profiles and DNA methylation profiles in endothelial colony forming cells (ECFCs) from three patients with MMD and two healthy individuals. Candidate gene mRNA expression and DNA methylation status were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and pyrosequencing analysis of an expanded ECFC sample set from nine patients with MMD and ten controls. We evaluated the diagnostic accuracy of the potential biomarkers identified here using receiver operating characteristic curve analyses and further measured major angiogenic factor expression levels using a tube formation assay and RT-qPCR. RESULTS: Five candidate genes were selected via integrated analysis; all five were upregulated by hypomethylation of specific promoter CpG sites. After further validation in an expanded sample set, we identified a candidate biomarker gene, sortilin 1 (SORT1). DNA methylation status at a specific SORT1 promoter CpG site in ECFCs readily distinguished patients with MMD from the normal controls with high accuracy (area under the curve 0.98, sensitivity 83.33%, specificity 100%). Furthermore, SORT1 overexpression suppressed endothelial cell tube formation and modulated major angiogenic factor and matrix metalloproteinase-9 expression, implying SORT1 involvement in MMD pathogenesis. CONCLUSION: s Our findings suggest that DNA methylation status at the SORT1 promoter CpG site may be a potential biomarker for MMD. PMID- 30309231 TI - Outcome Prediction Using Perfusion Parameters and Collateral Scores of Multi Phase and Single-Phase CT Angiography in Acute Stroke: Need for One, Two, Three, or Thirty Scans? AB - BACKGROUND AND PURPOSE: Collateral status is an important factor determining outcome in acute ischemic stroke (AIS). Hence, different collateral scoring systems have been introduced. We applied different scoring systems on single- and multi-phase computed tomography (CT) angiography (spCTA and mpCTA) and compared them to CT perfusion (CTP) parameters to identify the best method for collateral evaluation in patients with AIS. METHODS: A total of 102 patients with AIS due to large vessel occlusion in the anterior circulation who underwent multimodal CT imaging and who were treated endovascularly were included. Collateral status was assessed on spCTA and mpCTA using four different scoring systems and compared to CTP parameters. Logistic regression was performed for predicting favorable outcome. RESULTS: All collateral scores correlated well with each other and with CTP parameters. Comparison of collateral scores stratified by extent of perfusion deficit showed relevant differences between groups (P<0.01 for each). An spCTA collateral score discriminated best between favorable and unfavorable outcome as determined using the modified Rankin Scale 3 months after stroke. CONCLUSION: s Collateral status evaluated on spCTA may suffice for outcome prediction and decision making in AIS patients, potentially obviating further imaging modalities like mpCTA or CTP. PMID- 30309232 TI - Higher Blood Pressure during Endovascular Thrombectomy in Anterior Circulation Stroke Is Associated with Better Outcomes. AB - BACKGROUND AND PURPOSE: Reports investigating the relationship between in procedure blood pressure (BP) and outcomes in patients undergoing endovascular thrombectomy (EVT) due to anterior circulation stroke are sparse and contradictory. METHODS: Consecutive EVT-treated adults (modern stent retrievers, BP managed in line with the recommendations, general anesthesia, invasive BP measurements) were evaluated for associations of the rate of in-procedure systolic BP (SBP) and mean arterial pressure (MAP) excursions to >120%/<80% of the reference values (serial measurements at anesthesia induction) and of the reference BP/weighted in-procedure mean BP with post-procedure imaging outcomes (ischemic lesion volume [ILV], hemorrhages) and 3-month functional outcome (modified Rankin Scale [mRS], score 0 to 2 vs. 3 to 6). RESULTS: Overall 164 patients (70.7% pharmacological reperfusion, 80.5% with good collaterals, 73.8% with successful reperfusion) were evaluated for ILV (range, 0 to 581 cm3) and hemorrhages (incidence 17.7%). Higher rate of in-procedure SBP/MAP excursions to >120% was independently associated with lower ILV, while higher in-procedure mean SBP/MAP was associated with lower odds of hemorrhages. mRS 0-2 was achieved in 75/155 (48.4%) evaluated patients (nine had missing mRS data). Higher rate of SBP/MAP excursions to >120% and higher reference SBP/MAP were independently associated with higher odds of mRS 0-2, while higher ILV was associated with lower odds of mRS 0-2. Rate of SBP/MAP excursions to <80% was not associated with any outcome. CONCLUSION: s In the EVT-treated patients with BP managed within the recommended limits, a better functional outcome might be achieved by targeting in procedure BP that exceeds the preprocedure values by more than 20%. PMID- 30309233 TI - Intravenous Thrombolysis Prior to Mechanical Thrombectomy in Acute Ischemic Stroke: Silver Bullet or Useless Bystander? AB - BACKGROUND AND PURPOSE: Recent single-center series and meta-analyses suggest that mechanical thrombectomy (MT) without prior intravenous thrombolysis (IVT) might be equally effective to bridging therapy. We analyzed, within the Endovascular Treatment in Ischemic Stroke (ETIS) prospective observational registry, the angiographic and clinical outcomes after IVT+MT versus MT alone. METHODS: From December 2012 to December 2016, a total of 1,507 consecutive patients with a proximal arterial occlusion of the anterior circulation were treated by MT. Of these, 975 (64.7%) received prior IVT. Immediate angiographic and clinical outcomes at 90 days (modified Rankin Scale [mRS]) were compared between the two groups while checking for propensity score, matched-propensity score and by inverse probability of treatment weighting (IPTW) propensity score method. RESULTS: Favorable outcome (mRS 0 to 2) was more frequently achieved after IVT+MT (n=523, 53.6%) than after MT alone (n=222, 41.8%) with an unadjusted odds ratio (OR) for bridging therapy of 1.61 (95% confidence interval [CI], 1. 29 to 2.01). This difference remained not significant in matched-propensity score cohort (OR, 1.21; 95% CI, 0.90 to 1.63) although it remained according to adjusted propensity score (OR, 1.31; 95% CI, 1.02 to 1.68) and IPTW (OR, 1.37; 95% CI, 1.09 to 1.73) analyses. A significant difference was found in terms of excellent outcome (mRS 0 to 1) (adjusted OR, 1.63; 95% CI, 1.25 to 2.11) and successful reperfusion (adjusted OR, 1.58; 95% CI, 1.33 to 2.15). No differences in intracerebral hemorrhage or in allcause mortality within 90 days were found between groups. CONCLUSION: s IVT prior to MT is associated with increased excellent outcome and successful reperfusion rates. These findings support the use of bridging therapy. PMID- 30309235 TI - RNF213 Polymorphism in Intracranial Artery Dissection. PMID- 30309234 TI - Prognosis of Acute Intracranial Atherosclerosis-Related Occlusion after Endovascular Treatment. AB - BACKGROUND AND PURPOSE: Little is known about prognosis after endovascular therapy (EVT) for acute large artery occlusion (LAO) caused by underlying intracranial atherosclerotic stenosis (ICAS). Therefore, we investigated the prognosis following EVT according to the underlying etiology of LAO. METHODS: Patients from the Acute Stroke due to Intracranial Atherosclerotic occlusion and Neurointervention-Korean Retrospective (ASIAN KR) registry (n=720) were included if their occlusion was in the intracranial anterior circulation and their onset to-puncture time was <24 hours. Occlusion was classified according to etiology as follows: no significant stenosis after recanalization (Embolic group), and fixed significant focal stenosis in the occlusion site with flow impairment or re occlusion observed during EVT (ICAS group). Patients were excluded when significant extracranial carotid lesions existed, and when the intracranial occlusion was intractable to EVT so that the etiology was undetermined. The effect of angiographic etiologic classification on outcomes was evaluated using multivariable analysis that was adjusted for potential confounders. RESULTS: Among eligible patients (n=520), 421 and 99 were classified in the Embolic and ICAS groups, respectively. Patients in the Embolic and ICAS groups had similar successful reperfusion rates with EVT (79.6% vs. 76.8%, P=0.537) and 3-month functional independence (54.5% vs. 45.5%, P=0.104). In multivariable analysis, ICAS-related occlusion (odds ratio, 0.495; 95% confidence interval, 0.269 to 0.913; P=0.024) showed poorer 3-month functional independence compared to embolic occlusion. CONCLUSION: s After EVT, patients with acute ICAS-related occlusion have relatively poor functional outcomes compared to those with embolic occlusion. Novel strategies need to be developed to improve EVT outcomes for ICAS occlusion. PMID- 30309236 TI - Unplanned 30-Day Hospital Readmissions of Symptomatic Carotid and Vertebral Artery Dissection. PMID- 30309237 TI - Manual Thrombus Density Measurement Depends on the Method of Thrombus Delineation. PMID- 30309238 TI - Statin and the Risk of Ischemic Stroke or Transient Ischemic Attack in Head and Neck Cancer Patients with Radiotherapy. PMID- 30309239 TI - Counseling for improving adherence to antiretroviral treatment: a systematic review. AB - One-on-one counseling can be an effective strategy to improve patient adherence to HIV treatment. The aim of this systematic review is to examine articles with one-on-one counseling-based interventions, review their components and effectiveness in improving ART adherence. A systematic review, using the following criteria was performed: (i) experimental studies; (ii) published in Spanish, English or Portuguese; (iii) with interventions consisting primarily of counseling; (iv) adherence as the main outcome; (v) published between 2005 and 2016; (vi) targeted 18 to 60 year old, independent of gender or sexual identity. The author reviewed bibliographic databases. Articles were analyzed according to the type of study, type of intervention, period of intervention, theoretical basis for intervention, time used in each counseling session and its outcomes. A total of 1790 records were identified. Nine studies were selected for the review, these applied different types of individual counseling interventions and were guided by different theoretical frameworks. Counseling was applied lasting between 4 to 18 months and these were supervised through three to six sessions over the study period. Individual counseling sessions lasted from 7.5 to 90 minutes (Me. 37.5). Six studies demonstrated significant improvement in treatment. Counseling is effective in improving adherence to ART, but methods vary. Face-to-face and computer counseling showed efficacy in improving the adherence, but not the telephone counseling. More evidence that can determine a basic counseling model without losing the individualized intervention for people with HIV is required. PMID- 30309240 TI - Facilitators and barriers to HIV testing among Asians in the United States: a systematic review. AB - Asians have the highest rate of undiagnosed HIV in the United States. Limited research on factors implicated in HIV testing among this population presents a barrier to monitoring and addressing HIV testing disparities. To examine predictors of HIV testing among Asians in the United States, a systematic search of articles published from January 1997 to December 2017 was conducted using four electronic databases, including Medline, PubMed, PsycINFO, and Web of Science. Twenty-two articles were included according to predefined inclusion criteria: peer-reviewed, published in English, took place in the United States, included participants at least 18 years of age, reported data specifically on Asians or Asian subgroups, and assessed HIV testing. Included studies were assessed by methodological quality scoring. Individual-level factors such as HIV knowledge and HIV risk perceptions were commonly reported facilitators of HIV testing. Studies placed less attention on community, institutional, or structural level factors predicting HIV testing. Sorely warranted are high quality, longitudinal studies that examine HIV testing among Asians in the United States. Multi-level theoretical frameworks that examine HIV testing among Asians with attention to ethnic subgroups are needed to improve understanding of HIV testing and to develop targeted testing interventions. PMID- 30309241 TI - Screening for depression with the Edinburgh Postnatal Depression Scale and finding borderline personality disorder. AB - OBJECTIVE: The aim of the study was to explore the range of psychiatric diagnoses seen in pregnant women who score above the 'cut-off' on the Edinburgh Postnatal Depression Scale when this is used as a routine screening instrument in the antenatal period. METHOD: Subjects were all pregnant women referred to and seen by the Perinatal Consultation-Liaison Psychiatry Team of a tertiary public hospital over a 14-month period. Edinburgh Postnatal Depression Scale score at maternity 'booking-in' visit, demographic and clinical data were recorded and diagnoses were made according to Diagnostic and Statistical Manual of Mental Disorders (5th ed.) criteria following clinical interview(s) and review of documented past history. Data were analysed using descriptive statistics. RESULTS: A total of 200 patients who had completed the Edinburgh Postnatal Depression Scale were seen for assessment; 86 (43%) scored ?13 on Edinburgh Postnatal Depression Scale. Of those scoring 13 or more on Edinburgh Postnatal Depression Scale, 22 (25.6%) had a depressive disorder. In total, 12 patients (14%) had an anxiety disorder, 14 (16.3%) had borderline personality disorder and 13 (15.1%) had a substance use disorder. An additional 23 women (26.7%) had two or more borderline personality traits. CONCLUSION: Psychiatric assessment of women who scored 13 or more on the Edinburgh Postnatal Depression Scale at routine antenatal screening identified a significant number with borderline personality disorder or borderline personality traits rather than depressive or anxiety disorders. Clinical Practice Guidelines note the importance of further assessment for all women who score 13 or more on the Edinburgh Postnatal Depression Scale. The findings here suggest that this assessment should be made by a clinician able to identify personality pathology and organise appropriate and timely interventions. PMID- 30309242 TI - The social inclusion of young people with serious mental illness: A narrative review of the literature and suggested future directions. AB - BACKGROUND: Social inclusion involves objective participatory (e.g. education/employment) and subjective (e.g. sense of belonging/acceptance) elements across multiple domains. It has been associated with enhanced physical and mental wellbeing yet is a novel construct in the empirical literature (i.e. measures have not been sufficiently developed). AIMS: Young people with serious mental illness are reported to be socially excluded. It is unclear whether this is reflected in the social inclusion/exclusion literature. The aim of this narrative review is to determine whether such literature permits a comprehensive (i.e. multi-dimensional, objective and subjective) understanding of social inclusion among young people with serious mental illness. METHODS: Searches to identify studies related to the social inclusion and/or exclusion of young people with serious mental illness were conducted on 16 February 2016, 24 August 2016, 16 February 2017, 24 August 2017 and 16 February 2018 in PsycINFO, MEDLINE, the Cochrane Library, SCOPUS, Open Grey, Web of Science, Google and Google Scholar. RESULTS: There is a paucity of research in the explicit social inclusion literature involving young people either with or without serious mental illness as participants. Literatures exist in related independent areas of research (e.g. employment, social networks), but such studies employ heterogeneous methodologies. CONCLUSION: Multi-dimensional measures of social inclusion incorporating objective and subjective indicators must be developed for young people with and without serious mental illness. This will enable the generation of normative and clinical data. Existing evidence for the social exclusion of young people with serious mental illness comes from objective indicators in isolated domains (e.g. unemployment). Subjective indicators continue to be under researched. The above-described measures must be employed to further understanding of the apparent discrepancies between young people with serious mental illness and those without serious mental illness. This will elucidate the relationships between objective and subjective elements of social inclusion and the relationships between these elements and the psychological distress that young people with serious mental illness often experience. This has implications for intervention. PMID- 30309243 TI - Risks of Benzodiazepines in Chronic Obstructive Pulmonary Disease with Comorbid Posttraumatic Stress Disorder. AB - RATIONALE: Benzodiazepines are associated with mortality and poor outcomes among patients with chronic obstructive pulmonary disease (COPD), but use of benzodiazepines for dyspnea among patients with end-stage disease may confound this relationship. OBJECTIVE: Assess the mortality risks of long-term benzodiazepine exposure among patients with COPD and comorbid posttraumatic stress disorder (PTSD), patients with chronic non-respiratory indications for benzodiazepines. METHODS: We identified all patients with COPD and PTSD within the Veteran's Health Administration between 2010-12. We calculated propensity scores for benzodiazepine use, and compared overall and cause specific mortality of patients with long-term (>=90 days) benzodiazepine use relative to matched patients without use. Secondary analyses assessed propensity-adjusted survival by characteristics of benzodiazepine exposure. RESULTS: Among 44,555 eligible patients with COPD and PTSD, 23.6% received benzodiazepines long-term. In the matched sample of 19,552 patients, we observed no mortality difference (HR for long-term use 1.06, 95%CI 0.95-1.18), but greater risk of death by suicide among those with long-term use (HR 2.33, 95%CI 1.14-4.79). Among matched and unmatched patients, short-term benzodiazepine use, but not long-term use, was associated with increased mortality (short-term: HR 1.16, 95% CI 1.05-1.28; long-term: HR 1.03, 95% CI 0.94-1.13). CONCLUSIONS: Risks for respiratory compromise related to long-term benzodiazepine use in COPD may be less than previously estimated, but short-term use of benzodiazepines could still pose a mortality risk. Suicide associated with benzodiazepine use in this population warrants further investigation. PMID- 30309244 TI - Association of Fatigue With TPH2 Genetic Polymorphisms in Women With Irritable Bowel Syndrome. AB - Fatigue is the most common extraintestinal symptom in women with irritable bowel syndrome (IBS). Genetic polymorphisms of monoamines are associated with fatigue in many chronic diseases. In this pilot exploratory study, the primary aim was to determine whether genetic polymorphisms of tryptophan hydroxylase ( TPH1/TPH2), serotonin reuptake transporter ( SERT), or catechol-O-methyltransferase ( COMT) are associated with fatigue in women with IBS. Additionally, analysis explored whether these genetic associations with fatigue would be present when controlling for abdominal pain, psychological distress, feeling stressed, and sleepiness during the day. Secondary analysis of two randomized controlled trial baseline data sets in Caucasian women with IBS ( N = 185) was conducted. Participants kept a daily diary with one dimension (i.e., severity) for each of the 26 symptoms, including fatigue, for 28 days prior to randomization. DNA samples were tested for single-nucleotide polymorphisms (SNPs) of TPH1 (four SNPs) /TPH2 (one SNP), SERT (one SNP), and COMT (one SNP). Analysis of covariance was used to examine associations of percentage of diary days with moderate to very severe symptoms with genetic polymorphisms. Only one SNP, TPH2 rs4570625, was significantly associated with fatigue ( p = .005). T-allele (low functional) carriers of TPH2 (i.e., G/T or T/T genotypes) reported a greater percentage of days with moderate to very severe fatigue than G/G homozygotes ( p = .001). Reduced synthesis of tryptophan in the central nervous system may contribute to reports of fatigue in women with IBS. Understanding genetic risk factors for fatigue may elucidate preemptive strategies to reduce fatigue in individuals with IBS. PMID- 30309245 TI - Antipsychotic polypharmacy in the treatment of schizophrenia in China and Japan. AB - BACKGROUND: Although antipsychotic monotherapy is recommended as the main treatment for schizophrenia, antipsychotic polypharmacy is not rare in practice. However, longitudinal data on antipsychotic polypharmacy in schizophrenia treatment are limited. METHODS: This longitudinal database study described antipsychotic polypharmacy in the treatment of schizophrenia in real-world settings in China and Japan. We retrieved information about antipsychotic treatment for schizophrenia from January 2010 to December 2014 from two hospital Electronic Medical Records databases in China and one claims database, Japan Medical Data Centre in Japan. Eligible patients had a diagnosis of schizophrenia (International Classification of Diseases, Tenth Revision F20.x) and at least one prescription for first or second generation antipsychotics. Antipsychotic polypharmacy was defined as having more than one antipsychotic medication overlapping for ?60 days. The Japan Medical Data Centre study cohort was further stratified by employees (insurance beneficiaries) and their dependents. RESULTS: The study cohorts comprised 11,961 patients from China and 25,034 (10,661 employee sub-cohort and 14,373 dependent sub-cohort) from 14 days Japan Medical Data Centre in Japan. Most patients were prescribed monotherapy (87.3% in China and 80.1% in Japan), of which oral second-generation antipsychotics were the majority (78.9% in China and 65.8% in Japan). The prevalence rate of antipsychotic polypharmacy was 12.7% in China and 19.9% in Japan (13.7% in employees vs 24.5% in dependents). The most common combinations were two oral antipsychotics. Combinations of more than two drugs were uncommon in China (0.3%) but were prescribed for 5.3% of patients in Japan. Among patients treated with monotherapy, 12.6/100 person-years (11.8%) in China and 9.6/100 person-years (11.0%) in Japan switched to antipsychotic polypharmacy during follow-up. Younger patients were more likely to switch to antipsychotic polypharmacy than older patents in all study cohorts. CONCLUSION: The observed rates of antipsychotic polypharmacy ranged from 12.7% in China to 19.9% in Japan. Switching from monotherapy to antipsychotic polypharmacy was most likely to occur in younger patients with schizophrenia. PMID- 30309247 TI - Hurricanes and Mental Health. PMID- 30309246 TI - The relationship between vaginal ring use and intimate partner violence and social harms: formative research outcomes from the CHARISMA study in Johannesburg, South Africa. AB - Despite being designed for autonomous use, research suggests partner approval is often in women's microbicide use. Microbicide study participants have described many ways product use affects relationships, from improving sexual pleasure to increasing harm, including exacerbating intimate partner violence (IPV). As the dapivirine ring proceeds closer to licensure, supporting women's agency to use microbicides safely is a priority. We conducted 42 in-depth interviews with former participants of the Microbicide Trials Network (MTN)-020 trial of the dapivirine vaginal ring and their male partners in Johannesburg, South Africa, to explore how ring use and partnership dynamics interacted. We sampled women who reported harms or partner non-support and women with supportive partners. Male and female narratives revealed high background levels of IPV. Women described how study participation/ring use exacerbated violence, and for a few couples served as a rationale for additional abuse. In response, women described feeling powerless and fearful of conflict, resulting in product nonuse. For one participant violence was reduced, and for several others, empowerment was sparked. These findings suggest future providers have the opportunity to shift more women from a place of fear/violence to one of safety/empowerment through the integration of IPV screening and relationship counselling. PMID- 30309248 TI - Nanotechnology-Ocular Devices for Glaucoma Treatment: A Literature Review. AB - Nanotechnology enabled the development of materials and devices with great utility in different fields of medicine. By using engineered-based nano-devices and structures, human biological systems may be controlled and repaired at a molecular scale, ultimately leading to a biological benefit. In particular, in the field of glaucoma treatment, nanotechnology may, for example, enhance drug residence time on the ocular surface and ocular bioavailability, as well as improve surgical success by both optimizing postoperative scarring and providing a wider safety window. Further studies are still needed to entirely explain the pharmacodynamics of nanotechnology-based therapeutic approaches and prove their biological consequences in human eyes. This review aims to summarize the literature concerning the advances in nanotechnology, specifically regarding ocular devices applied to the treatment of glaucoma. PMID- 30309249 TI - Effects of gelatin prepared from calf bones rich in phosphorus on broiler performance, bone characteristics and digestive enzymes activity. AB - 1. Gelatin prepared from calf bones (GCB) is a novel source of high-quality protein and phosphorus. Its inclusion in broiler chicken diets may improve bone strength, plasma and digestive alkaline phosphatase activity (ALP), phosphorus digestibility and performance of broilers. Therefore, di-calcium phosphate in a corn-soy control diet was replaced with 12, 24, and 36 g/kg of GCB in a completely randomised design with four treatments of six replicates and 10 chicks in each pen. The trial lasted from 1 to 42 d of age. 2. Body weight and feed intake were measured weekly. Plasma calcium and phosphorus concentration along with plasma and digestive ALP were assayed throughout the trial. Trypsin, alpha amylase, lipase and total protease activity were assayed at 14 and 28 d of age. Tibia ash, calcium and phosphorus content and breaking strength were measured at 14, 28 and 42 d of age. Phosphorus digestibility was measured at 36 d of age. 3. Body weight and feed intake showed no significant differences between controls and diets containing 12 and 36 g/kg GCB. Tibia ash and tibia length were increased by supplementation of GCB (P <= 0.001). Tibia calcium and phosphorus content were increased by GCB inclusion at 14 d of age (P <= 0.001). Digestive alkaline phosphatase activity was increased and trypsin activity was reduced by inclusion of GCB (P <= 0.001; P <= 0.004). alpha-amylase activity decreased by inclusion of 12 and 24 g/kg GCB, whereas an increase in alpha-amylase activity was observed by inclusion of 36 g/kg GCB (P <= 0.001). Supplementation of diets with GCB increased phosphorus digestibility (P <= 0.01) and suppressed ileum growth during the experimental period. 4. Results of the current study showed that phosphorus from gelatin can greatly improve broiler bone characteristics and phosphorus digestibility and complete elimination of inorganic phosphate sources from broiler diets is feasible with inclusion of 36 g/kg high phosphorus gelatin. PMID- 30309250 TI - Associations Between Family Risk Factors and Child Neglect Types in U.S. Army Communities. AB - Recent theory and empirical research suggest that child neglect is a heterogeneous phenomenon characterized by various types. This study examined family risk factors associated with five neglect types including failure to provide physical needs, lack of supervision, emotional neglect, moral-legal neglect, and educational neglect in 390 substantiated cases of neglect in four U.S. Army communities. Family factors associated with elevated risk of each neglect type relative to other types were identified using multivariate regression. Relatively distinct sets of family risk factors were differentially associated with the neglect types. Family mental health problems and larger family size were associated with risk of failure to provide physical needs, childcare problems and larger family size were associated with risk of supervisory neglect, and family disagreements were associated with risk of emotional neglect. None of the family factors were associated with elevated risk of moral-legal or educational neglect. Results can inform the development of indicated and relapse prevention strategies for families affected by different neglect types. PMID- 30309251 TI - Genetic diversity and population structure analysis of eight local chicken breeds of Southern Xinjiang. AB - 1. The genetic diversity and population structure were studied for eight local chicken breeds, including Anjiyan (AN), Hetian Black (HH), Hetian Ma (HM), Aheqi (AH), Baicheng You (BC), Hejing (HJ), Tashkurghan (TS) and Ruoqiang (RQ), in the Southern Xinjiang region of China, using 20 microsatellite markers. 2. Total 336 alleles were obtained from all chicken breeds, with a mean of 16.8 alleles per locus. The polymorphism information content ranged from 0.444 to 0.911, with a mean of 0.729 and almost all of the loci showed significant deviation from Hardy Weinberg standards. The observed and expected heterozygosity of the eight breeds ranged from 0.5 to 0.677 and from 0.656 to 0.774, with the lowest observed in the AN and the highest in BC breed. The average breed genetic diversity was 0.655 for AN and 0.766 for BC chickens. 3. According to the neighbour-joining (NJ) method, three main clusters were identified in the NJ phylogenetic tree with AN and RQ breeds in one clade, HH and HM breeds in the second clade and TS, HJ, AH and BC breeds in the third clade. 4. Based on STRUCTURE analysis, the most likely cluster number of all breeds was K = 4, whereby HH and HM breeds formed one cluster and AH, BC, HJ and TS formed another, and RQ, AN chicken formed their own distinct cluster. These results indicated that HH and HM breeds had similar genetic background, as did the breeds of AH, BC, HJ and TS. RQ, AN breed had unique genetic backgrounds, distinct from the other breeds. Genetic introgression was detected from AN to HH and HM. 5. The results of the current study can be used as baseline genetic information to implement effective conservation programs and to make better use of these local chicken breeds, especially for the AN, RQ and TS breeds. PMID- 30309252 TI - Haven: Sharing receptive music listening to foster connections and wellbeing for people with dementia who are nearing the end of life, and those who care for them. AB - This paper reports on research exploring the effects of music played for 12 dyads: a care home resident ('resident') with dementia and someone closely connected to him/her ('carer'). Six individualised music interventions (3 live and 3 pre-recorded) were played by the first author on solo cello within five Scottish non-NHS care homes. All interventions were video-recorded. Semi structured interviews with carer participants, key staff, and managers explored their responses to interventions. Thick descriptions of video recordings and interview transcripts were thematically coded using Nvivo. A key finding was that structural elements of the interventions combined with characteristics of the music played facilitated an internalised experience of 'haven'; sonically transporting listeners away from their present reality and fulfilling the basic human needs for inclusion, comfort, identity, occupation and attachment. PMID- 30309253 TI - Perceived threat of Alzheimer's disease and related dementias among older Chinese Americans in subsidized housing: Through a cultural lens. AB - Purposes Low socioeconomic status and limited social support may put older residents in subsidized housing at high risk for developing fears of Alzheimer's disease or related dementias. This study examined the perceived threat of Alzheimer's disease or related dementias among older Chinese Americans in subsidized housing facilities in Phoenix, Arizona of the United States, and focused on the effect of cultural beliefs (i.e., beliefs toward Alzheimer's disease or related dementias, and beliefs toward intergenerational support) on the perceived threat of Alzheimer's disease or related dementias. Method Analyses were based upon a survey of 207 Chinese American older adults (Mage = 75.37, SD = 7.47) living in subsidized housing facilities in the Phoenix metropolitan area. Standardized survey questionnaires were delivered through face-to-face interviews. Results Multivariate analyses suggest that fatalism related beliefs about Alzheimer's disease or related dementias, rather than stigmatization, were related to higher levels of concerns for developing Alzheimer's disease or related dementias, while beliefs in intergenerational support were related to lower levels of perceived threat of Alzheimer's disease or related dementias. However, the protective effect of beliefs in intergenerational support tended to diminish in those living with higher levels of depressive symptoms. Discussion Cultural beliefs can entail both risks and strengths when low-income Chinese American elders attempt to comprehend the implications of Alzheimer's disease or related dementias. Health education or intervention programs need to address their fatalism beliefs toward Alzheimer's disease or related dementias, and facilitate the accessibility of intergenerational support for this group. PMID- 30309254 TI - Public knowledge of late-life cognitive decline and dementia in an international sample. AB - : Background and objectives One method of mitigating global increases in dementia prevalence involves assessing public knowledge and then educating laypeople. We measured knowledge of late-life pathological cognitive decline in a diverse, international sample using a standardized, validated instrument. RESEARCH DESIGN AND METHODS: We assessed 3619 international respondents recruited through Amazon's Mechanical Turk with a 44-item dementia knowledge survey and 18 sociodemographic items. Results Results suggested that the following sociodemographic variables are associated with less overall knowledge: young age, male gender, low educational attainment, born in a developing nation, of ethnic minority status, not married, and less prior dementia experience. Specific knowledge gaps emerged in cerebrovascular disease, delirium versus dementia, treatment of behavioral dementia symptoms, Alzheimer's disease genetics, Parkinson's disease symptoms, and characteristics of chronic traumatic encephalopathy and subjective cognitive decline. Discussion and implications: Findings may facilitate effective multinational dementia education initiatives by providing specific recommendations as to which sociodemographic populations and content knowledge domains will benefit the most from limited resources. PMID- 30309255 TI - Platelet Activation and Platelet-Leukocyte Aggregates in Type I Diabetes Mellitus. AB - Hyperglycemia alone may not explain the increased risk of cardiovascular diseases (CVDs) in patients with type 1 diabetes (T1D) compared with type 2. This study emphases on the evaluation of some platelet activity markers in patients with T1D, with relevance to some metabolic disorders as hyperlipidemia and hyperglycemia. This study was performed on 35 patients with T1D and 20 healthy controls. All participants were subjected to full history taking, clinical examination and assay of glycated hemoglobin (HbA1c), and lipid profile. The expression of CD62P and CD36 on platelets and the frequency of platelet-monocyte, and platelet-neutrophil aggregates were assessed by flow cytometry. Patients showed significantly higher expression of CD62P and CD36 than the control group. Platelets aggregates with monocytes were also higher among patients than the control group. Levels of CD36+ platelets, CD62P+ platelets, and platelet-monocyte aggregates revealed significant correlations with the levels of HbA1c, total cholesterol, low-density lipoprotein, and triglycerides. Hyperlipidemia and hyperglycemia accompanying T1D have a stimulatory effect on platelet activation which probably makes those patients vulnerable to CVD than nondiabetics. PMID- 30309256 TI - The Physiological Impact of Window Murals on Pediatric Patients. AB - OBJECTIVES: To examine the magnitude of impact of two nature-themed window murals on physiological processes, as measured by heart rate and blood pressure, of pediatric patients. BACKGROUND: Many children and adolescents find at least one aspect of the hospitalization process frightening or anxiety provoking. One physical feature linked to stress reduction is access to positive distractions. Views of nature are one of the most common forms of positive distractions in healthcare environments. Patient room windows are the most common way patients are exposed to natural elements. Exposure to views of nature is linked to a number of positive impacts on physiological outcomes. Unfortunately, not every patient room will be able to provide a nature-filled window view. In situations where nature scenes do not occur, enhanced nature views may be utilized to replicate many of the same benefits as actual nature views. METHODS: Pediatric patients were randomly assigned to one of the three room conditions: aquatic window mural, tree window mural, or control condition. The medical data of participants ( n = 90) who stayed in the rooms were gathered and evaluated for differences. RESULTS: Data analysis supports the notion that patient stress is heightened at the time of admission. Patients in the rooms with murals were found to have improvements in heart rate and systolic blood pressure in comparison to patients in control rooms, suggesting that the murals had an impact on physiological processes. Data also suggest that subject matter played a role, as patients in tree murals rooms had the most health-related outcomes. PMID- 30309257 TI - Reach and Adoption of a Randomized Weight Loss Maintenance Trial in Rural African Americans of Faith: The WORD (Wholeness, Oneness, Righteousness, Deliverance). AB - PURPOSE: There is minimal information regarding the Reach and Adoption of evidence-based weight loss maintenance interventions for African Americans of faith. DESIGN: The WORD (Wholeness, Oneness, Righteousness, Deliverance) was an 18-month, cluster randomized trial designed to reduce and maintain weight loss in African American adults of faith. Participants received the Diabetes Prevention Program adapted core weight loss program for 6 months, and churches were subsequently randomized to 12-month maintenance treatment or control. All participants underwent body weight and associated behavioral and psychosocial assessments at baseline, 6, 12, and 18 months. The current article focuses on assessing Reach and Adoption at baseline and 6 months using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. SETTING: Lower Mississippi Delta. PARTICIPANTS: Thirty churches, 61 WORD Leaders (WLs), and 426 participants. INTERVENTION: Group delivered by trained community members (WLs). MEASURES: Body mass index and percentage weight lost from baseline to 6 month follow-up were measured. Reach was assessed at participant, WL, and church levels through calculating participation rates and sociodemographics of each level. Adoption was assessed at church and WL levels. ANALYSIS: Descriptive statistics summarized baseline characteristics of each level. Continuous and categorical end point comparisons were made. RESULTS: Participants' participation rate was 0.84 (n = 437 agreed to participate, n = 519 eligible invited to participate); they were predominantly female, employed, and had a mean age of 49.8. Dropouts by 6 months were younger, had differential marital status, and religious attendance compared with retained participants. Church participation rate was 0.63 (n = 30 enrolled, n = 48 eligible approached) and the majority reported <=100 active members. The WL participation rate was 0.61 (n = 61 implemented intervention, n = 100 eligible approached); they were primarily female and aged 53.9 (mean). CONCLUSION: Recruitment, engagement, and delivery strategies employed by the WORD show promise of sustained engagement and adoption in other faith-based behavioral weight management programs for African Americans. PMID- 30309258 TI - Exosome: a novel mediator in drug resistance of cancer cells. AB - Exosomes are small membrane vesicles with a diameter of 40-100 nm, which are released into the intracellular environment. Exosomes could influence the genetic and epigenetic changes of receptor cells by promoting the horizontal transfer of various proteins or RNAs, especially miRNAs. Moreover, exosomes also play an important role in tumor microenvironment. Exosomes could promote the short- and long-distance exchanges of genetic information by acting as mediators of cell-to cell communication. In addition, exosomes participate in drug resistance of tumor cells by genetic exchange between cells. It is reported that exosomes could be absorbed by recipient cells and transmit chemoresistance from drug-resistant tumor cells to sensitive ones. Then understanding the mechanisms of chemotherapy failure and controlling tumor progression effectively will be a major challenge for us. Therefore, in this review, we will briefly reveal the role of exosomes in drug resistance. PMID- 30309260 TI - Cascading strategy in a large health system: Bridging gaps in hospital alignment through implementation. AB - Using any number of open system strategic frameworks, the planning process follows a fairly consistent trajectory: formulation, implementation, and evaluation. Most agree that the formulation and evaluation phases are the most straightforward, yet successful implementation remains elusive. If done thoughtfully, taking advantage of a complementary framework suitable for aligning facility-level initiatives with system priorities presents a feasible opportunity for health systems interested in cascading enterprise-wide strategy successfully. This study provides lessons learned from: (a) consulting literature addressing barriers to implementing strategy effectively, and (b) analyzing insights from a participatory action research study designed to overcome impediments to aligning hospital-level initiatives with enterprise-wide goals and objectives. The analysis provides a baseline examination of hospital alignment efforts that underscores best practices and exposes gaps in both process and evaluation. Results suggest specific tools may function to effectively engage internal stakeholders in a cooperative process capable of yielding preferred strategic outcomes, particularly through the implementation and evaluation phases. PMID- 30309259 TI - Palatal Measurements Pre- and Post-Furlow Cleft Palate Repair: Analysis of Palatal Lengthening and Comparison Within Cleft Types. AB - OBJECTIVE: The purpose of this study was to characterize intraoperative palatal lengthening with the modified Furlow cleft palatal repair and to determine whether lengthening correlated with preoperative cleft width, cleft type, or operating surgeon. DESIGN: Retrospective study. SETTING: Academic tertiary care pediatric hospital. PATIENTS: One hundred eighty pediatric patients undergoing primary or secondary palatoplasty using the Furlow technique. INTERVENTIONS: Cleft and palatal lengths and widths were measured pre- and post-Furlow cleft palatal repair. MAIN OUTCOME MEASURES: Immediate postoperative percentage change in surface palate length, straight palate length, and soft palate length. RESULTS: The average cleft widest width and width at the hard-soft palate junction were 10.2 and 9.5 mm, respectively, and varied with Veau cleft type. Following Furlow palatoplasty, lengths of the curved, straight, and soft palate increased by 7.5%, 15.8%, and 30.6%, respectively. Degree of palatal lengthening varied among surgeons and Veau cleft type but was not related to cleft width. Seven (4.0%) patients developed postoperative oronasal fistulas. Patients with a Veau IV cleft and larger cleft widths were at an increased risk for fistula formation. CONCLUSIONS: This study demonstrates that overall palatal lengthening occurs with the modified Furlow technique. Long-term follow-up studies are needed to determine the clinical relevance of these findings. PMID- 30309261 TI - Revisiting the public awareness of aphasia in Exeter: 16 years on. AB - BACKGROUND: Surveys of awareness of aphasia have been conducted worldwide. There has been no survey of change in awareness in one place over time. A survey in Exeter, UK in 2001 found awareness of aphasia was strikingly low. The aim of this study was to conduct a repeat survey using the same methods in the same city 16 years later to examine changes in awareness and knowledge. METHOD: We surveyed 167 shoppers in Exeter examining awareness and knowledge of aphasia. Awareness of stroke, stuttering, dyslexia and autism were examined for comparison. Demographic information was collected. RESULT: Thirty-four percent had heard of aphasia and 5% had some basic knowledge. Awareness of aphasia had improved significantly from 2001 to 2017, but basic knowledge had not. Awareness was higher in professional groups, such as lawyers and academics, and healthcare workers and in those who knew someone with aphasia. Awareness, but not knowledge, was higher in older respondents. Awareness of aphasia was significantly lower than awareness of all other conditions. CONCLUSION: We found a significant increase in awareness of aphasia in Exeter since 2001, but not knowledge. The implications of ongoing low levels of aphasia awareness, like inadequate funding and difficulty integrating into an ill-informed society, are discussed. PMID- 30309262 TI - Shift models for dose-finding in partially ordered groups. AB - Background Limited options are available for dose-finding clinical trials requiring group-specific dose selection. While conducting parallel trials for groups is an accessible approach to group-specific dose selection, this approach allows for maximum tolerated dose selection that does not align with clinically meaningful group order information. Methods The two-stage continual reassessment method is developed for dose-finding in studies involving three or more groups where group frailty order is known between some but not all groups, creating a partial order. This is an extension of the existing continual reassessment method shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the recommended maximum tolerated dose for this group should not exceed the maximum tolerated dose recommended for any other group. Results With limited alternatives for dose-finding in partially ordered groups, this method is compared to two alternatives: (1) an existing method for dose-finding in partially ordered groups which is less computationally accessible and (2) independent trials for each group using the two-stage continual reassessment method. Simulation studies show that when ignoring information on group frailty, using independent continual reassessment method trials by group, 30% of simulations would result in maximum tolerated dose selection that is out of order between groups. In addition, the two-stage continual reassessment method for partially ordered groups selects the maximum tolerated dose more often and assigns more patients to the maximum tolerated dose compared to using independent continual reassessment method trials within each group. Simulation results for the proposed method and the less computationally accessible approach are similar. Conclusion The proposed continual reassessment method for partially ordered groups ensures appropriate maximum tolerated dose order and improves accuracy of maximum tolerated dose selection, while allowing for trial implementation that is computationally accessible. PMID- 30309263 TI - Managing hepatitis C therapy failures and chronic kidney disease. AB - INTRODUCTION: Hepatitis C virus (HCV) infection leads to important morbidity and mortality through liver disease and extra-hepatic manifestations. Recent evidence suggests the role of HCV in developing chronic kidney disease (CKD); also, HCV adversely affects cardiovascular (CV) disease both in the general population and in patients with CKD. Areas covered: All-oral, interferon-free direct-acting antiviral agents (DAAs) are currently available; anti-HCV regimens based on DAAs are provided with high efficacy and safety and short treatment duration. However, some difficult-to-treat populations still exist including patients with CKD and those who failed previous DAA regimen. Expert commentary: Two DAAs regimens (elbasvir/grazoprevir and glecaprevir/pibrentasvir) are now recommended for the treatment of HCV in patients with advanced CKD, these combinations have shown great efficacy, according to two multicenter phase-3 trials (C-SURFER and EXPEDITION-4). These trials reported a minimal impact of baseline resistance associated substitutions (RASs) on treatment outcomes. The sofosbuvir/velpatasvir/voxaliprevir combination has been recommended as the first line option for DAAs failures, on the basis of the results given by two randomized clinical trials involving patients who had been previously received DAA-containing regimens (POLARIS 1-4 studies). It has been suggested that clinicians should consider RASs upon the introduction of DAA-based antiviral therapy. PMID- 30309264 TI - Copeptin and insulin-like growth factor binding protein-1 during follow-up after an acute myocardial infarction in patients with type 2 diabetes: A report from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 2 cohort. AB - PURPOSE: Copeptin and insulin-like growth factor binding protein-1 analysed at admission for a myocardial infarction in patients with type 2 diabetes mellitus predicts cardiovascular events. The present aim was to study the association between copeptin and insulin-like growth factor binding protein-1, the development of the levels over time, and if the predictive value remained when measured at hospital discharge and 3 months thereafter. METHODS: Copeptin and insulin-like growth factor binding protein-1 were analysed in patients (median age = 70, male = 68%) with type 2 diabetes mellitus + myocardial infarction at admission (n = 393), discharge (n = 309) and 3 months later (n = 288). The primary endpoint was cardiovascular event (cardiovascular death/non-fatal myocardial infarction/stroke) with the three time points as separate baselines. RESULTS: The median copeptin levels were 21.8 pmol/L at admission, 8.5 pmol/L at discharge and 8.4 pmol/L after 3 months, while insulin-like growth factor binding protein-1 levels continued to increase. There were significant correlations between the biomarkers at all occasions. During an average follow-up of 2.5 years, copeptin, but not insulin-like growth factor binding protein-1, predicted cardiovascular event at all occasions in unadjusted analyses. Copeptin remained as a predictor at discharge and after 3 months in the final multiple model (including: heart failure/age/creatinine clearance). CONCLUSION: The relationship between copeptin and insulin-like growth factor binding protein-1 during the initial phase of a myocardial infarction persisted in a less-stressful situation, and copeptin remained as a prognostic indicator at discharge and 3 months later. PMID- 30309265 TI - Laboratory of domesticity: Gender, race, and science at the Bermuda Biological Station for Research, 1903-30. AB - During the early twentieth century, the Bermuda Biological Station for Research (BBSR) functioned as a multipurpose scientific site. Jointly founded by New York University, Harvard University, and the Bermuda Natural History Society, the BBSR created opportunities for a mostly US-based set of practitioners to study animal biology in the field. I argue that mixed gender field stations like the BBSR supported professional advancement in science, while also operating as important places for women and men to experiment with the social and cultural work of identity formation, courtship and marriage, and social critique. Between 1903 and 1930, the BBSR functioned as a laboratory of domesticity, a temporary scientific household in British Bermuda where women and men interacted with established colonial ideologies about science, sex difference, and racial hierarchy in their public and private accounts of doing biology and socializing in the field. Viewing field stations as generative of multiple forms of labor offers a corrective to narratives within the history of biology, in which scientific practices are considered to be the principal forms of output produced by practitioners in the field. Understanding how women and men at the BBSR engaged with (and at times critiqued) the politics of gender and race from the periphery of U.S. networks of biology suggests that we might view field stations as shaping not only academic science but also domestic life and fields as disparate as fiction and the law. PMID- 30309266 TI - Diagnostic Assessment Reviews: is cost-effectiveness analysis helpful or necessary? AB - : Objective Diagnostic Assessment Reviews are part of the work programme of the National Institute of Health and Care Excellence (NICE) in England to evaluate emergent medical technologies and so ensure timely and consistent adoption within the National Health Service (NHS). New diagnostics have the potential to improve health outcomes and impact positively on health service resource use. This study sought to assess the quality of economic evidence informing Diagnostic Assessment Reviews. Methods We reviewed 27 Diagnostic Assessment Reviews that had been published by NICE as of 30 May 2017 by summarizing and interpreting the evidence that was used to carry out cost-effectiveness analyses. Common issues and challenges of the assessment process were illustrated. FINDINGS: DARs differed in the methods and assumptions used to construct economic models, and linkage of economic model and diagnostic findings. Even though some diagnostic technologies were estimated to be cost-effective, they were not always adopted for routine use in the NHS. The majority of Diagnostic Assessment Review economic models relied heavily on assumptions and expert opinion, with considerable uncertainty about the cost-effectiveness of diagnostic testing. Conclusions Diagnostic Assessment Reviews appraisals as commissioned by NICE typically feature varying evidence for diagnostic performance and limited evidence for resource implications and quality of life, often leading to recommendations for further research. Given the process opportunity cost, a two-stage topic selection process, with initial assessment specifying further research and proceeding to full assessment when adequate evidence is available may be more appropriate and help signal to diagnostics companies the type of research evidence required. PMID- 30309267 TI - 'The harmony of social theory in evaluation' - commentary on 'The art and science of non-evaluation evaluation'. PMID- 30309268 TI - Intranasal Leptin Relieves Sleep Disordered Breathing in Mice with Diet Induced Obesity. AB - RATIONALE: Leptin treats upper airway obstruction and alveolar hypoventilation in leptin deficient ob/ob mice. However, obese humans and mice with diet-induced obesity are resistant to leptin due to poor permeability of the blood-brain barrier. We propose that intranasal leptin will bypass leptin resistance and treat sleep disordered breathing in obesity. OBJECTIVES: To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with diet-induced obesity. METHODS: Male C57BL/6J mice were fed with a high fat diet for 16 weeks. A single dose of leptin (0.4 mg/kg) or bovine serum albumin (vehicle) were administered intranasally or intraperitoneally followed by either sleep studies (n=10) or energy expenditure measurements (n=10). A subset of mice was treated with leptin daily for 14 days for metabolic outcomes (n=20). In a separate experiment, retrograde viral tracers were used to examine connections between leptin receptors and respiratory motoneurons. MEASUREMENTS AND MAIN RESULTS: Acute intranasal but not intraperitoneal leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in NREM and REM sleep, independently of metabolic effects. Chronic intranasal leptin decreased food intake and body weight, while intraperitoneal leptin had no effect. Intranasal leptin induced signal transducer and activator of transcription 3 phosphorylation in hypothalamic and medullary centers, whereas intraperitoneal leptin had no effect. Leptin receptor positive cells were synaptically connected to respiratory motoneurons. CONCLUSIONS: In mice with diet induced obesity, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing, independently of body weight. PMID- 30309269 TI - Non-persistence to antiretroviral therapy among adults receiving HIV medical care in the United States. AB - Not taking medicine over a specific period of time-non-persistence to antiretroviral therapy (ART)-may be associated with higher HIV-viral load. However, national estimates of non-persistence among U.S. HIV patients are lacking. We examined the association between non-persistence and various factors, including sustained HIV-viral suppression (VS) stratified by adherence, and assessed reasons for non-persistence using Medical Monitoring Project (MMP) data. MMP conducts clinical and behavioral surveillance among cross-sectional representative samples of adults receiving HIV care in the U.S. We analyzed weighted MMP interview and medical record abstraction data collected between 6/2011-5/2015 from 18,423 patients self-reporting ART use. We defined non persistence as a self-initiated decision to not take ART for >=2 consecutive days in the past 12-months, non-adherence as missing >=1 ART dose during the past 3 days and sustained VS as all HIV-viral loads documented in medical record during the past 12-months as undetectable or <200 copies/mL. We used Rao-Scott chi square tests to examine the association between non-persistence and sociodemographic, behavioral, clinical, and medication-related factors. We examined the association between non-persistence and sustained VS, stratified by adherence, and present prevalence ratios (PRs) with 95% confidence intervals (CIs). Reasons for non-persistence were assessed. Overall, 7% of patients reported non-persistence. Drug use, depression and medication side effects were associated with non-persistence (P < 0.01). Non-persistence was associated with the lack of sustained VS (PR: .66, CI:63-.70); this association did not differ by adherence level. However, VS was lower among the non-persistent/adherent compared with the persistent/non-adherent [51% (CI:47-54) versus 61% (CI:36-46), P < 0.01]. The most prevalent reason for non-persistence was treatment fatigue (38%). Though few persons in HIV care reported non-persistence, our findings suggest that non-persistence is associated with lack of sustained VS, regardless of adherence. Routine screening for non-persistence during clinical appointments and counseling for those at risk for non-persistence may help improve clinical outcomes. PMID- 30309270 TI - Sample management for clinical biochemistry assays: Are serum and plasma interchangeable specimens? AB - The constrained economic context leads laboratories to centralize their routine analyses on high-throughput platforms, to which blood collection tubes are sent from peripheral sampling sites that are sometimes distantly located. Providing biochemistry results as quickly as possible implies to consolidate the maximum number of tests on a minimum number of blood collection tubes, mainly serum tubes and/or tubes with anticoagulants. However, depending on the parameters and their pre-analytical conditions, the type of matrix - serum or plasma - may have a significant impact on results, which is often unknown or underestimated in clinical practice. Importantly, the matrix-related effects may be a limit to the consolidation of analyses on a single tube, and thus must be known by laboratory professionals. The purpose of the present critical review is to put forward the main differences between using serum and plasma samples on clinical biochemistry analyses, in order to sensitize laboratory managers to the need for standardization. To enrich the debate, we also provide an additional comparison of serum and plasma concentrations for approximately 30 biochemistry parameters. Properties, advantages, and disadvantages of serum and plasma are discussed from a pre-analytical standpoint - before, during, and after centrifugation - with an emphasis on the importance of temperature, delay, and transport conditions. Then, differences in results between these matrices are addressed for many classes of biochemistry markers, particularly proteins, enzymes, electrolytes, lipids, circulating nucleic acids, metabolomics markers, and therapeutic drugs. Finally, important key-points are proposed to help others choose the best sample matrix and guarantee quality of clinical biochemistry assays. Moreover, awareness of the implications of using serum and plasma samples on various parameters assayed in the laboratory is an important requirement to ensure reliable results and improve patient care. PMID- 30309271 TI - Portrait of glial scar in neurological diseases. AB - Fibrosis is formed after injury in most of the organs as a common and complex response that profoundly affects regeneration of damaged tissue. In central nervous system (CNS), glial scar grows as a major physical and chemical barrier against regeneration of neurons as it forms dense isolation and creates an inhibitory environment, resulting in limitation of optimal neural function and permanent deficits of human body. In neurological damages, glial scar is mainly attributed to the activation of resident astrocytes which surrounds the lesion core and walls off intact neurons. Glial cells induce the infiltration of immune cells, resulting in transient increase in extracellular matrix deposition and inflammatory factors which inhibit axonal regeneration, impede functional recovery, and may contribute to the occurrence of neurological complications. However, recent studies have underscored the importance of glial scar in neural protection and functional improvement depending on the specific insults which involves various pivotal molecules and signaling. Thus, to uncover the veil of scar formation in CNS may provide rewarding therapeutic targets to CNS diseases such as chronic neuroinflammation, brain stroke, spinal cord injury (SCI), traumatic brain injury (TBI), brain tumor, and epileptogenesis. In this article, we try to describe the new portrait of glial scar and trending of research in neurological diseases to readers. PMID- 30309272 TI - Comment on: Inducing system-1-type diagnostic reasoning in second-year medical students within 15 minutes. PMID- 30309273 TI - In vitro fertilization outcomes in women with antiphospholipid antibodies circulation. AB - BACKGROUND: Antiphospholipid antibodies (aPL) have a multifaceted effect on the hemostatic system, damaging all its protective links. AIM: To study the effect of APA on outcomes of assisted reproductive technologies (ART). STUDY DESIGN: We examined 267 women with infertility, who planned pregnancy using ART. They included 178 women with IVF failure (I group) and 89 women with pregnancy after the IVF program (II group). The comparison group consisted of 80 pregnant women after IVF (male factor); a control group included 80 pregnant women with physiological pregnancy. Results of study demonstrated a high frequency of aPL circulation in a group of women with IVF failures. Overall, the proportion of aPL among all 267 women who planned pregnancy with ART was 32.6%. Elevated levels of aPL in the structure of causes of IVF failures (group I) were observed in 42.1% of them. Among women whose pregnancy occurred with ART (II group) the rate of APA was 19.1%. In the comparison group, in 6.3% of cases aPL circulation was observed. In the control group, the rate was 3.4%. CONCLUSION: Considering the high percentage of aPL circulation in the case of IVF failures, authors think that high titers of aPL are a temporary contraindication for IVF. Patients with a history of aPL circulation are required to receive anticoagulant therapy from the first days of the hormonal protocol. The drug of choice is a group of low molecular weight heparins (LMWH). An individual approach is extremely important with the possible identification of causes of IVF failures and selective therapy, which leads to a significant improvement in the outcomes of the IVF program. PMID- 30309274 TI - Assessment of fetal left ventricular modified myocardial performance index and its prognostic significance for adverse perinatal outcome in intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: To investigate the association between fetal left ventricular modified myocardial performance index (LMPI) and intrahepatic cholestasis of pregnancy (ICP). And to evaluate the value of LMPI in predicting adverse perinatal outcomes in ICP. STUDY DESIGN: In a cross-sectional case-control study, 40 women with ICP were compared with 40 gestational age-matched healthy controls. The isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET) were measured using the Doppler signals of the opening and closing of the mitral and aortic valves. LMPI was calculated as (ICT + IRT)/ET. An adverse perinatal outcome was defined with at least one of the following; nonreassuring fetal heart rate tracing, umbilical cord pH < 7.20, presence of meconium in amnion and neonatal intensive care unit (NICU) admission. RESULTS: Mean gestational age at delivery and mean birth weight were significantly lower and the incidences of cesarean section rate, nonreassuring fetal heart rate tracing, presence of meconium in amnion and NICU admission were significantly higher in the ICP group (p < 0.01). Mean LMPI, ICT and IRT values were significantly higher in the ICP group (p < 0.01). The area under the receiver operating characteristic (ROC) curve for LMPI in prediction of adverse perinatal outcome was 0.740 (95% CI: 0.607-0.873, p = 0.001) and a cut-off LMPI of 0.41 conferred a sensitivity of 85% and specificity of 61%. CONCLUSIONS: There is an impaired global ventricular function in ICP fetuses demonstrated by increased LMPI. High LMPI is associated with adverse perinatal outcome in ICP. PMID- 30309275 TI - Morphological characteristics of the sigmoid notch of the distal radius affect the stress distribution patterns in the distal radioulnar joint. AB - The aim of this study was to clarify the effects of morphological patterns of the sigmoid notch on the stress distribution across the articular surface of the distal radioulnar joint using a computed tomography osteoabsorptiometry method. Fourteen wrists from 13 patients were classified into two groups according to the type of sigmoid notch, namely the 'C' type and ski-slope sigmoids, and the percentages of high-density areas on the articular surface were quantitatively analysed. The percentage of the high-density area of the dorsal region in the ski slope sigmoid group was significantly greater than that of the 'C' type sigmoid group (16% vs 4.1%) and of the volar region of the ski-slope sigmoid group (16% vs 2.4%). The results indicate that bony morphological differences in the radial sigmoid notch affect the stress distribution pattern through the distal radioulnar joint. PMID- 30309276 TI - It Takes a Village Coach: Cost-Effectiveness of an Intervention to Improve Diet and Physical Activity Among Minority Women. AB - BACKGROUND: This study gauged the cost-effectiveness of a community-based health coaching intervention aimed at improving diet and physical activity among women in culturally diverse communities. METHODS: The Coalition for a Healthier Community for Utah Women and Girls recruited women from 5 cultural and ethnic groups and randomized them to receive quarterly versus monthly health coaching. Coaching was performed by trained community health workers from the targeted communities. Cost-effectiveness ratios were estimated to gauge the cost effectiveness of the intervention. RESULTS: Estimated quality-adjusted life years gained from both increased physical activity and improved diet were positive. Cost-effectiveness ratios varied by intervention arm, but all ratios fell within the favorable range described in the literature. CONCLUSIONS: This culturally adapted health coaching intervention was deemed to be cost-effective. Our findings suggest that to achieve the highest level of cost-effectiveness, programs should focus on enrolling at-risk women who do not meet recommended physical activity standards and/or dietary guidelines. PMID- 30309277 TI - The New Harvard Doctor of Public Health: Lessons From the Design and Implementation of an Innovative Program in Advanced Professional Leadership. AB - We documented lessons learned in the initial design and development of the new Harvard doctor of public health (DrPH) degree, an innovative professional public health doctorate designed to provide advanced education in the field of public health. Using data from program documents, personal participation in the development and administration of the degree, and initial students' results, we present key learnings from this experience and describe the program's goals and processes. Now entering its fifth year, the new Harvard DrPH program has enrolled about 70 students and graduated its first 2 classes in a program that combines advanced public health study with leadership development and field engagement. Development of this transformational innovation in advanced public health education required creative approaches to competency development and curriculum design, engagement of faculty to become supportive stakeholders, and substantial support for educational administration. Demand for a program of this type is strong. Continuous improvement is ongoing. PMID- 30309278 TI - Interprofessional conflict and conflict management in an educational setting. AB - BACKGROUND: Whenever health professionals work together as a team, conflict is inevitable - some would argue even necessary. However, conflict can have negative effects on patient care, job satisfaction, personal wellness, and professional productivity. PURPOSE: This study aims to describe interprofessional conflicts in a hospital setting from the perspective of three groups of health science students. METHODS: An online questionnaire survey collected data from 225 health science students (medicine, nursing, and social work) in Northern California (USA). Quantitative and qualitative analyses were conducted resulting in seven central themes of conflict. RESULTS: There are differences among health professional students in terms of how conflict is experienced and managed. Nursing students and medical students were more likely to take on the "victim" role when explaining their conflict, and their conflicts were more likely to be intra-professional. The most common cause of conflicts was related to hierarchy and power issues. The majority were dissatisfied with the way the conflict was resolved. CONCLUSIONS: Findings from this study can be used to design interprofessional curriculum to improve outcomes from conflicts and improve wellbeing, job satisfaction, and reduce patient turnover. PMID- 30309279 TI - Dynamic Assessment of Fluid Responsiveness in Surgical ICU Patients Through Stroke Volume Variation is Associated With Decreased Length of Stay and Costs: A Systematic Review and Meta-Analysis. AB - Static indices, such as the central venous pressure, have proven to be inaccurate predictors of fluid responsiveness. An emerging approach uses dynamic assessment of fluid responsiveness (FT-DYN), such as stroke volume variation (SVV) or surrogate dynamic variables, as more accurate measures of volume status. Recent work has demonstrated that goal-directed therapy guided by FT-DYN was associated with reduced intensive care unit (ICU) mortality; however, no study has specifically assessed this in surgical ICU patients. This study aimed to conduct a systematic review and meta-analysis on the impact of employing FT-DYN in the perioperative care of surgical ICU patients on length of stay in the ICU. As secondary objectives, we performed a cost analysis of FT-DYN and assessed the impact of FT-DYN versus standard care on hospital length of stay and mortality. We identified all randomized controlled trials (RCTs) through MEDLINE, EMBASE, and CENTRAL that examined adult patients in the ICU who were randomized to standard care or to FT-DYN from inception to September 2017. Two investigators independently reviewed search results, identified appropriate studies, and extracted data using standardized spreadsheets. A random effect meta-analysis was carried out. Eleven RCTs were included with a total of 1015 patients. The incorporation of FT-DYN through SVV in surgical patients led to shorter ICU length of stay (weighted mean difference [WMD], -1.43d; 95% confidence interval [CI], -2.09 to -0.78), shorter hospital length of stay (WMD, -1.96d; 95% CI, 2.34 to -1.59), and trended toward improved mortality (odds ratio, 0.55; 95% CI, 0.30-1.03). There was a decrease in daily ICU-related costs per patient for those who received FT-DYN in the perioperative period (WMD, US$ -1619; 95% CI, -2173.68 to -1063.26). Incorporation of FT-DYN through SVV in the perioperative care of surgical ICU patients is associated with decreased ICU length of stay, hospital length of stay, and ICU costs. PMID- 30309280 TI - Pharmacologic Management of Delirium in the ICU: A Review of the Literature. AB - PURPOSE: Conflicting data exists on the pharmacologic management of intensive care unit (ICU) delirium. This review appraises the current evidence of pharmacologic management of ICU delirium. MATERIALS AND METHODS: A systematic literature search of MEDLINE and Embase was conducted to answer the population, intervention, comparison, and outcome (PICO) question of: "Does the use of a pharmacologic agent compared to standard of care or placebo improve ICU delirium in a critically ill patient population?" RESULTS: After application of the PICO question and the inclusion and exclusion criteria, 13 articles were included. Of these articles, 7 were prospective randomized controlled trials, 1 was a prospective nonrandomized controlled trial, and 5 were retrospective investigations. The included articles differed in the agents evaluated, primary outcome, and method of identifying delirium. CONCLUSION: The variability of outcomes illustrates the need for a large-scale investigation to further evaluate the role of pharmacologic management of ICU delirium. PMID- 30309281 TI - Gestational vitamin D concentration and other risk factors versus fetal femur length. AB - INTRODUCTION: Vitamin D plays a crucial role in the development of healthy fetal bone tissue. Analysis of fetal bone parameters versus maternal vitamin D status is necessary to shed some light on the matter. The aim of the study was to investigate the relationship between maternal and cord vitamin D concentrations and other factors which might affect fetal bone development and femur length. MATERIAL AND METHODS: The study included 94 term pregnancies, delivered at the Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw. Fetal femur length was measured during an ultrasound examination on admission to the delivery unit. Total 25(OH)D concentrations were measured in maternal and cord blood. Direct interview with a dietician was used to collect lifestyle and nutrition data. Multiple regression analysis was used for statistical analysis. RESULTS: No statistically significant relationship was found between vitamin D concentrations and fetal femur length, either in maternal (p = 0.7709) or cord (p = 0.7751) blood samples, despite the fact that low vitamin D concentrations, which might indicate aberrations in fetal bone development, were detected in 50.0% of the mothers and 28.7% of the newborns. Also, no relationship was confirmed for the remaining parameters, including nutritional factors (calcium or caffeine intake, vitamin/mineral supplements). CONCLUSION: Low vitamin D concentrations during pregnancy and lifestyle factors had no negative associations with fetal femur length. PMID- 30309282 TI - Specific conditions for a selective deficit in memory for order in children with dyslexia. AB - Short-term memory (STM) models distinguish between item and order memorization. The present study aims to explore how item and order STM are affected by the nature of the stimuli, the sequential versus simultaneous mode of presentation, the visual versus auditory presentation modality, the possibility of verbal recoding. A total of 20 children with dyslexia were matched one-by-one with 20 typically reading children on sex, age (8-14 years), and grade. Computerized STM tasks were administered while manipulating type (item vs. order), stimuli (letters vs. colors), sequentiality, input and output modality, as well as the presence/absence of articulatory suppression and distractors. General Linear Model analyses were conducted on accuracy scores for item and order STM. Both item and order recall scores were lower for children with dyslexia. Although order STM in the visual input condition turned out to be more impaired than item STM in the dyslexic group, both item and order memory impairments become evident when verbal recoding is prevented through articulatory suppression. Moreover, dyslexic children, unlike typical readers, were not facilitated by the linguistic nature of the stimuli to be remembered. The present findings suggest that the often-reported selective impairment of serial memory in dyslexia is restricted to stimuli that are verbal in nature or can be verbally recoded, whereas both item and order memory impairments become evident when verbal recoding is prevented through articulatory suppression. The presence of distractors is particularly detrimental to STM in the dyslexic group. The sensitivity to distractors, suppression, and stimuli in STM is predictive of reading performance. PMID- 30309283 TI - Density estimation based on the Hounsfield unit value of cone beam computed tomography imaging of the jawbone system. AB - The aim of this study is to investigate the estimation of density from the Hounsfield unit of cone beam computed tomography data in dental imaging, especially for dental implant application. A jaw phantom with various known densities of anatomical parts (e.g. soft tissue, cortical bone, trabecular bone, tooth enamel, tooth dentin, sinus cavity, spinal cord and spinal disc) has been used to test the accuracy of the Hounsfield unit of cone beam computed tomography in estimating the mechanical density (true density). The Hounsfield unit of cone beam computed tomography data was evaluated via the MIMICS software using both two-dimensional and three-dimensional methods, and the results showed correlation with the true density of the object. In addition, the results revealed that the Hounsfield unit of cone beam computed tomography and bone density had a logarithmic relation, rather than a linear one. To this end, the correlation coefficient of logarithmic correlation (R2 = 0.95) is higher than the linear one (R2 = 0.77). PMID- 30309284 TI - Vaccine confidence plummets in the Philippines following dengue vaccine scare: why it matters to pandemic preparedness. AB - In November 2017, it was announced that the new dengue vaccine ("Dengvaxia") had risks for those not previously exposed to dengue. While some countries proceeded with adjusting guidance accordingly, the Philippines reacted with outrage and political turmoil with naming and shaming of government officials involved in purchasing the vaccine, as well as scientists involved in the vaccine trials and assessment. The result was broken public trust around the dengue vaccine as well heightened anxiety around vaccines in general. The Vaccine Confidence ProjectTM measured the impact of this crisis, comparing confidence levels in 2015, before the incident, with levels in 2018. The findings reflect a dramatic drop in vaccine confidence from 93% "strongly agreeing" that vaccines are important in 2015 to 32% in 2018. There was a drop in confidence in those strongly agreeing that vaccines are safe from 82% in 2015 to only 21% in 2018; similarly confidence in the effectiveness of vaccines dropped from 82% in 2015 to only 22%. This article highlights the importance of routinely identifying gaps or breakdowns in public confidence in order to rebuild trust, before a pandemic threat, when societal and political cooperation with be key to an effective response. PMID- 30309285 TI - Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice. AB - Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ~50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies. PMID- 30309286 TI - Progressive reduction of serum complement levels: a risk factor for relapse in patients with hypocomplementemia in systemic lupus erythematosus. AB - OBJECTIVE: Serologically active clinically quiescent (SACQ)-SLE is a subtype of systemic lupus erythematosus (SLE); most SACQ-SLE patients relapse. Although complement and/or anti-dsDNA level fluctuations during SACQ status are reportedly not useful for predicting relapse, they might be useful in specific clinical settings. We aimed to assess the correlation between future relapse and progressive reductions in serum complement levels following remission in patients with hypocomplementemia . METHODS: We retrospectively reviewed patients aged >=15 years who were treated with >=20 mg/day of prednisolone for remission induction. After achieving remission, the patients treated with prednisolone tapered to <=15 mg/day without relapse and followed by hypocomplementemia (first hypocomplementemia point) were analyzed. The primary outcome was the relapse during the first 24 months. RESULTS: Seventy-six patients were enrolled; 31 (40.8%) relapsed. A >=10% reduction after the first hypocomplementemia point in serum C3, C4, and CH50 levels was found in 10, 21, and 16 patients, respectively. Hazard ratios (95% confidence intervals) for relapse were 2.32 (0.92-5.12) for serum C3 levels and 2.46 (1.18-5.01) for serum C4 levels. Progressive reductions in serum C3 and C4 levels had relatively high specificity (93.3% and 82.2%) but limited sensitivity (22.6% and 41.9%) for predicting relapse. However, simultaneous progressive reduction in C3 levels and increase in anti-dsDNA antibody levels had the highest specificity (97.8%), and simultaneous progressive reduction in C4 levels or increase in anti-dsDNA antibody levels had the highest sensitivity (71.0%). CONCLUSION: Simultaneous progressive reductions in complement levels and increases in anti-dsDNA antibody levels may indicate future relapse SACQ-SLE patients. PMID- 30309287 TI - Pesticide exposure and risk of systemic lupus erythematosus in an urban population of predominantly African-American women. AB - OBJECTIVE: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. METHODS: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. RESULTS: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28-3.93). CONCLUSION: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings. PMID- 30309288 TI - Assessment of material loss of retrieved magnetically controlled implants for limb lengthening. AB - PURPOSE: We aimed to understand wear from the telescopic component of PRECICE nails, which are used for distraction osteogenesis of the femur or tibia. We also aimed to identify any correlation between implant performance and patient factors. METHODS: This retrieval study involved 11 magnetically controlled intramedullary nails from nine patients who had achieved the targeted leg length. All the nails were assessed macroscopically and microscopically for wear. All implants were radiographed to assess the internal mechanism. A Talyrond 365 (Taylor Hobson, Leicester, UK) roundness measuring machine was used to generate three-dimensional surface maps of the telescopic components to allow for measurement of wear. RESULTS: Visual assessment of all the nails showed evidence of wear from the telescopic component. The radiographs revealed that all the nails had intact internal mechanism and no evidence of fractured pins. The roundness measuring machine showed that the quantity of wear was lowest in the latest design of the PRECICE nail. There was no significant correlation between wear and the two patient factors (duration of the lengthening phase, the time of implantation) included in this study. CONCLUSION: This study is the first to investigate the performance of the three different designs of the PRECICE system with a focus on wear. We found that the latest design had the best implant performance. We are confident of the continued success of the PRECICE system and reassure surgeons and patients that they are unlikely to encounter problems with the implant related to wear. PMID- 30309289 TI - How Much Time Before Attempting Compulsory Licensing of Pharmaceuticals? A Non parametric Event History Model With P-splines. AB - Compulsory licensing (CL), provided by the Agreement on Trade-Related Aspects of Intellectual Property Rights, enables countries, including high-income countries, to ensure the protection of public health in the context of stringent intellectual property regimes. This study investigated associations between the time to attempted CL and a series of factors at the drug and country level. We used a dataset of all attempted CL that occurred from 1995 to 2014, calculated the duration as the difference in years between the year of global marketing of a certain drug and the year of attempted CL in a certain country, and applied a nonparametric event history model. We found that the Doha Declaration was quite effective in shortening the time to attempted CL. Additionally, even though global justice movements have encouraged some countries to attempt CL for various medicines since 2012, the time to CL attempts in this period became significantly longer compared to those that occurred immediately after the Doha Declaration. Our findings show that the subject of CL has not successfully expanded to oncology medicines from HIV/AIDS medicines and that recently approved medicines are not yet subjects of CL. Furthermore, our duration model suggests a learning by-doing effect in attempting CL: previous experience of CL not only triggers CL for the same drugs in other countries but also accelerates CL for other drugs within the country. PMID- 30309290 TI - Hard Currency, Solidarity, and Soft Power: The Motives, Implications, and Lessons of Cuban Health Internationalism. AB - This article explores Cuba's health assistance and support for other countries. It explores the rationale and motivations for Cuba's internationalism in health. It then details the various aspects of its health interventions, including emergency relief, strengthening of health systems, treatment programs, training of health professionals, engagement in multilateral cooperation, and biotechnology. The article analyzes the benefits of Cuba's health internationalism for Cuba and for others. It also explores potential adverse consequences and criticisms of Cuba's approach. The article concludes by noting that Cuba has been ahead of the game in integrating foreign policy and health policy and that its experience may hold lessons for other countries seeking to develop global health strategies. PMID- 30309291 TI - Don't Sugar Coat It: Glycemic Control in the Intensive Care Unit. AB - Stress hyperglycemia is the transient increase in blood glucose as a result of complex hormonal changes that occur during critical illness. It has been described in the critically ill for nearly 200 years; patient harm, including increases in morbidity, mortality, and lengths of stay, has been associated with hyperglycemia, hypoglycemia, and glucose variability. However, there remains a contentious debate regarding the optimal glucose ranges for this population, most notably within the past 15 years. Recent landmark clinical trials have dramatically changed the treatment of stress hyperglycemia in the intensive care unit (ICU). Earlier studies suggested that tight glucose control improved both morbidity and mortality for ICU patients, but later studies have suggested potential harm related to the development of hypoglycemia. Multiple trials have tried to elucidate potential glucose target ranges for special patient populations, including those with diabetes, trauma, sepsis, cardiac surgery, and brain injuries, but there remains conflicting evidence for most of these subpopulations. Currently, most international organizations recommend targeting moderate blood glucose concentration to levels <180 mg/dL for all patients in the intensive care unit. In this review, the history of stress hyperglycemia and its treatment will be discussed including optimal glucose target ranges, devices for monitoring blood glucose, and current professional organizations' recommendations regarding glucose control in the ICU. PMID- 30309292 TI - The ART of Antiretroviral Therapy in Critically Ill Patients With HIV. AB - The management of patients with human immunodeficiency virus (HIV) can be a complicated specialty within itself, made even more complex when there are so many unanswered questions regarding the care of critically ill patients with HIV. The lack of consensus on the use of antiretroviral medications in the critically ill patient population has contributed to an ongoing clinical debate among intensivists. This review focuses on the pharmacological complications of antiretroviral therapy (ART) in the intensive care setting, specifically the initiation of ART in patients newly diagnosed with HIV, immune reconstitution inflammatory syndrome (IRIS), continuation of ART in those who were on a complete regimen prior to intensive care unit admission, barriers of drug delivery alternatives, and drug-drug interactions. PMID- 30309293 TI - Do interpersonal fears mediate the association between childhood maltreatment and interpersonal skills deficits? A matched cross-sectional analysis. AB - OBJECTIVE: Childhood maltreatment, interpersonal fear and a specific kind of interpersonal skills deficit (preoperational thinking) have all been associated with persistent depressive disorder (PDD). We hypothesize that interpersonal fears mediate the association between childhood maltreatment and preoperational thinking. METHOD: A total of 108 matched participants have been examined cross sectionally (31 healthy controls, 30 patients with episodic depression and 47 patients with PDD) with the following instruments: the Childhood Trauma Questionnaire (CTQ-SF), a measure of interpersonal fear (CBASP Interpersonal Questionnaire) and the Lubeck Questionnaire of Preoperational Thinking. RESULTS: Patients with PDD reported significantly more childhood maltreatment than patients with episodic depression (d = 0.65) and healthy controls (d = 1.29). They also had more interpersonal fears (d = 0.71 and d = 2.11 respectively) and higher levels of preoperational thinking (d = 0.90 and d = 2.78 respectively). The association between childhood maltreatment and preoperational thinking was mediated through interpersonal fears. CONCLUSIONS: Our findings might have important implications for psychotherapy of PDD because they demonstrate how specific problems in social interactions can be associated with interpersonal fears that arise secondary to childhood maltreatment. PMID- 30309294 TI - Bayesian multivariate skew meta-regression models for individual patient data. AB - We examine a class of multivariate meta-regression models in the presence of individual patient data. The methodology is well motivated from several studies of cholesterol-lowering drugs where the goal is to jointly analyze the multivariate outcomes, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides. These three continuous outcome measures are correlated and shed much light on a subject's lipid status. One of the main goals in lipid research is the joint analysis of these three outcome measures in a meta-regression setting. Since these outcome measures are not typically multivariate normal, one must consider classes of distributions that allow for skewness in one or more of the outcomes. In this paper, we consider a new general class of multivariate skew distributions for multivariate meta regression and examine their theoretical properties. Using these distributions, we construct a Bayesian model for the meta-data and develop an efficient Markov chain Monte Carlo computational scheme for carrying out the computations. In addition, we develop a multivariate L measure for model comparison, Bayesian residuals for model assessment, and a Bayesian procedure for detecting outlying trials. The proposed multivariate L measure, Bayesian residuals, and Bayesian outlying trial detection procedure are particularly suitable and computationally attractive in the multivariate meta-regression setting. A detailed case study demonstrating the usefulness of the proposed methodology is carried out in an individual patient data multivariate meta-regression setting using 26 pivotal Merck clinical trials that compare statins (cholesterol-lowering drugs) in combination with ezetimibe and statins alone on treatment-naive patients and those continuing on statins at baseline. PMID- 30309295 TI - Tris-chelated complexes of nickel(II) with bipyridine derivatives: DNA binding and cleavage, BSA binding, molecular docking, and cytotoxicity. AB - Two nickel(II) complexes with substituted bipyridine ligand of the type [Ni(NN)3](ClO4)2, where NN is 4,4'-dimethyl-2,2'-bipyridine (dimethylbpy) (1) and 4,4'-dimethoxy-2,2'-bipyridine (dimethoxybpy) (2) have been synthesized, characterized, and their interaction with DNA and BSA studied by different physical methods. X-ray crystal structure of 1 shows a six-coordinate complex in a distorted octahedral geometry. DNA binding studies of 1 and 2 reveal that both complexes sit in DNA groove and then interact with neighboring nucleotides differently; 2 undergoes a partial intercalation. This is supprted by molecular docking studies, where hydrophobic interactions are aparent between 1 and DNA as compared to, hydrogen bonding, hydrophobic, and pi-pi interactions between 2 and DNA minor groove. Moreover, the two complexes exhibit oxidative cleavage of supercoiled plasmid DNA in the presence of hydrogen peroxide as an activator in the order of 1 > 2. In terms of interaction with BSA, the results of spectroscopic methods and molecular docking show that 1 binds with BSA only via hydrophobic contacts while 2 interacts through hydrophobic and hydrogen bonding. It has been extensively demonstrated that the nature of the methyl- and methoxy groups in ligands is a strong determinant of the bioactivity of nickel(II) complexes. This may justify the above differences in biomolecular interactions. In addition, the in vitro cytotoxicity of the complexes on human carcinoma cells lines (MCF-7, HT-29, and U-87) has been examined by MTT assay. According to our observations, 1 and 2 display cytotoxicity activity against selected cell lines. PMID- 30309296 TI - MicroRNA-181 Functions as an Antioncogene and Mediates NF-kappaB Pathway by Targeting RTKN2 in Ovarian Cancers. AB - MicroRNA (miR)-181 has been reported to participate in carcinogenesis and tumor progression in several malignant cancers, but its expression and biological functions in ovarian cancer have remained largely unclarified. Here, we first measured miR-181 expression in clinical ovarian cancers and found the expression levels of miR-181 were significantly lower in ovarian cancer tissues than that in adjacent tissues. Next, we screened and identified a direct miR-181 target, Rhotekin2 (RTKN2). A correlation between miR-181 and RTKN2 expression was also confirmed in clinical samples of ovarian cancers. Upregulation of miR-181 would specifically and markedly suppress RTKN2 expression. The miR-181-overexpressing subclones showed significant cell growth inhibition by cell apoptosis induction and significant impairment of cell invasiveness in SKOV3 and HO8910 ovarian cancer cells. To identify the mechanisms, we investigated the NF-kappaB pathway and found that nuclear factor-kappa B (NF-kappaB), B-cell lymphoma-2 (Bcl-2), and vascular endothelial growth factor (VEGF) were suppressed, whereas IkappaBalpha was promoted in miR-181-overexpressing cells. These findings indicate that miR 181 functions as a tumor suppressor and plays a substantial role in inhibiting the tumorigenesis and reversing the metastasis of ovarian cancer through RTKN2-NF kappaB signaling pathway in vitro. Taken together, we believe that miR-181 may be a promising therapeutic target for treating malignant ovarian cancers. PMID- 30309297 TI - Antenatal Microbial Colonization of Mammalian Gut. AB - The widely accepted dogma of intrauterine sterility and initial colonization of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta, and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations and to assess fetal colonization before parturition. To this end, we analyzed sterilely collected intestinal tissues, placenta, and amniotic fluid from rodent fetuses and tissues from autoptic human fetuses. Total bacterial DNA was extracted from collected samples and analyzed by Next Generation Sequencing (NGS) techniques using hypervariable 16S ribosomal RNA (rRNA) regions (V3-V4). Colonizing microbes were visualized in situ, using labeled probes targeting 16S ribosomal DNA by fluorescent in situ hybridization. The NGS analysis showed the presence of pioneer microbes in both rat and human intestines as well as in rodent placentas and amniotic fluids. Microbial communities showed fetus- and dam-dependent clustering, confirming the high interindividual variability of commensal microbiota even in the antenatal period. Fluorescent in situ hybridization analysis confirmed the microbes' presence in the lumen of the developing gut. These findings suggest a possible antenatal colonization of the developing mammalian gut. PMID- 30309298 TI - Decidualization of Human Endometrial Stromal Fibroblasts is a Multiphasic Process Involving Distinct Transcriptional Programs. AB - Decidual stromal cells differentiate from endometrial stromal fibroblasts (ESFs) under the influence of progesterone and cyclic adenosine monophosphate (cAMP) and are essential for implantation and the maintenance of pregnancy. They evolved in the stem lineage of placental (eutherian) mammals coincidental with the evolution of implantation. Here we use the well-established in vitro decidualization protocol to compare early (3 days) and late (8 days) gene transcription patterns in immortalized human ESF. We document extensive, dynamic changes in the early and late decidual cell transcriptomes. The data suggest the existence of an early signal transducer and activator of transcription (STAT) pathway dominated state and a later nuclear factor kappaB (NFKB) pathway regulated state. Transcription factor expression in both phases is characterized by putative or known progesterone receptor ( PGR) target genes, suggesting that both phases are under progesterone control. Decidualization leads to proliferative quiescence, which is reversible by progesterone withdrawal after 3 days but to a lesser extent after 8 days of decidualization. In contrast, progesterone withdrawal induces cell death at comparable levels after short or long exposure to progestins and cAMP. We conclude that decidualization is characterized by a biphasic gene expression dynamic that likely corresponds to different phases in the establishment of the fetal-maternal interface. PMID- 30309299 TI - Annual program review process: an enhanced process with outcomes. AB - The Accreditation Council for Graduate Medical Education's required Annual Program Review of Educational Effectiveness (APREE) has helped us improve our program and change its culture to one of continuous quality improvement. This report outlines our systematic process and describes specific outcomes it has produced over a 10-year period. We identified ways to enhance our APREE after reading articles that described various ways to conduct the process found in a PubMed and OvidSP search and relevant policies from our local Graduate Medical Education Office. After discussing options, we incorporated new ideas into our APREE and tasked our Program Evaluation Committee to track outcomes from objectives developed by faculty and residents during each APREE. Objectives from faculty and residents in 10 years of our APREE led to major improvements (e.g., increased board pass rate) in our program. In addition, the enhanced APREE process gradually changed our residency's culture to one that embraces continuous quality improvement. A systematic APREE process can engage residents and faculty in improving specific components of a residency. Besides providing outcomes for Web Ads and Self-Study items, the APREE models quality improvement techniques to residents, involves a wide array of stakeholders, and helps program stakeholders embrace continuous quality improvement. PMID- 30309300 TI - Community-acquired acute meningitis and encephalitis: a narrative review. AB - Meningitis and encephalitis are medical emergencies. Patients need prompt evaluation and immediate empiric therapy to reduce the likelihood of fatal outcomes and chronic neurological sequelae. Conjugate bacterial vaccines have significantly reduced the incidence of bacterial meningitis, especially in children. As the results of changes in patterns of bacterial drug sensitivity, ceftriaxone is now part of the recommended empiric treatment for bacterial meningitis and should be administered as early as possible. Neuroimaging delays the treatment of meningitis and is not needed in most cases. Adjunctive corticosteroid therapy is of benefit for many patients with meningitis and should be initiated in most adults before antibiotic therapy. Molecular testing can assist the specific diagnosis of encephalitis and should be based on the exposure history and geographic risk factors relevant to the patient, but non-infectious causes of encephalitis are also common. Empiric therapy for encephalitis should be directed at the most frequently identified infectious pathogen, herpes simplex virus type 1 (ie, intravenous aciclovir). Vaccines can protect against the major pathogens of childhood infections (measles, mumps, rubella, polio, varicella viruses), influenza viruses, and exotic pathogens that cause meningitis and encephalitis (rabies, Japanese encephalitis, dengue, yellow fever, tick-borne encephalitis viruses, Mycobacterium tuberculosis). PMID- 30309302 TI - Invictus Games, Sydney 2018. PMID- 30309301 TI - Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study. AB - OBJECTIVES: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival. DESIGN, SETTING AND PARTICIPANTS: Prospective population-based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 - 30 June 2013. MAIN OUTCOME MEASURES: Overall survival (maximum follow up, 24 months); factors associated with HCC surveillance participation and survival. RESULTS: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol-related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non-participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol-related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6-19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38-0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19-0.58). Conversely, higher Child Pugh class, alpha-fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality. CONCLUSIONS: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated. PMID- 30309304 TI - Trials and tribulations: improving outcomes for adolescents and young adults with rare and low survival cancers. PMID- 30309305 TI - Australia is responding to the complex challenge of overdiagnosis. PMID- 30309306 TI - Subclavian vein thrombosis with internal jugular vein extension in an Australian rules football player. PMID- 30309307 TI - Fifty years of RhD immunoglobulin (anti-D) therapy in Australia: celebrating a public health success story. PMID- 30309308 TI - Redefining the physician's role in the era of online health information. PMID- 30309309 TI - Absolute cardiovascular disease risk and lipid-lowering therapy among Aboriginal and Torres Strait Islander Australians. PMID- 30309310 TI - Absolute cardiovascular disease risk and lipid-lowering therapy among Aboriginal and Torres Strait Islander Australians. PMID- 30309312 TI - From Formby to Family Planning NSW. PMID- 30309311 TI - Bilateral primary meningococcal conjunctivitis in an Indigenous child. PMID- 30309313 TI - Mathematical modelling of vancomycin-resistant enterococci transmission during passive surveillance and active surveillance with contact isolation highlights the need to identify and address the source of acquisition. AB - BACKGROUND: Clinical studies and mathematical simulation suggest that active surveillance with contact isolation is associated with reduced vancomycin resistant enterococci (VRE) prevalence compared to passive surveillance. Models using pre- and post-intervention data that account for the imperfect observation and serial dependence of VRE transmission events can better estimate the effectiveness of active surveillance and subsequent contact isolation; however, such analyses have not been performed. METHODS: A mathematical model was fitted to surveillance data collected pre- and post-implementation of active surveillance with contact isolation in the haematology-oncology ward. We developed a Hidden Markov Model to describe undetected and observed VRE colonisation/infection status based on the detection activities in the ward. Bayesian inference was used to estimate transmission rates. The effectiveness of active surveillance was assumed to be via increased detection and subsequent contact isolation of VRE positive patients. RESULTS: We estimated that 31% (95% credible interval: 0.33-85%) of the VRE transmissions were due to cross transmission between patients. The ratio of transmission rates from patients with contact isolation versus those without contact isolation was 0.33 (95% credible interval: 0.050-1.22). CONCLUSIONS: The majority of the VRE acquisitions in the haematology-oncology ward was estimated to be due to background rates of VRE, rather than within ward patient to patient acquisition. The credible interval for cross-transmission was wide which results in a large degree of uncertainty in the estimates. Factors that could account for background VRE acquisition include endogenous acquisition from antibiotic selection pressure and VRE in the environment. Contact isolation was not significantly associated with reduced VRE transmission in settings where the majority of VRE acquisition was due to background acquisition, emphasising the need to identify and address the source of acquisition. As the credible interval for the ratio of VRE transmission in contact isolated versus non-contact isolated patients crossed 1, there is a probability that the transmission rate in contact isolation was not lower. Our finding highlights the need to optimise infection control measures other than active surveillance for VRE and subsequent contact isolation to reduce VRE transmission. Such measures could include antimicrobial stewardship, environmental cleaning, and hand hygiene. PMID- 30309314 TI - Genetic diversity and population structure analyses of Plectranthus edulis (Vatke) Agnew collections from diverse agro-ecologies in Ethiopia using newly developed EST-SSRs marker system. AB - BACKGROUND: Plectranthus edulis (Vatke) Agnew (locally known as Ethiopian dinich or Ethiopian potato) is one of the most economically important edible tuber crops indigenous to Ethiopia. Evaluating the extent of genetic diversity within and among populations is one of the first and most important steps in breeding and conservation measures. Hence, this study was aimed at evaluating the genetic diversity and population structure of this crop using collections from diverse agro-ecologies in Ethiopia. RESULTS: Twenty polymorphic expressed sequence tag based simple sequence repeat (EST-SSRs) markers were developed for P. edulis based on EST sequences of P. barbatus deposited in the GenBank. These markers were used for genetic diversity analyses of 287 individual plants representing 12 populations, and a total of 128 alleles were identified across the entire loci and populations. Different parameters were used to estimate the genetic diversity within populations; and gene diversity index (GD) ranged from 0.31 to 0.39 with overall mean of 0.35. Hierarchical analysis of molecular variance (AMOVA) showed significant but low population differentiation with only 3% of the total variation accounted for variation among populations. Likewise, cluster and STRUCTURE analyses did not group the populations into sharply distinct clusters, which could be attributed to historical and contemporary gene flow and the reproductive biology of the crop. CONCLUSIONS: These newly developed EST-SSR markers are highly polymorphic within P. edulis and hence are valuable genetic tools that can be used to evaluate the extent of genetic diversity and population structure of not only P. edulis but also various other species within the Lamiaceae family. Among the 12 populations studied, populations collected from Wenbera, Awi and Wolaita showed a higher genetic diversity as compared to other populations, and hence these areas can be considered as hot spots for in-situ conservation as well as for identification of genotypes that can be used in breeding programs. PMID- 30309316 TI - General practitioners' continuation and acceptance of medication changes at sectorial transitions of geriatric patients - a qualitative interview study. AB - BACKGROUND: Follow-up in general practice on medication initiated during hospitalisation is often perceived to be inadequate, which leads to unintended drug interaction and over- or underdosage of medication. Little is known about General Practitioners (GPs') views on medication changes during the transition from hospital to primary care. We conducted a qualitative interview study to understand GPs' views on the medication changes made for their patients by hospital physicians in a geriatric ward and the GPs' actions after discharge. METHODS: Qualitative semi-structured interviews comprising ten GPs from general practices in the Region of Southern Denmark, using a phenomenological approach. The GPs were selected strategically based on the principle of maximum variation. The analysis process was a cross-sectional analysis based on a phenomenological analysis. RESULTS: The GPs identified many reasons for the lack of medication continuation, including miscommunication between hospital doctors and GPs and delayed discharge letters. Several factors were involved, including patients not taking responsibility for their medication, no structure for follow-up visits to their GPs and for the renewal of their prescriptions. CONCLUSION: The main reason for the poor continuity of medication changes for geriatric patients at sector transition was neither the GPs' deliberate actions of removing the patients' medications, nor the patients' lack of compliance or of willingness to take the medication. It is largely due to procedural errors in the follow-up on the patient after discharge, due to the lack of a structured process and due to miscommunication between the primary sector and the hospital. PMID- 30309317 TI - Integrating omics datasets with the OmicsPLS package. AB - BACKGROUND: With the exponential growth in available biomedical data, there is a need for data integration methods that can extract information about relationships between the data sets. However, these data sets might have very different characteristics. For interpretable results, data-specific variation needs to be quantified. For this task, Two-way Orthogonal Partial Least Squares (O2PLS) has been proposed. To facilitate application and development of the methodology, free and open-source software is required. However, this is not the case with O2PLS. RESULTS: We introduce OmicsPLS, an open-source implementation of the O2PLS method in R. It can handle both low- and high-dimensional datasets efficiently. Generic methods for inspecting and visualizing results are implemented. Both a standard and faster alternative cross-validation methods are available to determine the number of components. A simulation study shows good performance of OmicsPLS compared to alternatives, in terms of accuracy and CPU runtime. We demonstrate OmicsPLS by integrating genetic and glycomic data. CONCLUSIONS: We propose the OmicsPLS R package: a free and open-source implementation of O2PLS for statistical data integration. OmicsPLS is available at https://cran.r-project.org/package=OmicsPLS and can be installed in R via install.packages("OmicsPLS"). PMID- 30309315 TI - Association genetics of acetophenone defence against spruce budworm in mature white spruce. AB - BACKGROUND: Outbreaks of spruce budworm (SBW, Choristoneura fumiferana Clem.) cause major recurrent damage in boreal conifers such as white spruce (Picea glauca [Moench] Voss) and large losses of forest biomass in North America. Although defensive phenolic compounds have recently been linked to chemical resistance against SBW, their genetic basis remains poorly understood in forest trees, especially in conifers. Here, we used diverse association genetics approaches to discover genes and their variants that may control the accumulation of acetophenones, and dissect the genetic architecture of these defence compounds against SBW in white spruce mature trees. RESULTS: Out of 4747 single nucleotide polymorphisms (SNPs) from 2312 genes genotyped in a population of 211 unrelated individuals, genetic association analyses identified 35 SNPs in 33 different genes that were significantly associated with the defence traits by using single locus, multi-locus and multi-trait approaches. The multi-locus approach was particularly effective at detecting SNP-trait associations that explained a large fraction of the phenotypic variance (from 20 to 43%). Significant genes were regulatory including the NAC transcription factor, or they were involved in carbohydrate metabolism, falling into the binding, catalytic or transporter activity functional classes. Most of them were highly expressed in foliage. Weak positive phenotypic correlations were observed between defence and growth traits, indicating little or no evidence of defence-growth trade-offs. CONCLUSIONS: This study provides new insights on the genetic architecture of tree defence traits, contributing to our understanding of the physiology of resistance mechanisms to biotic factors and providing a basis for the genetic improvement of the constitutive defence of white spruce against SBW. PMID- 30309319 TI - Post-transcriptional regulation of cancer/testis antigen MAGEC2 expression by TRIM28 in tumor cells. AB - BACKGROUND: Cancer/testis antigen MAGEC2 (also known as HCA587) is highly expressed in a wide variety of tumors and plays an active role in promoting growth and metastasis of tumor cells. However, little is known for the regulation of MAGEC2 expression in cancer cells. METHODS: Western blotting and quantitative RT-PCR were performed to analyze MAGEC2 expression. Co-immunoprecipitation assay was applied for detecting the endogenous interaction of MAGEC2 and TRIM28 in tumor cells. Overexpression and knockdown assays were used to examine the effects of TRIM28 on the expression of MAGEC2 protein. Immunohistochemistry (IHC) staining was performed in hepatocellular carcinoma patients to evaluate the association between the expression of MAGEC2 and TRIM28. Proteasome inhibitors MG132 or PS-341 and lysosome inhibitor Chloroquine (CQ) were used to inhibit proteasomal or lysosomal-mediated protein degradation respectively. RESULTS: We demonstrate that MAGEC2 interacts with TRIM28 in melanoma cells and MAGEC2 expression in tumor cells depends on the expression of TRIM28. The expression level of MAGEC2 protein was significantly reduced when TRIM28 was depleted in tumor cells, and no changes were observed in MAGEC2 mRNA level. Furthermore, expression levels of MAGEC2 and TRIM28 are positively correlated in MAGEC2 positive human hepatocellular carcinoma tissues (p = 0.0011). Mechanistic studies indicate that the regulatory role of TRIM28 on MAGEC2 protein expression in tumor cells depends on proteasome-mediated pathway. CONCLUSIONS: Our findings show that TRIM28 is necessary for MAGEC2 expression in cancer cells, and TRIM28 may serve as a new potential target for immunotherapy of cancer. PMID- 30309318 TI - Optimal cutoff of pretreatment neutrophil-to-lymphocyte ratio in head and neck cancer patients: a meta-analysis and validation study. AB - BACKGROUND: The prognostic role of neutrophil-to-lymphocyte ratio (NLR) has been proposed in head and neck squamous cell carcinoma (HNSCC). However, it is currently unclear which cutoff values of NLR could consistently and independently differentiate HNSCC patients to better and worse prognosis groups. METHODS: We performed a meta-analysis of prognostic significance of pretreatment NLR values, using data extracted from 24 relevant articles. Main outcomes were overall survival (OS) and disease-free survival (DFS) in HNSCC patients. Pooled hazard ratio (HR) and 95% confidence intervals (95%CI) were calculated using the random effect model for outcomes. Impacts of NLR cutoff values across the studies were assessed with a meta-regression analysis. Results were validated using an independent data set of patients (n = 540). RESULTS: Pretreatment high NLR values above the cutoff were significantly associated with shorter OS (HR = 1.96, 95%CI = 1.66-2.31) and DFS (HR = 1.90, 95%CI = 1.41-2.54). Of note, NLR cutoffs ranging from 1.9 to 6.0 did not affect HR of OS or DFS in meta-regression analyses. In an independent cohort, any NLR cutoff between 2 and 6 produced significant HR of OS, similarly. Instead of binary cutoffs, three subgroups of NLR (< 2, 2 to 6, and >= 6) showed significant differences of OS in survival analyses. CONCLUSIONS: Meta analyses confirmed that pretreatment NLR values above the cutoff were associated with shorter survival in HNSCC patients. However, the binary cutoffs of NLR values were variable across studies. Rather, pretreatment NLR values below 2 and above 6 using a three-tier classification (< 2, 2 to 6, and >= 6) could consistently imply better and worse prognosis in HNSCC patients, which could be readily translated to clinics. PMID- 30309320 TI - Characterization of and genetic variation for tomato seed thermo-inhibition and thermo-dormancy. AB - BACKGROUND: Exposing imbibed seeds to high temperatures may lead to either thermo inhibition of germination or thermo-dormancy responses. In thermo-inhibition, seed germination is inhibited but quickly resumed when temperatures are lowered. Upon prolonged exposure to elevated temperatures, thermo-dormancy may be induced and seeds are not able to germinate even at optimal temperatures. In order to explore underlying physiological and molecular aspects of thermo-induced secondary dormancy, we have investigated the physiological responses of tomato seeds to elevated temperatures and the molecular mechanisms that could explain the performance of tomato seeds at elevated temperature. RESULTS: In order to investigate how tomato seeds respond to high temperature we used two distinct tomato accessions: Solanum lycopersicum (cv. Moneymaker) (MM) and Solanum pimpinellifolium accession CGN14498 (PI). MM seeds did not germinate under high temperature conditions while seeds of PI reached a maximum germination of 80%. Despite the high germination percentage of PI, germinated seeds did not produce healthy seedling at 37 degrees C. By using a candidate gene approach we have tested if similar molecular pathways (abscisic acid (ABA) and gibberellic acid (GA)) present in lettuce and Arabidopsis, are regulating thermo-inhibition and thermo-dormancy responses in tomato. We showed that the ABA biosynthesis pathway genes NCED1 and NCED9 were upregulated whereas two of the GA-biosynthesis regulators (GA3ox1 and GA20ox1) were downregulated in tomato thermo-dormant seeds at elevated temperature. To identify novel regulators of tomato seed performance under high temperature, we screened a Recombinant Inbred Line (RIL) population derived from a cross between the two tomato accessions MM and PI for thermo inhibition and dormancy induction. Several QTLs were detected, particularly for thermo-dormancy, which may be caused by new regulators of thermo-inhibition and thermo-dormancy in tomato. CONCLUSIONS: None of the genes studied in this research were co-locating with the detected QTLs. The new QTLs discovered in this study will therefore be useful to further elucidate the molecular mechanisms underlying the responses of tomato seeds to high temperature and eventually lead to identification of the causal genes regulating these responses. PMID- 30309323 TI - An improved assay for rapid detection of viable Staphylococcus aureus cells by incorporating surfactant and PMA treatments in qPCR. AB - BACKGROUND: Staphylococcus aureus is an important human pathogen causing a variety of life-threatening diseases. Rapid and accurate detection of Staphylococcus aureus is a necessity for prevention of outbreaks caused by this pathogen. PCR is a useful tool for rapid detection of foodborne pathogens, however, its inability to differentiate DNA from dead cells and live cells in amplification severely limits its application in pathogen detection. The aim of this study was to develop an improved assay was developed by incorporating the sample treatments with a surfactant and propidium monoazide (PMA) in qPCR for detection of viable S. aureus cells. RESULTS: The cell toxic effect testing with the two surfactants showed that the viability of S. aureus was virtually not affected by the treatment with 0.5% triton x-100 or 0.025% sarkosyl. Triton x-100 was coupled with PMA for sample treatments for detection of viable S. aureus cells in artificially contaminated milk. The qPCR results indicated that the assay reached high an amplification efficiency of 98.44% and the live S. aureus cells were accurately detected from the triton-treated spiked milk samples by the PMA-qPCR assay. CONCLUSIONS: The qPCR assay combined with treatments of PMA and surfactants offers a sensitive and accurate means for detection of viable S. aureus cells. Cell toxic effect testing with the two surfactants showed that the viability of S. aureus was virtually not affected by the treatment with 0.5% triton x-100 or 0.025% sarkosyl. The information on sample treatment with surfactants to improve the dead cell DNA removal efficiency in qPCR by increasing PMA's permeability to dead cells can be used for other pathogens, especially for Gram-positive bacteria. PMID- 30309321 TI - Multidrug resistant Pseudomonas aeruginosa in Estonian hospitals. AB - BACKGROUND: We aimed to identify the main spreading clones, describe the resistance mechanisms associated with carbapenem- and/or multidrug-resistant P. aeruginosa and characterize patients at risk of acquiring these strains in Estonian hospitals. METHODS: Ninety-two non-duplicated carbapenem- and/or multidrug-resistant P. aeruginosa strains were collected between 27th March 2012 and 30th April 2013. Clinical data of the patients was obtained retrospectively from the medical charts. Clonal relationships of the strains were determined by whole genome sequencing and analyzed by multi-locus sequence typing. The presence of resistance genes and beta-lactamases and their origin was determined. Combined disk method and PCR was used to evaluate carbapenemase and metallo-beta-lactamase production. RESULTS: Forty-three strains were carbapenem-resistant, 11 were multidrug-resistant and 38 were both carbapenem- and multidrug-resistant. Most strains (54%) were isolated from respiratory secretions and caused an infection (74%). Over half of the patients (57%) were >= 65 years old and 85% had >=1 co morbidity; 96% had contacts with healthcare and/or had received antimicrobial treatment in the previous 90 days. Clinically relevant beta-lactamases (OXA-101, OXA-2 and GES-5) were found in 12% of strains, 27% of which were located in plasmids. No Ambler class B beta-lactamases were detected. Aminoglycoside modifying enzymes were found in 15% of the strains. OprD was defective in 13% of the strains (all with CR phenotype); carbapenem resistance triggering mutations (F170 L, W277X, S403P) were present in 29% of the strains. Ciprofloxacin resistance correlated well with mutations in topoisomerase genes gyrA (T83I, D87N) and parC (S87 L). Almost all strains (97%) with these mutations showed ciprofloxacin-resistant phenotype. Multi-locus sequence type analysis indicated high diversity at the strain level - 36 different sequence types being detected. Two sequence types (ST108 (n = 23) and ST260 (n = 18)) predominated. Whereas ST108 was associated with localized spread in one hospital and mostly carbapenem resistant phenotype, ST260 strains occurred in all hospitals, mostly with multi resistant phenotype and carried different resistance genotype/machinery. CONCLUSIONS: Diverse spread of local rather than international P. aeruginosa strains harboring multiple chromosomal mutations, but not plasmid-mediated Ambler class B beta-lactamases, were found in Estonian hospitals. TRIAL REGISTRATION: This trial was registered retrospectively in ClinicalTrials.gov ( NCT03343119 ). PMID- 30309322 TI - Rituximab, plasma exchange and immunoglobulins: an ineffective treatment for chronic active antibody-mediated rejection. AB - BACKGROUND: Chronic active antibody-mediated rejection (c-aABMR) is an important cause of allograft failure and graft loss in long-term kidney transplants. METHODS: To determine the efficacy and safety of combined therapy with rituximab, plasma exchange (PE) and intravenous immunoglobulins (IVIG), a cohort of patients with transplant glomerulopathy (TG) that met criteria of active cABMR, according to BANFF'17 classification, was identified. RESULTS: We identified 62 patients with active c-aABMR and TG (cg >= 1). Twenty-three patients were treated with the combination therapy and, 39 patients did not receive treatment and were considered the control group. There were no significant differences in the graft survival between the two groups. The number of graft losses at 12 and 24 months and the decline of eGFR were not different and independent of the treatment. A decrease of eGFR>=13 ml/min between 6 months before and c-aABMR diagnosis, was an independent risk factor for graft loss at 24 months (OR = 5; P = 0.01). Infections that required hospitalization during the first year after c-aABMR diagnosis were significantly more frequent in treated patients (OR = 4.22; P = 0.013), with a ratio infection/patient-year of 0.65 and 0.20 respectively. CONCLUSIONS: Treatment with rituximab, PE, and IVIG in kidney transplants with c aABMR did not improve graft survival and was associated with a significant increase in severe infectious complications. TRIAL REGISTRATION: Agencia Espanola de Medicametos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTR INM-2017-01. PMID- 30309324 TI - Osteoporosis development and vertebral fractures after abdominal irradiation in patients with gastric cancer. AB - BACKGROUND: Decrease in bone mineral density, osteoporosis development, bone toxicity and resulting insufficiency fractures as late effect of radiotherapy are not well known. Osteoporosis development related to radiotherapy has not been investigated properly and insufficiency fractures are rarely reported for vertebral bones. METHODS: Ninety-seven patients with gastric adenocarcinoma were evaluated for adjuvant treatment after surgery. While 73 out of 97 patients treated with adjuvant chemoradiotherapy comprised the study group, 24 out of 97 patients with early stage disease without need of adjuvant treatment comprised the control group. Bone mineral densities (BMD) of lumbar spine and femoral neck were measured by dual energy x-ray absorptiometry after surgery, and one year later in both groups. RESULTS: There was statistically significant decline in BMDs after one year in each group itself, however the decline in BMDs of the patients in the irradiated group was more pronounced when compared with the patients in the control group; p values were 0.02 for the decline in BMDs of lumbar spine, and 0.01 for femoral neck respectively. Insufficiency fractures were observed only in the irradiated patients (7 out of 73 patients) with a cumulative incidence of 9.6%. CONCLUSIONS: Abdominal irradiation as in the adjuvant treatment of gastric cancer results in decrease in BMD and osteoporosis. Insufficiency fracture risk in the radiation exposed vertabral bones is increased. Calcium and vitamin D replacement and other measures for prevention of osteoporosis and insufficiency fractures should be considered after abdominal irradiation. PMID- 30309325 TI - Validity and prognostic significance of sperm protein 17 as a tumor biomarker for epithelial ovarian cancer: a retrospective study. AB - BACKGROUND: Prior small studies have shown increased expression of sperm protein 17 (Sp17) in epithelial ovarian cancer (EOC) tissue and suggest Sp17 as a potential biomarker for EOC. However, how Sp17 expression varies with histology, grade, and stage of EOC and its expression in other ovarian neoplasms has not been defined. It is unknown whether patients with EOC have elevated serum Sp17 levels or if Sp17 expression is associated with survival outcomes. METHODS: The study included 982 patients with benign, borderline, and malignant ovarian neoplasms and normal ovary. There were 878 patients with tissue only, 39 with serum only, and 65 with matching serum and tissue. Immunohistochemical (IHC) staining with anti-Sp17 antibody was performed on tissue specimens and the intensity scored as weak, moderate, or strong. A sandwich enzyme-linked immunosorbent assay (ELISA) was performed to measure Sp17 sera concentrations. RESULTS: Sp17 expression was most commonly seen in serous cystadenomas (83%) and serous borderline tumors (100%). Of the 773 EOC specimens, 223 (30%) expressed Sp17. Grade and histology were significantly associated with Sp17 expression among EOC specimens (p < 0.001) on both univariate and multivariable analysis, with grade 1 serous adenocarcinomas showing the highest expression (51%). Sp17 expression was limited in other benign and non-epithelial malignant neoplasms. Neither Sp17 tissue expression nor serum concentration correlated with survival outcomes. Serum concentrations were higher in patients with Sp17 tissue expression, and the highest concentrations were noted among patients with serous and clear cell adenocarcinomas. CONCLUSIONS: Sp17 is highly expressed in benign, borderline, and low grade malignant serous ovarian neoplasms and can be quantified in serum. Sp17 expression may have diagnostic significance in this subset of patients. PMID- 30309326 TI - The relationship between college students' alexithymia and mobile phone addiction: Testing mediation and moderation effects. AB - BACKGROUND: To explore the relationship between college students' alexithymia and mobile phone addiction as well as the mediating effects of mental health and the moderating role of being a single child or not. METHODS: A total of 1034 college students from Changchun were assessed with the Toronto Alexithymia Scale (TAS 20), General Health Questionnaire (GHQ) and Mobile Phone Addiction Index (MPAI). RESULTS: Alexithymia was positively correlated with mental health and mobile phone addiction. Alexithymia had not only a direct impact on mobile phone addiction but also an indirect impact via mental health. For college students who were not only children, higher levels of alexithymia led to an increase in mobile phone addiction, whereas the influence of alexithymia on mobile phone addiction was much weaker among only children. CONCLUSION: Mental health has a partial mediating effect on the relationship between alexithymia and mobile phone addiction, and the relationship was significantly moderated by whether students were only children or not. PMID- 30309327 TI - Effect of Shenmai injection on cognitive function after cardiopulmonary bypass in cardiac surgical patients: a randomized controlled trial. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery that influences the clinical outcomes and quality of life of patients. This study aimed to evaluate the effects of Shenmai injection (SMI) on POCD of patients who underwent cardiac valve replacement under cardiopulmonary bypass (CPB). METHODS: This prospective, randomized, controlled trial was conducted from September 2014 to January 2017. Eighty-eight patients receiving cardiac valve replacement under CPB were randomized into the control (C) or the SMI (S) group. SMI (0.6 mL/kg) was administered intravenously from the time of anesthesia induction to the beginning of CPB. Cognitive function was assessed at 3 days before surgery and 3 days, 7 days, and 1 month after surgery using the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) score. The serum levels of neuroglobin (Ngb), hypoxia-inducible factor-1alpha (HIF-1alpha), and neuron-specific enolase (NSE) were measured at 30 min after induction (T0), immediately after the endonasal temperature rewarmed to 36 degrees C (T1), and 1 h (T2), 6 h (T3), 24 h (T4), 48 h (T5), and 72 h (T6) after CPB. RESULTS: Compared with the baseline values at T0, the serum Ngb levels in group C were significantly decreased at T1-2 and then increased at T3-6, while the levels in group S were decreased at T1-2 and increased at T4-6, compared to group C (p < 0.05). The serum HIF-1alpha levels at T1-4 and the serum NSE levels at T1-6 were significantly increased in both groups (p < 0.05). The serum levels of Ngb at T3, HIF-1alpha at T1-3, and NSE at T3-4,6 were lower in group S, compared to group C (p < 0.01). The MoCA-BJ scores were decreased at 3 and 7 days after surgery in both groups, and the MoCA-BJ scores in group S were higher than those in group C at 3 and 7 days after surgery (p < 0.01). CONCLUSION: Cognitive function is impaired postoperatively in patients who have undergone cardiac valve replacement under CPB. In addition, treatment with the traditional Chinese medicine SMI decreases the serum levels of Ngb, HIF-1alpha, and NSE as well as attenuates cognitive dysfunction. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov as ChiCTR-TRC-14004373 on March 11, 2014. PMID- 30309328 TI - Coexistence of gastric gastrointestinal stromal tumor, intro-abdominal and retroperitoneal liposarcomas -a case report. AB - BACKGROUND: Gastric gastrointestinal stromal tumor (GIST), intro-abdominal and retroperitoneal neoplasms are distinct tumors arising from different cell layers; therefore, coexistence of such tumors is relatively rare. CASE PRESENTATION: A man complained of early satiety for 2 mouths, whose upper gastrointestinal (GI) endoscopy showed a tumor arising from the greater curvature of gastric body and extending into the lumen. Abdominal computed tomography (CT) revealed coexistence of gastric, intro-abdominal and retroperitoneal masses. Wedge resection for gastric tumor, resection for intro-abdominal and retroperitoneal tumors were done. The postoperative histological examination suggested simultaneous development of a gastric GIST, intro-abdominal and retroperitoneal myxoid liposarcomas. CONCLUSION: Although both GISTs and liposarcomas originate from mesenchymal tissues, simultaneous development of a gastric GIST, intro-abdominal and retroperitoneal liposarcomas is the first such case to be reported in the literature. PMID- 30309329 TI - Gendered impact of solid fuel use on acute respiratory infections in children in China. AB - BACKGROUND: Indoor Air Pollution (IPA) is a serious environmental problem that can have detrimental effects on child health. In China, the major sources of indoor pollution are biomass fuel or solid cooking fuels and familial smoking. Previous studies posit that the effects of IAP on health outcomes may be worse for female children, but the empirical evidence has been mixed. METHODS: In this paper we use the China Health and Nutrition Survey to examine the association of solid fuel use and paternal smoking on acute respiratory infections (ARIs) in children focusing on child gender differences. We used conditional logistic regression to examine gender differences in incidents of ARIs in the 4 weeks prior to the survey collection. We modeled gender difference by including an interaction between child gender and solid fuel use and child gender and paternal smoking. We also conducted stratified analyses by child gender. RESULTS: When examining both genders together, female children exposed to solid fuel had an elevated risk of a ARIs, but the coefficient was not statistically significant. When using a stratified models by gender, female children had a higher risk of having ARIs in the past 4 weeks when exposed to solid fuels (OR=3.28; 95% CI 1.34 8.03) and paternal smoking (OR=2.27; 95% CI 1.08-4.77). Whereas neither exposure to solid fuel nor parental smoking had any significant influence on ARIs for male children. CONCLUSION: While many have hypothesized that female children may be more vulnerable to IAP, the empirical evidence has been limited. In our study we found empirical support for gender difference in the effects of solid cooking fuel use on ARIs. Gender differences in ARIs suggest that realized exposures, as opposed to ambient exposures, are likely higher for female children and are important to consider. PMID- 30309331 TI - Using simultaneous amplification and testing method for evaluating the treatment outcome of pulmonary tuberculosis. AB - BACKGROUND: To evaluate the utility of Simultaneous Amplification and Testing (SAT-TB) Method for monitoring anti-TB treatment response. METHODS: Serial morning sputum specimens were obtained from 377 active pulmonary tuberculosis (PTB) cases at baseline, weeks 2, months 2, 5 and 6 (newly diagnosed patients) or 8 (previously treated patients) for AmpSure assay, smear fluorescence microscopy (FM) and BACTEC MGIT 960 culture assay. RESULTS: After treatment of 2 weeks, sputum culture was positive in 280 patients (74.27%). Among whom, 219 patients tested positive for SAT-TB assay and 143 patients smear FM positive. The detection rate of SAT-TB (78.21%) was significantly higher than sputum FM (51.07%, chi2 = 45.128, P < 0.001). At the end of the second month of treatment, 157 patients (41.64%) were still culture-positive, 115 patients of them SAT-TB positive and 79 smear FM positive. The difference of detection rate between SAT TB (73.25%) and sputum FM (50.32%) was significant (chi2 = 17.480, P < 0.001). When patients underwent five months of treatment, 65 patients (17.24%) with sputum culture positive was defined as treatment failure. Among whom, 60 patients (92.31%) were SAT-TB positive and 38 patients (58.46%) were smear FM positive. The detection rate of SAT-TB assay was significantly higher than sputum FM (chi2 = 17.333, P < 0.001). CONCLUSION: Results of AmpSure assays for monitoring treatment responses can be obtained without waiting for the results of BACTEC MGIT 960 assays and most patients with treatment failures could be detected after 5 months. PMID- 30309332 TI - The acceptance of the clinical photographic posture assessment tool (CPPAT). AB - BACKGROUND: There is a lack of evidence-based quantitative clinical methods to adequately assess posture. Our team developed a clinical photographic posture assessment tool (CPPAT) and implemented this tool in clinical practice to standardize posture assessment. The objectives were to determine the level of acceptance of the CPPAT and to document predictors as well as facilitators of and barriers to the acceptance of this tool by clinicians doing posture re-education. METHODS: This is a prospective study focussing on technology acceptance. Thirty two clinician participants (physical therapists and sport therapists) received a 3-5 h training workshop explaining how to use the CPPAT. Over a three-month trial, they recorded time-on-task for a complete posture evaluation (photo - and photo-processing). Subsequently, participants rated their acceptance of the tool and commented on facilitators and barriers of the clinical method. RESULTS: Twenty-three clinician participants completed the trial. They took 22 (mean) +/- 10 min (SD) for photo acquisition and 36 min +/- 19 min for photo-processing. Acceptance of the CPPAT was high. Perceived ease of use was an indirect predictor of intention to use, mediated by perceived usefulness. Analysis time was an indirect predictor, mediated by perceived usefulness, and a marginally significant direct predictor. Principal facilitators were objective measurements, visualization, utility, and ease of use. Barriers were time to do a complete analysis of posture, quality of human-computer interaction, non-automation of posture index calculation and photo transfer, and lack of versatility. CONCLUSION: The CPPAT is perceived as useful and easy to use by clinicians and may facilitate the quantitative analysis of posture. Adapting the user-interface and functionality to quantify posture may facilitate a wider adoption of the tool. PMID- 30309330 TI - CsINV5, a tea vacuolar invertase gene enhances cold tolerance in transgenic Arabidopsis. AB - BACKGROUND: Vacuolar invertases (VINs) have been reported to regulate plant growth and development and respond to abiotic stresses such as drought and cold. With our best knowledge, the functions of VIN genes little have been reported in tea plant (Camellia sinensis L.). Therefore, it is necessary to develop research in this field. RESULTS: Here, we identified a VIN gene, CsINV5, which was induced by cold acclimation and sugar treatments in the tea plant. Histochemical assays results showed that the 1154 bp 5'-flanking sequence of CsINV5 drove beta glucuronidase (GUS) gene expression in roots, stems, leaves, flowers and siliques of transgenic Arabidopsis during different developmental stages. Moreover, promoter deletion analysis results revealed that an LTRE-related motif (CCGAAA) and a WBOXHVISO1 motif (TGACT) within the promoter region of CsINV5 were the core cis-elements in response to low temperature and sugar signaling, respectively. In addition, overexpression of CsINV5 in Arabidopsis promoted taproot and lateral root elongation through glucose-mediated effects on auxin signaling. Based on physiological and RNA-seq analysis, we found that overexpression of CsINV5 improved cold tolerance in transgenic Arabidopsis mainly by increasing the contents of glucose and fructose, the corresponding ratio of hexose to sucrose, and the transcription of osmotic-stress-related genes (P5CS1, P5CS2, AtLEA3, COR413-PM1 and COR15B) to adjust its osmotic potential. CONCLUSIONS: Comprehensive experimental results suggest that overexpression of CsINV5 may enhance the cold tolerance of plant through the modification of cellular sugar compounds contents and osmotic regulation related pathways. PMID- 30309333 TI - Study design and characteristics of the Luxembourg European Health Examination Survey (EHES-LUX). AB - BACKGROUND: The European Health Examination Survey in Luxembourg (EHES-LUX) is a population based survey performed from 2013 to 2015 with the aim to establish baseline information on the general health status of the Luxembourg population aged 25 to 64 years. The paper introduces the study design, recruitment method and representativeness of the sample, and summarizes the sociodemographic characteristics of participants and the prevalence of major health outcomes. METHODS: EHES-LUX is based on a random sample representative of the population of Luxembourg based on gender, age and district of residence. The sample size of the study was determined to provide accurate prevalence estimates for major chronic conditions. During two visits, data were collected from participants through a questionnaire (personal data, health status and health care), medical examinations (anthropometric measures, electrocardiogram and spirometry) and biological analysis (blood, urine and hair). Means and frequencies were used to describe the general characteristics of the population and a one-way ANOVA to test the representativeness of the sample and the comparability of participants and non-participants. RESULTS: A total of 1529 individuals participated in this study (participation rate of 24.1%). Differences between participants and non participants based on gender, age and district of residence were corrected by sampling weights. The mean age (+/-SD) of participants was 44.9 (+/-10.1) years, of which 52.8% were women. Based on clinical measurements, nearly 20% of participants were obese and more than one in three participants were overweight. From measurements (respectively from self-report), 22.0% (respectively 12.2%) were hypertensive, 49.3% (respectively 22.5%) had hypercholesterolemia, 3.5% (respectively 3.7%) had diabetes and 7.6% (respectively 6.0%) had depressive symptoms. CONCLUSIONS: This nationwide epidemiological study on the general health status of Luxembourg residents provides updated prevalence estimates on a range of major health conditions. This information can be used by health authorities to evaluate policies and public health initiatives. At European level, prevalence data obtained by this study following the EHES-Reference Committee (EHES-RC) recommendations, will be comparable between European countries participating in this program. PMID- 30309334 TI - The relationship between dispositional empathy, psychological distress, and posttraumatic stress responses among Japanese uniformed disaster workers: a cross sectional study. AB - BACKGROUND: Disaster workers suffer from psychological distress not only through the direct experience of traumatic situations but also through the indirect process of aiding disaster victims. This distress, called secondary traumatic stress, is linked to dispositional empathy, which is the tendency for individuals to imagine and experience the feelings and experiences of others. However, the association between secondary traumatic stress and dispositional empathy remains understudied. METHODS: To examine the relationship between dispositional empathy and mental health among disaster workers, we collected data from 227 Japan Ground Self-Defense Force personnel who engaged in international disaster relief activities in the Philippines following Typhoon Yolanda in 2013. The Impact of Event Scale-Revised and the Kessler Psychological Distress Scale were used to evaluate posttraumatic stress responses (PTSR) and general psychological distress (GPD), respectively. Dispositional empathy was evaluated through the Interpersonal Reactivity Index, which consists of four subscales: Perspective Taking, Fantasy, Empathic Concern, and Personal Distress. Hierarchial linear regression analyses were performed to identify the variables related to PTSR and GPD. RESULTS: High PTSR was significantly associated with high Fantasy (identification tendency, beta = 0.21, p < .01), high Personal Distress (the self oriented emotional disposition of empathy, beta = 0.18, p < .05), and no experience of disaster relief activities (beta = 0.15, p < .05). High GPD was associated with high Personal Distress (beta = 0.28, p < .001), marital status (married, beta = 0.22, p < .01), being female (beta = 0.18, p < .01), medical unit (beta = 0.18, p < .05), and no experience of disaster relief activities (beta = 0.13, p < .05). CONCLUSIONS: Among Japanese uniformed disaster workers, high PTSR was associated with two subtypes of dispositional empathy: the self oriented emotional disposition of empathy and high identification tendency, whereas high GPD was associated with high identification tendency. Educational interventions that aim to mitigate these tendencies might be able to relieve the psychological distress of disaster workers. PMID- 30309335 TI - Optic disk melanocytoma associated with polypoidal choroidal vasculopathy lesions, after combination treatment of photodynamic therapy and intavitreal aflibercept (Eylea), a case report. AB - BACKGROUND: We report a rare case of a woman with optic disk melanocytoma (ODMC) in conjunction with polypoidal choroidal vasculopathy (PCV). We also present, for the first time in literature, the clinical and morphological outcomes of the applied treatment, consisting of a session of photodynamic therapy (PDT) and three monthly intravitreal aflibercept injections. CASE PRESENTATION: An 83-year old Greek woman, complaining for visual decline at her left eye, referred to our department and was diagnosed with ODMC associated with PCV. At presentation, best corrected visual acuity (BCVA) was 2/10, fundus examination revealed a pigmented lesion covering partially the optic nerve head and extending into the peripapillary choroid and retina, while hard exudates were observed temporal to it. Blocked hypofluorescence in the area covered by the lesion and diffuse hyperfluorescence at its temporal rim were shown by fluorescein angiography (FA). Indocyanine green angiography (ICGA) identified 3 hyperfluorescent polypoidal lesions arising from the choroidal vasculature. Optical coherence tomography (OCT) revealed subretinal fluid and retinal pigment epithelium detachment (RPE) at the region corresponding to polyps. The treatment included a PDT session combined with 3 monthly intravitreal aflibercept injections. Three months since the treatment initiation, new BCVA was 5/10, ICGA demonstrated total polyps occlusion, while OCT detected RPE detachment without subretinal fluid. Ten months later, ODMC was stable, BCVA rose to 7/10, no polyps were present, and total resolution of RPE detachment was achieved. CONCLUSIONS: This is the first case report of PCV coexisting with ODMC, presenting both ICGA and OCT findings, and the applied treatment and its outcomes. Furthermore, we demonstrated that PDT combined with intravitreal aflibercept injections seems to be a promising treatment for PCV. PMID- 30309336 TI - DNA methylation patterns in peripheral blood mononuclear cells from Holstein cattle with variable milk yield. AB - BACKGROUND: Milk yield for Holstein cows has doubled over five decades due to genetic selection and changes to management, but the molecular mechanisms that facilitated this increase are mostly unknown. Epigenetic modifications to the cattle genome are a plausible molecular mechanism to cause variation in milk yield and our objective was to describe genome-wide DNA methylation patterns in peripheral blood mononuclear cells (PBMC) from mature Holstein dairy cows with variable milk yield. RESULTS: Whole genome MeDIP-seq was performed following DNA extraction from PBMC of 6 lactating dairy cows from 4 different herds that varied in milk yield from 13,556 kg to 23,105 kg per 305 day lactation. We describe methylation across the genome and for 13,677 protein coding genes. Repetitive element reads were primarily mapped to satellite (36.4%), SINE (29.1%), and LINE (23.7%) regions and the majority (78.4%) of CpG sites were sequenced at least once. DNA methylation was generally low upstream of genes with the nadir occurring 95 bp prior to the transcription start site (TSS). Methylation was lower in the first exon than in later exons, was highest for introns near the intron-exon junctions, and declined downstream as the distance from the gene increased. We identified 72 differentially methylated regions (DMR) between high milk yield cows and their control, and 252 DMR across herd environments. CONCLUSIONS: This reference methylome for cattle with extreme variation in milk yield phenotype provides a resource to more fully evaluate relationships between DNA methylation and phenotype in populations subject to selection. The detection of DMR in cows of varying milk yield suggests potential to exploit epigenetic variation in cattle improvement programs. PMID- 30309337 TI - Differentials in prevalence and correlates of metabolic risk factors of non communicable diseases among women in sub-Saharan Africa: evidence from 33 countries. AB - BACKGROUND: Even with the widespread recognition of non- communicable diseases (NCDs) in sub-Saharan Africa region, yet, sufficient evidence-based surveillance systems to confirm the prevalence and correlates of these diseases is lacking. In an attempt to understand the problem of NCDs in resource-constrained settings, this study was conducted to establish the pattern of the risk factors of NCDs in sub-Sahara Africa region. METHODS: The current Demographic and Health Survey (DHS) data sets from 33 countries in sub-Sahara Africa region were used in this study. The individual woman component of DHS 2008-2016 was used. The outcome variables include anemia, hypertension and body mass index (underweight, overweight and obesity). BMI was categorized into; underweight (BMI < 18.5 kg/m2), normal (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) and obesity (BMI >=30 kg/m2). Hemoglobin level: anemic < 12.0 g/dL (< 120 g/L) for women. Hypertension was defined as systolic blood pressure (SBP) >=140 mmHg and/or diastolic blood pressure (DBP) >=90 mmHg. Binary and multinomial logistic regression models were used to investigate the correlates of the variables. RESULTS: The percentage of hypertension was highest among women in Lesotho with about 17.3% and lowest among women in Burundi (1.0%). Anemia was prevalent among sub-Saharan Africa women; where more than half of the women from several countries were anemic with Gabon (60.6%) reporting the highest prevalence. The percentage of obesity in sub-Saharan Africa showed that Lesotho (19.9%), Gabon (18.9%) and Ghana (15.6%) were the prominent countries with obese women, while Madagascar (1.1%) had the minimum obese women. Body mass index was significantly associated with hypertension and anemia. The behavioural or modifiable factors of hypertension and body mass index were; smoking, fruits, vegetables and alcohol consumption. While the non-modifiable significant factors include; age, residence, religion, education, wealth index, marital status, employment and number of children ever born. However, anemia shared similar factors except that smoking and vegetable consumption were not statistically significant. In addition, involvement in exercise was associated with anemia and hypertension. CONCLUSION: The problem of NCDs and associated factors remains high among women of reproductive age in sub-Sahara region. The findings of this study suggest that promotion of regular positive health care-seeking behaviour, screening and early treatment are essential to mitigate the burden of NCDs. Furthermore, preventive interventions of NCDs risk factors should be strengthened among key population through behavior change communication with support from government and stakeholders in health care. PMID- 30309338 TI - Stabilization and reversal of child obesity in Andalusia using objective anthropometric measures by socioeconomic status. AB - BACKGROUND: Childhood obesity continues to be a significant public health issue worldwide. Recent national studies in Spain show a stable picture. However, prevalence and trends differ by socio-economic status, age, and region. We present the trend in childhood excess weight prevalence, aged 8-15 years, in Andalusia from 2011-2012 to 2015-2016 by socio-economic status. METHODS: Using the cross-sectional Andalusian Health Surveys, objective anthropometric measures were taken for a representative sample of 8-15 year olds in Andalusia in 2011 2012 and 2015-2016. Prevalence and changes in prevalence of excess weight (overweight plus obesity) were calculated, using both the WHO and IOTF criteria, overall and for sex, age and three different indicators of SES. RESULTS: Overall prevalence of excess weight decreased from 42.0% in 2011-2012 to 35.4% in 2015 2016. Overweight decreased from 28.2 to 24.2% and obesity from 13.8 to 11.2%. In 2011-2012 the prevalence of excess weight in boys was 46.0%and 37.9% in girls; in 2015-2016 the difference became significant with 41% of boys with excess weight compared with 30% in girls. CONCLUSIONS: Childhood excess weight prevalence in Andalusia has decreased slightly between 2011-2012 and 2015-2016. Notably, a decrease in obesity prevalence in girls aged 8-15 years was recorded. In 2011 2012 a social gradient for excess weight prevalence across three SES indicators was observed: in 2015-2016 this gradient disappeared. Nonetheless, prevalence remains too high. PMID- 30309339 TI - Successful resolution of coats disease by photodynamic therapy: a case report. AB - BACKGROUND: Coats disease is a retinal disease characterized by exudative retinal detachment due to abnormal retinal blood vessels. Coats disease is generally treated using laser photocoagulation and cryotherapy to ablate the abnormal retinal blood vessels. However, if abnormal blood vessels are present near the posterior pole of the eye and there is a severe exudative change there, it is difficult to perform these standard treatments. We describe a case of Coats disease with severe exudative retinal change and retinal vascular abnormality near the posterior pole for which we performed photodynamic therapy and successfully suppressed the disease and improved vision. CASE PRESENTATION: A 15 year-old Japanese boy presented to hospital with a chief complaint of decreased vision in his right eye. At the initial examination, corrected visual acuity of the right eye was 20/100. On the right fundus, exudative retinal detachment with subretinal haemorrhage was observed from the upper intermediate periphery to the posterior pole. Abnormal telangiectatic vessels and microaneurysms were found at the nasal peripheral retina. From these findings, we diagnosed the case as Coats disease. We conducted photodynamic therapy for the right eye. At 10 months after treatment, both the subretinal haemorrhage and the exudative retinal detachment had disappeared completely. Further, the retinal structure of the macula had recovered, and right vision had improved to 20/20. CONCLUSION: Photodynamic therapy may be an effective and safe treatment for Coats disease in cases that present with abnormal retinal vessels close to the posterior pole of the eye. PMID- 30309340 TI - Accurate prediction of protein-lncRNA interactions by diffusion and HeteSim features across heterogeneous network. AB - BACKGROUND: Identifying the interactions between proteins and long non-coding RNAs (lncRNAs) is of great importance to decipher the functional mechanisms of lncRNAs. However, current experimental techniques for detection of lncRNA-protein interactions are limited and inefficient. Many methods have been proposed to predict protein-lncRNA interactions, but few studies make use of the topological information of heterogenous biological networks associated with the lncRNAs. RESULTS: In this work, we propose a novel approach, PLIPCOM, using two groups of network features to detect protein-lncRNA interactions. In particular, diffusion features and HeteSim features are extracted from protein-lncRNA heterogenous network, and then combined to build the prediction model using the Gradient Tree Boosting (GTB) algorithm. Our study highlights that the topological features of the heterogeneous network are crucial for predicting protein-lncRNA interactions. The cross-validation experiments on the benchmark dataset show that PLIPCOM method substantially outperformed previous state-of-the-art approaches in predicting protein-lncRNA interactions. We also prove the robustness of the proposed method on three unbalanced data sets. Moreover, our case studies demonstrate that our method is effective and reliable in predicting the interactions between lncRNAs and proteins. AVAILABILITY: The source code and supporting files are publicly available at: http://denglab.org/PLIPCOM/ . PMID- 30309341 TI - Thymol turbidity test is associated with the risk of cyclops syndrome following anterior cruciate ligament reconstruction. AB - BACKGROUND: Cyclops nodule formation is a serious complication after anterior cruciate ligament (ACL) reconstruction. The purpose of our study was to investigate whether an increase in thymol turbidity test (TTT) values is involved in the development of cyclops nodule formation or cyclopoid scar formation following ACL reconstruction. METHODS: Between 2011 and 2014, 120 cases underwent outside-in ACL reconstruction. Forty-seven patients who had high TTT values were individually matched for age, sex, body mass index, and meniscus injury to a low TTT value group of 47 patients. The primary outcome was the occurrence of cyclops nodule formation or cyclopoid scar formation. All 94 patients were divided into 3 groups using surgical records and intra-operative video to enable a sub-analysis. The groups were a no-cyclops group, a cyclopoid group, and a cyclops group. Blood examinations, including TTT, and knee range of motion evaluations were performed before surgery, 3 months after surgery, and 1 year after surgery. RESULTS: There were no differences in preoperative demographic data between the two groups. TTT values did not significantly influence cyclopoid scar formation (OR, 1.67; 95% CI, 0.62 to 4.66; p = 0.362). However, patients with cyclops nodule formation showed significantly higher TTT values than the control patients. (OR, 9.34; 95% CI, 1.94 to 90.3; p = 0.002). Knee extension loss was observed in the cyclopoid and cyclops groups 3 months after reconstruction. In the cyclops group, arthroscopic resection of the cyclops nodule was performed 3 months after reconstruction. Eventually, almost full range of motion was restored in all patients. CONCLUSIONS: High TTT values before ACL reconstruction were an indicator of cyclops nodule formation. Furthermore, cyclopoid scar formations may not be the result of an individual's immune reaction but that of extension loss in the early post-reconstruction phase. PMID- 30309344 TI - iDASH secure genome analysis competition 2017. PMID- 30309343 TI - Prevalence of rotavirus infection among children with acute diarrhoea after rotavirus vaccine introduction in Kenya, a hospital cross-sectional study. AB - BACKGROUND: Rotavirus infection is the most common cause of acute gastroenteritis globally in children under 5 years of age and is responsible for approximately 5% of all child deaths yearly. Rotavirus vaccination is considered an effective public health strategy to prevent infection and reduce the severity of disease. Multi-centre country trials on rotavirus vaccines demonstrated efficacy rates of more than 85% in developed countries but only about 65% in developing nations. Rotavirus vaccination was introduced into the Kenya Expanded Programme on Immunization (KEPI) in 2014. The objective of our study was to determine the prevalence of rotavirus infection, severity of acute diarrhoea and to determine the rotavirus vaccination status among children aged 3-24 months presenting with acute diarrhoea at Kenyatta National Hospital after introduction of rotavirus vaccine in Kenya. METHODS: A total of 365 children aged 3-24 months presenting with acute diarrhoea at KNH were recruited from August 2016 to April 2017. Data on rotavirus vaccination status, nutritional status, feeding practices and sociodemographic characteristics were obtained and a full clinical evaluation of the patients was done. Severity of the gastroenteritis was assessed using the 20 point Vesikari Clinical Severity Scoring System. The children who were admitted were followed up for 7 days using hospital ward registers. Comorbid conditions were established from patient's clinical records and physical examination. Stool specimens from study participants were tested for rotavirus using a commercially available enzyme linked immunosorbent immunoassay kit- ProSpecT Rotavirus Microplate Assay. RESULTS: Majority of the children (96.7%) had received rotavirus vaccinations. The overall rotavirus prevalence was 14.5% and was higher among 17-24 months at 19.5%. The prevalence somewhat differed by gender, nutritional status, exclusive breastfeeding status, age and education level of mother/caregiver. Overall, a half of the children had severe acute diarrhoea and there were some differences in severity by child/mother characteristics. CONCLUSION: There is still burden of rotavirus diarrhoea after introduction of rotavirus vaccine and the prevalence varies by child characteristics. PMID- 30309345 TI - Is stemflow a vector for the transport of small metazoans from tree surfaces down to soil? AB - BACKGROUND: Stemflow is an essential hydrologic process shaping the soil of forests by providing a concentrated input of rainwater and solutions. However, the transport of metazoans by stemflow has yet to be investigated. This 8-week study documented the organisms (< 2 mm) present in the stemflow of different tree species. Because the texture of the tree bark is a crucial determination of stemflow, trees with smooth bark (Carpinus betulus and Fagus sylvatica) and rough bark (Quercus robur) were examined. RESULTS: Up to 1170 individuals per liter of stemflow were collected. For rotifers and nematodes, a highly positive correlation between abundance and stemflow yield was determined. Both taxa were predominant (rotifers: up to 70%, nematodes: up to 13.5%) in the stemflow of smooth-barked trees whereas in that of the oak trees collembolans were the most abundant organisms (77.3%). The mean number of organisms collected per liter of stemflow from the two species of smooth-barked trees was very similar. A higher number of nematode species was found in the stemflow of these trees than in the stemflow of rough-barked oak and all were typical colonizers of soil- and bark associated habitats. CONCLUSION: This pilot study showed for the first time that stemflow is a transport vector for numerous small metazoans. By connecting tree habitats (e.g., bark, moss, lichens or water-filled tree holes) with soil, stemflow may influence the composition of soil fauna by mediating intensive organismal dispersal. PMID- 30309342 TI - Design and methodology of the screening for CKD among older patients across Europe (SCOPE) study: a multicenter cohort observational study. AB - BACKGROUND: Decline of renal function is common in older persons and the prevalence of chronic kidney disease (CKD) is rising with ageing. CKD affects different outcomes relevant to older persons, additionally to morbidity and mortality which makes CKD a relevant health burden in this population. Still, accurate laboratory measurement of kidney function is under debate, since current creatinine-based equations have a certain degree of inaccuracy when used in the older population. The aims of the study are as follows: to assess kidney function in a cohort of 75+ older persons using existing methodologies for CKD screening; to investigate existing and innovative biomarkers of CKD in this cohort, and to align laboratory and biomarker results with medical and functional data obtained from this cohort. The study was registered at ClinicalTrials.gov, identifier NCT02691546, February 25th 2016. METHODS/DESIGN: An observational, multinational, multicenter, prospective cohort study in community dwelling persons aged 75 years and over, visiting the outpatient clinics of participating institutions. The study will enroll 2450 participants and is carried out in Austria, Germany, Israel, Italy, the Netherlands, Poland and Spain. Participants will undergo clinical and laboratory evaluations at baseline and after 12 and 24 months- follow-up. Clinical evaluation also includes a comprehensive geriatric assessment (CGA). Local laboratory will be used for 'basic' parameters (including serum creatinine and albumin-to-creatinine ratio), whereas biomarker assessment will be conducted centrally. An intermediate telephone follow-up will be carried out at 6 and 18 months. DISCUSSION: Combining the use of CGA and the investigation of novel and existing independent biomarkers within the SCOPE study will help to provide evidence in the development of European guidelines and recommendations in the screening and management of CKD in older people. TRIAL REGISTRATION: This study was registered prospectively on the 25th February 2016 at clinicaltrials.gov ( NCT02691546 ). PMID- 30309347 TI - Impact of the use of local fidaxomicin treatment algorithms for managing Clostridium difficile infection in hospitalized patients in southeastern United States. AB - BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is a major public health threat that results in increased length of stay, hospital readmissions, deaths, and economic burden. CDAD treatment is often guided by severity of disease. Although various tools exist to determine CDAD severity, real-world data evaluating the use of such tools in treatment algorithms are sparse. METHODS: A local CDAD treatment pathway was developed independently to guide fidaxomicin prescribing at wellStar Health System (WellStar) and at Lee Health (LH) and Sarasota Memorial Hospital (SMH). Each algorithm was designed locally by the stewardship pharmacist and was utilized to identify patients at high risk for C. difficile recurrence. Patient and clinical data was retrospectively gathered to evaluate the utility and outcomes of the treatment pathway. RESULTS: There were 262 patients that received fidaxomicin at these three hospitals during the study time period. Only 30% at WellStar and 20% at LH or SMH met the study criteria and adhered to the pathway requirements. After completion of fidaxomicin, 30-day recurrence rates at WellStar was 0 and at LH and SMH 7%. Clinical cure rates were 83% in WellStar and 93% in LH and SMH. CONCLUSIONS: The results from these two pathways show positive outcomes for the use of fidaxomicin in patients at high risk for CDAD recurrence. This data supports the potential utility of fidaxomicin against CDAD. PMID- 30309346 TI - Improving medication adherence in stroke survivors: the intervention development process. AB - BACKGROUND: Medications targeting stroke risk factors have shown good efficacy, yet adherence is suboptimal. A lack of underlying theory may contribute to the ineffectiveness of eliciting or sustaining behaviour change in many existing interventions targeting medication adherence in stroke. Intervention effectiveness and implementation could be enhanced by consideration of evidence base and theory to drive development. The purpose of this study is to identify appropriate components for a theory-driven and evidence-based medication adherence intervention for stroke survivors. METHODS: The Behaviour Change Wheel (BCW), a guide to intervention development, informed our systematic process of intervention development. Our earlier systematic review had identified important determinants of medication adherence that were mapped into the Theoretical Domains Framework (TDF), with Knowledge, Beliefs about consequences and Emotions found to be more influential. Utilising the BCW facilitated selection of intervention options and behaviour change techniques (BCTs); the active ingredients within an intervention. To further refine BCT selection, APEASE criteria were employed, allowing evaluation of potential BCTs within context: The National Health Service (NHS), United Kingdom (UK). RESULTS: Five intervention functions (Education, Persuasion, Training, Environmental Restructuring and Enablement) and five policy categories (Communication/marketing, Guidelines, Regulation, Environmental/social planning and Service provision) were identified as potential intervention options, underpinned by our systematic review findings. Application of APEASE criteria led to an initial pool of 21 BCTs being reduced to 11 (e.g. Habit Formation, Information about Health Consequences and Action Planning) identified as potential intervention components that would both be feasible and directly target the underlying determinants of stroke survivors' medication adherence. CONCLUSIONS: Careful consideration of underlying evidence and theory to drive intervention design, facilitated by the BCW, enabled identification of appropriate intervention components. BCTs including Habit Formation, Information about Health Consequences and Self-monitoring of Behaviour were considered potentially effective and appropriate to deliver within the NHS. Having reduced the pool of potential intervention components to a manageable number, it will now be possible to explore the perceived acceptability of selected BCTs in interviews with stroke survivors and healthcare professionals. This approach to intervention development should be generalisable to other chronic conditions and areas of behaviour change (e.g. exercise adherence). PMID- 30309349 TI - Logistic regression model training based on the approximate homomorphic encryption. AB - BACKGROUND: Security concerns have been raised since big data became a prominent tool in data analysis. For instance, many machine learning algorithms aim to generate prediction models using training data which contain sensitive information about individuals. Cryptography community is considering secure computation as a solution for privacy protection. In particular, practical requirements have triggered research on the efficiency of cryptographic primitives. METHODS: This paper presents a method to train a logistic regression model without information leakage. We apply the homomorphic encryption scheme of Cheon et al. (ASIACRYPT 2017) for an efficient arithmetic over real numbers, and devise a new encoding method to reduce storage of encrypted database. In addition, we adapt Nesterov's accelerated gradient method to reduce the number of iterations as well as the computational cost while maintaining the quality of an output classifier. RESULTS: Our method shows a state-of-the-art performance of homomorphic encryption system in a real-world application. The submission based on this work was selected as the best solution of Track 3 at iDASH privacy and security competition 2017. For example, it took about six minutes to obtain a logistic regression model given the dataset consisting of 1579 samples, each of which has 18 features with a binary outcome variable. CONCLUSIONS: We present a practical solution for outsourcing analysis tools such as logistic regression analysis while preserving the data confidentiality. PMID- 30309348 TI - Occurrence and characterization of methicillin-resistant Staphylococcus pseudintermedius in successive parturitions of bitches and their puppies in two kennels in Italy. AB - BACKGROUND: Multi-drug methicillin-resistant Staphylococcus pseudintermedius (MRSP) detection is rapidly increasing in microbial specimens from pets across Europe. MRSP has also been isolated from bitches and newborns in dog breeding kennels. This study assessed whether MRSP lineage differs between breeding kennels and is maintained over time. Post-partum bitches (at day 3 vaginal and day 3, 9 and 35 milk samples) and their litters (at day 3, 9 and 35 oral and abdominal skin samples) from two Italian breeding kennels (A and B) were sampled and MRSP was subsequently characterized via whole-genome sequencing and antibiotic susceptibility testing. The study was carried out from October 2014 to March 2016 and included successive parturitions from the same animals. RESULTS: The analysis revealed different situations in both investigated kennels. In kennel A, circulating strains were from 7-locus sequence types ST688, ST258 and closely related isolates of ST71, which included most isolates. In kennel B, only a new isolate, ST772, was detected. In addition, most isolates from both kennels had multi-resistant antibiotic profiles. MRSP was only isolated from litters of MRSP-positive bitches, thus suggesting that bitch-litter transmission is likely. CONCLUSIONS: Our data show that MRSP circulation can differ in different settings, that several clonal lineages can circulate together, and that vertical transmission appears common. MRSP colonization did not affect the health conditions of the bitches or of their litters. PMID- 30309350 TI - Logistic regression over encrypted data from fully homomorphic encryption. AB - BACKGROUND: One of the tasks in the 2017 iDASH secure genome analysis competition was to enable training of logistic regression models over encrypted genomic data. More precisely, given a list of approximately 1500 patient records, each with 18 binary features containing information on specific mutations, the idea was for the data holder to encrypt the records using homomorphic encryption, and send them to an untrusted cloud for storage. The cloud could then homomorphically apply a training algorithm on the encrypted data to obtain an encrypted logistic regression model, which can be sent to the data holder for decryption. In this way, the data holder could successfully outsource the training process without revealing either her sensitive data, or the trained model, to the cloud. METHODS: Our solution to this problem has several novelties: we use a multi-bit plaintext space in fully homomorphic encryption together with fixed point number encoding; we combine bootstrapping in fully homomorphic encryption with a scaling operation in fixed point arithmetic; we use a minimax polynomial approximation to the sigmoid function and the 1-bit gradient descent method to reduce the plaintext growth in the training process. RESULTS: Our algorithm for training over encrypted data takes 0.4-3.2 hours per iteration of gradient descent. CONCLUSIONS: We demonstrate the feasibility but high computational cost of training over encrypted data. On the other hand, our method can guarantee the highest level of data privacy in critical applications. PMID- 30309351 TI - Continuous or interrupted suture technique for hepaticojejunostomy? A national survey. AB - BACKGROUND: Hepaticojejunostomy is commonly used in hepato-bilio-pancreatic surgery and a crucial step in many surgical procedures, including pancreaticoduodenectomy. The most frequently used techniques are the interrupted suture and the continuous suture technique. Currently, there is no data available in regard to the utilization of these techniques. METHODS: In total, 102 hospitals in Germany were invited between September and November 2017 to participate in this survey. Using a paper-based questionnaire, data were collected on surgical technique and complication rates of hepaticojejunostomies. RESULTS: A total of 77 of the 102 addressed hospitals (76%) participated in the survey. On average, each hospital performed 71 hepaticojejunostomies per year - most often in the context of pancreaticoduodenectomy (71%). 24 (31%) hospitals exclusively use an interrupted suture technique, 7 (9%) hospitals solely a continuous suture technique, 3 (4%) hospitals perform a combination of continuous and interrupted suture technique and 43 (56%) hospitals decide on one of both techniques depending on intraoperative findings. According to the participants in this survey, the continuous suture technique is significantly faster than the interrupted suture technique in hepaticojejunostomy (p = 0,015). There were no significant differences in the overall complication rate (p = 0,902) and insufficiency rate (p = 1,000). CONCLUSIONS: In Germany, there is a heterogeneity in the technique used to create a hepaticojejunostomy. As our survey suggests that the use of continuous suture technique may offer an advantage in time without jeopardizing patient outcomes, the different techniques should be compared in a randomized controlled study. PMID- 30309353 TI - Privacy-preserving record linkage in large databases using secure multiparty computation. AB - BACKGROUND: Practical applications for data analysis may require combining multiple databases belonging to different owners, such as health centers. The analysis should be performed without violating privacy of neither the centers themselves, nor the patients whose records these centers store. To avoid biased analysis results, it may be important to remove duplicate records among the centers, so that each patient's data would be taken into account only once. This task is very closely related to privacy-preserving record linkage. METHODS: This paper presents a solution to privacy-preserving deduplication among records of several databases using secure multiparty computation. It is build upon one of the fastest practical secure multiparty computation platforms, called Sharemind. RESULTS: The tests on ca 10 million records of simulated databases with 1000 health centers of 10000 records each show that the computation is feasible in practice. The expected running time of the experiment is ca. 30 min for computing servers connected over 100 Mbit/s WAN, the expected error of the results is 2-40, and no errors have been detected for the particular test set that we used for our benchmarks. CONCLUSIONS: The solution is ready for practical use. It has well defined security properties, implied by the properties of Sharemind platform. The solution assumes that exact matching of records is required, and a possible future research would be extending it to approximate matching. PMID- 30309352 TI - The development of a Biobank of cancer tissue samples from World Trade Center responders. AB - BACKGROUND: World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. Studies of cancer incidence in this population have reported elevated risks of cancer compared to the general population. There is a need to supplement current epidemiologic cancer follow-up with a cancer tissue bank in order to better elucidate a possible connection between each cancer and past WTC exposure. This work describes the implementation of a tissue bank system for the WTC newly diagnosed cancers, focused on advancing the understanding of the biology of these tumors. This will ultimately impact the modalities of treatment, and the probability of success and survival of these patients. METHODS: WTC Responders who participated (as employees or volunteers) in the rescue, recovery and cleanup efforts at the WTC sites have been enrolled at Mount Sinai in the World Trade Center Health Program. Responders with cancer identified and validated through linkages with New York, New Jersey, Pennsylvania, and Connecticut cancer registries were eligible to participate in this biobank. Potential participants were contacted through letters, phone calls, and emails to explain the research study, consent process, and to obtain the location where their cancer procedure was performed. Pathology departments were contacted to identify and request tissue samples. RESULTS: All the 866 solid cancer cases confirmed by the Data Center at Mount Sinai have been contacted and consent was requested for retrieval and storage of the tissue samples from their cancer. Hospitals and doctors' offices were then contacted to locate and identify the correct tissue block for each patient. The majority of these cases consist of archival paraffin blocks from surgical patients treated from 2002 to 2015. At the time of manuscript writing, this resulted in 280 cancer samples stored in the biobank. CONCLUSIONS: A biobank of cancer tissue from WTC responders has been compiled with 280 specimens in storage to date. This tissue bank represents an important resource for the scientific community allowing for high impact studies on environmental exposures and cancer etiology, cancer outcome, and gene environment interaction in the unique population of WTC responders. PMID- 30309354 TI - Identification of cell types in a mouse brain single-cell atlas using low sampling coverage. AB - BACKGROUND: High throughput methods for profiling the transcriptomes of single cells have recently emerged as transformative approaches for large-scale population surveys of cellular diversity in heterogeneous primary tissues. However, the efficient generation of such atlases will depend on sufficient sampling of diverse cell types while remaining cost-effective to enable a comprehensive examination of organs, developmental stages, and individuals. RESULTS: To examine the relationship between sampled cell numbers and transcriptional heterogeneity in the context of unbiased cell type classification, we explored the population structure of a publicly available 1.3 million cell dataset from E18.5 mouse brain and validated our findings in published data from adult mice. We propose a computational framework for inferring the saturation point of cluster discovery in a single-cell mRNA-seq experiment, centered around cluster preservation in downsampled datasets. In addition, we introduce a "complexity index," which characterizes the heterogeneity of cells in a given dataset. Using Cajal-Retzius cells as an example of a limited complexity dataset, we explored whether the detected biological distinctions relate to technical clustering. Surprisingly, we found that clustering distinctions carrying biologically interpretable meaning are achieved with far fewer cells than the originally sampled, though technical saturation of rare populations such as Cajal-Retzius cells is not achieved. We additionally validated these findings with a recently published atlas of cell types across mouse organs and again find using subsampling that a much smaller number of cells recapitulates the cluster distinctions of the complete dataset. CONCLUSIONS: Together, these findings suggest that most of the biologically interpretable cell types from the 1.3 million cell database can be recapitulated by analyzing 50,000 randomly selected cells, indicating that instead of profiling few individuals at high "cellular coverage," cell atlas studies may instead benefit from profiling more individuals, or many time points at lower cellular coverage and then further enriching for populations of interest. This strategy is ideal for scenarios where cost and time are limited, though extremely rare populations of interest (< 1%) may be identifiable only with much higher cell numbers. PMID- 30309358 TI - Gestational hormone trajectories and early pregnancy failure: a reassessment. AB - BACKGROUND: Studies have commonly assessed the endocrinolgical status of women once miscarriage is threatened or suspected; few studies have explored the antecedent hormonal environment or used a longitudinal strategy. Using refined statistical techniques, we sought to re-evaluate whether gestational hormone trajectories in early pregnancy can identify future miscarriage in asymptomatic pregnancies. METHODS: This prospective cohort study followed 105 women over conception; 72 had normal term pregnancy outcomes while 33 experienced early pregnancy failure between 35 and 115 days of gestation. Participants attended a pre-conception and antenatal clinic at Newcastle University, United Kingdom (UK). Evaluation methods included ultrasound, clinical assessments of pregnancy progress and serial measurements of gestational hormones by radioimmunoassays. Linear mixed-effects regression analysis examined hormone relationships with pregnancy outcomes. RESULTS: Detailed longitudinal illustration of gestational hormones, antecedent to miscarriage indications, revealed early pathophysiological trends. In particular, oestradiol showed as marked a deviation from normal as progesterone before miscarriage was evident, reflecting a deficiency in the ovarian response to rising human chorionic gonadotrophin (hCG) levels. Regression analysis provided equations for gestational hormone slopes that significantly differentiated asymptomatic women with subsequent early pregnancy failure, compared to women with normal term pregnancies. Both progesterone and oestradiol displayed negative mean slopes in pregnancies destined for failure; in this group, both human placental lactogen (hPL) and hCG revealed mean positive trajectories that imitated normal pregnancies but at slower rates of increase. CONCLUSIONS: Oestradiol, progesterone and hCG trajectories, from 50 days of gestation, have good potential for revealing pathophysiology and for identifying which asymptomatic pregnancies are destined for subsequent failure. In asymptomatic patients where there is concern about viability and ultrasound diagnosis is ambiguous, a combined hormonal profile could contribute to guiding patient care decisions. PMID- 30309355 TI - Effect of exosomal miRNA on cancer biology and clinical applications. AB - Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics. PMID- 30309356 TI - Surgical resection for recurrent retroperitoneal leiomyosarcoma and liposarcoma. AB - BACKGROUND: Retroperitoneal soft tissue sarcomas (STS) include a number of histologies but are rare, with approximately 3000 cases in the USA per year. Retroperitoneal STS have a high incidence of local and distant recurrence. The purpose of this study was to review the University of Maryland Medical Center's (UMMC) treatment experience of retroperitoneal STS, where the patient population served represents a diverse socioeconomic and ethnic catchment. METHODS: IRB approval was obtained. We constructed a de-identified database of patients diagnosed with retroperitoneal liposarcomas (LPS) or leiomyosarcomas (LMS) treated at UMMC between 2000 and 2013. A total of 49 patients (Pts) with retroperitoneal STS met our eligibility criteria. Kaplan-Meier plots were used to graphically portray progression-free survival (PFS) and overall survival (OS). The log-rank test was used to compare time-to-event distributions. RESULTS: The median OS for all patients (Pts) was 6.3 years, and the 2-year OS rate was 81%. The median PFS for all Pts was 1.8 years, and the 2-year PFS rate was 45%. There was no difference in OS and PFS among LMS and LPS patients; the median OS for LMS was 3.8 years vs. LPS 6.4 years (p = 0.33), and the median PFS for LMS was 1.2 years vs. LPS 2.5 years (p = 0.28). There was a significant difference between histology and race (p = 0.001). LPS were primarily Caucasian 86% vs. 14% black, whereas LMS were primarily black 52% vs. 33% Caucasian. OS was influenced by functional status, gender, American Joint Committee on Cancer (AJCC) stage, grade, histology, tumor size, and extent of resection. PFS was influenced by AJCC stage, grade, and extent of resection. Neither adjuvant chemotherapy (1 Pt) nor neoadjuvant/adjuvant radiation therapy (18 Pts) influenced OS or PFS. There was a non-significant difference that Pts who could undergo resection of local recurrence had improved 2-year OS, with 100% LMS and LPS compared to 2-year OS of 71% (LMS) and 78% (LPS) not undergoing resection of local recurrence. CONCLUSIONS: This study suggests a higher incidence of leiomyosarcoma in the African-American population. This study confirms the prognostic importance of grade, tumor size, AJCC stage, histology, and extent of resection in patient outcomes, at a large substantially diverse academic medical center. Future research into the biological features of liposarcoma and leiomyosarcoma Pts imparting these characteristics will be important to define. PMID- 30309357 TI - The prevalence of hyperuricemia and its correlates in Ganzi Tibetan Autonomous Prefecture, Sichuan Province, China. AB - BACKGROUND: Hyperuricemia is a common and serious public health problem. There has been no broad epidemiological survey of hyperuricemia in China, especially in Tibetan area. This study was therefore investigated the prevalence of hyperuricemia and its correlated factors among people aged 18-85 years in Ganzi Tibetan Autonomous Prefecture, Sichuan Province, China. METHODS: We carried out a cross-sectional study among 3093 participants in Ganzi Tibetan Autonomous Prefecture using questionnaires in face-to-face interviews, anthropometric measurements and biochemical tests. We included 1416 subjects with complete data including serum uric acid and medical history to analyze the prevalence of hyperuricemia and correlated factors. Hyperuricemia was defined as a fasting serum uric acid level higher than 420 MUmol/L in men and 360 MUmol/L in women. RESULTS: The overall crude prevalence of hyperuricemia was 37.2%, and was greater in men than women (41% vs 34.4%, P = 0.011). The age-adjusted prevalence was 33.0%. Characteristics linked to hyperuricemia were farmers-herdsmen (OR: 1.749, 95% CI: 1.022-2.992), low to moderate education level (low OR:1.57, 95% CI: 1.102 2.237; moderate OR: 1.86, 95% CI: 1.167-2.963), current drinking (OR: 1.795, 95% CI: 1.193-2.702), hypertension (OR: 1.48, 95% CI: 1.091-2.006), higher body mass index (1 unit increase) (OR: 1.116, 95% CI: 1.077-1.156) and higher serum creatinine (1 unit increase) (OR: 1.046, 95% CI: 1.034-1.059). Serum uric acid was positively related to triglycerides and total cholesterol and negatively related to high density lipoprotein cholesterol in all subjects. Hyperuricemia was a risk factor for high triglyceride ((OR: 2.13, 95% CI: 1.156-3.9266) and high total cholesterol (OR: 2.313, 95% CI: 1.364-3.923) in men and for high low density lipoprotein cholesterol (OR: 2.696, 95% CI: 1.386-5.245) in women. CONCLUSION: There is a high prevalence of hyperuricemia in Ganzi Tibetan Autonomous Prefecture. The government needs to prevent and manage hyperuricemia in this area. PMID- 30309360 TI - Correction to: The private healthcare market and the sustainability of an innovative community nurses programme based on social entrepreneurship - CoNSENSo project. AB - Following publication of the original article [1], the author reported that their first names and last names were swapped. The original article has been corrected. PMID- 30309359 TI - Proof of concept in utilizing in-trans surface display system of Lactobacillus plantarum as mucosal tuberculosis vaccine via oral administration in mice. AB - BACKGROUND: Tuberculosis is one of the most common and deadliest infectious diseases worldwide affecting almost a third of the world's population. Although this disease is being prevented and controlled by the Bacille Calmette Guerin (BCG) vaccine, the protective efficacy is highly variable and substandard (0-80%) in adults. Therefore, novel and effective tuberculosis vaccine that can overcome the limitations from BCG vaccine need to be developed. RESULTS: A novel approach of utilizing an in-trans protein surface display system of Lactobacillus plantarum carrying and displaying combination of Mycobacterium tuberculosis subunit epitope antigens (Ag85B, CFP-10, ESAT-6, Rv0475 and Rv2031c) fused with LysM anchor motif designated as ACERL was constructed, cloned and expressed in Esherichia coli Rossetta expression host. Subsequently the binding capability of ACERL to the cell wall of L. plantarum was examined via the immunofluorescence microscopy and whole cell ELISA where successful attachment and consistent stability of cell wall binding up to 4 days was determined. The immunization of the developed vaccine of L. plantarum surface displaying ACERL (Lp ACERL) via the oral route was studied in mice for its immunogenicity effects. Lp ACERL immunization was able to invoke significant immune responses that favor the Th1 type cytokine response of IFN-gamma, IL-12 and IL-2 as indicated by the outcome from the cytokine profiling of spleen, lung, gastrointestinal tract (GIT), and the re-stimulation of the splenocytes from the immunized mice. Co-administration of an adjuvant consisting of Lactococcus lactis secreting mouse IL-12 (LcIL-12) with Lp ACERL was also investigated. It was shown that the addition of LcIL-12 was able to further generate significant Th1 type cytokines immune responses, similar or better than that of Lp ACERL alone which can be observed from the cytokine profiling of the immunized mice's spleen, lung and GIT. CONCLUSIONS: This study represents a proof of concept in the development of L. plantarum as a carrier for a non-genetically modified organism (GMO) tuberculosis vaccine, which may be the strategy in the future for tuberculosis vaccine development. PMID- 30309361 TI - Secure top most significant genome variants search: iDASH 2017 competition. AB - BACKGROUND: One of the 3 tracks of iDASH Privacy & Security Workshop 2017 competition was to execute a whole genome variants search on private genomic data. Particularly, the search application was to find the top most significant SNPs (Single-Nucleotide Polymorphisms) in a database of genome records labeled with control or case. In this paper we discuss the solution submitted by our team to this competition. METHODS: Privacy and confidentiality of genome data had to be ensured using Intel SGX enclaves. The typical use-case of this application is the multi-party computation (each party possessing one or several genome records) of the SNPs which statistically differentiate control and case genome datasets. RESULTS: Our solution consists of two applications: (i) compress and encrypt genome files and (ii) perform genome processing (top most important SNPs search). We have opted for a horizontal treatment of genome records and heavily used parallel processing. Rust programming language was employed to develop both applications. CONCLUSIONS: Execution performance of the processing applications scales well and very good performance metrics are obtained. Contest organizers selected it as the best submission amongst other received competition entries and our team was awarded the first prize on this track. PMID- 30309362 TI - Aortic arch cannulation with the guidance of transesophageal echocardiography for Stanford type A aortic dissection. AB - BACKGROUND: Aortic arch cannulation for an antegrade central perfusion during the surgery for Stanford type A aortic dissection can be performed within median sternotomy. We summarize the safety and convenient profile of the central cannulation strategy using the guidance of transesophageal echocardiography (TEE) in comparison to traditional femoral cannulation strategy. METHODS: Sixty-two patients with acute Stanford type A aortic dissection underwent aortic arch surgery in our hospital. All the patients were operated by the same surgeon. Cannulation was performed in 33 patients through the aortic arch under the guidance of TEE (Group A) and in 29 patients through the femoral artery (Group F). Under moderate hypothermic circulatory arrest, the brain is continuously perfused in an anterograde manner through the brachiocephalic and left common carotid arteries. Preoperative characeristics and surgical information were collected for each patient. Additionally, 30-day mortality rate and the incidence of the temporary neurological dysfunction were recorded as the outcomes. To compare the categorical variables, we used the chi-squared test. Continuous variables were compared using the t-test. RESULTS: Preoperative characteristics were almost similar between the two groups. The mean operation time (7.33 +/- 1.14 h vs. 8.93 +/- 2.59 h, P = 0.002) and the mean cardiopulmonary bypass (CPB) time (260.97 +/- 45.14 min vs. 298.28 +/- 95.89 min, P = 0.024) were significantly shorter in Group A than those in Group F. The 30-day mortality rates were 9.09 and 27.59% in Groups A and F, respectively (P = 0.057). And the incidences of temporary neurological dysfunction were 39.39 and 65.52% in Group A and F, respectively (P = 0.040). CONCLUSIONS: Aortic arch cannulation with the guidance of TEE during the aortic arch surgery is a simple, fast, safe, and less invasive technique for establishing cardiopulmonary bypass for Stanford type A aortic dissection. PMID- 30309364 TI - Privacy-preserving logistic regression training. AB - BACKGROUND: Logistic regression is a popular technique used in machine learning to construct classification models. Since the construction of such models is based on computing with large datasets, it is an appealing idea to outsource this computation to a cloud service. The privacy-sensitive nature of the input data requires appropriate privacy preserving measures before outsourcing it. Homomorphic encryption enables one to compute on encrypted data directly, without decryption and can be used to mitigate the privacy concerns raised by using a cloud service. METHODS: In this paper, we propose an algorithm (and its implementation) to train a logistic regression model on a homomorphically encrypted dataset. The core of our algorithm consists of a new iterative method that can be seen as a simplified form of the fixed Hessian method, but with a much lower multiplicative complexity. RESULTS: We test the new method on two interesting real life applications: the first application is in medicine and constructs a model to predict the probability for a patient to have cancer, given genomic data as input; the second application is in finance and the model predicts the probability of a credit card transaction to be fraudulent. The method produces accurate results for both applications, comparable to running standard algorithms on plaintext data. CONCLUSIONS: This article introduces a new simple iterative algorithm to train a logistic regression model that is tailored to be applied on a homomorphically encrypted dataset. This algorithm can be used as a privacy-preserving technique to build a binary classification model and can be applied in a wide range of problems that can be modelled with logistic regression. Our implementation results show that our method can handle the large datasets used in logistic regression training. PMID- 30309363 TI - Regulation of the Galpha-cAMP/PKA signaling pathway in cellulose utilization of Chaetomium globosum. AB - BACKGROUND: The canonical heterotrimeric G protein-cAMP/PKA pathway regulates numerous cellular processes in filamentous fungi. Chaetomium globosum, a saprophytic fungus, is known for producing many secondary metabolites, including cytotoxic chaetoglobosin A (ChA), as well as abundant cellulase and xylanase. RESULTS: Here we report on the functional characterization of this signaling pathway in C. globosum. We blocked the pathway by knocking down the putative Galpha-encoding gene gna1 (in the pG14 mutant). This led to impaired cellulase production and significantly decreased transcription of the major cellulase and xylanase genes. Almost all the glycohydrolase family genes involved in cellulose degradation were downregulated, including the major cellulase genes, cel7a, cel6a, egl1, and egl2. Importantly, the expression of transcription factors was also found to be regulated by gna1, especially Ace1, Clr1/2 and Hap2/3/5 complex. Additionally, carbon metabolic processes including the starch and sucrose metabolism pathway were substantially diminished, as evidenced by RNA-Seq profiling and quantitative reverse transcription (qRT)-PCR. Interestingly, these defects could be restored by simultaneous knockdown of the pkaR gene encoding the regulatory subunit of cAMP-dependent PKA (in the pGP6 mutant) or supplement of the cAMP analog, 8-Br-cAMP. Moreover, the Galpha-cAMP/PKA pathway regulating cellulase production is modulated by environmental signals including carbon sources and light, in which VelB/VeA/LaeA complex and ENVOY probably work as downstream effectors. CONCLUSION: These results revealed, for the first time, the positive role of the heterotrimeric Galpha-cAMP/PKA pathway in the regulation of cellulase and xylanase utilization in C. globosum. PMID- 30309365 TI - Gold nanoparticle distribution in advanced in vitro and ex vivo human placental barrier models. AB - BACKGROUND: Gold nanoparticles (AuNPs) are promising candidates to design the next generation NP-based drug formulations specifically treating maternal, fetal or placental complications with reduced side effects. Profound knowledge on AuNP distribution and effects at the human placental barrier in dependence on the particle properties and surface modifications, however, is currently lacking. Moreover, the predictive value of human placental transfer models for NP translocation studies is not yet clearly understood, in particular with regards to differences between static and dynamic exposures. To understand if small (3-4 nm) AuNPs with different surface modifications (PEGylated versus carboxylated) are taken up and cross the human placental barrier, we performed translocation studies in a static human in vitro co-culture placenta model and the dynamic human ex vivo placental perfusion model. The samples were analysed using ICP-MS, laser ablation-ICP-MS and TEM analysis for sensitive, label-free detection of AuNPs. RESULTS: After 24 h of exposure, both AuNP types crossed the human placental barrier in vitro, although in low amounts. Even though cellular uptake was higher for carboxylated AuNPs, translocation was slightly increased for PEGylated AuNPs. After 6 h of perfusion, only PEGylated AuNPs were observed in the fetal circulation and tissue accumulation was similar for both AuNP types. While PEGylated AuNPs were highly stable in the biological media and provided consistent results among the two placenta models, carboxylated AuNPs agglomerated and adhered to the perfusion device, resulting in different cellular doses under static and dynamic exposure conditions. CONCLUSIONS: Gold nanoparticles cross the human placental barrier in limited amounts and accumulate in placental tissue, depending on their size- and/or surface modification. However, it is challenging to identify the contribution of individual characteristics since they often affect colloidal particle stability, resulting in different biological interaction in particular under static versus dynamic conditions. This study highlights that human ex vivo and in vitro placenta models can provide valuable mechanistic insights on NP uptake and translocation if accounting for NP stability and non-specific interactions with the test system. PMID- 30309366 TI - Free triiodothyronine and global registry of acute coronary events risk score on predicting long-term major adverse cardiac events in STEMI patients undergoing primary PCI. AB - BACKGROUND: The aim of this study is to investigate the combined value of fT3 and GRACE risk score for cardiovascular prognosis in ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: Three hundred and thirty eight patients with STEMI who received successful primary PCI were enrolled in our study. All patients underwent (33.5 +/- 7.1) month's follow-up. Mace was defined as cardiac death and nonfatal myocardial infarction. RESULTS: Multivariate Cox analysis showed that both fT3 (HR = 0.462, 95%CI: 0.364-0.587, P < 0.001) and GRACE score (HR = 1.011, 95%CI: 1.004-1.018, P = 0.003) were independent predictors of Mace. Similarly, fT3 (HR = 0.495, 95%CI: 0.355-0.690, P < 0.001) and GRACE score (HR = 1.022, 95%CI: 1.011 1.034, P < 0.001) were the most important independent predictors of cardiac death. Kaplan-Meier analysis revealed that those patients with low fT3 and higher GRACE score had higher rates of Mace (Log-Rank chi2 = 25.087, P < 0.001). In ROC analysis, combining fT3 and GRACE risk score had a good area under the curve (AUC) value for Mace (AUC = 0.735, 95% CI: 0.680-0.790, P < 0.001), with net reclassification index of 11.1 and 5.3%, respectively. CONCLUSION: The low fT3 level, a common phenomenon, is a strong predictor of long-term poor prognosis in STEMI patients who underwent primary PCI. The combination of GRACE score and fT3 may be a more valuable predictor of Mace as compared to each measure alone. PMID- 30309368 TI - Supporting aboriginal and Torres Strait islander cultural educators and cultural mentors in Australian general practice education. AB - BACKGROUND: Promoting cultural competence of health professionals working with Aboriginal and Torres Strait Islander communities is key to improving health outcomes. Cultural Educators and Cultural Mentors (CE/ CMs) have critical roles in Australian general practice training, yet these are not well understood. METHODS: Guided by a CE/CM Network, our research team including experienced CE/CMs, used surveys and semi-structured interviews to explore these roles and investigate best practice in employment and support. Participants sampled from stakeholders involved in general practice education across Australia included CE/CMs, Medical Educators, General Practice Supervisors and Registrars, and representatives of Regional Training Organisations, Indigenous Health Training Posts and other key organisations. We undertook thematic analysis using a framework approach, refined further in team discussions that privileged views of CE/ CM members. RESULTS: Participants comprised 95 interviewees and 55 survey respondents. We organised our findings under three overarching themes: understandings about cultural education and mentoring; employment and support of CE/CMs; and delivery and evaluation of cultural education and mentoring. Our findings supported a central role for Aboriginal and Torres Strait Islander CE/CMs in face-to-face Registrar education about culture and history and related impacts on health and healthcare. Cultural education was reported to provide base line learning as preparation for clinical practice whilst cultural mentoring was seen as longitudinal, relationship-based learning. Mentoring was particularly valued by Registrars working in Aboriginal and Torres Strait Islander communities. Challenges described with employment and support included difficulties in finding people with skills and authority to undertake this demanding work. Remuneration was problematic, particularly for CMs whose work time is difficult to quantify, and who are often employed in other roles and sometimes not paid. Other improved support recommended included appropriate employment terms and conditions, flexibility in role definitions, and professional development. Recommendations concerning implementation and evaluation included valuing of cultural education, greater provision of mentoring, partnerships with Medical Educators, and engagement of CE/CMs in rigorous evaluation and assessment processes. CONCLUSIONS: Our research highlights the importance of the unique CE/CM roles and describes challenges in sustaining them. Professional and organisational support is needed to ensure delivery of respectful and effective cultural education within general practitioner training. PMID- 30309367 TI - Visceral pain: gut microbiota, a new hope? AB - BACKGROUND: Visceral pain is a complex and heterogeneous disorder, which can range from the mild discomfort of indigestion to the agonizing pain of renal colic. Regulation of visceral pain involves the spinal cord as well as higher order brain structures. Recent findings have linked the microbiota to gastrointestinal disorders characterized by abdominal pain suggesting the ability of microbes to modulate visceral hypersensitivity and nociception to pain. MAIN BODY: In this review we describe the neuroanatomical basis of visceral pain signaling and the existing evidence of its manipulation exerted by the gut microbiota. We included an updated overview of the potential therapeutic effects of dietary intervention, specifically probiotics and prebiotics, in alleviating hypersensitivity to visceral pain stimuli. CONCLUSIONS: The gut microbiota dramatically impacts normal visceral pain sensation and affects the mechanisms mediating visceral nociception. Furthermore, manipulation of the gut microbiota using prebiotics and probiotics plays a potential role in the regulation of visceral pain disorders. PMID- 30309369 TI - Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis. AB - Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis. PMID- 30309370 TI - Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme. AB - BACKGROUND: A decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non CCALD patients identified by screening. RESULTS: It is estimated that screening 780,000 newborns annually will identify 18 (95%CI 12, 27) boys with X-ALD, of whom 10 (95% CI 6, 15) will develop CCALD. It is estimated that screening may detect 7 (95% CI 3, 12) children with other peroxisomal disorders who may also have arisen symptomatically. If results for girls are returned an additional 17 (95% CI 12, 25) cases of X-ALD will be identified. The programme is estimated to cost an additional L402,000 (95% CI L399-407,000) with savings in lifetime health, social care and education costs leading to an overall discounted cost saving of L3.04 (95% CI L5.69, L1.19) million per year. Patients with CCALD are estimated to gain 8.5 discounted QALYs each giving an overall programme benefit of 82 (95% CI 43, 139) QALYs. CONCLUSION: Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs. PMID- 30309371 TI - Hip complaints differ across age and sex: a population-based reference data for the Hip disability and Osteoarthritis Outcome Score (HOOS). AB - BACKGROUND: The Hip disability and Osteoarthritis Outcome Score (HOOS) is a self administered hip-specific questionnaire intended to evaluate symptoms and functional limitations, and it is commonly used to evaluate interventions in individuals with hip dysfunction or hip osteoarthritis. The HOOS consists of 43 questions in five subscales: Pain, Symptoms, Function in daily living, Function in sport and recreation and Hip-Related Quality of Life. This study aimed to establish population-based reference values for the HOOS and to describe the variation of hip-related symptoms in an adult population. METHODS: The HOOS questionnaire was mailed to 840 individuals aged 18-84 years randomly retrieved from a national population record for the Skane region of Southern Sweden. RESULTS: The overall response rate was 67%. Older women and men consistently reported more hip-related complaints than those younger. There were significant differences between the oldest and the youngest age groups in all five subscales in women and men. CONCLUSIONS: Hip-related pain, symptoms, activity of daily life and quality of life varied with age and sex in this population-based cohort. Our findings show the importance of using age- and sex-matched reference values for evaluation of outcomes after interventions due to hip-related problems. PMID- 30309372 TI - The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD. AB - BACKGROUND: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) and its receptors are expressed in immune cells and are involved in the neuroinflammatory response. Thus, we recently developed and synthesized a non self-polymerizing analog of DA (CA140) and examined the effect of CA140 on neuroinflammation. METHODS: To determine the effects of CA140 on the neuroinflammatory response, BV2 microglial cells were pretreated with lipopolysaccharide (LPS, 1 MUg/mL), followed by treatment with CA140 (10 MUM) and analysis by reverse transcription-polymerase chain reaction (RT-PCR). To examine whether CA140 alters the neuroinflammatory response in vivo, wild-type mice were injected with both LPS (10 mg/kg, intraperitoneally (i.p.)) and CA140 (30 mg/kg, i.p.), and immunohistochemistry was performed. In addition, familial AD (5xFAD) mice were injected with CA140 or vehicle daily for 2 weeks and examined for microglial and astrocyte activation. RESULTS: Pre- or post-treatment with CA140 differentially regulated proinflammatory responses in LPS-stimulated microglia and astrocytes. Interestingly, CA140 regulated D1R levels to alter LPS-induced proinflammatory responses. CA140 significantly downregulated LPS-induced phosphorylation of ERK and STAT3 in BV2 microglia cells. In addition, CA140 injected wild-type mice exhibited significantly decreased LPS-induced microglial and astrocyte activation. Moreover, CA140-injected 5xFAD mice exhibited significantly reduced microglial and astrocyte activation. CONCLUSIONS: CA140 may be beneficial for preventing and treating neuroinflammatory-related diseases, including AD. PMID- 30309373 TI - The effect of bystander cardiopulmonary resuscitation on the survival of out-of hospital cardiac arrests: a systematic review and meta-analysis. AB - BACKGROUND: For many years, bystander cardiopulmonary resuscitation (BCPR) has been considered as a favorable factor to improve survival of out-of-hospital cardiac arrests (OHCAs). To examine the effect of BCPR on the survival of OHCAs and whether BCPR might also improve survival when the initial rhythm of OHCAs is limited, we performed a meta-analysis on published observational studies. METHODS: We did a systematic review to identify all studies published up to March, 2018, in any language, that reported the relation between BCPR and the survival of OHCAs. Using standard forms, two authors independently identified studies for inclusion and extracted information. The outcome was survival. Meta regression was done to ascertain weighted factors for the outcomes. RESULTS: Data were extracted from 19 studies involving 232,703 patients. Firstly, pooled odds ratio (OR) from 16 cohort studies showed that BCPR was associated with improved chance of survival of OHCAs compared with NO-BCPR (OR 1.95, 95% confidence interval [CI]: 1.66-2.30). Secondly, from 8 cohort studies of OHCAs whose initial rhythm is limited, the pooled OR was 2.10 (95% CI, 1.68-2.63) of 6 articles for shockable rhythm and 1.07 (95% CI, 0.37-3.13) of 2 articles for non-shockable rhythm. Meta-regression showed a relation between the survival of OHCAs and BCPR was influenced by area (p < 0.05). CONCLUSIONS: Based on currently available evidence, the findings of this meta-analysis suggest that BCPR increases the survival of OHCAs, and it also help OHCAs whose initial rhythm is shockable. That is to say BCPR is also helpful when emergency department response time is short. Therefore global priority should be given to increasing the incidence of BCPR by evidence-based best practice. PMID- 30309374 TI - Calcium-induced chloride secretion is decreased by Resveratrol in ileal porcine tissue. AB - OBJECTIVE: Chloride (Cl-) secretion is crucial for intestinal fluid secretion. Therefore, effects of the polyphenol Resveratrol (RSV) on Cl- secretion have been investigated. In a previous study, we observed effects of RSV on forskolin induced Cl- secretion in the porcine jejunum but not the ileum although RSV itself induced a transepithelial ion current that may represent Cl- secretion in the ileum. The aim of this study was to gain further insights regarding the effects of RSV on characteristics of Cl- secretion in the porcine ileum using the Ussing chamber technique (recording of short circuit currents (Isc) as a measure for epithelial net ion transfer). RESULTS: RSV increased the Isc in the porcine ileum but not in the porcine jejunum as is already known. This increase was absent in a Cl--free buffer system, indicating that RSV indeed induces Cl- secretion. However, the carbachol-induced Isc was significantly inhibited by RSV indicating an inhibition of Ca2+-induced Cl- secretion. The cellular basis for these contradictory, segment specific results of RSV on Cl- secretion has to be subjected to further studies. The results also underline, that is difficult to generalize effects of RSV between different intestinal locations, organs, cell culture models or species. PMID- 30309376 TI - Seasonal dynamics of canine antibody response to Phlebotomus perniciosus saliva in an endemic area of Leishmania infantum. AB - BACKGROUND: Canine leishmaniosis (CanL) is an important zoonotic parasitic disease, endemic in the Mediterranean basin. In this region, transmission of Leishmania infantum, the etiological agent of CanL, is through the bite of phlebotomine sand flies. Therefore, monitoring host-vector contact represents an important epidemiological tool, and could be used to assess the effectiveness of vector-control programmes in endemic areas. Previous studies have shown that canine antibodies against the saliva of phlebotomine sand flies are specific markers of exposure to Leishmania vectors. However, this method needs to be further validated in natural heterogeneous dog populations living in CanL endemic areas. METHODS: In this study, 176 dogs living in 12 different locations of an L. infantum endemic area in north-east Spain were followed for 14 months. Blood samples were taken at 5 pre-determined time points (February, August and October 2016; January and April 2017) to assess the canine humoral immune response to whole salivary gland homogenate (SGH) and to the single salivary 43 kDa yellow related recombinant protein (rSP03B) of Phlebotomus perniciosus, a proven vector of L. infantum naturally present in this region. Simultaneously, in all dogs, L. infantum infection status was assessed by serology. The relationship between anti SGH and anti-rSP03B antibodies with the sampling month, L. infantum infection and the location was tested by fitting multilevel linear regression models. RESULTS: The dynamics of canine anti-saliva IgG for both SGH and rSP03B followed the expected trends of P. perniciosus activity in the region. Statistically significant associations were detected for both salivary antigens between vector exposure and sampling month or dog seropositivity to L. infantum. The correlation between canine antibodies against SGH and rSP03B was moderate. CONCLUSIONS: Our results confirm the frequent presence of CanL vectors in the study area in Spain and support the applicability of SGH- and rSP03B-based ELISA tests to study canine exposure to P. perniciosus in L. infantum endemic areas. PMID- 30309377 TI - Knockdown of SETDB1 inhibits breast cancer progression by miR-381-3p-related regulation. AB - BACKGROUND: SET domain bifurcated 1 (SETDB1) has been widely considered as an oncogene playing a critical role in many human cancers, including breast cancer. Nevertheless, the molecular mechanism by which SETDB1 regulates breast cancer tumorigenesis is still unknown. METHODS: qRT-PCR assay or western blot analysis was performed to assess the expression level of SETDB1 mRNA or protein, respectively. siSETDB1, pCMV6-XL5-SETDB1, miR-381-3p mimic, or miR-381-3p inhibitor was transfected into cells to regulate the expression of SETDB1 or miR 381-3p. MiRNA directly interacted with SETDB1 was verified by luciferase reporter assay and RNA immunoprecipitation. CCK-8 assay, colony formation assay, flow cytometric analysis, and transwell assay were used to detect the abilities of cell proliferation, cell cycle progression and migration, respectively. Animal model of xenograft tumor was used to observe the regulatory effect of SETDB1 on tumor growth in vivo. RESULTS: We verified that SETDB1 mRNA level was upregulated in breast cancer tissues and cell lines, and SETDB1 depletion led to a suppression of cell proliferation, cell cycle progression and migration in vitro, as well as tumor growth in vivo. SETDB1 was verified to be a target of miR-381 3p. Moreover, miR-381-3p overexpression suppressed cell proliferation, cell cycle progression and migration, whereas SETDB1 abated miR-381-3p-mediated regulatory function on breast cancer cells. CONCLUSIONS: This study revealed that SETDB1 knockdown might suppress breast cancer progression at least partly by miR-381-3p related regulation, providing a novel prospect in breast cancer therapy. PMID- 30309378 TI - Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H. AB - BACKGROUND: The typical familial form of Alzheimer's disease (FAD) accounts for about 5% of total Alzheimer's disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-beta (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases. METHODS: We describe a targeted exome sequencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology. RESULTS: We overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Abeta(1-42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression. CONCLUSIONS: These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models. PMID- 30309375 TI - Protective role of the vulture facial skin and gut microbiomes aid adaptation to scavenging. AB - BACKGROUND: Vultures have adapted the remarkable ability to feed on carcasses that may contain microorganisms that would be pathogenic to most other animals. The holobiont concept suggests that the genetic basis of such adaptation may not only lie within their genomes, but additionally in their associated microbes. To explore this, we generated shotgun DNA sequencing datasets of the facial skin and large intestine microbiomes of the black vulture (Coragyps atratus) and the turkey vulture (Cathartes aura). We characterized the functional potential and taxonomic diversity of their microbiomes, the potential pathogenic challenges confronted by vultures, and the microbial taxa and genes that could play a protective role on the facial skin and in the gut. RESULTS: We found microbial taxa and genes involved in diseases, such as dermatitis and pneumonia (more abundant on the facial skin), and gas gangrene and food poisoning (more abundant in the gut). Interestingly, we found taxa and functions with potential for playing beneficial roles, such as antilisterial bacteria in the gut, and genes for the production of antiparasitics and insecticides on the facial skin. Based on the identified phages, we suggest that phages aid in the control and possibly elimination, as in phage therapy, of microbes reported as pathogenic to a variety of species. Interestingly, we identified Adineta vaga in the gut, an invertebrate that feeds on dead bacteria and protozoans, suggesting a defensive predatory mechanism. Finally, we suggest a colonization resistance role through biofilm formation played by Fusobacteria and Clostridia in the gut. CONCLUSIONS: Our results highlight the importance of complementing genomic analyses with metagenomics in order to obtain a clearer understanding of the host-microbial alliance and show the importance of microbiome-mediated health protection for adaptation to extreme diets, such as scavenging. PMID- 30309379 TI - In-hospital mortality of patients with cardiogenic shock after acute myocardial infarction; impact of early revascularization. AB - OBJECTIVES: The purpose of this study was to determine the frequency of in hospital mortality in 351 patients who developed cardiogenic shock after acute myocardial infarction and by determining this; we might find that how efficiently we could manage this serious condition in our population by knowing the factors which are associated with high mortality after cardiogenic shock. Moreover impact of early revascularization like thrombolytic therapy or angioplasty was also evaluated. RESULTS: Mean age was 65.41 +/- 7.78 years in our study. In-hospital mortality with cardiogenic shock after acute myocardial infarction was found to be 44.73%. Significant association of in-hospital mortality was noted with age, hypertension, diabetes mellitus and BMI. Patients receiving early revascularization were noted to have lower in-hospital mortality compared to those in whom revascularization was not done due to delayed presentation. This study concluded that there is a high frequency (44.73%) of in-hospital mortality in patients with cardiogenic shock after acute myocardial in our population. So, we recommend that for achieving a good outcome and to reduce in-hospital mortality; in addition to rapid diagnosis of this condition, underlying risk factors like hypertension and diabetes should be evaluated and managed accordingly and early revascularization should be done when possible. PMID- 30309380 TI - Evidence of patients' challenges and barriers related to usage of Implanon(r): scoping review protocol. AB - BACKGROUND: According to the United Nations Trends in Contraceptive Use 2015 report, at least one in ten married or in-union women in most regions of the world has an unmet need for family planning. Family Planning 2020 reports an estimate of almost 134 million married or in-union women of reproductive age who have an unmet need for modern methods of contraception in 2016 in participating countries. Family planning has therefore been highlighted as a global unmet need. Initiatives such as Family Planning 2020 aim to promote contraceptive use through Implanon(r) contraceptive implant. Implanon(r) has been reported to be a highly effective form of contraception. However, poor outcomes from users of the Implanon(r) have been reported in recent studies. The main objective of this review is to map the literature for the evidence on usage of Implanon(r) in order to reveal challenges and barriers. METHODS AND ANALYSIS: A scoping review searching evidence on Implanon(r) use will be conducted. Relevant studies will be identified from 1998 to present. The following databases: PubMed, MEDLINE, EBSCOhost, Google Scholar and Cochrane library will be searched for peer-reviewed literature. We will also search for grey literature in this study area. The eligibility criteria will guide the study selection. A data charting table will be designed to extract information from the literature. The results of this study will be reported by use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Data will be analysed using thematic analysis and the NVIVO software version 10. The mixed method appraisal tool (MMAT) will be used to assess the quality of included studies. DISCUSSION: We anticipate finding relevant studies on the use of Implanon(r). Evidence gathered from included studies will help us identify gaps in research and help guide future research on Implanon(r) usage. This information can also help guide implementers and users on challenges and barriers related to use of Implanon(r). SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017072926 . PMID- 30309381 TI - High-flow oxygen via tracheostomy facilitates weaning from prolonged mechanical ventilation in patients with restrictive pulmonary dysfunction: two case reports. AB - BACKGROUND: Weaning from prolonged mechanical ventilation is extremely difficult in tracheostomized patients with restrictive pulmonary dysfunction. High-flow oxygen via tracheostomy supplies heated and humidified oxygen gas at > 10 L/minute. However, little has been reported on the use of high-flow oxygen via tracheostomy during weaning from ventilators in patients with restrictive pulmonary dysfunction. We report successful weaning from ventilators in patients with restrictive pulmonary dysfunction using high-flow oxygen via tracheostomy. CASE PRESENTATION: The first patient is a 78-year-old Japanese man with severe pneumococcal pneumonia who was mechanically ventilated for more than 1 month after esophagectomy for esophageal cancer. After he underwent tracheostomy because of prolonged mechanical ventilation, restrictive pulmonary dysfunction appeared: tidal volume 230-240 mL and static compliance 14-15 mL/cmH2O with 10 cmH2O pressure support ventilation. He was weaned from the ventilator under inspiratory support with high-flow oxygen via tracheostomy over a period of 16 days (flow at 40 L/minute and fraction of inspired oxygen of 0.25). The second patient is a 69-year-old Japanese man who developed aspiration pneumonia after esophagectomy and received prolonged mechanical ventilation via tracheostomy. He developed restrictive pulmonary dysfunction. High-flow oxygen via tracheostomy (flow at 40 L/minute with fraction of inspired oxygen of 0.25) was administered with measurement of the airway pressure and at the entrance of the tracheostomy tube. The measured values were as follows: 0.21-0.3 cmH2O, 0.21-0.56 cmH2O, 0.54 0.91 cmH2O, 0.76-2.01 cmH2O, 1.17-2.01 cmH2O, and 1.76-2.01 cmH2O at 10 L/minute, 20 L/minute, 30 L/minute, 40 L/minute, 50 L/minute, and 60 L/minute, respectively. The airway pressures were continuously positive and did not become negative even during inspiration, suggesting that high-flow oxygen via tracheostomy reduces inspiratory effort. He was weaned from the ventilator under inspiratory support with high-flow oxygen via tracheostomy over a period of 12 days. CONCLUSIONS: High-flow oxygen via tracheostomy may reduce the inspiratory effort and enhance tidal volume by delivering high-flow oxygen and facilitate weaning from prolonged mechanical ventilation in patients with restrictive pulmonary dysfunction. PMID- 30309382 TI - Five-year effectiveness of short messaging service (SMS) for pre-diabetes. AB - OBJECTIVE: An observational post-randomized controlled trial (RCT) design was adopted to evaluate the long-term sustainability and maintenance of improved glycemic control, lipid profile, reduced progression to diabetes at 3-year following a 2-year short messaging service (SMS). We performed a naturalistic follow-up to the 104 participants of SMS intervention, a 2-year randomized controlled trial comparing the SMS to non-SMS for pre-diabetes. All participants were arranged screening for diabetes at 5-year assessment. Primary outcome of this post-RCT study was cumulative incidence of diabetes whereas secondary outcomes were the change in biometric data over a 5-year period. RESULTS: After a mean 57-month follow-up, 19 (18.3%) were lost to follow-up after the RCT period. Progression to diabetes occurred in 20 and 16 patients among the intervention and control group respectively, with no significant between-group difference (8.06 and 7.31 cases per 100 person years, respectively; Hazard Ratio in the intervention group, 1.184; 95% confidence interval, 0.612 to 2.288; p-value = 0.616). No significant effect of SMS on reduction in diabetes was observed in overall and pre-defined subgroups. The SMS intervention preserved the clinical benefits within the trial period but failed to transform from treatment efficacy to long-term effectiveness beyond 2 years after intervention. Trail registration ClinicalTrials.gov Identifier NCT01556880, retrospectively registered on March 16, 2012. PMID- 30309383 TI - No association of TP53 codon 72 and intron 3 16-bp duplication polymorphisms with breast cancer risk in Chinese Han women: new evidence from a population-based case-control investigation. AB - BACKGROUND: Many studies have demonstrated that the genetic variants of tumor suppressor gene TP53 contribute to the prediction of breast cancer risk. However, most of them focused on Europeans and Americans; the investigations about Asians, especially Chinese women, are scarce. Thus, the aim of this study was to explore the influence of TP53 codon 72 and intron 3 16-bp duplication polymorphisms on the breast cancer risk in Chinese women, especially those from eastern China. METHODS: Blood samples collected from 254 breast cancer patients and 252 healthy female individuals were investigated. Genotypes of the two polymorphisms were determined by direct sequencing and conventional PCR, respectively. RESULTS: Heterozygous Arg/Pro and homozygous Del/Del were the most frequent genotypes of the two polymorphisms, respectively. Heterozygous Arg/Pro had a higher prevalence in breast cancer cases (Padj = 0.10; ORadj = 1.43, 95% CI 0.93-2.18), and no homozygous 16-bp duplication (Ins/Ins) genotype was found in the whole 506 clinical samples. For the distributions of allele and haplotype frequencies, no statistically significant difference was observed between the two groups when multiple (additive, dominant and recessive) genetic models were utilized in the analysis (Padj > 0.05). CONCLUSION: The results suggested that the two TP53 polymorphisms did not affect breast cancer risk in Chinese Han women, but the heterozygous Arg/Pro may exist as the possible risk genotype of the codon 72 polymorphism in contrast to the homozygous Arg/Arg and Pro/Pro. PMID- 30309384 TI - New perspectives on substituted relational autonomy for shared decision-making in critical care. AB - In critical care when unconscious patients are assisted by machines, humanity is mainly ensured by respect for autonomy, realised through advance directives or, mostly, reconstructed by cooperation with relatives. Whereas patient-centred approaches are widely discussed and fostered, managing communication in complex, especially end-of-life, situations in open intensive care units is still a point of debate and a possible source of conflict and moral distress. In particular, healthcare teams are often sceptical about the growing role of families in shared decision-making and their ability to represent patients' preferences. New perspectives on substituted relational autonomy are needed for overcoming this climate of suspicion and are discussed through recent literature in the field of medical ethics. PMID- 30309386 TI - Methylation analysis of HOXA10 regulatory elements in patients with endometriosis. AB - OBJECTIVE: The pathogenesis of endometriosis is still mysterious, being retrograde menstruation and coelomic metaplasia the most accepted hypotheses. Recently, it has been proposed that endometriosis is caused by fine-tuning alterations of the female genital system development during the foetal life and that in utero exposition to endocrine disruptors can be one of the factors causing the disease, possibly acting on the methylation status of the genome. In this study, we have evaluated the methylation status of HOXA10 gene regulation regions in a cohort of 22 endometriosis patients respect to a control group of 6 healthy women. RESULTS: The methylation study was carried out on three CpG islands, previously described hypermethylated in the endometrium of endometriosis patients and include 22 CpG sites, 21 CpG sites and 10 CpG sites, respectively identified through the online platform MethPrimer. The analysis did not find significant differences between patients with endometriosis and healthy control individuals. These results confirm previous studies on genome wide methylation analysis in endometriosis patients. Therefore, other epigenetically altered genes should be considered more related to the pathogenesis of endometriosis. PMID- 30309385 TI - Surveillance of transmitted HIV-1 antiretroviral drug resistance in the context of decentralized HIV care in Senegal and the Ebola outbreak in Guinea. AB - OBJECTIVES: Disruption in HIV care provision may enhance the development and spread of drug resistance due to inadequate antiretroviral therapy. This study thus determined the prevalence of HIV-1 transmitted drug resistance (TDR) in settings of decentralized therapy and care in Senegal and, the Ebola outbreak in Guinea. Antiretroviral-naive patients were enrolled following a modified WHO TDR Threshold Survey method, implemented in Senegal (January-March 2015) and Guinea (August-September 2015). Plasma and dried blood spots specimens, respectively from Senegalese (n = 69) and Guinean (n = 50) patients, were collected for direct sequencing of HIV-1 pol genes. The Stanford Calibrated Population Resistance program v6.0 was used for Surveillance Drug Resistance Mutations (SDRMs). RESULTS: Genotyping was successful from 54/69 (78.2%) and 31/50 (62.0%) isolates. In Senegal, TDR prevalence was 0% (mean duration since HIV diagnosis 4.08 +/- 3.53 years). In Guinea, two patients exhibited SDRMs M184V (NRTI), T215F (TAM) and, G190A (NNRTI), respectively. TDR prevalence at this second site, however, could not be ascertained because of low sample size. Phylogenetic inference confirmed CRF02_AG predominance in Senegal (62.96%) and Guinea (77.42%). TDR prevalence in Senegal remains extremely low suggesting improved control measures. Continuous surveillance in both settings is mandatory and, should be done closest to diagnosis/transmission time and with larger sample size. PMID- 30309387 TI - Tim-3 expression and its role in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, and its mortality is still on the rise. Limited treatments and low chemotherapy sensitivity of HCC make new therapeutic strategies urgently needed. With the rise of immune checkpoint blockade, anti-CTLA-4 antibodies and anti-PD-1 antibodies have shown therapeutic effects in various tumors. T cell immunoglobulin mucin-3 (Tim-3), a newly discovered immune checkpoint molecule, plays a major role in the development of HCC. Tim-3 can be used to evaluate the prognosis and therapeutic effects in HCC, and Tim-3 intervention has shown anti-tumor effects in preclinical experiments. This review summarizes findings regarding Tim-3 and HCC in recent years and discusses the rationale of Tim-3 as a therapeutic target for HCC. PMID- 30309388 TI - Schwann cell-like differentiated adipose stem cells promote neurite outgrowth via secreted exosomes and RNA transfer. AB - BACKGROUND: Adipose derived stem cells can be stimulated to produce a growth factor rich secretome which enhances axon regeneration. In this study we investigated the importance of exosomes, extracellular vesicles released by many different cell types, including stem cells and endogenous nervous system Schwann cells (SCs), on neurite outgrowth. METHODS: Adipose derived stem cells were differentiated towards a Schwann cell-like phenotype (dADSCs) by in vitro stimulation with a mix of factors (basic fibroblast growth factor, platelet derived growth factor-AA, neuregulin-1 and forskolin). Using a precipitation and low-speed centrifugation protocol the extracellular vesicles were isolated from the medium of the stem cells cultures and also from primary SCs. The conditioned media or concentrated vesicles were applied to neurons in vitro and computerised image analysis was used to assess neurite outgrowth. Total RNA was purified from the extracellular vesicles and investigated using qRT-PCR. RESULTS: Application of exosomes derived from SCs significantly enhanced in vitro neurite outgrowth and this was replicated by the exosomes from dADSCs. qRT-PCR demonstrated that the exosomes contained mRNAs and miRNAs known to play a role in nerve regeneration and these molecules were up-regulated by the Schwann cell differentiation protocol. Transfer of fluorescently tagged exosomal RNA to neurons was detected and destruction of the RNA by UV-irradiation significantly reduced the dADSCs exosome effects on neurite outgrowth. In contrast, this process had no significant effect on the SCs-derived exosomes. CONCLUSIONS: In summary, this work suggests that stem cell-derived exosomes might be a useful adjunct to other novel therapeutic interventions in nerve repair. PMID- 30309390 TI - Safety and immunogenicity of plant-produced African horse sickness virus-like particles in horses. AB - African horse sickness (AHS) is caused by multiple serotypes of the dsRNA AHSV and is a major scourge of domestic equids in Africa. While there are well established commercial live attenuated vaccines produced in South Africa, risks associated with these have encouraged attempts to develop new and safer recombinant vaccines. Previously, we reported on the immunogenicity of a plant produced AHS serotype 5 virus-like particle (VLP) vaccine, which stimulated high titres of AHS serotype 5-specific neutralizing antibodies in guinea pigs. Here, we report a similar response to the vaccine in horses. This is the first report demonstrating the safety and immunogenicity of plant-produced AHS VLPs in horses. PMID- 30309389 TI - Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study. AB - BACKGROUND: PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS: This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naive at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS: There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of > 90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. CONCLUSIONS: The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. TRIAL REGISTRATION: Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015. PMID- 30309391 TI - A comprehensive regional neurochemical theory in depression: a protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder. AB - BACKGROUND: Magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that investigates the presence and concentrations of brain metabolites. In the context of major depressive disorder (MDD), MRS has revealed regional biochemical changes in GABA, glutamate, and choline across different brain compartments. Technical and methodological advances in MRS data acquisition, in particular proton-based 1H-MRS, have resulted in a significant increase in the incidence of reports utilizing the technique for psychiatric disorder research and diagnosis. The most recent comprehensive meta-analysis reviewing MRS in MDD stems from 2006. Using contemporary systemic reviews and meta-analysis, the aim is to first test a neurochemical circuit-based theory of depression and then to determine if clinical scores relate to metabolite concentrations before and during treatment. METHODS: Region-specific metabolite changes in MDD will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria will include participant age (18 to 65), English language studies, known regions of interest, and detailed documentation of 1H-MRS procedures. Reported brain regions will be standardized according neuroanatomical expertise allowing increased power of the meta-analysis. Regions of interest will initially include the hippocampus, thalamus, prefrontal cortex, anterior and posterior cingulate gyri, parietal lobe, and basal ganglia. Exclusion criteria will include comorbid psychiatric illness and drug use. Two independent reviewers will undertake all data extraction, while a third reviewer will check for reviewer discrepancies. Statistical analysis will be performed using STATA supplemented by Metan software and SPSS. DISCUSSION: This data will shed new light on the biochemical basis of depression in different brain regions, thereby highlighting the potential of MRS in identifying biomarkers and generating models of MDD and treatment response. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091494. PMID- 30309392 TI - External validation of the Scandinavian guidelines for management of minimal, mild and moderate head injuries in children. AB - BACKGROUND: Clinical decision rules (CDRs) aid in the management of children with traumatic brain injury (TBI). Recently, the Scandinavian Neurotrauma Committee (SNC) has published practical, evidence-based guidelines for children with Glasgow Coma Scale (GCS) scores of 9-15. This study aims to validate these guidelines and to compare them with other CDRs. METHODS: A large prospective cohort of children (< 18 years) with TBI of all severities, from ten Australian and New Zealand hospitals, was used to assess the SNC guidelines. Firstly, a validation study was performed according to the inclusion and exclusion criteria of the SNC guideline. Secondly, we compared the accuracy of SNC, CATCH, CHALICE and PECARN CDRs in patients with GCS 13-15 only. Diagnostic accuracy was calculated for outcome measures of need for neurosurgery, clinically important TBI (ciTBI) and brain injury on CT. RESULTS: The SNC guideline could be applied to 19,007/20,137 of patients (94.4%) in the validation process. The frequency of ciTBI decreased significantly with stratification by decreasing risk according to the SNC guideline. Sensitivities for the detection of neurosurgery, ciTBI and brain injury on CT were 100.0% (95% CI 89.1-100.0; 32/32), 97.8% (94.5-99.4; 179/183) and 95% (95% CI 91.6-97.2; 262/276), respectively, with a CT/admission rate of 42% (mandatory CT rate of 5%, 18% CT or admission and 19% only admission). Four patients with ciTBI were missed; none needed specific intervention. In the homogenous comparison cohort of 18,913 children, the SNC guideline performed similar to the PECARN CDR, when compared with the other CDRs. CONCLUSION: The SNC guideline showed a high accuracy in a large external validation cohort and compares well with published CDRs for the management of paediatric TBI. PMID- 30309394 TI - Digital PCR detection of plasmid DNA administered to the skeletal muscle of a microminipig: a model case study for gene doping detection. AB - OBJECTIVE: Doping control is an important and indispensable aspect of fair horse racing; genetic doping has been recently included to this. In this study, we aimed to develop a detection method of gene doping. A plasmid cloned with human erythropoietin gene (p.hEPO, 250 MUg/head) was intramuscularly injected into a microminipig. Subsequently, p.hEPO was extracted from 1 mL of plasma and detected by droplet digital polymerase chain reaction. RESULTS: The results confirmed that the maximum amount of plasmid was detected at 15 min after administration and the majority of the plasmid was degraded in the bloodstream within 1-2 days after administration. In contrast, low amounts of p.hEPO were detected at 2-3 weeks after administration. These results suggest that the proposed method to detect gene doping can help obtain information for experiments using horses. PMID- 30309395 TI - Racial/ethnic disparities in cortisol diurnal patterns and affect in adolescence. AB - Racial/ethnic minorities are more vulnerable to mental and physical health problems, but we know little about the psychobiological underpinnings of these disparities. In this study, we examined racial/ethnic differences in cortisol diurnal patterns and affect as initial steps toward elucidating long-term health disparities. A racially/ethnically diverse (39.5% White, 60.5% minority) sample of 370 adolescents (57.3% female) between the ages of 11.9 and 18 years (M = 14.65 years, SD = 1.39) participated in this study. These adolescents provided 16 cortisol samples (4 samples per day across 4 days), allowing the computation of diurnal cortisol slopes, the cortisol awakening response, and diurnal cortisol output (area under the curve), as well as daily diary ratings of high-arousal and low-arousal positive and negative affect. Consistent with prior research, we found that racial/ethnic minorities (particularly African American and Latino youth) exhibited flatter diurnal cortisol slopes compared to White youth, F (1, 344.7) = 5.26, p = .02, effect size g = 0.25. Furthermore, African American and Asian American youth reported lower levels of positive affect (both high arousal and low arousal) compared to White youth. Racial/ethnic differences in affect did not explain differences in cortisol patterns, suggesting a need to refine our models of relations between affect and hypothalamic-pituitary-adrenocortical activity. We conclude by proposing that a deeper understanding of cultural development may help elucidate the complex associations between affect and hypothalamic-pituitary-adrenocortical functioning and how they explain racial/ethnic differences in both affect and stress biology. PMID- 30309396 TI - Declining hepatitis E virus antibody prevalence in Phnom Penh, Cambodia during 1996-2017. AB - Hepatitis E virus (HEV) infection is endemic in Cambodia. However, little relevant data were available and there is no clue if HEV is an emerging or decreasing pathogen in that setting. The aim of our study was to describe temporal trends of anti-HEV IgG and IgM prevalences during the last two decades (1996-2017) in the context of population growth and urbanisation in Cambodia. A total of 2004 human plasma samples collected between 1996 and 2017 were tested for anti-HEV IgG and IgM using the commercial Wantai anti-HEV assays. Overall, the prevalences of anti-HEV IgG and IgM were 41.1% and 2.7%, respectively. Analysis by calendar period showed a decreasing trend of anti-HEV IgG prevalence over the last 21 years. After age- and gender-standardisation, the anti-HEV IgG prevalence rates decreased from 61.3% during the 1996-2000 period to 32.3% during the 2016-2017 period, but no trends were observed for anti-HEV IgM rates, which fluctuated around the overall one. In conclusion, our results suggest that HEV is not an emerging pathogen, but rather seems to circulate less in Cambodia, in particular, in Phnom Penh, since the prevalence of anti-HEV IgG has been significantly decreased during the past two decades. PMID- 30309397 TI - Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model. AB - BACKGROUND: Emerging adulthood is a peak period of risk for alcohol and illicit drug use. Recent advances in psychiatric genetics suggest that the co-occurrence of substance use and psychopathology arises, in part, from a shared genetic etiology. We sought to extend this research by investigating the influence of genetic risk for schizophrenia on trajectories of four substance use behaviors as they occurred across emerging adulthood. METHOD: Young adult participants of non Hispanic European descent provided DNA samples and completed daily reports of substance use for 1 month per year across 4 years (N = 30 085 observations of N = 342 participants). A schizophrenia polygenic score was included in two-level hierarchical linear models designed to test associations between genetic risk for schizophrenia, participant age, and four substance use phenotypes. RESULTS: Participants with a greater schizophrenia polygenic score experienced greater age related increases in the likelihood of using substances across emerging adulthood (p < 0.005). Additionally, our results suggest that the polygenic score was positively associated with participants' overall likelihood to engage in illicit drug use but not alcohol-related substance use. CONCLUSIONS: This study used a novel combination of polygenic prediction and intensive longitudinal methods to characterize the influence of genetic risk for schizophrenia on patterns of age related change in substance use across emerging adulthood. Results suggest that genetic risk for schizophrenia has developmentally specific effects on substance use behaviors in a non-clinical population of young adults. PMID- 30309398 TI - Effect of graded calcium supplementation in low-nutrient density feed on tibia composition and bone turnover in meat ducks. AB - Both genetic selection and increasing nutrient density for improving growth performance had inadvertently increased leg problems of meat ducks, which adversely affects animal welfare. We hypothesised that slowing weight gain with improving tibia quality probably enhanced tibial mechanical properties and alleviated leg deformities. Therefore, the present study aimed to evaluate the effect of graded Ca supplementation in a low-nutrient density (LND) diet on tibia composition and bone turnover in meat ducks. A total of 720 15-d-old male meat ducks were randomly assigned and fed a standard nutrient density positive control (PC) diet containing 0.9 % Ca, and four LND diets with 0.5, 0.7, 0.9 and 1.1 % Ca, respectively. Ducks fed the 0.5 % Ca LND diet and the PC diet had higher incidence of tibial dyschondroplasia (TD). When compared with the 0.5 % Ca LND diet, LND diets with >=0.7 % Ca significantly improved tibia composition, microarchitecture and mechanical properties, and consequently decreased the incidence of TD. Furthermore, LND diets with >=0.7 % Ca increased osteocyte specific gene mRNA expression, blocked the expression of osteoblast differentiation marker genes including osteocalcin, collagenase-1 and alkaline phosphatase (ALP), and also decreased the expression of osteoclast differentiation genes, such as vacuolar-type H+-ATPase, cathepsin K and receptor activator of NF-kappaB. Meanwhile bone markers such as serum ALP, osteocalcin (both osteoblast markers) and tartrate-resistant acid phosphatase (an osteoclast marker) were significantly decreased in at least 0.7 % Ca treated groups. These findings indicated that LND diets with >=0.7 % Ca decreased bone turnover, which subsequently increased tibia quality for 35-d-old meat ducks. PMID- 30309399 TI - Coverage mandates and market dynamics: employer, insurer and patient responses to parity laws. AB - Parity in coverage for mental health services has been a longstanding policy aim at the state and federal levels and is a regulatory feature of the Affordable Care Act. Despite the importance and legislative effort involved in these policies, evaluations of their effects on patients yield mixed results. I leverage the Employee Retirement Income Security Act and unique claims-level data that includes information on employers' self-insurance status to shed new light in this area after the implementation of two state parity laws in 2007 and federal parity a few years later. My empirics reveal evidence of strategic avoidance on behalf of insurers in both states prior to the passage of state parity, as well as positive increases in mental health care utilization after parity laws are implemented - but context matters. Policy heterogeneity across states and strategic behaviors by employers and commercial insurers substantively shape the benefits that ultimately flow to patients. Insights from this research have broad relevance to ongoing health policy debates, particularly as states retain great discretion over many health coverage decisions and as federal policy continues to evolve. PMID- 30309400 TI - Single-centre experience in stenting arterial shunts for adult CHD patients with single-ventricle physiology and pulmonary blood flow dependent on arterial shunts. AB - OBJECTIVES: The objectives of this study were to describe the approach to stenting arterial shunts in adult congenital patients with single-ventricle physiology and to assess the medium-term clinical and haemodynamic outcomes following stent insertion. BACKGROUND: Adult patients with single-ventricle physiology and pulmonary blood flow dependent on a surgically placed arterial shunt who did not progress to venous palliation are extremely challenging to manage. Progressive cyanosis secondary to narrowing of the shunt has a marked impact on exercise tolerance and results in intolerable well-being for these patients. Stenting arterial shunts in adult patients is one method that can help improve pulmonary blood flow. There is very limited information in the literature about this patient. METHODS: This is a retrospective study for arterial shunts stenting conducted between 2008 and 2016. The peripheral oxygen saturations, the NYHA status, the haemoglobin, and the degree of atrio-ventricular valve regurgitation as assessed on transthoracic echo were compared before and 6-12 months after procedures. RESULTS: There was a short-term improvement in oxygen saturations; the pre-procedure mean was 75.8 (SD 2.55)% (range 70-85%) and post procedure mean was 83 (SD 2.52)% (range 78-87%), with a p value of 0.04. Haemoglobin level decreased from a pre-procedure mean of 22.06-20.28 g/L 6 months post procedure (range 18.1-24.4 to 13-23.3 g/L), with a p value of 0.44. NYHA class decreased from a mean of 3.2-2.2 post procedure. Left atrial volume for four of the cases did not change (22.6-76.6 ml [mean 48.4 ml] to 29.6-72.9 ml [mean 52 ml], p value: 0.83). CONCLUSIONS: Stenting stenotic arterial shunts is a useful method to gain a medium-term improvement on the oxygen saturation and clinical symptoms, and may act as a useful intermediate step for further management plans. PMID- 30309401 TI - Safety of outpatient cardiac catheterisation in infants with single-ventricle or shunt-dependent biventricular congenital heart disease. AB - OBJECTIVE: We aimed to investigate the incidence and causes of readmission of infants with single-ventricle and shunt-dependent biventricular CHD following routine, outpatient cardiac catheterisation. BACKGROUND: Cardiac catheterisation is commonly performed in patients with single-ventricle and shunt-dependent biventricular CHD for haemodynamic assessment and surgical planning. Best practices for post-procedural care in this population are unknown, and substantial variation exists between centres. Outpatient catheterisation reduces parental anxiety and decreases cost. Our institutional strategy is to discharge patients following a 4- to 6-hour post-procedure observation period. METHODS: Retrospective cohort study using the Society of Thoracic Surgeons Database identified patients 23 hours. There were no differences in baseline characteristics between discharged and admitted patients. Patients who underwent intervention were more likely to be admitted. Patients with hypoplastic left heart syndrome did not have major adverse events or readmissions. No intra- or peri-procedural deaths occurred. CONCLUSIONS: Outpatient cardiac catheterisation may be a safe option for infants with single-ventricle and shunt-dependent biventricular CHD, with low readmission rates and minimal morbidity. PMID- 30309402 TI - Factors influencing satisfaction with oral contraceptive pills and injectables among past users in Kenya. AB - This study examines factors associated with satisfaction with oral pills and injectables among past users in Kenya based on a baseline survey for the 2-year prospective longitudinal study Improving Measurement of Unintended Pregnancy and Unmet Need for Family Planning conducted in 2016. Married women aged 15-39 years were interviewed using a structured questionnaire that captured information on reproduction, contraceptive knowledge and beliefs and attitudes towards contraception in general and towards specific methods. A multivariate logistic regression analysis was used to examine factors that influenced satisfaction with oral pills and injectables among past users in one urban site (Nairobi slums) and one predominantly rural site (Homa Bay in western Kenya). Results showed that dissatisfaction with pills and injectables is common among past users in both rural and urban Kenya (ranging from 39% to 56%). The distinctive contribution of the study lies in its ability to relate method-specific beliefs to overall satisfaction. Perception of effectiveness, ease of use and safety for long-term use had statistically significant influences on satisfaction with pills in both urban and rural sites while partner's approval was only important in Nairobi. For injectables, the perception of safety for long-term use was significant in the urban but not the rural site. Unlike pills, the belief that members of a woman's social network had used a method and found it satisfactory was a particularly powerful influence on satisfaction (AOR=2.8 in rural and 3.2 in urban). Perception of accessibility and fears about infertility were not found to be statistically associated with satisfaction for either pills or injectables. Surprisingly, the effects of all perceived contraceptive attributes were the same for major socio-demographic strata of the populations. The findings underscore the need for targeted counselling and community-based communication interventions to address negative and erroneous perceptions about family planning methods. PMID- 30309403 TI - Layer pullet preferences for light colors of light-emitting diodes. AB - Light colors may affect poultry behaviors, well-being and performance. However, preferences of layer pullets for light colors are not fully understood. This study was conducted to investigate the pullet preferences for four light-emitting diode colors, including white, red, green and blue, in a lighting preference test system. The system contained four identical compartments each provided with a respective light color. The pullets were able to move freely between the adjacent compartments. A total of three groups of 20 Chinese domestic Jingfen layer pullets (54 to 82 days of age) were used for the test. Pullet behaviors were continuously recorded and summarized for each light color/compartment into daily time spent (DTS), daily percentage of time spent (DPTS), daily times of visit (DTV), duration per visit, daily feed intake (DFI), daily feeding time (DFT), feeding rate (FR), distribution of pullet occupancy and hourly time spent. The results showed that the DTS (h/pullet.per day) were 3.9+/-0.4 under white, 1.4+/ 0.3 under red, 2.2+/-0.3 under green and 4.5+/-0.4 under blue light, respectively. The DTS corresponded to 11.7% to 37.6% DPTS in 12-h lighting periods. The DTV (times/pullet.per day) were 84+/-5 under white, 48+/-10 under red, 88+/-10 under green and 94+/-8 under blue light. Each visit lasted 1.5 to 3.2 min. The DFI (g/pullet.per day) were 27.6+/-1.7 under white, 7.1+/-1.6 under red, 15.1+/-1.1 under green and 23.1+/-2.0 under blue light. The DFT was 0.18 to 0.65 h/pullet.per day and the FR was 0.57 to 0.75 g/min. For most of the time during the lighting periods, six to 10 birds stayed under white, and one to five birds stayed under red, green and blue light. Pullets preferred to stay under blue light when the light was on and under white light 4 h before the light off. Overall, pullets preferred blue light the most and red light the least. These findings substantiate the preferences of layer pullets for light colors, providing insights for use in the management of light-emitting diode colors to meet pullet needs. PMID- 30309404 TI - Changes in fatty acid profile of Bovec sheep milk due to different pasture altitude. AB - Sheep rearing on mountain pastures is an ancestral tradition in northwestern Slovenia. The indigenous Bovec sheep are widespread there and are well adapted to the rough Alpine rearing conditions. Every year, after weaning, the sheep start grazing in the lowlands (L) and then gradually move to mountain pastures, and finally, to the highland (H) pastures of the Alps. Grazing positively affects the fatty acid (FA) composition in sheep milk fat with increased availability of polyunsaturated FA (PUFA) in grass, and subsequently, in milk. Consequently, the objective of this work was to study the FA profile in sheep milk during grazing in four geographical areas in the Alps. A total of 15 ewes of the Bovec sheep breed were randomly selected and milk samples from these ewes were taken at four different pasture locations that differed with regard to altitude: the L pasture location at an altitude of 480 m, the mountain pastures (M1 and M2) at altitudes of 1100 to 1300 m and 1600 to 1900 m, respectively, and the H pastures at altitudes of 2100 to 2200 m. Milk samples from the ewes were taken during the grazing season from April to September. The chemical and FA composition of the milk samples from each pasture location were determined. There were significant differences in the concentrations of FA among the L, M1, M2 and H milk samples. We observed decreases of the concentrations of saturated FA (SFA) in milk from L to H pastures. The concentration of alpha-linolenic FA, monounsaturated FA (MUFA), PUFA and n-3 PUFA in milk were increased significantly with pasture altitude. The n-6/n-3 PUFA ratio was reduced by the change of pasture altitude with the lowest value at the M1 pasture (1.5). The concentrations of total SFA decreased significantly and was lowest at the L pasture. Our results underline the importance of the effect of grazing in the Alpine region associated with pasture altitude on the FA profile of sheep milk. The first variation in FA concentration in sheep milk occurred between L and M1, although it was more evident on H pastures in the Alpine mountains. Changes of the FA profile in sheep milk due to pasture altitude were related to variation in FA concentration in the pasture and the botanical composition of the pasture location. PMID- 30309405 TI - [Expert consensus statement on standardized diagnosis and treatment of wasp sting in China]. AB - OBJECTIVE: To improve the diagnosis and treatment of wasp sting, summarize the experience, the experts from Chinese Society of Toxicology Poisoning and Treatment of Specialized Committee, Hubei Emergency Medicine Committee of Chinese Medical Association and Hubei Provincial Poisoning and Occupational Disease Union made the Expert consensus statement on standardized diagnosis and treatment of wasp stings in China on the development of domestic and oversea in this field. The consensus statement emphasized the idea of staged treatment, different treatments at different stages, and strived to achieve bundling and individuation. To achieve the four pairs of different concept as earlier as possible, the "two early" (early assessment and early treatment), the "two anti" (anti-anaphylaxis and anti-shock), namely the "two hormone" (adrenaline and glucocorticoid) and the "two hua" (hydration and alkalization), we could avoid or reduce subsequent organ failures, significantly shorten the course and improve prognosis of wasp sting victims. PMID- 30309393 TI - Sepsis-related deaths in the at-risk population on the wards: attributable fraction of mortality in a large point-prevalence study. AB - OBJECTIVE: Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. RESULTS: 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score >= 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%). PMID- 30309406 TI - [Effect of different crystalloids on internal environment in patients with septic shock receiving early fluid resuscitation: a prospective randomized controlled trial]. AB - OBJECTIVE: To compare the effect of 0.9% NaCl solution, Ringer solution, and acetate sodium potassium magnesium calcium glucose solution (ASPMCG solution) on internal environment in patients with septic shock receiving early fluid resuscitation. METHODS: A prospective randomized controlled trial was conducted. From June 2016 to January 2018, a total of 280 patients with septic shock admitted to intensive care unit (ICU) of Northern Jiangsu People's Hospital were enrolled. All eligible patients were randomly divided into 0.9% NaCl solution group (group N), Ringer solution group (group L) and ASPMCG solution group (group P) with random number table. In all patients, catheters were placed in the right internal jugular vein or subclavian vein and were infused with 30 mL/kg of corresponding crystalloid within 3 hours after admission. According to fluid responsiveness, the rehydration rate and fluid volume were determined by the researcher within 6 hours. Other treatments were based on the 2012 Surviving Sepsis Campaign (SSC) guidelines during the study. In this study, 6-hour or 24 hour fluid volume and 7-day exogenous insulin use were recorded. The changes in arterial blood pH, base excess (BE), blood glucose (Glu), lactic acid (Lac), and serum Na+, K+, Cl-, Ca2+ were observed at 0, 3, 6, 24 hours, and 3 days and 7 days of resuscitation. RESULTS: In this study, a total of 1 082 patients were admitted to the ICU, and patients who did not meet the diagnostic criteria for septic shock, death or discharge within 24 hours of ICU admission were excluded. Finally, 280 patients with septic shock were enrolled in the analysis, with 94 patients in group N, 94 patients in group L and 92 patients in group P. There was no significant difference in the amount of crystalloid, colloidal fluid, total fluid within 6 hours or 24 hours or exogenous insulin dose within 7 days among the three groups. After fluid resuscitation, blood Cl- concentration in the three groups was increased in different degrees, peaked at 24 hours, but it in group N was significantly higher than that in group L and group P (mmol/L: 107.5+/-5.6 vs. 106.1+/-4.8, 105.1+/-4.2, both P < 0.05). Moreover, blood Ca2+ concentration also showed an increased tendency, it was significantly lower at 3 hours and 6 hours in group N than that in group L and group P (mmol/L: 1.10+/-0.08 vs. 1.15+/ 0.09, 1.12+/-0.10 at 3 hours, 1.12+/-0.10 vs. 1.16+/-0.08, 1.15+/-0.09 at 6 hours, all P < 0.05). There was no significant difference in blood Cl- or Ca2+ between groups L and P (both P > 0.05). Arterial blood pH, BE, Glu, Lac, Na+, or K+ at each time point during fluid resuscitation also showed no difference among the three groups. CONCLUSIONS: Among patients with septic shock receiving early fluid resuscitation, compared with Ringer solution and ASPMCG solution, 0.9% NaCl solution may cause hyperchloremia and hypocalcemia, but has no significant effect on acid-base balance. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IOR-16009176. PMID- 30309407 TI - [Role of HMGB1-RAGE/TLRs-NF-kappaB signaling pathway on bone mesenchymal stem cells transplantation therapy for lipopolysaccaride-induced coagulation disorder rats]. AB - OBJECTIVE: To determine the effect of bone mesenchymal stem cells (BMSCs) in transplantation therapy for lipopolysaccharide (LPS)-induced coagulation disorder and the underlying mechanism of high mobility group protein B1-receptors for advanced glycation end products/Toll-like receptors-nuclear factor-kappaB (HMGB1 RAGE/TLRs-NF-kappaB) signaling pathway. METHODS: BMSCs of female Sprague-Dawley (SD) rats ageing 4-5 weeks old were extracted and cultivated in vitro, and the fourth-passaged BMSCs phenotype was identified by flow cytometry for transplantation in the following experimental study. The rats were randomly divided into normal saline (NS) control group, LPS group, and BMSC group according to the random number table with 15 rats in each group. Coagulation disorders model was reproduced by injection of 1 mg/kg LPS via saphenous vein, and the rats in the NS control group was injected with equal volume NS. Those in the BMSC group were infused BMSC 0.5 mL containing 1*106 cells via tail vein at 2 hours after LPS injection, and the rats in other groups were injected with equal volume NS. Abdominal aorta blood was collected at 1, 3 and 7 days post operation. Coagulation indexes such as platelet count (PLT), platelet volume distribution width (PDW), mean platelet volume (MPV), plateletcrit (PCT), platelet large cell ratio (P-LCR), activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), and fibrinogen (FIB) were determined. The mRNA levels and contents of HMGB1, RAGE, TLR2/4 and NF kappaB were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: (1) The cells cultured in vitro were spindle shaped or flat. The fourth passaged BMSCs phenotype was successfully identified by flow cytometry technology. (2) Coagulation indexes: compared with NS control group, PLT, PCT and FIB in LPS group were significantly decreased, PDW, MPV, P-LCP, and INR were significantly increased, and APTT, PT, and TT were significantly prolonged from the first day. Furthermore, those in LPS group were gradually ameliorated with prolongation of LPS induction time. The coagulation function abnormality induced by LPS was reversed by BMSCs with significant difference at 1 day as compared with LPS group [PLT (*109/L): 398.8+/-17.9 vs. 239.1+/-15.8, PCT (%): 0.35+/-0.04 vs. 0.23+/-0.06, FIB (g/L): 1.7+/-0.6 vs. 0.8+/-0.1, PDW (%): 12.4+/-1.6 vs. 16.2+/-1.5, MPV (fl): 11.0+/-1.6 vs. 13.7+/-1.1, P-LCP (%): 13.0+/-2.1 vs. 15.3+/ 2.7, INR: 1.52+/-0.17 vs. 1.82+/-0.19, APTT (s): 66.3+/-4.1 vs. 89.5+/-4.5, PT (s): 18.3+/-0.7 vs. 25.1+/-1.9, TT (s): 87.5+/-7.8 vs. 115.0+/-9.7, all P < 0.05], till 7 days. (3) HMGB1-RAGE/TLRs-NF-kappaB signaling pathway related molecules: compared with NS control group, the mRNA expressions and contents of HMGB1, RAGE, TLR2/4 and NF-kappaB were significantly increased in LPS group from the first day. However, the mRNA expressions and contents of the molecules in LPS group were gradually decreased with prolongation of LPS induction time. After BMSC intervention, the mRNA expressions and contents of molecules at 1 day were significantly lower than those of LPS group [HMGB1 mRNA (2-DeltaDeltaCt): 10.77+/ 0.04 vs. 24.51+/-3.69, HMGB1 content (MUg/L): 0.48+/-0.01 vs. 0.95+/-0.06; RAGE mRNA (2-DeltaDeltaCt): 11.57+/-1.11 vs. 18.08+/-0.29, RAGE content (MUg/L): 0.73+/-0.04 vs. 1.37+/-0.06; TLR2 mRNA (2-DeltaDeltaCt): 2.60+/-0.22 vs. 12.61+/ 0.27, TLR2 content (MUg/L): 0.81+/-0.03 vs. 1.59+/-0.09; TLR4 mRNA (2 DeltaDeltaCt): 2.95+/-0.52 vs. 4.06+/-0.11, TLR4 content (MUg/L): 0.80+/-0.09 vs. 1.18+/-0.11; NF-kappaB mRNA (2-DeltaDeltaCt): 1.29+/-0.06 vs. 7.79+/-0.25, NF kappaB content (MUg/L): 1.22+/-0.24 vs. 2.42+/-0.26, all P < 0.05], till 7 days. CONCLUSIONS: BMSCs administration could ameliorate the coagulation function in LPS-induced coagulation disorder rats and these might be associated with HMGB1 RAGE/TLRs-NF-kappaB signaling pathway inhibition. PMID- 30309408 TI - [Effect of Galectin-9/Tim-3 pathway on the polarization of M1/M2 subtype in murine macrophages induced by lipopolysaccharide]. AB - OBJECTIVE: To investigate the meaning and molecular mechanisms of Galectin-9/T cell immunoglobulin mucin-3 (Tim-3) pathway on lipopolysaccharide (LPS) induced murine macrophage M1/M2 subtype polarization. METHODS: The murine peritoneal macrophages RAW264.7 were cultured in vitro until the cells had matured with 80% 90% fusion rate. (1) The cells were cultured in serum-free medium and treated with 0 (blank control), 0.01, 0.1, 1, 10 and 100 mg/L LPS for 24 hours. Real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT qPCR) or Western Blot was used to determine the expressions of M1 macrophage markers such as interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and M2 macrophage markers such as arginase-1 (Arg-1), leukocyte differentiation antigen 206 (CD206), as well as Tim-3 and Galectin-9 in the cells. (2) The other mice peritoneal macrophages were divided into blank control group (cultured in serum-free DMEM medium for 24 hours), LPS treatment group (cultured in serum-free DMEM medium containing 0.1 mg/L LPS for 24 hours) and alpha-lactose pretreatment group (pretreated with serum-free DMEM containing 40 MUmol/L Galectin-9 signal antagonist 1 hour before LPS stimulation). Over closed Galectin-9 signal was used to verify the role of Galectin-9 in macrophage M1/M2 subtype polarization. RESULTS: (1) After stimulation with low concentrations of LPS (0.01 mg/L, 0.1 mg/L) for 24 hours, the expression of M1 markers was only slightly increased such as iNOS mRNA or not significantly changed such as IL-6 mRNA in macrophages, while the expressions of M2 markers such as Arg-1 mRNA and CD206 mRNA were significantly increased and peaked at LPS concentrations of 0.1 mg/L and 0.01 mg/L [compared with blank control group: Arg-1 mRNA (2-DeltaDeltaCt) was 1.85+/ 0.07 vs. 1.00+/-0.02, CD206 mRNA (2-DeltaDeltaCt) was 2.03+/-0.11 vs.1.00+/-0.05, both P < 0.01]. With the increase of LPS concentration, the expressions of IL-6 mRNA and iNOS mRNA continued to increase, while the expressions of Arg-1 mRNA and CD206 mRNA were gradually decreased, and the macrophage M1/M2 subtype polarization status changed. At the same time, the level of Tim-3 protein in macrophages was significantly up-regulated after stimulation with 0.01 mg/L LPS as compared with that of blank control group (Tim-3/GAPDH: 0.84+/-0.04 vs. 0.69+/ 0.02, P < 0.01), peaked at LPS concentrations of 0.1 mg/L, and then decreased with increasing LPS concentration. The intracellular Galectin-9 and supernatant secreted Galectin-9 (s-Galectin-9) protein levels showed no significant change after stimulation with low concentrations of LPS (0.01 mg/L, 0.1 mg/L), while then gradually decreased with the increase of LPS concentration. (2) Compared with blank control group, the mRNA expressions of M1 marker iNOS and M2 markers Arg-1 and CD206 were significantly increased in LPS treatment group, but IL-6 mRNA level was not changed significantly. The mRNA levels of IL-6 and iNOS were further elevated after pretreatment with alpha-lactose as compared with that of the LPS treatment group [IL-6 mRNA (2-DeltaDeltaCt): 1.44+/-0.02 vs. 1.14+/-0.11, iNOS mRNA (2-DeltaDeltaCt): 2.45+/-0.04 vs. 2.01+/-0.08, both P < 0.01], while the mRNA levels of Arg-1 and CD206 were significantly decreased [Arg-1 mRNA (2 DeltaDeltaCt): 0.75+/-0.01 vs. 1.85+/-0.02, CD206 mRNA (2-DeltaDeltaCt): 0.58+/ 0.02 vs. 2.03+/-0.14, both P < 0.01]. Meanwhile, the blocking of Galectin-9 signaling could also reduce the extracellular s-Galectin-9 (compared with LPS treatment group: s-Galectin-9/GAPDH was 0.10+/-0.01 vs. 0.23+/-0.02, P < 0.01), down-regulated the expressions of Tim-3 and Galectin-9 (Tim-3/GAPDH: 0.28+/-0.01 vs. 0.43+/-0.01, Galectin-9/GAPDH: 0.21+/-0.01 vs. 0.43+/-0.01, both P < 0.01). CONCLUSIONS: LPS regulates macrophage M1/M2 subtype polarization via Galectin 9/Tim-3 signaling pathway. Low-doses of LPS can limit the development of inflammation by accommodating the expression and secretion of Galectin-9 to polarize macrophages to M2. High-doses of LPS promotes the development of inflammation by down-regulating the expression and secretion of Galectin-9 to polarize macrophages to M1. PMID- 30309409 TI - [Effect of left ventricular global longitudinal strain on prognosis of septic/septic shock patients: a Meta analysis]. AB - OBJECTIVE: To systematically evaluate the effects of left ventricular global longitudinal strain (GLS) determined by two dimensional speckle tracking imaging technology (2D-STI) and left ventricular ejection fraction (LVEF) on the prognosis of patients with sepsis/septic shock. METHODS: Databases such as the National Library of Medicine PubMed database, Dutch medical abstracts Embase, Cochrane Library, Netherlands Elsevier, Springer and China biomedical literature database (CBMdisc), China National Knowledge Internet (CNKI), Wanfang database, China science and technology journal full-text database, Vip Chinese biomedical journal database were searched from the establishment of literature database to April 2018 to study GLS, LVEF and their relationships with mortality of septic/septic shock patients. The literatures screening and data collecting were independently conducted by two researchers, and the quality of the included literature was evaluated. The sensitivity and heterogeneity analysis were performed with RevMan 5.3 software, and the combined effects were calculated. Funnel plot was used to evaluate publication bias. RESULTS: A total of 6 articles including 5 English articles and 1 Chinese article were enrolled. There were 503 patients, 333 in the survival group and 170 in the death group. The quality of the literature was high, and the Newcastle-Ottawa scale (NOS) score was 8-9. Meta analysis showed that short-term mortality was associated with higher GLS in patients with sepsis/septic shock [standardized mean difference (SMD) = -0.47, 95% confidence interval (95%CI) = -0.76 to -0.18, Z = 3.16, P = 0.002], and there was no significant difference in LVEF between the survival group and the death group (SMD = 0.18, 95%CI = -0.03-0.39, Z = 1.64, P = 0.10). Sensitivity analysis was carried out for each effect index by removing each document one by one, and the results showed that there was no significant change in the combined effect before and after each document, indicating that the results were stable. The funnel plot showed that the effect points of each literature were roughly in the form of "inverted funnels" with a large symmetric distribution centered on the combined effect, but the number of studies included in this study was too small, so the publication bias could not be completely excluded. CONCLUSIONS: Compared with LVEF, GLS might be a more sensitive indicator for detecting myocardial dysfunction in patients with sepsis/septic shock and might have important predictive value for short-term mortality. PMID- 30309410 TI - [Effectiveness of Xuebijing in treatment of multiple organ dysfunction syndrome: a Meta analysis]. AB - OBJECTIVE: To systematical evaluate the effect of Xuebijing injection in the treatment of multiple organ dysfunction syndrome (MODS). METHODS: With the keywords including Xuebijing, multiple organ dysfunction syndrome, multiple organ dysfunction and multiple organ failure, PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), VIP and Wanfang Data from the database start until March 4th, 2018 were searched for relevant randomized controlled trials (RCTs) related to Xuebijing injection combined conventional treatment versus conventional treatment alone for MODS. The control group received conventional western medicine treatment, including etiological treatment, antibiotics, mechanical ventilation, nutritional support, and comprehensive treatment to maintain fluid, electrolyte, acid and alkali balance. The experimental group was given traditional western medicine combined with Xuebijing injection. The observation parameters included 7-day and 28-day mortality, acute physiology and chronic health evaluation II (APACHE II) and Marshall score, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), the number of platelets, activated partial thromboplastin time (APTT) and prothrombin time (PT). According to the inclusion and exclusion criteria, two evaluators independently screened the literature, extracted data and evaluated the methodological quality of the included studies. RevMan 5.3 software was used for Meta analysis. Funnel plot was used to analyze publication bias. RESULTS: A total of 35 RCTs and 2 131 patients were enrolled, including 1 076 in the experimental group and 1 055 in the control group. The results of Meta analysis showed that compared with control group, Xuebijing combined conventional treatment was in favor to decrease the mortality of patients with MODS [7-day mortality: odds ratio (OR) = 0.42, 99% confidence interval (99%CI) = 0.26-0.69, P < 0.000 01; 28-day mortality: OR = 0.31, 99%CI = 0.21-0.45, P < 0.000 01], also could obviously reduce critical condition degree of APACHE II score and the organ function of Marshall score [APACHE II: mean difference (MD) = 3.24, 99%CI = 2.00 4.49, P < 0.000 01; Marshall score: MD = 1.95, 99%CI = 0.50-3.40, P = 0.000 5]. Meanwhile, the results of conventional western medicine combined with Xuebijing in the removal of IL-6 and TNF-alpha, platelets increase and improvement of PT were better than those of conventional western medicine (IL-6: MD = 5.56, 99%CI = 1.44-9.68, P = 0.000 5; TNF-alpha: MD = 4.97, 99%CI = 3.44-6.50, P < 0.000 01; platelets: MD = -50.79, 99%CI = -74.84 to -26.74, P < 0.000 1; PT: MD = 4.55, 99%CI = 3.96-5.14, P < 0.000 01), however, there was no obvious advantage in improving APTT (MD = 0.96, 99%CI = -5.08-7.00, P = 0.68). The analysis of funnel map showed that the effect points of various studies were mainly centered on the amount of combined effect, and the "inverted funnel" type was generally symmetrical distribution. However, because the number of the included studies was less, the literature bias could not be completely eliminated. CONCLUSIONS: Xuebijing injection may through its strong cytokines clearance, platelet increase and blood coagulation improvement to protect the organ function in patients with MODS, so as to reduce the mortality and improve the prognosis. PMID- 30309411 TI - [Effect of caveolin-1 scaffolding domain peptides on heme oxygenase-1 activity increasing and M1/M2 phenotype polarization in rat alveolar macrophages induced by lipopolysaccharide]. AB - OBJECTIVE: To investigate the effect of caveolin-1 scaffolding domain (CSD) peptides on heme oxygenase-1 (HO-1) activity increasing and M1/M2 phenotype polarization in rat alveolar macrophages (AMs) induced by lipopolysaccharide (LPS). METHODS: Bioinformatics was used to analyze the binding of full-length wild-type CSD polypeptide and 101 amino acid deleted truncated mutant CSD polypeptide (Delta101CSD) to HO-1. Primary AMs were isolated from rats, when cell fusion reached 80%, they were synchronized with serum-free medium and divided into five groups: no treatment was given to the blank control group; LPS group was treated with 100 MUg/L LPS for 16 hours; LPS + hemin group was treated with 100 MUg/L LPS and 20 MUmol/L hemin for 16 hours; wild-type CSD polypeptide + LPS + hemin group was pretreated with 10 MUmol/L wild-type CSD polypeptide 6 hours before LPS treatment; Delta101CSD + LPS + hemin group was pretreated with 10 MUmol/L Delta101CSD polypeptide 6 hours before LPS treatment. After treatment for 16 hours, the co-localization between caveolin-1 (Cav-1) and HO-1 was displayed by confocal microscope; the mRNA expressions of inflammatory cytokines interleukin-1beta (IL-1beta) and monocyte chemoattractant protein-1 (MCP-1) and M1/M2 polarization cytokines tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), leukocyte differentiation antigen 206 (CD206) and IL-10 were determined by real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-qPCR); the HO-1 activity and nitric oxide (NO) production were determined by spectrophotometry. RESULTS: Bioinformatics analysis showed: both wild-type CSD and Delta101CSD peptides could bind to HO-1, and there was no significant difference in the binding ability between the two peptides, but the deletion of 101 Arg resulted in the disappearance of part of the binding region between Delta101CSD and HO-1. The results of laser confocal microscopy showed: the expressions of Cav-1 and HO-1 were lowed in the blank control group, and Cav-1 was bound to HO-1 in LPS group and LPS + hemin group. Both wild-type CSD and Delta101CSD peptides pretreatment could significantly reduce the binding of HO-1 to Cav-1 induced by LPS. HO-1 activity analysis showed: after LPS stimulation, the activity of HO-1 was significantly higher than that of the blank control group; the activity of HO-1 induced by LPS was increased by hemin; after pretreatment with two kinds of CSD peptides, the activity of HO-1 was further increased, and the effect of wild-type CSD peptide was more significant, which showed a statistically significant difference as compared with that of LPS + hemin group (pmol*mg-1*h-1: 3 683+/-266 vs. 2 408+/-132, P < 0.05). RT-qPCR results showed: LPS could induce elevation of cytokines and M1 markers and decrease of M2 markers, while hemin could inhibit LPS-induced inflammatory response and M1/M2 phenotypic polarization. Compared with LPS + hemin group, after pretreatment with wild-type CSD peptide, the levels of inflammatory factors in AMs were decreased, and the mRNA expression levels of TNF-alpha and iNOS, M1 markers, were decreased [TNF-alpha mRNA (2-DeltaDeltaCt): 6.82+/-0.05 vs. 8.70+/ 0.24, iNOS mRNA (2-DeltaDeltaCt): 331.50+/-32.05 vs. 506.70+/-0.10, both P < 0.05], and IL-10 mRNA expression level was increased (2-DeltaDeltaCt: 269.09+/ 6.54 vs. 119.05+/-3.30, P < 0.05). The deletion of 101 site partially weakened the inhibitory effect of CSD peptides on inflammatory factors and only reduced the expression of iNOS mRNA (2-DeltaDeltaCt: 429.11+/-8.92 vs. 506.70+/-0.10, P < 0.05), indicating that its ability to transform AMs from M1 phenotype to M2 phenotype was poor. The two peptides had no effect on the expression of CD206. CONCLUSIONS: Wild-type CSD had beneficial effects of anti-inflammation by reducing Cav-1 binding to HO-1 induced by LPS, restoring the HO-1 activity and driving M2 phenotype in alveolar macrophages. PMID- 30309412 TI - [An experiment on the pathogenesis of early biotrauma in ventilator-induced lung injury]. AB - OBJECTIVE: To investigate the pathogenesis of early biotrauma in ventilator induced lung injury (VILI). METHODS: Twenty-four 8-week-old male specific pathogen-free Sprague-Dawley (SD) rats weighing 250-300 g were randomly divided into sham group (S group), conventional mechanical ventilation group (L group) and high tidal volume (VT) mechanical ventilation group (H group) with 8 rats in each group. All rats received tracheostomy after anesthesia. Rats in S group received no mechanical ventilation but breathe room air spontaneously. All other parameters of the ventilator were the same in both mechanical ventilation groups, and the fraction of oxygen was set to 0.21, the rats in L group received 7 mL/kg VT, and those in H group received 28 mL/kg VT. Four hours after ventilation all rats were sacrificed and the lung tissues were harvested for wet/dry (W/D) ratio. Pathological injury score was evaluated by hematoxylin and eosin (HE) staining. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling stain (TUNEL) was performed to count the apoptosis cell in lung epithelial. Western Blot was performed to evaluate hemi-channel protein Pannexin-1 expression in lung homogenate. Bronchoalveolar lavage fluid (BALF) was collected, and the concentration of lactate dehydrogenase (LDH), isoprostane, adenosine triphosphate (ATP) and white cell count in BALF were measured. Yo-pro-1/propidium iodide (PI) double stain was performed to evaluate early apoptosis cell in BALF. RESULTS: There was no significant difference in lung injury between S group and L group. Compared with S group and L group, rats in H group showed significant lung injury, represented as alveolar rupture, inflammatory cell infiltration, interstitial edema and airway epithelial exfoliation, and the lung W/D ratio was increased significantly (5.1+/-0.2 vs. 4.4+/-0.2, 4.3+/-0.4, both P < 0.01), pathological score was significantly increased [4.00 (4.00, 8.00) vs. 1.00 (0, 4.00), 2.00 (0, 4.75), both P < 0.01], the white cell in BALF was significantly increased (*106/L: 2.97+/-0.46 vs. 1.03+/-0.26, 0.79+/-0.19, both P < 0.01), the level of LDH was significantly increased (U/L: 148.6+/-38.2 vs. 34.4+/-13.5, 78.6+/-13.9, both P < 0.01), and the expression of Pannexin-1 in lung homogenate was significantly increased (Pannexin-1/GAPDH: 0.89+/-0.21 vs. 0.48+/-0.25, 0.61+/-0.17, both P < 0.01), the ATP concentration in BALF was also significantly increased (nmol/L: 456.84+/-148.72 vs. 19.23+/-13.34, 113.26+/-57.90, both P < 0.01). There was no significant difference in the apoptosis cell in lung tissue or the apoptosis cell rate, isoprostane level in BALF among the three groups [apoptosis cell in lung (cells/HP): 4.00 (3.00, 5.00) vs. 5.00 (4.00, 6.00), 4.00 (3.25, 6.00); apoptosis cell rate in BALF: (0.57+/-0.20)% vs. (0.42+/-0.16)%, (0.58+/-0.19)%; isoprostane in BALF (MUg/L): 3.85+/-0.46 vs. 3.83+/-0.60, 3.59+/ 0.69, all P > 0.05]. CONCLUSIONS: The early pathogenesis of biotrauma in VILI is related to the release of inflammation mediator via membrane channel after activating by pressure stress, but not apoptosis and lipid peroxidation. PMID- 30309413 TI - [Study on the mechanism of hypertonic salt solution alleviates lung injury of rats at the early stage of severe scald]. AB - OBJECTIVE: To explore the mechanism of hypertonic salt solution (HS) alleviates lung injury of rats at the early stage of severe scald. METHODS: Thirty-two female Sprague-Dawley (SD) rats were randomly assigned to sham group, lactated Ringer solution (LR) group, HS200 group (200 mmol/L HS group, 1 L 200 mmol/L HS contained 955 mL LR and 45 mL 10% NaCl) and HS400 group (400 mmol/L HS group, 1 L 400 mmol/L HS contained 846 mL LR and 154 mL 10% NaCl), with 8 rats in each group. A 30% total body surface area (TBSA) III degree scalded model was reproduced by scalded on the back with 98 centigrade boiling water for 12 seconds, whereas those in the sham group were exposed to 37 centigrade water without liquid resuscitation. Rats in the three drug intervention groups were resuscitated with LR, 200 mmol/L HS and 400 mmol/L HS by caudal vein according to the Parkland formula, respectively. All rats were sacrificed at 8 hours after scald injury to harvest abdominal aorta blood and lung tissues. Interleukins (IL 6, IL-10 and IL-17) in serum were determined by enzyme-linked immunosorbent assay (ELISA). Samples from the lung tissue were used to measure malondialdehyde (MDA) and superoxide dismutase (SOD) levels by ultraviolet spectrophotometer. Expressions of p38 mitogen-activated protein kinase (p38MAPK) and extracellular regulated protein kinase 1/2 (ERK1/2) in the lung were determined by Western Blot. The lung tissue was stained with hematoxylin and eosin (HE), and the pathological changes were observed with a light microscope. RESULTS: Compared with the sham group, the lung tissues in the LR group were damage obviously, which accompanied with more inflammatory cell infiltration, cell edema and pulmonary septum thickening, and the levels of IL-6, IL-10, IL-17 in serum and MDA content, the phosphorylation of p38MAPK and ERK1/2 in lung tissues were increased whereas the activity of SOD was decreased. Compared with the LR group, the lung injury was significantly alleviated, the levels of IL-6, IL-17 in serum and MDA content and the phosphorylation of p38MAPK and ERK1/2 were decreased, and the levels of IL-10 and SOD were increased in both HS groups with a dose dependent manner. There were significant difference in above parameters between HS400 group and LR group [serum IL-6 (ng/L): 3.76+/-0.12 vs. 6.72+/-0.90, serum IL-10 (ng/L): 33.76+/-3.71 vs. 16.77+/-3.19, serum IL-17 (ng/L): 103.52+/-2.78 vs. 124.96+/-4.96, lung MDA (nmol/mg): 5.59+/-0.24 vs. 7.09+/-0.39, lung SOD (U/mg): 226.7+/-3.9 vs. 172.7+/-3.4, lung phosphorylation of p38MAPK (p p38MAPK)/p38MAPK: 0.15+/-0.09 vs. 0.35+/-0.19, lung phosphorylation of ERK1/2 (p ERK1/2)/ERK1/2: 0.27+/-0.01 vs. 0.70+/-0.01, all P < 0.01]. CONCLUSIONS: HS protected against lung injury induced by severe burns in rats with a dose dependent manner, and it was better than LR, and its possible mechanism was related with reducing the expression of p38MAPK and ERK1/2 pathway in lung tissue, increasing the level of anti-inflammatory cytokines and decreasing the release of pro-inflammatory cytokines, thus inhibiting excessive inflammation and oxidative stress injury in lung. PMID- 30309414 TI - [Effect of lung strain on breathing mechanics in dogs with acute respiratory distress syndrome]. AB - OBJECTIVE: To explore the effect of lung strain on breathing mechanics in dogs with acute respiratory distress syndrome (ARDS). METHODS: Twenty-four healthy male Beagle dogs were recruited to reproduce medium ARDS models with venous injection of 0.18 mL/kg oleic acid, and they were randomly assigned to five groups with random numbers table method. In lung protective ventilation (LPV) group (n = 4), the ventilation was supported for 24 hours with tidal volume (VT) at 6-8 mL/kg, and in lung strain 1.0, 1.5, 2.0, 2.5 groups (S1.0, S1.5, S2.0, S2.5 groups), the VT was calculated from lung strain, the volume recruitment by positive end expiratory pressure (VPEEP) and functional residual capacity (FRC). Five groups were given mechanical ventilation for 24 hours or until reaching the end point of the experiment [when the dosage of norepinephrine was higher than 1.4 MUg*kg-1*min-1, the blood pressure was still lower than 60 mmHg (1 mmHg = 0.133 kPa) for more than 30 minutes, which was regarded as the end point of the experiment]. Static lung compliance (Cst), airway plateau pressure (Pplat) and lung stress during the experiment were recorded. Linear regression analysis was used to fit the regression equations of lung strain and Cst descending rate, Pplat and lung stress for analyzing their relationships. RESULTS: The VT of group LPV was (7.1+/-0.5) mL/kg. With the increase of lung strain, VT was gradually increased. VT of group S1.0 [(7.3+/-1.8) mL/kg] was similar to group LPV. VT of groups S1.5, S2.0, S2.5 was significantly higher than that of group LPV (mL/kg: 13.3+/-5.5, 18.7+/-5.4, 20.1+/-7.4 vs. 7.1+/-0.5, all P < 0.05). Moreover, under the same lung strain, the difference in VT among individuals was large. The Cst of each group was decreased significantly at the end of the experiment as compared with that before model reproduction. With the increase of lung strain, the rate of Cst descending was increased, Cst dropped more significantly in groups S2.0 and S2.5 than that in groups S1.0 and S1.5 [(48.0+/-15.0)%, (54.4+/ 9.5)% vs. (25.9+/-13.7)%, (38.6+/-8.1)%, all P < 0.05]. Pplat and pulmonary stress at model reproduction in all groups were significantly higher than those before model reproduction, and they increased with the prolongation of ventilation time. Pplat and lung stress at 4 hours of ventilation in group S1.5 were significantly higher than those in group LPV [Pplat (cmH2O, 1 cmH2O = 0.098 kPa): 26.2+/-2.3 vs. 20.2+/-4.2, lung stress (cmH2O): 20.5+/-2.0 vs. 16.6+/-2.5, both P < 0.05], and they increased with lung strain increasing till to the end of experiment. It was shown by correlation analysis that lung strain was positively related with Cst descending rate, Pplat and lung stress at 4 hours of ventilation (r value was 0.716, 0.660, 0.539, respectively, all P < 0.05), which indicated a strong linear correlation. It was shown by fitting linear regression analysis that when lung strain increased by 1, Cst descending rate increased by 19.0% [95% confidence interval (95%CI) = 14.6-23.3, P = 0.000], Pplat increased by 10.8 cmH2O (95%CI = 7.9-13.7, P = 0.002), and the lung stress increased by 7.4 cmH2O (95%CI = 4.7-10.2, P = 0.002). CONCLUSIONS: In animal ARDS models, the larger the lung strain, the higher the Pplat and lung stress during mechanical ventilation, VT originated for lung strain 2.0 and 2.5 may further reduce Cst in ARDS models, when lung strain over 1.5, Pplat and lung stress increased significantly, which exceeded the safe range of LPV (35 cmH2O and 25 cmH2O, respectively), and further aggravated ventilator induced lung injury (VILI). PMID- 30309415 TI - [Clinical application of full age spectrum formula based on serum creatinine in patients with chronic kidney disease]. AB - OBJECTIVE: To compare the estimated glomerular filtration rates (eGFR) by five formulas based on serum creatinine (SCr), and to explore the diagnostic efficacy of full age spectrum (FAS) equation based on SCr for renal insufficiency in patients with chronic kidney disease (CKD). METHODS: 2 219 patients with CKD admitted to department of nephrology of Guangdong Provincial Second People's Hospital from December 2015 to January 2018 were enrolled. According to the diagnostic criteria of kidney disease outcomes quality initiative (K/DOQI), patients were divided into CKD 1-5 stages. In all patients, Tc-GFR was measured by clearance rate of 99mTc-diethylene triaminepen taacetic acid (99mTc-DTPA) within 1 month, and SCr was determined. The eGFR was calculated by Cockcrofi Gault (C-G) formula bases on SCr, Chinese modified modification of diet in renal disease (cMDRD) equation, Chronic Kidney Disease Epidemiology Collaboration Group (CKD-EPI) equation, measure and calculation (MC) equation and FAS equation, respectively, and body surface area (BSA) was used for correction of eGFR. The differences of Tc-GFR and eGFR calculated by different formulas were compared, and the correlations between eGFR calculated by different formulas and Tc-GFR were analyzed by Spearman correlation analysis. Tc-GFR was used as a reference standard to evaluate the bias, precision and accuracy of eGFR formulas, and the receiver operating characteristics (ROC) curve of each eGFR formula was plotted to evaluate its diagnostic efficacy for renal insufficiency in patients with CKD. RESULTS: According to the inclusion and exclusion criteria, 382 patients with CKD were enrolled in the final analysis. There were 31, 69, 92, 75 and 115 patients with CKD 1-5 stages, respectively. In all patients, the differences between Tc GFR and eGFR calculated by different formulas were statistically significant, and eGFR was positively correlated with Tc-GFR. The best correlation coefficient was between eGFR of cMDRD formula and Tc-GFR (r = 0.883, P = 0.000), and the lowest was of MC formula (r = 0.848, P = 0.000). The best correlation between the eGFR calculated by FAS formula and the Tc-GFR was in CKD 2 stage (r = 0.538, P = 0.000), and the lowest correlation was found in CKD 5 stage (r = 0.229, P = 0.014). Compared with Tc-GFR (the reference equation), the FAS formula showed the smallest bias [the difference between Tc-GFR and eGFR = 8.64, 95% confidence interval (95%CI) = 7.04-10.19], and the best accuracy [the percentage of eGFR falling into the range of Tc-GFR +/-30% (P30) = 42.67%, 95%CI = 37.69-47.65]; CKD EPI equation showed the best precision (QR of the difference between Tc-GFR and eGFR = 17.43, 95%CI = 15.33-21.28). ROC curve analysis showed that the area under the curve (AUC) of cMDRD formula was the largest (0.944), and the specificity was the highest (87.23%); the sensitivity of CKD-EPI formula was the highest (94.00%); and the AUC of MC formula was the smallest (0.918). The AUC of FAS formula was 0.940 (95%CI = 0.917-0.964, P = 0.000), it was higher than that of MC formula, but there was no significant difference between FAS formula and other formulas. When the cut-off value of eGFR calculated by FAS formula was 32.62 mL*min-1*1.73 m-2, the sensitivity, specificity, positive predictive value, negative predictive value was 93.00%, 81.56%, 83.64%, 11.54%, respectively. CONCLUSIONS: Compared with C-G formula, cMDRD formula, CKD-EPI formula and MC formula, FAS formula showed smaller bias and higher accuracy, and had higher specificity and sensitivity in the diagnosis of renal insufficiency in patients with CKD, which could be applied to the determination of GFR in early stage of CKD. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800017727. PMID- 30309416 TI - [Regulation of autophagy by GLT25D2 gene in acetaminophen-induced hepatotoxicity injury]. AB - OBJECTIVE: To investigate whether GLT25D2 gene regulates autophagy in acetaminophen (APAP)-induced hepatotoxicity injury. METHODS: GLT25D2+/+ wild-type C57BL/6J mice and GLT25D2-/- C57BL/6J mice were selected as subjects. (1) In vivo experiment: 20 for wild-type mice and 20 for GLT25D2-/- mice were respectively divided into phosphate buffer (PBS) control group and APAP intervention group according to random number table, with 10 mice in each group. The hepatotoxicity injury model of mice was reproduced by intraperitoneal injection of 25 g/L APAP solution 500 mg/kg. The PBS control group was intraperitoneally injected with the same amount of PBS. The mice were sacrificed immediately after model reproduction, and the liver tissues were harvested. Western Blot was used to detect the expressions of autophagy-related proteins ATG5, ATG7, microtubule associated protein 1 light chain 3 (LC3) and P62. The ultrastructural changes in liver tissue were observed under electron microscope to observe the level of autophagy. (2) In vitro experiment: primary hepatocytes extracted by two-step collagen perfusion from one GLT25D2+/+ wild-type mouse and one GLT25D2-/- mouse were divided into two parts respectively. One part was treated with 5 mmol/L APAP solution. The cells were harvested at 0, 8, and 12 hours, and the expressions of autophagy-related proteins ATG5, ATG7, LC3, and P62 were determined by Western Blot. The other part was transfected with the green fluorescent protein-LC3 plasmid (GFP-LC3) for 24 hours. The cells were cultured with PBS (PBS control group) or 5 mmol/L APAP (APAP intervention group) for 12 hours, and the positive expression of GFP-LC3 was observed under the fluorescence microscope, thereby reflecting the expression of autophagosomes. RESULTS: (1) In vivo experiment: compared with the corresponding PBS control group, the expressions of the positive-associated proteins ATG5, ATG7 and LC3-II in liver tissue of the APAP intervention group were down-regulated in the wild-type and GLT25D2-/- mice, while the expression of the negative correlation protein P62 was up-regulated, indicating that the overall level of autophagy decreased after treatment with APAP. Compared with wild-type mice, the expressions of autophagy positive correlation proteins ATG5 and ATG7 were up-regulated in GLT25D2-/- mice (ATG5/beta-actin: 1.21+/-0.29 vs. 0.84+/-0.19, ATG7/beta-actin: 1.29+/-0.14 vs. 1.54+/-0.40, both P > 0.05), LC3-II expression was slightly down-regulated (LC3 II/beta-actin: 0.52+/-0.06 vs. 0.58+/-0.06, P > 0.05), while negative correlation protein P62 was down-regulated (P62/beta-actin: 1.13+/-0.94 vs. 1.54+/-0.40, P > 0.05), indicating that the expression of autophagy in GLT25D2-/- mice was higher than that in wild-type mice. Ultrastructural observation under electron microscope showed that the number of autophagosomes in the liver tissue of wild type mice did not change significantly after APAP intervention as compared with that in PBS control group, but the number of autophagosomes in GLT25D2-/- mice was increased. (2) In vitro experiment: with the prolongation of APAP intervention, the expressions of ATG5 and ATG7 in the primary hepatocytes of wild type and GLT25D2-/- mice were up-regulated, LC3 was slightly fluctuated, and the expression of negative-related protein P62 was gradually down-regulated. The peak value or the trough value reached at 12 hours. It was indicated that the expression of autophagy in APAP-stimulated cells was enhanced with a time dependent manner. Compared with wild-type mice, the expressions of autophagy correlation proteins ATG5, ATG7, LC3-II and P62 were up-regulated in GLT25D2-/- mice at 12 hours (ATG5/beta-actin: 0.93+/-0.09 vs. 0.74+/-0.06, ATG7/beta-actin: 0.80+/-0.09 vs. 0.65+/-0.10, LC3-II/beta-actin: 1.35+/-0.30 vs. 1.15+/-0.20, P62/beta-actin: 0.36+/-0.02 vs. 0.31+/-0.03, all P > 0.05), indicating that the expression of autophagy was enhanced after gene knockout. Fluorescence microscopy showed that GFP-LC3 positive cells in both wild-type and GLT25D2-/- mice hepatocytes were significantly increased after APAP intervention as compared with those of PBS control group, and the proportion of GFP-LC3 positive cells in GLT25D2-/- mice was significantly higher than that in wild-type mice (0.64+/-0.08 vs. 0.36+/-0.05, P > 0.05). CONCLUSIONS: GLT25D2 is a negative regulator of autophagy. Knockout of GLT25D2 gene can enhance the autophagy level of APAP induced hepatotoxicity injury in mice. PMID- 30309417 TI - [Protective effects of endovascular cooling treatment on post-resuscitation syndrome and its mechanism]. AB - OBJECTIVE: To investigate the protective function of endovascular cooling method on post-resuscitation syndrome (PRS) in porcine cardiac arrest (CA) model and its mechanism. METHODS: Ventricular fibrillation (VF) was electrically induced and untreated for 8 minutes in 15 healthy male porcines, cardiopulmonary resuscitation (CPR) was then initiated. All successful recovery animals were randomly divided into two groups by random number table. In normal temperature group, the core temperature was maintained at (38.0+/-0.5) centigrade for 12 hours. In mild hypothermia group, the mild hypothermia treatment was initiated at 5 minutes after successful resuscitation, the treatment of rapid endovascular cooling was performed to reach the target cooling temperature of (33.0+/-1.0) centigrade, and then maintained until 6 hours after resuscitation. Rewarming was implemented at the rate of 0.7 centigrade/h until the body temperature reached (38.0+/-0.5) centigrade. Hemodynamic parameters including heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO) were continually monitored. Right femoral vein blood was collected before VF and 1, 2, 4, 6, 12 and 24 hours after resuscitation, respectively, and the serum concentrations of E-selectin, soluble thrombomodulin (sTM), and interleukin-1beta (IL-1beta) were determined with enzyme linked immunosorbent assay (ELISA). The survival of porcines at 24 hours after resuscitation was observed, and the neurological deficit score (NDS) was calculated for the surviving porcines. All animals were sacrificed, and brain, heart and lung tissues were collected, after hematoxylin and eosin (HE) staining, the histopathology changes were evaluated under a light microscopy. RESULTS: After 8-minute VF, 14 porcines were resuscitated successfully, 7 porcines in normal temperature group and 7 in mild hypothermia group respectively, with the resuscitation success rate of 93.3%. There was no significant difference in body weigh, core temperature, hemodynamics, or blood lactate as well as duration of CPR and the number of defibrillations between the two groups. The core temperature of normal temperature group was maintained at (38.0+/-0.5) centigrade, while in mild hypothermia group, the hypothermia was reduced to the hypothermia range (33.0+/-1.0) centigrade until 6 hours, then rewarmed to normothermia gradually [(38.0+/-0.5) centigrade]. Compared with those before VF, HR was significantly increased after resuscitation in both groups, and MAP and CO were decreased, then they tended to normal. There was no significant difference in hemodynamic parameter at all time points between the two groups. Compared with those before VF, the levels of E-selectin and sTM in serum of the two groups were increased significantly at 1 hour after resuscitation, and they were decreased gradually after reaching the peak at 6 hours, and IL-1beta was increased continuously with time. There was no significant difference in E selectin (MUg/L: 1.34+/-0.52 vs. 1.60+/-0.61), sTM (MUg/L: 19.13+/-0.34 vs. 19.24+/-0.73), or IL-1beta (ng/L: 25.73+/-0.87 vs. 25.32+/-0.25) before VF between normal temperature group and mild hypothermia group (all P > 0.05). The levels of E-selection, sTM and IL-1beta in mild hypothermia group were significantly lower than those in normal temperature group from 2 hours after resuscitation [E-selection (MUg/L): 11.15+/-2.73 vs. 16.04+/-3.23, sTM (MUg/L): 49.67+/-3.32 vs. 62.22+/-1.85, IL-1beta (ng/L): 140.51+/-6.66 vs. 176.29+/-18.51, all P < 0.05], and E-selection decreased to the baseline level at 12 hours (MUg/L: 1.17+/-0.65 vs. 1.60+/-0.61, P > 0.05). The 24-hour survival rates of two groups were both 100%. The NDS score of mild hypothermia group was obviously lower than that of normal temperature group (150.0+/-6.6 vs. 326.4+/-12.3, P < 0.05). In normal temperature group, neuronal cell necrosis was observed in the cerebral cortex at 24 hours after resuscitation, and nucleus was deeply stained. The myocardial necrosis and alveolar collapse was found. Meanwhile the infiltration of inflammatory cell could be found in the myocardium and alveolar. The brain, lung and myocardium injury were significantly milder in mild hypothermia group as compared with those in normal temperature group. CONCLUSIONS: The intravascular cooling therapy was a safe and effective method for inducing mild hypothermia after resuscitation. This cooling effect was fast and reliable, and the rewarming speed was controllable and stable. The protective mechanism of mild hypothermia on PRS may be related to inhibiting systemic inflammatory response and reducing vascular endothelial cell injury. PMID- 30309418 TI - [Effect of age on waiting time of emergency patients: a retrospective analysis of 219 299 patients in consecutive 2 years]. AB - OBJECTIVE: To evaluate whether patients aged over 70 years old is an independent predictor for prolonging the waiting time, and to know whether the population can be prioritized in the emergency grading system. METHODS: A retrospective analysis was conducted. All the clinical data of adult visitors to the emergency department of the Third Affiliated Hospital of Sun Yat-sen University from January 1st in 2016 to December 31st in 2017 were collected. All the patients received four emergency first aid triages and treated according to the emergency classification results. The relevant data of selected patients were retrieved from the hospital information system (HIS) including gender, age, triage level, triage department, outpatient service and initial diagnosis time. According to the conclusion of pre-phase analysis that the patients over 65 years old was not associated with waiting time, all subjects were divided into >= 70 years old group and < 70 years old group for further analysis. The waiting time was defined as the difference in registration time and the initial diagnosis time, and the patients were divided into two groups according to whether it exceeded the target waiting time (TWT). TWT was considered as follows according to each emergency triage level: level I instantly, level II 10 minutes, level III 30 minutes, level IV 60 minutes (subacute patients) or 2-4 hours (non-urgent patients). The multivariable Logistic regression analysis was conducted to determine whether the factor that aged over 70 years old was an independent predictor for prolonging waiting time over TWT. RESULTS: There were 272 989 adult visits recorded totally, of which obstetrics and gynecology department visits, incomplete personnel information, invalid diagnosis (or no diagnosis), triage level I, abnormal waiting time (the waiting time exceeded 99% of the average waiting time of all samples) records were excluded. Finally, 219 299 emergency patients were enrolled, with 102 218 male and 117 081 female, which showed an average age of (35.86+/-15.81) years, 208 082 patients (94.9%) in < 70 years old group, and 11 217 (5.1%) in >= 70 years old group. Totally 191 588 patients (87.4%) were diagnosed within the TWT, and the number was 86.5% (9 701/11 217) in the >= 70 years old group. Multivariate Logistic regression analysis indicated that age under 70 years old was independently associated with an exceeded TWT [adjusted odds ratio (OR) = 1.106, 95% confidence interval (95%CI) = 1.041-1.176, P = 0.001]. Meanwhile, visits during the peak period or low triage level was also a risk factor of exceeded TWT. According to the Logistic regression analysis of different departments and removing other factors, in the emergency internal medicine with the most elderly patients, the probability of exceeded TWT in >= 70 years old group was lessened (adjusted OR = 1.203, 95%CI = 1.121-1.291, P < 0.001). CONCLUSIONS: In the emergency pre-grading system, the elderly aged (>= 70 years old) was more likely to see a doctor in TWT than those under 70 years old, so they were easy to get priority treatment. PMID- 30309419 TI - [Design and application of a high flow oxygen device with adjustable PEEP valve]. AB - OBJECTIVE: Positive end-expiratory pressure (PEEP) is a common method to maintain alveolar patency in patients undergoing mechanical ventilation. However, in patients undergoing tracheotomy, alveolar collapse often occurs due to bedridden, aspiration, and other factors. There is currently no effective means to provide PEEP support for such patients. The application of a high-flow oxygen inhalation device with a PEEP valve was designed to provide patients with continuously adjustable PEEP, which helps to improve the patient's oxygenation and maintain the lung's physiological functions. PMID- 30309420 TI - [Autophagy and neuronal diseases]. AB - OBJECTIVE: Autophagy is a dynamic process that allows recycling of long-lived proteins and damaged organelles into biosynthetic materials for maintaining the normal cellular homeostasis. Recently, accumulating evidence has indicated that autophagy played important roles in the pathogenesis of neuronal diseases. In this article, the research progress of autophagy in the pathogenesis and regulation mechanism of common nervous system diseases were reviewed to deepen the understanding of autophagy, and arouse researchers' attention on dynamic regulation of autophagy and alleviating autophagic flow injury. PMID- 30309421 TI - [Hypocalcemia is an "accelerator" for the death of patients with nervous system injury]. AB - OBJECTIVE: In clinical diagnosis and treatment, the occurrence of hypocalcemia during severe nervous system damage is not uncommon but is easily neglected so that delayed treatment, further injurie and even death. It can provide theoretical support for the evaluation of the early identification in calcium ion imbalance and the development of standard calcium ion monitoring program for patients with critical disease by integrating the clinical symptoms induced by low blood calcium based on severe nervous system injury and analyzing the correlation among them. PMID- 30309422 TI - [Pivotal role of cell hyperactivation in the pathogenesis of different diseases and its mechanism]. AB - OBJECTIVE: Inflammasomes are key inflammatory signaling platforms that detect several stimulus derived from microbial substances and sterile environmental insults, eliciting pyroptosis and the release of cytokines. Recent studies have found that inflammasomes could also elicit cell hyperactivation which is defined as living cells that release interleukin-1 (IL-1). Hyperactive cells promote long term IL-1 release and then activate adaptive immune response, which has a pivotal role in the infection of Salmonella and Staphylococcus aureus, as well as in non lethal inflammatory sepsis. So it is of great significance to explore the pathogenesis of cell hyperactivation in several inflammatory diseases. Here, we summarized the possible pathogenesis of cell hyperactivation in different inflammatory diseases, such as infection, sepsis and acute respiratory distress syndrome (ARDS), providing a theoretical basis for clinical treatment of these diseases. PMID- 30309423 TI - [Expert Consensus on Adjuvant Therapy of Non-small Cell Lung Cancer from China Thoracic Surgeons (2018 Version)]. PMID- 30309424 TI - [Thematic Introduction of Perioperative Venous Thromboembolism Prophalaxis ?in Thoracic Surgery]. PMID- 30309425 TI - [Perioperative Venous Thromboembolism (VTE) Prophalaxis ?in Thoracic Cancer Patients: Chinese Experts Consensus]. PMID- 30309426 TI - [Risk Factors Associated with Venous Thromboembolism after Lung Cancer Surgery: A Single-center Study]. AB - BACKGROUND: The Previous study has indicated that the incidence of venous thromboembolism (VTE) after lung cancer surgery is not uncommon. The aim of this study is to analyze the risk factors of postoperative VTE in lung cancer patients and provide a clinical basis for further prevention and treatment of VTE. METHODS: This study was a single-center study. From July 2016 to December 2017, all patients with lung cancer who underwent surgery in our department were enrolled into this study. Except routine preoperative examinations, lower extremity Doppler ultrasound was performed in all patients before and after surgery to determine whether there was any newly developed deep venous thrombosis (DVT). Patients did not receive any prophylactic anticoagulant therapy before and after surgery. Patients were then divided into VTE group and control group according to whether VTE occurred after operation. Baseline data, surgical related data (surgery type, surgical procedure, etc.) and tumor pathological data (pathological type, vascular infiltration, pathological staging, etc.) were compared between the two groups. RESULTS: According to the inclusion criteria, a total of 339 patients undergoing lung cancer surgery were analyzed. There were 166 males and 173 females with an age range of 23-86 years. A total of 39 patients developed VTE after surgery, the incidence rate of postoperative VTE was 11.5%. Comparing the age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA), smoking status, underlying diseases, etc, there were no significant differences in other indicators except for significant differences in age; comparison between preoperative blood routine, blood biochemistry, coagulation, tumor markers, lung function, lower extremity venous ultrasound, preoperative carcinoembryonic antigen (CEA) levels, preoperative D-dimer levels, there were significant differences in lung function and lower extremity intermuscular vein expansion ratio. There were no significant differences in other indexes between the two groups. The duration of surgery, surgical procedure, bleeding volume, pathological type, pathological stage, vascular invasion, were compared between the two groups. There were statistical differences in surgical methods (thoracic vs thoracoscopic) and bleeding volume. There were no significant differences in other indicators. Univariate analysis showed that age, preoperative CEA level, preoperative D-dimer level, poor pulmonary function, lower extremity intermuscular vein dilation ratio, thoracotomy rate, length of surgery, and amount of bleeding were significantly risk factors (P<0.05). There were no significant correlations between pathological stage and pathological type and VTE. Multivariate logistic regression analysis showed that forced expiratory volume in one second (FEV1), surgical approach, and lower extremity intermuscular vein dilatation were independent risk factors for postoperative VTE in patients with lung cancer (P<0.05). CONCLUSIONS: The results of this study suggest that FEV1, surgical procedures, and lower extremity intermuscular vein dilation are independent risk factors for postoperative VTE in patients with lung cancer. PMID- 30309427 TI - [Analysis of the Incidence of Lower Extremity Venous Thrombosis and Its Related Risk Factors in Admitted Patients with Lung Cancer]. AB - BACKGROUND: Venous thromboembolism (VTE) is a recognized complication in lung cancer patients with higher morbidity and mortality. The purpose of this study is to determine the incidence of lower extremity venous thrombosis (LEDVT) in lung cancer patients and to reveal the risk factors for LEDVT during admission in our center. METHODS: We first connected 231 patients with lung cancer admitted to the Department of Lung Cancer Surgery, Tianjin Medical University General Hospital from July 2017 to December 2017. All these patients underwent color ultrasound examination of lower extremity vein on admission to analyze the incidence of LEDVT. At the same time, the incidence of LEDVT in patients with benign lung diseases on admission was used as control. In order to explore the possible risk factors for LEDVT in these patients with lung cancer, we further analyze the correlations between LEDVT and their clinical features. At the same time, we also analyze the relationship between LEDVT and Plasma D-Dimmer, fibrinogen (FIB), thrombin time (TT), activated partial thrombin time (APTT), prothrombin time (PT) and platelet (PLT) in these patients with lung cancer. RESULTS: Among 231 patients with lung cancer, the incidence rate of LEDVT on admission was 5.2% (12/231), and in 77 patients with benign lung disease, there was none of patients with LEDVT on admission. This result indicated that the admitted incidence rate of LEDVT in patients with lung cancer was significantly higher than that in patients with benign lung disease (P<0.05). Further analysis in patients with lung cancer found that there was higher incidence rate of LEDVT in distant metastasis group (including N3 lymph node metastasis) compared to in non-distant metastasis group (11.29%, 7/62 vs 2.96%, 5/169) (P<0.05). In patients with lung cancer, the median value of D-Dimer in LEDVT group was 1,534 mg/L (369 mg/L 10,000 mg/L), which was significantly higher than that in the non-LEDVT group (539 mg/L, 126 mg/L-1,000 mg/L) (P<0.05). There was no statistically significant difference in FIB, TT, APTT, PT and PLT between these two groups (P>0.05). CONCLUSIONS: The overall incidence of LEDVT in our central lung cancer patients was approximately 5%, significantly higher than that in patients with benign lung disease. Lung cancer patients with distant metastasis (including N3 lymph node metastasis) at admission were more likely to develop LEDVT, and these patients with higher D-Dimer values should be considered the possibility of VTE events. PMID- 30309428 TI - [Clinical Value Evaluation of Perioperative Prophylactic Anticoagulation Therapy for Lung Cancer Patients]. AB - BACKGROUND: The incidence of pulmonary embolism (PE) in lung cancer patients who underwent surgery increased during the perioperative period, and prophylactic anticoagulation therapy was important part of enhanced recovery after surgery (ERAS). However, the timing of preventive anticoagulation in patients with lung cancer remained controversial. This study was designed to investigate the safety and efficacy of perioperative prophylactic anticoagulation therapy for lung cancer patients. METHODS: Retrospective research was conducted on 562 lung cancer patients who underwent video-assisted thoracoscopic (VATS) anatomic pulmonary resections in West China Hospital from June 2016 to December 2016. 56 patients were treated with low molecular weight heparin (LMWH) anticoagulation 12 hours before operation until discharge, while the other 506 patients were treated with LMWH 24 hours after operation until discharge. The postoperative chest drainage volume, postoperative bleeding, pulmonary embolism incidence, and respiratory complications were analyzed. RESULTS: (1) There were no significant differences in prothrombin time (PT), activated partial thromboplastin time (APTT) and international normalized ratio (INR) between the pre-operation prophylactic anticoagulation group (PRE group) [(11.5+/-3.9) s, (27.8+/-3.5) s, (0.96+/-0.06) s] and the post-operation prophylactic anticoagulation group (POST group) [(11.4+/-1.4) s, (28.3+/-4.0) s, (0.98+/-0.07) s] (P=0.796, P=0.250, P=0.137), and there was no significant difference in Caprini score between the PRE group (3.1+/-1.8) and the POST group (3.3+/-1.5) (P=0.104). (2) There were no significant differences in anesthesia time and intraoperative bleeding between PRE group [(130.2+/-53.9) min, (76.8+/-49.3) mL] and POST group [(142.2+/-56.5) min, (73.7+/-41.6) mL] (P=0.067, P=0.201). (3) The total drainage volume in 72 hours after operation in PRE group [(728.1+/-505.7) mL] was significantly higher than that of POST group [(596.4+/-373.5) mL] (P=0.005), while there were no significant differences between the two groups in total postoperative drainage volume [(1,066.8+/-1,314.6) mL vs (907.8+/-999.8) mL, P=0.203]. (4) There were no significant differences between the two groups in pulmonary embolism incidence (1.785% vs 0.019%, P=0.525) and postoperative bleeding rates (1.785% vs 0.039%, P=0.300). (5) There were no significant differences between PRE group and POST group in subcutaneous emphysema incidence (1.785% vs 1.581%, P=0.989) and pulmonary infection rates (14.285% vs 6.324%, P=0.085). CONCLUSIONS: The clinical value of preoperative prophylactic anticoagulation is equal to postoperative prophylactic anticoagulation for lung cancer patients. PMID- 30309429 TI - [Diagnosis and Management of Postoperative Acute Pulmonary Embolism after Thoracic Surgeries - Experience of Diagnosis and Management for 37 Patients with Postoperative Acute Pulmonary Embolism after Thoracic Surgeries]. AB - BACKGROUND: Pulmonary embolism (PE) is one of the most severe complications after thoracic surgeries. Thus it is of great importance to learn the characteristics of acute PE after thoracic surgeries. This study summarized the clinical characteristics and experience on the diagnosis and treatment of 37 patients with postoperative acute pulmonary embolism, in order to improve its prophylaxis and management level. METHODS: We retrospectively reviewed 37 patients with postoperative acute pulmonary embolism following thoracic surgeries. Age, gender, body mass index (BMI), diagnosis, surgical procedure, onset time, clinical presentation, diagnosis and management were comprehensively analyzed. RESULTS: There were 16 males (43.2%) and 21 females (56.8%). The average age was (65.64+/ 6.29) years (range from 53 years to 82 years) and 32 patients were over 60 years. BMI ranged from 17.1 kg/m2 to 30.8 kg/m2 with median of 26.3 kg/m2. And 27 patients' BMI (73.0%) were over 25.0 kg/m2. Thirty-four patients (91.9%) were with malignancies. Median presentation time was the 4th day postoperatively, while 11 patients were presented on the 3rd day postoperatively which accounted for the most. Patients with acute pulmonary embolism accounted for 77.8% from 9 am to 9 pm. D-dimer (D-D) ranged from 1.0 MUg/mL-20.0 MUg/mL (FEU) with median of (7.09+/-4.45) MUg/mL (FEU) and 32 (86.5%) patients' D-D were over 3.00 MUg/mL (FEU). CONCLUSIONS: The survival rate of postoperative acute pulmonary embolism can be increased by fully understanding its clinical characteristics, early diagnosis and multiple disciplinary treatment. PMID- 30309430 TI - [Experience of Interventional Thrombolysis Therapy for Massive Pulmonary Thrombosis Embolism after Video-assisted Thoracoscopic Surgery for Lung Cancer]. AB - BACKGROUND: Pulmonary thrombosis embolism (PTE) is one of the most severe complications of perioperative radical mastectomy. Massive PTE is often accompanied by shock and hypotension which is characterized by rapid progression and high mortality. There is no standard for the treatment of these patients, which is thoracic surgery, and it is a critical issue in the thoracic surgeons. This article summarizes and analyzes the treatment of two patients with high-risk PTE at the early stage of postoperative lung cancer in our hospital. In addition, we discusses the diagnosis and treatment strategies of these cases to provide a reference for the thoracic surgeons. METHODS: We presented two patients with high risk PTE at the early stage after thoracic surgery for radical surgery in our hospital back in 2017. One case was treated with intravenous venous interventional thrombolysis, and the other was treated with thrombolysis alone. The treatment effect of two patients and the complications during the treatment has been recorded to detail and summarized. RESULTS: Both patients were female who aged 66 and 61 years old. The time point of pulmonary embolism was 48 h and 45 h after operation, and the time of interventional thrombolysis was 70 minutes and 50 minutes after onset respectively. After 120 minutes and 100 minutes, the drainage after interventional thrombolysis was 4,690 mL and 520 mL respectively. The hospitalization time after thrombolysis was 21 days and 14 days respectively. There was no obvious complication through a follow-up of 6 months. CONCLUSIONS: Early postoperative acute massive pulmonary embolism in lung cancer should be treated with pulmonary interventional thrombolysis as soon as possible. Compared with intravenous thrombolysis, pulmonary interventional thrombolysis shows accuracy, easy controlling of dosage, fast curative effect and low bleeding risk. PMID- 30309431 TI - [Occurrence of Venous Thromboembolism in Patients with Lung Cancer ?and Its Anticoagulant Therapy]. AB - Lung cancer is the first leading cause of morbidity and mortality in the world. Venous thromboembolism (VTE) is a recognized complication in patients with lung cancer, which is one of the leading cause of death in lung cancer patients. The cancer-related, patient-related and treatment-related factors are the main causes of VTE in lung cancer patients. Malignant cells can directly activate blood coagulation by producing tissue factor (TF), cancer procoagulance (CP), inflammatory factors and cytokines; And the one of predominant mechanisms in cancer-related thrombosis is the overexpression of TF. The 10th edition of the antithrombotic therapy guidelines for VTE with cancer patients (AT-10) published in 2016 by American College of Chest Physicians (APCC) recommended that anticoagulant therapy is the basic treatment for patients with lung cancer complicated with VTE; And low molecular-weight-heparin (LMWH) is preferred as an anticoagulant drug, but can be use with caution due to increasing risk of bleeding.?. PMID- 30309432 TI - [Diagnosis and Treatment Strategy of Pulmonary Embolism after Video-assisted Thoracic Lobectomy]. AB - BACKGROUND: To summarize the clinical features of patients with pulmonary embolism after lobectomy and to explore the methods of diagnosis and treatment of pulmonary embolism after lobectomy. METHODS: The clinical data of 6 patients with pulmonary embolism after lobectomy between July 2007 and July 2017 were retrospectively analyzed. RESULTS: Of the 6 patients, 3 died within 24 h of onset and 3 patients were cured and discharged. CONCLUSIONS: Pulmonary embolism after lobectomy is a rare postoperative complication in thoracic surgery. It is difficult to diagnose and has a high mortality rate. Preoperative thromboembolic risk assessment and postoperative prevention are important. PMID- 30309433 TI - [Factors Influencing the Progression Trend of Early Lung Cancer and CT Findings]. AB - BACKGROUND: It has been known that the volume doubling time (VDT) of different lung nodule types is different. At present, there is still a lack of studies about the volume doubling time of lung cancer with different pathological types. The purpose of the study is to explore the factors influencing the progression of the early-stage adenocarcinoma, and provide some reference for the follow-up strategy of lung nodules by retrospective analysis of the image data of 143 early stage adenocarcinoma. METHODS: 143 cases of the early adenocarcinoma were classified according to the 2015 World Health Organization Classification of Lung Tumors and the Eighth edition of the tumor-node-metastasis (TNM) classification of lung cancer. The volume doubling time was calculated with reference to the revised Schwartz formula. RESULTS: Among the 143 cases of the early adenocarcinoma, 50 cases (34.97%) were in progression. By multivarIate analysis, there were several factors associated with the progression of the early adenocarcinoma: the follow-up time, the dimension of nodule, the pathological type, the nodule type and the pathological stage. The VDT of lepidic predominant adenocarcinoma (LPA) is (594+/-272) d. The VDT of the invasive adenocarcinoma with lepidic part, but not predominant, is (520+/-285) d. The VDT of the invasive adenocarcinoma without lepidic part is (371+/-183) d. CONCLUSIONS: About 35% of the early adenocarcinoma is in progress. Whether with the lepidic component is a positive factor to the speed of tumor progression. PMID- 30309435 TI - Donor sperm production in heterologous recipients by testis germ cell transplantation in the dromedary camel. AB - The object of this study was to investigate if testis germ cell transplantation (TGCT) into a heterologous recipient would result in donor-origin spermatogenesis in the dromedary camel. First, we investigated a workable protocol for TGCT in camels, including donor cell isolation, enrichment by density gradient centrifugation (Percoll and Bovicoll), rete testis injection and microsatellite detection of donor and recipient genotypes. Second, the effects of three doses of Dolichos biflorus agglutinin (DBA), a glycoprotein that specifically binds to gonocytes or Type A spermatogonia, on testis germ cell depletion were investigated by direct injection into the rete testis of a male camel. Seven recipients were prepared with DBA treatment, two males were castrated at 4 weeks for depletion assessment and the remaining five received donor cells 4-6 weeks after treatment. On average, ~17 million cells were isolated per gram of testis tissue, with 19.5 +/- 1.9% DBA-positive (DBA+) cells. Percoll centrifugation yielded a 1.5-fold increase in DBA+ cells while Bovicoll centrifugation produced a 2.5-fold increase from the input cells of 18.6 +/- 2.1% DBA+ cells. Semen was collected from the recipients 13-20 weeks after transfer and the presence of donor DNA in the samples was determined using microsatellite markers. In two of the five recipients, all semen samples were shown to be positive for donor derived cells. These results demonstrate for the first time that: (1) heterologous testicular germ cell transplantation in camels is feasible and the recipients are able to produce spermatozoa of donor origin and (2) DBA can be used effectively to deplete endogenous stem cells. PMID- 30309436 TI - Maturation of buffalo oocytes invitro with acetyl-l-carnitine improves cryotolerance due to changes in mitochondrial function and the membrane lipid profile. AB - The effects of acetyl-L-carnitine (ALC) supplementation during IVM on subsequently vitrified buffalo oocytes were evaluated, followed by determination of the mitochondrial DNA copy number, measurement of mitochondrial membrane potential (MMP) and identification of the lipid profile of oocyte membranes as markers of oocyte quality after vitrification. Supplementation with ALC during IVM significantly improved the rates of oocyte cleavage and morula and blastocyst formation, and increased MMP after vitrification compared with unsupplemented vitrified oocytes (P < 0.05). Using a bidirectional orthogonal projection to latent structures discriminant analysis based on positive ion matrix-assisted laser desorption ionisation time-of-flight mass spectrometry data, five phospholipid ions (m/z 728.7 (phosphatidylcholine (PC) 32:3), 746.9 (PC 32:5), 760.6 (PC 34:1), 768.8 (PC P-36:3) and 782.6 (PC 36:4); P < 0.05) were identified as significantly more abundant in fresh oocytes than in unsupplemented vitrified oocytes. Meanwhile, three phospholipid ions (m/z 734.6 (PC 32:0), 760.6 (PC 34:1), and 782.6 (PC 36:4); P < 0.05) were more abundant in ALC-supplemented vitrified oocytes than in unsupplemented vitrified oocytes. Therefore, supplementation with ALC during IVM may improve buffalo oocyte quality after vitrification by enhancing mitochondrial function and altering the phospholipid composition of vitrified oocyte membranes. PMID- 30309434 TI - [Curative Effect of Aprepitant Preventing CINV]. AB - BACKGROUND: Chemotherapy is the most important method for cancer treatment. However, chemotherapy induced nausea and vomiting (CINV) has a profound effect on patients. In recent years, there have been new antiemetic drugs, such as aprepitant. We review the curative effect of aprepitant with tropisetron and dexamethasone for prevention of nausea and vomiting in patients receiving Cisplatin chemotherapy. METHODS: Observation is divided into three stages. Whole study phase (0-120 h after chemotherapy administration), acute phases (0-24 h), and delayed phase (24 h-120 h). The primary endpoints were complete response (CR) and complete prevention (CP) during the three different study phase. RESULTS: In the whole study phase, 86.02% of patients achieved CR; in acute phases and delayed phases were 89.25%, 87.1%, respectively. CP were 46.22%, 83.87%, 45.16%, respectively. Anti-CINV effect was significantly associated with age distribution (P=0.008). CONCLUSIONS: Aprepitant with tropisetron and dexamethasone prevented effectively CNIV for patients receiving Cisplatin chemotherapy. This combination could improve the quality of life and the compliance of patient with chemotherapy. PMID- 30309437 TI - Detection and Diagnostic Overall Accuracy Measures of Medical Tests. AB - BACKGROUND: Overall accuracy measures of medical tests are often used with unclear interpretations. OBJECTIVES: To develop methods of calculating the overall accuracy of medical tests in the patient population. METHODS: Algebraic equations based on Bayes' theorem. RESULTS: A new approach is proposed for calculating overall accuracy in the patient population. Examples and applications using published data are presented. CONCLUSIONS: The overall accuracy is the proportion of the correct test results. We introduce a clear distinction between the overall accuracy measures of medical tests that are aimed at the detection of a disease in a screening of populations for public health purposes in the general population and the overall accuracy measures of tests aimed at determining a diagnosis in individuals in a clinical setting. We show that the overall detection accuracy measure is obtained in a specific study that explores test accuracy among persons with known diagnoses and may be useful for public health screening tests. It is different from the overall diagnostic accuracy that could be calculated in the clinical setting for the evaluation of medical tests aimed at determining the individual patients' diagnoses. We show that the overall detection accuracy is constant and is not affected by the prevalence of the disease. In contrast, the overall diagnostic accuracy changes and is dependent on the prevalence. Moreover, it ranges according to the ratio between the sensitivity and specificity. Thus, when the sensitivity is greater than the specificity, the overall diagnostic accuracy increases with increasing prevalence, and vice versa, that is, when the sensitivity is lower than the specificity, the overall diagnostic accuracy decreases with increasing prevalence so that another test might be more useful for diagnostic procedures. Our paper suggests a new and more appropriate methodology for estimating the overall diagnostic accuracy of any medical test. This may be important for helping clinicians avoid errors. PMID- 30309439 TI - Crises and Turnaround Management: Lessons Learned from Recovery of New Orleans and Tulane University Following Hurricane Katrina. AB - By their very nature both man-made and natural disasters are unpredictable, and so we recommend that all health-care institutions be prepared. In this paper, the authors describe and make a number of recommendations, regarding the importance of crisis and turnaround management using as a model the New Orleans public health system and Tulane University Medical School post-Hurricane Katrina. Leadership skills, articulation of vision, nimble decision making, and teamwork are all crucial elements of a successful recovery from disaster. The leadership team demonstrated courage, integrity, entrepreneurship, and vision. As a result, it led to a different approach to public health and the introduction of new and innovative medical education and research programs. PMID- 30309438 TI - Screening to Detect Precursor Lesions of Pancreatic Adenocarcinoma in High-risk Individuals: A Single-center Experience. AB - OBJECTIVE OF THE WORK: Pancreatic cancer (PC) is a deadly disease that is most commonly diagnosed at an incurable stage. Early diagnosis is the most important factor for improving prognosis. Evidence is beginning to accumulate that screening and surveillance may lead to the early detection of precursor lesions and/or pancreatic cancer in asymptomatic individuals. Proper screening methods and identification of such precursor lesions may enable effective pre-emptive interventions to prevent further fatalities. The primary objective of this project was to examine the feasibility of identifying precursor or early cancerous lesions in high-risk individuals by endoscopic ultrasound (EUS) screening to prevent the deaths from pancreatic cancer. RESEARCH AIM: Pancreatic cancer screening guidelines, based on consensus opinions, have been applied in various tertiary centers around the world; however, evidence for effectiveness is lacking. At Rambam Health Care Campus, we have established a cohort of high-risk individuals, and we report our local 10-year experience results of screening for pancreatic cancer. METHODS: Between 2008 and 2018, a cohort of 123 asymptomatic high-risk individuals came for annual/biannual EUS screening for pancreatic cancer. Retrospective and prospectively collected data were obtained, analyzed, and compared on the basis of several variables. These variables include age at beginning of screening, gender, smoking, obesity, diabetes, and presence of tumor markers, as well as the patients' personal and family history of cancers. Findings on each EUS are described. RESULTS: Three patients out of 123 underwent potentially life-saving surgery as a result of this screening program. All of these three had only one first-degree relative (FDR) with pancreatic cancer at the time of their first screenings, but two eventually had a second FDR with PC. Findings from 296 EUS exams regarding smoking, obesity, and other risk factors are presented. Minor, possibly trivial, EUS findings are found to be common. Detection of precursor pancreatic lesions is feasible with EUS screenings. CONCLUSIONS: Adherence was an important limiting factor in screening. Better stratification of patients according to specific risk factors, including thorough genetics and family history, may direct when and how to initiate screening. International collaborations, such as the International Cancer of Pancreas Screening (CAPS) Consortium, of which Rambam is a collaborating partner, are needed to collate evidence for impact of screening to prevent pancreatic cancer morbidity and mortality, and are essential to achieve proof of concept. Different countries with varying health-care systems and budgets can find variance of appropriateness of screening procedures. PMID- 30309440 TI - Medical Imaging: From Roentgen to the Digital Revolution, and Beyond. AB - Today medical imaging is an essential component of the entire health-care continuum, from wellness and screening, to early diagnosis, treatment selection, and follow-up. Patient triage in both acute care and chronic disease, imaging guided interventions, and optimization of treatment planning are now integrated into routine clinical practice in all subspecialties. This paper provides a brief review of major milestones in medical imaging from its inception to date, with a few considerations regarding future directions in this important field. PMID- 30309441 TI - An Algorithm for Improving Hospital Performance Measures: A Department-centered Approach. AB - In recent years, it has become increasingly important to improve efficiency and economic balance in hospitals. The department chairperson (or Chair) contends with a production function consisting of inputs and outcomes, rife with managerial constraints. These constraints can be reduced with proper management by diverting resources and activity. Lack of a proper management algorithm at the department level is a significant impediment to improving operational efficiency in hospitals without significant additional costs. In this work we aimed to develop and implement a management algorithm in a teaching hospital department, in order to improve performances and quality of care. From September 2012 to December 2017 we developed a novel management algorithm for a surgical department and implemented it in the Head and Neck Surgery Department at Rambam Medical Center, Haifa, Israel. Changes were made to the organization structure and the concept of service provision. We defined core measures reflecting operative actions and outcomes and identified actions that could affect these measures. Based on our analysis of outcomes we constructed a management intervention process that defines operative actions leading to improved performance. The result was over 400% improvement in the department's outcome measures including quality, activity, and service. Analysis of data from the Israeli Ministry of Health revealed that the department's ranking in performance measures and volume improved from no. 14 of 23 departments in Israel in 2011, to no. 1 in 2013, which was sustained through 2014-2016. Improvement in efficiency also translated to economic balance and transformation from deficit to profitability. If this algorithm is implemented in the rest of the system, it is expected to improve the function of the hospital as a whole. Our results have the potential to foster the development of a new organizational culture of measurement and improvement in the hospital, and subsequently in the entire health system. PMID- 30309442 TI - Rumble Over Drug Rebates As Pharma, Payers Duke It Out. AB - Pharma says rebates are a primary driver of high drug prices because drug companies raise prices in response to payers' demands for rebates in exchange for preferred placement on their formularies. PBMs and payers object. They say the rebates they get from drugmakers are largely passed on to health plans and patients and save consumers billions of dollars in the form of lower premiums and copays. PMID- 30309443 TI - Medicare Expansion Steps Into the Political Limelight. AB - Democrats think that they've got a winning issue. Sen. Bernie's Sanders Medicare for All bill is gaining backers, but expanding access to coverage by the public payer may be more practicable. Sander's is just one of a bunch of Medicare expansion plans. They all have pros and cons, a major con being how to pay for it. PMID- 30309444 TI - It's Team Trump. But the Players Are From Think Tanks, Many With Koch Brother Roots. AB - With no experience in elected office, President Trump came into power with a thin bench. Many of the health care officials in his administration have been recruited from think tanks funded by the Koch brothers. And the Kochs and the president don't see eye to eye (to put it mildly). PMID- 30309445 TI - MS Drugs: Expensive, Often Lifelong, and Not Cost Effective. AB - Multiple sclerosis is an on-again, off-again condition that vexes patients and their loved ones. The unpredictability makes is difficult to manage in all respects, especially with escalating prices wreaking havoc with the cost effectiveness of the medications used to contain the disease. PMID- 30309447 TI - Seeking the Value in Value-Based Care. AB - The market forces pushing health care to evolve from volume to value are intensifying. At the same time, the culture change, capabilities, assets, methods, and mindset required to redefine the health care paradigm are staggering. Unlike corporate initiatives, we simply can't get there thinking quarter to quarter. But we will get there. PMID- 30309446 TI - Pharma APMs: A Learning Curve Awaits You, Pharma. AB - There are some valuable lessons for pharmaceutical manufacturers in provider alternative payment models (APMs), but whether pharmaceutical APMs succeed or fail will depend on finding solutions to operational and logistical challenges some of which are unique to the pharmaceutical industry. Pharmaceutical APMs may require the collection of information beyond the claims data that many provider APMs depend on. PMID- 30309448 TI - Real-World Analysis of Dispensed International Units of Coagulation Factor VIII and Resultant Expenditures for Hemophilia A Patients: A Comparison Between Standard Half-Life and Extended Half-Life Products. AB - PURPOSE: To identify international units (IUs) dispensed and consequent expenditures for standard half-life (SHL) versus extended half-life (EHL) recombinant factor VIII (rFVIII) replacement products in hemophilia A patients in a real-world setting. DESIGN: Two U.S. claims databases were analyzed. METHODOLOGY: Number of IUs dispensed and quarterly expenditures for rFVIII products were collected from the Optum Clinformatics Data Mart and Truven Health MarketScan Databases. Truven claims were also analyzed for factor IUs dispensed and expenditures for patients with data for >=3 months before and after switching to an EHL product. RESULTS: The Optum and Truven databases, respectively, included 276 (SHL, n=243; EHL, n=33) and 500 (SHL, n=409; EHL, n=91) hemophilia A patients. Median quarterly factor IUs dispensed in Optum were 10% higher with EHL versus SHL products over nine quarters, and 45% higher with EHL versus SHL products in Truven over 10 quarters. Median quarterly expenditures in the EHL cohort were 51% (individual quarterly medians range, 1%-101%) higher than in the SHL cohort in Optum and 122% higher (individual quarterly medians range, 1%-189%) in Truven. Twenty-nine Truven patients switched to an EHL product; median factor IUs dispensed varied quarterly. The lowest SHL and highest EHL values occurred in the quarter immediately before switching and the first quarter post-switch, respectively. Overall median quarterly expenditures were higher post-switch; this was consistent over seven quarters. CONCLUSION: We found higher expenditures over two years for hemophilia A patients using EHL versus SHL products. Switching to an EHL rFVIII product was associated with variable factor IUs dispensed and consistently higher expenditures. PMID- 30309450 TI - Effect of purple grape juice on the pharmacokinetics of digoxin: Results of a food-drug interaction study?. AB - OBJECTIVE: Digoxin is a glycosidic, cardiotonic plant extract with a narrow therapeutic window. The purpose of the study was to investigate the effects of purple grape juice on the pharmacokinetics of digoxin in rats. MATERIALS AND METHODS: A randomized, controlled, single- and multiple-dose study was conducted to evaluate the pharmacokinetic profiles of orally and intravenously administered digoxin. The plasma concentration of digoxin was determined by radioimmunoassay using a gamma counter, and a Caco-2 cell transport model was used to investigate the potential mechanism by which purple grape juice affects the pharmacokinetics of digoxin. RESULTS: The results show that multiple-dose purple grape juice caused a remarkable increase in the AUC, Cmax, and Ka of orally administered digoxin (p < 0.05); only a single dose increased the digoxin AUC0-infinity by 72.80% (p < 0.05). Other parameters were not significantly affected. The study of intravenously administered digoxin found no significant difference in the pharmacokinetic characteristics of the two dosing groups (p > 0.05). The Caco-2 transwell experiments indicated that both the pure purple grape juice and its ethyl acetate extract significantly inhibited digoxin basolateral-to-apical (B >A) transport at concentrations of 10%, 30%, and 50% with dose dependency. These results confirmed that the improvement in bioavailability of digoxin resulted from the inhibition of P-gp by purple grape juice at the level of the gastrointestinal wall. CONCLUSION: Purple grape juice can increase the bioavailability of orally administered digoxin, especially with multiple doses. This information suggests that co-administration of oral digoxin and purple grape juice may require a dose adjustment.?. PMID- 30309449 TI - Relationships between abdominal aortic calcification, glomerular filtration rate, and cardiovascular risk factors in patients with non-dialysis dependent chronic kidney disease?. AB - BACKGROUND: Abdominal aortic calcification (AAC) is an established risk factor for cardiovascular events in patients with chronic kidney disease (CKD). We hypothesized that AAC is associated with a decline in glomerular filtration rate (GFR) as well as with some other cardiovascular risk factors. MATERIALS AND METHODS: This is a cross-sectional analysis of baseline data from a randomized controlled clinical trial (RENEXC). A total of 151 patients (aged 66 +/- 14 years) with an average measured GFR (mGFR) of 22.5 +/- 8.2 mL/min/1.73m2, not on renal replacement therapy, irrespective of number of comorbidities, were included. GFR was measured with iohexol clearance and estimated using cystatin C- and creatinine-based equations (eGFR). AAC was evaluated with lateral lumbar X ray using the scoring system described by Kauppila. All patients underwent laboratory analyses, 24-hour ambulatory blood pressure monitoring, and standard echocardiography. Multiple linear regression analyses controlling for sex, age, cardiovascular comorbidities, and hypertension were performed. RESULTS: The prevalence of AAC in this group of patients was 73%, and 47% had severe calcification (AAC score >= 7). More men (76%) had AAC than women (69%). AAC score was associated with mGFR (p = 0.03), eGFR (p = 0.006), plasma albumin (p = 0.006), plasma phosphate (p = 0.01), pulse pressure (p = 0.004), left ventricular mass (LVM) (p = 0.02), left atrial volume (LAV; p < 0.001), and left atrial volume index (LAVI; p = 0.001). CONCLUSION: AAC was highly prevalent in CKD. The degree of calcification in the abdominal aorta was strongly associated with a decline in GFR, a decrease in plasma albumin, an increase in plasma phosphate, an increase in pulse pressure, and cardiac structural changes, such as an increase in LVM, LAV, and LAVI.?. PMID- 30309451 TI - Capillary hemangioma involved in filar lipoma: A case report. AB - Filar lipomas are a subtype of spinal lipomas wherein adipose tissue accumulation is restricted to the filum terminale. Embryologically, filar lipomas are considered to occur because of the failure of secondary neurulation, although the precise mechanism is not yet completely understood. Involvement of ectopic mesodermal, ectodermal, and endodermal tissues in spinal lipomas has been occasionally reported, and the origin of these ectopic tissues has been supposed to be migration of pluripotent tissues, which exist during secondary neurulation. We report an infantile case of capillary hemangioma involved in filar lipoma. To our knowledge, this is the first report of a case of intradural extramedullary capillary hemangioma at the filum terminale. We suspected that the filar lesion arose during the late phase of secondary neurulation based on the clinical, anatomical, and histological characteristics.?. PMID- 30309452 TI - [Editorial]. PMID- 30309453 TI - A Tale of Two Failures: A Guide to Shared Decision-Making for Heart and Renal Failure. PMID- 30309454 TI - Cardiorenal Syndrome: A Call to Action for a Pressing Medical Issue. PMID- 30309455 TI - Cardiorenal Syndrome: An Overview. AB - It is well established that a large number of patients with acute decompensated heart failure present with various degrees of heart and kidney dysfunction usually primary disease of heart or kidney often involve dysfunction or injury to the other. The term cardiorenal syndrome increasingly had been used without a consistent or well-accepted definition. To include the vast array of interrelated derangements and to stress the bidirectional nature of heart-kidney interactions, a new classification of the cardiorenal syndrome with 5 subtypes that reflect the pathophysiology, the time frame, and the nature of concomitant cardiac and renal dysfunction was proposed. Cardiorenal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which acute or chronic dysfunction of one organ may induce acute or chronic dysfunction to the other. Although cardiorenal syndrome was usually referred to as acute kidney dysfunction following acute cardiac disease, it is now clearly established that impaired kidney function can have an adverse impact on cardiac function. PMID- 30309456 TI - Epidemiology of Cardiorenal Syndrome. AB - Cardiorenal syndrome is a spectrum of disorders that emphasizes the bidirectional nature of cardiac and kidney injury. Observational and retrospective studies have helped us to understand the prevalence and burden of each of the 5 types of cardiorenal syndromes. Cardiorenal syndrome type 1 is the most common. The nature of epidemiologic data limits clear delineation between cardiorenal syndrome types 2 and 4. Overall, the presence of cardiac or renal dysfunction strongly predicts a poor outcome of the contrary organ. PMID- 30309457 TI - Pathophysiological Mechanisms in Cardiorenal Syndrome. AB - Cardiorenal syndrome represents the confluence of intricate hemodynamic, neurohormonal, and inflammatory pathways that initiate and propagate the maladaptive cross talk between the heart and kidneys. Several of these pathophysiological principles were described in older historical experiments. The last decade has witnessed major efforts in streamlining its definition, clinical phenotypes, and classification to improve diagnostic accuracy and deliver optimal goal-directed medical therapies. The ability to characterize the various facets of cardiorenal syndrome based on its pathophysiology is poised in an exciting vantage point, in the backdrop of several advanced diagnostic strategies, notably cardiorenal biomarkers that may help with accurate delineation of clinical phenotype, prognosis, and delivery of optimal medical therapies in future studies. This promises to help integrate precision medicine into the clinical diagnosis and treatment strategies for cardiorenal syndrome and, through a heightened understanding of its pathophysiology, to deliver appropriate therapies that will reduce its associated morbidity and mortality. PMID- 30309458 TI - Heart-Kidney Interactions in Cardiorenal Syndrome Type 1. AB - The exact significance of kidney function deterioration during acute decompensated heart failure (ADHF) episodes is still under debate. Several studies reported a wide percentage of worsening renal function (WRF) in ADHF patients ranging from 20% to 40%. This is probably because of different populations enrolled with different baseline kidney and cardiac function, varying definition of acute kidney injury (AKI), etiology of kidney dysfunction (KD), and occurrence of transient or permanent KD over the observational period. Current cardiorenal syndrome classification does not distinguish among the mechanisms leading to cardiac and renal deterioration. Cardiorenal syndrome type 1 (CRS-1) is the result of a combination of neurohormonal activation, fluid imbalance, arterial underfilling, increased renal and abdominal pressure, and aggressive decongestive treatment. A more complete mechanistic approach to CRS-1 should include evaluation of baseline kidney function, timing, course and magnitude of KD, and introduction of specific biomarkers able to identify early kidney damage. Therefore, clinical and laboratory parameters may yield a different combination among predisposing, precipitating, and amplifying factors that may influence cardiorenal syndrome development. Thus, CRS-1 is a heterogeneous syndrome that needs to be better defined and categorized taking into account clinical status, renal condition, and treatment. The application of universal definitions for WRF/AKI definition would be the first step to achieve a clear classification. PMID- 30309459 TI - Toward Precision Medicine in the Cardiorenal Syndrome. AB - Although the field of oncology has made significant steps toward individualized precision medicine, cardiology and nephrology still often use a "one size fits all" approach. This applies to the intersection of the heart-kidney interaction and the cardiorenal syndrome as well. Recent studies have shown that the prognostic implications of worsening renal function (WRF) in acute heart failure are variable; thus, there is a need to differentiate the implications of WRF to better guide precise care. This may best be performed with biomarkers that can give the clinician a real-time evaluation of the physiologic state at the time of developing WRF. This review will summarize current cardiac and renal biomarkers and their status in the evaluation of cardiorenal syndrome. Although we have made progress in our understanding of this syndrome, further investigation is needed to bring precision medicine into routine clinical practice for the care of patients with cardiorenal syndrome. PMID- 30309460 TI - Diuretics in the Management of Cardiorenal Syndrome. AB - The leading cause of death worldwide is cardiovascular disease. The heart and the kidneys are functionally interdependent, such that dysfunction in one organ may cause dysfunction in the other. By one estimate, more than 60% of patients with congestive heart failure develop chronic kidney disease. Volume overload and congestion are hallmarks of heart failure, and these findings are associated with severe symptoms and poor outcomes. Given the importance of congestion, diuretics remain a cornerstone of heart failure management. However, diuretic treatment remains largely empirical, with little evidence currently available to guide decisions. In this review, we discuss the pathophysiology of cardiorenal syndrome, the pharmacology of loop diuretics, mechanisms of diuretic resistance, and evidence-based treatment paradigms. PMID- 30309461 TI - Extracorporeal Isolated Ultrafiltration for Management of Congestion in Heart Failure and Cardiorenal Syndrome. AB - Acute decompensated heart failure has the highest rate of hospital readmission among all medical conditions and portends a significant financial burden on health care system. Congestion, the hallmark of acute decompensated heart failure, represents the primary reason for hospitalization and the driver of adverse outcomes in these patients. Although diuretic-based medical regimens remain the mainstay of management of acute decompensated heart failure, they often show suboptimal efficacy and safety profiles in this setting. Mechanical extraction of excess fluid through extracorporeal ultrafiltration therapy has been proposed as a mechanistically relevant option in this setting. The advent of simplified, portable, and user-friendly devices that are dedicated to ultrafiltration therapy for these patients has renewed the interest in this therapeutic modality. In this article, we provide a brief overview of the initial mechanistic studies followed by the key clinical findings of the most recent landmark trials. The shortcomings of these studies are discussed in detail because not only do they provide the appropriate context in which the results are to be interpreted, but more importantly they also highlight the existing knowledge gaps that need to be addressed in future studies. Finally, selected practical and conceptual considerations and controversies are reviewed with regard to evidence-based ultrafiltration therapy. PMID- 30309462 TI - Advanced Heart Failure Therapies and Cardiorenal Syndrome. AB - Heart failure (HF) is extremely prevalent and for those with end-stage (stage D) disease, 1-year survival is only 25-50%. Several studies have captured the mortality impact of kidney disease on patients with HF, and measures of kidney function are a component of many HF risk stratification scores. The management of advanced HF complicated by cardiorenal syndrome (CRS) is challenging, and irreversible kidney failure often limits patient candidacy for advanced HF therapies, such as transplant or left ventricular assist device therapy. Thus, prompt institution of aggressive therapy is warranted in stage D HF patients with CRS to prevent irreversible kidney failure. In this chapter, we discuss the assessment and management of patients with CRS with end-stage HF. In addition to discussing medical therapy aimed at decongestion and increased cardiac inotropy, we provide a summary of temporary circulatory support devices that can be considered for those whom hospice is not desired. In all circumstances, a close collaboration between the advanced HF specialist and nephrologist is needed to achieve the best patient outcomes. PMID- 30309463 TI - Working Toward an Improved Understanding of Chronic Cardiorenal Syndrome Type 4. AB - Chronic diseases of the heart and of the kidneys commonly coexist in individuals. Certainly combined and persistent heart and kidney failure can arise from a common pathologic insult, for example, as a consequence of poorly controlled hypertension or of severe diffuse arterial disease. However, strong evidence is emerging to suggest that cross talk exists between the heart and the kidney. Independent processes are set in motion when kidney function is chronically diminished, and these processes can have distinct adverse effects on the heart. The complex chronic heart condition that results from chronic kidney disease (CKD) has been termed cardiorenal syndrome type 4. This review will include an updated description of the cardiac morphology in patients who have CKD, an overview of the most likely CKD-sourced culprits for these cardiac changes, and the potential therapeutic strategies to limit cardiac complications in patients who have CKD. PMID- 30309465 TI - Polygenic Risk Scoring for Coronary Heart Disease: The First Risk Factor. PMID- 30309464 TI - Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention. AB - BACKGROUND: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. OBJECTIVES: This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. METHODS: Using a meta analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. RESULTS: The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. CONCLUSIONS: The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction. PMID- 30309466 TI - Percutaneous Intramyocardial Septal Radiofrequency Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - BACKGROUND: In patients with disabling symptoms caused by hypertrophic obstructive cardiomyopathy (HOCM), echocardiography-guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) could be a less invasive treatment option. OBJECTIVES: This study aimed to investigate the safety and efficacy of the PIMSRA for left ventricular outflow tract (LVOT) gradient reduction in HOCM. METHODS: The study enrolled 15 patients with HOCM. These patients underwent electrocardiography, imaging, and blood biochemistry examination over 6 months of follow-up. RESULTS: At 6 months of follow-up, patients showed significant reductions in peak LVOT gradients (resting gradient: from 88.00 [66.00] mm Hg to 11.00 [6.00] mm Hg; p = 0.001; stress-induced gradient: from 117.00 [81.00] mm Hg to 25.00 [20.00] mm Hg; p = 0.005) and interventricular septum (IVS) thickness (anterior IVS: from 25.00 [21.00] mm to 14.00 [12.00] mm; p = 0.001; posterior IVS: from 24.00 [21.00] mm to 14.00 [11.50] mm; p = 0.001). The reductions in IVS thickness and LVOT gradients were associated with improvement in New York Heart Association functional classification (from 3.00 [2.00] to 1.00 [1.00]; p < 0.001), total exercise time (from 6.00 [5.50] min to 9.00 [8.00] min; p = 0.007), and pro B-type natriuretic peptide levels (from 924.00 [370.45] pg/ml to 137.45 [75.73] pg/ml; p = 0.028). No patient had bundle branch block or complete heart block. CONCLUSIONS: PIMSRA is a safe and effective treatment approach for severe, symptomatic HOCM and results in sustained improvement in exercise capacity, persistent reduction in LVOT gradient, and sustained improvement in cardiac function. PMID- 30309467 TI - Searching for Surgical Alternatives in Hypertrophic Cardiomyopathy. PMID- 30309468 TI - Provider Specialty, Anticoagulation, and Stroke Risk in Patients With Atrial Fibrillation and Cancer. AB - BACKGROUND: It is unknown whether early cardiology involvement shortly after atrial fibrillation (AF) diagnosis is associated with favorable outcomes in AF patients who have cancer. OBJECTIVES: The purpose of this study was to examine the relationship between early cardiology involvement after AF diagnosis in patients with history of cancer. METHODS: This study examined associations of early cardiology involvement with oral anticoagulation use, stroke, and bleeding among nonvalvular AF patients (n = 388,045; mean age 68 +/- 15 years; 59% male) with a history of cancer (past or active) from the MarketScan database (2009 to 2014). International Classification of Disease-9th Revision-Clinical Modification codes in any position were used to identify cancer diagnosis prior to AF diagnosis. Provider specialty and filled anticoagulant prescriptions 3 months prior to and 6 months after AF diagnosis were obtained. Poisson regression models were used to compute the probability of an oral anticoagulant prescription fill, and Cox regression was used to estimate the risks of stroke and major bleeding. RESULTS: A total of 64,016 (17%) AF patients had a history of cancer. Cardiology involvement was less likely to occur among patients with a history of cancer than those without (relative risk [RR]: 0.92 [95% confidence interval (CI): 0.91 to 0.93]). Patients with history of cancer were less likely to fill prescriptions for anticoagulants (RR: 0.89 [95% CI: 0.88 to 0.90]) than those without cancer, and similar results were observed across cancer types. Patients with cancer were more likely to fill prescriptions for anticoagulants (RR: 1.48 [95% CI: 1.45 to 1.52]) if seen by a cardiologist. A reduced risk of stroke (hazard ratio: 0.89 [95% CI: 0.81 to 0.99]) was observed among all cancer patients who were seen by a cardiology provider, without an increased risk of bleeding (hazard ratio: 1.04 [95% CI: 0.95 to 1.13]). Similar results were observed when the analysis was stratified by active versus remote history of cancer. CONCLUSIONS: Although AF patients with cancer were less likely to see a cardiologist, or fill anticoagulant prescriptions, cardiology involvement was associated with increased anticoagulant prescription fills and favorable AF-related outcomes in AF patients with cancer. PMID- 30309469 TI - Atrial Fibrillation in Cancer Patients: Recognizing Gaps in Care. PMID- 30309470 TI - High Coronary Shear Stress in Patients With Coronary Artery Disease Predicts Myocardial Infarction. AB - BACKGROUND: Coronary lesions with low fractional flow reserve (FFR) that are treated medically are associated with higher revascularization rates. High wall shear stress (WSS) has been linked with increased plaque vulnerability. OBJECTIVES: This study investigated the prognostic value of WSS measured in the proximal segments of lesions (WSSprox) to predict myocardial infarction (MI) in patients with stable coronary artery disease (CAD) and hemodynamically significant lesions. The authors hypothesized that in patients with low FFR and stable CAD, higher WSSprox would predict MI. METHODS: Among 441 patients in the FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation II) trial with FFR <=0.80 who were randomized to medical therapy alone, 34 (8%) had subsequent MI within 3 years. Patients with vessel-related MI and adequate angiograms for 3-dimensional reconstruction (n = 29) were propensity matched to a control group with no MI (n = 29) by using demographic and clinical variables. Coronary lesions were divided into proximal, middle, and distal, along with 5-mm upstream and downstream segments. WSS was calculated for each segment. RESULTS: Median age was 62 years, and 46 (79%) were male. In the marginal Cox model, whereas lower FFR showed a trend (hazard ratio: 0.084; p = 0.064), higher WSSprox (hazard ratio: 1.234; p = 0.002, C-index = 0.65) predicted MI. Adding WSSprox to FFR resulted in a significant increase in global chi-square for predicting MI (p = 0.045), a net reclassification improvement of 0.69 (p = 0.005), and an integrated discrimination index of 0.11 (p = 0.010). CONCLUSIONS: In patients with stable CAD and hemodynamically significant lesions, higher WSS in the proximal segments of atherosclerotic lesions is predictive of MI and has incremental prognostic value over FFR. PMID- 30309471 TI - Precluding Revascularization in Stable Coronary Disease: The Power of Double Negatives. PMID- 30309473 TI - Could Timing Be Everything for Antibody-Mediated Congenital Heart Block? PMID- 30309472 TI - Home Monitoring for Fetal Heart Rhythm During Anti-Ro Pregnancies. AB - BACKGROUND: Fetal atrioventricular block (AVB) occurs in 2% to 4% of anti-Ro antibody-positive pregnancies and can develop in <24 h. Only rarely has standard fetal heart rate surveillance detected AVB in time for effective treatment. OBJECTIVES: Outcome of anti-Ro pregnancies was surveilled with twice-daily home fetal heart rate and rhythm monitoring (FHRM) and surveillance echocardiography. METHODS: Anti-Ro pregnant women were recruited from 16 international centers in a prospective observational study. Between 18 and 26 weeks' gestation, mothers checked FHRM twice daily with a commercially available Doppler monitor and underwent weekly or biweekly surveillance fetal echocardiograms. If FHRM was abnormal, a diagnostic echocardiogram was performed. Cardiac cycle length and atrioventricular interval were measured, and cardiac function was assessed on all echocardiograms. After 26 weeks, home FHRM and echocardiograms were discontinued, and mothers were monitored during routine obstetrical visits. Postnatal electrocardiograms were performed. RESULTS: Most mothers (273 of 315, 87%) completed the monitoring protocol, generating 1,752 fetal echocardiograms. Abnormal FHRM was detected in 21 mothers (6.7%) who sought medical attention >12 h (n = 7), 3 to 12 h (n = 9), or <3 h (n = 5) after abnormal FHRM. Eighteen fetuses had benign rhythms, and 3 had second- or third-degree AVB. Treatment of second-degree AVB <12 h after abnormal FHRM restored sinus rhythm. Four fetuses had first-degree AVB diagnosed by echocardiography; none progressed to second degree AVB. No AVB was missed by home FHRM or developed after FHRM. CONCLUSIONS: Home FHRM confirms the rapid progression of normal rhythm to AVB and can define a window of time for successful therapy. (Prospective Maternal Surveillance of SSA [Sjogren Syndrome A] Positive Pregnancies Using a Hand-held Fetal Heart Rate Monitor; NCT02920346). PMID- 30309474 TI - Stress Cardiomyopathy Diagnosis and Treatment: JACC State-of-the-Art Review. AB - Stress cardiomyopathy is an acute reversible heart failure syndrome initially believed to represent a benign condition due to its self-limiting clinical course, but now recognized to be associated with a non-negligible rate of serious complications such as ventricular arrhythmias, systemic thromboembolism, and cardiogenic shock. Due to an increased awareness and recognition, the incidence of stress cardiomyopathy has been rising (15-30 cases per 100,000 per year), although the true incidence is unknown as the condition is likely underdiagnosed. Stress cardiomyopathy represents a form of neurocardiogenic myocardial stunning, and while the link between the brain and the heart is established, the exact pathophysiological mechanisms remain unclear. We herein review the proposed risk factors and triggers for the syndrome and discuss a practical approach to diagnosis and treatment of the patients with stress cardiomyopathy, highlighting potential challenges and unresolved questions. PMID- 30309475 TI - Cardiac Shock Care Centers: JACC Review Topic of the Week. AB - Despite advances over the past decade, the incidence of cardiogenic shock secondary to acute myocardial infarction has increased, with an unchanged mortality near 50%. Recent trials have not clarified the best strategies in treatment. While dedicated cardiac shock centers are being established, there are no standardized agreements on the utilization of mechanical circulatory support and the timeliness of percutaneous coronary intervention strategies. In some centers and prospective registries, outcomes after placement of advanced mechanical circulatory support prior to reperfusion therapy with percutaneous coronary intervention have been encouraging with improved survival. Here, we suggest systems of care with a treatment pathway for patients with acute myocardial infarction complicated by cardiogenic shock. PMID- 30309476 TI - Does Radial Artery Harvest for Coronary Surgery Compromise Forearm Blood Flow to 22 Years Post-Operative? PMID- 30309477 TI - High-Molecular-Weight von Willebrand Factor Multimer Ratio: A Novel Biomarker for Low-Flow, Low-Gradient Aortic Stenosis Subclassification. PMID- 30309478 TI - Direct Oral Anticoagulants Halve Thromboembolic Events After Cardioversion of AF Compared With Warfarin. PMID- 30309479 TI - Free Androgen Index as a Biomarker of Increased Cardiovascular Risk in Postmenopausal Women. PMID- 30309480 TI - Reply: Free Androgen Index as a Biomarker of Increased Cardiovascular Risk in Postmenopausal Women. PMID- 30309481 TI - Impaired cutaneous T-cell attracting chemokine elevation and adipose-derived stromal cell migration in a high-glucose environment cause poor diabetic wound healing. AB - Diabetic wound care is a major health care concern. The major cause of non healing of wounds in patients with diabetes mellitus (DM) patients mainly involves poor glycemic control, which hinders the migration of progenitor cells including mesenchymal stem cells to the wound site. In this study, we introduced adipose-derived stromal cells (ADSCs) into wound sites and demonstrated that the local transplantation of ADSCs accelerated DM-related wound healing. Furthermore, the migration ability of ADSCs, which diminishes in a high-glucose environment, was partially restored by the exogenous replenishment of the cutaneous T-cell attracting chemokine (CTACK/CCL27). Our findings suggest that CTACK is a potential novel therapeutic target in DM-related wound healing. PMID- 30309482 TI - Lentiviral-mediated microRNA-26b up-regulation inhibits proliferation and migration of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a frequently occurred malignancy worldwide with a high mortality. The treatment for HCC is still controversial. Emerging evidences have demonstrated that microRNAs (miRs) play a role in HCC. This study aims to investigate the effects of lentiviral-mediated miRNA-26b (miR-26b) on the proliferation and metastasis of HCC cells. The normal hepatic cell line HL-7702 and HCC cell lines HepG2 (without metastatic potential), SMMC-7721 (with low metastatic potential) and MHCC97H (with high metastatic potential) were purchased for our experiment. The lentiviral-mediated miR-26b overexpression (miR-26b-LV) and low expression (sh-miR-26b) were constructed to transfect the cells. The miR 26b expression and expressions of Karyopherin alpha-2 (KPNA2), matrix metalloproteinase 1 (MMP-1), MMP-7 and MMP-14 were determined by RT-qPCR and western blot analysis. The proliferation and metastasis of transfected HCC cells were detected by MTT and Transwell assay respectively. The miR-26b expressions were decreased significantly in MHCC97H cells. With lentiviral-mediated miR-26b overexpression, the proliferation and migration of HepG2, MHCC97H and SMMC-7721 cells were decreased significantly. The RT-qPCR and western blot analysis results revealed that the mRNA and protein expressions of KPNA2, MMP-1, MMP-7 and MMP-14 were decreased by lentiviral-mediated miR-26b overexpression. All the above indexes in the HepG2, MHCC97H and SMMC-7721 cells treated by sh-miR-26b exhibited opposite trends. These results show that overexpressed miR-26b could inhibit the proliferation and metastasis of HCC cells significantly, which provides a novel target and theoretical foundation for the treatment of HCC. PMID- 30309483 TI - MicroRNA-21 is upregulated during intestinal barrier dysfunction induced by ischemia reperfusion. AB - This study aimed to investigate the expression of miRNA-21 during intestinal barrier dysfunction induced by intestinal ischemia reperfusion. Forty SPF SD rats were divided into 5 groups randomly. Intestinal ischemia-reperfusion injury (IRI) was induced by mesenteric artery occlusion for 1 h and reperfusion for 1 h, and the rats were sacrificed at 1, 3, 6 and 12 h after reperfusion. Fresh intestine tissues were immediately isolated for the measurement of transepithelial electrical resistance (TER). The levels of cytokines, ICAM-1, DAO, iFABP and MPO in serum were determined by ELISA. Intestinal tight junction proteins occludin and claudin-1 were detected by immunofluorescence analysis and Western blot analysis. miR-21 expression in intestinal tissues was measured by RT-PCR. Compared with sham group, the levels of pro-inflammatory cytokines TNF-alpha and IL-6 and ICAM-1, DAO, iFABP and MPO increased while IL-10 level decreased in intestinal ischemia-reperfusion group. In addition, the levels of intestinal tight junction proteins occludin and claudin-1 decreased while miR-21 level increased in intestinal ischemia-reperfusion group, compared with sham group. In conclusion, miR-21 expression is upregulated during intestinal barrier dysfunction induced by IRI. miR-21 may play an important role in the regulation of intestinal barrier function. PMID- 30309484 TI - The ghrelin and orexin activity in testicular tissues of patients with idiopathic non-obstructive azoospermia. AB - The aim of the present study is to evaluate the presence of ghrelin and orexin in the testicular tissue of patients who have undergone microscopic testicular sperm extraction (micro-TESE) due to idiopathic non-obstructive azoospermia. Seventy azoospermic cases were included in this study; serum hormone levels were measured and genetic investigations were performed. The patients were divided into two groups: micro-TESE (+) and micro-TESE (-). The number of Leydig cells and stained cells in the seminiferous tubules were counted under a light microscope, and we analyzed ghrelin and orexin activity. The relationship between serum hormone levels and ghrelin and orexin distributions in testicular tissue was evaluated according to micro-TESE results. While sperm was found in 33 cases (47.1%), micro TESE was negative in 37 cases (52.9%). Peptide hormone activity in testicular tissue was higher in micro-TESE (+) cases. However, interstitial orexin (p = 0.038) and ghrelin (p = 0.002) activity showed statistically meaningful differences. Many different peptides, genes, and other unknown mechanisms play important roles in testicular function. In particular, the peptides orexin and ghrelin may play regulatory roles in testicular function in humans. PMID- 30309485 TI - Prognostic predictive value of TLR4 polymorphisms in Han Chinese population with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease and is an important cause of sudden death in patients of all ages. The aim of this study was to find out whether Toll-like receptor-4 (TLR4) polymorphism is associated with HCM. To explore the association between TLR4 gene polymorphisms and HCM, 486 HCM patients and 214 healthy controls were enrolled in a case control study of Chinese Han population. Two single nucleotide polymorphisms (SNPs) in the promoter region of TLR4 gene, -728G > C (rs11536865) and -2081G > A (rs10983755), were genotyped by PCR restriction fragment length polymorphism (PCR RFLP). The associations between TLR4 SNPs and overall survival (OS) of HCM patients were analyzed by the Kaplan-Meier estimation method and Cox proportional hazards regression analysis. Serum TLR4 level was determined by ELISA. Our results showed that the C allelic frequency of -728G > C and A allelic frequency of -2081G > A were higher in HCM patients than those in controls (P < 0.001). The ratios of genotype frequencies for both SNPs were associated with HCM susceptibility under three genetic models (P < 0.01). Two SNPs were also associated with the OS in HCM patients (P < 0.001). The CC genotype of -728G > C and AA genotype of -2081G > A were associated with poor prognosis of HCM (P < 0.001). Moreover, HCM patients had a higher serum TLR4 level compared with the controls (242.6 pg/ml versus 135.7 pg/ml, P = 0.027). In addition, significant associations were observed between CC genotype of -728G > C or AA genotype of 2081G > A and plasma TLR4 level (P < 0.01). The results of this study indicated that TLR4 polymorphisms may be a genetic susceptibility factor for HCM in the Han Chinese population. PMID- 30309486 TI - Influence of prostate size on the perioperative and postoperative outcome of transurethral plasmakinetic enucleation of the prostate: Results of 892 patients with 3 years of follow-up. AB - To explore the influence of prostate size on the outcome of Plasmakinetic enucleation of the prostate (PkEP) for the treatment of benign prostate hyperplasia (BPH), The data of 892 patients with symptomatic BPH who underwent PkEP were retrospectively reviewed. Among them, 199 (22.31%) had the prostate size smaller than 40 g (Group 1), 409 (45.85%) between 40 and 79 g (Group 2), 197 (22.09%) between 80 and 120 g (Group 3), and 87 (9.75%) larger than 120 g (Group 4). Perioperative variables, perioperative and postoperative complications were recorded. Patients were followed up for 36 months postoperatively. The efficiency of the surgery increased as the prostate size increased. Greater decreases in hemoglobin were noted in groups with larger prostates, while the duration of catheterization after the operation was similar across all groups. During the 3 year follow-up, the postoperative improvement in International Prostate Symptom Score (IPSS), Quality of Life (QOL), maximal flow rate (Qmax) and post-void residual urine volume (PVR), as well as longterm complications including urethral stricture and bladder-neck contracture were comparable across the 4 groups. These findings revealed that PkEP is more efficient for large prostate and can treat all prostates regardless of the size with equivalent symptom relief and micturition improvement. PMID- 30309487 TI - Did AFP-L3 save ultrasonography in community screening? AB - In the community screening, those subjects with elevated serum alpha-fetoprotein (AFP) required further abdomen ultrasonography (US) to detect hepatocellular carcinoma (HCC). However, some chronic hepatitis patients might have elevated AFP. AFP-L3, has been proposed to differentiate HCC and hepatitis in elevated AFP cases in Japan for decades, but the utility is limited outside Japan. We conducted this study to elucidate the role of AFP-L3 in the community and the possibility of saving unnecessary US. A total of 56,702 subjects underwent a large-scale healthcare screening in Tainan county in 2004. Among them, 286 residents with AFP more than 20 ng/ml further received US and 169 (59%) had stored baseline sera were enrolled into this study in 2013. Their AFP and AFP-L3 levels were further detected. HCC patients were initially identified through US and personal history. Among 169 studied sera, only 148 (87.6%) samples still had AFP level more than 20 ng/ml after a 10-years frozen period. The decrease of AFP level was significant (481.3 +/- 2093.8 ng/ml and 456.1 +/- 2095.3 ng/ml in paired-T test, p < 0.001). Focusing on these 148 cases, 23 (15.5%) HCC cases were diagnosed at the baseline screening. There was no difference of AFP-L3 level between HCC and non-HCC cases. Using AFP-L3 to predict HCC, the area under Receiver Operating Characteristic curve was as low as 52%, p = 0.757. Too long frozen period might lower the quality of stored sera. Additionally, AFP-L3 might not provide more information for HCC identification to save advanced US examinations in the community screening. PMID- 30309488 TI - Senior-Loken syndrome with IQCB1 mutation in Taiwan. PMID- 30309489 TI - Photopsia, an unusual manifestation of optic chiasm compression by sphenoid sinus chodorma. PMID- 30309490 TI - Barrett's ablation: blowing hot, blowing cold. PMID- 30309491 TI - The dawn of a new era: performance measurement for the pathologic diagnosis of Barrett's esophagus-associated dysplasia. PMID- 30309492 TI - Is 35 the new 50? Challenges in determining colonoscopy surveillance recommendations for young patients with incidentally detected adenomas. PMID- 30309493 TI - The FUSE enigma: Wide-angle or wide-minded? PMID- 30309494 TI - EUS versus transpapillary drainage of malignant biliary obstruction: still a long way to go. PMID- 30309495 TI - Trends in the timing of inpatient ERCP relative to cholecystectomy need to be improved. PMID- 30309496 TI - Response. PMID- 30309497 TI - HAX1 is associated with neuronal apoptosis and astrocyte proliferation after spinal cord injury. AB - HS1-associated protein X-1 (HAX1) is a class of multifunctional protein, participated in various physiological processes such as cell apoptosis, proliferation and motility. However, the HAX1 expression and function in the spinal cord injury (SCI) pathological process have not been investigated. In our current research, the rat model of SCI was established, and then we explored the possible role of HAX1 after SCI. The results of western blot indicated that HAX1 was present in sham operated control group and significantly elevated at 3 days post SCI, then declined gradually. Immunohistochemical studies indicated HAX1 expression was enhanced significantly in white and gray matter at 3 days post SCI compared with sham operated group. Double immunofluorescence staining showed the proportion of cells, double-labeled HAX1 and neurons, astrocytes, increased significantly at 3 days post SCI. In addition, co-localization of HAX1/active caspase-3 and HAX1/PCNA was tested in cells. Furthermore, over-expression of HAX1 inhibited neuronal apoptosis in vitro, and in astrocytes HAX1 silencing could down-regulate PCNA expression post LPS treatment. Meanwhile, CCK8 assay showed that knockdown of HAX1 could inhibit the astrocyte proliferation. In summary, our data indicated that HAX1 might play significant roles in pathological process of neuronal apoptosis and astrocyte proliferation during SCI. PMID- 30309498 TI - Establishment and characterization of a new triple-negative canine mammary cancer cell line. AB - Canine mammary tumor (CMT) has always been an ideal animal model for human breast cancer (HBC) research, however, there is a lack of various established CMT cell lines corresponding to HBC cell lines. This study was designed to establish a new type of CMT cell line. The primary tumor, CMT-7364, was identified as the intraductal papillary carcinoma, and showed negative immunoreactivity to estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER-2) by immunohistochemistry (IHC) analysis. The CMT-7364 cell line from this primary tumor also shows a negative immunoreactivity to ER, PR, and HER 2, and was negative to epithelial cell markers and positive to mesenchymal cell markers by immunocytochemistry (ICC) analysis. This cell line, which has been stably cultured for more than 115 passages, and was characterized by epithelial origin with the expression of the epithelial antigen by ICC analysis and invasion ability by transwell analysis. In vivo, tumor mass and metastases in the lung were found after inoculating the CMT-7364 cells in the nude mice model, and the immune-complete mice model respectively. The tissues from the xenograft tumor were also negative to ER, PR, and HER-2 by IHC analysis. Thus, a novel triple negative canine mammary cancer cell line, CMT-7364, was successfully established, which could be used as a promising model for the research of immunotherapy and Epithelial-Mesenchymal Transition (EMT) mechanism of the triple-negative breast cancer both in canine and human. PMID- 30309499 TI - Anti-aging protective effect of L-carnitine as clinical agent in regenerative medicine through increasing telomerase activity and change in the hTERT promoter CpG island methylation status of adipose tissue-derived mesenchymal stem cells. AB - The identification of factors that reduce the senescent tendency of the mesenchymal stem cells (MSCs) upon expansion has great potential for cellular therapies in regenerative medicine. Previous studies have shown the aging protective effect of L-carnitine (LC). On the other hand, reduction in proliferation potential and age-dependent decline in number and functions of MSCs were accompanied by telomere shortening, reduction in telomerase activity and epigenetic changes. The aim of this study was to evaluate the effects of LC on aging of MSCs through telomerase activity assessment and the investigation of methylation status of the hTERT gene promoter. Telomerase activity and hTERT promoter methylation investigation was performed with PCR-ELISA TRAP assay and methylation specific PCR (MSP), respectively. Also, beta-galactosidase (SA-beta gal) staining was used to calculate the percentage of senescent cells. The results showed that the LC could efficiently promote the telomerase activity. In addition, the percentage of senescent cells had significantly decreased and changes in the methylation status of the CpG islands in the hTERT promoter region under treatment with LC were seen. In conclusion, it seems that LC could improve the aging-related features due to increasing the telomerase activity, decreasing aging, and changing the methylation status of hTERT promoter; it could potentially beneficial for enhancing the application of aged-MSCs in regenerative medicine. PMID- 30309500 TI - Spermatological characteristics of the family Glypthelminthidae (Digenea, Plagiorchioidea) inferred from the ultrastructural study of Glypthelmins staffordi Tubangui, 1928. AB - The present study describes the ultrastructural organization of the mature spermatozoon of the digenean Glypthelmins staffordi (Glypthelminthidae) by means of transmission electron microscopy. Live digeneans were collected from the Chinese edible frog (Hoplobatrachus rugulosus) in Udon Thani Province (Thailand). The ultrastructural study reveals that the mature spermatozoon of G. staffordi is a filiform cell, which is tapered at both extremities. It exhibits the Bakhoum et al.'s type IV of spermatozoon of digeneans characterized by the 9+'1' axonemes of trepaxonematan Platyhelminthes, the presence of the association "external ornamentation-cortical microtubules", the external ornamentation located in the posterior part of the anterior region, the arrangement of parallel cortical microtubules in two bundles and with its maximum number located in the anterior part of the sperm cell, and the presence of two mitochondria. Other characteristics are the presence of spine-like bodies, a posterior extremity containing only the nucleus, and the presence of a large amount of glycogen granules. Results of the present study are particularly compared with the existing data in other families of the Plagiorchioidea, namely the Brachycoeliidae, the Haematoloechidae, the Omphalometridae and the Plagiorchiidae. PMID- 30309501 TI - Fractal dimension in the evaluation of different treatments of muscular injury in rats. AB - OBJECTIVES: To evaluate alterations from different therapies in muscular injury using the Fractal Dimension (FD) method. METHODS: 35 animals were allocated in Control Group (C), Injury Control Group (IC), Injury Low Level Laser Therapy Group (ILT), Injury Platelet Rich Plasma Group (IP), and Injury LLLT and PRP Group (ILP). The animals suffered a stretch injury in gastrocnemius muscle and after that IP and ILP groups received PRP application. The ILT and ILP groups received daily LLLT applications for seven days. After seven days the animals were euthanized and the gastrocnemius muscle removed and frozen. The muscles were stained with Hematoxylin and Eosin (HE) and Picrosirius Red, for observation of the morphology of the injury and semi-quantitative and quantitative analysis through the Fractal Dimension (FD) method. RESULTS: In the qualitative and semi quantitative analysis, in relation to IC group, the ILT presented a reduction in rounded fibers and the IP in angular fibers. The ILP group demonstrated a reduction in both polymorphic fibers and inflammatory infiltrate. The FD of the muscles stained with HE was higher in the groups that suffered the injury when compared to the C group (p < 0.05); the FD of the collagen demonstrated no statistical difference between the groups. CONCLUSION: Both treatments were able to accelerate injury repair, and the association of both presented better results than the isolated applications. However, the FD method showed no sensitivity to differentiate the treatments, either in the histological aspects or the injury in collagen. PMID- 30309502 TI - Macroscopic and microscopic study of the tongue of the aardvark (Orycteropus afer, Orycteropodidae). AB - The aim of this study was to describe the morphology of the tongue in the aardvark (Orycteropus afer). The tongues from one adult and one three-week old aardvark females and one neonate aardvark were studied. The tongue was elongated in the adult and young aardvarks and had a triangular apex in the rostral part of the tongue. Its dorsal surface was covered by numerous papillae divided into mechanical papillae, present in the form of abundant conical or drop-like filiform papillae, and taste papillae in the form of numerous fungiform papillae and three vallate papillae arranged in a V-shape in the caudal part of the tongue (one papilla was located centrally and caudally with respect to the remaining two papillae). The vallate papillae were round with conical pseudopapillae on their surface. They were surrounded by an annular pad, which was formed by filiform papillae with conical tip. Numerous openings of barrel-shaped taste buds were present in the epithelium covering the surface of fungiform papillae, and in the epithelium of inner walls of the vallate papillae. The serous von Ebner's glands were located beneath the vallate papillae. The mucoserous Weber's glands were PAS, AB pH2.5, pH1.0 and AB/PAS positive and HDI-weakly positive. PMID- 30309503 TI - Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. AB - Alterations of Endothelial cells (ECs) play a critical role in different pathogenesis of many serious human diseases, and dysfunction of the vascular endothelium is an indicator for human disorders. Endothelial dysfunction is considered to be an early indicator for atherosclerosis, which is characterised by overexpression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Hydrogen peroxide (H2O2) released via neutrophils is an important mediator of endothelial cell function. Ambient production of superoxide anion (O2-) and subsequently H2O2 at low levels is critical for regulating endothelial cell functions and proliferation. In this study, we investigated the effects of H2O2 on the expression of adhesion molecules VCAM-1 and ICAM-1 in cultured human umbilical vein endothelial cells (HUVECs). Intracellular superoxide anion production was detected by using p-Nitro Blue Tetrazolium (NBT) assay. Our results showed that administration of 100MUM of H2O2 on HUVECs for 2, 6, 12 and 24 h induced a time dependent increase in ICAM-1 and VCAM-1 mRNA and protein expression levels with a significant increase observed from 6 h. HUVECs exposed to H2O2 exhibit increased O2-, suggesting that H2O2 induced oxidative stress may be a reasonable for atherosclerosis. This increase can be reduced by the flavonoid, N-acetyl cysteine (NAC). The modulation of endothelial cell function through this mechanism may underlie the contribution of H2O2 to the development of vascular disease. PMID- 30309505 TI - Rho-associated kinase inhibitor enhances the culture condition of isolated mouse salivary gland cells in vitro. AB - Hyposalivation because of curative radiation therapy in patients with head and neck cancer is a major concern. At present, there is no effective treatment for hyposalivation, highlighting the importance of cell therapy as a new therapeutic approach. To provide functional cells for cell replacement therapy, it is important to overcome the limitations of current in vitro culture methods for isolated salivary gland cells. Here, we suggest an improved culture condition method for the cultivation of isolated salivary gland cells. The dissociated submandibular salivary gland cells of mice were seeded and treated with Rho associated kinase (ROCK) inhibitor (Y-27632), which resulted in an increase in their cell adhesion, viability, migration, and proliferation. In particular, ROCK inhibitor treatment maintained the expression of alpha-amylase in the primary cultured salivary gland cells for a long time as compared with untreated cells. The expression of C-Met, a ductal cell marker, was increased in cells treated with ROCK inhibitor. This modified culture condition may serve as an easy and convenient tool for culturing primary salivary gland cells for their application in hyposalivation therapy. PMID- 30309504 TI - Tumor-targeting Salmonella typhimurium A1-R overcomes partial carboplatinum resistance of a cancer of unknown primary (CUP). AB - Cancer of unknown primary (CUP) is metastatic disease without a known primary and therefore very difficult to identify effective therapy. Previously, we demonstrated partial efficacy of Salmonella typhimurium A1-R (S. typhimurium A1 R) alone and carboplatinum alone (CAR) on a CUP patient tumor in the patient derived xenograft (PDOX) model. The aim of the present study was to investigate the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. The CUP tumors were implanted orthotopically into the left supraclavicular fossa of nude mice to match the site from which they were resected from the patient. CUP PDOX models were divided randomly into the following 4 groups after the tumor volume reached 100 mm3: G1: untreated group; G2: CAR (30 mg/kg, i.p., weekly, 2 weeks); G3: S. typhimurium A1-R (5x107 CFU/body, i.v., weekly, 2 weeks).; G4: S. typhimurium A1-R combined with CAR (S. typhimurium A1-R; 5x107 CFU/body, i.v., weekly, 2 weeks; CAR, 30 mg/kg, i.p., weekly, 2 weeks). Each group comprised 7 mice. All mice were sacrificed on day 15. Tumor volume and body weight were measured twice a week. S. typhimurium A1-R and CAR moderately inhibited tumor growth compared to the untreated group on day 15 (P < 0.001 and P < 0.001, respectively). S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to S. typhimurium A1-R monotherapy or CAR monotherapy on day 15 (P = 0.004 and P = 0.001, respectively). The present report demonstrates that S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model. PMID- 30309506 TI - Morphology and ultrastructure of pink cusk-eel (Genypterus blacodes, Schneider 1801) spermatozoa by scanning and transmission electron microscopy. AB - In this study, the morphology and ultrastructure of Genypterus blacodes spermatozoa were characterized through scanning and transmission electron microscopy. Findings revealed that the G. blacodes spermatozoa can be differentiated into three major parts: a spherical head without an acrosome (typical for externally fertilizing fish), a short mid-piece, and a long flagellum. The mean length of the spermatozoa was 57.6 +/- 6.08 MUm, with flagella accounting for 56.2 +/- 7.2 MUm. The head was 1.47 +/- 0.2 MUm long, and 0.89 +/- 0.06 MUm wide. The mid-piece had a total dimension of 0.72 +/- 0.16 MUm, and was 0.31 +/- 0.02 MUm in length and 0.6 +/- 0.05 MUm in width. It was located lateral to the nucleus and contained 4 or 5 spherical mitochondria. The mitochondria were separated from the axoneme by a cytoplasmic canal. The main piece of the flagellum had short irregular side-fins, and the axoneme was composed of the typical 9 + 2 microtubular doublet structure enclosed by a cell membrane. The present study reveals that G. blacodes sperm can be categorized as a primitive type. This study is the first to provide comprehensive details on the morphology and ultrastructure of spermatozoa in G. blacodes. PMID- 30309507 TI - Postnatal maturation of the intestinal epithelial barrier in prairie voles. AB - Intestinal epithelium develops during gestation and continues to mature post natally into a selective barrier that will protect the individual while still allowing passage of nutrients. Until fully mature, the risk of translocation of microorganisms, toxins or antigens into the sub-epithelial tissue is high and could result in pathologies with life-altering consequences, or even premature death. Because of their monogamous mating system, prairie voles are an emerging model for studying the role of the intestinal microbiota in modulating social behavior via the microbiota-gut-brain-behavior axis. However, knowledge about the voles' intestinal barrier maturation is lacking. Understanding the maturation of the intestine epithelial barrier can complement the extensive behavioral literature for future studies involving the vole gut-brain axis. In this study, we characterized intestinal barrier function by demonstrating that two-week-old prairie voles have high paracellular absorption of FITC-dextran molecules prior to markedly decreased permeability at three weeks of age. In light of the fundamental role of tight junctions in maintaining epithelial integrity regulating intestinal permeability, we examined tight junction gene expression profiles. Transmission electron microscopy was used to visualize tight junction structure. Our results provide a timeline for intestinal barrier maturation and point to tight junction proteins involved in this process in prairie voles. PMID- 30309508 TI - Correlation between valvular interstitial cell morphology and phenotypes: A novel way to detect activation. AB - Valvular interstitial cells (VICs) constitute the major cell population in heart valves. Quiescent fibroblastic VICs are seen in adult healthy valves. They become activated myofibroblastic VICs during development, in diseased valves and in vitro. 2D substrate stiffness within a 5-15 kPa range along with high passage numbers promote VIC activation in vitro. In this study, we characterize VIC quiescence and activation across a 1-21 kPa range of substrate stiffness and passages. We define a cell morphology characterization system for VICs as they transform. We hypothesize that VICs show distinct morphological characteristics in different activation states and the morphology distribution varies with substrate stiffness and passage number. Four VIC morphologies - tailed, spindle, rhomboid and triangle - account for the majority of VIC in this study. Using alpha-smooth muscle actin (alpha-SMA), non-muscle myosin heavy chain B (SMemb) and transforming growth factor beta (TGF-beta) as activation markers for validation, we developed a system where we categorize morphology distribution of VIC cultures, to be potentially used as a non-destructive detection method of activation state. We also show that this system can be used to force stiffness induced deactivation. The reversibility in VIC activation has important implications in in vitro research and tissue engineering. PMID- 30309509 TI - Neurochemical properties of neurospheres infusion in experimental-induced seizures. AB - Cell replacement through neural stem cells has been a promising alternative therapy for neurodegenerative diseases. It was evaluated the possible protect and/or prevent role of neurospheres in experimental models of epilepsy by the use of biomarkers of oxidative stress and histopathological analysis. After 1 h of the epileptic inductions by pilocarpine, pentylenotetrazole and picrotoxin, rats were infused with a suspension of 2 * 106 cells/0.25 mL, marked with Qtracker(r) 655, via caudal vein. In the control group epilepsy was not induced, but received the cell infusion under the same conditions of other groups. After 30 days, the rats were euthanized, and the removal of the brain was proceeded to later perform the assays oxidative stress and histopathology analysis. Thiobarbituric acid and nitrite levels were elevated in epileptic groups treated with neurospheres, and the levels of reduced glutathione, superoxide dismutase and catalase were reduced when compared to non-treated groups. The performance of oxidative enzymes from pilocarpine group treated with neurospheres showed slight increase. Histopathological evaluation observed distribution of neurospheres throughout the brain tissue, with viable cells and in process of differentiation in the pilocarpine group, but with differentiation and regeneration compromised in epilepsy by picrotoxin and pentylenetetrazole due to a microenvironment of oxidative stress. Neural stem cell therapy has a promising potential for protection in the pilocarpine epilepsy model, suggesting that the antioxidant system of neurospheres could reduce oxidative damage generated by seizure. PMID- 30309510 TI - Unusual light-reflecting pigment cells appear in the Xenopus neural tube culture system in the presence of guanosine. AB - Isolation and culture of Xenopus laevis neural tubes resulted in differentiation of melanophores and iridophores from neural crest cells; the differentiated melanophores and iridophores were then maintained in culture for more than 6 months. Guanosine has been reported to promote reflecting platelet formation in melanin-producing pigment cells; however, the process of pigment organellogenesis is still unclear. In the present study, unusual light-reflecting pigment cells were observed upon addition of guanosine to the neural tube culture system, which contained melanosomes specific to melanophores, and reflecting platelets specific to iridophores. Ultrastructural studies suggested that irregularly shaped reflecting platelets were formed from stage II melanosomes (the early stage of melanosome formation) in these unusual pigment cells. PMID- 30309511 TI - Mitigation of stress from gastric mucosal injuries by mulberry extract may occur via nitric oxide synthase signaling in mice. AB - Acute gastric mucosal injuries are serious clinical problems worldwide and are principally found with different types of stresses in animals. A constant challenge is to find original plant products that can combat stress. In the present study, we examined the effects of big-leaf mulberry extracts on stomach injury, and the activity of nitric oxide synthases (NOS) and total antioxidant activity (TAO) in the gastric mucosae of mice during water immersion and restraint stress (WIRS). Our data showed that WIRS-exposed mice produced several injuries and showed an enhanced iNOS, reduced eNOS activity, and decreased TAO activity in the stomach, whereas pretreatment with big-leaf mulberry extracts increased TAO activitiy. The data from our immunohistochemical study indicated that both iNOS and eNOS were expressed in parietal cells and blood vessels, while nNOS was only weakly expressed in parietal cells. In conclusion, our findings suggested that big-leaf mulberry mitigated WIRS-induced stomach injuries, and NOS signaling may play important roles in the mouse stomach during the recovery process. PMID- 30309512 TI - ICBP90 mediates Notch signaling to facilitate human hepatocellular carcinoma growth. AB - The Notch signaling pathway plays a key role in cell proliferation and development that is closely related to an inverted CCAAT box binding protein (ICBP90), but little is known about whether there is a correlation between Notch signaling and ICBP90. The aim of the current study was to elucidate this. MTT assay and flow cytometry were used to determine the proliferation, cell cycle and apoptosis of HepG2 or Hepa1-6 cells treated by N-[N-(3,5-difluorophenacetyl)-L alanyl]-S-phenylglycine t-butyl ester (DAPT), a specific inhibitor of the Notch pathway. RT-PCR, Western Blot and in situ immunofluorescence staining were employed to examine expression of ICBP90 in the cells. DAPT caused inhibition of the activation of the Notch signaling pathway, followed by preventing the cells at the G0/G1 phases to enter S and G2/M phases. ICBP90 and Hes-1 proteins were highly expressed in the untreated cells. The reduced levels of Notch intracellular domain (NICD) protein were observed in the DAPT-treated cells, thereby bringing about the down-regulation of ICBP90 with the increment of the DAPT dose. Consistent with this, knockdown of the Hes-1 gene, which encodes a critical transcriptional factor in the Notch pathway, also led to the attenuation of ICBP90. On the contrary, Jagged-1, a Notch ligand, facilitated ICBP90 production. Adriamycin could result in the reduction of ICBP90, which was not accompanied with the alteration of Hes-1. ICBP90 was almost fully distributed within the nuclei, but Hes-1 was visible within both the cytoplasm and nuclei. Our novel findings strongly indicate that inactivation of the Notch signaling pathway impedes hepatocellular carcinoma progress via reduction of ICBP90. PMID- 30309513 TI - Cardiac myofibroblast induces decreased expression of major histocompatibility complex class II (Ia) on rat monocyte/macrophages. AB - The up-regulation of HLA antigens is important during heart inflammatory events and myofibroblasts may modulate the expression of this molecule in tissues. To test this possibility, the effect of cardiac myofibroblast:macrophage contact and the production of myofibroblast inhibitor factor(s) on the macrophage HLA (Ia) expression were studied. Listeria monocytogenes-elicited Ia + peritoneal macrophages (high Ia expression) were co-cultured with cardiac myofibroblasts for 3 and 7 days (myofibroblast contact). Proteosa peptone-elicited macrophages (low Ia expression) were cultured for 3 days with interferon gamma (INF-gamma) and myofibroblast conditioned medium (FCM). Ia expression was analyzed by immunofluorescence and by radioimmune assay. Myofibroblast contact induced decreased expression of Ia molecule on macrophages (p < 0.001). This was confirmed by the radioimmune analysis in macrophage: myofibroblast co-cultures (p < 0.001). Double staining for Ia and CD14 showed that only CD14 positive cells (macrophages) expressed Ia molecule. FCM was capable of diminishing Ia expression induced by INF-gamma on macrophages (p < 0.001). Decreased Ia macrophage expression induced by myofibroblasts could be important in the heart inflammation's resolution, probably involving Ia redistribution on cell: cell contact and myofibroblast inhibitor factor production. PMID- 30309514 TI - Ameliorative effect of zinc oxide nanoparticles on cyclophosphamide induced testicular injury in adult rat. AB - Despite its wide range of application, cyclophosphamide (CP) exhibits a wide range of adverse effects including reproductive toxicity. The emerging field of zinc oxide nanoparticles (ZnO NPs) therapy may provide a new hope for prevention of CP induced gonadal toxicity. Herein, we aim to investigate the possible role of ZnO NPs as a new strategy to protect against CP induced testicular injury. Sixty adult male albino rats were divided into 3 groups; control, CP treated and CP + ZnO NPs treated groups. CP group was injected with CP (5 mg/kg/day), whereas CP + ZnO NPs group was concomitantly injected with CP and ZnO NPs (5 mg/kg/day). Testicular specimens were processed for histological, ultrastructural and c-kit immunohistochemical study. Biochemical analysis for tissue malondialdehyde and serum testosterone was done in addition to sperm morphology assay and cytogenetic study. Our results revealed that CP induced deleterious testicular histopathological, biochemical and genetic alterations that were effectively prevented by ZnO NPs. PMID- 30309515 TI - Postnatal neural crest stem cells from hair follicle interact with nerve tissue in vitro and in vivo. AB - Neural crest stem cells that located in the postnatal hair follicle (HF-NCSC) are considered a promising tool for treatment of nervous system diseases and injuries. It is well known that HF-NCSC can be used in the spinal cord and sciatic nerve reparation but their ability to restore brain structures is poorly studied. In this article we are investigating the interaction between HF-NCSC and a nerve tissue (embryonic and adult). We have found out that HF-NCSC isolated from adult mice grow and differentiate in accordance with the mouse embryo developmental stage when co-cultured with the embryonic nerve tissue. The HF-NCSC migration is slower in the late embryonic tissue co-culture system compared to the early one. This phenomenon is related to the motor function of the cells but not to their proliferation level. We have demonstrated that the embryonic nerve tissue maintains HF-NCSC an undifferentiated status, while an adult brain tissue inhibits the cell proliferation and activates the differentiation processes. Besides, HF-NCSC pre-differentiated into the neuronal direction shows a higher survival and migration rate after the transplantation into the adult brain tissue compared to the undifferentiated HF-NCSC. Thus, we have investigated the postnatal HF-NCSC response to the nerve tissue microenvironment to analyze their possible application to the brain repair processes. PMID- 30309516 TI - Obesity-induced upregulation of miR-361-5p promotes hepatosteatosis through targeting Sirt1. AB - OBJECTIVE: Obesity is associated with an increased risk of many metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain poorly understood. Recent studies have demonstrated that MicroRNA-mediated gene silencing plays an important role in hepatic triglyceride (TG) metabolism. In the present study, we aimed to investigate the pathological function of miR-361-5p in the development of NAFLD. METHODS: Expression levels of miR-361-5p was determined by quantitative real-time PCR in livers of obese mice and NAFLD patients. Liver tissues from mice with miR-361-5p overexpression or inhibition were collected and analyzed by TG contents, gene expression profile. RESULTS: Expression of miR-361-5p was increased in the livers of two obese mouse models and NAFLD subjects. Overexpression of miR-361-5p in C57BL/6 mice led to hepatosteatosis, whereas inhibition of miR-361-5p expression in db/db mice improved TG accumulation and insulin sensitivity. Mechanistically, we identified Sirt1 as a direct target gene of miR-361-5p and re-introduction of Sirt1 largely abolished the metabolic action of miR-361-5p. CONCLUSIONS: Our results demonstrated the role of miR-361-5p in the regulation of hepatic TG homeostasis, which may provide potential therapeutic target for hepatosteatosis. PMID- 30309517 TI - How 'Scroll Free' was your September? PMID- 30309518 TI - Phenolic compounds and antioxidant activities of tea-type infusions processed from sea buckthorn (Hippophae rhamnoides) leaves. AB - Sea buckthorn (Hippophae rhamnoides, SB) leaves contain wide-ranging bioactive compounds. Processing of the leaves into beverages/food presents great potential for supporting human health. The research aimed to investigate the impact of different processing methods on phenolic compounds and antioxidant activities of tea-type infusions prepared from SB leaves. Leaves of two SB cultivars, 'Terhi' and 'Tytti', were processed with different methods commonly used for tea processing. Phenolic compounds in the infusions were analyzed with High Performance Liquid Chromatography-Diode-Array Detection and High-Performance Liquid Chromatography Electrospray Ionization-Tandem Mass Spectrometry. Isorhamnetin-3-O-glucoside-7-O-rhamnoside, isorhamnetin-3-O-rutinoside and kaempferol-3-O-hexoside-7-O-rhamnoside were the three major flavonol glycosides, stachyurin and casuarinin were the most abundant ellagitannins. The infusions of 'Tytti' contained more total phenolics than those of 'Terhi' (p < 0.05). High temperature processing resulted in higher content of total phenolics and ellagitannins in the infusions compared with low temperatures (p < 0.05). Thermal processing decreased the antioxidant activities of the infusions. PMID- 30309519 TI - Hydrolysis and oxidation of lipids in mussel Mytilus edulis during cold storage. AB - Change in quality of mussels (Mytilus edulis) meat when stored at 4 degrees C was evaluated by determining volatile basic nitrogen (TVB-N), peroxide value (POV), thiobarbituric acid reactive substance (TBARS), total oxidation (TOTOX), lipid class, fatty acid (FA), phosphatidylcholine (PC) and phosphatidylcholine (PE) content, and glycerophospholipid (GP) molecular species. After 4 days of storage, the percentages of triacylglycerol and polar lipid as well as the contents of PC, PE and major GP molecular species significantly decreased (P < 0.05), while the percentages of free FA and monoacylglycerol significantly increased (P < 0.05), indicating the hydrolysis of lipids. The increase in activities of phospholipase and lipase during storage suggests that they may contribute to the hydrolysis of lipids. The cold storage also resulted in significantly increased POV, TBARS and TOTOX as well as lipoxygenase activity (P < 0.05) but slightly decreased percentage of polyunsaturated FA (PUFA), indicating the occurrence of lipid oxidation. PMID- 30309520 TI - Antioxidative effects of flavonoids and their metabolites against hypoxia/reoxygenation-induced oxidative stress in a human first trimester trophoblast cell line. AB - This study aimed to investigate the cytoprotective effects of flavonoids, their metabolites alone or in combination against hypoxia/reoxygenation induced oxidative stress in the transformed human first trimester trophoblast cell line (HTR-8/SVneo). Oxidative stress was achieved with hypoxia followed by reoxygenation and the following assays were performed: MTT, CellToxTM Green Cytotoxicity, CellTiter-Glo(r), NADP/NADPH-GloTM, ROS-GloTM/H2O2, GSH/GSSG-GloTM and Caspase-Glo(r) 3/7 assays. HTR-8/SVneo cells, pre-treated for 24 h with flavonoids or their metabolites were protected significantly from oxidative stress. Flavonoids were associated with ROS modulation, reducing the generation of superoxide/hydrogen peroxide. The activities of caspases 3/7 were also significantly reduced significantly in HTR-8/SVneo cells pre-treated with flavonoids. This study has shown for the first time that 24 h pre-treatment with flavonoids, their metabolites alone or in combination, protected against HR induced oxidative stress in the trophoblast cell line. These data indicate that dietary flavonoids may be beneficial to placental health and invasion during early gestation. PMID- 30309522 TI - Particulate organohalogens in edible brown seaweeds. AB - Brown algae, rich in antioxidants and other bioactive compounds, are important dietary seaweeds in many cultures. Like other marine macroalgae, brown seaweeds are known to accumulate the halogens iodine and bromine. Comparatively little is known about the chemistry of chlorine in seaweeds. We used synchrotron-based X ray absorption spectroscopy to measure total non-volatile organochlorine and bromine in five edible brown seaweeds: Laminaria digitata, Fucus vesiculosus, Pelvetia canaliculata, Saccharina latissima, and Undaria pinnatifida. Organochlorine concentrations range from 120 to 630 mg.kg-1 dry weight and organobromine from 150 to 360 mg.kg-1, comprising mainly aromatic organohalogens in both cases. Aliphatic organochlorine exceeds aliphatic organobromine but is positively correlated with it among the seaweeds. Higher organochlorine levels appear in samples with more lipid moieties, suggesting lipid chlorination as a possible formation pathway. Particulate organohalogens are not correlated with antioxidant activity or polyphenolic content in seaweed extracts. Such compounds likely contribute to organohalogen body burden in humans and other organisms. PMID- 30309521 TI - Influence of fried food and oil type on the distribution of polar compounds in discarded oil during restaurant deep frying. AB - Deterioration of frying oil greatly affects the nutrition of fried foods. In this study, influence of fried food and oil type on the distribution of polar compounds in oils at total polar compound (TPC) of 24%, 25% and 27% was evaluated. Both food and oil significantly affected the composition of frying oil (P < 0.01) and the effect of oil was relatively more significant than that of food. Five groups of polar compounds were presented: triglyceride oligomer (TGO), triglyceride dimer (TGD), oxidized triglyceride monomer (oxTGM), diglyceride (DG) and free fatty acid (FFA). TGD and DG had the highest contents, up to 6.9%-7.5% and 8.1%-8.9% respectively, while FFA had the lowest content with 1.4%-1.7%. The compound of the greatest concern in frying oil, oxTGM, varied from 4.6% to 4.8%, when TPC reached 24%-27%. Data will be expected to provide the evidence for toxicological evaluation of fried oils and foods in restaurants. PMID- 30309523 TI - Comparative studies on the yield and characteristics of myofibrillar proteins from catfish heads and frames extracted by two methods for making surimi-like protein gel products. AB - Fish protein isolates (FPI) were recovered from catfish heads and frames by alkaline extraction (AE) and salt extraction (SE) and made into surimi-like gels. Protein patterns and content, moisture, color, and texture of cooked protein gels were compared with commercial products. Sodium-dodecyl-sulfate poly acrylamide gel electrophoreses (SDS-PAGE) indicated that the integrity of major myofibrillar proteins was maintained during the extraction process, and the protein patterns were almost the same with that of the commercial surimi products. The yields of AE-FPI (heads: 36%; frames: 55%) were much higher (p < 0.05) than that of SE-FPI (heads: 9%; frames: 16%). Firmness of cooked protein gels made from heads was similar with that made from frames. Firmness of cooked protein gels made from FPI extracted by the SE method (heads: 0.45 kg/cm2; frames: 0.43 kg/cm2) was significantly lower (p < 0.05) than that made from FPI extracted by the AE method (heads: 1.96 kg/cm2; frames: 1.85 kg/cm2). PMID- 30309524 TI - Point-of-use detection of ascorbic acid using a spectrometric smartphone-based system. AB - A rapid and portable analytical methodology has been developed for ascorbic acid (Vitamin C) quantification from aqueous samples using a spectrometric smartphone based system for the first time. The method employs point-of-use approaches both for sample preparation and sample measurement, demonstrating the capability for mobile quality control of pharmaceutical and food products. Our approach utilizes an oxidation-reduction reaction between ascorbic acid and methylene blue, followed by a dispersive liquid-liquid microextraction (DLLME) to extract the aqueous-phase methylene blue into organic media. Then, a back-extraction procedure is employed to transfer the methylene blue to aqueous media, followed by analysis of the sample's absorption spectrum using the spectrometric smartphone-based system. The DLLME and back-extraction procedures are optimized by use of a two-step multivariate optimization strategy. Finally, vitamin C supplements and orange juice are used as real-world samples to assess the applicability of the smartphone-based method, which is successfully compared with the standard laboratory-based approach. PMID- 30309525 TI - Development and validation of a method for simultaneous determination of trace levels of five macrocyclic lactones in cheese by HPLC-fluorescence after solid liquid extraction with low temperature partitioning. AB - A highly sensitive analytical method was developed and validated, following international guidelines, for the determination of the residues of five macrocyclic lactones (MLs) (abamectin, doramectin, eprinomectin, ivermectin and moxidectin) in cheese. The extracts were concentrated by rotary-evaporation and derivatized; no clean-up was necessary. Despite matrix complexity, no significant matrix-effect was verified, and standards were prepared in solvents. Linear working ranges varied from 0.25 to 5.0 MUg L-1. Excellent limits of quantification (0.58-0.87 MUg kg-1), mean recoveries (91-103%), and repeatability and intermediate precision (<5.8%) were obtained. Twenty-two samples of bovine and non-bovine cheeses were analyzed. Twenty-one samples showed residues of at least one ML (between 0.59 and 15.3 MUg kg-1), but moxidectin was never detected; a sample of mozzarella was free of MLs. To the best of our knowledge, this is the first method describing the simultaneous evaluation of these MLs in cheese using HPLC and fluorescence detection. PMID- 30309526 TI - Rapid quantification of the adulteration of fresh coconut water by dilution and sugars using Raman spectroscopy and chemometrics. AB - Here, for the first time, we developed Raman spectroscopy in combination with chemometrics for the quantification of adulteration of fresh coconut water by dilution, and its masking with sugars. Coconut water was extracted from young Costa Rican coconuts and heat treated to emulate pasteurization. Samples were then adulterated by dilution with water and single sugars, mixtures of sugars, and high-fructose corn syrup (HFCS). A total of 155 samples were analysed with Raman spectroscopy at 785 nm excitation and 620 spectra analysed with chemometrics. Results showed successful quantification of dilution and adulteration with single sugars between 1.9 and 2.6%, masking of dilution with mixtures of sugars at 9.8%, and masking of dilution with HFCS at 7.1%. It can be concluded that Raman spectroscopy has significant potential as a rapid accurate analytical method for the detection of adulteration in this product, with the ability to discern small abnormalities in sugar ratios within coconut water. PMID- 30309527 TI - Effect of pH and holding time on the characteristics of protein isolates from Chenopodium seeds and study of their amino acid profile and scoring. AB - Alkali extraction and acid precipitation methods were adopted to isolate protein from quinoa and album seeds of variety Chenopodium. Different pH dispersions (3 11) of isolated proteins were prepared and effects of pH and holding time on protein characteristics were evaluated. The pH-10 of extraction medium was found suitable for protein extraction on the basis of yield, purity, solubility and colour having isoelectric pH of 4.5. Yield and purity of protein isolates (PI) of quinoa and album varied from 8.12 to 12.22%; 74.19 to 85.07% and 7.71 to 10.98%; 77.16 to 86.12%, respectively. Overall, pH and time had significant effect on functional properties of PI of both seeds. Quinoa PI had higher emulsifying activity, emulsion stability, water binding capacity and dispersibility, whereas, foaming capacity and stability were higher for album PI. Nutritional indices were 64.20 and 64.58 for quinoa and album PI, respectively, whereas, amino acid scoring (FAO, 2013) indicated, isoleucine, leucine and valine as the limiting amino acids. PMID- 30309528 TI - Antioxidant activity of a winterized, acetonic rye bran extract containing alkylresorcinols in oil-in-water emulsions. AB - Naturally derived antioxidants are in high demand as the food industry strives to meet consumer preferences for non-synthetic additives. Alkylresorcinols (ARs) represent a novel class of natural antioxidants that can be derived from a natural waste stream (bran) and have the potential to inhibit lipid peroxidation given their phenolic structure. The antioxidant activity of rye bran extract containing ARs was investigated in an oil-in-water emulsion and was found to inhibit lipid oxidation reactions. The concentration of ARs in the continuous phase of emulsions was measured to understand partitioning behavior, as this is known to impact antioxidant activity. It was found that a majority of the ARs were associated with the lipid phase and those in the continuous phase were associated with surfactant micelles, perhaps inhibiting their interaction with water-soluble pro-oxidants. These results show that a rye bran extract containing ARs can function as a radical scavenging antioxidant in lipid dispersions. PMID- 30309529 TI - Chloroplast-rich material from the physical fractionation of pea vine (Pisum sativum) postharvest field residue (Haulm). AB - An innovative procedure for plant chloroplasts isolation has been proposed, which consists of juice extraction by physical fractionation from plant material and recovery of its chloroplast-rich fraction (CRF) by centrifugation. This simple method has been applied to pea vine haulm subjected to different post-harvest treatments: blanching, storage at different relative humidity values and fermentation. Additionally, freeze storage of the extracted juice was carried out. The macronutrient (total lipids, proteins, ash and carbohydrates) and micronutrient (fatty acids, chlorophylls, beta-carotene, alpha-tocopherol and ascorbic acid) content and composition of the CRF have been determined. The CRF isolated from fresh pea vine haulm is a potential source of essential micronutrients (alpha-linolenic acid, beta-carotene, alpha-tocopherol) and carbohydrates, whereas the post-harvest treatments trialled have a detrimental effect on the nutritional content. Industrial applications for the recovered nutritionally rich fraction, such as food supplement ingredient or animal feeding, are likely envisaged, while optimising the use of green haulm. PMID- 30309530 TI - Report on the 2nd International Symposium on Phytochemicals in Medicine and Food (4-7 April 2017, FuZhou, China). AB - The second International Symposium on Phytochemicals in Medicine and Food (2 ISPMF), organized by the Phytochemical Society of Europe (PSE), the Phytochemical Society of Asia (PSA) and the International Society for Chinese Medicine (ISCM), was held on 4-7 April 2017 in FuZhou, China. This symposium created a stage for more than 290 scientists from 33 countries to discuss the latest research in phytochemicals for food and human health. The program comprised 14 plenary lectures, 27 invited talks, 49 short oral presentations, a graduate student forum consisting of 22 oral presentations, and more than 110 posters. 2-ISPMF received supports from several international journals. PMID- 30309531 TI - Isolation of antioxidative compounds from Micromelum minutum guided by preparative thin layer chromatography-2,2-diphenyl-1-picrylhydrazyl (PTLC-DPPH) bioautography method. AB - The application of preparative thin layer chromatography-2,2-diphenyl-1 picrylhydrazyl (PTLC-DPPH) bioautography technique successfully isolated a lignan sesamin (1), two prenylated coumarins (2 and 3) and a marmesin glycosides (4) from Micromelum minutum methanol bark extract. Compounds 2 and 3 were identified as new compounds whereas 1 and 4 were first isolated from Micromelum genus. Structural identification of all compounds were done by detailed spectroscopic analyses and comparison with literature data. Antioxidant capacities of extract, active fraction and compounds were measured based on DPPH free radical savenging activity, oxygen radical absorbance capacity (ORAC) and beta-carotene bleaching. The DPPH activity of methanol extract and its fraction present the IC50 values of 54.3 and 168.9 ug/mL meanwhile the beta-carotene bleaching results were 55.19% and 5.75% respectively. The ORAC measurements of M. minutum extract, compounds 2 and 4 showed potent antioxidant activity with the values of 5123, 5539 and 4031 umol TE/g respectively. PMID- 30309532 TI - Bioactive compounds of beetroot and utilization in food processing industry: A critical review. AB - Beetroot is recognized as health promoting food due to presence of essential components such as vitamins, minerals, phenolics, carotenoids, nitrate, ascorbic acids and betalains that promote health. Betalains occur in two forms i.e. betacyanin (red-violet pigment) and betaxanthin (yellow-orange pigment) and are recognizable commercially as a food dye due to non-precarious, non-toxic, non carcinogenic and non-poisonous nature. Beetroot is premeditated as a boon for the food industry and used as food colorant or additive in food products such as ice cream, yogurts and other products. The beetroot extract is used to improve the redness in tomato pastes, soups, sauces, desserts, jams, jellies, sweets and breakfast cereals. Overall objective of this review is to provide a brief knowledge about the valuable phytochemicals and bioactive compounds present in beetroot and their association with health benefits, beetroot processing for food application and their effect on beetroot pigment. PMID- 30309533 TI - Distribution and effects of natural selenium in soybean proteins and its protective role in soybean beta-conglycinin (7S globulins) under AAPH-induced oxidative stress. AB - The effects of selenium (Se) on the protein content, amino acid profile, secondary structure and subunit composition of soy proteins and its distribution were evaluated, as was the effect of peroxyl radicals produced by thermal decomposition of AAPH on the conformational changes of Se-enriched beta conglycinin (S-7S). The Se biofortification ability of soy was very strong, 7S had strongest ability to incorporate Se, and lower amounts of inorganic Se existed in Se-enriched beans. Se could promote protein synthesis and thus improve the protein content, increase the total amino acid content with a decrease in cysteine, combine into low-molecular-weight proteins, and influence the secondary structure of soybean proteins. Se was involved in the relevant protein changes in surface hydrophobicity, intrinsic fluorescence, infrared absorption and solubility and played an antioxidant role as an effectual "protector" to reduce the influence of peroxyl radical oxidation on S-7S, thereby maintaining the structural rearrangement between aggregation and protein unfolding. PMID- 30309535 TI - Peels of tucuma (Astrocaryum vulgare) and peach palm (Bactris gasipaes) are by products classified as very high carotenoid sources. AB - Tucuma (Astrocaryum vulgare) and peach palm (Bactris gasipaes) are Amazonian fruits with high potential to be used as source of carotenoids due to the remarkable yellow-orange colour of their pulp and peel. In this study, for the first time, both the extraction of carotenoids from the peel of tucuma and peach palm fruits and their carotenoid profile were investigated. The carotenoid contents of the peel of both fruits were higher than those found in the pulp. The highest yield of carotenoids from both fruit peels were obtained at the solid liquid ratio of 1:7 (w/v), 80 min of shaking and by adding 30% of ethyl acetate in acetone, being beta-carotene the major carotenoid (7.8 and 7.3 mg/100 g for tucuma and peach palm, respectively), followed by gamma-carotene and delta carotene. Thus, peels of tucuma and peach palm fruits were classified as very high carotenoid sources to be used by any potential interested industry. PMID- 30309534 TI - Synergistic effect of mixture of two proline-rich-protein salivary families (aPRP and bPRP) on the interaction with wine flavanols. AB - In this study, we have evaluated by HPLC-DAD, DLS and MALDI-TOF a synergic effect of the coexistence of two salivary-PRP fractions (basic-PRPs and acidic PRPs) on the interaction with flavanols. Results obtained showed noticeable enhancement of the interaction between (epi)catechin and PRPs when both types of proteins are blended. Up to 30 soluble aggregates have been tentatively identified with molecular weight from 4680 to 35,851. (epi)Catechins seem to bind preferentially bPRPs than aPRPs, although the medium size aggregates flavanol-bPRPs formed could favour the interaction with aPRPs giving rise to soluble mixed aggregates. PMID- 30309536 TI - Structural elucidation of fucoidan from Cladosiphon okamuranus (Okinawa mozuku). AB - Fucoidan is a sulphated polysaccharide, made up mainly of l-fucose, which is found in brown seaweeds. Its chemical structure is diverse and depends on maturity, species and geographical location. The objective of this study was to elucidate the chemical structure of fucoidan from Cladosiphon okamuranus harvested in Japan. The fucoidan was subject to purification prior to monosaccharide profiling, sulphate content determination, and linkage analysis. Our results showed that Japanese Cladosiphon okamuranus fucoidan contained 70.13 +/- 0.22 wt% fucose and 15.16 +/- 1.17 wt% sulphate. Other minor monosaccharides found were d-xylose, d-galactose, d-mannose, d-glucose, d-arabinose, d-rhamnose and d-glucuronic acid. Linkage analysis revealed that fucopyranoside units along the backbone are linked, through alpha-1,3-glycosidic bonds, with fucose branching at C-2, and one sulphate group at C-4 per every three fucose units, i.e. the structure of fucoidan from Japanese Cladosiphon okamuranus is [->3) alpha-fuc(1->]0.52[->3)-alpha-fuc-4-OSO3-(1->]0.33[->2)-alpha-fuc]0.14. PMID- 30309537 TI - Diffuse light affects the contents of vitamin C, phenolic compounds and free amino acids in lettuce plants. AB - Enhancement of the diffuse solar radiation to which lettuce plants were exposed clearly affected the vitamin C content and the quantitative and qualitative patterns of phenolic compounds and free amino acids (AA) in the leaves. Although the enhanced level of diffuse light was detrimental to the contents of vitamin C and total phenolic compounds, lowering them by 10-46% and 8-11%, respectively, the content of di-caffeoyltartaric acid increased from 0.26 +/- 0.19 to 0.52 +/- 0.10 MUmol 100 g-1 f.w. for plants harvested in summer. The effect of diffuse light on AA depended on the total amount of global radiation incident on the plants. Considering the lowest amount of global radiation, the enhanced diffuse light increased the AA content from 766 +/- 89 to 849 +/- 90 MUmol 100 g-1 f.w. By contrast, under the highest level of global radiation, diffuse light decreased the amount of AA from 990 +/- 16 to 830 +/- 76 MUmol 100 g-1 f.w. PMID- 30309538 TI - Solid-state fermentation of black rice bran with Aspergillus awamori and Aspergillus oryzae: Effects on phenolic acid composition and antioxidant activity of bran extracts. AB - Black rice bran (BRB) was fermented in solid state using Aspergillus awamori and Aspergillus oryzae for 5 days at 30 degrees C, and then the alcoholic extracts of the fermented BRB were examined in terms of phenolic acid composition and antioxidant activity (DPPH radical scavenging and tyrosinase inhibitory activity). A pre-treatment, moisturizing and autoclaving prior to the fermentation, decreased total phenolic content (TPC) by decomposing the anthocyanin in BRB, but the fermentation increased TPC. Protocatechuic acid and ferulic acid showed the most significant increases, reaching their maximum values by the fermentation for 3 days: 1660.6 ug/g for the extract of BRB fermented by A. awamori. The radical scavenging activity and tyrosinase inhibitory activity of the alcoholic extracts increased by the pre-treatment and fermentation, in accordance with the increase in phenolic acid content. The solid-state fermentation was an effective process to raise the phenolic acid content and antioxidant activity of the extract. PMID- 30309539 TI - Chemical profiles and antioxidant properties of roasted rice hull extracts in bulk oil and oil-in-water emulsion. AB - We conducted in vitro assays to investigate the antioxidant properties of aqueous or ethanolic extracts of roasted rice hulls. Phenolic compound contents were analyzed via HPLC, and comprehensive chemical profiles were obtained via 1H NMR and 1H-H COSY NMR. Rice hulls were roasted at 150, 180, and 230 degrees C for 20 min, after which the aqueous and 70% ethanol extracts were obtained. In vitro assays showed that rice hulls roasted at 230 degrees C possessed very strong antioxidant properties (p < 0.05). Comprehensive chemical profiles determined via NMR showed that roasting increased the contents of specific amino acids and monosaccharides and reduced the organic acid contents. p-Coumaric, vanillic, and ferulic acids were the most dominant phenolic compounds present in the sample. Added roasted rice hull extracts enhanced the oxidative stability of bulk oil and in O/W emulsions at 60 degrees C. However, the extracts accelerated lipid oxidation rates of oils heated at 180 degrees C. PMID- 30309540 TI - Modifying Robusta coffee aroma by green bean chemical pre-treatment. AB - Green Robusta beans were subjected to pre-treatment with the aim of reducing the perceived aroma difference between Arabica and Robusta coffee. Treatment was a short soaking procedure with varying concentrations of acetic acid (up to 5%). Samples were subjected to thermal treatment (roasted) and ground to a standardised particle size distribution. Aroma compounds were evaluated by headspace analysis using solid-phase microextraction and gas chromatography-mass spectrometry. Pre-treatment significantly affected aroma formation during roasting and resulted in a modified level of pyrazines, furanic compounds and sulfur-containing compounds (p < 0.05). Principal component analysis illustrated that the aroma profile of the pre-treated Robusta coffee was closer to the target Arabica coffee after roasting. Sensory results confirmed that the aroma of the 2% acetic acid pre-treated Robusta brew was similar to Arabica; the maximum inclusion level of Robusta coffee in a blend could be increased from 20% to 80%. PMID- 30309541 TI - Microwave and ultrasound pre-treatments to enhance anthocyanins extraction from different wine lees. AB - Wine lees are rich in anthocyanins (AC), natural colorants with health promoting properties. The extraction kinetics of AC from different wine lees in conventional solid-liquid extraction were studied for the first time. The influence of parameters such as temperature, solid-liquid ratio (RS-L) and type of solvent (hydro-alcoholic mixtures) was also studied. Furthermore, microwaves (MW) and ultrasounds (US) were used as pre-treatments (a prior step to the conventional extraction) in order to increase AC yield. Maximum extraction yield (2.78 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) was achieved after 15 min at 25 degrees C, with a RS-L of 1/10 (g/mL) and with a 50%vol. ethanol mixture. When MW were used AC extraction yield was doubled (6.20 mgMALVIDIN-EQUIVALENTS/gDRY-LEES) and the required time to achieve a constant yield was reduced (from 15 min to 90 s). Meanwhile, US only shortened extraction time in less proportion (from 15 to 5 min). Putative identification of main extract compounds was performed by LC/MS MS. PMID- 30309542 TI - Characteristics of flavonol glycosides in bean (Phaseolus vulgaris L.) seed coats. AB - Seed coats of coloured dry beans contain biologically active compounds. Flavonol glycosides were identified from acetone extracts of seed coats of black beans, pinto beans, and red kidney beans and evaluated for antioxidant activity. High Performance Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (HPLC MS/MS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging capacity were used to measure flavonols and antioxidant capacity, respectively. The main flavonol glycosides in black beans were the 3-O-glycosides of kaempferol, quercetin and myricetin; pinto beans contained kaempferol 3-O-glycosides, while red kidney beans contained quercetin 3-O-glycoside and quercetin 3-O-rutinoside (rutin). A flavonol triglycoside was identified in dark red kidney bean. Despite differences in total flavonol content, extracts from Eclipse, (black bean) and Windbreaker (pinto bean) had the significantly higher antioxidant activities than other bean seed coats. Results suggest seed coats of Windbreaker and Eclipse may have potential as functional food ingredients, though benefits may not be simply due to flavonols. PMID- 30309543 TI - Effect of sex on the nutritional value of house cricket, Acheta domestica L. AB - Since January 2018, insects have been recognised as novel foods in the EU, but their nutritional value varies, and factors affecting their nutritional composition have been debated. We investigated the effect of sex on the nutritional value and chemical composition of the house cricket (Acheta domestica L.). Both sexes were rich in protein and lipids. The proximate composition was partly influenced by sex; females contained a significantly higher amount of lipids (18.3-21.7 vs 12.9-16.1 g/100 g dry matter, p = 0.0001) and fewer proteins than males (61.2-64.9 vs 66.3-69.6 g/100 g dry matter, p = 0.0001). Males contained more chitin (p = 0.0015) and nitrogen chains (p = 0.0003) than females. Only the ash (p = 0.4314) and nitrogen-free extract (p = 0.4871) were uninfluenced by sex. Furthermore, nutrient quality expressed as essential amino acid (72.3-77.1), thrombogenicity (1.22-1.45), and atherogenicity indices (0.53 0.58) did not differ between sexes (p > 0.05). PMID- 30309544 TI - Effect of anthocyanins on lipid oxidation and microbial spoilage in value-added emulsions with bilberry seed oil, anthocyanins and cold set whey protein hydrogels. AB - The objective of this work was to explore the storage properties of a structured oil-in-water emulsion containing both water- and fat-soluble bioactive compounds from bilberries (Vaccinium myrtillus L.). Bilberry seed oil (BSO) was dispersed in a continuous aqueous phase of anthocyanins (AC) and whey protein isolate. The microstructure was evaluated using light microscopy and the effect of anthocyanins on lipid oxidation and microbial growth was investigated. The results showed that it was possible to generate a stable emulsion structure that resisted phase separation during 25 weeks of storage. Gas chromatography-mass spectrometry measurements of the fatty acids in the BSO during storage showed that AC had a protective effect against lipid oxidation. The AC did not have an antimicrobial effect against the investigated strains Zygosaccharomyces bailii (ATCC 42476) and Aspergillus niger (ATCC 6275 (M68)). PMID- 30309545 TI - Comparison of real-time PCR methods for quantification of European hake (Merluccius merluccius) in processed food samples. AB - The quantification of species in commercial products is limited by analytical shortcomings, as most of them provide semiquantitative results. An exception is real-time PCR, which can provide quantitative results using hybridization probes. In the present work, this technique has been applied to the absolute, absolute relative and relative quantification of the most valued hake species in European markets, Merluccius merluccius (European Hake). The best quantification results for this species in binary mixtures with non-target species (Merluccius capensis) and using a species-specific real-time PCR MMER_VIC system was achieved using a relative quantification approach (MLL as reference system). Absolute quantification using the MLL nuclear system has been demonstrated as appropriate for the quantification of the Merluccius genus in food model samples. This study reveals the impact of different reference systems (MLL and HAKE) in the absolute relative and relative quantification approaches, showing that the nuclear MLL system performed better than the mitochondrial HAKE system. PMID- 30309546 TI - Effect of guar gum on the physicochemical properties and in vitro digestibility of lotus seed starch. AB - The effect of guar gum (GG) on the physicochemical properties and digestibility of lotus seed starch (LS) subjected to autoclaving-cooling were investigated. Compared to LS alone, LS with 0.03% or 0.15% GG displayed higher crystallinity and short-range order, resulting in the formation of a denser crystal structure. It might contribute to the reduced swelling power, final viscosity, and setback viscosity for those complexes. Coating effect and hydrophilicity were more apparent in LS containing 0.30%, 0.60%, or 0.90% GG, which weakened their crystal structure and increased swelling power, final viscosity, and setback viscosity. The addition of GG delayed starch digestion in vitro, decreased the content of rapidly digestible starch, and increased the content of resistant starch, especially when 0.30% GG was added to 30% LS. The changes in crystal structure and viscosity partially explained the reduced digestibility. PMID- 30309547 TI - A unified approach for high-throughput quantitative analysis of the residues of multi-class veterinary drugs and pesticides in bovine milk using LC-MS/MS and GC MS/MS. AB - This paper reports a unified sample preparation approach for high-throughput multi-residue analysis of veterinary drugs and pesticides in a single sub-sample of bovine milk. The sample (5 g) was deproteinized with acetonitrile before an aliquot (I) was withdrawn, and the remainder was phase-separated using MgSO4 and NaCl. The acetonitrile layer (II) was recovered and the extracts combined, cleaned, and solvent-exchanged before the concentrations of veterinary drugs and pesticides were measured by ultra-fast liquid chromatography tandem mass spectrometry (UFLC-MS/MS). As a unique approach, extract II was analyzed simultaneously using gas chromatography tandem mass spectrometry (GC-MS/MS). Method performance for 78 drugs and 238 pesticides complied with CD 2002/657/EC and SANTE/11813/2017 guidelines, respectively, with significant savings in time and cost. Thus, it would be ideal for regulatory analysis of analytes ranging from non-polar organochlorine pesticides to polar drugs, including penicillins, quinolones, and tetracyclines. PMID- 30309548 TI - Preparation of an intelligent pH film based on biodegradable polymers and roselle anthocyanins for monitoring pork freshness. AB - This study aims to develop an intelligent indicating film based on biodegradable polymers incorporated with roselle anthocyanins to monitor pork freshness. Three different films were prepared by using two substances of starch, polyvinyl alcohol and chitosan. The UV-vis spectra and color of anthocyanins changed at pH 2-12. SEM photographs showed that the compatibility of films was improved with the addition of anthocyanins. Furthermore, the polyvinyl alcohol/chitosan/roselle anthocyanins film had the highest tensile strength (98.28 MPa). The starch/polyvinyl alcohol/roselle anthocyanins film had the highest antioxidant activity (524.07%) and the best color stability. The starch/polyvinyl alcohol/roselle anthocyanins film showed visible changes from red to green when employed to monitor the freshness of pork stored at 25 degrees C, before the TVB N value of the pork gradually increased to the rejection limit (15 mg/100 g) at 36 h. Therefore, the indicator film can be used to monitor pork freshness for intelligent packaging. PMID- 30309549 TI - Novel insight into the role of withering process in characteristic flavor formation of teas using transcriptome analysis and metabolite profiling. AB - Withering is an indispensable process for improving flavors in green, black and white teas during their manufacturing. The effects of the withering process on the formation of tea flavors were investigated using transcriptome and metabolite profiling in withered tea leaves. A total of 3268, 23,282 and 25,185 differentially expressed genes (DEGs) were identified at 3 h (68%, water content), 12 h (61%) and 24 h (48%) of the withering process, respectively. The DEGs, involved in flavonoid biosynthesis were significantly downregulated, which could be correlated with the reduction of catechins. Enhancement of terpenoids and alpha-linolenic acid metabolism could trigger an increase in the total content and number of volatiles. The increase in free amino acid-content could be related to 261 DEGs. Our study suggests that dehydration stress during withering induced significant changes in the gene transcription and content of the tea flavor compounds, which promoted the special flavors in various teas. PMID- 30309550 TI - High-sensitivity determination of cadmium and lead in rice using laser-induced breakdown spectroscopy. AB - Stability and sensitivity of toxic elements determination is still unsatisfactory in agricultural product using laser-induced breakdown spectroscopy (LIBS). A simple and low cost sample pretreatment method named solid-liquid-solid transformation method was proposed in this work. The target analytes of cadmium (Cd) and lead (Pb) from rice samples were prepared through ultrasound assisted extraction in hydrochloric acid solution. The solution was dropped on the glass slide after centrifuging process and was further dried on a heater. Finally, the glass slide contained the analytes was carried out for LIBS determination. Compare with conventional pellet method, the spectral intensity of Cd and Pb element were enhanced significantly using LIBS. The limits of detection were 2.8 and 43.7 MUg/kg, respectively. The limits of quantification were 9.3 and 145.7 MUg/kg, respectively. The results demonstrated that LIBS coupled with ultrasound assisted extraction should be a promising tool to detect toxic elements in rice. PMID- 30309551 TI - Impact of a post-fermentative maceration with overripe seeds on the color stability of red wines. AB - With the purpose of modulating the copigmentation equilibria of red wines, an environmentally sustainable process was performed based on post-fermentative addition of overripe seeds (OS). Simple (SW) and double (DW) addition were performed to produce different enrichment of phenolics from seeds, hence different copigmentation/polymerization ratios. The determination of the phenolic composition showed different global increases in OS-macerates wines (catechin, epicatechin, gallic acid and procyanidins B1 and B2). The double post-maceration (DW) was more effective than the simple post-maceration addition to improve the phenolic structure of wines. The application of Differential Tristimulus Colorimetry could assess the effects of this practice on the color characteristics and stability of wines. Results highlighted that both simple and double assays underwent colorimetric improvements against the control wines (CW, no seeds addition). DW led to the highest chromatic stability, showing lower lightness, higher chroma values and bluish hues than CW. This color difference was visually detectable. PMID- 30309552 TI - Inhibitory effects of dietary soy isoflavone and gut microbiota on contact hypersensitivity in mice. AB - Soy isoflavones (SIs) are abundant in soybeans and have inhibitory effects on contact hypersensitivity (CHS), which is often used as a mouse model for allergic contact dermatitis (ACD); however, their therapeutic mechanisms remain unknown. We studied the suppressive activity of dietary SI and gut microbiota on dinitrofluorobenzene (DNFB)-induced CHS. Low-dose SI diets alleviated DNFB induced ear swelling and oedema and decreased infiltration of Gr-1-positive cells into ear tissue. In addition, dietary SIs also decreased interleukin-1beta and chemokine (C-X-C motif) ligand 1 production in ear tissue compared to controls. Furthermore, ciprofloxacin and metronidazole treatments blocked the suppressive activity of dietary SIs on CHS, whereas vancomycin treatment had a marginal effect. These antibiotic treatments differed in their effects on the gut microbiota composition. These results demonstrated that consumption of physiologically relevant doses of SIs reduced CHS symptoms, and suggested that the gut microbiota influenced their suppressive activities on CHS. PMID- 30309553 TI - Characterization and storage stability of chlorophylls microencapsulated in different combination of gum Arabic and maltodextrin. AB - Detailed investigations on the physicochemical and structural characterization of chlorophyll loaded microcapsules and their storage stability have not previously been conducted. Therefore, our objective was to encapsulate unstable chlorophylls using different blends of gum Arabic (GA) and maltodextrin (MD) (GA-MD ratios of 5:5, 3:7, and 0:10) by spray-drying to improve storage stability of chlorophylls. An increase in concentration of MD in wall materials was associated with lower moisture content (0.56%), higher encapsulation efficiency (77.19%), chlorophyll content (46.78 ug/g dry powder), degree of crystallinity, and thermal stability of microcapsules. Furthermore, FTIR, XRD, and DSC analyses confirmed inclusion of chlorophylls within microcapsules. The entrapment of chlorophylls within microcapsules enhanced their storage stability at all temperatures (4, 20, and 40 degrees C) for ten days; notably, microcapsules coated with MD alone showed the highest storage stability (94.7-97.5%). In conclusion, microencapsulation of chlorophylls using MD alone was optimal for enhancing chlorophylls' storage stability. PMID- 30309554 TI - Determination of serotonin in nuts and nut containing products by liquid chromatography tandem mass spectrometry. AB - An ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed for the determination of serotonin in raw and roasted nuts (almond, Brazil nut, cashew, chestnut, coconut, hazelnut, Macadamia nut, pecan, peanut, pine nut, pistachio and walnut) as well as nut products (nut containing snack bars, chocolate and spreads) for the first time. Water extraction without prior defatting was performed to leach serotonin from complex matrices of nuts. Mean recoveries ranged from 64.2 +/- 9.6 to 94.7 +/- 20.1%. Limit of detection and limit of quantification were between 0.4 and 2.3 and 1.0-7.4 ng/g, respectively. Repeatability and reproducibility values were below 2%. Serotonin content of nuts ranged from 0.05 +/- 0.01 (pine nut) to 155 +/- 57.0 ug/g (walnut) in raw nuts while it was between 0.03 +/- 0.00 (Macadamia nut) and 15.3 +/- 1.27 ug/g (pecan) in roasted nuts. Serotonin in nut products was found to range from 0.09 +/- 0.00 to 8.99 +/- 0.92 ug/g, depending on the nuts they contain. PMID- 30309555 TI - Development of a DNA metabarcoding method for the identification of fifteen mammalian and six poultry species in food. AB - Meat products are prone to adulteration by the replacement of meat from more expensive animal species with meat from cheaper sources. We present a DNA metabarcoding method allowing the identification and differentiation of 15 mammalian and six poultry species in foodstuffs. The method, developed on the MiSeq(r) platform, targets a mitochondrial 16S rDNA region recently found to be suitable for the differentiation of 300 mammalian species. We designed a novel primer pair for poultry and applied it in combination with the primer pair for mammalian species in a duplex assay. The applicability of the method was investigated by analysing DNA extracts from muscle, DNA extract mixtures and extracts from model sausages. Our results indicated that the species of interest can be identified, differentiated and detected down to a proportion of 0.1%. Since 96 samples can be sequenced in one run, the method has high potential for application in routine analysis. PMID- 30309556 TI - Comparisons of nutritional constituents in soybeans during solid state fermentation times and screening for their glucosidase enzymes and antioxidant properties. AB - This research was the first to demonstrate the variations of nutritional constituents, glucosidase properties and antioxidant activities in soybeans during different solid state fermentation times (germination -> 5 periods for 12 days) with Tricholoma matsutake. Total isoflavones were significantly reduced (2661.54 -> 1559.04 MUg/g) with the increase of aglycone contents (107.61 -> 1285.66 MUg/g, 12 times) for fermentation, whereas amino acid and fatty acid slightly increased. Among them, daidzein (43.2 -> 43.6 -> 421.9 -> 721.4 -> 634.0 MUg/g), genistein (52.7 -> 24.4 -> 339.5 -> 546.6 -> 512.8 MUg/g) and glutamic acid (0.3 -> 1.7 -> 3.9 -> 6.6 -> 16.1 mg/g) markedly increased between germinated and fermented soybeans. Total phenolic contents and antioxidant abilities also considerably increased, especially, ABTS displayed the predominant scavenging capacities (33.1 -> 94.8%) at 200 MUg/ml, followed by DPPH (11.9 -> 87.0%) and hydroxyl (11.2 -> 49.2%) radicals. Interestingly, alpha-glucosidase inhibition (11.8 -> 84.9%) and beta-glucosidase (3.1 -> 40.3 unit/g) exhibited the highest activities after 9 days. Our results implied that fermented soybeans may be contributed to enhance the soybean value in nutrition and biological effect aspects to development of new functional foods. PMID- 30309557 TI - Characterization of three different types of extracellular vesicles and their impact on bacterial growth. AB - Recently body fluids have been found to contain a class of nanoparticles released from cells, referred to as extracellular vesicles; exosomes are a type of small diameter extracellular vesicle. We selected three types of sample: milk-derived exosomes, adipose-derived stem cell exosomes, and nanoparticles extracted from coconut water, to investigate their morphology, particle size distribution, protein content, and microRNA expression levels. Among the vesicles investigated, coconut nanoparticles had the greatest size distribution, and the protein content of coconut nanoparticles differed from that of mammalian exosomes. Using fluorescence microscopy, we determined that DiI-labeled extracellular vesicles could be absorbed by bacteria. Prominently, milk-derived exosomes could promote the growth of Escherichia coli K-12 MG1655 and Lactobacillus plantarum WCFS1. The studied extracellular vesicles could alter bacterial gene expression. Overall, this study identified differences in exogenous extracellular vesicles from different sources and revealed their supportive effects on microbial growth to make better utilization of microbial resources. PMID- 30309558 TI - Extraction, structural characterization and stability of polyhydroxylated naphthoquinones from shell and spine of New Zealand sea urchin (Evechinus chloroticus). AB - The extraction of polyhydroxylated naphthoquinone (PHNQ) pigments from the shell and spines of the New Zealand sea urchin Evechinus chloroticus was evaluated using six different macroporous resins as an alternative to using organic solvent extraction alone. Four of the resins evaluated in this study (D4006, D4020, D101 and NKA-9) provided the best extraction of PHNQ pigments in terms of the overall adsorption and desorption of E. chloroticus PHNQ pigments from the resins. Organic solvents alone had a higher yield of PHNQs than the resins. The PHNQ composition was characterised by high-performance liquid chromatography (HPLC) with diode-array detection and mass spectrometry. Five PHNQ compounds (spinochromes E, B, C, A and echinochrome A), and three aminated PHNQ compounds (spinamine E, echinamines A and B) were identified. The pigments were found to be prone to degradation on exposure to light, with the aminated PHNQ pigments being the least stable. PMID- 30309559 TI - Taste-guided isolation of sweet-tasting compounds from grape seeds, structural elucidation and identification in wines. AB - This work aimed at improving knowledge about sweetness in dry wines. Following on from the empirical observations of winegrowers, we assessed the contribution of grape seeds to wine sensory properties. An inductive fractionation method guided by gustatometry was used to isolate and characterize sweet-tasting compounds from grapes. Fractionation of grape seed macerates was achieved by liquid-liquid extraction, centrifugal partition chromatography (CPC) and preparative HPLC. Then, the structures of the purified compounds were elucidated by use of FTMS and NMR. Five compounds were identified: two new compounds, 2-hydroxy-3 methylpentanoic-2-O-beta-glucopyranoside (H3MP-G) and 2-hydroxy-4-methylpentanoic 2-O-beta-glucopyranoside acids (H4MP-G), along with gallic-4-O-beta glucopyranoside acid (AG-G), 3-indolyl-(2R)-O-beta-d-glycoside lactic acid (ILA G) and epi-DPA-3'-O-beta-glucopyranoside acid (epi-DPA-G). These compounds exhibited various levels of sweetness in a hydro-ethanolic solution and in white and red wines. Additionally, H3MP-G, H4MP-G and epi-DPA-G were identified for the first time in grapes and wines, whereas AG-G has already been reported in white grapes but never in wine. PMID- 30309560 TI - Wine production using free and immobilized kefir culture on natural supports. AB - The aim of the present study was to perform simultaneous alcoholic and malolactic wine fermentations using free or immobilized kefir culture at a wide temperature range (5-45 degrees C). Repeated batch fermentations were carried out for a period up to 29 months, suggesting a high operational stability of the systems, while malic acid conversion and ethanol productivity up to 70.9% and 36.9 g/(Ld) were noted. Volatile acidity was at levels typically found in wines (<1.0 g acetic acid/L) in most cases, although increased values were recorded in wines produced at 5 degrees C, but no vinegar taint was detected. Fusel alcohols were at levels usually found in wines, but were reduced at 5 degrees C. Application of PCA to minor volatiles showed that the fermentation temperature rather than the nature of kefir culture had a significant effect. Noticeably, all products were accepted by the panel during the preliminary sensory evaluation. PMID- 30309561 TI - A value-added approach to improve the nutritional quality of soybean meal byproduct: Enhancing its antioxidant activity through fermentation by Bacillus amyloliquefaciens SWJS22. AB - The action of beta-glucosidase and protease of Bacillus amyloliquefaciens SWJS22 in the fermentation of soybean meal caused a significant increase 1): in total phenolic and flavonoid contents with two-fold or higher, largely associated with daidzein, glycitein, genistein, protocatechuic, and p-hydroxybenzoic, gallic acids; 2): the amount of peptides <3 kDa, maillard reaction intermediate and maillard reaction product with five-, three- and twenty-one-fold, respectively. The significant increase in the amount of antioxidant components in the lyophilised fermented soybean meal supernatant (LFSMS) was associated with the improved antioxidant activity. Namely, the DPPH radical scavenging activity, reducing power, and oxygen radical absorbance capacity of the LFSMS generally increased, and LFSMS (at doses >250 mg/kg body weight) improved the activities of superoxide dismutase, glutathione peroxidase, catalase and total antioxidant capacity, and inhibited the formation of malondialdehyde in mouse serum and liver (p < 0.05). Therefore, LFSMS could be used as functional food ingredients. PMID- 30309562 TI - UV and storage stability of retinol contained in oil-in-water nanoemulsions. AB - This study was performed to examine the stability of retinol contained within oil in-water (O/W) emulsions under UV and during storage at different temperatures. O/W emulsions were prepared using different emulsifiers and oil concentrations. The stability of the retinol contained in the O/W emulsions was investigated by measuring the percentage of residual retinol in the samples after UV exposure and storage at different temperatures (4, 25, and 40 degrees C). The oil concentration of the emulsion had a greater impact on UV stability than the type of emulsifier used, whereas the storage stability at different temperatures was affected by both the choice of emulsifier and the oil concentration. The storage stability of the retinol contained in the O/W emulsions may be related to the lipid oxidation properties of the emulsions rather than the latter's physical stability. Experiments with EDTA and different oil types were performed to confirm this theory. PMID- 30309563 TI - Screening of antimicrobials in animal-derived foods with desorption corona beam ionization (DCBI) mass spectrometry. AB - The relatively new technique, desorption corona beam ionization (DCBI), was coupled with an ion-trap mass spectrometer for the rapid detection of 10 antimicrobials in animal-derived food. Under positive ion mode, 10 common antimicrobials were identified without prior sample preparation. With simple pre treatment, semi-quantification based on peak area was achieved. There was a good correlation (R2 > 0.99) in the rational linear ranges (1-3 orders of magnitude) for all 10 target analytes. Compared with a conventional liquid chromatographic method, the DCBI-MS method was highly sensitive; e.g., roxithromycin was detected at 0.02 ug/g, whereas the value was 0.2 mg/kg in the European Union Commission Regulation (No 37/2010) and 0.3 MUg/mL in a recently reported LC method. The proposed method allowed for the simple, rapid, sensitive and specific detection of antimicrobials in animal-derived foods. Our approach could be used for other atmospheric pressure chemical ionization (APCI) related ambient mass spectrometry methods to detect other compounds. PMID- 30309564 TI - Effect of hulling methods and roasting treatment on phenolic compounds and physicochemical properties of cultivars 'Ohadi' and 'Uzun' pistachios (Pistacia vera L.). AB - The aim of this study was to identify phenolic compounds and measure the physicochemical properties of two pistachio (Pistacia vera L.) cultivars ('Uzun' and 'Ohadi'). For this purpose, the pistachios were subjected to four different hulling methods (wet hulling-WT, brine hulling-BR, wet-dry hulling-WD, and dry dry hulling-DD) and a standard roasting treatment. Phenolic compounds were analyzed by HPLC-DAD-ESI-MSn. Twelve phenolics were identified and quantified in the samples, 10 of which were flavonoid and two non-flavonoid phenolic acids. In both cultivars, the major compounds were found to be gallic acid and catechin followed by eriodictyol-7-O-glucoside and eriodictyol. The dry-dry hulling method treated sample had higher antioxidant capacity, total phenol content, and phenolic compounds than the other hulling methods in both pistachio cultivars. After the roasting treatment, the antioxidant capacity, phenolic content, and a* value increased while the L* and b* values decreased. PMID- 30309565 TI - Determination of lipophilic marine toxins in fresh and processed shellfish using modified QuEChERS and ultra-high-performance liquid chromatography-tandem mass spectrometry. AB - A simple QuEChERS method coupled with ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to improve the extraction efficiency of lipophilic marine toxins (yessotoxins, dinophysistoxins, okadaic acid, azazspiracids, and spirolides) in fresh and processed shellfish products. The proposed method included freezing and dispersive solid-phase extraction with graphene oxide as the sorbent to clean complex matrices containing lipids (e.g., free fatty acids) and pigments. Quantification was performed using matrix-matched calibration curves. Recoveries were 85%-117.4% and the relative standard deviation for precision was less than 10% for marine toxins in fresh and processed shellfish products. The limits of detection (signal-to noise = 3) and quantification (signal-to-noise = 10) were 0.10-1.47 and 0.32-4.92 MUg/kg, respectively. The validated QuEChERS method, coupled with UPLC-MS/MS, was applied successfully to determine lipophilic marine toxins in fresh and processed shellfish samples. PMID- 30309566 TI - Traditional rose liqueur - A pink delight rich in phenolics. AB - Chemical composition and colorimetric parameters of alcoholic liqueurs prepared from rose petals were evaluated by comparing the potential of three cultivars ('Amadeus', 'Colossal Meidiland' and 'Rosanna') and three traditional methods of preparation (fresh/air-dried petals extracted in 50% ethanol or aqueous sucrose syrup). Extraction was performed at room temperature for 2 weeks. High performance liquid chromatography/mass spectrometry was used to confirm the presence of 6 anthocyanins, 4 flavanols, 4 phenolic acids, 2 hydrolysable tannins and 31 flavonols in petal liqueurs. The highest concentrations of anthocyanins were determined in extracts from 'Amadeus' petals, followed by 'Colossal Meidiland' and finally, 'Rosanna'. The best extraction yields and optimal colour characteristics were achieved by ethanolic extraction of dry petals followed by fresh petal extraction in ethanol and, finally, extraction in sucrose syrup. Air dehydration of 'Amadeus' petals prior to extraction in 50% ethanol yielded rose liqueur with the best all round characteristics. PMID- 30309567 TI - Exploring the impacts of postharvest processing on the aroma formation of coffee beans - A review. AB - The aim of this review is to describe the volatile aroma compounds of green coffee beans and evaluate sources of variation in the formation and development of coffee aroma through postharvest processing. The findings of this survey showed that the volatile constituents of green coffee beans (e.g., alcohols, aldehydes, and alkanes) have no significant influence on the final coffee aroma composition, as only a few such compounds remain in the beans after roasting. On the other hand, microbial-derived, odor-active compounds produced during removal of the fruit mucilage layer, including esters, higher alcohols, aldehydes, and ketones, can be detected in the final coffee product. Many postharvest processing including drying and storage processes could influence the levels of coffee aroma compositions, which remain to be elucidated. Better understanding of the effect of these processes on coffee aroma composition would assist coffee producers in the optimal selection of postharvest parameters that favor the consistent production of flavorful coffee beans. PMID- 30309568 TI - In vivo anti-hyperuricemic and xanthine oxidase inhibitory properties of tuna protein hydrolysates and its isolated fractions. AB - This study follows recent attempts to discover natural xanthine oxidase (XO) inhibitors from foods, focusing herein on under-researched fish proteins. The anti-hyperuricemic function of tuna flesh hydrolysate (TPH) produced using Alcalase 2.4L was confirmed in potassium oxonate-induced hyperuricemic rats. TPH was separated using 80 wt% aqueous ethanol. The ethanol-soluble fraction (ESF) abundant in small peptides (<1000 Da) afforded the highest XO inhibition. Separation of ESF by Sephadex G-15 and UPLC/MS/MS revealed 13 di-/tri-peptides (12 are newly identified XO inhibitors). Their XO inhibitory activities were assessed using corresponding synthetic peptides via an improved HPLC method. Results indicate that Phe-containing peptides were more potent XO inhibitors than Trp-containing peptides, with Phe-His having the highest XO inhibitory activity (IC50 = 25.7 mM). Molecular docking studies revealed the importance of two hydrogen bonds and one pi-pi stacking interaction with Phe-914 in XO for XO peptide inhibitor binding. Phe-containing di-/tri-peptides could be potent XO inhibitors against hyperuricemia. PMID- 30309569 TI - Sensory descriptive and comprehensive GC-MS as suitable tools to characterize the effects of alternative winemaking procedures on wine aroma. Part I: BRS Carmem and BRS Violeta. AB - This study analyzed the volatile composition and aroma profile of BRS Carmem and BRS Violeta red wines elaborated from traditional and two alternative winemaking procedures: grape pre-drying and submerged cap. The wines contained higher concentration of acetates (ranging from 303 mg L-1 to 905 mg L-1) and ethyl and methyl esters (ranging from 138 mg L-1 to 415 mg L-1). The BRS Carmem wines were described as fruity due to the higher concentration of esters and BRS Violeta wines were described as vegetal mainly due to the higher concentration of terpenes and methoxyphenols. C6 alcohols also influenced the vegetal notes of BRS Violeta wines from traditional and submerged cap procedures and the pre-dried wines also presented a relevant jam note possibly due to the presence of 2 phenylethyl acetate. The changes in winemaking procedures can possibly lead to changes in the aromatic profile of red wines in a positive way, improving the wine aroma quality. PMID- 30309570 TI - Kinetics of lipid oxidation in omega fatty acids rich blends of sunflower and sesame oils using Rancimat. AB - Blended sunflower (SO) (50-80%) and sesame oils (SEO) (20-50%) were evaluated for thermo-oxidative stability (induction period, IP), oxidation kinetics (rate constant, k), synergy and shelf-life (25 degrees C) (IP25) using Rancimat (100, 110, 120, and 130 degrees C). The Arrhenius equation (ln k vs. 1/T) and activated complex theory (ln k/T vs. 1/T) were used to estimate activation energies, activation enthalpies and entropies, which varied from 92.05 to 99.17 kJ/mol, 88.83 to 95.94 kJ/mol, -35.58 to -4.81 J/mol K, respectively (R2 > 0.90, p < 0.05). Oil blend (OB) with 1:1 SO to SEO exhibited greatest synergy (115%), highest IP (100 degrees C) (13.2 vs. 6.1 h) and most extended IP25 (193 vs. 110 days) with a nutritionally stable composition of omega-fatty acids (omega9, 34.5 vs. 28.7%; omega6, 49 vs. 52%) compared with SO. Better retention of lignans (6205 vs. 3951 mg/kg) and tocopherols (332 vs. 189 mg/kg) were also noted in OB compared with SO alone. PMID- 30309571 TI - Encapsulation of grape seed phenolic-rich extract within W/O/W emulsions stabilized with complexed biopolymers: Evaluation of their stability and release. AB - The ability of electrostatic complexes made up of sodium caseinate (NaCAS) and a polysaccharide, carboxymethyl cellulose (CMC) or gum Arabic (GA), to retain polyphenols from grape seed extract when encapsulated in W1/O/W2 emulsions was compared to that of the single NaCAS (1%). Both electrostatic complexes (0.5% NaCAS - 0.375% CMC and 0.5% NaCAS - 0.5%GA at pH 5.6) used as hydrophilic emulsifiers in W1/O/W2 were able to stabilize the O/W2 interface for 14 days, even though their protein content was reduced by a 50% regarding that of the emulsions only stabilized with NaCAS. Moreover, interfacial adsorption did not show significant differences between NaCAS-polysaccharide electrostatic complexes and the single NaCAS. In terms of interfacial barrier properties, the rate of polyphenol release during storage was not affected by the type of hydrophilic emulsifier. Since polyphenol transport in W1/O/W2 emulsions was diffusion controlled, interfacial adsorption was considered the main factor limiting polyphenol retention. PMID- 30309572 TI - Discrimination of Brazilian lager beer by 1H NMR spectroscopy combined with chemometrics. AB - 1H NMR spectroscopy combined with chemometrics was employed to discriminate lager beer samples from two different classes, according to their style and information provided on the label. Partial replacement of barley malt by adjuncts is a common practice adopted by large breweries, which can lead to a decrease in diastatic power, requiring the use of exogenous enzymes. For this reason, small variations in the spectral profile can occur in the carbohydrates region. Many studies have focused on differentiating beers according to type and brewing process. However, there have no studies concerning the discrimination of beers of the same type that differ only in style, using 1H NMR spectroscopy. In this study PCA (first three components explained 81.5% of the dataset variability), PLS-DA and SIMCA models proved to be powerful tool with predict power higher than 90% for distinguishing lager beers based on the raw materials employed in the brewing process. PMID- 30309573 TI - Variations in chlorophyll and carotenoid contents and expression of genes involved in pigment metabolism response to oleocellosis in citrus fruits. AB - Yellow or green spots related to pigment changes found at the early stage of oleocellosis can cause severe economic damage. However, little information exists on pigment changes during oleocellosis development, so this study investigated the main changes in chlorophyll and carotenoid metabolites and related gene expression. Among the variations, the increased contents of chlorophyll a and b, and decreased concentrations of lutein, beta-cryptoxanthin, zeaxanthin, violaxanthin, alpha-carotene and beta-carotene were responsible for chlorophyll and carotenoid changes, respectively. Regarding gene expression, the up-regulated genes, magnesium chelatase subunit H (MgCh), magnesium-protoporphyrin IX monomethyl ester (oxidative) cyclase 1/2 (MPEC1/2), protochlorophyllide reductase a, chloroplastic 1/2 (PORA1/2) and chlorophyllide a oxygenase (CAO), regarding chlorophyll synthesis as well as the down-regulated genes, phytoene synthase (PSY), phytoene dehydrogenase (PDS), lycopene beta-cyclase (LCYb), and zeaxanthin epoxidase 1/2 (ZEP 1/2) and the up-regulated genes (+)-abscisic acid 8' hydroxylase 1/2 (ABA-HX 1/2), regarding carotenoid metabolism, constituted the major variations in oleocellosis peels. PMID- 30309574 TI - A review of microencapsulation methods for food antioxidants: Principles, advantages, drawbacks and applications. AB - Bioactivities and numerous health benefits against a number of oxidative stress related diseases have been attributed to the role of dietary antioxidants. The development of physical (spray drying, lyophilization, supercritical fluid precipitation and solvent evaporation), physico-chemical (coacervation, liposomes and ionic gelation) and chemical encapsulation techniques (interfacial polymerization and molecular inclusion complexation) enable to obtain healthier and acceptable bioactive compounds. This review focuses on the impacts of microencapsulation techniques on the encapsulation characteristics of food antioxidants. Additionally, this study also provides detailed information on the principles, effective parameters, advantages, disadvantages and applications of microencapsulation techniques. PMID- 30309575 TI - Evaluation of near-infrared (NIR) and Fourier transform mid-infrared (ATR-FT/MIR) spectroscopy techniques combined with chemometrics for the determination of crude protein and intestinal protein digestibility of wheat. AB - The potential of using the near-infrared (NIR) and Fourier transform mid-infrared (ATR-FT/MIR) spectroscopy for the determination of intestinal crude protein (CP) digestibility (IPD) of wheat was evaluated. For CP, the best NIR model showed an excellent prediction performance (R2 = 0.98); the best MIR model also gave an excellent prediction performance (R2 = 0.96). Regarding to IPD, the best model obtained by NIR technique showed approximate quantitative predictive ability (R2 = 0.68), and the best model generated by MIR technique obtained similar prediction performance (R2 = 0.67). NIR models generally showed better predictive abilities than MIR models, which may be due to the MIR spectra record fundamental molecular vibrations and can be more easily affected by multiple interferences. The amide I and II bands played important roles in the development of PLS models for CP and IPD. Results from this study demonstrated the potential of using IR spectroscopy for the prediction of nutrient digestibility while more efforts are required to improve the performance of NIR and ATR-FT/MIR spectroscopy in predicting the IPD of wheat. PMID- 30309576 TI - Impact of consumer behavior on furan and furan-derivative exposure during coffee consumption. A comparison between brewing methods and drinking preferences. AB - This study examined the influence of consumer behavior on furan, 2-methylfuran, 3 methylfuran, 2,5-dimethylfuran and 2,3-dimethylfuran exposure in coffee. Coffees brewed using a filter, fully automatic, capsule machine or reconstituted instant coffee were found to have a significant different cup concentrations of furan derivatives. Coffee brewed with the fully automatic machine contained the highest furan and furan derivative concentrations (99.05 ug/L furan, 263.91 ug/L 2 methylfuran, 13.15 ug/L 3-methylfuran and 8.44 ug/L 2,5-dimethylfuran) whereas soluble coffee did not contain detectable levels, thereby contributing least to a consumer's dietary exposure. Furan and furan derivative concentrations were found to decrease significantly upon cooling, reducing consumer exposure by 8.0-17.2 % on average once the coffee reached drinking temperature 55-60 degrees C, in ceramic cups. Serving coffee in a ceramic or disposable cup were found to influence the cooling dynamics of the coffee but did not statistically influence the consumers exposure at a given temperature. PMID- 30309577 TI - Effects of heat-moisture treatment after citric acid esterification on structural properties and digestibility of wheat starch, A- and B-type starch granules. AB - In this study, wheat starch, A- and B-type starch granules were firstly treated with citric acid (CT) and then subjected to heat-moisture treatment (HMT). The maximum thermo-stable resistant starch (RS) contents reached 71.52%, 71.27%, 71.58% for CT-HMT wheat starch, A- and B-type starch granules, respectively. The hydrolysis kinetic parameters (Cinfinity and k) reduced after CT-HMT. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results revealed that the endothermic and crystalline peaks of CT-HMT starch samples disappeared. Scanning electron microscopy (SEM) results showed that more collapses and destructiveness appeared on the surfaces of CT-HMT starch granules. The esterification reaction became stronger during HMT according to Fourier transform-infrared (FT-IR) spectroscopy analysis, which was consistent with the results of degree of substitution. Raman spectroscopy presented similar structural properties results with XRD and FT-IR. These results suggest that CT prior to HMT is a useful method for preparing high amount of thermally stable RS. PMID- 30309578 TI - Glycine betaine reduces chilling injury in peach fruit by enhancing phenolic and sugar metabolisms. AB - Glycine betaine (GB) treatment is useful to reduce chilling injury (CI) of several kinds of fruits including peach. However, the regulatory mechanism remains unknown. In this study, peach fruit was treated with 10 mmol L-1 GB solution for 10 min. The effects of GB treatment on CI, phenolic and soluble sugar metabolism were investigated in this study. Moreover, phenylpropanoid and soluble sugar content, and enzyme activities associated with phenolic and sugar metabolisms were also measured. The results showed that GB reduced CI and maintained high levels of total phenolic and flavonoid content. The activities of phenylpropanoid metabolism-related enzymes were significantly enhanced by GB. Higher content of sucrose and lower contents of fructose and glucose were observed in GB-treated fruits. Therefore, our results showed that GB could enhance chilling tolerance of peach through regulating phenolic and sugar metabolisms, and maintaining high levels of individual phenolic and sucrose content. PMID- 30309579 TI - Effects of skim milk pre-acidification and retentate pH-restoration on spray drying performance, physico-chemical and functional properties of milk protein concentrates. AB - This study investigates the effects of pre-acidification (pH 6.7-5.4) of skim milk, followed by pH-restoration of the retentates, on spray-drying performance, physico-chemical properties and functionality of the resulting milk protein concentrate (MPC). Powder recovery decreased with decreasing pH of pre acidification but improved with pH-restoration. Colloidal calcium was gradually solubilized with decreasing pH of pre-acidification but was slightly recovered by pH-restoration. Dissociation of micellar caseins increased with decreasing pH of pre-acidification of skim milk and was further increased by pH-restoration. Casein micelles maintained their overall structures at pre-acidification pH of 6.7-6.0, and partially disintegrated into loosely entangled aggregates at pH 5.7 5.4; while after pH-restoration, micelles generally maintained their overall structures at pre-acidification pH of 6.0, and completely disintegrated at pH 5.7 5.4. Solubility and emulsifying properties of MPC improved with decreasing pH of pre-acidification and with pH-restoration. Heat stability of MPC declined with decreasing pH of pre-acidification but improved with pH-restoration. PMID- 30309580 TI - Transcriptome and proteome analyses of the molecular mechanisms associated with coix seed nutritional quality in the process of breeding. AB - In present study, the content of main nutrients in wild coix seed were significantly higher than cultivated coix seed. Transcriptome and proteome were combined to provide new insight of the molecular mechanisms linked to nutritional quality of wild coix seed and cultivated coix seed by RNA sequencing and isobaric tags for relative and absolute quantification techniques. A total of 20,039 genes and 471 proteins exhibited differential expression level in cultivated coix seed when compared with wild coix seed. These genes and proteins revealed that the pathway of flavonoids biosynthesis, starch and sucrose metabolism, lipid metabolism and amino acid metabolism were linked to nutritional quality of coix seed. Our results provided transcriptomics and proteomics information with respect to the molecular mechanisms of nutritional changes of coix seed, identified key genes and proteins that associated with the metabolism and accumulation of nutrients, and helped clarify the mechanisms of nutrient differences. PMID- 30309581 TI - Simultaneous determination and risk assessment of fipronil and its metabolites in sugarcane, using GC-ECD and confirmation by GC-MS/MS. AB - A sensitive gas chromatographic method using a modified QuEChERS technique is reported for simultaneous determination, dissipation and risk assessment of fipronil and its metabolites in sugarcane and soil. Recoveries were 80.7-98.5% with precision within 1.4-16.5% estimated at the limits of detection (LOD) 0.0015 0.002 ug g-1 and limits of quantification (LOQ) 0.005 ug g-1. Fipronil dissipated with half-life (T1/2) of 2.8-4.3 days while for total fipronil it was 3.7-6.0 days following application of fipronil (5% SC) in sugarcane fields at recommended (100 g a.i. ha-1) and double the recommended (200 g a.i. ha-1) doses. Estimated pre-harvest intervals (PHI) for fipronil were 20.3-27.0 days in sugarcane plants, and for total fipronil the corresponding values were 28.2-37.8 days. No dietary risk was observed due to fipronil (RQd < 1) 5 days after application. Potential risk exists towards algae and soil macro-organism (RQs > 1), but for earthworms it was safe (RQs < 1). PMID- 30309582 TI - Extraction of lycopene using a lecithin-based olive oil microemulsion. AB - Incorporation of many water-insoluble nutraceuticals into aqueous formulations can present a real challenge for food industry. Hence, establishment of novel technologies for concurrent extraction and solubilisation of lipophilic compounds might be of a great interest. The main objective of the present study was to prepare olive oil microemulsions using different proportions of lecithin, 1 propanol, olive oil and water to examine their abilities to form microemulsion as well as extraction of lycopene from industrial tomato pomace. Lycopene extraction using 1 g tomato pomace and 4 extraction cycles applying 5 g microemulsion composed of lecithin: 1-propanol: olive oil: water (53.33:26.67:10:10 wt%) resulted in the highest extraction efficiency (88%). Such biocompatible and food grade microemulsion containing lycopene can be applied in many food formulations where it can present a good solubility in aqueous and non-polar media and can improve the health-promoting properties of both lycopene and olive oil. PMID- 30309583 TI - The synthesis and characterization of a xanthan gum-acrylamide-trimethylolpropane triglycidyl ether hydrogel. AB - To improve the thermal stability and adsorption performance, xanthan gum was modified with acrylamide and trimethylolpropane triglycidyl ether (TTE). The modified xanthan gum (XGTTE) was characterized by Fourier transform infrared (FT IR) spectroscopy, X-ray diffractogram (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The characteristic peaks at 3449, 1655, 1611 and 1420 cm-1 in the FT-IR confirm the modification. The XGTTE crystal grew well upon addition of TTE. The XRD and DSC data revealed that the XGTTE enhanced its thermal stability. Analysis of SEM revealed that the grafting introduced major changes on the microstructure making it porous and resulting in the adsorption of crystal violet (CV) with flocculation. The CV adsorption capacity of the hydrogel with different dosages of TTE (XGTTE2, XGTTE3, XGTTE4, XGTTE5 and XGTTE6) were between 28.13 with 35.12 mg/g. In addition, the adsorption capacity, thermal stability, and swelling property of XGTTE4 were the best. PMID- 30309584 TI - Use of a smartphone for visual detection of melamine in milk based on Au@Carbon quantum dots nanocomposites. AB - Gold nanoparticles@Carbon quantum dots nanocomposites (Au@CQDs) were designed for analyzing melamine in milk visually. Fluorescent emission of Au@CQDs enhanced with the increase of melamine concentration. A calibration curve (R2 = 0.9856) and fluorescence standard array were established for detection of melamine in the range of 1 MUM-10 MUM. Limit of quantification and limit of detection were 12 nM and 3.6 nM, respectively. The approximate concentration of melamine adulterated in milk samples were detected visually by the fluorescence standard array and smartphone. The accurate concentration was obtained by the calibration curve and portable fluorescence spectrometer with recoveries of 105.64%-102.75% and less than 2% of coefficient of variation (CV) (n = 18). This performance was consistent with that of the high-performance liquid chromatography (HPLC) method (recoveries of 105.56%-107.95% with 2.24%-3.56% of CVs). The Au@CQDs-based fluorescent method for visual and accurate detection of melamine in milk was presented and showed strong application potential. PMID- 30309585 TI - Discrimination of geographical origins of Chinese acacia honey using complex 13C/12C, oligosaccharides and polyphenols. AB - The aim of this study was to predict the geographical origin of acacia honey of China through analysis of physicochemical parameters combination with chemometrics. Samples from six different origins were investigated on parameters of delta13C value, oligosaccharides and polyphenols, using EA-IRMS/LC-IRMS, GC-MS and HPLC-MS, respectively. The results indicated that the delta13C value of honey from Gansu region were lower than those of other regions. Oligosaccharides of honey from Shanxi and Shaanxi regions were both higher than other four regions. Polyphenols of honey from Shandong region was the highest and were better parameters than both delta13C and oligosaccharides in discrimination of geographical origins. Partial Least Square Discriminant Analysis (PLS-DA) showed that when all 31 different parameters were combined, a correct classification rate of 94.12% could be achieved using external cross validation method. In conclusion, the method in discrimination of geographical can be used to provide reliable and useful reference information. PMID- 30309586 TI - beta-Agarase immobilized on tannic acid-modified Fe3O4 nanoparticles for efficient preparation of bioactive neoagaro-oligosaccharide. AB - beta-Agarase was immobilized by using tannic acid modified-Fe3O4 magnetic nanoparticles (TA-MNPs) as a supportmaterial. The MNPs were synthesized by improved chemical coprecipitation method and modified with TA for agarase immobilization. TA-MNPs and immobilized beta-agarase were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and thermal gravimetric analysis (TGA), all of which indicated the successful surface modification of MNPs with TA and the immobilization of beta agarase. The optimal immobilization conditions for 25 mg TA-MNPs included 100 r/min oscillation speed, immobilization time of 2 h, immobilization temperature of 15 degrees C, and initial beta-agarase concentration of 3 mL (480 U). Immobilized beta-agarase showed better pH and thermal stability and excellent reusability than the free enzyme. Results revealed the promising application of beta-agarase-TA-MNPs for the preparation of neoagaro-oligosaccharides with different averagepolymerizationdegrees and varying activities in the antioxidant. PMID- 30309587 TI - Integration of (+)-catechin and beta-sitosterol to achieve excellent radical scavenging activity in emulsions. AB - Novel amphiphilic antioxidant, (+)-catechin-beta-sitosterol (CS), was designed and successfully prepared with integration of (+)-catechin and beta-sitosterol through the linkage of succinic acid. Sequential esterification was carried out to connect (+)-catechin and beta-sitosterol. The identity of CS was confirmed by NMR, IR and MS spectroscopies. DSC analysis revealed that DeltaH of CS was much lower than those of (+)-catechin and beta-sitosterol, indicating ameliorated crystallinity. The logP measurement demonstrated significantly increased lipophilicity. Then excellent antioxidant activities of the novel antioxidant in typical polyunsaturated lipid O/W and W/O emulsions were unveiled applying beta sitosterol bleaching assay and 5-dodecanoylaminofluorescein (DAF) fluorescent probe method. The antioxidative behavior of CS in emulsion was beyond the polar paradox hypothesis and could be rationalized by effective accumulation at oil/water interface owing to its amphiphilic nature. This study offers a promising solution for development of naturally derived amphiphilic antioxidants for lipid-based systems. PMID- 30309588 TI - Effect of glazing and rosemary (Rosmarinus officinalis) extract on preservation of mud shrimp (Solenocera melantho) during frozen storage. AB - In this study, glazing with water and rosemary (Rosmarinus officinalis) extract were applied on frozen mud shrimp (Solenocera melantho) and stored at -20 degrees C for 24 weeks. Quality loss and protein and lipid changes of shrimp were evaluated by total volatile basis nitrogen (TVB-N), drip loss, moisture distribution, sulfhydryl content (SH), disulfide bond, intrinsic fluorescence intensity, lipid content, free fatty acids (FFA), peroxide value (PV), fluorescent compounds and sensory characteristics. Results showed that unglazed mud shrimp exhibited significant quality decline after 16 weeks of frozen storage. Glazing treatment significantly reduced quality loss, protein degradation, and lipid oxidative damage of shrimp during the 24 weeks of frozen storage, compared to the unglazed control sample. Glazing with rosemary extract was more effective in controlling quality changes in frozen mud shrimp with lower TVB-N, drip loss, PV, FFA and higher lipid content and sensory scores. PMID- 30309589 TI - Effects of protein S-nitrosylation on the glycogen metabolism in postmortem pork. AB - The aim of this study was to investigate the effects of protein S-nitrosylation on the glycogen metabolism in postmortem pork. The pork samples were incubated with control (0.9% NaCl), nitric oxide synthase (NOS) inhibitor, or NO donor for 4 and 12 h at 4 degrees C. Results indicate that NOS inhibitor treatment led to significantly lower level of glycogen and higher lactate content at 24 h compared those of control and NO donor treatments (P < 0.05). The pH of NOS inhibitor treatment was significantly lower than other treatments, which indicates the fast glycolysis during postmortem aging (P < 0.05). In addition, the activities of glycolytic enzymes including GP, GAPDH and PK were significantly different among three treatments (P < 0.05) possibly due to the different modification of protein S-nitrosylation. These results suggest that NO could regulate the glycogen metabolism through modulating the activities of glycolytic enzymes by protein S nitrosylation. PMID- 30309590 TI - Rapid purification of lysozyme by mixed-mode adsorption chromatography in stirred fluidized bed. AB - The commercial STREAMLINE Direct HST adsorbent was employed to investigate the adsorption characteristics of lysozyme in complex chicken egg white (CEW). The effects of operating parameters, including adsorption pH, ionic strength, and hydrophobicity of liquids on binding capacity, were examined using a well-mixed contactor. To determine the elution strategy, the experiments were carried out in a small packed bed. The lysozyme was completely eluted by 0.5 M NaCl in 40 mM carbonate buffer (pH 12) at a high liquid velocity of 200 cm/h. The effect of rotating speed on fluidization characteristics was further investigated by using a stirred fluidized bed process. Smoother fluidization was observed when the rotating speed reached 200 rpm and lysozyme was directly recovered from highly viscous CEW in a single step with a high yield of 94.3% and a purification factor of 15.7. PMID- 30309591 TI - Improving medium chain fatty acid production in Escherichia coli by multiple transporter engineering. AB - Medium-chain fatty acids (C6-C10, MCFAs) represent valuable molecules for food and pharmaceutical industries. However, MCFAs in Escherichia coli induce stresses and toxicity, reducing final yields. These phenotypes could be alleviated if MCFA export from cells was accelerated, yet information on proteins responsible for exporting MCFAs remains limited. Here, a panel of 17 genes or operons was screened. Overexpressing resistance nodulation cell division family transporter acrE, mdtE and mdtC increased MCFA titer by 46.4%, 65.2% and 33.8%, whereas overexpressing transcriptional activators soxS, marA and multidrug efflux pumps cmr, fadL decreased MCFA titer by 42.5%, 27.8%, 37.6% and 29.5%, respectively. Furthermore, the effect of multiple transporter engineering was investigated. Overexpressing acrE, mdtE and mdtC together with deleting cmr increased MCFA production by more than two-fold. This study demonstrated the efficient efflux pump specifically for MCFAs and this multiple transporter engineering strategy can be employed to synthesize other bio-products toxic to microorganisms. PMID- 30309592 TI - Multiple tests on saffron find new adulterant materials and reveal that Ist grade saffron is rare in the market. AB - Among spices, Saffron is among the most extensively interrogated for purity and authenticity. Numerous methods have been recommended for authentication of Saffron samples and for detection of adulterants for codex compliance. However, none of these methods can fulfill both of these important quality criteria. This study describes a three step approach to achieving this goal by including the established ISO3632 method and two additional methods based on microscopic examination and DNA barcoding. We provide results showing the utility of these methods both independently and in combination for quality evaluation of 36 commercial saffron samples. Our results show that use of the ISO3632 approach alone can reveal the color and aroma but not the genetic origin of the material or distinguish between synthetic components versus natural ingredients. Also, the microscopic observation method can give a preliminary indication of saffron authenticity, but used alone it is unable to quantify purity. Finally, a relatively new method based on the use of DNA barcodes can authenticate the biological origin of the saffron, but here results may be misleading if auto adulterating materials are present. Overall, our study reveals that through the combined use of all three methods, saffron authentication can substantially improved. PMID- 30309593 TI - Preservative effects of fish gelatin coating enriched with CUR/betaCD emulsion on grass carp (Ctenopharyngodon idellus) fillets during storage at 4 degrees C. AB - This study investigated the effects of a novel edible coating combining fish gelatin with curcumin/beta-cyclodextrin (CUR/betaCD) emulsion on the quality of grass carp fillets (GCFs) during storage at 4 degrees C. For all samples, the quality parameters, including weight loss, pH, total volatile basic nitrogen (TVB N), peroxide value (PV), thiobarbituric acid (TBA) value, SDS-PAGE, free amino acids (FAA), microbiological (total viable counts (TVC), Pseudomonas counts, yeasts and molds, and H2S-producing bacteria), color and sensorial characteristics, were tested periodically. The coatings containing CUR/betaCD emulsions exhibited better preservative effects than gelatin/betaCD coating. Therefore, fish gelatin coating enriched with CUR/betaCD emulsion can be used as an effective way to maintain the quality of GCF and extend its shelf life during storage at 4 degrees C. PMID- 30309595 TI - Physicochemical properties and phenolic content of honey from different floral origins and from rural versus urban landscapes. AB - The composition of honey influences how beneficial it is to human health. This study evaluated the physiochemical properties and total phenolic content (TPC) of single vs. multi-floral Irish and selected international honeys, and whether properties varied according to hive location. Oilseed rape honey had the lowest TPC of Irish unifloral honeys. Heather honey had the highest TPC, similar to Manuka honey (Mean +/- SD = 68.16 +/- 2.73 and 62.43 +/- 10.03 respectively), and the TPC of ivy honey was approximately half that of heather. Urban multi-floral honeys contained higher TPC (28.26 +/- 13.63) than rural honeys (20.32 +/- 11.54). Physiochemical properties varied according to floral origin, and whether hives were in urban or rural sites. Irish heather honey had similar physiochemical characteristics to Manuka honey. This first examination of Irish honey confirms that TPC and physiochemical properties vary with honey type and hive location, and suggests that Irish heather honey should be examined for potential health benefits. PMID- 30309594 TI - Trans-alpha-glucosylation of stevioside by the mutant glucansucrase enzyme Gtf180 DeltaN-Q1140E improves its taste profile. AB - The adverse health effects of sucrose overconsumption, typical for diets in developed countries, necessitate use of low-calorie sweeteners. Following approval by the European Commission (2011), steviol glycosides are increasingly used as high-intensity sweeteners in food. Stevioside is the most prevalent steviol glycoside in Stevia rebaudiana plant leaves, but it has found limited applications in food products due to its lingering bitterness. Enzymatic glucosylation is a strategy to reduce stevioside bitterness, but reported glucosylation reactions suffer from low productivities. Here we present the optimized and efficient alpha-glucosylation of stevioside using the mutant glucansucrase Gtf180-DeltaN-Q1140E and sucrose as donor substrate. Structures of novel products were elucidated by NMR spectroscopy, mass spectrometry and methylation analysis; stevioside was mainly glucosylated at the steviol C-19 glucosyl moiety. Sensory analysis of the alpha-glucosylated stevioside products by a trained panel revealed a significant reduction in bitterness compared to stevioside, resulting in significant improvement of edulcorant/organoleptic properties. PMID- 30309596 TI - Lipophilization of EGCG and effects on antioxidant activities. AB - A green, fast, and efficient method for synthesizing lipophilic epigallocatechin gallate (EGCG) derivatives was set up for the first time. EGCG was lipophilized by esterification in order to promote its application in lipid products and to possibly enhance its bioactivity. A high conversion of EGCG was achieved. Three monoesters of the EGCG derivatives were confirmed by high performance liquid chromatography-mass spectrometry, and the predominant one was identified as 4'-O palmitoyl EGCG by nuclear magnetic resonance. The EGCG derivatives exhibited good radical scavenging capacities. In lard the solubility of EGCG derivatives was enhanced 470 times compared to EGCG, and they exhibited excellent antioxidative activity in the oil. These results indicate that the palmitoylated EGCG derivatives may be used as potent antioxidants in lipophilic medium, such as edible oils and fatty foods. In addition, this method can be applied to commercial application, producing antioxidants to substitute for synthetic ones like tert-butylhydroquinone. PMID- 30309597 TI - On-line screening and identification of free radical scavenging compounds in Angelica dahurica fermented with Eurotium cristatum using an HPLC-PDA-Triple-TOF MS/MS-ABTS system. AB - Eurotium cristatum, a beneficial fungus isolated from Fuzhuan tea, was used to ferment Angelica dahurica for the first time. The antioxidant capacities of the extracts before and after fermentation were compared using ABTS, DPPH and FRAP assays. The results showed that the antioxidant capacities of the extracts acquired using organic solvents were greater after fermentation. Moreover, based on a comparison of the HPLC chromatograms, the chemical composition of Angelica dahurica changed substantially during fermentation. To further understand the changes in its antioxidant constituents, an on-line HPLC-PDA-Triple-TOF-MS/MS ABTS system was employed. Twelve antioxidants belonging to three different classes were detected and identified, and their antioxidant capacities were preliminarily evaluated. The results indicated that the substances produced during the fermentation of Eurotium cristatum played important roles in enhancing the antioxidant capacity. PMID- 30309598 TI - Structure-activity relationship of procyanidins on advanced glycation end products formation and corresponding mechanisms. AB - Nonenzymatic glycosylation (NEG) can generate advanced glycation end products (AGEs) and its intermediates alpha-dicarbonyl compounds, which contribute to the risk of diabetes. This study investigated the anti-glycation mechanisms and structure-activity relationship of (+)-catechin (CC) and (-)-epicatechin (EC). The results showed that the effect of CC on inhibiting AGEs was significantly better than that of EC (p < 0.05). By exploring the mechanism, we found that there was no significant difference in the ability of CC and EC to capture alpha dicarbonyl compounds. But CC was found to be more efficient than EC to inhibit RO, OH and CHO radicals generation, which may be the primary reason that CC was more effective than EC on AGEs inhibition. What's more, CC showed better inhibitory effect on beta-glucosidase that was close to the molecular docking study. Our results will provide a theoretical foundation for development of different structure of procyanidins as natural AGEs inhibitors in food and medicine. PMID- 30309599 TI - In vitro and in vivo hypoglycemic effects of cyanidin 3-caffeoyl-p hydroxybenzoylsophoroside-5-glucoside, an anthocyanin isolated from purple fleshed sweet potato. AB - Anthocyanins are major components of purple sweet potatoes (PSP) with antioxidant, anti-obesity, and antidiabetic activity. In this study, we evaluated the hypoglycemic effects of 12 individual anthocyanins purified from PSP (Korean variety Shinzami). We separated the anthocyanins using liquid chromatography with diode array detection and electrospray ionization/mass spectrometry (LC-DAD ESI/MS). Three anthocyanins were selected through a radical scavenging activity test. We examined whether individual anthocyanins inhibited glucose secretion in HepG2 cells (hepatic gluconeogenesis). Additionally, we determined the effect of each anthocyanin on fasting blood glucose levels in 6-week-old male C57BL/6J mice fed a 60% high-fat diet for 14 weeks. Mice were evaluated at 0, 1, 2, and 4 h after oral administration of anthocyanins (80 mg/kg), an anthocyanin-rich fraction (80 mg/kg), positive control (metformin, 80 mg/kg), and distilled water (control). Cyanidin 3-caffeoyl-p-hydroxybenzoylsophoroside-5-glucoside (PEAK9) was the main PSP anthocyanin that inhibited hepatic glucose secretion and reduced blood glucose. PMID- 30309600 TI - The preparation and physiochemical characterization of rapeseed protein hydrolysate-chitosan composite films. AB - The composite films were prepared by mixing rapeseed protein hydrolysate with chitosan. Upon increasing the degree of hydrolysis, rapeseed protein enhanced its compatibility with chitosan, thus making composite films denser. The tensile strength of films was increased from 16.04 to 23.46 MPa with increasing the degree of hydrolysis from 0% to 12%. Moreover, addition of chitosan enhances the mechanical properties of the rapeseed protein films, the alpha-helix content in the secondary structure of the rapeseed protein from 15.4% to 25.0%. And it is hydrogen bonding, the main force between two components that contributed to good compatibility, which supported by analyses of Fourier transform infrared spectroscopy and scanning electron microscopy. The results of the antibacterial properties of the composite film with 12% degree of hydrolysis were better compared with the chitosan film. Taken together, our results provide insights for the further application of rapeseed protein in making edible films. PMID- 30309601 TI - Characterization by gas chromatography-olfactometry of the most odour-active compounds in Italian balsamic vinegars with geographical indication. AB - Odour-active compounds in three traditional balsamic vinegars from Modena (TB) and seven balsamic vinegars from Modena (PGI) were determined by gas chromatography-olfactometry (GC-O) using frequency of detection methodology (modified frequency, MF, %). The main odour compounds (mean MF > 60%) were 2,3 butanedione (75%), acetic acid (70%), furan-2-carbaldehyde (62%), 1-(furan-2 yl)ethanone (62%), 2-methylpropanoic acid (66%), butanoic acid (78%), 3 methylbutanoic acid (83%), 2-phenylethyl acetate (65%), 2-hydroxy-3 methylcyclopent-2-en-1-one (61%), 2-phenylethan-1-ol (84%), 3-hydroxy-2 methylpyran-4-one (60%), (5-formylfuran-2-yl)methyl acetate (68%), 2-phenylacetic acid (69%) and 4-hydroxy-3-methoxybenzaldehyde (86%). All odour impact compounds were grouped into 7 categories according to their aromatic character: cheesy butter-lactic, sweet, flower, empyreumatic, fruity, chemical and miscellaneous. Balsamic vinegars from Modena showed lower values for the sweet category whereas for the miscellaneous and chemical categories they exhibited higher values than those found in traditional balsamic vinegars from Modena. A principal component analysis showed that both types of vinegars from Modena could be clearly differentiated based on olfactometric data. PMID- 30309602 TI - Isolation and molecular identification of Lactobacillus with probiotic potential from abomasums driven rennet. AB - Lactobacillus species are beneficial for the functional food industry and preventive medicine. The complex microflora of traditional cheese depends on the cheese types (e.g., homemade rennets). Here, the abomasum driven rennet was assessed for the existence of lactobacilli. For differentiating lactobacilli, the bacterial suspension was screened for the acid and bile resistance. The isolated bacteria were evaluated for antibiotic susceptibility and antagonistic impacts on other pathogenic bacteria. The 16S rDNA gene was evaluated by the amplified ribosomal DNA restriction analysis (ARDRA) recruiting the restriction enzyme Taq I and compared to the virtually digested patterns of previous reports on lactobacilli. The isolates were examined by random amplified polymorphic DNA (RAPD) and distinctive lactobacilli were sequenced. ARDRA and RAPD data showed three distinct lactobacilli strains, including L. acidophilus, L. planetarum, and L. fermentum. The homemade rennet is proposed as the novel source of probiotic strains as an alternative to the traditional cheeses. PMID- 30309603 TI - Spray drying microencapsulation of betalain rich extracts from Escontria chiotilla and Stenocereus queretaroensis fruits using cactus mucilage. AB - In this work the capacity of Opuntia ficus indica mucilage as a wall agent in the microencapsulation of Escontria chiotilla and Stenocereus queretaroensis pulp and skin pigments through a spray drying process was studied. The acidified mucilage was used as an extracting medium for betalains present in the skin of these fruits. The shear-thinning behavior of the mucilage-betalain solutions was suitable for spray drying, wherein microcapsules with smooth and spherical morphologies were observed by SEM and characterized by FTIR. Additionally, microcapsules of mucilage achieved the retention of betalains at more than 90% after three months of storage. The colors obtained from the redissolution of the powders from skin and pulp samples do not present significant differences; therefore, the use of skin fruits can be a source of colorants, taking advantage of waste from other processes, promoting a culture of the use of environmentally friendly technologies. PMID- 30309604 TI - Comparative evaluation of the volatile profiles and taste properties of roasted coffee beans as affected by drying method and detected by electronic nose, electronic tongue, and HS-SPME-GC-MS. AB - In this study, room-temperature drying, solar drying, heat pump drying (HPD), hot air drying, and freeze drying were applied to investigate the volatile profiles and taste properties of roasted coffee beans by using electronic nose, electronic tongue, and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Results indicated that the drying process markedly affected pH, total titratable acidity, total solids, and total soluble solids. Significant differences existed among all samples based on drying method; and the HPD method was superior for preserving ketones, phenols, and esters. Principal component analysis (PCA) combined with E-nose and E-tongue radar charts as well as the fingerprint of HS-SPME-GC-MS could clearly discriminate samples from different drying methods, with results obtained from hierarchical cluster analysis (the Euclidean distance is 0.75) being in agreement with those of PCA. These findings may provide a theoretical basis for the dehydration of coffee beans and other similar thermo-sensitive agricultural products. PMID- 30309605 TI - Analytical methods in food additives determination: Compounds with functional applications. AB - This work describes the 25 classes of food additives that contain about 230 compounds with technological, sensorial and/or microbiological functionalities. These compounds are added to foods at the processing, packaging and transport steps, to improve the standard of quality, durability and stability of the product and adjust the colour, smell and flavour attributes. Food industries need to follow national and international quality standards that establish the conditions under which food additives may be used, and the food safety is guaranteed by strict quality control. This review describes the analytical techniques used in identification and quantification of food additives in foodstuffs, highlighting the main characteristics of each method (spectroscopy, chromatography and electroanalysis), and indicating the advantages and disadvantages typical of the methods used. Perspectives of the chemical analysis in the food industries are also discussed. PMID- 30309606 TI - Identification and mechanism evaluation of a novel osteogenesis promoting peptide from Tubulin Alpha-1C chain in Crassostrea gigas. AB - Marine shellfish provides a series of biofunctionality account of its high protein level. In this study, the osteogenic effect of a novel peptide, YRGDVVPK, from Crassostrea gigas protein hydrolysates on preosteoblast MC3T3-E1 proliferation was examined. Synthetic peptide with 100 nM significantly promoted the proliferation of MC3T3-E1 cells for a treatment of 72 h assayed by MTT method, and which was confirmed by the increase of alkaline phosphatase (ALP) activity. The peptide, YRGDVVPK, was docked with integrin alpha5beta1 (PDB ID: 3VI4), which is a surface receptor of MC3T3-E1. The interaction of the peptide with integrin alpha5beta1 (PDB ID: 3VI4) was analyzed by the molecular modeling algorithm of CDOCKER, which showed a more stable combination than the original ligand. The results suggested the novel peptide could promote the preosteoblast MC3T3-E1 proliferation probably by activating the signaling pathway of MAPK, which is induced through binding with peptide YRGDVVPK. PMID- 30309607 TI - Effect of interesterified blend-based fast-frozen special fat on the physical properties and microstructure of frozen dough. AB - To better understand the effect of interesterified blend-based fast-frozen special fat (IBSF) on the quality of frozen dough, the physical properties and microstructure of frozen dough were investigated. The presence of IBSF in the frozen dough increased the gelatinization enthalpy (from 0.16 to 0.26 J/g) and decreased the degree of retrogradation (from 81.3% to 53.8%). The frozen dough added with IBSF also exhibited enhanced extensibility and greater flexibility. Data of DSC and Low-field NMR demonstrated that addition of IBSF significantly reduced the freezable water content and mobility of free water. SEM analysis showed that the starch granules were arranged in the gluten network of frozen dough. Compared with the corresponding physical blend-based special fat and commercial special fat, IBSF not only exhibited favorable influence on the quality of frozen dough, but didn't have trans-fatty acid. These results suggest that IBSF is promising in the preparation of prefrozen fast food. PMID- 30309608 TI - Effect of phosphates on gelling characteristics and water mobility of myofibrillar protein from grass carp (Ctenopharyngodon idellus). AB - Effect of phosphates on the heat-induced gel characteristics of myofibrillar protein (MP) from grass carp was investigated. Both heating and phosphates exerted significant influences. Heating induced more elastic, water-holding and less flowing gel. But phosphates had diverse effects at different temperatures. At 4 degrees C and 40 degrees C, phosphate as a dominant factor reduced the gel elasticity and resistance and increased flowability with increasing levels of phosphates. Furthermore, 280 mg/kg sodium pyrophosphate (SPP) or 440 mg/kg sodium triphosphates (STP) transformed MP from weak gel into concentrated solution. It clarified phosphates disentangled MP macromolecules and inhibited their aggregation and pre-gelation at low temperature. At 80 degrees C, heating accompanied with phosphates governed MP gelation. The appropriate level of phosphates (SPP superior to STP) endowed MP-phosphate gels with the lowest flowability and greatest elasticity, textural properties as well as finest microstructures. Besides, phosphates entrapped a portion of weak immobile water more tightly into smaller-sized pores of protein network. PMID- 30309609 TI - Metabolite characterization of powdered fruits and leaves from Adansonia digitata L. (baobab): A multi-methodological approach. AB - The metabolite profiling of extracts from Adansonia digitata L. (baobab) fruit pulp and leaf, and the quantification of their major components, was conducted by means of reverse-phase, high-performance liquid chromatography with photodiode array detection, coupled to electrospray ion-trap mass spectrometry (RP-HPLC-PDA ESI-MS/MS) and high field nuclear magnetic resonance (NMR) spectroscopy. Water soluble metabolites from chemical classes including sugars, amino acids, organic acids, and phenolic compounds, were identified, in addition to metabolites soluble in organic solvents such as triacylglycerides, sterols, and fatty acids, and most of these were quantified. The profiling of the primary and secondary metabolites of baobab fruit and leaves addresses the limited knowledge of the chemical composition of baobab, and helps support and explain the growing evidence on its nutritional and biological properties, and provide suggestions about the possible uses of baobab fruit and leaves by food, pharmaceutical and cosmetic industries. PMID- 30309610 TI - Ellipsoid Zone Change According to Glaucoma-Stage Advancement. PMID- 30309613 TI - Accuracy of electrocardiographic imaging using the method of fundamental solutions. AB - Solving the inverse problem of electrocardiology via the Method of Fundamental Solutions has been proposed previously. The advantage of this approach is that it is a meshless method, so it is far easier to implement numerically than many other approaches. However, determining the heart surface potential distribution is still an ill-posed problem and thus requires some form of Tikhonov regularisation to obtain the required distributions. In this study, several methods for determining an "optimal" regularisation parameter are compared in the context of solving the inverse problem of electrocardiology via the Method of Fundamental Solutions. It is found that the Robust Generalised Cross-Validation method most often yields epicardial potential distributions with the least relative error when compared to the input distribution. The study also compares the inverse solutions obtained with the Method of Fundamental Solutions with those obtained in a previous study using the boundary element method. It is found that choosing the best solution methodology and regularisation parameter determination method depends on the particular scenario being considered. PMID- 30309611 TI - Modeling the Axon as an Active Partner with the Growth Cone in Axonal Elongation. AB - Forces generated by the growth cone are vital for the proper development of the axon and thus brain function. Although recent experiments show that forces are generated along the axon, it is unknown whether the axon plays a direct role in controlling growth cone advance. Here, we use analytic and finite element modeling of microtubule dynamics and the activity of the molecular motors myosin and dynein to investigate mechanical force balance along the length of the axon and its effects on axonal outgrowth. Our modeling indicates that the paradoxical effects of stabilizing microtubules and the consequences of microtubule disassembly on axonal outgrowth can be explained by changes in the passive and active mechanical properties of axons. Our findings suggest that a full understanding of growth cone motility requires a consideration of the mechanical contributions of the axon. Our study not only has potential applications during neurodevelopment but might also help identify strategies to manipulate and promote axonal regrowth to treat neurodegeneration. PMID- 30309612 TI - Characterization of TDP-43 RRM2 Partially Folded States and Their Significance to ALS Pathogenesis. AB - The human protein TDP-43 is a major component of the cellular aggregates found in amyotrophic lateral sclerosis and other neurodegenerative diseases. Insoluble cytoplasmic aggregates isolated from the brain of amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients contain ubiquitinated, hyperphosphorylated, and N-terminally truncated TDP-43. Truncated fragments of TDP-43 identified from patient tissues contain part of the second RNA recognition motif (RRM2) and the disordered C-terminus, indicating that both domains can be involved in aggregation and toxicity. Here, we focus on RRM2. Using all-atom replica-averaged metadynamics simulations with NMR chemical shift restraints, we characterized the atomic structure of non-native states of RRM2, sparsely populated under native conditions. These structures reveal the exposure to the solvent of aggregation-prone peptide regions, normally buried in the native state, supporting a role in aggregation for the partially folded states of RRM2. PMID- 30309615 TI - Corrigendum to "JAK/STAT signaling prevents excessive apoptosis to ensure maintenance of the interfollicular stalk critical for Drosophila oogenesis" [Dev. Biol. 438 (2018) 1-9]. PMID- 30309614 TI - [Paranoid personality disorder and criminal offense]. AB - BACKGROUND: Currently, all of the studies that focus on the relationship between paranoia and criminal offenses exclusively concern subjects suffering from a delusional paranoid disorder. However, subjects with single paranoid personality disorder, without any associated delusional disorder, are not uncommon in forensic practice. OBJECTIVES: This study aims to describe the offenses committed by subjects suffering from a single paranoid personality disorder and to compare them with the offenses committed by the subjects affected by a paranoid delusional disorder associated with paranoid personality disorder. Our initial hypothesis is that both populations have a comparable criminological profile. METHODS: Based on a 17 year-long experience carried out in the framework of a forensic assessment, we have selected all subjects presenting a paranoid personality disorder, whether single or associated with paranoid delusional disorder. The selected individuals were divided into two groups according to whether they presented paranoid delusional disorder or not. The offenses were grouped into criminal categories. The alpha risk was fixed at 1%. Data analysis is done by SAS software version 9.4. RESULTS: In a sample of 106 subjects presenting a paranoid personality disorder, including 4 women and 102 men, we found 79 subjects with a single paranoid personality and 27 with an associated paranoid delusional disorder. The average age at the time of the offense was 41 for those with single personality disorders and 49 for those with paranoid delusional disorders. Both groups had forensic antecedents (41%, 11/27 of paranoid delusional disorder and 51%, 40/79 of single paranoid personality disorder). Psychiatric history was more frequent in the paranoid delusional disorder group (59%, 16/27) than in the single paranoid personality disorder group (13%, 10/79). History of addiction was comparable in terms of alcohol abuse (26% in both groups) and other substances (7.5%, 2/27 of paranoid delusional disorder and 9%, 7/79 of single paranoid personality disorder). Comparison of the two groups highlighted significant differences in the type of criminal offenses committed (Fisher's exact test: P=0.0003, alpha risk <0.0001). The offenses committed by delusional authors essentially came down to verbal or physical violence, including homicide (44%, 12/27), and were usually focused on a designated persecutor. Sexual violence was rare. On the other hand, paranoid personality disorder was associated with a wider variety of offenses. Sexual offenses (including 28 rapes, 35%, 28/79) were thus almost as frequent as murder, and attempted murder (38%, 30/79). This diversity of committed offenses was found in their forensic antecedents. In these subjects, the logic of omnipotence may had over ruled the logic of revenge. CONCLUSION: We conducted a retrospective study on 106 subjects with paranoid personality disorder, including 27 subjects with associated paranoid delusional disorder. The comparison of the two groups demonstrated significant differences in offenses. Verbal and physical but non sexual violence, committed in a delusional logic, was found among delusional subjects, while the forms of violence were more multiform in the single paranoid personality disorder group, frequently including sexual violence. This is, as far as we know, the first study describing the medico-legal acting-out of paranoid personalities. These results, which will need to be confirmed by future studies, point out the importance of the criminological risk that may be associated with paranoid personality disorder, without any associated delusional disorder. PMID- 30309616 TI - National Surgical Quality Improvement Program analysis of unplanned reoperation in patients undergoing low anterior resection or abdominoperineal resection for rectal cancer. AB - BACKGROUND: The rate of unplanned reoperation for rectal cancer can provide information about surgical quality. We sought to determine factors associated with unplanned reoperation after low anterior resection and abdominoperineal resection for patients with rectal cancer and outcomes after these reoperations. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to conduct this retrospective study. Patients who underwent elective low anterior resection and abdominoperineal resection for rectal cancer from 2012-2014 were identified. The primary outcomes were 30-day reoperation rates and postoperative complications. RESULTS: A total of 454 low anterior resection patients (5.9%) and 289 abdominoperineal resection patients (8.1%) required reoperation within 30 days of their index operation. The most common reasons for reoperation were infection, bleeding, and bowel obstruction. Multivariate analysis revealed that male sex (odds ratio: 1.5, P = .001), poor functional status (odds ratio: 2.2, P = .04), operative time (odds ratio: 1.001, P = .01), low preoperative albumin (odds ratio: 0.79, P = .04), and lack of ostomy (odds ratio, 0.66, P = .005) were independent risk factors for reoperation after low anterior resection. Smoking (odds ratio: 1.7, P = .001), chronic obstructive pulmonary disease (odds ratio: 1.8, P = .03), poor functional status (odds ratio: 2.1, P = .032), operative time (odds ratio: 1.003, P < .001), low preoperative albumin (odds ratio: 0.69, P = .007), and open approach (odds ratio: 1.5, P = .02) were independent risk factors for reoperation after abdominoperineal resection. Postoperative complication rates are high for those undergoing reoperation, often leading to non-home discharge (P < .001) after reoperation. CONCLUSION: Reoperation after low anterior resection and abdominoperineal resection for rectal cancer is not uncommon. This study highlights the indications for reoperation, potentially modifiable preoperative risk factors for reoperation, and the morbidity associated with such operations. PMID- 30309617 TI - Feeding Jejunostomy after esophagectomy cannot be routinely recommended. Analysis of nutritional benefits and catheter-related complications. AB - BACKGROUND: Patients undergoing esophagectomy for cancer usually deal with malnourishment which increases postoperative morbimortality. The objective of this paper is to analyze the nutritional benefits of feeding jejunostomy (FJ) for early postoperative enteral nutrition (EN) and directly-related complications. MATERIAL AND METHODS: Retrospective study of 100 patients undergoing esophagectomy for cancer between 2008 and 2016. RESULTS: FJ was placed in 47 patients. 82.98% reached EN requirements in FJ group, with a median EN re-start of 1.9 days and median days to objective requirements of 5 days. 51.06% developed directly-related FJ complication, 91.66% of them mild ones (gastrointestinal or catheter-related). 2 patients (4.25%) required re-intervention. No significant differences were shown in total protein and albumin seric levels during first postoperative week and in anastomotic leak rate between both groups (p > 0.05). CONCLUSIONS: Feeding jejunostomies are associated with a great number of complications although most are not life-threatening. Since its nutritional benefit is not proven FJ cannot routinely recommended after esophagectomy. However, the optimal pathway for EN reintroduction, including direct oral intake, is still a matter of debate. PMID- 30309618 TI - Commentary: A timely statement - Reducing the impact of violence on the health status of African-Americans: Literature review and recommendations from the Society of Black Academic Surgeons. PMID- 30309619 TI - What do quantitative ratings and qualitative comments tell us about general surgery residents' progress toward independent practice? Evidence from a 5-year longitudinal cohort. AB - BACKGROUND: This study examines the alignment of quantitative and qualitative assessment data in end-of-rotation evaluations using longitudinal cohorts of residents progressing throughout the five-year general surgery residency. METHODS: Rotation evaluation data were extracted for 171 residents who trained between July 2011 and July 2016. Data included 6069 rotation evaluations forms completed by 38 faculty members and 164 peer-residents. Qualitative comments mapped to general surgery milestones were coded for positive/negative feedback and relevance. RESULTS: Quantitative evaluation scores were significantly correlated with positive/negative feedback, r = 0.52 and relevance, r = -0.20, p < .001. Themes included feedback on leadership, teaching contribution, medical knowledge, work ethic, patient-care, and ability to work in a team-based setting. Faculty comments focused on technical and clinical abilities; comments from peers focused on professionalism and interpersonal relationships. CONCLUSIONS: We found differences in themes emphasized as residents progressed. These findings underscore improving our understanding of how faculty synthesize assessment data. PMID- 30309620 TI - Educational interventions aimed at the transition from surgical training to surgical practice. AB - The transition from surgical training to surgical practice is a critical juncture in the career progression of surgeons. This period is associated with myriad challenges that need to be addressed through specific educational interventions to ensure delivery of safe care to patients and to support the career aspirations of junior surgeons entering the practice environment. These interventions should be based on principles of contemporary surgical education and training, and focus on the needs of surgery residents and junior surgeons entering practice. The specific systems of patient care in which the junior surgeons will work should also be considered while planning and implementing such educational interventions. Senior surgeon colleagues within these systems should play key roles in supporting the junior surgeons entering practice, and may require special training to serve as effective mentors, preceptors, and coaches. Professional societies should play a key role in establishing national standards regarding the educational programs aimed at this transition and develop programs to complement local efforts to address various needs. The American College of Surgeons Division of Education has developed a spectrum of innovative programs that are aimed at this important transition. PMID- 30309621 TI - Universal health coverage: breakthrough or great white elephant? AB - Will the Sustainable Development Goal 3 sub-goal "Achieve universal health coverage, including financial risk protection, access to quality essential health care services and...safe, effective, quality and affordable essential medicines and vaccines for all" be judged a breakthrough or a great white elephant in implementation, when we look back with the clear eyes of hindsight in 2030? What are the ways in which this agenda might play out in implementation and why might it do so? Drawing on a desk review, this Essay explores dominant ideas, ideology, institutions, and interests in relation to global versus Ghana national health priorities since the WHO constitution came into effect in 1948, to reflect on these questions. PMID- 30309622 TI - PTBP1 promotes tumorigenesis by regulating apoptosis and cell cycle in colon cancer. AB - Increased expression of polypyrimidine tract-binding protein 1 (PTBP1) has been observed in human ovarian tumors, glioblastomas, and breast cancer, but its biological roles in tumorigenesis is not fully clear. In the present research, we investigated the biological role of PTBP1 in colon cancer. We found that PTBP1 was overexpressed both in colon cancer cell lines and tissues. Tissue microarray analysis (TMA) indicated that low PTBP1 expression predicted a favorable overall survival for colon cancer patients. Using small interfering RNA technology, we found that down-regulation of PTBP1 significantly inhibited colon cancer cell growth/proliferation, and induced cell cycle arrest as well as apoptosis in vitro. Western blot analysis showed that siRNA PTBP1 could up-regulate the expression of cytoC, p53 and Bax as well as down-regulated p85, p-AKT, cyclinD1, CDK4 and Bcl2 compared to the control. Furthermore, Caspase-3 and PARP1 were activated when PTBP1 is knockdown. This study implies that PTBP1 plays an important role in tumorigenesis of colon cancer. PMID- 30309624 TI - What Proportion of Patients With Heart Failure and Left Ventricular Ejection Fraction 40% to 49% Fulfill the Criteria for Heart Failure With Mid-Range Ejection Fraction? PMID- 30309625 TI - Comparison of the Diagnostic Accuracy of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients <80 to those >80 Years of Age with Heart Failure. AB - Plasma N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is known to increase with age, however, the performance of this biomaker is unclear in patients >80. This study sought to define the diagnostic accuracy of plasma NTproBNP in patients >80 in a large unselected population of heart failure (HF) patients admitted to a Tertiary Hospital in the United Kingdom. 1,995 consecutive patients over a 12 month period were screened for HF through our NTproBNP led HF service. 413 patients had their first presentation of HF and 36.1% of these patients were >80. There was a reduction in accuracy of NTproBNP with age according to the area under the curve, with an area under the curve for all HF patients of 0.734 and a 7.5% reduction in receiver operating characteristic curve area for patients >80 years compared with those under 60 to 79 years of age. The lowest NTproBNP recorded for patients with HF >80 years of age was 466 pg/ml. In HF patients >80, 40.6% patients were diagnosed with HFrEF, 31.1% with HFpEF and 28.2% with HFmrEF. Overall NTproBNP is less accurate at identifying HF in patients >80 years of age and the lowest NTproBNP recorded for a HF patient was 466 pg/ml suggesting that the NTproBNP threshold for ruling out HF in patients >80 years of age should be modified. PMID- 30309623 TI - [Issues of oral targeted therapies in daily clinical practice: 5th edition of the congress of pharmacology of anticancer drugs]. AB - Oral targeted therapies are a growing class of medication. After clinical trials conducted on a selected population, these molecules are usually approved at a fixed dose. However, oral tyrosine kinase inhibitors are characterized by a large intra and inter-individual pharmacokinetic variability, and a narrow therapeutic index. Hence, their prescription is hazardous and unsafe in non-selected people from daily clinical practice. The increasing number of available targeted therapies point out new challenges. These challenges should especially concern prescription for out of the ordinary patients, rules for dose adjustment according to factors of frailty. The ultimate goal is to ensure a safe and individualized prescription. Moreover, many of these molecules are metabolized by the CYP3A4, leading to a serious risk of drug interaction. These interactions might involve not only conventional medicine but also alternative and complementary medicines. These latter are more and more common but oncologists often lack experience about them. Finally, the oral route raises the issues of adherence, and the question of its assessment should now become a permanent part of patients care. PMID- 30309626 TI - Patient-Centered Decision-Making of Revascularization Strategy for Left Main or Multivessel Coronary Artery Disease. AB - Patient preference plays an important role in daily practice; however, its implication has not been well investigated regarding treatment strategy for complex coronary artery disease. We prospectively evaluated a trend of patient centered decision-making of revascularization strategy in patients with multivessel or unprotected left main coronary artery disease. A standardized protocol that favors coronary artery bypass graft surgery (CABG) as the primary treatment of choice, rather than percutaneous coronary intervention, was adopted. According to the protocol, patients decided whether or not they received CABG. Among the 763 consecutively enrolled patients, 293 patients (38%) consented to receive CABG. Fifty-six percent of patients with a high Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score chose CABG. SYNTAX score was independently correlated with consent to receive CABG in each patient SYNTAX score stratum. In-stent restenosis was an independent predictor of choosing CABG in patients with low and intermediate SYNTAX scores. Unprotected left main coronary artery disease was negatively correlated with the decision to choose CABG in patients with intermediate SYNTAX score. Reasons for declining CABG included refusal of open-heart surgery in 318 patients (68%), mild presentation of angina symptoms in 132 patients (28%), low self-confidence to expect long-term survival in 120 patients (26%), and economic factors in 10 patients (2%). Short term major adverse cardiac and cerebrovascular events occurred in about 1% of patients without significant differences between the 2 groups. In conclusion, despite the preferred use of the CABG protocol, more than half of the patients declined CABG. Patient-centered decision-making as well as heart team approach should be considered in real-world practice situations. PMID- 30309627 TI - Meta-Analysis of Bleeding Risk Prediction Scores in Patients After Percutaneous Coronary Intervention on Dual Antiplatelet Therapy. AB - The duration and type of dual antiplatelet therapy (DAPT) prescribed to patients after percutaneous coronary intervention (PCI) involves carefully balancing reduced ischemia and increased bleeding risk for individual patients. Whereas multiple bleeding risk scores exist, the performance of these models to predict long-term bleeding in the setting of DAPT across different settings and populations is unclear. Therefore, we performed a systematic review and meta analysis to compare the performance of current bleeding risk prediction scores for predicting major long-term bleeding events in patients on DAPT post-PCI. Based on a search of MEDLINE (January 1, 1946 to March 3, 2017) and EMBASE (January 1, 1974 to March 3, 2017) for studies published in the English language, we identified 10 published studies of 11 risk unique risk prediction models across a wide variety of settings. Area under the receiver operating characteristic curve (AUC) was used to measure discrimination, when available. Our findings reveal that the prediction models created to date demonstrate only modest accuracy, with the reported AUCs ranging from 0.54 to 0.89; aggregated AUC 0.68 (95% confidence intervals 0.65 to 0.72). Although only 5 studies (50%) reported measures of calibration, the reported models were reasonably well calibrated. Only 3 models (33%) were externally validated. Meta-regression demonstrated lack of influence by age (p = 0.99) or length of follow up (p = 0.42). Sensitivity analysis did not significantly change the results. Novel prediction models are warranted to aid in maximizing the benefit of DAPT after PCI while minimizing harm. PMID- 30309628 TI - Acute and Subacute Triggers of Cardiovascular Events. AB - Inability to predict short-term cardiovascular (CV) events and take immediate preemptive actions has long been the Achilles heel of cardiology. However, certain triggers of these events have come to light. Although these triggers are nonspecific and are part of normal life, studying their temporal relationship with the onset of CV events provides an opportunity to alert high-risk atherosclerotic patients who may be most vulnerable to such triggers, the "vulnerable patient". Herein, we review the literature and shed light on the epidemiology and underlying pathophysiology of different triggers. We describe that certain adrenergic triggers can precipitate a CV event within minutes or hours; whereas triggers that elicit an immune or inflammatory response such as infections may tip an asymptomatic "vulnerable patient" to become symptomatic days and weeks later. In conclusion, healthcare providers should counsel high risk CV patients (e.g., in secondary prevention clinics or those with coronary artery Calcium >75th percentile) on the topic, advise them to avoid such triggers, take protective measures once exposed, and seek emergency care immediately after becoming symptomatic after such triggers. Furthermore, clinical trials targeting triggers (prevention or intervention) are needed. PMID- 30309629 TI - Nonspecific electrocardiographic abnormalities are associated with increased length of stay and adverse cardiac outcomes in prehospital chest pain. AB - BACKGROUND: Nonspecific ST-T repolarization (NST) abnormalities alter the ST segment for reasons often unrelated to acute myocardial ischemia, which could contribute to misdiagnosis or inappropriate treatment. We sought to define the prevalence of NST patterns in patients with chest pain and evaluate how such patterns correlate with the eventual etiology of chest pain and course of hospitalization. METHODS: This was a prospective observational study that included consecutive prehospital chest pain patients from three tertiary care hospitals in the U.S. Two independent reviewers blinded from clinical data audited the prehospital 12-lead ECG for the presence or absence of NST patterns (i.e., right or left bundle branch block, left ventricular hypertrophy with strain pattern, ventricular pacing, ventricular rhythm, or coarse atrial fibrillation). The primary outcome was 30-day major adverse cardiac events (MACE) defined as cardiac arrest, acute heart failure, post-discharge infarction, or all cause death. RESULTS: The final sample included 750 patients (age 59 +/- 17, 58% males). A total of 40 patients (5.3%) experienced 30-MACE and 131 (17.5%) had NST patterns. The presence of NST patterns was an independent multivariate predictor of 30-day MACE (9.9% vs. 4.4%, OR = 2.2 [95% CI = 1.1-4.5]. Patients with NST patterns had increased median length of stay (1.0 [IQR 0.5-3] vs. 2.0 [IQR 1-4] days, p < 0.05) independent of the etiology of chest pain. CONCLUSIONS: One in six prehospital ECGs of patients with chest pain has NST patterns. This pattern is associated with increased length of stay and adverse cardiac outcomes, suggesting the need of preventive measures and close follow up in such patients. PMID- 30309630 TI - Animal models in addiction research: A dimensional approach. AB - Drug addiction affects approximately 10% of the population and these numbers are rising. Treatment and prevention of addiction are impeded by current diagnostic systems, such as DSM-5, which are based on outcomes rather than processes. Here, we review the importance of adopting a dimensional framework, specifically the Research Domain Criteria (RDoC), to identify protective and vulnerability mechanisms in addiction. We discuss how preclinical researchers should work within this framework to develop animal models based on domains of function. We highlight RDoC paradigms related to addiction and discuss how these can be used to investigate the biological underpinnings of an addiction cycle (i.e., binge/intoxication, negative affect, and craving). Using this information, we then outline the critical role of animal research in ongoing revisions to the RDoC matrix (specifically the functional significance of domains, constructs and subconstructs) and its contribution to the development and refinement of addiction theories. We conclude with an overview of the contribution that animal research has made to the development of pharmacological and behavioural treatments for addiction. PMID- 30309631 TI - [Multifocal chalazodermic amyloidosis: The concept of immunoglobulinemic elastopathy]. AB - INTRODUCTION: Impairment of dermal elastic tissue occurs in different entities associated with immunoglobulins or immunoglobulin-derived protein-secreting clonal plasma cell proliferations, such as amyloid elastosis, anetodermic nodular amyloidosis or monoclonal gammopathy-associated cutis laxa. We report a case of cutaneous immunoglobulinemic amyloidosis revealed by a unique chalazodermic presentation and we review elastic tissue impairment in patients with monoclonal gammopathies. OBSERVATION: A 67-year-old woman consulted for non-infiltrated anetodermic lesions on the upper left quadrant of her abdomen present for ten years. She also had a chalazodermic plaque with abnormal skin wrinkling and laxity in her right axilla. Biopsies revealed deep dermal and subcutaneous amyloid deposits. Immunohistochemistry with lambda light chain was positive. Orcein staining and electron microscopy showed extensive elastolysis. The patient presented no signs of systemic involvement, but a very small amount of monoclonal IgGlambda gammopathy was detected during follow-up. DISCUSSION: This is a unique chalazodermic presentation of immunoglobulinemic amyloidosis that does not fit into a clearly-defined nosological setting. It highlights the complex interactions between immunoglobulin-derived proteins, including light and heavy chains, and elastic tissue components, leading to different types of impairment of the latter. We therefore suggest the unifying concept of immunoglobulinemic elastopathy, underscoring the need to screen for monoclonal gammopathy in patients presenting elastic tissue impairments. PMID- 30309632 TI - Prognostic value of pre-embolisation MRI features of uterine fibroids in uterine artery embolisation. AB - AIM: To evaluate the prognostic value of pretreatment pelvic magnetic resonance imaging (MRI) features in uterine artery embolisation (UAE) for symptomatic fibroids. MATERIALS AND METHODS: MRI characteristics of 109 fibroids (>=3 cm) in 70 patients were analysed retrospectively. Imaging was performed 1.8+/-1.3 (SD) months before and 6.6+/-1.8 months after UAE. On pretreatment images, signal intensity (SI) of fibroids was compared with that of the myometrium and skeletal muscle on T1- and T2-weighted sequences; the contrast enhancement pattern and localisation of fibroids were also analysed. Fibroid volume reduction (VR) was assessed by control imaging. The numerical analogue quality-of-life score was obtained before and after UAE. Statistical analysis was performed using the Mann Whitney U-test, Kruskal-Wallis test, and Wilcoxon signed-rank test. RESULTS: The mean fibroid volume decreased by 51.1+/-30.8% during the 6.6+/-1.8 months (p<0.001). Mean quality-of-life score improved by 48.2+/-27.6 points (p<0.001). The mean VR of submucosal fibroids (82.1+/-18.5%) was greater than that of intramural (49.4+/-30.7%) and subserosal (43+/-28.3%) fibroids (p<0.001 for both). Fibroids that were isointense/hyperintense to myometrium on T2-weighted images showed a better response than hypointense fibroids (63.7+/-25.8% versus 48.6+/-31.3%, respectively; p=0.041). On contrast-enhanced images, isointense/hyperintense fibroids showed a better VR than hypointense fibroids (61.3+/-27.4% versus 47.6+/-31.6%, respectively; p=0.035). Baseline fibroid volume of <50 cm3 was also associated with favourable imaging outcome (p=0.021). T2 SI compared to skeletal muscle and T1 SI compared to myometrium or skeletal muscle did not show association with VR. CONCLUSIONS: Localisation, T2 SI, contrast enhancement, and <50 cm3 fibroid volume were associated with better VR; these may help with treatment decisions. PMID- 30309633 TI - Surgical Resection of Endobronchial Glandular Papilloma. PMID- 30309634 TI - Recovery from stuttering in preschool-age children: 9 year outcomes in a clinical population. AB - PURPOSE: The first purpose was to define the recovery rate in children who stutter in a clinical sample, adding self-report to validate recovery status. The second purpose was to explore whether children who were judged to be recovered showed subjective experiences that might be interpreted as coping behaviors used to control speech fluency. METHODS: In this longitudinal study, preschool-age children whose parents consulted a speech-language pathologist about stuttering were followed for 9 years. At follow-up, children's self-reports on stuttering were reported, as well as traditional criteria on recovery (parental and expert judgment). The Overall Assessment of the Speaker's Experience of Stuttering (OASES) was used to collect children's experiences with speaking. RESULTS: Eleven of the 15 children (73%) were judged by parents and clinicians to have recovered from stuttering. However, when considering children's self-reports, 9 children (60%) might be considered to have recovered. In addition, 3 children who were judged to be recovered reported experiences with speaking that were uncommon, even compared to children who continued to stutter. CONCLUSION: In this exploratory study of a clinical population, the recovery rate in children that received treatment for stuttering appeared to be comparable to a non-clinical population. Considering self-reports can improve validity of assessing the "recovery rate". Moreover, recovery in children may not be effortless; instead, it may be the result of conscious or unconscious coping behavior. Future studies are recommended to consider self-reports to improve validity of recovery, and to document experiences with speaking to explore effortless, spontaneous fluency versus controlled fluency. PMID- 30309635 TI - Conducting sensitivity analyses to identify and buffer power vulnerabilities in studies examining substance use over time. AB - INTRODUCTION: A priori power analysis is increasingly being recognized as a useful tool for designing efficient research studies that improve the probability of robust and publishable results. However, power analyses for many empirical designs in the addiction sciences require consideration of numerous parameters. Identifying appropriate parameter estimates is challenging due to multiple sources of uncertainty, which can limit power analyses' utility. METHOD: We demonstrate a sensitivity analysis approach for systematically investigating the impact of various model parameters on power. We illustrate this approach using three design aspects of importance for substance use researchers conducting longitudinal studies base rates, individual differences (i.e., random slopes), and correlated predictors (e.g., co-use) and examine how sensitivity analyses can illuminate strategies for controlling power vulnerabilities in such parameters. RESULTS: Even large numbers of participants and/or repeated assessments can be insufficient to observe associations when substance use base rates are too low or too high. Large individual differences can adversely affect power, even with increased assessments. Collinear predictors are rarely detrimental unless the correlation is high. CONCLUSIONS: Increasing participants is usually more effective at buffering power than increasing assessments. Research designs can often enhance power by assessing participants twice as frequently as substance use occurs. Heterogeneity should be carefully estimated or empirically controlled, whereas collinearity infrequently impacts power significantly. Sensitivity analyses can identify regions of model parameter spaces that are vulnerable to bad guesses or sampling variability. These insights can be used to design robust studies that make optimal use of limited resources. PMID- 30309636 TI - Introduction. PMID- 30309637 TI - Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Imaging for Diagnosis, Tumor Response to Treatment and Liver Response to Radiation. AB - Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) comprise the majority of primary liver cancers. Both HCC and ICC have characteristic imaging appearances on multiphase computed tomography (CT) and magnetic resonance imaging (MRI). Several locoregional therapies, including radiation therapy, are used to treat unresectable disease and residual or recurrent tumor. The tumor response following locoregional therapies has variable imaging manifestations. Focal liver reaction, the imaging changes of the liver following radiation treatment, should be recognized and not mistaken for tumor. We review the diagnostic imaging of HCC and ICC, imaging of tumor response to treatment, and imaging of the liver response to radiation. PMID- 30309638 TI - Radiotherapy for Hepatocellular Carcinoma. AB - For patients with unresectable or medically inoperable hepatocellular carcinoma, there are many local and regional therapies available, including stereotactic body radiotherapy, radiofrequency ablation, and transcatheter embolic approaches. This article will describe these treatment options and review the current comparative literature, suggesting that stereotactic body radiotherapy provides similar or better tumor control and a favorable side effect profile. PMID- 30309639 TI - A Contemporary Update on the Role of Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases in the Evolving Landscape of Oligometastatic Disease Management. AB - Metastases to the liver are common, and stereotactic body radiation therapy (SBRT) is a recognized tool for ablation of liver metastases. Colorectal cancers commonly metastasize to the liver, and long-term survival is possible after metastasectomy. However, many patients are not candidates for surgical resection, which opened the door to early studies investigating noninvasive techniques such as liver SBRT. Multiple prospective trials have demonstrated excellent local control with this approach coupled with an excellent safety record. The oligometastatic disease state is now appreciated across many histologies, and treatment of liver metastases as a component of oligometastatic disease management has emerged as a rational and relevant strategy. To this end, recent randomized studies in oligometastatic non-small-cell lung cancer demonstrated improved progression-free survival with consolidative local therapy, and this approach is the topic of ongoing cooperative group studies inclusive of patients with an array of primary histologies. Further, there is a push to explore the role of radiation as a means to enhance the efficacy of immune enabling drugs. Recent prospective data evaluating the safety and response of SBRT with anti-CTLA 4 therapy for patients with lung or liver metastasis demonstrated clinical benefit (out of field immune-related partial response or immune-related stable disease >=6 months) in about a quarter of enrolled patients. Interestingly, SBRT to liver metastases was found to elicit a greater systemic immune response than SBRT to lung metastases. Classic management paradigms for metastatic disease are rapidly being supplanted by approaches that are improving outcomes for patients previously offered best supportive care or palliation alone. In this article, we will review the established and emerging potential indications for liver SBRT in this new era of oncologic care. PMID- 30309640 TI - Clinical Case Panel: Treatment Alternatives for Inoperable Hepatocellular Carcinoma. AB - Surgical resection or liver transplantation offers the best chance of cure for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients are not good candidates for liver resection due to locally advanced disease or compromised liver function. Moreover, liver transplantation waiting lists are long. For those cases not amenable for resection, a variety of local treatment modalities are available, such as image-guided ablative procedures, transarterial chemoembolization, and radioembolization, as well as external beam radiation. HCC presentation can vary considerably in size, number, and location of lesions. The management of inoperable HCC is, therefore, quite complex, and there is a lack of consensus on the best local treatment modality for each type tumor presentation. Here, we present 4 clinical case scenarios representative of commonly seen cases in the clinical setting, with different therapeutic perspectives from institutions with high expertise in the management of HCC. PMID- 30309641 TI - Proton Beam Therapy and Carbon Ion Radiotherapy for Hepatocellular Carcinoma. AB - Charged particle therapy with proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) has emerged as a promising radiation modality to minimize radiation hepatotoxicity while maintaining high rates of tumor local control. Both PBT and CIRT deposit the majority of their dose at the Bragg peak with little to no exit dose, resulting in superior sparing of normal liver tissue. CIRT has an additional biological advantage of increased relative biological effectiveness, which may allow for increased hypofractionation regimens. Retrospective and prospective studies have demonstrated encouragingly high rates of local control and overall survival and low rates of hepatotoxicity with PBT and CIRT. Ongoing randomized trials will evaluate the value of PBT over photons and other standard liver-directed therapies and future randomized trials are needed to assess the value of CIRT over PBT. PMID- 30309642 TI - Radiation-Induced Liver Disease and Modern Radiotherapy. AB - Modern radiotherapy techniques have enabled high focal doses of radiation to be delivered to patients with primary and secondary malignancies of the liver. The current clinical practice of radiation oncology has benefitted from decades of research that have informed how to achieve excellent local control and survival outcomes with minimal toxicities. Still, one of the most devastating consequences of radiation to the liver remains a challenge: radiation-induced liver disease (RILD). Here, we will review the current understanding of classic and nonclassic RILD from a clinical perspective, the evaluation and management of patients who are at risk of developing RILD, methods to reduce the likelihood of RILD using modern radiation techniques, and the diagnosis and treatment of radiation-related liver toxicities. PMID- 30309643 TI - Evolving Systemic Therapy in Hepatocellular Carcinoma: Current Management and Opportunities for Integration With Radiotherapy. AB - The majority of patients with hepatocellular carcinoma (HCC) present with advanced disease. While first-line therapy with sorafenib is considered standard of care for patients with advancedHCC, outcomes remain poor. Despite early evidence of antitumor activity from Phase II trials of multiple other tyrosine kinase inhibitors, Phase III trials have largely failed to show an improvement insurvival outcomes over sorafenib. Given the encouraging early results with liver-directed radiotherapy for patients with advanced HCC, there is an increased interest in combination of these therapies tooptimize patient outcomes and improve survival by maximizing both local and distant disease control. Phase II trials of checkpoint inhibitors in HCC have also reported encouraging results, and Phase IIItrials are ongoing. Trials of combining radiotherapy with immunotherapy in solid tumors have shown intriguing results, potentially reflecting the opportunity for synergistic effects with the use of both modalities. PMID- 30309644 TI - Radiotherapy for Biliary Tract Cancers. AB - Biliary tract cancers (BTCs), including intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder cancers, are a heterogeneous cohort of tumors that tend to present with advanced stage and with high rates of recurrence after surgical resection. While liver-directed radiotherapy was traditionally restricted to the palliative setting given concerns over hepatotoxicity, modern radiotherapy techniques have enabled safe and effective treatment of a variety of hepatic tumors, thereby expanding the role of liver-directed radiotherapy in the management of BTCs. For resected BTCs, adjuvant chemoradiotherapy is recommended for patients with involved lymph nodes and positive resection margins. For patients with hilar cholangiocarcinomas, neoadjuvant chemoradiotherapy is recommended prior to orthotopic liver transplantation. Finally, for patients with unresectable disease, definitive radiotherapy in addition to systemic therapy represents a potential opportunity to maximize both local control and overall survival. In this review, we will discuss the evidence supporting the use of liver-directed radiotherapy for BTCs, as well as ongoing clinical investigations. PMID- 30309645 TI - Cholangiocarcinoma and Gallbladder Cases: An Expert Panel Case-Based Discussion. AB - Cholangiocarcinoma and gallbladder malignancies are aggressive gastrointestinal malignancies with management dependent on resectability, comorbidities, and location. A multidisciplinary discussion with medical oncologists, radiation oncologists, and surgeons is necessary to determine the optimal treatment approach for each patient. Surgical resection offers the best chance for a long term cure. Recent studies, such as the phase II SWOG S0809 and the phase III BILCAP study have highlighted the importance of adjuvant treatment with radiation therapy and chemotherapy, respectively, in resected disease. In patients with unresectable disease chemotherapy and chemoradiation therapy to a high dose can improve overall survival and locoregional control. In this expert panel we have brought together radiation oncologists and a medical oncologist to provide case based feedback on their institutional practices. PMID- 30309646 TI - Combined treatment with cinnamaldehyde and PTH enhances the therapeutic effect on glucocorticoid-induced osteoporosis through inhibiting osteoclastogenesis and promoting osteoblastogenesis. AB - The study was to investigate the effect of combining treatment with cinnamaldehyde and parathyroid hormone (1-34) (PTH) on glucocorticoid-induced osteoporosis (GIO) and compare with monotherapy. Forty Sprague-Dawley male rats with GIO were divided into four groups randomly: control group (CON group, N = 10); group that intragastric administration with cinnamaldehyde (CIN group, N = 10); group that subcutaneous injection with PTH, three times per week(PTH group, N = 10); both administration with cinnamaldehyde and PTH (CIN + PTH group, N = 10). Distal femurs were harvested for hematoxylin and eosin (H&E) staining, micro CT scanning and immunohistochemical analysis. Murine mesenchymal stem cells were cultured and dealt with the presence of dexamethasone(DEX group), DEX + cinnamaldehyde(DEX + CIN group), DEX + PTH(DEX + PTH group) or DEX + cinnamaldehyde + PTH(DEX + CIN + PTH group). Alkaline phosphatase (ALP) staining was performed subsequently. The results showed that bone formation in CIN + PTH group was notably promoted compared with other groups. And the expression of tartrate-resistant acid phosphatase (trap) and runt-related transcription factor 2 (runx2) in CIN + PTH group were down-regulated and up-regulated respectively compared with PTH group. In vitro study revealed that ALP-positive cell number in DEX + CIN + PTH group was obviously enhanced compared with other groups. The study revealed that combined treatment with cinnamaldehyde and PTH enhances the therapeutic effect on GIO through inhibiting osteoclastogenesis and promoting osteoblastogenesis. PMID- 30309647 TI - Long non-coding RNA FLVCR1-AS1 contributes to the proliferation and invasion of lung cancer by sponging miR-573 to upregulate the expression of E2F transcription factor 3. AB - Lung cancer is one of the most common causes of cancer-related death all over the world. In recent years, long non-coding RNAs (lncRNAs) have been reported to play critical roles in the development and progression of human malignancies. In the present study, we aimed to study the role and mechanism of FLVCR1-AS1 in human non-small cell lung cancer (NSCLC). Results revealed that FLVCR1-AS1 was markedly upregulated in NSCLC tissues and cell lines. Knockdown of FLVCR1-AS1 significantly inhibited the proliferation, migration, invasion and promoted apoptosis of NSCLC cells, and suppressed tumor growth of NSCLC in vivo. Moreover, we explored regulatory mechanism, and found that FLVCR1-AS1 functioned as a competing endogenous RNA (ceRNA) by directly binding to miRNA-573, and E2F transcription factor 3 (E2F3) was identified as a down-stream target of miR-573. FLVCR1-AS1 positively regulated E2F3 expression through inhibiting miR-573 in NSCLC cells. Our findings suggested that FLVCR1-AS1/miR-573/E2F3 axis was an important signaling pathway in mediating tumorigenesis and progression of NSCLC, and further indicated that FLVCR1-AS1 could be a novel diagnostic biomarker and therapeutic target for NSCLC. PMID- 30309648 TI - Disproportionately high levels of HGF induce the degradation of the c-met receptor through the proteasomal degradation pathway. AB - Hepatocyte growth factor (HGF) receptor is a member of the receptor tyrosine kinases (RTKs) and has been reported to perform diverse functions in various cell types during both the developmental and adult stages. Among different roles, HGF is best known for its angiogenic effects of inducing the migration of endothelial cells. Because angiogenesis is one of the prerequisite steps for tumor metastasis, HGF-dependent cell migration has to be tightly controlled. However, the underlying mechanisms regulating the optimum level of HGF/c-met signaling have been poorly understood. In this study, we tested whether the migration of endothelial cells is regulated by a negative feedback mechanism under disproportionately large amounts of HGF. Data from endothelial cell migration assays showed that HGF activity increased as its concentration increased, but declined beyond a certain point. Under limiting conditions, amounts of phosphorylated Erk and Akt surged, reaching a plateau in which the enhanced level was more or less maintained. The c-met receptor was degraded when unnecessarily large amounts of HGF were present. Under these conditions, HGF could no longer activate downstream signaling pathways even if cells were re-treated with optimal amounts of HGF. Excessive doses of HGF increased the phosphorylation of tyrosine residue 1003 involved in the ubiquitination of c-met, and phosphorylated c-met was diverted toward the proteasomal degradation pathway. Taken together, HGF/c met signaling is tightly regulated by a negative feedback loop through an ubiquitin-proteasomal degradation pathway. PMID- 30309649 TI - Green leaf volatile-burst in Arabidopsis is governed by galactolipid oxygenation by a lipoxygenase that is under control of calcium ion. AB - Plants form green leaf volatiles (GLVs) almost instantly after tissue disruption caused by damages, such as herbivore damage. This rapid formation of GLVs, namely GLV-burst, is an essential factor for the plants' GLV-dependent direct and indirect defenses. However, mechanism of GLV-burst remains unknown. We observed that the formation of monogalactosyldiacylglycerol hydroperoxides (MGDG-OOHs) by Arabidopsis lipoxygenase 2 (AtLOX2) governs GLV-burst in Arabidopsis. Addition of a Ca2+ selective chelating reagent, BAPTA, during tissue disruption effectively suppressed the formation of MGDG-OOHs as well as GLV-burst. This suppression was relieved by the addition of Ca2+. Therefore, we propose that Ca2+-dependent activation of AtLOX2 facilitates GLV-burst formation as observed in leukotriene formation, which is regulated by Ca2+-dependent activation of LOXs in animal cells. PMID- 30309650 TI - Oxysterols selectively promote short-term apoptosis in tumor cell lines. AB - Oxysterols are 27-carbon oxidation products of cholesterol metabolism. Oxysterols possess several biological actions, including the promotion of cell death. Here, we examined the ability of several oxysterols to induce short-term death in cancerous (human breast cancer and mouse skin melanoma cells) and non-cancerous (human endothelial cells and lung fibroblasts) cell lines. We determined cell viability, Ki67 expression, cell cycle regulation, and apoptosis after 24-h incubations with oxysterols. We found that different oxysterols had different effects on the studied parameters. Moreover, the effects depended on cell type and oxysterol concentration. Three cytotoxic oxysterols (7-ketocholesterol, cholestane-3beta-5alpha-6beta-triol, and 5alpha-cholestane-3beta,6beta-diol) inhibited the S phase and stimulated the G0/G1 or G2/M phases. These oxysterols promoted apoptosis, determined with Annexin V and propidium iodide assays. These results showed that different oxysterols have cytotoxic effects depending on the cell line. The findings suggest a potential pharmacological utility of cytotoxic oxysterols. PMID- 30309651 TI - Identification of peptide based B-cell epitopes in Zika virus NS1. AB - Zika virus (ZIKV), a mosquito-borne flavivirus that has recently emerged globally, poses a major threat to public health. To control this emerging disease, accurate diagnostics are required for monitoring current ZIKV outbreaks. Owing to the high nucleotide sequence similarity and cross-reactivity of ZIKV with other members of the Flaviviridae family, discrimination from other flavivirus infections is often difficult in endemic areas. ZIKV NS1 induces major virus-specific antibodies and is therefore utilized as a serological marker for ZIKV diagnosis. To identify ZIKV specific epitopes for clinical application, 33 NS1 peptides that are 15-30 amino acid in length covering whole NS1 were synthesized and analyzed linear B-cell epitopes with 38 human serum samples (20 ZIKV-positive and 18 ZIKV-negative). As a result of screening, eight epitope regions were identified. In particular, the Z8 and Z14 peptides located in the beta-ladder surface region showed higher levels of binding activity in ZIKV positive sera without cross-reactivity to other flaviviruses. These identified sensitive and specific epitopes provide a tool for design of diagnostics and structure-based vaccine antigens for ZIKV infection. PMID- 30309652 TI - Spin label EPR suggests the presence of cholesterol rich domains in cultured insect cell membranes. AB - Different spin labels were incorporated to the membranes of cultured insect UFL AG-286 cells in order to characterize their physical properties by Electron Paramagnetic Resonance spectroscopy (EPR). The spectrum of the spin label 12-SASL incorporated to cell membranes was similar as those obtained in membrane model systems composed of eggPC/cholesterol. However, the spectrum of the spin label CSL, chemically related to cholesterol, was drastically different in the two systems. Interestingly, when cell cholesterol content was reduced using methyl beta cyclodextrin, an EPR spectrum similar to those of model membranes was obtained. The analysis of these experiments suggests the existence of cholesterol rich regions in UFL-AG-286 cell membranes. PMID- 30309653 TI - Upregulation of miR-199 attenuates TNF-alpha-induced Human nucleus pulposus cell apoptosis by downregulating MAP3K5. AB - MicroRNA-199 has been reported to play a potential role in the apoptosis of Human nucleus pulposus cells. However, the effect of miR-199 in regulating Human nucleus pulposus cell injury induced by TNF-alpha has not been previously illustrated. This study searched to probe the effect and the molecular mechanism of miR-199 on Human nucleus pulposus cell injury induced by TNF-alpha. Using the TNF-alpha model of Human nucleus pulposus cell in vitro, we found that miR-199 was extremely decreased in Human nucleus pulposus cells after TNF-alpha treatment. Knockdown the expression of miR-199 by recombinant adeno-associated viral vector infection markedly promoted the apoptosis of Human nucleus pulposus cells induced by TNF-alpha treatment, whereas miR-199 overexpression significantly decreased Human nucleus pulposus cell apoptosis. Both Dual luciferase reporter and western blot assay proved that MAP3K5 was a direct target gene of miR-199, and miR-199 inhibited the expression of MAP3K5 via binding to its 3'-UTR. Furthermore, we proved that overexpression of miR-199 could inhibit the expression of MAP3K5 at the transcription and translation levels, whereas the inhibition of miR-199 could upregulate the expression of MAP3K5. Moreover, MAP3K5 was highly expressed in TNF-alpha treated Human nucleus pulposus cells and the apoptosis rate induced by TNF-alpha was associated with the increase in MAP3K5 expression. Importantly, knockdown the expression of MAP3K5 apparently abrogated the inhibitory effect of miR-199 mimics on TNF-alpha induced Human nucleus pulposus cell apoptosis. In conclusion, these results indicate that upregulation of miR-199 could inhibit Human nucleus pulposus cells injury through downregulation of MAP3K5 expression, providing an important molecular target mechanism for Human nucleus pulposus cells injury. PMID- 30309654 TI - The ubiquitin ligase RNF38 promotes RUNX1 ubiquitination and enhances RUNX1 mediated suppression of erythroid transcription program. AB - RUNX1 is a member of RUNX transcription factors and plays important roles in hematopoiesis. RUNX1 function is under the tight control through posttranslational modifications, including phosphorylation and ubiquitination. We previously developed a luminescence-based binding assay (AlphaScreen) to systematically detect RUNX1-interacting E3 ubiquitin ligases. In this study, we showed that a nuclear ubiquitin ligase RNF38 induced ubiquitination of RUNX1. RNF38-induced RUNX1 ubiquitination did not promote RUNX1 degradation, but rather stabilized RUNX1 protein. We also found that RNF38 enhanced RUNX1-mediated transcriptional repression of the erythroid master regulator KLF1 in K562 cells. Consequently, RNF38 cooperated with RUNX1 to inhibit erythroid differentiation of K562 cells. Thus, our study identified RNF38 as a novel E3 ligase that modifies RUNX1 function without inducing its degradation. PMID- 30309655 TI - Mechanostress resistance involving formin homology proteins: G- and F-actin homeostasis-driven filament nucleation and helical polymerization-mediated actin polymer stabilization. AB - The actin cytoskeleton has two faces. One side provides the relatively stable scaffold to maintain the shape of cell cortex fit to the organs. The other side rapidly changes morphology in response to extracellular stimuli including chemical signal and physical strain. Our series of studies employing single molecule speckle analysis of actin have revealed diverse F-actin lifetimes spanning a range of seconds to minutes in live cells. The dynamic part of the actin turnover is tightly coupled with actin nucleation activities of formin homology proteins (formins), which serve as rapid and efficient F-actin restoration mechanisms in cells under physical stress. More recently, our two studies revealed stabilization of F-actin either by actomyosin contractile force or by helical rotation of processively-actin polymerizing diaphanous-related formin mDia1. These findings quantitatively explain our proposed anti mechanostress cascade in that G-actin released from F-actin upon loss of tension triggers frequent nucleation and subsequent fast elongation of F-actin by formins. This formin-restored F-actin may become specifically stabilized over long distance by helical polymerization-mediated filament untwisting. In this review, we discuss how and to what extent formins-mediated F-actin restoration might confer mechanostress resistance to the cell. We also give thought to the possible involvement of helical polymerization-mediated filament untwisting in the formation of diverse actin architectures including chirality control. PMID- 30309656 TI - Obesity in Yap transgenic mice is associated with TAZ downregulation. AB - Obesity is characterized by an expansion of white adipose tissue (WAT) mass, which mainly consists of adipocytes. During the commitment and differentiation of adipocytes, PPARgamma functions as a key transcriptional factor for adipogenesis, and is associated with its suppressive coregulator, TAZ. Previous studies have shown the importance of TAZ in adipogenesis using an in vitro model; however, the understanding of its role in adipogenesis in vivo remains limited. Here, we report a unique obese mouse model that is associated with TAZ downregulation, which arose from the overexpression of Yap, a Taz paralog. YAP activation facilitated Hippo signaling feedback, which induced a compensatory reduction in YAP, subsequently neutralizing its functional activity. This feedback also induced TAZ suppression and exclusion from the nucleus. In Yap transgenic mice, TAZ downregulation in adipose stem cells activated PPARgamma, leading to their differentiation into mature adipocytes and consequently increased adipose tissue. These results highlight the in vivo necessity of TAZ for adipocyte commitment and differentiation, which could provide insight into anti-obesity therapeutics. PMID- 30309658 TI - Downregulation of miR-223 and miR-19a induces differentiation and promotes recruitment of osteoclast cells in giant-cell tumor of the bone via the Runx2/TWIST-RANK/RANKL pathway. AB - Giant-cell tumor (GCT) of the bone is an invasiveness and high recurrent bone tumor that is considered borderline or potentially malignant. To explore the molecular mechanism leading to bone destruction and identify novel targets for treatment, we conducted silencing of miR-223 and miR-19a in stromal giant cells and identified TWIST and Runx2 as their target genes. We investigated the impact of these microRNAs and their target genes on stromal giant cells that promote the differentiation of monocyte/macrophages into osteoclast cells and recruitment to the bone microenvironment, which in turn enhances the bone destruction capacity of GCT. MiR-223 and miR-19a were found to regulate the expression of TWIST and Runx2, influence the RANKL-RANK pathway and the expression of MCP-1, and finally regulate the pathophysiological process of osteolytic bone destruction. Our results indicate that re-expression of miR-223 and miR-19a induces an inhibitory effect on the bone destruction capacity of GCT, suggesting that re-expression of miR-223 and miR-19a can be a novel strategy for the treatment of GCT. PMID- 30309657 TI - Phencynonate mediates antidepressant response by activating sirtuin 6-SOD2/Prdx6 pathway. AB - Major depression is a highly prevalent disorder with no effective medical treatments available. Recent evidence has shown that sirtuins (SIRTs) signaling has been implicated to play an essential in the pathogenesis of depression. Here in this study, we aimed to investigate the potential role of the phencynonate hydrochloride (PHH) in rat models of chronic unpredictable mild stress (CUMS) induced depression. SIRT6 expression was up-regulated by PHH via increasing NAD+/NADH ratio in the prefrontal cortex. PHH was able to suppress CUMS-induced oxidative stress and enhance the antioxidant capacity and antioxidant proteins activity, such as superoxide dismutase 2 (SOD2) and peroxiredoxin 6 (Prdx6). In vitro study, we found that SIRT6 directly bound to SOD2 and Prdx6 and deacetylated them at Lys68/122 and Lys63/209, which were acetylated by p300/CBP associated factor (PCAF). Finally, we showed that PHH ameliorated CUMS-induced depressive phenotypes by up-regulating SIRT6 deacetylation activity. In summary, PHH-mediating SIRT6 pathway is required for antidepressant response and PHH can be used as a novel therapeutic to effectively treat depression. PMID- 30309659 TI - One 3-oxoacyl-(acyl-Carrier-protein) reductase functions as 17beta-hydroxysteroid dehydrogenase in the estrogen-degrading Pseudomonas putida SJTE-1. AB - Pseudomonas putida SJTE-1 can utilize 17beta-estradiol (E2) as its carbon source, while the enzymes for E2 transformation in this strain is still unclear. 17beta hydroxysteroid dehydrogenases (17beta-HSD) can catalyze the reduction/oxidation at C17 site of steroid hormone specifically, critical for steroid transformation. Here a novel 3-oxoacyl-(acyl-carrier protein) (ACP) reductase (ANI02794.1) was identified as it could bbeta-estradiol, and was proved to be capable of functioning as 17beta-HSD. Sequences alignment showed it contained the two consensus regions and the conserved residues of short-chain dehydrogenase/reductase (SDR). Its encoding gene was cloned and over-expressed in Escherichia coli BL21(DE3) strain, and the recombinant protein was purified by the metal-ion affinity chromatography with the yield of 18 mg/L culture. HPLC (High Performance Liquid Chromatography) detection showed this enzyme could convert 17beta-estradiol into estrone using NAD+ as cofactor. Its Km value was 0.082 mM and its Vmax value was 0.81 mM/s; its transformation efficiency of 17beta-estradiol into estrone was over 96.6% in five minutes. Its optimal temperature was 37 degrees C and optimal was pH 9.0; the divalent ions had different effects on the enzymatic activity. In conclusion, this 3-oxoacyl-ACP reductase functioned as 17beta-HSD in P. putida SJTE-1 and played important role in its estrogen metabolism. PMID- 30309660 TI - A case of thoracic actinomycosis presenting as sudden paraplegia. PMID- 30309661 TI - Varicella Zoster Virus vasculopathy in a patient treated with immune checkpoint inhibitor for lung cancer. PMID- 30309662 TI - Fatal Fusobacterium necrophorum infection with gynecological Lemierre's syndrome. PMID- 30309663 TI - [Identification of Mycobacterium parascrofulaceum in a patient presenting with chronic osteomyelitis]. PMID- 30309664 TI - Zone I Flexor Digitorum Profundus Repair: A Surgical Technique. AB - We present an all-inside technique for zone I flexor tendon repair that combines suture anchor fixation with buried back-up fixation. The back-up fixation uses transosseous tunnels and a dorsal counterincision to allow a suture tied dorsal to the distal phalanx and buried. This technique is strong and permits early active range of motion. The dorsal tie-over does not require a suture button and, therefore, does not imperil the nail matrix. The surgical technique is herein described including the proposed anesthesia (wide awake), the incisions (midlateral), the exposures, and the repair itself. PMID- 30309665 TI - Treatment of Kienbock's Disease With Neutral Ulnar Variance by Distal Capitate Shortening and Arthrodesis to the Base of the Third Metacarpal Bone. AB - PURPOSE: We evaluated whether a surgical technique combining distal capitate shortening and arthrodesis to the base of the third metacarpal bone for the treatment of the early stages (stages II and IIIA) of Kienbock's disease with neutral ulnar variance resulted in pain relief, improvement in wrist motion, or changes in the radiographic evaluation. METHODS: This retrospective study reviewed 22 patients with early stages of Kienbock's disease with neutral ulnar variance, treated by distal capitate shortening and arthrodesis to the base of the third metacarpal bone. Patients were divided into 2 groups by disease stage: stage II (n = 12) and stage IIIA (n = 10). There were 8 women and 14 men, with an average age of 35.7 years. The following parameters were measured before and after surgery: visual analog scale (VAS) for pain evaluation, grip strength, range of motion (ROM), ulnar variance, carpal height index, lunate height index, and the scapholunate and scaphocapitate angles. The patients were evaluated in accordance with Modified Mayo Wrist Score (MMWS). RESULTS: The average follow-up period was 30.5 months (range, 26-36 months). The stage II group showed significant improvements in the mean VAS (58-5), ROM (57% to 73%), grip strength (54% to 75%), and MMWS (51-78). Patients in the stage IIIA group showed nonsignificant changes in mean VAS score (64-42.5), ROM (52.5% to 55.5%), grip strength (46.5% to 57.5%), and MMWS (36-50.5). Significant decreases in the carpal height index and scaphocapitate angle, and an increase in scapholunate angle in all stage IIIA patients were observed. CONCLUSIONS: Distal capitate shortening with capitometacarpal arthrodesis can alleviate pain and improve ROM and grip strength in patients with stage II Kienbock's disease, but not in those with stage IIIA. Moreover, it cannot prevent carpal collapse, especially in stage IIIA of the disease. We do not recommend this technique for treating stage IIIA patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 30309666 TI - Correlation of transforming growth factor beta-1 vitreous levels with clinical severity of proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment. AB - OBJECTIVE: To correlate the vitreous concentration of transforming growth factor beta-1 (TGF beta-1) with the degree of clinical severity of proliferative vitreoretinopathy (PVR). DESIGN: A prospective, observational, cross-sectional study carried out on cases and controls. PARTICIPANTS: The study included 40 patients with a diagnosis of PVR secondary to rhegmatogenous retinal detachment. METHODS: Vitreous was obtained in patients undergoing pars plana vitrectomy by rhegmatogenous retinal detachment, who were treated during the period from August 2015 to June 2016, in a national reference centre for ophthalmological care in Mexico City, Mexico. The levels of TGFbeta-1 were quantified by ELISA technique. An ANOVA test was performed for the comparison of the different groups, together with a post-hoc Dunns test. A statistically significant difference was considered when obtaining P <.05. RESULTS: The levels of TGFbeta-1 were quantified, and the following means were found for each group: In the group with PVR grade A, 1150.6 +/- 452.08 pg / ml, PVR grade B: 1129.6 +/- 365.54 pg / ml, and PVR grade C: 1146.4 +/- 330.21 pg / ml. The statistical analysis did not find significant differences when comparing the different PVR groups. (P=.53). However, when performing the differential analysis for each level of severity, a statistically significant increase in the expression of TGFbeta-1 was observed in the group of patients with PVR-A at a greater number of days of evolution of the detachment. (P=.03). There were no statistically significant differences for PVR-B and PVR-C (P=.16 and P=.16, respectively). CONCLUSION: Although the levels of TGFbeta-1 are not directly related to the clinical severity grade, suggesting that there must be other factors involved in the advanced stages of PVR, TGFbeta-1 may have greater relevance during the initial stages of the clinical course by promoting the epithelial-mesenchymal transition due to its greater expression in PVR-A. Thus, it can be concluded that each isoform plays a very particular role in the complex process of PVR. PMID- 30309667 TI - Glycemic disorders and their impact on lung function. Cross-sectional study. AB - BACKGROUND AND OBJECTIVE: Diabetes mellitus can affect the lungs, in its various structures and functions. Current research is being conducted to establish the clinical impact of hyperglycaemia on lung function. The objective of this study is to determine if the glycaemic state (euglycaemic, prediabetes or diabetes) is associated with a decrease in lung volume, determined by spirometry. PATIENTS AND METHODS: An analytical cross-sectional study was carried out at the Ticoman General Hospital in Mexico City. Glucose and glycosylated haemoglobin concentration were used as the parameters to determine if the subjects had a glycaemic disorder. They were further categorised into euglycaemic, prediabetic and diabetic subjects according to ADA criteria guidelines. The subjects underwent forced spirometry testing, obtaining expiratory volume at the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow (FEP). The lung volumes between the groups were compared. RESULTS: A total of 55 subjects were studied; 43 women, and 12 men; 14 euglycaemic, 9 prediabetic, and 32 with diabetes. Diabetic individuals presented a %FEP decrease compared to the prediabetic and euglycaemic subjects. The fasting serum glucose values correlated with decrease of %FEV1, FEV1/FVC and %FEP, while the HbA1c concentration only correlated with the decrease of %FEP. CONCLUSIONS: Subjects with diabetes have a lower %PEF than euglycaemic and prediabetic subjects, while the %FEV1, %FVC and the FEV1/FVC ratio do not vary between the different glycaemic states. Acute glycaemic non-control correlated with a decrease in more spirometric parameters than chronic glycaemic non-control. PMID- 30309668 TI - Graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is the most frequent and potentially fatal complication of an allogeneic hematopoietic progenitor cell transplantation. It appears when immunocompetent T cells from donor origin recognise antigens from recipient origin as foreign. The immune response activates donor T cells and destroys recipient tissues. The clinical picture of this immune response is called acute and chronic GVHD. Acute GVHD is the main fatal complication during the first months after allogeneic hematopoietic progenitor cell transplantation, while chronic GVHD accounts for a significant long-term fraction of the mortality, morbidity and reduced quality of life of patients. Our goal is to review the frequency, clinical manifestations, diagnosis, treatment and prevention of GVHD. PMID- 30309669 TI - Field studies on the effects of Marteilia sp. on growth of mussel Mytilus galloprovincialis in Thermaikos Gulf. AB - Global warming may accelerate growth and distribution of pathogens influencing aquatic organisms' diseases and human health. Despite the extensive research, the biology, cellular development and life cycle and of Marteilia sp. parasites as well as the influence of parasitic infection on the hosts are not fully understood. The aim of this study was to investigate the effect of Marteilia sp. prevalence and infection intensity on mussels' growth rate and morphometric characteristics under natural conditions in Thermaikos Gulf, a major bivalve production area in Greece, during a five-month growth period. The length, width, height and weight of the infected mussels were significantly lower compared to non-infected and the decrease was proportional to the intensity of mussel infection by the parasite. Moreover, the estimation of allometric relations between length, height, width and weight revealed significantly lower growth of mussel wet weight in relation to shell length for infected mussels compared to healthy ones. The negative effect of marteiliosis on the shell length growth rate of infected mussels was also confirmed by von Bertalanffy equations. PMID- 30309670 TI - Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration. AB - Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis. PMID- 30309671 TI - Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5 b]pyridine derivatives as potent and selective TAM inhibitors. AB - The TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-b]pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds 28 and 25 demonstrated high activity and selectivity in vitro against AXL and MER, with IC50 value of 0.77 nM and 9 nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound 10Bb, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition. PMID- 30309672 TI - [Care pathway diversity of patients with multiple sclerosis between French regions]. AB - BACKGROUND: The aim of this study is to analyze and to compare data from 2015, focusing on hospital care for patients with multiple sclerosis from three French regions with different characteristics in terms of prevalence, size and number of multiple sclerosis competencies and resource centers. METHODS: All hospital admissions from the PMSI MCO 2015 database, with a principal or related diagnosis (PD-RD) of G35* ("multiple sclerosis") were extracted. We also extracted chemotherapy treatments administered in hospital, during admissions with a significant associated diagnosis (SAD) of G35*, if the PD or RD was coded Z512 ("non-tumor chemotherapy"). The analyzed regions corresponded to those of 2015, some of which have since merged. RESULTS: There were 95,359 hospital admissions for multiple sclerosis in France in 2015 among a total cohort of 21,102 patients, resulting in a total cost of ? 54.1m. Patients with MS were managed mainly in the ambulatory setting, which accounted for 88.5 % of all admissions. The Rhone-Alpes region represented 7.6 % of national admissions for MS, 9.6 % of patients, and 14 % of inpatient days, contributing 10.4 % of the national cost of MS care. 58.4 % of stays were managed by the two main multiple sclerosis centers. The Nord-Pas-de Calais region represented 9.8 % of national admissions, 10 % of patients, 6.6 % of inpatient days, and 9.1 % of the national cost. 29.8 % of stays were managed by the main multiple sclerosis center. The Centre region represented 2.7 % of stays, 2.8 % of patients, 3.1 % of inpatient days, and 2.8 % of the national cost. 28.4 % of stays were managed by the main multiple sclerosis center. CONCLUSION: This study highlights the diversity of multiple sclerosis hospital management and care between these three regions. PMID- 30309673 TI - Deep sternal wound infection after bilateral internal thoracic artery grafting: Insights from a Japanese national database. AB - OBJECTIVES: Despite its survival benefits, bilateral internal thoracic artery (BITA) grafting is not commonly utilized due to concerns over deep sternal wound infection (DSWI). The present study investigated the early outcome of BITA grafting and analyzed the risk of DSWI using a Japanese national database (the Japan Adult Cardiovascular Surgery Database). METHODS: Data from 560 hospitals were used. Between April 2012 and December 2015, BITA was harvested in 14,249 patients, corresponding to 32.6% of isolated coronary artery bypass cases. DSWI was defined as a wound infection requiring surgical intervention and/or the administration of antibiotics. Multiple logistic regression analysis was employed to model the risk of DSWI. RESULTS: The mean age was 67.1 years. The prevalence of diabetes, renal failure, hemodialysis, and liver dysfunction was 51.8%, 21.2%, 7.8%, and 1.2%, respectively. The incidence of DSWI and operative mortality was 1.6 (234 patients) and 1.6% (226 patients), respectively. The operative mortality rate in patients with DSWI was 13.7% (32 patients). The off-pump technique was used in 72.8%, with a conversion rate of 2.5%. Female sex, diabetes mellitus, chronic lung disease, renal failure, liver dysfunction, ejection fraction <=60%, shock status, reoperation, preoperative intra-aortic balloon pump use, and an increased operative time were independent risk factors for DSWI after BITA grafting. The off-pump technique did not reduce the risk of DSWI. CONCLUSIONS: The present study showed that early outcomes of BITA grafting were satisfactory regarding DSWI and operative mortality. The current data are informative to predict the risk of DSWI when performing BITA grafting. PMID- 30309674 TI - Emergency department use is high after esophagectomy and feeding tube problems are the biggest culprit. AB - OBJECTIVES: Esophagectomy is a complex operation with potential for prolonged recovery. We aimed to identify the incidence of and risk factors for any and frequent emergency department visits within 1 year of esophagectomy. METHODS: A retrospective cohort study was performed looking at consecutive esophagectomies at a tertiary Canadian center (1999-2014). Multivariable analyses identified factors associated with any emergency department visits and frequent emergency department use (>=3 visits) within 1 year postesophagectomy. RESULTS: There were 520 esophagectomies with in-hospital mortality of 6% (n = 31). Of those discharged, 29.7% (n = 145) had >= 1 emergency department visit. Most common causes were feeding tube problems (39.3%; n = 57) and dysphagia/stricture (13.1%; n = 19). Higher income (adjusted odds ratio [aOR], 1.22; 95% confidence interval [CI], 1.04-1.42 per $10,000) and use of hybrid/minimally invasive esophagectomy (aOR, 3.24; 95% CI, 1.71-6.11) were independently associated with having emergency department visits. Patients with hybrid/minimally invasive esophagectomy were discharged earlier than others (P < .0001). Living outside of our metropolitan area (aOR, 0.36; 95% CI, 0.27-0.49) and having surgery in the later years of the study period (aOR, 0.91; 95% CI, 0.86-0.97; P = .006) were both independently associated with lower odds of emergency department visits. Forty-three patients (8.8%) were frequent emergency department users, with the most common causes of repeat emergency visits being feeding tube problems. Living outside of our metropolitan area was associated with lower odds of frequent emergency visits (aOR, 0.25; 95% CI, 0.14-0.45). CONCLUSIONS: There is high emergency department use within 1 year postesophagectomy. Patients living farther away from our hospital had a lower rate of emergency department use. It is possible that they are utilizing emergency departments nearer to home; this needs further study. Feeding tube problems are the biggest culprits and are potentially modifiable. PMID- 30309675 TI - Button Battery Safety: Industry and Academic Partnerships to Drive Change. AB - The pediatric button battery (BB) hazard has been recognized for several decades. In 2012, the National Button Battery Task Force was established, and most manufacturers have improved warning labels, more secure packaging, and made BB compartments in products are more secure. Tissue neutralization before BB removal (ie, honey or sucralfate/Carafate(r)) is an effective way to reduce the rate of BB injury. In absence of visible perforation, 0.25% sterile acetic acid esophageal tissue irrigation at time of BB removal is recommended as a neutralization strategy to mitigate injury progression. Future BB design changes could eliminate esophageal tissue injury. PMID- 30309676 TI - Cognitive Constraints Shape Public Debate on the Risks of Synthetic Biology. AB - We consider efforts to understand public perceptions of synthetic biology, describing a novel cognitive science approach indicating that cognitive biases constrain risk perceptions of synthetic biology. We discuss the implications of these findings and outline how they may be harnessed to improve the quality of public debate. PMID- 30309677 TI - New Diagnostic Criteria for the Localization of Insulinomas with the Selective Arterial Calcium Injection Test: Decision Tree Analysis. AB - PURPOSE: To explore optimal diagnostic criteria for localizing insulinomas with the selective arterial calcium injection (SACI) test using decision tree analysis. MATERIALS AND METHODS: A retrospective study included 86 vessels of 18 patients (5 men, 13 women; mean age 67 y; range, 49-73 y) with insulinomas who underwent SACI test between June 2007 and May 2016. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas. Two patients had multiple tumors. To identify optimal diagnostic criteria, decision tree analysis was performed, and sensitivity, specificity, and accuracy of the conventional and the proposed new diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 * plasma insulin concentration before calcium injection [ICpre]) were compared. RESULTS: The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 * ICpre and maximum insulin concentration > 60.3 MUIU/mL or (ii) ICpost > 2.7 * ICpre and maximum insulin concentration < 60.3 MUIU/mL with ICpre being >= 7.5 MUIU/mL. Sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2; sensitivity, specificity, and accuracy of conventional criteria were 100%, 69.0%, and 79.1%. CONCLUSIONS: New diagnostic criteria for localization of insulinomas with the SACI test yielded higher diagnostic performance than conventional criteria. PMID- 30309678 TI - The combination of retinoic acid and estrogen can increase germ cells genes expression in mouse embryonic stem cells derived primordial germ cells. AB - Generation of germ cells from embryonic stem cells in vitro could have great application for treating infertility. The temporal expression profile of several genes was expressed at different stages of germ cell development and examined in differentiation the mouse embryonic stem cells. Cells were treated in three groups of control, with 10-8 M of all-trans retinoic acid and the combination of 10-9 M of 17beta-Estradiol and retinoic acid for 7, 12, 17 or 22 days. Quantitative RT-PCR and Immunofluorescent were used to investigate the possible inductive effects of estrogen on mouse embryonic stem cell-derived primordial germ cells. mRNA expression of Oct4 and Dazl were downregulated in embryonic stem cells by the retinoic acid group, whereas Mvh transcription was reduced by retinoic acid and estrogen group in these cells compared to the control group. But, retinoic acid with estrogen group-treated cells exhibited increased mRNA expression of Stra8, Fragilis, Sycp3, GDF9, and Stella compared to untreated controls. The expression of Stella and Mvh proteins were remarkably increased in cell colonies. This study shows that estrogen affects the expression of specific markers of primordial germ cells. Also, estrogen and retinoic acid speed up and increase the level of expression of specific markers. PMID- 30309679 TI - LRP5 controls cardiac QT interval by modulating the metabolic homeostasis of L type calcium channel. AB - BACKGROUND: Low-density lipoprotein receptor-related protein 5 (LRP5) has been intensively studied as a co-receptor for beta-catenin-dependent Wnt signaling. Emerging evidences have demonstrated beta-catenin-independent functions of LRP5. However, the biological role of LRP5 in the mammalian heart is largely unknown. METHODS AND RESULTS: Conditional cardiac-specific Lrp5 knockout (Lrp5-CKO) mice were generated by crossing Lrp5flox/flox mice with alphaMHC/MerCreMer mice. Lrp5 CKO mice consistently displayed normal cardiac structure and function. Telemetric electrocardiogram recordings revealed a short QT interval in Lrp5-CKO mice, which was tightly linked to the striking abbreviation of action potential duration (APD) in ventricular myocytes. The analysis of whole-cell currents indicated that a reduction in activity and protein expression of L-type calcium channel (LTCC), rather than other ion channels, contributed to the abnormality in APD. Furthermore, we showed that Lrp5 ablation induced a significant convergence of CaV1.2alpha1c proteins to the endoplasmic reticulum. Consequently, increased proteasomal degradation of these proteins was observed, which was independent of the Wnt/beta-catenin signaling pathway. CONCLUSIONS: LRP5 directly modulates the degradation of LTCC to control cardiac QT interval. These findings provide compelling evidence for the potential role of LRPs in cardiac electrophysiology. PMID- 30309680 TI - General practice preventive health care in non-obstructive coronary artery disease determined by coronary computed tomography angiography. AB - BACKGROUND: The aim of this study was to compare changes in health service utilization, preventive medical management, and cholesterol levels in patients without coronary artery disease (CAD) or with non-obstructive CAD as determined by coronary computed tomography angiography (CTA). METHODS: Single-center five year observational registry-based cohort study of consecutive patients with chest pain undergoing coronary CTA with subsequent 12 months follow-up in general practice. RESULTS: We included 3032 patients with a normal test result (n = 2179) or a diagnosis of non-obstructive CAD (n = 853) by coronary CTA. Median age was 55 (interquartile range: 47-63) years and 44% were males. After coronary CTA, the probability of a decrease in consultations with general practitioner was higher in patients with no CAD compared to patients with non-obstructive CAD (adjusted OR = 0.81 [95% CI: 0.68-0.96], P = 0.016). Accordingly, patients with non obstructive CAD more frequently received prescriptions on lipid-lowering medical therapy (adjusted OR = 4.50 [95% CI: 3.31-6.12], P < 0.001) than patients with no CAD after coronary CTA. In patients with non-obstructive CAD, mean total cholesterol reduction was 0.51 (P < 0.001) compared to 0.13 mmol/L (P < 0.001) in patients without non-obstructive CAD. The relative reduction in low-density lipoprotein was 14% higher (P < 0.001) in patients with compared to patients without non-obstructive CAD after coronary CTA. CONCLUSIONS: Coronary CTA with subsequent follow-up in general practice has the potential to align health service utilization that prioritizes high-risk patients and facilitate optimized preventive management. PMID- 30309681 TI - Muscle squeezing immediately after coronary reperfusion therapy using postconditioning with lactate-enriched blood. AB - BACKGROUND: We recently reported a new approach for cardioprotection, postconditioning with lactate-enriched blood (PCLeB), and a patient with ST segment elevation myocardial infarction (STEMI), in whom muscle squeezing of the culprit coronary artery was observed immediately after reperfusion with PCLeB. In this study, we examined the prevalence of muscle squeezing immediately after reperfusion in patients with anterior STEMI treated using PCLeB. METHODS AND RESULTS: PCLeB is a modified postconditioning protocol that comprises intermittent reperfusion and timely coronary injections of lactated Ringer's solution. We treated 30 consecutive patients with anterior STEMI using PCLeB. Among the 30 patients, 4 patients exhibited muscle squeezing of the left anterior descending artery (LAD) immediately after reperfusion. We performed follow-up coronary angiography in 23 patients and found another patient who exhibited muscle squeezing of the LAD. Thus, of 30 patients, 5 were confirmed to have myocardial bridging and 4 exhibited muscle squeezing immediately after reperfusion with PCLeB. No patient died or experienced re-hospitalization for heart failure or recurrent ischemic events at 6 months except for one patient with malignancy. CONCLUSION: Muscle squeezing immediately after reperfusion therapy is not a rare phenomenon in patients with anterior STEMI treated using PCLeB. PMID- 30309682 TI - Fluoroquinolones and the risk of aortopathy: A systematic review and meta analysis. AB - OBJECTIVE: To investigate the association between fluoroquinolones use and development of aortopathy. METHODS: A systematic review and meta-analysis was conducted following PRISMA and MOOSE guidelines for reporting systematic reviews of observational studies. Multiple databases were searched and two authors independently screened studies for eligibility. Newcastle Ottawa scale was used to assessed the quality of included studies. Primary outcome of interest was development of aortic aneurysm or dissection among fluoroquinolones users in comparison to non-users. An inverse variance model meta-analysis was used to pool odds ratio or hazards ratio from included studies to calculate the overall effect estimate. Pre specified subgroups analyses were also conducted to explore sources of heterogeneity. RESULTS: Three observational studies that enrolled 941,639 subjects met the inclusion criteria and were included in the final analysis. All studies were of a good methodological quality. Current use of fluoroquinolones, defined as within 60 days from development of the primary outcome, was associated with significantly elevated risk of developing aortic aneurysm and/or dissection in comparison to controls, (OR = 2.04; 95% CI [1.67, 2.48]). There was only a mild degree of between study heterogeneity, I2 = 33%. The association remains robust among all subgroups analyses. CONCLUSION: Our findings indicate that current fluoroquinolone use was significantly associated with increased risk of aortic aneurysm and dissection. Health care providers need to be aware of this serious association and use fluoroquinolones judiciously in order to minimize the risk of the serious sequela of aortopathy. PMID- 30309683 TI - Insulin like growth factor binding protein 2 (IGFBP-2) for risk prediction in patients with severe aortic stenosis undergoing Transcatheter Aortic Valve Implantation (TAVI). AB - INTRODUCTION: Severe aortic stenosis (AS) caused by degenerative calcification is the most frequent acquired valvular heart disease worldwide and mortality rates are considerably high. Transcatheter Aortic Valve Implantation (TAVI) is a well established method for valve replacement in high risk patients with AS. However, there is a lack of reliable predictors for patients undergoing TAVI since commonly used scores were developed for surgical populations. MATERIALS AND METHODS: 208 patients subjected to TAVI were included in this study. Plasma samples were obtained before TAVI and were evaluated for IGFBP-2 using commercially available ELISA kits. IGFBP-2 levels were analyzed for their ability for risk prediction after TAVI. RESULTS: IGFBP-2 levels measured before TAVI correlated significantly with left ventricular ejection fraction, EUROSCORE and other functional and prognostic parameters like the 6-minute walking test. When patients were retrospectively divided in two groups with a cut-off of serum IGFBP 2 levels of 275 ng/ml, IGFBP-2 was a strong predictor for 30-day and one-year mortality (3% vs. 11%, p = 0.05 and 18.2% vs. 46.2%; p < 0.001 respectively). Compared to an EUROSCORE above 20 or an STS score cut-off above 8, IGFBP-2 plasma levels above 275 ng/ml outperformed the established risk score for prediction of one-year mortality as assessed by NRI (0.65 95% CI 0.37-0.94; p < 0.001 and 0.54 95% CI 0.25-0.82; p < 0.001, respectively). CONCLUSIONS: Our results indicate that IGFBP-2 could serve as new outcome predictor for patients undergoing TAVI procedure. By providing additional information to the commonly used EUROSCORE, IGFPB-2 analysis could further assist Heart Team decision making. PMID- 30309684 TI - Behind enemy lines: How to enlarge heart transplant criteria. PMID- 30309685 TI - From serendipity to clinical relevance: How clinical psychology and neuroscience converged to illuminate psychoneuroendocrinology. AB - Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues. PMID- 30309687 TI - Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. AB - BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS >=4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. PMID- 30309688 TI - Corrigendum to "Interventions promoting exclusive breastfeeding up to six months after birth: A systematic review and meta-analysis of randomized controlled trials" [Int. J. Nurs. Stud. 80 (April) (2018) 94-105]. PMID- 30309686 TI - Racial discrimination and leukocyte glucocorticoid sensitivity: Implications for birth timing. AB - RATIONALE: Psychological stress-induced cortisol elevations appear to contribute to preterm birth. Yet, some studies suggest that the biological ramifications of racial discrimination-associated stress are unique and may involve development of decreased glucocorticoid sensitivity despite normalized cortisol levels. OBJECTIVE: In this study, we examined the effects of racial discrimination on maternal cortisol output, leukocyte glucocorticoid sensitivity, and the degree of correspondence between cortisol levels and birth timing in an African American cohort. METHOD: A generally healthy prospective cohort was enrolled at 28-32 weeks gestation (n = 91). The Experiences of Discrimination scale was administered, whole blood collected, and plasma cortisol levels, cytokine levels, and leukocyte counts quantified for examination of patterns of endogenous feedback. RESULTS: Racial discrimination in the mid-tertile was associated with greater maternal cortisol levels than the bottom tertile among women reporting internalizing responses (b* = 0.68, p = 0.001). Decreased leukocyte glucocorticoid sensitivity was witnessed at greater frequencies of experiences of racial discrimination, as evidenced by decreased correspondence between maternal cortisol levels and plasma IL-8 levels, monocyte counts, and lymphocyte counts (p values <= 0.043). The association between maternal cortisol levels and birth timing differed by discrimination tertile (p values <= 0.005), with greater cortisol levels predictive of earlier birth among women without (b* = -0.59, p < 0.001) but not with racial discrimination (ps >= 0.497). CONCLUSION: We provide novel evidence of decreased glucocorticoid sensitivity at increasing frequency of exposure to racial discrimination. Our findings suggest that the biology of preterm birth may depend upon racial discriminatory exposures, favoring pathways dependent upon glucocorticoid-induced increases in leukocyte tissue surveillance versus glucocorticoid resistance-associated inflammatory aberrations at increasing levels of exposure. Precision approaches to prenatal care are sorely needed to combat preterm birth, particularly among African American women, with efforts dependent upon further research examining the pathways contributing to the syndrome dependent upon the totality of an individual's exposures. PMID- 30309689 TI - Adherence to lifestyle-related cancer prevention guidelines and breast cancer incidence and mortality. AB - PURPOSE: Breast cancer is the most common cancer in women. Many lifestyle factors have been associated with an increased risk of breast cancer incidence and mortality. An index-based approach to analyzing adherence to American Cancer Society (ACS) guidelines as a whole may better explain associations between lifestyle variables and breast cancer incidence and mortality. METHODS: We created an index based on American Cancer Society-specific guidelines, including body mass index (BMI), physical activity, alcohol intake, tobacco use, daily time spent watching television, and certain dietary habits. Cox proportional hazards regression was used to model the association between the lifestyle index and primary breast cancer and breast cancer-specific mortality in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) cohort. RESULTS: We identified 7088 women with incident breast cancer, 1162 deaths overall, and 462 deaths due to breast cancer. Compared with the lowest quintile of lifestyle index score (meeting fewest guidelines), women in the highest quintile had a 24% lower risk of breast cancer (hazard ratio [HR] = 0.76, 95% CI: 0.70, 0.82) and 37% lower risk of all-cause mortality (HR = 0.63, 95% CI: 0.53, 0.76), while the association with breast cancer-specific mortality was nonsignificant. CONCLUSIONS: Healthier prediagnosis lifestyle is associated with a decreased risk of breast cancer and all-cause mortality in the NIH-AARP cohort. PMID- 30309691 TI - [Diffuse lesions]. PMID- 30309692 TI - [Cervical pain of unusual cause]. PMID- 30309690 TI - Do the health benefits of education vary by sociodemographic subgroup? Differential returns to education and implications for health inequities. AB - PURPOSE: Evidence suggests education is an important life course determinant of health, but few studies examine differential returns to education by sociodemographic subgroup. METHODS: Using National Longitudinal Survey of Youth 1979 (n = 6158) cohort data, we evaluate education attained by age 25 years and physical health (PCS) and mental health component summary scores (MCS) at age 50 years. Race / ethnicity, sex, geography, immigration status, and childhood socioeconomic status (cSES) were evaluated as effect modifiers in birth year adjusted linear regression models. RESULTS: The association between education and PCS was large among high cSES respondents (beta = 0.81 per year of education, 95% CI: 0.67, 0.94), and larger among low cSES respondents (interaction beta = 0.39, 95% CI: 0.06, 0.72). The association between education and MCS was imprecisely estimated among White men (beta = 0.44; 95% CI: -0.03, 0.90), while, Black women benefited more from each year of education (interaction beta = 0.91; 95% CI: 0.19, 1.64). Similarly, compared to socially advantaged groups, low cSES Blacks, and low and high cSES women benefited more from each year of education, while immigrants benefited less from each year of education. CONCLUSIONS: If causal, increases in educational attainment may reduce some social inequities in health. PMID- 30309693 TI - Amiodarone and the thyroid physiology, pathophysiology, diagnosis and management. AB - Although amiodarone is considered the most effective antiarrhythmic agent, its use is limited by a wide variety of potential toxicities. The purpose of this review is to provide a comprehensive "bench to bedside" overview of the ways amiodarone influences thyroid function. We performed a systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1950 and 2017. Amiodarone was searched using the terms adverse effects, hypothyroidism, myxedema, hyperthyroidism, thyroid storm, atrial fibrillation, ventricular arrhythmia, and electrical storm. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. We included 163 germane references in this review. Because amiodarone is one of the most frequently prescribed antiarrhythmic drugs in the United States, the mechanistic, diagnostic and therapeutic information provided is relevant for practicing clinicians in a wide range of medical specialties. PMID- 30309694 TI - Breakfast consumption in relation to lowered risk of psychological disorders among Iranian adults. AB - OBJECTIVES: This study aims to find whether breakfast consumption is associated with human mental health. STUDY DESIGN: This cross-sectional study was conducted to investigate the association between breakfast consumption and psychological disorders, including depression and anxiety, among Iranian adults. METHODS: This cross-sectional study was conducted on 4378 general public adults in Isfahan, Iran. Breakfast consumption was assessed using a validated detailed dietary habits' questionnaire. Depression and anxiety were screened using an Iranian validated Hospital Anxiety and Depression Scale questionnaire. Psychological distress was examined by means of Iranian validated version of General Health Questionnaire (GHQ-12 items). Depression, anxiety, and psychological distress were defined based on standard criteria. RESULTS: Overall, 13.95% (n = 611) of study participants had anxiety, 28.62% (n = 1253) were depressive, and 23.18% (n = 1015) had psychological distress. After controlling for potential confounding variables, participants with every day breakfast consumption had lower odds for depression (odds ratio [OR]: 0.49, 95% confidence interval [95% CI]: 0.36-0.66) compared with those with the least frequent intake of breakfast, even after further adjustment for body mass index [BMI] (OR: 0.47, 95% CI: 0.34-0.63). Frequent breakfast consumption was inversely associated with anxiety before (OR: 0.53, 95% CI: 0.37-0.76, P < 0.001) and after controlling for BMI (OR: 0.52, 95% CI: 0.36-0.75, P < 0.001). The same findings were obtained for psychological distress (OR: 0.46, 95% CI: 0.33-0.62, P < 0.001). CONCLUSION: We found an inverse association between breakfast consumption and depression, anxiety, and psychological distress among Iranian adults. Further prospective studies are needed to confirm these findings. PMID- 30309695 TI - Coverage of Abortion in Select U.S. Newspapers. AB - BACKGROUND AND OBJECTIVES: News coverage can shape public understanding of policy issues in important ways. In the last decade, many new state-level abortion restrictions have been passed, often based on claims about the safety of abortion care, yet little is known about recent news coverage of abortion. This study analyzes a sample of news on abortion in the United States and explores the implications for reproductive health policymakers, practitioners, and advocates. METHODS: We analyzed a sample of news and opinion articles containing the term "abortion" published in three major U.S. newspaper sources in 2013 and 2016. The total sample was 783 unique pieces. We coded for story topics, references to fetal personhood, women's stories, and basic abortion facts. Three trained coders conducted the coding, with intercoder reliability rates ranging from 0.777 to 1.0. FINDINGS: Most of the time abortion appears in the news, it is merely mentioned, rather than discussed substantively. Abortion is covered as a political issue more than a health issue. The personal experiences of people who get abortions are present in only 4% of the sample, and language personifying the fetus appears more often than women's abortion stories. State abortion restrictions are newsworthy, yet basic facts on the commonality and safety of abortion are virtually absent. CONCLUSIONS: This study suggests that the news does not support public understanding of abortion as a common, safe part of reproductive health care. Such framing may undermine public support for policies that protect access to this common health care service. PMID- 30309696 TI - Knockdown of DSPP inhibits the migration and invasion of glioma cells. AB - Dentin sialophosphoprotein (DSPP) is a member of the SIBLING (Small integrin binding ligand N-linked glycoproteins) family of phosphoglycoproteins and has been proved to contribute to the migration of a variety of solid tumor cells. However, whether DSPP participates in the pathogenic process of glioma remains unknown. In this study, we aimed to investigate the expression and biological function of DSPP in human glioma cells. We demonstrated through Western blot that DSPP is overexpressed in glioma tissues comparing to normal brain tissues. To investigate the role of DSPP in glioma carcinogenesis, we reduced the DSPP expression by small interfering RNA (siRNA) and found that DSPP silencing significantly inhibited the migration and invasion of glioma cells, the critical characteristics of glioma. Furthermore, we showed that DSPP down-regulation significantly decreased the activation of the AKT/mTOR/p70S6K pathway in glioma cells. Taken together, these findings indicate that knockdown of DSPP inhibits glioma cells migration and invasion, suggesting that targeting DSPP might be a potentially effective therapeutic strategy for treating glioma. PMID- 30309698 TI - Response to: Chikungunya in Bolivia: Still a Neglected Disease? PMID- 30309697 TI - Usefulness of compounds with monacolin K in a case of statins intolerance. AB - Many patients with familial hypercholesterolaemia (FH) or in secondary prevention situations and with statin intolerance do not achieve LDL-C targets, and require treatment with PCSK9 inhibitors (iPCSK9) and ezetimibe. The case is presented on a patient with FH and total intolerance to statins. Treatment with iPCSK9 and ezetimibe failed to achieve her LDL-C target. A compound with red yeast rice derivatives containing 3mg of monacolin K was added, with good therapeutic compliance, and a very good control of LDL-C. The addition of red yeast rice derivatives containing low doses of monacolin K, together with IPCSK9 in patients with total intolerance to statins, may open a new path to obtain LDL-C targets in patients with high/very high cardiovascular risk. PMID- 30309699 TI - [Health literacy in patients with type 2 diabetes: A cross-sectional study using the HLS-EU-Q47 questionnaire]. AB - OBJECTIVE: The aim of this study was to determine the level of health literacy of diabetic patients aged 50 to 75 years, from Ourense, Spain, as well as its relationship with the glycated haemoglobin (HbA1c) concentration and cardiovascular risk of the patient. MATERIAL AND METHODS: Cross-sectional study using a self-completed questionnaire. From a multi-stage sampling, urban, type 2 diabetic patients were randomly included. The level of health literacy, using the HLS-EU-Q47 questionnaire, the last concentration of HbA1c, and both total and fatal cardiovascular risk at 10 year follow-up, measured using the UKPDS (U.K. Prospective Diabetes Study) algorithm, were determined. The age, gender, level of education, level of social support, social class, and comorbidities were used as covariates. RESULTS: A total of 103 patients were analysed. Out of all the patients, 81.5% (84) had an unsuitable health literacy level (29.1% had an inadequate level and 52.4% had a problematic level). A clear association was seen between a higher level of health literacy and higher levels of education. Moreover, the level of health literacy was seen to be inversely related to the level of control of the patients' diabetes measured on the basis of their HbA1c (P=.03) concentration. However, no such association was found with the cardiovascular risk (P=.3). CONCLUSIONS: The results of the present study show that the level of literacy of the analysed population was insufficient, and that its improvement could result in a better outcome in the treatment of diabetic patients. PMID- 30309702 TI - Adoptive T Cell Therapy: New Avenues Leading to Safe Targets and Powerful Allies. AB - Adoptive transfer of TCR-engineered T cells is a potent therapy, able to induce clinical responses in different human malignancies. Nevertheless, treatment toxicities may occur and, in particular for solid tumors, responses may be variable and often not durable. To address these challenges, it is imperative to carefully select target antigens and to immunologically interrogate the corresponding tumors when designing optimal T cell therapies. Here, we review recent advances, covering both omics- and laboratory tools that can enable the selection of optimal T cell epitopes and TCRs as well as the identification of dominant immune evasive mechanisms within tumor tissues. Furthermore, we discuss how these techniques may aid in a rational design of effective combinatorial adoptive T cell therapies. PMID- 30309700 TI - Injection of Saline Into the Biopsy Tract and Rapid Patient Rollover Decreases Pneumothorax Size Following Computed Tomography-Guided Transthoracic Needle Biopsy. AB - PURPOSE: To determine if saline tract injection and rapid patient rollover following computed tomography (CT)-guided transthoracic needle biopsy (TTNB) affects pneumothorax incidence and size. METHODS: A retrospective cohort design was used to compare 278 patients who underwent post-biopsy saline injection and rapid rollover so that the biopsy site was dependent (N = 180) to a control group with routine post-biopsy care (N = 98). Post-procedure radiographs and CT were assessed for presence and size of pneumothorax, as well as requirement for chest tube placement. RESULTS: Pneumothorax size as estimated on post-procedure CT was 3.33% in the treatment group and 6.63% in the control group (P < .05). There was also a reduction in chest tube placements in the treatment group (3.9% vs 10%, P < .05). On post-procedure radiographs, pneumothorax rates were 20% in the treatment group, and 25% in the control group (P > .05). CONCLUSION: Saline injection with rapid patient rollover following TTNB significantly decreased pneumothorax size and chest tube placement but not incidence. PMID- 30309701 TI - Reply to "Letter to the Editor in response to the article, 'The epidemiology of oral human papillomavirus infection in healthy populations: A systematic review and meta-analysis'". PMID- 30309703 TI - [Left localization of biliobronchial fistula: Exceptional complication of hepatic hydatidosis]. AB - INTRODUCTION: The biliobronchial fistula of hydatic origin is a rare complication and the left localization is exceptional. OBSERVATION: We report the case of a 26 year-old patient from the rural area who was referred to us for treatment of biliptysis. The thoracic and abdominal computed tomography diagnosed a left biliobronchial fistula was. Management consisted of primary endoscopic sphincterotomy, followed by left exclusive thoracotomy surgery to treat pulmonary, hepatic and diaphragmatic repair. The evolution was favorable with disappearance of the biliptysie. CONCLUSION: The diagnosis of left biliobronchial fistula requires a precise assessment not only by the imagery but also the bronchial fibroscopy allowing the acurate localisation of the lesion before any surgical enterprise. PMID- 30309705 TI - An improved quantification method for 12 linear dimethylsiloxanes and 1 cyclic dimethylsiloxane in polydimethylsiloxane using gas chromatography-flame ionization detector:Development strategy and accuracy. AB - PDMS 200 fluid (the mixture) was used as standard for quantification of linear dimethylsiloxanes (L5-L16) in environmental matrices. However, the quantification of individual dimethylsiloxane in PDMS 200 fluid by GC-FID was not established or detailed described in many real studies. To solve this problem, we did this research and the principal results were as follows: fifteen compounds in PDMS 200 fluid, including D7, L5 to L16 (12 linear dimethylsiloxanes) and 2 unknown compounds, were identified using GC-MS. Retention indices (RI) of L8 to L16 were first given. Meanwhile, we found that the "effective carbon number (ECN) concept" was applicable for responses of dimethylsiloxanes in FID. Based on GC-FID, a new quantification method for compounds in PDMS 200 fluid was established, detailed described and used to calculate the content of individual dimethylsiloxane in PDMS 200 fluid. Compared with the results from external standard method, internal standard method and normalization method, the new quantification method was more accurate and stable, especially for D7 at low content. PMID- 30309704 TI - Development and evaluation of semi-destructive, ultrasound assisted extraction method followed by gas chromatography coupled to mass spectrometry enabling discrimination of red lipstick samples. AB - In this study, the effective and robust semi-destructive ultrasound assisted extraction (UAE) method followed by gas chromatography coupled to mass spectrometry (GC-MS) method used for analysis of red lipsticks samples was developed, optimized and evaluated. 43 red lipsticks of a very similar hue representing of 21 different manufacturers were investigated. The red lipsticks (approximately 0.05 mg) were applied on a disc (of o 2 mm) placed on specially designed stand printed with a 3D printer. In order to optimize the main factors affecting extraction process, Doehlert experimental design with response surface methodology was applied. The optimal for all analysed lipsticks UAE extraction conditions were: 21 min - time, 35 degrees C - temperature of the ultrasonic bath, and the 100 MUL of extraction mixture of acetonitrile, methanol and acetone (50:30:20, v/v/v). The developed, qualitative UAE/GC-MS method was evaluated and then successfully used for the differentiation of 43 red lipsticks. In this case, the two approaches were utilized: the visual inspection of chromatograms and the likelihood ratio model. The results confirmed that the proposed method has a great potential in lipsticks differentiation and after adaptation to real samples it seems to be a good alternative to the methods routinely used in forensic science investigations. PMID- 30309707 TI - Pure natural orifice transluminal endoscopic surgery for rectal cancer: Ta-TME and CME without abdominal assistance. AB - AIM: To report our institution's experiences with pure transanal total mesorectal excision (TME) of rectal cancer using single-port equipment and to discuss the feasibility and safety of the technique. METHODS: Between February and December 2017, 12 patients who were selected underwent NOTES TME in our institution. The preoperative assessment included blood analyses with carcinoembryonic antigen serum concentration, full colonoscopy, pelvic magnetic resonance imaging (MRI), and computed tomography (CT) of the abdomen and chest. RESULTS: Ten patients (male:female, 6:4) treated with transanal TME with colorectal anastomosis in our institution were reviewed. Pure TME was performed without laparoscopic assistance in 6 of 10 patients. The mean operative time was 303.5 min. The median distal margin was 2.1 (0.2-4.2) cm. The median number of harvested lymph nodes is 17.5. Except one patient with anastomotic leak, most patients started dietary intake on postoperative day (POD) 3 and were discharged on POD 7. Anastomotic leak was the only postoperative complication. CONCLUSION: This study showed that pure natural orifice transluminal endoscopic surgery (NOTES) TME with coloanal anastomosis for rectal cancer is safe and feasible in selected cases. PMID- 30309706 TI - Discovery of beta2- adrenoceptor agonists in Curcuma zedoaria Rosc using label free cell phenotypic assay combined with two-dimensional liquid chromatography. AB - Traditional Chinese Medicines (TCMs) have been widely used in clinical practice, and provided a rich source for discovering new drug leads. However, efficient identification of active molecules responsible for the therapeutic effects of complex TCMs is still highly challenging. Here, we combined label-free cell phenotypic assay with two dimensional liquid chromatography (2DLC) to identify potential beta2-adrenoceptor (beta2-AR) agonists related to anti-asthmatic effect of Curcuma zedoaria Rosc (C.zedoaria), a commonly used TCM. The ethyl acetate extract of C.zedoaria was first fractionated into 26 fractions. Label-free cell phenotypic profiling was then used to locate the active sites. Orthogonal second dimensional (D2) separation was performed on two fractions displaying agonistic effect at the beta2-AR, combined with screening of the D2 fractions to track the activity. Finally, this approach led to the isolation of three known diarylheptanoids, among which diarylheptanoid b exhibited the most potent agonistic activity with an EC50 value of 5.93 MUM. This result was further demonstrated through the chemical synthesis of diarylheptanoid b. It is the first time to discover that diarylheptanoids could activate the beta2-AR, which may be responsible for the anti-asthmatic effect of C.zedoaria observed traditionally and in clinical application. This study also demonstrates the potential of this integrated strategy for identifying active ingredients and determining the basis of therapeutic materials in complex TCMs. PMID- 30309708 TI - Association of erythrocyte n-3 polyunsaturated fatty acids with incident type 2 diabetes in a Chinese population. AB - BACKGROUND & AIMS: The association between circulating n-3 polyunsaturated fatty acid (PUFA) biomarkers and incident type 2 diabetes in Asian populations remains unclear. We aimed to examine the association of erythrocyte n-3 PUFA with incident type 2 diabetes in a Chinese population. METHODS: A total of 2671 participants, aged 40-75 y, free of type 2 diabetes at baseline, were included in the present analysis. Incident type 2 diabetes cases (n = 213) were ascertained during median follow-up of 5.6 years. Baseline erythrocyte fatty acids were measured by gas chromatography. We used multivariable Cox regression models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of type 2 diabetes across quartiles of erythrocyte n-3 PUFA. RESULTS: After adjustment for potential confounders, HRs (95% CIs) of type 2 diabetes were 0.68 (0.47, 1.00), 0.77 (0.52, 1.15), and 0.63 (0.41, 0.95) in quartiles 2-4 of docosapentaenoic acid (C22:5n-3) (P-trend = 0.07), compared with quartile 1; and 1.08 (0.74, 1.60), 1.03 (0.70, 1.51), and 0.57 (0.38, 0.86) for eicosapentaenoic acid (C20:5n 3) (P-trend = 0.007). No association was found for docosahexaenoic acid (C22:6n 3) or alpha-linolenic acid (C18:3n-3). CONCLUSIONS: Erythrocyte n-3 PUFA from marine sources (C22:5n-3 and C20:5n-3), as biomarkers of dietary marine n-3 PUFA, were inversely associated with incident type 2 diabetes in this Chinese population. Future prospective investigations in other Asian populations are necessary to confirm our findings. PMID- 30309709 TI - Circulating microRNAs and adipokines as markers of metabolic syndrome in adolescents with obesity. AB - BACKGROUND: Circulating microRNAs (miRNAs) as valuable biomarkers yielded important insights into the pathogenesis of obesity. AIM: This study aimed to describe the circulating miRNA profile for adolescences and its association with the circulating levels leptin and adiponectin according to specific degree of obesity. METHODS: RT-PCR and immunoassy analysis were used to study circulating miRNA profile, adipokines; adiponectin (A), leptin (L), and L/A ratio as well as other factors of metabolic syndrome (MS) in 250 adolescents with severe obesity. RESULTS: In morbidly obese adolescents, we identified at least 10 circulating miRNAs, including increased concentrations of miRNAS; miR-142-3p, miR-140-5p, miR 222 miR-143, miR-130, and decreased concentrations of miR-532-5p, miR-423-5p, miR 520c-3p, miR-146a, and miR-15a, which were strongly linked to measures of BMI, WHtR, adipokines; adiponectin, leptin, L/A ratio, and other MS related biomarkers such as FBS, insulin, HOMA-IR, C-peptide, and circulated plasma lipids such as TG, HDL-C, and LDL-C. CONCLUSION: Circulating miRNAs showed significant association with plasma levels of adipokines; adiponectin, leptin, and L/A ratios in adolescents with severe obesity. The study provides that regulation of miRNAs expression is associated with adipokines, and other related MS metabolic factors. Thus, early detection of any changes in circulating miRNAs profiles may play a promising role in identifying obese children or adolescents who may suffer from severe metabolic syndrome. PMID- 30309710 TI - Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells. AB - Targeted adoptive immunotherapy with engineered T cells is a promising treatment for refractory hematologic malignancies. However, many patients achieving early complete remissions ultimately relapse. Immunosuppressive ligands are expressed on tumor and supportive cells in the tumor microenvironment (TME). When activated, T cells express associated "checkpoint" receptors. Binding of co inhibitory ligands and receptors may directly contribute to T-cell functional exhaustion. It is not known whether all T cells engineered to express chimeric antigen receptors (CARs) are subject to checkpoint-mediated regulation. It is also unknown whether distinct CAR signaling moieties modulate T-cell responsiveness to these inhibitory pathways. We have, therefore, directly compared functional co-inhibition in engineered T cells identically targeted to the tumor-associated antigen CD123, but distinct in their mode of T-cell activation: via the endogenous T-cell receptor (ENG), or downstream of CD28 or 41BB-containing CARs. In all cases, we have observed antigen-independent T-cell activation associated with upregulation of the co-inhibitory receptors programmed cell death protein 1 (PD-1, CD279), Tim-3 and Lag-3. Notably, CD28.CAR T cells were uniquely susceptible to PD-1/PD-L1 mediated checkpoint inhibition. Together, our data indicate that PD-1/PD-L1 checkpoint blocking agents may be considered clinically when CD28.CAR T cells do not perform optimally in human trials. PMID- 30309712 TI - Public Health Costs for Northern Territory and South Australian Cardiac Surgery Patients. AB - BACKGROUND: The cost of performing cardiac surgery in the public health system in Australia is unclear. This paper analyses the cost of cardiac surgery performed at Flinders Medical Centre (FMC), South Australia, comparing cost by procedure, rheumatic valvular heart disease status, Aboriginality and location. METHODS: This study is a retrospective, population-based analysis of cardiac surgery data held in the Cardiac Surgery Registry cross-referenced to cost data provided by the FMC Department of Finance and Patient Travel, Accommodation and Transport Services at the Royal Darwin Hospital. 795 patients who underwent cardiac surgery at FMC from 1 July 2014 to 30 June 2016 were included. RESULTS: Across all procedures, Northern Territory (NT) Aboriginal patients had a mean total cost of $78,506 which was $24,113 more than NT non-Aboriginal, $28,443 more than South Australian (SA) Aboriginal and $22,955 more than SA non-Aboriginal patients. The total cost of a patient undergoing a repeat sternotomy (reoperative procedure) was found to be significantly higher than a primary procedure ($85,797 versus $59,097). In patients undergoing valve surgery procedures, those identified with rheumatic heart disease had a higher mean total cost than those without (a difference of $25,094). Significantly, the rheumatic patient group showed a higher proportion of reoperative procedures (19% versus 5%). CONCLUSIONS: The cost of treating NT Aboriginal cardiac surgical patients remotely has a significant financial impact upon the health care delivery system, as does the impact of rheumatic heart disease. This study found that the cost for the NT Aboriginal patient group was substantially higher than the NT non-Aboriginal, SA Aboriginal and SA non-Aboriginal patient groups. The additional cost to family and dislocation of social structures is not able to be calculated, but would also clearly weigh heavily on both patient groups. These findings suggest that future health funding models should recognise Aboriginality, remoteness and rheumatic heart disease. PMID- 30309711 TI - Initial Experience of the Use of 3-Factor Prothrombin Complex Concentrate and Thromboembolic Complications After Cardiac Surgery. AB - BACKGROUND: 3-factor prothrombin complex concentrate (3F-PCC) may provide a valuable treatment option for coagulopathy in cardiac surgery patients. However, it may expose patients to increased risk of thromboembolic events. Accordingly, we compared the incidence of thromboembolic events between patients exposed to 3F PCC and those receiving conventional therapy. METHODS: Demographic, operative and postoperative data was obtained in a cohort of consecutive patients exposed to 3F PCC and a contemporaneous control population. Propensity-score matching was performed for risk adjustment. Unadjusted and adjusted patient demographics and incidence of thromboembolism were compared. RESULTS: Patients receiving 3F-PCC (PCC) were younger (mean age PCC: 64+/-14.2 vs. No PCC: 67.6+/-11.6, p=0.022), and less likely to have diabetes or previous myocardial infarction. PCC patients experienced more prolonged aortic cross clamp times (mean time in minutes PCC: 119.9+/-58.8 vs. No PCC: 92.3+/-54), more complex cardiac surgeries and were more likely to have received more fresh frozen plasma (FFP), cryoprecipitate and red blood cells. Despite this, both unadjusted and adjusted 30-day mortality and readmission rates were similar between groups. There were 9 (9.2%) and 34 (6.8%) (p=0.40) thromboembolic events in the unadjusted PCC and control groups respectively. Adjusted risk for thromboembolic event rates was also comparable (Odds ratio: 1.512, 95% Confidence Interval 0.401-5.7, p=0.541). CONCLUSIONS: 3 factor prothrombin complex concentrate was administered to patients at greater risk of complications including bleeding. Our initial experience suggests that the use of PCC does not appear to increase thromboembolic risks compared to conventional treatment. PMID- 30309713 TI - Kidneys. PMID- 30309714 TI - CKD Due to a Novel Mitochondrial DNA Mutation: A Case Report. AB - In human kidney disease, mitochondrial ultrastructural damage has long been recognized. Although the extent to which such mitochondrial changes contribute to human kidney disease is uncertain, experimental studies clearly demonstrate that mitochondrial damage can instigate pathogenetic processes that drive ongoing kidney disease. Clinical credence for this experimentally based hypothesis is provided by the development of kidney disease in patients with primary mitochondrial disorders. In this regard, substantial interest surrounds the occurrence of kidney disease in primary mitochondrial cytopathies, a heterogeneous group of conditions in which mutations in mitochondrial DNA (mtDNA) or nuclear DNA impair the functionality of components of the mitochondrial respiratory chain. We describe a novel mtDNA mutation in a patient who developed chronic kidney disease. The patient exhibited mitochondrial abnormalities in both muscle and kidney, chronic tubulointerstitial changes, and recurrent episodes of rhabdomyolysis. We outline mechanisms that may underlie the occurrence of chronic kidney disease in the setting of this novel mtDNA mutation. We also underscore the need to consider in relevant kidney diseases the presence of an underlying mitochondrial cytopathy because the latter more commonly exists than is generally recognized. PMID- 30309715 TI - Performance evaluation and first clinical experience with the Varian RGSC module for breath detection of 15 lung cancer patients. AB - The University Hospital of Dusseldorf, Germany (UKD) recently installed the Respiratory Gating for Scanners module (RGSC) (Varian Medical Systems, Palo Alto, USA). The aim of this article is to report on the commissioning and clinical implementation of the RGSC system. The steps encompassed the validation of the manufacturer's specifications including functionality tests using a commercial and in-house developed breathing phantom, to establish calibration procedures, and clinical workflow analysis involving breath acquisition and patient data evaluation. In this context also the RGSC signal without motion was performed to assess the calibration procedure. Reproducibility test were conducted as well with breathing phantoms. Fifteen clinical breath curves were examined in order to assess the impact of treatment related uncertainties such as noises of the CT, patient positioning, movement of the CT table, unintended patient motion. Finally, different binning approaches were assessed and the effect on the CT reconstructions and methodic advantages were investigated. All technical specifications of the manufacturer were confirmed. A baseline drift of 1.83mm of the measured breath curve occurred during longitudinal movement of the CT table. This drift is smaller if the direction of table motion coincides precisely with the level of calibration. If the calibration is carried out on extensions for patient positioning we measured a baseline drift up to 6mm. It was found that especially for a combination of a ceiling mounted IR-camera and amplitude based 4D-CT reconstructions, precise calibration is prerequisite. The evaluations of patient breath curves and corresponding CT reconstructions revealed patient specific aspects and variations, respectively. Consequently patient selection criteria need to be established in parallel with the technical implementation and validation phase of respiratory gating. PMID- 30309717 TI - Organic contaminants removal from industrial wastewater by CTAB treated synthetic zeolite Y. AB - Due to environmental issues, wastewater treatment is a main concern for most industries and providing access to clean and affordable water is one of the big challenges. Besides, industrial wastewater contains many pollutants, one of the most toxic contaminants is organics. Currently, zeolites are widely used as an adsorbent to remove such pollutants. This study examines a surfactant modified zeolite Y (SMZY), as an applicable solution, to get over this problem. Here, zeolite Y, synthesized from bentonite, is used as an adsorbent basis. Then, it is characterized by XRD, FTIR, BET, SEM, and TGA. Next, it is modified by hexadecyltrimethyl ammonium bromide (CTAB) surfactant in different concentrations. These SMZYs are used to adsorb organic contaminants of an olefin plant wastewater. Based on adsorption capacity evaluated by several isotherms, such as Langmuir, Freundlich, Sips and Dubinin-Radushkevich, total organic carbon (TOC) content of wastewater reduced up to 89%. The optimum modification method and possible mechanism for obtaining this result is presented in the current research. Furthermore, to understand the nature of adsorption process, Van der Waals, hydrophobic, and electrostatic interactions are determined. The results indicate that adsorption process depends on both hydrophobic and electrostatic interactions. PMID- 30309716 TI - Cardiac troponin I in dogs anaesthetized with propofol and sevoflurane: the influence of medetomidine premedication and inspired oxygen fraction. AB - OBJECTIVE: To investigate changes in serum cardiac troponin I (cTnI) concentrations in dogs in which medetomidine was used for sedation or for premedication prior to anaesthesia with propofol and sevoflurane. STUDY DESIGN: Prospective clinical study. ANIMALS: A total of 66 client-owned dogs. METHODS: The dogs were sedated with medetomidine (0.04 mg kg-1) intravenously (IV) (group M; n = 20) and left to breath room air or anaesthetized with propofol (6.5 +/- 0.76 mg kg-1 IV) and sevoflurane (4.5% vaporizer setting) in oxygen (group P + S; n = 20) or with medetomidine (0.04 mg kg-1 IV), propofol (1.92 +/- 0.63 mg kg-1) and sevoflurane (3% vaporizer setting) in oxygen (group M + P + S; n = 26), respectively. After 35 minutes, medetomidine was antagonized with atipamezole (0.1 mg kg-1 intramuscularly). Blood samples for serum cTnI determination were taken before sedation or anaesthesia, 6 and 12 hours and 4 days thereafter. Serum cTnI concentrations were measured with the Architect STAT Troponin-I assay. RESULTS: Before sedation or anaesthesia, cTnI concentrations were above the detection limit in 22 out of 66 (33%) of dogs. Compared to basal values, cTnI concentrations significantly increased at 6 and 12 hours in all groups and at day 4 in group M. There were no differences in cTnI concentration between groups at baseline, at 6 hours and at 4 days. At 12 hours, cTnI concentrations were significantly higher in groups M and P + S, respectively, compared to group M + P + S. CONCLUSIONS AND CLINICAL RELEVANCE: Oxygenation during anaesthesia and reduction of propofol and sevoflurane dose due to the sparing effects of medetomidine might have played a role in alleviation of myocardial hypoxic injury as indicated by the less severe and short-lived increase of cTnI in the M + P + S group. PMID- 30309718 TI - Potential use of waste foundry sand in dual process (photocatalysis and photo Fenton) for the effective removal of phenazone from water: Slurry and fixed-bed approach. AB - In this study, degradation of a pharmaceutical drug, Phenazone (PNZ) has been carried out via heterogeneous photocatalysis, photo-Fenton and in-situ dual process (photocatalysis + photo-Fenton) in suspension and fixed-mode under artificial UV-A as well as under natural solar radiations. Waste material such as foundry sand (FS) was exploited as a supplement for iron in case of photo-Fenton reaction. The distinct processes including photocatalysis and photo-Fenton were found to be competent for the degradation of PNZ as both processes revealed an almost 90-95% removal of PNZ after 180 min of UV irradiations. The degradation was improved to a great extent with remarkable reduction in treatment time of PNZ to almost 105 min when these two individual processes were combined together within the same unit. An almost 14% synergy of dual process over distinct processes was obtained. For fixed-bed studies, TiO2 immobilized hollow circular composite disc already containing FS was utilized which yielded an almost 96% reduction in the concentration of PNZ after 4 h of solar irradiations. The disc was recycled 10 times and its stability and activity was confirmed through XRD, SEM/EDS, and DRS. The mineralization of PNZ was confirmed through significant reduction in COD and generation of anions during the treatment process. The transformation products were examined through GC-MS analysis. The novel technique of in-situ dual process especially in fixed-mode visualized in this study by employing renewable energy and durable catalyst can represent a viable solution to various industries for the treatment of wastewater comprising of bio recalcitrant pollutants. PMID- 30309719 TI - Post-fire attitudes and perceptions of people towards the landscape character and development in the rural Peloponnese, a case study of the traditional village of Leontari, Arcadia, Greece. AB - Fires played an integral role in shaping the rural Mediterranean landscape. However, the decoupling of social-ecological systems of landscapes led to rural degradation and rendered traditional settlements vulnerable to fire. A questionnaire survey conducted at the traditional village of Leontari, in the Peloponnese, Greece, investigates respondents' perceptions towards particular interventions that would affect the landscape character and development of the village after the 2007 forest fires. Results suggest that the values of a location can play a major role in determining the perceptions of respondents. Overall respondents were "place attached" with an increased awareness of the local landscape character that guided their preferences for rural development, however, some sociodemographic group differences were found. Women compared to men were more sensitive to the impact of the forest fire and people over 65 years of age were more positive in restoring the original vegetation compared to younger in age people. PMID- 30309720 TI - Body mass index and mortality in people with and without diabetes: A UK Biobank study. AB - BACKGROUND AND AIMS: To investigate the association of body mass index with all cause, cardiovascular and cancer mortality in individuals with and without diabetes. METHODS AND RESULTS: We used data on 490,852 participants from the UK Biobank, with linkage to national mortality data between 2006 and 2016. Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (95%CI) for all-cause, cardiovascular and cancer mortality within body mass index categories in people with and without diabetes adjusting for potential confounders. 24,789 (5.0%) participants reported having diabetes at baseline. Over a median follow-up of 6.9 years, 13,896 participants died, of which 1800 had diabetes. Compared with normal body mass index (18.5-24.9 kg/m2), mortality risk in the overweight group (25.0-29.9 kg/m2) was 33% lower in people with diabetes (HR 0.67, 95%CI 0.62-0.73) and 12% lower in participants without (HR 0.88, 95%CI 0.85-0.90). For class I obesity (30.0-34.9 kg/m2), mortality risk was 35% lower in participants with diabetes (HR 0.65, 95%CI 0.59-0.71) and 5% lower in participants without (HR 0.95, 95%CI 0.91-0.99). For class III obesity (>=40 kg/m2), there was a 10% non-significant lower mortality risk compared to normal body mass index in people with diabetes (HR 0.90, 95%CI 0.77-1.05); in contrast, the risk was 29% higher in people without diabetes (HR 1.29, 95%CI 1.13-1.45). Similar patterns were observed for cardiovascular mortality but not for cancer mortality. CONCLUSION: The impact of obesity on the risk of mortality was dependent on the presence of diabetes: for the same level of obesity, mortality risk was higher in people without diabetes compared to those with diabetes. PMID- 30309721 TI - A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: An NRG oncology/gynecologic oncology group study. AB - OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status <= 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of >=40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615]. PMID- 30309722 TI - Patients with BRCA mutations have superior outcomes after intraperitoneal chemotherapy in optimally resected high grade ovarian cancer. AB - OBJECTIVES: To compare the outcomes after intraperitoneal (IP) chemotherapy in patients with and without pathogenic BRCA mutations. METHODS: Patients with high grade ovarian cancer who were treated with adjuvant IP chemotherapy in the initial setting between 2005 and 2016 were identified. Outcomes were compared between patients with pathogenic mutations in BRCA (BRCA+) and those who tested negative or were unknown (BRCA-). RESULTS: A total of 100 eligible patients were identified. The median follow-up was 47.0 months (range, 6.6-144.1 months). Of these 100 patients, 77 patients underwent BRCA testing; 25 patients (32%) were BRCA+ (23 germline, 2 somatic). No differences were noted between groups with respect to number of IP cycles, stage, or residual disease after surgery. The median progression-free survival (PFS) was longer in the BRCA+ group; median PFS was not reached in the BRCA+ group compared to 17.3 months in the BRCA- group (HR = 0.38; 95% CI 0.20-0.73, P = 0.003). Median overall survival (OS) was longer in the BRCA+ group at 110.4 months versus 67.1 months (HR = 0.28, 95% CI 0.11-0.73, P = 0.009). CONCLUSIONS: Pathogenic BRCA mutations are more common than expected in optimally resected ovarian cancer patients selected for IP therapy. IP therapy was associated with a dramatic improvement in PFS and OS in BRCA+ patients compared with BRCA- patients. This improvement is greater than has been reported for BRCA+ patients with IV chemotherapy. The magnitude of this benefit suggests that patients with pathogenic mutations in BRCA may benefit from IP therapy. PMID- 30309723 TI - [Paediatric research in Spain: Challenges and priorities. INVEST-AEP Platform]. AB - Research is the cornerstone of medical progress. Paediatric research has its own nuances and represents an additional challenge due to the intrinsic characteristics of the paediatric population compared with adults. Despite the tremendous importance of childhood health and its impact during adulthood, society is still not convinced about the importance of conducting research in paediatrics. This also applies to paediatricians themselves, who think about research as a discipline that does not directly involve them. The Spanish Academy of Paediatrics has developed a specific research platform- INVEST-AEP- to try to help and answer the challenges associated with paediatric research in the society This article reflects the current status of paediatric research in Spain, and the goals achieved over the last few years due to the effort of paediatric researchers. In addition, a deeper analysis is provided as regards: a) the barriers that represent a hurdle for the development of broad and competitive paediatric research in our day to day work; b) the limited incentives and specific pre- and post-doctoral training; c) the high clinical burden for paediatricians or; d) the lack of specific infrastructure and dedicated funding for paediatrics. The mission, vision and values of INVEST-AEP are to develop an accessible roadmap for the development and implementation of paediatric research in Spain for the next few years. PMID- 30309724 TI - An improved force-based impedance control method for the HDU of legged robots. AB - Hydraulic drive mode enables legged robots to have excellent characteristics, such as greater power-to-weight ratios, higher load capacities, and faster response speeds than other robots. Nowadays, highly integrated valve-controlled cylinder, called hydraulic drive unit (HDU), is employed to drive the joints of these robots. However, various robot control issues exist. For example, during the walking process of legged robots, different obstacles are encountered, making it difficult to control such robots because the load characteristics of the ends of their feet change with the environment. Furthermore, although the adoption of HDU has resulted in high-performance robot control, the hydraulic systems of these robots still have problems, such as strong nonlinearity, and time-varying parameters. Consequently, robot control is very difficult and complex. This paper proposes an improved second-order dynamic compliance control system, impedance control, for HDU. The control system is designed to rectify the issues affecting the impedance control accuracy of the dynamic compliance serial-parallel composition between the HDU force control inner loop and the impedance control outer loop. Specifically, it consists of a compliance-enhanced controller and a feedforward compensation controller for the force control inner loop. Furthermore, the dynamic compliance composition of the inner and outer HDU control loops is rearranged. The results of experiments conducted indicate that the proposed method significantly improves the control accuracy compared to that of traditional force-based impedance control. PMID- 30309725 TI - Weak feature enhancement in machinery fault diagnosis using empirical wavelet transform and an improved adaptive bistable stochastic resonance. AB - Machinery vibration signal is a typical multi-component signal and fault features are often submerged by some interference components. To accurately extract fault features, a weak feature enhancement method based on empirical wavelet transform (EWT) and an improved adaptive bistable stochastic resonance (IABSR) is proposed. This method makes full use of the signal decomposition performance of EWT and the signal enhancement of the IABSR to achieve the purpose of fault feature enhancement in low frequency band of FFT spectrum. Firstly, EWT is used as the preprocessing program of bistable stochastic resonance (BSR) to decompose the machinery vibration signal into a set of sub-components. Then, the sensitive component that contains main fault information is further input into BSR system to enhance fault features with the assistance of residual noises. Finally, the fault features are identified from fast Fourier transform (FFT) spectrum of the BSR output. To achieve the optimal BSR output, the IABSR method based on salp swarm algorithm (SSA) is presented. Compared with the tradition adaptive BSR (ABSR), the IABSR optimizes not only the BSR system parameters but also the calculation step size. Two case studies on machinery fault diagnosis demonstrate the effectiveness and superiority of the proposed method. In addition, the proposed method is easy to implement and is robust to noise to some extent. PMID- 30309726 TI - Decentralized adaptive neural prescribed performance control for high-order stochastic switched nonlinear interconnected systems with unknown system dynamics. AB - In this paper, the problem of decentralized adaptive neural backstepping control is investigated for high-order stochastic nonlinear systems with unknown interconnected nonlinearity and prescribed performance under arbitrary switchings. For the control of high-order nonlinear interconnected systems, it is assumed that unknown system dynamics and arbitrary switching signals are unknown. First, by utilizing the prescribed performance control (PPC), the prescribed tracking control performance can be ensured, while the requirement for the initial error is removed. Second, at each recursive step, only one adaptive parameter is constructed to overcome the over-parameterization, and RBF neural networks are employed to tackle the difficulties caused by completely unknown system dynamics. At last, based on the common Lyapunov stability method, the decentralized adaptive neural control method is proposed, which decreases the number of learning parameters. It is shown that the designed common controller can ensure that all the signals in the closed-loop system are semi-globally uniformly ultimately bounded (SGUUB), and the prescribed tracking control performance is guaranteed under arbitrary switchings. The simulation results are presented to further illustrate the effectiveness of the proposed control scheme. PMID- 30309727 TI - Embracing 3D Complexity in Leaf Carbon-Water Exchange. AB - Leaves are a nexus for the exchange of water, carbon, and energy between terrestrial plants and the atmosphere. Research in recent decades has highlighted the critical importance of the underlying biophysical and anatomical determinants of CO2 and H2O transport, but a quantitative understanding of how detailed 3D leaf anatomy mediates within-leaf transport has been hindered by the lack of a consensus framework for analyzing or simulating transport and its spatial and temporal dynamics realistically, and by the difficulty of measuring within-leaf transport at the appropriate scales. We discuss how recent technological advancements now make a spatially explicit 3D leaf analysis possible, through new imaging and modeling tools that will allow us to address long-standing questions related to plant carbon-water exchange. PMID- 30309728 TI - MMP-9 Upregulation is Attenuated by the Monoclonal TLR2 Antagonist T2.5 After Oxygen-Glucose Deprivation and Reoxygenation in Rat Brain Microvascular Endothelial Cells. AB - BACKGROUND: Blood-brain barrier (BBB) disruption plays a key role in the pathophysiology of acute ischemic stroke. Matrix metalloproteinases-2/9 (MMP-2/9) have been shown to participate in the disruption of the BBB and hemorrhagic transformation after cerebral ischemia. Toll-like receptor 2 (TLR2) may also be correlated with endothelial cell injury during ischemia-reperfusion events. However, the correlation between MMP-2/9 and TLR2 on endothelial cells after ischemia has not yet been evaluated. The aim of the study was to evaluate the impact of TLR2 and MMP-2/9 on tight junction proteins (TJs) after oxygen-glucose deprivation and reoxygenation (OGDR). MATERIALS AND METHODS: Rat primary brain microvascular endothelial cells (BMECs) were cultured. Quantitative real-time PCR and western blotting were used to measure the mRNA and proteins expression of TLR2 and MMP-2/-9. The protein expression of TJs was detected by western blotting and immunofluorescence. RESULTS: MMP-9 significantly increased after OGDR. Protein and mRNA expression of TLR2 was also upregulated. However, claudin-5, occludin, collagen-IV, and ZO-1 were decreased after OGDR. When monoclonal anti TLR2 antibody (T2.5) was added to BMECs after OGDR, MMP-9 was significantly downregulated, whereas occludin and collagen-IV had a tendency to increase. CONCLUSION: TLR2 antagonist T2.5 is able to downregulate the expression of MMP-9, and may constitute a therapeutic option for restoration of the BBB after OGDR. PMID- 30309729 TI - Plasma miR-126 and miR-143 as Potential Novel Biomarkers for Cerebral Atherosclerosis. AB - BACKGROUND: Cerebral atherosclerosis is the most important mechanism for ischemic stroke. However, specific plasma biomarkers to assess atherosclerosis susceptibility are still lacking. Circulating miRNAs have been shown to be promising biomarkers for various pathologic conditions. We investigated whether plasma miR-126 and miR-143 could be used as biomarkers for identifying and evaluating cerebral atherosclerosis. Results showed that miR-143 and miR-126 might participate in the process of atherosclerosis and were minimally affected by cerebral infarction. Using Pearson correlation analysis, we showed that miR 126 and miR-143 were correlated with the presence and severity of cerebral atherosclerosis. The ability of miR-126 and miR-143 to differentiate atherosclerosis patients from healthy controls was demonstrated via a receiving operating characteristic curve with high specificity and sensitivity. Our data thus indicate that miR-126 and miR-143 may be potential specific biomarkers for atherosclerosis. PMID- 30309730 TI - TBS as a Tool to Differentiate the Impact of Antiresorptives onCortical and Trabecular Bone in Children With OsteogenesisImperfecta. AB - INTRODUCTION/BACKGROUND: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. METHODOLOGY: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. RESULTS: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p = 0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p = 0.007), as was the difference between aBMD and TBS (p < 0.001). CONCLUSIONS: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI. PMID- 30309731 TI - Magnetic compression anastomosis (magnamosis) in a porcine esophagus: Proof of concept for potential application in esophageal atresia. AB - BACKGROUND: Magnetic compression anastomosis (magnamosis) is the process of forming a sutureless anastomosis of the gastrointestinal tract using two magnetic Harrison rings. It has been shown to be effective in stomach, small bowel and colon, but has not been implemented in the esophagus. A pure esophageal atresia porcine model was developed to test the concept. METHODS: Five pigs weighing between 35 and 65 kg were used. In all pigs, a percutaneous endoscopic gastrostomy (PEG) tube was placed, and a right thoracotomy was performed. Esophageal atresia was simulated by transecting the esophagus with a cutting stapler, and magnets were placed endoscopically to approximate the two ends of the esophagus. In the first pig, the tissue within the magnetic ring was excised endoscopically to achieve immediate patency. In the second pig, approximation of the blind esophageal ends was reinforced with 3-4 externally-placed sutures but immediate patency was not performed. In the last three pigs, both external suture reinforcement and immediate patency were performed. The pigs survived for 10-14 days and received nutrition through PEG tube. At necropsy, an esophagram was performed, the specimen was explanted and a leak test was performed. RESULTS: The first pig died in the early postoperative period from a leak owing to separation of the magnets. The second pig died from aspiration before the anastomosis formed. The last three pigs survived until the study endpoint. The third pig had a contained leak owing to the staple line being placed between the magnets; this was not clinically significant. The last two pigs had well-formed anastomoses. Burst tests showed no leak when injecting saline up to 30 mmHg. CONCLUSION: Magnamosis is technically feasible for esophagoesophageal anastomoses. A survival model for pure esophageal atresia was developed and refined in pigs. Further work in this area may lead to clinical use in humans. PMID- 30309732 TI - Intestinal malrotation in infants with omphalocele: A systematic review and meta analysis. AB - PURPOSE: The management of intestinal malrotation in infants with omphalocele varies among surgeons. Herein, we aimed to determine whether infants with omphalocele should be investigated for malrotation. METHODS: Using a defined search strategy, three investigators identified all studies reporting patients with omphalocele and malrotation. Outcome measures included: 1. incidence of malrotation; 2. correlation with the abdominal size defect in patients with omphalocele; 3. risk of volvulus in those not investigated for malrotation; 4. incidence of adhesive bowel obstruction in those who underwent Ladd's procedure. The meta-analysis was conducted according to PRISMA guidelines and using RevMan 5.3. RESULTS: Of 111 articles analyzed, 12 (3888 children) reported malrotation in 136 patients (3.5%). Malrotation was equally found in patients with major (15.2%) and minor (13.6%; p = 0.52) omphalocele. A volvulus was more common in children who had Ladd's procedure (8%) than in those who did not (1%; p = 0.03). Adhesive bowel obstruction rate was similar in both groups (5% vs. 3%; p = 0.21). CONCLUSION: The incidence of malrotation in infants with omphalocele is low but probably underreported, and is not influenced by the size of the defect. At present, there is no evidence in the literature to support investigations to detect malrotation in infants with omphalocele. TYPE OF STUDY: Therapeutic. LEVEL OF EVIDENCE: III. PMID- 30309733 TI - The effect of intravenous lipid emulsions and mucosal adaptation following massive bowel resection. AB - AIMS AND OBJECTIVES: Fish oil (FO) lipid emulsion and a new lipid emulsion (SMOF) are important treatments for intestinal failure-associated liver disease. We evaluated the efficacy of FO and SMOF lipid emulsion on intestinal mucosal adaptation using a total parenteral nutrition (TPN)-supported rat model of short bowel syndrome. MATERIAL & METHODS: Sprague-Dawley rats underwent jugular vein catheterization and 90% small bowel resection and were divided into three groups: TPN with soy bean oil lipid emulsion (SO group), FO lipid emulsion (FO group), or SMOF (SMOF group). On day 13, the rats were euthanized, and the small intestine was harvested. The microscopic morphology and crypt cell proliferation rate (CCPR) were then evaluated. RESULTS: The villus height of the ileum in the SMOF group was significantly higher than in the SO group. The crypt depth of the intestine in the SMOF group was significantly lower than in the SO group. The CCPRs of the intestine in the FO and SMOF groups were both higher than in the SO group. CONCLUSIONS: Lipid emulsion affected the bowel morphology, such as the mucosa as well as the intestinal smooth muscle. Further studies are needed to clarify the mechanisms. PMID- 30309734 TI - Emergency department discharge following successful radiologic reduction of ileocolic intussusception in children: A protocol based prospective observational study. AB - PURPOSE: Pediatric intussusception's first line treatment consists of fluoroscopic guided air enema reduction. Postprocedure, these patients are usually admitted overnight for observation. The purpose of our study was to document the results of emergency department (ED) observation and discharge protocol after successful reduction of ileocolic intussusception. METHODS: A prospective observational study was conducted after implementation of an ED protocol for ileocolic intussusception from 10/2014 to 7/2017 and compared these patients to a historical cohort immediately prior to protocol initiation (10/2011 9/2014). Data collected included demographics, total time in the ED and hospital, enema reduction, recurrence, and requirement for operative intervention. Results reported as means with standard deviation and medians reported with interquartile ranges (IQR). RESULTS: 115 patients were treated with the prospective protocol and were compared to a 90 patient historical cohort. Reduction was successful in 84%-89% of cases. Median hospital time after enema was shorter in the protocol group [4.8 h (4.25, 14.97) versus 19.7 h (13.9, 33.45), p < 0.01]. Only 33% of patients were admitted following the protocol; the most common admission reason was persistent abdominal discomfort. CONCLUSION: ED observation and discharge after successful air enema reduction in children with ileocolic intussusception are safe, facilitate early discharge, and reduce hospital resource utilization. LEVEL OF EVIDENCE: III. PMID- 30309736 TI - C-terminal site-specific PEGylated Exendin-4 analog: A long-acting glucagon like Peptide-1 receptor agonist, on glycemic control and beta cell function in diabetic db/db mice. AB - PEG modification is a common clinical strategy for prolonging the half-life of therapeutic proteins or polypeptides. In a previous work, we have successfully synthesized PEG-modified Exendin-4 (PE) by conjugating a 20 kDa PEG to the C terminal of Exendin-4. Then, we introduced an integrative characterization for PE to evaluate its hypoglycemic activity and pharmacokinetic properties. The normoglycemic efficacies and therapeutic activity of PE were investigated in db/db mice. The hypoglycemic time after single administration of PE on db/db mice was prolonged from 8.4 h to 54.9 h. In multiple treatment with PE, the fasting blood glucose in various PE dosages (50, 150, and 250 nmol/kg) were remarkably reduced, and the glycosylated hemoglobin level was decreased to 2.0%. When the in vivo single- and multiple-dose pharmacokinetics of PE were examined in Sprague Dawley rats, the half-life was prolonged to 31.7 h, and no accumulation effect was observed. Overall, this study provided a novel promising therapeutic approach to improving glucose-controlling ability and extending half-life without accumulation in vivo for long-acting treatment of type-2 diabetes. PMID- 30309737 TI - Targeted Temperature Management in Pediatric Neurocritical Care. AB - Targeted temperature management encompasses a range of clinical interventions to regulate systemic temperature, and includes both induction of varying degrees of hypothermia and fever prevention ("targeted normothermia"). Targeted temperature management plays a key role in the contemporary management of critically ill neonates and children with acute brain injury. Yet, many unanswered questions remain regarding optimal temperature management in pediatric neurocritical care. The introduction highlights experimental studies that have evaluated the neuroprotective efficacy of therapeutic hypothermia and explored possible mechanisms of action in several brain injury models. The next section focuses on three major clinical conditions in which therapeutic hypothermia has been evaluated in randomized controlled trials in pediatric populations: neonatal hypoxic-ischemic encephalopathy, postcardiac arrest encephalopathy, and traumatic brain injury. Clinical implications of targeted temperature management in pediatric neurocritical care are also discussed. The final section examines some of the factors that may underlie the limited neuroprotective efficacy of hypothermia that has been observed in several major pediatric clinical trials, and outlines important directions for future research. PMID- 30309735 TI - Towards a Quantitative Understanding of Cell Identity. AB - Cells have traditionally been characterized using expression levels of a few proteins that are thought to specify phenotype. This requires a priori selection of proteins, which can introduce descriptor bias, and neglects the wealth of additional molecular information nested within each cell in a population, which often makes these sparse descriptors qualitative. Recently, more unbiased and quantitative cell characterization has been made possible by new high-throughput, information-dense experimental approaches and data-driven computational methods. This review discusses such quantitative descriptors in the context of three central concepts of cell identity: definition, creation, and stability. Collectively, these concepts are essential for constructing quantitative phenotypic landscapes, which will enhance our understanding of cell biology and facilitate cell engineering for research and clinical applications. PMID- 30309738 TI - Argasid and ixodid systematics: Implications for soft tick evolution and systematics, with a new argasid species list. AB - The systematics of the genera and subgenera within the soft tick family Argasidae is not adequately resolved. Different classification schemes, reflecting diverse schools of scientific thought that elevated or downgraded groups to genera or subgenera, have been proposed. In the most recent classification scheme, Argas and Ornithodoros are paraphyletic and the placement of various subgenera remains uncertain because molecular data are lacking. Thus, reclassification of the Argasidae is required. This will enable an understanding of soft tick systematics within an evolutionary context. This study addressed that knowledge gap using mitochondrial genome and nuclear (18S and 28S ribosomal RNA) sequence data for representatives of the subgenera Alectorobius, Argas, Chiropterargas, Ogadenus, Ornamentum, Ornithodoros, Navis (subgen. nov.), Pavlovskyella, Persicargas, Proknekalia, Reticulinasus and Secretargas, from the Afrotropical, Nearctic and Palearctic regions. Hard tick species (Ixodidae) and a new representative of Nuttalliella namaqua (Nuttalliellidae), were also sequenced with a total of 83 whole mitochondrial genomes, 18S rRNA and 28S rRNA genes generated. The study confirmed the utility of next-generation sequencing to retrieve systematic markers. Paraphyly of Argas and Ornithodoros was resolved by systematic analysis and a new species list is proposed. This corresponds broadly with the morphological cladistic analysis of Klompen and Oliver (1993). Estimation of divergence times using molecular dating allowed dissection of phylogeographic patterns for argasid evolution. The discovery of cryptic species in the subgenera Chiropterargas, Ogadenus and Ornithodoros, suggests that cryptic speciation is common within the Argasidae. Cryptic speciation has implications for past biological studies of soft ticks. These are discussed in particular for the Ornithodoros (Ornithodoros) moubata and Ornithodoros (Ornithodoros) savignyi groups. PMID- 30309739 TI - Management of acute liver failure. Clinical guideline from the Catalan Society of Digestology. AB - Acute liver failure is an uncommon and severe disease characterised by a rapid onset of severe hepatocellular failure in individuals without previous liver disease. Initial management of this entity determines the outcome of the patient. Initial contact with the acute liver failure patients usually occurs in the emergency department, digestology clinic or, in more severe cases, intensive care units. The management of acute liver failure patients in all these cases must be multidisciplinary, involving surgeons and hepatologists who are experts in this condition, meaning those from hospitals with active liver transplant programmes. This article reviews the current body of evidence concerning the medical management of acute liver failure patients, from the suspected diagnosis and initial management to intensive medical treatment, including the need for an emergency liver transplantation. Moreover, we also review the use of artificial liver support systems in this setting. PMID- 30309741 TI - Structural and Druggability Landscape of Frizzled G Protein-Coupled Receptors. AB - Class Frizzled G protein-coupled receptors (GPCRs), which includes the Smoothened receptor (SMO) and 10 Frizzled receptors (FZDs), are responsible for mediating fundamental signaling in embryonic development and tissue homeostasis. Dysregulation of these receptors can lead to cancer. Structural understanding of these molecules has provided insight to their function and signaling, and guided drug discovery. To date, the structures of the multi- and individual domains of SMO, 14 FZD extracellular domains, and the transmembrane domain (TMD) of FZD4, have been reported. Here, we review all reported frizzled family structures and diverse signalosome models, with an emphasis on the different ligand binding sites and lipid binding grooves, aiming to uncover the druggability landscape of the frizzled GPCR family. PMID- 30309740 TI - Indications for neuromuscular ultrasound: Expert opinion and review of the literature. AB - Over the last two decades, dozens of applications have emerged for ultrasonography in neuromuscular disorders. We wanted to measure its impact on practice in laboratories where the technique is in frequent use. After identifying experts in neuromuscular ultrasound and electrodiagnosis, we assessed their use of ultrasonography for different indications and their expectations for its future evolution. We then identified the earliest papers to provide convincing evidence of the utility of ultrasound for particular indications and analyzed the relationship of their date of publication with expert usage. We found that experts use ultrasonography often for inflammatory, hereditary, traumatic, compressive and neoplastic neuropathies, and somewhat less often for neuronopathies and myopathies. Usage significantly correlated with the timing of key publications in the field. We review these findings and the extensive evidence supporting the value of neuromuscular ultrasound. Advancement of the field of clinical neurophysiology depends on widespread translation of these findings. PMID- 30309742 TI - What diseases do 'Siddha' practitioners treat? Morbidity profile of adult outpatients attending traditional medicine health facilities in a district of South India. AB - BACKGROUND: Siddha system is a complementary system of medicine popular in South India. Information on common morbidities for which people seek care in Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy (AYUSH) systems and especially in Siddha hospitals is very limited. This knowledge will help in prioritizing diseases and developing standard treatment guidelines. OBJECTIVES: The present study was designed with the aim to describe the morbidity profile of the adult patients attending Siddha Out Patient Department (OPD) at Government Hospitals in Erode district of Tamil Nadu. MATERIALS AND METHODS: A facility-based cross sectional descriptive study was conducted among adult (15-59 years) patients, who attended Siddha Hospital OPDs during February, 2014. Two block level health facilities were randomly selected from ten block hospitals offering Siddha services in Erode district of Tamil Nadu. Information on socio-demographic characteristics like age, gender and education was captured using a pre-tested proforma. Diagnosis was done by treating Siddha practitioners as per reporting format. Data were single entered and analyzed using EpiData software. RESULTS: Of the total 1786 patients who attended the Siddha OPD, 1720 (96%) completed the interviews. Mean (Standard Deviation) age of participants was 41 (11) years and 913 (53%) were females; 20% had no formal education. Of 1720 participants, arthritis (21%), neuritis (10%), fungal diseases (7%) were the top three morbidities, with arthritis and neuritis being most common morbidities in both males and females. CONCLUSION: Arthritis, neuritis and fungal diseases were the most common morbidities, for which patients sought care in Siddha hospitals. These morbidities can be considered for preparing standard treatment guidelines under the national programme. PMID- 30309743 TI - Titanium clasp fabricated by selective laser melting, CNC milling, and conventional casting: a comparative in vitro in vitro study. AB - PURPOSE: This study aimed to investigate the effects of selective laser melting (SLM), milling methods, and casting on the behavior of titanium clasp. METHODS: The clasp and its die simulating the molar were designed using 3D software. Clasp specimens were fabricated using SLM approaches (SLM Ti) and computerized numerical control (CNC) milling technology (Milling CPTi). Cast clasps of the same forms were also prepared as controls using titanium alloy powder (Cast Ti) and commercial pure titanium (Cast CPTi), following the conventional casting methods. The surface roughness and accuracy of clasps were analyzed. The changes in retentive force and permanent deformation were measured up to 10,000 insertion/removal cycles. One-way analysis of variance and Tukey's test or Kruskal-Wallis H test were performed for data analysis and comparisons. RESULTS: The Milling CPTi clasps had a smoother inner surface than the other groups (p<0.05). The accuracy of the inner surface showed no significant difference among the groups, whereas that of the outer surface showed significant differences (p<0.05). The SLM Ti clasp had significantly higher retentive forces than the other groups (p<0.05), but it rapidly reduced after 2000 insertion/removal cycles until the fracture of all specimens was at 4000 cycles. The Milling CPTi clasps had more permanent deformation, but the rate of reduction of retentive force was only 9.5% (at 10,000 cycles). CONCLUSIONS: Milling has the potential to replace casting for fabricating removable partial denture (RPD) titanium clasps. However, SLM should be further improved for fabricating RPD titanium clasps before clinical application. PMID- 30309744 TI - A single dose of African horse sickness virus (AHSV) VP2 based vaccines provides complete clinical protection in a mouse model. AB - African horse sickness is a severe, often fatal, arboviral disease of equids. The control of African horse sickness virus (AHSV) in endemic countries is based currently on the use of live attenuated vaccines despite some biosafety concerns derived from its biological properties. Thus, experimental vaccination platforms have been developed over the years in order to avoid the biosafety concerns associated with the use of attenuated vaccines. Various studies showed that baculovirus-expressed AHSV-VP2 or modified Vaccinia Ankara virus expressing AHSV VP2 (MVA-VP2) induced virus neutralising antibodies and protective immunity in small animals and horses. AHSV is an antigenically diverse pathogen and immunity against AHS is serotype-specific. Therefore, AHS vaccines for use in endemic countries need to induce an immune response capable of protecting against all existing serotypes. For this reason, current live attenuated vaccines are administered as polyvalent preparations comprising combinations of AHSV attenuated strains of different serotypes. Previous studies have shown that it is possible to induce cross-reactive virus neutralising antibodies against different serotypes of AHSV by using polyvalent vaccines comprising combinations of either different serotype-specific VP2 proteins, or MVA-VP2 viruses. However, these strategies could be difficult to implement if induction of protective immunity is highly dependent on using a two-dose vaccination regime for each serotype the vaccine intends to protect against. In our study, we have tested the protective capacity of MVA-VP2 and baculovirus-expressed VP2 vaccines when a single dose was used. Groups of interferon alpha receptor knock-out mice were inoculated with either MVA-VP2 or baculovirus-expressed VP2 vaccines using one dose or the standard two-dose vaccination regime. After vaccination, all four vaccinated groups were challenged with AHSV and clinical responses, lethality and viraemia compared between the groups. Our results show that complete clinical protection was achieved after a single vaccination with either MVA-VP2 or baculovirus sub unit VP2 vaccines. PMID- 30309745 TI - Herpes zoster in the context of varicella vaccination - An equation with several variables. AB - BACKGROUND: Varicella and herpes zoster (HZ), diseases both caused by the varicella zoster virus (VZV), are vaccine-preventable. However, the hypothesis that childhood varicella vaccination may increase the incidence of HZ hinders varicella universal routine vaccination (URV) implementation in many countries. METHODS: This non-systematic and narrative review of the literature considers the burden of varicella and HZ, and the effectiveness of the respective vaccines. We present the factors involved in the interplay between varicella vaccination and HZ incidence, including the roles of exogenous and endogenous boosting. We review HZ incidence model predictions, and compare these with real-world evidence, which has accumulated since varicella URV was introduced. CONCLUSION: Although more research and longer surveillance are needed, available real-world evidence has not confirmed the model-predicted increase in HZ incidence, associated with childhood varicella URV. Although there is a rising incidence of HZ globally, this trend appears to be predominantly the result of an aging population. Vaccination against varicella in childhood provides significant benefits with respect to the medical, societal and economic burdens of the disease. Therefore, a theoretical concern of an increased burden of HZ with varicella vaccination programs should not prevent children from being protected against the disease. PMID- 30309746 TI - The need to improve access to rabies post-exposure vaccines: Lessons from Tanzania. AB - BACKGROUND: Rabies is preventable through prompt administration of post-exposure prophylaxis (PEP) to exposed persons, but PEP access is limited in many rabies endemic countries. We investigated how access to PEP can be improved to better prevent human rabies. METHODS: Using data from different settings in Tanzania, including contact tracing (2,367 probable rabies exposures identified) and large scale mobile phone-based surveillance (24,999 patient records), we estimated the incidence of rabies exposures and bite-injuries, and examined health seeking and health outcomes in relation to PEP access. We used surveys and qualitative interviews with stakeholders within the health system to further characterise PEP supply and triangulate these findings. RESULTS: Incidence of bite-injury patients was related to dog population sizes, with higher incidence in districts with lower human:dog ratios and urban centres. A substantial percentage (25%) of probable rabies exposures did not seek care due to costs and limited appreciation of risk. Upon seeking care a further 15% of probable rabies exposed persons did not obtain PEP due to shortages, cost barriers or misadvice. Of those that initiated PEP, 46% did not complete the course. If no PEP was administered, the risk of developing rabies following a probable rabies exposure was high (0.165), with bites to the head carrying most risk. Decentralized and free PEP increased the probability that patients received PEP and reduced delays in initiating PEP. No major difficulties were encountered by health workers whilst switching to dose sparing ID administration of PEP. Health infrastructure also includes sufficient cold chain capacity to support improved PEP provision. However, high costs to governments and patients currently limits the supply chain and PEP access. The cost barrier was exacerbated by decentralization of budgets, with priority given to purchase of cheaper medicines for other conditions. Reactive procurement resulted in limited and unresponsive PEP supply, increasing costs and risks to bite victims. CONCLUSION: PEP access could be improved and rabies deaths reduced through ring-fenced procurement, switching to dose-sparing ID regimens and free provision of PEP. PMID- 30309747 TI - Can CRP velocity in right iliac fossa pain identify patients for intervention? A prospective observational cohort study. AB - INTRODUCTION: Previous studies have shown single CRP measurements at time of presentation to have limited predictive benefit for appendicitis. Our objective was to determine the diagnostic utility of serial CRP measurements (to determine CRP velocity [CRPv]) in patients with right iliac fossa (RIF) pain. METHODS: A single-centre prospective observational study was conducted on adult patients admitted with RIF pain. CRP was measured on admission, at midnight, and the following morning. Appendicitis was diagnosed on histopathology, or diagnostic imaging in non-operatively managed patients. Therapeutic interventions included all appropriate operative procedures and effective non-operative treatment with antibiotics. Logistic regression was used to generate predictors of therapeutic intervention, and then used to create a new risk score incorporating CRPv. RESULTS: 98 of 112 (87.5%) participants had complete CRP data. 58 patients met the criteria for appendicitis (59.2%). Most patients presented with intermediate Modified Alvarado Scores (MAS) 5-6 (40.8%) or Appendicitis Inflammatory Response Scores (AIRS) 5-8 (49%). Our risk score had an AUROC of 0.88 (95% CI 0.81-0.96) in predicting therapeutic intervention. This score was superior to MAS, AIRS, and single admission biomarker measurements. Patients with an increasing CRPv had 14 times the odds (OR 14.07, 95% CI 0.63-315.2) of complicated appendicitis, and no cases of complicated appendicitis were observed in patients with a flat CRPv. CONCLUSIONS: CRP velocity is superior to single CRP at predicting intervention. Our v-Score shows promise as a decision making-aide by predicting the need for surgical intervention in RIF pain. A flat CRPv identifies a group of patients with a very low risk of complicated appendicitis. PMID- 30309748 TI - Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound. AB - The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage. PMID- 30309749 TI - Reliability of Sonoelastography in Ductal Carcinoma. AB - The objective of the study was to evaluate the reliability of sonoelastography in ductal carcinoma in patients in primary and secondary health care settings. Google Scholar, PubMed, Medline, Medscape, Wikipedia and NCBI were searched in January 2018 for all original research and review articles to identify relevant studies. Two reviewers selected the articles independently for based on the title and abstract. The selection criteria were sonoelastography accuracy for diagnosing ductal carcinoma as index text, B-mode sonography, and micropure imaging; surgery and histologic findings were used as reference text; and benign and malignant breast abnormalities and ductal carcinoma were used as target conditions. Two reviewers extracted the data on selected study characteristics, and the results were used to construct the tables and figures. Fifteen studies on ductal carcinoma were found. The overall sensitivity of sonoelastography in diagnosing ductal carcinoma was 85.7%, and the specificity, 79.8%. On the basis of the literature review, it was concluded that sonoelastography has high sensitivity and specificity in diagnosing ductal carcinoma. PMID- 30309750 TI - A rare cause of hematochezia after colonoscopy. PMID- 30309751 TI - The risk of Parkinson's disease in inflammatory bowel disease: A systematic review and meta-analysis. AB - BACKGROUND: Several studies have reported an increased prevalence of Parkinson disease (PD) amongst patients with inflammatory bowel disease (IBD) with conflicting results. We aimed to evaluate the risk of PD in the IBD population by conducting a meta-analysis (MA). METHODS: A systematic review with MA of the existing literature was conducted. The main outcome of interest was the incidence of developing PD in patients previously diagnosed with IBD. RESULTS: Four studies were included in this MA. The overall risk of PD in IBD was significantly higher than controls (RR 1.41, 95% c.i. 1.19-1.66). Crohn's disease had a 28% increased risk of PD and ulcerative colitis had a 30% increased risk of PD compared to controls (CD: RR 1.28, 95% c.i. 1.08-1.52, UC: RR 1.30, 95% c.i. 1.15-1.47). CONCLUSION: The MA detected an increased risk of PD in the IBD population and CD/UC subgroup. These results merit further clinical validation in future studies. PMID- 30309752 TI - A stochastic epigenetic Mendelian oligogenic disease model for type 1 diabetes. AB - The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high-to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes. PMID- 30309753 TI - Females are dying more than males by suicide in Bangladesh. PMID- 30309754 TI - Rhythms of the Genome: Circadian Dynamics from Chromatin Topology, Tissue Specific Gene Expression, to Behavior. AB - Circadian rhythms in physiology and behavior evolved to resonate with daily cycles in the external environment. In mammals, organs orchestrate temporal physiology over the 24-h day, which requires extensive gene expression rhythms targeted to the right tissue. Although a core set of gene products oscillates across virtually all cell types, gene expression profiling across tissues over the 24-h day showed that rhythmic gene expression programs are tissue specific. We highlight recent progress in uncovering how the circadian clock interweaves with tissue-specific gene regulatory networks involving functions such as xenobiotic metabolism, glucose homeostasis, and sleep. This progress hinges on not only comprehensive experimental approaches but also computational methods for multivariate analysis of periodic functional genomics data. We emphasize dynamic chromatin interactions as a novel regulatory layer underlying circadian gene transcription, core clock functions, and ultimately behavior. Finally, we discuss perspectives on extending the knowledge of the circadian clock in animals to human chronobiology. PMID- 30309755 TI - Tumescence Anesthesia Solution-Assisted Laser Ablation Treatment of Lower Limb Varicose Veins: The Effect of Temperature of the Tumescence Anesthesia Solution on Intraoperative and Postoperative Pain, Clinical Observations, and Comprehensive Nursing Care. AB - PURPOSE: To investigate the effect of cold and room temperature tumescence anesthesia solution (TAS) on the treatment of lower limb varicose veins via endovenous laser ablation. DESIGN: On the basis of the TAS temperature, patients were divided into two groups: group A (n = 26) received room temperature (24 degrees C) TAS, and group B (n = 25) received cold (4 degrees C) TAS. METHODS: A numerical rating scale was used to evaluate pain. Perioperative and intraoperative nursing care and clinical observations were performed following a generalized standard. FINDINGS: Percentages of patients who felt pain in groups A and B were 69.2% and 36.0%. Average numerical rating scale scores of patients in the two groups (A and B) on the day of surgery and on postoperative days 1, 2, and 3 were 4.3 versus 2.1, 3.5 versus 1.0, 3.0 versus 0.8, and 1.6 versus 0.3, respectively. CONCLUSIONS: Cold TAS reduces intraoperative and postoperative pain more effectively than room temperature. PMID- 30309756 TI - Multidisciplinary palliative care at the end of life of critically ill patient. PMID- 30309757 TI - Personalised approach in follicular lymphoma. PMID- 30309759 TI - Coconut oil protects against light-induced retina degeneration in male Wistar rats. AB - The retinoprotective effect of Cocos nucifera oil (CNO) was investigated. Twenty male Wistar rats weighing 140 g and 180 g were randomly divided into four groups comprising of five animals each. The control group received distilled water. Retinal degeneration was induced in the remaining three groups by exposing the animals to 5,000 lux of bright white light for two hours. Prior to the light exposure, the light model group (LMG) received distilled water for 14 days, low Cocos nucifera oil (LCNO) group received 5 ml/kg of CNO for 14 days, and the high Cocos nucifera oil (HCNO) group received 10 ml/kg of CNO for 14 days. The treatments continued for 7 days after exposure to light. On the eight day, the animals were euthanised and their retinas isolated. The right retinas and occipital cortices of the animals were prepared for histological evaluation while the homogenates of the left retinas were used for biochemical assay. The results show that CNO significantly (p < 0.05) reduced caspase-3 activity from 1.15 +/- 0.054 ng/ml to 0.434 +/- 0.095 ng/ml (LMG versus LCNO) and malondialdehyde concentration. There was no significant difference in the total antioxidant capacity in the retinas of the rats. However, LMG showed a significant increase in catalase activity. CNO was able to preserve the retinal morphology while LMG showed a distorted retinal layer and significant reduction (p < 0.05) in retina thickness. CNO was unable to prevent perineural vacuolations in the occipital cortices of the rats. In conclusion, Cocos nucifera oil produced retino protective effect via anti-oxidative and anti-apoptotic mechanisms. PMID- 30309760 TI - Borderline hemoglobin A2 levels in northern Thai population: HBB genotypes and effects of coinherited alpha-thalassemia. AB - INTRODUCTION: Identification of beta-thalassemia carrier in prenatal screening relies on the elevated Hb A2 level. Borderline Hb A2 levels pose a diagnostic challenge. We determined the HBB genotypes in subjects with borderline Hb A2 in northern Thailand and studied the effects of coinherited alpha0-thalassemia on Hb A2 levels. METHODS: Blood samples with Hb A2 3.1-10.0% from 2193 samples submitted for prenatal thalassemia screening were selected. Information on HBB genotypes and coinherited alpha0-thalassemia were collected. All samples with unknown HBB genotypes underwent an automated DNA sequencing. The Hb A2 levels were compared according to the coinherited alpha0-thalassemia. RESULTS: HBB mutations were found in 298 (98.7%) of 302 samples with Hb A2 4.0-10.0%. In the 106 samples with Hb A2 3.1-3.9%, six had HBB mutations; four Hb Dhonburi [codon 126 (T > G)], one CAP site mutation [CAP + 1 (A > C)] and one beta0-thalassemia [codon 41/42 (-TTCT)] with a coinherited HBD mutation [nt-77 (T > C)]. The Hb A2 levels in beta-thalassemia carriers with and without coinherited alpha0 thalassemia were not significantly different. CONCLUSIONS: HBB mutations in northern Thais with borderline Hb A2 levels comprise an unstable variant Hb Dhonburi and CAP + 1 (A > C) mutation. Coinherited HBD mutation lowers Hb A2 and can cause a misidentification of a beta-thalassemia carrier. PMID- 30309761 TI - Autologous Stem-Cell Transplantation Outcomes for Relapsed Metastatic Germ-Cell Tumors in the Modern Era. AB - BACKGROUND: High-dose chemotherapy (HDCT) with autologous stem-cell transplantation (aSCT) has been a standard therapy for relapsed metastatic germ cell tumors (GCTs) over the last 2 decades, but there have been many changes in practice over time with respect to stem-cell source, mobilization, and conditioning regimens. Mobilization is impaired with greater cisplatin exposure. PATIENTS AND METHODS: Patients with relapsed GCT who received HDCT/aSCT at Dana Farber Cancer Institute between 1997 and 2017 were identified. Diagnosis, first line chemotherapy, stem-cell mobilization, HDCT, toxicity, and survival outcomes were annotated and descriptively summarized. Univariable associations of clinicopathologic features and relapse and survival were assessed. Time-to-event analyses were performed by HDCT type and duration. RESULTS: Thirty-five eligible patients were identified. The most common regimen before HDCT was paclitaxel, ifosfamide, and cisplatin, and it resulted in a high rate of successful initial mobilization (95%). Ten patients (29%) were mobilized with filgrastim and plerixafor (CXCR4 antagonist). All plerixafor-treated patients were mobilized with sufficient cells for 2 transplants. Oxazaphosphorine (cyclophosphamide or ifosfamide)-containing (O-C) HDCT was provided between 1997 and 2008, and subsequent patients were treated with high-dose carboplatin plus etoposide (CE). O-C HDCT was associated with excessive cardiac (33%), severe liver (93%), and renal dysfunction compared to CE. Two O-C-treated patients died of drug-related lung toxicity. Fifty-one percent of the cohort experienced relapse, and 46% died. CONCLUSION: Plerixafor has a role in stem-cell mobilization and aSCT for relapsed GCT when cisplatin in bridging before HDCT may be problematic. O-C and CE HDCT regimens have different toxicity patterns that are clinically meaningful. PMID- 30309762 TI - Moral attitudes and willingness to enhance and repair cognition with brain stimulation. AB - BACKGROUND: The availability of technological means to enhance and repair human cognitive function raises questions about the perceived morality of their use. However, we have limited knowledge about the public's intuitive attitudes toward uses of brain stimulation. Studies that enlighten us about the public's willingness to endorse specific uses of brain stimulation on themselves and others could provide a basis to understand the moral psychology guiding intuitions about neuromodulation and opportunities to inform public education and public policy. OBJECTIVE: Hypothesis: We expected that subjects would be less willing to enhance or repair cognitive functions perceived as more "core" to "authentic" self-identity, prioritize brain stimulation uses for themselves, and more willing to enhance "core" functions in others. Across specific hypothetical uses, we expected the moral acceptability of specific uses to be associated with subjects' willingness to endorse them. METHODS: We administered two surveys to the public in which subjects were asked to report how willing they would be to enhance or repair specific cognitive abilities using a hypothetical brain stimulation device called "Ceremode". RESULTS: Among 894 subjects, we found that subjects were more willing to use technologies to repair other people than themselves. They were most inclined to repair core functions in others. Subjects' ratings of the moral acceptability of specific uses was related to their reported willingness to use brain stimulation. CONCLUSION: Moral acceptability is related to the public's willingness to use brain stimulation. These findings suggest that the public endorses a generous approach to applying brain stimulation for cognitive gains in others. Further, this study establishes a basis to guide moral psychological studies of cognitive modification and social processes that guide attitudes toward and uses of brain stimulation. PMID- 30309763 TI - Electric Field-Induced Release and Measurement Liquid Biopsy for Noninvasive Early Lung Cancer Assessment. AB - Previously, we detected circulating tumor DNA that contained two EGFR mutations (p.L858R and exon19 del) in plasma of patients with late-stage non-small-cell lung carcinoma (NSCLC) using the electric field-induced release and measurement (EFIRM) platform. Our aim was to determine whether EFIRM technology can detect these mutations in patients with early-stage NSCLC. Prospectively, 248 patients with radiographically determined pulmonary nodules were recruited. Plasma was collected before biopsy and histologic examination of the nodule. Inclusion criteria were histologic diagnosis of benign nodule (control) and stage I or II adenocarcinoma harboring either p.L858R or exon19 delEGFR mutations. Plasma samples were available from 44 patients: 23 with biopsy-proven benign pulmonary nodules and 21 with stage I or II adenocarcinoma (12 p.L858R and 9 exon19 delEGFR variants). Samples were analyzed for the EGFR mutations using the EFIRM platform. Assay sensitivity was 92% for p.L858R (11 of 12 samples positive) and 77% for exon19 del (7 of 9 samples positive). Specificity was 91% with two false-positive results in 23 patients with EGFR-positive nodules and 95% for the entire 44 patient series. Concordance was 100% with identical mutations discovered in plasma and nodule biopsy. The EFIRM platform is able to noninvasively detect two EGFR mutations in individuals with early-stage NSCLC. PMID- 30309764 TI - Coronary CTA enhanced with CTA based FFR analysis provides higher diagnostic value than invasive coronary angiography in patients with intermediate coronary stenosis. AB - BACKGROUND: CTA based FFR, a software based application, enhances diagnostic value of coronary computed tomography angiography (CTA) examination. However it remains unknown whether it improves accuracy over the gold standard of invasive coronary angiography (ICA) in predicting functionally significant coronary stenosis. The aim of our study was to compare diagnostic accuracies of coronary CTA, CTA based FFR, and ICA, with invasive FFR as the reference standard in patients with intermediate stenosis on CTA. METHODS: 96 intermediate stenoses (50 90%) from 90 subjects, with intermediate pre-test probability of CAD, who underwent coronary CTA were analyzed. Each patient had subsequent ICA with FFR. CTA based FFR (cFFR v2.1, Siemens) analysis was performed on-site. The stenoses with invasive FFR<=0.8 were considered hemodynamically significant. RESULTS: 41/96 stenoses were hemodynamically significant (FFR<=0.8). While the area under ROC curves (AUC) for identification of significant stenosis evaluated on QCA (0.653), visual ICA (0.652), qCTA (0.690) and visual CTA (0.660) did not significantly differ, the AUC for CTA based FFR (0.835) was significantly higher (p = 0.004, p = 0.004, p = 0.010, p = 0.007, respectively). The accuracies of CTA based FFR, qCTA and QCA were 76%, 63% and 58% respectively. CONCLUSION: Our results suggest that diagnostic potential of routine coronary CTA, augmented with CTA based FFR analysis, is superior to ICA in patients with intermediate stenosis. PMID- 30309758 TI - Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial. AB - BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter >=7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21 day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65.5% [95% CI 61.6-69.4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75.6% [95% CI 72.0-79.0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43.3 months of observation (IQR 36.2-51.8), 2.5-year progression-free survival from end of induction was 87.8% (95% CI 83.9-90.8) in PET complete responders and 72.0% (63.1-79.0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0.4, 95% CI 0.3-0.6, p<0.0001). According to Lugano 2014 criteria, 2.5-year progression-free survival in complete metabolic responders was 87.4% (95% CI 83.7-90.2) and in non-complete metabolic responders was 54.9% (40.5-67.3; HR 0.2, 95% CI 0.1-0.3, p<0.0001). INTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. FUNDING: F Hoffmann-La Roche. PMID- 30309765 TI - Feasibility of dynamic myocardial CT perfusion using single-source 64-row CT. AB - BACKGROUND: Dynamic myocardial computed tomography perfusion (CTP) is an emerging technique to diagnose significant coronary stenosis. However, this procedure has not been reported using single-source 64-row CT. OBJECTIVE: To investigate the radiation dose and the diagnostic performance of dynamic CTP to diagnose significant stenosis by catheter exam. METHODS: We prospectively included 165 patients who underwent CTP exam under adenosine stress using a single-source 64 row CT. MBF was calculated using the deconvolution technique. Quantitative perfusion ratio (QPR) was defined as the myocardial blood flow (MBF) of the myocardium with coronary stenosis divided by the MBF of the myocardium without significant stenosis or infarct. Of the 44 patients who underwent subsequent coronary angiography, we assessed the diagnostic performance to diagnose >=50% stenosis by quantitative coronary analysis (QCA). RESULTS: The average effective dose of dynamic CTP and the entire scans were 2.5 +/- 0.7 and 7.3 +/- 1.8 mSv, respectively. The MBF of the myocardium without significant stenosis was 1.20 +/- 0.32 ml/min/g, which significantly decreased to 0.98 +/- 0.24 ml/min/g (p < 0.01) in the area with >=50% stenosis by CT angiography. The QPR of the myocardium with QCA >=50% stenosis was significantly lower than 1 (0.84 +/- 0.32, 95% confidence interval (CI), 0.77-0.90, p < 0.001). The accuracy to detect QCA >=50% stenosis was 82% (95%CI, 74-88%) using CT angiography alone and significantly increased to 87% (95%CI, 80-92%, p < 0.05) including QPR. CONCLUSION: Dynamic myocardial CTP could be performed using 64-row CT with a low radiation dose and would improve the diagnostic performance to detect QCA >=50% stenosis than CT angiography alone. PMID- 30309767 TI - Bipolar Ablation Delivered Between the Pulmonary and Aortic Valve Cusps. PMID- 30309768 TI - Early morbidity and mortality after single-stage bilateral total knee replacement. AB - INTRODUCTION: Single-stage bilateral total knee replacement (TKR) has the advantages of requiring only one hospital stay and one anesthesia session, having a shorter rehabilitation period, and reducing the cost of patient care. However, this strategy is controversial because of the perioperative risk. We hypothesized that this strategy did not cause early perioperative mortality and that the early morbidity and readmission rates would be low when patients are selected based on their ASA score. METHODS: This single-center retrospective study analyzed a cohort of ASA-1 and ASA-2 patients who underwent single-stage bilateral TKR over an 8-year period (2009 to 2016). The study cohort consisted of 116 patients, mainly women with mean age of 69 years at inclusion; 22.4% of patients were ASA-1 and 77.6% were ASA-2. Death and early complications during the first 90 days postoperative, the early readmission rate and the blood-sparing strategy were analyzed using the clinical and paraclinical data collected during the hospital stay, during the convalescent care center stay, and during the follow-up visits at 6 weeks and 3 months postoperative. The analysis was completed using the intrahospital software Clinicom, which allowed us to trace all the events and episodes for each patient. RESULTS: The early mortality rate was 0%. There were five major complications (4.3%) and thirteen minor complications (11%). The early readmission rate was 5.2%. Homologous blood transfusion was performed in 36% of patients. Administration of tranexamic acid reduced this rate to 24.3% versus 44% in patients not taking it (p=0.06). CONCLUSION: The perioperative mortality in this selected population is zero and the early morbidity is acceptable. The early readmission rate is also low. Thus proposing single-stage bilateral TKR to patients meeting the criteria defined in this study is a valid strategy. LEVEL OF EVIDENCE: IV, retrospective cohort study. PMID- 30309769 TI - Can Listeners Hear Who Is Singing? The Role of Listener Experience in Singer Discrimination Across Pitch. AB - OBJECTIVE/HYPOTHESIS: Previous research has shown that listeners are unable to identify who is singing across pitch when the voices are unfamiliar to them. Implementing a very short training period, however, greatly improves this ability, but only when the voices being compared are of different voice category. The objective of this study was to determine whether experienced listeners with highly developed knowledge of voice categories can more easily discriminate between singers across pitch. METHODS/DESIGN: This study used an ABX paradigm where listeners heard two different singers singing "ah" at the same pitch. Listeners identified which of the two singers produced a third "ah" at a different pitch. Stimuli were recorded from two baritones, two tenors, two mezzo sopranos, and two sopranos across a 1.5 octave range. Data were collected from 42 inexperienced listeners and 27 experienced listeners. RESULTS: Experienced listeners were better at singer discrimination across pitch than were inexperienced listeners for all conditions except same-category comparisons at the interval of the third. Experienced listeners were better at singer discrimination across pitch than were slightly trained listeners for all conditions except same-category female singers at all pitch intervals. CONCLUSIONS: The ability to discriminate singers across pitch is the greatest for experienced listeners, followed by slightly trained inexperienced listeners, followed by inexperienced listeners. PMID- 30309766 TI - The addition of chemotherapy in the definitive management of high risk prostate cancer. AB - In attempt to improve long-term disease control outcomes for high-risk prostate cancer, numerous clinical trials have tested the addition of chemotherapy (CTX) either adjuvant or neoadjuvant-to definitive local therapy, either radical prostatectomy (RP) or radiation therapy (RT). Neoadjuvant trials generally confirm safety, feasibility, and pre-RP PSA reduction, but rates of pathologic complete response are rare, and no indications for neoadjuvant CTX have been firmly established. Adjuvant regimens have included CTX alone or in combination with androgen deprivation therapy (ADT). Here we provide a review of the relevant literature, and also quantify utilization of CTX in the definitive management of localized high-risk prostate cancer by querying the National Cancer Data Base. Between 2004 and 2013, 177 patients (of 29,659 total) treated with definitive RT, and 995 (of 367,570 total) treated with RP had CTX incorporated into their treatment regimens. Low numbers of RT + CTX patients precluded further analysis of this population, but we investigated the impact of CTX on overall survival (OS) for patients treated with RP +/- CTX. Disease-free survival or biochemical recurrence-free survival are not available through the National Cancer Data Base. Propensity-score matching was conducted as patients treated with CTX were a higher-risk group. For nonmatched groups, OS at 5-years was 89.6% for the CTX group vs. 95.6%, for the no-CTX group (P < 0.01). The difference in OS between CTX and no-CTX groups did not persist after propensity-score matching, with 5 year OS 89.6% vs. 90.9%, respectively (Hazard ratio 0.99; P = 0.88). In summary, CTX was not shown to improve OS in this retrospective study. Multimodal regimens such as RP followed by ADT, RT, and CTX; or RT in conjunction with ADT followed by CTX-have shown promise, but long-term follow-up of randomized data is required. PMID- 30309770 TI - Outcomes of Intubation-induced Vocal Fold Motion Impairment. AB - OBJECTIVE: Vocal fold motion impairment (VFMI) is a potential consequence of intubation. Studies describing the natural course of this complication are largely case reports. This study aims to evaluate outcomes for a cohort of patients who endured varying degrees of vocal fold immobility or hypomobility post-intubation. STUDY DESIGN: Retrospective chart review. METHODS: Upon excluding known causes of VFMI, such as surgeries and tumors involving the head and neck, VFMI cases (ICD-9 diagnosis code 478.3) were identified from 2008 to 2014 at a regional healthcare institution. A total of 2,387 were identified and of those, 25 were intubation-induced VFMI cases. This cohort was then examined for notable features. RESULTS: With a mean prolonged intubation duration of 6.55 days, 68% of cases resulted in left unilateral, 8% right unilateral, and 24% bilateral VFMI. Overall, 80% of patients experienced a recovery outcome (voice improvement or restoration of vocal fold mobility). Median recovery time was 4.31 months (mean, 6.51 months; range, 19-715 days). In cases of unilateral VFMI, 95% of cases had a recovery outcome. In cases of bilateral VFMI, 33% of cases had a recovery outcome. Additionally, bilateral cases showed a statistically significant association with an approximately 36-fold lower odds of recovery than unilateral cases (odds ratio, 0.0278; 95% confidence interval, 0.0020-0.3868; P value, 0.0077). CONCLUSIONS: Intubation-induced VFMI is rare. In this cohort, most cases resulted from prolonged intubation. While spontaneous recovery was the most common outcome, full remission was not guaranteed in every case. A sizable proportion of cases revealed bilateral motion impairment which was less likely to resolve. Our results are informative for tracheostomy decision-making and differential diagnoses for post-intubation laryngeal symptomatology. PMID- 30309771 TI - The Effects of Age and Gender on Laryngeal Aerodynamics in the Children Population. AB - OBJECTIVES: Normal voice can be differentiated from dysphonic voices by comparing their characteristics using an established normative database. Pediatric normative data using the Phonatory Aerodynamic System (PAS) have been established in a preliminary study for English-speaking children. However, aerodynamic measures, including physical characteristics varying by geographic region, race, and culture, must be investigated between children with different native languages. Aerodynamic analysis of connected speech requires the collection of language-specific samples and the establishment of language-specific norms. Thus, the main purpose of the present study was to establish pediatric normative data using the PAS for a large pediatric population of healthy Turkish-speaking children of 4-17.11years of age. Another research aim was to determine age dependent and/or gender-dependent aerodynamic parameters for this pediatric population. METHODS: In total, 120 children were divided into four age groups: Group I, 4-5.11 years; Group II, 6-9.11 years; Group III, 10-13.11 years; and Group IV, 14-17.11years. An equal number of male and female participants were assigned to each group. The PENTAX Medical PAS Model 6600 was used. Descriptive statistics for 56 parameters across six protocols were expressed as mean, standard deviation, and range values. Each protocol was analyzed for age, gender, and age-gender interaction. RESULTS: Age was the most predominant factor, affecting 37 of the 56 aerodynamic parameters investigated. Gender and age-gender factors were observed at an equal frequency, each affecting 16 parameters. Pitch related parameters were the most altered parameters in each protocol. Age-gender interaction was observed in parameters related to the expiratory airflow. CONCLUSIONS: This study established the normative values of phonatoary aerodynamics for a large pediatric population with a wide age range and developed a normative database for healthy Turkish-speaking children. This is the first study to investigate running speech protocol in aerodynamic assessment. PMID- 30309772 TI - Accuracy of SS-OCT biometry compared with partial coherence interferometry biometry for combined phacovitrectomy with internal limiting membrane peeling. AB - PURPOSE: To evaluate the accuracy of a swept-source optical coherence tomography (SS-OCT) biometer compared with a standard partial coherence interferometry (PCI) biometer in terms of phacovitrectomy for vitreomacular pathology and cataract. SETTING: Department of Ophthalmology, Ludwig-Maximilians-University Munich, Germany. DESIGN: Prospective, nonrandomized, single center consecutive case series. METHODS: Patients with age-related cataract, regular corneal astigmatism less than 1.25 diopters (D) and a clinically significant vitreomacular pathology (epiretinal membrane [ERM], macular hole, or vitreomacular traction [VMT] syndrome) who had combined phacovitrectomy with internal limiting membrane peeling were enrolled. Objective and manifest refraction, corrected distance visual acuity, SS-OCT biometry, and PCI biometry were obtained preoperatively and 3 months postoperatively. The refractive prediction error and mean absolute error (MAE) were calculated for each biometric device with the Haigis formula. The percentage of eyes with a prediction error within +/-0.50 D or less were calculated. RESULTS: The study comprised 79 eyes of 79 patients. The mean refractive prediction error of all eyes was -0.27 D +/- 0.76 (SD) for the PCI biometer and -0.28 +/- 0.57 D for the SS-OCT biometer (P = .802), and the MAE was 0.61 +/- 0.53 D and 0.46 +/- 0.43 D, respectively (P = .012). A prediction error within +/-0.50 D or less was observed in 55 eyes (70%) with the SS-OCT biometer compared with 42 eyes (53%) with the PCI biometer (P = .0001). The MAE with the SS-OCT biometer was statistically significantly lower in eyes with ERMs or macular holes compared with the PCI biometer (P = .043 and P = .028, respectively), whereas no statistically significant difference was observed in eyes with VMT syndrome (P = .286). CONCLUSIONS: The SS-OCT biometer showed a statistically significant lower MAE compared with the PCI biometer, and it is recommended for precise intraocular lens power calculations in combined phacovitrectomy for cataract and vitreomacular diseases. PMID- 30309773 TI - Electron microscopy of silicone irrigation/aspiration tips involved in posterior capsule rupture. AB - We describe 2 cases of posterior capsule rupture caused by Alcon reusable silicone irrigation/aspiration (I/A) tips. Scanning electron microscopy and reflected light microscopy of these tips revealed burring of the inner metallic shafts and tears in the silicone sleeves. A review of surgical video revealed that posterior capsule ruptures caused by the I/A tips occurred when the posterior capsule was aspirated either through the aspiration port or through a tear in the silicone sleeve. Contact of the posterior capsule with the sharp metallic burrs on the inner metal tube can result in posterior capsule rupture. PMID- 30309774 TI - Assessment of subjective refraction with a clinical adaptive optics visual simulator. AB - PURPOSE: To clinically validate an adaptive optics visual simulator (VAO) that measures subjective refraction and visual acuity. SETTING: Optics Laboratory, University of Murcia, Murcia, Spain. DESIGN: Prospective case series. METHODS: Using the adaptive optics visual simulator, 2 examiners measured the subjective refraction and visual acuity in healthy eyes of volunteers; 1 examiner also used a trial frame as a gold standard. The interexaminer reproducibility and agreement with the gold standard were estimated using the following statistical parameters: limits of agreement from Bland-Altman analysis, significance between differences (P value), and intraclass correlation coefficient (ICC). RESULTS: Seventy-six eyes of 38 volunteers were measured. Interexaminer reproducibility for subjective refraction was excellent (ICC >=0.96; P > .05), with low 95% confidence interval (CI) values for the power vectors M (spherical equivalent of the given refractive error), J0 (Jackson cross-cylinder, axes at 180 degrees and 90 degrees), and J45 (Jackson cross-cylinder, axes at 45 degrees and 135 degrees) (+/-0.51 diopter [D], +/-0.14 D, and +/-0.14 D, respectively). No significant differences in subjective refraction and visual acuity were found between the visual simulator and gold standard (P > .05), with 95% CIs for M, J0, and J45 (subjective refraction) of +/-0.67 D, +/-0.14 D, and +/-0.16 D, respectively, and a +/-0.10 logarithm of the minimum angle of resolution (visual acuity). CONCLUSION: Subjective refraction results using the adaptive optics visual simulator agreed with those of the gold standard and can be used as the baseline for visual simulation of any optical corneal profile or intraocular lens design for refractive surgery patients. PMID- 30309775 TI - Evaluation of crystalline lens and intraocular lens tilt using a swept-source optical coherence tomography biometer. AB - PURPOSE: To evaluate crystalline lens and intraocular lens (IOL) tilt using a swept-source optical coherence tomography (SS-OCT) biometer (IOLMaster 700). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. DESIGN: Retrospective case series. METHODS: The study patients were evaluated for 1) repeatability of the crystalline lens tilt measurement, 2) preoperative crystalline lens and postoperative IOL tilt in right eyes, 3) mirror symmetry between right eyes and left eyes, 4) the correlation between preoperative crystalline lens and postoperative IOL tilt, and 5) the correlation between the magnitude of lens tilt and ocular parameters. RESULTS: The study comprised 333 patients. The repeatability was 0.1 degrees for tilt magnitude and 3.0 degrees for tilt direction. Both the crystalline lens and IOL had anterior tilt of the nasal portion with mean tilt magnitudes of 3.7 degrees +/- 1.1 (SD) (range 0.4 to 6.9 degrees) for the crystalline lens and 4.9 +/- 1.8 degrees (range 1.6 to 10.7 degrees) for the IOL. There was mirror symmetry between right eyes and left eyes. The mean IOL tilt magnitude exceeded crystalline lens tilt by 1.2 +/- 1.1 degrees (range -3.2 to 4.0 degrees), and the 2 values were significantly correlated (all P < .01). The magnitude of crystalline lens tilt significantly increased with decreasing axial length and with increasing angle alpha (all P < .05). CONCLUSIONS: The repeatability of crystalline lens tilt measurements using the SS OCT biometer was excellent. There was mirror symmetry between the right eyes and left eyes. Preoperative crystalline lens tilt could be used to predict the postoperative IOL tilt. The lens tilt magnitude was greater in short eyes and in eyes with larger angle alpha. PMID- 30309777 TI - Adjuvant Therapy in Patients With Completely Resected Non-small-cell Lung Cancer: Current Status and Perspectives. AB - Patients with early-stage non-small-cell lung cancer undergo surgery with curative intent. Many of these patients relapse and, therefore, adjuvant therapies are important for improving survival of these patients. Adjuvant chemotherapy has been established and increases the 5-year survival rate. Here, we discuss systemic treatment strategies for further improving outcome of patients with completely resected non-small-cell lung cancer. PMID- 30309776 TI - Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity. AB - OBJECTIVE: Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS: Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. RESULTS AND CONCLUSIONS: Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity. PMID- 30309779 TI - Letter to the editor on: Bariatric surgery improves the employment rate in people with obesity: 2-year analysis. PMID- 30309778 TI - Large series examining laparoscopic adjustable gastric banding as a salvage solution for failed gastric bypass. AB - BACKGROUND: The Roux-en-Y gastric bypass (RYGB) has long been considered the gold standard of weight loss procedures. However, there is limited evidence on revisional options with both minimal risk and long-term weight loss results. OBJECTIVE: To examine percent excess weight loss, change in body mass index (BMI), and complications in patients who underwent laparoscopic adjustable gastric banding (LAGB) over prior RYGB. SETTING: Academic hospital. METHODS: Retrospective analysis of a single-center prospectively maintained database. Three thousand ninety-four LAGB placements were reviewed; 139 were placed in patients with prior RYGB. RESULTS: At the time of LAGB, the median BMI was 41.3. After LAGB, we observed weight loss or stabilization in 135 patients (97%). The median maximal weight loss after LAGB was 37.7% excess weight loss and -7.1 change in BMI (P < .0001). At last follow-up visit, the median weight loss was 27.5% excess weight loss and -5.3 change in BMI (P < .0001). Median follow-up was 2.48 years (.01-11.48): 68 of 132 eligible (52%) with 3-year follow-up, 12 of 26 eligible (44%) with 6-year eligible follow-up, and 3 of 3 eligible (100%) with >10-year follow-up. Eleven bands required removal, 4 for erosion, 4 for dysphagia, and 3 for nonband-related issues. CONCLUSIONS: LAGB over prior RYGB is a safe operation, which reduces the surgical risks and nutritional deficiencies often seen in other accepted revisional operations. Complication rates were consistent with primary LAGB. Weight loss is both reliable and lasting, and it can be considered as the initial salvage procedure in patients with failed gastric bypass surgery. PMID- 30309780 TI - Trans-fatty Acids and Survival in Renal Transplantation. AB - OBJECTIVE: High consumption of trans-fatty acids (TFAs) is associated with increased mortality. DESIGN AND METHODS: Observational cohort study of 1.988 Norwegian renal transplant recipients with a median follow-up time of 9.6 years. We assessed multivariable adjusted associations between plasma levels of industrial and ruminant TFAs with patient and graft survival. Plasma phospholipid fatty acid levels were determined by gas chromatography at 10 weeks after transplantation. RESULTS: During follow-up, there were 595 deaths, and 805 grafts were lost. Plasma industrial TFA levels dropped from 0.3 wt% in years 1999-2004 to reach a plateau of 0.2 wt% from year 2005 and beyond, whereas plasma levels of ruminant TFAs remained stable throughout the study period. In the former era (years 1999 to 2004, n = 902), we found multivariable adjusted associations between plasma industrial TFA levels and mortality (hazard ratio 4.44, P = .02) and graft loss (hazard ratio 4.22, P = .01). In the latter era (years 2005 to 2011, n = 1,086), there were no associations between plasma industrial TFA levels and patient or graft survival. Plasma ruminant TFAs were not associated with mortality or graft loss in either eras. CONCLUSION: In this Norwegian transplant cohort, plasma industrial TFA levels dropped from around 0.3 wt% in the former era to 0.2 wt% in the latter era. While plasma industrial TFA was significantly associated with survival in the former era, no associations were found with survival in the latter era. This finding suggests that lowering industrial TFA consumption from modest to low levels could possibly influence health beneficially after renal transplantation. PMID- 30309781 TI - The Association of Nutritional Factors and Skin Autofluorescence in Persons Receiving Hemodialysis. AB - OBJECTIVE: Advanced glycation end products (AGEs) are uremic toxins that result from hyperglycemia, oxidative stress, and systemic inflammation. AGEs are also formed in food during cooking. On the other hand, malnutrition may contribute to AGE formation through its association with oxidative stress and inflammation. AGE accumulation can be measured by skin autofluorescence (SAF) and elevated SAF is independently associated with higher mortality on hemodialysis (HD). We aimed to investigate associations between SAF, dietary AGE intake, and markers of malnutrition in persons receiving HD. DESIGN AND METHODS: This was a single center cross-sectional study that included 120 participants on HD dialyzing at least 3 times per week for 3-4 hours. SAF was measured using an Autofluorescence Reader. Dietary AGE, energy, protein and fat intake, handgrip strength (HGS), anthropometric measurements and biochemistry were also assessed. The Subjective Global Assessment was performed to evaluate the nutritional status. RESULTS: SAF was higher in malnourished participants and correlated negatively with serum albumin and cholesterol, HGS and energy, protein and fat intake and positively with C-reactive protein and chronological age; SAF did not correlate with dietary AGE intake. Multivariable linear regression analysis showed that diabetes, smoking, serum albumin, HGS, protein intake, and dialysis vintage were independent predictors of increased SAF. CONCLUSIONS: Markers of malnutrition were more important determinants of increased SAF than high dietary AGE intake in this HD population. Nutritional interventions aiming to reduce SAF by correcting malnutrition should therefore be investigated. The observed association between higher SAF and malnutrition may in part explain the previously reported association between higher SAF and mortality on HD. PMID- 30309782 TI - High Animal and Vegetarian Protein Intake in Hemodialysis Patients. PMID- 30309783 TI - Volume Based Resuscitation and Intestinal Microcirculation after Ischaemia/Reperfusion Injury: Results of an Exploratory Aortic Clamping Study in Pigs. AB - OBJECTIVES: In the presence of ischaemia/reperfusion (I/R) induced endothelial injury, volume administration may not correlate with increased microcirculation. The aim of this study was to evaluate intestinal microcirculation after standardised sequential volume loading in an animal model of I/R injury following supracoeliac aortic clamping. METHODS: This was a prospective exploratory pilot animal study. Intestinal I/R injury was induced in eight pigs during experimental thoraco-abdominal aortic repair. After 6 h of I/R, microcirculatory blood flow (mFlux, measured in the ileum using direct laser speckle contrast imaging) and macrohaemodynamic parameters (using trans-cardiopulmonary thermodilution) were measured and measurements were repeated after each of four sequential volume loading steps (VLS1 - 4). Each load was administered over 5 min followed by another 5 min for equilibration. RESULTS: All animals survived until after VLS4. After 6 h of I/R cardiac output (CO) (p < .001) and mFlux (p < .001) had both decreased. CO increased again after VLS1 (p < .001) and VLS2 (p = .036), whereas mFlux did not change. In contrast, mFlux further decreased after VLS3 (p < .01) and VLS4 (p < .001), whereas CO did not change anymore. Extravascular lung water continued to increase after VLS2 (p = .046) and VLS4 (p = .049). CONCLUSIONS: I/R leads to impaired intestinal microcirculation, which was not restored by volume administration in spite of improved CO. In contrast, further volume administration exceeding preload reserves was associated with additional decreases in the intestinal microcirculation. The potentially negative effect of excessive volume resuscitation after I/R injury should encourage further translational research. PMID- 30309784 TI - The Importance of Patency of Tibial Run Off Arteries on Clinical Outcomes After Stenting for Chronic Total Occlusions in the Superficial Femoro-popliteal Artery. AB - OBJECTIVE/BACKGROUND: The aim was to evaluate the impact of patent tibial arteries on stenting for chronic total occlusions (CTO) in superficial femoropopliteal artery (SFA) lesions. Additionally, the efficacy of additive tibial percutaneous transluminal angioplasty (PTA) was evaluated. METHODS: A total of 238 limbs in 199 patients with de novo SFA CTO lesions treated with bare nitinol stents between 2009 and 2015 were retrospectively identified. These limbs were divided into two groups (group A [number of patent tibial arteries at baseline angiogram >= 2, 127 limbs in 104 patients] vs. group B [number of patent tibial arteries at baseline angiogram <= 1, 111 limbs in 95 patients]). Furthermore, the efficacy of additive tibial PTA on stenting for SFA CTO lesions was evaluated by comparing subgroups (group B with tibial PTA vs. without tibial PTA). The primary end point was freedom from major adverse limb events (MALE) two years after PTA, defined as a composite of ischaemic driven target lesion revascularisation (TLR) and major amputation. RESULTS: Group A had a significantly higher MALE free survival rate two years after PTA compared with group B (80.9% vs. 43.5%; p < .001), which was mainly driven by higher TLR free survival rates (80.9% vs. 45.9%; p < .001). In subgroup analysis, patients in group B with tibial PTA had significantly higher MALE free survival rate at two years compared with those without tibial PTA (65.5% vs. 26.2%; p = .001). CONCLUSION: The presence of patent tibial arteries was an important predictor of MALE after PTA for SFA CTO lesions. Furthermore, additional tibial PTA on SFA CTO stenting might be beneficial for clinical outcomes. PMID- 30309785 TI - Corneal confocal microscopy as a tool for detecting diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes: ADDITION-Denmark. AB - AIMS: In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes. METHODS: CCM, nerve conduction studies, and assessment of symptoms and clinical deficits of DPN were undertaken in 144 participants with type 2 diabetes and 25 controls. DPN was defined according to the Toronto criteria for confirmed DPN. RESULTS: Corneal nerve fiber density (CNFD) was lower both in participants with confirmed DPN (n = 27) and in participants without confirmed DPN (n = 117) compared with controls (P = 0.04 and P = 0.01, respectively). No differences were observed for CNFD (P = 0.98) between participants with and without DPN. There were no differences in CNFL and CNBD between groups (P = 0.06 and P = 0.29, respectively). CNFD was associated with age, height, total- and LDL cholesterol. CONCLUSIONS: CCM could not distinguish patients with and without neuropathy, but CNFD was lower in patients with type 2 diabetes compared to controls. Age may influence the level of CCM measures. PMID- 30309786 TI - Digital health to support early infant diagnosis of HIV. PMID- 30309788 TI - Airway reflux: an emerging topic in respiratory medicine. PMID- 30309787 TI - Evaluation of the HIV Infant Tracking System (HITSystem) to optimise quality and efficiency of early infant diagnosis: a cluster-randomised trial in Kenya. AB - BACKGROUND: The HIV Infant Tracking System (HITSystem) is a web-based intervention linking providers of early infant diagnosis, laboratory technicians, and mothers and infants to improve outcomes for HIV-exposed infants. We aimed to evaluate the efficacy of the HITSystem on key outcomes of early infant diagnosis. METHODS: We did a cluster-randomised trial at six hospitals in Kenya, which were matched on geographic region, resource level, and volume of patients (high, medium, and low). We randomly allocated hospitals within a matched pair to either the HITSystem (intervention; n=3) or standard of care (control; n=3). A random number generator was used to assign clusters. Investigators were unaware of the randomisation process. Eligible participants were mothers aged 18 years or older with an infant younger than 24 weeks presenting for their first early infant diagnosis appointment. The primary outcome was complete early infant diagnosis retention, which was defined as receipt of all indicated age-specific interventions until 18 months post partum (for HIV-negative infants) or antiretroviral therapy initiation (for HIV-positive infants). Analysis was per protocol in all randomised pairs judged eligible, excluding infant deaths and those who moved or were transferred to another health facility. Modified intention-to-treat sensitivity analyses judged all infant deaths and transfers as incomplete early infant diagnosis retention. Separate multivariable logistic regression analyses were done with intervention group, hospital volume, and significant covariates as fixed effects. This trial is registered with ClinicalTrials.gov, number NCT02072603; the trial has been completed. FINDINGS: Between Feb 16, 2014, and Dec 31, 2015, 895 mother-infant pairs were enrolled. Of these, 87 were judged ineligible for analysis, 26 infants died, and 92 pairs moved or were transferred to another health facility. Thus, data from 690 mother infant pairs were analysed, of whom 392 were allocated to the HITSystem and 298 to standard of care. Mother-infant pairs were followed up to Sept 30, 2017. Infants diagnosed as HIV-positive were followed up for a median of 2.1 months (IQR 1.6-4.8) and HIV-negative infants were followed up for a median of 17.0 months (IQR 16.6-17.6). Infants enrolled in the HITSystem were significantly more likely to receive complete early infant diagnosis services compared with those assigned standard of care (334 of 392 [85%] vs 180 of 298 [60%]; adjusted odds ratio [OR] 3.7, 95% CI 2.5-5.5; p<0.0001). No intervention effect was recorded at high-volume hospitals, but strong effects were seen at medium-volume and low volume hospitals. Modified intention-to-treat analyses for complete early infant diagnosis were also significant (334 of 474 [70%] vs 180 of 334 [54%]; adjusted OR 2.0, 95% CI 1.4-2.7; p<0.0001). No adverse events related to study participation were reported. INTERPRETATION: The HITSystem intervention is effective and feasible to implement in low-resource settings. The HITSystem algorithms have been modified to include HIV testing at birth, and an adapted HITSystem 2.0 version is supporting HIV-positive pregnant women to prevent perinatal transmission and optimise maternal and infant outcomes. FUNDING: National Institute of Child Health and Human Development. PMID- 30309789 TI - Beneficial Effects of School-based Mindfulness Training On Impulsivity in Healthy Adolescents: Results From a Pilot Randomized Controlled Trial. AB - BACKGROUND: Since impulsivity is associated with unhealthy behaviors in adolescents, interventions targeting impulsivity could positively affect such behaviors. Whether integrating mindfulness training (MT) into standard school based health education could improve impulsivity is unknown. PURPOSE: To obtain preliminary estimates of effect of MT integrated in standard high school health education on impulsivity. METHODS: Two high schools in Massachusetts were randomized to school-based health education plus MT (HE-MT) or to health education plus attention control (HE-AC). The outcome was change in impulsivity at end of treatment (EOT) and 6 months after EOT. RESULTS: Students (n = 53; 30 HE-MT, 23 HE-AC) were on average 14.5years old and 40% belonged to ethnic minorities. Compared to the control condition, HE-MT had significant effects on impulsivity at EOT (beta = -9.7; SE = 3.8, p = 0.01), while smaller, non significant differences were seen 6 months after EOT. CONCLUSION: This rigorous pilot study suggests that MT could have a beneficial effect on impulsivity in adolescents. Improvements in impulsivity could have important implications should future larger studies show that such improvements result in healthier behaviors. PMID- 30309790 TI - The Efficacy and Safety of Korean Herbal Medicine in a Patient with Endometrioma of The Ovary: A Case Report. AB - OBJECTIVE: The objective of our study is to report our experience of treatment of a patient with endometrioma who was diagnosed with blood deficiency and blood stasis. METHODS: A 36-years-old Korean woman diagnosed with endometrioma of the right ovary complained of pelvic pain around the menstrual periods, vaginal discharge, and swelling and itching of the pudenda. The patient was administered the modified Gyejibokryeong-hwan (GBH) and the Bogol-gongjin-dan (BGD) for 6 months. RESULTS: After treatment, the size of the endometrioma in the right ovary was reduced to 17 * 11 * 10 mm from 25 * 21 * 17 mm before treatment. The level of CA 125 decreased from 47.2 U/ml at baseline to 34.3 U/ml after treatment. The level of CA 125 after treatment was within normal range. After treatment, the pelvic pain around the menstrual periods (VAS 7->1), vaginal discharge (VAS 4 >1), and swelling and itching of the pudenda (VAS 5->2) decreased from the baseline values. CONCLUSION: Herbal medicine is a potential alternative therapy for patients with endometrioma of the ovary. Further studies, including case control studies and RCTs based on an international standard and higher methodological quality, are needed. PMID- 30309791 TI - Letter to the editor regarding: Rowe et al. Using social media for patient reported outcomes: a study of genital appearance and sexual function in adult bladder exstrophy patients. PMID- 30309792 TI - Association of SNP-SNP Interactions Between RANKL, OPG, CHI3L1, and VDR Genes With Breast Cancer Risk in Egyptian Women. AB - BACKGROUND: Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low-penetrant alleles of cancer-related genes and gene-gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), chitinase-3-like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP) SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women. PATIENTS AND METHODS: Data of 115 BC patients and 120 cancer-free controls were studied. Association tests were conducted using logistic regression models. RESULTS: Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL rs9533156 and OPG-rs2073618; OPG-rs2073618 with CHI3L1-rs4950928, VDR-rs2228570 and VDR-rs1544410; OPG-rs2073617 and VDR-rs1544410; VDR-rs2228570 and VDR rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32-52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B. CONCLUSION: Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene-gene interaction may help predict BC risk and prognosis. PMID- 30309793 TI - Predictors of preterm birth. AB - Cervical length (CL) measured by transvaginal ultrasound examination (TVUE) best identifies the risk for preterm birth (PTB). It identifies women at risk who can benefit from corticosteroids or in utero transfer. Early screening improves effectiveness of tocolysis. It reduces iatrogenicity and cost. In preterm premature rupture of membranes (PPROM), CL is devoid of infectious risk and predicts duration of the latency phase but not the risk of perinatal sepsis. Asymptomatic women at risk should be screened at a 2-week interval starting from 16 to 18 weeks, up to 24 weeks. CLs <10th centile are at risk of PTB, especially with decrease in CL after 16 weeks. Repeat ultrasound improves predictive values. Stable CL calls for term delivery. Funneling does not improve predictivity of CL. In twin pregnancies, CL reduces unnecessary interventions. In symptomatic women, fetal fibronectin performs less than CL. Its combination with inconclusive CL has not emerged productive through randomized controlled trials (RCTs), and studies with homogeneous management for preterm labor (PTL) suggest that up to 15% of unjustified hospitalizations and treatment could be avoided. PMID- 30309794 TI - Maxillary osteomyelitis associated with osteopetrosis: Systematic review. AB - Osteopetrosis is a rare condition which presents increased bone density and deficient bone remodeling. The consequential complications include cranial nerve impairment due compression, bone fractures, and osteomyelitis. Maxillary osteomyelitis is uncommon even in osteopetrosis patients. This is a systematic review of the literature regarding the management and outcomes of maxillary osteomyelitis in patients with autosomal dominant osteopetrosis (ADO) type II. A case of this specific pathology is reported. There are 18 cases of maxillary osteomyelitis associated with ADO type II reported in the literature. The mean age of the patients reported was 33.5 (SD 15.9) years, and the male:female ratio was 1:1. Antibiotic therapy was variable, and amoxicillin with clavulanic acid was the main choice (33.33%). Surgery or sequestrectomy was performed in 88.89% of the studies. Complete healing was achieved in only 44.4% of cases. The treatment protocols remain controversial and often do not lead to complete healing. In the case that we report, complete healing was achieved after prolonged antibiotic therapy, hyperbaric oxygen therapy, and partial resection. In conclusion, the management of maxillary osteomyelitis in ADO type II patients is challenging, and complete resolution of the process is dependent on multiple interventions. PMID- 30309795 TI - Osteogenic capacity of diluted platelet-rich plasma in ectopic bone-forming model: Benefits for bone regeneration. AB - Platelet-rich plasma (PRP) with normal and below-normal physiological concentrations of platelets is designated as diluted PRP (dPRP). The aims of this study are to evaluate whether bone mineral matrix in combination with dPRP possesses osteogenic capacity; and whether the differences in dynamics and osteogenic process pattern depend on different platelet concentrations, to what extent, and also what could be benefits for bone regeneration in clinical practice. Three types of implants were made: BMM-bone mineral matrix alone; dPRP/10-bone mineral matrix mixed with dPRP (concentration of platelets 10 times lower than physiological level) and dPRP/3-bone mineral matrix mixed with dPRP (concentration of platelets 3 times lower than physiological level). A subcutaneous implantation model in Balb/c mice was used. The implants were analyzed using expression analysis of bone-related genes, histochemical, immunohistochemical and histomorphometrical analysis. All types of implants induced creation of necessary preconditions for supporting osteogenic processes, but did not induce visible young bone growth. Implant types dPRP/10 and dPRP/3 showed very similar and significantly better stimulatory effects on osteogenic processes than bone matrix alone. In this study, significant ectopic osteogenic potential of concentration of platelets in PRP that are lower than physiological level in blood plasma in combination with bone mineral matrix was demonstrated. Diluted platelet-rich plasma could be a promising and useful adjuvant therapeutic agent in bone regeneration. PMID- 30309796 TI - The impact of harvest length and detachment of the interosseous membrane on donor site morbidity following free fibula flap surgery-a biomechanical experimental study. AB - PURPOSE: The fibula flap has been established for orofacial reconstruction following ablative surgery. Donor-site morbidity of the lower leg may be explained by the harvest technique and particularly by detachment of the M. extensor halluces longus (EHL) and M. extensor digitorum longus (EDL). MATERIAL AND METHODS: On cadaveric lower leg specimens, the tendons of the EHL and EDL were dissected at the proximal phalanges and loaded with corresponding weights. The average displacement of the muscle was evaluated during the harvesting procedure. RESULTS: Cumulative detachment of the interosseous membrane caused considerable displacement of the EHL but less impairment of the EDL. Segmental and cumulative osteotomy of the fibula implicated significant displacement of both EHL and EDL. CONCLUSION: A recommendation can be given for cautious selection of osteotomy site of the fibula and for limited sacrifice of the fibula and adjacent attachments of the extensors to keep local-site morbidity at a minimum. PMID- 30309797 TI - Fear of adverse events should not prevent the use of appropriate antihypertensive drug therapy. AB - A recent publication reported that Systolic Blood Pressure Intervention Trial participants with 10-year cardiovascular disease risk less than 11.5% derived more harm than benefit from intensive treatment. The authors consider that serious adverse events (SAEs) are of equal importance to that of either all-cause death or the primary composite outcome (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes). Under this premise, one death would correspond to 2.7 SAEs and a primary outcome to 1.8 SAEs overall, and to be between 6 and 18 times as important as an SAE in the intensive treatment group. In our opinion, patient utility should be considered when clinical decisions are made for the treatment of hypertension. PMID- 30309798 TI - Hemophagocytic Lymphohistiocytosis in a Patient With Multiple Myeloma. PMID- 30309800 TI - Dynamic changes in the reflex exam of patients with sub-axial cervical stenosis. AB - Though dynamic changes in the physical exam of patients being evaluated for cervical spine pathology have been reported, there is limited information on the prevalence and clinical features associated with reflex changes in a population undergoing surgical evaluation for cervical spine pathology. Fifty-one patients with at least grade 1 cervical stenosis on MRI underwent initial surgical evaluation for cervical spine pathology. All patients received complete neurologic examinations including dynamic reflex testing in three positions (neck neutral, extended, and flexed) by 2 spine surgeons. The average age was 58.7 years (range, 34-80), with 28 (55%) patients being male. Stenosis at the symptomatic levels was grade 1 in 18 patients (35%), grade 2 in 11 (21%), and grade 3 in 22 (43%). Twenty-one patients (41%) had a dynamic change in reflex exam. The most common change in reflex exam was seen in the Hoffman's reflex with 14 patients (28%). Patients with grade 3 stenosis were more likely to have a static Hoffman's reflex (64%) compared with grade 1 (17%) and grade 2 (18%) (p < 0.05). Patients with grade 3 stenosis had a higher rate of either a static or dynamic Hoffman's reflex (82%) compared with grade 1 (44%) (p < 0.05), but there was no difference between grade 3 and grade 2 (64%) (Table 2). Dynamic changes in reflex exam are commonly seen in patients being evaluated for symptomatic cervical stenosis. The routine neurologic exam can be supplemented with dynamic reflex testing, especially in cases where clinical history or imaging is concerning for cervical myelopathy. PMID- 30309799 TI - Effectiveness of strategies to improve health-care provider practices in low income and middle-income countries: a systematic review. AB - BACKGROUND: Inadequate health-care provider performance is a major challenge to the delivery of high-quality health care in low-income and middle-income countries (LMICs). The Health Care Provider Performance Review (HCPPR) is a comprehensive systematic review of strategies to improve health-care provider performance in LMICs. METHODS: For this systematic review we searched 52 electronic databases for published studies and 58 document inventories for unpublished studies from the 1960s to 2016. Eligible study designs were controlled trials and interrupted time series. We only included strategy-versus control group comparisons. We present results of improving health-care provider practice outcomes expressed as percentages (eg, percentage of patients treated correctly) or as continuous measures (eg, number of medicines prescribed per patient). Effect sizes were calculated as absolute percentage-point changes. The summary measure for each comparison was the median effect size (MES) for all primary outcomes. Strategy effectiveness was described with weighted medians of MES. This study is registered with PROSPERO, number CRD42016046154. FINDINGS: We screened 216 477 citations and selected 670 reports from 337 studies of 118 strategies. Most strategies had multiple intervention components. For professional health-care providers (generally, facility-based health workers), the effects were near zero for only implementing a technology-based strategy (median MES 1.0 percentage points, IQR -2.8 to 9.9) or only providing printed information for health-care providers (1.4 percentage points, -4.8 to 6.2). For percentage outcomes, training or supervision alone typically had moderate effects (10.3-15.9 percentage points), whereas combining training and supervision had somewhat larger effects than use of either strategy alone (18.0-18.8 percentage points). Group problem solving alone showed large improvements in percentage outcomes (28.0-37.5 percentage points), but, when the strategy definition was broadened to include group problem solving alone or other strategy components, moderate effects were more typical (12.1 percentage points). Several multifaceted strategies had large effects, but multifaceted strategies were not always more effective than simpler ones. For lay health-care providers (generally, community health workers), the effect of training alone was small (2.4 percentage points). Strategies with larger effect sizes included community support plus health-care provider training (8.2-125.0 percentage points). Contextual and methodological heterogeneity made comparisons difficult, and most strategies had low quality evidence. INTERPRETATION: The impact of strategies to improve health-care provider practices varied substantially, although some approaches were more consistently effective than others. The breadth of the HCPPR makes its results valuable to decision makers for informing the selection of strategies to improve health-care provider practices in LMICs. These results also emphasise the need for researchers to use better methods to study the effectiveness of interventions. FUNDING: Bill & Melinda Gates Foundation, CDC Foundation. PMID- 30309801 TI - Acute reversal of dabigatran with Idarucizumab for intravenous thrombolysis as acute stroke treatment. AB - Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke (AIS) is contraindicated in patient taking either Factor Xa inhibitors or direct thrombin inhibitors. Idarucizumab completely reverses the biologic effect of dabigatran within minutes. Intravenous rt-PA treatment results in a significant benefit in functional outcome when administered 3-4.5 h after stroke onset or last seen normal time. There is little reported data and no large-scale studies of the reversal of dabigatran with Idarucizumab for the purpose of treating AIS with IV rt-PA. We describe the case of a 73 year old male with AIS and active dabigatran use. Idarucizumab was administered per an approved medical center protocol and the patient was subsequently treated with IV rt-PA. The patient had a severe stroke with no other contraindications to IV rt-PA other than dabigatran use. The patient was administered Idarucizumab and IV rt-PA was given. Within 24 h of treatment, the patient had minimal stroke deficits. Imaging revealed a right middle cerebral artery patchy infarct. The patient was restarted on dabigatran therapy for his atrial fibrillation and was discharged to a skilled nursing facility for rehabilitation. The patient did not experience any symptomatic or asymptomatic intracranial hemorrhage after treatment or through day 90. Though no randomized evidence exists for the risk of IV rt-PA after dabigatran reversal with Idarucizumab, the case experiences are mounting. This case of successful stroke treatment after reversal adds to the anecdotal literature and supports the study of dabigatran reversal with Idarucizumab for thrombolysis in AIS. PMID- 30309802 TI - A retrospective comparison of sac and lobe morphology between ruptured and unruptured intracranial aneurysms. AB - There are few reliable morphologic indices to aid in the determination of an intracranial aneurysm's rupture risk. We sought to characterize morphological characteristics of aneurysm sacs and their lobes that are associated with ruptured status at time of initial evaluation with diagnostic angiography. These factors could be associated with an aneurysm's risk of rupturing. We retrospectively reviewed all aneurysms imaged with digital subtraction angiography (DSA) at a single institution over five years. Patients presenting with aneurysmal subarachnoid hemorrhage (aSAH) were assigned to the ruptured group, and those presenting without aSAH were assigned to the unruptured group. Angiograms were evaluated for the presence of various morphological parameters. Binary logistic regression was used to assess their associations between groups. A total of 331 aneurysms among 241 patients were included in the analysis. Posterior circulation, larger size ratio, and the presence of two or more lobes were associated with aneurysm rupture (p < 0.001 for each). Aneurysms containing a lobe with a greater height than width were observed more frequently in the ruptured group (OR 5.26, 95% CI 2.66-10.41). In the receiver operating characteristic (ROC) curves, mean diameter had an AUC of 0.72 and an optimum threshold of 2.85 mm. For size ratio, the AUC was 0.70 and the optimum threshold was 2.02. A larger SR was observed in ruptured aneurysms. The presence of multiple lobes and greater lobe height than width were associated with rupture status as well. These factors merit investigation in a prospective study. PMID- 30309803 TI - EEG and autonomic responses to nociceptive stimulation in disorders of consciousness. AB - Since behavioral responses to external stimuli of patients presenting disorders of consciousness (DoC) are often difficult to qualify, covert physiological correlates of responsivity are deemed as potentially valuable tools to help assessment procedures. While noxious stimuli seem good candidates to explore DoC patients' responsivity, autonomic and electrophysiological correlates of pain detection in DoC patients are still debated. This research aims at investigating autonomic and cortical activation as covert measure of residual somatosensory and nociceptive processes in patients in vegetative state. Twenty-one patients received touch- and pain-related stimulations while autonomic and cortical measures were recorded, with minimal stress for them. Results showed an increased frontal and parietal activation in response to both touch and pain stimuli. Pain related stimulation was however associated with greater delta parietal response, lower left frontal activation, and increased electrodermal and heart rate measures. Present findings suggest that both somatic stimulations could induce measurable central responses, which might mirror basic attention orientation and perceptual processes. Nonetheless, the nociceptive stimulation in particular seemed to induce a more consistent and informative pattern of covert response even if we used a mild pain-induction procedure. PMID- 30309805 TI - Clinical differences in patients with Parkinson's disease according to tandem gait performance. AB - Some of patients with Parkinson's disease (PD) have abnormal tandem gait (TG) performance without any symptoms and signs of cerebellar dysfunction. Clinical difference between patients with good and poor TG performance has not yet been studied. We report the relationship between tandem gait performance and clinical characteristics including 37 patients with PD who had no evidence of cerebellar dysfunction. Using tandem gait test, the patients were divided into two groups (good-TG and poor-TG). We evaluated the two groups with Montreal Cognitive Assessment (MoCA), Mini Mental Status Examination (MMSE), Frontal Assessment Batter (FAB), Beck Depression Index (BDI-II), REM Sleep Behavior Disorder Single Question Screen (RBD1Q), MDS-UPDRS items related to axial disability and freezing. Fifteen participants were classified as good-TG group and 22 were as poor-TG group. Participants in good-TG group had higher MoCA score and lower BDI II score. The proportion of participants who answered "yes" to RBD1Q was lower in good-TG group (27%, 4 of 15) than that in poor-TG group (55%, 12 of 22). All participants in good-TG group marked "0" for the MDS-UPDRS item 2.13 which addresses freezing event over the past week, whereas 18% (4 of 22) of participants in poor-TG group marked "1". In conclusion, tandem gait performance may be related to various clinical characteristics including cognitive function, mood, RBD, and freezing in patients with PD. PMID- 30309804 TI - Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt-Jakob disease. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease. It is invariably fatal and displays a short clinical disease stage. The key event in sCJD is the propagation of a beta-sheet rich conformer of the physiological PrPC protein, known as PrPSc. Neuropathological disease characteristics include gliosis, neuronal loss and spongiform degeneration; disease clinical manifestations refer to mental and visual disabilities, cognitive impairment, gait or limb ataxia, myoclonus and mutism. Definite sCJD diagnosis requires post-mortem brain material histopathological examination. However, highly certain pre-mortem differential diagnosis is desired to exclude other treatable disorders and to reduce disease transmission risks. Detection and/or quantification of cerebrospinal fluid (CSF) biomarkers reflecting neuronal damage and PrPC misfolding in the diseased brain significantly enhance pre-mortem diagnosis. Previously established and newly identified biomarkers are used towards this direction. Increased CSF Neurofilament light chain (NFL) concentrations have been reported in several neurological disorders, including prion diseases. In the present study, we analyzed CSF NFL levels in two independent patient cohorts, consisting of highly suspected sCJD cases that were further classified as sCJD or non-CJD according to established diagnostic criteria. CSF NFL concentrations were increased in sCJD compared to non-CJD cases in both cohorts (area under the curve (with 95% confidence interval) equal to 0.89 (0.82 to 0.97) and 0.86 (0.77 to 0.96), respectively. CSF NFL was associated neither to age nor to sex but correlated with total-tau concentrations in both cohorts. Overall, our data provide independent validation of CSF NFL utility in sCJD differential diagnosis. PMID- 30309806 TI - Impact of venous thromboembolism during admission for meningioma surgery on hospital charges and postoperative complications. AB - Surgical resection of meningiomas has been associated with high rates of venous thromboembolic events (VTE) as compared with all other intracranial tumors. There is a paucity of data regarding the clinical complications and comorbidities associated with this cohort yet the underlying pathophysiological mechanism for this tumor-specific finding remains unclear. Our goal was to determine the various impacts of VTE on meningioma surgery in a large cohort of inpatient admissions. This retrospective analysis utilized discharge data from the National Inpatient Sample (NIS) from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between patients with and without VTE. Of 20,259 patients, 426 (2.1%) experienced a VTE. Compared to the non-VTE cohort, patients that experienced a VTE were older (62.7 +/- 13.7 vs. 57.2 +/- 14.7; p < 0.001), were more commonly male (38.0% vs 30.1%; p = 0.001), had longer hospitalizations (18.8 vs 6.6 days; p < 0.001), and incurred significantly greater hospital charges ($195,837 vs $74,434; p < 0.001). VTE patients experienced significantly higher rates of acute postoperative complications including shock, hemorrhage, wound dehiscence, infection, intracerebral hemorrhage, hemiparesis/hemiplegia, stroke, and death during admission. Odds ratio of aforementioned postsurgical complications remained significantly higher both before and after adjusting for age and sex (all p < 0.01). Occurrence of VTE in patients undergoing meningioma resection portends greater hospital charges, most likely attributed to longer lengths of admission. Increased postoperative complications and mortality in the VTE group warrants further investigation and wariness of the surgeon when treating surgical candidates of meningioma. PMID- 30309808 TI - A celebration of World Pharmacist Day 2018 focusing to strengthen the pharmacy services at an oncology-based hospital in Nepal: Inspiration for others in developing countries. PMID- 30309807 TI - FokI as a genetic factor of intervertebral disc degeneration: A PRISMA-compliant systematic review of overlapping meta-analyses. AB - The association of FokI (rs2228570), a polymorphism of the vitamin D receptor gene, with intervertebral disc degeneration (IDD) has been investigated in a multitude of studies. However, conflicting results of these studies led to emergence of several meta-analyses over the past few years. Despite the increased statistical power, these meta-analyses have failed to provide uniform and conclusive data on the relationship of FokI with IDD. The aim of this study was to present a comprehensive review based on the most up-to-date meta-analyses on the association of FokI with IDD. A comprehensive search of all major databases was conducted to identify meta-analyses investigating relation between FokI and IDD. No date or language restrictions were applied. The Jadad decision algorithm was utilized to evaluate included meta-analyses and identify the one providing the best evidence. A total of 7 meta-analyses (n = 2580 original patients), that included six to ten case control studies, analyzed the association of FokI polymorphism with IDD. The meta-analysis of the highest quality supported the notion that overall there is no statistically significant association between FokI polymorphism and IDD. However, the authors showed that Caucasians have a reduced risk of IDD and Hispanics have an increased risk of IDD in the dominant and dominant/homozygous/heterozygous models of FokI polymorphism. While currently there is no evidence of an association between FokI polymorphism and IDD in the general population, ethnic predisposition has been shown. PMID- 30309809 TI - Accuracy of objective tests for diagnosing adult asthma in symptomatic patients: A systematic literature review and hierarchical Bayesian latent-class meta analysis. AB - BACKGROUND: We obtain summary estimates of the accuracy of additional objective tests for the diagnosis of adult asthma using systematic review and meta-analysis of diagnostic test accuracy studies. METHODS: Medline, Embase, and other relevant electronic databases were searched for papers published between January 1989 and December 2016. Studies were included if they evaluated the diagnostic accuracy of objective tests, including airway reversibility (AR), airway hyperresponsiveness (AHR), and fractionated exhaled nitric oxide (FeNO) for the diagnosis of adult asthma in patients with symptoms suggestive of asthma. If papers were assessed appropriate using the adapted QUADAS-2 tool, meta-analysis was conducted using the hierarchical bivariate model. This hierarchical model accounts for both within and between study variability. RESULTS: Sixteen studies reported the performance of the evaluated objective tests at presentation. For diagnosis of adult asthma, overall sensitivity and specificity for AR were 0.39 (95% confidence interval [CI] 0.18 to 0.66) and 0.95 (95% CI 0.86 to 1.00); for AHR, 0.86 (95% CI 0.61 to 1.00) and 0.95 (95% CI 0.77 to 1.00); for FeNO, 0.65 (95% CI 0.53 to 0.77) and 0.83 (95% CI 0.75 to 0.90). Comprehensive comparison of three diagnostic tools for adult asthma using the back-calculated likelihood rate (LR) showed that AR and AHR corresponded to a higher LR+, and AHR gave a lower LR-. CONCLUSIONS: In the current situation of no gold standard for diagnosis of adult asthma, AR and AHR are appropriate for ruling-in the true diagnosis, and AHR is superior for ruling-out a diagnosis. Since each objective test had a specific characteristic, it should be chosen depending on the situation, such as the capacity of the institution and the conditions of patients. PMID- 30309810 TI - Characteristics and determinants of dietary intake and physical activity in a group of patients with multiple chemical sensitivity. AB - BACKGROUND AND OBJECTIVE: Multiple chemical sensitivity (MCS) is a complex, acquired, chronic syndrome of multifactorial etiology with multiple symptoms. The aim of the study was to assess the nutritional habits, dietary characteristics and physical activity, as well as their determinants, of a population diagnosed with MCS, which may allow for a more precise approach to nutritional improvement. PATIENTS AND METHOD: A descriptive, cross-sectional study in patients diagnosed with MCS. Information was collected using adapted questionnaires. Data included presence of comorbidities, nutritional (use of supplements, types of diet) and food purchasing habits. Dietary intake, food intolerances, and physical activity were also recorded. RESULTS: The study included of 52 patients (48 female) aged 50.9+/-10.3 years. Diagnosis of MCS was commonly associated to chronic fatigue syndrome (70.1%), fibromyalgia (65.4%), or electrosensitivity (51.9%). The most common comorbidities were irritable bowel, gastroesophageal reflux, and depression/anxiety-depressive disorder. Exclusion diets were followed by 57.7%, 52.1% commonly used supplements (6.4+/-5.2 per person), and 16.0% took more than 10 daily. A high proportion of volunteers did not take the recommended amounts of dairy products (84.3%), fruit (82.3%), and cereals (64.7%), the foods to which intolerance was greatest. As regards physical activity, active subjects only represented 12.5%. CONCLUSIONS: The data collected support the need to improve food pattern and to perform physical activity according to individual characteristics. Nutritional education and diet personalization could prevent incomplete, monotonous, and unbalanced diets which impair quality of life and physiological status. PMID- 30309811 TI - Chyle fistula as complication of thyroid surgery in malignant pathology. AB - INTRODUCTION: Cervical chyle fistula (CF) is exceptional, and there is no agreement on its treatment. The study objective was to assess the efficacy of conservative and surgical treatment in this condition. METHOD: Study population: Patients undergoing thyroid surgery who experience CF after the procedure. Study groups: 1) Group with conservative treatment: CF with flow rates less than 300cm3/day, late or collected in the neck; and 2) Group with surgical treatment: early CF with flow rates greater than 300 cm3/day. STUDY VARIABLES: Cure rates and rate of conversion to surgery were analyzed. RESULTS: Nine patients experienced CF. Conservative treatment was started in all of them, in 67% (n=6) with curative intent. Fifty percent of treated cases were resolved (n=3). The remaining patients were hospitalized after more than 150 days of treatment to add absolute diet and parenteral nutrition. The condition resolved in one patient, and the other two were referred for surgery. In the remaining patients (33%, n=3), surgery was indicated as the initial definitive treatment. A cervical approach, with ligature and transfixion stitch of the thoracic duct, was used. In one of the patients, who also had chylothorax, thoracoscopy was also performed. In the two patients where conservative treatment failed, cervicotomy was indicated, identifying in both the lymphatic reflux point. Fistula resolved in all operated patients. CONCLUSIONS: Conservative treatment was effective in 66% of low flow CFs. Surgery effectively and rapidly resolves fistulas with a high flow or not responding to conservative treatment. PMID- 30309812 TI - Gestational diabetes mellitus in a multiethnic population in Spain: Incidence of and factors associated to impaired glucose tolerance one year after delivery. AB - BACKGROUND AND AIM: Women with history of gestational diabetes mellitus (GDM) are at increased risk for diabetes. Ethnicity may modify such risk, but no studies have been conducted in our environment. The aim of this study was to assess the incidence of type 2 diabetes mellitus and prediabetes one year after delivery in women with GDM and in a multiethnic background and to identify the associated factors. PATIENTS AND METHODS: A retrospective analysis of a prospective, observational cohort of women with GDM who attended annual postpartum follow-up visits at Hospital del Mar from January 2004 to March 2016. RESULTS: Three hundred and five women attended postpartum follow-up visits. Of these, 47.2% were Caucasian, 22% from South-Central Asia, 12% from Latin America, and 10% from Morocco and East Asia. Incidence rates of type 2 diabetes mellitus and prediabetes in these patients were 5.2 and 36.6%, respectively. In a multivariate analysis, non-Caucasian origin (OR=3.15, 95% CI [1.85-5.39]), recurrent gestational diabetes (OR=2.26, 95% CI [1.11-4.59]), and pre-pregnancy body mass index (OR=1.09, 95% CI [1.04-1.15]) were independent predictors of impaired glucose tolerance. CONCLUSIONS: In a multiethnic Spanish population of women with GDM, incidence of impaired glucose tolerance in the first year after delivery was 41.8%, with a three-fold increased risk for women of non-Caucasian ethnicity. PMID- 30309813 TI - Epidemiology of late preterm and early term births - An international perspective. AB - Late preterm (34-36 weeks of gestational age (GA)), and early term (37-38 weeks GA) birth rates among singleton live births vary from 3% to 6% and from 15% to 31%, respectively, across countries, although data from low- and middle-income countries are sparse. Countries with high preterm birth rates are more likely to have high early term birth rates; many risk factors are shared, including pregnancy complications (hypertension, diabetes), medical practices (provider initiated delivery, assisted reproduction), maternal socio-demographic and lifestyle characteristics and environmental factors. Exceptions include nulliparity and inflammation which increase risks for preterm, but not early term birth. Birth before 39 weeks GA is associated with adverse child health outcomes across a wide range of settings. International rate variations suggest that reductions in early delivery are achievable; implementation of best practice guidelines for obstetrical interventions and public health policies targeting population risk factors could contribute to prevention of both late preterm and early term births. PMID- 30309814 TI - [Management of Gitelman syndrome during pregnancy reporting 12 cases]. AB - INTRODUCTION: Gitelman syndrome is a rare hereditary renal tubulopathy, responsable of hypokalemia and hypomagnesaemia-related ionic disorders, which management is poorly codified during pregnancy. We report 12 cases of pregnancies with Gitelman syndrome and we compare our data with those of literature. MATERIAL AND METHODS: It is a report of 12 pregnancies in 5 patients with Gitelman syndrome between 2002 and 2016. Follow up and outcome of pregnancy, delivery modalities and maternal-fetal prognosis have been collected. RESULTS: In our serie, maximum kaliemie observed was 3.4mmol/L, with an average potassium, over all pregnancies of 2.3mmol/L. Oral potassium and magnesium supplementation at the end of pregnancy were 8900mg/day and 460mg/day, respectively. There were no serious maternal complications. Two pregnancies were complicated by intrauterine growth retardation in a context of preeclampsia. There is a large disparity in the methods of anesthetic management of these patients. Materno-fetal prognosis at 1 month post-partum is good. CONCLUSION: Gitelman syndrome is a rare pathology where there is a lack of homogeneity in management of pregnancy. Monitoring of monthly ionogram is necessary. The goal is to obtain stable, non-symptomatic kaliemias, which will never be standardized even in increasing treatment. The most important is to inform and detect situations at risk of decompensation, including vomiting or the use of certain anesthetics. In agreement with literature data, monitoring of fetal growth and the amount of amniotic fluid in the third trimester is still warranted. These pregnancies require the development of a common care in multidisciplinary consultation meeting. PMID- 30309815 TI - [L. Marpeau in reply to the article by P. Rozenberg. To the question of elective induction of labor at 39 weeks of gestation, the answer lies in the question. Gynecol Obstet Fertil Senol;46:481-488]. PMID- 30309816 TI - Evaluation of long-term safety, tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (>=1 to <4 years old) with Lennox Gastaut syndrome: Final results from randomized study 303. AB - OBJECTIVE: Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (>=1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS). METHODS: Study 303 (ClinicalTrials.gov identifier NCT01405053) was a multicenter, randomized, open-label, Phase III trial. Patients were randomized (2:1) to oral suspension rufinamide (<=45 mg/kg/day) or any other investigator-chosen antiepileptic drug (AED) for a 2-year treatment period. Primary safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs. Behavioral effects were assessed via the Child Behavior Checklist (CBCL) using the Total Problems score and change from baseline in CBCL Total Problems score. CBCL subscores were also evaluated. RESULTS: The Safety Analysis Set included 37 patients (rufinamide: n = 25; any other AED: n = 12). TEAE incidence was similar between the rufinamide (88.0%) and any-other-AED groups (83.3%); serious TEAE incidence was also similar between treatment groups (40.0% and 41.7%, respectively). Between treatment groups, the difference in the least squares mean CBCL Total Problems score across time was not significant (p = 0.7083), behavior outcomes were similar across all endpoints, and there were no consistent trends in CBCL subscores. SIGNIFICANCE: Long-term (2 years) adjunctive rufinamide was well tolerated in pediatric patients with LGS. Behavioral outcomes were comparable between the rufinamide and any-other-AED groups, however the small sample size and difficulties assessing behavior in this population should be noted. The challenges of this study raise the issue of revising how studies in very young children with rare and complex epilepsies are performed. PMID- 30309817 TI - The Predictive Role of Biomarkers for the Detection of Acute Kidney Injury After Partial or Radical Nephrectomy: A Systematic Review of the Literature. AB - CONTEXT: Postoperative acute kidney injury (AKI) is a serious complication after kidney surgery, associated with prolonged hospital stay, high morbidity, and mortality. Biomarkers represent a tool of increasing importance to identify renal impairment after partial nephrectomy (PN) or radical nephrectomy (RN) in order to optimize and anticipate the diagnosis of AKI. OBJECTIVE: The goal of this systematic review is to investigate current insights on the role of biomarkers in predicting renal impairment in patients undergoing PN or RN. EVIDENCE ACQUISITION: A systematic review was conducted up to November 30, 2017 through PubMed, Scopus, and Embase databases, to identify eligible studies evaluating the role of biomarkers for the prediction of AKI after PN or RN. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria were applied to select articles. EVIDENCE SYNTHESIS: According to the study selection criteria, 10 publications were included with a total number of 728 patients. Incidence of AKI was 26.7% (range: 9-58%). Based on the evidence reviewed, serum cystatin C and urinary neutrophil gelatinase-associated lipocalin (NGAL) showed a significant correlation with serum creatinine rise postoperatively, emerging as potential noninvasive and early biomarkers of AKI in patients undergoing renal surgery. In this setting, serum cystatin C and urinary NGAL have preceded the rise in serum creatinine peak from 3 up to 24h, even in case of mild renal damage. CONCLUSIONS: The literature underlines the potential usefulness of biomarkers such as cystatin C and NGAL as promising and early tools to predict AKI after PN or RN. However, no strong evidence in support of their use is available to date and further investigations are awaited. PATIENT SUMMARY: We looked at the role of biomarkers in predicting renal injury in patients undergoing partial or radical nephrectomy. Serum cystatin C and urinary neutrophil gelatinase-associated lipocalin have emerged as promising noninvasive, accurate, and early biomarkers. PMID- 30309818 TI - HOXA9, PCDH17, POU4F2, and ONECUT2 as a Urinary Biomarker Combination for the Detection of Bladder Cancer in Chinese Patients with Hematuria. AB - BACKGROUND: DNA methylation biomarkers for bladder cancer (BCa) have not been evaluated extensively in the Chinese population. OBJECTIVE: To develop and validate a urinary biomarker combination of methylation assays in a group of Chinese patients with hematuria. DESIGN, SETTING, AND PARTICIPANTS: A total of 192 urine samples were collected and evaluated from patients with microscopic or gross hematuria, including 97 BCa patients and 95 controls with benign diseases. A two-stage study was conducted: the first stage being assay construction and the second stage being assay validation. Eighty-one urine samples were analyzed for the hypermethylation of eight selected genes in stage 1 and then a four-gene panel was constructed. An additional 111 urine samples were analyzed using the four-gene panel (including HOXA9, PCDH17, POU4F2, and ONECUT2) for independent validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The positive predictive value (PPV) and negative predictive value (NPV) were calculated for the combination methylation assay. Uni- and multivariate binary logistic regression analyses (backward elimination, conditional) were performed to calculate the association between BCa and each predictor variable. RESULTS AND LIMITATIONS: The combination assay of HOXA9, PCDH17, POU4F2, and ONECUT2 was selected based on the results of multivariate logistic regression analysis in stage 1. Using a strategy of three-level risk stratification, the assay yielded a consistent PPV of 100%. With an estimated BCa prevalence of 10% in a general hematuria population, the assay would result in an overall NPV of 98%. This combined methylation biomarker would yield an overall area under the receiver operating characteristic curve of 0.871 (with a sensitivity of 90.5% and a specificity of 73.2%) if using the prediction model from multivariate regression analysis. In addition, over half of BCa cases would be predicted accurately and ~60% of unnecessary cystoscopies could be spared. This study had several limitations. First, the sample size was relatively small. Second, it was performed in a case-control population rather than in a natural hematuria cohort. CONCLUSIONS: A combination methylation assay of HOXA9, PCDH17, POU4F2, and ONECUT2 resulted in high PPV and NPV in Chinese patients with hematuria. With accurate risk prediction, the urinary biomarker combination could spare a sizeable proportion of low-risk patients from extensive and invasive examination. PATIENT SUMMARY: In the present study, we looked at the predictive performance of a urinary biomarker combination of HOXA9, PCDH17, POU4F2, and ONECUT2. We found that this urinary biomarker combination may help discriminate bladder cancer from other benign diseases in patients with hematuria, resulting in a reduction of unnecessary invasive examination in patients at low risk. PMID- 30309820 TI - Impact of DNA lesion repair, replication and formation on the mutational spectra of environmental carcinogens: Aflatoxin B1 as a case study. AB - In a multicellular organism, somatic mutations represent a permanent record of the past chemical and biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy. These three factors result in a richly contoured sequence context-dependent mutational spectrum that, from appearances, is distinct for most individual forms of DNA damage. Such a mutagenic legacy, if appropriately decoded, can reveal the local history of genome-altering events such as chemical or pathogen exposures, metabolic stress, and inflammation, which in turn can provide an indication of the underlying causes and mechanisms of genetic disease. Modern tools have positioned us to develop a deep mechanistic understanding of the cellular factors and pathways that modulate a mutational process and, in turn, provide opportunities for better diagnostic and prognostic biomarkers, better exposure risk assessment and even actionable therapeutic targets. The goal of this Perspective is to present a bottom-up, lesion-centric framework of mutagenesis that integrates the contributions of lesion replication, lesion repair and lesion formation to explain the complex mutational spectra that emerge in the genome following exposure to mutagens. The mutational spectra of the well-studied hepatocarcinogen aflatoxin B1 are showcased here as specific examples, but the implications are meant to be generalizable. PMID- 30309819 TI - In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin's Lymphomas. AB - Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19 specific CAR-transduced T cell products (CD19.CARTs), 2G (with CD28 only) and 3G (CD28 and 4-1BB), were infused simultaneously in 16 patients with relapsed or refractory non-Hodgkin's lymphoma. 3G CD19.CARTs had superior expansion and longer persistence than 2G CD19.CARTs. This difference was most striking in the five patients with low disease burden and few circulating normal B cells, in whom 2G CD19.CARTs had limited expansion and persistence and correspondingly reduced area under the curve. Of the 11 patients with measurable disease, three achieved complete responses and three had partial responses. Cytokine release syndrome occurred in six patients but was mild, and no patient required anti-IL-6 therapy. Hence, 3G CD19.CARTs combining 4-1BB with CD28 produce superior CART expansion and may be of particular value when treating low disease burden in patients whose normal B cells are depleted by prior therapy. PMID- 30309821 TI - Portuguese in vitro antibiotic susceptibilities favor current nontuberculous mycobacteria treatment guidelines. AB - SETTING: Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans for which effective treatment is challenging. There is, however, very little information on the prevalence of NTM drug resistance in Portugal. OBJECTIVE AND DESIGN: Our aim was to analyze the drug susceptibility testing (DST) performed in NTM at the Portuguese National Health Institute Dr. Ricardo Jorge from February 2003 to February 2016. A total of 262 DST were included in the analysis. RESULTS: Most (94%) M. avium intracellulare complex isolates showed in vitro susceptibility to clarithromycin. All M. kansasii isolates were susceptible to rifampicin and ethambutol and 97.1% were susceptible to isoniazid. The majority of rapidly growing mycobacteria (RGM) demonstrated in vitro susceptibility to amikacin, clarithromycin and cefoxitin. However, in RGM there was a marked increase on the relative risk of having sulfamethoxazole resistance in isolates resistant to ciprofloxacin compared to susceptible isolates. CONCLUSION: Tested NTM in Portugal revealed in vitro susceptibility to most of the antimicrobials currently recommended for treatment. However, our results also suggest that sulfamethoxazole should be avoided in treatment of RGM resistant to ciprofloxacin (or vice versa). Further trials that correlate the in vitro DST results with the clinical outcome are needed in order to reach conclusions on efficient antimicrobial therapy. PMID- 30309822 TI - "Cold Card" to Guide Responders in the Assessment and Care of Cold-Exposed Patients. AB - INTRODUCTION: A concise, easy-to-use decision aid "Cold Card" that can be carried in the field by wilderness search and rescue teams or medical responders to advise on assessment and care of cold-exposed patients was created. METHODS: A 2 sided card was designed to summarize the important principles established by the Wilderness Medical Society practice guidelines for hypothermia. The card was continually updated through feedback from several content experts. The card was then distributed for further feedback from members of the Search and Rescue Volunteer Association of Canada and enrollees of the Baby It's Cold Outside web based educational program. This additional feedback was used to create the final iteration of the card. RESULTS: On the front "ASSESS COLD PATIENT" side, the level of cold exposure or hypothermia is accomplished by evaluating (as either normal or impaired function) consciousness, movement, shivering, and alertness on a series of concentric rings. The important treatment actions are provided for each cold-exposure level. The back "CARE FOR COLD PATIENT" side provides the required elements and principles of use for a hypothermia wrap. The Cold Card is available for free download and unlimited use for education or in-field instruction by any individual or group. The card should be printed on heavy, waterproof stock (13*18 cm) for use in all weather conditions. CONCLUSIONS: Key elements of hypothermia evaluation and field care have been summarized on a small portable card for laypersons, trained rescuers, and first responders. PMID- 30309823 TI - Emergency Medical Services and Remote Medical Oversight in Sequoia and Kings Canyon National Parks, 2011-2013. AB - INTRODUCTION: The University of California San Francisco Fresno Department of Emergency Medicine provides base hospital support for the Sequoia and Kings Canyon National Parks (SEKI) emergency medical services (EMS) system. This descriptive epidemiologic study reports reasons the park EMS system is used and interventions provided, detailing the nature of patient encounters, type and frequency of injuries and interventions, reasons for base hospital contact, and patient dispositions. METHODS: Patient charts for all EMS encounters in SEKI from 2011 to 2013 were included, and relevant data were extracted by a single reviewer. RESULTS: Of the 704 charts reviewed, 570 (81%) were frontcountry patient encounters (within 1.6 km [1 mi] of a paved road); 100 (14%) were backcountry; and 34 (5%) occurred in undefined locations. Regarding sex and age, 58% of patients were men; 22% were younger than 18 y, and 15% were 65 y or older. More than 80% of calls occurred during the months of June through August. The most common complaints were extremity trauma (24%), torso trauma (13%), and lacerations (9%). Almost 50% of patients were transferred to a higher level of care. Medications were administered to 37% of patients, with oxygen being the most common. Procedures were performed 49% of the time, primarily intravenous access and splinting. Base hospital contact was made 38% of the time, most commonly (54%) for advice regarding disposition. CONCLUSIONS: SEKI EMS providers encounter a wide variety of patients in various settings, including the backcountry. Resource allocation, training, and protocol development should be tailored to meet their needs. PMID- 30309824 TI - Fatal Pulmonary Edema in a Child After Jellyfish Stings in Korea. AB - Jellyfish have been increasing at a global scale in recent years. These blooms not only have deleterious effects on marine ecosystems, they also increase the risk of jellyfish stings and accompanying envenomation. Here, we report a fatal case of pulmonary edema caused by jellyfish envenomation in a child in Korea. The patient died 4 h after envenomation despite cardiopulmonary resuscitation. Nemopilema nomurai was the suspected species of jellyfish encountered by the patient, although we are unable to confirm this. With this case report, we aim to inform on the serious issue of toxicity associated with jellyfish species that bloom mainly along Korean, east Chinese, and Japanese shores and to discuss appropriate first aid methods in case of jellyfish stings. PMID- 30309825 TI - Giant Intracranial Cystic Lesion in a Child. PMID- 30309826 TI - Russell's Viper Envenomation-Associated Addisonian Crisis. AB - Snakebite envenomation is an important public health problem in tropical countries. We report a case of bilateral adrenal hemorrhage in a 28-y-old man with Russell's viper bite that occurred in the Sathyamangalam forest range in the Indian state of Tamil Nadu. In this case, a combination of early bite recognition, hospital-based supportive care, corticosteroid therapy, and timely administration of polyvalent antivenom resulted in a favorable clinical outcome. PMID- 30309827 TI - Medical Incidents and Evacuations on Wilderness Expeditions for the Northwest Outward Bound School. AB - INTRODUCTION: Outdoor education (OE) expeditions travel far from definitive care and have unique epidemiology. Most OE expedition studies have examined a single organization and results may not generalize. This study examines the injuries, illnesses, medical evacuations, and nonmedical incidents of the Northwest Outward Bound School (NWOBS) to broaden our understanding and demonstrate commonalities within the field. METHODS: This retrospective database review examined incidents and evacuations on NWOBS expeditions from June 1, 2014 through October 31, 2016. Incident rates, evacuation rates, and incident type frequencies were calculated. Frequencies of incidents during different expedition time periods were compared with a 1-sample chi2 test. The odds ratio that each type of incident would require evacuation was calculated and compared with other incident types using Fisher exact test. RESULTS: The study period included 59,058 program days, 277 incidents, 143 medical incidents, 75 medical evacuations, and no fatalities. Injuries occurred at a rate of 1.64 per 1000 program days and illnesses at a rate of 0.78 per 1000 program days. The most common injuries were strains, sprains, and trauma or infection of the skin and soft tissue. Most injuries occurred while backpacking, hiking, or moving around camp. The most common illnesses were nausea, vomiting, diarrhea, abdominal pain, asthma, respiratory infections, and urinary tract infections. The medical incidents with the highest odds of evacuation were fractures, urinary tract infections, abdominal pain, and asthma. CONCLUSIONS: Results from the NWOBS database are consistent with those from other expeditionary OE programs. These findings should guide risk-management strategies and staff medical training. PMID- 30309828 TI - Coronectomy root retrievals: a review of 92 cases. AB - BACKGROUND: Coronectomy has become an increasingly prescribed surgical treatment for mandibular third molars that are deemed to pose a risk to the inferior dental nerve. Retention of the roots poses a risk of need for root retrieval in the future if symptoms are present. Long-term outcomes and the symptoms that lead to root retrieval via coronectomy have not been well documented or studied, and this has understandably led to hesitation in some clinicians in offering the procedure. The current series assesses patients who have undergone root retrieval, their reported indications for removal, and the histopathologic status of the removed roots. STUDY DESIGN: A total of 92 cases of root retrievals via coronectomy carried out at Guy's Dental Hospital are included in this analysis. Data were collected retrospectively from patient records regarding patient symptoms, clinical and radiographic findings, function of the inferior dental nerve, and histologic results. RESULTS: The mean age of patients in the study group was 31.6years (range 19-70 years), with a female-to-male ratio of 62:18 (77.5% female). Mean time to the second surgery for root retrieval was 17 months. In "successfully" performed coronectomies, 75.3% (61 of 81) of root pulps appeared vital histopathologically. Mucosal tenderness (39 of 81 [48.1%]) was the most common symptom leading to root retrieval. CONCLUSIONS: Root retrieval after coronectomy should be based on findings from sound clinical and radiographic examinations. In the presence of obvious indications, such as an unhealed socket resulting from retained enamel or soft tissue infection after eruption of roots, then retrieval should be performed with confidence that resolution would occur. However, if the coronectomy root appears an unlikely culprit, then the clinician should consider and investigate alternative diagnoses, such as overerupted upper third molars causing trauma, temporomandibular dysfunction, and the dental status of the adjacent tooth as potential causes of symptoms. PMID- 30309829 TI - Benign and malignant odontogenic neoplasms of the jaws show a concordant nondiscriminatory p63/p40 positive immunophenotype. AB - OBJECTIVES: Antibody p40, which recognizes exclusively DeltaNp63 but not TAp63, has shown diagnostic utility in salivary gland and sinonasal tract malignancies. Although p63 immunophenotypic characterization of odontogenic lesions has been reported, p40 expression has not been previously studied. We aimed to study p40 immunoreactivity in odontogenic tumors (OTs) and odontogenic cysts (OCs) and to investigate possible discriminatory properties of the combined p63/p40 immunoprofile in OTs and OCs. STUDY DESIGN: Fourteen ameloblastomas, 7 adenomatoid odontogenic tumors, 6 calcifying epithelial odontogenic tumors, 1 squamous odontogenic tumor, 4 primary intraosseous odontogenic carcinomas, 5 calcifying odontogenic cysts, 4 glandular odontogenic cysts, 3 odontogenic keratocysts, 3 dentigerous cysts, and 1 each radicular and orthokeratinized cysts were stained for p63 (4A4) and p40 (BC28) antibodies. RESULTS: Ameloblastoma, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor, squamous odontogenic tumor, and primary intraosseous odontogenic carcinoma demonstrated concordant p63+/p40+ immunophenotype. P40, similar to p63, highlighted almost all lesional cells of OTs and, overall, the full thickness of the epithelial lining of the cystic areas of OCs and ameloblastoma. The keratin layer of OKC and the adluminal ductal and mucous cells of GOC were p63-/p40-. CONCLUSIONS: Both DeltaNp63 and TAp63 isoforms are present in neoplastic and developmental odontogenic lesions; and p63/p40 immunophenotype is nondiscriminatory pertaining to benign and malignant OTs and OCs. PMID- 30309830 TI - Impact of salivary hypofunction on incidence of orofungal infections with use of topical steroids for management of oral lichen planus and xerostomia. AB - OBJECTIVES: The aim of this study was to determine if salivary hypofunction increases the incidence of oral fungal infections (OFIs) after topical steroid use for the management of oral lichen planus (OLP). STUDY DESIGN: Patients with a diagnosis of OLP, treated for at least 2 weeks with topical steroids, had baseline salivary flow evaluations completed, and had a follow-up visit within 5 weeks of steroids being prescribed were assessed. Patients were evaluated for clinical signs of fungal infection at follow-up visits. RESULTS: Forty-Seven patients (91% female) met the inclusion criteria, with 21.3% developing an OFI after topical steroid use. Demographic characteristics, type of OLP, steroid used, and antifungal used did not impact the development of an OFI. The mean stimulated salivary flow was significantly lower in the group that developed an OFI compared with the group that did not develop an OFI (8.31 mL/15min vs 15.4 mL/15min, respectively; P = 0.0006). A higher incidence of OFIs occurred in the low stimulated flow group versus the normal flow group (39% vs 4%, respectively). Most patients in the OFI group received a preventative antifungal (90%). CONCLUSIONS: OFIs increased after steroid treatment in patients with OLP who had low stimulated salivary flows. Antifungals (90%) were not effective in preventing OFIs in patients with OLP who had salivary hypofunction and were treated with topical steroids. PMID- 30309831 TI - Nanobodies as novel therapeutic agents in envenomation. AB - BACKGROUND: An effective therapy against envenoming should be a priority in view of the high number scorpion stings and snakebites. Serum therapy is still widely applied to treat the envenomation victims; however this approach suffers from several shortcomings. The employment of monoclonal antibodies might be an outcome as these molecules are at the core of a variety of applications from protein structure determination to cancer treatment. The progress of activities in the twilight zone between genetic and antibody engineering have led to the development of a unique class of antibody fragments. These molecules possess several benefits and lack many possible disadvantages over classical antibodies. Within recombinant antibody formats, nanobodies or single domain antigen binding fragments derived from heavy chain only antibodies in camelids occupy a privileged position. SCOPE OF REVIEW: In this paper we will briefly review the common methods of envenomation treatment and focus on details of various in vivo research activities that investigate the performance of recombinant, monoclonal nanobodies in venom neutralization. MAJOR CONCLUSIONS: Nanobodies bind to their cognate target with high specificity and affinity, they can be produced in large quantities from microbial expression systems and are very robust even when challenged with harsh environmental conditions. Upon administering, they rapidly distribute throughout the body and seem to be well tolerated in humans posing low immunogenicity. GENERAL SIGNIFICANCE: Scorpion and snake envenomation is a major issue in developing countries and nanobodies as a venom-neutralizing agent can be considered as a valuable and promising candidate in envenomation therapy. PMID- 30309832 TI - Eliciting the Impact of Digital Consulting for Young People Living With Long-Term Conditions (LYNC Study): Cognitive Interviews to Assess the Face and Content Validity of Two Patient-Reported Outcome Measures. AB - BACKGROUND: Digital consulting, using email, text, and Skype, is increasingly offered to young people accessing specialist care for long-term conditions. No patient-reported outcome measures (PROMs) have been evaluated for assessing outcomes of digital consulting. Systematic and scoping reviews, alongside patient involvement, revealed 2 candidate PROMs for this purpose: the patient activation measure (PAM) and the physician's humanistic behaviors questionnaire (PHBQ). PAM measures knowledge, beliefs, and skills that enable people to manage their long term conditions. PHBQ assesses the presence of behaviors that are important to patients in their physician-patient interactions. OBJECTIVE: This study aimed to assess the face and content validity of PAM and PHBQ to explore whether they elicit important outcomes of digital consulting and whether the PROMs can isolate the digital consultation component of care. METHODS: Participants were drawn from 5 clinics providing specialist National Health Service care to 16- to 24-year olds with long-term health conditions participating in the wider LYNC (Long-Term Conditions, Young People, Networked Communications) study. Overall, 14 people undertook a cognitive interview in this substudy. Of these, 7 participants were young people with either inflammatory bowel disease, cystic fibrosis, or cancer. The remaining 7 participants were clinicians who were convenience sampled. These included a clinical psychologist, 2 nurses, 3 consultant physicians, and a community youth worker practicing in cancer, diabetes, cystic fibrosis, and liver disease. Cognitive interviews were transcribed and analyzed, and a spreadsheet recorded the participants' PROM item appraisals. Illustrative quotes were extracted verbatim from the interviews for all participants. RESULTS: Young people found 11 of the PAM 13 items and 7 of the additional 8 PAM 22 items to be relevant to digital consulting. They were only able to provide spontaneous examples of digital consulting for 50% (11/22) of the items. Of the 7 clinicians, 4 appraised all PAM 13 items and 20 of the PAM 22 items to be relevant to evaluating digital consulting and articulated operationalization of the items with reference to their own digital consulting practice with greater ease than the young people. Appraising the PHBQ, in 14 of the 25 items, two-thirds of the young people's appraisals offered digital consulting examples with ease, suggesting that young people can detect and discern humanistic clinician behaviors via digital as well as face-to-face communication channels. Moreover, 17 of the 25 items were appraised as relevant by the young people. This finding was mirrored in the clinician appraisals. Both young people and the clinicians found the research task complex. Young participants required considerably more researcher prompting to elicit examples related to digital consulting rather than their face-to-face care. CONCLUSIONS: PAM and PHBQ have satisfactory face and content validity for evaluating digital consulting to warrant proceeding to psychometric evaluation. Completion instructions require revision to differentiate between digital and face-to-face consultations. PMID- 30309833 TI - Drug Repositioning to Accelerate Drug Development Using Social Media Data: Computational Study on Parkinson Disease. AB - BACKGROUND: Due to the high cost and low success rate in new drug development, systematic drug repositioning methods are exploited to find new indications for existing drugs. OBJECTIVE: We sought to propose a new computational drug repositioning method to identify repositioning drugs for Parkinson disease (PD). METHODS: We developed a novel heterogeneous network mining repositioning method that constructed a 3-layer network of disease, drug, and adverse drug reaction and involved user-generated data from online health communities to identify potential candidate drugs for PD. RESULTS: We identified 44 non-Parkinson drugs by using the proposed approach, with data collected from both pharmaceutical databases and online health communities. Based on the further literature analysis, we found literature evidence for 28 drugs. CONCLUSIONS: In summary, the proposed heterogeneous network mining repositioning approach is promising for identifying repositioning candidates for PD. It shows that adverse drug reactions are potential intermediaries to reveal relationships between disease and drug. PMID- 30309834 TI - Patient Perceptions of Their Own Data in mHealth Technology-Enabled N-of-1 Trials for Chronic Pain: Qualitative Study. AB - BACKGROUND: N-of-1 (individual comparison) trials are a promising approach for comparing the effectiveness of 2 or more treatments for individual patients; yet, few studies have qualitatively examined how patients use and make sense of their own patient-generated health data (PGHD) in the context of N-of-1 trials. OBJECTIVE: The objective of our study was to explore chronic pain patients' perceptions about the PGHD they compiled while comparing 2 chronic pain treatments and tracking their symptoms using a smartphone N-of-1 app in collaboration with their clinicians. METHODS: Semistructured interviews were recorded with 33 patients, a consecutive subset of the intervention group in a primary study testing the feasibility and effectiveness of the Trialist N-of-1 app. Interviews were transcribed verbatim, and a descriptive thematic analysis was completed. RESULTS: Patients were enthusiastic about recording and accessing their own data. They valued sharing data with clinicians but also used their data independently. CONCLUSIONS: N-of-1 trials remain a promising approach to evidence based decision making. Patients appear to value their roles as trial participants but place as much or more importance on the independent use of trial data as on comparative effectiveness results. Future efforts to design patient-centered N-of 1 trials might consider adaptable designs that maximize patient flexibility and autonomy while preserving a collaborative role with clinicians and researchers. PMID- 30309835 TI - Tailored, Therapist-Guided Internet-Based Cognitive Behavioral Therapy Compared to Care as Usual for Patients With Rheumatoid Arthritis: Economic Evaluation of a Randomized Controlled Trial. AB - BACKGROUND: Internet-based cognitive behavioral therapy can aid patients with rheumatoid arthritis with elevated levels of distress to enhance their quality of life. However, implementation is currently lacking and there is little evidence available on the (cost-) effectiveness of different treatment strategies. OBJECTIVE: Cost-benefit ratios are necessary for informing stakeholders and motivating them to implement effective treatment strategies for improving health related quality of life (HRQoL) of patients with rheumatoid arthritis. A cost effectiveness study from a societal perspective was conducted alongside a randomized controlled trial on a tailored, therapist-guided internet-based cognitive behavioral therapy (ICBT) intervention for patients with rheumatoid arthritis with elevated levels of distress as an addition to care as usual (CAU). METHODS: Data were collected at baseline or preintervention, 6 months or postintervention, and every 3 months thereafter during the 1-year follow-up. Effects were measured in terms of quality-adjusted life years (QALYs) and costs from a societal perspective, including health care sector costs (health care use, medication, and intervention costs), patient travel costs for health care use, and costs associated with loss of labor. RESULTS: The intervention improved the quality of life compared with only CAU (Delta QALYs=0.059), but at a higher cost (Delta=?4211). However, this increased cost substantially reduced when medication costs were left out of the equation (Delta=?1863). Of all, 93% (930/1000) of the simulated incremental cost-effectiveness ratios were in the north-east quadrant, indicating a high probability that the intervention was effective in improving HRQoL, but at a greater monetary cost for society compared with only CAU. CONCLUSIONS: A tailored and guided ICBT intervention as an addition to CAU for patients with rheumatoid arthritis with elevated levels of distress was effective in improving quality of life. Consequently, implementation of ICBT into standard health care for patients with rheumatoid arthritis is recommended. However, further studies on cost reductions in this population are warranted. TRIAL REGISTRATION: Nederlands Trial Register NTR2100; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2100 (Archived by WebCite at http://www.webcitation.org/724t9pvr2). PMID- 30309836 TI - Applying Persuasive Design Techniques to Influence Data-Entry Behaviors in Primary Care: Repeated Measures Evaluation Using Statistical Process Control. AB - BACKGROUND: Persuasive design is an approach that seeks to change the behaviors of users. In primary care, clinician behaviors and attitudes are important precursors to structured data entry, and there is an impact on overall data quality. We hypothesized that persuasive design changes data-entry behaviors in clinicians and thus improves data quality. OBJECTIVE: The objective of this study was to use persuasive design principles to change clinician data-entry behaviors in a primary care environment and to increase data quality of data held in a family health team's reporting system. METHODS: We used the persuasive systems design framework to describe the persuasion context. Afterward, we designed and implemented new features into a summary screen that leveraged several persuasive design principles. We tested the influence of the new features by measuring its impact on 3 data quality measures (same-day entry, record completeness, and data validity). We also measured the impacts of the new features with a paired pre post t test and generated XmR charts to contextualize the results. Survey responses were also collected from users. RESULTS: A total of 53 users used the updated system that incorporated the new features over the course of 8 weeks. Based on a pre-post analysis, the new summary screen successfully encouraged users to enter more of their data on the same day as their encounter. On average, the percentage of same-day entries rose by 10.3% for each user (P<.001). During the first month of the postimplementation period, users compensated by sacrificing aspects of data completeness before returning to normal in the second month. Improvements to record validity were marginal over the study period (P=.05). Statistical process control techniques allowed us to study the XmR charts to contextualize our results and understand trends throughout the study period. CONCLUSIONS: By conducting a detailed systems analysis and introducing new persuasive design elements into a data-entry system, we demonstrated that it was possible to change data-entry behavior and influence data quality in a reporting system. The results show that using persuasive design concepts may be effective in influencing data-entry behaviors in clinicians. There may be opportunities to continue improving this approach, and further work is required to perfect and test additional designs. Persuasive design is a viable approach to encourage clinician user change and could support better data capture in the field of medical informatics. PMID- 30309838 TI - Seven days in medicine: 3-9 October 2018. PMID- 30309839 TI - ProDiet: A Phase II Randomized Placebo-controlled Trial of Green Tea Catechins and Lycopene in Men at Increased Risk of Prostate Cancer. AB - Epidemiologic studies suggest that diet can alter prostate cancer risk. This study aimed to establish the feasibility and acceptability of dietary modification in men at increased risk of prostate cancer. Men were invited with a PSA level of 2.0-2.95 ng/mL or 3.0-19.95 ng/mL with negative prostate biopsies. Randomization (3 * 3 factorial design) to daily green tea and lycopene: green tea drink (3 cups, unblinded) or capsules [blinded, 600 mg flavan-3-ol () epigallocatechin-3-gallate (EGCG) or placebo] and lycopene-rich foods (unblinded) or capsules (blinded, 15 mg lycopene or placebo) for 6 months. Primary endpoints were randomization rates and intervention adherence (blinded assessment of metabolites) at 6 months with secondary endpoints of acceptability (from interviews), safety, weight, blood pressure, and PSA. A total of 133 of 469 (28.4%) men approached agreed to be randomized and 132 were followed-up (99.2%). Mean lycopene was 1.28 [95% confidence intervals (CI), 1.09-1.50, P = 0.003] times higher in the lycopene capsule group and 1.42 (95% CI, 1.21-1.66; P < 0.001) times higher in the lycopene-enriched diet group compared with placebo capsules. Median EGCG was 10.7 nmol/L (95% CI, 7.0-32.0) higher in in the active capsule group and 20.0 nmol/L (95% CI, 0.0-19.0) higher in the green tea drink group compared with placebo capsules (both P < 0.001). All interventions were acceptable and well tolerated although men preferred the capsules. Dietary prevention is acceptable to men at risk of prostate cancer. This intervention trial demonstrates that a chemoprevention clinical trial is feasible. Cancer Prev Res; 11(11); 687-96. (c)2018 AACR. PMID- 30309840 TI - Clinical and Regulatory Considerations for Central Venous Catheters for Hemodialysis. AB - Central venous catheters remain a vital option for access for patients receiving maintenance hemodialysis. There are many important and evolving clinical and regulatory considerations for all stakeholders for these devices. Innovation and transparent and comprehensive regulatory review of these devices is essential to stimulate innovation to help promote better outcomes for patients receiving maintenance hemodialysis. A workgroup that included representatives from academia, industry, and the US Food and Drug Administration was convened to identify the major design considerations and clinical and regulatory challenges of central venous catheters for hemodialysis. Our intent is to foster improved understanding of these devices and provide the foundation for strategies to foster innovation of these devices. PMID- 30309837 TI - Efficacy and Moderation of Mobile App-Based Programs for Mindfulness-Based Training, Self-Compassion Training, and Cognitive Behavioral Psychoeducation on Mental Health: Randomized Controlled Noninferiority Trial. AB - BACKGROUND: Mindfulness-based interventions, self-compassion training, and cognitive behavioral therapy have garnered much evidence in its salutary effects on mental health. With increasing application of smartphone and mobile technology on health promotion, this study investigated the efficacy and possible moderators of mindfulness, self-compassion, and cognitive behavioral psychoeducation training mobile apps in the improvement of mental health. OBJECTIVE: The aim of this study was to examine the efficacy of 3 mobile app-based programs: mindfulness-based program, self-compassion program, and cognitive behavioral psychoeducation program in improving mental well-being and reducing psychological distress. Changes in mindful awareness and self-compassion were also assessed. To further delineate the suitability of each program for different types of individuals, individual difference variables (ie, discomfort with emotions and tolerance for ambiguity) were explored for potential moderation. METHODS: This study was a 3-arm, randomized, controlled, noninferiority trial examining the efficacy of mindfulness-based program, self-compassion program, and cognitive behavioral psychoeducation. Participants were randomized into either 1 of the 3 conditions. Throughout the 4-week, 28-session program, participants spent 10-15 min daily reviewing the course content and practicing various related exercises. At preprogram, postprogram, and 3-month follow-up, participants also completed Web-based measures of mental well-being, psychological distress, mindful awareness, and self-compassion as well as the proposed moderators. RESULTS: Among the 2161 study participants, 508 and 349 completed the post- and 3-month follow up assessment, respectively. All 3 conditions (mindfulness-based program: N=703; cognitive behavioral psychoeducation: N=753; self-compassion program: N=705) were found to be efficacious in improving mental well-being and reducing psychological distress. All conditions enhanced mindful awareness at postprogram. Significant interaction effect was found on self-compassion; cognitive behavioral psychoeducation and self-compassion program, but not mindfulness-based program, significantly enhanced self-compassion at postprogram. No significant differences regarding usage and users' satisfaction were found among the 3 conditions. None of the proposed moderators were found to be significant. CONCLUSIONS: Mindfulness based, self-compassion, and cognitive behavioral psychoeducation mobile apps were efficacious in improving mental well-being and reducing psychological distress among adults at postprogram and 3-month follow-up. Future app-based psychological training programs should consider gamification and personalization of content or feedback to enhance engagement and mitigate the high attrition rates that are common in app-based health promotion programs. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) ChiCTR-TRC-13003468; http://www.chictr.org.cn/hvshowproject.aspx?id=6220 (Archived by WebCite at http://www.webcitation.org/734PlOz50). PMID- 30309841 TI - NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy. AB - Parkin-mediated mitophagy is a quality control pathway that selectively removes damaged mitochondria via the autophagic machinery. Autophagic receptors, which interact with ubiquitin and Atg8 family proteins, contribute to the recognition of damaged mitochondria by autophagosomes. NDP52, an autophagy receptor, is required for autophagic engulfment of damaged mitochondria during mitochondrial uncoupler treatment. The N-terminal SKICH domain and C-terminal zinc finger motif of NDP52 are both required for its function in mitophagy. While the zinc finger motif contributes to poly-ubiquitin binding, the function of the SKICH domain remains unclear. Here, we show that NDP52 interacts with mitochondrial RNA poly(A) polymerase (MTPAP) via the SKICH domain. During mitophagy, NDP52 invades depolarized mitochondria and interacts with MTPAP dependent on the proteasome but independent of ubiquitin binding. Loss of MTPAP reduces NDP52-mediated mitophagy, and the NDP52-MTPAP complex attracts more LC3 than NDP52 alone. These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria. PMID- 30309842 TI - Optimization of Acquisition and Analysis Methods for Clinical Dynamic Susceptibility Contrast MRI Using a Population-Based Digital Reference Object. AB - BACKGROUND AND PURPOSE: The accuracy of DSC-MR imaging CBV maps in glioblastoma depends on acquisition and analysis protocols. Multisite protocol heterogeneity has challenged standardization initiatives due to the difficulties of in vivo validation. This study sought to compare the accuracy of routinely used protocols using a digital reference object. MATERIALS AND METHODS: The digital reference object consisted of approximately 10,000 simulated voxels recapitulating typical signal heterogeneity encountered in vivo. The influence of acquisition and postprocessing methods on CBV reliability was evaluated across 6912 parameter combinations, including contrast agent dosing schemes, pulse sequence parameters, field strengths, and postprocessing methods. Accuracy and precision were assessed using the concordance correlation coefficient and coefficient of variation. RESULTS: Across all parameter space, the optimal protocol included full-dose contrast agent preload and bolus, intermediate (60 degrees ) flip angle, 30-ms TE, and postprocessing with a leakage-correction algorithm (concordance correlation coefficient = 0.97, coefficient of variation = 6.6%). Protocols with no preload or fractional dose preload and bolus using these acquisition parameters were generally less robust. However, a protocol with no preload, full dose bolus, and low (30 degrees ) flip angle performed very well (concordance correlation coefficient = 0.93, coefficient of variation = 8.7% at 1.5T and concordance correlation coefficient = 0.92, coefficient of variation = 8.2% at 3T). CONCLUSIONS: Schemes with full-dose preload and bolus maximize CBV accuracy and reduce variability, which could enable smaller sample sizes and more reliable detection of CBV changes in clinical trials. When a lower total contrast agent dose is desired, use of a low flip angle, no preload, and full-dose bolus protocol may provide an attractive alternative. PMID- 30309844 TI - The Woven EndoBridge Finally Coming Home across the Atlantic: What to Expect? PMID- 30309843 TI - MR Venous Flow in Sigmoid Sinus Diverticulum. AB - BACKGROUND AND PURPOSE: Case reports demonstrate that coiling of a sigmoid sinus diverticulum can treat pulsatile tinnitus. We hypothesized that MR imaging 4D flow and computational fluid dynamics would reveal distinct blood flow patterns in the venous outflow tract in these patients. MATERIALS AND METHODS: Patients with pulsatile tinnitus of suspected venous etiology underwent MR imaging at 3T, using venous phase contrast-enhanced MR angiography, 4D flow, and 2D phase contrast. The contrast-enhanced MRA contours were evaluated to determine the presence and extent of a sigmoid sinus diverticulum. Computational fluid dynamics analysis was performed using the 4D flow inlet flow and the luminal contours from contrast-enhanced MRA as boundary conditions. In addition, computational fluid dynamics was performed for the expected post treatment conditions by smoothing the venous geometry to exclude the sigmoid sinus diverticulum from the anatomic boundary conditions. Streamlines were generated from the 4D flow and computational fluid dynamics velocity maps, and flow patterns were examined for the presence of rotational components. RESULTS: Twenty-five patients with pulsatile tinnitus of suspected venous etiology and 10 control subjects were enrolled. Five (20%) of the symptomatic subjects had sigmoid sinus diverticula, all associated with an upstream stenosis. In each of these patients, but none of the controls, a stenosis-related flow jet was directed toward the opening of the sigmoid sinus diverticulum with rotational flow patterns in the sigmoid sinus diverticulum and parent sigmoid sinus on both 4D flow and computational fluid dynamics. CONCLUSIONS: Consistent patterns of blood flow can be visualized in a sigmoid sinus diverticulum and the parent sinus using 4D flow and computational fluid dynamics. Strong components of rotational blood flow were seen in subjects with sigmoid sinus diverticula that were absent in controls. PMID- 30309845 TI - Balloon-Guide Catheters Are Needed for Effective Flow Reversal during Mechanical Thrombectomy. AB - BACKGROUND AND PURPOSE: Blood flow management in the carotid artery during mechanical thrombectomy is crucial for safety and effectiveness. There is an ongoing discussion about whether balloon-guide catheters or large-bore sheaths are needed for effective flow management. We compared general flow characteristics of proximal aspiration through a large-bore sheath and a balloon guide catheter in a porcine in vivo model. MATERIALS AND METHODS: We investigated blood flow in a porcine common carotid artery with and without aspiration (VacLok syringe and Penumbra pump, Pump MAX) through an 8F-long sheath and an 8F balloon guide catheter. Blood hemodynamics were assessed via continuous duplex sonography. RESULTS: Average vessel diameter and baseline blood flow were 4.4 +/- 0.2 mm and 244 +/- 20 mL/min, respectively. For the 8F sheath, pump aspiration resulted in a significant flow reduction (225 +/- 25 mL/min, P < .001), but with a persisting antegrade stream. Manual aspiration resulted in collapse of the vessel in 2 of 7 measurements and oscillatory flow with antegrade systolic and retrograde diastolic components in the remaining 5 measurements. Net flow was antegrade (52 +/- 44 mL/min) in 3 and retrograde (-95 +/- 52 mL/min) in the remaining 2 measurements. For balloon-guide catheters, balloon inflation always resulted in flow arrest. Additional pump or manual aspiration resulted in significant flow reversal of -1100 +/- 230 and -468 +/- 46 mL/min, respectively (both, P < .001). CONCLUSIONS: Only balloon-guide catheters allow reliable blood flow arrest and flow reversal in combination with aspiration via syringes or high flow pump systems. Aspiration through an 8F sheath results in either collapse of the vessel or oscillatory flow, which can result in a net antegrade or retrograde stream. PMID- 30309847 TI - GMC investigators get training to include system issues in fitness to practise decisions. PMID- 30309846 TI - Cerebral Blood Flow and Marrow Diffusion Alterations in Children with Sickle Cell Anemia after Bone Marrow Transplantation and Transfusion. AB - BACKGROUND AND PURPOSE: Hematopoietic marrow hyperplasia and hyperperfusion are compensatory mechanisms in sickle cell anemia. We have observed marrow diffusion and arterial spin-labeling perfusion changes in sickle cell anemia following bone marrow transplantation. We aimed to compare arterial spin-labeling perfusion and marrow diffusion/ADC values in patients with sickle cell anemia before and after bone marrow transplantation or transfusion. MATERIALS AND METHODS: We reviewed brain MRIs from patients with sickle cell anemia obtained during 6 consecutive years at a children's hospital. Quantitative marrow diffusion values were procured from the occipital and sphenoid bones. Pseudocontinuous arterial spin labeling perfusion values (milliliters/100 g of tissue/min) of MCA, anterior cerebral artery, and posterior cerebral artery territories were determined. Territorial CBF, whole-brain average CBF, and marrow ADC values were compared for changes before and after either bone marrow transplantation or transfusion. Bone marrow transplantation and transfusion groups were compared. Two-tailed paired and unpaired Student t tests were used; P < .05 was considered significant. RESULTS: Fifty-three examinations from 17 patients with bone marrow transplantation and 29 examinations from 9 patients with transfusion were included. ADC values significantly increased in the sphenoid and occipital marrow following bone marrow transplantation in contrast to patients with transfusion (P > .83). Whole-brain mean CBF significantly decreased following bone marrow transplantation (77.39 +/- 13.78 to 60.39 +/- 13.62 ml/100 g tissue/min; P < .001), without significant change thereafter. CBF did not significantly change following the first (81.11 +/- 12.23 to 80.25 +/- 8.27 ml/100 g tissue/min; P = .47) or subsequent transfusions. There was no significant difference in mean CBF between groups before intervention (P = .22). CONCLUSIONS: Improved CBF and marrow diffusion eventuate following bone marrow transplantation in children with sickle cell anemia in contrast to transfusion therapy. PMID- 30309848 TI - Selective loss of function variants in IL6ST cause Hyper-IgE Syndrome with distinct impairments of T cell phenotype and function. AB - Hyper-IgE Syndromes comprise a group of inborn errors of immunity. STAT3 deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in PBMCs as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T helper 17-enriched subsets) and non-conventional CD8+ T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T cell subsets. PMID- 30309849 TI - Finely-tuned regulation of AMP-activated protein kinase (AMPK) is crucial for human adult erythropoiesis. AB - AMP-activated protein kinase is a heterotrimeric complex containing alpha, beta, and gamma subunits involved in maintaining integrity and survival of murine red blood cells (RBC). Indeed, Ampk alpha1-/-, Ampk b1-/- and Ampk gamma1-/- mice present a hemolytic anemia and their RBC show elasticity defects in their plasma membrane. The membrane composition evolves continuously along erythropoiesis and during RBC maturation; defects due to the absence of AMPK could be initiated during erythropoiesis. Therefore, we aim to study the role of AMPK during human erythropoiesis. Our data show that AMPK activation followed 2 distinct phases in primary erythroblasts. The phosphorylation of AMPK (Thr172) and its target ACC (Ser79) is elevated in immature (GPAlow) erythroblasts, then decreased conjointly with the erythroid differentiation. In erythroblasts, the knockdown of the alpha1 catalytic subunit by shRNA induces a decrease in cell proliferation and alterations in the expression of membrane proteins (BAND3 and GPA) associated with an increase in phosphorylation of ADDUCIN (Ser726) AMPK activation in mature (GPAhigh) erythroblasts through the use of direct activators (GSK621 and 991) induces cell cycle arrest in the S phase, the induction of autophagy and caspase dependent apoptosis, whereas no such effect is observed in similarly-treated immature erythroblasts. Thus, our work suggests that AMPK activation during the final stages of erythropoiesis is deleterious. As the use of direct AMPK activators is being considered as a therapeutic treatment in several pathologies (diabetes, acute myeloid leukemia), this observation is pivotal. Our data highlighted the importance of the finely-tuned regulation of AMPK during human erythropoiesis. PMID- 30309850 TI - Association of anemia with health-related quality of life and survival: a large population-based cohort study. AB - Anemia is highly prevalent, especially in older individuals. In selected populations, anemia has been reported to be associated with impaired survival and health-related quality of life. However, data on this impact in the general population are rare. Furthermore, discussions on the optimal definition of anemia have not been conclusive. We used survival data, scores from a health-related quality of life questionnaire (RAND-36), and hemoglobin concentration from 138670 subjects participating in the Lifelines cohort, aged 18-93 years. Anemia was defined according to World Health Organization criteria and was further classified in participants >60 years. Anemia was present in 5510 subjects (4.0%) of who 516 individuals older than 60 years were anemic (2.8%). Anemia had no impact on overall survival and limited impact on health-related quality of life in individuals <60 years. In contrast, in individuals >60 years anemia significantly impaired overall survival and health-related quality of life. The lower health-related quality of life was mainly observed in subscales representing physical functioning. Especially anemia of chronic inflammation was associated with worse overall survival and decreased health-related quality of life. Multivariate models confirmed that anemia was an independent risk factor for decreased health-related quality of life in older individuals. Finally, women with a hemoglobin concentration between 12.0-13.0 g/dL (considered anemia in men, but not in women) experienced a significantly lower health-related quality of life. This large prospective population-based study indicates that anemia is associated with worse overall survival and health-related quality of life in older individuals, but not in younger individuals. This study challenges the sex dependent definition of anemia in individuals >60 years, and suggests that the optimal definition of anemia, in the perspective of health-related quality of life, in both men and women >60 years is a hemoglobin concentration <13.0 g/dL (8.0 mmol/L). PMID- 30309851 TI - Targeting the ER-mitochondria interface sensitizes leukemia cells towards cytostatics. AB - Combination chemotherapy has proved to be a favorable strategy to treat acute leukemia. However, the introduction of novel compounds remains challenging and is hindered by a lack of understanding their mechanistic interaction with established drugs. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug resistant cells and patient derived xenograft cells by combining the recently introduced protein disulfide isomerase inhibitor PS89 with cytostatics. In leukemic cells, a proteomics based target fishing approach disclosed that PS89 impacts a whole network of endoplasmic reticulum homeostasis proteins. We elucidate that the strong apoptosis induction in combination with cytostatics is orchestrated by the PS89 target B-cell receptor-associated protein 31, which transduces apoptosis signals at the ER-mitochondria interface. Activation of caspase-8 and cleavage of BAP31 stimulate a pro-apoptotic crosstalk including endoplasmic reticulum calcium release and increased reactive oxygen species levels resulting in amplification of mitochondrial apoptosis. This study promotes PS89 as a novel chemosensitizing agent for acute leukemia treatment and uncovers that targeting the endoplasmic reticulum-mitochondria network of cell death is a promising approach in combination therapy. PMID- 30309853 TI - CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth. AB - Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenvironment formation and tumor growth. Using the CCR5 antagonist maraviroc and a neutralizing anti-CCL5 antibody, we found that CCL5 secreted by Classic Hodgkin lymphoma cells recruited Mesenchymal-stromal cells and monocytes. Education of Mesenchymal-stromal cells by tumor cell conditioned medium enhanced Mesenchymal-stromal cells proliferation and CCL5 secretion. In turn, educated Mesenchymal-stromal cell conditioned medium increased the clonogenic growth of tumor cells and monocyte migration, but these effects were reduced by maraviroc. Monocyte education by tumor cell conditioned medium induced their growth and reprogrammed them towards immunosuppressive tumor-associated macrophages that expressed IDO and PD-L1 and secreted IL-10, CCL17 and TGF-beta. Educated-monocyte conditioned medium slowed the growth of phytohemagglutinin activated lymphocytes. Maraviroc decreased tumor cell growth and synergized with doxorubicin and brentuximab vedotin. A three-dimensional heterospheroid assay showed that maraviroc counteracted both the formation and viability of heterospheroids generated by co-cultivation of tumor cells with Mesenchymal stromal cell and monocytes. In mice bearing tumor cell xenografts, maraviroc reduced tumor growth by more than 50% and inhibited monocyte accumulation, without weight loss. Finally, in classic Hodgkin lymphoma human tumor tissues, CCL5 and CD68 expression correlated positively, and patients with high CCL5 levels had poor prognosis. PMID- 30309852 TI - Targeted next generation sequencing reveals high mutation frequency of CREBBP, BCL2 and KMT2D in high-grade B-cell lymphoma with MYC and BCL2 and /or BCL6 rearrangements. PMID- 30309854 TI - Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. AB - The role of subclonal TP53 mutations defined by a variant allele frequency of <20% has not been addressed in acute myeloid leukemia yet. We, therefore, analyzed their prognostic value in a cohort of 1537 patients with newly diagnosed disease, prospectively treated within 3 trials of the German-Austrian Acute Myeloid Leukemia Study Group. Mutational analysis was performed by targeted deep sequencing and patients with TP53 mutations were categorized by their variant allele frequency into groups of >40%, 20%-40% and <20%, respectively. A total of 108 TP53 mutations were found in 98 patients (6.4%). Among those, 61 patients showed variant allele frequencies >40%,19 between 20% and 40% and 18 <20%. Compared to specimens with clonal TP53 mutations, those with subclonal ones showed significantly fewer complex karyotypes and chromosomal losses. In either TP53 mutated group, patients experienced significantly fewer complete responses (P <0.001) and had worse overall and event-free survival rates (P <0.0001). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of acute myeloid leukemia, the adverse prognostic effect of TP53 mutations remained significant for all TP53 mutated subgroups. These data suggest that subclonal TP53 mutations are a novel prognostic parameter in acute myeloid leukemia and emphasize the usefulness of next-generation sequencing technologies for risk stratification in that disorder. The study was registered as ClinicalTrials.gov number, NCT00146120. PMID- 30309856 TI - Professor must be supervised for three years after improperly pursuing emotional relationship with patient. PMID- 30309857 TI - FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. AB - Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals, East Hanover, NJ) is a CD19 directed genetically-modified autologous T-cell immunotherapy. On August 30, 2017, the U.S. Food and Drug Administration approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR and minimal residual disease (MRD) < 0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% CI 50% - 75%) and all CRs had MRD < 0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurological events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit-risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval. PMID- 30309855 TI - Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. AB - The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific Cox15 knockout mouse (Cox15 sm/sm ). Rapamycin treatment restored autophagic flux, which was impaired in naive Cox15 sm/sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15 sm/sm mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15 sm/sm animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in Cox15 sm/sm muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1-dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin. PMID- 30309858 TI - Deep Learning to Distinguish Recalled but Benign Mammography Images in Breast Cancer Screening. AB - PURPOSE: False positives in digital mammography screening lead to high recall rates, resulting in unnecessary medical procedures to patients and health care costs. This study aimed to investigate the revolutionary deep learning methods to distinguish recalled but benign mammography images from negative exams and those with malignancy. EXPERIMENTAL DESIGN: Deep learning convolutional neural network (CNN) models were constructed to classify mammography images into malignant (breast cancer), negative (breast cancer free), and recalled-benign categories. A total of 14,860 images of 3,715 patients from two independent mammography datasets: Full-Field Digital Mammography Dataset (FFDM) and a digitized film dataset, Digital Dataset of Screening Mammography (DDSM), were used in various settings for training and testing the CNN models. The ROC curve was generated and the AUC was calculated as a metric of the classification accuracy. RESULTS: Training and testing using only the FFDM dataset resulted in AUC ranging from 0.70 to 0.81. When the DDSM dataset was used, AUC ranged from 0.77 to 0.96. When datasets were combined for training and testing, AUC ranged from 0.76 to 0.91. When pretrained on a large nonmedical dataset and DDSM, the models showed consistent improvements in AUC ranging from 0.02 to 0.05 (all P > 0.05), compared with pretraining only on the nonmedical dataset. CONCLUSIONS: This study demonstrates that automatic deep learning CNN methods can identify nuanced mammographic imaging features to distinguish recalled-benign images from malignant and negative cases, which may lead to a computerized clinical toolkit to help reduce false recalls. PMID- 30309859 TI - Collaboration between academics and industry in clinical trials: cross sectional study of publications and survey of lead academic authors. PMID- 30309861 TI - New onset atrial fibrillation, prominent chest wall veins, and dyspnoea. PMID- 30309862 TI - Mouse Models for Cancer Immunotherapy Research. AB - Immunotherapy has revolutionized cancer therapy, largely attributed to the success of immune-checkpoint blockade. However, there are subsets of patients across multiple cancers who have not shown robust responses to these agents. A major impediment to progress in the field is the availability of faithful mouse models that recapitulate the complexity of human malignancy and immune contexture within the tumor microenvironment. These models are urgently needed across all malignancies to interrogate and predict antitumor immune responses and therapeutic efficacy in clinical trials. Herein, we seek to review pros and cons of different cancer mouse models, and how they can be used as platforms to predict efficacy and resistance to cancer immunotherapies.Significance: Although immunotherapy has shown substantial benefit in the treatment of a variety of malignancies, a key hurdle toward the advancement of these therapies is the availability of immunocompetent preclinical mouse models that recapitulate human disease. Here, we review the evolution of preclinical mouse models and their utility as coclinical platforms for mechanistic interrogation of cancer immunotherapies. Cancer Discov; 8(11); 1358-65. (c)2018 AACR. PMID- 30309863 TI - Heartbeat: commuting and cardiovascular health. PMID- 30309860 TI - Gfi1aa and Gfi1b set the pace for primitive erythroblast differentiation from hemangioblasts in the zebrafish embryo. AB - The transcriptional repressors Gfi1(a) and Gfi1b are epigenetic regulators with unique and overlapping roles in hematopoiesis. In different contexts, Gfi1 and Gfi1b restrict or promote cell proliferation, prevent apoptosis, influence cell fate decisions, and are essential for terminal differentiation. Here, we show in primitive red blood cells (prRBCs) that they can also set the pace for cellular differentiation. In zebrafish, prRBCs express 2 of 3 zebrafish Gfi1/1b paralogs, Gfi1aa and Gfi1b. The recently identified zebrafish gfi1aa gene trap allele qmc551 drives erythroid green fluorescent protein (GFP) instead of Gfi1aa expression, yet homozygous carriers have normal prRBCs. prRBCs display a maturation defect only after splice morpholino-mediated knockdown of Gfi1b in gfi1aa qmc551 homozygous embryos. To study the transcriptome of the Gfi1aa/1b double-depleted cells, we performed an RNA-Seq experiment on GFP-positive prRBCs sorted from 20-hour-old embryos that were heterozygous or homozygous for gfi1aa qmc551 , as well as wt or morphant for gfi1b We subsequently confirmed and extended these data in whole-mount in situ hybridization experiments on newly generated single- and double-mutant embryos. Combined, the data showed that in the absence of Gfi1aa, the synchronously developing prRBCs were delayed in activating late erythroid differentiation, as they struggled to suppress early erythroid and endothelial transcription programs. The latter highlighted the bipotent nature of the progenitors from which prRBCs arise. In the absence of Gfi1aa, Gfi1b promoted erythroid differentiation as stepwise loss of wt gfi1b copies progressively delayed Gfi1aa-depleted prRBCs even further, showing that Gfi1aa and Gfi1b together set the pace for prRBC differentiation from hemangioblasts. PMID- 30309865 TI - Associations of egg consumption with cardiovascular disease. PMID- 30309864 TI - Regarding associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults. PMID- 30309866 TI - Healthy dietary pattern with daily egg consumption might be the true factor associated with decreased risks of cardiovascular diseases and mortality. PMID- 30309867 TI - Cardiovascular benefit of egg consumption is most unlikely. PMID- 30309868 TI - Please allow me to introduce myself. PMID- 30309869 TI - Ce n'est qu'un au revoir. PMID- 30309871 TI - Managing long term indwelling urinary catheters. PMID- 30309870 TI - When to include clinical study reports and regulatory documents in systematic reviews. AB - Reporting bias is a major threat to the validity and credibility of systematic reviews. This article outlines the rationale for accessing clinical study reports and other regulatory documents (regulatory data) as a means of addressing reporting bias and identifies factors that may help decide whether (or not) to include regulatory data in systematic reviews. The article also describes the origins and current state of regulatory data access and summarises a survey of current systematic reviewers' practices in considering regulatory data for inclusion in systematic reviews. How to access and extract regulatory data is not addressed. Organisations and other stakeholders such as Cochrane should encourage the use of data from clinical study reports as an important source of data in reviews of pharmaceutical interventions particularly when the intervention in question is of high importance and the risk of reporting bias is great. PMID- 30309872 TI - 2008-2018: a decade of recommendations for systemic lupus erythematosus. PMID- 30309873 TI - Care Quality Commission finds growing inequalities in access to health and social care in England. PMID- 30309874 TI - A new triple threat to CLL. PMID- 30309875 TI - Three strikes to a hemophilic joint bleed. PMID- 30309876 TI - Brain iron in sickle cell disease? PMID- 30309877 TI - Patchy hematopoiesis mimicking bone metastasis. PMID- 30309878 TI - Hyperviscosity syndrome in splenic marginal zone lymphoma. PMID- 30309879 TI - Prevention of perinatal nicotine-induced bone marrow mesenchymal stem cell myofibroblast differentiation by augmenting the lipofibroblast phenotype. AB - Perinatal nicotine exposure drives the differentiation of alveolar lipofibroblasts (LIFs), which are critical for lung injury repair, to myofibroblasts (MYFs), which are the hallmark of chronic lung disease. Bone marrow-derived mesenchymal stem cells (BMSCs) are important players in lung injury repair; however, how these cells are affected with perinatal nicotine exposure and whether these can be preferentially driven to a lipofibroblastic phenotype are not known. We hypothesized that perinatal nicotine exposure would block offspring BMSCs lipogenic differentiation, driving these cells toward a MYF phenotype. Since peroxisome proliferator activated-receptor gamma (PPARgamma) agonists can prevent nicotine-induced MYF differentiation of LIFs, we further hypothesized that the modulation of PPARgamma expression would inhibit nicotine's myogenic effect on BMSCs. Sprague Dawley dams were perinatally administered nicotine (1 mg/kg bodyweight) with or without the potent PPARgamma agonist rosiglitazone (RGZ), both administered subcutaneously. At postnatal day 21, BMSCs were isolated and characterized morphologically, molecularly, and functionally for their lipogenic and myogenic potentials. Perinatal nicotine exposure resulted in decreased oil red O staining, triolein uptake, expression of PPARgamma, and its downstream target gene adipocyte differentiation-related protein by BMSCs, but enhanced alpha-smooth muscle actin and fibronectin expression, and activated Wnt signaling, all features indicative of their inhibited lipogenic, but enhanced myogenic potential. Importantly, concomitant treatment with RGZ virtually blocked all of these nicotine-induced morphologic, molecular, and functional changes. Based on these data, we conclude that BMSCs can be directionally induced to differentiate into the lipofibroblastic phenotype, and PPARgamma agonists can effectively block perinatal nicotine-induced MYF transdifferentiation, suggesting a possible molecular therapeutic approach to augment BMSC's lung injury/repair potential. PMID- 30309880 TI - Chimeric padlock and iLock probes for increased efficiency of targeted RNA detection. AB - Many approaches exist to detect RNA using complementary oligonucleotides. DNA ligation-based techniques can improve discrimination of subtle sequence variations, but they have been difficult to implement for direct RNA analysis due to the infidelity and inefficiency of most DNA ligases on RNA. In this report, we have systematically studied if ribonucleotide substitutions in padlock probes can provide higher catalytic efficiencies for Chlorella virus DNA ligase (PBCV-1 DNA ligase) and T4RNA ligase 2 (T4Rnl2) on RNA. We provide broad characterisation of end-joining fidelity for both enzymes in RNA-templated 3'-OH RNA/5'-pDNA chimeric probe ligation. Both ligases showed increased ligation efficiency towards chimeric substrates on RNA. However, end-joining fidelity of PBCV-1 DNA ligase remained poor, while T4Rnl2 showed a somewhat better end-joining fidelity compared to PBCV-1 DNA ligase. The recently presented invader padlock (iLock) probes overcome the poor end-joining fidelity of PBCV-1 DNA ligase by the requirement of target dependent 5' flap removal prior to ligation. Here we show that two particular ribonucleotide substitutions greatly improve activation and ligation rate of chimeric iLock probes on RNA. We characterised the end-joining efficiency and fidelity of PBCV-1 DNA ligase and T4Rnl2 with chimeric iLock probes on RNA and found that both enzymes exhibit high ligation fidelities for single nucleotide polymorphisms on RNA. Finally, we applied the chimeric probe concept to directly differentiate between human and mouse ACTB mRNA in situ demonstrating chimeric padlock and iLock probes as superior to their DNA equivalents. PMID- 30309881 TI - APOBEC1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver. AB - Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in-vitro RNA editing, A1cf-/- mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in A1cf-/- mice and no changes in either liver- or intestine-specific A1CF transgenic mice. Rbm47 liver-specific knockout (Rbm47LKO) mice demonstrated reduced editing in a subset (11 of 20) RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity) in intestine-specific (Rbm47IKO) mice with only 5 of 53 targets exhibiting C-to-U RNA editing. Double knockout of A1cf and Rbm47 in liver (ARLKO) eliminated apoB RNA editing and reduced editing in the majority of other targets, with no changes following adenoviral APOBEC1 administration. Intestinal double knockout mice (ARIKO) demonstrated further reduced editing (<10% activity) in 4 of 5 of the residual APOBEC1 targets identified in ARIKO mice. These data suggest that A1CF and RBM47 each function independently, yet interact in a tissue-specific manner, to regulate the activity and site selection of APOBEC1 dependent C-to-U RNA editing. PMID- 30309882 TI - Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. AB - OBJECTIVE: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). METHODS: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. RESULTS: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. CONCLUSIONS: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS. PMID- 30309883 TI - Detrimental effects of intracerebral haemorrhage on patients with CADASIL harbouring NOTCH3 R544C mutation. PMID- 30309885 TI - Librarians are health professionals too. PMID- 30309886 TI - The central region of CNOT1 and CNOT9 stimulates deadenylation by the Ccr4-Not nuclease module. AB - Regulated degradation of cytoplasmic mRNA is important for the accurate execution of gene expression programmes in eukaryotic cells. A key step in this process is the shortening and removal of the mRNA poly(A) tail, which can be achieved by the recruitment of the multi-subunit Ccr4-Not nuclease complex via sequence-specific RNA-binding proteins or the microRNA machinery. The Ccr4-Not complex contains several modules that are attached to its large subunit CNOT1. Modules include the nuclease module, which associates with the MIF4G domain of CNOT1 and contains the catalytic subunits Caf1 and Ccr4, as well as the module containing the non catalytic CNOT9 subunit, which binds to the DUF3819 domain of CNOT1. To understand the contributions of the individual modules to the activity of the complex, we have started to reconstitute sub-complexes of the human Ccr4-Not complex containing one or several functional modules. Here, we report the reconstitution of a pentameric complex including a BTG2-Caf1-Ccr4 nuclease module, CNOT9 and the central region of CNOT1 encompassing the MIF4G and DUF3819 domains. By comparing the biochemical activities of the pentameric complex and the nuclease module, we conclude that the CNOT1-CNOT9 components stimulate deadenylation by the nuclease module. In addition, we show that a pentameric complex containing the melanoma-associated CNOT9 P131L variant is able to support deadenylation similar to a complex containing the wild-type CNOT9 protein. PMID- 30309884 TI - Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. AB - Fibromax is a diagnostic tool composed of the combination of 4 non-invasive biomarker panels for the diagnosis of steatosis (SteatoTest), necrosis and inflammation (ActiTest and NashTest-2) and fibrosis (FibroTest). The purpose of this study was to assess the performance of these biomarker panels in patients with type 2 diabetes mellitus (T2DM). All patients underwent routine labs, a 75 g oral glucose tolerance test, a liver proton magnetic resonance spectroscopy (1H MRS) to measure intrahepatic triglyceride content, and a percutaneous liver biopsy to establish the diagnosis of non-alcoholic steatohepatitis (NASH) and to grade and stage the disease in those patients with non-alcoholic fatty liver disease (NAFLD) by 1H-MRS. For determination of the scores, plasma samples were blindly provided to establish the SteatoTest, ActiTest, NashTest-2 and FibroTest scores. A total of 220 patients with T2DM were included in this study. When the ability of the SteatoTest to identify patients with T2DM with NAFLD by 1H-MRS was assessed, the overall performance expressed as the area under the receiver operating characteristic curve was 0.73 (95% CI 0.65 to 0.81). The performance of the ActiTest and NashTest-2 to diagnose definite NASH among patients with T2DM was 0.70 (95% CI 0.63 to 0.77) and 0.69 (95% CI 0.62 to 0.76), respectively. Regarding the FibroTest score, its performance to identify patients with moderate or advanced fibrosis was 0.67 (95% CI 0.58 to 0.76) and 0.72 (95% CI 0.61 to 0.83), respectively. Non-invasive panels for the diagnosis of steatosis, NASH and/or fibrosis, which were developed and validated in non-diabetic cohorts, underperformed when applied to a large cohort of patients with T2DM. Results from non-diabetic populations should not be extrapolated to patients with T2DM. PMID- 30309887 TI - Shortened IV Antibiotic Course for Uncomplicated, Late-Onset Group B Streptococcal Bacteremia. AB - : : media-1vid110.1542/5804909691001PEDS-VA_2018-0345Video Abstract BACKGROUND: Guidelines recommend a prolonged course (10 days) of intravenous (IV) antibiotic therapy for infants with uncomplicated, late-onset group B Streptococcus (GBS) bacteremia. Our objective was to determine the frequency with which shorter IV antibiotic courses are used and to compare rates of GBS disease recurrence between prolonged and shortened IV antibiotic courses. METHODS: We performed a multicenter retrospective cohort study of infants aged 7 days to 4 months who were admitted to children's hospitals in the Pediatric Health Information System database from 2000 to 2015 with GBS bacteremia. The exposure was shortened IV antibiotic therapy, defined as discharge from the index GBS visit after a length of stay of <=8 days without a peripherally inserted central catheter charge. The primary outcome was readmission for GBS bacteremia, meningitis, or osteomyelitis in the first year of life. Outcomes were analyzed by using propensity-adjusted, inverse probability-weighted regression models. RESULTS: Of 775 infants who were diagnosed with uncomplicated, late-onset GBS bacteremia, 612 (79%) received a prolonged IV course of antibiotic therapy, and 163 (21%) received a shortened course. Rates of treatment with shortened IV courses varied by hospital (range: 0%-67%; SD: 20%). Three patients (1.8%) in the shortened IV duration group experienced GBS recurrence, compared with 14 patients (2.3%) in the prolonged IV duration group (adjusted absolute risk difference: -0.2%; 95% confidence interval: -3.0% to 2.5%). CONCLUSIONS: Shortened IV antibiotic courses are prescribed among infants with uncomplicated, late-onset GBS bacteremia, with low rates of disease recurrence and treatment failure. PMID- 30309888 TI - Uncomplicated Late-Onset Group B Streptococcal Bacteremia: Can We Do Less Than 10 Days IV? PMID- 30309889 TI - BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment. AB - BH3-mimetics are promising drugs for hematologic malignancies that trigger cell death by promoting the release of pro-apoptotic BCL2 family members from anti apoptotic proteins. Multiple myeloma is considered to be a disease dependent mainly on MCL1 for survival based mostly on studies using cell lines. We used a BH3-mimetic toolkit to study the dependency on BCL2, BCLXL or MCL1 in malignant plasma cells from 60 patients. Dependencies were analyzed using an unbiased BH3 mimetics cell-death clustering by k-means. In the whole cohort of patients, BCL2 dependency was mostly found in the CCND1 subgroup (83%). Of note, MCL1 dependence significantly increased from 33% at diagnosis to 69% at relapse, suggesting a plasticity of the cellular dependency favoring MCL1 dependencies at relapse. In addition, 35% of overall patient samples showed co-dependencies on either BCL2/MCL1 or BCLXL/MCL1. Finally, we identified a group of patients not targeted by any of the BH3-mimetics, predominantly at diagnosis in patients not presenting the common recurrent translocations. Mechanistically, we demonstrated that BAK is crucial for cell death induced by MCL1 mimetic A1210477, according to the protection from cell death observed by BAK knock-down as well as the complete and early disruption of MCL1/BAK complexes upon A1210477 treatment. Interestingly, this complex was also dissociated in A1210477 resistant cells, but free BAK was simultaneously recaptured by BCLXL, supporting the role of BCLXL in A1210477 resistance. In conclusion, our study opens the way to rationally use venetoclax and/or MCL1 BH3-mimetics for clinical evaluation in myeloma both at diagnosis and relapse. PMID- 30309890 TI - Reversing anti-factor Xa agents and the unmet needs in trauma patients. AB - Andexanet alfa, a reversing agent for anticoagulants that inhibit factor Xa, has recently been licensed in the United States. We discuss the impact of this licensure on current practice and review in detail the problems of a neglected and growing clinical area: reversing the anticoagulation effect of factor Xa inhibitors in bleeding trauma patients. We identify areas of practice that need research so that care of bleeding trauma patients receiving direct factor Xa inhibitors can be improved. PMID- 30309891 TI - Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. AB - The mechanisms by which exposure to heparin initiates antibody responses in many, if not most, recipients are poorly understood. We recently demonstrated that antigenic platelet factor 4 (PF4)/heparin complexes activate complement in plasma and bind to B cells. Here, we describe how this process is initiated. We observed wide stable variation in complement activation when PF4/heparin was added to plasma of healthy donors, indicating a responder "phenotype" (high, intermediate, or low). Proteomic analysis of plasma from these healthy donors showed a strong correlation between complement activation and plasma immunoglobulin M (IgM) levels (r = 0.898; P < .005), but not other Ig isotypes. Complement activation response to PF4/heparin in plasma displaying the low donor phenotype was enhanced by adding pooled IgM from healthy donors, but not monoclonal IgM. Depletion of IgM from plasma abrogated C3c generation by PF4/heparin. The complement activating features of IgM are likely mediated by nonimmune, or natural, IgM, as cord blood and a monoclonal polyreactive IgM generate C3c in the presence of PF4/heparin. IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin. Anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. These studies demonstrate that variability in plasma IgM levels correlates with functional complement responses to PF4/heparin. Polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells. These studies provide new insights into the evolution of the heparin-induced thrombocytopenia immune response and may provide a biomarker of risk. PMID- 30309892 TI - Military environmental health on Operation RUMAN. AB - Operation RUMAN was the British government's combined military and humanitarian operations to provide relief to the British Overseas Territories in the Caribbean. This paper provides a short summary of the role played by environmental health during the operation and the importance of environmental health considerations at all stages of disaster management. PMID- 30309893 TI - The 'peace role' of healthcare during war: un derstanding the importance of medical impartiality. AB - This article argues that medical personnel of armed forces occupy a 'peace role', which continues and dominates their professional ethos during armed conflict. The specific role and its associated legal and ethical obligations are elaborated, and on that basis arguments are provided why and how the work of military healthcare providers is interpreted as a continuation of peace during war. PMID- 30309894 TI - Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy. AB - Lipoprotein glomerulopathy (LPG) is a rare renal disease, characterized by lipoprotein thrombi in glomerular capillaries. A series of apoE mutations have been associated with LPG development. We previously showed that three mutants based on apoE3 sequence, in which an arginine was substituted by proline, are thermodynamically destabilized and aggregation-prone. To examine whether other LPG-associated apoE3 mutations induce similar effects, we characterized three nonproline LPG-associated apoE3 mutations, namely, R25C (apoEKyoto), R114C (apoETsukuba), and A152D (apoELasVegas). All three apoE3 variants are found to have significantly reduced helical content and to be thermodynamically destabilized, both in lipid-free and lipoprotein-associated form, and to expose a larger portion of hydrophobic surface to the solvent compared with WT apoE3. Furthermore, all three apoE3 variants are aggregation-prone, as shown by dynamic light-scattering measurements and by their enhanced capacity to bind the amyloid probe thioflavin T. Overall, our data suggest that the LPG-associated apoE3 mutations R25C, R114C, and A152D induce protein misfolding, which may contribute to protein aggregation in glomerular capillaries. The similar effects of both LPG associated proline and nonproline mutations on apoE3 structure suggest that the thermodynamic destabilization and enhanced aggregation of apoE3 may constitute a common underlying mechanism behind the pathogenesis of LPG. PMID- 30309895 TI - Activation of liver X receptor plays a central role in antiviral actions of 25 hydroxycholesterol. AB - Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). We previously reported that 25HC induced CH25H expression in a liver X receptor (LXR)-dependent manner, implying that LXR can play an important role in antiviral infection. In this study, we determined that activation of LXR by 25HC or synthetic ligands [T0901317 (T317) or GW3965] inhibited infection of herpes simplex virus type 1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXRalpha, LXRbeta, or CH25H expression in HepG2 cells by CRISPR/Cas9 method increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. Lack of interferon (IFN)-gamma expression also increased cell susceptibility to viral infection. However, it attenuated, but did not block, the inhibition of LXR on HSV-1 infection. In addition, expression of CH25H, but not IFN-gamma, was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Metabolism of 25HC into 25HC-3-sulfate (25HC3S) by cholesterol sulfotransferase-2B1b moderately reduced the antiviral actions of 25HC because 25HC3S is a weaker inhibitor of HSV 1 infection than 25HC. Furthermore, administration of T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, we demonstrate an antiviral system of 25HC with involvement of LXR activation, interaction between CH25H and IFN gamma, and 25HC metabolism. PMID- 30309896 TI - Increasing the representation of women in JGP to reduce bias and sexual harassment. PMID- 30309897 TI - Increasing Timely Family Meetings in Neonatal Intensive Care: A Quality Improvement Project. AB - OBJECTIVES: Timely multidisciplinary family meetings (TMFMs) promote shared decision-making. Despite guidelines that recommend meetings for all patients with serious illness, our NICU TMFM rate was 10%. In this study, we aimed to document a meeting within 5 days of hospitalization for 50% of all new NICU patients hospitalized for >=5 days within 1 year of introducing interventions. METHODS: A multidisciplinary improvement team used the Model for Improvement to achieve the study aim by targeting key drivers of change. To make meetings easier, we introduced scheduling and documentation tools. To make meetings more customary, we provided education and reminders to professionals. We defined a TMFM as a documented discussion between a parent, a neonatologist, and a nonphysician professional, such as a nurse, within 5 days of hospitalization. We used statistical process control charts to assess the monthly proportion of new patients with a TMFM. In surveys and feedback sessions, family and clinician satisfaction with communication was assessed. RESULTS: TMFM documentation tripled during the intervention year when compared with the previous year (28 of 267 [10.5%] vs 70 of 224 [31.3%]; P < .001), revealing evidence of special cause variation on the statistical process control chart. Clinicians predominantly used ad hoc documentation instead of our scheduling and documentation tools. Parental satisfaction with care and communication did not vary significantly after interventions. Most physicians reported satisfaction with meetings. Nurses reported feeling empowered to request meetings. CONCLUSIONS: An academic, quaternary-care NICU tripled TMFM documentation after introducing a multifaceted intervention. This improvement may represent changes in professionals' attitudes about providing and documenting family meetings. PMID- 30309899 TI - The U1 snRNP subunit LUC7 modulates plant development and stress responses via regulation of alternative splicing. AB - Introns are removed by the spliceosome, a large macromolecular complex composed of five ribonucleoprotein subcomplexes (U snRNP). The U1 snRNP, which binds to 5' splice sites, plays an essential role in early steps of the splicing reaction. Here, we show that Arabidopsis thaliana LETHAL UNLESS CBC 7 (LUC7) proteins, which are encoded by a three-member gene family in Arabidopsis, are important for plant development and stress resistance. We show that LUC7 are U1 snRNP accessory proteins by RNA immunoprecipitation experiments and LUC7 protein complex purifications. Transcriptome analyses revealed that LUC7 proteins are not only important for constitutive splicing, but also affect hundreds of alternative splicing events. Interestingly, LUC7 proteins specifically promote splicing of a subset of terminal introns. Splicing of LUC7-dependent introns is a prerequisite for nuclear export, and some splicing events are modulated by stress in a LUC7 dependent manner. Taken together, our results highlight the importance of the U1 snRNP component LUC7 in splicing regulation and suggest a previously unrecognized role of a U1 snRNP accessory factor in terminal intron splicing. PMID- 30309901 TI - A Ycf2-FtsHi heteromeric AAA-ATPase complex is required for chloroplast protein import. AB - Chloroplasts import thousands of nucleus-encoded preproteins synthesized in the cytosol through the TOC and TIC translocons on the outer and inner envelope membranes, respectively. Preprotein translocation across the inner membrane requires ATP; however, the import motor has remained unclear. Here, we report that a 2-MDa heteromeric AAA-ATPase complex associates with the TIC complex and functions as the import motor, directly interacting with various translocating preproteins. This 2-MDa complex consists of a protein encoded by the previously enigmatic chloroplast gene Ycf2 and five related nuclear-encoded FtsH-like proteins, namely FtsHi1, FtsHi2, FtsHi4, FtsHi5, and FtsH12. These components are each essential for plant viability and retain the AAA-type ATPase domain, but only FtsH12 contains the zinc-binding active site generally conserved among FtsH type metalloproteases. Further, even the FtsH12 zinc-binding site is dispensable for its essential function. Phylogenetic analyses suggest that all AAA-type members of the Ycf2/FtsHi complex including Ycf2 evolved from the chloroplast encoded membrane-bound AAA-protease FtsH of the ancestral endosymbiont. The Ycf2/FtsHi complex also contains an NAD-malate dehydrogenase, a proposed key enzyme for ATP production in chloroplasts in darkness or in non-photosynthetic plastids. These findings advance our understanding of this ATP-driven protein translocation system that is unique to the green lineage of photosynthetic eukaryotes. PMID- 30309902 TI - Sweet and Juicy: Identification and Origins of the Dry Alleles in Sorghum. PMID- 30309903 TI - A Force-Generating Machine in the Plant's Power House: A Pulling AAA ATPase Motor Drives Protein Translocation into Chloroplasts. PMID- 30309900 TI - Sweet Sorghum Originated through Selection of Dry, a Plant-Specific NAC Transcription Factor Gene. AB - Sorghum (Sorghum bicolor) is the fifth most popular crop worldwide and a C4 model plant. Domesticated sorghum comes in many forms, including sweet cultivars with juicy stems and grain sorghum with dry, pithy stems at maturity. The Dry locus, which controls the pithy/juicy stem trait, was discovered over a century ago. Here, we found that Dry gene encodes a plant-specific NAC transcription factor. Dry was either deleted or acquired loss-of-function mutations in sweet sorghum, resulting in cell collapse and altered secondary cell wall composition in the stem. Twenty-three Dry ancestral haplotypes, all with dry, pithy stems, were found among wild sorghum and wild sorghum relatives. Two of the haplotypes were detected in domesticated landraces, with four additional dry haplotypes with juicy stems detected in improved lines. These results imply that selection for Dry gene mutations was a major step leading to the origin of sweet sorghum. The Dry gene is conserved in major cereals; fine-tuning its regulatory network could provide a molecular tool to control crop stem texture. PMID- 30309898 TI - Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study. AB - BACKGROUND: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. METHODS: We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. RESULTS: At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. CONCLUSIONS: AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction. PMID- 30309904 TI - Methylammonium-free, high-performance, and stable perovskite solar cells on a planar architecture. AB - Currently, perovskite solar cells (PSCs) with high performances greater than 20% contain bromine (Br), causing a suboptimal bandgap, and the thermally unstable methylammonium (MA) molecule. Avoiding Br and especially MA can therefore result in more optimal bandgaps and stable perovskites. We show that inorganic cation tuning, using rubidium and cesium, enables highly crystalline formamidinium-based perovskites without Br or MA. On a conventional, planar device architecture, using polymeric interlayers at the electron- and hole-transporting interface, we demonstrate an efficiency of 20.35% (stabilized), one of the highest for MA-free perovskites, with a drastically improved stability reached without the stabilizing influence of mesoporous interlayers. The perovskite is not heated beyond 100 degrees C. Going MA-free is a new direction for perovskites that are inherently stable and compatible with tandems or flexible substrates, which are the main routes commercializing PSCs. PMID- 30309905 TI - In vivo modeling of human neuron dynamics and Down syndrome. AB - Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient specific modeling of cortical development, physiology, and pathogenesis. PMID- 30309906 TI - Controlled crack propagation for atomic precision handling of wafer-scale two dimensional materials. AB - Although flakes of two-dimensional (2D) heterostructures at the micrometer scale can be formed with adhesive-tape exfoliation methods, isolation of 2D flakes into monolayers is extremely time consuming because it is a trial-and-error process. Controlling the number of 2D layers through direct growth also presents difficulty because of the high nucleation barrier on 2D materials. We demonstrate a layer-resolved 2D material splitting technique that permits high-throughput production of multiple monolayers of wafer-scale (5-centimeter diameter) 2D materials by splitting single stacks of thick 2D materials grown on a single wafer. Wafer-scale uniformity of hexagonal boron nitride, tungsten disulfide, tungsten diselenide, molybdenum disulfide, and molybdenum diselenide monolayers was verified by photoluminescence response and by substantial retention of electronic conductivity. We fabricated wafer-scale van der Waals heterostructures, including field-effect transistors, with single-atom thickness resolution. PMID- 30309907 TI - Identity inference of genomic data using long-range familial searches. AB - Consumer genomics databases have reached the scale of millions of individuals. Recently, law enforcement authorities have exploited some of these databases to identify suspects via distant familial relatives. Using genomic data of 1.28 million individuals tested with consumer genomics, we investigated the power of this technique. We project that about 60% of the searches for individuals of European descent will result in a third-cousin or closer match, which theoretically allows their identification using demographic identifiers. Moreover, the technique could implicate nearly any U.S. individual of European descent in the near future. We demonstrate that the technique can also identify research participants of a public sequencing project. On the basis of these results, we propose a potential mitigation strategy and policy implications for human subject research. PMID- 30309908 TI - Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis driven translocation. AB - The 26S proteasome is the primary eukaryotic degradation machine and thus is critically involved in numerous cellular processes. The heterohexameric adenosine triphosphatase (ATPase) motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo electron microscopy structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination and how ATP-binding, -hydrolysis, and phosphate-release events are coordinated within the AAA+ (ATPases associated with diverse cellular activities) motor to induce conformational changes and propel the substrate through the central pore. PMID- 30309909 TI - Observation of the topological Anderson insulator in disordered atomic wires. AB - Topology and disorder have a rich combined influence on quantum transport. To probe their interplay, we synthesized one-dimensional chiral symmetric wires with controllable disorder via spectroscopic Hamiltonian engineering, based on the laser-driven coupling of discrete momentum states of ultracold atoms. Measuring the bulk evolution of a topological indicator after a sudden quench, we observed the topological Anderson insulator phase, in which added disorder drives the band structure of a wire from topologically trivial to nontrivial. In addition, we observed the robustness of topologically nontrivial wires to weak disorder and measured the transition to a trivial phase in the presence of strong disorder. Atomic interactions in this quantum simulation platform may enable realizations of strongly interacting topological fluids. PMID- 30309910 TI - Measuring the teamwork performance of teams in crisis situations: a systematic review of assessment tools and their measurement properties. AB - BACKGROUND: Educational interventions to improve teamwork in crisis situations have proliferated in recent years with substantial variation in teamwork measurement. This systematic review aimed to synthesise available tools and their measurement properties in order to identify the most robust tool for measuring the teamwork performance of teams in crisis situations. METHODS: Searches were conducted in Embase (via OVID), PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Education Resources Information Center, Medline and Medline In Process (via OVID) (through 12 January 2017). Studies evaluating the measurement properties of teamwork assessment tools for teams in clinical or simulated crisis situations were included. Two independent reviewers screened studies based on predetermined criteria and completed data extraction. Risk of bias was assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. RESULTS: The search yielded 1822 references. Twenty studies were included, representing 13 assessment tools. Tools were primarily assessed in simulated resuscitation scenarios for emergency department teams. The Team Emergency Assessment Measure (TEAM) had the most validation studies (n=5), which demonstrated three sources of validity (content, construct and concurrent) and three sources of reliability (internal consistency, inter rater reliability and test-retest reliability). Most studies of TEAM's measurement properties were at no risk of bias. CONCLUSIONS: A number of tools are available for assessing teamwork performance of teams in crisis situations. Although selection will ultimately depend on the user's context, TEAM may be the most promising tool given its measurement evidence. Currently, there is a lack of tools to assess teamwork performance during intraoperative crisis situations. Additional research is needed in this regard. PMID- 30309911 TI - Research paradigm that tackles the complexity of in situ care: video reflexivity. PMID- 30309912 TI - Work-life balance behaviours cluster in work settings and relate to burnout and safety culture: a cross-sectional survey analysis. AB - BACKGROUND: Healthcare is approaching a tipping point as burnout and dissatisfaction with work-life integration (WLI) in healthcare workers continue to increase. A scale evaluating common behaviours as actionable examples of WLI was introduced to measure work-life balance. OBJECTIVES: (1) Explore differences in WLI behaviours by role, specialty and other respondent demographics in a large healthcare system. (2) Evaluate the psychometric properties of the work-life climate scale, and the extent to which it acts like a climate, or group-level norm when used at the work setting level. (3) Explore associations between work life climate and other healthcare climates including teamwork, safety and burnout. METHODS: Cross-sectional survey study completed in 2016 of US healthcare workers within a large academic healthcare system. RESULTS: 10 627 of 13 040 eligible healthcare workers across 440 work settings within seven entities of a large healthcare system (81% response rate) completed the routine safety culture survey. The overall work-life climate scale internal consistency was alpha=0.830. WLI varied significantly among healthcare worker role, length of time in specialty and work setting. Random effects analyses of variance for the work-life climate scale revealed significant between-work setting and within-work setting variance and intraclass correlations reflected clustering at the work setting level. T-tests of top versus bottom WLI quartile work settings revealed that positive work-life climate was associated with better teamwork and safety climates, as well as lower personal burnout and burnout climate (p<0.001). CONCLUSION: Problems with WLI are common in healthcare workers and differ significantly based on position and time in specialty. Although typically thought of as an individual difference variable, WLI appears to operate as a climate, and is consistently associated with better safety culture norms. PMID- 30309913 TI - Clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme. AB - BACKGROUND: Glaucoma referral filtering schemes have operated in the UK for many years. However, there is a paucity of data on the false-negative (FN) rate. This study evaluated the clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme (GERS), estimating both the false-positive (FP) and FN rates. METHOD: Outcome data were collected for patients newly referred through GERS and assessed in 'usual-care' clinics to determine the FP rate (referred patients subsequently discharged at their first visit). For the FN rate, glaucoma suspects deemed not requiring referral following GERS assessment were invited to attend for a 'reference standard' examination including all elements of assessment recommended by National Institute for Health and Care Excellence (NICE) by a glaucoma specialist optometrist. A separate 33 cases comprising randomly selected referred and non-referred cases were reviewed independently by two glaucoma specialist consultant ophthalmologists to validate the reference standard assessment. RESULTS: 1404 patients were evaluated in GERS during the study period; 651 (46.3%) were referred to the Hospital Eye Service (HES) and 753 (53.6%) were discharged. The FP rate in 307 assessable patients referred to the HES was 15.5%. This study reviewed 131 (17.4%) of those patients not referred to the HES through the GERS scheme; 117 (89.3%) were confirmed as not requiring hospital follow-up; 14 (10.7%) required follow-up, including 5 (3.8%) offered treatment. Only one patient (0.8%) in this sample met the GERS referral criteria and was not referred (true FN). There were no cases of missed glaucoma or non glaucomatous pathology identified within our sample. CONCLUSION: The Manchester GERS is an effective glaucoma filtering scheme with a low FP and FN rate. PMID- 30309914 TI - Response to Comment on "U-Th dating of carbonate crusts reveals Neandertal origin of Iberian cave art". AB - Slimak et al challenge the reliability of our oldest (>65,000 years) U-Th dates on carbonates associated with cave paintings in Spain. They cite a supposed lack of parietal art for the 25,000 years following this date, along with potential methodological issues relating to open-system behavior and corrections to detrital or source water 230Th. We show that their criticisms are unfounded. PMID- 30309917 TI - Erratum for the Research Article "Saturn's magnetic field revealed by the Cassini Grand Finale" by M. K. Dougherty, H. Cao, K. K. Khurana, G. J. Hunt, G. Provan, S. Kellock, M. E. Burton, T. A. Burk, E. J. Bunce, S. W. H. Cowley, M. G. Kivelson, C. T. Russell, D. J. Southwood. PMID- 30309915 TI - Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. AB - Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens. PMID- 30309916 TI - Thyroid hormone signaling specifies cone subtypes in human retinal organoids. AB - The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue (S), green (M), and red (L) cones of the retina enable high-acuity daytime and color vision. To determine the mechanism that controls S versus L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone-degrading and -activating proteins within the retina ensures low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining mechanisms of human development with promising utility for therapeutics and vision repair. PMID- 30309919 TI - Japan needs gender equality. PMID- 30309920 TI - News at a glance. PMID- 30309918 TI - Structure and dynamics of the yeast SWR1-nucleosome complex. AB - The yeast SWR1 complex exchanges histone H2A in nucleosomes with Htz1 (H2A.Z in humans). The cryo-electron microscopy structure of the SWR1 complex bound to a nucleosome at 3.6-angstrom resolution reveals details of the intricate interactions between components of the SWR1 complex and its nucleosome substrate. Interactions between the Swr1 motor domains and the DNA wrap at superhelical location 2 distort the DNA, causing a bulge with concomitant translocation of the DNA by one base pair, coupled to conformational changes of the histone core. Furthermore, partial unwrapping of the DNA from the histone core takes place upon binding of nucleosomes to SWR1 complex. The unwrapping, as monitored by single molecule data, is stabilized and has its dynamics altered by adenosine triphosphate binding but does not require hydrolysis. PMID- 30309921 TI - Leaks put Italy's underground lab in jeopardy. PMID- 30309922 TI - NASA's next Mars rover aims to explore two promising sites. PMID- 30309924 TI - Protein evolution earns chemistry Nobel. PMID- 30309923 TI - Replumbing the lymphatic system. PMID- 30309925 TI - DNA printers poised to jump from paragraphs to pages. PMID- 30309926 TI - A new leaf. PMID- 30309927 TI - Vive la resistant vines! PMID- 30309928 TI - An alternative urban green carpet. PMID- 30309929 TI - Next-generation self-healing materials. PMID- 30309931 TI - A common trick for transferring bacterial DNA. PMID- 30309930 TI - Dimerization quality control via ubiquitylation. PMID- 30309932 TI - Treg cells-the next frontier of cell therapy. PMID- 30309933 TI - Anti-CRISPRs on the march. PMID- 30309934 TI - Easy access to elusive radical reactions. PMID- 30309935 TI - Return of results and data to study participants. PMID- 30309936 TI - Editor's note: Harassment policy. PMID- 30309938 TI - Preventing chemical release in hurricanes. PMID- 30309937 TI - PPR virus threatens wildlife conservation. PMID- 30309939 TI - Circuits for care. PMID- 30309940 TI - Building blocks of the human brain. PMID- 30309942 TI - Mind-boggling brain development. PMID- 30309941 TI - The effortless custody of automatism. PMID- 30309943 TI - A fragile existence. PMID- 30309944 TI - Neuronal specification in space and time. AB - To understand how neurons assemble to form functional circuits, it is necessary to obtain a detailed knowledge of their diversity and to define the developmental specification programs that give rise to this diversity. Invertebrates and vertebrates appear to share common developmental principles of neuronal specification in which cascades of transcription factors temporally pattern progenitors, while spatial cues modify the outcomes of this temporal patterning. Here, we highlight these conserved mechanisms and describe how they are used in distinct neural structures. We present the questions that remain for a better understanding of neuronal specification. Single-cell RNA profiling approaches will potentially shed light on these questions, allowing not only the characterization of neuronal diversity in adult brains, but also the investigation of the developmental trajectories leading to the generation and maintenance of this diversity. PMID- 30309945 TI - Glia as architects of central nervous system formation and function. AB - Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function. Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function. PMID- 30309946 TI - Microglia and early brain development: An intimate journey. AB - Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole body context. PMID- 30309947 TI - Homology, neocortex, and the evolution of developmental mechanisms. AB - The six-layered neocortex of the mammalian pallium has no clear homolog in birds or non-avian reptiles. Recent research indicates that although these extant amniotes possess a variety of divergent and nonhomologous pallial structures, they share a conserved set of neuronal cell types and circuitries. These findings suggest a principle of brain evolution: that natural selection preferentially preserves the integrity of information-processing pathways, whereas other levels of biological organization, such as the three-dimensional architectures of neuronal assemblies, are less constrained. We review the similarities of pallial neuronal cell types in amniotes, delineate candidate gene regulatory networks for their cellular identities, and propose a model of developmental evolution for the divergence of amniote pallial structures. PMID- 30309949 TI - Genome hypermobility by lateral transduction. AB - Genetic transduction is a major evolutionary force that underlies bacterial adaptation. Here we report that the temperate bacteriophages of Staphylococcus aureus engage in a distinct form of transduction we term lateral transduction. Staphylococcal prophages do not follow the previously described excision replication-packaging pathway but instead excise late in their lytic program. Here, DNA packaging initiates in situ from integrated prophages, and large metameric spans including several hundred kilobases of the S. aureus genome are packaged in phage heads at very high frequency. In situ replication before DNA packaging creates multiple prophage genomes so that lateral-transducing particles form during normal phage maturation, transforming parts of the S. aureus chromosome into hypermobile regions of gene transfer. PMID- 30309948 TI - A hot and fast ultra-stripped supernova that likely formed a compact neutron star binary. AB - Compact neutron star binary systems are produced from binary massive stars through stellar evolution involving up to two supernova explosions. The final stages in the formation of these systems have not been directly observed. We report the discovery of iPTF 14gqr (SN 2014ft), a type Ic supernova with a fast evolving light curve indicating an extremely low ejecta mass (~0.2 solar masses) and low kinetic energy (~2 * 1050 ergs). Early photometry and spectroscopy reveal evidence of shock cooling of an extended helium-rich envelope, likely ejected in an intense pre-explosion mass-loss episode of the progenitor. Taken together, we interpret iPTF 14gqr as evidence for ultra-stripped supernovae that form neutron stars in compact binary systems. PMID- 30309950 TI - Entropy-driven stability of chiral single-walled carbon nanotubes. AB - Single-walled carbon nanotubes are hollow cylinders that can grow centimeters long via carbon incorporation at the interface with a catalyst. They display semiconducting or metallic characteristics, depending on their helicity, which is determined during their growth. To support the quest for a selective synthesis, we develop a thermodynamic model that relates the tube-catalyst interfacial energies, temperature, and the resulting tube chirality. We show that nanotubes can grow chiral because of the configurational entropy of their nanometer-sized edge, thus explaining experimentally observed temperature evolutions of chiral distributions. Taking the chemical nature of the catalyst into account through interfacial energies, we derive structural maps and phase diagrams that will guide a rational choice of a catalyst and growth parameters toward a better selectivity. PMID- 30309951 TI - Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates. AB - Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols. PMID- 30309953 TI - Ketyl radical reactivity via atom transfer catalysis. AB - Single-electron reduction of a carbonyl to a ketyl enables access to a polarity reversed platform of reactivity for this cornerstone functional group. However, the synthetic utility of the ketyl radical is hindered by the strong reductants necessary for its generation, which also limit its reactivity to net reductive mechanisms. We report a strategy for net redox-neutral generation and reaction of ketyl radicals. The in situ conversion of aldehydes to alpha-acetoxy iodides lowers their reduction potential by more than 1 volt, allowing for milder access to the corresponding ketyl radicals and an oxidative termination event. Upon subjecting these iodides to a dimanganese decacarbonyl precatalyst and visible light irradiation, an atom transfer radical addition (ATRA) mechanism affords a broad scope of vinyl iodide products with high Z-selectivity. PMID- 30309952 TI - Key-and-lock commodity self-healing copolymers. AB - Self-healing materials are notable for their ability to recover from physical or chemical damage. We report that commodity copolymers, such as poly(methyl methacrylate)/n-butyl acrylate [p(MMA/nBA)] and their derivatives, can self-heal upon mechanical damage. This behavior occurs in a narrow compositional range for copolymer topologies that are preferentially alternating with a random component (alternating/random) and is attributed to favorable interchain van der Waals forces forming key-and-lock interchain junctions. The use of van der Waals forces instead of supramolecular or covalent rebonding or encapsulated reactants eliminates chemical and physical alterations and enables multiple recovery upon mechanical damage without external intervention. Unlike other self-healing approaches, perturbation of ubiquitous van der Waals forces upon mechanical damage is energetically unfavorable for interdigitated alternating/random copolymer motifs that facilitate self-healing under ambient conditions. PMID- 30309954 TI - Electrical generation and detection of spin waves in a quantum Hall ferromagnet. AB - Spin waves are collective excitations of magnetic systems. An attractive setting for studying long-lived spin-wave physics is the quantum Hall (QH) ferromagnet, which forms spontaneously in clean two-dimensional electron systems at low temperature and in a perpendicular magnetic field. We used out-of-equilibrium occupation of QH edge channels in graphene to excite and detect spin waves in magnetically ordered QH states. Our experiments provide direct evidence for long distance spin-wave propagation through different ferromagnetic phases in the N = 0 Landau level, as well as across the insulating canted antiferromagnetic phase. Our results will enable experimental investigation of the fundamental magnetic properties of these exotic two-dimensional electron systems. PMID- 30309955 TI - A normal student parent. PMID- 30309956 TI - The engineering of the giant dragonflies of the Permian: revised body mass, power, air supply, thermoregulation and the role of air density. AB - An engineering examination of allometric and analogical data on the flight of giant Permian insects (Protodonata, Meganeura or griffinflies) indicates that previous estimates of the body mass of these insects are too low and that the largest of these insects (wingspan of 70 cm or more) would have had a mass of 100 150 g, several times greater than previously thought. Here, the power needed to generate lift and fly at the speeds typical of modern large dragonflies is examined together with the metabolic rate and subsequent heat generated by the thoracic muscles. This evaluation agrees with previous work suggesting that the larger specimens would rapidly overheat in the high ambient temperatures assumed in the Permian. Various extant mechanisms of thermoregulation are modelled and quantified, including behaviour, radiation and the constraints on convective respiration and evaporation imposed by air flow through spiracles. However, the effects of these on cooling an overheated insect are found to be limited. Instead, an examination of the heat budget in the flight medium indicates that, at about 1.6 bar (160 kPa), thermoregulation supply enters into equilibrium and, even at high ambient temperatures, overheating can be avoided and enough oxygen sourced. This approach indicates how fossil biology can be used to examine past atmospheres. PMID- 30309957 TI - SRF'ing and SAP'ing - the role of MRTF proteins in cell migration. AB - Actin-based cell migration is a fundamental cellular activity that plays a crucial role in a wide range of physiological and pathological processes. An essential feature of the remodeling of actin cytoskeleton during cell motility is the de novo synthesis of factors involved in the regulation of the actin cytoskeleton and cell adhesion in response to growth-factor signaling, and this aspect of cell migration is critically regulated by serum-response factor (SRF) mediated gene transcription. Myocardin-related transcription factors (MRTFs) are key coactivators of SRF that link actin dynamics to SRF-mediated gene transcription. In this Review, we provide a comprehensive overview of the role of MRTF in both normal and cancer cell migration by discussing its canonical SRF dependent as well as its recently emerged SRF-independent functions, exerted through its SAP domain, in the context of cell migration. We conclude by highlighting outstanding questions for future research in this field. PMID- 30309958 TI - Stress response regulation and the hemodynamic response. PMID- 30309959 TI - Navigating genetic diversity by painting the bacteria red. PMID- 30309960 TI - Nematic twist-bend phase in an external field. AB - The response of the nematic twist-bend ([Formula: see text]) phase to an applied field can provide important insight into the structure of this liquid and may bring us closer to understanding mechanisms generating mirror symmetry breaking in a fluid of achiral molecules. Here we investigate theoretically how an external uniform field can affect structural properties and the stability of [Formula: see text] Assuming that the driving force responsible for the formation of this phase is packing entropy, we show, within Landau-de Gennes theory, that [Formula: see text] can undergo a rich sequence of structural changes with the field. For the systems with positive anisotropy of permittivity, we first observe a decrease of the tilt angle of [Formula: see text] until it transforms through a field-induced phase transition to the ordinary prolate uniaxial nematic phase (N). Then, at very high fields, this nematic phase develops polarization perpendicular to the field ([Formula: see text]). For systems with negative anisotropy of permittivity, the results reveal new modulated structures. Even an infinitesimally small field transforms [Formula: see text] to its elliptical counterpart ([Formula: see text]), where the circular base of the cone of the main director becomes elliptic. With stronger fields, the ellipse degenerates to a line, giving rise to a nonchiral periodic structure, the nematic splay-bend ([Formula: see text]), where the two nematic directors are restricted to a plane. The three structures-[Formula: see text], [Formula: see text], and [Formula: see text]-with a modulated polar order are globally nonpolar. But further increase of the field induces phase transitions into globally polar structures with nonvanishing polarization along the field's direction. We found two such structures, one of which is a polar and chiral modification of [Formula: see text], where splay and bend deformations are accompanied by weak twist deformations ([Formula: see text]). Further increase of the field unwinds this structure into a polar nematic ([Formula: see text]) of polarization parallel to the field. PMID- 30309961 TI - Thermodynamic favorability and pathway yield as evolutionary tradeoffs in biosynthetic pathway choice. AB - The structure of the metabolic network contains myriad organism-specific variations across the tree of life, but the selection basis for pathway choices in different organisms is not well understood. Here, we examined the metabolic capabilities with respect to cofactor use and pathway thermodynamics of all sequenced organisms in the Kyoto Encyclopedia of Genes and Genomes Database. We found that (i) many biomass precursors have alternate synthesis routes that vary substantially in thermodynamic favorability and energy cost, creating tradeoffs that may be subject to selection pressure; (ii) alternative pathways in amino acid synthesis are characteristically distinguished by the use of biosynthetically unnecessary acyl-CoA cleavage; (iii) distinct choices preferring thermodynamic-favorable or cofactor-use-efficient pathways exist widely among organisms; (iv) cofactor-use-efficient pathways tend to have a greater yield advantage under anaerobic conditions specifically; and (v) lysine biosynthesis in particular exhibits temperature-dependent thermodynamics and corresponding differential pathway choice by thermophiles. These findings present a view on the evolution of metabolic network structure that highlights a key role of pathway thermodynamics and cofactor use in determining organism pathway choices. PMID- 30309963 TI - Ultrafast epithelial contractions provide insights into contraction speed limits and tissue integrity. AB - By definition of multicellularity, all animals need to keep their cells attached and intact, despite internal and external forces. Cohesion between epithelial cells provides this key feature. To better understand fundamental limits of this cohesion, we study the epithelium mechanics of an ultrathin (~25 MUm) primitive marine animal Trichoplax adhaerens, composed essentially of two flat epithelial layers. With no known extracellular matrix and no nerves or muscles, T. adhaerens has been claimed to be the "simplest known living animal," yet is still capable of coordinated locomotion and behavior. Here we report the discovery of the fastest epithelial cellular contractions known in any metazoan, to be found in T. adhaerens dorsal epithelium (50% shrinkage of apical cell area within one second, at least an order of magnitude faster than other known examples). Live imaging reveals emergent contractile patterns that are mostly sporadic single-cell events, but also include propagating contraction waves across the tissue. We show that cell contraction speed can be explained by current models of nonmuscle actin myosin bundles without load, while the tissue architecture and unique mechanical properties are softening the tissue, minimizing the load on a contracting cell. We propose a hypothesis, in which the physiological role of the contraction dynamics is to resist external stresses while avoiding tissue rupture ("active cohesion"), a concept that can be further applied to engineering of active materials. PMID- 30309962 TI - Discovery of a small-molecule inhibitor of specific serine residue BAD phosphorylation. AB - Human BCL-2-associated death promoter (hBAD) is an apoptosis-regulatory protein mediating survival signals to carcinoma cells upon phosphorylation of Ser99, among other residues. Herein, we screened multiple small-molecule databases queried in a Laplacian-modified naive Bayesian-based cheminformatics platform and identified a Petasis reaction product as a site-specific inhibitor for hBAD phosphorylation. Based on apoptotic efficacy against mammary carcinoma cells, N cyclopentyl-3-((4-(2,3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) benzamide (NPB) was identified as a potential lead compound. In vitro biochemical analyses demonstrated that NPB inhibited the phosphorylation of hBAD specifically on Ser99. NPB was observed to exert this effect independently of AKT and other kinase activities despite the demonstration of AKT-mediated BAD-Ser99 phosphorylation. Using a structure-based bioinformatics platform, we observed that NPB exhibited predicted interactions with hBAD in silico and verified the same by direct binding kinetics. NPB reduced phosphorylation of BAD-Ser99 and enhanced caspase 3/7 activity with associated loss of cell viability in various human cancer cell lines derived from mammary, endometrial, ovarian, hepatocellular, colon, prostatic, and pancreatic carcinoma. Furthermore, by use of a xenograft model, it was observed that NPB, as a single agent, markedly diminished BAD phosphorylation in tumor tissue and significantly inhibited tumor growth. Similar doses of NPB utilized in acute toxicity studies in mice did not exhibit significant effects. Hence, we report a site-specific inhibitor of BAD phosphorylation with efficacy in tumor models. PMID- 30309965 TI - Arsentate Induced CHLOROSIS 1/ TRANSLOCON at the outer envelope membrane of CHLOROPLASTS 132 Protects Chloroplasts from Arsenic Toxicity. AB - Arsenic (As) is highly toxic to plants and detoxified primarily through complexation with phytochelatins (PCs) and other thiol compounds. To understand the mechanisms of As toxicity and detoxification beyond PCs, we isolated an arsenate-sensitive mutant of Arabidopsis (Arabidopsis thaliana), arsenate induced chlorosis 1 (aic1), in the background of the PC synthase defective mutant cadmium sensitive 1-3 (cad1-3). Under arsenate stress, aic1 cad1-3 showed larger decreases in chlorophyll content and the number and size of chloroplasts than cad1-3 and a severely distorted chloroplast structure. The aic1 single mutant was also more sensitive to arsenate than wild type (Col-0). As concentrations in the roots, shoots and chloroplasts were similar between aic1 cad1-3 and cad1-3. Using genome resequencing and complementation, TRANSLOCON AT THE OUTER ENVOLOPE MEMBRANE OF CHLOROPLAST 132 (TOC132) was identified as the mutant gene, which encodes a translocon protein involved in the import of preproteins from the cytoplasm into the chloroplasts. Proteomic analysis showed that the proteome of aic1 cad1-3 chloroplasts was more affected by arsenate stress than that of cad1 3. A number of proteins related to chloroplast ribosomes, photosynthesis, compound synthesis and thioredoxin systems were less abundant in aic1 cad1-3 than in cad1-3 under arsenate stress. Our results indicate that chloroplasts are a sensitive target of As toxicity and AIC1/Toc132 plays an important role in protecting chloroplasts from As toxicity. PMID- 30309964 TI - RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE dependent repression. AB - NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2 RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings. PMID- 30309966 TI - K+ efflux antiporters 4, 5 and 6 mediate pH and K+ homeostasis in endomembrane compartments. AB - KEA4, KEA5, and KEA6 are members of the Arabidopsis thaliana K+ efflux antiporter (KEA) family that share high sequence similarity, but whose function remains unknown. Here, we show their gene expression pattern, subcellular localization, and physiological function in Arabidopsis. KEA4, KEA5, and KEA6 had a similar tissue expression pattern and the three KEA proteins localized to the Golgi, the trans-Golgi network (TGN), and the pre-vacuolar compartment (PVC)/multivesicular bodies (MVB), suggesting overlapping roles of these proteins in the endomembrane system. Phenotypic analyses of single, double, and triple mutants confirmed functional redundancy. The triple mutant kea4 kea5 kea6 had small rosettes, short seedlings, and was sensitive to low K+ availability and to the sodicity imposed by high salinity. Also, the kea4 kea5 kea6 mutant plants had a reduced luminal pH in the Golgi, TGN, PVC, and vacuole, in accordance with the K/H exchange activity of KEA proteins. Genetic analysis indicated that KEA4, KEA5, KEA6 and endosomal Na+/H+exchanger (NHX) 5 and NHX6 acted coordinately to facilitate the endosomal pH homeostasis and salt tolerance. Neither cancelling nor overexpressing the vacuolar antiporters NHX1 and NHX2 in the kea4 kea5 kea6 mutant background altered the salt-sensitive phenotype. The NHX1 and NHX2 proteins in the kea4 kea5 kea6 mutant background could not suppress the acidity of the endomembrane system but brought the vacuolar pH close to wild-type values. Together, these data signify that KEA4, KEA5, and KEA6 are endosomal K+ transporters functioning in maintaining pH and ion homeostasis in the endomembrane network. PMID- 30309967 TI - Enzyme fusion removes competition for geranylgeranyl diphosphate in carotenogenesis. AB - Geranylgeranyl diphosphate (GGPP), a prenyl diphosphate synthesized by GGPP synthase (GGPS), represents a metabolic hub for the synthesis of key isoprenoids, such as chlorophylls, tocopherols, phylloquinone, gibberellins, and carotenoids. Protein-protein interactions and the amphipathic nature of GGPP suggest metabolite channeling and/or competition for GGPP among enzymes that function in independent branches of the isoprenoid pathway. To investigate substrate conversion efficiency between the plastid-localized GGPS isoform GGPS11 and phytoene synthase (PSY), the first enzyme of the carotenoid pathway, we used recombinant enzymes and determined their in vitro properties. Efficient phytoene biosynthesis via PSY strictly depended on simultaneous GGPP supply via GGPS11. In contrast, PSY could not access freely diffusible GGPP or time-displaced GGPP supply via GGPS11, presumably due to liposomal sequestration. To optimize phytoene biosynthesis, a chimeric GGPS11-PSY metabolon (PYGG) was constructed. PYGG converted GGPP to phytoene almost quantitatively in vitro and did not show the GGPP leakage typical of the individual enzymes. PYGG expression in Arabidopsis resulted in orange-colored cotyledons, which are not observed if PSY or GGPS11 are overexpressed individually. This suggests insufficient GGPP substrate availability for chlorophyll biosynthesis achieved through GGPP flux redirection to carotenogenesis. Similarly, carotenoid levels in PYGG-expressing callus exceeded that in PSY- or GGPS11-overexpression lines. The PYGG chimeric protein may assist in provitamin A biofortification of edible plant parts. Moreover, other GGPS fusions may be used to redirect metabolic flux into the synthesis of other isoprenoids of nutritional and industrial interest. PMID- 30309968 TI - Enlisting commensal microbes to resist antibiotic-resistant pathogens. AB - The emergence of antibiotic-resistant bacterial pathogens is an all-too-common consequence of antibiotic use. Although antibiotic resistance among virulent bacterial pathogens is a growing concern, the highest levels of antibiotic resistance occur among less pathogenic but more common bacteria that are prevalent in healthcare settings. Patient-to-patient transmission of these antibiotic-resistant bacteria is a perpetual concern in hospitals. Many of these resistant microbes, such as vancomycin-resistant Enterococcus faecium and carbapenem-resistant Klebsiella pneumoniae, emerge from the intestinal lumen and invade the bloodstream of vulnerable patients, causing disseminated infection. These infections are associated with preceding antibiotic administration, which changes the intestinal microbiota and compromises resistance to colonization by antibiotic-resistant bacteria. Recent and ongoing studies are increasingly defining commensal bacterial species and the inhibitory mechanisms they use to prevent infection. The use of next-generation probiotics derived from the intestinal microbiota represents an alternative approach to prevention of infection by enriching colonization with protective commensal species, thereby reducing the density of antibiotic-resistant bacteria and also reducing patient to-patient transmission of infection in healthcare settings. PMID- 30309969 TI - In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy. AB - OBJECTIVES: In autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3 methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM. METHODS: IgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA). RESULTS: Passive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease. CONCLUSION: This study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM. PMID- 30309970 TI - Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. AB - QUESTION: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? METHODS: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. RESULTS: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. CONCLUSION: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to target is feasible. TRIAL REGISTRATION NUMBER: 1574. PMID- 30309971 TI - Patient organisation-led initiatives can play an important role in raising awareness about Raynaud's phenomenon and encourage earlier healthcare utilisation for high-risk groups. PMID- 30309973 TI - Safety of benzodiazepines and opioids in interstitial lung disease: a national prospective study. AB - Safety concerns are a barrier to prescribing benzodiazepines (BDZs) and opioids in interstitial lung disease (ILD). We therefore examined the association of BDZs and opioids on risk of admission to hospital and death.We conducted a population based longitudinal cohort study of fibrotic ILD patients starting long-term oxygen therapy in Sweden between October 2005 and December 2014. Effects of BDZs and opioids on rates of admission to hospital and mortality were analysed using Fine-Gray and Cox regression while adjusting for potential confounders.We included 1603 patients (61% females). BDZs were used by 196 (12%) patients and opioids were used by 254 (15%) patients. There was no association between BDZs and increased admission. Treatment with high- versus low-dose BDZs was associated with increased mortality (subdistribution hazard ratio (SHR) 1.46, 95% CI 1.08 1.98 versus 1.13, 95% CI 0.92-1.38). Opioids showed no association with increased admission. Neither low-dose opioids (<=30 mg.day-1 oral morphine equivalent) (SHR 1.18, 95% CI 0.96-1.45) nor high-dose opioids (>30 mg.day-1 oral morphine equivalent) (SHR 1.11, 95% CI 0.89-1.39) showed association with increased mortality.This first ever study to examine associations between BDZ and opioid use and harm in ILD supports the use of opioids and low-dose BDZs in severely ill patients with respiratory compromise. PMID- 30309972 TI - Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review. AB - Background: The global loss to follow-up (LTFU) rate among drug-resistant TB (DR TB) patients remains high at 15%. We conducted a systematic review to explore interventions to reduce LTFU during DR-TB treatment.Methods: We searched for studies published between Jan. 2000 and Dec. 2017 that provided any form of psychosocial or material support for patients with DR-TB. We estimated point estimates and 95% confidence intervals (CI) of the proportion LTFU. We performed subgroup analyses and pooled estimates using an exact binomial likelihood approach.Findings: We included 35 DR-TB cohorts from 25 studies. Cohorts that received any form of psychosocial or material support had lower LTFU rates than those that received standard care. Psychosocial support throughout treatment - via counselling sessions or home visits - was associated with lower LTFU rates compared to when support was provided through a limited number of visits or not at all, with pooled proportions LTFU of 8.4% (4.0-16.7%) and 20.5% (15.2-27.0%), respectively.Conclusion: Our review suggests psychosocial support should be provided throughout DR-TB treatment in order to reduce treatment LTFU. Future studies should explore the potential of providing self-administered therapy complemented with psychosocial support during the continuation phase. PMID- 30309974 TI - Maternal blood pressure and hypertensive disorders during pregnancy and childhood respiratory morbidity: the Generation R Study. AB - Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific. PMID- 30309975 TI - Triple therapy versus single and dual long-acting bronchodilator therapy in chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - We performed a meta-analysis to compare the impact of triple combination therapy with inhaled corticosteroids (ICSs), long-acting beta2-agonists (LABAs), and long acting muscarinic receptor antagonists (LAMAs) versus LABA/LAMA combination or single long-acting bronchodilator therapy in chronic obstructive pulmonary disease. ICS/LABA/LAMA combination reduced the risk of exacerbation (relative risk: 0.70, 95%CI 0.53-0.94) and improved trough FEV1 (mean difference, mL: +37.94, 95%CI 18.83-53.89) versus LABA/LAMA combination. The protective effect of triple combination therapy versus LABA/LAMA combination against the risk of exacerbation was greater in patients with blood eosinophil counts >=300 cells per uL (relative risk: 0.57, 95%CI 0.48-0.68). While ~38 patients had to be treated for one year with ICS/LABA/LAMA combination to prevent one exacerbation compared to LABA/LAMA combination, the number needed to treat was ~21 when compared to single long-acting bronchodilator therapy. The risk of pneumonia did not differ between ICS/LABA/LAMA combination and comparators; the number needed to harm was ~195 and it decreased to ~34 when considering the study that included fluticasone furoate in the triple combination. This meta-analysis suggests that patients on single long-acting bronchodilator therapy or LABA/LAMA combination, who still have exacerbations and have blood eosinophil count >=300 cells per uL, could benefit from ICS/LABA/LAMA combination. PMID- 30309976 TI - What is early COPD and why is it important? AB - There is increasing interest in the origins of chronic obstructive pulmonary disease (COPD), as it is envisaged that preventive efforts and treatment can modify its clinical course. The concept of early COPD is not new, but it has recently regained interest, given new population data, recent cellular and molecular advances and insights from clinical trials. To date, many knowledge gaps in the nature of early COPD still exist, mainly because COPD has always been considered a disease of the elderly, and little attention has been paid to the pathological changes occurring in the lungs of individuals at risk before they develop clinically evident COPD. Future studies should focus on identifying early pathological manifestations of COPD in order to prevent its progression in susceptible individuals. In this review, we aim to summarise what is known on early COPD, from the epidemiological, cellular and clinical perspectives. PMID- 30309977 TI - Tuberculosis in the European Union and European Economic Area: a survey of national tuberculosis programmes. AB - How many European Union (EU) and European Economic Area (EEA) countries have national tuberculosis (TB) control plans/strategies, and what are the priority actions/populations and barriers to implementation?In order to answer this question, a survey of EU/EEA national TB programme leads was undertaken.The response rate was 100% (31 countries). 55% of countries reported having a national TB strategy, all of which were in implementation; five countries were preparing a strategy. 74% had a defined organisational TB control structure with central coordination and 19% had a costed programme budget; few organisational structures included patient/civil society representation. The most frequently mentioned priority TB control actions were: reaching vulnerable population groups (80%), screening for active TB in high-risk groups (63%), implementing electronic registries (60%), contact tracing and outbreak investigation (60%), and tackling multidrug-resistant TB (60%). Undocumented migrants were the most commonly (46%) identified priority population. Perceived obstacles to implementation included barriers related to care recipients (lack of TB knowledge, treatment seeking/adherence), care providers (including need for specialist training of nurses and doctors) and health system constraints (funding, communication between healthcare and social care systems).This survey has provided an insight into TB control programmes across the EU/EEA that will inform the development of a TB strategy toolkit for member states. PMID- 30309978 TI - Matching-adjusted indirect comparison of benralizumab versus interleukin-5 inhibitors for the treatment of severe asthma: a systematic review. AB - Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that directly depletes eosinophils. Its relative efficacy versus other IL-5-targeted treatments for patients with severe, uncontrolled asthma is not yet fully characterised.We performed a matching-adjusted indirect comparison (MAIC) of benralizumab versus mepolizumab and reslizumab. Trials were selected through systematic review and evaluation of trial methods. Benralizumab patient-level data were weighted to match treatment-effect-modifying patient characteristics of comparator trials before indirect efficacy comparisons.After matching adjustment, benralizumab and mepolizumab reduced exacerbations versus placebo by 52% and 49%, respectively (rate ratio [RR] 0.94, 95% CI 0.78-1.13; n=1524) and reduced the rate of exacerbations requiring hospitalisation/emergency department visit by 52% and 52%, respectively (RR 1.00, 95% CI 0.57-1.75; n=1524). Benralizumab and mepolizumab similarly improved pre-bronchodilator forced expiratory volume in 1 s at 32 weeks (difference 0.03 L, 95% CI -0.06-0.12; n=1443). Benralizumab and reslizumab patient populations were too dissimilar to generate a sufficient effective sample size to produce a reliable estimate for MAIC.MAIC is a robust way to indirectly compare treatment efficacies from trials with heterogeneous patient populations. When baseline patient characteristics were matched across asthma trials, benralizumab and mepolizumab yielded similar efficacy. PMID- 30309981 TI - No surge in illicit cigarettes after implementation of menthol ban in Nova Scotia. AB - BACKGROUND: In May 2015, the Canadian province of Nova Scotia became the first jurisdiction in the world to ban menthol cigarettes specifically. The tobacco industry warned that 'the primary effect of this law will be to increase the illegal tobacco market in Nova Scotia'. This is the first attempt to examine the impact of the menthol ban on trends in illicit cigarettes. DATA AND METHODS: Data on the number of illicit cigarettes seized in Nova Scotia covering the period from 2007/2008 to 2017/2018 was obtained from the Provincial Tax Commission. Data from before and after the ban are compared. RESULTS: According to the local authorities, while the enforcement efforts in Nova Scotia have not declined, the number of seized illicit cigarettes declined significantly, from >60 000 cartons in 2007/2008 to <10 000 cartons in 2017/2018. Since the menthol ban, the seizure volume remained stable, with no statistically significant difference in the number of cigarettes seized before and after the menthol ban (t=-0.71, p=0.55). There were only a few small seizures of menthol cigarettes in the year following the ban, after which there have been no further seizures of menthol cigarettes. DISCUSSION: Contrary to the tobacco industry's assertions, there was no surge in illicit cigarettes after the 2015 ban on menthol cigarette sales in Nova Scotia. Credible, industry-independent evidence on illicit cigarette trade is desperately needed to support the implementation of tobacco control policies. PMID- 30309979 TI - Salmonella SipA mimics a cognate SNARE for host Syntaxin8 to promote fusion with early endosomes. AB - SipA is a major effector of Salmonella, which causes gastroenteritis and enteric fever. Caspase-3 cleaves SipA into two domains: the C-terminal domain regulates actin polymerization, whereas the function of the N terminus is unknown. We show that the cleaved SipA N terminus binds and recruits host Syntaxin8 (Syn8) to Salmonella-containing vacuoles (SCVs). The SipA N terminus contains a SNARE motif with a conserved arginine residue like mammalian R-SNAREs. SipAR204Q and SipA1 435R204Q do not bind Syn8, demonstrating that SipA mimics a cognate R-SNARE for Syn8. Consequently, Salmonella lacking SipA or that express the SipA1-435R204Q SNARE mutant are unable to recruit Syn8 to SCVs. Finally, we show that SipA mimicking an R-SNARE recruits Syn8, Syn13, and Syn7 to the SCV and promotes its fusion with early endosomes to potentially arrest its maturation. Our results reveal that SipA functionally substitutes endogenous SNAREs in order to hijack the host trafficking pathway and promote Salmonella survival. PMID- 30309980 TI - PP2A-B55 promotes nuclear envelope reformation after mitosis in Drosophila. AB - As a dividing cell exits mitosis and daughter cells enter interphase, many proteins must be dephosphorylated. The protein phosphatase 2A (PP2A) with its B55 regulatory subunit plays a crucial role in this transition, but the identity of its substrates and how their dephosphorylation promotes mitotic exit are largely unknown. We conducted a maternal-effect screen in Drosophila melanogaster to identify genes that function with PP2A-B55/Tws in the cell cycle. We found that eggs that receive reduced levels of Tws and of components of the nuclear envelope (NE) often fail development, concomitant with NE defects following meiosis and in syncytial mitoses. Our mechanistic studies using Drosophila cells indicate that PP2A-Tws promotes nuclear envelope reformation (NER) during mitotic exit by dephosphorylating BAF and suggests that PP2A-Tws targets additional NE components, including Lamin and Nup107. This work establishes Drosophila as a powerful model to further dissect the molecular mechanisms of NER and suggests additional roles of PP2A-Tws in the completion of meiosis and mitosis. PMID- 30309982 TI - The matrix domain of the Gag protein from avian sarcoma virus contains a PI(4,5)P2-binding site that targets Gag to the cell periphery. AB - The Gag protein of avian sarcoma virus (ASV) lacks an N-myristoyl (myr) group, but contains structural domains similar to those of HIV-1 Gag. Similarly to HIV 1, ASV Gag accumulates on the plasma membrane (PM) before egress; however, it is unclear whether the phospholipid PI(4,5)P2 binds directly to the matrix (MA) domain of ASV Gag, as is the case for HIV-1 Gag. Moreover, the role of PI(4,5)P2 in ASV Gag localization and budding has been controversial. Here, we report that substitution of residues that define the PI(4,5)P2-binding site in the ASV MA domain (reported in a companion manuscript), interfere with Gag localization to the cell periphery and inhibit the production of virus-like particles (VLPs). We show that co-expression of Sprouty2 (Spry2) or the pleckstrin homology domain of phospholipase Cd (PH-PLC), two proteins that bind PI(4,5)P2, affects ASV Gag trafficking to the PM and budding. Replacement of the N-terminal 32 residues of HIV-1 MA, which encode its N-terminal myr signal and its PI(4,5)P2-binding site, with the structurally equivalent N-terminal 24 residues of ASV MA created a chimera that localized at the PM and produced VLPs. In contrast, the homologous PI(4,5)P2-binding signal in ASV MA could target HIV-1 Gag to the PM when substituted, but did not support budding. Collectively, these findings reveal a basic patch in both ASV and HIV-1 Gag capable of mediating PM binding and budding for ASV but not for HIV-1 Gag. We conclude that PI(4,5)P2 is a strong determinant of ASV Gag targeting to the PM and budding. PMID- 30309983 TI - Structural basis for targeting avian sarcoma virus Gag polyprotein to the plasma membrane for virus assembly. AB - For most retroviruses, including HIV-1, binding of the Gag polyprotein to the plasma membrane (PM) is mediated by interactions between Gag's N-terminal myristoylated matrix (MA) domain and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the PM. The Gag protein of avian sarcoma virus (ASV) lacks the N myristoylation signal but contains structural domains having functions similar to those of HIV-1 Gag. The molecular mechanism by which ASV Gag binds to the PM is incompletely understood. Here, we employed NMR techniques to elucidate the molecular determinants of the membrane-binding domain of ASV MA (MA87) to lipids and liposomes. We report that MA87 binds to the polar head of phosphoinositides such as PI(4,5)P2. We found that MA87 binding to inositol phosphates (IPs) is significantly enhanced by increasing the number of phosphate groups, indicating that the MA87-IP binding is governed by charge-charge interactions. Using a sensitive NMR-based liposome-binding assay, we show that binding of MA87 to liposomes is enhanced by incorporation of PI(4,5)P2 and phosphatidylserine. We also show that membrane binding is mediated by a basic surface formed by Lys-6, Lys-13, Lys-23, and Lys-24. Substitution of these residues to glutamate abolished binding of MA87 to both IPs and liposomes. In a joint manuscript, we further report that mutation of these lysine residues diminishes Gag assembly on the PM and inhibits ASV particle release. These findings provide a molecular basis for ASV Gag binding to the inner leaflet of the PM and advance our understanding of the basic mechanisms of retroviral assembly. PMID- 30309984 TI - Metabolic origin of the fused aminoacyl tRNA synthetase, glutamyl-prolyl tRNA synthetase. AB - About 1 billion years ago, in a single-celled holozoan ancestor of all animals, a gene fusion of two tRNA synthetases formed the bifunctional enzyme, glutamyl prolyl tRNA synthetase (EPRS). We propose here that a confluence of metabolic, biochemical, and environmental factors contributed to the specific fusion of glutamyl- (ERS) and prolyl- (PRS) tRNA synthetases. To test this idea we developed a mathematical model that centers on the precursor-product relationship of glutamic acid and proline, as well as metabolic constraints on free glutamic acid availability near the time of the fusion event. Our findings indicate that proline content increased in the proteome during the emergence of animals, thereby increasing demand for free proline. Together, these constraints contributed to a marked cellular depletion of glutamic acid and its products, with potentially catastrophic consequences. In response, an ancient organism invented an elegant solution in which genes encoding ERS and PRS fused to form EPRS, forcing co-expression of the two enzymes, and preventing lethal dysregulation. The substantial evolution- ary advantage of this co-regulatory mechanism is evidenced by the persistence of EPRS in nearly all extant animals. PMID- 30309985 TI - Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization. AB - Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int 1 (WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD6 Using MS analysis and a phospho-state- and -site specific antibody, we found that Ser-648, located in the FZD6 C terminus, is efficiently phosphorylated by casein kinase 1 epsilon (CK1epsilon) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1epsilon-mediated FZD6 phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1epsilon-targeted phosphomotif reduced FZD6 surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD6 Phospho-Ser-648 FZD6 immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD6 protein expression, suggesting that FZD6 phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD6 in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD6 rather than asymmetric protein distribution accounts for polarized receptor signaling. PMID- 30309986 TI - NRF2 transcriptionally activates the heat shock factor 1 promoter under oxidative stress and affects survival and migration potential of MCF7 cells. AB - Functional up-regulation of heat shock factor 1 (HSF1) activity through different post-translational modifications has been implicated in the survival and proliferation of various cancers. It is increasingly recognized that the HSF1 gene is also up-regulated at the transcriptional level, a phenomenon correlated with poor prognosis for patients with different cancers, including breast cancer. Here, we analyzed the transcriptional up-regulation of HSF1 in human cells upon arsenite- or peroxide-induced oxidative stress. Sequential promoter truncation coupled with bioinformatics analysis revealed that this activation is mediated by two antioxidant response elements (AREs) located between 1707 and 1530 base pairs upstream of the transcription start site of the HSF1 gene. Using shRNA-mediated down-regulation, chromatin immunoprecipitation of NRF2, site-directed mutagenesis of the AREs, and DNaseI footprinting of the HSF1 promoter, we confirmed that Nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2) interacts with these AREs and up-regulates HSF1 expression. We also found that BRM/SWI2 related gene 1 (BRG1), a catalytic subunit of SWI2/SNF2-like chromatin remodeler, is involved in this process. We further show that NRF2-dependent HSF1 gene regulation plays a crucial role in cancer cell biology, as interference with NRF2 mediated HSF1 activation compromised survival, migration potential, and the epithelial-to-mesenchymal transition and autophagy in MCF7 breast cancer cells exposed to oxidative stress. Taken together, our findings unravel the mechanistic basis of HSF1 gene regulation in cancer cells and provide molecular evidence supporting a direct interaction between HSF1 and NRF2, critical regulators of two cytoprotective mechanisms exploited by cancer cells. PMID- 30309987 TI - Is establishing a specialist back pain assessment and management service in primary care a safe and effective model? Twelve-month results from the Back pain Assessment Clinic (BAC) prospective cohort pilot study. AB - OBJECTIVES: To report on the design, implementation and evaluation of the safety and effectiveness of the Back pain Assessment Clinic (BAC) model. DESIGN: BAC is a new, community-based specialist service for assessing and managing neck and low back pain (LBP). The BAC pilot was supported by a Victorian Department of Health and Human Services grant and was evaluated using the Victorian Innovation Reform Impact Assessment Framework (VIRIAF). Data were obtained by auditing BAC activity (22 July 2014 to 30 June 2015) and conducting surveys and interviews of patients, stakeholders and referrers. SETTING: Tertiary and primary care. PARTICIPANTS: Adult patients with neck and LBP referred for outpatient surgical consultation. MAIN OUTCOME MEASURES: VIRIAF outcomes: (1) access to care; (2) appropriate and safe care; (3) workforce optimisation and integration; and (4) efficiency and sustainability. RESULTS: A total of 522 patients were seen during the pilot. Most were referred to hospital services by general practitioners (87%) for LBP (63%) and neck pain (24%). All patients were seen within 10 weeks of referral and commenced community-based allied health intervention within 2-4 weeks of assessment in BAC. Of patients seen, 34% had medications adjusted, 57% were referred for physiotherapy, 3.2% to pain services, 1.1% to rheumatology and 1.8% for surgical review. Less MRI scans were ordered in BAC (6.4%) compared with traditional spinal surgical clinics (89.8%), which translated to a cost-saving of $52 560 over 12 months. Patient and staff satisfaction was high. There have been no patient complaints or adverse incidents. CONCLUSION: Evaluation of the BAC pilot suggests it is a potentially safe and cost-saving alternative model of care. Results of the BAC pilot merit further evaluation to determine the potential cost-effectiveness, longer term and broader societal impact of implementing BAC more widely. PMID- 30309988 TI - Making sense of recovery after traumatic brain injury through a peer mentoring intervention: a qualitative exploration. AB - OBJECTIVE: To explore the acceptability of peer mentoring for people with a traumatic brain injury (TBI) in New Zealand. DESIGN: This is a qualitative descriptive study exploring the experiences reported by mentees and mentors taking part in a feasibility study of peer mentoring. Interviews with five mentees and six mentors were carried out. Data were analysed using conventional content analysis. SETTING: The first mentoring session took place predischarge from the rehabilitation unit. The remaining five sessions took place in mentees' homes or community as preferred. PARTICIPANTS: Twelve people with TBI took part: six mentees (with moderate to severe TBI; aged 18-46) paired with six mentors (moderate to severe TBI >12 months previously; aged 21-59). Pairing occurred before mentee discharge from postacute inpatient brain injury rehabilitation. Mentors had been discharged from rehabilitation following a TBI between 1 and 5 years previously. INTERVENTION: The peer mentoring programme consisted of up to six face-to-face sessions between a mentee and a mentor over a 6-month period. The sessions focused on building rapport, exploring hopes for and supporting participation after discharge through further meetings and supported community activities. RESULTS: Data were synthesised into one overarching theme: making sense of recovery. This occurred through the sharing of experiences and stories; was pivotal to the mentoring relationship; and appeared to benefit both mentees and mentors. Mentors were perceived as valued experts because of their personal experience of injury and recovery, and could provide support in ways that were different from that provided by clinicians or family members. Mentors required support to manage the uncertainties inherent in the role. CONCLUSIONS: The insight mentors developed through their own lived experience established them as a trusted and credible source of hope and support for people re-engaging in the community post-TBI. These findings indicate the potential for mentoring to result in positive outcomes. PMID- 30309989 TI - Young age at school entry and attention-deficit hyperactivity disorder-related symptoms during primary school: results of a prospective cohort study conducted at German Rudolf Steiner Schools. AB - OBJECTIVES: Young age at school entry (ASE) for students has been related to their impaired mental health in higher grades. To avoid the negative health consequences of young ASE, preschool examinations and individual school entry deferral for young children are routinely performed by some school authorities. We aimed to investigate whether ASE was associated with attention-deficit hyperactivity disorder (ADHD)-related symptoms in pupils attending schools using a selective school enrolment procedure. DESIGN: Prospective open cohort study with baseline assessments at school entry and two follow-ups in the second and fourth grades. SETTING: Up to 128 Rudolf Steiner Schools (Waldorf Schools) located within Germany. PARTICIPANTS: Of the 3079 children from whom data were gathered in the second or fourth grade, 2671 children born between 1 July 2001 and 31 October 2002 (age at baseline: mean 6.7, min 5.91, max 7.24 years, 50% girls) were selected for analysis to avoid bias introduced by individuals at the edges of the ASE distribution. MAIN OUTCOME MEASURES: ADHD-related symptoms were assessed at school entry and second and fourth grades by parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire (Hyperactivity-Inattention Subscale). RESULTS: The agreement between parent reported and teacher-reported symptoms was poor (intra-class correlation: 0.41 and 0.44 in second and fourth grade assessments, respectively). Regarding teacher reports, ASE was negatively associated with ADHD-related symptoms in the second grade (regression coefficient beta=-0.66 per year, P=0.0006) and fourth grade (beta=-0.56, P=0.0014). Associations remained after adjusting for potential confounders and pre-existing symptoms at baseline. Regarding parent reports, associations were markedly weaker in both grades (second grade: beta=-0.22, P=0.12; fourth grade: beta=-0.09, P=0.48). CONCLUSIONS: Using a prospective study design and comprehensive adjustment for confounding and baseline symptoms, we confirmed prior evidence of the association between young ASE and teacher reported ADHD symptoms in primary school. PMID- 30309990 TI - Cohort Study of Pulmonary Tuberculosis (COSMOTB) identifying drug-resistant mutations: protocol for a prospective observational study in Korea. AB - INTRODUCTION: Drug-resistant tuberculosis (TB) is a global concern. The proper diagnosis and management of drug-resistant TB are critical for improving treatment outcome. Molecular-based genotypic drug-susceptibility testing (DST) was developed to identify drug-resistant TB; however, discordant results from phenotypic and genotypic DST analyses have alarmed clinicians and raised concerns about the test's utility. Moreover, the characteristics of disputed mutations are not well studied and only based on retrospective study findings. METHODS AND ANALYSIS: We describe a 28-month prospective observational cohort study ongoing at two university-affiliated hospitals in South Korea. The cohort study will enrol and evaluate 600 adults with pulmonary TB. Relevant clinical and epidemiological data will be collected prospectively and participants will be evaluated at each hospital during anti-TB treatment to identify factors associated with TB treatment outcomes. Respiratory specimens will be collected at select visits. After generating a well-characterised cohort, patterns of drug resistance on both phenotypic and genotypic DSTs and associated mutations including the disputed mutation will be evaluated. We will also identify various clinical and socioeconomic factors that affect the causes of drug resistance and their clinical outcomes. ETHICS AND DISSEMINATION: The study protocol is approved by the Institutional Review Boards of Chungbuk National University Hospital and Chungnam National University Hospital. Study results will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: KCT0002594. PMID- 30309991 TI - Burden of seasonal influenza in sub-Saharan Africa: a systematic review protocol. AB - INTRODUCTION: Measures of epidemiological burdens are an important contribution to estimating disease severity and determining the at-risk populations for seasonal influenza. In the absence of these data, it is extremely difficult for policy-makers to decide on how to distribute limited resources. This systematic review will synthesise the literature on reported burden of seasonal influenza (eg, morbidity and mortality) in sub-Saharan Africa. METHOD AND ANALYSIS: We will include published epidemiological studies that capture the burden estimation of seasonal influenza between 1 January 2000 and 31 August 2018. Studies that have reported disease burden estimates associated to influenza-like illness, acute respiratory illness, acute lower respiratory illness, severe acute respiratory illness and severe or very severe pneumonia using laboratory-confirmed influenza cases will be included. We will perform a multiple electronic database search in PubMed, Embase, African Journals Online, Cochrane, Web of science, CINAHL and Google scholar for eligible studies. The reference lists of relevant studies will also be hand-searched for potentially eligible studies. The titles and abstracts of identified records will be screened independently by two authors. The full text articles of potentially eligible studies will be assessed independently by two authors. Discrepancies will be resolved by discussion, and by a third author if the first two authors fail to come to a consensus. The measures of the burden of influenza will be aggregated using a meta-analysis for homogeneous studies and narrative synthesis if the studies are heterogeneous. The strength of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: This systematic review will use publicly available data; and as such, no formal ethical review is required. Our findings will be published in a peer-reviewed journal and also disseminated through conferences and stakeholder meetings. PROSPERO REGISTRATION NUMBER: CRD42017074091. PMID- 30309992 TI - Detection and treatment initiation for depression and alcohol use disorders: facility-based cross-sectional studies in five low-income and middle-income country districts. AB - OBJECTIVES: To estimate the proportion of adult primary care outpatients who are clinically detected and initiate treatment for depression and alcohol use disorder (AUD) in low-income and middle-income country (LMIC) settings. DESIGN: Five cross-sectional studies. SETTING: Adult outpatient services in 36 primary healthcare facilities in Sodo District, Ethiopia (9 facilities); Sehore District, India (3); Chitwan District, Nepal (8); Dr Kenneth Kaunda District, South Africa (3); and Kamuli District, Uganda (13). PARTICIPANTS: Between 760 and 1893 adults were screened in each district. Across five districts, between 4.2% and 20.1% screened positive for depression and between 1.2% and 16.4% screened positive for AUD. 96% of screen-positive participants provided details about their clinical consultations that day. PRIMARY OUTCOMES: Detection of depression, treatment initiation for depression, detection of AUD and treatment initiation for AUD. RESULTS: Among depression screen-positive participants, clinical detection of depression ranged from 0% in India to 11.7% in Nepal. Small proportions of screen positive participants received treatment (0% in Ethiopia, India and South Africa to 4.2% in Uganda). Among AUD screen-positive participants, clinical detection of AUD ranged from 0% in Ethiopia and India to 7.8% in Nepal. Treatment was 0% in all countries aside Nepal, where it was 2.2%. CONCLUSIONS: The findings of this study suggest large detection and treatment gaps for adult primary care patients, which are likely contributors to the population-level mental health treatment gap in LMIC. Primary care facilities remain unfulfilled intervention points for reducing the population-level burden of disease in LMIC. PMID- 30309993 TI - Triangulating abuse liability assessment for flavoured cigar products using physiological, behavioural economic and subjective assessments: a within-subjects clinical laboratory protocol. AB - INTRODUCTION: In the USA, Food and Drug Administration regulations prohibit the sale of flavoured cigarettes, with menthol being the exception. However, the manufacture, advertisement and sale of flavoured cigar products are permitted. Such flavourings influence positive perceptions of tobacco products and are linked to increased use. Flavourings may mask the taste of tobacco and enhance smoke inhalation, influencing toxicant exposure and abuse liability among novice tobacco users. Using clinical laboratory methods, this study investigates how flavour availability affects measures of abuse liability in young adult cigarette smokers. The specific aims are to evaluate the effect of cigar flavours on nicotine exposure, and behavioural and subjective measures of abuse liability. METHODS AND ANALYSES: Participants (projected n=25) are healthy smokers of five or more cigarettes per day over the past 3 months, 18-25 years old, naive to cigar use (lifetime use of 50 or fewer cigar products and no more than 10 cigars smoked in the past 30 days) and without a desire to quit cigarette smoking in the next 30 days. Participants complete five laboratory sessions in a Latin square design with either their own brand cigarette or a session-specific Black & Mild cigar differing in flavour (apple, cream, original and wine). Participants are single-blinded to cigar flavours. Each session consists of two 10-puff smoking bouts (30 s interpuff interval) separated by 1 hour. Primary outcomes include saliva nicotine concentration, behavioural economic task performance and response to various questionnaire items assessing subjective effects predictive of abuse liability. Differences in outcomes across own brand cigarette and flavoured cigar conditions will be tested using linear mixed models. ETHICS AND DISSEMINATION: The Virginia Commonwealth University Institutional Review Board approved the study (VCU IRB: HM20007848). Dissemination channels for study findings include scientific journals, scientific meetings, and policy briefs. TRIAL REGISTRATION NUMBER: NCT02937051. PMID- 30309994 TI - Is care based on comprehensive geriatric assessment with mobile teams better than usual care? A study protocol of a randomised controlled trial (The GerMoT study). AB - INTRODUCTION: Comprehensive geriatric assessment (CGA) is a multidimensional, interdisciplinary diagnostic process used to determine the medical, psychological and functional capabilities of frail older people. The primary aim of our current study is to confirm whether CGA-based outpatient care is superior than usual care in terms of health-related outcomes, resource use and costs. METHODS AND ANALYSIS: The Geriatric Mobile Team trial is designed as a single-centre randomised, controlled, assessor-blinded (at baseline) trial. All participants will be identified via local healthcare registries with the following inclusion criteria: age >=75 years, >=3 different diagnoses and >=3 visits to the emergency care unit (with or without admittance to hospital) during the past 18 months. Nursing home residency will be an exclusion criterion. Baseline assessments will be done before the 1:1 randomisation. Participants in the intervention group will, after an initial CGA, have access to care given by a geriatric team in addition to usual care. The control group receives usual care only. The primary outcome is the total number of inpatient days during the follow-up period. Assessments of the outcomes: mortality, quality of life, health care use, physical functional level, frailty, dependence and cognition will be performed 12 and 24 months after inclusion. Both descriptive and analytical statistics will be used, in order to compare groups and for analyses of outcomes over time including changes therein. The primary outcome will be analysed using analysis of variance, including in-transformed values if needed to achieve normal distribution of the residuals. ETHICS AND DISSEMINATION: Ethical approval has been obtained and the results will be disseminated in national and international journals and to health care leaders and stakeholders. Protocol amendments will be published in ClinicalTrials.gov as amendments to the initial registration NCT02923843. In case of success, the study will promote the implementation of CGA in outpatient care settings and thereby contribute to an improved care of older people with multimorbidity through dissemination of the results through scientific articles, information to politicians and to the public. TRIAL REGISTRATION NUMBER: NCT02923843; Pre-results. PMID- 30309995 TI - Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study). AB - INTRODUCTION: Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only. METHODS AND DESIGN: The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment. ETHICS AND DISSEMINATION: Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal. TRIAL REGISTRATION NUMBER: DRKS0006547; EudraCT2014-001991-76; Pre-result. DATE OF REGISTRATION: 30 October 2014; 24 February 2017. PMID- 30309997 TI - The role of anti-HBs in hepatitis B reactivation during direct-acting antiviral therapy for chronic hepatitis C. AB - BACKGROUND: Hepatitis B reactivation in patients with resolved HBV can occur during hepatitis C treatment with direct-acting antivirals, but only a few cases have been described. It is not clear which patients are at risk for HBV reactivation and how to manage them. METHODS: Three patients (all hepatitis B surface antigen [HBsAg]-negative, antibody to hepatitis B core [anti-HBc] positive and HBV DNA negative) experienced a late HBV reactivation 12 weeks post treatment but were able to control their viraemia. HCV RNA, HBV DNA, anti-HBc and anti-HBs were measured in these patients and in 37 HBsAg-negative, anti-HBc positive, HBV DNA negative control patients during direct-acting antiviral therapy for chronic hepatitis C. RESULTS: Baseline anti-HBs do not differ between patients with and without HBV reactivation. Patients with HBV reactivation, however, significantly increased their anti-HBs at time of reactivation, while patients without HBV reactivation show stable anti-HBs during therapy (P=0.007). CONCLUSIONS: Anti-HBs might be an important marker to delineate patients at risk for clinically significant HBV reactivation. PMID- 30309996 TI - The truth and fiction in aspiration physics: may the forces be with you. PMID- 30309998 TI - [Usefulness of Nutritional Enforcement by Percutaneous Gastrostomy in Successful Omentoplasty for Empyema with Fistula]. AB - Omentoplasty has been accepted as an effective surgical procedure for fistulated empyema. However, it is difficult for patients with poor nutritional status because their omental volume is often too poor to be applied for omentoplasty. Percutaneous endoscopic gastrostomy(PEG) is useful for long-term nutritional management. There is no report on safety and usefulness of PEG before omentoplasty. We report a case of omentoplasty that was successfully performed after nutritional enforcement by using percutaneous endoscopic gastrostomy in a patient of postoperative empyema with fistula. PMID- 30309999 TI - [A Single-knot Lock Procedure for Adjustment of Artificial Chordae in Mitral Valve Repair]. AB - We describe a simple and reproducible technique for adjustment of neochordal length in mitral valve repair with a single-knot lock procedure. A small loop with polytetra fluoroethylene(CV-4)is secured on the papillary muscle as an anchor for the neochordae. A needle with CV-5 suture is passed through the anchor loop, and both ends of the suture are passed through the free edge of the prolapsed mitral leaflet. A single knot is made on the leaflet with the 2 ends of each suture thread, and the ends of each pair of suture threads are secured with small hemostatic clamps. The hemostatic clamps are suspended over the edge of the wound to apply traction to the single knot. The knot is locked with this tension and the friction between the threads. The saline injection test is applied, and the height of the artificial chordae is adjusted by sliding the knot to the appropriate position. After valve competency is obtained, the knot is held by curved hemostatic forceps, and the threads of the suture are tied on the leaflet. This technique for adjustment of neochordal length is quick, reliable, reproducible, and increases the technical possibilities for mitral valve repair. PMID- 30310000 TI - [Hybrid Treatment for Aortic Arch Aneurysm Concomitant with Right Subclavian Artery Aneurysm]. AB - A 78-year-old man was hospitalized for aortic arch aneurysm concomitant with right subclavian artery aneurysm. Maximum diameter of each aneurysm was 65 mm and 40 mm, respectively. Both aneurysms clearly needed to be treated. However, simultaneous surgery of total arch replacement (TAR) and right subclavian artery grafting carries both technical difficulty of surgical exposure and considerable risk of bilateral recurrent nerve palsy. Thus, to avoid these serious problems, we chose hybrid treatment. TAR was performed as the 1st procedure, followed by stent graft placement to right subclavian artery aneurysm. At the 1st procedure, an 8 mm graft was anastomosed to right common carotid artery in end to side fashion. This was used for cerebral perfusion, and after that, another end of this graft was anastomosed to a branch of quadrant graft which was anastomosed to brachiocephalic artery. Then, right common carotid artery was ligated at proximal portion to create a proximal landing zone. As the 2nd procedure, excluder leg was deployed via right axillary artery without difficulty. He was discharged with uneventful postoperative course. PMID- 30310001 TI - [Treatment of Mediastinitis after Open Heart Surgery Using Negative Pressure Wound Therapy with Irrigation]. AB - Mediastinitis occurs after open heart surgery in a small number of cases. When it occurs, early diagnosis and treatment are important. A 69-year-old male patient suffered from mediastinitis after total aortic arch replacement. He has cured completely by negative pressure wound therapy (NPWT) with irrigation method. The vacuum-assisted closure( VAC) method is very useful for wound repair and has recently been used to treat mediastinitis. However, the use of VAC alone does not always result in complete cure. NPWT with irrigation is a very useful infection control method. Performing NPWT before VAC might contribute to improving the outcomes of mediastinitis treatment. However, it is difficult to decide when to switch from NPWT with irrigation to VAC. PMID- 30310002 TI - [Pacemaker Dislocation into the Peritoneal Cavity]. AB - A 16-day-old neonate with congenital complete atrioventricular block underwent epicardial pacemaker implantation under the rectus. Four months later, abodominal X-ray imaging revealed dislocation of the generator from the abdomen to the pelvis. The infant was diagnosed with intraperitoneal pacemaker dislocation. However, there were no abdominal manifestations or complications associated with the bowel, urinary tract, and vascular system. Surgical refixation was performed in a hybrid room. Fluoroscopy helped avoid bowel injury when removing the generator from the peritoneal cavity. The pacing lead, which was adherent and entangled with the omentum, was released under direct vision. The generator was placed in a new pocket created in the subcutaneous layer of the anterior fascia of the rectus. PMID- 30310003 TI - [Omental Flap for the Device Infection of the HeartMate II]. AB - Case 1:An 18-year-old male underwent emergent left extracorporeal ventricular assist device(eVAD) implantation for a cardiogenic shock because of dilated cardiomyopathy (DCM). After listing for heart transplant, he underwent a HeartMate II implantation as bridge-to-bridge(BTB) therapy. The omental flap was simultaneously used to prevent device infection that could have been induced by the infected malgranulation around the cannulas of the eVAD. Eventually, he was discharged and waiting for transplantation. Case 2:A 30-year-old male with DCM underwent emergent eVAD implantation for left ventricular support, centrifugal veno-pulmonary artery extracorporeal membrane oxygenation (ECMO) for right ventricular and respiratory support, and mitral valve replacement. After weaning of ECMO, he was listed for a heart transplant and underwent a HeartMate II implantation as BTB therapy. However, liver dysfunction and malnutrition prolonged wound healing. Despite applying vacuum assist closure device to promote wound healing, part of the driveline and pump housing were exposed. Therefore, radical debridement and omentopexy were performed for infection control. He was discharged after complete wound healing. PMID- 30310004 TI - [Surgical Treatment of Acute Infective Endocarditis after Transcatheter Aortic Valve Replacement]. AB - Infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) is a rare complication, but has a high mortality. An 86-year-old female with symptomatic severe aortic stenosis underwent TAVR at our hospital and she was discharged without complication after 10 days. She was readmitted with high fever and acute heart failure 1 month later. Blood culture revealed Staphylococcus, and echocardiography showed vegetation on the septal cusp of the tricuspid valve and perforation at the membranous ventricular septum. We decided to perform emergency operation due to active infection and intracardiac complication despite appropriate antibiotic treatment. The infected valve was replaced with a bioprosthetic valve and the right ventricular (RV)-left ventricular (LV) communication was closed with a bovine pericardial patch. The patient received the antibiotics for 6 week and was transferred to the previous facility. PMID- 30310005 TI - [Surgical Treatment of Papillary Fibroelastoma Developed in the Left Ventricle]. AB - Papillary fibroelastomas are rare benign cardiac tumors, which generally arise from the valvular endocardium. Although they have little hemodynamics effects, they can cause some life threatening events such as cerebral embolization. We herein report a case of 68-year-old female with a mobile left ventricular mass of 10 mm in diameter. It was accidentally found on the anterior papillary muscle by echocardiography under evaluation of the angina pectoris. Resection of the left ventricular mass was performed through the mitral valve. Coronary artery bypass grafting to left anterior descending artery was also performed using the left intra-thoracic artery. Pathological finding of the tumor was papillary fibroelastoma. Post-operative course was uneventful, with no recurrence about a year. PMID- 30310007 TI - [Two-staged Operation for Bilateral Giant Bullae Successfully Performed with Veno venous Extracorporeal Membrane Oxygenation( V-V ECMO) for First Surgery]. AB - 57-year-old man with bilateral giant lung bullae was admitted to our hospital for dyspnea on exertion as his chief complaint. The size and shape of right lung bullae were bigger and more complicated than those of left lung bullae. He underwent 2-staged bullectomy by video-assisted thoracoscopic surgery (VATS). Left lung bullectomy was expected to be more safely done, and was performed with veno-venous extracorporeal membrane oxygenation( V-V ECMO) prior to right side without any complications. The right lung bullectomy was performed 6 months after 1st operation without V-V ECMO. These reoperations were necessary due to postoperative air leak, however, his respiratory condition was well maintained by his left lung which had already been remarkably improved. PMID- 30310006 TI - [Excision of a Left Ventricular Papillary Fibroelastoma via Right Thoracotomy with a Small Skin Incision]. AB - A 75-year-old woman was referred to our hospital for surgical treatment of a left ventricular mass. Echocardiography demonstrated a mobile left ventricular mass originating from the apex of the anteroseptal wall. Cardiac magnetic resonance imaging showed low signal intensity on T1 images and high signal intensity on T2 images. A right 4th intercostal thoracotomy with a small skin incision was performed, and cardiopulmonary bypass was established via the right femoral artery and vein and the right jugular vein. After cardiac arrest, we approached the tumor through the mitral valve via a left atrial incision. Resection of the tumor was difficult owing to its deep location;however, we could successfully resect it using an endoscope. Histopathological diagnosis confirmed a papillary fibroelastoma. Postoperative course was uneventful. A papillary fibroelastoma originating from the left ventricular wall is rare. Although a right thoracotomy is a useful approach for the management of a cardiac mass, careful planning is needed to obtain access to a mass in deep location. PMID- 30310008 TI - [Lung Adenosquamous Cell Carcinoma in which the Administration of Nivolumab Became Untenable due to Bleeding from Small Intestine Metastasis]. AB - A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively. PMID- 30310009 TI - [Modified David-Komeda Repair for Ventricular Septal Perforation Complicated with Severe Postoperative Acute Respiratory Distress Syndrome;Report of a Case]. AB - A 61-year-old man presented by ambulance with dyspnea. He was diagnosed with myocardial infarction complicated with ventricular septal perforation (VSP), and intraaortic balloon pumping support and intensive care were started. Because of instability of hemodynamic status, modified David-Komeda operation with double patch was performed in the subacute phase of VSP. Although he developed acute respiratory distress syndrome( ARDS) on the 21st day after operation, he was successfully treated with corticosteroid pulse therapy and artificial ventilation. He was transferred to a rehabilitation hospital on the 141st postoperative day. PMID- 30310010 TI - [Stenosis of the Right Coronary Limb of Interposed Artificial Graft 28 Years After Cabrol Technique;Report of a Case]. AB - Cabrol technique is one of the modified Bentall procedures. However, it has become nearly obsolete over the years because of reports of stenosis, thrombosis, and occlusion of the interposed graft. A 76-year-old man, who had undergone Cabrol technique 28 years before, presented with worsening exertional dyspnea and, was diagnosed with mitral valve regurgitation and tricuspid valve regurgitation. Preoperative angiography revealed stenosis of the right limb of the interposed artificial graft, and he underwent coronary artery bypass grafting (CABG) in addition to mitral valve replacement (MVR) and tricuspid annuloplasty (TAP). Patients who underwent procedures such as Cabrol technique and Piehler technique using interposed artificial grafts reconstructing coronary arteries, should be regularly checked with imaging examinations. PMID- 30310011 TI - [Pseudo-false Aneurysm of the Left Ventricle after Acute Myocardial Infarction;Report of a Case]. AB - A 77-year-old man was admitted to a regional hospital to undergo investigation of abnormal electrocardiographic findings. Coronary angiography revealed 99% stenosis of the right coronary artery(RCA) segment 3 and 75% stenosis of the left anterior descending artery (LAD)segment 7. Left ventriculography revealed an aneurysm at the inferior wall of the left ventricle. On computed tomography and echocardiography, a saccular aneurysm at the inferior wall, 15 mm in diameter, was observed. Under the suspicion of a ventricular false aneurysm resulting from myocardial infarction, aneurysmectomy, patch closure of the aneurysmal orifice and coronary artery bypass grafting to the LAD and RCA were performed. No pericardial adhesion to the ventricular aneurysm was observed. His postoperative course was uneventful, and he was discharged from the hospital on the 28th postoperative day in good condition. The pathological examination revealed residual cardiomyocytes with the aneurysmal wall. PMID- 30310012 TI - [Papillary Fibroelastoma of the Pulmonary Valve;Report of a Case]. AB - We herein present a rare case of a papillary fibroelastoma on the pulmonary valve. A 66-year-old female underwent a graft replacement of the ascending aorta and an aortic valve replacement. Subsequent biannual checks have been performed as a follow up to surgery. An echocardiography, 3 years post surgery, revealed a growing mass, 13 mm in diameter, which was attached to the pulmonary valve. Upon surgery, the mass, which lacked a stalk, was found attached to the right semilunar cusp of the pulmonary valve. The cusp was resected with the mass in order to ensure a complete resection, and as we were unable to repair the pulmonary valve, it needed to be replaced with a mechanical valve. The pathological examination of the resected mass resulted in our diagnosis of a papillary fibroelastoma. The patient is now doing well 2 years after the surgery without any recurrence of the tumor. PMID- 30310013 TI - [Sternal Nonunion after Open Heart Surgery through a Partial Sternotomy;Report of a Case]. AB - Sternal nonunion is an uncommon complication after a sternal wound and some cases have been reported as a complication of open heart surgery. A 28-year-old male suffered from persistent sternal pain. Six years ago, open heart surgery was performed through a partial sternotomy with transverse sternotomy. The sternal nonunion was repaired using 3 sternal wires and 1 absorbable sternal pin. Three years later, the patient experienced recurrence of persistent sternal pain with clicking, because all of the sternal wires had ruptured and the sternal healing was incomplete. The patient was treated with adequate debridement and a technique using metal plates and autogenous bone grafts, which provided excellent pain relief. A transverse sternotomy potentially exposes the patient to the risk of sternal nonunion, which should be treated using autogenous bone grafting. PMID- 30310014 TI - [Inflammatory Pulmonary Myofibroblast Tumor Suspected of Pulmonary Metastasis of the Lung Cancer;Report of a Case]. AB - Inflammatory myofibroblastic tumor (IMT) of the lung is a rare disease. The patient underwent the chemoradiotherapy for primary left lung cancer which showed complete responce (CR) by the treatment. A different nodule of 10 mm in diameter was found in the left lung by computed tomography (CT). Positron emission tomography(PET) showed positive detection correspond to the nodule ( SUVmax 4.82). A partial lung resection was carried out, and the tumor was diagnosed as IMT pathologically. PMID- 30310015 TI - [Pulmonary Chondroma;Report of a Case]. AB - A 66-year-old man was pointed out a nodular shadow in the right lower lobe by chest computed tomography (CT) 4 years ago. Since the size of the shadow has been increasing for 4 years, he hospitalized for surgery. Partial resection of the right lower lobe was performed. Histopathologically, the tumor was composed of cartilage tissue without epithelial components, and was diagnosed as a chondroma. Postoperative course was uneventful and there has been no recurrence at 1 years and 8 months after surgery. PMID- 30310016 TI - [Anesthesia and Anesthesia-related Technology]. AB - Although there is no remarkable change of anesthetics or anesthesia methods in recent years, several new technologies are used for safety management of cardiac, lung or thoracic surgery. Stroke volume variation (SVV) monitoring indicates SVV, a parameter to optimize fluid infusion and is used to avoid edema or congestive heart damage due to over hydration. SmartPilot View, a pharmacokinetic simulator during anesthesia, represents the measured effective site concentration of anesthetics and contributes the optimization of induction and maintenance of anesthesia. Pressure controlled ventilation-volume guarantee (PCV-VG) is a ventilation mode that can secure preset tidal volume even under PCV to avoid hypoxemia and hypercapnia, even when unexpected airway pressure raised. AutoFlow system supplies tidal volume at the lowest airway pressure and has the function of maintaining tidal volume while keeping low airway pressure according to the change of pulmonary compliance. In 2017, we modified the position of cuff air delivery lumen while maintaining the strength and elasticity of double-lumen tube (DLT) made by a company to avoid deflation failure of bronchial cuff by our team. PMID- 30310018 TI - [Mechanical Ventilation]. AB - Mechanical ventilation is a useful treatment option for respiratory insufficiency following thoracic and cardiovascular surgery. Ventilation mode is classified as volume-controlled-ventilation(VCV) and pressure-controlled ventilation(PCV). Non invasive ventilation(NIV) without tracheal intubation has been recently developed and is effective in patients with chronic obstructive pulmonary disease (COPD) exacerbation. Several pulmonary complications by mechanical ventilation such as ventilator-induced lung injury(VILI) or ventilator-associated pneumonia(VAP) could be avoided with NIV. According to the protocol published from Japanese Society of Intensive Care Unit, Japanese Society of Respiratory Care Medicine, and Japan Academy of Critical Care Nursing, both spontaneous awakening trial(SAT) and spontaneous breathing trial(SBT) are recommended at the weaning from mechanical ventilation. I herein describe the utility of mechanical ventilation in patients with major pulmonary resection, myasthenia gravis, lung transplantation, and cardiac surgery, for each. We should understand not only the utility but also the non-physiological condition during mechanical ventilation. PMID- 30310017 TI - [Role of Perioperative Extracorporeal Membrane Oxygenation in Cardiothoracic Surgery]. AB - Extracorporeal membrane oxygenation (ECMO) is a temporary mode of providing life support by totally/partially augmenting heart and lung function over a few days to weeks. More than 30,000 cases involving ECMO usage in adults have been reported worldwide since the introduction of this unique therapy, and its applications continue to evolve rapidly. In recent times, ECMO plays a key role not only in the domain of critical care in intensive care units, but is also useful in the field of cardiothoracic surgery;it provides cardiopulmonary support intra- and post-operatively, respiratory support for primary graft dysfunction after lung transplantation and serves as a bridge to lung transplantation. The purpose of this review is to analyze the indications, modes of application, and complications of ECMO use in the field of cardiothoracic surgery. PMID- 30310019 TI - [Minimally Invasive Cardiac Surgery with Thoracoscopy]. AB - Minimally invasive cardiac surgery (MICS) with high quality thoracoscopy has been widespread. MICS has been very well established for mitral valve repair because of its anatomical condition. For aortic valve surgery and coronary artery surgery, MICS has not been so widespread in comparison to mitral valve surgery, but there has yet room for further development. Here we review current status of thoracoscopy for MICS. PMID- 30310020 TI - [Latest Monitoring Systems for Vital Signs in Cardiothoracic Surgery]. AB - In this review article, the latest monitoring systems for vital signs in cardiothoracic surgery, including a multi-wavelength pulse oximeter, a transcutaneous blood gas monitoring system, a modified pulmonary artery catheter, and modern less-invasive cardiac output measurement systems are introduced. These less-invasive and real-time/continuous monitoring technologies would provide useful information for perioperative care after cardiothoracic surgeries, and improve the outcomes of surgeries. PMID- 30310021 TI - [Imaging Diagnosis and Interventional Radiology for Thoracic Surgery]. AB - Recent introduction of multidetector-row computed tomography(MDCT) with more than 64 scanners enabled high-speed scanning in wide range of the body. Electrocardiogram (ECG) gated scanning and 4-dimensional imaging provides precise evaluation of cardiac and vascular diseases. Fine vascular structures such as the artery of Adamkiewicz can be visualized due to improved spatial and temporal resolution of CT and magnetic resonance imaging(MRI). Interventional radiology also plays important roles in combination with surgical treatment. Complicated vascular embolization before and after surgery can be performed more safely using current microcatheters with increased flexibility and trackability and various kinds of detachable coils. Chylothorax also come to be treated by interventional radiology. Transnodal lymphography can visualize lymphatic leak followed by thoracic duct embolization. Radiofrequency ablation and cryoablation for thoracic tumors, which is usually performed by real-time CT fluoroscopy, is expected to be officially approved. Newly developed techniques will further improve thoracic imaging diagnosis. Dual energy CT technology and new reconstruction technique can decrease the radiation dose without deteriorating image quality. Iodine imaging by dual energy CT can visualize vascular perfusion. Four-dimensional flow image of MRI can image vascular flow-dynamics without using contrast material. PMID- 30310022 TI - [Reinforcement Materials for Thoracic Surgery]. AB - Recently, various types of artificial and biological materials have been used for hemostasis or control of air leakage in thoracic surgery. These reinforcement materials are essential for thoracic surgery. Therefore, surgeons must know their characteristics and appropriate usage. In this review, the authors describe the recent development of reinforcement materials in thoracic surgery. PMID- 30310023 TI - [Energy Device and Soft Coagulation System in Thoracic Surgery]. AB - While the recent emergence of energy-based surgical techniques and soft coagulation has made surgical procedures less invasive, the safety and proper use of such advances have yet to be investigated. Herein we review the experimental and clinical use of ultrasonically-activated coagulating shears, a vessel sealing system, incorporating ultrasonic and vessel sealing technology, and a soft coagulation system in thoracic surgery. All energy devices have been reported to be safe for use on pulmonary vessels, and use in combination with a ligature appears to be adequate. The thoracic duct has been reported to be sealed with sufficient pressure using energy devices, which are expected to prevent chylothorax formation. Bipolar scissors can be safely and efficiently applied for dissection of pulmonary vessels without damage to the vessel wall. Monopolar soft coagulation can be applied to shrink bullous changes and stop air leakage or bleeding within the lung. PMID- 30310024 TI - [Intraoperative Transesophageal Echocardiography]. AB - Transesophageal echocardiography (TEE) provides real-time information on both morphology and hemodynamics without radiation exposure or contrast media, interruption of surgical procedures, or need for transferring the patient to other division, and thus can be used as intraoperative monitoring as well as diagnostic imaging. TEE is helpful for confirming the adequacy of routine surgical procedures, ruling out an occurrence of unexpected adverse events, or even navigating the manipulations of cannulae and catheters. In mitral valve repair, TEE assessment is essential for secure success and making a decision of 2nd pump run with a strategy for re-repair. In acute aortic dissection, TEE is often the only information source for making treatment strategy or detecting unexpected events. TEE provides unique information on properties of tissues, thrombus, or blood, which cannot be identified even with fluoroscopy, thus TEE is to be used efficiently in the hybrid operating room (OR). In thoracic surgery, TEE is helpful for assessing an invasion of tumor to the adjacent structures including the aorta or heart. With all these capabilities of TEE, it should be fully utilized to optimize the outcomes of thoracic and cardiovascular surgeries. PMID- 30310025 TI - [Cerebral Blood Flow Monitoring and Motor Evoked Potentials]. AB - Near infra-red spectroscopy (NIRS) and motor evoked potentials (MEP) have been used to monitor brain and spinal cord ischemia. NIRS calculates oxygen saturation of hemoglobin, based on the modified Beer-Lambert law. It correlates with the change in regional tissue blood flow. However, the technology is not matured enough for the measured value to be used as an index of tissue oxygenation, so that relative change should be carefully followed. Myogenic MEP has widely been used to monitor spinal cord ischemia, since the introduction of pulse train transcranial electrical stimulation. It evaluates motor pathways from the cortex to the muscle. Therefore it is influenced by non-spinal cord factors such as peripheral nerve ischemia. It is highly sensitive and shows changes in the early phase of spinal cord ischemia. On the other hand, its vulnerability to anesthesia requires special anesthetic consideration, and baseline amplitude fluctuation is common. Specificity is thus low, and the results should be interpreted together with the operative findings. PMID- 30310026 TI - [Cardiopulmonary Bypass System and Perfusion]. AB - In addition to maintaining circulation and gas exchange, the heart-lung machine is responsible for ensuring a bloodless field, retrieve of blood, suppression of metabolism, blood dilution and concentration, and myocardial protection. The heart-lung machine has 2 kinds of circuits having different characteristics, that is an open circuit and a closed circuit. Either a roller pump or a centrifugal pump is used in the machine. Gas exchange is performed by using a membrane type oxygenator. Venting, suction, myocardial protection circuit are important items in the machine. Safety devices and troubleshooting are required for safety management of the heart-lung machine. PMID- 30310027 TI - [Simulator for Surgical Training]. AB - Dr. William Halsted started residency-based surgical training at Johns Hopkins University in 1889. On the job training(OnJT) conducted there is an in-hospital training that residents imitate what senior doctors are doing with their patients. [ See one, do one, teach one] is the word briefly expressing this traditional training. Since then all surgeons learned surgery from the mentors and senior doctors in this way. In this OnJT, surgeons spent many years and years and accumulated experience and tried to crime up step by step from beginners to experts. Off-the-job training (OffJT) is, in other words, "planned experience". In OffJT, surgeons can experience every kind of skill by simulation. They can experience rare but critical situations, repeat the procedures while experiencing failures many times in trial and error fashion without putting any risk to the patient. In this report, currently available simulators and when and how to utilize them are introduced. Dry lab or synthetic model, wet lab or animal tissue/organ, live animal, cadaver and virtual simulation are presented and discussed. PMID- 30310028 TI - [Surgical Devices for Minimally Invasive Cardiac Surgery(MICS)]. AB - Minimally invasive cardiac surgery(MICS)rapidly has become popular in recent years. To perform meticulous surgical procedures in the limited space, specially designed surgical instruments are very useful. For excellent exposure of the surgical target, thoracoscopic system with high imaging quality such as 4K or 3D HD endoscopy is often used. An articulated rib spreader and/or soft tissue retractor is also useful since those instruments do not interfere with other surgical instruments. A suture catcher is used to pull traction sutures through the chest wall. There are various types of atrial retractor designed for MICS. For fine manipulation in the limited space, long-shafted forceps, needle holders, and scissors are necessary. Those instruments reach deeply located targets and do not interfere surgeon's and endoscopic view or other instruments. A knot pusher is another essential device to tie knots through a small incision. The automatic tying device is available outside the country. For cardiopulmonary bypass, cannulas designed for peripheral access are used. Most of those cannulas have multiple side holes that work well for excellent perfusion and drainage. There are also specially designed aortic cross-clamps. To make surgeons more comfortable and improve quality of MICS, surgical devices for MICS need to be further innovated. PMID- 30310029 TI - [Surgical Ablation Devices]. AB - Fundamental procedure of arrhythmia surgery is to bock conduction of macro reentry or focal activation. Traditional "cut and sew" technique is effective to make a conduction block without any special devices although it is time consuming and there is some bleeding risk. Surgical ablation devices are easily able to make a conduction block during surgery. It could undergo the minimally invasive cardiovascular surgery (MICS) -maze procedure through the right mini thoracotomy. It is most important to make complete conduction block because incomplete ablation causes residual conduction, resulting in recurrence of atrial fibrillation or atrial tachycardia. Moreover, the left atrial clip is new surgical treatment for atrial fibrillation. This device could avoid thrombus formation and make a conduction block arising from the left atrial appendage. PMID- 30310030 TI - [Prosthetic Valve]. AB - In valvular disease treatment, it is extremely important to ensure good hemodynamics, to avoid thromboembolism and hemorrhagic complications, and to avoid reoperation. Due to the development of prosthetic valves, remarkable improvement in these results has been obtained. In recent years, the using rate of bioprosthetic valve has increased with the improvement of the durability of the bioprosthetic valve. Furthermore, a new bioprosthetic valve has also been developed, and it seems possible that the treatment strategy for valve disease such as valve selection of prosthetic valve and reoperation at the remote phase will change dramatically in the near future. PMID- 30310031 TI - [Endovascular Technology for Thoracic Aortic Pathology]. AB - A quarter of a century has passed since development and application of stent graft technology. The application field has widened to aortic arch and thoracoabdominal area, with the development of stent grafts such as frozen elephant trunk, debranching plus thoracic endovascular aneurysm repair(TEVAR) and fenestrated/branched stent graft. Further development of stent-graft technology will continue to bring about less invasive intervention and better results for patients with thoracic aortic pathology. PMID- 30310032 TI - [Transcatheter Aortic Valve Implantation for Sever Aortic Valve Stenosis]. AB - Since reimbursements for transcatheter aortic valve implantation(TAVI) for severe aortic valve stenosis began in 2013, TAVI has spread rapidly in Japan. TAVI is currently performed in nearly 100,000 cases a year worldwide, and more than 4,000 procedures performed annually in Japan. The TAVI valves available in Japan are Edwards' "SAPIEN" and the Medtronic "Evolut R". The "SAPIEN" is a balloon expanding valve and can be placed via a transfemoral or transapical approach. In contrast, the "Evolut R" is a self-expanding valve and can be placed via the transfemoral, transsubclavian or direct aortic approach. The surgical indications for TAVI are high-risk patients in whom surgical aortic valve replacement (SAVR) cannot be performed by conventional thoracotomy, and dialysis patients are excluded. With the evolution of the associated devices, the performance of TAVI has become comparable to that of SAVR. The outcomes of TAVI in Japan are particularly good compared with the results of the world. Globally, TAVI treatment is being adopted in intermediate- to low-risk patients as well as in high-risk patients. TAVI treatment is expected to continue to spread in the future. PMID- 30310033 TI - [Intraaortic Balloon Pumping(IABP) and Impella]. AB - Intraaortic balloon pumping(IABP)has been used in more than 20,000 cases annually in Japan and this old device may be used differently by less invasive approach via axillar artery, which enabled the patients to ambulate for rehabilitation. Impella, a newly developed microaxial blood pump, has been used as a less invasive left ventricular assist device in more than 50 case in the last 6 months since its approval in Japan. Our experiences in 11 patients indicated that it improved not only cardiac output, but also cardiac function, which resulted in cardiac recovery in 5 patients. Technical advances in less invasive mechanical circulatory support may play an important role in thoracic surgery as well as cardiology. PMID- 30310034 TI - [Implantable Ventricular Assist Device]. AB - For patients with "stage D refractory heart failure" as stated by the The Japanese Circulation Society (JCS) 2017/The Japanese Heart Failure Society (JHFS) 2017 Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure, extensive therapeutic methods including implantation of ventricular assist device (VAD) and/or heart transplantation, as well as terminal care. An implantable VAD is a device designed to support patients for a long term of several years. This device has its most part buried in the body with its driveline penetrated out through the skin to connect with a controller and butteries. In Japan, implantable VADs started to be used in 2011, and now 3 devices are available in a commercial basis, that is, EVAHEART 2, HeartMate II and Jarvik 2000. They are available when a patient has been listed as a candidate for heart transplantation, and recently the usage of implantable VAD as destination therapy that is applied for patients who are not eligible for heart transplantation but would get benefit from circulatory support, enough to be free from hospital-bound status and enjoy high quality of life. If this device can prove to improve heart failure patients' symptoms, resulting in decreasing medical expense, surely it would be widely accepted as a promising therapy to treat heart failure. PMID- 30310035 TI - [Robot Assisted Thoracic Surgery Procedure]. AB - The advantages of robot-assisted surgery include true 3-dimensional imaging with binocular glasses and the use of multiarticular forceps that allow the performance of high-precision operations. This report described the surgical techniques of robot assisted major pulmonary resection and subxiphoid robot assisted thymectomy. Future developments in the field of robotic engineering will lead to the creation of systems that allow for more advanced surgical techniques. We hope that robotic assisted surgery will be safely introduced into many medical facilities. PMID- 30310036 TI - [Thoracoscopic Surgery]. AB - Thoracoscopic devices have become essential in general thoracic surgery. In the past 30 years, many reports about thoracoscopic surgery have expanded the indications to include malignant neoplasms. Various optional procedures including uniportal, non-intubated, robotic, and needlescopic techniques have been developed and more than 70% of lung cancer operations are currently performed using thoracoscopy in Japan. Although there are many choices for minimally invasive surgery, the long-term outcome of these options remains unclear. In addition, training systems for younger surgeons have not provided exposure to novel optional methods, as there are few high-volume centers in Japan. PMID- 30310037 TI - [Virtual Bronchoscopic Navigation( VBN) and Electromagnetic Navigation System]. AB - Recently small peripheral lesions have been discovered due to development of computed tomography (CT) instruments and dissemination of CT examination etc. Histological or cytological diagnosis for peripheral lesions is recommended to be performed. The diagnostic yield for peripheral pulmonary lesion depends on the size. Transbronchial lung biopsy (TBLB) was developed using techniques such as navigation system( vitual bronchoscopic navigation:VBN), endobronchial ultrasonography(EBUS) using guide sheath(GS), extremely small bronchoscope and the like for lesions of 2.0 cm or less. VBN is a method in which virtual bronchoscopy images of the bronchial path to the peripheral lesion are produced and used as a guide to navigate the bronchoscope. In the randomized controlled trial, it was reported that VBN not only improves the diagnostic rate but also shortens the total examination time. The American College of Chest Physician (ACCP) guidelines recommend the use of EBUS-GS, VBN for the bronchoscopic diagnosis of peripheral pulmonary lesions. Bronchial navigation method using a magnetic field (electromagnetic navigation:EMN) to link the navigation system and the actual bronchoscope in real time has appeared. This new technique, electromagnetic navigational bronchoscopy (ENB) promises accurate navigation to peripheral pulmonary target lesion. Bronchoscopic navigation is also used for marking in thoracoscopic surgery, and it is greatly expected not only as a tool for simply diagnosing but also as a treatment technique in the future. PMID- 30310038 TI - [Bronchoscopy and Interventional Pulmonology]. AB - Recent advance in bronchology and interventional pulmonology contributes to improve the quality of patient care in thoracic surgery. Narrow band imaging (NBI) combined with high definition bronchoscopy clearly visualize the aberrant tumor vessels on the mucosa of endobronchial malignancy. It helps the preoperative surgical planning for the clear bronchial margin during the surgery. The index of hemoglobin (IHb) show the approximate amount of hemoglobin within the mucosal surface and we use the IHb for the evaluation of local circulation of bronchial anastomosis after bronchoplasty. Endobronchial ultrasound-guided transbronchial needle aspiration( EBUS-TBNA) is now the best 1st test for the mediastinal staging in patients with lung cancer. The enough anatomical knowledge and adequate training of EBUS-TBNA is important to achieve high diagnostic yield with safety. Endobronchial occlusion therapy using endobronchial Watanabe spigot (EWS) is a novel therapeutic approach for the patients with persistent air leakage and bronchial fistula. We use the EWS for the empyema cases with pleural fistula in combination with negative pressure wound therapy. In addition, EWS can be applicable for the refractory broncho-gastric tube fistula in patients with esophageal cancer. The hybrid stent which was fully covered metallic stent is approved in Japan in 2014. This novel stent provide the more chance of stent insertion not only for the patients with airway stenosis but also for the broncho esophageal fistula. PMID- 30310039 TI - [Photodynamic Therapy]. AB - Photodynamic therapy( PDT) is a method consider "medical treatment" in which a drug( i.e., photosensitizer) is incorporated into a tumor and a laser beam of a wavelength corresponding thereto generates a reaction consider "elicits a phototoxic reaction that kills the tumor cells". It is a less invasive treatment that has a tumor-selective cell killing effect and has been established as a standard therapy for centrally located early stage lung cancer. Most patients with centrally located early stage lung cancer are heavy smokers, and cardiopulmonary function is often deteriorated owing to pulmonary emphysema or heart disease. Centrally located early stage lung cancer is known to occur frequently as synchronous or metachronous neoplasm. Taking the patient's background into consideration, PDT that does not affect the pulmonary function may be considered as a promising treatment. Herein, we outline the current applications of PDT and its future prospects. PMID- 30310040 TI - [Techniques to Identify Inter-segmental Planes]. AB - There are several different approaches to identify inter-segmental planes in segmentectomy. Inflation-deflation lines can be made by inflating the lung after clumping or resecting the target bronchus, or inflate the target bronchus by jet ventilation, direct tubing, or applying a slip-knot. Indocyanine green can be injected intravenously after resecting or clumping the target pulmonary artery to identify the target segment under an infra-red thoracoscope. Indocyanine green can also be injected through a target bronchus. Virtual-assisted lung mapping (VAL-MAP) is a bronchoscopic multispot dye marking technique. Although VAL-MAP was developed to localize small pulmonary nodules, the multiple marks that provide geometric information on the lung enables application of VAL-MAP to segmentectomy, putting more emphasis on resection margins than accurate identification of intersegmental planes. As such, VAL-MAP is particularly useful in extended or complex segmentectomies. There are advantages and disadvantages in each method. The rapid progress of technology is likely to advance each method further. Taking these into consideration, surgeons need to choose an appropriate technique and possibly combination of these techniques to obtain optimal outcomes in segmentectomy. PMID- 30310041 TI - [Automatic Linear Stapler]. AB - The automatic linear stapler becomes the necessary device in today's chest surgery. These made simple and uniform suture techniques possible, but it is important to fully understand the usage and characteristics of automatic linear stapler for safe stapling. In this paper, we focus on the currently used stapler and describe its mechanism and its characteristics. PMID- 30310042 TI - [Sentinel Lymph Node Diagnosis for Lung Cancer]. AB - Many researchers have reported that the sentinel node (SN) theory has been established for lung cancer. However, sentinel node navigation surgery (SNNS) has not yet become a routine medical procedure in lung cancer surgery. SN identification is important for efficient retrieval of micrometastases. Methods for identifying SNs include the dye method and the radioisotope (RI) method, but methods such as the indocyanine green (ICG) method, computed tomographic lymphography (CTLG), and the magnetic method are also being studied. More careful surgical adaptation is required for reduction surgery for early lung cancer, and rapid intraoperative diagnosis is frequently used. SN lymph nodes may be used as an indicator for selecting lymph nodes to be diagnosed intraoperatively. SN identification is considered an important method for ensuring that reduction surgery is curative. Furthermore, if overlooking lymph node metastases can be avoided by using intraoperative rapid diagnosis of micrometastases, we believe that the safety of reduction surgery will be enhanced. In addition, SN identification provides a theoretical basis to support the omission of lymph node dissection. Future developments of SN research and technology are expected. PMID- 30310043 TI - [Continuous Chest Drainage Systems in Thoracic Surgery]. AB - In the management of chest drain after thoracic surgery, it is important to egest fluid and air which accumulate in the pleural cavity and to gain information such as air leakage, bleeding or pus discharge. To achieve these purpose, continuous chest drainage system is necessary for thoracic surgery. In addition, we have to understand the particularity in the pleural cavity and the structure of continuous chest drainage system. Traditional drainage system is based on 3 bottle system. Recently, we can use new drainage system, such as Thopaz, which is called digital drainage system. There are several studies comparing digital drainage system with traditional drainage system, but the superiority of digital drainage system to traditional drainage system is not confirmed. PMID- 30310044 TI - [Intraoperative Nerve Monitoring System during Esophagectomy to Prevent Recurrent Laryngeal Nerve Palsy]. AB - Recurrent laryngeal nerve (RLN) palsy can result in motility disorders of the vocal cord muscles and/or fatal respiratory complications. Procedures aimed at checking for intraoperative RLN injuries have not been established. Intraoperative nerve monitoring( IONM) informs electromyographic activity of the vocal cord muscles to a surgeon by visual and aural signals. In this chapter, we introduce methods for using IONM during esophageal cancer surgery. Since we introduced IONM, several cases in which surgeons have had difficulty visually identifying the RLN have been reported. In those cases, the RLN was definitively identified using IONM. IONM can be used safely, simply, and promptly during esophageal cancer surgery for identifying the RLN to prevent and predict postoperative RLN palsy. This useful device is possible to improve the safety of the surgical procedures subsequently. PMID- 30310045 TI - [Indocyanine Green Fluorescence Navigated Surgery for Esophageal Cancer]. AB - Indocyanine green (ICG) fluorescence imaging provides high sensitivity and significant contrast because of its low inherent autofluorescence background and high tissue penetration. Recent studies have shown that ICG fluorescence can visualize the blood flow of the gastric conduit in patients undergoing esophagectomy. We have reported the usefulness of ICG fluorescence imaging as a tool of navigation surgery under esophagectomy. We focused on the ICG fluorescence blood speed on the gastric conduit wall and demonstrated that intraoperative navigation of the blood speed by ICG fluorescence imaging in the gastric conduit wall is a useful means to predict the risk of anastomotic leakage after esophagectomy. Based on the progress of optical electronic equipment, ICG fluorescence imaging can be utilized during endoscopic surgery for gastrointestinal malignancies. Furthermore, robotic surgery is accepted in the Japanese insurance system this year. In near future, ICG fluorescence navigation surgery will improve along with the progress of minimally invasive surgery including the robotic surgery. PMID- 30310046 TI - [High-resolution Manometry for Esophageal Motility Disorders]. AB - High-resolution manometry (HRM) has significant contribution in the field of esophageal motility disorders recently. The development of HRM has categorized various esophageal motility disorders focusing on patterns of esophageal motor function. Additionally, the Chicago classification criteria are widely used for manometric diagnosis. HRM provides functional imaging of the esophagus. HRM has closely spaced pressure sensors and displays pressure variations as pressure topography plots. In the analysis of HRM according to the Chicago classification, a hierarchical categorization of motility disorders is made after evaluation of the individual swallow patterns. First the lower esophageal sphincter (LES) function, and subsequently the esophageal pressure patterns are used to make a diagnosis. The hierarchical flow-chart has 4 groups; (1) incomplete LES relaxation( achalasia or esophagogastric junction outflow obstruction), (2) major motility disorders, (3) minor motility disorders, (4) normal esophageal motility. HRM is the gold standard for diagnosis of esophageal motility disorders. PMID- 30310047 TI - Safety and Efficacy of Once-Daily Prolonged-Release Tacrolimus in Living Donor Liver Transplantation: An Open-Label, Prospective, Single-Arm, Phase 4 Study. AB - BACKGROUND After liver transplantation (LT), nonadherence to immunosuppressants due to the complex regimen can lead to graft rejection and loss. This study assessed the efficacy and safety of conversion from twice-daily tacrolimus (Bid Tac) to once-daily prolonged-release tacrolimus (OD-Tac) in living donor LT (LDLT) recipients. MATERIAL AND METHODS Among patients who underwent LDLT between November 2015 and October 2016, those who agreed to participate in this study were screened, and those with good general condition and stable liver functions were enrolled. Participants underwent a conversion from Bid-Tac to OD-Tac with a dose ratio of 1: 1 at about 10-14 weeks after LDLT and were followed-up for 24 weeks. RESULTS Thirty-one patients were enrolled. The median number of conversion days after LDLT was 12.3 weeks (range, 10.3-13.8). Adherence was evaluated during the outpatient visits at weeks 2, 4, 8, 16, and 24 after Tac conversion, and 100% adherence was observed at all time points. There were no cases of acute rejection, graft loss, or patient death after Tac conversion. Nineteen cases of adverse events occurred in 11 patients (35.5%), none of which were severe. Alopecia was the most common, affecting 3 (9.7%) patients, followed by pruritus (n=2, 6.45%). There were no changes in renal function or in liver function test, serum glucose level, and lipid profile. CONCLUSIONS Early Tac conversion from Bid Tac to OD-Tac is safe and feasible. However, further studies are needed to elucidate its long-term effects. PMID- 30310048 TI - Egg Quality and Pregnancy Outcome in Young Infertile Women with Diminished Ovarian Reserve. AB - BACKGROUND This study investigated the quality and quantity of eggs and embryos as well as the clinical pregnancy outcome in young infertile women with diminished ovarian reserve (DOR) after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). MATERIAL AND METHODS We retrospectively reviewed records of 4285 infertile women and divided them into 3 groups according to age and ovarian reserve: young women with normal ovarian reserve (n=1695), young women with DOR (n=1121), and older women with DOR (n=1469). RESULTS In young women with DOR, the proportion of high-quality embryos was significantly higher than in older women with DOR and lower than in young women with normal ovarian reserve (P<0.01). The proportions of ovulation cancellation, ovulation without egg acquisition, and ovulation without available embryos in young women with DOR were significantly higher than in young women with normal ovarian reserve. The rates of biochemical pregnancy, clinical pregnancy, and embryo implantation in young women with DOR were significantly higher than in older women with DOR, and lower than in young women with normal ovarian reserve. The miscarriage rate was 19.17% in young women with DOR, significantly lower than in older women with DOR (33.90%), and higher than in young women with normal ovarian reserve. CONCLUSIONS Young women with DOR have ovarian hypo-response and low numbers of acquired eggs and embryos, but the possibilities of high-quality embryo and good clinical pregnancy are higher once eggs are acquired. The indications to IVF/ICSI can be widened and active treatments should be administered for these women. PMID- 30310049 TI - A Case of Severe Anti-N-Methyl D-Aspartate (Anti-NMDA) Receptor Encephalitis with Refractory Autonomic Instability and Elevated Intracranial Pressure. AB - BACKGROUND Anti-N-methyl D-Aspartate (anti-NMDA) receptor encephalitis is a rare autoimmune panencephalitis that typically presents with acute psychiatric disturbances and neurological deficits. Anti-NMDA receptor encephalitis is associated with certain tumors, most commonly ovarian teratomas. First-line therapy typically involves immunotherapy and tumor resection, if present, with up to 53% of patients experiencing improvement within 4 weeks. Cardiac arrhythmias and increased intracranial pressure have been reported in anti-NMDA receptor encephalitis, but these complications have usually been self-limited. CASE REPORT We report the case of a previously healthy, obese 21-year-old female who presented with acute encephalopathy. Her psychiatric and neurological function rapidly deteriorated, warranting intubation and mechanical ventilation. Lumbar puncture was performed. Cerebrospinal fluid (CSF) opening pressure was elevated and a lumbar drain was placed. Infectious disease work-up was negative and anti NMDA receptor antibodies were present in the CSF and serum. Initial treatment included intravenous immunoglobulin (IVIG) therapy, plasmapheresis, methylprednisolone, and bilateral salpingoophorectomy, without clinical improvement. Second-line immunotherapy with cyclophosphamide and rituximab was then administered. The patient also developed intermittent episodes of severe bradycardia and asystole that remained refractory to treatment and required placement of a permanent cardiac pacemaker. CONCLUSIONS Anti-NMDA receptor encephalitis presents with rapidly progressive psychiatric and neurologic dysfunction and can develop a severe and prolonged course with limited response to treatment. Patients can develop severe autonomic dysfunction with bradycardia and asystole that may require placement of permanent cardiac pacemakers. Elevated intracranial pressure may also be associated with anti-NMDA receptor encephalitis, and might contribute to the autonomic instability. PMID- 30310050 TI - Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis. AB - A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis. PMID- 30310051 TI - Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia. AB - Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4+ T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia. Loss-of-function and gain-of-function assays in vitro and in vivo revealed that membrane-localized and cytoplasm-localized lnc-INSR promoted Treg distribution and decreased the percentage of cytotoxic T lymphocytes, which induced tumor growth. Through direct binding with INSR, lnc-INSR blocked the INSR ubiquitination site, causing abnormal activation of INSR and the phosphatidylinositide 3-kinase/AKT-signaling pathway. These results indicated that lnc-INSR might promote immune suppression by enhancing Treg-cell differentiation and serve as valuable therapeutic targets in the immunosuppressive tumor microenvironment. PMID- 30310052 TI - PLZF play as an indirect facilitator of thymic retention for the innate-like T cells to aquire innate-like functions. PMID- 30310053 TI - Long noncoding RNA neuroblastoma-associated transcript 1 gene inhibits malignant cellular phenotypes of bladder cancer through miR-21/SOCS6 axis. AB - Bladder cancer (BC) is one of the most common tumors in the urinary system. Noncoding RNAs are considered to take part in cellular phenotypes and are emerging as diagnostic and prognostic biomarkers of BC. The aim of this study is to investigate the clinical significance of neuroblastoma- associated transcript 1 (NBAT1) gene and its effects on malignant cellular phenotypes in BC. NBAT1 gene was low-expressed in BC tissues and cell lines and its low-expression was related with high pathological grade and metastasis of BC. Upregulation of NBAT1 gene depressed cell viability and invasiveness of KK47 and T24 cells and arrested KK47 and T24 cells at G1 stage. In addition, NBAT1 could target silence the expression of miR-21-5p in RNA-induced silencing complex-dependent manner. KK47 and T24 cells with miR-21-5p knockdown showed reduced cell viability, G1-stage arrest, and depressed invasiveness. MiR-21-5p mediates the regulatory effects of NBAT1 on malignant cellular phenotypes of BC cells. Moreover, SOCS6 gene was a target gene of miR-21-5p, and miR-21-5p modulated malignant cellular phenotypes of KK47 and T24 cells through targeted silencing of SOCS6. In conclusion, low-expression of NBAT1 is associated with the progress and metastasis of BC, and NBAT1 inhibits malignant cellular phenotypes through miR-21-5p/SOCS6 axis in BC. Our findings help to elucidate the tumorigenesis of BC, and future study will provide a novel therapeutic target for BC. PMID- 30310054 TI - VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study. AB - Vascular endothelial growth factor A (VEGFA) dysfunction may contribute to a number of pathological processes that characterize psychotic disorders. However, the influence of VEGFA gene variants on clinical and neuroimaging phenotypes in psychotic disorders has yet to be shown. In the present study, we examined whether different VEGFA gene variants influence psychosis risk, symptom severity, cognition, and brain volume. The study group included 480 probands (Bipolar I disorder with psychosis, n = 205; Schizoaffective disorder, n = 112; Schizophrenia, n = 163) and 126 healthy controls that were recruited across six sites in the B-SNIP consortium. VEGFA variants identified for analysis (rs699947, rs833070, and rs2146323) were quantified via SNP chip array. We assessed symptoms and cognition using standardized clinical and neuropsychological batteries. The dorsolateral prefrontal cortex (DLPFC), medial temporal lobe, and hippocampal volumes were quantified using FreeSurfer. In our sample, VEGFA rs2146323 A- carriers showed reduced odds of being a proband (p = 0.037, OR = 0.65, 95% CI = 0.43-0.98) compared to noncarriers, but not for rs699947 or rs833070. In probands, rs2146323 A- carriers demonstrated fewer hallucinations (p = 0.035, Cohen's d = 0.194), as well as significantly greater DLPFC (p < 0.05, Cohen's d = -0.21) and parahippocampal volumes (p < 0.01, Cohen's d = -0.27). No clinical or neuroimaging associations were identified for rs699947 or rs833070. In general, we found that the three SNPs exhibited several significant negative relationships between psychosis symptoms and brain structure. In the probands and control groups, positive relationships were identified between several cognitive and brain volume measures. The findings suggest VEGFA effects in the DLPFC and hippocampus found in animals may also extend to humans. VEGFA variations may have important implications in identifying dimensional moderators of function that could be targeted through VEGFA-mediated interventions. PMID- 30310055 TI - Integrative analysis of transcriptomics and clinical data uncovers the tumor suppressive activity of MITF in prostate cancer. AB - The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology. PMID- 30310056 TI - Effects of tumor necrosis factor-alpha polymorphism on the brain structural changes of the patients with major depressive disorder. AB - Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-alpha, contributes to the neuroanatomical changes in MDD. In this cross sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-alpha expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity. PMID- 30310057 TI - Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation. AB - DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers. PMID- 30310058 TI - A cysteine-based molecular code informs collagen C-propeptide assembly. AB - Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen's C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca2+ in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization. The resulting cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers. Moreover, the code applies across all of the sequence-diverse fibrillar collagens. These results provide new insight into how evolution leverages disulfide networks to fine-tune protein assembly, and will inform the ongoing development of designer proteins that assemble into specific oligomeric forms. PMID- 30310059 TI - Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription. AB - Metrics commonly used to describe antibiotic efficacy rely on measurements performed on bacterial populations. However, certain cells in a bacterial population can continue to grow and divide, even at antibiotic concentrations that kill the majority of cells, in a phenomenon known as antibiotic tolerance. Here, we describe a form of semi-heritable tolerance to the key anti mycobacterial agent rifampicin, which is known to inhibit transcription by targeting the beta subunit of the RNA polymerase (RpoB). We show that rifampicin exposure results in rpoB upregulation in a sub-population of cells, followed by growth. More specifically, rifampicin preferentially inhibits one of the two rpoB promoters (promoter I), allowing increased rpoB expression from a second promoter (promoter II), and thus triggering growth. Disruption of promoter architecture leads to differences in rifampicin susceptibility of the population, confirming the contribution of rifampicin-induced rpoB expression to tolerance. PMID- 30310061 TI - Space- and time-resolved small angle X-ray scattering to probe assembly of silver nanocrystal superlattices. AB - The structure of nanocrystal superlattices has been extensively studied and well documented, however, their assembly process is poorly understood. In this work, we demonstrate an in situ space- and time-resolved small angle X-ray scattering measurement that we use to probe the assembly of silver nanocrystal superlattices driven by electric fields. The electric field creates a nanocrystal flux to the surface, providing a systematic means to vary the nanocrystal concentration near the electrode and thereby to initiate nucleation and growth of superlattices in several minutes. Using this approach, we measure the space- and time-resolved concentration and polydispersity gradients during deposition and show how they affect the superlattice constant and degree of order. We find that the field induces a size-selection effect that can reduce the polydispersity near the substrate by 21% leading to better quality crystals and resulting in field strength-dependent superlattice lattice constants. PMID- 30310060 TI - Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features. AB - The CCCTC-binding zinc-finger protein (CTCF)-mediated network of long-range chromatin interactions is important for genome organization and function. Although this network has been considered largely invariant, we find that it exhibits extensive cell-type-specific interactions that contribute to cell identity. Here, we present Lollipop, a machine-learning framework, which predicts CTCF-mediated long-range interactions using genomic and epigenomic features. Using ChIA-PET data as benchmark, we demonstrate that Lollipop accurately predicts CTCF-mediated chromatin interactions both within and across cell types, and outperforms other methods based only on CTCF motif orientation. Predictions are confirmed computationally and experimentally by Chromatin Conformation Capture (3C). Moreover, our approach identifies other determinants of CTCF mediated chromatin wiring, such as gene expression within the loops. Our study contributes to a better understanding about the underlying principles of CTCF mediated chromatin interactions and their impact on gene expression. PMID- 30310062 TI - State-recycling and time-resolved imaging in topological photonic lattices. AB - Photonic lattices-arrays of optical waveguides-are powerful platforms for simulating a range of phenomena, including topological phases. While probing dynamics is possible in these systems, by reinterpreting the propagation direction as time, accessing long timescales constitutes a severe experimental challenge. Here, we overcome this limitation by placing the photonic lattice in a cavity, which allows the optical state to evolve through the lattice multiple times. The accompanying detection method, which exploits a multi-pixel single photon detector array, offers quasi-real time-resolved measurements after each round trip. We apply the state-recycling scheme to intriguing photonic lattices emulating Dirac fermions and Floquet topological phases. We also realise a synthetic pulsed electric field, which can be used to drive transport within photonic lattices. This work opens an exciting route towards the detection of long timescale effects in engineered photonic lattices and the realisation of hybrid analogue-digital simulators. PMID- 30310063 TI - Spectral field mapping in plasmonic nanostructures with nanometer resolution. AB - Plasmonic nanostructures and -devices are rapidly transforming light manipulation technology by allowing to modify and enhance optical fields on sub-wavelength scales. Advances in this field rely heavily on the development of new characterization methods for the fundamental nanoscale interactions. However, the direct and quantitative mapping of transient electric and magnetic fields characterizing the plasmonic coupling has been proven elusive to date. Here we demonstrate how to directly measure the inelastic momentum transfer of surface plasmon modes via the energy-loss filtered deflection of a focused electron beam in a transmission electron microscope. By scanning the beam over the sample we obtain a spatially and spectrally resolved deflection map and we further show how this deflection is related quantitatively to the spectral component of the induced electric and magnetic fields pertaining to the mode. In some regards this technique is an extension to the established differential phase contrast into the dynamic regime. PMID- 30310064 TI - Unbiased biocatalytic solar-to-chemical conversion by FeOOH/BiVO4/perovskite tandem structure. AB - Redox enzymes catalyze fascinating chemical reactions with excellent regio- and stereo-specificity. Nicotinamide adenine dinucleotide cofactor is essential in numerous redox biocatalytic reactions and needs to be regenerated because it is consumed as an equivalent during the enzymatic turnover. Here we report on unbiased photoelectrochemical tandem assembly of a photoanode (FeOOH/BiVO4) and a perovskite photovoltaic to provide sufficient potential for cofactor-dependent biocatalytic reactions. We obtain a high faradaic efficiency of 96.2% and an initial conversion rate of 2.4 mM h-1 without an external applied bias for the photoelectrochemical enzymatic conversion of alpha-ketoglutarate to L-glutamate via L-glutamate dehydrogenase. In addition, we achieve a total turnover number and a turnover frequency of the enzyme of 108,800 and 6200 h-1, respectively, demonstrating that the tandem configuration facilitates redox biocatalysis using light as the only energy source. PMID- 30310065 TI - Charging dynamics of an individual nanopore. AB - Meso-porous electrodes (pore width " 1 um) are a central component in electrochemical energy storage devices and related technologies, based on the capacitive nature of electric double-layers at their surfaces. This requires that such charging, limited by ion transport within the pores, is attained over the device operation time. Here we measure directly electric double layer charging within individual nano-slits, formed between gold and mica surfaces in a surface force balance, by monitoring transient surface forces in response to an applied electric potential. We find that the nano-slit charging time is of order 1 s (far slower than the time of order 3 * 10-2 s characteristic of charging an unconfined surface in our configuration), increasing at smaller slit thickness, and decreasing with solution ion concentration. The results enable us to examine critically the nanopore charging dynamics, and indicate how to probe such charging in different conditions and aqueous environments. PMID- 30310066 TI - Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells. AB - Plasma membrane tension regulates many key cellular processes. It is modulated by, and can modulate, membrane trafficking. However, the cellular pathway(s) involved in this interplay is poorly understood. Here we find that, among a number of endocytic processes operating simultaneously at the cell surface, a dynamin independent pathway, the CLIC/GEEC (CG) pathway, is rapidly and specifically upregulated upon a sudden reduction of tension. Moreover, inhibition (activation) of the CG pathway results in lower (higher) membrane tension. However, alteration in membrane tension does not directly modulate CG endocytosis. This requires vinculin, a mechano-transducer recruited to focal adhesion in adherent cells. Vinculin acts by controlling the levels of a key regulator of the CG pathway, GBF1, at the plasma membrane. Thus, the CG pathway directly regulates membrane tension and is in turn controlled via a mechano chemical feedback inhibition, potentially leading to homeostatic regulation of membrane tension in adherent cells. PMID- 30310068 TI - Pol MU dGTP mismatch insertion opposite T coupled with ligation reveals promutagenic DNA repair intermediate. AB - Incorporation of mismatched nucleotides during DNA replication or repair leads to transition or transversion mutations and is considered as a predominant source of base substitution mutagenesis in cancer cells. Watson-Crick like dG:dT base pairing is considered to be an important source of genome instability. Here we show that DNA polymerase (pol) MU insertion of 7,8-dihydro-8'-oxo-dGTP (8 oxodGTP) or deoxyguanosine triphosphate (dGTP) into a model double-strand break DNA repair substrate with template base T results in efficient ligation by DNA ligase. These results indicate that pol MU-mediated dGTP mismatch insertion opposite template base T coupled with ligation could be a feature of mutation prone nonhomologous end joining during double-strand break repair. PMID- 30310069 TI - Immune-mediated neuropathies. AB - Since the discovery of an acute monophasic paralysis, later coined Guillain-Barre syndrome, almost 100 years ago, and the discovery of chronic, steroid-responsive polyneuropathy 50 years ago, the spectrum of immune-mediated polyneuropathies has broadened, with various subtypes continuing to be identified, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In general, these disorders are speculated to be caused by autoimmunity to proteins located at the node of Ranvier or components of myelin of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. Owing to the numerous subtypes of the immune mediated neuropathies, making the right diagnosis in daily clinical practice is complicated. Moreover, treating these disorders, particularly their chronic variants, such as CIDP and MMN, poses a challenge. In general, management of these disorders includes immunotherapies, such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the emergence of more disease-specific immunotherapies should broaden the therapeutic options for these disabling diseases. PMID- 30310067 TI - Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever. AB - Lassa fever (LF), caused by Lassa virus (LASV), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. LF is a WHO priority disease and, together with rabies, a major health burden in West Africa. Here we present the development and characterization of an inactivated recombinant LASV and rabies vaccine candidate (LASSARAB) that expresses a codon optimized LASV glycoprotein (coGPC) and is adjuvanted by a TLR-4 agonist (GLA SE). LASSARAB elicits lasting humoral response against LASV and RABV in both mouse and guinea pig models, and it protects both guinea pigs and mice against LF. We also demonstrate a previously unexplored role for non-neutralizing LASV GPC-specific antibodies as a major mechanism of protection by LASSARAB against LF through antibody-dependent cellular functions. Overall, these findings demonstrate an effective inactivated LF vaccine and elucidate a novel humoral correlate of protection for LF. PMID- 30310070 TI - Spatially-resolved fluorescence-detected two-dimensional electronic spectroscopy probes varying excitonic structure in photosynthetic bacteria. AB - Conventional implementations of two-dimensional electronic spectroscopy typically spatially average over ~1010 chromophores spread over ~104 micron square area, limiting their ability to characterize spatially heterogeneous samples. Here we present a variation of two-dimensional electronic spectroscopy that is capable of mapping spatially varying differences in excitonic structure, with sensitivity orders of magnitude better than conventional spatially-averaged electronic spectroscopies. The approach performs fluorescence-detection-based fully collinear two-dimensional electronic spectroscopy in a microscope, combining femtosecond time-resolution, sub-micron spatial resolution, and the sensitivity of fluorescence detection. We demonstrate the approach on a mixture of photosynthetic bacteria that are known to exhibit variations in electronic structure with growth conditions. Spatial variations in the constitution of mixed bacterial colonies manifests as spatially varying peak intensities in the measured two-dimensional contour maps, which exhibit distinct diagonal and cross peaks that reflect differences in the excitonic structure of the bacterial proteins. PMID- 30310072 TI - The quantum-confined Stark effect in layered hybrid perovskites mediated by orientational polarizability of confined dipoles. AB - The quantum-confined Stark effect (QCSE) is an established optical modulation mechanism, yet top-performing modulators harnessing it rely on costly fabrication processes. Here, we present large modulation amplitudes for solution-processed layered hybrid perovskites and a modulation mechanism related to the orientational polarizability of dipolar cations confined within these self assembled quantum wells. We report an anomalous (blue-shifting) QCSE for layers that contain methylammonium cations, in contrast with cesium-containing layers that show normal (red-shifting) behavior. We attribute the blue-shifts to an extraordinary diminution in the exciton binding energy that arises from an augmented separation of the electron and hole wavefunctions caused by the orientational response of the dipolar cations. The absorption coefficient changes, realized by either the red- or blue-shifts, are the strongest among solution-processed materials at room temperature and are comparable to those exhibited in the highest-performing epitaxial compound semiconductor heterostructures. PMID- 30310071 TI - Generation of orthotopically functional salivary gland from embryonic stem cells. AB - Organoids generated from pluripotent stem cells are used in the development of organ replacement regenerative therapy by recapitulating the process of organogenesis. These processes are strictly regulated by morphogen signalling and transcriptional networks. However, the precise transcription factors involved in the organogenesis of exocrine glands, including salivary glands, remain unknown. Here, we identify a specific combination of two transcription factors (Sox9 and Foxc1) responsible for the differentiation of mouse embryonic stem cell-derived oral ectoderm into the salivary gland rudiment in an organoid culture system. Following orthotopic transplantation into mice whose salivary glands had been removed, the induced salivary gland rudiment not only showed a similar morphology and gene expression profile to those of the embryonic salivary gland rudiment of normal mice but also exhibited characteristics of mature salivary glands, including saliva secretion. This study suggests that exocrine glands can be induced from pluripotent stem cells for organ replacement regenerative therapy. PMID- 30310073 TI - A transportome-scale amiRNA-based screen identifies redundant roles of Arabidopsis ABCB6 and ABCB20 in auxin transport. AB - Transport of signaling molecules is of major importance for regulating plant growth, development, and responses to the environment. A prime example is the spatial-distribution of auxin, which is regulated via transporters to govern developmental patterning. A critical limitation in our ability to identify transporters by forward genetic screens is their potential functional redundancy. Here, we overcome part of this functional redundancy via a transportome, multi targeted forward-genetic screen using artificial-microRNAs (amiRNAs). We generate a library of 3000 plant lines expressing 1777 amiRNAs, designed to target closely homologous genes within subclades of transporter families and identify, genotype and quantitatively phenotype, 80 lines showing reproducible shoot growth phenotypes. Within this population, we discover and characterize a strong redundant role for the unstudied ABCB6 and ABCB20 genes in auxin transport and response. The unique multi-targeted lines generated in this study could serve as a genetic resource that is expected to reveal additional transporters. PMID- 30310075 TI - Broad phylogenetic analysis of cation/proton antiporters reveals transport determinants. AB - Cation/proton antiporters (CPAs) play a major role in maintaining living cells' homeostasis. CPAs are commonly divided into two main groups, CPA1 and CPA2, and are further characterized by two main phenotypes: ion selectivity and electrogenicity. However, tracing the evolutionary relationships of these transporters is challenging because of the high diversity within CPAs. Here, we conduct comprehensive evolutionary analysis of 6537 representative CPAs, describing the full complexity of their phylogeny, and revealing a sequence motif that appears to determine central phenotypic characteristics. In contrast to previous suggestions, we show that the CPA1/CPA2 division only partially correlates with electrogenicity. Our analysis further indicates two acidic residues in the binding site that carry the protons in electrogenic CPAs, and a polar residue in the unwound transmembrane helix 4 that determines ion selectivity. A rationally designed triple mutant successfully converted the electrogenic CPA, EcNhaA, to be electroneutral. PMID- 30310074 TI - Immune-suppression by OsHV-1 viral infection causes fatal bacteraemia in Pacific oysters. AB - Infectious diseases are mostly explored using reductionist approaches despite repeated evidence showing them to be strongly influenced by numerous interacting host and environmental factors. Many diseases with a complex aetiology therefore remain misunderstood. By developing a holistic approach to tackle the complexity of interactions, we decipher the complex intra-host interactions underlying Pacific oyster mortality syndrome affecting juveniles of Crassostrea gigas, the main oyster species exploited worldwide. Using experimental infections reproducing the natural route of infection and combining thorough molecular analyses of oyster families with contrasted susceptibilities, we demonstrate that the disease is caused by multiple infection with an initial and necessary step of infection of oyster haemocytes by the Ostreid herpesvirus OsHV-1 uVar. Viral replication leads to the host entering an immune-compromised state, evolving towards subsequent bacteraemia by opportunistic bacteria. We propose the application of our integrative approach to decipher other multifactorial diseases that affect non-model species worldwide. PMID- 30310076 TI - Indoleacetate decarboxylase is a glycyl radical enzyme catalysing the formation of malodorant skatole. AB - Skatole is a malodorous compound that contributes to the characteristic smell of animal faeces. Although skatole has long been known to originate from bacterial tryptophan fermentation, the enzyme catalysing its formation has so far remained elusive. Here we report the use of comparative genomics for the discovery of indoleacetate decarboxylase, an O2-sensitive glycyl radical enzyme catalysing the decarboxylation of indoleacetate to form skatole as the terminal step of tryptophan fermentation in certain anaerobic bacteria. We describe its biochemical characterization and compare it to other glycyl radical decarboxylases. Indoleacetate decarboxylase may serve as a genetic marker for the identification of skatole-producing environmental and human-associated bacteria, with impacts on human health and the livestock industry. PMID- 30310077 TI - Identifying triplet pathways in dilute pentacene films. AB - Building efficient triplet-harvesting layers for photovoltaic applications requires a deep understanding of the microscopic properties of the components involved and their dynamics. Singlet fission is a particularly appealing mechanism as it generates two excitons from a single photon. However, the pathways of the coupled triplets into free species, and their dependence on the intermolecular geometry, has not been fully explored. In this work, we produce highly ordered dilute pentacene films with distinct parallel and herringbone dimers and aggregates. Using electron paramagnetic resonance spectroscopy, we provide compelling evidence for the formation of distinct quintet excitons in ambient conditions, with intrinsically distinctive electronic and kinetic properties. We find that the ability of quintets to separate into free triplets is promoted in the parallel dimers and this provides molecular design rules to control the triplets, favouring either enhanced photovoltaic efficiency (parallel) or strongly bound pairs that could be exploited for logic applications (herringbone). PMID- 30310079 TI - Immune-mediated neuropathies. PMID- 30310081 TI - PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling. AB - Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFalpha-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR 1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis. PMID- 30310082 TI - The influence of container geometry and thermal conductivity on evaporation of water at low pressures. AB - Evaporation is a ubiquitous phenomenon that occurs ceaselessly in nature to maintain life on earth. Given its importance in many scientific and industrial fields, extensive experimental and theoretical studies have explored evaporation phenomena. The physics of the bulk fluid is generally well understood. However, the near-interface region has many unknowns, including the presence and characteristics of the thin surface-tension-driven interface flow, and the role and relative importance of thermodynamics, fluid mechanics and heat transfer in evaporation at the surface. Herein, we report a theoretical study on water evaporation at reduced pressures from four different geometries using a validated numerical model. This study reveals the profound role of heat transfer, not previously recognized. It also provides new insight into when a thermocapillary flow develops during water evaporation, and how the themocapillary flow interacts with the buoyancy flow. This results in a clearer picture for researchers undertaking fundamental studies on evaporation and developing new applications. PMID- 30310080 TI - High fidelity CRISPR/Cas9 increases precise monoallelic and biallelic editing events in primordial germ cells. AB - Primordial germ cells (PGCs), the embryonic precursors of the sperm and egg, are used for the introduction of genetic modifications into avian genome. Introduction of small defined sequences using genome editing has not been demonstrated in bird species. Here, we compared oligonucleotide-mediated HDR using wild type SpCas9 (SpCas9-WT) and high fidelity SpCas9-HF1 in PGCs and show that many loci in chicken PGCs can be precise edited using donors containing CRISPR/Cas9-blocking mutations positioned in the protospacer adjacent motif (PAM). However, targeting was more efficient using SpCas9-HF1 when mutations were introduced only into the gRNA target sequence. We subsequently employed an eGFP to-BFP conversion assay, to directly compare HDR mediated by SpCas9-WT and SpCas9 HF1 and discovered that SpCas9-HF1 increases HDR while reducing INDEL formation. Furthermore, SpCas9-HF1 increases the frequency of single allele editing in comparison to SpCas9-WT. We used SpCas9-HF1 to demonstrate the introduction of monoallelic and biallelic point mutations into the FGF20 gene and generate clonal populations of edited PGCs with defined homozygous and heterozygous genotypes. Our results demonstrate the use of oligonucleotide donors and high fidelity CRISPR/Cas9 variants to perform precise genome editing with high efficiency in PGCs. PMID- 30310078 TI - GSK3beta: a plausible mechanism of cognitive and hippocampal changes induced by erythropoietin treatment in mood disorders? AB - Mood disorders are associated with significant psychosocial and occupational disability. It is estimated that major depressive disorder (MDD) will become the second leading cause of disability worldwide by 2020. Existing pharmacological and psychological treatments are limited for targeting cognitive dysfunctions in mood disorders. However, growing evidence from human and animal studies has shown that treatment with erythropoietin (EPO) can improve cognitive function. A recent study involving EPO-treated patients with mood disorders showed that the neural basis for their cognitive improvements appeared to involve an increase in hippocampal volume. Molecular mechanisms underlying hippocampal changes have been proposed, including the activation of anti-apoptotic, antioxidant, pro-survival and anti-inflammatory signalling pathways. The aim of this review is to describe the potential importance of glycogen synthase kinase 3-beta (GSK3beta) as a multi potent molecular mechanism of EPO-induced hippocampal volume change in mood disorder patients. We first examine published associations between EPO administration, mood disorders, cognition and hippocampal volume. We then highlight evidence suggesting that GSK3beta influences hippocampal volume in MDD patients, and how this could assist with targeting more precise treatments particularly for cognitive deficits in patients with mood disorders. We conclude by suggesting how this developing area of research can be further advanced, such as using pharmacogenetic studies of EPO treatment in patients with mood disorders. PMID- 30310083 TI - Single molecule localization microscopy coupled with touch preparation for the quantification of trastuzumab-bound HER2. AB - All breast cancers are assessed for levels of human epidermal growth factor receptor 2 (HER2). Fluorescence in situ hybridization (FISH) and immunohistochemistry are currently used to determine if a patient is eligible for anti-HER2 therapy. Limitations of both tests include variability and relatively long processing times. Additionally, neither test determines whether HER2 contains the extracellular domain. While truncated in some tumors, this domain is required for binding of the therapeutic antibody trastuzumab. Here, trastuzumab was used to directly detect HER2 with quantitative single molecule localization microscopy (qSMLM). In proof of concept studies, our new method rapidly quantified both HER2 density and features of nano-organization. In cultured cells, the method was sensitive to subtle variations in HER2 expression. To assess patient samples, we combined qSMLM with tissue touch preparation (touch prep-qSMLM) and examined large areas of intact membranes. For cell lines and patient samples, HER2 copy numbers from FISH showed a significant positive correlation with detected densities from qSMLM and trended with HER2 cluster occupancy. PMID- 30310084 TI - Landscape of alternative splicing in Capra_hircus. AB - Alternative splicing (AS) is a fundamental regulatory process in all higher eukaryotes. However, AS landscapes for a number of animals, including goats, have not been explored to date. Here, we sequenced 60 samples representing 5 tissues from 4 developmental stages in triplicate using RNA-seq to elucidate the goat AS landscape. In total, 14,521 genes underwent AS (AS genes), accounting for 85.53% of intron-containing genes (16,697). Among these AS genes, 6,342 were differentially expressed in different tissues. Of the AS events identified, retained introns were most prevalent (37.04% of total AS events). Functional enrichment analysis of differential and specific AS genes indicated goat AS mainly involved in organ function and development. Particularly, AS genes identified in leg muscle were associated with the "regulation of skeletal muscle tissue development" GO term. Given genes were associated with this term, four of which (NRG4, IP6K3, AMPD1, and DYSF) might play crucial roles in skeletal muscle development. Further investigation indicated these five genes, harbored 13 ASs, spliced exclusively in leg muscle, likely played a role in goat leg muscle development. These results provide novel insights into goat AS landscapes and a valuable resource for investigation of goat transcriptome complexity and gene regulation. PMID- 30310085 TI - Quantitative B-lymphocyte deficiency and increased TCRgammadelta T-lymphocytes in acute infectious spondylodiscitis. AB - Acute infectious spondylodiscitis (AIS) is a serious infection of the spine with rising incidence and a mortality of 3-6%. The role of the immune system in AIS is largely unknown. We performed extensive B and T-lymphocyte phenotyping in patients with AIS at diagnosis and after treatment cessation. In this prospective multicentre study, flow cytometric analysis of T and B-lymphocyte subsets was performed in 35 patients at diagnosis and 3 months after treatment cessation. We additionally analysed levels of immunoglobulins and IgG subclasses, serum level and genetic variants of mannose-binding lectin, and somatic hypermutation. A total of 22 (61%) patients had B-lymphocytes below reference limit at baseline, persisting in 7 (30%) patients at follow-up. We found a lower proportion of CD19 + CD27 + IgD+ marginal zone B-lymphocytes and a higher proportion of gammadelta+ T-lymphocyte receptors compared with controls at both time points. Immunoglobulin levels were elevated at baseline compared to follow-up, and not associated with absolute B-lymphocyte count. In conclusion, a large proportion of AIS patients presented with profound B-lymphocyte deficiency, only partly reversible at follow up. Identification of immune dysfunction related to AIS may allow for future targeted therapeutic interventions to restore host immunity. PMID- 30310086 TI - Circulating miR-1254 predicts ventricular remodeling in patients with ST-Segment Elevation Myocardial Infarction: A cardiovascular magnetic resonance study. AB - Reliable noninvasive prognostic biomarkers for left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) are needed. This study aimed to evaluate a panel of circulating microRNAs (miRNAs) as biomarkers of LV remodeling using cardiovascular magnetic resonance (CMR). We prospectively evaluated patients with a first STEMI treated with primary percutaneous coronary intervention who underwent CMR imaging at 1 week and 6 months after STEMI (n = 70). miRNAs were measured using PCR-based technologies in plasma samples collected at admission. The associations between miRNAs and LV diastolic and systolic volumes, and ejection fraction at 6-months were estimated in adjusted models. Median age was 60 years, 71.4% were male. miR-1254 was significantly associated in univariate analyses. Patients in the highest tertile of miR-1254 exhibited lower values of LVEDVI and LVESVI and higher values of LVEF at 1 week. After comprehensive multivariate adjustment including clinical, CMR variables, hs troponin-T and NT-proBNP, miRNA-1254 was associated with decreasing LVESVI (P = 0.006), and borderline negative associated with LVEDVI (P = 0.063) at 6-months. miR-1254 also exhibited a significant positive association with increasing LVEF during follow-up (P < 0.001). Plasma miRNA-1254 predicted changes in LV volumes and LVEF at 6 months after STEMI. The value of miR-1254 to inform tailored treatment selection and monitor ongoing efficacy deserves further investigation. PMID- 30310088 TI - The Smallest Diplodocid Skull Reveals Cranial Ontogeny and Growth-Related Dietary Changes in the Largest Dinosaurs. AB - Sauropod dinosaurs were the largest terrestrial vertebrates; yet despite a robust global fossil record, the paucity of cranial remains complicates attempts to understand their paleobiology. An assemblage of small diplodocid sauropods from the Upper Jurassic Morrison Formation of Montana, USA, has produced the smallest diplodocid skull yet discovered. The ~24 cm long skull is referred to cf. Diplodocus based on the presence of several cranial and vertebral characters. This specimen enhances known features of early diplodocid ontogeny including a short snout with narrow-crowned teeth limited to the anterior portion of the jaws and more spatulate teeth posteriorly. The combination of size plus basal and derived character expression seen here further emphasizes caution when naming new taxa displaying the same, as these may be indicative of immaturity. This young diplodocid reveals that cranial modifications occurred throughout growth, providing evidence for ontogenetic dietary partitioning and recapitulation of ancestral morphologies. PMID- 30310087 TI - Interplay between P. gingivalis, F. nucleatum and A. actinomycetemcomitans in murine alveolar bone loss, arthritis onset and progression. AB - Increasing evidence supports the association of periodontitis with rheumatoid arthritis. Even though a prominent role has been postulated for Porphyromonas gingivalis, many bacterial species contribute to the pathogenesis of periodontal disease. We therefore investigated the impact of Porphyromonas gingivalis as well as other major pathobionts on the development of both, periodontitis and arthritis in the mouse. Pathobionts used - either alone or in combination - were Porphyromonas gingivalis, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomintans. Periodontitis was induced via oral gavage in SKG, DBA/1 and F1 (DBA/1 * B10.Q) mice and collagen-induced arthritis was provoked via immunization and boost with bovine collagen type II. Alveolar bone loss was quantified via micro computed tomography, arthritis was evaluated macroscopically and histologically and serum antibodies were assessed. Among the strains tested, only F1 mice were susceptible to P. gingivalis induced periodontitis and showed significant alveolar bone loss. Bone loss was paralleled by antibody titers against P. gingivalis. Of note, mice inoculated with the mix of all three pathobionts showed less alveolar bone loss than mice inoculated with P. gingivalis alone. However, oral inoculation with either F. nucleatum or A. actinomycetemcomintans alone accelerated subsequent arthritis onset and progression. This is the first report of a triple oral inoculation of pathobionts combined with collagen-induced arthritis in the mouse. In this interplay and this particular genetic setting, F. nucleatum and A. actinomycetemcomitans exerted a protective impact on P. gingivalis induced alveolar bone loss. By themselves they did not induce periodontitis yet accelerated arthritis onset and progression. PMID- 30310089 TI - Extremely low genetic diversity in a circumpolar dragonfly species, Somatochlora sahlbergi (Insecta: Odonata: Anisoptera). AB - We present the first empirical treatment of the northernmost breeding dragonfly, Somatochlora sahlbergi. We sequenced populations from United States, Canada, Finland, Sweden and Norway for cytochrome oxidase I (COI) and D2 region of 28s. We found that, despite geographic barriers across its vast arctic range, S. sahlbergi is a single species. Not only does it appear to interbreed across its entire range, there also seems to be almost no variation among European and North American populations in their COI gene fragment (the barcode gene), which is usually extremely variable. We further found that characters thought to be diagnostic for the larvae of S. sahlbergi were absent in our European samples. We review and re-describe the habitat of this species based on new findings from recent field observations. Finally, we report for the first time the likely presence of this species in Japan. We hope our findings will encourage further study of this species and other under-studied insect taxa that inhabit the remote Arctic. PMID- 30310090 TI - Author Correction: Impact of hormone receptor status and distant recurrence-free interval on survival benefits from trastuzumab in HER2-positive metastatic breast cancer. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30310091 TI - No Reliable Evidence for a Neanderthal-Chatelperronian Association at La Roche-a Pierrot, Saint-Cesaire. AB - The demise of Neanderthals and their interaction with dispersing anatomically modern human populations remain some of the most contentious issues in palaeoanthropology. The Chatelperronian, now generally recognized as the first genuine Upper Palaeolithic industry in Western Europe and commonly attributed to the Neanderthals, plays a pivotal role in these debates. The Neanderthal authorship of this techno-complex is based on reported associations of Neanderthal skeletal material with Chatelperronian assemblages at only two sites, La Roche-a-Pierrot (Saint-Cesaire) and the Grotte du Renne (Arcy-sur-Cure). The reliability of such an association has, however, been the subject of heated controversy. Here we present a detailed taphonomic, spatial and typo technological reassessment of the level (EJOP sup) containing the Neanderthal skeletal material at Saint-Cesaire. Our assessment of a new larger sample of lithic artifacts, combined with a systematic refitting program and spatial projections of diagnostic artifacts, produced no reliable evidence for a Neanderthal-Chatelperronian association at the site. These results significantly impact current models concerning the Middle-to-Upper Palaeolithic transition in Western Europe and force a critical reappraisal of who exactly were the makers of the Chatelperronian. PMID- 30310092 TI - Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. AB - Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19 cell model. In AMD cells, we observed significant down-regulation of the MDP-coding MT-RNR2 gene, and remarkably reduced levels of all five oxidative phosphorylation (OXPHOS) complex I-V protein subunits that are involved in the electron transport chain; these results suggested mitochondrial toxicity and abnormal OXPHOS complex protein subunits' levels in AMD cells. However, treatment of AMD cells with SHLP2: (1) restored the normal levels of OXPHOS complex protein subunits, (2) prevented loss of viable cells and mitochondria, (3) increased the number of mtDNA copies, (4) induced anti-apoptotic effects, and (5) attenuated amyloid-beta-induced cellular and mitochondrial toxicity. Cumulatively, our findings established the protective role of SHLP2 in AMD cells in vitro. In conclusion, this novel study supports the merit of SHLP2 in the treatment of AMD, a primary retinal disease that is a leading cause of blindness among the elderly population in the United States as well as worldwide. PMID- 30310093 TI - Antibiotic export by efflux pumps affects growth of neighboring bacteria. AB - Cell-cell interactions play an important role in bacterial antibiotic resistance. Here, we asked whether neighbor proximity is sufficient to generate single-cell variation in antibiotic resistance due to local differences in antibiotic concentrations. To test this, we focused on multidrug efflux pumps because recent studies have revealed that expression of pumps is heterogeneous across populations. Efflux pumps can export antibiotics, leading to elevated resistance relative to cells with low or no pump expression. In this study, we co-cultured cells with and without AcrAB-TolC pump expression and used single-cell time-lapse microscopy to quantify growth rate as a function of a cell's neighbors. In inhibitory concentrations of chloramphenicol, we found that cells lacking functional efflux pumps (DeltaacrB) grow more slowly when they are surrounded by cells with AcrAB-TolC pumps than when surrounded by DeltaacrB cells. To help explain our experimental results, we developed an agent-based mathematical model, which demonstrates the impact of neighbors based on efflux efficiency. Our findings hold true for co-cultures of Escherichia coli with and without pump expression and also in co-cultures of E. coli and Salmonella typhumirium. These results show how drug export and local microenvironments play a key role in defining single-cell level antibiotic resistance. PMID- 30310094 TI - Alterations in the connection topology of brain structural networks in Internet gaming addiction. AB - Internet gaming addiction (IGA), as the most popular subtype of Internet addiction, is becoming a common and widespread mental health concern, but there are still debates on whether IGA constitutes a psychiatric disorder. The view on the brain as a complex network has developed network analysis of neuroimaging data, revealing that abnormalities of brain functional and structural systems are related to alterations in brain network configuration, such as small-world topology, in neuropsychiatric disorders. Here we applied network analysis to diffusion-weighted MRI data of 102 gaming individuals and 41 non-gaming healthy individuals to seek changes in the small-world topology of brain structural networks in IGA. The connection topology of brain structural networks shifted to the direction of random topology in the gaming individuals, irrespective of whether they were diagnosed with Internet gaming disorder. Furthermore, when we simulated targeted or untargeted attacks on nodes, the connection topology of the gaming individuals' brain structural networks under no attacks was comparable to that of the non-gaming healthy individuals' brain structural networks under targeted attacks. Alterations in connection topology provide a clue that Internet gaming addicted brains could be as abnormal as brains suffering from targeted damage. PMID- 30310095 TI - Spotlight on islands: on the origin and diversification of an ancient lineage of the Italian wall lizard Podarcis siculus in the western Pontine Islands. AB - Groups of proximate continental islands may conceal more tangled phylogeographic patterns than oceanic archipelagos as a consequence of repeated sea level changes, which allow populations to experience gene flow during periods of low sea level stands and isolation by vicariant mechanisms during periods of high sea level stands. Here, we describe for the first time an ancient and diverging lineage of the Italian wall lizard Podarcis siculus from the western Pontine Islands. We used nuclear and mitochondrial DNA sequences of 156 individuals with the aim of unraveling their phylogenetic position, while microsatellite loci were used to test several a priori insular biogeographic models of migration with empirical data. Our results suggest that the western Pontine populations colonized the islands early during their Pliocene volcanic formation, while populations from the eastern Pontine Islands seem to have been introduced recently. The inter-island genetic makeup indicates an important role of historical migration, probably due to glacial land bridges connecting islands followed by a recent vicariant mechanism of isolation. Moreover, the most supported migration model predicted higher gene flow among islands which are geographically arranged in parallel. Considering the threatened status of small insular endemic populations, we suggest this new evolutionarily independent unit be given priority in conservation efforts. PMID- 30310097 TI - Propensity-score-matched evaluation of under-recognition of acute kidney injury and short-term outcomes. AB - Acute kidney injury (AKI) is a common disease, but diagnosis is usually delayed or missed in hospitalized patients. The aim of this study was to investigate the impact of under-recognition of AKI (beyond 3 days after AKI onset) on short-time prognosis. Of 785 patients with under-recognition of AKI and 616 patients with timely-recognition of AKI were propensity matched in a 1:1 ratio. The two groups, with a total of 482 matched patients (241:241), were comparable in baseline covariates. Under-recognition of AKI was not associated with 30-day all-cause mortality in the logistic regression model with covariate adjustment (OR = 1.01, 95% CI = 0.62-1.64, p = 0.967). Sensitivity analyses and subgroup analyses also proved the association. There were also no significant differences in causes of 30-day mortality, in-hospital mortality, recovery of renal function at discharge, length of hospital stay, length of intensive care unit stay or hospitalization costs between the two groups, although timely-recognition group had more chance of renal consult and a little more interventions for AKI. In conclusion, under recognition of AKI may not be associated with poor short-term outcomes of adult hospitalized patients via these propensity-score-matched analyses. PMID- 30310096 TI - Heat-stress triggers MAPK crosstalk to turn on the hyperosmotic response pathway. AB - Cells make decisions based on a combination of external and internal signals. In yeast, the high osmolarity response (HOG) is a mitogen-activated protein kinase (MAPK) pathway that responds to a variety of stimuli, and it is central to the general stress response. Here we studied the effect of heat-stress (HS) on HOG. Using live-cell reporters and genetics, we show that HS promotes Hog1 phosphorylation and Hog1-dependent gene expression, exclusively via the Sln1 phosphorelay branch, and that the strength of the activation is larger in yeast adapted to high external osmolarity. HS stimulation of HOG is indirect. First, we show that HS causes glycerol loss, necessary for HOG activation. Preventing glycerol efflux by deleting the glyceroporin FPS1 or its regulators RGC1 and ASK10/RGC2, or by increasing external glycerol, greatly reduced HOG activation. Second, we found that HOG stimulation by HS depended on the operation of a second MAPK pathway, the cell-wall integrity (CWI), a well-known mediator of HS, since inactivating Pkc1 or deleting the MAPK SLT2 greatly reduced HOG activation. Our data suggest that the main role of the CWI in this process is to stimulate glycerol loss. We found that in yeast expressing the constitutively open channel mutant (Fps1-Delta11), HOG activity was independent of Slt2. In summary, we suggest that HS causes a reduction in turgor due to the loss of glycerol and the accompanying water, and that this is what actually stimulates HOG. Thus, taken together, our findings highlight a central role for Fps1, and the metabolism of glycerol, in the communication between the yeast MAPK pathways, essential for survival and reproduction in changing environments. PMID- 30310098 TI - Male-specific association between subclinical hypothyroidism and the risk of non alcoholic fatty liver disease estimated by hepatic steatosis index: Korea National Health and Nutrition Examination Survey 2013 to 2015. AB - Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease encompassing a broad spectrum of pathologic changes in the liver. Metabolic derangements are suggested to be main causes of NAFLD. As thyroid hormone is a main regulator of energy metabolism, there may be a link between NAFLD and thyroid function. In previous studies, the association between NAFLD and thyroid function was not conclusive. The aim of this study was to clarify the relationship between NAFLD and thyroid function, focusing on subclinical hypothyroidism, using nationwide survey data representing the Korean population. NAFLD was defined as a hepatic steatosis index of 36 or higher. Based on the analysis of nationwide representative data, subclinical hypothyroidism was related to a high risk of NAFLD in males, but not in females. Our study showed that thyroid function might play a substantial role in the development of NAFLD, especially in males. Further study to elucidate the underlying mechanism of gender specific association of mild thyroid dysfunction and NAFLD would be required. PMID- 30310099 TI - The effect of breastmilk and saliva combinations on the in vitro growth of oral pathogenic and commensal microorganisms. AB - Neonates are exposed to microbes in utero and at birth, thereby establishing their microbiota (healthy microbial colonisers). Previously, we reported significant differences in the neonatal oral microbiota of breast-fed and formula fed babies after first discovering a primal metabolic mechanism that occurs when breastmilk (containing the enzyme xanthine oxidase) and neonatal saliva (containing highly elevated concentrations of the substrates for xanthine oxidase: xanthine and hypoxanthine). The interaction of neonatal saliva and breast milk releases antibacterial compounds including hydrogen peroxide, and regulates the growth of bacteria. Using a novel in vitro experimental approach, the current study compared the effects of this unique metabolic pathway on a range of bacterial species and determined the period of time that microbial growth was affected. We demonstrated that microbial growth was inhibited predominately, immediately and for up to 24 hr following breastmilk and saliva mixing; however, some microorganisms were able to recover and continue to grow following exposure to these micromolar amounts of hydrogen peroxide. Interestingly, growth inhibition was independent of whether the organisms possessed a catalase enzyme. This study further confirms that this is one mechanism that contributes to the significant differences in the neonatal oral microbiota of breast-fed and formula-fed babies. PMID- 30310100 TI - Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas and Other Glucose-lowering Therapies for Three Acute Outcomes. AB - Although the glucose lowering effect of dipeptidyl peptidase-4 (DPP4) inhibitors is well established, several potential serious acute safety concerns have been raised including acute kidney injury, respiratory tract infections, and acute pancreatitis. Using the UK-based Clinical Practice Research Datalink (CPRD), we identified initiators (365-day washout period) of DPP4 inhibitors and relevant comparators including initiators of sulfonylureas, metformin, thiazolidinediones, and insulin between January 2007 and January 2016 to quantify the association between DPP4 inhibitors and three acute health events - acute kidney injury, respiratory tract infections, and acute pancreatitis. The associations between drug and study outcomes were estimated using Cox proportional hazard models adjusted for deciles of high-dimensional propensity scores and number of additional glucose lowering agents. After controlling for potential confounders, the risk was not significantly increased or decreased for initiators of DPP4 inhibitors compared to sulfonylureas (hazard ratio (HR) [95% confidence interval (CI)] for acute kidney injury: 0.81 [0.56-1.18]; HR for respiratory tract infections: 0.93 [0.84-1.04]; HR for acute pancreatitis 1.03 [0.42-2.52], metformin (HR for respiratory tract infection 0.91 [0.65-1.27]), thiazolidinediones (HR for acute kidney injury: 1.12 [0.60-2.10]; HR for respiratory tract infections: 1.02 [0.86-1.21]; HR for acute pancreatitis: 1.21 [0.25-5.72]), or insulin (HR for acute kidney injury: 1.40 [0.77-2.55]; HR for respiratory tract infections: 0.74 [0.60-0.92]; HR for acute pancreatitis: 1.01 [0.24-4.19]). Initiators of DPP4 inhibitors were associated with an increased risk of acute kidney injury when compared to metformin initiators (HR [95% CI] for acute kidney injury: 1.85 [1.10-3.12], although this association was attenuated when DPP4 inhibitor monotherapy was compared to metformin monotherapy exposure as a time-dependent variable (HR 1.39 [0.91-2.11]). Initiation of a DPP4 inhibitor was not associated with an increased risk of acute kidney injury, respiratory tract infections, or acute pancreatitis compared to sulfonylureas or other glucose-lowering therapies. PMID- 30310102 TI - Glutamate alleviates intestinal injury, maintains mTOR and suppresses TLR4 and NOD signaling pathways in weanling pigs challenged with lipopolysaccharide. AB - This experiment aimed to explore whether glutamate (Glu) had beneficial effects on intestinal injury caused by Escherichia coli LPS challenge via regulating mTOR, TLRs, as well as NODs signaling pathways. Twenty-four piglets were allotted to 4 treatments including: (1) control group; (2) LPS group; (3) LPS + 1.0% Glu group; (4) LPS + 2.0% Glu group. Supplementation with Glu increased jejunal villus height/crypt depth ratio, ileal activities of lactase, maltase and sucrase, and RNA/DNA ratio and protein abundance of claudin-1 in jejunum and ileum. In addition, the piglets fed Glu diets had higher phosphorylated mTOR (Ser2448)/total mTOR ratio in jejunum and ileum. Moreover, Glu decreased TNF alpha concentration in plasma. Supplementation with Glu also decreased mRNA abundance of jejunal TLR4, MyD88, IRAK1, TRAF6, NOD2 and increased mRNA abundance of ileal Tollip. These results indicate that Glu supplementation may be closely related to maintaining mTOR and inhibiting TLR4 and NOD signaling pathways, and concomitant improvement of intestinal integrity under an inflammatory condition. PMID- 30310101 TI - The CTLA-4 rs231775 GG genotype is associated with favorable 90-day survival in Caucasian patients with sepsis. AB - Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a surface protein on T cells, that has an inhibitory effect on the host immune reaction and prevents overreaction of the immune system. Because the functional single-nucleotide polymorphism (SNP) rs231775 of the CTLA-4 gene is associated with autoimmune diseases and because of the critical role of the immune reaction in sepsis, we intended to examine the effect of this polymorphism on survival in patients with sepsis. 644 septic adult Caucasian patients were prospectively enrolled in this study. Patients were followed up for 90 days. Mortality risk within this period was defined as primary outcome parameter. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality risk among GG homozygous patients (n = 101) than among A allele carriers (n = 543; 22% and 32%, respectively; p = 0.03565). Furthermore, the CTLA-4 rs231775 GG genotype remained a significant covariate for 90-day mortality risk after controlling for confounders in the multivariate Cox regression analysis (hazard ratio: 0.624; 95% CI: 0.399-0.975; p = 0.03858). In conclusion, our study provides the first evidence for CTLA-4 rs231775 as a prognostic variable for the survival of patients with sepsis and emphasizes the need for further research to reveal potential functional associations between CTLA-4 and the immune pathophysiology of sepsis. PMID- 30310103 TI - Stressful conditions reveal decrease in size, modification of shape but relatively stable asymmetry in bumblebee wings. AB - Human activities can generate a wide variety of direct and indirect effects on animals, which can manifest as environmental and genetic stressors. Several phenotypic markers have been proposed as indicators of these stressful conditions but have displayed contrasting results, depending, among others, on the phenotypic trait measured. Knowing the worldwide decline of multiple bumblebee species, it is important to understand these stressors and link them with the drivers of decline. We assessed the impact of several stressors (i.e. natural toxin-, parasite-, thermic- and inbreeding- stress) on both wing shape and size and their variability as well as their directional and fluctuating asymmetries. The total data set includes 650 individuals of Bombus terrestris (Hymenoptera: Apidae). Overall wing size and shape were affected by all the tested stressors. Except for the sinigrin (e.g. glucosinolate) stress, each stress implies a decrease of wing size. Size variance was affected by several stressors, contrary to shape variance that was affected by none of them. Although wing size directional and fluctuating asymmetries were significantly affected by sinigrin, parasites and high temperatures, neither directional nor fluctuating shape asymmetry was significantly affected by any tested stressor. Parasites and high temperatures led to the strongest phenotype modifications. Overall size and shape were the most sensitive morphological traits, which contrasts with the common view that fluctuating asymmetry is the major phenotypic marker of stress. PMID- 30310105 TI - Development of lentiviral vectors for efficient glutamatergic-selective gene expression in cultured hippocampal neurons. AB - Targeting gene expression to a particular subset of neurons helps study the cellular function of the nervous system. Although neuron-specific promoters, such as the synapsin I promoter and the alpha-CaMKII promoter, are known to exhibit selectivity for excitatory glutamatergic neurons in vivo, the cell type specificity of these promoters has not been thoroughly tested in culture preparations. Here, by using hippocampal culture preparation from the VGAT-Venus transgenic mice, we examined the ability of five putative promoter sequences of glutamatergic-selective markers including synapsin I, alpha-CaMKII, the vesicular glutamate transporter 1 (VGLUT1), Dock10 and Prox1. Among these, a genomic fragment containing a 2.1 kb segment upstream of the translation start site (TSS) of the VGLUT1 implemented in a lentiviral vector with the Tet-Off inducible system achieved the highest preferential gene expression in glutamatergic neurons. Analysis of various lengths of the VGLUT1 promoter regions identified a segment between -2.1 kb and -1.4 kb from the TSS as a responsible element for the glutamatergic selectivity. Consistently, expression of channelrhodopsin under this promoter sequence allowed for selective light-evoked activation of excitatory neurons. Thus, the lentiviral system carrying the VGLUT1 promoter fragment can be used to effectively target exogenous gene expression to excitatory glutamatergic neurons in cultures. PMID- 30310104 TI - Attenuation of replication by a 29 nucleotide deletion in SARS-coronavirus acquired during the early stages of human-to-human transmission. AB - A 29 nucleotide deletion in open reading frame 8 (ORF8) is the most obvious genetic change in severe acute respiratory syndrome coronavirus (SARS-CoV) during its emergence in humans. In spite of intense study, it remains unclear whether the deletion actually reflects adaptation to humans. Here we engineered full, partially deleted (-29 nt), and fully deleted ORF8 into a SARS-CoV infectious cDNA clone, strain Frankfurt-1. Replication of the resulting viruses was compared in primate cell cultures as well as Rhinolophus bat cells made permissive for SARS-CoV replication by lentiviral transduction of the human angiotensin converting enzyme 2 receptor. Cells from cotton rat, goat, and sheep provided control scenarios that represent host systems in which SARS-CoV is neither endemic nor epidemic. Independent of the cell system, the truncation of ORF8 (29 nt deletion) decreased replication up to 23-fold. The effect was independent of the type I interferon response. The 29 nt deletion in SARS-CoV is a deleterious mutation acquired along the initial human-to-human transmission chain. The resulting loss of fitness may be due to a founder effect, which has rarely been documented in processes of viral emergence. These results have important implications for the retrospective assessment of the threat posed by SARS. PMID- 30310106 TI - Modeling the Transmission Dynamics of Clonorchiasis in Foshan, China. AB - Clonorchiasis, known as the Chinese liver fluke disease, is caused by Clonorchis sinensis infection with food-borne liver fluke, which is transmitted via snails to freshwater fish and then to human beings or other piscivorous mammals. Clonorchis sinensis infection is mainly related to liver and biliary disorders, especially cholangiocarcinoma, and has an increased human-health impact due to the greater consumption of raw freshwater fish. In this article, we propose a deterministic model to describe the spread of clonorchiasis among human-snail fish populations and use the model to simulate the data on the numbers of inspected and infected individuals of Foshan City, located in Guangdong Province in the southeast of P.R China, from 1980-2010. Mathematical and numerical analyses of the model are carried out to understand the transmission dynamics of clonorchiasis and explore effective control measures for the local outbreaks of the disease. We find that (i) the transmission of clonorchiasis from cercariae to fish plays a more important role than that from eggs to snails and from fish to humans; (ii) As the cycle of infection-treatment-reinfection continues, it is unlikely that treatment with drugs alone can control and eventually eradicate clonorchiasis. These strongly suggest that a more comprehensive approach needs to include environmental modification in order to break the cercariae-fish transmission cycle, to enhance awareness about the disease, and to improve prevention measures. PMID- 30310109 TI - Engineering a branching sucrase for flavonoid glucoside diversification. AB - Enzymatic glycosylation of flavonoids is an efficient mean to protect aglycons against degradation while enhancing their solubility, life time and, by extension, their bioavailability which is critical for most of their applications in health care. To generate a valuable enzymatic platform for flavonoid glucosylation, an alpha-1,2 branching sucrase belonging to the family 70 of glycoside-hydrolases was selected as template and subsequently engineered. Two libraries of variants targeting pair-wise mutations inferred by molecular docking simulations were generated and screened for quercetin glucosylation using sucrose as a glucosyl donor. Only a limited number of variants (22) were retained on the basis of quercetin conversion and product profile. Their acceptor promiscuity towards five other flavonoids was subsequently assessed, and the automated screening effort revealed variants showing remarkable ability for luteolin, morin and naringenin glucosylation with conversion ranging from 30% to 90%. Notably, naringenin and morin, a priori considered as recalcitrant compounds to glucosylation using this alpha-transglucosylases, could also be modified. The approach reveals the potential of small platforms of engineered GH70 alpha transglucosylases and opens up the diversity of flavonoid glucosides to molecular structures inaccessible yet. PMID- 30310108 TI - Integrated and efficient diffusion-relaxometry using ZEBRA. AB - The emergence of multiparametric diffusion models combining diffusion and relaxometry measurements provides powerful new ways to explore tissue microstructure, with the potential to provide new insights into tissue structure and function. However, their ability to provide rich analyses and the potential for clinical translation critically depends on the availability of efficient, integrated, multi-dimensional acquisitions. We propose a fully integrated sequence simultaneously sampling the acquisition parameter spaces required for T1 and T2* relaxometry and diffusion MRI. Slice-level interleaved diffusion encoding, multiple spin/gradient echoes and slice-shuffling are combined for higher efficiency, sampling flexibility and enhanced internal consistency. In vivo data was successfully acquired on healthy adult brains. Obtained parametric maps as well as clustering results demonstrate the potential of the technique to provide eloquent data with an acceleration of roughly 20 compared to conventionally used approaches. The proposed integrated acquisition, which we call ZEBRA, offers significant acceleration and flexibility compared to existing diffusion-relaxometry studies, and thus facilitates wider use of these techniques both for research-driven and clinical applications. PMID- 30310110 TI - Global pentapeptide statistics are far away from expected distributions. AB - The relationships between polypeptide composition, sequence, structure and function have been puzzling biologists ever since first protein sequences were determined. Here, we study the statistics of occurrence of all possible pentapeptide sequences in known proteins. To compensate for the non-uniform distribution of individual amino acid residues in protein sequences, we investigate separately all possible permutations of every given amino acid composition. For the majority of permutation groups we find that pentapeptide occurrences deviate strongly from the expected binomial distributions, and that the observed distributions are also characterized by high numbers of outlier sequences. An analysis of identified outliers shows they often contain known motifs and rare amino acids, suggesting that they represent important functional elements. We further compare the pentapeptide composition of regions known to correspond to protein domains with that of non-domain regions. We find that a substantial number of pentapeptides is clearly strongly favored in protein domains. Finally, we show that over-represented pentapeptides are significantly related to known functional motifs and to predicted ancient structural peptides. PMID- 30310107 TI - The role of Mean Platelet Volume/platelet count Ratio and Neutrophil to Lymphocyte Ratio on the risk of Febrile Seizure. AB - Systemic inflammatory response has been implicated as a contributor to the onset of febrile seizures (FS). The four novel indices of the inflammatory response such as, neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), platelet count (PLT) ratio and red blood cell distribution width (RDW) have been investigated in FS susceptibility and FS types (simple febrile seizure and complex febrile seizure). However, the potential role of these inflammatory markers and MPV/PLT ratio (MPR) in Chinese children with FS has yet to be fully determined. This study investigated the relevance of NLR, MPV, PLT, MPR and RDW in febrile children with and without seizures. 249 children with FS and 249 age matched controls were included in this study. NLR and MPR were calculated from complete blood cell counts prior to therapy. Differences in age, gender and these inflammatory markers between the FS group and the control group were evaluated using the chi-square test, t-test or logistic regression analysis. Receiver Operating Characteristic (ROC) curve was used to determine the optimal cut-off value of NLR and MPR for FS risk. Interactions between NLR and MPR on the additive scale were calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). It has been shown that the elevated NLR and MPR levels were associated with increased risk of FS. The optimal cut-off values of NLR and MPR for FS risk were 1.13 and 0.0335 with an area under the curve (AUC) of 0.768 and 0.689, respectively. Additionally, a significant synergistic interaction between NLR and MPR was found on an additive scale. The mean levels of MPV were lower and NLR levels were higher in complex febrile seizure (CFS) than simple febrile seizure (SFS), and the differences were statistically significant. ROC analysis showed that the optimal cut-off value for NLR was 2.549 with 65.9% sensitivity and 57.5% specificity. However, no statistically significant differences were found regarding average values of MPR and RDW between CFS and SFS. In conclusion, elevated NLR and MPR add evidence to the implication of white cells subsets in FS risk, and our results confirmed that NLR is an independent, albeit limited, predictor in differentiating between CFS and SFS. Moreover, NLR and MPR may have a synergistic effect that can influence the occurrence of FS. PMID- 30310111 TI - The interplay between adipose-derived stem cells and bladder cancer cells. AB - Tissue engineering approaches offer alternative strategies for urinary diversion after radical cystectomy. Possible triggering of cancer recurrence remains, however, a significant concern in the application of stem-cell based therapies for oncological patients. Soluble mediators secreted by stem cells induce tissue remodelling effects, but may also promote cancer cells growth and metastasis. We observed a substantial increase in the concentration of IL-6 and IL-8 in the secretome of adipose-derived stem cells (ASCs) co-cultured with bladder cancer cells. Concentrations of GM-CSF, MCP-1 and RANTES were also elevated. Bioactive molecules produced by ASCs increased the viability of 5637 and HT-1376 cells by respectively 15.4% and 10.4% (p < 0.0001). A trend in reduction of adhesion to ECM components was also noted, even though no differences in beta-catenin expression were detected. When HT-1376 cells were co-cultured with ASCs their migration and invasion increased by 24.5% (p < 0.0002) and 18.2% (p < 0.002). Expression of p-ERK1/2 increased in 5637 cells (2.2-fold; p < 0.001) and p-AKT in HB-CLS-1 cells (2.0-fold; p < 0.001). Our results confirm that ASCs crosstalk with bladder cancer cells in vitro what influences their proliferation and invasive properties. Since ASCs tropism to tumour microenvironment is well documented their application towards post-oncologic reconstruction should be approached with caution. PMID- 30310112 TI - Dendritic processing of spontaneous neuronal sequences for single-trial learning. AB - Spontaneous firing sequences are ubiquitous in cortical networks, but their roles in cellular and network-level computations remain unexplored. In the hippocampus, such sequences, conventionally called preplay, have been hypothesized to participate in learning and memory. Here, we present a computational model for encoding input sequence patterns into internal network states based on the propagation of preplay sequences in recurrent neuronal networks. The model instantiates two synaptic pathways in cortical neurons, one for proximal dendrite somatic interactions to generate intrinsic preplay sequences and the other for distal dendritic processing of extrinsic signals. The core dendritic computation is the maximization of matching between patterned activities in the two compartments through nonlinear spike generation. The model performs robust single trial learning with long-term stability and independence that are modulated by the plasticity of dendrite-targeted inhibition. Our results demonstrate that dendritic computation enables somatic spontaneous firing sequences to act as templates for rapid and stable memory formation. PMID- 30310114 TI - Insight into the draft whole-genome sequence of the dermatophyte Arthroderma vanbreuseghemii. AB - Next-generation technologies have prompted efforts towards generating a large repertoire of whole-genome sequences. The dermatophyte Arthroderma vanbreuseghemii has been considered as a good model in which to conduct molecular biological studies on this fungal group. Despite the considerable repertoire of molecular tools developed for this fungus, the lack of genomic data has represented a major limitation, preventing effective implementation of those tools. Herein, the authors report the first draft whole-genome sequence of this dermatophytic species. The size of the draft genome was 23 Mb, exhibiting a GC content of 48.1%. Given the significance of secreted proteases in tissue invasion, a comparative analysis of genes encoding extracellular proteases was performed between A. vanbreuseghemii and other dermatophytes. Furthermore, genes that might be involved in DNA repair also were compared among dermatophytes. Moreover, the complete mitochondrial genome of A. vanbreuseghemii was obtained and shown to consist of 24,287 bp with a GC content of 24%. In conclusion, the availability of genomic data for A. vanbreuseghemii is expected to facilitate the implementation of the molecular tools established for this fungus, enhancing our understanding of the biology of dermatophytes. PMID- 30310113 TI - Assessing the regional carbon sink with its forming processes- a case study of Liaoning province, China. AB - Assessing the regional carbon sink sets the basis of regional carbon management, which involves many measures but has large uncertainties. Carbon sink assessment scheme based on its forming processes (CSF) is a recently proposed measure but repeatly calculates emission from water erosion and ignored human inducing carbon inputs. Therefore, we revised the CSF by calculating the direct outputs from land surface and adding human returned carbon (HC) to the input. The revised CSF thus involved gross primary productivity (GPP), ecosystem respiration (ER), carbon removal from cropland (CRC), emission from reactive carbon (ERC), emission from water erosion (Ewat), and HC, which can be obtained from public data sources. Then the revised CSF was applied to the Liaoning province of China. The estimated carbon input of Liaoning province during 2000-2014 was 114.77 +/- 8.41 TgC yr-1, while the carbon output was 110.48 +/- 8.38 TgC yr-1. The difference between input and output induced a carbon sink of 4.30 +/- 2.20 TgC yr-1, accounting for 3.75% of total carbon input. The carbon sink spatially decreased from northeast to southwest, which was highly correlated with that of GPP. However, though its forming fluxes significantly increased from 2000 to 2014, the carbon sink showed a decreasing trend. In addition, the revised scheme only needed published and public data, which made it serve as an alternative approach for regional carbon budget assessment. PMID- 30310115 TI - Spatiotemporal dynamics and risk factors for human Leptospirosis in Brazil. AB - Leptospirosis is an emerging neglected tropical disease with a worldwide significant global health burden. Between 2000 and 2016, there were 63,302 cases of human leptospirosis and 6,064 deaths reported in Brazil. We modeled the spatiotemporal risk dynamics of human leptospirosis morbidity and lethality, and attributed an easily interpretable risk-based priority index (PI) for all Brazilian federative units to suggest improvements to the national surveillance system. We also developed a conceptual framework of causality and estimated the effects of environmental and socioeconomic determinants of morbidity and lethality. Spatiotemporal risk patterns of morbidity and lethality differed. For morbidity, the pattern was mainly spatial, whereas lethality was mainly explained by the spatiotemporal interaction. The hypothesized causal model explained a relevant fraction of the heterogeneity in the spatial and spatiotemporal interaction patterns. The increase in soil moisture, precipitation, poverty, and the decrease in the proportion of urban households, acted as risk factors. The increase in the proportion of households in which waste is directly collected and in temperature were preventive factors. The structured temporal trend was increasing for morbidity and decreasing for lethality. In terms of morbidity, it was clear that the prioritization should be focused in a couple of states, mainly Acre. In terms of lethality, the allocation of resources need not be as asymmetric, but there was nonetheless a prioritization order. The proposed approach can be used to characterize spatiotemporal dynamics of other diseases and to inform decision makers. PMID- 30310116 TI - Minimally invasive surgery for colorectal cancer remains underutilized in Germany despite its nationwide application over the last decade. AB - Minimally invasive surgery (MIS) has superior short-term outcomes than open surgery (OS) for colorectal cancer (CRC). However, a nationwide dataset has not been analysed to confirm these findings. We evaluated the distribution and outcomes of MIS for CRC from 2005 to 2015; all in-patients with CRC surgery procedure codes were identified from hospital data, which are entered into the nationwide diagnosis-related group database and forwarded anonymised to the Federal Bureau of Statistics. We determined absolute MIS, morbidity, and mortality rates for specific sub-categories, including procedure type. We identified 345,913 in-patient files. The MIS rate increased from 6.4% (n = 2366; 2005) to 28.5% (n = 8363; 2015), with the highest rates for sigmoid colon (38%) and rectal (39%) resections. The overall conversion rate was 14.4%, without noticeable improvement over time. International Classification of Disease codes related to postoperative complications were documented more frequently after OS than after MIS. OS was associated with a higher mortality rate (4.7%) than MIS (1.8%) (P < 0.001), even after stratifying patients according to the resection site. Use of MIS remains low in Germany compared with that in other European countries. Underutilization of MIS has to be addressed in the future by promoting structured training programs and standardization of laparoscopic surgery. PMID- 30310117 TI - Gravure Printing of Water-based Silver Nanowire ink on Plastic Substrate for Flexible Electronics. AB - Gravure printing is a promising technique for large-scale printed electronics. However, gravure printing of silver nanowires (AgNWs) so far has been limited in terms of resolution and electrical conductivity. In this study, gravure printing of water-based AgNW ink on a flexible substrate is demonstrated. By tailoring the ink properties, printing conditions and post-printing treatment, gravure printing enables printing of high-resolution, highly conductive AgNW patterns in large areas, with resolution as fine as 50 um and conductivity as high as 5.34 * 104 S cm-1. The printed AgNW patterns on the flexible substrate show excellent flexibility under repeated bending. All these characteristics demonstrate the excellent potential of gravure printing of AgNWs for developing large-area flexible electronics. PMID- 30310118 TI - Effects of aspirin-loaded graphene oxide coating of a titanium surface on proliferation and osteogenic differentiation of MC3T3-E1 cells. AB - Graphene oxide (GO) has attracted considerable attention for biomedical applications such as drug delivery because of its two-dimensional structure, which provides a large surface area on both sides of the nanosheet. Here, a new method for titanium (Ti) surface modification involving a GO coating and aspirin (A) loading (A/Ti-GO) was developed, and the bioactive effects on mouse osteoblastic MC3T3-E1 cells were preliminarily studied. The X-ray photoelectron spectrometry indicated new C-O-N, C-Si-O-C, and C-N=C bond formation upon GO coating. Remarkably, the torsion test results showed stable bonding between the GO coating and Ti under a torsional shear force found in clinical settings, in that, there was no tearing or falling off of GO coating from the sample surface. More importantly, through pi-pi stacking interactions, the release of aspirin loaded on the surface of Ti-GO could sustain for 3 days. Furthermore, the A/Ti-GO surface displayed a significantly higher proliferation rate and differentiation of MC3T3-E1 cells into osteoblasts, which was confirmed by a water-soluble tetrazolium salt-8 (WST-8) assay and alkaline phosphatase activity test. Consequently, Ti surface modification involving GO coating and aspirin loading might be a useful contribution to improve the success rate of Ti implants in patients, especially in bone conditions. PMID- 30310119 TI - Robust Enhancement of Lentivirus Production by Promoter Activation. AB - Lentiviral vectors are a valuable tool to deliver exogenous genes for stable expression in cells. While much progress has been made in processing lentiviral vector-containing culture medium, it remains to be explored how the production of lentiviral vector from producer cells can be increased. We initially found that co-expression of the SPRY domain-containing SOCS box protein 1 (SPSB1) promotes the production of human immunodeficiency virus type 1 (HIV-1) and lentiviral vector with increased expression of the Gag and envelope proteins and activation of the HIV-1 LTR and CMV promoter. The presence of AP-1, NF-kappaB and CREB/ATF recognition sites in these promoters prompted us to utilize human T-lymphotropic virus type 1 (HTLV-1) Tax for lentiviral vector production because Tax activates all these transcription factors. Co-expression of a small amount of Tax markedly increased both the expression of viral structural proteins in producer cells and release of lentiviral vector particles, resulting in a more than 10-fold enhancement of transduction efficiency. Of note, the Tax protein was not detected in the lentiviral vector particles concentrated by ultracentrifugation, supporting the safety of this preparation. Collectively, these results indicate that promoter activation in producer cells represents a promising approach to preparing high-titer lentiviral vectors. PMID- 30310120 TI - Abscisic and Jasmonic Acids Contribute to Soybean Tolerance to the Soybean Aphid (Aphis glycines Matsumura). AB - Plant resistance can provide effective, economical, and sustainable pest control. Tolerance to the soybean aphid has been identified and confirmed in the soybean KS4202. Although its resistance mechanisms are not fully understood, evidence suggests that enhanced detoxification of reactive oxygen species (ROS) is an active system under high aphid infestation. We further explored tolerance by evaluating the differences in constitutive and aphid-induced defenses in KS4202 through the expression of selected defense-related transcripts and the levels of the phytohormones abscisic acid (ABA), jasmonic acid (JA), JA-isoleucine (JA Ile), cis-(+)-12-oxo-phytodienoic acid (OPDA), and salicylic acid (SA) over several time points. Higher constitutive levels of ABA and JA, and basal expression of ABA- and JA-related transcripts were found in the tolerant genotype. Conversely, aphid-induced defenses in KS4202 were expressed as an upregulation of peroxidases under prolonged aphid infestation (>7 days). Our results point at the importance of phytohormones in constitutive defense in KS4202 tolerance to the soybean aphid. Understanding the underlying mechanisms of tolerance will assist breeding for soybean with these traits, and perhaps help extend the durability of Rag (Resistance to Aphis glycines)-mediated resistance genes. PMID- 30310121 TI - GSK3beta in the prefrontal cortex: a molecular handle specific to addiction pathology? PMID- 30310122 TI - 2.0 A resolution crystal structure of human polkappa reveals a new catalytic function of N-clasp in DNA replication. AB - Human polymerase kappa (polkappa) is a distinct Y-family DNA polymerase with a unique N-terminal N-clasp domain. The N-clasp renders polkappa's high efficiency and accuracy in DNA replication and lesion bypass. How N-clasp empowers polkappa in replication remains unclear due to the disordering of N-clasp. Here, we present a 2.0-A resolution crystal structure of a polkappa ternary complex with DNA and an incoming nucleotide. The structure-function study reveals an ordered N clasp domain that brings conserved and functionally important residues in contact with the replicating basepair in the active site and contributes to the nucleotidyl transfer reaction. Particularly, a fully ordered Lys25 from the N clasp domain is in H-bonding with the alpha- and gamma-phosphates of the incoming nucleotide. K25A mutation reduces the polymerase activity of polkappa significantly. This lysine is structurally analogous to a conserved lysine in the A-family DNA polymerases in the closed form. In contrast, Lys25 in the previous structures of polkappa does not have any contacts with the incoming nucleotide, resembling an open form of a DNA polymerase. Based on structural and functional similarity, we propose a local open/closed mechanism for polkappa in DNA replication catalysis, which mimics the common mechanism for all DNA polymerases. PMID- 30310124 TI - Recontacting patients in clinical genetics services: recommendations of the European Society of Human Genetics. AB - Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting. PMID- 30310123 TI - Transcriptome analysis of the genes regulating phytohormone and cellular patterning in Lagerstroemia plant architecture. AB - Plant architecture is a popular research topic because plants with different growth habits that may generate economic or ornamental value are in great demand by orchards and nurseries. However, the molecular basis of the architecture of woody perennial plants is poorly understood due to the complexity of the phenotypic and regulatory relationships. Here, transcriptional profiling of dwarf and non-dwarf crapemyrtles was performed, and potential target genes were identified based on the phenotype, histology and phytohormone metabolite levels. An integrated analysis demonstrated that the internode length was explained mainly by cell number and secondarily by cell length and revealed important hormones in regulatory pathway of Lagerstroemia architecture. Differentially expressed genes (DEGs) involved in phytohormone pathways and cellular patterning regulation were analysed, and the regulatory relationships between these parameters were evaluated at the transcriptional level. Exogenous indole-3-acetic acid (IAA) and gibberellin A4 (GA4) treatments further indicated the pivotal role of auxin in cell division within the shoot apical meristem (SAM) and suggested an interaction between auxin and GA4 in regulating the internode length of Lagerstroemia. These results provide insights for further functional genomic studies on the regulatory mechanisms underlying Lagerstroemia plant architecture and may improve the efficiency of woody plant molecular breeding. PMID- 30310125 TI - Floristic diversity in different urban ecological niches of a southern European city. AB - The present paper aimed at studying the vertical and horizontal spatial distribution, species richness and diversity of vascular plants in different urban ecological niches (urban habitats) by means of the case study of Bologna (Italy), a typical densely populated southern European city. A total of 477 species were found in the study area of the historical city centre, 30% of which were alien species. Alien plant species were mainly present among phanerophytes, while native plants were mainly therophytes and hemicryptophytes. The habitats that mostly contributed to the species total richness were semi-natural soils, followed by paved areas, walls, rooftops and manholes. The number of exclusive species decreased according to the selectiveness of the habitat, with manholes and rooftops being the most selective. The presence of hemicryptophytes constant decreased going from 27% of more humid habitats to 5% of more arid habitats, so that they can be considered a water availability biomarker. Urban habitat quality, measured by the number of native species, was directly proportional to the strength of selective factors and inversely proportional to the rate of disturbance, with roofs and semi-natural soils having, respectively, the highest and lowest quality. Finally, a relation between species richness and street characteristics, like width, orientation and type of flooring, was demonstrated. PMID- 30310126 TI - Detection of the carbapenemase gene blaVIM-5 in members of the Pseudomonas putida group isolated from polluted Nigerian wetlands. AB - There are increasing concerns about possible dissemination of clinically relevant antibiotic resistance genes, including genes encoding for carbapenemases in the environment. However, little is known about environmental distribution of antibiotic resistance in Africa. In this study, four polluted urban wetlands in Nigeria were investigated as potential reservoirs of carbapenem-resistant bacteria (CRB). CRB were isolated from the wetlands, characterized by Blue-Carba test, MIC determinations and whole genome sequencing (WGS). Nine of 65 bacterial isolates identified as members of the Pseudomonas putida group (P. plecoglossicida and P. guariconensis, respectively) harboured the metallo-beta lactamase gene blaVIM-5. WGS revealed the blaVIM-5 in three novel Tn402-like class 1 integron structures containing the cassette arrays aadB|blaVIM-5|blaPSE 1, aadB|blaVIM-5|aadB|blaPSE-1, and blaVIM-5|aadB|tnpA|blaPSE-1|smr2|tnpA, respectively. Strains carrying the aadB|blaVIM-5|blaPSE-1 cassette also carried an identical integron without blaVIM-5. In addition, the strains harboured another Tn402-like class 1 integron carrying bcr2, several multidrug resistance efflux pumps, and at least one of ampC, aph(3")-lb, aph(6)-ld, tetB, tetC, tetG, floR, and macAB. This is the first report of a carbapenemase gene in bacteria from environmental sources in Nigeria and the first report of blaVIM-5 in environmental bacteria isolates. This result underscores the role of the Nigerian environment as reservoir of bacteria carrying clinically relevant antibiotic resistance genes. PMID- 30310127 TI - Short-term effect of Eucalyptus plantations on soil microbial communities and soil-atmosphere methane and nitrous oxide exchange. AB - Soil greenhouse gas (GHG) emissions are a significant environmental problem resulting from microbially-mediated nitrogen (N) and carbon (C) cycling. This study aimed to investigate the impact of Eucalyptus plantations on the structure and function of a soil microbial community, and how resulting alterations may be linked to GHG fluxes. We sampled and monitored two adjacent Eucalyptus plantations-a recently logged site that harbored new seedlings and an adult plantation-and compared them to a site hosting native vegetation. We used 16S rRNA gene sequencing and qPCR amplifications of key nitrogen and methane cycle genes to characterize microbial structure and functional gene abundance and compared our data with soil parameters and GHG fluxes. Both microbial community attributes were significantly affected by land use and logging of Eucalyptus plantations. The genes nosZ and archaeal amoA were significantly more abundant in native forest than in either young or old Eucalyptus plantations. Statistical analyses suggest that land use type has a greater impact on microbial community structure and functional gene abundance than Eucalyptus rotation. There was no correlation between GHG fluxes and shifts in microbial community, suggesting that microbial community structure and functional gene abundance are not the main drivers of GHG fluxes in this system. PMID- 30310128 TI - Induction of the viable but non-culturable state in bacterial pathogens by household cleaners and inorganic salts. AB - Effective monitoring of microbial pathogens is essential for a successful preventive food safety and hygiene strategy. However, as most monitoring strategies are growth-based, these tests fail to detect pathogenic bacteria that have entered the viable but non-culturable (VBNC) state. The present study reports the induction of the VBNC state in five human pathogens by commercially available household cleaners in combination with inorganic salts. We determined that non-ionic surfactants, a common ingredient in household cleaners, can induce the VBNC state, when combined with salts. A screening study with 630 surfactant/salt combinations indicates a correlation between the hydrophobicity of the surfactant and VBNC induction in L. monocytogenes, E. coli, S. enterica serovar Typhimurium, S. aureus and toxin-producing enteropathogenic E. coli. Cells that were exposed to combinations of surfactants and salts for 5 min and up to 1 h lost their culturability on standard growth media while retaining their ATP production, fermentation of sugars and membrane integrity, which suggests intact and active metabolism. Screening also revealed major differences between Gram-negative and Gram-positive bacteria; the latter being more susceptible to VBNC induction. Combinations of such detergents and salts are found in many different environments and reflect realistic conditions in industrial and domestic surroundings. VBNC cells present in industrial environments, food processing plants and even our daily routine represent a serious health risk due to possible resuscitation, unknown spreading, production of toxins and especially their invisibility to routine detection methods, which rely on culturability of cells and fail to detect VBNC pathogens. PMID- 30310129 TI - Selective interactions between diverse STEs organize the ANT-C Hox cluster. AB - The three-dimensional organization of the eukaryotic genome is important for its structure and function. Recent studies indicate that hierarchies of chromatin loops underlie important aspects of both genomic organization and gene regulation. Looping between insulator or boundary elements interferes with enhancer-promoter communications and limits the spread active or repressive organized chromatin. We have used the SF1 insulator in the Drosophila Antennapedia homeotic gene complex (ANT-C) as a model to study the mechanism and regulation of chromatin looping events. We reported previously that SF1 tethers a transient chromatin loop in the early embryo that insulates the Hox gene Sex comb reduce from the neighbor non-Hox gene fushi tarazu for their independent regulation. To further probe the functional range and connectivity of SF1, we used high-resolution chromosomal conformation capture (3C) to search for SF1 looping partners across ANT-C. We report here the identification of three distal SF1 Tether Elements (STEs) located in the labial, Deformed and Antennapedia Hox gene regions, extending the range of SF1 looping network to the entire complex. These novel STEs are bound by four different combinations of insulator proteins and exhibit distinct behaviors in enhancer block, enhancer-bypass and boundary functions. Significantly, the six STEs we identified so far map to all but one of the major boundaries between repressive and active histone domains, underlining the functional relevance of these long-range chromatin loops in organizing the Hox complex. Importantly, SF1 selectively captured with only 5 STEs out of ~20 sites that display similar insulator binding profiles, indicating that presence of insulator proteins alone is not sufficient to determine looping events. These findings suggest that selective interaction among diverse STE insulators organize the Drosophila Hox genes in the 3D nuclear space. PMID- 30310130 TI - The effects of aquarium culture on coral oocyte ultrastructure. AB - As the world's oceans are currently threatened by anthropogenic pollution and climate change, coral breeding has become an important conservation method, since it can limit marine organisms' exposure to sub-optimal environment conditions. However, the aquarium environment is inherently different from the ocean, and this could manifest in physiological changes in the reared organisms, particularly with respect to their reproduction. Therefore, the aim of this study was to observe and compare the ultrastructure of the oocytes from wild Oxypora lacera and Echinopora gemmacea with the oocytes from cultured corals using transmission electron microscope. The oocytes from Wild O. lacera and E. gemmacea were larger than cultured ones, though their microvillus layers were significantly thiner. Internally, lipid granule areas and yolk material density in the oocytes of wild O. lacera and E. gemmacea were ~25% lower than in their cultured counterparts. Food availability and the presence and availability of symbiotic dinoflagellates (genus Symbiodinium) may have played a role in driving these lipid-based differences, in particular, as cultured corals had limited potential for heterotrophic feeding. These data will aid in future coral husbandry efforts. PMID- 30310131 TI - Increase in resistance to anticancer drugs involves occludin in spheroid culture model of lung adenocarcinoma A549 cells. AB - Chemoresistance is a serious issue in the therapy of many cancers, but the molecular mechanism is little understood. The mRNA level of occludin (OCLN), a tight junctional protein, was increased in the cisplatin (CDDP), doxorubicin (DXR), 7-ethyl-10-hydroxy-camptothecin, or gemcitabine-resistant human lung adenocarcinoma A549 cells. Here, we investigated the regulatory mechanism and pathophysiological role of OCLN. OCLN was mainly localized at tight junctions in A549 and CDDP-resistant A549 (A549/CDDP) cells. The level of p-Akt in A549/CDDP cells was higher than that in A549 cells, and the mRNA and protein levels of OCLN were suppressed by a phosphoinositide 3-kinase (PI3K)/Akt pathway inhibitor, LY 294002, suggesting that a PI3K/Akt pathway is involved in the elevation of OCLN expression. The overexpression of OCLN in A549 cells decreased paracellular permeability to DXR. Cytotoxicity to CDDP was unaffected by OCLN-overexpression in 2D culture model. In 3D culture model, the spheroid size, hypoxic level, and cell viability were significantly elevated by CDDP resistance, but not by OCLN overexpression. The accumulation inside the spheroids and toxicity of DXR were correlated with OCLN expression. Our data suggest that OCLN is not directly involved in the chemoresistance, but it enhances chemoresistance mediated by suppression of accumulation of anticancer drugs inside the spheroids. PMID- 30310132 TI - Magnetization switching of multi-state magnetic structures with current-induced torques. AB - Spintronic devices often require the ability to locally change the magnetic configuration of ferromagnetic structures on a sub-micron scale. A promising route for achieving this goal is the use of heavy metal/ferromagnetic heterostructures where current flowing through the heavy metal layer generates field-like and anti-damping like torques on the magnetic layer. Commonly, such torques are used to switch magnets with a uniaxial anisotropy between two uniformly magnetized states. Here, we use such torques to switch magnetization in Ta/Ni0.80Fe0.20 heterostructures with uniaxial and biaxial anisotropy, where in the latter the magnetization is non-uniform. The anisotropies are induced by shape and the magnetic state is monitored using the planar Hall effect. As structures with several easy axes induced by shape can be part of a magnetic memory element, the results pave the way for multi-level magnetic memory with spin-orbit torque switching. PMID- 30310133 TI - Human exposure factors as potential determinants of the heterogeneity in city specific associations between PM2.5 and mortality. AB - Multi-city population-based epidemiological studies of short-term fine particulate matter (PM2.5) exposures and mortality have observed heterogeneity in risk estimates between cities. Factors affecting exposures, such as pollutant infiltration, which are not captured by central-site monitoring data, can differ between communities potentially explaining some of this heterogeneity. This analysis evaluates exposure factors as potential determinants of the heterogeneity in 312 core-based statistical areas (CBSA)-specific associations between PM2.5 and mortality using inverse variance weighted linear regression. Exposure factor variables were created based on data on housing characteristics, commuting patterns, heating fuel usage, and climatic factors from national surveys. When survey data were not available, air conditioning (AC) prevalence was predicted utilizing machine learning techniques. Across all CBSAs, there was a 0.95% (Interquartile range (IQR) of 2.25) increase in non-accidental mortality per 10 ug/m3 increase in PM2.5 and significant heterogeneity between CBSAs. CBSAs with larger homes, more heating degree days, a higher percentage of home heating with oil had significantly (p < 0.05) higher health effect estimates, while cities with more gas heating had significantly lower health effect estimates. While univariate models did not explain much of heterogeneity in health effect estimates (R2 < 1%), multivariate models began to explain some of the observed heterogeneity (R2 = 13%). PMID- 30310135 TI - DH44 neurons: gut-brain amino acid sensors. PMID- 30310134 TI - Hydroxyurea Treated beta-Thalassemia Children Demonstrate a Shift in Metabolism Towards Healthy Pattern. AB - Augmentation of fetal hemoglobin (HbF) production has been an enduring therapeutic objective in beta-thalassemia patients for which hydroxyurea (HU) has largely been the drug of choice and the most cost-effective approach. A serum metabolomics study on 40 patients with beta-thalassemia prior to and after administration of HU was done along with healthy controls. Treated patients were divided further into non-responders (NR), partial (PR) and good (GR) per their response. 25 metabolites that were altered before HU therapy at p <= 0.05 and fold change >2.0 in beta-thalassemia patients; started reverting towards healthy group after HU treatment. A prediction model based on another set of 70 HU treated patients showed a good separation of GR from untreated beta-thalassemia patients with an overall accuracy of 76.37%. Metabolic pathway analysis revealed that various important pathways that were disturbed in beta-thalassemia were reverted after treatment with HU and among them linoleic acid pathway was most impactfully improved in HU treated patients which is a precursor of important signaling molecules. In conclusion, this study indicates that HU is a good treatment option for beta-thalassemia patients because in addition to reducing blood transfusion burden it also ameliorates disease complications by shifting body metabolism towards normal. PMID- 30310136 TI - Sodium tanshinone IIA sulfonate protects ARPE-19 cells against oxidative stress by inhibiting autophagy and apoptosis. AB - Oxidative stress in retinal pigment epithelium (RPE) is considered to be a major contributor to the development and progression of age-related macular degeneration (AMD). Previous investigations have shown that sodium tanshinone IIA sulfonate (STS) can alleviate oxidative stress in haemorrhagic shock-induced organ damage and cigarette smoke-induced chronic obstructive pulmonary disease in mice. However, whether STS has a protective effect in ARPE-19 cells under oxidative stress and its exact mechanisms have not yet been fully elucidated. In the present study, we utilized H2O2 to establish an oxidative stress environment. Our findings show that STS activated the PI3K/AKT/mTOR pathway to inhibit autophagy and diminished the expression of the autophagic proteins Beclin 1, ATG3, ATG7 and ATG9 in ARPE-19 cells under oxidative stress. Detection of the intrinsic apoptosis-related factors BAX, mitochondrial membrane potential (MMP), caspase-9, caspase-3 and BCL-2, as well as the extrinsic apoptosis-related factors c-FLIP, v-FLIP and caspase-8, confirmed that STS inhibited the intrinsic and extrinsic apoptotic pathways, and attenuated apoptosis in ARPE-19 cells under oxidative stress conditions. These findings shed new light on the protective effects of STS in ARPE-19 cells and its mechanisms under oxidative stress to provide novel and promising therapeutic strategies for AMD. PMID- 30310137 TI - Novel Classification of Early-stage Systemic Hypertensive Changes in Human Retina Based on OCTA Measurement of Choriocapillaris. AB - The traditional classification of hypertensive retinopathy was based on the Keith Wagener-Barker (KWB) grading, which is a subjective scaling system, and it is difficult to distinguish between the first and second grades. Retinal and choroidal vasculatures are affected by systemic hypertension, although retinal vasculature changes with age, axial length, intraocular pressure, and retinal diseases. It is necessary to establish a new objective method to assess hypertensive vascular changes. In the present study, we have examined the vasculature of the macular choriocapillaris in order to establish a new objective method to assess hypertensive vascular changes using optical coherence tomography angiography (OCTA). Choriocapillaris vessel density (VD), vessel length, and vessel diameter index in a 3 * 3 mm macular area were measured by OTCA in a total of 567 volunteers (361 healthy subjects and 206 subjects with systemic hypertension) who attended a basic health check-up. Ocular factors, systemic factors, and medications were evaluated. We detected significant differences in normative choriocapillaris vasculature between the left and right eyes in 53 healthy subjects and revealed correlations between age, intraocular pressure, axial length, and choriocapillaris vasculature in 308 healthy subjects. Normative foveal VD was correlated with age only and the efficiency was weak. The analysis of 206 right eyes (KWB grade 0, 159 eyes; grade 1, 35 eyes; and grade 2, 12 eyes) revealed that foveal VD was strongly correlated with KWB grade only (P < 0.001). This is the first report suggesting that OCTA for foveal choriocapillaris measurement by OCTA would might provide the advantage of evaluating be objective method for evaluating the progression of systemic hypertension. PMID- 30310138 TI - Atomic scale insight into the effects of Aluminum doped Sb2Te for phase change memory application. AB - To date, the unpleasant trade-off between crystallization speed and thermal stability for most phase change materials is detrimental to achieve phase change memory (PCM) with both features of high-speed and good-retention. However, it is proved that Al doping in Sb2Te, served as storage media in PCM, favors both a high writing speed (6 ns) and a good retention (103 degrees C), as well as a low power consumption. Judging by experimental and theoretical investigations, doped Al atoms prefer to replace Sb in Sb2Te lattice, strongly bonded with 6 Te atoms, to form a homogeneous phase. While in amorphous Al doped Sb2Te (AST), Al atoms are in tetrahedral environment, firmly bonded with four Sb/Te atoms. The strong bonding in Al centered tetrahedron in amorphous AST can obstruct the collective motion of Sb atoms near the matrix boundary, leading to the improvement in thermal stability and the confinement in grain size. PMID- 30310139 TI - Gravity-dependent change in the 'light-from-above' prior. AB - In environments where orientation is ambiguous, the visual system uses prior knowledge about lighting coming from above to recognize objects, determine which way is up, and reorient the body. Here we investigated the extent with which assumed light from above preferences are affected by body orientation and the orientation of the retina relative to gravity. We tested the ability to extract shape-from-shading with seven human male observers positioned in multiple orientations relative to gravity using a modified KUKA anthropomorphic robot arm. Observers made convex-concave judgments of a central monocularly viewed stimulus with orientations of a shading gradient consistent with being lit from one of 24 simulated illumination directions. By positioning observers in different roll tilt orientations relative to gravity and when supine, we were able to monitor change in the light-from-above prior (the orientation at which a shaded disk appears maximally convex). The results confirm previous findings that the light from-above prior changes with body orientation relative to gravity. Interestingly, the results varied also with retinal orientation as well as an additional component that was approximately twice the frequency of retinal orientation. We use a modelling approach to show that the data are well predicted by summing retinal orientation with cross-multiplied utricle and saccule signals of the vestibular system, yielding gravity-dependent biases in the ability to extract shape-from-shading. We conclude that priors such as light coming from above appear to be constantly updated by neural processes that monitor self orientation to achieve optimal object recognition over moderate deviations from upright posture at the cost of poor recognition when extremely tilted relative to gravity. PMID- 30310140 TI - Food predictability and social status drive individual resource specializations in a territorial vulture. AB - Despite increasing work detailing the presence of foraging specializations across a range of taxa, limited attention so far has been given to the role of spatiotemporal variation in food predictability in shaping individual resource selection. Here, we studied the exploitation of human-provided carrion resources differing in predictability by Canarian Egyptian vultures (Neophron percnopterus majorensis). We focussed specifically on the role of individual characteristics and spatial constraints in shaping patterns of resource use. Using high resolution GPS data obtained from 45 vultures tracked for 1 year, we show that individual vultures were repeatable in both their monthly use of predictable and semi-predicable resources (feeding station vs. farms) and monthly levels of mobility (home range size and flight activity). However, individual foraging activities were simultaneously characterized by a high degree of (temporal) plasticity in the use of the feeding station in specific months. Individual rank within dominance hierarchy revealed sex-dependent effects of social status on resource preference in breeding adults, illustrating the potential complex social mechanisms underpinning status-dependent resource use patterns. Our results show that predictable food at feeding stations may lead to broad-scale patterns of resource partitioning and affect both the foraging and social dynamics within local vulture populations. PMID- 30310143 TI - The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol. AB - On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP-RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP-RTSG pathology panel. PMID- 30310144 TI - SPOP mutations disrupt phase separation. PMID- 30310141 TI - Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. AB - The stereotypical distribution of TAR DNA-binding 43 protein (TDP-43) aggregates in frontotemporal lobar degeneration (FTLD-TDP) suggests that pathological TDP-43 spreads throughout the brain via cell-to-cell transmission and correlates with disease progression, but no in vivo experimental data support this hypothesis. We first develop a doxycycline-inducible cell line expressing GFP-tagged cytoplasmic TDP-43 protein (iGFP-NLSm) as a cell-based system to screen and identify seeding activity of human brain-derived pathological TDP-43 isolated from sporadic FTLD TDP and familial cases with Granulin (FTLD-TDP-GRN) or C9orf72 repeat expansion mutations (FTLD-TDP-C9+). We demonstrate that intracerebral injections of biologically active pathogenic FTLD-TDP seeds into transgenic mice expressing cytoplasmic human TDP-43 (lines CamKIIa-hTDP-43NLSm, rNLS8, and CamKIIa-208) and non-transgenic mice led to the induction of de-novo TDP-43 pathology. Moreover, TDP-43 pathology progressively spreads throughout the brain in a time-dependent manner via the neuroanatomic connectome. Our study suggests that the progression of FTLD-TDP reflects the templated cell-to-cell transneuronal spread of pathological TDP-43. PMID- 30310142 TI - Large-scale nanoporous metal-coated silica aerogels for high SERS effect improvement. AB - We investigate the optical properties and surface-enhanced Raman scattering (SERS) characteristics of metal-coated silica aerogels. Silica aerogels were fabricated by easily scalable sol-gel and supercritical drying processes. Metallic nanogaps were formed on the top surface of the nanoporous silica network by controlling the thickness of the metal layer. The optimized metallic nanogap structure enabled strong confinement of light inside the gaps, which is a suitable property for SERS effect. We experimentally evaluated the SERS enhancement factor with the use of benzenethiol as a probe molecule. The enhancement factor reached 7.9 * 107 when molecules were adsorbed on the surface of the 30 nm silver-coated aerogel. We also theoretically investigated the electric field distribution dependence on the structural geometry and substrate indices. On the basis of FDTD simulations, we concluded that the electric field was highly amplified in the vicinity of the target analyte owing to a combination of the aerogel's ultralow refractive index and the high-density metallic nanogaps. The aerogel substrate with metallic nanogaps shows great potential for use as an inexpensive, highly sensitive SERS platform to detect environmental and biological target molecules. PMID- 30310145 TI - New targets for cancer immunotherapy. PMID- 30310146 TI - Oncogenic mRNA modification explained. PMID- 30310147 TI - sigma1 Receptor ligand binding: an open-and-shut case. PMID- 30310148 TI - CNS infection and immune privilege. AB - Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNS infections and ask whether immune privilege may provide protection for certain pathogens and promote their latency. PMID- 30310149 TI - Benefit of the MitraClip for mitral regurgitation. PMID- 30310150 TI - Survival not improved by defibrillator VEST. PMID- 30310151 TI - Cardiovascular benefit of albiglutide. PMID- 30310152 TI - Epidemic T2DM, early development and epigenetics: implications of the Chinese Famine. AB - The gene-environment interactions resulting from famine and the subsequent increased intergenerational risk of type 2 diabetes mellitus (T2DM) have contributed to the current epidemic of T2DM in China, which poses major social, health and economic challenges. The epidemic of T2DM could threaten national development in China through premature morbidity and mortality from T2DM and associated non-communicable diseases. The Chinese Famine (1959-1961), as a contributor to the nation's current national T2DM epidemic, provides an important and urgent public health warning. The effects of the famine give a strong message that research and actions that address the prevention of T2DM cannot be confined to lifestyle measures, as used in the landmark Da Qing study and the lifestyle prevention programmes and pharmaceutical interventions used in Western nations. To stem the T2DM epidemic, a new paradigm for prevention of T2DM must be developed. This paradigm should include a very strong emphasis on pregnancy planning and maternal and child health during and after the pregnancy. Without action, intergenerational cycles initiated by epigenetic modifications resulting from adverse environmental stimuli during the critical window of early development in utero might continue to fuel the T2DM epidemic in future generations. PMID- 30310153 TI - The alpha-cell in diabetes mellitus. AB - Findings from the past 10 years have placed the glucagon-secreting pancreatic alpha-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, alpha-cells and beta-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the alpha-cell compartment to serve as a source of new beta-cells in models of extreme beta-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote alpha-cell replication and maintenance of alpha cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus. PMID- 30310155 TI - Root-zone fertilization improves crop yields and minimizes nitrogen loss in summer maize in China. AB - It is urgently to minimize nitrogen (N) loss while simultaneously ensuring high yield for maize in China. A two-year field experiment was conducted to determine the effects of root-zone fertilization (RZF) and split-surface broadcasting (SSB) on grain yield, N use efficiency (NUE), and urea-15N fate under different N rates (135, 180 and 225 kg ha-1). Results showed that RZF increased grain yield by 11.5%, and the N derived from fertilizer (Ndff%) by 13.1-19.6%, compared with SSB. The percentage of residual 15N in the 0-80 cm soil was 37.2-47.4% after harvest; most 15N (64.4-67.4%) was retained in the top 20 cm. RZF significantly increased the N apparent recovery efficiency (NARE) and 15N recovery in maize by 14.3-37.8% and 21.9-30.0%, respectively; while decreased N losses by 11.2-24.2%, compared with SSB. The RZF of urea can be considered a slow-release fertilizer, which better matches maize N demand and effectively reduces N losses. Overall, RZF achieved yields as high as the SSB, but with a 20-25% reduction in N application. These results help improve our understanding of N fate in the maize cropping system, and may help guide recommendations for N management in southeastern China. PMID- 30310154 TI - Quinoxaline protects zebrafish lateral line hair cells from cisplatin and aminoglycosides damage. AB - Hair cell (HC) death is the leading cause of hearing and balance disorders in humans. It can be triggered by multiple insults, including noise, aging, and treatment with certain therapeutic drugs. As society becomes more technologically advanced, the source of noise pollution and the use of drugs with ototoxic side effects are rapidly increasing, posing a threat to our hearing health. Although the underlying mechanism by which ototoxins affect auditory function varies, they share common intracellular byproducts, particularly generation of reactive oxygen species. Here, we described the therapeutic effect of the heterocyclic compound quinoxaline (Qx) against ototoxic insults in zebrafish HCs. Animals incubated with Qx were protected against the deleterious effects of cisplatin and gentamicin, and partially against neomycin. In the presence of Qx, there was a reduction in the number of TUNEL-positive HCs. Since Qx did not block the mechanotransduction channels, based on FM1-43 uptake and microphonic potentials, this implies that Qx's otoprotective effect is at the intracellular level. Together, these results unravel a novel therapeutic role for Qx as an otoprotective drug against the deleterious side effects of cisplatin and aminoglycosides, offering an alternative option for patients treated with these compounds. PMID- 30310157 TI - Clinical utility of expanded carrier screening: results-guided actionability and outcomes. AB - PURPOSE: Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. METHODS: Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. RESULTS: Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. CONCLUSION: ECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring. PMID- 30310156 TI - Effects of Thymoquinone on radiation enteritis in mice. AB - Radiation enteritis is an old but emerging question induced by the application of radiation. However, no effective drugs for radiation enteritis in clinic. In this study, we found that thymoquinone (TQ) could mitigate intestinal damages induced by irradiation. After exposure to irradiation, TQ-treated improved the irradiated mice survival rate, ameliorated intestinal injury and increased the numbers of intestinal crypts. Furthermore, Lgr5+ ISCs and their daughter cells, including Vil1+ enterocytes, Ki67+ cells and lysozyme+ Paneth cells, were all significantly increased with TQ treatment. In addition, P53, gammaH2AX, caspase8, caspase9 and caspase3 expression were all reduced by TQ. Our data showed that TQ modulated DNA damages and decreased the apoptosis in the small intestine. TQ might be used for radiation enteritis treatment. PMID- 30310160 TI - ACE inhibitors preserve cognitive function. PMID- 30310158 TI - Placental FKBP51 mediates a link between second trimester maternal anxiety and birthweight in female infants. AB - Prenatal distress is associated with adverse outcomes in affected offspring. Alterations in placental glucocorticoid signalling and subsequent foetal overexposure to glucocorticoids have been implicated as an underlying mechanism. Infant sex is emerging as an important factor in disease susceptibility. This study aimed to examine the effects of maternal distress across pregnancy on birth outcomes and placental glucocorticoid genes in a sex-dependent manner. Participants completed psychological distress questionnaires throughout pregnancy. Placental HSD11B2, NR3C1 and FKBP51 were analysed by real time PCR and cortisol was measured in new-born hair. Second trimester stress was negatively correlated with birthweight in males and positively correlated with placental NR3C1 mRNA in females. Second trimester anxiety was negatively correlated with birthweight and placental FKBP51 mRNA in females. In mediation analysis, placental FKBP51 mRNA expression was found to mediate the link between prenatal anxiety and birthweight. New-born cortisol was negatively correlated with second trimester anxiety and positively correlated with female placental FKBP51 mRNA levels. Again, FKBP51 mRNA was found to mediate the link between anxiety and new born cortisol. These results highlight a role for FKBP51 in the placental response to prenatal distress in females. The precise role that placental FKBP51 has in foetal and infant development has not been extensively studied and warrants further investigations. PMID- 30310161 TI - Changes in volume of various retinal layers over time in early and intermediate age-related macular degeneration. AB - PURPOSE: To evaluate longitudinally volume changes in inner and outer retinal layers in early and intermediate age-related macular degeneration (AMD) compared to healthy control eyes using optical coherence tomography (OCT). METHODS: 71 eyes with AMD and 31 control eyes were imaged at two time points: baseline and after 2 years. Automated OCT layer segmentation was performed using OrionTM. This software is able to measure volumes of retinal layers with distinct boundaries including Retinal Nerve Fibre Layer (RNFL), Ganglion Cell-Inner Plexiform Layer (GCIPL), Inner Nuclear Layer (INL), Outer Plexiform Layer (OPL), Outer Nuclear Layer (ONL), Photoreceptors (PR) and Retinal Pigment Epithelium-Bruch's Membrane complex (RPE-BM). The mean retinal layer volumes and volume changes at 2 years were compared between groups. RESULTS: Mean GCIPL and INL volumes were lower, while PR and RPE-BM volumes were higher in AMD eyes than controls at baseline (all P < 0.05) and year 2 (all P < 0.05). In AMD eyes, RNFL and ONL volumes decreased by 0.0232 (P = 0.033) and 0.0851 (P = 0.001), respectively. In contrast, OPL and RPE-BM volumes increased in AMD eyes by 0.0391 (P = 0.000) and 0.0209 (P = 0.000) respectively. Moreover, there were significant differences in longitudinal volume change of OPL (P = 0.02), ONL (P = 0.008) and RPE-BM (P = 0.02) between AMD eyes and controls. CONCLUSIONS: There were abnormal retinal layer volumes and volume changes in eyes with early and intermediate AMD. PMID- 30310159 TI - Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells. AB - Limbal epithelial stem cells (LESC) maintenance requires communication between stem cells and neighboring stromal keratocytes. Extracellular vesicles (EVs) are important for intercellular communication in various stem cell niches. We explored the regulatory roles of limbal stromal cell (LSC)-derived exosomes (Exos), an EV sub-population, in limbal epithelial cells (LEC) in normal and diabetic limbal niche and determined differences in Exo cargos from normal and diabetic LSC. Wound healing and proliferation rates in primary normal LEC were significantly enhanced upon treatment by normal Exos (N-Exos), but not by diabetic Exos (DM-Exos). Western analysis showed increased Akt phosphorylation in wounded LECs and organ-cultured corneas treated with N-Exos, compared to untreated wounded cells and DM-Exos treated fellow corneas, respectively. N-Exos treated organ-cultured corneas showed upregulation of putative LESC markers, keratin 15 (K15) and Frizzled-7, compared to the DM-Exos treated fellow corneas. By next generation sequencing, we identified differentially expressed small RNAs including microRNAs in DM-Exos vs. N-Exos. Overall, N-Exos have greater effect on LEC proliferation and wound healing than DM-Exos, likely by activating Akt signaling. The small RNA differences in Exos from diabetic vs. normal LSC could contribute to the disease state. Our study suggests that exosomes may serve as novel therapeutic tools for diabetic cornea. PMID- 30310162 TI - The Impact of Caesarean Section on the Risk of Childhood Overweight and Obesity: New Evidence from a Contemporary Cohort Study. AB - Caesarean section (CS) rates are increasing globally and exceed 50% in some countries. Childhood obesity has been linked to CS via lack of exposure to vaginal microflora although the literature is inconsistent. We investigated the association between CS birth and the risk of childhood obesity using the nationally representative Growing-Up-in-Ireland (GUI) cohort. The GUI study recruited randomly 11134 infants. The exposure was categorised into normal vaginal birth (VD) [reference], assisted VD, elective (planned) CS and emergency (unplanned) CS. The primary outcome measure was obesity defined according to the International Obesity Taskforce criteria. Statistical analysis included multinomial logistic regression with adjustment for potential confounders. Infants delivered by elective CS had an adjusted relative risk ratio (aRRR) = 1.32; [95% confidence interval (CI) 1.01-1.74] of being obese at age three years. This association was attenuated when macrosomic children were excluded (aRRR = 0.99; [95% CI 0.67-1.45]). Infants delivered by emergency CS had an increased risk of obesity aRRR = 1.56; [95% CI 1.20-2.03]; this association remained after excluding macrosomic children. We found insufficient evidence to support a causal relationship between elective CS and childhood obesity. An increased risk of obesity in children born by emergency CS, but not elective, suggests that there is no causal effect due to vaginal microflora. PMID- 30310163 TI - A break in parental interaction does not affect the temporal dependency of infant social engagement, but disrupts non-social engagement. AB - Infant looking patterns during interaction offer an early window into social and nonsocial engagement. Recent evidence indicates that infant looks exhibit temporal dependency-one look duration predicts the next look duration. It is unknown, however, whether temporal dependency emerges as infants structure their own looking or whether it is influenced by interaction. We examined whether a perturbation of social interaction affected temporal dependency. Using the Face to-Face/Still-Face procedure, we compared temporal dependency during parental interaction (the Face-to-Face & Reunion episodes) to parental non-responsiveness (the Still-Face episode). Overall, the durations of successive infant looks were predictable; past behavior constrained current behavior. The duration of one look at the parent (Face Look) predicted the duration of the next Face Look. Likewise, the duration of a look at any place that was not the parent's face (Away Look) predicted the duration of the next Away Look. The temporal dependency of Face Looks (social engagement) was unaffected by the Still-Face perturbation, but the temporal dependency of Away Looks (nonsocial engagement) declined during the Still-Face. Infant temporal structuring of engagement during social looking is not dependent on parental interaction while the disruption of interaction affects infants' structuring of their own non-social engagement. PMID- 30310164 TI - Multi-compartment scaffold fabricated via 3D-printing as in vitro co-culture osteogenic model. AB - The development of in vitro 3D models to get insights into the mechanisms of bone regeneration could accelerate the translation of experimental findings to the clinic, reducing costs and duration of experiments. This work explores the design and manufacturing of multi-compartments structures in poly(epsilon-caprolactone) (PCL) 3D-printed by Fused Filament Fabrication technique. The construct was designed with interconnected stalls to host stem cells and endothelial cells. Cells were encapsulated within an optimised gellan gum (GG)-based hydrogel matrix, crosslinked using strontium (Sr2+) ions to exploit its bioactivity and finally, assembled within compartments with different sizes. Calcium (Ca2+) crosslinked gels were also used as control for comparison of Sr2+ osteogenic effect. The results obtained demonstrated that Sr2+ ions were successfully diffused within the hydrogel matrix and increased the hydrogel matrix strength properties under compressive load. The in vitro co-culture of human-TERT mesenchymal stem cells (TERT- hMSCs) and human umbilical vein endothelial cells (HUVECs), encapsulated within Sr2+ ions containing GG-hydrogels and inter connected by compartmentalised scaffolds under osteogenic conditions, enhanced cell viability and supported osteogenesis, with a significant increase of alkaline phosphatase activity, osteopontin and osteocalcin respect with the Ca2+ crosslinked GG-PCL scaffolds. These outcomes demonstrate that the design and manufacturing of compartmentalised co-culture of TERT-hMSCs and HUVEC populations enables an effective system to study and promote osteogenesis. PMID- 30310165 TI - Physiological changes for drought resistance in different species of Phyllanthus. AB - The Phyllanthus genus is widely distributed in tropical and subtropical areas of the world and present several pharmacological applications. Drought is a restrictive factor for crop development and production, and is becoming a severe problem in many regions of the world. The species Phyllanthus amarus and Phyllanthus niruri were subjected to drought stress for varying periods of time (0, 3, 5, 7, and 10 days), and afterwards, leaves were collected and evaluated for physiological and biochemical responses, such as oxidative stress markers and drought-associated defense mechanisms. Results show that P. amarus has an endogenously higher level of variables of the oxidative/antioxidant metabolism, and P. niruri presents the most significant changes in those variables when compared to control and stressed plants. For both Phyllanthus species, drought stress induces higher levels of organic acids such as malic, succinic, and citric acids, and amino acids such as proline, GABA, alanine, and valine. Moreover, P. niruri plants respond with greater glucose and corilagin contents. Therefore, considering the evaluated metabolic changes, P. amarus is better adapted to drought-stress, while P. niruri presents an acclimation strategy that increases the corilagin levels induced by short-term drought stress. PMID- 30310167 TI - Plasticity of a holobiont: desiccation induces fasting-like metabolism within the lichen microbiota. AB - The role of host-associated microbiota in enduring dehydration and drought is largely unknown. We have used lichens to study this increasingly important problem because they are the organisms that are optimally adapted to reoccurring hydration/dehydration cycles, and they host a defined and persistent bacterial community. The analysis of metatranscriptomic datasets from bacterial communities of the lung lichen (Lobaria pulmonaria (L.) Hoffm.), sampled under representative hydration stages, revealed significant structural shifts and functional specialization to host conditions. The hydrated samples showed upregulated transcription of transport systems, tRNA modification and various porins (Omp2b by Rhizobiales), whereas the desiccated samples showed different functions related to stress adaption prominently. Carbohydrate metabolism was activated under both conditions. Under dry conditions, upregulation of a specialized ketone metabolism indicated a switch to lipid-based nutrition. Several bacterial lineages were involved in a functional transition that was reminiscent of a 'fasting metaorganism'. Similar functional adaptions were assigned to taxonomically unrelated groups, indicating hydration-related specialization of the microbiota. We were able to show that host-associated bacterial communities are well adapted to dehydration by stress protection and changes of the metabolism. Moreover, our results indicate an intense interplay in holobiont functioning under drought stress. PMID- 30310166 TI - An extracellular [NiFe] hydrogenase mediating iron corrosion is encoded in a genetically unstable genomic island in Methanococcus maripaludis. AB - Certain methanogens deteriorate steel surfaces through a process called microbiologically influenced corrosion (MIC). However, the mechanisms of MIC, whereby methanogens oxidize zerovalent iron (Fe0), are largely unknown. In this study, Fe0-corroding Methanococcus maripaludis strain OS7 and its derivative (strain OS7mut1) defective in Fe0-corroding activity were isolated. Genomic analysis of these strains demonstrated that the strain OS7mut1 contained a 12-kb chromosomal deletion. The deleted region, termed "MIC island", encoded the genes for the large and small subunits of a [NiFe] hydrogenase, the TatA/TatC genes necessary for the secretion of the [NiFe] hydrogenase, and a gene for the hydrogenase maturation protease. Thus, the [NiFe] hydrogenase may be secreted outside the cytoplasmic membrane, where the [NiFe] hydrogenase can make direct contact with Fe0, and oxidize it, generating hydrogen gas: Fe0 + 2 H+ -> Fe2+ + H2. Comparative analysis of extracellular and intracellular proteomes of strain OS7 supported this hypothesis. The identification of the MIC genes enables the development of molecular tools to monitor epidemiology, and to perform surveillance and risk assessment of MIC-inducing M. maripaludis. PMID- 30310168 TI - Genome-wide association identifies methane production level relation to genetic control of digestive tract development in dairy cows. AB - The global temperatures are increasing. This increase is partly due to methane (CH4) production from ruminants, including dairy cattle. Recent studies on dairy cattle have revealed the existence of a heritable variation in CH4 production that enables mitigation strategies based on selective breeding. We have exploited the available heritable variation to study the genetic architecture of CH4 production and detected genomic regions affecting CH4 production. Although the detected regions explained only a small proportion of the heritable variance, we showed that potential QTL regions affecting CH4 production were located within QTLs related to feed efficiency, milk-related traits, body size and health status. Five candidate genes were found: CYP51A1 on BTA 4, PPP1R16B on BTA 13, and NTHL1, TSC2, and PKD1 on BTA 25. These candidate genes were involved in a number of metabolic processes that are possibly related to CH4 production. One of the most promising candidate genes (PKD1) was related to the development of the digestive tract. The results indicate that CH4 production is a highly polygenic trait. PMID- 30310170 TI - Retraction Note: Cardiac structural remodeling in hypertensive cardiomyopathy. AB - The authors are retracting this article [1]. In their recent work the authors have found that the degree of fibrosis in the different walls of the left atrium in pigs with hypertensive cardiomyopathy is the same. Sirius Red staining (another method to test for fibrosis) showed that there was no difference between the different walls. The authors are unable to explain this inconsistency. All authors agree with this retraction. PMID- 30310169 TI - The Japanese Society of Hypertension-Digest of plan for the future. PMID- 30310171 TI - Association of histamine with hypertension-induced cardiac remodeling and reduction of hypertrophy with the histamine-2-receptor antagonist famotidine compared with the beta-blocker metoprolol. AB - The association of histamine with adverse cardiac remodeling in chronic pressure overload has not received much attention. A pilot study in spontaneously hypertensive rats (SHRs) indicated a reduction of left ventricular hypertrophy (LVH) with a histamine-2-receptor (H2R) antagonist (famotidine). This finding prompted a detailed investigation of temporal variation in myocardial histamine and H2R expression and the cardiovascular response to H2R antagonism compared with that of the conventional beta-blocker metoprolol. Reduction of LVH is known to reduce the risk of adverse cardiovascular events. The myocardial histamine content and H2R expression increased with age in SHRs but not in normotensive Wistar rats. The cardiovascular response to famotidine (30 mg kg-1) was compared with that of metoprolol (50 mg kg-1) in 6-month-old male SHRs treated for 60 days. The decrease in diastolic blood pressure and improvement in cardiac function induced by famotidine and metoprolol were comparable. Both treatments caused the regression of LVH as assessed from the hypertrophy index, histomorphometry, B type natriuretic peptide (BNP), pro-collagen 1, and hydroxyproline levels. Calcineurin-A expression (marker of pathological remodeling) decreased, and Peroxiredoxin-3 expression (mitochondrial antioxidant) increased in response to the treatments. The myocardial histamine levels decreased with the treatments. The age-dependent increase in myocardial histamine and H2R in the SHRs signifies their association with progressive cardiac remodeling. The regression of LVH and improvement in cardiac function by famotidine further demonstrates the role of histamine in cardiac remodeling. Hypertrophy of cultured cardiac cells upon exposure to histamine and the H2R agonist amthamine substantiates the role of histamine in cardiac remodeling. The cardiovascular response to famotidine is comparable to that of metoprolol, suggesting repurposing of H2R antagonists for the management of hypertensive heart disease. PMID- 30310172 TI - Bayesian spatiotemporal analysis for association of environmental factors with hand, foot, and mouth disease in Guangdong, China. AB - Hand, foot, and mouth disease (HFMD) remains a significant public health and economic burden in parts of China, particularly Guangdong Province. Although the association between meteorological factors and HFMD has been well documented, significant gaps remain in our understanding of the potential impact of environmental factors. Using county-level monthly HFMD data from China CDC and environmental data from multiple sources, we used spatiotemporal Bayesian models to evaluate the association between HFMD and environmental factors including vegetation index, proportion of artificial surface, road capacity, temperature and humidity, and assessed the spatial and temporal dynamic of the association. Statistically significant correlation coefficients from -0.056 to 0.36 (all P < 0.05) were found between HFMD incidence and all environmental factors. The contributions of these factors for HFMD incidence were estimated to be 16.32%, 12.31%, 14.61%, 13.53%, and 2.63%. All environmental factors including vegetation index (Relative Risk: 0.889; Credible Interval: 0.883-0.895), artificial surface (1.028; 1.022-1.034), road capacity (1.033; 1.028-1.038), temperature (1.039; 1.028-1.05), and relative humidity (1.015; 1.01-1.021) were statistically retained in the final spatiotemporal model. More comprehensive environmental factors were identified as associating with HFMD incidence. Taking these environmental factors into consideration for prevention and control strategy might be of great practical significance. PMID- 30310173 TI - Growth and superconductivity of niobium titanium alloy thin films on strontium titanate (001) single-crystal substrates for superconducting joints. AB - Aiming to introduce NbTi alloy superconducting joints for REBa2Cu3O7-delta (REBCO, RE: rare-earth element) superconducting wires, NbTi alloy thin films were deposited at room temperature on SrTiO3 (STO) (001) single-crystal substrates, which have a high lattice matching with REBCO (001). The strain, crystallinity, surface morphology, and superconducting property of the films with various thicknesses were investigated. The NbTi films grew in the orientation with (110)NbTi//(001)STO:[001]NbTi and [11-0] NbTi//[100]STO; that is, the NbTi lattices had two directions in the (110) of NbTi. The strain decreased and the crystallinity improved as the film thickness increased. The films were found to crystallize immediately at the interface between the films and substrates by cross-sectional scanning transmission electron microscopy. The flat surfaces of the films have mesh-like morphologies due to the growth of elongated NbTi grains along the [100] and [010] of the STO, reflecting the in-plane two directions of the NbTi lattices. The superconducting transition temperature of the films increased with improvement in the crystallinity of the films. The preparation of superconducting NbTi alloy thin films with sufficient crystallinity at room temperature suggested the possibility of forming the films on REBCO and the applicability of the films as superconducting joints. PMID- 30310174 TI - Anodal transcranial direct current stimulation prevents methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced neurotoxicity by modulating autophagy in an in vivo mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of protein inclusions and the loss of dopaminergic neurons. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulating technique that has demonstrated promising results in clinical studies of PD. Despite accumulating evidence indicating that tDCS exerts a protective effect, the mechanism underlying its activity remains unknown. In the present study, we first investigated the neuroprotective effect of tDCS in a 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and then evaluated the effect of tDCS on the autophagy pathway. tDCS improved behavioral alterations, increased tyrosine hydroxylase protein levels and suppressed alpha synuclein protein levels in MPTP-treated mice. MPTP-treated mice subjected to tDCS also had lower levels of autophagy-related proteins, such as microtubule associated protein 1 light chain 3 and AMP-activated protein kinase, and higher levels of mechanistic target of rapamycin and p62. In addition, the protein levels of phosphoinositide 3-kinase and brain-derived neurotrophic factor were higher, and the levels of unc-51-like kinase 1 were lower in MPTP-treated mice subjected to tDCS. Our findings suggest that tDCS protected against MPTP-induced PD in a mouse model by modulating autophagy. PMID- 30310175 TI - BCAT1 and miR-2504: novel methylome signature distinguishes spindle/desmoplastic melanoma from superficial malignant peripheral nerve sheath tumor. AB - Superficial/cutaneous malignant peripheral nerve sheath tumor is a rare soft tissue neoplasm that shares morphological, immunohistochemical, and molecular features with spindle/desmoplastic melanoma. We aimed to identify a methylome signature to distinguish these two entities. We analyzed 15 cases of spindle/desmoplastic melanoma and 15 cases of cutaneous malignant peripheral nerve sheath tumor in 23 men and 7 women. DNA from formalin-fixed, paraffin embedded tissues was extracted and processed using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. Using a home-grown informatics pipeline, we identified differentially methylated positions between the two entities. Functional network analysis for enrichment signatures was performed using DAVID tools. Identified differentially methylated positions were compared with the Cancer Genome Atlas's cutaneous melanoma dataset and a recently published malignant peripheral nerve sheath tumor dataset to assess the specificity of the identified signature. Unsupervised hierarchical clustering showed different patterns of methylation in cutaneous malignant peripheral nerve sheath tumor and spindle/desmoplastic melanoma. Two probes, cg20783223 and cg13332552, colocalized in the promoter region of BCAT1 and miR-2504. Pathway analysis highlighted enrichment in a subset of genes involved in breast and gastric cancer centered on BCAT1 and downstream activated genes in the mTOR pathway. Our study identifies BCAT1 as a novel methylome signature distinguishing spindle/desmoplastic melanoma from cutaneous malignant peripheral nerve sheath tumor. PMID- 30310176 TI - Aberrant receptor tyrosine kinase signaling in lipofibromatosis: a clinicopathological and molecular genetic study of 20 cases. AB - Lipofibromatosis is a rare pediatric soft tissue tumor with predilection for the hands and feet. Previously considered to represent "infantile fibromatosis", lipofibromatosis has distinctive morphological features, with mature adipose tissue, short fascicles of bland fibroblastic cells, and lipoblast-like cells. Very little is known about the genetic underpinnings of lipofibromatosis. Prompted by our finding of the FN1-EGF gene fusion, previously shown to be a characteristic feature of calcifying aponeurotic fibroma (CAF), in a morphologically typical case of lipofibromatosis that recurred showing features of CAF, we studied a cohort of 20 cases of lipofibromatosis for this and other genetic events. The cohort was composed of 14 males and 6 females (median age 3 years; range 1 month-14 years). All primary tumors showed classical lipofibromatosis morphology. Follow-up disclosed three local recurrences, two of which contained calcifying aponeurotic fibroma-like nodular calcifications in addition to areas of classic lipofibromatosis, and no metastases. By FISH and RNA sequencing, four cases were positive for FN1-EGF and one case each showed an EGR1 GRIA1, TPR-ROS1, SPARC-PDGFRB, FN1-TGFA, EGFR-BRAF, VCL-RET, or HBEGF-RBM27 fusion. FN1-EGF was the only recurrent fusion, suggesting that some cases of "lipofibromatosis" may represent calcifying aponeurotic fibroma lacking hallmark calcifications. Several of the genes involved in fusions (BRAF, EGFR, PDGFRB, RET, and ROS1) encode receptor tyrosine kinases (RTK), or ligands to the RTK EGFR (EGF, HBEGF, TGFA), suggesting a shared deregulation of the PI3K-AKT-mTOR pathway in a large subset of lipofibromatosis cases. PMID- 30310177 TI - Histopathologic findings in breast surgical specimens from patients undergoing female-to-male gender reassignment surgery. AB - Breast reduction surgery or mastectomy following administration of androgen therapy is part of the female-to-male gender reassignment process. Details regarding the histopathologic findings in breast tissue from patients undergoing female-to-male gender reassignment surgery are limited. We reviewed hematoxylin and eosin-stained sections of breast tissue from 148 patients who underwent breast reduction surgery or mastectomy as part of the female-to-male gender reassignment process at our institution between January 2014 and May 2017. The spectrum of histologic features in each case was catalogued. The median patient age was 27 years (range 18-60 years). Lobular atrophy was seen to some degree in 73% of cases and was prominent in 42%. A predominantly fibrotic stroma was seen in 45% of cases and areas resembling the fibrous stage of gynecomastia were seen in 41%. Other features included variably ectatic ducts in 96% of cases, cysts in 42%, apocrine metaplasia in 32%, fibroadenomatous change in 27%, usual ductal hyperplasia in 26%, and pseudoangiomatous stromal hyperplasia in 19%. Five cases (3%) demonstrated atypical hyperplasia (atypical ductal hyperplasia in 2; atypical lobular hyperplasia in 2; both atypical ductal hyperplasia and atypical lobular hyperplasia in 1). One case demonstrated high grade ductal carcinoma in situ. No invasive carcinomas were identified. In conclusion, the majority of breast specimens from patients undergoing female-to-male gender reassignment demonstrate at least some degree of lobular atrophy as well as ectatic ducts, fibrous stroma, and areas resembling the fibrous stage of gynecomastia. Only rare cases showed atypical lesions; the clinical significance of these lesions in this setting is uncertain. PMID- 30310179 TI - Isolation and structure determination of a new cytotoxic peptide, curacozole, from Streptomyces curacoi based on genome mining. AB - Using genome mining, a new cytotoxic peptide named curacozole was isolated from Streptomyces curacoi. Through ESI-MS and NMR analyses, curacozole was determined to be a macrocyclic peptide containing two isoleucine, two thiazole and three oxazole moieties. Curacozole exhibited potent cytotoxic activity against HCT116 and HOS cancer cells. The proposed biosynthetic gene cluster of curacozole was identified and compared with that of the related compound YM-216391. PMID- 30310178 TI - Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility. AB - Multiple morphological abnormalities of flagella (MMAF) are human reproduction disorders due to the dysplastic development of sperm flagella. The spermatozoa of men with MMAF manifest absent, short, coiled, bent, and/or irregular-caliber flagella. Previous studies revealed genetic contributions to human MMAF, but known MMAF-associated genes only explained approximately 50% MMAF cases. In this study, we employed human whole-exome sequencing for genetic analysis and identified biallelic mutations of CFAP251 (cilia- and flagella-associated protein 251, also known as WDR66) in three (5%) of 65 Han Chinese men with MMAF. All these CFAP251 mutations are loss-of-function. The population genome data suggested that these CFAP251 mutations are extremely rare (only heterozygous) or absent from human populations. Our functional assays of gene expression and immunofluorescence staining in a CFAP251-deficient man, together with previous experimental evidence from model organisms, suggested that CFAP251 is involved in flagellar functions. Our observations suggested that CFAP251 is associated with sperm flagellar development and human male infertility. PMID- 30310181 TI - Potential regrowth of dental tissue with stem cells from baby teeth. PMID- 30310180 TI - Multiplexed, high-throughput measurements of cell contraction and endothelial barrier function. AB - Vascular leakage, protein exudation, and edema formation are events commonly triggered by inflammation and facilitated by gaps that form between adjacent endothelial cells (ECs) of the vasculature. In such paracellular gap formation, the role of EC contraction is widely implicated, and even therapeutically targeted. However, related measurement approaches remain slow, tedious, and complex to perform. Here, we have developed a multiplexed, high-throughput screen to simultaneously quantify paracellular gaps, EC contractile forces, and to visualize F-actin stress fibers, and VE-cadherin. As proof-of-principle, we examined barrier-protective mechanisms of the Rho-associated kinase inhibitor, Y 27632, and the canonical agonist of the Tie2 receptor, Angiopoietin-1 (Angpt-1). Y-27632 reduced EC contraction and actin stress fiber formation, whereas Angpt-1 did not. Yet both agents reduced thrombin-, LPS-, and TNFalpha-induced paracellular gap formation. This unexpected result suggests that Angpt-1 can achieve barrier defense without reducing EC contraction, a mechanism that has not been previously described. This insight was enabled by the multiplex nature of the force-based platform. The high-throughput format we describe should accelerate both mechanistic studies and the screening of pharmacological modulators of endothelial barrier function. PMID- 30310182 TI - Wipes for ultimate loupes care. PMID- 30310183 TI - More whistleblowing cases reported to GDC than any other health regulator. PMID- 30310184 TI - Dentistry and medicine degrees are best value for money. PMID- 30310185 TI - Union seeks views of academic dentists on working in higher education. PMID- 30310186 TI - Unrivalled alternative to amalgam. PMID- 30310187 TI - Mary Vesty (Reeves). PMID- 30310188 TI - Let there be light. PMID- 30310190 TI - Software buy-out. PMID- 30310189 TI - Are you a keen runner? PMID- 30310191 TI - Using photography to enhance GP trainees' reflective practice and professional development. AB - Creative and abstract thinking encouraged by photography. PMID- 30310192 TI - Time to rejuvenate your patient dental chairs? PMID- 30310194 TI - Nearly 900 DCPs risk removal from register over compliance. PMID- 30310193 TI - Paediatric dentists' identification and management of underweight and overweight children. PMID- 30310195 TI - Network, learn and have fun at oral health conference. PMID- 30310196 TI - Minimise your mercury output. PMID- 30310198 TI - Homeless oral care conference. PMID- 30310197 TI - Antibiotic prophylaxis: Back from the brink. PMID- 30310199 TI - Malocclusion: Modern clinical research. PMID- 30310201 TI - Pain-less prevention. PMID- 30310200 TI - Dentists, decay and diet: weighing in on the BMI debate. PMID- 30310202 TI - Dental anomalies - what is referred? And what should be? PMID- 30310204 TI - British National Formulary: Instant interactions online. PMID- 30310205 TI - Dentists seek action to improve school meals. PMID- 30310203 TI - Assessing a training programme for primary care dental practitioners in endodontics of moderate complexity: Pilot data on skills enhancement and treatment outcomes. PMID- 30310207 TI - Easy slide flossers for easy flossing. PMID- 30310206 TI - Exclusive distribution deal announced. PMID- 30310208 TI - BDA AGMs. PMID- 30310210 TI - Toothpaste with a 'heart of glass'. PMID- 30310209 TI - Belongingness and its implications for undergraduate health professions education: a scoping review. AB - Belongingness improves academic performance and student retention. PMID- 30310211 TI - Experts issue guidance on best care for dentures. PMID- 30310212 TI - Add-on innovation. PMID- 30310213 TI - Clinical audit training improves undergraduates' performance in root canal therapy. AB - The standards of record keeping also got better. PMID- 30310215 TI - Advertising watchdog bans Kinder's online games and websites for children. PMID- 30310214 TI - Out of hours: Someone has to do nights. PMID- 30310216 TI - The perfect smile - Part 3. PMID- 30310218 TI - Encouraging surgical flexibility. PMID- 30310217 TI - Workshop for new authors and peer reviewers. PMID- 30310219 TI - Job satisfaction backed by training. PMID- 30310221 TI - HIV/AIDS: Running away? PMID- 30310220 TI - Reflecting... PMID- 30310222 TI - Prevention and empathetic dentistry vital in managing child dental caries. PMID- 30310224 TI - Oral and maxillofacial surgery, three volume set, third edition. PMID- 30310223 TI - Clinicians call for ban on sales of energy drinks to children. PMID- 30310226 TI - Are we all prescribing antibiotics too differently? PMID- 30310225 TI - Exploring the feasibility of general health promotion in UK dental primary care: ENGAGE in Scotland. AB - Introduction Despite UK dental guidance recommending opportunistic health promotion, it's rare for GDPs to discuss more than oral hygiene with their patients. The ENGAGE intervention incorporates UK guidance and evidence-based behaviour change techniques to motivate patients to make lifestyle changes (reduce smoking, alcohol consumption and/or improve diet). It was designed to take less than five minutes and be delivered during a routine dental check-up, and includes a take-home patient handout signposting to free NHS lifestyle counselling helpline services.Aims To determine the feasibility (patient and GDP acceptance) of implementing ENGAGE in Scottish dental primary care. The overall aim is to examine feasibility UK-wide before testing its effectiveness for influencing patient outcomes in a multi-centre UK trial.Methods Study 1: patient survey: N = 1000 adults from all health boards in Scotland were randomly selected from an NHS data base of medical patients and emailed the study invitation and link to an online questionnaire. Study 2: GDP workshop, audit, survey: N = 50 GDPs across Scotland were invited to participate in the training workshop (limited to the first 20 applicants), implement the intervention with their next 20 adult patients in for a check-up, audit their experience, then complete an online questionnaire.Results Study 1: 200 people completed the survey (52% male; 37% were 55 years or younger; 90% had visited their dentist in the previous 12 months). Less than (<) 15% were asked about their smoking, alcohol intake and/or diet when they last visited their dentist for a check-up; <10% would be embarrassed/offended if their dentist or dental hygienist asked them lifestyle questions during a dental check-up; more than (>) 70% would be reassured by the professionalism of their dentist or dental hygienist if they were asked; <4% would be embarrassed/offended if given a leaflet with NHS helpline information by their dentist. Study 2: N = 18 GDPs from nine out of 14 NHS regional health boards in Scotland delivered the ENGAGE intervention to 335 patients (averaging 18 patients each). N = 17/18 participants agreed that this intervention could be delivered during a check-up, was an improvement on what they currently did and thought that it may make a difference to what their patients thought, felt, and/or did about reducing health risk.Conclusion The ENGAGE intervention is feasible to implement in Scottish dental primary care. Comments from patient and GDP participants will inform its development and further feasibility studies set in other UK regions. PMID- 30310227 TI - Growing dental corporate. PMID- 30310229 TI - Indemnity policies for all. PMID- 30310228 TI - Relationships: Intimacy and ambiguity. PMID- 30310230 TI - The easy way to successful regeneration. PMID- 30310231 TI - Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. AB - This corrects the article DOI: 10.1038/nrd.2018.136. PMID- 30310232 TI - Cancer stem cell pipeline flounders. PMID- 30310233 TI - Drug repurposing: progress, challenges and recommendations. AB - Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing. PMID- 30310235 TI - Patent watch: Selective GABAA receptor modulators: intellectual property landscape. PMID- 30310237 TI - Capitation care fee banding: aspects of reliability and validity of an online tool. PMID- 30310238 TI - Effect of cold stratification on seed germination in Solidago * niederederi (Asteraceae) and its parental species. AB - In this study, we investigated the influence of cold stratification on seed germination in S. * niederederi, a hybrid between the North American S. canadensis and the European S. virgaurea, using fruit samples collected in 2016 in Poland. We aimed to test the hypothesis that the low temperature exposure decreases the final percentage and speed of seed germination in the hybrid and its parental species. For each species, sets of 100 achenes in three replications were mixed with dry sand and stored in Petri dishes in darkness for 12 weeks, at 18 degrees C and + 4 degrees C, and + 25 degrees C. The seeds were incubated for 21 d at room temperature (+25 degrees C), under the 12 h photoperiod (630 lx). We showed a lack of significant differences in: (i) the final percentage of germinated seeds of studied species stored at the same conditions, (ii) the final percentage of germinated seeds between the applied stratification conditions in the hybrid and its parental species, and (iii) the mean values of Timson's index, mean germination time, and coefficient of velocity of germination between the stratification conditions in each species. The statistically significant inter specific differences in the mean germination time parameter after the +25 degrees C treatment suggest that the seeds of S. * niederederi are able to germinate faster than the seeds of its parental species. However, to improve our knowledge of naturalization and invasion abilities of S. * niederederi by sexual reproduction, the seed germination and seedling survival of the hybrid should be tested in the field. PMID- 30310239 TI - Non-random extinctions dominate plant community changes in abandoned coppices. AB - 1. The plant community structure of European lowland forests has changed dramatically in the 20th century, leading to biodiversity decline at various spatial scales. However, due to methodological difficulties associated with simultaneous changes in species diversity and composition, ecological processes behind the changes are still poorly understood. 2. We analysed temporal changes in forest plant community after the mid-20th century abandonment of coppicing in a typical Central European forest, which had been managed as coppice for centuries. We used 122 semi-permanent plots first surveyed in the 1950s shortly after the last coppicing and again in the 2000s after half a century of natural succession. We used a novel Temporal Nestedness Analysis to disentangle the immigration and extinction processes underlying temporal changes in community structure and tested whether species gains and losses were ecologically random. 3. The studied vegetation has shifted from the species-rich assemblages of a relatively open and low-nutrient forest towards the impoverished flora of a closed-canopy forest dominated by a few shade-adapted species. The significant reduction of beta diversity, i.e. compositional heterogeneity among plots, indicated taxonomic homogenization of the forest understorey. Temporal species turnover was only a minor component of the community change and recent assemblages are nested subsets of the former ones. Ecologically non-random extinctions dominated these changes. Light-demanding species with a persistent seed-bank were the most prone to extinction, while species with high specific leaf area substantially increased in frequency. 4. Synthesis and applications. The dominant process after the abandonment of coppicing was the ecologically non random extinction of light-demanding species leading to an impoverished, temporally nested plant community structure. This development is typical for many abandoned lowland coppice forests and poses a significant threat to forest biodiversity in Europe. If forestry and conservation policies continue to prefer closed-canopy stands, many endangered species are likely to pay their extinction debts. To restore declining or even locally extinct species, canopy opening in abandoned coppices is urgently needed. PMID- 30310240 TI - Potent HIV-1 Protease Inhibitors: Stereoselective Synthesis of a Dipeptide Mimic. AB - The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity. PMID- 30310241 TI - Plant trait effects on soil organisms and functions. AB - Global change alters the composition and functioning of ecosystems by creating novel environmental conditions and thereby selecting for specific traits of organisms. Thus, trait-based approaches are promising tools to more mechanistically understand compositional and functional shifts in ecological communities as well as the dependency of response and effect traits upon global change. Such approaches have been particularly successful for the study of plant communities in terrestrial ecosystems. However, given the intimate linkages between aboveground and belowground compartments as well as the significance of plants as integrating organisms across those compartments, the role of plant traits in affecting soils communities has been understudied. This special issue contains empirical studies and reviews of plant trait effects on soil organisms and functions. Based on those contributions, we discuss here plasticity in trait expression, the context-dependency of plant trait effects, time lags in soil biotic responses to trait expression, and limitations of measured plant traits. We conclude that plant trait-based approaches are an important tool to advance soil ecological research, but also identify critical limitations and next steps. PMID- 30310242 TI - STEREOCONTROLLED SYNTHESIS OF HIV-l PROTEASE INHIBITORS WITH C2-AXIS OF SYMMETRY. AB - An efficient and stereocontrolled synthesis of various C2-symmetric HIV-l protease inhibitors is described, starting from commercially available and inexpensive D-mannitol. PMID- 30310234 TI - Regulatory T cells in the treatment of disease. AB - Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer. PMID- 30310243 TI - N,N'-Disuccinimidyl Carbonate: A Useful Reagent for Alkoxycarbonylation of Amines. AB - An efficient and mild method for alkoxycarbonylation of amines is described, utilizing commercially available N,N'-disuccinimidyl carbonate. PMID- 30310244 TI - INTRAMOLECULAR AND INTERMOLECULAR HYDROXYL REACTIVITY DIFFERENCES IN GINKGOLIDES A, B AND C AND THEIR CHEMICAL APPLICATIONS. AB - An investigation of the chemistry of ginkgolides A, B and C (1) has revealed an unusual interaction between the hydroxyl groups at C(1) and C(10) which activates their deprotonation to give 2 and provides a method for the interconversion of 1C and 1B. The ginkgolide 7-enol system 7 is more stable than the corresponding 7 keto form 6, which is easily made by selective Jones oxidation of ginkgolide C. PMID- 30310236 TI - Therapeutic strategies targeting connexins. AB - The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges. PMID- 30310245 TI - SYNTHESIS AND OPTICAL RESOLUTION OF HIGH AFFINITY P2-LIGANDS FOR HIV-1 PROTEASE INHIBITORS. AB - Racemic bis-tetrahydrofuran ligand 6 was efficiently synthesized utilizing catalytic cobaloxime 10 mediated radical cyclization as the key step. Optical resolution of the racemic alcohol with immobilized-Amano lipase, afforded optically pure ligands. PMID- 30310246 TI - Geographical Distances Between Separated Parents: A Longitudinal Analysis. AB - Using detailed geocoded microdata from the British Household Panel Survey and longitudinal random-effects models, we analyse the determinants and trajectories of geographical distances between separated parents. Findings of particular note include the following: (1) post-separation linked lives, proximities and spatial constraints are characterised by important gender asymmetries; (2) the formation of new post-separation family ties (i.e. new partners and children) by fathers is linked to moves over longer distances away from the ex-partner than for mothers; (3) the distribution of pre-separation childcare responsibilities is relevant for determining post-separation proximity between parents; and (4) most variation in the distance between ex-partners occurs in the immediate period following separation (approximately the first year), suggesting that the initial conditions around separation can have long-lasting implications for the types of family life, ties and contact experienced in the years after separation. PMID- 30310247 TI - Regional Diffusion of Divorce in Turkey. AB - While demographic change has been well documented for many Western countries, much less is known about demographic transitions in other countries, including Turkey. Demographic change in European societies can be characterized by, amongst others, increased prevalence of divorce. Although it is often argued that life courses in Turkey follow a more traditional path, little is known on determinants and patterns of divorce, despite the major socioeconomic changes Turkey has undergone over the past decades. We study the levels of divorce of women in Turkey from 1973 to 2008 to explain patterns of divorce, looking at the role of individual characteristics and the regional context. We use the Demographic Health Surveys (2003/2008), complemented with regional data on divorce, urbanization, and GDP per capita. Applying a multilevel approach, distinguishing 12 regions, we hypothesize that regions where divorce is already more prevalent, more urbanized regions, and wealthier regions in terms of GDP per capita will increase the probability of divorce. Our analyses show that levels of divorce increased over the past decades but huge regional variation remains. Sociocultural and socioeconomic factors explain this trend, and in particular urbanization and GDP per capita are key determinants for divorce. PMID- 30310249 TI - Screening and analysis of acetyl-cholinesterase (AChE) inhibitors in the context of Alzheimer's disease. AB - Acetyl-cholinesterase enzyme (AChE) is a known target for identifying potential inhibitors against Alzheimer diseases (AD). Therefore, it is of interest to screen AChE with the CNS-BBB database. An AChE enzyme is a member of hydrolase family is activated by acetylcholine (ACh), so, targeting the AChE enzyme with the potential inhibitor may block the binding of the ACh. In this study we carried out virtual screening of drug-like molecules from Chemical Diversity Database particularly CNS-BBB compounds, to identify potential inhibitors using Glide docking program. Top ranking ten compounds, which have lower Glide Score when compared to known drugs (Tacrine and Galantamine) for AChE. For top three molecules MD simulation was carried out and calculated binding free energy. We report the best binding compounds with AChE compared to known drugs (Taine and Galantamine) for AD. We further document the salient features of their molecular interaction with the known target. Three molecules (1-benzyl-3-(2- hydroxyethyl) N-[2-(3-pyridyl)ethyl]-3-pyrrolidinecarboxamide, N-{3[benzyl(methyl)amino]propyl} 1,5-dimethyl-4-oxo-4,5-dihydro- 1H-pyrrolo[3,2-c]quinoline-2-carboxamide, and 6 chloro-N-[2-(diethylamino)-2-phenylethyl]-4-oxo-4H-chromene-2-carboxamide) have 196.36, -204.27, -214.40 kJ/mol, binding free energy values respectively which are much lower than values calculated for the reference ligands Tacrine and Galantamine having -119.65 and -142.18 kJ/mol respectively. Thus these molecules can be very novel potential inhibitors against AChE involved in Alzheimer's disease. PMID- 30310250 TI - Phytochemical analysis and broad spectrum antimicrobial activity of ethanolic extract of Jasminum mesnyi Hance leaves and its solventpartitioned fractions. AB - Jasminum mesnyi Hance (yellow jasmine, Family Oleaceae) belongs to an important subclass of Jasminum family whose biological significance is under explored. The current study pertains to isolation of various solvent extracts fractions and their anti-bacterial effects on the Gram-positive and Gram-negative bacterial pathogens. Ethanolic extract of J. mesnyi Hance leaves was subjected to further partitioning using different solvents with increasing polarity to get different solvent fractions. Different extracts were analysed for their phytochemical constitutents and were evaluated for their antibacterial activity against a number of diseases causing bacteria. Diethylether fraction (DEF) showed remarkable inhibition of growth of Aeromonas hydrophila and Vibrio parahaemolyticus with inhibition zones of 17 and 19mm, respectively at 250 MUg. On the other hand, the hexane fraction (HF) was found to be more effective against Gram- positive test bacterial pathogens (Bacillus anthracis and Bacillus subtilis) with inhibition zones of 19.6 mm and 17.5 mm, respectively. The phytochemical screening of different test fractions revealed the predominant presence of cardiac glycosides, sterols and terpenoids in DEF and HF, while Ethylacetate fraction (EAF) and methanol fractions (MF) were found rich in flavonoids and phenols with moderate amount of other reference metabolites. PMID- 30310251 TI - In silico analysis of onion chitinases using transcriptome data. AB - Chitinases are glycoside hydrolase (GH) family of proteins having multifaceted roles in plants. It is of interest to identify and characterize chitinase encoding genes from the popular bulbous plant onion (Allium cepa L.). We have used the EST sequences for onion chitinases to elucidate its functional features using sequence, structure and functional analysis. These contigs belong to the GH19 chitinases family according to domain architecture analysis. They have highly conserved chitinase motifs including motifs exclusive to plant chitinases as implied using the MEME based structural characterization. Estimation of biochemical properties suggested that these proteins have features to form stable and hydrophilic proteins capable of localizing extracellular and in vacuoles. Further, they have multiple cellular processes including defense role as inferred by DeepGO function prediction. Phylogenetic analysis grouped them as class I and class VII plant chitinase, with possible abundance of class I chitinase in onion. These observations help in the isolation and functional validation of onion chitinases. PMID- 30310252 TI - Bioinformation Informs the Allostasiome: Translational Environmental Restoration (TER) for the Climate Crisis Medical Emergency. AB - Health care is optimized when the best evidence base (BEB) is translated into policies whose effectiveness can be verified. Bioinformation disseminates BEB and is critical to translational health care. The survival of all prokaryotes and eukaryotes, including mammals, and ultimately our species, depends upon their ability to adapt to changes in their micro-environmental milieu and to the challenges of their surrounding macro-environment. Disturbances in the organism's macro-environment, such as the stressful stimuli derived from environmental changes akin to the current climate crisis, alter its physiological, cytological, biological, epigenetic and molecular microenvironment, and trigger concerted allostatic responses to regain homeostasis. Individual patient data analysis advocates the allostasiome as the specific pattern of biological events and pathways each individual organism undergoes to regain a balanced state of homeostasis following macro-environmental insults. Translational Environmental Restoration (TER) is the translation of BEB in climate change research into effective and efficacious policies for restorative renewal of our macro environment. Patient-centered translational health care in the current climate crisis depends upon defining and characterizing the allostasiome as a complex systemic process intertwined with TER. Bioinformation is timely and critical to climate crisis research in general and to TER specifically, because it informs and disseminates the best available evidence for each subject's allostasiome. Concerted research must define and characterize BEB of the multi-dimensional medical emergency produced by the current climate crisis. Novel lines of investigation, including allostasione research, increasingly depend on bioinformation for dissemination, and are foundational for TER, one plausible solution to this complex health care crisis. PMID- 30310248 TI - Risk Factors for Antisocial Behavior in Low- and Middle-Income Countries: A Systematic Review of Longitudinal Studies. AB - Violent crime is a major cause of social instability, injury, and death in low- and middle-income countries. Longitudinal studies in high-income countries have provided important evidence on developmental precursors of violence and other antisocial behaviors. However, there may be unique influences or different risk factor effects in other social settings. Extensive searches in seven languages and screening of over 60,000 references identified 39 longitudinal studies of antisocial behavior in low- and middle-income countries. Many risk factors have roughly the same average effects as when studied in high-income countries. Stability of aggression over a 3-year period is almost identical across low- and middle-income countries and high-income countries. Dimensions of comorbid psychopathology such as low self-control, hyperactivity, and sensation seeking are associated with antisocial behavior in low- and middle-income countries, but some early physical health factors have consistently weak or null effects. PMID- 30310253 TI - Towards Personalized Medicine: An Improved De Novo Assembly Procedure for Early Detection of Drug Resistant HIV Minor Quasispecies in Patient Samples. AB - The third-generation sequencing technology, PacBio, has shown an ability to sequence the HIV virus amplicons in their full length. The long read of PaBio offers a distinct advantage to comprehensively understand the virus evolution complexity at quasispecies level (i.e. maintaining linkage information of variants) comparing to the short reads from Illumina shotgun sequencing. However, due to the highnoise nature of the PacBio reads, it is still a challenge to build accurate contigs at high sensitivity. Most of previously developed NGS assembly tools work with the assumption that the input reads are fairly accurate, which is largely true for the data derived from Sanger or Illumina technologies. When applying these tools on PacBio high-noise reads, they are largely driven by noise rather than true signal eventually leading to poor results in most cases. In this study, we propose the de novo assembly procedure, which comprises a positivefocused strategy, and linkage-frequency noise reduction so that it is more suitable for PacBio high-noise reads. We further tested the unique de novo assembly procedure on HIV PacBio benchmark data and clinical samples, which accurately assembled dominant and minor populations of HIV quasispecies as expected. The improved de novo assembly procedure shows potential ability to promote PacBio technology in the field of HIV drug-resistance clinical detection, as well as in broad HIV phylogenetic studies. PMID- 30310254 TI - Focus on the gut-brain axis: Multiple sclerosis, the intestinal barrier and the microbiome. AB - The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results. PMID- 30310255 TI - Hepatocellular carcinoma in Latin America: Diagnosis and treatment challenges. AB - Latin America, a region with a population greater than 600000000 individuals, is well known due to its wide geographic, socio-cultural and economic heterogeneity. Access to health care remains as the main barrier that challenges routine screening, early diagnosis and proper treatment of hepatocellular carcinoma (HCC). Therefore, identification of population at risk, implementation of surveillance programs and access to curative treatments has been poorly obtained in the region. Different retrospective cohort studies from the region have shown flaws in the implementation process of routine surveillance and early HCC diagnosis. Furthermore, adherence to clinical practice guidelines recommendations assessed in two studies from Brazil and Argentina demonstrated that there is also room for improvement in this field, similarly than the one observed in Europe and the United States. In summary, Latin America shares difficulties in HCC decision making processes similar to those from developed countries. However, a transversal limitation in the region is the poor access to health care with the consequent limitation to standard treatments for overall population. Specifically, universal health care access to the different World Health Organization levels is crucial, including improvement in research, education and continuous medical training in order to expand knowledge and generation of data promoting a continuous improvement in the care of HCC patients. PMID- 30310257 TI - Colonoscopy attachments for the detection of precancerous lesions during colonoscopy: A review of the literature. AB - Although colonoscopy has been proven effective in reducing the incidence of colorectal cancer through the detection and removal of precancerous lesions, it remains an imperfect examination, as it can fail in detecting up to almost one fourth of existing adenomas. Among reasons accounting for such failures, is the inability to meticulously visualize the colonic mucosa located either proximal to haustral folds or anatomic curves, including the hepatic and splenic flexures. In order to overcome these limitations, various colonoscope attachments aiming to improve mucosal visualization have been developed. All of them - transparent cap, Endocuff, Endocuff Vision and Endorings - are simply mounted onto the distal tip of the scope. In this review article, we introduce the rationale of their development, present their mode of action and discuss in detail the effect of their implementation in the detection of lesions during colonoscopy. PMID- 30310258 TI - VSL#3 can prevent ulcerative colitis-associated carcinogenesis in mice. AB - AIM: To investigate the effects of VSL#3 on tumor formation, and fecal and intestinal mucosal microbiota in azoxymethane/dextran sulfate sodium (AOM/DSS) induced mice model. METHODS: C57BL/6 mice were administered AOM/DSS to develop the ulcerative colitis (UC) carcinogenesis model. Mice were treated with 5-ASA (75 mg/kg/d), VSL#3 (1.5 * 109 CFU/d), or 5-ASA combined with VSL#3 by gavage from the day of AOM injection for three months (five days/week). The tumor load was compared in each group, and tumor necrosis factor (TNF-alpha) and interleukin (IL)-6 levels were evaluated in colon tissue. The stool and intestinal mucosa samples were collected to analyze the differences in the intestinal microbiota by 16s rDNA sequencing method. RESULTS: VSL#3 significantly reduced the tumor load in AOM/DSS-induced mice model and decreased the level of TNF-alpha and IL-6 in colon tissue. The model group had a lower level of Lactobacillus and higher level of Oscillibacter and Lachnoclostridium in fecal microbiota than the control group. After the intervention with 5-ASA and VSL#3, Bacillus and Lactococcus were increased, while Lachnoclostridium and Oscillibacter were reduced. 5-ASA combined with VSL#3 increased the Lactobacillus and decreased the Oscillibacter. The intestinal mucosal microbiota analysis showed a lower level of Bifidobacterium and Ruminococcaceae_UCG-014 and higher level of Alloprevotella in the model group as compared to the control group. After supplementation with VSL#3, Bifidobacterium was increased. 5-ASA combined with VSL#3 increased the level of both Lachnoclostridium and Bifidobacterium. CONCLUSION: VSL#3 can prevent UC associated carcinogenesis in mice, reduce the colonic mucosal inflammation levels, and rebalance the fecal and mucosal intestinal microbiota. PMID- 30310256 TI - New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. AB - The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients. PMID- 30310259 TI - Potential involvement of heat shock proteins in pancreatic-duodenal homeobox-1 mediated effects on the genesis of gastric cancer: A 2D gel-based proteomic study. AB - AIM: To identify functional proteins involved in pancreatic-duodenal homeobox-1 (PDX1)-mediated effects on gastric carcinogenesis. METHODS: A PDX1-overexpressed model was established by transfecting gastric cancer cell line SGC7901 with pcDNA3.1(+)-PDX1 vector (SGC-PDX1). Transfection with empty pcDNA3.1 vector (SGC pcDNA) served as control. Comparative protein profiles of the two groups were analyzed by two-dimensional electrophoresis based-proteomics (2DE gel-based proteomics). The differential proteins identified by 2DE were further validated by qRT-PCR and immunoblotting. Finally, co-immunoprecipitation was used to determine any direct interactions between PDX1 and the differential proteins. RESULTS: 2DE gel proteomics identified seven differential proteins in SGC-PDX1 when compared with those in SGC-pcDNA. These included four heat shock proteins (HSPs; HSP70p1B, HSP70p8, HSP60, HSP27) and three other proteins (ER60, laminin receptor 1, similar to epsilon isoform of 14-3-3 protein). Immunoblotting validated the expression of the HSPs (HSP70, HSP60, HSP27). Furthermore, their expressions were lowered to 80%, 20% and 24%, respectively, in SGC-PDX1, while PDX1 exhibited a 9-fold increase, compared to SGC-pcDNA. However, qRT-PCR analysis revealed that mRNA levels of the HSPs were increased in SGC-PDX1, suggesting that the expression of the HSPs was post-translationally regulated by the PDX1 protein. Finally, co-immunoprecipitation failed to identify any direct interaction between PDX1 and HSP70 proteins. CONCLUSION: This study demonstrates the potential involvement of HSPs in PDX1-mediated effects on the genesis of gastric cancer. PMID- 30310260 TI - Evaluation of elastography combined with serological indexes for hepatic fibrosis in patients with chronic hepatitis B. AB - AIM: To investigate the value of ultrasound elastography combined with serological indexes in diagnosing liver fibrosis and assessing its severity. METHODS: A total of 338 chronic hepatitis B (CHB) patients were divided into a disease group (patients with hepatic fibrosis) and control group (subjects without hepatic fibrosis). The disease group was further divided into S1-S4 according to the degree of fibrosis. Independent risk factors for hepatic fibrosis were analyzed using multivariate logistic regression. The diagnostic values of hepatic fibrosis from different indicators were compared using receiver operating characteristic (ROC) curves. The combination of elastography and serological indexes was explored to assess the severity of hepatic fibrosis. RESULTS: The multivariate logistic regression analysis results revealed that shear wave velocity (SWV), hyaluronic acid (HA), type IV collagen (CIV) and aspartate aminotransferase-to-platelet ratio index (APRI) significantly affected the occurrence of hepatic fibrosis. The ROC curve revealed that the accuracy of the diagnosis of hepatic fibrosis for SWV and HA were 87.3% and 84.8%, respectively. The accuracy of SWV combined with HA was 88.9%. The multiple linear regression analysis revealed that SWV, aspartate aminotransferase (AST)/alanine aminotransferase (ALT), HA, CIV, APRI and fibrosis index based on the 4 factor (FIB-4) were screened as statistically significant independent factors. The established regression equation was: Fibrosis level = -4.046 + 1.024 * SWV + 1.170 * AST/ALT + 0.011 * HA + 0.020 * CIV + 0.719 * APRI + 0.379 * FIB-4. CONCLUSION: SWV combined with serological indexes can improve the accuracy of diagnosis for CHB hepatic fibrosis. Serum indexes can help diagnose the degree of hepatic fibrosis. PMID- 30310261 TI - Risk factors for liver disease among adults of Mexican descent in the United States and Mexico. AB - AIM: To compare the prevalence of chronic liver disease (CLD) risk factors in a representative sample of Mexican-Americans born in the United States (US) or Mexico, to a sample of adults in Mexico. METHODS: Data for Mexican-Americans in the US were obtained from the 1999-2014 National Health and Nutrition Examination Survey (NHANES), which includes persons of Mexican origin living in the US (n = 4274). The NHANES sample was restricted to Mexican-American participants who were 20 years and older, born in the US or Mexico, not pregnant or breastfeeding, and with medical insurance. The data in Mexico were obtained from the 2004-2013 Health Worker Cohort Study in Cuernavaca, Mexico (n = 9485). The following known risk factors for liver disease/cancer were evaluated: elevated aminotransferase levels (elevated alanine aminotransferase was defined as > 40 IU/L for males and females; elevated aspartate aminotransferase was defined as > 40 IU/L for males and females), infection with hepatitis B or hepatitis C, metabolic syndrome, high total cholesterol, diabetes, obesity, abdominal obesity, and heavy alcohol use. The main independent variables for this study classified individuals by country of residence (i.e., Mexico vs the US) and place of birth (i.e., US-born vs Mexico born). Regression analyses were used to investigate CLD risk factors. RESULTS: After adjusting for socio-demographic characteristics, Mexican-American males were more likely to be obese, diabetic, heavy/binge drinkers or have abdominal obesity than males in Mexico. The adjusted multivariate results for females also indicate that Mexican-American females were significantly more likely to be obese, diabetic, be heavy/binge drinkers or have abdominal obesity than Mexican females. The prevalence ratios and prevalence differences mirror the multivariate analysis findings for the aforementioned risk factors, showing a greater risk among US-born as compared to Mexico-born Mexican-Americans. CONCLUSION: In this study, Mexican-Americans in the US had more risk factors for CLD than their counterparts in Mexico. These findings can be used to design and implement more effective health promotion policies and programs to address the specific factors that put Mexicans at higher risk of developing CLD in both countries. PMID- 30310262 TI - Cerebral lipiodol embolism related to a vascular lake during chemoembolization in hepatocellular carcinoma: A case report and review of the literature. AB - A male patient underwent conventional transcatheter chemoembolization for advanced recurrent hepatocellular carcinoma (HCC). Even after the injection of 7 mL of lipiodol followed by gelatin sponge particles, the flow of feeding arteries did not slow down. A repeat angiography revealed a newly developed vascular lake draining into systemic veins; however, embolization was continued without taking noticing of the vascular lake. The patient's level of consciousness deteriorated immediately after the procedure, and non-contrast computed tomography revealed pulmonary and cerebral lipiodol embolisms. The patient's level of consciousness gradually improved after 8 wk in intensive care. In this case, a vascular lake emerged during chemoembolization and drained into systemic veins, offering a pathway carrying lipiodol to pulmonary vessels, the most likely cause of this serious complication. We should be aware that vascular lakes in HCC may drain into systemic veins and can cause intratumoral arteriovenous shunts. PMID- 30310263 TI - Activator protein-1 contributes to the NaCl-induced expression of VEGF and PlGF in RPE cells. AB - Purpose: Systemic hypertension is a risk factor of neovascular age-related macular degeneration; consumption of dietary salt resulting in extracellular hyperosmolarity is a main cause of hypertension. Extracellular hyperosmolarity was shown to induce expression of angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), in RPE cells. The aim of the present study was to determine whether the hyperosmotic expression of growth factor genes in RPE cells is mediated by activator protein-1 (AP-1), and whether c-Fos and c-Jun genes are regulated by extracellular osmolarity. Methods: Hyperosmotic media were made up with the addition of NaCl or sucrose. Gene expression was quantified with real-time reverse transcription (RT) PCR, and protein secretion was investigated with enzyme-linked immunosorbent assay (ELISA). Nuclear factor of activated T cell 5 (NFAT5) was depleted with siRNA. DNA binding of AP-1 protein was evaluated with electrophoretic mobility shift assay (EMSA). Results: High NaCl and the addition of sucrose triggered expression of the c-Fos gene, but not of the c-Jun gene. High NaCl also increased the levels of c-Fos and phosphorylated c-Jun proteins and the level of DNA binding of AP-1. Hypoosmolarity decreased the expression of the c-Fos and c-Jun genes. NaCl-induced expression of the c-Fos gene was in part mediated by NFAT5. Autocrine/paracrine activation of fibroblast growth factor and adenosine A1 receptors is involved in mediating NaCl-induced expression of the c-Fos gene. Pharmacological inhibition of the AP-1 activity decreased the NaCl-induced expression of the HIF-1alpha, NFAT5, VEGF, PlGF, and TGF-beta2 genes, and prevented the NaCl-induced secretion of PlGF but not of VEGF. Conclusions: The data indicate that AP-1 is activated in RPE cells in response to extracellular hyperosmolarity and mediates in part via the NaCl-induced expression of VEGF and PlGF, and secretion of PlGF. It is suggested that high consumption of dietary salt may exacerbate the angiogenic response of RPE cells in part via activation of AP-1. PMID- 30310264 TI - Microbiological study of dacryocystitis in northwest of Iran. AB - Background: The prevalence of bacterial pathogens isolated from patients with acute and chronic dacryocystitis and the pattern of antibiotic susceptibility tests are varied in each region. Moreover, the management of dacryocystitis is only based on clinical observations without microbiological evaluation. The present study aimed to identify epidemiologic and etiologic factors of dacryocystitis in our geographical area. Materials and methods: This cross sectional and analytical study was carried out in the ophthalmology department of Hamadan University of Medical Sciences (northwest of Iran) during 2016-2017. Nasolacrimal duct discharges were inoculated to culture media including blood agar, eosin methylene blue, chocolate agar, and Sabouraud agar for the determination of microbial agents. Disc diffusion method with MAST antibiogram discs was used for antibiotic susceptibility tests, according to the Clinical and Laboratory Standards Institute, 2017. Results: Of the total 129 patients enrolled in the study, 34.1% had acute dacryocystitis and 65.9% showed chronic type. The result of culture was positive in 75.2% of patients. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Pseudomonas spp., and Candida albicans were the most prevalent microorganisms. The most sensitive antibiotics used against prevalent bacteria were ciprofloxacin (75.9%), ceftriaxone (73.6%), vancomycin (67.8%), and chloramphenicol (60.9%), respectively. Conclusion: The present study is useful for determining the appropriate antibiotic for systemic treatment of dacryocystitis in our region. Ciprofloxacin and vancomycin are the most sensitive antibiotics against the most common isolated microorganisms in both age groups (under and above 10 years) that can be used for empirical therapy of dacryocystitis in both acute and chronic type. PMID- 30310266 TI - Blind spots in medical students with color vision deficiency. PMID- 30310265 TI - Comparison of central corneal thickness measurements in corneal edema using ultrasound pachymetry, Visante anterior-segment optical coherence tomography, Cirrus optical coherence tomography, and Pentacam Scheimpflug camera tomography. AB - Purpose: To compare the central corneal thickness (CCT) measurements in subjects with corneal edema using ultrasound pachymetry, Visante anterior-segment optical coherence tomography (OCT), Cirrus OCT, and Pentacam Scheimpflug camera tomography. Methods: This prospective cross-sectional study included 46 eyes of 33 patients with corneal edema and a CCT exceeding 550 MUm evaluated by ultrasound pachymetry, Visante OCT, Cirrus OCT, and Pentacam. Two observers measured each eye twice. Intraobserver and interobserver reproducibility were determined and agreement among the devices calculated. Results: CCT was measured in 40 eyes of 29 patients. Regardless of the CCT, the measurements obtained using Visante OCT, Cirrus CCT, and ultrasound pachymetry were well correlated. Interobserver and intraobserver reproducibility were high among the three devices. Pentacam overestimated the results compared with the other devices, and ultrasound pachymetry was unmeasurable in six (13%) eyes with very thick and opaque corneas. In eyes with mild corneal edema (CCT 551-650 MUm), measurements from the four devices were comparable. Conclusion: All devices reliably measured the CCT <650 MUm. In eyes with edema exceeding 650 MUm, CCT measurements from the Visante OCT, Cirrus OCT, and ultrasound pachymetry devices showed good reproducibility and were well correlated, while the Pentacam overestimated the values compared to the other devices. Pentacam and ultrasound pachymetry should not be used in eyes with extreme corneal edema and opacity. PMID- 30310268 TI - Characteristics of diabetic macular edema on optical coherence tomography may change over time or after treatment. AB - Purpose: To investigate optical coherence tomography (OCT) characteristics in diabetic macular edema (DME) over time and after treatment. Patients and methods: OCT morphological features in DME eyes treated with ranibizumab with at least 1 year of follow-up were retrospectively analyzed. Results: Thirty-five eyes were included. From baseline to Month 12, mean visual gain was 7.2+/-13.6 letters and mean central retinal thickness reduction was 61.9+/-121.8 MUm. Fovea-involving ellipsoid zone (EZ) disruption was significantly associated with final vision of <70 letters. Subretinal fluid at baseline was present only in eyes naive to previous intravitreal pharmacotherapy and was related to better visual gain and fewer injections. Treatment-naive eyes had shorter DME duration and less EZ damage. Conclusion: DME characteristics on OCT may change over time or after treatment. Subretinal fluid may be associated with earlier change and less EZ damage in DME. PMID- 30310269 TI - Patient-centered care must be measured through patient-centered means. PMID- 30310267 TI - Neovascular age-related macular degeneration: intraocular inflammatory cytokines in the poor responder to ranibizumab treatment. AB - Purpose: To determine the levels of interleukin (IL)-6, vascular endothelial growth factor-A, platelet-derived growth factor, placental growth factor (PLGF), and other cytokines in the aqueous fluid of patients with neovascular age-related macular degeneration who respond poorly to ranibizumab. Patients and methods: This is an observational, prospective study. Thirty-two eyes from 30 patients were included in the study: 11 patients who responded poorly to ranibizumab and were switched to aflibercept (AF group), 8 patients who received ranibizumab and photodynamic therapy (PDT group), and 13 patients who responded to ranibizumab (control group). Aqueous fluid samples were collected for analysis of cytokine levels at baseline and after 1, 2, and 3 months of treatment. The effect of treatment on cytokine levels was compared between the study groups and between different time points using a linear mixed-effect regression model. Results: In the AF group, there was an increase in vascular endothelial growth factor-C, IL 7, and angiopoeitin-2 levels (P=0.01) and a decrease in intercellular adhesion molecule and IL-17 levels (P=0.01) between baseline and 3 months. After adjustment for age, sex, race, and type of lesion at baseline, the PLGF level was higher (P=0.02) and the IL-7 level was lower (P=0.04) in the ranibizumab non responder group than in the ranibizumab responder group. Conclusion: Switching from ranibizumab to aflibercept did not reduce intraocular levels of angiogenesis cytokines, but resulted in improvement of central subfield thickness. PLGF levels were higher in poor responders to ranibizumab. The response of lesions to medication might be related to the stage of choroidal neovascularization. Trial registration: www.ClinicalTrial.gov (NCT02218177c). PMID- 30310270 TI - Working mechanisms of dyadic, psychosocial, activating interventions for people with dementia and informal caregivers: a qualitative study. AB - Background: People living with dementia (PWD) and their informal caregivers often report difficulties in maintaining their usual activities. Several dyadic, psychosocial, activating interventions were developed to create insight into how to cope with limitations in a practical way and to increase skills for maintaining personal activities. Effects of these interventions varied so far. More knowledge on the working mechanisms of activating interventions might help to increase their impact. This study will provide more insights into the working mechanisms of three dyadic, psychosocial, activating interventions as the participating PWD, caregivers, and coaches perceived them during the interventions. Participants and methods: We used a qualitative design with semi structured interviews of 34 dyads that included 27 PWD, 34 caregivers, and 19 coaches. The data were analyzed with the constant comparative method. Results: Many PWD and caregivers found capacity-building approaches beneficial. We identified "empowerment" as the core theme. Three working mechanisms explained why the interventions were perceived as having a beneficial impact: 1) enabling activities without providing false hope; 2) exploring the most important personal activity needs of the PWD and caregivers; and 3) a solution-focused approach to adapt, test, and practice activities. An individualized approach contributed to positive change. Conclusion: For the overarching working mechanism empowerment, expertise in the field of dementia and psychological skills of coaches seem to be important. Assessing the needs, capacities, and limitations of both the PWD and the caregivers to take part in activities seems to be key, as well as the communication about it and the skills to teach a solution-focused approach. Studies on the impact of psychosocial and activating interventions might benefit from considering outcome measures directed at empowerment, along with aspects such as hope and belief in one's own capacities versus traditional outcome measures as mood, burden, or quality of life. PMID- 30310271 TI - The impact of 2011 and 2017 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines on allocation and pharmacological management of patients with COPD in Taiwan: Taiwan Obstructive Lung Disease (TOLD) study. AB - Background: This nationwide study was performed to evaluate the evolution of distributions of patients with COPD according to the 2011 and 2017 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines and to assess the concordance between the prescribed medications and the pharmacological management recommended by the two distinct classification systems in Taiwan. Subjects and methods: Data were retrospectively retrieved from stable COPD patients in 11 participating hospitals across Taiwan. Patients were grouped according to GOLD 2011 and 2017 guidelines respectively. Definitions of undertreatment and overtreatment were based on the pharmacological recommendations in the individual guidelines. Results: A total of 1,053 COPD patients were included. The percentages of patients in GOLD 2011 groups A, B, C and D were 18.4%, 40.6%, 6.7% and 34.2%, respectively. When reclassified according to the GOLD 2017, the percentages of group A and B increased to 23.3% and 63.2%, and groups C and D decreased to 1.9% and 11.6%, respectively. Up to 67% of patients in GOLD 2011 groups C and D were reclassified to GOLD 2017 groups A and B. The pharmacological concordance rate was 60.9% for GOLD 2011 and decreased to 44.9% for GOLD 2017. Overtreatment was found in 29.5% of patients according to GOLD 2011 and the rate increased to 46.1% when classified by the GOLD 2017. The major cause of overtreatment was unnecessary inhaled corticosteroids and the main cause of undertreatment was a lack of maintenance long-acting bronchodilators. Conclusion: The distribution of COPD patients in Taiwan was more uneven with the GOLD 2017 than with the GOLD 2011. A pharmacological discordance to the guidelines was identified. Updated guidelines with reclassification of COPD patients resulted in more discordance between prescribed medications and the guidelines. Physicians should make proper adjustments of the prescriptions according to the updated guidelines to ensure the mostly appropriate treatment for COPD patients. PMID- 30310272 TI - Bispectral index in hypercapnic encephalopathy associated with COPD exacerbation: a pilot study. AB - Background: Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. Objective: The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. Patients and methods: A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation-Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. Results: BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6-69) for RSS score of 4 to 92.2 (95% CI: 90.1-94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=-0.757, r=0.701, and r=0.615, respectively; P<0.001 for all). In the stable phase after discharge, BIS showed values considered as normal for a wake state (94.6; 95% CI: 91.7-97.9). Conclusion: BIS may be useful for the objective early detection and automatic monitoring of the intensity of hypercapnic encephalopathy in ECOPD, facilitating the early detection and follow-up of this condition, which may avoid management problems in these patients. PMID- 30310273 TI - Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA. AB - Background: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to very severe COPD. Methods: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 MUg, glycopyrrolate (GP) MDI 18 MUg, formoterol fumarate (FF) MDI 9.6 MUg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. Results: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George's Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups. Conclusion: These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators. PMID- 30310274 TI - 1H-NMR-based metabolic profiling of healthy individuals and high-resolution CT classified phenotypes of COPD with treatment of tiotropium bromide. AB - Background: Heterogeneity of COPD results in different therapeutic effects for different patients receiving the same treatment. COPD patients need to be individually treated according to their own characteristics. The purpose of this study was to explore the differences in different CT phenotypic COPD by molecular metabolites through the use of metabolomics. Methods: According to the characteristics of CT imaging, 42 COPD patients were grouped into phenotype E (n=20) or phenotype M (n=24). Each COPD patient received tiotropium bromide powder for inhalation for a therapeutic period of 3 months. All subjects were assigned into phenotype E in pre-therapy (EB, n=20), phenotype E in post-therapy (EA, n=20), phenotype M in pre-therapy (MB, n=22), phenotype M in post-therapy (MA, n=22), or normal control (N, n=24). The method of metabolomics based on 1H nuclear magnetic resonance (1H-NMR) was used to compare the changes in serum metabolites between COPD patients and normal controls and between different phenotypes of COPD patients in pre- and post-therapy. Results: Patients with COPD phenotype E responded better to tiotropium bromide than patients with COPD phenotype M in terms of pulmonary function and COPD assessment test scores. There were differences in metabolites in COPD patients vs normal control people. Differences were also observed between different COPD phenotypic patients receiving the treatment in comparison with those who did not receive treatment. The changes of metabolites involved lactate, phenylalanine, fructose, glycine, asparagine, citric acid, pyruvic acid, proline, acetone, ornithine, lipid, pyridoxine, maltose, betaine, lipoprotein, and so on. These identified metabolites covered the metabolic pathways of amino acids, carbohydrates, lipids, genetic materials, and vitamin. Conclusion: The efficacy of tiotropium bromide on COPD phenotype E is better than that of phenotype M. Metabolites detected by 1H NMR metabolomics have potentialities of differentiation of COPD and healthy people, discrimination of different COPD phenotypes, and giving insight into the individualized treatment of COPD. PMID- 30310275 TI - Effects of core size and PEG coating layer of iron oxide nanoparticles on the distribution and metabolism in mice. AB - Introduction: In vivo distribution of polyethylene glycol (PEG)ylated functional nanoparticles is vital for determining their imaging function and therapeutic efficacy in nanomedicine. However, contradictory results have been reported regarding the effect of core size and PEG surface of the nanoparticles on biodistribution. Methods: To clarify this ambiguous understanding, using iron oxide nanoparticles (IONPs) as a model system, we investigated the effect of core size and PEG molecule weights on in vivo distribution in mice. Three PEGylated IONPs, including 14 nm IONP@PEG2,000, 14 nm IONP@PEG5,000, and 22 nm IONP@PEG5,000, were prepared with a hydrodynamic size of 26, 34, and 81 nm, respectively. The blood pharmacokinetics and tissue distribution were investigated in detail. Results: The results indicated that the PEG layer, rather than core size, played a dominant role in determining the half-life time of IONPs. Specifically, increased molecular weight of the PEG layer led to a longer half-life time. These PEGylated IONPs were mainly excreted by liver clearance. While the PEG molecular layer constituted the key factor to determine the clearance ratio, core size affected the clearance rate. Conclusion: Complete blood count analysis and histopathology suggested excellent biocompatibility of PEGylated IONPs for future clinical trials. PMID- 30310276 TI - Determination of dose enhancement caused by AuNPs with Xoft(r) Axxent(r) Electronic (eBxTM) and conventional brachytherapy: in vitro study. AB - Purpose: The purpose of this study was to determine dose enhancement (DE) and the possible clinical benefits associated with the inclusion of gold nanoparticles (AuNPs) in cancer cells irradiated by either an 192Ir brachytherapy source or a Xoft(r) Axxent(r) Electronic (eBxTM) Brachytherapy. Patients and methods: Brachytherapy DE caused by AuNPs is investigated using two methods, namely 192Ir and eBxTM Brachytherapy. The second method, which was recently introduced clinically, operates at ~50 kV, which is also the optimal beam energy for DE. In this in vitro study, two cancer cell lines, lung (A549) and prostate (DU145), were used. Cells were incubated with 1 mM (2% w/w) concentration of AuNPs of ~15 nm in size. The control groups were exposed to a range of doses from 0 (control) to 6 Gy, with eBxTM and 192Ir sources separately. A clonogenic assay was conducted to determine cell survival curves. Results: High dose enhancement factor (DEF) values were achieved in treated groups with low concentration of AuNPs with the 50 kV energy associated with the eBxTM. The DE levels in eBxTM for Du145 and A549 cells were found to be 2.90 and 2.06, respectively. The results showed DEFs measured for the same cell lines using 192Ir brachytherapy to be 1.67 and 1.54 for Du145 and A549 cancer cells, respectively. This clearly indicates that much higher DE values are obtained in the case of eBxTM X-ray brachytherapy compared to 192Ir gamma brachytherapy. Conclusion: The higher DE values obtained with eBxTM compared to 192Ir brachytherapy can be attributed to the lower average energy of the former and being closer to the optimal energy for DE. This could potentially be utilized by medical practitioners and clinicians to achieve the same tumor control with a significantly lower dose from the eBxTM compared to the 192Ir brachytherapy treatment, thus bringing huge benefits to the brachytherapy treated patients. PMID- 30310277 TI - Comparative effects of magnetic and water-based hyperthermia treatments on human osteosarcoma cells. AB - Introduction: Hyperthermia (HT) based on magnetic nanoparticles (MNPs) represents a promising approach to induce the apoptosis/necrosis of tumor cells through the heat generated by MNPs submitted to alternating magnetic fields. However, the effects of temperature distribution on the cancer cells' viability as well as heat resistance of various tumor cell types warrant further investigation. Methods: In this work, the effects induced by magnetic hyperthermia (MHT) and conventional water-based hyperthermia (WHT) on the viability of human osteosarcoma cells at different temperatures (37 degrees C-47 degrees C) was comparatively investigated. Fe-Cr-Nb-B magnetic nanoparticles were submitted either to alternating magnetic fields or to infrared radiation generated by a water-heated incubator. Results: In terms of cell viability, significant differences could be observed after applying the two HT treatment methods. At about equal equilibrium temperatures, MHT was on average 16% more efficient in inducing cytotoxicity effects compared to WHT, as assessed by MTT cytotoxicity assay. Conclusion: We propose the phenomena can be explained by the significantly higher cytotoxic effects initiated during MHT treatment in the vicinity of the heat-generating MNPs compared to the effects triggered by the homogeneously distributed temperature during WHT. These in vitro results confirm other previous findings regarding the superior efficiency of MHT over WHT and explain the cytotoxicity differences observed between the two antitumor HT methods. PMID- 30310279 TI - Erratum: Antioxidant and hepatoprotective role of selenium against silver nanoparticles [Corrigendum]. AB - [This corrects the article on p. 7789 in vol. 12, PMID: 29123393.]. PMID- 30310278 TI - Targeted nonviral gene therapy in prostate cancer. AB - Prostate cancer is the second-most widespread cancer in men worldwide. Treatment choices are limited to prostatectomy, hormonal therapy, and radiotherapy, which commonly have deleterious side effects and vary in their efficacy, depending on the stage of the disease. Among novel experimental strategies, gene therapy holds great promise for the treatment of prostate cancer. However, its use is currently limited by the lack of delivery systems able to selectively deliver the therapeutic genes to the tumors after intravenous administration without major drawbacks. To remediate this problem, a wide range of nonviral delivery approaches have been developed to specifically deliver DNA-based therapeutic agents to their site of action. This review provides an overview of the various nonviral delivery strategies and gene therapy concepts used to deliver therapeutic DNA to prostate cancer cells, and focuses on recent therapeutic advances made so far. PMID- 30310280 TI - Carboxymethyl chitosan nanoparticles loaded with bioactive peptide OH-CATH30 benefit nonscar wound healing. AB - Background: Nonscar wound healing is a desirable treatment for cutaneous wounds worldwide. Peptide OH-CATH30 (OH30) from king cobra can selectively regulate the innate immunity and create an anti-inflammatory micro-environment which might benefit nonscar wound healing. Purpose: To overcome the enzymatic digestion and control release of OH30, OH30 encapsulated in carboxymethyl chitosan nanoparticles (CMCS-OH30 NP) were prepared and their effects on wound healing were evaluated. Methods: CMCS-OH30 NP were prepared by mild ionic gelation method and properties of the prepared CMCS-OH30 NP were determined by dynamic light scattering. Encapsulation efficiency, stability and release profile of OH30 from prepared CMCS-OH30 NP were determined by HPLC. Cytotoxicity, cell migration and cellular uptake of CMCS-OH30 NP were determined by conventional methods. The effects of prepared CMCS-OH30 NP on the wound healing was investigated by full thickness excision animal models. Results: The release of encapsulated OH30 from prepared CMCS-OH30 NP was maintained for at least 24 h in a controlled manner. CMCSOH30 NP enhanced the cell migration but had no effects on the metabolism and proliferation of keratinocytes. In the full-thickness excision animal models, the CMCS-OH30 NP treatment significantly accelerated the wound healing compared with CMCS or OH30 administration alone. Histopathological examination suggested that CMCS-OH30 NP promoted wound healing by enhancing the granulation tissue formation through the re-epithelialized and neovascularized composition. CMCS-OH30 NP induced a steady anti-inflammatory cytokine IL10 expression but downregulated the expressions of several pro-inflammatory cytokines. Conclusion: The prepared biodegradable drug delivery system accelerates the healing and shows better prognosis because of the combined effects of OH30 released from the nanoparticles. PMID- 30310282 TI - Immunomodulatory properties of graphene oxide for osteogenesis and angiogenesis. AB - Background: The osteo-immunomodulatory properties of biomaterials play an important role in the outcomes of bone regeneration. Graphene oxide (GO) has been widely applied in many research fields due to its unique properties. However, the immunomodulatory properties of GO as a biomaterial for bone tissue engineering are still unclear. Materials and methods: In this study, we evaluated the Inflammatory response of RAW264.7 cells influenced by GO. Then the osteogenic differentiation of BMSCs, and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) by stimulation with GO/RAW 264.7-conditioned culture medium were accessed. We also further investi gated the possible mechanisms underlying the osteo- and angio-immunomodulatory effects of GO. Results: Our results showed that GO stimulates the secretion of oncostatin M, tumor necrosis factor alpha and other factors through the nuclear factor-kappaB pathway. GO/RAW264.7-conditioned medium promoted the osteogenic differentiation of BMSCs, stimulated upregulation of the HUVECs of vascular-related receptors, and promoted their tube formation in vitro. Conclusion: In conclusion, our research shows that GO, as a biomaterial, can induce the formation of a beneficial osteo immunomodulatory environment and is a promising biomaterial for bone tissue engineering. PMID- 30310281 TI - Restriction of H1N1 influenza virus infection by selenium nanoparticles loaded with ribavirin via resisting caspase-3 apoptotic pathway. AB - Introduction: Ribavirin (RBV) is a broad-spectrum antiviral drug. Selenium nanoparticles (SeNPs) attract much attention in the biomedical field and are used as carriers of drugs in current research studies. In this study, SeNPs were decorated by RBV, and the novel nanoparticle system was well characterized. Madin Darby Canine Kidney cells were infected with H1N1 influenza virus before treatment with RBV, SeNPs, and SeNPs loaded with RBV (Se@RBV). Methods and results: MTT assay showed that Se@RBV nanoparticles protect cells during H1N1 infection in vitro. Se@RBV depressed virus titer in the culture supernatant. Intracellular localization detection revealed that Se@RBV accumulated in lysosome and escaped to cytoplasm as time elapsed. Furthermore, activation of caspase-3 was resisted by Se@RBV. Expressions of proteins related to caspase-3, including cleaved poly-ADP-ribose polymerase, caspase-8, and Bax, were downregulated evidently after treatment with Se@RBV compared with the untreated infection group. In addition, phosphorylations of phosphorylated 38 (p38), JNK, and phosphorylated 53 (p53) were inhibited as well. In vivo experiments indicated that Se@RBV was found to prevent lung injury in H1N1-infected mice through hematoxylin and eosin staining. Tunel test of lung tissues present that DNA damage reached a high level but reduced substantially when treated with Se@RBV. Immunohistochemical test revealed an identical result with the in vitro experiment that activations of caspase-3 and proteins on the apoptosis pathway were restrained by Se@RBV treatment. Conclusion: Taken together, this study elaborates that Se@RBV is a novel promising agent against H1N1 influenza virus infection. PMID- 30310283 TI - Hydrophobically modified chitosan nanoliposomes for intestinal drug delivery. AB - Background: Encapsulation of hydrophilic drugs within liposomes can be challenging. Methods: A novel chitosan derivative, O-palmitoyl chitosan (OPC) was synthesized from chitosan and palmitoyl chloride using methane-sulfonic acid as a solvent. The success of synthesis was confirmed by Fourier transform infra-red (FT-IR) spectroscopy and proton NMR spectroscopy (H-NMR). Liposomes encapsulating ferrous sulphate as a model hydrophilic drug for intestinal delivery were prepared with or without OPC inclusion (Lipo-Fe and OPC-Lipo-Fe). Results: Entrapment of iron was significantly higher in OPC containing liposomes compared to controls. Quantitative iron absorption from the OPC liposomes was significantly higher (1.5-fold P<0.05) than free ferrous sulphate controls. Qualitative uptake analysis by confocal imaging using coumarin-6 dye loaded liposomes also indicated higher cellular uptake and internalization of the OPC containing liposomes. Conclusion: These findings suggest that addition of OPC during liposome preparation creates robust vesicles that have improved mucoadhesive and absorption enhancing properties. The chitosan derivative OPC therefore provides a novel alternative for formulation of delivery vehicles targeting intestinal absorption. PMID- 30310284 TI - Antibacterial and biodegradable tissue nano-adhesives for rapid wound closure. AB - Background: Although various organic tissue adhesives designed to facilitate would healing are gaining popularity in diverse clinical applications, they present significant inherent limitations, such as rejection, infections, toxicity and/or excessive swelling. It is highly desirable to develop efficient, biocompatible and anti-bacterial tissue adhesives for skin wound healing. Purpose: Inspired by the fact that inorganic nanoparticles can directly glue tissues through the "nanobridging effect", herein disulfide bond-bridged nanosilver-decorated mesoporous silica nanoparticles (Ag-MSNs) was constructed as an effective and safe tissue adhesive with antibacterial and degradable properties for wound closure and healing. Materials and methods: Ag-MSNs was fabricated by controlled reduce of ultrasmall nanosilvers onto the both surface and large pore of biodegradable MSNs. The obtained MSNs were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and measurement of size distribution, zeta potential, and mesopore properties. Furthermore, adhesion strength test, anti bacterial assessment, mouse skin wound model, and MTT assays were used to investigate the tissue adhesive property, antibacterial effect, biodegradability and biocompatibility of the Ag-MSNs. Results: Ag-MSNs exhibited not only strong adhesive properties but also excellent antibacterial activities than that of MSNs. Importantly, this antibacterial nano-adhesive achieved rapid and efficient closure and healing of wounds in comparison to sutures or MSNs in a mouse skin wound model. Furthermore, Ag-MSNs with fast degradable behavior caused little cellular toxicity and even less systemic toxicity during wound healing. Conclusion: Our findings suggest that biodegradable Ag-MSNs can be employed as the next generation of nano-adhesives for rapid wound closure and aesthetic wound healing. PMID- 30310285 TI - Clinical outcomes of patients with major depressive disorder treated with either duloxetine, escitalopram, fluoxetine, paroxetine, or sertraline. AB - Purpose: To compare treatment outcomes in patients with major depressive disorder treated with duloxetine, escitalopram, fluoxetine, paroxetine, or sertraline for up to 6 months. Patients and methods: Data were taken from a 6-month prospective, observational study that included 1,549 major depressive disorder patients without sexual dysfunction in 12 countries. We report the overall results and those from Asian countries. Depression severity was measured using the Clinical Global Impression and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Clinical and functional remissions were defined as having a QIDS-SR16 <6, and as having a rating of <3 on all three Sheehan Disability Scale items and no reduced productivity, respectively. Mixed effects modeling with repeated measures analysis and generalized estimating equation models were used. Propensity scores were included in the models. Results: The mixed effects modeling with repeated measures regression models showed that the Clinical Global Impression rating during follow-up was significantly lower in those patients treated with duloxetine compared with escitalopram (0.40, 95% CI 0.25 to 0.56); fluoxetine (0.22, 95% CI 0.05 to 0.38); paroxetine (0.38, 95% CI 0.23 to 0.54); and sertraline (0.32, 95% CI 0.16 to 0.49). The QIDS-SR16 of duloxetine-treated patients was significantly lower than those treated with escitalopram (1.58, 95% CI 1.03 to 2.12); fluoxetine (1.48, 95% CI 0.90 to 2.06); paroxetine (1.53, 95% CI 1.00 to 2.07); and sertraline (1.19, 95% CI 0.61 to 1.78). The probability of clinical remission of the patients treated with escitalopram, fluoxetine, paroxetine, and sertraline was lower than those treated with duloxetine (OR 0.46, 95% CI 0.33 to 0.64; OR 0.42, 95% CI 0.29 to 0.61; OR 0.40, 95% CI 0.29 to 0.56; OR 0.50, 95% CI 0.35 to 0.71; respectively). The regression analysis of functional remission also showed more favorable results for duloxetine, with OR ranging from 0.43, 95% CI 0.31 to 0.60 for paroxetine to 0.49, 95% CI 0.35 to 0.70 for sertraline. The results for the Asian countries were generally consistent. Conclusion: Duloxetine-treated patients had better 6 month outcomes in terms of depression severity and clinical and functional remission, compared with selective serotonin reuptake inhibitor-treated patients. PMID- 30310286 TI - A multicentric pharmacovigilance study: collection and analysis of adverse drug reactions in relapsing-remitting multiple sclerosis patients. AB - Purpose: We performed a pharmacovigilance study of 10 drugs used in patients with relapsing-remitting multiple sclerosis (RR-MS). Our aim was to provide an overview of the safety of these drugs by the evaluation of reported expected and unexpected adverse reactions. Patients and methods: We collected and analyzed adverse drug reactions from RR-MS patients belonging to four hospitals in three Italian regions, for a period of 24 months. Results: We received a total of 411 adverse reactions, of which 84.18% were expected and only 15.82% were unexpected. We found no correlation between the number of reported adverse reactions and the route of administration (injectable/intravenous drugs N=224, oral drugs N=187). However, oral agents have caused a greater number of unexpected moderate-to severe adverse reactions while, in injectable and infusion therapies, they have been evaluated as mild-moderate adverse reactions. Conclusion: Our results underscore the importance of monitoring the safety profile of multiple sclerosis therapies, with particular attention to oral agents that have been introduced later in the clinical practice. PMID- 30310288 TI - Perceived control moderates the relationship between anxiety and in-hospital complications after ST segment elevation myocardial infarction. PMID- 30310287 TI - Efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy for HER2-positive breast cancer: a systematic review and meta-analysis. AB - The concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) has been proposed to improve the pathologic complete response (pCR) rate, although there are conflicting views about its efficacy and safety. The purpose of this study was to evaluate the efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based NAC for human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer. We systematically searched PubMed, Embase, and Cochrane databases from inception until July 1, 2017, for relevant articles. A total of 13 studies were included in the meta-analysis. The results showed that the pCR rate was significantly higher in the concurrent use of trastuzumab and anthracycline group (45%) than that in the nonconcurrent use group (32%) (OR: 2.36, 95% CI: 1.69-3.30, P<0.0001). Besides, the pooled absolute rate of breast conservation surgery (BCS) was 48% (95% CI: 0.35-0.61) and 38% (95% CI: 0.14-0.62) in the experimental and control groups, respectively (OR: 1.10, 95% CI: 0.64-1.90, P=0.73). No significant differences were found in the left ventricular ejection fraction (LVEF), which decreased by >10% (OR: 1.26, 95% CI: 0.55-2.88, P=0.59), and in terms of cardiac failure (OR: 2.17, 95% CI: 0.24-19.84, P=0.49), when comparing the concurrent use of trastuzumab and anthracyclines with their nonconcurrent use. In conclusion, the concurrent use of trastuzumab and anthracycline-based NAC for certain HER2 positive locally advanced breast cancers significantly improves the pCR rates without obvious increases in the cardiotoxicity. PMID- 30310290 TI - POEMS syndrome complicated with multiple ischemic vascular events: case report and review of literature. AB - POEMS syndrome (acronym consisting of: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is an uncommon disorder associated with an underlying plasma cell dyscrasia. There is no single specific test for POEMS, and due to its rarity and heterogeneity, patients are often mis- or underdiagnosed. Castleman disease (CD) is a rare lymphoproliferative disorder, closely related to POEMS syndrome; ~11%-30% of POEMS patients are associated with concomitant CD. In contrast to frequently published reports on vascular events in POEMS syndrome affecting coronary arteries or lower limbs, cases of cerebrovascular events are rarely mentioned in literature. We hereby report a patient with POEMS syndrome accompanied by CD who presented recurrent strokes and splenic infarction. PMID- 30310291 TI - Metabolic syndrome and the incidence of hepatocellular carcinoma: a meta-analysis of cohort studies. AB - Background: Patients with metabolic syndrome (MetS) were suggested to have a higher risk of hepatocellular carcinoma (HCC), although the results of previous cohort studies are not consistent. Aim: To perform an updated meta-analysis to evaluate the association between MetS and subsequent incidence of HCC. Methods: Relevant cohort studies were identified by searching PubMed and Embase databases. Cochrane's Q-test and I 2 statistic were used to analyze the heterogeneity. Random effects model was used for the meta-analysis. Results: Six cohort studies with 127,198 participants and 1,293 HCC cases during follow-up were included. Patients with MetS had a significantly higher incidence of HCC in studies with MetS defined by the revised National Cholesterol Education Program's Adults Treatment Panel III (risk ratio [RR]: 1.43, 95% CI: 1.19-1.72, p<0.001; I 2=29%) or International Diabetes Federation criteria (RR: 1.59, 95% CI: 1.13-2.23, p=0.008; I2=0%). Results of subgroup analysis showed that the presence of MetS was associated with a higher incidence of HCC in males (RR: 1.75, 95% CI: 1.28 2.38, p<0.001) but not in females (RR: 1.18, 95% CI: 0.76-1.84, p=0.46), and the association between MetS and higher risk of HCC was consistent regardless whether alcohol intake was adjusted. Although both were significant, MetS conferred higher risk of HCC in carriers of hepatitis B virus when compared with general population (p=0.06). Conclusion: The presence of MetS is associated with significantly increased incidence of HCC in male participants. PMID- 30310292 TI - Predictive value of LDH kinetics in bevacizumab treatment and survival of patients with advanced NSCLC. AB - Background: The combination of bevacizumab and chemotherapy is still one of the standard treatments for advanced non-small-cell lung cancer (NSCLC) patients in the new era of targeted therapy. Although a high level of baseline lactate dehydrogenase (LDH) was found to predict survival benefit from bevacizumab in patients with metastatic colorectal cancer, the predictive value of serum level of LDH in NSCLC patients treated with bevacizumab has not been investigated yet. Moreover, dynamic evaluation of serum level of LDH changes may be more informative and promising in predicting patients' prognosis. We thus sought to analyze LDH kinetics and evaluate its predictive role in the response and survival of advanced NSCLC patients treated with bevacizumab. Method: We retrospectively collected and analyzed a total of 161 advanced NSCLC patients who had undergone treatment with bevacizumab. Univariate and multivariate logistic regression analyses of serum level of LDH were used for response analyses, and Cox models for both overall survival (OS) and progression-free survival analyses (PFS). Longitudinal analysis of LDH was performed using a mixed-effect regression model. Results: On multivariate Cox models, increase of serum level of LDH after 4 cycles with bevacizumab (INC4) treatment was shown to be the independent risk factor for OS (hazard ratio =2.17, 95% CI: 1.21-3.90, P=0.009), and the serum level of LDH after 2 cycles (LDH2) and the increase of LDH after 6 cycles with bevacizumab (INC6) treatment were the predictive factors for PFS (hazard ratio =2.33, 95% CI: 1.38-3.93, P=0.001; hazard ratio =1.96, 95% CI: 1.27-3.03, P=0.002, respectively). Patients with increase of serum level of LDH after 2 cycles of treatment with bevacizumab (INC2) (odds ratio =3.75, 95% CI: 1.83-7.68, P<0.001) were more likely to attain stable disease/progressive disease on multivariate logistic regression analyses, while patients with complete response (CR)/partial response (PR) experienced a reduction of serum level of LDH every 2 cycles (Coef =-0.076, std error =0.017, P<0.001) over time. Conclusion: Dynamic changes of LDH were superior to baseline LDH in predicting prognosis of NSCLC patients treated with bevacizumab. Serum level of LDH reducing over time was a potential biomarker for patients to achieve good clinical response (CR/PR) to bevacizumab. PMID- 30310289 TI - Does the medical literature remain inadequately described despite having reporting guidelines for 21 years? - A systematic review of reviews: an update. AB - Purpose: Reporting guidelines (eg, Consolidated Standards of Reporting Trials [CONSORT] statement) are intended to improve reporting standards and enhance the transparency and reproducibility of research findings. Despite accessibility of such guidelines, researchers are not required to adhere to them. Our goal was to determine the current status of reporting quality in the medical literature and examine whether adherence of reporting guidelines has improved since the inception of reporting guidelines. Materials and methods: Eight reporting guidelines, such as CONSORT, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), STrengthening the Reporting of OBservational studies in Epidemiology (STROBE), Quality of Reporting of Meta-analysis (QUOROM), STAndards for Reporting of Diagnostic accuracy (STARD), Animal Research: Reporting In Vivo Experiments (ARRIVE), Consolidated Health Economic Evaluation Reporting Standards (CHEERS), and Meta-analysis of Observational Studies in Epidemiology (MOOSE) were examined. Our inclusion criteria included reviews published between January 1996 to September 2016 which investigated the adherence to reporting guidelines in the literature that addressed clinical trials, systematic reviews, observational studies, meta-analysis, diagnostic accuracy, economic evaluations, and preclinical animal studies that were in English. All reviews were found on Web of Science, Excerpta Medical Database (EMBASE), MEDLINE, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Results: Among the general searching of 26,819 studies by using the designed searching method, 124 studies were included post screening. We found that 87.9% of the included studies reported suboptimal adherence to reporting guidelines. Factors associated with poor adherence included non-pharmacological interventions, year of publication, and trials concluding with significant results. Improved adherence was associated with better study designs such as allocation concealment, random sequence, large sample sizes, adequately powered studies, multiple authorships, and being published in journals endorsing guidelines. Conclusion: We conclude that the level of adherence to reporting guidelines remains suboptimal. Endorsement of reporting guidelines by journals is important and recommended. PMID- 30310293 TI - LINC00152 promotes the growth and invasion of oral squamous cell carcinoma by regulating miR-139-5p. AB - Background: LINC00152 plays a crucial role in tumorigenesis and progression of multiple types of cancer. However, the biological significance of LINC00152 and its potential role in oral squamous cell carcinoma (OSCC) remain to be determined. In the present study, we investigated the role of LINC00152 and the underlying mechanism of its oncogenic activity in OSCC. Materials and methods: The expression of LINC00152 in OSCC tissues and cell lines was detected using qRT PCR. Cell proliferation, colony formation, migration, and invasion were measured using a cell counting kit, colony formation assay, wound healing, and transwell invasion assays, respectively. The target gene of LINC00152 was confirmed using a dual-luciferase reporter assay and qRT-PCR. A nude mouse model was established to analyze the function of LINC00152 in vivo. Results: LINC00152 expression was significantly upregulated in OSCC tissues and cell lines compared with that in normal counterparts. Upregulated LINC00152 served as an independent prognostic predictor in patients with OSCC. Moreover, knockdown of LINC00152 inhibited cell proliferation, colony formation, migration, and invasion, and suppressed the epithelial to mesenchymal transition in vitro, as well as impairing tumor growth in vivo. A mechanistic investigation indicated that LINC00152 could directly bind to miR-139-5p in OSCC. LINC00152 expression was inversely correlated with miR-139 expression in OSCC tissues. Conclusion: Taken together, these results suggested that LINC00152 may function as oncogene in OSCC and could be a potential therapeutic target in patients with OSCC. PMID- 30310294 TI - Integrated pharmacokinetic-pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections. AB - Objectives: Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three antipseudomonal carbapenems (imipenem, meropenem [MER], and doripenem [DOR]) are available commercially against MDR GNB in Singapore. The study aims to determine the most optimal empiric carbapenem dosing regimens (CDR) and evaluate their cost effectiveness for GNB-BSI in the face of increasing MDR GNB. Methods: Carbapenem minimum inhibitory concentrations (MICs) were generated for non-repeat GNB-BSI obtained in 2013-2014 from two hospitals. Monte Carlo simulations were used to assess the cumulative fraction of response (CFR) of various CDRs using the percentage of time above MIC for 40% (%T > MIC of 40%) as the pharmacokinetic (PK)-pharmacodynamic (PD) parameter for efficacy. Carbapenem costs were based on patient antibiotic costs. Antibiotic cost-effectiveness was calculated as total daily drug cost/CFR. Results: A total of 1,140 bloodstream isolates were collected. They comprised 116 Acinetobacter baumannii, 237 Pseudomonas aeruginosa, and 787 Enterobacteriaceae. All CDRs achieved ~40, ~80, and >=90% CFRs against A. baumannii, P. aeruginosa, and Enterobacteriaceae, respectively. Against P. aeruginosa, MER 2 g every 8 h infused over 3 h and DOR 1 g every 8 h infused over 4 h achieved CFRs 84 and 81%, respectively. Against Enterobacteriaceae, the cost of MER 2 g every 8 h infused over 3 h was the lowest among the three carbapenems at $0.40/percentage of CFR. Conclusion: This study demonstrates the utility of PK-PD modeling to formulate the optimal selection of a cost-effective empiric CDR in antibiotics guidelines and formulary inclusion. The findings support the selection of high MER doses of prolonged infusions as empiric coverage for GNB-BSI in our institutions. PMID- 30310295 TI - Prevalence and molecular characteristics of mcr-1 colistin resistance in Escherichia coli: isolates of clinical infection from a Chinese University Hospital. AB - Background: Colistin has been considered as one of the most effective treatments in clinical infections, especially multidrug-resistant (MDR) bacteria-infected patients. The mcr-1 gene leads to polymyxin resistance in China. The present study investigated the prevalence of mcr-1 in a Chinese teaching hospital, and the molecular phenotypes of the positive strains were analyzed. Methods: A total of 1,112 Escherichia coli strains were collected from a Chinese University Hospital from January 2015 to January 2016. The mcr-1 gene was detected by PCR. All positive specimens were subjected to susceptibility testing, clinical analysis, phylogenetic analysis, DNA Southern blot hybridization, and gene sequencing. Results: Six (0.6%) strains of mcr-1-positive E. coli were susceptible to imipenem, meropenem, and tigecycline, except for one that presented moderate levels of tigecycline resistance. The six isolates were resistant to cefotaxime and cefepime and divided into six types of sequences. These positive strains carried a total of three plasmids: approximately 33, 61, and >92 kb plasmids. All patients were eventually cured using different types of antibiotics and discharged. Conclusion: The current study showed that the mcr-1 gene was responsible for the majority of colistin resistance in clinical isolates of E. coli. The gene can be transferred into plasmids containing other drug resistance genes by plasmid-DNA conjugation, which might cause severe consequences in drug-resistant strains. Thus, the widespread popularity of mcr-1 gene should be prevented. PMID- 30310296 TI - Inhibitory effects of fluoroquinolone antibiotics on Babesia divergens and Babesia microti, blood parasites of veterinary and zoonotic importance. AB - Aim: This study aimed to evaluate the inhibitory effects of fluoroquinolone antibiotics, including enrofloxacin, enoxacin, trovafloxacin, norfloxacin, and ofloxacin, on the in vitro and in vivo growth of Babesia divergens and Babesia microti parasites, respectively. Materials and methods: The in vitro and in vivo inhibitory effects of fluoroquinolone antibiotics against B. divergens and B. microti, respectively were evaluated using fluorescence-based assay. Additionally, combination therapies of highly effective fluoroquinolone antibiotics (enrofloxacin, enoxacin, and trovafloxacin) with diminazene aceturate, luteolin, or pyronaridine tetraphosphate were tested on the in vitro cultures of B. divergens. Results: Enrofloxacin, trovafloxacin, and enoxacin were the most effective fluoroquinolones against the in vitro growth of B. divergens, followed by norfloxacin and ofloxacin. Furthermore, a combination of enoxacin or trovafloxacin with either diminazene aceturate, luteolin, or pyronaridine tetraphosphate significantly enhanced the inhibitory effect on the growth of B. divergens in in vitro cultures. In mice infected by B. microti, enoxacin and diminazene aceturate combination therapy exhibited a potential antibabesial effect. Conclusion: These results suggest that safe and cheap fluoroquinolone, such as enoxacin, might be used for the treatment of clinical cases caused by Babesia spp. in animals or humans. PMID- 30310297 TI - Decompression nerve surgery for diabetic neuropathy: a structured review of published clinical trials. AB - Aim: To assess lower extremity decompression nerve surgery (DNS) to treat the consequences of diabetic distal symmetric peripheral neuropathy (DPN). Research design and methods: MEDLINE, PubMed, and related registries were searched through December 2017 to identify randomized, quasi-randomized or observational trials that evaluated the efficacy of lower extremity DNS on pain relief (primary outcome) or other secondary outcomes. Observational studies were included, given investigators' reluctance to use sham surgery controls. Outcome effect size was estimated, and a weighted average was calculated. Results: Eight of 23 studies evaluated pain relief, including a double-blind randomized controlled trial (with a sham surgery leg), an unblinded trial with a nonsurgical control leg, and 6 observational studies. All reported substantial pain relief post-DNS with average effect sizes between two and five. Unexpectedly, the double-blind trial showed improvement in the sham leg comparable to the DNS leg and exceeding the improvement observed in the nonsurgical leg in the unblinded study. Sensory testing showed generally favorable results supporting DNS, and nerve conduction velocities increased post-DNS relative to deterioration in controls. Ultrasound revealed fusiform nerve swelling near compression sites. Morphological results of DNS were generally favorable but inconsistent, whereas hemodynamic measures showed a positive effect on arterial parameters, as did transcutaneous oximetry (improved microcirculation). The incidence of initial and recurrent neuropathic diabetic foot ulcers appeared reduced post-DNS relative to the contralateral foot (borderline significant). Conclusion: The data remain insufficient to recommend DNS for painful DPN, given conflicting and unexpectedly positive results involving sham surgery relative to unblinded controls. The generally supportive sensory and nerve conduction results are compromised by methodological issues, whereas more favorable results support DNS to prevent new or recurrent neuropathic foot ulcers. Future studies need to clarify subject selection vis-a vis DPN vs superimposed compressed nerves, utilize appropriate validated instruments, and readdress use of sham surgical controls in light of recent results. PMID- 30310298 TI - Inadequate identification of fatty liver disease, obesity, and metabolic syndrome by family physicians. AB - Background: Nonalcoholic fatty liver disease (NAFLD) is an emerging condition and is constituted as a vital public health epidemic globally. This study evaluated the process of identification and documentation of NAFLD and metabolic syndrome in correlation with those diagnosed with obesity. Methods: Participants included 352 patients older than 18 years who were diagnosed with fatty liver disease. We performed a cross-sectional study between August 2016 and September 2017. Categorical variables were extracted and analyzed using SPSS. The body mass index (BMI) was determined by the study staff and compared with the data retrieved from the family physician's database. Results: Patients who presented documented BMI in their past medical history showed to be significantly higher than those without documentation of BMI (29+4.4 vs 25.7+4.6 kg/m2, P<0.01). For instance, 54% of patients with NAFLD were documented in the electronic medical record (EMR) by the family physician, with higher documentation rate among males than females. Moreover, 72% qualified for documentation of metabolic syndrome, but only 5% were documented in their EMR. Patients with significant obesity and obesity-related conditions were more likely to have documentation in their EMR. Discussion: Further analyses supported the conclusion that family physicians inadequately identify BMI in the EMR for overweight, obesity, metabolic syndrome, and fatty liver disease. Additional efforts are necessary to improve knowledge of proper identification of NAFLD and metabolic syndrome. PMID- 30310299 TI - Metabolic syndrome and blood pressure: are they related or not? PMID- 30310301 TI - Focus on the use of antidepressants to treat pediatric functional abdominal pain: current perspectives. AB - Chronic abdominal pain is frequently encountered in pediatric practice. A large proportion of cases meet Rome criteria for abdominal pain-functional gastrointestinal disorders (AP-FGIDs). These disorders are costly and, in some cases, lead to impairment of daily functioning and overall quality of life. Pathophysiologic mechanisms include early stressful events, visceral hypersensitivity, dysmotility, changes in intestinal microbiota, and altered central nervous system processing. They are considered disorders of the brain-gut interaction. The diagnosis is made on clinical grounds using symptom-based criteria (Rome criteria). Anxiety and depressive symptoms are more prevalent in patients with AP-FGIDs. Therefore, attention has been directed to the use of neuromodulators as potential interventions for AP-FGIDs. Antidepressants are one type of neuromodulators, and one of the most studied drugs for the management of AP-FGIDs in adult and pediatric population. Data available in pediatric population have significant limitations including nonuniform methodology with different study designs and primary endpoints. Evidence of the efficacy of antidepressants in the management of pediatric AP-FGIDs is not consistent. There is an urgent need for well-designed randomized clinical trials using age appropriate validated outcome measures. Careful consideration must be given to adverse effects, particularly increased suicidal ideation. PMID- 30310302 TI - Serial changes in vessel walls of renal arteries after catheter-based renal artery denervation: insights from volumetric computed tomography analysis. AB - Aim: Radiofrequency ablation of peri-arterial renal autonomic nerves has been studied as a potential therapeutic option for resistant hypertension. While recent clinical trials have reported its efficacy, there is paucity of data addressing the effects of the procedure on renal arteries, such as changes in vessel and lumen areas. Herein, the effect of atheroma burden on renal arteries after renal denervation was assessed using computed tomography (CT) imaging. Materials and methods: Serial renal artery CT imaging was conducted in 38 patients from the EnligHTNTM I study, a prospective, multicenter study evaluating the efficacy of the EnligHTN multi-electrode radiofrequency ablation catheter in resistant hypertensive subjects. Cross-sectional images of renal arteries at 1 mm intervals were acquired using commercially available software (3mensio Structural Heart version 5.1). Vessel and lumen areas were manually traced in each image. Vessel wall volume (VWV) and percent vessel wall volume (P-VWV) were calculated. The measurements within the ablation (first 30 mm segments) and the non-ablation (subsequent 30 mm segment after the first bifurcation of renal arteries) zones were compared. Results: On serial evaluation, greater increase in P-VWV and VWV was observed in the ablation zone (change in P-VWV, 6.7%+/-5.1% vs 3.6%+/-2.8%, P=0.001; change in VWV, 106.3+/-87.4 vs 23.0+/-18.2 mm3, P=0.001). Receiver operating characteristic analysis demonstrated baseline P-VWV in the ablation zone >37.1% as an optimal cutoff value to predict its substantial progression after the procedure (area under the curve=0.88, sensitivity 89.8%, specificity 79.1%). Conclusion: Change in vessel wall was greater within the segments receiving renal artery denervation. Baseline VWV predicted its substantial increase after the procedure. These observations suggest that atheroma burden within the renal arteries is a potential contributing factor to vascular changes after renal sympathetic denervation. PMID- 30310303 TI - Erratum: The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty [Corrigendum]. AB - [This corrects the article on p. 127 in vol. 11, PMID: 30100750.]. PMID- 30310300 TI - Diabetic gastroparesis: current challenges and future prospects. AB - Diabetic gastroparesis (DMGP) is a condition of delayed gastric emptying after gastric outlet obstruction has been excluded. Symptoms of nausea, vomiting, early satiety, bloating, and abdominal pain are associated with DMGP. Uncontrolled symptoms can lead to overall poor quality of life and financial burdens on the healthcare system. A combination of antiemetics and prokinetics is used in symptom control; metoclopramide is the main prokinetic available for clinical use and is the only U.S. Food and Drug Administration-approved agent in the United States. However, a black box warning in 2009 reporting its association with tardive dyskinesia and recommending caution in chronically using this agent beyond 3 months has decreased its role in clinical practice. There is an unmet need for new prokinetics with good efficacy and safety profiles. Currently, there are several new drugs with different mechanisms of action in the pipeline that are under investigation and show promising preliminary results. Surgically combining gastric electrical stimulation with pyloroplasty is considered "gold" standard. Advances in therapeutic endoscopic intervention with gastric per-oral endoscopic pyloromyotomy have also been shown to improve gastric emptying and gastroparesis (GP) symptoms. In this review, we will comment on the challenges encountered when managing patients with DMGP and provide an update on advances in drug development and endoscopic and surgical interventions. PMID- 30310304 TI - Perineural invasion in endometriotic lesions contributes to endometriosis associated pain. AB - Purpose: Recent studies have shown that abnormal distribution of pelvic nerves contributes to endometriosis-associated pain. However, the relationship between neurogenesis and pain severity in endometriosis still remains uncertain, which makes it an enigma for both gynecologists as well as neuropathologists. In this study, we tried to explore a special phenomenon, perineural invasion (PNI), in deep infiltrating endometriosis (DIE) and investigated the correlation between PNI- and DIE-associated pain. Patients and methods: The study was conducted in the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Sun Yat-sen University from June 2012 to January 2015. In total, 64 patients with DIE were enrolled. They received laparoscopically surgical resection of endometriotic lesions. The Kruskal-Wallis and Mann-Whitney tests were used for comparisons of enumeration data. Spearman rank correlation was used for linear analysis. Results: Immunohistochemical analysis demonstrated that PNI was commonly found in DIE lesions. Patients were divided into PNI (+) group and PNI ( ) group. The visual analog scale scores of dysmenorrhea, dyspareunia, and chronic pelvic pain were higher in PNI (+) group than in PNI (-) group. Also, we found significantly increased density of newly formed nerve fibers as well as microvessels in lesions of PNI (+) group. Further, double immunofluorescence showed a closely spatial nerve-vessel network in the endometriotic lesion of PNI (+) group. More importantly, correlation analysis revealed positive relation between the density of newly formed nerve fibers in the lesion and the density of microvessels in lesions of PNI (+) group. Conclusion: This study suggests that PNI in endometriotic lesions plays an important role in endometriosis-associated pain, mainly through a mechanism named "neuroangiogenesis". PMID- 30310306 TI - Anatomical analysis of the distribution patterns of occipital cutaneous nerves and the clinical implications for pain management. AB - Purpose: Establishing the distribution patterns of occipital cutaneous nerves may help us understand their contribution to various occipital pain patterns and ensure that a proper local injection method for treatment is employed. The aim of this study was to demonstrate the detailed distribution patterns of the greater occipital nerve (GON), lesser occipital nerve (LON), and third occipital nerve (TON) using the modified Sihler's staining technique. Methods: Ten human cadavers were manually dissected to determine the nerve distributions. Specimens from eight human cadavers were treated using the modified Sihler's staining. Results: In all cases, distinct GON branches proceeded laterally and were intensively distributed in the superolateral area from their emerging point. Very thin twigs were observed at the middle-trisected area, which had a fan-like shape, in the middle-upper occipital region. Conclusion: The LON and TON distribution areas were biased to the lateral side below the superior nuchal line, although these nerves exhibited multiple interconnections or overlapping areas with the GON. Furthermore, a nerve rarified zone in the shape of an inverted triangle was identified in the middle occipital area. Our findings improve our understanding of the occipital nerve anatomy and will aid in the management of occipital pain in clinical practice. PMID- 30310305 TI - Chronic 17beta-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats. AB - Background: The prevalence of craniofacial pain disorders show sexual dimorphism with generally more common appearance in women suggesting the influence of estradiol, but the exact cause remains unknown. The common point in the pathogenesis of these disorders is the activation of trigeminal system. One of the animal experimental models of trigeminal activation is the orofacial formalin test, in which we investigated the effect of chronic 17beta-estradiol pretreatment on the trigeminal pain-related behavior and activation of trigeminal second-order neurons at the level of spinal trigeminal nucleus pars caudalis (TNC). Methods: Female Sprague Dawley rats were ovariectomized and silicone capsules were implanted subcutaneously containing cholesterol in the OVX group and 17beta-estradiol and cholesterol in 1:1 ratio in the OVX+E2 group. We determined 17beta-estradiol levels in serum after the implantation of capsules. Three weeks after operation, 50 uL of physiological saline or 1.5% of formalin solution was injected subcutaneously into the right whisker pad of rats. The time spent on rubbing directed to the injected area and c-Fos immunoreactivity in TNC was measured as the formalin-induced pain-related behavior, and as the marker of pain-related neuronal activation, respectively. Results: The chronic 17beta estradiol pretreatment mimics the plasma levels of estrogen occurring in the proestrus phase and significantly increased the formalin-induced pain-related behavior and neuronal activation in TNC. Conclusion: Our results demonstrate that the chronic 17beta-estradiol treatment has strong pronociceptive effect on orofacial formalin-induced inflammatory pain suggesting modulatory action of estradiol on head pain through estrogen receptors, which are present in the trigeminal system. PMID- 30310307 TI - Comparing the injectate spread and nerve involvement between different injectate volumes for ultrasound-guided greater occipital nerve block at the C2 level: a cadaveric evaluation. AB - Purpose: The spread patterns between different injectate volumes have not yet been investigated in ultrasound-guided greater occipital nerve (GON) block at the C2 level. This cadaveric study was undertaken to compare the spread pattern and nerve involvements of different volumes of dye using this technique. Materials and methods: After randomization, ultrasound-guided GON blocks with 1 or 5 mL dye solution were performed at the C2 level on the right or left side of five fresh cadavers. The suboccipital regions were dissected, and nerve involvement was investigated. Results: Ten injections were successfully completed. In all cases of 5 mL dye, we observed the deeply stained posterior neck muscles, including the suboccipital triangle space. The suboccipital and third occipital nerves, in addition to GONs, were consistently stained when 5-mL dye was used in all injections (100%). Although all GONs were successfully stained in the 1-mL dye cases, three of five injections (60%) concomitantly stained the third occipital nerves. Conclusion: The clinical efficacy of this technique using the 5-mL injectate seems unlikely to arise from the blockade of GON alone. Instead, its efficacy likely arises from the blockade of most nerves originating from the dorsal ramus of the upper cervical spinal nerve at the suboccipital area. Even using 1 mL of injectate may not guarantee blockade of the GON alone. PMID- 30310308 TI - Motion style acupuncture therapy for shoulder pain: a randomized controlled trial. AB - Background: Strategies for preventing the persistence of pain and disability beyond the acute phase in shoulder pain patients are critically needed. Conventional acupuncture therapy (CAT) or motion style acupuncture therapy (MSAT) alone results in relative improvements in painful conditions in shoulder pain patients; combined interventions may have more global effects. The aim of this study is to evaluate the efficacy and safety of MSAT vs CAT for shoulder pain. Methods: A randomized controlled trial using a factorial design was conducted from January 2014 to December 2015. Patients with a primary complaint of one sided shoulder pain participated at three study sites. Eligible individuals were randomly assigned to receive MSAT plus minimal CAT (mCAT), CAT plus minimal MSAT (mMSAT), MSAT plus CAT, or mMSAT plus mCAT for 6 weeks in a 1:1:1:1 ratio. The primary outcome was change in shoulder pain intensity (measured using visual analog scale). The secondary outcomes included change in function of the shoulder joint (Constant-Murley score) and the health-related quality of life (Short Form 36 Health Survey). Moreover, perceived credibility of acupuncture was measured using the Treatment Credibility Scale. The outcomes were assessed at baseline and at 6, 10, and 18 weeks after randomization. Analysis of covariance with the baseline score adjustment had been used to determine the primary end point. The between-group differences of MSAT vs mMSAT and CAT vs mCAT were estimated, respectively, after tests of interaction between the two-dimensional interventions. All main analyses followed the intention-to-treat principle. Results: A total of 164 patients completed the study. MSAT was superior to mMSAT in alleviating pain intensity at 10 weeks (P=0.024), and it was maintained for 18 weeks (P=0.013). Statistically significant differences were found when comparing MSAT with mMSAT for improvement in shoulder function (6 weeks, P=0.01; 10 weeks, P=0.006; and 18 weeks, P=0.01), physical health (10 weeks, P=0.023 and 18 weeks, P=0.015), and mental health (18 weeks, P=0.05). No significant differences were found in CAT when compared with mCAT. Conclusion: After 18 weeks of treatment, pain and joint functions are improved more with MSAT than with minimal motion style acupuncture or conventional acupuncture in patients with shoulder pain. PMID- 30310309 TI - Bayesian analysis of the effect of transcranial direct current stimulation on experimental pain sensitivity in older adults with knee osteoarthritis: randomized sham-controlled pilot clinical study. AB - Purpose: Previous studies have indicated that transcranial direct current stimulation (tDCS) with the anode over the motor cortex and the cathode over the contralateral supraorbital region is effective in reducing clinical pain in patients with chronic pain, but these studies have not focused on experimental pain sensitivity. Therefore, the aim of this study was to examine the effect of tDCS on experimental pain sensitivity in older adults with knee osteoarthritis (OA). Patients and methods: Forty community-dwelling participants aged 50-70 years with knee OA pain were randomly assigned to receive five daily sessions of 2 mA tDCS for 20 minutes (n = 20) or sham tDCS (n = 20) using a parallel group design. A multimodal quantitative sensory testing battery was completed, including heat pain, pressure pain threshold (PPT), punctate mechanical pain, and conditioned pain modulation (CPM). Results: The active tDCS group showed greater increases in heat pain thresholds and tolerances, PPTs, and CPM, and reductions in punctate pain. In addition, beneficial changes in experimental pain measures were associated with reductions in clinical pain. Future studies are needed to extend these findings to better understand the underlying mechanisms of tDCS as well as to optimize treatment parameters including number and duration of stimulation sessions. Conclusion: Our findings demonstrate that tDCS reduces experimental pain sensitivity, and these beneficial changes in experimental pain measures were associated with reductions in clinical pain. PMID- 30310310 TI - To what extent are patients with migraine able to predict attacks? AB - Purpose: Premonitory symptoms (PSs) of migraine are those that precede pain in a migraine attack. Previous studies suggest that treatment during this phase may prevent the onset of pain; however, this approach requires that patients be able to recognize their PSs. Our objectives were to evaluate patients' actual ability to predict migraine attacks based on their PSs and analyze whether good predictors meet any characteristic profile. Patients and methods: This prospective, observational study included patients with migraine with and without aura. Patients' baseline characteristics were recorded. During a 2-month follow up period, patients used a mobile application to record what they believed to be PSs and later to record the onset of pain, if this occurred. When a migraine attack ended, patients had to complete a form on the characteristics of the episode (including the presence of PSs not identified prior to the attack). Results: Fifty patients were initially selected. A final total of 34 patients were analyzed, recording 229 attacks. Of whom, 158 (69%) were accompanied by PSs and were recorded prior to the pain onset in 63 (27.5%) cases. A total of 67.6% of the patients were able to predict at least one attack, but only 35.3% were good predictors (>50% of attacks). There were only 11 cases in which a patient erroneously reported their PSs (positive predictive value: 85.1%). Good predictors were not differentiated by any specific clinical characteristic. However, a range of symptoms were particularly predictive; these included photophobia, drowsiness, yawning, increased thirst, and blurred vision. Conclusion: A large majority of patients with migraine experienced a PS and were able to predict at least one attack. Besides, only a small percentage of patients were considered as good predictors; however, they could not be characterized by any specific profile. Nonetheless, when patients with migraine believed that they were experiencing PSs, they were frequently correct. PMID- 30310311 TI - PKCbetaII-induced upregulation of PGP9.5 and VEGF in postoperative persistent pain in rats. AB - Purpose: Postoperative pain is a common clinical problem. In this study, we aimed to investigate the role of protein kinase C betaII (PKCbetaII) in the progression of postoperative pain following skin/muscle incision and retraction (SMIR) surgery. Materials and methods: SMIR postoperative pain model was established in rats, akin to a clinical procedure. The expression level and location of p PKCbetaII were observed in dorsal root ganglion (DRG) or spinal cord from SMIR operated rats by Western blotting and immunofluorescence. In addition, the effects of PKCbetaII on the expression of protein gene product 9.5 (PGP9.5) or vascular endothelial growth factor (VEGF) were assessed by using pharmacological activator and inhibitor of PKCbetaII. Moreover, mechanical withdrawal threshold (MWT) was assessed before or after SMIR-operated rats were treated with inhibitor or activator of PKCbetaII. Results: The expression of PKCbetaII in DRG and spinal cord was significantly increased after SMIR surgery (P < 0.001, P < 0.01) and expression of PKCbetaII was located in the neurons of the spinal cord, and magnocellular neurons, non-peptide neurons, and peptide neurons in DRG. Besides, compared with skin/muscle incision group, retraction caused a marked increase in the expression of PKCbetaII and a significant decrease of MWT (P < 0.001, P < 0.05). The activator of PKCbetaII greatly increased the expression of PGP9.5 and VEGF (P < 0.05, P < 0.01) and enhanced MWT (P < 0.001), while inhibitor of PKCbetaII decreased the expression of PGP9.5 and VEGF and attenuated MWT (P < 0.05, P < 0.01, P < 0.001). Conclusion: Activation of PKCbetaII signaling pathways might be an important mechanism in the progression of postoperative pain. PMID- 30310313 TI - Effects of controlled ovarian stimulation on toxicity of TAC chemotherapy in early breast cancer patients. AB - Background: Oocyte and embryo cryopreservation, using controlled ovarian stimulation (COS), are common fertility preservation methodologies in breast cancer patients receiving gonadotoxic neo (adjuvant) chemotherapy (CT). The effects of COS and peak estradiol levels on CT-induced side effects are unknown. Patients and methods: Eighteen patients with stage II and III breast cancer underwent oocyte or embryo cryopreservation at Leiden University Medical Center before receiving docetaxel, adriamycin, and cyclophosphamide (TAC) CT (COS group). A control group (N=18) was retrospectively selected from breast cancer patients, aged between 18 and 40, who underwent TAC CT without fertility preservation. CT -induced toxicity in the 2 groups was compared using chi2 analysis. Associations between peak estradiol levels and distinct stimulation protocols and side effects in the COS group were investigated by using regression analysis. Results: Patient characteristics between both groups were similar, except for a lower age in the COS group vs the control group (30.5 vs 35.2 years, P=0.005). No differences were seen in grade III/IV side effects between both groups. In the COS group, an increase in thrombopenia grade I/II was seen, while grade I/II stomatitis and constipation were significantly lower in the COS group as compared with the control group (P=0.006 and P=0.008, respectively). In the COS group, no association was found between the peak estradiol levels and distinct stimulation protocols and side effects of CT. Conclusion: COS prior to TAC CT was not associated with an increase in grade III/IV side effects. Interestingly, COS may have a protective effect on mucositis and constipation. Moreover, the peak estradiol levels and distinct stimulation protocols had no effect on grade III/IV side effects in our study. PMID- 30310312 TI - Prognostic value of the combination of microsatellite instability and BRAF mutation in colorectal cancer. AB - Purpose: The aim of this study was to investigate the prognostic value of the combination of microsatellite instability (MSI) and BRAF V600E mutation in colorectal cancer (CRC). Materials and methods: We compare the prognosis difference among CRC patients with four subtypes according to MSI and BRAF mutation, ie, microsatellite stable/BRAF wild type (MSS/BRAFwt), MSS/BRAF mutation (MSS/BRAFmut), MSI/BRAFwt, and MSI/BRAFmut, by pooling the previous related reports and public available data sets till December 2017 for the first time. Results: Twenty-seven independent studies comprising 24,067 CRC patients were included. Meta-analysis suggested that, compared with MSS/BRAFwt subtype, MSS/BRAFmut was associated with shorter overall survival (OS) (N=25, HR = 2.018, 95% CI = 1.706-2.388, P=2.220E-16), while there was a trend of association of MSI/BRAFmut with OS (N=13, HR = 1.324, 95% CI = 0.938-1.868, P=1.096E-01) and no association of MSI/BRAFwt with OS (N=17, HR = 0.996, 95% CI = 0.801-1.240, P=9.761E-01). Compared with MSI/ BRAFwt subtype, MSI/BRAFmut was a poor factor for OS (N=22, HR = 1.470, 95% CI = 1.243-1.740, P=7.122E-06). Compared with MSS/BRAFmut subtype, both MSI/BRAFwt (N=11, HR = 0.560, 95% CI = 0.433-0.725, P=1.034E-05) and MSI/BRAFmut (N=16, HR = 0.741, 95% CI = 0.567-0.968, P=2.781E 02) were favorable for OS. Subgroup analysis revealed similar results in all subgroups except the subgroup of stage IV cancer, in which MSI showed poor effects on OS in BRAF wild-type patients (N=6, HR = 1.493, 95% CI = 1.187-1.879, P=6.262E-04) but not in BRAF-mutated patients (N=5, HR = 1.143, 95% CI = 0.789 1.655, P=4.839E-01). Meta-analysis regression and test of interaction revealed no interaction of MSI with BRAF mutation when evaluating the associations of MSI/BRAF mutation subtypes with OS in CRC. Conclusion: Among the four subtypes according to MSI and BRAF mutation, MSS/BRAFmut was a poor prognostic factor, while MSS/BRAFwt and MSI/BRAFwt were comparable and favorable and MSI/BRAFmut was moderate in CRC. The combination of MSI/BRAF mutations could facilitate the planning of individualized treatment strategies and prognosis improvement in CRC. PMID- 30310314 TI - KLF6-SV1 is a new prognostic biomarker in postoperative patients with non-small cell lung cancer. AB - Objectives: Non-small cell lung cancer (NSCLC) is aggressive and associated with a poor prognosis. Recent studies have revealed that several genes are involved in the origin and progression of NSCLC. Kruppel-like factor 6 (KLF6) inactivation has been shown in some malignant tumors. KLF6-SV1, as one of the alternatively spliced KLF6 isoforms, has been found to be correlated with metastatic potential and poor survival in some cancers. The purpose of this study was to investigate the clinical and prognostic significance of KLF6-SV1 expression in NSCLC patients after curative resection. Patients and methods: A total of 79 patients were enrolled in this study. Enumeration data were analyzed using the chi-squared test or Fisher's exact probability test. Measurement data were represented as average+/-SD and t-test (homoscedasticity) or t'-test (homoscedasticity uneven). Univariate analysis was performed by modeling Kaplan-Meier survival curves. The log-rank test was used to calculate the survival rate. Multivariate analysis was carried out by the use of the Cox proportional hazard model. Results: KLF6-SV1 expression was correlated with pN (P<0.05) and pTNM stage (P<0.05). The expression of KLF6-SV1 in the adenocarcinoma group was significantly higher than that in the squamous cell carcinoma group (P<0.05). The 5-year survival rate for 79 NSCLC patients was 40.5%, and it was significantly associated with differentiation (P<0.05), pN (P<0.01), pTNM stage (P<0.01) and high expression of KLF6-SV1 (P<0.01). Cox multivariate regression demonstrated that differentiation, pN and KLF6-SV1 expression were independent factors for the 5-year survival rate. Conclusion: KLF6-SV1 expression in adenocarcinoma was significantly higher than that in the squamous cell carcinoma, and high expression of KLF6-SV1 was significantly associated with pN and pTNM stage and poor survival in NSCLC patients. PMID- 30310315 TI - Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis. AB - Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2 negative (HER2-) gastric cancer patients. Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2- samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses. Results: The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2- samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3+/ 1,260.4 vs 1,157+/-586.6, P=0.015) and insertion of large fragment (1,125.6+/ 457.4 vs 500+/-138.9, P=0.002) in HER2+ samples were higher than those in HER2- samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2- samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2- samples. Conclusion: Differences in genomic landscape between HER2+ and HER2- gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2- gastric cancer. PMID- 30310316 TI - Villoglandular adenocarcinoma of cervix: pathologic features, clinical management, and outcome. AB - Background: The objective of the study was to investigate the management and prognosis of patients with villoglandular adenocarcinoma (VGA) of the uterine cervix. Materials and methods: The clinical presentation, pathology, management, and prognosis of 41 patients with VGA or other types of cervical adenocarcinoma (ADC) were retrospectively reviewed. Results: During the patient follow-up period, the proportion of VGA was 8.1% in the cervical ADC cohort (41/507). The median age of the patients with VGA was 41.0 years. The most common presenting symptom was cervical contactive bleeding. There were 38 patients classified as FIGO stage IA1-IB. The median follow-up period was 38.5 months. There were no patient deaths, and only one patient showed recurrence. One of the patients delivered a healthy baby at 34 weeks of gestation prior to treatment with radical hysterectomy. The HPV HC2 test results showed that most patients were positive for HPV infection. HPV 16, 18, and 56 were positive in the 8 patients with HPV type test results. There were significant differences in the grade, depth of stromal invasion, lymph node metastasis, and recurrence between the VGA cases of FIGO stage I and the other types of cervical ADC of FIGO stage I (p<0.05). Conclusion: This study confirmed that VGA is a type of well-differentiated cervical cancer characterized by shallow stromal invasion, less lymph node metastasis. VGA is associated with less recurrence than other types of cervical ADC. PMID- 30310317 TI - Galectin-3 and beta-catenin are associated with a poor prognosis in serous epithelial ovarian cancer. AB - Purpose: This study was designed to explore the expression levels of Galectin-3 (Gal-3) and beta-catenin in serous epithelial ovarian cancer (SEOC), the linkage between their expressions, and the clinicopathological features of SEOC patients. Patients and methods: Seventy-four SEOC patients' specimens were detected for Gal 3 and beta-Catenin expressions using immunohistochemistry, and the association between beta-catenin or Gal-3 protein expressions and clinicopathological features, treatment effects, and prognosis were analyzed using SPSS 19.0. Western blot was used to analyze protein expressions of Wnt/beta-catenin pathway in ovarian cancer cell lines. Results: There was a statistically significant positive correlation between Gal-3 and beta-catenin expressions in SEOC (r=0.304 and P=0.001). Gal-3 expression was related to the grade (P=0.037), clinical stage (P=0.034), platinum resistance (P=0.030), and recurrence (P=0.001) in SEOC. There was a significant correlation between beta-catenin with recurrence in SEOC (P=0.035). Platinum resistance (P=0.003) and Gal-3 expression (P<0.001) were independent risk factors for poorer overall survival (OS). OS of the strongly positive Gal-3 group was significantly lower than that of the negative and weakly positive groups (log-rank test, P=0.001). OS of the positive beta-catenin group was lower than that of the negative beta-catenin group (log-rank test, P=0.034). Downregulating Gal-3 expression attenuated the protein expressions of Wnt/beta catenin pathway in ovarian cancer cell lines. Conclusion: Gal-3 might activate Wnt/beta-catenin signaling pathway in SEOC. Hence, Gal-3 may serve as a prognostic factor for SEOC. Targeting Gal-3 may be a promising new treatment approach for SEOC. PMID- 30310319 TI - Erratum: Epidermal growth factor receptor gene mutations in non-small-cell lung cancer cells are associated with increased radiosensitivity in vitro [Erratum]. AB - [This corrects the article on p. 3551 in vol. 10.]. PMID- 30310318 TI - Benefit of adjuvant radiotherapy following narrow-margin hepatectomy in patients with intrahepatic cholangiocarcinoma that adhere to major vessels. AB - Purpose: To evaluate the role of adjuvant radiotherapy after narrow-margin (<1.0 cm) resection in patients with intrahepatic cholangiocarcinoma (ICC) adherent to major vessels. Patients and methods: This retrospective study included 70 ICC patients. Forty-nine patients received narrow-margin (<1.0 cm) hepatectomy and 21 patients underwent wide-margin (>=1.0 cm) hepatectomy (Group C). Twenty-six of 49 were treated with postoperative radiotherapy (Group A), while the remaining 23 did not receive radiotherapy (Group B). Clinical outcomes were compared in the 3 groups. Toxicities of radiotherapy were evaluated. Results: With a median follow up time of 42 months, the 3-year overall survival (OS) and disease-free survival rates were 55% and 44% for Group A, 20% and 10% for Group B, and 65% and 33% for Group C, respectively. The OS and disease-free survival in Groups A and C were comparable and improved compared to Group B (Group A vs B, P=0.011 and P=0.031; and Group C vs B, P=0.031 and P=0.105). Multivariate analysis showed that receiving narrow-margin resection only (adjusted hazard ratio: 3.73; 95% CI: 1.36 10.25; P=0.001) was a significant poor prognostic risk factor of OS. Group B experienced more intrahepatic recurrence and extrahepatic recurrence than Groups A and C. For Groups A and B, the 3-year intrahepatic recurrence rates were 36% vs 67% (P=0.133) and extrahepatic recurrence rates were 43% vs 65% (P=0.007). Only 2 patients in Group A suffered from grade 3 toxicities. No patient developed classic or nonclassic radiation-induced liver disease. Conclusion: Postoperative radiotherapy following narrow-margin hepatectomy seems to be efficacious and well tolerated in patients with ICC adjacent to major vessels. PMID- 30310320 TI - Identification of WDR12 as a novel oncogene involved in hepatocellular carcinoma propagation. AB - Background: Hepatocellular carcinoma (HCC) is one of the most common malignant cancer worldwide. Importantly, the precise mechanisms causing HCC pathogenicity are still unknown. The identification of potential oncogenes plays significant roles in finding novel therapeutic targets for human HCC. Purpose: WDR12 (WD repeat protein 12), a member of WD repeats family, plays crucial roles in the ribosome biogenesis pathway. However, Whether WDR12 contributes to HCC development remains unknown. The objective of this study was to elucidate the role of WDR12 in HCC development. Methods: The expression level of WDR12 in HCC tissues and adjacent non-tumor tissues were detected form Gene Expression Omnibus (GEO) database. The expression level of WDR12 in HCC cell lines were examined by RT-PCR and western blot. Kaplan-Meier analysis were used to analyze the effect of WDR12 level on overall and disease-free survival of HCC patients. To examine whether WDR12 supports development of HCC, we inhibited expression of WDR12 by using an shRNA-encoding lentivirus system. Effects of WDR12 knockdown were evaluated on cell-growth, cell-proliferation and cell-migration. The mechanisms involved in HCC cells growth, proliferation and migration were analyzed by western blot assay. Results: In silico analysis of HCC data sets showed that elevated expression of WDR12 correlated with high serum AFP level, high vascular invasion, high histologic grade and high TNM stage in HCC patients. Furthermore, up-regulated expression of WDR12 significantly correlated with the short overall survival and recurrence time of HCC patients. The shRNA-mediated knockdown of WDR12 expression resulted in reduced proliferation and migration of HepG2 and Huh 7 cells. Notably, inhibition of WDR12 resulted in decreased phosphorylation of AKT, mTOR and S6K1. Conclusion: Our study indicates that WDR12 contributes to HCC propagation, and indicates that suppression of WDR12 may be a potential strategy for human HCC treatment. PMID- 30310321 TI - An intronic genetic variation of MGMT affects enhancer activity and is associated with glioma susceptibility. AB - Purpose: O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in repairing damaged DNA caused by alkylating agents. A number of cancer susceptibility loci have been recognized as enhancer variants. This study aimed to explore the significance of enhancer variants of MGMT in glioma susceptibility. Patients and methods: A retrospective case-control study consisting of 150 glioma patients and 327 controls was conducted to test whether enhancer variants of MGMT are associated with glioma susceptibility. Genotypes were determined by Sequenom MassARRAY technology. Associations were estimated by logistic regression. Biochemical assays were used to examine the function of glioma susceptibility locus. Results: We found that the A allele of rs10764901, an intronic variant of MGMT, was associated with a significantly decreased risk of glioma. The rs10764901 AA genotype carriers had an OR of 0.49 (95% CI, 0.24 0.98; P=0.045) compared with the rs10764901 GG genotype. When the rs10764901 AG and AA genotypes were pooled for analysis, a significantly decreased risk of glioma was also found (OR, 0.63; 95% CI, 0.43-0.93; P=0.021). Functional analyses showed that the rs10764901 A allele drove a lower luciferase expression and had higher transcription factor binding affinity than the G allele. Conclusion: An enhancer variant of MGMT rs10764901 affects the regulatory activity of enhancer by altering the binding affinity of transcription factors and is associated with glioma susceptibility. PMID- 30310322 TI - Young age is an independent adverse prognostic factor in early stage breast cancer: a population-based study. AB - Objective: To compare the prognosis of young breast cancer patients with the older ones. Patients and methods: Utilizing the Surveillance, Epidemiology, and End Results database, we identified 150,588 female breast cancer patients diagnosed during 2003-2014, including 6,668 patients younger than 35 years and 143,920 patients aged between 35 and 60 years. Kaplan- Meier analysis was performed to compare the prognosis of these two groups. Univariate and multivariate Cox proportional hazard models were utilized to identify independent prognostic factors and calculate the HR and 95% CI. Subgroup analysis was performed stratified according to the lymph node status and estrogen receptor (ER) status. Results: The young patients presented with more aggressive clinicopathological characteristics, including larger tumor size (P<0.001), more lymph node metastasis (P<0.001), higher grade (grades III and IV, P<0.001), more ER/progesterone receptor absence (P<0.001), and more human epidermal growth factor receptor 2 overexpression (P<0.001). The patients younger than 35 years presented with inferior breast cancer-specific survival (BCSS) and overall survival (OS) (log-rank, P<0.001) in comparison with the older ones. In the multivariable Cox proportional hazard regression analysis, young age remained to be an independent adverse prognostic factor in operable breast cancer in terms of BCSS (HR, 1.200; 95% CI, 1.110-1.297; P<0.001) and OS (HR, 1.111; 95% CI, 1.032 1.196; P=0.005). In the subgroup analysis, young age remained a significant adverse prognostic factor in N0 (BCSS), N1, and ER-positive subgroups (P<0.05). Conclusion: Young age is an independent adverse prognostic factor in operable breast cancer. Young patients may receive more intensive treatment than older ones. PMID- 30310323 TI - Modeling determinants of satisfaction with health care in youth with inflammatory bowel disease: a cross-sectional survey. AB - Purpose: Patient satisfaction is frequently used as a health care quality measure despite methodological challenges. By the example of pediatric inflammatory bowel disease (IBD), we assessed factors associated with low satisfaction and examined differences by type of provider. Patients and methods: In a cross-sectional design, a 32-item questionnaire and global questioning were used to assess satisfaction in patients aged 15-25 years. Determinants of low satisfaction were identified by logistic regression (OR with 95% CI). Separate models were calculated for patient-related variables such as age, socioeconomic status (SES), health status (emotional, somatic, quality of life) or region of residence (step 1), and impact of provider (pediatric specialist, adult specialist, no specialist) (step 2). As secondary analysis, we studied the effect of additional indicators such as waiting time, consultation time, and an IBD Management Quality Index (IMQI) on effect estimates (step 3). Results: A total of 567 cases were available for analysis (response 48.2%). The strongest predictors of low satisfaction were anxiety symptoms (OR 2.49, CI 1.14 to 5.45). In step 2, not being seen by a specialist (1.89, 1.16 to 3.10) and having been with the new provider for less than 12 months (1.71, 1.03 to 2.83) were associated with low satisfaction. Satisfaction with adult care provider was similar to pediatric care if adjusted for anxiety, health status, and time with provider (0.95, 0.59 to 1.51). Presence of other quality indicators (step 3), waiting time >30 minutes, consultation time <15 minutes, and low IMQI were all associated with low satisfaction. Age, SES, and region of residence were not found to affect satisfaction in any of the models. Conclusion: Anxiety symptoms were most strongly associated with low patient satisfaction. The relevance of recent provider change and not being seen by a specialist underlines the importance of well-planned transition in this age group. PMID- 30310325 TI - A burning question: does hot green tea drinking increase the risk of esophageal squamous cell carcinoma? PMID- 30310324 TI - Very hot tea drinking increases esophageal squamous cell carcinoma risk in a high risk area of China: a population-based case-control study. AB - Background: Previous studies on the association between green tea drinking and esophageal squamous cell carcinoma (ESCC) risk show inconsistent results. Materials and methods: We conducted a large population-based case-control study from 2010 to 2013 in a high-risk area of China, in which 1,355 ESCC cases and 1,962 controls were recruited. Information on lifelong tea drinking was collected via face-to-face interviews using an electronic structured questionnaire. ORs with 95% CIs were estimated using unconditional logistic regression models. Results: Most tea drinkers were males and consumed exclusively green tea. After adjustment for potential confounders, among men the OR of ever green tea drinking for ESCC risk was 1.52 (95% CI: 1.24-1.85), compared with never tea drinking. The excess risk increased monotonically with earlier age at starting, longer duration, more intensity, and accumulation of tea drinking. The OR of drinking very hot green tea for ESCC risk was 2.15 (95% CI: 1.52-3.05), compared with never drinking tea. For accumulation of tea drinking and the risk of ESCC, a non linear relationship was observed. Before the accumulation of tea drinking reached 5 L/day*years, drinking tea showed a mild protective effect; then the ORs sharply increased to around 2.0 from 5 L/day*years to 25 L/day*years, and leveled off thereafter. The non-linear relationship was further modified by tea temperature. The joint effect of tea drinking and alcohol consumption on ESCC risk was also significant (P=0.019). Conclusion: Very hot tea drinking significantly increases the risk of ESCC among Chinese men, which is particularly evident among alcohol drinkers. PMID- 30310326 TI - Sampling strategies for selecting general population comparison cohorts. AB - Background: For a patient cohort, access to linkable population-based registries permits sampling of a comparison cohort from the general population, thereby contributing to the understanding of the disease in a population context. However, sampling without replacement in random order can lead to immortal time bias by conditioning on the future. Aim: We compared the following strategies for sampling comparison cohorts in matched cohort studies with respect to time to ischemic stroke and mortality: sampling without replacement in random order; sampling with replacement; and sampling without replacement in chronological order. Methods: We constructed index cohorts of individuals from the Danish general population with no particular trait, except being alive and without ischemic stroke on the index date. We also constructed index cohorts of persons aged >50 years from the general population. We then applied the sampling strategies to sample comparison cohorts (5:1 or 1:1) from the Danish general population and compared outcome risks between the index and comparison cohorts. Finally, we sampled comparison cohorts for a heart failure cohort using each strategy. Results: We observed increased outcome risks in comparison cohorts sampled 5:1 without replacement in random order compared to the index cohorts. However, these increases were minuscule unless index persons were aged >50 years. In this setting, sampling without replacement in chronological order failed to sample a sufficient number of comparators, and the mortality risks in these comparison cohorts were lower than in the index cohorts. Sampling 1:1 showed no systematic difference between comparison and index cohorts. When we sampled comparison cohorts for the heart failure patients, we observed a pattern similar to when index persons were aged >50 years. Conclusion: When index persons were aged >50 years, ie, had high outcome risks, sampling 5:1 without replacement introduced bias. Sampling with replacement or 1:1 did not introduce bias. PMID- 30310327 TI - Parental nicotine replacement therapy and offspring bronchitis/bronchiolitis and asthma - a nationwide population-based cohort study. AB - Background: Prior evidence shows that environmental tobacco smoke is a risk factor for respiratory tract infections, wheeze, and asthma. Nicotine replacement therapy has been shown to increase smoking cessation. However, no prior studies have explored if parental use decreases the risk of bronchitis/bronchiolitis and asthma in the offspring. Objective: To examine whether nicotine replacement therapy varenicline, given to parents, was associated with a reduction in bronchitis/bronchiolitis and/or asthma in their children. Methods: This study is a population-based cohort study, linking data from nationwide registers, and using a within-individual design that minimizes selection effects and controls for time-invariant confounding factors. Participants included 37,420 parents with a collected prescription of varenicline with 72,392 offspring <18 years of age. Exposure was defined as collected prescriptions of varenicline among the parents. Primary outcomes were offspring hospital visits for bronchitis/bronchiolitis (ICD10: J20 or J21) and offspring hospital visits for asthma (ICD10: J45). Results: Parental varenicline treatment was associated with a lower rate of visits for bronchitis/bronchiolitis in their children (incidence rate ratio [IRR]=0.67; 95% CI=0.50-0.91), but no association was found for asthma (IRR=1.08; 95% CI=0.97-1.19). The rate reduction of bronchitis/bronchiolitis was similar when we restricted data to children aged 0-3 years (IRR=0.71; 95% CI=0.52-0.97) and to maternal varenicline treatment (IRR=0.64; 95% CI=0.43-0.96). When restricting the outcomes to unplanned visits only (ie, excluding booked appointments, followups, and referrals), no associations were found (IRR=0.72, 95% CI=0.51-1.02). Conclusion: In this cohort study, nicotine replacement treatment in parents was associated with reduced hospital visits for bronchitis/bronchiolitis in their children. PMID- 30310329 TI - Erythropoiesis-stimulating agents and cardiovascular events in patients with myelodysplastic syndrome and multiple myeloma. AB - Introduction: Erythropoiesis-stimulating agent (ESA) treatment has been associated with an increased risk of venous thromboembolism (VTE) in patients with solid tumors and with an increased risk of cardiovascular events in patients with chronic kidney disease. The ESA-related risk in patients with hematological neoplasms remains unclear. We, therefore, aimed to assess the ESA-related risk of VTE, myocardial infarction (MI), and stroke in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). Materials and methods: We conducted a population-based cohort study in Denmark, using medical databases to identify 2,114 MDS patients and 3,105 MM patients diagnosed in 2004-2013. Incidence rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE, MI, and stroke associated with ESA treatment were computed. HRs were calculated in time-dependent Cox regression and adjusted for age, sex, MDS prognosis group, comorbidities, and treatments. Results: Incidence rates per 1,000 person-years for VTE, MI, and stroke were 10.8, 8.2, and 16.0 in MDS patients, and 21.9, 10.2 and 9.9 in MM patients without ESA treatment, respectively. MDS patients with ESA treatment had a 1.6-fold increased risk of MI (HR 1.60 [95% CI 0.90-2.86]) and an almost twofold increased risk of stroke (HR 1.94 [95% CI 1.28-2.94]). Adjusted HR for VTE was 1.04 (95% CI 0.57-1.89) compared with MDS patients without ESAs. In MM patients with ESAs compared with patients without ESAs, HRs were 1.41 (95% CI 0.96-2.08) for VTE, 1.23 (95% CI 0.68-2.20) for MI, and 1.63 (95% CI 0.96-2.77) for stroke. Conclusion: ESA use was associated with stroke in MDS patients. Among MM patients, ESA treatment was associated with a higher risk of all cardiovascular events, although all CIs included equivalence. PMID- 30310328 TI - COPD in patients after heart transplantation is associated with a prolonged hospital stay, early posttransplant atrial fibrillation, and impaired posttransplant survival. AB - Objectives: COPD is associated with reduced physical activity, an increased risk for pulmonary infections, and impaired survival in nontransplant patients. The aim of this study was to investigate the influence of COPD in patients after heart transplantation (HTX). Methods: We performed an observational retrospective single-center study of 259 patients receiving HTX at Heidelberg University Hospital between 2003 and 2012. Patients were stratified by the Tiffeneau index (forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC]) <0.70 before HTX. The analysis included demographics, posttransplant medication, length of the initial hospital stay after HTX, early posttransplant atrial fibrillation (AF), mortality, and causes of death. Results: In total, 63 (24.3%) patients had an FEV1/FVC <0.70. These patients showed a prolonged hospital stay after HTX (52.0 days vs 43.4 days, mean difference (MD) = 8.6 days, 95% CI: 0.2, 17.0 days), a higher rate of early posttransplant AF (19.0% vs 8.2%, MD = 10.8%, 95% CI: 0.4%, 21.2%), and an increased 30-day mortality (9.5% vs 2.6%, HR = 3.79, 95% CI: 1.16, 12.40). Kaplan- Meier analysis showed a significant inferior 5-year survival in patients with an FEV1/FVC <0.70, along with a higher percentage of death due to transplant failure and infection/sepsis. In addition, a multivariate analysis for mortality within 5 years after HTX indicated an FEV1/FVC <0.70 as a significant risk factor for impaired 5-year posttransplant survival (HR =4.77, 95% CI: 2.76, 8.22). Conclusion: COPD in patients after HTX is associated with a prolonged hospital stay, early posttransplant AF, and impaired posttransplant survival. PMID- 30310330 TI - Chronic diseases in the children of women with maternal thyroid dysfunction: a nationwide cohort study. AB - Objective: Maternal thyroid disease (TD) during pregnancy is associated with adverse birth outcomes, but little is known on its long-term outcomes. We aimed to examine if children born to mothers with TD have increased disease risk during childhood and adolescence. Patients and methods: A register-based cohort study was conducted on all live born children in Denmark from 1989 to 2013, including the association between maternal TD during pregnancy and somatic and psychiatric diseases in the children. Cox proportional hazards models were used to compute hazard ratios (HRs) according to the type of maternal TD, Graves' disease, and Hashimoto's thyroiditis. Results: A total of 2,618 children were born to women with Graves' disease, 760 to women with Hashimoto's thyroiditis (exposed), and 1,557,577 to women without any TD (unexposed). The median follow-up time for children born to mothers with Graves' disease was 9.3 years (25/75 percentile 5.4/13.9 years) and with Hashimoto's thyroiditis was 4.8 years (25/75 percentile 2.5/8.2 years). In children exposed to maternal Graves' disease in utero, the adjusted HR of TD was 12.83 (95% CI, 9.74-16.90), Graves' disease was 34.3 (95% CI, 20.23-58.35), and type 1 was diabetes 2.47 (95% CI, 1.46-4.18). In children exposed to maternal Hashimoto's thyroiditis, the adjusted HR of Hashimoto's thyroiditis was 24.04 (95% CI, 5.89-97.94). Conclusion: Our data suggest that children born to women with Graves' disease and Hashimoto's thyroiditis have excess long-term morbidities in childhood and adolescence. We particularly found an increased risk of any TD and type 1 diabetes to be diagnosed in children exposed in utero to Graves' disease. These novel findings are relevant for pediatricians, stressing the importance of history of maternal disease when evaluating children with suspected endocrine disorders. PMID- 30310331 TI - Thai women's experiences of and responses to domestic violence. AB - Purpose: Domestic violence has been linked to many health consequences. It can impact women's mental, physical, sexual, and reproductive health, and all of these effects can be long lasting. Despite the growing awareness of the deleterious effects of domestic violence in Thailand, there have been few nation wide studies that have examined the issue and its consequences. In fact, Thailand has not examined intimate partner violence incidence for the past 20 years. This study aimed to investigate the consequences of domestic violence across the country. Subjects and methods: A cross-sectional study was conducted in four areas of Thailand: central, southern, northern, and northeastern. One province in each area was selected by simple random sampling techniques. One thousand four hundred and forty-four married or cohabiting females in a heterosexual union, aged 20-59 years, were included in the sample and were interviewed about their experiences of psychological, physical, and sexual violence by their male partners. Results: One thousand four hundred and forty-four women completed the interviews. Sixteen percent of respondents encountered domestic violence in its various psychological, physical, or sexual forms. In the majority of cases, all forms of domestic violence were exerted repeatedly. Four-fifths of women who faced domestic violence reported that it had an impact on their physical and mental health as well as employment. This study also found that half of the domestic violence survivors reported their children had witnessed violent situations. These women exercised four coping strategies to deal with their domestic violence: 1) counseling; 2) requesting help from others; 3) fighting back; and 4) running away from home. Conclusion: The findings confirm that domestic violence has implications that extend beyond health and result in the deterioration of the quality of women's lives. These results underscore that domestic violence is a serious problem that must be addressed in Thai society. PMID- 30310333 TI - Modified transtibial versus anteromedial portal techniques for anterior cruciate ligament reconstruction, a comparative study. AB - Purpose: This study compared the accessory anteromedial portal (AAMP) and the modified transtibial technique (MTTT)" for single-bundle anterior cruciate ligament (ACL) reconstruction. Patients and methods: Sixty active adult patients with ACL tear were randomly assigned into two equal groups who were treated surgically. One group was operated on using AAMP and the other group through MTTT. Both the groups had the same postoperative course and were followed for 1 year after surgery. The follow-up included Lysholm and International Knee Documentation Committee (IKDC) subjective knee evaluation forms, IKDC objective knee examination form, and radiological evaluation. Results were evaluated and compared with each other. Results: There was no significant difference in subjective effects or clinical examination between the two groups. Regarding radiological angles, the AAMP had more oblique graft orientation in the coronal plane than the MTTT, but both were found to be more slanted than native ACL. Also, the MTTT had succeeded to place the graft and tunnel more obliquity than the traditional non-anatomic TTT and better than the anatomic ranges despite having the graft inclination of the AAMP higher than the MTTT. The complaints from the patients and subjective scoring were found to be positively related to graft stability. Patients with healthier preoperative subjective state had a smoother postoperative period and better outcome. Conclusion: This study offers simple modifications to the transtibial technique to allow near anatomic ACL reconstruction with similar results comparable to the AAMP and with fewer complications. PMID- 30310332 TI - Mechanisms and the clinical relevance of complex drug-drug interactions. AB - As a result of an increasing aging population, the number of individuals taking multiple medications simultaneously has grown considerably. For these individuals, taking multiple medications has increased the risk of undesirable drug-drug interactions (DDIs), which can cause serious and debilitating adverse drug reactions (ADRs). A comprehensive understanding of DDIs is needed to combat these deleterious outcomes. This review provides a synopsis of the pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms that underlie DDIs. PK mediated DDIs affect all aspects of drug disposition: absorption, distribution, metabolism and excretion (ADME). In this review, the cells that play a major role in ADME and have been investigated for DDIs are discussed. Key examples of drug metabolizing enzymes and drug transporters that are involved in DDIs and found in these cells are described. The effect of inhibiting or inducing these proteins through DDIs on the PK parameters is also reviewed. Despite most DDI studies being focused on the PK effects, DDIs through PD can also lead to significant and harmful effects. Therefore, this review outlines specific examples and describes the additive, synergistic and antagonistic mechanisms of PD-mediated DDIs. The effects DDIs on the maximum PD response (E max) and the drug dose or concentration (EDEC50) that lead to 50% of E max are also examined. Significant gaps in our understanding of DDIs remain, so innovative and emerging approaches are critical for overcoming them. PMID- 30310334 TI - Bilateral femoroacetabular impingement syndrome managed with different approaches: a case report. AB - Purpose: The purpose of this case report is to present the successful management of symptomatic bilateral femoroacetabular impingement (FAI) syndrome in a patient who underwent surgical treatment on one side and non-surgical treatment on the other side. Methods: We evaluated the treatment outcome of a young female presenting with bilateral FAI syndrome of cam morphology. A follow-up was performed at 5 years following surgical treatment on the right hip and 2 years following non-surgical treatment on the left hip. The evaluation included a clinical examination, patient-reported outcome measurements (PROM), plain radiographs, and magnetic resonance imaging (MRI). Results: The patient experienced subjective improvements bilaterally. The clinical examination revealed differences in range of motion between the surgically treated and the non-surgically treated sides, with internal rotation differing the most (20 degrees vs almost 0 degrees ). Flexion was, however, the same on both sides (125 degrees ). The PROM results were satisfactory on both sides, with slightly better results for the surgically treated side (the short version of the International Hip Outcome Tool [iHOT-12]: 96.9 vs 90, the Copenhagen Hip and Groin Outcome Score [HAGOS]: 90-100 vs 65-100). On the surgically treated side, the alpha angle decreased by 19 degrees postoperatively. An MRI did not reveal any injury to the cartilage or labrum on either side. Conclusion: This patient with bilateral FAI syndrome treated with arthroscopic surgery on one side and physiotherapy together with reduced physical activity on the other side, presented with good results bilaterally at follow-up. PMID- 30310335 TI - Accurate empathy of romantic partners increases pain ratings but promotes recovery. AB - Background: Perceived empathy is a commonly used strategy to cope with pain and is crucial for maintaining intimacy in dyadic relationships. Materials and methods: This study used the cold pressor test to investigate how perceived empathy and relationship type interact with the subjective perception of pain and objective measures of recovery time, using heart rate as an index. One hundred and ninety participants were recruited, including 49 friend dyads and 46 romantic partner dyads. Perceived empathy was manipulated by adopting three levels as the experimental conditions: high, accurate, and low. Results: In the subjective perception stage, the results showed a significant interaction of relationship type and empathy with pain reporting, indicating that romantic partners reported more pain than friends under the accurate empathy condition. There were no differences between the two groups in the high and low perceived empathy conditions. In the self-recovery stage, the results showed that romantic partners had less pain tolerance than friends in all three perceived empathy conditions. On the other hand, romantic partners recovered faster than friends under the accurate empathy condition, but not under the high and low perceived empathy conditions. Conclusion: These results suggest that perceived accurate empathy is necessary for romantic relationships when coping with pain. The findings deepen our understanding of the mechanism of perceived empathy, and the ways in which it modulates psychological and physiological responses in a social context. PMID- 30310336 TI - The effect of perspective taking on the mediation process. AB - Background: Previous research demonstrated several benefits of strategic perspective taking in the field of intergroup relations and, more specifically, in the negotiation processes aimed at conflict resolution. The present study, which analyzes the effect of perspective taking and mediation in a conflict setting, corroborates the psychological models that hypothesize the positive effects of the assumption of the competitor's perspective on having intergroup conflict and lessening of negative consequences. Materials and methods: After being involved in an epistolary debate on a topic for which their ingroup had very contrasting views compared to an outgroup, participants were asked to use a feeling thermometer to assess their level of intergroup hostility. Mediation was then used as a conflict-resolution strategy for half of the participants. Furthermore, the assumption of perspective was manipulated, resulting in a 2 (conflict: presence vs absence) * 2 (perspective taking: presence vs absence) * 2 (mediation: presence vs absence) between-subjects design. Finally, participants were asked to use the same feeling thermometer to evaluate whether feelings of hostility diminished. Results: The results show that in conflict situations, the level of hostility decreases the most when the mediation process is accompanied by perspective taking. Conclusion: The results extend recent results about the advantages of a significant social ability - perspective taking - for improving intergroup relations. PMID- 30310337 TI - Exploration of potential objective and subjective daily indicators of sleep health in normal sleepers. AB - Purpose: While the concept of "sleep health" has only recently been defined, how it relates to both subjective and objective sleep parameters is yet to be determined. The current study aimed to identify potential indicators of poorer sleep health, from subjective and objective daily sleep characteristics, in normal sleepers. Participants and methods: Eighty-three individuals aged 18-65 years with no history of sleep disorders, chronic physical or psychiatric illnesses, or substance misuse were recruited from the North of England. Secondary analysis of a series of standardized studies, which included psychometrics, actigraphy, and an in-lab polysomnography (PSG) component, was undertaken. Questions from several psychometric sleep scales were combined to create an aggregate measure of sleep health status. Subjective sleep continuity was assessed by 2-week sleep diary. Objective measures comprised two continuous weeks of actigraphy and two nights of in-lab PSG. Results: Significant negative correlations were evident between sleep health scores and both diary-derived subjective sleep latency (SL; diary) and actigraphy-derived SL (actigraphy). This was reflected by independent samples t-test between high and low sleep health groups. No relationships between sleep health and PSG parameters were observed. Regression analyses indicated sleep latencies from both the sleep diary and actigraphy as significant predictors, explaining 28.2% of the variance in sleep health. Conclusion: Perceived increases in SL appear to be a primary indicator of declining sleep health in normal sleepers. The majority of objective sleep parameters, including gross PSG sleep parameters, appear not to be sensitive to sleep health status in normal sleepers. Future research is needed to understand the physical and psychological correlates of sleep health in larger samples. PMID- 30310339 TI - "Toxic" bedside teaching: patient impact. PMID- 30310340 TI - Integrated pathology and radiology learning for a musculoskeletal system module: an example of interdisciplinary integrated form. PMID- 30310338 TI - Online information and support needs of young people with cancer: a participatory action research study. AB - Purpose: The Internet is a fully integrated part of young people's life and it is pivotal that online resources are developed to maximize the potential of the Internet to support those living with and beyond cancer. We sought to understand how young people with a cancer diagnosis use the Internet and to what extent information and support needs are met by existing online resources. Patients and methods: This was a participatory action research study involving 21 young people participating in workshops and individual interviews. Participants aged 13-24 years were diagnosed with a range of cancers. Young people were on treatment or had completed treatment; some had experienced relapse. Workshops consisted of participatory methods including focus group discussions, interactive activities, and individual thought, encompassing online resources used; when, how and what they were searching for, whether resources were helpful and how they could be improved. Results: Young people reported using communication platforms, entertainment sites, social media, medical websites, charity websites, and search engines to find information and support. Different online use and needs were described throughout their cancer timeline and online use was generally driven by negative emotions. Seven factors influenced access and engagement: 1) where young people were on their cancer timeline; 2) external influencing factors, such as family and environments; 3) emotional drivers; 4) what young people search for online; 5) resources, websites, and digital platforms used by young people; 6) availability, accessibility, and assessment of online information and resources; 7) emotional responses to using online resources. Conclusion: The way young people access and engage with online resources is complex with multiple influencing factors including powerful emotional drivers and responses to Internet searching. There is a need to develop resources that support the holistic needs of young people and this should be done in collaboration with young people. PMID- 30310341 TI - Promoting wellness and stress management in residents through emotional intelligence training. AB - Background: US physicians are experiencing burnout in alarming numbers. However, doctors with high levels of emotional intelligence (EI) may be immune to burnout, as they possess coping strategies which make them more resilient and better at managing stress. Educating physicians in EI may help prevent burnout and optimize their overall wellness. The purpose of our study was to determine if educational intervention increases the overall EI level of residents; specifically, their stress management and wellness scores. Participant and methods: Residents from pediatrics and med-ped residency programs at a university-based training program volunteered to complete an online self-report EI survey (EQ-i 2.0) before and after an educational intervention. The four-hour educational workshop focused on developing four EI skills: self-awareness; self-management; social awareness; and social skills. We compared de-identified median score reports for the residents as a cohort before and after the intervention. Results: Thirty-one residents (20 pediatric and 11 med-ped residents) completed the EI survey at both time intervals and were included in the analysis of results. We saw a significant increase in total EI median scores before and after educational intervention (110 vs 114, P=0.004). The stress management composite median score significantly increased (105 vs 111, P<0.001). The resident's overall wellness score also improved significantly (104 vs 111, P=0.003). Conclusions: As a group, our pediatric and med-peds residents had a significant increase in total EI and several other components of EI following an educational intervention. Teaching EI skills related to the areas of self-awareness, self-management, social awareness, and social skill may improve stress management skills, promote wellness, and prevent burnout in resident physicians. PMID- 30310342 TI - Medical students' perspectives on learning preferences within clinical settings. PMID- 30310344 TI - From final-year medical student to resident: changes in learning preferences. PMID- 30310343 TI - Addressing racial bias in wards. AB - Health disparities fall along racial lines, in part, due to structural inequalities limiting health care access. The concept of race is often taught in health professions education with a clear biologic underpinning despite the significant debate in the literature as to whether race is a social or biologic construct. The teaching of race as a biologic construct, however, allows for the simplification of race as a risk factor for disease. As health care providers, it is part of our professional responsibility and duty to patients to think and talk about race in a way that is cognizant of broader historical, political, and cultural literature and context. Openly discussing the topic of race in medicine is not only uncomfortable but also difficult given its controversies and complicated context. In response, we provide several evidence-based steps to guide discussions around race in clinical settings, while also hopefully limiting the use of bias and racism in the practice of medicine. PMID- 30310345 TI - Current perspectives on the role of body painting in medical education. AB - Body painting is a popular teaching and learning tool within medical education. Art-based approaches, such as body painting, allow students to learn in a fun and engaging manner. They are particularly useful for students who struggle with cadaveric study of anatomy. Body painting is not only limited to use for anatomical study, but it can also be beneficial as a mechanism for introducing clinical examination and associated communication skills. The use of vibrant color adds to its appeal and is often cited as the mechanism through which students effectively learn. PMID- 30310346 TI - Pre-matriculation clinical experience positively correlates with Step 1 and Step 2 scores. AB - Background: This study investigates whether students with pre-matriculation, formalized, clinical experience performed better in Step 1 and Step 2 of the United States Medical Licensing Exams (USMLE) compared to students without formal pre-matriculation clinical experience. Methods: This research investigation was a retrospective cohort study conducted at the University of Arizona College of Medicine in Tucson, Arizona, USA, and analyzed students in the Class of 2017 and Class of 2018. Formal clinical experience was defined as registered nurses, physician assistants, nurse practitioners, paramedics, emergency medical technicians, or licensed practical nurses for any amount of time prior to matriculation, as well as scribing for at least 6 months prior to matriculation. Students with any amount of shadowing experience were not considered to have clinical experience. The authors performed multiple regression analyses to investigate the effects of formal clinical experience on USMLE exam performance. Statistical significance was defined as P<0.05. All statistical analyses were performed using SAS 9.4. Results: Our study had a total of 227 students from the two classes, with 40 (17.6%) having formal pre-matriculation clinical experience, as already defined. Nine (3.96%) students were not assessed in USMLE Step 1 calculations, and 61 (26.9%) students were not assessed in USMLE Step 2 calculations due to an absence of recorded USMLE scores. Formal pre-matriculation clinical experience was a statistically significant positive predictor of USMLE Step 1 score (P=0.03) and USMLE Step 2 score (P<0.010). Conclusion: Formal pre matriculation clinical experience, as defined previously, positively correlates with an increase in USMLE Step 1 and Step 2 scores. PMID- 30310347 TI - Are we on the right track? Answers from a national survey of Thai graduates' perceptions during the transition to the 6-year PharmD program. AB - Purpose: To serve the higher demands of pharmaceutical services, pharmacy education in Thailand has shifted from 5-year BPharm program to 6-year PharmD program with two specialization tracks: pharmaceutical care (PC) and industrial pharmacy (IP). This study aimed to compare the perceptions regarding professional competencies, pharmacy profession, and planned workplace between graduates with 5 year BPharm and 6-year PharmD and between those with PC and IP specialty. Methods: A cross-sectional national survey using a paper-pencil self-administered questionnaire was distributed to all new graduates attending the pharmacy licensure examination in March 2015. Results: Of all 1,937 questionnaires distributed, 1,744 were returned and completed (90% response rate). Pharmacy graduates rated highest on their competencies in professional ethics, followed by PC services and system management. They rated low confidence in medication selection procurement and pharmaceutical industry competencies. The 6-year PharmD graduates showed higher confidence in ethics and professional pride than the 5 year BPharm graduates. Graduates with PC specialty rated higher perceived competency in PC, system management, primary care, and consumer protection domains, while the IP graduates were superior in IP and medication selection and procurement domains, and most graduates (PC and IP) intended to work mainly in a hospital or a community pharmacy. Hospital was preferred for the PC graduates, and the IP graduates were more likely to work in pharmaceutical industry, regulation and consumer protection, sales and marketing, and academia. Conclusion: With some gaps still to be filled, the transition from 5-year BPharm to 6-year PharmD program with specialty tracks gave extra confidence to graduates in their specialty competencies and professional pride, leading to differences in preferred workplace. The findings of this study reflect that Thai pharmacy education continues to adjust to the needs of the society and the changing health care environments. Longitudinal monitoring to observe this transition is needed for both curriculum adjustment and competency of the graduates. PMID- 30310348 TI - Response to the article titled "The role of smartphone game applications in improving laparoscopic skills". PMID- 30310349 TI - Relationship between buprenorphine adherence and relapse, health care utilization and costs in privately and publicly insured patients with opioid use disorder. AB - Background: Treatment for opioid use disorder is important because of the negative health, societal and economic consequences of illicit opioid use, but treatment adherence can be a challenge. This study assessed the association between buprenorphine medication-assisted treatment (MAT) adherence and relapse, health care utilization and costs. Patients and methods: Patients with opioid use disorder who were newly initiating a buprenorphine MAT regimen were identified in the 2008-2014 MarketScan(r) Commercial and Medicaid Databases and followed for 12 months after their earliest outpatient pharmacy claim for buprenorphine. Adherence was categorized using proportion of days covered (PDC) with buprenorphine, and patients with PDC>=0.80 were classified as adherent. Descriptive and adjusted analyses compared relapse prevalence, utilization and costs, all measured in the 12 months following buprenorphine MAT initiation, of adherent patients to patients in non-adherent PDC categories (PDC<0.20, 0.20<=PDC<0.40, 0.40<=PDC<0.60, 0.60<=PDC<0.80). Results: Adherent patients were 37.1% of the Commercial sample (N=16,085) and 41.3% of the Medicaid sample (N=5,688). In both samples, non-adherent patients were significantly more likely than adherent patients to relapse and to have hospitalizations and emergency department visits. As a result, as buprenorphine MAT adherence increased, pharmacy costs increased, but medical costs decreased. Total costs (pharmacy plus medical costs) in the 12 months following buprenorphine MAT initiation decreased with adherence in Commercial patients ($28,525 for PDC<0.20 to $17,844 for PDC>=0.80). A slight decrease in total costs in the 12 months following buprenorphine MAT initiation was also observed in Medicaid patients ($21,292 for PDC<0.20 to $18,621 for PDC>=0.80). After adjustment, total costs of adherent patients in the Commercial sample ($17,519) were significantly lower compared with those of non-adherent patients (range $20,294-$24,431). In the Medicaid sample, adjusted total costs were not significantly different between adherence groups. Conclusion: Buprenorphine MAT adherence in the 12 months following treatment was associated with reduced odds of relapse and reduced unadjusted medical costs. For Commercial patients who were adherent to treatment, the adjusted total costs were predicted to be 30% lower than those for patients with PDC<0.20. PMID- 30310350 TI - Analysis of psychotropic drug-related deaths in south Osaka. AB - Objective: The aim of this study was to investigate the occurrence of deaths due to psychotropic drugs in south Osaka during a 10-year period and discuss societal factors from a medical viewpoint. Methods: Psychotropic drug-related deaths were retrospectively investigated based on the forensic postmortem data of 1,746 decedents in 2005-2014, and we excluded cases in which stimulant drugs were detected. Of these, 133 cases (7.6%) were found to be psychotropic drug-related deaths and were analyzed. Results: Psychotropic drug-related deaths occurred in 78 males (59%; age range, 14-95 years) and 55 females (41%; 20-84 years). The direct cause of death was acute drug intoxication in many cases, and of these, acute combined drug intoxication due to the use of multiple drugs accounted for 76% of the deaths. Most of these victims were found to have gastrointestinal and cardiovascular diseases. Cases of psychotropic drug-related deaths had especially poor medical conditions. In addition, tests were positive for blood alcohol in 23% of the cases. Conclusion: The descriptive results revealed several factors that may be related to psychotropic drug-related deaths. To prevent drug abuse, several factors were deemed to be important, including improvements in the medical state of an individual, the avoidance of social isolation, and from a medical standpoint, the management of prescription drugs by medical personnel. PMID- 30310351 TI - Dual CLAVATA3 Peptides in Arabidopsis Shoot Stem Cell Signaling. AB - Plant shoot stem cell pool is constantly maintained by a negative feedback loop through peptide-receptor mediated signaling pathway. CLAVATA3 (CLV3) encode a 96 amino-acid protein which is processed to 12-amino-acid or arabinosylated 13-amino acid peptides, acting as a ligand signal to regulate stem cell homeostasis in the shoot apical meristem (SAM). Although arabinosylated 13-amino-acid CLV3 peptide (CLV3p) shows more significant binding affinity to its receptors and biological activities in the SAM, the physiological function of two mature forms of CLV3p remained an unresolved puzzle in the past decade due to the technical difficulties of arabinosylation modification in the peptide synthesis. Here, we analyzed the role of two mature CLV3 peptides with newly synthesized arabinosylated peptide. Beside shoot meristem phenotypes, arabinosylated CLV3p showed the conventional trait of CLV2-dependent root growth inhibition. Moreover, both 12-amino-acid and arabinosylated 13-amino-acid CLV3 peptides have analogous activities in shoot stem cell signaling. Notably, we demonstrated that non arabinosylated 12-amino acid CLV3p can affect shoot stem cell signaling at the physiological level unlike previously suggested (Ohyama et al., 2009; Shinohara and Matsubayashi, 2013; Shinohara and Matsubayashi, 2015). Therefore, these results support the physiological role of the 12-amino-acid CLV3p in shoot stem cell signaling in the deficient condition of arabinosylated 13-amino-acid CLV3p in Arabidopsis thaliana. PMID- 30310352 TI - Tosanoidesannepatrice, a new basslet from deep coral reefs in Micronesia (Perciformes, Percoidei, Serranidae). AB - The new species Tosanoidesannepatrice sp. n. is described from four specimens collected at depths of 115-148 m near Palau and Pohnpei in Micronesia. It differs from the other three species of this genus in life color and in certain morphological characters, such as body depth, snout length, anterior three dorsal fin spine lengths, caudal-fin length, and other characters. There are also genetic differences from the other four species of Tosanoides (d ~ 0.04-0.12 in mtDNA cytochrome oxidase I). This species is presently known only from Palau and Pohnpei within Micronesia, but it likely occurs elsewhere throughout the tropical western Pacific. PMID- 30310353 TI - Two new species of genus Limnias from Thailand, with keys to congeners (Rotifera, Gnesiotrocha). AB - Two new species and two morphological variant taxa of sessile rotifers found during a survey of Thai rotifers are reported upon. Living specimens were collected and identified from twelve sampling sites. The specimens were photographed, and prepared for SEMs of dorsal plates and trophi. Two new species of genus Limnias are recognized. Limniaslenis sp. n. possesses a corona with a relatively shallow ventral sinus, and a dorsal plate without any projection, whereas Limniasnovemceras sp. n. carries a corona with a deep and wide ventral sinus, and a dorsal plate with nine projections. Two morphological variants of Limniasmelicerta are discussed, which are designated as L.melicerta SH and L.melicerta LH on the basis of the length of the horns on their dorsal plates. Moreover, both a dichotomous key and a formula key are provide including all Limnias species known to date. PMID- 30310354 TI - First records of Gnathia Leach, 1814 and Tachaea Schioedte & Meinert, 1879 from South Korea, with descriptions of two new species (Isopoda, Cymothoida, Cymothooidea). AB - Two new species of cymothoid isopods, Gnathiakoreana sp. n. and Tachaeakoreaensis sp. n., are described from South Korea. The genera Gnathia Leach, 1814 and Tachaea Schioedte & Meinert, 1879 are recorded for the first time in South Korea. Gnathiakoreana sp. n. is distinguished from its congeners by having the smooth dorsal surface of the pereon, the strongly ridged unornamented paraocular ornamentation, the strong bifid mediofrontal process, and the serrated superior frontolateral process. Tachaeakoreaensis sp. n. is distinguished from its congeners by having the expanded propodus with serrated inferior margins in pereopods 1-3, the propodus with serrated inferodistal margins in pereopods 4-7, one seta on the apical lobe of the maxilla, and ten robust setae on the posterior margin of the pleotelson. PMID- 30310355 TI - A revision of the genus Eurhoptus LeConte, 1876 (Curculionidae, Cryptorhynchinae) of America north of Mexico. AB - The genus Eurhoptus LeConte, 1876 is revised for America north of Mexico. Eight species are recognized including E.pyriformis LeConte, 1876, E.sordidus (LeConte, 1876), E.curtus (Hamilton, 1893), resurrected name, and five new species as follows: E.rileyi new species (type locality, Texas, Hidalgo County, Bentsen Rio Grande State Park), E.imbricatus new species (type locality, Texas, Bandera County, Lost Maples State Natural Area), E.cariniventris new species (type locality, Texas, Bandera County, Lost Maples State Natural Area), E.occidentalis new species (type locality, Texas, Brewster County, Big Bend National Park), and E.aenigmaticus new species (type locality, Alabama, Winston County, Bankhead National Forest). Descriptions or redescriptions, and images of taxonomically important structures are presented for all species. A key to the eight species is included. PMID- 30310356 TI - Two new species of genus Magadhaideus Long & Chen, 2017 from China (Hemiptera: Fulgoromorpha: Achilidae). AB - Two new species of the planthopper genus Magadhaideus Long & Chen, 2017 from China, Magadhaideusluchunensis sp. n. and Magadhaideuspingbianensis sp. n., are described and illustrated. Photographs of the new species are provided and a key to species of Magadhaideus is also given. PMID- 30310357 TI - Ecological diversity of a snake assemblage from the Atlantic Forest at the south coast of Paraiba, northeast Brazil. AB - Despite an increase in studies focusing on snake ecology and composition in the northeastern Atlantic Forest, several poorly studied sites and environments remain. The aim of this study was to assess species richness and natural history attributes of the snakes of an assemblage in the Restinga, Tabuleiro and Forest environments of the Atlantic Forest of the south coast of Paraiba, northeastern Brazil. A total of 151 individuals of 27 species, 23 genera, and six families of snakes were found. The most effective sampling methods were time-constrained searches and incidental encounters. Species sampled most frequently were the blindsnake Epictiaborapeliotes, the Boa Constrictor Boaconstrictor, the Brown Vinesnake Oxybelisaeneus, and the Brazilian False Coral Snake Oxyrhopustrigeminus. The snake fauna is characterized mainly by terrestrial species found in open-area environments of Restinga and Tabuleiro, and with most species feeding on amphibians and small mammals. The rarefaction curve did not reach the asymptote and new species should be recorded for south coast of Paraiba in future studies. Despite the richness and composition of snakes of the south coast being similar to other areas in the state, there is a lack of some species typically linked to forests, and this is probably because of the high level of deforestation that the south area of the state has suffered. PMID- 30310358 TI - New records of Niceforo's big-eared bat, Trinycterisnicefori (Sanborn, 1949) (Chiroptera, Phyllostomidae), from the state of Maranhao, Brazil. AB - Niceforo's big-eared bat, Trinycterisnicefori (Sanborn, 1949), is a monotypic species which has been recorded in a number of Brazilian states, but has a disjunct distribution in this country. This study presents the first record of T.nicefori in the Brazilian state of Maranhao. The specimens were collected in the municipalities of Godofredo Viana and Candido Mendes, in fragments of the Amazon forest. One male (forearm: 38.00 mm, weight: 6 g) and one female (39.68 mm, 8 g) specimens were collected. The specimens presented chestnut-colored fur, and a chin with a pair of dermal pads arranged in a V-shape, without a central papilla. The COI gene sequences were plotted in the BOLD Systems platform, which confirmed the morphological identification of the species, with a 99.1% similarity in the male, and 99.4% in the female to existing sequences. This record extends the known distribution of T.nicefori in Brazil by approximately 310 km to the most eastern part of the Amazon Biome. PMID- 30310359 TI - A checklist of marine bryozoan taxa in Scottish sea regions. AB - Contemporary and historical bryozoan records were compiled to provide a comprehensive checklist of species in Scottish waters. The checklist comprises 218 species in 58 families, with representatives from each of the extant bryozoan orders. The fauna was relatively sparse compared to other regions for which bryozoan checklists were available e.g. New Zealand and Australia. Six non indigenous bryozoan species from the Scottish seas region were included in the checklist. Baseline information on species distributions, such as that presented in this checklist, can be used to monitor and manage the impact of human activities on the marine environment, and ultimately preserve marine biodiversity. PMID- 30310360 TI - Living alone in Japan: Relationships with happiness and health. AB - BACKGROUND: One-person households are the most common type of household in Japan, but relatively little is known about the causes and potential consequences of the rise in solo living in young adulthood. OBJECTIVE: I address two questions: What accounts for the rise in one-person households in young adulthood? How is solo living in young adulthood related to well-being? METHODS: I use census data to evaluate how much of the growth in one-person households at ages 20-39 between 1985 and 2010 is explained by change in marital behavior and how much is explained by other factors. I then use data from the 2000-2010 rounds of the Japanese General Social Survey to examine whether and why men and women living alone differ from those living with others in terms of happiness and self-rated health. RESULTS: Results of the first set of analyses indicate that changes in marital behavior explain all of the increase in one-person households for men and three-fourths of the increase for women. Results of the second set of analyses indicate that those living alone are significantly less happy than those living with others, whereas the two groups do not differ with respect to self-rated health. The observed differences in happiness are not explained by differences in subjective economic well-being or social integration. CONCLUSIONS: The relatively small magnitude of estimated differences in happiness and health provides little evidence to suggest that the projected rise in one-person households is likely to play a significant role in contributing to lower levels of well-being among young adults in Japan. PMID- 30310361 TI - Automatic Segmentation of 3D Perivascular Spaces in 7T MR Images Using Multi Channel Fully Convolutional Network. PMID- 30310362 TI - Non-rigid Brain MRI Registration Using Two-stage Deep Perceptive Networks. PMID- 30310363 TI - Factors Contributing to Missed Visits for Medical Care among Human Immunodeficiency Virus-Infected Adults in Seoul, Korea. AB - Background: It is important that patients with human immunodeficiency virus (HIV) remain under medical care to improve their health and to reduce the potential for HIV transmission. We explored factors associated with missed visits for HIV medical care according to age group. Methods: Data were derived from a city-wide, cross-sectional survey of 812 HIV-infected adults in Seoul. Multiple logistic analyses were used to explore predictors of missed visits. Results: Of the 775 subjects, 99.3% were treated with antiretroviral therapy (ART) and 12.5% had missed a scheduled appointment for HIV medical care during the past 12 months. Compared with the group aged >= 50 years, the 20-34-years and 35-49-years groups were strongly associated with missed visits (adjusted odds ratio [aOR], 5.0 and 2.2, respectively). When divided by age group, lower education level (aOR, 3.0) in subjects aged 20-34 years, low income (aOR, 3.5), National Medical Aid beneficiary (aOR, 0.3), and treatment interruption due to side effects of ART (aOR, 3.4) in subjects aged 35-49 years, and National Medical Aid beneficiary (aOR, 7.1) in subjects aged >= 50 years were associated with missed visits. Conclusion: In conclusion, younger age was a strong predictor of missed visits for HIV medical care. However, the risk factors differed according to age group, and the strongest predictor in each age group was related to socioeconomic status. PMID- 30310364 TI - ArmA and RmtB Were the Predominant 16S RMTase Genes Responsible for Aminoglycoside-resistant Isolates in Korea. AB - Pathogenic gram-negatives that produce 16S ribosomal RNA methyltransferases (16S RMTases) have already been distributed all over the world. To investigate the predominance of aminoglycoside resistance associated with 16S RMTases in Korea, we collected a total of 222 amikacin resistant Gram-negative clinical isolates from patient specimens between 1999 and 2015 from three hospital banks across Korea. ArmA and rmtB were the predominant 16S RMTase genes responsible for aminoglycoside-resistant isolates circulating in Korean community settings although only one rmtA-producing isolate was detected in 2006. PMID- 30310366 TI - Comparison of the Clinicopathologic Characteristics of Intraductal Papillary Neoplasm of the Bile Duct according to Morphological and Anatomical Classifications. AB - Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a recently defined entity and its clinical characteristics and classifications have yet to be established. We aimed to clarify the clinical features of IPNB and determine the optimal morphological classification criteria. Methods: From 2003 to 2016, 112 patients with IPNB who underwent surgery were included in the analysis. After pathologic reexamination by a specialized biliary-pancreas pathologist, previously suggested morphological and anatomical classifications were compared using the clinicopathologic characteristics of IPNB. Results: In terms of histologic subtypes, most patients had the intestinal type (n = 53; 48.6%) or pancreatobiliary type (n = 33; 30.3%). The simple "modified anatomical classification" showed that extrahepatic IPNB comprised more of the intestinal type and tended to be removed by bile duct resection or pancreatoduodenectomy. Intrahepatic IPNB had an equally high proportion of intestinal and pancreatobiliary types and tended to be removed by hepatobiliary resection. Morphologic classifications and histologic subtypes had no effect on survival, whereas a positive resection margin (75.9% vs. 25.7%; P = 0.004) and lymph node metastasis (75.3% vs. 30.0%; P = 0.091) were associated with a poor five-year overall survival rate. In the multivariate analysis, a positive resection margin and perineural invasion were important risk factors for survival. Conclusion: IPNB showed better long-term outcomes after optimal surgical resection. The "modified anatomical classification" is simple and intuitive and can help to select a treatment strategy and establish the proper scope of the operation. PMID- 30310368 TI - Chronic Kidney Disease and Hepatitis B Virus Surface Antigenemia. PMID- 30310367 TI - Coronary Artery Bypass Grafting with Arterial Grafts in Patients with Kawasaki Disease Affecting the Coronary Artery: a Korean Single-Center Study. AB - Background: This study aimed to review the long-term clinical outcomes and graft patency of coronary artery bypass grafting (CABG) using arterial grafts in patients with Kawasaki disease (KD) affecting the coronary artery. Methods: Twenty patients with KD who underwent CABG from January 2002 to June 2014 were enrolled. There were 4 male (20%) and 16 female (80%) patients with ages at operation ranging from 2 to 42 years (median, 17.5 years). Our routine operative strategy was off-pump CABG with arterial grafts. The mean follow-up duration was 59.5 +/- 48.5 months (range, 1-159 months). Coronary angiogram or computed tomography angiogram was used to evaluate graft patency in 16 patients (80%). Results: All patients survived CABG without late mortality. Left internal thoracic arteries were used in 19 patients, while right internal thoracic arteries were used in 10 patients. Right gastroepiploic arteries were used in 3 patients, and a saphenous vein graft (SVG) was used in 1 patient. Among the 20 patients, 2 patients underwent coronary reintervention with balloon angioplasty because of graft failure. Two patients underwent coronary reintervention because of new obstructive lesions that were not significant at the time of the initial operation. Patency rates at 5 and 10 years were 94% and 87%, respectively. The rate of freedom from coronary reintervention at 10 years was 82%. Conclusion: Off pump CABG with mainly arterial graft revascularization may be considered a good surgical option for coronary lesions caused by KD. PMID- 30310369 TI - Grandparenthood in Europe. PMID- 30310365 TI - Chronic Hepatitis B Infection Is Significantly Associated with Chronic Kidney Disease: a Population-based, Matched Case-control Study. AB - Background: Hepatitis B virus (HBV) infection leads to hepatic and extrahepatic manifestations including chronic kidney disease (CKD). However, the association between HBV and CKD is not clear. This study investigated the association between chronic HBV infection and CKD in a nationwide multicenter study. Methods: A total of 265,086 subjects who underwent health-check examinations in 33 hospitals from January 2015 to December 2015 were enrolled. HBV surface antigen (HBsAg) positive cases (n = 10,048), and age- and gender-matched HBsAg negative controls (n = 40,192) were identified. CKD was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 or proteinuria as at least grade 2+ of urine protein. Results: HBsAg positive cases showed a significantly higher prevalence of GFR < 60 mL/min/1.73 m2 (3.3%), and proteinuria (18.9%) than that of the controls (2.6%, P < 0.001, and 14.1%, P < 0.001, respectively). In the multivariate analysis, HBsAg positivity was an independent factor associated with GFR < 60 mL/min/1.73 m2 along with age, blood levels of albumin, bilirubin, anemia, and hemoglobin A1c (HbA1c). Likewise, HBsAg positivity was an independent factor for proteinuria along with age, male, blood levels of bilirubin, protein, albumin, and HbA1c. A subgroup analysis showed that HBsAg positive men but not women had a significantly increased risk for GFR < 60 mL/min/1.73 m2. Conclusion: Chronic HBV infection was significantly associated with a GFR < 60 mL/min/1.73 m2 and proteinuria (>= 2+). Therefore, clinical concern about CKD in chronic HBV infected patients, especially in male, is warranted. PMID- 30310370 TI - What do we know about grandparents? Insights from current quantitative data and identification of future data needs. AB - Against the background of a 'new wave' of empirical studies investigating various aspects of grandparenthood across a broad range of regional contexts, this article aims to take stock of what has been achieved so far and which lessons we can learn from this for the future. Our focus is on the measurement of grandparenthood and grandparenting in quantitative social surveys and the implications this has for the substantive questions we can ask and the answers we can get out of such data. For several broader questions-who is a grandparent and when does this transition happen; what does it mean to be a grandparent; and what are the implications of grandparenthood for families?-we review previous questionnaire items from a variety of surveys as well as studies in which they were used. We identify relevant issues related to these questions which cannot be adequately addressed with currently available data, but should be considered in new or ongoing survey projects. The answers provided by recent studies as well as the many still open questions identified here indicate excellent prospects for scholarship on grandparents in the years to come. PMID- 30310371 TI - Trends in the prevalence of grandparents living with grandchild(ren) in selected European countries and the United States. AB - Research from the United States has shown significant increases in the prevalence of three-generation households and in households consisting solely of grandparents and grandchildren. Such shifts in household composition, which are associated with socio-economic disadvantage, may reflect the activation of grandparents as a latent network of support in response to social and demographic changes such as rising partnership disruption. However, to date, little is known in Europe about trends in grandparent households or whether these households are also likely to be disadvantaged. Moreover, we know little about how the familistic and defamilised policy environments in Europe may affect the activation of such latent kin networks. Employing the Integrated Public Use Microdata Series-International and the Office for National Statistics' Longitudinal Study for England and Wales, we used multivariate techniques to investigate changes in prevalence over time in co-residence with a grandchild across Austria, England and Wales, France, Greece, Portugal, Romania, and the United States. We expected increases in grandparent households in Portugal and Greece, familistic societies with few public alternatives to family support. However, only Romania (like the US) showed an increase in the percentage of people aged 40 and over co-residing with their grandchildren in three-generation households between the late 1970s and 2002. Given rises in poverty and limited support for low-income families in Romania, rises in grandparent coresidence may reflect a coping strategy among poorer families to increasing financial hardship. Regardless of the trends, grandparent households in all the countries studied remained associated with socio-economic disadvantage. PMID- 30310372 TI - Grandparenting, education and subjective well-being of older Europeans. AB - We study whether grandparenthood is associated with older people's subjective well-being (SWB), considering the association with life satisfaction of having grandchildren per se, their number, and of the provision of grandchild care. Older people's education may not only be an important confounder to control for, but also a moderator in the relation between grandparenthood-related variables and SWB. We investigate these issues by adopting a cross-country comparative perspective and using data from the Survey of Health, Ageing and Retirement in Europe covering 20 countries. Our results show that grandparenthood has a stronger positive association with SWB in countries where intensive grandparental childcare is not common and less socially expected. Yet, this result is driven by a negative association between grandparenthood without grandparental childcare and SWB that we only found in countries where intensive grandparental childcare is widespread. Therefore, in accordance with the structural ambivalence theory, we argue that in countries where it is socially expected for grandparents to have a role as providers of childcare, not taking on such a role may negatively influence SWB. However, our results show that grandparental childcare (either intensive or not) is generally associated with higher SWB. Overall, we do not find support for a moderating effect of education. We also do not find striking differences by gender in the association between grandparenthood and SWB. The only noteworthy discrepancy refers to grandmothers being often more satisfied when they provide grandchild care. PMID- 30310373 TI - Grandparents providing childcare in Italy. AB - Research on the choices of childcare arrangements in Italy shows the fundamental role of grandparents in providing informal childcare. Therefore, it is important to understand how grandparents provide different types of childcare, especially in terms of differences in their socio-economic, demographic and physical status, jointly with the characteristics of their grandchildren. Grandparents aged 50 and over with at least one non-co-resident grandchild aged 13 years or less were selected from the 2009 Italian household survey. Multilevel multinomial logistic regression models for grandmothers and grandfathers were used to identify the determinants of the probability of providing childcare intensively, occasionally or during school holidays rather than never. The probability of a grandparent providing intensive childcare is significantly reduced by being: male, unmarried, in bad health and with inadequate economic resources. Nevertheless, when analysing the probability of providing childcare occasionally or during holidays, the individual characteristics of grandparents and grandchildren are less significant compared to intensive childcare, meaning that grandparents provide non-intensive care regardless of their individual characteristics, and this is particularly true for grandmothers. Results confirm the fundamental importance of grandparents in providing informal childcare in Italy, and they offer useful information to understand the individual characteristics associated with different types of grandparental childcare. PMID- 30310374 TI - Grandparenting after parental divorce: The association between non-resident parent-child meetings and grandparenting in Italy. AB - Previous studies have shown that parental divorce has negative consequences on parent-child relationships and that these effects extend to relations between grandchildren and their grandparents. After parental divorce, grandchildren have less intense and lower quality relations with their grandparents. Some studies suggest that this negative association between union dissolution in the middle generation and grandparent-grandchild relations is explained by the post-divorce residential arrangements and, to a lesser extent, by the gatekeeping role exercised by the resident parent. The role of the frequency of meetings between the non-resident parent and his/her children, however, has been often overlooked in this literature. Using cross-sectional data from the Italian Family and Social Subject Survey, our study explores the extent to which frequent meetings between non-resident separated or divorced parents and their children below age 14 are correlated with grandparent involvement in looking after their grandchildren. The results show that young children who have very frequent meetings with their non resident parents are more likely to receive care from their grandparents than are those who meet the non-resident parents once a week or less frequently. PMID- 30310375 TI - Family reciprocity of older Singaporeans. AB - Reciprocity is a powerful motivation in social life. We study what older people give to their family for help received. Data are from the Panel on Health and Aging of Singaporean Elderly, Wave 2 (2011; persons aged 62+; N = 3103). Giving and receiving help are with family members other than spouse in the same household, in the past year. Types of help given and received are money, food/clothes/other material goods, housework/cooking, babysitting grandchildren, emotional support/advice, help for personal care, and help for going out. Multivariate models predict each type of giving help, with independent variables about the older person's resources, needs, and help received. Reciprocity is demonstrated by positive relationships between receiving and giving help. Results show two kinds of reciprocity: "nontangibles for tangibles" and "same for same." First, older people give their time and effort in return for money and material goods. This aligns with contemporary Singapore circumstances, in that older people tend to have ample time but limited financial resources, while family members (often midlife children) have the reverse. Second, same-for-same exchanges, such as housework both given and received, are shared tasks in families or normative behaviors in Singapore society. The results replicate and extend prior ones for Singapore. We discuss prospects for change in frequency and shape of family reciprocity as the state continues to modernize. PMID- 30310376 TI - Adjustment to retirement: effects of resource change on physical and psychological well-being. AB - A 1-year longitudinal study was conducted to examine the effects of retirement resources on the physical and psychological well-being of Hong Kong Chinese retirees during the transition to retirement. This study consisted of two assessments: Time 1 was conducted 6 months before retirement, while Time 2 was implemented 6 months after retirement. Personal resources and physical and psychological well-being were measured in the two assessments. The final sample contained 128 retirees who completed both assessments. Compared with Time 1, the retirees reported fewer financial resources at Time 2. Change in cognitive resources was significantly predictive of the changes in physical functioning, life satisfaction, psychological well-being, and psychological distress during the transition period. The findings of this longitudinal study reveal that in addition to financial, physical, and social resources that have often been emphasized in the past literature, mental resources also play an important role in positive adjustment to retirement. Future retirement planning programs are recommended to include modules for strengthening cognitive, emotional, and motivational resources of retired persons. PMID- 30310379 TI - Retraction: DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy. AB - [This retracts the article DOI: 10.3389/fncel.2017.00258.]. PMID- 30310377 TI - The acute physiological effects of high- and low-velocity resistance exercise in older adults. AB - The aim of the present study was to determine if workload matched, high-velocity (HVE) and low-velocity (LVE) resistance exercise protocols, elicit differing acute physiological responses in older adults. Ten older adults completed three sets of eight exercises on six separate occasions (three HVE and three LVE sessions). Systolic blood pressure, diastolic blood pressure and blood lactate were measured pre- and post-exercise, heart rate was measured before exercise and following each set of each exercise. Finally, a rating of perceived exertion was measured following each set of each exercise. There were no significant differences in blood lactate (F(1,9) = 0.028; P = 0.872; etaP2 = 0.003), heart rate (F(1,9) = 0.045; P = 0.837; etaP2 = 0.005), systolic blood pressure (F(1,9) = 0.023; P = 0.884; etaP2 = 0.003) or diastolic blood pressure (F(1,9) = 1.516; P = 0.249; etaP2 = 0.144) between HVE and LVE. However, LVE elicited significantly greater ratings of perceived exertion compared to HVE (F(1,9) = 13.059; P = 0.006; etaP2 = 0.592). The present workload matched HVE and LVE protocols produced comparable physiological responses, although greater exertion was perceived during LVE. PMID- 30310378 TI - Low blood pressure levels for fall injuries in older adults: the Health, Aging and Body Composition Study. AB - Fall injuries cause morbidity and mortality in older adults. We assessed if low blood pressure (BP) is associated with fall injuries, including sensitivity analyses stratified by antihypertensive medications, in community-dwelling adults from the Health, Aging and Body Composition Study (N = 1819; age 76.6 +/- 2.9 years; 53% women; 37% black). Incident fall injuries (N = 570 in 3.8 +/- 2.4 years) were the first Medicare claims event from clinic visit (7/00-6/01) to 12/31/08 with an ICD-9 fall code and non-fracture injury code, or fracture code with/without a fall code. Participants without fall injuries (N = 1249) were censored over 6.9 +/- 2.1 years. Cox regression models for fall injuries with clinically relevant systolic BP (SBP; <= 120, <= 130, <= 140, > 150 mmHg) and diastolic BP (DBP; <= 60, <= 70, <= 80, > 90 mmHg) were adjusted for demographics, body mass index, lifestyle factors, comorbidity, and number and type of medications. Participants with versus without fall injuries had lower DBP (70.5 +/- 11.2 vs. 71.8 +/- 10.7 mmHg) and used more medications (3.8 +/- 2.9 vs. 3.3 +/- 2.7); all P < 0.01. In adjusted Cox regression, fall injury risk was increased for DBP <= 60 mmHg (HR = 1.25; 95% CI 1.02-1.53) and borderline for DBP <= 70 mmHg (HR = 1.16; 95% CI 0.98-1.37), but was attenuated by adjustment for number of medications (HR = 1.22; 95% CI 0.99-1.49 and HR = 1.12; 95% CI 0.95 1.32, respectively). Stratifying by antihypertensive medication, DBP <= 60 mmHg increased fall injury risk only among those without use (HR = 1.39; 95% CI 1.02 1.90). SBP was not associated with fall injury risk. Number of medications or underlying poor health may account for associations of low DBP and fall injuries. PMID- 30310380 TI - Corrigendum: Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats. AB - [This corrects the article DOI: 10.3389/fncir.2018.00028.]. PMID- 30310381 TI - Corrigendum: Deliberation and Procedural Automation on a Two-Step Task for Rats. AB - [This corrects the article DOI: 10.3389/fnint.2018.00030.]. PMID- 30310382 TI - Corrigendum: Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew). AB - [This corrects the article DOI: 10.3389/fphar.2018.00869.]. PMID- 30310383 TI - Corrigendum: Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective. AB - [This corrects the article DOI: 10.3389/fmicb.2018.00950.]. PMID- 30310384 TI - Corrigendum: Variability of Bacterial Essential Genes Among Closely Related Bacteria: The Case of Escherichia coli. AB - [This corrects the article DOI: 10.3389/fmicb.2018.01059.]. PMID- 30310385 TI - Corrigendum: Therapeutic Effect of Intestinal Autochthonous Lactobacillus reuteri P16 Against Waterborne Lead Toxicity in Cyprinus carpio. AB - [This corrects the article DOI: 10.3389/fimmu.2018.01824.]. PMID- 30310386 TI - Corrigendum: Populus trichocarpa PtNF-YA9, a Multifunctional Transcription Factor, Regulates Seed Germination, Abiotic Stress, Plant Growth and Development in Arabidopsis. AB - [This corrects the article DOI: 10.3389/fpls.2018.00954.]. PMID- 30310387 TI - Corrigendum: Low-Light Dependence of the Magnetic Field Effect on Cryptochromes: Possible Relevance to Plant Ecology. AB - [This corrects the article DOI: 10.3389/fpls.2018.00121.]. PMID- 30310388 TI - Telemedicine and Geriatrics in France: Inventory of Experiments. AB - Telemedicine is now in vogue, being deployed through computer and communication tools in various health fields, such as diabetology, nephrology, dermatology, neurology, and cardiology. With population ageing, geriatrics is coming into sharp focus. Telemedicine practices differ for home-based or institutionalized patients in long-term care homes. We take a look at telemedicine projects in France concerning the elderly. PMID- 30310389 TI - The Influence of Heavy Metals and Trace Elements on Comatose Patients with Severe Traumatic Brain Injury in the First Week of Admission. AB - Purpose: The aim of this study is to investigate the possible role of heavy metals (lead and cadmium) and imbalance of trace elements (chromium, iron, zinc, copper, and manganese) in death among patients with severe traumatic brain injury. Material and Methods: A case-control study was conducted with 64 comatose patients with severe TBI, in the Department of Anesthesiology and Reanimation, Ibn Sina University Hospital and Hospital of Specialties in Rabat, Morocco; 22 healthy volunteers were recruited in Blood Transfusion Center of Rabat. Blood samples were collected from TBI patients, in the first week (3h after admission and each 48h during one week) and from healthy volunteers one time. Concentration of heavy metals and trace elements in serum was determined by electrochemical atomic absorption spectrometry. Statistical analysis was performed using Statistical software (SPSS) and the cases and controls were compared using the Mann-Whitney U test and Student's t-test for cadmium according to gender and final evolution. A P-value <0.05 was considered to be statistically significant. Results: Our data showed that the difference of heavy metals concentration (lead and cadmium) between patients and healthy subjects was not statistically significant. However, the difference of some trace elements concentration (iron, copper, chromium, and selenium) between patients and healthy subjects was statistically significant. According to the final evolution, the concentration of manganese was higher in dead patients and statistically significant (p = 0.04) for heavy metals; the concentration of lead was not statistically significant while the concentration in cadmium was statistically significant (p = 0.004). By sex, lead and cadmium were statistically significant, respectively p = 0.02, p = 0.001, and cadmium was higher in women, while lead was higher in men. Conclusion: Among all studied heavy metals (lead and cadmium) and trace elements (iron, zinc, copper, selenium, chromium, and manganese), manganese and cadmium may play a role in the death of patients from severe traumatic brain injury. PMID- 30310390 TI - Sex- and Age-Specific Optimal Anthropometric Indices as Screening Tools for Metabolic Syndrome in Chinese Adults. AB - Objectives: To compare the predictive ability of six anthropometric indices for identification of metabolic syndrome (MetS) and to determine their optimal cut off points among Chinese adults. Methods: A total of 59,029 participants were enrolled. Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), a body shape index (ABSI), body roundness index (BRI), and conicity index (CI) were measured. Receiver-operating characteristic curves analyses were performed to determine the discriminatory power of these indices for the identification of cardiometabolic risks and diagnosis of MetS. The differences in the area under the curve (AUC) values among the indices were evaluated. The Youden index was used to determine the optimal cut-off points. Results: WHtR and BRI exhibited the highest AUC values for identifying MetS and most cardiometabolic risk factors in both sexes, whereas ABSI showed the lowest AUC value. The general optimal cut-off points in women were 23.03 kg/m2 for BMI, 77.25 cm for WC, 0.490 for WHtR, and 3.179 for BRI; those in men were 24.64 kg/m2 for BMI, 87.25 cm for WC, 0.510 for WHtR, and 3.547 for BRI. The AUC values and cut-off points of the indices were also analyzed in each age and BMI category. Conclusions: In Chinese adults, WHtR and BRI showed a superior predictive power for MetS in both sexes, which can be used as simple and effective screening tools for cardiometabolic risks and MetS in clinical practice. PMID- 30310391 TI - Do we really know the duration of pain after rib fracture? AB - Introduction: The duration of pain after rib fracture is the question physicians are most frequently asked. The duration of pain following a traumatic rib fracture without any comorbidity is not widely published. Aim: We report our experience to investigate the duration of pain following isolated traumatic rib fractures without any traumatic comorbidity. Material and methods: We examined 182 patients with isolated rib fracture without any trauma to other body parts. The numeric rating scale (NRS) for pain was used to rate the level of pain. The NRS pain scores were evaluated in the emergency department at presentation, on the 15th day, and at the 3rd and 6th months of trauma. The Mann-Whitney U test was performed for the statistical analysis. Results: The pain level of young patients on the 15th day and at the third month and sixth month was lower than that in the old group, and the difference was statistically significant. While patients with two rib fractures had a higher pain level in the emergency room than those with one rib fracture, there was no statistically significant difference at other time points. In patients with anterior fractures, the pain level was significantly lower than in the lateral and posterior regions, whereas in the lateral fractures, the pain score was significantly higher than others at all time points except at the 6th month. The pain score of displaced fractures was significantly higher than that of non-displaced ones at all time points except the 6-month follow-up. Conclusions: Rib fractures cause significant pain and need appropriate medication. The time of the 6th month could be an important milestone. PMID- 30310392 TI - Evaluation of the metabolic response to open and minimally invasive resection of the oesophagus due to oesophageal cancer. AB - Aim: The aim of this study was to compare the metabolic response in the early postoperative period after radical resection of stage I and II oesophageal cancer applying a minimally invasive procedure and an open procedure involving classical laparotomy and thoracotomy. Material and methods: Serum concentrations of interleukin 6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), and total serum protein (TP) and leukocyte count (WBC) in blood collected on the day of surgery prior to the procedure (day 0) and on days 1, 2 and 7 after the surgery were measured in two groups of patients undergoing oesophageal resection due to cancer: applying a minimally invasive procedure involving laparoscopy and videothoracoscopy (group A) and applying a classical procedure involving full opening of the chest and abdominal cavity (group B). The study involved a total of 24 patients divided into two groups of 12 patients each. Results: Tumour necrosis factor-alpha concentration was lower in group A compared to group B on day 0, PCT concentration was lower in group A compared to group B on day 2 after surgery, and on the remaining days TNF alpha and PCT concentrations were not statistically different between groups. Conclusions: Lower concentration of PCT on post-surgery day 2 in the group of patients undergoing minimally invasive oesophageal resection seems to be associated with a smaller perioperative injury. Lower TNF-alpha concentration in serum collected on day 0 in the group of patients undergoing minimally invasive resection is associated with a lower stage of oesophageal cancer in this group. PMID- 30310393 TI - Graft vasculopathy in a Wistar rat model of heterotopic heart transplantation depending on gender matching between donors and recipients. AB - Introduction: Heart transplant is an accepted treatment modality in end-stage heart failure. The graft coronary artery vasculopathy is a main concern to explain the heterogeneity of the rejection process according to the gender of the donor and recipient. Aim: To assess the severity and type of mechanisms leading to failure of the graft. Material and methods: Experimental allogenic heart transplantation in the abdomen was performed on Wistar rats depending on the gender of the donor and recipient (F - female; M - male) in four groups (FF, FM, MM MF). The donor heart was implanted in the abdominal cavity of the recipient. Complete time of observation was 10 weeks. Bromodeoxyuridine was administered intraperitoneally to detect proliferating cells. Results: There was 42.5% graft survival in all experiments. The mean time of graft survival was 60 +/-18, 54 +/ 29, 58 +/-23 and 64 +/-18 days (FF, FM, MM and MF) and no significant difference was found in graft survival time among the four experimental groups (p = 0.73). None of the heart weight changes reached statistical significance. Conclusions: The use of an animal experimental model helps to understand the mechanisms leading to graft failure and to compare the changes that occur in rats to human hearts. The gender matching affects the survival of the transplanted heart and severity of the graft vasculopathy. PMID- 30310394 TI - Primary pulmonary sarcoma - long-term treatment outcomes and prognostic factors. AB - Introduction: Primary pulmonary sarcoma (PPS) is a rare type of non-epithelial malignant tumour of the lungs. Lung sarcomas are usually of metastatic character, originating from the primary tumour located in another organ. Pathomorphological diagnosis is difficult and therefore definitive diagnosis is usually determined after surgical treatment. Five-year survival of radical operated patients is 42 69%. Aim: To evaluate prognostic factors in PPS. Material and methods: Twenty-two patients who underwent surgical treatment between 1994 and 2009 were analysed. Results: Ten types of sarcomas were identified. All 22 analysed patients underwent operations and in 14 (63.6%) cases it was R0 resection (pneumonectomies, lobectomies, non-anatomical resections). In 8 out of 22 patients a locally advanced form was identified. Median overall survival (OS) in the group of all patients was 22 months, 5- and 10-year OS was 27% and 18% respectively, whereas in patients who underwent non-anatomical lung resections it was 80% and 60% respectively with median OS of 213 months. Overall survival was dependent on gender, completeness of treatment and size of tumour. Haemoptysis was a poor prognostic factor. Primitive neuroectodermal tumour was a type of sarcoma with a negative effect on progression-free survival. No impact of age, type of sarcoma, degree of histological malignancy, stage or adjuvant treatment on OS was noted. Conclusions: Primary radical surgical resection prolongs patient survival. Patients with tumours larger than 5 cm and men have worse prognoses. Future studies conducted on larger groups of patients diagnosed with PPS are necessary. PMID- 30310395 TI - Effects of carbon dioxide insufflation on anastomosis remodeling at a carotid artery site in rabbits. AB - Introduction: Use of carbon dioxide (CO2) insufflation (CDI) on the surgical field during heart surgery has become widespread, and in some units routine. Aim: To assess the effects of CDI on endothelial dysfunction in a carotid artery model in rabbits. Material and methods: Twelve randomly selected rabbits were divided into two groups. Right carotid arteries of the animals were transected and sutured with running suture technique. Then, 1 l/min CO2 insufflation was initiated with a 45 degrees angle. In the control group, the anastomotic field was irrigated with 0.1 ml/s flow of 0.9% saline. At day 28, the carotid artery segments were removed and prepared for histological specimens. Results: In the cross-sections of the control group vessel samples, thickening of the tunica intima was observed. Scoring the quantity of endothelial nitric oxide synthase (e NOS) and alpha-smooth muscle actin (alpha-SMA) positive staining revealed a nonsignificant difference between the experimental groups (p = 0.07). In the CO2 group, the intimal hyperplasia (p = 0.2) and the thickness of the tunica media (p = 0.2) were indistinguishable when compared to the control group. The mean luminal diameters and luminal areas of the experimental groups were all evaluated by histomorphometry and a significant differences was found between luminal areas (p = 0.016). On the other hand, no significant difference was found between mean luminal diameters (p = 0.055). Conclusions: Our study indicated that CDI can affect endothelial cell damage and the mean luminal diameters. PMID- 30310397 TI - What do we know about Tietze's syndrome? AB - Tietze's syndrome is a benign, self-limiting arthropathy, without purulent character. The disease most often involves articulations: sternocostal, sternoclavicular, or costochondral joints. The characteristic symptoms are tenderness, pain and edema involving one of the aforementioned joints on one side. Diagnosis of Tietze's syndrome is based on physical examination (increase of palpation tenderness in the affected joint), laboratory tests (increase of inflammatory parameters) and imaging studies (USG, MRI). Differential diagnosis of Tietze's syndrome is based on exclusion of costal cartilage inflammation, coronary syndrome and inflammatory changes in the lung and pleura. Most commonly the treatment is conservative, in resistant cases surgical. PMID- 30310398 TI - Prognostic scales in advanced heart failure. AB - Heart transplantation (HT) is the treatment of choice for patients with advanced heart failure (HF) who remain symptomatic despite optimal medical therapy. Due to the shortage of organs for transplantation and constantly increasing number of patients placed on waiting lists, accurate risk stratification is a crucial element of management in this population. Prognostic scales allow one to evaluate the patient prognosis, estimate the potential benefits of therapy and identify those patients most likely to benefit from advanced methods of treatment. In this review, we describe prognostic scales in advanced HF, concentrating on commonly used tools - the Heart Failure Survival Score (HFSS) and Seattle Heart Failure Model (SHFM) - as well as on the new promising scales for evaluating waiting list mortality and post-transplant outcomes. PMID- 30310396 TI - Obesity in patients with end-stage heart failure. AB - Obesity poses an increasing problem in patients with end-stage heart failure (HF). The most commonly used indicator of obesity is body mass index. The value of this parameter is widely taken into consideration when selecting the best way of treatment for patients with advanced HF. The aim of this paper is to outline the recent knowledge about obesity in the abovementioned group of patients. PMID- 30310401 TI - Carotid baroreceptor activation therapy for resistant hypertension and heart failure: a report of two cases. PMID- 30310399 TI - Surgical treatment of elderly patients with severe aortic stenosis in the modern era - review. AB - Surgical treatment of severe aortic stenosis offers good early and long-term results, even in elderly patients. Despite the implementation of percutaneous methods for the very high-risk group, surgical valve replacement remains the gold standard. The advanced age of patients should not be the only indicator limiting the possibility of surgery. In this review we present the most important information on the results of aortic stenosis surgical treatment in the groups of older patients. New methods such as percutaneous and minimally invasive methods of surgery are also discussed. Additionally, the presented information is referred to current guidelines for the treatment of severe aortic stenosis. PMID- 30310400 TI - The use of stem cells in ischemic heart disease treatment. AB - Ischemic heart disease is a major cause of death and disabilities worldwide. Unfortunately, not all patients are suitable for direct revascularization. Cell based therapies may be alternative options because of their potential to promote neovascularisation and endothelial repair, improving myocardial perfusion. The success of cell-based therapies depends on the type of implanted stem cells, delivery method and underlying disease. Several different cell populations including bone marrow-derived mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), CD34+, CD133+, endothelial progenitor cells, adipose-derived mesenchymal stromal cells (ASCs) and stem cells from placenta and umbilical cord have been investigated. Presently, no consensus exists about the best cell type for clinical regenerative therapy. Because the system of coronary arteries in the ischemic area is poor and most of the coronary artery is significantly narrowed or closed, direct implantation of stem cells in the ischemic area of the heart muscle appears an attractive method. PMID- 30310402 TI - Minimally invasive direct coronary artery bypass grafting in a 17-year-old patient with left anterior descending coronary artery compression in follow-up after arterial switch operation. PMID- 30310403 TI - Pulmonary artery sling diagnosed and corrected in an 11-year-old boy with refractory pulmonary infections and childhood-onset asthma. PMID- 30310404 TI - Mouse models for hepatitis B virus research. AB - Hepatitis B virus (HBV) infection remains a major global health problem; indeed, there are 250 million carriers worldwide. The host range of HBV is narrow; therefore, few primates are susceptible to HBV infection. However, ethical constraints, high cost, and large size limit the use of primates as suitable animal models. Thus, in vivo testing of therapies that target HBV has been hampered by the lack of an appropriate in vivo research model. To address this, mouse model systems of HBV are being developed and several are used for studying HBV in vivo. In this review, we summarize the currently available mouse models, including HBV transgenic mice, hydrodynamic injection-mediated HBV replicon delivery systems, adeno-associated virus-mediated HBV replicon delivery systems, and human liver chimeric mouse models. These developed (or being developed) mouse model systems are promising and should be useful tools for studying HBV. PMID- 30310405 TI - Protective effect of water extract of guibi-tang against pulmonary inflammation induced by cigarette smoke and lipopolysaccharide. AB - Water extract of guibi-tang (GB), a traditional Chinese, Japanese, and Korean herbal medicine, is used to treat memory impairment, insomnia, and peptic ulcers. The aim of this study was to investigate the protective effects of GB on pulmonary inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). C57BL/6 mice were used to develop a pulmonary inflammation model by exposing them to CS for 1 h per day for 7 days. LPS was intranasally administered to mice under mild anesthesia on day 5. GB was administered 1 h before CS exposure at doses of 50 or 100 mg/kg for 7 days. Our results showed that GB suppressed the CS and LPS induced elevation in inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), with significant reductions in protein, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 levels. Histological studies revealed that GB decreased the inflammatory cell infiltration into lung tissue caused by CS- and LPS-exposure. GB also significantly decreased the CS and LPS-induced expression of inducible nitric oxide synthase (iNOS) in the lung tissue. Taken together, GB effectively attenuated airway inflammation caused by CS and LPS. These results indicate that GB is a potential therapeutic herbal formula for pulmonary inflammatory disease. PMID- 30310406 TI - Dose dependence and durability of the therapeutic effects of Asparagus cochinchinensis fermented extract in an ovalbumin-challenged asthma model. AB - The butanol extract of Asparagus cochinchinensis roots fermented with Weissella cibaria (BAfW) significantly suppressed the inflammatory response induced by lipopolysaccharide (LPS) treatment in RAW264.7 cells. To investigate the dose dependence and durability of BAfW on the anti-asthma effects, alterations in key parameters were measured in ovalbumin (OVA)-challenged Balb/c mice treated with the different doses of BAfW at three different time points. The number of immune cells, OVA-specific IgE level, thickness of respiratory epithelium and mucus score decreased significantly in a dose-dependent manner in response to treatment with 125 to 500 mg/kg BAfW (P<0.05), although the highest level was detected in the 500 mg/kg treated group. Moreover, the decrease in these parameters was maintained from 24 to 48 h in the 500 mg/kg of BAfW treated group. At 72 h, the effects of BAfW on the number of immune cells, OVA-specific IgE level and thickness of respiratory epithelium partially disappeared. Overall, this study provides the first evidence that the anti-asthma effect of BAfW may reach the maximum level in OVA-challenged Balb/c mice treated with 500 mg/kg and that these effects can last for 48 h. PMID- 30310407 TI - Inhibitory effects of Pycnogenol(r), a pine bark extract, in a rat model of testosterone propionate-induced benign prostatic hyperplasia. AB - Benign prostate hyperplasia (BPH) is a male reproductive disease that has gained increasing importance in recent years. The present study investigated whether Pycnogenol(r) (PYC), a standardized French maritime pine bark extract, could prevent BPH induced by testosterone propionate (TP) in rats. Male Sprague-Dawley rats were randomly divided into five groups of six rats. One group was used as a normal control rats and the other groups received subcutaneous injections of TP for 4 weeks to induce BPH. In the two treatment groups, PYC (20 or 40 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the induction of TP. All rats were sacrificed at the scheduled termination time, the prostates were weighed, and histopathologic examinations were conducted. Dihydrotestosterone (DHT) levels in serum and the prostate were measured, and the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 proteins was investigated. BPH-treated animals showed increases in the relative weight of the prostate, higher concentrations of DHT in serum and the prostate, and higher expression of PCNA and Ki-67 in the prostate; in contrast, PYC-treated animals had significant reductions in these factors compared with the BPH animals. These findings indicated that PYC inhibited the development of BPH and that this was closely associated with a reduction in DHT concentration. PMID- 30310408 TI - Successful development of squamous cell carcinoma and hyperplasia in RGEN mediated p27 KO mice after the treatment of DMBA and TPA. AB - To evaluate the carcinogenicity of p27 knockout (KO) mice with RNA-guided endonuclease (RGENs)-mediated p27 mutant exon I gene (IDelta), alterations in the carcinogenic phenotypes including tumor spectrum, tumor suppressor proteins, apoptotic proteins and cell cycle regulators were observed in p27 (IDelta) KO mice after treatment with 7,12-Dimethylbenz[a]anthracene (DMBA) and 12-O tetradecanoylphorbol-13-acetate (TPA)(DT) for 5 months. The target region (544~571 nt) in exon I of the p27 gene was successfully disrupted in p27 (IDelta) KO mice using the RGEN-induced non-homologous end joining (NHEJ) technique. After DT exposure for 5 months, a few solid tumors (identified as squamous cell carcinoma) developed on the surface of back skin of DT-treated p27 (IDelta) KO mice. Also, squamous cell hyperplasia with chronic inflammation was detected in the skin dermis of DT-treated p27 (IDelta) KO mice, while the Vehicle+p27 (IDelta) KO mice and WT mice maintained their normal histological skin structure. A significant increase was observed in the expression levels of tumor suppressor protein (p53), apoptotic proteins (Bax, Bcl-2 and Caspase-3) and cell-cycle regulator proteins (Cyclin D1, CDK2 and CDK4) in the skin of DT-treated p27 (IDelta) KO mice, although their enhancement ratio was varied. Taken together, the results of the present study suggest that squamous cell carcinoma and hyperplasia of skin tissue can be successfully developed in new p27 (IDelta) KO mice produced by RGEN-induced NHEJ technique following DT exposure for 5 months. PMID- 30310409 TI - Neither polyphenol-rich red wine nor fenofibrate affects the onset of type-1 diabetes mellitus in the BB rat. AB - Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when beta-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted beta-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances. PMID- 30310410 TI - Erratum: Protective effects of cultured and fermented ginseng extracts against scopolamine-induced memory loss in a mouse model. AB - [This corrects the article on p. 37 in vol. 34, PMID: 29628975.]. PMID- 30310412 TI - Protective Effects of Yinchenhao Decoction on Cholesterol Gallstone in Mice Fed a Lithogenic Diet by Regulating LXR, CYP7A1, CYP7B1, and HMGCR Pathways. AB - The study attempted to elucidate whether lipid genes are closely associated with lipid metabolic abnormalities during the lithogenic time and how Yinchenhao Decoction (YCHD) works on the transcriptions of lipid genes against cholesterol gallstone model. C57BL/6J mice fed on lithogenic diet (LD) were used for model establishment and randomized into 5 groups. All groups received LD for different weeks with isometrically intragastric administration of YCHD or NS. Biochemical tests were measured and liver tissues were harvested for histological and genetic detection. It was found that all groups with increasing LD showed a following tendency of gallstone incidence, bile cholesterol, phospholipids, total bile acid, and cholesterol saturation index (CSI). Conversely, YCHD could significantly normalize the levels of gallstone incidence, bile lipids, and CSI (CSI<1). As lithogenic time progressed, ABCG5, ABCG8, PPAR-alpha, and ABCB4 were upregulated, and SREBP2, CYP7A1, and CYP7B1 were downregulated, while CYP7A1, CYP7B1, LXR, and HMGCR mRNA were increased 3-fold under the administration of YCHD. It was concluded that abnormal expressions of the mentioned genes may eventually progress to cholesterol gallstone. CYP7A1, CYP7B1, LXR, and HMGCR mRNA may be efficient targets of YCHD, which may be a preventive drug to reverse liver injury, normalize bile lipids, facilitate gallstone dissolution, and attenuate gallstone formation. PMID- 30310411 TI - Difference of Liver and Kidney Metabolic Profiling in Chronic Atrophic Gastritis Rats between Acupuncture and Moxibustion Treatment. AB - Acupuncture and moxibustion proved to be very effective in chronic atrophic gastritis (CAG). According to the Chinese traditional medicine theory, chronic diseases have an influence on the function of liver and kidney. However, there is little research to demonstrate this theory. This study is aimed at assessing the 1H NMR-based metabolic profiling in liver and kidney of CAG rats and comparing the difference between electroacupuncture and moxibustion treatment. Male SD rats were subjected to CAG modeling by intragastric administration of mixture of 2% sodium salicylate and 30% alcohol coupled with compulsive sporting and irregular fasting for 12 weeks and then treated by electroacupuncture or moxibustion at Liangmen (ST 21) and Zusanli (ST 36) acupoints for 2 weeks. A 1H NMR analysis of liver and kidney samples along with histopathological examination and molecular biological assay was employed to assess and compare the therapeutic effects of electroacupuncture and moxibustion. CAG brought characterization of metabolomic signatures in liver and kidney of rats. Both electroacupuncture and moxibustion treatment were found to normalize the CAG-induced changes by restoring energy metabolism, neurotransmitter metabolism, antioxidation metabolism, and other metabolism, while the moxibustion treatment reversed more metabolites related to energy metabolism in liver than electroacupuncture treatment. CAG did have influence on liver and kidney of rats. Both of these treatments had good effects on CAG by reversing the CAG-induced perturbation in liver and kidney. For regulating the energy metabolism in liver, the moxibustion played more important role than electroacupuncture treatment. PMID- 30310414 TI - Foreword. PMID- 30310413 TI - A Prospective Randomized, Controlled, Double-Blind Trial of the Efficacy Using Centella Cream for Scar Improvement. AB - Objective: This study was performed to evaluate the efficacy of Centella asiatica extract in cream, a preparation for the prevention of scar development of the split-thickness skin graft (STSG) donor site. Methods: A prospective randomized, double-blind control study was performed to evaluate the efficacy of Centella cream in 30 patients who underwent a STSG operation. Both Centella cream and placebo were applied equally to the donor site at least 2 weeks after epithelialization was completed. A scar assessment using the Vancouver Scar Scale (VSS) was taken at 4, 8, and 12 weeks. Results: Of the original 30 patients, 23 patients completed evaluation. There were significant differences in pigmentation parameter of VSS and comparative total VSS scores between 4 and 12 weeks in Centella cream group. Conclusion: The effect of Centella cream on scar development of a STSG operation may be attainable in terms of better pigmentation. By means of objective measurements and longer follow-up times, Centella cream may prove to be an alternative product for hypertrophic scar amelioration. PMID- 30310415 TI - What is Takotsubo (Stress) Cardiomyopathy? AB - Takotsubo/stress cardiomyopathy (TC) or apical ballooning syndrome is an increasingly recognised entity around the world. It is an acute reversible cardiac syndrome that has a striking female predominance, with approximately 90 % of cases occurring in women, the vast majority of whom are post-menopausal. Chest pain and dysponea are the most common presenting symptoms. The symptoms and signs are similar to those in other acute cardiac conditions characterised by acute myocardial ischemia or heart failure. A characteristic feature of the syndrome is its relationship to emotional or physical stressful triggers. The process of diagnosing TC is, to a large extent, one of exclusion of other conditions that it mimics. The Mayo Clinic diagnostic criteria are the most widely used. Since acute coronary syndrome is often suspected before the diagnosis of TC is made, initial treatment is often similar to that for an acute myocardial infarction. However, after the diagnosis of TC is confirmed, treatment is supportive with monitoring and treatment of complications. The vast majority of patients with TC have good prognosis with complete resolution of systolic dysfunction. PMID- 30310416 TI - Pulmonary Hypertension. AB - Pulmonary hypertension is said to occur when the mean pulmonary arterial pressure exceeds 25 mmHg at rest or 30 mmHg during exercise. There are many causes but the term Pulmonary arterial hypertension (PAH) is used to describe a rare group of illnesses that share histopathological similarities in the small muscularised pulmonary arterioles leading to vascular remodelling (plexogenic pulmonary arteriopathy) and progressive elevation in the pulmonary vascular resistance. Left untreated, patients die as a consequence of right heart failure and the mortality approaches that of commonly encountered malignancies. There is no effective cure. Most treatment for PAH patients has focused on the endothelial cell vascular dysfunction known to occur in these disorders and indeed agents such as endothelin receptor antagonists, phosphodiesterase pathway V inhibitors and prostacyclin analogues have been shown to improve morbidity and delay rate of deterioration. More recently evidence has emerged that they may have a positive impact on survival. These agents have also been applied to treat patients with chronic thromboembolic pulmonary hypertension (CTEPH) and selected patients with CTEPH may also benefit from pulmonary thromboendarterectomy. For a small number of patients with PAH lung transplantation may be considered. PMID- 30310417 TI - Coronary Flow Velocity Reserve Assessment with Transthoracic Doppler Echocardiography. AB - Coronary flow velocity reserve (CFVR) reflects global coronary atherosclerotic burden, endothelial function and state of the microvasculature. It could be measured using transthoracic Doppler echocardiography in a non-invasive, feasible, reliable and reproducible fashion, following a standardised protocol with different vasodilatory stimuli. CFVR measurement is a recommended complement to vasodilator stress echocardiography. It could serve as a diagnostic tool for coronary microvascular dysfunction and in the setting of epicardial coronary artery stenoses could help in identification and assessment of functional significance of coronary lesions and follow-up of patients after coronary interventions. CFVR has also a prognostic significance in different clinical situations. PMID- 30310419 TI - Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy (TTC) is an acute, stress-induced cardiomyopathy with an increased prevalence in post-menopausal women. The syndrome is most frequently precipitated by an acute emotional or physical stressor and mimics acute myocardial infarction with symptoms, electrocardiogram (ECG) changes and cardiac troponin elevation that are indistinguishable from those caused by plaque rupture or coronary thrombosis. Diagnosis of TTC is made when coronary angiography reveals no obstructive coronary artery disease and the left ventricle demonstrates apical ballooning and basal hypercontractility. Other ventricular patterns have also been described. An abnormal myocardial response to the catecholamine surge from an emotional or a physical stressor is implicated in the pathophysiology, but the reasons for the high prevalence of TTC presentations in post-menopausal women are unknown. Several mechanisms including multi-vessel coronary vasospasm, endothelial and coronary microvascular dysfunction and direct catecholamine toxicity have been proposed. No specific guidelines for treatment of TTC have been established, but treatment is based on the American Heart Association/American College of Cardiology guidelines for acute coronary syndrome/acute myocardial infarction and heart failure guidelines. In this review article, we discuss the characteristic clinical presentation of TTC and the commonly proposed mechanisms. PMID- 30310418 TI - Chemotherapy-related Cardiomyopathy. AB - Advances in chemotherapeutic agents have resulted in significantly improved cancer survival rates. Cardiac toxicity, however, has emerged as a leading cause of morbidity, both during and years after treatment. One of the most common manifestations of cardiotoxicity is that of heart failure and left ventricular systolic dysfunction. In this review, current opinions and guidelines in this field are discussed, with particular focus on the most common culprits, the anthracyclines, and the monoclonal antibody, trastuzumab. PMID- 30310420 TI - Risk Stratification in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a hereditary primary myocardial disease that is most commonly due to mutations within genes encoding sarcomeric contractile proteins and is characterised by left ventricular hypertrophy in the absence of a cardiac or systemic cause. Although the overall prognosis is relatively good with an annual mortality rate <1 %, the propensity to potentially fatal ventricular arrhythmias is the most feared complication. The identification of patients at risk of arrhythmogenic sudden cardiac death (SCD) is an essential component in disease management. Aborted SCD and malignant ventricular arrhythmias are the most powerful risk factors for SCD and ICD implantation is recommended in such circumstances. The selection of patients who may benefit from ICD therapy for primary prevention purposes is more challenging. The heterogeneous nature of the disease and the variation in trigger factors provides an adequate explanation for the low predictive accuracy of most conventional risk factors in isolation. A new risk model for risk stratification proposed by the European Society of Cardiology HCM outcome group shows promise but requires validation in different cohorts. The ICD is the only effective therapy in preventing SCD for the disease with a relatively low adverse event rate, but most deaths occur in relatively young patients. However, it is also difficult to ignore the complications with the ICD, therefore, the strive to perfect risk stratification in HCM should continue to ensure that only the most high-risk patients receive an ICD. PMID- 30310422 TI - Diuretic Therapy in Heart Failure - Current Approaches. AB - The use of diuretics is common in patients with heart failure (HF), to relieve the congestive symptoms of HF. Although they are widely used, there are limited data on their ability to modulate HF-related morbidity and mortality. Diuretic efficacy may be limited by adverse neurohormonal activation and by 'congestion like' symptoms. Diuretics are an extremely useful and varied class of agent for the management of hypervolaemic states. This review summarises the basic features of diuretics, including their mechanism of action, indications and adverse effects in heart failure. PMID- 30310421 TI - Novel Biomarkers in Heart Failure Beyond Natriuretic Peptides - The Case for Soluble ST2. AB - Despite more effective management of heart failure over the past few decades, its burden as a chronic disease has grown and is expected to continue to rise, representing a major health problem for years to come. Having reliable tools for early diagnosis and risk stratification can help managing the condition more efficiently. In this context, the interest for biomarkers has increased considerably in the last years following the useful clinical role of B-type natriuretic peptides. These biomarkers have been extensively studied and have become established diagnostic and prognostic biomarkers in heart failure. Despite their usefulness, limitations still remain a problem in clinical practice and the search for new biomarkers has therefore continued. Amongst the most promising newer biomarkers, soluble ST2 deserves further consideration. The present review will focus on the role of this new biomarker in the context of heart failure. PMID- 30310423 TI - Sudden Cardiac Death in Athletes. AB - Physical activity confers substantial health benefits to healthy individuals and patients alike. Occasionally, however, exercise may act as a trigger for arrhythmic death in athletes who harbor an occult pathological substrate. The majority of sudden cardiac deaths (SCDs) in young athletes (<=35 years old) are secondary to inherited cardiac diseases, while ischaemic heart disease predominates in older athletes. In the absence of compulsory national or international registries of SCD in athletes, it is difficult to define the exact scale of the problem. In addition, the lack of post-mortem evaluation by pathologists with expertise in cardiac adaptation to exercise and inherited cardiac diseases casts doubt to the reliability of the reported causes. The proposed preventative strategies focus primarily on preventing deaths by cardiovascular evaluation of athletes and the use of automated external defibrillators in athletic venues. Cardiovascular screening of first-degree relatives, though often neglected, has the potential to avert further tragedies given the inherited nature of most conditions predisposing to SCD in the young. This article provides an overview of the epidemiology and causes of SCD in athletes and explores potential prevention strategies. PMID- 30310424 TI - The Diagnosis and Clinical Implications of Interatrial Block. AB - Impaired interatrial conduction or interatrial block is now well-documented but is not described as an individual electrocardiographic (ECG) pattern in the majority of ECG literature. In fact the term atrial abnormality has been adopted to encompass both left atrial enlargement (LAE) and interatrial block. In this paper, we maintain that interatrial blocks and atrial enlargement are separate entities, and that interatrial blocks, similar to other types of blocks at sinoatrial, AV junctional, and ventricular level, exhibit a specific ECG pattern that may present first, second, and third degree types of conduction block. The third degree or advanced interatrial block (A-IAB) is frequently associated with atrial fibrillation/atrial flutter (AF/AFl), and constitutes a true newly described syndrome. PMID- 30310425 TI - At the Heart of Brain Disorders - Preventing Cognitive Decline and Dementia. AB - Vascular risk factors are shared by heart and brain. Vascular brain injury (small vessel disease, stroke) alone or combined with neurodegenerative pathology (beta amyloid depositions) brings about either cognitive decline and vascular dementia or Alzheimer's disease. Long-term exposure to vascular risk factors precedes the onset of neurocognitive diseases by one or two decades. Early detection and control of modifiable vascular risk factors seem to be the only current strategies to prevent cognitive impairment and dementia. PMID- 30310427 TI - Foreword. PMID- 30310426 TI - Cholesteryl Ester Transfer Protein Inhibitors - Future Soon to be REVEALed. AB - Reduction of the remaining residual cardiovascular risk is a clinical unmet need currently being addressed through a combination of further reduction of plasma concentrations of low-density lipoproteins (LDLs) and increasing plasma concentrations of high-density lipoproteins (HDLs). This brief review sets out the so-called HDL hypothesis and summarises the clinical results of the family of drugs, which function to raise plasma HDL concentration through inhibition of cholesteryl ester transfer proteins (CEPT). PMID- 30310428 TI - The Syndrome of Inter-atrial Conduction Block. AB - The formulation of the syndrome of interatrial conduction block is an important step for improved identification of patients at high risk of developing atrial fibrillation (those with advanced, that is, third degree interatrial block, which includes retrograde instead of normal activation of the left atrium). The rationale and potential benefits of prophylactic antiarrhythmic treatment of patients with advanced interatrial block currently seems not sufficiently convincing and requires further study including prospective trials. In addition to the identified future directions for research in this syndrome, it seems important also to explore novel electrocardiogram (ECG) methods (e.g. new electrode positions and ECG leads) for improved characterisation of the atrial electrical events. Oesophageal electrocardiography and vectorcardiography are old, venerable and unjustifiably forgotten ECG techniques: their additional use of for better diagnosis of interatrial conduction block is highly commendable. PMID- 30310429 TI - Stroke Prevention in Atrial Fibrillation - The Use of NOACs in Everyday Clinical Practice. AB - Non-antivitamin K oral anticoagulants (NOACs) have recently emerged as a new class of antithrombotic drugs. Four large-scale, randomised controlled trials (RCT) accredited dabigatran, rivaroxaban and edoxaban with evident advantages for stroke prevention in atrial fibrillation (AF) compared with warfarin. The superiority concerns not only the manageability but also the antithrombotic efficacy and safety. Aspects of real-life clinical experience with NOAC for stroke prevention in AF are analysed in an attempt to underline some practical differences. If at present the individualisation of the NOAC class drugs is still a subject of debate it is probable that in the near future we will be able to adapt the drug and dosages to individual patient's profile. PMID- 30310430 TI - Myocardial Infarction With Non-obstructive Coronary Arteries - Diagnosis and Management. AB - MI with non-obstructive coronary arteries (MINOCA) is an enigma that is being increasingly recognised with the frequent use of angiography following acute MI. To diagnose this condition, it is important to determine the multiple potential underlying mechanisms that may be responsible, many of which require different treatments. This review evaluates the contemporary diagnosis and management of MINOCA. PMID- 30310431 TI - Takotsubo Syndrome - Stress-induced Heart Failure Syndrome. AB - Takotsubo syndrome has been established as an entity in the past 30 years, particularly with the introduction of interventional angiography for investigation of chest pain. Typically, it occurs in middle-aged females as a response to a stressful event, such as bad news, death, accident, natural disaster, etc. but there is not always a specific trigger. Takotsubo mimics acute myocardial infarction with electrocardiogram changes and elevated troponins. On interventional angiography the coronary arteries are normal with typical apical ballooning of the left ventricle. This feature led to its descriptive name, given by Japanese cardiologists, as the left ventricle resembles a lobster trap with a narrow neck extending into a round ventricle. This leads to a reduction in cardiac function. Takotsubo is believed to be a response to catecholamine release following a stressful event resulting in temporary myocardial damage. It usually has a benign course with spontaneous return of cardiac function. However it may recur and in a small percentage of patients can result in sudden cardiac death with arrhythmia, acute myocardial infarction and cardiac rupture. It is usually treated symptomatically depending on the severity of presentation. PMID- 30310434 TI - A Practical Clinical Approach to the Diagnosis and Treatment of Patients with Pulmonary Hypertension. AB - Pulmonary hypertension is defined by a mean pulmonary artery pressure of >25 mmHg at rest or 30 mmHg during exercise. There are many causes and currently diseases causing the condition are classified into five groups. The greatest elevation in pulmonary arterial pressure is found among those disorders in group 1 (known as pulmonary arterial hypertension [PAH]) and research and targeted therapy has focused on this group in particular, although patients in group 4 (chronic thromboembolic PH [CTEPH]) also receive advanced pulmonary vasodilator therapy. The symptoms of PH are often vague and the diagnosis is frequently missed or delayed. Efforts are therefore being made to improve awareness of PH among clinicians to enable prompt referral to a PH unit to confirm the diagnosis and instigate appropriate therapy. Multi-disciplinary team (MDT) discussion is necessary if patients with PH require surgical intervention or become pregnant. For patients in the other PH groups, treatment is usually concentrated on the primary disorder. A small number of patients with PAH will respond to calcium channel-blocking agents. Specific targeted therapy is often given in combination depending on the patients functional performance status. Available agents include phosphodiesterase type V inhibitors, endothelin receptor antagonists, prostglandin analogues and nitric oxide. Many novel agents are under review. For carefully selected patients surgical options, include lung transplantation, pulmonary thromboendarterectomy and atrial septostomy. PMID- 30310432 TI - Sleep-disordered Breathing in Heart Failure. AB - Sleep-disordered breathing affects over half of patients with heart failure (HF) and is associated with a poor prognosis. It is an under-diagnosed condition and may be a missed therapeutic target. Obstructive sleep apnoea is caused by collapse of the pharynx, exacerbated by rostral fluid shift during sleep. The consequent negative intrathoracic pressure, hypoxaemia, sympathetic nervous system activation and arousals have deleterious cardiovascular effects. Treatment with continuous positive airway pressure may confer symptomatic and prognostic benefit in this group. In central sleep apnoea, the abnormality is with regulation of breathing in the brainstem, often causing a waxing-waning Cheyne Stokes respiration pattern. Non-invasive ventilation has not been shown to improve prognosis in these patients and the recently published SERVE-HF trial found increased mortality in those treated with adaptive servoventilation. The management of sleep-disordered breathing in patients with HF is evolving rapidly with significant implications for clinicians involved in their care. PMID- 30310433 TI - Home Blood Pressure Monitoring. AB - Hypertension is the most common preventable cause of cardiovascular disease. Home blood pressure monitoring (HBPM) is a self-monitoring tool that can be incorporated into the care for patients with hypertension and is recommended by major guidelines. A growing body of evidence supports the benefits of patient HBPM compared with office-based monitoring: these include improved control of BP, diagnosis of white-coat hypertension and prediction of cardiovascular risk. Furthermore, HBPM is cheaper and easier to perform than 24-hour ambulatory BP monitoring (ABPM). All HBPM devices require validation, however, as inaccurate readings have been found in a high proportion of monitors. New technology features a longer inflatable area within the cuff that wraps all the way round the arm, increasing the 'acceptable range' of placement and thus reducing the impact of cuff placement on reading accuracy, thereby overcoming the limitations of current devices. PMID- 30310435 TI - Cardiac Amyloid - An Update. AB - Cardiac amyloidosis is a condition characterised by rapidly progressive heart failure and poor prognosis. The two main subtypes, immunoglobulin light chains (AL) and transthyretin (ATTR), have been investigated extensively in recent years. Cardiac imaging has advanced with the widespread use of cardiac MRI with late gadolinium enhancement imaging and newer techniques including T1 mapping to quantify amyloid burden. Nuclear imaging has developed as a highly accurate method to confirm cardiac amyloid deposits non-invasively with very high sensitivity in ATTR amyloidosis. Despite advances in imaging, cardiac biopsy remains the gold standard diagnostic test to confirm and type amyloidosis. Hereditary ATTR amyloidosis of V122I type has been the focus of important studies in the past year, due to the high prevalence of the amyloidogenic allele in patients of African descent. Recent research concluded a significant number of Afro-Caribbean heart failure patients are likely to have undiagnosed cardiac amyloidosis. Misdiagnosis may lead to inappropriate treatment with potentially harmful 'standard' heart failure medications with no evidence base in amyloidosis. Treatment options have, until recently, been limited but cardiac amyloidosis is the focus of novel therapeutic regimes. New insights into the pathophysiological mechanisms resulting in disease have suggested exciting targets for drug therapy. PMID- 30310436 TI - Sudden Cardiac Death Risk Stratification - An Update. AB - Sudden cardiac death (SCD) remains a major public health problem worldwide, yet current methods to identify those at greatest risk are inadequate. High-risk individuals may benefit from potentially life-saving treatment, such as insertion of an implantable-cardioverter defibrillator (ICD). However, such treatments are expensive and have their own associated risks. Furthermore, most cases of SCD occur in the general adult population who may be relatively asymptomatic but yet have an underlying predisposition to SCD. Hence, there is great interest and clinical need in improving methods for risk stratification of SCD to identify those at greatest risk and implement the most appropriate treatment. This review provides an update on current risk-stratification methods for SCD in high-risk groups, in particular patients with reduced left ventricular function following acute myocardial infarction and those with non-ischaemic dilated cardiomyopathy, and highlights some novel methods that may have a role to play in future risk stratification schemes. Approaches and challenges for SCD risk stratification among the general public are also discussed. PMID- 30310438 TI - Foreword. PMID- 30310437 TI - Home Orthostatic Training in Elderly Patients with Vasovagal Syncope - A Prospective Randomised Controlled Trial. AB - Aim: The aim of this study was to assess the effect of home orthostatic training (HOT) on autonomic reflexes in elderly patients with vasovagal syncope (VVS). Methods: Design and Setting: A single-blind randomised control trial was conducted at Eastbourne District General Hospital, East Sussex NHS Trust. Patients: Individuals with recurrent syncope underwent tilt-table testing between August 2007 and October 2009.Those with at least two syncopal episodes and tilt test proven VVS were recruited. Participants were divided into those aged >65 years (O65) and those aged <65 years (U65). Interventions: Patients in the O65 group were randomised 1:1 to receive active HOT (O65+) or sham HOT (O65-). The U65 group received active HOT. Participants performed HOT/sham HOT and recorded their training and symptoms. Patients had a repeat tilt test at 3 months. Outcome Measures: Time to syncope at repeat tilt-table testing, low-frequency heart rate variability (LF-HRV), high-frequency heart rate variability (HF-HRV), mean upslope baroreflex sensitivity (BRS) and mean downslope BRS were assessed. Results: A total of 106 patients with recurrent syncope underwent tilt-table testing. Of these, 45 consecutive patients (30 in the O65 group and 15 in the U65 group) were recruited. Two, one and three patients withdrew or were lost-to follow-up in the O65+, O65-, and U65 groups, respectively. Symptomatic benefit occurred in four (31 %) of the O65+, four (29 %) of the O65-, and six (50 %) of the U65. None of the autonomic measures changed significantly in any group. No difference was seen with HF-HRV, LF-HRV mean upslope BRS and mean downslope BRS. Fifty per-cent of the O65+ group stopped training because of back pain. Time constraint (25 %) was the most common reason for cessation in the U65 group. Conclusions: Despite good tilt training compliance, no improvement in autonomic measures in any group was shown. The most common reason for cessation of training was back pain in the elderly groups. This study does not support the use of HOT in elderly patients. PMID- 30310439 TI - European Cardiology Review partners with the International Society of Cardiovascular Pharmacotherapy. PMID- 30310442 TI - Guest Editorial Challenges in Resistant Hypertension. AB - Hypertension is the major risk factor for disease and premature death. Although the efficacy of antihypertensive therapy is undisputed, few patients reach target blood pressure. Steps to improve treatment and control include assessment of global cardiovascular risk for the individual patient, improving caregiver support, education and organisation, increasing treatment persistence, using out of office blood pressure monitoring more often, detecting secondary hypertension forms, and referring patients with remaining uncontrolled hypertension to a specialist hypertension centre. In conclusion, there is room for improvement of blood pressure control in hypertensive patients. The clinical benefit of improved blood pressure control may be considerable. This may be particularly true for patients with resistant hypertension. PMID- 30310440 TI - Resistant Hypertension: A Real Entity Requiring Special Treatment? AB - Resistant hypertension (RH) was defined many years ago as a clinical situation in which blood pressure remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. This operative definition was aimed at identifying a subset of hypertensive patients requiring a more extensive clinical workup in order to achieve an adequate blood pressure control. An oversimplification of this picture led to consider RH as a separate clinical entity requiring special, expensive treatments, such as renal denervation and baroreceptor activating therapy. In this review we will discuss the utility and the shortcomings of the definition of RH and the possible consequences for treatment. PMID- 30310441 TI - Clinical Diagnosis and Management of Resistant Hypertension. AB - Resistant hypertension (RHT) is variably defined as insufficient blood pressure (BP) response to multiple drug treatment. Prevalence of RHT has been thoroughly studied in the recent years, ranging from about 5 to 30 % in various cohorts. Initial management of patients with apparent RHT requires identification of true treatment resistance by out-of-office BP measurements, assessment of adherence and screening for treatable causes of uncontrolled BP. Endorsement of lifestyle modifications and maximisation of the doses of a suitable regimen, preferably with the further addition of an aldosterone antagonist, are the mainstay of treatment. An invasive approach to RHT, mainly represented by renal nerve ablation, should be kept for persistently severe cases managed in a specialised hypertension centre. PMID- 30310443 TI - Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis. AB - Tissue characterisation capabilities are continuing to evolve and proving to be valuable in the non-invasive diagnosis of clinically-heterogeneous manifestations of myocarditis. The authors investigate how cardiovascular magnetic resonance imaging offers an increasingly reliable alternative to invasive biopsy for clinically-stable patients, and how this tool - with further longitudinal study - will improve the overall understanding of the natural course of myocarditis. PMID- 30310444 TI - Accuracy of Positron Emission Tomography as a Diagnostic Tool for Lead Endocarditis: Design of the Prospective Multicentre ENDOTEP Study. AB - Background: Rates of pacemaker implantation are steadily increasing and as patients are living longer, endovenous leads remain implanted for an extended period of time thereby increasing the risk of cardiac implantable electronic device (CIED) infection. Investigating fever of unknown origin in patients with implanted pacemakers can be challenging. Recently, 18F-fluorodeoxyglucose positron emission tomography/computerised tomography (18F-FDG-PET/CT) scanning has been used as a diagnostic tool for lead endocarditis in small studies. Objectives: ENDOTEP is a prospective and multicentre study designed to evaluate the accuracy of 18F-FDG-PET/CT scanning in the diagnosis of lead endocarditis. Methods: A total of 250 patients referred for pacemaker extraction due to suspicion of an infected device will be prospectively enrolled in six French regional centres for investigation and treatment of CIED infection. 18F-FDG PET/CT scanning (index test) will be performed in each patient in the 48 hours preceding lead extraction. Bacteriological cultures (reference standard) will assess the presence of lead endocarditis, blind to 18F-FDG-PET/CT results. Enrolment started in June 2015 and is expected to end by June 2017. The primary objective will be to establish the sensitivity of the 18F-FDG-PET/CT scan for lead endocarditis. Secondary objectives will include other accuracy parameters, inter-observer agreement in the interpretation of 18F-FDG-PET/CT scanning, the influence of previous antibiotic therapy on 18F-FDG-PET/CT diagnostic accuracy and assessment of septic emboli associated to lead endocarditis. Conclusion: The ENDOTEP study will examine the ability of 18F-FDG-PET/CT scanning to avoid possible false-positive results, as is common using the current usual diagnostic strategy and may lead to unnecessary extraction of implants in patients with suspected lead infection. PMID- 30310445 TI - Left Ventricular Remodelling: A Problem in Search of Solutions. AB - Cardiac remodelling (REM) is a generally unfavourable process that leads to left ventricular dilation in response to cardiac injury, predominantly acute myocardial infarction (AMI). REM occurs in around 30 % of anterior infarcts despite timely primary coronary intervention and the use of drugs, i.e. angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs), beta-blockers, aldosterone inhibitors and statins. In order to diagnose REM, many imaging modalities (echocardiography, cardiac magnetic resonance, scintigraphy) are employed together with an increasing number of serum biomarkers including microRNAs. The most widely used definition of REM is a >20 % increase in left ventricular end-diastolic volume (LVEDV). There is also evidence that regression of REM can occur, i.e. reverse REM. The latter is defined as a >=10 % decrease in left ventricular end-systolic volume (LVESV) and confers a more favourable outcome. Many therapeutic agents may be used during primary intervention and over the long term; however, few have demonstrated significant benefits. Revascularisation, anti-REM surgery and, where indicated, cardiac resynchronisation therapy can be of benefit. Gene therapy by sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA-2a) transfer has been investigated but data from the Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2) trial were disappointing. Progenitor cell therapy shows promise. In conclusion, therapy for REM remains inadequate. PMID- 30310448 TI - Professor Keith AA Fox. PMID- 30310446 TI - Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection. AB - Cardioprotection is a common goal of new therapeutic strategies in patients with coronary artery disease and/or left ventricular dysfunction. Myocardial damage following ischaemia/reperfusion injury lead to left ventricular adverse remodelling through many mechanisms arising from different cell types in different myocardial districts, namely the border and remote zone. Cardioprotection must face this complex, dynamic network of cooperating units. In this scenario, thyroid hormones can represent an effective therapeutic strategy due to the numerous actions and regulating mechanisms carried out at the level of the myocytes, interstitium and the vasculature, as well as to the activation of different pro-survival intracellular pathways involved in cardioprotection. PMID- 30310449 TI - Foreword. PMID- 30310447 TI - Uric Acid and Cardiovascular Disease: An Update. AB - In recent years, serum uric acid (SUA) as a determinant of cardiovascular (CV) risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia SUA are at increased risk of cardiac, renal and vascular damage and CV events. There is now some evidence to suggest that urate lowering treatment may reduce CV risk in this group and, thus, may represent a new strategy in risk reduction. PMID- 30310451 TI - Fractional Flow Reserve Assessment of Coronary Artery Stenosis. AB - Objective proof of focal lesions is mandatory, and the best invasive method of physiological testing is fractional flow r eserve (FFR). The increased trans stenotic gradient is measured via the guiding catheter and pressure transducer on a 0.014" coronary wire at maximal hyperaemia induced by adenosine. Patients with a FFR of less than 0.8 should undergo myocardial revascularisation by percutaneous coronary intervention or coronary artery bypass graft, particularly if the proximal and middle segments of the main coronary arteries and large side branches are affected; there is no prognostic revascularisation benefit in patients with moderate stenoses and FFR greater than 0.80. FFR assessment of coronary lesions is superior to other invasive morphological studies, such as intracoronary ultrasound or optical coherence tomography. Its use in non-culprit vessels in acute coronary syndromes is currently under scrutiny. Recent advances in computed tomographic technique allow non-invasive assessment of FFR, but clinical validation has yet to be obtained. PMID- 30310452 TI - Guest Editorial: Controversies in Fractional Flow Reserve. AB - Fractional flow reserve (FFR) has been identified as the optimal diagnostic tool to identify significant coronary lesion. However, current evidence does not support this role. The optimal diagnostic strategy should give highly sensitive and specific results with lowest cost and accomplishing this task has been made more difficult in the era following the COURAGE trial. PMID- 30310450 TI - Management of Refractory Angina Pectoris. AB - With improvements in survival from coronary artery disease (CAD) and an ageing population, refractory angina (RA) is becoming an increasingly common clinical problem facing clinicians in routine clinical practice. These patients experience chronic symptoms in the context of CAD, characterised by angina-type pain, which is uncontrolled despite optimal pharmacological, interventional and surgical therapy. Although mortality rates are no worse in this cohort, patients experience a significantly impaired quality of life with disproportionately high utilisation of healthcare services. It has been increasingly recognised that the needs of RA patients are multifactorial and best provided by specialist multi disciplinary units. In this review, we consider the variety of therapies available to clinicians in the management of RA and discuss the promise of novel treatments. PMID- 30310453 TI - Prediction of Post Percutaneous Coronary Intervention Myocardial Ischaemia. AB - Following revascularisation the majority of patients obtain symptom relief and improved quality of life. However, myocardial ischaemia may recur or persist in a significant patient subset. Symptom recurrence is usually attributed to inaccurate evaluation of epicardial stenosis, incomplete revascularisation or stent failure and disease progression. However, technological advances with modern imaging and/or physiological evaluation of epicardial plaques have not solved this issue. Conversely, recent clinical studies have shown that abnormal coronary vasomotion and increased myocardial resistance are frequent determinants of post-percutaneous coronary intervention (PCI) myocardial ischaemia. Strategies to enhance prediction of post-PCI angina include proper selection of patients undergoing revascularisation, construction of clinical prediction models, and further invasive evaluation at the time of coronary angiography in those with high likelihood. PMID- 30310454 TI - Optical Coherence Tomography For the Detection of the Vulnerable Plaque. AB - Morphological characteristics of the atheromatous plaque have been associated with the development of plaque rupture and the pathogenesis of acute coronary syndromes (ACS). Plaques with a specific morphological phenotype that are at high risk of causing ACS are called vulnerable plaques, and can be identified in vivo through the use of intracoronary imaging. Optical coherence tomography (OCT) is a high-resolution intravascular imaging modality that enables detailed visualization of atheromatous plaques. Consequently, OCT is a valuable research tool for examining the role of morphological characteristics of atheromatous plaques in the progression of coronary artery disease and plaque destabilisation, which leads to the clinical manifestation of ACS. This article summarises the pathophysiological insights obtained by OCT imaging in the formation and rupture of the vulnerable plaque. PMID- 30310457 TI - European Cardiology Review partners with the International Society of Cardiovascular Pharmacotherapy. PMID- 30310456 TI - Viewpoint: Role of Mind-body Therapies in the Management of Cardiovascular Disorders. AB - Cardiovascular disorders (CVD) are the leading cause of death across the globe. The estimated cost to the National Health Service and UK economy is L30 billion. These costs continue to escalate despite major advances in pharmacotherapy and devices, which, in part, is due to improved survival, but also greater resource utilisation per patient. Hence, there is a need to develop cost-effective adjunctive therapies beyond conventional strategies. Mind-body therapies- including mindfulness and meditation, emotional regulation, practicing 'heartfelt' emotions including gratitude and compassion- may be novel low-cost approaches to reduce morbidity and mortality in CVD. PMID- 30310458 TI - Cardiovascular Pharmacotherapies Focus: Are low doses of direct-acting oral anticoagulants justified and appropriate in patients with nonvalvular atrial fibrillation? PMID- 30310455 TI - Cardiovascular Management of Adults with Marfan Syndrome. AB - Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse. This autosomal dominantly inherited condition, which was first reported in 1895 and was more fully described in 1931, is characterised by abnormal Fibrillin-1 protein (FBN1) (discovered in 1990), which is encoded by the FBN1 gene (reported in 1991). In the 1970s, the life expectancy of people with MFS was 40-50 years, mainly due to increased risk of aortic dissection or heart failure from aortic or mitral regurgitation. However, due to advances in medical and surgical therapy, life expectancy has improved dramatically and is now comparable to that of the general population. We discuss the cardiac manifestations of MFS, the incidence of arrhythmia in this population, the standard of medical care for arrhythmia and valve insufficiency, and a new use of preventive medication to preserve the integrity of the aortic wall in patients with MFS. PMID- 30310461 TI - Foreword. PMID- 30310460 TI - Featuring: Dr Valentin Fuster. PMID- 30310459 TI - Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation: Assessment, Monitoring and Treatment Reversal. AB - It is essential to prevent thromboembolic events in atrial fibrillation. The risks of thromboembolic and haemorrhagic events must be carefully assessed and weighed against one another, both in routine situations and in relation to invasive procedures. Vitamin K antagonists, until recently the first-line treatment for prophylaxis against thromboembolic events in patients with atrial fibrillation, have various drawbacks. Direct-acting oral anticoagulants overcome these limitations and are efficacious and safe. The recent developments of tests to monitor anticoagulant levels, and of target-specific reversal agents for these newer drugs, has facilitated their use in several situations, including emergencies. For these reasons, the European Society of Cardiology and other scientific societies now recommend direct-acting oral anticoagulants as first line treatment for preventing thromboembolic events in atrial fibrillation. PMID- 30310462 TI - Guest Editorial: Reducing Risk in Familial Hypercholesterolaemia and Severe Dyslipidaemia: Novel Drugs Targeting PCSK9. PMID- 30310463 TI - Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL receptors on the hepatocyte surface and therefore is essential for effective removal of LDL particles from circulation. Genetic and biochemical studies have established that altered PCSK9 functionality influences both LDL cholesterol levels and cardiovascular risk. This has prompted development of inhibitory strategies targeting PCSK9. Study of monoclonal PCSK9 antibodies has progressed to the clinic, where they have been found to lower LDL cholesterol levels and reduce cardiovascular event rates in large, clinical outcome trials. The use of PCSK9 inhibitors in the setting of dyslipidaemia is reviewed. PMID- 30310465 TI - ISCP Guest Editorial: Cardiovascular Disease Prevention in Diabetes. PMID- 30310464 TI - Familial Hypercholesterolaemia Diagnosis and Management. AB - Familial hypercholesterolaemia is the most common monogenic disorder associated with premature coronary artery disease. Mutations are most frequently found in the LDL receptor gene. Clinical criteria can be used to make the diagnosis; however, genetic testing will confirm the disorder and is very useful for cascade screening. Early identification and adequate treatment can improve prognosis, reducing negative clinical cardiovascular outcomes. Patients with familial hypercholesterolaemia are considered at high cardiovascular risk and the treatment target is LDL cholesterol <2.6 mmol/l or at least a 50 % reduction in LDL cholesterol. Patients require intensive treatment with statins and ezetimibe and/or colesevelam. Recently, proprotein convertase subtilisin/kexin type 9 inhibitors have been approved for the management of familial hypercholesterolaemia on top of statins. PMID- 30310466 TI - Nicorandil and Long-acting Nitrates: Vasodilator Therapies for the Management of Chronic Stable Angina Pectoris. AB - Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates exert anti-angina properties via activation of nitric oxide (NO) signalling pathways, triggering vascular smooth muscle cell relaxation. Nicorandil has additional actions as an arterial K+ ATP channel agonist, resulting in more "balanced" arterial and venous vasodilatation than nitrates. Ultimately, these drugs prevent angina symptoms through reductions in preload and diastolic wall tension and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. While there is some evidence to suggest a modest reduction in cardiovascular events among patients with stable angina treated with nicorandil compared to placebo, this prognostic benefit has yet to be proven conclusively. In contrast, there is emerging evidence to suggest that chronic use of long-acting nitrates might cause endothelial dysfunction and increased cardiovascular risk in some patients. PMID- 30310468 TI - Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator. AB - Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension. PMID- 30310467 TI - Neuroendocrine System Regulatory Mechanisms: Acute Coronary Syndrome and Stress Hyperglycaemia. AB - Neurohormonal systems are activated in the early phase of acute coronary syndromes to preserve circulatory homeostasis, but prolonged action of these stress hormones might be deleterious. Cortisol reaches its peak at 8 hours after the onset of symptoms, and individuals who have continued elevated levels present a worse prognosis. Catecholamines reach 100-1,000-fold their normal plasma concentration within 30 minutes of ischaemia, therefore inducing the propagation of myocardial damage. Stress hyperglycaemia induces inflammation and endothelial dysfunction, and also has procoagulant and prothrombotic effects. Patients with hyperglycaemia and no diabetes elevated in-hospital and 12-month mortality rates. Hyperglycaemia in patients without diabetes has been shown to be an appropriate independent mortality prognostic factor in this type of patient. PMID- 30310469 TI - Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). AB - Coronary artery disease (CAD) is the leading cause of death worldwide. Despite notable advances in understanding the nature of atherosclerotic processes and the use of effective medications such as statins, there remains a significant residual risk. Even after optimal medical treatments and precise revascularisations, the recurrence of MI remains at approximately one-third for 5 years after an acute coronary syndrome (ACS). Over the past two decades, compelling data from animal and human studies has clearly identified atherosclerosis as an inflammatory disease of the arterial wall, but clinical applications related to this accumulated knowledge are still scarce. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence that an anti-inflammatory intervention with the monoclonal antibody canakinumab reduces cardiovascular events in well-treated CAD patients without affecting LDL cholesterol levels. This article presents a brief description of the role of inflammation in atherogenesis and examines selected anti-inflammatory interventions and their potential use in CAD-affected individuals. PMID- 30310470 TI - Cardiovascular Implications of Sphingomyelin Presence in Biological Membranes. AB - Sphingomyelin (SM) is a type of sphingolipid found within plasma, cellular membranes and plasma lipoproteins. Here we highlight the basic biochemical features of SMs and their role in biological membranes. We further discuss evidence of the association between SM and cardiovascular diseases such as atherosclerosis, valvular disease, heart failure and diabetes mellitus. PMID- 30310473 TI - Effect of Percutaneous Coronary Intervention on Heart Rate Variability in Coronary Artery Disease Patients. AB - Patients with coronary artery disease (CAD) have a state of autonomic imbalance with a sympathetic predominance. Autonomic dysfunction has been linked to an increased risk of cardiovascular morbidity and mortality. Heart rate variability (HRV) analysis is one of the most encouraging non-invasive diagnostic models and is increasingly used for the assessment of autonomic dysfunction. Percutaneous coronary intervention (PCI) is considered the gold standard in CAD treatment. Revascularisation through PCI eliminates the state of sympathetic hyperactivity, restores the normal cardiac autonomic modulation that can be assessed by HRV measurement. PMID- 30310471 TI - Assessing the Haemodynamic Impact of Coronary Artery Stenoses: Intracoronary Flow Versus Pressure Measurements. AB - Fractional flow reserve (FFR)-guided percutaneous coronary intervention results in better long-term clinical outcomes compared with coronary angiography alone in intermediate stenoses in stable coronary artery disease (CAD). Coronary physiology measurements have emerged for clinical decision making in interventional cardiology, but the focus lies mainly on epicardial vessels rather than the impact of these stenoses on the myocardial microcirculation. The latter can be quantified by measuring the coronary flow reserve (CFR), a combined pressure and flow index with a strong ability to predict clinical outcomes in CAD. However, combined pressure-flow measurements show 30-40 % discordance despite similar diagnostic accuracy between FFR and CFR, which is explained by the effect of microvascular resistance on both indices. Both epicardial and microcirculatory involvement has been acknowledged in ischaemic heart disease, but clinical implementation remains difficult as it requires individual proficiency. The recent introduced pressure-only index instantaneous wave-free ratio, a resting adenosine-free stenosis assessment, led to a revival of interest in coronary physiology measurements. This review focuses on elaborating the coronary physiological parameters and potential of combined pressure-flow measurements in daily clinical practice. PMID- 30310474 TI - Guest Editorial: Is Cardio-oncology Ready for Algorithms? PMID- 30310472 TI - The Newest Generation of Drug-eluting Stents and Beyond. AB - There has been a great evolution in the development of coronary stents in order to avoid both restenosis and thrombosis. Improvements have led to improvements in the design and conformation of metallic or resorbable structures, with an adequate balance between trackability and radial force, the development of antiproliferative drugs and the polymers to control release and allow adequate endothelialisation and an optimal duration of the antiplatelet regimen. Some suggestions are provided about the ideal characteristics of future coronary stents. PMID- 30310475 TI - Cardio-oncology: A Focus on Cardiotoxicity. AB - Cardio-oncology is a recently developed field in cardiology aimed at significantly reducing cardiovascular morbidity and mortality and improving quality of life in cancer survivors. Cancer survival rates have been constantly increasing, mainly because of the advent of new, more potent and targeted therapies. However, many of the new therapies - along with some of the older chemotherapeutic regimens such as anthracyclines - are potentially cardiotoxic, which is reflected increasingly frequently in the published literature. Cardiotoxicity adversely affects prognosis in cancer patients, thus its prevention and treatment are crucial to improve quality and standards of care. This review aims to explore the existing literature relating to chemotherapy- and radiotherapy-induced cardiotoxicity. An overview of the imaging modalities for the identification of cardiotoxicity and therapies for its prevention and management is also provided. PMID- 30310477 TI - Featuring: Dr Patrick Serruys. AB - Prof Patrick Serruys is an expert in interventional cardiology, He and a colleague developed drug-eluting stents, which drastically reduced restenosis after procedures. He later devised a fully biodegradable drug-eluting scaffold so a permanent metallic stent would not need to be implanted in patients. He previously led on establishing the methodology of quantitative coronary angiography. Along with having an office "full of diplomas and medals", he has won career achievement awards from TCT and the American College of Cardiology, as well as the gold medal of the European Society of Cardiology. He acknowledges that introducing something new has immense ethical issues and advises practitioners to remain curious and open to novelty. PMID- 30310476 TI - New Advances in the Management of Refractory Angina Pectoris. AB - Refractory angina is a significant clinical problem and its successful management is often extremely challenging. Defined as chronic angina-type chest pain in the presence of myocardial ischaemia that persists despite optimal medical, interventional and surgical treatment, current therapies are limited and new approaches to treatment are needed. With an ageing population and increased survival from coronary artery disease, clinicians will increasingly encounter this complex condition in routine clinical practice. Novel therapies to target myocardial ischaemia in patients with refractory angina are at the forefront of research and in this review we discuss those in clinical translation and assess the evidence behind their efficacy. PMID- 30310478 TI - Diabetes Management - Lowering Cardiovascular Risk. AB - Diabetes mellitus is one of the most common diseases to plague the present day. Sixty percent of mortality in diabetic patients is caused by coronary artery disease. Numerous studies have shown that improving glycaemic control helps manage microvascular complications. On the other hand, some studies have shed light on the fact that a too tight glycaemic control can have adverse effects, especially on patients with high cardiovascular risk. Thus 'the lower the better' attitude should be exchanged for 'the earliest the best' attitude. A multidisciplinary approach should therefore be undertaken in order to achieve a proper management of the cardiovascular risk for diabetic patients. This includes using hypoglycaemic agents, antihypertensive medication and statins to balance the myriad of cardiovascular risk factors. PMID- 30310480 TI - Antiplatelet and Lipid-lowering Drugs in Hypertension. AB - Antiplatelet therapy, and low-dose acetylsalicylic acid (ASA) in particular, is recommended in hypertensive patients with previous cardiovascular events and is considered in hypertensive patients with reduced renal function or a high cardiovascular (CV) risk, provided blood pressure is well-controlled. Acetylsalicylic acid is not recommended in low-to-moderate risk hypertensive patients in whom absolute benefit and harm are equivalent. Further trials evaluating antithrombotic therapy including newer agents in hypertension are needed. Women at high and moderate risk of pre-eclampsia are advised to take a low dose of ASA daily from 12 weeks of gestation until delivery. In addition to their lipid-lowering effects, statins induce a small blood pressure reduction. The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines recommend using statin therapy in hypertensive patients at moderate-to-high CV risk to achieve the target low-density lipoprotein (LDL) cholesterol value <3 mmol/l (115 mg/dl). For individuals with manifest CV disease or at very high CV risk, a more aggressive LDL target of <1.8 mmol/l (70 mg/dl) is recommended. PMID- 30310479 TI - The Role of Non-alcoholic Fatty Liver Disease in Cardiovascular Disease. AB - Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in western countries and is closely related to the metabolic syndrome. When NAFLD is associated with hepatocellular damage and inflammation (non-alcoholic steatohepatitis [NASH]) it can lead to severe liver disease. However, it has become clear that NAFLD is also associated with an increased risk of cardiovascular disease (CVD), independently of classical known risk factors for the latter. In the current review we briefly summarise the current clinical evidence on the role of NAFLD in CVD and discuss the potential mechanisms by which NAFLD can be linked to the pathophysiology of CVD. PMID- 30310481 TI - Clinical Use of Cardiac Magnetic Resonance in Systemic Heart Disease. AB - A systemic disease is one that affects a number of organs and tissues, or the body as a whole. Systemic diseases include endocrine, metabolic, nutritional, multisystem (rheumatic) and HIV disease. Cardiovascular involvement is a common and underestimated problem in systemic diseases, and may present with disease associated cardiac involvement at diagnosis or later in the course of the systemic disease. The cardiac involvement in these diseases is usually silent or oligo-symptomatic and includes different pathophysiological mechanisms such as, myocardial inflammation, infarction, diffuse, subendocardial vasculitis, valvular disease and different patterns of fibrosis. Furthermore, acuity of heart involvement may be underestimated due to non-specific cardiac signs, and finally, most of patients are female and unable to exercise, due to arthritis or muscular discomfort/weakness or may have limited acoustic window, due to increased breast size. Cardiovascular magnetic resonance (CMR), due to its ability to reliably assess cardiac anatomy, function, inflammation, stress perfusion-fibrosis, aortic distensibility, and iron and fat deposition, constitutes an excellent tool for early diagnosis of heart involvement, risk stratification, treatment evaluation and long-term follow-up of patients with cardiac disease due to systemic diseases. PMID- 30310482 TI - Syncope in the Elderly. AB - A rapid change in ageing demographic is taking place worldwide such that healthcare professionals are increasingly treating old and very old patients. Syncope in the elderly is a challenging presentation that is under-recognised, particularly in the acute care setting. The reason for this is that presentation in the older person may be atypical: patients are less likely to have a prodrome, may have amnesia for loss of consciousness and events are frequently unwitnessed. The older patient thus may present with a fall rather than transient loss of consciousness. There is an increased susceptibility to syncope with advancing age attributed to age-related physiological impairments in heart rate and blood pressure, and alterations in cerebral blood flow. Multi-morbidity and polypharmacy in these complex patients increases susceptibility to syncope. Cardiac causes and more than one possible cause are also common. Syncope is a major cause of morbidity and mortality and is associated with enormous personal and wider health economic costs. In view of this, prompt assessment and early targeted intervention are recommended. The purpose of this article is to update the reader regarding the presentation and management of syncope in this rapidly changing demographic. PMID- 30310483 TI - Diabetes Mellitus and Heart Failure. AB - Diabetes mellitus and heart failure are two multifaceted entities characterised by high morbidity and mortality. Early epidemiological and prospective studies have observed the frequent co-existence of both conditions. Importantly, diabetes mellitus can precipitate or worsen heart failure due to the accumulation of advanced glycation end products, oxidative stress, inflammatory status impairment, decay of intracellular calcium, changes in microRNAs expression, not to mention atherosclerosis progression and coronary artery disease. Heart failure also impairs glucose metabolism through less well-known mechanisms. Attention must especially be given in the treatment as there are frequently adverse interactions between the two diseases and novel agents against diabetic cardiomyopathy are under investigation. As several missing links still exist in the connection between heart failure and diabetes mellitus we will review, in this article, the most recent data underlying the interaction of them and provide an overview of the most important clinical perspectives. PMID- 30310484 TI - Pharmacological Treatment of Patients with Chronic Systolic Heart Failure. AB - Chronic heart failure is characterised by neuroendocrine activation as an attempt of the body to maintain pump function of the heart and blood pressure for the perfusion of peripheral tissues. While this neuroendocrine activation is beneficial in the short term, it induces maladaptive remodeling of the heart with continuous deterioration of left ventricular function. Accordingly, pharmacological treatment of patients with heart failure aims at protecting the heart from this neuroendocrine activation, which is represented in particular by the sympathetic nervous and the renin-angiotensin-aldosterone systems. While this concept is based on evidence from numerous large randomised placebo-controlled studies in patients with systolic heart failure, about half of the patients with heart failure have preserved systolic function, and most studies antagonising neuroendocrine activation were not successful in these latter patients. Here, we review the pathophysiological changes that occur in patients with heart failure and provide an overview on the mechanisms and clinical evidence of currently applied pharmacological treatment in patients with systolic heart failure. PMID- 30310485 TI - Mitral Regurgitation - A Multidisciplinary Challenge. AB - Mitral regurgitation is an increasing valvular disease that represents a difficult management challenge. Surgical treatment for degenerative mitral regurgitation is the standard of care treatment. Percutaneous therapies have emerged rapidly over the past years as an option for treatment of mitral regurgitation for selected, predominantly high-risk patients. Catheter-based devices mimic these surgical approaches with less procedural risk. Mitraclip(r) implantation mimics the surgical edge-to-edge leaflet repair technique, reducing the regurgitant area. We review the increasing evidence with the Mitraclip device reported to date. PMID- 30310486 TI - Ventricular Assist Devices - Evolution of Surgical Heart Failure Treatment. AB - End-stage heart failure represents a substantial worldwide problem for the healthcare system. Despite significant improvements (medical heart failure treatment, implantable cardioverters, cardiac resyschronisation devices), long term survival and quality of life of these patients remains poor. Heart transplantation has been an effective therapy for terminal heart failure, but it remains limited by an increasing shortage of available donor organs along with strict criteria defining acceptable recipients. For the last 50 years, mechanical alternatives to support the circulation have been investigated; however, during the early years device development has been marked in general by slow progress. However, in the past two decades, the technology has evolved dramatically. The purpose of this review is to give a short summary on the evolution of ventricular assist device (VAD) therapy and to give perspectives for future treatment of heart failure. PMID- 30310487 TI - Foreword. PMID- 30310488 TI - The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology. AB - Low-density lipoprotein cholesterol (LDL-C) is a most important risk factor for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD) and a major focus of CVD risk reduction with lifestyle and statins. Unfortunately residual risk of CVD remains in patients with familial hypercholesterolaemia and/or statin intolerance in whom adequate LDL-C lowering is not accomplished with lifestyle and statins. PCSK9 is a serine protease that binds the LDL receptor (LDL-R) and acts as a chaparone for endocytosis and shuttling the PCSK9-LDLR complex to lysosomes for degradation. In the absence of PCSK9 the LDLR-LDL-C complex dissociates and LDL-R is recycled back to the cell surface. Humanised monoclonal antibodies (evolocumab, alirocumab, bocolicumab) have been developed that increase LDL-R by ~2-fold and lower LDL-C by up to 75 percent. This effect is synergistic to that of statins with the only common adverse effect is a local injection site reaction. At present, ongoing Phase III CVD outcome trials with PCSK9 inhibitors offer promise that patients with LDL-C levels that remain elevated can decrease CVD events and related mortality. PMID- 30310489 TI - Statins: Practical Considerations - A Review. AB - Statins are currently the most efficacious and widely prescribed lipid-lowering medications. The 2013 ACC/AHA cholesterol guidelines provide a dramatic shift in treatment approach with a focus on fixed-dose statins matched to individual risk scores. Statin intolerance is not uncommon and can be challenging to diagnose and manage; however, several therapeutic strategies have been successful in achieving statin tolerance. Statin use is also associated with liver enzyme elevations and increased risk of incident diabetes, but studies show these individuals benefit from statins. Several guidelines exist and statin use is expected to increase with the new cholesterol guidelines bringing along new challenges for prescribers. This review article will provide practical considerations for statin use and management of statin intolerance. PMID- 30310490 TI - Current Treatment of Familial Hypercholesterolaemia. AB - Familial hypercholesterolaemia is an autosomal-dominant disorder associated with mutations in the LDL receptor gene resulting in markedly elevated plasma low density lipoprotein cholesterol levels. FH is significantly underrecognised with as many as 1 in 300 having the heterozygous form and 1 in 1 million having the homozygous form of the disease. Early diagnosis and treatment of FH is paramount to reduce the risk of premature atherosclerotic cardiovascular disease and death. The goal of treatment is to reduce LDL-C by 50 % from baseline levels with lifestyle modification, pharmacologic lipid-lowering therapy, LDL apheresis and in rare cases, liver transplantation. Pharmacologic treatment ranges from statin medications to newer agents such as lomitapide, mipomersin and PCSK9 inhibitors. Combination therapy is frequently required to achieve goal lipoprotein level reductions and prevent complications. PMID- 30310491 TI - The Brugada Syndrome - Diagnosis, Clinical Implications and Risk Stratification. AB - The Brugada syndrome (BrS) is a hereditary arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals without overt structural heart disease. Currently, its diagnosis is mainly based on the presence of a spontaneous or Na+-channel blocker induced so-called "type 1" Brugada electrocardiographic (ECG) pattern typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal spaces. Presently the main unresolved clinical problem in the BrS is the identification of patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD). Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern and either history of aborted cardiac arrest or documented sustained ventricular tachycardia (class I) or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmias. However, the majority of BrS patients are asymptomatic when diagnosed and have generally low risk (0.5 % annually or lower) and therefore are not indicated for ICD. Most of SCD victims in the BrS have had no symptoms prior to the fatal event and therefore were not protected with an ICD. Currently there are no reliable methods to identify these potential victims of SCD. Although some ECG markers such as QRS fragmentation and infero-lateral early repolarisation have been demonstrated to signify increased arrhythmic risk their value still needs to be confirmed in large prospective studies. Novel risk assessment strategies need to be developed based on computerised quantitative ECG analysis of large digital ECG databases in patients with BrS and their relatives, and combined assessment of the most important factors of ventricular arrhythmogenesis. PMID- 30310492 TI - Evaluation and Management of ST-elevation Myocardial Infarction and Shock. AB - Cardiogenic shock is the deadliest complication of acute ST-elevation myocardial infarction. Prompt recognition and intervention are critical for patient survival. The diagnosis of cardiogenic shock is primarily a clinical one based on signs and symptoms of low cardiac output and heart failure, and can be confirmed with placement of a pulmonary arterial catheter. Vasopressor and inotropic therapies are typically required, and in severe cases, an intra-aortic balloon pump can provide additional haemodynamic support. Although mortality for cardiogenic shock associated with ST-elevation myocardial infarction remains high, early reperfusion strategies primarily via percutaneous coronary intervention or coronary artery bypass graft surgery have led to improved outcomes. PMID- 30310493 TI - Echocardiographic Evaluation of Aortic Stenosis - Normal Flow and Low Flow Scenarios. AB - The echocardiographic evaluation of the patient with aortic stenosis (AS) has evolved in recent years, beyond confirming the diagnosis and measuring the resting mean pressure gradient or valve area. New echocardiographic approaches have developed to address the clinical dilemmas related to discordant haemodynamic data, asymptomatic haemodynamically severe AS and low-flow, low gradient AS in order to better evaluate the disease severity, enhance the risk stratification of patients and provide important prognostic information. This article reviews the echocardiographic evaluation of the AS patient and focuses on the echocardiographic assessment of the haemodynamic severity, the prediction of clinical outcome and the use of echocardiography to guide patient management in the presence of normal flow and low flow scenarios. PMID- 30310494 TI - Update on Cardiac Resynchronisation Therapy for Heart Failure. AB - Cardiac resynchronisation therapy (CRT) is well accepted therapy for the treatment of symptomatic systolic heart failure in defined patient subgroups. Large clinical trials over the past 20 years have shown that patients with a left ventricular (LV) systolic dysfunction and interventricular conduction delay benefit from this therapy. Recent advances in this field include the expansion indications for CRT to patients with mild heart failure and to those with a mildly depressed ejection fraction that require frequent right ventricular pacing. In addition, although CRT guidelines have included indications in atrial fibrillation, it is now clear that this is most effective when pacing is utilised nearly 100 % of the time, often requiring atrioventricular (AV) junction ablation. Strategies for optimising LV lead placement based on identifying late mechanical contraction or electrical delay are promising for maximising CRT response. Finally, the role of routine AV delay optimisation is no longer recommended based on the results of multicentre trials. PMID- 30310495 TI - Gaps in the Heart Failure Guidelines. AB - There are still many aspects of heart failure care for which gaps remain in the evidence base, resulting in gaps in the guidelines. We aim to highlight these guideline gaps including areas that warrant further research and other areas where new data are forthcoming. PMID- 30310496 TI - Renal Denervation After Symplicity HTN-3 - Back to Basics. Review of the Evidence. AB - Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment resistant hypertension, a condition defined as office blood pressure elevation despite prescription of at least three antihypertensive drugs including a diuretic. However, the impressive fall in blood pressure reported after RDN in Symplicity HTN-2, the first randomised study, and multiple observational studies has not been confirmed in the US sham controlled trial Symplicity HTN-3 and four subsequent prospective randomised studies, all published or presented in 2014. The blood pressure reduction documented in earlier studies may be largely due to non-specific effects such as improvement of drug adherence in initially poorly adherent patients (Hawthorne effect), placebo effect and regression to the mean. The overall blood pressure lowering effect of RDN seems rather limited and the characteristics of true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparent drug-resistant hypertension, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment and with true resistant hypertension who may respond to RDN. PMID- 30310498 TI - Rhythm Management of the Atrial Fibrillation Patient: Practical Implementation of the 2012 ESC Guidelines. AB - A symposium at the 2014 European Society of Cardiology (ESC) congress reviewed the 2012 update of the ESC guideline on rhythm management of atrial fibrillation (AF) patients. The guidelines now include catheter ablation of AF as first-line therapy in selected patients with symptomatic, paroxysmal AF. A panel comprising electrophysiologists and cardiologists discussed four clinical cases that illustrated the challenges faced in the day-to-day treatment of AF patients and how these guidelines can help inform treatment decisions. Among the key discussions were the importance of early treatment of AF and the dilemma faced in treating AF patients with recently implanted stent, where the risk of stroke must be balanced against the risk of stent thrombosis. The panel considered that among selected patients with paroxysmal AF and no structural heart disease, catheter ablation is reasonable as first-line therapy. PMID- 30310497 TI - Hypertension in Chronic Kidney Disease - Role of Arterial Calcification and Impact on Treatment. AB - Hypertension contributes to the progression of kidney diseases as well as to the occurrence of cardiovascular events such as myocardial infarction, heart failure and stroke. The prevalence of hypertension is elevated in patients with kidney disease, and increases progressively as glomerular filtration rate falls. A better understanding of the mechanisms leading to hypertension in renal diseases has been gained in recent years; in this article we will review the pathogenesis of hypertension in chronic kidney disease (CKD) with a special focus on vascular calcification because calcification is associated with an increased incidence of cardiovascular morbidity in CKD patients. Although calcification of large arteries and blood pressure increase with age, few studies have specifically investigated a possible connection between these two factors as determinants of the severity of hypertension in CKD. Finally, we will review the trends in hypertension treatment in CKD patients. Expanded understanding of the role of CKD as both a cause and a target of hypertension highlights key points of pathophysiology of hypertension and may contribute to the identification of new strategies for its prevention and treatment. PMID- 30310499 TI - Prognostic impact of high c-Met expression in ovarian cancer: a meta-analysis. AB - High c-Met expression has been observed in epithelial ovarian cancer (EOC). However, its clinicopathological impacts remain controversial. We conducted this meta-analysis to evaluate the pathologic and prognostic significance of c-Met overexpression in patients with EOC. A systematic computerized search of the electronic databases PubMed, PMC, EMBASE, and Google scholar (up to April 2018) was carried out. From seven studies, 568 patients with EOC were included in the meta-analysis. Although there was no statistical significance, EOCs with c-Met overexpression tended to show higher FIGO stage (III-IV) (odds ratio = 2.18, 95% confidence interval: 0.86-5.53, p = 0.10) and higher rate of lymph node metastasis (odds ratio = 3.05, 95% confidence interval: 0.85-10.98, p = 0.09), compared with tumors with low c-Met expression. In terms of prognosis, patients with c-Met-high EOC showed significantly worse survival than those with c-Met-low tumor (hazard ratio = 2.11, 95% confidence interval: 1.51-2.94, p < 0.0001). In conclusion, this meta-analysis indicates that high c-Met expression represents an adverse prognostic marker for patients with EOC. PMID- 30310500 TI - A miRNA Combination as Promising Biomarker for Hepatocellular Carcinoma Diagnosis: A Study Based on Bioinformatics Analysis. AB - Background: miRNAs dysregulate in hepatocellular carcinoma (HCC), showing promise for diagnostic biomarkers which may be found through exploration of differentially expressed miRNAs when comparing HCC and normal liver tissues. Materials and Methods: In the present research, candidate miRNAs were selected and verified using screening dataset GSE12717 and training dataset GSE10694, respectively. A miRNA combination was constructed using stepwise logistic regression analysis and validated using two datasets GSE74618 and TCGA. Target genes of miRNAs in the combination were obtained using a miRNA target gene prediction database. Functional analysis was conducted using an online tool DAVID. We also analyzed the mRNA-Seq data of project LIHC from TCGA to identify the hub target genes of the miRNAs. Results: A miRNA combination, which is composed of hsa-miR-221 and hsa-miR-29c was defined in this study. The miRNA combination is more effective in discriminating HCC patients from normal individuals than individual miRNAs. Additionally, the combined miRNAs showed a lower misdiagnosis rate than AFP in HCC diagnosis. In terms of the functional analysis, a total of 27 target genes of hsa-miR-221 and 96 target genes of hsa miR-29c were obtained. Among which, INSIG1 was the common target of the two miRNAs. It was also found that both previously mentioned miRNAs played important roles in the regulation of transcription, cell proliferation, and involvement in cancer-related pathways. Lastly, 2 hub target genes of hsa-miR-221 and 16 hub target genes of hsa-miR-29c were obtained. Conclusion: We established a miRNA combination as a promising tool for HCC diagnosis, and the target genes we predicted provide possible points of penetration for researching these two miRNAs in HCC. PMID- 30310501 TI - Weekly versus triweekly cisplatin plus intensity-modulated radiotherapy in locally advanced nasopharyngeal carcinoma: A propensity score analysis with a large cohort. AB - Purpose: To directly compare the efficacy and acute toxicities of intensity modulated radiotherapy (IMRT) concurrent with weekly cisplatin (40 mg/m2) to high dose concurrent cisplatin (100 mg/m2) at three-week intervals. Materials and Methods: A total of 3,799 patients diagnosed with locally advanced nasopharyngeal carcinoma (NPC) at Sun Yat-Sen University Cancer Center between January 2010 and December 2013 were retrospectively reviewed. Propensity score analysis was conducted to balance the baseline characteristics between the groups, which allowed us to draw reliable conclusions. The efficacy and safety profiles were then assessed in the well-balanced large cohort. Results: The risk of distant metastasis was lower among the patients treated with weekly concurrent cisplatin than among those treated with the triweekly regimen (hazard ratio [HR], 0.45; P = .028). However, the disease-free survival, loco-regional relapse-free survival and overall survival rates were similar. The weekly group showed significantly higher rates of grade 3-4 thrombocytopenia, but lower rates of grade 3-4 mucositis, nausea and vomiting than the triweekly group. Conclusion: IMRT concurrent with a weekly cisplatin regimen was associated with significantly improved distant metastasis-free survival in locally advanced NPC. Differences in the selected acute toxicities between the weekly and triweekly concurrent cisplatin regimens were noted. PMID- 30310502 TI - PI3K/Akt/HIF-1alpha signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells. AB - Background: Our previous studies have demonstrated that human papillomaviruse (HPV)-16 oncoproteins promoted epithelial-mesenchymal transition (EMT), leading to non-small cell lung cancer (NSCLC) progression, but the underlying molecular mechanisms still remain unclear. PI3K/Akt/HIF-1alpha signaling pathway has been reported to mediate hypoxia-induced EMT. In this study, we further explored the role of PI3K/Akt/HIF-1alpha signaling pathway in HPV-16 oncoprotein-induced EMT in NSCLC cells. Methods: A549 and NCI-H460 NSCLC cells were transiently transfected with pEGFP-HPV-16 E6 or E7 constructs. Western blotting and RT-qPCR were respectively performed to determine the protein and mRNA expression of EMT related transcription factors. HPV-16 E6 or E7-transfected NSCLC cells were co transfected with specific HIF-1alpha-siRNA or pretreated with different concentrations of LY294002, a specific PI3K inhibitor, followed by the analysis of expression of EMT-related transcription factors. The correlation between HIF 1alpha and EMT-related transcription factors in NSCLC tissues was analyzed by immunohistochemical staining and Spearman rank correlation coefficient. Results: HPV-16 E6 and E7 oncoproteins upregulated the expression of Slug and Twist1, the EMT-related transcription factors, at both protein and mRNA levels in A549 and NCI-H460 cells. The co-transfection with specific HIF-1alpha-siRNA, but not the non-specific (NS)-siRNA, significantly abrogated HPV-16 oncoprotein-induced upregulation of ZEB1, Snail1, Slug, and Twist1 at both protein and mRNA levels. Additionally, pretreatment with LY294002 obviously blocked HPV-16 E6- and E7 induced Snail1, Slug, and Twist1 protein expression in A549 and NCI-H460 cells. Further analysis of clinical specimens showed that HIF-1alpha protein was strongly expressed in NSCLC tissues, which was positively correlated with ZEB1, Snail1, Slug, and Twist1 protein expression. Conclusions: PI3K/Akt/HIF-1alpha may contribute to the progression of HPV-associated NSCLC via mediating the expression of EMT-related transcription factors in NSCLC cells. PMID- 30310503 TI - The Predictive Value of Albumin-to-Alkaline Phosphatase Ratio for Overall Survival of Hepatocellular Carcinoma Patients Treated with Trans-Catheter Arterial Chemoembolization Therapy. AB - Background: We have previously reported the prognostic value of the albumin-to alkaline phosphatase ratio (AAPR) for advanced hepatocellular carcinoma (HCC) patients who are not receiving any standard anticancer therapy. However, the prognostic value of the AAPR for HCC patients treated with trans-catheter arterial chemoembolization therapy (TACE) was not investigated. Methods: We retrospectively analysed 372 HCC patients treated with TACE (the training cohort) and applied receiver operating characteristic curves (ROC curves) to identify the best cut-off value for the AAPR in this cohort. Then, univariate analyses by the Kaplan-Meier method and multivariate analysis by a Cox proportional hazards regression model were conducted. Both comparisons of the ROC curves and the likelihood ratio test (LRT) were employed to evaluate the abilities of different factors in predicting the survival of patients in this cohort. Finally, the prognostic value of the AAPR was validated in two cohorts: one included 202 HCC patients treated with supportive care (validation cohort I), and the other included 82 HCC patients treated with TACE (validation cohort II). Results: We identified 0.439 as the best cut-off value of the AAPR by ROC curve analysis. An AAPR > 0.439 was significantly correlated with a lower frequency of Child-Pugh grade B, portal vein tumour thrombus (PVTT), T3-4 and lymph node metastasis (P < 0.05). The median overall survival (OS) of the patients with an AAPR > 0.439 was significantly longer than that of those with an AAPR <= 0.439 (58.4 m vs 17.8 m, respectively, P < 0.001). The AAPR was identified as an independent prognostic factor after univariate and multivariate analyses (HR = 0.636, P = 0.003). The independent prognostic value of the AAPR was also confirmed in validation cohorts I and II. Additionally, we substituted the AAPR for the Child-Pugh grade in the CLIP system and integrated the AAPR into the TNM system. We found that the area under the curve (AUC) of the AAPR-CLIP system was significantly larger than that of the CLIP and the TNM when predicting 3-month, 6-month, 1-year and 2-year survival (P < 0.05). There was no significant difference between the AUCs for the AAPR-CLIP and the AAPR-TNM. The LRT suggested that both AAPR-CLIP and AAPR-TNM had significantly larger chi2 values and smaller AIC values than that of their corresponding primary system (P < 0.05). Conclusions: The AAPR was an independent prognostic index for the HCC patients treated with TACE. Both AAPR-CLIP and AAPR TNM outperformed their corresponding primary system in predicting OS in the current study. PMID- 30310504 TI - Eukaryotic translation initiation factor 5A-2 involves in doxorubicin-induced epithelial-mesenchymal transition in oral squamous cell carcinoma cells. AB - Background: Epithelial-mesenchymal transition (EMT) is considered to be vital during chemotherapy resistance in oral squamous cell carcinoma (OSCC). Recently, eukaryotic initiation factor 5A-2 (eIF5A-2), a potential oncogene, has been reported to be involved in chemotherapy resistance in human cancers. Materials and Methods: N1-guanyl-1,7-diaminoheptane (GC7, a novel eIF5A-2 inhibitor) or siRNA on responses to doxorubicin were examined in OSCC cells. Cytotoxicity and protein expression were evaluated by CCK-8 and EdU incorporation assay and western blotting. Tca8113 cells were used for establishment and treatment of tumor xenografts in vivo. Results: Low concentration of GC7 (5MUMU) significantly enhanced doxorubicin cytotoxicity in both epithelial phenotype OSCC cells (Cal27) and mesenchymal phenotype OSCC cells (HN30 and Tca8113). EMT process promoted by doxorubicin in Cal27 cells could be reversed by GC7. Additionally, GC7 induced mesenchymal-epithelial transition (MET) in HN30 and Tca8113 cells. Silencing of eIF5A-2 by specific siRNA exhibited the similar effects. The synergistic cytotoxicity of doxorubicin/GC7 combination was not induced in Twist-1, an EMT driving factor, silenced Cal27, HN30, and Tca8113 cells. GC7 also synergized doxorubicin to inhibit tumor growth in vivo treatment. Conclusions: Our study strongly proved that combined treatment with GC7 may boost the therapeutic effect of doxorubicin in OSCC by inhibiting the EMT. PMID- 30310505 TI - Prognostic value of PD-L1 expression in resected lung adenocarcinoma and potential molecular mechanisms. AB - Background: The prognostic role of PD-L1 expression in surgically resected lung adenocarcinoma (ADC) remains controversial. The present study was aimed to clarify the role of PD-L1 expression in predicting prognosis and to investigate its biological function in ADC. Materials and Methods: The association between PD L1 expression and clinical outcomes in patients with resected ADC was analyzed using immunohistochemistry (IHC) in our cohort (n=104), externally validated by a meta-analysis of 13 published studies. The biological role of PD-L1 in ADC was explored using gene set enrichment analysis (GSEA). Results: Positive PD-L1 expression in tumor cells was observed in 38.5% (40/104). High PD-L1 expression levels were significantly correlated with poor overall survival (P=0.008). Furthermore, the meta-analysis also showed that positive PD-L1 expression was associated with shorter OS than negative PD-L1 expression (HR= 1.75, 95% CI: 1.26 2.42; P<0.001). In subgroup analysis stratified according to ethnicity, the pooled results demonstrated that increased PD-L1 expression was an unfavorable prognostic factor for Asian populations (HR= 2.11, 95% CI: 1.48-3.02; P<0.001), but not for non-Asian populations (HR=1.16, 95% CI: 0.63-2.11, P=0.64). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with positive lymph node metastasis (OR=1.74, 95% CI: 1.23-2.46; P=0.002) and male (OR=1.56, 95% CI: 1.02-2.37; P=0.04). GSEA revealed PD-L1 expression levels positively correlated with immune process or immune-related pathways. Conclusion: PD-L1 expression is an important negative prognostic factor in resected ADC. This finding has important implications for immunotherapy targeting the PD-1/PD-L1 pathway in patients with resected ADC. PMID- 30310506 TI - Efficacy of surgery and prophylactic cranial irradiation in stage II and III small cell lung cancer. AB - Background: The role of surgery for stage II and III small cell lung cancer (SCLC) remains controversial. The use of prophylactic cranial irradiation (PCI) for resected SCLC was limited. This study aimed to assess the efficacy of surgery in patients with stage II and III SCLC, and evaluate the value of PCI on resected disease. Methods: A total of 269 consecutive patients with stage II-IIIA SCLC were retrospectively reviewed from January 2010 to December 2015. Of these, 116 patients received surgical resection, and 153 underwent non-surgical treatment. Resected patients were matched 1:1 with non-surgical patients (n=70 in each group). Results: The median follow-up was 30 months. The 1-, 3- and 5-year overall survival (OS) for matched patients were 80.0%, 44.3% and 31.7% in surgical group, and 80.0%, 24.3% and 20.0% in non-surgical group (P=0.009), respectively. Multivariate analysis in matched patients showed that surgery (HR=0.603, 95%CI: 0.404-0.900) and PCI (HR=0.637, 95%CI: 0.427-0.950) were independent prognostic factors for OS. In subgroup analysis, OS benefit related to surgery was marginal for stage II (P=0.09) and IIIA patients (P=0.061), but was significant for selected stage IIIA patients who received adjuvant chemo radiation and PCI (P=0.01). PCI was associated with improved OS for non-surgical patients (P=0.036), and stage IIIA of surgical patients (P=0.047). Conclusions: These findings suggest a potential OS benefit of surgery in stages II and IIIA patients, particularly in selected stage IIIA patients who received adjuvant chemo-radiation and PCI. The use of PCI for surgical patients with stage IIIA was associated with improved OS. PMID- 30310507 TI - A Refined Staging Model for Resectable Pancreatic Ductal Adenocarcinoma Incorporating Examined Lymph Nodes, Location of Tumor and Positive Lymph Nodes Ratio. AB - Background: Nodal status and tumor site are prognostic factors for resectable pancreatic ductal adenocarcinoma (PDAC). Parameters for nodal status are diverse, and the number of examined lymph nodes (eNs) needed for good prognosis are uncertain. We try to modify staging system of resectable PDAC with parameters mentioned above by recursive partitioning analysis. Methods: Patients from the Surveillance, Epidemiology, and End Results (SEER) database were divided into training cohort and internal validation cohort, randomly. PDAC patients from Sun Yat-sen University Cancer Center were regarded as external validation cohort. The training cohort was used to refine staging model by recursive partitioning analysis, while the internal validation cohort and the external validation cohort were applied to assess discriminatory capacity of staging model. For parameters included in the modified model, their effects were studied. Results: The number of eNs, tumor site and tumor size were risk factors for positive nodal status. Lymph nodes ratio (LNR), tumor site, eNs and T stages of 8th the American Joint Committee on Cancer (AJCC) were selected to develop a refined model, dividing patients into 5 groups of different outcomes, preceding 8th AJCC classification. Besides, we found that (1) for small PDAC (diameter < 1cm), lymph node metastasis was rarely found; (2) enough eNs were needed to ensure better prognosis of node negative patients; (3) tumors in the head of pancreas were prone to lymph nodes metastasis; (4) for node-positive patients, LNR was a better nodal parameter compared to positive lymph nodes (pNs). Conclusion: Our improved staging system helps to illuminate the interactions among tumor site, size and eNs. PMID- 30310508 TI - Prevalence of and risk factors for presenting initial respiratory symptoms in patients undergoing surgery for lung cancer. AB - Background: Patients with early stage lung cancer seldom present initial respiratory symptoms, causing a delayed diagnosis and missed opportunity to receive operation. This study aimed to investigate the prevalence of initial respiratory symptoms and identity what factors would predispose lung cancer patients to present initial respiratory symptoms in patients undergoing lung cancer surgery. Methods: A retrospective chart review was conducted on 3,203 patients undergoing surgery for primary lung cancer. The prevalence of initial respiratory symptoms was investigated and the comparisons of clinicopathological parameters were performed between patients with and without initial respiratory symptoms or between patients with single and multiple initial respiratory symptoms. Independent risk factors for presenting initial respiratory symptoms or multiple initial respiratory symptoms were identified using a logistic regression. Results: A total of 1,474 (46.0%) patients with lung cancer were admitted to hospital due to present initial respiratory symptoms. Symptom clusters of cough or sputum (33.1%) and bloody sputum or hemoptysis (16.7%) presented as the two major chief complaints for medical consultation while chest pain (6.9%) and chest distress or dyspnea (5.6%) remained relatively unusual. Multiple analyses found that coexisting chronic obstructive pulmonary disease (OR=1.70, 95% CI=1.41-2.05), tumor size >3 cm (OR=2.27, 95% CI=1.93-2.67), squamous cell carcinoma (OR=2.22, 95% CI=1.86-2.65), tumor located in left lower lung (OR=1.39, 95% CI=1.10-1.74) and advanced tumor stage (OR=1.27, 95% CI=1.06 1.52) were independent risk factors for presenting initial respiratory symptoms. Furthermore, current smoking (OR=1.36, 95% CI=1.07-1.73), tumor size >3 cm (OR=1.53, 95% CI=1.21-1.93) and squamous cell carcinoma (OR=1.68, 95% CI=1.32 2.15) were demonstrated to be independent risk factors for presenting multiple initial respiratory symptoms. Conclusions: Presenting initial respiratory symptoms was the common cause for medical consultation in patients undergoing lung cancer surgery. Patients with lung cancer in larger tumor size or squamous cell carcinoma more likely presented initial and even multiple initial respiratory symptoms. PMID- 30310509 TI - TP53 codon 72 Polymorphism and bladder cancer risk: a meta-analysis and emphasis on the role of tumor or smoking status. AB - Background: Various studies had explored the relationship between TP53 codon 72 polymorphisms and the risk of bladder cancer (BC). However, their results remained inconsistent and the definite role of smoking or tumor status associated with this polymorphism in BC cases was seldom involved. Hence, this meta-analysis was to disclose such associations. Methods: Systematical and comprehensive retrieval of online databases PubMed, PMC, EMBASE and Web of Science were conducted to obtain eligible studies, up to May 30th, 2018. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were utilized to assess the associations between TP53 codon 72 polymorphisms and BC susceptibilities under five genetic comparison models. Results: Ultimately, this meta-analysis enrolled 22 applicable studies with 3,791 BC cases and 4,917 controls. Our results suggested that the variant genotypes were associated with BC risk in Asian subgroup (allele model: OR=1.19, 95% CI=1.04-1.34; dominant model: OR=1.27, 95% CI=1.06-1.52; homozygote model: OR=1.36, 95% CI=1.03-1.80), while negative outcomes were presented in Caucasians. In the relationship between TP53 codon 72 polymorphisms and BC tumor stage in Asian group, positive results were presented in allele model: OR=1.68, 95% CI=1.04-2.72; dominant model: OR=2.46, 95% CI=1.08-5.61; heterozygous model: OR=2.32, 95% CI=1.04-5.14; homozygote model: OR=2.66, 95% CI=1.04-6.81. However, no evidence was revealed between this polymorphism and BC tumor grade. Besides, significant associations were displayed between TP53 codon 72 polymorphism and smoking status (allele model: OR=1.40, 95% CI=1.06-1.84; dominant model OR=1.72, 95% CI=1.18-2.50; heterozygous model: OR=1.77, 95% CI=1.19-2.64). Conclusion: Taken together, our results shed light on that TP53 codon 72 polymorphism was significantly associated with the susceptibility to BC in Asians. In addition, positive associations were also revealed between this polymorphism and tumor stage/smoking status in BC cases. PMID- 30310510 TI - Gene expression and single nucleotide polymorphism of ATP7B are associated with platinum-based chemotherapy response in non-small cell lung cancer patients. AB - Objectives: Platinum-based chemotherapy is first-line treatment for non-small cell lung cancer (NSCLC) patients. The efficacy is limited by drug resistance. Recent studies suggest that ATP7B, a copper efflux transporter, may be involved in platinum resistance. However, the clinical significance of ATP7B expression in NSCLC is controversial. Moreover, the effects of single nucleotide polymorphisms (SNPs) in ATP7B gene on the response to platinum-based chemotherapy are scarcely understood. The aim of our study is to evaluate the clinical value of ATP7B in NSCLC patients and explore the interrelationships between ATP7B SNPs and protein expression, and their association with chemotherapy response. Materials and Methods: A total of 247 NSCLC patients were recruited in this study. Among them, 158 patients who received platinum-based chemotherapy were used to explore the interrelationships between ATP7B SNPs, protein expression and chemotherapy response, while 89 patients who underwent surgical resection were used to further investigate the association between ATP7B SNPs and expression level. We genotyped 15 SNPs of ATP7B by Sequenom MassARRAY and determined ATP7B protein levels by immunohistochemistry. Results: Patients with ATP7B-negative tumors had improved chemotherapeutic response (p=0.025) and better overall survival (p=0.044) compared with the patients with ATP7B-positive tumors. The multivariate Cox regression analysis revealed that ATP7B expression was an independent prognostic factor (HR=0.639, 95%CI=0.424-0.962, p=0.032). Moreover, we found that the rs9526814 GG genotype was significantly associated with favorable response to platinum-based chemotherapy when compared with TT+TG genotypes (OR=0.362, 95CI%=0.140-0.935, p=0.036). Mechanistically, rs9526814 GG genotype showed a strong trend towards reduced expression level of ATP7B compared with the TT+TG genotypes (p= 0.048). Conclusion: Our findings indicate that ATP7B rs9526814 may contribute to platinum resistance by influencing ATP7B gene expression and can be used as a potential biomarker to predict the sensitivity of platinum-based chemotherapy in NSCLC patients. PMID- 30310511 TI - Prognostic Stratification of Advanced Gastric Signet Ring Cell Carcinoma by Clinicopathological Factors and GALNT14 Genotype. AB - Background: Gastric signet ring cell carcinoma (SRCC) is a histologic variant characterized by abundant intracytoplasmic mucin. Although it has been recognized that gastric adenocarcinoma harboring this feature has poorer prognosis, prognostic stratification within gastric SRCCs themselves has not been clearly defined. N-acetylgalactosaminyltransferase14 (GALNT14) genotype has been associated to poorer treatment outcome in mucinous type colorectal cancer. Here we incorporated clinicopathological factors and GALNT14 genotype to stratify prognosis of advanced gastric SRCC. Methods: Totally 347 gastric SRCC patients were retrospectively enrolled for GALNT14 genotyping. Clinicopathological factors were included for prognosis stratification. Results: Of the 347 patients, 341 underwent radical-intent gastrectomy and 6 received palliative gastrectomy. Kaplan-Meier analysis for overall survival indicated that Tumor-Node-Metastasis staging could only stratify the patients into three prognosis-distinguishable groups: group-1 (stage IA); group-2 (stage IB/IIA) and group-3 (the remaining Tumor-Node-Metastasis stages combined). Multivariate Cox-proportional hazard models for group-3 patients revealed GALNT14 "TT" genotype (P = 0.0482). Tumor size (P = 0.0009), node status (P <0.0001), metastasis status (P = 0.0096), and perineural invasion (P = 0.037) independently associated with unfavorable OS. Exploratory subgroup analysis showed that GALNT14"TT" genotype was associated with unfavorable OS in SRCCs with more aggressive phenotypes: node status >0 (P = 0.0013), lymphatic invasion (P = 0.021), vascular invasion (P = 0.0076) and perineural invasion (P = 0.0161). Accordingly, a scoring system was established capable of stratifying advanced gastric SRCC patients into three distinguishable prognostic subgroups. Conclusions: Gastric SRCC could be stratified into different prognostic subgroups by combining clinicopathological factors and GALNT14 genotype. PMID- 30310512 TI - Improved survival in ovarian cancer, with widening survival gaps of races and socioeconomic status: a period analysis, 1983-2012. AB - Introduction: Ovarian cancer is the first leading cause of cancer-related deaths among gynecologic malignancies, and the 7th most common female cancer worldwide. However, previous studies on changes in the long-term survival of ovarian cancer were limited. Methods: Our data were extracted from Surveillance, Epidemiology, and End Results (SEER) registries to assess the incidence and relative survival changes of patients with ovarian cancer during 1983-2012. Patients with ovarian cancer were stratified by age, race, and socioeconomic status (SES). Cox regression analysis and Spearman rank correlation analysis were performed by STATA 12 software. Results: The overall incidence of ovarian cancer per 100,000 decreased from 13.7 to 12.4 to 10.8 over three decades with peak incidence occurring in the 70+ age group at 47.6, 45.7 and 40.2 in each respective decade. Median survival improved from 34 months to 46 months to 52 months over three decades, with the 5-year relative survival rate (RSR) increasing from 39.3% to 43.4% to 45.4% (p < 0.0001). However, Whites showed higher median survival (34 months) than Blacks (27 months) in the first decade, and the survival difference significantly increased to 16 months in the third decade. Additionally, the median survival difference between the low-poverty group and high poverty group increased from 4 months to 12 months in the three decades. Discussion: This study demonstrated the decreasing incidence of ovarian cancer with an observed improvement in relative survival over three decades in a large sample. However, the survival gaps among races and SESs significantly widened over the three decades. PMID- 30310514 TI - Proposal for a New TNM Stage based on the 7th and 8th American Joint Committee on Cancer pTNM Staging Classification for Gastric Cancer. AB - Background: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for gastric cancer incorporated several new changes. We aimed to assess the comparative prognostic values of the 7th and 8th AJCC pTNM staging systems in patients with gastric cancer (GC), and accordingly, to put forward a refined staging classification. Methods: The SEER database was queried to identify GC patients between 2004 and 2009. GC patients from Sun Yat-sen University Cancer Center (SYSUCC) were used as external validation data. The Kaplan-Meier method and Cox proportional hazards regression models were used to analyze cause-specific survival (CSS). The prognostic performance of different staging schemes was assessed using the concordance index (c-index), Akaike's information criterion (AIC), and likelihood ratio chi2 test. Results: In the SEER cohort, stage migration occurred in 8.74% of patients. Survival analysis showed that it was better to treat T4bN0M0 + T4aN2M0 as stage IIIB and T4bN3bM0 as stage IV. Based on this, we established a new staging system which exhibited a superior c-index (0.7501) to the 7th and 8th AJCC staging systems (0.7498 and 0.7500, respectively). The new staging system also outperformed the 7th and 8th AJCC staging systems in terms of AIC and the likelihood ratio chi2 test. The predictive superiority of the new staging system remained valid in the SYSUCC database. Conclusions: We demonstrated that some stage modifications in the 8th AJCC pathologic staging were unnecessary. Therefore we established a new staging system, which was superior to the 7th and 8th staging systems. PMID- 30310515 TI - Adrenal incidentaloma: machine learning-based quantitative texture analysis of unenhanced CT can effectively differentiate sPHEO from lipid-poor adrenal adenoma. AB - Objective: To evaluate the feasibility and accuracy of machine learning based texture analysis of unenhanced CT images in differentiating subclinical pheochromocytoma (sPHEO) from lipid-poor adenoma (LPA) in adrenal incidentaloma (AI). Methods: Seventy-nine patients with 80 LPA and 29 patients with 30 sPHEO were included in the study. Texture parameters were derived using imaging software (MaZda). Thirty texture features were selected and LPA was performed for the features selected. The number of positive features was used to predict results. Logistic multiple regression analysis was performed on the 30 texture features, and a predictive equation was created based on the coefficients obtained. Results: LPA yielded a misclassification rate of 19.39% in differentiating sPHEO from LPA. Our predictive model had an accuracy rate of 94.4% (102/108), with a sensitivity of 86.2% (25/29) and a specificity of 97.5% (77/79) for differentiation. When the number of positive features was greater than 8, the accuracy of prediction was 85.2% (92/108), with a sensitivity of 96.6% (28/29) and a specificity of 81% (64/79). Conclusions: Machine learning based quantitative texture analysis of unenhanced CT may be a reliable quantitative method in differentiating sPHEO from LPA when AI is present. PMID- 30310516 TI - Systematic Review and Meta-Analysis on the Association between Polymorphisms in Genes of IL-12 Signaling Pathway and Hepatocellular Carcinoma Risk. AB - We performed an updated meta-analysis and systematic review to explore the associations between polymorphisms in genes of IL-12 signaling pathway and hepatocellular carcinoma (HCC) risk. Diverse databases were retrieved to identify entire available studies, and odds ratios (ORs) correspondence with 95% confidence intervals (CIs) were performed to assess their associations. Finally, 6 polymorphisms in five genes of the IL-12 signaling pathway were extracted from 39 case-control studies, 26 publications. We identified that STAT4-rs7574865 polymorphism was significantly associated with an increased risk of HCC in allelic contrast, dominant, homozygote and recessive models. However, we failed to uncover any significant association between other polymorphisms in genes of IL 12 signaling pathway and HCC risk, including IL18-rs1946518 and -rs187238, IFN gamma-rs2430561, IL12A-rs568408, IL12B-rs3212227 and STAT4-rs7574865. When the subgroup analysis was conducted based on Hardy-Weinberg Equilibrium (HWE) status, we identified that IFN-gamma-rs2430561 polymorphism was significantly associated with an increased risk of HCC in homozygote and recessive models of these studies whose control groups were conformed to HWE. To sum up, our study suggests that STAT4-rs7574865 is a risk factor for HCC. Further well-designed large sample size studies are warranted to shed new light on these findings. PMID- 30310517 TI - LncRNA PVT1 promotes malignant progression in squamous cell carcinoma of the head and neck. AB - Long non-coding RNAs (lncRNAs) are potentially critical regulators of cancer malignant behaviours. Aberrant expression and dysfunction of lncRNA PVT1 have been reported in multiple human cancers. However, its role in squamous cell carcinoma of the head and neck (SCCHN) remains largely unknown. Our current study demonstrated that PVT1 expression was increased in SCCHN. High PVT1 expression was positively correlated with SCCHN clinical parameters including T classification, clinical stages and cervical lymph node metastasis. More importantly, high PVT1 expression predicted a poor prognosis in SCCHN patients. Gain-of function and loss-of function studies further indicated that PVT1 promoted the proliferation and invasion of SCCHN both in vitro and in vivo, which was accompanied by epithelial-mesenchymal transition and enhanced cancer stem cell-like properties. Further mechanistic investigation revealed that PVT1 activated Wnt/beta-catenin signalling pathway, and inhibition of Wnt/beta-catenin signalling reversed the malignant progression caused by PVT1 overexpression. Together, our study reveals that PVT1 accelerates the malignant progression of SCCHN and represents a potential biomarker and therapeutic target in SCCHN. PMID- 30310513 TI - The Role of MicroRNAs in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers, leading to the second cancer-related death in the global. Although the treatment of HCC has greatly improved over the past few decades, the survival rate of patients is still quite low. Thus, it is urgent to explore new therapies, especially seek for more accurate biomarkers for early diagnosis, treatment and prognosis in HCC. MicroRNAs (miRNAs), small noncoding RNAs, are pivotal participants and regulators in the development and progression of HCC. Great progress has been made in the studies of miRNAs in HCC. The key regulatory mechanisms of miRNAs include proliferation, apoptosis, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance and autophagy in HCC. And exosomal miRNAs also play important roles in proliferation, invasion, metastasis, and drug resistance in HCC by regulating gene expression in the target cells. In addition, some miRNAs, including exosomal miRNAs, can be as potential diagnostic and prediction markers in HCC. This review summarizes the latest researches development of miRNAs in HCC in recent years. PMID- 30310518 TI - CX3CL1 involves in breast cancer metastasizing to the spine via the Src/FAK signaling pathway. AB - C-X3-C chemokine ligand 1 (CX3CL1) has been shown to be involved in the development of multiple tumors. Our previous study demonstrated that CX3CL1 may be involved in the process of metastasis of various malignant tumors to the spine, including breast cancer, but the molecular mechanism was still unknown. In the present study, we found that the receptor CX3CR1 was overexpressed in the spinal metastases of breast cancer than in para-tumor tissue. In terms of CX3CL1, it was significantly more expressed in normal spinal cancellous bone than in limbs. However, CX3CR1 was not expressed at a high level in every breast cancer cell compared with the human mammary epithelial cell line MCF-10A. In addition, CX3CL1 did promote the migration and invasion abilities of MDA-MB-231 cells. However, CX3CL1 has no obvious effect on cell growth. Furthermore, CX3CL1 induced chemotaxis of tumor cells via the Src/FAK signaling pathway. The migration index enhanced by CX3CL1 was dramatically declined using Bosutinib and PF-00562271, which are the inhibitors of Src and FAK signaling pathways, respectively. Therefore, CX3CL1 in spinal cancellous bone attracts CX3CR1-expressing tumor cells to the spine and enhances their migration and invasion abilities through the Src/FAK signaling pathway. PMID- 30310519 TI - Outpatient acupuncture effects on patient self-reported symptoms in oncology care: a retrospective analysis. AB - Background: Increased access to complementary therapies such as acupuncture at academic medical centers has created new opportunities for management of cancer and cancer treatment related symptoms. Methods: Patients presenting for acupuncture treatment during calendar year 2016 at an outpatient integrative medicine clinic in a comprehensive cancer center were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS; 16 symptoms, score 0-10, 10 worst possible) before and after each visit. ESAS subscales analyzed included global (GDS; score 0-90), physical (PHS, 0-60) and psychological distress (PSS, 0 20). ESAS symptom score change pre/post acupuncture treatment & from baseline visit to first follow up were evaluated by paired t-test. Results: Of 375 participants [mean age 55.6, 68.3% female, 73.9% white, most common cancer diagnosis of breast (32.8%) and thoracic/head & neck (25.9%)], 73.3% had at least one follow up acupuncture treatment [mean 4.6 (SD 5.1) treatments]. Highest/worst symptoms at baseline were poor sleep (3.92), fatigue (3.43), well-being (3.31), and pain (3.29). Statistically significant reduction/improvement (pre/post) was observed for all ESAS symptoms and subscales for the initial acupuncture treatment (p <0.001). Hot flashes had the highest mean reduction (-1.93), followed by fatigue (-1.72), numbness/tingling (-1.70), and nausea (-1.67). Clinically significant reductions were also observed for ESAS subscales of GDS ( 12.2), PHS (-8.5), and PSS (-2.6). For symptom change from initial acupuncture treatment to first follow up (pre/pre), statistically and clinically significant improvement was observed for spiritual pain (-1.10; p<0.001) and ESAS subscale of GDS (-6.09; p=0.048). Clinical response rates (reduction >=1) on follow up were highest for symptoms of spiritual pain (58.9%), dry mouth (57.8%) and nausea (57.3%). Conclusions: Outpatient acupuncture was associated with immediate & longitudinal significant improvement across a range of symptoms commonly experienced by individuals during cancer care. Further research is needed to better understand frequency of treatments needed in clinical practice to help maintain benefit. PMID- 30310520 TI - Inhibition of Phospholipase D1 mRNA Expression Slows Down the Proliferation Rate of Prostate Cancer Cells That Have Transited to Androgen Independence. AB - To explore the role of phospholipase D1 (PLD1) mRNA in transition of prostate cancer (PCa) cells to androgen independence, we used Arraystar Human LncRNA Microarray V3.0 to detect and compare the differential expression of PLD1 and its signaling pathway-related gene in standard androgen dependence prostate cancer (ADPC) cell line LNCaP before and after the occurrence of androgen independence prostate cancer (AIPC) transition. In addition, we used the shRNA lentiviral vector to inhibit the PLD1 mRNA expression and observed its effect on LNCaP cell proliferation after AIPC transition by using MTS method. The results showed that the expression level of PLD1 mRNA was increased by 373-fold after AIPC transition (P<0.05); the PI3K/AKT signaling pathway-related gene expression was also elevated (P<0.05); the growth rate of LNCaP cells that had transited to androgen independence was reduced by about 30% when the PLD1 mRNA expression was inhibited by the shRNA lentivirus as compared with the negative control group (P<0.05). All these results suggest that PLD1 mRNA and the related PI3K/AKT signaling pathway may play an important role in AIPC. Down-regulating the expression of PLD1 mRNA could to some extent inhibit the proliferation rate of PCa cells after AIPC transition. PMID- 30310521 TI - Downregulation of Activin A Receptor Type 2A Is Associated with Metastatic Potential and Poor Prognosis of Colon Cancer. AB - Aims: Activin A receptor type 2A (ACVR2A) is a membrane receptor in the transforming growth factor- beta (TGF-beta signaling pathway, which is involved in the regulation of cell proliferation, migration, and apoptosis. The aim of this study was to examine the expression profiles and biological functions of ACVR2A in colon cancer. Methods: ACVR2A expression was investigated using the GSE39582 database and two validation cohorts. An in vitro study of cell proliferation and migration of human colon cell lines was also performed. Results: In the GSE39582 database (n= 497), expression of ACVR2A mRNA was identified as a prognostic factor by linear regression analysis. In one validation cohort of 15 patients with stage IV cancer, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) consisting of 193 cases, reduced ACVR2A protein expression correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between low ACVR2A mRNA or protein expression and worse survival were also observed in the GSE39582 database and the TMA validation cohort (all P < 0.05). Moreover, our in vitro studies showed a remarkable increase in cell migration in ACVR2A knockdown cells. Conclusions: Our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis and may serve as a prognostic marker in patients with colon cancer. PMID- 30310522 TI - Risk of upgrading from prostate biopsy to radical prostatectomy pathology: Is magnetic resonance imaging-guided biopsy more accurate? AB - Background: This study compared magnetic resonance imaging-guided biopsy (MRI-GB) and transrectal ultrasound guided biopsy (TRUS-GB) with the final histology of the radical prostatectomy (RP) specimen. Methods: Our subjects were 229 patients with prostate cancer (PCa), proven histopathologically using MRI-GB or TRUS-GB, who underwent RP at our center between December 2015 and December 2016. The main group included 92 patients who underwent MRI-GB and the control group included 137 patients who underwent 12-core TRUS-GB. Histological findings for RP specimens were compared with those from biopsies. We also evaluated predictors of upgraded Gleason score (GS), using uni- and multivariate analyses. Results: Upgraded GS between biopsy and RP specimen occurred to 22.7% (52/229) of the cohort overall. In univariate analysis, prostate-specific antigen density (PSAD) (P<0.001), prostate volume (PV) < 30 ml (P<0.001), biopsy modality (P=0.027), biopsy GS (P=0.032) and measured MRI lymph node metastasis (P=0.018) were prognostic factors. Multivariate logistic regression analysis showed PV < 30 ml (P<0.001) and biopsy modality (P=0.001) were independent predictors of upgraded GS. Conclusions: MRI-GB may enhance the diagnostic accuracy of prostate cancer detection in final histopathology with lower rate of upgraded GS than TRUS-GB. Also, PV < 30 ml and biopsy modality were independent predictors of upgraded GS. PMID- 30310523 TI - Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis. AB - Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only ("other-only first metastasis"). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1% 62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer. PMID- 30310524 TI - Whole-Genome Sequence of the Novel Antarctobacter heliothermus Strain SMS3, Found in Association with the Marine Diatom Skeletonema marinoi. AB - As part of an ongoing investigation into the microbiome of the marine diatom Skeletonema marinoi, the bacterial strain SMS3 was isolated from a culture of S. marinoi strain ST54, which had been propagated from a sample of top layer marine sediments taken from the Swedish west coast. We present here the sequenced genome of this bacterium, which we place in the taxon Antarctobacter heliothermus, based on a phylotaxonomic analysis and its high 16S rRNA sequence similarity to the A. heliothermus type strain DSM 11445T. Its 5,331,190 bp genome consists of a circular chromosome and three circular plasmids, and contains 5,019 CDSs. Strain SMS3 contains a phosphatidylcholine synthase gene, as well as genes involved in DMSP degradation, both of which imply a potential symbiotic relationship with its host. PMID- 30310525 TI - Isolation and genomic characterization of six endophytic bacteria isolated from Saccharum sp (sugarcane): Insights into antibiotic, secondary metabolite and quorum sensing metabolism. AB - Six endophytic bacteria were isolated from Saccharum sp (sugarcane) grown in the parish of Westmoreland on the island of Jamaica located in the West Indies. Whole genome sequence and annotation of the six bacteria show that three were from the genus Pseudomonas and the other three were from the genera Pantoea, Pseudocitrobacter, and Enterobacter. A scan of each genome using the antibiotics and secondary metabolite analysis shell (antiSMASH4.0) webserver showed evidence that the bacteria were able to produce a variety of secondary metabolites. In addition, we were able to show that one of the organisms, Enterobacter sp RIT418 produces N-acyl-homoserine lactones (AHLs), which is indicative of cell-cell communication via quorum sensing (QS). PMID- 30310526 TI - Low temperature flow lithography. AB - Flow lithography (FL) is a microfluidic technique distinguished for its ability to produce hydrogel microparticles of various geometrical and chemical designs. While FL is typically performed in room temperature, this paper reports a new technique called low temperature flow lithography that uses low synthesis temperature to increase the degree of polymerization of microparticles without compromising other aspects of flow lithography. We suggest that decreased oxygen diffusivity in low temperature is responsible for the increase in polymerization. Microparticles that exhibit a higher degree of polymerization display a more developed polymer network, ultimately resulting in a more defined morphology, higher incorporation of materials of interest, and improved functional performance. This work demonstrates the increase in the degree of polymerization by examining the temperature effect on both the physical and chemical structures of particles. We show applications of this technique in synthesizing thin microparticles and enhancing microparticle-based detection of microRNA. Low temperature FL offers a simple and easy method of improving the degree of polymerization, which can be implemented in a wide range of FL applications. PMID- 30310527 TI - Oral mucosa-on-a-chip to assess layer-specific responses to bacteria and dental materials. AB - The human oral mucosa hosts a diverse microbiome and is exposed to potentially toxic biomaterials from dental restoratives. Mucosal health is partly determined by cell and tissue responses to challenges such as dental materials and pathogenic bacteria. An in vitro model to rapidly determine potential layer specific responses would lead to a better understanding of mucosal homeostasis and pathology. Therefore, this study aimed to develop a co-cultured microfluidic mucosal model on-a-chip to rapidly assess mucosal remodeling and the responses of epithelial and subepithelial layers to challenges typically found in the oral environment. A gingival fibroblast-laden collagen hydrogel was assembled in the central channel of a three-channel microfluidic chamber with interconnecting pores, followed by a keratinocyte layer attached to the collagen exposed in the pores. This configuration produced apical and subepithelial side channels capable of sustaining flow. Keratinocyte, fibroblast, and collagen densities were optimized to create a co-culture tissue-like construct stable over one week. Cells were stained and imaged with epifluorescence microscopy to confirm layer characteristics. As proof-of-concept, the mucosal construct was exposed separately to a dental monomer, 2-hydroxylethyl methacrylate (HEMA), and the oral bacteria Streptococcus mutans. Exposure to HEMA lowered mucosal cell viability, while exposure to the bacteria lowered trans-epithelial electrical resistance. These findings suggest that the oral mucosa-on-a-chip is useful for studying oral mucosal interactions with bacteria and biomaterials with a histology-like view of the tissue layers. PMID- 30310528 TI - Knockout of Mpv17-Like Protein (M-LPH) Gene in Human Hepatoma Cells Results in Impairment of mtDNA Integrity through Reduction of TFAM, OGG1, and LIG3 at the Protein Levels. AB - Human Mpv17-like protein (M-LPH) has been suggested to participate in prevention of mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage. To clarify the molecular mechanism of M-LPH function, we knocked out M-LPH in human hepatoma HepG2 using CRISPR-Cas9 technology. An increase in mtDNA damage in M-LPH KO HepG2 cells was demonstrated by PCR-based quantitation and 8-hydroxy-2' deoxyguanosine (8-OHdG) measurement. Furthermore, confocal immunofluorescence analysis and Western blot analysis of mitochondrial extracts demonstrated that M LPH-KO caused reductions in the protein levels of mitochondrial transcription factor A (TFAM), an essential factor for transcription and maintenance of mtDNA, and two DNA repair enzymes, 8-oxoguanine DNA glycosylase (OGG1) and DNA ligase 3 (LIG3), both involved in mitochondrial base excision repair (BER). Accordingly, it was suggested that the increase in mtDNA damage was due to a cumulative effect of mtDNA instability resulting from deficiencies of TFAM and diminished ability for BER arising from deficiencies in BER-related enzymes. These findings suggest that M-LPH could be involved in the maintenance of mtDNA, and therefore mitochondrial function, by protecting proteins essential for mtDNA stability and maintenance, in an integrated manner. PMID- 30310529 TI - Effects of the Aphanizomenon flos-aquae Extract (Klamin(r)) on a Neurodegeneration Cellular Model. AB - Cyanobacteria have been recognized as a source of bioactive molecules to be employed in nutraceuticals, pharmaceuticals, and functional foods. An extract of Aphanizomenon flos-aquae (AFA), commercialized as Klamin(r), was subjected to chemical analysis to determine its compounds. The AFA extract Klamin(r) resulted to be nontoxic, also at high doses, when administered onto LAN5 neuronal cells. Its scavenging properties against ROS generation were evaluated by using DCFH-DA assay, and its mitochondrial protective role was determined by JC-1 and MitoSOX assays. Klamin(r) exerts a protective role against beta amyloid- (Abeta-) induced toxicity and against oxidative stress. Anti-inflammatory properties were demonstrated by NFbetaB nuclear localization and activation of IL-6 and IL-1beta inflammatory cytokines through ELISA. Finally, by using thioflavin T (ThT) and fluorimetric measures, we found that Klamin(r) interferes with Abeta aggregation kinetics, supporting the formation of smaller and nontoxic structures compared to toxic Abeta aggregates alone. Altogether, these data indicate that the AFA extract may play a protective role against mechanisms leading to neurodegeneration. PMID- 30310530 TI - Gingival-derived mesenchymal stem cells: An endless resource for regenerative dentistry. AB - The gingiva, the masticatory portion of the oral mucosa, is excised and discarded frequently during routine dental treatments and following tooth extraction, dental crown lengthening, gingivectomy and periodontal surgeries. Subsequent to excision, healing eventually happens in a short time period after gingival surgery. Clinically, the gingival tissue can be collected very easily and, in the laboratory, it is also very easy to isolate gingival-derived mesenchymal stem cells (GMSCs) from this discarded gingival tissue. GMSCs, a stem cell population within the lamina propria of the gingival tissue, can be isolated from attached and free gingiva, inflamed gingival tissues, and from hyperplastic gingiva. Comparatively, they constitute more attractive alternatives to other dental derived mesenchymal stem cells due to the availability and accessibility of gingival tissues. They have unique immunomodulatory functions and well-documented self-renewal and multipotent differentiation properties. They display positive signals for Stro-1, Oct-4 and SSEA-4 pluripotency-associated markers, with some co-expressing Oct4/Stro-1 or Oct-4/SSEA-4. They should be considered as the best stem cell source for cell-based therapies and regenerative dentistry. The clinical use of GMSCs for regenerative dentistry represents an attractive therapeutic modality. However, numerous biological and technical challenges need to be addressed prior to considering transplantation approaches of GMSCs as clinically realistic therapies for humans. PMID- 30310532 TI - Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem? AB - Treatment of hepatitis C virus (HCV) infection has evolved greatly through the recent decade. The availability of direct-acting antiviral agents (DAAs) targeting the functional proteins of HCV has resulted in the introduction of DAA based combination therapies, providing an optimal rate of treatment success. Among the DAAs, NS5A inhibitors are used in most of the introduced and approved HCV antiviral regimens. Resistance-associated substitutions (RASs) are amino acid substitutions in HCV protein sequences that result in decreased antiviral efficacy of the HCV DAAs. Among the HCV RASs, the NS5A RASs were found to effectively modify and decrease treatment response to NS5A inhibitor-containing regimens. As a baseline predictor of treatment response, NS5A RAS draws attention for pretreatment testing in targeted patient groups. Given NS5A RASs are either naturally-occurring or DAA-selected, the application of NS5A RAS testing can be considered in two settings of NS5A inhibitor-naive patients and NS5A inhibitor experienced patients. Less than 5% of NS5A inhibitor-naive patients harbor naturally-occurring NS5A RAS with high resistance level (> 100X resistance fold change). In NS5A inhibitor-naive patients, NS5A RAS testing accompanied by treatment optimization cannot increase treatment response more than 2%-3%, while in NS5A inhibitor-experienced patients, > 75% are found to have NS5A RASs > 100X and NS5A RAS testing in this group of patients seems to be reasonable. This editorial will address the debate on the application of NS5A RAS testing and will discuss if the NS5A RAS testing has any role in clinical management of hepatitis C. PMID- 30310531 TI - Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells. AB - Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (self-renewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous, muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancer stem cells (CSCs) via G-protein coupled receptors S1Pn (n = 1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptor-activated downstream effectors influenced the rate of self-renewal and should be further explored as regeneration-related targets. Considering malignant transformation, it is essential to control the level of self-renewal capacity. Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged or dead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations explored pharmacological tools that target sphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation. PMID- 30310533 TI - Challenge of hepatitis C in Egypt and hepatitis B in Mauritania. AB - Egypt has one of the highest prevalence rates of hepatitis C virus (HCV) in the world, mostly with genotype 4 that is highly associated with severe fibrosis. As a consequence, hepatocellular carcinoma has become the leading cause of cancer in this country. Mauritania is a highly endemic area for hepatitis B virus (HBV). HBV and HCV could both be iatrogenically transmitted through infected blood products, infected needles, and medical equipment improperly sterilized. Adequate and efficient healthcare and public health measures with good surveillance programs, access for screening, prevention strategies, and successful treatment are needed to halt the spread of these diseases. Herein, we have reviewed the epidemiology, modes of transmission, predisposing factors, and novel treatment modalities of these viruses. We have proposed practices and interventions to decrease the risk of transmission of HCV and HBV in the affected countries, including strict adherence to standard precautions in the healthcare setting, rigorous education and training of patients and healthcare providers, universal screening of blood donors, use of safety-engineered devices, proper sterilization of medical equipment, hepatitis B vaccination, as well as effective direct-acting antiviral agents for the treatment of HCV. PMID- 30310535 TI - Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy. AB - Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non responders with Child-Pugh B through future clinical trials. PMID- 30310534 TI - Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets. PMID- 30310537 TI - Hepatocellular carcinoma occurrence in DAA-treated hepatitis C virus patients: Correlated or incidental? A brief review. AB - Hepatitis C virus (HCV) chronic infection induces liver fibrosis and cirrhosis but is also responsible for a significant portion of hepatocellular carcinoma (HCC) occurrence. Since it was recognized as a causative factor of chronic hepatitis, there have been multiple efforts towards viral eradication, leading to the first-generation HCV treatment that was based on interferon (IFN)-alpha and its analogs, mainly PEGylated interferon-alpha (PEG IFNalpha). Sustained virological response (SVR), defined as the absence of detectable RNA of HCV in blood serum for at least 24 wk after discontinuing the treatment, was accepted as a marker of viral clearance and was achieved in approximately one-half of patients treated with PEG IFNalpha regimens. Further research on the molecular biology of HCV gave rise to a new generation of drugs, the so-called direct antiviral agents (DAAs). DAA regimens, as implied by their name, interfere with the HCV genome or its products and have high SVR rates, over 90%, after just 12 wk of per os treatment. Although there are no questions about their efficacy or their universality, as they lack the contraindication for advanced liver disease that marks PEG IFNalpha, some reports of undesired oncologic outcomes after DAA treatment raised suspicions about possible interference of this treatment in HCC development. The purpose of the present review is to investigate the validity of these concerns based on recent clinical studies, summarize the mechanisms of action of DAAs and survey the updated data on HCV-induced liver carcinogenesis. PMID- 30310536 TI - Current evidence on the management of hepatitis B in pregnancy. AB - Hepatitis B virus (HBV) infection is one of the main public health problems across the globe, since almost one third of the world population presents serological markers of contact with the virus. A profound impact on the epidemiology has been exerted by universal vaccination programmes in many countries, nevertheless the infection is still widespread also in its active form. In the areas of high endemicity (prevalence of hepatitis B surface antigen positivity > 7%), mother-to-child transmission represents the main modality of infection spread. That makes the correct management of HBV in pregnancy a matter of utmost importance. Furthermore, the infection in pregnancy needs to be carefully assessed and handled not only with respect to the risk of vertical transmission but also with respect to gravid women health. Each therapeutic or preventive choice deserves to be weighed upon attentively. On many aspects evidence is scarce or controversial. This review will highlight the latest insights into the paramount steps in managing HBV in pregnancy, with particular attention to recommendations from recent guidelines and data from up-do-date research syntheses. PMID- 30310538 TI - Progression and status of antiviral monitoring in patients with chronic hepatitis B: From HBsAg to HBV RNA. AB - As alternative indexes of hepatitis B virus (HBV), covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and peripheral blood RNA known as pgRNA, have been advocated as novel serum markers for prediction of prognosis and treatment response in chronic hepatitis B (CHB). Since the availability of commercial quantitative assays of HBsAg in 2011, HBsAg has been widely used for predicting treatment response of patients with CHB. Patients who received interferon therapy have shown a sharper reduction of HBsAg level than those who received nucleoside drug (NAs) therapy. Upon peginterferon treatment, sustained responders have presented a larger reduction of HBsAg level than the non-responders. An absence of HBsAg decline, together with < 2log reduction in HBV DNA at week 12, can serve as a stopping rule in HBsAg-negative patients infected with genotype D HBV. A sharp reduction of HBsAg titer in the NAs therapy is a predictor of HBsAg clearance in long-term treatment. HBcrAg, which consists of three species of related proteins sharing an identical 149 amino acid sequence, including HbcAg, hepatitis B e antigen (HBeAg), and a truncated 22-kDa precore protein, is still detectable in situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved. Therefore, HBcrAg remains a measurable serum marker to correlate with cccDNA in this situation. The decline in HBcrAg has been observed with NAs therapy and the pattern of decline might provide prognostic information on the risk of HBV post-treatment reactivation. Peripheral blood RNA, which is known as pgRNA, directly derives from cccDNA and reflects intrahepatic cccDNA level. Quantitative pgRNA has been suggested to be helpful in CHB management. However, commercial quantitative assays are lacking. Additionally, the use of simultaneous and continuous clearance of HBV RNA and HBV DNA in serum has been suggested to be a safe stopping rule of NAs therapy for patients with CHB. However, clinical studies of large sample sizes are needed to prove the feasibility and significance of using serum HBV RNA as the assessment standard of antiviral therapy in CHB and the safety of the stopping rule in clinics. PMID- 30310540 TI - Chronic hepatitis B virus monoinfection at a university hospital in Zambia. AB - AIM: To characterize antiviral therapy eligibility among hepatitis B virus (HBV) infected adults at a university hospital in Zambia. METHODS: Hepatitis B surface antigen-positive adults (n = 160) who were HIV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), platelet count, hepatitis B e-antigen, and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination, AST-to-platelet ratio index, and transient elastography. In antiviral therapy-naive individuals, we described HBV stages and antiviral therapy eligibility per World Health Organization (WHO) and by HBV test (routine vs clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatment-experienced individuals, we described medication side effects, adherence, and viral suppression. RESULTS: The median age was 33 years, 71.9% were men, and 30.9% were diagnosed with HBV through a clinically-driven test with the remainder identified via routine testing (at the blood bank, community events, etc.). Among 120 treatment-naive individuals, 2.5% were categorized as immune tolerant, 11.7% were immune active, 35.6% were inactive carriers, and 46.7% had an indeterminate phenotype. Per WHO guidelines, 13 (10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical vs routine settings (adjusted odds ratio, 8.33; 95%CI: 2.26-29.41). Among 40 treatment-experienced HBV patients, virtually all took tenofovir, and a history of mild side effects was reported in 20%. Though reported adherence was good, 12 of 29 (41.4%) had HBV DNA > 20 IU/mL. CONCLUSION: Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up. PMID- 30310539 TI - Metabolic syndrome does not affect sustained virologic response of direct-acting antivirals while hepatitis C clearance improves hemoglobin A1c. AB - AIM: To determine whether successful treatment with directacting antivirals (DAA) is associated with improvements in hemoglobin A1c (HbA1c) and if type 2 diabetes mellitus (T2DM) or metabolic syndrome affects sustained virologic response (SVR). METHODS: We performed a retrospective analysis of all hepatitis C virus (HCV) patients at the VA Greater Los Angeles Healthcare System treated with varying DAA therapy between 2014-2016. Separate multivariable logistic regression was performed to determine predictors of HbA1c decrease >= 0.5 after DAA treatment and predictors of SVR 12-wk post treatment (SVR12). RESULTS: A total of 1068 patients were treated with DAA therapy between 2014-2016. The presence of T2DM or metabolic syndrome did not adversely affect SVR12. 106 patients had both HCV and T2DM. Within that cohort, patients who achieved SVR12 had lower mean HbA1c pre treatment (7.35 vs 8.60, P = 0.02), and lower mean HbA1c post-treatment compared to non-responders (6.55 vs 8.61, P = 0.01). The mean reduction in HbA1c after treatment was greater for those who achieved SVR12 than for non-responders (0.79 vs 0.01, P = 0.03). In adjusted models, patients that achieved SVR12 were more likely to have a HbA1c decrease of >= 0.5 than those that did not achieve SVR12 (adjusted OR = 7.24, 95%CI: 1.22-42.94). CONCLUSION: In HCV patients with T2DM, successful treatment with DAA was associated with a significant reduction in HbA1c suggesting that DAA may have a role in improving insulin sensitivity. Furthermore, the presence of T2DM or metabolic syndrome does not adversely affect SVR12 rates in patients treated with DAA. PMID- 30310542 TI - Protecting kidneys in liver transplant patients: A pathway to preventive interventions. AB - Acute kidney injury (AKI) is a frequent postoperative complication after liver transplantation. The etiology is multifactorial, including perioperative renal status, surgery related events, and postoperative immunosuppression therapy. The role of renal hypoperfusion and hepatic ischemia-reperfusion injury as causes of early AKI are now being increasingly recognized. Further studies should focus on therapies that would attenuate this injury. PMID- 30310541 TI - Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis: Case report and systematic literature review. AB - AIM: To systematically review liver disease associated with hemophagocytic lymphohistiocytosis (HLH), propose reasonable contraindications for liver transplantation for liver failure in HLH, and report an illustrative case. METHODS: Systematic review according to PRISMA guidelines of hepatic manifestations of HLH using computerized literature search via PubMed of articles published since 1980 with keywords ("hemophagocytic lymphohistiocytosis" or "HLH") AND ("liver" or "hepatic"). Two authors independently performed literature search and incorporated articles into this review by consensus. Illustrative case report presented based on review of medical chart, and expert re-review of endoscopic photographs, radiologic images, and pathologic slides. RESULTS: A 47 year-old Caucasian male, was hospitalized with high-grade pyrexia, rash, total bilirubin = 45 g/dL, moderately elevated hepatic transaminases, ferritin of 3300 ng/dL, leukopenia, and profound neutropenia (absolute neutrophil count < 100 cells/mm3). Viral serologies for hepatitis A, B, and C were negative. Abdominal computed tomography scan and magnetic resonance imaging revealed no hepatic or biliary abnormalities. Pathologic analysis of liver biopsy revealed relatively well-preserved hepatic parenchyma without lymphocytic infiltrates or macrophage invasion, except for sparse, focal hepatocyte necrosis. Bone marrow biopsy and aspirate revealed foamy macrophages engulfing mature and precursor erythrocytes, consistent with HLH. Interleukin-2 receptor (CD25) was highly elevated, confirming diagnosis of HLH according to Histiocytic Society criteria. Patient initially improved after high-dose prednisone therapy. Patient was judged not to be a liver transplant candidate despite model for end stage liver disease (MELD) score = 33 because liver failure was secondary to severe systemic disease from HLH, including septic shock, focal centrilobular hepatocyte necrosis from hypotension, bone marrow failure, and explosive immune activation from HLH. The patient eventually succumbed to overwhelming sepsis, progressive liver failure, and disseminated intravascular coagulopathy. Systematic review reveals liver injury is very common in HLH, and liver failure can sometimes occur. Data on liver transplantation for patients with HLH are very limited, and so far the results have shown a generally much worse prognosis than for other liver transplant indications. Liver transplantation should not be guided solely by MELD score, but should include liver biopsy results and determination whether liver failure is from intrinsic liver injury vs multisystem (extrahepatic) organ failure from HLH. CONCLUSION: This case report illustrates that liver transplantation may not be warranted when liver failure associated with HLH is primarily from multisystem failure from HLH. Liver biopsy may be very helpful in determining the severity and pathophysiology of the liver disease. PMID- 30310543 TI - Role of imaging methods in diagnosis and treatment of Morton's neuroma. AB - Among the many causes of forefoot pain, Morton's neuroma (MN) is often suspected, particularly in women, due to its high incidence. However, there remain controversies about its relationship with symptomatology and which diagnostic and treatment choices to choose. This article mainly focuses on the role of the various imaging methods and their abilities to support an accurate diagnosis of MN, ruling out other causes of forefoot pain, and as a way of providing targeted imaging-guided therapy for patients with MN. PMID- 30310544 TI - Optimized cardiac magnetic resonance imaging inversion recovery sequence for metal artifact reduction and accurate myocardial scar assessment in patients with cardiac implantable electronic devices. AB - Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is the gold standard for imaging myocardial viability. An important application of LGE CMR is the assessment of the location and extent of the myocardial scar in patients with ventricular tachycardia (VT), which allows for more accurate identification of the ablation targets. However, a large percentage of patients with VT have cardiac implantable electronic devices (CIEDs), which is a relative contraindication for cardiac magnetic resonance imaging due to safety and image artifact concerns. Previous studies showed that these patients can be safely scanned on 1.5 T scanners provided that an adequate imaging protocol is adopted. Nevertheless, imaging patients with a CIED result in metal artifacts due to the strong frequency off-resonance effects near the device; therefore, the spins in the surrounding myocardium are not completely inverted, and thus give rise to hyperintensity artifacts. These artifacts obscure the myocardial scar tissue and limit the ability to study the correlation between the myocardial scar structure and the electro-anatomical map during catheter ablation. In this study, we developed a modified inversion recovery technique to alleviate the CIED-induced metal artifacts and improve the diagnostic image quality of LGE images in patients with CIEDs without increasing scan time or requiring additional hardware. The developed technique was tested in phantom experiments and in vivo scans, which showed its capability for suppressing the hyperintensity artifacts without compromising myocardium nulling in the resulting LGE images. PMID- 30310545 TI - Korean single-center experience with femoral access closure using the ExoSeal device. AB - AIM: To report 17-mo experience of femoral artery puncture site closure during angiographic procedures using ExoSeal vascular closure devices (VCDs). METHODS: Between November 2015 and April 2017, we performed 179 diagnostic and interventional angiographic procedures via a common femoral arterial access. The ExoSeal VCD was used at the puncture site to achieve hemostasis in 125 patients. We evaluated the technical and procedural success rates, the complications, and the factors affecting the hemostasis time of the ExoSeal VCDs. RESULTS: Technical and procedural successes were achieved in 176 cases (98.0%) and 128 cases (71.5%), respectively. Device failure occurred in 3 (1.7%) cases. In 1 case (0.6%) a small hematoma developed, but there were no major complications. Among the hemostasis-relevant variables, a history of drinking alcohol, low platelet (PLT) count, and high prothrombin time-international normalized ratio (commonly known as PT-INR) values were the statistically significant predictors of the need for longer manual compression (MC). There was no difference in the success rates between the repeat and single ExoSeal procedure groups, and repeated use of the ExoSeal did not affect hemostasis time. CONCLUSION: The ExoSeal VCD effectively achieves hemostasis, with few complications. Longer light MC may be needed with alcohol drinkers, low PLT count, and high PT-INR values. PMID- 30310546 TI - The karyotypes and evolution of ZZ/ZW sex chromosomes in the genus Characidium (Characiformes, Crenuchidae). AB - Available data on cytotaxonomy of the genus Characidium Reinhardt, 1867, which contains the greatest number of species in the Characidiinae (Crenuchidae), with 64 species widely distributed throughout the Neotropical region, were summarized and reviewed. Most Characidium species have uniform diploid chromosome number (2n) = 50 and karyotype with 32 metacentric (m) and 18 submetacentric (sm) chromosomes. The maintenance of the 2n and karyotypic formula in Characidium implies that their genomes did not experience large chromosomal rearrangements during species diversification. In contrast, the internal chromosomal organization shows a dynamic differentiation among their genomes. Available data indicated the role of repeated DNA sequences in the chromosomal constitution of the Characidium species, particularly, in sex chromosome differentiation. Karyotypes of the most Characidium species exhibit a heteromorphic ZZ/ZW sex chromosome system. The W chromosome is characterized by high rates of repetitive DNA accumulation, including satellite, microsatellite, and transposable elements (TEs), with a varied degree of diversification among species. In the current review, the main Characidium cytogenetic data are presented, highlighting the major features of its karyotype and sex chromosome evolution. Despite the conserved karyotypic macrostructure with prevalent 2n = 50 chromosomes in Characidium, herein we grouped the main cytogenetic information which led to chromosomal diversification in this Neotropical fish group. PMID- 30310547 TI - The use of adjuvants to local anesthetics: benefit and risk. PMID- 30310548 TI - Modalities in managing postherpetic neuralgia. AB - Postherpetic neuralgia (PHN) is the most troublesome side effect of Herpes Zoster (HZ), which mainly affects the elderly and immunocompromised populations. Despite the current advancement of treatments, PHN persists in many individuals influencing their daily activities and reducing their quality of life. Anticonvulsants, antidepressants, topical therapies including lidocaine and capsaicin, and opioids, are the most widely used therapies for the treatment of PHN. These medications come with their adverse effects, so they should be used carefully with the elderly or with patients with significant comorbidities. Other measures like botulinum toxin, nerve blocks, spinal cord stimulation, and radiofrequency have also contributed significantly to the management of PHN. However, the efficacy, safety, and tolerability of these invasive methods need to be carefully monitored when administering them. Early diagnosis and early initiation of treatment can reduce the burden associated with PHN. The zoster vaccine has effectively reduced the incidence of HZ and PHN. In this article, we discuss the treatment options available for the management of PHN, mainly focusing on the efficacy and safety of different therapeutic modalities. PMID- 30310550 TI - Therapeutic alternatives in painful diabetic neuropathy: a meta-analysis of randomized controlled trials. AB - Background: One of the most frequent problems caused by diabetes is the so called painful diabetic neuropathy. This condition can be treated through numerous types of therapy. The purpose of this study was to analyze, as a meta-analysis, different treatments used to alleviate painful diabetic neuropathy, with the aim of generating results that help making decisions when applying such treatments to tackle this pathology. Methods: A search was conducted in the main databases for Health Sciences, such as PUBMED, Web of Science (WOS), and IME biomedicina (Spanish Medical Reports in Biomedicine), to gather randomized controlled trials about treatments used for painful diabetic neuropathy. The analyzed studies were required to meet the inclusion criteria selected, especially those results related to pain intensity. Results: Nine randomized controlled trials were chosen. The meta-analysis shows significant positive effects for those treatments based on tapentadol [g: -1.333, 95% CI (-1.594; -1.072), P < 0.05], duloxetine [g: -1.622, 95 % CI (-1.650; -1.594), P < 0.05], pregabalin [g: -0.607, 95% CI ( 0.980; -0.325), P < 0.05], and clonidine [g: -0.242, 95 % CI (-0.543; -0.058), P < 0.05]. Conclusions: This meta-analysis indicates the effectiveness of the treatments based on duloxetine, gabapentin and pregabalin, as well as other drugs, such as tapentadol and topic clonidine, whose use is better prescribed in more specific situations. The results provided can help increase the knowledge about the treatment of painful diabetic neuropathy and also in the making of clinical practice guidelines for healthcare professionals. PMID- 30310549 TI - Radiation safety: a focus on lead aprons and thyroid shields in interventional pain management. AB - C-arm fluoroscopy is useful equipment in interventional pain management because it helps to guide correct needle targeting for the accurate injection and drug delivery. However, due to increased use of C-arm fluoroscopy in various pain procedures, the risk of radiation exposure is a significant concern for pain physicians. The harmful biological effects of ionizing radiation on the human body are well known. It is therefore necessary to strive to reduce radiation exposure. Lead aprons with thyroid shields are the most fundamental radiation protective devices for interventional procedures, and are very effective. However, the operator's radiation safety cannot be guaranteed because pain physicians seem to lack sufficient interest, knowledge, and awareness about radiation safety. Also, inappropriate care and use of radiation protective devices may result in a higher risk of radiation exposure. The purpose of this article was to review the literature on radiation safety with a focus on lead aprons and thyroid shields and present recommendations related to those devices during C-arm fluoroscopic-guided interventions by pain physicians. PMID- 30310551 TI - Comparison of 4 mg dexamethasone versus 8 mg dexamethasone as an adjuvant to levobupivacaine in fascia iliaca block-a prospective study. AB - Background: To compare the effects of adding two different doses of dexamethasone on the duration and quality of the fascia iliaca block in patients undergoing proximal femoral fracture surgery. Methods: A total of 60 patients (age 18-70 years) undergoing proximal femoral nailing surgery under spinal anesthesia were given fascia iliaca block after random assignment to one of the two groups: Group H received an injection of levobupivacaine (0.5%) 28 ml with 2 ml (8 mg) dexamethasone, and Group L received an injection of levobupivacaine (0.5%) 28 ml with dexamethasone 1 ml (4 mg) with 1 ml normal saline. Assessment of the duration of analgesia and the total tramadol requirement over 48 hours were noted after a successful block. Results: The duration of analgesia was found to be significantly longer in Group H (17.02 +/- 0.45 h) than in the Group L patients (14.29 +/- 0.45 h) with a p-value of 0.000. Postoperative analgesic requirement (amount of tramadol in mg) was significantly higher in Group L (Q2: 200.0; IQR: 100.0, 200.0) as compared to Group H (Q2: 100.0; IQR: 100.0, 200.0) with a p value of 0.034. No patient showed any sign of neurotoxicity. Conclusions: Dexamethasone, in a dose of 8 mg, is superior to 4 mg when used as an adjuvant with levobupivacaine in the FIB. Though both prolonged analgesia and were effective in reducing oral/intravenous analgesics, 8 mg dexamethasone can be recommended as a more efficacious adjuvant to local anesthetics in the FIB. PMID- 30310552 TI - Adaptation and validation of body maps for musculoskeletal pain location in patients with severe obesity. AB - Background: Although a variety of instruments implement body maps for the precise identification of pain symptoms, no instrument has been validated for use in people with obesity. This study reports the adaptation and validation of body maps for musculoskeletal pain location in people with obesity. Methods: Nine key anatomical regions were highlighted based on the original images of the Nordic Musculoskeletal Questionnaire body maps. Adult silhouettes were generated from photographs of men and women with obesity. The body dimensions were adjusted to take into account the different body fat distribution patterns of people with obesity. The validity of the images was assessed by 12 experts. Subsequently, a data collection stage was performed with 58 patients with severe obesity from both sexes. The reproducibility of the images was tested by comparison with the original images. Results: The results of the validation pilot study indicated that the adapted images facilitated the location of musculoskeletal pain in men and women with obesity. The reproducibility of the original and adapted versions of the body maps indicated good agreement for pain over the last 12 months and 7 days (80% vs. 79.7%). Pain scores in the last 12 months indicated good and high sensitivity and specificity for all body areas (60.9% vs. 89.1%). Considering pain in the last 7 days, high sensitivity and specificity for all areas of the body (85.1% vs. 70.1%). Conclusions: The body maps developed in this study are reliable and valid to identify the location of pain in people with obesity. PMID- 30310553 TI - Comparison of effectiveness for fluoroscopic cervical interlaminar epidural injections with or without steroid in cervical post-surgery syndrome. AB - Background: Neck and back pain are leading sources of disability placing substantial burden on health care systems. Surgical interventions in managing chronic neck pain secondary to various disorders continue to increase. Even though surgical interventions are effective, a significant proportion of patients continue to have symptomatology and develop cervical post-surgery syndrome. This study was performed to know the effectiveness of cervical interlaminar epidural injections with or without steroids. Methods: The effectiveness of fluoroscopic cervical interlaminar epidural injections in post-surgery syndrome was evaluated in a randomized, active controlled trial. The study population included 116 patients assigned to 2 groups. Group 1 received cervical interlaminar epidural injections with local anesthetic alone and Group 2 received injection with local anesthetic and steroids. The main outcomes were defined as significant improvement (greater than 50%) of pain relief using the numeric rating scale and/or functional status improvement using the Neck Disability Index (NDI). Results: Both groups had similar results with significant improvement (>= 50% pain relief and functional status improvement) in 69% of the patients in Group I, whereas, in Group II, 71% of the patients showed significant improvement at the end of 2 years. During a 2-year period, the average number of procedures was 5 to 6, with an average of approximately 12 weeks of significant improvement per procedure. Conclusions: Fluoroscopic cervical interlaminar epidural injections administered in cervical post-surgery syndrome using local anesthetic, regardless of the use of steroids, may be effective in approximately 70% of the patients at 2-year follow-up. PMID- 30310554 TI - The comparison of two different intraarticular injections using a sonographic anterolateral approach in patients with osteoarthritic knee. AB - Background: The intraarticular (IA) injection has become popular for the management of the osteoarthritic knee without an effusion. The success rate of IA injection would be better if it was able to be visually confirmed. We hypothesized that an anterolateral approach, which targets the synovial membrane of the lateral condyle using ultrasound, would provide an equivalent alternative to the anterolateral approach, targeting the synovial membrane of the medial condyle for IA injection of the knee. Methods: A total of 96 knees with osteoarthritis were randomized placed into the two groups, which were group I (anterolateral approach to the medial condyle) and group II (anterolateral approach to the lateral condyle). The primary outcome was to compare the success rate of the two methods of IA injection. The required length of the needle for injection was also measured and compared. Pain intensity was assessed using the Numeric Rating Scale in order to evaluate the success of injection. Results: There were no significant differences in the success rate between both groups. The success rate of group I and group II were 87.8% (95%, CI 78.7-97.0) and 91.5% (95%, CI 83.6-99.5), respectively (P = 0.549). The needle depth was 5.0 +/- 0.8 (3.0 to 6.1 cm) in group I, and 3.0 +/- 0.8 (1.5 to 5 cm) in group II (P < 0.001). Conclusions: The anterolateral approach to the lateral femoral condyle, using ultrasound, is an alternative method to the approach targeting the medial femoral condyle, using shorter needle. PMID- 30310555 TI - Complication of epiduroscopy: a brief review and case report. AB - Epiduroscopy is defined as a percutaneous, minimally invasive endoscopic investigation of the epidural space. Periduroscopy is currently used mainly as a diagnostic tool to directly visualize epidural adhesions in patients with failed back surgery syndrome (FBSS), and as a therapeutic action in patients with low back pain by accurately administering drugs, releasing inflammation, washing the epidural space, and mechanically releasing the scars displayed. Considering epiduroscopy a minimally invasive technique should not lead to underestimating its potential complications. The purpose of this review is to summarize and explain the mechanisms of the side effects strictly related to the technique itself, leaving aside complications considered typical for any kind of extradural procedure (e.g. adverse reactions due to the administration of drugs or bleeding) and not fitting the usual concept of epiduroscopy for which the data on its real usefulness are still lacking. The most frequent complications and side effects of epiduroscopy can be summarized as non-persistent post-procedural low back and/or leg discomfort/pain, transient neurological symptoms (headache, hearing impairment, paresthesia), dural puncture with or without post dural puncture headache (PDPH), post-procedural visual impairment with retinal hemorrhage, encephalopathy resulting in rhabdomyolysis due to a dural tear, intradural cyst, as well as neurogenic bladder and seizures. We also report for first time, to our knowledge, a case of symptomatic pneumocephalus after epiduroscopy, and try to explain the reason for this event and the precautions to avoid this complication. PMID- 30310556 TI - The use of sonographic guidance in caudal epidural steroid injections. PMID- 30310557 TI - Identification and Characterization of Mycobacterium Tuberculosis Isolates from Cattle Owners in North Western and North Eastern Parts of Rural Ethiopia. AB - Tuberculosis (TB) is a major global public health problem resulting in a considerable morbidity and mortality worldwide. Ethiopia ranks 8th among the 22 high TB burden countries. Establishing an appropriate and improved intervention strategy to prevent and control tuberculosis requires the presence of evidence based data on the genetic diversity of its causative agent. The current research work, therefore, was to differentiate strains of Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients who own cattle in North Eastern and North Western parts of Ethiopia using molecular techniques. Sputum samples were collected from Acid Fast Bacilli (AFB) positive pulmonary tuberculosis patients and cultured on Lowenstein-Jensen (LJ) medium containing glycerol and sodium pyruvate. Deoxyribonucleic acid (DNA) was extracted from each positive culture, spoligotyping and single nucleotide polymorphisms were performed to further differentiate strains of M. tuberculosis, after deletion typing PCR confirmed that all the isolates were Mycobacterium tuberculosis. The mean age of study participants was 35.7 years (18-63 years) + 13.24. The majority (55.7%) were from North Gondar zone. Spoligotyping revealed that (47/50) 94% had interpretable patterns and 3 lineages namely; East-Africa-Indian (57.4%), Euro-American-African (EAA lineage-Lineage 4) 38.3% and Ethiopian (lineage-7) 2/50 (4.3%). Lineage 7 was registered in North Wollo zone only. In this study 8 clusters (with cluster size ranging from 2-8), 8 unique and 10 new patters were recorded. Spoligotype International Types (SIT) (21, 25, 26, 35, 53, 109, 149 and 289), were found as clusters and of these SIT 25 (7) and SIT 289 (8) were the predominant ones. Our study proved that 3 Mycobacterium tuberculosis lineages, namely; the ancient, intermediate between the modern lineages as well as modern were identified. Besides, considerable clustering was seen, which indicates the presence of current TB transmission in the study areas. PMID- 30310558 TI - Mechanical Properties of the Periodontal System and of Dental Constructs Deduced from the Free Response of the Tooth. AB - The biomechanical behaviour of the periodontal ligament (PDL) is still not well understood although this topic has been studied for almost 100 years. This study reports on clinical and mathematical studies to determine the constitutive law of the PDL. A set of mechanical parameters of the tooth-PDL system is obtained, and a new method for the evaluation of these parameters from the free response of the tooth is introduced. This response is produced by repeated impacts applied to the gingival tissue in the apical part of the tooth investigated-with the aid of a Periotest exciter. A Doppler ultrasound probe is utilized to determine the response of the tooth-PDL system. The parameters evaluated from these measurements can be considered as the elastometric properties of the dental system investigated. A modal analysis/system identification method is utilized to estimate these parameters. The investigations are carried out for different teeth abutments, both with and without a dental bridge/fixed partial prosthesis (FPP). The differences between the responses of the systems in these two cases are determined with the new method proposed. They are discussed with regard to the specific purposes of the FPP. The study demonstrates that this method can provide the dentist with the necessary objective evaluations regarding the properties and health of the tooth-PDL system, as well as of the construct that is obtained after installing a dental bridge. PMID- 30310559 TI - Enhanced cell dehydration tolerance and photosystem stability facilitate the occupation of cold alpine habitats by a homoploid hybrid species, Picea purpurea. AB - Homoploid hybrid speciation (HHS), characterized by hybrid speciation without a change in chromosome number and facilitated by ecological divergence, is well known in angiosperms but rare in gymnosperms. Picea purpurea as one of two demonstrably conifer diploid hybrid species in gymnosperms has been found to occupy colder alpine habitats than its parents. However, studies on whether leaf frost tolerance and hydraulic safety exhibit transgressive segregation and thus play a role in conifer HHS are still lacking. In this study, we compared the frost tolerance of photosystem stability (the maximum efficiency of PSII, F v/F m), pressure-volume parameters, and xylem resistance to dysfunction of leaves (current-year twigs) and stems (annual shoots) between P. purpurea and its progenitors. The results indicated that P. purpurea had significantly lower osmotic potential at full turgor, water potential at turgor loss point, water potential at 12 % loss of conductance of stem, the maximum hydraulic conductance of stem and the temperature causing a 50 % reduction in initial F v/F m than its parental species. In contrast, the leaf and stem xylem pressure inducing 50 % loss of hydraulic conductivity (leaf Psi50 and stem Psi50, respectively) and hydraulic safety margin in leaf Psi50, stem Psi50 in P. purpurea showed no significant difference with those of P. wilsonii, but significantly larger than those of P. likiangensis. This suggests that the frost tolerance of photosystem stability and the cell dehydration tolerance in P. purpurea are superior to its parental species, facilitating its successful colonization and establishment in colder habitats. PMID- 30310560 TI - Qubit crossover in the endohedral fullerene Sc3C2@C80. AB - The core-shell structure of endohedral fullerenes results in good protection of the encapsulated spin carriers from the environment. In this research, the quantum coherence behavior of the endohedral fullerene Sc3C2@C80 in CS2 solution is characterized from 5 K to room temperature. Below the critical temperature of around 140 K, the inner group is hindered, and the EPR spectrum consists of a single broad line. The spin carriers display a maximum phase memory time of 17.2(7) MUs at 10 K. In the high temperature region, the inner group is mobile, and the EPR spectrum consists of 22 homogeneously broadened lines due to isotropic hyperfine coupling. The maximum phase memory time for each transition is around 139(1) ns at 200 K which allows arbitrary superposition state manipulations to be performed. This research demonstrates that Sc3C2@C80 displays temperature-crossover behaviour due to weak interaction between the Sc3C2 core and the C80 shell. PMID- 30310561 TI - Polariton chemistry: controlling molecular dynamics with optical cavities. AB - Molecular polaritons are the optical excitations which emerge when molecular transitions interact strongly with confined electromagnetic fields. Increasing interest in the hybrid molecular-photonic materials that host these excitations stems from recent observations of their novel and tunable chemistry. Some of the remarkable functionalities exhibited by polaritons include the ability to induce long-range excitation energy transfer, enhance charge conductivity, and inhibit or accelerate chemical reactions. In this review, we explain the effective theories of molecular polaritons which form a basis for the interpretation and guidance of experiments at the strong coupling limit. The theoretical discussion is illustrated with the analysis of innovative applications of strongly coupled molecular-photonic systems to chemical phenomena of fundamental importance to future technologies. PMID- 30310562 TI - Near-infrared fluorescence probes to detect reactive oxygen species for keloid diagnosis. AB - Development of molecular probes for the detection of reactive oxygen and nitrogen species (RONS) is important for the pathology and diagnosis of diseases. Although an abnormally high RONS level has been identified in keloids - a benign dermal tumour developed after lesion, the ability of employing RONS probes for keloid detection has not yet been exploited. Herein, we report two near-infrared (NIR) fluorescent probes (CyTF and CyBA) that can specifically distinguish keloid fibroblasts from normal dermal fibroblasts. Both CyTF and CyBA show a 15-fold NIR fluorescence enhancement at 717 nm upon reaction with RONS. However, because CyTF has higher specificity towards ONOO- than CyBA, CyTF can detect stimulated fibroblasts in a more sensitive way, showing 3.76 and 2.26-fold fluorescence increments in TGF-beta1 stimulated dermal fibroblasts and keloid fibroblasts, respectively. Furthermore, CyTF permits specific detection of implanted keloid fibroblasts in a xenograft live mouse model. Our work thus developed a new optical imaging approach that has the potential for early diagnosis and drug screening of keloids. PMID- 30310563 TI - Identification of a diagnostic structural motif reveals a new reaction intermediate and condensation pathway in kraft lignin formation. AB - Kraft lignin, the main by-product of the pulping industry, is an abundant, yet highly underutilized renewable aromatic polymer. During kraft pulping, the lignin undergoes extensive structural modification, with many labile native bonds being replaced by new, more recalcitrant ones. Currently little is known about the nature of those bonds and linkages in kraft lignin, information that is essential for its efficient valorization to renewable fuels, materials or chemicals. Here, we provide detailed new insights into the structure of softwood kraft lignin, identifying and quantifying the major native as well as kraft pulping-derived units as a function of molecular weight. De novo synthetic kraft lignins, generated from (isotope labelled) dimeric and advanced polymeric models, provided key mechanistic understanding of kraft lignin formation, revealing different process dependent reaction pathways to be operating. The discovery of a novel kraft-derived lactone condensation product proved diagnostic for the identification of a previously unknown homovanillin based condensation pathway. The lactone marker is found in various different soft- and hardwood kraft lignins, suggesting the general pertinence of this new condensation mechanism for kraft pulping. These novel structural and mechanistic insights will aid the development of future biomass and lignin valorization technologies. PMID- 30310564 TI - Synergistic formal ring contraction for the enantioselective synthesis of spiropyrazolones. AB - The rapid generation of molecular complexity from simple reactants is a key challenge in organic synthesis. Spiro compounds, underrepresented 3D motifs in chemical libraries, represent a challenge due to the creation of spiro quaternary carbon and the need to control the 3D shape in one step. Herein, we report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs. We detected the key palladium activated intermediate in its protonated form by mass spectrometry and characterized its structure by infrared spectroscopy and DFT calculations, allowing us to propose a conceivable mechanistic pathway for this reaction. PMID- 30310565 TI - Diverse secondary C(sp3)-H bond functionalization via site-selective trifluoroacetoxylation of aliphatic amines. AB - We describe a coinage-metal-catalyzed site-selective oxidation of secondary C(sp3)-H bonds for aliphatic amine substrates. Broad amine scope, good functional compatibility and late-stage diversification are demonstrated with this method. The steric demand of the beta-substituents controlled diastereoselectivities under this catalytic system. The site selectivity favors secondary C(sp3)-H bonds over tertiary ones underscoring the unique synthetic potential of this method. PMID- 30310566 TI - Nitric oxide activation facilitated by cooperative multimetallic electron transfer within an iron-functionalized polyoxovanadate-alkoxide cluster. AB - A series of NO-bound, iron-functionalized polyoxovanadate-alkoxide (FePOV alkoxide) clusters have been synthesized, providing insight into the role of multimetallic constructs in the coordination and activation of a substrate. Upon exposure of the heterometallic cluster to NO, the vanadium-oxide metalloligand is oxidized by a single electron, shuttling the reducing equivalent to the {FeNO} subunit to form a {FeNO}7 species. Four NO-bound clusters with electronic distributions ranging from [VV3VIV2]{FeNO}7 to [VIV5]{FeNO}7 have been synthesized, and characterized via 1H NMR, infrared, and electronic absorption spectroscopies. The ability of the FePOV-alkoxide cluster to store reducing equivalents in the metalloligand for substrate coordination and activation highlights the ultility of the metal-oxide scaffold as a redox reservoir. PMID- 30310567 TI - Rhodium catalyzed cascade cyclization featuring B-H and C-H activation: one-step construction of carborane-fused N-polyheterocycles. AB - A one-pot strategy for efficient and facile synthesis of C,B-substituted carborane-fused N-polyheterocycles is reported. A rhodium catalyzed cascade cyclization of carboranyl N-arylimines with vinyl ketones enables the effective construction of three new B-C and C-C bonds in one reaction. Both carboranyl B-H and aryl C-H bonds are sequentially activated, leading to a series of previously unavailable C,B-substituted carborane-fused cyclopenta[b]quinoline derivatives, for potential applications in pharmaceuticals and materials, in a step-economical manner. The successful isolation and structural identification of a key intermediate provide solid evidence for the reaction mechanism, involving a tandem sequence of regioselective B-H activation, alkene insertion, nucleophilic cyclization, C-H activation, nucleophilic cyclization, dehydration and oxidative aromatization. PMID- 30310568 TI - How can infra-red excitation both accelerate and slow charge transfer in the same molecule? AB - A UV-IR-Vis 3-pulse study of infra-red induced changes to electron transfer (ET) rates in a donor-bridge-acceptor species finds that charge-separation rates are slowed, while charge-recombination rates are accelerated as a result of IR excitation during the reaction. We explore the underpinning mechanisms for this behavior, studying IR-induced changes to the donor-acceptor coupling, to the validity of the Condon approximation, and to the reaction coordinate distribution. We find that the dominant IR-induced rate effects in the species studied arise from changes to the density of states in the Marcus curve crossing region. That is, IR perturbation changes the probability of accessing the activated complex for the ET reactions. IR excitation diminishes the population of the activated complex for forward (activationless) ET, thus slowing the rate. However, IR excitation increases the population of the activated complex for (highly activated) charge recombination ET, thus accelerating the charge recombination rate. PMID- 30310569 TI - Silylated cyclopentadienes as competent silicon Lewis acid catalysts. AB - The synthesis and characterization of silicon Lewis acid complexes that incorporate highly electron-deficient cyclopentadienes is reported. Several pentacarboxycyclopentadienyl and monocarboxytetracyanocyclopentadienyl complexes were prepared. A comparison of their reactivities for catalysis of the allylation of an electron-deficient benzaldehyde was established. The use of a monocarboxytetracyano silylium donor was shown to be effective for the allylation or arylation of a variety of electrophiles via an anion abstraction pathway. PMID- 30310570 TI - Ring-opening hydroarylation of monosubstituted cyclopropanes enabled by hexafluoroisopropanol. AB - Ring-opening hydroarylation of cyclopropanes is typically limited to substrates bearing a donor-acceptor motif. Here, the transformation is achieved for monosubstituted cyclopropanes by using catalytic Bronsted acid in hexafluoroisopropanol (HFIP) solvent, constituting a rare example where such cyclopropanes engage in intermolecular C-C bond formation. Branched products are obtained when electron-rich arylcyclopropanes react with a broad scope of arene nucleophiles in accord with a simple SN1-type ring-opening mechanism. In contrast, linear products are obtained when cyclopropylketones react with electron-rich arene nucleophiles. In the latter case, mechanistic experiments and DFT-calculations support a homo-conjugate addition pathway. PMID- 30310571 TI - Mechanistic investigations into the cyclization and crystallization of benzobisoxazole-linked two-dimensional covalent organic frameworks. AB - Although many diverse covalent organic frameworks (COFs) have been synthesised over the past decade, our fundamental understanding of their nucleation and growth during the crystallization process has progressed slowly for many systems. In this work, we report the first in-depth mechanistic investigation detailing the role of nucleophilic catalysts during the formation of two distinct benzobisoxazole (BBO)-linked COFs. The BBO-COFs were constructed by reacting 1,3,5-tris(4-formylphenyl)benzene (TFPB) and 1,3,5-tris(4-formylphenyl)triazine (TFPT) C 3-symmetric monomers with a C 2-symmetric o-aminophenol substituted precursor using different nucleophiles (e.g. NaCN, NaN3, and NaSCH3). Our experimental and computational results demonstrate that the nucleophiles help initiate an oxidative dehydrogenation pathway by producing radical intermediates that are stabilized by a captodative effect. We also demonstrate that the electron deficient TFPT monomer not only aids in enhancing the crystallinity of the BBO-COFs but also participates in the delocalization of the radicals generated to help stabilize the intermediates. PMID- 30310573 TI - Simulation-guided engineering of an enzyme-powered three dimensional DNA nanomachine for discriminating single nucleotide variants. AB - Single nucleotide variants (SNVs) are important both clinically and biologically because of their profound biological consequences. Herein, we engineered a nicking endonuclease-powered three dimensional (3D) DNA nanomachine for discriminating SNVs with high sensitivity and specificity. Particularly, we performed a simulation-guided tuning of sequence designs to achieve the optimal trade-off between device efficiency and specificity. We also introduced an auxiliary probe, a molecular fuel capable of tuning the device in solution via noncovalent catalysis. Collectively, our device produced discrimination factors comparable with commonly used molecular probes but improved the assay sensitivity by ~100 times. Our results also demonstrate that rationally designed DNA probes through computer simulation can be used to quantitatively improve the design and operation of complexed molecular devices and sensors. PMID- 30310575 TI - Correction: The intramolecular hydrogen bonded-halogen bond: a new strategy for preorganization and enhanced binding. AB - [This corrects the article DOI: 10.1039/C8SC01973H.]. PMID- 30310572 TI - Reversible ON-OFF switching of single-molecule-magnetism associated with single crystal-to-single-crystal structural transformation of a decanuclear dysprosium phosphonate. AB - {Dy5(EDDC)2(MU3-AcO)2(MU5-C15H11PO3)(MU4-C15H11PO3)(MU2 AcO)2(AcO)2(H2O)(CH3OH)2}2(MU4-C2O4).xH2O (I), where H2EDDC is N',N'',E,N',N'',E N',N''-(ethane-1,2-diylidene)dipyrazine-2-carbohydrazide and C15H11PO3H2 is 9 anthrylmethylphosphonic acid, is found to undergo two consecutive single-crystal to-single-crystal transformations. The first is under UV irradiation (lambda = 365 nm for 3 d in air) to {Dy5(EDDC)2(MU3-AcO)2(MU5-C15H11PO3)2(MU2 AcO)2(AcO)2(H2O)3}2(MU4-C2O4).xH2O (I-UV) where the two CH3OH are replaced by two H2O and the second by annealing under N2 at 100 degrees C on a diffractometer or under Ar in a glovebox to {Dy5(EDDC)2(MU3-AcO)2(MU5-C15H11PO3)2(MU2 AcO)4(H2O)}2(MU4-C2O4) (I-A-N2 or I-A-Ar) where it has lost two H2O molecules. The second transformation is reversible by exposure to air at room temperature (I A-N2-cool). While the overall structures are the same (retaining the space group P21/c), there is a considerable expansion of the unit cell from I (8171 A3) to I UV (8609 A3) and I-A-N2 (8610 A3) and the coordinations of the Dy atoms undergo major reconstructions. This is associated with switching the single-molecule magnetism (SMM) from OFF for I to ON for I-UV and to OFF again for I-A-Ar in air. Such a switching mechanism associated with the retention of crystallinity is unique in the chemistry of dysprosium. The structure of the molecule is formed from two symmetry related pentamers joined by an oxalate. A related compound containing two isolated neutral pentamers {Dy5(EDDC)2(MU3-AcO)2(MU5 C15H11PO3)2(MU2-AcO)3(AcO)2(H2O)2}{Dy5(EDDC)2(MU3-AcO)2(MU5-C15H11PO3)(MU4 C15H11PO3)(MU2-AcO)3(AcO)2(CH3OH)2}.2CHCl3 (II) has also been isolated with closely related Dy coordination and it exhibits similar SMM behaviour in zero field. PMID- 30310574 TI - A highly site-selective radical sp3 C-H amination of azaheterocycles. AB - This report describes the development of a novel C-H amination strategy using both a Cu(ii) Lewis acid and an organic hydrogen atom transfer catalyst to activate benzylic C-H bonds adjacent to aromatic N-heterocycles. This simple methodology demonstrates very high selectivity towards azaheterocycles without using exogenous directing groups and affords excellent site selectivity in substrates with more than one reactive position. A wide range of heterocyclic structures not compatible with previously reported catalytic systems have proven to be amenable to this approach. Mechanistic investigations strongly support a radical-mediated H-atom abstraction, which explains the observed contrast to known closed-shell Lewis acid catalyzed processes. PMID- 30310577 TI - Bronsted/Lewis acid sites synergistically promote the initial C-C bond formation in the MTO reaction. AB - The methanol-to-olefin (MTO) reaction is an active field of research due to conflicting mechanistic proposals for the initial carbon-carbon (C-C) bond formation. Herein, a new methane-formaldehyde pathway, a Lewis acid site combined with a Bronsted acid site in zeolite catalysts can readily activate dimethyl ether (DME) to form ethene, is identified theoretically. The mechanism involves a hydride transfer from Al-OCH3 on the Lewis acid site to the methyl group of the protonated methanol molecule on the adjacent Bronsted acid site leading to synchronous formation of methane and Al-COH2 + (which can be considered as formaldehyde (HCHO) adsorbed on the Al3+ Lewis acid sites). The strong electrophilic character of the Al-COH2 + intermediate can strongly accelerate the C-C bond formation with CH4, as indicated by the significant decrease of activation barriers in the rate-determining-step of the catalytic processes. These results highlight a synergy of extra-framework aluminum (EFAl) Lewis and Bronsted sites in zeolite catalysts that facilitates initial C-C bond formation in the initiation step of the MTO reaction via the Al-COH2 + intermediate. PMID- 30310576 TI - Switchable gate-opening effect in metal-organic polyhedra assemblies through solution processing. AB - Gate-opening gas sorption is known for metal-organic frameworks, and is associated with structural flexibility and advantageous properties for sensing and gas uptake. Here, we show that gate-opening is also possible for metal organic polyhedra (MOPs), and depends on the molecular organisation in the lattice. Thanks to the solubility of MOPs, several interchangeable solvatomorphs of a lantern-type MOP were synthesised via treatment with different solvents. One phase obtained through use of methanol induced a gate-opening effect in the lattice in response to carbon dioxide uptake. The sorption process was thoroughly investigated with in situ powder X-ray diffraction and simultaneous adsorption experiments. Meanwhile, solution processing of this flexible phase using THF led to a permanently porous phase without a gate-opening effect. Furthermore, we find that we can change the metallic composition of the MOP, and yet retain flexibility. By showing that gate-opening can be switched on and off depending on the solvent of crystallisation, these findings have implications for the solution based processing of MOPs. PMID- 30310578 TI - Exploring a new ligand binding site of G protein-coupled receptors. AB - Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcholine receptors. Our results indicate that unlike synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket. We also discovered that the most recently resolved crystal structure of the LTB4 receptor comprised a bound inverse agonist, which extended its benzamidine moiety to the same binding pocket discovered in this work. Analysis on all resolved GPCR crystal structures indicated that this new pocket could exist in most receptors. Our findings provide new opportunities for GPCR drug discovery. PMID- 30310579 TI - Exploration of biocompatible AIEgens from natural resources. AB - Luminogens with aggregation-induced emission (AIEgens) characteristics have been well developed and applied in various areas such as bio-imaging, theranostics, organic photoelectronics and chemo/bio sensors. However, most of the reported AIEgens suffer from the disadvantages of complex organic synthesis and high cost, as well as being environmentally unfriendly and hard to degrade, which have largely limited their real applications. In this work, we discovered berberine chloride, a natural isoquinoline alkaloid isolated from Chinese herbal plants, as an unconventional rotor-free AIEgen with bright solid-state emission and water soluble characteristics. Single crystal structure analysis and optical property, viscosity, and host-guest interaction studies suggested that intramolecular vibration and twisted intramolecular charge transfer were responsible for the AIE phenomenon of berberine chloride. Moreover, berberine chloride was biocompatible and could specifically target lipid droplets in a fluorescence turn-on and wash free manner, demonstrating the great potential of natural products as promising AIE probes. PMID- 30310580 TI - Diastereo- and enantioselective copper catalyzed hydroallylation of disubstituted cyclopropenes. AB - A highly diastereo- and enantioselective protocol for the hydroallylation of 1,1- and 1,2-disubstituted cyclopropenes has been developed utilizing an in situ formed copper hydride. A variety of allyl electrophiles could be utilized yielding a diverse range of trisubstituted cyclopropanes. Finally a preliminary enantioselective variant could be established employing a recently described P stereogenic xantphos derivative as ligand. PMID- 30310581 TI - Size-dependent rate acceleration in the silylation of secondary alcohols: the bigger the faster. AB - Relative rates for the reaction of secondary alcohols carrying large aromatic moieties with silyl chlorides carrying equally large substituents have been determined in organic solvents. Introducing thoroughly matching pairs of big dispersion energy donor (DED) groups enhanced rate constants up to four times, notably depending on the hydrogen bond donor ability of the solvent. A linear correlation between computed dispersion energy contributions to the stability of the silyl ether products and experimental relative rate constants was found. These results indicate a cooperation between solvophobic effects and DED-groups in the kinetic control of silylation reactions. PMID- 30310582 TI - Tunable stiffness of graphene oxide/polyacrylamide composite scaffolds regulates cytoskeleton assembly. AB - The stiffness of the extracellular matrix (ECM) not only provides mechanical resistance to support the cellular shape, but also plays significant roles in many cell functions. However, it's difficult to utilize traditional substrate materials to investigate cell behaviors under physical microenvironments due to their unphysiological stiffness or intrinsic secondary effects. Herein, a stiffness-tunable graphene oxide/polyacrylamide composite scaffold was fabricated to investigate the effect of substrate stiffness on cytoskeleton assembly and specific gene expression during cell growth. In the composite structure, the polyacrylamide (PAAm) hydrogel plays an exceptional role in controlling the substrate stiffness; in contrast, graphene oxide (GO) sheets not only provide permissive surfaces for cell adhesion and growth, but also effectively eliminate the secondary effects of the PAAm hydrogel. It's found that substrate stiffness could affect cell morphology and cytoskeleton assembly via specific genetic pathways. Therefore, the composite structure can be considered an attractive candidate as a scaffold and provides potential to elucidate the disease association of ECMs. PMID- 30310583 TI - Identifying site-dependent reactivity in oxidation reactions on single Pt particles. AB - Catalytic nanoparticles are heterogeneous in their nature and even within the simplest particle various surface sites exist and influence the catalytic reactivity. Thus, detailed chemical information at the nanoscale is essential for understanding how surface properties and reaction conditions direct the reactivity of different surface sites of catalytic nanoparticles. In this work, hydroxyl-functionalized N-heterocyclic carbene molecules (NHCs) were anchored to the surface of Pt particles and utilized as chemical markers to detect reactivity variations between different surface sites under liquid and gas phase oxidizing conditions. Differences in the chemical reactivity of surface-anchored NHCs were identified using synchrotron-radiation-based infrared nanospectroscopy with a spatial resolution of 20 nanometers. By conducting IR nanospectroscopy measurements, along with complementary spatially averaged IR and X-ray spectroscopy measurements, we identified that enhanced reactivity occurred on the particles' periphery under both gas and liquid phase oxidizing conditions. Under gas phase reaction conditions the NHCs' hydroxyl functional groups underwent preferential oxidization to the acid along the perimeter of the particle. Exposure of the sample to harsher, liquid phase oxidizing conditions induced modification of the NHCs, which was mostly identified at the particle's periphery. Analysis of X-ray absorption spectroscopy measurements revealed that exposure of the sample to oxidizing conditions induced aromatization of the NHCs, presumably due to oxidative dehydrogenation reaction, along with reorientation of the NHCs from perpendicular to parallel to the Pt surface. These results, based on single particle measurements, demonstrate the high reactivity of surface sites that are located at the nanoparticle's periphery and the influence of reaction conditions on site-dependent reactivity. PMID- 30310584 TI - Biomass-mediated ZSM-5 zeolite synthesis: when self-assembly allows to cross the Si/Al lower limit. AB - A family of Al-rich ZSM-5 zeolites with Si/Al = 8 +/- 0.5 was prepared according to a biomass-mediated supramolecular approach. A combination of advanced characterisation techniques and periodic density functional theory (DFT) calculations unraveled the purity and stability of un-expected Al-enriched ZSM-5 structures, hence allowing to cross the frontier of Si/Al lower limit. In addition, these Al-rich ZSM-5 zeolites demonstrated high catalytic activity in n hexane cracking and methanol conversion into hydrocarbons, being in line with the presence of numerous Bronsted acid sites. PMID- 30310585 TI - Mononuclear complexes of a tridentate redox-active ligand with sulfonamido groups: structure, properties, and reactivity. AB - The design of molecular complexes of earth-abundant first-row transition metals that can catalyze multi-electron C-H bond activation processes is of interest for achieving efficient, low-cost syntheses of target molecules. To overcome the propensity of these metals to perform single-electron processes, redox-active ligands have been utilized to provide additional electron equivalents. Herein, we report the synthesis of a novel redox active ligand, [ibaps]3-, which binds to transition metals such as FeII and CoII in a meridional fashion through the three anionic nitrogen atoms and provides additional coordination sites for other ligands. In this study, the neutral bidentate ligand 2,2'-bipyridine (bpy) was used to complete the coordination spheres of the metal ions and form NEt4[MII(ibaps)bpy] (M = Fe (1) or Co (1-Co)) salts. The FeII salt exhibited rich electrochemical properties and could be chemically oxidized by 1 and 2 equiv. of ferrocenium to form singly and doubly oxidized species, respectively. The reactivity of 1 towards intramolecular C-H bond amination of aryl azides at benzylic and aliphatic carbon centers was explored, and moderate to good yields of the resulting indoline products were obtained. PMID- 30310587 TI - A new structure-activity relationship for cyanine dyes to improve photostability and fluorescence properties for live cell imaging. AB - A new set of cyanine-indole dyes was synthesized, characterized by optical and cytotoxic properties and subsequently applied for live cell imaging. Furthermore, these dyes were postsynthetically linked covalently to the 2'-position of uridine anchors in presynthesized oligonucleotides using the copper(i)-catalyzed azide alkyne cycloaddition in order to evaluate their photostability and imaging properties in living cells. The nucleophilicity at position C-2 of the indole part of the dyes was elucidated as key for a new structure-activity relationship that served as a rational guide to improve the photostability and optical properties of these green-emitting dyes for live cell imaging of nucleic acids. While the photostability rises exponentially with decreasing nucleophilicity, thermal bleaching experiments confirmed an opposite trend supposing that the superoxide radical anion is mainly responsible for the photobleaching of the dyes. Furthermore, the cytotoxicities of the dyes were tested in HeLa cells and moderate to low LD50 values were obtained. This interdisciplinary strategy allowed us to identify one dye with excellent optical properties and even better photostability and decreased cytotoxicity compared to a cyanine-indole dye that bears an additional cyclooctatetraene group as a triplet state quencher. PMID- 30310586 TI - Prediction of disulfide dihedral angles using chemical shifts. AB - Cystine residues result from the formation of disulfide bonds between pairs of cysteine residues. This cross linking of the backbone is essential for the structure and activity of peptides and proteins. The conformation of a cystine side chain can be described using five dihedral angles, chi1, chi2, chi3, chi2', and chi1', with cystines favouring certain combinations of these angles. 2D NMR spectroscopy is ideally suited for structure determination of disulfide-rich peptides, because of their small size and constrained nature. However, only limited information of the cystine side chain conformation can be determined by NMR spectroscopy, leading to ambiguity in the deduced 3D structures. Resolving accurate structures is important as disulfide-rich peptides have proven to be promising drug candidates in a number of fields, either as bioactive leads or scaffolds. Using a database of NMR chemical shifts combined with crystallographic structures, we have developed a method called DISH that uses support vector machines to predict the dihedral angles of cysteine side chains. It is able to successfully predict chi2 angles with 91% accuracy, and has improved performance over existing prediction methods for chi1 angles, with 87% accuracy. For 81% of cysteine residues, DISH successfully predicted both the chi1 and chi2 angles. By revisiting published solution structures of peptides determined using NMR spectroscopy, we assessed the impact of additional cystine dihedral restraints on the quality of 3D models. DISH improved the resolution and accuracy, highlighting the potential for improving the understanding of structure-activity relationships and rational development of peptide drugs. PMID- 30310588 TI - Slow magnetic relaxation in octahedral low-spin Ni(iii) complexes. AB - Herein we report the first examples of single-molecule magnet (SMM) behaviour in S = 1/2 Ni(iii) complexes. We find that low-spin 3d7 trans-[NiIII(cyclam)(X)2]Y complexes (cyclam = 1,4,8,11-tetraazacyclotetradecane; X and Y are singly charged anions) exhibit field-induced slow relaxation of magnetization for O-donor axial ligands (nitrate) but not for N-donor variants (isothiocyanate). Experimental and electronic structure computational investigations indicate that intrinsic spin polarisation of low-spin Ni(iii) is modulated significantly by local coordination geometry and supramolecular interactions. Solid state dilution of Ni(iii) with diamagnetic Co(iii) ions forms a related complex salt, [Ni x Co1-x (cyclam)(NO3)2](NO3).2HNO3 (0.1 < x < 1), which preserves slow magnetic dynamics, thus supporting a molecular component to slow relaxation. An initial analysis of magnetic relaxation lifetime fits best to a combination of Raman and direct relaxation processes. PMID- 30310589 TI - Characterisation of redox states of metal-organic frameworks by growth on modified thin-film electrodes. AB - The application of metal-organic framework (MOF) materials in electrochemical and electrochromic devices remains rare. One of the main reasons for this is the inability to readily access their detailed electrochemistry. The inherent insolubility of these materials does not allow interrogation by traditional solution-based electrochemical or spectroscopic methods. In this study, we report a straightforward alternative approach to the spectroelectrochemical study of MOFs. We have used two systems as exemplars in this study, MFM-186 and MFM-180. The method involves chemical modification of a working electrode to attach MOF materials without using corrosive reagents such as inorganic acids or bases which otherwise could limit their application in device development. MFM-186 demonstrates the formation of a stable radical species [MFM-186]+ on electrochemical oxidation, and this has been characterised by electrochemical, spectroelectrochemical and EPR spectroscopic techniques coupled to DFT analysis. PMID- 30310591 TI - Achieving convenient CO2 electroreduction and photovoltage in tandem using potential-insensitive disordered Ag nanoparticles. AB - Photovoltaic-electrochemical (PV-EC) systems can not only make full use of solar energy, but also transform CO2 into organic molecules. However, it is difficult to achieve PV-EC systems since most CO2 reduction catalysts are potential dependent. This paper describes the rational design of potential-insensitive disordered Ag, which can achieve more than 90% faradaic efficiency (FE) for CO within a wide voltage range of 1.1 V in an electroreduction CO2 system. The system shows attractive activity under different photovoltage conditions in a PV EC system. By employing in situ attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS), we address the origin of the volcano peak of FE on Ag nanoclusters to understand the mechanism of the carbon dioxide reduction reaction (CO2RR). In addition, we find that the CO2RR on disordered Ag nanoparticles is a proton-electron coupling transfer (PECT) reaction mechanism, which may result in high activity in a wide potential range. PMID- 30310590 TI - Synthesis and reactivity of a nickel(ii) thioperoxide complex: demonstration of sulfide-mediated N2O reduction. AB - The thiohyponitrite ([SNNO]2-) complex, [K(18-crown-6)][L tBuNiII(kappa2-SNNO)] (L tBu = {(2,6-iPr2C6H3)NC( t Bu)}2CH), extrudes N2 under mild heating to yield [K(18-crown-6)][L tBuNiII(eta2-SO)] (1), along with minor products [K(18-crown 6)][L tBuNiII(eta2-OSSO)] (2) and [K(18-crown-6)][L tBuNiII(eta2-S2)] (3). Subsequent reaction of 1 with carbon monoxide (CO) results in the formation of [K(18-crown-6)][L tBuNiII(eta2-SCO)] (4), [K(18-crown-6)][L tBuNiII(S,O:kappa2 SCO2)] (5), [K(18-crown-6)][L tBuNiII(kappa2-CO3)] (6), carbonyl sulfide (COS) (7), and [K(18-crown-6)][L tBuNiII(S2CO)] (8). To rationalize the formation of these products we propose that 1 first reacts with CO to form [K(18-crown-6)][L tBuNiII(S)] (I) and CO2, via O-atom abstraction. Subsequently, complex I reacts with CO or CO2 to form 4 and 5, respectively. Similarly, the formation of complex 6 and COS can be rationalized by the reaction of 1 with CO2 to form a putative Ni(ii) monothiopercarbonate, [K(18-crown-6)][L tBuNiII(kappa2-SOCO2)] (11). The Ni(ii) monothiopercarbonate subsequently transfers a S-atom to CO to form COS and [K(18-crown-6)][L tBuNiII(kappa2-CO3)] (6). Finally, the formation of 8 can be rationalized by the reaction of COS with I. Critically, the observation of complexes 4 and 5 in the reaction mixture reveals the stepwise conversion of [K(18-crown-6)][L tBuNiII(kappa2-SNNO)] to 1 and then I, which represents the formal reduction of N2O by CO. PMID- 30310592 TI - An ultrasensitive flow cytometric immunoassay based on bead surface-initiated template-free DNA extension. AB - Proteins lack the duplication mechanism like nucleic acids, so the connection of immunoassays with effective nucleic acid amplification techniques has become a powerful way for the detection of trace protein biomarkers in biological fluids. However, such immunoassays generally suffer from rather stringent DNA sequence design and complicated operations. Herein, we propose a simple but highly sensitive flow cytometric immunoassay (FCI) by employing on-bead terminal deoxynucleotidyl transferase (TdT)-initiated template-free DNA extension as an effective signal amplification pathway (TdT-FCI), and gold nanoparticles (AuNPs) co-functionalized with both the detection antibody and a 3'-OH oligonucleotide (ODN) as the transducer to bridge the immunoassay and subsequent TdT-mediated DNA amplification. The target antigen can sandwich with the capture antibody immobilized on the magnetic beads (MBs) and the detection antibody on the AuNPs to bring a lot of ODNs onto the surface of MBs. Each ODN on the MBs can be effectively elongated by TdT in a template-free manner to produce a long poly(T) tail, which will then bind to many 6-carboxyfluorescein (FAM)-labeled poly(A)25. Since each AuNP can carry multiple ODNs and each extended ODN can ultimately capture numerous FAM-poly(A)25, efficiently amplified fluorophore accumulation on the MBs can be achieved. The fluorescent MBs can be individually interrogated with a flow cytometer and thus quantitative analysis of the target antigen can be realized. Coupled with the powerful flow cytometry analysis, the simple but efficient TdT-based signal amplification mechanism has pushed the detection limit of prostate specific antigen (PSA) down to a low level of 0.5 pg mL-1. Furthermore, based on an elegant bead size-encoding principle, we have further advanced the TdT-FCI for multiplexed antigen detection in a single reaction. Sharing the unique merits of simple design and operation, efficient signal amplification, powerful signal readout and the capability for multiplexed analysis, this TdT-FCI provides a versatile tool for detecting trace antigen biomarkers towards clinical diagnosis as well as prognosis. PMID- 30310593 TI - A photochemical layer-by-layer solution process for preparing organic semiconducting thin films having the right material at the right place. AB - The synergistic action of properly integrated semiconducting materials can bring about sophisticated electronic processes and functions. However, it is often a great challenge to achieve optimal performance in organic devices because of the limited control over the distribution of different materials in active layers. Here, we employ a unique photoreaction-based layer-by-layer solution process for preparing ternary organic photovoltaic layers. This process is applicable to a variety of compounds from wide-band-gap small molecules to narrow-band-gap pi extended systems, and enables the preparation of multicomponent organic semiconducting thin films having the right compound at the right place. The resulting ternary photovoltaic devices afford high internal quantum efficiencies, leading to an approximately two times higher power-conversion efficiency as compared to the corresponding binary bulk-heterojunction system. This work opens up new possibilities in designing materials and active layers for solution processed organic electronic devices. PMID- 30310594 TI - A snapshot of the electrochemical reaction layer by using 3 dimensionally resolved fluorescence mapping. AB - The coupling between electrochemistry and fluorescence confocal laser scanning microscopy (FCLSM) allows deciphering the electrochemical and/or redox reactivity of electroactive fluorophores. This is demonstrated with phenoxazine electrofluorogenic species frequently used in bioassays by mapping the variation of fluorescence intensity with respect to the distance from the electrode. The electrochemical conversion of resorufin dye (RF) to non-fluorescent dihydroresorufin (DH) leads to a sharp decrease of the fluorescence signal in the vicinity of the electrode. In contrast, the direct reduction of resazurin (RZ) to DH leads to an unexpected maximum fluorescence intensity localized further away from the surface. This observation indicates that the initial electron transfer (heterogeneous) is followed by a chemical comproportionation step (homogeneous), leading to the formation of RF within the diffusion layer with a characteristic concentration profile. Therefore, in situ FCLSM affords a direct way to monitor such chemical reactivity in space and to decipher a new redox pathway that cannot be resolved solely by electrochemical means. PMID- 30310595 TI - Acceleration of CO2 insertion into metal hydrides: ligand, Lewis acid, and solvent effects on reaction kinetics. AB - The insertion of CO2 into metal hydrides and the microscopic reverse decarboxylation of metal formates are important elementary steps in catalytic cycles for both CO2 hydrogenation to formic acid and methanol as well as formic acid and methanol dehydrogenation. Here, we use rapid mixing stopped-flow techniques to study the kinetics and mechanism of CO2 insertion into transition metal hydrides. The investigation finds that the most effective method to accelerate the rate of CO2 insertion into a metal hydride can be dependent on the nature of the rate-determining transition state (TS). We demonstrate that for an innersphere CO2 insertion reaction, which is proposed to have a direct interaction between CO2 and the metal in the rate-determining TS, the rate of insertion increases as the ancillary ligand becomes more electron rich or less sterically bulky. There is, however, no rate enhancement from Lewis acids (LA). In comparison, we establish that for an outersphere CO2 insertion, proposed to proceed with no interaction between CO2 and the metal in the rate-determining TS, there is a dramatic LA effect. Furthermore, for both inner- and outersphere reactions, we show that there is a small solvent effect on the rate of CO2 insertion. Solvents that have higher acceptor numbers generally lead to faster CO2 insertion. Our results provide an experimental method to determine the pathway for CO2 insertion and offer guidance for rate enhancement in CO2 reduction catalysis. PMID- 30310596 TI - Silyl-mediated photoredox-catalyzed Giese reaction: addition of non-activated alkyl bromides. AB - The emergence of photoredox catalysis has enabled the discovery of mild and efficient conditions for the generation of a variety of radical reaction platforms. Herein is disclosed the development of a conjugate addition reaction of non-activated alkyl bromides to Michael acceptors under visible-light photoredox catalysis. Optimization of the reaction was achieved using high throughput experimentation (HTE) tools to enable the identification of mild, general and practical reaction conditions. A diverse set of alkyl bromides was successfully added to cyclic or acyclic alpha,beta-unsaturated esters and amides. The features of this transformation allowed also access to a key intermediate of Vorinostat(r), an HDAC inhibitor used to fight cancer and HIV. PMID- 30310597 TI - Radical-mediated direct C-H amination of arenes with secondary amines. AB - Aryl dialkyl amines, valuable subunits of a wide range of effect chemicals, are accessed by intramolecular amination of aromatic C-H bonds employing UV photolysis of N-chloroamines. The reactions show good functional group tolerance and allow access to a range of fused and bridged polycyclic structures. The homogeneous reaction conditions allow for the one-pot conversion of secondary amines to their arylated derivatives. Experimental and theoretical evidence supports the involvement of electrophilic aminium radicals which react via direct ortho-attack on the arene. PMID- 30310598 TI - Photocatalytic reverse polarity Povarov reaction. AB - A visible light mediated iridium photocatalysed reverse polarity Povarov reaction of aryl imines and electron deficient alkenes is described. Operating via a putative nucleophilic alpha-amino radical, generated by a proton coupled electron transfer process, addition to a range of conjugated electron deficient alkene substrates affords substituted tetrahydroquinoline products in high yields and with typically good to excellent diastereoselectivity in favor of the trans diastereoisomer. Sub-stoichiometric quantities of Hantzsch ester were found to be key to initiate the overall redox-neutral, free radical cyclization cascade. This new reaction complements existing two electron Lewis acid mediated variants and expands the capabilities of imine umpolung chemistry to synthetically relevant cyclisation methodology. PMID- 30310599 TI - Theory for polariton-assisted remote energy transfer. AB - Strong-coupling between light and matter produces hybridized states (polaritons) whose delocalization and electromagnetic character allow for novel modifications in spectroscopy and chemical reactivity of molecular systems. Recent experiments have demonstrated remarkable distance-independent long-range energy transfer between molecules strongly coupled to optical microcavity modes. To shed light on the mechanism of this phenomenon, we present the first comprehensive theory of polariton-assisted remote energy transfer (PARET) based on strong-coupling of donor and/or acceptor chromophores to surface plasmons. Application of our theory demonstrates that PARET up to a micron is indeed possible. In particular, we report two regimes for PARET: in one case, strong-coupling to a single type of chromophore leads to transfer mediated largely by surface plasmons while in the other case, strong-coupling to both types of chromophores creates energy transfer pathways mediated by vibrational relaxation. Importantly, we highlight conditions under which coherence enhances or deteriorates these processes. For instance, while exclusive strong-coupling to donors can enhance transfer to acceptors, the reverse turns out not to be true. However, strong-coupling to acceptors can shift energy levels in a way that transfer from acceptors to donors can occur, thus yielding a chromophore role-reversal or "carnival effect". This theoretical study demonstrates the potential for confined electromagnetic fields to control and mediate PARET, thus opening doors to the design of remote mesoscale interactions between molecular systems. PMID- 30310600 TI - Sensitized triplet-triplet annihilation upconversion in water and its application to photochemical transformations. AB - Sensitized triplet-triplet annihilation (TTA) is a promising mechanism for solar energy conversion, but so far its application has been practically completely limited to organic solvents and self-assembled or solid state systems. Combining water-soluble ruthenium complex-pyrene dyads with particularly long excited-state lifetimes as sensitizers and highly fluorescent commercial anthracenes as acceptors/annihilators, we were able to achieve green-to-violet upconversion with unprecedented quantum yields in pure water. Compared to the only known system exploiting sensitized TTA in homogeneous aqueous solution, we improve the overall photon upconversion efficiency by a full order of magnitude and present the very first example for a chemical transformation on a laboratory scale via upconversion in water. Specifically, we found that a thermodynamically challenging carbon-chlorine bond activation can be driven by green photons from an inexpensive continuous wave light source in the presence of dissolved oxygen. Our study is thus potentially relevant in the context of cleaning water from halogenated (toxic) contaminants and for sustainable photochemistry in the most environmentally friendly solvent. PMID- 30310601 TI - Oxidative strong metal-support interactions (OMSI) of supported platinum-group metal catalysts. AB - Supported platinum-group metal (PGM) catalysts are widely used in many important industrial processes. Metal-support interaction is of great importance in tailoring their catalytic performance. Here, we report the first example of oxidative strong metal-support interactions (OMSIs) between PGM and hydroxyapatite (HAP) which can be extended to PGM and ZnO. It occurred under high temperature oxidation conditions accompanied by the encapsulation of PGM by HAP and electron transfer between PGM and HAP. With this OMSI, the aggregation and leaching of PGMs were significantly inhibited, resulting in an excellent catalytic stability and much improved reusability of supported Pt and Pd catalysts, respectively. This is the first time to find that PGMs can manifest OMSI which benefits the stabilization of PGM catalysts under oxidative reaction conditions. This new type of SMSI not only contributed to a deeper understanding of SMSI but also provided a new way to develop new stable PGM catalysts. PMID- 30310602 TI - Programmable one-pot synthesis of heparin pentasaccharides enabling access to regiodefined sulfate derivatives. AB - Heparin (H) and heparan sulfate (HS) belong to the glycosaminoglycan (GAG) family of oligosaccharides, and their sequences and sulfation patterns are known to regulate the functions of various proteins in biological processes. Among these, the 6-O-sulfation of HS/H contributes most significantly to the structural diversity and binding interactions. However, the synthesis of HS with defined sulfation patterns remains a major challenge. Herein, we report a highly efficient and programmable one-pot method for the synthesis of protected heparin pentasaccharides using thioglycoside building blocks with optimized relative reactivities to allow the selective deprotection and preparation of regiodefined sulfate derivatives. PMID- 30310603 TI - Engineering a bifunctional copper site in the cupredoxin fold by loop-directed mutagenesis. AB - Copper sites in proteins are designed to perform either electron transfer or redox catalysis. Type 1 and CuA sites are electron transfer hubs bound to a rigid protein fold that prevents binding of exogenous ligands and side reactions. Here we report the engineering of two Type 1 sites by loop-directed mutagenesis within a CuA scaffold with unique electronic structures and functional features. A copper-thioether axial bond shorter than the copper-thiolate bond is responsible for the electronic structure features, in contrast to all other natural or chimeric sites where the copper thiolate bond is short. These sites display highly unusual features, such as: (1) a high reduction potential despite a strong interaction with the axial ligand, which we attribute to changes in the hydrogen bond network and (2) the ability to bind exogenous ligands such as imidazole and azide. This strategy widens the possibility of using natural protein scaffolds with functional features not present in nature. PMID- 30310604 TI - Dewetting transitions coupled to K-channel activation in cytochrome c oxidase. AB - Cytochrome c oxidase (CcO) drives aerobic respiratory chains in all organisms by transducing the free energy from oxygen reduction into an electrochemical proton gradient across a biological membrane. CcO employs the so-called D- and K channels for proton uptake, but the molecular mechanism for activation of the K channel has remained elusive for decades. We show here by combining large-scale atomistic molecular simulations with graph-theoretical water network analysis, and hybrid quantum/classical (QM/MM) free energy calculations, that the K-channel is activated by formation of a reactive oxidized intermediate in the binuclear heme a 3/CuB active site. This state induces electrostatic, hydration, and conformational changes that lower the barrier for proton transfer along the K channel by dewetting pathways that connect the D-channel with the active site. Our combined results reconcile previous experimental findings and indicate that water dynamics plays a decisive role in the proton pumping machinery in CcO. PMID- 30310605 TI - New Ru(ii) photocages operative with near-IR light: new platform for drug delivery in the PDT window. AB - A series of Ru(ii) complexes bearing the tridentate 2,6-di(quinolin-2-yl)pyridine (dqpy) ligand were designed to undergo photoinduced ligand dissociation with red/near-IR light. The complexes [Ru(dqpy)(L)(CH3CN)]2+, where L = 2,2' bipyridine (bpy, 1), 4,4'dimethyl-2,2'-bipyridine (Me2bpy, 2), and 1,10 phenanthroline (phen, 3). Complexes 1-3 exhibit red-shifted lowest energy metal to-ligand charge transfer (MLCT) absorption maxima at ~600 nm, as compared to the corresponding tpy (2,2';6',2''-terpyridine) complexes with MLCT bands at ~565 nm which appear as shoulders to the MLCT bands at ~455 nm. This shift is attributed to the lower energy LUMO afforded by the dqpy ligand when compared to tpy, as evidenced by the shift of the first reduction wave to ~0.3 V more positive potentials in the former. In addition, the lowest MLCT maximum of [Ru(dqpy)(acac)(CH3CN)]+ (4; acac- = acetylacetonate) is observed at 770 nm, attributed to the additional increase in energy of the HOMO afforded by the presence of the pi-donating acac- ligand and supported by calculations. Complexes 1-3 undergo ligand substitution upon irradiation with red light, lambda irr >= 610 nm, and the ligand substitution photochemistry of 4 is accessible with near IR light, lambda irr >= 715 nm and lambda irr = 735 nm. Complexes 1-4 exhibit similar quantum yields of ligand exchange, Phi L, with 450 and 600 nm irradiation, however, that of 4 is 2-3 times greater than those measured for 1-3. This enhancement is explained by the difference in ligand contributions to the HOMO. Density functional theory calculations predict partial dqpy pipi* character in the MLCT states of 1-3 and a mixed Ru/acac- -> dqpy metal/ligand-to-ligand charge transfer (ML-LCT) state in 4. The photoreactivity of 1-4 with tissue penetrating red and near-IR light, together with their exceptional dark stability (>48 h), makes the new Ru(ii)-dqpy platform ideal for the development of new complexes for photoinduced drug release and for other applications that require broad absorption from the ultraviolet and visible ranges into the near-IR, such as solar energy conversion. PMID- 30310606 TI - Insights into the mechanism and aging of a noble-metal free H2-evolving dye sensitized photocathode. AB - Dye-sensitized photo-electrochemical cells (DS-PECs) form an emerging technology for the large-scale storage of solar energy in the form of (solar) fuels because of the low cost and ease of processing of their constitutive photoelectrode materials. Preparing such molecular photocathodes requires a well-controlled co immobilization of molecular dyes and catalysts onto transparent semiconducting materials. Here we used a series of surface analysis techniques to describe the molecular assembly of a push-pull organic dye and a cobalt diimine-dioxime catalyst co-grafted on a p-type NiO electrode substrate. (Photo)electrochemical measurements allowed characterization of electron transfer processes within such an assembly and to demonstrate for the first time that a CoI species is formed as the entry into the light-driven H2 evolution mechanism of a dye-sensitized photocathode. This co-grafted noble-metal free H2-evolving photocathode architecture displays similar performances to its covalent dye-catalyst counterpart based on the same catalytic moiety. Post-operando time-of-flight secondary ion mass spectrometry (ToF-SIMS) analysis of these photoelectrodes after extensive photoelectrochemical operation suggested decomposition pathways of the dye and triazole linkage used to graft the catalyst onto NiO, providing grounds for the design of optimized molecular DS-PEC components with increased robustness upon turnover. PMID- 30310607 TI - A redox-activated theranostic nanoagent: toward multi-mode imaging guided chemo photothermal therapy. AB - Development of tumor microenvironment responsive and modulating theranostic nano systems is of great importance for specific and efficient cancer therapy. Herein, we report a redox-sensitive nanoagent combining manganese dioxide (MnO2) and gold nanoshell coated silicon nanoparticles for synergistic chemo-photothermal therapy of hypoxia solid tumors. In highly reducing tumor tissues, the outer MnO2 nanosheet with the loaded drug would be dissociated by intracellular glutathione (GSH), resulting in on-demand drug release, as well as generating Mn2+ ions which provided high contrast magnetic resonance imaging (MRI), and fluorescence imaging (FI) in vitro and in vivo. While upon near-infrared (NIR) light irradiation, the gold nanoshell modulated the hypoxic tumor microenvironment via increasing blood flow, achieving enhanced photothermal therapy (PTT) and chemotherapy. After tail vein injection into tumor-bearing mice and monitoring in real time, the intelligent redox-activated nanoagent exhibited high tumor accumulation and powerful synergistic chemo-photothermal therapy efficiency. The proposed work developed a noninvasive strategy to modulate the tumor microenvironment and enhance the anticancer therapeutic effect. We believe that this single nano platform exhibits promising potential as a comprehensive theranostic agent to enhance the efficacies of synergistic cancer therapy. PMID- 30310609 TI - Unraveling reaction networks behind the catalytic oxidation of methane with H2O2 over a mixed-metal MIL-53(Al,Fe) MOF catalyst. AB - Reaction paths underlying the catalytic oxidation of methane with H2O2 over an Fe containing MIL-53(Al) metal-organic framework were studied by periodic DFT calculations. Not only the activation of methane, but the full reaction network was considered, which includes the formation of the active site, the overoxidation of methane to CO2 and the decomposition of H2O2 to H2O and O2. Calculations indicate that the activation barrier for the initial activation of the Fe sites upon reaction with H2O2 is comparable to that of the subsequent C-H activation and also of the reaction steps involved in the undesirable overoxidation processes. The pronounced selectivity of the oxidation reaction over MIL-53(Al,Fe) towards the target mono-oxygenated CH3OH and CH3OOH products is attributed to the limited coordination freedom of the Fe species encapsulated in the extended octahedral [AlO6] structure-forming chains, which effectively prevents the direct overoxidation paths prior to product desorption from the active sites. Importantly, our computational analysis reveals that the active sites for the desired methane oxidation are able to much more efficiently promote the direct catalytic H2O2 decomposition reaction, rendering thus the current combination of the active site and the reactants undesirable for the prospective methane valorization process. PMID- 30310608 TI - Visualization of methylglyoxal in living cells and diabetic mice model with a 1,8 naphthalimide-based two-photon fluorescent probe. AB - Methylglyoxal (MGO), a dicarbonyl metabolite, is the most studied precursor of advanced glycation end-products (AGEs) and its elevated levels have also been associated with various pathologies. Hence, the development of effective methods for monitoring MGO in live cells and in vivo is of great importance for ascertaining the onset and progress of related diseases. Herein, we designed and synthesized an endoplasmic reticulum-targeting two-photon fluorescent probe called NI-OPD for the detection of MGO with high selectivity, sensitivity, and hypotoxicity. The probe was successfully applied for monitoring MGO in living cells and a diabetic mice model. The two-photon fluorescence images confirmed that the endogenous MGO in the liver and kidney tissues of diabetic mice is higher than that of normal mice. Furthermore, it revealed that after treatment with metformin, a widely used hypoglycemia drug, the diabetic mice showed a decreased concentration of MGO in liver and kidney tissues. Thus, NI-OPD may serve as a useful tool for the detection of MGO and for studying the relationships between MGO and pathological and biological processes in biosystems. PMID- 30310610 TI - Interfacing porphyrins and carbon nanotubes through mechanical links. AB - We describe the synthesis of rotaxane-type species composed of macrocyclic porphyrin rings mechanically interlocked with SWCNT threads. The formation of mechanically interlocked SWCNTs (MINTs) proceeds with chiral selectivity, and was confirmed by spectroscopic and analytical techniques and adequate control experiments, and corroborated by high-resolution electron microscopy. From a thorough characterization of the MINTs through UV-vis-NIR absorption, fluorescence, Raman, and transient absorption spectroscopy we analyse in detail the electronic interactions of the porphyrins and the SWCNTs in the ground and excited states. PMID- 30310611 TI - Synthesis and structural characterization of inverse-coordination clusters from a two-electron superatomic copper nanocluster. AB - We have synthesized and structurally characterized a series of centred cuboctahedral copper clusters, namely [Cu13{S2CNR2}6{C[triple bond, length as m dash]CR'}4](PF6), 1a-d (where a: R = n Bu, R' = CO2Me; b: R = n Bu, R' = CO2Et; c: R = iPr, R' = CO2Et; d: R = n Pr, R' = 3,5-(CF3)2C6H3); [Cu12(MU12 S){S2CNR2}6{C[triple bond, length as m-dash]CR'}4], 2a-c; [Cu12(MU12 Cl){S2CNR2}6{C[triple bond, length as m-dash]CR'}4](PF6), 3a-e (where e: R = n Bu, R' = Ph); [Cu12(MU12-Br){S2CN n Bu2}6{C[triple bond, length as m dash]CPh}4](PF6), 4e; and [Cu12(MU12-Cl)(MU3-Cl){S2CN n Bu2}6{C[triple bond, length as m-dash]CCO2Me}3]+ 5a. Cluster 1a is the first structurally characterized copper cluster having a Cu13 centered cuboctahedral arrangement, a miniature of the bulk copper fcc structure. Furthermore, the partial Cu(0) character in the 2-electron superatoms 1 was confirmed by XANES. Inverse coordination clusters 2-5 are the first examples of copper clusters containing main group elements (Cl, Br, S) with a hyper-coordination number, twelve. A combined theoretical and experimental study was performed, which shows that the central copper (formally Cu1-) in nanoclusters 1 can be replaced by chalcogen/halogen atoms, resulting in the formation of clusters 2-5 which show enhanced luminescence properties and increase in the ionic component of the host guest interaction as Br ~ Cl > S > Cu, which is consistent with the Cu-X Wiberg indices. The new compounds have been characterized by ESI-MS, 1H, 13C NMR, IR, UV visible, emission spectroscopy, and the structures 2a-b, 3d-e, 4e and 5a were established by X-ray diffraction analysis. PMID- 30310612 TI - Enhancement of triplet-sensitized upconversion in rigid polymers via singlet exciton sink approach. AB - To increase the practical usefulness of solid-state sensitized upconversion (UC) materials as components of solar energy harvesting systems, it is important to identify and suppress loss mechanisms, and increase the UC quantum yield (Phi UC). Here we focus on a benchmark UC system consisting of the emitter 9,10 diphenylanthracene (DPA) and the sensitizer platinum octaethylporphyrin (PtOEP) in a rigid poly(methyl methacrylate) (PMMA) matrix, and show that one of the major losses originates from Forster resonant energy transfer (FRET) from DPA back to PtOEP. Even though DPA emission lies within the PtOEP transparency window, the quantitative assessment of singlet exciton diffusion for samples with a high DPA content evidences that long-range FRET results in effective exciton trapping by PtOEP. A dramatic factor-of-6 reduction of the DPA emission quantum yield occurs even at PtOEP concentrations as low as 0.05 wt%. To alleviate this problem, we demonstrate a new concept based on the introduction of highly emissive sink sites to trap the singlet excitons produced upon annihilation prior to their quenching by the sensitizer. For DPA/PtOEP blends in PMMA, 1,6-bis-[2,5 di(dodecyloxyphenyl)ethynyl]pyrene is shown to be a useful sink, which results in 1.5-fold increase of the Phi UC. A maximum Phi UC of 2.7% was achieved, which is among the highest reported values for rigid sensitized UC polymers. PMID- 30310613 TI - Accelerated active phase transformation of NiO powered by Pt single atoms for enhanced oxygen evolution reaction. AB - Phase transformation of electrode materials widely occurs in electrocatalytic reactions. Metal oxides are promising electrocatalysts for the oxygen evolution reaction (OER); their phase transformation is a key step for the multi-electron OER, and requires extra overpotential. However, little attention has been paid to accelerating and enhancing the phase transformation. Here, we report for the first time that single-atom Pt incorporated into the bulk crystalline phase of porous NiO nanocubes (0.5 wt% Pt/NiO) can greatly promote the active phase (NiOOH) evolution. The Pt doping was achieved by a scalable nanocasting approach using SiO2 as the hard template. In comparison with Pt/NiO samples with PtO2 nanoparticles segregated at the NiO surface (1 wt% Pt), as well as atomistic Pt atoms solely bound at the surface by atomic layer deposition, the bulk Pt doping shows the strongest power in facilitating active phase transformation, which leads to improved OER activity with reduced overpotential and Tafel slope. Experiential data revealed that the charge-transfer from Pt to Ni through O leads to a local weaker Ni-O bond. First principles calculations confirmed that rather than acting as an active site for the OER, monatomic Pt effectively increases the phase transformation rate by reducing the migration barrier of nearby Ni atoms. Our discoveries reveal the relationships of the heteroatom doped structure and phase transformation behavior during the electrochemical process and offer a new route for designing high-performance electrocatalysts. PMID- 30310615 TI - Dipolar exchange quantum logic gate with polar molecules. AB - We propose a two-qubit gate based on dipolar exchange interactions between individually addressable ultracold polar molecules in an array of optical dipole traps. Our proposal treats the full Hamiltonian of the 1Sigma+ molecule NaCs, utilizing a pair of nuclear spin states as storage qubits. A third rotationally excited state with rotation-hyperfine coupling enables switchable electric dipolar exchange interactions between two molecules to generate an iSWAP gate. All three states are insensitive to external magnetic and electric fields. Impacts on gate fidelity due to coupling to other molecular states, imperfect ground-state cooling, blackbody radiation and vacuum spontaneous emission are small, leading to potential fidelity above 99.99% in a coherent quantum system that can be scaled by purely optical means. PMID- 30310614 TI - Probing the oxidation state of transition metal complexes: a case study on how charge and spin densities determine Mn L-edge X-ray absorption energies. AB - Transition metals in inorganic systems and metalloproteins can occur in different oxidation states, which makes them ideal redox-active catalysts. To gain a mechanistic understanding of the catalytic reactions, knowledge of the oxidation state of the active metals, ideally in operando, is therefore critical. L-edge X ray absorption spectroscopy (XAS) is a powerful technique that is frequently used to infer the oxidation state via a distinct blue shift of L-edge absorption energies with increasing oxidation state. A unified description accounting for quantum-chemical notions whereupon oxidation does not occur locally on the metal but on the whole molecule and the basic understanding that L-edge XAS probes the electronic structure locally at the metal has been missing to date. Here we quantify how charge and spin densities change at the metal and throughout the molecule for both redox and core-excitation processes. We explain the origin of the L-edge XAS shift between the high-spin complexes MnII(acac)2 and MnIII(acac)3 as representative model systems and use ab initio theory to uncouple effects of oxidation-state changes from geometric effects. The shift reflects an increased electron affinity of MnIII in the core-excited states compared to the ground state due to a contraction of the Mn 3d shell upon core-excitation with accompanied changes in the classical Coulomb interactions. This new picture quantifies how the metal-centered core hole probes changes in formal oxidation state and encloses and substantiates earlier explanations. The approach is broadly applicable to mechanistic studies of redox-catalytic reactions in molecular systems where charge and spin localization/delocalization determine reaction pathways. PMID- 30310617 TI - Glass wool: a novel support for heterogeneous catalysis. AB - Heterogeneous catalysis presents significant advantages over homogeneous catalysis such as ease of separation and reuse of the catalyst. Here we show that a very inexpensive, manageable and widely available material - glass wool - can act as a catalyst support for a number of different reactions. Different metal and metal oxide nanoparticles, based on Pd, Co, Cu, Au and Ru, were deposited on glass wool and used as heterogeneous catalysts for a variety of thermal and photochemical organic reactions including reductive de-halogenation of aryl halides, reduction of nitrobenzene, Csp3-Csp3 couplings, N-C heterocycloadditions (click chemistry) and Csp-Csp2 couplings (Sonogashira couplings). The use of glass wool as a catalyst support for important organic reactions, particularly C C couplings, opens the opportunity to develop economical heterogeneous catalysts with excellent potential for flow photo-chemistry application. PMID- 30310616 TI - Nickel(0)-catalyzed linear-selective hydroarylation of unactivated alkenes and styrenes with aryl boronic acids. AB - Herein, we describe the first linear-selective hydroarylation reaction of unactivated alkenes and styrenes with aryl boronic acids, which was achieved by introducing a directing group on the alkenes. This efficient, scalable reaction serves as a method for modular assembly of structurally diverse alkyl arenes, including gamma-aryl butyric acid derivatives, which are widely utilized as chemical building blocks for the synthesis of various drugs and other biologically active compounds. PMID- 30310618 TI - Conjugated double helices via self-dimerization of alpha,alpha' dianilinotripyrrins. AB - A new motif for artificial double helices was developed on the basis of alpha,alpha'-disubstituted tripyrrin. alpha,alpha'-Dibromotripyrrin 3 was prepared by gentle bromination at the pyrrolic alpha-positions of 5,10 diphenyltripyrrane followed by oxidation with DDQ. Nucleophilic substitution reactions of 3 with anilines proceeded efficiently to furnish a series of alpha,alpha'-dianilinotripyrrins 4-11, which displayed monomeric and dimeric forms depending upon the solvent used for crystallization and the structures of the substituted anilines. Dimeric forms show double helical structures with smooth pi-conjugation as indicated by their absorption spectra. van't-Hoff plot analyses revealed that the dimerizations in CDCl3 are enthalpy-driven. Larger association constants of the dimerization are attained for 3,5-di-t-butylanilino- and 3,5-bis(trifluoromethyl)anilino-substituted tripyrrins (7 and 8) via additional multiple intermolecular interactions. In a nonpolar and aprotic solvent, tripyrrins (9 and 10) bearing bulkier 1-naphthylamino and mesitylamino groups do not dimerize but undergo unique tautomerization. PMID- 30310619 TI - Bis-pyrene probes of foldamer conformation in solution and in phospholipid bilayers. AB - Exploring the detailed structural features of synthetic molecules in the membrane phase requires sensitive probes of conformation. Here we describe the design, synthesis and characterization of bis(pyrene) probes that report conformational changes in membrane-active dynamic foldamers. The probes were designed to distinguish between left-handed (M) and right-handed (P) screw-sense conformers of 310-helical alpha-aminoisobutyric acid (Aib) peptide foldamers, both in solution and in bilayer membranes. Several different bis(pyrene) probes were synthesized and ligated to the C-terminus of Aib tetramers that had different chiral residues at the N-terminus, residues that favored either an M or a P screw sense in the 310-helix. The readily synthesized and conveniently incorporated N acetyl-1,2-bis(pyren-1'-yl)ethylenediamine probe proved to have the best properties. In solution, changes in foldamer screw-sense induced substantial changes in the ratio of excimer/monomer fluorescence emission (E/M) for this reporter of conformation, with X-ray crystallography revealing that opposite screw-senses produce very different interpyrene distances in the reporter. In bilayers, this convenient and sensitive fluorescent reporter allowed, for the first time, an investigation of how the chirality of natural phospholipids affects foldamer conformation. PMID- 30310620 TI - PDMS-coated hypercrosslinked porous organic polymers modified via double postsynthetic acidifications for ammonia capture. AB - A hypercrosslinked porous organic polymer was modified by post-oxidation and post sulfonation to obtain a porous platform with a high density of acidic groups. Such an acidified material exhibits record high NH3 adsorption capacity per surface area, fast adsorption rate, and recyclability at low desorption temperature. Noticeably, the coating of the polymer with PDMS represents a facile and efficient route to enable both a significant improvement of low-pressure NH3 adsorption capacity (~40-fold enhancement; from 0.04 to 1.41 mmol g-1) with respect to the non-modified polymer at 500 ppm and hydrophobicity associated with the selective sorption of NH3 over water vapor (hydrophilic for the non-coated material). This material is easy to prepare, cost-effective, and scalable to mass production. PMID- 30310621 TI - Rhodium-catalyzed ortho-heteroarylation of phenols: directing group-enabled switching of the electronic bias for heteroaromatic coupling partner. AB - The directed oxidative C-H/C-H cross-coupling reactions between a functionalized arene and a heteroarene typically exhibit an electronic bias for the heteroaromatic coupling partner. Disclosed herein is a conception of directing group enabled-switching of the electronic bias for coupling partner from the electron-deficient to electron-rich heteroarene, demonstrating that the modification of the directing group may match the latent reactivity of heteroarene substrates caused by the distinctly different electronic nature. In this work, we develop a Rh(iii)-catalyzed ortho-heteroarylation of phenols with greatly important electron-rich heteroarenes such as benzothiophene, benzofuran, thiophene, furan and pyrrole via two-fold C-H activation, which presents broad substrate scopes of both phenols and electron-rich heteroarenes and shows the advantage of tolerance of reactive functional groups, especially halogen. This work also provides a new strategy for the construction of pi-conjugated furan fused heteroacenes prevalent in materials science in dramatically simplified procedures, which makes the protocol highly applicable. PMID- 30310622 TI - Machine intelligence decrypts beta-lapachone as an allosteric 5-lipoxygenase inhibitor. AB - Using machine learning, targets were identified for beta-lapachone. Resorting to biochemical assays, beta-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of beta-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies. PMID- 30310623 TI - Adaptive responses of sterically confined intramolecular chalcogen bonds. AB - The responsive behavior of an entity towards its immediate surrounding is referred to as an adaptive response. The adaptive responses of a noncovalent interaction at the molecular scale are reflected from its structural and functional roles. Intramolecular chalcogen bonding (IChB), an attractive interaction between a heavy chalcogen E (E = Se or Te) centered sigma hole and an ortho-heteroatom Lewis base donor D (D = O or N), plays an adaptive role in defining the structure and reactivity of arylchalcogen compounds. In this perspective, we describe the adaptive roles of a chalcogen centered Lewis acid sigma hole and a proximal Lewis base (O or N) in accommodating built-in steric stress in 2,6-disubstituted arylchalcogen compounds. From our perspective, the IChB components (a sigma hole and the proximal Lewis base) act in synergism to accommodate the overwhelming steric force. The adaptive responses of the IChB components are inferred from the observed molecular structures and reactivity. These include (a) adaptation of a conformation without IChBs, (b) adaptation of a conformation with weak IChBs, (c) twisting the skeletal aryl ring while maintaining IChBs, (d) ionization of the E-X bond (e.g., X = Br) to relieve stress and (e) intramolecular cyclization to relieve steric stress. A comprehensive approach, involving X-ray data analysis, density functional theory (DFT) calculations, reaction pattern analysis and principal component analysis (PCA), has been employed to rationalize the adaptive behaviors of IChBs in arylchalcogen compounds. We believe that the perception of ChB as an adaptive/stimulus responsive interaction would profit the futuristic approaches that would utilise ChB as self-assembly and molecular recognition tools. PMID- 30310624 TI - Combined reversible switching of ECD and quenching of CPL with chiral fluorescent macrocycles. AB - Straightforward synthesis and resolution of a series of chiral fluorescent macrocycles are presented, together with their electronic circular dichroism (ECD), strong excimer fluorescence (EF, lambda 300 to 650 nm) and allied highly circularly polarized luminescence (CPL, g lum up to 1.7 * 10-2). The ECD, EF and CPL responses are strongly affected by the presence of metal ions (Na+, Ba2+) thanks to deep conformational changes. While ECD signals can be almost completely reversibly inverted upon the complexation/decomplexation of metal ions in a typical binary response, CPL signals are reversibly quenched concomitantly. The designed macrocycles display thus a remarkable combination of both +/- ECD and on/off CPL reversible switching. PMID- 30310626 TI - Facile and systematic access to the least-coordinating WCA [(RFO)3Al-F-Al(ORF)3]- and its more Lewis-basic brother [F-Al(ORF)3]- (RF = C(CF3)3). AB - By reaction of the Lewis acid Me3Si-F-Al(ORF)3 with a series of [PF6]- salts, gaseous PF5 and Me3Si-F are liberated and salts of the anion [F-Al(ORF)3]- ([f al]-; RF = C(CF3)3) can be obtained. By addition of another equivalent of Me3Si-F Al(ORF)3 to [f-al]-, gaseous Me3Si-F is released and salts of the least coordinating anion [(RFO)3Al-F-Al(ORF)3]- ([al-f-al]-) are formed. Both procedures work for a series of synthetically useful cations including Ag+, [NO]+, [Ph3C]+ and in very clean reactions with 5 g batch sizes giving excellent yields typically exceeding 90%. In addition, the synthesis of Me3Si-F-Al(ORF)3 has been optimized and scaled up to 85 g batches in an one-pot procedure. These anions could previously only be obtained by difficult to control decomposition reactions of [Al(ORF)4]- or by halide abstraction reactions with Me3Si-F Al(ORF)3, generating relatively large countercations that are unsuited for further use as universal starting materials. Especially [al-f-al]- is of interest for the stabilization of reactive cations, since it is even weaker coordinating than [Al(ORF)4]- and more stable against strong electrophiles. This bridged anion can be seen as an adduct of [f-al]- and Al(ORF)3. Thus, it is similarly Lewis acidic as BF3 and eventually reacts with nucleophiles (Nu) from the reaction environment to yield Nu-Al(ORF)3 and [f-al]-. This prevents working with [al-f al]- salts in ethereal or other donor solvents. By contrast, the [f-al]- anion is no longer Lewis acidic and may therefore be used for reactions involving stronger nucleophiles than the [al-f-al]- anion can withstand. Subsequently it may be transformed into the [al-f-al]- salt by simple addition of one equivalent of Me3Si-F-Al(ORF)3. PMID- 30310625 TI - Tuning the reactivity of nitriles using Cu(ii) catalysis - potentially prebiotic activation of nucleotides. AB - During the transition from prebiotic chemistry to biology, a period of solution phase, non-enzymatic activation of (oligo)nucleotides must have occurred, and accordingly, a mechanism for phosphate activation must have existed. Herein, we detail results of an investigation into prebiotic phosphate activation chemistry using simple, prebiotically available nitriles whose reactivity is increased by Cu2+ ions. Furthermore, although Cu2+ ions are known to catalyse the hydrolysis of phosphodiester bonds, we found this deleterious activity to be almost completely suppressed by inclusion of amino acids or dipeptides, which may suggest a productive relationship between protein and RNA from the outset. PMID- 30310627 TI - Machine learning meets volcano plots: computational discovery of cross-coupling catalysts. AB - The application of modern machine learning to challenges in atomistic simulation is gaining attraction. We present new machine learning models that can predict the energy of the oxidative addition process between a transition metal complex and a substrate for C-C cross-coupling reactions. In turn, this quantity can be used as a descriptor to estimate the activity of homogeneous catalysts using molecular volcano plots. The versatility of this approach is illustrated for vast libraries of organometallic catalysts based on Pt, Pd, Ni, Cu, Ag, and Au combined with 91 ligands. Out-of-sample machine learning predictions were made on a total of 18 062 compounds leading to 557 catalyst candidates falling into the ideal thermodynamic window. This number was further refined by searching for candidates with an estimated price lower than 10 US$ per mmol. The 37 catalyst finalists are dominated by palladium phosphine ligand combinations but also include the earth abundant transition metal (Cu) with less common ligands. Our results indicate that modern statistical learning techniques can be applied to the computational discovery of readily available and promising catalyst candidates. PMID- 30310629 TI - Catalyst-dependent selectivity in sulfonium ylide cycloisomerization reactions. AB - Divergent catalysis is an emerging field whereby access to structurally diverse compounds from a common precursor is achieved through controlled reaction pathways. Herein we present an unusual example of pi-acid catalyst dependent selectivity in the cycloisomerization of alkene-tethered sulfonium ylides. Computational mechanistic studies revealed how the ability of palladium to cycle through oxidation states largely controls the selectivity. PMID- 30310628 TI - The coordination chemistry of CmIII, AmIII, and AcIII in nitrate solutions: an actinide L3-edge EXAFS study. AB - Understanding actinide(iii) (AnIII = CmIII, AmIII, AcIII) solution-phase speciation is critical for controlling many actinide processing schemes, ranging from medical applications to reprocessing of spent nuclear fuel. Unfortunately, in comparison to most elements in the periodic table, AnIII speciation is often poorly defined in complexing aqueous solutions and in organic media. This neglect - in large part - is a direct result of the radioactive properties of these elements, which make them difficult to handle and acquire. Herein, we surmounted some of the handling challenges associated with these exotic 5f-elements and characterized CmIII, AmIII, and AcIII using AnIII L3-edge X-ray absorption spectroscopy (XAS) as a function of increasing nitric acid (HNO3) concentration. Our results revealed that actinide aquo ions, An(H2O) x 3+ (x = 9.6 +/- 0.7, 8.9 +/- 0.8, and 10.0 +/- 0.9 for CmIII, AmIII, and AcIII), were the dominant species in dilute HNO3 (0.05 M). In concentrated HNO3 (16 M), shell-by-shell fitting of the extended X-ray fine structure (EXAFS) data showed the nitrate complexation increased, such that the average stoichiometries of Cm(NO3)4.1+/-0.7(H2O)5.7+/ 1.3 (1.1+/-0.2)-, Am(NO3)3.4+/-0.7(H2O)5.4+/-0.5 (0.4+/-0.1)-, and Ac(NO3)2.3+/ 1.7(H2O)8.3+/-5.2 (0.7+/-0.5)+ were observed. Data obtained at the intermediate HNO3 concentration (4 M) were modeled as a linear combination of the 0.05 and 16 M spectra. For all three metals, the intermediate models showed larger contributions from the 0.05 M HNO3 spectra than from the 16 M HNO3 spectra. Additionally, these efforts enabled the Cm-NO3 and Ac-NO3 distances to be measured for the first time. Moreover, the AnIII L3-edge EXAFS results, contribute to the growing body of knowledge associated with CmIII, AmIII, and AcIII coordination chemistry, in particular toward advancing understanding of AnIII solution phase speciation. PMID- 30310630 TI - A synergistic LUMO lowering strategy using Lewis acid catalysis in water to enable photoredox catalytic, functionalizing C-C cross-coupling of styrenes. AB - Easily available alpha-carbonyl acetates serve as convenient alkyl radical source for an efficient, photocatalytic cross-coupling with a great variety of styrenes. Activation of electronically different alpha-acetylated acetophenone derivatives could be effected via LUMO lowering catalysis using a superior, synergistic combination of water and (water-compatible) Lewis acids. Deliberate application of fac-Ir(ppy)3 as photocatalyst to enforce an oxidative quenching cycle is crucial to the success of this (umpolung type) transformation. Mechanistic particulars of this dual catalytic coupling reaction have been studied in detail using both Stern-Volmer and cyclic voltammetry experiments. As demonstrated in more than 30 examples, our water-assisted LA/photoredox catalytic activation strategy allows for excess-free, equimolar radical cross-coupling and subsequent formal Markovnikov hydroxylation to versatile 1,4-difunctionalized products in good to excellent yields. PMID- 30310631 TI - Microwave-assisted functionalization of the Aurivillius phase Bi2SrTa2O9: diol grafting and amine insertion vs. alcohol grafting. AB - Microwave-assisted functionalization of the layered Aurivillius phase Bi2SrTa2O9 by alcohols is thoroughly investigated. The grafting of linear aliphatic and bulky alcohols is studied as a function of the starting material, underlining the importance of the prefunctionalization of the layered perovskite, for instance by butylamine. In addition, the functionalization by alpha,omega-alkanediols is explored. alpha,omega-alkanediols bearing long alkyl chains (n C > 3) adopt an unprecedented pillaring arrangement, whereas 1,3-propanediol and ethyleneglycol adopt a bilayer arrangement, only one out of the two hydroxyl groups being coordinated. Finally, the reactivities of alcohols and amines towards insertion are compared: the preferential reactivity of the two functional groups appears to be strongly dependent of the reaction conditions, and especially of the water content. This study is further extended to the case of amino-alcohol insertion. In this case, the amine group is preferentially bound, but it is possible to control the grafting of the alcohol moiety, thus going from a bilayer arrangement to a pillaring one. This work is of particular importance to be able to functionalize easily and rapidly layered oxides with elaborated molecules, bearing several different potentially reactive groups. PMID- 30310633 TI - Antibody-nucleotide conjugate as a substrate for DNA polymerases. AB - Here we report on the development of an antibody-modified nucleotide and its sequence-selective incorporation into nascent DNA catalysed by DNA polymerases. Although the modification of the nucleotide is several orders of magnitude larger than the natural dNTP substrate and even exceeds the size of the DNA polymerase, it is well accepted by the enzyme. Moreover, the recognition of the antibody is not abolished by the conjugation but can be recognized by a secondary antibody that is conjugated to a signal-generating enzyme (i.e., horse radish peroxidase). This product can thus be exploited for a colorimetric read-out of nucleotide incorporation by the naked eye that allows detection of DNA as low as 10 amol. In future, assays like the one described herein might allow nucleic acid diagnostics at single nucleotide resolution without any laboratory equipment. PMID- 30310632 TI - Metal-free alkene oxy- and amino-perfluoroalkylations via carbocation formation by using perfluoro acid anhydrides: unique reactivity between styrenes and perfluoro diacyl peroxides. AB - We present a strategy for metal-free, alkene difunctionalization-type, oxy- and amino-perfluoroalkylations, using perfluoro acid anhydrides as practical and user friendly perfluoroalkyl sources. This method provides efficient access to oxy perfluoroalkylation products via carbocation formation due to the unique reactivity between styrenes and bis(perfluoroacyl) peroxides generated in situ from perfluoro acid anhydrides. This reaction is also applicable to metal-free intramolecular amino-perfluoroalkylation of styrenes bearing a pendant amino group. Synthetic utility of the oxy-trifluoromethylation products was confirmed by demonstrating derivatization via hydrolysis, elimination, and acid-catalyzed substitution with carbon nucleophiles. The mechanism of the carbocation formation was investigated experimentally and theoretically. PMID- 30310634 TI - Correlated dynamics in aqueous proton diffusion. AB - The aqueous proton displays an anomalously large diffusion coefficient that is up to 7 times that of similarly sized cations. There is general consensus that the proton achieves its high diffusion through the Grotthuss mechanism, whereby protons hop from one molecule to the next. A main assumption concerning the extraction of the timescale of the Grotthuss mechanism from experimental results has been that, on average, there is an equal probability for the proton to hop to any of its neighboring water molecules. Herein, we present ab initio simulations that show this assumption is not generally valid. Specifically, we observe that there is an increased probability for the proton to revert back to its previous location. These correlations indicate that the interpretation of the experimental results need to be re-examined and suggest that the timescale of the Grotthuss mechanism is significantly shorter than was previously thought. PMID- 30310635 TI - meta-C-H arylation of fluoroarenes via traceless directing group relay strategy. AB - While several methods for the ortho selective arylation of fluoroarenes, meta functionalisation has never been achieved. We report a new methodology, based on the traceless directing group relay concept, leading to the first meta-selective (hetero)arylation of fluoroarenes. In this strategy, CO2 is introduced as a transient directing group, to control a Pd-catalysed arylation meta to the fluoro functionality, prior to its release in a sequential, one-pot fashion. This method has shown compatibility with a number of functional groups and substitution patterns in both the fluoroarene core and aryl iodide coupling partners, and proceeds with complete meta-selectivity and mono vs. bis-arylation selectivity. PMID- 30310636 TI - Can percolation theory explain the gelation behavior of diblock copolymer worms? AB - It is well known that polymerization-induced self-assembly (PISA) offers an efficient synthetic route for the production of highly anisotropic diblock copolymer worms. When prepared in aqueous media, such worms form thermoresponsive free-standing hydrogels that are (i) readily sterilizable, (ii) can act as a 3D matrix for the culture of normal mammalian cells and (iii) can induce stasis in human stem cell colonies. Herein we critically examine the gelation behavior of two types of diblock copolymer worms in terms of recent advances in percolation theory for rigid rods, which explicitly account for the effect of rod length polydispersity. More specifically, we use small-angle X-ray scattering (SAXS) to determine the weight-average worm contour length, L w, and the mean worm cross sectional radius, R. This approach enables a direct comparison to be made between the theoretical critical worm volume fraction, phi c, required for gelation and the experimental values indicated by rheological measurements and tube inversion experiments. Given that these diblock copolymer worms are relatively flexible rather than truly rod-like, reasonably good agreement between these two parameters is observed, particularly for shorter, relatively stiff worms. For longer, more flexible worms a proportionality constant of approximately two is required to reconcile theory with experimental values for phi c. These findings are expected to have important implications for the aqueous gelation behavior exhibited by various other anisotropic nanoparticles, such as cellulose nanocrystals and semicrystalline block copolymer rods, and also fibril-forming small molecule (e.g. dipeptide) gelators. PMID- 30310637 TI - Shape-memory and self-healing functions of DNA-based carboxymethyl cellulose hydrogels driven by chemical or light triggers. AB - Photoresponsive nucleic acid-based carboxymethyl cellulose (CMC) hydrogels are synthesized, and their application as shape-memory and self-healing functional matrices are discussed. One system involves the preparation of a carboxymethyl cellulose hydrogel crosslinked by self-complementary nucleic acid duplexes and by photoresponsive trans-azobenzene/beta-cyclodextrin (beta-CD) supramolecular complexes. Photoisomerization of the trans-azobenzene to the cis-azobenzene results in a hydrogel exhibiting lower stiffness due to the separation of the azobenzene/beta-CD bridging units. The hydrogel is switched between high and low stiffness states by the cyclic and reversible light-induced isomerization of the azobenzene units between the trans and cis states. The light-controlled stiffness properties of the hydrogel are used to develop a shape-memory hydrogel, where the duplex bridging units act as permanent memory in the quasi-liquid shapeless state of the hydrogel. A second system in the study is a carboxymethyl cellulose hydrogel crosslinked by the K+-stabilized G-quadruplex bridging units and by trans-azobenzene/beta-CD complexes. The resulting hydrogel includes dual-trigger functionalities, where the trans-azobenzene/beta-CD complexes can be reversibly formed and dissociated through the trans and cis photoisomerization of the azobenzene units, and the K+-stabilized G-quadruplexes can be reversibly dissociated and reformed in the presence of 18-crown-6-ether/K+-ions. The signal responsive crosslinked hydrogel reveals controlled stiffness properties, where the hydrogel crosslinked by the trans-azobenzene/beta-CD and K+-ion-stabilized G quadruplex reveals high stiffness and the hydrogel crosslinked only by the K+-ion stabilized G-quadruplexes or only by the trans-azobenzene/beta-CD complexes reveals low stiffness properties. The controlled stiffness properties of the hydrogel are used to develop shape-memory hydrogels, where the trans azobenzene/beta-CD complexes or the K+-ion-stabilized G-quadruplexes act as permanent memories in the shapeless and quasi-liquid states of the hydrogels. In addition, the hydrogel that includes two types of stimuli-responsive crosslinking units is used as a self-healing matrix, where each of the triggers guides the self-healing processes. PMID- 30310639 TI - A Case series of candy cane limb syndrome after laparoscopic Roux-en-Y gastric bypass. AB - Candy cane syndrome is a rare complication reported in bariatric patients following Roux-en-Y gastric bypass. It occurs when there is an excessive length of roux limb proximal to gastrojejunostomy, creating the possibility for food particles to lodge and remain in the blind redundant limb. Patients present with non-specific symptoms such as abdominal pain associated with nausea and vomiting. Most remain undiagnosed as the disease process is poorly described. We report three cases of candy cane syndrome treated successfully at our institution. PMID- 30310638 TI - Enantioselective fluorination of homoallylic alcohols enabled by the tuning of non-covalent interactions. AB - The study of the enantioselective fluorination of homoallylic alcohols via chiral anion phase transfer (CAPT) catalysis using an in situ generated directing group is described. Multivariate correlation analysis, including designer pi interaction derived parameters, revealed key structural features affecting the selectivity at the transition state (TS). Interpretation of the parameters found in the model equation highlights the key differences as well as similarities for the reaction of homoallylic and allylic substrates. A similar T-shaped pi interaction was found to occur between the substrate and the catalyst. The tuning of this crucial interaction by identification of the best combination of phosphoric acid catalyst and boronic acid directing group allowed for the development of a methodology to access gamma-fluoroalkenols in typically high enantioselectivities (up to 96% ee). PMID- 30310640 TI - Thoracic spinal cord injury without radiologic abnormality in a pediatric patient case report. AB - Spinal Cord Injury Without Radiologic Abnormality (SCIWORA) accounts for up to 19% of spinal cord related lesions in pediatric population, mostly comprising the cervical spine. A 2-year-old patient is presented, who suffered a motor-vehicle accident. After being admitted, neither X-Ray nor spinal TC scan showed any structural abnormalities. Neurological examination showed complete sensory and motor loss under T7 as well as bladder and bowel dysfunction. Magnetic resonance imaging (MRI) showed spinal cord lesion extending from T7 to T10. The patient was treated with external immobilization and physical therapy. Thoracic SCIWORA is an uncommon diagnosis that should be considered in pediatric patients who suffer spinal trauma. Spinal cord MRI has proven to be the most accurate modality for diagnosis. PMID- 30310641 TI - Aortic valve reconstruction with autologous pericardium in a patient with osteogenesis imperfecta. AB - Cardiac valve surgery for patients with osteogenesis imperfecta is associated with a high incidence of complications such as perioperative bleeding and valve detachment. In this report, we present a patient who was diagnosed with osteogenesis imperfecta and severe aortic insufficiency and also discussed treatment options. PMID- 30310642 TI - Spontaneous resolution of a spontaneous steinstrasse: a case report. AB - A 63-year-old man presented with a 4-day history of right sided loin-to-groin pain. Computed tomography imaging revealed a 22 mm by 7 mm volume of contiguous ureteric calculi at the right vesicoureteric junction. Spontaneous steinstrasse was diagnosed with no recent history of extracorporeal shock wave lithotripsy (ESWL) or other urological intervention to the right kidney. Metabolic testing was negative. An initial plan was made for urgent primary ureteroscopy and lithotripsy, however, the patient spontaneously passed 20-25 calculi at home whilst awaiting his operation date. He was reviewed in clinic and his symptoms had resolved. His ureteroscopy was cancelled. This case represents an example of spontaneous steinstrasse with no identified causative factors, a rare occurrence on which little literature is available presenting a management dilemma to the treating clinician. The case described resolved prior to intervention prompting us to suggest that spontaneous steinstrasse can be initially managed conservatively, as in ESWL-associated steinstrasse. PMID- 30310643 TI - Trans-luminal repair of a ruptured AAA with Type Ia and Type II endoleaks. AB - Ruptured abdominal aortic aneurysm (rAAA) with an associated Type II endoleak is rare. Emergent surgical repair is often necessary and may be associated with high morbidity and mortality. We report an alternative unique trans-luminal repair strategy in an 84-year-old male who presented with a rAAA with prior EVAR, and Type Ia and Type II endoleaks. The operative strategy consisted of proximal endograft extension into the para-renal aorta, followed by staged sac embolization using glue. Postoperatively, the patient recovered well from the repair, and follow-up imaging demonstrated a stable repair. PMID- 30310644 TI - A case of type II Mirizzi syndrome treated by simple endoscopic means. AB - Mirizzi syndrome is an uncommon complication of chronic cholelithiasis. Advancement in radiological modalities and minimally invasive surgery has led to improved pre-operative diagnoses and more laparoscopic cholecystectomies. But for unsuitable surgical candidates, endoscopy can be the definitive treatment. In this case, we present a 67-year-old man with type II Mirizzi syndrome treated by simple endoscopic means. PMID- 30310645 TI - Synchronous malignant phyllodes tumour and invasive lobular carcinoma-case report and review. AB - Synchronous phyllodes tumour and invasive lobular carcinoma is an extremely rare event. We report these concurrent diagnoses in a patient observed in an ipsilateral breast, suspected due to breast risk factors (family history and lobular carcinoma in situ) and the presence of malignant phyllodes. Screening breast magnetic resonance imaging was able to identify the carcinoma which was occult in other imaging. An understanding of the possibility of dual diagnoses may lead to additional investigations for its identification. Treatment may then be tailored to the individual's pathology. PMID- 30310646 TI - Ectopic jejunal pancreas with pancreatitis mistaken for a post-transplant lymphoproliferative disease in an immunosuppressed kidney transplant patient. AB - An ectopic pancreas, also known as pancreatic rest or heterotopic pancreas, consists of pancreatic tissue found in a location with no continuity with the anatomic pancreas. This lesion can occasionally cause gastrointestinal obstruction, ulceration or become inflamed and cause ectopic pancreatitis. We present the case of a 29-year-old immunocompromised female patient due to a previous kidney transplant. She presented with nausea and vague abdominal discomfort and was admitted for investigation and treatment of an acute kidney injury. A small bowel mass of unknown etiology was incidentally found on abdominal computed tomography imaging. Due to the high suspicion of a post transplant lymphoproliferative disease, a surgical exploration took place and revealed the presence of a pancreatic rest with chronic pancreatitis. Ectopic pancreas diagnosis is challenging and surgical exploration is warranted when a neoplastic process is suspected. PMID- 30310647 TI - Renal clear cell carcinoma metastasis to submandibular gland: case report and review of the literature. AB - Metastases from renal clear cell carcinoma (RCCC) to the head and neck (HN) region are rare, representing 8-14% of all RCCC metastases, with the thyroid gland being the most common site of RCCC metastasis in the HN. Metastatic tumors that are located in the salivary glands have a prevalence of 5%, while the submandibular gland is only involved in 1% of the cases. We present the case of a 74-year-old female patient with metastasis to the submandibular gland, 11 years after radical nephrectomy for a RCCC. PMID- 30310648 TI - Ascaris lumbricoides and its almost deadly complication. AB - Parasitic infections are still a burden in developing countries. The lack of sanitation and hygiene measures can result in an increase in morbidity and mortality due to parasitic infections. Surgery may be needed to treat serious complications caused by some of these parasites. Ascaris lumbricoides is one of the most common parasites and although infections are usually mild, severe complications, although rare, still exist. We present a case of a patient from the Ecuadorean Amazon region with limited access to drinking water. She presented to the emergency room with abdominal pain and a mass in the abdomen. After surgery, a mass with a perforation due to Ascaris was discovered. After discharge and due to lack of follow up and self-care, she became infected again, this time making her prognosis more complex and her clinical presentation more difficult. However, after proper clinical and surgical management, patient fully recovered. PMID- 30310649 TI - Adenocarcinoma arising in a colonic interposition after esophagectomy for benign stricture and review of the literature. AB - Colon interposition in oesophageal replacement after oesophagectomy for benign strictures is associated with significant perioperative complications that carry high morbidity and mortality. Long-term sequelae such as further strictures and colonic redundancy are frequent. Adenocarcinoma in the colonic graft is rare. A 70-year-old female presented to our clinic with symptoms of dysphagia. When she was 51 years, she underwent left colonic oesophageal interposition for an oesophageal stricture caused by caustic ingestion. Studies revealed colonic adenocarcinoma in interposed colonic graft, with latero-cervical lymph nodes. She was proposed to neoadjuvant chemotherapy. Although long-term risk analysis is lacking, it's not unreasonable to propose endoscopic screening according to general colonic cancer guidelines in patients with colonic interposition in oesophageal replacement after oesophagectomy. PMID- 30310650 TI - Giant myxoid liposarcoma of the gluteal region: case report of patient caused delay of surgical treatment and review of the literature. AB - Although adult soft tissue sarcoma is a rare disease, it needs individual treatment by an experienced, interdisciplinary team. We present an exceptional case of a 36-year-old woman suffering from a giant intermediate grade myxoid liposarcoma of the left buttock. She had been seen 4 years earlier but refused to undergo any treatment by then. Now suffering from a foul, ulcerating and superinfected tumor she agreed to surgical treatment. Despite delay, treatment could be performed according to the most up to date sarcoma guidelines which are discussed, including a brief review of the literature. PMID- 30310651 TI - Massive retroperitoneal dedifferentiated liposarcoma in a young patient. AB - Liposarcomas are rare malignant tumors that mostly develop in the retroperitoneum. They have a broad behavioral spectrum, from small masses of tissue to highly aggressive tumors. The dedifferentiation process occurs in up to 10% and it's most likely to occur in the retroperitoneum, a process that not only changes its components but also its prognosis. These tumors can grow to a massive size since most of them do not give any symptoms until they invade the adjacent structures. Timely detection and surgery could avoid all these potentially lethal scenarios. We present a case of a 34-year-old patient, who reported a growing mass in her abdomen that reached massive proportions but remained untreated due to lack of sufficient access to healthcare facilities in her geographic location. After complete removal of the mass the patient underwent complete recovery, dedifferentiated liposarcoma was the final diagnosis. PMID- 30310652 TI - Big-data and machine learning to revamp computational toxicology and its use in risk assessment. AB - The creation of large toxicological databases and advances in machine-learning techniques have empowered computational approaches in toxicology. Work with these large databases based on regulatory data has allowed reproducibility assessment of animal models, which highlight weaknesses in traditional in vivo methods. This should lower the bars for the introduction of new approaches and represents a benchmark that is achievable for any alternative method validated against these methods. Quantitative Structure Activity Relationships (QSAR) models for skin sensitization, eye irritation, and other human health hazards based on these big databases, however, also have made apparent some of the challenges facing computational modeling, including validation challenges, model interpretation issues, and model selection issues. A first implementation of machine learning based predictions termed REACHacross achieved unprecedented sensitivities of >80% with specificities >70% in predicting the six most common acute and topical hazards covering about two thirds of the chemical universe. While this is awaiting formal validation, it demonstrates the new quality introduced by big data and modern data-mining technologies. The rapid increase in the diversity and number of computational models, as well as the data they are based on, create challenges and opportunities for the use of computational methods. PMID- 30310653 TI - Delayed death following paraquat poisoning: three case reports and a literature review. AB - Paraquat (PQ) poisoning is principally reported in developing countries. However, most fatalities occur elsewhere due to the induction of multi-organ failure. PQ poisoning can hardly be managed by clinical practice, and no specific antidote has come into existence yet. Here three cases, including 17-, 20-, and 23-year old men, who were poisoned with PQ, have been reported. Furthermore, the literature regarding biological mechanisms, clinical manifestation, and treatment of PQ-induced toxicity was reviewed. Patients who, either intentionally or accidentally, ingested PQ earlier were initially found to be stable at the emergency department (ED). Therefore, they were discharged from the hospital under a follow-up. However, after several days, the patients were referred to the hospital for the second time and despite cardiovascular resuscitation (CPR) efforts, they suddenly expired. The delayed death following exposure to PQ was reported for inducing gradual progressive pulmonary fibrosis, metabolic acidosis, neurotoxicity, renal failure, and liver injury in poisoned patients. Therefore, PQ-intoxicated patients should be supervised for up to several weeks, and kept in the hospital for a longer period of time. Clinical manifestations and laboratory findings are beneficial markers that act as useful predictors of PQ poisoning. PMID- 30310654 TI - Perturbation of microRNA signalling by doxorubicin in spermatogonial, Leydig and Sertoli cell lines in vitro. AB - We have previously shown that in addition to its widely recognised cardiotoxicity, the chemotherapeutic doxorubicin (DOX) is able to induce transcriptional, microRNA (miRNA) and DNA methylation changes in the mouse testis. These changes perturb pathways involved in stress/cell death and survival and testicular function and lead to germ cell loss and reproductive organ damage. Here, we further investigated the differential miRNA expression induced by DOX in mouse spermatogonial (GC1), Leydig (TM3) and Sertoli (TM4) cell lines in vitro. We began by performing cell cycle analysis of the three mouse testicular cell lines to evaluate their sensitivity to DOX and thus select suitable doses for miRNA profiling. In keeping with our in vivo data, the spermatogonial cell line was the most sensitive, and the Sertoli cell line the most resistant to DOX induced cell cycle arrest. We then further demonstrated that each cell line has a distinct miRNA profile, which is perturbed upon treatment with DOX. Pathway analysis identified changes in the miRNA-mediated regulation of specialised signalling at germ-Sertoli and Sertoli-Sertoli cell junctions following treatment with DOX. Amongst the most significant disease categories associated with DOX induced miRNA expression were organismal injury and abnormalities, and reproductive system disease. This suggests that miRNAs play significant roles in both normal testicular function and DOX-induced testicular toxicity. Comparison of our in vitro and in vivo data highlights that in vitro cell models can provide valuable mechanistic information, which may also help facilitate the development of biomarkers of testicular toxicity and high-throughput in vitro screening methods to identify potential testicular toxicants. PMID- 30310655 TI - Hemolytic and cellular toxicology of a sulfanilamide-based nonionic surfactant: a niosomal carrier for hydrophobic drugs. AB - Biocompatible surfactants are of diverse pharmaceutical interest due to their ability to self-assemble into nano-particulate systems which can be used for single-step drug loading, based upon the hydrophobic-hydrophobic interaction between a hydrophobic drug and the lipophilic part of a surfactant molecule. However, surfactants are associated with cytotoxicity and hemolysis due to their amphiphilic interaction with cellular membranes. This study reports a novel membrane-compatible surfactant, synthesized from sulfanilamide and its self micellization into niosomes. The surfactant was synthesized in a single step reaction via the introduction of an alkyl chain in the sulfanilamide moiety by conjugation with deconyl chloride. The synthesized surfactant (S-SDC) was characterized by 1H and 13C NMR, mass spectrometry and single crystal XRD. The S SDC niosomes were explored for drug delivery with clarithromycin as a model drug. The biocompatibility of the surfactant was investigated through hemolysis and cytotoxicity. The surfactant presented a very low critical micellar concentration (CMC) of 0.04 mM and entrapped 65% of the drug which was released in a sustained manner, over 12 h, at acidic and physiological pH. The vesicles were spherical in shape with 234 +/- 3.61 nm mean diameter and a narrow size distribution. Niosomes were hemocompatible and nontoxic to cellular membrane. The results suggested the sulfanilamide based surfactant can be applied as a novel and cell membrane compatible niosomal drug delivery vehicle. PMID- 30310656 TI - Effect of the calcination process on CdO-ZnO nanocomposites by a honey-assisted combustion method for antimicrobial performance. AB - This work reports on honey as a combustion agent of CdO : ZnO nanocomposites and the effects of further annealing (100 degrees C, 200 degrees C, 300 degrees C and 400 degrees C) on their structural, optical, morphological, elemental, electrical and antimicrobial properties are investigated. X-ray diffraction spectra confirm the cubic and hexagonal structure of CdO : ZnO nanocomposites at 400 degrees C. When the calcination temperature was increased, the crystallinity, absorbance, bandgap, luminescence intensity, morphological dispersion and mean particle size were also increased. HR-TEM imaging confirmed spherical particles with an average particle size of ~49 nm. The electrical conductivity of the CdO : ZnO nanoparticles was investigated. The antimicrobial activity of CdO : ZnO nanocomposites was tested for various bacterial and fungal organisms using a zone inhibition method. PMID- 30310657 TI - The mitochondrial pathway is involved in sodium fluoride (NaF)-induced renal apoptosis in mice. AB - The objective of the present study was to explore the molecular mechanism of apoptosis induced by sodium fluoride (NaF) in the mouse kidney by using the methods of flow cytometry, quantitative real-time polymerase chain reaction (qRT PCR), western blotting, and experimental pathology. 240 four-week-old ICR mice were randomly divided into 4 groups and exposed to different concentrations of NaF (0 mg kg-1, 12 mg kg-1, 24 mg kg-1 and 48 mg kg-1) for a period of 42 days. The results demonstrated that NaF increased cell apoptosis and the depolarization of the mitochondrial membrane potential (MMP), and that the mitochondrial pathway was involved in NaF-induced apoptosis. Alteration of the mitochondrial pathway was characterized by significantly increasing mRNA and protein expression levels of cytosolic cytochrome c (Cyt c), the second mitochondrial activator of caspases/direct inhibitors of the apoptosis binding protein with low pI (Smac/Diablo), the serine protease high-temperature-requirement protein A2/Omi (HtrA2/Omi), the apoptosis inducing factor (AIF), endonuclease G (Endo G), cleaved-cysteine aspartate specific protease-9 (cleaved-caspase-9), cleaved cysteine aspartate specific protease-3 (cleaved-caspase-3), Bcl-2 antagonist killer (Bak), Bcl-2 associated X protein (Bax), Bcl-2 interacting mediator of cell death (Bim), cleaved-poly-ADP-ribose polymerase (cleaved-PARP), p-p53, and decreasing mRNA and protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl extra large (Bcl-xL), and X chromosome-linked inhibitors of apoptosis proteins (XIAPs). To our knowledge, the mitochondrial pathway is reported for the first time in NaF-induced apoptosis of the human or animal kidney. Also, this study provides novel insights for further studying fluoride-induced nephrotoxicity. PMID- 30310658 TI - Effects of exposure of adult mice to multi-walled carbon nanotubes on the liver lipid metabolism of their offspring. AB - Objective: To explore the toxicity of multi-walled carbon nanotubes (MWCNTs) on the liver lipid metabolism of offspring mice and the possible mechanisms involved. Method: Virgin female (16-18 g) and male (18-20 g) C57BL/6 mice were randomly divided into two groups: Control group and Test group. After anesthesia with chloral hydrate, the mice were administered 50 MUL saline or dust solution by intratracheal instillation (Control group: 50 MUL saline; Test group: 15 mg kg 1 MWCNTs). Mice were injected with these doses once a week for 13 weeks. Then, male and female mice in the same group were allowed to mate to produce offspring. The pups were fed with normal diet until the end of the experiment (12 weeks old). The offspring mice were sacrificed by decapitation to detect the blood biochemistry and the expression of genes and proteins. Results: Compared with the Control group, MWCNTs significantly reduced the weight of offspring mice (male and female) and led to histopathological changes in the liver tissues. The expression of liver fat synthesis gene significantly increased (P < 0.05 or P < 0.01). The expression of genes and proteins involved in the inflammatory reactions appeared to be abnormal (P < 0.05 or P < 0.01). Conclusion: Exposure of adult mice to MWCNTs can affect the expression of fatty acid synthesis genes in the liver tissues of offspring mice, leading to disruption of liver function and accumulation of lipid droplets in the hepatocytes. The imbalance between M1 and M2 liver macrophage phenotypes may be one of the underlying mechanisms of action of MWCNTs leading to disordered fatty acid synthesis in offspring mice. PMID- 30310659 TI - Evidence for cardiotoxicity associated with sertraline in rats. AB - Sertraline is an antidepressant that is frequently prescribed to treat depression, obsessive-compulsive disorder, panic disorder, and anxiety. This drug had a safe cardiotoxicity profile, until the reporting of cases of sertraline associated cardiotoxicities in the early 2000s. Since then, there have been conflicting results on the cardiotoxicity of this drug. In the study reported here we aimed to identify the cardiotoxic effects of sertraline by evaluating serum cardiac biomarkers, such as serum aspartate aminotransferase (AST), creatinine phosphokinase-myoglobin band (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin T (cTn-T) levels as well as electrocardiographic parameters, DNA damage in cardiomyocytes, and histological findings of heart tissue in rats that were administered oral doses of 5, 10, or 20 mg kg-1 of sertraline for 28 days. Additionally, to investigate the possible mechanisms underlying cardiotoxicity, glutathione and malondialdehyde levels in cardiac tissue were determined to evaluate oxidative stress. According to our results, AST, LDH, and cTn-T levels were significantly increased in the 10 and 20 mg kg-1 sertraline groups when compared to the control group. Heart rates were increased, PR intervals prolonged, a short QTc value was observed, and T-wave amplitudes were decreased significantly in the 20 mg kg-1 sertraline group when compared to the control group. Significant DNA damage was observed in the high-dose groups. Histopathological investigations also revealed some degenerative changes in the 10 and 20 mg kg-1 sertraline groups. Glutathione levels were significantly decreased in the 10 and 20 mg kg-1 sertraline groups when compared with the control group. In conclusion, our findings support the cardiotoxic potential of sertraline and also suggest that oxidative stress may play a role in the toxicity of sertraline. PMID- 30310660 TI - NF-kappaB-vimentin is involved in steroidogenesis stimulated by di-n-butyl phthalate in prepubertal female rats. AB - This study was aimed at assessing steroidogenesis stimulated by low-dose exposure to DBP in prepubertal female rats. Animals were gavaged with DBP from postnatal day 21 to 33 at 0, 1, 10 and 500 mg kg-1 day-1. 500 mg kg-1 day-1 was selected since it was used in numerous studies and the inhibitory effect could be observed at this dosage. After treatment, hormone levels in serum were detected by enzyme linked immunosorbent assay. mRNA and protein expressions of vimentin, nuclear factor-kappaB (NF-kappaB) p65 and phosphorylation of NF-kappaB p65 (p-p65) were assayed by quantitative real-time polymerase chain reaction (qRT-PCR) assay, western blotting, and immunohistochemistry, respectively. Uterus weights, progesterone levels in serum, and protein expression of vimentin and p-p65 in ovaries increased significantly after the animals were exposed to DBP at 1 mg kg 1 day-1. Additionally, steroidogenesis and vimentin expression stimulated by DBP were blocked when the activity of NF-kappaB p65 was inhibited by the NF-kappaB inhibitor, pyrrolidine dithiocarbamic acid (PDTC). These results strongly suggested that DBP may activate uterus development by up-regulated steroidogenesis through the NF-kappaB-vimentin signaling pathway. PMID- 30310662 TI - Oxidative stress and mitochondrial impairment mediated apoptotic cell death induced by terpinolene in Schizosaccharomyces pombe. AB - Terpinolene is one of the most abundant monoterpenes used as a food supplement or odorant in cosmetics and the pharmaceutical industry. In this study, we aimed to assess apoptotic, oxidative and cytotoxic effects of terpinolene. We used the fission yeast (Schizosaccharomyces pombe) as a promising uni-cellular model organism in molecular toxicology and cell death research, due to its resemblance to mammalian cells at the molecular level. After terpinolene exposure (200-800 mg L-1), the IC50 and LC50 were calculated as 349.17 mg L-1 and 593.87 mg L-1. Cells, stained with acridine orange/ethidium bromide and DAPI, showed apoptotic nuclear morphology, chromatin condensation and fragmentation. 2,7 Dichlorodihydrofluorescein diacetate (DCFDA) fluorescence gradually increased (1.5-2-fold increase) in correlation with increasing concentrations of terpinolene (200-800 mg L-1). Mitochondrial impairment at higher concentrations of terpinolene (400-800 mg L-1) was shown by Rhodamine 123 staining. Real-time PCR experiments showed significant increases (1.5-3-fold) in SOD1 and GPx1 levels (p < 0.05) as well as 2-2.5-fold increases (p < 0.05) in pro-apoptotic factors, Pca1 and Sprad9. The potential effects of terpinolene on programmed cell death and the underlying mechanisms were clarified in unicellular model fungi, Schizosaccharomyces pombe. PMID- 30310661 TI - In vivo toxicology of carbon dots by 1H NMR-based metabolomics. AB - Owing to the promising applications of C-dots in biomedical engineering, concerns about their safety have drawn increasing attention recently. In this study, mice were intraperitoneally injected at different C-dot concentrations (0, 6.0, 12.0 and 24.0 mg kg-1) once every 2 days for 30 days. A 1H NMR-based metabolic approach supplemented with biochemical analysis and histopathology was used for the first time to explore the toxicity of C-dots in vivo. Histopathological inspection revealed that C-dots did not induce any obvious impairment in tissues. Biochemical assays showed no significant alterations of most measured biochemical parameters in tissues and serum, except for a slight reduction of the albumin level in serum as well as AChE activity in the liver and kidneys. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis and SUS-plots disclosed that C-dots not only triggered the immune system but also disturbed the function of cell membranes as well as the normal liver clearance, indicating that the 1H NMR based metabolomics approach provided deep insights into the toxicity of C dots in vivo and gained an advantage over traditional toxicological means, and should be helpful for the understanding of its toxic mechanism. PMID- 30310663 TI - Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats. AB - Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer and people are exposed to various amounts on a daily basis. This study was designed to evaluate the genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of DEHP (100, 200 and 400 mg kg-1 per day DEHP) administered daily to rats by oral gavage for 28 days. The rats were divided into five groups including oil control, positive control (MMS) and treatment groups (100, 200 and 400 mg kg-1 per day DEHP). They were euthanized at the end of the experiment, organ and body weights were recorded and serum was collected for biochemical and hormone analysis. The genotoxic effect was measured in blood and sperm using the Comet assay. The testes, epididymis, prostate gland and seminal vesicle were collected and stained with hematoxylin and eosin for histopathologic analysis. Epithelial height, luminal and tubular diameters (MUM) in seminiferous tubules were also measured. Moreover, the study revealed an increase in the DNA damage level in both blood lymphocytes and sperm. At the end of the experiment, the tail intensity showed a significant increase in the 100 mg kg-1 per day (p = 0.032), 200 mg kg-1 per day (p = 0.019) and 400 mg kg-1 per day (p = 0.012) dose groups compared to the control group in blood. Furthermore, testosterone was decreased in all treatment groups compared to the control group. Besides, DEHP caused a significant decrease in the leukocyte levels (p = 0.017) and hemoglobin content, as well as an increased mean cell volume (MCV) count (p = 0.029) in the 400 mg kg 1 per day group when compared to the control values. It is important to indicate that there were apoptotic cells seen in the lumen of testes in the 200 and 400 mg kg-1 per day dose groups using the Tunel method. Therefore, with this study, it has been illustrated that DEHP caused DNA damage in blood and sperm and concrete negative effects on the reproductive system in rats from the pre-pubertal period to the pubertal period. This is a unique study since there has not been any other study that presents the indicated level of DNA damage while considering the genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of DEHP. PMID- 30310664 TI - Chronic exposure to acephate triggers ROS-mediated injuries at organismal and sub organismal levels of Drosophila melanogaster. AB - The present study demonstrates ROS-mediated organismal and sub-organismal injuries in Drosophila melanogaster following chronic acephate exposure. Larvae and adults of Drosophila were reared on food supplemented with sub-lethal concentrations (1-6 MUg mL-1) of acephate (LC50 8.71 MUg mL-1). The longevity of the treated adults was reduced to half at 6 MUg mL-1 exposure along with declined neuromuscular coordination and physical activities. Apparent developmental defects in the compound eyes were confirmed through the detection of apoptotic lesions in larval eye imaginal discs. The larval gut manifested tissue damage at various sites. Neural and fat cell viability was reduced by ~1.89- and ~3.38-fold at 6 MUg mL-1 acephate treatment, respectively. A significant reduction in hemocyte viability confirmed the immunotoxic potential of acephate. Nearly 1-3 fold enhancement in the expression of OS markers (MDA, protein carbonyl contents, SOD, catalase and HSP70) in the treated larvae served as evidence of ROS production. The post-treatment increase in CYP450 and GST activities reflects the 'switch-on' states of the phase-I and phase-II detoxification mechanism. The genotoxic potential of acephate was confirmed through alkaline single cell gel electrophoresis. Thus, the findings of the present study validate the fact that besides traditional cholinesterase inhibition, chronic sub-lethal exposure to acephate potentially induces ROS-mediated toxic responses in Drosophila. PMID- 30310666 TI - The developmental toxicity, bioaccumulation and distribution of oxidized single walled carbon nanotubes in Artemia salina. AB - With the increasing production and applications of single walled carbon nanotubes (SWCNTs), concerns about the likelihood of SWCNTs being present in the aquatic environment and the subsequent effects on aquatic organisms are emerging. This work aimed to investigate the developmental toxicity, bioaccumulation and distribution of oxidized SWCNTs (O-SWCNTs) in a marine model organism, Artemia salina (A. salina). The results indicated that the hatching rates of capsulated and decapsulated cysts were decreased as the O-SWCNT concentration increased from 0 to 600 mg L-1 at 12, 18, 24 and 36 h. For instar I, II and III larvae exposure to 600 mg L-1, the mean mortality rates were 36.1%, 57.9% and 45.2%, respectively. Both the body length and swimming speed showed a concentration dependent decrease after exposure to O-SWCNTs for 24 h. The inhibition of swimming may be caused by (1) the malformation of gills; (2) the attachment of O SWCNTs on the gills. Reactive oxygen species (ROS) and antioxidant enzyme (catalase, superoxide dismutase and glutathione peroxidase) activities substantially increased following exposure, indicating that the toxic effects were related to oxidative stress. O-SWCNTs can be ingested, accumulated and excreted by A. salina, and distributed in the intestine, lipid vesicles and phagocytes. However, the accumulated O-SWCNTs were not completely excreted by A. salina. Uptake kinetics data showed that the O-SWCNT content increased from 1 to 48 h followed by a decrease from 48 to 72 h in the range from 0.08 to 5.7 mg g-1. The combined results so far indicate that O-SWCNTs have the potential to affect aquatic organisms when released into the marine ecosystems. PMID- 30310665 TI - Emodin induces liver injury by inhibiting the key enzymes of FADH/NADPH transport in rat liver. AB - Emodin is a natural anthraquinone derivative that occurs in many Chinese medicinal herbs. It might induce liver damage, but the mechanism is not clear. In this research, seven groups of Sprague-Dawley (SD) rats with three doses of emodin were used. The liver injury was examined by analyzing biochemical indexes and histopathology. Altered proteins between the control group (CG) and the liver injury group were determined by proteomic technology. The results showed that emodin causes liver injury in a time- and dose-dependent manner. In the high dosage 1-week group (HG1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was downregulated, and the activity of malate dehydrogenase (MDH) was inhibited by emodin. These might cause the inhibition of FADH or NADH/NADPH transport from the cytoplasm to mitochondria. The WB results showed that the inhibition of FADH/NADPH transport induced a high activity of caspase-9 and caspase-3, and the expressions of cytochrome c (Cyt C), caspase-9 and caspase-3 were high in HG1, which might lead to mitochondrial apoptosis pathway activation. In addition, whatever the HG1 or low-dose group (LG), the effects of emodin on mitochondria were observed. Overall, for the first time, we showed that emodin inhibited proton transport and induced the activation of the mitochondrial apoptosis pathway, which might be the reason for liver injury. PMID- 30310667 TI - Shikonin-mediated up-regulation of miR-34a and miR-202 inhibits retinoblastoma proliferation. AB - Retinoblastoma (RB) is an ocular tumor that occurs mainly in children. The pathogenesis of RB is not well understood, and its treatment strategies are very limited. Shikonin is widely reported as an anti-tumor agent. However, its effect on RB is still unknown. MTT assay was performed to detect the proliferation ability of two RB cell lines, Y-79 and WERI-Rb-1, upon treatment with Shikonin. Colony formation assay was conducted to examine the clonogenic ability of Shikonin-treated cells. Real-time PCR and western blotting were performed for expression analysis of miRNAs and MYCN, respectively. Luciferase activity assay was conducted to test the inhibition mechanism of miR-34a and miR-202 on MYCN. Shikonin could effectively inhibit the proliferation of RB cells and upregulate the expressions of miR-34a and miR-202. MiR-34a and miR-202 could directly target the mRNA degradation of oncogene MYCN, and the inhibitory effect of Shikonin was largely weakened by restoring the MYCN protein expression. Shikonin-mediated up regulation of miR-34a and miR-202 inhibits RB proliferation, partially mediated through MYCN. PMID- 30310668 TI - Triazophos-induced toxicity in zebrafish: miRNA-217 inhibits nup43. AB - Triazophos is a highly toxic organophosphorus pesticide, causing acute toxicity to brain tissue, and neurotoxicity and embryotoxicity to animals. Therefore, triazophos is considered as a public health problem due to its acute hazard index. MicroRNAs (miRNAs), a class of endogenous noncoding RNAs, can regulate the expression of target gene(s) by mediating mRNA cleavage or translational repression in organisms exposed to environmental chemicals. We found that nup43 is targeted by miR-217, which was significantly regulated in adult zebrafish (Danio rerio) exposed to triazophos (phenyl-1,2,4-triazolyl-3-(o,o-diethyl thionophosphate)). The expression of nup43 in both mRNA and protein levels was downregulated in a dose-dependent manner upon stimulation with triazophos. A dual luciferase reporter assay demonstrated that miR-217 interacted with the 3' untranslated regions (3'-UTR) of nup43. The expression of nup43 in both mRNA and protein level was reduced in ZF4 cells when transfected with an miR-217 mimic, but increased when transfected with an miR-217 inhibitor. As a result, nup43 is targeted by miR-217 upon triazophos exposure. We suggest that miR-217 could be a potential toxicological biomarker for triazophos. PMID- 30310669 TI - Evaluation of the antioxidant, antibacterial and anticancer (lung cancer cell line A549) activity of Punica granatum mediated silver nanoparticles. AB - This work aimed to synthesize silver nanoparticles via an environmentally benign route, using the aqueous extract of Punica granatum as a precursor as well as a stabilizing and reducing agent. The as-synthesized silver nanoparticles were confirmed using UV-visible spectroscopy with an absorbance peak at 450 nm and were thereafter further confirmed using dynamic light scattering (DLS), High Resolution Transmission Electron Microscopy (HR-TEM) and X-Ray Diffraction (XRD). TEM analysis revealed 6-45 nm and spherically dispersed nanoparticles and XRD showed the crystalline nature of the nanoparticles. The free radical scavenging activity of the nanoparticles for DPPH and intracellular reactive oxidative species (ROS) production were observed using dihydroethidium (DHE) non fluorescent stain and a CellROX(r) Deep Red fluorescent probe. Antibacterial assays against the most common Gram negative (Escherichia coli) and Gram positive (Staphylococcus aureus) bacteria showed a higher zone of inhibition against S. aureus. Furthermore, the anti-cancerous activity of the biologically synthesized silver nanoparticles was revealed by the inhibited cell growth of lung cancer A549 cells and no cytotoxicity was observed. This may be due to their ability to arrest the cell cycle at G1 phase. Thus, this work provides a gateway to explore more about the anticancer properties of biogenically synthesized silver nanoparticles and these biologically prepared silver nanoparticles have the potential to be utilized in biomedical science. PMID- 30310670 TI - Bioactive nano-metal-organic frameworks as antimicrobials against Gram-positive and Gram-negative bacteria. AB - More effective antibiotics are needed to overcome the problem of multidrug resistance. The antibacterial efficacies of three Zn-based nano metal-organic frameworks (nMOFs) - IRMOF-3, MOF-5, and Zn-BTC - were explored, both alone and as mixtures with ampicillin and kanamycin. When tested against Escherichia coli, Staphylococcus aureus, Staphylococcus lentus, and Listeria monocytogenes, the nMOF/drug mixtures demonstrated synergistic (IRMOF-3/kanamycin) or additive (other nMOF/drug combinations) effects compared with the nMOFs or antibiotics alone. Zn-Based nMOFs can reduce the burden of the new discovery of antimicrobial pharmaceuticals by increasing the potency of existing antibiotics. PMID- 30310672 TI - Genoprotective effects of gallic acid against cisplatin induced genotoxicity in bone marrow cells of mice. AB - Chemotherapeutic drugs are used for the treatment of cancer. However, the use of these drugs is limited due to their side effects on normal cells. One of the measures to detect chemoprotection of plant extracts is to evaluate their anticlastogenic effects. In this study, we report the anticlastogenic effect of gallic acid (GA) against cisplatin (Csp), a chemotherapeutic drug, in Swiss albino mice. Three different doses of GA (100, 200 and 400 mg per kg bw) were administered orally to the experimental animals in 0.2 mL quantity for 5 days at 24 hour intervals. Cisplatin, the positive control agent (10 mg per kg bw), was administered intraperitoneally (i.p.) in 0.1 mL quantity. Overall, the results showed that the pretreatment of GA caused a remarkable decrease in Csp induced micronucleus frequency and DNA damage in bone marrow cells of mice. The results suggest that GA showed potent antigenotoxic effects against Csp induced damage in mice bone marrow cells. PMID- 30310671 TI - Cellular responses of hyaluronic acid-coated chitosan nanoparticles. AB - In recent years, nanotechnology has been proven to offer promising biomedical applications for in vivo diagnostics and drug delivery, stressing the importance of thoroughly investigating the biocompatibility of potentially translatable nanoparticles (NPs). Herein, we report the cellular responses of uncoated chitosan NPs (CS NPs) and hyaluronic acid-coated chitosan NPs (HA-CS NPs) when introduced into Chinese hamster ovary cells (CHO-K1) in a dose-dependent manner (2.5, 0.25, 0.025, 0.0025, and 0.00025 mg mL-1) at two time points (24 and 48 h). MTS assay, cell proliferation, showed a decrease in the viability of cells when treated with 0.25 and 2.5 mg mL-1 CS NPs. When exposed to high doses of CS NPs, the lactate dehydrogenase (LDH) enzyme started to leak out of the cells and the cellular levels of mitochondrial potentials were significantly reduced accompanied by a high production of intracellular reactive oxygen species (ROS). Our study provides molecular evidence of the biocompatibility offered by HA-CS NPs, through ROS scavenging capabilities rescuing cells from the oxidative stress, showing no observed cellular stress and thereby revealing the promising effect of anionic hyaluronic acid to significantly reduce the cytotoxicity of CS NPs. Our findings are important to accelerate the translation and utilization of HA-CS NPs in drug delivery, demonstrating the pronounced effect of surface modifications on modulating the biological responses. PMID- 30310673 TI - Molecular insight to size and dose-dependent cellular toxicity exhibited by a green synthesized bioceramic nanohybrid with macrophages for dental applications. AB - Improvising bioceramics for enhancing their biocompatibility and physical properties has been a focus area for the dental industry. To further explore this area, this study reports a novel green synthesis and molecular in vitro biocompatibility of calcium aluminosilicate-chitosan nanohybrid (CAS-CH). The nanohybrids were synthesized by using a high energy ball milling (HEBM) technique and then characterized for their physiochemical properties using standard techniques including scanning electron microscopy (SEM) and dynamic light scattering (DLS). In vitro cytotoxicity evaluation of a synthesized nanohybrid was made with a RAW264.7 cell line using cell viability assays, such as, MTT, cellular morphology analysis, induction of oxidative stress, and apoptosis. CAS CH nanohybrids were synthesized at three milling time points: 1H, 2H, and 3H. With increasing milling time, we found a reduction in sizes of particles and increased zeta potential. Viability of cells was found to be decreased with an increase in concentration. Moreover, toxic effects like ROS generation and apoptosis were reduced with increasing milling time. Computational and experimental analysis elucidated the mechanism of toxicity as a consequence of influential functionality of Sod1 and p53 proteins due to interaction and internalization of the nanohybrids with amino acid residues via hydrogen bonds and hydrophobic interactions. The detailed study depicted a novel way of synthesizing biocompatible bioceramic nanohybrids with a mechanistic insight of its cytotoxicity profile. PMID- 30310674 TI - tert-Butylhydroperoxide induces apoptosis in RAW264.7 macrophages via a mitochondria-mediated signaling pathway. AB - Macrophage apoptosis occurs throughout all stages of atherosclerosis, mainly induced by oxidized low density lipoproteins (Ox LDLs), leading to the formation of necrotic cores. Nevertheless, the mechanism of macrophage apoptosis induced by Ox LDLs is not yet clearly understood. In this study, a model of RAW264.7 macrophages exposed to an Ox LDL analogue, i.e. tert-butylhydroperoxide (t-BHP), was established. We thoroughly evaluated the viability and apoptosis of RAW264.7 cells treated with t-BHP at different time intervals. t-BHP treatment decreases the viability of RAW264.7 cells in a dose- and time-dependent manner (IC50: 400 MUM) and also induces a loss of the mitochondrial membrane potential (MMP) in RAW264.7 cells. Moreover, the activation of Bid, up-regulation of Bcl-2, and down regulation of Bax, as well as the proteolysis of pro-caspase 3 and cleavage of PARP, were all also observed in t-BHP treated RAW264.7 cells. Finally, we concluded that t-BHP induces the apoptosis of macrophages via a mitochondria mediated signaling pathway. PMID- 30310675 TI - A 90-day subchronic toxicity study of submerged mycelial culture of Cordyceps militaris in rats. AB - Cordyceps militaris (C. militaris) is a parasitic fungus that grows on the larvae of Lepidoptera. It is a well-known fungus with immunomodulatory activity. The study was conducted to clarify the edible safety of C. militaris mycelium for long term use. Eighty Sprague-Dawley (SD) rats were divided into four groups (10 males and 10 females in each group). Rats were orally administrated with reverse osmosis water or 2000, 3000 and 4000 mg per kg BW per day freeze dried C. militaris mycelium powder for 90 consecutive days. Clinical observation was carried out daily. The body weight and feed intake of the rats were recorded weekly. At the end of the study, all rats were sacrificed and the blood and organs were collected for hematology, clinical biochemistry and histopathological examination. All animals survived until the end of the study. During the study period, no abnormality occurred in clinical signs, body weight, feed intake, ophthalmological examination and urinalysis. There were no significant differences upon gross necropsy between the treatment and control group. Hematology, clinical biochemistry parameters and histopathological examination showed no treatment-related change. According to the results, the no-observed adverse-effect level of C. militaris mycelium is 4000 mg per kg BW per day for male and female SD rats. PMID- 30310677 TI - Correction: Goodbye to the bioassay. AB - [This corrects the article DOI: 10.1039/C8TX00004B.]. PMID- 30310678 TI - Fibro-osseous pseudotumor of the digit: Case report and surgical experience with extensive digital lesion abutting on neurovascular bundles. AB - Background: Fibro-osseous pseudotumor (FOPD) of the digit is a rare benign lesion of subcutaneous tissue characterized by fibroblastic proliferation and osteoid formation. Herein, we present a case of massive FOPD lesion in the base of ring finger with extensive involvement of the neurovascular bundles with challenging surgical approach. Case description: A 27-year old female patient, presented with 7-months history of a progressively enlarging mass on her left hand. Upon assessment, the mass was located over the proximal phalanx of the left ring finger with extensive involvement of the 4th web space. Her neurovascular examination was normal. Radiological investigations showed partial involvement of the radial sided bundle together with complete involvement of the ulnar sided neurovascular bundle. The patient was bothered by the mass being painful with overlying skin ulceration. She was taken afterwards to the operating room where the mass was dissected freely from those bundles while preserving the radial and ulnar structures. The resected margins were however, positive for residual lesions due to the extensive nature of the mass. The patient was informed about the need for close follow-ups for both clinical and radiological signs of lesion recurrence pending early surgical intervention. Conclusion: FOPD although benign, a soft tissue osteosarcoma is one of the differential diagnosis. Meticulous attention to the clinical, pathological and histological features of FOPD is required. Early diagnosis and treatment of FOPD is very crucial in optimizing the overall outcome. Pre-operative planning with various radiological modalities was of great help anticipating the surgical course. PMID- 30310676 TI - Less toxic zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes derived from 2-benzoylpyridine N,N-dimethylthiosemicarbazone: synthesis, crystal structures, cytotoxicity and investigations of mechanisms of action. AB - Four metal complexes based on 2-benzoylpyridine N,N-dimethylthiosemicarbazone (Bp44mT) were designed. Free ligand and zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes all demonstrated pronounced activity, which was indicated using the growth inhibition test in vitro. Interestingly, most of the compounds were found to be selective against hepatocellular carcinoma (HepG2) cells but had little effect on normal hepatocyte (QSG7701) cells. In particular, Zn(Bp44mT)2 (1) exhibited toxicity on QSG7701 cells which approximately 12-fold lower than that on HepG2 cells. The studies of mechanisms of action indicated that 1 induced reactive oxygen species (ROS) generation in a dose-dependent manner via the mitochondria transduction pathway. Protein analyses showed that 1 significantly promoted p21 and p53 gene expression, causing caspase-3 activation. PMID- 30310679 TI - Acute kidney injury increases the rate of major morbidities in cytoreductive surgery and HIPEC. AB - Introduction: Acute kidney injury (AKI) following cardiovascular surgery has been shown to increase costs and overall morbidity and mortality. The incidence, risk factors, and outcomes of AKI following other types of major surgeries have not been as well characterized. We sought to study the incidence of AKI following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) per the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Materials and methods: Patients undergoing CRS and HIPEC between 2013 and 2015 were included. Demographic and perioperative data were compared between patients who experienced AKI versus controls using appropriate statistical analysis between categorical and continuous variables. AKI was recorded by a Certified Professional in Healthcare Quality (CPHQ) and defined as a rise in serum creatinine by >= 0.3 mg/dL within 48 h (KDIGO criteria). Results: Fifty-eight consecutive patients undergoing CRS and HIPEC were included. Twelve (20.7%) patients were recorded to develop AKI. This was the most common complication recorded by the CPHQ member. There was one 30-day mortality secondary to cerebral infarction. AKI patients had a longer hospitalization period (14.2 +/- 6.9 vs. 9.5 +/- 3.3 days, p = 0.002), and a higher rate of major complications (50.00% vs. 15.21%; p = 0.018). Readmission rate was similar (p = 0.626). Multivariate regression identified excessive blood loss during surgery as a major predictor of AKI occurrence, and pre-existing comorbidities and postoperative AKI as predictors of major morbidities following CRS and HIPEC. Conclusion: AKI following CRS and HIPEC appears to be a common complication which is associated with further major morbidities. Current quality improvement programs may be under-reporting this incidence. PMID- 30310680 TI - Trueperella bernardiae: an unusual cause of septic thrombophlebitis in an injection drug user. AB - The clinical spectrum of human disease caused by Trueperella bernardiae is poorly described, partly as a result of historical difficulties with microbial identification. With the introduction of powerful new technologies, such as matrix-assisted desorption ionization-time of flight mass spectrometry, into routine microbiology laboratories, new insights into diseases caused by such organisms are being made. Here we report a case of septic thrombophlebitis with bacteraemia caused by this organism, together with a retrospective description of laboratory isolation of this organism over a period of 6 years in a hospital in London, UK. PMID- 30310681 TI - Epidermal growth factor receptor mutated oligometastatic adeno-squamous lung cancer transformation to small cell lung cancer. AB - A 66-year-old non-smoker was diagnosed with stage IIIB, epidermal growth factor receptor (EGFR) mutated, squamous cell lung carcinoma. Treatment included chemotherapy, 35 fractions of radiotherapy and later Gefitinib for 3.5 years. On progression he developed a solitary brain and liver lesion. The brain lesion was excised and histology revealed adenocarcinoma of a lung primary. Afatanib was commenced for 1 further year. At the second time of progression re-biopsy identified small cell carcinoma. He completed four cycles of Carboplatin and Etoposide however deteriorated on completion of chemotherapy. EGFR directed treatment is associated with improved patient outcomes. It has been suggested that EGFR mutated squamous cell carcinoma more likely represent mixed morphology or poorly differentiated adenocarcinoma. Patients with oligometastatic progression can be treated beyond progression however the addition of a local therapy may be required. Small cell transformation is described as a rare mechanism of resistance to EGFR treatment as in our case. PMID- 30310683 TI - Preface from European Respiratory Society President 2018 Mina Gaga and European Respiratory Society Early-Career Member Committee Chair Lieuwe D. J. Bos. PMID- 30310682 TI - Estimating the mutational fitness effects distribution during early HIV infection. AB - The evolution of HIV during acute infection is often considered a neutral process. Recent analysis of sequencing data from this stage of infection, however, showed high levels of shared mutations between independent viral populations. This suggests that selection might play a role in the early stages of HIV infection. We adapted an existing model for random evolution during acute HIV-infection to include selection. Simulations of this model were used to fit a global mutational fitness effects distribution to previously published sequencing data of the env gene of individuals with acute HIV infection. Measures of sharing between viral populations were used as summary statistics to compare the data to the simulations. We confirm that evolution during acute infection is significantly different from neutral. The distribution of mutational fitness effects is best fit by a distribution with a low, but significant fraction of beneficial mutations and a high fraction of deleterious mutations. While most mutations are neutral or deleterious in this model, about 5% of mutations are beneficial. These beneficial mutations will, on average, result in a small but significant increase in fitness. When assuming no epistasis, this indicates that, at the moment of transmission, HIV is near, but not on the fitness peak for early infection. PMID- 30310684 TI - Novel insights into the effects of cigarette smoke on the airway epithelial surface-lessons learned at the European Respiratory Society International Congress 2018 in Paris. PMID- 30310685 TI - New players in chronic lung disease identified at the European Respiratory Society International Congress in Paris 2018: from microRNAs to extracellular vesicles. PMID- 30310686 TI - Clinical physiology and sleep: highlights from the European Respiratory Society Congress 2018 presented by early career members. PMID- 30310687 TI - Airways diseases: asthma, COPD and chronic cough highlights from the European Respiratory Society Annual Congress 2018. PMID- 30310688 TI - Highlights from the European Respiratory Society 2018 Annual Congress: environment and epidemiology (assembly 6). PMID- 30310689 TI - European Respiratory Society International Congress 2018: insights from the paediatric assembly. PMID- 30310690 TI - Insights from the European Respiratory Society 2018 Annual International Congress in the fields of thoracic surgery and lung transplantation. PMID- 30310692 TI - Respiratory infection: insights from assembly 10 of the European Respiratory Society 2018 Annual Congress. PMID- 30310691 TI - European Respiratory Society International Congress best abstract preview from the allied respiratory professionals from assembly 9. PMID- 30310693 TI - Abstracts from the European Respiratory Society Annual Conference 2018 on Thoracic Oncology. PMID- 30310694 TI - Highlights from the 2018 European Respiratory Society Congress presentations on interstitial lung diseases. PMID- 30310695 TI - Key topics in pulmonary vascular diseases (assembly 13) from the European Respiratory Society 2018 Parisian Congress. PMID- 30310696 TI - Preview of highlighted presentations from the European Respiratory Society' clinical assembly. PMID- 30310697 TI - Normative Values of Peripapillary Retinal Nerve Fiber Layer Thickness in a Middle Eastern Population. AB - Purpose: Peripapillary retinal nerve fiber layer (pRNFL) thickness is subject to high variability. Normative values of pRNFL thickness remain undocumented in the Middle East. The aim of our study is to assess the normative values of pRNFL thickness in a Middle Eastern population. Methods: A retrospective chart review of 74 patients was conducted. Outpatients who had presented to the ophthalmology clinic at the Jordan University Hospital between January 2016 and July 2018 were consecutively sampled. Measurements had been recorded using Fourier-domain optical coherence tomography. Multivariable regression models were developed to generate predicted normative values with adjustments to candidate confounders. Results: The mean global pRNFL thickness was 99 +/- 11 MUm. The mean quadrantic pRNFL thickness increased from the nasal quadrant (75 +/- 16 MUm) to the temporal (82 +/- 20 MUm), superior (114 +/- 20 MUm), and inferior (125 +/- 20 MUm) quadrants. Gender and eye sidedness did not contribute to the variability in pRNFL thickness. The relationship between aging and pRNFL thinning is independent of diabetes mellitus type 2 and systemic hypertension. Both systemic conditions significantly predicted pRNFL changes despite negative fundoscopic findings. Conclusions: Our set of predicted normative data may be used to interpret measurements of pRNFL thickness in Middle Eastern patients. Our findings suggest that systemic conditions with potential ocular manifestations may require consideration in predictive models of pRNFL thickness, even in the absence of gross fundoscopic findings. Normative data from additional Middle Eastern populations are required to appraise our models, which adjust for common clinical confounders. PMID- 30310698 TI - Effects of Oral Supplementation with Docosahexaenoic Acid (DHA) plus Antioxidants in Pseudoexfoliative Glaucoma: A 6-Month Open-Label Randomized Trial. AB - Purpose: To assess the effects of antioxidant oral supplementation based on docosahexaenoic acid (DHA) in pseudoexfoliative (PEX) glaucoma. Patients and Methods: A prospective 6-month open-label randomized controlled trial was conducted in patients with PEX glaucoma and adequate intraocular pressure (IOP) control. Patients in the DHA group received a high-rich DHA (1 g) nutraceutical formulation. Ophthalmological examination, DHA erythrocyte membrane content (% total fatty acids), plasma total antioxidant capacity (TAC), plasma malondialdehyde (MDA), and plasma IL-6 levels were assessed. Results: Forty-seven patients (DHA group 23, controls 24; mean age 70.3 years) were included. In the DHA group, the mean IOP in the right eye decreased from 14.7 [3.3] mmHg at baseline to 12.1 [1.5] mmHg at 6 months (P=0.01). In the left eye, IOP decreased from 15.1 [3.3] mmHg at baseline to 12.2 [2.4] mmHg at 6 months (P=0.007). DHA erythrocyte content increased in the DHA group, with significant differences versus controls at 3 months and 6 months (8.1% [0.9] vs. 4.4% [0.7]; P < 0.0001). At 6 months and in the DHA group only, TAC levels as compared with baseline increased significantly (919.7 [117.9] vs. 856.9 [180.3] uM copper-reducing equivalents; P=0.01), and both MDA (4.4 [0.8] vs. 5.2 [1.1] nmol/mL; P = 0.02) and IL-6 (2.8 [1.3] vs. 4.7 [2.3] pg/mL; P=0.006) levels were lower than in controls. Conclusions: Targeting pathophysiology mechanisms of PEX glaucoma by reducing oxidative stress and inflammation with a high-rich DHA supplement might be an attractive therapeutic approach. Despite the short duration of treatment, decrease in IOP supports the clinical significance of DHA supplementation. PMID- 30310699 TI - Trends in Route of Hysterectomy after the Implementation of a Comprehensive Robotic Training Program. AB - Objective: To evaluate trends in surgical approach for hysterectomy following the introduction and implementation of a comprehensive robotic surgery program. Methods: A retrospective review of all hysterectomies done at two institutions, a community hospital and a suburban, tertiary-care teaching hospital, in the same health system over a five-year period, January 2010 through December 2014. A robotic surgery training program was implemented during the first year of the study and trends in route of hysterectomy were evaluated in the subsequent years. Results: A total of 5175 patients undergoing hysterectomy, for both benign and malignant indications, were included in the study. There was a significant decrease in the percent of cases performed through an abdominal approach at both the community and teaching hospitals (19.3% decline at each institution). There was an inversely related significant increase in the percent of robotic procedures at both the community and teaching hospitals (44.5% and 17%, respectively). A decrease in number of cases performed vaginally over this period was only noted in the community hospital site (25.2% decrease), and there was a slightly higher rate of vaginal hysterectomies at the teaching hospital over this study period (21.9% in 2010, 24.1% in 2014). Conclusion: The decrease in number of abdominal and laparoscopic hysterectomies and increase in number of robotic hysterectomies that was seen are consistent with national trends. The initiation of a robotic training program did not prevent the proliferation of use of the robot but did aim to ensure proficiency on the robot prior to gaining privileges for patient use. This type of comprehensive training and monitoring program could be applied to future technologic advances to ensure a standard level of surgical proficiency. Trends in route of hysterectomy are clearly multifactorial and involve patient, provider, and location-specific factors that are likely to continue to change. PMID- 30310700 TI - Improved Value of Individual Prenatal Care for the Interdisciplinary Team. AB - Objective: Innovative models of prenatal care are needed to improve pregnancy outcomes and lower the cost of care. We sought to increase the value of traditional prenatal care by using a new model (PodCare) featuring a standardized visit schedule and coordination of care within small interdisciplinary teams in an academic setting. Methods: Prenatal providers and clinic staff were divided into four "Pods". Testing and counseling topics were assigned to visits based on gestational age. Interdisciplinary weekly Pod meetings provided coordination of care. A retrospective chart review was performed. The primary endpoints were the number of prenatal care visits and number of providers seen. Results: After PodCare implementation, more patients choose care with the low-risk physician team (42% compared to 26%). Study subjects included 85 women in 2013 and 165 women in 2014. The median number of visits decreased from 13 to 10 (p < 0.00004) and the median number of providers seen decreased from 7 to 5 (p < 0.0000008). Conclusion: PodCare increased the value of individual prenatal care by decreasing the number of visits, increasing continuity, and providing care coordination. The model provides a robust experience in interdisciplinary care. The PodCare model may be successful at other academic institutions. PMID- 30310701 TI - Treatment of Chronic Hepatitis C Can Improve Glycemic Control in Patients with Type 2 Diabetes. AB - A 73-year-old female patient with a history of type 2 DM for seven years was admitted to our out-patient clinic with a complaint of frequent hypoglycemic episodes. She was receiving basal- bolus insulin treatment. She underwent liver transplantation 20 months ago due to end stage liver disease caused by HCV infection genotype 1b. While she was still on tacrolimus for liver transplantation, she received direct acting antiviral agents including fix dose ledipasvir-sofosbuvir with ribavirin. Biochemical analysis showed fasting plasma glucose of 105 mg/dl and postprandial glucose of 200 mg/dl, glycosylated hemoglobin A1c of 4.8%, and c-peptide of 3.17 ng/ml. After achieving successfully virologic response with antiviral therapy, the patient stayed euglycemic and was no longer in need to any medication including insulin and the patient was followed only by dietary regulation. Achievement of the virological response in treatment of HCV infection can improve not only the liver status, but also the extrahepatic manifestations including type 2 DM. PMID- 30310702 TI - Aggressive Metastatic GATA3-Positive Sarcomatoid Carcinoma with Rapid Progression and Invasion of the Liver. AB - Objective. GATA3-positive sarcomatoid carcinoma has never been documented in the past. It is a case of aggressive tumor, positive for GATA3, which should be further studied for its prognostic and therapeutic significance. PMID- 30310703 TI - Iterative Rupture of the Patellar Tendon: A Case Report of an Original Technique for Revision Reconstruction Using an Adjustable Loop and an Artificial Ligament. AB - Chronic rupture of the patellar tendon is a severe injury that leads to dramatic functional consequences including lack of extension and walking difficulty. Surgery is the gold standard to treat this type of injury, but revision reconstructions are problematic because an ipsilateral graft was often harvested for the initial surgery. Because fibrotic tissues on the patellar tendon need to be debrided, another graft must be added to reinforce the tendon. We reported the case of a former semiprofessional handball player, a 29-year-old man who presented an iterative rupture with the fracture of the transverse patellar tunnel 6 months after reconstruction using a semitendinosus graft and suture repair. We performed revision reconstruction surgery using an artificial ligament placed between the extensor mechanism and the tibia for extra-articular reinforcement to maintain extensor mechanism continuity. Two adjustable loops were also used to repair the patellar tendon tear. At 2-year follow-up, the patient was able to resume the practice of handball at a competitive level with good clinical and functional results. This technique can therefore be used as a salvage procedure for chronic iterative rupture of the patellar tendon. PMID- 30310704 TI - Raloxifene Has No Efficacy in Reducing the High Bone Turnover and the Risk of Spontaneous Vertebral Fractures after Denosumab Discontinuation. AB - At denosumab discontinuation, an antiresorptive agent is prescribed to reduce the high bone turnover, the rapid bone loss, and the risk of spontaneous vertebral fractures. We report the case of a woman treated with aromatase inhibitors and denosumab for 5 years. Raloxifene was then prescribed to prevent the rebound effect. Raloxifene was ineffective to reduce the high bone turnover and to avoid spontaneous clinical vertebral fractures. We believe that among the antiresorptive treatments, the most powerful bisphosphonates should be favored, and their administration adapted according to the serial follow-up of bone markers. PMID- 30310705 TI - Variations in the branching pattern of the celiac trunk and its clinical significance. AB - Celiac trunk is the artery of foregut, arising from the abdominal aorta at the level of T12/L1 vertebral body. It extends approximately 1.5 to 2 cm horizontally forwards before dividing into three branches: left gastric, common hepatic, and splenic arteries. Out of the three ventral branches of abdominal aorta, celiac trunk is more prone to have variations. During routine dissection of abdomen for undergraduate students we found some rare variations in the branching pattern of the celiac trunk. Absence of celiac trunk with hepatomesenteric trunk, quadrifurcation with dorsal pancreatic artery arising from it, quadrifurcation with middle colic artery arising from it, left inferior phrenic artery arising from celiac trunk, highly tortuous splenic artery supplying distal 1/3rd of transverse colon and hepatosplenic trunk. Knowledge of such variations is essential for liver and pancreas transplantations, pancreaticoduodenectomy, radiological abdominal interventions, laproscopic surgeries, and in trauma of the abdomen. PMID- 30310706 TI - Development of the pulmonary pleura with special reference to the lung surface morphology: a study using human fetuses. AB - In and after the third trimester, the lung surface is likely to become smooth to facilitate respiratory movements. However, there are no detailed descriptions as to when and how the lung surface becomes regular. According to our observations of 33 fetuses at 9-16 weeks of gestation (crown-rump length [CRL], 39-125 mm), the lung surface, especially its lateral (costal) surface, was comparatively rough due to rapid branching and outward growing of bronchioli at the pseudoglandular phase of lung development. The pulmonary pleura was thin and, beneath the surface mesothelium, no or little mesenchymal tissue was detectable. Veins and lymphatic vessels reached the lung surface until 9 weeks and 16 weeks, respectively. In contrast, in 8 fetuses at 26-34 weeks of gestation (CRL, 210-290 mm), the lung surface was almost smooth because, instead of bronchioli, the developing alveoli faced the external surfaces of the lung. Moreover, the submesothelial tissue became thick due to large numbers of dilated veins connected to deep intersegmental veins. CD34-positive, multilayered fibrous tissue was also evident beneath the mesothelium in these stages. The submesothelial tissue was much thicker at the basal and mediastinal surfaces compared to apical and costal surfaces. Overall, rather than by a mechanical stress from the thoracic wall and diaphragm, a smooth lung surface seemed to be established largely by the thick submesothelial tissue including veins and lymphatic vessels until 26 weeks. PMID- 30310707 TI - From dentistry students' points of view: do anatomy classes we took actually boost our learning during clinic? AB - The aim of medical education is to teach the essence of practical skills alongside with the theoretical knowledge. Teaching anatomy, as the center of medical education, should be leading to use this knowledge as a skill during clinical period. According to the rising numbers of dentistry faculties' experiences, inappropriate education results in misguidance during clinic. Thus, this study was conducted to find about the pre-clinical and clinical dentistry students' points of view on the helpfulness of anatomy classes in achieving clinical goals. Present descriptive cross-sectional study evaluated Guilan University of Medical Sciences' pre-clinical and clinical dentistry students' opinions on the effectiveness of anatomy classes during their clinical period in 2017. The sampling method used here was census via questionnaire and scoring was according to Likert scaling system. Analyses showed that anatomy of the nervous system was the most assistive course, which helped dentistry students during their clinical period (P<0.001). The least scored course was visceral organs and that means they did not use most of their learnings from classes with this topic (P<0.001). They also stated that other important factors such as using cadavers and moulages in practical sessions, teaching clinical skills theoretically before practical sessions and performing group activities are crucial for them to recall important details of the relevant courses during clinical period. Results of this study suggests that alongside with the various topics of anatomy courses, other factors like professors' characteristics and their teaching methods are also of important factors helping the dentistry students throughout clinic. PMID- 30310708 TI - Anatomical and radiological angiographic study of the coronary ostia in the adult human hearts and their clinical significance. AB - This study was carried out to investigate the morphometric parameters and variations of coronary ostia in the hearts of adult human cadavers and coronary angiographs. The hearts of 60 adult human cadavers and 400 coronary angiographs were used in this study. The root of the aorta was carefully dissected to clear aortic sinuses, coronary ostia, and sinutubular junction (STJ). Number, locations, internal diameter distance between coronary ostia and their corresponding STJ, sinus bottom, and valve commissures were investigated. The anterior aortic sinus (AAS) revealed a single ostium for right coronary artery (RCA) in 77.5% of male and 80% of female hearts. This ostium gave a common origin for RCA and third coronary artery (TCA) in 15% of male and 20% of female hearts. However, two separate ostia for RCA and TCA origin were seen in 20% of male and 15% of female hearts. Moreover, three ostia were seen in one male and one female hearts within AAS. Meanwhile, the left posterior aortic sinus showed a single ostium for left coronary artery (LCA) in 97.5% of male and 95% of female hearts and two ostia in one male and one female hearts. The ostia were commonly seen below STJ and less commonly were observed above STJ. The distance between the bottom of aortic sinus and LCA ostium was longer than that of RCA. The internal diameter of RCA ostium was significantly (P<0.05) narrower than that of LCA but with no significant sex difference. Moreover, anomalous of coronary ostia was observed in seven out 400 angiographs and in two cadaveric hearts. Knowledge the morphometric parameters and anatomical variations of coronary ostia helps the cardiac surgeons to overcome the possible difficulties that could occur during surgical and radiological coronary interventions. PMID- 30310709 TI - Prevalence of diffuse idiopathic skeletal hyperostosis among elderly subjects referred for radiological investigation in tertiary hospital at Oman. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by calcification of different entheseal sites including the anterior longitudinal ligament of the spine. There is no documented information about DISH in Oman. This study determined the prevalence of DISH and associated factors among elderly subjects in a national tertiary care referral hospital in Oman. This retrospective study reviewed chest X-rays of all patients aged more than 50 years, referred to the radiology department of Sultan Qaboos University Hospital in the year 2016, based on the Resnick's criteria. The prevalence was expressed as proportions across age groups and sex. Chi-square test and logistic regression analysis was done to determine the association of the age and sex with DISH. A total of 1305 chest X rays of patients were reviewed. The overall prevalence of DISH was 10%, with male to female ratio of 1.56:1. The odds ratio for males and increasing age were 1.63 (95% confidence interval [CI], 1.12-2.3; P<0.05) and 1.34 (95% CI, 1.14-1.58; P<0.001) respectively. The prevalence increased with age to maximum of 13% in the age group of <=80. The pre-stage DISH prevalence was 9.3% and more frequently observed among males. Prevalence of DISH in the national tertiary care referral center in Oman is lower than in Jewish population, almost similar to Japanese, but higher than in Koreans. DISH prevalence is positively associated with age and sex. It is necessary to take appropriate precautionary measures to target the ageing population in Oman, especially elderly males. PMID- 30310710 TI - Stem cell transplantation and functional recovery after spinal cord injury: a systematic review and meta-analysis. AB - Spinal cord injury is a significant cause of motor dysfunctions. There is no definite cure for it, and most of the therapeutic modalities are only symptomatic treatment. In this systematic review and meta-analysis, the effectiveness of stem cell therapy in the treatment of the spinal cord injuries in animal models was studied and evaluated. A systematic search through medical databases by using appropriate keywords was conducted. The relevant reports were reviewed in order to find out cases in which inclusion and exclusion criteria had been fulfilled. Finally, 89 articles have been considered, from which 28 had sufficient data for performing statistical analyses. The findings showed a significant improvement in motor functions after cell therapy. The outcome was strongly related to the number of transplanted cells, site of injury, chronicity of the injury, type of the damage, and the induction of immune-suppression. According to our data, improvements in functional recovery after stem cell therapy in the treatment of spinal cord injury in animal models was noticeable, but its outcome is strongly related to the site of injury, number of transplanted cells, and type of transplanted cells. PMID- 30310711 TI - Exogenous spermidine ameliorates tubular necrosis during cisplatin nephrotoxicity. AB - The hallmark of cisplatin-induced acute kidney injury is the necrotic cell death in the kidney proximal tubules. However, an effective approach to limit cisplatin nephrotoxicity remains unknown. Spermidine is a polyamine that protects against oxidative stress and necrosis in aged yeasts, and the present study found that exogenous spermidine markedly attenuated tubular necrosis and kidney dysfunction, but not apoptosis, during cisplatin nephrotoxicity. In addition, exogenous spermidine potently inhibited oxidative/nitrative DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) activation and ATP depletion after cisplatin injection. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly increased DNA damage, PARP1 activation and ATP depletion, resulting in acceleration of tubular necrosis and kidney dysfunction. Finally, exogenous spermidine removed severe cisplatin injury induced by ODC inhibition. In conclusion, these data suggest that spermidine protects kidneys against cisplatin injury through DNA damage and tubular necrosis, and this finding provides a novel target to prevent acute kidney injury including nephrotoxicity. PMID- 30310712 TI - A young couple's grave found in the Rakhigarhi cemetery of the Harappan Civilization. AB - The Harappan Civilization, one of the earliest complex societies in the world, flourished on the Indian subcontinent. Although many additional Harappan settlements and cemeteries have been discovered and investigated, no coupled burials at Harappan cemeteries have been reported to date. In 2013-2016, we excavated the cemetery of the Rakhigarhi site (Haryana), the largest city of the Harappan Civilization. At the site, we found a grave that turned out to be a coupled (joint) burial of the primary type. This report is the first anthropologically confirmed case of coupled burial from a Harappan cemetery. PMID- 30310713 TI - Exploration of the fetus with gross anomaly: a case of pseudo prune belly syndrome. AB - Prune belly syndrome is a rare congenital anomaly usually presented with triad characteristic feature of deficient abdominal muscles, cryptorchidism, and urinary tract anomalies. Here, we present a case with all the characteristic features of prune belly and the associated secondary features which were observed on detailed dissection and exploration of the fetus. PMID- 30310715 TI - A rare double profunda femoris artery in a female cadaver. AB - The profunda femoris artery (PFA) represents the first and largest branch of the femoral artery in the thigh. A series of anatomical variations are reported, mostly concerning its point of origin and its altered trajectories within the lower limb. We present a rare case of a double PFA, where each separate branch followed the expected arterial pattern. Our case aim to alert surgeons and radiologists for the possibility to encounter an unexpected vascular alternation. Knowledge of topographical anatomy of the PFA and its variations is essential for possible complications after interventional procedures to be avoided. PMID- 30310714 TI - Double pouched, sigmoid gallbladder that can cause a diagnostic dilemma to radiologists: a case report. AB - Gallbladder shows frequent variations in position, shape, interior, and its duct system. These variations may go unnoticed lifelong; however, they may predispose it for cholecystitis and cholelithiasis. We observed a double pouched gallbladder in an adult male cadaver. The gallbladder was folded to have a sigmoid shape. It had two broad pouches: anterior and posterior and a narrow isthmus in between. Its anterior pouch was covered by peritoneum, whereas the posterior pouch was covered by extrahepatic connective tissue. We discuss the clinical and radiological importance of the case. PMID- 30310717 TI - Persistent right umbilical vein: a study using serial sections of human embryos and fetuses. AB - Persistent right umbilical vein (PRUV) is a common anomaly of the venous system. Although candidates for future PRUV were expected to occur more frequently in earlier specimens, evaluation of serial horizontal sections from 58 embryos and fetuses of gestational age 5-7 weeks found that only two of these embryos and fetuses were candidates for anomalies. In a specimen, a degenerating right umbilical vein (UV) joined the thick left UV in a narrow peritoneal space between the liver and abdominal cavity, and in the other specimen, a degenerating left UV joined a thick right UV in the abdominal wall near the liver. In these two specimens, the UV drained into the normal, umbilical portion of the left liver. These results strongly suggested that, other than the usual PRUV draining into the right liver, another type of PRUV was likely to consist of the right UV draining into the left liver. PMID- 30310716 TI - Right and left common carotid arteries arising from the branchiocephalic, a rare variation of the aortic arch. AB - The aortic arch may present a plethora of anatomical variations, which my cause a cluster of complications in interventional procedures in surgery and angiography. We present a rare case of a common origin of both the common carotids arteries from the brachiocephalic trunk (anonymous artery), with the left common carotid artery emerging from the initial portion of it, forming a small common trunk. The great importance towards an excellent knowledge of the topographical aortic arch anatomy is stressed out. PMID- 30310718 TI - Erratum: Interobserver and intraobserver reliability of different methods of examination for presence of palmaris longus and examination of fifth superficial flexor function. AB - [This corrects the article on p. 79 in vol. 51, PMID: 29984051.]. PMID- 30310719 TI - Breast Implants and Lymphoma: What Is the Risk for Your Patient? PMID- 30310720 TI - Assessing the Plain Language Planner for Communication About Common Palliative Care Medications. AB - Using plain language to communicate about oncology and palliative care medications and symptoms is recommended as a communication strategy to address patient/family health literacy demands. This study tested the Plain Language Planner(c), a provider tool for communicating about medication and symptoms using plain language. Prior to and immediately following an oncology and palliative care nurse educational session, participants (n = 87) role-played about a symptom and medication. Common symptoms (nausea, constipation, and anxiety) and medications were selected. Self-evaluation and peer evaluation addressing the extent of plain language used during the role-play were rated. Plain language characteristics improved post educational role-play sessions for nurses. The largest improvement in plain language was the inclusion of the brand and generic names of medication in relating the drug to the symptom. The pocket guide provided during the educational session was consulted by 86% of nurses during the postsession role-play. Brief training with the Plain Language Planner may improve provider communication and meet patient/family health literacy needs. This resource may be a valuable asset to other health-care disciplines working in oncology and palliative care contexts. PMID- 30310723 TI - Brentuximab Vedotin Infusion Reaction Management: A Case Study. AB - We report a case of a grade 3 (Common Terminology Criteria for Adverse Events [CTCAE]) infusion reaction to brentuximab vedotin (Adcetris), in a patient with refractory Hodgkin lymphoma, at a large National Cancer Institute-designated cancer center in the Midwest (National Cancer Institute, 2010). Acute infusion reaction management and subsequent premedication strategies are outlined. Ms. R is a 30-year-old woman who presented with stage IV Hodgkin lymphoma at the age of 29. Initial staging revealed lymphadenopathy above and below the diaphragm, as well as fluorodeoxyglucose (FDG)-avid lung lesions, splenic lesions, and multiple sites of bony involvement. Bone marrow biopsy was negative. She was treated with six cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), to which she obtained a complete response by positron emission tomography-computed tomography (PET-CT) criteria. Ten months after chemotherapy completion, she presented with new PET-avid adenopathy in the cervical and paratracheal regions, and a biopsy revealed recurrent Hodgkin lymphoma. Salvage chemotherapy was administered with ifosfamide carboplatin, and etoposide (ICE). After two cycles of salvage chemotherapy, a PET-CT confirmed a complete response, and she proceeded to an autologous stem cell transplant with a preparative regimen of carmustine, etoposide, cytosine arabinoside, and melphalan (BEAM). Brentuximab vedotin consolidation therapy was prescribed in the post transplant consolidation setting, beginning 45 days after stem cell reinfusion, given the patient's high risk for recurrence. This strategy was based upon the results of the AETHERA phase III clinical trial (Moskowitz et al., 2015), showing improvement in progression-free survival with brentuximab vedotin consolidation therapy, post autologous transplant. The first dose of brentuximab vedotin was administered without difficulty, at full dose (1.8 mg/kg) at a standard infusion time of 30 minutes. The second dose of brentuximab vedotin was complicated by nausea, chest pain, and dysphagia within 10 minutes of medication initiation. Upon the emergence of these symptoms, the brentuximab vedotin infusion was held. Vital signs were stable, with a temperature of 36.9C, pulse 84, respirations of 20, and blood pressure of 107/67 mm Hg. Oxygen saturations were 99% on room air. Diphenhydramine (50 mg) was administered intravenously (IV), along with 20 mg of IV famotidine. An electrocardiogram (ECG) was obtained, which was unremarkable, showing normal sinus rhythm. Fifteen minutes later, the symptoms of chest pain and shortness of breath persisted, so hydrocortisone at 100 mg IV was administered, with an additional 25 mg of IV diphenhydramine and 20 mg of IV famotidine. Intraveous granisetron was given for nausea. Thirty minutes after onset, the chest pain was persistent, and oxygen saturations were normal. Hydrocortisone (50 mg) was administered intravenously, and Ms. R's condition improved, with resolution of her symptoms within 30 minutes of the second hydrocortisone dose. The brentuximab vedotin was restarted 30 minutes after symptom resolution at a decreased infusion rate to be administered over 60 minutes. Thirty minutes later, however, Ms. R developed tingling and numbness in her feet and tongue. The brentuximab vedotin infusion was again held, and 100 mg of IV methylprednisolone was administered. Ms. R's symptoms resolved within 40 minutes, and the brentuximab vedotin infusion was able to be continued over a prolonged period of more than 4 hours. Vital signs were checked every 15 minutes during the infusion reaction and remained stable throughout. The infusion was discontinued with 40 mg of drug remaining, due to the prolonged infusion time. Given the clear benefits of brentuximab consolidation in improving progression free survival post transplant (Moskowitz et al., 2015) in high-risk Hodgkin lymphoma, it was thought the benefit of brentuximab vedotin consolidation outweighed the possible risks of subsequent infusions. Upon reviewing the available literature regarding brentuximab vedotin hypersensitivity reactions, which will be outlined in the discussion summary, we instituted the premedication strategy for subsequent infusions outlined in the Table on p 628. Standard epinephrine and methylprednisolone were available at the bedside in the event of any anaphylactic reaction. This regimen was chosen based on the clinical rationale for H1 and H2 blockade, as well as corticosteroid and antipyretic coverage, in the prevention of hypersensitivity reactions, not classified as anaphylaxis. With the institution of the outlined premedications, Ms. R tolerated subsequent infusions well, at full dose and at standard infusion rates, with no documented infusion reactions, and was able to complete a total of 16 cycles of consolidation therapy. PMID- 30310721 TI - Cancer Pain Management: Opioid Analgesics, Part 2. AB - Opioid analgesics are the cornerstone of moderate to severe cancer pain management, and do not have ceiling doses unless unmanageable adverse effects occur. Oral, short-acting pure MU agonists such as morphine are most frequently used, but other agents and administration formulations allow finding the right opioid and dose for most patients. In addition, clinicians must understand the metabolism, pharmacokinetics, and elimination of particular drugs to individualize opioid selection, select initial doses, and appropriately escalate doses to satisfactory pain relief or uncontrollable toxicity. Anticipation and proactive management of possible adverse effects, particularly constipation, confusion or delirium, opioid-specific adverse effects, and opioid abuse, are also integral to primary and secondary prophylaxis and management. PMID- 30310724 TI - Role of the Advanced Practice Provider in Clinical Trials: Contributions to the Management of Patients Receiving Inotuzumab Ozogamicin. PMID- 30310725 TI - Advice About Screening for Prostate Cancer With Prostate-Specific Antigen. PMID- 30310722 TI - Managing Drug Interactions in Cancer Therapy: A Guide for the Advanced Practitioner. AB - Mrs. P is a 30-year-old woman who presented to our bone marrow transplant program with myelodysplastic syndrome (MDS). She received a haploidentical allogeneic stem cell transplant with a conditioning regimen consisting of busulfan and cyclophosphamide. This treatment was followed by post-transplant immunosuppression for graft-versus-host disease (GVHD) with cyclophosphamide, mycophenolate mofetil (MMF), and tacrolimus (see Table 1 for medication list). Tacrolimus levels were monitored twice a week with adjustment to a goal range of between 5 and 10 ng/mL. We initiated tacrolimus at a dose of 0.03 mg/kg by mouth twice daily (rounded to 2 mg by mouth twice daily). Drug interactions were assessed by the clinical pharmacist prior to admission, routinely with medication changes, and then upon discharge. PMID- 30310726 TI - Venetoclax: A Novel Treatment for Patients With del(17p) Chronic Lymphocytic Leukemia. PMID- 30310727 TI - The Oncology Care Model for Advanced Practitioners. PMID- 30310728 TI - New PET/CT Features for the Evaluation of Tumor Response. AB - With the emerging multi-modality imaging performed at multiple time points for each patient, it becomes more important to analyze the serial images quantitatively, select and combine both complementary and contradictory information from various sources, for accurate and personalized evaluation of tumor response to therapy. PMID- 30310729 TI - Efficacy of Adjunctive Hyperbaric Oxygen Therapy in Osteoradionecrosis. AB - Osteoradionecrosis (ORN) is a common consequence resulting from radiation in patients with cancer. Presently, hyperbaric oxygen therapy (HBOT) is proposed to have a role in improving wound healing in ORN patients. There is no strong scientific evidence to confirm the benefits of HBOT for treatment of ORN as an adjunctive treatment. This study aimed to determine the benefits of adjunctive treatment of HBOT in ORN. A retrospective study was conducted at the Srinagarind Hospital, the Faculty of Medicine, Khon Kaen University, Thailand, between 2011 and 2017. The patients diagnosed with ORN, who received adjunctive HBOT before the operation, were enrolled. Complete healing of wounds was the primary outcome. There were 84 ORN patients with a mean age of 58.78 years; 54.76% were male and 45.24% were female. HBOT had a role significant in improving wound healing of ORN patients with stages 1 and 2. Poisson regression analysis showed that stage 3 of ORN negatively correlated with the number of HBOT dives (p = 0.001, incidence rates ratio = 0.85). In conclusion, HBOT improved wound healing of ORN patients with stages 1 and 2. In addition, stage 2 of ORN patients significantly required the highest number of HBOT dives compared to other types of ORN to promote wound healing, whereas stage 3 patients, who underwent bone debridement combined with HBOT, initiated to success of treatment process and required a smaller number of dives. PMID- 30310730 TI - The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) alpha is Indispensable for ERalpha-mediated Physiological Responses and AF-1 Activity. AB - Estrogen has various physiological functions and the estrogen receptor (ER) is a key regulator of those functions. ERalpha is a ligand-dependent transcription factor and that activity is mediated by the transactivating function-1 (AF-1) in the N-terminal domain and transactivating function-2 (AF-2) in the C-terminal ligand-binding domain. The functions of ERalpha AF-1 and AF-2 have been characterized by various in vitro experiments, however, there is still less information about the in vivo physiological functions of ERalpha AF-1 and AF-2. Recently, we established a genetically mutated ERalpha AF-2 knock-in mouse (AF2ERKI) that possesses L543A, L544A mutated-ERalpha. This AF-2 core mutation disrupted AF-2 function and resulted in ERalpha null phenotypes. This mouse model revealed that proper AF-2 core structure and function are indispensable for ERalpha-mediated physiological responses and AF-1 functionality. AF2ER mutation reverses the ERalpha antagonists to agonists and that activity is mediated by AF 1 solely. The pure antagonist, ICI182780/fulvestrant, activated several estrogen mediated physiological responses in the AF2ERKI mouse. The AF2ERKI mouse model will be able to discern estrogen physiological functions which involve AF-1. PMID- 30310731 TI - Clustering of fMRI data: the elusive optimal number of clusters. AB - Model-free methods are widely used for the processing of brain fMRI data collected under natural stimulations, sleep, or rest. Among them is the popular fuzzy c-mean algorithm, commonly combined with cluster validity (CV) indices to identify the 'true' number of clusters (components), in an unsupervised way. CV indices may however reveal different optimal c-partitions for the same fMRI data, and their effectiveness can be hindered by the high data dimensionality, the limited signal-to-noise ratio, the small proportion of relevant voxels, and the presence of artefacts or outliers. Here, the author investigated the behaviour of seven robust CV indices. A new CV index that incorporates both compactness and separation measures is also introduced. Using both artificial and real fMRI data, the findings highlight the importance of looking at the behavior of different compactness and separation measures, defined here as building blocks of CV indices, to depict a full description of the data structure, in particular when no agreement is found between CV indices. Overall, for fMRI, it makes sense to relax the assumption that only one unique c-partition exists, and appreciate that different c-partitions (with different optimal numbers of clusters) can be useful explanations of the data, given the hierarchical organization of many brain networks. PMID- 30310732 TI - Resource availability and adjustment of social behaviour influence patterns of inequality and productivity across societies. AB - Animal societies vary widely in the diversity of social behaviour and the distribution of reproductive shares among their group members. It has been shown that individual condition can lead to divergent social roles and that social specialisation can cause an exacerbation or a mitigation of the inequality among group members within a society. This work, however, has not investigated cases in which resource availability varies between different societies, a factor that is thought to explain variation in the level of cooperation and the disparities in reproductive shares within each social group. In this study, I focus on how resource availability mediates the expression of social behaviour and how this, in turn, mediates inequality both within and between groups. I find that when differences in resource availability between societies persist over time, resource-rich societies become more egalitarian. Because lower inequality improves the productivity of a society, the inequality between resource-rich and resource-poor societies rises. When resource availability fluctuates over time, resource-rich societies tend to become more unequal. Because inequality hinders the productivity of a society, the inequality between resource-rich and resource poor societies falls. From the evolutionary standpoint, my results show that spatial and temporal variation in resource availability may exert a strong influence on the level of inequality both within and between societies. PMID- 30310733 TI - Conserved microbiota among young Heliconius butterfly species. AB - Background: Insects are the most diverse group of animals which have established intricate evolutionary interactions with bacteria. However, the importance of these interactions is still poorly understood. Few studies have focused on a closely related group of insect species, to test the similarities and differences between their microbiota. Heliconius butterflies are a charismatic recent insect radiation that evolved the unique ability to use pollen as a protein source, which affected life history traits and resulted in an elevated speciation rates. We hypothesize that different Heliconius butterflies sharing a similar trophic pollen niche, harbor a similar gut flora within species, population and sexes. Methods: To test our hypothesis, we characterized the microbiota of 38 adult male and female butterflies representing six species of Heliconius butterflies and 2 populations of the same species. We sequenced the V4 region of the 16S rRNA gene with the Roche 454 system and analyzed the data with standard tools for microbiome analysis. Results: Overall, we found a low microbial diversity with only 10 OTUs dominating across all individuals, mostly Proteobacteria and Firmicutes, which accounted for 99.5% of the bacterial reads. When rare reads were considered, we identified a total of 406 OTUs across our samples. We identified reads within Phyla Chlamydiae, found in 5 butterflies of four species. Interestingly, only three OTUs were shared among all 38 individuals (Bacillus, Enterococcus and Enterobacteriaceae). Altogether, the high individual variation overshadowed species and sex differences. Thus, bacterial communities were not structured randomly with 13% of beta-diversity explained by species, and 40 rare OTUs being significantly different across species. Finally, 13 OTUs, including the intercellular symbiont Spiroplasma, varied significantly in relative abundance between males and females. Discussion: The Heliconius microbial communities in these 38 individuals show a low diversity with few differences in the rare microbes between females, males, species or populations. Indeed, Heliconius butterflies, similarly to other insects, are dominated by few OTUs, mainly from Proteobacteria and Firmicutes. The overall low microbial diversity observed contrasts with the high intra-species variation in microbiome composition. This could indicate that much of the microbiome maybe acquired from their surroundings. The significant differences between species and sexes were restricted to rare taxa, which could be important for microbial community stability under changing conditions as seen in other host-microbiome systems. The presence of symbionts like Spiroplasma or Chlamydiae, identified in this study for the first time in Heliconius, could play a vital role in their behavior and evolution by vertical transmission. Altogether, our study represents a step forward into the description of the microbial diversity in a charismatic group of closely related butterflies. PMID- 30310734 TI - Assessment of genomic changes in a CRISPR/Cas9 Phaeodactylum tricornutum mutant through whole genome resequencing. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, co-opted from a bacterial defense natural mechanism, is the cutting edge technology to carry out genome editing in a revolutionary fashion. It has been shown to work in many different model organisms, from human to microbes, including two diatom species, Phaeodactylum tricornutum and Thalassiosira pseudonana. Transforming P. tricornutum by bacterial conjugation, we have performed CRISPR/Cas9-based mutagenesis delivering the nuclease as an episome; this allowed for avoiding unwanted perturbations due to random integration in the genome and for excluding the Cas9 activity when it was no longer required, reducing the probability of obtaining off-target mutations, a major drawback of the technology. Since there are no reports on off-target occurrence at the genome level in microalgae, we performed whole-genome Illumina sequencing and found a number of different unspecific changes in both the wild type and mutant strains, while we did not observe any preferential mutation in the genomic regions in which off-targets were predicted. Our results confirm that the CRISPR/Cas9 technology can be efficiently applied to diatoms, showing that the choice of the conjugation method is advantageous for minimizing unwanted changes in the genome of P. tricornutum. PMID- 30310735 TI - Association of CYBA gene (-930 A/G and 242 C/T) polymorphisms with oxidative stress in breast cancer: a case-control study. AB - Background: Oxidative stress (OS) is a key characteristic feature in cancer initiation and progression. Among multiple cancers, NADPH oxidase (NOX) dependent free radical production is implicated in oxidative stress. P22phox, a subunit of NADPH oxidase encoded by the CYBA gene has functional polymorphisms associated with various complex diseases. The present study was aimed to examine the importance and association of the functional polymorphisms of CYBA gene (-930 A/G and 242 C/T) with the oxidative stress in breast cancer (BC) development and progression. Materials and Methods: We have performed a case-control study on 300 breast cancer patients and 300 healthy individuals as controls to examine the role of CYBA gene -930 A/G and 242 C/T single nucleotide polymorphisms (SNPs) using As-PCR and PCR-RFLP assays and its association with OS as measured by plasma MDA levels. Linkage disequilibrium (LD) plots were generated using Haploviewtool and Multifactor dimensionality reduction (MDR) analysis was applied to assess high-order interactions between the SNPs. The Insilco analysis has been performed to predict the effect of SNPs on the gene regulation using online tools. Results: We have found that genotype frequencies of CYBA gene -930 A/G and 242C/T polymorphism were significantly different between controls and BC patients (p < 0.05). The haplotype combination -930G/242C and -930G/242T were associated with 1.44 & 1.56 folds increased risk for breast cancer respectively. Further, the MDA levels were higher in the patients carrying -930G/242C and -930G/242T haplotype (p < 0.001). Our results have been substantiated by Insilco analysis. Conclusion: Results of the present study suggest that GG genotype of -930 A/G polymorphism, -930G/242C and -930G/242T haplotypes of CYBA gene polymorphisms have shown association with higher MDA levels in breast cancer patients, signify that elevated oxidative stress might aid in increased risk for breast cancer initiation and progression. PMID- 30310737 TI - Targeting restoration sites to improve connectivity in a tiger conservation landscape in India. AB - Background: Maintaining and restoring connectivity between source populations is essential for the long term viability of wide-ranging species, many of which occur in landscapes that are under pressure to meet increasing infrastructure needs. Identifying barriers in corridors can help inform conservation and infrastructure development agencies so that development objectives can be achieved without compromising conservation goals. Here, we use the tiger landscape in central India as a case study to identify barriers, associate them with existing infrastructure, and quantify the potential improvement by restoring or mitigating barriers. Additionally, we propose an approach to categorize linkages based on their current status within and between Protected Areas (PAs). Methods: We generated a hybrid landuse-landcover map of our study area by merging datasets. We used least-cost methods and circuit theory to map corridors and generate linkage metrics. We mapped barriers and used the improvement score (IS) metric to quantify potential improvement by restoring or mitigating them. Based on criteria that represent the status of corridors between-PAs and populations within-PAs, we ranked linkages into one of four categories: Cat1-linkages that currently have high quality and potential for tiger connectivity and should be maintained, Cat2W-linkages where focus on habitat and tiger populations may improve connectivity, Cat2B-linkages where focus on reducing barriers between PAs may improve connectivity, and Cat3-linkages where effort is needed to both reduce barriers between PAs and improve tiger populations and habitat within PAs. We associated barriers with infrastructure and present maps to show where restoration or mitigation measures can be targeted to have the highest potential impact. Results: We mapped 567 barriers within 30 linkages in this landscape, of which 265 barriers intersect with infrastructure (694 km of roads, 150 km of railway, 48 reservoirs, 10 mines) and 302 barriers are due to land-use or gaps in forest cover. Eighty-six barriers have both roads and railways. We identified 7 Cat1, 4 Cat2w, 9 Cat2b, and 10 Cat3 linkages. Eighty surface mines and thermal power plants are within 10 km of the least-cost paths, and more coal mines are closer to connectivity areas where linkages are narrow and rank poorly on both axes. Discussion: We present spatial and quantitative results that can help conservation practitioners target mitigation and restoration efforts. India is on the path to rapid economic growth, with infrastructure development planned in biodiversity-rich areas. The mitigation hierarchy of avoiding, minimizing, and offsetting impacts due to proposed development projects can be applied to corridors in this landscape. Cross-sectoral cooperation at early stages of project life-cycles to site, design, and implement solutions can maintain connectivity while meeting infrastructure needs in this rapidly changing landscape. PMID- 30310736 TI - Influence of mutation bias and hydrophobicity on the substitution rates and sequence entropies of protein evolution. AB - The number of amino acids that occupy a given protein site during evolution reflects the selective constraints operating on the site. This evolutionary variability is strongly influenced by the structural properties of the site in the native structure, and it is quantified either through sequence entropy or through substitution rates. However, while the sequence entropy only depends on the equilibrium frequencies of the amino acids, the substitution rate also depends on the exchangeability matrix that describes mutations in the mathematical model of the substitution process. Here we apply two variants of a mathematical model of protein evolution with selection for protein stability, both against unfolding and against misfolding. Exploiting the approximation of independent sites, these models allow computing site-specific substitution processes that satisfy global constraints on folding stability. We find that site specific substitution rates do not depend only on the selective constraints acting on the site, quantified through its sequence entropy. In fact, polar sites evolve faster than hydrophobic sites even for equal sequence entropy, as a consequence of the fact that polar amino acids are characterized by higher mutational exchangeability than hydrophobic ones. Accordingly, the model predicts that more polar proteins tend to evolve faster. Nevertheless, these results change if we compare proteins that evolve under different mutation biases, such as orthologous proteins in different bacterial genomes. In this case, the substitution rates are faster in genomes that evolve under mutational bias that favor hydrophobic amino acids by preferentially incorporating the nucleotide Thymine that is more frequent in hydrophobic codons. This appearingly contradictory result arises because buried sites occupied by hydrophobic amino acids are characterized by larger selective factors that largely amplify the substitution rate between hydrophobic amino acids, while the selective factors of exposed sites have a weaker effect. Thus, changes in the mutational bias produce deep effects on the biophysical properties of the protein (hydrophobicity) and on its evolutionary properties (sequence entropy and substitution rate) at the same time. The program Prot_evol that implements the two site-specific substitution processes is freely available at https://ub.cbm.uam.es/prot_fold_evol/prot_fold_evol_soft_main.php#Prot_Evol. PMID- 30310738 TI - Osteology of a forelimb of an aetosaur Stagonolepis olenkae (Archosauria: Pseudosuchia: Aetosauria) from the Krasiejow locality in Poland and its probable adaptations for a scratch-digging behavior. AB - Aetosaurs are armored basal archosaurs that played a significant role in land ecosystems during the Late Triassic (237-201 Ma). The polish species Stagonolepis olenkae Sulej, 2010 described from the Krasiejow locality (southern Poland) is one of the oldest known representatives of the group. Abundant and well-preserved material, including partially articulated specimens, allows a detailed description of the forelimbs in this species. The forelimbs of S. olenkae are the most similar to that of large aetosaurs like Desmatosuchus smalli, Desmatosuchus spurensis, Longosuchus meadei, Typothorax coccinarum or Stagonolepis robertsoni. Several characters recognized in the forelimbs of S. olenkae suggest its adaptation for scratch-digging. The most salient of these features are: short forearm, carpus, and hands, with the radius shorter than the humerus, carpus and manus shorter than the radius (excluding terminal phalanges); a prominent deltopectoral crest that extends distally on the humerus and a wide prominent entepicondyle, a long olecranon process with well-marked attachment of triceps muscle; hooked, laterally compressed, claw-like terminal phalanges with ornamentation of small pits (indicative of well-developed keratin sheaths). S. olenkae might have used its robust forelimbs to break through the compacted soil with its claws and proceed to dig in search of food in softened substrate with the shovel-like expansion at the tip of its snout. The entire forelimb of S. olenkae is covered by osteoderms, including the dorsal surface of the hand, which is unusual among aetosaurs and have not been noted for any species up to date. PMID- 30310739 TI - Potential impacts of finfish aquaculture on eelgrass (Zostera marina) beds and possible monitoring metrics for management: a case study in Atlantic Canada. AB - Eelgrass (Zostera marina) has been designated an Ecologically Significant Species in Atlantic Canada. The development and rapid expansion of netpen finfish aquaculture into sensitive coastal habitats has raised concerns about the impacts of finfish aquaculture on eelgrass habitats. To date, no studies have been done in Atlantic Canada to examine these impacts or to identify potential monitoring variables that would aid in the development of specific conservation and management objectives. As a first step in addressing this gap, we examined differences in environmental variables, eelgrass bed structure and macroinfauna communities at increasing distances from a finfish farm in Port Mouton Bay, a reference site in adjacent Port Joli Bay, and published survey results from other sites without finfish farms along the Atlantic Coast of Nova Scotia. Drawing on research done elsewhere and our results, we then identified possible metrics for assessing and monitoring local impacts of finfish aquaculture on eelgrass habitats. Our results suggest some nutrient and organic enrichment, higher epiphyte loads, lower eelgrass cover and biomass, and lower macroinfauna biomass closer to the farm. Moreover, community structure significantly differed between sites with some species increasing and others decreasing closer to the farm. Changes in the macroinfauna community could be linked to observed differences in environmental and eelgrass bed variables. These results provide new insights into the potential impacts of finfish aquaculture on eelgrass habitats in Atlantic Canada. We recommend a suite of measures for assessment and monitoring that take into account response time to disturbance and account for different levels of eelgrass organizational response (from physiological to community). PMID- 30310741 TI - Effects of mangrove removal on benthic organisms in the Siangshan Wetland in Hsinchu, Taiwan. AB - Mangrove degradation is a well-documented trend, but the spread of mangroves within the Siangshan Wetland in Hsinchu, Taiwan, runs contrary to that trend. The spread of mangroves changes the structure and functions of habitats for benthic organisms, causes infilling of estuaries and flooding and creates breeding grounds for small black mosquitoes. A large-scale mangrove-removal project was undertaken by the Hsinchu City Government from October 2015 to March 2016. They also investigated the consequences of mangrove removal on benthic organisms and adjacent habitats from October 2015 to September 2016, and the density, species count, Shannon-Wiener index (H'), and Pielou's evenness index (J') of the mangrove and non-mangrove regions were compared. In this study, we used satellite telemetry images to monitor fluctuations in mangrove density from 2006 to 2016. The non-mangrove region exhibited more variations than the mangrove region. After mangrove removal, species returned to their original habitats and noteworthy biological values significantly increased in the mangrove regions. This study presents evidence to argue that mangrove removal benefits benthic organisms. The results indicate that mangrove removal can be an appropriate habitat rehabilitation strategy for benthic organisms. The ecological findings of this study can inform coastal managers or other officials who seek to steward mangrove biomass. PMID- 30310742 TI - A new species of Brachycephalus (Anura: Brachycephalidae) from southern Brazil. AB - A new miniaturized frog of the genus Brachycephalus (Anura: Brachycephalidae) is described from Morro Santo Anjo in the municipality of Massaranduba, Santa Catarina, southern Brazil. Specimens were collected from the leaf litter between 470 and 540 above sea level. The new species is distinguished from all its congeners by the combination of the following characters: (1) body robust and bufoniform; (2) size snout-vent length 9.9-11.7 mm for males and 10.0-12.9 mm for females; (3) smooth dorsum; (4) general color (in life) orange with white dots and stripe in the middle of the head and along its vertebral column; (5) iris completely black; (6) advertisement call composed of note groups; (7) isolated notes with 1-3 pulses; and (8) short isolated notes (0.002-0.027 s). An estimate of the male density of the new species is also presented. Phylogenetic information indicates that the new species is part of the southernmost clade of Brachycephalus, which includes Brachycephalus fuscolineatus, B. albolineatus, and B. boticario. The severe anthropogenic impacts in and around the type locality indicate that immediate actions should be taken to ensure the long-term preservation of the new species. PMID- 30310743 TI - Seeing spots: quantifying mother-offspring similarity and assessing fitness consequences of coat pattern traits in a wild population of giraffes (Giraffa camelopardalis). AB - Polymorphic phenotypes of mammalian coat coloration have been important to the study of genetics and evolution, but less is known about the inheritance and fitness consequences of individual variation in complex coat pattern traits such as spots and stripes. Giraffe coat markings are highly complex and variable and it has been hypothesized that variation in coat patterns most likely affects fitness by camouflaging neonates against visually hunting predators. We quantified complex coat pattern traits of wild Masai giraffes using image analysis software, determined the similarity of spot pattern traits between mother and offspring, and assessed whether variation in spot pattern traits was related to fitness as measured by juvenile survival. The methods we described could comprise a framework for objective quantification of complex mammal coat pattern traits based on photographic coat pattern data. We demonstrated that some characteristics of giraffe coat spot shape were likely to be heritable, as measured by mother-offspring regression. We found significant variation in juvenile survival among phenotypic groups of neonates defined by multivariate clustering based on spot trait measurement variables. We also found significant variation in neonatal survival associated with spot size and shape covariates. Larger spots (smaller number of spots) and irregularly shaped or rounder spots (smaller aspect ratio) were correlated with increased survival. These findings will inform investigations into developmental and genetic architecture of complex mammal coat patterns and their adaptive value. PMID- 30310744 TI - A new species of the odorous frog genus Odorrana (Amphibia, Anura, Ranidae) from southwestern China. AB - The genus Odorrana is widely distributed in the mountains of East and Southeastern Asia. An increasing number of new species in the genus have been recognized especially in the last decade. Phylogenetic studies of the O. schmackeri species complex with wide distributional range also revealed several cryptic species. Here, we describe a new species in the species complex from Guizhou Province of China. Phylogenetic analyses based on mitochondrial DNA indicated the new species as a monophyly clustered into the Odorrana clade and sister to O. schmackeri, and nuclear DNA also indicated it as an independent lineage separated from its related species. Morphologically, the new species can be distinguished from its congeners based on a combination of the following characters: (1) having smaller body size in males (snout-vent length (SVL) <43.3 mm); (2) head longer than wide; (3) dorsolateral folds absent; (4) tympanum of males large and distinct, tympanum diameter twice as long as width of distal phalanx of finger III; (5) two metacarpal tubercles; (6) relative finger lengths: II < I < IV < III; (7) tibiotarsal articulation reaching to the level between eye to nostril when leg stretched forward; (8) disks on digits with circum-marginal grooves; (9) toes fully webbed to disks; (10) the first subarticular tubercle on fingers weak; (11) having white pectoral spinules, paired subgular vocal sacs located at corners of throat, light yellow nuptial pad on the first finger in males. PMID- 30310745 TI - What's for dinner? Diet and potential trophic impact of an invasive anuran Hoplobatrachus tigerinus on the Andaman archipelago. AB - Amphibian invasions have considerable detrimental impacts on recipient ecosystems. However, reliable risk analysis of invasive amphibians still requires research on more non-native amphibian species. An invasive population of the Indian bullfrog, Hoplobatrachus tigerinus, is currently spreading on the Andaman archipelago and may have significant trophic impacts on native anurans through competition and predation. We carried out diet analyses of the invasive H. tigerinus and native anurans, across four habitat types and two seasons; we hypothesized that (i) small vertebrates constitute a majority of the H. tigerinus diet, particularly by volume and (ii) the diet of H. tigerinus significantly overlaps with the diet of native anurans, thereby, leading to potential competition. We assessed the diet of the invasive H. tigerinus (n = 358), and individuals of the genera Limnonectes (n = 375) and Fejervarya (n = 65) and found a significant dietary overlap of H. tigerinus with only Limnonectes. Small vertebrates, including several endemic species, constituted the majority of H. tigerinus, diet by volume, suggesting potential impact by predation. Prey consumption and electivity of the three anurans indicated a positive relationship between predator-prey body sizes. Individuals of H. tigerinus and Fejervarya chose evasive prey, suggesting that these two taxa are mostly ambush predators; individuals of Limnonectes chose a mixture of sedentary and evasive prey indicating that the species employs a combination of 'active search' and 'sit and wait' foraging strategies. All three species of anurans mostly consumed terrestrial prey. This intensive study on a genus of newly invasive amphibian contributes to knowledge of the impact of amphibian invasions, and elucidates the feeding ecology of H. tigerinus, and species of the genera Limnonectes and Fejervarya. We also stress the necessity to evaluate prey availability and volume in future studies for meaningful insights into diet of amphibians. PMID- 30310740 TI - Conceptual and empirical advances in Neotropical biodiversity research. AB - The unparalleled biodiversity found in the American tropics (the Neotropics) has attracted the attention of naturalists for centuries. Despite major advances in recent years in our understanding of the origin and diversification of many Neotropical taxa and biotic regions, many questions remain to be answered. Additional biological and geological data are still needed, as well as methodological advances that are capable of bridging these research fields. In this review, aimed primarily at advanced students and early-career scientists, we introduce the concept of "trans-disciplinary biogeography," which refers to the integration of data from multiple areas of research in biology (e.g., community ecology, phylogeography, systematics, historical biogeography) and Earth and the physical sciences (e.g., geology, climatology, palaeontology), as a means to reconstruct the giant puzzle of Neotropical biodiversity and evolution in space and time. We caution against extrapolating results derived from the study of one or a few taxa to convey general scenarios of Neotropical evolution and landscape formation. We urge more coordination and integration of data and ideas among disciplines, transcending their traditional boundaries, as a basis for advancing tomorrow's ground-breaking research. Our review highlights the great opportunities for studying the Neotropical biota to understand the evolution of life. PMID- 30310746 TI - The potential contribution of miRNA-200-3p to the fatty acid metabolism by regulating AjEHHADH during aestivation in sea cucumber. AB - The sea cucumber (Apostichopus japonicus) has become a good model organism for studying environmentally-induced aestivation by a marine invertebrate more recently. In the present study, we hypothesized that miRNA-200-3p may contribute to establish rapid biological control to regulate fatty acid metabolism during a estivation. The peroxisomal bi-functional enzyme (EHHADH) is a crucial participant of the classical peroxisomal fatty acid beta-oxidation pathway, the relative mRNA transcripts and protein expressions of EHHADH were analyzed in intestine from sea cucumbers experienced long-term aestivation. Both mRNA transcripts and protein expressions of EHHADH in intestine decreased significantly during deep-aestivation as compared with non-aestivation controls. Analysis of the 3' UTR of AjEHHADH showed the presence of a conserved binding site for miR-200-3p. Level of miR-200-3p showed an inverse correlation with EHHADH mRNA transcripts and protein levels in intestine, implicating miR-200-3p may directly targeted AjEHHADH by inducing the degradation of AjEHHADH mRNA in the aestivating sea cucumber, further dual-luciferase reporter assay validated the predicted role of miRNA-200-3p in regulating AjEHHADH. In order to further understand their regulatory mechanism, we conducted the functional experiment in vivo. The overexpression of miR-200-3p in sea cucumber significantly decreased mRNA and protein expression levels of AjEHHADH. Taken together, these findings suggested the potential contribution of miRNA-200-3p to the fatty acid metabolism by regulating AjEHHADH during aestivation in sea cucumber. PMID- 30310748 TI - The efficacy of Virkon-S for the control of saprolegniasis in common carp, Cyprinus carpio L. AB - Background: Saprolegnia parasitica is a fish pathogen that causes severe economic losses worldwide. Virkon-S is a well-known disinfectant known to exhibit antimicrobial activities against bacteria, viruses, and fungi. In this study, we tested the anti-fungal activity of Virkon-S against S. parasitica, the major causal agent of saprolegniasis. Methods: The lowest concentration of Virkon-S that prevented germination or the visible growth of spores and the percent spore germination were determined using potato dextrose agar plates containing different concentrations of Virkon-S. The cytotoxic effect was evaluated using the Ez-Cytox Cell Viability Assay with epithelioma papulosum cyprini (EPC) cells grown in L-15 medium and acute toxicity tests were carried out with cultured fingerlings of common carp for 96 h. Artificial infection with S. parasitica was performed by placing the fish in tanks containing zoospores of S. parasitica after descaling and wounding at three positions. The diseased fish were kept in tanks containing 2, 4, and 10 ppm of Virkon-S for 10 days to observe the treatment effect. Results: The in vitro assay results showed that Virkon-S could inhibit spore germination and the resulting mycelial growth at a concentration as low as 4 ppm. No cytotoxic effect on EPC cells was observed even at a concentration as high as 100 ppm. Additionally, no acute toxicity in the common carp was observed at 10 ppm following 96 h exposure. Ten days of treatment with 4 and 10 ppm Virkon-S resulted in complete reversal of artificially-induced saprolegniasis in the common carp. Discussion: This data indicates that Virkon-S can be used for the control of saprolegniasis without harmful effects in fish. However, further research on the effect in humans and food supplies is necessary. PMID- 30310747 TI - Effects of knee extension with different speeds of movement on muscle and cerebral oxygenation. AB - Background: One of the mechanisms responsible for enhancing muscular hypertrophy is the high metabolic stress associated with a reduced muscular oxygenation occurring during exercise, which can be achieved by reducing the speed of movement. Studies have tested that lowered muscle oxygenation artificially induced by an inflatable cuff, could provoke changes in prefrontal cortex oxygenation, hence, to central fatigue. It was hypothesized that (1) exercising with a slow speed of movement would result in greater increase in cerebral and greater decrease in muscle oxygenation compared with exercises of faster speed and (2) the amount of oxygenation increase in the ipsilateral prefrontal cortex would be lower than the contralateral one. Methods: An ISS Imagent frequency domain near infrared spectroscopy (NIRS) system was used to quantify oxygenation changes in the vastus lateralis muscle and prefrontal cortex (contra- and ipsilateral) during unilateral resistance exercises with different speeds of movement to voluntary fatigue. After one maximal repetition (1RM) test, eight subjects performed three sets of unilateral knee extensions (~50% of 1RM), separated by 2 min rest periods, following the pace of 1 s, 3 s and 5 s for both concentric and eccentric phases, in a random order, during separate sessions. The amount of change for NIRS parameters for muscle (DeltaHb: deoxyhemoglobin, DeltaHbO: oxyhemoglobin, DeltaHbT: total hemoglobin, DeltaStO2: oxygen saturation) were quantified and compared between conditions and sets by two-way ANOVA RM. Differences in NIRS parameters between contra- and ipsilateral (lobe) prefrontal cortex and conditions were tested. Results: Exercising with slow speed of movement was associated to larger muscle deoxygenation than normal speed of movement, as revealed by significant interaction (set * condition) for DeltaHb (p = 0.01), and by significant main effects of condition for DeltaHbO (p = 0.007) and DeltaStO2 (p = 0.016). With regards to the prefrontal cortex, contralateral lobe showed larger oxygenation increase than the ipsilateral one for DeltaHb, DeltaHbO, DeltaHbT, DeltaStO2 in each set (main effect of lobe: p < 0.05). Main effects of condition were significant only in set1 for all the parameters, and significant interaction lobe * condition was found only for DeltaHb in set1 (p < 0.05). Discussion: These findings provided evidence that speed of movement influences the amount of muscle oxygenation. Since the lack of oxygen in muscle is associated to increased metabolic stress, manipulating the speed of movement may be useful in planning resistance-training programs. Moreover, consistent oxygenation increases in both right and left prefrontal lobes were found, suggesting a complementary interaction between the ipsi- and contralateral prefrontal cortex, which also seems related to fatigue. PMID- 30310749 TI - Predicting academic career outcomes by predoctoral publication record. AB - Background: For students entering a science PhD program, a tenure-track faculty research position is often perceived as the ideal long-term goal. A relatively small percentage of individuals ultimately achieve this goal, however, with the vast majority of PhD recipients ultimately finding employment in industry or government positions. Given the disparity between academic career ambitions and outcomes, it is useful to understand factors that may predict those outcomes. Toward this goal, the current study examined employment status of PhD graduates from biomedical sciences programs at the University of Colorado Anschutz Medical Campus (CU AMC) and related this to metrics of predoctoral publication records, as well as to other potentially important factors, such as sex and time-since degree, to determine if these measures could predict career outcomes. Methods: Demographic information (name, PhD program, graduation date, sex) of CU AMC biomedical sciences PhD graduates between 2000 and 2015 was obtained from University records. Career outcomes (academic faculty vs. non-faculty) and predoctoral publication records (number and impact factors of first-author and non-first-author publications) were obtained via publicly available information. Relationships between predoctoral publication record and career outcomes were investigated by (a) comparing faculty vs. non-faculty publication metrics, using t-tests, and (b) investigating the ability of predoctoral publication record, sex, and time-since-degree to predict career outcomes, using logistic regression. Results: Significant faculty vs. non-faculty differences were observed in months since graduation (p < 0.001), first-author publication number (p = 0.001), average first-author impact factor (p = 0.006), and highest first-author impact factor (p = 0.004). With sex and months since graduation as predictors of career outcome, the logistic regression model was significant (p < 0.001), with both being male and having more months since graduation predicting career status. First-author related publication metrics (number of publications, average impact factor, highest impact factor) all significantly improved model fit (chi2 < 0.05 for all) and were all significant predictors of faculty status (p < 0.05 for all). Non-first-author publication metrics did not significantly improve model fit or predict faculty status. Discussion: Results suggest that while sex and months since graduation also predict career outcomes, a strong predoctoral first author publication record may increase likelihood of obtaining an academic faculty research position. Compared to non-faculty, individuals employed in faculty positions produced more predoctoral first-author publications, with these being in journals with higher impact factors. Furthermore, first-author publication record, sex, and months since graduation were significant predictors of faculty status. PMID- 30310750 TI - Co-occurrence patterns of litter decomposing communities in mangroves indicate a robust community resistant to disturbances. AB - Background: Mangroves are important coastal ecosystems known for high photosynthetic productivity and the ability to support marine food chains through supply of dissolved carbon or particular organic matter. Most of the carbon found in mangroves is produced by its vegetation and is decomposed in root associated sediment. This process involves a tight interaction between microbial populations, litter chemical composition, and environmental parameters. Here, we study the complex interactions found during litter decomposition in mangroves by applying network analysis to metagenomic data. Methods: Leaves of three species of mangrove trees typically found in the southeast of Brazil (Rhizophora mangle, Laguncularia racemosa, and Avicennia schaueriana) were collected in separate litter bags and left on three different mangroves for 60 days. These leaves were subsequently used for metagenome sequencing using Ion Torrent technology. Sequences were annotated in MG-RAST and used for network construction using MENAp. Results: The most common phyla were Proteobacteria (classes Gamma and Alphaproteobacteria) followed by Firmicutes (Clostridia and Bacilli). The most abundant protein clusters were associated with the metabolism of carbohydrates, amino acids, and proteins. Non-metric multidimensional scaling of the metagenomic data indicated that substrate (i.e., tree species) did not significantly select for a specific community. Both networks exhibited scale-free characteristics and small world structure due to the low mean shortest path length and high average clustering coefficient. These networks also had a low number of hub nodes most of which were module hubs. Discussion: This study demonstrates that under different environmental pressures (i.e., plant species or mangrove location) the microbial community associated with the decaying material forms a robust and stable network. PMID- 30310751 TI - In search of an optimum sampling algorithm for prediction of soil properties from infrared spectra. AB - Background: The use of visible-near infrared (vis-NIR) spectroscopy for rapid soil characterisation has gained a lot of interest in recent times. Soil spectra absorbance from the visible-infrared range can be calibrated using regression models to predict a set of soil properties. The accuracy of these regression models relies heavily on the calibration set. The optimum sample size and the overall sample representativeness of the dataset could further improve the model performance. However, there is no guideline on which sampling method should be used under different size of datasets. Methods: Here, we show different sampling algorithms performed differently under different data size and different regression models (Cubist regression tree and Partial Least Square Regression (PLSR)). We analysed the effect of three sampling algorithms: Kennard-Stone (KS), conditioned Latin Hypercube Sampling (cLHS) and k-means clustering (KM) against random sampling on the prediction of up to five different soil properties (sand, clay, carbon content, cation exchange capacity and pH) on three datasets. These datasets have different coverages: a European continental dataset (LUCAS, n = 5,639), a regional dataset from Australia (Geeves, n = 379), and a local dataset from New South Wales, Australia (Hillston, n = 384). Calibration sample sizes ranging from 50 to 3,000 were derived and tested for the continental dataset; and from 50 to 200 samples for the regional and local datasets. Results: Overall, the PLSR gives a better prediction in comparison to the Cubist model for the prediction of various soil properties. It is also less prone to the choice of sampling algorithm. The KM algorithm is more representative in the larger dataset up to a certain calibration sample size. The KS algorithm appears to be more efficient (as compared to random sampling) in small datasets; however, the prediction performance varied a lot between soil properties. The cLHS sampling algorithm is the most robust sampling method for multiple soil properties regardless of the sample size. Discussion: Our results suggested that the optimum calibration sample size relied on how much generalization the model had to create. The use of the sampling algorithm is beneficial for larger datasets than smaller datasets where only small improvements can be made. KM is suitable for large datasets, KS is efficient in small datasets but results can be variable, while cLHS is less affected by sample size. PMID- 30310752 TI - An automated, high-throughput method for standardizing image color profiles to improve image-based plant phenotyping. AB - High-throughput phenotyping has emerged as a powerful method for studying plant biology. Large image-based datasets are generated and analyzed with automated image analysis pipelines. A major challenge associated with these analyses is variation in image quality that can inadvertently bias results. Images are made up of tuples of data called pixels, which consist of R, G, and B values, arranged in a grid. Many factors, for example image brightness, can influence the quality of the image that is captured. These factors alter the values of the pixels within images and consequently can bias the data and downstream analyses. Here, we provide an automated method to adjust an image-based dataset so that brightness, contrast, and color profile is standardized. The correction method is a collection of linear models that adjusts pixel tuples based on a reference panel of colors. We apply this technique to a set of images taken in a high throughput imaging facility and successfully detect variance within the image dataset. In this case, variation resulted from temperature-dependent light intensity throughout the experiment. Using this correction method, we were able to standardize images throughout the dataset, and we show that this correction enhanced our ability to accurately quantify morphological measurements within each image. We implement this technique in a high-throughput pipeline available with this paper, and it is also implemented in PlantCV. PMID- 30310753 TI - Trophic state (TSISD) and mixing type significantly influence pelagic zooplankton biodiversity in temperate lakes (NW Poland). AB - Background: Lake depth and the consequent mixing regime and thermal structure have profound effects on ecosystem functioning, because depth strongly affects the availability of nutrients, light, and oxygen. All these conditions influence patterns of zooplankton diversity. Zooplankton are a key component of the aquatic environment and are essential to maintaining natural processes in freshwater ecosystems. However, zooplankton biodiversity can be different regard to depth, mixing type and trophic state. Therefore, the aim of this study was to examine how depth and mixing regime affect zooplankton diversity in lakes. We also investigated the vertical distribution of diversity across a trophic gradient of lakes. Methods: A total of 329 zooplankton samples from 79 temperate lakes (36 polymictic and 43 dimictic) were collected. The biodiversity of zooplankton was calculated using species richness (SR) and the Shannon index (SI). An index based on Secchi disc visibility was used to determine the trophic state index (TSISD) of lakes. The one-way ANOVA with Duncan's post hoc test were used to determine differences in zooplankton biodiversity between mictic lake types and thermal layers. To find the best predictors for zooplankton biodiversity a multiple stepwise regression was used. The rarefaction method was used to evaluate the impact of mixing types, thermal layers, and the TSISDon zooplankton biodiversity indices. A Sorensen similarity analysis and nonmetric multidimensional scaling (NMDS) were performed to describe the similarity patterns in species composition among lakes. Results: We identified a total of 151 taxa from 36 polymictic and 43 dimictic lakes. Lake depth and the TSISD were significantly correlated with the biodiversity of lake zooplankton. The results of ANOVA and Duncan tests show that mictic type and thermal zones had a significant effect on zooplankton biodiversity. The rarefaction curve showed significant differences in zooplankton biodiversity, which was greater in lakes with lower trophic state. Ordination by NMDS showed clustering of different mictic types, thermal layers, and composition changes throughout the TSISDprofile. Moreover, we determined that polymictic lakes are more heterogeneous than dimictic lakes in regard to zooplankton similarities. Discussion: Both mictic lake types were characterized by varying levels of zooplankton biodiversity, which is shaped by the communities' response to lake depth, thermal layers and TSISD values. The zooplankton SR and SI (during daylight hours) depends greatly on the mixing type. Lake type also indicates the importance of the metalimnion in shaping zooplankton biodiversity in dimictic lakes. In addition, data from NW Polish lakes indicated that the increase of the TSISD leads to taxonomic shifts and has a negative effect on the diversity of all groups of zooplankton. PMID- 30310754 TI - Ultraconserved elements (UCEs) illuminate the population genomics of a recent, high-latitude avian speciation event. AB - Using a large, consistent set of loci shared by descent (orthologous) to study relationships among taxa would revolutionize among-lineage comparisons of divergence and speciation processes. Ultraconserved elements (UCEs), highly conserved regions of the genome, offer such genomic markers. The utility of UCEs for deep phylogenetics is clearly established and there are mature analytical frameworks available, but fewer studies apply UCEs to recent evolutionary events, creating a need for additional example datasets and analytical approaches. We used UCEs to study population genomics in snow and McKay's buntings (Plectrophenax nivalis and P. hyperboreus). Prior work suggested divergence of these sister species during the last glacial maximum (~18-74 Kya). With a sequencing depth of ~30* from four individuals of each species, we used a series of analysis tools to genotype both alleles, obtaining a complete dataset of 2,635 variable loci (~3.6 single nucleotide polymorphisms/locus) and 796 invariable loci. We found no fixed allelic differences between the lineages, and few loci had large allele frequency differences. Nevertheless, individuals were 100% diagnosable to species, and the two taxa were different genetically (F ST = 0.034; P = 0.03). The demographic model best fitting the data was one of divergence with gene flow. Estimates of demographic parameters differed from published mtDNA research, with UCE data suggesting lower effective population sizes (~92,500-240,500 individuals), a deeper divergence time (~241,000 years), and lower gene flow (2.8-5.2 individuals per generation). Our methods provide a framework for future population studies using UCEs, and our results provide additional evidence that UCEs are useful for answering questions at shallow evolutionary depths. PMID- 30310755 TI - Relationships between neuropsychological and antisaccade measures in multiple sclerosis patients. AB - Background: The Stroop test is frequently used to assess deficits in inhibitory control in people with multiple sclerosis (MS). This test has limitations and antisaccade eye movements, that also measure inhibitory control, may be an alternative to Stroop. Objectives: The aim of this study was twofold: (i) to investigate if the performance in the antisaccade task is altered in patients with MS and (ii) to investigate the correlation between performances in neuropsychological tests, the Stroop test and the antisaccade task. Methods: We measured antisaccades (AS) parameters with an infrared eye tracker (SMIRED 250 Hz) using a standard AS paradigm. A total of 38 subjects diagnosed with MS and 38 age and gender matched controls participated in this study. Neuropsychological measures were obtained from the MS group. Results: Patients with MS have higher error rates and prolonged latency than controls in the antisaccade task. There was a consistent association between the Stroop performance and AS latency. Stroop performance but not AS latency was associated with other neuropsychological measures in which the MS group showed deficits. Conclusions: Our findings suggest that AS may be a selective and independent measure to investigate inhibitory control in patients with MS. More studies are necessary to confirm our results and to describe brain correlates associated with impaired performance in the antisaccade task in people diagnosed with MS. PMID- 30310756 TI - Epidemiological characteristics and factors affecting length of hospital stay for children and adults with burns in Zunyi, China: a retrospective study. AB - Objective: Burn wounds are a global public health problem, and a large number of casualties are caused by burns each year. In this study, we explored the epidemiological characteristics associated with burns and the factors affecting the length of hospital stay (LOS) in children and adults with burn wounds. Methods: Records of patients with burns in the Affiliated Hospital of Zunyi Medical University from January 1, 2014 to August 31, 2016 were retrieved. Information on demographic characteristics, mechanism of burns, first treatment received, clinical details of burns, and LOS were extracted from hospital medical records. Results: A total of 465 children and 327 adults with burns were identified over about 2.5 years. The ratio of male to female children with burn wounds was 1.6 and 2.3 in adults. The epidemiological characteristics of burns, including gender, season, location, etiology, degree and site, differed between children and adults. There were differences in external remedies used (e.g., traditional Chinese medicine powder) and wound protection (towels covering wounds) between children and adults, but few patients had both protected wounds and did not use external remedies. LOS was reduced with age (hazard ratio [HR] = 0.993) and skin grafting (HR = 0.339). LOS increased with the male gender (HR = 1.234), deep partial thickness burns (HR = 3.128), and full-thickness burns (HR = 1.791). LOS was increased when total body surface area (TBSA) of burns reached from 10% to 29% (HR = 3.978), when TBSA was greater than 30% (HR = 1.787), and heat vs. non-heat etiologies (HR = 1.497). Conclusion: Our findings for the epidemiological characteristics of burns in children and adults in Zunyi will help with a targeted awareness campaign and improve knowledge of first-aid and wound treatment. PMID- 30310757 TI - A new limestone-dwelling species of Micryletta (Amphibia: Anura: Microhylidae) from northern Vietnam. AB - We report on a new species of the genus Micryletta from limestone karst areas in northern Vietnam, which is described on the basis of molecular and morphological evidence. Micryletta nigromaculata sp. nov. is restricted to narrow areas of subtropical forests covering karst massifs in Cat Ba National Park (Hai Phong Province) and Cuc Phuong National Park (Ninh Binh Province) at elevations of 90 150 m a.s.l. In the phylogenetic analyses, the new species is unambiguously positioned as a sister lineage to all remaining species of Micryletta. We also discuss genealogical relationships and taxonomic problems within the genus Micryletta, provide molecular evidence for the validity of M. erythropoda and discuss the taxonomic status of M. steinegeri. We suggest the new species should be considered as Endangered (B1ab(iii), EN) following the IUCN's Red List categories. A discussion on herpetofaunal diversity and conservation in threatened limestone karst massifs in Southeast Asia is provided. PMID- 30310758 TI - Design and Study of a Smart Cup for Monitoring the Arm and Hand Activity of Stroke Patients. AB - This paper presents a new platform to monitor the arm and hand activity of stroke patients during rehabilitation exercises in the hospital and at home during their daily living activities. The platform provides relevant data to the therapist in order to assess the patients physical state and adapt the rehabilitation program if necessary. The platform consists of a self-contained smart cup that can be used to perform exercises that are similar to everyday tasks such as drinking. The first smart cup prototype, the design of which was based on interviews regarding the needs of therapists, contains various sensors that collect information about its orientation, the liquid level, its position compared to a reference target and tremors. The prototype also includes audio and visual displays that provide feedback to patients about their movements. Two studies were carried out in conjunction with healthcare professionals and patients. The first study focused on collecting feedback from healthcare professionals to assess the functionalities of the cup and to improve the prototype. Based on this paper, we designed an improved prototype and created a visualization tool for therapists. Finally, we carried out a preliminary study involving nine patients who had experienced an ischemic or hemorrhagic stroke in the previous 24 months. This preliminary study focused on assessing the usability and acceptability of the cup to the patients. The results showed that the cup was very well accepted by eight of the nine patients in monitoring their activity within a rehabilitation center or at home. Moreover, these eight patients had almost no concerns about the design of the cup and its usability. PMID- 30310760 TI - A Novel Antibacterial Membrane Electrode Based on Bacterial Cellulose/Polyaniline/AgNO3 Composite for Bio-Potential Signal Monitoring. AB - We propose a flexible, dry, and antibacterial electrode with a low and stable skin electrode contact impedance for bio-potential signal monitoring. We fabricated a bacterial cellulose/polyaniline/AgNO3 nanocomposite membrane (BC/PANI/AgNO3) and used it for bio-potential signal monitoring. The bacterial cellulose (BC) provides a 3-D nanoporous network structure, and it was used as a substrate material in the BC/PANI/AgNO3 nanocomposite membrane. Polyaniline (PANI) and AgNO3, acting as conductive and antibacterial components, respectively, were polymerized and deposited on the surfaces of BC nanofibers to produce uniform thin film membrane with flexible, antibacterial, and conductive properties. Various measurements were conducted, in terms of antibacterial activity, skin electrode contact impedance, and qualitative analysis of ECG signal recordings. The BC/PANI/AgNO3 membrane revealed 100% antibacterial activities against both the Staphylococcus aureus and Escherichia coli bacteria. The skin electrode contact impedance of the proposed BC/PANI/AgNO3 electrode is lower than that of the Ag/AgCl gel electrode, with the same active area. In addition, the electrocardiogram (ECG) signals acquired with the proposed electrodes have stable characteristic waveforms, and they are not contaminated by noise. The waveform fidelity of the BC/PANI/AgNO3 membrane electrodes over 800 ECG cardiac cycles is 99.49%, and after the electrodes were worn for 24 hours, a fidelity of 98.40% was recorded over the same number of cardiac cycles. With the low and stable skin electrode contact impedance, the proposed dry BC/PANI/AgNO3 membrane electrode provided high fidelity for ECG signal recordings, thus offering a potential approach for bio-potential signal monitoring. With the above benefits, the novel flexible and dry BC/PANI/AgNO3 electrode has a significant antibacterial. Most of all, it is the first research to develop antibacterial in the electrode design. PMID- 30310761 TI - Improved Detection of Lung Fluid With Standardized Acoustic Stimulation of the Chest. AB - Accumulation of excess air and water in the lungs leads to breakdown of respiratory function and is a common cause of patient hospitalization. Compact and non-invasive methods to detect the changes in lung fluid accumulation can allow physicians to assess patients' respiratory conditions. In this paper, an acoustic transducer and a digital stethoscope system are proposed as a targeted solution for this clinical need. Alterations in the structure of the lungs lead to measurable changes which can be used to assess lung pathology. We standardize this procedure by sending a controlled signal through the lungs of six healthy subjects and six patients with lung disease. We extract mel-frequency cepstral coefficients and spectroid audio features, commonly used in classification for music retrieval, to characterize subjects as healthy or diseased. Using the [Formula: see text]-nearest neighbors algorithm, we demonstrate 91.7% accuracy in distinguishing between healthy subjects and patients with lung pathology. PMID- 30310759 TI - Integrating Brain Implants With Local and Distributed Computing Devices: A Next Generation Epilepsy Management System. AB - Brain stimulation has emerged as an effective treatment for a wide range of neurological and psychiatric diseases. Parkinson's disease, epilepsy, and essential tremor have FDA indications for electrical brain stimulation using intracranially implanted electrodes. Interfacing implantable brain devices with local and cloud computing resources have the potential to improve electrical stimulation efficacy, disease tracking, and management. Epilepsy, in particular, is a neurological disease that might benefit from the integration of brain implants with off-the-body computing for tracking disease and therapy. Recent clinical trials have demonstrated seizure forecasting, seizure detection, and therapeutic electrical stimulation in patients with drug-resistant focal epilepsy. In this paper, we describe a next-generation epilepsy management system that integrates local handheld and cloud-computing resources wirelessly coupled to an implanted device with embedded payloads (sensors, intracranial EEG telemetry, electrical stimulation, classifiers, and control policy implementation). The handheld device and cloud computing resources can provide a seamless interface between patients and physicians, and realtime intracranial EEG can be used to classify brain state (wake/sleep, preseizure, and seizure), implement control policies for electrical stimulation, and track patient health. This system creates a flexible platform in which low demand analytics requiring fast response times are embedded in the implanted device and more complex algorithms are implemented in offthebody local and distributed cloud computing environments. The system enables tracking and management of epileptic neural networks operating over time scales ranging from milliseconds to months. PMID- 30310762 TI - Choosing Wisely Campaign - Innovations in Cardiovascular Science and The United States Healthcare System. AB - The United States (US) is the third most expensive health care system in the world, but despite that, the US ranked last in the top 50 countries of the world when it comes to the performance measures, such as healthcare efficiency, life expectancy, health care costs, and gross domestic product (GDP) percentage. The spending health care cost keeps increasing and most of the healthcare costs go to waste. Due to this reason, it is therefore extremely important to focus on improving the quality and to bring the costs in appropriate control. To avoid this issue, the Choosing Wisely Campaign (CWC) came into being in 2012. The CWC encourages discussions between providers and patients regarding the care based on the evidence base, free from harm, duplicative or redundant tests/procedures that the patient already received, and whether medications, tests, or procedures are really necessary. Although diagnostic tests or procedures are highly valued for decision-making, unnecessary testing creates harmful health services and an economic impact on the healthcare system. The CWC has spread widely throughout the world but has many challenges which are limiting the CWC in further adoption and spread in the US. To overcome challenges in implementing and spreading the CWC, the government, physicians, social media, and mass media play an important role. PMID- 30310763 TI - Improved Dose Conformity for Adjacent Targets: A Novel Planning Technique for Gamma Knife Stereotactic Radiosurgery. AB - Purpose In the current Gamma Knife (GK) planning system (GammaPlan, version 10.2, Elekta AB, Stockholm, Sweden), multiple adjacent brain metastasis (BMs) had to be planned sequentially if BMs were drawn separately, leading to less conformal target dose in the composite plan due to inter-target dose contribution and fine tuning of the shots being quite tedious. We proposed a method to improve target dose conformality and planning efficiency for such cases. Methods and Materials Fifteen patients with multiple BMs treated on the Leksell GK Perfexion system were retrospectively replanned in the Institutional Review Board (IRB) approved study. The recruitment criterion was all the BMs should be entirely encompassed within the maximum dose grid allowed in the GammaPlan. The BMs were first planned sequentially as routine clinic cases. The contours of the BMs were then exported to the VelocityAI (Varian, CA, USA) to generate a composite contour after a union operation, and all the BMs were planned again simultaneously using this composite contour in the GammaPlan. The inverse planning (IP) was employed in both methods with the same treatment time allowed for a fair plan comparison. Dose evaluation was performed in the VelocityAI with all planning magnetic resonance (MR) images, structure set and dose were exported to the VelocityAI. The dosimetery parameters, including conformality index (CI), V20Gy, V16Gy, V12Gy, and V5Gy, were compared between the two methods. Results The planning results from both methods were reviewed qualitatively and quantitatively. The proposed method exhibited superior CI, except for an outlier case with very tiny BMs. The mean and standard deviation (std.) of the Paddick CI for all patients were 0.76+/-0.11 for the proposed method, comparing to 0.69+/-0.13 for the sequential method. The V20Gy, V16Gy, V12Gy, and V5Gy for the proposed method were 10.9+/-0.9%, 9.5+/ 10.2%, 6.2+/-16.4% and 3.3+/-21.8%, all lower than those from the sequential method. Conclusions The proposed method showed improved target dose conformality for all cases except for very tiny BMs. Planning efficiency is considerably better with the combined target technique. The improved dose conformality will be beneficial to patients in long term with lowered risk of radiation necrosis after GK stereotactic radiosurgery (SRS). PMID- 30310764 TI - An open-source software ecosystem for the interactive exploration of ultrafast electron scattering data. AB - This paper details a software ecosystem comprising three free and open-source Python packages for processing raw ultrafast electron scattering (UES) data and interactively exploring the processed data. The first package, iris, is graphical user-interface program and library for interactive exploration of UES data. Under the hood, iris makes use of npstreams, an extensions of numpy to streaming array processing, for high-throughput parallel data reduction. Finally, we present scikit-ued, a library of reusable routines and data structures for analysis of UES data, including specialized image processing algorithms, simulation routines, and crystal structure manipulation operations. In this paper, some of the features or all three packages are highlighted, such as parallel data reduction, image registration, interactive exploration. The packages are fully tested and documented and are released under permissive licenses. PMID- 30310765 TI - Successful sequential treatment of refractory tumors caused by small cell carcinoma transformation and EGFR-T790M mutation diagnosed by repeated genetic testing in a patient with lung adenocarcinoma harboring epidermal growth factor receptor mutations: A case report. AB - NSCLC patients with EGFR mutations respond to EGFR-TKIs; however, the management of refractory tumors to EGFR-TKIs remains unclear. We demonstrated that repeated genetic testing might be useful for detecting resistance mechanisms as well as for decision-making in EGFR mutated NSCLC patients, following the emergence of resistance to the initial EGFR-TKIs. A 69-year-old man was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion. After tumor re-growth treated with erlotinib and chemotherapy, he was diagnosed with an SCLC transformation and administered chemotherapy to treat the SCLC. After the resistance of chemotherapy, the EGFR-T790M mutation by liquid biopsy was detected and treated him with osimertinib, which resulted in a clinical response. PMID- 30310766 TI - Usefulness of conventional magnetic resonance imaging, diffusion tensor imaging and neurite orientation dispersion and density imaging in evaluating postoperative function in patients with cervical spondylotic myelopathy. AB - Objective: The objective of this study was to evaluate the usefulness of T2 high signal intensity (T2-HSI) and decreased anteroposterior diameter (APD), diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in evaluating postoperative cervical cord function. Methods: The study included 57 postoperative cervical spondylotic myelopathy patients. Clinical evaluation and functional recovery assessments were performed using the modified Japanese Orthopaedic Association (mJOA) score and recovery rate. The presence of T2-HSI and decreased APD was recorded for exploring the relevance. Spearman correlation was applied to investigate the relationships between DTI and NODDI metrics and mJOA score. Multiple comparisons of T2 signal intensity, APD and diffusion metrics were evaluated by using multiple linear regression. Results: Only the recovery rate was significantly different between T2-HSI and non-T2-HSI (nT2-HSI) patients (chi2 = 4.466, p = 0.045). Significant differences were not observed between cervical cords with and without decreased APD. Diffusion metrics, including fractional anisotropy (p = 0.0005), mean diffusivity (p = 0.0008), radial diffusivity (p = 0.0003) and intracellular volume fraction (p = 0.001), were significantly correlated with mJOA score. The ability of T2 signal intensity (p = 0.421) and APD (p = 0.420) to evaluate the postoperative function was inferior to that of fractional anisotropy (p = 0.002), mean diffusivity (p = 0.001), radial diffusivity (p = 0.001) and intracellular volume fraction (p = 0.004). Conclusion: Conventional magnetic resonance imaging signs could be considered as a reference to make an approximate assessment, whereas DTI and NODDI could be better quantitative tools for evaluating the postoperative function and may help in interpreting residual symptoms. The translational potential of this article: DTI and NODDI could provide reliable postoperative evaluation and analysis for cervical spondylotic myelopathy patients. PMID- 30310768 TI - Welcoming talent? A comparative study of immigrant entrepreneurs' entry policies in France, Germany and the Netherlands. AB - This article explores the admission policies for self-employed non-EU immigrants wanting to start or move their business to the European Union (EU). Selecting immigrant entrepreneurs is a specific and understudied policy strand in the battle for talent. No common EU policy is available (yet) and although national policies do show some similarity, they differ in respect of how and who decides if an entrepreneur serves a national economic interest. By presenting a first time model for defining the level of welcoming, this study adds an instrument to the toolbox of both scholars and policy makers for evaluating immigration policies. Whether a policy is welcoming depends on material criteria, such as entry conditions giving the entrepreneur a fair chance and on the formal criteria of the applicable procedures and the actors involved in the decision-making process. The body of the article constitutes of a legal comparison between French, German and Dutch entry policies for non-EU entrepreneurs. The article concludes that a future EU policy on welcoming immigrant entrepreneurs must set standards for a large variety of entrepreneurs, allow for the economic interest to be broadly defined and have, at the least, transparent and practical procedures. PMID- 30310767 TI - Novel heterozygous mutations in the PGAM2 gene with negative exercise testing. AB - Pathogenic variants in the PGAM2 gene are associated with glycogen storage disease type X (GSDX) and is characterized by exercise induced muscle cramping, weakness, myoglobinuria, and often tubular aggregates in skeletal muscle. We report here a patient diagnosed with GSDX at 52 years of age with a normal increase in post-exercise lactate with both anaerobic and aerobic exercise. Genetic testing found two novel PGAM2 variants (c.426C > A, p.Tyr142Ter and c.533delG, p.Gly178Alafs*31). PMID- 30310769 TI - Perception of peri-menopausal and postmenopausal Lebanese women on osteoporosis: A cross-sectional study. AB - Introduction: Osteoporosis is a generalized skeletal disorder characterized by decreased bone mineral density and microarchitectural deterioration, resulting in increased susceptibility to fractures. The prevalence of osteoporosis in Lebanon, defined as T-score <-2.5 at the total hip using NHANES gender-specific database was estimated to be 31% among postmenopausal women. Purpose: To assess the general perception of osteoporosis among women in Lebanon as well as their general knowledge of its lifestyle, risk factors, diagnostic, preventive and therapeutic measures. Methods: A cross-sectional study was conducted in Lebanon between January and December 2017. Women above the age of 50 were invited to participate. A standardized questionnaire regarding the perception of personal risk of osteoporosis and fractures was used. Risk factors for osteoporosis, previous fractures or falls, family history of fracture, smoking, alcohol consumption, and secondary causes of osteoporosis were evaluated. Data were recorded on excel and analyzed on SPSS using variety of descriptive analysis, ANOVA tests, and others. P value <0.05 was considered to be statistically significant. Results: From 396 interviewed women, 85% were in menopause and were more likely to be diagnosed with osteoporosis. 45% knew the true definition of osteoporosis and their most frequent source of information was doctors. Around 60% had heard of BMD screening but only 54.5% of those women actually did it. Conclusion: This study reveals that osteoporosis knowledge and perception is low among the Lebanese woman aged 50 years and older. PMID- 30310771 TI - Guidelines for establishing an etching procedure for dislocation density measurements on multicrystalline silicon samples. AB - With multicrystalline silicon becoming the main material used for photovoltaic applications and dislocations being one of the main material limitations to better solar cell efficiency, etch pit density measurements are gaining more importance. Traditionally, etch pit density measurements are based on selective etching of silicon samples. The majority of the etchants have been developed for monocrystalline samples with known orientation, while those developed for multicrystalline samples have been less investigated and might need some optimization. In this study, we use and compare the PVScan tool, which provides a quick way to assess dislocation density on selectively etched samples, and microscope image analysis. We show how the etching methods used for dislocation density measurements can affect the results, and we suggest how to optimize the Sopori etching procedure for multicrystalline silicon samples with high dislocation densities. We also show how the Sopori etchant can be used to substitute Secco while maintaining a high precision of dislocation density measurements, but without the toxic hexavalent chromium compounds. PMID- 30310772 TI - Personalized medicines - are pharmacists ready for the challenge? AB - The field of personalized medicine affords multiple opportunities to pharmacists, and pharmacists have specific knowledge, skills and abilities that make them uniquely suited to advance the use of personalized medicine as a clinical tool. The pharmacy profession as a whole, however, has been slow to embrace the concept of clinical pharmacogenetics and is now facing a critical juncture that can potentially redefine the professional identity of the pharmacist. Before practice transformation can occur, however, it is important for our profession to ask and fully explore the following question: Are pharmacists ready for the challenge of personalized medicine? When assessing the readiness of pharmacy for personalized medicine, one must consider factors that are specific to the individual pharmacist as well as systematic considerations that allow pharmacists to successfully integrate personalized medicine into their individual practice area. These include factors such as education and training, competency, an attitude of engagement and adequate support and guidance. Personnel, information technology and laboratory infrastructure are also critical elements that are required, and financially sustainable practice models must be developed. Successful advancement of clinical pharmacogenetics will also require the profession to clearly define their vision of what success looks like and where it wants to be at the end of the transformational journey. Without a clear destination, we will continue to move as individuals in different directions and fail to progress as a whole. While pharmacists might not be completely ready for the challenge of pharmacogenetics, they are most certainly up to facing the challenge. The time is right and the stage is set for pharmacy to embark on another transformative journey - a journey that will redefine the role of the pharmacist and will secure a place for pharmacy in the era of personalized medicine and beyond. PMID- 30310773 TI - Assessment of meatal stenosis in neonates undergoing circumcision using Plastibell Device with two different techniques. AB - Purpose: It was intended to compare meatal stenosis (MS) as a late complication of neonatal circumcision by using two different methods of Plastibell Device circumcision. Materials and methods: A total of 2,307 healthy term newborns (6-36 hours) who were born between 2007 and 2009 in Niknafs Medical Center of Rafsanjan, Iran, were simply randomized into two groups in a controlled, nonblinded clinical trial. In group A (1,102 neonates), the frenulum was maintained intact without any manipulation, and in group B (1,205 neonates) frenular hemostasis was performed in all cases by thermal cautery. MS was assessed by follow-up visits that were made for all cases at the 24-72 hours, 60th day, 12th month, and 16th month after circumcision. Results: At 2 months follow-up visit, the rate of MS in group A was 4.9% (54) and in group B was 5.9% (71), which was not statistically significant. After 12 months, MS in group A was 8.5% (94) and in group B was 13.7% (165), which was statistically significant (P<0.001). At 16 months after circumcision, in the frenulum intact group, MS was 13.8% (152) and in the cautery group, it was 18.9% (228), which was compatible with significant difference (P=0.001). Conclusion: Our experience with large group of cases revealed that neonatal circumcision by using Plastibell Device with intact frenulum technique decreases the rate of delayed MS. PMID- 30310770 TI - Association between lower estimated premorbid intelligence quotient and smoking behavior in patients with schizophrenia. AB - Aim: We aimed to investigate the involvement of premorbid intelligence quotient in higher prevalence of smoking in patients with schizophrenia. Methods: Participants included 190 patients with schizophrenia (mean +/- standard deviation age: 37.7 +/- 10.8 years; 88 males and 102 females) and 312 healthy individuals (mean +/- standard deviation age: 38.1 +/- 13.8; 166 males and 146 females), matched for age, sex, and ethnicity (Japanese). Premorbid intelligence quotient was estimated using the Japanese Adult Reading Test and distress symptoms were assessed using the Hopkins Symptom Check List. Current smoking information was collected according to self-declarations. Results: As expected, the smoking rate was higher, while mean education level and Japanese Adult Reading Test scores were significantly lower, in patients with schizophrenia than in healthy individuals (p < 0.01). The mean education level and Japanese Adult Reading Test scores were significantly lower in the smoker group than in the non smoker group in both patients and healthy individuals (p < 0.05). In the patient group alone, Hopkins Symptom Check List subscale and total scores were significantly higher in the smoker group than in the non-smoker group (p < 0.05). A multivariate regression analysis showed that the Japanese Adult Reading Test score was a significant and negative predictor for smoking (p < 0.001, odds ratio = 0.97; 95% confidence interval: 0.96-0.99). Conclusion: Our results suggest that lower estimated premorbid intelligence quotient is an important variable in elucidating smoking behavior in humans and may be associated with higher prevalence of smoking in patients with schizophrenia. PMID- 30310774 TI - Preparation and Evaluation of Lipid-Based Liquid Crystalline Formulation of Fenofibrate. AB - Background: Many drugs have poor water solubility and so the oral delivery of such drugs is usually associated with limitation of low bioavailability and lack of dose proportionality. Lipid-based liquid crystal (LC) systems are excellent potential formulations for increasing dissolution and bioavailability of drugs. The aim of the present study was to formulate lipid-based LC containing fenofibrate (FFB) as a hydrophobic drug. Materials and Methods: The studied variables included lipid and stabilizer concentrations and the type of stabilizer. The LC formation was identified by the polarized optical microscopic method. The effects of variables on formulation characteristics such as particle size, drug release, and rheological behavior were evaluated. Results: The results showed that the prepared formulations had the particle size between 42 and 503 nm. The drug release profiles showed that FFB had the continuous release from the formulations and the highest dissolution efficiency was seen in formulation prepared by 1.5% of glyceryl monostearate and 0.5% of Pluronic F127 as the stabilizer. The change of stabilizer type from colloidal silica to Pluronic F127 increased the drug release, significantly. Conclusions: In the most formulations of FFB LCs, the DE% was more than the pure drug, and therefore, it seems that the liquid crystalline formulations can be effective for enhancing drug release. Furthermore, drug release rate depended on the stabilizer type so that the presence of colloidal silica caused slower drug release compared to Pluronic F127. PMID- 30310775 TI - The Relationship between Dietary Patterns with Blood Pressure in Iranian Army Staffs. AB - Background: Hypertension is one of the most common noncommunicable diseases in the world. One of the most effective factors on blood pressure (BP) is nutrition. The aim of this study was to examine the relationship between dietary patterns and BP among military staffs. Materials and Methods: The study was carried out among 405 military staffs between 22 and 51 years old. Demographic, anthropometric information, and BP of participants were evaluated by standard methods. The dietary intakes were collected using a food frequency questionnaire (FFQ). Dietary patterns were identified using a posteriori method, factor analysis, and based on the FFQ. To check the relationship between BP and dietary patterns, we used multivariate linear regression in different models, relationship were adjusted for Age, sex, marital, smoking, income, body mass index, waist-to-hip ratio, family history of hypertension, energy intake, and physical activity level. Results: Two dominant dietary patterns were identified in the participants: Healthy and western pattern. The association of dietary patterns with systolic BP (SBP) and diastolic BP (DBP) was exhibited in different models. There was no relationship between SBP and DBP with healthy pattern (P = 0.269 and P = 0.638, respectively) and western pattern (P = 0.648 and P = 0.315, respectively) after adjustments. Conclusion: Our findings indicated that dietary patterns did not have any significant relationship with SBP and DBP after adjustment for confounders in the healthy military. To identify the dietary patterns associated with BP in healthy military, more strong design studies and more participants should be conducted in the future. PMID- 30310776 TI - SOFT Syndrome: The First Case in Iran. AB - Primordial dwarfism (PD) is a group of rare genetically heterogeneous disorders consisted of disorders with intrauterine growth retardation continued through the life. SOFT syndrome with characteristics of short stature, onychodysplasia, facial dysmorphism, and hypotrichosis has been presented as a subtype of PD. Only 20 cases of SOFT syndrome have been reported in world to date, but none of them were not in Iran. Our case was 6.5-year-old girl with a complaint of growth retardation including height of 97 cm (Z = -4.6 standard deviation [SD]) and weight of 14 kg (Z = -4 SD) referred to growth clinic. She had a prominent forehead, triangular face, short limbs, malformed nails, and crowded teeth and her psychomotor function was normal. Laboratory and karyotype tests were normal while she was homozygous for c.G491A mutation of POC1A gene thus SOFT syndrome diagnosis was confirmed for her and recombinant growth hormone therapy was discontinued. PMID- 30310777 TI - Retraction: The Role of Stem Cell Therapy in Multiple Sclerosis: An Overview of the Current Status of the Clinical Studies. AB - [This retracts the article on p. 46 in vol. 5, PMID: 27110543.]. PMID- 30310778 TI - Erratum: A Randomized Double-blind Placebo-controlled Trial to Assess the Effect of Tamarind seed in Premature Ejaculation. AB - [This corrects the article on p. 59 in vol. 7, PMID: 29862208.]. PMID- 30310780 TI - Bone marrow infiltration of histiocytic sarcoma. PMID- 30310779 TI - Multiple myeloma in Korea: risk stratification and initial treatment. PMID- 30310782 TI - Multifocal large aggregates of pseudo-Gaucher cells in chronic myeloid leukemia. PMID- 30310781 TI - Methacrylate pulmonary embolism after percutaneous vertebroplasty. PMID- 30310783 TI - Pseudo-Chediak-Higashi granules in myeloid cells in therapy-related AML with RUNX1-RUNX1T1. PMID- 30310784 TI - Clinical features and survival outcomes of patients with lymphoplasmacytic lymphoma, including non-IgM type, in Korea: a single-center experience. AB - Background: The incidence of lymphoplasmacytic lymphoma (LPL) is lower in Asian than in Western populations. Few studies have described the clinical features and treatment outcomes of patients with LPL, including non-IgM LPL, in East Asia. Methods: We retrospectively analyzed patients diagnosed with LPL at Asan Medical Center between January 2001 and March 2016. We evaluated the clinical features and survival outcomes of patients with LPL and non-IgM LPL and compared these data with those of patients with LPL/Waldenstrom's macroglobulinemia (WM). Results: The median age at diagnosis of patients with LPL was 61.5 years (range, 34-77 yr); most patients were male (91%). Approximately three-quarters of the 22 patients with LPL were in the low or intermediate risk groups according to the International Prognostic Scoring System for Waldenstrom's Macroglobulinemia classification. The median follow-up duration was 75 months [95% confidence interval (CI), 48-102 mo], and the median overall survival (OS) was 81 months (95% CI, 0-167 mo). The number of patients in the non-IgM LPL group who exhibited extramedullary involvement was higher than in the LPL/WM group. OS of the LPL/WM group was improved compared with that of the non-IgM LPL group [median not reached vs. 10.0 mo (95% CI, 0-36.7); P=0.05]. Conclusion: We present a single center experience of 22 patients with LPL, including a non-IgM cohort, in Korea. The treatment of non-IgM LPL was heterogeneous, and patients with non-IgM LPL showed a higher 5-year mortality rate and more adverse prognostic factors than those with LPL/WM. PMID- 30310785 TI - The prognostic impact of lymphocyte subsets in newly diagnosed acute myeloid leukemia. AB - Background: Tumor-infiltrating lymphocytes, which form a part of the host immune system, affect the development and progression of cancer. This study investigated whether subsets of lymphocytes reflecting host-tumor immunologic interactions are related to the prognosis of patients with acute myeloid leukemia (AML). Methods: Lymphocyte subsets in the peripheral blood of 88 patients who were newly diagnosed with AML were analyzed by quantitative flow cytometry. The relationships of lymphocyte subsets with AML subtypes, genetic risk, and clinical courses were analyzed. Results: The percentages of T and NK cells differed between patients with acute promyelocytic leukemia (APL) and those with AML with myelodysplasia-related changes. In non-APL, a high proportion of NK cells (>16.6%) was associated with a higher rate of death before remission (P=0.0438), whereas a low proportion of NK cells (<=9.4%) was associated with higher rates of adverse genetic abnormalities (P=0.0244) and relapse (P=0.0567). A multivariate analysis showed that the lymphocyte subsets were not independent predictors of survival. Conclusion: Lymphocyte subsets at diagnosis differ between patients with different specific subtypes of AML. A low proportion of NK cells is associated with adverse genetic abnormalities, whereas a high proportion is related to death before remission. However, the proportion of NK cells may not show independent correlations with survival. PMID- 30310786 TI - Syndecan-1 (sCD138) levels in chronic lymphocytic leukemia: clinical and hematological correlations. AB - Background: Syndecan-1 (sCD138) has recently been suggested to predict the clinical course of early-stage chronic lymphocytic leukemia (CLL), but few studies have been reported. This study assessed the role of syndecan-1 in the prognosis of patients with CLL and its correlation with other prognostic markers. Methods: This prospective study was performed in the hematology department of an Indian tertiary care center, over nineteen months (Jun. 2009-Jan. 2011). Forty nine new patients with CLL presented during this period and were included. Twenty age- and gender-matched healthy patients served as controls, and six patients with multiple myeloma were included as positive controls. Baseline serum syndecan 1 concentrations were measured for all patients at presentation using ELISA (Diaclone, Besancon, France). At baseline, patients were divided into low (N=10), intermediate (N=18) and high (N=21) risk cohorts. Serum syndecan-1 levels in these patient subgroups were compared with clinical and laboratory parameters. Results: The median syndecan-1 level in patients with CLL (73.32 ng/mL, range, 28.71-268.0 ng/mL) was marginally higher than that in healthy patients (63.10 ng/mL, range, 55.0-75.11 ng/mL). At presentation, syndecan-1 levels in patients with CLL correlated strongly with symptomatic disease (cytopenias, P=0.004) and higher clinical stage (Rai stage III and IV, P=0.001) markers and poorly with beta2-microglobulin level (P=0.270), diffuse BM infiltration (P=0.882), and surrogate mutation status markers (CD 38, P=0.174 and ZAP-70, P=0.459). Syndecan 1 levels dichotomized by the median value were higher with progressive disease markers, e.g. shorter lymphocyte doubling time (LDT, P=0.015) and increased treatment (P=0.099). Conclusion: In CLL, serum syndecan-1 (sCD138) levels at presentation correlate with disease burden, and higher baseline levels may predict early treatment. PMID- 30310787 TI - Effectiveness of L-asparaginase-based regimens compared to anthracycline-based regimens in newly diagnosed extranodal NK/T-cell lymphoma, nasal type: a single Mexican center experience. AB - Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) has a high prevalence in Asia and Latin American countries, such as Mexico, where it encompasses 40% of all T-cell non-Hodgkin lymphomas. Historically, responses to anthracycline-based therapies have been disappointing. Since data about the effectiveness of L-asparaginase-based regimens in Mexico are limited, we compared both therapies in our center. Methods: We performed a retrospective cohort of patients with newly diagnosed ENKTCL, who were divided into two groups for treatment and analysis (group 1: L-asparaginase-based regimen and group 2: anthracycline-based regimen) between 2001 and 2016. Results: Of 36 patients with newly-diagnosed ENKTCL, 33 received at least one cycle of chemotherapy (22 in group 1 and 11 in group 2). Over a median follow-up interval of 17 months (range, 0-167), a complete response (CR) was observed in 45.5% of patients in group 1, compared to 27% of group 2 (P=0.45). Progression was more frequently observed in group 2 than in group 1 (54.5% vs. 18.4%, P=0.04). The median overall survival (OS) was 44 months in group 1, compared to 5 months in group 2 (P=0.012). The multivariate analysis showed that failure to achieve a CR after first-line therapy was the only significant factor for OS (HR, 3.04; 95% CI, 1.4-6.5; P=0.005). Conclusion: L-asparaginase-based regimens for patients with newly diagnosed ENKTCL confer a survival advantage over anthracycline-based regimens. PMID- 30310788 TI - Smudge cell percentage as a surrogate marker for ZAP-70 expression in patients with chronic lymphocytic leukemia. AB - Background: This study aimed to evaluate the prognostic value of smudge cell percentage as a surrogate marker for zeta-chain-associated protein kinase 70 (ZAP 70) expression in chronic lymphocytic leukemia (CLL) patients. Methods: Sixty three newly diagnosed CLL patients were investigated at the Hematology Department of the Medical Research Institute of Alexandria University with complete blood count, lactate dehydrogenase, beta2 microglobulin levels, ZAP-70 expression, and estimation of the percentage of smudge cells. Results: The percentage of smudge cells ranged from 2 to 58% with a mean of 24.03+/-13.98%. Higher percentages of smudge cells (>30%) were statistically significantly associated with markers of better prognosis (negative ZAP-70, early-stage disease according to the Binet and Rai staging systems, as well as low and intermediate risk CLL prognostic index). The percentage of smudge cells showed significantly negative correlation with the ZAP-70 expression and higher area under the curve for prediction of ZAP-70 positivity with better survival for 36 months in patients with >30% smudge cells. Conclusion: The percentage of smudge cells at presentation of newly diagnosed CLL patients could be used as a surrogate marker for ZAP-70 expression and an additional prognostic marker for disease progression. PMID- 30310789 TI - Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. AB - Background: Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies. Methods: This subset analysis includes diffuse large B cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1-3), and dexamethasone (40 mg PO d 1 4) followed by filgrastim (10 mcg/kg/d sc. through collection). Results: We successfully collected stem cells from all patients, with a median of 7.9*106/kg of body weight (range, 4.4 to 17.3*106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5). Conclusion: For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective. PMID- 30310790 TI - The incidence of venous thromboembolism is not lowin Korean patients with advanced pancreatic cancer. AB - Background: Pancreatic cancer is among the most common malignancies associated with venous thromboembolism (VTE). Asian patients are known to have a lower incidence of VTE compared to Caucasian patients. However, few studies have investigated the incidence of VTE in Asian patients with pancreatic cancer. Methods: This retrospective review of medical records was performed on 505 patients with histopathologically proven advanced stage pancreatic cancer, from January 2006 to December 2012, at Soonchunhyang University Hospitals. Results: Ninety-four patients (18.6%) had at least one pulmonary embolism (PE), deep vein thrombosis (DVT), or splanchnic vein thrombosis (SVT); 38 patients had isolated SVT; and 56 patients (11.1%) had at least one classic VTE (PE and/or DVT of lower extremities). Patients with more advanced stages of pancreatic cancer (distant metastatic stage, recurrence) or who had received chemotherapy had a higher incidence of classic VTE. Patients who were simultaneously diagnosed with pancreatic cancer and classic VTE had a poorer prognosis than patients with subsequent VTEs. There was a significant difference in overall survival (OS) between the presence and absence of a concurrent classic VTE diagnosis (median: OS, 2.1 mo vs. 10.7 mo; P<0.001). Even when VTE included SVT, the result was similar (P<0.001). Conclusion: In Korean patients with advanced pancreatic cancer, the incidence of VTEs is comparable to that of Caucasian patients. We also found that pancreatic cancer patients with concurrent VTEs had a poor prognosis compared to patients who developed VTEs later. PMID- 30310791 TI - A cross-sectional retrospective study to analyze the underlying causes and clinical characteristics of children with reactive thrombocytosis at a Korean tertiary medical center. AB - Background: Reactive thrombocytosis (RT) is a common condition among children, although no studies have examined the etiology or clinical characteristics of RT among Korean children. Methods: This retrospective study evaluated children with RT at a single Korean tertiary center during a 10-year period. Results: RT accounted for 13.5% of children who were admitted to the pediatric ward (4,113/30,355): mild RT, 82.7%; moderate RT, 14.1%; severe RT, 1.1%; and extreme RT, 2.1%. There was a negative correlation between platelet count and Hb level (P=0.008). There were positive correlations between platelet count and WBC (P=0.001), erythrocyte sedimentation rate (ESR) (P=0.007), and admission duration (P=0.006). The most common cause of RT was infection and the second most common was Kawasaki disease (KD). The highest proportion of lower respiratory tract infection was observed in extreme RT (P<0.001). The proportion of KD was highest in extreme RT (P<0.001) and in children aged 1-7.9 years (P<0.001). The proportion of refractory KD was highest in extreme RT (P=0.005). In cases of KD, there was a positive correlation between platelet count and fever duration (P=0.006). Non-KD autoimmune inflammation was only observed in mild/moderate RT, and its proportion was highest in children aged 8-18 years (P<0.001). Conclusion: In children, more severe RT was associated with lower Hb, increased WBC, ESR, and prolonged admission. With respiratory infection or KD, extreme RT was associated with more severe disease course. PMID- 30310793 TI - A misleading presentation of T cell/histiocyte rich B-cell lymphoma mimicking osteomyelitis. PMID- 30310792 TI - Spectrum of mitochondrial genome instability and implication of mitochondrial haplogroups in Korean patients with acute myeloid leukemia. AB - Background: Mitochondrial DNA (mtDNA) mutations may regulate the progression and chemosensitivity of leukemia. Few studies regarding mitochondrial aberrations and haplogroups in acute myeloid leukemia (AML) and their clinical impacts have been reported. Therefore, we focused on the mtDNA length heteroplasmies minisatellite instability (MSI), copy number alterations, and distribution of mitochondrial haplogroups in Korean patients with AML. Methods: This study investigated 74 adult patients with AML and 70 controls to evaluate mtDNA sequence alterations, MSI, mtDNA copy number, haplogroups, and their clinical implications. The hypervariable (HV) control regions (HV1 and HV2), tRNAleu1 gene, and cytochrome b gene of mtDNA were analyzed. Two mtDNA minisatellite markers, 16189 poly-C (16184CCCCCTCCCC16193, 5CT4C) and 303 poly-C (303CCCCCCCTCCCCC315, 7CT5C), were used to examine the mtDNA MSI. Results: In AML, most mtDNA sequence variants were single nucleotide substitutions, but there were no significant differences compared to those in controls. The number of mtMSI patterns increased in AML. The mean mtDNA copy number of AML patients increased approximately 9-fold compared to that of controls (P<0.0001). Haplogroup D4 was found in AML with a higher frequency compared to that in controls (31.0% vs. 15.7%, P=0.046). None of the aforementioned factors showed significant impacts on the outcomes. Conclusion: AML cells disclosed more heterogeneous patterns with the mtMSI markers and had increased mtDNA copy numbers. These findings implicate mitochondrial genome instability in primary AML cells. Therefore, mtDNA haplogroup D4 might be associated with AML risk among Koreans. PMID- 30310794 TI - Massive splenomegaly: flow cytometry as a diagnostic tool for systemic mastocytosis. PMID- 30310795 TI - Emergence of chronic myeloid leukemia following autologous stem cell transplantation in a young woman with multiple myeloma. PMID- 30310796 TI - Philadelphia-positive mixed phenotype acute leukemia presenting with PML-RARalpha fusion transcript without t(15;17) on cytogenetic studies. PMID- 30310797 TI - Low-grade follicular lymphoma involvement of the bone marrow with a mixed paratrabecular, diffuse, and massive pattern expressing typical mantle cell lymphoma immunophenotype CD23-/FMC7+: a case report. PMID- 30310798 TI - Erratum: Evaluation of thrombocytopenia in the hematology clinic: a case series from a large tertiary care center. AB - [This corrects the article on p. 166 in vol. 53, PMID: 29963525.]. PMID- 30310799 TI - Colonoscopy learning curves for colorectal surgery fellow trainees: experiences with the 15-year colonoscopy training program. AB - Purpose: This study aimed to analyze the learning curves for colorectal surgery fellows in a colonoscopy training program. Methods: Between May 2003 and February 2017, 60 surgical fellows joined our 1-year colonoscopy training program as trainees and performed 43,784 cases of colonoscopy. All trainees recorded their colonoscopy experiences prospectively into the database. After excluding 6 trainees, who had experience with performing more than 50 colonoscopies before participating in our training program or who discontinued our training program with experience performing less than 300 colonoscopies, this study included 54 trainees who had performed 39,539 colonoscopy cases. We analyzed the cecal intubation rate (CIR) and cecal intubation time (CIT) using the cumulative sum (Cusum) technique and moving average method to assess the technical colonoscopy competence. Results: Overall, the CIR by the trainees was 80.7%. The median number of cases of colonoscopy performed during the training period for each trainee was 696 (range, 322-1,669). The trainees were able to achieve a 90% CIR with 412 and 493 procedures when analyzed using the moving average and the Cusum, respectively. Using the moving average method, CIRs after 150, 300, and 400 procedures were 67.0%, 84.1%, and 89.2%, respectively. The CIT of trainees continuously decreased until 400 successful cases. Median CITs were 9.4, 8.3, and 7.4 minutes at 150, 300, and 400 successful cases, respectively. Conclusion: We found that more than 400 cases of experience were needed for technical competence in colonoscopy. Continuous teaching and monitoring is required until trainees become sufficiently competent. PMID- 30310800 TI - Focal change of the pancreatic texture using a direct injection mixture of N butyl cyanoacrylate and lipiodol in the pig model: a strategy for preventing pancreatic leakage during pancreatic surgery. AB - Purpose: A soft texture of the pancreas is one of the most important predisposing factors for a pancreatic fistula. Thus, in a porcine model, we investigated a method to harden the pancreas locally by directly injecting an artificial material. Methods: During the laparotomy, 51 samples from 17 pigs, including 13 survival models, were randomly divided into 3 groups and either received a direct injection into the pancreas of MHL (1:4 mixture of histoacryl [n-butyl cyanoacrylate] and lipiodol) (group E) or saline (group C) or only received a pinprick into the pancreas without injecting a substance (sham). We measured the change in the pancreatic hardness after the injection using a durometer and examined the histological change of the pancreas using the fibrosis grade in the survival model. Results: The postinjection hardness of the pancreas was significantly increased in group E compared to group C and the sham group (P < 0.001). Pathologically, all cases in group E showed a severe fibrotic change, whereas the other groups demonstrated mild to no fibrosis (P < 0.001). The fibrosis in group E was localized to the area of the injection, while the surrounding areas were preserved. Conclusion: The direct injection of MHL could induce focal hardening and fibrotic changes in the pancreas of the porcine model. PMID- 30310801 TI - Prognostic influence of 3-dimensional tumor volume on breast cancer compared to conventional 1-dimensional tumor size. AB - Purpose: The prognostic influence of 3-dimensional tumor volume (Tv) on breast cancer compared to conventional 1-dimensional tumor size (T) was investigated. Methods: Analysis was performed on a cohort of 8,996 primary breast cancer patients who were initially diagnosed with TNM stage I-III. Tumor size was defined as the maximum tumor dimension, and Tv was calculated by the equation of (4pi * r1 * r2 * r3)/3; r1, r2, and r3 were defined as half of the largest, intermediate, and shortest dimension of the tumor, respectively. Tv was classified into Tv1, Tv2, and Tv3 according to the cut off values of 2.056 cm3 and 20.733 cm3. Results: The survival curves according to both the T and Tv categories were clearly differentiated (all P < 0.001), as were those for staging by T and Tv (all P < 0.001). In T1 and T2 tumors, the Tv1 group showed superior survival over the Tv2 group (T1, P < 0.001; T2, P = 0.001). Univariate and multivariate analysis both indicated that Tv was a significant prognostic factor (both P < 0.001). The receiver operating characteristic curve showed that the area under the curves were 0.712 (P < 0.001) for Tv and 0.699 (P < 0.001) for T. Positive correlations were observed between the number of positive nodes and T (coefficient = 0.325; P < 0.001), and between the number of positive nodes and Tv (coefficient = 0.321; P < 0.001). Conclusion: Tv classification works well for predicting the prognosis of breast cancer, and it is a better predictor than conventional T classification in several aspects. Further studies are needed to validate the practical usefulness of Tv classification in clinical settings. PMID- 30310802 TI - Midterm body composition changes after open distal gastrectomy for early gastric cancer. AB - Purpose: This study evaluated midterm changes in body composition after open distal gastrectomy for early gastric cancer. Methods: Data from 138 gastric cancer patients who underwent open distal gastrectomy at Kyungpook National University Chilgok Hospital between January 2011 and December 2012 were collected and reviewed. Patients with pathological stage I gastric cancer and with no comorbidities at diagnosis were enrolled. Body composition data from segmental multifrequency bioelectrical impedance analysis were obtained preoperatively and at 1, 2, and 3 years after surgery. Results: The mean body weight losses at 1 and 3 years after surgery were 6.1 kg and 5.8 kg, respectively (P < 0.001). The protein mass, skeletal muscle mass, and fat-free mass decreased continuously until 3 years after surgery (0.5 kg, 1.6 kg, and 2.4 kg, respectively; P < 0.001). The average body fat mass and visceral fat area loss at 1 year after surgery were 4.7 kg and 20.5 cm2, respectively (P < 0.001). After 1 postoperative year, the body fat mass and visceral fat areas increased continuously, up to 12.2 kg and 74.2 cm2 at 3 years after surgery, respectively (+1.4 kg and +1.2 cm2, respectively). Conclusion: More intense nutritional and exercise programs may be important after gastric cancer surgery, especially during the first postoperative year. PMID- 30310803 TI - Significance of lymph node metastasis in the survival of stage IV colorectal cancer by hematogenous metastasis. AB - Purpose: Although lymph node (LN) metastasis is an important prognostic marker of colorectal cancer (CRC), the effect of LN metastasis on the survival of stage IV CRC is debated yet. Methods: LN status and survivals as well as clinicopathological features of synchronous stage IV CRC patients, operated for 8 years, were analyzed. Patients with hematogenous metastases were included only but those with peritoneal seeding or preoperative adjuvant therapy were not included. Results: Total 850 patients were enrolled and 77 (9.1%) were without LN metastases (N0M1). N0M1 patients were older and have favorable pathological features including lower CEA than patients with LN metastasis (N + M1). The pathologically poor features accumulated with N stage progression within N + M1. N0M1 had better 5-year overall survival (OS) and disease free survival than N + M1. And 5-year OS's within N + M1 group were stratified and different according to N stage progression, although the effect of N stage progression is different according to curative resection or not. When compared with stage III, 5-year OS of N0M1 with curative resection was comparable to that of anyTN2aM0 and was better than anyTN2bM1. Conclusion: LN metastasis is a significant prognostic factor in stage IV by hematogenous metastasis, too. N stage progression accumulates pathologically poor prognostic factors. However, the effect on survival of each N stage progression differs depending on curative resection or not of the hematogenous metastases. PMID- 30310804 TI - Intraoperative abortion of adult living donor liver transplantation: 15 cases from 1,179 cases in 20 years of experience in a single center. AB - Purpose: This study aimed to report intraoperative abortion of adult living donor liver transplantation (LDLT). Methods: From June 1997 to December 2016, 1,179 adult LDLT cases were performed. 15 cases (1.3%) of intraoperative abortions in LDLT were described. Results: Among 15 cases, 5 intraoperative abortions were donor-related, and remaining 10 cases were recipient-related. All donor-related abortions were due to unexpected steatohepatitis. Among remaining 10 recipient related intraoperative abortions, unexpected extension of hepatocellular carcinoma was related in 5 cases. Two cases of intraoperative abortions were related to bowel inflammation, and 2 cases were associated with severe adhesion related to previous treatment. One recipient with severe pulmonary hypertension was also aborted. Conclusion: Complete prevention of aborted LDLT is still not feasible. In this regard, further efforts to minimize intraoperative abortion are required. PMID- 30310806 TI - Methods used in the study, Evaluation of a polyurethane foam dressing impregnated with 3% povidone-iodine (Betafoam) in a rat wound model, led to unreliable results. PMID- 30310805 TI - Usefulness of dynamic risk stratification in pediatric patients with differentiated thyroid carcinoma. AB - Purpose: Recently, the American Thyroid Association (ATA) dynamic risk stratification (DRS) has been verified to be more valuable than the static anatomical staging system for predicting prognosis in patients with differentiated thyroid carcinoma (DTC). The purpose of this retrospective study was to compare the clinical usefulness of DRS, which is based on the response to initial treatment, with that of ATA initial risk stratification in pediatric patients. Methods: A total of 144 pediatric patients underwent thyroid operation from August 1982 to December 2013 at Yonsei University Hospital (Seoul, Korea). Among them, 128 patients with complete clinical data were enrolled in this study. Clinicopathologic features and surgical outcomes were retrospectively analyzed by medical chart review. The mean follow-up duration was 11.5 years. Results: The mean tumor size was 2.1 cm; 80.4% of patients were diagnosed with conventional papillary thyroid carcinoma, and 7.0% of patients were diagnosed with follicular thyroid carcinoma. Low-risk patients had the highest probability of an excellent response to initial treatment (66.6%). High-risk patients had the highest probability of a structural incomplete response (100%) and the lowest probability of an excellent response (11.1%). The ATA risk stratification and the DRS system were independent risk factors for disease-free survival (DFS) (P = 0.041 and P < 0.001, respectively). Conclusion: The DRS system, which is based on the response to initial treatment, can offer more useful prognostic information compared with ATA risk stratification in pediatric patients with DTC. PMID- 30310807 TI - A Systematic Review and Meta-Analysis of Randomized Trials Comparing Two-Stage with One-Stage Brachio-Basilic Vein Fistulas. AB - Purpose: There is currently debate if brachio-basilic vein fistula (BBVF) should be performed as a one-stage or two-stage procedure. The aim of the present study was to perform a systematic review and meta-analysis on BBVF staging. Materials and Methods: On February 25, 2016, a search for randomized-controlled trials (RCTs) on BBVF procedures was performed in MEDLINE and Scopus databases. Meta analyses were performed with fixed-effect or random-effects models as appropriate with risk ratios (RRs). The primary efficacy and safety outcome measures were BBVF maturation and development of complications, respectively. Specific types of complications, including loss of functional secondary patency and long-term complications were all secondary outcome measures. Results: We identified three RCTs reporting on 126 patients. Maturation failure of two-stage BBVFs (3/47, 6.4%) was less frequent than one-stage BBVFs (16/79, 20.3%; RR, 0.27; P=0.02). Complication rates of two-stage and one-stage BBVFs were similar (RR, 0.80; P=0.54), but on sensitivity analysis these were less likely to occur with two stage BBVFs (37% vs. 69% for one-stage BBVFs; RR, 0.57; P=0.03). Two-stage BBVFs were less likely to lose their functional secondary patency (21.3% vs. 31.6% for one-stage BBVFs; RR, 0.61; P=0.11). This non-significant trend became significant (RR, 0.36; P=0.02) on sensitivity analysis. There was no difference in specific complication rates of the two study groups. Conclusion: Among candidates for BBVF fistula, there is evidence to suggest that two-stage BBVFs achieve higher maturation rates compared to one-stage BBVFs. The evidence for difference in long term secondary patency is less robust, calling for further research. PMID- 30310808 TI - A Comparison of Manual and Three-Dimensional Modalities in Predicting Nellix Polymer Volume. AB - Purpose: Achieving an effective seal with the Nellix endovascular aneurysm system is dependent on filling the stent bags with an appropriate volume of polymer. Calculating this volume preoperatively is essential and can be performed manually or using three-dimensional (3D) software. The aim of this project was to compare the accuracy of these two methods relative to the actual polymer volume used. Materials and Methods: Consecutive patients undergoing Nellix aneurysm repair were included in this retrospective study. Operation notes were analysed for the polymer volume used intra-operatively. Predicted volumes for all patients had been calculated on picture archiving and communication system (PACS) using a manual 'segmental cylinder' method. Computed tomography angiograms were then re analysed using the Synapse 3D PACS update. The difference between groups was assessed using a paired t-test. Results: Twenty-eight patients were included in the analysis; 26 men (92.9%) and 2 women (7.1%); median age 80.9 years (interquartile range, 72.5-84.5 years). The mean volume of polymer used was 103 mL. The mean manual-derived prediction was 100.1 mL (P=0.365) and 3D-derived prediction 110.2 mL (P<0.001). Manual prediction led to an average 2.8% underestimate of polymer volume whilst 3D prediction led to an average 7.0% overestimate. Conclusion: Calculating predicted polymer volume for the Nellix system is more accurate using a manual approach then the 3D alternative. Whilst this method is more time-consuming, there is no significant difference when compared to the actual volume used. Quicker 3D software predictions can be utilised, but their tendency to overestimate should be recognized and taken into account during planning. PMID- 30310809 TI - The Advantage of Common Femoral Endarterectomy Alone or Combined with Endovascular Treatment. AB - Purpose: Although common femoral artery endarterectomy (CFAE) is regarded as the standard treatment modality for common femoral artery (CFA) disease, availability of advanced endovascular techniques has resulted in an increased number of CFA disease being treated. We evaluated clinical outcomes in a contemporary series of patients who were treated for CFA disease using endarterectomy alone or combined with endovascular treatment. Materials and Methods: We retrospectively reviewed 46 patients from November 2001 through December 2007. The treated lesions were divided into 4 groups based on operative procedure: group I (n=11), CFAE alone; group II (n=15), CFAE and iliac artery (IA) endovascular treatment; group III (n=6), CFAE and superficial femoral artery (SFA) endovascular treatment; group IV (n=14), CFAE and IA and SFA endovascular treatment or bypass surgery. Results: The degree of CFA steno-occlusion was not different among the groups. The 3-year primary patency rates of each group were 88.9+/-10.5%, 60.0+/-14.5%, 62.5+/ 21.3%, and 83.9+/-10.4%, respectively. The 3-year primary assisted patency rates were 100%, 70.0+/-13.0%, 62.5+/-21.3%, and 89.3+/-10.4%, while 3-year secondary patency rates were 100%, 80.0+/-13.0%, 62.5+/-21.3%, and 92.3+/-7.4%, respectively. There was no procedure-related mortality. Significant improvement of ankle-brachial index was achieved in all groups. Conclusion: CFAE alone is the treatment of choice for excellent patency and clinical improvement in steno occlusive lesions confined to the CFA. In multiple steno-occlusive diseases, this procedure could be combined with endovascular procedures to reduce the operative risk in conditions with high morbidity. PMID- 30310810 TI - Selective Shunting Based on Dual Monitoring with Electroencephalography and Stump Pressure for Carotid Endarterectomy. AB - Purpose: The aim of this study is to analyze postoperative outcomes for carotid endarterectomy (CEA) in addition to the preoperative clinical characteristics related to selective shunting based on dual monitoring with stump pressure (SP) and electroencephalography (EEG). Materials and Methods: We retrospectively reviewed medical records of 70 patients who underwent CEA from March 2010 to December 2017. CEA was performed under general anesthesia and selective shunting was done if the SP was lower than 35 mmHg regardless of EEG or if intraoperative EEG showed any changes different from preoperative one regardless of SP. Results: There was no postoperative 30-day adjusted mortality or adverse cardiac events. Three patients (4.3%) had postoperative minor stroke finally reaching pre operative neurologic status at the time of discharge. Twenty-six patients (37.1%) used shunting and severe contralateral internal carotid stenosis or occlusion was related to shunting (P<0.010). There were larger number of symptomatic patients in shunt group in spite of no statistical significance (P=0.116). Conclusion: Perioperative stroke rate was 4.3% for CEA under general anesthesia based on dual intraoperative monitoring with SP and EEG. There was no 30-day adjusted mortality and adverse cardiac event. Severe stenosis or occlusion of contralateral internal carotid artery is related to shunting (P<0.010). PMID- 30310811 TI - Aortic Isthmus Narrowing after Endovascular Repair of Acute Traumatic Aortic Transection. AB - Purpose: The traumatic transection is located in the normal sized aortic isthmus where the angle is curved. We found a reversal of upper and lower blood pressure differences among patients who underwent thoracic endovascular aortic repair (TEVAR) for transection of the thoracic aorta. We investigated the isthmus stenosis in patients who underwent TEVAR for aortic injury using computed tomography. Materials and Methods: Sixteen patients who underwent TEVAR for transection were divided in two groups: the aortic narrowing (AN) group and the non-aortic narrowing (NAN) group. AN was defined as stent graft folding more than 5 mm at the isthmus confirmed by computed tomography. The length of aorta at isthmus, pseudoaneurysm, and angle of isthmus were measured. Results: AN was noted in five patients (31.3%). The area index in the NAN group (2.16+/-0.35 cm2/m2) was larger than that in the AN group (1.74+/-0.77 cm2/m2). The size of the pseudoaneurysm in the NAN group (31.9+/-4.2 mm) was smaller than that in the AN group (37.4+/-7.5 mm). The distance from the subclavian artery in the NAN group (15.7+/-9.3 mm) was longer than that in the AN group (8.4+/-3.2 mm) but not statistically significant. The angle of the isthmus in the NAN group (131+/-6 degrees) was larger than that in the AN group (107+/-3 degrees), and this was the only statistically significant difference (P=0.002). Conclusion: AN by stent graft folding should be considered when performing TE-VAR in aortic injury with an acute angle of the isthmus less than 110 degrees. PMID- 30310812 TI - Corrigendum: Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression. AB - [This corrects the article DOI: 10.3389/fcell.2018.00048.]. PMID- 30310813 TI - Corrigendum: Cystathionine beta-Synthase Is Necessary for Axis Development in vivo. AB - [This corrects the article DOI: 10.3389/fcell.2018.00014.]. PMID- 30310814 TI - Smoking Ban in Psychiatric Inpatient Unit: An Iranian Study on the Views and Attitudes of the Mental Health Staff and Psychiatric Patients. AB - Although the move to smoke-free mental health inpatient settings is an internationally common and popular trend, these policies are neither implemented nor supported by any national program in Iran. This study investigates the attitude of mental health staff and psychiatric patients toward smoking cessation in 2 psychiatric inpatient units (psychosomatic and adult general psychiatry) in the Taleghani general hospital in Tehran. One hundred and twenty participants of this cross-sectional study consist of 30 mental health staff and 90 psychiatric patients. An eight-item questionnaire was used for collecting information. Both staff and patients expressed a positive attitude towards smoking cessation. Patients favoured the implementation of these policies and expressed a more positive attitude towards the feasibility. Sixty-three percent of patients and 57% of staff were opposed to smoking in the units. Seventy percent of patients reported the smoke-free ban as a feasible policy compared to 45% of staff who did the same. The implementation of the smoke-free policy has more support in both staff and patients than the continuation of smoking in psychiatric units. There is a need for an ongoing education and training for mental health care providers, in order to have a successful implementation of smoke-free policy. PMID- 30310815 TI - Glucocorticoid Receptor and Adipocyte Biology. AB - Glucocorticoids are steroid hormones that play a key role in metabolic adaptations during stress, such as fasting and starvation, in order to maintain plasma glucose levels. Excess and chronic glucocorticoid exposure, however, causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. Studies in animal models of metabolic disorders frequently demonstrate that suppressing glucocorticoid signaling improves insulin sensitivity and metabolic profiles. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. The adipocyte is one cell type that contributes to whole body metabolic homeostasis under the influence of GR. Glucocorticoids' functions on adipose tissues are complex. Depending on various physiological or pathophysiological states as well as distinct fat depots, glucocorticoids can either increase or decrease lipid storage in adipose tissues. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes. These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes. PMID- 30310817 TI - Impact and Lessons Learned from a National Consortium for Participatory Health Research: PartKommPlus-German Research Consortium for Healthy Communities (2015 2018). AB - Integrated strategies of health promotion at the municipal level are receiving particular attention in public health policy and practice in Germany. These strategies are intended to provide a coordinated approach to health promotion during the entire lifespan, with a particular focus on vulnerable communities. They are also intended to be participatory in both their design and implementation, involving all sectors of the social welfare, educational and healthcare systems, civil society, and the general public. PartKommPlus-German Research Consortium for Healthy Communities is examining such strategies using participatory forms of research. The goal is to determine how participation can best be planned and implemented and what effects this participation has. In this article the work of PartKommPlus from the first funding phase (2015-2018) will be described with particular attention to the lessons learned and the forms of impact which are being considered as part of the participatory research process. PMID- 30310816 TI - Omalizumab for Severe Asthma: Beyond Allergic Asthma. AB - Different subsets of asthma patients may be recognized according to the exposure trigger and the frequency and severity of clinical signs and symptoms. Regarding the exposure trigger, generally asthma can be classified as allergic (or atopic) and nonallergic (or nonatopic). Allergic and nonallergic asthma are distinguished by the presence or absence of clinical allergic reaction and in vitro IgE response to specific aeroallergens. The mechanisms of allergic asthma have been extensively studied with major advances in the last two decades. Nonallergic asthma is characterized by its apparent independence from allergen exposure and sensitization and a higher degree of severity, but little is known regarding the underlying mechanisms. Clinically, allergic and nonallergic asthma are virtually indistinguishable in exacerbations, although exacerbation following allergen exposure is typical of allergic asthma. Although they both show several distinct clinical phenotypes and different biomarkers, there are no ideal biomarkers to stratify asthma phenotypes and guide therapy in clinical practice. Nevertheless, some biomarkers may be helpful to select subsets of atopic patients which might benefit from biologic agents, such as omalizumab. Patients with severe asthma, uncontrolled besides optimal treatment, notwithstanding nonatopic, may also benefit from omalizumab therapy, although currently there are no randomized double-blind placebo controlled clinical trials to support this suggestion. However, omalizumab discontinuation according to each patient's response to therapy and pharmacoeconomical analysis are questions that remain to be answered. PMID- 30310818 TI - VEGFR2 Expression Is Differently Modulated by Parity and Nulliparity in Mouse Ovary. AB - Parity and nulliparity exert opposite effects on women's health, as parity is considered a protective factor for several reproductive diseases. This study is aimed at determining if ovarian VEGF and VEGFR2 expression are differently modulated in the ovaries of parous and nulliparous mice. To this end primiparous and nulliparous fertile mice were sacrificed at postovulatory stage. Whole ovaries, corpus luteum, and residual stromal tissues were analyzed to assess VEGF/VEGFR2 expression levels. Ovarian mRNA amounts of Vegfa (120 and 164) and Vegfr2 were comparable between primiparous and nulliparous mice; both isoforms and receptor were accumulated mainly in corpus luteum tissues. VEGF 120 and 164 protein accumulation and distribution mirrored that of mRNA. Conversely, VEGFR2 protein content was significantly higher in ovaries of nulliparous mice and was more efficiently phosphorylated in ovaries of primiparous mice. In both groups, VEGFR2 was preferentially expressed in corpus luteum, while its phosphorylated form was equally distributed in two somatic compartments. We suggest that parity influences VEGFR2/phospho-VEGFR2 expression and tissue distribution. This difference could be part of a more complex mechanism that at least in mice is activated after the first pregnancy and likely aims to preserve female health. PMID- 30310819 TI - In Vitro Antibacterial Activity of Propyl-Propane-Thiosulfinate and Propyl Propane-Thiosulfonate Derived from Allium spp. against Gram-Negative and Gram Positive Multidrug-Resistant Bacteria Isolated from Human Samples. AB - Background: The aim of this study was to compare the in vitro antibacterial activity of two compounds derived from Alliaceae, PTS (propyl-propane thiosulfinate), and PTSO (propyl-propane-thiosulfonate), with that of other antibiotics commonly used against bacteria isolated from humans. Materials and Methods: A total of 212 gram-negative bacilli and 267 gram-positive cocci isolated from human clinical samples and resistant to at least one group of antibiotics were selected. In order to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) to various antibiotics as well as PTS and PTSO, all isolates underwent broth microdilution assay. Results: PTS showed moderate activity against Enterobacteriaceae with MIC50 (and MBC50) and MIC90 (and MBC90) values of 256-512 mg/L, while PTSO showed greater activity with MIC50 and MIC90 values of 64-128 mg/L and MBC50 and MBC90 values of 128-512 mg/L. These data show the bactericidal activity of both compounds and indicate that PTSO was more active than PTS against this group of bacteria. Both compounds showed lower activity against P. aeruginosa (MIC50 = 1024 mg/L, MIC90 = 2048 mg/L, MBC50 = 2048 mg/L, and MBC90 = 2048 mg/L, for PTS; MIC50 = 512 mg/L, MIC90 = 1024 mg/L, MBC50 = 512 mg/L, and MBC90 = 2048 mg/L, for PTSO) compared to those obtained in others nonfermenting gram-negative bacilli (MIC50 = 128 mg/L, MIC90 = 512 mg/L, MBC50 = 128 mg/L, and MBC90 = 512 mg/L, for PTS; MIC50 = 64 mg/L, MIC90 = 256 mg/L, MBC50 = 64 mg/L, and MBC90 = 256 mg/L, for PTSO) and also indicate the bactericidal activity of both compounds against these groups of bacteria. Finally, the activity against S. aureus, E. faecalis, and S. agalactiae was higher than that observed against enterobacteria, especially in the case of PTSO (MIC50 = 8 mg/L, MIC90 = 8 mg/L, MBC50 = 32 mg/L, and MBC90 = 64 mg/L, in S. aureus; MIC50 = 4 mg/L, MIC90 = 8 mg/L, MBC50 = 8 mg/L, and MBC90 = 16 mg/L, in E. faecalis and S. agalactiae). Conclusion: PTS and PTSO have a significant broad spectrum antibacterial activity against multiresistant bacteria isolated from human clinical samples. Preliminary results in present work provide basic and useful information for development and potential use of these compounds in the treatment of human infections. PMID- 30310820 TI - Association of p16 as Prognostic Factors for Oropharyngeal Cancer: Evaluation of p16 in 1470 Patients for a 16 Year Study in Northeast China. AB - Human papillomavirus (HPV) is an etiological risk factor for oropharyngeal squamous cell carcinomas (OPSCC). Our study investigates the prevalence, prognostic, and clinicopathologic features of HPV-related oropharyngeal cancer in Northeast China and elucidates the involvement of p16 in the tumorigenesis and progression of OPSCC. Specimens from 1470 OPSCC patients collected from 2000 to 2016 were analyzed using the status of HPV by polymerase chain reaction (PCR) and p16 immunohistochemistry. Overexpression of p16 was observed in 81 (5.51%) of the 1470 cases, and HPV positive was present in 78 cases (5.31%) of the 1470 cases. HPV positive and p16 overexpression have a good concordance. However, we found that the etiological fraction of HPV in cancers of the OPSCCs was obviously lower in Northeast China than other cohorts previously reported. Interestingly, nearly 89% of patients with p16 expression were smokers, and nearly 70% of patients with p16 expression had a history of alcohol. Our study also demonstrates that p16 expression is significantly associated with early stage primary OPSCCs and the patients with p16 expression tend to show better survival following surgery and radiotherapy. PMID- 30310821 TI - Ongoing HIV Replication During ART Reconsidered. AB - Lorenzo-Redondo et al. recently analyzed HIV RNA sequences in plasma virus and proviral DNA sequences in lymph nodes (LN) and peripheral blood mononuclear cells (PBMC) from samples collected over a 6-month period from 3 individuals following initiation of antiretroviral therapy (ART) and concluded that ongoing HIV replication occurred in LN despite ART and that this replication maintained the HIV reservoir. We analyzed the same sequences and found that the dataset was very limited (median of 5 unique RNA or DNA sequences per sample) after accounting for polymerase chain reaction resampling and hypermutation and that the few remaining DNA sequences after 3 and 6 months on ART were not more diverse or divergent from those in pre-ART in any of the individuals studied. These findings, and others, lead us to conclude that the claims of ongoing replication on ART made by Lorenzo Redondo et al. are not justified from the dataset analyzed in their publication. PMID- 30310822 TI - Variability in Emergency Medicine Provider Decisions on Hospital Admission and Antibiotic Treatment in a Survey Study for Acute Bacterial Skin and Skin Structure Infections: Opportunities for Antimicrobial Stewardship Education. AB - Background: Acute bacterial skin and skin structure infections (ABSSSIs) are a frequent cause of emergency department (ED) visits. Providers in the ED have many decisions to make during the initial treatment of ABSSSI. There are limited data on the patient factors that influence these provider decisions. Methods: An anonymous survey was administered to providers at 6 EDs across the United States. The survey presented patient cases with ABSSSIs >=75 cm2 and escalating clinical scenarios including relapse, controlled diabetes, and sepsis. For each case, participants were queried on their decision for admission vs discharge and antibiotic therapy (intravenous, oral, or both) and to rank the factors that influenced their antibiotic decision. Results: The survey was completed by 130 providers. For simple ABSSSI, the majority of providers chose an oral antibiotic and discharged patients home. The presence of recurrence or controlled diabetes resulted in more variation in responses. Thirty-four (40%) and 51 (60%) providers chose intravenous followed by oral antibiotics and discharged the recurrence and diabetes cases, respectively. Presentation with sepsis resulted in initiation with intravenous antibiotics (122, 95.3%) and admission (125, 96.1%) in most responses. Conclusions: Variability in responses to certain patient scenarios suggests opportunities for education of providers in the ED and the development of an ABSSSI clinical pathway to help guide treatment. PMID- 30310823 TI - HIV-2 Primary Infection in a French 69-Year-Old Bisexual Man. AB - More than 1 million individuals, mainly in West Africa, are thought to be infected with HIV-2. Acute HIV-2 infection is rarely observed, only 2 primary infections have been described to date. We report a detailed case of HIV-2 primary infection in a 69-year-old French bisexual Caucasian man, thereby providing valuable insights into HIV-2 early infection. PMID- 30310824 TI - Breast ultrasound lesions recognition: end-to-end deep learning approaches. AB - Multistage processing of automated breast ultrasound lesions recognition is dependent on the performance of prior stages. To improve the current state of the art, we propose the use of end-to-end deep learning approaches using fully convolutional networks (FCNs), namely FCN-AlexNet, FCN-32s, FCN-16s, and FCN-8s for semantic segmentation of breast lesions. We use pretrained models based on ImageNet and transfer learning to overcome the issue of data deficiency. We evaluate our results on two datasets, which consist of a total of 113 malignant and 356 benign lesions. To assess the performance, we conduct fivefold cross validation using the following split: 70% for training data, 10% for validation data, and 20% testing data. The results showed that our proposed method performed better on benign lesions, with a top "mean Dice" score of 0.7626 with FCN-16s, when compared with the malignant lesions with a top mean Dice score of 0.5484 with FCN-8s. When considering the number of images with Dice score >0.5 , 89.6% of the benign lesions were successfully segmented and correctly recognised, whereas 60.6% of the malignant lesions were successfully segmented and correctly recognized. We conclude the paper by addressing the future challenges of the work. PMID- 30310825 TI - Probing the non-equilibrium transient state in magnetite by a jitter-free two color X-ray pump and X-ray probe experiment. AB - We present a general experimental concept for jitter-free pump and probe experiments at free electron lasers. By generating pump and probe pulse from one and the same X-ray pulse using an optical split-and-delay unit, we obtain a temporal resolution that is limited only by the X-ray pulse lengths. In a two color X-ray pump and X-ray probe experiment with sub 70 fs temporal resolution, we selectively probe the response of orbital and charge degree of freedom in the prototypical functional oxide magnetite after photoexcitation. We find electronic order to be quenched on a time scale of (30 +/- 30) fs and hence most likely faster than what is to be expected for any lattice dynamics. Our experimental result hints to the formation of a short lived transient state with decoupled electronic and lattice degree of freedom in magnetite. The excitation and relaxation mechanism for X-ray pumping is discussed within a simple model leading to the conclusion that within the first 10 fs the original photoexcitation decays into low-energy electronic excitations comparable to what is achieved by optical pump pulse excitation. Our findings show on which time scales dynamical decoupling of degrees of freedom in functional oxides can be expected and how to probe this selectively with soft X-ray pulses. Results can be expected to provide crucial information for theories for ultrafast behavior of materials and help to develop concepts for novel switching devices. PMID- 30310826 TI - Understanding premarital pregnancies among adolescents and young women in Ouagadougou, Burkina Faso. AB - In developing countries, young women between 15 and 24 years of age account for more than 40% of unsafe abortions due to the high number of unwanted and/or out of-wedlock pregnancies. However, much about the profile of adolescents and young women who usually experience premarital pregnancies remains unknown. This study sought to understand the risk of pregnancy before marriage among adolescents and young women in Ouagadougou, Burkina Faso. By using longitudinal data from a demographic surveillance system, we tested the explanatory power of two theoretical assumptions on premarital childbearing in sub-Saharan Africa, which assumptions are the cultural inheritance model and the social capital model. The results confirmed the explanatory power of the cultural inheritance model on the one hand and partially confirmed the power of the social capital model on the other hand. These results highlight the need for a multipronged approach to sexual and reproductive health for young people. Efforts against premarital pregnancies among adolescents and young women would be more effective if they were based on participatory approaches, incorporating actions at both community and institutional levels, as suggested by the recent Global Accelerated Action for the Health of Adolescents logical framework. PMID- 30310827 TI - VERNONIA AMYGDALINA DELILE EXHIBITS A POTENTIAL FOR THE TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA. AB - The World Health Organization (WHO) has been on front line to encourage developing countries to identify medicinal plants that are safe and easily available to patients. Traditional medicine represents the first-treatment choice for the healthcare of approximately 80% of people living in developing countries. Also, its use in the United States has increased by 38% during within the last decade of the 20th century alone. Therefore, the aim of the present study was to explore the efficacy of a medicinal plant, Vernonia amygdalina Delile (VAD), as a new targeted therapy for the management of acute promyelocytic leukemia (APL), using HL-60 cells as a test model. To address our specific aim, HL-60 promyelocytic leukemia cells were treated with VAD. Live and dead cells were determined by acridine orange and propidium iodide (AO/PI) dye using the Cellometer Vision. The extent of DNA damage was evaluated by the comet assay. Cell apoptosis was evaluated by flow cytometry assessment. Data obtained from the AO/PI assay indicated that VAD significantly reduced the number of live cells in a dose-dependent manner, showing a gradual increase in the loss of viability in VAD-treated cells. We observed a significant increase in DNA damage in VAD treated cells compared to the control group. Flow cytometry data demonstrated that VAD induced apoptosis in treated cells compared to the control cells. These results suggest that induction of cell death, DNA damage, and cell apoptosis are involved in the therapeutic efficacy of VAD. Because VAD exerts anticancer activity in vitro, it would be interesting to perform clinical trials to confirm its effectiveness as an anticancer agent towards the treatment of APL patients. PMID- 30310828 TI - Contrast enhancement efficacy of iodinated contrast media: Effect of molecular structure on contrast enhancement. AB - Purpose: To investigate the contrast enhancement in DSA images based on the X-ray absorption characteristics of iodinated contrast media. Methods: We have derived a new formula of predicting the pixel value ratio of two different contrast media and designate it as "Contrast Enhancement Ratio (CER)". In order to evaluate the accuracy of CER, we have evaluated the relationship between CER and pixel value ratio for all combinations of eleven iodinated contrast media. The non-ionic iodinated contrast media, iopamidol, iomeprol, iopromide, ioversol, iohexol, and iodixanol, were evaluated in this study. Each contrast medium was filled in the simulated blood vessel in our constructed anthropomorphic phantom, and DSA images were obtained using an angiographic imaging system. To evaluate the contrast enhancement of the contrast medium, the mean pixel value was calculated from all pixel values in the vascular image. Results: CER was indicated to agree well with the pixel value ratio of two different contrast medium solutions and showed a good accuracy. CER was also shown to have a good linear relation to the pixel value ratio when the iodine concentration was constant. This means that the molecular structure of the contrast media affects contrast enhancement efficacy. Furthermore, in evaluation of contrast enhancement of iodinated contrast media by using the weight factor (that is a key factor in CER) ratio, Iodixanol, and iopamidol, and iomeprol have the same ability of contrast enhancement in DSA images, and iohexol shows the lowest ability. Conclusions: We have derived a new formula (CER) of predicting the pixel value ratio of two different contrast medium solutions, and shown that CER agreed well with the pixel value ratio for blood vessel filled with eleven contrast media. PMID- 30310829 TI - Liquid-Liquid extraction of phenolic compounds in systems based on acetonitrile + water + polyvinylpyrrolidone at 298.15 K. AB - This paper contains data related to the research paper entitled "Organic two phase system based on acetonitrile + water + polyvinylpyrrolidone, a novel concept of liquid-liquid equilibrium: phase diagrams and phenolic compounds partitioning". Data of phase equilibrium were obtained using the cloud point method. After this step, some blending points were chosen to perform the phenolic compounds partitioning (gallic acid, quercetin dihydrate and cyanidin 3-O glucoside chloride). PMID- 30310831 TI - Global database of FRP-to-masonry bond strength tests. AB - Quantifying the bond strength between fibre-reinforced-polymer (FRP) composites and substrates is essential to the design of FRP retrofit systems. This paper collates a database of 1583 individual tests across 56 published experimental campaigns investigating the FRP-to-masonry bond strength through shear pull tests. Included in the database is all available information characterizing the test arrangement, geometric and mechanical properties of the constituents, as well as the failure load and failure mode. PMID- 30310830 TI - Experimental and theoretical structural/spectroscopical correlation of enterobactin and catecholamide. AB - Here we report the IR spectra of FeEnterobactin in catecholate conformations ([CatFeEB]3-) obtained by DFT calculations using PBE/QZVP and their correlation it with its experimental counterpart [SalH3FeEB]0. Fragments of FeEnterobactin and Enterobactin (H6EB) are elucidated from their MALDI-TOF mass spectrometry, and the dependence of the frontier orbitals (HOMO and LUMO) with the catecholamide dihedral angles of H6EB is reported. The frequency distribution of catecholamide dihedral angle of H6EB was carried-out using molecular dynamics (MD). The data presented enriches the understanding of [CatFeEB]3 - and H6EB frequency distribution and reactivity. PMID- 30310832 TI - Dataset on the patterns of electricity consumption in public universities in southwestern Nigeria. AB - In this data article, a thorough dataset on patterns of electricity use in Nigerian public universities was presented. Three relatively old public universities with staff and students' halls of residences were purposively selected. The selected universities were Obafemi Awolowo University, Ile-Ife (OAU), Federal University of Technology, Akure (FUTA), and University of Ibadan (UI). Data were obtained through the administration of a structured questionnaire on electricity end users in the universities sampled. For the data collection, the electricity end users in public universities were stratified into users in university staff offices, staff residences, student residences, and commercial units. Electricity users were selected using systematic random sampling and accidental sampling techniques. In OAU, FUTA and UI, 217, 137 and 164 students, respectively were sampled; 30, 3, and 61 households in OAU, FUTA, and UI, respectively were sampled while 28, 6, and 18 commercial units in OAU, FUTA and UI, respectively were also sampled. The sample size determined for staff in OAU, FUTA and UI were 139, 81 and 182, respectively. The data obtained were analyzed using radar charts. The information provided in this data article will encourage investigation into electricity management strategies, critical success factors for electricity management, planning, and policy formulation towards the realization of sustainable campuses. PMID- 30310833 TI - Data of embedded humidity sensors, sample weights, and measured pore volume distribution for eight screed types. AB - Four cement-based and four calcium-sulphate-based screed types are investigated. The samples have a diameter of 300 mm and a height of 35 or 70 mm. Up to ten humidity sensors are embedded directly during the concreting of the screed samples. Thus, the humidity over the sample height is monitored during hardening, hydration, evaporation, and oven drying. Furthermore, the screed samples are weighed during every measurement to determine the total mass and the corresponding moisture loss. To define the pore system precisely, mercury intrusion porosimetry as well as gas adsorption is performed. According to the data, the entire pore volume distribution is known. The measured pore diameters range from 0.8 nm to 100 um and the total porosity of the examined screeds ranges between 11% and 22%. Based on these measurement data, moisture transport, pore saturation as well as sorption isotherms and their hysteresis may be calculated quantitatively as described in "Monitoring of the absolute water content in porous materials based on embedded humidity sensors" (Strangfeld and Kruschwitz, 1921). PMID- 30310834 TI - Data on micrometeorological parameters and Energy Fluxes at an intertidal zone of a Tropical Coastal Ocean. AB - Data on the micrometeorological parameters and Energy Fluxes at an intertidal zone of a Tropical Coastal Ocean was carried out on an installed eddy covariance instruments at a Muka head station in the north-western end of the Pinang Island (5 degrees 28'06''N, 100 degrees 12'01''E), Peninsula Malaysia. The vast source of the supply of energy and heat to the hydrologic and earth's energy cycles principally come from the oceans. The exchange of energies via air-sea interactions is crucial to the understanding of climate variability, energy, and water budget. The turbulent energy fluxes are primary mechanisms through which the ocean releases the heat absorbed from the solar radiations to the environment. The eddy covariance (EC) system is the direct technique of measuring the micrometeorological parameters which allow the measurement of these turbulent fluxes in the time scale of half-hourly basis at 20 Hz over a long period. The data being presented is the comparison of the two-year seasonality patterns of monsoons variability on the measured microclimate variables in the southern South China Sea coastal area. PMID- 30310835 TI - Data related to the nanoscale structural and compositional evolution in resistance change memories. AB - The data included in this article provides additional supplementary information on our recent publication describing "Inducing tunable switching behavior in a single memristor" [1]. Analyses of micro/nano-structural and compositional changes induced in a resistive oxide memory during resistive switching are carried out. Chromium doped strontium titanate based resistance change memories are fabricated in a capacitor-like metal-insulator-metal structure and subjected to different biasing conditions to set memory states. Transmission electron microscope based cross-sectional analyses of the memory devices in different memory states are collected and presented. PMID- 30310836 TI - Data to assess the mediation effect of perceived responsibility for environmental damage on the relationship between moral identity and green consumption. AB - This Data in Brief article is for Study 3 in the manuscript # JEVP-2018-140 ("The Impact of Moral Identity on Consumers' Green Consumption Tendency: The Role of Perceived Responsibility for Environmental Damage"). It examines whether responsibility for environmental damage mediates the relationship between moral identity and green consumption. The data was collected using lab experiment. Participants were randomly assigned to moral-identity-activated condition and moral-identity-not-activated condition. The choice of eco-friendly product relative to conventional counterpart was measured. Responsibility for environmental damage was measured through a six-item scale. 65 American undergraduate students took part in the experiment. Data was analyzed employing SPSS. Logistic regression and mediation analysis were used as statistical tool of analysis. PMID- 30310837 TI - Squamous cell carcinoma arising from a chromomycosis lesion caused by Rhinocladiella aquaspersa with postsurgical recurrence of chromomycosis. PMID- 30310838 TI - Closed reduction of a posterior sternoclavicular joint dislocation: A case report. AB - Sternoclavicular joint dislocation (SCJD) is a rare injury; there are only two reported cases of SCJD that have occurred during judo practice. We present a case of an 18-year-old male athlete who fell while practicing judo and experienced upper left chest pain. He was diagnosed with posterior SCJD at another institute before being transferred to our hospital. Closed reduction was initially not possible using traditional methods. Reduction was eventually accomplished by clamping the proximal end of the clavicle using bone forceps and rotating it while pulling it upward. Many authors have reported that closed reduction is difficult if not performed within 48 h after SCJD injury. However, we were able to achieve closed reduction approximately 72 h after injury. We found that reduction might be easily accomplished by pulling the proximal end of the clavicle up and rotating it when other closed reduction methods are unsuccessful. PMID- 30310839 TI - Penetrating shrapnel injury to the chest presenting as a delayed tracheoesophageal fistula (TEF). A case report. AB - Tracheo-esophageal fistulae (TEF) due to trauma are rare. We report a case of a delayed TEF caused by a shrapnel from a blast. A 25-year-old male was admitted to the hospital after sustaining a blast injury. A contrast CT scan of the chest and neck revealed the presence of metallic shrapnel in close proximity to the tracheo esophageal groove at the level of the thoracic inlet. Bronchoscopy revealed 0.5 cm tear in the membranous trachea while esophagoscopy and contrast swallow were normal. Coughs after starting fluid intake triggered a repeat endoscopy that showed a large TEF at 22 cm from the incisors. He underwent surgical repair through a collar incision and limited sternotomy. The TEF extended for 2 cm. The esophagus was repaired in two layers, the membranous trachea was sutured primarily, and an interposition strap muscle flap was placed. A contrast swallow on postoperative day 7 revealed the presence of a small leak into the trachea that was treated conservatively. Traumatic TEF are rare and should be suspected in patients with injuries to proximal structures. Delay in diagnosis and appropriate management can conceivably lead to death. PMID- 30310841 TI - Utility of a long arm extension cast in management of pediatric fractures: A technique revisited. AB - A long arm cast with the elbow extended is a useful but often forgotten technique to manage some pediatric fractures. Specifically, proximal forearm fractures of both the radius and ulna, olecranon fractures, flexion-type supracondylar fractures and type II Monteggia fractures are well managed in this manner. Although some of these fractures are seen infrequently, timely diagnosis and treatment are essential to prevent complications. In this article, we present a review of the evaluation and management of these fractures in children, and a description of the technique used to apply a long arm cast in extension. PMID- 30310840 TI - Inferior shoulder dislocation after shortening osteotomy of the humerus. A case report. AB - We present a case of a post-surgical complete dislocation after excessive proximal humeral shortening osteotomy performed in a patient operated on for atrophic non-union of a proximal humeral fracture. This complication has not been previously reported. The dislocation occurred due to extensive laxity of the soft tissue envelope, predominantly the deltoid muscle, as well as rotator cuff tear. The reconstructive procedure consisted of vertical duplication of the capsule, reinforcement of the repair with coracoacromial ligament, tenodesis of the long head of the biceps tendon to the conjoined tendon and distal transfer of the deltoid muscle. The repair was reinforced with transarticular Steinmann pins. 15 months after surgery, there is an inferior subdislocation present, with full reduction in active abduction. Patient is pain-free at rest, and pain grade 4 in VAS scale in activity with loading. PMID- 30310842 TI - Early failure of a locked titanium plate in a proximal humeral fracture: Case report and metallurgic analysis. AB - Angular stability locking plates are commonly used in proximal humeral fractures, especially in old patients with osteoporotic bones. These implants show good results in short and midterm follow-up, but complications are not uncommon. Here we present a case report to describe a case of early failure of a proximal angular stability plate implanted in a 72 years old female with a highly unstable two part proximal humeral fracture. An optical and metallurgic analysis was also conducted to study the modalities of failure. We concluded that anatomic reduction and restoration of the medial cortical support are crucial in order to minimize the mechanical load on the bone-metal interface and to prevent mechanical failure, in particular when the fracture rim drop in the weak point of the plate that was found in the proximal two symmetric holes (Holes E). PMID- 30310843 TI - Application of three-dimensional printing technology in orbital floor fracture reconstruction. AB - Importance: Orbital floor fracture is common among patients suffering from facial trauma. Open reduction and reconstruction of the orbital floor with Medpor is the treatment of choice in our centre to correct diplopia and enophthalmos. Objective: Application of locally available 3D printing service in perioperative planning of orbital floor reconstruction with porous polyethylene. Design: We present two patients who suffered from orbital floor fracture complicated by diplopia. Open reduction and orbital floor reconstruction with Medpor was performed with the guidance of a 3D printed customized model of the orbital floor defect. Participants: Both patients were admitted through the Emergency Department to surgical ward after facial trauma. CT scan of the face showed orbital floor fracture with entrapment of inferior rectus muscle. Clinically patients also suffered from diplopia on extreme gaze. Results: With the aid of 3D printed model, it shortened operative time and duration of anaesthesia. Defect specific Medpor could be trimmed and molded easily from the model and thus reduced fatigue of the material. Furthermore, the model was helpful in patient education and explanation of the surgical procedure. Conclusions and relevance: Application of 3D printing in medical specialties is rapidly developing in the past few years. In orbital floor fracture reconstruction, 3D printed model provides a customized solution, decreases operative time and duration of anaesthesia. PMID- 30310844 TI - Successful reconstruction of a post-traumatic defect of 16 cm of the distal femur by modified Capanna's technique (vascularised free fibula combined with allograft) - A case report and technical note. AB - Reconstruction of large defects following trauma in the distal femur are a surgical challenge. These cases usually require multiple procedures and are associated with poor functional outcomes. We managed a post-traumatic distal femur defect of 16 cm using the modified Capanna's technique - combination of a vascularised free fibula and an allograft - and achieved a successful union at 6 months and also a good functional outcome with knee flexion of 100 degrees . The patient received a vascularised free fibula which was pegged into an allograft which was sculptured to bridge the defect. The construct was fixed with a locking compression plate on the lateral side. With the allograft providing structural stability and the vascularised free fibula enhancing biology, our technique which involves the expertise of an orthopaedic surgeon and a plastic surgeon is a useful single stage procedure to manage large post-traumatic bone defects. PMID- 30310845 TI - Trimalleolar fracture and associated Achilles tendon rupture: Ten year follow up of an unusual water-skiing injury. AB - A 49 year old professional fitness instructor sustained a high velocity rotational injury to his right ankle while waterski-ing. The ski bindings did not release, exacerbating the injury. This resulted in a trimalleolar fracture and a rupture of his Achilles tendon. A trimalleolar fracture in association with a rupture of the Achilles tendon has not been previously reported. This combination of injuries posed a dilemma in treatment options and postoperative management. The authors felt that ensuring that the Achilles tendon healed with no shortening was the priority for future function in this professional athlete. It was decided to treat the Achilles tendon rupture by open repair and to place the ankle in equinus postoperatively. It was also decided to openly reduce and internally fix the medial and lateral malleolar fractures before immobilising the ankle in equinus. Any residual stiffness in the ankle, subtalar and midtarsal joints would be treated with aggressive physiotherapy. It was felt that the rotational forces may have resulted in a degree of degloving around the ankle. Care was therefore taken in the choice and placement of the surgical incisions. In spite of this, the lateral surgical wound broke down postoperatively, needing treatment with a fasciocutaneous flap. When reviewed at ten years following the injury, the patient was continuing to work as a fitness instructor with a view to continuing to retirement in five years at the age of 65. There was a slight decrease in dorsiflexion of the right ankle but flexion was full and movement of the subtalar and midtarsal joints were also full. There remained 1 cm of wasting of the right calf. Radiology of the ankle showed no joint space narrowing or evidence of degenerative change at ten years following the injury. PMID- 30310846 TI - Bosworth fracture dislocation of the ankle: - Two case reports with perioperative illustration. AB - The Bosworth fracture dislocation of the ankle is rare and present difficulties in treatment if not immediately recognized. Here we present two cases with pre- and postoperative x-rays and perioperative image of the dislocation. The fracture dislocations were further complicated by talocrural dislocations and were treated with open reduction and internal fixation. PMID- 30310847 TI - Identity of growing pulsatile mass lesion of the scalp after blunt head injury: Case reports and literature review. AB - A growing pulsatile lump of the scalp rarely occurs after blunt head injury. In this condition, the lump may be a delayed-onset traumatic vascular scalp injury such as a pseudoaneurysm or an arteriovenous fistula (AVF). We describe two cases of delayed-onset traumatic vascular scalp injuries: one involved a pseudoaneurysm of the superficial temporal artery, and the other, an AVF fed by the occipital artery. We reviewed reported cases of delayed-onset traumatic vascular scalp injury and discuss the features, diagnosis and treatment. When a growing lump of the scalp is encountered, ultrasonography may be useful in searching for vascular injuries. PMID- 30310848 TI - Asymmetric bilateral hip dislocations and unilateral femoral head fracture: A CASE report. AB - Hip is a stabilized joint due to the surrounding ligaments, and muscles, which can dislocate as a result of high energy trauma, high-level falls, and motor vehicle accidents. Traumatic hip dislocations can either be isolated or simultaneously with acetabular and proximal femur fractures. At the same time injury of sciatic, femoral or obturator nerves can be seen. However, avascular necrosis of femoral head, posttraumatic osteoarthritis, and heterotopic ossifications can be seen as prolonged complications. The period prior to the reduction, severity of the trauma, and performing open or close reductions are the major contributors of the prognosis. As an extremely rare entity, bilateral asymmetrical hip dislocations are reported as the 0.01-0.02% of all joint dislocations. Accompanying proximal femoral fractures are pointed out 17%, one of them is femoral head fractures which are orthopedic emergencies that need to be fixed with surgery. However, high incidence of AVN is reported at the end of 2 years even if following early reductions. In our article, traumatic bilateral asymmetric hip dislocations and femoral head fracture is described in the context of a diagnosis, treatment and follow-up. PMID- 30310849 TI - Black-white mental status trajectories: What ages do differences emerge? AB - Objectives: Studies of older U.S. adults have consistently found that African Americans perform worse on cognitive measures than whites, but there are inconsistencies as to whether these findings hold over time. Moreover, studies have focused on adults 51 and older, without considering younger ages; thus it is unclear the age at which these disparities surface. The present study examines black-white disparities in mental status trajectories among adults as young as 25 years over a 25-year period. Method: Data come from the Americans' Changing Lives Study (ACL) (n = 3,617). Participants, ranging from ages 25-100 years old at baseline, were followed from 1986 to 2011 over 5 waves. Mental status was assessed at each wave using a 5-item Short Portable Mental Status Questionnaire. Growth models were used to estimate the associations between age, race, baseline status, and longitudinal changes in mental status, controlling for sociodemographic (e.g., education, income) and other health risk factors (diabetes, stroke, tobacco use, depression). Results: Racial disparities were seen beginning in midlife and this relationship was curvilinear. Specifically, blacks had a steeper rate of mental status decline than whites and these disparities persisted after accounting for social and health risk factors (b = 0.0090, p < 0.0001). Discussion: Study findings demonstrate disparities emerge at middles ages and worsen as age increases. This finding highlights the importance of addressing racial disparities in cognition across a larger part of the adult life course. By doing so, we may better be able to capture early-life exposures that influence later-life cognitive outcomes and ultimately lead to disparities. PMID- 30310850 TI - A novel detection method of cleaved plasma high-molecular-weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment. AB - Introduction: Accumulation of beta-amyloid is a pathological hallmark of Alzheimer's disease (AD). beta-Amyloid activates the plasma contact system leading to kallikrein-mediated cleavage of intact high-molecular-weight kininogen (HKi) to cleaved high-molecular-weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed. Methods: HKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate. Results: We generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores. Discussion: High levels of plasma HKc could be used as an innovative biomarker for AD. PMID- 30310851 TI - Evolution of dementia diagnosis over time (1988-2013): Evidence from French and English cohorts. Implication for secular trends analyses. AB - Introduction: The aims of this study are to examine the evolution of clinical dementia diagnosis over 3 decades and to investigate secular trends of dementia. Methods: Four cohorts covering a period from 1988 to 2013 were used: the Personnes Agees Quid and Three-City-Bordeaux studies, and the Cognitive Function and Aging Study (CFAS) I and II. Mini-Mental State Examination scores at clinical diagnosis were evaluated over a 24-year follow-up period in French studies. An algorithmic approach was applied to CFAS I and II to provide dementia prevalence and incidence estimates. Results: A significant increase of the Mini-Mental State Examination score at diagnosis was observed until 2000 and a significant decrease after. We reported a prevalence of 8.8% for CFAS I (1990-1993) compared with a prevalence of 6.5% in CFAS II (2008-2011). The 2-year incidence rate was estimated at 31.2/1000 (95% confidence interval = 28.0-34.8) for CFAS I and 15.0/1000 (95% confidence interval = 13.5-16.7) for CFAS II. Discussion: Applying a stable algorithm to different cohorts across time can provide a robust method for time trends estimation. PMID- 30310853 TI - The road to a first-class research institute: creating an exceptional environment, recruiting outstanding scientists, producing high-impact work, and nurturing a culture of innovation-Preface to the 60th anniversary special issue. PMID- 30310852 TI - Association between transcatheter aortic valve implantation or replacement and mortality, and major adverse events after coronary artery bypass grafting. AB - Background: In recent years, many people are opting for minimally invasive surgery in China. Patients undergoing transcatheter aortic valve implantation or replacement (TAVIR) with previous coronary artery bypass grafting (CABG) have higher risks of death and major complications. Materials/methods: PubMed and Embase were searched for all comparison studies between TAVIR with and without prior CABG and mortality as a primary outcome, irrespective of surgical risk, to investigate whether patients with prior CABG can undergo TAVIR. Randomized controlled trials and propensity-score-matched cohort studies were eligible for inclusion. The outcomes of interest included 30-day, 6-month, and 1-year mortality and 30-day complications. If significant heterogeneity was found in the random-effects meta-analyses, a sensitivity analysis that individually removed each study was conducted. Results: Five studies reported results on patients undergoing TAVIR with or without prior CABG. Compared with the non-CABG cohort, the CABG cohort showed no significant difference in the 30-day, 6-month, and 1 year mortality and the 30-day risk of major complications, except life threatening bleeding. However, for the 30-day risk of life-threatening bleeding, the morbidity of CABG cohort was significantly lower than that of the non-CABG cohort (risk ratio 0.555; 95% confidence interval 0.35-0.85; P = 0.006; I 2 = 0%). Conclusions: Patients with prior CABG can undergo TAVIR. Patients undergoing TAVIR without prior CABG need more attention because of a higher risk of life threatening bleeding. PMID- 30310854 TI - Roles of H3K36-specific histone methyltransferases in transcription: antagonizing silencing and safeguarding transcription fidelity. AB - Histone H3K36 methylation is well-known for its role in active transcription. In Saccharomyces cerevisiae, H3K36 methylation is mediated solely by SET2 during transcription elongation. In metazoans, multiple H3K36-specific methyltransferases exist and contribute to distinct biochemical activities and subsequent functions. In this review, we focus on the H3K36-specific histone methyltransferases in metazoans, and discuss their enzymatic activity regulation and their roles in antagonizing Polycomb silencing and safeguarding transcription fidelity. PMID- 30310856 TI - Structural roles of lipid molecules in the assembly of plant PSII-LHCII supercomplex. AB - In plants, photosystem II (PSII) associates with light-harvesting complexes II (LHCII) to form PSII-LHCII supercomplexes. They are multi-subunit supramolecular systems embedded in the thylakoid membrane of chloroplast, functioning as energy converting and water-splitting machinery powered by light energy. The high resolution structure of a PSII-LHCII supercomplex, previously solved through cryo electron microscopy, revealed 34 well-defined lipid molecules per monomer of the homodimeric system. Here we characterize the distribution of lipid-binding sites in plant PSII-LHCII supercomplex and summarize their arrangement pattern within and across the membrane. These lipid molecules have crucial roles in stabilizing the oligomerization interfaces of plant PSII dimer and LHCII trimer. Moreover, they also mediate the interactions among PSII core subunits and contribute to the assembly between peripheral antenna complexes and PSII core. The detailed information of lipid-binding sites within PSII-LHCII supercomplex may serve as a framework for future researches on the functional roles of lipids in plant photosynthesis. PMID- 30310855 TI - Cancer stem cells and tumorigenesis. AB - Cancer is one of the most serious diseases all over the world, and the cancer stem cell (CSC) model accounts for tumor initiation, metastasis, drug resistance, and relapse. The CSCs within tumor bulk have the capacity to self-renew, differentiate, and give rise to a new tumor. The self-renewal of CSCs is precisely regulated by various modulators, including Wnt/beta-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, chromatin remodeling complexes, and non-coding RNAs. CSCs reside in their niches that are also involved in the self-renewal maintenance of CSCs and protection of CSCs from chemotherapy, radiotherapy, and even endogenous damages. Moreover, CSCs can also remodel their niches to initiate tumorigenesis. The mutual interactions between CSCs and their niches play a critical role in the regulation of CSC self-renewal and tumorigenesis as well. Many surface markers of CSCs have been identified, and these markers become first choices for CSC targeting. Due to heterogeneity and plasticity, targeting CSCs is still a big challenge for tumor elimination. In this review, we summarize recent progresses on the biological features of CSCs and targeting strategies against CSCs. PMID- 30310858 TI - Hessian single-molecule localization microscopy using sCMOS camera. AB - Single-molecule localization microscopy (SMLM) has the highest spatial resolution among the existing super-resolution imaging techniques, but its temporal resolution needs further improvement. An sCMOS camera can effectively increase the imaging rate due to its large field of view and fast imaging speed. Using an sCMOS camera for SMLM imaging can significantly improve the imaging time resolution, but the unique single-pixel-dependent readout noise of sCMOS cameras severely limits their application in SMLM imaging. This paper develops a Hessian based SMLM (Hessian-SMLM) method that can correct the variance, gain, and offset of a single pixel of a camera and effectively eliminate the pixel-dependent readout noise of sCMOS cameras, especially when the signal-to-noise ratio is low. Using Hessian-SMLM to image mEos3.2-labeled actin was able to significantly reduce the artifacts due to camera noise. PMID- 30310857 TI - PTB/nPTB: master regulators of neuronal fate in mammals. AB - PTB was initially discovered as a polypyrimidine tract-binding protein (hence the name), which corresponds to a specific RNA-binding protein associated with heterogeneous ribonucleoprotein particle (hnRNP I). The PTB family consists of three members in mammalian genomes, with PTBP1 (PTB) expressed in most cell types, PTBP2 (also known as nPTB or brPTB) exclusively found in the nervous system, and PTBP3 (also known as ROD1) predominately detected in immune cells. During neural development, PTB is down-regulated, which induces nPTB, and the expression of both PTB and nPTB becomes diminished when neurons mature. This programed switch, which largely takes place at the splicing level, is critical for the development of the nervous system, with PTB playing a central role in neuronal induction and nPTB guarding neuronal maturation. Remarkably, sequential knockdown of PTB and nPTB has been found to be necessary and sufficient to convert non-neuronal cells to the neuronal lineage. These findings, coupled with exquisite understanding of the molecular circuits regulated by these RNA-binding proteins, establish a critical foundation for their future applications in regenerative medicine. PMID- 30310859 TI - Dissection of structural dynamics of chromatin fibers by single-molecule magnetic tweezers. AB - The accessibility of genomic DNA, as a key determinant of gene-related processes, is dependent on the packing density and structural dynamics of chromatin fiber. However, due to the highly dynamic and heterogeneous properties of chromatin fiber, it is technically challenging to study these properties of chromatin. Here, we report a strategy for dissecting the dynamics of chromatin fibers based on single-molecule magnetic tweezers. Using magnetic tweezers, we can manipulate the chromatin fiber and trace its extension during the folding and unfolding process under tension to investigate the dynamic structural transitions at single molecule level. The highly accurate and reliable in vitro single-molecule strategy provides a new research platform to dissect the structural dynamics of chromatin fiber and its regulation by different epigenetic factors during gene expression. PMID- 30310861 TI - Quantification of Total and Mutant Huntingtin Protein Levels in Biospecimens Using a Novel alphaLISA Assay. AB - The neurodegenerative Huntington's disease (HD) is caused by a polyglutamine (polyQ) amplification in the huntingtin protein (HTT). Currently there is no effective therapy available for HD; however, several efforts are directed to develop and optimize HTT-lowering methods to improve HD phenotypes. To validate these approaches, there is an immediate need for reliable, sensitive, and easily accessible methods to quantify HTT expression. Using the AlphaLISA platform, we developed two novel sensitive and robust assays for quantification of HTT in biological samples using commercially available antibodies. The first, a polyQ independent assay, measures the total pool of HTT, while the second, a polyQ dependent assay, preferentially detects the mutant form of HTT. Using purified HTT protein standards and brain homogenates from an HD mouse model, we determine a lower limit of quantification of 1 and 3 pm and optimal reproducibility with CV values lower than 7% for intra- and 20% for interassay. In addition, we used the assays to quantify HTT in neural stem cells generated from patient-derived induced pluripotent stem cells in vitro and in human brain tissue lysates. Finally, we could detect changes in HTT levels in a mouse model where mutant HTT was conditionally deleted in neural tissue, verifying the potential to monitor the outcome of HTT-lowering strategies. This analytical platform is ideal for high-throughput screens and thus has an added value for the HD community as a tool to optimize novel therapeutic approaches aimed at modulating HTT protein levels. PMID- 30310862 TI - Eye Movement-Related Confounds in Neural Decoding of Visual Working Memory Representations. AB - A relatively new analysis technique, known as neural decoding or multivariate pattern analysis (MVPA), has become increasingly popular for cognitive neuroimaging studies over recent years. These techniques promise to uncover the representational contents of neural signals, as well as the underlying code and the dynamic profile thereof. A field in which these techniques have led to novel insights in particular is that of visual working memory (VWM). In the present study, we subjected human volunteers to a combined VWM/imagery task while recording their neural signals using magnetoencephalography (MEG). We applied multivariate decoding analyses to uncover the temporal profile underlying the neural representations of the memorized item. Analysis of gaze position however revealed that our results were contaminated by systematic eye movements, suggesting that the MEG decoding results from our originally planned analyses were confounded. In addition to the eye movement analyses, we also present the original analyses to highlight how these might have readily led to invalid conclusions. Finally, we demonstrate a potential remedy, whereby we train the decoders on a functional localizer that was specifically designed to target bottom-up sensory signals and as such avoids eye movements. We conclude by arguing for more awareness of the potentially pervasive and ubiquitous effects of eye movement-related confounds. PMID- 30310863 TI - Conflicted between Goal-Directed and Habitual Control, an fMRI Investigation. AB - "Slips of action" occur in everyday life when we momentarily lose sight of a goal (for example, when in a rush or distracted). Associative models propose that these habitual responses can be activated via a direct stimulus-response (S-R) mechanism, regardless of the current hedonic value of the outcome. The slips-of action task (SOAT) has been extensively used in both healthy and pathological populations to measure habit tendencies, the likelihood of making erroneous responses for devalued outcomes. Inspection of behavioral performance does not reveal, however, whether the impairments were due to impaired goal-directed control or aberrantly strong habit formation. In the current study, we used functional MRI while human participants performed both the instrumental training and SOAT test phases, to elucidate the relative contributions of these mechanisms to performance on the SOAT. On trials in which conflict arises between competing goal-directed and habitual responses, we observed increased activation across areas including the anterior cingulate cortex, paracingulate gyrus, lateral orbitofrontal cortex (OFC), insula, and inferior frontal gyrus (IFG). Responding for devalued outcomes was related to increased activation in the premotor cortex and cerebellum, implicating these regions in habitual responding. Increased activation in the caudate, dorsolateral prefrontal cortex (dlPFC), and frontal pole during training was associated with better performance during the test phase, indicative of goal-directed action control. These results endorse interpretation of the SOAT in terms of competing goal-directed and habitual mechanisms and highlight that cognitive control processes present an additional bottleneck for successful performance on this task. PMID- 30310860 TI - Preparation of particulate polymeric therapeutics for medical applications. AB - Particulate therapeutics fabricated from polymeric materials have become increasingly popular over the past several decades. Generally, polymeric systems are easy to synthesize and have tunable parameters, giving them significant potential for wide use in the clinic. They come in many different forms, including as nanoparticles, microparticles, and colloidal gels. In this review, we discuss the current preparation methods for each type of platform, as well as some representative applications. To achieve enhanced performance, lipid coatings and other surface modification techniques for introducing additional functionality are also mentioned. We hope that, by outlining the various methods and techniques for their preparation, it will be possible to provide insights into the utility of these polymeric platforms and further encourage their development for biomedical applications. PMID- 30310865 TI - Observation of long-range dipole-dipole interactions in hyperbolic metamaterials. AB - Dipole-dipole interactions (V dd) between closely spaced atoms and molecules are related to real photon and virtual photon exchange between them and decrease in the near field connected with the characteristic Coulombic dipole field law. The control and modification of this marked scaling with distance have become a long standing theme in quantum engineering since dipole-dipole interactions govern Van der Waals forces, collective Lamb shifts, atom blockade effects, and Forster resonance energy transfer. We show that metamaterials can fundamentally modify these interactions despite large physical separation between interacting quantum emitters. We demonstrate a two orders of magnitude increase in the near-field resonant dipole-dipole interactions at intermediate field distances (10 times the near field) and observe the distance scaling law consistent with a super Coulombic interaction theory curtailed only by absorption and finite size effects of the metamaterial constituents. We develop a first-principles numerical approach of many-body dipole-dipole interactions in metamaterials to confirm our theoretical predictions and experimental observations. In marked distinction to existing approaches of engineering radiative interactions, our work paves the way for controlling long-range dipole-dipole interactions using hyperbolic metamaterials and natural hyperbolic two-dimensional materials. PMID- 30310864 TI - Estradiol Drives the Anorexigenic Activity of Proopiomelanocortin Neurons in Female Mice. AB - Energy balance is regulated by anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons of the hypothalamic arcuate nucleus. POMC neurons make extensive projections and are thought to release both amino acid and peptide neurotransmitters. However, whether they communicate directly with NPY/AgRP neurons is debated. Initially, using single-cell RT-PCR, we determined that mouse POMCeGFP neurons express Slc17a6 (Vglut2) and Slc18a2 (Vmat2), but not Slc31a1 (Vgat) mRNA, suggesting glutamate and non-canonical GABA release. Quantitative (q)RT-PCR of POMCeGFP cells revealed that Vglut2 and Vmat2 expression was significantly increased in E2 versus oil-treated, ovariectomized (OVX) female mice. Since 17beta-estradiol (E2) is anorexigenic, we hypothesized that an underlying mechanism is enhancement of POMC signaling. Therefore, we optogenetically stimulated POMC neurons in hypothalamic slices to examine evoked release of neurotransmitters onto NPY/AgRP neurons. Using brief light pulses, we primarily observed glutamatergic currents and, based on the paired pulse ratio (PPR), determined that release probability was higher in E2- versus oil-treated, OVX female, congruent with increased Vlgut2 expression. Moreover, bath perfusion of the Gq-coupled membrane estrogen receptor (ER) agonist STX recapitulated the effects of E2 treatment. In addition, high frequency (20 Hz) stimulation generated a slow outward current that reversed near Ek+ and was antagonized by naloxone, indicative of beta-endorphin release. Furthermore, individual NPY/AgRP neurons were found to express Oprm1, the transcript for MU-opioid receptor, and DAMGO, a selective agonist, elicited an outward current. Therefore, POMC excitability and neurotransmission are enhanced by E2, which would facilitate decreased food consumption through marked inhibition of NPY/AgRP neurons. PMID- 30310866 TI - Transformation of alcohols to esters promoted by hydrogen bonds using oxygen as the oxidant under metal-free conditions. AB - One-pot oxidative transformation of alcohols into esters is very attractive, but metal-based catalysts are used in the reported routes. We discovered that the basic ionic liquid 1-ethyl-3-methylimidazolium acetate ([EMIM] OAc) could effectively catalyze this kind of reaction using O2 as an oxidant without any other catalysts or additives. The oxidative self-esterification of benzylic alcohols or aliphatic alcohols and cross-esterification between benzyl alcohols and aliphatic alcohols could all be achieved with high yields. Detailed study revealed that the cation with acidic proton and basic acetate anion could simultaneously form multiple hydrogen bonds with the hydroxyl groups of the alcohols, which catalyzed the reaction very effectively. As far as we know, this is the first work to carry out this kind of reaction under metal-free conditions. PMID- 30310867 TI - Upgrading traditional liquid electrolyte via in situ gelation for future lithium metal batteries. AB - High-energy lithium metal batteries (LMBs) are expected to play important roles in the next-generation energy storage systems. However, the uncontrolled Li dendrite growth in liquid electrolytes still impedes LMBs from authentic commercialization. Upgrading the traditional electrolyte system from liquid to solid and quasi-solid has therefore become a key issue for prospective LMBs. From this premise, it is particularly urgent to exploit facile strategies to accomplish this goal. We report that commercialized liquid electrolyte can be easily converted into a novel quasi-solid gel polymer electrolyte (GPE) via a simple and efficient in situ gelation strategy, which, in essence, is to use LiPF6 to induce the cationic polymerization of the ether-based 1,3-dioxolane and 1,2-dimethoxyethane liquid electrolyte under ambient temperature. The newly developed GPE exhibits elevated protective effects on Li anodes and has universality for diversified cathodes including but not restricted to sulfur, olivine-type LiFePO4, and layered LiNi0.6Co0.2Mn0.2O2, revealing tremendous potential in promoting the large-scale application of future LMBs. PMID- 30310869 TI - Approaching the forbidden fruit of reaction dynamics: Aiming reagent at selected impact parameters. AB - Collision geometry is central to reaction dynamics. An important variable in collision geometry is the miss-distance between molecules, known as the "impact parameter." This is averaged in gas-phase molecular beam studies. By aligning molecules on a surface prior to electron-induced dissociation, we select impact parameters in subsequent inelastic collisions. Surface-collimated "projectile" molecules, difluorocarbene (CF2), were aimed at stationary "target" molecules characterized by scanning tunneling microscopy (STM), with the observed scattering interpreted by computational molecular dynamics. Selection of impact parameters showed that head-on collisions favored bimolecular reaction, whereas glancing collisions led only to momentum transfer. These collimated projectiles could be aimed at the wide variety of adsorbed targets identifiable by STM, with the selected impact parameter assisting in the identification of the collision geometry required for reaction. PMID- 30310868 TI - Secondary building units as the turning point in the development of the reticular chemistry of MOFs. AB - The secondary building unit (SBU) approach was a turning point in the discovery of permanently porous metal-organic frameworks (MOFs) and in launching the field of reticular chemistry. In contrast to the single-metal nodes known in coordination networks, the polynuclear nature of SBUs allows these structures to serve as rigid, directional, and stable building units in the design of robust crystalline materials with predetermined structures and properties. This concept has also enabled the development of MOFs with ultra-high porosity and structural complexity. The architectural, mechanical, and chemical stability of MOFs imparted by their SBUs also gives rise to unique framework chemistry. All of this chemistry -including ligand, linker, metal exchange, and metallation reactions, as well as precisely controlled formation of ordered vacancies- is carried out with full retention of the MOF structure, crystallinity, and porosity. The unique chemical nature of SBUs makes MOFs useful in many applications including gas and vapor adsorption, separation processes, and SBU-mediated catalysis. In essence, the SBU approach realizes a long-standing dream of scientists by bringing molecular chemistry (both organic and inorganic) to extended solid-state structures. This contribution highlights the importance of the SBUs in the development of MOFs and points to the tremendous potential still to be harnessed. PMID- 30310870 TI - Kinetic approach to superconductivity hidden behind a competing order. AB - Exploration for superconductivity is one of the research frontiers in condensed matter physics. In strongly correlated electron systems, the emergence of superconductivity is often inhibited by the formation of a thermodynamically more stable magnetic/charge order. Thus, to develop the superconductivity as the thermodynamically most stable state, the free-energy balance between the superconductivity and the competing order has been controlled mainly by changing thermodynamic parameters, such as the physical/chemical pressure and carrier density. However, such a thermodynamic approach may not be the only way to materialize the superconductivity. We present a new kinetic approach to avoiding the competing order and thereby inducing persistent superconductivity. In the transition-metal dichalcogenide IrTe2 as an example, by using current pulse-based rapid cooling of up to ~107 K s-1, we successfully kinetically avoid a first order phase transition to a competing charge order and uncover metastable superconductivity hidden behind. Because the electronic states at low temperatures depend on the history of thermal quenching, electric pulse applications enable nonvolatile and reversible switching of the metastable superconductivity, a unique advantage of the kinetic approach. Thus, our findings provide a new approach to developing and manipulating superconductivity beyond the framework of thermodynamics. PMID- 30310871 TI - Queer reproductive justice? AB - In the past half-century, there have been some notable shifts in English language feminist and queer scholarship and activism about procreation, marriage and family. In particular, there has been a striking increase in emphasis on genetic and biological family creation in queer and lesbian, gay, bisexual and transgender kinship practices, in contradistinction to earlier emphases on escape from the norms and demands of heteronormative patriarchy. During the gay liberation movement, older concepts of 'families we choose' were not defined by (nor meant necessarily to include) the creation of children as kin. The contemporary shift transpires amidst racial, national and economic disparities around the ability of people to 'couple' or to access reproductive technology. In line with early feminist and queer studies, this commentary calls for a broadening of the view of reproduction, and for more direct engagement between the primarily critical discourse on reproductive justice and the frequently celebratory discourse on queer families. PMID- 30310872 TI - Efficient construction of match strength distributions for uncertain multi-locus genotypes. AB - Natural variation in biological evidence leads to uncertain genotypes. Forensic comparison of a probabilistic genotype with a person's reference gives a numerical strength of DNA association. The distribution of match strength for all possible references usefully represents a genotype's potential information. But testing more genetic loci exponentially increases the number of multi-locus possibilities, making direct computation infeasible. At each locus, Bayesian probability can quickly assemble a match strength random variable. Multi-locus match strength is the sum of these independent variables. A multi-locus genotype's match strength distribution is efficiently constructed by convolving together the separate locus distributions. This convolution construction can accurately collate all trillion trillion reference outcomes in a fraction of a second. This paper shows how to rapidly construct multi-locus match strength distributions by convolution. Function convergence demonstrates that distribution accuracy increases with numerical resolution. Convolution construction has quadratic computational complexity, relative to the exponential number of reference genotypes. A suitably defined random variable reduces high-dimensional computational cost to fast real-line arithmetic. Match strength distributions are used in forensic validation studies. They provide error rates for match results. The convolution construction applies to discrete or continuous variables in the forensic, natural and social sciences. Computer-derived match strength distributions elicit the information inherent in DNA evidence, often overlooked by human analysis. PMID- 30310873 TI - The relationship between amplitude of low frequency fluctuations and gray matter volume of the mirror neuron system: Differences between low disability multiple sclerosis patients and healthy controls. AB - The study of the relationship between function and structure of the brain could be particularly interesting in neurodegenerative diseases like multiple sclerosis (MS). The aim of the present work is to identify differences of the amplitude of low frequency fluctuations (ALFF) in the mirror neuron system (MNS) between MS patients and healthy controls and to study the relationship between ALFF and the gray matter volume (GMV) of the regions that belong to the MNS. Relapsing remitting MS patients with minor disability were compared to healthy controls (HC) using resting-state functional magnetic resonance imaging (fMRI), anatomic T1 weighted images and diffusion tensor imaging (DTI). Region of interest (ROI) analyses was performed in the MNS regions. A decrease of ALFF in MS patients was observed in the left inferior frontal gyrus (IFG). Furthermore, a correlation between ALFF in the IFG and the GMV of the left inferior parietal lobule (IPL) was identified. This relationship was different for MS patients than for HC, which may be associated with changes in diffusivity measures which were impaired in MS patients. MS patients with low disability may show ALFF differences in the MNS without clinical correspondence. This functional difference may be associated with cortical and subcortical changes related to the disease. PMID- 30310875 TI - Gut microbiota linked to autoimmune uveitis. PMID- 30310874 TI - Behaviors and Risks for Cardiovascular Disease Among Muslim Women in the United States. AB - Purpose: This study examines statistical associates of cardiovascular disease risk factors, as defined by the American Heart Association's Life's Simple Seven, among Muslim women who reside in the United States. Methods: Data collected nationally through the 2015 Muslim Women's Health project were analyzed (N=373). Logistic regression models estimated associations between sample characteristics and diet, exercise, alcohol consumption, blood pressure, cholesterol, and weight. Results: Over half of respondents reported exercising regularly (64%) and maintaining a healthy diet (85%); 20% consumed alcohol. About 5% reported having high cholesterol, 4% had high blood pressure, and 42% reported being overweight. Perceived and experienced stigma were associated with alcohol use (odds ratio [OR]=1.085, p<0.001) and being overweight (OR=0.938, p<0.001). Married respondents had 42% lower odds of exercising and 83% lower odds of drinking alcohol. Compared to foreign-born respondents, U.S.-born respondents had 2.9 higher odds of drinking alcohol and 2.7 higher odds of having high cholesterol (OR=2.931, p<0.001; OR=2.732, p<0.01, respectively). Significant effects were also found when examining the statistical impact of of age, Islamic sect, and education on cardiovascular disease risk factors. Conclusion: With increasing focus on precision medicine, personalized healthcare, and patient-centered medical homes (all interventions designed to promote disease prevention and assist in managing chronic health conditions) better understanding the health of understudied populations is imperative to the success of these interventions. Our findings suggest countervailing forces may affect the health of American Muslim women; therefore, additional studies with this hard-to-reach population are warranted and will be informative to improving overall population health in the United States, an overarching priority for both public health practitioners and medical providers. PMID- 30310877 TI - Announcement of New Associate Editors. PMID- 30310876 TI - The Need for Local, Multidisciplinary Collaborations to Promote Advances in Physical Activity Research and Policy Change: The Creation of the Boston Physical Activity Resource Collaborative (BPARC). AB - This commentary describes the development, vision, and initial progress of the newly-founded Boston Physical Activity Resource Collaborative (BPARC). Our aims are to move the field of physical activity forward, with broader dissemination and translation, by creating a local Boston and Massachusetts hub for researchers, practitioners, advocates, and policymakers. Participants come from multiple academic and medical centers, local advocacy groups, and government agencies, all of whom are working on components of physical activity promotion. We have had initial success in collaborating on study design, methodology, and grant applications. Future endeavors aim to produce streamlined methods and products with maximal impact for the field of physical activity research, policy, and practice. PMID- 30310878 TI - Strain Analysis of the Right Ventricle Using Two-dimensional Echocardiography. AB - Right ventricular (RV) systolic dysfunction has been identified as an independent prognostic marker of many cardiovascular diseases. However, there are problems in measuring RV systolic function objectively and identification of RV dysfunction using conventional echocardiography. Strain echocardiography is a new imaging modality to measure myocardial deformation. It can measure intrinsic myocardial function and has been used to measure regional and global left ventricular (LV) function. Although the RV has different morphologic characteristics than the LV, strain analysis of the RV is feasible. After strain echocardiography was introduced to measure RV systolic function, it became more popular and was incorporated into recent echocardiographic guidelines. Recent studies showed that RV global longitudinal strain (RVGLS) can be used as an objective index of RV systolic function with prognostic significance. In this review, we discuss RVGLS measurement, normal reference values, and the clinical importance of RVGLS. PMID- 30310879 TI - Breast Arterial Calcification: A Potential Surrogate Marker for Cardiovascular Disease. AB - Breast arterial calcifications (BAC), frequently observed on screening mammography, have been considered as an incidental finding without increased risk for breast cancer. They are medial calcifications and therefore, are indicative of arteriosclerosis. Previous studies indicated that the risk factors of BAC partly overlap with those of cardiovascular disease (CVD), and the presence of BAC is associated with prevalent and incident CVD. This suggests that medial arterial calcification might contribute to CVD through a pathway distinct from the intimal atherosclerotic process. A recent study showed that the presence and severity of BAC are associated with the presence of coronary artery calcification or plaques on coronary computed tomography angiography in asymptomatic women aged more than 40 years. In addition, BAC provided an independent and incremental predictive value over conventional risk factors. Given that population-based mammography screening is currently recommended in asymptomatic women, the evaluation of BAC may be helpful in identifying high-risk women without additional cost or radiation exposure. PMID- 30310880 TI - Cardiac Structural or Functional Changes Associated with CHA2DS2-VASc Scores in Nonvalvular Atrial Fibrillation: A Cross-Sectional Study Using Echocardiography. AB - BACKGROUND: CHA2DS2-VASc is the most widely accepted scoring system for atrial fibrillation (AF) to assess stroke risk, although little has been revealed regarding the accompanying cardiac functional/structural changes. This echocardiography study was undertaken to understand the changes related to CHA2DS2-VASc scores. METHODS: A total of 4,795 nonvalvular AF patients were enrolled for the cohort, from which 591 were excluded as they did not meet the inclusion criteria. Based on the CHA2DS2-VASc scores, the remaining 4,204 patients included in the study were divided into 4 groups: 0 to 1 (n = 991); 2 to 3 (n = 1,642); 4 to 6 (n = 1,407); 7 to 9 (n = 164). RESULTS: Increase in the left ventricular mass index and prevalence of left ventricular hypertrophy (LVH) were observed with elevating CHA2DS2-VASc scores (p < 0.05 for all). Diastolic parameters such as left atrial volume index (LAVI) and the ratio of early diastolic mitral inflow velocity to early diastolic velocity of the mitral annulus (E/E') also increased significantly in the higher CHA2DS2-VASc score groups (p < 0.001 for all), although two-way ANOVA analysis showed that such incremental diastolic impairment was independent of hypertension. LVH (hazard ratio [HR], 3.609; confidence interval [CI], 2.426-5.369; p < 0.001) and E/E' (HR, 1.087; CI, 1.054-1.121; p < 0.001) were independent risk factors for CHA2DS2 VASc scores 2 or higher. CONCLUSIONS: Our findings suggest that increasing CHA2DS2-VASc scores are associated with impaired diastolic function that may represent high left atrial pressure favoring thrombogenic propensity. PMID- 30310881 TI - Left Ventricular Diastolic Function: The Link between CHA2DS2-VASc Score and Ischemic Stroke in Patients with Atrial Fibrillation. PMID- 30310882 TI - Sequential Changes in Left Ventricular Systolic Myocardial Deformation Mechanics in Children with Recurrent Kawasaki Disease. AB - BACKGROUND: Sequential changes in left ventricular (LV) systolic function over time in patients with recurrent episodes of Kawasaki disease (KD) remain unclear. METHODS: Twenty-five children with recurrent KD were retrospectively studied. Using conventional echocardiographic parameters and myocardial deformation analysis, systolic LV function in children in initial and recurrent KD episodes were compared with separate control groups, comprising 15 controls each. Recurrent KD was defined as occurring at an interval of >=2 months between the initial and recurrent episodes. RESULTS: The interval range between initial and recurrent episodes of KD was 3-103 months. In children with KD, 8 (32%) were <1 year of age at the initial episode, 10 (40%) had a recurrence within 1 year of the initial episode, and 4 (16%) and 5 (20%) were intravenous immune globulin nonresponders in initial and recurrent episodes, respectively. In both the initial and recurrent episodes of KD, the mean LV longitudinal peak systolic epsilon was all within normal range. However, when compared to controls, mean LV longitudinal peak systolic epsilon was decreased in patients with KD in the acute phases of both the initial and recurrent episodes. When compared to controls, mean LV longitudinal peak systolic epsilon was decreased in patients with KD in the convalescent phase of the recurrent episodes. CONCLUSIONS: Subclinical decreases in myocardial systolic deformation, as evidenced by decreased LV longitudinal peak systolic epsilon, may persist in children in the convalescent phase of recurrent KD; further studies involving larger numbers of patients may be needed for verification. PMID- 30310883 TI - End-Stage Renal Disease Impairs the Multidirectional Movements of the Common Carotid Artery: Assessment Using Dimensional Speckle-Tracking Carotid Strain Ultrasonography. AB - BACKGROUND: Arterial stiffening is a major contributing factor in the development of cardiovascular disease in patients with end-stage renal disease (ESRD). However, there is no gold standard for evaluating arterial stiffness. This study aimed to evaluate the newly developed speckle-tracking carotid strain imaging method in assessing arterial stiffness in patients with ESRD. METHODS: In total, 85 patients with normal renal function (controls) and 36 with ESRD were enrolled in this single-center study. Carotid B-mode ultrasonography was performed for all patients. Arterial stiffness indices and strain parameters of the common carotid arteries were analyzed. Values were compared between the groups, and multivariate linear regression analysis was performed to assess the impact of ESRD on carotid strain. RESULTS: There were no differences in the intima-media thickness, beta stiffness index, and arterial compliance, but arterial distensibility was lower, and the elastic modulus and pulse wave velocity beta (PWV) were higher among patients with ESRD (all p < 0.05), whether assessed in the longitudinal or transverse plane. Both longitudinal and transverse strain rates were reduced in patients with ESRD (all p < 0.05). In multivariate analyses, ESRD independently reduced both transverse radial strain and strain rate (all p < 0.05), and the transverse circumferential strain and strain rate (p < 0.05). However, all conventional aortic stiffness indices and longitudinal strain parameters were not associated with ESRD. CONCLUSIONS: Speckle-tracking carotid strain ultrasonography was successfully performed in both normal subjects and patients with ESRD. Multidirectional carotid strain analyses may provide more value than conventional aortic stiffness indices for risk stratification in patients with ESRD. PMID- 30310884 TI - Early Experiences Using Cocoon Occluders for Closure of a Ventricular Septal Defect. AB - BACKGROUND: Transcatheter device closure of ventricular septal defect (VSD) has become an attractive alternative to surgery. We report here on our early experiences of transcatheter closure of VSD using Cocoon devices, which are now available in Korea. METHODS: We reviewed the medical records and angiographic images of 13 patients who underwent transcatheter closure of VSD with a Cocoon occluder at Samsung Medical Center. The median patient age was 5.8 years, and the median patient weight was 20.3 kg. RESULTS: The device was successfully implanted in all patients. The follow-up period was 10 +/- 6 months, and no mortality was observed. An immediate residual leak on the next day was detected in 7 patients (including 4 with perimembranous VSD). However, 6 months later, a residual leak was observed only in 2 patients with perimembranous VSD and 1 patient with muscular VSD. Early conduction abnormalities were observed in 3 patients, all of whom had perimembranous VSD, but no significant complete atrioventricular block was observed. One patient experienced newly developed significant aortic regurgitation that decreased spontaneously but still existed at the 6 month follow-up. No hemolysis or embolization was noted on the next day or during the follow-up period. CONCLUSIONS: Cocoon devices can be used safely and effectively for VSD closure. However, residual leaks and conduction abnormalities may occur early after implantation, especially in patients with perimembranous VSD. Although normal conduction was recovered, long-term evaluation remains essential. PMID- 30310885 TI - Impact of Natural Mild Hypothermia in the Early Phase of ST-Elevation Myocardial Infarction: Cardiac Magnetic Resonance Imaging Study. AB - BACKGROUND: Mild hypothermia (32-35 degrees C) during acute myocardial ischemia has been considered cardioprotective in animal studies. We sought to determine the association of between natural mild hypothermia and myocardial salvage as assessed by cardiac magnetic resonance imaging (CMR) in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: In 291 patients with STEMI, CMR was performed a median of 3 days after the index event. Body temperature was collected for 24 hours after PCI. Fifty-one patients (17.5%) had natural mild hypothermia (less than 35 degrees C) during the day after PCI, and 240 (82.5%) did not. RESULTS: The primary endpoint, the myocardial salvage index, was significantly higher in the natural mild hypothermia group than in the normothermia group (median [IQR], 50 [37-64] vs. 43 [30-56], p = 0.013). The myocardial area at risk between the 2 groups did not differ (39 [22-51] vs. 35 [24-44], p = 0.361), nor did the infarct size (16 [10 28] vs. 20 [12-27], p = 0.301), presence of microvascular obstruction (57% vs. 60%, p=0.641), or hemorrhagic infarction (43% vs. 46%, p = 0.760). A multivariable linear regression showed a significant association between the lowest body temperature and myocardial salvage index (beta = -0.191, p = 0.001). CONCLUSIONS: In patients with STEMI undergoing primary PCI, natural mild hypothermia within 24 hours is associated with greater salvaged myocardium. PMID- 30310886 TI - "Macaroni Sign" in Takayasu Arteritis. PMID- 30310888 TI - A multi-responsive cross-linked supramolecular polymer network constructed by mussel yield coordination interaction and pillar[5]arene-based host-guest complexation. AB - Here a novel cross-linked supramolecular polymer network with thermal, pH, and H2S responsiveness was prepared inspired by mussel yield catechol-Fe3+ coordination and pillar[5]arene-based host-guest interactions. PMID- 30310887 TI - Supporting the Self-Management of Chronic Pain Conditions with Tailored Momentary Self-Assessments. AB - To better support the self-management of chronic pain, this paper investigates how those living with the condition prefer to self-assess their pain levels using smartphones. Our work consists of three stages: design ideation and review, an in lab user study with 10 participants resulting in nine candidate interfaces, and a 3 week field trial of two further honed measures with 12 participants. This research firstly yields a better understanding of participants' strong and sometimes contrasting preferences regarding their self-assessment of pain intensity. We additionally contribute two novel interfaces that support accurate, quick, and repeated use along with other participant-valued interactions (e.g., familiar, relatable, and highly usable). In particular, we focus on designing tailored measures that both enhance respondent motivation as well as minimize the difficulty of meaningful self-assessment by supporting the cog-nitive effort in translating a subjective experience into a single numerical value. PMID- 30310889 TI - Si nanoflake-assembled blocks towards high initial coulombic efficiency anodes for lithium-ion batteries. AB - Assisted by artificial amorphous copper silicate, Si with a flake-like structure was obtained through a facile magnesiothermic reduction. The Si anodes exhibit excellent cyclic performance and rate performance. Particularly, a high initial coulombic efficiency of 85%-89% was obtained due to their greatly reduced surface and internal defects. PMID- 30310890 TI - A polyhedral oligomeric silsesquioxane/molecular sieve codoped molecularly imprinted polymer for gastroretentive drug-controlled release in vivo. AB - Flotation drug delivery system (FDDS) is recognized as an efficient means to improve the therapeutic efficiency and enhance the drug bioavailability. Herein, we have developed a molecularly imprinted polymer (MIP) against capecitabine (CAP) to fabricate a FDDS by exploiting polyhedral oligomeric silsesquioxane (POSS) and Mobil composition of matter no. 41 (MCM-41) as the codopant. The synergistic effect of POSS and MCM-41 endows MIPs with enhanced imprinting effect and improved mass transfer efficiency. The impacts of the type of dopant, the type of functional monomer, the template/functional monomer ratio and the functional monomer/cross-linker ratio on imprinting effect have been investigated in detail. The POSS/MCM-41 codoped MIPs present favourable sustained release property in vitro and in vivo, displaying a high relative bioavailability of 173.4%. The proposed MIPs with high selectivity and superior physical and chemical stability exhibit potential as an alternative drug carrier applied in FDDS. PMID- 30310891 TI - Quantitative analysis of cell-free synthesized membrane proteins at the stabilized droplet interface bilayer. AB - We report the functional synthesis and quantification of membrane proteins-alpha hemolysin from Staphylococcus aureus and the multidrug transporter EmrE from Escherichia coli-at the stabilized droplet interface bilayer using an in vitro transcription-translation system. The system developed here can expand the list of integral membrane proteins applicable for quantitative functional analysis. PMID- 30310892 TI - On-chip photodynamic therapy - monitoring cell metabolism using electrochemical microsensors. AB - We introduce a new system which combines metabolic monitoring using electrochemical microsensors with photodynamic therapy on-chip for the first time. Oxygen consumption of T-47D breast cancer cells was measured during therapy with protoporphyrin IX. We determined the efficacy of the therapy and revealed its recovery effects, which underlines the high relevance of continuous monitoring. PMID- 30310893 TI - An unexpected thermal-ring-rearrangement of benzochromenes to inden-3-yl naphthols with pTsOH. AB - Described here is the first report of an unexpected thermal-ring rearrangement (TRR) of benzochromenes to indene derivatives promoted by pTsOH. This cascade ring-rearrangement proceeds through the protonation of benzochromenes by an acid catalyst followed by ring-opening and ring-closure by an intramolecular Friedel Crafts cyclization to provide a new bicyclic framework, inden-3-yl-naphthols bearing a quaternary center, which also exhibited atropisomerism. Regioselectivity, broad substrate scope, high yields, solvent-free conditions and atom economy are the additional high points of this ring-rearrangement. PMID- 30310894 TI - Unusual effects in single molecule tautomerization: hemiporphycene. AB - Parent hemiporphycene, a recently obtained constitutional isomer of porphyrin, exists in room temperature solutions and polymer matrices in the form of two trans tautomers interconverting via double hydrogen transfer. Using confocal fluorescence microscopy, it was possible to monitor tautomerization in single hemiporphycene molecules embedded in a PMMA film by monitoring the spectral and temporal evolution of their fluorescence spectra. The emission spectra of the two tautomeric forms are similar to those obtained from ensemble studies. However, the analysis of temporal spectral evolution reveals effects not detected in the bulk. For some single molecules, a large decrease of tautomerization rate was observed. This is interpreted as an indication of multidimensional character of the tautomerization coordinate and coupling of the reaction with the polymer relaxation processes. In addition, fluorescence lifetimes obtained for single molecules are significantly shorter than those measured for the bulk. It is proposed that the shortening is caused by environment-induced distortion of the molecule, which enhances the S0<- S1 internal conversion rate by lowering the barrier to excited state single hydrogen transfer. This effect seems to reflect the specific morphology of thin (30 nm) polymer samples, because it is not observed in ensemble studies carried out using thick (tens of micrometers or more) PMMA films. PMID- 30310895 TI - Enhanced luminescence and energy transfer in Mn2+ doped CsPbCl3-xBrx perovskite nanocrystals. AB - Manganese ion (Mn2+) doped CsPbCl3-xBrx nanocrystals (NCs) with dual emissions have emerged as a promising candidate for white light emitting devices. The luminescence properties of Mn2+ doped CsPbCl3-xBrx NCs were studied by steady state and time-resolved photoluminescence (PL) spectroscopy at temperature ranging from 80 to 300 K. The Mn2+ doped NCs with varied Br compositions were synthesized by means of Cl-to-Br anion exchange. The obtained doped NCs exhibited a tunable narrow band-edge emission band from 405 to 500 nm with a lengthened PL lifetime and a wide Mn2+ emission band at 600 nm with a shortened PL lifetime as the Br composition increases. It was interestingly found that PL intensity of the Mn2+ emission band was significantly enhanced by replacing Cl ions with Br and reached the maximum value in Mn2+:CsPbCl2.15Br0.85 NCs. Especially at low temperature (80 K), the intensity ratios of Mn2+ emission to band-edge emission increased ~80 times in Mn2+:CsPbCl2.15Br0.85 NCs, compared with Mn2+:CsPbCl3 ones. The temperature-dependent energy-transfer efficiencies of Mn2+:CsPbCl3 and Mn2+:CsPbCl2.15Br0.85 NCs from excitons in NCs to Mn2+ ions were obtained. The PL enhancement of Mn2+ in CsPbCl3-xBrx NCs was attributed to Br composition dependent exciton energy transfer to Mn2+. PMID- 30310896 TI - The functional and organoleptic characterization of a dairy-free dessert containing a novel probiotic food ingredient. AB - New eating habits and diversification of tastes of consumers have led to the scientific community and the food industry to expand the range of probiotic foods and novel probiotic ingredients. Scant information is available about the viability and functionality of probiotics during shelf life and its effect on the nutritional characteristics of dairy-free products. The aim of the study was to formulate a fermented dairy-free dessert using a novel food ingredient based on a pumpkin by-product and containing Lactobacillus casei (ATCC(r)393TM) (NFI). The effect of NFI and the soluble solids (SS) of soy milk on the probiotic viability, physical stability, colour, and firmness of dairy-free dessert was studied using a response surface methodology. The different levels of SS and NFI significantly (p < 0.05) affected the response variables. Thereafter, two formulations were selected and the physico-chemical, nutritional and organoleptic characterization were evaluated. The L. casei count reached the desired therapeutic level (>107 UFC mL-1) after gastrointestinal digestion at 21 days of storage. In general, both the fermentation process and storage reduced (p < 0.05) the content of phytic acid, raffinose and stachyose, which implies a nutritional improvement of the final product. Scores above 5.0 on a 9-point scale were obtained for colour, odour, texture and overall acceptability in the consumer acceptance test. Therefore, a dairy-free dessert with good physical properties, suitable nutritional characteristics, and sensorial acceptability could be successfully formulated with the NFI. PMID- 30310897 TI - The in situ growth of ultrathin Fcc-NiPt nanocrystals on graphene for methanol and formic acid oxidation. AB - Due to the increasing demand for energy, improving the current density of fuel cells is an urgent issue. Here we report a bifunctional electrocatalyst for fuel cells involving methanol or formic acid oxidation. A nanocomposite consisting of 7.2 nm NiPt nanocrystals, which are grown in situ on graphene nanosheets (NiPt/GN), has been prepared via a solution thermal decomposition method. The NiPt/GN nanocatalyst presents specific activities as high as 41.1 mA cm-2 and 42.9 mA cm-2 for methanol oxidation and formic acid oxidation, respectively, outperforming most reported catalysts. Moreover, it retains 76.3% of this activity after 900 cycles of methanol oxidation. Additionally, in comparison with general NiPt nanoparticles, the NiPt/GN nanocatalyst shows higher electrocatalytic activity in methanol and formic acid oxidation. All these results indicate that ultrathin NiPt nanocrystals grown in situ on graphene nanosheet substrates can significantly improve performance as a bifunctional electrocatalyst. PMID- 30310898 TI - Influence of the metals and ligands in dinuclear complexes on phosphopeptide sequencing by electron-transfer dissociation tandem mass spectrometry. AB - Phosphorylation is one of the most important protein modifications, and electron transfer dissociation tandem mass spectrometry (ETD-MS/MS) is a potentially useful method for the sequencing of phosphopeptides, including determination of the phosphorylation site. Notably, ETD-MS/MS typically provides useful information when the precursor contains more than three positive charges. It is not yet used as an analysis method for large-scale phosphopeptide production due to difficulties occurring in the production of acidic phosphopeptides having more than three positive charges. To increase the charge state of phosphopeptides, we used dinuclear metal complexes, which selectively bind to the phosphate group in phosphopeptides with the addition of positive charge(s). Dinuclear copper, zinc, and gallium complexes were tested and it was found that the type of metal present in the complex strongly affected the affinity of the phosphorylated compounds and their ETD fragmentation. The dinuclear copper complex interacted weakly with the phosphate groups and ETD-induced peptide fragmentation was largely suppressed by the presence of Cu2+, which worked as an electron trap. The dinuclear gallium complex was strongly bound to a phosphate group. However, the ligand binding to gallium acted as an electron trap and the presence of dinuclear gallium complex in the precursor for ETD-MS/MS hampered the sequencing of the phosphopeptides, as in the case of dinuclear copper complexes. In contrast, dinuclear zinc complexes efficiently bind to phosphopeptides with an increase in the charge state, facilitating phosphopeptide sequencing by ETD-MS/MS. The fragmentation of the ligand and peptide backbone in the dinuclear zinc-phosphopeptide complex were competitively induced by ETD. These processes are influenced by the ligand structure and so the detailed ETD fragmentation pathways were investigated using density functional theory calculations. PMID- 30310899 TI - High performance electronic devices based on nanofibers via a crosslinking welding process. AB - Recently, metal oxide nanofibers fabricated by electrospinning have been considered as promising components for next-generation electronic devices. Unfortunately, the nanofiber-based electronic devices usually exhibited inferior electrical performance, due to the high contact resistance between the nanofibers and the inferior interfacial adhesion between the nanofibers and the substrate. In this report, an amine-hardened epoxy resin was selected as an adhesion agent to weld nanofiber junctions and improve the interfacial adhesion performance. It was confirmed that the physical properties of the nanofibers were greatly improved after the crosslinking welding process. Taking advantage of the welding process, field-effect transistors (FETs) based on In2O3 nanofiber networks (NFNs) with various nanofiber densities were integrated and investigated. It was found that the FETs based on In2O3 NFNs with a nanofiber density of 0.4 MUm-1 exhibited the optimal electrical performance. When high-k ZrOx was integrated into the FETs as the dielectric layer, the FETs based on In2O3 NFNs/ZrOx exhibited superior performance, including a MUFE of 13.2 cm2 V-1 s-1, an Ion/Ioff of 107, and an SS of 90 mV per decade. The crosslinking welding process is a simple, versatile and low-cost technique, which has great possibility for various applications. PMID- 30310900 TI - A catalytic one-step synthesis of peptide thioacids: the synthesis of leuprorelin via iterative peptide-fragment coupling reactions. AB - A catalytic one-step synthesis of peptide thioacids was developed. The oxygen sulfur atom exchange reaction converted the carboxy group at the C-terminus of the peptides into a thiocarboxy group with suppressed epimerization. This method was successfully applied to the synthesis of the peptide drug leuprorelin via an iterative fragment-coupling protocol. PMID- 30310901 TI - Single-molecule DNA visualization using AT-specific red and non-specific green DNA-binding fluorescent proteins. AB - The recent advances in the single cell genome analysis are generating a considerable amount of novel insights into complex biological systems. However, there are still technical challenges because each cell has a single copy of DNA to be amplified in most single cell genome analytical methods. In this paper, we present a novel approach to directly visualize a genomic map on a large DNA molecule instantly stained with red and green DNA-binding fluorescent proteins without DNA amplification. For this visualization, we constructed a few types of fluorescent protein-fused DNA-binding proteins: H-NS (histone-like nucleoid structuring protein), DNA-binding domain of BRCA1 (breast cancer 1), high mobility group-1 (HMG), and lysine tryptophan (KW) repeat motif. Because H-NS and HMG preferentially bind A/T-rich regions, we combined A/T specific binder (H-NS mCherry and HMG-mCherry as red color) and a non-specific complementary DNA binder (BRCA1-eGFP and 2(KW)2-eGFP repeat as green color) to produce a sequence-specific two-color DNA physical map for efficient optical identification of single DNA molecules. PMID- 30310902 TI - Bimetallic metal organic frameworks with precisely positioned metal centers for efficient H2 storage. AB - We demonstrated that the ratio and position of two different metal ions, Pd and Cu, can be precisely controlled within MOFs through predesigned metal clusters. These MOF structures incorporating Pd-Cu paddle wheel units were synthesised simply by reacting Pd-Cu acetate metal clusters and tritopic organic linkers at room temperature. Pd-Cu open metal sites were found to be uniformly distributed throughout the MOFs with a ca. 1 : 1 ratio. The incorporation of Pd into the MOF structure also led to enhanced affinity towards H2 with Qst values up to 8.9 kJ mol-1. PMID- 30310903 TI - Vibrational spectroscopic monitoring and biochemical analysis of pericellular matrix formation and maturation in a 3-dimensional chondrocyte culture model. AB - Isolated and monolayer expanded chondrocytes are not the ideal cell form to produce a cartilage matrix. In articular cartilage, each chondrocyte is surrounded by a 2-4 MUm thick collagen VI-rich pericellular matrix (PCM) forming a chondron. Freshly extracted chondrons form a more cartilage-like extracellular matrix (ECM) than chondrocytes and their surrounding PCM is thought to maintain the chondrocyte phenotype. To regenerate articular cartilage, preserving and/or regenerating a functional PCM is essential. In this study, a highly biomimicking hyaluronic acid (HA) hydrogel was used as a 3-dimensional system to culture freshly isolated bovine chondrons (with an intact PCM) and chondrocytes (without a PCM) for up to 21 days. We assessed the HA hydrogel's capacity to maintain and potentially re-generate PCM formation by both biochemical and immunological analyses of the key components of the PCM. For the first time, synchrotron based Fourier transform infrared (SR-FTIR) microspectroscopy was utilised to reveal the dynamic process of PCM re-generation. At day 1, highly specific collagen VI staining was visible within chondron containing HA hydrogels. In contrast, collagen VI was absent at day 1 but punctate, focal staining increased during the culture period of chondrocyte containing HA hydrogels. Chondron containing HA hydrogels produced more collagen II and GAGs than the chondrocyte containing HA hydrogels. Principal component analysis (PCA) of spectra in fingerprint regions of the chondrocyte-containing constructs at day 7, 14 and 21 culturing showed clear spectral differences. The clusters of day 14 and day 21 samples were closer to the chondron samples, while the day 7 samples were closer to chondrocytes. PCA scores in the lipid region revealed no major differences between chondrocyte and chondron samples, but showed that the cultured chondrocyte samples at day 7, day 14 and day 21 clustered together. These data would indicate that SR-FTIR microspectroscopy can help to better understand the PCM formation and maturation in tissue engineered models, which involves subtle changes in collagen and aggrecan. PMID- 30310904 TI - EurOgels: A ferromagnetic semiconductor with a porous structure prepared via the assembly of hybrid nanorods. AB - EuO is unique, because it belongs to the few solids combining semiconducting properties (Egap = 1.1 eV) with native ferromagnetism. For future applications of EuO, e.g. as spin-filters or for sensors, one has to learn how defined nanostructures can be prepared. Unlike other ceramic oxides, there are no established soft-chemistry routes (e.g. sol-gel) towards EuO nanomaterials e.g. porous materials. This is due to the labile nature of the oxidation state Eu(+ii). We present a particle-based method leading to a EuO aerogel. Instead of making the target material directly, we use nanoparticles of an organic-inorganic hybrid phase (Eu2O3-benzoate) and assemble those into an aerogel, followed by the transformation into phase-pure EuO. It is shown that organic aldehydes act as capping agents for controlling the morphogenesis of the hybrid particles. Depending on the steric demand of the aldehyde, one obtains plate-like particles or nanorods with increasing aspect ratio. The particles form a gel, when the aspect ratio is increased to >20. After supercritical drying, one receives a nanorod-based aerogel. Treatment of the latter with Eu-vapor leads to reduction of the Eu2O3 domains to EuO while retaining the aerogel structure. Proof of ferromagnetism in the resulting EuO aerogel was delivered by SQUID measurements. PMID- 30310905 TI - Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models. AB - Numerous studies propose that epigallocatechin-3-gallate (EGCG), an abundant polyphenol in green tea, has anti-cancer properties. However, its mechanism of action in breast cancer remains unclear. This study investigated the capacity of EGCG to suppress breast cancer cell growth in vitro and in vivo, characterizing the underlying mechanisms, focusing on the effect of EGCG on glucose metabolism. EGCG reduced breast cancer 4T1 cell growth in a concentration- (10-320 MUM) and time- (12-48 h) dependent manner. EGCG induced breast cancer apoptotic cell death at 24 h, as evidenced by annexin V/PI, caspase 3, caspase 8 and caspase 9 activation. Furthermore, EGCG affected the expression of 16 apoptosis-related genes, and promoted mitochondrial depolarization. EGCG induced autophagy concentration-dependently in 4T1 cells by modulating the levels of the autophagy related proteins Beclin1, ATG5 and LC3B. Moreover, EGCG affected glucose, lactate and ATP levels. Mechanistically, EGCG significantly inhibited the activities and mRNA levels of the glycolytic enzymes hexokinase (HK), phosphofructokinase (PFK), and lactic dehydrogenase (LDH), and to a lesser extent the activity of pyruvate kinase (PK). In addition, EGCG decreased the expression of hypoxia-inducible factor 1alpha (HIF1alpha) and glucose transporter 1 (GLUT1), critical players in regulating glycolysis. In vivo, EGCG reduced breast tumor weight in a dose dependent manner, reduced glucose and lactic acid levels and reduced the expression of the vascular endothelial growth factor (VEGF). In conclusion, EGCG exerts an anti-tumor effect through the inhibition of key enzymes that participate in the glycolytic pathway and the suppression of glucose metabolism. PMID- 30310906 TI - Isomerization barriers and resonance stabilization for the conrotatory and disrotatory isomerizations of nitrogen containing tricyclo moieties. AB - The isomerizations of 3,4-diazatricyclo[4.1.0.02,7]hept-3-ene and 3,4 diazatricyclo[4.1.0.02,7]heptane to their corresponding products were studied by ab initio calculations. Structures were determined at the multiconfiguration self consistent field level and energies calculated at the single state second-order MRMP level. The isomerization of 3,4-diazatricyclo[4.1.0.02,7]hept-3-ene occurs through four unique pathways with barriers of 36.1 and 37.9 kcal mol-1 for the allowed channels, while those for the forbidden channels were 44.3 and 56.5 kcal mol-1. The 12.2 kcal mol-1 disparity in the disrotatory barriers is explained through electron delocalization in the transition state. The 3,4 diazatricyclo[4.1.0.02,7]heptane structure has eight separate reaction channels for isomerization, and the allowed barriers ranged from 37.4-43.3 kcal mol-1 while the forbidden barriers ranged from 49.5-57.3 kcal mol-1. Resonance stabilization for two of the forbidden pathways results in a relative energy lowering. The energy difference in the four allowed barriers is due mainly to steric considerations. The isomerization of 3,4,5-triazatricyclo[4.1.0.02,7]hept 3-ene through the disrotatory channel was studied to help identify stabilization effects from pi bond electrons and lone pair electrons: pi bond electrons showed greater contribution for molecular stabilization than lone pair electrons. PMID- 30310907 TI - Exploring the electronic structure of aluminum metal-organic framework Basolite A100: solid-state synchronous fluorescence spectroscopy reveals new charge excitation/relaxation pathways. AB - We investigated the electronic structure of a metal-organic framework (MOF), for the first time, by solid-state synchronous fluorescence spectroscopy in comparison with "conventional" fluorescence spectroscopy. The solid-state synchronous fluorescence spectra of aluminum MOF Basolite A100 in the UV-visible range at 25 degrees C are significantly narrower than the commonly used "conventional" fluorescence spectra. More importantly, the solid-state synchronous fluorescence spectra reveal major electronic transitions and fine molecular interactions in the MOF not available from the commonly used analysis. The following distinct pathways of charge excitation, followed by relaxation, are observed in Basolite A100: (a) a narrow resonance due to the monomer of the BDC linker at 308 nm, (b) an optical bandgap at 355 nm, and (c) absorption by excimers due to the ligand-to-ligand charge transfer (LLCT) between the two BDC linkers at ca. 387 nm. Furthermore, we accurately determine the optical bandgap in Basolite A100, for the first time, by solid-state enhanced resolution synchronous (excitation) spectroscopy. Finally, changes in the inter-linker LLCT interactions in the activated and hydrated forms of Basolite A100 are revealed by solid-state enhanced resolution synchronous (excitation) spectroscopy. PMID- 30310908 TI - Acylhydrazone functionalized benzimidazole-based metallogel for the efficient detection and separation of Cr3. AB - Chromium(iii) is a kind of microelement and can be converted to the more toxic chromium(vi), which is a carcinogen, by redox cycling. Thus, the development of novel materials for the detection and removal of Cr3+ is a very important issue. A novel metallogel chemosensor (BMG-Fe) based on functionalized benzimidazole (BM) and Fe3+ was constructed, which could fluorescently detect and separate Cr3+. The detection limit of BMG-Fe for Cr3+ is 2.62 * 10-8 M, and it exhibited high sensitivity and selectivity for Cr3+. Meanwhile, the absorbing percentage of BMG-Fe for Cr3+ is 96.36%, indicating a high separation rate. Interestingly, the sensitivity and ingestion capacity of BMG-Fe for Cr3+ are better than that of the simple organogel (BMG). So, the metallogel BMG-Fe could be utilized for the efficient removal of heavy metal ions from waste water. PMID- 30310909 TI - Umpolung cyclization reaction of N-cinnamoylthioureas in the presence of DBU. AB - A novel regioselective cyclization reaction of N-cinnamoylthioureas leading to six- or five-membered heterocyclic compounds was developed. N-Cinnamoylthioureas in the presence of trifluoroacetic acid (TFA) underwent the well-established intramolecular cycloaddition reaction to give 2-imino-2,3,5,6-tetrahydro-4H-1,3 thiazin-4-ones in good yields. On the other hand, the reaction with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) proceeded in an unprecedented "umpolung" cyclization fashion to afford five-membered 2-imino-1,3-thiazolidin-4-ones and/or 2-thioxoimidazolidine-4-ones. The reaction was considered to occur via a cycloadduct of DBU with the cinnamoyl moiety followed by intramolecular attack of the thiourea group. PMID- 30310910 TI - High-frequency pulsed electron-electron double resonance spectroscopy on DNA duplexes using trityl tags and shaped microwave pulses. AB - Accurate distances between two trityl paramagnetic tags site-specifically attached to DNA duplexes were measured by pulsed electron-electron double resonance spectroscopy at 180 and 260 GHz microwave frequencies. Up to a threefold increase in the sensitivity of 260 GHz PELDOR measurements was achieved by using shaped broad-band microwave pulses. PMID- 30310911 TI - Regiocontrol in the cobalt-catalyzed hydrosilylation of alkynes. AB - Hydrofunctionalizations of unsaturated hydrocarbons are key strategies for the synthesis of functionalized building blocks. Here, we report highly versatile cobalt-catalyzed hydrosilylations of alkynes that operate with minute amounts of the inexpensive, bench-stable pre-catalyst Co(OAc)2.4H2O under mild conditions (0.1-1 mol%, THF, r.t., 1 h). Near-perfect regiocontrol/stereocontrol was induced by the choice of the ligand: bidentate phosphines afforded (E)-beta-vinylsilanes; alpha-vinylsilanes formed with bipyridine ligands. PMID- 30310912 TI - Regulating polymer adsorption on colloid by surface morphology. AB - The study of polymer adsorption on colloidal particles has attracted intensive attention. In this work, we investigated polymer adsorption on substrate colloidal particles with two complementary morphologies, one of which has bulges (raspberry-like) on the surface and the other of which has holes instead (strawberry-like). Compared to the bulges, the holes on the colloidal particles were found to prevent polymer adsorption and this effect was dependent on the relative dimensions of the polymer coil and hole. This surface morphology effect was attributed mainly to the reduced polymer accessibility to the adsorption sites in holes when the hydrodynamic size of the polymer coil is larger than the hole, due to the size limiting effect. When the hydrodynamic size of the polymer coil is smaller than that of the holes, no difference in polymer adsorption was observed between raspberry-like and strawberry-like colloids. This study provides a strategy for regulating polymer adsorption on colloidal particles by adjusting the fine structures on the surface, which may be advantageous when limited chemical compositions are allowed. For example, protein adsorption on colloidal drugs may be found to be significantly reduced when colloids with surface holes are used. PMID- 30310913 TI - Synthesis, photochemical and in vitro cytotoxic evaluation of benzoselenazole based aminosquaraines. AB - Squaraine dyes have recently attracted interest as potential second generation photosensitizers for photodynamic therapy. Several cationic aminosquaraine dyes bearing benzoselenazole terminal nuclei were synthezised and their cytotoxic activity was tested against four different human tumor cell lines - breast (MCF 7), non-small cell lung (NCI-H460), cervical (HeLa) and hepatocellular (HepG2) carcinomas - and against a non-tumor porcine liver primary cell line (PLP2), both in the absence of light and under irradiation. All dyes, which displayed strong absorption within the phototherapeutic window, were found to exhibit photodynamic activity and were shown to be, in most cases, more cytotoxic, both in the dark and upon irradiation, than their benzothiazole analogues. PMID- 30310914 TI - Oil-induced formation of branched wormlike micelles in an alcohol propoxysulfate extended surfactant system. AB - The addition of oil to an extended surfactant-water system (sodium tetrapropylene glycol (2-ethyl)octyl ether sulfate, C10PO4SO4Na) induces the elongation of spherical micelles into oil-swollen branched wormlike micelles (WLMs) near the phase inversion point of the surfactant-oil-water (SOW) system. The hydrophilic lipophilic-difference (HLD) framework, which has been associated with surfactant curvature, was successfully used to predict the conditions under which WLMs are produced for both polar and non-polar oils. At HLD = 0, the formation of low curvature surfactant structures including WLMs and liquid crystals are favored in water-rich systems. Micellar growth begins around HLD = -0.5, and reaches a plateau upon the formation of a branched WLM network at HLD = 0. Above the entanglement concentration, the branched WLMs exhibit Maxwell and shear thinning behavior which is suitable for the suspension of nanoparticles, among others. PMID- 30310915 TI - Palladium-catalyzed intramolecular carboborylation of 1,3-diene and synthesis of ABCD ring of communesins. AB - A palladium-catalyzed intramolecular carboborylation of 1,3-diene has been developed for the synthesis of iminoindolines with a quaternary carbon centre. This method was applied to a substrate bearing several functional groups to afford a complex iminoindoline, which was subsequently converted into an ABCD ring model compound of communesins via an intramolecular Friedel-Crafts-type reaction. PMID- 30310916 TI - Rh-Catalyzed diastereoselective desymmetrization of enone tethered cyclohexadienones via tandem arylative cyclization. AB - The rhodium-catalyzed arylative cyclization of enone tethered-cyclohexadienones has been developed with high efficiency, thus providing cis-fused bicyclic enones in good yields and with excellent diastereoselectivities. Furthermore, this mild transformation has a broad range of substrate scope and excellent functional group tolerance. In addition, bicyclic products have an enone functionality, which can be a synthetically valuable handle for further transformations. PMID- 30310917 TI - Comment on: The future is near: focus on myopia. PMID- 30310918 TI - Effectiveness of bariatric surgery in diabetes prevention in high-risk Asian individuals. AB - INTRODUCTION: Obesity is a key risk factor in the development of Type 2 diabetes mellitus (T2DM). Bariatric surgery causes a large amount of durable weight loss in those with clinically severe obesity. We reported the effect of weight loss via bariatric surgery on DM prevention in those at high risk of developing DM. METHODS: This was a retrospective cohort study of 44 patients with obesity (mean body mass index 43.8 kg/m2) and pre-DM who underwent bariatric surgery and were followed up for up to three years. We also reviewed a non-surgical cohort of patients with obesity and pre-DM seen at the weight management clinic. RESULTS: 91% of patients attained normal glycaemic status at one year after bariatric surgery. At the three-year follow-up, 87.5% of the patients maintained normoglycaemia. None of the patients developed T2DM after surgery. 26.9% of patients achieved absolute weight loss at one year after bariatric surgery and maintained this at two and three years post surgery (p < 0.001 vs. baseline). The homeostatic model assessment-insulin resistance index in patients also decreased from 5.50 at baseline to 1.20, 1.14 and 1.44 at one, two and three years, respectively (p < 0.001). CONCLUSION: Bariatric surgery produces significant weight loss, and leads to reversion from the pre-diabetic state to normal glycaemic status and reduction of the incident DM rate in those with pre-DM and morbid obesity. PMID- 30310919 TI - Can you interpret the ECG under stress? AB - Stress (Takotsubo) cardiomyopathy (SC) is a cardiomyopathy characterised by transient myocardial dysfunction, commonly triggered by a surge in catecholamine. Electrocardiographic features may mimic other conditions, such as myocardial infarction. We presented two cases of SC and reviewed the electrocardiographic features of this disease entity. PMID- 30310920 TI - Comment on: Isolated thrombocytopenia in childhood: what if it is not immune thrombocytopenia? PMID- 30310921 TI - Hereditary stomatocytosis: an unusual cause of severe neonatal jaundice. PMID- 30310922 TI - Clinics in diagnostic imaging (190). Subacute combined degeneration of the spinal cord (SCD). AB - A 54-year-old man presented with progressive onset of lower limb paraesthesias, sensory ataxia, gait instability and lower limb weakness. Laboratory findings revealed low serum B12 levels. Magnetic resonance imaging showed long-segment symmetrically increased T2 signal within the dorsal columns of the spinal cord in the lower thoracic spine. The conglomeration of findings was consistent with a diagnosis of subacute combined degeneration of the spinal cord (SCD). Aside from mild residual paraesthesias, the patient's symptoms largely resolved after treatment with intramuscular injections of vitamin B12. The clinical presentation, pathophysiology, clinical and radiologic differential diagnosis, and management of SCD were described. PMID- 30310923 TI - Author's reply. PMID- 30310924 TI - Author's reply. PMID- 30310925 TI - The concomitant lateral meniscus injury increased the pivot shift in the anterior cruciate ligament-injured knee. AB - PURPOSE: Concomitant meniscus injuries in the anterior cruciate ligament (ACL) have been suggested to exacerbate rotational laxity. However, the effect is supposed to be so small, if any, that some quantitative pivot-shift measurement is needed. The purpose of this prospective study was to determine the effect of meniscus tear on rotational laxity in ACL-deficient knees by an quantitative measurement. It was hypothesized that a concomitant meniscus tear, especially a lateral one, would induce greater pivot shift. METHODS: Fifty-seven unilateral ACL-injured patients (26 men and 31 women, mean age: 24 +/- 10 years) were included. The pivot-shift test was performed prior to ACL reconstruction, while a quantitative evaluation using an electromagnetic system to determine tibial acceleration and a clinical grading according to the IKDC were performed. Meniscus injuries were diagnosed arthroscopically, and concomitant meniscus tear was confirmed in 32 knees. RESULTS: The clinical grade was not different between the ACL-injured knees of patients with and without meniscus tear (n.s.). Tibial acceleration did not show a statistical significant difference (meniscus-injured knees: 1.6 +/- 1.1 m/s2 versus meniscus-intact knees: 1.2 +/- 0.7 m/s2, n.s.). However, the subgroup analysis demonstrated that there was increased tibial acceleration in ACL-deficient knees with lateral meniscus tear (2.1 +/- 1.1 m/s2, n = 13) compared with meniscus-intact knees (p < 0.05), whereas rotational laxity did not increase in the medial meniscus-injured and bilateral-injured knees (1.2 +/- 0.9 m/s2, n = 12, n.s. and 1.4 +/- 1.1 m/s2, n = 7, n.s., respectively). CONCLUSION: A concomitant meniscus tear, especially a lateral meniscus tear, has a significant impact on rotational laxity in ACL-injured knees. When a large pivot shift is observed in the ACL-injured knee, a concomitant meniscus tear should be suspected and an aggressive treatment would be considered. Meniscus injuries should be inspected carefully when substantial pivot shift is encountered in ACL-injured knees. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 30310927 TI - [The development of early cancer detection in Germany]. AB - Cancer is one of the most relevant chronic diseases in the German population, but not all neoplastic entities are eligible for early cancer detection (ECD) programs. In 1971, ECDs were introduced as population-wide screenings for the first time in the catalogue of benefits of the West German statutory health insurance funds. However, the implementation at that time was rarely systematic. Concurrently, a discussion on the perspectives of ECD arose in the former German Democratic Republic, where a structured program was not prepared in the country until the late 1980s.A national cancer plan (NCP) was initiated in 2008 and its area of action #1 was titled "Further development of ECD". In April 2013, the law for the development of early cancer detection and quality assurance by clinical cancer registries was passed, which adopted major suggestions of the NCP. Consequently, the pertinent recommendations of the EU guidelines for the screening of the breast, cervix, and colon-rectum are currently being implemented.Public opinion in Germany with regard to ECDs has changed in recent years from unanimous consent to a rather critical distance. While ineffective and inefficient preventive action is being replaced by quality-assured screening procedures, public discussion about the fundamental reasonability of ECDs is controversial as never before. PMID- 30310926 TI - Heart toxicity from breast cancer radiotherapy : Current findings, assessment, and prevention. AB - BACKGROUND: Late cardiac toxicities caused by (particularly left-sided) breast radiotherapy (RT) are now recognized as rare but relevant sequelae, which has prompted research on risk structure identification and definition of threshold doses to heart subvolumes. The aim of the present review was to critically discuss the clinical evidence on late cardiac reactions based on dose-dependent outcome reports for mean heart doses as well as doses to cardiac substructures. METHODS: A literature review was performed to examine clinical evidence on radiation-induced heart toxicities. Mean heart doses and doses to cardiac substructures were focused upon based on dose-dependent outcome reports. Furthermore, an overview of radiation techniques for heart protection is given and non-radiotherapeutic aspects of cardiotoxicity in the multimodal setting of breast cancer treatment are discussed. RESULTS: Based on available findings, the DEGRO breast cancer expert panel recommends the following constraints: mean heart dose <2.5 Gy; DmeanLV (mean dose left ventricle) < 3 Gy; V5LV (volume of LV receiving >=5 Gy) < 17%; V23LV (volume of LV receiving >=23 Gy) < 5%; DmeanLAD (mean dose left descending artery) < 10 Gy; V30LAD (volume of LAD receiving >=30 Gy) < 2%; V40LAD (volume of LAD receiving >=40 Gy) < 1%. CONCLUSION: In addition to mean heart dose, breast cancer RT treatment planning should also include constraints for cardiac subvolumes such as LV and LAD. The given constraints serve as a clinicians' aid for ensuring adequate heart protection. The individual decision between sufficient protection of cardiac structures versus optimal target volume coverage remains in the physician's hand. The risk of breast cancer specific mortality and a patient's cardiac risk factors must be individually weighed up against the risk of radiation-induced cardiotoxicity. PMID- 30310928 TI - Frailty: we need valid and reliable tools in critical care. PMID- 30310929 TI - [German Society for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) congress 2018-A view to the future]. PMID- 30310930 TI - Correction to: Mapping and characterization of wheat stem rust resistance genes SrTm5 and Sr60 from Triticum monococcum. AB - In the original publication, the IWGSC assembly is incorrectly referenced. PMID- 30310932 TI - [Fewer complications with more than six adrenalectomies per year]. PMID- 30310931 TI - LncRNA MEG3 impacts proliferation, invasion, and migration of ovarian cancer cells through regulating PTEN. AB - OBJECTIVE AND DESIGN: We investigated the expressions of lncRNA MEG3 and PTEN in ovarian cancer tissues and their effects on cell proliferation, cycle and apoptosis of ovarian cancer. METHODS: Expression levels of MEG3 in ovarian cancer cell lines and normal ovarian cell lines were detected by qRT-PCR. Cell viability was detected by MTT assay. Cell apoptosis and cell cycle distribution were measured by flow cytometry. Cell invasion capability was tested by transwell assay. Cell migration capacity was tested by wound healing. The xenograft model was constructed to explore the effect of lncRNA MEG3 on ovarian cancer in vivo. RESULT: Compared with normal ovarian cells, expression levels of MEG3 and PTEN were relatively lower in ovarian cancer cells. There was a positive correlation between the expression of PTEN and the expression of MEG3. Enhanced expression level of PTEN suppressed SKOV3 cell proliferation, increased cell apoptosis rate, and decreased cell invasion and migration. CONCLUSION: LncRNA MEG3 and PTEN were down-regulated in ovarian cancer cells. LncRNA MEG3 regulated the downstream gene PTEN in ovarian cancer cells to prohibit cell proliferation, promote apoptosis and block cell cycle progression. PMID- 30310933 TI - Combined extra-/intrathoracic correction of pectus carinatum and other asymmetric chest wall deformities : A novel technique. AB - OBJECTIVE: Description of a novel technique to surgically correct (asymmetric) pectus carinatum and other chest deformities using a metal bar without fixation to the ribs. INDICATIONS: Severe thoracic deformity, extensive psychological strain, social isolation, pain and respiratory complaints. Pseudarthrosis or insufficient correction of a thoracic deformity after prior surgery. Distinctive deformities. CONTRAINDICATIONS: Acute infections. Postoperative intrathoracic scaring in revision cases can be challenging. SURGICAL TECHNIQUE: One-lung ventilation is used. Through two 3-4 cm long bilateral incisions to the thorax, an introducer is guided into the thorax under thoracoscopic supervision and then guided through an intercostal space out of the thorax again. A 1 cm presternal incision is performed and nylon threads are attached to the introducer bilaterally. Then the preshaped metal bar can be placed following the nylon threads. Once the metal bar is placed, the deformity is instantly corrected. Bilateral stabilizers are fixed with wire cerclage. Fixation on the ribs is not necessary. POSTOPERATIVE MANAGEMENT: Postoperative thorax x-ray. Intensive ventilation exercises. Implant removal after 2-3 years. RESULTS: The technique was used in 10 primary pectus carinatum or combined pectus carinatum and excavatum deformities as well as in 6 revision cases (3 female, 13 male, age 13 32 years). Follow-up ranged from 3-15 months postoperatively. Cosmetic results were excellent. Revision surgery required in 2 patients (one rib fracture and one local implant irritation). PMID- 30310934 TI - Parallel generation of easily selectable multiple nephronal cell types from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) provide a source for the generation of defined kidney cells and renal organoids applicable in regenerative medicine, disease modeling, and drug screening. These applications require the provision of hPSC-derived renal cells by reproducible, scalable, and efficient methods. We established a chemically defined protocol by application of Activin A, BMP4, and Retinoic acid followed by GDNF, which steered hPSCs to the renal lineage and resulted in populations of SIX2+/CITED1+ metanephric mesenchyme- (MM) and of HOXB7+/GRHL2+ ureteric bud (UB)-like cells already by 6 days. Transcriptome analysis corroborated that the PSC-derived cell types at day 8 resemble their renal vesicle and ureteric epithelial counterpart in vivo, forming tubular and glomerular renal cells 6 days later. We demonstrate that starting from hPSCs, our in vitro protocol generates a pool of nephrogenic progenitors at the renal vesicle stage, which can be further directed into specialized nephronal cell types including mesangial-, proximal tubular-, distal tubular, collecting duct epithelial cells, and podocyte precursors after 14 days. This simple and rapid method to produce renal cells from a common precursor pool in 2D culture provides the basis for scaled-up production of tailored renal cell types, which are applicable for drug testing or cell-based regenerative therapies. PMID- 30310936 TI - Wallis interspinous device versus discectomy for lumbar disc herniation : A comparative study. AB - The aim of this study was to assess the efficacy of the Wallis interspinous device for treating lumbar disc herniation (LDH) as well as to investigate whether the device could reduce the incidence of recurrent herniation in comparison with disc excision alone. A total of 72 patients with LDH were treated with primary discectomy and the Wallis interspinous device was implanted in 36. Clinical outcomes were evaluated with a visual analog scale (VAS) for low back and leg pain and the Oswestry Disability Index (ODI) before and after surgery. The incidence of recurrent disc herniation after the operation was also evaluated. There was a significant improvement (p < 0.01) in the clinical outcomes assessed by the VAS and ODI scores compared with preoperative values in both groups. Up to the final follow-up, there were no significant differences between the two groups in VAS and ODI scores (p > 0.05). In addition, there was no significant difference regarding the incidence of recurrent disc herniation between the two groups (13.9% vs. 16.6%, p > 0.05). Of the patients five underwent second discectomy or fusion surgery. The Wallis interspinous device was unable to improve the already good clinical outcome after discectomy for LDH and prevent or reduce recurrence of herniated disc in the current follow-up interval. Whether the device for should be used for LDH should be carefully considered before surgery. PMID- 30310937 TI - miR-455-5p downregulation promotes inflammation pathways in the relapse phase of relapsing-remitting multiple sclerosis disease. AB - MicroRNA-455-5p (miR-455-5p) seems to have an anti-inflammatory role in the immune system since its expression is induced by IL-10 cytokine. Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the central nervous system that is caused by an autoimmune inflammatory attack against the myelin insulation of neurons. The expression level of miR-455-5p and its role in MS pathogenesis has yet to be elucidated. We found that miR-455-5p expression was highly correlated with disease severity in MS patients. miR-455-5p expression inversely correlates with its inflammatory-predicted targets (MyD88 and REL) in relapse- and remitting-phase patients. Luciferase assays confirm that MyD88 and REL are direct targets of miR-455-5p. This study represents the first report of the miR-455-5p acts as an anti-inflammatory role in MS, at least partially through targeting MyD88 and REL. This study may provide important information for the use of miR-455-5p as a novel strategy to improve the severity of disease and control inflammation and attack in MS patients. PMID- 30310935 TI - [Sacral neuromodulation for refractory overactive bladder]. AB - Sacral neuromodulation (SNM) is a minimally invasive, established treatment modality for overactive bladder (OAB) as well as for other pelvic functional disorders, such as non-obstructive urinary retention and fecal incontinence. A pacemaker implanted in the upper buttocks delivers mild electrical pulses to the sacral nerves thereby modulating pathological afferent signals from pelvic end organs. The current article conveys the current knowledge on the indications, contraindications, mechanism of action, implantation technique, efficacy and complications of SNM for the treatment refractory OAB. PMID- 30310938 TI - Stapedial reflex threshold predicts individual loudness tolerance for people with autistic spectrum disorders. AB - People with autism spectrum disorder (ASD) frequently show the symptoms of oversensitivity to sound (hyperacusis). Although the previous studies have investigated methods for quantifying hyperacusis in ASD, appropriate physiological signs for quantifying hyperacusis in ASD remain poorly understood. Here, we investigated the relationship of loudness tolerance with the threshold of the stapedial reflex and with contralateral suppression of the distortion product otoacoustic emissions, which has been suggested to be related to hyperacusis in people without ASD. We tested an ASD group and a neurotypical group. The results revealed that only the stapedial reflex threshold was significantly correlated with loudness tolerance in both groups. In addition to reduced loudness tolerance, people with lower stapedial reflex thresholds also exhibited higher scores on the Social Responsiveness Scale-2. PMID- 30310940 TI - Left Ventricular Mass Quantification by Two-Dimensional Echocardiography in a Pediatric Population: Correlation with Cardiac Magnetic Resonance Imaging. AB - Quantification of left ventricular (LV) mass by echocardiography has not been validated against the gold standard of cardiac magnetic resonance imaging (CMR) in the pediatric population. The purpose of this study was to compare LV mass by two-dimensional and conventional M-mode echocardiography versus CMR in children. Consecutive CMR studies were paired with echocardiograms and retrospectively analyzed in children age <= 16 years (3 days old to 16 years old). Studies performed > 3 months between modalities and single ventricle anatomy were excluded. Unindexed LV mass was calculated using M-mode, area-length (AL), and truncated ellipsoid (TE) methods via echocardiography, and compared to cine stack CMR images. There were 46 patients included in the study (both MRI and echocardiography). Good correlations were observed for LV mass measured by CMR and all echocardiographic methods: M-mode (R = 0.965), AL (R = 0.975), and TE (R = 0.975). There was a significant overestimation using TE echocardiography, by a mean of 10.5 g (95% confidence interval 5.7-15.2 g, p < 0.05). There was no significant over- or underestimation of LV mass observed by M-mode or AL echocardiographic measurements, with tight limits of agreement when compared to CMR (95% confidence interval - 5.2 to 4.4 g and - 1.5 to 6.7 g, respectively). Interobserver agreement was good for each of the echocardiographic measurements, but inferior with M-mode (ICC, 0.89) compared to two-dimensional methods (ICC, 0.97). Echocardiographic estimates of LV mass have good correlation with CMR in children. Performance comparison showed AL echocardiographic method provides the most accurate measurement of LV mass with the best reproducibility compared to other methods. PMID- 30310939 TI - Routine Septal Myectomy During Subaortic Stenosis Membrane Resection: Effect on Recurrence Rates. AB - Recurrence of subaortic stenosis (SubAS) is up to ~ 19% following resection. Historically, treatment has consisted of membrane resection alone. This study investigated the effect of routine septal myectomy in addition to membrane resection. A single-center retrospective review was performed in all patients < 18 years of age undergoing membrane resection with septal myectomy for SubAS from 2003 to 2013. Demographic, perioperative, and follow-up data were collected. Freedom from reoperation and risk factors for reoperation were determined. 107 patients (median age 4.8 years) were included. There was one in-hospital death, five patients (5%) requiring pacemaker, and no iatrogenic ventricular septal defects. Follow-up was 80% complete and median follow-up was 4.9 years (range 0.5 12 years). Fourteen (16%) subjects required reoperation. Freedom from reoperation was 98% at 1 year, 86% at 5 years, and 69% at 10 years (Fig. 1). There was no difference in decrease of peak gradient between subjects who did and did not require reoperation (- 47 vs. - 40 mmHg; p = 0.59). In univariate analysis, chromosomal anomaly (hazard ratio [HR] 5.0, p = 0.02), smaller body surface area (HR 0.1, p = 0.03), and younger age at surgery (HR 0.7, p = 0.01) were significantly associated with reoperation. The routine use of myectomy with membrane excision did not result in a lower rate of reoperation or higher rates of complications compared to historical controls. Younger age, smaller size, and chromosomal anomaly were associated with increased risk for reoperation. Patients with these risk factors may benefit from more intensive long-term follow-up. PMID- 30310942 TI - The role of cervical color Doppler ultrasound in the diagnosis of brain death. AB - PURPOSE: Brain death (BD) is defined as the irreversible destruction of all brain functions. It is usually diagnosed through a clinical examination, but in certain circumstances, ancillary examinations (such as digital subtraction angiography (DSA), transcranial color Doppler (TCD), computed tomography angiography (CTA), magnetic resonance angiography (MRA), or radionuclide scanning) are required as confirmatory tests. In many countries, cervical color Doppler sonography (CCD) is not recognized as a valid test. The aim of our study is to assess its accuracy as a non-invasive, inexpensive, and easily available examination to determine cerebral circulatory arrest (CCA). METHODS: We performed a retrospective study in which 123 patients with clinical diagnosis of BD underwent bedside cervical color Doppler as an additional examination for CCA assessment. We compared these cervical color Doppler findings with the results of validated ancillary tests such as CTA, TCD, and DSA. RESULTS: Cervical color Doppler exams showed a sensitivity of 78% (96/123 patients) in detecting CCA compared to standard ancillary tests. Twenty-seven patients showed a persistent diastolic flow in one or two of the four arterial vessels examined and thus considered as false negatives. CONCLUSION: Our results show that cervical color Doppler may become a reliable and safe technique in detecting CCA, which can shorten the time for declaring brain death. In particular, in patients lacking good bone windows at transcranial color Doppler, cervical color Doppler of the cervical internal carotids and vertebral arteries could be recommended to increase the sensitivity of transcranial color Doppler, or as an alternative bedside examination. PMID- 30310941 TI - CT and MR imaging of orbital inflammation. AB - PURPOSE: Orbital inflammation can be idiopathic or in the context of a specific disease and it can involve different anatomical orbital structures. On imaging, inflammatory disease is frequently mistaken for infection and malignant tumors, and its underlying cause is often not determined. Through this article we aim to improve orbital inflammation diagnosis and underlying inflammatory diseases recognition. METHODS: The imaging protocols and characteristics of orbital inflammation were reviewed. RESULTS: A decision tree for the evaluation of these patients is provided. First, a combination of clinical and radiological clues is used to recognize inflammation, in particular to differentiate it both from orbital infection and tumor. Subsequently, different radiological patterns are recognized, often allowing the differentiation of the several orbital inflammatory diseases. CONCLUSION: The use of adequate imaging protocols and subsequent evaluation allow the recognition of an orbital lesion as inflammatory and the diagnosis of the underlying inflammatory disease. All in all, a proper treatment can be established, and at times, a biopsy can be avoided. PMID- 30310943 TI - CT, conventional, and functional MRI features of skull lymphoma: a series of eight cases in a single institution. AB - OBJECTIVE: With the hypothesis that the combination of CT, conventional, and functional MRI can indicate a possible diagnosis of skull lymphoma, this study aimed to systematically explore CT, conventional, and functional MRI features of this rare entity. MATERIALS AND METHODS: This retrospective study included eight patients with pathologically confirmed skull lymphomas. CT and conventional MRI findings, including the location, size, attenuation/signal intensity, cystic/necrosis, hemorrhage, calcification, enhancement, skull change, brain parenchyma edema and adjacent structure invasion, were reviewed. We also reviewed multi-parametric functional MR imaging features obtained from diffusion-weighted imaging (DWI, n = 4), susceptibility-weighted imaging (SWI, n = 3) and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted imaging (DSC-PWI, n = 1). RESULTS: The eight patients in this series consisted of five males and three females, with a mean age of 51.1 years. All skull lymphomas showed the tumors extending to extra- and intra-cranial spaces with permeative destruction of the intervening skull. Intratumoral cystic/necrosis was seen in one case. Hemorrhage or calcification was absent. Dural mater infiltration was detected in all cases. Two clivus lymphomas encased internal carotid artery without narrowing the lumen. Three cases invaded brain parenchyma with moderate edema. The tumors demonstrated high signal on DWI with low ADC values comparing to muscles. SWI images showed little intratumoral hemorrhage and vessel. Low relative cerebral blood volume (rCBV) value was detected. CONCLUSIONS: Skull lymphomas commonly presented as a homogenous solid tumor extending either intra- or extra-cranially with permeative bone destruction. Restricted diffusion, little intratumoral susceptibility signal, and lower perfusion may indicate a specific diagnosis. Multi-parametric functional MRI may be a promising tool for the diagnosis of skull lymphomas. PMID- 30310944 TI - Quantitative mapping of specific proteins in biological tissues by laser ablation ICP-MS using exogenous labels: aspects to be considered. AB - Laser ablation (LA) coupled with inductively coupled plasma mass spectrometry (ICP-MS) is a versatile tool for direct trace elemental and isotopic analysis of solids. The development of new strategies for quantitative elemental mapping of biological tissues is one of the growing research areas in LA-ICP-MS. On the other hand, the latest advances are related to obtaining not only the elemental distribution of heteroatoms but also molecular information. In this vein, mapping of specific proteins in biological tissues can be done with LA-ICP-MS by use of metal-labelled immunoprobes. However, although LA-ICP-MS is, in principle, a quantitative technique, critical requirements should be met for absolute quantification of protein distribution. In this review, progress based on the use of metal-labelled antibodies for LA-ICP-MS mapping of specific proteins is reported. Critical requirements to obtain absolute quantitative mapping of specific proteins by LA-ICP-MS are highlighted. Additionally, illustrative examples of the advances made so far with LA-ICP-MS are provided. Graphical abstract In the proposed critical review, last advances based on the use of metal labelled antibodies and critical requirements for LA-ICP-MS quantitative mapping of specific proteins are tackled. PMID- 30310946 TI - Clinical significance of assertive community treatment among adolescents. AB - PURPOSE: The efficacy of assertive community treatment for children and adolescents is proven in the United States, but remains controversial in Europe. Moreover, most studies showing positive outcomes of assertive community treatment are limited to statistically significant differences and do not consider whether the treatment is also subjectively clinically meaningful for the patient. Using a naturalistic sample, the present study aims to assess statistical and clinical significance of an assertive community treatment unit for adolescents in Europe. METHODS: Linear mixed-effects models and reliable change indices were used to respectively assess the statistical and clinical significance of assertive community treatment in 179 adolescents (mean age = 15.76, SD = 1.76) with severe mental illnesses. RESULTS: Difficulties related to mental health (measured by the Health of the Nation Outcome Scales for Children and Adolescents, HoNOSCA) and overall functioning (measured by the Global Assessment of Functioning scale) statistically improved (all ps < 0.001) from admission to discharge. Additionally, a considerable proportion of patients (from 14% to 21%) clinically recovered to functional levels. CONCLUSION: Our results support the fact that assertive community treatment can have convincing and positive clinical outcomes in European settings. PMID- 30310945 TI - The prevalence of mental disorders in Taiwanese prisons: a nationwide population based study. AB - PURPOSE: In Taiwan, few studies explored the morbidity of mental disorders among prisoners. The purpose of this study is conducted to estimate the prevalence of mental disorders in Taiwanese prisoners. METHODS: Based on Nationwide population based databank, 82,650 prisons were studied for mental disorders. Mental disorders were assessed with the International Classification of Diseases 9th revision Clinical Modification (ICD-9-CM). RESULT: The prevalence of mental disorders among prisoners was estimated 11.31%. Female prisons exhibited a higher prevalence than males (17.82% vs. 10.56%, p < 0.01). Among all cases that were diagnosed with the contents of mental disorder, anxiety, dissociative and somatoform disorders was the most frequent disease (total: 49.48%, female: 59.42%, male: 47.55%) followed by special symptoms or syndromes (total: 38.24%, female: 33.20%, male: 39.22%), drug dependence (total: 15.41%, female: 9.22%, male: 16.61%), episodic mood disorders (total: 13.56%, female: 26.15%, male: 11.12%), nondependent abuse of drugs (total: 11.23%, female: 2.77%, male: 12.87%) and depressive disorder (total: 11.23%, female: 11.66%, male: 11.14%). CONCLUSION: A substantial proportion of prisoners reported having mental disorders. The results suggests the necessity of comprehensive assessment and more treatment programs that offer alternatives to incarceration of mental health for the criminal justice system in Taiwan. PMID- 30310947 TI - Metal Tolerance Capability of Helichrysum microphyllum Cambess. subsp. tyrrhenicum Bacch., Brullo & Giusso: A Candidate for Phytostabilization in Abandoned Mine Sites. AB - Sardinia was known as an important mine pole in Europe during his history. Still after decades from mine closure, 75.000.000 m3 of mine waste, rich in heavy metals, were left abandoned causing a huge environmental legacy on the mine district area. Consequently, cost effective remediation is required. In this frame, phytoremediation is considered a feasible candidate. This research was focused on Helichrysum microphyllum subsp. tyrrhenicum, which is pioneer in xeric soils with low-functions, like mine tailings. The aim of this study was to evaluate its ability to extract heavy metals from mine soils and accumulate them in plant tissues and its suitability for phytostabilization. Sundry samples of soil, roots and epigean organ were collected through field sampling and analysed in order to obtain metals concentration and mineralogical characteristics. Our results indicate that this species tolerates high concentration of zinc, lead and cadmium, behaving as a species suitable for phytostabilization. PMID- 30310948 TI - Preparation and Characterization of Herbicide Mecoprop Imprinted Polymer and Its Application as a Selective Sorbent in Water Sample. AB - Bulk polymerization method was used to prepare a homogeneous molecularly imprinted polymer (MIP) for the specific extraction of herbicide mecoprop (MCPP). Thereafter, the binding performance of this functional polymer was evaluated under optimal condition, compared to a non-imprinted polymer. From the Scatchard plot analysis, two types of binding sites were detected in the MIP, the high affinity binding sites with a KD (equilibrium dissociation constant) of 6.4 uM and the low affinity ones with a KD of 55.9 uM. In addition, the possibility of using synthesized MIP for MCPP extraction from environmental aqueous samples was explored. The adsorption capacity of MIP in spiked bottled water and groundwater samples showed that the polymer could effectively extract MCPP from bottled water and groundwater (p < 0.05) with the recovery of 70.5% and 65.1%, respectively, demonstrating the potential of imprinted polymers for cost-effective and effective water treatment. PMID- 30310949 TI - Historical Pollution of an Urban Watershed Based in Geochemical, Geoacumulation, and EROD Activity in PLHC-1 Analyses in Sediment Cores. AB - In the present study, the environmental changes over the past 100 years in the Cambe River watershed in Southern Brazil were investigated. For this, a sediment core was collected to examine the distribution of metals, polycyclic aromatic hydrocarbons (PAHs), and ecotoxicological markers. The core corresponds from 1914 to 2012, which was obtained by the decay of 210Pb. Changes in the study area also were examined by: Geoaccumulation index (Igeo) and enrichment factor (EF), sediment quality guidelines (SGQs), and ethoxyresorufin-O-deethylase (EROD) activity in Poeciliopsis lucida hepatocellular carcinoma (PLHC-1) cells line. The Sigma16 PAHs ranged from 242.6 to 40,775 ng g-1, with pyrogenic source at the beginning of the core, which likely corresponds to the burning of forests to establish the city and the later use of fossil fuels from 1960 to 2012. In the 1930s, most of metals presented a concentration below the background. After the 1930s, high concentrations can be associated with the intense use of fertilizers (Cd, Cu, Zn, Hg) and increases in urban traffic (Zn and Pb). Igeo showed that the distribution of Cu is considered moderately to strongly polluted, and the EF of Pb was considered as moderately polluted. Statistical analyses showed a strong relation between the presence of the ANP, FLU, PHE, BaP, IND, and Bghi compounds and the induction of EROD activity, and no correlation with heavy metals. A prediction model for the linear regression was obtained between the ANP and BaP concentrations and the EROD activity, with an accuracy of 99%. PMID- 30310950 TI - PAHs Accumulations in Plant Leaves Around Coal-Fired Power Plant and Identification of their Potential Use as Bioindicators. AB - The purpose of this study was to investigate polycyclic aromatic hydrocarbons (PAHs) accumulation in leaves of different plant species growing in the neighborhood of coal-fired power plant (CPP) and to identify potential bioindicators for PAHs pollution monitoring. The study was performed in 8 sites in the surrounding areas of CPP. PAHs concentrations in leaves of 21 plant species growing within 1 km of CPP ranged from 0.043 to 4.52 ug g-1. A higher mean concentration of PAHs was found in leaves of perennial herbs and shrubs compared with annual herbs and trees. Herbaceous plants had the highest concentrations of 5-6 rings PAHs, and 4-ring PAHs mainly existed in shrubs. For 2 to 3-rings PAHs, there was no significant difference among herbaceous plants trees and shrubs. Then, four representative plants were further chosen for investigating the effect of CPP on the spatial distribution patterns of PAH compounds. No distinct difference in the level of 2- to 3-rings PAHs was observed on Broussonetia kaempferi Sieb, whereas 4 rings, 5-6 rings, and Sigma16PAHs had regional statistical differences. PAHs in Kalimeris indica (L.) Sch.-Bip had significant regional statistical differences. With the change of distance, the concentration of PAHs showed a significant decrease. Taraxacum mongolicum tended to capture the largest amount of both total PAHs and 5- to 6-ring PAHs, especially to BaP. These results could improve scientific evidence for the screening of bioindicators, in particular, T. mongolicum could be a priority. PMID- 30310951 TI - Source Apportionment of PM10 Over Three Tropical Urban Atmospheres at Indo Gangetic Plain of India: An Approach Using Different Receptor Models. AB - The present work is the ensuing part of the study on spatial and temporal variations in chemical characteristics of PM10 (particulate matter with aerodynamic diameter <= 10 MUm) over Indo Gangetic Plain (IGP) of India. It focuses on the apportionment of PM10 sources with the application of different receptor models, i.e., principal component analysis with absolute principal component scores (PCA-APCS), UNMIX, and positive matrix factorization (PMF) on the same chemical species of PM10. The main objective of this study is to perform the comparative analysis of the models, obtained mutually validated outputs and more robust results. The average PM10 concentration during January 2011 to December 2011 at Delhi, Varanasi, and Kolkata were 202.3 +/- 74.3, 206.2 +/- 77.4, and 171.5 +/- 38.5 MUg m-3, respectively. The results provided by the three models revealed quite similar source profile for all the sampling regions, with some disaccords in number of sources as well as their percent contributions. The PMF analysis resolved seven individual sources in Delhi [soil dust (SD), vehicular emissions (VE), secondary aerosols (SA), biomass burning (BB), sodium and magnesium salt (SMS), fossil fuel combustion, and industrial emissions (IE)], Varanasi [SD, VE, SA, BB, SMS, coal combustion, and IE], and Kolkata [secondary sulfate (Ssulf), secondary nitrate, SD, VE, BB, SMS, IE]. However, PCA-APCS and UNMIX models identified less number of sources (besides mixed type sources) than PMF for all the sampling sites. All models identified that VE, SA, BB, and SD were the dominant contributors of PM10 mass concentration over the IGP region of India. PMID- 30310953 TI - Value proposition of PSMA-targeted alpha-particle radioligand therapy in metastatic prostate cancer. PMID- 30310954 TI - ? PMID- 30310955 TI - ? PMID- 30310956 TI - ? PMID- 30310957 TI - Displaced medial clavicle fractures: operative treatment with locking compression plate fixation. AB - OBJECTIVES: Medial clavicle fractures are rare injuries and historically treated non-operatively. Displaced medial clavicle fractures, however, have a higher incidence of delayed- or non-union compared to non- displaced medial clavicle fractures and might benefit from operative treatment. We describe below a new technique for treating intra-articular fractures or extra-articular fractures with a small medial fragment using special locking plates and present the results of our operatively treated patients. METHODS: First we describe our technique for treating very medial fractures with the radial (VA)-LCPTM Distal Humerus Plate (DePuy Synthes, Switzerland). Second, a retrospective cohort study was performed. All patients operated on for a displaced medial clavicle fracture between 2010 and 2017 were included. Primary outcome was the QuickDASH score and the Subjective Shoulder Value (SSV). Secondary outcomes were operative complications including mal- or non-union and implant removal. RESULTS: All 15 patients were available for follow-up. Fourteen patients were included in our analysis. One patient was excluded due to severe concomitant injuries. Six patients were treated with the radial (VA)-LCPTM Distal Humerus Plate, eight patients with the LCPTM Superior Anterior Clavicle Plate with lateral extension (DePuy Synthes, Switzerland) and one with a LCP 3.5 plate. The mean follow-up was 39 months (range 9-79). The mean QuickDASH score was 0.81 (range 0-4.50, SD +/- 1.44) and the mean SSV was 96 (range 80-100, SD +/- 6.53). One patient had an early revision operation and developed an infection after 1.5 years. No mal- or non unions occurred. Eight patients had their implants removed. CONCLUSIONS: Operative treatment of displaced medial clavicle fractures with well-fitting 'small fragment' locking plates provides an excellent long-term functional outcome. Intra-articular fractures or extra-articular fractures with a small medial fragment can be treated with the radial (VA)-LCPTM Distal Humerus Plate. PMID- 30310958 TI - The impact of timing of antibiotics on in-hospital outcomes after major emergency abdominal surgery. AB - BACKGROUND: Patients undergoing major open emergency abdominal surgery experience high morbidity and mortality rates and often have sepsis at admission. The purpose of this study was to evaluate the association between antibiotic timing and in-hospital outcomes such as complications, need for reoperation, length of stay, and 30-day mortality. METHODS: This retrospective observational cohort study was conducted between January 2010 and December 2015 including patients that were triaged through the emergency department for subsequent major open abdominal surgery. All relevant perioperative data were extracted from medical records. The outcomes of interest were development of in-hospital postoperative complications, reoperations, length of stay, and 30-day mortality, all in association with antibiotic timing, categorized according to 0-6, 6-12, or > 12 h from triage. Multivariate logistic regression was performed to evaluate adjusted outcomes associated with antibiotic timing. RESULTS: A total of 408 patients were included, of whom 107 (26.2%) underwent at least one reoperation and 55.4% had at least one postoperative complication. These complications consisted of 26% surgical complications and 74% medical complications. Of the surgical complications, 73% were Clavien-Dindo >= 3. The median length of stay was 9 days and the overall 30-day mortality was 17.9%. The data showed that the development of complications, need for reoperation, 30-day mortality, and the length of stay were significantly correlated to delayed antibiotic administration of more than 12 h from admission. CONCLUSIONS: Antibiotic administration more than 12 h from triage was associated with a significantly increased risk of postoperative complications, need for reoperation, 30-day mortality, and a prolonged length of stay, when compared to patients that received antibiotic treatment 0-6 h and 6-12 h after triage. Our data suggest that prophylactic antibiotics should be administered to all patients undergoing major open emergency abdominal surgery; however, the dose and duration cannot be concluded on the basis of our data and should be further examined. PMID- 30310959 TI - Prevalence, risk factors and therapeutic aspects of injuries and accidents in women with epilepsy. AB - BACKGROUND: Epilepsy-related injuries and accidents (ERIA) are a frequent cause of hospitalisation and represent a relevant burden for patients with epilepsy. In particular, osteoporosis and other gender-specific aspects may increase the risk of seizure-related fractures and injuries in women with epilepsy. AIM AND SCOPE: The aim of this analysis is to determine the prevalence and clinical nature of ERIA in a cohort of women with epilepsy, to identify possible determinants including osteoporosis and to give an overview of the current knowledge of clinically important prophylactic and therapeutic aspects. RESULTS: In total, 167 women (mean age 39.0 years, range 18-67 years) with established diagnosis of epilepsy (mean disease duration 18.2 years, range 0-64) were analysed for the occurrence of ERIA. Overall, 22 patients (13.2%) reported at least one ERIA (mean number 3.4, +/- 3.1) during the last three months prior to enrollment. The most frequent types of ERIA were lacerations (n = 7/22; 31.8%), abrasions, cuts, bruises or hematoma (n = 6/22, 27.3%), burns (n = 3/22, 13.6%), and fractures (n = 3/22, 13.6%). Moreover, one seizure-related road traffic accident with consecutive trauma (4.5%) was reported. Ictal falls, periictal abnormalities of behaviour and missing seizure freedom were associated with ERIA. Furthermore, female patients with ERIA had a significantly reduced quality of life (QoL, p = 0.002) and increased anxiety (p = 0.008) compared to patients without ERIA. A review of the pertinent literature suggests decreased bone mineral density and use of enzyme-inducing AEDs to be risk factors for ERIA in women with epilepsy. CONCLUSION: ERIA represent relevant complications for women with epilepsy and are associated with a lower QoL and anxiety compared with non-affected controls. Improvement of anticonvulsive treatment and therapy for osteoporosis or osteomalacia may help to decrease ERIA and the associated burden. PMID- 30310962 TI - Phloretin reduces cell injury and inflammation mediated by Staphylococcus aureus via targeting sortase B and the molecular mechanism. AB - Sortase B (SrtB) is a vital virulence factor that plays a critical role in Staphylococcus aureus (S. aureus) infections, indicating that it could be a latent target for S. aureus infections. In this study, phloretin, a natural compound that primarily exists in the pericarp and velamen of apples and pears, shows little anti-S. aureus activity, but significantly inhibited SrtB activity in vitro. The results of lactate dehydrogenase release and live/dead cell assays suggested that phloretin reduced human alveolar epithelial cell damage caused by S. aureus. Additionally, an adhesion assay confirmed that phloretin lowered the colony count of S. aureus in human alveolar cells. Phloretin treatment significantly attenuated the inflammatory response in macrophage cells (J774) co cultured with S. aureus as determined by an enzyme-linked immune-sorbent assay. Furthermore, the results of molecular dynamics simulation, site-directed mutagenesis, and fluorescence spectroscopy quenching indicated that phloretin was directly located in the active pocket of SrtB and blocked substrate binding, leading to the loss of SrtB activity. These results indicate that phloretin is a possible candidate for treatment of S. aureus infections. PMID- 30310960 TI - Acute effects of methadone on EEG power spectrum and event-related potentials among heroin dependents. AB - Methadone as the most prevalent opioid substitution medication has been shown to influence the neurophysiological functions among heroin addicts. However, there is no firm conclusion on acute neuroelectrophysiological changes among methadone treated subjects as well as the effectiveness of methadone in restoring brain electrical abnormalities among heroin addicts. This study aims to investigate the acute and short-term effects of methadone administration on the brain's electrophysiological properties before and after daily methadone intake over 10 weeks of treatment among heroin addicts. EEG spectral analysis and single-trial event-related potential (ERP) measurements were used to investigate possible alterations in the brain's electrical activities, as well as the cognitive attributes associated with MMN and P3. The results confirmed abnormal brain activities predominantly in the beta band and diminished information processing ability including lower amplitude and prolonged latency of cognitive responses among heroin addicts compared to healthy controls. In addition, the alteration of EEG activities in the frontal and central regions was found to be associated with the withdrawal symptoms of drug users. Certain brain regions were found to be influenced significantly by methadone intake; acute effects of methadone induction appeared to be associative to its dosage. The findings suggest that methadone administration affects cognitive performance and activates the cortical neuronal networks, resulting in cognitive responses enhancement which may be influential in reorganizing cognitive dysfunctions among heroin addicts. This study also supports the notion that the brain's oscillation powers and ERPs can be utilized as neurophysiological indices for assessing the addiction treatment traits. PMID- 30310961 TI - Cognitive and socio-cognitive functioning of chronic non-medical prescription opioid users. AB - RATIONALE: Non-medical prescription opioid use (NMPOU) has become a major public health issue in the USA and is also increasing in Europe. However, little is known about neuropsychological associations of NMPOU-specifically regarding social cognition, which is essential for social functioning and treatability of opioid dependence. Previous studies with heroin users and opioid-substituted patients reported deficits in various cognitive functions, but these results are likely confounded by comorbid physical and psychiatric diseases, overdose associated hypoxia, and adulteration of street heroin. Therefore, the purpose of the present study was to investigate social and non-social cognition in a relatively pure NMPOU sample taking opioid analgesics or antitussives. METHODS: We assessed 23 individuals with NMPOU objectively confirmed by hair analyses and 29 opioid-naive, healthy controls, employing a comprehensive neuropsychological test battery. RESULTS: Significant impairments were found between NMPOU individuals and controls regarding the cognitive domains of attention (p < .01, Hedge's g = .85), declarative memory (p < .05, g = .66), and global cognitive empathy (p < .01, g = 0.99)-the latter included problems with emotion recognition from faces, voices, and complex scenes. Opioid hair concentrations transformed to morphine equivalents were negatively correlated with global cognitive empathy (r = - 0.52, p < .01), suggesting dose-dependent deficits. CONCLUSION: In contrast to stimulant users primarily displaying deficits in emotional empathy, opioid users showed relatively selective impairments in measures of cognitive empathy, with dose-dependent effects suggesting potential opioid-induced deficits and involvement of the opioid-system in processes of cognitive empathy. These results have important implications for future interventions of opioid dependence targeting social functioning and consequently enhancing therapy outcome and preventing relapse. PMID- 30310963 TI - Overexpressed recombinant quorum quenching lactonase reduces the virulence, motility and biofilm formation of multidrug-resistant Pseudomonas aeruginosa clinical isolates. AB - The increasing occurrence of resistance among Pseudomonas aeruginosa clinical isolates necessitates finding alternatives to antibiotics for controlling the infection of such pathogenic bacteria. In this study, lactonase gene ahl-1 from Bacillus weihenstephanensis isolate-P65 was successfully cloned and expressed in Escherichia coli BL21 (DE3) under the control of T7 promoter for utilizing its quorum quenching activity against three multidrug-resistant (MDR) P. aeruginosa clinical isolates. The biological activity of the overexpressed lactonase enzyme (Ahl-1), tested using a synthetic signal and Chromobacterium violaceum CV026 as a biosensor, displayed good catalytic activity using hexanoyl homoserine lactone (HHL) as a substrate and Chromobacterium violaceum (CV026) as a biosensor (77.2 and 133 nm min-1 for the crude and the purified Ahl-lactonase enzymes, respectively). Upon challenging its ability to inhibit the virulence of three MDR P. aeruginosa clinical isolates, recombinant Ahl-1 successfully prevented the accumulation of acylhomoserine lactone signals resulting in a significant reduction in the investigated virulence determinants; protease (from 40 up to 75.5%), pyocyanin (48-75.9%), and rhamnolipids (52.7-63.4%) (P value < 0.05). Ahl 1 also displayed significant inhibitory activities on the swarming motility and biofilm formation of the three tested MDR P. aeruginosa clinical isolates (P value < 0.05). Consequently, Ahl-1 lactonase enzyme in this study is considered a promising therapeutic agent to inhibit P. aeruginosa pathogenicity with no fear of emergence of resistance. PMID- 30310964 TI - M cell-targeting strategy enhances systemic and mucosal immune responses induced by oral administration of nuclease-producing L. lactis. AB - Efficient delivery of antigens to the gut-associated lymphoid tissue (GALT) is the most critical step for the induction of mucosal immunity by oral vaccines. As M cells are the main portal for luminal antigens into the GALT, the M cell targeting of antigens affords a promising strategy toward the development of effective oral vaccines. Lactococcus lactis is a fascinating recombinant host for oral vaccines, as they survive and produce antigens in the gut and have a particularly safe profile for human use. In this study, we developed and evaluated an M cell-targeting oral immunization system using recombinant L. lactis strains. For the purpose, we generated an L. lactis strain that secretes a model antigen fused with the OmpH beta1alpha1 domain of Yersinia enterocolitica, which has been shown to bind to a complement C5a receptor on the M cell surface. As the model antigen, Staphylococcus aureus nuclease was used for fusion, resulting in L. lactis-expressing Nuc-OmpH (LL/Nuc-OmpH). Ex vivo intestinal loop assays showed that the amount of Nuc-OmpH taken up into Peyer's patches was more than that of the unfused nuclease (Nuc). In addition, oral administration of the recombinant L. lactis strains to mice demonstrated that LL/Nuc-OmpH-induced nuclease-specific fecal IgA and serum IgG titers were significantly higher than those induced by LL/Nuc. These results indicate that OmpH works as an M cell targeting molecule when fused with antigens secreted from L. lactis and that the M cell-targeting strategy affords a promising platform for L. lactis-based mucosal immunization. PMID- 30310965 TI - Enhancement in the catalytic activity of Sulfolobus solfataricus P2 (+)-gamma lactamase by semi-rational design with the aid of a newly established high throughput screening method. AB - (-)-gamma-Lactam ((-)-2-azabicyclo[2.2.1]hept-5-en-3-one) has attracted increasing attention as the chiral intermediate of carbocyclic nucleosides most of which serve as pharmaceutical agents such as anti-HIV/HBV drugs abacavir and carbovir. So far, developing in vitro (+)-gamma-lactamase-mediated biotransformation has been one of the most efficient approaches for the production of (-)-gamma-lactam. In this study, the catalytic activity of the (+) gamma-lactamase from Sulfolobus solfataricus P2 was engineered by semi-rational design. Molecular docking and molecular dynamics simulation were carried out to target the key positions relevant to catalytic activity. Nine amino acid residues were selected for site saturation mutagenesis. To expedite the screening process, a sensitive colorimetric high-throughput screening method was established based on the Rimini test which was originally applied to distinguish primary amines from secondary amines. The screening process resulted in the achievement of several efficient mutants: V203N, V203Q, I336H, I336R, and Y388H. Synergy effects led to four final mutants (V203N/I336R, V203N/Y388H, I336R/Y388H, and V203N/I336R/Y388H) with enhanced enzyme activity after the combination of positive single mutants. The best mutant V203N/Y388H/I336R displayed a 21-fold higher enzyme efficiency (kcat/KM) compared to the wild-type enzyme. The result demonstrated that the biotransformation using the triple mutant as the catalyst reached > 49% conversion and > 99% enantiomeric excess at 80 degrees C after 2 h, which made it a good catalyst candidate to produce (-)-gamma-lactam. The possible mechanism responsible for the improvement in the catalytic activity was explicated by analyzing the protein-ligand binding modes and interaction between the protein and the ligand. PMID- 30310966 TI - Peculiarities and biotechnological potential of environmental adaptation by Geobacillus species. AB - The genus Geobacillus comprises thermophilic bacilli capable of endospore formation. The members of this genus provide thermostable proteins and can be used in whole cell applications at elevated temperatures; therefore, these organisms are of biotechnological importance. While these applications have been described in previous reviews, the present paper highlights the environmental adaptations and genome diversifications of Geobacillus spp. and their applications in evolutionary-protein engineering. Despite their obligate thermophilic properties, Geobacillus spp. are widely distributed in nature. Because several isolates demonstrate remarkable properties for cell reproduction in their respective niches, they seem to exist not only as endospores but also as vegetative cells in diverse environments. This suggests their excellence in environmental adaptation via genome diversification; in fact, evidence suggests that Geobacillus spp. were derived from Bacillus spp. while diversifying their genomes via horizontal gene transfer. Moreover, when subjected to an environmental stressor, Geobacillus spp. diversify their genomes using inductive mutations and transposable elements to produce derivative cells that are adaptive to the stressor. Notably, inductive mutations in Geobacillus spp. occur more rapidly and frequently than the stress-induced mutagenesis observed in other microorganisms. Owing to this, Geobacillus spp. can efficiently generate mutant genes coding for thermostable enzyme variants from the thermolabile enzyme genes under appropriate selection pressures. This phenomenon provides a new approach to generate thermostable enzymes, termed as thermoadaptation-directed enzyme evolution, thereby expanding the biotechnological potentials of Geobacillus spp. In this review, we have discussed this approach using successful examples and major challenges yet to be addressed. PMID- 30310967 TI - Defining and classifying terminology for medication harm: a call for consensus. AB - PURPOSE: The multiplicity in terms and definitions of medication-related harm has been a long-standing challenge for health researchers, clinicians, and regulatory bodies. The purpose of this narrative review was to report the diversity of terms; compare definitions, classifications, and models describing medication harm; and suggest which may be useful in both clinical practice and the research setting. METHODS: A narrative review of key studies defining and/or classifying medication harm terminology was undertaken. RESULTS: This review found that numerous terms are used to describe medication harm, and that there is a lack of consistency in current definitions, classifications, and applications. This lack of consistency applied across clinical jurisdictions and regulatory terminologies. A number of limitations in current definitions and classifications were identified. These included the exclusion of key types of medication harm events, ambiguous wording, and a lack of clarity and consensus on subclassifications. In general, there was some overlap in key models from the literature and these were presented to describe similarities and differences. CONCLUSION: Without uniformity quantifying, comparing, combining, or extrapolating medication harm data, such as a rate of harm in a specific population, is a challenge for those involved in medication safety and pharmacovigilance. There is a pressing need for further discussion and international consensus on this topic. Adoption of standard descriptors by practitioner groups, regulatory and policy organisations would foster quality improvement and patient safety. PMID- 30310968 TI - Aspergillus galactomannan detection: Trichoderma as a cause of positive results. AB - Aspergillus galactomannan immunoassay is a main diagnostic and monitoring tool in medical mycology. However, the specificity of the method can be skewered by the presence of several other fungi. Trying to diagnose a possible fungal infection of the lower respiratory tract in a haematology patient, it appeared that the fungus Trichoderma longibrachiatum is an additional probable cause of positive galactomannan results. Although, that Trichoderma is a rare but emerging pathogen in immunocompromised patients, the above information could be a caution point in the clinical evaluation of diagnostic results. PMID- 30310969 TI - Various Phyllosphere and Soil Bacterial Communities of Natural Grasses and the Impact Factors in a Copper Tailings Dam. AB - Copper mining caused severe damage to the ecological environment of mining areas. The combination of microbe and plant remediation has an application potential in improving the absorption and transformation efficiency of heavy metals. The phyllosphere is the largest biointerface on the planet, and bacteria are the dominant microbial inhabitants of the phyllosphere, believed to be critical to plant growth and health. This study investigated the phyllospheric and soil bacteria communities using high-throughput sequencing, and endophyte infection statuses of four natural grasses by toluidine blue heparin assay. Results showed variation in phyllospheric bacterial community structure. Gammaproteobacteria were the most abundant bacterial population. Bacilli were found in the phyllosphere of Bothriochloa ischaemum and Imperata cylindrica, while Clostridia were only found in Calamagrostis epigejos. Alphaproteobacteria were the dominant bacteria in soil. In addition, bacterial communities were influenced by endophytic infection statuses. Oxalobacteraceae was associated with soil carbon and sulfur. Enterobacteriaceae had negative correlation with the ratio of soil carbon and nitrogen, and had positive correlation with Cd content. These results offer useful insights into phyllospheric bacterial community variance in four different natural grasses in a copper tailings dam. PMID- 30310970 TI - Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET. AB - PURPOSE: This study aimed to determine the correlation between DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) status and the response to streptozocin in advanced well-differentiated pancreatic neuroendocrine tumors (WD panNETs). METHODS: To test the hypothesis that MGMT deficiency was required for an alkylating drug response, we retrospectively reviewed the response of 13 patients with WD panNETs to alkylating agents in relation to MGMT status. We also studied MGMT expression in streptozocin resistance using panNET cell lines. RESULTS: The cohort included 54% of patients with and 46% without MGMT expression. Among these, 83.3% (5/6) of MGMT-negative cases showed a partial response to streptozocin. In contrast, only 14.2% (1/7) of MGMT-positive cases showed a partial response (P = 0.013). Induced expression of MGMT in BON1 cells (a panNET cell line with undetectable endogenous MGMT) produced streptozocin resistance. Knockdown of MGMT in QGP1 cells, which express MGMT endogenously, did not alter the response to streptozocin. CONCLUSIONS: We observed a relationship between MGMT status and streptozocin response in both patients and cell culture. Despite limited cases examined, high concordance of negative expression of MGMT and response to streptozocin treatment suggest that MGMT expression can be a potential biomarker for this treatment. PMID- 30310972 TI - ? PMID- 30310971 TI - Efficacy of glaucoma drainage devices in uveitic glaucoma and a meta-analysis of the literature. AB - PURPOSE: To assess the efficacy of glaucoma drainage devices (GDD) in uveitic glaucoma and non-uveitic glaucoma, and to perform a meta-analysis of previously published results to compare with our data. METHODS: Retrospective case-control study, in which all eyes that underwent GDD surgery were included from 2015 onwards. Cases were defined as patients with uveitic glaucoma. Patients with non uveitic glaucoma served as controls. To compare our results, a review of the literature was performed using PubMed database. RESULTS: A total of 99 eyes were included (38 with uveitic glaucoma). The preoperative IOP was 25.9 +/- 7.7 mmHg and 27.9 +/- 9.6 mmHg for patients with and without uveitis (p = 0.277). No significant differences were found between patients with and without uveitis in the final IOP or reduction in IOP (44.9% vs. 42.8%, respectively). Within the first year after surgery, 13.2% of cases developed macular edema (vs. 6.6%; p = 0.267) and 15.8% a transient hypotony (vs. 8.2%; p = 0.242). A meta-analysis of 24 studies showed a postoperative weighted mean difference of - 17.8 mmHg and 2.2 lower number of IOP-lowering medications in uveitic glaucoma (compared to - 13.2 mmHg and 3.5 in the current study, respectively). CONCLUSION: GDD surgery in patients with uveitis has a similar effect on IOP as in patients without uveitis. The risks of developing macular edema and hypotony were slightly higher in patients with uveitis, but the results were not statistically significant. These findings are in line with previous reports, though data on the efficacy of GDD surgery and macular edema in uveitic glaucoma is scarce. PMID- 30310973 TI - Food Footprint as a Measure of Sustainability for Grazing Dairy Farms. AB - Livestock productions require significant resources allocation in the form of land, water, energy, air, and capital. Meanwhile, owing to increase in the global demand for livestock products, it is wise to consider sustainable livestock practices. In the past few decades, footprints have emerged as indicators for sustainability assessment. In this study, we are introducing a new footprint measure to assess sustainability of a grazing dairy farm while considering carbon, water, energy, and economic impacts of milk production. To achieve this goal, a representative farm was developed based on grazing dairy practices surveys in the State of Michigan, USA. This information was incorporated into the Integrated Farm System Model (IFSM) to estimate the farm carbon, water, energy, and economic impacts and associated footprints for ten different regions in Michigan. A multi-criterion decision-making method called VIKOR was used to determine the overall impacts of the representative farms. This new measure is called the food footprint. Using this new indicator, the most sustainable milk production level (8618 kg/cow/year) was identified that is 19.4% higher than the average milk production (7215 kg/cow/year) in the area of interest. In addition, the most sustainable pasture composition was identified as 90% tall fescue with 10% white clover. The methodology introduced here can be adopted in other regions to improve sustainability by reducing water, energy, and environmental impacts of grazing dairy farms, while maximizing the farm profit and productions. PMID- 30310976 TI - [The dissection of fresh brain : An optimized method for clinical autopsies]. PMID- 30310974 TI - A scavenging system against internal pathogens promoted by the circulating protein apoptosis inhibitor of macrophage (AIM). AB - An internal system designed to ward off and remove unnecessary or hazardous materials is intrinsic to animals. In addition to exogenous pathogens, a number of self-molecules, such as apoptotic or necrotic dead cells, their debris, and the oxides or peroxides of their cellular components, are recognized as extraneous substances. It is essential to eliminate these internal pathogens as quickly as possible because their accumulation can cause chronic inflammation as well as autoimmune responses, possibly leading to onset or progression of certain diseases. Apoptosis inhibitor of macrophage (AIM, also called CD5L) is a circulating protein that is a member of the scavenger receptor cysteine-rich superfamily, and we recently found that during acute kidney injury, AIM associates with intraluminal dead cell debris accumulated in renal proximal tubules and enhances clearance of luminal obstructions, thereby facilitating repair. Thus, AIM acts as a marker for phagocytes so that they can efficiently recognize and engulf the debris as their targets. In this chapter, we give an overview of the professional and non-professional phagocytes, and how soluble scavenging molecules such as AIM contribute to improvement of diseases by stimulating phagocytic activity. PMID- 30310975 TI - The SLC6A3 3'-UTR VNTR and intron 8 VNTR polymorphisms association in the time estimation. AB - OBJECTIVE: The present study investigated the association of 3'-UTR VNTR and intron 8 VNTR polymorphisms with a time estimation task performance. MATERIALS AND METHODS: One hundred and eight men in a Brazilian Northeast population (18-32 years old) participated in the experiment. The 3'-UTR VNTR and intron 8 VNTR polymorphisms were associated alone and combined to absolute error (AE) and relative error (RE) in a time estimation task (target duration: 1 s, 4 s, 7 s and 9 s). RESULTS: We found an association of the behavioral variable with intron 8 VNTR for the time intervals of 1 s and 9 s (p < 0.001) and polymorphisms combinatorial effect for 1 s (p <= 0.05). CONCLUSION: The intron 8 VNTR polymorphism and the combinatorial effect can modulate the time estimate in the domain of supra seconds, and thus our study indicates a role of the dopamine transporter in the neurobiological areas related to the time intervals judgment. PMID- 30310977 TI - [Liver injury induced by immune checkpoint inhibitor-therapy : Example of an immune-mediated drug side effect]. AB - BACKGROUND: Drug-induced liver injury is increasing, especially in elderly patients with polymedication and multimorbidity. OBJECTIVES: Clinicopathologic correlation of immune-mediated liver injury, specifically liver injury following therapy with immune checkpoint inhibitors against PD-1, PDL-1, and CTLA4. METHODS: Histologic assessment of liver biopsies of nine patients after therapy with immune checkpoint inhibitors and correlation with clinical parameters. RESULTS: In all nine patients, liver injury was apparent after variable administration of immune checkpoint inhibitors. Transaminase levels were increased up to a maximum of 3818 U/l. Liver histology showed liver injury resembling autoimmune hepatitis respective cholangitis. In two patients, veno occlusive disease was seen. Corticosteroid therapy was initiated in eight patients, subsequently four patients showed decreasing transaminases and five patients died of tumor progress. In three patients, it remains unclear whether liver injury by immune checkpoint inhibitors may have ultimately contributed to the fatal course, especially in one patient with liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Therapy with immune checkpoint inhibitors may lead to potentially fatal immune phenomena in susceptible patients, which may affect liver and/or other organs independently. Other causes of hepatopathy need to be ruled out clinically and/or histologically. PMID- 30310978 TI - Correction to: The effect of functional overreaching on parameters of autonomic heart rate regulation. AB - The original version of this article unfortunately contained a mistake. The presentation of Equation was incorrect. PMID- 30310979 TI - Whole body cryotherapy, cold water immersion, or a placebo following resistance exercise: a case of mind over matter? AB - PURPOSE: The use of cryotherapy as a recovery intervention is prevalent amongst athletes. Performance of high volume, heavy load resistance exercise is known to result in disturbances of muscle function, perceptual responses and blood borne parameters. Therefore, this study investigated the influence of cold water immersion (CWI), whole body cryotherapy (WBC) or a placebo (PL) intervention on markers of recovery following an acute resistance training session. METHODS: 24 resistance trained males were matched into a CWI (10 min at 10 degrees C), WBC (3- and 4 min at - 85 degrees C) or PL group before completing a lower body resistance training session. Perceptions of soreness and training stress, markers of muscle function, inflammation and efflux of intracellular proteins were assessed before, and up to 72 h post exercise. RESULTS: The training session resulted in increased soreness, disturbances of muscle function, and increased inflammation and efflux of intracellular proteins. Although WBC attenuated soreness at 24 h, and positively influenced peak force at 48 h compared to CWI and PL, many of the remaining outcomes were trivial, unclear or favoured the PL condition. With the exception of CRP at 24 h, neither cryotherapy intervention attenuated the inflammatory response compared to PL. CONCLUSION: There was some evidence to suggest that WBC is more effective than CWI at attenuating select perceptual and functional responses following resistance training. However, neither cryotherapy intervention was more effective than the placebo treatment at accelerating recovery. The implications of these findings should be carefully considered by individuals employing cryotherapy as a recovery strategy following heavy load resistance training. PMID- 30310980 TI - Dopamine versus epinephrine for fluid-refractory septic shock in neonates. PMID- 30310981 TI - Epinephrine versus dopamine in neonatal septic shock: author's reply. PMID- 30310982 TI - Management of elderly hip fractures by an orthopaedic trauma surgeon reduces surgical delays but does not improve outcomes compared to non-trauma surgeons. AB - PURPOSE: Recent literature on hip fractures has focussed on the optimal environment for best outcomes. One factor that has not been studied is the managing surgeon's training background. Our study aims to examine if hip fracture patients managed by fellowship-trained orthopaedic trauma surgeons have better outcomes compared to non-trauma trained general orthopaedic surgeons. METHODS: This is a retrospective study performed at a tertiary hospital with an established orthogeriatric co-managed hip fracture care pathway. All surgically treated elderly hip fracture patients over a period of 2 years were included and divided into 2 groups based on the managing surgeon: trauma and non-trauma. Patient characteristics, fracture and surgery information, post-operative complications, 1 year mortality and the Modified Barthel Index (MBI) scores were collected and compared. RESULTS: 871 patients were included. 32.1% (N = 280) were managed by trauma surgeons and 67.9% (N = 591) by non-trauma surgeons. There was no significant difference in the MBI scores pre-operatively and at 6 and 12 months post-operatively between the 2 groups. There was no difference in the incidence of postoperative complications and mortality. However, patients managed by trauma surgeons had significantly shorter time to surgery (p = 0.028) and higher proportion of surgeries performed within 48 h (p = 0.039). Trauma surgeons also took a shorter time to fix intertrochanteric fractures (p = 0.000). CONCLUSIONS: This study did not find any difference in the functional outcomes of hip fracture patients managed by trauma surgeons or non-trauma surgeons. However, trauma surgeons had faster times to surgery and shorter surgical times when fixing intertrochanteric fractures. PMID- 30310984 TI - Deciphering the prognostic significance of autoimmune disorders in myelodysplastic syndromes. PMID- 30310983 TI - Genetic, evolutionary and phylogenetic aspects of the plastome of annatto (Bixa orellana L.), the Amazonian commercial species of natural dyes. AB - MAIN CONCLUSION: The plastome of B. orellana reveals specific evolutionary features, unique RNA editing sites, molecular markers and the position of Bixaceae within Malvales. Annatto (Bixa orellana L.) is a native species of tropical Americas with center of origin in Brazilian Amazonia. Its seeds accumulate the apocarotenoids, bixin and norbixin, which are only found in high content in this species. The seeds of B. orellana are commercially valued by the food industry because its dyes replace synthetic ones from the market due to potential carcinogenic risks. The increasing consumption of B. orellana seeds for dye extraction makes necessary the increase of productivity, which is possible accessing the genetic basis and searching for elite genotypes. The identification and characterization of molecular markers are essential to analyse the genetic diversity of natural populations and to establish suitable strategies for conservation, domestication, germplasm characterization and genetic breeding. Therefore, we sequenced and characterized in detail the plastome of B. orellana. The plastome of B. orellana is a circular DNA molecule of 159,708 bp with a typical quadripartite structure and 112 unique genes. Additionally, a total of 312 SSR loci were identified in the plastome of B. orellana. Moreover, we predicted in 23 genes a total of 57 RNA-editing sites of which 11 are unique for B. orellana. Furthermore, our plastid phylogenomic analyses, using the plastome sequences available in the plastid database belonging to species of order Malvales, indicate a closed relationship between Bixaceae and Malvaceae, which formed a sister group to Thymelaeaceae. Finally, our study provided useful data to be employed in several genetic and biotechnological approaches in B. orellana and related species of the family Bixaceae. PMID- 30310985 TI - Validation of the Marginal Zone Lymphoma International Prognostic Index. AB - The Marginal Zone Lymphoma International Prognostic Index (MALT-IPI) was recently developed for use in patients with mucosa-associated lymphoid tissue (MALT) lymphoma based on age, serum lactate dehydrogenase level, and Ann Arbor stage. In this study, we aimed to validate the MALT-IPI. A total of 455 MALT lymphoma patients were included in this study from between January 2005 and February 2017. Event-free survival (EFS), progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) were the primary outcomes. Of the 455 patients, MALT-IPI low-, intermediate-, and high-risk groups included 309 (67.9%), 126 (27.7%), and 20 (4.4%) individuals, respectively. When comparing the low-risk group (L MALT-IPI) with the intermediate-high-risk group (I-H MALT-IPI), EFS, PFS, CSS, and OS were significantly different (p = 0.000, p = 0.000, p = 0.027, and p = 0.037). The International Prognostic Index and the Follicular Lymphoma International Prognostic Index failed to predict the prognosis of MALT lymphoma. Use of the MALT-IPI significantly differentiated L MALT-IPI from I-H MALT-IPI with respect to EFS, PFS, CSS, and OS. MALT-IPI is a valuable tool for the prediction of MALT lymphoma prognosis. PMID- 30310986 TI - Adjunctive Thermoprotection During Percutaneous Thermal Ablation Procedures: Review of Current Techniques. AB - Although rare, unintended thermal injury to organs surrounding the ablation zone can lead to severe complications. Over the past 15 years, different protective methods have been developed to limit risk of complications, and expand indications to include more challenging lesions in various locations including liver, kidney, lung and bone. The most frequently used techniques include hydrodissection, carbodissection, balloon interposition and probe torqueing. In most cases, tumours can be physically separated from sensitive structures, reducing risk of thermal injury. Endoluminal cooling/warming is an alternative option for complex ablations close to the ureter or major bile ducts. Different techniques may be combined to achieve successful protection in locations with complex anatomy. The purpose of this review is to provide an overview of available protective measures and discuss respective advantages/drawbacks. PMID- 30310987 TI - Caring for the person with cancer and the role of digital technology in supporting carers. AB - PURPOSE: Informal carers may experience a range of unmet needs during the caring period and, at times, lack support to adequately manage care of the person with cancer and balance personal family and work commitments. The aim of this study was to understand the needs of informal carers of people with cancer and how digital technology may be used to address carers' needs. METHODS: Focus groups and semi-structured interviews were conducted with 45 carers. Carers discussed supports and services they used to address their needs, barriers to accessing support, and how digital technology could assist in meeting their needs. RESULTS: Carers used informal support such as friends and family and formal support including respite and community groups during the caring period. Barriers to accessing support included reluctance to seek external help, sensitivities associated with prioritising carers' needs over patients' needs, and the adequacy of information received. Technology was reported to have the potential to allow carers' privacy to seek support; however, carers' attitudes towards technology differed. CONCLUSIONS: Carers require support during the caring period to help balance their own needs with the needs of the person receiving cancer treatment. Digital technology may provide an opportunity to deliver support to carers; however, further research is needed to assess the appropriateness of these interventions to inform improved health outcomes for this vulnerable group. PMID- 30310988 TI - Missed opportunities for physical activity management at key points throughout the chemotherapy pathway for colorectal survivors: an observational interview study. AB - PURPOSE: Physical activity (PA) is central to self-management for people with colorectal cancer (CRC) to support health behaviour and function secondary to cancer treatment. However, there is limited evidence on how health professionals (HPs) promote PA during cancer treatment. This study aimed to investigate how and when PA is promoted throughout the chemotherapy pathway among colorectal cancer survivors. METHODS: A qualitative study was conducted with adults with CRC receiving chemotherapy at a large cancer centre. Cross-sectional observation of clinical consultations was conducted at four points during the chemotherapy pathway: prior, midpoint, final cycle, and 8 weeks following chemotherapy. Following completion of treatment, audio-recorded, semi-structured interviews were conducted with patients and HPs and transcribed verbatim. Codes and themes were identified and triangulated from all the data using framework analysis. Observational themes are reported and complimented by interview data. RESULTS: Throughout the chemotherapy pathway (pre, midpoint, end), many opportunities were missed by HPs to promote PA as a beneficial means to maintain functioning and ameliorate cancer treatment side effects. When discussed, PA levels were used only to determine fitness for future oncological treatment. No PA promotion was observed despite patients reporting low PA levels or treatment side effects. Post treatment, PA promotion was more routinely delivered by HPs, as evidenced by problem-solving and onward referrals to relevant HPs. CONCLUSION: PA promotion was largely absent during treatment despite it being a key component of patient self-management following treatment. This suggests considerable missed opportunities for HPs to provide cancer survivors with PA evidence-based interventions. Further research is necessary to identify how best to ensure PA is promoted throughout the cancer journey. IMPLICATION FOR CANCER SURVIVORS: These findings suggest many may not be receiving support to be physically active during treatment. PMID- 30310989 TI - Usefulness of slice encoding for metal artifact correction (SEMAC) technique for reducing metal artifacts after total knee arthroplasty. AB - PURPOSE: To evaluate the usefulness of a novel MRI sequence strategy in the assessment of the periprosthetic anatomical structures after primary total knee arthroplasty. METHODS: Two MR sequences were retrospectively compared for the imaging of 15 patients with implanted cruciate-retaining/fixed-bearing TKAs (DePuy, PFC Sigma): a slice encoding sequence for metal artifact correction (SEMAC) and a standard sequence. Images were acquired on a 1.5-T system. The degree of artifact reduction was assessed using several qualitative (Likert-type scale) (artifact size, distorsion, blur, image quality, periprosthetic bone, posterior cruciate ligament, lateral collateral ligament, medial collateral ligament, patella tendon, popliteal vessels) and quantitative (artifact volume, Insall-Salvati index, length of patella/tendon, prosthesis dimensions) parameters by blinded reads performed by four investigators. The SEMAC sequences were statistically compared with the standard sequence using Wilcoxon test. Additionally, the intraclass correlation coefficient (ICC) for interobserver agreement was calculated. RESULTS: Higher levels of blurring were found with SEMAC compared to standard sequences (p < 0.001). All other qualitative parameters improved significantly with the application of SEMAC. In comparison with conventional sequences, the artifact volume was reduced by 59% utilizing SEMAC. Thus, the artifact reduction improved the precision of measurements such as Insall-Salvati index and length of patella/tendon (p < 0.001). The dimension of the tibial component (Ti alloy/polyethylene) revealed accurate values with both MRI sequences. A sufficient interobserver agreement among all readers was found with SEMAC, qualitatively ICC 0.9 (range 0.8-1) as well as quantitatively ICC 0.95 (range 0.92-0.98). CONCLUSIONS: SEMAC effectively reduces artifacts caused by metallic implants after total knee arthroplasty relative to standard imaging. This allows for an improved assessment of periprosthetic anatomical structures. This might enable an improved detectability of postoperative complications in the future. LEVEL OF EVIDENCE: Diagnostic Study Level III. PMID- 30310990 TI - CIC fusion-positive sarcoma of the spermatic cord. AB - In addition to germ cell tumors and tumors of the sex cord stroma, the WHO classification of testis and paratesticular tumors also contains malignant soft tissue tumors. Among them, liposarcomas of the spermatic cord are the most common entities. Other mesenchymal tumors with smooth muscle, skeletal muscle, fibroblastic/myofibroblastic, or nerve sheath differentiation are rare. Ewing sarcoma is composed of uniform small round cells and typically characterized by translocations of the EWSR1 gene. In rare cases, Ewing sarcoma-like tumors lack an EWSR1 gene fusion. Some of these tumors harbor a specific CIC translocation. However, Ewing-like sarcoma has up to now never been described in the testis or spermatic cord. The present case describes the first EWSR1-negative, undifferentiated round cell sarcoma with CIC translocation of the spermatic cord. Potential differential diagnoses are discussed. PMID- 30310991 TI - Exercise and the control of muscle mass in human. AB - During the course of life, muscle mass undergoes many changes in terms of quantity and quality. Skeletal muscle is a dynamic tissue able to hypertrophy or atrophy according to growth, ageing, physical activity, nutrition and health state. The purpose of the present review is to present the mechanisms by which exercise can induce changes in human skeletal muscle mass by modulating protein balance and regulating the fate of satellite cells. Exercise is known to exert transcriptional, translational and post-translational regulations as well as to induce epigenetic modifications and to control messenger RNA stability, which all contribute to the regulation of protein synthesis. Exercise also regulates the autophagy-lysosomal and the ubiquitin-proteasome pathways, the two main proteolytic systems in skeletal muscle, indicating that exercise participates to the regulation of the quality control mechanisms of cellular components and, therefore, to muscle health. Finally, activation, proliferation and differentiation of satellite cells can be enhanced by exercise to induce muscle remodelling and hypertrophy. Each of these mechanisms can potentially impact skeletal muscle mass, depending on the intensity, duration and frequency with which the signal appears. PMID- 30310992 TI - Resveratrol long-term treatment differentiates INS-1E beta-cell towards improved glucose response and insulin secretion. AB - The clonal INS-1E beta-cell line has proven to be instrumental for numerous studies investigating the mechanisms of glucose-stimulated insulin secretion. The composition of its culture medium has not changed over the years, although some compounds have been recently highlighted for their effects on tissue differentiation. The present study investigated the effects of long-term treatment of INS-1E cells with 1 MUM resveratrol on glucose-stimulated insulin secretion, testing an extended glucose dose response. The data demonstrate that chronic exposure to low-dose resveratrol expands the range of the glucose dose response of INS-1E cells beyond 15 mM glucose. We also assessed whether such beneficial effects could be retained after resveratrol withdrawal from the culture medium. This was not the case as INS-1E cells deprived of resveratrol returned to the phenotype of naive cells, i.e., exhibiting a plateau phase at 15 mM glucose. Of note, although resveratrol has antioxidant properties, it cannot substitute for beta-mercaptoethanol normally present in the medium of INS-1E cells as a reducing agent. In conclusion, the addition of resveratrol as a standard component of the culture medium of INS-1E cells improves glucose stimulated insulin secretion. PMID- 30310993 TI - Aggregation and degradation scales for prion-like domains: sequence features and context weigh in. AB - Protein aggregation in vivo is generally combated by extensive proteostatic defenses. Many proteostasis factors specifically recognize aggregation-prone features and re-fold or degrade the targeted protein. However, protein aggregation is not uncommon, suggesting that some proteins employ evasive strategies to aggregate in spite of the proteostasis machinery. Therefore, in addition to understanding the inherent aggregation propensity of protein sequences, it is important to understand how these sequences affect proteostatic recognition and regulation in vivo. In a recent study, we used a genetic mutagenesis and screening approach to explore the aggregation or degradation promoting effects of the canonical amino acids in the context of G-rich and Q/N rich prion-like domains (PrLDs). Our results indicate that aggregation propensity scales are strongly influenced by the interplay between specific PrLD features and proteostatic recognition. Here, we briefly review these results and expand upon their potential implications. In addition, a preliminary exploration of the yeast proteome suggests that these proteostatic regulation heuristics may influence the compositional features of native G-rich and Q/N-rich domains in yeast. These results improve our understanding of the features affecting the aggregation and proteostatic regulation of prion-like domains in a cellular context, and suggest that the sequence space for native prion-like domains may be shaped by proteostatic constraints. PMID- 30310994 TI - Proteomic profiling of yeast heterochromatin connects direct physical and genetic interactions. AB - Heterochromatin domains are stably repressed chromatin structures composed of a core assembly of silencing proteins that condense adjacent nucleosomes. The minimal heterochromatin structure can serve as a platform for recruitment of complementary regulatory factors. We find that a reconstituted budding yeast heterochromatin domain can act as a platform to recruit multiple factors that play a role in regulating heterochromatin function. We uncover the direct interaction between the SIR heterochromatin complex and a chromosomal boundary protein that restricts the spread of heterochromatin. We find that the SIR complex relieves a mechanism of auto-inhibition within the boundary protein Yta7, allowing the Yta7 bromodomain to engage chromatin. Our results suggest that budding yeast shares with other eukaryotes the ability to establish complex heterochromatin domains that coordinate multiple mechanisms of silencing regulation through physical interactions. PMID- 30310995 TI - Neuromotor rehabilitation in spina bifida: the need of randomized controlled trials. PMID- 30310996 TI - Combination therapy comprising irreversible electroporation and hydroxycamptothecin loaded electrospun membranes to treat rabbit VX2 subcutaneous cancer. AB - Irreversible electroporation (IRE) is a kind of promising cancer treatment technology. However, local recurrence still occurs because of incomplete ablation. The aim of this study was to investigate the combined therapy of IRE and a hydroxycamptothecin loaded electrospun membrane (EM/HCPT) to treat rabbit VX2 subcutaneous cancer. HCPT loaded membranes were developed by electrospinning. Mechanical test and in vitro drug release study of EM/HCPT were performed. 24 rabbits with subcutaneous VX2 tumor were randomly divided into four groups: the control group, the EM/HCPT group, the IRE ablation group, and the IRE + EM/HCPT group. The tumor cells were ablated by IRE first, followed by subcutaneous implantation of EM/HCPT to release HCPT constantly in order to damage the residual cancer cells. The tumor inhibition efficacy was assessed by the tumor real-time monitoring, histological and immunofluorescent analyses, and transmission electron microscopy (TEM) examination. Assessment of the release from EM/HCPT showed that HCPT release lasted for about 7 days. The in vivo antitumor efficacy assessment, histological and immunofluorescent analyses, and TEM examination showed that IRE + EM/HCPT had the best tumor inhibition ability. In addition, the biochemical analyses and hematoxylin and eosin (H&E) staining of normal organs indicated that IRE + EM/HCPT treatment was safe. Our study provided a new concept in cancer treatment and might promote the application of IRE. PMID- 30310997 TI - The Evolving Cardiovascular Disease Risk Scores for Persons with Diabetes Mellitus. AB - PURPOSE OF REVIEW: We briefly introduce the concept and use of cardiovascular disease (CVD) risk scores and review the methodology for CVD risk score development and validation in patients with diabetes. We also discuss CVD risk scores for diabetic patients that have been developed in different countries. RECENT FINDINGS: Patients with diabetes have a gradient of CVD risk that needs to be accurately assessed. Numerous CVD risk scores for diabetic patients have been created in various settings. The methods to develop risk scores are highly diverse and each choice has its own pros and cons. A well-constructed risk score for diabetic patients may be advocated by guidelines and adopted by healthcare providers to help determine preventive strategies. New risk factors are being investigated in order to improve the predictive accuracy of current risk scores. A suitable CVD risk score for the diabetes population should be accurate, low cost, and beneficial to outcome. While the performance (accuracy) has all been internally validated, validation on external populations is still needed. Cost effectiveness and clinical trials demonstrating improvement in outcomes are limited and should be the target of future research. PMID- 30311000 TI - An amino-functionalized mesoporous silica (KIT-6) as a sorbent for dispersive and ultrasonication-assisted micro solid phase extraction of hippuric acid and methylhippuric acid, two biomarkers for toluene and xylene exposure. AB - The authors described a new application of amino-functionalized KIT-6 for dispersive ultrasonication-assisted micro solid phase extraction of hippuric acid (HA) and methyl hippuric acid (MHA) from human urine and water samples. In the first step, an amino-functionalized mesoporous silica of type KIT-6 was synthesized. It was characterized by field emission scanning electron microscopy, Fourier transform infrared spectrometry, nitrogen adsorption-desorption analysis, thermogravimetry and X-ray diffraction. Following sorption and desorption with 1.0 mL methanol/NH4OH (1%; v/v), HA and MHA were quantified by HPLC with UV detection. Various important parameters were optimized by Box-Behnken design. Under optimized conditions, The limit of detections (LOD) were calculated by a signal-to-noise ratio of 3, which were 0.5 MUg L-1 and 0.2 MUg L-1 for HA and MHA, respectively, and the calibration plot is linear in the 1-1000 MUg L-1 concentration range. Only small matrix effects were found. The method was successfully implemented for the sensitive determination of HA and MHA in (spiked) human urine samples. Graphical abstract Schematic of a sorbent for dispersive micro solid phase extraction coupled with ultrasonic power. It consists of amino functionalized KIT-6 and was used for the simultaneous preconcentration and determination of low levels of hippuric and methyl hippuric acid in urine and water samples. PMID- 30310999 TI - Role of Echocardiography in Assessment of Cardioembolic Sources: a Strong Diagnostic Resource in Patients with Ischemic Stroke. AB - PURPOSE OF REVIEW: This review will discuss the most frequent sources of cardiac embolism and the role of echocardiography in these different clinical settings, and, in addition, provide suggestions about the choice between transthoracic (TTE) and transesophageal echocardiography (TEE). RECENT FINDINGS: Stroke is the third leading cause of death in industrial countries, and 15-40% of all ischemic strokes are due to cardioembolism. TTE and TEE are cornerstones in the detection of cardioembolic sources and provide fundamental information about the embolic risk and most suitable treatment of these patients, improving long-term outcomes. Echocardiography is a widely available, inexpensive, and safe diagnostic tool that is almost free from contraindication, and these elements allow the common use of this technique in almost all the patients with ischemic stroke. The most common cardioembolic sources include left atrial appendage thrombosis during atrial fibrillation; vegetations in infective endocarditis; cardiac masses including left ventricular thrombosis, cardiac tumors, etc.; atherosclerotic plaques; and passageways within the heart serving as conduits for paradoxical embolization, e.g., patent foramen ovale. PMID- 30311001 TI - Internet of things for knowledge administrations by wearable gadgets. AB - The novel gadgets are associated constantly at a quick phase for the development of Internet of Things (IoT). Wearable gadgets are another gathering development in those available gadgets. The recent method in gadgets is to coordinate with IoT and idea is implementing the remote sensor systems that convey novel encounters in day by day exercises. Here, I exhibit a regular day to day existence application including a Wireless Sensor Networks (WSN) for gaming situation. By using this, the physical factors of sports person are estimated and directed by wearable gadgets to Wireless Sensor Networks. The end goal to incorporate diverse equipment stages and to present an administration situated semantic middleware arrangement hooked on a solitary request also utilization of Enterprise Service Bus (ESB) is introduced as a scaffold to ensure coordination of the distinctive conditions and interoperability. Through proposed method everyone can procure information by introducing framework to fresh client. Those clients would be able to get to the information through a wide assortment of gadgets (cell phones, tablets, and PCs) and working frameworks (Android, Windows, Linux, iOS, and so on). Finally we introduced one case study of football match for monitoring 11 players and acquiring data's and to predict the real time situation in football ground. PMID- 30310998 TI - The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. AB - Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury. PMID- 30311003 TI - Assessing Performance and Quality After Non-ST Segment Elevation Acute Coronary Syndromes. AB - PURPOSE OF REVIEW: This review summarizes and discusses the evidence base supporting current performance and quality measures used in assessing institutions in their care of patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS). RECENT FINDINGS: Professional societies in the USA and Europe have developed performance and quality measures for NSTE-ACS. These measures are reviewed and updated periodically to reflect the most important evidence from the literature. In the USA, the ACC/AHA Task Force on Performance Measures published the updated 2017 AHA/ACC Clinical Performance and Quality Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction. In Europe, the ESC Acute Cardiac Care Association published the 2017 Quality Indicators for acute myocardial infarction. These documents build on guidelines previously developed and published by the two organizations. They include detailed reviews of current and past studies establishing that adherence with guidelines improves clinical outcomes. Both measure sets provide quantitative methodologies to assess program performance. Institutional programs that focus on these validated measures can increase guideline adherence, streamline and standardize care processes, and reduce morbidity and mortality. Performance and quality measures have become a critical part of healthcare today, allowing patients, providers, administrators, and payors to assess patient care objectively. They are also becoming an important component of value-based payment programs. To be fair, and useful, for internal institutional assessment, in comparing different institutions, and for value-based payments, only validated performance measures such as these should be employed. PMID- 30311002 TI - Building an Adult Congenital Heart Program: Critical Components and Important Allies. AB - PURPOSE OF THE REVIEW: The purpose of this review is to illustrate specific challenges and opportunities in the building of an adult congenital heart disease (ACHD) program and to highlight critical components and important allies. RECENT FINDINGS: With more than 1.4 million adults with congenital heart disease in the USA alone, access to specialized, compassionate, high-quality comprehensive care requires a shift toward more aggressive expansion of ACHD care, especially in the context of sparse ACHD provider representation in the vast majority of adult medical centers. The effective build of an ACHD program requires measured escalation in management of ACHD complexity matched with cultivation of key resources and clinical services ranging from congenital cardiac surgery and interventional cardiology to acquired heart disease as well as partnerships with non-cardiac specialists. By reframing ACHD care as a shared goal between patients, providers, hospitals, pharmaceutical and device industry, and payers, a potent business model can be built around the developing ACHD program to facilitate acquisition of these key resources. PMID- 30311006 TI - Child and adolescent psychiatry in Slovenia in comparison with other European countries. PMID- 30311007 TI - Parental socioeconomic position and risk of ADHD in offspring: a cohort study of 9648 individuals in Denmark 1976-2013. AB - The strength of the association between parental socioeconomic position (SEP) and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring is found to vary substantially, perhaps due to the negligence of possible changes in parental life course SEP. The present study investigated the association between parental SEP in adulthood and risk of ADHD diagnosis in offspring and whether parental childhood SEP modified this association. The study population included 9648 live born singletons followed in the Psychiatric Central Register from birth in 1976 1996 until 2013. Cox regression was used to estimate hazard ratios for ADHD diagnosis according to parental SEP in adulthood. The results showed that low parental SEP in adulthood was associated with higher risk of ADHD diagnosis in offspring, also after adjustment for possible confounders. Thus, offspring of parents with low SEP in adulthood had 4.52 (95% CI 2.81-7.26) times higher hazard of ADHD diagnosis compared with offspring of parents with high SEP in adulthood. Further, parental childhood SEP was found to modify the observed association. Thus, offspring of parents with downward social mobility from childhood to adulthood and offspring of parents with stable low SEP experienced the highest risk of ADHD diagnosis, followed by offspring of parents with upward social mobility, compared with offspring of parents with stable high SEP. The results suggest that it is important to take into account the possibility of social mobility as changes in parental life course SEP from childhood to adulthood seem to influence the risk of ADHD diagnosis in offspring. PMID- 30311005 TI - Asymptomatic Severe Aortic Valve Stenosis-When to Intervene: a Review of the Literature, Current Trials, and Guidelines. AB - PURPOSE OF REVIEW: The optimal treatment for asymptomatic patients with severe aortic valve stenosis (AS) is not clearly known. Here, we review the available data on the management of such patients. RECENT FINDINGS: Half of patients with severe AS are asymptomatic at the time of diagnosis, and are at risk for adverse events, including sudden cardiac death. A significant proportion of these patients develop AS-related symptoms within 1 or 2 years. Clinical and echocardiographic characteristics are predictors of poor outcomes and can guide treatment decisions. Several non-randomized studies and meta-analyses have suggested benefit from early AVR for asymptomatic severe AS, including improved all-cause, cardiovascular, and valve-related mortality. Based on the available information, current guidelines suggest aortic valve replacement in the presence of specific characteristic, including left ventricular dysfunction and very severe AS with significantly elevated gradients. Although the available data suggests early AVR improves the clinical outcomes of these patients, most patients in current practice are managed conservatively. Six randomized trials are ongoing to better elucidate the ideal management of asymptomatic severe AS patients. PMID- 30311004 TI - Immunotherapy for Brain Tumors. AB - OPINION STATEMENT: Despite aggressive surgery, radiation, and systemic chemotherapy, the prognosis for patients diagnosed with malignant brain tumors remains extremely poor, and standard treatments carry significant risks for long term neurocognitive deficits. There is a clear and urgent need for the development of more effective treatments that will add minimal toxicity to standard therapies for invasive brain cancers. Cancer immunotherapy is a treatment modality that holds promise for the delivery of tumor-specific cytotoxicity, with the potential to eliminate brain tumor cells without harming the eloquent brain. PMID- 30311009 TI - Effect of Bilayer CeO2-x/ZnO and ZnO/CeO2-x Heterostructures and Electroforming Polarity on Switching Properties of Non-volatile Memory. AB - Memory devices with bilayer CeO2-x/ZnO and ZnO/CeO2-x heterostructures sandwiched between Ti top and Pt bottom electrodes were fabricated by RF-magnetron sputtering at room temperature. N-type semiconductor materials were used in both device heterostructures, but interestingly, change in heterostructure and electroforming polarity caused significant variations in resistive switching (RS) properties. Results have revealed that the electroforming polarity has great influence on both CeO2-x/ZnO and ZnO/CeO2-x heterostructure performance such as electroforming voltage, good switching cycle-to-cycle endurance (~ 102), and ON/OFF ratio. A device with CeO2-x/ZnO heterostructure reveals good RS performance due to the formation of Schottky barrier at top and bottom interfaces. Dominant conduction mechanism of high resistance state (HRS) was Schottky emission in high field region. Nature of the temperature dependence of low resistance state and HRS confirmed that RS is caused by the formation and rupture of conductive filaments composed of oxygen vacancies. PMID- 30311008 TI - Diagnosis and Management of Chagas Cardiomyopathy in the United States. AB - PURPOSE OF REVIEW: Chagas cardiomyopathy is an emerging form of non-ischemic cardiomyopathy in the USA. This review aims to summarize current concepts in pathophysiology, disease transmission, medical therapy, and heart transplantation for patients with chronic Chagas cardiomyopathy. RECENT FINDINGS: The incidence of Chagas cardiomyopathy is increasing in the USA, driven mainly by immigration from countries where Chagas disease is endemic. Chagas cardiomyopathy is a chronic, progressive myocarditis, with hallmark features of biventricular dysfunction, ventricular arrhythmias, thromboembolic complications, and a high risk of mortality. Currently, there is no effective treatment for chronic Chagas cardiomyopathy. Heart transplantation is the only treatment for patients with end stage Chagas cardiomyopathy, but is associated with unique challenges including risk of reactivation. As the prevalence of Chagas cardiomyopathy increases in the USA, practitioners must be aware of the unique challenges in diagnosis and management that Chagas cardiomyopathy presents. PMID- 30311010 TI - Modern Approaches to Evacuating Intracerebral Hemorrhage. AB - PURPOSE OF REVIEW: The present review aims to discuss the recent advances in surgical management of spontaneous intracerebral hemorrhage (ICH), safety and efficacy of minimally invasive surgical techniques, and the existing evidence supporting their use. RECENT FINDINGS: Newer surgical techniques, collectively referred to as minimally invasive surgery (MIS), have been evaluated and studied in management of ICH. Stereotactic evacuation of intracerebral hemorrhage using aspiration-irrigation technique has showed significant reductions in the hematoma volume with minimal intra-operative bleeding. Catheter-based evacuation in combination with use of recombinant tissue plasminogen activator (rt-PA) produces lysis and drainage of spontaneous ICH and intraventricular hemorrhage (IVH) rapidly with minimal major adverse events. Recent advances in the management of spontaneous ICH highlights potential advantages including safety and efficacy in clot lysis and reduction in hematoma volume especially with image-guided catheter based drainage and concurrent use of rt-PA. Controlled trials are required to conclusively establish standard surgical techniques and rt-PA dosage, before incorporating minimally invasive surgery plus rt-PA, as a standard of care in patients with spontaneous ICH. PMID- 30311011 TI - Internet of Things with Maximal Overlap Discrete Wavelet Transform for Remote Health Monitoring of Abnormal ECG Signals. AB - In this paper, MODWT is used to decompose the Electrocardiography (ECG) signals and to identify the changes of R waves in the noisy input ECG signal. The MODWT is used to handle the arbitrary changes in the input signal. The R wave's detctected by the proposed framework is used by the doctors and careholders to take necessary action for the patients. MATLAB simulink model is used to develop the simulation model for the MODWT method. The performance of the MODWT based remote health monitoring system method is comparatively analyzed with other ECG monitoring approaches such as Haar Wavelet Transformation (HWT) and Discrete Wavelet Transform (DWT). Sensitivity, specificity, and Receiver Operating Characteristic (ROC) curve are calculated to evaluate the proposed Internet of Things with MODWT based ECG monitoring system. We have used MIT-BIH Arrythmia Database to perform the experiments. PMID- 30311012 TI - Did the Romans introduce the Egyptian mongoose (Herpestes ichneumon) into the Iberian Peninsula? AB - New finds of bones of the Egyptian Mongoose (Herpestes ichneumon), one from Portugal and one from Spain, were directly 14C dated to the first century AD. While the Portuguese specimen was found without connection to the Chalcolithic occupation of the Pedra Furada cave where it was recovered, the Spanish find, collected in the city of Merida, comes from a ritual pit that also contained three human and 40 dog burials. The finds reported here show that the Egyptian mongoose, contrary to the traditional and predominant view, did not first arrive in the Iberian Peninsula during the Muslim occupation of Iberia. Instead, our findings are consistent with the hypothesis that the species was first introduced by the Romans, or at least sometime during the Roman occupation of Hispania. Therefore, radiocarbon dating of new archaeological finds of bones of the Egyptian Mongoose (Herpestes ichneumon) in the Iberian Peninsula push back the confirmed presence of the species in the region by approximately eight centuries, as the previously oldest dated record is from the ninth century. With these new dates, there are now a total of four 14C dated specimens of Egyptian mongooses from the Iberian Peninsula, and all of these dates fall within the last 2000 years. This offers support for the hypothesis that the presence of the species in Iberia is due to historical introductions and is at odds with a scenario of natural sweepstake dispersal across the Straits of Gibraltar in the Late Pleistocene (126,000-11,700 years ago), recently proposed based on genetic data. PMID- 30311014 TI - Correction to: Efficacy of certolizumab pegol with and without concomitant use of disease-modifying anti-rheumatic drugs over 4 years in psoriatic arthritis patients: results from the RAPID-PsA randomized controlled trial. AB - The above article originally published with an error present in Discussion section and presented correctly in this article. The original article was corrected. PMID- 30311013 TI - Challenges in Aortic Stenosis: Review of Antiplatelet/Anticoagulant Therapy Management with Transcatheter Aortic Valve Replacement (TAVR): TAVR with Recent PCI, TAVR in the Patient with Atrial Fibrillation, and TAVR Thrombosis Management. AB - PURPOSE OF REVIEW: This review aims to describe the current evidence and consensus recommendations around antiplatelet and anticoagulant management in three common clinical scenarios in transcatheter aortic valve replacement (TAVR): (1) recent percutaneous coronary intervention (PCI) preceding TAVR, (2) atrial fibrillation (AF) management in patients undergoing TAVR, and (3) bioprosthetic valve thrombosis management in TAVR. RECENT FINDINGS: Several small clinical trials have evaluated the use of single vs. dual antiplatelet therapy in patients undergoing TAVR, with most recent data favoring single antiplatelet therapy. There are several trials currently enrolling and in follow-up that evaluate the use of anticoagulants in combination with single and dual antiplatelet therapy for patients with AF undergoing TAVR, but as yet, there is no data to support a clear strategy. The use of DAPT after PCI continues to potentially shorten in patients undergoing elective PCI, thus prolonged DAPT may not be necessary post TAVR for the sake of PCI. Bioprosthetic valve thrombosis occurs more commonly than previously thought, but has uncertain clinical significance. In observational studies, antiplatelet therapy has little effect on bioprosthetic valve thrombosis, whereas anticoagulation is effective in both prevention and treatment of thrombosis. DAPT is currently recommended for 1-6 months for all patients without an indication for oral anticoagulation who undergo TAVR; however, there is a growing amount of evidence for single antiplatelet therapy. In the special situation of patients who have recently undergone PCI, the length of DAPT will depend on stent selection (BMS vs. DES), but may not be significantly prolonged unless the patient experienced an acute coronary syndrome prior to TAVR. There is no clear, optimal antithrombotic strategy for patients with AF who undergo TAVR, but avoidance of triple therapy by using OAC and low dose ASA seems to be reasonable. OAC, not DAPT, is now known to prevent bioprosthetic valve thrombosis in TAVR and SAVR patients; however, the optimal therapy remains unknown. For patients who develop bioprosthetic valve thrombosis, OAC for 3-6 months, and repeat imaging is recommended to document resolution. PMID- 30311015 TI - What's New. PMID- 30311016 TI - Fueling Clean Household Environments. PMID- 30311017 TI - Australian Indigenous Land Management, Ecological Knowledge and Languages for Conservation. AB - Many Indigenous Australians hold cultural, ecological and language knowledge, but common representations of Indigenous Australians focus on social disadvantage and poor comparisons with other Australians in education, employment and health. Indigenous Land Management works with Indigenous people's cultural, ecological and language expertise, employing Indigenous people in activities contributing to biodiversity conservation. The Interplay research surveyed 841 Indigenous people in remote communities. Those employed in land management reported greater participation in cultural activities, language knowledge, and belief that their land was looked after. These related assets provide an opportunity for policy approaches based on Indigenous people's strengths and contribution to Australia. PMID- 30311018 TI - A novel approach to assess cerebral and coronary perfusion after cardiac arrest. AB - BACKGROUND: Several indices exist to assess cerebral perfusion after cardiac arrest (CA). We aimed to investigate a new approach allowing absolute flow and microvascular resistance measurement based on selective arterial continuous thermodilution before and after CA resuscitation in a porcine model. METHODS: In anaesthetised pigs, intravascular absolute cerebral blood flow (CBF) and absolute coronary blood flow (ABF) with corresponding microvascular resistances were measured. CA was induced using overdrive pacing with 3 (group 1, n = 5) or 5 min (group 2, n = 8) of no flow. After resuscitation, CBF was performed at baseline, at 15 min (T15) and at 30 min (T30). Thereafter, CBF in the contralateral cerebral artery and ABF were measured. RESULTS: The protocol could not be completed in three pigs from group 2 due to haemodynamic instability. In the entire cohort, CBF was significantly lower at T30 after CA (0.026 +/- 0.02 L/min vs 0.040 +/- 0.03 at baseline; p = 0.03) and cerebral microvascular resistances were significantly higher (3202 +/- 1838 Woods units vs 2014 +/- 1015 at baseline; p = 0.04). ABF and resistances remained stable at baseline, as compared to T30 (0.122 +/- 0.05 vs. 0.143 +/- 0.06 L/min; p = 0.15 and 563 +/- 203 vs. 478 +/- 181 Woods units; p = 0.36, respectively). At T30, no significant differences in cerebral flow dynamics were observed between groups. CONCLUSIONS: ABF and CBF measurement after CA resuscitation is feasible with thermodilution technique, allowing accurate monitoring and measurements. This novel approach allows simultaneous measurements of flow and microvascular resistances. This animal model simplifies cerebral perfusion measurements and allows to test new therapies to reduce cerebral injury post cardiac arrest. PMID- 30311019 TI - Ferric pyrophosphate citrate: interactions with transferrin. AB - There are several options available for intravenous application of iron supplements, but they all have a similar structure:-an iron core surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrin and distributed throughout the body, with most of the iron supplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity. A new parenteral iron formation, ferric pyrophosphate citrate (FPC), has a novel structure that differs from conventional intravenous iron formulations, consisting of an iron atom complexed to one pyrophosphate and two citrate anions. In this study, we show that FPC can directly transfer iron to apo transferrin. Kinetic analyses reveal that FPC donates iron to apo-transferrin with fast binding kinetics. In addition, the crystal structure of transferrin bound to FPC shows that FPC can donate iron to both iron-binding sites found within the transferrin structure. Examination of the iron-binding sites demonstrates that the iron atoms in both sites are fully encapsulated, forming bonds with amino acid side chains in the protein as well as pyrophosphate and carbonate anions. Taken together, these data demonstrate that, unlike intravenous iron formulations, FPC can directly and rapidly donate iron to transferrin in a manner that does not expose cells and tissues to the damaging effects of free, redox-active iron. PMID- 30311021 TI - Clinical results and medical costs of thoracic endovascular aortic repair in patients over 80 years of age. AB - Thoracic endovascular aortic repair (TEVAR) is expected to be minimally invasive, especially in older patients. However, clinical results of TEVAR in octogenarians including medical costs are limited. Between 2010 and 2016, a total of 57 patients over 80 years of age (mean age 84.1 +/- 3.4 years) underwent TEVAR at our hospital. The proximal landing zone (PLZ) was zone 0 in 7 patients (12.3%), zone 1 in 10 patients (17.5%), zone 2 in 9 patients (15.8%), zone 3 in 13 patients (22.8%), and zone 4 in 18 patients (31.6%). The mean follow-up time was 23 +/- 19 months (range 1-71 months). The follow-up rate was 96.5%. The hospital mortality rate was 1.8%. Stroke occurred in three patients (zone 0: 2, zone 3: 1, 5.3%). The mean hospital stay was 21.8 +/- 21.4 days (range 5-98 days), and the rate of being discharged home was 84.2%. The 1-year and 3-year survival rates were 76.1% and 55.1% and the 1-year and 3-year re-intervention-free rates of the thoracic aorta were 97.6% and 94.5%, respectively. The mean total cost by the time of hospital discharge was Y5,360,000 +/- 2,360,000. The clinical results of TEVAR in patients over 80 years of age are acceptable with early postoperative recovery, low mortality and morbidity, and midterm durability. PMID- 30311020 TI - Studies on the activation of isocitrate dehydrogenase kinase/phosphatase (AceK) by Mn2+ and Mg2. AB - Isocitrate dehydrogenase kinase/phosphatase (AceK) is a bifunctional enzyme with both kinase and phosphatase activities that are activated by Mg2+. We have studied the interactions of Mn2+and Mg2+ with AceK using isothermal titration calorimetry (ITC) combined with molecular docking simulations and show for the first time that Mn2+ also activates the enzyme activities. However, Mn2+ and Mg2+ exert their effects by different mechanisms. Although they have similar binding constants (of 1.11 * 105 and 0.98 * 105 M-1, respectively) for AceK and induce conformational changes of the enzyme, they do not compete for the same binding site. Instead Mn2+ appears to bind to the regulatory domain of AceK, and its effect is transmitted to the active site of the enzyme by the conformational change that it induces. The information in this study should be very useful for understanding the molecular mechanism underlying the interaction between AceK and metal ions, especially Mn2+ and Mg2+. PMID- 30311022 TI - Shape optimization of a centrifugal blood pump by coupling CFD with metamodel assisted genetic algorithm. AB - A centrifugal blood pump is a common type of pump used as a left ventricular assist device in the medical industries. Therefore, the improvement of the device bio-compatibility to reduce the blood damage and to increase the efficiency has become a major challenge. In the current work, a metamodel-assisted genetic algorithm is employed to simultaneously optimize the impeller and volute geometries of a typical centrifugal blood pump. The overall shape of the base design is inspired from HeartMate3 LVAD, and the main dimensions of the base design including inlet and outlet radius, blade angle distribution, volute cross section area distribution, etc., are designed in our laboratory. Three different scenarios are investigated using three different objective functions, i.e., (1) hydraulic efficiency, (2) pressure head, and (3) hemolysis index (HI). The results showed that the shape optimized by pump efficiency has also nearly the same level of HI as the shape optimized by HI. Hence, to reduce computation time, one can use efficiency instead of HI as an objective function. However, one must check the HI level after such optimization to see whether it is within the acceptable range of HI for such bio application. PMID- 30311023 TI - Cadaver donation: structural integrity of pulmonary homografts harvested 48 h post mortem in the juvenile ovine model. AB - Cryopreserved pulmonary homograft (CPH) implantation remains the gold standard for reconstruction of the right ventricular outflow tract (RVOT). Harvesting homografts < 24-h post mortem is the international norm, thereby largely excluding cadaveric donors. This study examines the structural integrity and stability of ovine pulmonary homografts harvested after a 48-h post mortem period, cryopreserved and then implanted for up to 180 days. Fifteen ovine pulmonary homografts were harvested 48-h post mortem and cryopreserved. Five CPH served as a control group (group 1; n = 5). CPH were implanted in the RVOT of juvenile sheep and explanted after 14 days (group 2; n = 5) and 180 days (group 3; n = 5). Leaflet integrity was evaluated by strength analysis, using tensile strength (TS), Young's modulus (YM) and thermal denaturation temperature (Td), and morphology, including haematoxylin and eosin (H&E), Picrosirius red staining, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and von Kossa stains. Echocardiography confirmed normal function in all implants. In explants, no reduction in TS, YM or Td could be demonstrated and H&E showed mostly acellular leaflet tissue with no difference on Picrosirius red. TEM demonstrated consistent collagen disruption after cryopreservation in all three groups, with no morphological deterioration during the study period. von Kossa stains showed mild calcification in group 3. No deterioration of structural integrity could be demonstrated using strength or morphological evaluations between the controls and implant groups over the study period. Extending the post mortem harvesting time of homografts beyond 24 h did not appear to negatively affect the long-term performance of such transplanted valves in this study. PMID- 30311024 TI - High patient satisfaction with a simplified BRCA1/2 testing procedure: long-term results of a prospective study. AB - PURPOSE: In the BRCAsearch study, unselected breast cancer patients were prospectively offered germline BRCA1/2 mutation testing through a simplified testing procedure. The purpose of the present study was to evaluate satisfaction with the BRCAsearch testing procedure and, furthermore, to report on uptake rates of prophylactic surgeries among mutation carriers. METHODS: Pre-test information was provided by a standardized invitation letter instead of in-person genetic counseling. The patients were offered contact with a genetic counselor for telephone genetic counseling if they felt a need for that. Mutation carriers were telephoned and given a time for a face-to-face post-test genetic counseling appointment. Non-carriers were informed about the test result through a letter. One year after the test results were delivered, a study-specific questionnaire was mailed to the study participants who had consented to testing. The response rate was 83.1% (448 of 539). RESULTS: A great majority (96.0%) of the responders were content with the method used for providing information within the study, and 98.7% were content with having pursued genetic testing. 11.1% answered that they would have liked to receive more oral information. In an adjusted logistic regression model, patients with somatic comorbidity (OR 2.56; P = 0.02) and patients born outside of Sweden (OR 3.54; P = 0.01) were more likely, and patients with occupations requiring at least 3 years of university or college education (OR 0.37; P = 0.06) were less likely to wanting to receive more oral information. All 11 mutation carriers attended post-test genetic counseling. At a median follow-up of 2 years, the uptake of prophylactic salpingo-oophorectomy was 100%, and the uptake of prophylactic mastectomy was 55%. CONCLUSIONS: Satisfaction with a simplified BRCA1/2 testing procedure was very high. Written pre-test information has now replaced in-person pre-test counseling for breast cancer patients in our health care region. PMID- 30311025 TI - Correction to: Long-term results after stapled hemorrhoidopexy: a survey study with mean follow-up of 12 years. AB - Unfortunately, the 7th author's family name was incorrectly published in the original publication. The complete correct name should read as follows. PMID- 30311026 TI - Recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma. AB - Blockade of programmed cell death-1 (PD-1) has become one of the most promising immunotherapies for many human cancers. However, immune-related adverse events can be produced by anti-PD-1 therapy. Uveitis is a rare but potentially devastating side effect of anti-PD-1 therapy. Delay in diagnosis or improper treatment may eventually lead to irreversible blindness. Therefore, it is important for the oncologist and the ophthalmologist to recognize and manage this adverse event properly in patients receiving anti-PD-1 therapy in a timely manner. Here we present a grade 4 panuveitis with bilateral serous retinal detachment following treatment with nivolumab for metastatic renal cell carcinoma. Oral prednisone, topical steroid eye drops, periorbital injection of steroid and finally intravitreal injection of steroid implant were administered in our patient. We observed that intravitreal injection of dexamethasone implant, but not the periorbital injection of steroid or the steroid eye drops, was effective to control the posterior uveitis and serous retinal detachment. Oral prednisone was also effective, but it might affect the efficacy of anti-PD-1 therapy and promote tumor growth. We also summarize 15 cases of uveitis reported to date related to nivolumab or pembrolizumab therapy in the present study. The symptoms, signs, potential underlying mechanisms and treatment options regarding this adverse event are discussed. PMID- 30311027 TI - Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. AB - CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients. PMID- 30311029 TI - COX6B1 relieves hypoxia/reoxygenation injury of neonatal rat cardiomyocytes by regulating mitochondrial function. AB - OBJECTIVE: Mitochondrial dysfunction plays a pivotal role in various pathophysiological processes of heart. Cytochrome oxidase subunit 6B1 (COX6B1) is a subunit of cytochrome oxidase. METHODS: Cardiomyocytes were isolated from neonatal SD rats (within 24 h of birth) by repeating digestion of collagenase and trypsin. COX6B1 over-expression and hypoxia/reoxygenation was conducted on neonatal rat cardiomyocytes. Cell viability, apoptosis rates, mitochondria membrane potential and mitochondrial permeabilization transition pores (mPTPs) were then determined respectively by Cell performing Counting Kit-8 (CCK-8), Annexin-V/PI assay, JC-1 assay, mPTP assay. The expression of cyto C and apoptosis-related factors were detected by RT-Qpcr and Western blot. RESULTS: Hypoxia/reoxygenation increased apoptosis and mPTP levels, and decreased mitochondria membrane potential in I/R and I/R + EV groups. COX6B1 over expression increased mitochondria cyto C, pro-caspase-3, pro-caspase-9 and bcl-2, while it decreased cytosol cyto C, cleaved-caspase-3, cleaved-caspase-9 and bax compared to I/R + EV group. CONCLUSION: COX6B1 protected cardiomyocytes from hypoxia/reoxygenation injury by reducing ROS production and cell apoptosis, during which reduction of the release of cytochrome C from mitochondria to cytosol was involved. Our study demonstrated that COX6B1 may be an candidate target gene in preventing hypoxia/reoxygenation injury of cardiomyocytes. PMID- 30311028 TI - Effect of four trace elements on Paenibacillus polymyxa Pp-7250 proliferation, activity and colonization in ginseng. AB - Trace elements are essential nutrients for the growth of microorganisms and play an important role in their proliferation. Hence, the purpose of this paper is to explore the optimal C and N sources for large-scale culture of Paenibacillus polymyxa, and to screen trace elements that can promote their proliferation and improve the activity. First, the concentration of Paenibacillus polymyxa Pp-7250, the number of spores were used as evaluation index. It was found that the four trace elements Cu2+, Fe2+, Mn2+, and Zn2+ could promote the proliferation of Paenibacillus polymyxa at their optimal concentrations. Next, when using wheat starch as carbon source and soybean meal as nitrogen source, it was most suitable for large-scale culture. Finally, field experiments were carried out, and it was discovered that the combination of four trace elements plus the wheat soybean meal group could significantly improve the disease prevention, growth promotion ability of Pp-7250 and its colonization in ginseng. Moreover, the ability of Pp 7250 to transform ginseng roots and leaf saponins were also significantly improved. The group also affected the rhizosphere bacterial community of ginseng and the number showed a significant promotion or inhibition. PMID- 30311030 TI - Development and prospective validation of a novel weighted quantitative scoring system aimed at predicting the pathological features of cystic renal masses. AB - OBJECTIVES: To develop and prospectively validate a novel weighted quantitative scoring system based on CT findings, namely, the renal cyst index (RCI), aimed at preoperatively predicting the pathological features of cystic renal masses (CRMs). METHODS: The RCI was based on four critical features of CRMs: the cyst wall, septal, nodule, and cyst contents. These parameters were scored with 1, 2, or 3 points. Weight coefficients for these parameters were determined by the multivariable logistic regression. The odds ratio (OR) and 95% confidence interval (95% CI) were used to summarise the results. The RCI was defined as the sum of these four weight coefficients. Malignancy risk prediction models were built based on the retrospective evaluation of 441 patients. We also compared the prediction ability of the RCI with the Bosniak classification in the 441 patients and applied these novel models to 152 masses resected in our institution to prospectively validate the efficiency of the RCI. RESULTS: The wall point (OR = 5.71 [95% CI = 1.734-18.808, p = 0.004, point = 2], OR = 12.665 [95% CI = 3.750 42.770, p < 0.001, point = 3]), septal point (OR = 3.325 [95% CI = 1.272-8.692, p = 0.014, point = 3]), nodule point (OR = 4.588 [95% CI = 1.429-14.729, p < 0.001, point = 2], OR = 17.032 [95% CI = 5.017-57.820, p = 0.010, point = 3]), content point (OR = 22.822 [95% CI = 1.041-495.995, p = 0.047, point = 2], OR = 2.723 [95% CI = 1.296-10.696, p = 0.015, point = 3]), and RCI (OR = 1.247 [95% CI = 1.197-1.299, p < 0.001]) were significantly associated with malignancy. Masses with an RCI < 6 were regarded as benign masses; masses with an RCI >= 10 were regarded as malignant masses. The malignancy risk of masses with an RCI > 6 but < 10 were determined by a nomogram. The prediction ability of the RCI was significantly superior to the Bosniak classification for Bosniak IIF and III masses (AUC: 0.912 vs. 0.753, p = 0.001). The RCI also accurately predicted the pathological features of 152 masses. CONCLUSION: The RCI is a reliable quantitative scoring system in predicting the malignancy risk of CRMs, and it outperformed the Bosniak classification system in some ways. KEY POINTS: * The renal cyst index (RCI) is a useful weighted quantitative classification system based on CT findings for diagnosing cystic renal masses. * The RCI outperforms the Bosniak classification system in some ways, especially for Bosniak IIF and III masses. * Masses with an RCI < 6 can be regarded as a simple cyst, while those with an RCI > 10 can be regarded as malignant masses. PMID- 30311031 TI - Evaluation of the effect of image noise on CT perfusion measurements using digital perfusion phantoms. AB - OBJECTIVES: To assess the influence of image noise on computed tomography (CT) perfusion studies, CT perfusion software algorithms were evaluated for susceptibility to image noise and results applied to clinical perfusion studies. METHODS: Digital perfusion phantoms were generated using a published deconvolution model to create time-attenuation curves (TACs) for 16 different combinations of blood flow (BF; 30/60/90/120 ml/100 ml/min) and flow extraction product (FEP; 10/20/30/40 ml/100 ml/min) corresponding to values encountered in clinical studies. TACs were distorted with Gaussian noise at 50 different strengths to approximate image noise, performing 200 repetitions for each noise level. A total of 160,000 TACs were evaluated by measuring BF and FEP with CT perfusion software, comparing results for the maximum slope and Patlak models with those obtained with a deconvolution model. To translate results to clinical practice, data of 23 patients from a CT perfusion study were assessed for image noise, and the accuracy of reported CT perfusion measurements was estimated. RESULTS: Perfusion measurements depend on image noise as means and standard deviations of BF and FEP over repetitions increase with increasing image noise, especially for low BF and FEP values. BF measurements derived by deconvolution show larger standard deviations than those performed with the maximum slope model. Image noise in the evaluated CT perfusion study was 26.46 +/- 3.52 HU, indicating possible overestimation of BF by up to 85% in a clinical setting. CONCLUSIONS: Measurements of perfusion parameters depend heavily upon the magnitude of image noise, which has to be taken into account during selection of acquisition parameters and interpretation of results, e.g., as a quantitative imaging biomarker. KEY POINTS: * CT perfusion results depend heavily upon the magnitude of image noise. * Different CT perfusion models react differently to the presence of image noise. * Blood flow may be overestimated by 85% in clinical CT perfusion studies. PMID- 30311032 TI - Cardio-pulmonary MRI for detection of treatment response after a single BPA treatment session in CTEPH patients. AB - OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with balloon pulmonary angioplasty (BPA) in inoperable patients. Sensitive non invasive imaging methods are missing to detect treatment response after a single BPA treatment session. Therefore, the aim of this study was to measure treatment response after a single BPA session using cardio-pulmonary MRI. MATERIALS AND METHODS: Overall, 29 patients with CTEPH were examined with cardio-pulmonary MRI before and 62 days after their initial BPA session. Pulmonary blood flow (PBF), first-pass bolus kinetic parameters, and biventricular mass and function were determined. Multiple linear regression analysis was implemented to estimate the relationship of PBF change in the treated lobe with treatment change of full width at half maximum (FWHM), cardiac output (CO), ventricular mass index (VMI), pulmonary transit time (PTT) and PBF change in the non-treated lobes. Paired Wilcoxon rank sum test and Spearman rho correlation were used. RESULTS: After BPA regional PBF increased in the treated lobe (p < 0.0001) as well as in non-treated lobes (p = 0.015). PBF treatment changes in the treated lobe were significantly larger compared with the non-treated lobes (p = 0.0049). Change in NT proBNP, MRI derived mean pulmonary artery pressure (mPAP), PTT, FWHM, right ventricular (RV) ejection fraction, RV stroke volume, CO, VMI and PBF in the non-treated lobes correlated with PBF change in the treated lobe (p < 0.05). PBF changes in the treated lobe were independently predicted by PTT as well as PBF change in the non treated lobes. CONCLUSION: Cardio-pulmonary MRI detects and quantifies treatment response after a single BPA treatment session. KEY POINTS: * Two months after BPA regional parenchymal pulmonary perfusion (PBF) increased in the total lung parenchyma (p = 0.005), the treated lobes (p < 0.0001) and non-treated lobes (p = 0.015). * The PBF treatment changes in the treated lobe were significantly larger than in the non-treated lobes (p = 0.0049). * Change in NT proBNP, MRI-derived mean pulmonary artery pressure, pulmonary transit time, full width at half maximum, right ventricular (RV) ejection fraction, RV stroke volume, cardiac output, ventricular mass index and PBF in the non-treated lobes correlated with PBF change in the treated lobe (p < 0.05). PMID- 30311033 TI - Three-Dimensional Evaluation of Static and Dynamic Effects of Botulinum Toxin A on Glabellar Frown Lines. AB - BACKGROUND: The use of injectable solutions for aesthetic purposes has increased tremendously, but lacks objective support. We aimed at assessing static and dynamic effects of botulinum toxin A (BoNTA) on glabellar lines by use of an objective three-dimensional methodology. METHODS: We prospectively collected three-dimensional stereographic photographs of two different facial expressions (pretreatment, 30 and 90 days posttreatment) in 21 patients, receiving a total of 20 units of BoNTA in both corrugator supercilii muscles. The primary endpoint was the three-dimensional static and dynamic surface irregularity, and secondary endpoints were the glabellar line scale and overall patient satisfaction. Blinded retrospective data analysis and statistical evaluation were performed with p < 0.05 considered statistically significant. RESULTS: Static glabellar lines (neutral facial expression) were significantly reduced by - 17% and - 24% on day 30 and 90 posttreatment, respectively (vs. pretreatment; both p < 0.0001). Dynamic glabellar frown lines (firmest possible bilateral eye closure) demonstrated a reduction of surface irregularity by - 26% and - 21% on day 30 and 90 posttreatment, respectively (vs. pretreatment; both p < 0.0001). The subjective dynamic glabellar line scale documented a statistically significant improvement on day 30 posttreatment (mean +/- SD: 1.5 +/- 0.8; p < 0.05) versus pretreatment (2.8 +/- 1.0). Polled patients confirmed a subjective wrinkle improvement 90 days posttreatment. CONCLUSION: The presented setup detected even subtle changes of BoNTA treatment for facial wrinkling and is a promising asset for scientific evaluations of clinical studies analyzing the outcome and duration of efficacy of injectable solutions on the face. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30311034 TI - Effects of Silicone Implants on the Mammary Gland: Ultrasonographic and 3D Study. AB - BACKGROUND: Breast implants may be responsible for secondary deformities produced by parenchymal atrophy. However, few studies in the literature have reported changes in breast tissue after augmentation surgery. In this study, the breast thickness of patients undergoing breast augmentation was monitored by ultrasound, and correlations with surface, volume and projection measurements were examined. METHODS: We studied the parenchymal thickness at the lower pole of the breast with ultrasound in 36 women (72 breasts). In another group of 33 patients (66 breasts), we studied the thickness at the upper and lower poles along the meridian of each breast by ultrasound and measured the anthropometric metrics, volume and projection of the breast with a 3D camera. RESULTS: Midline measurements close to the areola showed reduced thickness at the lower pole, with 31.8% at the midpoint of the lower pole and 42% at the infra-areolar level (p < 0.0001). At the upper pole, there was a decrease of 14.6% (p < 0.001), but the thickness was increased by 6% and 38% at more cranial levels. No correlations with volume were found. Anatomical implants produced more atrophy at the lower pole, and round implants at the upper pole. More atrophy was found with subfascial than submuscular augmentation. Compared with the expected values, the final volume was very similar, but the projection was 29% less. Surface measurements changed significantly up to 4 months postoperatively and remained stable thereafter. CONCLUSIONS: Implants affect significatively the thickness of the glandular tissue. All changes occur very soon postoperatively but stabilize after 4 months. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30311035 TI - Removal of Polyurethane Implants. AB - : Polyurethane (PU) implants are associated with great difficulties in extraction if secondary surgery is needed. The published data are contradictory, often misleading, making the decision for the secondary surgery complicated, the time period and the procedure itself not optimal, thus negatively influencing the final result. MATERIALS AND METHODS: Typical videos of PU implant removal in different periods after primary surgeries with polyurethane implants were selected for the study. The videos show the strength and extent of the tissue ingrowth and the manipulations needed for implant extraction in different periods from the initial procedure. Classifications of the types of adhesion and adhesion patterns are introduced. CONCLUSIONS: The data provided in this article facilitate the decision-making process if secondary surgery is indicated. Secondary surgery should be performed in the first 30 days after the initial surgery or in the period after 6 months. The optimal layer for removal of the PU implant depends on the time after the primary surgery. The polyurethane implant should be exchanged after 1 month if the properties of the polyurethane foam are expected to be used. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30311036 TI - A phase II study of imatinib mesylate and letrozole in patients with hormone receptor-positive metastatic breast cancer expressing c-kit or PDGFR-beta. AB - Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-beta positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2.5 mg PO once daily until disease progression or unacceptable toxicity. Results There were no complete responses and five partial responses for an objective response rate of 11%. An additional 16 patients had stable disease lasting at least 24 weeks for a clinical benefit rate of 46.7%. The median progression-free and overall survival was 8.7 months (95% confidence interval: 3.8-11.4 months) and 44.3 months (95% confidence interval: 34.0-55.3 months), respectively. The most common grade 3 or higher treatment related adverse events were fatigue and diarrhea, occurring in 9 (20%) and 7 patients (16%), respectively. Conclusion The combination of imatinib mesylate and letrozole is well tolerated but appears to have limited efficacy in the treatment of hormone receptor-positive metastatic breast cancer. PMID- 30311037 TI - Role of closed drain after multi-level posterior spinal surgery in adults: a randomised open-label superiority trial. AB - PURPOSE: To explore the role of closed suction drain in multi-level posterior spinal surgery. METHODS: We performed prospective, open-label, randomised control, superiority trial with parallel design and 1:1 allocation. A total of 161 patients undergoing posterior spinal surgery involving more than one motion segment at a dedicated spine surgery department were randomly allocated into "drain" or "no-drain" groups, based on which surgical drain was employed at the end of surgery. After excluding six cases with intraoperative dural tear, the data of 80 patients in "drain" and 75 patients in "no-drain" group were analysed. Primary outcome was total perioperative blood loss (sum of intraoperative blood loss, volume of drain if present and volume aspirated if patient developed collection in relation to surgical wound). The secondary outcomes were transfusion requirements, wound healing and complications. RESULTS: Both groups were comparable with respect to baseline characteristics. Total perioperative blood loss was significantly higher in "drain" group (716 +/- 312.97 ml vs 377.9 +/- 295.72 ml, p < 0.0001). Number and volume of post-operative aspirations were significantly higher in "no-drain" group whereas transfusion requirements were significantly higher in "drain" group. Except for one case of superficial wound inflammation in either group, there were no complications. Subgroup analysis revealed that the results were applicable for surgeries involving "two/three" levels and "more than three" levels. CONCLUSIONS: The practice of not using closed surgical drains after multi-level posterior spinal surgery reduces post operative blood loss and transfusion requirements. But this comes with the disadvantage of increased wound soakage and need for post-operative wound aspirations. The risks of benefits of "drain" and "no drain" must be carefully weighed and an informed choice be taken. These slides can be retrieved under Electronic Supplementary Material. PMID- 30311038 TI - Reply to the Letter to the Editor of S. Shahsavari et al. concerning "Predicting medical complications in spine surgery: evaluation of a novel online risk calculator" by M. F. Kasparek et al. (Eur Spine J: doi: 10.1007/s00586-018-5707 9). PMID- 30311039 TI - Mental-Physical Multimorbidity in Youth: Associations with Individual, Family, and Health Service Use Outcomes. AB - Prevalence, correlates, and outcomes of youth with comorbid mental and physical conditions (i.e., multimorbidity) were examined in this cross-sectional study. Participants were 92 youth (14.5 years [SD 2.7]; 69.6% female) and their parents. Mental disorder was assessed using structured interviews and physical health using a standardized questionnaire. Twenty-five percent of youth had multimorbidity and no child or parent demographic or health characteristics were correlated with multimorbidity. Youth with multimorbidity reported similar quality of life and better family functioning [B = - 4.80 (- 8.77, - 0.83)] compared to youth with mental disorder only (i.e., non-multimorbid). Youth with multimorbidity had lower odds of receiving inpatient services [OR = 0.20 (0.05, 0.85)] and shorter stays in hospital for their mental health [OR = 0.74 (0.57, 0.91)] over the past year. Family functioning was found to mediate the association between youth multimorbidity and length of stay [alphabeta = 0.14 (0.01, 0.27)]. Findings reinforce the need for family-centered youth mental health care. PMID- 30311040 TI - Modeling Human Volunteers in Multidirectional, Uni-axial Sled Tests Using a Finite Element Human Body Model. AB - A goal of the Human Research Program at National Aeronautics and Space Administration (NASA) is to analyze and mitigate the risk of occupant injury due to dynamic loads. Experimental tests of human subjects and biofidelic anthropomorphic test devices provide valuable kinematic and kinetic data related to injury risk exposure. However, these experiments are expensive and time consuming compared to computational simulations of similar impact events. This study aimed to simulate human volunteer biodynamic response to unidirectional accelerative loading. Data from seven experimental studies involving 212 volunteer tests performed at the Air Force Research Laboratory were used to reconstruct 13 unique loading conditions across four different loading directions using finite element human body model (HBM) simulations. Acceleration pulses and boundary conditions from the experimental tests were applied to the Global Human Body Models Consortium (GHBMC) simplified 50th percentile male occupant (M50-OS) using the LS-Dyna finite element solver. Head acceleration, chest acceleration, and seat belt force traces were compared between the experimental and matched simulation signals using correlation and analysis (CORA) software and averaged into a comprehensive response score ranging from 0 to 1 with 1 representing a perfect match. The mean comprehensive response scores were 0.689 +/- 0.018 (mean +/- 1 standard deviation) in two frontal simulations, 0.683 +/- 0.060 in four rear simulations, 0.676 +/- 0.043 in five lateral simulations, and 0.774 +/- 0.013 in two vertical simulations. The CORA scores for head and chest accelerations in these simulations exceeded mean scores reported in the original development and validation of the GHBMC M50-OS model. Collectively, the CORA scores indicated that the HBM in these boundary conditions closely replicated the kinematics of the human volunteers across all loading directions. PMID- 30311041 TI - Was It Good for Her? An Alternative Perspective on Life History Theory, Female Same-Sex Sexuality, and Pleasure. PMID- 30311043 TI - Shame and Non-suicidal Self-injury: Conceptualization and Preliminary Test of a Novel Developmental Model among Emerging Adults. AB - Non-suicidal self-injury (NSSI) is particularly prevalent during adolescence and emerging adulthood. The salience of shame during these developmental periods suggests that shame may be inherently linked to NSSI, and at least partially explain the high rates of NSSI observed among youth. In this article, a theoretical developmental model relating shame and NSSI is proposed, and results from a preliminary test of a sub-set of cross-sectional relationships in this model is presented. In the model tested, it was hypothesized that adverse caregiving experiences in prior development (i.e., childhood to late adolescence) like parental invalidation and child maltreatment, established predictors of NSSI, would be linked to proximal episodes of NSSI (i.e., past year) through current shame-proneness (i.e., experiencing shame in a trait-like manner) and internalizing shame-coping (i.e., responding to shame through attacking one's self and withdrawing). It was also hypothesized that some key proximal predictors of NSSI during youth development, such as low body esteem, increased loneliness and heightened psychological distress, would be linked to proximal NSSI via shame proneness and internalizing shame-coping. Using structural equation modelling, it was observed that data, obtained via self-reports completed by 573 emerging adults (age in years: M = 20.7, SD = 2.20, 69.1% female, NSSI history: n = 220, where most recent NSSI episode was within a year of study participation) recruited throughout Australia between June 2013 and June 2014, fit the hypothesized model well. Tests of indirect effects indicated that current shame proneness and internalizing shame-coping significantly linked perceived parental invalidation and prior experiences of child maltreatment to proximal NSSI, though this relationship was, unexpectedly, an inverse one in relation to child maltreatment. Current shame-proneness was also linked to proximal NSSI via internalizing shame-coping, current loneliness, and current psychological distress, but not through current body esteem. Finally, proximal self-evaluations of body esteem, loneliness and increased psychological distress were linked to recent NSSI through internalizing shame-coping. The theory and findings presented in this article contribute to a deeper developmental understanding of NSSI among youth, highlight crucial pathways between adverse caregiving experiences and NSSI, and illuminate important shame-based mechanisms that potentially warrant clinical attention for at-risk individuals. Future research directions and clinical recommendations are discussed. PMID- 30311042 TI - Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial. AB - AIM: The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2. METHODS: In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model. RESULTS: Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0-1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09-2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41-4.84, p = 0.005) were the only significant poor prognostic factors for OS. CONCLUSION: Age >= 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS. PMID- 30311044 TI - A novel Serratia sp. ZS6 isolate derived from petroleum sludge secretes biosurfactant and lipase in medium with olive oil as sole carbon source. AB - Biosurfactants emulsify lipids, facilitating their exposure to microorganisms in water. Secretion of biosurfactant together with lipase can enhance oil assimilation by microorganisms. In this study, we show the analysis of the biosurfactant and lipase producing microbe originating from oil-sludge. The enrichment of the biosurfactant-producing ZS6 strain from the mixed culture of sludge-derived microbes in medium with olive oil as sole carbon source was monitored using the modified T-RFLP (or mT-RFLP) methodology. Phylogenetic tree analysis based on 16S rDNA sequences suggested that ZS6 belonged to a member of Serratia sp. Serratia sp. ZS6 secreted both a serrawettin-type biosurfactant and lipase in medium with olive oil as sole carbon source. By using an in-gel lipase assay followed by LC-MS/MS analysis, we identified the amino acid sequences of the ZS6 lipase, which belonged to the lipase subfamily III of the family I. Its lipolytic activity was found to be enhanced by salinity, calcium, and methanol. Together, we show that the novel isolate Serratia sp. ZS6 secretes both biosurfactant and lipase which makes it useful for applications such as in food industry wastewater treatment and biodiesel production. PMID- 30311045 TI - Towards Conceptualizing Language Learning Curiosity in SLA: An Empirical Study. AB - Why do some students frequently ask questions and actively seek out answers in the classroom, while others avoid this? Many language teachers might have commonly asked themselves this question. The present study is an empirical investigation of the concept of curiosity in the field of second language acquisition (SLA). Using a mixed-methods design, we aim to conceptualize language learning curiosity (LLC) within the framework of interest/deprivation (I/D) model of curiosity (Litman and Jimerson in J Personal Assess 82(2): 147-157, 2004. https://doi.org/10.1207/s15327752jpa8202_3 ) and see how it may be recognizably distinct from L2 psychological constructs, as well as how it connects with related constructs such as willingness to communicate, enjoyment, and anxiety. To measure LLC and depict its underlying dimensions, a new curiosity scale was developed and validated in this study. Overall, our results suggest that LLC can be conceived as an affective-cognitive variable reflecting an inquiry-driven interest and desire to learn and use a foreign language. PMID- 30311047 TI - Exploring the relationship between nonalcoholic fatty liver disease and pancreatic cancer by computed tomographic survey: comment. PMID- 30311046 TI - Initial laparoscopy and optimized approach for unilateral nonpalpable testis: review of 8-year single-center experience. AB - PURPOSE: We evaluated the role of initial laparoscopy and optimized approach in cases of unilateral nonpalpable testis. METHODS: Seventy-four patients with nonpalpable testes were presented. We excluded 9 patients, with palpable testes under anesthesia. Laparoscopy was offered to 65 patients. Contralateral testis hypertrophy with length >= 1.8 cm was confirmed in 47 patients. Ultrasound results were available for 35 patients. RESULTS: Age ranged from 1 to 10 years. Of 65 nonpalpable testes, right side comprised 23 (35.4%) and the left 42 (64.6%). Laparoscopy revealed intra-abdominal testis in 18 patients (27.7%), blind-ending vessels and vas in 8 (12.3%), and vas and vessels traversing the internal ring in 39 (60%). Treatment of intra-abdominal testes included Fowler Stephens orchiopexy in 7 patients, laparoscopic orchiopexy in 9, and laparoscopic orchiectomy in 2. In 8 patients with blind-ending vas and vessels, laparoscopy was terminated. In 39 patients with vas and vessels traversing the internal ring, scrotal exploration was performed in 36 patients with closed internal ring and inguinal exploration in 3 with open internal ring. Vanished testes were present in 43/47(91.5%) of patients with contralateral testis hypertrophy >= 1.8 cm. Ultrasound detected the presence of a testis in only 4/11 (36.3%) of patients, although it could not identify vanished testis. CONCLUSIONS: Initial laparoscopy should be retained as one of the standard treatment for nonpalpable testis. It was the only required modality in 26 patients (40%) and optimized further treatment in 39 patients (60%) by evaluation of the condition of the internal ring. PMID- 30311048 TI - Approach to pediatric renal tumors: an imaging review. AB - Renal tumors comprise 7% of all childhood cancers. A wide variety of renal tumors can affect the pediatric kidneys, which can be broadly classified as primary benign tumors, primary malignant tumors, and metastatic lesions. This article aims to enumerate usual benign and malignant renal tumors that can occur in childhood and emphasizes the characteristic imaging appearances which aid in their differential diagnosis. Additionally, the leading role of the Radiologist in primary diagnosis of renal infiltration by hematological malignancies and contiguous invasion by neuroblastoma is also introduced and unraveled. Imaging protocol comprises initial Ultrasound evaluation with subsequent computed tomography (CT) and/or Magnetic resonance imaging (MRI), all of which are invaluable in confirming the diagnosis, documenting the organ of origin, describing extent of local and distant spread. The complimentary role of nuclear medicine studies in delineating differential renal function, post-operative complications, and metastasis is also highlighted. PMID- 30311049 TI - Uncommon malignant renal tumors and atypical presentation of common ones: a guide for radiologists. AB - OBJECTIVE: While the typical imaging features of the more common RCC subtypes have previously been described, they can at times have unusual, but distinguishing features. Rarer renal tumors span a broad range of imaging features, but they may also have characteristic presentations. We review the key imaging features of atypical presentations of malignant renal tumors and uncommon malignant renal tumors. CONCLUSION: Renal tumors have many different presentation patterns, but knowledge of the distinguishing MR and CT features can help identify both atypical presentation of common malignancies and uncommon renal tumors. PMID- 30311050 TI - Comparison of health-related quality of life after transarterial chemoembolization and transarterial radioembolization in patients with unresectable hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to compare quality of life (QoL) after two different transarterial therapies [transarterial chemoembolization (TACE) and transarterial radioembolization (TARE)] for patients with unresectable hepatocellular carcinoma (HCC) to assess tumor therapy in palliative situation additional to traditional aims like survival or image response. MATERIAL AND METHODS: QoL was evaluated with two validated questionnaires (EORTC QLQ-30 and EORTC HCC18) before and 14d after treatment in 94 initial therapies (TACE n = 67; TARE n = 27). QoL changes after treatment were analyzed. Tumor response was evaluated using RECIST/WHO/mRECIST/EASL criteria. A multivariate linear regression was undertaken to identify potential influence factors on change of QoL. RESULTS: Mean return rate of questionnaires was 71.3% allowing analysis of 67 therapies (TACE n = 46; TARE n = 21). Initial global health status/QoL was significantly higher in TACE (62.5%) compared to TARE with 50.8%. Absolute global health decrease was higher in TACE (- 10.5%) compared to TARE (- 4.8%, p = 0.396). Also relative global health decrease was higher in TACE (- 16.82%) compared to TARE (- 9.37%). Findings for other items were corresponding, as less impairment was found for TARE compared to TACE for physical/social functioning, fatigue and pain. Objective mRECIST response rate was 22.8% in TACE and 21.1% in TARE. CONCLUSION: Neither TACE nor TARE showed a major decrease in QoL after first treatment. TACE showed a slightly but not significantly higher decrease, so this study is not clearly in favor for one treatment. But with the addition that TARE showed less decrease even in patients with higher tumor burden and lower baseline. PMID- 30311051 TI - An Islamic Religious Spiritual Health Training Model for Patients. AB - Fear and anxiety caused by acute diseases, despair and sorrow resulting from chronic illness, are spiritual reactions which require care. Spiritual care should be done based on a training model. This study was conducted to design and validate "an Islamic religious spiritual health training model for patients." Content analysis was applied for health education models and motivation theories in this qualitative study. Based on the components of the spiritual care model of Sound Heart, compatible concepts were adopted and formulated to a model. Model was designed by using the three-step theory synthesis of Walker and Avant, in order to predispose the conversion of emotions derived from fear and sorrow to emotions filled with confidence and security, as well as behavioral adaptation to diseases. For problem-focused and emotion-focused adaptation, the disease should be introduced as a challenge through improving the patient's relationship with God and by developing courage and optimism. Patients can then reach Sound Heart and healthy behavior after improving relationships with themselves, people, and nature, using religious norms and development of commitment, control, and motivation. The patients' progress can be assessed by daily self-control. Spiritual consulters should act as mentor when performing and instructing spiritual health. They should make themselves competent and empowered for helping patients and managing their harmful emotions. The model emphasizes on: patient- and family-focused approach, self-care, home care, and engaging patients' logos. PMID- 30311052 TI - High-sensitivity cardiac troponin T and severity of cerebral white matter lesions in patients with acute ischemic stroke. AB - INTRODUCTION: Cardiac troponin (hs-cTnT) is a sensitive marker of myocardial injury and has been linked to incident dementia. The underlying mechanism of that observation is still unknown. Given that severity of cerebral small vessel disease is a predictor of cognitive decline, we aimed to explore whether there is an association between hs-cTnT and severity of white matter lesions (WML) as a marker of cerebral small vessel disease in patients with ischemic stroke. METHODS: We analyzed consecutive acute ischemic stroke patients admitted to Charite-University Hospital, Berlin from 2011 to 2013. Severity of WML was graded on 3T-MRI using the age-related white matter severity score (ARWMS). Patients with hs-cTnT elevation suggestive of acute coronary syndrome (ACS) were excluded (hs-cTnT > 52 ng/l or dynamic change of hs-cTnT > 50%, ESC guideline). We performed unadjusted and adjusted quantile regression models to assess the association between increased hs-cTnT (dichotomized at the 99th percentile, 14 ng/l) and severity of WML. RESULTS: A total of 860 patients was analyzed (median age 73 years, 44.8% female, median ARWMS 6). Patients with elevated hs-cTnT had more extensive WML than those without (median ARWMS 8 vs. 5, adjusted beta for 50th percentile 1.12, 95% CI 0.41-1.84). The association between WML and hs-cTnT elevation was strongest in patients with severe WML (adjusted beta 1.77, 95% CI 0.26-3.27 for 80th WML percentile). CONCLUSION: Elevated hs-cTnT levels were associated with extent of WML in acute stroke patients. Further studies are needed to assess whether hs-cTnT can be used to identify stroke patients at risk for cognitive decline. PMID- 30311054 TI - Roles of potential plant hormones and transcription factors in controlling leaf senescence and drought tolerance. AB - Plant leaves offer an exclusive windowpane to uncover the changes in organs, tissues, and cells as they advance towards the process of senescence and death. Drought-induced leaf senescence is an intricate process with remarkably coordinated phases of onset, progression, and completion implicated in an extensive reprogramming of gene expression. Advancing leaf senescence remobilizes nutrients to younger leaves thereby contributing to plant fitness. However, numerous mysteries remain unraveled concerning leaf senescence. We are not still able to correlate leaf senescence and drought stress to endogenous and exogenous environments. Furthermore, we need to decipher how molecular mechanisms of the leaf senescence and levels of drought tolerance are advanced and how is the involvement of SAGs in drought tolerance and plant fitness. This review provides the perspicacity indispensable for facilitating our coordinated point of view pertaining to leaf senescence together with inferences on progression of whole plant aging. The main segments discussed in the review include coordination between hormonal signaling, leaf senescence, drought tolerance, and crosstalk between hormones in leaf senescence regulation. PMID- 30311055 TI - Variation in Rates of Fatal Police Shootings across US States: the Role of Firearm Availability. AB - The USA has very high rates of homicide by police compared to other high-income countries, with approximately 1000 civilians killed annually. The overwhelming majority of these police homicides are fatal shootings. Over the past 5 years, several comprehensive, real-time, data repositories, drawn largely from news reporting, have kept track of incidents in which civilians die during an encounter with the police and have become widely available. Data from these repositories, which are more complete than data available from federal data systems, have been used to explore fatal police shootings of civilians, often with a focus on racial disparities in police shootings of unarmed civilians, and have consistently found that police are more likely to shoot unarmed African American men than unarmed White men. Although numerous studies have examined how rates of police killings of civilians are related to several ecologic determinants of these events, no peer-reviewed study to date has examined the extent to which variation in police involved firearm homicides is explained by firearm prevalence while adjusting for violent crime rates (the most well established ecologic factor associated with fatal police shootings). The current cross-sectional state-level analysis uses data on the number of civilians shot and killed by police in the line of duty, aggregated over 2015-2017. Data come from the Washington Post's "Fatal Force Database", which assembles the information from news reports and other sources. Data provided include information on whether the victim was armed, and, if so, with what weapon. Explanatory ecologic variables in our models include the violent crime rate, the percentage of the state population that is non-White, poverty rate, and urbanization, along with a validated proxy for firearm prevalence. We find that rates of police shooting deaths are significantly and positively correlated with levels of household gun ownership, even after accounting for the other explanatory variables. The association is stronger for the shooting of armed (with a gun) rather than unarmed victims. PMID- 30311056 TI - From the predictable to the unexpected: kelp forest and benthic invertebrate community dynamics following decades of sea otter expansion. AB - The recovery of predators has the potential to restore ecosystems and fundamentally alter the services they provide. One iconic example of this is keystone predation by sea otters in the Northeast Pacific. Here, we combine spatial time series of sea otter abundance, canopy kelp area, and benthic invertebrate abundance from Washington State, USA, to examine the shifting consequences of sea otter reintroduction for kelp and kelp forest communities. We leverage the spatial variation in sea otter recovery to understand connections between sea otters and the kelp forest community. Sea otter increases created a pronounced decline in sea otter prey-particularly kelp-grazing sea urchins-and led to an expansion of canopy kelps from the late 1980s until roughly 2000. However, while sea otter and kelp population growth rates were positively correlated prior to 2002, this association disappeared over the last two decades. This disconnect occurred despite surveys showing that sea otter prey have continued to decline. Kelp area trends are decoupled from both sea otter and benthic invertebrate abundance at current densities. Variability in kelp abundance has declined in the most recent 15 years, as it has the synchrony in kelp abundance among sites. Together, these findings suggest that initial nearshore community responses to sea otter population expansion follow predictably from trophic cascade theory, but now, other factors may be as or more important in influencing community dynamics. Thus, the utility of sea otter predation in ecosystem restoration must be considered within the context of complex and shifting environmental conditions. PMID- 30311058 TI - Functional recovery of daily living and sports activities after cosmetic bilateral tibia lengthening. AB - PURPOSE: The aims of this study were to evaluate the recovery of physical function and to investigate whether there are factors that adversely affect functional recovery after cosmetic bilateral lengthening of the tibia. METHODS: One hundred twenty-five healthy individuals who had undergone bilateral cosmetic tibia lengthening by the lengthening and then nail (LATN) method, lengthening over intramedullary nail (LON) method or intramedullary skeletal kinetic distractor (ISKD) were included in the study. Functional outcomes were evaluated using the Sports Activity Rating Scale (SARS), International Knee Documentation Committee (IKDC) Subjective Knee Form and patient self-reported ability scores. RESULTS: SARS and IKDC scores decreased at post-operative one year and improved significantly at post-operative two years. SARS and IKDC scores recovered similarly to pre-operative levels. Average patient self-reported ability scores at post-operative two years were 94.6 and 89.9 for daily living and light sports, respectively. However, the average score for moderate-to-strenuous sports was 68.1 and 39 patients (31.2%) recorded below average score for the moderate-to strenuous sports. CONCLUSIONS: Patients who had undergone bilateral cosmetic tibial lengthening may expect almost full recovery of daily and light sports activities at post-operativetwo years. However, several patients may feel some limitation in moderate-to-strenuous sports activities. PMID- 30311057 TI - Chronic Aichi Virus Infection in a Patient with X-Linked Agammaglobulinemia. PMID- 30311053 TI - The role of clinical and neuroimaging features in the diagnosis of CADASIL. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 +/- 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield. PMID- 30311060 TI - Journal of Bone and Mineral Metabolism Best Paper Award 2018. PMID- 30311059 TI - Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: clinical and histological observations. AB - PURPOSE: Osteoarthritis (OA) is characterized by articular cartilage degeneration and subchondral bone sclerosis. OA can benefit of non-surgical treatments with collagenase-isolated stromal vascular fraction (SVF) or cultured-expanded mesenchymal stem cells (ASCs). To avoid high manipulation of the lipoaspirate needed to obtain ASCs and SVF, we investigated whether articular infusions of autologous concentrated adipose tissue are an effective treatment for knee OA patients. METHODS: The knee of 20 OA patients was intra-articularly injected with autologous concentrated adipose tissue, obtained after centrifugation of lipoaspirate. Patients' articular functionality and pain were evaluated by VAS and WOMAC scores at three, six and 18 months from infusion. The osteogenic and chondrogenic ability of ASCs contained in the injected adipose tissue was studied in in vitro primary osteoblast and chondrocyte cell cultures, also plated on 3D bone scaffold. Knee articular biopsies of patients previously treated with adipose tissue were analyzed. Immunohistochemistry (IHC) and scanning electron microscopy (SEM) were performed to detect cell differentiation and tissue regeneration. RESULTS: The treatment resulted safe, and all patients reported an improvement in terms of pain reduction and increase of function. According to the osteogenic or chondrogenic stimulation, ASCs expressed alkaline phosphatase or aggrecan, respectively. The presence of a layer of newly formed tissue was visualized by IHC staining and SEM. The biopsy of previously treated knee joints showed new tissue formation, starting from the bone side of the osteochondral lesion. CONCLUSIONS: Overall our data indicate that adipose tissue infusion stimulates tissue regeneration and might be considered a safe treatment for knee OA. PMID- 30311062 TI - Comparative effect of platelet-rich plasma, platelet-poor plasma, and fetal bovine serum on the proliferative response of periodontal ligament cell subpopulations. AB - OBJECTIVES: Cell-based therapies involve the need to expand cell cultures ex vivo for their subsequent implantation in an autologous manner. An important limitation regarding this technology is the use of fetal bovine serum (FBS) that has critical safety limitations. Platelet-derived fractions represent an autologous source of growth factors that may be used for the expansion of these cell cultures. Periodontal ligament (PDL) cells comprise a heterogeneous cell population that may not necessarily respond in a uniform manner to proliferative stimuli. The aim of this study was to evaluate the ability of two platelet derived fractions, platelet-rich plasma (PRP) and platelet-poor plasma (PPP) and FBS on the proliferative response of different subpopulations of PDL cell cultures. MATERIALS AND METHODS: PDL cells were characterized and then exposed to PRP, PPP, or FBS during 2, 5, or 14 days to analyze cell proliferation and clonogenic capability. Cell proliferation was evaluated through immunofluorescence for Ki67 and by tracing carboxyfluorescein diacetate succinimidyl ester (CFSE) dye in combination with mesenchymal stem cell markers using flow cytometry. RESULTS: Both PRP and PPP stimulated PDL cell proliferation and their clonogenic ability. We found a significant increase of CD73- and CD90 positive cells after PRP or PPP treatment, compared to FBS. Otherwise, no differences were found regarding the response of CD146-or CD105-positive cells when stimulated with PRP, PPP, or FBS. CONCLUSION: PRP and PPP can stimulate the proliferation and clonogenicity of PDL cell populations including cells positive for CD90 and CD73 markers. CLINICAL RELEVANCE: These findings may have implications for future therapies aiming to stimulate periodontal regeneration using autologous growth factors. PMID- 30311061 TI - Efficacy of a drug composed of herbal extracts on postoperative discomfort after surgical removal of impacted mandibular third molar: a randomized, triple-blind, controlled clinical trial. AB - OBJECTIVES: This study investigated and compared the effectiveness of a phytotherapeutic drug composed of herbal extracts on postsurgical discomfort after mandibular third molar surgery. MATERIALS AND METHODS: Eighty-two patients requiring the surgical removal of a mandibular third molar were randomly assigned to receive placebo (group 1), ibuprofen (group 2), and a phytotherapeutic drug (composed of baicalin, 190 mg; bromelain, 50 mg; escin, 30 mg) (group 3). Drugs were administered after tooth extraction twice a day for 5 days. The primary outcome, pain, was evaluated using a visual analogue scale at 2 h, 6 h, 12 h, 24 h, 48 h, and 7 and 10 days after surgery. The secondary outcomes were the changes in maximum mouth opening and facial contours (mm) between baseline and at 24 h, 72 h, and 7 and 10 days after surgery. RESULTS: Compared to the baseline, all treatments demonstrated an improvement in the primary and secondary outcomes. Moreover, compared to groups 1 and 2, patients in group 3 yielded a significant reduction of the postoperative pain score at 12 h (p < 0.001), 24 h (p = 0.010), and 48 h (p = 0.048) after surgery. The mean reduction of the swelling and trismus was similar between groups. CONCLUSIONS: The results of this study suggest that a postoperative administration of a phytotherapeutic drug was found to be effective in postoperative pain management after the surgical removal of impacted mandibular third molars. CLINICAL RELEVANCE: The phytotherapeutic drug composed of herbal extract determined a decrease in the severity of postoperative pain compared to ibuprofen and placebo. PMID- 30311063 TI - Prevalence of degenerative joint disease of the temporomandibular joint: a systematic review. AB - OBJECTIVES: The purpose of this systematic review was to evaluate evidence about the prevalence of degenerative joint disease (DJD) of the temporomandibular joints (TMJ). MATERIALS AND METHODS: We performed search on electronic databases and gray literature from their inception to January 2018. Studies reporting prevalence data of DJD on TMJ were included. DJD was assessed through clinical and imaging diagnosis. Studies risk of bias was evaluated using the Critical Appraisal Checklist for Studies Reporting Prevalence Data. RESULTS: From 1082 studies, 32 were identified, and the sample size included 3435 subjects. They were clustered into two groups: the first comprised studies that reported prevalence of DJD in TMJ secondary to rheumatic systemic diseases like juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) and the second group comprised studies that reported prevalence of DJD on temporomandibular disorder patients. The prevalence of DJD on JIA patients ranged from 40.42% (n = 47) to 93.33% (n = 15) and on RA patients from 45.00% (n = 20) to 92.85% (n = 56). Among TMD patients, the prevalence of DJD reported according to patients ranged from 18.01% (n = 1038) to 84.74% (n = 118) and reported according to joints ranged from 17.97% (n = 178) to 77.23% (n = 224). CONCLUSION: This review attempts to high prevalence of DJD in patients with systemic rheumatic disease and a less prevalent, but still high, occurrence in patients with TMD without systemic involvement. CLINICAL RELEVANCE: Specialist doctors and dentists should be alert to not underestimate and to correctly diagnose DJD of the TMJ early in patients with rheumatic disease and TMD. PMID- 30311064 TI - Patient Monitoring System Using Cognitive Internet of Things. AB - In this article, we ponder multi-user medical image transmission using Cognitive Multiple-input Multiple-output (MIMO) Multi-carrier Code-division-multiple-access (MC-CDMA) system to monitor patient information. We investigate the performance of such system in the communication layer and application layer of internet of things (IOT). Patient monitoring system plays vital role in the hospital particularly in the emergency ward to resolve certain problems such as maintaining glucose level in the body, maintaining minimum sugar levels under emergency conditions. IOT find tremendous application in the hospital to deal with certain issues such as injection of drug to the patients by doctor from remote places, monitoring patients heart beats, sugar level by the concerned doctors. MIMO finds many applications in medical field to enrich data rate while communication patient information at faster rate. We utilize MC-CDMA system to accommodate large user patients information and to transmit such information with high resolution by eliminating channel impairments. We are utilizing Cognitive spectrum for medical image transmission of higher bandwidth applications. We realize Double-space-time transmit diversity as MIMO profile to boost up throughput. We perform multi-carrier modulation using IDFT at the transmitter .we carryout demodulation employing DFT at the hospital. We introduce Multi-carrier communication to fulfil the need of bandwidth efficiency and to diminish frequency selectivity effects.In the application layer, we estimate patient's information with aid of block-nulling decoding algorithm. Moreover we analyze the quality of image of D-STTD MC-CDMA system with turbo style of channel encoder to manifest medical image with high resolution with less signal strength. We conclude that Cognitive D-STTD MC-CDMA system provides reliable communication for the application of IOT and also transfer high resolution medical image with less signal strength in order to observe patient status by doctor. PMID- 30311066 TI - Intertrochanteric fracture visualization and analysis using a map projection technique. AB - Understanding intertrochanteric fracture distribution is an important topic in orthopedics due to its high morbidity and mortality. The intertrochanteric fracture can contain high-dimensional information including complicated 3D fracture lines, which often make it difficult to visualize or to obtain valuable statistics for clinical diagnosis and prognosis applications. This paper proposed a map projection technique to map the high-dimensional information into a 2D parametric space. This method can preserve the 3D proximal femur surface and structure while visualizing the entire fracture line with a single plot/view. Using this method and a standardization technique, a total of 100 patients with different ages and genders are studied based on the original radiographs acquired by CT scan. The comparison shows that the proposed map projection representation is more efficient and rich in information visualization than the conventional heat map technique. Using the proposed method, a fracture probability can be obtained at any location in the 2D parametric space, from which the most probable fracture region can be accurately identified. The study shows that age and gender have significant influences on intertrochanteric fracture frequency and fracture line distribution. Graphical abstract Generation of 2D parametric map for intertrochanteric fracture probability visualization. PMID- 30311065 TI - Artesunate-Loaded and Near-Infrared Dye-Conjugated Albumin Nanoparticles as High Efficiency Tumor-Targeted Photo-Chemo Theranostic Agent. AB - Herein, a tumor-targeted multifunctional theranostic agent was synthetized using a facile method, combining four clinically approved materials: artesunate (Arte), human serum albumin (HSA), folic acid (FA), and indocyanine green (ICG). The obtained nanocomposites (FA-IHA NPs) showed an excellent photo- and physiological stability. The ICG in the FA-IHA NPs was used not only for near infrared (NIR) fluorescence imaging, but also for photothermal and photodynamic (PTT-PDT) therapy under a single NIR irradiation. In addition, the NIR irradiation (808 nm, 1 W/cm2) could trigger Arte release that showed enhanced chemotherapeutic effect. Through fluorescence imaging, the cell uptake and tumor accumulation of FA-IHA NPs were observed in vitro and in vivo, analyzed by confocal microscopy and NIR fluorescence imaging in tumor xenograft mice. Based on the diagnostic results, FA IHA NPs at 24 h post injection and combined with NIR irradiation (808 nm, 1 W/cm2) could efficiently suppress tumor growth through a photo-chemo combination therapy, with no tumor recurrence in vitro and in vivo. The obtained results suggested that FA-IHA NPs are promising photo-chemo theranostic agents for future clinical translation. PMID- 30311067 TI - Historical forensic pathology - a "new" discipline. PMID- 30311068 TI - The characteristics of all-terrain vehicle (ATV)-related deaths: A forensic autopsy data-based study. AB - Using forensic autopsy-based data from a regional medical examiner office in the midwestern U.S. with a mixed small urban-rural population, we describe the characteristics of all-terrain vehicle (ATV)-related deaths occurring between 2000 and 2018. During this period, there were 25 ATV-related deaths. There was a strong male predominance with 22 male and 3 female decedents. The average age at death was 35 years, with a range from 10 to 82 years, and a bimodal age distribution with one peak at 10-19 years old, and a second peak at 60-69 years old. The most common cause of death was blunt trauma (n = 22), with the remainder being torso compression (n = 1), drowning (n = 1) and hypothermia (n = 1). Of the 22 blunt trauma deaths, 15 were due to head trauma. The most common mechanism of accident was roll-over (n = 11), followed by striking a stationary object (n = 6). Of the stationary objects struck, the most common was cable wire fencing accounting for 3 of the 6. A survival period following discovery of the body was present in 11 of the 25 deaths. Postmortem toxicology was positive for ethanol in 7 deaths and tramadol in 1 death. PMID- 30311069 TI - Recent Updates on Chronic Myelomonocytic Leukemia. AB - PURPOSE OF REVIEW: The goal of this review is to provide a practical and comprehensive update on changes in the classification of chronic myelomonocytic leukemia (CMML) and a summary of the most recent developments in our understanding of its genomic landscape, prognostic models, and therapeutic approaches. RECENT FINDINGS: The 2017 revision of the World Health Organization (WHO) classification includes substantial changes to the subclassification CMML. The clinical utility of the newly revised subclassification scheme is discussed. In addition, we provide an overview of the genetic changes involved in the pathogenesis of CMML and discuss the clinical utility of the more recently developed molecularly integrated prognostic models and their management and therapeutic implications. Finally, we provide an overview of the currently available treatment options for patients with CMML. The classification of CMML as well as our understanding of its genomic landscape and optimal treatment approaches has advanced significantly over the past decade but remains in flux. PMID- 30311072 TI - Autonomic Disturbances in Acute Cerebrovascular Disease. AB - Autonomic disturbances often occur in patients with acute cerebrovascular disease due to damage of the central autonomic network. We summarize the structures of the central autonomic network and the clinical tests used to evaluate the functions of the autonomic nervous system. We review the clinical and experimental findings as well as management strategies of post-stroke autonomic disturbances including electrocardiographic changes, cardiac arrhythmias, myocardial damage, thermoregulatory dysfunction, gastrointestinal dysfunction, urinary incontinence, sexual disorders, and hyperglycemia. The occurrence of autonomic disturbances has been associated with poor outcomes in stroke patients. Autonomic nervous system modulation appears to be an emerging therapeutic strategy for stroke management in addition to treatments for sensorimotor dysfunction. PMID- 30311071 TI - Correction to: Radiolabeled PLGA Nanoparticles for Effective Targeting of Bendamustine in Tumor Bearing Mice. AB - The typesetter did not use the Fig. 6 provided by the author with his proof corrections, and instead duplicated Fig. 7 by the Fig. 6 caption. The original article has been corrected. PMID- 30311073 TI - A comparison of propofol-to-BIS post-operative intensive care sedation by means of target controlled infusion, Bayesian-based and predictive control methods: an observational, open-label pilot study. AB - PURPOSE: We evaluated the feasibility and robustness of three methods for propofol-to-bispectral index (BIS) post-operative intensive care sedation, a manually-adapted target controlled infusion protocol (HUMAN), a computer controlled predictive control strategy (EPSAC) and a computer-controlled Bayesian rule-based optimized control strategy (BAYES). METHODS: Thirty-six patients undergoing short lasting sedation following cardiac surgery were included to receive propofol to maintain a BIS between 40 and 60. Robustness of control for all groups was analysed using prediction error and spectrographic analysis. RESULTS: Although similar time courses of measured BIS were obtained in all groups, a higher median propofol effect-site concentration (CePROP) was required in the HUMAN group compared to the BAYES and EPSAC groups. The time course analysis of the remifentanil effect-site concentration (CeREMI) revealed a significant increase in CeREMI in the EPSAC group compared to BAYES and HUMAN during the case. Although similar bias and divergence in control was found in all groups, larger control inaccuracy was observed in HUMAN versus EPSAC and BAYES. Spectrographic analysis of the system behavior shows that BAYES covers the largest spectrum of frequencies, followed by EPSAC and HUMAN. CONCLUSIONS: Both computer-based control systems are feasible to be used during ICU sedation with overall tighter control than HUMAN and even with lower required CePROP. EPSAC control required higher CeREMI than BAYES or HUMAN to maintain stable control. Clinical trial number: NCT00735631. PMID- 30311070 TI - Polycystic Ovary Syndrome: Implication for Drug Metabolism on Assisted Reproductive Techniques-A Literature Review. AB - Polycystic ovary syndrome (PCOS) affects 6-10% of women and could be considered one of the most common endocrine alterations in women of reproductive age. The syndrome is characterized by several hormonal and metabolic alterations, including insulin resistance and hyperandrogenism, which play a severe detrimental role in the patient's fertility. We aimed to offer an overview about drug metabolism in the PCOS population. Nevertheless, we did not find any study that directly compared drug metabolism between PCOS and healthy women. We therefore decided to summarize briefly how hormonal and insulin sensitizer drugs act differently in healthy and PCOS women, who show altered steroidogenesis by theca cells and metabolic imbalance, focusing especially on assisted reproductive techniques. To date, data about drug metabolism in the PCOS population appears to be extremely limited. This important gap could have significant implications for therapeutic approaches and future perspectives: the dosage of drugs commonly used for the treatment of PCOS women should be tailored according to each patient's characteristics; we should implement new clinical trials in order to identify the best pharmacologic strategy for PCOS patients undergoing in vitro fertilization (IVF); it would be advisable to create an international expert panel to investigate the drug metabolism in the PCOS population. PMID- 30311074 TI - Association between junk food consumption and cardiometabolic risk factors in a national sample of Iranian children and adolescents population: the CASPIAN-V study. AB - AIMS: Only a few studies have attempted to assess the relationship between junk food consumption and cardiometabolic risk factors in Iranian children and adolescents; therefore, the aim of our study was to determine the association between junk food intake and cardiometabolic risk factors in this population. STUDY DESIGN: This is a cross-sectional study. METHODS: A total of 14,400 students were selected from 30 provinces of Iran using multistage, stratified cluster sampling method. Information about student's lifestyle, health behaviors and health status was obtained through a validated questionnaire. Blood pressure was measured and anthropometric indices were calculated. Blood samples were drawn from 3,303 students for biochemical tests. In our study, sugar-sweetened beverages, salty snacks, sweets and fast foods were considered as junk foods. RESULTS: The mean age of participants was 12.42 +/- 2.97 years. Those with metabolic syndrome were more likely to live in urban areas (P = 0.004) and have higher BMI (P < 0.0001). Junk food intake was not related to metabolic syndrome; however, it was associated with increased odds of high BP (OR 1.23, 95% CI 1.09, 1.39), high SBP (OR 1.38, 95% CI 1.09, 1.75), and high DBP (OR 1.18, 95% CI 1.04, 1.35), overweight (OR 1.22, 95% CI 1.08, 1.39) and excess weight (OR 1.14, 95% CI 1.04, 1.25). CONCLUSIONS: Junk food consumption plays an important role in childhood overweight and is related to high blood pressure in this population. LEVEL OF EVIDENCE: Level III, case-control analytic studies. PMID- 30311075 TI - Pediatric tibia and femur fractures in patients weighing more than 50 kg (110 lb): mini-review on current treatment options and outcome. AB - The main objective of this paper is to review the current literature on treatment of tibial and femur fractures in children and adolescents guided by body weight in patients weighing 50 kg (110 lb) or more. A secondary aim of this mini-review was to determine, as per literature review, whether weight > 50 kg (110 lb) is an identifiable factor associated with increased complication rate. A search of the PubMed/MEDLINE, EMBASE and Cochrane Database of Systematic Reviews databases from 1954 to September 2017 was performed to identify papers related to pediatric tibia and femur fractures in children weighing more than 50 kg (110 lb). Abstracts were screened, and relevant full-text articles were retrieved for further review. Reference sections of identified papers were also screened to identify further literature. All levels of evidence were included. Overall, seven full-text articles dealing with pediatric tibia or femur fractures in patients weighing more than 50 kg (110 lb), and one article reporting on both femur and tibia fractures in this patients' population, have been identified (n = 8 full text article included). The articles reviewed a total of 679 children. In particular, 48/438 femur shaft fractures (mean weight: 51.7 kg or 113.9 lb) and 91/241 tibia fractures (mean weight: 53.3 kg or 117.5 lb) met the inclusion criteria. The overall rate of complications was 27.9%. In particular, the rate of complication was 51.7 and 29.6% in children with femur and tibia fracture weighing more than 50 kg (110 lb), respectively (p < 0.05). Elastic stable intramedullary nailing (ESIN) has become the treatment of choice for displaced tibia and femur shaft fractures in children between six and 12-15 years of age. Unstable fracture pattern, higher age and higher weight have been reported as potential risk factors associated with poor outcomes in children and adolescents treated with ESIN for displaced long bone fractures of the lower extremity, in particular femur shaft fractures. Despite these findings, data reporting exclusively on ESIN-treated long bone fractures in children weighing 50 kg (110 lb) or more remain scant. PMID- 30311077 TI - First genetic detection and characterization of canine parvovirus from diarrheic dogs in Zambia. AB - Although canine parvovirus (CPV) causes severe gastroenteritis in dogs globally, information on the molecular epidemiology of the virus is lacking in many African countries. Here, 32 fecal samples collected from diarrheic dogs in Zambia were tested for CPV infection using molecular assays. CPV was detected in 23 samples (71.9%). Genetic characterization revealed the predominance of CPV-2c (91.3%). This finding differs from previous reports in Africa, which indicated that CPV-2a and CPV-2b were most prevalent. Phylogenetically, most Zambian CPVs formed a distinct cluster. This is the first report on the molecular characterization of CPV in Zambia. PMID- 30311076 TI - Development of a new recombinant p24 ELISA system for diagnosis of bovine leukemia virus in serum and milk. AB - Bovine leukemia virus (BLV) is a retrovirus that causes enzootic bovine leucosis. Here, we designed a p24 enzyme-linked immunosorbent assay (ELISA) to detect antibodies specific for BLV capsid protein p24 (encoded by the gag gene) in bovine serum samples. The p24 gene was inserted into an Escherichia coli expression system, and recombinant proteins (GST-p24, p24, and His-p24) were purified. His-p24 was the most suitable antigen for using in the ELISA. The cut off point was calculated from a receiver operating characteristic curve derived from a set of 582 field samples that previously tested positive or negative by BLV-CoCoMo-qPCR-2, which detects BLV provirus. The new p24 ELISA showed almost the same specificity and sensitivity as a commercial gp51 ELISA kit when used to test field serum samples, and allowed monitoring of p24 antibodies in raw milk and whey. Comparing the results for the p24 ELISA and gp51 ELISA revealed that p24 antibodies were detected earlier than gp51 antibodies in three out of eight calves experimentally infected with BLV, indicating improved detection without diminishing BLV serodiagnosis. Thus, the p24 ELISA is a robust and reliable assay for detecting BLV antibodies in serum or milk, making it is a useful tool for large-scale BLV screening. PMID- 30311078 TI - Diabetic Dyslipidemia: Epidemiology and Prevention of Cardiovascular Disease and Implications of Newer Therapies. AB - PURPOSE OF REVIEW: Dyslipidemia in patients with T2DM confers significant additional risk of adverse outcomes to patients with cardiovascular disease (CVD). These patients carry residual risk of adverse outcomes despite optimal management with conventional therapy such as lifestyle changes and statin therapy. The role of both nonstatin monotherapy in statin-intolerant patients and combination therapy with statins in patients with high risk of CVD events has been well studied. We sought to review the role of newer therapies in risk reduction in these patients. RECENT FINDINGS: Traditionally, non-statin options have included medications such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids. Recently, drugs such as ezetimibe, inclisiran, and PCSK9 inhibitors have been studied with favorable results without an increased risk of developing new onset diabetes. These medications hold the promise of increasing options to reduce cardiovascular risk in patients with T2DM. The role of newer non-statin therapies in patients with diabetic dyslipidemia in combination with statins needs to be further explored. PMID- 30311079 TI - Enteric duplication cysts in children: varied presentations, varied imaging findings. AB - Enteric duplication cysts (EDCs) are rare congenital malformations formed during the embryonic development of the digestive tract. They are usually detected prenatally or in the first years of life. The size, location, type, mucosal pattern and presence of complications produce a varied clinical presentation and different imaging findings. Ultrasonography (US) is the most used imaging method for diagnosis. Magnetic resonance (MR) and computed tomography (CT) are less frequently used, but can be helpful in cases of difficult surgical approach. Conservative surgery is the treatment of choice. Pathology confirms the intestinal origin of the cyst, showing a layer of smooth muscle in the wall and an epithelial lining inside, resembling some part of the gastrointestinal tract (GT). We review the different forms of presentation of the EDCs, showing both the typical and atypical imaging findings with the different imaging techniques. We correlate the imaging findings with the surgical results and the final pathological features. TEACHING POINTS: * EDCs are rare congenital anomalies from the digestive tract with uncertain pathogenesis. * More frequently, diagnosis is antenatal, with most EDCs occurring in the distal ileum. * Ultrasonography is the method of choice for diagnosis of EDCs. * Complicated EDCs can show atypical imaging findings. * Surgery is necessary to avoid complications. PMID- 30311080 TI - Correction to: Considerations in the Use of Body Mass Change to Estimate Change in Hydration Status During a 161-Kilometer Ultramarathon Running Competition. AB - In Table 2 of the original publication, an error was made in the calculations for endogenous substrate oxidation which, subsequently, altered the values for total change in body mass. PMID- 30311082 TI - The self-disproportionation of enantiomers (SDE) of alpha-amino acid derivatives: facets of steric and electronic properties. AB - alpha-Amino acids (alpha-AAs) are in extremely high demand in nearly every sector of the food and health-related chemical industries and continue to be the subject of intense multidisciplinary research. The self-disproportionation of enantiomers (SDE) is an emerging and one of the least studied areas of alpha-AA or enantiomeric properties, critically important for their production and application. In the present work, we report a detailed study of the SDE via achiral, gravity-driven column chromatography for a set of N-acylated, N carbonylated, N-fluoroacylated, and N-thioacylated alpha-amino acid esters. As well as thioacylation, attention was paid to the effect of altering the R group of the ester functionality, the side chain, or that of the acyl group attached to the amide nitrogen, whereby it was found that electron-withdrawing groups in the latter moiety had a pronounced effect on the magnitude and behavior of the resulting SDE phenomenon. Intriguingly, in the case of N-fluoroacylated derivatives, by favoring the formation of dimeric associates and effecting a strong bias toward homochiral associates over heterochiral associates, the SDE magnitude was greatly reduced contrary to intuitive expectations. Energy estimates resulted from DFT calculations. PMID- 30311081 TI - Sternal Injuries in Sport: A Review of the Literature. AB - Sternal fractures were first described in published literature in the 19th century as a complication of traumatic injury. Though sternal fracture and other sternal injuries have been described in trauma literature, there remains a paucity of literature with regards to sternal injury in sport. Sternal injury may include disruption at the body, manubrium and xiphoid process, or at associated sternoclavicular, manubriosternal, and xiphisternal joints. In the athlete it is imperative to evaluate sternal injury with consideration of potentially devastating cardiothoracic complications. Return-to-play protocols should be individualized, taking into account subjective history, objective physical examination and diagnostics, current clinical guidelines, and individual sport specific considerations. The literature regarding sternal injury is reviewed, with emphasis on sport-specific pathology, management, and return to play. PMID- 30311084 TI - Efficacy of photobiomodulation on accelerating bone healing after tooth extraction: a systematic review. AB - Post-extraction healing of the socket may take up to 24 weeks to complete. This systematic review aims to evaluate whether photobiomodulation accelerates bone healing in those sockets. A search strategy was developed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Cochrane Library, and Scopus electronic databases were searched for in vivo studies with restrictions on the year (< 50 years old) and language (English). After applying the inclusion criteria, ten studies were selected for review. Test subjects included humans (3), rats (5), and rabbits (2), either healthy or with specified systemic condition(s). Laser parameters applied varied between studies significantly. Six studies measured bone density or bone trabeculae percentage, while remaining studies measured secondary outcome measures such as osteogenesis markers, patient's self-reported pain scores, and clinical epithelial regeneration. No side effects of photobiomodulation have been reported. Higher concentration of osteogenesis markers Ocn and Runx2 were consistently reported across studies, as well as higher percentage of bony trabeculae and bone density. Within the limitations of this review, improvement in bone repair can be found when using photobiomodulation in extraction sockets. PMID- 30311083 TI - Types of advanced optical microscopy techniques for breast cancer research: a review. AB - A cancerous cell is characterized by morphological and metabolic changes which are the key features of carcinogenesis. Adenosine triphosphate (ATP) in cancer cells is primarily produced by aerobic glycolysis rather than oxidative phosphorylation. In normal cellular metabolism, nicotinamide adenine dinucleotide (NADH) is considered as a principle electron donor and flavin adenine dinucleotide (FAD) as an electron acceptor. During metabolism in a cancerous cell, a net increase in NADH is found as the pathway switched from oxidative phosphorylation to aerobic glycolysis. Often during initiation and progression of cancer, the developmental regulation of extracellular matrix (ECM) is restricted and becomes disorganized. Tumor cell behavior is regulated by the ECM in the tumor micro environment. Collagen, which forms the scaffold of tumor micro environment also influences its behavior. Advanced optical microscopy techniques are useful for determining the metabolic characteristics of cancerous, normal cells and tissues. They can be used to identify the collagen microstructure and the function of NADH, FAD, and lipids in living system. In this review article, various optical microscopy techniques applied for breast cancer research are discussed including fluorescence, confocal, second harmonic generation (SHG), coherent anti-Stokes Raman scattering (CARS), and fluorescence lifetime imaging (FLIM). PMID- 30311085 TI - Effects of antibacterial photodynamic therapy on salivary mutans streptococci in 5- to 6-year-olds with severe early childhood caries. AB - Antibacterial photodynamic therapy (A-PDT) has been shown to kill oral bacteria in the planktonic culture, dental plaque, and biofilm. This study sought to assess the antimicrobial effect of A-PDT with toluidine blue O (TBO) and diode laser on salivary mutans streptococci in 5-6-year-olds with severe early childhood caries (SECC). This case-control study was conducted on 56 children with SECC divided into four groups, namely 0.1 mg/mL TBO, diode laser (633 nm, 20 mW, 6 J/cm2), combination of the two, and no intervention control group. A-PDT was performed on days 1 and 3. Salivary samples were collected before and after A PDT on days 1 and 3, and 1 and 2 weeks after the second intervention (day 3). Samples were cultured on mitis salivarius agar, and after incubation, the colonies were counted. Data were subjected to repeated measures ANOVA, ANCOVA, and paired comparisons with least square difference and Tukey's test. Bacterial count significantly decreased on days 1 and 3, and 1 and 2 weeks after the second intervention. Bacterial count also decreased following the use of TBO and laser separately, but these reductions were not significant (P > 0.05). Within the limitations of this study, antimicrobial efficacy of TBO + laser was higher than that of diode laser or TBO alone. Durability of treatment increased with double dose therapy. This modality may be used to decrease the colony count of salivary mutans streptococci in children with SECC. PMID- 30311086 TI - Spectroscopic study of breath ethylene via the mouth and nose. AB - The development of new techniques for breath analysis searching for objective biomarkers of oxidative stress showed promise in non-invasive disclosing health information of the well-being of a person. Although numerous biomarkers have been identified so far using breath analysis, very little is known about their origin if they are metabolic or providing from mouth contamination. For the introduction of breath tests into clinical practice, standardization of sample collection needs to be taken into account. Breath analysis has been performed using laser photoacoustic spectroscopy to evaluate exhaled breath by mouth and nose before and after brushing with toothpaste/baking soda in order to identify the important endogenous biomarkers without contaminant sources. As a known biomarker of oxidative stress in the human body, it is important to accurately assess ethylene from exhaled air. Differences in the concentrations of exhaled ethylene are observed after using toothpaste and baking soda. The levels of ethylene are lower for nose breathing compared with mouth breathing. However, the differences are not significant proving that ethylene is generally endogenous but may still exist some contamination, depending of the oral hygiene of each person. These results may lead to a procedure, whereby subjects should be instructed to use toothpaste before each breath test sampling, to avoid the possibility of contamination of endogenous biomarkers. PMID- 30311087 TI - Multi-wavelength laser treatments of spider nevi. AB - Spider nevi (SN) are one of common vascular diseases. Different treatment techniques have been described for SN previously, including electrocoagulation, argon laser, pulsed dye lasers (PDL), pulsed potassium titanylphosphate laser (KTP), and 1064-nm neodymium yttrium-aluminum-garnet (Nd:YAG) laser. These methods are effective but may require good technical management, multiple treatments, and often result in scarring or pigmentation. Multi-wavelength laser combined with 595-nm PDL followed by 1064-nm Nd:YAG and can be selectively absorbed by hemoglobin in vessels. The 595-nm laser can target shallow vessels whereas the 1064-nm laser may target deeper vessels due to the different penetration capacities of these wavelengths. Moreover, Nd:YAG absorption is remarkable increased following by PDL treatment. Multi-wavelength laser treatments have been successfully used for vascular diseases but there is little experience in SN therapy. Consequently, these treatment parameters have not been established for SN, particularly in Asian patients with Fitzpatrick skin type (FST) IV. Report experience with using multi-wavelength laser for SN treatment in Asian patients with FST IV. Forty-three SN lesions received multi-wavelength laser treatments via a PDL followed by an Nd:YAG laser. The treatment was performed at 7 mm spot size at 9.5-11 J/cm2, 10 ms with PDL, followed by Nd:YAG at 40-50 J/cm2, 15 ms. The laser treatments were performed with a single pass without overlap. Complete resolution was observed in 40 lesions and an 80-90% improvement in the other three lesions after one treatment session. One patient had superficial scarring. Four patients had hyperpigmentation that resolved within 3 months. Multi-wavelength laser treatments are fast and effective interventions for SN treatment in Asian patients with minimal adverse effects when appropriate parameters are set. PMID- 30311089 TI - Charles Edgar Metz, Ph.D. (1942-2012): pioneer in receiver operating characteristic (ROC) analysis. PMID- 30311090 TI - Short- and Long-term Mortality Risk After Acute Pulmonary Embolism. AB - PURPOSE OF REVIEW: Acute pulmonary embolism is a major cause of morbidity and mortality in the USA and throughout the world. This review will summarize recent developments in short- and long-term mortality risk assessment after an acute pulmonary embolism. RECENT FINDINGS: Recent guidelines have emphasized risk stratification of acute PE patients on the basis of blood pressure, right ventricular size, and biomarker status. Ongoing work is testing various acute treatment strategies for improvement of symptom burden, length of stay, quality of life, and possibly mortality risk reduction. Long-term outcomes among subjects with acute PE are less well studied. Long-term mortality largely correlates with baseline co-morbidity burden, although there may be an association between acute PE severity and long-term outcomes. Acute PE risk stratification and treatment, as well as long-term follow-up of patients with acute PE, are rapidly developing areas and many promising innovations are underway. PMID- 30311092 TI - Delirium and modified-release prednisone in an elderly woman with rheumatoid arthritis. PMID- 30311091 TI - Transcriptional profile of a bioethanol production contaminant Candida tropicalis. AB - The fermentation process is widely used in the industry for bioethanol production. Even though it is widely used, microbial contamination is unpredictable and difficult to control. The problem of reduced productivity is directly linked to competition for nutrients during contamination. Yeasts representing the Candida species are frequently isolated contaminants. Elucidating the behavior of a contaminant during the fermentation cycle is essential for combatting the contamination. Consequently, the aim of the current study was to better understand the functional and transcriptional behavior of a contaminating yeast Candida tropicalis. We used a global RNA sequencing approach (RNA-seq/MiSeq) to analyze gene expression. Genes with significantly repressed or induced expression, and related to the fermentations process, such as sugar transport, pyruvate decarboxylase, amino acid metabolism, membrane, tolerance to high concentrations of ethanol and temperatures, nutrient suppression), and transcription-linked processes, were identified. The expression pattern suggested that the functional and transcriptional behavior of the contaminating yeast during fermentation for bioethanol production is similar to that of the standard yeast Saccharomyces cerevisiae. In addition, the analysis confirmed that C. tropicalis is an important contaminant of the alcoholic fermentation process, generating bioethanol and viability through its tolerance to all the adversities of a fermentation process essential for the production of bioethanol. According on the gene expression profile, many of these mechanisms are similar to those of S. cerevisiae strains currently used for bioethanol production. These mechanisms can inform studies on antimicrobials, to combat yeast contamination during industrial bioethanol production. PMID- 30311093 TI - The role of the Fracture Liaison Service (FLS) in subsequent fracture prevention in the extreme elderly. AB - BACKGROUND: Several guidelines recommend a bone and fall-related osteoporosis risk assessment in all patients with fracture and age > 50 years. In practice, however, there is no consensus whether screening > 85 years is useful. AIM: To evaluate the subsequent fracture risk in all patient > 85 years, comparing the two populations of Fracture Liaison Service (FLS) attenders and non-attenders. METHODS: All patients > 85 years that presented at the FLS with a non-vertebral fracture were included in the study during a 5-year period (September 2004 and December 2009). Excluded were pathologic fractures, death < 30 days, or patients on osteoporosis treatment. in patients that attended the FLS, assessment of bone mineral density and fall-risk factors were screened. In both the attenders and non-attenders groups, mortality and subsequent fracture rates were scored during a follow-up of 2 years. RESULTS: 282 patients fulfilled inclusion criteria for screening, of which 160 (57%) patients did not attend the FLS. 122 patients were screened for osteoporosis and fall-related risk of whom 72 were diagnosed with osteoporosis. Subsequent fracture risk in both groups was 19%. Medical treatment was started in 51 patients, of which 15 patients developed a subsequent fracture. Cox-regression analysis indicated a significantly lower mortality rate, but not a diminished subsequent fracture rate in the FLS screened population compared to the non-attenders. CONCLUSION: The advantage of a FLS in reducing subsequent fracture risk in patients > 85 years seems to be limited. In practice a large proportion of these patients are not screened. PMID- 30311095 TI - A new chemoinformatics approach with improved strategies for effective predictions of potential drugs. AB - BACKGROUND: Fast and accurate identification of potential drug candidates against therapeutic targets (i.e., drug-target interactions, DTIs) is a fundamental step in the early drug discovery process. However, experimental determination of DTIs is time-consuming and costly, especially for testing the associations between the entire chemical and genomic spaces. Therefore, computationally efficient algorithms with accurate predictions are required to achieve such a challenging task. In this work, we design a new chemoinformatics approach derived from neighbor-based collaborative filtering (NBCF) to infer potential drug candidates for targets of interest. One of the fundamental steps of NBCF in the application of DTI predictions is to accurately measure the similarity between drugs solely based on the DTI profiles of known knowledge. However, commonly used similarity calculation methods such as COSINE may be noise-prone due to the extremely sparse property of the DTI bipartite network, which decreases the model performance of NBCF. We herein propose three strategies to remedy such a dilemma, which include: (1) adopting a positive pointwise mutual information (PPMI)-based similarity metric, which is noise-immune to some extent; (2) performing low-rank approximation of the original prediction scores; (3) incorporating auxiliary (complementary) information to produce the final predictions. RESULTS: We test the proposed methods in three benchmark datasets and the results indicate that our strategies are helpful to improve the NBCF performance for DTI predictions. Comparing to the prior algorithm, our methods exhibit better results assessed by a recall-based evaluation metric. CONCLUSIONS: A new chemoinformatics approach with improved strategies was successfully developed to predict potential DTIs. Among them, the model based on the sparsity resistant PPMI similarity metric exhibits the best performance, which may be helpful to researchers for identifying potential drugs against therapeutic targets of interest, and can also be applied to related research such as identifying candidate disease genes. PMID- 30311094 TI - Neural Mechanisms Linking Emotion with Cardiovascular Disease. AB - PURPOSE OF REVIEW: The present review discusses brain circuits that are engaged by negative emotions and possibly linked to cardiovascular disease risk. It describes recent human brain imaging studies that relate activity in these brain circuits to emotional processes, peripheral physiology, preclinical pathophysiology, as well as clinical outcomes. RECENT FINDINGS: Negative emotions and the regulation of negative emotions reliably engage several brain regions that cross-sectional and longitudinal brain imaging studies have associated with CVD risk markers and outcomes. These brain regions include the amygdala, anterior cingulate cortex, medial prefrontal cortex, and insula. Other studies have applied advanced statistical techniques to characterize multivariate patterns of brain activity and brain connectivity that associate with negative emotion and CVD-relevant peripheral physiology. Brain imaging studies on emotion and cardiovascular disease risk are expanding our understanding of the brain-body bases of psychosocial and behavioral risk for cardiovascular disease. PMID- 30311096 TI - Antibiotics and Cure Rates in Childhood Febrile Urinary Tract Infections in Clinical Trials: A Systematic Review and Meta-analysis. AB - PURPOSE: Urinary tract infections (UTIs) are common bacterial infections among children. OBJECTIVE: To systematically review the antimicrobials used for febrile UTIs in paediatric clinical trials and meta-analyse the observed cure rates and reasons for treatment failure. MATERIALS AND METHODS: We searched Medline, Embase and Cochrane central databases between January 1, 1990, and November 24, 2016, combining MeSH and free-text terms for: "urinary tract infections", AND "therapeutics", AND "clinical trials" in children (age range 0-18 years). Two independent reviewers assessed study quality and performed data extraction. The major outcome measures were clinical and microbiological cure rates according to different antibiotics. RESULTS: We identified 2762 published studies and included 30 clinical trials investigating 3913 cases of paediatric febrile urinary tract infections. Children with no underlying condition were the main population included in the trials (n = 2602; 66.5%). Cephalosporins were the most frequent antibiotics studied in trials (22/30, 73.3%). Only a few antibiotics active against resistant UTIs have been tested in randomised clinical trials, mainly aminoglycosides. The average point cure rate of all investigational drugs was estimated to 95.3% (95% CI 93.5-96.9%). Among 3002 patients for whom cure and failure rates were reported, only 3.9% (3.9%; 118/3002) were considered clinically to have treatment failure, while 135 (4.5%; 135/3002) had microbiological failure. CONCLUSIONS: We observed high treatment cure rates, regardless of the investigational drug chosen, the route of administration, duration and dosing. This suggests that future research should prioritise observational studies and clinical trials on children with multi-drug-resistant infections. PMID- 30311097 TI - Psychosocial Stressors at Work and Ambulatory Blood Pressure. AB - PURPOSE OF REVIEW: Psychosocial stressors at work from the demand-latitude and effort-reward imbalance models are adverse exposures affecting about 20-25% of workers in industrialized countries. This review aims to summarize evidence on the effect of these stressors on blood pressure (BP). RECENT FINDINGS: Three systematic reviews have recently documented the effect of these psychosocial stressors at work on BP. Among exposed workers, statistically significant BP increases ranging from 1.5 to 11 mmHg have been observed in prospective studies using ambulatory BP (ABP). Recent studies using ABP have shown a deleterious effect of these psychosocial stressors at work on masked hypertension as well as on blood pressure control in pharmacologically treated patients. Evidence on the effect of these psychosocial stressors on BP supports the relevance to tackle these upstream factors for primary prevention and to reduce the burden of poor BP control. There is a need for increased public health and clinical awareness of the occupational etiology of high BP, hypertension, and poor BP control. PMID- 30311099 TI - Do not omit the grade of malignancy when correlating the lobar location of diffuse gliomas and the risk of preoperative epileptic seizures. PMID- 30311098 TI - The ATP-binding cassette (ABC) transporter OsABCG3 is essential for pollen development in rice. AB - BACKGROUND: The pollen wall, which protects male gametophyte against various stresses and facilitates pollination, is essential for successful reproduction in flowering plants. The pollen wall consists of gametophyte-derived intine and sporophyte-derived exine. From outside to inside of exine are tectum, bacula, nexine I and nexine II layers. How these structural layers are formed has been under extensive studies, but the molecular mechanisms remain obscure. RESULTS: Here we identified two osabcg3 allelic mutants and demonstrated that OsABCG3 was required for pollen development in rice. OsABCG3 encodes a half-size ABCG transporter localized on the plasma membrane. It was mainly expressed in anther when exine started to form. Loss-function of OsABCG3 caused abnormal degradation of the tapetum. The mutant pollen lacked the nexine II and intine layers, and shriveled without cytoplasm. The expression of some genes required for pollen wall formation was examined in osabcg3 mutants. The mutation did not alter the expression of the regulatory genes and lipid metabolism genes, but altered the expression of lipid transport genes. CONCLUSIONS: Base on the genetic and cytological analyses, OsABCG3 was proposed to transport the tapetum-produced materials essential for pollen wall formation. This study provided a new perspective to the genetic regulation of pollen wall development. PMID- 30311100 TI - Countrywide Survey for MERS-Coronavirus Antibodies in Dromedaries and Humans in Pakistan. AB - Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a zoonotic pathogen capable of causing severe respiratory disease in humans. Although dromedary camels are considered as a major reservoir host, the MERS-CoV infection dynamics in camels are not fully understood. Through surveillance in Pakistan, nasal (n = 776) and serum (n = 1050) samples were collected from camels between November 2015 and February 2018. Samples were collected from animal markets, free-roaming herds and abattoirs. An in-house ELISA was developed to detect IgG against MERS CoV. A total of 794 camels were found seropositive for MERS-CoV. Prevalence increased with the age and the highest seroprevalence was recorded in camels aged > 10 years (81.37%) followed by those aged 3.1-10 years (78.65%) and <= 3 years (58.19%). Higher prevalence was observed in female (78.13%) as compared to male (70.70%). Of the camel nasal swabs, 22 were found to be positive by RT-qPCR though with high Ct values. Moreover, 2,409 human serum samples were also collected from four provinces of Pakistan during 2016-2017. Among the sampled population, 840 humans were camel herders. Although we found a high rate of MERS CoV antibody positive dromedaries (75.62%) in Pakistan, no neutralizing antibodies were detected in humans with and without contact to camels. PMID- 30311101 TI - Phylogeography, Transmission, and Viral Proteins of Nipah Virus. AB - Nipah virus (NiV), a zoonotic paramyxovirus belonging to the genus Henipavirus, is classified as a Biosafety Level-4 pathogen based on its high pathogenicity in humans and the lack of available vaccines or therapeutics. Since its initial emergence in 1998 in Malaysia, this virus has become a great threat to domestic animals and humans. Sporadic outbreaks and person-to-person transmission over the past two decades have resulted in hundreds of human fatalities. Epidemiological surveys have shown that NiV is distributed in Asia, Africa, and the South Pacific Ocean, and is transmitted by its natural reservoir, Pteropid bats. Numerous efforts have been made to analyze viral protein function and structure to develop feasible strategies for drug design. Increasing surveillance and preventative measures for the viral infectious disease are urgently needed. PMID- 30311102 TI - The impact of geriatric nutritional risk index on surgical outcomes after esophagectomy in patients with esophageal cancer. AB - BACKGROUND: Geriatric Nutritional Index (GNRI) was shown to be closely associated with nutrition-related complications and mortality in elderly hospitalized patients. Impact of GNRI on postoperative outcomes in surgically treated esophageal squamous cell carcinoma (ESCC) patients has not been evaluated extensively. METHODS: A total of 240 patients with ESCC who underwent radical esophagectomy with two- or three-field lymphadenectomy between April 2000 and April 2012 were included in this retrospective study. GNRI formula was as follows: 1.489 * albumin (g/dl) + 41.7 * current weight/ideal weight. Patients were categorized as GNRI-low (GNRI < 92) or GNRI-high (GNRI >= 92) according to the receiver operating characteristics (ROC) curves generated for multiple logistic regression analysis using 5-year overall survival as the end point. The impact of GNRI status on short- and long-term outcomes of curative surgery for ESCC was examined. RESULTS: There were 44 (18.3%) and 196 (82.7%) patients in the GNRI-low and GNRI-high groups, respectively. Among the investigated demographic factors, the rate of nodal metastasis and pathological stage were significantly higher in the GNRI-low group than in the GNRI-high group (p < 0.01 and p < 0.01, respectively). Univariate analysis of postoperative complications revealed that the rate of lung complications was significantly higher in the GNRI-low group than in the GNRI-high group (p = 0.024), while GNRI was not an independent risk factor for the development of lung complications by multivariate analysis (Odds Ratio: 1.746; p = 0.126). 5-year overall survival (OS) was significantly lower in the GNRI-low group than in the GNRI-high group (p < 0.01). Moreover, GNRI was an independent prognostic factor for OS [Hazard ratio: 1.687; 95% confidence interval (CI): 1.038-2.742; p = 0.035], but not for cancer-specific survival. Analysis with stratification by tumor stage revealed that both OS and Cancer Specific Survival (CSS) were worse in patients with low GNRI than those with high GNRI only among those with stage III ESCC (34.4% vs. 52.1%, p = 0.049 and 36.1% vs. 57.2%, p = 0.041, respectively). In the stage III ESCC, primary tumor size tends to be greater in the GNRI-low group than in the GNRI-high group (5.69 vs. 4.75 cm, p = 0.085) and the incidence of preoperative dysphagia was significantly higher in the GNRI-low group than in the GNRI-high group (74% vs. 45.9%, p = 0.032). CONCLUSION: GNRI was closely associated with long-term survival after curative surgery in patients with stage III ESCC. Intensive follow-up after surgery should be performed for ESCC patients with low GNRI. PMID- 30311103 TI - Frequency and Correlates of Subjective Cognitive Impairment in HIV Disease. AB - The increasing prevalence of older adults living with HIV has raised growing concerns about a possible rise in the incidence of neurocognitive disorders due to HIV and other age-related factors. In typical aging, subjective cognitive impairment (SCI) among individuals with normal neurocognitive functioning may be an early manifestation of an incipient neurocognitive disorder. The current study examined the frequency and correlates of SCI in 188 HIV-infected adults without performance-based neurocognitive deficits or a current psychiatric disorder and 133 HIV seronegative comparison participants. All participants completed the Prospective and Retrospective Memory Questionnaire and Profile of Mood States Confusion/Bewilderment scale. Consistent with the diagnostic criteria proposed by Jessen et al. (Alzheimers Dement 10(6):844-852, 2014), participants were classified with SCI if their scores on either of the self-reported measures was greater than 1.5 SD above the normative mean. A logistic regression controlling for current mood complaints and lifetime history of substance use disorders revealed that HIV infection increased the odds of SCI (odds ratio= 4.5 [1.6, 15.4], p = 0.004). Among HIV+ individuals, SCI was associated with lower performance-based learning and delayed memory scores (Cohen's d range 0.41-0.42.) and poorer global everyday functioning (odds ratio= 8.5 [2.6, 15.9]), but not HIV disease severity (ps > 0.10). In a sample of individuals without neurocognitive impairment or elevated mood symptoms, HIV disease was associated with a nearly fivefold increased odds of SCI compared to seronegative individuals, which may indicate an increased risk for developing major neurocognitive disorders as these HIV+ individuals age. PMID- 30311104 TI - The Longitudinal Association between Social Support on HIV Medication Adherence and Healthcare Utilization in the Women's Interagency HIV Study. AB - Social support is associated with HIV-related health outcomes. However, few studies have explored this longitudinally. We assessed psychometric properties of the Medical Outcomes Study's Social Support Survey among women in the Women's Interagency HIV Study, and explored the longitudinal effects of social support on HIV medication adherence (HIV-positive women) and healthcare utilization (HIV positive and negative women). The 15 questions loaded into two factors, with Cronbach's Alpha > 0.95. Over 3 years, perceived emotional support was associated with optimal medication adherence (OR 1.19, 95% CI 1.10-1.28) and healthcare utilization (OR 1.16, 95% CI 1.05-1.27), and tangible social support with adherence only (OR 1.18, 95% CI 1.08-1.27) when controlling for covariates, including core sociodemographic characteristics and depressive symptoms. Interventions to further understand the drivers of sub-types of social support as well as enhance sustained social support may assist with optimizing care of women with and at risk for HIV. PMID- 30311105 TI - Alcohol Use and Sexual Risk Behavior in Young Women: A Qualitative Study. AB - Alcohol use and sexual behavior co-occur frequently in young women, increasing risk for HIV and other sexually transmitted infections. To inform preventive interventions, we used qualitative methods to better understand how women think about the contribution of alcohol use to sexual risk-taking. Young women (N = 25; M = 22.8 years; 64% White) were recruited from a community-based reproductive health clinic to attend focus groups; a semi-structured agenda was used to investigate both a priori explanatory mechanisms as well as participant-driven explanations for the alcohol-sex association. Women reported that alcohol reduced their social anxiety, helped them to feel outgoing and confident, and lowered inhibitions and other barriers to sexual encounters (consistent with alcohol expectancies). During drinking events, women described being less concerned with risks, less discriminating regarding sexual partners, and less likely to insist on safer sex practices (consistent with alcohol myopia). These empirical findings support previous theory-based guidance for tailoring preventive programs for alcohol use and sexual risk reduction for young women. PMID- 30311107 TI - Patient scheduling based on a service-time prediction model: a data-driven study for a radiotherapy center. AB - With the growth of the population, access to medical care is in high demand, and queues are becoming longer. The situation is more critical when it concerns serious diseases such as cancer. The primary problem is inefficient management of patients rather than a lack of resources. In this work, we collaborate with the Centre Integre de Cancerologie de Laval (CICL). We present a data-driven study based on a nonblock approach to patient appointment scheduling. We use data mining and regression methods to develop a prediction model for radiotherapy treatment duration. The best model is constructed by a classification and regression tree; its accuracy is 84%. Based on the predicted duration, we design new workday divisions, which are evaluated with various patient sequencing rules. The results show that with our approach, 40 additional patients are treated daily in the cancer center, and a considerable improvement is noticed in patient waiting times and technologist overtime. PMID- 30311106 TI - Comprehensive two-dimensional gas chromatography-mass spectrometry combined with multivariate data analysis for pattern recognition in Ecuadorian spirits. AB - The current methodology used in quality control of Ecuadorian beverages such as Pajaro azul, Puro and Pata de vaca is carried out by using conventional gas chromatography; however, it does not allow the fingerprinting of these Ecuadorian spirit beverages and their possible cases of adulteration. In order to overcome this drawback, comprehensive two-dimensional gas chromatography-mass spectrometry (GC * GC-MS) was combined with multivariate data analysis, revealing that compounds like citronellal, citronellol, geraniol, methyl anthranilate, (-)-trans alpha-bergamotene, (-)-cis-alpha-bergamotene and D-limonene can be considered key elements for pattern recognition of these traditional beverages and product adulteration cases. Thus, the two-dimensional chromatographic fingerprints obtained by GC * GC-MS coupled with chemometric analysis, using Principal Component Analysis and Fisher-ratio can be considered as a potential strategy for adulteration recognition, and it may used as a quality assurance system for Ecuadorian traditional spirits. PMID- 30311108 TI - C6orf106 accelerates pancreatic cancer cell invasion and proliferation via activating ERK signaling pathway. AB - C6orf106 was highly expressed in lung and breast cancer, and proposed as clinicopathologic factor for the development of those types of cancer. However, its expression in pancreatic cancer and the mechanism that C6orf106 functions as an oncogene has not been confirmed. In the present study, we found that C6orf106 was also up-regulated in pancreatic cancer tissues and cell lines. Furthermore, C6orf106 expression was associated with advanced T stage (P = 0.010), positive regional lymph node metastasis (P = 0.012), and advanced TNM stage (P = 0.006). In vitro experiments also showed that C6orf106 served a tumor enhancer in pancreatic cancer, through increasing the expression of Snail, Cyclin D1 and Cyclin E1, and reducing the expression of E-cadherin via activating extracellular signal-regulated kinase (ERK)- p90-kDa ribosomal S6 kinases (P90RSK) signaling pathway. The addition of ERK inhibitor PD98059 counteracted the upregulation of Snail, Cyclin D1 and Cyclin E1, and restored the expression of E-cadherin, which indicated that C6orf106 was an upstream factor of ERK signaling pathway. Taken together, the present study indicates that C6orf106 facilitates invasion and proliferation of pancreatic cancer cells, likely via activating ERK-P90RSK signaling pathway. PMID- 30311109 TI - The impact of aerobic and anaerobic training regimes on blood pressure in normotensive and hypertensive rats: focus on redox changes. AB - This study was aimed to assess the impact of aerobic and anaerobic type of exercise on blood pressure and redox status in normotensive and hypertensive rats. After 1 week of preconditioning feeding and 1 week of preconditioning running regimen, Wistar albino rats (n = 72; bw: 270 +/- 50 g) were randomly assigned to three groups according to running protocol (high-intensity interval training (HIIT) or moderate-intensity training (MIT)): sedentary control, MIT, HIIT; spontaneous hypertensive sedentary control (SHR), SHR + MIT and SHR + HIIT. Blood pressure (BP) measurement was performed by a tail-cuff noninvasive method BP system. After 48 h of rest following the final training, the rats were fasted for 24 h and sacrificed under ketamine/xylazine anesthesia and blood samples were collected. The level of the next prooxidants were measured: superoxide anion radical (O2-); hydrogen peroxide (H2O2); nitrite level (NO2-) and index of lipid peroxidation (thiobarbituric acid reactive substances), and the activity of antioxidative enzymes: reduced glutathione (GSH) superoxide dismutase (SOD) and catalase (CAT) activity. After the last week of running, HIIT strongly affected SP, DP, and HR in SHR rats compared to other hypertensive rats, as well as after MIT in normotensive conditions. We have found that HIIT training protocol induced a higher increase of O2- and H2O2 as compared to MIT. Findings of the present study pointed out that contrary to normotensive conditions, in hypertensive conditions both training regimes reduced the BP levels, which was more prominent in case of HIIT. In addition, MIT seems to be connected with milder disturbance of pro-oxidant production and better antioxidant response. PMID- 30311110 TI - Correction to: Differences in cancer survival by sex: a population-based study using cancer registry data. AB - In the original publication of the article, the concluding paragraph of the Discussion section was inadvertently missed and is provided below. PMID- 30311111 TI - The relationship of weight suppression to treatment outcomes during behavioral weight loss. AB - Many adults enter behavioral weight loss (BWL) programs at a weight below their highest lifetime weight. The discrepancy between highest lifetime weight and current weight is known as weight suppression (WS). Research has yet to characterize WS during BWL or investigate its relation to weight loss outcomes or treatment acceptability. Adults (N = 272) in a 12-month BWL program were assessed. WS was calculated by subtracting measured baseline weight from self reported highest lifetime weight. Participants with higher WS lost significantly less weight than those with lower WS during treatment, although they still had clinically meaningful weight losses (e.g., participants with WS above the median: 7.8 kg; participants with WS below the median: 12.0 kg). WS was unrelated to weight losses at 24-month follow-up. Controlling for weight loss, treatment acceptability was unrelated to WS. BWL appears appropriate for those with high WS, but future research should aim to improve outcomes in this group. PMID- 30311112 TI - Platelet-rich plasma as a potential therapeutic approach against lead nitrate- and/or gamma radiation-induced hepatotoxicity. AB - Because of the potential regenerative and cytoprotective effects of its content of numerous bioactive growth factors and cytokines, platelet-rich plasma (PRP) became an attractive biomaterial for therapeutic purposes. Therefore, the current study was designed to investigate the potential therapeutic effect of PRP against lead nitrate- and/or gamma-radiation-induced hepatotoxicity. To do so, hepatotoxicity was induced in rats by intraperitoneal administration of lead nitrate (7.5 mg/kg) thrice weekly for two consecutive weeks and/or a whole-body gamma-irradiation at a single dose of 6 Gy. Activated PRP (0.5 ml/kg) was injected subcutaneously 24 h after the last dose of lead nitrate and/or gamma irradiation and continued twice weekly for three successive weeks. Lead nitrate intoxication and/or gamma-irradiation resulted in a significant elevation of serum alanine transaminase and aspartate transaminase activities accompanied with a significant decrease in serum levels of total protein and albumin. Further, a significant increase in malondialdehyde level and nitric oxide content accompanied with a significant decrease in the reduced glutathione content and the enzyme activities of glutathione-S-transferase, superoxide dismutase, and catalase were observed. Additionally, hepatic extracellular signal-regulated kinase (ERK) and Akt signaling pathways were stimulated. PRP treatment notably ameliorated the induced cell injury, reduced the intracellular oxidative and interestingly increased the upregulation of phosphorylated ERK1/2 and Akt. Moreover, PRP treatment relieved lead nitrate and/or gamma-radiation-induced hepatic histological damages. In conclusion, this study sheds the light on a probable therapeutic role of PRP against lead nitrate- and/or gamma-radiation induced hepatotoxicity which might attribute to its ability to activate ERK and Akt signaling pathways. PMID- 30311113 TI - Comparative effects of arsenite (As(III)) and arsenate (As(V)) on whole plants and cell lines of the arsenic-resistant halophyte plant species Atriplex atacamensis. AB - Whole plants and hypocotyl-derived calli of the halophyte plant species Atriplex atacamensis were exposed to 50 MUM arsenate (As(V)) or 50 MUM arsenite (As(III)). At the whole plant level, As(III) was more toxic than As(V): it reduced plant growth, stomatal conductance, photosystem II efficiency while As(V) did not. In roots, As accumulated to higher level in response to As(III) than in response to As(V). Within root tissues, both arsenate and arsenite were identified in response to each treatment suggesting that oxidation of As(III) may occur. More than 40% of As was bound to the cell wall in the roots of As(V)-treated plants while this proportion strongly decreased in As(III)-treated ones. In leaves, total As and the proportion of As bound to the cell wall were similar in response to As(V) and As(III). Non-protein thiol increased to higher extent in response to As(V) than in response to As(III) while ethylene synthesis was increased in As(III)-treated plants only. Polyamine profile was modified in a contrasting way in response to As(V) and As(III). At the callus level, As(V) and As(III) 50 MUM did not reduce growth despite an important As accumulation within tissues. Calli exposed to 50 MUM As did not increase the endogenous non-protein thiol. In contrast to the whole plants, arsenite was not more toxic than arsenate at the cell line level and As(V)-treated calli produced higher amounts of ethylene and malondialdehyde. A very high dose of As(V) (1000 MUM) strongly reduced callus growth and lead to non-protein thiols accumulation. It is concluded that As(III) was more toxic than As(V) at the plant level but not at the cellular level and that differential toxicity was not fully explained by speciation of accumulated As. Arsenic resistance in A. atacamensis exhibited a cellular component which however did not reflect the behavior of whole plant when exposed to As(V) or As(III). PMID- 30311114 TI - Response to the letter sent by Dr. Viroj Wiwanitkit entitled "Coffee waste, vector control and dengue". PMID- 30311115 TI - Evaluation of corrosion control products on a distribution system through crowdsourcing. AB - Crowdsourcing of citizens was used to determine the effectiveness of corrosion control in a water distribution system. This study examines the frequency and severity of "Red Water" complaints over a period of 4 years, and two different corrosion control chemicals, polyphosphate and zinc orthophosphate. The data revealed that the frequency of Red Water complaints was higher when using zinc orthophosphate while the severity (higher iron) was higher when using polyphosphates. Varying the dose of zinc orthophosphate to account for cold months induced a greater number of customer complaints. Moreover, corrosion coupons studies suggest similar performance of both corrosion inhibitor products. The corrosion and complaints might be driven by microbial-induced processes in which diatoms might play a significant role. PMID- 30311116 TI - Spatial variability and seasonal toxicity of dredged sediments from Guanabara Bay (Rio de Janeiro, Brazil): acute effects on earthworms. AB - The toxicity of dredged sediments from Guanabara Bay (Rio de Janeiro, Brazil) was evaluated using acute bioassays with Eisenia andrei and metal determination. The sediments were collected in August 2014 (winter) and February 2015 (summer) and in five areas distributed along the Bay: Port of Rio de Janeiro, Port of Niteroi, Meriti River mouth, Iguacu River mouth, and the Environmental Protection Area (APA) of Guapimirim. The sediments were mixed with a ferralsol (a representative Brazilian tropical soil) in proportions varying between 0 (pure soil) and 30%. The acute bioassays with E. andrei followed a standard protocol (ISO 11268 2:2012). Total metal determination in the sediments was performed by ICP-OES. The medium lethal earthworm concentration (LC50) was estimated through PriProbit analysis. The sediments from the APA of Guapimirim, which is a control area at the Guanabara Bay, were the only ones whose total metal concentrations were in agreement with the limits established by Brazilian law for land disposal of dredged sediments. However, the sediments collected in the APA of Guapimirim were the most toxic ones among the study areas due to very high contents of salts in these materials. Winter sediments were generally more toxic compared to the summer ones due to the increase of metal concentrations and salt precipitation to bottom sediments during the winter. The exceptions were (i) the sediments from APA of Guapimirim, where the toxicity in the summer (LC50 = 3.99%) and winter (LC50 = 4.60%) were relatively similar to each other, since the toxicity is linked to salt in excess; and (ii) the Iguacu River mouth, where the presence of mangrove areas might be associated with the filtering of pollution sources (winter LC50 = 12.67%; summer LC50 = 11.58%). In the Port of Rio de Janeiro, LC50 obtained in the winter (7.30%) was almost three times lower than that found in the summer (19.64%). The sediments from Meriti River mouth showed the highest total metal concentrations, were the most toxic sediments among the study areas (excluding the APA of Guapimirim), and its winter LC50 (6.64%) was almost twice lower than that obtained in the summer (12.55%). By following the same tendency, summer LC50 (17.52%) found for the sediment collected in the Port of Niteroi was also higher than the value found in the winter (12.34%). Finally, the dredged sediments from Guanabara Bay were toxic to earthworms in mixtures with pure ferralsol and winter samples were generally more toxic than the summer ones, in agreement with the increase of metal and salt concentrations during the winter. PMID- 30311117 TI - Organochlorine pesticide residues in sediment and water from Nairobi River, Kenya: levels, distribution, and ecological risk assessment. AB - Production and use of most organochlorine pesticides (OCPs) was banned through the Stockholm Convention on persistent organic pollutants. However, appreciable amounts are still detected in the environment due to their persistence, illegal use, and releases from contaminated soils and obsolete stocks. The present study investigated the levels of OCP residues in Nairobi River. Sediment and water samples were collected from three sites along the river and screened for 17 OCPs using gas chromatography electron capture detector (GC-ECD). Mean pesticide residues ranged from 0.01 to 41.9 MUg kg-1 in sediment and below detection limit to 39.7 ng L-1 in water. In sediment alpha-HCH, beta-HCH, gamma-HCH, heptachlor epoxide, and p,p'-DDD were detected in all samples, while alpha-HCH, gamma-HCH, delta-HCH, heptachlor epoxide, endosulfan I, and endrin were detected in all water samples. Levels of OCPs in water were below the WHO maximum allowable limits for surface water. However, values higher than the sediment quality guidelines for sediment samples in Racecourse Road Bridge and Outering Road Bridge were reported, thus confirming the toxicity to aquatic organisms. Consequently, as these compounds are known to bio-accumulate in fatty tissues, continued use of the river water poses a health risk to animals and humans. PMID- 30311118 TI - Transport of polycyclic aromatic hydrocarbons in a highly vulnerable karst underground river system of southwest China. AB - The concentration and fluxes of polycyclic aromatic hydrocarbons (PAHs) were investigated in a karst underground river system in southwest China. Groundwater, particles, and sediments from underground river, topsoil, and surface water were monitored, allowing establishment of a conceptual model of PAH transport at the watershed scale. The results showed that PAHs could be transported from the surface to the subsurface through two migration pathways, which were slow-flowing water in the karst fissure and fast-flowing water in conduits. During rainfall events, increasing PAH levels (concentrations and fluxes) at the underground river exit indicated that hydrodynamic force could facilitate PAH transport. The PAHs in water were dominated by dissolved PAHs, accounting for 58.7% of total, especially in the freely dissolved phase, in which SPM-associated PAHs accounted for 41.3% of the total PAHs. Low molecular weight PAHs dominated transport and were mainly transported in dissolved form, whereas high molecular weight PAHs were dominated by SPM-associated transport during the rainfall events. A significantly positive correlation was observed between two-ring and three-ring freely dissolved PAHs and dissolved organic carbon (p < 0.01), respectively. Moreover, PAHs with four to five rings were relatively more abundant in the dissolved organic matter (DOM) associated phase than in the freely dissolved phase, suggesting a major role of DOM in their transport during rainfall events. The trend of PAH fluxes suggested that particle-facilitated transport was another dominant cause of PAH mobilization. PMID- 30311119 TI - Decolorization and reusing of PET depolymerization waste liquid by electrochemical method with magnetic nanoelectrodes. AB - This work is aimed at electrochemical decolorization of real waste liquid which obtained in the PET depolymerization process. Firstly, PET fabrics were glycolysized by utilizing excess ethylene glycol (EG). Then, the glycolysis product was mixed with water and purified through repeated crystallization to get bis(2-hydroxyethyl) terephthalate (BHET) crystal. At last, the waste liquid of the depolymerization process was electrochemical decolorized by utilizing chitosan/Fe3O4 nanoparticles as the dispersed electrodes under a DC voltage. The UV-Vis absorptions at 338, 531, and 635 nm which were due to the dyes in the waste liquid decreased with the electrolysis time. In contrast, slight change of absorption of EG (at 322 nm) indicated that EG was not destroyed in the electrolytic process. The variation of color removal efficiency with dosage of chitosan/Fe3O4 nanoparticles, applied voltage, concentration of electrolyte, pH and electrolytic time were investigated. The max color removal efficiency was 87.24%. PET fabrics were depolymerized by using the decolorized waste liquid or mixture of decolorized waste liquid and EG (1:1 v/v), and the yields of BHET were 72.3% and 76.6%, respectively. The products were BHET without dyes which were confirmed by DSC and FTIR spectroscopy. Graphical abstract. PMID- 30311120 TI - Advanced oxidation processes for water/wastewater treatment. PMID- 30311121 TI - Comparison of hypocrellin B-mediated sonodynamic responsiveness between sensitive and multidrug-resistant human gastric cancer cell lines. AB - OBJECTIVES: The aim of this study was to compare the different responses to hypocrellin B (HB)-mediated sonodynamic treatment between human gastric adenocarcinoma cell line SGC7901 and SGC7901/ADR. METHODS: Tumor cells in culture dishes (35-mm diameter) were exposed to planar ultrasound at an intensity of 0.5 W/cm2 for 60 s combined with/without 2.5 MUM HB. Cell viability was determined by MTT and Guava ViaCount assay. Production of reactive oxygen species (ROS) and destabilization of the mitochondrial membrane potential were assessed by flow cytometry. Apoptosis was analyzed using annexin-PE/7-amino-actinomycin D staining. The cell membrane integrity was estimated by isothiocyanate-dextran (FD500) uptake assay. Ultrastructural alterations on the membrane surface were observed by scanning electron microscopy. The membrane fluidity was also compared between the two cell lines using spectrophotometry. RESULTS: Compared with SGC7901 cells, HB-mediated sonodynamic therapy (HB-SDT) showed higher cytotoxic in SGC7901/ADR cells at the same treatment doses. Abundant intracellular ROS, a decrease in the mitochondrial membrane potential, and an increased rate of apoptosis were detected in the SDT group of both cell lines, wherein SGC7901/ADR cells showed a much more higher rate. Cell membrane permeability was remarkably enhanced after HB-SDT application. In addition, relatively severe cell damage was observed under scanning electron microscopy after HB-SDT treatment in SGC7901/ADR cells compared with SGC7901 cells. CONCLUSIONS: These results suggest that HB-SDT could induce apoptosis in SGC7901 and SGC7901/ADR cells via production of ROS. SGC7901/ADR was found to be more sensitive to HB-SDT than SGC7901 cells under the same experimental condition. Meanwhile, a noteworthy difference in cell membrane injury between SGC7901 and SGC7901/ADR cells was detected. The decreased membrane fluidity in SGC7901/ADR cells may be one of the reasons for its increased membrane damage. PMID- 30311122 TI - Joint X-ray/NMR structure refinement of multidomain/multisubunit systems. AB - Data integration in structural biology has become a paradigm for the characterization of biomolecular systems, and it is now accepted that combining different techniques can fill the gaps in each other's blind spots. In this frame, one of the combinations, which we have implemented in REFMAC-NMR, is residual dipolar couplings from NMR together with experimental data from X-ray diffraction. The first are exquisitely sensitive to the local details but does not give any information about overall shape, whereas the latter encodes more the information about the overall shape but at the same time tends to miss the local details even at the highest resolutions. Once crystals are obtained, it is often rather easy to obtain a complete X-ray dataset, however it is time-consuming to obtain an exhaustive NMR dataset. Here, we discuss the effect of including a priori knowledge on the properties of the system to reduce the number of experimental data needed to obtain a more complete picture. We thus introduce a set of new features of REFMAC-NMR that allow for improved handling of RDC data for multidomain proteins and multisubunit biomolecular complexes, and encompasses the use of pseudo-contact shifts as an additional source of NMR-based information. The new feature may either help in improving the refinement, or assist in spotting differences between the crystal and the solution data. We show three different examples where NMR and X-ray data can be reconciled to a unique structural model without invoking mobility. PMID- 30311123 TI - Vitex negundo and its medicinal value. AB - Natural products are rich in several potent bioactive compounds, targeting complex network of proteins involved in various diseases. Vitex negundo (VN), commonly known as "chaste tree", is an ethnobotanically important plant with enormous medicinal properties. Different species of Vitex vary in chemical composition, thus producing different phytochemicals. Several bioactive compounds have been extracted from leaves, seeds, roots in form of volatile oils, flavonoids, lignans, iridoids, terpenes, and steroids. These bioactive compounds exhibit anti-inflammatory, antioxidant, antidiabetic, anticancer, antimicrobial. VN is typically known for its role in the modulation of cellular events like apoptosis, cell cycle, motility of sperms, polycystic ovary disease, and menstrual cycle. VN, reportedly, perturbs many cancer-signaling pathways involving p-p38, p-ERK1/2, and p-JNK in LPS-elicited cells, N-terminal kinase (JNK), COX-1 pathways, MAPK, NF-kappaB, tumor necrosis factor alpha (TNF-alpha), Akt, mTOR, vascular endothelial growth factor, hypoxia-inducible factor (HIF 1alpha). Several bioactive compounds obtained from VN have been commercialized and others are under investigation. This is the first review presenting up-to date information about the VN, its bioactive constituents and their mode of action. PMID- 30311124 TI - Bioguided isolation, characterization and media optimization for production of Lysolipins by actinomycete as antimicrobial compound against Xanthomonas citri subsp. citri. AB - Citrus Canker disease is one of the most important disease in citrus production worldwide caused by gram-negative bacterial pathogen Xanthomonas citri subsp. citri, leading to great economic losses. Currently, a spray of copper-based bactericides is the primary measure for citrus canker management. However, these measures can lead to the contamination of soil by metal contamination, but also the development of copper-resistant Xanthomonas populations. Considering the need to discovery new alternatives to control the citrus canker disease, actinomycetes isolated from the Brazilian Caatinga biome and their crude extracts were tested against different strains of Xanthomonas citri subsp. citri. Streptomyces sp. Caat 1-54 crude extract showed the highest antibiotic activity against Xcc. The crude extract dereplication was performed by LC-MS/MS. Through bioassay-guided fractionation strategy, the antimicrobial activity was assigned to Lysolipins, showing a MIC around 0.4-0.8 ug/mL. Growth media optimization using statistical experimental design increased the Lysolipins production in three-fold production. The preventive and curative effects of the optimized crude extract obtained by experimental design of Caat-1-54 against citrus canker were evaluated in potted 'Pera' sweet orange nursery trees. Caat 1-54 extract was effective in preventing new infections by Xcc on leaves but was not able to reduce Xcc population in pre established citrus canker lesions. Streptomyces sp. Caat 1-54 extract is a promising, environmentally-friendly source of antimicrobial compound to protect citrus trees against citrus canker. PMID- 30311125 TI - Novel combination of tanshinone I and lenalidomide induces chemo-sensitivity in myeloma cells by modulating telomerase activity and expression of shelterin complex and its associated molecules. AB - Shelterin complex and its associated molecules are imperative for proper functioning and maintenance of human telomeres. These molecules in association with human telomerase have been found altered in most cancers including multiple myeloma thereby proposed them as suitable therapeutic targets. Further, due to aggressive and recurring behavior of myeloma novel, efficacious and safe therapeutic agents for disease prevention are primary requirements for treatment of this disease. This maiden attempt evaluated the anti-proliferative properties of tanshinone I (TanI) alone or in combination with lenalidomide (Len) on myeloma cancer cell lines (RPMI8226 and U226). Further, after drug treatment levels of telomerase activity (TA) and molecular expression (mRNA & protein) of shelterin complex and its associated molecules have also been investigated. Results demonstrated that, TanI significantly inhibited proliferation of myeloma cells in dose and time dependent manner as observed through cytotoxicity assay. Additionally, induction of apoptosis by TanI and in combination with Len was observed in myeloma cells through propidium iodide (PI) staining, annexin V FITC/PI staining, TUNEL and caspase-3/7 activity assays. Further, drug treatment significantly decreased (p < 0.01) TA and molecular expression of ACD, TERF2IP and TANK1 in comparison to vehicle control (0.1% DMSO) myeloma cells. Thus, this maiden in-vitro study provided initial evidences of therapeutic potential of TanI alone or in combination with chemotherapeutic agent Len as novel anticancer agents in myeloma cells which need further evaluation in future. Lastly, down regulation of TA and decreased expression of these molecules underscores their potential as plausible therapeutic targets. PMID- 30311126 TI - Antimycobacterial activity of an anthracycline produced by an endophyte isolated from Amphipterygium adstringens. AB - The search for new compounds effective against Mycobacterium tuberculosis is still a priority in medicine. The evaluation of microorganisms isolated from non conventional locations offers an alternative to look for new compounds with antimicrobial activity. Endophytes have been successfully explored as source of bioactive compounds. In the present work we studied the nature and antimycobacterial activity of a compound produced by Streptomyces scabrisporus, an endophyte isolated from the medicinal plant Amphipterygium adstringens. The active compound was detected as the main secondary metabolite present in organic extracts of the streptomycete and identified by NMR spectroscopic data as steffimycin B (StefB). This anthracycline displayed a good activity against M. tuberculosis H37Rv ATCC 27294 strain, with MIC100 and SI values of 7.8 ug/mL and 6.42, respectively. When tested against the rifampin mono resistant M. tuberculosis Mtb-209 pathogen strain, a better activity was observed (MIC100 of 3.9 ug/mL), suggesting a different action mechanism of StefB from that of rifampin. Our results supported the endophyte Streptomyces scabrisporus as a good source of StefB for tuberculosis treatment, as this anthracycline displayed a strong bactericidal effect against M. tuberculosis, one of the oldest and more dangerous human pathogens causing human mortality. PMID- 30311127 TI - Evaluation of growth and gene expression of Mycoplasma hyopneumoniae and Mycoplasma hyorhinis in defined medium. AB - Mycoplasmas belong to the Mollicutes class and possess low GC content and lack a cell wall, and also simplified metabolic pathways. Due to its reduced metabolic ability mycoplasmas are fastidious organisms growing with difficult under laboratory conditions. Its complex nutritional requirements render mycoplasmas to depend on external supplies of biosynthetic precursors. Aiming to develop and test defined media that could be used as a tool for Mycoplasma research, Mycoplasma hyopneumoniae and Mycoplasma hyorhinis were cultivated in a complex medium supplemented with serum (Friis broth) and in four different defined media (YUS, YUSm, CMRL and CMRL+, that was developed in the present study). The cell concentration of both Mycoplasma species was assessed, by flow cytometry. Cellular viability was also analyzed in all defined media, indicating the presence of viable mycoplasma cells. All the defined media tested were able to maintain cell concentrations and viability and, amongst them, CMRL+ was the most suitable. For both Mycoplasma species, only the CMRL+ media showed similar cell density when compared to the complex medium. The transcriptional response of M. hyopneumoniae in CMRL+ broth was assessed by RT-qPCR, and the transcriptional profile of 18 genes in three cultures conditions (standard, heat shock and oxidative stress) was analyzed demonstrating gene expression regulation in response to the medium composition and to the culture conditions tested. The medium developed enables the definition of mycoplasmal nutritional requirements and metabolic pathways as well as genetic analysis. PMID- 30311128 TI - Cell line cytotoxicity, antiadipogenic and glucose uptake activity of Sarcostemma brevistigma Wight. & Arn. AB - Nature has gifted us with abundant plants possessing medicinal virtues which can cure several illnesses. Currently, diabetes mellitus is a severe threat to human well-being across the world due to the rapidly increasing incidence of diabetes. New effective bioactive drugs are in need, as plants do harbour and are proven to have potential antidiabetic activity than the present hypoglycemic medicines used in clinical therapy. In this study, in vitro cytotoxicity, glucose uptake, and anti-adipogenic activities of the plant extract (methanolic extract) of S. brevistigma were examined using 3T3L1 cell lines. The studies interpreted by MTT cytotoxicity assay and glucose uptake assay by using 3T3-L1 cell lines, it was found that a very low dosage (1 ng/mL) of plant extract showed lesser cytotoxicity effect (1.42%) and considerably higher glucose uptake activity of 38.04% which is equivalent to the glucose uptake shown by 100 nm insulin (40.10%). Though plant extract has antidiabetic activity, it is important to study whether it has any other related side effects when used at higher concentrations. Therefore, in this study, the appropriate non-toxic concentration was optimized. PMID- 30311129 TI - Monoclonal antibodies in cancer immunotherapy. AB - Nowadays, in cancer treatments, immunotherapy which can be classified as a cancer type specific therapy is more popular than non-specific therapy methods such as surgery, radiotherapy and chemotherapy. The main aim of immunotherapy is to enable patients' immune system to target cancer cells and destroy them. The mainly used treatment methods in cancer immunotherapy are cancer vaccines, adoptive cell therapy, cytokines and monoclonal antibodies. In this review, we discuss the immunotherapy approaches, especially monoclonal antibodies which are mostly used in cancer immunotherapy in clinical applications. PMID- 30311130 TI - iPhosY-PseAAC: identify phosphotyrosine sites by incorporating sequence statistical moments into PseAAC. AB - Protein phosphorylation is one of the most fundamental types of post translational modifications and it plays a vital role in various cellular processes of eukaryotes. Among three types of phosphorylation i.e. serine, threonine and tyrosine phosphorylation, tyrosine phosphorylation is one of the most frequent and it is important for mediation of signal transduction in eukaryotic cells. Site-directed mutagenesis and mass spectrometry help in the experimental determination of cellular signalling networks, however, these techniques are costly, time taking and labour associated. Thus, efficient and accurate prediction of these sites through computational approaches can be beneficial to reduce cost and time. Here, we present a more accurate and efficient sequence-based computational method for prediction of phosphotyrosine (PhosY) sites by incorporation of statistical moments into PseAAC. The study is carried out based on Chou's 5-step rule, and various position-composition relative features are used to train a neural network for the prediction purpose. Validation of results through Jackknife testing is performed to validate the results of the proposed prediction method. Overall accuracy validated through Jackknife testing was calculated 93.9%. These results suggest that the proposed prediction model can play a fundamental role in the prediction of PhosY sites in an accurate and efficient way. PMID- 30311131 TI - Antioxidant responses of Triticum aestivum plants to petroleum-derived substances. AB - Winter common wheat (Triticum aestivum L.) plants were cultivated on petroleum products contaminated soils with and without using biopreparation ZB-01. We determined the impact of soil contamination with petrol, diesel fuel and engine oil on selected antioxidant enzymes and the levels of antioxidants in the leaves of winter wheat. The impact of petroleum products on selected morphological characteristics of the plants, levels of nutrients and heavy metals was also assessed. Winter wheat was relatively resistant to soil contamination with petroleum products, and did not show a significant impact on the morphological characteristics of the plants. The levels of nutrients and heavy metals in the plants depended on the type of pollutant and the analyzed component.? Biopreparation ZB-01 generally resulted in an increase in calcium levels in the plants.? The winter wheat plants growing in soil contaminated with engine oil were characterized by higher levels of zinc, lead, manganese and cadmium than the control plants.? Biopreparation applied to the soil contaminated with petrol resulted in a slight increase in the levels of lead and zinc in the plants.? The petroleum products affected the activity of antioxidant enzymes and the levels of antioxidants in the plants.? The general markers of soil contaminated with diesel fuel and petrol were POD activity and proline levels. Use of the ZB-01 biopreparation caused an increase in the levels of proline and -SH groups and an increase in the levels of carbon and calcium in the plants and had no effect on the morphological characteristics of plants.?. PMID- 30311133 TI - Structure-function of the cytochrome b6f lipoprotein complex: a scientific odyssey and personal perspective. AB - Structure-function studies of the cytochrome b6f complex, the central hetero oligomeric membrane protein complex in the electron transport chain of oxygenic photosynthesis, which formed the basis for a high-resolution (2.5 A) crystallographic solution of the complex, are described. Structure-function differences between the structure of subunits of the bc complexes, b6f, and bc1 from mitochondria and photosynthetic bacteria, which are often assumed to function identically, are discussed. Major differences which suggest that quinone dependent electron transport pathways can vary in b6f and bc1 complexes are as follows: (a) an additional c-type heme, cn, and bound single copies of chlorophyll a and beta-carotene in the b6f complex; and (b) a cyclic electron transport pathway that encompasses the b6f and PSI reaction center complexes. The importance of including lipid in crystallization of the cytochrome complex, or with any hetero-oligomeric membrane protein complex, is emphasized, and consequences to structure-function of b6f being a lipoprotein complex discussed, including intra-protein dielectric heterogeneity and resultant pathways of trans membrane electron transport. The role of the b6f complex in trans-membrane signal transduction from reductant generated on the p-side of the electron transport chain to the regulation of light energy to the two photosystems by trans-side phosphorylation of the light-harvesting chlorophyll protein is presented. Regarding structure aspects relevant to plastoquinol-quinone entrance-egress: (i) modification of the p-side channel for plastoquinone access to the iron-sulfur protein would change the rate-limiting step in electron transport; (ii) the narrow niche for entry of plastoquinol into b6f from the PSII reaction center complex would seem to require close proximity between the complexes. PMID- 30311132 TI - Evaluation of the toxicity of leaches from hydrothermal sulfide deposits by means of a delayed fluorescence-based bioassay with the marine cyanobacterium Cyanobium sp. NIES-981. AB - The commercial use of metals such as copper, lead, and zinc has markedly increased in recent years, resulting in increased interest in deep-sea mining of seafloor hydrothermal sulfide deposits. However, the full extent of the impact of deep-sea mining at hydrothermal field deposits on the environment remains unclear. In addition to impacting the deep sea, the leaching of heavy metals from extracted sulfide mineral may also affect the upper ocean zones as the sulfide rock is retrieved from the seafloor. Here, we used a delayed fluorescence-based bioassay using the marine cyanobacterium Cyanobium sp. NIES-981 to evaluate the toxicity of three sulfide core samples obtained from three drill holes at the Izena Hole, middle Okinawa Trough, East China Sea. Leaches from two of the cores contained high concentrations of zinc and lead, and they markedly inhibited delayed fluorescence in Cyanobium sp. NIES-981 compared with control. By examining the toxicity of artificial mixed-metal solutions with metal compositions similar to those of the leaches, we confirmed that this inhibition was a result of high zinc and lead concentrations into the leaches. In addition, we conclude that this delayed fluorescence-based bioassay is a viable method for use by deep-sea mining operations because it is quicker and requires less laboratory space and equipment than the standard assay. PMID- 30311134 TI - Determination of optimum carcass weight for meat quality and fatty acid composition in fat-tailed male and female Chall lambs. AB - The aim of this study was to determine the optimum carcass weight for meat quality and fatty acid composition in fat-tailed Chall lambs. Thirty lambs (15 male and 15 female) were allotted to three carcass weight groups: (1) light carcass weight (LCW 10-15 kg), (2) moderate carcass weight (MCW 15-20 kg), and (3) heavy carcass weight (HCW 20-25 kg). Back fat thickness and intramuscular fat (IMF) content were greater (P < 0.05) for HCW and female groups than their counterparts, respectively. Drip loss was lower (P < 0.05) for female and HCW lamb groups than male and LCW group, respectively. Female and LCW lambs had lower (P < 0.05) shear force compared with their corresponding male and HCW groups. Meat from LCW and MCW lambs had higher lightness (L* value; 43.6, 43.5 vs. 39.9), while redness (a* value; 13.6, 13.9 vs. 15.4) was greater for HCW and female (13.7 vs. 14.9) lambs compared with their counterparts (P < 0.05). The MCW lambs produced meat with higher overall acceptability compared with other two groups (P < 0.05). The HCW lambs contained lower polyunsaturated fatty acids (PUFA), polyunsaturated fatty acids to saturated fatty acids (P:S) ratio, and n-3 PUFA compared with LCW group (P < 0.05). Results show that as the animal grow faster and achieved HCW, the IMF content also increased mainly as storage triglyceride, while functional fats consisting long-chain omega-3 did not increase proportionately. In addition, the study also demonstrates that using IMF for predicting or assessing meat quality aspects such as juiciness and flavor or the nutritional value of meat relating to health claimable fatty acids would not be appropriate. PMID- 30311135 TI - Hepatitis B-positive health-care workers: why they should not switch to non exposure-prone jobs. PMID- 30311136 TI - Has the era of dual-gated myocardial perfusion SPECT and PET arrived? PMID- 30311137 TI - Bayesian Parameter Identification for Turing Systems on Stationary and Evolving Domains. AB - In this study, we apply the Bayesian paradigm for parameter identification to a well-studied semi-linear reaction-diffusion system with activator-depleted reaction kinetics, posed on stationary as well as evolving domains. We provide a mathematically rigorous framework to study the inverse problem of finding the parameters of a reaction-diffusion system given a final spatial pattern. On the stationary domain the parameters are finite-dimensional, but on the evolving domain we consider the problem of identifying the evolution of the domain, i.e. a time-dependent function. Whilst others have considered these inverse problems using optimisation techniques, the Bayesian approach provides a rigorous mathematical framework for incorporating the prior knowledge on uncertainty in the observation and in the parameters themselves, resulting in an approximation of the full probability distribution for the parameters, given the data. Furthermore, using previously established results, we can prove well-posedness results for the inverse problem, using the well-posedness of the forward problem. Although the numerical approximation of the full probability is computationally expensive, parallelised algorithms make the problem solvable using high performance computing. PMID- 30311138 TI - A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy. AB - Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is a clinically heterogeneous disorder affecting fatty acid and amino acid metabolism. Presentations range from a severe neonatal form with hypoglycemia, metabolic acidosis, and hepatomegaly with or without congenital anomalies to later-onset lipid storage myopathy. Genetic testing for MADD traditionally comprises analysis of ETFA, ETFB, and ETFDH. Patients may respond to pharmacological doses of riboflavin, particularly those with late-onset MADD due to variants in ETFDH. Increasingly other genes involved in riboflavin transport and flavoprotein biosynthesis are recognized as causing a MADD phenotype. Flavin adenine dinucleotide synthase (FADS) deficiency caused by biallelic variants in FLAD1 has been identified in nine previous cases of MADD. FLAD1 missense mutations have been associated with a riboflavin-responsive phenotype; however the effect of riboflavin with biallelic loss of function FLAD1 mutations required further investigation. Herein we describe a novel, truncating variant in FLAD1 causing MADD in an 8-year-old boy. Fibroblast studies showed a dramatic reduction in FADS protein with corresponding reduction in the FAD synthesis rate and FAD cellular content, beyond that previously documented in FLAD1-related MADD. There was apparent biochemical and clinical response to riboflavin treatment, beyond that previously reported in cases of biallelic loss of function variants in FLAD1. Early riboflavin treatment may have attenuated an otherwise severe phenotype. PMID- 30311139 TI - The Effect of Continuous Intravenous Glucagon on Glucose Requirements in Infants with Congenital Hyperinsulinism. AB - BACKGROUND/AIMS: Continuous intravenous glucagon is frequently used in the management of severe congenital hyperinsulinism (HI), but its efficacy in these patients has not been systematically evaluated. The aim of this study was to describe the use of continuous intravenous glucagon and to evaluate its effect on the glucose infusion rate (GIR) requirement in infants with HI. METHODS: Retrospective chart review of children with HI who received continuous intravenous glucagon for prevention of hypoglycemia at the Children's Hospital of Philadelphia between 2003 and 2013. RESULTS: Forty (22 male) infants were included, and median (IQR) age at glucagon treatment was 29 (23, 54) days. Median glucagon dose was 205 (178, 235) mcg/kg/day and duration of treatment was 5 (3, 9) days. GIR reduced from 18.5 (12.9, 22.8) to 11 (6.6, 17.5) mg/kg/min 24 h after starting glucagon (p < 0.001), and hypoglycemia frequency reduced from 1.9 (1.3, 2.9) to 0.7 (0.3, 1.2) episodes per day. Vomiting (n = 11, 13%), rash (n = 2, 2%), and respiratory distress (n = 15, 19%) were seen during glucagon treatment. CONCLUSION: An intravenous glucagon infusion reduces the required GIR to maintain euglycemia, decreasing the risks associated with the administration of high fluid volume or fluids with high-glucose concentrations. PMID- 30311141 TI - Case of Neonatal Fatality from Neuromuscular Variant of Glycogen Storage Disease Type IV. AB - Glycogen storage disease type IV (GSD-IV), or Andersen disease, is a rare autosomal recessive disorder that results from the deficiency of glycogen branching enzyme (GBE). This in turn results in accumulation of abnormal glycogen molecules that have longer outer chains and fewer branch points. GSD-IV manifests in a wide spectrum, with variable phenotypes depending on the degree and type of tissues in which this abnormal glycogen accumulates. Typically, GSD-IV presents with rapidly progressive liver cirrhosis and death in early childhood. However, there is a severe congenital neuromuscular variant of GSD-IV that has been reported in the literature, with fewer than 20 patient cases thus far. We report an unusual case of GSD-IV neuromuscular variant in a late preterm female infant who was born to non-consanguineous healthy parents with previously healthy children. Prenatally, our patient was found to have decreased fetal movement and polyhydramnios warranting an early delivery. Postnatally, she had severe hypotonia and respiratory failure, with no hepatic or cardiac involvement. Extensive metabolic and neurological workup revealed no abnormalities. However, molecular analysis by whole-exome sequencing revealed two pathogenic variants in the GBE1 gene. Our patient was thus a compound heterozygote of the two pathogenic variants: one of these was inherited from the mother [p.L490WfsX5 (c.1468delC)], and the other pathogenic variant was a de novo change [p.E449X (c.1245G>T)]. As expected in GSD-IV, diffuse intracytoplasmic periodic acid-Schiff-positive, diastase-resistant inclusions were found in the cardiac myocytes, hepatocytes, and skeletal muscle fibers of our patient. PMID- 30311140 TI - Auxiliary Partial Orthotopic Liver Transplantation for Monogenic Metabolic Liver Diseases: Single-Centre Experience. AB - PURPOSE: Auxiliary partial orthotopic liver transplantation (APOLT) in metabolic liver disease (MLD) has the advantage of correcting the metabolic defect, preserving the native liver for gene therapy in the future with the possibility of withdrawal of immunosuppression. METHODS: Retrospective analysis of safety and efficacy of APOLT in correcting the underlying defect and its impact on neurological status of children with MLD. RESULTS: A total of 13 APOLT procedures were performed for MLD during the study period. The underlying aetiologies being propionic acidemia (PA)-5, citrullinemia type 1 (CIT1)-3 and Crigler-Najjar syndrome type 1 (CN1)-5 cases respectively. Children with PA and CIT1 had a median of 8 and 4 episodes of decompensation per year, respectively, before APOLT and had a mean social developmental quotient (DQ) of 49 (<3 standard deviations) as assessed by Vineland Social Maturity Scale prior to liver transplantation. No metabolic decompensation occurred in patients with PA and CIT1 intraoperatively or in the immediate post-transplant period on protein-unrestricted diet. Patients with CN1 were receiving an average 8-15 h of phototherapy per day before APOLT and had normal bilirubin levels without phototherapy on follow-up. We have 100% graft and patient survival at a median follow-up of 32 months. Progressive improvement in neurodevelopment was seen in children within 6 months of therapy with a median social DQ of 90. CONCLUSIONS: APOLT is a safe procedure, which provides good metabolic control and improves the neurodevelopment in children with selected MLD. PMID- 30311142 TI - Immunoparesis in symptomatic multiple myeloma at diagnosis affects PFS with bortezomib-containing induction therapy, but not ASCT consolidation. AB - In novel agent era, the impact of immunoparesis at diagnosis on outcomes in symptomatic multiple myeloma (MM) remains unclear. We reviewed medical records of 147 MM patients at Beijing Chao Yang hospital. Most patients exhibited immunoparesis at diagnosis (84%). After a median follow-up of 27 months (range 1 78 months), in the group with immunoparesis at diagnosis, there was a very significantly shorter progression-free survival (PFS) than in the group without immunoparesis (estimated PFS of not reached vs 25 months, P = 0.001). Patients with suppressed Immunoglobulins (Igs) had the tendency to have a shorter OS than patients without suppression (estimated OS of not reached vs 38 months, P = 0.06). In multivariate analysis, the negative impact of immunoparesis on PFS was confirmed. In addition, achievement of both at least VGPR and at least CR was significantly higher in patients with preserved uninvolved Igs than in those with suppression of at least one uninvolved Ig. However, the negative impact of immunoparesis on response was not confirmed in a multivariate analysis. These results suggest immunoparesis in patients with symptomatic MM at diagnosis is an independent poor prognostic factor for upfront bortezomib-containing regimen. PMID- 30311144 TI - PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment. AB - As the population of older individuals grows worldwide, researchers have increasingly focused their attention on identifying key molecular targets of age related cognitive impairments, with the aim of developing possible therapeutic interventions. Two such molecules are the intracellular cyclic nucleotides, cAMP and cGMP. These second messengers mediate fundamental aspects of brain function relevant to memory, learning, and cognitive function. Consequently, phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, are promising targets for the development of cognition-enhancing drugs. Inhibitors that target PDEs work by elevating intracellular cAMP. In this review, we provide an overview of different PDE inhibitors, and then we focus on pharmacological and physiological effects of PDE3 inhibitors in the CNS and peripheral tissues. Finally, we discuss findings from experimental and preliminary clinical studies and the potential beneficial effects of the PDE3 inhibitor cilostazol on age-related cognitive impairments. In the innovation pipeline of pharmaceutical development, the antiplatelet agent cilostazol has come into the spotlight as a novel treatment for mild cognitive impairment. Overall, the repurposing of cilostazol may represent a potentially promising way to treat mild cognitive impairment, Alzheimer's disease, and vascular dementia. In this review, we present a brief summary of cAMP signaling and different PDE inhibitors, followed by a discussion of the pharmacological and physiological role of PDE3 inhibitors. In this context, we discuss the repurposing of a PDE3 inhibitor, cilostazol, as a potential treatment for age-related cognitive impairment based on recent research. PMID- 30311143 TI - From LBR-101 to Fremanezumab for Migraine. AB - Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration. PMID- 30311145 TI - Quality indicators in radiation oncology: proposal of the Spanish Society of Radiation Oncology (SEOR) for a continuous improvement of the quality of care in oncology. AB - PURPOSE: Current cancer treatment options include surgical intervention, radiotherapy, and chemotherapy. The quality of the provision of each of them and their effective coordination determines the results in terms of benefit/risk. Regarding the radiation oncology treatments, there are not stabilised quality indicators to be used to perform control and continuous improvement processes for healthcare services. Therefore, the Spanish Society of Radiation Oncology has undertaken a comprehensive project to establish quality indicators for use with the information systems available in most Spanish healthcare services. METHODS: A two-round Delphi study examines consensus of several possible quality indicators (n = 28) in daily practice. These indicators were defined after a bibliographic search and the assessment by radiation oncology specialists (n = 8). They included aspects regarding treatment equipment, patient preparation, treatment, and follow-up processes and were divided in structure, process, and outcome indicators. RESULTS: After the evaluation of the defined quality indicators (n = 28) by an expert panel (38 radiation oncologist), 26 indicators achieved consensus in terms of agreement with the statement. Two quality indicators did not achieve consensus. CONCLUSIONS: There is a high degree of consensus in Spanish Radiation Oncology specialists on which indicators in routine clinical practice can best measure quality. These indicators can be used to classify services based on several parameters (patients, equipments, complexity of the techniques used, and scientific research). Furthermore, these indicators allow assess our current situation and set improvements' objectives. PMID- 30311147 TI - Occurrence of aflatoxins in rice and in cassava (Manihot esculenta) products (meal, bread) produced in Guyana. AB - A survey was conducted on Guyana's main staple foods, rice, cassava meal and cassava bread to determine the presence and concentration of aflatoxins (AFs) using enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC) with fluorescence detection for concurrence. Aflatoxins are secondary metabolites of the fungus Aspergillus and can be a health risk to humans and animals. Results were compared with European Union Commission (EUC) maximum levels of total aflatoxins of 10 MUg/kg. Various types of rice (paddy, steamed paddy, cargo rice, white rice and parboiled rice) were randomly collected either directly from the field and rice mills in Guyana during the November 2015/March 2016 season. Of the total 186 composite samples of rice fractions collected from field and mills, 10% (19) had AF concentrations greater than the maximum EUC level of 10 MUg/kg. Fifteen samples had aflatoxin concentrations ranging from 10 to 171 MUg/kg, mean 54.4 MUg/kg; four samples were outliers. Since Guyanese consume mainly white and parboiled rice, composite samples were taken along the marketing chain at points of sale to determine the presence of AFs. Of the sixty samples of white rice collected, 6.7% (4) had AF concentrations greater than the EUC regulatory limits ranging from 31.9 to 131 MUg/kg, mean 80.8 MUg/kg. For the 57 samples of parboiled rice, 3.5% (2) samples exceeded the limit with values of 72.6 and 407 MUg/kg. Forty (40) samples each of cassava meal and cassava bread were analysed fresh and after 2 months of storage, and no sample exceeded the ELISA detection limit of 0.5 MUg/kg. PMID- 30311148 TI - Role of color Doppler ultrasound in the early diagnosis of a major complication after percutaneous renal biopsy: two case reports. AB - Percutaneous renal biopsy (PRB) is an important procedure in the diagnostic and prognostic evaluation of renal disorders. Despite the relative simplicity, it can be a possible cause of iatrogenic renovascular injury. We describe two cases of iatrogenic pseudoaneurysm, a major post-biopsy complication, in two pediatric patients with persistent micro- and macro-hematuria, promptly diagnosed using color Doppler ultrasound, confirmed with renal arteriography and treated with embolization. PMID- 30311149 TI - Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment. AB - PURPOSE: Tissue engineered heart valves (TEHV) are being investigated to address the limitations of currently available valve prostheses. In order to advance a wide variety of TEHV approaches, the goal of this study was to develop a cardiac valve bioreactor system capable of conditioning living valves with a range of hydrodynamic conditions as well as capable of assessing hydrodynamic performance to ISO 5840 standards. METHODS: A bioreactor system was designed based on the Windkessel approach. Novel features including a purpose-built valve chamber and pressure feedback control were incorporated to maintain asepsis while achieving a range of hydrodynamic conditions. The system was validated by testing hydrodynamic conditions with a bioprosthesis and by operating with cell culture medium for 4 weeks and living cells for 2 weeks. RESULTS: The bioreactor system was able to produce a range of pressure and flow conditions from static to resting adult left ventricular outflow tract to pathological including hypertension. The system operated aseptically for 4 weeks and cell viability was maintained for 2 weeks. The system was also able to record the pressure and flow data needed to calculate effective orifice area and regurgitant fraction. CONCLUSIONS: We have developed a single bioreactor system that allows for step wise conditioning protocols to be developed for each unique TEHV design as well as allows for hydrodynamic performance assessment. PMID- 30311150 TI - Ultra-short Celiac Disease Is a Distinct and Milder Phenotype of the Disease in Children. AB - BACKGROUND AND AIMS: Approximately 10% of children with celiac disease (CD) have ultra-short celiac disease (USCD), where histological abnormalities are limited to the duodenal bulb. The aim of our retrospective study was to identify clinical and serological characteristics at baseline and at follow-up of children with USCD. METHODS: All children that were diagnosed with CD in our unit during 7/2010 12/2017, in whom biopsies were taken from duodenal bulb and second part, were included. We compared disease characteristics and course between children with USCD and children with involvement in the second part of the duodenum. RESULTS: Out of 3740 children who underwent upper gastrointestinal endoscopies, 648 were diagnosed with CD. Seventy-one (11%) of those children had limited involvement in the duodenal bulb. The USCD group included more females (P = 0.021), were older (P = 0.005), had a lower prevalence of diarrhea (P = 0.003), anemia (P = 0.007), anti-tissue transglutaminase (TTG) antibodies count (P < 0.001) at presentation, lower frequency of endoscopic abnormality, lower Marsh score, and a trend toward shorter time to the normalization of anti-TTG antibodies under a gluten-free diet compared to the extensive CD. There were no differences in body mass index or duration of symptoms before diagnosis. CONCLUSION: Children with USCD presented with a distinct phenotype of milder symptoms, lower celiac serology, and milder endoscopic and histological findings, with a trend toward faster normalization under a gluten-free diet compared to those with extensive CD. Further studies are needed to determine the long-term course and prognosis of USCD. PMID- 30311146 TI - TLR4 Polymorphisms and Expression in Solid Cancers. AB - Toll-like receptors (TLRs) are a type of pattern-recognition receptor (PRR) that are part of the innate immune system known to recognize pathogen-associated molecular patterns and thereby play a crucial role in host immune response. Among the various known TLRs, TLR4 is one of the most extensively studied PRRs expressed by immune, certain nonimmune, and tumor cells. When TLR4 binds with the bacterial lipopolysaccharide, it induces production of proinflammatory cytokines, chemokines, and effector molecules as part of the immune response. Continuous exposure to pathogens and TLR4 signaling results in chronic inflammation that may further lead to malignant transformation. TLR4 is a highly polymorphic gene, and genetic variations are known to influence host immune response, leading to dysregulation of signaling pathway, which may affect an individual's susceptibility to various diseases, including cancer. Furthermore, TLR4 expression in different tumor types may also serve as a marker for tumor proliferation, differentiation, metastasis, prognosis, and patient survival. This review aims to summarize various reports related to TLR4 polymorphisms and expression patterns and their influences on different cancer types with a special focus on solid tumors. PMID- 30311151 TI - The Clinicopathological Correlations of hTERC Amplification with Esophageal Squamous Cell Precursor Lesions. AB - BACKGROUND: Esophageal squamous cell precursor lesions remain one of the most controversial topics in pathology and clinical management. AIMS: To analyze the dysregulation of human telomerase RNA component (hTERC) in esophageal squamous cell precursor lesions and the clinicopathological correlations with the characteristics of esophageal squamous cell precursor lesions. METHODS: Florescence in situ hybridization was performed to detect hTERC amplification in different gradings of esophageal squamous cell precursor lesions. With retrospective follow-up data, clinicopathological correlations between hTERC and esophageal squamous cell precursor lesions were subjected to logistic regression analysis. RESULTS: hTERC amplification gradually increased with upgrading of dysplasia, reaching the highest level in high-grade intraepithelial neoplasia, and there was a significant difference between the low-grade intraepithelial neoplasia group and the high-grade intraepithelial neoplasia group (P = 0.00). Logistic regression analysis showed that hTERC amplification was correlated with both dysplasia grading and ulcer characteristics of esophageal squamous cell precursor lesions (P < 0.05). CONCLUSIONS: hTERC amplification with increasing grading of esophageal squamous cell precursor lesions and the presence of ulcer characteristics might provide an important molecular and pathological marker for the diagnosis and clinical prognosis of esophageal squamous cell precursor lesions, especially for those ambiguous cases with more divergence in classification. PMID- 30311152 TI - Incidence and Management of Infusion Reactions to Infliximab in an Alternate Care Setting. AB - BACKGROUND: Infliximab is a chimeric anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody that ameliorates inflammation when it binds to and neutralizes TNF-alpha. It is often used in patients with Crohn's disease and ulcerative colitis to reduce the severity of disease symptoms and induce disease remission. Infusions are generally administered in the hospital setting due to concerns over patient safety, and limited data exist regarding the incidence and management of infusion reactions (IRs) in an alternate care setting without direct physician oversight. AIMS: The aim of this study was to evaluate the incidence of IRs following administration of infliximab and associated management approaches in an alternate care setting. METHODS: A retrospective chart review of 796 patients with Crohn's disease or ulcerative colitis that received a combined 5581 infusions with one home infusion provider between January 2014 and November 2016 was conducted. Timing, severity, management approach, and outcomes of IRs were abstracted and analyzed. RESULTS: A total of 109 infusion reactions (2.0% of all infusions) were recorded in 62 patients (7.8% of all patients). The majority of these reactions were acute and mild or moderate in severity and resolved with rate adjustments and/or medication. Emergency room visits were required in 0.1% of all infusions, and 0.3% of all infusions were not completed due to a reaction. CONCLUSIONS: IRs to infliximab were uncommon and mostly mild or moderate in severity. Resolution of the IR and continuation of therapy was achieved in most patients through a management approach that included prompt recognition and initial treatment via rate adjustments and medications according to physician's orders. PMID- 30311154 TI - Reduced Imaging Radiation Exposure and Costs Associated with Anti-Tumor Necrosis Factor Therapy in Crohn's Disease. AB - BACKGROUND: Radiation exposure from diagnostic imaging may increase cancer risk of Crohn's disease (CD) patients, who are already at increased risk of certain cancers. AIM: To compare imaging radiation exposure and associated costs in CD patients during the year pre- and post-initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: Adults were identified from a large US claims database between 1/1/2005 and 12/31/2009 with >= 1 abdominal imaging scan and 12 months of enrollment before and after initiating therapy with anti-TNF or corticosteroids. Imaging utilization, radiation exposure, and healthcare costs pre- and post-initiation were examined. RESULTS: Anti-TNF treated patients had significantly fewer imaging examinations the year prior to initiation than corticosteroid-treated patients. Cumulative radiation doses before initiation were significantly higher for corticosteroid patients compared to anti-TNF patients (22.3 vs. 17.7 millisieverts, P = 0.0083). After therapy initiation, anti-TNF-treated patients had significantly fewer imaging examinations (2.9 vs. 5.2, P < 0.0001) and less radiation exposure (7.4 vs. 15.4 millisieverts, P <0.0001) than corticosteroid-treated patients in the follow-up period. Reductions in imaging costs adjusted for 1000 patient-years after initiation of therapy were - $275,090 and - $121,960 (P = 0.0359) for anti-TNF versus corticosteroid patients, respectively. CONCLUSIONS: This analysis demonstrated that patients treated with anti-TNF agents have fewer imaging examinations, less radiation exposure, and lower healthcare costs associated with imaging than patients treated with corticosteroids. These benefits do not account for additional long-term benefits that may be gained from reduced radiation exposure. PMID- 30311153 TI - Underserved Does Not Mean Undeserved: Unfurling the HCV Care in the Safety Net. PMID- 30311155 TI - Endoscopic Indication of Endoscopic Submucosal Dissection for Early Gastric Cancer Is Not Compatible with Pathologic Criteria in Clinical Practice. AB - BACKGROUND: The inappropriate selection of patients with early gastric cancer (EGC) for endoscopic submucosal dissection (ESD) may lead to additional surgery because of a non-curative resection. This study was performed to assess the accuracy of clinical decisions in ESD for EGC. METHODS: A total of 607 cases of EGC treated by ESD were prospectively enrolled from January 2011 to June 2014 at a single academic hospital. The 607 EGCs were divided into three groups (overestimated, same-estimated, and underestimated) based on pre-procedure endoscopic findings (indication) and pathological diagnosis after ESD (criteria). We evaluated the discrepancy rates between pre-procedure indication and pathological criteria, and then analyzed the pre-procedure factors that could influence the occurrence of the discrepancies. RESULTS: The absolute, expanded, and beyond the expanded indication has its accuracy on curability criteria in 87%, 77.6%, and 55.6% of cases, respectively. The ratio of overall indication criteria discrepancies was 250/607 (41.2%). The curability was significantly lower in the underestimated group compared to the overestimated and same estimated groups (41.6% vs. 94.6%, 94.4%, p < 0.001). In multivariate analysis examining the predictive factors for discrepancies in the 598 EGCs with absolute/expanded indications, the endoscopic size >= 20 mm [odds ratio (OR) 2.493, confidence interval (CI) 1.546-4.022, p < 0.001], presence of ulcers (OR 1.712, CI 1.070-2.738, p = 0.025), patient age < 60 years (OR 1.689, CI 1.044 2.733, p = 0.033), and undifferentiated type EGC on forceps biopsy (OR 5.397, CI 2.027-14.369, p = 0.001) were all associated with discrepancies. CONCLUSIONS: Indication judged by pre-procedural endoscopy is not sufficiently accurate to be used as a good measurement for post-procedural criteria. PMID- 30311157 TI - ASO Author Reflections: Narrow-Band Imaging: A Novel Imaging Method in Minimally Invasive Surgery. PMID- 30311158 TI - Why Travel for Complex Cancer Surgery? Americans React to 'Brand-Sharing' Between Specialty Cancer Hospitals and Their Affiliates. AB - INTRODUCTION: Leading cancer hospitals have increasingly shared their 'brand' with smaller hospitals through affiliations. Because each brand evokes a distinct reputation for the care provided, 'brand-sharing' has the potential to impact the public's ability to differentiate the safety and quality within hospital networks. The general public was surveyed to determine the perceived similarities and differences in the safety and quality of complex cancer surgery performed at top cancer hospitals and their smaller affiliate hospitals. METHODS: A national, web-based KnowledgePanel (GfK) survey of American adults was conducted. Respondents were asked about their beliefs regarding the quality and safety of complex cancer surgery at a large, top-ranked cancer hospital and a smaller, local hospital, both in the presence and absence of an affiliation between the hospitals. RESULTS: A total of 1010 surveys were completed (58.1% response rate). Overall, 85% of respondents felt 'motivated' to travel an hour for complex surgery at a larger hospital specializing in cancer, over a smaller local hospital. However, if the smaller hospital was affiliated with a top-ranked cancer hospital, 31% of the motivated respondents changed their preference to the smaller hospital. When asked to compare leading cancer hospitals and their smaller affiliates, 47% of respondents felt that surgical safety, 66% felt guideline compliance, and 53% felt cure rates would be the same at both hospitals. CONCLUSIONS: Approximately half of surveyed Americans did not distinguish the quality and safety of surgical care at top-ranked cancer hospitals from their smaller affiliates, potentially decreasing their motivation to travel to top centers for complex surgical care. PMID- 30311159 TI - Expanding with Air: Proceed with Caution. PMID- 30311156 TI - Prevalence and Clinical Features of Celiac Disease in Healthy School-Aged Children. AB - BACKGROUND/AIMS: The aim of this study was to determine the prevalence of celiac disease (CD) in healthy school-aged children in the northern region of Cyprus and to investigate the existence of potential markers that may accompany CD. This is the first study to measure the prevalence of CD in the northern region of Cyprus. METHODS: This study included 3792 school-aged children who were between the ages of 6 and 10 years between January 2015 and October 2016. CD was screened using total serum IgA, IgA anti-tissue transglutaminase (tTG), and IgA antiendomysial (EMA) antibodies. Subjects with selective IgA deficiency were further tested for IgG-tTG. Small intestinal biopsies were performed on all subjects with tTG antibody positivity. Risk factors and symptoms related to CD were evaluated using questionnaires in both the CD and control groups. RESULTS: Of the 3792 subjects, 39 were antibody positive (IgA-tTG was positive only in 14 subjects, IgA-tTG plus IgA-EMA in 21 subjects, and IgG-tTG in 4 subjects). IgA deficiency was detected in 11 subjects (0.29%). IgG-tTG was positive in 4 subjects with IgA deficiency (36.3%). Intestinal biopsies were performed on 28 of the 39 seropositive subjects. The biopsy findings of 15 children were consistent with CD (IgA-tTG positive in 3, IgA-tTG and IgA-EMA positive in 10, and IgG-tTG positive in 2). Thus, biopsies confirmed CD in 1:256 children (0.39%). CONCLUSIONS: Our study, which is the first study of school-aged children from the northern region of Cyprus, revealed that CD is a prevalent disease in this region. PMID- 30311160 TI - ASO Author Reflections: Solitary Pulmonary Lesion in Patients with Cancer History. PMID- 30311161 TI - Perceptions of Barriers Towards Active Surveillance for Low-Risk Prostate Cancer: Results From a National Survey of Radiation Oncologists and Urologists. AB - PURPOSE: The reasons for low clinical adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. Thus, we conducted a national survey of radiation oncologists (ROs) and urologists (UROs) to elucidate perceived barriers to AS for low-risk PCa. METHODS: In 2017, we undertook a four wave mail survey of 1855 ROs and UROs. The survey instrument assessed attitudes about possible barriers towards AS for low-risk PCa. We used Pearson Chi square and multivariable logistic regression analyses to identify physician characteristics associated with attitudes about AS. RESULTS: We received 691 completed surveys for an overall response rate of 37.3%. A majority of respondents indicated that they felt comfortable recommending AS (90.0%), agreed that high-level evidence supports it (82.3%), and considered AS equally effective for survival compared with surgery and radiation therapy (84.4%). UROs were less likely to agree that patients were not interested in AS for low-risk PCa compared with ROs (16.5 vs. 48.9%; adjusted odds ratio [OR] 0.18, p < 0.001). Similarly, UROs were less likely to concur patients avoid AS because of repeat prostate biopsies than ROs (36.3 vs. 55.4%; adjusted OR 0.41, p < 0.001). ROs and UROs were more likely to agree that patients preferred treatments delivered by the respondent's specialty. CONCLUSIONS: Physician perceptions of patient lack of interest in AS, need for repeat prostate biopsies, and biases of patient treatment preferences in favor of their own specialty treatments represent key barriers to AS. Shared decision making may be a meaningful approach to engaging patients in conversations about treatment decisions. PMID- 30311162 TI - Impact of Chemoradiation-to-Surgery Interval on Pathological Complete Response and Short- and Long-Term Overall Survival in Esophageal Cancer Patients. AB - BACKGROUND: The impact of the neoadjuvant chemoradiation-to-surgery (CRT-S) interval in patients with esophageal cancer is not clear. We aimed to determine the relationship between CRT-S interval and pathological complete response rate (pCR) and overall survival (OS). METHODS: National Cancer Data Base patients with CRT followed by surgery were studied. CRT-S interval was studied as a continuous (weeks) and categorical variable (quintiles: 15-37, 38-45, 46-53, 54-64, and 65 90 days, with n = 1016, 1063, 1081, 1083, and 938 patients, respectively). RESULTS: A total of 5181 patients were included; 81% had adenocarcinoma. There was a significant increase of pCR rate across quintiles (18%, 21%, 24%, 25%, and 29%, p < 0.001) and per week increase of CRT-S interval [odds ratio (OR) 1.11, p < 0.001]. The 90-day mortality increased as CRT-S increased across quintiles (5.7%, 6.2%, 6.8%, 8.5%, and 8.2%, p = 0.02) and through weeks (OR 1.05, p = 0.03). Mean OS across CRT-S quintiles was 36.4, 35.1, 33.9, 33.2, and 30.7 months, respectively. Multivariate Cox regression showed significantly worse OS per week increase in CRT-S interval [hazard ratio (HR) 1.02, p = 0.02], especially among the last quintile (CRT-S = 65-90 days: HR 1.2, p = 0.009). The squamous cell carcinoma (SCC) and pCR groups had similar OS across CTR-S intervals. CONCLUSIONS: Despite the higher pCR rate with longer CRT-S interval, surgery is optimal less than 65 days after CRT to avoid worse 90-day mortality and achieve better OS. In patients with SCC and those with pCR, prolonged CRT-S interval had no impact on OS. Further studies are needed to consolidate our findings. PMID- 30311163 TI - ASO Author Reflections: Improving Identification of Intraductal Papillary Mucinous Neoplasm Patients at Risk-Current Status and the Role of IPMN Molecular Biomarkers. PMID- 30311164 TI - Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both? AB - BACKGROUND: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS: Regional failure was infrequent (<= 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity. PMID- 30311165 TI - ASO Author Reflections: The Sentinel Lymph Node in Melanoma: Now More Important Than Ever. PMID- 30311166 TI - ASO Author Reflections: The Whole Transcriptome Landscape of Circulating Tumor Cells in Nonmetastatic Breast Cancer. PMID- 30311167 TI - Long-Term Outcomes of Robot-Assisted Surgery in Patients with Colorectal Cancer. AB - BACKGROUND: Robotic technology has been proven to be a safe alternative to conventional laparoscopy with regards to the peri- and postoperative clinical outcomes. Oncological outcomes have been scarcely examined. The purpose of this study was to examine the disease-free survival in relation to the two surgical approaches: robot-assisted surgery and conventional laparoscopy. In addition, all cause mortality and recurrence-free survival were investigated. METHODS: Between January 2010 and December 2015, patients, undergoing either laparoscopic or robot assisted elective, curative-intended surgery for colorectal cancer were included. RESULTS: A total of 9184 patients underwent surgery in the study period: 5978 patients for colon cancer and 3206 patients for rectal cancer. Among patients with colon cancer, 331 patients (5.5%) underwent robot-assisted surgery, and 449 patients (14.0%) underwent robot-assisted surgery in the rectal cancer group. In the adjusted analyses, the hazard ratio (HR) for disease-free survival, for patients with colon cancer was 0.91 [95% confidence interval (CI) 0.71-1.18]. For patients with rectal cancer, the adjusted HR was 0.83 (95% CI 0.65-1.06). No difference in all-cause mortality and recurrence-free survival were observed. CONCLUSIONS: The study demonstrated comparable rates of disease-free survival, all-cause mortality, and recurrence-free survival when comparing robot-assisted surgery with conventional laparoscopy in patients with colorectal cancer. PMID- 30311168 TI - Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer. AB - BACKGROUND: The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer. METHODS: An integrated unbiased approach was applied to derive a composite risk score for prognosis based on miRNA expression in primary breast tumors in 1051 breast cancer patients from The Cancer Genome Atlas (TCGA). Further analysis of the risk score with metastasis/recurrence was performed using the TCGA data set and validated in a separate patient population using small RNA sequencing. RESULTS: The three-miRNAs risk score (miR-19a, miR-93, and miR-106a) was developed using the TCGA cohort, which predicted poor prognosis (p = 0.0005) independently of known clinical risk factors. The prognostic value was validated in another three following independent cohorts: GSE19536 (p = 0.0009), GSE22220 (p = 0.0003), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (p = 0.0023). The three-miRNAs risk score predicted bone recurrence in TCGA (p = 0.0052), and the findings were validated in another independent population of patients who experienced bone recurrence and age/stage-matched patients without any recurrence. The three-miRNAs risk score enriched multiple metastasis-related gene sets such as angiogenesis and epithelial mesenchymal transition in a gene set-enrichment analysis. CONCLUSIONS: The authors developed the novel miRNA-based risk score, which is a promising biomarker for prediction of worse survival and bone recurrence potential in breast cancer. PMID- 30311169 TI - Epigenetic Status of CDO1 Gene May Reflect Chemosensitivity in Colon Cancer with Postoperative Adjuvant Chemotherapy. AB - BACKGROUND: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor gene, and its expression is regulated by promoter DNA methylation in human cancer. The metabolic product mediated by CDO1 enzyme increases mitochondrial membrane potential (MMP), putatively representing chemoresistance. The aim of this study is to investigate the functional relevance of CDO1 gene in colon cancer with chemotherapy. PATIENTS AND METHODS: We investigated 170 stage III colon cancer patients for CDO1 methylation by using quantitative methylation-specific polymerase chain reaction (PCR). To elucidate the functional role of CDO1 gene in colorectal cancer (CRC) biology, we established cell lines that stably express CDO1 gene and evaluated chemosensitivity, MMP, and tolerability assay including anaerobic environment. RESULTS: Hypermethylation of CDO1 gene was an independent prognostic factor for stage III colon cancer on multivariate prognostic analysis. Surprisingly, patients with CDO1 hypermethylation exhibited better prognosis than those with CDO1 hypomethylation in stage III colon cancer with postoperative chemotherapy (P = 0.03); however, a similar finding was not seen in those without postoperative chemotherapy. In some CRC cell lines, forced expression of CDO1 gene increased MMP accompanied by chemoresistance and/or tolerance under hypoxia. CONCLUSION: CDO1 methylation may be a useful biomarker to increase the number of stage III colon cancer patients who can be saved by adjuvant therapy. Such clinical relevance may represent the functionally oncogenic property of CDO1 gene through MMP activity. PMID- 30311170 TI - The effects of sampling lateralization on bilateral inferior petrosal sinus sampling and desmopressin stimulation test for pediatric Cushing's disease. AB - PURPOSE: Bilateral inferior petrosal sinus sampling (BIPSS) is useful for differential diagnosis of adult Cushing's disease (CD) but may not be so reliable in pediatric cases. The purpose of this study was to evaluate the sensitivity of BIPSS before and after desmopressin stimulation in pediatric CD, and to explore related factors of false-negative results and meanings of sampling lateralization. METHODS: We retrospectively analyzed 16 pediatric CD patients who underwent 17 BIPSS procedures from 2006 to 2017. CD was diagnosed if inferior petrosal sinus (IPS) to peripheral adrenocorticotropic hormone (ACTH) ratio was >2 at baseline or >3 after desmopressin stimulation. Sampling lateralization was yielded if interpetrosal sinus gradient was >1.4. Magnetic resonance imaging (MRI) was conducted. All the patients underwent surgery and the diagnosis was confirmed. RESULTS: The sensitivity was 64.7% (11/17) at baseline and 83.3% (10/12) after desmopressin stimulation. After stimulation, BIPSS reached its best sensitivity at 3 min. Sampling lateralization rate was 62.5% and 63.6% before and after stimulation, and the accordant rate with actual tumor lateralization was 50.0% and 42.9%, respectively. The accuracy of MRI in predicting the tumor lateralization was 80.0%. Sampling lateralization rate (81.8% in true-positive, 20.0% in false-negative, p = 0.036) and ACTH at dominant IPS (p = 0.001) was lower among false-negative patients. CONCLUSIONS: The sensitivity of BIPSS in pediatric CD was low at baseline, but increased after desmopressin stimulation. Sampling lateralization cannot accurately indicate the tumor lateralization, but the absence of sampling lateralization with low ACTH at IPS is a hint of false negative cases in BIPSS. PMID- 30311171 TI - Effects of dehydroepiandrosterone (DHEA) supplementation on sexual function in premenopausal infertile women. AB - PURPOSE: To investigate the effects of dehydroepiandrosterone (DHEA) supplementation on female sexual function in premenopausal infertile women of advanced ages. METHODS: This observational study was conducted in an academically affiliated private fertility center. Patients included 87 premenopausal infertile women, 50 of whom completed the study including the Female Sexual Function Index (FSFI) questionnaires and comprehensive endocrine evaluation before and 4-8 weeks after initiating 25 mg of oral micronized DHEA TID. RESULTS: Age of patients was 41.1 +/- 4.2 years, BMI 24.4 +/- 6.1 kg/m2, 86% were married, and 42% were parous. Following supplementation with DHEA, all serum androgen levels increased (each P < 0.0001), while FSH levels decreased by 2.6 +/- 4.4 from a baseline of 10.3 +/- 5.4 mIU/mL (P = 0.009). The FSFI score for the whole study group increased by 7% (from 27.2 +/- 6.9 to 29.2 +/- 5.6; P = 0.0166). Domain scores for desire increased by 17% (P = 0.0004) and by 12% for arousal (P = 0.0122); lubrication demonstrated an 8% trend towards improvement (P = 0.0551), while no changes in domain scores for orgasm, satisfaction, or pain were observed. Women in the lowest starting FSFI score quartile (<25.7), experienced a 6.1 +/- 8.0 (34%) increase in total FSFI score following DHEA supplementation. Among these women, improvements in domain categories were noted for desire (40%), arousal (46%), lubrication (33%), orgasm (54%), satisfaction (24%), and pain (25%). CONCLUSIONS: This uncontrolled observational study implies that supplementation with DHEA improves sexual function in older premenopausal women with low baseline FSFI scores. PMID- 30311172 TI - Bio-guided Purification and Mass Spectrometry Characterisation Exploring the Lysozyme-like Protein from Enterococcus lactis Q1, an Unusual Marine Bacterial Strain. AB - Lactic acid bacteria produce various antibacterial peptides such as bacteriocins that are active against pathogenic and spoilage microorganisms. Very little attention has been paid to the production of lysozyme as an antimicrobial enzyme. The present work represents one of the few studies reporting lysozyme production by enterococci. Indeed, this study was first conducted to evaluate the antimicrobial activity of Enterococcus lactis Q1, an enterocin P-producing strain previously isolated from fresh shrimp (Penaeus vannamei), against multidrug resistant clinical isolates. Results showed significant inhibitory activity (P < 0.05) towards diverse pathogens. The purification of the antimicrobial substances produced by Q1 strain leads to the isolation of two active fractions. The SDS PAGE and mass spectrometry analyses of fraction number 2 (fraction 2) revealed the presence of a protein with molecular mass of 14.3 kDa. Additionally, the experimental results are consistent with mass spectra of industrial lysozyme (Fluka ref. 62970). The lysozyme produced by Enterococcus lactis Q1 strain was confirmed by a plate method against Micrococcus luteus ATCC 4698. Also, sensitivity of the Q1 strain to different concentrations of lysozyme was investigated. For the first time, this study shows that E. lactis Q1 produces lysozyme which could be an excellent candidate in food biopreservation or production of functional foods to promote health benefits. PMID- 30311173 TI - Physicochemical and Antimicrobial Properties of Oleoresin Capsicum Nanoemulsions Formulated with Lecithin and Sucrose Monopalmitate. AB - Oleoresin capsicum (OC) is an extract of chili pepper containing the active agent capsaicin. In this study, OC-loaded nanoemulsions were prepared by microfluidization and stabilized with sucrose monopalmitate (SMP) and lecithin. The difference in size and distribution of droplets determined the nanoemulsion behavior mainly due to the interaction of emulsifiers between oil and aqueous phase. The hydrophilic interaction between SMP and aqueous phase and the hydrophobic interaction between lecithin and oil phase were monitored with NMR relaxometry. OC nanoemulsion fabricated with SMP showed the best transparency with smallest droplet size (around 34 nm) and stable with glycerol after 28 days at ambient storage. Lecithin containing nanoemulsions showed improved bioactivity as showing antioxidant (0.82 mg DPPH/L) and antimicrobial (3.40 log for Escherichia coli and 4.37 log for Staphylococcus aureus) activity. Finally, results have important implications to determine the appropriate formulation conditions for OC with food-grade surfactants to be used in pharmaceuticals and food industry. PMID- 30311176 TI - Self-Inflicted Injury-Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP-SI): a new surveillance tool for detecting self-inflicted injury events in emergency departments. AB - OBJECTIVES: To assess the performance of the Canadian Hospitals Injury Reporting and Prevention Program's newly developed self-harm surveillance tool (CHIRPP-SI) designed to improve emergency department (ED) hospital surveillance of youth self inflicted injury (SI). METHODS: This was a prospective, single-centre cohort study from February 2015 to September 2015. Eligible participants were aged 6 17.99 years and presented to the ED with a primary mental health complaint. The frequency of SI cases was extracted from three data sources (CHIRPP-SI, medical chart, and the National Ambulatory Care Reporting System Metadata (NACRS)). Cohen's kappa statistic was used to examine the level of agreement between data sources. RESULTS: Of the 250 participants who received a medical chart review, 70 completed the CHIRPP-SI. Of those who did not complete the CHIRPP-SI, 86% (n = 154) reported no SI related to their presentation, 12% (n = 22) declined to participate without specifying self-injury status, and 2% (n = 4) were unable to be interviewed prior to discharge. The three sources of surveillance data varied considerably; the medical chart captured the highest frequency of individuals reporting SI related to their ED visit (33.6%), followed by the CHIRPP-SI (28.0%), and the NACRS database (8.4%). The CHIRPP-SI captured the method of SI and the place of occurrence in 100% of individuals, and the bodily location harmed in 98.6% of individuals. CONCLUSIONS: Study findings highlight the disparity between different sources of data, in relation to the capture of paediatric SI, presenting to hospital EDs. If greater details of SI events are to be identified, surveillance tools such as the CHIRPP-SI should be considered. PMID- 30311177 TI - Because it's 2018: the need for early career development for female anesthesiologists. PMID- 30311174 TI - Identification of Auxin Activity Like 1, a chemical with weak functions in auxin signaling pathway. AB - KEY MESSAGE: A new synthetic auxin AAL1 with new structure was identified. Different from known auxins, it has weak effects. By AAL1, we found specific amino acids could restore the effects of auxin with similar structure. Auxin, one of the most important phytohormones, plays crucial roles in plant growth, development and environmental response. Although many critical regulators have been identified in auxin signaling pathway, some factors, especially those with weak fine-tuning roles, are still yet to be discovered. Through chemical genetic screenings, we identified a small molecule, Auxin Activity Like 1 (AAL1), which can effectively inhibit dark-grown Arabidopsis thaliana seedlings. Genetic screening identified AAL1 resistant mutants are also hyposensitive to indole-3 acetic acid (IAA) and 2,4-dichlorophenoxyacetic acid (2,4-D). AAL1 resistant mutants such as shy2-3c and ecr1-2 are well characterized as mutants in auxin signaling pathway. Genetic studies showed that AAL1 functions through auxin receptor Transport Inhibitor Response1 (TIR1) and its functions depend on auxin influx and efflux carriers. Compared with known auxins, AAL1 exhibits relatively weak effects on plant growth, with 20 uM and 50 uM IC50 (half growth inhibition chemical concentration) in root and hypocotyl growth respectively. Interestingly, we found the inhibitory effects of AAL1 and IAA could be partially restored by tyrosine and tryptophan respectively, suggesting some amino acids can also affect auxin signaling pathway in a moderate manner. Taken together, our results demonstrate that AAL1 acts through auxin signaling pathway, and AAL1, as a weak auxin activity analog, provides us a tool to study weak genetic interactions in auxin pathway. PMID- 30311175 TI - Molecular role of cytokinin in bud activation and outgrowth in apple branching based on transcriptomic analysis. AB - KEY MESSAGE: Axillary bud activation and outgrowth were dependent on local cytokinin, and that bud activation preceded the activation of cell cycle and cell growth genes in apple branching. Cytokinin is often applied to apple trees to produce more shoot branches in apple seedlings. The molecular response of apple to the application of cytokinin, and the relationship between bud activation and cell cycle in apple branching, however, are poorly understood. In this study, RNA sequencing was used to characterize differential expression genes in axillary buds of 1-year grafted "Fuji" apple at 4 and 96 h after cytokinin application. And comparative gene expression analyses were performed in buds of decapitated shoots and buds of the treatment of biosynthetic inhibitor of cytokinin (Lovastatin) on decapitated shoots. Results indicated that decapitation and cytokinin increased ZR content in buds and internodes at 4-8 h, and induced bud elongation at 96 h after treatment, relative to buds in shoots receiving the Lovastatin treatment. RNA-seq analysis indicated that differential expression genes in auxin and cytokinin signal transduction were significantly enriched at 4 h, and DNA replication was enriched at 96 h. Cytokinin-responsive type-A response regulator, auxin polar transport, and axillary meristem-related genes were up regulated at 4 h in the cytokinin and decapitation treatments, while qRT-PCR analysis showed that cell cycle and cell growth genes were up-regulated after 8 h. Collectively, the data indicated that bud activation and outgrowth might be dependent on local cytokinin synthesis in axillary buds or stems, and that bud activation preceded the activation of cell cycle genes during the outgrowth of ABs in apple shoots. PMID- 30311178 TI - Building eHealth and Telepsychiatry Capabilities: Three Educational Reports Across the Learning Continuum. PMID- 30311179 TI - Identification of a new turncurtovirus in the leafhopper Circulifer haematoceps and the host plant species Sesamum indicum. AB - Turncurtoviruses (family: Geminiviridae; genus: Turncurtovirus) appear to have a high degree of genetic variation in Iran. Leafhoppers of the species Circulifer haematoceps (Mulsant and Rey, 1855) (family: Cicadellidae) were collected in 2014 from three geographical regions in south-eastern Iran (Orzoeyeh, Jiroft and Sirjan; Kerman province) and screened for the presence of turncurtoviruses using a combination of PCR and rolling circle amplification (RCA) methods. Eleven genomes of turncurtovirus were recovered and sequenced. Leafhoppers were sampled off sesame (S. indicum L.) and turnip (Brassica rapa sub sp. rapa). Thus, we identified three symptomatic sesame plants (yellowing, boat-shaped leaf curling, vein swelling on the lower leaf surfaces) from sesame farms in Jiroft. In these samples, we identified the same turncurtovirus as in the leafhoppers and have named it sesame curly top virus (SeCTV). Collectively, these SeCTV share > 98% genome-wide pairwise identity and ~ 87.3% to a recently identified turncurtovirus (sesame yellow mosaic virus; SeYMV) from sesame in Pakistan (GenBank accession MF344550). The SeCTV and SeYMV sequences share < 70% genome-wide pairwise identity with isolates of Turnip curly top virus and Turnip leaf roll virus, the two species in the genus Turncurtovirus. Based on the pairwise identities and phylogenetic analysis, SeCTV (n = 12) and SeYMV (n = 1) represent two strains of a new species in the genus Turncurtovirus. PMID- 30311180 TI - Resignment: Infection is grateful to Prof. Alexander von Graevenitz. PMID- 30311181 TI - Sodium Valproate Ameliorates Neuronal Apoptosis in a Kainic Acid Model of Epilepsy via Enhancing PKC-Dependent GABAAR gamma2 Serine 327 Phosphorylation. AB - GABA is a dominant inhibitory neurotransmitter in the brain and A type GABA receptor (GABAAR) phosphorylation is critical for GABA-mediated inhibitory effect. However, its role in the neuroprotective effect of sodium valproate (VPA), a prevalent drug for treating patients with epilepsy, remains elusive. The present study was conducted to explore the role of GABAAR phosphorylation in the neuroprotection of VPA against a kainic acid-induced epileptic rat model and the potential molecular mechanisms. Neuronal apoptosis was evaluated by TUNEL assay, PI/Annexin V double staining, caspase-3 activity detection and Bax and Bcl-2 proteins expression via Western blot analysis. The primary rat hippocampal neurons were cultivated and cell viability was measured by CCK8 detection following KA- or free Mg2+-induced neuronal impairment. Our results found that VPA treatment significantly reduced neuronal apoptosis in the KA-induced rat model (including reductions of TUNEL-positive cells, caspase-3 activity and Bax protein expression, and increase of Bcl-2 protein level). In the in vitro experiments, VPA at the concentration of 1 mM for 24 h also increased cell survival and suppressed cell apoptosis in KA- or no Mg2+-induced models via CCK8 assay and PI/Annexin V double staining, respectively. What is more important, the phosphorylation of gamma2 subunit at serine 327 residue for GABAAR was found to be robustly enhanced both in the KA-induced epileptic rat model and neuronal cultures following KA exposure after VPA treatment, while no evident alteration was found in terms of GABAAR beta3 phosphorylation (408 or 409 serine residue). Additionally, pharmacological inhibition of protein kinase C (PKC) clearly abrogated the neuroprotective potential of VPA against KA- or free Mg2+ associated neuronal injury, indicating a critical role of PKC in the effect of GABAAR gamma2 serine 327 phosphorylation in VPA's protection. In summary, our work reveals that VPA mitigates neuronal apoptosis in KA-triggered epileptic seizures, at least, via augmenting PKC-dependent GABAAR gamma2 phosphorylation at serine 327 residue. PMID- 30311182 TI - Auricular Vagus Nerve Stimulation Exerts Antiinflammatory Effects and Immune Regulatory Function in a 6-OHDA Model of Parkinson's Disease. AB - According to epidemiologic studies, smoking appears to downregulate the prevalence of Parkinson's disease (PD), possibly due to antiinflammatory mechanisms via activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs). This receptor also appears to play a role in T-cell differentiation. Recently, it has become apparent that the innate immune system participates in PD pathogenesis. The aim of this study was to evaluate the effects of auricular vagus nerve stimulation (aVNS) on substantia nigra (SN) dopaminergic neurodegeneration and the associated neuroinflammation and immune responses in a rat PD model. Adult male Wistar rats were unilaterally administered 6 hydroxydopamine (6-OHDA) to the medial forebrain bundle, followed by aVNS treatment after surgery. Following motor behavioral tests, the expression of tyrosine hydroxylase (TH) in the SN and the levels of inflammatory cytokines in the ventral midbrain were evaluated. In addition, changes in the trends of subsets of CD4+ T lymphocytes in the SN were measured by immunofluorescence staining. Western blotting was used to evaluate the alpha7 nAChR protein level. Compared with 6-OHDA treats rats, aVNS treatment significantly improved motor deficits, increased TH and alpha7 nAChR expression, and reduced the levels of inflammatory cytokines (tumor necrosis factor-a (TNF-alpha) and interleukin-1beta (IL-1beta)) (p < 0.05). Additionally, aVNS increased the numbers of regulatory T (Treg) cells while decreasing T helper (Th)17 cells. aVNS exerted neuroprotective effects against dopaminergic damage, possibly by suppressing the evolution of inflammation and modulating innate immune responses. Thus, aVNS may be a potential promising therapy in the future. PMID- 30311183 TI - Addition of frontal EEG to adult home sleep apnea testing: does a more accurate determination of sleep time make a difference? AB - RATIONALE: Home sleep apnea testing (HSAT) typically does not include electroencephalogram (EEG) monitoring for sleep assessment. In patients with insomnia and low sleep efficiency, overestimation of the sleep period can result from absence of EEG, which will reduce sleep disordered breathing (SDB) indices and may lead to a false-negative result. OBJECTIVE: To validate a single channel frontal EEG for scoring sleep versus wake against full EEG during polysomnography, and then to examine the utility of adding this single channel EEG to standard HSAT to prevent false-negative results. METHODS: Epoch-by-epoch validation for sleep scoring of single channel EEG versus full PSG was first performed in 21 subjects. This was followed by a separate retrospective analysis of 207 consecutive HSATs in adults performed in a university-affiliated sleep center using the Somte (Compumedics) HSAT with one frontal EEG as well as chin EMG, nasal airflow, oxyhemoglobin saturation, respiratory effort, pulse rate, and body position. Each study was scored twice, with (HSATEEG) and without the EEG signal visible (HSATPolygraphy), to calculate AHI4 and RDI and the effect on OSA diagnosis and severity. Analyses were repeated in 69 patients with poor sleep suggesting insomnia plus Epworth Sleepiness Scale < 7 as well as in 38 patients ultimately shown to have sleep efficiency < 70% on HSAT with EEG. MEASUREMENTS AND MAIN RESULTS: Single channel and full EEG during polysomnography agreed on sleep versus wake in 92-95% of all epochs. HSAT without EEG overestimated the sleep period by 20% (VST = 440 +/- 76 min vs TST = 356 +/- 82 min), had a false negative rate of 8% by AHI4 criteria, and underestimated disease severity in 11% of all patients. Sub-group analysis of patients with subjective poor sleep suggesting insomnia did not change the results. Patients later shown to have low sleep efficiency had lower SDB indices and a 20.8% false negative rate of sleep apnea diagnosis. CONCLUSIONS: Although overall false negative rates using HSATPolygraphy were moderate, suggesting utility for ruling out OSA, there was a specific subgroup in whom there were significant missed diagnoses. However, we were unable to identify this subgroup a priori. PMID- 30311185 TI - Effects of Lactobacillus acidophilus and Bifidobacterium bifidum Probiotics on the Expression of MicroRNAs 135b, 26b, 18a and 155, and Their Involving Genes in Mice Colon Cancer. AB - A wide range of sources supports that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. In this case, it seems that the probiotics may have a possible molecular mechanism via microRNAs (miRNAs). The present study is aimed to evaluate the effects of Lactobacillus acidophilus and Bifidobacterium bifidum probiotics on the expression of miRNAs 135b, 26b, 18a, and 155 and their target genes, including APC, PTEN, KRAS, and PU.1 in mouse azoxymethane (AOM)-induced colon cancer. Thirty-eight male BALB/c mice were randomly divided into four groups: the control, AOM, Lactobacillus acidophilus, and Bifidobacterium bifidum to deliberate the effects of the probiotics on the miRNAs and their target genes. Except for the control group, the rest groups were weekly given AOM (15 mg/kg, s.c) in three consecutive weeks to induce mouse colon cancer. The animals were given 1.5 g powders of L. acidophilus (1 * 109 cfu/g) and B. bifidum (1 * 109 cfu/g) in 30 cc drinking water in the related groups for 5 months. At the end of the study, the animals were sacrificed and their blood and colon samples were removed for the molecular analyses. The results showed that the expression of the miR-135b, miR-155, and KRAS was increased in the AOM group compared to the control group in both the plasma and the colon tissue samples, and the consumption of the probiotics decreased their expression. Moreover, the miR-26b, miR-18a, APC, PU.1, and PTEN expressions were decreased in the AOM group compared to the control group and the consumption of the probiotics increased their expressions. It seems that Lactobacillus acidophilus and Bifidobacterium bifidum though increasing the expression of the tumor suppressor miRNAs and their target genes and decreasing the oncogenes can improve colon cancer treatment. PMID- 30311186 TI - A post-liberal theory of stratification. AB - The iconic 'liberal theory' of stratification fails to attend to the many types of downward mobility and wage loss generated by late-industrial stratification systems. Although the liberal theory and its close cousins assume that loss and failure will be interpreted in individualistic terms, recent developments suggest instead that they are generating solidary groups that are increasingly locked into zero-sum contest and successfully mobilized by politicians and other norm entrepreneurs. These developments imply a Marxisant future for late-industrial inequality that bears scant resemblance to the highly individualized, unstructured, and non-conflictual stratification system envisaged by the liberal theory. We outline a new post-liberal theory of stratification that better captures the forces making for change and resistance in late-industrial societies. PMID- 30311184 TI - Obesity modulates the association between sleep apnea treatment and CHI3L1 levels but not CHIT1 activity in moderate to severe OSA: an observational study. AB - PURPOSE: The inflammatory markers chitinase-3-like protein 1 (CHI3L1) and chitotriosidase (CHIT1) have both been associated with cardiovascular complications. The aim of this preliminary observational study was to assess the roles and interaction of obstructive sleep apnea (OSA) severity and body mass index (BMI) with plasma CHI3L1 levels and CHIT1 activity in patients with moderate to severe OSA. The second aim was to assess the roles and interaction of positive airway pressure (PAP) treatment and BMI on the expression of the same proteins. METHODS: The study included 97 OSA patients with an apnea-hypopnea index (AHI) >= 15 and full usage of PAP treatment after 4 months. Plasma CHI3L1 levels and CHIT1 activity were measured before and after treatment. RESULTS: Multiple linear regression analysis demonstrated an independent association of BMI on CHI3L1 levels (p < 0.05) but not on CHIT1 activity. The OSA severity markers (AHI and oxygen desaturation index) did not independently or in interaction with BMI levels associate with CHI3L1 levels or with CHIT1 activity (p > 0.05). A two-way repeated measures ANOVA revealed a significant interaction between PAP treatment effect (before vs. after) and BMI groups (< 35 kg/m2 vs. >= 35 kg/m2) on CHI3L1 levels (p = 0.03) but not on CHIT1 activity (p = 0.98). CONCLUSIONS: Obesity independently associated with CHI3L1 levels. Association between OSA severity and CHI3L1 levels or CHIT1 activity (independent of or dependent on obesity level) could not be confirmed. However, decrease was observed in CHI3L1 levels after PAP treatment in severely obese OSA patients but not in those less obese. PMID- 30311187 TI - Anti-D quantification in relation to anti-D titre, middle cerebral artery Doppler measurement and clinical outcome in RhD-immunized pregnancies. AB - BACKGROUND: The optimal strategy to monitor RhD-immunized pregnancies is not evident. Whether a quantitative analysis of anti-D antibodies adds valuable information to anti-D titre is unclear. The aim of this study was to evaluate the relevance of anti-D quantification in routine monitoring of RhD-immunized pregnancies. MATERIALS AND METHODS: In a retrospective study, 64 consecutive pregnancies in 61 immunized women with anti-D titre >=128 at any time during pregnancy were included. According to routine, at titre >=128, anti-D quantification was performed by flow cytometry and the peak systolic velocity in the middle cerebral artery was measured by ultrasound. Decisions for treatment with intrauterine blood transfusion were based on increased peak systolic velocity in the middle cerebral artery. RESULTS: Increasing anti-D concentrations correlated well to increasing anti-D titres, but at each titre value, there was a large interindividual variation, in the determined anti-D concentration. Intrauterine transfusions were initiated in 35 pregnancies according to algorithms based on ultrasound measurements, at anti-D concentrations of 2.4-619 IU/ml and titre 128-16 000. Sixty pregnancies resulted in a live-born child, three in miscarriage and one in termination of pregnancy. During the perinatal care in the neonatal intensive care unit, thirty-one of the neonates were treated with blood exchange transfusions and/or red cell transfusions and 47 were treated with phototherapy. CONCLUSION: Anti-D quantification does not add further information compared to anti-D titre, in defining a critical level to start monitoring RhD-immunized pregnancies with Doppler ultrasound. PMID- 30311188 TI - Electroencephalographic evidence for improved visual working memory performance during standing and exercise. AB - While a substantial body of research has investigated the effects of aerobic exercise on cognitive performance, few have monitored exercise-concurrent cognitive processes via electroencephalography and fewer still using an event related potential (ERP) approach. As such, little is known regarding how the temporal dynamics of cognitive processing are influenced during aerobic activity. Here, we aimed to elucidate the influence of aerobic exercise on the temporal dynamics of concurrent visual working memory (VWM) performance. Participants performed a VWM retro-cue task at rest and during aerobic exercise across two postural modalities: seated (using a stationary bicycle) and standing upright (using a treadmill). Three consecutive phases of the VWM processing pipeline were assessed by means of lateralized ERPs: access of VWM representations, response selection, and response execution. Aerobic exercise and upright posture were found to have significant effects on VWM performance, facilitating processing speed in the retro-cue task. This facilitation arose primarily at an intermediary stage between the phases of accessing VWM representations and response selection. Our findings hold implications not only for understanding the influence of aerobic activity on VWM, but also for contemporary models of VWM that are built exclusively on data recorded during stationary, seated conditions. PMID- 30311189 TI - SMART - Not Always Only "Stroke-Like". AB - Stroke-like migraine attacks after radiation therapy (SMART) is a syndrome observed in a delayed fashion in patients following brain radiation therapy. It is a rare but important differential diagnosis of migraine in these patients, often presenting with migraine-like headache. In addition, there may be focal neurological deficits or seizures. In general, it is regarded as a reversible condition, therefore termed stroke-like. Our case illustrates that there may also be ischemic stroke associated with SMART leading to an unfavorable course, even after prior remission. PMID- 30311190 TI - Rosiglitazone up-regulates glial fibrillary acidic protein via HB-EGF secreted from astrocytes and neurons through PPARgamma pathway and reduces apoptosis in high-fat diet-fed mice. AB - The anti-diabetic drug and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, rosiglitazone, alters astrocyte activation; however, its mechanism remains less-known. We hypothesized participation of epidermal growth factor receptor (EGFR), known to control astrocyte reactivity. We first detected that rosiglitazone promoted glial fibrillary acidic protein (GFAP) expression in primary astrocytes as well as the mouse cerebral cortex, associated with increased EGFR activation. Screening for EGFR ligands revealed a rosiglitazone mediated increase of heparin-binding epidermal growth factor (HB-EGF) in astrocytes, resulting in HB-EGF release into culture medium and mouse cerebrospinal fluid too. Treatment with HB-EGF-siRNA and EGFR inhibitors showed that the rosiglitazone-induced HB-EGF and p-EFGR were interdependent, which participated in GFAP increase. Interestingly, we observed that rosiglitazone could induce cellular and secreted-HB-EGF in neurons also, contributing toward the activated EGFR-induced GFAP in astrocytes. Probing whether these effects of rosiglitazone were PPARgamma-linked, revealed potential PPARgamma-responsive elements within HB-EGF gene. Moreover, gel-shift, site-directed mutagenesis, chromatin-immunoprecipitation and luciferase-reporter assays demonstrated a PPARgamma-dependent HB-EGF transactivation. Subsequently, we examined effects of rosiglitazone in a high-fat diet-fed diabetes mouse model, and supporting observations in the normal cortical cells, identified a rosiglitazone-induced GFAP, astrocyte and neuronal HB-EGF and secreted-HB-EGF in the cerebral cortex of diabetic mice. Moreover, assessing relevance of increased HB-EGF and GFAP revealed an anti-apoptotic role of rosiglitazone in the cerebral cortex, supported by a GFAP-siRNA as well as HB-EGF-siRNA-mediated increase in cleaved caspase 3 and 9 levels in the rosiglitazone-treated astrocyte-neuron coculture. Overall, our study indicates that rosiglitazone may protect the brain, via a PPARgamma-dependent HB-EGF/EGFR signaling and increased GFAP. PMID- 30311191 TI - Detection of anti-type VII collagen IgE antibodies in epidermolysis bullosa acquisita. AB - BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare pemphigoid disease involving autoantibodies to type VII collagen (COL7), a major structural component of anchoring fibrils. IgE autoantibodies to type XVII collagen (BP180) have been identified in bullous pemphigoid (BP), the prototype of pemphigoid diseases. Although the pathogenic relevance of IgG anti-COL7 has been investigated, that of IgE in EBA remains unclear. OBJECTIVE: To reveal the presence and pathogenic relevance of IgE anti-COL7 in EBA. METHODS: We examined IgE antibodies in 109 EBA patients by indirect immunofluorescence (IIF) and ELISA. RESULTS: IIF with normal human skin revealed IgE reactivity in the basement membrane zone in 29 (26.6%) cases. To verify whether the IgE antibodies were specific to COL7, we performed IIF with 21 clearly positive cases and the skin of a patient with dystrophic epidermolysis bullosa, which does not involve COL7. All cases showed negative results, indicating that IgE antibodies were specific to COL7. In a modified IgG COL7 ELISA for IgE, 16 (14.7%) cases were positive (3 and 13 cases were negative and positive on IIF, respectively). We compared anti-COL7 IgG and IgE and found a weak but significant correlation (r=0.459, p<0.0001). EBA is clinically divided into a mechanobullous (MB, non inflammatory) type and an inflammatory (INF) type resembling BP. Of the IIF positive cases, 11 of 30 (36.7%) had INF and 9 of 48 (18.8%) had MB. CONCLUSIONS: This study is the first to demonstrate the presence of circulating anti-COL7 IgE in EBA patients, which may correlate with the clinical phenotype. This article is protected by copyright. All rights reserved. PMID- 30311192 TI - Mechanical stress protects against osteoarthritis via regulation of the AMPK/NF kappaB signaling pathway. AB - Mechanical stress plays a key role in regulating cartilage degradation in osteoarthritis (OA). The aim of this study was to evaluate the effects and mechanisms of mechanical stress on articular cartilage. A total of 80 male Sprague-Dawley rats were randomly divided into eight groups (n = 10 for each group): control group (CG), OA group (OAG), and CG or OAG subjected to low-, moderate-, or high-intensity treadmill exercise (CL, CM, CH, OAL, OAM, and OAH, respectively). Chondrocytes were obtained from the knee joints of rats; they were cultured on Bioflex 6-well culture plates and subjected to different durations of cyclic tensile strain (CTS) with or without exposure to interleukin-1beta (IL 1beta). The results of the histological score, immunohistochemistry, enzyme linked immunosorbent assay, and western-blot analyses indicated that there were no differences between CM and CG, but OAM showed therapeutic effects compared with OAG. However, CH and OAH experienced more cartilage damage than CG and OAG, respectively. CTS had no therapeutic effects on collagen II of normal chondrocytes, which is consistent with findings after treadmill exercise. However, CTS for 4 hr could alleviate the chondrocyte damage induced by IL-1beta by activating AMP-activated protein kinase (AMPK) phosphorylation and suppressing nuclear translocation of nuclear factor (NF)-kappaB p65. Our findings indicate that mechanical stress had no therapeutic effects on normal articular cartilage and chondrocytes; mechanical stress only caused damage with excessive stimulation. Still, moderate biomechanical stress could reduce sensitization to the inflammatory response of articular cartilage and chondrocytes through the AMPK/NF-kappaB signaling pathway. PMID- 30311194 TI - Crossing U.S. Borders While Pregnant: An Increasingly Complex Reality. AB - In response to the Eighth Amendment to the Constitution of Ireland, which states that the fetus and the mother have equal rights to life and that nearly all abortions are therefore illegal, many Irish feminists sported luggage tags that read "HEALTHCARE NOT AIRFARE." The expression-which recently became a popular twitter hashtag for pro-choice citizens of Ireland leading up to the historic referendum to repeal that abortion ban-refers to the fact that pregnant women from Ireland have long been forced to travel to other European countries in order to legally terminate their pregnancies. In the United States, there is also a deep and challenging relationship between borders and reproductive health. However, that relationship is not understood as clearly as it appears to be in the Irish context. We urgently need to pay careful attention to the interconnections between U.S. border politics and reproductive health care access and to take concrete steps to address resultant injustices. PMID- 30311193 TI - Estimating the hospital costs of inpatient harms. AB - OBJECTIVE: To estimate the additional hospital costs associated with inpatient medical harms occurring during an index inpatient admission and costs from subsequent readmissions within 90 days. DATA SOURCE: 2009 to 2011 Healthcare Cost and Utilization Project's State Inpatient Databases from 12 states. STUDY DESIGN: We compare hospital costs incurred by patients experiencing a specific harm during their hospital stay to the costs incurred by similar patients who did not experience that harm. DATA EXTRACTION: We extracted records for adult patients admitted for a reason other than rehabilitation or mental health, were at risk of a harm, and were admitted for less than a year. PRINCIPAL FINDINGS: The costliest inpatient harms, such as surgical site infections and severe pressure ulcers, are associated with approximately $30 000 in additional index stay costs per harm. Less costly harms, such as catheter- or hospital-associated urinary tract infections and venous thromboembolism, can add $6000 to $13 000. Birth and obstetric traumas add as little as $100. CONCLUSIONS: Our analysis represents rigorous estimates of the hospital costs of a variety of inpatient harms; these should be of interest to health care administrators and policy makers to identify areas for cost savings to the health care system. PMID- 30311195 TI - Justifying Conscience Clauses. AB - In "Disentangling Conscience Protections," in this issue of the Hastings Center Report, Nadia Sawicki offers a taxonomy of conscience protection laws (conscience clauses) that highlights the expansive protections they can offer to health professionals who refuse to provide a medical service for reasons of conscience. Conscience clauses can protect health professionals from adverse actions by public actors (such as administrative agencies, prosecutors, and government funders) or private actors (such as employers, private professional associations, and injured patients), and they can also protect health professionals from being subject to adverse actions for their beliefs, their conduct, or harm that results from their conduct. This taxonomy provides an accurate description of the broad range of protections conscience clauses can offer and thereby is a valuable contribution to the scholarly literature on conscientious objection in health care. But it remains to consider whether the distinctions Sawicki identifies disentangle conscience protections beyond merely providing a taxonomy. In particular, does the taxonomy identify relevant distinctions in relation to determining whether a conscience clause is justified? PMID- 30311196 TI - Investing in Parenthood. AB - The recent child custody case Weisberger v Weisberger raises a number of ethical issues concerning the rights and responsibilities of parents. Chavie Weisberger, thirty-five, and her husband, both members of an ultraorthodox Hasidic community, appeared before a religious court in 2008 to obtain a divorce. There are two sharply contrasting legal rulings in this case. Setting aside the legally significant fact that Chavie had signed the divorce agreement with the clause requiring her to raise her children Hasidic, which decision is ethically more defensible and why? Were Chavie's parental rights violated when the court removed her children from her care? Should her ex-husband have been awarded full custody on the ground that this was in the children's best interest, and is this the right standard to use in making custody decisions? What parental responsibilities did Chavie and her ex-husband have, and were they satisfactorily discharging them? A theory of the moral foundations of parenthood should provide answers to these questions among others. Joseph Millum, in his excellent new book The Moral Foundations of Parenthood, does this and more. His theory encompasses accounts of the foundation and content of parental rights and responsibilities, the acquisition of parental responsibilities, and the standards governing parental decision-making. PMID- 30311197 TI - Amyloid in the Brain, Alzheimer's on the Mind. AB - Twenty percent of patients diagnosed with Alzheimer's disease by experts like me in fact don't have elevated amyloid and so, in fact, don't have Alzheimer's. What they do have is the subject of intense research, and there are many possibilities. A recent study of one thousand brain autopsies from older adults with a range of cognitive impairment showed at least 230 combinations of neuropathology. The point is that while the disease will be treatable, we're unlikely to defeat it as we did polio and smallpox. We're going to have to learn how to live with Alzheimer's as an at least somewhat treatable disease. To do so, we need to think outside the biomedical box. PMID- 30311198 TI - Defining Life and Regulating Reproductive Choice. AB - If you blinked you may have missed it. The Department of Health and Human Services published its strategic plan for the 2018-2022 fiscal years, which includes the statement that HHS accomplishes its mission through programs and initiatives that serve and protect "Americans at every stage of life, from conception." Of note, the "from conception" language is new and, depending on the direction President Trump's administration plans to go, could have profound implications for the regulation of reproductive services ranging from abortion to in vitro fertilization (IVF). PMID- 30311199 TI - Disentangling Conscience Protections. AB - Earlier this year, the U.S. Department of Health and Human Services announced its intent to strengthen enforcement of legal protections for health care providers' conscience rights. It proposed regulations that would give the DHHS Office of Civil Rights greater authority to ensure that recipients of federal funding comply with federal conscience laws. This recent development creates an opportunity for scholars and policy-makers to revisit the perennial debate about whether and how law should protect health care providers' rights of conscience. Arguments about who should be protected, what actions should be protected, and whether there should be any limitations on the exercise of conscience rights have brought us no closer to a resolution. However, there is one remaining avenue for analysis that has, surprisingly, received very little attention-the question of how providers are protected, and from what consequences. Existing U.S. conscience laws immunize health care providers from a wide range of adverse consequences including civil liability, criminal prosecution, administrative penalties, adverse action by employers, and discrimination by private actors, among others. However, academic and public policy debates rarely acknowledge the breadth of these protections. It is essential to disentangle this network of possible protections. PMID- 30311201 TI - At the Borders of Bioethics. AB - What are the boundaries of bioethics? Where does bioethics give way to other kinds of ethics-organizational ethics, environmental ethics, social ethics, or just ethics? According to one commonly cited account of the origin of bioethics, the field always had a relatively broad remit; it was supposed to be about the ethics of the life sciences in general. In the early days of bioethics, however, the topic that seemed most in need of critical attention was the encounter between experts in medicine and the laity-doctors or medical researchers on the one hand and patients or medical research subjects on the other. Even given the narrow focal point, however, bioethics very naturally expanded. Much of the September-October 2018 issue of the Hastings Center Report either argues or assumes that bioethics extends well beyond into social ethics. A special report published as a supplement to this issue pushes the point explicitly. PMID- 30311202 TI - How Bioethics Can Shape Artificial Intelligence and Machine Learning. AB - Artificial intelligence and machine learning have the potential to revolutionize the delivery of health care. But designing machine learning-based decision support systems is not a merely technical challenge. It also requires attention to bioethical principles. As AI and machine learning advance, bioethical frameworks need to be tailored to address the problems that these evolving systems might pose, and the development of these automated systems also needs to be tailored to incorporate bioethical principles. PMID- 30311203 TI - Whom to Engage in Patient-Engaged Research? Reflection on Selection. AB - Engaging patients in research has come to be viewed as a vital component of high quality research, and funders now regard engaging patients and other stakeholders as a core criterion for funding decisions. In response, numerous empirical and conceptual papers have emerged to guide the process of engagement. However, as Emily Largent and colleagues rightly note, the inquiry of whom to engage has received less attention. While several teams have suggested that the selection of patients for engagement is an important consideration, researchers generally have little guidance on how to undertake this process. To that end, Largent and colleagues offer an important contribution to the literature. I agree with their argument regarding the centrality of critically examining which patients to engage in research and with their recommendations to maximize the positive goals of patient engagement. However, three issues warrant further consideration. PMID- 30311204 TI - A Medical Pedagogy of Mutual Suffering. AB - Who's afflicted? Early in Nicole Piemonte's book Afflicted: How Vulnerability Can Heal Medical Education and Practice, she quotes an email from a physician whose voice sets the problem and tone. He describes himself as someone "who has intended well" but then "nearly burned out because of the insidious process of physician formation that left me a mess at the threshold of the suffering of other human beings." His confessional manifesto regrets "the sad things I have seen and done." His narrative then turns to redemption: "I was-pardon the sentiment-loved back into a good medical practice as a form of growing wisdom and care" (pp. x-xi). Afflicted is written for those who hear this voice speaking for many others. PMID- 30311205 TI - Evidence and Human Genome Editing. AB - In July, the United Kingdom's Nuffield Council on Bioethics issued a report on human genome editing in which it said that editing a human embryo's genome to reduce the possibility that the future child will inherit a genetic disorder could be ethically acceptable when certain conditions are met: the intended use of genome-editing interventions secures and is consistent with the "welfare of the future person" and does not "increase disadvantage, discrimination or division in society." Yet the Council noted that if current legal restrictions on the use of heritable genome-editing interventions were lifted, the interventions should be used only in the context of "well-designed and supervised studies" to ensure that they are safe and effective. Some people might contend that it is premature to talk about what kind of evidence-and how much-will be needed to gauge the safety and effectiveness of genome-editing interventions since the United Kingdom, the United States, and several other countries currently prohibit clinical trials that involve transferring into a woman an embryo whose genome was edited. Yet based on an analysis of evidentiary disputes involving several medical technologies (an analysis that I conducted with my Hastings colleague Michael Gusmano for a forthcoming book, Debating Modern Medical Technologies: The Politics of Safety, Effectiveness, and Patient Access), I suggest that now is the time to start the conversation about evidentiary standards for the use of genome editing in reproductive medicine. PMID- 30311206 TI - When Societal Structural Issues Become Patient Problems: The Role of Clinical Ethics Consultation. AB - The debate about health insurance coverage and the related issue of unequal access to health care turn on fundamental questions of justice, but for an individual patient like DM, the abstract question about who is deserving of health insurance becomes a very concrete problem that has a profound impact on care and livelihood. DM's circumstances left him stuck in the hospital. A satisfactory discharge plan remained elusive; his insurance coverage severely limited the number and type of facilities that would accept him; and his inadequate engagement in his own rehabilitation process limited discharge options even further. Despite extensive involvement with the psychiatry, social work, physical therapy, and occupational therapy teams, DM consistently made "bad" decisions. He repeatedly refused antibiotics and did not consistently work with rehab services to improve his strength and mobility. Although the clinicians wanted to provide him with the best care possible, he often seemed unwilling to do the things necessary to achieve this care-or perhaps his depression rendered him unable to do so. He also tended to take out his frustration on staff members caring for him. All of this was, in turn, very frustrating for the staff. It may be easy, however, to make too much of DM's role, to see his choices as more important than his circumstances. A major goal of the ethics consultants was to reframe DM's predicament for the staff members involved in his care. PMID- 30311207 TI - Patient-Engaged Research: Choosing the "Right" Patients to Avoid Pitfalls. AB - To ensure that the information resulting from research is relevant to patients, the Patient-Centered Outcomes Research Institute eschews the "traditional health research" paradigm, in which investigators drive all aspects of research, in favor of one in which patients assume the role of research partner. If we accept the premise that patient engagement can offer fresh perspectives that shape research in valuable ways, then at least two important sets of questions present themselves. First, how are patients being engaged-and how should they be engaged? Second, which patients are being engaged-and which patients should be? This set has received relatively less attention, and the neglect is surprising, given that the "who" question is conceptually prior to the question of "how." This article focuses attention on the "who" of patient engagement in research. First, we provide background on the rationale for patient engagement, underscoring the importance of ensuring the representativeness of engaged patients. Second, we present what little is known about patients engaged in PCORI-funded research. Third, we identify and discuss the ethical implications of ways in which current practices of patient identification and recruitment may lead to a lack of representativeness. These practices include reliance on the well-connected and well-informed, reliance on patients who are not well trained or well-informed, and reliance on patient advocacy organizations. Finally, we consider several strategies for addressing these pitfalls in order to maximize the positive goals of patient engagement. Patient engagement is intended to address the inability of researchers, funders, and others to fully represent patient views and priorities, but without sufficient attention, the patients selected for this role may still leave important gaps. PMID- 30311208 TI - Solidarity: Careful What We Wish For. AB - In his well-researched new book, Solidarity and Justice in Health and Social Care, Ruud ter Meulen traces the history of the concept of solidarity and describes the important role that it can play in health care. He contrasts solidarity with other normative concepts, such as autonomy and justice. According to ter Meulen, solidarity entails a commitment and willingness to help others who are "in need of it due to circumstances out of their control" (p. 170). Thus, solidarity exists when people act for the sake of other people who are vulnerable in some way. Ter Meulen treats solidarity as a distinct normative concept and believes that it is critical for health care. No doubt insofar as social ties and cohesion are good for health, so is solidarity. PMID- 30311209 TI - Foresight over hindsight: Mandatory publication of clinical research protocols prior to conduct. PMID- 30311210 TI - Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity. AB - Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota. PMID- 30311211 TI - What's the "buzz" about propolis? Propolis-induced systemic contact dermatitis. PMID- 30311212 TI - Naloxone for opioid-exposed newborn infants. AB - BACKGROUND: Naloxone, a specific opioid antagonist, is available for the treatment of newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. It is unclear whether newborn infants may benefit from this therapy and whether naloxone has any harmful effects. OBJECTIVES: To determine the effect of naloxone on the need for and duration of neonatal unit stay in infants of mothers who received opioid analgesia prior to delivery or of mothers who have used a prescribed or non prescribed opioid during pregnancy. SEARCH METHODS: We searched the following databases in February 2018: the Cochrane Central Register of Controlled Trials (the Cochrane Library 2018, Issue 1), MEDLINE (OvidSP), MEDLINE In process & Other Non-Indexed Citations (OvidSP), Embase (OvidSP), CINAHL (EBSCO), Maternity and Infant Care (OvidSP), and PubMed. We searched for ongoing and completed trials in the WHO International Clinical Trials Registry Platform and the EU Clinical Trials Register. We checked the reference lists of relevant articles to identify further potentially relevant studies. SELECTION CRITERIA: Randomised controlled trials comparing the administration of naloxone versus placebo, or no drug, or another dose of naloxone to newborn infants with suspected or confirmed in utero exposure to opioid. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of Cochrane Neonatal with separate evaluation of trial quality and data extraction by two review authors and synthesis of data using risk ratio, risk difference, and mean difference. MAIN RESULTS: We included nine trials, with 316 participants in total, that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opioid analgesia prior to delivery. None of the included trials investigated infants born to mothers who had used a prescribed or non-prescribed opioid during pregnancy. None of these trials specifically recruited infants with cardiorespiratory or neurological depression. The main outcomes reported were measures of respiratory function in the first six hours after birth. There is some evidence that naloxone increases alveolar ventilation. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding). AUTHORS' CONCLUSIONS: The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. Given concerns about the safety of naloxone in this context, it may be appropriate to limit its use to randomised controlled trials that aim to resolve these uncertainties. PMID- 30311213 TI - Family presence during resuscitation in emergency departments: professionals' attitudes in Brazil. AB - AIM: The study explored the views and attitudes of nurses and physicians on family presence during resuscitation in emergency departments in Brazil. BACKGROUND: International emergency associations endorse family presence during resuscitation; however, the extent to which it is practiced remains unclear, particularly in the Brazilian context. Research of emergency staff views and attitudes towards this practice is desirable so that actions can be identified to support families at the bedside. METHODS: A qualitative research was conducted. Thirty-two health professionals (11 physicians and 21 nurses) working in two emergency departments in southern Brazil were purposefully recruited in January 2015. In-depth interviews were conducted, and data were analysed using content analysis. FINDINGS: Nurses and physicians found family presence during resuscitation controversial and the general attitude towards this practice was negative. They reported that 'changes are needed' to adapt hospital infrastructures for family presence, and to train staff to respond to the information and emotional needs of families. DISCUSSION: Translating a family nursing framework into clinical practice involves the need for reassessing educational and management policies in clinical contexts. CONCLUSION: This research brings new understanding about the attitudes of some Brazilian nurses and physicians on the implementation of family presence during resuscitation and identifies the need to develop policies and strategies to improve family presence in emergency departments. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Hospital based policies are required to improve family-centred care in emergency departments while providing a criterion of legality and safety to professionals to invite families to be present during invasive procedures. Also, family-focused education in health science degrees, continuing education and in the community is required. PMID- 30311214 TI - Long-chain polyunsaturated fatty acid supplementation in the first year of life affects brain function, structure, and metabolism at age nine years. AB - The present study sought to determine whether supplementation of long-chain polyunsaturated fatty acids (LCPUFA) during the first year of life influenced brain function, structure, and metabolism at 9 years of age. Newborns were randomly assigned to consume formula containing either no LCPUFA (control) or formula with 0.64% of total fatty acids as arachidonic acid (ARA; 20:4n6) and variable amounts of docosahexaenoic acid (DHA; 22:6n3) (0.32%, 0.64%, or 0.96% of total fatty acids) from birth to 12 months. At age 9 years (+/-0.6), 42 children enrolled in a follow-up multimodal magnetic resonance imaging (MRI) study including functional (fMRI, Flanker task), resting state (rsMRI), anatomic, and proton magnetic resonance spectroscopy (1 H MRS). fMRI analysis using the Flanker task found that trials requiring greater inhibition elicited greater brain activation in LCPUFA-supplemented children in anterior cingulate cortex (ACC) and parietal regions. rsMRI analysis showed that children in the 0.64% group exhibited greater connectivity between prefrontal and parietal regions compared to all other groups. In addition, voxel-based analysis (VBM) revealed that the 0.32% and 0.64% groups had greater white matter volume in ACC and parietal regions compared to controls and the 0.96% group. Finally, 1 H MRS data analysis identified that N-acetylaspartate (NAA) and myo-inositol (mI) were higher in LCPUFA groups compared to the control group. LCPUFA supplementation during infancy has lasting effects on brain structure, function, and neurochemical concentrations in regions associated with attention (parietal) and inhibition (ACC), as well as neurochemicals associated with neuronal integrity (NAA) and brain cell signaling (mI). PMID- 30311215 TI - The effects of fluorescent labels on Abeta42 aggregation detected by fluorescence correlation spectroscopy. AB - Fluorescence-based methods are promising for measuring amyloid beta (Abeta) oligomers, given their capacity to analyse a sample at the single-molecule level. As the attachment of fluorescent labels may influence the biochemical properties of the Abeta oligomers, the effects of fluorescent labels on Abeta oligomers must be evaluated. In this paper, we compared the impacts of five different fluorescent dyes on the aggregation of Abeta42 oligomers using fluorescence correlation spectroscopy (FCS). We found that fluorescent labels of BODIPY(r) FL C5 (BP), N-hydroxysuccinimide rhodamine B ester (RB) and rhodamine B isothiocyanate (RITC) increased the propensity of labelled Abeta42 oligomers to aggregate, whereas 6-(fluorescein-5-carboxamido) hexanoic acid succinimidyl ester (5-SFX) and fluorescein 5(6)-isothiocyanate (5(6)-FITC) decreased the propensity of labelled Abeta42 oligomers to aggregate. This difference originated from the different electric charges and hydrophobicity of the fluorescent dyes. These results provide valuable information for establishing different aggregation models for Abeta42 oligomers in vitro using FCS. PMID- 30311216 TI - An Exploratory Study of Predictors of Relationship Commitment for Cisgender Female Partners of Transgender Individuals. AB - The current exploratory study investigates which variables predict commitment among cisgender women currently in a relationship with a transgender-identified partner. This study includes variables specific to gender diverse couples such as years in the relationship, amount of prior knowledge about transgender identity, and gender role beliefs. Also included are the general relationship factors of satisfaction, quality of alternatives, investment size, and the outcome variable of commitment, as described in the Investment Model of Commitment. Using convenience sampling from online support groups, the sample was n = 138 cisgender female partners. The findings of the regression analyses indicate one's personal resilience and the number of years in the relationship prior to transition are significantly related to partner commitment, with satisfaction mediating both associations. The longer a participant was in the relationship at the time of a gender transition of a partner, the less satisfaction they report, thus reducing commitment to the relationship. Additionally the more personal resilience a partner endorses, the higher the relationship satisfaction, and in turn, more commitment is reported. The results offer information about the important factors related to staying in relationships during and after a gender transition. PMID- 30311217 TI - Differential diagnosis of late-type reactions to injected local anaesthetics: Inflammation at the injection site is the only indicator of allergic hypersensitivity. AB - BACKGROUND: Anaphylaxis-like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms. OBJECTIVES: To assess the frequency and symptoms of late-type hypersensitivity occurring several hours after LA injections. METHODS: We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work-up of LA-associated late-type reactions. RESULTS: Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late-type allergic LA hypersensitivity was confirmed. CONCLUSIONS: Late-type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions. PMID- 30311219 TI - The Future of Migraine Prevention. AB - Barring unforeseen circumstances, we anticipate the arrival of the first mechanism-specific class of molecules for migraine prevention in 2018. Despite many ground-breaking advances in the field over the last several years, these agents, broadly identified as calcitonin gene-related peptide-based pharmaceuticals, have captured the imagination and attention of the lay press and much of the headache community. This paper will address the factors, both class specific and systems-based, that are likely to affect the launch, access, compliance, and adherence related to this new class, as well as attempt to place these novel medications in context of the current state and anticipated changes in headache medicine. PMID- 30311218 TI - An Implementation Study of Relationship Checkups as Home Visitations for Low Income At-Risk Couples. AB - Couples with the greatest need for relationship health maintenance and intervention are often least able to afford and access it; therefore, accessible, affordable, effective, and brief interventions are needed to improve relationship health for those who need it most. Consequently, this paper examined whether a brief relationship intervention could be effectively implemented with a low income, underserved population. All enrolled participants (N = 1,312) received the Relationship Checkup, which consists of an assessment and a feedback session delivered in their homes or at a local clinic at their request. Measures assessed relationship satisfaction, communication, psychological and physical aggression, and intimacy at baseline and 1-month follow-up, and program and relationship satisfaction at 6-month follow-up. All participants reported significant improvements on all outcomes with small effect sizes. However, moderation analyses suggested that distressed couples reported significantly larger effects across the board. Overall, participants reported that they were highly satisfied with the intervention both immediately after its delivery and 6 months later. Findings provide preliminary support for the effectiveness of this brief checkup and point to the utility of offering these kinds of low-cost brief interventions in flexible formats for those who might have the most difficulty accessing them. PMID- 30311220 TI - ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. AB - ZC3H13 is a canonical CCCH zinc finger protein, which harbors a somatic frame shift mutation in colorectal cancer (CRC). However, its expression and biological function were still uncertain. In the current study, we found that ZC3H13 was served as a tumor suppressor in CRC cells, which decreased the expression of Snail, Cyclin D1, and Cyclin E1, and increased the expression of Occludin and Zo 1 through inactivating Ras-ERK signaling pathway. Furthermore, reduction of ZC3H13 associated with advanced TNM stage (p = 0.02), positive regional lymph node metastasis ( p = 0.01). Taken together, the current study indicated that ZC3H13 may be an upstream regulator of Ras-ERK signaling pathway and suppressed invasion and proliferation of CRC. PMID- 30311221 TI - Aging: Drawing a Map for the Future. AB - I live on a short street in a small town, Hastings-on-Hudson, some fifteen miles up the Hudson River from New York City. Over the past decade a number of families have moved in, with about sixteen children among them. More than a bit housebound now because of old age and watching them romping about, I try to imagine what their world will be like when they have reached my present age, some eighty years from now. But I have a problem. I just can't imagine it. The demographic changes now appearing on the horizon will force unforeseeable changes. What would it have been like in 1930, when I was born, if someone then had to project the future of aging? They could not have guessed. Some momentous changes are now emerging, and they are bound to change the aging picture. What's being done to respond to those growing pressures? PMID- 30311222 TI - Co-creating Environments: Empowering Elders and Strengthening Communities through Design. AB - Working with elders around the world has taught me that those living in grass huts in Africa with children at their feet are often happier than people in assisted-living homes with a chandelier over their heads. My work in design consultancy and in fifteen years of running a nonprofit, Ibasho, that aims to co create socially integrated and sustainable communities that value their elders has allowed me to learn much about how architects and designers can contribute to helping people live a good life in late life. People often need supportive services or other adaptations as they age, but do they really need-or want-the luxury environment few are accustomed to? The challenge for architects and designers is not to create a built environment whose carefully curated facades hide lives of quiet desperation. It is to help elders access the support they need without upending their lives or severing virtually all ties to their communities. PMID- 30311223 TI - What Can Thinking Like a Gerontologist Bring to Bioethics? AB - I am a social gerontologist, broadly defined as a social scientist who studies how later life is experienced, structured, and controlled in a society and in social settings. Although gerontology is often confused with geriatrics (a medical specialty), gerontologists are typically not clinicians but may study issues related to old age and health care such as the societal conditions that shape how medical care is provided and financed and how early exposure to education relates to later life health. In this essay, I argue that thinking like a gerontologist is important when considering what makes a good life in late life. To think like a gerontologist is to consider the cultural and societal values-past and present-that shape the experience of aging, to recognize people as complex beings whose individual lives do not follow predictable patterns or easily identified trajectories, and to recognize our own habits of regarding older persons as "other" and the consequences of "othering" for older persons and social systems. After a brief history of gerontology, highlighting a few core concepts that gerontologists share, I propose three important questions to consider regarding a good life in late life. PMID- 30311224 TI - Improving Long-Term Care by Finally Respecting Home-Care Aides. AB - The American system of long-term care is disorganized and expensive. Obtaining care for a loved one is a confusing and difficult journey. When it comes to paying for that care, a bit over half who receive care are supported at least partially by insurance, and those with no insurance pay entirely out of pocket. The costs are exorbitant. What makes the system function is reliance on unpaid family members, who care for their loved ones often at considerable cost to themselves. As the baby boom generation ages, this creaky system will become increasingly dysfunctional, and a likely shortage of caregivers will be at the heart of the difficulties. The supply of unpaid family caregivers will become limited, as the ratio of people in the category of ages forty-five to sixty-four compared to those who are eighty and older shrinks from just above seven to one in 2010 to just above four to one in 2030. Paid caregivers will be needed to take up the slack, yet they are poorly paid, work under very difficult conditions, and receive little respect from the health care system. In this essay, I discuss the circumstances facing these paid home-care workers and a possible path forward, illustrating the current problems by drawing on interviews I conducted for a book length study published in 2017. PMID- 30311226 TI - About the Special Report. PMID- 30311225 TI - Age-Friendly Initiatives, Social Inequalities, and Spatial Justice. AB - Discourse on communities and aging traditionally has focused on the availability, accessibility, and quality of local services to support older adults in need of assistance. More recently, however, a growing worldwide "age-friendly" movement has pushed the conceptualization of community supports for an aging society beyond service provision. The term "age friendly" is used in considering how various aspects of a community facilitate or impede the health and well-being of individuals as they experience long lives. Frameworks on age friendliness include attention to health and community services for older adults but also encompass other aspects of communities, such as the physical design of outdoor spaces and buildings, the diversity of mobility options for drivers and nondrivers alike, and the availability of safe, affordable, and various types of housing. Age friendly frameworks also highlight how the very social fabric of a community can influence older residents' quality of life. Over the past decade, a growing number of cities and communities have launched age-friendly initiatives as organized and comprehensive efforts to make localities better for residents as they age. This essay begins to explore how AFIs can address social inequalities in health and aging. It concludes by describing how embedding a spatial justice lens within age-friendly efforts could help AFIs realize more fully the changes that they seek to create at the local, national, and global levels. PMID- 30311227 TI - Becoming Good Citizens of Aging Societies. AB - The ethical dimensions of an aging society are larger than the experience of chronic illness, the moral concerns of health care professionals, or the allocation of health care resources. What, then, is the role of bioethics in an aging society, beyond calling attention to these problems? Once we've agreed that aging is morally important and that population-level aging across wealthy nations raises ethical concerns that cannot be fixed through transhumanism or other appeals to transcend aging and mortality through technology, what is our field's contribution? We argue that it is time for bioethics to turn toward social justice and problems of injustice and that part of doing so is articulating a concept of good citizenship in an aging society that goes beyond health care relationships. PMID- 30311228 TI - How Do We Fund Flourishing? Maybe Not through Health Care. AB - The health policy community has a growing interest in the impact of nonmedical determinants of health, such as housing, nutrition, and social supports, on both health outcomes and costs. This interest has been spurred by the Affordable Care Act's emphasis on prevention, Robert Wood Johnson's grant-making focus on a Culture of Health, and an uptick of research demonstrating the potential returns to health care from investments in social services. Much of this policy-making, grant making, and research has focused on older Americans. The direct policy implications of this strategy can be elusive. It has become clear that more than medicine will be necessary to improve older Americans' health status. Real improvement likely requires the development of additional social service offerings, including housing that is accessible to people with disabilities, Meals on Wheels-type nutrition supports, and transportation. But who should bear the costs and control the finances associated with these programs? In this essay, I explore the question of how policy-makers should consider financing nonmedical investments in older Americans' health. As the reader will recognize, I stop short of arguing for what will work. Rather, I identify the strands of an emerging strategy-namely, for health care dollars to be diverted into social service programming-and offer several cautions. It may be that policy-makers still wish to continue down this path, but my hope is that this essay will allow them to so with greater attention to the risks and unintended consequences of that strategy. PMID- 30311229 TI - Realizing and Maintaining Capabilities: Late Life as a Social Project. AB - One central and unfortunately unavoidable characteristic of the aging process is its association with chronic physiological deterioration. Frailty, cognitive impairment, and physical conditions such as cardiovascular disease and vision and hearing loss are more frequent in this phase of life, and these conditions translate into an increasing need for care and support of multiple kinds. In traditional bioethical scholarship, these distinctive features of aging have been examined predominantly through a health-focused lens. My main contention in this essay, however, is that viewing aging within bioethics as primarily a health problem, to be addressed through frameworks for decision-making or for resource allocation, is inadequate. My aim is to consider how the health conditions associated with aging affect older people's lives in a much more expansive way than has typically been acknowledged. Just as importantly, I intend to show how shifting our bioethical imagination in this way raises different and challenging questions about what a good life in late life consists in and about what is owed to older people, in their personal and social lives, as a matter of justice. PMID- 30311230 TI - Taking a Systems Approach to Chronic Illness in Old Age. AB - We are living through a demographic transition from a world in which there were lots of young people and very few older adults to one in which the numbers in these age groups are becoming more evenly balanced. One reason for this is that more of us are living into our seventies, eighties, nineties, and beyond. That is the good news. Unfortunately, the chance of developing chronic illnesses (including diabetes, arthritis, and dementia) is typically higher for people in these older age groups than for those who are younger. Because we do not know how to cure these illnesses, many of us will spend at least some of this extra time with one or more chronic illness. While we are more likely than in the past to live into older age, we are likely to be living with illness when we get there. That raises a challenge: how should we respond to this change? PMID- 30311231 TI - About The Hastings Center. PMID- 30311232 TI - Population Aging and the Sustainability of the Welfare State. AB - Many older people need external support for their daily living. A large minority of older adults with low or modest pension incomes face financial strains from the high cost of illness, and many older people in urban areas live in social isolation. Indeed, population aging has become a policy topic of concern. The policy debate since the end of the twentieth century about the future of public pensions and health and long-term care programs has increasingly framed the growing numbers of older people in alarmist terms. Unfounded claims about the unaffordability and unsustainability of social policies supporting older people have become common currency, often disguised as concerns about intergenerational justice. Such claims and concerns hinder clear thinking about proper social and fiscal policies, housing, health care, and labor markets to safeguard the well being of older people in aging societies. PMID- 30311233 TI - Solidarity and Care Coming of Age: New Reasons in the Politics of Social Welfare Policy. AB - Aging brings about the ordeal of coping. Younger people also cope, but for those in old age, the ordeal is so often elegiac, forced upon the self by changing functions within the body and by the outside social world, with its many impediments to the continuity of former roles, pursuits, and self-identities. Coping with change can be affirming, but when what is being forgone seems more valuable than what lies ahead, it is travail. For most, the coping is managed more moderately by a sense of resignation. This is especially true for those who survive into profound old age, when one is viewed as if being old is one's essential identity and nature. We must recognize and affirm difference and change without stigmatizing or losing sight of the specific capabilities and circumstances of the individual. This is what I think the often-used, but less often clearly defined, notion of a "person-centered" orientation should signify. Individuals age, but so do societies, not simply because they have a large population over age sixty-five, but in the sense that societies as a whole are also buffeted by significant disruption in orders of meaning. Aging has a public as well as a private manifestation, a social as well as a personal embodiment, and how it is paid attention to in culture, politics, and policy makes a great difference to how aging is concretely experienced in human lives. In this essay, I explore how the moral imagination nurtured by the practices of solidarity and care-and nurturing them in turn-can come of age-and how these practices can take their rightful place in an ethically mature political culture. PMID- 30311234 TI - Advance Directives for Refusing Life-Sustaining Treatment in Dementia. AB - Aid-in-dying laws in the United States have two important restrictions. First, only patients who are terminally ill, defined as having a prognosis of six months or less to live, qualify. Second, at the time the patients take the lethal medication, they must be competent to make medical decisions. This means that an advance directive requesting aid in dying for a later time when the patient lacks decision-making capacity would be invalid. However, many people are more concerned about avoiding living into severe dementia for years-a time when they will lack decision-making capacity-than they are about preventing suffering or the loss of dignity or autonomy for a few months at the end of life. Gillian Bennett is an example of someone determined not to live into severe dementia. She opted for preemptive suicide in 2014, explaining why in a letter she posted online: "Every day I lose bits of myself, and it's obvious that I am heading toward the state that all dementia patients eventually get to: not knowing who I am and requiring full-time care." A major problem with Bennett's solution, however, is that the individual is likely thereby to be giving up some "good time." A legal alternative to preemptive suicide is to create an advance directive stating the circumstances under which one wants not to receive any lifesaving or life-sustaining treatment, even the most basic and noninvasive. This option is our focus in this paper: how to create effective advance directives to avoid living into severe dementia. To be relevant to progressive dementia, the directive would need to state what kinds of care should be withheld and when. At the same time, advance directives for severe dementia face serious challenges. Before addressing these, we review the normative force of directives themselves. PMID- 30311235 TI - The Extended Body: On Aging, Disability, and Well-being. AB - Insofar as many older adults fit some definition of disability, disability studies and gerontology would seem to have common interests and goals. However, there has been little discussion between these fields. The aim of this paper is to open up the insights of disability studies as well as philosophy of disability to discussions in gerontology. In doing so, I hope to contribute to thinking about the good life in late life by more critically reflecting upon the meaning of the body, ability, and the variability of each. My central argument is that we should conceptualize age-associated bodily variations and abilities not in terms of individual capacity, but in terms of what I call "the extended body." It is in light of the meaning of embodiment and ability in general that we must think differently and more capaciously about the meaning of late life in particular. PMID- 30311237 TI - Housing, the Built Environment, and the Good Life. AB - At any age, the pursuit of a good life is easier in a physical environment that promotes health, supports activities important to self-fulfillment, and facilitates connections to the larger community. In old age, the home and neighborhood environments are particularly important: they are the locations where older people spend most their time, and they can have a great impact on independence, social connection, feelings of self-worth, and physical and emotional well-being. Within the urban planning field, home and neighborhood characteristics are important dimensions of debates about the measurement of human progress and quality of life, particularly as an alternative to purely economic measures. They are also key issues in public health, particularly as they relate to physical, social, and mental well-being. Here, we focus on how to improve the fit of environments for people as they age. PMID- 30311238 TI - Precarious Aging: Insecurity and Risk in Late Life. AB - Population aging and longevity in the context of declining social commitments raise concerns about disadvantage, inequality, and the well-being of older people. In this short piece, we use the concept of precarity as a lens to understand new and sustained forms of insecurity that affect late life, and we illustrate how these risks, when experienced over time and in relation to conditions such as austerity, can deepen disadvantage. PMID- 30311239 TI - "Tho' much is taken, much abides": A Good Life within Dementia. AB - In writing these essays, we were asked to consider, "What makes a good life in late life?" I thought instantly, perhaps like many people, of photos and stories of older people taking up new careers and new hobbies-running marathons and soup kitchens, starting organic farms. This response is right and proper. Older people can leverage wisdom and creativity to make wonderful contributions to their communities and should be celebrated for doing so. But this happy picture is incomplete. We live longer than ever before, and with that long life, many of us can expect disability. This is the product of medical success. We are less likely to die from cancer, a heart attack, or a stroke; we survive with chronic illnesses and their associated disabilities. A good life in late life, for many of us, will be a life with disability. For this essay, I focus on dementia, a common and ultimately fatal illness, and one that typically lasts many years from the start of symptoms to the end. More than five million Americans currently suffer from dementia; fifteen million paid and volunteer caregivers help support them. What would a good life with dementia look like? How would it change from the early phase, when cognitive impairment and other challenges are relatively modest, to the final phase marked by severe cognitive and physical decline? PMID- 30311240 TI - Adolescent morphine exposure increases nociceptive behaviors in rat model of formalin test. AB - The number of adolescents who use illicit drugs has increased dramatically. Adolescence is a critical period for brain development and maturation. The importance of the study of pain perception and the possible mechanisms involved is crystal clear. Up until now, there has been no evidence regarding the long term effect of adolescence morphine administration on pain perception. The objective of the present study was to investigate long-lasting effect of adolescent morphine exposure on pain perception as well as analgesic response to a single dose of morphine injection. Adolescent and adult rats received morphine or saline, and then after 30 days of washout period, formalin test was performed. To evaluate morphine analgesia, in a separate group of animals, formalin test was performed after injection of a single dose of morphine during adulthood. The results demonstrated that the adolescent rats treated by morphine exhibited higher pain-related behaviors compared to the control group, while the same results were not observed in adult rats that had been treated by morphine. Moreover, there was no significant difference in analgesic response to a single dose of morphine between two experimental groups. This study demonstrates enduring effect of morphine exposure during adolescence on pain perception. PMID- 30311241 TI - Methods to improve the estimation of time-to-event outcomes when data is de identified. AB - Technological advancements in recent years have sparked the use of large databases for research. The availability of these large databases has administered a need for anonymization and de-identification techniques, prior to publishing the data. This de-identification alters the data, which in turn can impact the results derived post de-identification and potentially lead to false conclusions. The objective of this study is to investigate if alterations to a de identified time-to-event data set may improve the accuracy of the estimates. In this data set, a missing time bias was present among censored patients as a means to preserve patient confidentiality. This study investigates five methods intended to reduce the bias of time-to-event estimates. A simulation study was conducted to evaluate the effectiveness of each method in reducing bias. In situations where there was a large number of censored patients, the results of the simulation showed that Method 4 yielded the most accurate estimates. This method adjusted the survival times of censored patients by adding a random uniform component such that the modified survival time would occur within the final year of the study. Alternatively, when there was only a small number of censored patients, the method that did not alter the de-identified data set (Method 1) provided the most accurate estimates. PMID- 30311242 TI - Evaluation of the protective effects of beta-blockers in the management of acute exacerbations of chronic obstructive pulmonary disease. AB - WHAT IS KNOWN AND OBJECTIVE: The purpose of this study was to evaluate the association between early beta-blocker continuation and major inpatient events in patients hospitalized for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: This single centre, retrospective, investigational review board approved cohort study evaluated patients admitted for a primary diagnosis of AECOPD. Patients were evaluated based on early continuation of a beta-blocker whether a beta-blocker was initiated within 24 hours of admission and continued for at least 72 hours. Patients with AECOPD who did not receive beta-blockers were assigned to the control group. Major inpatient events were a composite outcome composed of arrhythmias, myocardial infarction (MI) and death. Safety data were collected on the incidences of bradycardia, bronchospasms and hypotension. RESULTS AND DISCUSSION: Of the 96 patients admitted for AECOPD, fifty-five patients were included in the early beta-blocker group and forty-one patients in the control group. Early beta-blocker utilization was associated with a significantly lower rate of major inpatient events compared with the control group (40% vs 80.5%; P < 0.001). Arrhythmias were significantly less common in the early beta-blocker group (30.9% vs 65.9%; P = 0.001); however, there were no significant differences in the rates of MI (9.1% vs 14.6%; P = 0.54), death (0 vs 0) or safety outcomes between groups. WHAT IS NEW AND CONCLUSION: beta-blocker therapy could result in a paradigm shift in managing chronic obstructive pulmonary disease patients from a true cardiopulmonary approach. This retrospective cohort study demonstrated early beta-blocker continuation in patients admitted for an AECOPD was associated with less major inpatient events, primarily arrhythmias. PMID- 30311243 TI - Quantifying the association between progression-free survival and overall survival in oncology trials using Kendall's tau. AB - This paper considers methods for estimating the association between progression free and overall survival in oncology trials. Copula-based, nonparametric, and illness-death model-based methods are reviewed. In addition, the approach based on an underlying illness-death model is generalized to allow general parametric models. The performance of these methods, in terms of bias and efficiency, is investigated through simulation and also illustrated using data from a clinical trial of treatments for colon cancer. The simulations suggest that the illness death model-based method provides good estimates of Kendall's tau across several scenarios. In some situations, copula-based methods perform well but their performance is sensitive to the choice of copula. The Clayton copula is most appropriate in scenarios, which might realistically reflect an oncology trial, but the use of copula models in practice is questionable. PMID- 30311244 TI - Drug-drug interactions among drugs prescribed for nontuberculous mycobacterial infection and epilepsy: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: Multi-drug combinations often make chemotherapy difficult owing to drug-drug interactions (DDIs). We report a rare and difficult to-treat case due to DDIs between drugs for Mycobacterium avium complex (MAC) infection and antiepileptic drugs. CASE DESCRIPTION: A 70-year-old Japanese woman was diagnosed as having pulmonary MAC disease. She had a history of symptomatic epilepsy, which was successfully treated with phenytoin and phenobarbital. Serum phenytoin concentrations increased upon the initiation of MAC infection treatment. WHAT IS NEW AND CONCLUSION: We evaluated DDIs and adjusted the dosage of drugs by monitoring the serum drug level. PMID- 30311245 TI - Early adipose deposits in sheep: comparative analysis of the perirenal fat transcriptome of Assaf and Churra suckling lambs. AB - Adipose deposits influence the quality of ruminant carcasses, and in suckling lambs, internal types of adipose deposits represent a notable proportion of total fat. The aim of this study was to perform a comparative analysis of the perirenal fat transcriptomes of suckling lambs from two breeds with different growth and carcass characteristics. The perirenal fat tissue from 14 suckling lambs (Assaf, n = 8; Churra, n = 6) was used for the RNA-seq analysis. The functional enrichment analysis of the 670 highly expressed genes (>150 fragments per kilobase of exon per million fragments mapped) in the perirenal fat transcriptome of both breeds revealed that the majority of these genes were involved in energy processes. The expression of the UCP1 gene, a classical biomarker of brown fat, and the presence of multilocular adipocytes in the two breeds supported the presence of brown fat at the transition stage towards white fat tissue. The differential expression analysis performed identified 373 differentially expressed genes (DEGs) between the two compared breeds. Brown/white fat gene biomarkers were not included in the list of DEGs. In Assaf lambs, DEGs were enriched in Gene Ontology (GO) biological processes related to fatty-acid oxidation, whereas in Churra lambs, the majority of the significantly enriched GO terms were related to cholesterol synthesis, which suggests that upregulated DEGs in Assaf lambs are implicated in fat burning, whereas the Churra upregulated DEGs are linked to fat accumulation. These results can help to increase knowledge of the genes controlling early fat deposition in ruminants and shed light on fundamental aspects of adipose tissue growth. PMID- 30311246 TI - Constrained empirical-likelihood confidence regions in nonignorable covariate missing data problems. AB - Missing covariates in regression analysis are a pervasive problem in medical, social, and economic researches. We study empirical-likelihood confidence regions for unconstrained and constrained regression parameters in a nonignorable covariate-missing data problem. For an assumed conditional mean regression model, we assume that some covariates are fully observed but other covariates are missing for some subjects. By exploitation of a probability model of missingness and a working conditional score model from a semiparametric perspective, we build a system of unbiased estimating equations, where the number of equations exceeds the number of unknown parameters. Based on the proposed estimating equations, we introduce unconstrained and constrained empirical-likelihood ratio statistics to construct empirical-likelihood confidence regions for the underlying regression parameters without and with constraints. We establish the asymptotic distributions of the proposed empirical-likelihood ratio statistics. Simulation results show that the proposed empirical-likelihood methods have a better finite sample performance than other competitors in terms of coverage probability and interval length. Finally, we apply the proposed empirical-likelihood methods to the analysis of a data set from the US National Health and Nutrition Examination Survey. PMID- 30311247 TI - The association between gratitude and burden in Australian mental health carers: a cross-sectional study. AB - The level of carer burden has increased as carers take on more responsibility for mental health consumers as a result of the contemporary shift in the delivery of services from institutional to community settings. Interventions are required to mitigate mental health carer burden. Therefore, we examined the association between dispositional gratitude and burden in a cross-sectional survey of 231 Australian mental health carers. Dispositional gratitude was assessed by the S GRAT, and carer burden was measured using the Involvement Evaluation Questionnaire. The results of a general linear model demonstrated that higher levels of a lack of sense of deprivation were significantly associated with lower levels of tension, worrying and urging. In contrast, higher levels of simple appreciation were significantly associated with higher levels of supervision, worrying and urging. Our findings highlight that gratitude interventions should focus on promoting a lack of sense of deprivation and appreciation of others in order to reduce mental health carer burden. PMID- 30311248 TI - Testosterone preserves endothelial function through regulation of S1P1/Akt/FOXO3a signalling pathway in the rat corpus cavernosum. AB - The aim of the study was to investigate how testosterone regulating endothelial function in the corpus cavernosum of rats. A total of 32 male Sprague-Dawley (SD) rats, 10-weeks-old, were divided randomly into four groups: normal control group (Control); castration group (Castration); the other 16 rats were castrated followed by testosterone supplementation (orally) every day for 8 weeks: castration +10 mg/kg (lower dose) testosterone group (Castration +LT) and castration +20 mg/kg (high dose) testosterone group (Castration +HT). The data showed that androgen deficiency in the Castration group could induce oxidative stress to attenuate endothelial function, manifested by the impairment of endothelial intercellular junction and endothelial content. This was in parallel with a significant decrease in Akt, Akt target and FOXO3a phosphorylation. Testosterone supplementation in the Castration +LT and Castration +HT groups could greatly preserve testosterone serum levels, endothelial function and erectile function through activation of sphingosine-1-phosphate receptor 1 (S1P1)/Akt/FOXO3a pathway. Together, this study suggested that S1P1/Akt/FOXO3a pathway was involved in endothelial dysfunction in the context of androgen deficiency and oxidative stress, which might further explain the mechanism of androgen deficiency inducing ED. PMID- 30311249 TI - Application of polycaprolactone, chitosan, and collagen composite as a nanofibrous mat loaded with silver sulfadiazine and growth factors for wound dressing. AB - Fabrication of nanofibrous biomaterials composed of natural and synthetic materials that incorporated with antibiotic and growth factors with controlled release manner is an attractive topic in wound healing. The purpose of this study was to prepare optimal composite of materials as biomimetic nanofibrous mats for application in wound healing. The mat was prepared of polycaprolactone (PCL) in the bottom, chitosan/poly ethylene oxide (Cs/PEO) in the middle, and PCL/collagen (PCL/Coll) in the top layer. A panel of standard characterization tests of nanofibrous mat was performed and its compatibilities in strength and integration were confirmed. Middle layer was loaded with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and silver sulfadiazine (SSD) was incorporated in the bottom layer as an anti-infection factor. Then, on the dorsum of rats, a 400-mm2 wound was created and surrounded by a silicone ring to control the usual tissue contractions. Nanofibrous mats with or without growth factors were applied as wound dressings and at day 14, the healing process was evaluated. At day 14, the treated group by designed mat showed faster epithelialization and angiogenesis. Silicone ring in the test group was desirable in wound closure compared to the control group. Reformation of skin tissue was manifested in a shorter time. This composite nanofibrous mat could be introduced as a dynamic and effective candidate for wound dressing. PMID- 30311250 TI - Metamizole (dipyrone)-induced agranulocytosis: Does the risk vary according to ethnicity? AB - WHAT IS KNOWN AND OBJECTIVE: Based on spontaneous reports from Spain, it is claimed that the British, Irish and Scandinavians are at a greater risk of dipyrone-induced agranulocytosis. This report examines the evidence. COMMENT: Although interethnic differences in drug response are well known, there are no reliable epidemiologic data to support the above claim. Available information on chlorpromazine suggests variable ethnic sensitivities to drug-induced agranulocytosis. Agranulocytosis induced by at least four drugs has been associated with variant HLA alleles. Preliminary evidence also suggests that the presence of specific variant HLA alleles may sensitize individuals to dipyrone induced agranulocytosis. There are historical reasons to suspect that the three populations referred to may share some key genetic features, including the potentially culprit variant HLA alleles, that predispose them to dipyrone-induced agranulocytosis. WHAT IS NEW AND CONCLUSION: The possibility that the British, Irish and Scandinavians show higher susceptibility than other populations to dipyrone-induced agranulocytosis cannot be ruled out. If this complication is linked to specific HLA allele(s), populations with higher frequency of variant HLA allele(s) may be at a greater risk. If confirmed, screening for the risk allele may be useful in reducing the risk of dipyrone-induced agranulocytosis. PMID- 30311251 TI - Inverse cationic ITP for separation of methadone enantiomers with sulfated beta cyclodextrin as chiral selector. AB - Chiral ITP of the weak base methadone using inverse cationic configurations with H+ as leading component and multiple isomer sulfated beta-CD (S-beta-CD) as leading electrolyte (LE) additive, has been studied utilizing dynamic computer simulation, a calculation model based on steady-state values of the ITP zones, and capillary ITP. By varying the amount of acidic S-beta-CD in the LE composed of 3-morpholino-2-hydroxypropanesulfonic acid and the chiral selector, and employing glycylglycine as terminating electrolyte (TE), inverse cationic ITP provides systems in which either both enantiomers, only the enantiomer with weaker complexation, or none of the two enantiomers form cationic ITP zones. For the configuration studied, the data reveal that only S-methadone migrates isotachophoretically when the S-beta-CD concentration in the LE is between about 0.484 and 1.113 mM. Under these conditions, R-methadone migrates zone electrophoretically in the TE. An S-beta-CD concentration between about 0.070 and 0.484 mM results in both S- and R-methadone forming ITP zones. With >1.113 mM and < about 0.050 mM of S-beta-CD in the LE both enantiomers are migrating within the TE and LE, respectively. Chiral inverse cationic ITP with acidic S-beta-CD in the LE is demonstrated to permit selective ITP trapping and concentration of the less interacting enantiomer of a weak base. PMID- 30311252 TI - FAANG, establishing metadata standards, validation and best practices for the farmed and companion animal community. AB - The Functional Annotation of ANimal Genomes (FAANG) project aims, through a coordinated international effort, to provide high quality functional annotation of animal genomes with an initial focus on farmed and companion animals. A key goal of the initiative is to ensure high quality and rich supporting metadata to describe the project's animals, specimens, cell cultures and experimental assays. By defining rich sample and experimental metadata standards and promoting best practices in data descriptions, deposition and openness, FAANG champions higher quality and reusability of published datasets. FAANG has established a Data Coordination Centre, which sits at the heart of the Metadata and Data Sharing Committee. It continues to evolve the metadata standards, support submissions and, crucially, create powerful and accessible tools to support deposition and validation of metadata. FAANG conforms to the findable, accessible, interoperable, and reusable (FAIR) data principles, with high quality, open access and functionally interlinked data. In addition to data generated by FAANG members and specific FAANG projects, existing datasets that meet the main-or more permissive legacy-standards are incorporated into a central, focused, functional data resource portal for the entire farmed and companion animal community. Through clear and effective metadata standards, validation and conversion software, combined with promotion of best practices in metadata implementation, FAANG aims to maximise effectiveness and inter-comparability of assay data. This supports the community to create a rich genome-to-phenotype resource and promotes continuing improvements in animal data standards as a whole. PMID- 30311253 TI - The Effect of LVAD Pressure Sensitivity on the Assisted Circulation Under Consideration of a Mitral Insufficiency: An In Vitro Study. AB - Current left ventricular assist devices (LVADs) differ with respect to their pump characteristics as described by the pump characteristic curve (also called HQ curve). Pressure sensitive LVADs depict a flat characteristic curve while most available LVADs have a steep, less pressure sensitive characteristic curve. This in vitro study investigated the effect of LVAD pressure sensitivity with a focus on the afterload of the right ventricle (RV) which is one out of many factors influencing right heart failure (RHF). To this end, two laboratory pumps differing in pressure sensitivity were tested as LVAD in an established, active mock circulation loop (MCL). The MCL represented patients with left heart failure and mitral insufficiency as another contributing factor to RV afterload. The results show that the pressure-volume loop (PV-loop) of the left ventricle (LV) undergoes a leftward and thus somewhat of a downward-shift for highly pressure sensitive support. Consequently, the LV is unloaded to a higher degree at comparable arterial blood pressure and identical cardiac output, pulmonary and systemic vascular resistance and ventricular contractility. This causes a concomitant decrease of RV afterload. This effect seems to be due to increased unloading during systole. In case of a severe concomitant mitral insufficiency and looking at left atrial pressure, the difference is 18.5%. Without mitral insufficiency, the difference is reduced to 10.2%. PMID- 30311255 TI - Sleep duration and sleeping difficulties among adolescents: exploring associations with school stress, self-perception and technology use. AB - Sleeping problems are increasing among adolescents worldwide. This study aimed to describe the prevalence of self-reported sleep duration and sleeping difficulties, as well as to explore their associations with school stress, self perception, that is how adolescents perceive their appearance and happiness, and technology use among adolescents. Data were collected in 2015 using a questionnaire. A total of 937 ninth grade adolescents, 15-16 years, from a city in western Sweden participated, resulting in a response rate of 83%. The result showed that 55% of the adolescents slept less than the recommended 8 hours per night and 11% had sleeping difficulties. School stress and technology use were associated with short sleep duration. School stress and self-perception were associated with sleeping difficulties. The girls had worse outcomes for sleeping difficulties, school stress, self-perception and technology use than the boys. Based on the results, there is a need for school nurses to implement preventive measures to improve adolescents' sleep. PMID- 30311256 TI - The association between a mixing ability test and patient reported chewing ability in patients treated for oral malignancies. AB - INTRODUCTION: Mastication has been assessed in several ways in the past. Both patients reported and objective assessment methods have been developed. The University Medical Center (UMC) Utrecht has developed a mixing ability test (MAT) using a two-coloured wax tablet. The present study investigates the association between the mixing ability test and a chewing related questionnaire in patients treated for oral malignancies. PATIENTS AND METHODS: In a cohort study, patients treated for oral malignancies were assessed 4-6 weeks before and 4-6 weeks after treatment, as well as 6 months, 1 year and 5 years after treatment. The mixing ability test was assessed using 10 and 20 chewing strokes and was compared to seven questions about several aspects of mastication. Regression analysis was performed and density plots were drawn for statistical analysis. RESULTS: One hundred and twenty-three patients were included in this study. The questionnaire was less predictive for the 10-chewing stroke test and the test was less discriminatory for different food types than the 20-chewing stroke mixing ability test. Three questions about the ability to chew solid, soft and thickened liquid food types were found to be significantly predictive for the 20-chewing stroke test. Threshold values on the mixing ability index were around 20 for the ability to chew solid food types and 24 for soft food types. CONCLUSION: The 10-chewing stroke mixing ability test is less suitable than 20-chewing strokes for patients with and treated for oral cancer. The 20-chewing stroke mixing ability test has a fair association with self-reported outcomes. PMID- 30311254 TI - Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project. AB - The Functional Annotation of Animal Genomes (FAANG) project aims to identify genomic regulatory elements in both sexes across multiple stages of development in domesticated animals. This study represents the first stage of the FAANG project for the horse, Equus caballus. A biobank of 80 tissue samples, two cell lines and six body fluids was created from two adult Thoroughbred mares. Ante mortem assessments included full physical examinations, lameness, ophthalmologic and neurologic evaluations. Complete blood counts and serum biochemistries were also performed. At necropsy, in addition to tissue samples, aliquots of serum, ethylenediaminetetraacetic acid (EDTA) plasma, heparinized plasma, cerebrospinal fluid, synovial fluid, urine and microbiome samples from all regions of the gastrointestinal and urogenital tracts were collected. Epidermal keratinocytes and dermal fibroblasts were cultured from skin samples. All tissues were grossly and histologically evaluated by a board-certified veterinary pathologist. The results of the clinical and pathological evaluations identified subclinical eosinophilic and lymphocytic infiltration throughout the length of the gastrointestinal tract as well as a mild clinical lameness in both animals. Each sample was cryo-preserved in multiple ways, and nuclei were extracted from selected tissues. These samples represent the first published systemically healthy equine-specific biobank with extensive clinical phenotyping ante- and post-mortem. The tissues in the biobank are intended for community-wide use in the functional annotation of the equine genome. The use of the biobank will improve the quality of the reference annotation and allow all equine researchers to elucidate unknown genomic and epigenomic causes of disease. PMID- 30311257 TI - A tribute to a true conservation innovator, Brad McRae, 1966-2017. AB - Powerful innovations can occur when a concept is taken from one field and used to solve a problem in an unrelated field. In fact, it has been shown that as the distance between a problem solver's field of technical expertise and the focal field of a problem increase, so does the probability of success. This article is protected by copyright. All rights reserved. PMID- 30311258 TI - Cellular neurothekeoma: Report of two cases with unusual immunohistochemical features. AB - Cellular neurothekeoma (CNT) is a dermal lesion with still unknown histogenesis, characterized by immunohistochemical staining for NKI/C3, NSE, MiTF, CD10 and CD68, whereas S100 protein, desmin and cytokeratins are negative. Particularly, in several studies NKI/C3 has been reported as a strong marker of CNT. We describe herein the clinical, histopathological and immunohistochemical features of two cases morphologically consistent with myxoid CNT, one of which showing some atypical features, both characterized by negative immunohistochemical staining for NKI/C3. Our findings stress the importance of morphology in diagnosing CNT and underline the fact that NKI/C3 can fail to stain cases belonging to the "neurothekeoma family." In selected cases of CNT, an expanded immunohistochemical panel is mandatory to differentiate this tumor from other dermal lesions. PMID- 30311259 TI - Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. AB - BACKGROUND: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. METHODS: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates. RESULTS: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. CONCLUSIONS: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. PMID- 30311260 TI - Acquired perforating calcific collagenosis in a drug addict with rhabdomyolysis and transient hypercalcemia. AB - Acquired perforating calcific collagenosis (APCC), which is characterized by the calcification of dermal collagen fibers with subsequent transepidermal elimination and perforation, is an extremely rare entity. Thus far, it has only been reported in a patient with direct contact exposure to calcium chloride. Here, we report a unique case of APCC occurring in a drug addict admitted for rhabdomyolysis. The present case is a 20-year-old male patient hospitalized for drug-related rhabdomyolysis and multiple organ damage. During hospitalization, he gradually developed unusual skin rashes. There were multiple confluent umbilicated and keratotic erythematous to brownish papules and plaques with scratch-like linear plaques on his lower abdomen, inguinal areas and gluteal sulci. Also, multiple well-demarcated flesh-colored rough, hard and thin plaques with a "crepe paper"-like texture were found on the bilateral popliteal fossae, olecranon fossae and axillae. The histopathology of two biopsied lesions demonstrated acquired perforating calcific collagenosis. The lesions appeared during the rhabdomyolysis-related hypercalcemia phase and resolved spontaneously after the calcium level returned to normal. This is the first reported case of disseminated APCC occurring during transient hypercalcemia due to rhabdomyolysis. PMID- 30311261 TI - Intradialytic alkalization affects calcium balance and PTH level. PMID- 30311262 TI - The benefit of adding oral simethicone in bowel preparation regimen for the detection of colon adenoma: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Simethicone is an anti-foaming agent commonly used during colonoscopy. Although several randomized trials have shown that oral simethicone in the bowel preparation regimen may improve bowel cleanness, whether it improves adenoma detection rate (ADR) or polyp detection rate remains undetermined. The aim of this study was to determine if oral simethicone in bowel preparation regimen before colonoscopy improves the ADR. METHODS: A comprehensive literature review was conducted using PubMed, SDOL, Cochrane Library, and ProQuest databases through December 2017. Randomized controlled trials that compared bowel preparation regimens with simethicone versus those without it were included. Effect estimates from each study were extracted and underwent meta-analysis using appropriate models. The primary outcomes were ADR and polyp detection rate, and secondary outcomes included bowel preparation, bubble score, and withdrawal time. RESULTS: Twelve published randomized controlled studies with 6003 participants were included for meta-analysis. There was no difference in the overall ADR (pooled risk ratio = 1.06, 95% confidence interval = 0.91-1.24) and right-side ADR (risk ratio = 1.50, 95% confidence interval = 0.82-2.75) between the groups with or without simethicone. However, the addition of simethicone improved adenoma detected per patient (2.20 +/- 1.36 vs 1.63 +/- 0.89) according to one of the included studies. Meta-regression revealed that the baseline ADR < 25% of the included studies was associated with significant benefit of oral simethicone; the number needed to treat was 15. CONCLUSIONS: The adjunction of oral simethicone significantly improved bowel preparation quality and might benefit adenoma detection in specific settings with low baseline ADR. PMID- 30311263 TI - Identification of key genes in prostate cancer gene expression profile by bioinformatics. AB - The aim of this study was to identify key candidate genes in prostate cancer. The gene expression profiles of GSE32448, GSE45016, GSE46602 and GSE104749 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between prostate cancer and normal samples were identified by R language. The gene ontology functional and pathway enrichment analyses of DEGs were performed by the Database for Annotation, Visualization and Integrated Discovery software followed by the construction of protein-protein interaction network. Hub gene identification was performed by the plug-in cytoHubba in Cytoscape software. The 217 DEGs were significantly enriched in biological processes including epithelial cell differentiation, response to estradiol and several pathways, mainly associated with protein digestion and absorption pathway in prostate cancer. Epithelial cell adhesion molecule, twist family basic helix loop-helix transcription factor 1, CD38 molecule and vascular endothelial growth factor A were identified as hub genes. The expression levels of hub genes were consistent with data obtained in The Cancer Genome Atlas for prostate adenocarcinoma. These hub genes may be used as potential targets for prostate cancer diagnosis and treatment. PMID- 30311265 TI - Is CD1a useful for leishmaniasis diagnosis in the New World? PMID- 30311264 TI - A meta-analysis of valve-in-valve and valve-in-ring transcatheter mitral valve implantation. AB - OBJECTIVES: We performed a meta-analysis of transcatheter mitral valve implantation (TMVI) for deteriorated bioprosthetic valves (valve-in-valve [VIV] TMVI) and/or failed annuloplasty rings (valve-in-ring [VIR]-TMVI), comparing observed early (30-day) mortality with predicted operative mortality. BACKGROUND: It remains unclear whether VIV/VIR-TMVI reduces mortality as compared with redo MVS. METHODS: MEDLINE and EMBASE were searched current through 24 July 2018 using Web-based search engines (PubMed and OVID) to identify studies including >=10 patients undergoing VIV/VIR-TMVI. For each study, data regarding observed 30-day mortality and predicted operative mortality (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM]) were used to generate risk ratios (RRs) and 95% confidence intervals (CIs). Study-specific estimates were combined using the inverse variance-weighted average of logarithmic RRs in the random-effects model. One-group meta-analyses of 30-day/late (including 30-day) mortality rates were also performed in the random-effects model. RESULTS: Of 270 potentially relevant articles screened initially, 17 eligible studies including a total of 1017 patients undergoing VIV/VIR-TMVI were identified. In all but four studies, the STS-PROM was available and varied from 7.7% to 22.0% (weighted mean, 11.5%). Pooled analyses of all VIV/VIR-TMVI studies demonstrated the 30-day mortality rate of 5.4% (95%CI, 4.0-6.8%), the midterm (1- to 5-year) mortality rate of 13.7% (95%CI, 9.0-18.5%), and significantly lower observed 30-day mortality than predicted operative mortality (RR, 0.67; 95%CI, 0.49-0.91; P = 0.01). CONCLUSIONS: VIV/VIR-TMVI brought about relatively low early and midterm (1- to 5 year) mortality, and observed 30-day mortality was significantly lower than predicted operative mortality. PMID- 30311267 TI - Retraction: Lu, T. Bayesian inference on mixed-effects location scale models with skew-t distribution and mismeasured covariates for longitudinal data. Statist. Med. 2017;36:2614-2629. doi: 10.1002/sim.7315. AB - The above article from Statistics in Medicine published online 18 April 2017, in Wiley Online Library (http://www.onlinelibrary.wiley.com) and in Volume 36, pp. 2614-2629, has been retracted by agreement between the Journal Editors, Ralph D'Agostino, Simon Day, Els Goetghebeur, Joel Greenhouse, John Wiley & Sons Ltd, and the author. The article has been retracted by the author due to some text overlap with other materials previously published by the author. The retraction is not due to any accusation of plagiarism or misconduct. PMID- 30311266 TI - Circuit-theory applications to connectivity science and conservation. AB - Conservation practitioners have long recognized ecological connectivity as a global priority for preserving biodiversity and ecosystem function. In the early years of conservation science, ecologists extended principles of island biogeography to assess connectivity based on source patch proximity and other metrics derived from binary maps of habitat. From 2006 to 2008, the late Brad McRae introduced circuit theory as an alternative approach to model gene flow and the dispersal or movement routes of organisms. He posited concepts and metrics from electrical circuit theory as a robust way to quantify movement across multiple possible paths in a landscape, not just a single least-cost path or corridor. Circuit theory offers many theoretical, conceptual, and practical linkages to conservation science. We reviewed 459 recent studies citing circuit theory or the open-source software Circuitscape. We focused on applications of circuit theory to the science and practice of connectivity conservation, including topics in landscape and population genetics, movement and dispersal paths of organisms, anthropogenic barriers to connectivity, fire behavior, water flow, and ecosystem services. Circuit theory is likely to have an effect on conservation science and practitioners through improved insights into landscape dynamics, animal movement, and habitat-use studies and through the development of new software tools for data analysis and visualization. The influence of circuit theory on conservation comes from the theoretical basis and elegance of the approach and the powerful collaborations and active user community that have emerged. Circuit theory provides a springboard for ecological understanding and will remain an important conservation tool for researchers and practitioners around the globe. PMID- 30311268 TI - Underrepresentation of women in Parkinson's disease trials. PMID- 30311269 TI - Can spermatozoa be retrieved in non-obstructive azoospermic patients with high FSH level?: A retrospective cohort study. AB - We aimed in this retrospective study to evaluate non-surgical preoperative parameters and testicular histopathology in determining the sperm retrieval rate (SRR) in non-obstructive azoospermic (NOA) patients. We evaluated the data of 1,395 consecutive patients who underwent 1st time micro-dissection testicular sperm extraction (micro-TESE) that was done by fifteen different senior andrologists and a consequent undefined number of biologists assisting them in the operative rooms from January 2010 to May 2013 in a specialised IVF centre. Our study did not demonstrate any statistical significance between the mean age, the mean duration of infertility and finally, the mean of FSH levels of the patients with positive and negative micro-TESE outcomes (p-value 0.391, 0.543, 0.767 respectively). Moreover, our study did not demonstrate any association between different types of hormonal therapy prior to micro-TESE and patients with positive micro-TESE outcome (p-value 0.219). Interestingly, our study showed positive associations between the testicular histopathology SCO (sertoli cell only syndrome) and high FSH and sperm retrieval rate (p < 0.001, 0.02 respectively). Logistic regression analysis revealed high statistical significance between sperm retrieval rate and high FSH level and testicular histopathology (OR 1.6, 0.21, 95% CI lower 1.2, 0.008 and upper 2.1, 0.06 and finally p 0.003, <0.001 respectively). This study reveals that preoperative testicular biopsy is unnecessary to predict the sperm retrieval rate in NOA patients. PMID- 30311270 TI - Eliminating the need for routine monthly postdialysis serum urea nitrogen measurement: A method for monitoring Kt/V and normalized protein catabolic rate using conductivity determined dialyzer clearance. AB - Many dialysis machines can compute dialyzer sodium clearances at multiple time points during a dialysis treatment using conductivity. For a given treatment, the average dialyzer sodium clearance (K), when combined with treatment time (t), and the estimated urea distribution volume (V, usually based on either anthropometry or bioimpedance), can be used to estimate Kt/V, an important measure of hemodialysis adequacy. While this conductivity-derived value for Kt/V correlates moderately with Kt/V calculated from predialysis and postdialysis serum urea nitrogen (SUN) values (urea reduction ratio, URR), the ultrafiltration volume, and session length it is, unfortunately, not sufficiently accurate to replace URR based Kt/V. Here we underline the potential utility of an alternative method to estimate Kt/V (a variant of a technique originally proposed by Gotch and Levin and their colleagues) using conductivity-derived sodium clearance (K) that does not require routine measurement of the postdialysis SUN but which should closely track Kt/V computed in the usual fashion. The increased accuracy with the new method is explained by the use of a patient-specific value of V, which is an average value calculated from several dialysis sessions where both conductivity dialyzer clearance and predialysis and postdialysis SUN have been measured. Once this patient-specific conductivity/URR-based value for V has been determined, it can be used to calculate Kt/V for subsequent treatments in which conductivity based dialyzer clearances are measured, but around which predialysis and postdialysis SUN values have not been obtained. (If the predialysis SUN values for such a subsequent treatment are also measured, then a normalized protein catabolic rate that closely tracks the value from conventional urea modeling, can also be determined.) By reducing the number of postdialysis SUN measurements needed to monitor hemodialysis adequacy this new method of estimating Kt/V by conductivity should save staff time and laboratory costs, increase patient and staff safety, and decrease error rates associated with improper postdialysis blood sampling technique. PMID- 30311271 TI - Prediction of treatment response in rheumatoid arthritis patients using genome wide SNP data. AB - Although a number of treatments are available for rheumatoid arthritis (RA), each of them shows a significant nonresponse rate in patients. Therefore, predicting a priori the likelihood of treatment response would be of great patient benefit. Here, we conducted a comparison of a variety of statistical methods for predicting three measures of treatment response, between baseline and 3 or 6 months, using genome-wide SNP data from RA patients available from the MAximising Therapeutic Utility in Rheumatoid Arthritis (MATURA) consortium. Two different treatments and 11 different statistical methods were evaluated. We used 10-fold cross validation to assess predictive performance, with nested 10-fold cross validation used to tune the model hyperparameters when required. Overall, we found that SNPs added very little prediction information to that obtained using clinical characteristics only, such as baseline trait value. This observation can be explained by the lack of strong genetic effects and the relatively small sample sizes available; in analysis of simulated and real data, with larger effects and/or larger sample sizes, prediction performance was much improved. Overall, methods that were consistent with the genetic architecture of the trait were able to achieve better predictive ability than methods that were not. For treatment response in RA, methods that assumed a complex underlying genetic architecture achieved slightly better prediction performance than methods that assumed a simplified genetic architecture. PMID- 30311272 TI - Continuous Surface Polymerization via Fe(II)-Mediated Redox Reaction for Thick Hydrogel Coatings on Versatile Substrates. AB - The development of versatile generalized strategies for easy surface modification is of immense scientific interest. Herein, a novel mechanism to form functional hydrogel coatings on a wide variety of substrate materials including polymers, polymeric resins, ceramics, and intermetallic compounds, enabling easy change of the surface wettability and lubrication property, is reported. In situ polymerization and hydrogel coating formation is initiated by free radicals generated through the redox reaction between Fe2+ and S2 O8 2- at the solid liquid interface, which shows controllable growth kinetics. Hydrogel modification is fast, controllable, and performed in mild conditions at room temperature. The chemical components, thickness, and network structure of the hydrogel coating can be well controlled. The surface catalytically initiated radical polymerization method allows reinitiation of the polymerization when the grafted hydrogel coating is polished away, and allows continuous surface polymerization to form multi-interpenetrating network hydrogel coatings. Interestingly, it is fully compatible with 3D-printing technology, and by using 3D-printed composites as the catalytic template, it demonstrates an extreme advantage for engineering 3D hollow hydrogel objects with various complex structures. The versatility of this method makes it generate potential applications in the field of surface/interface and biological engineering. PMID- 30311273 TI - A Tunable Optofluidic Microlaser in a Photostable Conjugated Polymer. AB - The optofluidic laser has become an important platform for biological sensing and medical diagnosis. To date, fluorescent dyes and proteins have been widely utilized as gain materials for biological analysis due to their good biocompatibility, but the limited photostability restricts their reliability and sensitivity. Here, an optofluidic microlaser with an ultralow threshold down to 7.8 uJ cm-2 in the ultrahigh-Q whispering-gallery microcavity, which is filled with a biocompatible conjugated polymer, is demonstrated. This conjugated polymer exhibits a significant enhancement in the lasing stability compared with a typical laser dye (Nile red). In the experiment, after 20 min of illumination with the excitation intensity of 23.2 MW cm-2 , the lasing intensity of the conjugated polymer experiences a decrease of less than 10%, while the lasing feature of Nile red completely disappears. Additionally, by mechanically stretching the resonator, the lasing frequency can be fine-tuned with the range of about 2 nm, exceeding the free spectral range of the resonator. PMID- 30311274 TI - Prevalence, comorbidity and factors associated with sleeping, crying and feeding problems at 1 month of age: A community-based survey. AB - AIM: To examine, in a community cohort of healthy one-month-old infants, (i) the prevalence of early infant sleeping, crying and feeding problems; (ii) the extent to which they co-exist; and (iii) infant and mother characteristics associated with each problem alone and with comorbid problems. METHODS: A survey at 4 weeks of infant age examined the presence of infant sleeping, crying and feeding problems (yes/no); parenting self-efficacy; rating of self as a tense person; and doubts about parenting at bedtime. RESULTS: A total of 770 mothers (39% of those approached) with a total of 781 infants (11 twins) took part. Infant sleeping, crying and feeding problems were reported by 38.5, 27.4 and 25.2% of mothers, respectively. On comorbidity, 25.5% reported one problem, 20.5% reported two and 7.3% reported all three problems. Mothers of first-born infants reported more crying problems and comorbid problems. Mothers who described themselves as a 'tense person' reported more infant feeding problems. Maternal doubt and low self efficacy were consistently associated with each type of infant problem and comorbid problems (adjusting for other factors). CONCLUSION: Mothers expressing doubt and low parenting self-efficacy may benefit from additional support and guidance on normal infant behaviour. PMID- 30311275 TI - Full-Parameter Omnidirectional Thermal Metadevices of Anisotropic Geometry. AB - Since the advent of transformation optics and scattering cancelling technology, a plethora of unprecedented metamaterials, especially invisibility cloaks, have been successfully demonstrated in various communities, e.g., optics, acoustics, elastic mechanics, dc electric field, dc magnetic field, and thermotics. A long held captivation is that transformation-optic metamaterials of anisotropic or noncentrosymmetric geometry (e.g., ellipsoids) commonly come along with parameter approximation/simplification or directional functions. Here, a synthetic paradigm with strictly full parameters and omnidirectionality is reported simultaneously to address this long-held issue for molding heat flow and experimentally demonstrate a series of noncentrosymmetric thermal metadevices. It changes the usual perception that transformation thermotic/dc/acoustic metamaterials are just a direct and simplified derivatives of the transformation-optic counterpart. Instead, the proposed methodology solves an intriguingly important and challenging problem that is not possibly achievable for transformation-optic metamaterials. The approach is rigorous, exact, robust, and yet elegantly facile, which may open a new avenue to manipulating the Laplacian and wave-dynamic fields in ways previously inconceivable. PMID- 30311276 TI - Street food research worldwide: a scoping review. AB - BACKGROUND: Street foods vary with respect to their nutritional value and safety characteristics and contribute to a sizable proportion of food intake in many populations worldwide. Therefore, the present study aimed to describe the coverage in the scientific literature of different health-related and socio economic aspects of street food consumption and trading. METHODS: Three electronic databases (searched from inception to 16 October 2017), a hand-search of relevant journals and backward citation tracking were used to identify eligible scientific articles with a main objective of investigating or reporting specific results on health-related or socio-economic aspects of street food. Papers published in English, Portuguese, French, Spanish or Italian, as well as English abstracts of papers published in other languages, were assessed. The selected articles were evaluated by two independent researchers and described according to year of publication, geographical distribution, definition of street food, main topics addressed and target population. RESULTS: In total, 441 papers were selected. The number of publications has increased in recent years, almost half of them being published after 2012. Almost three-quarter of the articles were from Africa or Asia. Most studies addressed food safety (85.5%), whereas street food availability and consumption were much less frequently investigated (30.3%). The focus of the studies was usually the food (mostly its microbiological contamination) and the vendors (mostly their food handling), whereas consumers and vending sites were seldom evaluated. More than half of the studies did not specify a definition for street food. CONCLUSIONS: Efforts are needed for a more widespread and comprehensive assessment of different issues related to street food availability and consumption in different settings, especially regarding street food offer, nutritional composition, and patterns of purchase and consumption by the population. PMID- 30311277 TI - Family education and support for families at psychosocial risk in Europe: Evidence from a survey of international experts. AB - There is overwhelming consensus among policy makers, academics, and professionals about the need to support families in their childrearing tasks. Consequently, European countries have been encouraged to develop family support interventions aimed at guaranteeing children's rights, targeting particularly those children in situations of psychosocial risk. While a certain amount of evidence exists regarding how family support is generally delivered in certain European countries, with a particular focus on parenting initiatives, this paper aims to take existing evidence one step further by providing an updated review focusing on two core components of the Council of Europe's Recommendation on Positive Parenting: families at psychosocial risk as the target population, and family education and support initiatives as the delivery format. The scope of the study was therefore broad, in both geographical and conceptual terms. An online survey was conducted with experts from 19 European countries to gather information regarding how they perceive family education and support initiatives for families at psychosocial risk. Both quantitative and qualitative data were analysed by computing frequencies/percentages and by following a thematic synthesis method, respectively. The results revealed both similarities and disparities as regards provider profiles, intervention characteristics, and quality standards. Practical implications are discussed, such as the need to diversify initiatives for at-risk families in accordance with the tenets of progressive universalism, the ongoing need for an evidence-based, pluralistic approach to programmes, and the skills and qualifications required in the family support workforce. This study constitutes a first step towards building a common family support framework at a European level, which would encompass family support and parenting policies aimed at families at psychosocial risk. PMID- 30311278 TI - Magnetic Interaction of Multifunctional Core-Shell Nanoparticles for Highly Effective Theranostics. AB - The controlled size and surface treatment of magnetic nanoparticles (NPs) make one-stage combination feasible for enhanced magnetic resonance imaging (MRI) contrast and effective hyperthermia. However, superparamagnetic behavior, essential for avoiding the aggregation of magnetic NPs, substantially limits their performance. Here, a superparamagnetic core-shell structure is developed, which promotes the formation of vortex-like intraparticle magnetization structures in the remanent state, leading to reduced dipolar interactions between two neighboring NPs, while during an MRI scan, the presence of a DC magnetic field induces the formation of NP chains, introducing increased local inhomogeneous dipole fields that enhance relaxivity. The core-shell NPs also reveal an augmented anisotropy, due to exchange coupling to the high anisotropy core, which enhances the specific absorption rate. This in vivo tumor study reveals that the tumor cells can be clearly diagnosed during an MRI scan and the tumor size is substantially reduced through hyperthermia therapy by using the same FePt@iron oxide nanoparticles, realizing the concept of theranostics. PMID- 30311279 TI - Differential effects of chronic 17beta-oestradiol treatment on rat behaviours relevant to depression. AB - Sex differences are a prominent feature of the pathophysiology of psychiatric disorders, such as major depressive disorder, which affects women at a higher incidence than men. Research suggests that the most potent endogenous oestrogen, 17beta-oestradiol, may have therapeutic potential in treating depression. However, preclinical studies have produced mixed results, likely as a result of various methodological factors such as treatment duration. The present study aimed to investigate the effects of ovariectomy and chronic 17beta-oestradiol treatment via a s.c. silastic implant on behaviours relevant to depression in adult female Sprague-Dawley rats. Rats were assessed in the forced swim test, saccharin preference test and novel object recognition memory test, as well as for possible confounding behaviours, including locomotion and anxiety (open field test) and motivation and anxiety (novelty suppressed feeding test). Treatment effects were verified using body and uterus weight, as well as serum concentrations of 17beta-oestradiol, progesterone and testosterone. Compared to ovariectomised rats, chronic 17beta-oestradiol treatment enhanced saccharin preference and novel object recognition performance. There were no group differences in passive or active coping behaviour when assayed using the forced swim test. Taken together, these results support an antidepressant-like action of oestrogens but highlight that the beneficial effects of chronic 17beta-oestradiol treatment may be related to specific depression-related symptoms, particularly anhedonia and memory. PMID- 30311280 TI - Post-streptococcal glomerulonephritis: Some reduction in a disease of disparities. AB - AIM: A retrospective Auckland-wide (total population approximately 1.4 million) study of hospital admissions from 2007 to 2015 was conducted to assess trends in admissions for acute post-streptococcal glomerulonephritis (APSGN) in children aged 0-14 years. METHODS: International Statistical Classification of Diseases (ICD10) discharge codes were used to identify potential cases of APSGN, and electronic clinical records and laboratory data were compared with established case definitions for definite or probable APSGN. RESULTS: A total of 430 cases of APSGN were identified (definite n = 337, probable n = 93), with a mean annual incidence of 15.2/100 000 (95% confidence interval (CI) 14.9-15.6). Incidence (0 14 years) was 17 times higher in Pacific peoples (50.2/100 000, 95% CI 48.6-51.8) and almost 7 times higher in Maori (19.6/100 000, 95% CI 18.6-20.7) than European/other populations (2.9/100 000, 95% CI 2.7-3.1). Multivariate analysis found ethnicity, deprivation, male gender, age (peak 3-8 years) and season (summer/autumn) to be associated with admission risk. Admission rates showed a significant change of -9.0% (95% CI -10.4, 7.4%) per year, with 2011 being an exception. Low C3 complement, hypertension, elevated streptococcal titres, oedema and heavy proteinuria were present in 94, 65, 67, 52 and 49% of cases, respectively. Relying on ICD10 codes without further review of clinical notes would result in an overcount of cases by 25%. CONCLUSIONS: There is severe disparity in APSGN admission rates, with a disproportionate burden of disease for Pacific and Maori children and those living in deprived circumstances. Rates trended downward from 2007 to 2015. PMID- 30311282 TI - Differential responsivity of neurons in perirhinal cortex, lateral entorhinal cortex, and dentate gyrus during time-bridging learning. AB - Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo-conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP). Our results show early associative changes in single neuron firing rate as well as theta oscillations in lateral entorhinal cortex (EC) and dentate gyrus (DG), and increases in the number of responsive neurons in perirhinal cortex. In both EC and DG, a subset of neurons from conditioned animals exhibited an elevated baseline firing rate and large responses to the conditioned stimulus and trace period. A similar population of cells has been seen in DG and in medial, but not lateral, EC during spatial tasks, suggesting that lateral EC contains cells responsive to a temporal associative task. In contrast to recent studies in our laboratory that found significant CA1 contributions to long-term memory, the activity profiles of neurons within EC and DG were similar for conditioned and pseudoconditioned rabbits during post consolidation sessions. Collectively these results demonstrate that individual subregions of medial temporal lobe differentially support new and remotely acquired memories. Neuron firing profiles were similar on training trials when conditioned responses were and were not exhibited, demonstrating that these temporal lobe regions represent the CS-US association and do not control the behavioral response. The analysis of theta activity revealed that theta power was modulated by the conditioning stimuli in both the conditioned and pseudoconditioned groups and that although both groups exhibited a resetting of phase to the corneal airpuff, only the conditioned group exhibited a resetting of phase to the whisker conditioned stimulus. PMID- 30311281 TI - The interactive effects of perceived peer drinking and personality profiles on adolescent drinking: a prospective cohort study. AB - AIMS: (1) To classify Australian adolescents according to their alcohol consumption trajectories; and (2) to assess the direct and interactive effects of perceived peer drinking (PPD) and personality on adolescent drinking. DESIGN: Prospective cohort study comprising secondary analysis of six waves of prospective data (collected between 2014 and 2016) from the control arm of the Climate Schools Combined Study. SETTING: Nineteen schools across three Australian states. PARTICIPANTS: A total of 1492 socio-demographically diverse students (mean age at baseline: 13.47; 68% female; 82% born in Australia). MEASUREMENTS: Alcohol consumption trajectories were assessed using self-reported sipping of alcohol, full standard drink consumption, binge drinking and quantity and frequency of alcohol consumption. One item assessed PPD and personality was assessed using the Substance Use Risk Profile Scale. FINDINGS: Eight hundred and sixty-four (58%) adolescents consumed alcohol across the study period. Four drinking trajectories were identified: abstaining (n = 513; reference group); onset (n = 361; initiated after baseline); persistent (n = 531; initiated prior to baseline); and decreasing (n = 50; consumed alcohol at baseline but ceased or decreased thereafter). A significant PPD * anxiety sensitivity (AS) interaction affected probability of belonging to the onset (P < 0.001) and persistent (P = 0.003) trajectories. The effect of PPD on probability of belonging to the onset trajectory was only significant when adolescents reported low [95% confidence interval (CI) = 1.464-2.646, P < 0.001], but not high AS. The effect of PPD on probability of belonging to the persistent drinking trajectory was stronger at low (95% CI = 2.144-3.283, P < 0.001), compared with high (95% CI = 1.440-2.308, P < 0.001) AS. CONCLUSIONS: In Australian adolescents, self-reported drinking onset and persistent drinking appear to be more strongly associated with perceived peer drinking in those with low anxiety sensitivity than those with high anxiety sensitivity. PMID- 30311283 TI - Room-Temperature Ultrabroadband Photodetection with MoS2 by Electronic-Structure Engineering Strategy. AB - Photodetection using semiconductors is critical for capture, identification, and processing of optical information. Nowadays, broadband photodetection is limited by the underdeveloped mid-IR photodetection at room temperature (RT), primarily as a result of the large dark currents unavoidably generated by the Fermi-Dirac distribution in narrow-bandgap semiconductors, which constrains the development of some modern technologies and systems. Here, an electronic-structure strategy is proposed for designing ultrabroadband covering mid- and even far-IR photodetection materials operating at RT and a layered MoS2 is manifested with an engineered bandgap of 0.13 eV and modulated electronic state density. The sample is designed by introducing defect energy levels into layered MoS2 and its RT photodetection is demonstrated for wavelengths from 445 nm to 9.5 um with an electronic state density-dependent peak photoresponsivity of 21.8 mA W-1 in the mid-IR region, the highest value among all known photodetectors. This material should be a promising candidate for modern optoelectronic devices and offers inspiration for the design of other optoelectronic materials. PMID- 30311284 TI - Closure of the anterior and posterior fontanelle in the New Zealand population: A computed tomography study. AB - AIM: Significant ethnic variation has been demonstrated in the closure of the anterior fontanelle (AF); however, to date, this has not been investigated in the Maori/Pasifika population. METHODS: The computed tomography scans of 163 individuals (116 Maori/Pasifika and 47 New Zealand (NZ) European) aged between birth and 4 years were retrospectively analysed to investigate the surface area (SA) and time of closure of the anterior and posterior fontanelles in New Zealand. RESULTS: The Maori/Pasifika group showed clinical AF closure (SA < 114 mm2 ) rates of 25% at 4-6 months, increasing to 47% at 10-12 months and 80% at 13 18 months. The posterior fontanelle was clinically unfused in 17% of the Maori/Pasifika group aged <1 month and in 7% of the 1-3-month-old group. No cases of posterior fontanelle non-fusion were identified in the NZ European population. CONCLUSION: This study establishes normal values for AF size and closure frequency for the first time in the paediatric Maori/Pasifika population. PMID- 30311285 TI - 2018 Academic Emergency Medicine Consensus Conference: Advancing Pediatric Emergency Medicine Education Through Research and Scholarship. AB - To achieve high-quality emergency care for pediatric patients nationwide, it is necessary to define the key elements for pediatric emergency medicine (PEM) education and scholarship that would: 1) close the gaps in fundamental PEM education and 2) promote systems and standards that assure an ongoing communication of best practices between tertiary pediatric institutions, general (nonchildren's) hospital emergency departments, and urgent care centers. A working group of medical educators was formed to review the literature, develop a framework for consensus discussion at the breakout session, and then translate their findings into recommendations for future research and scholarship. The breakout session consensus discussion yielded many recommendations. The group concluded that future progress depends on multicenter collaborations as a PEM education research network and a unified vision for PEM education that bridges organizations, providers, and institutions to assure the best possible outcomes for acutely ill or injured children. PMID- 30311286 TI - Reversible Self-Assembling of Boryl Radical Anions to Their Diradicals with Tunable Singlet Ground States. AB - Two novel boron-centered diradicals 1Na-1Na and 1K-1K were synthesized by the self-assembling of the corresponding radical salts 1Na and 1K, respectively. 1Na 1Na was obtained by re-dissolving the crystals of the radical salt 1Na in toluene, while 1K-1K was directly obtained by the reduction of dimesitylpyridine borane (1) with potassium in THF. The diradicals can be converted back to their radical anions in THF solutions, forming a reversible process. EPR spectroscopy and SQUID measurements, together with theoretical calculations, show that the diradicals have singlet ground states with excited triplet states. Their singlet triplet energy gaps are tunable with metals. PMID- 30311287 TI - Talking about overweight and obesity in rural Australian general practice. AB - As many patients' sole point of contact with the health care system, primary health care physicians (general practitioners [GPs] in Australia) are often positioned as key players in responding to rates of overweight and obesity in dominant public discourse. However, research from Western industrialised countries suggests that GPs may not be prepared for, or confident in, having conversations about overweight and obesity with patients. Little attention has been given to this topic in Australia, particularly in the context of rural health. The aim of this study was to understand how GPs in two rural settings in Victoria, Australia talk about overweight and obesity with patients. Working from a multidisciplinary perspective, a qualitative study design was adopted, and semi structured interviews were conducted with seven GPs and seven GP patients living in two rural communities between January and April, 2016. Data was coded manually and thematic analysis was used to explore the data. The findings of this study support the argument that, in contrast to dominant messages within public health discourses, GPs may not be best placed to act as the primary actors in responding to overweight and obesity as they are constructed in epidemiological terms. In fact, the perspectives of GP study participants suggest that to do so would compromise important dimensions of general medical practice that make it simultaneously a human practice. Instead, more balanced, holistic approaches to discussing and responding to overweight and obesity with patients could be taken up in local, interdisciplinary collaborations between different health professionals and patients, which utilise broader social supports. Focussing on long-term, incremental programs that consider the whole person within their particular socio-cultural environment would be a productive means of working with the complexities of overweight and obesity. However, structural level changes are required to ensure such initiatives are sustainable in rural practice. PMID- 30311288 TI - High-fat diet and type 2 diabetes induced disruption of the oestrous cycle and alteration of hormonal profiles, but did not affect subpopulations of KNDy neurones in female rats. AB - Apart from the primary metabolic symptoms of obesity and/or diabetes, there are numerous secondary problems, including disruptions of the reproductive system. The KNDy neurones, which express kisspeptin, neurokinin B and dynorphin A and are located in the arcuate nucleus of the hypothalamus (ARC), are important regulators of reproduction. Their functions are highly influenced by metabolic and hormonal status. We have previously shown that, in male rats with experimentally-induced diabetes type 2 (but not with high-fat diet-induced obesity), there are alterations in the number of these cells. In the present study, we hypothesised that a high-fat diet (HFD) and/or diabetes type 2 (DM2) in female rats affect the oestrous cycle, hormonal profiles and the number of kisspeptin-immunoreactive, neurokinin B-immunoreactive and/or dynorphin A immunoreactive neurones in the ARC. Rats were assigned to one of three groups: a control group fed a regular chow diet, a high-fat diet group (HFD) and a diabetic group (DM2), with both of the latter two groups receiving a high calorie diet (50% of energy from lard). The third group was additionally treated with streptozotocin to induce DM2. Their oestrous cycles was monitored and their metabolic and hormonal status were assessed. We found that HFD and DM2 female rats, despite having significant alterations in their metabolic and hormonal profiles, as well as disruptions of the oestrous cycle, showed no changes in the number of the kisspeptin-immunoreactive, neurokinin B-immunoreactive and/or dynorphin A-immunoreactive neurones in the ARC. However, slight differences in the rostrocaudal distribution of these neurones among groups were reported. In conclusion, the data from the present study, together with our previously published results in males, indicate sex differences in the response of KNDy neurones to DM2 but not to HFD conditions. PMID- 30311289 TI - Transient hepatitis B immunity passively acquired from transfusion of packed red blood cells. PMID- 30311290 TI - Discover Tomorrow. PMID- 30311291 TI - Special Educational Lecture. PMID- 30311294 TI - Program. PMID- 30311292 TI - AUA Postgraduate Lecture. PMID- 30311295 TI - Message from Asia. PMID- 30311296 TI - JUA Symposium. PMID- 30311297 TI - Congress President's Welcome Message. PMID- 30311298 TI - SIU Lecture. PMID- 30311300 TI - EAU Lecture. PMID- 30311299 TI - Faculty List. PMID- 30311302 TI - Up-to-Date. PMID- 30311301 TI - Unmoderated Poster. PMID- 30311304 TI - Nursing Program. PMID- 30311303 TI - ACU Lecture. PMID- 30311305 TI - AUA Lecture. PMID- 30311306 TI - Moderated Poster. PMID- 30311307 TI - Educational Lecture. PMID- 30311309 TI - Asia Urological Symposium. PMID- 30311308 TI - UAA Lecture. PMID- 30311310 TI - Special Lecture. PMID- 30311311 TI - JUA UAA International Oral. PMID- 30311312 TI - Electrocarving during Electrodeposition Growth. AB - Shape- and size-controlled synthesis of micro/nanostructures is of fundamental importance in many applications of physics and chemistry. Wet chemical growth methods have achieved shape- and size-controlled synthesis of colloidal nanocrystals of various compositions. Compared with wet chemical methods, electrochemical deposition (ECD) yields micro/nanostructures affixed to a substrate, but the resulting structures are poorly controlled. Herein, the controllable electrochemical fabrication of well-defined silver-oxide clathrate micro/nanostructures is realized by intentionally manipulating the previously neglected electrocarving process during electrodeposition growth (MEDEG). Most importantly, the dominance of the electrocarving and the electrodeposition growth process can be immediately manipulated by varying the deposition voltage and/or the composition of the electrolyte. Unique delta-wing-, arrowhead-, and butterfly like silver-oxide clathrate structures are created using the MEDEG method. MEDEG complements the capability of ECD for controllable synthesis of micro/nanostructures of various materials directly on a substrate. The study details the mechanisms that may enable MEDEG to become a competitive alternative to traditional wet chemical methods in the controllable synthesis of micro/nanostructures. This understanding of MEDEG should motivate applications in fields which demand well-defined micro/nanostructures affixed to a substrate. PMID- 30311313 TI - Low-intensity exercise therapy with high frequency improves physical function and mental and physical symptoms in patients with haematological malignancies undergoing chemotherapy. AB - This study aimed to investigate the effects of low-intensity exercise therapy (LIET) on the physical and mental symptoms and functions in patients with haematological malignancies undergoing chemotherapy. Forty-four patients hospitalised for chemotherapy performed LIET. The exercise intensity of LIET was defined as achieving <40% of the predicted maximum heart rate calculated using the Karvonen formula. LIET consisted of aerobic and resistance training, which was carried out on weekdays. The intervention was omitted in the case of poor general health status and strong patient refusal. Muscular and physical function, activities of daily living (ADLs), psychological distress and quality of life (QOL) were evaluated upon initiation of rehabilitation and at discharge. Participants were divided into high- and low-frequency groups according to their LIET frequency. Two-way repeated-measures analysis of variance was used for statistical analysis. In the high-frequency group, muscle function was maintained, while physical function, ADLs, psychological distress and QOL were significantly improved. However, in the low-frequency group, muscle function of the lower limb was significantly reduced and no other improvement was observed. Low-intensity exercise therapy could be a potential treatment strategy for patients with haematological malignancies undergoing chemotherapy who are unable to perform mid- or high-intensity exercise. PMID- 30311314 TI - Pass the parcel: Service provider views on bridging gaps for youth with dual diagnosis of intellectual disability and mental health disorders in regional areas. AB - AIM: Youth with both intellectual disability (ID) and mental health (MH) disorders (dual diagnosis) have complex physical and MH needs that can make providing integrated care for this complex group challenging. We conducted a mixed methods needs assessment to identify gaps and challenges in care delivery, identify bridges for these and identify what works well in existing services. METHODS: Our research team recruited service providers (n = 126) caring for youth aged 14-24 years with a dual diagnosis in the Illawarra Shoalhaven region of New South Wales, Australia, to participate in focus group interviews. Data were transcribed and analysed thematically. RESULTS: We identified six themes related to caring for youth with dual diagnosis in regional areas: access to services and information about services, communication between service providers and with clients and carers, the divide between MH and ID, early intervention and health promotion, capacity building of service providers and capacity building of clients and carers. Across these themes, service providers highlighted the transition from child to adult services as a particularly challenging time for clients, families and carers. CONCLUSIONS: Our data suggest several approaches to break down silos and to facilitate collaboration between current services for youth with a dual diagnosis, including increasing specialised ID/MH services and building the capacity of current disability and MH service providers. Our results provide important information to provide quality and integrated care for youth with complex health needs. PMID- 30311315 TI - The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles. AB - The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting-state functional magnetic resonance imaging (rs-fMRI) data of healthy adult individuals (N = 85; 19-85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster-specific FC profiles in independent data from healthy older individuals (N = 25; 65-89 years). Results showed that the human CBF is functionally organized into distinct anterior-medial and posterior-lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior-medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior-lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion-specific FC profiles was reproduced in independent rs-fMRI data of healthy older individuals acquired in a typical clinical setting. Rs-fMRI-based assessments of subregion-specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders. PMID- 30311316 TI - Using deep autoencoders to identify abnormal brain structural patterns in neuropsychiatric disorders: A large-scale multi-sample study. AB - Machine learning is becoming an increasingly popular approach for investigating spatially distributed and subtle neuroanatomical alterations in brain-based disorders. However, some machine learning models have been criticized for requiring a large number of cases in each experimental group, and for resembling a "black box" that provides little or no insight into the nature of the data. In this article, we propose an alternative conceptual and practical approach for investigating brain-based disorders which aim to overcome these limitations. We used an artificial neural network known as "deep autoencoder" to create a normative model using structural magnetic resonance imaging data from 1,113 healthy people. We then used this model to estimate total and regional neuroanatomical deviation in individual patients with schizophrenia and autism spectrum disorder using two independent data sets (n = 263). We report that the model was able to generate different values of total neuroanatomical deviation for each disease under investigation relative to their control group (p < .005). Furthermore, the model revealed distinct patterns of neuroanatomical deviations for the two diseases, consistent with the existing neuroimaging literature. We conclude that the deep autoencoder provides a flexible and promising framework for assessing total and regional neuroanatomical deviations in neuropsychiatric populations. PMID- 30311317 TI - Quantifying the axonal pathways directly stimulated in therapeutic subcallosal cingulate deep brain stimulation. AB - Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from patient-specific computational models. This connectomic-based biophysical modeling strategy has proven successful in improving the clinical response to SCC DBS therapy, but the DBS models used to date have been relatively simplistic, limiting the precision of the pathway activation estimates. Therefore, we used the most detailed patient-specific foundation for DBS modeling currently available (i.e., field-cable modeling) to evaluate SCC DBS in our most recent cohort of six subjects, all of which were responders to the therapy. We quantified activation of four major pathways in the SCC region: forceps minor (FM), cingulum bundle (CB), uncinate fasciculus (UF), and subcortical connections between the frontal pole and the thalamus or ventral striatum (FP). We then used the percentage of activated axons in each pathway as regressors in a linear model to predict the time it took patients to reach a stable response, or TSR. Our analysis suggests that stimulation of the left and right CBs, as well as FM are the most likely therapeutic targets for SCC DBS. In addition, the right CB alone predicted 84% of the variation in the TSR, and the correlation was positive, suggesting that activation of the right CB beyond a critical percentage may actually protract the recovery process. PMID- 30311318 TI - What Is the Specificity of the Aortic Dissection Detection Risk Score in a Low prevalence Population? AB - BACKGROUND: Acute aortic syndrome (AAS) is a time-sensitive and difficult-to diagnose aortic emergency. The American Heart Association (AHA) proposed the acute aortic dissection detection risk score (ADD-RS) as a means to reduce miss rate and improve time to diagnosis. Previous validation studies were performed in a high prevalence population of patients. We do not know how the rule will perform in a lower-prevalence population. This is important because application of a rule with low specificity would increase imaging rates and complications. Our goal was to assess if the diagnostic accuracy of the score would be maintained in a low-prevalence population that we are attempting to risk stratify in the emergency department (ED). METHODS: Retrospective cohort of patients age 18 years old and older who presented to two tertiary care EDs from January 1, 2015, to December 31, 2015, and underwent a computed tomographic angiography to rule out AAS. Two trained reviewers extracted data using a standardized data collection form. AAS was defined according to accepted radiologic standards. The components of the AHA risk score were defined a priori. Agreement was measured using kappa statistic. Sensitivity, specificity, and positive and negative likelihood ratios with 95% confidence intervals (CIs) were calculated. Analysis was performed using SAS 9.4 University Edition. RESULTS: A total 370 patients underwent computed tomography for suspected AAS. Chief presenting symptoms were chest pain (207, 58%), back pain (26, 7%), abdominal pain (32, 8.6%), syncope (7, 2.6%), and symptoms of stroke (6, 1.6%). AAS was finally diagnosed in 12 (3.2%) patients: five (1.4%) type A aortic dissection, four (1%) type B aortic dissection, two (0.5%) an aortic intramural hematoma, no penetrating aortic ulcer, and one a ruptured abdominal aortic aneurysm. The presence of one or more ADD risk markers (ADD-RS >= 1) was associated with a sensitivity of 100% (95% CI = 73.5%-100%) and a specificity of 12.3% (95% CI = 9.1%-16.2%) for the diagnosis of AAS. The negative likelihood ratio was 0 and the positive likelihood ratio was 1.14 (95% CI = 1.1-1.2). CONCLUSIONS: Our study confirms that in North America the prevalence of AAS in those undergoing advanced imaging is low. The ADD-RS in this population has a low specificity. A lack of defined inclusion criteria and a low specificity limits the application of this rule in practice. PMID- 30311320 TI - Neuroimaging in Psychiatric Disorders: A Bibliometric Analysis of the 100 Most Highly Cited Articles. AB - BACKGROUND AND PURPOSE: Extensive research has been conducted to find neuroimaging biomarkers for psychiatric disorders. This study aimed at identifying trends of the 100 most highly cited articles on neuroimaging in primary psychiatric disorders. METHODS: The most highly cited original research articles were identified and analyzed, following searches of MEDLINE and Web of Science All Databases. RESULTS: The top 100 articles ranked by yearly citation (from 137.5 to 31.1) were published between 1989 and 2017. Depressive disorders (30 articles), schizophrenia spectrum and other psychotic disorders (27), autism spectrum disorder (17), substance-related and addictive disorders (7), and post traumatic stress disorder (7) were among the most studied conditions. Functional magnetic resonance imaging (42), structural magnetic resonance imaging (30), and positron emission tomography (22) were the most utilized neuroimaging modalities. While 85 articles investigated the pathophysiology of psychiatric disorders (including 7 focusing on developmental changes and 1 on genetic susceptibility), 15 articles studied the impact of treatment, including antidepressants (6), deep brain stimulation (4), antipsychotics (3), behavior therapy (3), and exercise (1). The analysis also identified the most contributing authors, countries (the United States: 71 articles, the United Kingdom: 8, Canada: 5, and China: 5), and journals (JAMA Psychiatry: 20 articles and Biological Psychiatry: 17). Ninety eight studies were prospective, and two were retrospective. The sample size ranged from 3 to 1,188 (median: 21). CONCLUSIONS: Our study identified intellectual milestones in the utility of neuroimaging in investigating primary psychiatric disorders. The historic trends could help guide future research in this field. PMID- 30311319 TI - Preparation Techniques Used to Make Single-Unit Crowns: Findings from The National Dental Practice-Based Research Network. AB - PURPOSE: To: (1) determine which preparation techniques clinicians use in routine clinical practice for single-unit crown restorations; (2) test whether certain practice, dentist, and patient characteristics are significantly associated with these techniques. MATERIALS AND METHODS: Dentists in the National Dental Practice Based Research Network participated in a questionnaire regarding preparation techniques, dental equipment used for single-unit crown preparations, scheduled chair time, occlusal clearance determination, location of finish lines, magnification during preparation, supplemental lighting, shade selection, use of intraoral photographs, and trimming dies. Survey responses were compared by dentist and practice characteristics using ANOVA. RESULTS: Of the 2132 eligible dentists, 1777 (83%) responded to the survey. The top two margin configuration choices for single-unit crown preparation for posterior crowns were chamfer/heavy chamfer (65%) and shoulder (23%). For anterior crowns, the most prevalent choices were the chamfer (54%) and the shoulder (37%) configurations. Regarding shade selection, a combination of dentist, assistant, and patient input was used to select anterior shades 59% of the time. Photographs are used to communicate shade selection with the laboratory in about half of esthetically demanding cases. The ideal finish line was located at the crest of gingival tissue for 49% of respondents; 29% preferred 1 mm below the crest; and 22% preferred the finish line above the crest of tissue. Average chair time scheduled for a crown preparation appointment was 76 +/- 21 minutes. Practice and dentist characteristics were significantly associated with margin choice including practice type (p < 0.001), region (p < 0.001), and years since graduation (p < 0.001). CONCLUSIONS: Network dentists prefer chamfer/heavy chamfer margin designs, followed by shoulder preparations. These choices were related to practice and dentist characteristics. PMID- 30311321 TI - Identification of retinal homeobox (rax) gene-dependent genes by a microarray approach: The DNA endoglycosylase neil3 is a major downstream component of the rax genetic pathway. AB - BACKGROUND: The retinal homeobox (rx/rax) gene is a transcription factor expressed in the developing eye field that is necessary for normal eye development. rax is necessary for retinal specification and stem cell development. The genetic program of early retinal development, including rax expression, can be induced in naive ectoderm by activation of insulin-like growth factor (IGF) signaling. We have undertaken a microarray-based approach to identify rax-dependent IGF-induced genes. RESULTS: We identified 21 IGF-induced genes that exhibit at least a two-fold decrease in expression when rax expression is knocked down. Ten of these genes were expressed in the developing eye, eight were expressed in the ciliary marginal zone of the mature tadpole retina, and four could significantly rescue the rax knockdown phenotype. One of these, the nei endonuclease VIII-like 3 (neil3) gene, rescued the rax knockdown phenotype to a remarkable degree. We found that neil3 is necessary for normal retinal lamination and retinal neuron differentiation. CONCLUSIONS: We have identified neil3 as a component of the rax genetic pathway necessary for normal retinal progenitor cell development. neil3 is involved in the base excision DNA repair pathway, suggesting that this pathway is essential for normal rax-dependent progenitor cell development in the mature retina. Developmental Dynamics 247:1199 1210, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30311323 TI - Computed tomographic bronchial collapsibility values over 50% may be detected in healthy dogs. AB - Bronchomalacia and bronchial collapse are important causes of chronic coughing in dogs. The current reference standard diagnostic tests for these problems are flexible bronchoscopy and biopsy. Previous human studies have also supported inspiration/expiration computed tomography (CT) as a diagnostic test. The current prospective, pilot study aimed to determine whether inspiration/expiration CT is also a feasible test for quantifying bronchial collapsibility in dogs. Thoracic CT images were acquired using a 64-row multidetector CT for 10 healthy Beagle dogs during maximal inspiration and expiration. For each scan, one observer measured transverse sectional areas of the mainstem and lobar bronchi, and the dorsal and ventral segmental bronchi of the left cranial lobar bronchus. Diameters for each bronchus were also measured in transverse, sagittal, and dorsal planes. Bronchial collapsibility (%) was calculated as the difference between inspiration/expiration transverse sectional areas divided by the inspiration transverse sectional areas. Mean bronchial collapsibility of all bronchi was 38.20 +/- 15.17%. A collapsibility of over 50% was found in the dorsal (n = 7) and ventral (n = 4) segmental bronchi of the left cranial lobar bronchus, and the left caudal (n = 5) and right middle (n = 2) lobar bronchus. Bronchial collapsibility measurements were greater in the dorsal and ventral segmental bronchi of the left cranial lobar bronchus and the left caudal lobar bronchus (P < 0.001). Findings supported inspiration/expiration CT as a modality to noninvasively assess bronchial collapse in dogs and a bronchial collapsibility value greater than 50% for detecting pathologic bronchial collapse in clinically affected dogs. PMID- 30311322 TI - The neuroanatomical basis of the Gambler's fallacy: A univariate and multivariate morphometric study. AB - Human decision-making can be irrational, as in the case of the gambler's fallacy (GF). Converging evidence from behavioral and functional neuroimaging studies has suggested that a hyperactive cognitive system and a hypo-active affective system contribute to the false world model that generates the GF. However, the neuroanatomical basis underlying the GF remains unclear. The current study addressed this issue by collecting high-resolution magnetic resonance anatomical images from a large sample of 350 healthy Chinese adults. Univariate voxel-based morphometry (VBM) analysis suggested that the gray matter volume (GMV) in the anterior cingulate cortex (ACC) and medial temporal lobe (MTL) (two regions of the cognitive system) showed negative correlations with the degree of GF, while the GMV in the striatum and orbitofrontal cortex (OFC; two regions of the affective system) showed positive correlations. Further multivariate VBM analysis showed that the GMV in these regions could potentially predict the degree of GF. Moreover, a mediation analysis suggested that the GMV in MTL, ACC, and OFC mediated the relationships between the cognitive abilities or affective decision making performance and the GF. Results of our study help us to understand the potential neural bases of the cognitive system's constructive role and the affective system's destructive role in decision making. PMID- 30311324 TI - Long-term Mortality in Pediatric Firearm Assault Survivors : A Multicenter, Retrospective, Comparative Cohort Study. AB - OBJECTIVES: The objective was to determine whether children surviving to hospital discharge after firearm assault (FA) and nonfirearm assault (NFA) are at increased risk of mortality relative to survivors of unintentional trauma (UT). Secondarily, the objective was to elucidate the factors associated with long-term mortality after pediatric trauma. METHODS: This was a multicenter, retrospective cohort study of pediatric patients aged 0 to 16 years who presented to the three trauma centers in San Francisco and Alameda counties, California, between January 2000 and December 2009 after 1) FA, 2) NFA, and 3) UT. The Social Security Death Master File and the California Department of Public Health Vital Statistics (2000 2014) were queried through December 31, 2014, to identify those who died after surviving their initial hospitalization and to delineate cause of death. Multivariate Cox proportional hazards regression was performed to determine associations between exposure to assault and long-term mortality. RESULTS: We analyzed 413 FA, 405 NFA, and 7,062 UT patients who survived their index hospital visit. A total of 75 deaths occurred, including 3.9, 3.2, and 0.7% of each cohort, respectively. Two-thirds of all long-term deaths were due to homicide. After multivariate adjustment, adolescent age, male sex, black race/ethnicity, and public insurance were independent risk factors for long-term mortality. FA (adjusted hazard ratio [AHR] = 1.8, 95% confidence interval [CI] = 0.82-4.0) and NFA (AHR = 1.9, 95% CI = 0.93-3.9) did not convey a statistically significant difference in risk of long-term mortality compared to UT. Being assaulted by any means (with or without a firearm), however, was an independent risk factor for long-term mortality in the full study population (AHR = 1.9, 95% CI = 1.01-3.4) and among adolescents (AHR = 1.9, 95% CI = 1.01-3.6). CONCLUSION: Children and adolescents who survive assault, including by firearm, have increased long-term mortality compared to those who survive unintentional, nonviolent trauma. PMID- 30311325 TI - Grassroots Intervention to Increase Appointment of Pediatric Emergency Care Coordinators in Massachusetts Emergency Departments. AB - OBJECTIVES: Appointment of a pediatric emergency care coordinator (PECC) is considered the single best intervention to improve pediatric emergency care and has been recommended for all U.S. general emergency departments (EDs) for more than a decade. Unfortunately, many EDs do not adhere with this recommendation. In 2017, we performed a grassroots intervention to establish a PECC in every Massachusetts ED. METHODS: We conducted annual surveys of all 73 Massachusetts EDs from 2014 to 2018. Data collection included ED visit volumes, presence of a pediatric area, and PECC status. The intervention in 2017-2018 included e-mails and telephone calls to every ED director to not only assess PECC status but also encourage him/her to appoint one as needed. RESULTS: Survey response rates were > 85% in all years and 100% during 2016 to 2018. While Massachusetts EDs did not materially change over time (in terms of visit volumes or presence of a pediatric area), the 2017 intervention increased the percentage of EDs with an appointed PECC. Specifically, PECCs were present in approximately 30% of EDs during 2014 to 2016, climbed to 85% in 2017, and reached 100% in 2018. Most of the newly appointed PECCs were physicians. CONCLUSIONS: Through a relatively simple grassroots intervention, we increased the appointment of PECCs in Massachusetts EDs from 30% to 100%. In addition to providing PECCs with online educational materials, ongoing work is focused on building community, identifying best practices, and implementing interventions at the local level. PMID- 30311326 TI - The total value of time of children undergoing treatment: A contingent valuation from the perspective of parents in the orthopaedic department of a Dutch hospital. AB - AIM: Children spend substantial amounts of time receiving medical care (patients' time), and this patients' time plays an important role in parental choices for paediatric care. However, it is usually ignored in economic evaluations. This is a concern because economic evaluations are increasingly being used to inform child health policy decision-making. This study aims to quantify the time children spend receiving medical care and attach a monetary value to it for use in economic evaluations. It applied the parents' perspective. Consequently, the derived money values are the time values for both child and the accompanying parent. METHODS: We used the contingent valuation methodology. We collected data on 83 children undergoing orthopaedic treatment in a Dutch hospital. Accompanying parents were asked to quantify and value the patients' time of their children. We separately explored travel, waiting and treatment time. We also checked whether the monetary valuation varied across parents' financial situation, children's health and level of pain. RESULTS: Parents were willing to pay about ?33 (confidence interval (CI) 21.2-48.1) for a 1-day reduction in treatment time; about ?11.5 (CI 4.2-19.1) for an hour's reduction in waiting time; and about ?4.5 (CI 1.5-7.4) for an hour's reduction in travel time. In addition, respondents with better financial conditions have, on average higher, willingness to pays. CONCLUSIONS: To our knowledge, this is the first instance that patients' time of children has been monetarily valued. This methodology can be used to further develop economic evaluations of paediatric care and could be applied to larger samples with varying clinical conditions. PMID- 30311327 TI - National Study of Self-reported Pediatric Areas in United States General Emergency Departments. AB - OBJECTIVES: While many U.S. emergency departments (ED) have a "pediatric ED," there are, to our knowledge, no accepted criteria for this type of ED. We investigated the prevalence, distribution, staffing, and characteristics of self reported pediatric areas in U.S. general EDs. METHODS: We conducted a survey of all 5,273 U.S. EDs to characterize emergency care in 2015. We then surveyed 130 of the 426 general EDs who reported having a pediatric area. Data collection for the second survey included confirmation of a pediatric area and information on that area's structure and staffing. RESULTS: The national survey (85% response) showed 10% of general EDs reported a pediatric area. Only 16% of all U.S. EDs had a pediatric emergency care coordinator (PECC). EDs with larger visit volumes, or in the Northeast or South, were more likely to have a pediatric area. Nine states had no general EDs with pediatric areas. Among general EDs with a pediatric area, 75% had a PECC and 74% had a board-certified or board-eligible pediatric emergency medicine (PEM) physician on staff. Ninety-three percent had designated pediatric beds. Rarely (3%) was the pediatric area just a separate waiting area within a general ED, without any PECC or PEM physician present. CONCLUSIONS: We found that 10% of U.S. general EDs had a pediatric area and that this prevalence varies nationwide. Moreover, only 16% of U.S. EDs had a PECC. Further studies on the impact of ED structure and staffing on pediatric care and patient outcomes are urgently needed. As a long-term objective, a standardized definition of a pediatric ED would not only help quality improvement efforts but also help families make more informed choices about where to bring their children to receive care. PMID- 30311328 TI - The non-acute coronary syndrome related ST-elevation patterns (NASTEP) conundrum: War helmets, Greek letters, and... "shark fins". PMID- 30311329 TI - Canine and feline emphysematous gastritis may be differentiated from gastric emphysema based on clinical and imaging characteristics: Five cases. AB - Gastric pneumatosis is an imaging finding defined as the presence of gas foci in the gastric wall. In humans, this imaging feature can result from one of two separate clinical entities: life-threatening emphysematous gastritis or clinically benign gastric emphysema. This retrospective case series study describes the clinical and imaging features in five animals diagnosed with spontaneous gastric pneumatosis without gastric dilatation-volvulus. Three canine and two feline cases of spontaneous gastric pneumatosis were identified on radiographic and ultrasonographic examinations. In addition to gastric pneumatosis, one dog and two cats presented concomitant systemic signs such as lethargy, hematemesis, anemia, or leukocytosis. Two dogs remained asymptomatic or presented mild gastrointestinal signs. Portal gas was described in two dogs and one cat, and pneumoperitoneum in one dog. These features were not considered clinically significant. The dog and two cats with systemic signs were euthanized due to clinical deterioration and diagnosed with emphysematous gastritis. The gastric pneumatosis of both dogs without systemic signs resolved while on medical management without antibiotic therapy. These latter cases were interpreted as consistent with gastric emphysema. Findings from the current study indicated that gastric pneumatosis can occur without gastric dilatation-volvulus in cats and dogs and that a combination of clinical and imaging characteristics may help to differentiate between potentially life-threatening emphysematous gastritis and relatively benign gastric emphysema. More studies are needed to determine the etiology and risk factors associated with these conditions. PMID- 30311330 TI - Improving access to haemophilia therapies-Beyond humanitarian aid. PMID- 30311331 TI - Wafer-Scale Fabrication of Ultrathin Flexible Electronic Systems via Capillary Assisted Electrochemical Delamination. AB - Electronic systems on ultrathin polymer films are generally processed with rigid supporting substrates during fabrication, followed by delamination and transfer to the targeted working areas. The challenge associated with an efficient and innocuous delamination operation is one of the major hurdles toward high performance ultrathin flexible electronics at large scale. Herein, a facile, rapid, damage-free approach is reported for detachment of wafer-scale ultrathin electronic foils from Si wafers by capillary-assisted electrochemical delamination (CAED). Anodic etching and capillary action drive an electrolyte solution to penetrate and split the polymer/Si interface, leading to complete peel-off of the electronic foil with a 100% success rate. The delamination speed can be controlled by the applied voltage and salt concentration, reaching a maximum value of 1.66 mm s-1 at 20 V using 2 m NaCl solution. Such a process incurs neither mechanical damage nor chemical contamination; therefore, the delaminated electronic systems remain intact, as demonstrated by high-performance carbon nanotube (CNT)-based thin-film transistors and integrated circuits constructed on a 5.5 cm * 5.0 cm parylene-based film with 4 um thickness. Furthermore, the CAED strategy can be applied for prevalent polymer films and confers great flexibility and capability for designing and manufacturing diverse ultrathin electronic systems. PMID- 30311332 TI - Prevalence and risk factors of delirium and subsyndromal delirium in Chinese older adults. AB - AIM: To study the prevalence and risk factors of delirium and subsyndromal delirium (SSD) in Chinese older adults with acute medical illnesses. METHODS: A prospective cohort study was carried out in acute general medical wards in a university-affiliated hospital in Hong Kong. Patients were assessed by the confusion assessment method by geriatricians within 6 h after admission and classified into three mutually exclusive groups, namely delirium, SSD and those without both conditions. Predisposing factors and precipitating factors of delirium and SSD were retrieved from collateral information, clinical charts and electronic clinical records. RESULTS: A total of 575 patients with mean age of 80.8 years were recruited. A total of 73% of the patients did not have delirium, 15.8% of patients had delirium and 11.3% of patients had SSD. On multivariate analysis, patients with delirium or SSD were more likely to be current users of psychotropic medications, had hearing and visual impairment, had a major neurocognitive disorder as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, and with a lower Barthel Index 20 points version than those without both conditions. Significant predisposing and precipitating factors of delirium included psychotropic medications, acute stroke and other causes of organic brain syndromes. Predisposing and precipitating factors of delirium and SSD were almost identical. CONCLUSIONS: Delirium and SSD are common among Chinese older adults with acute medical illnesses, with a combined prevalence of delirium and SSD of 27%. Important precipitating and predisposing factors include psychotropic medications, acute ischemic stroke and other causes of organic brain syndromes. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311333 TI - Mirror-Image Dependence: Targeting Enantiomeric G-Quadruplex DNA Using Triplex Metallohelices. AB - Natural d-DNA and l-DNA are mirror-image counterparts. However, because of the inherent flexibility and conformation diversity of DNA, it is still not clear how enantiomeric compounds recognize d-DNA and l-DNA. Herein, taking G-quadruplex (G4) DNA as an example that has diverse conformations and distinct biofunctions, the binding of ten pairs of iron triplex metallohelices to d- and l-G4 DNA were evaluated. The Delta-enantiomer binds to d-DNA and the Lambda-enantiomer binds to l-DNA, exhibiting almost the same stabilization effect and binding affinity. The binding affinity of the Delta-metallohelix with d-G4 is nearly 70-fold higher than that of Lambda-metallohelix binding d-G4. Delta-Metallohelix binding to d-G4 follows a two-step binding process driven by a favorable enthalpy contribution to compensate for the associated unfavorable entropy. PMID- 30311334 TI - Inhibition of kynurenine aminotransferase II attenuates hippocampus-dependent memory deficit in adult rats treated prenatally with kynurenine. AB - A combination of genetic and environmental factors contributes to schizophrenia (SZ), a catastrophic psychiatric disorder with a hypothesized neurodevelopmental origin. Increases in the brain levels of the tryptophan metabolite kynurenic acid (KYNA), an endogenous antagonist of alpha7 nicotinic acetylcholine and NMDA receptors, have been implicated specifically in the cognitive deficits seen in persons with SZ. Here we evaluated this role of KYNA by adding the KYNA precursor kynurenine (100 mg/day) to chow fed to pregnant rat dams from embryonic day (ED) 15 to ED 22 (control: ECon; kynurenine treated: EKyn). Upon termination of the treatment, all rats received normal rodent chow until the animals were evaluated in adulthood (postnatal days 56-85). EKyn treatment resulted in increased extracellular KYNA and reduced extracellular glutamate in the hippocampus, measured by in vivo microdialysis, and caused impairments in hippocampus dependent learning in adult rats. Acute administration of BFF816, a systemically active inhibitor of kynurenine aminotransferase II (KAT II), the major KYNA synthesizing enzyme in the brain, normalized neurochemistry and prevented contextual memory deficits in adult EKyn animals. Collectively, these results demonstrate that acute inhibition of KYNA neosynthesis can overcome cognitive impairments that arise as a consequence of elevated brain KYNA in early brain development. PMID- 30311335 TI - A Near-Infrared Photoswitchable Protein-Fluorophore Tag for No-Wash Live Cell Imaging. AB - FR-1V, a fluorene-based aldehydic chromophore, binds its target protein as an imine to yield a highly bathochromic pigment, CF-2, a prototypic protein-dye tagging system whose NIR emission can be spatiotemporally switched ON by rapid UV light activation. This is achieved through photoisomerization of the imine and its subsequent protonation. We demonstrate a no-wash protocol for live cell imaging of subcellular compartments in a variety of mammalian cell lines with minimal fluorescence background. PMID- 30311336 TI - Psychometric evaluation of a Chinese version of Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema in women with gynaecological cancer surgery. AB - The prevalence of lower limb lymphoedema and its impact in gynaecological cancer patients is underestimated. However, a valid and reliable scale to measure lower leg lymphoedema in Taiwan has not been available. The purpose of the study was to translate the English version of Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema into a Chinese version (Lymph-ICF-LL-C), and evaluate the psychometric properties of the Lymph-ICF-LL-C in Taiwanese women with gynaecological cancer surgery. A total of 170 women with gynaecological cancer surgery were recruited to examine the Lymph-ICF-LL-C. The Lymph-ICF-LL-C shows satisfactory internal consistency (Cronbach's alphas >= 0.84) and stability test-retest reliability (Intraclass correlation coefficient >=0.55-0.90) at a 2 week interval. Exploratory factor analysis showed that 68.53% of the total variance was explained by a five-factor solution. The concurrent validity of the Lymph-ICF-LL-C was evidenced by a significant correlation with a fatigue scale (r = 0.46, p < 0.01) and with the bilateral difference of lower limb circumference (r = 0.24-0.36, all p < 0.01). The Lymph-ICF-LL-C can be used for assessing the life impact of lower limb lymphoedema, allowing appropriate interventions to prevent further deterioration and complications. PMID- 30311337 TI - Determinants of clinical presentation on outcomes in older patients with myocardial infarction. AB - AIM: Myocardial infarction without chest pain misleads the clinician, resulting in a diagnosis delay and an increase of mortality. The main objective of the present study was to determine the risk factors of atypical presentation in older patients with myocardial infarction. METHODS: All consecutive patients aged >=75 years presenting with myocardial infarction and hospitalized in the cardiology intensive care unit were included in the present prospective multicenter observational study. All patients benefited from both specialized cardiac management and geriatric assessment. RESULTS: A total of 215 consecutive patients were included. The mean age was 85 +/- 6 years. A total of 142 patients (66%) had a typical presentation (i.e. chest pain) and 73 patients (34%) had an atypical clinical presentation (i.e. no chest pain). A total of 29 (13.5%) patients died within 30 days of the index hospitalization. Higher Cumulative Illness Rating Score-Geriatric severity index score (P = 0.019) and initial atrial fibrillation (P = 0.022) were predictive of 30-day all-cause mortality. Typical presentation (P = 0.010) was a protective factor of 30-day all-cause mortality. A Cumulative Illness Rating Score for Geriatrics total score increase (P = 0.0003) and residing in a nursing home (P = 0.024) emerged as independent risk factors for atypical presentation. CONCLUSIONS: In "real-life" elderly patients, comorbidities influence the prognosis of myocardial infarction, but also clinical presentation. Identification of patients at risk of atypical presentation; that is, patients with multiple comorbid conditions, might help refine the prognostic value in older patients with myocardial infarction. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311338 TI - Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis. AB - AIM: Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. METHODS: A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. RESULTS: The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. CONCLUSIONS: The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311339 TI - Sunlight-Driven Water Transport via a Reconfigurable Pump. AB - Fast and controllable water transport in microchannels has implications for many applications. A combination of stimuli-responsive asymmetrical changes in the geometry and gradient in the surface wettability offers the possibility to accelerate the transport and realize controllability. Herein, we introduce a meters-long sunlight-powered reconfigurable water pump constructed by tubular poly(dimethylsiloxane) (PDMS) premixed with chemically reduced graphene oxide (rGO), in which the inner wall is modified with thermal-sensitive poly(N isopropylacrylamide) hydrogel (PNIPAm). This sunlight-powered water pump delivers a record-high advance speed of 1.5 mm s-1 and 13.6 kg h-1 m-2 under 1.5 sun. Theoretical and experimental results reveal that the remarkable performance results from the synergistic effect of the contact-angle gradient arising from the reversible hydrophilic/hydrophobic switch of PNIPAm and the capillary force arising from the geometric deformation of the microchannel. PMID- 30311340 TI - Synthesis of Macrocycles Derived from Substituted Triazines. AB - A triazine ring derivatized with morpholine, an N-alkyl-N'-BOC-hydrazine (alkyl=isopropyl or benzyl) and the diethylacetal of glycinylpropionaldehyde undergoes spontaneous dimerization in good yields upon acid-catalyzed deprotection. The resulting 24-member macrocycles can be characterized by NMR spectroscopy, mass spectrometry, and single crystal X-ray diffraction. In the solid state, both homodimers adopt a taco-like conformation. Although each shows pi-pi stacking between the triazine rings, different patterns of hydrogen bonds emerge. The crystal structure of the isopropyl dimer shows that it includes two molecules of trifluoracetic acid per macrocycle. The trifluoroacetate anion charge balances the protonated triazines, which engage in bifurcated hydrogen bonds with the carbonyl acceptor of the distant glycine. This carbonyl also forms a hydrogen bond with the NH of the proximate glycine. The crystal structure of the benzyl derivative does not include trifluoracetic acid. Instead, two hydrogen bonds form, each between a glycine NH and the lone pair of the C=N nitrogen of the hydrazine group. In the solid state, both molecules present the alkyl side chains and morpholine groups in close proximity. A heterodimer is accessible in approximately statistical yields-along with both homodimers-by mixing the two protected monomers prior to subjecting them to deprotection. PMID- 30311341 TI - Exploration of Maori household experiences of food insecurity. AB - AIM: Researchers explored how food insecurity was experienced in Maori households and how this can affect hauora (well-being). METHODS: This Maori-centred research was conducted in New Zealand by Maori dietetic students with Maori supervision. Kaupapa Maori methodology guided the inductive thematic analysis of observational and discussion data (40+ hours per household) from four Maori households (18 individuals) that participated in a 3-month ethnographic-style investigation in 2011. RESULTS: Four themes were identified. 'Overcoming socioeconomic hardship' was most clearly observed within the low-income whanau (family), however, all whanau had experienced food insecurity. This experience had short- and long-term impacts on well-being. Other themes identified strategies whanau developed to reduce the severity of food insecurity: sharing food, gardening food, and teaching food and nutrition skills. Selected text for themes revealed expressed Maori values and/or hauora influences. The values of manaakitanga (sharing food/hospitality), whanaungatanga (family relationships) and kaitiakitanga (caring for the environment) were observed and analysed deductively. CONCLUSIONS: All households had experienced income-related food insecurity, and its short- and long-term impacts on well-being were observed. Whanau had developed many strategies to reduce the severity of food insecurity, relying on support from extended whanau and the wider community, but households remained food insecure. Health and other professionals should advocate for social justice and policy solutions that change systems perpetuating social and health inequity. All households need sufficient income to afford basic needs including food. When basic needs are met, households and individuals can thrive and make meaningful contributions to society. PMID- 30311342 TI - Single-Site Molybdenum on Solid Support Materials for Catalytic Hydrogenation of N2 -into-NH3. AB - Very stable in operando and low-loaded atomic molybdenum on solid-support materials have been prepared and tested to be catalytically active for N2 -into NH3 hydrogenation. Ammonia synthesis is reported at atmospheric pressure and 400 degrees C with NH3 rates of approximately 1.3*103 MUmol h-1 gMo -1 using a well defined Mo-hydride grafted on silica (SiO2-700 ). DFT modelling on the reaction mechanism suggests that N2 spontaneously binds on monopodal [(=Si-O-)MoH3 ]. Based on calculations, the fourth hydrogenation step involving the release of the first NH3 molecule represents the rate-limiting step of the whole reaction. The inclusion of cobalt co-catalyst and an alkali caesium additive impregnated on a mesoporous SBA-15 support increases the formation of NH3 with rates of circa 3.5*103 MUmol h-1 gMo -1 under similar operating conditions and maximum yield of 29*103 MUmol h-1 gMo -1 when the pressure is increased to 30 atm. PMID- 30311343 TI - Usable implantation depth for watchman left atrial appendage occlusion is greater with appendage angiography than transesophageal echocardiography. AB - OBJECTIVES: To compare left atrial appendage (LAA) angiography to transesophageal echocardiography (TEE) for assessing usable LAA depth. BACKGROUND: TEE is typically employed for procedural measurement of LAA ostial diameter and depth. Since angiography enhances distal LAA anatomy, we sought to compare angiography to TEE for determining usable LAA depth. METHODS: Seventy five Watchman device cases were retrospectively evaluated. Two independent cardiologists measured intraoperative LAA ostial diameter and depth at standard 0 degrees , 45 degrees , 90 degrees , and 135 degrees TEE omniplane views and in the right anterior oblique (RAO) 30 degrees , caudal (CAUD) 30 degrees angiographic view. RESULTS: The average age and CHA2 DS2 VASc score were 74 (+/-7.2) years and 4.6 (+/-1.3), respectively. The average ostial diameter and depth (mm) by TEE were 0 degrees : 19.6 and 26.5; 45 degrees : 17.5 and 26.6; 90 degrees : 18.3 and 25.1; 135 degrees : 19.5 and 23.3. The ostial diameter and depth (mm) by RAO 30 degrees CAUD 30 degrees angiography were 21.1 and 29.7. This angiographic view corresponds to a TEE view between 90 degrees and 135 degrees . In comparison to angiography, TEE 90 degrees underestimated the LAA ostial diameter by 2.9 +/- 3.7 mm (P < 0.001) and by 1.9 +/- 4.0 mm at TEE 135 degrees (P < 0.01); Pearson's r 0.53 angiography/TEE 90 degrees and 0.50 angiography/TEE 135 degrees . More importantly, TEE 90 degrees underestimated the true usable LAA depth by 5.4 +/- 5.8 mm (P < 0.001) and by 7.3 +/- 6.1 mm at TEE 135 degrees (P < 0.001); Pearson's r 0.39 angiography/TEE 90 degrees and 0.30 angiography/TEE 135 degrees . CONCLUSIONS: Compared to TEE, LAA angiography provides additional depth information and may be particularly valuable when patients have insufficient depth for Watchman by TEE measures. PMID- 30311344 TI - Prevalence and predictors of inappropriate prescribing according to the Screening Tool of Older People's Prescriptions and Screening Tool to Alert to Right Treatment version 2 criteria in older patients discharged from geriatric and internal medicine wards: A prospective observational multicenter study. AB - AIM: To evaluate the prevalence and predictors of potentially inappropriate medications (PIM) and potential prescribing omissions (PPO) in hospital discharged older patients, according to the recently updated Screening Tool of Older People's Prescriptions and Screening Tool to Alert to Right Treatment version 2 criteria. METHODS: This was a multicenter prospective observational study of patients aged >=65 years consecutively discharged from geriatric and internal medicine wards. Each patient underwent a comprehensive geriatric assessment, and PIM and PPO at discharge were determined according to the Screening Tool of Older People's Prescriptions and Screening Tool to Alert to Right Treatment version 2 criteria. A multivariate logistic regression was carried out to identify variables independently associated with PIM and PPO. RESULTS: Among 726 participants (mean age 81.5 years, 47.8% women), the prevalence of PIM and PPO were 54.4% and 44.5%, respectively. Benzodiazepines and proton-pump inhibitors were the drugs most frequently involved with PIM, whereas PPO were often related to 5-alpha reductase inhibitors, angiotensin-converting enzyme inhibitors, statins and drugs for osteoporosis. The number of medications (OR 1.22, 95% CI 1.15-1.28) and discharge from geriatric units (OR 0.55, 95% CI 0.40-0.75) were associated with PIM, whereas PPO were independently associated with discharge from geriatric wards (OR 0.44, 95% CI 0.31-0.62), age (OR 1.04, 95% CI 1.02-1.07), comorbidities (OR 1.17, 95% CI 1.04-1.30) and the number of drugs (OR 1.12, 95% CI 1.05-1.18). CONCLUSIONS: Inappropriate prescribing is highly prevalent among hospital-discharged older patients, and is associated with polypharmacy and discharge from internal medicine departments. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311345 TI - Does long-term care insurance reduce the burden of medical costs? A retrospective elderly cohort study. AB - AIM: To examine whether long-term care insurance (LTCI) reduces medical utilization and the burden of medical costs of beneficiaries. METHODS: The elderly cohort database of the National Health Insurance Service during 2005-2013 was used. The participants were 3029 beneficiaries who received consecutive LTCI services. We carried out a 1:3 case-control match on the propensity score to select a comparison group, and the final participants were 12 116 people, including 9087 who formed the control group. The dependent variables were semi annually measured medical utilizations (inpatient, outpatient and drug prescription) and the burden of medical costs at the individual level. This study applied the method of generalized estimating equations to the data. RESULTS: The present study showed that the number of hospitalizations of beneficiaries significantly decreased compared with non-beneficiaries (ratio 0.95, 95% CI 0.95 0.96). Similarly, the length of stay of beneficiaries also showed a significant reduction compared with non-beneficiaries (ratio 0.76, 95% CI 0.73-0.79). The number of outpatient visits and receipt of drug prescriptions of beneficiaries and non-beneficiaries increased marginally. The burden of medical costs of beneficiaries reduced considerably compared with non-beneficiaries (ratio 0.80, 95% CI 0.77-0.83). CONCLUSIONS: The study results show that the burden of medical costs for LTCI beneficiaries were significantly reduced compared with non beneficiaries, despite the rise in medical costs among older adults. The positive effect of LTCI supports continuous implementation and expansion of the LTCI service for non-beneficiaries who require care assistance. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311346 TI - Effect of maturation conditions on light and temperature requirements during seed germination of Citrullus colocynthis from the Arabian Desert. AB - Seed germination of Citrullus colocynthis, as in many other species of Cucurbitaceae, is inhibited by light, particularly at low temperatures. Germination response to light and temperature has been attributed to day length and temperature during seed maturation. This study assessed the effects of these factors on the germination response of C. colocynthis to temperature and light quality. Ripe fruits were collected from natural habitats during December and February and germinated at three temperatures (15/25, 20/30 and 25/35 degrees C) in five light treatments (dark, white light and Red:Far Red (R:FR) ratios of 0.30, 0.87 and 1.19). Additionally, unripe fruits were also collected from natural habitats and completed their maturation in growth chambers under different day lengths (6, 16 and 24 h of darkness) at 10/20 degrees C, and in darkness at both 10/20 degrees C and 25/35 degrees C. Mature seeds of the different treatments were germinated in the same five light treatments at 15/25 degrees C. Germination was significantly higher in the dark than that in any light treatment. Seeds matured at higher temperatures (i.e. seeds from the December collection and those matured at 25/35 degrees C) had significantly higher germination than those matured at lower temperatures (i.e. seeds from the February collection and those matured at 10/20 degrees C). Dark germination was significantly higher for the December collection than for the February collection. Seeds of the two collections germinated in the dark only at 15/25 degrees C. However, seeds matured in a growth chamber at 10/20 degrees C in darkness germinated at 15/25 degrees C in all light treatments, except for the R:FR ratio 0.30. Seeds of the different treatments failed to germinate in FR-rich light. This study demonstrates that both temperature and day length during seed maturation play significant roles in the germination response of C. colocynthis. Additionally, the dark requirement for germination is likely beneficial for species with the larger seeds, such as C. colocynthis, which produce bigger seedlings that are able to emerge from deep soils and are competitively superior under dense vegetation and resource-limited conditions. PMID- 30311347 TI - 18 O-Pi uptake measurements indicate fast metabolisation of phosphate in tree roots. AB - Phosphorus (P) nutrition of beech ecosystems depends on soil processes, plant internal P cycling and P acquisition. P uptake of trees in the field is currently not validated due to the lack of an experimental approach applicable in natural forests. Application of radiolabeled tracers such as 33 P and 32 P is limited to special research sites and not allowed in natural environments and, furthermore, only one stable isotope of P namely 31 P exist. One alternative tool to measure P acquisition in the field could be the use of 18 O-enriched 31 P-phosphate (Pi ). Pi uptake rates calculated from the enrichment in 18 O atom% of dried root material after 18 O-enriched Pi application via nutrient solution was always lower compared to 33 P incorporation, did not show increasing rates of Pi uptake at P deficiency under controlled conditions and did not reveal seasonal fluctuations in the field. Consequently, a clear correlation between 33 P-based and 18 O-based Pi uptake by roots could not be established. The replacement of 18 O by 16 O from water in the 18 O-enriched Pi during Pi root influx, but most probably after Pi uptake into roots due to metabolic activities is highly evident and indicates high and fast turnover of Pi . Hence, the use of 18 O-enriched Pi as an alternative tool to estimate Pi acquisition of trees in the field needs considering 18 O atom% of root water. This article is protected by copyright. All rights reserved. PMID- 30311348 TI - Relationship between long-chain omega-3 polyunsaturated fatty acid intake and ankle brachial index, pulse wave velocity and resting heart rate in a sample of overweight adults: A secondary analysis of baseline data in the HealthTrack study. AB - AIM: The present study aimed to explore the association between dietary long chain omega-3 polyunsaturated fatty acid (LCn3PUFA) intake and cardiovascular risk indicators (ankle brachial index, resting heart rate and brachial-ankle pulse wave velocity) in a clinical sample of overweight and obese participants volunteering for a weight loss trial. METHODS: This was a secondary analysis of baseline data from the HealthTrack study (n = 351). LCn3PUFA intake was calculated via a diet history and the association with ankle brachial index, resting heart rate and brachio-ankle pulse wave velocity was explored using linear regression after controlling for covariates. RESULTS: LCn3PUFA intake was inversely associated with ankle brachial index (R2 change = 0.021, F change (1, 339) = 8.864, P < 0.05) and resting heart rate (R2 change = 0.014, F change (1, 342) = 5.337, P < 0.05) but not with brachio-ankle pulse wave velocity (R2 change = 0.001, F change (1, 339) = 0.725, P > 0.05). CONCLUSIONS: In this clinical sample of overweight adults, LCn3PUFA consumption was significantly associated with a lower resting heart rate, adding to the current evidence on the potential benefits of LCn3PUFA consumption. It also supports the value of targeting a diet rich in this nutrient when planning future dietetic approaches. Relationships with ankle brachial index and pulse wave velocity require further investigation. Future research should assess the effect of changes in dietary LCn3PUFA intake on novel cardiovascular risk indicators. PMID- 30311349 TI - Extreme male developmental trajectories of homotopic brain connectivity in autism. AB - It has been proposed that autism spectrum disorder (ASD) may be characterized by an extreme male brain (EMB) pattern of brain development. Here, we performed the first investigation of how age-related changes in functional brain connectivity may be expressed differently in females and males with ASD. We analyzed resting state functional magnetic resonance imaging data of 107 typically developing (TD) females, 114 TD males, 104 females, and 115 males with ASD (6-26 years) from the autism brain imaging data exchange repository. We explored how interhemispheric homotopic connectivity and its maturational curvatures change across groups. Differences between ASD and TD and between females and males with ASD were observed for the rate of changes in connectivity in the absence of overall differences in connectivity. The largest portion of variance in age-related changes in connectivity was described through similarities between TD males, ASD males, and ASD females, in contrast to TD females. We found that shape of developmental curvature is associated with symptomatology in both males and females with ASD. We demonstrated that females and males with ASD tended to follow the male pattern of developmental changes in interhemispheric connectivity, supporting the EMB theory of ASD. PMID- 30311350 TI - A Retrospective Study on Erythropoiesis Stimulating Agent Dose Reducing Potential of an Anti-Platelet Activation Membrane Dialyzer in Hemodialysis Patients. AB - Our previous small-scale trial demonstrated an erythropoiesis stimulating agent (ESA)-sparing potential of the TORAYLIGHT NV (NV) dialyzer in hemodialysis patients with high interleukin-6 levels. We now retrospectively explored this ESA sparing potential of the NV dialyzer in 122 and 129 prevalent dialysis patients who were on the NV and conventional polysulfone (PS) dialyzers, respectively, for 12 months. ESA resistance index (ERI) increased with the PS dialyzers whereas neither ERI nor ESA dose changed with the NV dialyzer. Analyses of baseline ERI or ESA dose-based subgroups revealed a decrease in ERI and ESA dose with the NV dialyzer in patients with a baseline ERI >=12 IU.dL/week.kg.g Hb (P < 0.05) and in those with a baseline ESA dose >6000 IU/week (P < 0.001), respectively. Neither ERI nor ESA dose improved in the corresponding subgroups on the PS dialyzers. These findings suggest that NV dialyzer can improve ESA responsiveness in hemodialysis patients with advanced ESA resistance. PMID- 30311351 TI - The role of psychology in a multidisciplinary psychiatric inpatient setting: Perspective from the multidisciplinary team. AB - OBJECTIVES: Psychologists routinely work in psychiatric inpatient settings and it is acknowledged that they cannot work in isolation from the multidisciplinary team. The aim of this study was to examine the multidisciplinary team's perspective on the role of psychology within the acute psychiatric inpatient setting. DESIGN: A qualitative approach was taken utilizing semi-structured interviews for data collection. METHODS: Interviews were undertaken with 12 multidisciplinary team members (occupational therapists, psychiatric nurses, psychiatrists, and clinical managers) examining their perspectives on the role of psychology within the acute psychiatric inpatient setting. Thematic analysis was used to analyse data. RESULTS: The analysis identified two key themes 'psychological treatments', which describes the perceived function of psychology on the ward, and 'integrated psychological working' outlining key issues that psychologists should consider when working in multidisciplinary teams. CONCLUSIONS: Psychology is seen by multidisciplinary team members as an integral, but not first line, treatment option in the psychiatric inpatient setting. Both direct work and indirect work were valued by multidisciplinary staff participants. The multidisciplinary team do not have a clear understanding of the role of psychology. Education dialogue about the role are required. PRACTITIONER POINTS: The role of psychology in the psychiatric inpatient setting is valued by the multidisciplinary team. Psychology was not viewed as a first-line treatment option in the psychiatric inpatient setting but an 'add-on' to medical treatment. Psychology was a valued source of support for skilling-up and offering reflective space to the multidisciplinary team. Psychologists need to better promote their role and their skills to the multidisciplinary team. PMID- 30311352 TI - Methodology for the analysis and comparison of protocols for glycaemic control in intensive care. AB - RATIONALE, AIMS, AND OBJECTIVES: The practice of glycaemic control of critically ill patients admitted to intensive care units (ICUs) is guided by clinical management protocols, designed locally by the ICUs. These protocols differ significantly in their aims and methods. The aim of this study was to develop a standardized methodology for the systematic and objective analysis and comparison of protocols for glycaemic control implemented in any ICU. METHOD: The protocols for glycaemic control implemented in seven ICUs of a UK-based ICU network were analysed using techniques of inductive content analysis, through an open coding process and the framework method. This involved the identification and classification of protocol instructions for glycaemic control, as well as of the processes and decisions pertaining to each of these instructions. These were used to develop a framework for the structured and systematic description and comparison of the protocols' contents, and to develop a technique for the protocols' graphic visualization. RESULTS: The following elements were identified or developed: (1) 35 quantifiable variables and 11 non-quantifiable subjects that could be present in an ICU protocol for glycaemic control, to be used as a framework for the description and comparison of contents; (2) a technique for condensing a protocol into a single, comprehensive flowchart; (3) using these flowcharts, a method for assessing the complexity and comprehensiveness of the protocols. CONCLUSIONS: The methodology developed in this study will allow for any future work analysing the contents of glycaemic control protocols to be carried out in a structured and standardized way. This may be done either as a standalone study, or as the essential first step in any investigation on the impact of new protocols. In turn, the methodology will facilitate the performance of regional, national, and international comparisons, demonstrating the usefulness of this study at a global scale. PMID- 30311354 TI - Resilience in critical care nurses - is it desirable? PMID- 30311355 TI - BACCN Conference 2018 Highlights. PMID- 30311353 TI - Construction of an efficient genomic editing system with CRISPR/Cas9 in the vector mosquito Aedes albopictus. AB - Aedes (Stegomyia) albopictus, also known as the Asian tiger mosquito, is a mosquito that originated in Asia. In recent years, it has become increasingly rampant throughout the world. This mosquito can transmit several arboviruses, including dengue, Zika and chikungunya viruses, and is considered a public health threat. Despite the urgent need of genome-engineering to analyse specific gene functions, progress in genetical manipulation of Ae. albopictus has been slow due a lack of efficient methods and genetic markers. In the present study, we established targeted disruptions in two genes, kynurenine hydroxylase (kh) and dopachrome conversion enzyme (yellow), to analyse the feasibility of generating visible phenotypes with genome editing by the CRISPR/Cas9 system in Ae. albopictus. Following Cas9-sgRNA RNP injection into the posterior end of pre blastoderm embryos, 30%-50% of fertile survivors produced alleles that failed to complement existing kh and yellow mutations. Complete eye and body pigmentation defects were readily observed in G1 pupae and adults, indicating successful generation of highly heritable mutations. We conclude that the CRISPR/Cas9 mediated gene editing system can be used in Ae. albopictus and that it can be adopted as an efficient tool for genome-scale analysis and biological study. This article is protected by copyright. All rights reserved. PMID- 30311357 TI - Twitter Chat Dates - time 7-8 p.m. PMID- 30311356 TI - BACCN Conference 2019 - Super early bird rate! PMID- 30311358 TI - Learn Zone Update - Tim Collins, BACCN Professional Advisor. PMID- 30311359 TI - Meet the National Board. PMID- 30311361 TI - CC3N Competency Framework - Ann Price. PMID- 30311360 TI - Taking Organ Transplantation to 2020 Oversight Group (TOT2020) - insights from Trish McCready. PMID- 30311362 TI - Are you interested in joining the BACCN national board? PMID- 30311363 TI - What's in this issue. PMID- 30311364 TI - BACCN Member Benefits - For Individuals. PMID- 30311366 TI - Regional Events. PMID- 30311365 TI - Did you know.... BACCN member grants. PMID- 30311367 TI - Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label, prospective, randomized, parallel group comparison trial. AB - The effects of dapagliflozin (DAP) and pioglitazone (PIO) on body weight and glycaemic control were compared in patients with type 2 diabetes mellitus. Seventy-one patients on PIO were either switched to DAP (n = 36) at 5 mg per day or continued on PIO (n = 35). Primary endpoints were superiority of body weight loss and non-inferiority of HbA1c level after 24 weeks with DAP. Body weight decrease was greater with DAP than with PIO (75.3 +/- 14.9 to 71.3 +/- 15.1 kg vs. 74.7 +/- 13.8 to 75.2 +/- 13.9 kg; P < 0.01). Change in the HbA1c level was comparable (P = 0.64). The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and urinary albumin : creatinine ratio (ACR) decreased only with DAP (NT-proBNP, P < 0.01; ACR, P = 0.02), and the change in NT-proBNP correlated negatively with baseline NT-proBNP level (rho = -0.68, P < 0.01) and log-converted ACR (rho = -0.35, P < 0.05). DAP promotes body weight loss in type 2 diabetes mellitus and may decrease fluid retention, thus reducing the occurrence of cardiovascular events. PMID- 30311368 TI - Elusive Therapeutic Effect of PCSK9 Inhibitors on Lipoprotein(a) Levels. PMID- 30311369 TI - Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes. AB - In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes. The GSVS then reviewed and analyzed available resources of relevant somatic data, and performed integrative germline variant curation exercises. The committee determined that somatic hotspots could be systematically integrated into moderate evidence of pathogenicity (PM1). Tumor RNA sequencing data showing altered splicing may be considered as strong evidence in support of germline pathogenicity (PVS1) and tumor phenotypic features such as mutational signatures be considered supporting evidence of pathogenicity (PP4). However, at present, somatic data such as focal loss of heterozygosity and mutations occurring on the alternative allele are not recommended to be systematically integrated, instead, incorporation of this type of data should take place under the advisement of multidisciplinary cancer center tumor-normal sequencing boards. PMID- 30311370 TI - Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community-driven standards. AB - Harmonization of cancer variant representation, efficient communication, and free distribution of clinical variant-associated knowledge are central problems that arise with increased usage of clinical next-generation sequencing. The Clinical Genome Resource (ClinGen) Somatic Working Group (WG) developed a minimal variant level data (MVLD) representation of cancer variants, and has an ongoing collaboration with Clinical Interpretations of Variants in Cancer (CIViC), an open-source platform supporting crowdsourced and expert-moderated cancer variant curation. Harmonization between MVLD and CIViC variant formats was assessed by formal field-by-field analysis. Adjustments to the CIViC format were made to harmonize with MVLD and support ClinGen Somatic WG curation activities, including four new features in CIViC: (1) introduction of an assertions feature for clinical variant assessment following the Association of Molecular Pathologists (AMP) guidelines, (2) group-level curation tracking for organizations, enabling member transparency, and curation effort summaries, (3) introduction of ClinGen Allele Registry IDs to CIViC, and (4) mapping of CIViC assertions into ClinVar submission with automated submissions. A generalizable workflow utilizing MVLD and new CIViC features is outlined for use by ClinGen Somatic WG task teams for curation and submission to ClinVar, and provides a model for promoting harmonization of cancer variant representation and efficient distribution of this information. PMID- 30311371 TI - ClinGen's GenomeConnect registry enables patient-centered data sharing. AB - GenomeConnect, the NIH-funded Clinical Genome Resource (ClinGen) patient registry, engages patients in data sharing to support the goal of creating a genomic knowledge base to inform clinical care and research. Participant self reported health information and genomic variants from genetic testing reports are curated and shared with public databases, such as ClinVar. There are four primary benefits of GenomeConnect: (1) sharing novel genomic data-47.9% of variants were new to ClinVar, highlighting patients as a genomic data source; (2) contributing additional phenotypic information-of the 52.1% of variants already in ClinVar, GenomeConnect provided enhanced case-level data; (3) providing a way for patients to receive variant classification updates if the reporting laboratory submits to ClinVar-97.3% of responding participants opted to receive such information and 13 updates have been identified; and (4) supporting connections with others, including other participants, clinicians, and researchers to enable the exchange of information and support-60.4% of participants have opted to partake in participant matching. Moving forward, ClinGen plans to increase patient-centric data sharing by partnering with other existing patient groups. By engaging patients, more information is contributed to the public knowledge base, benefiting both patients and the genomics community. PMID- 30311372 TI - The progression of the ClinGen gene clinical validity classification over time. AB - In order for ClinGen to maintain up-to-date gene-disease clinical validity classifications for use by clinicians and clinical laboratories, an appropriate timeline for reevaluating curated gene-disease associations will need to be determined. To provide guidance on how often a gene-disease association should be recurated, a retrospective analysis of 30 gene curations was performed. Curations were simulated at one-year intervals starting with the year of the first publication to assert disease-causing variants in the gene to observe trends in the classification over time, as well as factors that influenced changes in classification. On average, gene-disease associations spent the least amount of time in the "Moderate" classification before progressing to "Strong" or "Definitive." In contrast, gene-disease associations that spent five or more years in the "Limited" classification were most likely to remain "Limited" or become "Disputed/Refuted." Large population datasets contributed to the reclassification of several gene-disease associations from "Limited" to "Disputed/Refuted." Finally, recent advancements in sequencing technology correlated with an increase in the quantity of case-level evidence that was curated per paper. This study provided a number of key points to consider when determining how often to recurate a gene-disease association. PMID- 30311373 TI - The clinical imperative for inclusivity: Race, ethnicity, and ancestry (REA) in genomics. AB - The Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group highlights the need to develop guidance on race, ethnicity, and ancestry (REA) data collection and use in clinical genomics. We present quantitative and qualitative evidence to characterize: (1) acquisition of REA data via clinical laboratory requisition forms, and (2) information disparity across populations in the Genome Aggregation Database (gnomAD) at clinically relevant sites ascertained from annotations in ClinVar. Our requisition form analysis showed substantial heterogeneity in clinical laboratory ascertainment of REA, as well as marked incongruity among terms used to define REA categories. There was also striking disparity across REA populations in the amount of information available about clinically relevant variants in gnomAD. European ancestral populations constituted the majority of observations (55.8%), allele counts (59.7%), and private alleles (56.1%) in gnomAD at 550 loci with "pathogenic" and "likely pathogenic" expert-reviewed variants in ClinVar. Our findings highlight the importance of implementing and supporting programs to increase diversity in genome sequencing and clinical genomics, as well as measuring uncertainty around population-level datasets that are used in variant interpretation. Finally, we suggest the need for a standardized REA data collection framework to be developed through partnerships and collaborations and adopted across clinical genomics. PMID- 30311374 TI - ClinGen Allele Registry links information about genetic variants. AB - Effective exchange of information about genetic variants is currently hampered by the lack of readily available globally unique variant identifiers that would enable aggregation of information from different sources. The ClinGen Allele Registry addresses this problem by providing (1) globally unique "canonical" variant identifiers (CAids) on demand, either individually or in large batches; (2) access to variant-identifying information in a searchable Registry; (3) links to allele-related records in many commonly used databases; and (4) services for adding links to information about registered variants in external sources. A core element of the Registry is a canonicalization service, implemented using in memory sequence alignment-based index, which groups variant identifiers denoting the same nucleotide variant and assigns unique and dereferenceable CAids. More than 650 million distinct variants are currently registered, including those from gnomAD, ExAC, dbSNP, and ClinVar, including a small number of variants registered by Registry users. The Registry is accessible both via a web interface and programmatically via well-documented Hypertext Transfer Protocol (HTTP) Representational State Transfer Application Programming Interface (REST-APIs). For programmatic interoperability, the Registry content is accessible in the JavaScript Object Notation for Linked Data (JSON-LD) format. We present several use cases and demonstrate how the linked information may provide raw material for reasoning about variant's pathogenicity. PMID- 30311376 TI - Genetic database software as medical devices. AB - This article provides a primer on medical device regulations in the United States, Europe, and Canada. Software tools are being developed and shared globally to enhance the accessibility and usefulness of genomic databases. Interactive software tools, such as email or mobile alert systems providing variant classification updates, are opportunities to democratize access to genomic data beyond laboratories and clinicians. Uncertainty over the reliability of outputs, however, raises concerns about potential harms to patients, especially where software is accessible to lay users. Developers may also need to contend with unfamiliar medical device regulations. The application of regulatory controls to genomic software could improve patient and user safety, but could also stifle innovation. Legal uncertainty for developers is compounded where software applications are made available globally (implicating multiple regulatory frameworks), and directly to lay users. Moreover, there is considerable uncertainty over the application of (evolving) medical device regulations in the context of both software and genetics. In this article, criteria and examples are provided to inform determinations of software as medical devices, as well as risk classification. We conclude with strategies for using genomic communication and interpretation software to maximize the availability and usefulness of genetic information, while mitigating the risk of harm to users. PMID- 30311375 TI - Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants. AB - The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ~827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1 specific guidelines for the assessment and classification of variants identified in this clinically actionable gene. PMID- 30311377 TI - The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria. AB - The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy associated genes. PMID- 30311378 TI - Scaling resolution of variant classification differences in ClinVar between 41 clinical laboratories through an outlier approach. AB - ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with MSDs between the laboratories (650 variants). Next, MSDs were filtered for variants with >=3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications, which will improve the care of patients with, or at risk for, genetic disorders. PMID- 30311379 TI - ClinGen advancing genomic data-sharing standards as a GA4GH driver project. AB - The Clinical Genome Resource (ClinGen)'s work to develop a knowledge base to support the understanding of genes and variants for use in precision medicine and research depends on robust, broadly applicable, and adaptable technical standards for sharing data and information. To forward this goal, ClinGen has joined with the Global Alliance for Genomics and Health (GA4GH) to support the development of open, freely-available technical standards and regulatory frameworks for secure and responsible sharing of genomic and health-related data. In its capacity as one of the 15 inaugural GA4GH "Driver Projects," ClinGen is providing input on the key standards needs of the global genomics community, and has committed to participate on GA4GH Work Streams to support the development of: (1) a standard model for computer-readable variant representation; (2) a data model for linking variant data to annotations; (3) a specification to enable sharing of genomic variant knowledge and associated clinical interpretations; and (4) a set of best practices for use of phenotype and disease ontologies. ClinGen's participation as a GA4GH Driver Project will provide a robust environment to test drive emerging genomic knowledge sharing standards and prove their utility among the community, while accelerating the construction of the ClinGen evidence base. PMID- 30311380 TI - Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. AB - The ClinGen PTEN Expert Panel was organized by the ClinGen Hereditary Cancer Clinical Domain Working Group to assemble clinicians, researchers, and molecular diagnosticians with PTEN expertise to develop specifications to the 2015 ACMG/AMP Sequence Variant Interpretation Guidelines for PTEN variant interpretation. We describe finalized PTEN-specific variant classification criteria and outcomes from pilot testing of 42 variants with benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS), and conflicting (CONF) ClinVar assertions. Utilizing these rules, classifications concordant with ClinVar assertions were achieved for 14/15 (93.3%) BEN/LBEN and 16/16 (100%) PATH/LPATH ClinVar consensus variants for an overall concordance of 96.8% (30/31). The variant where agreement was not reached was a synonymous variant near a splice donor with noncanonical sequence for which in silico models cannot predict the native site. Applying these rules to six VUS and five CONF variants, adding shared internal laboratory data enabled one VUS to be classified as LBEN and two CONF variants to be as classified as PATH and LPATH. This study highlights the benefit of gene-specific criteria and the value of sharing internal laboratory data for variant interpretation. Our PTEN-specific criteria and expertly reviewed assertions should prove helpful for laboratories and others curating PTEN variants. PMID- 30311381 TI - The value of genomic variant ClinVar submissions from clinical providers: Beyond the addition of novel variants. AB - With the increasing use of clinical genomic testing across broad medical disciplines, the need for data sharing and curation efforts to improve variant interpretation is paramount. The National Center for Biotechnology Information (NCBI) ClinVar database facilitates these efforts by serving as a repository for clinical assertions about genomic variants and associations with disease. Most variant submissions are from clinical laboratories, which may lack clinical details. Laboratories may also choose not to submit all variants. Clinical providers can contribute to variant interpretation improvements by submitting variants to ClinVar with their own assertions and supporting evidence. The medical genetics team at Geisinger's Autism & Developmental Medicine Institute routinely reviews the clinical significance of all variants obtained through clinical genomic testing, using published ACMG/AMP guidelines, clinical correlation, and post-test clinical data. We describe the submission of 148 sequence and 155 copy number variants to ClinVar as "provider interpretations." Of these, 192 (63.4%) were novel to ClinVar. Detailed clinical data were provided for 298 (98.3%), and when available, segregation data and follow-up clinical correlation or testing was included. This contribution marks the first large scale submission from a neurodevelopmental clinical setting and illustrates the importance of clinical providers in collaborative efforts to improve variant interpretation. PMID- 30311382 TI - Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group. AB - The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Group's (AWG) protocol for evidence synthesis and semi quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list. PMID- 30311383 TI - Updated recommendation for the benign stand-alone ACMG/AMP criterion. AB - The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group set out to refine the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG/AMP) variant pathogenicity recommendations for stand-alone rule BA1 (a variant with minor allele frequency [MAF] > 0.05 is benign), by clarifying how it should be used and specifying a set of variants that should be exempted from this rule. We cross-referenced ClinVar and Exome Aggregation Consortium data to identify variants for which there was a plausible argument for pathogenicity and the variant exists in one or more population data sets at MAF > 0.05. We identified nine such variants that were present in these data sets that may not be benign. The ACMG/AMP criteria were applied to these variants that resulted in four pathogenic and five variants of uncertain significance. We have refined benign rule BA1 by clarifying terms used to describe its use, which databases we recommend using, and assumptions made about this rule. We also recognized an initial list of nine variants for which there was some evidence of pathogenicity even though the MAF was high for these variants. We specify processes whereby individuals can petition ClinGen for amendments to our variant-specific assertions and the criteria experts should use when setting a numerically lower threshold for BA1 for specific genes. PMID- 30311384 TI - Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework. AB - The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan-like syndrome with loose anagen hair. The curated evidence supporting each gene disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy. PMID- 30311385 TI - On the verge of diagnosis: Detection, reporting, and investigation of de novo variants in novel genes identified by clinical sequencing. AB - The variable evidence supporting gene-disease associations contributes to the difficulty of accurate variant reporting in a clinical setting. An evidence-based scoring system for evaluating the clinical validity of gene-disease associations, proposed by ClinGen, considers experimental as well as genetic evidence. De novo variants are heavily weighted, given the overall rarity in the genome and their contribution to human disease, however they are reported as "genes of unknown significance" in our center when there is insufficient evidence for the gene disease assertion. We report a collection of 21 de novo variants in genes of unknown clinical significance ascertained via clinical testing, of which eight of 21 (38%) are predicted to cause loss of function. These genes were subjected to ClinGen scoring to assess the strength of gene-disease relationships. Using a cutoff for moderate high or strong, 10 of 21 genes now have sufficient evidence to qualify as likely pathogenic or pathogenic variants. Sharing such cases with phenotypic data is imperative to strengthen available genetic evidence to ultimately upgrade clinical validity classifications and facilitate accurate molecular diagnosis. PMID- 30311387 TI - ClinVar at five years: Delivering on the promise. AB - The increasing application of genetic testing for determining the causes underlying Mendelian, pharmacogenetic, and somatic phenotypes has accelerated the discovery of novel variants by clinical genetics laboratories, resulting in a critical need for interpreting the significance of these variants and presenting considerable challenges. Launched in 2013 at the National Center for Biotechnology Information, National Institutes of Health, ClinVar is a public database for clinical laboratories, researchers, expert panels, and others to share their interpretations of variants with their evidence. The database holds 600,000 submitted records from 1,000 submitters, representing 430,000 unique variants. ClinVar encourages submissions of variants reviewed by expert panels, as expert consensus confers a high standard. Aggregating data from many groups in a single database allows comparison of interpretations, providing transparency into the concordance or discordance of interpretations. In its first five years, ClinVar has successfully provided a gateway for the submission of medically relevant variants and interpretations of their significance to disease. It has become an invaluable resource for the clinical genetics community seeking guidance from consensus interpretations. Building on the platform of providing transparency and leveraging aggregation of variant interpretations, ClinVar is now well positioned to help the clinical genetics community improve interpretations. PMID- 30311386 TI - Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. AB - Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL. PMID- 30311388 TI - ClinVar database of global familial hypercholesterolemia-associated DNA variants. AB - Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients. PMID- 30311389 TI - ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. AB - Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants. PMID- 30311390 TI - Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene. AB - The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes. PMID- 30311391 TI - Latent profile analysis of psychosis liability in a community-derived sample of adolescents: Links with mental health difficulties, suicidal ideation, bipolar like experiences and psychotic-like experiences. AB - AIM: The main goal of the present study was to explore the latent structure of schizotypy as an indicator of psychosis liability, in a community-derived sample of adolescents. Links to mental health difficulties, prosocial behaviour, suicidal ideation, bipolar-like experiences and psychotic-like experiences (PLEs) (severity and distress) were compared across schizotypy latent profiles. METHOD: The present research included 1588 adolescents selected by a stratified random cluster sampling. The Oviedo Schizotypy Assessment Questionnaire (ESQUIZO-Q), The Paykel Suicide Scale (PSS), The Strengths and Difficulties Questionnaire (SDQ), The Prodromal Questionnaire-Brief (PQ-B), The Mood Disorder Questionnaire (MDQ), The Penn Matrix Reasoning Test (PMRT), The Family Affluence Scale-II (FAS-II), and The Oviedo Infrequency Scale (INF-OV) were used. RESULTS: Using latent profile analysis four latent classes (LC) were identified: "Positive schizotypy" (14.1%, n = 224), "Low schizotypy" (51.9%, n = 825), "Social Disorganization schizotypy" (27.2%, n = 432), and "High schizotypy" (6.7%, n = 107). The "High schizotypy" class scored higher on several psychometric indicators of psychopathology (ie, mental health difficulties, suicide ideation, bipolar-like experiences and PLEs) relative to the other three LC. CONCLUSION: Four groups of adolescents with different patterns of schizotypal traits and different clinical pathological meaning were found. Deficits found across schizotypy latent profiles, resembling those found in patients with psychosis and ultra-high risk samples. The identification of homogeneous subgroups of adolescents potentially at risk for psychosis may help us in the prevention of psychotic-spectrum disorders and mental health problems. PMID- 30311392 TI - An expanded modern coexistence theory for empirical applications. AB - Understanding long-term coexistence of numerous competing species is a longstanding challenge in ecology. Progress requires determining which processes and species differences are most important for coexistence when multiple processes operate and species differ in many ways. Modern coexistence theory (MCT), formalised by Chesson, holds out the promise of doing that, but empirical applications remain scarce. We argue that MCT's mathematical complexity and subtlety have obscured the simplicity and power of its underlying ideas and hindered applications. We present a general computational approach that extends our previous solution for the storage effect to all of standard MCT's spatial and temporal coexistence mechanisms, and also process-defined mechanisms amenable to direct study such as resource partitioning, indirect competition, and life history trade-offs. The main components are a method to partition population growth rates into contributions from different mechanisms and their interactions, and numerical calculations in which some mechanisms are removed and others retained. We illustrate how our approach handles features that have not been analysed in the standard framework through several case studies: competing diatom species under fluctuating temperature, plant-soil feedbacks in grasslands, facilitation in a beach grass community, and niche differences with independent effects on recruitment, survival and growth in sagebrush steppe. PMID- 30311393 TI - Clinicopathologic characteristics and outcome of patients with different EGFR mutations. AB - AIM: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations. METHODS: We retrospectively analyzed the EGFR mutation pattern and its association with clinical-pathological characteristics from 100 cases of nonsmall-cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients with advanced EGFR-mutated NSCLC were enrolled and treated with icotinib (oral administration, 125 mg, thrice per day). RESULTS: Among 100 patients, 85 and 15 had common and uncommon mutations, respectively. Four patients had a single mutation in 18 or 20 exon, and 11 had a complex mutation with del-19 or L858R. There was no significant association between the presence of different mutation type and the type of any clinical and pathological characteristics. Prolonged but not significant progression-free survival (PFS) was noted in patients with common EGFR mutations (18.07 [14.00-26.23] vs 12.9 [8.43-23.27], P = 0.056). Patients without brain metastases had increased PFS to icotinib than those with brain metastases (18.07 [95% confidence interval, CI 14.77-27.03] vs 13.17 [95% CI 8.63-22.63], P = 0.038). CONCLUSION: Uncommon EGFR mutations comprised 15% of all mutated patients, in which most were complex mutations. Compared with common EGFR mutation, uncommon EGFR mutations were associated with a modest sensitivity to EGFR TKIs. Our findings will be helpful to make clinical decision and select the appropriate therapy for EGFR-mutated NSCLC patients. PMID- 30311394 TI - Evidence-based Danish guidelines for screening of diabetic retinopathy. AB - PURPOSE: Diabetic retinopathy (DR) is among the leading causes of visual loss in the working-age population. It is generally accepted that screening of DR is cost effective and can detect DR before it becomes sight-threatening to allow timely treatment. METHODS: A group of retinal specialists was formed by the Danish Ophthalmological Society with the aim to formulate contemporary evidence-based guidelines for screening of DR in order to implement these in the Danish screening system. RESULTS: We hereby present evidence for DR-screening regarding (1) classification of DR, (2) examination techniques, (3) screening intervals and (4) automated screening. It is our recommendation that the International Clinical Retinopathy Disease Severity Scale should be used to classify DR. As a minimum, mydriatic two-field disc- and macular-centred images are required. In the case of suspected clinically significant diabetic macular oedema, supplementary optical coherence tomography can increase the diagnostic accuracy. There is solid evidence to support a flexible, individualized screening regimen. In particular, it is possible to prolong screening intervals to 24-48 months for patients with no or mild nonproliferative diabetic retinopathy (NPDR), but it is also possible to use extended intervals of 12-24 months for patients with moderate NPDR given that these are well-regulated regarding glycaemic control (HbA1c <= 53 mmol/mol) and blood pressure (<=130/80 mmHg). Automated screening of DR is encouraging but is not ready for implementation at present. CONCLUSION: Danish evidenced-based guidelines for screening of DR support high-quality imaging and allow flexible, individualized screening intervals with a potential for extension to patients with low risk of DR progression. PMID- 30311395 TI - The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes. AB - OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration >=50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), beta2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction. PMID- 30311397 TI - Safety and efficacy of self-apposing Stentys drug-eluting stent in left main coronary artery PCI: Multicentre LM-STENTYS registry. AB - BACKGROUND: There is a paucity of data on left main (LM) percutaneous coronary intervention (PCI) therapy with dedicated DES platforms. The LM-STENTYS is a multicenter registry aimed at evaluating clinical outcome after PCI of LM performed with a self-apposing Stentys DES implantation. METHODS: The registry consists of 175 consecutive patients treated with Stentys DES implanted to LM. The primary endpoint was the composite of major adverse cardiac and cerebral events (MACCE) defined as cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), and stroke assessed after 1 year. The secondary endpoint was stent thrombosis (ST) at 1 year. RESULTS: The median age was 69 years (IQR, 62-78 years). Acute coronary syndrome (ACS) was the presenting diagnosis in 117 (66.9%) patients [74 (63.2%) unstable angina, 31 (26.5%) NSTEMI, 12 (10.3%) STEMI] and stable angina (SA) was present in 58 (33.1%) patients. The median SYNTAX score was 23.0 (IQR, 18.7-32.2) in the SA group and 25.0 (IQR, 20.0 30.7) in the ACS group. During 1-year follow-up in the SA group two (3.4%) MACCE occurred, both of them were cardiac deaths. In ACS patients there were 19 (16.2%) MACCE [9 (7.7%) cardiac deaths, 11 (9.4%) MIs, 11(9.4%) TLR, 1(0.9%) stroke]. Altogether, three (1.7%) cases of acute ST were noted, all of them in ACS subset. CONCLUSION: LM PCI using self-apposing Stentys DES showed favorable clinical outcomes at 1-year in patients with SA. Events of ST in the ACS group warrant further research. PMID- 30311396 TI - Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells. AB - Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects and toxicity in psychiatric patients. However, the mechanisms underlying the cardiovascular side effects of amitriptyline remain largely undefined. This study aimed to determine the effects of amitriptyline on angiogenic capability of vascular endothelial cells in physiological settings and identify its mechanism of action. The ex vivo aortic ring angiogenesis and in vitro-cultured endothelial cell tube formation assay were used to assess the effects of amitriptyline on endothelial angiogenic capability. It was demonstrated that amitriptyline impaired the angiogenesis of aortic rings, which was similar to that found in aortic rings with haploinsufficiency of the ASM gene. In cultured mouse microvascular endothelial cells (MVECs), amitriptyline impaired the proliferation and tube formation under basal condition, which were accompanied by attenuated angiogenic signalling pathways such as endothelial nitric oxide synthase, Akt and Erk1/2 pathways. Mechanistically, amitriptyline inhibited autophagic flux without affecting autophagosome biogenesis at basal condition. ASM gene silencing or autophagy inhibition mimics the inhibitory effects of amitriptyline on endothelial cell proliferation and tube formation. Collectively, our data suggest that amitriptyline inhibits endothelial cell proliferation and angiogenesis via blockade of ASM-autophagic flux axis. It is implicated that the cardiovascular side effects of amitriptyline may be associated with its inhibitory action on physiological angiogenesis. PMID- 30311398 TI - Ecological validity of social interaction tests in rats and mice. AB - Different rat and mouse models are used in studies of social interactions. Simple behavioral measures, which are commonly used in the laboratory, allow to perform relatively short experiments and to use multiple brain manipulation techniques. However, too much focus on the simplest behavioral models generates a serious risk of reducing ecological validity or even studying phenomena which would never happen outside of the laboratory. In this review, we discuss the suitability of mice and rats as model organisms for studying social behaviors, with focus on social transmission of fear paradigms. First, we briefly introduce the concept of domestication and what impact it had on laboratory rodents. Then, we present two aspects of social behaviors, sociability and dominance, which are crucial for social organization in these species. Finally, we present experimental models used for studying how animals transmit information about danger between each other, and how these models may reflect what happens in the natural environment. We discuss the difficulties that arise from our limited knowledge of rat and mouse ecology, especially their social life. We also explore the subject of balancing ecological validity and controllability in rodent models of social behaviors, the latter being particularly important for studying brain activity. Although it is very challenging, an efficient program for social neuroscience research should, in our opinion, aim at bridging the gap between laboratory and field studies. PMID- 30311399 TI - Structural analysis of impact of physical, cognitive and social status on the incidence of disability in community-dwelling people aged >=75 years. AB - AIM: The present study aimed to propose a structural model to explain the interaction of physical, cognitive and social domains of health status in the incidence of disability in community-dwelling people aged >=75 years. METHODS: We analyzed 185 older adults (mean age 79.4 years, 58.4% female) who participated in a baseline assessment from 2012 to 2013. They were followed for incident certification of care needs in the national long-term care insurance certification system during the 2 years. Baseline assessments included several measurements related to the physical, cognitive and social domains of health status. We compared the model fit index between two hypothesis models - the parallel model and the hierarchical model - using structural equation modeling. RESULTS: During the follow-up period, 15 participants (8.1%) were newly certified as requiring personal support from the long-term care insurance system. The structural equation modeling showed that the hierarchical model, indicating that cognitive and social status were indirectly associated with disability through physical status, had a better fit with the data than the parallel model, indicating that physical, cognitive and social status each were directly associated with disability. CONCLUSIONS: The present results suggest that cognitive and social status might indirectly affect disability incidence through physical aging. Further research is required to examine the temporal relationship between physical, cognitive and social change using data over several time periods. Geriatr Gerontol Int 2018; **: **-**. PMID- 30311400 TI - First-in-human experience with Aortix intraaortic pump. AB - BACKGROUND: There are limited options for percutaneous mechanical circulatory support (pMCS) in patients requiring high-risk percutaneous coronary intervention. OBJECTIVES: This first-in-human, single-center study aimed to evaluate the safety and feasibility of a novel pMCS device in high-risk percutaneous coronary intervention patients. METHODS: Aortix (Procyrion, Houston, Texas) is a pMCS device deployed in the descending aorta via the femoral artery that uses axial flow to provide cardiac unloading and augment renal and systemic perfusion. We assessed the use and effect of the Aortix device in six patients undergoing high-risk PCI. All patients had impaired left ventricular function, complex coronary disease, renal dysfunction, and suitable iliofemoral anatomy for Aortix placement via transfemoral approach. We recorded periprocedural events including hemodynamic effects of the device on cardiac output and urine output. We then followed patients up to 30 days following the PCI procedure for adverse events. RESULTS: Aortix delivery (18 Fr sheath) took 4-9 min, mean support time was 70 (range 47-95) min, and mean flow rate through the device was 3.5 L/min. During support, mean rate of urine output increased 10-fold (range 2.5-25.0x). Estimated GFR improved at discharge compared with baseline (mean increase 6.95 +/ 8.09 mL/min). There were no device failures and PCI was successful in all patients. Aortix was removed and hemostasis was achieved with a vascular closure device and manual pressure. No patients experienced adverse events or hemodynamic compromise. No clinically significant hemolysis occurred (mean LDH 239.2 +/- 73.6 mU/mL at baseline and 206.4 +/- 82.2 mU/mL at discharge). No vascular access complications were observed. CONCLUSIONS: Aortix, a novel pMCS device, was successfully deployed and retrieved in all initial patients undergoing high-risk PCI. We noted no significant hemolysis with temporary use of this axial flow device. Improvement in eGFR suggests a potential renal protective effect and is an important area for future investigation in patients with impaired left ventricular function and renal dysfunction. PMID- 30311401 TI - Role of betaine in liver injury induced by the exposure to ionizing radiation. AB - Oxidative stress, apoptosis, and fibrosis may play a major role in the development of radiation-induced liver damage. Betaine, a native compound widely present in beetroot, was reported to possess hepato-protective properties. The objective of this study was to investigate the influence of betaine on radiation induced liver damage. Animals were exposed to 9 Gy applied in 3 doses of 3 Gy/wk. Betaine (400 mg/kg/d), was orally supplemented to rats after the first radiation dose, and daily during the irradiation period. Animals were sacrificed 1 day after the last dose of radiation. The results showed that irradiation has induced oxidative stress in the liver denoted by a significant elevation in malondialdehyde, protein carbonyl, and 8-hydroxy-2-deoxyguanosine with a significant reduction in catalase activity and glutathione (GSH) content. The activity of the detoxification enzyme cytochrome P450 (CYP450) increased while GSH transferase (GSH-T) decreased. The activity of the apoptotic marker caspase-3 increased concomitant with increased hyaluronic acid, hydroxyproline, laminin (LN), and collagen IV. These alterations were associated with a significant increase of gamma-glutamyl transferase, alkaline phosphatase and alanine and aspartate aminotransferase markers of liver dysfunction. Betaine treatment has significantly attenuated oxidative stress, decreased the activity of CYP450, enhanced GSH-T, reduced the activity of caspase-3, and the level of fibrotic markers concomitant with a significant improvement of liver function. In conclusion, betaine through its antioxidant activity and by enhancing liver detoxification and reducing apoptosis may alleviate the progression of liver fibrosis and exert a beneficial impact on radiation-induced liver damage. PMID- 30311402 TI - Environmental effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes mellitus. AB - OBJECTIVE: This study aimed to explore the effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes. MATERIALS AND METHODS: A three-way, cross-over, randomised study was performed in adults with type 1 diabetes mellitus (n = 10). The pharmacodynamics profile of a single dose of short-acting insulin (insulin lispro) was investigated, using a controlled environmental chamber, under three environmental conditions: (a) temperature: 15 degrees C and humidity: 10%; (b) temperature: 30 degrees C and humidity: 10%; and (c) temperature: 30 degrees C and humidity: 60%. A euglycaemic glucose clamp technique ensured constant blood glucose of 100 mg/dL (5.5 mmol/L). The following pharmacodynamic endpoints were calculated: maximum glucose infusion rate (GIRmax ), time to GIRmax (tGIRmax ), total area under the curve (AUC) for GIR from 0-6 hours (AUCGIR.0-6h ), and partial AUCs (AUCGIR.0-1h , AUCGIR.0-2h and AUCGIR.2-6h ). RESULTS: Higher temperature (30 degrees C) under 10% fixed humidity conditions resulted in greater GIRmax (P = 0.04) and a later tGIR.max (P = 0.049) compared to lower temperature (15 degrees C). Humidity did not affect any pharmacodynamic parameter. When the combined effects of temperature and humidity were explored, tGIR.max (P = 0.008) occurred earlier, with a lower late insulin pharmacodynamic effect (AUCGIR.2-6h ; P = 0.017) at a temperature of 15 degrees C and humidity of 10% compared to a temperature of 30 degrees C and humidity of 60%. CONCLUSIONS: High ambient temperature resulted in a greater insulin peak effect compared to low ambient temperature, with the contribution of high relative humidity apparent only at high ambient temperature. This suggests that patients with type 1 diabetes mellitus who are entering higher environmental temperatures, with or without high humidity, could experience more hypoglycaemic events. PMID- 30311403 TI - Disorder Engineering in Monolayer Nanosheets Enabling Photothermic Catalysis for Full Solar Spectrum (250-2500 nm) Harvesting. AB - A persistent challenge in classical photocatalyst systems with extended light absorption is the unavoidable trade-off between maximizing light harvesting and sustaining high photoredox capability. Alternatively, cooperative energy conversion through photothermic activation and photocatalytic redox is a promising yet unmet scientific proposition that critically demands a spectrum tailored catalyst system. Here, we construct a solar thermal-promoted photocatalyst, an ultrathin "biphasic" ordered-disordered D-HNb3 O8 junction, which performs two disparate spectral selective functions of photoexcitation by ordered structure and thermal activated conversion via disordered lattice for combinatorial photothermal mediated catalysis. This in situ synthetically immobilized lattice distortion, constrained to a single-entity monolayer structure not only circumvents interfacial incompatibility but also triggers near field temperature rise at the catalyst-reactant complexes' proximity to promote photoreaction. Ultimately, a generic full solar conversion improvement for H2 fuel production, organic transformation and water purification is realized. PMID- 30311404 TI - Epidemiology and secular trends of malignant lymphoma in Japan: Analysis of 9426 cases according to the World Health Organization classification. AB - This study provides an overview of the epidemiology and secular trends of malignant lymphoma in Japan. Using data from clinics and hospitals throughout Japan, we analyzed 9426 cases of malignant lymphoma diagnosed in 2007-2014. We show that the proportion of follicular lymphoma and methotrexate-associated lymphoproliferative disorder increased during this time, as did the onset age for follicular lymphoma and diffuse large B-cell lymphoma. Significant increases in onset age for follicular lymphoma and diffuse large B-cell lymphoma were observed in both men and women (all P values <0.0001 except for P = 0.0448 for the latter disease in women). Further studies are required to determine the reasons for the higher proportion of and onset age for these lymphomas. Additionally, we believe that continued observation of these trends is necessary. PMID- 30311405 TI - The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. AB - It is a well-known fact that RNA is the target of a plethora of modifications which currently amount to over a hundred. The vast majority of these modifications was observed in the two most abundant classes of RNA, rRNA and tRNA. With the recent advance in mapping technologies, modifications have been discovered also in mRNA and in less abundant non-coding RNA species. These developments have sparked renewed interest in elucidating the nature and functions of those "epitransciptomic" modifications in RNA. N6-methyladenosine (m6 A) is the best understood and most frequent mark of mRNA with demonstrated functions ranging from pre-mRNA processing, translation, miRNA biogenesis to mRNA decay. By contrast, much less research has been conducted on 5-methylcytosine (m5C), which was detected in tRNAs and rRNAs and more recently in poly(A)RNAs. In this review, we discuss recent developments in the discovery of m5C RNA methylomes, the functions of m5C as well as the proteins installing, translating and manipulating this modification. Although our knowledge about m5C in RNA transcripts is just beginning to consolidate, it has become clear that cytosine methylation represents a powerful mechanistic strategy to regulate cellular processes on an epitranscriptomic level. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > tRNA Processing RNA Turnover and Surveillance > Regulation of RNA Stability. PMID- 30311407 TI - Taxonogenomics description of Parabacteroides timonensis sp. nov. isolated from a human stool sample. AB - Intensive efforts have been made to describe the human microbiome and its involvement in health and disease. Culturomics has been recently adapted to target formerly uncultured bacteria and other unclassified bacterial species. This approach enabled us to isolate in the current study a new bacterial species, Parabacteroides timonensis strain Marseille-P3236T , from a stool sample of a healthy 39-year-old pygmy male. This strain, is an anaerobic, gram-negative, nonspore-forming motile rod. Its genome is made up of 6,483,434 bp with 43.41% G+C content, 5046 protein-encoding genes, and 84 RNA genes. We herein provide the full description of Parabacteroides timonensis strain Marseille-P3236T through the taxonogenomic approach. PMID- 30311406 TI - Tumor-driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL-8. AB - Tumor-associated macrophages (TAMs) are abundant population of inflammatory cells which play an essential role in remodeling tumor microenvironment and tumor progression. Previously, we found the high density of TAMs was correlated with lymph node metastasis and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Therefore, this study was designed to investigate the mechanisms of interaction between TAMs and PDAC. THP-1 monocytes were the exposure to conditioned media (CM) produced by PDAC cells; then, monocyte recruitment and macrophage differentiation were assessed. CM from PDAC attracted and polarized THP-1 monocytes to tumor-driven like macrophages. mRNA expression cytokine profiling and ELISA identified the IL-8 secretion was increasing in tumor-driven like macrophages, and STAT3 pathway was involved. Addition of exogenous recombinant human IL-8 promoted PDAC cells motility in vitro and metastasis in vivo via upregulating Twist expression, which mediated epithelial-mesenchymal transition in cancer cells. What is more, IL-8 expression level in tumor stroma by immunohistochemical analysis was related to lymph node metastasis, the number of tumor CD68 but not CD163 positive macrophages and patient outcome. Taken together, these findings shed light on the important interplay between cancer cells and TAMs in tumor microenvironment and suggested that IL-8 signaling might be a potential therapeutic target for PDAC. PMID- 30311408 TI - Integrated profiling identifies caveolae-associated protein 1 as a prognostic biomarker of malignancy in glioblastoma patients. AB - AIMS: Glioblastoma (GBM) is a lethal disease of the central nervous system with high mortality, and novel therapeutic targets and strategies for GBM are urgently needed. Caveolae-associated protein 1 (CAVIN1) is an essential caveolar component encoding gene and has been poorly studied in glioma. To this end, in this study, we evaluated CAVIN1 expression in glioma tissue as well as the correlation between CAVIN1 expression and prognosis in glioma patients using the data collected from clinical samples or from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt, and Gene Expression Omnibus (GEO) data sets. METHODS: Survival analysis was performed with the Kaplan-Meier curve and log-rank test. The predictive role of CAVIN1 in progressive malignancy in glioma was evaluated by using a receiver operator characteristic (ROC) curve. Gene ontology (GO), Gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) methods were used to interpret the functions of CAVIN1 in GBM. RESULTS: CAVIN1 expression was elevated in GBM compared with that in low-grade glioma and nontumor brain samples and was correlated with unfavorable outcomes in glioma patients. Additionally, CAVIN1 could serve as an independent predictive factor for progressive malignancy in GBM. Furthermore, CAVIN1 was associated with disrupted angiogenesis and immune response in the tumor microenvironment of GBM. CONCLUSIONS: We identified CAVIN1 as a prognostic biomarker and potential target for developing novel therapeutic strategies against GBM. PMID- 30311409 TI - Geriatric Nutritional Risk Index for independent walking function in maintenance hemodialysis patients: A single-facility retrospective cohort study. AB - AIM: The target Geriatric Nutritional Risk Index (GNRI) for patients on chronic maintenance hemodialysis is unclear. We aimed to determine the relationship between the GNRI and independent walking ability in such patients. METHODS: In the present retrospective cohort study, 90 patients receiving chronic maintenance hemodialysis were included. Logistic regression analyses were carried out to evaluate the relationship between the GNRI and independent walking ability. Receiver operating characteristic curve analysis was carried out to determine the cut-off GNRI for predicting independent walking ability. RESULTS: Multivariate logistic regression analysis showed significant differences in age (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.6-0.9), creatinine generation rate percentage (OR 1.1, 95% CI 1.0-1.2), GNRI (OR 1.4, 95% CI 1.1-1.8; P < 0.01) and urea removal rate (OR 0.3, 95% CI 0.1-0.9; P < 0.05). The cut-off GNRI for independent walking ability was 86.7 (area under the curve 0.80, sensitivity 92.1%, specificity 66.7%, positive hit ratio 86.6%, negative hit ratio 78.3%). The factors correlated with survival in the univariate analysis were the GNRI, equilibrated Kt/V, urea removal rate, clear space rate, salt intake amount (P < 0.01), number of days of hospitalization and %creatinine generation rate (P < 0.05). The Cox proportional hazard regression model showed an OR of 0.77 (95% CI 0.32-1.8) at a GNRI <86/GNRI >=86. In the multivariate survival analysis, we observed no significant differences in any of the factors. CONCLUSIONS: GNRI was correlated with walking ability, which indicated that GNRI might predict future walking ability; also, a GNRI of 87 might be the target for maintaining walking ability. Geriatr Gerontol Int 2018; 18: 1556-1561. PMID- 30311410 TI - Developing a scale to measure Japanese nurses' individual readiness for deployment to disasters. AB - Japan is a disaster-prone country, and Japanese registered nurses (RN) should be evaluated for their individual readiness for unexpected dispatches. The aim of the present study was to develop and validate a scale for measuring individual readiness of Japanese RN for disasters. In our previous study in 2014, we developed a Japanese version of the Readiness Estimate and Deployability Index, which was originally developed in the USA in 1997. Considering the cultural and characteristic aspects of Japanese RN social skills, a preliminary version of the instrument was constructed in a pilot study. In the main survey, construct validity, internal consistency, and concurrent validity of the self-evaluation instrument were assessed in a sample of 964 RN, and its psychometric properties were evaluated. A six dimensional, 37 item tool called the Japanese Disaster Nursing Readiness Evaluation Index (JDNREI) was developed. The Cronbach's alpha for the scale was .93. The reliability of the six dimensions was acceptable, and the validity was supported by confirmatory factor analysis. The JDNREI, whose validity and reliability were evaluated, might enable RN to recognize and assess their level of individual readiness for future disasters. PMID- 30311411 TI - Twenty years of Nursing and Health Sciences. PMID- 30311412 TI - Qualitative exploration of fear of childbirth and preferences for mode of birth among Japanese primiparas. AB - Antenatal fear of childbirth (FOC) is associated with negative effects, such as postnatal traumatic symptoms. As the birth-related culture of East Asian countries differs from that in Western countries, the aim of the present qualitative, descriptive study was to explore FOC, perceptions for Caesarean section (CS), and obstetric analgesia (OA) among Japanese primiparas. The qualitative, descriptive study included focus group interviews with 11 primiparous women, which were conducted in a birth house and a maternity hospital in a metropolitan area of Japan in 2013. As a result, seven categories emerged from the analysis: Maternal and child risk, pain, losing control, uncertainty, prolonged labor, poor family support and loneliness before hospitalization. All participants denied having a preference for CS birth due to fear. Opposing values of OA were identified in women who chose OA and those who did not. In conclusion, it is necessary to increase clinical awareness that the objects of fear are diverse. Furthermore, diverse values regarding OA should be understood and equally respected by health-care professionals. PMID- 30311413 TI - Message from the president of the Society for Nursing and Health Sciences. PMID- 30311414 TI - Message from the outgoing president of the Society for Nursing and Health Sciences. PMID- 30311415 TI - Nursing schools on the increase as the 18 year old population decreases in Japan. AB - Baccalaureate nursing programs have been on the increase in Japan in the past few decades. However, the 18 year old population is on the decline. While nursing programs have been increasing, the number of high school graduates has decreased. The paradoxical phenomenon has started to affect nursing education, including shortages in faculty members and in clinical sites. The purpose of the present study was to identify actual or potential problems as a result of so many nursing schools having opened in the past few decades, and to make recommendations for nurse educators in Japan. PMID- 30311416 TI - Understanding the direct and indirect costs of a first episode of psychosis program: Insights from PAFIP of Cantabria, Spain, during the first year of intervention. AB - AIM: Early intervention psychiatric services for patients with psychosis aim to limit the most damaging outcomes and reduce the patient's risk of social drift, decreasing illness severity and thus containing healthcare costs. There is a scarcity of studies that focus on first-episode psychosis (FEP), and those few that have been published only looked at direct health costs, but not at indirect costs, which make up the bulk of the budget. Our study aims to explore the short term (1-year follow-up) economic cost of a FEP Program, including both direct and indirect costs. METHODS: Data were collected retrospectively from the clinical records of 157 patients included in the Programa Atencion Fases Iniciales de Psicosis, from Marques de Valdecilla University Hospital, Santander. Our data collection sheet collated data from direct and indirect costs associated with the illness. Data were also extracted from the Cantabria Health Service Records. STATA 15.0 was used for statistical analysis. RESULTS: On average, the total costs during the first year were ?48 353.51 per patient, with direct healthcare costs being ?13 729.47 (28.39%), direct non-medical costs ?108.6 (0.22%), and indirect costs ?34 515.44 (71.39%). We found that hospitalization costs were higher in males (p = 0.081) and in cannabis users (p = 0.032). The number of relapses increased both, hospitalization and treatment costs (r = 0.40 p = 0.000; r = 0.24 p = 0.067, respectively). CONCLUSIONS: Intensive Early Intervention in Psychosis Services may result in cost savings by decreasing hospitalization, premature mortality, disability, unemployment, and legal problems; however, the first year after diagnosis would represent the one with the highest costs. PMID- 30311417 TI - Microbial communities in the nepheloid layers and hypoxic zones of the Canary Current upwelling system. AB - Eastern boundary upwelling systems (EBUSs) are among the most productive marine environments in the world. The Canary Current upwelling system off the coast of Mauritania and Morocco is the second most productive of the four EBUS, where nutrient-rich waters fuel perennial phytoplankton blooms, evident by high chlorophyll a concentrations off Cape Blanc, Mauritania. High primary production leads to eutrophic waters in the surface layers, whereas sinking phytoplankton debris and horizontally dispersed particles form nepheloid layers (NLs) and hypoxic waters at depth. We used Catalyzed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) in combination with fatty acid (measured as methyl ester; FAME) profiles to investigate the bacterial and archaeal community composition along transects from neritic to pelagic waters within the "giant Cape Blanc filament" in two consecutive years (2010 and 2011), and to evaluate the usage of FAME data for microbial community studies. We also report the first fatty acid profile of Pelagibacterales strain HTCC7211 which was used as a reference profile for the SAR11 clade. Unexpectedly, the reference profile contained low concentrations of long chain fatty acids 18:1 cis11, 18:1 cis11 11methyl, and 19:0 cyclo11-12 fatty acids, the main compounds in other Alphaproteobacteria. Members of the free-living SAR11 clade were found at increased relative abundance in the hypoxic waters in both years. In contrast, the depth profiles of Gammaproteobacteria (including Alteromonas and Pseudoalteromonas), Bacteroidetes, Roseobacter, and Synechococcus showed high abundances of these groups in layers where particle abundance was high, suggesting that particle attachment or association is an important mechanisms of dispersal for these groups. Collectively, our results highlight the influence of NLs, horizontal particle transport, and low oxygen on the structure and dispersal of microbial communities in upwelling systems. PMID- 30311418 TI - Synthesis and Microtubule-Destabilizing Activity of N-Cyclopropyl-4-((3,4 dihydroquinolin-1(2H)-yl)sulfonyl)benzamide and its Analogs. AB - While clinically useful, microtubule-targeting agents are limited by factors that include their susceptibility to multidrug resistance. A series of aryl sulfonamides, terminally substituted with an amide or carboxylic acid, was synthesized and assayed for biological activity in two human cancer cell lines. The resulting antiproliferative activity data demonstrated that an amide was superior to a carboxylic acid in the para position. The most potent compound (3) had an IC50 for growth inhibition in the low micromolar range, caused cells to accumulate in G2 M of the cell cycle, and led to depolymerization of microtubules. It was also not susceptible to the P-glycoprotein drug efflux pump that underpins the resistance of cells to long-term drug treatment schedules. PMID- 30311419 TI - Molecular Mimics of Heterogeneous Metal Phosphides: Thermochemistry, Hydride Proton Isomerism, and HER Reactivity. AB - A new series of low-valent dinuclear molybdenum complexes bearing phosphido or phosphinidene bridging ligands was synthesized as a structural model of heterogeneous metal phosphide catalysts. Addition of acid to a monocationic Mo2 MU-P complex results in phosphide protonation, affording a dicationic Mo2 -MU-PH species. Alternatively, reaction of an isoelectronic Mo2 -MU-P precursor with LiBEt3 H gives a Mo2 H-MU-P complex. Mixing these species, one bearing a Mo-H and the other a P-H bond, results in facile H2 production at room temperature. PMID- 30311420 TI - Genotypic and phenotypic characterization of Escherichia coli isolated from mollusks in Brazil and the United States. AB - The aim of this study was to determine the serogroups, antimicrobial resistance and genetic diversity of Escherichia coli isolates from samples of bivalve mollusks collected along Santa Catarina coast, Brazil, and from the Chesapeake Bay, Maryland, USA. One hundred forty-one E. coli isolates were characterized for serogroups with 181 specific O antisera and antimicrobial susceptibility using the disk diffusion method. The genetic diversity was assessed using pulsed-field gel electrophoresis (PFGE). The results showed that among the isolates, 19.9% were classified as multi-drug resistant (MDR) and resistance was most frequently observed to cephalothin, nitrofurantoin, and ampicillin. The predominant serogroups were O6, O8, and O38. Some serogroups were recognized as pathogenic E. coli. PFGE dendrograms indicated extensive genetic diversity among the isolates. Although characteristics of the E. coli isolates were highly variable, it is important to note that E. coli belonging to pathogenic serogroups and MDR isolates are present in mollusks of both study areas. This is the first report on the phenotypic and genotypic characterization of E. coli from mollusks from Santa Catarina and the Chesapeake Bay that should encourage studies focusing on comparison of isolates across countries. PMID- 30311422 TI - Comparison of intestinal microbes in female and male Chinese concave-eared frogs (Odorrana tormota) and effect of nematode infection on gut bacterial communities. AB - The Chinese concave-eared frog (Odorrana tormota) is a rare and threatened species with remarkable sexual dimorphism. Intestinal microbes are understood to play important roles in animal physiology, growth, ecology, and evolution. However, little is known about the intestinal microbes in female and male frogs, as well as the contributing effect by gut infesting nematodes to the co-habiting bacteria and their function in degradation food rich in chitin. Here, this study analyzed the microbiota of the intestinal tract of both female and male, healthy as well as nematode-infested concave-eared frogs using high throughput 16S rRNA sequencing and metagenomic techniques. The results showed that the bacterial composition of the microbiota at the phylum level was dominated by Firmicutes, Verrucomicrobia, Bacteroidetes, and Proteobacteria. The study also revealed that the community composition below the class level could be represent sex differences, particularly with regard to Enterobacteriales, Enterobacteriaceae, Peptostreptococcaceae, and Rikenellaceae, among others. Carbohydrate-active enzyme-encoding genes and modules were identified in related gut bacteria by metagenomic analysis, with Bacteroidia, Clostridia, and gammaproteobacteria predicted to be the main classes of chitin-decomposing bacteria in the frog intestine. In addition, the abundance of some bacteria significantly increased or decreased in nematode-infected hosts compared with healthy individuals, including Verrucomicrobia, Verrucomicrobiae, Negativicutes, Actinobacteria, and Bacilli, among others. This indicates that nematode infection may affect the richness and composition of some gut bacteria. PMID- 30311421 TI - Clinical implication of subcategorizing T2 category into T2a and T2b in TNM staging of breast cancer. AB - Regarding TNM staging in breast cancer, T2 category is currently not divided into subcategories even though it covers a wider range of tumor sizes than T1 category. Using Korean Breast Cancer Registry database, data of 41 071 women diagnosed as non-metastatic T2 breast cancer between 2001 and 2014 were analyzed. Cutoff value for optimal tumor size was approximated by receiver operating characteristic (ROC) curve to subcategorize T2 tumors. Overall survival (OS) was compared between two subcategories. Median follow-up period was 65 months. Of 41 071 patients, 4504 (11.0%) died. Based on ROC curve analysis, 3.0 cm was selected as the cutoff value. Five-year OS rate was 91% in patients with breast tumors <=3.0 cm (T2a) and 86% in patients with breast tumors >3.0 cm (T2b) (log-rank P < 0.001). T2b subcategory showed worse OS than T2a subcategory regardless of node status (log-rank P < 0.001 for all node categories). Within every subgroup defined by primary OS analysis covariates, T2b subcategory consistently showed worse outcome compared to T2a subcategory. By multivariate analysis, T2b subcategory was a significant independent prognostic factor of OS (hazard ratio: 1.26, 95% CI = 1.18-1.34). T2 category of breast cancer could be subcategorized into T2a and T2b with a cutoff value of 3 cm. These subcategories definitely showed different OSs even after adjusted for known prognostic factors. Subcategorization of T2 category might be useful for predicting prognosis more accurately and tailoring adjuvant therapy. PMID- 30311423 TI - Australia's innovation in youth mental health care: The headspace centre model. AB - AIM: headspace is Australia's innovation in youth mental healthcare and comprises the largest national network of enhanced primary care, youth mental health centres world-wide. headspace centres aim to intervene early in the development of mental ill-health for young people aged 12 to 25 years by breaking down the barriers to service access experienced by adolescents and emerging adults and providing holistic healthcare. Centres have been progressively implemented over the past 12 years and are expected to apply a consistent model of integrated youth healthcare. Internationally, several countries are implementing related approaches, but the specific elements of such models have not been well described in the literature. METHOD: This paper addresses this gap by providing a detailed overview of the 16 core components of the headspace centre model. RESULTS: The needs of young people and their families are the main drivers of the headspace model, which has 10 service components (youth participation, family and friends participation, community awareness, enhanced access, early intervention, appropriate care, evidence-informed practice, four core streams, service integration, supported transitions) and six enabling components (national network, Lead Agency governance, Consortia, multidisciplinary workforce, blended funding, monitoring and evaluation). CONCLUSION: Through implementation of these core components headspace aims to provide easy access to one-stop, youth-friendly mental health, physical and sexual health, alcohol and other drug, and vocational services for young people across Australia. PMID- 30311425 TI - Complete but not partial inhibition of glutamate transporters exacerbates cortical excitability in the R6/2 mouse model of Huntington's disease. AB - AIM: Deficient glutamate reuptake occurs in the cerebral cortex of Huntington's disease (HD) patients and murine models. Here, we examine the effects of partial or complete blockade of glutamate transporters on excitatory postsynaptic currents (EPSCs) of cortical pyramidal neurons (CPNs). METHODS: Whole-cell patch clamp recordings of CPNs in slices from symptomatic R6/2 mice and wild-type (WT) littermates were used to examine the effects of selective or concurrent inhibition of glutamate reuptake transporters. RESULTS: Selective inhibition of the glial glutamate transporter 1 (GLT-1) or the glutamate aspartate transporter (GLAST) produced slight decreases in decay time of evoked EPSCs in CPNs from WT and R6/2 mice with no significant differences between genotypes. In contrast, concurrent inhibition of both transporters with DL-TBOA induced a significant increase in area and decay time and this effect was significantly greater in R6/2 CPNs. Furthermore, full blockade also reduced spontaneous EPSC frequency and exacerbated epileptiform activity in CPNs from symptomatic R6/2 mice. CONCLUSIONS: R6/2 CPNs are more sensitive to glutamate accumulation during full inhibition of both glutamate transporters, and these neurons have homeostatic mechanisms to cope with inhibition of GLT-1 or GLAST by a mechanism that involves upregulation of either transporter when the other is deficient. PMID- 30311426 TI - JCD Commentary for September 2018. PMID- 30311424 TI - Safety of combined PD-1 pathway inhibition and radiation therapy for non-small cell lung cancer: A multicentric retrospective study from the GFPC. AB - INTRODUCTION: Randomized prospective studies on patients with metastatic non small-cell lung cancers (NSCLCs) showed that anti-programmed death-1 (PD-1) agents notably improved 2-year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing. METHODS: We retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes. RESULTS: Among 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra- or extracranial irradiation courses, any grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune-related AE (IRAE). Respective 1- and 2-year OS rates were 48.8% and 29.1%, while 1- and 2-year progression-free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS. CONCLUSION: Radiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities. PMID- 30311427 TI - Rheology of hyaluronic acid and dynamic facial rejuvenation: Topographical specificities. AB - Sound knowledge of the rheology of hyaluronic acids is fundamental for facial rejuvenation procedures. Hyaluronic acid implants are subjected to complex mechanical forces within the facial tissues that vary depending on the anatomical region. Analysis of these forces is important to establish the rheological specifications of hyaluronic acid implants in each specific zone. This approach will optimize the correction of age-related loss of volume, since the filler will be chosen as a function of the mechanics of the anatomical zone, with the objective to respect facial dynamics. PMID- 30311428 TI - Mandatory medication content in the curricula of six health care personnel types with patient contact in Denmark. AB - Medication use is a complex process involving different types of health care personnel. This study investigated and compared mandatory medication content in the curricula of six types of health care personnel with patient contact. Using content analysis, three independent raters analysed the mandatory medication content for physicians, pharmacists, pharmaconomists, nurses, health care assistants and support workers in the Capital Region of Denmark. Three dimensions were analysed as follows: communication with patients about medication, medication use or pharmacology and medication formulation and production. ECTS credits were totalled for courses analysed to have high or medium content, and inter-rater reliability was tested with Fleiss' kappa. The total mandatory medication content for pharmacists was 197.0 ECTS, physicians 136.0 ECTS, pharmaconomists 123.3 ECTS, nurses 52.0 ECTS, health care assistants 17.8 ECTS and support workers 0.0 ECTS. Communication with patients about medication was included to the greatest extent in the educations of pharmaconomists (112.0 ECTS), pharmacists (37.5 ECTS) and physicians (25.0 ECTS). Knowledge about medication use and pharmacology was taught primarily to pharmacists (146.5 ECTS), physicians (123.6 ECTS) and pharmaconomists (89.8 ECTS) and to a lesser extent nurses (52.0 ECTS), health care assistants (17.8 ECTS) and support workers (0.0 ECTS). Medication formulation and production were taught only to pharmacists (93.0 ECTS) and pharmaconomists (25.1 ECTS). Mapping the basic competencies about medication taught to each of the six health care personnel types can lead to a better understanding of how they can complement each other in patient care. The study points to weaknesses in medication curriculum content for health care personnel with the most patient contact. PMID- 30311430 TI - Sentinel lymph node mapping by near-infrared fluorescence imaging and contrast enhanced ultrasound in healthy dogs. AB - Sentinel lymph node (SLN) mapping is a valuable and crucial diagnostic procedure in staging malignancies. We compared two non-invasive techniques, near-infrared (NIR) fluorescence imaging and contrast-enhanced ultrasound (CEUS), to identify the SLNs in three superficial anatomical regions in an animal model. Six healthy laboratory dogs were included in a proof-of-concept trial. A NIR fluorescent dye (Indocyanine Green) and microbubbles (Sonovue) were consecutively injected subdermally in the Inguinal, axillary and popliteal region to map the SLNs. Transcutaneous NIR fluorescence imaging identified SLNs in 17 out of a total of 18 occasions. CEUS identified SLNs in all regions (18/18). Whereas NIR fluorescence imaging performed better in the visualization of the afferent lymphatic tract, CEUS demonstrated different filling patterns of the SLNs, a feature potentially critical for the concept of SLN mapping in cancer patients. Both NIR fluorescence imaging and CEUS are safe, non-invasive, practical and accurate methods to perform real-time transcutaneous SLN mapping with potential in a clinical setting. PMID- 30311429 TI - S-S-PEG-COOH Self-Assembled Monolayer on Gold Surface Enabled a Combined Assay for Serological EBV Antibody Isotypes. AB - PURPOSE: Epstein-Barr virus (EBV) is a ubiquitous human gamma herpes virus that infects human epithelial cells and B lymphocytes. It would be potentially valuable to develop novel combined assays to benefit screening for large panels of samples of EBV infectious diseases. EXPERIMENTAL DESIGN: A simple antigen probed biochip that is modified with S-S-PEG-COOH and is used as a label-free high-throughput screening method for a combined detection of EBV capsid antigen IgM antibody, capsid antigen IgG antibody, and nuclear antigen IgG antibody. RESULTS: This protein biochip has similar feasibility, sensitivity, and specificity in comparison with Liaison chemiluminescent immunoassay (CLIA). Detection limit of the EBV antibodies by the biochip is almost identical to that by CLIA-L (2.91 U mL-1 vs 3.00 U mL-1 for EBNA-1 IgG, 8 U mL-1 vs10 U mL-1 for EBV-VCA IgG, and 3.5 U mL-1 vs 10 U mL-1 for EBV-VCA IgM). Tests of the three serological antibodies against EBV by the biochip are consistent with the CLIA-L method in 274 clinical sera, respectively. Finally, the combined biochip is successfully utilized for diagnostic identification of EBV infection in 14 patients with infectious mononucleosis (IM) and 25 patients with systemic lupus erythematosus SLE, as well as additional 10 known real-time PCR positive patients. CONCLUSIONS AND CLINICAL RELEVANCE: This biochip format will enable concurrent detection of antibodies against EBV infection and confirm infection status of EBV. It will be a versatile tool for large-scale epidemiological screening in view of its miniaturization and high throughput. PMID- 30311431 TI - Discerning the Primary Carcinoma in Malignant Peritoneal and Pleural Effusions Using Imaging Mass Spectrometry-A Feasibility Study. AB - PURPOSE: Malignant effusions challenge diagnostic accuracy due to cytomorphologic overlaps between various malignant primaries. Workup of this material to establish a correct diagnosis is time consuming and limited by the sparsity of material. In order to circumvent these drawbacks, the use of MALDI imaging MS (IMS) as a diagnostic platform has been explored. EXPERIMENTAL DESIGN: Cytology cell blocks from malignant effusions (serous ovarian carcinoma and several non ovarian carcinomas including gastric adenocarcinoma) containing at least 30% neoplastic cells are selected for generation of cytology microarrays (CMA). CMA sections are transferred to conductive glass slides, subjected to on-tissue tryptic digestion, and matrix application for MALDI-IMS analysis. RESULTS: Supervised classification analysis identifies serous ovarian carcinomas as the source of malignant effusions with a sensitivity of 85.7% when compared to samples from all other included primary sites. When compared to gastric adenocarcinoma, serous ovarian carcinoma samples can be delineated with a sensitivity of 97.3%. CONCLUSION AND CLINICAL RELEVANCE: These preliminary results highlight that MALDI-IMS allows subtyping of malignant effusions to identify the precise origin of neoplastic cells. While achieving similar results compared to classical approaches such as immunocytology, more material is conserved that will be available for further tests. PMID- 30311432 TI - Correlation between corneal and retinal neurodegenerative changes and their association with microvascular perfusion in type II diabetes. AB - PURPOSE: The pathophysiology of diabetic neurodegeneration and microvasculopathy remains controversial. Neurosensory layer thickness and corneal nerve fibre loss represent potential biomarkers of neuropathy. The purpose of this cross-sectional study was to determine the correlation between these neurodegenerative features and their association with retinal microvascular integrity in patients with type II diabetes without retinopathy. METHODS: Nerve fibre length (NFL), density (NFD) and branch density (NBD) were assessed using corneal confocal microscopy. Spectralis optical coherence tomography (OCT) was used for peripapillary retinal nerve fibre layer (RNFL), and macular RNFL, ganglion cell (GCL), inner plexiform (IPL) and inner nuclear layer (INL) thicknesses. Parafoveal vessel density (PVD) was determined using OCT angiography. RESULTS: We analysed 118 eyes of 61 patients. Peripapillary RNFL, macular RNFL, GCL, IPL and INL were 101 +/- 8, 29 +/- 3, 43 +/- 4, 36 +/- 3 and 36 +/- 3 MUm. NFL, NFD and NBD were 12.3 +/- 4.4 mm/mm2 , 17.8 +/- 7.4/mm2 and 26.7 +/- 15.2/mm2 . Corneal nerve fibre variables were neither associated with inner retinal thicknesses nor PVD. A significant positive correlation was found between macular GCL, IPL and peripapillary RNFL with deep capillary plexus PVD (p <= 0.05). CONCLUSION: Our results indicate that corneal and retinal neurodegeneration are independent changes early in type II diabetes and that distinct retinal, but not corneal neurodegenerative features, are associated with retinal microvascular perfusion. PMID- 30311433 TI - Change in the intestinal bacterial community structure associated with environmental microorganisms during the growth of Eriocheir sinensis. AB - As an important organ to maintain the host's homeostasis, intestinal microbes play an important role in development of the organism. In contrast to those of terrestrial animals, the intestinal microbes of aquatic organisms are affected by environmental microorganisms (including water microorganisms and sediment microorganisms). In the present study, the compositional differences of intestinal microbes in three representative developmental stages of the Chinese mitten crab (Eriocheir sinensis) were studied. Meanwhile, network association analysis, and visualization of the water microorganisms of the crabs' habitat, the environment microorganisms in the pond, and the intestinal microbes, was carried out. The results showed that the gut microbiota diversity index decreased continuously with age, and the four bacteria of Aeromonas (Proteobacteria), Defluviitaleaceae (Firmicutes), Candidatus Bacilloplasma (Tenericutes), and Dysgonomonas (Bacteroidetes) were the "indigenous" flora of the crab. In the network-related analysis with the environment, we found that as the culture time increased, the effect of environmental microorganisms on the intestinal microbes of crabs gradually decreased, and the four "indigenous" bacteria were always unaffected by the environmental microorganisms. The results of this study identified the core bacteria of the crab and, for the first time, studied the relationship between intestinal environmental microorganisms, which will aid the practical production of crabs and will promote research into the relationship between specific bacteria and the physiological metabolism of crabs. PMID- 30311434 TI - Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions. AB - BACKGROUND: The 'placebo effect' and 'nocebo effect' are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a 'no treatment' arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of 'drucebo' (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy. METHODS: This preferred reporting items for systematic reviews and meta-analysis-compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer. RESULTS: Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open-label conditions. The contribution of the drucebo effect to statin-associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta-analysis) of the results. CONCLUSIONS: The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life-prolonging lipid-lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect. PMID- 30311436 TI - HLA-DPB1*64:01N and DPB1*701:01 sequence extensions by single molecule real-time DNA sequencing. AB - Pacific Bioscience's SMRT sequencing was used to confirm and extend HLA DPB1*64:01N and 701:01. PMID- 30311435 TI - Clinical and imaging characteristics of PFO-related stroke with different amounts of right-to-left shunt. AB - INTRODUCTION: Right-to-left shunt (RLS) induced by a patent foramen ovale (PFO) is associated with an increased risk of cryptogenic stroke (CS). However, little is known about the relationship between the amount of RLS and the stroke pattern. In this study, we aimed to evaluate the distinct clinical features of PFO-related CS in different RLS degrees resulting from PFO. METHODS: This is a cohort study of 222 CS patients admitted to the Tongji Hospital from 1st May 2014 to 31st April 2017. All patients underwent contrast transcranial Doppler examination. And then, 121 (54.5%) were classified as non-RLS group, while 76 (34.2%) were classified as mild RLS group and 25 (11.3%) were large RLS group according to the number of micro-emboli signals. The groups were compared with respect to their clinical and neuroimaging characteristics. RESULTS: In terms of risk factors of stroke, the prevalence of hypertension was lower in mild group (p = 0.002). Regarding the infarct patterns in different CS patients, we found that the multiple cortical lesions were more frequently observed (p<0.001) with increasing RLS in DWI. Moreover, there was a rising trend in the proportion of small lesions (<=1 cm) with an increasing RLS (p < 0.01). And as RLS increased, the posterior circulation was more likely to be influenced (p < 0.05). In addition, the serum cholesterol concentration was lower in the large RLS group, compared to the non RLS group (p = 0.003) and mild RLS group (p = 0.008). While the mean platelet volume (MPV) in mild group was significantly higher than that of non-RLS group (p = 0.013). CONCLUSION: Patients with larger RLS show more infarction in posterior circulation, higher frequency of small lesions or multiple cortical lesions. The results of our study indicate that the infarct patterns might be a clue of PFO related stroke. PMID- 30311437 TI - Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction. AB - AIMS: Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short-term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH). METHODS AND RESULTS: Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta-analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post-IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta-analysis Global Group in Chronic Heart Failure score-predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD-treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan-Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload-corrected exercise pulmonary capillary wedge pressure at the 6 months post-IASD study were associated with HFH. CONCLUSIONS: The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large-scale ongoing randomized studies are required to confirm the potential benefit of this therapy. PMID- 30311439 TI - A change in the bacterial community of spider mites decreases fecundity on multiple host plants. AB - Bacterial symbionts may influence the fitness of their herbivore hosts, but such effects have been poorly studied across most invertebrate groups. The spider mite, Tetranychus truncatus, is a polyphagous agricultural pest harboring various bacterial symbionts whose function is largely unknown. Here, by using a high throughput 16S rRNA amplicon sequencing approach, we characterized the bacterial diversity and community composition of spider mites fed on five host plants after communities were modified following tetracycline exposure. We demonstrated that spider mite bacterial diversity and community composition were significantly affected by host plants and antibiotics. In particular, the abundance of the maternally inherited endosymbionts Wolbachia and Spiroplasma significantly differed among spider mites that were reared on different plant species and were completely removed by antibiotics. There was an overall tendency for daily fecundity to be lower in the mites with reduced bacterial diversity following the antibiotic treatment. Our data suggest that host plants and antibiotics can shape spider mite bacterial communities and that bacterial symbionts improve mite performance. PMID- 30311440 TI - Serum cryptococcal antigen titre as a diagnostic tool and a predictor of mortality in HIV-infected patients with cryptococcal meningitis. AB - OBJECTIVES: The aim was to determine the effectiveness of the serum cryptococcal antigen (CrAg) test in the diagnosis of concurrent cryptococcal meningitis (CM) and as a predictor of mortality in HIV-infected patients. METHODS: In this retrospective study, all HIV-infected patients admitted to Shanghai Public Health Clinical Center from 1 January 2014 to 31 August 2016 were screened for serum CrAg using the latex agglutination test. Serum CrAg-positive patients underwent lumbar puncture to confirm CM prior to the initiation of appropriate antifungal therapy and were followed up for at least 6 months. RESULTS: One hundred and four (7.1%) of the total of 1474 HIV-infected patients screened were serum CrAg positive. CM was diagnosed in the majority of serum CrAg-positive patients (71.3%; 67 of 94) and was confirmed in all (46 of 46) of the patients with headache or coma and in 43.8% (21 of 48) of patients without neurological symptoms. CrAg titres >= 1:1024 showed a sensitivity of 82.5% and a specificity of 86.7% for the diagnosis of concurrent CM (P < 0.001). The positive predictive value for CM in this population was 94.3%. A total of 13 serum CrAg-positive patients [13.8%; 95% confidence interval (CI) 7.5-22.4%] died (11 as a result of CM and two others as a result of bacterial pneumonia) despite early antifungal treatment initiation. Serum CrAg titres >= 1:1024 predicted all-cause mortality (hazard ratio 3.69; P = 0.03). CONCLUSIONS: Serum CrAg titres >= 1:1024 not only were associated with concurrent CM but also predicted mortality. HIV-infected patients with a positive serum CrAg test during screening should receive lumbar punctures regardless of symptoms to rule out CM and patients with serum CrAg titres >= 1:1024 should be offered immediate care. PMID- 30311438 TI - Time to jump on the bandwagon: the Journal of Cachexia, Sarcopenia and Muscle in 2018. PMID- 30311441 TI - Yeast transformation efficiency is enhanced by TORC1- and eisosome-dependent signaling. AB - Transformation of baker's yeast (Saccharomyces cerevisiae) plays a key role in several experimental techniques, yet the molecular mechanisms underpinning transformation are still unclear. The addition of amino acids to the growth and transformation medium increases transformation efficiency. Here, we show that target of rapamycin complex 1 (TORC1) activated by amino acids enhances transformation via ubiquitin-mediated endocytosis. We created mutants of the TORC1 pathway, alpha-arrestins, and eisosome-related genes. Our results demonstrate that the TORC1-Npr1-Art1/Rsp5 pathway regulates yeast transformation. Based on our previous study, activation of this pathway results in up to a 200 fold increase in transformation efficiency, or greater. Additionally, we suggest DNA may be taken up by domains at the membrane compartment of Can1 (MCC) in the plasma membrane formed by eisosomes. Yeast studies on transformation could be used as a platform to understand the mechanism of DNA uptake in mammalian systems, which is clinically relevant to optimize gene therapy. PMID- 30311442 TI - Opposite diastolic effects of omecamtiv mecarbil versus dobutamine and ivabradine co-treatment in pigs with acute ischemic heart failure. AB - Acute ischemic cardiogenic shock is associated with poor prognosis, and the impact of inotropic support on diastolic function in this context is unclear. We assessed two suggested new inotropic strategies in a clinically relevant pig model of ischemic acute heart failure (AHF): treatment with the myosin activator omecamtiv mecarbil (OM) or dobutamine and ivabradine (D+I). Left ventricular (LV) ischemia was induced in anesthetized pigs by coronary microembolization (n = 12). The animals then received OM (bolus 0.75 mg/kg, followed by 0.5 mg/kg per h) (n = 6) or D+I (5 MUg/kg per min + 0.29 +/- 0.16 mg/kg) (n = 6), respectively. Ischemia reduced the stroke volume (SV), despite the increased left atrial pressure associated with impaired LV early relaxation, systolic dilatation, and LV late diastolic stiffness. Both treatments improved systolic ejection, but only D+I increased the SV from 26 +/- 5 to 33 +/- 5 mL. D+I enhanced LV early relaxation (Tau; from 45 +/- 11 to 29 +/- 4 msec) and prolonged the diastolic time (DT) from 338 +/- 60 to 352 +/- 40 msec. In contrast, OM prolonged Tau (42 +/- 5 to 62 +/- 10 msec) and shortened the DT (from 326 +/- 68 to 248 +/- 84 msec). Our data suggest that enhanced early relaxation by D+I improves LV pump function in postischemic acute heart failure. In contrast, OM worsened lusitropy in this model. PMID- 30311443 TI - Spontaneous regression of lung squamous cell carcinoma with synchronous mediastinal progression: A case report. AB - Spontaneous regression (SR) of cancer implies the partial or complete disappearance of malignant disease without or with adequate medical treatment. Typically, SR of cancer is a sporadic event, especially in non-small cell lung cancer (NSCLC). Although the underlying mechanism of SR remains unknown, stimulation of an immunological response has been proposed. Herein, we report the case of a 56-year-old woman exhibiting SR of NSCLC with a mediastinal disease. Despite regression of the primary site after a lung biopsy, simultaneous progression of mediastinal lymph node metastasis occurred. Specimens obtained by surgical resection pathologically confirmed both primary and metastatic sites. Reportedly, primary and metastatic tumors shrink synchronously in SR of metastatic NSCLCs. Thus, the fact that the SR of NSCLC can present inconsistent development in primary and metastatic sites should be considered, and direct intervention is recommended if physicians diagnose this phenomenon. PMID- 30311445 TI - Successful treatment for various arrhythmias in an older patient treated with pilsicainide for paroxysmal supraventricular tachycardia. PMID- 30311446 TI - Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis. PMID- 30311444 TI - Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first-line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients' survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short-term treatment, defined as primary resistance. The present study is aimed to explore the role of stress-inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib-induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor-AKT and phosphor-AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC. PMID- 30311447 TI - Estimation of life expectancy with gait speed for cancer screening decisions in older adults. PMID- 30311448 TI - Photo- and pH- Dual-Responsive beta-Cyclodextrin-Based Supramolecular Prodrug Complex Self-Assemblies for Programmed Drug Delivery. AB - Despite the fact that progress has been made in the application of supramolecular prodrug self-assemblies to enhance the functionality of drug-delivery systems, corresponding research on multi-responsive supramolecular prodrug self-assemblies for programmed drug delivery is still limited. In this paper, the synthesis and self-assembly behavior of supramolecular prodrug complexes (SPCs) with beta cyclodextrin-acylhydrazone-doxorubicin (beta-CD-hydrazone-DOX) and the targeting of azobenzene-terminated poly[2-(dimethylamino)ethyl methacrylate] (Azo-PDMA-FA) as a building block were investigated. The obtained SPCs could also form self assemblies on the basis of their amphiphilic nature. Next, SPC-based multi compartment vesicles and complex micelles, which were confirmed by transmission electron microscopy and dynamic/static light scattering, were obtained with good reversibility under alternative visible light or UV irradiation. Furthermore, three-stage programmed drug-delivery behavior was observed from dual-responsive SPC-based self-assemblies by utilizing UV and pH stimuli. Specifically, the SPCs first self-assembled into multicompartmental vesicles, which was accompanied by a slow release of DOX. Next, UV-light irradiation induced the dissociation of beta CD/Azo, which led to morphology transition and a slight increase in the rate of release of DOX. Upon transferring the self-assemblies to phosphate-buffer solution (pH 5.0), the release rates increased notably as a result of the broken acylhydrazone bond. Finally, basic cell experiments further demonstrated that the SPC-based self-assemblies could be internalized into cancer cells, which suggests their promise for applications in cancer therapy. PMID- 30311449 TI - A new strategy for seamless gene editing and marker recycling in Saccharomyces cerevisiae using lethal effect of Cwp1. AB - Technologies development for seamless gene editing and marker recycling has allowed frequent genomic engineering in Saccharomyces cerevisiae for desired laboratory strains and cell factory. Alternative new approaches are still required for complicated scenarios. In this study, we report that inducible overexpression of cell wall protein 1 (Cwp1) by galactose addition confers yeast cells a robust growth inhibition. Direct repeats flanking the Gal-CWP1:selectable marker cassette allow for its homology recombination excision and counter selection upon galactose addition, therefore enable seamless gene editing and marker recycling. We used this strategy and efficiently generated scarless Ade8 deletion mutants. Our results highlight the utility of lethal effect of Cwp1 overexpression a new counter selection strategy and a simple and efficient method for seamless gene editing and marker recycling in S. cerevisiae and potentially other fungi. PMID- 30311451 TI - Oxytocin receptor gene variants are associated with emotion recognition and resilience, but not with false-belief reasoning performance in healthy young Korean volunteers. AB - AIMS: A growing body of literature has indicated that oxytocin is associated with several domains of social cognition and behavior. Nevertheless, the effects of oxytocin receptor gene (OXTR) polymorphisms on social phenotypes remain unclear. Therefore, we aimed to explore the genetic influence of OXTR variants on social cognition (social perception and theory of mind) and resilience in healthy individuals. METHODS: We examined the influence of 10 common OXTR variants on social cognitive abilities, including facial emotion recognition and theory of mind, and trait resilience in 264 unrelated, healthy participants. RESULTS: We found a significant association between the A-C haplotype at rs237887-rs2268490 and facial affect recognition. In addition, the single marker rs2254298 was significantly associated with participants' scores on the Connor-Davidson Resilience Scale. In contrast, variations in OXTR did not affect participants' performance on the false-belief reasoning task. CONCLUSIONS: Single makers or haplotypes at OXTR may contribute to individual differences in facial emotion recognition and psychological resilience. PMID- 30311452 TI - Two novel alleles, HLA-A*32:01:01:09 and 32:01:01:10, identified by Pacific Bioscience's SMRT sequencing. AB - Pacific Bioscience's SMRT DNA sequencing was used to identify two novel intronic variants of HLA-A*32:01:01:01. PMID- 30311450 TI - Clinicopathological features and prognosis of patients with gastric neuroendocrine tumors: A population-based study. AB - BACKGROUND: Despite its rarity, studies have shown the incidence of gastric neuroendocrine tumors (G-NETs) is increasing. This study investigated the risk factors affecting the survival of G-NETs patients and their prognosis over time. METHOD: A retrospective analysis of 506 G-NETs patients who underwent surgery for nonmetastatic disease from the Surveillance, Epidemiology and End Result database from 1988 to 2011 was conducted. Multivariate Cox regression analyses identified the prognostic factors affecting overall survival (OS) and disease-specific survival (DSS). Three-year conditional survival (COS3 and CDS3) estimates at "x" year after treatment were calculated as follows: COS3 = OS(x + 3)/OS(x) and CDS3 = DSS(x + 3)/DSS(x). RESULTS: The 1-, 3-, and 5-year OS rates of all patients after surgery were 90.2%, 77.3%, and 68.8%, respectively. The 1-, 3-, and 5-year DSS rates after surgery were 93.9%, 84.5%, and 80.9%, respectively. In the multivariate analysis, age, tumor grade, and T stage were independent prognostic factors of OS and DSS (all P < 0.05). With 1-, 3-, and 5-year survivorship, the COS3 improved by +5.2 (82.2%), +7.2 (84.4%), and +8.5 (85.5%), respectively, and the CDS3 improved by +4.4 (89.4%), +9.1 (94.1%), and +12.5 (97.5%), respectively. Notably, the CDS3 improved dramatically among patients with advanced stage disease (eg, N0 stage: 93.0%-98.9%, Delta5.9% vs N1 stage: 52.0%-95.7%, Delta43.7%). CONCLUSION: For G-NETs patients, age, tumor grade, T stage, and N stage were the clinicopathological factors significantly associated with prognosis. There were excellent outcomes for most G-NETs patients, with a CDS3 of greater than 90% across all independent prognostic factors after 5 years of survival. PMID- 30311453 TI - Anisotropically Aligned Cell-Laden Nanofibrous Bundle Fabricated via Cell Electrospinning to Regenerate Skeletal Muscle Tissue. AB - For muscle regeneration, a uniaxially arranged micropattern is important to mimic the structure of the natural extracellular matrix. Recently, cell electrospinning (CE) has been tested to fabricate cell-laden fibrous structures by embedding cells directly into micro/nanofibers. Although homogenous cell distribution and a reasonable cell viability of the cell-laden fibrous structure fabricated using the CE process are achieved, unique topographical cues formed by an aligned fibrous structure have not been applied. In this study, a CE process to achieve not only homogeneous cell distribution with a high cell viability, but also highly aligned cells, which are guided by aligned alginate fibers is employed. To attain the aligned cell-laden fibrous structure, various processing conditions are examined. The selected condition is applied using C2C12 myoblast cells to ensure the biocompatibility and guidance of cell elongation and alignment. As a control, a cell-printed scaffold using a 3D bioprinter is used to compare the efficiency of cell alignment and differentiation of myoblasts. Highly arranged, multinucleated cell morphology is confirmed in the CE scaffold, which successively facilitates myogenic differentiation. It is believed that this study will be a new platform for obtaining cell alignment and will significantly benefit the efforts on muscle regeneration. PMID- 30311454 TI - Assessing health-related quality of life in heart failure patients attending an outpatient clinic: a pragmatic approach. AB - AIMS: Improving quality of life (QoL) in heart failure patients is a key management objective. Validated health-related QoL (HR-QoL) measurement tools have been incorporated into clinical trials but not routinely into daily practice. The aims of this study were to investigate the acceptability and feasibility of implementing validated HR-QoL instruments into heart failure clinics and to examine the impact of patient characteristics on HR-QoL. METHODS AND RESULTS: One hundred and sixty-three patients attending heart failure clinics at a UK tertiary centre were invited to complete three HR-QoL assessments: the Minnesota Living with Heart Failure Questionnaire (MLHFQ); the EuroQoL 5D-3L (EQ 5D-3L); and the Kansas City Cardiomyopathy Questionnaire (KCCQ) in that order. Data on patient demographics, co-morbidities, New York Heart Association (NYHA) class, plasma B-type natriuretic peptide (BNP), renal function, and left ventricular ejection fraction were recorded. 94% of patients attending clinic were willing to participate. The EQ-5D-3L had all questions answered by 92% of patients, compared with 86% and 51% for the MLHFQ and KCCQ, respectively. HR-QoL significantly correlated with NYHA class using each tool (MLHFQ, r = 0.59; KCCQ, r = -0.61; EQ-5D-3L, r = -0.44, all P < 0.01). However, within each NYHA class, there was a widespread of HR-QoL scores. There was no association between patient demographics, left ventricular ejection fraction, plasma B-type natriuretic peptide, or renal function with HR-QoL using any tool. CONCLUSIONS: Health related QoL assessment by validated questionnaire was acceptable to patients and feasible to perform in routine practice. Although NYHA class correlated significantly with HR-QoL scores, there was high variability in HR-QoL within each NYHA class, highlighting its limitation as the sole assessment of HR-QoL. Clinicians should encourage the assessment of HR-QoL to facilitate patient centred care and make more specific use of HR-QoL measurement tools. PMID- 30311455 TI - Clinical Features of Benign Essential Blepharospasm in Korean Patients. AB - PURPOSE: To analyze the clinical features of benign essential blepharospasm in Korean patients. METHODS: Patients diagnosed with benign essential blepharospasm in Kim's Eye Hospital from November 2014 to December 2016 were evaluated using a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for blepharospasm development, and relieving and aggravating factors. RESULTS: Of the 101 patients enrolled, 78 (77.2%) were women. The mean age was 64.9 years old. Hypertension was the most common medical disorder (42.6%), followed by diabetes mellitus. The majority of the patients were non-smokers (83.2%) and drank less than a cup of a caffeinated beverage a day (30.7%). Fifty-seven percent of patients reported no stressful events immediately prior to symptom development. Fatigue and stress were aggravating factors in more than 55% of patients; rest was the most common relieving factor (35.6%). CONCLUSIONS: Here, we report the clinical features of benign essential blepharospasm in Korean patients for the first time. The results were consistent with previous reports showing that the majority of benign essential blepharospasm patients are women and non-smokers. In contrast to previous reports though, fatigue and stress were aggravating factors, and the most common relieving factor was rest. No stressful events had immediately preceded the development of blepharospasm in 57.4% of patients. This report may aid in treating and counseling patients with benign essential blepharospasm. PMID- 30311456 TI - Changes in Tear Meniscus Height Following Lower Blepharoplasty as Measured by Optical Coherence Tomography. AB - PURPOSE: The lower eyelid serves important roles in tear distribution and drainage. The purpose of this study was to measure the tear meniscus height (TMH) with anterior segment optical coherence tomography after lower blepharoplasty. METHODS: A total of 52 eyes from 26 patients treated between July 2012 and June 2015 were included in the study. A transcutaneous or transconjunctival approach was performed, depending on whether (1) the supportive lower lid orbicularis oculi muscle was tightened, (2) the middle lamella was elongated, (3) minimal fat was removed or transpositioned, and (4) lateral canthal support was established. Marginal reflex distance 2 and marginal nose distance were analyzed with Image J software. TMH was measured with anterior segment optical coherence tomography. A paired t-test and Wilcoxon signed-rank test were used for statistical comparisons. RESULTS: Marginal reflex distance 2 decreased and marginal nose distance increased with both surgical techniques. TMH decreased from 337.3 +/- 117.9 to 289.3 +/- 69.1 MUm (p = 0.024) in patients who had transcutaneous lower blepharoplasty, but increased from 186.5 +/- 35.5 to 274.8 +/- 58.3 MUm (p = 0.000) in patients who had transconjunctival lower blepharoplasty. Medial and lateral TMHs decreased significantly from 228.8 +/- 80.7 to 152.7 +/- 42.1 MUm (p = 0.008) in patients with transcutaneous lower blepharoplasty. TMH was significantly restored after lower blepharoplasty with either approach. CONCLUSIONS: Enhancing the lower eyelid position combined with orbicularis muscle tightening and lateral canthal support can normalize the TMH following lower eyelid blepharoplasty. PMID- 30311457 TI - Clinical Features of Herpes Simplex Keratitis in a Korean Tertiary Referral Center: Efficacy of Oral Antiviral and Ascorbic Acid on Recurrence. AB - PURPOSE: To describe the clinical manifestations of herpes simplex keratitis (HSK) in a tertiary referral center in South Korea and to determine whether ascorbic acid treatment prevents recurrence of herpetic epithelial keratitis. METHODS: This retrospective cohort study included all consecutive patients with herpetic keratitis referred to our center from January 2010 to January 2015. Clinical features, ocular complications, and recurrences were recorded. RESULTS: In total, 149 eyes of the 133 patients (72 male and 61 female) were followed for an average of 24.6 +/- 13.2 months. Sixteen (12.0%) patients had bilateral HSK. The most frequent HSK subtype was epithelial keratitis (49.7%), which was followed by stromal keratitis (23.5%). Epithelial keratitis was the most likely subtype to recur. Complications occurred in 122 (81.9%) eyes. The most common complication was corneal opacity. Recurrences were observed in 48 (32.2%) eyes. The recurrence rates were lower in the prophylactic oral antiviral agent group (16 / 48 eyes, 33.3% vs. 49 / 101 eyes, 48.5%) and the ascorbic acid treatment group (13 / 48 eyes, 27.1% vs. 81 / 101 eyes, 70.3%) compared with the groups without medications. Univariate logistic regression analysis revealed that both factors significantly reduced the risk of recurrence (acyclovir: odds ratio, 0.25; 95% confidence intervals, 0.12 to 0.51; ascorbic acid: odds ratio, 0.51; 95% confidence intervals, 0.20 to 0.91). CONCLUSIONS: This retrospective study described the clinical findings of HSK in a tertiary referral center in South Korea. Prophylactic oral antiviral agent treatment and oral ascorbic acid administration may lower the risk of recurrence. PMID- 30311458 TI - Development of Submacular Hemorrhage in Neovascular Age-related Macular Degeneration: Influence on Visual Prognosis in a Clinical Setting. AB - PURPOSE: This study aimed to evaluate changes in visual acuity before and after the development of submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) and to compare the visual outcomes between patients with and without hemorrhage. METHODS: This retrospective observational study included 124 patients with neovascular AMD. Patients who developed a submacular hemorrhage involving the fovea were included in the hemorrhage group (n = 55). Patients with no sign of submacular hemorrhage during the follow-up period were included in the no-hemorrhage group (n = 69). Visual outcomes were compared between the two groups. RESULTS: The logarithm of the minimal angle of resolution best-corrected visual acuity (BCVA) before the development of submacular hemorrhage, once the hemorrhage had developed, and 6 months after the development of hemorrhage was 0.59 +/- 0.45, 1.24 +/- 0.57, and 0.99 +/- 0.64, respectively. BCVA was significantly worse 6 months after the hemorrhage compared to before the hemorrhage (p < 0.001). The BCVA before the development of hemorrhage (measured at a mean of 12.9 months after diagnosis) was comparable to that of the no hemorrhage group (mean, 0.58 +/- 0.37 at a mean of 12.4 months). However, the BCVA 6 months after identification of hemorrhage (mean, 21.5 months) was significantly worse in the hemorrhage group than in the no-hemorrhage group (mean, 0.73 +/- 0.44 at mean 21.2 months) (p = 0.018). CONCLUSIONS: Visual acuity was significantly worse after hemorrhage than before hemorrhage, even after treatment. In addition, patients with submacular hemorrhage had markedly worse visual outcomes than patients without hemorrhage. This result suggests that the development of hemorrhage during the treatment course of neovascular AMD has a devastating effect on visual prognosis. PMID- 30311459 TI - Effect of Nd:YAG Laser Capsulotomy on Anterior Segment Parameters in Patients with Posterior Capsular Opacification after Phacovitrectomy. AB - PURPOSE: To compare changes in anterior segment parameters after Nd:YAG laser capsulotomy in eyes that underwent either combined phacovitrectomy or cataract surgery. METHODS: This retrospective study enrolled 37 eyes of 35 patients with posterior capsular opacification treated with combined phacovitrectomy (group A), and 35 eyes of 32 patients with posterior capsular opacification treated with cataract surgery (group B). Anterior segment parameters, including anterior chamber depth (ACD), anterior chamber angle, and anterior chamber volume, were measured by a Pentacam before Nd:YAG laser capsulotomy and 1 hour, 1 day, 1 week, 1 month, and 3 months after this treatment. RESULTS: In the cataract surgery group, the ACD was significantly lower 1 day (3.75 +/- 0.74 mm), 1 week (3.73 +/- 0.24 mm), and 3 months (3.74 +/- 0.33 mm) after Nd:YAG laser capsulotomy compared with the pretreatment value (4.20 +/- 0.62 mm, p = 0.002). By contrast, the ACD did not change significantly over time in the combined phacovitrectomy group. The ACD differed significantly between the two groups at 1 week, 1 month, and 3 months after capsulotomy. There were no significant changes in the anterior chamber volume, anterior chamber angle, central corneal thickness, or pupil size from before to after capsulotomy in either group. A non-significant trend toward myopic shift was observed in group A (p = 0.072) and B (p = 0.055). CONCLUSIONS: The results of the present study may help determine the power of the intraocular lens in patients who underwent combined surgery or cataract surgery and who will receive Nd:YAG laser capsulotomy. PMID- 30311460 TI - Posterior Vitreous Structures Evaluated by Swept-source Optical Coherence Tomography with En Face Imaging. AB - PURPOSE: To evaluate posterior vitreous structures using swept-source (SS) optical coherence tomography (OCT) with en face imaging. METHODS: We retrospectively reviewed OCT images of healthy individuals who did not have intra ocular disease. We obtained high-definition horizontal and vertical line scans crossing the fovea and 3D scans using SS-OCT, with the 3D scan centered between the fovea and the optic-nerve head. An enhanced vitreous visualization function was used to highlight vitreous structures. En face mode was used to measure the area of Martegiani (AM) and bursa premacularis (BP). We performed all measurements using a built-in function of the viewing software. RESULTS: We enrolled 24 eyes from 12 healthy individuals. The mean patient age was 28.7 +/- 4.6 years (range, 24 to 39 years). The mean AM and BP areas were 5.73 +/- 0.88 and 18.76 +/- 6.95 mm2, respectively. In en face imaging, AM shape was most frequently a vertical oval (18 / 22, 81.8%), while the predominant BP shape was round (16 / 20, 80.0%). AM was in contact with the optic disc, either at the temporal-disc margin (13 eyes, 59.1%) or the nasal optic-disc margin (9 eyes, 40.9%). CONCLUSIONS: Posterior vitreous structures, such as AM and BP, were readily visualized using en face imaging with SS-OCT. Investigating normal vitreous configuration might help in understanding changes in vitreous structures associated with retinal pathology. PMID- 30311461 TI - Effects of Choroidal Thickness on Refractive Outcome Following Cataract Surgery in Primary Angle Closure. AB - PURPOSE: To identify the preoperative biometric factors, including subfoveal choroidal thickness (CT), associated with refractive outcome after cataract surgery in eyes with primary angle closure (PAC). METHODS: This study included 50 eyes of 50 PAC patients who underwent uneventful cataract surgery. Preoperatively, anterior segment parameters including anterior chamber depth (ACD) and lens vault were determined by anterior segment optical coherence tomography. Subfoveal CT was measured by spectral domain optical coherence tomography enhanced depth imaging before and at one month after surgery. Mean refractive error (MRE) was calculated as the difference in spherical equivalent between actual postoperative refraction determined one month postoperatively and that predicted using each of three IOL calculation formulas (SRK/II, SRK/T, and Haigis). Regression analyses were performed to investigate potential associations between MRE and putative factors. RESULTS: Mean ACD was 1.9 +/- 0.4 mm, and preoperative subfoveal CT was 250.8 +/- 56.9 MUm. The SRK/T (MRE, 0.199 +/- 0.567 diopters [D]) and Haigis (MRE, 0.190 +/- 0.727 D) formulas showed slight hyperopic shift, while the SRK/II formula demonstrated a myopic shift (MRE, 0.077 +/- 0.623 D) compared with that expected after cataract surgery. Mean absolute refractive error was not significantly different between formulas. Higher preoperative lens vault and shallower ACD were associated with a hyperopic shift in all formulas, but not in a statistically significant manner. Thicker preoperative subfoveal choroid was associated with a myopic shift after cataract surgery in all formulas (SRK/II: beta = -0.511, p < 0.001; SRK/T: beta = -0.652, p < 0.001; Haigis: beta = -0.671, p < 0.001). Greater postoperative reduction of subfoveal CT was associated with a myopic shift after cataract surgery in all formulas (SRK/II: beta = -0.511, p < 0.001; SRK/T: beta = -0.652, p < 0.001; Haigis: beta = -0.671, p < 0.001). CONCLUSIONS: Our results indicate that preoperative subfoveal CT and the difference between pre- and postoperative subfoveal CT are significant factors for predicting refractive error after cataract surgery in PAC patients. These findings should be considered when performing cataract surgery to optimize visual outcomes. PMID- 30311462 TI - Effects of Early Postoperative Intraocular Pressure after Ahmed Glaucoma Valve Implantation on Long-term Surgical Outcomes. AB - PURPOSE: To evaluate the long-term effects of early postoperative intraocular pressure (IOP) after Ahmed glaucoma valve (AGV) implantation on long-term surgical outcomes. METHODS: This retrospective, non-randomized study included 100 eyes of 100 patients who underwent AGV surgery. We divided the enrolled patients into four groups according to the presence of transient hypotony within the first postoperative week or the presence of a hypertensive phase during the first three postoperative months. Postoperative IOP, the number of glaucoma medications, and cumulative success rate were compared among the groups. RESULTS: There was significantly better IOP control and a better success rate in the non hypertensive phase group 2 years postoperatively. However, no significant difference was found in the IOP or success rate at 2 years postoperatively between the transient hypotony and non-hypotony groups. Further subgroup analysis showed that the non-hypotony, non-hypertensive phase group had a significantly higher success rate (100%) at 2 years postoperatively. CONCLUSIONS: We can predict the long-term prognosis after AGV implantation by considering the early postoperative IOP state and the presence of a hypertensive phase. PMID- 30311463 TI - Influence of Vitrectomy-related Factors on the Outcome of Ahmed Glaucoma Valve Implantation. AB - PURPOSE: To evaluate the outcome of Ahmed glaucoma valve (AGV) implantation in eyes with refractory secondary glaucoma following pars plana vitrectomy (PPV) and the associated prognostic factors. METHODS: A total of 146 eyes in 146 patients who underwent AGV implantation after PPV (followed up for >=1 year) were included. AGV implantation was considered successful when the intraocular pressure (IOP) was 6 to 21 mmHg regardless of using IOP-lowering medication. The hazard ratios (HRs) associated with surgical failure were determined with Cox proportional analysis. RESULTS: The most common cause for PPV was complications of proliferative diabetic retinopathy (50%). The mean and peak IOPs between PPV and AGV implantation were 26.9 +/- 6.6 and 35.9 +/- 10.2 mmHg, respectively. AGV implantation was performed on average 18.7 months after PPV, and its overall success rate was 80.1% during a mean follow-up period of 43.6 months. In multivariate analyses, rubeosis observed before AGV implantation (HR, 4.07; 95% confidence interval, 1.57 to 10.6; p = 0.004) and higher peak IOP before AGV (HR, 1.04; 95% confidence interval, 1.00 to 1.07; p = 0.034) were predictive of failure. However, no PPV-related factors were associated with the surgical outcome of AGV implantation. CONCLUSIONS: The outcome of AGV implantation is good in refractory glaucoma following PPV. Rubeosis after PPV and higher peak IOP before AGV are risk factors for poor outcomes. Patients who undergo PPV should be followed for the development of rubeosis and IOP control. PMID- 30311464 TI - Positional Intraocular Pressure of Vitrectomized and Normal Fellow Eyes. AB - PURPOSE: To compare posture-induced intraocular pressure (IOP) changes in vitrectomized eyes and normal eyes of patients who had vitrectomy in one eye. METHODS: A total of 31 patients older than 20 years of age who underwent vitrectomy were enrolled in the study. At least six months after vitrectomy, we measured IOP in both eyes using a rebound tonometer 10 minutes after the patient assumed sitting, supine, right lateral decubitus, and left lateral decubitus positions. Patients with a history of ocular surgery (not including vitrectomy) or recent medication use associated with IOP were excluded. IOP and ocular parameters of vitrectomized and normal fellow eyes were compared. For the decubitus position, IOP values of dependent and nondependent eyes were compared. RESULTS: No significant difference was observed in IOP between vitrectomized and normal eyes in the sitting and supine positions. The IOP for dependent eyes (on the lower side in the lateral decubitus position) was significantly higher than the IOP for nondependent eyes in both right lateral decubitus (right vitrectomized eye 19.31 +/- 4.20 vs. 16.71 +/- 4.02 mmHg, p < 0.001; left vitrectomized eye 18.35 +/- 1.75 vs. 16.04 +/- 3.02 mmHg, p = 0.003) and left lateral decubitus (right vitrectomized eye 17.32 +/- 4.63 vs. 19.15 +/- 3.83 mmHg, p = 0.004; left vitrectomized eye 16.19 +/- 1.81 vs. 18.12 +/- 2.29 mmHg, p < 0.001) positions. CONCLUSIONS: IOP was higher in the dependent than the nondependent eye in the lateral decubitus position, for both vitrectomized and nonoperated eyes. PMID- 30311465 TI - Effective Delivery of Exogenous Compounds to the Optic Nerve by Intravitreal Injection of Liposome. AB - PURPOSE: To improve the treatment efficiency of optic nerve diseases by delivering therapeutic materials to the optic nerve directly. METHODS: We tried to optimize liposomal composition to deliver a payload to the optic nerve efficiently when it is injected intravitreally. After loading dexamethasone into this liposome, we tested the therapeutic effect of liposomes in this treatment using a murine model of ischemic optic neuropathy. RESULTS: Our optimized liposome can deliver its payload to the optic nerve more efficiently than other tested compositions. Moreover, dexamethasone-loaded liposomes had a significant therapeutic effect in a murine model of ischemic optic neuropathy. CONCLUSIONS: Here, we demonstrate the optimal composition of liposomes that could efficiently deliver intravitreally injected exogenous compounds to the optic nerve. We expect that the intravitreal injection of liposomes with the suggested composition would improve the delivery efficacy of therapeutic compounds to the optic nerve. PMID- 30311466 TI - Adult onset xanthogranuloma associated with IgG4-related disease. PMID- 30311467 TI - High-grade Mucoepidermoid Carcinoma of the Lacrimal Gland. PMID- 30311468 TI - Ocular Ischemic Syndrome as the Initial Presenting Feature of Cytomegalovirus Retinitis. PMID- 30311469 TI - Postoperative Hemorrhagic Occlusive Retinal Vasculitis with Intracameral Vancomycin. PMID- 30311470 TI - Corrigendum: Pharmacotherapy and ROP: Going Back to the Basics. AB - This corrects the article DOI: 10.22608/APO.201853. PMID- 30311471 TI - Torch Ginger (Etlingera elatior): A Review on its Botanical Aspects, Phytoconstituents and Pharmacological Activities. AB - In order to propose a prospective candidate for novel complementary phytopharmaceuticals, one of Zingiberaceae family plant, Etlingeraelatior or torch ginger, was being evaluated. The aim of this review was to provide a comprehensive literature research focused on the botanical aspects, nutritional quality, phytoconstituents and pharmacological activities of E. elatior. Researches on this particular plant were conducted in Malaysia (55.5%), Indonesia (33.3%), Thailand (8.3%) and Singapore (2.7%). This review article has revealed that the most prominent pharmacological activities were anti-microbial, anti oxidant and anti-tumor activities in consistent with the dominated levels of flavonoids, terpenoids and phenols. However, extended and integrated research should be converged towards intensive investigations concerning to isolated phytoconstituents and its bioactivities, pharmacokinetics, bioavailability, molecular mechanism of its specific pharmacological activities, safety and efficacy studies for further development. PMID- 30311473 TI - Effects of Salinity on Survival and Growth of Gurami Sago (Osphronemus goramy, Lacepede, 1801) Juveniles. AB - BACKGROUND AND OBJECTIVE: Gurami Sago Osphronemus goramy (O. goramy) are an herbivorous freshwater finfish species native in Indonesia. This species has not yet been cultured commercially in brackish water. A 60-days study was conducted to evaluate the effects of salinity on survival and growth of O. goramy. MATERIALS AND METHODS: Two independent experiments were performed to determine the effects of salinity on survival and growth of juvenile O. goramy, first one was to determine the median lethal salinity (MLS-5096 h) and second one was to assess the survival and growth at different sub-lethal salinities. In MLS-5096 h study 0.0, 4.0, 8.0, 12.0 and 16.0 ppt salinities were used to initially find out the salinity tolerance range. Accordingly, a definitive salinity tolerance test was done in next phase to find out exact median lethal salinity by directly transferring the test species to 13.0, 14.0, 15.0 and 16.0 ppt salinity for 96 h. The median lethal salinity of O. goramy was estimated at 14.0 ppt. In the second experiment, survival and growth of the O. goramy were recorded at salinities 4.0, 8.0 and 12.0 ppt along with 0.0 ppt as control during 60 days. RESULTS: Osigni goramy exhibited lowest final average weight at 12.0 ppt salinity and significantly highest at 4.0 ppt salinity. Highest SGR and weight gain were obtained at 4.0 ppt followed by 0 ppt, 8 ppt and 12 ppt salinity. All treatments were significantly (p<0.05). Survival rate of O. goramy varied between 76.45% (at 0.0 ppt) and 66.66% (at 12.0 ppt). CONCLUSION: The O. goramy grew and survived satisfactorily at 0.0 to12.0 ppt salinities, implying that the species can be cultured commercially in brackish water, in view of in Indonesia, there are many abandoned shrimp ponds. PMID- 30311472 TI - Blood Biochemical Profile in Fertile and Repeat Breeder Ongole Cross Breed Cows. AB - BACKGROUND AND OBJECTIVE: Repeat breeding is a major problem in beef cows. The objective of the present study was to determine the blood biochemical levels in repeat breeder and fertile Ongole cross breed cows. MATERIALS AND METHODS: This study compared the blood biochemical profiles from 30 repeat breeders and 30 fertile Ongole cross breed cows. Plasma glucose, total cholesterol, total protein and urea nitrogen concentrations were examined in repeat breeder cows and compared with those of fertile cows. Blood samples were collected from the caudal vein into anticoagulant-coated tubes. Cells were removed from plasma by centrifugation and blood glucose, total cholesterol and urea nitrogen concentrations were measured using commercially available kits; a non-commercial kit was used to determine total protein content. RESULTS: Significantly different blood profiles between repeat breeder and fertile cows were reported. Specifically, repeat breeder cows had lower levels of glucose, total cholesterol and total protein, but higher levels of urea nitrogen than fertile cows. CONCLUSION: Finally, a low level of total protein, total cholesterol and glucose, accompanied by a high level of urea nitrogen, may cause reproductive problems in repeat breeders. Additionally, present findings indicated that biochemical blood profiling could be used as a diagnostic tool for repeat breeding. PMID- 30311474 TI - Applicability of Different Molecular Markers Techniques for Genetic Distinguish Between Two Genera Cressa Linn. and Cuscuta Yunck. Family Convolvulaceae. AB - BACKGROUND AND OBJECTIVE: The DNA fingerprinting is used to determine the relationship between species in the same genus or between genera related to the same family. The aim of this study was to determine the relationships between two samples related to the same family Convolvulaceae, representing two genera, Cressa Linn. and Cuscuta Yunck. by RAPD, ISSR and SCoT molecular techniques (PCR based DNA fingerprint). MATERIALS AND METHODS: The RAPD, ISSR and SCoT based DNA fingerprinting techniques were implemented to identify the fingerprint diversity between two genera, Cressa Linn. and Cuscuta Yunck-belonging to the family Convolvulaceae. RESULTS: Applying of RAPD technique revealed that using OP-A02, OP-A09, OP-A10, OP-C04 and OP-M01 primers recorded 60, 83.33, 100, 50 and 70.66% polymorphism, respectively. On the other hand, ISSR technique recorded 40, 50, 100, 66.67, 33.33 and 37.5% polymorphism with 44B, HB-08, HB-09, HB-10, HB-11 and HB-12 primers, respectively. However, amplification of SCoT technique, SCoT 1, SCoT 2, SCoT 3, SCoT 4, SCoT 6, SCoT 8, SCoT 10 and SCoT 12 primers recorded 33.33, 28.57, 14.28, 66.66, 25, 40, 42.85 and 50%, respectively . The total polymorphism recorded 73.33, 54.58 and 37.7% for RAPD, ISSR and SCoT techniques, respectively. CONCLUSION: The result of this study indicated that SCoT technique was more efficient and sustainable for distinguish between two genera under investigation. PMID- 30311475 TI - Allelopathic Potentials of Artrmisia monosperma and Thymus vulgaris on Growth and Physio-Biochemical Characteristics of Pea Seedlings. AB - BACKGROUND AND OBJECTIVE: Several medicinal plants are reported as having allelochemicals potentials and favorable results have been obtained in this regard. The present investigation aimed to evaluate the effect of different concentrations of leaf aqueous extract of two medicinal plants, Artrmisia monosperma and Thymus vulgaris on growth criteria, physio-biochemical attributes and antioxidant enzyme activities of pea (Pisum sativum L.) seedlings. MATERIALS AND METHODS: Germination of pea was performed in Petri dishes under different concentrations (0, 2, 4, 6, 8 and 10%) of leaf aqueous extracts of the two medicinal plants collected from natural habitats in Saudi Arabia. At the end of experiment (10 days), the growth and physio-biochemical characteristics of pea seedlings were measured. The data were statistically analyzed by one-way ANOVA analysis of variance using SPSS program. RESULTS: Leaf aqueous extracts of A. monosperma and T. vulgaris reduced germination capability, shoot and root length, total free amino acids and proline content. Contrariwise, there was an increase in carbohydrates, proteins, K+, Ca2+ and the activity of antioxidant enzymes. Lipid peroxidation and H2O2 contents were significantly enhanced with increasing concentrations of both extracts. The highest inhibitory or stimulatory effects of leaf aqueous extract were observed at concentrations 8 and 10%. T. vulgaris was more effective than A. monosperma. CONCLUSION: This investigation indicated that the two medicinal plants had allelopathic compounds with strong potential, which may play important role in weed control and used as an alternative of chemical compounds. The aqueous extract of T. vulgaris has allelopathic potential more than A. monosperma and could be evaluated as an allelopathic species. PMID- 30311476 TI - Existence Arbuscula Mycorrhiza and Its Application Effect to Several Variety of Corn Plant (Zeal mays L.) in Marginal Dry Land. AB - BACKGROUND AND OBJECTIVE: Arbuscula mycorrhiza (AM) have a very large function in symbiosis with plant roots, it's very important to be studied further because AM utilization is an alternative solution to improve the yield of corn plant in poor land. Until now the productivity of corn plant, especially in Southeast Sulawesi, Indonesia is lower than it's genetic potential, one of the causes is the cultivation of many plant done in sub optimal land with low technology applications especially the use of organic and biological fertilizer very low. This study aimed to observe the presence of AM and evaluate the growth and productivity of corn plant that AM inoculated. MATERIALS AND METHODS: The study consisted two series of experiments, namely (1) Existence arbuscula mycorrhiza in rhizosphere of dominant weed (bladygrass) in dry land in Kendari, Southeast Sulawesi, Indonesia, was observed descriptively, (2) Effect of arbuscula mycorrhiza to several variety of corn plant (Zea mays L.) in Marginal dry land. The experiment was arranged based Randomized Block Design (RBD) consisted of eight treatments corn variety. RESULTS: The results showed that spore populations were found in rhizosphere of dominant weed was 792-901 spores 100 g-1 soil, 70 90% roots infection. Some genera found are Glomus, Gigasphora, Acaulospora, Entrophospora, Scutellospora. Symbiosis effect of arbuscula mycorrhiza with plant growth indicates that Phosphorus uptake was highest in Batu Putih variety. However the highest in yield was show in Dana variety. Compared with the lowest production, the production difference was higher in Dana 47.70%. CONCLUSION: Existence of arbuscula mycorrhiza in dominant weed rhizosphere in dry land is very high. The response of various varieties of maize plants to arbuscula mycorrhiza indicates that local varieties have a higher adaptability compared with introduction varieties. PMID- 30311477 TI - Possible Protective Role of Whey Protein on the Rat's Liver Tissues Treated with Nandrolone decanoate. AB - BACKGROUND AND OBJECTIVE: Nandrolone and whey protein are used as supplementary food and athletic food. The aim of this study was to evaluate the possible histological and ultrastructural alterations in the liver of adult rats after treatment of the anabolic androgenic steroids (Nandrolone decanoate) and whey protein. MATERIALS AND METHODS: Twenty eight Wistar Albino male rats were used in the present study divided into 4 groups: Control group received 0.5 mL of saline solution by oral, Nandrolone group injected intramuscular (10 mg kg-1 b.wt./week for 3 months), whey protein group treated by oral (5 mg kg-1 b.wt./week for 3 months) and Nandrolone and whey protein group. At the end of the experimentation, all the rats were sacrificed and liver samples were processed for histological and ultrastructural examination. Haematoxylin and eosin stains for general histological examination and Mallory trichrome stain for collagen fibers. RESULTS: Light microscopy examination of the liver of the nandrolone group showed bleeding and widening of the blood sinusoids. Degeneration, vacuolation, coagulative necrosis and pyknotic nuclei were observed. In addition, increased collagen fibers were detected. Whey protein group showed more or less normal hepatocytes, blood sinusoids and collagen fibers. The nandrolone and whey protein group illustrated normal appearance of hepatocytes with vacuolation in some of the hepatocytes and normal blood sinusoids and collagen fibers were noticed. Electron microscopic examination of the nandrolone group showed depletion of the nuclear chromatin, damaged mitochondria, increased of lysosomes, some lipid droplets, damaged blood sinusoids and space of Disse and increased of Kupffer cells, whereas the whey protein group appeared normal. The nandrolone and whey protein group showed well developed hepatocytes, regular space of Disse and normal hepatic sinusoids. CONCLUSIONS: Whey protein may be ameliorate the hepatic architecture after treatment with nandrolone. PMID- 30311478 TI - Protein Profile and Ammonia Excretion of Mud Crab Scylla serrata with Recirculation System. AB - BACKGROUND AND OBJECTIVE: Mud crabs have a high level of cannibalism so as to increase the growth of maximum mud crab and reduce the level of stress it is necessary environmental manipulation that supports it as a container maintenance with dark and bright conditions. This study aimed to determine the optimum container condition for survival and growth of mud crab by protein profile and ammonia excretion. MATERIALS AND METHODS: Mud crab derived from the fisherman Pasuruan East Java with initial weight 45-65 g kept in containers (60*40*30 cm3) in recirculation systems for 42 days with feeding trash fish restricted by 5% twice daily. The study was conducted with two treatments and three replications of bright containers and dark containers. Several stress indicators including protein retention, total serum protein, ammonia secretion were determined and growth performance of the mud crab was also evaluated. RESULTS: The dark container resulted in optimum condition for mud crab indicated by the highest survival 30+/-6%, specific growth rate 0.44+/-0.02%/day, absolute longevity 1.29+/-0.03 cm, absolute weight growth 10.5+/-0.31 g, protein retention 15.59+/ 0.46% and feed conversion ratio 6.38+/-0.27. CONCLUSION: This study concluded that better growth performance was observed in dark container for nursery of mud crabs. PMID- 30311479 TI - Effects of Aphidius gifuensis Release on Insect Communities and Diversity in Tobacco Fields of Yunnan Province, China. AB - BACKGROUND AND OBJECTIVES: The biocontrol agent Aphidius gifuensis has widely been released and applied since 1997 to control Myzus persicae in tobacco fields of Yunnan Province, southwestern China, but its ecological effects on the local insect community and diversity have not been described. Biological control agents may effect a diversity of organisms as well as the target for control but such trophic cascades have seldom been studied. This study aimed to explore the effects of A. gifuensis on the insect community and diversity in tobacco fields after long-term release and expansion of the biocontrol agent in Yunnan Province. MATERIALS AND METHODS: The effects of A. gifuensis on species composition, importance value, species richness, diversity indices and evenness index were studied for insect community samples obtained via field surveys and malaise trap collection in Yunnan Province. RESULTS: A total of 39 insect species and 1 spider, principally belonging to 40 families and 13 orders in tobacco fields of Yunnan Province were identified. Among these, there were 20 pests, 14 natural enemies and 6 others, constituting 50, 35 and 15% of total species sampled, respectively. Within insect communities, M. persicae, Empoasca flavescens and Drosophila melanogaster were the dominant species and Spodoptera litura, one unidentified species (Ichneumonidae), Sphex haemorrhoidalis, Vespa veutinaauraris, Aedes albopictus, A. gifuensis and Liriomyza huidobrensis were the subdominant species. From June to August, the relative density of A. gifuensis gradually increased and concomitantly the total relative density of other natural enemies exhibited a slight decline in July and marked increase in August. The relative density of M. persicae significantly increased in July and then declined precipitously in August. Moreover, the values of Simpson index, Shannon-Wiener index and Pielou index were greater than 0.50, 1.50 and 0.50, respectively, indicating high insect diversity. CONCLUSION: Beneficial insects, in addition to the biocontrol agent are relatively abundant in tobacco fields of Yunnan Province, marking improvement in the local insect community diversity after a long-term release of the biocontrol agent A. gifuensis, which, by land area, constitutes one of the largest natural enemy control programs in the world. PMID- 30311480 TI - Implement of Biotic and Abiotic Stress for Enhancement and Production of Capsaicin in Suspension Cultures of Capsicum annum spp. AB - BACKGROUND AND OBJECTIVE: Pepper (Capsicum annuum L.) is one of the major vegetable and spice crops grown worldwide. This study highlighted the economic and importance process for in vitro capsaicin production from pepper plant. As well as to study the effect of MS medium supplemented with 2,4-D in combinations with 0.2 mg L-1 Kin. for callus and suspension production was implemented. As well as, the influence of A. niger as biotic and methyl jasmonate as abiotic elicitors on capsaicin accumulation was investigated. MATERIALS AND METHODS: For this purpose, callus cultures were prepared from seeds of pepper and subcultured. After 28 days, calli formation (%), fresh weight (g/Jar) and dry weight (g/Jar) was calculated. Cell number and packed cell volume were calculated from their cell suspension. In the end, capsaicin was extracted and colorimetrically quantified. RESULTS: The highest percentage of calli formation was recorded with hypocotyl, leaf and root explants, respectively. The MS medium fortified with 3.0 mg L-1 2,4-D+0.2 mg L-1 Kin. In addition, the maximum P.C.V was recorded after 16 days of cultivation on the same medium. Furthermore, it was found that fortified MS medium with 1.5% of A. niger in combination with 100 MUM of methyl jasmonate achieved of cell growth parameters and capsaicin accumulation in significant rate during 16 days of cultivation. CONCLUSION: Fortified of MS medium with 3.0 mg L-1 2,4-D+0.2 mg L-1 Kin. showed the optimized medium for both callus and suspension production. Moreover, augmentation of MS medium with 1.5% of A. niger in combination with 100 MUM of methyl jasmonate enhanced of capsaicin accumulation in significant rate during 16 days of cultivation. PMID- 30311481 TI - Anticariogenic Activities of Derris reticulata Ethanolic Stem Extract Against Streptococcus mutans. AB - BACKGROUND AND OBJECTIVE: Streptococcus mutans is a dominant causative pathogen of dental caries, which is a major oral health problem affecting million people worldwide. Derris reticulata is a medicinal plant possessing antimicrobial activity against several Gram-positive pathogenic bacteria. None the less, its effects on growth and cariogenic properties of S. mutans has not been clearly established. This study aimed to investigate the antibacterial and anti cariogenic activities of the D. reticulata ethanolic stem extract. MATERIALS AND METHODS: The TLC analysis was performed to authenticate the D. reticulata sample. Minimum inhibition concentration and minimum bactericidal concentration were determined by using broth dilution and drop plate methods, respectively. Sucrose dependent and sucrose independent-adherences, biofilm formation and glycolytic pH drop assays were performed to evaluate the anticariogenic activity. RESULTS: The ethanolic stem extract of D. reticulata possessed the antibacterial activity against S. mutans with the MIC and MBC of 0.875+/-0.250 and 1.750+/-0.500 mg mL 1, respectively. The extract at the lower concentrations of sub-MIC also had significant inhibitory actions against the cariogenic properties of S. mutans, including surface adherence, biofilm formation and glycolytic acid production. CONCLUSION: The D. reticulata stem extract had a substantial anticariogenic activities and thus potentially be developed as an oral health care product for dental caries prevention in the near future. PMID- 30311482 TI - Performance of Barki Lambs Fed on Rations Containing Olive Cake with or Without Polyethylene Glycol. AB - BACKGROUND AND OBJECTIVE: Olive by-products could be a suitable alternative feedstuffs ingredient in ruminants rations. This study was carried out to evaluate effects of replacing clover hay by olive cake with or without addition of poly ethylene glycol in growing lambs ration. METHODOLOGY: Thirty five Barki lambs averaged 34 kg body weight and 5 months old were divided into 5 groups (7 animals of each) according to live weight for 90 days feeding trial. Olive cake was treated mechanically by hummer mill, screened to produce screening olive cake (treated olive cake, TOC). RESULTS: Data of dry matter and organic matter digestibility were decreased with ration containing 20% TOC from ration or 67% from clover hay comparing with others. No significant differences were observed among groups in crude protein digestibility. Total digestible nutrients (TDN) as an energy measurement for the experimental rations cleared that replacing process of clover hay by TOC up to 20% of DM intake or 67% of clover hay, given lower values (65.32 and 66.80%). The rumen pH values were not affected by the different experimental rations including control. The highest rumen NH3 was recorded with lambs fed ration containing 33% TOC without PEG instead of clover hay, while the lowest values was recorded with that group fed ration containing 33% TOC with PEG. No significant differences were detected in total gain, ADG as well as feed efficiency among the experimental rations. Dry matter intake slightly increased with feeding growing lambs on TOC containing rations except R5 compared to the control group. CONCLUSION: Summing up partially de-stoned olive cake by screening could be used in replacing clover hay for growing lamb rations, at inclusion levels up to 33 and 67% with or without poly ethylene glycol, with no adverse on performance of growing lambs. PMID- 30311483 TI - Cytological Effects of Bleaching Agent (Quneex) on Plant Cells and Plant DNA. AB - BACKGROUND AND OBJECTIVE: There have been a number of reported drawbacks and efficacy issues regarding the use of bleaching agents in the plant industry. This study was conducted to determine the cytological effects of the bleaching agent (Quneex) on the plant cells and plant DNA using the Allium cepa assay. MATERIALS AND METHODS: It was subjected sixteen root meristems of A. cepa to different concentrations of the bleaching agent (0.1, 0.2, 0.3, 0.4 and 0.5%) with different periods of time (6, 12 and 24 h). Recovery was done for 6, 12 and 24 h after exposure. RESULTS: The mitotic index significantly decreased with time and also decreased with increase in the concentration of the bleaching agent. Abnormal chromosomal changes reflecting mutagenesis including stickiness, laggards, bridges, C-metaphase, star-metaphase, binucleation, polyploidy, disturbance and multinucleation were observed in the different concentrations and periods of time. After recovery, a slow increase in the mitotic index was observed. All treatments with or without recovery for 12 and 24 h resulted in reduction in the amount of DNA. CONCLUSION: Bleaching agents similar to Quneex containing sodium hypochlorite have mutagenic properties that can be potentially hazardous to the environment and also to humans. Thus, there is a need to regulate the use and disposal of such chemicals into the environment particularly to the sewers, to prevent contamination of potable water, plant and biodiverse aquatic animals. PMID- 30311484 TI - Taxonomic Importance of Pollen Morphology for Some Species of Brassicaceae. AB - BACKGROUND AND OBJECTIVE: Pollen morphology is one of the significant tools in solving some taxonomic problems on the family, generic or specific level and has become part of the multidisciplinary and collaborative approach in plant systematic and evolution. Therefore, this study aimed to investigate and describe the pollen morphology of 10 species belongs to 9 genera and five tribes of Brassicaceae from eastern region of Saudi Arabia by using light and scanning electron microscope. MATERIALS AND METHODS: To study the pollen morphology for ten species representing 9 genera and 5 tribes of Brassicaceae the Light Microscope (LM) and Scanning Electron Microscope (SEM). For the SEM the pollen was placed directly on brass stubs without treatment and mounted onto a metallic stub with a double-sided adhesive tape. Gold coating of few nanometers was applied using sputter coating machine (Quorum, Q150R ES, UK) to avoid charging and capture high quality images. Two statistical program; PRIMER 6, version 6.1.6 and SPSS version 16are used to fine the relationships among the studied species. RESULTS: The shape of pollen grains recorded three types; prolate, subprolate and prolate-spheroidal, the main types were prolate. The apertures were tricolpate in all studied species. Exine ornamentation of studied species recorded two types; reticulate and coarsely reticulate. The results of numerical analysis showed that species were grouped into two major clusters and each cluster divided into two groups. CONCLUSION: The results show that the morphology of pollen grains cannot be useful for taxonomical classification of the tribes but can be useful for differentiate between species belong to the same genera. PMID- 30311485 TI - Line*Tester Analysis of Heterosis and Combining Ability in Tomato (Lycopersicon esculentum Mill.) Fruit Quality Traits. AB - BACKGROUND AND OBJECTIVES: Quality of vegetable and fruit crops play an important role for economical use of resources by the consumers. Among the various vegetable crops, tomato is used in different forms such as fresh and for the preparation of different byproducts. The main objective of this study was to carry out line and tester analysis of heterosis and combing ability of tomato fruit traits. MATERIALS AND METHODS: The present study was carried at Agricultural and Veterinary Training and Research Station, King Faisal University, Al-Ahsa, Saudi Arabia during 2012 and 2014. The experimental material consisted of F1 population developed by crossing five lines of tomato viz., K10 (L1), TY197 (L2), RAM2 (L3), S. Mar (L4) and Lian (L5) with 2 testers, namely Sultan7 (T1) and Castle Rock (T2) manually. The experiment was laid out by following the Randomized Complete Block Design (RCBD) with three replications. RESULTS: The cross 1*4 proved the best for fruit length, diameter, firmness and weight; 1*7 for number of locales; 2*4 for TSS and the lowest fruit thickness over mid-parents. The variance values of general combining ability (GCA) were higher than the specific combining ability (SCA) for all the traits except the fruit thickness. While, additive and none additive components were similar in fruit thickness. CONCLUSION: The SCA effects showed that the cross 1*4 was the best in fruit weight, 1*6 in firmness, 2*3 in fruit diameter and weight, 2*5 in number of locales, 2*6 in fruit thickness and 2*7 in TSS. The magnitude of additive variance was more pronounced for all the seven characters of interest of fruit quality both when F = 0 and F = 1 except for fruit thickness. The presence of excess additive variance was confirmed by the study results for most of the investigated traits of tomato crop. The study findings indicated the improved lines and testers for histerosis analysis for cross pollination to obtain improved tomato high quality and high yielding cultivars. PMID- 30311486 TI - Microbiota of Honeybees, Apis mellifera Adansonii (Hymenoptera: Apidae) from Selected Ecozones, South West Nigeria. AB - BACKGROUND AND OBJECTIVES: Honeybees explore their environment in search of nectar and pollens including water whose sources are contaminated by variety of microbes. This has both negative and positive economic implications on health status of honeybees, the consumers of the products including the quality of the products. Hence, the study was designed to investigate the effect of geographical locations on the occurrence and diversity of microbiota on the external integument and the digestive gut of adult worker honeybees, Apis mellifera adansonii. MATERIALS AND METHODS: The honeybee samples were sourced from Ondo, Ogun, Oyo and Osun of South West Nigeria. The samples were subjected to microbiological analyses using standard techniques. Two-ways ANOVA was used for statistical test of the data. RESULTS: The microbiota of the studied samples includes Corynebacterium kutsceri, Corynebacterium xerosis, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Micrococcus luteus, Micrococcus varians and Staphylococcus aureus which were gram-positive bacteria, while gram-negative bacteria include Aeromonas veronii, Citrobacter diversus, Citrobacter freundii, Klebsiella oxytoca, Klebsiella pneumonia and Pseudomonas aeruginosa. Fungi isolates include Aspergillus parasiticus, Aspergilus flavus, Aspergilus fumigatus, Aspergilus niger and Rhizopus stolonifer. Most microbiota were not cosmopolitan across selected ecozones of south west, Nigeria except for Aspergillus fumigatus. The number of identified species of microbiota either in the digestive guts or on the external integument of worker honeybees from selected ecozones varies from one ecozone to another. There was significant species diversity of microbiota on external integument than in digestive guts of adult workers of A. mellifera adansonii from selected ecozones in South West, Nigeria. CONCLUSION: The study showed that both the external integument and the digestive guts of A. mellifera adansonii exhibited variety of microbial flora providing research exploration opportunity for probable microbes of economic and geographical importance. PMID- 30311487 TI - Prevalence of Ochratoxin A in Poultry Feed and Meat from Jordan. AB - BACKGROUND AND OBJECTIVE: Ochratoxin A (OTA) is a fungal metabolite produced in feed and could be transmitted to food chain through animal and considered as one of the potent carcinogenic compound. This study aimed to evaluate the levels of Ochratoxin A in both poultry feed and meat in Jordan. MATERIALS AND METHODS: About 129 samples representing feed, corn and poultry meat were collected from different location of Jordan market and evaluated for Ochratoxin A by ELISA. RESULTS: About 38.5% of feed sample, 50.0% of corn sample, 100.0% of feed sample found under sun light were containing an Ochratoxin A (OTA) with an average concentration of 2.90+/-0.26, 2.35+/-0.32, 10.30+/-0.59 MUg kg-1, respectively. Also the results showed that between 66.0% (12 sample) to 100.0% (54 sample of the analyzed organs meat sample contains OTA with a concentration ranging from 1.89+/-0.07-7.68+/-0.12 MUg kg-1. CONCLUSION: The results indicated that none of the tested samples exceeded the maximum limit set by the EU limits of <50.0 ng km 1 in poultry feeds. PMID- 30311488 TI - Association Mapping for Flowering Time and Moisture Loss of Grains in Maize Tropical Germplasm. AB - BACKGROUND AND OBJECTIVE: With the advent of high-scale genotyping platforms, association studies have become important tools for finding genomic regions of interest in breeding programs, due to the fact that their improved more accuracy than the other tools. The aim of this work was to map genomic regions associated with grain maturation in common maize strains. MATERIALS AND METHODS: For linkage disequilibrium mapping, 72 strains were previously genotyped for SNP markers on the 650K platform and their respective genotypic values were predicted for male and female flowering and area below the moisture curve. The analysis of association between the SNPs markers and the characters was performed using mixed linear model and stepwise multiple regression. RESULTS: The significant associations detected for male and female flowering were found to be distributed in all chromosomes, with a higher concentration in genomic regions of chromosomes 1, 2, 3, 5, 9 and 10. For the area below the moisture curve, it was found a smaller number of significant associations, being concentrated in the chromosomes 1, 2, 3, 6, 9 and 10 and absent in chromosomes 4 and 8. By stepwise analysis, it obtained complete models that account for 79, 93 and 56% of the variation for the genotypic values, respectively, with the identification of genomic regions pre dominantly on chromosomes 1 and 3. CONCLUSION: Thus, the detection of similar and distinct genomic regions for these traits, reveals the potential for the use of significant associations detected in chromosomes 1 and 3 to obtain the germplasm maturity required in breeding programs. PMID- 30311489 TI - Molecular Identification and Sequencing of Mycoplasma gallisepticum Recovered from Broilers in Egypt. AB - BACKGROUND AND OBJECTIVES: Avian mycoplasmosis, particularly Mycoplasma gallisepticum (MG) is one of the infectious diseases associated with economic losses in Egyptian poultry industry. Thus, this study was aimed to determine the prevalence, serological identification, molecular characterization, sequencing and minimum inhibitory concentration of M. gallisepticum isolated from diseased broilers in Egypt. MATERIALS AND METHODS: A total of 351 samples (227 tissue samples "tracheas and air sacs" and 124 tracheal swabs) and 71 sera were collected from diseased broilers. The conventional (isolation and biochemical) and molecular methods (PCR) were performed for detection of M. gallisepticum and virulence-associated gene (mgc2). The serum plate agglutination (SPA) test and enzyme-linked immunosorbent assay (ELISA) were applied on sera for determination of the presence of antibodies against M. gallisepticum. The minimal inhibitory concentration test (MIC) was used to determine the sensitivity of two sequenced M. gallisepticum strains to anti-mycoplasma agents. RESULTS: The total recovery rate of Mycoplasma from 351 samples from broilers was 45.29% (159) in which M. gallisepticum showed a prevalence of 62.89% (100/159). Serological identification of M. gallisepticum in 71 collected sera using SPA and ELISA were 54.9 and 40.8% with the highest geometric mean titer of ELISA for M. gallisepticum (699.08 and 495.92). Molecular characterization of Mycoplasma using PCR showed that 50% (3/6) of tested isolates were identified as M. gallisepticum based on 16SrRNA. Also, the mgc2 gene was detected in 50% (3/6) M. gallisepticum isolates. Two positive PCR mgc2 specific genes of M. gallisepticum isolates were subjected to gene target sequencing (GTS) to verify that these two isolates were M. gallisepticum. The minimal inhibitory concentration test (MIC) was applied to determine the sensitivity of these two sequenced M. gallisepticum strains to anti-mycoplasma agents. The first M. gallisepticum isolate was sensitive to tilmicosin, tiamulin and spiramycin. The second M. gallisepticum isolate showed sensitivity to tiamulin, spiramycin and tilmicosin. CONCLUSION: These results summarized the necessity of monitoring the Egyptian poultry farms for avian mycoplasmosis. Also, further studies are required for controlling of mycoplasma in all stages of the poultry industry production chain to avoid different losses in Egypt. PMID- 30311490 TI - Timed up-and-go and 2-minute walk test in patients with multiple sclerosis with mild disability: reliability, responsiveness and link with perceived fatigue. AB - BACKGROUND: Mobility limitations are frequent in patients with multiple sclerosis (MS), and could already be present in patients with so-called mild neurological disability (Expanded Disability Status Scale<=4). Assessing mobility in these patients is therefore of paramount importance. Timed upand- go test (TUG) and 2 minute walk test (2MWT) are two clinically feasible tests which reliability and responsiveness are unknown among these patients. Whether fatigue, which is the number one symptom among these patients, is linked to these limitations remains unknown. AIM: To explore the intrarater reliability and minimal detectable change (MDC95), as an index of responsiveness, of TUG and 2MWT. To explore their link with perceived fatigue among patients with multiple sclerosis (MS). DESIGN: Cross sectional observational study, including two measures. SETTING: Two university hospital outpatient centers. POPULATION: Patients (N=63, 49 seen twice) with MS with mild disability (Expanded Disability Status Scale<=4). METHODS: 2MWT and TUG were performed twice in one occasion and repeated 2 weeks later. Modified fatigue impact scale (MFIS) was used to assess fatigue. Intraclass coefficient correlations were calculated for immediate and 2-week reliability. MDC95 were computed. Correlations between mobility indices and fatigue were explored using Spearman's rho. RESULTS: Mobility was impaired in comparison to normative values (2MWT: -4.9% from normative distance; TUG: +32% from normative time). The immediate reliability was excellent for both the 2MWT (ICC=0.98) and TUG (ICC=0.98). Reliability at 2 weeks was excellent for 2MWT (ICC=0.95) and very good for TUG (ICC=0.90). MDC95 were respectively 20m (2MWT) and 1.3s (TUG). Both measures were significantly weakly correlated to total MFIS (rho=-0.37 and 0.39, respectively; p<0.01). CONCLUSIONS: The 2MWT and TUG are highly reliable and responsive in the assessment of respectively the walking capacity and general mobility of patients with MS with mild disability. Mobility impairments are linked to perceived fatigue among these patients. CLINICAL REHABILITATION IMPACT: TUG and 2MWT are easy to administer and could be reliably used in so called mildly disabled patients with MS to assess mobility limitation. PMID- 30311491 TI - Is virtual reality effective in improving the motor performance of children with developmental coordination disorder? A systematic review. AB - INTRODUCTION: Although virtual reality (VR) is an increasingly popular approach within studies that propose interventions for children with developmental coordination disorder (DCD), evidence on the effectiveness of VR remains debatable. The aim of this study was to synthesise evidence on the effectiveness of VR interventions for motor performance improvement in children with DCD. EVIDENCE ACQUISITION: Searches were conducted in the MEDLINE/PubMed, Scopus, Web of Science and ERIC databases to select studies published from 1 January 2006 to 30 November 2017. Two independent reviewers performed the primary study selection based on titles, abstracts and full-text reading; this selection included randomised controlled trials (RCTs) that applied VR interventions to children with DCD and assessed outcomes related to motor performance. The methodological quality of the studies included in the search was assessed through the PEDro scale. PRISMA guidelines and Cochrane recommendations for systematic reviews were followed. The effect size of each intervention was calculated to allow for the interpretation of clinical effects, and the body of evidence was synthesised through the GRADE approach. EVIDENCE SYNTHESIS: A total of 2,160 publications were retrieved; by the end of the selection process, twelve RCTs had been included. Of these twelve, seven were classified as having high methodological quality. Only three studies satisfied the homogeneity conditions to be assessed through the GRADE system, which showed a low level of evidence in favour of VR for improving the motor performance of children with DCD. CONCLUSIONS: Not enough evidence currently exists to support or refute the use of VR over non-VR interventions for improving motor performance in children with DCD. Despite the potential for improving the motor performance of DCD children, the absence of specific protocols prevents formal recommendations of VR for these children. Future studies should consider VR protocols that are more specific regarding the tasks, features and target motor skills to be developed by DCD children. In addition, comparisons of similar groups at baseline, the concealment of allocation and the blinding of assessors are internal validity aspects which deserve researchers' attention. PMID- 30311492 TI - Comparison of three scales to evaluate personality traits in Parkinson's disease: which one to use? AB - BACKGROUND: Personality traits have gained interest in the field of disability and stress, because they may either prompt or deny compliance. They can also foster motivation and influence outcome. Parkinson disease (PD) is a disabling and stressful condition that requires coping strategies and rehabilitation plans. Three constructs and their relative scales have been a matter of investigation, namely Dispositional Optimism (DO), Locus-of-Control (LOC), and Sense-of- Coherence (SOC). AIM: The present study compared the psychometric properties of three constructs in Parkinson's Disease (PD). The health-related variables were: Emotional Distress (ED), Quality of Life (HR- QoL) and Activities of Daily Living (ADL). The final objective was to provide guidance on scale selection to be implemented in clinical protocols. DESIGN: A cross sectional study. SETTING AND POPULATION: Participants with PD (n =84) from community-based general physicians. METHODS: PD patients completed 3 self-report scales, namely Life Orientation Test -Revised (LOT-R, measuring Dispositional Optimism), Internal and External Locus Of Control (LOC-int. LOC-ext) and Sense of Coherence (SOC). All participants had Magnetic Resonance Imaging. The MDS-UPDRS and the Barthel scale were compiled by the investigator with the assistance of a caregiver. RESULTS: LOC-ext was the only scale to be associated with PD severity and disability (P<0.05). A higher level of LOC-ext was also associated with a higher level of ED (p<0.005). LOT-R was inversely associated with ED. Subjects in the highest tertile had a 41% lower ED (p<0.001). SOC was also inversely associated with degree of ED. Subjects in the highest tertile have a 44% lower ED (P<0.01). Moreover, HR-QoL is associated with several parameters, but LOT-R is the one with the strongest association (P<0.001). CONCLUSIONS: DO and SOC are predictive of important end-points, namely HR-QoL and ED. DO is even better under this respect. Conversely, those clinicians who are more interested in motor problems may find LOC more suitable. DO may be the most efficient construct to use in PD because of its favorable psychometric properties. CLINICAL REHABILITATION IMPACT: DO, LOC and SOC are constructs to be implemented in both research and clinical PD protocols. It is recommended to implement these, because they have predictive value especially when HR-QoL and ED are studied. PMID- 30311493 TI - Inertial sensors versus standard systems in gait analysis: a systematic review and meta-analysis. AB - INTRODUCTION: The increasing popularity of inertial sensors in clinical practice is not supported by precise information on their reliability or guidelines for their use in rehabilitation. The authors investigated the state of the literature concerning the use of inertial sensors for gait analysis in both healthy and pathological adults comparing traditional systems. Furthermore, trying to define directions for clinicians. EVIDENCE ACQUISITION: In accordance with the PRISMA statement, authors searched in PubMed, Web of Science and Scopus all paper published from January 1st, 2005 until December 31st, 2017. They included both healthy and pathological adults' subjects as population, wearable or inertial sensors used for gait analysis and compared with classical gait analysis performed in a Motion Lab as intervention and comparison, gait parameters as outcomes. Considering the methodological quality, authors focused on: sample; description of the study; type of gait analysis used for comparison; type of sensor; sensor placement on the body; gait task requested. EVIDENCE SYNTHESIS: From a total of 888 articles, 16 manuscripts were selected and 7 of them were considered for meta-analysis for different gait parameters. Demographic data, tested devices, reference systems, test procedures and outcomes were analyzed. CONCLUSIONS: Our results show a good agreement between inertial sensors and classical gait analysis for some gait parameters, supporting their use as a solution for capturing kinematic information over an extended space and time and even outside a laboratory in real-life conditions. Authors can support the use of portable inertial sensors for a practical gait analysis in clinical setting with good reliability. It will then be the experience of the clinician to direct the decision-making process. PMID- 30311495 TI - ? PMID- 30311494 TI - Treatment of fractured maxillary anterior teeth in the young patient with Cerec composite partial veneers. A case report AB - Children with attention-deficit hyperactivity disorder ADD/ ADHD are often difficult to be treated. If the anterior teeth have to be treated in case of trauma, the patient and the therapist quickly come to their limits. In the present case, with the help of the Cerec and composite partial veneers, an attempt was made to divide the treatment into two relatively short treatment periods for the patient. The two phases were interrupted by a longer construction and grinding phase. The composite partial veneers showed acceptable aesthetics. The patient and the parents experienced the three-phase Cerec treatment as very pleasant and less stressful than other treatments, and were highly satisfied with the restorations. A long-term prognosis cannot be made at the present time, the clinical studies are missing. PMID- 30311496 TI - Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling post myocardial infarction in rats. AB - Exercise training is beneficial for preserving cardiac function post myocardial infarction (MI), but the underlying mechanisms are not well understood. We investigated one possible mechanism, brain-derived neurotrophic factor (BDNF) tropomyosin-related kinase B (TrkB) signaling with the TrkB blocker, ANA-12 (0.5 mg/kg/day). Male Wistar rats underwent sham surgery or ligation of left descending coronary artery. Surviving MI rats were allocated to sedentary MI with vehicle (Sed-MI-Veh), exercise MI with vehicle (ExT-MI-Veh) and exercise MI with ANA-12 (ExT-MI-ANA-12). Exercise training was done 5 days/week for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated by echocardiography and Millar catheter. Mature BDNF (mBDNF) and downstream effectors of BDNF-TrkB signaling, Ca2+/calmodulin dependent protein kinase II (CaMKII), Akt and adenosine monophosphate-activated protein kinase (AMPK), were assessed in the non infarct area of the LV by Western blotting. Exercise training increased stroke volume (SV) and cardiac index, and attenuated the decrease in ejection fraction (EF) and the increase in LV end-diastolic pressure (LVEDP) post MI. ANA-12 blocked the improvement of EF and attenuated the increases in SV and cardiac index, but did not affect LVEDP. Exercise training post MI prevented decreases in mBDNF, phosphorylated CaMKII (p-CaMKII), p-Akt and p-AMPKalpha expression. These effects were all blocked by ANA-12 except for p-AMPKalpha. In conclusion, exercise-induced improvement of EF is mediated by the BDNF-TrkB axis and downstream effectors CaMKII and Akt. BDNF-TrkB signaling appears to contribute to the improvement in systolic function by exercise training. PMID- 30311497 TI - Development of an Instrument to Assess Work Productivity in Individuals With Voice Disorders: The Work Hoarse. AB - OBJECTIVES: Vocal function is critical to employability in the modern era. Although research clearly demonstrates that a disordered voice affects quality of life, few studies have attempted to quantitate the effects of a disordered voice on work productivity. The Voice-Related Statements battery, which originally had 20 items, was previously developed to qualitatively describe how an individual's dysphonia affects his or her job performance. The aim of this study was to refine and reduce the item number and provide preliminary validation of this shortened instrument. METHODS: The Voice-Related Statements instrument was administered to employed patients with dysphonia in conjunction with 2 additional instruments: the Voice Handicap Index (VHI) and the Work Productivity and Activity Impairment questionnaire (WPAI). Response distributions and intercorrelations were examined for item reduction. Exploratory factor analysis was conducted on retained items. Correlations were performed with other voice-related instruments. Reliability was tested using a coefficient of stability. RESULTS: One hundred seventy-four employed patients with dysphonia were enrolled in this study. Six items were removed because of redundancy, factor analysis, and cognitive interview results. Exploratory factor analysis revealed a 1-factor structure explaining 66.28% of the total variance. The final 8-item instrument demonstrated good internal consistency (Cronbach alpha = 0.93), with a moderately robust correlation with the VHI ( r = 0.68, P < .001) and WPAI work impairment measures ( r = 0.63, P < .001). The VHI showed a much weaker correlation with WPAI work impairment ( r = 0.48, P < .001). Test-retest reliability was good (0.83, P < .01). CONCLUSIONS: An 8-item instrument to qualitatively measure the impact of a disordered voice at work has been developed and is called the Work Hoarse. This instrument is a better measure of voice-related work productivity impairment than the VHI and will augment quantitative work productivity instruments that are currently available. PMID- 30311498 TI - Paradoxical Arteriole Constriction Compromises Cytosolic and Mitochondrial Oxygen Delivery in the Isolated Saline-Perfused Heart. AB - The isolated saline-perfused heart is utilized extensively to study cardiac physiology. Previous isolated heart studies demonstrated lower tissue oxygenation than in vivo based on myoglobin oxygenation and mitochondria redox state. These data, consistent with small anoxic regions, suggest that the homeostatic balance between work and oxygen delivery is impaired. We hypothesized these anoxic regions are caused by inadequate local perfusion due to a paradoxical arteriole constriction (PAC) generated by a disrupted vasoregulatory network. We tested this hypothesis by applying two exogenous vasodilatory agents, adenosine and cromakalim, to relax vascular tone in an isolated, saline-perfused, working rabbit heart. Oxygenation was monitored using differential optical transmission spectroscopy and full spectral fitting. Increases in coronary flow over control with adenosine (27 +/- 4 mL/min) or cromakalim (44 +/- 4 mL/min) were associated with proportional spectral changes indicative of myoglobin oxygenation and cytochrome oxidase (COX) oxidation consistent with a decrease in tissue anoxia. Quantitatively, adenosine decreased deoxymyoglobin optical density across the wall by .053 +/- .008 OD while the reduced form of COX was decreased by .039 +/- .005 OD. Cromakalim was more potent decreasing deoxymyoglobin and reduction level of COX by .070 +/- .019 OD and .062 +/- .019 OD, respectively. These effects were not species specific as Langendorff perfused mouse hearts treated with adenosine demonstrated similar changes. These data are consistent with PAC as a major source of regional anoxia during saline heart perfusion. We suggest that the vasoregulatory network is disrupted by the washout of interstitial vasoactive metabolites, in vitro. PMID- 30311499 TI - Factors affecting the decision to initiate antiretroviral therapy in the era of treatment-as-prevention: synthesis of evidence from qualitative research in high income settings. AB - The emergence of treatment-as-prevention has made early initiation of antiretroviral treatment (ART) a "universal" policy. This review synthesizes qualitative research findings on barriers and facilitators of ART initiation in Organization for Economic Co-operation and Development (OECD) countries published since 2010. Ten articles describing seven research studies were included in the review. Findings confirmed ART initiation as a complicated process involving careful deliberation of the personal risks and benefits of treatment within the broader contexts of everyday life for people living with HIV (PLHIV). They also highlight interpersonal dynamics and concern for the public as increasingly important factors in shaping the decision to initiate treatment. The review provides valuable information for understanding treatment behaviour and maximizing treatment options brought forth by new biomedical advances. PMID- 30311500 TI - Effect of Polydeoxyribonucleotide on Angiogenesis and Wound Healing in an In Vitro Model of Osteoarthritis. AB - Osteoarthritis (OA) is degenerative disease, leading to pain and functional disability. It is reported that polydeoxyribonucleotide (PDRN) is a suitable therapy for OA. However, the therapeutic mechanisms of PDRN in OA are not fully understood. To investigate the effect of PDRN in an in vitro model of OA, interleukin (IL)-1beta or phosphate-buffered saline (PBS) was used to treat a human chondrocytic cell line in hypoxic conditions for 24 h (IL-1beta group or control group). PDRN was then used to treat IL-1beta group cells for 24 h (PDRN group). By Label-Based Human Antibody Array 1000, angiopoietin-2 (ANG-2), platelet-derived growth factor (PDGF), angiostatin, and endostatin, which were related to angiogenesis, were chosen for further validation studies. Quantitative real-time reverse transcription polymerase chain reaction and western blot analysis validated that the levels of PDGF and ANG-2, which were related to pro angiogenesis, were significantly increased in the PDRN group compared with those in the control group or the IL-1beta group. However, the levels of endostatin and angiostatin, which were related in anti-angiogenesis, were significantly decreased in the PDRN group compared with those in the control group or the IL 1beta group. In the same manner, vascular endothelial growth factor, which was a mediator of angiogenesis, was significantly increased in the PDRN group compared with those in the control group or the IL-1beta group. Furthermore, wound closure was significantly increased in the PDRN group compared with the control group or the IL-1beta group by in vitro scratch assay. Moreover, PDRN decreased expression of metalloproteinase 13, as a catabolic factor for OA, but increased expression of aggrecan, which was an anabolic factor for OA. These data suggest that PDRN may promote angiogenesis and wound healing via down-regulation of catabolism and up-regulation of anabolism in an in vitro model of OA. PMID- 30311501 TI - Exosomes Derived from IDO1-Overexpressing Rat Bone Marrow Mesenchymal Stem Cells Promote Immunotolerance of Cardiac Allografts. AB - BACKGROUND: The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance. METHODS: Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips. RESULTS: Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL 1, miR-540-3p, and a downregulation of miR-338-5p. CONCLUSION: Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts. PMID- 30311502 TI - Inactivation of Pseudomonas aeruginosa biofilms formed under high shear stress on various hydrophilic and hydrophobic surfaces by a continuous flow of ozonated water. AB - The inactivation of Pseudomonas aeruginosa biofilms grown on glass under high shear stress and exposed to a range of dissolved ozone concentrations (2, 5 and 7 ppm) at 10 and 20 min was investigated. The regression equation, log reduction (biofilm) = 0.64 + 0.59*(C - 2) + 0.33*(T - 10), described the dependence of biofilm inactivation on the dissolved ozone concentration (C, ppm) and contact time (T, min). The predicted D-values were 11.1, 5.7 and 2.2 min at 2, 5 and 7 ppm, respectively. Inactivation of biofilms grown on various surfaces was tested at a single dissolved ozone concentration of 5 ppm and a single exposure time of 20 min. Biofilms grown on plastic materials showed inactivation results similar to that of biofilms on glass, while biofilms grown on ceramics were statistically significantly more difficult to inactivate, suggesting the importance of utilizing non-porous materials in industrial and clinical settings. PMID- 30311503 TI - Structural and in vitro in vivo evaluation for taste masking. AB - INTRODUCTION: Although many techniques, such as complexation and microencapsulation, are used to mask the unpleasant taste of drugs, the success of all masking processes is evaluated in the same way. To evaluate the success of a masking process, a masked formulation must pass two tests: a structural test and an in vitro in vivo test. Areas covered: This review article highlights structural evaluation and in vitro in vivo evaluation of a taste-masking process. The structural evaluation has two criteria: the absence of any chemical interaction between the drug and the masking agent and the molecular distribution of drug in the network of masking agent. The in vitro in vivo section can be verified by electronic tongues, dissolution test, and volunteers and it should confirm that the final product, after applying the masking process, will have a lower rank in terms of taste. Expert opinion: This critical review helps researchers and industrial partners to evaluate a taste-masking process in a systematic way, leading to better understanding of taste-masking process and consequently improving the efficiency of masked dosage forms while hindering the unpleasant taste of drugs. This will ultimately improve the quality of life of many patients. PMID- 30311504 TI - The Self-Efficacy of Certified Athletic Trainers in Assessing and Managing Sport Related Concussions. AB - CONTEXT: : Diagnostic and return-to-play assessments of athletes with sport related concussions (SRCs) have changed dramatically over the past decade. Currently, SRC assessment and management has taken a multifaceted approach, with new SRC measures being developed yearly. However, to date, no researchers have examined certified athletic trainers' (ATs') self-efficacy in assessing and managing a patient with an SRC. OBJECTIVE: : To examine the self-efficacy of ATs in assessing and managing athletes with SRCs, with a secondary purpose of examining job setting (high school and college). DESIGN: : Cross-sectional study. SETTING: : Web-based questionnaire. PATIENTS OR OTHER PARTICIPANTS: : A total of 94 ATs (high school setting = 54.3%, n = 51; collegiate setting = 45.7%, n = 43) completed an online survey, for a response rate of 9.2%. MAIN OUTCOME MEASURE(S): : The survey contained 3 primary subsections: demographics, self-efficacy in assessing SRCs, and self-efficacy in managing SRCs. Possible self-efficacy ratings for SRC assessment and management in the survey ranged from 0 to 100. Multivariate analyses of variance were performed to identify differences in the self-efficacy of high school and collegiate ATs in assessing and managing athletes with SRCs. RESULTS: : The self-efficacy of all 94 participants in their assessment of SRCs was 60.34 +/- 14.5 and in their management of SRCs was 55.30 +/- 14.1. Collegiate ATs reported higher self-efficacy in the assessment of SRCs using balance ( P < .001) and the King-Devick test ( P = .04), and their responses approached significance for vestibular-ocular motor screening ( P = .05). Additionally, their self-efficacy in the management of SRCs was greater using balance ( P < .001) and vestibular-ocular therapy ( P = .01) compared with high school ATs. CONCLUSIONS: : Athletic trainers had moderate self-efficacy regarding their assessment and management of SRCs. Collegiate ATs had higher self efficacy in newer SRC assessment and management tools than high school ATs. PMID- 30311505 TI - Comparison of Sino-Nasal Outcome Test 22 Symptom Scores in Rhinogenic and Odontogenic Sinusitis. AB - Background Odontogenic maxillary sinusitis (OMS) and rhinogenic sinusitis (RS) are the main types of chronic rhinosinusitis (CRS) and have a significant impact on health-related quality of life (HRQL), but the difference in HRQL and symptom presentation between them has not been specifically evaluated to date. Obejctive: Our aim was to compare patterns of symptoms and HRQL disease-specific domains in patients affected with these 2 types of CRS. Methods A group of 201 patients with CRS (99 with rhinogenic and 102 with odontogenic origin) completed the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire before treatment. Data sets were analyzed by using principal component analysis (PCA) to identify a set of symptom components together with the items excluded from PCA, which were then analyzed for differences between patients with OMS and RS. Results PCA of SNOT-22 items identified 5 components: "rhinologic," "extranasal rhinologic," "ear/facial," "sleep and functional disturbance," and "emotional disturbance." Sneezing was excluded from PCA and treated as separate outcome variable and was significantly worse in RS patients. Patients with OMS scored significantly higher scores with regard to emotional disturbance, while RS patients scored significantly worse in sleep and functional disturbance. The extra symptom "malodor" was the most different symptom and was significantly worse in OMS patients. The total SNOT-22 score was not significantly different between the groups. Conclusion With controlling of covariates that may influence the severity of the disease, this study showed some significant differences in symptom patterns and HRQL impairment between patients with OMS and RS. Malodor is the most characteristic feature of OMS. Therefore, OMS should always be suspected in patients complaining of bad breath. PMID- 30311506 TI - Materialising links between air pollution and health: How societal impact was achieved in an interdisciplinary project. AB - Societal impact is an increasingly important imperative of academic funding. However, there is little research to date documenting how impact is accomplished in practice. Drawing on insights from Actor-Network Theory, we explore the research-policy interface within an interdisciplinary research project on the relationships between air pollution and human health. Health policy impact was important to the researchers for moral as well as pragmatic reasons but it was a goal that was seen as potentially in tension with that of doing science. In fields such as air pollution and health, networks of policymakers and researchers are inevitably entangled, and we found that processes of engagement operated to delineate science from policy. Health was initially black-boxed and under explicated, used as a signifier in itself for societal impact. By mobilising networks of policy actors, brought together in workshops to rank the importance of policy scenarios for the research team, the connections between air pollution and health were materialised and made actionable. This was achieved by framing existing data sets, emission technologies, policy expertise, pollutant species and human health in particular ways and, in doing so, excluding others. The process of linking air pollution and health research to achieve societal impact not only influenced how these phenomena were known but, critically, enabled and constrained potential policy responses. Tracing these research arrangements made the material discursive processes of 'impact' visible and analysable as objects of social science scholarship, and therefore generated a productive site for critically engaging with processes of environment and health science and policy. PMID- 30311507 TI - Testing for comorbid conditions among people with HIV in medical care. AB - People living with HIV (PLWH) are frequently affected by comorbid medical conditions. Despite the importance of diagnosing and treating these conditions, testing rates for common comorbidities often fall short of primary care recommendations for PLWH. Clinical care data were obtained from the 2012 New York City (NYC) Medical Monitoring Project (MMP), a multi-site surveillance project that includes demographically representative cohorts of PLWH receiving medical care. Medical record abstraction data were analyzed to determine testing frequencies for potential comorbid conditions, including tuberculosis, hepatitis B and C, diabetes, syphilis, gonorrhea, and chlamydia, and to assess demographic, behavioral, and clinical factors associated with testing. Among the NYC MMP cohort (N = 439), testing frequencies ranged from 18% for hepatitis B to 66% for diabetes in a 12-month period. In multivariate analyses, having three or more medical visits with a CD4 or HIV viral load test over 12 months was significantly associated with sexually transmitted infection (STI) and hepatitis C testing. Compared with Black PLWH, Latino/Hispanics were more likely to be tested for hepatitis C and Whites were less likely to be tested for diabetes. Self-reported sexual risk behaviors were not associated with testing for STI, and history of injection drug use was not associated with testing for hepatitis C. These results indicate a need for improved risk assessment, adherence to clinical guidelines, and integration of primary care services with HIV care. PMID- 30311508 TI - RE: 'evaluation of ureteral lesions in ureterorenoscopy: impact of access sheath use'. PMID- 30311509 TI - Alienation and beauty in medical photography. AB - Though photography was initially touted to overtake medical illustration as a more objective medium, today photographs are underused in medical texts. The concern with aesthetics and the relationship between the body and the patient combined to shape the future of medical photography, and in some ways medicine itself. Closely examining two cases - Duchenne's 'Mecanisme de la Physionomie Humaine' (1856), and Grant's 'An Atlas of Anatomy' (1962) - I consider the role of alienation and beauty in medical photography and the evocative questions each raised in medical history. This is adapted from a talk given at RCPE. PMID- 30311510 TI - Novel Homozygous Deletion in STRADA Gene Associated With Polyhydramnios, Megalencephaly, and Epilepsy in 2 Siblings: Implications for Diagnosis and Treatment. AB - Mutations in the STE20-related kinase adaptor alpha ( STRADA) gene have been reported to cause an autosomal recessive neurodevelopmental disorder characterized by infantile-onset epilepsy, developmental delay, and craniofacial dysmorphisms. To date, there have been 17 reported individuals diagnosed with STRADA mutations, 16 of which are from a single Old Order Mennonite cohort and share a deletion of exons 9-13. The remaining individual is of consanguineous Indian descent and has a homozygous single-base pair duplication. We report a novel STRADA gene deletion of exons 7-9 in 2 sisters from nonconsanguineous parents, as well as an improvement in seizure control in 1 sibling following treatment with sirolimus, an m-Tor inhibitor of potential benefit to patients with this genetic mutation. PMID- 30311511 TI - Psychopathy and Perception of Vulnerability to Criminal Victimization. AB - This study replicates and extends prior research indicating that individuals with elevated psychopathic traits are better able to identify vulnerability to criminal victimization. Specifically, the current study aims to further assess this finding, examine if criminal experience aids in the assessment in vulnerability to criminal victimization, and determine if the finding generalizes to females and non-Caucasians. Through an online survey, participants (undergraduate students; n = 247) viewed several videos of people walking alone down a hallway and subsequently rated the vulnerability to criminal victimization of the depicted person. Higher levels of psychopathic traits (measured by the Elemental Psychopathy Assessment) correlated with more accurate assessments of vulnerability when males were assessing videos of males of their same race. Prior criminal behavior, however, did not relate to better accuracy, despite its relation to psychopathic traits. Results for females were not consistent with findings for males, indicating the finding may not generalize across gender. The current findings suggest one mechanism that might explain why those with elevated psychopathic traits are more likely to offend is that they are adept at identifying vulnerability. However, this was only true for males of the same race as the "victim." PMID- 30311512 TI - Child Loss, Social Capital, and Depressive Symptoms Among Elderly Adults in Urban and Rural China. AB - OBJECTIVE: The purpose of this study was to examine the moderating effects of individual and community social capital on the relationship between child loss and depressive symptoms among elderly adults in China. METHOD: A sample of 2,581 elderly adults in 272 rural communities and 826 elderly adults in 116 urban communities was drawn from Chinese Health and Retirement Longitudinal Studies. Hierarchical linear modeling was applied in the analysis. RESULTS: Social participation as an indicator of individual social capital has a buffering effect on depressive symptoms among rural bereaved parents while it is not beneficial for urban bereaved parents. In contrast, community social capital may be a protective factor for the mental health of urban bereaved parents, but no so for those in rural areas. DISCUSSION: These findings highlight the complex interplay of social capital and broader socio-cultural contexts in rural and urban China and suggest policy implications. PMID- 30311513 TI - Experimental Approaches for Improving the Assessment of Partner Violence. AB - Intimate partner violence (IPV) is a serious and widespread problem. Unfortunately, like many other private behaviors, self-report is one of the few practical means of assessing IPV. Despite its known limitations, few studies have examined methods for improving the assessment of IPV through self-report, particularly in research contexts. The current study examined implicit goal priming (IGP) and restricted response latencies (RRL), which have previously been used successfully to improve reporting of other types of sensitive information. Participants in the IGP condition engaged in a word-matching task intended to subliminally prime an honesty goal immediately before completing the IPV self report measure. In the RRL condition, the amount of time participants were allotted to answer each question was restricted to 3 s. Using a pilot sample of 71 cohabiting/married couples, we currently provide experimental support for the utility of the IGP task for increasing the frequency of reported IPV, as well as agreement between self-reports and partner reports, particularly when used in conjunction with the RRL method. We found the strongest and most consistent effects for women's reports of severe IPV perpetration and victimization, which is important given the extreme nature of these forms of IPV and because they are frequently underreported by women. We also found evidence to support the use of these methods to enhance reporting of other forms of IPV and provide additional directions for future research. PMID- 30311514 TI - Clostridium difficile infection in Johannesburg, South Africa. AB - OBJECTIVES: The incidence of Clostridium difficile infection is increasing, resulting in significant in-patient morbidity and mortality. We describe the characteristics of Clostridium difficile infection in patients admitted to a tertiary Academic Hospital in Johannesburg, South Africa. METHODS: This was a retrospective record review of 154 adult in-patients with confirmed Clostridium difficile infection undertaken between 1 January 2013 and 30 June 2014. RESULTS: Overall, 83 (53.9%) patients were female and the median age was 39 years. The most common symptoms were watery diarrhea (92.9%) and fever (27.3%). Overall, 145 (97.9%) patients had been exposed to antibiotics in the last 30 days, 54 (35.1%) to immunosuppressives, 48 (31.2%) to gastric acid suppressants, and 65 (42.2%) patients had previous hospital admissions. Only two cases were community acquired. In total, 73 (47.4%) patients died. There was no difference in outcomes of HIV-positive patients compared to HIV-negative patients; however, the clinical features were more marked in the HIV-negative patients. Non-survivors tended to have a greater number of severity indicators compared to the survivors. CONCLUSION: Patients with Clostridium difficile infection in this study were younger and had a higher mortality than that reported in the Western world. Most infections were hospital-acquired. PMID- 30311515 TI - The Prevalence of Intimate Partner Violence, Associated Risk Factors, and Other Moderating Effects: Findings From the Kenya National Health Demographic Survey. AB - Intimate partner violence (IPV) is not only a fundamental violation of human rights but also a major public health problem. IPV is the most predominant form of violence committed by men against women. Therefore, our study sought to determine the prevalence of IPV and other moderating factors associated with IPV among these women. This study utilized data from the 2014 Kenya Demographic and Health Survey (KDHS), a nationally representative household-based survey that utilizes a two-stage sampling design. Data was weighted and analyzed using Stata 12 for Windows. A total of 3,028 women were interviewed for the analysis. A majority of the women were aged between 20 and 29 years (1,305; 43.1%), with a greater proportion married (2,329; 76.9%) and identified as Protestant (2,181; 72.1%). On adjusted analysis, factors associated with experiencing IPV included women who: were aged between 40 and 49 years belonging to religions other than Catholic, Protestant, or practiced no religion, resided in urban areas, were currently working, had a poor Wealth Index, were not sexually assertive, had one sexual partner other than their husband/spouse, received money, gifts, or favors in return for sex, had no knowledge on HIV, had husbands/partners aged above 50 years, experienced an early sexual debut of less than 18 years and felt that their partners were justified in beating them. Gender-based violence is complex and multifaceted affecting individuals, families, and society at large and should be addressed from different spectrums of intervention. There is a need for interventions that reduce and prevent IPV through empowering women, creating jobs to accumulate wealth, creating a conducive environment within workplaces for those employed, educating women, and empowering school-aged children to avert IPV. PMID- 30311516 TI - Olodaterol for the treatment of chronic obstructive pulmonary disease: a narrative review. AB - INTRODUCTION: Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 ug, a long-acting beta2 adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy. Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD. Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death. LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea. PMID- 30311518 TI - Veterinary behaviorists should be the first, not the last, resort for optimal patient care. PMID- 30311517 TI - Gender, Escalatory Tendencies, and Verbal Aggression in Intimate Relationships. AB - This study examined the relationship between gender, escalatory tendencies, and the use of verbal aggression among four types of heterosexual dyads: couples with no verbal aggression, man-only verbal aggression, woman-only verbal aggression, and both-partner verbal aggression. The study was based on a community sample of 65 couples (130 men and women). The findings show that while there is no gender difference in the prevalence and incidence of verbal aggression, there is a difference in the levels of motivation to put one's partner "in his or her place" and avoid a confrontation with one's partner. Thus, there is a gender difference in escalatory tendency. This difference is evident in the greater motivation to put one's partner in his or her place observed among women, as compared with men, and in the lower motivation to avoid confrontation observed among women, as compared with men. Moreover, unlike among men, among women, the motivation to put one's partner in his place is higher than the motivation to avoid confrontation. It follows that the escalatory tendency among women is greater than the escalatory tendency among men. The findings also demonstrate significant gender differences in motivations and escalatory tendencies within the different types of dyads examined. These findings establish the relationship between escalation and aggression and also provide a glimpse into the mechanisms that sustain that relationship. PMID- 30311519 TI - ECG of the Month. PMID- 30311520 TI - Successful chemical ablation of an intraorbital cyst caused by an eyelid injury and iatrogenic ankyloblepharon formation in a duck. AB - CASE DESCRIPTION A client-owned 2-year-old 1.8-kg (4-lb) male pet Rouen duck (Anas platyrhynchos domesticus) was evaluated because of severe swelling around the left eye following traumatic injury to the upper and lower eyelids and 2 associated surgeries that resulted in the removal of the entire upper and lower eyelid margins. CLINICAL FINDINGS At initial evaluation, ankyloblepharon of the left eye was observed, with no upper or lower eyelid margins and a large, round, fluctuant subcutaneous mass over the left orbit. Orbital exploration and histologic examination revealed a benign cyst consisting of fibrous tissue, conjunctiva, and skeletal muscle bundles. Bacterial culture of cystic fluid yielded few Staphylococcus delphini. TREATMENT AND OUTCOME Excision of the cyst and evisceration of the left globe were performed, and once daily treatment with orally administered enrofloxacin suspension (12.6 mg/kg [5.7 mg/lb]) and meloxicam (1 mg/kg [0.45 mg/lb]) was initiated. Over the next 4 days, the cyst redeveloped and progressively enlarged. Accumulated fluid was aspirated from the cyst, and 20 mg of gentamicin was injected intraorbitally with ultrasound guidance. Over the subsequent 27-month period, no recurrence of clinical signs or adverse effects were reported by the owner. CLINICAL RELEVANCE To the authors' knowledge, this is the first report of cyst formation after adnexal injury and evisceration in birds and its successful treatment with intralesional gentamicin injection. Findings emphasized the importance of preserving lacrimal puncta during adnexal or eye removal surgeries in birds. Intralesional injection of gentamicin with the goal of destroying fluid-producing cells may be a safe and effective way to treat intraorbital cysts in birds and other species, although additional research would be required to confirm this. PMID- 30311521 TI - Perspectives in Professional Education: Reassessing courses required for admission to colleges of veterinary medicine in North America and the Caribbean to decrease stress among first-year students. AB - OBJECTIVE To identify courses in which first-year veterinary students struggled academically and to survey veterinarians as to their opinions on existing prerequisite courses and proposed alternatives. DESIGN Electronic surveys. SAMPLE Associate deans for academic affairs at colleges of veterinary medicine and practicing veterinarians in North America and the Caribbean. PROCEDURES Surveys were sent to associate deans of academic affairs seeking information on courses in which first-year veterinary students most commonly struggled academically. The 6 courses most commonly listed as prerequisites for admission to veterinary college were identified, and practitioners were asked to rank the relative importance of those courses for preparing students for veterinary college and to rank the importance of 7 potential alternative courses. RESULTS Data were obtained from 21 associate deans and 771 practicing veterinarians. First-year veterinary students most commonly struggled academically in anatomy, physiology, and histology courses, but these courses were rarely included as prerequisites for admission. Practicing veterinarians agreed that anatomy and physiology should be considered as possible alternatives to 1 or more current prerequisite courses, such as organic chemistry and physics. CONCLUSIONS AND CLINICAL RELEVANCE First year veterinary students commonly encountered academic difficulties in anatomy, physiology, and histology. Because few surveyed veterinary colleges include these courses as prerequisites for admission, many students were exposed to this material for the first time as veterinary students, potentially adding to their academic difficulties and causing stress and anxiety. To help address this situation, veterinary colleges might consider replacing 1 or more current prerequisite courses (eg, organic chemistry and physics) with anatomy, physiology, and histology. PMID- 30311522 TI - kappa Light-chain monoclonal gammopathy and cast nephropathy in a horse with multiple myeloma. AB - CASE DESCRIPTION A 27-year-old Dutch Warmblood mare was evaluated because of a history of lethargy, reluctance to move, weight loss, persistent hyperproteinemia, and recurrent episodes of mild lameness. CLINICAL FINDINGS Hematologic evaluation revealed anemia (RBC concentration, 3.84 * 106 cells/MUL), thrombocytopenia (47 * 103 thrombocytes/MUL), and hyperproteinemia (total protein concentration, 11.2 g/dL) with hyperglobulinemia and hypoalbuminemia. Results of protein electrophoresis of serum and urine samples indicated a monoclonal gammopathy; the paraprotein was identified as a kappa light chain. On abdominal ultrasonographic examination, hypoechoic nodules were visualized in the spleen. Results of cytologic examination of a splenic fine-needle aspirate and histologic examination of a bone marrow biopsy sample were consistent with plasma cell myeloma. TREATMENT AND OUTCOME Treatment was declined owing to the age of the horse and poor prognosis. The horse was discharged from the hospital, and the owner was given palliative care instructions. The horse was euthanized 2 weeks later because of recurrent episodes of lethargy, anorexia, and signs of colic. Necropsy confirmed the diagnosis of multiple (plasma cell) myeloma. Plasma cell aggregates in the liver, spleen, bone marrow, and kidney and the presence of cast nephropathy were identified on histologic examination. CLINICAL RELEVANCE Multiple myeloma is rarely reported in horses. A monoclonal peak on serum protein electrophoresis should raise the suspicion of neoplasia, specifically multiple myeloma. The findings for this patient confirmed the importance of considering neoplasia in horses with nonspecific clinical signs. PMID- 30311524 TI - Risk factors for temporary tracheostomy tube placement following surgery to alleviate signs of brachycephalic obstructive airway syndrome in dogs. AB - OBJECTIVE To identify risk factors for temporary tracheostomy tube placement (TTTP) following surgery for alleviation of signs associated with brachycephalic obstructive airway syndrome (BOAS) in dogs. DESIGN Retrospective case-control study. ANIMALS 122 client-owned dogs with BOAS that underwent surgery to alleviate clinical signs (BOAS surgery). PROCEDURES The medical records database of a veterinary teaching hospital was searched to identify dogs that underwent BOAS surgery from January 2007 through March 2016. Of the 198 dogs identified, 12 required postoperative TTTP (cases); 110 of the remaining 186 dogs were randomly selected as controls. Data regarding signalment and select preoperative, intraoperative, and postoperative variables were extracted from the medical record of each dog. Variables were compared between cases and controls and evaluated for an association with the odds of postoperative TTTP. RESULTS Body condition score, tracheal diameter-to-thoracic inlet ratio, staphylectomy technique, and mortality rate did not differ significantly between cases and controls. The odds of postoperative TTTP increased approximately 30% (OR, 1.3) for each 1-year increase in patient age. Postoperative administration of corticosteroids and presence of pneumonia were also positively associated with the odds of postoperative TTTP. Median duration of hospitalization was significantly longer for cases than controls. CONCLUSIONS AND CLINICAL RELEVANCE Age was positively associated with the odds of TTTP in dogs after BOAS surgery, and TTTP led to prolonged hospitalization. Thus, early identification and intervention may be beneficial for dogs with BOAS. The associations between TTTP and postoperative corticosteroid use or pneumonia were likely not causal, but reflective of patient disease severity. PMID- 30311525 TI - Pathology in Practice. PMID- 30311526 TI - Subcutaneous ureteral bypass for treatment of bilateral ureteral obstruction in a cat with retroperitoneal paraganglioma. AB - CASE DESCRIPTION A 7-year-old female domestic shorthair cat was referred for evaluation of azotemia and unilateral hydronephrosis. CLINICAL FINDINGS Abdominal ultrasonography revealed right-sided hydronephrosis and dilation of the proximal aspect of the ureter; the left kidney was small with irregular margins. A highly vascular, irregular retroperitoneal mass, not clearly associated with the ureteral obstruction, was also visualized. Surgical exploration confirmed a retroperitoneal mass involving the caudal mesenteric artery and both ureters, with hydroureter on the right side. TREATMENT AND OUTCOME A subcutaneous ureteral bypass (SUB) device was surgically implanted to treat right ureteral obstruction, and the mass was biopsied. Shortly after surgery, progressive azotemia and hyperkalemia were detected; ultrasonographic examination revealed left-sided hydronephrosis and hydroureter, which was suspected secondary to inflammation of the mass causing a left-sided ureteral obstruction. A second surgery was performed to place an SUB device for the left kidney and remove the retroperitoneal mass; both ureters were ligated at the mid- and distal aspects and then transected and removed with the mass. A neuroendocrine paraganglioma was identified by histopathologic evaluation of the mass. Hydronephrosis improved (right kidney) or resolved (left kidney) after surgery, and azotemia improved. Chemotherapeutic intervention was declined. Markers of renal function were static during the 14-month follow-up period. At the last follow-up evaluation, the patient was reportedly doing well, and both SUB devices were patent. CLINICAL RELEVANCE This was the first report of retroperitoneal paraganglioma in a domestic cat causing bilateral ureteral obstruction. Bilateral SUB device placement enabled en bloc mass resection and provided long-term relief of ureteral obstruction. PMID- 30311527 TI - What Is Your Diagnosis? PMID- 30311528 TI - Effect of injection site on dexmedetomidine-ketamine induced sedation in leopard geckos (Eublepharis macularius). AB - OBJECTIVE To evaluate whether the sedative effects of a combination of dexmedetomidine and ketamine differed when it was administered IM in a hind limb versus a forelimb of leopard geckos (Eublepharis macularius). DESIGN Randomized crossover study. ANIMALS 9 healthy adult leopard geckos. PROCEDURES Each gecko received a combination of dexmedetomidine (0.1 mg/kg [0.045 mg/lb]) and ketamine (10 mg/kg [4.5 mg/lb]; DK), IM, in a forelimb and hind limb in a randomized order and with a 7-day interval between treatments. All geckos received atipamezole (1 mg/kg [0.45 mg/lb], SC) 45 minutes after DK administration. Palpebral and righting reflexes, jaw tone, and superficial pain and escape responses were each assessed on a 3-point scale, and the scores for those variables were summed to calculate a sedation score. Those variables and heart and respiratory rates were evaluated at predetermined times before and for 1 hour after DK administration. RESULTS For the forelimb treatment, mean sedation score was higher and mean heart rate was lower than the corresponding values for the hind limb treatment at most time points after DK administration. The righting reflex remained intact for all 9 geckos following the hind limb treatment but became absent in 7 geckos following the forelimb treatment. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent of DK-induced sedation was greater when the combination was injected IM in a forelimb versus a hind limb of leopard geckos, likely owing to a hepatic first-pass effect following hind limb injection. In reptiles, IM hind limb administration of drugs that undergo hepatic metabolism and excretion is not recommended. PMID- 30311529 TI - Pathology in Practice. PMID- 30311530 TI - What Is Your Neurologic Diagnosis? PMID- 30311531 TI - Wellbeing in the veterinary workplace: Collaboration and culture are key. PMID- 30311532 TI - Owner satisfaction with use of videoconferencing for recheck examinations following routine surgical sterilization in dogs. AB - OBJECTIVE To evaluate owner satisfaction with a home-based, synchronous videoconferencing telemedicine application as an alternative to in-clinic appointments for conducting recheck examinations after surgical sterilization in dogs. DESIGN Randomized controlled clinical trial. ANIMALS 30 client-owned dogs undergoing elective surgical sterilization and postsurgical recheck examination between September 27, 2017, and February 23, 2018. PROCEDURES Dogs were randomly assigned to have their recheck examinations performed remotely (the telemedicine group) or at the veterinary clinic (the control group). After the recheck examination, owners completed a survey regarding their satisfaction with the recheck examination and their dogs' behavior during it. Information regarding the surgery and recheck examination was obtained from the electronic medical record. Mann-Whitney U tests were used to compare results between the telemedicine and control groups. RESULTS Owners were equally satisfied with recheck examinations performed by videoconference and in-clinic appointments. Owners of dogs in the telemedicine group indicated that their dogs were less afraid during the virtual appointment, compared with what was typical for them during in-clinic appointments, but the difference was not statistically significant. Most owners who completed a postsurgical recheck examination by videoconferencing preferred this method for similar appointments in the future. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that owners were satisfied with videoconferencing as a means of conducting a postsurgical recheck examination. Further research is needed to assess videoconferencing's ability to reduce signs of fear in dogs during veterinary examinations, its economic feasibility, and the willingness of veterinarians and animal owners to adopt the technology. PMID- 30311533 TI - Effects of topical ophthalmic application of 0.5% proparacaine hydrochloride on aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs. AB - OBJECTIVE To evaluate the effects of topical ophthalmic application of 0.5% proparacaine hydrochloride solution (PHCL; containing 0.01% benzalkonium chloride as preservative) on aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs. DESIGN Clinical trial. ANIMALS 25 client-owned dogs with infected corneal ulcers (24 unilaterally affected and 1 bilaterally affected; only 1 eye included/dog) examined between June 2008 and May 2011. PROCEDURES Swab samples for aerobic bacterial culture were collected from the periphery of each corneal ulcer before and approximately 1 minute after topical ophthalmic application of 1 drop of PHCL. Numbers of aerobic bacterial species isolated from affected eyes were compared between sample collection points and between other variables (ie, side [left or right] of affected eye, prior treatments, and patient age, sex, and neuter status). RESULTS There was no significant difference between numbers of aerobic bacterial species isolated per eye or overall aerobic bacterial culture results (positive or negative) before versus after PHCL application. Similarly, prior treatment had no significant effect on aerobic bacterial culture results for samples collected at either point. The most commonly isolated bacteria before and after PHCL application were Staphylococcus spp (40% and 48%, respectively), followed by Streptococcus spp (23% and 22%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE Topical ophthalmic application of PHCL did not significantly affect aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs as assessed in this study. Therefore, topical ophthalmic PHCL application could be useful in clinical settings prior to sample collection to relieve patient discomfort and to aid in sample acquisition without compromising aerobic bacterial culture results. PMID- 30311534 TI - Demyelinating disease of the central nervous system associated with Pembrolizumab treatment for metastatic melanoma. AB - Immune checkpoint inhibitors are used in metastatic melanoma with good efficacy and safety profile. We report the first case of an inflammatory demyelinating disease of the central nervous system during treatment with Pembrolizumab and discuss the evidence in the literature supporting its causative role. The patient had a good clinical recovery after intravenous steroids, plasma exchange and discontinuation of Pembrolizumab. Due to the expected increase in the importance of immune checkpoint inhibitors in cancer treatment, it is important to be aware of neurological adverse events, as early treatment usually leads to good clinical responses. PMID- 30311535 TI - Helminths of Wild Boar ( Sus scrofa) in the Calabrian Region of Southern Italy. AB - In Calabria, as in other Italian regions, the wild boar (Sus scrofa) population has increased considerably in the last few years. The presence of this wild ungulate, a huntable species, was detected throughout this region. Wild boars are a host for many endoparasites, some of which are zoonotic. Our aim was to acquire data on the prevalence endoparasites in wild boar in the region of Calabria, Italy, where such information is limited. We used 60 wild boars culled during the 2014-15 hunting season. We used FLOTAC dual techniques for fecal microscopic exams, as well as qualitative and quantitative microscopic examination with a sensitivity level of 2 eggs/g of feces. The research has underlined the remarkable diffusion of gastrointestinal helminths, particularly Ascaris suum, in wild boar of the areas of Sila and Presila in the province of Catanzaro, Calabria. PMID- 30311536 TI - Hidden cost of pembrolizumab therapy. PMID- 30311537 TI - Multiple Factors Associated With Child Abuse Perpetration: A Nationwide Population-Based Retrospective Study. AB - Differences in child abuse perpetration between individuals with and without mental disorders remain obscure. This study compared the risk difference and further investigated the association between the category of mental disorders and child abuse perpetration. A total of 681,970 adults from the 2002 to 2013 Taiwan National Health Insurance Research Database were analyzed, including 340,985 patients with psychiatric disorders (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 290.x-319.x) and 340,985 sex- and age-matched individuals without psychiatric disorders. Child abuse perpetration (ICD-9-CM N-codes 995.5x and E-code E967) was the outcome variable. Matched analyses indicated that the risk of child abuse among patients with psychiatric disorders (0.25%) was significantly higher than that among those without psychiatric disorders (0.16%; odds ratio [OR] = 1.464, p < .0001). Among the six categories of mental disorders, the prevalence rates of committing child abuse were significantly higher for personality disorders, substance use, and affective disorders (0.56%, 0.45%, and 0.40%, respectively; p < .0001). Compared with anxiety disorders, substance use disorders were significantly associated with higher odds of child abuse perpetration (OR = 2.032, p < .05), especially physical abuse (OR = 2.018, p < .0001). Psychiatric morbidity was associated with higher odds of child abuse, with substance use determined as the major risk category. Screening high-risk families by using the associated factors is crucial. PMID- 30311538 TI - Warmth, Competence, and Blame: Examining Mothers of Sexually Abused Children Within the Stereotype Content Model. AB - Research shows that nonoffending mothers are frequently held at fault for child sexual abuse (CSA), by both society and professionals, with contradictory explanations for the fault. For example, the same maternal characteristic can be used to assign blame or alleviate blame (i.e., single mothers have been held more at fault for their child's CSA and less at fault). The purpose of this study was to assess a theoretically based model that could account for these different reasons. We tested the stereotype content model (SCM), which examines the content of stereotypes toward target groups, by focusing on perceptions of that group's levels of warmth and competence. We sampled 136 undergraduate participants who read a vignette describing CSA, and completed the SCM with the mother of the victim as the target, and measures of mother fault. Our results showed that participants fell into three SCM groups of mother fault: (a) Moderate Contemptuous Prejudice (i.e., low competence, low warmth); (b) Admiration (i.e., moderate competence, high warmth); and (c) Very Contemptuous Prejudice (i.e., very low competence, very low warmth). Each cluster also held unique emotions toward the mother, as predicted by the SCM. Results further showed that assigned levels of fault were significant, but that fault did not vary by SCM group, lending support to the ideas that the SCM can be applied to this group and that different participants assign fault for different reasons. PMID- 30311539 TI - Bully-Victims: An Analysis of Subtypes and Risk Characteristics. AB - Bully-victims are often found to be the most high-risk group involved in bullying, yet limited prior research has explored differences among bully victims. This study aims to fill that gap by exploring within-group differences of youth involved in both bullying perpetration and victimization. In a nationally representative sample of 165 youth ages 5 to 17, four bully-victim types were created using cutoff points based on the amount of perpetration and victimization reported: high bully-victims ( n = 38), aggression predominant bully-victims ( n = 67), victimization predominant bully-victims ( n = 23), and moderate bully-victims ( n = 37). Analyses revealed distinct differences among the groups, particularly relating to traumatic symptoms, types of bullying involvement, and nonvictimization adversity. The findings confirm that there is heterogeneity among bully-victims. The most substantial difference was found between the high group and the moderate group, with the high group significantly more likely to report depression ( p < .05) and anxiety symptoms ( p < .05), and more than two times more likely to experience past-year adversity than the moderate group. The findings from this study indicate that youth involved in high amounts of both perpetration and victimization are considerably more at risk of traumatic symptoms and nonvictimization adversity than youth involved in fewer bullying behaviors. These findings can be used to inform both research and practice, particularly in regard to targeted evidence-based interventions that meet the unique needs of each type. PMID- 30311540 TI - Impact of gamma'gamma' fibrinogen interaction with red blood cells on fibrin clots. AB - AIM: gamma' fibrinogen has been associated with thrombosis. Here the interactions between gamma'gamma' or gammaAgammaA fibrinogen and red blood cells (RBCs), and their role on fibrin clot properties were studied. MATERIALS & METHODS: Atomic Force microscopy (AFM)-based force spectroscopy, rheological, electron and confocal microscopy, and computational approaches were conducted for both fibrinogen variants. RESULTS & CONCLUSION: AFM shows that the recombinant human (rh)gamma'gamma' fibrinogen increases the binding force and the frequency of the binding to RBCs compared with rhgammaAgammaA, promoting cell aggregation. Structural changes in rhgamma'gamma' fibrin clots, displaying a nonuniform fibrin network were shown by microscopy approaches. The presence of RBCs decreases the fibrinolysis rate and increases viscosity of rhgamma'gamma' fibrin clots. The full length of the gamma' chain structure, revealed by computational analysis, occupies a much wider surface and is more flexible, allowing an increase of the binding between gamma' fibers, and eventually with RBCs. PMID- 30311541 TI - Model Victims of Hate: Victim Blaming in the Context of Islamophobic Hate Crime. AB - Prior research has explored victim blaming in the context of hate, often depicting hate crime victims as relatively passive recipients of harassment and violence. In reality, victims often do engage with their perpetrators, and the present research explored the effect that victim behavior might have on observer reactions to Islamophobic hate crimes. Participants completed a measure of Islamophobia and read a scenario in which a White man verbally harassed a victim in the park before physically assaulting him. We manipulated both the victim's identity (White or South Asian Muslim) and the victim's response to the perpetrator's verbal harassment (the victim either ignored the offensive comments, verbally reacted to them, or became physically confrontational). When the victim was portrayed as passive and nonresponding, the South Asian Muslim victim attracted lower victim blame, higher perpetrator blame, and increased certainty that the offense was a hate crime. As the victim's behavior became more aggressive, victim blaming increased and perpetrator blaming decreased, but only for the South Asian Muslim victim. It appeared that observers scrutinized the behavior of the South Asian Muslim victim in a way they did not for the White victim, such that sympathy toward the Muslim hate crime victim was tied to his "good behavior." We propose that observers hold expectations of the model hate crime victim, one who is a racialized, religious, or sexual minority who accepts harassment passively and with good behavior; deviation from this script results in a loss of sympathy and an increase in victim blaming. Finally, those higher in Islamophobia displayed reduced perpetrator blame, guilt, and sentences but greater victim blame when the crime targeted a South Asian Muslim as opposed to White victim. PMID- 30311542 TI - Canagliflozin-loaded magnetic nanoparticles as potential treatment of hypoxic tumors in combination with radiotherapy. AB - AIM: To synthesize magnetic nanoparticles loaded with the SGLT2-inhibitor canagliflozin (CANA) and evaluate its anticancer potential under normoxic and hypoxic conditions in combination or not with radiotherapy. MATERIAL & METHODS: Iron oxide nanoparticles were synthesized via an alkaline hydrolytic precipitation of iron precursor in the presence of poly(methacrylic acid)-graft poly(ethyleneglycol methacrylate). CANA was conjugated to the nanoparticles using N-ethyl-N'-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide chemistry. The anticancer efficacy of the nanoparticles was evaluated in cancer cell lines and in a mouse PDV C57 tumor model. RESULTS: In the mouse xenograft cancer model, the combination of CANA-loaded nanoparticles with radiotherapy (in the presence of an external magnetic field at the tumor site) exhibited higher antitumor activity compared with the combination of free CANA with radiotherapy. CONCLUSION: The results obtained indicate the potential that the combination of selective delivery of a SGLT2 inhibitor such as CANA with radiotherapy holds as an anticancer treatment. PMID- 30311544 TI - Is It Love or Is It Control? Assessing Warning Signs of Dating Violence. AB - The purpose of this study was to develop and evaluate the Relationship Red Flags Scale, a measure of ability to recognize warning signs of dating violence. The factor structure and psychometric properties of this measure were tested with independent samples of college women and men, and test-retest reliability was assessed with college women. Specifically, our first study examined the factor structure, validity, and reliability of the Relationship Red Flags measure with a sample of 433 undergraduate women. Confirmatory factor analyses provided support for a 25-item five-factor structure (i.e., Monitoring Behaviors, Controlling Behaviors, Demeaning Behaviors, Threatening and Aggressive Behaviors, and Jealous and Possessive Behaviors). Internal consistency reliability was adequate and the validity of the measure was supported for use with college women (negative correlations were found among measures of warning signs and acceptance of dating violence). Our second study replicated these findings with an independent sample of 330 college men. Finally, a third investigation found that the measure demonstrated adequate test-retest reliability with an independent sample of 47 college women. PMID- 30311543 TI - Role of AhR in regulating cancer stem cell-like characteristics in choriocarcinoma. AB - Choriocarcinoma is sensitive to chemotherapy. However, drug resistance has become one of the major problems in recent years. Previous studies have shown that many tumors contained a small fraction of cells that exhibited enhanced tumor initiating potential and stem cell-like properties. It is hypothesized that cancer stem cells (CSCs) are organized in a cellular hierarchy. They also have the qualities of self-renewal, chemoresistance, and so on. The identification of CSCs in choriocarcinoma and the mechanism contributing to their qualities remain largely unknown. This study focused on the role of AhR, a transcription factor abundantly expressed in many different types of cancer, in the regulation of the expansion of choriocarcinoma CSCs and the exact molecular mechanisms. Spheroid cells isolated from choriocarcinoma in serum-free conditions have stem cell-like characteristics. The expression and nuclear translocation of AhR were markedly elevated in spheroid cells. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) significantly increased the spheroid-forming efficiency, chemotherapy resistance, and ability to form tumor xenografts of the cells, whereas AhR knockdown, using short hairpin RNA (shRNA), dramatically reduced stem cell properties. Mechanistically, activating the beta-catenin pathway might be an essential biological function of AhR during the regulation of the CSC characteristics. This study also identified ABCG2, which plays an important role in CSCs, as a direct target of AhR. Together, these results strongly suggested the participation of AhR in choriocarcinoma carcinogenesis. Targeting AhR may provide a novel therapeutic opportunity for choriocarcinoma. PMID- 30311545 TI - Pulmonary function patterns and their association with genotype and phenotype in adult cystic fibrosis patients. AB - BACKGROUND: While cystic fibrosis (CF) lung disease is generally considered to be an obstructive disorder, other pulmonary function patterns (PFP) may occur. Furthermore, little is known about possible associations between PFP and genotype or phenotypical characteristics. METHODS: Cross-sectional study including CF patients aged 16 years or more, identifying different PFP and exploring associations between PFP and genotype or phenotypical characteristics. RESULTS: Obstructive PFP was most prevalent in our population (n = 80), comprising obstructive lung disease (62.5%), small airway (obstructive) disease (11.2%), and mixed obstructive-restrictive disorder (1.3%). However, one in four adult CF patients did not show any obstruction at all: normal (13.7%) or restrictive (8.8%) lung disease and isolated diffusion disorder (2.5%). Obstructive PFP was associated with a greater proportion of CF-related diabetes mellitus (CFRD) (P = 0.04), Pseudomonas aeruginosa colonization (P = 0.02) and frequent exacerbators (P = 0.04). We observed no association between PFP and genotype. CONCLUSIONS: Obstructive PFP remains the most common pulmonary function pattern in adult CF and is associated with CFRD, Pseudomonas aeruginosa colonization and frequent exacerbators. PMID- 30311546 TI - Differences in non-specific physical symptom levels and pressure pain thresholds between patients with masticatory myofascial pain and arthralgia. AB - OBJECTIVE: To compare the levels of non-specific physical symptoms and pressure pain threshold (PPT) found in patients with masticatory myofascial pain with those found in patients with temporomandibular arthralgia alone. METHODS: The study followed an observational and cross-sectional protocol. A total of 64 female patients were evaluated for the presence of painful TMD, non-specific physical symptom levels, and PPT. RESULTS: The group of patients with masticatory myofascial pain presented a lower mean for PPT as well as a higher mean for standardized T-Scores for non-specific physical symptom levels. CONCLUSION: Statistically significant differences were found in non-specific physical symptom levels and PPT between patients with an exclusive diagnosis of masticatory myofascial pain and patients with a diagnosis, also exclusive, of temporomandibular arthralgia. PMID- 30311547 TI - Animal Visitation to Wild Pig ( Sus scrofa) Wallows and Implications for Disease Transmission. AB - Knowledge of animal visitation to locations where species aggregate is valuable for evaluating potential pathways of inter- and intra-specific transmission of infectious diseases. There is no research evaluating the potential of wallows created by invasive wild pigs ( Sus scrofa) as locations of transmission of infectious diseases. We monitored wild pig wallows by using trail cameras to determine the frequency with which wild pigs and native vertebrate species visited wallows and to characterize these interactions for their potential for disease transmission. We placed cameras from 20 June 2016 to 21 September 2016 at 16 individual wallows within 10 wallowing sites. Wild pigs of both sexes visited wallows frequently (115 total visits) for varying durations and exhibited wallowing and drinking behavior. We also observed 12 native mammalian and avian wildlife species using wallows at various frequencies (165 total visits). Of particular interest, nine of these species were observed drinking from wallows. Given the high frequency of wild pig visits to wallows and the drinking behavior they and native wildlife species exhibited, these locations might have an important role in transmission of diseases. PMID- 30311548 TI - Women's sanitation practices in informal settlements: A multi-level analysis of factors influencing utilisation in Nairobi, Kenya. AB - For decades, countries throughout the world have failed to meet sanitation related development goals. Access to safe sanitation is undeniably linked to improved health outcomes; yet, 2.4 billion people, globally, still lack access. The persistent failure to meet sanitation goals suggests that our understanding of the factors that influence sustainable sanitation access and utilisation is incomplete. Despite growing availability of toilets in informal settlements, there is evidence that women, in particular, may adopt other strategies for managing their sanitation needs. Empirical data documenting the motivations underlying such practices in sub-Saharan Africa are limited. This study uses cross-sectional data collected in 2016 from women in Mathare Valley Informal Settlement in Nairobi, Kenya. Boosted and logistic regressions were used to investigate which factors were associated with women's common sanitation patterns. Lack of privacy and insecurity at toilets and neighbourhood disorganisation emerged as important factors - particularly for women who reported regularly using buckets or plastic bags for urination/defecation. These findings suggest that availability of toilets may not be enough to eliminate sanitation-related health risks in informal settlements. Future interventions may need to address other barriers to sanitation access if sustainable gains in this important public health area are to be achieved. PMID- 30311549 TI - Freeing Oneself From Intimate Partner Violence: A Follow-Up of Women Who Contacted an Anti-violence Center in Italy. AB - This study examines the situation of women ( N = 124) who had presented themselves to an anti-violence center in Italy in the previous 3-5 years. At follow-up, 37.3% had no contact with the perpetrator, 22.7% had stayed with him, and 39.8% had "forced" contact. Almost half of the sample was still subjected to intimate partner violence (IPV). Compared to women with "no contact," the risk of IPV was 5.9 times higher for women who stayed with the perpetrator, and 10.5 times higher for women with "forced" contact. These results confirm that ending IPV does not depend exclusively on women's choices. PMID- 30311550 TI - Approach to and management of abnormalities in plasma sodium. AB - The differential diagnosis between hypertonic, isotonic and hypotonic hyponatremia are presented. The help of some usual serum (urea, uric acid and TCO2) and urine parameters (mainly osmolality and sodium concentration) are discussed and help to determine the best treatment. Morbidity associated with untreated hyponatremia and with the different treatment available is also discussed. Who to prevent and treat ODS (osmotic demyelating syndrome) is recalled. The pathophysiology and treatment of hypernatremia are also discussed. PMID- 30311551 TI - The Own-Race Bias and the cerebral hemispheres. AB - The Own-Race Bias (ORB) is the ability to better recognize and categorize a face when the depicted person belongs to the observer's ethnicity group. The relationship between the ORB and hemispheric asymmetries has been poorly explored, and the present study was aimed at investigating this relationship, as well as that between the ORB and the bias to better recognize own gender faces. Female and male Caucasian participants categorized the ethnicity of Caucasian and Asian female and male facial stimuli in a divided visual field paradigm. In a control experiment the same stimuli were presented centrally, confirming the ORB. Importantly, the lateralized presentation reversed the bias with higher accuracy and shorter response times in the categorization of Asian than Caucasian faces. This reversed bias was significant for female and male faces, and it was observed when stimuli were presented in the left but not in the right visual field, revealing the crucial role of the right hemisphere in face processing. These results shed new light on the hemispheric abilities in the categorization of facial features, and they are compared to previous evidence of cerebral asymmetries for facial age, gender and identity, both in healthy participants and in neurological patients. PMID- 30311553 TI - Evaluation of Noise Reduction Algorithms in Hearing Aids for Multiple Signals From Equal or Different Directions. AB - One objective way to evaluate the effect of noise reduction algorithms in hearing aids is to measure the increase in signal-to-noise-ratio (SNR). To this end, Hagerman and Olofsson presented a method where multiple recordings take place and the phase of one signal is inverted between the measurements. This phase inversion method allows one to separate signal and noise at the output of the hearing aid so that the increase in SNR can be evaluated. However, only two signals can be distinguished, for example, speech and noise. As many realistic situations include more than two signals, we extend the method to an arbitrary number of signals. Two different approaches are discussed. For the first one, groups of the signals are created and presented in such a way that the basic phase inversion method can be used. The second, more efficient approach defines a linear system of equations considering all signals. As the robustness of this approach depends on the structure of the system matrix, the design of this matrix is described in detail. To prove the concept, the proposed efficient method was applied to a setup in which nine different signals were presented by eight loudspeakers, and an analysis of errors was performed. With this setup, a state of-the-art hearing aid was analyzed for four different settings, that is, with the digital noise reduction or the directional microphones turned on or off. As a result, the SNRs for all directions can be investigated individually. PMID- 30311552 TI - Effects of Slow- and Fast-Acting Compression on Hearing-Impaired Listeners' Consonant-Vowel Identification in Interrupted Noise. AB - There is conflicting evidence about the relative benefit of slow- and fast-acting compression for speech intelligibility. It has been hypothesized that fast-acting compression improves audibility at low signal-to-noise ratios (SNRs) but may distort the speech envelope at higher SNRs. The present study investigated the effects of compression with a nearly instantaneous attack time but either fast (10 ms) or slow (500 ms) release times on consonant identification in hearing impaired listeners. Consonant-vowel speech tokens were presented at a range of presentation levels in two conditions: in the presence of interrupted noise and in quiet (with the compressor "shadow-controlled" by the corresponding mixture of speech and noise). These conditions were chosen to disentangle the effects of consonant audibility and noise-induced forward masking on speech intelligibility. A small but systematic intelligibility benefit of fast-acting compression was found in both the quiet and the noisy conditions for the lower speech levels. No detrimental effects of fast-acting compression were observed when the speech level exceeded the level of the noise. These findings suggest that fast-acting compression provides an audibility benefit in fluctuating interferers when compared with slow-acting compression while not substantially affecting the perception of consonants at higher SNRs. PMID- 30311554 TI - The construct validity of a new screening measure of functional cognitive ability: The menu task. AB - This study evaluated the construct validity of the Menu Task (MT): a new performance-based screening measure of functional cognition. We enrolled 114 community dwelling adults (55 years or older) in the study: all participants completed the MT and four other neuropsychological screening measures. Construct validity was evaluated using a three-step hierarchical regression model with the MT as the dependent variable. Demographic control variables were entered at step 1, followed by the Brief Interview of Mental Status (BIMS), and the Trail Making Test A (TMT A) at step 2, and finally TMT B and the Montreal Cognitive Assessment (MoCA) at step 3. It was hypothesised that measures sensitive to executive functioning (TMT B and MoCA) would significantly explain MT performance after controlling for demographic variables and adding measures of cognitive function to the model, providing additional evidence for construct validity of the MT. All three steps of the model were statistically significant (p < 0.01). Inclusion of measures sensitive to executive function in step 3 explained 30% of variability in MT score (adjusted R2 = 0.30). Our findings provide further empirical support for the construct validity of the MT, and offer implications for the use of the MT in acute and post-acute care settings. PMID- 30311556 TI - Design Framework for a Data Mart in the Neonatal Intensive Care Unit. AB - Neonates who are critically ill are cared for in a neonatal intensive care unit (NICU) for continuous monitoring of their conditions. Physiological parameters such as heart rate, respiratory wave form, blood oxygen saturation, and body temperature are constantly monitored in the NICU. However, NICUs are not always equipped with a computer system for analyzing such data, identifying critical events, and providing decision support for a neonatologist. Therefore, a specialized computer system, commonly known as a data mart, should be developed for the NICU. An architectural framework for the design and development of an automated system for data collection, storage, and analysis for the NICU is proposed in this paper. Our study also deals with the implementation of advanced transformation functions such as fuzzy grouping and fuzzy lookup for data preparation and preprocessing. Furthermore, based on Kimball's dimensional modeling, a data gathering and accumulation system, fact constellation schema (galaxy schema) has been built with previously identified neonatal processes. Finally, an information delivery component has been proposed, wherein the neonatal data can be both analyzed with different data mining algorithms and visualized with various metrics. Our pioneering work demonstrates methods that streamline the process of data collection, data storage, analysis, and decision making, which in turn increases efficiency in the NICU and saves lives. Our study, presented in this paper, describes the design and development process and discusses its utility in the NICU. Our results indicate that data mart is best suited for effective decision-making in the NICU. PMID- 30311557 TI - Machine-Learning Prediction of Drug-Induced Cardiac Arrhythmia: Analysis of Gene Expression and Clustering. AB - A marked delay in the electrical repolarization of heart ventricles is characterized by prolongation of the Q-T wave (QT) interval on a surface electrocardiogram. Such a delay can lead to potentially life-threatening cardiac arrhythmia (torsades de pointes). Such prolongation is also a widely accepted cardiac safety biomarker in drug development. Current preclinical drug-safety assays include patch clamp analysis to evaluate drug-related blockade of cardiac repolarizing ion currents. Recently reported patch clamp assay results have shown predictive sensitivities and specificities in the ranges of 64%-82% and 75%-88%, respectively. In this project, we use a support vector machine classifier to find mean sensitivities and specificities of 85% and 90%, respectively, across 77 drug subclassifications. Clustering by gene expression profile similarities shows that drugs known to prolong the QT interval do not always form distinct groups, but the number of groups is limited. The most common biological network links associated with these groups involve genes linked with fatty acid metabolism, G proteins, intracellular glutathione, immune responses, apoptosis, mitochondrial function, electron transport, and mitogen-activated protein kinases. These results suggest that machine-learning analysis of gene expression and clustering may augment cardiac safety predictions for improving drug-safety assessments. PMID- 30311555 TI - Gender differences in sociodemographic and behavioural factors associated with BMI in an adult population in rural Burkina Faso - an AWI-Gen sub-study. AB - BACKGROUND: The global health transition is linked with an increased burden of non-communicable diseases with cardiovascular diseases leading the epidemic. In sub-Saharan Africa (SSA), the prevalence of obesity has increased during the past decades and there is a need to investigate the associated driving factors. In Burkina Faso obesity remains low, especially in rural areas. In this study we recruited middle-aged adults, as part of a larger study on genetic and environmental contributions to cardiometabolic disease among Africans. OBJECTIVES: To investigate the distribution of BMI and prevalence of obesity in a cross-sectional population-based study and to determine the sociodemographic and behavioural correlates with BMI. METHODS: Participants (N = 2,076) were recruited from the Nanoro Health and Demographic Surveillance System area and were aged 40 60 years. We applied hierarchical modelling to identify factors associated with BMI and structural equation modelling to identify mediated effects of sociodemographic and behavioural variables on BMI. RESULTS: Data are presented on 2,076 participants (49.9% female). Men had significantly higher BMI than women with medians of 21.1 (19.2 - 23.4) vs 19.8 (18.1 - 21.6) (p < 0.001), and there were significantly more underweight women compared to men (31.0% vs 17.4%) (p < 0.001). More men were overweight and obese than women (11.9% vs 5.2% and 2.2% vs 1.4%). Socioeconomic status was the major contributor to increased BMI for men, and education was the main contributor in women. Tobacco smoking and chewing, and problematic alcohol consumption were associated with a decrease in BMI in men and women. CONCLUSION: Overweight and obesity are relatively low among adults in rural Burkina Faso, and men had a higher median BMI than women. Behavioural factors, including tobacco use and alcohol consumption, contributed to a decrease in BMI, whereas socioeconomic status and education (which were both generally low in this community) contributed to an increase in BMI. PMID- 30311558 TI - Review of Endometriosis Diagnosis through Advances in Biomedical Engineering. AB - Endometriosis is characterized as the ectopic presence of endometrium in various locations within the abdominal cavity, such as the fallopian tube, the pouch of Douglas, the ovaries, outside the ovaries, and more. The inner lining of the uterus, endometrium, is a dynamic tissue that undergoes morphological and functional changes cyclically. The proliferation of endometrial cells during menstruation is influenced by increasing circulating estrogen levels. Adult progenitor stem cells are likely responsible for this remarkable regenerative capacity and hence, enhanced capacity to generate endometriosis. This chronic estrogen-dependent disease is characterized by the ectopic endometrial implant. The disorder occurs in 6%-10% of reproductive-aged women and in 35%-50% of women with pelvic pain and infertility. Currently, the preferred diagnostic methods are laparoscopic inspection by transvaginal ultrasound, MRI, and sensors. Diagnoses with transvaginal ultrasound have 92.7% sensitivity and 97% specificity in detecting endometriotic lesions. On average, MRI diagnoses of DIE have 74% sensitivity and 95% specificity. Lastly, chemical sensors have 91.7% sensitivity and 90.0% specificity in detecting endometriosis. The standard of care includes personalizing the treatment plan based on the individual's set of symptoms and their severity. Advances in biomedical engineering have aided professionals in personalizing the course of treatments as well as to increasing the quality of life of these patients through various therapies for managing pain. Because no one theory provides a full explanation for the manifestation of the disease, hormonal therapies, targeted therapeutics, and surgical options have emerged as elements of disease management. Clinicians are in the process of developing advanced pharmaceutical drugs with specific orphan target receptors of the ectopic tissue. Possible complications that accompany the condition include dyspareunia, hyperalgesia, infertility, and many others. PMID- 30311559 TI - Autophagy and Hallmarks of Cancer. AB - Autophagy is a catabolic program that is responsible for the degradation of dysfunctional or unnecessary proteins and organelles to maintain cellular homeostasis. Mechanistically, it involves the formation of double-membrane autophagosomes that sequester cytoplasmic material and deliver it to lysosomes for degradation. Eventually, the material is recycled back to the cytoplasm. Abnormalities of autophagy often lead to human diseases, such as neurodegeneration and cancer. In the case of cancer, increasing evidence has revealed the paradoxical roles of autophagy in both tumor inhibition and tumor promotion. Here, we summarize the context-dependent role of autophagy and its complicated molecular mechanisms in the hallmarks of cancer. Moreover, we discuss how therapeutics targeting autophagy can counter malignant transformation and tumor progression. Overall, the findings of studies discussed here shed new light on exploiting the complicated mechanisms of the autophagic machinery and relevant small-molecule modulators as potential antitumor agents to improve therapeutic outcomes. PMID- 30311560 TI - Mechanism and Regulation of Autophagy in Cancer. AB - Autophagy, or self-eating, is a catabolic process that plays a crucial role in cellular homeostasis by carrying out bulk degradation of defective or superfluous proteins as well as worn-out organelles through a specialized structure, the autophagosome, which in turn fuses with the lysosome. Autophagy also alleviates cellular stress induced by nutrient deprivation, metabolic disturbance, hypoxia, and the like, by recycling intracellular constituents. This role of autophagy, to provide metabolic precursors especially upon starvation, might also contribute to the survival of cancer cells. The role of autophagy in cancer cells is ambiguous given that its downregulation or upregulation has been observed to depend on cancer stage and pathological grade. Autophagy has been found to exhibit a dual effect on tumorigenesis where it functions to suppress tumor progression by eliminating factors that cause genome instability while promoting survival of cancer cells under unfavorable conditions like therapeutic stress. This review aims to explain the mechanism, regulation, and the dual role of autophagy in cancer. PMID- 30311561 TI - A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics. AB - The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemo-immuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-kappaB), and Snail highlight the novel roles for RKIP in the control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types. PMID- 30311562 TI - Linking Autophagy and the Dysregulated NFkappaB/ SNAIL/YY1/RKIP/PTEN Loop in Cancer: Therapeutic Implications. AB - The role of autophagy in the pathogenesis of various cancers has been well documented in many reports. Autophagy in cancer cells regulates cell proliferation, viability, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, and responses to chemotherapeutic and immunotherapeutic treatment strategies. These manifestations are the result of various regulatory gene products that govern autophagic, biochemical, and molecular mechanisms. In several human cancer cell models, the presence of a dysregulated circuit-namely, NFkappaB/SNAIL/YY1/RKIP/PTEN-that plays a major role in the regulation of tumor cell unique characteristics just listed for autophagy-regulated activities. Accordingly, the autophagic mechanism and the dysregulated circuit in cancer cells share many of the same properties and activities. Thus, it has been hypothesized that there must exist a biochemical/molecular link between the two. The present review describes the link and the association of each gene product of the dysregulated circuit with the autophagic mechanism and delineates the presence of crosstalk. Crosstalk between autophagy and the dysregulated circuit is significant and has important implications in the development of targeted therapies aimed at either autophagy or the dysregulated gene products in cancer cells. PMID- 30311563 TI - Driving Cytotoxic Natural Killer Cells into Melanoma: If CCL5 Plays the Music, Autophagy Calls the Shots. AB - Autophagy is a quality control process executed at the basal level in almost all cell types. However, in cancer cells, autophagy is activated by several stimuli, including hypoxia. Depending on tumor type, stage, and genetic context, autophagy is a double-edged sword. Autophagy promotes regression in newly established tumors; however, it supports tumor progression in well-established tumors by maintaining cancer cell survival under stress conditions. These data, in addition to the emerging role of autophagy in impairing antitumor immunity, have attracted significant interest in developing autophagy inhibitors as a new approach to cancer treatment. The enthusiasm for developing selective drugs inhibiting autophagy has been seriously challenged by the discovery that most autophagy related proteins display nonautophagic functions. Autophagy inhibitors chloroquine and hydroxychloroquine are currently being investigated in several clinical trials in combination with standard anticancer therapies. Here, we provide a brief overview on the nonautophagic function of autophagy-related proteins and summarize the major mechanisms whereby autophagy modulation could positively or negatively impact cancer therapies. We also focus on the emerging role of targeting autophagy in the improvement of NK-mediated antitumor immunity through the regulation of CCL5 and its receptors' expression in melanoma, and we provide some clues revealing how autophagy modulators could be exploited to improve cancer immunotherapies. PMID- 30311564 TI - Herbal Medicine in the Mitigation of Reactive Oxygen Species, Autophagy, and Cancer: A Review. AB - Since the discovery of autophagy in the mid-2000s, the interest in autophagy related processes within the scientific community has been burgeoning. Countless authors have investigated its function in cellular homeostasis, but arguably of higher importance is its role during pathology. Although primarily a catabolic process, in cancer cells autophagy has numerous downstream effects, being observed to be both pro- and anti-apoptotic. One of the primary factors mediating this differential role of autophagy is the accumulation or sequestration of reactive oxygen species (ROS). Until recently, despite its increasing popularity in the Western world, the efficacy of herbal supplements has been largely anecdotal. Herein, we reviewed the ten most commonly studied herbs in cancer research and their impact on ROS regulation, on the activation and inhibition of autophagy, and ultimately on cancer cell death. PMID- 30311565 TI - Molecular Responses of Cancers by Natural Products: Modifications of Autophagy Revealed by Literature Analysis. AB - Although numerous bibliometric studies have examined various aspects of cancer research, the landscape of scientific studies focusing on natural products in cancer research has not been characterized. Using the Web of Science Core Collection online database, we identify and analyze scientific articles on natural products in cancer-related research. English is the language of publication for 99% of articles. In general, annual citation count of an article increases quickly after publication, reaches a plateau in the second year, stays in this plateau for 10 yr, and then begins to fall. The five most contributing journal categories are medicinal chemistry, contributing the most at 1890 articles (24% of 8012 articles); oncology (20%, with 1572 articles); pharmacology and pharmacy (19%, with 1557); biochemistry and molecular biology (15%, with 1225); and plant sciences (11%, with 883 articles). The United States and Spain yield a larger number of articles with high average citations, and China has been increasing since 2009. Apoptosis and cytotoxicity are the two most-frequently used keywords. Effects of natural products on autophagy with a relevance to cancer are mentioned in 69 publications. Our literature analysis reveals a dynamically evolving landscape and an increasing volume of research investigations that are focused on the study of natural products in the context of cancer. Curcumin, flavonoids, and resveratrol are the most-frequently mentioned natural products. Cancer of the breast, prostate, and colon are the most-frequently mentioned cancers. PMID- 30311566 TI - The Control of Meiotic Recombination in the Human Genome. AB - Meiotic recombination plays a key role in reshuffling haplotypes in human populations and thus affects evolution profoundly. However, our understanding of recombination dynamics is largely limited to descriptions of variation in populations and families. Higher-resolution analysis (<= 0.0001 cM) of de novo recombination events in human sperm DNA has revealed clustering into very narrow hotspots (1-2 kb) that generally coincide with abrupt breakdown of linkage disequilibrium. Recent findings have highlighted an unexpected molecular control of the distribution of meiotic double-strand breaks (DSBs) in mammals by a rapidly evolving gene in trans, PR-domain-containing 9 (PRDM9), and specific DNA sequence motifs in cis. In addition, the understanding of new regulators in DSB repair processes has allowed the delineation of recombination pathways that have two major outcomes, cross-overs and non-cross-overs, which have distinct mechanistic roles and consequences for genome evolution. Further molecular studies are needed to gain information about how hotspots originate, function, and evolve. PMID- 30311567 TI - Methods for Detecting Human Meiotic Recombination Hotspots. AB - Traditional methods for analyzing meiotic recombination in humans are limited. Recently developed in vitro and in silico assays together are useful for confirmation and detection of meiotic recombination hotspots from population polymorphism data. These techniques are significant both for understanding the nature of human meiotic recombination and for applications such as association studies. PMID- 30311568 TI - Role of the Tristetraprolin (Zinc Finger Protein 36 Homolog) Gene in Cancer. AB - Cancer is a complicated transformational progression that fiercely changes the appearance of cell physiology as well as cells' relations with adjacent tissues. Developing an oncogenic characteristic requires a wide range of modifications in a gene expression at a cellular level. This can be achieved by activation or suppression of the gene regulation pathway in a cell. Tristetraprolin (TTP or ZFP36) associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA destabilizing elements (AREs) located in their 3'-untranslated regions. TTP is an attractive target for therapeutic use and diagnostic tools due to its characteristic appearance in cancer tissue alone. Thus, the illumination of TTP in diverse types of cancer might deliver additional effective remedies in the coming era for cancer patients. The objective of this review is to familiarize the reader with the TTP proteins, focus on efficient properties that endow them with their effective oncogenic potential, describe their physiological role in cancer cells, and review the unique properties of TT, and of TTP-driven cancer. PMID- 30311569 TI - Comprehensive Analysis of Phytochemical Constituents and Ethnopharmacological Investigation of Genus Datura. AB - The genus Datura comprises wild shrub plants that belong to the Solanaceae family. Naturally, they possess both medicinal and poisonous properties due to the presence of many biologically active phytochemical constituents. Traditionally, Datura had been used for mystic and religious purposes, as a natural drug to treat asthma, pain, gout, boils, abscesses, and wounds, and as psychoactive infusions and fumitories. Different Datura species exhibit diverse ethnopharmacological activities against different diseases, and many ancient and traditional cultures have used various forms of Datura to treat ailments and to prevent many diseases. In this article, we comprehensively summarize various phytochemical constituents isolated from Datura, their pharmacological properties against different diseases, parts of the plants used as traditional therapeutic agents, regions where they are located, and botanical descriptions of different Datura species. The ethnopharmacological properties of Datura may provide new insights for discovery and development of natural drugs. Further research is needed for the investigation of mechanisms of action and to develop safety profiles of the phytochemical constituents isolated from Datura species. PMID- 30311570 TI - Current State of Knowledge on Salivary Gland Cancers. AB - Salivary gland cancers (SGCs), categorized as head and neck cancers (HNCs), constitute about 6% of head and neck cancer diagnoses based on estimate by American Head and Neck Society. Salivary gland tumors originate from different glandular cell types and are thus morphologically diverse. These tumors arise from any of the three major and various minor salivary glands. The incidence of SGCs has slowly increased during the last four decades. The etiology of SGCs is mostly unknown; however, specific gene mutations are associated with certain types of salivary tumors. Treatment options include surgical resection, radiation therapy (RT), chemotherapy, and multimodality therapy. HNC patients treated with RT often develop xerostomia and salivary hypofunction due to damaged salivary glands. In this review, we discuss etiology of SGCs, present findings on the role of autophagy in salivary tumorigenesis, review adverse effects of radiation treatment, and examine remedies for restoration of salivary function. PMID- 30311571 TI - The Microbiome of Oral Cancer. AB - The pathogenesis of oral cancer is complex, and not all relevant factors involved in it have been determined. In particular, the role of the microbiota is not well understood because of difficulties in isolating and culturing its organisms. However, the recent development of metagenomic sequencing allows the discovery of all the DNA sequences in a specimen, and thus, the microbiome is now under intensive investigation. Studies of the bacteriome, the mycobiome, and the virome have revealed new organisms and have uncovered various differences between healthy persons and patients with oral cancer. In addition, sequencing of human samples shows the existence of DNA sequences that may be from novel microbes but are actually of unknown origin and so are referred to as the dark matter. The large volumes of data that are being produced by sequencing projects must be studied further to reveal novel pathogens and new pathways in the development of oral cancer. PMID- 30311572 TI - Immunotherapeutic Approaches to Head and Neck Cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive disease with multiple mechanisms to impair immune-mediated recognition and control of tumor cell proliferation and metastasis. Based on successes experienced with cancer immunotherapy in the treatment of other solid tumors, considerable efforts are underway to develop immunotherapeutics that can enhance the host antitumor response to HNSCC. Promising results in preclinical studies and early clinical trials have been reported, prompting the FDA to approve the use of the immune checkpoint PD-1 receptor antagonist pembrolizumab for the treatment of platinum refractory recurrent or metastatic HNSCC in 2016. Ongoing clinical trials are investigating the use of various immunotherapies, such as vaccines, adoptive T cell transfer, and immune modulating antibodies alone or in conjunction with traditional treatment modalities, to achieve more efficacious, more durable, and less toxic treatments. In this article, we provide a basic review of the role of the immune system in developing malignancy, and we discuss some notable mechanisms of immune evasion in HNSCC. We highlight current approaches and published clinical results of immunotherapy in the treatment of HNSCC. PMID- 30311573 TI - p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy. AB - Head and neck cancers are deadly diseases that are diagnosed annually in approximately half a million individuals worldwide. Growing evidence supporting a role for cancer stem cells (CSCs) in the pathobiology of head and neck cancers has led to increasing interest in identifying therapeutics to target these cells. Apart from the canonical tumor-suppressor functions of p53, emerging research supports a significant role for this protein in physiological stem cell and CSC maintenance and reprogramming. Therefore, p53 has become a promising target to sensitize head and neck CSCs to chemotherapy. In this review, we highlight the role of p53 in stem cell maintenance and discuss potential implications of targeting p53 to treat patients with head and neck cancers. PMID- 30311574 TI - An Updated Review of Oral Cancer Stem Cells and Their Stemness Regulation. AB - Cancer stem cells (CSCs; also known as tumor-initiating cells) are a small population of cancer cells that retain characteristics similar to those of normal stem cells. CSCs are known to be responsible for metastasis, drug resistance, and cancer recurrence. Thus, controlling CSCs may provide an effective therapeutic intervention that inhibits tumor growth and aggressiveness. Despite the importance of targeting CSCs in cancer therapy, the detailed nature of oral CSCs remains underexplored. This article reviews the current understanding of oral CSCs, with emphasis on recent advances in novel signaling pathways involved in their stemness regulation. PMID- 30311575 TI - Regulation of Epithelial Cell Proliferation, Differentiation, and Plasticity by Grainyhead-Like 2 During Oral Carcinogenesis. AB - Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis. PMID- 30311576 TI - Immunotherapy for EBV-Associated Nasopharyngeal Carcinoma. AB - Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies in southern China and Southeast Asia. Unfortunately, 70% of NPC patients have locally advanced disease at the first diagnosis. Radiotherapy alone and concurrent chemoradiotherapy are important treatment approaches for NPC, but they have a limited effect on patients with locally advanced or distantly metastatic disease. 1-5 Nevertheless, the unique immune environment of the EBV-associated NPC provides rational targets for immunotherapy. Diverse types of immunotherapies are actively being studied, including adoptive immunotherapy, therapeutic vaccines, immune checkpoint inhibitors, lytic-induction therapy, and viral immunotherapy. Specifically, adoptive immunotherapy with lymphocyte infusion was well tolerated and effective in 71.4% of patients combined with first-line chemotherapy. Several therapeutic vaccines and PD-1/PD-L1 pathway checkpoint inhibitors have shown promising clinic outcomes at phase I/II clinical trials. Moreover, EBV-lytic inducing therapy and viral immunotherapy for NPC are also being investigated. In this review, we summarized the current status, advantages, and disadvantages of each immunotherapy for EBV-associated NPC, which may shed light on developing safer and more effective treatment modalities in the future. PMID- 30311577 TI - Surveillance of HPV-Positive Head and Neck Squamous Cell Carcinoma with Circulating and Salivary DNA Biomarkers. AB - Head and neck squamous cell carcinoma (HNSCC) manifests in the mucosal epithelial lining of the oral cavity, oropharynx, hypopharynx, nasopharynx or larynx and has a tremendous disease burden worldwide. Smoking and alcohol consumption were once major risk factors, but HPV-associated infection has emerged as the major contributor to HNSCC occurrence in developed countries. Circulating biomarker evaluations in biofluids, also known as liquid biopsy, are an attractive alternative for cancer screening as they are minimally invasive, potentially low cost, and easily repeatable on a serial basis. This review summarizes the current knowledge and potential of assessing circulating blood and salivary HPV DNA and HPV antibodies for the surveillance of HPV-positive HNSCC. Additionally, the biological underpinnings of the presence and relevance of circulating HPV DNA is discussed. PMID- 30311579 TI - Interleukin-1 Beta +3594 C/T Gene Polymorphism and Susceptibility to Sepsis: A Meta-Analysis. AB - Emerging evidence has indicated that the interleukin-1B (IL-1B) +3954 C > T polymorphism may affect individual susceptibility to sepsis. However, the results of published studies are inconclusive. The aim of this meta-analysis was to elucidate the association of this polymorphism with sepsis risk. Eligible studies were identified by a search of electronic databases. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were applied to assess the associations between the IL-1B +3954 C > T polymorphism and sepsis risk. Six case-control studies were included in this meta-analysis. The pooled analysis indicated that the IL-1B +3954 C > T polymorphism significantly decreased the risk of sepsis under the homozygote model (TT vs. CC: OR = 0.57, 95% CI:0.37-0.88). In stratified analysis, we found that the protective effect of the IL-1B +3954 C > T polymorphism on sepsis risk remained significant in the subgroup of Caucasians and for high-quality studies. In conclusion, the IL-1B +3954 C > T polymorphism is associated with decreased sepsis risk in Caucasians. Further well-designed studies with large sample sizes are required to confirm this conclusion. PMID- 30311578 TI - Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem Cells: Characterization, Differentiation, and Applications in Cartilage Tissue Engineering. AB - Articular cartilage defects have very limited self-repair potential, and traditional bone marrow-stimulating therapy is not effective. Cartilage tissue engineering using bone marrow mesenchymal stem cells (BMSCs) and adipose tissue derived mesenchymal stem cells (ADSCs) is considered an attractive treatment for cartilage lesions and osteoarthritis. However, studies proved that both BMSCs and ADSCs have their own advantages and shortcomings, including their sources, isolation methods, characterizations and differentiation potential. Understanding the properties and differences between ADSCs and BMSCs is important for clinical application in cartilage regeneration. This review provides an overview of BMSCs and ADSCs based on their characterization, isolation. Then, we summarized their differentiation potential in different experimental conditions. Finally, we discuss the applications of BMSCs and ADSCs in scaffold-free and scaffold-based cartilage tissue engineering. Based on different properties of BMSCs and ADSCs, and patient's physical condition, a more suitable therapeutic strategy can be selected. PMID- 30311580 TI - The Mechanisms of Dietary Phytoestrogen as a Potential Treatment and Prevention Agent against Alzheimer's Disease. AB - Alzheimer's disease (AD) is a major dementia disease worldwide with an increasing incidence rate among the elderly. It is a neurodegenerative disease with symptoms starting slowly and then progressing over time. There has been extensive research on AD prevention and treatment; however, there is no cure as of yet. Several drugs are being researched for the treatment and prevention of AD, with a rising interest in specific dietary compounds as potential interventions with lower side effects. One such dietary compound being tested is phytoestrogen. Phytoestrogens are chemically, structurally, and functionally similar to estrogen, which has numerous functions as a cognition-promoting agent; although, as a supplement it can be damaging. Phytoestrogens have the unique ability to substitute for estrogen in elderly individuals with Alzheimer's disease and depleted estrogen levels. This paper aims to contribute to the collective understanding of phytoestrogen's role in the treatment and prevention of Alzheimer's disease by describing its various mechanisms, including its ability to decrease amyloid beta peptide production, promote calcium outflow and acetylcholine release, and reduce Tau protein phosphorylation. The paper also addresses phytoestrogen's role as an anti-inflammatory and antioxidant agent for the cholinergic neurons associated with Alzheimer's disease. PMID- 30311581 TI - The Study of Nrf2 Signaling Pathway in Ovarian Cancer. AB - Ovarian cancer is one of the most malignant gynecological tumors in the world, with a high fatality rate and resistance to chemotherapy. Much basic research has revealed that oxidative stress is involved in tumor occurrence and development processes and is associated with tumor progression as well as metastasis. In recent years, oxidative stress has been proven to have a close connection with malignant biological behavior in ovarian cancer, and this topic has garnered increasing attention. This article reviews the research aimed toward elucidating the relationship between oxidative stress and ovarian cancer. PMID- 30311582 TI - The Trace Element Zinc in the Composition of Native Chorionic Gonadotropin. AB - Human chorionic gonadotropin (hCG) is a most important regulator of embryogenesis and spermatogenesis. Equally important for the development of the fetus is the trace element zinc, which is essential for sustainable fetal development. The involvement of hCG and zinc in the first trimester of pregnancy (embryogenesis) led us to question the possibility of their structural cooperation and inclusion in the native molecule chorionic gonadotropin and zinc atoms. At the same time, we found increasing stability of the hormonal structure in the background of hCG interaction with zinc. Thus, the aim of our research was to study the possible zinc presence in the molecule of native hCG. The drug chorionic gonadotropin (1000 IU lyophilisate) was selected as the object of investigation, representing the native hormone that was derived from the urine of pregnant women. For detection of ionized zinc, we used stripping voltammetry and mass spectrometry with inductively coupled plasma at a high resolution (up to 7.10 g/L). The research of nonmineralized samples of chorionic gonadotropin lyophilisate proved its absence in free zinc. Premineralization of the samples made it possible to reveal zinc presence in nine to 17 atoms/molecule of hormone. Detecting bound zinc in the composition of native chorionic gonadotropin confirms its role as an important structural element, capable of producing compound stability and ensuring specific activity during pregnancy. The composition of native chorionic gonadotropin and a major amount of zinc in the bound state, compared to a relatively small amount of free particles, indicates the existence of the sufficiently strong intramolecular bond of hCG and zinc for maintaining active pregnancy. This fact will allow us to design methods for maintaining stable medication during pregnancy on the basis of regulation of trace-element composition in a patient's blood. PMID- 30311583 TI - The Use of Scaffolds in Cartilage Regeneration. AB - Scaffolds are important tools in tissue engineering and play a unique role in tissue regeneration and repair of damaged tissues. A variety of natural, synthetic, and composite scaffold types can be used in cartilage tissue engineering. The limited capability of cartilage to repair itself has always been a problem during recovery from damage. The success of cartilage regeneration is dependent on a couple of factors, but the basic properties of scaffolds are biocompatibility, degradability under physiological conditions, and structural support for cell attachment. In this review, we summarize the use of different scaffold types in cartilage regeneration. PMID- 30311584 TI - A Putative Association of Interleukin-1beta Promoter Polymorphisms and IL-1beta Levels in Saudi Diabetic Patients. AB - Type 2 diabetes mellitus (T2DM) is a well-known endocrine disorder affecting a significant number of individuals across the globe. Risk factors such as inflammation, obesity, high blood glucose level, cardiovascular disease, and genetic alteration are believed to be the reason for T2DM onset. The current study was intended to envisage the possible association between polymorphisms in the interleukin-1beta (IL-1beta) promoter and IL-1beta serum levels in Saudi T2DM patients. Biochemical parameters such as fasting blood glucose (FBS), percentage glycosylated hemoglobin (HbAic), and lipid profile were measured spectrophotometrically. Serum insulin levels were measured using an immunochemistry analyzer. The commercial enzyme-linked immune assay (ELISA) kit was used to estimate the level of IL-1beta in the serum samples. The Sanger sequencing method was adopted to determine single-nucleotide polymorphisms (SNPs) in the IL-1beta promoter. We observed a significant (P < 0.001) elevation in FBS, Hb1Ac, insulin, and low-density lipoprotein cholesterol in T2DM patients compared with control individuals. Similarly, IL-1beta level were found to be increased by 221% in T2DM patients compared with controls. A nonsignificant genotypic association was observed in the IL-1beta gene at the -511C/T and -31C/T positions in T2DM patients compared with control individuals. However, a significant association (P < 0.05) was observed at the allelic level. Further studies on larger sample sizes are recommended to establish the exact role of IL-1beta polymorphism in the pathogenesis of T2DM and its genetic risk. PMID- 30311585 TI - Zika Virus: A Critical Analysis and Pharmaceutical Perspectives. AB - Zika virus belongs to family of viruses 'Flaviviridae' and spreads mostly by daytime-active Aedes mosquitoes. The resulting infection is known as Zika fever. It is usually asymptomatic or often causes mild symptoms, which are very similar to dengue fever. The Aedes aegypti mosquito is also responsible for dengue and chikungunya viruses. Zika virus can spread by crossing the placental barrier from a pregnant mother to a fetus, which can result in microcephaly, severe brain malformations including Guillain-Barre syndrome (GBS), and other birth defects. Until now, there is no specific treatment of Zika fever disease, and Zika virus illness cannot be prevented by medications or vaccines. According to WHO, no vaccine is likely to be available until 2020. The only way of preventing this disease is to prevent the mosquito bites. This article presents the history of Zika virus, its reported cases including microcephaly and GBS, and a comparison of its symptoms with those of dengue and chikungunya diseases, as well as preventive measures. With advances in research and technology, knowledge about the Zika virus has grown, yet some questions remain unanswered regarding Zika virus's genetic diversity, pathophysiology, transmission vectors and reservoirs, potential synergetic of coinfection with other related arboviruses, and treatment. These problems highlight the need for further research to achieve adequate the surveillance, infection management, optimized treatment, and public health mediations in Zika virus outbreaks. This article contributes to our understanding of the disease mechanism, genome structure, diagnosis, transmission, and preventive strategies to combat Zika virus infection. PMID- 30311586 TI - Interferon-Free Regimen for Hepatitis C: Insight and Management. AB - The rapid development of direct-acting antiviral agents (DAA) for hepatitis C virus (HCV) therapy dramatically altered the treatment landscape of this disease. The DAA regimen is associated with various advantages including high sustained virological response (SVR) with minimum side effects and low pill load and specific inhibition of viral replication, which lowers dependence on the host cell. This regimen has substantially replaced conventional (interferon) therapy with high cure rates (> 90%) in most HCV populations. This review provides insight into clinical studies of NS3/4A protease inhibitors, NS5B viral polymerase inhibitor (nucleotide and non-nucleotide), and NS5A inhibitors, alone and in combination. PMID- 30311588 TI - Role of Transforming Growth Factor Family of Peptides in Health and Diseases. PMID- 30311590 TI - Estimating the incidence of first-episode psychosis using population-based health administrative data to inform early psychosis intervention services. AB - BACKGROUND: Discrepancies between population-based estimates of the incidence of psychotic disorder and the treated incidence reported by early psychosis intervention (EPI) programs suggest additional cases may be receiving services elsewhere in the health system. Our objective was to estimate the incidence of non-affective psychotic disorder in the catchment area of an EPI program, and compare this to EPI-treated incidence estimates. METHODS: We constructed a retrospective cohort (1997-2015) of incident cases of non-affective psychosis aged 16-50 years in an EPI program catchment using population-based linked health administrative data. Cases were identified by either one hospitalization or two outpatient physician billings within a 12-month period with a diagnosis of non affective psychosis. We estimated the cumulative incidence and EPI-treated incidence of non-affective psychosis using denominator data from the census. We also estimated the incidence of first-episode psychosis (people who would meet the case definition for an EPI program) using a novel approach. RESULTS: Our case definition identified 3245 cases of incident non-affective psychosis over the 17 year period. We estimate that the incidence of first-episode non-affective psychosis in the program catchment area is 33.3 per 100 000 per year (95% CI 31.4 35.1), which is more than twice as high as the EPI-treated incidence of 18.8 per 100 000 per year (95% CI 17.4-20.3). CONCLUSIONS: Case ascertainment strategies limited to specialized psychiatric services may substantially underestimate the incidence of non-affective psychotic disorders, relative to population-based estimates. Accurate information on the epidemiology of first-episode psychosis will enable us to more effectively resource EPI services and evaluate their coverage. PMID- 30311591 TI - Cryptococcal Capsules in Cerebrospinal Fluid Visible on Hemocytometer. PMID- 30311592 TI - Genetic risk score based on fat mass and obesity-associated, transmembrane protein 18 and fibronectin type III domain containing 5 polymorphisms is associated with anthropometric characteristics in South Brazilian children and adolescents. AB - The prevalence of childhood obesity has increased worldwide. Although it is considered a polygenic inheritance disease, little is known about its susceptibility when the additive effect is considered. The aim of this study is to investigate whether the genetic risk score (GRS) based on previously associated obesity polymorphisms (SNP) rs9939609 (fat mass and obesity-associated (FTO)), rs6548238 (transmembrane protein 18 (TMEM18)) and rs16835198 (fibronectin type III domain containing 5 (FNDC5)) could serve as a predictor for anthropometric characteristics in a sample of Brazilian children and adolescents. This is a cross-sectional study with 1471 children and adolescents aged 6-17 years. BMI, waist circumference (WC) and percentage of body fat and metabolic parameters were verified. In all, three SNP were genotyped by TaqManTM allelic discrimination. The metabolic and anthropometric parameters were compared between the genotypes, and the unweighted and weighted GRS (GRS and wGRS, respectively) were created to test the additive effect of these genetic polymorphisms on anthropometric parameters. The prevalence of overweight plus obesity was 41 %. Significant associations were identified for FTO rs9939609, TMEM18 rs6548238 and FNDC5 rs16835198 and for GRS and wGRS with anthropometric phenotypes. The higher score of wGRS was associated with obesity (OR: 2.65, 95 % CI 1.40, 5.04, P=0.003) and with greater WC (OR: 2.91, 95 % CI 1.57, 5.40, P=0.001). Our results suggest that these genetic variants contribute to obesity susceptibility in children and adolescents and reinforce the idea that the additive effect may be useful to elucidate the genetic component of obesity. PMID- 30311593 TI - Impact of dietary macronutrient profile on feline body weight is not consistent with the protein leverage hypothesis. AB - The protein leverage hypothesis proposes that the need to prioritise protein intake drives excess energy intake (EI) when the dietary ratio of protein to fat and carbohydrate is reduced. We hypothesised that cats may become prone to overconsuming energy content when moderate protein diets were offered, and considered the potential influence of fat and carbohydrate on intake. To determine the effect of dietary protein and macronutrient profile (MNP) on EI, weight and body composition, cats (1-4 years) were offered food in excess of energy requirements (ER). A total of six diets were formulated, containing moderate (approximately 7 % w/w; approximately 22 % metabolisable energy (ME)) or high (approximately 10 % w/w; approximately 46 % ME) protein and varying levels of carbohydrate and fat. For 4 weeks, 120 cats were offered 100 % of their individual ER of a diet at the MNP selected by adult cats (50:40:10 protein energy ratio:fat energy ratio:carbohydrate energy ratio). EI, body weight (BW), body composition, activity and palatability were measured. Subsequently, cats were offered one of the six diets at 200 % of their individual ER for 4 weeks when measurements were repeated. Cats offered excess high protein diets had higher EI (kJ/kg) throughout, but at 4 weeks BW was not significantly different to baseline. Cats offered excess moderate protein diets reduced EI and gradually lost weight (average loss of 0.358 (99 % CI 0.388, 0.328) kg), irrespective of fat:carbohydrate and initial palatability. The data do not support the protein leverage hypothesis. Furthermore, cats were able to adapt intake of a wet diet with high protein in an overfeeding environment within 28 d. PMID- 30311594 TI - Maternally inherited rRNA triggers de novo nucleolus formation in porcine embryos. AB - SummaryThe present study examines the role of RNA polymerase I (RPI)-mediated transcription, maternally inherited rRNA and nucleolar proteins in the resumption of fibrillogranular nucleoli during embryonic genome activation (EGA) in porcine embryos. Late 4-cell embryos were incubated in the absence (control) or presence of actinomycin D (AD) (0.2 MUg/ml for inhibition of RPI; 2.0 MUg/ml for inhibition of total transcription) and late 2-cell embryos were cultured to the late 4-cell stage with 0.2 MUg/ml AD to block EGA. Embryos were then processed for reverse-transcriptase polymerase chain reaction (RT-PCR), and for autoradiography (ARG), transmission electron microscopy (TEM), fluorescence in situ hybridization (FISH), silver staining and immunofluorescence (for RPI). Embryos in the control group displayed extranucleolar and intranucleolar ARG labelling, and exhibited de novo synthesis of rRNA and reticulated functional nucleoli. Nucleolar proteins were located in large foci. After RPI inhibition, nucleolar precursors transformed into segregated fibrillogranular structures, however no fibrillar centres were observed. The localization of rDNA and clusters of rRNA were detected in 57.1% immunoprecipitated (IP) analyzed nucleoli and dispersed RPI; 30.5% of nuclei showed large deposits of nucleolar proteins. Embryos from the AD-2.0 group did not display any transcriptional activity. Nucleolar formation was completely blocked, however 39.4% of nuclei showed rRNA clusters; 85.7% of nuclei were co-localized with nucleolar proteins. Long-term transcriptional inhibition resulted in the lack of ARG and RPI labelling; 40% of analyzed nuclei displayed the accumulation of rRNA molecules into large foci. In conclusion, maternally inherited rRNA co-localized with rDNA and nucleolar proteins can initiate a partial nucleolar assembly, resulting in the formation of fibrilogranular structures independently on activation of RPI-mediated transcription. PMID- 30311595 TI - Moderate coffee consumption is inversely associated with the metabolic syndrome in the Korean adult population. AB - Results from studies investigating the association between coffee consumption and the metabolic syndrome in Koreans have been inconsistent and remain controversial. We examined coffee intake in relation to the metabolic syndrome using data from the Korea National Health and Nutrition Examination Survey 2012 2015, with 8387 adults aged 19-64 years. Furthermore, we conducted a stratified analysis by obesity status (BMI <25 v. >=25 kg/m2) to examine whether the association varied by obesity status. A 112-item FFQ was used to assess diet. Multivariable logistic regression models were used to determine the association of coffee consumption (<1, 1-2, 3-4 and >=5 times/d) and the metabolic syndrome. Compared to people who consumed <1 time/d of coffee, the OR for the metabolic syndrome in those who consumed 3-4 times/d of coffee was 0.75 (95 % CI 0.58, 0.97). However, >=5 times/d of coffee consumption was not significantly associated with the metabolic syndrome. By obesity status, in non-obese people, those consuming more coffee had lower odds of the metabolic syndrome, showing a significant linear trend (P-trend=0.0248). In obese people, the OR for the metabolic syndrome in people with 3-4 times/d of coffee consumption v. <1 time/d was 0.68 (95 % CI 0.50, 0.93), but >=5 times/d of coffee consumption showed a non significant positive association. Our findings suggest that moderate coffee consumption of 3-4 times/d is inversely associated with the metabolic syndrome in Korean adults. The association between heavy coffee consumption of >=5 times/d and the metabolic syndrome varied by obesity status. PMID- 30311596 TI - The right to choose treatment-without-treatment: respecting civil rights or an unprecedented manifestation of 'reverse stigma'? AB - Recently the Norwegian Health Minister ordered the creation of medication-free treatment wards as a result of the lobbying by patients' groups and activists. The idea behind this is that patients should have the right to choose their treatment, but for the first time, with this arrangement, the user/patient does not choose between treatment options; he literally determines by himself what efficacious treatment is. In our opinion this is another step towards a 'reverse stigma' which denies patients the right to be considered as such and eventually kicks them out of the health care system, deprives them of the right for proper treatment and care and instead puts them at the jurisdiction of the much cheaper and ineffective social services. PMID- 30311597 TI - Opinion paper: poor response to treatment of depression in people in high occupational levels. AB - The working environment may have a significant effect on response to treatment of depression and this issue has not yet been sufficiently addressed in the scientific literature. There is evidence showing that being engaged in high-level positions can be an obstacle to the success of treatment. This article discusses the few evidence in the literature and some of the possible mechanisms involved. Specific personality attributes and difficulties in adapting to depression may delay access to care and may also reduce treatment compliance. The presence of stress in jobs that require high cognitive function and lack of social support may be elements that hinder the recovery process. Residual symptoms that impact on cognitive functions may undermine adherence to treatment and adversely affect the response. The implications of these issues are potentially relevant for clinical practice in the treatment of depression and for future research. PMID- 30311598 TI - Voluntary policies on checkout foods and healthfulness of foods displayed at, or near, supermarket checkout areas: a cross-sectional survey. AB - OBJECTIVE: To determine if voluntary policies on supermarket checkout foods are associated with a difference in the healthfulness of foods displayed at, or near, supermarket checkout areas. DESIGN: Cross-sectional survey of foods at, or near, supermarket checkouts categorised as less healthy or not according to the Food Standards Agency's Nutrient Profiling Model. SETTING: One city in Eastern England (population about 125 000). SUBJECTS: All stores in nine supermarket groups open for business in June-July 2017 in the study city. Supermarket checkout food policies were categorised as clear and consistent, vague or inconsistent, or none. RESULTS: In thirty-three stores, 11 434 checkout food exposures were recorded, of which 8010 (70.1 %) were less healthy; and 2558 foods in areas near checkouts, of which 1769 (69.2 %) were less healthy. After adjusting for a marker of store size, the odds of a checkout food exposure being 'less healthy' was lower in stores with vague or inconsistent checkout policies (OR=0.63; 95 % CI 0.49, 0.80) and in stores with clear and consistent checkout policies (OR=0.33; 95 % CI 0.24, 0.45), compared with no policy. There was no difference in the odds of foods near, but not at, checkouts being less healthy according to checkout food policy. CONCLUSIONS: Supermarket checkout food policies were associated with lower odds of checkout foods but not foods near, but not at, checkouts being less healthy. Further research is required to explore impacts on purchasing and consumption. PMID- 30311599 TI - Affective and interpersonal psychopathic traits associated with reduced corpus callosum volume among male inmates. AB - BACKGROUND: Psychopathy is a personality disorder associated with severe emotional and interpersonal consequences and persistent antisocial behavior. Neurobiological models of psychopathy emphasize impairments in emotional processing, attention, and integration of information across large-scale neural networks in the brain. One of the largest integrative hubs in the brain is the corpus callosum (CC) - a large white matter structure that connects the two cerebral hemispheres. METHOD: The current study examines CC volume, measured via Freesurfer parcellation, in a large sample (n = 495) of incarcerated men who were assessed for psychopathic traits using the Hare Psychopathy Checklist-Revised (PCL-R). RESULTS: Psychopathy was associated with reduced volume across all five sub-regions of the CC. These relationships were primarily driven by the affective/interpersonal elements of psychopathy (PCL-R Factor 1), as no significant associations were found between the CC and the lifestyle/antisocial traits of psychopathy. The observed effects were not attributable to differences in substance use severity, age, IQ, or total brain volume. CONCLUSIONS: These findings align with suggestions that core psychopathic traits may be fostered by reduced integrative capacity across large-scale networks in the brain. PMID- 30311600 TI - Agreement of body adiposity index (BAI) and paediatric body adiposity index (BAIp) in determining body fat in Brazilian children and adolescents. AB - OBJECTIVE: To evaluate agreement of the body adiposity index (BAI) and paediatric body adiposity index (BAIp) in estimating body fat compared with dual-energy X ray absorptiometry (DXA) and to propose cut-off points for these indices to classify excess adiposity in Brazilian children and adolescents. DESIGN: Cross sectional study. Measures of weight, height, hip circumference, BMI and body fat percentage (%BF) assessed by DXA were taken, and BAI and BAIp were calculated. The Bland-Altman plot was used to estimate agreement between the methods, and the receiver-operating characteristic curve to determine the cut-off points for BAI and BAIp per age and sex in comparison with DXA. SETTING: Vicosa, Minas Gerais, Brazil. SUBJECTS: Children and adolescents aged 8-19 years (n 1049). RESULTS: Of the children and adolescents, 52.4 % were girls. BAI and BAIp had satisfactory performance by the receiver-operating characteristic curve, except for the 18-19 years age group, whose BAIp had better predictive capacity than BAI. The agreement analysis showed that BAI overestimated %BF by 2.64 %, on average, using DXA; while BAIp underestimated %BF by 3.37 %. CONCLUSIONS: BAI and BAIp showed low agreement with the body fat obtained by DXA, requiring caution when interpreting body composition data in children and adolescents. PMID- 30311602 TI - Chemical vapor deposition and characterization of two-dimensional molybdenum dioxide (MoO2) nanoplatelets. AB - We report on the chemical vapor deposition synthesis of MoO2 nanoplatelets by sublimation of MoO3 and its reduction in a hydrogen atmosphere at 750 degrees C. When grown on Si/SiO2 substrates, the platelets primarily assume a rhomboidal shape and have thicknesses ranging from several to tens of nm. The morphology of MoO2 crystals was found to depend on the chemical nature of substrates. MoO2 platelets on Si/SiO2 were characterized by a number of microscopic and spectroscopic techniques, and the electrical measurements revealed the metallic nature of their conductivity averaging at 2400 +/- 1000 S cm-1. Raman spectroscopy of MoO2 platelets on graphene indicates their strong hole injection property. Small thickness, planar morphology, high chemical stability and metallic conductivity of ultrathin MoO2 platelets make them potentially interesting for integration different other two-dimensional materials in a variety of electronic structures and devices. PMID- 30311601 TI - The chloroplast 2-cysteine peroxiredoxin functions as thioredoxin oxidase in redox regulation of chloroplast metabolism. AB - Thiol-dependent redox regulation controls central processes in plant cells including photosynthesis. Thioredoxins reductively activate, for example, Calvin Benson cycle enzymes. However, the mechanism of oxidative inactivation is unknown despite its importance for efficient regulation. Here, the abundant 2-cysteine peroxiredoxin (2-CysPrx), but not its site-directed variants, mediates rapid inactivation of reductively activated fructose-1,6-bisphosphatase and NADPH dependent malate dehydrogenase (MDH) in the presence of the proper thioredoxins. Deactivation of phosphoribulokinase (PRK) and MDH was compromised in 2cysprxAB mutant plants upon light/dark transition compared to wildtype. The decisive role of 2-CysPrx in regulating photosynthesis was evident from reoxidation kinetics of ferredoxin upon darkening of intact leaves since its half time decreased 3.5 times in 2cysprxAB. The disadvantage of inefficient deactivation turned into an advantage in fluctuating light. Physiological parameters like MDH and PRK inactivation, photosynthetic kinetics and response to fluctuating light fully recovered in 2cysprxAB mutants complemented with 2-CysPrxA underlining the significance of 2-CysPrx. The results show that the 2-CysPrx serves as electron sink in the thiol network important to oxidize reductively activated proteins and represents the missing link in the reversal of thioredoxin-dependent regulation. PMID- 30311604 TI - The degree of invasiveness has no influence on the rate of incidental durotomies in surgery for lumbar spinal canal stenosis. Data from the German Spine Registry. AB - BACKGROUND: Risk factors for incidental durotomies are good documented claimed from some authors the degree of invasiveness as a direct risk factor on this serious complication. We compared the rate of incidental durotomies and its dependence from the degree of invasiveness. METHODS: The German Spine Registry could document 6016 surgeries for lumbar spinal canal stenosis, n= 2539 microsurgical decompression and n= 2371 open decompression with stabilization. RESULTS: Both groups were identical concerning age and sex of patients: mean age 77,1 +/- 1,60, female 58%, male 32%. There were 410 incidental durotomies, group 1 209 (8,23%), group 2 201 (8,47%). This difference is statistically not relevant (p=0,75). A surgical therapy is documented in 345 (84%) cases: suture with/ without fibrin glue: group 1= 162 and group 2= 183. 59 patients had a persistent fistula that needed treatment with a lumbar drain: group 1 n=30 and group 2 =29. CONCLUSIONS: The groups decompression vs. decompression plus fusion are statistically comparable. Although the stabilization with instrumentation is a more invasive procedure with longer operation times, more trauma tissue and blood loss in comparison with microsurgical decompression no difference in the rate of incidental durotomies was found. PMID- 30311603 TI - A Single Lateral Rectus Abdominis Approach for the Surgical Treatment of Complicated Acetabular Fractures: A Clinical Evaluation Study of 59 Patients. AB - BACKGROUND This study aimed to evaluate outcome following a single lateral rectus abdominis surgical approach for complicated acetabular fractures, involving anterior and posterior columns. MATERIAL AND METHODS From January 2012 to March 2016, 59 patients, including 36 anterior column hemitransverse fractures, 18 two column fractures, and five T-type complicated acetabular fractures, were treated with a single lateral rectus abdominis approach and fixed by plates and cannulated lag screws. Anterior column fractures were fixed with 3.5 mm reconstruction plates; posterior column fractures were fixed with 6.5 mm cannulated lag screws. The quality of surgical reduction (using the Matta criteria), functional outcome (using the modified Merle d'Aubigne and Postel scoring system), and postoperative complications were assessed with 24-month follow-up. RESULTS Fifty-nine patients (mean age, 45 years; range, 18-64 years) including 39 men and 20 women underwent surgery. Mean intraoperative blood loss was 514.6 ml (range, 150-830 ml) and mean operating time was 86.3 min (range, 42 145 min). Anatomical reduction was good in 40 cases (67.8%), fair in 15 cases (25.4%), and poor in four cases (6.8%). The modified Merle d'Aubigne score was excellent in 39 cases (66.1%), good in 14 cases (23.7%), fair in five cases (8.5%), and poor in one case (1.7%). At follow-up, there were five cases of peritoneal damage, eight cases of obturator nerve dysfunction, and four cases of postoperative traumatic arthritis. CONCLUSIONS The single lateral rectus abdominis surgical approach for the treatment of complicated acetabular fractures was minimally invasive with good anatomical exposure and good outcomes. PMID- 30311605 TI - The influence of clinical and radiological parameters in treatment of ruptured intracranial aneurysms: a single center 7-year retrospective cohort study. AB - BACKGROUND: In many clinical trials endovascular procedures are suggested as the treatment of choice for aneurysmal Subarachnoid Hemorrhage (aSAH) whenever possible. However, in clinical practice this management is often controversial. The aim of this study is to analyze factors involved in this decision. METHODS: Our study included 317 consecutive cases of aSAH between 2010 and 2016, assessing clinical and neuroradiological features to evaluate their role in this choice. RESULTS: In our series coiling was preferred in 119 (37.6%) patients, while 198 (62.4%) were treated surgically. On univariate analysis location of aneurysms (p < 0.001), GCS score on admission (p: 0.105), degree of midline shift (p:0.015), Fisher' score (p: 0.002) and presence of vessels in the aneurysmal neck (p: 0.071) proved the most relevant factors in the choice. Also multivariate analysis confirmed the location and Fisher' grade as influential factors. Conversely, other radiological parameters, such as morphology, aspect and dome-neck ratio, presence of pre-operative vasospasm or hydrocephalus were not associated with this decision. CONCLUSIONS: The decision process in aSAH requires a multidisciplinary team, to singularly evaluate each patient. We found that the location of aneurysms in Vertebro-Basilar circulation, PCoM and ICA, greater GCS score, absence of vessels in the aneurysmal neck, lower midline shift and Fisher' score are factors influencing in choosing coiling. Conversely, morphology, Aspect and Dome-Neck ratio proved not relevant to this decision, due to technological improvement and increasing skills in the endovascular treatment. PMID- 30311606 TI - Electrical characterization and examination of temperature-induced degradation of metastable Ge0.81Sn0.19 nanowires. AB - Metastable germanium-tin alloys are promising materials for optoelectronics and optics. Here we present the first electrical characterization of highly crystalline Ge0.81Sn0.19 nanowires grown in a solution-based process. The investigated Ge0.81Sn0.19 nanowires reveal ohmic behavior with resistivity of the nanowire material in the range of ~1 * 10-4Omega m. The temperature-dependent resistivity measurements demonstrate the semiconducting behavior. Moreover, failure of devices upon heating to moderate temperatures initiating material degradation has been investigated to illustrate that characterization and device operation of these highly metastable materials have to be carefully conducted. PMID- 30311607 TI - Development of efficient palladium catalysts for alkoxycarbonylation of alkenes. AB - Herein, we report a general and efficient Pd-catalysed alkoxycarbonylation of sterically hindered and demanding olefins including a variety of tri-, tetra substituted and 1,1-disubstituted alkenes. In the presence of 1,3-bis(tert butyl(pyridin-2-yl)phosphanyl)propane L3 or 1,4-bis(tert-butyl(pyridin-2 yl)phosphanyl)butane L4 the desired esters are obtained in good yields and selectivities. Similar transformation is obtained using tertiary ether as showcased in the carbonylation of MTBE to the corresponding linear ester in high yield and selectivity. PMID- 30311608 TI - CuAAC click chemistry for the enhanced detection of novel alkyne-based natural product toxins. AB - In the context of discovering and quantifying terminal alkyne-based natural products, here we report the combination of CuAAC click chemistry with LC-MS for the detection of polyether toxins (prymnesins) associated with harmful algal blooms. The added-value of the CuAAC-based approach is evident from our ability to detect novel prymnesin-like compounds in algal species with previously uncharacterised toxins. PMID- 30311609 TI - Cationic polymer-based plasmonic sensor array that discriminates proteins. AB - Breaking the restrictions of a lock-and-key sensing strategy which relies only on the most dominant interactions between the sensing element and target, here, we develop a colorimetric sensor array with three kinds of cationic polymers (polydiallyl dimethylammonium chloride (PDDA), chitosan (CTS), and cetyltrimethylammonium bromide (CTAB)) as nonspecific receptors. Diverse interactions between cationic polymers and proteins make gold nanoparticles (Au NPs) exhibit different aggregation behaviors, resulting in changes in color and absorbance of Au NPs. Based on the diverse colorimetric response patterns, seven proteins were successfully discriminated visually at the 20 nM level by linear discrimination analysis (LDA). Furthermore, the practicability of the sensor array was validated by the successful identification of proteins without any overlap in human serum samples. PMID- 30311610 TI - Thermally induced carbonation of Ca(OH)2 in a CO2 atmosphere: kinetic simulation of overlapping mass-loss and mass-gain processes in a solid-gas system. AB - Thermally induced carbonation of Ca(OH)2 in a CO2 atmosphere is a reaction exhibiting particular features, including stoichiometric completeness to form CaCO3 and a kinetic advantage over the carbonation of CaO particles. This study aims to gain further insight into the reaction mechanisms of CO2 capture by Ca(OH)2 and CaO. It focuses on the kinetic modeling of the carbonation of Ca(OH)2 as a consecutive reaction in a solid-gas system. The kinetic behaviors of the thermal decomposition of Ca(OH)2 in an inert gas atmosphere and of the overall process of thermally induced carbonation of Ca(OH)2 in a CO2 atmosphere were investigated using thermal analyses and other complementary techniques. Based on kinetic results, the overall reaction of the thermally induced carbonation of Ca(OH)2 in a CO2 atmosphere was separated by a kinetic deconvolution analysis into two consecutive reaction steps: the thermal decomposition of Ca(OH)2 and the subsequent carbonation of the CaO intermediate. The relationship between the two component reaction processes was well illustrated by a consecutive shrinkage of the dual reaction interfaces of Ca(OH)2-CaO and CaO-CaCO3. The continuous supply of water vapor and CO2 to the CaO-CaCO3 interface from different directions was suggested to be the physico-geometrical advantageous feature of the carbonation of Ca(OH)2. PMID- 30311611 TI - The influence of aqueous solvent on the electronic structure and non-adiabatic dynamics of indole explored by liquid-jet photoelectron spectroscopy. AB - Understanding how the electronic structure of an aqueous solute is intricately bound up with the arrangement of a host liquid provides insight into how non adiabatic photochemistry takes place in the condensed phase. For example, the presence of water provides additional solute-solvent interactions compared to non polar solvents: changing the stability of ionized products and modifying the energies of low-lying excited valence states, as well as moving the point of intersection between potential surfaces. Thus, the locations and topography of conical intersections between these surfaces also change. The overall impact of the aqueous environment can be to modify the intricate photochemical and non radiative pathways taking place after photoexcitation. Time-resolved photoelectron spectroscopy (TRPES) in a liquid micro-jet is implemented here to investigate the influence of water on the electronic structure and dynamics of indole, the chromophore of the amino acid tryptophan. TRPES is used to establish ultrafast relaxation pathways that vary as a function of excitation wavelength. In our experiment, aqueous indole was excited with femtosecond pulses centered at 292 nm and 266 nm. The vertical excitation energy of aqueous indole is extracted and found to be lowered by 0.5 eV in water relative to the gas phase. In the TRPES study, the spectral signature of 1La and evidence of solvated electron formation on an ultrafast timescale are observed. Our data also points to a possible contribution of the dissociative pisigma* state, which can be accessed by a conical intersection (CI) with the 1La state. PMID- 30311612 TI - Synthesis, structure and magnetic properties of two mixed-valence icosanuclear nanocages. AB - The reactions of 3,3'-bis(5-mercapto-1,2,4-triazole) with Co(ii) and Ni(ii) ions, respectively, gave two nanospheric mixed-valence icosanuclear cage-like complexes [M20L12](SO4)2.6DMF.CH3OH.3H2O (M = Co, 1; Ni, 2) with the in situ generated oxalyldithiosemicarbazide (H4L) as ligand. The eight octahedral M(ii) ions and twelve square-planar M(iii) ions in the two complexes are linked by twelve three connecting linkers of L4- to build an icosanuclear [MII8MIII12L12]4+ nanocage with an inner cubic MII8 cage core. Their cage skeletons are stable in water. The sulphate anions reside over the cage portals. The magnetic measurements of the two complexes revealed the presence of dominant antiferromagnetic interactions between the metal ions in both complexes. PMID- 30311613 TI - Quantitative relationship between cavitation and shear rheology. AB - Cavitation rheology is a powerful, simple, and inexpensive technique to study the moduli of polymer gels, however its use has not yet become widespread because few studies to date have directly compared this technique to traditional oscillatory shear rheology. Herein, we report a quantitative relationship between the gel modulus determined using cavitation and shear rheology for three series of model gels whose networks are composed of (1) permanently covalent, (2) dynamic covalent, and (3) physical hydrogen-bond crosslinks. We determine a simple proportionality constant that allows for conversion of the moduli obtained from both types of experiments and is highly dependent on the bond energy responsible for gelation. This study provides a framework for researchers in a broad range of disciplines who can exploit the ease of cavitation rheology and place their results in the context of traditional oscillatory shear rheology. PMID- 30311614 TI - Synthesis and anticholinesterase activity of 2-substituted-N-alkynylindoles. AB - In this paper, we report a protocol for the preparation of 2-substituted-N alkynylindoles via metalation of N-alkynylindoles followed by the capture of a 2 indolyl lithium intermediate with different electrophiles. The reactivity of the indoles prepared was also demonstrated through the reaction with CBr4/Ph3P for the preparation of 2-gem-dibromovinyl N-alkynylindoles and the hydrotelluration reaction of N-alkynylindoles, which led to vinylic tellurides. Some compounds prepared showed AChE inhibitory potential in the low micromolar range similar to that obtained with donepezil, a commercially available cholinesterase inhibitor. PMID- 30311615 TI - Exploring non-adiabatic approximations to the exchange-correlation functional of TDDFT. AB - A decomposition of the exact exchange-correlation potential of time-dependent density functional theory into an interaction component and a kinetic component offers a new starting point for non-adiabatic approximations. The components are expressed in terms of the exchange-correlation hole and the difference between the one-body density matrix of the interacting and Kohn-Sham systems, which must be approximated in terms of quantities accessible from the Kohn-Sham evolution. We explore several preliminary approximations, evaluate their fulfillment of known exact conditions, and test their performance on simple model systems for which available exact solutions indicate the significance of going beyond the adiabatic approximation. PMID- 30311616 TI - Structure and stimuli-responsiveness of all-DNA dendrimers: theory and experiment. AB - We present a comprehensive theoretical and experimental study of the solution phase properties of a DNA-based family of nanoparticles - dendrimer-like DNA molecules (DL-DNA). These charged DNA dendrimers are novel macromolecular aggregates, which hold high promise in targeted self-assembly of soft matter systems in the bulk and at interfaces. To describe the behaviour of this family of dendrimers (with generations ranging from G1 to G7), we use a theoretical model in which base-pairs of a single DL-DNA molecule are modeled by charged monomers, whose interactions are chosen to mimic the equilibrium properties of DNA correctly. Experimental results on the sizes and conformations of DL-DNA are based on static and dynamic light scattering; and molecular dynamics simulations are employed to model the equilibrium properties of DL-DNA, which compare favorably to the findings from experiments while at the same time providing a host of additional information and insight into the molecular structure of the nanostructures. We also examine the salt-responsiveness of these macromolecules, finding that despite the strong screening of electrostatic interactions brought about by the added salt, the macromolecules shrink only slightly, their size robustness stemming from the high bending rigidity of the DNA-segments. The study of these charged dendrimer systems is an important field of research in the area of soft matter due to their potential role for various interdisciplinary applications, ranging from molecular cages and carriers for drug delivery in a living organism to the development of dendrimer- and dendron-based ultra-thin films in the area of nanotechnology. These findings are essential to determine if DL-DNA is a viable candidate for the experimental realization of cluster crystals in the bulk, a novel form of solid with multiple site occupancy. PMID- 30311617 TI - Synthesis of corrugated C-based nanostructures by Br-corannulene oligomerization. AB - The structure and electronic properties of carbon-based nanostructures obtained by metal surface assisted synthesis is highly dependent on the nature of the precursor molecule. Here, we report on a combined scanning tunneling microscopy, soft X-ray spectroscopy and density functional theory investigation on the surface assisted polymerization of Br-corannulene at Ag(110) and on the possibility of building a mesh of pi-conjugated polymers starting from buckyball shaped molecules. Indeed, the corannulene units form one-molecule-wide ribbons in which the natural concavity of the precursor molecule is maintained. These C based nanostructures are corrugated and merge into a covalent network on the surface. PMID- 30311618 TI - Controllable and reversible DNA translocation through a single-layer molybdenum disulfide nanopore. AB - A challenge that remains to be solved in the high-throughput and low-cost nanopore DNA sequencing is that DNA translocates through the nanopore too quickly to be sequenced with enough accuracy. Here, we present a proof of principle study of slowing down DNA translocation across the molybdenum disulfide nanopore and even reversing its translocation direction by adjusting the proportion of molybdenum atoms to sulfur atoms at the nanopore boundary. When the proportion is smaller than 0.17, the electro-osmotic flow moves in the opposite direction to the electric force exerted on the DNA molecule and the more sulfur atoms at the nanopore boundary, the stronger the electro-osmotic flow is. For the nanopore with the proportion equal to 0.17, the electro-osmotic force exerted on DNA is smaller than the electrophoretic force, DNA can be captured and its translocation speed was found to be almost three times smaller than the speed through nanopores with the proportion larger than 0.27. However, for nanopores with the proportion smaller than 0.08, DNA would even be pushed away and prevented from entering the nanopore so that its translocation direction would be reversed. The theoretical study performed here provides a new means for controlling DNA transport dynamics in both translocation velocity and direction, which would facilitate better and cheaper nanopore DNA sequencing in the future. PMID- 30311619 TI - Effects of the intake of white wheat bread added with garlic and resistant starch: action on calcium bioavailability and metabolic parameters of growing Wistar rats. AB - Wheat bread is a widely consumed food and is suitable for the introduction of functional ingredients. The aim of this work was to study the effects of bread with garlic and resistant starch as a fiber source on physiological, metabolic, and functional parameters using an in vivo Wistar rat model. Rats were fed with three diets: a control diet prepared according to the American Institute of Nutrition (C), and two semisynthetic diets containing wheat bread (B) and wheat bread with garlic, resistant starch and calcium citrate (BGR). Fresh feces were weighed and lactobacilli (L) and Enterobacteriaceae (E) were analyzed at different times: 1, 20, 45 and 60 days. The pH of the caecal content was recorded and at the end of the study changes in the bone mineral density of total skeleton (ts BMD), femur (F-BMD), spine (S-BMD) and tibia (T-BMD) were determined. Lipoprotein profile was assessed, atherogenic indexes were calculated and malonaldehyde content was measured in the serum and liver. In relation to gut microbiota, the BGR group showed an increase in the L/E ratio with respect to the other groups which was correlated with a lower cecal pH. Besides, the BGR group presented lower weight and a more favourable metabolic profile. In relation to bone measurements, the BGR group presented higher values of ts BMC, ts BMD, F BMD, and T-BMD than the B group. Thus, bread with resistant starch, garlic and calcium citrate showed a prebiotic effect increasing calcium bioavailability and deposition in bones, compared with wheat bread. The observed beneficial health effects allow us to consider the design of healthier breads. PMID- 30311620 TI - Copper-induced cell death and the protective role of glutathione: the implication of impaired protein folding rather than oxidative stress. AB - Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane. PMID- 30311621 TI - Interaction study of cancer cells and fibroblasts on a spatially confined oxygen gradient microfluidic chip to investigate the tumor microenvironment. AB - This paper reports a single-layered microfluidic device for studying the interaction of cancer cells and fibroblasts in an oxygen gradient. This gradient can be established from 1.9% to 18.8% using a spatially confined oxygen scavenging chemical reaction. Due to the spatial design of the chip, only cancer cells can sustain low oxygen conditions when co-cultured with fibroblasts in the adjacent channels, simulating the cell-cell interactions of the hypoxic cancer cells and the surrounding fibroblasts in tumor microenvironment in vivo. Moreover, a cell migration assay is performed on the chip for studying the tumor invasion ability. The results show that the migration speed of B16 cells is increased by hypoxia and the co-culture with L929 cells. In addition, we use ELISA to quantify the migration-related cytokines transforming growth factor beta1 (TGF-beta1) in the microfluidic system. Our results confirm interaction between cancer cells and fibroblasts. This microfluidic device provides new insight for the investigation of tumor microenvironment and cell interactions. PMID- 30311622 TI - Outbreak of Brucella melitensis infection in Eastern Sicily: risk factors, clinical characteristics and complication rate. AB - Brucellosis is one of the most common zoonoses in the world, especially in Southern Italy, where many cases are still recorded every year. 128 cases of brucellosis were observed in Messina (Sicily) in 2016, representing a tenfold increase in the number of cases of brucellosis expected. The aim of this multicenter retrospective study was to analyze clinical and microbiological aspects of a brucellosis outbreak in the province of Messina in 2016, the incidence of its complications and the treatment combinations applied. The principal transmission route was through the ingestion of unpasteurized fresh cheese. The mean latency period between the onset of the symptoms and diagnosis was 35.58 +/- 42.75 days. A late diagnosis increases the risk of developing complications. Drug-resistant strains of B. melitensis to Trimethoprim/Sulfamethoxazole and Ciprofloxacin were found in blood cultures of 58.4% patients. Brucellosis is still present in Sicily. A diagnostic delay predisposes to complications requiring prolonged therapies. The finding of Brucella melitensis strains resistant to the most widespread treatments is worrisome and needs further investigation. Moreover, the use of alternative combination antibiotic therapy is recommended. PMID- 30311623 TI - Immunovirological outcome and HIV-1 DNA decay in a small cohort of HIV-1-infected patients deintensificated from Abacavir/Lamivudine/Dolutegravir to Lamivudine plus Dolutegravir. AB - Combination abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) is approved as a first line treatment for antiretroviral naive patients. This report investigated the immunovirological outcome and total HIV-1 DNA decay in a small cohort of naive HIV-1-positive patients treated with this regimen. In the presence of viral suppression and increased lymphocyte T CD4+ cells, the quantitative analysis of total HIV-1 DNA content revealed a significant decay after 12 months of treatment. Subsequently, we deintensificated the treatment of these patients from (ABC/3TC/DTG) to lamivudine plus dolutegravir (3TC/DTG) after 12 months of virological suppression, as a strategy of "induction-maintenance" therapy. The analysis of HIV-1 RNA viral load, total HIV-1 DNA, CD4+ T lymphocyte count and CD8+ HLA-DR+ T lymphocyte percentage after a mean 3.5 months of therapy deintensification showed no significant difference with respect to data detected after 12 months of ABC/3TC/DTG treatment in the presence of continuous viral suppression. These results indicate that the deintensification of highly active antiretroviral therapy (HAART) from ABC/3TC/DTG to 3TC/DTG effectively controls HIV-1 replication and in the early period does not induce any significant variations of total HIV-1 DNA. This suggests that HAART deintensification might be proposed as a therapeutic evolution in the treatment of HIV-1 infection. PMID- 30311624 TI - Is the Unyvero i60 ITI multiplex PCR system a promising test in the diagnosis of infective endocarditis from heart valves? AB - The aim of this study was to evaluate the new commercial Unyvero i60 ITI multiplex PCR system (Curetis, Holzgerlingen, Germany) on native cardiac valves in comparison with made in-house 16S rRNA PCR amplification (91E/13BS primers) and conventional microbiological techniques. Forty-four patients (30 men, 14 women) with suspected infective endocarditis (IE) were included in this evaluation corresponding to 30 aortic valves and 14 mitral valves. IE was definite for 40 patients using the modified Duke criteria. 16S rRNA PCR amplification was successful in 22 patients (55%). The Unyvero i60 ITI cartridge yielded a positive result in 16 patients (40%). Among the 40 cases, the etiological agent was not included in the panel of Unyvero i60 ITI cartridge for 14 cases. Moreover, for S. aureus, the Unyvero i60 ITI cartridge quickly yielded the susceptibility to meticillin. The result of the experiment was available after 5 hours whereas 16S rRNA PCR amplification-sequencing needs 14 hours of manipulation. If the manufacturer incorporates new targets able to detect more endocarditis agents such as viridans streptococci, the Unyvero i60 ITI cartridge may be a promising and easy-to-use test. PMID- 30311625 TI - Proteolytic activity of non-albicans Candida and Candida albicans in oral cancer patients. AB - Oral Candida infections can be life-threatening in medically compromised patients. In particular non-albicans Candida strains are virulent. However, our knowledge is sparse on how proteolytic these strains are in patients with oral cancer. Our study aimed to investigate differences in proteolytic activity of non albicans Candida and Candida albicans isolated from oral cancer patients. The hypothesis was based on anticipated different invasive capacity of the strains. Clinical and reference yeast samples from our laboratory were used for analyses. Candida strains were grown in yeast peptone glucose and the activity of Candida proteinases of broken cell fractions were analysed by MDPF-gelatin zymography. Fluorometric assay was used to compare activities of proteolytic enzymes and degradation assays were performed using CLDN 4 and plasma fibronectin. Clear differences were seen in the proteolytic activity between the studied non albicans Candida and C. albicans strains. C. tropicalis had the highest proteolytic activity followed by strains of C. krusei and C. glabrata. The results confirmed our study hypothesis by showing differences between the non albicans Candida and Candida albicans strains studied. Higher proteolytic activity may thus have an effect on the virulence of non-albicans Candida strains in oral cancer patients. PMID- 30311626 TI - Incidence, risk factors and outcomes of malignancies after kidney transplantation in Singapore: a 12-year experience. AB - INTRODUCTION: Data on post-kidney transplantation (KTX) malignancy is limited in our region, leading to challenges in the care of renal allograft recipients. We aimed to examine the epidemiology, risk factors and outcomes of post-KTX patients. METHODS: A retrospective cohort study was conducted of 491 patients who underwent KTX from 1 January 2000 to 31 December 2011. Data linkage analysis was done between our centre and the National Registry of Disease Office to determine the standardised incidence ratio (SIR), standardised mortality ratio (SMR) and risk factors for malignancy after KTX. RESULTS: 31 patients (61.3% male) developed malignancy during this period, and their median age at diagnosis was 50 (range 15-65) years. Median time to malignancy diagnosis was 2.6 (range 0.3-7.9) years, with cumulative incidence of 1%, 4% and 10% at one, five and ten years, respectively. The commonest malignancy type was lymphoma, followed by kidney cancer, colorectal cancer and malignancy of the male genital organs. Multivariate analysis identified cyclosporine use as an independent risk factor for malignancy. Compared to the general population, KTX recipients had higher malignancy and mortality rates after malignancy diagnosis (SIR 3.36; SMR 9.45). Survival rates for KTX recipients with malignancy versus those without malignancy were 100%, 93% and 64% versus 97%, 93% and 83% at one, five and ten years, respectively. CONCLUSION: KTX was associated with higher mortality and incidence of malignancy. Newer immunosuppressive agents and induction therapies were not found to be risk factors for malignancy, possibly due to our relatively small sample size. PMID- 30311627 TI - Ectopic breast tissue in the vulva masquerading as an abscess. PMID- 30311628 TI - Complicated intra-abdominal infections: a prospective validation study of the WSES Sepsis Severity Score. AB - INTRODUCTION: The World Society of Emergency Surgery (WSES) has recently developed and validated a sepsis severity score for complicated intra-abdominal infections (cIAIs). We aimed to prospectively study the validity of this score in our local setting and compare it with global findings. METHODS: In a prospective study of 100 consecutive adult patients with cIAIs treated at Al-Ain Hospital, United Arab Emirates, from October 2014 to January 2016, we studied the demography of patients, disease, risk factors, WSES Sepsis Severity Score, management, hospital stay and mortality. Our findings were compared with those from a recent global multicentre prospective study from 53 countries (n = 4,496). RESULTS: Compared with global data, our patients had significantly more men (p < 0.0001) and were younger (p < 0.0001), had more appendicitis and perforated peptic ulcers (p < 0.0001), significantly lower sepsis severity score (p < 0.0001) and more delays in surgical intervention (p = 0.001). Nevertheless, they had similar adequate source control (p = 0.54) and surgical reinterventions (p = 0.63). Overall, our patients had significantly lower mortality rate (our study: 1.0% vs. global data: 9.3%; p = 0.001). A direct logistic regression model showed that the WSES Sepsis Severity Score significantly predicted mortality (p < 0.0001) but not our hospital's setting compared with other hospitals (p = 0.18). CONCLUSION: Although patient demography and our hospital's setting significantly differed from other international hospitals, the WSES Sepsis Severity Score was very accurate in predicting mortality among our patients, which supports its generalisability for all patient populations worldwide. PMID- 30311629 TI - Relationship of salusin-alpha and salusin-beta levels with atherosclerosis in patients undergoing haemodialysis. AB - INTRODUCTION: In patients undergoing haemodialysis, cardiovascular mortality and morbidity, characterised by accelerated atherosclerosis and increased inflammation, are elevated. Salusins are newly defined molecules in the atherosclerotic processes, and while salusin-alpha (Sal-alpha) acts as an antiatherogenic factor, salusin-beta (Sal-beta) has a proatherogenic role. Their roles are as yet undefined in patients undergoing haemodialysis. METHODS: In this cross-sectional study, salusin levels, carotid intima-media thickness (CIMT) from the common carotid artery and pulse wave velocity (PWV) were measured for 180 patients undergoing haemodialysis and 90 healthy controls. RESULTS: Mean Sal alpha and Sal-beta levels in patients undergoing haemodialysis (Sal-alpha: 726.4 +/- 578.7 pg/mL; Sal-beta: 1,080.4 +/- 757.1 pg/mL) and healthy controls (Sal alpha: 325.8 +/- 303.7 pg/mL; Sal-beta: 268.1 +/- 409.0 pg/mL) were determined. Negative correlation was observed between Sal-alpha levels and CIMT (patients undergoing haemodialysis: r = -0.330, p < 0.0001; healthy controls: r = -0.223, p = 0.035) and PWV (patients undergoing haemodialysis: r = -0.210, p = 0.005; healthy controls: r = -0.378, p < 0.0001) in both groups. In patients undergoing haemodialysis, positive correlation was observed between Sal-beta/Sal-alpha ratio and CIMT (r = 0.190, p = 0.012) and PWV (r = 0.155, p = 0.041). On subgroup analysis, Sal-alpha levels were found to be low in patients with diabetes mellitus. CONCLUSION: Patients undergoing haemodialysis have higher Sal-beta and Sal-alpha levels, and their higher Sal-beta/Sal-alpha ratio, in comparison with healthy controls, might have cardiovascular risk implications. PMID- 30311630 TI - Lentiviral-based reporter constructs for profiling chondrogenic activity in primary equine cell populations. AB - Successful clinical translation of mesenchymal stem cell (MSC)-based therapies for cartilage repair will likely require the implementation of standardised protocols and broadly applicable tools to facilitate the comparisons among cell types and chondroinduction methods. The present study investigated the utility of recombinant lentiviral reporter vectors as reliable tools for comparing chondrogenic potential among primary cell populations and distinguishing cellular level variations of chondrogenic activity in widely used three-dimensional (3D) culture systems. Primary equine MSCs and chondrocytes were transduced with vectors containing combinations of fluorescent and luciferase reporter genes under constitutive cytomeglavirus (CMV) or chondrocyte-lineage (Col2) promoters. Reporter activity was measured by fluorescence imaging and luciferase assay. In 3D cultures of MSC aggregates and polyethylene glycol-hyaluronic acid (PEG-HA) hydrogels, transforming growth factor beta 3 (TGF-beta3)-mediated chondroinduction increased Col2 reporter activity, demonstrating close correlation with histology and mRNA expression levels of COL2A1 and SOX9. Comparison of chondrogenic activities among MSC populations using a secretable luciferase reporter revealed enhanced chondrogenesis in bone-marrow-derived MSCs relative to MSC populations from synovium and adipose tissues. A dual fluorescence reporter - enabling discrimination of highly chondrogenic (Col2-GFP) cells within an MSC population (CMV-tdTomato) - revealed marked heterogeneity in differentiating aggregate cultures and identified chondrogenic cells in chondrocyte-seeded PEG-HA hydrogels after 6 weeks in a subcutaneous implant model - indicating stable, long-term reporter expression in vivo. These results suggested that lentiviral reporter vectors may be used to address fundamental questions regarding chondrogenic activity in chondroprogenitor cell populations and accelerate clinical translation of cell-based cartilage repair strategies. PMID- 30311631 TI - Cricoid force: time to put it to one side. PMID- 30311633 TI - Allergic contact dermatitis caused by clindamycin. PMID- 30311634 TI - Reviewing the cost-effectiveness of long-acting reversible contraceptive methods in an Australian context. AB - BACKGROUND: Relative to the oral contraceptive pill, uptake of long-acting reversible contraceptive methods (LARCs) in Australia continues to be lower than might be suggested by the evidence on their clinical and economic benefits. AIM: To undertake a critical appraisal of published economic evaluations of LARCs to assess the generalisability of their results to the Australian healthcare context. MATERIALS AND METHODS: A search of the literature was conducted to identify studies of economic evaluations of LARCs using the Medline, Embase and PubMed databases. The quality of the studies was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: A total of 1009 citations were screened, from which 20 papers, typically reporting the cost per pregnancy avoided, were reviewed. The overall quality of the studies varied but was generally poor (average score of 62/100). To aid comparisons, results have been grouped under the headings IUS (all hormonal intrauterine systems), IUDs (all non-hormonal intrauterine devices), injectables (all contraceptive injections) and implants (all subdermal contraceptive implants). Overall, the results indicated that LARCs were more effective and less costly than oral contraceptives. CONCLUSIONS: Despite evidence that LARCs represent value for money, limitations in study quality and approaches must be taken into account when applying these results to Australia. Differences in healthcare settings aside, LARCs may also have benefits beyond their effect on pregnancy that might be captured in broader analyses, such as cost-benefit analyses using willingness to pay methods. These would capture benefits beyond health, which seem to be particularly relevant to contraception. PMID- 30311635 TI - Rural/urban residence and childhood and adolescent cancer survival in the United States. AB - BACKGROUND: To the authors' knowledge, no previous study has examined the relationship between rural/urban residence and childhood or adolescent cancer survival in the United States. Using the Surveillance, Epidemiology, and End Results 18 registries database, the authors examined childhood and adolescent cancer survival by rural/urban residence as defined by Rural-Urban Continuum Codes (RUCCs). METHODS: The authors obtained data from Surveillance, Epidemiology, and End Results 18 registries for individuals diagnosed at ages birth to 19 years with a first primary malignant cancer from 2000 through 2010. Rural/urban residence at the time of diagnosis was defined using both metropolitan/nonmetropolitan county classifications and individual RUCC categories. Cox proportional hazards regression was used to compute adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between rural/urban residence and cancer survival. The authors also examined effect modification by age group, sex, race/ethnicity, and cancer type. RESULTS: Among 41,879 cancer cases, approximately 54.7% were non-Hispanic white, 54.3% were male, and 90.4% lived in a metropolitan county. Individuals living in nonmetropolitan counties versus metropolitan counties had a similar risk of cancer death (HR, 1.03; 95% CI, 0.94-1.13) as did those living in nonmetropolitan rural counties with <2500 individuals nonadjacent to a metropolitan area versus those living in metropolitan counties of >=1 million individuals (HR, 0.98; 95% CI, 0.71-1.37). Evidence for effect modification largely was absent. CONCLUSIONS: The results of the current study suggest that childhood and adolescent cancer survival in the United States does not vary by rural/urban residence at the time of diagnosis as defined by RUCCs. The widespread availability of public health insurance for children and adolescents and a nationwide network of pediatric cancer providers may explain this finding. PMID- 30311632 TI - Genetic determinants of childhood and adult height associated with osteosarcoma risk. AB - BACKGROUND: Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk. METHODS: The authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry. RESULTS: Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93*10-5 and Padjusted =.034]). CONCLUSIONS: A genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology. PMID- 30311636 TI - Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis. AB - Modifications to the extracellular matrix (ECM) can be either causal or consequential of disease processes including arthritis and cancer. In arthritis, the cartilage ECM is adversely affected by the aberrant behaviours of inflammatory cells, synoviocytes and chondrocytes, which secrete a plethora of cytokines and degradative proteases. In cancer, the ECM and stromal cells are linked to disease severity, and metalloproteinases are implicated in metastasis. There have been some successes in the field of targeted therapies, but efficacy depends upon the type and stage of disease. ECM targets are becoming increasingly attractive for drug delivery, owing to changes in ECM structure and composition in the diseased state, and the long in vivo half-life of its components. This review will highlight various strategies for targeting therapeutics to arthritic joints, including antibody and peptide-mediated drug delivery platforms to aid delivery to the ECM and retention at disease sites. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 30311637 TI - Upper limb disorders in anaesthetists - a survey of Association of Anaesthetists members. AB - Upper limb disorders (affecting the hand, arm and neck) are common. The nature of anaesthetists' work poses a potential extra risk from poor posture that may contribute to the development of upper limb disorders in this professional group. However, to date, the problem has received scant attention in the literature. Following a 2 to 3-month period of publicity via newsletter, email and social media, all 10,231 electronically accessible members of the Association of Anaesthetists were invited by email to complete an online survey that was administered by a third-party company. A total of 3884 usable responses were received (38%). Analysis of possible risk factors found a significant association between upper limb disorders and years since starting anaesthetic training, having children (irrespective of respondents' sex or the number of children) and right-handedness. Years of practice and having children are less modifiable identified risk factors. However, right-handedness may be linked to the ergonomic design of the environment/equipment used within this specialty and may thus be a potentially modifiable risk factor worthy of further investigation. PMID- 30311638 TI - Differences in molecular features of triple-negative breast cancers based on the age at diagnosis. AB - BACKGROUND: Although the proportion of triple-negative breast cancers (TNBCs) diagnosed among older women is low, the number of TNBC cases is substantial because of the high incidence of breast cancer after the age of 65 years. The molecular features of TNBC in this age group have not been well described. METHODS: This study examined a population-based cohort of women with stage I to III TNBC diagnosed between the ages of 25 and 91 years with the PAM50 gene expression subtyping assay. The concordance between the TNBC classification by immunohistochemistry and the gene expression classification by PAM50, the expression of individual genes, and 5-year recurrence and breast cancer mortality in older women (>=65 years old) and younger women (<50 years old) was assessed. RESULTS: The molecular subtype distribution in TNBC was significantly different according to the age at diagnosis. TNBC was more likely to be classified as basal like in women younger than 50 years (sensitivity, 0.91; 95% confidence interval, 0.77-0.97) than women 65 years old or older (sensitivity, 0.72; 95% confidence interval, 0.48-0.87); 35% of clinical TNBC cases in the latter group were the human epidermal growth factor receptor 2 (HER2)-enriched subtype by molecular classification. Older women with TNBC also had significantly higher expression of ERBB2 and lower expression of all 10 proliferation-associated genes tested (P < .01). The risk of breast cancer death within 5 years was significantly higher in women with TNBC in comparison with women with hormone receptor-positive cancers in all age groups. CONCLUSIONS: This study revealed differences in molecular subtypes among clinical TNBC cases based on patient age. A potentially targetable HER2-enriched group raises the possible need for intrinsic subtyping in older women with TNBC. PMID- 30311639 TI - Implementation of planar proton minibeam radiation therapy using a pencil beam scanning system: A proof of concept study. AB - PURPOSE: Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose-rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments. METHODS: Monte Carlo simulations (TOPAS v3.1.p2) were used to design a suitable multislit collimator to implement planar pMBRT for conventional pencil beam scanning settings. Dose distributions (depth-dose curves, lateral profiles, Peak-to-Valley Dose Ratio (PVDR) and dose-rates) for different proton beam energies were assessed by means of Monte Carlo simulations and experimental measurements in a water tank using commercial ionization chambers and a new p-type silicon diode, the IBA RAZOR. An analytical intensity modulated dose calculation algorithm designed to optimize the weight of individual Bragg peaks composing the field was also developed and validated. RESULTS: Proton minibeams were then obtained using a brass multislit collimator with five slits measuring 2 cm * 400 MUm in width with a center-to-center distance of 4 mm. The measured and calculated dose distributions (depth-dose curves and lateral profiles) showed a good agreement. Spread-out Bragg peaks (SOBP) and homogeneous dose distributions around the target were obtained by means of intensity modulation of Bragg peaks, while maintaining spatial fractionation at shallow depths. Mean dose-rates of 0.12 and 0.09 Gy/s were obtained for one iso-energy layer and a SOBP conditions in the presence of multislit collimator. CONCLUSIONS: This study demonstrates the feasibility of implementing pMBRT on a PBS system. It also confirms the reliability of RAZOR detector for pMBRT dosimetry. This newly developed experimental methodology will support the design of future preclinical research with pMBRT. PMID- 30311640 TI - Allergic contact dermatitis caused by nickel in an eyebrow pencil. PMID- 30311641 TI - Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer. AB - BACKGROUND: With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be. METHODS: A qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers. RESULTS: A total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine-based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5 fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early-phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles. CONCLUSION: Despite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found. PMID- 30311642 TI - Meta-analysis of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer. AB - BACKGROUND: Neoadjuvant chemotherapy for breast cancer has the potential to achieve a pathological complete response in up to 40 per cent of patients, converting disease that was initially node-positive to node-negative. This has raised the question of whether sentinel lymph node biopsy could be an alternative to axillary lymph node dissection in these patients. The aim was to undertake a systematic review and meta-analysis of the accuracy and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy proven node-positive breast cancer. METHODS: A literature search was conducted using PubMed, Ovid MEDLINE, Embase and Web of Science databases up to 30 April 2017. Inclusion criteria for studies were pathological confirmation of initial node-positive disease, and sentinel lymph node biopsy performed after neoadjuvant chemotherapy followed by axillary lymph node dissection. RESULTS: A total of 13 studies met the inclusion criteria and were included in the analysis (1921 patients in total). The pooled estimate of identification rate was 90 (95 per cent c.i. 87 to 93) per cent and the false-negative rate was 14 (11 to 17) per cent. In subgroup analysis, the false-negative rate with use of dual mapping was 11 (6 to 15) per cent, compared with 19 (11 to 27) per cent with single mapping. The false-negative rate was 20 (13 to 27) per cent when one node was removed, 12 (5 to 19) per cent with two nodes removed and 4 (0 to 9) per cent with removal of three or more nodes. CONCLUSION: Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with biopsy-proven node-positive breast cancer is accurate and reliable, but requires careful patient selection and optimal surgical techniques. PMID- 30311646 TI - Snapshot quiz. PMID- 30311643 TI - From retribution to reconciliation after critical events in surgery. PMID- 30311647 TI - Snapshot quiz. PMID- 30311648 TI - Erratum for "Combination of traditional mutation and metabolic engineering to enhance ansamitocin P-3 production in Actinosynnema pretiosum" (Vol. 114, Issue 12, pp. 2794-2806). PMID- 30311649 TI - Antidiabetic, Antihyperlipidemic, and Antioxidant Activities of Mulberry Lees Fermented Products in Diabetic Mice. AB - Mulberry lees are the sediment in the bottom of the barrel, which can be obtained from the processing of mulberry wine, and they are considered as low-value byproducts. In this study, mulberry lees were extracted with ethanol, and then fermented with Monascus pilosus to obtain fermented products (M * M). Male ICR mice were diabetes induced by STZ, and then oral administration of fermented products. The results showed that fermented products could reduce 31.9% to 47.9% plasma glucose, 25.8% to 48.2% total cholesterol, and 16.7% to 25% triglyceride levels in diabetic mice, and it can greatly lower the malondialdehyde (MDA) content by 26.4% to 59.7% but raise antioxidant enzyme activity in the liver of the mice. Moreover, fermented products not only could reduce AST and ALT activity of the diabetic mice, thereby alleviating liver inflammation, but also lowered the urea nitrogen and creatinine levels, improved glomerulus volume, and reduced swelling and inflammation in the kidneys. It was concluded that mulberry lees fermented products could be served as a value-added resource for human health. PMID- 30311650 TI - The M6 cell: A small-field bistratified photosensitive retinal ganglion cell. AB - We have identified a novel, sixth type of intrinsically photosensitive retinal ganglion cell (ipRGC) in the mouse-the M6 cell. Its spiny, highly branched dendritic arbor is bistratified, with dendrites restricted to the inner and outer margins of the inner plexiform layer, co-stratifying with the processes of other ipRGC types. We show that M6 cells are by far the most abundant ganglion cell type labeled in adult pigmented Cdh3-GFP BAC transgenic mice. A few M5 ipRGCs are also labeled, but no other RGC types were encountered. Several distinct subnuclei in the geniculate complex and the pretectum contain labeled retinofugal axons in the Cdh3-GFP mouse. These are presumably the principle central targets of M6 cells (as well as M5 cells). Projections from M6 cells to the dorsal lateral geniculate nucleus were confirmed by retrograde tracing, suggesting they contribute to pattern vision. M6 cells have low levels of melanopsin expression and relatively weak melanopsin-dependent light responses. They also exhibit strong synaptically driven light responses. Their dendritic fields are the smallest and most abundantly branched of all ipRGCs. They have small receptive fields and strong antagonistic surrounds. Despite deploying dendrites partly in the OFF sublamina, M6 cells appear to be driven exclusively by the ON pathway, suggesting that their OFF arbor, like those of certain other ipRGCs, may receive ectopic input from passing ON bipolar cells axons in the OFF sublayer. PMID- 30311651 TI - MIDLINE THALAMIC INPUTS TO THE AMYGDALA: ULTRASTRUCTURE AND SYNAPTIC TARGETS. AB - One of the main subcortical inputs to the basolateral nucleus of the amygdala (BL) originates from a group of dorsal thalamic nuclei located at or near the midline, mainly from the central medial (CMT) and paraventricular (PVT) nuclei. Although similarities between the responsiveness of BL, CMT, and PVT neurons to emotionally arousing stimuli suggest that these thalamic inputs exert a significant influence over BL activity, little is known about the synaptic relationships that mediate these effects. Thus, the present study used Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracing and electron microscopy to shed light on the ultrastructural properties and synaptic targets of CMT and PVT axon terminals in the rat BL. Virtually all PHAL-positive CMT and PVT axon terminals formed asymmetric synapses. While CMT and PVT axon terminals generally contacted dendritic spines, a substantial number ended on dendritic shafts. To determine if these dendritic shafts belonged to principal or local-circuit cells, we used immunoreactivity for calcium/calmodulin-dependent protein kinase II (CAMKIIalpha) as a selective marker of principal BL neurons. In most cases, dendritic shafts postsynaptic to PHAL-labeled CMT and PVT terminals were immunopositive for CaMKIIalpha. Overall, these results suggest that CMT and PVT inputs mostly target principal BL neurons such that when CMT or PVT neurons fire, little feed-forward inhibition counters their excitatory influence over principal cells. These results are consistent with the possibility that CMT and PVT inputs constitute major determinants of BL activity. This article is protected by copyright. All rights reserved. PMID- 30311652 TI - The Will to Meaning: Seeking the Why of Our Existence. PMID- 30311653 TI - No survival improvement of contralateral prophylactic mastectomy among women with invasive lobular carcinoma. AB - BACKGROUND AND OBJECTIVE: The prognosis of contralateral prophylactic mastectomy (CPM) in women with breast cancer has been widely reported. Here, we evaluated the survival outcome among patients with invasive lobular carcinoma (ILC) to determine the potential benefit of CPM. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify patients with ILC diagnosed between 1998 and 2010. Survival differences were compared between unilateral mastectomy and CPM. Propensity score matching and risk-stratified subgroup analyses were conducted to reduce selection bias. RESULTS: Among 10 226 patients with ILC, 21.8% women underwent CPM, and the rate of CPM nearly tripled over a 13 year period. Kaplan-Meier curves and hazard ratio (HR) of non-breast cancer specific survival (non-BCSS) in multivariate analysis reflected a pre-existing selection bias in the present cohort. A Cox proportional hazard model confirmed that patients who received CPM had significantly better BCSS and overall survival (OS) in the prematching population (BCSS: HR = 0.90; OS: HR = 0.93). However, the survival improvement could not be achieved in the postmatching cohort. None of the defined subgroups had OS benefits when CPM was performed. CONCLUSIONS: CPM offers no survival advantage to patients with ILC. The role of CPM among ILC women should be further investigated by incorporating more objective factors. PMID- 30311654 TI - Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer's disease. AB - A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid beta (Abeta) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Abeta deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Abeta plaques across age in three APP overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Abeta deposition patterns described in AD. PMID- 30311655 TI - Cardiovascular and other competing causes of death among patients with cancer from 2006 to 2015: An Australian population-based study. AB - BACKGROUND: With improved cancer survivorship, cardiovascular disease (CVD) and other noncancer events compete with cancer as the underlying cause of death, but the risks of mortality in competing-risk settings have not been well characterized. METHODS: The authors identified 21,637 individuals who had a first cancer registered between 2006 and 2013, with follow-up to 2015, in the Australian population-based Tasmanian Cancer Registry. The cumulative incidence of deaths from specific competing events was assessed in competing-risk analyses. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) for deaths from noncancer causes were calculated for comparison with the general population. RESULTS: Overall, 8844 deaths were observed, with 1946 (22%) from competing events. The cumulative incidence of deaths from CVD increased significantly with age at first cancer diagnosis and exceeded other competing events at age >=65 years. The risk of death from CVD was more common than expected in the first year of follow-up (SMR, 1.44 [95% confidence interval, 1.26-1.64]; AER, 36.8 per 10,000 person-years). The SMR and AER for CVD deaths varied by first cancer site, indicating increased risks after a first diagnosis of lung cancer, hematologic malignancy, and urinary tract cancer. For other noncancer events, the SMRs increased significantly for deaths from infectious disease and respiratory disease and were highest in the first year of follow-up. CONCLUSIONS: CVD was the leading cause of competing mortality among Tasmanian patients with cancer who were diagnosed from 2006 to 2013. The higher than expected occurrence of death from CVD and other noncancer events during the first year after a cancer diagnosis highlights the importance of early preventive interventions. PMID- 30311658 TI - President's Message: A Research Coach is Key to a Researcher's Success. PMID- 30311656 TI - CHL1 expression differentiates Hurthle cell carcinoma from benign Hurthle cell nodules. AB - BACKGROUND AND OBJECTIVES: Hurthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid cancer. Currently, cytologic analysis of fine-needle aspiration biopsy is limited in distinguishing benign Hurthle cell neoplasms from malignant ones. The aim of this study was to determine whether differences in the expression of specific genes could differentiate HCC from benign Hurthle cell nodules by evaluating differential gene expression in Hurthle cell disease. METHODS: Eighteen benign Hurthle cell nodules and seven HCC samples were analyzed by whole-transcriptome sequencing. Bioinformatics analysis was carried out to identify candidate differentially expressed genes. Expression of these candidate genes was re-examined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was quantified by immunohistochemistry. RESULTS: Close homolog of L1 (CHL1) was identified as overexpressed in HCC. CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase million in HCC compared with benign Hurthle cell tumors. This was confirmed by qRT-PCR. Moreover, the immunoreactivity score of the CHL1 protein was significantly higher in HCC compared with benign Hurthle cell nodules. CONCLUSIONS: CHL1 expression may represent a novel and useful prognostic biomarker to distinguish HCC from benign Hurthle cell disease. PMID- 30311657 TI - Recommendations for identifying pathogenic Vibrio spp. as part of disease surveillance programmes in recirculating aquaculture systems for Pacific white shrimps (Litopenaeus vannamei). AB - Due to their pathogenic potential, identifying Vibrio species from recirculating aquaculture systems (RAS) for Pacific white shrimp (Litopenaeus vannamei) is of great importance to determine the risk for animal's as well as for the consumer's health. The present study compared identification results for a total of 93 Vibrio isolates, including type strains and isolates from shrimp aquaculture. Results from biochemical identifications, 16S rRNA sequencing, sequencing of the uridylate kinase encoding gene pyrH and analysis of the protein spectra assessed by MALDI-TOF MS were compared. The results achieved by these different methods were highly divergent for many of the analysed isolates and for several Vibrio spp difficulties in reliably identifying occurred. These difficulties mainly resulted from missing entries in digital databases, a low number of comparable isolates analysed so far, and high interspecific similarities of biochemical traits and nucleotide sequences between the closely related Vibrio species. Due to the presented data, it can be concluded that for identifying Vibrio spp. from samples in routine diagnostics, it is recommended to use MALDI-TOF MS analysis for a quick and reliable identification of pathogenic Vibrio sp. Nevertheless, editing the database, containing the main spectra of Vibrio is recommended to achieve reliable identification results. PMID- 30311659 TI - Evaluation and treatment of female stress urinary incontinence after pelvic radiotherapy. AB - INTRODUCTION: Pelvic radiotherapy is associated with both acute and chronic voiding dysfunction. A review of the success and complications of surgical treatments for female stress urinary incontinence after pelvic radiotherapy has not been summarized in the published literature. METHODS: A systematic review of female stress urinary incontinence after pelvic radiotherapy was conducted using MeSH terminology (1988-2018). RESULTS: There is limited published literature on the treatment of stress urinary incontinence in women following pelvic radiotherapy. Long term indwelling urethral catheter should be avoided in all women given the risk of iatrogenic hypospadias. Surgical treatments can be classified into those for the intact versus failed outlet. Urethral bulking injections have been studied in a prospective fashion specifically in women with stress urinary incontinence after radiotherapy and although not randomized, have the highest level of evidence. Patients should be screened for a history of prior radiotherapy before considering sling placement. Artificial urinary sphincter is associated with a high rate of erosion after prior radiotherapy. The role of Burch colposuspension in patients with prior radiotherapy is poorly defined. Urinary diversion should be considered for patients with a devastated outlet. CONCLUSIONS: Since the long-term effects of radiotherapy on lower urinary tract voiding function are typically irreversible and progressive, further research is needed to mitigate the adverse effects of irradiation and identify more durable treatment options for women with radiation induced bladder dysfunction and stress urinary incontinence. PMID- 30311660 TI - Increased dietary protein-to-lipid ratio improves survival during naturally occurring pancreas disease in Atlantic salmon, Salmo salar L. AB - This study demonstrated that increased dietary protein-to-lipid ratio (P/L-ratio) improved survival of farmed Atlantic salmon naturally affected by pancreas disease (PD). In addition to diet, body weight (BW) and delousing mortality prior to the PD outbreak also contributed significantly (p < 0.05) to explain the observed variation in PD-associated mortality. Subsequent to the PD outbreak, large amount of fish failed to grow and caused thin fish with poor condition (runts). At the end of the trial, significantly (p < 0.05) lower amounts of runt fish and increased amount of superior graded fish where detected among fish fed increased P/L-ratio and within the fish with the largest BWs prior to PD. Diet, BW and delousing mortality contributed significantly (p < 0.05) to explain the variation in the amount of superior graded fish, whereas BW and diet explained the variation in the amount of runt fish. A significant (p < 0.01) negative linear relationship was observed between the amount of superior graded fish and the total mortality, whereas a positive linear relationship was detected between percentage of fillets with melanin and the total mortality. Thus, increased dietary P/L-ratio seem to reduce the mortality and impaired slaughter quality associated with PD. PMID- 30311661 TI - Recent advances in microfluidic cell sorting techniques based on both physical and biochemical principles. AB - Microfluidic technologies for isolating cells of interest from a heterogeneous sample have attracted great attentions, due to the advantages of less sample consumption, simple operating procedure, and high separation accuracy. According to the working principles, the microfluidic cell sorting techniques can be categorized into biochemical (labeled) and physical (label-free) methods. However, the inherent drawbacks of each type of method may somehow influence the popularization of these cell sorting techniques. Using the multiple complementary isolation principles is a promising strategy to overcome this problem, therefore there appears to be a continuing trend to integrate two or more sorting methods together. In this review, we focus on the recent advances in microfluidic cell sorting techniques relied on both physical and biochemical principles, with emphasis on the mechanisms of cell separation. The biochemical cell sorting techniques enhanced by physical principles and the physical cell sorting techniques enhanced by biochemical principles, are first introduced. Then, we highlight on-chip magnetic-activated cell sorting, on-chip fluorescence-activated cell sorting, multi-step cell sorting and multi-principle cell sorting techniques, which are based on both physical and biochemical separation mechanisms. Finally, the challenges and future perspectives of the integrated microfluidics for cell sorting are discussed. PMID- 30311663 TI - SpHMA1 is a Chloroplast Cadmium Exporter Protecting Photochemical Reactions in the Cd Hyperaccumulator Sedum plumbizincicola. AB - Sedum plumbizincicola is able to hyperaccumulate cadmium (Cd), a nonessential and highly toxic metal, in the above-ground tissues, but the mechanisms for its Cd hypertolerance are not fully understood. Here, we show that the heavy metal ATPase 1 (SpHMA1) of S. plumbizincicola plays an important role in chloroplast Cd detoxification. Compared with the HMA1 ortholog in the Cd nonhyperaccumulating ecotype of Sedum alfredii, the expression of SpHMA1 in the leaves of S. plumbizincicola was >200 times higher. Heterologous expression of SpHMA1 in Saccharomyces cerevisiae increased Cd sensitivity and Cd transport activity in the yeast cells. The SpHMA1 protein was localized to the chloroplast envelope. SpHMA1 RNA interference (RNAi) transgenic plants and CRISPR/Cas9-induced mutant lines showed significantly increased Cd accumulation in the chloroplasts compared with wild-type plants. Chlorophyll fluorescence imaging analysis revealed that the photosystem II of SpHMA1 knockdown and knockout lines suffered from a much higher degree of Cd toxicity than wild type. Taken together, these results suggest that SpHMA1 functions as a chloroplast Cd exporter and protects photosynthesis by preventing Cd accumulation in the chloroplast in S. plumbizincicola and hyperexpression of SpHMA1 is an important component contributing to Cd hypertolerance in S. plumbizincicola. PMID- 30311662 TI - The WRKY transcription factor, WRKY13, activates PDR8 expression to positively regulate cadmium tolerance in Arabidopsis. AB - Cadmium (Cd) extrusion is an important mechanism conferring Cd tolerance by decreasing its accumulation in plants. Previous studies have identified an Arabidopsis ABC transporter, PDR8, as a Cd extrusion pump conferring Cd tolerance. However, the regulation of PDR8 in response to Cd stress is still largely unknown. In this study, we identified an Arabidopsis cadmium-tolerant dominant mutant, designated xcd3-D, from the XVE-tagging T-DNA insertion lines by a gain-of-function genetic screen. The corresponding gene was cloned and shown to encode a nuclear WRKY transcription factor WRKY13. Expression of WRKY13 was induced by Cd stress. Overexpression of WRKY13 resulted in decreased Cd accumulation and enhanced Cd tolerance, whereas loss-of-function of WRKY13 led to increased Cd accumulation and sensitivity. Further analysis showed that WRKY13 activates the transcription of PDR8 by directly binding to its promoter. Genetic analysis indicated that WRKY13 acts upstream of PDR8 to positively regulate Cd tolerance. Our results provide evidence that WRKY13 directly targets PDR8 to positively regulate Cd tolerance in Arabidopsis. PMID- 30311664 TI - Allergic contact dermatitis caused by mupirocin and pimecrolimus. PMID- 30311665 TI - Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction. AB - AIM: To investigate if Multiple Sclerosis (MS) lesion characteristics affect functional brain connectivity (FC) during bladder voiding. METHODS: Twenty-seven ambulatory female patients with MS completed our functional magnetic resonance imaging (fMRI)/urodynamic testing (UDS) platform. Individual fMRI activation maps were generated at initiation of voiding. FC patterns of these regions were calculated and compared. Similarity of the FC pattern from one patient relative to all others was expressed by a parameter FC_sim. A statistical analysis was performed to reveal the relationship of the existence of an enhancing brain lesion, the size of the largest lesion and the ability to void spontaneously to this FC similarity measure. RESULTS: FC_sim values were significantly lower for patients with an enhancing MS lesion (11.7 +/- 3.1 vs 5.3 +/- 2.1 P < 0.001). Lesion size smaller than 20 mm inversely correlated significantly with FC_sim (R = -0.43, P = 0.05). Patients with the ability to void spontaneously had a higher FC_sim value (12.0 +/- 2.8 vs 9.3 +/- 4.4 s, P = 0.08). Patients that exhibited a decrease of compliance also showed a significantly lower FC_sim value (11.3 +/- 3.5 vs 4.7 +/- 0.7, P < 1e-5). CONCLUSION: FC connectivity analysis derived from an fMRI task-based study including repetitive voiding cycles is able to quantify the heterogeneity of connectivity patterns in the brain of MS patients. FC similarity decreased with maximum lesion size or the presence of enhancing lesions affecting the ability to void spontaneously. PMID- 30311666 TI - Perfluorodecalin-infused patch in picosecond and Q-switched laser-assisted tattoo removal: Safety in Fitzpatrick IV-VI skin types. AB - BACKGROUND: The topical transparent perfluorodecalin-infused (PFD) silicone patch has been demonstrated to reduce epidermal whitening produced in association with laser-assisted tattoo removal. This optical clearing agent has enabled multiple laser passes to be made in one treatment session. Previous studies using the PFD patch have showed enhanced clearance with picosecond and Q-Switched lasers on blue/black tattoos in Fitzpatrick skin types I-III. We sought to explore the safety and efficacy of using the PFD patch with Q-Switched and picosecond lasers in Fitzpatrick skin types IV-VI. STUDY DESIGN/MATERIALS AND METHOD: A retrospective, single institution chart review was used to assess the safety of treating tattoos using the PFD patch with Q-Switched and picosecond lasers in Fitzpatrick skin types IV-VI. A total of 14 patients, ages 23-66 with Fitzpatrick skin types IV-VI were treated with the PFD patches and liquid PFD using the picosecond (532, 785, and 1064 nm) and the Q-switched Nd:YAG (1064 nm). The treated tattoos contained blue, black, red, green, purple, and pink ink. Patient reported adverse events were evaluated. RESULTS: The PFD patch and liquid PFD were used with the picosecond (532, 785, 1064 nm) and the Q-switched Nd:YAG (1064 nm) lasers to treat tattoos safely in 14 patients with Fitzpatrick skin types IV VI. Furthermore, the PFD patch was used safely when treating tattoo containing blue, black, red, green, purple and pink ink. Multiple passes were better tolerated in patients when using the PFD patch. No adverse effects were reported. CONCLUSION: Our retrospective chart review supports the safety and efficacy of the PFD patch in protecting the epidermis from thermal injury during laser assisted tattoo removal of multicolored tattoos in patients with Fitzpatrick skin types IV-VI. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30311667 TI - Four-year follow-up on 68 patients with a new post-operatively adjustable long term implant for post-prostatectomy stress incontinence: ProACTTM. AB - AIMS: This paper presents 4-year follow-up results for patients enrolled in a pivotal study conducted to support an FDA premarket approval application (PMAA). The study evaluated the safety and efficacy of the ProACT Adjustable Continence Therapy for the treatment of post-prostatectomy stress urinary incontinence (SUI). METHODS: The clinical study involved 11 clinical sites and enrolled 160 subjects, all male. A total of 124 subjects met study criteria and 123 were implanted with ProACT. Baseline and outcomes for 68 patients who completed 4-year follow-up visits are reported. Endpoints included 24-h pad weight, Incontinence Quality of Life Questionnaire (I-QOL), UCLA Prostate Cancer Index-Urinary Function (PCI-UF), residual volume, and incidence and severity of device or procedure-related adverse events. RESULTS: Statistically significant improvements during follow-up were observed in 24-h pad weight, for which the mean pre-implant urine loss was 293 g, which was reduced at 4 years to 73 g (P < 0.001). Reductions in pad weight were observed across all levels of pre-implant SUI severity. Significant improvements were also seen in quality of life as measured by the I-QOL (P < 0.001) as well as measures of urinary function and pad use. One procedure-related SAE (retention) was reported among the 68 subjects; the SAE was resolved without clinical meaningful sequalae. CONCLUSIONS: These results confirm the long-term safety and efficacy of this newly FDA-approved therapy, showing significant improvements in both objective and subjective measures of SUI in mild, moderate, and severely incontinent male patients. The implant procedure is minimally invasive, and complications are generally mild and easily resolvable. PMID- 30311668 TI - Psychometric evaluation of the Texas revised inventory of grief in a sample of bereaved family caregivers. AB - The Texas Revised Inventory of Grief (TRIG) was developed to measure the intensity of grief after the death of a close person. It consists of two scales: TRIG I (past behaviors) and TRIG II (present feelings). Because of inconsistencies in previous validations, the instrument needs to be further validated, hence the aim of this study was to evaluate the psychometric properties of the TRIG in a sample of bereaved family caregivers in Sweden. The TRIG was translated to Swedish according to standard principles, and 129 bereaved family caregivers completed the questionnaire. Parallel analysis was used to decide the number of factors to extract, followed by confirmatory factor analysis. An ordinal version of Cronbach's alpha was used to evaluate the internal consistency of the scales. Construct validity was tested against the Hospital Anxiety and Depression Scale (HADS). The factor analyses resulted in one factor being retained for both scales. The internal consistency was excellent (alpha > 0.9) for both scales. Construct validity was supported by strong correlations between TRIG I and TRIG II as well as moderate correlations between the TRIG scales and HADS. In conclusion, the TRIG has sound psychometric qualities and the two scales should be treated as unidimensional measures of grief. Hence, the instrument is suited to be used in the context of palliative care. PMID- 30311669 TI - Pathogenicity of Pasteurella sp. in lumpsuckers (Cyclopterus lumpus L.). AB - The incidence of disease caused by Pasteurella sp. in farmed lumpsuckers in Norway has been steadily increasing in recent years, causing significant economic losses and fish welfare issues. The disease affects all life stages, both in hatcheries and after release into salmon cages. Therefore, it is important to establish robust challenge models, to be used for vaccine development. Exposure experiments via intramuscular and intraperitoneal injection underlined the high virulence of the bacteria, whereas the cohabitation and bath models allowed the chronic symptoms of the disease to be studied more accurately. Skin lesions and haemorrhage at the base of fins were observed in the more acute cases of the disease. Symptoms including white spots over the skin, especially around the eyes, characterized the chronic cases. The latter were most prominent from the bath challenge model. Histopathology indicated a systemic pattern of disease, whereas qPCR analysis from head kidney showed that bacteria may be present in survivor fish at the end of the challenges. In all the challenge models investigated, Pasteurella sp. was re-isolated from the fish, thus fulfilling Koch's postulates. These findings highlight the importance of screening of lumpsuckers prior to transfer to minimize the risks of carrying over asymptomatic carriers. PMID- 30311670 TI - Sex, ADHD symptoms, and CHRNA5 genotype influence reaction time but not response inhibition. AB - People showing symptoms of attention deficit hyperactivity disorder (ADHD) often present an impairment of reaction time and response inhibition. These executive functions are influenced by nicotinergic acetylcholine receptors (nAchr) as mediators of cholinergic signaling, and show differences between both sexes. We examined the effects of two functional polymorphisms rs3841324 (S/L) and rs16969968 (G/A) of the cholinergic gene CHRNA5, ADHD symptoms and sex on response inhibition/reaction time in the Stop Signal Task. In the analyses, 183 participants (52.4% females) were included. In participants carrying the diplotype (SS_GG), men with ADHD symptoms responded faster, while men without ADHD symptoms were slower than women (F = 5.313; p = 0.023; etap 2 = 0.034). Although explorative, this threefold interaction on reaction time but not response inhibition extend previous findings, suggesting a moderating effect of ADHD symptoms in men carrying the CHRNA5 diplotype SS_GG and might inspire research on genotype- and gender-specific ADHD medication. PMID- 30311671 TI - Aging increases the expression of vasopressin receptors in both the kidney and urinary bladder. AB - AIMS: The goal of this study was to determine whether aging effects the expression of V1a and V2 vasopressin receptors in the urinary bladder mucosa (UBM) and kidney. METHODS: UBM and kidneys were obtained from young (3 months-of age) and old (25-30 months-of-age) female Fisher 344 rats. Tissue samples were analyzed by western blotting for V1a and V2 receptor expression, and rat plasma levels of vasopressin levels were measured by ELISA. RESULTS: V1a and V2 receptors were detected in both the UBM and kidneys. Aging significantly (P < 0.05) increased the expression of V2 receptors by 2.80 +/- 0.52 and 6.52 +/- 1.24 fold in the UBM and kidneys, respectively. Aging also increased V1a receptor expression in the kidneys (5.52 +/- 1.05 fold; P < 0.05), but not in the UBM. To the best of our knowledge, because this is the first detection of V2 receptors in the mammalian bladder mucosa, we also probed human UBM for V2 receptors and observed high expression in human UBM. Unlike V1a and V2 receptors, aging had only a minor effect on plasma vasopressin levels (8% increase). CONCLUSIONS: V2 receptors are substantially increased in the aging UBM. The role of these receptors in UBM is as yet undefined, but given their presence and action in the kidneys, the possible effect of these receptors in free water regulation should be considered. The large age-related increase in the expression of V2 receptors in both the UBM and kidney may contribute to the effectiveness of desmopressin in age-related nocturia. PMID- 30311672 TI - The real "danger" lies in the failure to confront fundamentals. AB - Can we formulate a framework that would provide an agreed upon basis for discussions of immune behaviour? An attempt to do this is, in the end, the main goal of this essay. If you tell a physicist that you have invented a perpetual motion machine, he would not spend any time trying to reveal the flaw. Rather, he would shrug you off because in his framework, such a machine is an impossibility. However, immunologists lacking an agreed upon, preferably default, framework spend their time chasing into dead-end alleys or take refuge in descriptive empiricism. This will be illustrated using Danger theory, which ignores fundamentals to generate a framework believed to obviate the need for a Self (S) Nonself (NS) discrimination and which is claimed to be bolstered with monogamous data (observation married to a single explanation). The arguments presented here apply to all NS-marker theories (pathogenicity, discontinuity, localization, danger, etc.). PMID- 30311673 TI - Designing humans: A human rights approach. AB - Advances in genomic technologies such as CRISPR-Cas9, mitochondrial replacement techniques, and in vitro gametogenesis may soon give us more precise and efficient tools to have children with certain traits such as beauty, intelligence, and athleticism. In this paper, I propose a new approach to the ethics of reproductive genetic engineering, a human rights approach. This approach relies on two claims that have certain, independent plausibility: (a) human beings have equal moral status, and (b) human beings have human rights to the fundamental conditions for pursuing a good life. I first argue that the human rights approach gives us a lower bound of when reproductive genetic engineering would be permissible. I then compare this approach with other approaches such as the libertarian, perfectionist, and life worth living approaches. Against these approaches, I argue that the human rights approach offers a novel, and more plausible, way of assessing the ethics of reproductive genetic engineering. PMID- 30311674 TI - Etiology of nocturia response in men with diminished bladder capacity. AB - AIMS: To test the hypothesis that patients with nocturia owing to diminished global or nocturnal bladder capacity improve via increased bladder capacity. METHODS: This is a retrospective analysis of voiding diaries completed at a VA urology clinic between 2008-2017. Inclusion required patients aged at least 18 years, male, undergoing treatment for nocturia, and having completed at least two 24-hour voiding diaries >=1 month apart. Patients were divided into two cohorts: responders (any decline in nocturia) and non-responders (no change or any increase in nocturia). Patients were further sub-stratified as having low global bladder capacity (maximum voided volume [MVV] <200 mL) versus low nocturnal bladder capacity (nocturnal maximum voided volume [NMVV] <200 mL and MVV >=200 mL). Wilcoxon rank-sum was applied with a Bonferroni correction to test significance. RESULTS: Forty pre- and post-treatment diaries from 27 patients, and 19 pre- and post-treatment diaries from 17 patients were identified as having low global and low nocturnal bladder capacity, respectively. Nocturia responders with low global bladder capacity demonstrated significant decline compared to non responders in nocturnal urine volume (NUV) (-140 vs +75, P < 0.01) and nocturnal bladder capacity index (NBCi) (-0.59 vs +0.23, P < 0.01). Patients with low nocturnal bladder capacity similarly demonstrated decreased NUV (-30 vs +160, P = 0.04) and NBCi (-1.4 vs +0.33, P < 0.01). There was no significant change in MVV or NMVV for either group. CONCLUSIONS: Treatment directed at lowering nocturnal urine production and enabling patients to consistently void at capacity is a rational strategy to treat nocturia in patients with low bladder capacity. PMID- 30311675 TI - Diet, Gut Microbes and Host Mate Choice: Understanding the significance of microbiome effects on host mate choice requires a case by case evaluation. AB - All organisms live in close association with microbes. However, not all such associations are meaningful in an evolutionary context. Current debate concerns whether hosts and microbes are best described as communities of individuals or as holobionts (selective units of hosts plus their microbes). Recent reports that assortative mating of hosts by diet can be mediated by commensal gut microbes have attracted interest as a potential route to host reproductive isolation (RI). Here, the authors discuss logical problems with this line of argument. The authors briefly review how microbes can affect host mating preferences and evaluate recent findings from fruitflies. Endosymbionts can potentially influence host RI given stable and recurrent co-association of hosts and microbes over evolutionary time. However, observations of co-occurrence of microbes and hosts are ripe for misinterpretation and such associations will rarely represent a meaningful holobiont. A framework in which hosts and their microbes are independent evolutionary units provides the only satisfactory explanation for the observed range of effects and associations. PMID- 30311676 TI - Uroflow measurement combined with electromyography testing of the pelvic floor in healthy children. AB - AIMS: To investigate if the standard protocol for uroflowmetry, recommended by the International Children's Continence Society, remains accurate when integrating EMG measurement by means of superficial electrodes. METHODS: A cross sectional study was conducted including healthy children. Group A performed two direct repetitions of uroflowmetry in combination with electromyography (uroflow/EMG). Group B performed a preceding measurement of isolated uroflowmetry, followed by two randomized measurements of uroflowmetry with and without EMG. Interpretation of uroflow curve was assessor blinded by a pediatric urologist and secondly performed using the flow index methodology. Statistical analysis compared different voids within each group and between group A and B. RESULTS: Eighty-three children were included and 206 uroflow measurements were obtained. In both groups statistical findings confirmed the hypothesis that it is preferable to perform an additional measurement before the use of uroflow/EMG. Although both groups showed improvement between voids, the group with initial uroflow measurement followed by uroflow/EMG measurement showed more improvement in concern of curve pattern. An initially better first void in group A, but no statistical difference between the second void in group A and uroflow/EMG testing in group B further demonstrates a higher improvement in group B. This suggests the use of a precedent uroflowmetry without EMG is preferable to immediate testing with EMG. CONCLUSIONS: It should be mandatory to perform one measurement in advance to ensure the reliability of the results. It is suggested to initiate the procedure with a single uroflowmetry measurement followed by one measurement of uroflow with EMG testing. PMID- 30311677 TI - Insights on UNC-104-dynein/dynactin interactions and their implications on axonal transport in Caenorhabditis elegans. AB - Bidirectional cargo transport in neurons can be explained by two models: the "tug of-war model" for short-range transport, in which several kinesin and dynein motors are bound to the same cargo but travel in opposing directions, and by the "motor coordination model" for long-range transport, in which small adaptors or the cargo itself activates or deactivates opposing motors. Direct interactions between the major axonal transporter kinesin-3 UNC-104(KIF1A) and the dynein/dynactin complex remains unknown. In this study, we dissected and evaluated the interaction sites between UNC-104 and dynein as well as between UNC 104 and dynactin using yeast two-hybrid assays. We found that the DYLT-1(Tctex) subunit of dynein binds near the coiled coil 3 (CC3) of UNC-104, and that the DYRB-1(Roadblock) subunit binds near the CC2 region of UNC-104. Regarding dynactin, we specifically revealed strong interactions between DNC-6(p27) and the FHA-CC3 stretch of UNC-104, as well as between the DNC-5(p25) and the CC2-CC3 region of UNC-104. Motility analysis of motors and cargo in the nervous system of Caenorhabditis elegans revealed impaired transport of UNC-104 and synaptic vesicles in dynein and dynactin mutants (or in RNAi knockdown animals). Further, in these mutants UNC-104 clustering along axons was diminished. Interestingly, when dynamic UNC-104 motors enter a stationary UNC-104 cluster their dwelling times are increased in dynein mutants (suggesting that dynein may act as an UNC 104 activator). In summary, we provide novel insights on how UNC-104 interacts with the dynein/dynactin complex and how UNC-104 driven axonal transport depends on dynein/dynactin in C. elegans neurons. PMID- 30311678 TI - Finding Wealth in Waste: Irreplicability Re-Examined. AB - Irreplicability is framed as crisis, blamed on sloppy science motivated by perverse stimuli in research. Structural changes to the organization of science, targeting sloppy science (e.g., open data, pre-registration), are proposed to prevent irreplicability. While there is an unquestionable link between sloppy science and failures to replicate/reproduce scientific studies, they are currently conflated. This position can be understood as a result of the erosion of the role of theory in science. The history, sociology, and philosophy of science reveal alternative explanations for irreplicability to show it is part of proper, informative and valuable science. Irreplicability need not equate research waste. Sloppy science is the problem, also when results do replicate. Hence, the solution should focus on opposing sloppy research. PMID- 30311679 TI - An innovative, non-invasive sensation meter allows for a more comprehensive understanding of bladder sensation events: A prospective study in participants with normal bladder function. AB - AIMS: There is currently no standardized method of characterizing changes in bladder sensation during bladder filling outside of the urodynamics laboratory. The purpose of this investigation was to characterize real-time bladder sensation events using a sensation meter during oral hydration in individuals with normal bladder function. METHODS: Participants enrolled in an accelerated hydration study drank 2 L Gatorade-G2(r) and utilized a sensation meter to record real-time bladder sensation (0-100%), verbal sensory thresholds, and sensation descriptors of "tense," "pressure," "tingling," "painful," and "other" for two consecutive fill-void cycles. RESULTS: Data from 21 participants (12 females/9 males) were obtained and demonstrated an average of 8-9 sensation events (significant changes in sensation) per fill with no differences in the total number of sensation events and volume between sensation events (fill 1 vs fill 2). An increased number of sensation events occurred at higher capacity quartiles. Event descriptors of "pressure" and "tingling" were the most commonly chosen descriptors in both fills. CONCLUSIONS: The innovative sensation meter includes the sensation event descriptors of "tense," "tingling," "pressure," and "painful," to enable a more comprehensive understanding of bladder sensation as well as real-time identification, quantification, and characterization of sensation events. The study demonstrates 8-9 events per fill, acceleration of sensation during filling, and unique sensation event descriptor patterns. This technology may be helpful in the identification of novel sensation patterns associated with overactive bladder (OAB) and aging. PMID- 30311680 TI - Pelvic floor muscle training is better than hypopressive exercises in pelvic organ prolapse treatment: An assessor-blinded randomized controlled trial. AB - AIMS: To verify if hypopressive exercises (HEs) can improve pelvic organ prolapse (POP) symptoms equally or better than pelvic floor muscle training (PFMT). METHODS: Randomized controlled trial. Symptomatic women with untreated stage II POP according to the Pelvic Organ Prolapse Quantification System (POP-Q) having the ability to contract their pelvic floor muscles were invited. The outcome measures were POP symptoms as measured by specific questions and Prolapse Quality of Life (P-QoL); POP severity as measured by POP-Q; and PFM function. Intervention consisted by 12 weeks of PFMT or an HE home exercise program with bimonthly sessions with a physiotherapist. The protocol consisted of three initial sessions to learn how to perform the exercises correctly, followed by 3 months of exercise with monthly progression. Volunteers filled out exercise diaries to record their compliance. RESULTS: PFMT presented better results in terms of the following symptoms: a bulge/lump from or in the vagina, heaviness or dragging on the lower abdomen, and stress incontinence. PFMT also presented better results regarding the Prolapse impact and role, social and personal limitations of P-QoL. Regarding the total number of symptoms at the end, the PFMT group presented a mean of 1.7 (+/-1.2), and the HE group presented a mean of 2.8 (+/-1,1); the effect size was 1.01 in favor of the PFMT group (95%CI = 1.002 1.021). CONCLUSION: Both groups exhibited improvements in POP symptoms, quality of life, prolapse severity, and PFM function. PFMT was superior to HE for all outcomes. PMID- 30311681 TI - Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. AB - Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long-term rapamycin in relatively healthy, middle-aged marmosets. PMID- 30311682 TI - Neurophysiologic study in idiopathic overactive bladder. AB - AIM: Idiopathic overactive bladder (OAB) is a prevalent, mystifying disorder with a questionable neurogenic background. We aimed to investigate the possible subtle neuropathic affection underlying its pathogenesis. METHODS: A cross-sectional cut off study was carried out on a series of 38 females with idiopathic OAB and 22 healthy matched female volunteers. The following was performed: symptom score questionnaire, determination of pudendal nerve terminal motor latency (PNTML), sacral reflexes' latencies, pudendal somatosensory evoked potentials, and needle electromyography of the external anal and urethral sphincters. RESULTS: A highly significant prolongation of PNTMLs and sacral reflexes latencies among the patients group was detected (P >= 0.001). Pudendal somatosensory evoked potentials showed non- significance among the two studied groups (P >= 0.05). External anal sphincter neuropathic affection was detected in 27 patients (71%) and external urethral sphincter neuropathic affection was detected in 30 patients (78.9%). The clitoral anal reflex showed the highest sensitivity and specificity among the neurophysiologic tests used in assessing the neuropathic affection (86.7 and 83%, respectively), followed by PNTML (83.3 and 80%, respectively). CONCLUSION: Pudendal neuropathy is the dominating possible attributing factor in the pathogenesis underlying idiopathic OAB. An integrated clinical, urodynamic, and electro-physiological assessment is recommended for evaluation of any overactive bladder patients. PMID- 30311683 TI - The toxic edge-A novel treatment for refractory erythema and flushing of rosacea. AB - PURPOSE: Rosacea is a common, chronic facial skin disease that affects the quality of life. Treatment of facial erythema with intradermal botulinum toxin injection has previously been reported. The primary objective of the study was the safety and efficacy of thermal decomposition of the stratum corneum using a novel non-laser thermomechanical system (Tixel, Novoxel, Israel) to increase skin permeability for Botulinum toxin in the treatment of facial flushing of rosacea. METHODS: A retrospective review of16 patients aged 23-45 years with Fitzpatrick Skin Types II to IV and facial erythematotelangiectatic rosacea treated by Tixel followed by topical application of 100 U of abobotulinumtoxin. A standardized high-definition digital camera photographed the patients at baseline and 1, 3, and 6 months after the last treatment. Objective and subjective assessments of the patients were done via Mexameter, the Clinicians Erythema Assessment (CEA), and Patients self-assessment (PSA) scores and the dermatology life quality index (DLQI) validated instrument. RESULTS: The average Maxameter, CEA, and PSA scores at 1, 3, and 6 months were significantly improved compared with baseline (all had a P-value <0.001). DLQI scores significantly improved with an average score of 18.6 at baseline at 6 months after treatment (P < 0.001). Self-rated patient satisfaction was high. There were no motor function side-effects or drooping. CONCLUSION: Thermal breakage of the stratum corneum using the device to increase skin permeability for botulinum toxin type A in the treatment of facial flushing of rosacea seems both effective and safe. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30311684 TI - An Intravenous Fish Oil Based Lipid Emulsion successfully treats intractable pruritus and cholestasis in a patient with MVID. AB - A PN-dependent 3-year-old male with MVID presented with a history of worsening jaundice and severe pruritus. He was managed at an outside institution with low dose soybean oil-based lipid emulsion (SOLE) Intralipid(r) (Fresenius-Kabi, Uppsala, Sweden) at 0.2 g/kg/day as a strategy to prevent PN-associated liver disease (PNALD). At 11 months of age he complained of significant pruritus without dermatologic findings. Ursodiol and diphenhydramine were administered with partial resolution. This article is protected by copyright. All rights reserved. PMID- 30311685 TI - Risk of prolapse and urinary complications in adult spina bifida patients with neurogenic acontractile detrusor using clean intermittent catheterization versus Valsalva voiding. AB - AIMS: To assess the relative risks of pelvic organ prolapse (POP) and urinary complications in adult spina bifida patients with neurogenic acontractile detrusor voiding with Valsalva versus those using clean-intermittent catheterization (CIC). METHODS: We conducted a retrospective analysis including all spina bifida patients with neurogenic acontractile detrusor with a minimum follow-up of 12 months. Patients were then divided in two groups according to their bladder management: voiding with Valsalva versus CIC. The primary endpoint was any de novo or worsened rectal and/or pelvic organ prolapse (POP) diagnosed during follow-up. The secondary outcome was urinary complications defined as febrile urinary tract infections (UTI) and/or urolithiasis and/or renal failure. RESULTS: Fifty-five patients (50.9% were males) met the inclusion/exclusion criteria: 28 voiding with Valsalva and 27 performing CIC. At baseline, the rates of vaginal prolapse (44.4% vs 50%; P = 0.99), and rectal prolapse/intussusception (25.9% vs 21.4%; P = 0.76) were similar in both groups. After a median follow-up of 80.6 and 65.6 months, respectively (P = 0.29), the rate of de novo or worsened rectal prolapse/intussusception was higher in the Valsalva voiding group than in the CIC group (32.1% vs 3.7%; P = 0.01). De novo or worsened vaginal prolapses were also more common in the Valsalva voiding group, but it did not reach statistical significance (33.3% vs 11.1%; P = 0.29). CONCLUSIONS: Valsalva voiding might be harmful in adult spina bifida patients with neurogenic acontractile detrusor as it may increase the risk of rectal prolapse/intussusception. Overall, the prevalence of POP and rectal prolapse was high in both groups. PMID- 30311686 TI - Recommendations for conducting invasive urodynamics for men with lower urinary tract symptoms: Qualitative interview findings from a large randomized controlled trial (UPSTREAM). AB - AIMS: To capture in-depth qualitative evidence regarding attitudes to and experiences of urodynamic testing among men with lower urinary tract symptoms (LUTS) at each end of the clinical pathway. METHODS: Semi-structured interview study conducted within the Urodynamics for Prostate Surgery: Randomized Evaluation of Assessment Methods (UPSTREAM) trial, which randomized men to a care pathway including urodynamics or routine non-invasive tests from 26 secondary care urology sites across England. Men were interviewed after assessments but prior to treatment, or after surgery for LUTS. Men were purposively sampled to include those who had urodynamics and those who did not, and diversity in demographic characteristics and symptom burden. Interviews were analyzed using inductive thematic analysis. RESULTS: Forty-one men participated (25 pre treatment, 16 post-surgery), ages 52-89. The 16 men who had not previously experienced urodynamics said they would accept the test in their assessment, but some were apprehensive or wanted more information. The 25 men who had experienced urodynamics all found it acceptable, though some reported pain, infection, or embarrassment. Embarrassment was minimized by informing patients what the procedure would be like, and ensuring privacy. Urodynamics was valued for its perceived diagnostic insight. Information deficits were reported before, during, and after the test. How and when results were explained and the adequacy of explanations varied. CONCLUSIONS: Urodynamics is acceptable to men with LUTS and generally well-tolerated. To ensure patients are prepared and informed, good communication before and during the procedure is essential. Privacy should be prioritized, and test results discussed promptly and in sufficient detail. Staff require training and guidance in these areas. PMID- 30311687 TI - Ultrasonographic intraoperative monitoring and follow-up of Kaposi's sarcoma nodules under treatment with intralesional vincristine. AB - BACKGROUND: Intralesional vincristine is an effective treatment for Kaposi's sarcoma (KS) nodules on the skin, but there is little evidence of its action through imaging techniques. Ultrasonography can be an adjunctive tool in the diagnosis and management of KS skin lesions, but data in the literature are few. MATERIALS AND METHODS: Five patients with classic KS nodules were treated with intralesional vincristine. Ultrasonographic and color Doppler assessment were performed during vincristine injection and monitoring was repeated 1 and 3 months after the procedure. Partial response was defined as a reduction of more than 50% lesion volume and reduction of the vascular signal; complete response as a resolution of lesion associated with the absence of vascular signal. RESULTS: Six KS nodules were included in the study. On ultrasonography examination, KS nodules appeared as oval or round, hypoechoic, homogeneous structures, with intralesional vascularization, more prominent in the deepest pole of the nodule. At month 1, 4 nodules achieved a complete response, while two nodules showed a partial response and were retreated with intralesional vincristine. At month 3, all lesions achieved a complete response. CONCLUSION: Ultrasonography may be a valuable tool in assessing clinical response to intralesional vincristine therapy of cutaneous KS nodules. PMID- 30311688 TI - Increased odds of bladder and bowel symptoms in early Parkinson's disease. PMID- 30311689 TI - Whole-Heart Spiral Simultaneous Multi-Slice First-Pass Myocardial Perfusion Imaging. AB - PURPOSE: To develop and evaluate a simultaneous multislice (SMS) spiral perfusion pulse sequence with whole-heart coverage. METHODS: An orthogonal set of phase cycling angles following a Hadamard pattern was incorporated into a golden-angle (GA) variable density spiral perfusion sequence to perform SMS imaging at different multiband (MB) factors. Images were reconstructed using an SMS extension of L1-SPIRiT that we have termed SMS-L1-SPIRiT. The proposed sequence was evaluated in 40 subjects (10 each for MB factors of 1, 2, 3, and 4). Images were blindly graded by 2 cardiologists on a 5-point scale (5, excellent). To quantitatively evaluate the reconstruction performance against images acquired without SMS, the MB =1 data were used to retrospectively simulate data acquired at MB factors of 2 to 4. RESULTS: Analysis of the SMS point-spread function for the desired slice showed that the proposed sampling strategy significantly canceled the main-lobe energy of the other slices and has low side-lobe energy resulting in an incoherent temporal aliasing pattern when rotated by the GA. Retrospective experiments demonstrated the SMS-L1-SPIRiT method removed aliasing from the interfering slices and showed excellent agreement with the ground-truth MB =1 images. Clinical evaluation demonstrated high-quality perfusion images with average image-quality scores of 4.3 +/- 0.5 (MB =2), 4.2 +/- 0.5 (MB =3), and 4.4 +/- 0.4 (MB =4) with no significant quality difference in image quality between MB factors (P = 0.38). CONCLUSION: SMS spiral perfusion at MB factors 2, 3, and 4 produces high-quality perfusion images with whole-heart coverage in a clinical setting with high sampling efficiency. PMID- 30311690 TI - Obstetric fistula: The role of physiotherapy: A report from the Physiotherapy Committee of the International Continence Society. AB - AIMS: To discuss the role of physiotherapy in the management of women who have suffered an obstetric fistula, referring to research findings when appropriate and available, and the experiences of clinical specialists in the field. METHODS: The experiences of physiotherapists who have worked in countries where obstetric fistula is prevalent, and the limited literature available, were considered in producing this consensus document on behalf of the ICS Physiotherapy Committee. RESULTS: The role of physiotherapy both pre- and post-fistula repair was identified, and is multi-faceted. Women may have general rehabilitation needs based on the obstructed labor itself and subsequent care. All affected women may benefit from pelvic floor muscle assessment, education and exercises to optimize the outcome of their surgery; further pelvic floor physiotherapy may be indicated for those who experience persistent genitourinary dysfunction following closure of the fistula. CONCLUSIONS: Further robust research is required to confirm the effectiveness of physiotherapy in the management of women who have suffered an obstetric fistula and the optimum development of such services. Based on the available literature and the experience of physiotherapists in the field, there was consensus within the ICS Physiotherapy Committee that patient outcomes can be improved if physiotherapy is provided as part of the multidisciplinary team. Physiotherapy should not be overlooked when fistula services are being developed. PMID- 30311691 TI - Mirabegron as a treatment for overactive bladder symptoms in men (MIRACLE study): Efficacy and safety results from a multicenter, randomized, double-blind, placebo controlled, parallel comparison phase IV study. AB - AIMS: To evaluate the efficacy and safety of mirabegron in males with overactive bladder (OAB) symptoms. METHODS: In total, 464 males with OAB symptoms were enrolled from 14 institutes and were sorted into either the mirabegron 50 mg (n = 310) or placebo (n = 154) groups. The change in (i) the mean number of 24-h micturition episodes; (ii) OAB Symptom Scale (OABSS); and (iii) International Prostate Symptom Score (IPSS) from baseline to 12 weeks of treatment were compared between the two groups. Safety assessments included treatment-emergent adverse events, blood pressure, pulse rate, postvoid residual volume, and maximum urinary flow rate. After 12 weeks, the study was extended for 14 additional weeks by administering mirabegron 50 mg to both groups. RESULTS: The reduction in the mean number of 24-h micturition episodes from baseline to 12 weeks of treatment was similar between the two groups. However, significantly greater changes from baseline to 12 weeks were observed in total OABSS, OABSS urgency incontinence score (Q4), IPSS storage subscore (Q2 + Q4 + Q7), and IPSS urgency score (Q4) in the mirabegron group (P = 0.01 for all). According to the extended study, the changes of all efficacy variables from baseline to 26 weeks were similar between both groups. The safety assessment results were also similar between the two groups at 12 and 26 weeks. CONCLUSION: A daily 50 mg dose of mirabegron for 12 weeks reduced OAB symptoms in men, and no significant adverse events compared to the placebo group were noted. PMID- 30311693 TI - Aptamer-targeted DNA nanostructures with doxorubicin to treat protein tyrosine kinase 7-positive tumours. AB - OBJECTIVES: Aptamer sgc8c is a short DNA sequence that can target protein tyrosine kinase 7 (PTK7), which was overexpressed on many tumour cells. This study aimed to fabricate a novelty DNA nanostructure drug delivery system target on PTK7-positive cells-CCRF-CEM (human T-cell ALL). METHODS: Aptamer-modified tetrahedron DNA was synthesized through one-step thermal annealing process. The sgc8c-TDNs (s-TDNs) loading DOX complexes were applied to investigate the effect to PTK7-negative and -positive cells. RESULTS: When s-TDN:DOX acted on PTK7 positive and -negative cells respectively, the complexes exhibited specific toxic effect on PTK7-positive cells but not on PTK7-negative Ramos cells in vitro research. CONCLUSIONS: In this work, we successfully constructed a PTK7-targeting aptamer-guided DNA tetrahedral nanostructure (s-TDN) as a drug delivery system via a facile one-pot synthesis method. The results showed that s-TDN:DOX exhibited enhanced cytotoxicity against PTK7-positive CCRF-CEM cells, with a minor effect against PTK7-negative Ramos cells. Hence, this functionalized TDNs drug delivery system displayed its potential application in targeting PTK7 positive tumour T-cell acute lymphoblastic leukaemia. PMID- 30311692 TI - Efficacy of transcutaneous stimulation of the posterior tibial nerve compared to percutaneous stimulation in idiopathic overactive bladder syndrome: Randomized control trial. AB - AIM: To evaluate the non-inferiority of the transcutaneous electrical stimulation technique, as compared with the percutaneous therapy (PTNS), regarding the efficacy in symptoms and QoL improvement in patients with overactive bladder (iOAB). METHODS: Patients with overactive detrusor (DO) and persisting symptoms after first-line or second-line treatment were randomized to receive either transcutaneous therapy or PTNS 1 day a week (30 min at 20 Hz and 200 cycles/s) for 12 weeks. Data from a 3-day voiding diary and a self-reported QoL questionnaire were collected pre-treatment and at week 12. Non-inferiority was analyzed by estimating the mean change (95% confidence interval) of daytime micturition frequency. Statistical significance level was set at P < 0.05. RESULTS: Sixty-eight patients were included (67.6% women), mean age 59.6 years (SD 16.1). According to ITT analysis, daytime frequency decreased in both groups without statistically significant differences between them at the end of the treatment (adjusted difference 0.8; 95%CI; -0.1; 1.7); nor were differences in symptoms improvement for the variables collected through the 3-day voiding diary. Both techniques lessened urgency incontinence episodes by more than 50% and greatly improved the QoL. There were no relevant side effects and overall adherence to the treatment was 89.7%. CONCLUSIONS: This is the first RCT that evaluates the efficacy of the transcutaneous technique compared to the PTNS, and demonstrates non-inferiority in decreasing daytime frequency. Reduction in urgency incontinence episodes and improvement of QoL were also observed. These results and ease of application of transcutaneous neuromodulation may lead to a greater prescribing of this technique. PMID- 30311694 TI - A framework for motion correction of background suppressed arterial spin labeling perfusion images acquired with simultaneous multi-slice EPI. AB - PURPOSE: When using simultaneous multi-slice (SMS) EPI for background suppressed (BGS) arterial spin labeling (ASL), correction of through-plane motion could introduce artefacts, because the slices with most effective BGS are adjacent to slices with the least BGS. In this study, a new framework is presented to correct for such artefacts. METHODS: The proposed framework consists of 3 steps: (1) homogenization of the static tissue signal over the different slices to eliminate most inter-slice differences because of different levels of BGS, (2) application of motion correction, and (3) extraction of a perfusion-weighted signal using a general linear model. The proposed framework was evaluated by simulations and a functional ASL study with intentional head motion. RESULTS: Simulation studies demonstrated that the strong signal differences between slices with the most and least effective BGS caused sub-optimal estimation of motion parameters when through-plane motion was present. Although use of the M0 image as the reference for registration allowed 82% improvement of motion estimation for through-plane motion, it still led to residual subtraction errors caused by different static tissue signal between control and label because of different BGS levels. By using our proposed framework, those problems were minimized, and the accuracy of CBF estimation was improved. Moreover, the functional ASL study showed improved detection of visual and motor activation when applying the framework as compared to conventional motion correction, as well as when motion correction was completely omitted. CONCLUSION: When combining BGS-ASL with SMS-EPI, particular attention is needed to avoid artefacts introduced by motion correction. With the proposed framework, these issues are minimized. PMID- 30311695 TI - Prevalence and predictors of anal incontinence 6 years after first delivery. AB - AIMS: The main aim of the present study, was to explore prevalence and predictors of anal incontinence (AI) experienced 6 years after first delivery. METHODS: In this longitudinal prospective cohort study, participants in a previous study answered questions about AI 6 years after first delivery using postal or digital questionnaires. Prevalence of AI was calculated, and multivariable logistic regression analyses were applied. RESULTS: A total of 731 (48%) of the original participants who gave birth to their first child between May 2009 and December 2010 responded 6 years after first delivery. There was a significant reduction in reports of one or more AI symptoms from late pregnancy (33%; 95%CI: 30.3, 37.2) to 6 years after first delivery (21%; 95%CI:18.4, 24.4, P = 0.028). Older age at first delivery, BMI (>=35), active bowel disease, and previous problems with bowel evacuation and urgency when going to the toilet predicted AI at 6 years. Long-term AI was also associated with instrumental first delivery (Odds ratio (OR):1.8; 95%CI:1.1, 2.8) and sustaining a perianal tear grade three or four at first delivery (OR:3.0; 95%CI:1.3, 6.8). CONCLUSIONS: Prevalence of AI was significantly reduced from late pregnancy, still 21% experienced AI 6 years after first delivery. Findings from the present study indicate that an added focus on modifiable risk factors for AI such as BMI, OASIS and history of PFDs increase the risk of AI in the long term, may be beneficial in reducing incontinence problems the short- and long-term. PMID- 30311696 TI - The ENTRAMI technique: Endoscopic transgluteal minimal invasive technique for implantation of a pudendal electrode under full visual control: A cadaver study. AB - AIM: The aim of this article is to describe a minimal invasive trans gluteal endoscopic approach to implant a pudendal electrode for neuromodulation under full visual control. METHODS: Eight trans gluteal approaches were performed on four cadavers. The sacral transforaminal percutaneous technique was performed to implant the electrode. The electrode was then picked up and placed under visual control next to the pudendal nerve. RESULTS: The first trocar was placed in the upper lateral quadrant of the gluteal region. The 0 degrees optical system was used to help with the pneumodissection to identify the sciatic nerve. At that point a second 3 mm trocar was placed to insert a dissecting grasping forceps. In some cases, a second 3 mm trocar was placed. A step by step dissection, based on anatomical findings, was necessary to be able to locate the pudendal nerve. The electrode, which was placed percutaneously and transforaminal through S3 or S4, was picked up and placed under full visual control next to the pudendal nerve, slightly entering the Alcock's canal. The electrode was placed in an ideal manner, meaning that all 4-contact points of the electrode are in parallel and in contact with the targeted nerve. The electrode was fixed in that ideal position at the level of the sacrospinous ligament. After placement of that electrode, an X-ray of the pelvic area was done. CONCLUSIONS: The ENTRAMI technique allows optimal pudendal electrode placement under full visual control and should now be tested in a clinical setting. PMID- 30311697 TI - Silyl Group-Directed 6-exo-dig Iodocyclization of Homopropargylic Carbamates and Amides. AB - Iodocyclization of silyl group-substituted homopropargylic carbamates and amides proceeded via 6-exo-dig mode to afford 6-vinylene-4,5-dihydro-1,3-oxazines in moderate to quantitative yields. This is the first report for silyl group-solely directed iodocyclization of alkynes utilizing the beta-silyl effect. Under these mild reaction conditions, various functionalities such as secondary alcohol, acetal, urea, and sulfide were tolerated. PMID- 30311698 TI - N-Boc-Amides in Cross-Coupling Reactions. AB - Since 2015, the use of amides as electrophilic partners in cross-coupling reactions has experienced exponential growth. Diverse amide derivatives have been studied and among them N-Boc-amides have shown good activities towards various cross-coupling reactions and presents, in our view, an important synthetic usefulness. This review describes the recent developments of these chemical transformations involving N-Boc-amides. PMID- 30311700 TI - Molecular Functionalization of Two-Dimensional MoS2 Nanosheets. AB - Molybdenum disulfide (MoS2 ) nanosheets have attracted great scientific interest for their remarkable electronic and optical properties. During the last few years significant progress on exfoliation methods of such nanosheets allowed the development of surface functionalization in covalent or noncovalent fashion. Markedly, the chemical modification allows tailoring and tuning the optical and electronic characteristics of MoS2 , opening new avenues for the potentiality of MoS2 -based hybrids in diverse technological fields. Physisorption of organic molecules onto MoS2 through the development of numerous van der Waals interactions is the most widely approach employed for the surface noncovalent immobilization of organic species onto MoS2 nanosheets. Conversely, developed strategies for the edge and in-plane covalent functionalization of MoS2 mainly concern chemistry at S vacancies, direct C-S bond formation, and coordination of S edges at metal centers. Herein, we focus into the most representative molecular doping strategies and material designing of MoS2 -based hybrid nanostructures carrying photo- and/or electro-active components. Key points related with the exfoliation routes, the surface functionalization approaches and their impact on the electronic properties of the functionalized nanosheets are comprehensively discussed, offering a toolbox for scientists of different disciplines interested in putting a step forward in the field of transition-metal dichalcogenide-based materials. PMID- 30311699 TI - Serelaxin attenuates renal inflammation and fibrosis in a mouse model of dilated cardiomyopathy. AB - NEW FINDINGS: What is the central question of this study? The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance? Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure. ABSTRACT: Serelaxin has been demonstrated to attenuate renal fibrosis and inflammation in cardiorenal disease. In the present study, we tested the hypothesis that serelaxin can prevent the decline in renal function in dilated cardiomyopathy (DCM) by targeting renal fibrosis and inflammation. Male transgenic mice with DCM (n = 16) and their wild-type littermates (WT; n = 20) were administered either vehicle or serelaxin (500 MUg kg-1 day-1 ; subcutaneous minipumps; 8 weeks). Cardiac function was assessed via echocardiography before and during the eighth week of serelaxin treatment. Renal function and inflammation as well as cardiac and renal fibrosis were assessed at the end of the study. Serelaxin had minimal effect on cardiac function (P >= 0.99). Tubulointerstitial and glomerular fibrosis were ~3-fold greater in vehicle-treated DCM mice compared with vehicle treated WT mice (P <= 0.001). Renal mRNA expression of Tnfalpha and Il1alpha were ~4- and ~3-fold greater, respectively, in vehicle-treated DCM mice compared with vehicle-treated WT mice (P <= 0.05). Tubulointerstitial and glomerular fibrosis were 46 and 45% less, respectively, in serelaxin-treated DCM mice than in vehicle treated DCM mice (P <= 0.01). Renal cortical mRNA expression of Tnfalpha and Il1alpha were 56 and 58% less, respectively, in the former group compared with the latter (P <= 0.05). The urinary albumin:creatinine ratio was ~3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P = 0.02). The urinary albumin:creatinine ratio was not significantly different between vehicle treated DCM mice and serelaxin-treated DCM mice (P = 0.38). These data suggest that serelaxin can attenuate renal fibrosis and inflammation and has the potential to exert renoprotective effects in DCM. PMID- 30311701 TI - Efficacy and safety of elbasvir/grazoprevir in participants with HCV genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: final results from the randomized C-CORAL study. AB - BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with HCV infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study. Treatment-naive, HIV-negative, cirrhotic and non cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia. PMID- 30311702 TI - Porcine signal regulatory protein alpha binds to human CD47 to inhibit phagocytosis: Implications for human hematopoietic stem cell transplantation into severe combined immunodeficient pigs. AB - BACKGROUND: Severe combined immunodeficient (SCID) pigs are an emerging animal model being developed for biomedical and regenerative medicine research. SCID pigs can successfully engraft human-induced pluripotent stem cells and cancer cell lines. The development of a humanized SCID pig through xenotransplantation of human hematopoietic stem cells (HSCs) would be a further demonstration of the value of such a large animal SCID model. Xenotransplantation success with HSCs into non-obese diabetic (NOD)-derived SCID mice is dependent on the ability of NOD mouse signal regulatory protein alpha (SIRPA) to bind human CD47, inducing higher phagocytic tolerance than other mouse strains. Therefore, we investigated whether porcine SIRPA binds human CD47 in the context of developing a humanized SCID pig. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from SCID and non-SCID pigs. Flow cytometry was used to assess whether porcine monocytes could bind to human CD47. Porcine monocytes were isolated from PBMCs and were subjected to phagocytosis assays with pig, human, and mouse red blood cell (RBC) targets. Blocking phagocytosis assays were performed by incubating human RBCs with anti-human CD47 blocking antibody B6H12, non-blocking antibody 2D3, and nonspecific IgG1 antibody and exposing to human or porcine monocytes. RESULTS: We found that porcine SIRPA binds to human CD47 in vitro by flow cytometric assays. Additionally, phagocytosis assays were performed, and we found that porcine monocytes phagocytose human and porcine RBCs at significantly lower levels than mouse RBCs. When human RBCs were preincubated with CD47 antibodies B6H12 or 2D3, phagocytosis was induced only after B6H12 incubation, indicating the lower phagocytic activity of porcine monocytes with human cells requires interaction between porcine SIRPA and human CD47. CONCLUSIONS: We have shown the first evidence that porcine monocytes can bind to human CD47 and are phagocytically tolerant to human cells, suggesting that porcine SCID models have the potential to support engraftment of human HSCs. PMID- 30311703 TI - Shortening of apparent transverse relaxation time of inorganic phosphate as a breast cancer biomarker. AB - Phosphorus MRS offers a non-invasive tool for monitoring cell energy and phospholipid metabolism and can be of additional value in diagnosing cancer and monitoring cancer therapy. In this study, we determined the transverse relaxation times of a number of phosphorous metabolites in a group of breast cancer patients by adiabatic multi-echo spectroscopic imaging at 7 T. The transverse relaxation times of phosphoethanolamine, phosphocholine, inorganic phosphate (Pi ), glycerophosphocholine and glycerophosphatidylcholine were 184 +/- 8 ms, 203 +/- 17 ms, 87 +/- 8 ms, 240 +/- 56 ms and 20 +/- 10 ms, respectively. The transverse relaxation time of Pi in breast cancer tissue was less than half that of healthy fibroglandular tissue. This effect is most likely caused by an up-regulation of glycolysis in breast cancer tissue that leads to interaction of Pi with the GAPDH enzyme, which forms part of the reversible pathway of exchange of Pi with gamma adenosine tri-phosphate, thus shortening its apparent transverse relaxation time. As healthy breast tissue shows very little glycolytic activity, the apparent T2 shortening of Pi due to malignant transformation could possibly be used as a biomarker for cancer. PMID- 30311704 TI - Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multicenter water-fat MRI. AB - PURPOSE: An approach for the automated segmentation of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in multicenter water-fat MRI scans of the abdomen was investigated, using 2 different neural network architectures. METHODS: The 2 fully convolutional network architectures U-Net and V-Net were trained, evaluated, and compared using the water-fat MRI data. Data of the study Tellus with 90 scans from a single center was used for a 10-fold cross-validation in which the most successful configuration for both networks was determined. These configurations were then tested on 20 scans of the multicenter study beta cell function in JUvenile Diabetes and Obesity (BetaJudo), which involved a different study population and scanning device. RESULTS: The U-Net outperformed the used implementation of the V-Net in both cross-validation and testing. In cross-validation, the U-Net reached average dice scores of 0.988 (VAT) and 0.992 (SAT). The average of the absolute quantification errors amount to 0.67% (VAT) and 0.39% (SAT). On the multicenter test data, the U-Net performs only slightly worse, with average dice scores of 0.970 (VAT) and 0.987 (SAT) and quantification errors of 2.80% (VAT) and 1.65% (SAT). CONCLUSION: The segmentations generated by the U-Net allow for reliable quantification and could therefore be viable for high-quality automated measurements of VAT and SAT in large-scale studies with minimal need for human intervention. The high performance on the multicenter test data furthermore shows the robustness of this approach for data of different patient demographics and imaging centers, as long as a consistent imaging protocol is used. PMID- 30311706 TI - Striking cessation of cataplexy by opioids. PMID- 30311705 TI - 3.0 T relaxation time measurements of human lymph nodes in adults with and without lymphatic insufficiency: Implications for magnetic resonance lymphatic imaging. AB - The purpose of this work was to quantify 3.0 T (i) T1 and T2 relaxation times of in vivo human lymph nodes (LNs) and (ii) LN relaxometry differences between healthy LNs and LNs from patients with lymphatic insufficiency secondary to breast cancer treatment-related lymphedema (BCRL). MR relaxometry was performed over bilateral axillary regions at 3.0 T in healthy female controls (105 LNs from 20 participants) and patients with BCRL (108 LNs from 20 participants). Quantitative T1 maps were calculated using a multi-flip-angle (20, 40, 60 degrees ) method with B1 correction (dual-TR method, TR1 /TR2 = 30/130 ms), and T2 maps using a multi-echo (TE = 9-189 ms; 12 ms intervals) method. T1 and T2 were quantified in the LN cortex and hilum. A Mann-Whitney U-test was applied to compare LN relaxometry values between patients and controls (significance, two sided, p < 0.05). Linear regression was applied to evaluate how LN relaxometry varied with age, BMI, and clinical indicators of disease. LN substructure relaxation times (mean +/- standard deviation) in healthy controls were T1 cortex, 1435 +/- 391 ms; T1 hilum, 714 +/- 123 ms; T2 cortex, 102 +/- 12 ms, and T2 hilum, 119 +/- 21 ms. T1 of the LN cortex was significantly reduced in the contralateral axilla of BCRL patients compared with the axilla on the surgical side (p < 0.001) and compared with bilateral control values (p < 0.01). The LN cortex T1 asymmetry discriminated cases from controls (p = 0.004) in a multiple linear regression, accounting for age and BMI. Human 3.0 T T1 and T2 relaxation times in axillary LNs were quantified for the first time in vivo. Measured values are relevant for optimizing acquisition parameters in anatomical lymphatic imaging sequences, and can serve as a reference for novel functional and molecular LN imaging methods that require quantitative knowledge of LN relaxation times. PMID- 30311707 TI - NREM sleep EEG slow waves in autistic and typically developing children: Morphological characteristics and scalp distribution. AB - Autism is a developmental disorder with a neurobiological aetiology. Studies of the autistic brain identified atypical developmental trajectories that may lead to an impaired capacity to modulate electroencephalogram activity during sleep. We assessed the topography and characteristics of non-rapid eye movement sleep electroencephalogram slow waves in 26 boys aged between 6 and 13 years old: 13 with an autism spectrum disorder and 13 typically developing. None of the participants was medicated, intellectually disabled, reported poor sleep, or suffered from medical co-morbidities. Results are derived from a second consecutive night of polysomnography in a sleep laboratory. Slow waves (0.3-4.0 Hz; >75 uV) were automatically detected on artefact-free sections of non-rapid eye movement sleep along the anteroposterior axis in frontal, central, parietal and occipital derivations. Slow wave density (number per minute), amplitude (uV), slope (uV s-1 ) and duration (s) were computed for the first four non-rapid eye movement periods. Slow wave characteristics comparisons between groups, derivations and non-rapid eye movement periods were assessed with three-way mixed ANOVAs. Slow wave density, amplitude, slope and duration were higher in anterior compared with most posterior derivations in both groups. Children with autism spectrum disorder showed lower differences in slow waves between recording sites along the anteroposterior axis than typically developing children. These group differences in the topography of slow wave characteristics were stable across the night. We propose that slow waves during non-rapid eye movement sleep could be an electrophysiological marker of the deviant cortical maturation in autism linked to an atypical functioning of thalamo-cortical networks. PMID- 30311708 TI - Weak and inconsistent associations between melanic darkness and fitness-related traits in an insect. AB - The idea that the fitness value of body coloration may be affected by biochemically mediated trade-offs has received much research attention. For example, melanization is believed to interact with other fitness-related traits via competition for substrates, costs associated with the synthesis of melanin or pleiotropic effects of the involved genes. However, genetic correlations between coloration and fitness-related traits remain poorly understood. Here, we present a quantitative-genetic study of a coloration trait correlated to melanin-based cuticular darkness ('darkness', hereafter) in a geometrid moth, Ematurga atomaria. This species has considerable variation in larval appearance. We focus on correlations between larval darkness and fitness-related growth performance traits. Both a half-sib analysis and an 'animal model' approach revealed moderately high heritabilities of larval darkness and indices of growth performance. Heritability estimates of darkness derived from the animal model were, however, considerably higher than those based on the half-sib model suggesting that the determination of coloration includes genetic interactions and epigenetic effects. Importantly, on the host plant with the largest sample size, we found no evidence for either genetic or environmental correlations between darkness and growth parameters. On an alternative host plant, there was some indication of positive genetic and negative environmental correlation between these traits. This shows that respective relationships are environment-specific. Nevertheless, the overall pattern of weak and inconsistent correlations between larval coloration and growth parameters does not support universal trade-offs between these traits and suggests that physiological costs of producing colour patterns do not necessarily interfere with adaptive evolution of coloration. PMID- 30311709 TI - Perceived career opportunities, commitment to the supervisor, social isolation: Their effects on nurses' well-being and turnover. AB - AIM: This research investigated the relationship between perceived career opportunities, affective commitment to the supervisor, and social isolation from colleagues on the one hand and nurses' well-being and turnover intentions on the other. In addition, this study explored the mediating role of affective commitment to the organisation in these relationships. BACKGROUND: Previous research suggested that organisational commitment explained the effect of nurses' work environment on their turnover intentions. However, less is known about how organisational commitment may contribute to explain nurses' well-being. METHOD: This research used a cross-sectional design. A sample of 244 nurses completed a questionnaire survey. RESULTS: Results indicated that affective commitment to the organisation partially mediates the relationships between perceived career opportunities, affective commitment to the supervisor, and social isolation on one hand, and turnover intentions and well-being on the other hand. CONCLUSION: This study showed that the way nurses assess various aspects of their work experience transposes to their emotional bond to their organisation, which in turn explains their well-being and turnover intentions. IMPLICATIONS FOR NURSING MANAGEMENT: This paper identifies factors that could contribute to reduce nurses' intent to quit and promote their well-being. PMID- 30311710 TI - Psychometric evaluation of the simplified Japanese version of the Athens Insomnia Scale: The Fukushima Health Management Survey. AB - We investigated the psychometric properties of the simplified Japanese version of the Athens Insomnia Scale (AIS-SJ) using baseline data from the Fukushima Health Management Survey. Data from 22 878 men and 27 669 women aged 16 years and older were analysed (Mage = 52.9 +/- 18.6). Participants lived in the Fukushima evacuation zone and experienced the Great East Japan Earthquake. The AIS-SJ was used to assess participants' insomnia symptoms, and its validity was examined by administering the Kessler 6-item Psychological Distress Scale (K6) and assessing education, self-rated health and disaster-related experiences. A confirmatory factor analysis revealed that the two-factor model was a better fit than the one factor model. The AIS-SJ and its subscales had acceptable reliability (Cronbach's alpha, 0.81). Test of measurement invariance confirmed strict invariance across groups for the participants' characteristics of gender and mental illness history, but not for participants' age. AIS-SJ scores exhibited a near-normal distribution (skewness, 0.45; kurtosis, -0.89). There were significant age differences only among women, and gender differences in AIS-SJ scores with small effect sizes. The AIS-SJ scores had weak-to-moderate correlations with mental illness history, bereavement, experiencing the tsunami, experiencing the nuclear power plant incident, housing damage and losing one's job (polyserial correlations, 0.36, 0.17, 0.13, 0.18, 0.13, and 0.15, respectively), and strong correlations with self-rated health (polyserial correlation, 0.51), psychological distress (rs , 0.60) and post-traumatic stress disorder (rs , 0.60). The AIS-SJ is a useful instrument for assessing community dwellers' insomnia symptoms. PMID- 30311711 TI - Effects of variation in resource acquisition during different stages of the life cycle on life-history traits and trade-offs in a burying beetle. AB - Individual variation in resource acquisition should have consequences for life history traits and trade-offs between them because such variation determines how many resources can be allocated to different life-history functions, such as growth, survival and reproduction. Since resource acquisition can vary across an individual's life cycle, the consequences for life-history traits and trade-offs may depend on when during the life cycle resources are limited. We tested for differential and/or interactive effects of variation in resource acquisition in the burying beetle Nicrophorus vespilloides. We designed an experiment in which individuals acquired high or low amounts of resources across three stages of the life cycle: larval development, prior to breeding and the onset of breeding in a fully crossed design. Resource acquisition during larval development and prior to breeding affected egg size and offspring survival, respectively. Meanwhile, resource acquisition at the onset of breeding affected size and number of both eggs and offspring. In addition, there were interactive effects between resource acquisition at different stages on egg size and offspring survival. However, only when females acquired few resources at the onset of breeding was there evidence for a trade-off between offspring size and number. Our results demonstrate that individual variation in resource acquisition during different stages of the life cycle has important consequences for life-history traits but limited effects on trade-offs. This suggests that in species that acquire a fixed-sized resource at the onset of breeding, the size of this resource has larger effects on life history trade-offs than resources acquired at earlier stages. PMID- 30311712 TI - Cysteine synthase A overexpression in Corynebacterium glutamicum enhances l isoleucine production. AB - Cysteine synthase A (CysK) catalyzes the last reaction of l-cysteine synthesis in bacteria, but its moonlighting functions have been revealed recently. In this study, CysK was overexpressed in Corynebacterium glutamicum IWJ001, an l isoleucine producer. Compared with the control IWJ001/pDXW-8, IWJ001/pDXW-8-cysK cells grew fast during log phase, and produced 26.5% more l-isoleucine in flask fermentation and 23.5% more l-isoleucine in fed-batch fermentation. The key genes aspC, lysC, hom, thrB, ilvA, and ilvBN involved in l-isoleucine biosynthesis were all upregulated in IWJ001/pDXW-8-cysK, compared with IWJ001/pDXW-8. In addition, IWJ001/pDXW-8-cysK cells were longer and thicker than IWJ001/pDXW-8 cells. Compared with IWJ001/pDXW-8, the membrane permeability increased 15.8% and biofilm formation ability decreased 71.3% for IWJ001/pDXW-8-cysK cells. The results demonstrate that CysK overexpression in C. glutamicum is a good approach to enhance l-isoleucine production. PMID- 30311713 TI - Screening, diagnosis and treatment of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice. AB - Iron deficiency is common in patients with chronic heart failure (CHF) and is associated with reduced exercise performance, impaired health-related quality of life and an increased risk of mortality, irrespective of whether or not anaemia is present. Iron deficiency is a serious but treatable condition. Several randomized controlled clinical trials have demonstrated the ability of intravenous (IV) iron, primarily IV ferric carboxymaltose (FCM), to correct iron deficiency in patients with heart failure with reduced ejection fraction (HFrEF), resulting in improvements in exercise performance, CHF symptoms and health related quality of life. The importance of addressing the issue of iron deficiency in patients with CHF is reflected in the 2016 European Society of Cardiology (ESC) heart failure guidelines, which recognize iron deficiency as an important co-morbidity, independent of anaemia. These guidelines recommend that all newly diagnosed heart failure patients are routinely tested for iron deficiency and that IV FCM should be considered as a treatment option in symptomatic patients with HFrEF and iron deficiency (serum ferritin < 100 ug/L, or ferritin 100-299 ug/L and transferrin saturation < 20%). Despite these specific recommendations, there is still a lack of practical, easy-to-follow advice on how to diagnose and treat iron deficiency in clinical practice. This article is intended to complement the current 2016 ESC heart failure guidelines by providing practical guidance to all health care professionals relating to the procedures for screening, diagnosis and treatment of iron deficiency in patients with CHF. PMID- 30311714 TI - Ear, nose, and throat surgical access for remote living Indigenous children: What is the least costly model? AB - RATIONALE, AIMS, AND OBJECTIVES: This costing evaluation compares three service delivery models for ear, nose, and throat (ENT) surgery for remote living Indigenous children to improve their hearing outcomes, with the aim to identify the least costly model. METHODS: The main outcome measure presented was the incremental cost difference between the base case (Model 1) and two alternative models (Model 2, 3). The costs in 2017 Australian dollars are assessed from two viewpoints: (1) health system perspective, and (2) patients and their families including travel out-of-pocket expenses, presented separately according to the funding source. RESULTS: Findings indicate that the least costly model offered low-risk ENT surgery from a state funded hospital in a remote setting, with high use of videoconference technology: TeleHealth (Model 3) could save $3626 to $5067 per patient, compared with patients travelling to a regional centre public hospital (Model 1). A federally funded scheme which allowed groups of patients to access a direct flight charter transfer to the private hospital in regional centre (Model 2) reduced the cost by $2178 to $2711 per patient when compared with standard care (Model 1). From a societal perspective, Model 1 required out of-pocket patient expenses, with greater time away from home, and hence appears the least preferred option. CONCLUSIONS: The sensitivity analyses also demonstrate that Model 3 would be the more economical model for providing ENT surgery for remote living children. By proving an accurate assessment of the true costs of delivering these important ear and hearing health services, strategic health service planners may be better informed and sufficient budgets can be allocated to provide improved service delivery. The benefits of Model 3, over Models 1 or 2, would also incorporate improvements to patient safety as a result of reducing patient travel, which should in-turn, reduce failure-to-attend rates. PMID- 30311715 TI - A Review of Spinal and Peripheral Neuromodulation and Neuroinflammation: Lessons Learned Thus Far and Future Prospects of Biotype Development. AB - BACKGROUND: There is increasing literature evidence both clinically and experimentally on the existence of potent, adaptive interactions between the central and peripheral aspects of the neuroimmune system in the genesis and maintenance of chronic neuropathic extremity pain and nociceptive back pain. The neuroinflammatory pathways are modulated by the interaction of pro- and anti inflammatory cytokines and chemokines, which are released by peripheral immune system-derived cell species (macrophages and leukocytes). This review examines the possible impact of spinal and peripheral neurostimulation on the inflammatory response in the context of acute and chronic pain pathologies of different origin. STUDY DESIGN: A narrative review of preclinical and clinical studies addressed to the spinal cord and peripheral nerve stimulation and neuroinflammation. METHODS: Available literature was reviewed on neurostimulation technologies and both acute and chronic low-grade inflammation to identify primary outcome measures and to provide an overview of postulated mechanisms of action of neurostimulation on host inflammatory responses. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles. RESULTS: A comprehensive review of the literature indicates an alternate or synergistic mechanism of action of neurostimulation, beyond modulating somatosensory pain pathways, in modifying inflammatory response associated with chronic pain, by promoting a systemic anti-inflammatory state with upregulation of anti-inflammatory mediators. CONCLUSIONS: These preliminary findings may have important implications on the potential applications of neurostimulation as an anti-inflammatory therapy and the role of molecular profiling as a preimplant screening modality and post-implant outcome validation. Thus, future targeted clinical and experimental research is highly warranted in this particular novel field of neuromodulation. PMID- 30311716 TI - Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite? AB - Obesity is believed to be a promoter of type 2 diabetes mellitus (T2DM). Reports indicate that severe obesity in childhood and adolescence increases the risk of T2DM in youth and young adults. T2DM, which is commonly asymptomatic, frequently is not recognized until random blood glucose is measured. Screening blood glucose levels measured in obese individuals are more effective for identifying undiagnosed persons, than screening the general population and therefore introduces a selection bias for discovery. The following commentary will indicate why these observations do not indicate that obesity is the cause of T2DM. Also, it will be shown that the insulin resistance of T2DM occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. This insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with T2DM. Moreover, this early muscle insulin resistance is the etiology of the hyperlipidemia and excess fat accumulation characteristic of T2DM. PMID- 30311717 TI - Surface-Driven Keto-Enol Tautomerization: Atomistic Insights into Enol Formation and Stabilization Mechanisms. AB - Tautomerisation of simple carbonyl compounds to their enol counterparts on metal surfaces is envisaged to enable an easier route for hydrogenation of the C=O bond in heterogeneously catalyzed reactions. To understand the mechanisms of enol formation and stabilization over catalytically active metal surfaces, we performed a mechanistic study on keto-enol tautomerization of a monocarbonyl compound acetophenon over Pt(111) surface. By employing infrared reflection adsorption spectroscopy in combination with scanning tunneling microscopy, we found that enol can be formed by building a ketone-enol dimer, in which one molecule in the enol form is stabilized through hydrogen bonding to the carbonyl group of the second ketone molecule. Based on the investigations of the co adsorption behavior of acetophenone and hydrogen, we conclude that keto-enol tautomerization occurs in the intramolecular process and does not involve hydrogen transfer through the surface hypothesized previously. PMID- 30311718 TI - Should emergentologists follow up on patients diagnosed with UTI having negative urine cultures? Implications for processing post-discharge laboratory results. AB - OBJECTIVES: After patients are discharged from the emergency department (ED), follow-up of test results focuses on abnormal values. In the elderly, non specific symptoms can result in an incorrect diagnosis of urinary tract infection (UTI). This study compared the outcomes of patients discharged from the ED with a diagnosis of UTI based on urine culture results. METHODS: We conducted a retrospective cohort study using linked health databases and chart review of a random sample of elderly patients (age > 65 years) discharged from the Ottawa Hospital ED between 2006 and 2014 with a diagnosis of UTI. Patients were categorized based on whether urine cultures were positive and bacterial sensitivity to prescribed antibiotics. Primary outcome was return to ED, admission to hospital, or death within 30 days. RESULTS: A total of 1001 patients were included in the study (401 culture-negative; 474 culture-positive antibiotic sensitive; 126 culture positive antibiotic-insensitive). Patients were elderly (mean age 80 years, SD 7.6) with a high prevalence of dementia (18.0%). Almost a third of patients (n = 313, 31.3%) experienced an outcome. Compared to culture positive antibiotic-sensitive patients, culture negative patients (adjOR 1.45, 95% CI 1.07-1.97) and culture-positive antibiotic-insensitive patients (adjOR 1.49, 95% CI 0.90-2.14) were significantly more likely to experience an outcome (P = 0.04). CONCLUSIONS: Patients discharged from the ED with a diagnosis of UTI have an increased risk of return to ED, urgent readmission or death if the uropathogen is insensitive to the prescribed antibiotic or if the culture is negative. Patients diagnosed with UTI with a negative culture may need further assessment. PMID- 30311719 TI - Rh-Catalyzed Removable Directing Group Assisted sp2 or sp3-C-H Bond Functionalization. AB - In recent years, transition-metal-catalyzed C-H activation has become a key strategy in the field of organic synthesis. Among the various transition metal complexes, rhodium complexes are widely used as catalysts in a variety of C-H functionalization reactions due to their high reactivity and selectivity. In addition, because a number of rhodium complexes in various oxidation states are available, this results in diverse reaction patterns. Regioselectivity, an important issue in C-H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain target functionalized compounds, it is also necessary to use a directing group that can be easily removed. Removable directing group-assisted C-H activation by rhodium catalysts has given us a fruitful combination for achieving certain types of functionalization reactions. Hence, a wide range of directed-C-H functionalization reactions catalyzed by rhodium complexes has been reported to date. In this review, we discuss Rh-catalyzed C-H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N-heteroaromatic derivatives. PMID- 30311720 TI - Two's company, is three a crowd? Ethical cognition in decision making and the role of industry third parties in pediatric diabetes care. AB - Families of children with diabetes increasingly obtain health information from a variety of sources. Doctor-patient relationships have accordingly become more fluid and dynamic with input from other parties. These outside parties include representatives from the diabetes health care industry-industry third parties (ITPs). This review is an exploration of the ethical principles and cognitive processes involved when doctors and patients negotiate around health care practices and the role of ITPs in that dialogue. Ethical principles of conflicts of interest, beneficence (act in the best interests of the patient), non maleficence (act so as to do no harm) and justice (act so as to allocate resources fairly or justly) are relevant considerations. Reflexive and analytic thinking and various cognitive biases also play a significant part in clinical decision making. A complex case example is analyzed to highlight a process of ethical cognition in decision making to ensure high-value care and optimal patient outcomes. PMID- 30311721 TI - Gut microbiome can be restored without adverse events after Helicobacter pylori eradication therapy in teenagers. AB - OBJECTIVES: The effect of Helicobacter pylori eradication on the gut microbiota of teenagers is unknown; hence, this study aimed to assess changes in the gut microbiome after H. pylori eradication therapy in teenagers. MATERIALS AND METHODS: Changes in gut microbiota before and after H. pylori eradication were prospectively investigated in eight students without any underlying diseases, via next-generation sequencing of 16S rDNA. Twenty-four stool samples were collected, and operational taxonomic unit analysis was performed. As secondary analyses, alpha and beta diversity were evaluated. Furthermore, pre-treatment microbiome compositions were compared with those 1 week and 2 months after treatment. RESULTS: Alpha diversity analysis revealed that both species richness and evenness were recovered to pre-treatment levels at 2 months after eradication therapy. Slight but non-significant differences were observed in bacterial species abundance between pre- and post-treatment samples, upon beta diversity analysis. Although the relative abundance of Bacteroidetes tended to increase and that of Actinobacteria significantly decreased immediately after eradication therapy, the taxonomic composition was similar to that before treatment and at 2 months post-eradication. However, two students showed significant changes in the gut microbiota in relative abundances at the level of the phylum, class, and order. CONCLUSIONS: Although H. pylori eradication therapy caused short-term dysbiosis, microbial diversity was restored in healthy teenagers. However, as the relative abundance of gut microbiota in some cases remained altered, the effect of H. pylori eradication therapy on the gut microbiome should be continuously monitored. PMID- 30311723 TI - Fluoro-less ablation: Fleeting fad or way of the future? PMID- 30311722 TI - Enteric RET inhibition attenuates gastrointestinal secretion and motility via cholinergic signaling in rat colonic mucosal preparations. AB - BACKGROUND: The expression of RET in the developing enteric nervous system (ENS) suggests that RET may contribute to adult intestinal function. ENS cholinergic nerves play a critical role in the control of colonic function through the release of acetylcholine (ACh). In the current study, we hypothesized that a RET mediated mechanism may regulate colonic ion transport and motility through modulation of cholinergic nerves. METHODS: The effect of RET inhibition on active ion transport was assessed electrophysiologically in rat colonic tissue mounted in Ussing chambers via measurements of short circuit current (Isc) upon electrical field stimulation (EFS) or pharmacologically with cholinergic agonists utilizing a gastrointestinal (GI)-restricted RET inhibitor. We assessed the effect of the RET inhibitor on propulsive motility via quantification of fecal pellet output (FPO) induced by the acetylcholinesterase inhibitor neostigmine. KEY RESULTS: We found that enteric ganglia co-expressed RET and choline acetyltransferase (ChAT) transcripts. In vitro, the RET kinase inhibitor GSK3179106 attenuated the mean increase in Isc induced by either EFS or carbachol but not bethanechol. In vivo, GSK3179106 significantly reduced the prokinetic effect of neostigmine. CONCLUSION AND INFERENCES: Our findings provide evidence that RET-mediated mechanisms regulate colonic function by maintaining cholinergic neuronal function and enabling ACh-evoked chloride secretion and motility. We suggest that modulating the cholinergic control of the colon via a RET inhibitor may represent a novel target for the treatment of intestinal disorders associated with increased secretion and accelerated GI transit such as irritable bowel syndrome with diarrhea (IBS-D). PMID- 30311724 TI - Comparison the effects of topical application of olive and calendula ointments on Children's diaper dermatitis: A triple-blind randomized clinical trial. AB - This study compares the effective of of topical application of olive and calendula ointments on childrens' diaper dermatitis (DD). This triple-blind clinical trial was conducted on 73 healthy children under the age of 2 years with non-severe and not infected DD, referred to a pediatric healthcare center in Tabriz, Iran. The children were assigned to 1.5% olive ointment (n = 37) and 1.5% calendula ointment (n = 39) using a random block method with the ratio of 2:2. The severity of DD in both groups was measured and compared on a six-point scale on days 0 (before the intervention) and 3, 5, and 7 after interventions. The findings releaved there was not significant stastistical difference between the olive oil and calendula groups in terms of severity of DD in the third, fifth and seventh days. No adverse effect was reported from either of the medications in this study. The external validity and consequently the ability to generalize the findings may be diminished as this study was conducted at a single site. Owing to olive ointment and calendula ointment providing the same results in the healing of DD, olive ointment can be used as an alternative case to DD. PMID- 30311726 TI - Does the Electronic Structure of Mobius Annulenes Follow Heilbronner's Ideas? AB - It is shown, on the example of the monocyclic cyclononatetraenyl cation, C9H9+ , that the fully-variational optimization of modern ab initio wavefunctions based on spin-coupled generalized valence bond (SCGVB) theory vindicates, in a surprising level of detail, essential features of Heilbronner's ideas for the electronic structure of Mobius annulenes such as the arrangement of overlapping carbon 2p atomic orbitals along a Mobius strip, leading to a phase inversion between the first and last orbitals. In the SCGVB description, the aromaticity of this Mobius system with eight pi electrons follows from the extensive resonance between VB structures. PMID- 30311725 TI - Maxime "Max" Kuczynski: Father of Peruvian Public Health and of the 66th President of Peru. AB - Maxime Kuczynski (1890-1967), a medical pioneer born in Poland, was renowned for his work in tropical medicine in the Peruvian jungle, especially on Bartonella baciliformis, the cutaneous form known as verruga peruana of deadly Oroya fever. His unique university training in anthropology, philosophy, and parasitology lead to a participatory observational method of practicing medicine. At the request of the Peruvian President, he ventured into the Peruvian Amazon in 1936 to establish a public health service in partnership with indigenous populations. In June 2016, his son Pedro Pablo Kuczynski, a former Prime Minister of Peru, was elected the 66th President of Peru. PMID- 30311727 TI - Comparison of perfusion values after percutaneous transluminal angioplasty according to the severity of ischaemia in the diabetic foot. AB - Percutaneous transluminal angioplasty (PTA) is now more frequently used to improve tissue perfusion in ischemic diabetic feet. However, there are concerns about its feasibility and effectiveness in severely ischaemic feet. This study aimed to compare the perfusion values after PTA according to the ischaemic degree of diabetic feet. This study included 133 ischaemic diabetic feet. The foot transcutaneous oxygen pressure (TcPO2 ) and toe pressure were measured before the procedure and every second postoperative week for 6 weeks. The patients were divided into three groups according to ischaemic severity on the basis of TcPO2 and toe pressures. In the "severely ischaemic" group, the TcPO2 increased from 7.5 +/- 4.9 to 40.3 +/- 11.3 mm Hg (5.4-fold) 6 weeks after the PTA (P < 0.001). The toe pressure increased from 8.5 +/- 8.8 to 42.2 +/- 19.3 mm Hg (5.0-fold, P < 0.001). In the "mild" group, the TcPO2 increased from 35.4 +/- 2.5 to 41.8 +/- 12.4 mm Hg (1.2-fold, P = 0.003), and the toe pressure increased from 45.7 +/- 12.3 to 54.3 +/- 31.3 mm Hg (1.2-fold, P > 0.05). Results of the "intermediate" group were in between. The most severely ischaemic group had the most dramatic increase of tissue perfusion after PTA. As such, PTA can be an effective method for increasing tissue perfusion even in the severely ischaemic diabetic feet. PMID- 30311728 TI - Reported obstructive sleep apnea does not diminish the cardiometabolic health benefits from a comprehensive lifestyle intervention program. AB - Obstructive sleep apnea (OSA) commonly coexists with the metabolic syndrome, a condition for which behavioral changes are often prescribed. Whether OSA diminishes the cardiometabolic health benefits from lifestyle interventions remains unclear. We evaluated 278 consecutive metabolic syndrome participants enrolled in a 12-week comprehensive lifestyle intervention program. The changes in blood pressure (BP), along with other metabolic health parameters, from baseline to follow-up were compared between those with and without OSA. Mean age was 52.4 +/- 10.9 years and 37% were male. At enrollment, mean body mass index (BMI) was 38.2 +/- 7.7 kg/m2 . OSA was reported in 126 of 269 final participants (47%). At baseline, participants with reported OSA were more likely to be male, older, have a higher BMI, waist and neck size (all P < 0.05). At program completion, participants with (-5.8 +/- 16.1/-3.0 +/- 10.0 mm Hg) and without OSA (-4.7 +/- 13.1/-3.3 +/- 8.2 mm Hg) had significant reductions in systolic and diastolic BP as well as BMI, fasting glucose, and triglyceride levels. There were no significant differences in the absolute or percentage changes in BP or other metabolic parameters between groups. Our findings support that patients with the metabolic syndrome can derive substantial health benefits, including reductions in BP, by a lifestyle intervention program regardless of the presence of OSA. PMID- 30311729 TI - CRISPR Gene Editing in Yeast: An Experimental Protocol for an Upper-Division Undergraduate Laboratory Course. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) are a revolutionary tool based on a bacterial acquired immune response system. CRISPR has gained widespread use for gene editing in a variety of organisms and is an increasingly valuable tool for basic genetic research, with far-reaching implications for medicine, agriculture, and industry. This lab is based on the premise that upper division undergraduate students enrolled in a Life Sciences curriculum must become familiar with cutting edge advances in biotechnology that have significant impact on society. Toward this goal, we developed a new hands-on laboratory exercise incorporating the use of CRISPR-Cas9 and homology directed repair (HDR) to edit two well-characterized genes in the budding yeast, Saccharomyces cerevisiae. The two genes edited in this exercise, Adenine2 (ADE2) and Sterile12 (STE12) affect metabolic and developmental processes, respectively. Editing the premature stop codons in these genes results in clearly identifiable phenotypes that can be assessed by students in a standard laboratory course setting. Making use of this basic eukaryotic model organism facilitates a laboratory exercise that is inexpensive, simple to organize, set up, and present to students. This exercise enables undergraduate students to initiate and follow up on all stages of the CRISPR gene editing process, from identification of guide RNAs, amplification of an appropriate HDR fragment, and analysis of mutant phenotypes. The organization of this protocol also allows for easy modification, providing additional options for editing any expressed genes within the yeast genome to produce new mutations, or recovery of existing mutants to wild type. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):592 601, 2018. PMID- 30311730 TI - Exploration of an interactive "Virtual and Actual Combined" teaching mode in medical developmental biology. AB - Biochemistry and molecular techniques are used for the development of the scientific practice of students. To improve both the teaching and learning quality and promote the students' motivation, this article outlines an interactive "Virtual Simulation and Actual Operation Combined" approach by using a tailored virtual practice-learning platform and participated by students and lectures, as well as a curriculum secretary. The implementation of the Virtual Simulation Laboratory provides a series of learning resources, which the students can access in their own time; and the participation of the curriculum secretary also makes the class more interactive and efficient. This method incorporates an experimental platform and a virtual experiment class to utilize fully both the traditional and virtual teaching methods and thereby promote effective student learning. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):585-591, 2018. PMID- 30311731 TI - Nodular fasciitis of the parotid gland: A challenging diagnosis on FNA. AB - BACKGROUND: Nodular fasciitis (NF) is a clonal, self-limited proliferation that has only rarely been described in the parotid gland. Because of its potential to mimic benign and malignant parotid neoplasms clinically, radiographically, and cytomorphologically, NF is often managed with unnecessary surgery, which is associated with a risk for significant surgical complications. The purpose of this study is to present the clinical and cytomorphologic findings for NF of the parotid gland by fine-needle aspiration (FNA). METHODS: The pathology archives of the authors' respective institutions were searched for salivary gland FNA cytology specimens with a confirmed diagnosis of NF. The clinical history, pathologic diagnosis, cytomorphologic findings, and immunocytochemical results were recorded. RESULTS: A total of 15 cases were identified; the average age was 37 years, and 10 patients (66.7%) were female. Five cases (33.3%), all treated surgically, showed recurrence within an average timeframe of 1.6 months. Only 3 cases (20.0%) were classified as definitive, probable, or suggestive of NF. On average, smears were composed of predominantly single (69.2%), spindled cells (100.0%) with short unipolar (76.9%) and/or bipolar processes (38.5%), round (61.5%) or elongated (84.6%) nuclei, and inconspicuous nucleoli (53.8%). In 69.2%, a tissue-culture appearance was shown, and 76.9% contained myxoid stroma. In 46.2%, a minimal amount of cytologic atypia was shown. CONCLUSIONS: Keeping NF in the differential for any bland, single, spindled cell proliferation with elongated cytoplasmic processes and bland nuclei may prompt the clinician to consider more conservative management in the correct clinical context. PMID- 30311732 TI - Material Design Concept of Lithium-Excess Electrode Materials with Rocksalt Related Structures for Rechargeable Non-Aqueous Batteries. AB - Dependence on lithium-ion batteries for automobile applications is rapidly increasing, and further improvement, especially for positive electrode materials, is indispensable to increase energy density of lithium-ion batteries. In the past several years, many new lithium-excess high-capacity electrode materials with rocksalt-related structures have been reported. These materials deliver high reversible capacity with cationic/anionic redox and percolative lithium migration in the oxide/oxyfluoride framework structures, and recent research progresses on these electrode materials are reviewed. Material design strategies for these lithium-excess electrode materials are also described. Future possibility of high energy non-aqueous batteries with advanced positive electrode materials is discussed for more details. PMID- 30311733 TI - Validity of the DSM-5 anxious distress specifier for major depressive disorder. AB - BACKGROUND: DSM-5 introduced the anxious distress specifier in recognition of the clinical significance of anxiety in depressed patients. Recent studies that supported the validity of the specifier did not use measures that were designed to assess the criteria of the specifier but instead approximated the DSM-5 criteria from scales that were part of an existing data base. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined the validity of the specifier diagnosed with a semistructured interview. METHODS: Two hundred sixty patients with a principal diagnosis of major depressive disorder were evaluated with semistructured diagnostic interviews. The patients were rated on clinician rating scales of depression, anxiety and irritability, and completed self-report measures. RESULTS: Approximately three-quarters of the depressed patients met the criteria for the anxious distress specifier. Patients with anxious distress had a higher frequency of anxiety disorders, particularly panic disorder and generalized anxiety disorder, as well as higher scores on measures of anxiety, depression, and anger. The patients meeting the anxious distress subtype reported higher rates of drug use disorders, poorer functioning during the week before the evaluation, and poorer coping ability compared to the patients who did not meet the anxious distress specifier. Moreover, anxious distress was associated with poorer functioning and coping after controlling for the presence of an anxiety disorder. CONCLUSIONS: The results of the present study indicate that anxious distress is common in depressed patients and support the validity of the DSM-5 anxious distress specifier. PMID- 30311734 TI - Ultrafast removal of Cd(II) by green cyclodextrin metal-organic framework based nanoporous carbon: adsorption mechanism and application. AB - Heavy metals contaminated water has been identified as a significant threat to human health. To develop safe and rapid water treatment techniques is necessary. Herein, we synthesized an eco-friendly gamma-cyclodextrin MOF-based nanoporous carbon (gamma-CD MOF-NPC) material and conducted comprehensive characterization, and found its rapid and effective Cd(II) removal capacity. The gamma-CD MOF-NPC could effectively sequester most of cadmium ions within 1 min, and it still demonstrated excellent adsorption ability under various conditions, including different pH, adsorbent dosage and coexisting ions. The adsorption was primarily due to the effect of ion exchange of oxygen containing functional groups by studying zeta potential and Fourier transform infrared spectroscopy. Flow-through experiments further proved the rapid Cd(II) removal capacity and potential of the practical application of gamma-CD MOF-NPC in water treatment with the cytotoxic data. PMID- 30311735 TI - Surface Nonpolarization of g-C3 N4 by Decoration with Sensitized Quantum Dots for Improved CO2 Photoreduction. AB - Photocatalytic conversion of CO2 can provide a solution for simultaneously addressing global warming and solar fuel generation. However, its applicability is presently limited by the unsatisfactory photoconversion efficiency of the state-of-art photocatalysts. In this regard, enhancing CO2 adsorption through surface modification could be an efficient way to improve the photoconversion efficiency. Herein, doping of nonpolar carbon quantum dots (CQDs) onto g-C3 N4 is reported for the construction of a metal-free heterojunction photocatalyst (CQDs/g-C3 N4 ). CQDs offer several advantages such as band-gap reduction and electron-withdrawing effect to improve light absorption and photocarrier separation efficiency. However, this study reveals that nonpolar CQDs could also improve CO2 adsorption, photoinduced H2 production, reaction kinetics, and alter CO2 photoreduction pathways to generate CH4 . Consequently, the CQDs/g-C3 N4 could generate six times more CO and CH4 without detectable H2 compared to pristine g-C3 N4 , under similar conditions. Therefore, this study demonstrates a promising strategy for efficient adsorption, activation, and subsequent photoreduction of CO2 by nonpolar surface modification of g-C3 N4 . PMID- 30311736 TI - The Fat Mass- and Obesity-Associated (FTO) Gene to Obesity: Lessons from Mouse Models. AB - OBJECTIVE: Genetic variants at the fat mass- and obesity-associated (FTO) locus are strongly associated with obesity-related traits by regulating neighboring genes. Nevertheless, it is possible that FTO protein is directly involved in mechanisms regulating body composition and adiposity. Here, the in vivo biological functions of FTO in the risk for obesity were studied by reviewing murine models. METHODS: The effects of the locus-specific manipulations of the murine Fto gene on metabolic-related phenotypes in genetically modified mouse models were reviewed and summarized into the following three categories: growth and body composition, eating behaviors, and metabolic homeostasis. RESULTS: The mouse models showed different phenotypes depending on target tissues and methods for gene manipulation. Mice harboring deletions or point mutations at the Fto locus had high metabolic rates, while FTO-overexpressing mice showed dyslipidemia. Both deletion and overexpression of the Fto gene led to abnormal eating behaviors. Intriguingly, several phenotypes were differently expressed depending on developmental timing of the genetic manipulations. For instance, a germ line deletion decreased total body fat mass, while the deletion in adult mice increased it. CONCLUSIONS: The results highlight that FTO is critical not only for body composition but also normal development, and its function might differ depending on the stage of development. PMID- 30311737 TI - Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice. AB - Dendritic morphology is a critical determinant of neuronal connectivity, and calcium signaling plays a predominant role in shaping dendrites. Altered dendritic morphology and genetic mutations in calcium signaling are both associated with neurodevelopmental disorders (NDDs). In this study we tested the hypothesis that dendritic arborization and NDD-relevant behavioral phenotypes are altered by human mutations that modulate calcium-dependent signaling pathways implicated in NDDs. The dendritic morphology of pyramidal neurons in CA1 hippocampus and somatosensory cortex was quantified in Golgi-stained brain sections from juvenile mice of both sexes expressing either a human gain-of function mutation in ryanodine receptor 1 (T4826I-RYR1), a human CGG repeat expansion (170-200 CGG repeats) in the fragile X mental retardation gene 1 (FMR1 premutation), both mutations (double mutation; DM), or wildtype mice. In hippocampal neurons, increased dendritic arborization was observed in male T4826I RYR1 and, to a lesser extent, male FMR1 premutation neurons. Dendritic morphology of cortical neurons was altered in both sexes of FMR1 premutation and DM animals with the most pronounced differences seen in DM females. Genotype also impaired behavior, as assessed using the three-chambered social approach test. The most striking lack of sociability was observed in DM male and female mice. In conclusion, mutations that alter the fidelity of calcium signaling enhance dendritic arborization in a brain region- and sex-specific manner and impair social behavior in juvenile mice. The phenotypic outcomes of these mutations likely provide a susceptible biological substrate for additional environmental stressors that converge on calcium signaling to determine individual NDD risk. PMID- 30311738 TI - Cost-effectiveness of rapid on-site evaluation of the adequacy of FNA cytology samples performed by nonpathologists. AB - BACKGROUND: Rapid on-site evaluation (ROSE) can increase adequacy and reduce needle passes in fine-needle aspiration cytology (FNAC) procedures. However, ROSE increases the cost of FNAC. Costs may be reduced if ROSE is performed by an alternate evaluator (AE), such as a cytotechnologist (CT), endoscopist, or pulmonologist, rather than a cytopathologist (CP). Studies have shown that AEs can perform ROSE with high accuracy but are generally not as accurate as CPs. The objective of this study was to evaluate the impact of AEs on the cost effectiveness of ROSE. METHODS: A cost model, based on a mathematical sampling model, was developed. The cost model was used to compare the impact of the evaluator type on overall costs. RESULTS: CTs were likely to be cost-effective for simple procedures and were unlikely to be cost-effective for only the most complex procedures. The model demonstrated the tradeoff in cost savings from using AEs and the potential costs associated with repeated procedures due to the lower accuracy of AEs. CONCLUSIONS: The cost-effectiveness of AEs is context dependent. AEs can be cost-effective even if they are less accurate than CPs. AEs are likely to be cost-effective in most contexts. PMID- 30311739 TI - Organotypic Brain Slice Cultures. AB - Ex vivo cell culture models are of particular interest for neurobiologists, as these allow the study of brain cells in an isolated environment. Organotypic brain slice cultures allow growth of three-dimensional brain tissue that conserves the cellular architecture. This unit describes the preparation and culturing of organotypic brain slices from mice. In three basic protocols, the general procedure, the specific preparation of chopper slices, and slicing of whole-brain vibratome sections are described. Support protocols explain the use of postnatal or adult mice, the preparation of coronal or sagittal slices, the preparation of co-cultures, post-processing of slices, the use of extra filter membranes, and the re-use of membrane inserts. This unit provides an easy-to understand methodological introduction to brain slice cultures. (c) 2018 by John Wiley & Sons, Inc. PMID- 30311740 TI - The competitiveness of solvent adsorption on polar-embedded stationary phases. AB - Solvation processes on polar embedded stationary phases were investigated by determination of excess isotherms in binary acetonitrile/water mobile phase. The obtained results indicate the competitiveness of acetonitrile and water adsorption on heterogeneous surfaces of chemically bonded stationary phases. The calculation of excess isotherm as a volume of excessively accumulated solvent confirms the competitiveness of solvents' adsorption in qualitative and quantitative meaning. Corresponding excess isotherms of water and acetonitrile are symmetrical with respect to the x-axis. It confirms that the displaced volume of acetonitrile is replaced by an equal volume of water and vice versa. Additionally, fitting the two-site adsorption model to experimental data provides quantitative values with low experimental errors. The obtained results confirm the advantage of volumetric assumption of excess adsorption over direct adsorption layers of solvents, which is commonly postulated. PMID- 30311741 TI - Outcomes of 1,639 hepatectomies for non-colorectal non-neuroendocrine liver metastases: a multicenter analysis. AB - BACKGROUND: Whether non-colorectal non-neuroendocrine liver metastasis (NCNNLM) should be treated surgically remains unclear. METHODS: Data regarding 1,639 hepatectomies performed between 2001 and 2010 for 1,539 patients with NCNNLM were collected from 124 institutions. Patient characteristics, types of primary tumor, characteristics of liver metastases, and post-hepatectomy outcomes were analyzed. RESULTS: The five most frequent primary tumors were gastric carcinoma (540 patients [35%]), gastrointestinal stromal tumor (204 patients [13%]), biliary carcinoma (150 patients [10%]), ovarian cancer (107 patients [7%]), and pancreatic carcinoma (77 patients [5%]). R0/1 hepatectomy was achieved in 90% of patients, with 1.5% in-hospital mortality rate. Overall and disease-free survival rates of 1,465 patients included in survival analysis were 41% and 21%, respectively, at 5 years, and 28% and 15%, respectively, at 10 years. Five-year survival associated with the five frequent primary tumors were 32%, 72%, 17%, 52%, and 31%, respectively, and factors predictive of a poor outcome differed by the primary tumor type. CONCLUSIONS: Our data indicated that hepatectomy is safe for NCNNLM and that patient prognoses vary depending on the type of primary tumors. Indications for hepatectomy should be determined with reference to survival rates and risk factors specific to each of the various types of primary tumor. PMID- 30311742 TI - Heart rate variability as a biomarker of anxious depression response to antidepressant medication. AB - BACKGROUND: There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects. METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N = 1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N = 309) versus nonanxious (N = 413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8 weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. RESULTS: Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach. PMID- 30311743 TI - Effects and safety of atmospheric low-temperature plasma on bacterial reduction in chronic wounds and wound size reduction: A systematic review and meta analysis. AB - The use of atmospheric low-temperature plasma (AP) on chronic wounds and its effect on microbial bioburden in open wounds has not been explored with a systematic review and meta-analysis. PRISMA guidelines were followed and PubMed, Embase, CENTRAL, and CINAHL databases searched for randomised controlled trials (RCTs), which compared AP with no AP for the management of open, chronic wounds. The primary outcomes of reduction of bioburden or wound size were included. Meta analyses were performed; odds ratio (OR) and 95% confidence intervals (CIs) were extracted and pooled in a random effects model. Four RCTs investigated the effect of AP on chronic wound healing. Chronic wounds treated with AP did not show a significant improvement in healing (AP vs control: OR = 1.46; 95% CI = 0.89-2.38; P = 0.13). Five further RCTs investigated the reduction of bioburden in wounds, but AP demonstrated no significant reduction of bioburden (AP vs control: OR = 0.85; 95% CI = 0.45-1.62; P = 0.63). All nine RCTs recorded the presence of any severe adverse events (SAEs) in the 268 patients studied, with only one unrelated SAE identified in each group (AP vs control: OR = 1.00; 95% CI = 0.05-19.96; P = 1.00). Use of AP in wound care is safe, but the retrieved evidence and meta analysis show that there is no clinical benefit of AP in chronic open wounds using currently available AP device settings. PMID- 30311744 TI - Optical excitation and detection of neuronal activity. AB - Optogenetics has emerged as an exciting tool for manipulating neural activity, which in turn, can modulate behavior in live organisms. However, detecting the response to the optical stimulation requires electrophysiology with physical contact or fluorescent imaging at target locations, which is often limited by photobleaching and phototoxicity. In this paper, we show that phase imaging can report the intracellular transport induced by optogenetic stimulation. We developed a multimodal instrument that can both stimulate cells with subcellular spatial resolution and detect optical pathlength (OPL) changes with nanometer scale sensitivity. We found that OPL fluctuations following stimulation are consistent with active organelle transport. Furthermore, the results indicate a broadening in the transport velocity distribution, which is significantly higher in stimulated cells compared to optogenetically inactive cells. It is likely that this label-free, contactless measurement of optogenetic response will provide an enabling approach to neuroscience. PMID- 30311745 TI - Highly Efficient Organic Blue Electroluminescent Materials and Devices with Mesoscopic Structures. AB - Due to the difficulty in achieving high efficiency and high color purity simultaneously, blue emission is the limiting factor for the performance and stability of OLEDs. Since 2003, we have been working on organic light-emitting diodes (OLEDs), especially on blue light. After a series of molecular designs, novel strategies have been proposed from different aspects. At first, highly efficient deep blue emission could be achieved through molecular design with highly twisted structure to suppress fluorescence quenching and redshift. Deep blue emitters with high efficiency in solid state, a twisted structure with aggregation induced emission (AIE) characteristics was incorporated to inhibit molecular aggregation, and triplet-triplet fusion (TTF) and hybridized localized charge transfer (HLCT) were adopted to increase the ratio of triplet exciton used. Secondly, a highly efficient blue OLED could be achieved through improving charge transport. New electron transport materials (ETMs) with wide band gap were developed to control charge transport balance in devices. Thirdly, a highly efficient deep blue emission could be achieved through a mesoscopic structure of out-coupling layer. A mesoscopic photonic structured organic thin film was fabricated on the top of metal electrode by self-aggregation in order to improve the light out-coupling efficiency. PMID- 30311746 TI - Blood flow reversal from the external into the internal carotid artery-New insights into the hemodynamics at the carotid bifurcation. AB - BACKGROUND: Complex blood flow patterns are a well-known phenomenon at the carotid bifurcation. However, unlike for the descending aorta, a blood flow reversal has not been detected at the carotid bifurcation, so far. METHODS: In 17 subjects, flow patterns with focus on blood flow reversal were examined at the carotid bifurcation with vector flow imaging. RESULTS: We found a blood flow reversal from the external carotid artery (ECA) into the internal carotid artery (ICA) in 13 of 25 (52%) carotid bifurcations. The blood flow reversal ranged 5.3 +/- 1.7 mm (range 2.6-8.3 mm) distally to the beginning of the ECA and lasted 105 +/- 59 ms (range 32-225 ms). The mean peak systolic velocity within the blood flow reversal was 12.5 +/- 4.6 cm/s (range 5-18 cm/s). CONCLUSION: A blood flow reversal from the ECA into the ICA during the systole is a frequent finding at the carotid bifurcation. Considering ischemic stroke, retrograde embolism from plaques in the proximal ECA into the ICA might play a role. PMID- 30311747 TI - A Novel PBPK Modeling Approach to Assess Cytochrome P450 Mediated Drug-Drug Interaction Potential of the Cytotoxic Prodrug Evofosfamide. AB - Evofosfamide is a cytotoxic small-molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug-drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration-time curve (AUC) ratios of midazolam were above 0.80, indicating that induction of CYP3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and PBPK modeling showed no clinically relevant inhibition via CYP2B6, CYP2D6, and CYP3A4. In conclusion, PBPK models were used to supplement in vitro information of a cytotoxic compound. This approach may set a precedent for future studies of cytotoxic drugs, potentially reducing the need for clinical DDI studies and providing more confidence in the clinical use of approved cytotoxic compounds for which DDI information is sparse. PMID- 30311748 TI - Pulmonary function assessment post-left ventricular assist device implantation. AB - AIM: The lungs-and particularly the alveolar-capillary membrane-may be sensitive to continuous flow (CF) and pulmonary pressure alterations in heart failure (HF). We aimed to investigate long-term effects of CF pumps on respiratory function. METHODS AND RESULTS: We conducted a retrospective study of patients with end stage HF at our institution. We analysed pulmonary function tests [e.g. forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 )] and diffusing capacity of the lung for carbon monoxide (DLCO ) from before and after left ventricular assist device (LVAD) implantation and compared them with invasive haemodynamic studies. Of the 274 patients screened, final study analysis involved 44 patients with end-stage HF who had CF LVAD implantation between 1 February 2007 and 31 December 2015 at our institution. These patients [mean (standard deviation, SD) age, 50 (9) years; male sex, n = 33, 75%] received either the HeartMate II (Thoratec Corp.) pump (77%) or the HeartWare (HeartWare International Inc.) pump. The mean (SD) left ventricular ejection fraction was 21% (13%). At a median of 237 days post-LVAD implantation, we observed significant DLCO decrease (-23%) since pre-implantation (P < 0.001). DeltaDLCO had an inverse relationship with changes in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) from pre-LVAD to post-LVAD implantation: DeltaDLCO to DeltaPCWP (r = 0.50, P < 0.01) and DeltaDLCO to DeltaRAP (r = 0.39, P < 0.05). We observed other reductions in FEV1 , FVC, and FEV1 /FVC between pre LVAD and post-LVAD implantation. In mean (SD) values, FEV1 changed from 2.3 (0.7) to 2.1 (0.7) (P = 0.005); FVC decreased from 3.2 (0.8) to 2.9 (0.9) (P = 0.01); and FEV1 /FVC went from 0.72 (0.1) to 0.72 (0.1) (P = 0.50). Landmark survival analysis revealed that DeltaDLCO from 6 months after LVAD implantation was predictive of death for HF patients [hazard ratio (95% confidence interval), 0.60 (0.28-0.98); P = 0.03]. CONCLUSIONS: Pulmonary function did not improve after LVAD implantation. The degree of DLCO deterioration is related to haemodynamic status post-LVAD implantation. The DeltaDLCO within 6 months post-operative was associated with survival. PMID- 30311749 TI - Teratosphaeria stem canker of Eucalyptus: two pathogens, one devastating disease. AB - BACKGROUND: Teratosphaeria gauchensis and T. zuluensis are closely related fungi that cause Teratosphaeria (previously Coniothyrium) stem canker disease on Eucalyptus species propagated in plantations for commercial purposes. This disease is present in many countries in which Eucalyptus trees are planted, and continues to spread with the international trade of infected plant germplasm. TAXONOMY: Fungi, Ascomycota, Pezizomycotina, Dothideomycetes, Dothideomycetidae, Capnodiales, Teratosphaeriaceae, Teratosphaeria. IDENTIFICATION: The causal agents form dark masses of pycnidia that are visible on the surface of distinct stem cankers that typically form on young green stem tissues. Accurate diagnosis of the causal agents requires DNA sequence data. HOST RANGE: Nine species of Eucalyptus are known to be affected. Of these, E. grandis and its hybrids, which include some of the most important planting stock globally, appear to be particularly vulnerable. DISEASE SYMPTOMS: Small necrotic lesions develop on young green stem tissue. These lesions coalesce to form large cankers that exude gum. Epicormic shoots develop below the girdling canker and, in severe cases, trees die. USEFUL WEBSITES: Mycobank, https://www.mycobank.org; Publications of the Forestry and Agricultural Biotechnology Institute (FABI), https://www.fabinet.up.ac.za/index.php/journals. PMID- 30311750 TI - Elimination of Australian epidemic strain (AES1) pseudomonas aeruginosa in a pediatric cystic fibrosis center. AB - INTRODUCTION: In this cohort study spanning an 18-year period, we evaluated the prevalence and associated mortality rate of epidemic strains of pseudomonas aeruginosa (PsA), especially Australian Epidemic Strain Type 1 (AES1), in a pediatric cystic fibrosis center practicing cohort segregation and early PsA eradication. METHODS: Cohort segregation was introduced in January 2000. PsA clonal strain was determined by pulse-field-gel-electrophoresis (PFGE) at the time of routine collection of airway specimens. Children with PsA underwent eradication treatment with anti-pseudomonal antibiotics over 2-3 months. We analyzed changes in prevalence and mortality from 1999 to 2016. RESULTS: The prevalence of AES1 declined from 69 (20%) in 1999 to 16 (5.4%) in 2006, to 1 (0.4%) in 2016. The prevalence of PsA overall diminished less over the same period, from 128 (37%) patients in 1999 to 57 (23%) in 2016. New acquisition of AES1 became less common over time, with no new cases identified from 2011. Those who contracted AES1 had a greater risk of death than those who did not (Odds Ratio 4.9, 95%CI 2.5-9.6). Patients with other AES PsA types were uncommon (AES2 n = 5, AES5 n = 2, AES14 n = 3, AES19 n = 1). CONCLUSIONS: Cohort segregation was associated with reduction in AES1 prevalence ascertained by PFGE surveillance for patients in a single large pediatric cystic fibrosis center. Other alterations in practice such as early eradication treatment may also have contributed to reduced PsA prevalence. These factors combined with the transition of chronically infected patients over time to adult centers has eliminated AES1 from our clinic, with an accompanying mortality decrease. PMID- 30311751 TI - Design and control of system for elbow rehabilitation: Preliminary findings. AB - BACKGROUND: The use of an exoskeleton elbow is considered an effective treatment in several pathologies, including post-stroke complications, traumatic brain injury (TBI) and spinal cord injury (SCI), as well as in patients with neurodegenerative disorders. The effectiveness of rehabilitation is closely linked to a suitably chosen therapy. The treatment can be performed only by specialized personnel, significantly supported by the use of automated devices. OBJECTIVES: The aim of this study was to present a novel exoskeleton for elbow rehabilitation without a complicated control system. MATERIAL AND METHODS: Single degree-of-freedom (SDOF) solution in constructing the prototype of an elbow exoskeleton for rehabilitation purposes has been applied. The simplicity of the actuation mechanism was set as one of the priorities in the design; thus, a single-axis stepper motor with a controller was found to be adequate for providing a reliable and precise source of motion for the exoskeleton. RESULTS: Technological development may provide novel solutions, such as an exoskeleton - a wearable, external structure which supports or (in selected applications) even replaces the muscle actuation in the patient. The reported advantages of the proposed exoskeleton reflect current state-of-the-art. The proposed control strategy relies on closed-loop position control, performance, low manufacturing cost, and predicted performance in a rehabilitation scenario. All these factors play an important role in establishing the directions for further research, e.g., an integrated force sensor in the device, measurements of torque interactions on the elbow joint, and assessment and response to an overload of articulation. CONCLUSIONS: This study suggests not only the clinical but also the possible economic and logistical advantages offered by the portability of the system, and its effective support for therapists applying an elbow exoskeleton. PMID- 30311752 TI - Corneal biomechanical properties in patients with Hashimoto's thyroiditis. AB - BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune endocrine disorder that results from a dysregulation of the immune system leading to an immune attack on the thyroid gland. It has potential effects on different organs and tissues. OBJECTIVES: The aim of the study was to investigate the effect of HT on corneal biomechanical properties using the ocular response analyzer (ORA). MATERIAL AND METHODS: A total of 48 patients with HT and 49 healthy subjects were enrolled in the study. The mean age of the patients and healthy subjects was 42.33 +/-11.96 and 40.20 +/-12.60 years, respectively (p = 0.39). All of the subjects underwent a full ophthalmological examination, including visual acuity, corneal pachymetry by topography, biomicroscopy, and funduscopy. Corneal biomechanical properties, including corneal hysteresis (CH) and corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOPg) and corneal compensated IOP (IOPcc) were measured with the ORA. RESULTS: Central corneal thickness (CCT) in the patient group and the control group were not significantly different (p = 0.65). Corneal hysteresis of the HT patients was significantly lower than that of the control group (p = 0.005). There were no statistically significant differences in CRF between the 2 groups (p = 0.53). Goldmann-correlated IOP and IOPcc were higher in the HT patients, but only IOPcc showed a statistically significant difference (p = 0.001). CONCLUSIONS: In conclusion, our data shows that HT affects corneal biomechanical properties by decreasing CH. Thus, IOPcc measured with the ORA should be taken into account when determining accurate IOP values in patients with HT. PMID- 30311753 TI - Corrigendum: Differences Between Single and Double Eyelid Anatomy in Asians Using Ultrasound Biomicroscopy. AB - This corrects the article DOI: 10.1097/APO.0000000000000185. PMID- 30311754 TI - Biochemical following-up of treated acromegaly. Limitations of the current determinations of IGF-1 and perspective. AB - INTRODUCTION: Acromegaly is a rare disease caused by excess growth hormone (GH) secretion leading to an excess IGF-1 which is the major mediator of GH action. EVIDENCE ACQUISITION: Biochemical diagnosis of GH excess is accomplished by the combined measurement of baseline serum IGF-I concentration and the response of GH on an oral glucose tolerance test (OGTT). Several drawbacks regarding the interpretation of biochemical tests that include measurement of GH have been widely described in the literature, including different protocols for obtaining serum samples, great differences in the results obtained by different immunoassays, different cut-off points used to differentiate the normal status of the hypersecretion of GH. EVIDENCE SYNTHESIS: Clinical guidelines related to the diagnosis and management of patients with acromegaly state that "normal" IGF-I concentrations, (within an established age-and sex- reference range), excludes the diagnosis of active acromegaly , and mean disease control in patients who have received treatment. But many factors may exert influence over IGF-I measurement or interpretation and limit its value as a biological marker of disease activity. Major drawbacks of IGF-I measurements derive both from its own physiology, to the divergences in results obtained from different biochemical methods used for their quantification, to the heterogeneous ways of expressing the results obtained and to the lack of uniformity of the cut-offs to define treatment effectiveness. All these issues make it difficult to compare the results obtained by different authors. CONCLUSIONS: We will focus on the issues regarding the measurement and interpretation of IGF-I concentrations in the management of acromegaly patients. PMID- 30311755 TI - [DENGUE FEVER IN RUSSIA: PROBLEMS OF DIAGNOSTICS]. AB - The authors report clinical and laboratory data concerning a case of hemorrhagic dengue fever introduced to Ul'yanovsk by a tourist who had spent holiday in Vietnam. The clinical picture of the disease is described along with results of clinical and laboratory analyses. The approaches to the evaluation of the patient's health status during the period of primary examination and medical care as well as the problems that arose after the final diagnosis was established are discussed. PMID- 30311757 TI - [CARDIOVASCULAR DISEASES: EVALUATION OF PERSISTING DISORDERS IN THE BLOOD CIRCULATION SYSTEM AND DISABILITY, CRITERIA FOR SEVERITY OF INVALIDISM]. AB - A most important indicator of population health, its social and economic wellbeing is premature disability. 10.3 mln people had to retire from their jobs due to disability during the ten-year period from 2005 to 2014. The number of elderly subjects among them was twice that of the younger ones, with the leading cause of disability being blood circulation disorders (61,9%). At the same time, the fraction of old subjects in the group of invalids suffering from coronary heart disease and idiopathic hypertension accounted for only 58,9% and 40,9% respectively. The quantitative evaluation of persistent dysfunction of the cardiovascular system related to circulatory disturbances included in ICD class IX and to those referred to other classes is based mainly on an assessment of the following clinical and functional manifestations: pain syndrome (cardialgia or angina); hypertensive syndrome; pulmonary hypertension; arrhythmia; syncope. Other aspects of pathological process are taken into consideration, such as its form and severity, presence and frequency of exacerbations, magnitude, involvement of target organs, complications. The gerontological slant of disabling cardiovascular pathology accounts for its social significance (idiopathic hypertension, coronary heart disease, chronic heart failure) which requires the adequate solution of the problem of healthcare provisions taking account of the current demographic situation and increased life expectancy within the older population suffering from a number of chronic diseases. PMID- 30311756 TI - Is severe hypocalcemia immediately life-threatening? AB - Objective: Severe hypocalcemia (Ca <1.9 mmol/L) is often considered an emergency because of a potential risk of cardiac arrest or seizures. However, there is little evidence to support this. The aim of our study was to assess whether severe hypocalcemia was associated with immediately life-threatening cardiac arrhythmias or neurological complications. Methods: A retrospective observational study was carried out over a 2 years period in the Adult Emergency Department (ED) of Nantes University Hospital. All patients who had a protein-corrected calcium concentration measure were eligible for inclusion. Patients with multiple myeloma were excluded. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED. Results: A total of 41,823 patients had protein-corrected calcium (pcCa) concentrations measured, 155 had severe hypocalcaemia, 22 were excluded because of myeloma leaving 133 for analysis. Median pcCa concentration was 1.73 mmol/L [1.57-1.84]. Seventeen (12.8%) patients presented a life threatening condition, 14 (10.5%) neurological and 3 (2.2%) cardiac during ED stay. However these complications could be explained by the presence of underlying co-morbidities and or electrolyte disturbances other than hypocalcaemia. Overall 24 (18%) patients died in hospital. Vitamin D deficiency, chronic kidney disease and hypoparathyroidism were the most frequently found causes of hypocalcemia. Conclusion: 13% of patients with severe hypocalcaemia presented a life threatening cardiac or neurological complication on the ED. However a perfectly valid alternative cause could account for these complications. Further research is warranted to define the precise role of hypocalcaemia. PMID- 30311759 TI - The contradictory world of tetracyclines. PMID- 30311758 TI - Gender differences in clinical characteristics, medical management, risk factor control, and long-term outcome of patients with stable coronary artery disease: from the CORONOR registry. AB - BACKGROUND: Conflicting information exists about whether sex differences modulate outcome in patients with coronary artery disease (CAD). Our aim was to analyze baseline characteristics, medical management, risk factor control, and long-term outcome according to gender in patients with stable CAD. METHODS: We analyzed data from the contemporary multicenter CORONOR registry, which included 4184 consecutive outpatients with stable CAD. Follow-up was performed at 5 years with adjudication of clinical events. RESULTS: There were 3252 (77.7%) men and 932 (22.3%) women. Women were older than men, more likely to have hypertension, and less likely to smoke. They had more frequent angina but less frequent multivessel CAD. Evidence-based medications were widely used with only few differences according to gender. Women had a poorer control of cardiovascular risk with higher systolic blood pressure and LDL-cholesterol. The composite endpoint - cardiovascular death, myocardial infarction, or ischemic stroke - occurred in 536 patients. When adjusted for baseline characteristics, five-year outcomes were similar for women and men for the composite endpoint (Hazard ratio [95% confidence interval]: 1.03 [0.81-1.31], p=0.817). CONCLUSIONS: In contemporary practice, women with stable CAD had a poorer control of cardiovascular risk. However, at 5-year follow-up, cardiovascular outcomes were similar for both genders. PMID- 30311760 TI - [TYPICAL ERRORS IN THERAPY OF GASTROESOPHAGEAL REFLUX DISEASE]. AB - Aim: To analyze compliance of doctors with the clinical guidelines for the management of patients with gastroesophageal reflux disease (GERD) under outpatient clinic conditions. Material and methods: An anonymous questionnaire study involving 104 general practitioners was undertaken. The questionnaires included items concerning lifestyle modifications, the use of proton pump inhibitors (PPI), dosage and time of their administration, combined therapy and endoscopic control. Results: The analysis of the filled questionnaires demonstrated that 15,6% of the doctors always discuss the necessity changing lifestyle with GERD patients, 75% of the doctors discuss it but occasionally, and 9,4% never hold such discussions. 56,7% of the doctors begin treatment from double doses of proton pump inhibitors regardless of the endoscopic stage of esophagus damage. The mode of PPI administration is at variance with that recommended by the instruction in 61,5% of the cases. The basic course of erosive esophagitis treatment lasts 4, 2, and 8 weeks in 45,2%, 9,6%, and 45,2% of the cases. Treatment of GERD starts from combined therapy in 14,4% of the cases. Monotherapy with PPI is inefficient in 85,6% of the cases. Endoscopic control of erosive esophagitis is practiced by 51,9% of the doctors, 48,1% of the respondents recommend this diagnostic procedure only in the absence of clinical effect. Conclusion: Our analysis revealed typical mistakes in the treatment of patients with GERD, demonstrated the importance of expert control and support of training physicians, and introduction of modern quality standards into the practical management of patients with this pathology. PMID- 30311761 TI - [SYSTEMIC LUPUS ERYTHEMATOSUS WITH LUPUS NEPHRITIS IN THE ELDERLY (CLINICAL OBSERVATION)]. AB - We report a clinical case of SLE in a women affected at the age of 63 years who had recurrent nephrotic syndrome with the development of renal insufficiency at the onset and a good outcome of therapy with a large total dose cyclophosphamide. PMID- 30311763 TI - [PITUITARY ADENOMA APOPLEXY]. AB - We present 3 cases of pituitary adenoma apoplexy in young women (one microadenoma and two macroadenomas). The possible risk factors, clinical presentation and outcome of pituitary apoplexy are discussed. Diagnostic errors as regards pituitary adenoma apoplexy are analyzed. PMID- 30311762 TI - [A CASE OF FAMILIAL PULMONARY AND HEPATIC ECHINOCOCCOSIS)]. AB - Echinococcus granulosus still remains a widespread disease. Moreover, there is a large number of patients in whom it is diagnosed rather late because its clinical presentation can be unspecific and symptoms vary. We report a familial case of the disease. Its specific feature was the onset with the bilateral pulmonary process and late involvement of the liver. This excluded other pulmonary diseases, such as pneumonia, tuberculosis or cancer. PMID- 30311764 TI - [KYOTO CONSENSUS - THE NEW ETIOLOGICAL CLASSIFICATION OF CHRONIC GASTRITIS AND ITS DISCUSSION]. AB - The main provisions and headings of the new etiological classification of chronic gastritis are discussed in the context of recent data on the true role of Helicobacter pylori infection in the development of this pathology. The methods and results of the authors ' investigations into gastric microflora are presented along with information about the frequency of detection of its different forms, concentration of microbial forms in gastric mucosa, their pathogenic properties including urease activity, and possible contribution to chronic gastritis etiology. The possibility of alcoholic and chemical chronic gastritis is discussed along with the role of these conditions in the development of stomach cancer. Special emphasis is laid on the disagreement between the adopted consensuses and principles of evidence-based medicine. PMID- 30311765 TI - [THE HISTORY OF DEPARTMENT OF FACULTY THERAPY, AT THE VORONEZH HIGHER EDUCATION INSTITUTION (ON THE OCCASION OF THE CENTENARY ANNIVERSARY OF N.N. BURDENKO VORONEZH STATE MEDICAL UNIVERSITY)]. AB - The article is devoted to the history of the Department of Faculty Therapy, N.N. Burdenko Voronezh State Medical University. The history of its creation is inextricably linked to the Derpth (Yurievsky) University that was transferred to Voronezh in 1918. While the Department of Faculty Therapy remained in Voronezh, it several times changed location making use of various city hospitals as its branches. It simultaneously expanded its activities by organizing courses of physical therapy, endocrinology, and other medical disciplines. The article focuses on the events pertaining to the formation and development of the Department of Faculty Therapy, main directions and achievements of its scientific work. PMID- 30311766 TI - Walking Among California Adults. AB - This policy brief describes two types of walking among California adults: walking for transportation and walking for leisure. Using data from the 2013-14 California Health Interview Survey, the study found that the prevalence of both types of walking has increased since 2003. The prevalence of walking for both transportation and leisure varies withage, income, race/ethnicity, and neighborhood safety and cohesion. Additional efforts by state and local policymakers, as well as by communities, are needed to reduce disparities and promote walking among adults. PMID- 30311767 TI - Few California Children and Adolescents Meet Physical Activity Guidelines. AB - This policy brief describes physical activity among California children and adolescents. Using data from the California Health Interview Survey (CHIS), the study found that only 31 percent of children ages 5-11 and 18 percent of adolescents ages 12-17 meet the physical activity guidelines of engaging in at least one hour of physical activity every day. Neighborhood characteristics, including safety and proximity to parks, are related to physical activity levels among youth. Also, among older children, boys are more active than girls. Additional efforts by state and local policymakers, as well as communities, are needed to promote physical activity to increase the proportion of children and adolescents achieving recommended amounts of physical activity. PMID- 30311768 TI - Demand for improved sanitation in an urban informal settlement in India: role of the local built environment. AB - Sanitation uptake is a pressing challenge, especially in India, and sanitation demand in urban informal settlements and slums has been understudied relative to rural areas. Given the spatial and socioeconomic disadvantage of these settings, research suggests that the built environment may relate to sanitation demand, but this has not been tested. This study utilizes data on a large urban informal settlement in Maharashtra, India, examining built environment predictors including housing security, water access, and proximity to existing common sanitation, in association with sanitation demand. Results indicate that household size, home ownership, individual household water sources, and open defecation avoidance are significantly associated with interest in a toilet. Further, interactions between (1) water source and home ownership, and (2) open defecation and distance to shared sanitation, are associated with interest in a toilet. These findings support the role of the built environment in shaping sanitation demand in urban informal settlements. PMID- 30311769 TI - Evaluating the feasibility of a personal particle exposure monitor in outdoor and indoor microenvironments in Shanghai, China. AB - Existing particulate matter (PM) monitors have too low spatiotemporal resolution to properly characterize individual exposure doses. In order to support health impact assessment, it is essential to develop a better method to assess individual exposure by taking account of varied environments in which people spend their time. Compact light-scattering PM monitors can potentially fill this need. This study was conducted to evaluate feasibility of a low-cost PM monitor (Plantower PMS 7003) in indoor and roadside outdoor microenvironments compared to research-grade instruments in Shanghai, China. The monitors exhibited excellent performance with a high linear response and low bias values both in outdoor and indoor tests. The monitors also showed little confounding bias in low relative humidity environments. Taking into account the accessibility and portability of this monitor, the monitors were able to detect the dynamic nature of individual exposures and provide data and knowledge about human exposure assessments. PMID- 30311770 TI - The impact of self-control cues on subsequent monetary risk-taking. AB - BACKGROUND AND AIMS: The "process-model" of self-control proposes that the ego depletion effect is better explained by a switch between interest in "have-to" labor and cognitive "want-to" leisure, rather than being mainly due to a decrease in cognitive resources, as advanced by the "strength-model" of self-control. However, it is currently difficult to disentangle the "process-model" from the "strength-model" of self-control. Here, we employed a stepwise approach, featuring three studies, for testing the process model of self-control. METHODS: In Study 1, we created a list of 30 self-control events for characterizing "have to" conducts in the daily life. In Study 2, mental visualization of effortful self-control events ("have-to") and monetary risk-taking ("want-to") were employed for testing the strength-model of self-control. In Study 3, to test the process-model of self-control, participants were simply required to read self control (or neutral) sentences. RESULTS: Study 1 provided evidence regarding external validly for the list of self-control events. Study 2 showed that mental visualization of effortful self-control events increases subsequent monetary risk taking. Study 3 highlighted that the brief apparition of a self-control-related sentence was sufficient for increasing risk-taking. These patterns were evidenced in the trial with the less advantageous gain/loss ratio. DISCUSSION: Altogether these findings support the process-model of self-control in showing that triggering the semantic content of a "have-to" conduct, without its actual execution, is sufficient for modulating subsequent "want-to" activity. CONCLUSION: These findings could contribute to advancing current knowledge on how the high availability of ready-to-consume rewards in modern environments is redefining humans' self-control ability. PMID- 30311771 TI - Object attachment: Humanness increases sentimental and instrumental values. AB - BACKGROUND AND AIMS: People who hoard form intense attachments to their possessions and save items for sentimental and instrumental reasons. Feeling socially excluded may encourage these individuals to anthropomorphize objects (i.e., perceive them as human-like) to fulfill unmet belonging needs, which may increase the sentimental and instrumental values of objects, and then lead to stronger object attachment. METHODS: We randomly assigned 331 participants with excessive acquisition tendencies to be excluded, included, or overincluded in an online ball-tossing game before presenting them with five objects that had human characteristics. Participants then completed measures assessing anthropomorphism, sentimental and instrumental values, and object attachment. RESULTS: Inconsistent with this study hypothesis, socially excluded participants did not rate unowned objects as more human-like than the included or overincluded participants; however, stronger anthropomorphism predicted greater instrumental and sentimental values, which then predicted greater object attachment. DISCUSSION AND CONCLUSIONS: Sentimental and instrumental values may explain how stronger anthropomorphism may lead to greater object attachment. Learning that leads to anthropomorphism may help us better understand object attachment. PMID- 30311772 TI - Thermal processing food-related toxicants: a review. AB - Heterocyclic aromatic amines, acrylamide, 5-hydroxymethylfurfural, furan, polycyclic aromatic hydrocarbons, nitrosamines, acrolein, chloropropanols and chloroesters are generated toxicants formed in some foodstuffs, mainly starchy and protein-rich food during thermal treatment such as frying, roasting and baking. The formation of these chemical compounds is associated with development of aromas, colors and flavors. One of the challenges facing the food industry today is to minimize these toxicants without adversely affecting the positive attributes of thermal processing. To achieve this objective, it is essential to have a detailed understanding of the mechanism of formation of these toxicants in processed foods. All reviewed toxicants in that paper are classified as probable, possible or potential human carcinogens and have been proven to be carcinogenic in animal studies. The purpose of that review is to summarize some of the most frequent occurring heat-generated food toxicants during conventional heating, their metabolism and carcinogenicity. Moreover, conventional and microwave heating were also compared as two different heat treatment methods, especially how they change food chemical composition and which thermal food toxicants are formed during specific method. PMID- 30311773 TI - Paper-based lateral flow strip assay for the detection of foodborne pathogens: principles, applications, technological challenges and opportunities. AB - As a representative colorimetic biosnesor, paper-based LFSA have emerged as a promising and robust tool that can easily and instansly detect the presence of target biological components in food sample. Recently, LFSAs have gained a considerable attention as an alternative method for rapid diagnosis of foodborne pathogens to the conventional culture-based assays such as plate counting and PCR. One major drawback of the current LFSAs for the detection of pathogenic bacteria is the low sensitivity, limiting its practical applications in POCT. Not like many other protein-based biomarkers that are present in nM or pM range, the number of pathogenic bacteria that cause disease can be as low as few CFU/ml. Here, we review current advances in LFSAs for the detection of pathogenic bacteria in terms of chromatic agents and analyte types. Furthermore, recent approaches for signal enhancement and modifications of the LFSA architecture for multiplex detection of pathogenic bacteria are included in this review, together with the advantages and limitations of each techniques. Finally, the technological challenges and future prospect of LFSA-based POCT for the detection of pathogenic bacteria are discussed. PMID- 30311775 TI - Editorial Comment on END-2018-0229-OR.R2. PMID- 30311774 TI - VNUT and VMAT2 segregate within sympathetic varicosities and localize near preferred CaV2 isoforms in rat tail artery. AB - ATP and norepinephrine (NE) are co-released from peripheral sympathetic nerve terminals. Whether they are stored in the same vesicles has been debated for decades. Preferential dependence of NE or ATP release on Ca2+ influx through specific CaV2 isoforms suggests that NE and ATP are stored in separate vesicle pools, but simultaneous imaging of NE and ATP containing vesicles within single varicosities has not been reported. We conducted immunohistochemical studies of Vesicular Monoamine Transporter 2 (VMAT2/SLC18A2) and Vesicular Nucleotide Translocase (VNUT/SLC17A9) as markers of vesicles containing NE and ATP in sympathetic nerves of the rat tail artery. A large fraction of varicosities exhibited neighbouring, rather than overlapping, VNUT and VMAT2 fluorescent puncta. VMAT2 but not VNUT colocalized with synaptotagmin 1 (Syt1). CaV2.1, CaV2.2 and CaV2.3 are expressed in nerves in the tunica adventitia. VMAT2 preferentially localized adjacent to CaV2.2 and CaV2.3, rather than CaV2.1. VNUT preferentially localized adjacent to CaV2.3 > CaV2.2 >> CaV2.1. Using wire myography, inhibition of field-stimulated vasoconstriction with the CaV2.3 blocker SNX-482 (0.25 uM) mimicked the effects of the P2X inhibitor suramin (100 uM) rather than the alpha-adrenergic inhibitor phentolamine (10 uM). Variable sensitivity to SNX-482 and suramin between animals closely correlated with CaV2.3 staining. We conclude that a majority of ATP and NE stores localize to separate vesicle pools that employ different synaptotagmin isoforms and that localize near different CaV2 isoforms to mediate vesicle release. CaV2.3 appears to play a previously unrecognized role in mediating ATP release in the rat tail artery. PMID- 30311776 TI - The Benefit of Minced Cartilage Over Isolated Chondrocytes in Atelocollagen Gel on Chondrocyte Proliferation and Migration. AB - Objective Autologous chondrocyte implantation is a necessary procedure for the repair of articular cartilage defects; however, isolated chondrocyte implantation requires a 2-step procedure (for harvesting and implantation) and is limited by cytotoxicity due to enzymatic digestion. Therefore, in this in vitro study, we evaluated the possible benefit of using minced cartilage embedded in a 3 dimensional culture scaffold and fixed with fibrin glue, in comparison with isolated chondrocytes in atelocollagen, to induce cell migration, proliferation, and matrix production, using cartilage from patients with knee joint osteoarthritis. Design Cartilage fragments were obtained from 7 female patients with knee osteoarthritis (OA) and embedded in atelocollagen gels. As a control, chondrocytes were isolated and embedded in gels in the same manner. These composites were cultured for 3 weeks, and cell proliferation and matrix production were evaluated using histology and immunochemistry. Results Histologically, minced cartilage showed cell migration from the cartilage fragments into the gel, with the Bern score and cell count in the minced cartilage group being significantly higher than those in the control group. Immunohistochemistry revealed that the number of Ki67-positive cells, the expression of LECT-1 and TGF-beta, and the glycosaminoglycan content were significantly higher in the minced cartilage than in the control group. Minced cartilage exhibited superior cell migration, proliferation, and glycosaminoglycan content than isolated chondrocytes. Conclusion Our findings support that minced cartilage has a favorable potential for cell proliferation and matrix production compared with the isolated chondrocytes after enzymatic treatment. PMID- 30311777 TI - Limited Knowledge and Mixed Interest in Pre-Exposure Prophylaxis for HIV Prevention Among People Who Inject Drugs. AB - People who inject drugs (PWID) experience sexual and injection-related HIV risks, but uptake of pre-exposure prophylaxis (PrEP) for HIV prevention among PWID has been low. Improving PrEP uptake in this population will require understanding of PrEP knowledge and interest. In 2017, we conducted in-depth, semistructured interviews with HIV-uninfected PWID and key informants (PrEP and harm reduction providers) in the US Northeast. Thematic analysis of coded data explored PrEP knowledge and the factors that influence PrEP interest. Among PWID (n = 33), median age was 36 years, 55% were male, 67% were white, and 24% identified as Hispanic/Latino. Accurate PrEP knowledge among PWID was low, which key informants (n = 12) attributed to PrEP marketing focused on other risk populations, as well as healthcare providers' lack of time and unwillingness to discuss PrEP with PWID. There was a discrepancy between self-reported HIV risk behaviors, which were common, and HIV risk perceptions, which varied and strongly influenced PrEP interest. Most PWID and key informants thought that PrEP would be most beneficial for those who shared syringes, used discarded syringes, engaged in transactional sex, or were homeless. Improving uptake of PrEP for HIV prevention among high risk PWID will require education to increase PrEP knowledge and addressing factors that negatively influence PrEP interest such as perceptions regarding low HIV risk and the process for obtaining PrEP. This may require specialized PrEP marketing and outreach efforts and improved capacity of healthcare providers to effectively assess HIV risk (and perceptions) and communicate the benefits of PrEP to at-risk PWID. PMID- 30311778 TI - Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions. AB - Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors. These conditions alter the intestinal environment through direct bacterial killing, changes to pH that influence bacterial stabilities or growth, or influence nutrient availability that direct population profiles. In this review, we examine some of the contributing risk factors for elderly associated CDI and the toll they take on the microbiome. PMID- 30311779 TI - Diagnostic Accuracy, Prescription Behavior, and Watchful Waiting Efficacy for Pediatric Acute Otitis Media. AB - Current guidelines recommend "watchful waiting" (WW) as an alternative to immediate antibiotic treatment. Continued high rates of antibiotic use suggest that WW may be underutilized. We conducted a retrospective chart review of 474 pediatric acute otitis media (AOM) cases at a clinic in central Pennsylvania. We assessed physical examination findings, diagnostic behavior, WW utilization, prescription writing, and filling in cases of pediatric AOM to evaluate the underutilization of WW. We evaluate diagnostic consistency with published guidelines and rates of antibiotic prescription resulting from misdiagnosis. We report WW instructions and compliance, and prescription filling behaviors. Fifty percent of AOM diagnoses in this sample were not supported by physical examination findings. The majority of these AOM diagnoses received antibiotic prescriptions, suggesting that unsupported diagnoses translated to injudicious prescribing. WW instructions corresponded to 57% fewer filled prescriptions and longer fill delay. We discuss the implications and recommendations to improve antibiotic stewardship. PMID- 30311780 TI - Second coming: the re-emergence and modernization of immunotherapy by vaccines as a component of leprosy control. PMID- 30311781 TI - In vitro antioxidant and enzyme inhibitory properties of Rubus caesius L. AB - The genus Rubus (Rosaceae) has great potential for and a history of use as natural agents in several traditional folk remedies. Based on this concept, this study focused on the antioxidant activities and enzyme inhibitory effects of extracts and fractions from Rubus caesius. Different chemical assays were performed to detect antioxidant capacity, namely, free radical scavenging (ABTS and DPPH assays), reducing power (CUPRAC and FRAP), phosphomolybdenum and metal chelating. Enzyme inhibitory effects were tested towards cholinesterases (AChE and BChE), tyrosinase, alpha-amylase and alpha-glucosidase. In addition, total amounts of phenolics and flavonoids were detected by colorimetric assays. Among the samples, the ethyl acetate fraction exhibited the strongest antioxidant potential with its higher concentration of total phenolics. The highest AChE and alpha-amylase inhibitory activities were observed in the diethyl ether fraction, while the n-butanol fraction had the strongest anti-tyrosinase inhibitor ability. The present study demonstrated that R. caesius may be considered a source of biologically active compounds to develop novel functional products or drugs in the pharmaceutical field. PMID- 30311782 TI - Response of Paracoccidioides lutzii to the antifungal camphene thiosemicarbazide determined by proteomic analysis. AB - AIM: To perform the proteomic profile of Paracoccidioides lutzii after treatment with the compound camphene thiosemicarbazide (TSC-C) in order to study its mode of action. METHODS: Proteomic analysis was carried out after cells were incubated with TSC-C in a subinhibitory concentration. Validation of the proteomic results comprised the azocasein assay, western blot and determination of the susceptibility of a mutant to the compound. RESULTS: Proteins related to metabolism, energy and protein fate were regulated after treatment. In addition, TSC-C reduces the proteolytic activity of the protein extract similarly to different types of protease inhibitors. CONCLUSION: TSC-C showed encouraging antifungal activity, working as a protease inhibitor and downregulating important pathways impairing the ability of the fungi cells to produce important precursors. PMID- 30311783 TI - Haunting Expectations of Hospital Births Challenged by Traditional Midwives. AB - In Balochistan, Pakistan, hospitals are not the desired location for childbirth, but an affective economy of obstetric care, deceit, and clinical tactics of control has emerged, redirecting women away from midwives toward biomedical obstetrics. This economy manifests in forms such as coercing expectant mothers to deliver in the clinic rather than the home by generating fear in them and their kin through a narrative of imminent maternal and child harm. Drawing from ethnographic research, I show why Baloch midwives' ethical expertise and affective responses to iatrogenically induced emergencies haunt the postcolonial state and constrain biomedicine's haunting expectations of hospital/clinical births. PMID- 30311784 TI - Molecular investigation to RNA and protein based interaction induced in vivo biocompatibility of phytofabricated AuNP with embryonic zebrafish. AB - Implication of gold nanoparticles in industrial and day-to-day life products at extensive scale has raised concern about their toxicity to environment and human health. Moreover, quest of new technologies for production of biocompatible nanoparticles increased. This study explores the molecular toxicology of AuNP with enlightenment of their green synthesis using medicinal plant extract as reducing and stabilizing agent. Synthesized CAuNP were characterized for their physiochemical properties by standard techniques like FESEM, TEM, DLS, UV-Vis spectroscopy and FTIR. GCMS analysis revealed the involvement of -OH compounds for CAuNP synthesis. Determined size and zeta potential of CAuNP was found to be 21 +/- 08 nm and -24 +/- 11 mV with SPR peak at 554 nm. LC50 of CAuNP with zebrafish embryos was 69 +/- 12 ug/ml compared to 52 +/- 06 ug/ml of AuNP. Gold nanoparticles were found to exhibit concentration dependent morphological abnormalities with acute effect at cellular and molecular level. Experimental and computational analysis depicted the nanotoxicity of gold nanoparticles as a consequence of oxidative stress generation leading to apoptosis due to their influential interaction with Sod1, He1a and tp53 mRNA and proteins. The investigation deciphered the nanotoxicity of gold nanoparticles and suggested the implication of new green methodology for their future productions. PMID- 30311785 TI - The birth of viromics: an interview with Forest Rohwer. AB - The editor of Future Microbiology, Alice Greenway, speaks to Forest Rohwer from San Diego State University (CA, USA) following his talk entitled 'Counting all the world's phage' at ASM Microbe 7-11 June 2018. PMID- 30311786 TI - Quality of Life and Symptom Burden 1 Month After Concussion in Children and Adolescents. AB - We conducted a prospective study of children and adolescents (n = 176; mean age = 13.0 +/-2.7 years; 38% female) assessed acutely post-concussion and again 30 days later. We investigated the association between symptom burden and quality of life (QOL) outcomes, as well as the effect of age on QOL. We assessed QOL using patient-reported Pediatric Quality of Life Inventory 4.0, and symptoms using the Health and Behavior Inventory (HBI). Acute (<2 days post-injury) HBI ratings demonstrated a low correlation ( R2 = 0.08) with physical health QOL and a moderate correlation with psychosocial health QOL ( R2 = 0.21) 30 days post concussion. HBI ratings 30 days post-concussion demonstrated a moderately high correlation with physical health QOL ( R2 = 0.35) and psychosocial health QOL ( R2 = 0.57). Age was not significantly associated with physical or psychosocial QOL ratings. Impairments in QOL following concussion may identify children and adolescents who need additional referral to address persistent symptoms at this time. PMID- 30311787 TI - Ultra-Fast On-Site Molecular Detection of Foodborne Pathogens Using a Combination of Convection Polymerase Chain Reaction and Nucleic Acid Lateral Flow Immunoassay. AB - Rapid detection and timely treatment of diseases caused by foodborne pathogens is important for improving the curative efficiency and preventing the spread of disease. In this study, we developed an assay utilizing a recently introduced ultra-fast convection polymerase chain reaction (cPCR) in conjunction with a simple nucleic acid lateral flow (NALF) immunoassay for ultra-fast on-site molecular detection of foodborne pathogens. Two Salmonella enterica serovars, Salmonella Enteritidis and Salmonella Typhimurium, and Escherichia coli O157:H7 were used as the target pathogens. We confirmed the specific amplification of the target species with specifically designed modified primer sets for cPCR in singleplex and duplex modes. After cPCR amplification, we compared the detection specificity and sensitivity using agarose gel electrophoresis and NALF assays with one or two test lines. The cPCR amplicons were readily and sensitively detected using the NALF assay, and the sensitivity was comparable with that of agarose gel electrophoresis. To confirm the application of the assay in real-life samples, the assay was used to test artificially contaminated milk. Without sample pre-enrichment, the limit of detection (LOD) was 4.5 * 103 colony-forming units (CFU)/mL for Salmonella species; 4.5 * 104 CFU/mL to differentiate Salmonella Enteritidis and Salmonella Typhimurium; and 2.3 * 103 CFU/mL for E. coli O157:H7, in a duplex assay. With a 6 h pre-enrichment, the LOD was 4.5 CFU/mL for Salmonella Enteritidis and Salmonella Typhimurium, and 2.3 CFU/mL for E. coli O157:H7. The cPCR amplification took only 14 min, and the NALF assay took ca. 5 min. The total analysis time was less than 20 min. Based on these observations, we propose that the developed assay is simple, ultra-fast, and applicable for on-site detection of foodborne pathogens. PMID- 30311788 TI - Vaccine-preventable anal infections by human papillomavirus among HIV-infected men who have sex with men. AB - AIM: HIV-infected men who have sex with men (MSM) show the highest prevalence of anal HPV infection. Anal prevalence of the HPVs targeted by the quadrivalent HPV vaccine (4vHPV) and nonavalent HPV vaccine (9vHPV) was estimated in this population. MATERIALS & METHODS: Anal specimens were collected from HIV-infected MSM attending a sexually transmitted infection/HIV center. Specimens were analyzed using the Linear Array HPV Genotyping Test. RESULTS: A total of 49.5 and 71.2% of the 313 enrolled MSM harbored at least one of the 4vHPV and 9vHPV types, respectively. A significantly decreasing trend was observed for the prevalence of both 4vHPV (p = 0.04) and 9vHPV types (p < 0.001) across age classes. CONCLUSION: A substantial proportion of HIV-infected MSM do not harbor a current anal infection with vaccine-preventable HPVs. The potential benefit of the 4vHPV versus 9vHPV vaccination in these subjects, including older MSM, should be investigated. PMID- 30311789 TI - Thoughts on Chemistry, Manufacturing, and Control of Cell Therapy Products for Clinical Application. AB - Cell therapy has emerged as a promising new treatment in medicine, which is expected to be able to cure diseases by repairing, replacing, and regenerating tissues, as well as through immune modulation. However, challenges remain in ensuring consistent quality, clinical efficacy, and safety profiles because of the diversity of cell types and clinical indications for cell therapy products (CTPs), as well as different and complex manufacturing process. Therefore, scientific consensus and regulatory measurements are urgently warranted to promote the translation of the latest scientific advances and innovative manufacturing technologies into clinical application. This article aims to propose perspectives on the manufacturing, quality study, and quality control of CTPs and provide considerations and opinions in the regulation of CTPs. PMID- 30311791 TI - Corrigendum. PMID- 30311790 TI - Know your enemy: managing resistant Gram-negative infections. AB - Report from the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2018), Madrid, Spain, 21-24 April 2018 Gram-negative bacteria such as Klebsiella, Acinetobacter and Pseudomonas cause some of the most serious infections and are increasingly resistant to multiple drugs and in some cases, to all available antibiotics. Management of infections caused by these organisms is a global challenge that has serious implications for every hospital and department and therefore every delegate attending ECCMID 2018. PMID- 30311792 TI - Candidate Treponema pallidum biomarkers uncovered in urine from individuals with syphilis using mass spectrometry. AB - AIM: A diagnostic test that could detect Treponema pallidum antigens in urine would facilitate the prompt diagnosis of syphilis. MATERIALS & METHODS: Urine from 54 individuals with various clinical stages of syphilis and 6 controls were pooled according to disease stage and interrogated with complementary mass spectrometry techniques to uncover potential syphilis biomarkers. RESULTS & CONCLUSION: In total, 26 unique peptides were uncovered corresponding to four unique T. pallidum proteins that have low genetic sequence similarity to other prokaryotes and human proteins. This is the first account of direct T. pallidum protein detection in human clinical samples using mass spectrometry. The implications of these findings for future diagnostic test development is discussed. Data are available via ProteomeXchange with identifier PXD009707. PMID- 30311793 TI - The central role of pneumococcal colonization in the pathogenesis and control of pneumococcal diseases. PMID- 30311794 TI - Reporting Insulin Pump Accuracy: Trumpet Curves According to IEC 60601-2-24 and Beyond. AB - Accuracy of insulin pump basal rate delivery, if tested according to the standard IEC 60601-2-24 for infusion pumps, shall be presented as a trumpet curve. This way of graphical presentation is common; however, it is often misunderstood and misinterpreted by people. It is often assumed that a trumpet curve shows the error rate as a function of time, thus implying an increasing accuracy in the course of time. On the contrary, the horizontal axis of a trumpet curve shows increasingly long observation windows. In addition, trumpet curves display only extreme values, that is, those windows with minimal and maximal deviation, which might not be representative for the total deviation. This commentary provides information regarding the calculations and the interpretation of trumpet curves and proposes alternative approaches. PMID- 30311795 TI - Core/shell multicellular spheroids on chitosan as in vitro 3D coculture tumor models. AB - An ideal in vitro drug screening model is important for the drug development. In addition to monoculture systems, 3 dimensional (3D) coculture systems are extensively used to simulate the in vivo tumor microenvironment as cell-cell and cell-extracellular matrix interactions within the tumor tissues can be mimicked. In this study, in vitro 3D suspension coculture multicellular spheroids with core/shell cell distribution were developed on chitosan-coated surfaces. Based on the characteristic of chitosan inhibiting cell adhesion, SW620 (colon cancer cell line), 3A6 (mesenchymal stem-like cell line) and Hs68 (foreskin fibroblast line) cells could aggregate to form 3D coculture spheroids with intimate cell contacts. When cells were cocultured on chitosan, 3A6 and Hs68 cells always located in the core of spheroids and were completely enveloped by SW620 cells due to their N cadherin protein expression following the differential adhesion hypothesis. The core cells could be the feeder layers to stimulate the shell SW620 cells to enhance their mitochondria activity. Moreover, 3D coculture core/shell multicellular spheroids could enhance the resistance of SW620 cells against the cytotoxicity effect of chemotherapy drugs. To sum up, based on the specificity of the core/shell coculture multicellular spheroids, a novel in vitro tumor model was proposed in this study. PMID- 30311796 TI - Allogenic Pure Platelet-Rich Plasma Therapy for Rotator Cuff Disease: A Bench and Bed Study. AB - BACKGROUND:: Although platelet-rich plasma (PRP) is a popular option for rotator cuff disease, the underlying mechanism of PRP and its clinical indications are unclear. Further, some kinds of PRP might be detrimental to patients. Allogenic PRP prepared through a standardized process and fully characterized could eliminate variations in PRP as well as uncertainties regarding its use in each patient, which could provide clues about its mechanism of action and indications for its use. PURPOSE:: To assess the effects of pure PRP on tenocytes with or without inflammation in an in vitro study and to evaluate the safety and efficacy of a fully characterized pure PRP injection in patients with rotator cuff disease in a clinical study. STUDY DESIGN:: Controlled laboratory study and cohort study; Level of evidence, 3. METHODS:: For the in vitro study, tenocytes were enzymatically isolated and cultured from patients with rotator cuff tear and treated with or without interleukin 1beta (IL-1beta) and PRP. Gene expression and protein synthesis of pro- and anti-inflammatory cytokines, enzymes and their inhibitors, matrix synthesis, and cell viability were evaluated. For the clinical study, a total of 17 patients with rotator cuff disease received ultrasonography guided subacromial PRP injection and were followed for 6 months. Pain, range of motion, muscle strength, shoulder function, and overall satisfaction in patients were compared with the results in a propensity score-matched control group who received corticosteroid (triamcinolone acetonide 40 mg). RESULTS:: PRP induced inflammation in the absence of inflammation and ameliorated inflammation in IL 1beta-induced tendinopathic conditions by regulation of cytokines such as IL 1beta, cyclooxygenase 2, microsomal prostaglandin E synthase 1, vasoactive intestinal peptide, and downstream matrix metalloproteinases. No general or local adverse events were noted with regard to allogenic PRP injection. Whereas steroid injection showed earlier improvement in some kinds of pain and functional scores, PRP generally showed comparable effects with steroid injection in all clinical outcomes at 6 months. CONCLUSION:: This study showed that allogenic pure PRP had pleiotropic effects on tenocytes depending on inflammation and that it did not cause adverse events but rather decreased pain and improved shoulder function to a degree comparable with steroid injection in patients with rotator cuff disease. CLINICAL RELEVANCE:: Allogenic PRP could be a treatment option for rotator cuff disease. PMID- 30311797 TI - John Terry Maltsberger - Suicidologist Extraordinaire. PMID- 30311798 TI - Differences in Characteristics and Exposure to Stressors Between Persons With and Without Diagnosed Mental Illness Who Died by Suicide in Victoria, Australia. AB - BACKGROUND: Mental illness is an established risk factor for suicide. To develop effective prevention interventions and strategies, the demographic characteristics and stressors (other than, or in addition to, mental illness) that can influence a person's decision to die by suicide need to be identified. AIM: To examine cases of suicide by the presence or absence of a diagnosed mental illness (mental illness status) to identify differences in factors associated with suicide in the groups. METHOD: Logistic regression analyses were used to investigate mental illness status and exposure to stressors among 2,839 persons who died by suicide in Victoria, Australia (2009-2013), using the Victorian Suicide Register. RESULTS: Females, metropolitan residents, persons treated for physical illness/injury, those exposed to stressors related to isolation, family, work, education, and substance use and those who had made a previous suicide attempt had increased odds of having a diagnosed mental illness. Employed persons had decreased odds of having a diagnosed mental illness. LIMITATIONS: The retrospectivity of data collection as well as the validity and reliability of some of the data may be questionable owing to the potential for recall bias. CONCLUSION: The point of intervention for suicide prevention cannot always be a mental health professional; some people who die by suicide either do not have a mental illness or have not sought help. PMID- 30311799 TI - Attachment Styles and Posttraumatic Growth Among Suicide-Loss Survivors. AB - BACKGROUND AND AIMS: The world loses approximately one million people to suicide every year, leaving behind many suicide-loss survivors, family members and friends, who are significantly affected by the traumatic loss. Yet some suicide loss survivors not only manage to cope with the loss, but actually experience posttraumatic growth (PTG). To date, no studies have fully examined the psychological processes that underlie this personal positive change. We hypothesized that attachment style would predict PTG and this association would be mediated by self-disclosure and social support. METHOD: A community sample of 131 suicide-loss survivors (108 women), aged 18-70, self-reported on attachment style, self-disclosure, social support, and PTG. RESULTS: Securely attached individuals scored highest on PTG compared with other attachment styles. A structural equation model confirmed that self-disclosure and social support mediated the association between attachment and PTG. Suicide-loss survivors with secure attachment tended to self-disclose more and to perceive greater support from others than did suicide-loss survivors with insecure attachment, thus enhancing their chances of PTG. LIMITATIONS: The sample comprised mostly female participants, and the findings may not be directly generalizable to male suicide loss survivors. CONCLUSION: Our results suggest that different psychological interventions should be utilized for suicide-loss survivors with particular attachment styles. Psychotherapies aiming to modify internal working models may be useful for enhancing PTG among survivors characterized by insecure attachment styles. PMID- 30311800 TI - Trauma-Related Shame, Sexual Assault Severity, Thwarted Belongingness, and Perceived Burdensomeness Among Female Undergraduate Survivors of Sexual Assault. AB - BACKGROUND AND AIM: This study evaluated trauma-related shame as a mediator of the association between sexual assault severity and perceived burdensomeness and thwarted belongingness. METHOD: A total of 164 female undergraduates who reported attempted or completed sexual assault completed self-report measures of sexual assault, trauma-related shame, perceived burdensomeness, and thwarted belongingness. RESULTS: Using path analysis, trauma-related shame mediated the association between sexual assault severity and perceived burdensomeness, and between sexual assault severity and thwarted belongingness. LIMITATIONS: The findings of this study are limited by the retrospective, self-report, and cross sectional nature of these data, and do not allow for causal inference. CONCLUSION: Trauma-related shame warrants additional investigation as a mechanism that explains the association between sexual assault and psychosocial risk factors for suicidal ideation and behavior. PMID- 30311801 TI - Family, Health, and Poverty Factors Impacting Suicide Attempts in Cambodian Women. AB - BACKGROUND: Our recent report demonstrates that 5.5% of Cambodian women have previously attempted suicide. Despite these high rates and critical need for intervention, research on suicide attempts in Cambodia is lacking, and life saving information on suicide prevention is therefore unknown. AIMS: This study explores factors impacting Cambodian women suicide attempts. METHOD: A total of 1,801 women participated in the large national survey during which 100 of these women (5.5%) reported at least one suicide attempt. Of the 100 participants 76 provided qualitative reasons for the suicide attempts. Only the 76 who provided the reasons for suicide attempt were included for analysis in this study. RESULTS: Four major themes emerged: (1) family conflict, (2) emotional distress, (3) poverty, and (4) illness. Family conflict, emotional distress, poverty, and illness were all interrelated with each other; for example, women without money were unable to pay for treatment of otherwise treatable illnesses. LIMITATIONS: Owing to the nature of the data collection, member checking could not be conducted. CONCLUSION: Cumulative and intertwined personal, interpersonal, and contextual-level factors impacting suicide attempts included emotional distress, illness, family conflict, and poverty. Findings highlight points of intervention at individual, familial, and contextual levels to prevent suicide. PMID- 30311802 TI - Computer-aided identification of novel anti-paracoccidioidomycosis compounds. AB - AIM: The shape-based virtual screening was used for the identification of new compounds anti-paracoccidioidomycosis (PCM). MATERIALS & METHODS: The study was performed according to the following steps: collection and curation of a dataset of quinolinyl N-oxide chalcones with anti-PCM activity, development and validation of shape-based models, application of the best model for virtual screening, and experimental validation. RESULTS & CONCLUSION: Among 31 computational hits, eight compounds showed potent antifungal activity and low cytotoxicity for mammalian cells. The checkerboard assay showed that most promising hit (compound 3) displayed additive effects with the antifungal cotrimoxazole and amphotericin B. Therefore, the shape-based virtual screening allowed us to discover promising compounds in prospective hit-to-lead optimization studies for tackling PCM. PMID- 30311804 TI - Advancing therapies in metastatic castration-resistant prostate cancer. AB - INTRODUCTION: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T. Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies. Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival. PMID- 30311803 TI - A journey from the endothelium to the tumor tissue: distinct behavior between PEO PCL micelles and polymersomes nanocarriers. AB - Polymeric nanocarriers must overcome several biological barriers to reach the vicinity of solid tumors and deliver their encapsulated drug. This study assessed the in vitro and in vivo passage through the blood vessel wall to tumors of two well-characterized polymeric nanocarriers: poly(ethyleneglycol-b-epsilon caprolactone) micelles and polymersomes charged with a fluorescent membrane dye (DiO: 3,3'-dioctadecyloxacarbo-cyanine perchlorate). The internalization and translocation from endothelial (human primary endothelial cells HUVEC) to cancer cells (human tumor cell line HCT-116) was studied in conventional 2D monolayers, 3D tumor spheroids, or in an endothelium model based on transwell assay. Micelles induced a faster DiO internalization compared to polymersomes but the latter crossed the endothelial monolayer more easily. Both translocation rates were enhanced by the addition of a pro-inflammatory factor or in the presence of tumor cells. These results were confirmed by early in vivo experiments. Overall, this study pointed out the room for the improvement of polymeric nanocarriers design to avoid drug losses when crossing the blood vessel walls. PMID- 30311805 TI - Angiotensin II type 1 receptor blockers prevent aortic arterial stiffness in elderly patients with hypertension. AB - BACKGROUNDS AND AIMS: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of ARBs in aged patients with essential hypertension are not entirely investigated. METHODS: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. RESULTS: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared to patients without essential hypertension. In correlation analysis, PWV was associated positively with age, hypertension duration, and carotid atherosclerosis. However, there was no relationship between PWV and gender in aged patients with essential hypertension. In a perspective study, 6-12 months administration of ARBs (losartan, 50 mg/day; telmisartan, 40 mg/day; valsartan 80 mg/day; irbesartan, 150 mg/day) remarkably reduced PWV in aged patients with essential hypertension. Regression analyses of multiple factors indicated that the effects of ARBs on arterial stiffness were not associated with the reduction of blood pressure. CONCLUSION: ARB treatment is a negative risk factor of arterial stiffness in aged patients with essential hypertension. PMID- 30311806 TI - Cyclic peptide-based nanostructures as efficient siRNA carriers. AB - RNA interference shows a great strategy for biological studies; however, delivering of small interfering RNA (siRNA) remains challenging. Although several delivery vehicles, including cell-penetrating peptides, have been developed, their implementation is often restricted because of their endosomal entrapment. Herein, we report the formation of self-assembled nanostructures from rationally designed cyclic peptides and explore them for efficient delivery of functional biomacromolecules such as siRNA into mammalian cells. The newly obtained soft materials make stable complexes with siRNAs, thereby increasing their stability and deliver fluorescent labelled siRNA inside the cells as evident from confocal microscopy analysis. Flow cytometry analysis reveals that significant uptake of FAM-siRNA occurs in the presence of peptide nanostructures compared with siRNA alone. Peptide nanostructure-mediated delivery of very low concentration of siRNA causes significant knockdown of the target gene as observed at protein level by Western blot analysis, which is comparable to lipofectamine, commercially available transfection agent. PMID- 30311807 TI - Air-Perfused 23-Gauge Sutureless Diabetic Vitrectomy for Control of Intraoperative Bleeding during Removal of Fibrovascular Membrane. AB - PURPOSE: To demonstrate the advantages and efficacy of an air-perfused membrane dissection to control intraoperative bleeding in 23-gauge sutureless vitrectomy for proliferative diabetic retinopathy with severe fibrovascular membranes. Meterials and Methods: A prospective, consecutive, interventional case series of 15 eyes that underwent air-perfused diabetic vitrectomy (air vitrectomy group) for removal of the membranes was compared with a retrospective, membrane-matched case series of 10 eyes that underwent conventional diabetic vitrectomy (conventional vitrectomy group). The main outcome measures were real vitrectomy time, intraoperative and postoperative complications, and anatomic and functional successes at the final examination. RESULTS: The incidence of intraoperative retinal tears was 30% (3/10 eyes) in the conventional vitrectomy group and 20% (3/15 eyes) in the air vitrectomy group (p > 0.05). The postoperative complications such as vitreous hemorrhage or tractional retinal detachment were not common in both groups during the 6-month follow-up (p > 0.05). In addition, the final anatomic and functional success rates did not differ significantly between the groups (p > 0.05). However, the vitrectomy time was significantly shorter in the air vitrectomy group (67.0 +/- 21.8 min) than in the conventional group (84.6 +/- 21.1 min) (p = 0.04). CONCLUSION: Air-perfused vitrectomy showed comparable anatomic and functional success rates and shorter surgical time, compared with conventional vitrectomy in diabetic eyes with severe fibrovascular membranes. We suppose that the shortened surgical time in the air vitrectomy group is related to less intraoperative bleeding and more efficient hemostasis. PMID- 30311808 TI - Night shift work and osteoporosis: evidence and hypothesis. AB - Osteoporosis is an important public health problem worldwide. Among the countries with a very high population risk of fractures, there are those with the highest level of economic development. Osteoporotic fractures are the main cause of disability among elderly people, and the resultant disabilities require particularly large financial support associated not only with the direct treatment of the fracture but also with the necessity for long-term rehabilitation and care for the disabled person. Many well-established factors can have impact on bone mass and fracture risk. Recently, it has been hypothesized that working during nighttime which leads to endocrine disorders may have an indirect impact on bone physiology among night shift workers. Therefore, it can be presumed that the night shift work may contribute to the etiology of osteoporosis. The aim of our work was to make a review of the epidemiological evidence on the association between night shift work and bone mineral density or fracture risk as well as to discuss the potential biological mechanisms linking the work under this system with the development of osteoporosis. We have identified only four studies investigating the association between system of work and bone mineral density or fracture risk among workers. The findings of three out of four studies support the hypothesis. None of the studies has investigated a potential relationship between night shift work and bone turnover markers. Given that there have been no epidemiological studies in European countries that would concern working populations and the noticeable difference in the risk of osteoporosis between communities, further studies are warranted to elucidate the problem. It is presumed that further in-depth studies will not only identify the underlying factors of the disease but also contribute to developing guidelines for policy makers and employers for primary prevention of osteoporosis in workplace. PMID- 30311809 TI - The association between exposure to second-hand smoke and major depressive disorder in perimenopausal women: results from apopulation-based study. AB - PURPOSE: The aim of this study was to test the hypothesis that exposure to second hand smoke (SHS) would be positively associated with major depressive disorder (MDD) in perimenopausal women from a population-based perspective, after adjustment for all potential confounders. METHODS: This study used the National Health and Nutrition Examination Survey (NHANES) database, 2005-2012, to report on MDD in perimenopausal women. RESULTS: The odds ratio (OR) for MDD increased when there was a smoker was in the home, as compared to not having a smoker in the home (aOR = 2.97, 95% confidence interval [CI] = 1.15-7.67); however, in the non-poor group, the OR for MDD showed no difference between those who had or did not have a smoker in their home. For participants who self-rated their health condition as excellent, very good or good, the OR for MDD increased; it also increased if there were smokers in the home, as compared to those without smokers in the home (aOR = 2.58, 95% CI = 1.08-6.14). CONCLUSIONS: The present study results augment our understanding of the clinical and public health significance of SHS, as well as the role of various socioeconomic and self-rated health conditions, in perimenopausal women. Key messages An increasing OR for MDD was demonstrated with regard to health status such as CVD, chronic respiratory tract disease, arthritis, thyroid problems, lower eGFR, fair or poor self-rated health condition, and elevated CRP level. Participants who self-rated their health condition as excellent, very good or good had an increased OR for MDD. The OR also increased if the women had smokers in their home versus women who did not have smokers in the home. PMID- 30311810 TI - Morningness-eveningness and social anxiety symptoms: the influence of depression symptoms on the indirect effect through punishment sensitivity and experiential avoidance. AB - Social anxiety has recently been linked to morningness-eveningness; however, the psychological mechanisms underlying this relationship are not well known. As such, the purpose of the current study is to propose a model by which morningness eveningness is related to social anxiety symptoms through punishment sensitivity and experiential avoidance within an adult American, community sample recruited via Amazon's Mechanical Turk (MTurk). It was hypothesized that experiential avoidance and punishment sensitivity would be associated with increased social anxiety symptoms and that morningness-eveningness would be negatively related to social anxiety symptoms. Furthermore, eveningness was hypothesized to be associated with increased punishment sensitivity and in turn, greater experiential avoidance. Lastly, the relationship between morningness-eveningness and social anxiety was hypothesized to be mediated by punishment sensitivity among the group with high depression levels, but not among the group with lesser depression symptoms. The results indicated that eveningness was related to social anxiety symptoms through experiential avoidance, and that depression symptoms influenced the relationship between morningness-eveningness and punishment sensitivity such that, in those high in depression symptoms, there was a significant association between eveningness and punishment sensitivity, but not among those with lower depression levels. The study findings build upon existing chronobiological research and addresses inconsistencies in previous literature. PMID- 30311811 TI - A Preliminary Investigation of the Intersection of Race and Disabilities among Inmates in the U.S. State Prison System. AB - The American prison system is overcrowded with minorities in general, and African Americans, in particular. The Department of Justice notes that more than 50% of the prison population have some type of mental disability. In this study, we examine the intersection between race and disabilities in the U.S. State prison system. Using the Rehabilitation Services Administration data set, the study highlights the prevalence and type of disabilities in the prison inmate population. Results demonstrate that African American inmates are overrepresented among inmates with disabilities, are more likely to have mental disabilities relative to physical disabilities, and these results hold for various types of mental disabilities including cognitive, psychosocial, and other mental disabilities. Study limitations and directions for future research are also discussed. PMID- 30311812 TI - Association of the plasma aldosterone concentration, left atrial deformation and ambulatory blood pressure in never-treated early hypertensive patients. AB - Left atrial (LA) strain is known to exhibit an early progressive reduction in hypertensive patients with diastolic dysfunction. However, an association of the renin-angiotensin-*aldosterone system (RAAS) with LA deformation has not been found in these patients. We aimed to investigate the association of plasma aldosterone concentration (PAC) and 24-hour ambulatory blood pressure monitoring (ABPM) with LA and left ventricle (LV) deformation in never-treated early hypertensive patients. This cross-sectional study included 101 never-treated subjects who were registered in a working group at The Catholic University of Korea. The patients were divided into a hypertension group (n = 71), which was defined as having a systolic blood pressure (BP) >=130 mm Hg and/or a diastolic BP >=80 mm Hg based on ABPM, and a control group (n = 30). Enrolled patients underwent conventional and speckle tracking echocardiography, ABPM, and measurement of pulse wave velocity, PAC, and plasma renin activity. Compared with the control group, the hypertension group had significantly increased PAC, global longitudinal strain (GLS), atrial reservoir strain, atrial pump strain, and atrial systolic strain rate. LA pump strain was independently associated with nighttime systolic BP. PAC was correlated with GLS but not LA deformation in hypertensive patients without clinically apparent target organ damage. The raised LV pressure secondary to the nocturnal systemic pressure overload might be more strongly associated with LA deformation than with the RAAS. PMID- 30311813 TI - Platelet volume indices for the prognosis of acute ischemic stroke patients with intravenous thrombolysis. AB - OBJECTIVE: We aimed to investigate whether platelet volume indices (PVIs) were associated with an unfavorable clinical outcome in acute ischemic stroke (AIS) patients undergoing intravenous thrombolysis (IVT). METHODS: We defined a modified Rankin Scale (mRS) score of 3-6 at 90 days as an unfavorable outcome. Logistic regression analysis was performed to find out whether mean platelet volume (MPV), platelet distribution width (PDW), MPV/platelet count (PC) ratio and PDW/PC ratio were associated with poor prognosis. A Spearman correlation test was carried out to assess the relationship between variables. RESULTS: Overall, 183 patients were included in this study. Multivariate logistic regression analysis revealed that MPV (adjusted odds ratio [OR] 1.52, 95% confidence interval [CI]: 1.01-2.29, p = 0.044) and PDW-sd (adjusted OR 1.30, 95% CI: 1.06 1.59, p = 0.011) were independent predictors of the poor outcome. There was a trend of incremental OR when compared higher tertile of MPV with lower ones (second tertile, adjusted OR 2.52,95% CI:1.02-6.21, p = 0.045; third tertile, adjusted OR 2.61, 95% CI: 1.12-6.09, p = 0.027). Besides, we found a significant positive correlation between MPV and PDW-sd (or =0.874, p < 0.001). CONCLUSION: MPV and PDW-sd were independent predictors for 90-day outcomes in stroke patients receiving thrombolysis. PMID- 30311814 TI - Managing complications of hypertension in aortic valve stenosis patients. AB - INTRODUCTION: Hypertension is highly prevalent in aortic valve stenosis (AS) patients as the prevalence of both disorders increases with age. Hypertension and associated stiffening of the large arteries increase afterload and thereby influence both the transvalvular flow and the remodeling of the aortic root and the left ventricle during AS progression. Area covered: The present review gives an overview on complications of hypertension in AS, how these can be diagnosed, and potentially may be managed. Expert commentary: Hypertension-mediated cardiovascular (CV) damage in AS is associated with increased morbidity and a twofold higher mortality even in asymptomatic patients, and also limits the symptomatic and survival benefit from valve replacement. Data from registries and post hoc analyses from outcome studies in AS suggest that treatment with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers, respectively, is safe and associated with improved survival and reduced CV events in these patients. However, optimal blood pressure (BP) target in AS patients is not documented, and strict BP control in the early postoperative phase in AS patients treated with transcatheter aortic valve replacement (TAVR) may be associated with adverse events. Thus, randomized studies on BP management in asymptomatic AS and post-TAVR patients are highly needed. PMID- 30311815 TI - Study of Haralick's and GLCM Texture Analysis on 3D Medical Images. AB - Medical field has highly evolved with advancements in the technologies which prove to be beneficial for radiologists and patients for better diagnosis. The era of medical science provides best healthcare solutions with the help of medical images. Till now, 2D MRIs played a prominent role in early detection of disease but with latest technologies taking over the charge, 3D MRIs are highly effective and great in demand now-a-days. With the aid of advanced techniques such as edge detection, segmentation and texture analysis on these images the disease detection may become much easier. Texture of any image is recognized by distribution of gray levels in the neighborhood. The Texture Analysis plays an important role in study of medical images. It identifies the prominent features of an image and highlights the same using different feature extraction technique. In this paper, 3D MRI of human brain is considered and texture analysis based on Haralick's and GLCM texture features is performed. Haralick's feature explains the image intensities of each pixel and their relationship with neighborhood pixels. The entire data set consists of 40 brain tumor patients, out of which a sample has been depicted. The analysis of different features such as Contrast, Correlation, Energy, Homogeneity and Entropy is carried out. Further, the study highlights about the highly useful features for early detection of brain tumor disease. PMID- 30311816 TI - What's Right With Men? Gender Role Socialization and Men's Positive Functioning. AB - This study explored relations between conformity to masculine norms, gender role conflict, hope, and psychological well-being among a sample of 389 men from a university, with a predominantly White student body, located in the Midwestern United States. Bivariate correlations revealed that men's conformity to masculine norms and gender role conflict were positively correlated. Bivariate correlations revealed no significant relations between conformity to masculine norms, trait hope, and psychological well-being. Gender role conflict was associated with decreased hope and psychological well-being. Results of path analysis explained relations between conformity to masculine norms, gender role conflict, trait hope, and psychological well-being. This indicates that gender role conflict may contribute to lower trait hope and psychological well-being for college men. Although several aspects of conformity to masculine norms had positive associations with hope, these relations were significant and negative when men experienced gender role conflict. This work fills an important gap in the literature by examining the unique relations of conformity to masculine norms and gender role conflict to men's positive functioning. Results are discussed within the context of positive psychological theories including Frederickson's broaden and build theory of positive emotions, hope theory, Ryff's model of psychological well-being, and self-determination theory. Implications and future directions are discussed. PMID- 30311817 TI - In utero Zika virus exposure and schizophrenia. PMID- 30311818 TI - Assessment of light transmission aggregometry on the routine coagulation analyzer Sysmex CS-2500 using CE-marked agonists from Hyphen Biomed. AB - Light transmission aggregometry (LTA) is still considered as the "gold standard" for platelet function assessment but, as acompletely manual technology, it is labour intensive. This challenge can be overcome by performing platelet aggregometry in anautomated method on a routine coagulation analyzer. We aimed to compare and correlate results obtained from a traditional manual LTA solution realized in our Reference Center with an optimized automated system using CE marked agonist reagents. Platelet rich plasma from patients with suspected platelet disorders, von Willebrand disease or antiplatelet therapy have been assessed using a wide range of agonist concentrations. Results were expressed as Maximal Platelet Aggregation and correlation was analyzed using the Passing and Bablok regression test. Platelet aggregometry studies were performed in 49 samples. Maximal aggregation response with ADP (0.5-10 MUM), collagen (2 mg/MUL), ristocetin (1.2 mg/mL) and arachidonic acid (1 mM) agonists showed significant correlation between the two aggregometers (p< .001). We observed a more variable response using lowconcentrations of ADP (<=5 MUM). Moreover, we also noted discrepancies with the low dose of ristocetin, showing excessive paradoxical agglutination with the CS-2500, suggesting that a lower ristocetin dose should be used with this system. These data show that CS-2500 has the advantages of a walk away technology and the use of CE-marked reagents also permit the possibility of an easier certification. PMID- 30311819 TI - Determinants of glycemic control among diabetes mellitus patients in a tertiary clinic in Gaborone, Botswana: findings and implications. AB - BACKGROUND AND AIMS: Glycemic control among patients with diabetes mellitus is associated with a marked reduction of both macrovascular and microvascular complications; however, glycemic control remains an elusive goal worldwide. The aim of this study was to determine factors associated with glycemic control among patients attending a tertiary clinic in Botswana as limited information to date. METHODS: Cross-sectional study in a tertiary clinic in Gaborone, Botswana. Patients were recruited between 21 July 2015 and 21 September 2015. The majority of the randomly recruited patients (368/380-96.8%) had documentation of glycemic control (HbA1c) within three months of study recruitment and were subsequently included in the analysis. Glycemic control was categorized as desirable, suboptimal and poor if HbA1c was <7%, 7-9% and >9%, respectively. Data were analyzed using SPSS for descriptive statistics including both bivariate and multinomial logistic regression. A value of p < 0.05 was considered statistically significant. RESULTS: The analyzed study population consisted of 258/368 (70.1%) females with a mean age (SD) of 56.7 +/- 13.6 years. Means (SDs) for diabetes duration and glycated hemoglobin were 7.2 +/- 7.1 years and 7.97 +/- 2.02%, respectively. Of the 368 patients, 136 (36.95%) and 132/368 (35.86%) had desirable and suboptimal glycemic control, respectively. Older age, attending the clinic for more or equal to 3 years and not being on insulin were associated with both desirable and suboptimal glycemic control whereas duration of diabetes between 5 and 10 years was associated with poor glycemic control. CONCLUSIONS: The majority of patients had poor glycemic control. Older age and not being on insulin were associated with better glycemic control. The fact that patients on insulin had poor glycemic control calls for more research to determine the timing of insulin initiations and dosing schedule factors as these will help to improve overall glycemic control in Botswana and elsewhere. PMID- 30311820 TI - Histological Effects of the Combined Administration of Eldecalcitol and a Parathyroid Hormone in the Metaphyseal Trabeculae of Ovariectomized Rats. AB - Intermittent administration of human parathyroid hormone (1-34) (hPTH(1-34)) promotes anabolic action in bone by stimulating bone remodeling, while eldecalcitol, an analog of active vitamin D3, suppresses osteoclastic bone resorption, and forms new bone by minimodeling. We have examined the biological effects of combined administration of eldecalcitol and hPTH(1-34) on 9-week-old Wistar rats that underwent an ovariectomy (OVX) or Sham operation. They were divided into a Sham group, OVX with vehicle (OVX group), OVX with 10 ug/kg/day of hPTH(1-34) (PTH group), OVX with 20 ng/kg/day of eldecalcitol (eldecalcitol group) or OVX with 10 MUg/kg/day of hPTH(1-34), and 20 ng/kg/day of eldecalcitol (combined group) for 4 or 8 weeks. As a consequence, the combined group showed a marked increase in bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) than OVX and had the highest bone mineral density (BMD) compared with other groups. OVX and PTH groups exhibited a high osteoblastic surface/bone surface (Ob.S/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS) indices and many TRAP-reactive osteoclasts. Contrastingly, eldecalcitol and combined groups tended to attenuate the indices of osteoclastic surface/bone surface (Oc.S/BS) and Ob.S/BS than that the other groups. The combined group revealed histological profiles of minimodeling- and remodeling-based bone formation. Thus, the combined administration of eldecalcitol and hPTH(1-34) augments their anabolic effects by means of minimodeling and remodeling. PMID- 30311821 TI - Reasons and outcomes for patients receiving ICS/LABA agents prior to, and one month after, emergency department presentations for acute asthma. AB - OBJECTIVE: Asthma is a common emergency department (ED) presentation. This study examined factors associated with inhaled corticosteroids/long-acting beta-agonist (ICS/LABA) use; and management and outcomes before and after ED presentation. METHODS: Secondary analysis of a prospective cohort study; adults treated for acute asthma in Canadian EDs underwent a structured interview before discharge and were followed-up four weeks later. Patients received oral corticosteroids (OCS) at discharge and, at physician discretion, most received ICS or ICS/LABA inhaled agents. Analyses focused on ICS/LABA vs "other" treatment groups at ED presentation. RESULTS: Of 807 enrolled patients, 33% reported receiving ICS/LABA at ED presentation; 62% were female, median age was 31 years. Factors independently associated with ICS/LABA treatment prior to ED presentation were: having an asthma action plan; using an asthma diary/peak flow meter; influenza immunization; not using the ED as usual site for prescriptions; ever using OCS and currently using ICS. Patients were treated similarly in the ED and at discharge; however, relapse was higher in the ICS/LABA group, even after adjustment. CONCLUSION: One-third of patients presenting to the ED with acute asthma were already receiving ICS/LABA agents; this treatment was independently associated with preventive measures. While ICS/LABA management improves control of chronic asthma, patients using these agents who develop acute asthma reflect higher severity and increased risk of future relapse. PMID- 30311822 TI - Participant Evaluation of Twelve-Step Group Linkage for Jailed Women With Alcohol Use Disorder. AB - Jailed women are an underserved population with elevated rates of alcohol use disorders. Brief jail stays make delivery of case management and traditional alcohol treatment impractical yet women face significant reentry challenges with few help resources. Accounting for these challenges, linking jailed women with a twelve-step program volunteer for a one-on-one meeting has been hypothesized to provide a means of support that can transition with women after jail discharge. In-jail meetings are theoretically consistent with the common twelve-step practice of conducting twelve-step calls. The acceptability and content of a one on-one, in-jail meeting with a twelve-step volunteer were explored using qualitative data collected through interviews with 72 women directly following their in-jail volunteer meeting. Participants found the meeting to be acceptable and to contain many useful elements, and content was in line with the standard twelve-step calls. Findings are encouraging both for the potential utility of the intervention and for dissemination of similar linkage approaches. PMID- 30311823 TI - Effectiveness of robotics in improving upper extremity functions among people with neurological dysfunction: a systematic review. AB - PURPOSE: The primary focus of this review was to find out the effectiveness of robotics in improving upper extremity functions among people with neurological problems in the arena of physical rehabilitation. MATERIAL AND METHODS: Two reviewers independently scrutinized the included studies. The selected studies underwent quality assessment by Physiotherapy Evidence Database (PEDro) scale. Randomized Controlled Trial (RCT) having a score of four or more were included in the review. A search was conducted in PUBMED, MEDLINE, CINAHL, EMBASE, PROQUEST, science direct, Cochrane Library, PEDro and Google Scholar. RESULTS: A total of 202 studies were identified. After removal of duplication, inclusion and exclusion criteria's n = 23 studies were included in the review process. For analysis, only the primary outcome measures of the studies were taken into account. Studies finally included in analysis were n = 21. The included studies were 19 in stroke, 1 in cerebral palsy (CP) and 1 study in multiple sclerosis (MS). No RCTs were reportedly found in spinal cord injury (SCI), Parkinson and motor neuron disease (MND). CONCLUSIONS: Studies related to stroke showed a clear definiteness in the improvement of upper extremity functions. On the contrary, there still remains a need for quality trials in CP, MS to establish the efficacy of robotics in upper extremity rehabilitation. PMID- 30311824 TI - Herpetic Anterior Uveitis - Analysis of Presumed and PCR Proven Cases. AB - PURPOSE: To describe the demographics and clinical characteristics of patients with herpetic anterior uveitis (HAU), and compare characteristics by pathogen, recurrence, and association to iris atrophy. METHODS: Multicenter, retrospective study of AU patients diagnosed clinically and by polymerase chain reaction (PCR). RESULTS: The study included 112 eyes in 109 patients: 54 (48.2%) HSV, 34 (30.4%) VZV, 2 (1.8%) CMV, and 22 (19.6%) unspecified diagnosis. HSV eyes, compared to VZV, had a higher recurrence rate, corneal involvement, KPs, iris atrophy, elevated IOP and posterior synechia (p < 0.05). VZV patients had more frequent immunomodulatory treatments and history of systemic herpetic disease (p < 0.05). Fifty-nine (52.7%) eyes had recurrent disease. Iris atrophy was associated with a higher prevalence of posterior synechia, dilated distorted pupil, and high IOP (p < 0.05). CONCLUSION: Different HAU-causing Herpesviridae produce common clinical findings; therefore, PCR should be used more often to confirm specific diagnosis. Iris atrophy was associated with more severe disease. PMID- 30311825 TI - Effects of alpha-Lipoic Acid, Carnosine, and Thiamine Supplementation in Obese Patients with Type 2 Diabetes Mellitus: A Randomized, Double-Blind Study. AB - Type 2 diabetes mellitus (T2DM) is evolving to an epidemic of the modern world. T2DM is associated with a number of pathological complications, including cardiovascular disease that is mostly promoted by the increased oxidative stress in type 2 diabetic patients. We performed a randomized double-blind placebo controlled trial to investigate the effectiveness of an individualized oral supplementation with alpha-lipoic acid (ALA), carnosine, and thiamine. For that purpose, 82 obese type 2 diabetic patients were randomly assigned to 2 groups, and were either supplemented daily with 7 mg ALA/kg body weight, 6 mg carnosine/kg body weight, and 1 mg thiamine/kg body weight or placebo for 8 weeks. An array of biochemical tests including the estimation of oxidative stress and platelet aggregation were performed at baseline and at follow-up. Moreover, the antiplatelet activity of each of the supplement's components was determined ex vivo at human and washed rabbit platelets. Glucose and HbA1c levels were significantly reduced after supplementation (135.7 +/- 19.5 mg/dL vs. 126.5 +/- 16.8 mg/dL and 8.3% +/- 0.3% vs. 6.03% +/- 0.58%, respectively, P < .05); however, insulin was significantly increased (3.6 +/- 0.7 MUIU/mL vs. 6.8 +/- 0.2 MUIU/mL, P < .05). The patients treated with the supplement recorded higher follow-up values for HOMA-IR and HOMA-beta, and a significant drop in serum hydroperoxide level. Only ALA inhibited platelets aggregation ex vivo through ADP, platelet activating factor, arachidonic acid, epinephrine, collagen, and thrombin pathways. Daily supplementation with an individualized ALA, carnosine, and thiamine supplement effectively reduced glucose concentration in type 2 diabetic patients, probably by increasing insulin production from the pancreas. In addition to that, the reduction of oxidative stress and inhibition of platelet aggregation could potentially provide greater cardiovascular protection. Further studies are needed to fine-tune the supplementation dose-response effects in T2DM patients. PMID- 30311826 TI - Father 2 Son: The Impact of African American Father-Son Sexual Communication on African American Adolescent Sons' Sexual Behaviors. AB - Parent-child sexual communication has been associated with reducing adolescent sexual risk behaviors. Limited research on parent-child sexual communication has been conducted on African American (AA) adolescent males who are at increased risk of sexually transmitted infections (STIs) including HIV/AIDS. The purpose of this research was to examine AA father-son sexual communication and the effect of contextual factors on the sexual risk behaviors. The final sample consisted of 96 AA adolescent males, ages 16-21 years. Structural equation modeling was used to examine the variables of interest (neighborhood characteristics, father-son closeness and connectedness, father-son communication, sexual permissiveness, condom attitudes, sexual risk behaviors). A path model was developed and tested. Results demonstrated that AA father-son closeness and connectedness were related to father-son communication. AA father-son communication was negatively related to sons' permissiveness and positively related to condom attitudes. Sons' permissiveness positively predicted their sexual risk behaviors. AA sons' condom attitudes did not negatively or positively predict their sexual risk behaviors. The findings from this study demonstrate that AA father-son communication is an important factor in decreasing AA adolescent males' sexual risk behaviors and HIV risk. PMID- 30311827 TI - Effect of baseline brain activity on response to low-frequency rTMS/intensive occupational therapy in poststroke patients with upper limb hemiparesis: a near infrared spectroscopy study. AB - BACKGROUND: The beneficial effects of the combination therapy of low-frequency repetitive transcranial magnetic stimulation of nonlesional hemisphere and intensive occupational therapy (LF-rTMS/OT) on upper limb hemiparesis have been well established in poststroke patients. However, there is no information on the effect of brain activity on LF-rTMS/OT treatment outcome. METHOD: A total of 59 poststroke patients with upper limb hemiparesis received 15-day LF-rTMS/OT. Motor function of the affected upper limb was evaluated before and after the treatment. We also conducted functional near-infrared spectroscopy (fNIRS) before the treatment and calculated the laterality index (LI) based on the change in oxy hemoglobin in the primary sensorimotor cortex and supplementary motor cortex. The correlation between LI before LF-rTMS/OT and observed improvement in upper limb motor function was analyzed. RESULTS: Motor recovery was significantly more pronounced in patients with unaffected hemisphere dominance in both hemispheres (LI of -1 to 0) than in those with affected hemisphere dominance in the lesional hemisphere (LI of 0 to 1). There was a significant negative correlation between LI and improvement in upper limb motor function. DISCUSSION: The results demonstrated that patients with a shift in brain activity to the noninjured cerebral cortex exhibited better motor recovery following LF-rTMS/OT. The findings suggest that evaluation of brain asymmetry before LF-rTMS/OT with fNIRS can help predict the response to LF-rTMS/OT. PMID- 30311828 TI - Prevalence of asthma and allergic disorders in regional, rural, and indigenous children aged 6-8 years in Tasmania. AB - OBJECTIVE: Asthma and allergic diseases are poorly described in rural areas. The objective of this study was, therefore, to determine the prevalence of wheezing, asthma, and other allergic disorders among children living in regional and rural Tasmania. METHODOLOGY: Data from a cross-sectional survey using standardized questionnaires of asthma, allergic conditions and food allergies were collected from 39 primary schools across North West Tasmania. We enrolled 1075 children between 6 and 8 years. The main outcomes were prevalences of wheezing, asthma, and other allergic disorders further stratified by sex and indigenous status. RESULTS: Baseline characteristics were as follows: median age 8.1 years (IQR: 7.6, 8.7) with equal sex distribution, most (80.1%) attended public schools and 11.0% identified as indigenous. We report prevalences of current wheezing (22.7%), allergic rhinoconjunctivitis (16.3%) and atopic eczema (16.6%), with higher prevalences among boys (except eczema). Food allergies were reported in 8.6% and food-related anaphylaxis in 1.6% of the sample. Indigenous children had significantly higher prevalence of current wheezing (indigenous 31.1% versus non indigenous 21.6%; p = 0.02). Further, children with current wheezing and no asthma diagnosis, had similar prevalence of other atopic diseases (hayfever 31.4%, eczema 44.0%, and food reaction 23.2%) compared with diagnosed asthmatics, although likely shared the illness. CONCLUSIONS: Childhood asthma is more prevalent in regional Tasmania compared with national estimates, especially among indigenous children. This appears not to be driven by an allergic response. Also, a significant proportion of children are likely to have undiagnosed asthma which has implications for rural health service delivery. PMID- 30311829 TI - Can Topical Use of Ginseng or Ginsenosides Accelerate Wound Healing? PMID- 30311830 TI - Systematic review of light exposure impact on human circadian rhythm. AB - Light is necessary for life, and artificial light improves visual performance and safety, but there is an increasing concern of the potential health and environmental impacts of light. Findings from a number of studies suggest that mistimed light exposure disrupts the circadian rhythm in humans, potentially causing further health impacts. However, a variety of methods has been applied in individual experimental studies of light-induced circadian impacts, including definition of light exposure and outcomes. Thus, a systematic review is needed to synthesize the results. In addition, a review of the scientific evidence on the impacts of light on circadian rhythm is needed for developing an evaluation method of light pollution, i.e., the negative impacts of artificial light, in life cycle assessment (LCA). The current LCA practice does not have a method to evaluate the light pollution, neither in terms of human health nor the ecological impacts. The systematic literature survey was conducted by searching for two concepts: light and circadian rhythm. The circadian rhythm was searched with additional terms of melatonin and rapid-eye-movement (REM) sleep. The literature search resulted to 128 articles which were subjected to a data collection and analysis. Melatonin secretion was studied in 122 articles and REM sleep in 13 articles. The reports on melatonin secretion were divided into studies with specific light exposure (101 reports), usually in a controlled laboratory environment, and studies of prevailing light conditions typical at home or work environments (21 studies). Studies were generally conducted on adults in their twenties or thirties, but only very few studies experimented on children and elderly adults. Surprisingly many studies were conducted with a small sample size: 39 out of 128 studies were conducted with 10 or less subjects. The quality criteria of studies for more profound synthesis were a minimum sample size of 20 subjects and providing details of the light exposure (spectrum or wavelength; illuminance, irradiance or photon density). This resulted to 13 qualified studies on melatonin and 2 studies on REM sleep. Further analysis of these 15 reports indicated that a two-hour exposure to blue light (460 nm) in the evening suppresses melatonin, the maximum melatonin-suppressing effect being achieved at the shortest wavelengths (424 nm, violet). The melatonin concentration recovered rather rapidly, within 15 min from cessation of the exposure, suggesting a short term or simultaneous impact of light exposure on the melatonin secretion. Melatonin secretion and suppression were reduced with age, but the light-induced circadian phase advance was not impaired with age. Light exposure in the evening, at night and in the morning affected the circadian phase of melatonin levels. In addition, even the longest wavelengths (631 nm, red) and intermittent light exposures induced circadian resetting responses, and exposure to low light levels (5-10 lux) at night when sleeping with eyes closed induced a circadian response. The review enables further development of an evaluation method of light pollution in LCA regarding the light-induced impacts on human circadian system. PMID- 30311831 TI - Electrosurgery: short-circuit between education and practice. AB - INTRODUCTION: Electrosurgery is used in 80% of surgical procedures. The technique allows surgeons to skilfully dissect tissues and achieve haemostasis. Since improper use of electrosurgery can lead to serious adverse events, training is required to potentially reduce the number and severity of these events. In this study we evaluate education and training in electrosurgery for surgical residents. MATERIAL AND METHODS: Residents from six surgical subspecialties in the Netherlands were invited to anonymously complete a digital questionnaire about training, supervision and adverse events regarding electrosurgery. RESULTS: Of the 197 respondents, 69% had received some form of training; mostly a single theoretical lecture. The feeling of competence in theory and practical skills was positively rated by 39% and 71%, respectively. Moreover, 35% judged the theoretical knowledge of their supervisors as insufficient and 65% changed their electrosurgical application technique to the preference of the supervisor. 30% of the residents had encountered a serious adverse event (e.g., burn wounds) related to the application of electrosurgery. CONCLUSIONS: The training of residents in theoretical aspects of electrosurgery is limited. Residents are not satisfied with the acquired theoretical knowledge of themselves and of their supervisors. Since adverse events related to electrosurgery occur frequently, more extensive education for both residents and their supervisors is needed to enhance patient safety. PMID- 30311832 TI - Black Sexual Minority Men's Disclosure of Sexual Orientation Is Associated With Exposure to Homonegative Religious Messages. AB - Previous research has highlighted the homonegative atmospheres of many religious communities in Western society and their harmful impact on Black sexual minority (SM) people's mental and physical health. However, few studies have examined the relationship between sexual orientation disclosure to church members and exposure to homonegative religious messages in religious settings. This online quantitative study investigated this relationship among a sample of 320 Black SM men. The participants for this study were recruited nationally from across the United States and had a mean age of 34 years. Descriptive statistics and linear regression analyses were conducted. Findings indicated that sexual orientation disclosure to church members was significantly associated with exposure to homonegative religious messages, even when controlling for geographic region of residence and denominational affiliation. Black SM men who had higher levels of disclosure were exposed to fewer homonegative religious messages. The implications of these findings for health research and clinical work with Black SM men are discussed in detail. PMID- 30311833 TI - Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma. AB - The receptor tyrosine kinase MET is frequently involved in malignant transformation and inhibiting its activity in MET-dependent cancers is associated with improved clinical outcomes. Emerging evidence also suggests that mitochondria play an essential role in tumorigenesis and Dynamin Related Protein (DRP1), a key component of the mitochondrial fission machinery, has emerged as an attractive therapeutic target. Here, we report that inhibiting MET activity with the tyrosine kinase inhibitor MGCD516 attenuates viability, migration, and invasion of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines in vitro, and significantly retards tumor growth in vivo. Interestingly, MGCD516 treatment also results in altered mitochondrial morphology in these cell lines. Furthermore, inhibiting MET pharmacologically or knocking down its expression using siRNA, decreases DRP1 activity alluding to possible crosstalk between them in these two cancers. Consistently, a combination of MGCD516 and mdivi-1, a quinazolinone reported to inhibit mitochondrial fission, is more effective in attenuating proliferation of NSCLC and MPM cell lines than either drug alone. Considered together, the present study has uncovered a novel mechanism underlying mitochondrial regulation by MET that involves crosstalk with DRP1, and suggests that a combination therapy targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM. PMID- 30311834 TI - Mean platelet volume and neutrophil to lymphocyte ratio as parameters to indicate the severity of suicide attempt. AB - This study was designed to compare the complete blood count (CBC) values of 38 violent suicidal attempt (VSA) and 38 nonviolent suicidal attempt (NVSA) patients and 38 healthy controls, particularly mean platelet volume (MPV) and neutrophil to lymphocyte ratio (NLR). MPV was found to be significantly higher (P = 0.000), and PLT was found to be significantly lower in the VSA group (P = 0.001). NLR was found to be significantly higher (P = 0.005) in the VSA group. The area under the receiver operating characteristic curve of MPV levels for VSA was 0.78 and 0.68 for NLR in the VSA group when compared with the NVSA group. PMID- 30311835 TI - Top Ten Tips for Palliative Care Clinicians Caring for Heart Failure Patients. AB - Heart failure (HF) is an increasingly prevalent condition with a very high symptom burden. To address challenges faced by palliative care clinicians, we assembled a team of experts to provide high-yield tips for the management of these patients. Prognosis is unpredictable in HF and many patients and physicians overestimate survival. Ejection fraction, notably, is not predictive of prognosis. It is important to have thorough discussions about implantable cardioverter defibrillators in terminally ill HF patients. Diuresis is the mainstay of managing volume overload and dyspnea in these patients and it is important to be aggressive and creative to achieve symptom relief. However, HF patients have a high burden of comorbidities and have many symptoms beyond dyspnea as well. Management in hospice remains challenging for these patients, with a significant risk for readmission to the hospital. Almost a quarter of HF patients discharged to hospice from the hospital die in less than three days. PMID- 30311836 TI - Human albumin purification: a modified and concise method. AB - BACKGROUND: Among different proteins of blood, albumin is considered a unique protein due to having special properties. Now, various protocols are used for the albumin purification worldwide, each of them has its own advantages and disadvantages. Meanwhile, a common method which is often used for the production of albumin is a combination of Cohn along with different types of chromatography. The aim of the present study was to create a concise and cost-effective albumin purification method by employing a conventional method with some modifications. METHODS: In this research, the albumin was purified from human serum using chilled ethanol, followed by chromatographic methods. The purity of harvested albumin was evaluated by cellulose acetate membrane electrophoresis (CAME) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Western blotting (WB) analysis and thermostability were used for functional and stability measurement assessment, respectively. RESULTS: SDS-PAGE and CAME showed that the purity of purified human albumin was about 99%. Purified human albumin showed a single band with a molecular weight of 66 kDa. The results were validated by WB analysis .Also, the thermostability of purified albumin was same as the commercial albumin. CONCLUSION: This method can be a robust technique for purification of albumin in order to use clinical and research approaches. PMID- 30311837 TI - Oral kinematics: examining the role of edibility and valence in the in-out effect. AB - Previous research has revealed a stable preference for words with inward consonantal-articulation patterns (from the front to the back of the mouth; e.g. BENOKA), over outward-words (from the back to the front; e.g. KENOBA). Following the oral approach-avoidance account suggesting that the in-out effect is due to the resemblance between consonantal-articulations patterns and ingestion/expectoration, recent findings have shown that when judging inward outward names for objects with particular oral functions, valence did not modulate the effect while the oral function did. To replicate and examine further the role of edibility and valence in shaping the in-out effect, we asked participants (N = 545) to rate inward and outward names for edible and non-edible products while controlling for valence. Results revealed that the motor-to-affect link was only observed for edible products, regardless of valence. PMID- 30311838 TI - Twitches, Blinks, and Fidgets: Important Generators of Ongoing Neural Activity. AB - Animals and humans continuously engage in small, spontaneous motor actions, such as blinking, whisking, and postural adjustments ("fidgeting"). These movements are accompanied by changes in neural activity in sensory and motor regions of the brain. The frequency of these motions varies in time, is affected by sensory stimuli, arousal levels, and pathology. These fidgeting behaviors can be entrained by sensory stimuli. Fidgeting behaviors will cause distributed, bilateral functional activation in the 0.01 to 0.1 Hz frequency range that will show up in functional magnetic resonance imaging and wide-field calcium neuroimaging studies, and will contribute to the observed functional connectivity among brain regions. However, despite the large potential of these behaviors to drive brain-wide activity, these fidget-like behaviors are rarely monitored. We argue that studies of spontaneous and evoked brain dynamics in awake animals and humans should closely monitor these fidgeting behaviors. Differences in these fidgeting behaviors due to arousal or pathology will "contaminate" ongoing neural activity, and lead to apparent differences in functional connectivity. Monitoring and accounting for the brain-wide activations by these behaviors is essential during experiments to differentiate fidget-driven activity from internally driven neural dynamics. PMID- 30311839 TI - Comparing physical activity estimates in children from hip-worn Actigraph GT3X+ accelerometers using raw and counts based processing methods. AB - This study examined differences in physical activity (PA) estimates provided from raw and counts processing methods. One hundred and sixty-five children (87 girls) wore a hip-mounted ActiGraph GT3X+ accelerometer for 7 days. Data were available for 129 participants. Time in moderate PA (MPA), vigorous PA (VPA) and moderate vigorous PA (MVPA) were calculated using R-package GGIR and ActiLife. Participants meeting the wear time criteria for both processing methods were included in the analysis. Time spent in MPA (-21.4 min.d-1, 95%CI -21 to -20) and VPA (-36 min.d-1, 95%CI -40 to -33) from count data were higher (P < 0.001) than raw data. Time spent in MVPA between the two processing methods revealed significant differences (All P < 0.001). Bland-Altman plots suggest that the mean bias for time spent in MPA, VPA and MVPA were large when comparing raw and count methods. Equivalence tests showed that estimates from raw and count processing methods across all activity intensities lacked equivalence. Lack of equivalence and poor agreement between raw and count processing methods suggest the two approaches to estimate PA are not comparable. Further work to facilitate the comparison of findings between studies that process and report raw and count physical activity data may be necessary. PMID- 30311840 TI - Health Practitioners' Perceptions of Falls and Fall Prevention in Older People: A Metasynthesis. AB - Fall prevention has received a great deal of consideration and funding, however fall rates have not reduced accordingly. Health practitioners are key stakeholders in the process of implementing fall prevention evidence into their clinical assessment and management of older people at risk of falling. Investigating health practitioners' clinical experiences and perceptions has been identified as a means to enhance the translation of knowledge. Four databases were searched for studies exploring health practitioners' perceptions of falls and fall prevention. A metasynthesis of eight qualitative studies was conducted. The findings suggest that health practitioners face substantial barriers in the implementation of fall prevention practices. These include personal, interpersonal, and clinical barriers in addition to limitations of the research evidence. This knowledge hopes to enhance targeted dissemination of knowledge, reducing the research-practice gap and improving clinical outcomes for older people at risk of falls. PMID- 30311841 TI - "I Gotta Go With Modern Technology, So I'm Gonna Give 'em the Narcan": The Diffusion of Innovations and an Opioid Overdose Prevention Program. AB - Fatal opioid overdoses can be prevented by opioid overdose prevention programs (OOPPs). The present study qualitatively examined the diffusion process of an OOPP among 30 persons who inject drugs (PWIDs) in an opioid-saturated community. Purposive sampling was used to recruit participants into three groups based on familiarity with the OOPP. Findings revealed that participants often adopted the OOPP, which was offered by a local harm reduction organization, if first exposed by staff hosting and implementing it. Barriers to adoption included belief that OOPP training was lengthy or unnecessary, lack of perceived relative advantage, nonengagement with the host organization, and trepidation of administering withdrawal-causing medication to fellow PWIDs. Participants outside of networks diffusing the OOPP were isolated from other PWIDs. Staff from the host organization were influential in encouraging OOPP adoption, which underscores their importance in the effort to reduce fatal overdoses. PMID- 30311842 TI - Effects of Low-to-Moderate Doses of Gamma Radiation on Mouse Hematopoietic System. AB - In this study, we investigated the effects of low-to-moderate doses of radiation in mice, given our limited understanding of the health risks associated with these exposures. Here, we demonstrate the different responses of the CD2F1 mouse hematopoietic system to low-to-moderate (0.5, 1, 3 or 5 Gy) doses of gamma radiation. After 3 and 5 Gy of 60Co total-body irradiation (TBI), mouse blood cell counts were decreased and maintained below baseline up to 28-42 days. In contrast, after 0.5 Gy TBI, lymphocyte and monocyte counts increased, and peaked from day 3 to day 14. Radiation doses at 0.5 and 1 Gy did not cause cell death or T-cell subpopulation changes in spleen and thymus, whereas the clonogenicity of mouse bone marrow (BM) progenitor cells was significantly suppressed on the first day after 0.5-5 Gy TBI, and these low levels were maintained up to 42 days. Although a transient recovery in total colony forming units (CFUs) was shown in mouse BM at days 14 and 21 after 0.5 Gy TBI, the early-stage multipotential progenitor colonies (CFU-GEMM) remained at a significantly low level compared to those of the sham-irradiated (0 Gy) controls. Consistently, the level of stem cell factor (SCF) in BM cells was decreased after low-to-moderate TBI. Serum from individual mice was collected after irradiation and 23 cytokines/chemokines were measured; massive releases of cytokines and chemokines were observed at day 3 postirradiation in a dose-dependent manner. When human hematopoietic CD34+ cells were cultured with the serum collected from mice irradiated at different doses, a significant decrease of CFU-GEMM colonies in the CD34+ cells was observed. Our data suggest that low-to-moderate doses of radiation induced cellular responses that are cell type-dependent. The early stage multipotential progenitor cells in mouse BM were the most sensitive cells even to low-dose irradiation compared to spleen and thymic cells, and 0.5 Gy TBI induced hematopoietic cell injury from day 1 to the end of our experiment, day 42 postirradiation. Radiation-induced decrease of SCF in mouse BM and increase in circulating pro-inflammatory factors may be responsible for the enhanced sensitivity of hematopoietic progenitor cells to radiation. PMID- 30311843 TI - Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery. AB - Hyperinsulinemic hypoglycemia syndrome (HIHG) is a rare complication of roux-en-Y gastric bypass surgery. The pathology is associated with an excessive function of pancreatic beta-cells, and requires pancreas resection in patients that are recalcitrant to nutritional and pharmacological interventions. The exact prevalence is not clearly understood and the underlying mechanisms not yet fully characterized. We herein sought to perform histological and molecular examination of pancreatic sections obtained from a patient who developed HIHG as a complication of gastric bypass compared to 3 weight-matched controls. We studied markers of cellular replication and beta-cell differentiation by immunohistochemistry and immunofluorescence. HIHG after gastric bypass was characterized by a profound increase in beta-cell mass. Cellular proliferation was increased in islets and ducts compared to controls, suggesting unrestrained proliferation in HIHG. We also detected beta-cell differentiation markers in duct cells and occasional duct cells displaying both insulin and glucagon immunoreactivity. These histological observations suggest that beta-cell differentiation from ductal progenitor cells could also underly beta-cell mass expansion in HIHG. Altogether, our results can be construed to demonstrate that HIHG after gastric bypass is characterized by abnormal beta-cell mass expansion, resulting from both unrestrained beta-cell replication and neogenesis. PMID- 30311844 TI - Dosimetry of a Carbon Dioxide Laser for Black Tattoo Removal in a Rat Model. AB - OBJECTIVE: To determine the optimal parameters of power, energy, and time for the application of a carbon dioxide laser for Tribal Black ink tattoo removal. BACKGROUND DATA: The use of antiquated techniques to remove tattoos demonstrates the difficulty of making advances in this field. Studies by the American Society for Dermatologic Surgery have shown that 5% of the global population has at least one tattoo on the body, with 10% of them wanting a tattoo to be removed. Laser removal has been studied and improved as a less invasive and safer method of surgical removal; however, the ideal dosimetry is not yet established. MATERIALS AND METHODS: Thirty-three male Wistar rats were anesthetized and tattooed in the dorsal region in a quadrangular manner. The rats were distributed under low/null luminosity for 4 months into three equal and random groups for the application of the laser, namely, G1 (P = 0.6 W, Et = 0.9 J), G2 (P = 0.8 W, Et = 1, 2 J), and G3 (P = 1 W, Et = 1.5 J), with the application time standardized to 0.15 sec with 10 passes per application. The procedure was repeated at intervals of 4 weeks until 10 cycles of laser application were completed. The images were studied using the ImageJ program and histological analysis and subjected to the one-way ANOVA test for Tukey's multiple comparison post-test. RESULTS: We observed a significant difference between groups 1 and 3 and between groups 2 and 3. CONCLUSIONS: The laser with the parameters of P = 1 W, Et = 1.5 J, and t = 0.15 sec yields better Tribal Black ink removal results. PMID- 30311845 TI - Age Dependence of Radiation-Induced Genomic Instability in Mouse Hematopoietic Stem Cells. AB - Age at exposure is a critical factor that influences the risk of radiation induced leukemia. Accumulating evidence suggests that ionizing radiation can induce genomic instability and promote leukemogenesis in hematopoietic stem cells (HSCs); however, the influence of age on this phenomenon has not been elucidated. In this study, infant (1-week-old) or adult (14-week-old) C3H/He mice received sham or 4 Gy whole-body irradiation, and bone marrow cells were transplanted to recipients at day 1 or 60 postirradiation. Twelve days after bone marrow transplant, we analyzed the radiation-induced genomic instability by scoring the frequency of DNA damage and micronucleus formation in colony-forming units-spleen (CFU-Ss). We observed significant increases in DNA damage and micronucleus formation in CFU-Ss of the 4 Gy irradiated adult cells transplanted at day 1 or 60 postirradiation. However, the frequency of DNA damage focus and micronucleus formation in CFU-Ss of 4 Gy irradiated infant cells transplanted at day 1 or 60 postirradiation was relatively decreased. Quantitative differences in the reactive oxygen species and cells expressing inducible nitric oxide synthase in CFU-Ss suggested that age-dependent radiation-induced genomic instability may result from chronic oxidative stress by pro-inflammatory states in HSC descendants after radiation exposure. PMID- 30311846 TI - Skin-controlled release lipid nanosystems of pranoprofen for the treatment of local inflammation and pain. AB - AIM: The design and development of pranoprofen (PF) nanostructured lipid carriers (NLCs) for topical treatment of local inflammation and pain. MATERIALS & METHODS: PF-NLCs were designed and optimized by central rotatable composite design. A physicochemical characterization was addressed. Release and skin permeation were performed in Franz diffusion cells. In vivo anti-inflammatory efficacy was assayed in mice and tolerance study in humans. RESULTS: PF-NLCs F7 and F10 provided sustained release, good stability and optimal skin retention avoiding systemic undesired side effects. Anti-inflammatory activity was enhanced, suggesting an improved efficacy as compared with standard formulation. No skin irritancy was detected. CONCLUSION: Topical PF-NLCs F7 and F10 could be effective and safe new therapeutic tools for the treatment of local inflammation and pain. [Formula: see text]. PMID- 30311847 TI - Diabetes Is Associated with Cognitive Decline in Middle-Aged Patients. AB - BACKGROUND: Diabetes is a major contributor to dementia in the elderly. Identifying mild cognitive decline in younger individuals with diabetes could aid in preventing the progression of the disease. The aim of our study is to compare whether patients with diabetes experience greater cognitive decline than those without diabetes. METHODS: We conducted a cross-sectional study using population based recruitment to identify a cohort of individuals with diabetes and corresponding control group without diabetes of 55-65 years of age. We defined diabetes according to the American Diabetes Association and conducted a battery of standardized neuropsychological tests consisting of nine verbal and nonverbal tasks assessing three cognitive domains. We defined cognitive decline as an abnormal test in one or more of the domains. We used hierarchical regression to predict abnormal cognitive function by diabetes status, adjusting for gender, education, hypertension, and depression. RESULTS: We included 142 patients with diabetes and 167 control group patients. Those with diabetes had a mean age of 59 +/- 4 years, 54% were women, the mean education level was 11 +/- 4.5 years of schooling, and their hemoglobin A1c was 8.6 +/- 2.5. They had an overall lower mean of all five executive function measures, all seven attention measures, and all five memory measures (P < 0.05). In multivariate analyses, all executive function beta coefficients for diabetes were significant, whereas attention had four out of seven and memory had four out of five. CONCLUSIONS: Diabetes is associated with cognitive decline in younger patients with diabetes. Preventive strategies should be developed for the prevention of dementia in younger populations. PMID- 30311848 TI - An Intimate Partner Violence Prevention Intervention in a Nurse Home Visitation Program: A Randomized Clinical Trial. AB - BACKGROUND: Intimate partner violence (IPV) is a significant public health problem with many negative consequences, particularly for pregnant women. This randomized trial investigated the effectiveness of an IPV preventive intervention embedded within the Nurse Family Partnership (NFP) program. MATERIALS AND METHODS: Participants enrolled over a 20-month period and were interviewed at baseline and 1- and 2-year follow-up. Eligibility criteria included first pregnancy, eligible for the nutrition program Women, Infants, and Children (WIC), English or Spanish speaking, and at least 15 years of age. All women initially referred and screened were randomized to either intervention (NFP+) or control (NFP only) condition. The final sample consisted of 238 women completing baseline assessments; retention was 81% at 2-year follow-up. RESULTS: Analyses indicated that there were no main effects: the intervention affected participants differently depending on their baseline experience with IPV. For physical violence victimization, an interaction between baseline victimization and treatment was found; the intervention reduced victimization at 1 year (and approached significance at 2 years), but only among women who had not experienced past-year physical victimization at baseline. For sexual violence victimization, another interaction emerged; women in the intervention group were more likely to report sexual violence victimization at 2-year follow-up, but only among participants who had reported sexual victimization at baseline. The only effect on IPV perpetration was psychological perpetration at 2-year follow-up; again, the treatment effect was moderated by baseline perpetration. The intervention reduced psychological perpetration for participants who were nonperpetrators at baseline, but had no effect on those reporting perpetration. CONCLUSIONS: Overall, findings suggest that the intervention was effective in reducing some forms of violence among those not experiencing IPV at baseline, but was ineffective or potentially harmful for those already experiencing IPV. PMID- 30311849 TI - Nonsurgical Periodontal Treatment by Erbium:Yag Laser Promotes Regression of Gingival Overgrowth in Patient Taking Cyclosporine A: A Case Report. AB - OBJECTIVE AND BACKGROUND: To report on a case of cyclosporine A-related gingival overgrowth (GO) treated by conventional scaling and Erbium:YAG laser that unexpectedly showed complete healing with normalization of the gingiva, making unnecessary further surgical treatment for gingival volume reduction. Since Erbium:YAG laser was approved in 1997 by the U.S. Food and Drug Administration for hard and soft tissue treatments in dentistry, several studies have been published to demonstrate its efficacy for bone cutting, plaque and subgingival calculus removal, and antiseptic effects both on soft and hard periodontal tissues. METHODS: We report herewith the case of a patient undergoing cyclosporine A therapy, affected by GO who underwent scaling and full mouth disinfection with chlorhexidine 2% rinses, followed by Erbium:YAG laser treatment of gingival pseudopockets, without surgical removal of the overgrown gingiva. RESULTS: Unexpectedly, complete healing of the periodontal tissues was observable after one single laser application and no adjunctive surgical procedure was necessary. CONCLUSIONS: Erbium:YAG laser could be considered a really effective option for the nonsurgical treatment of drug-induced GO, avoiding the surgical procedures and also promoting a fast healing and a patient compliance surely higher than conventional techniques. PMID- 30311850 TI - Mediation analyses of Internet-facilitated cognitive behavioral intervention for maternal depression. AB - This study evaluated the putative mediating mechanisms of an Internet-facilitated cognitive-behavioral therapy (CBT) intervention for depression tailored to economically disadvantaged mothers of preschool-age children. The CBT mediators were tested across two previously published randomized controlled trials which included the same measures of behavioral activation, negative thinking, and savoring of positive events. Trial 1 included 70 mothers with elevated depressive symptoms who were randomized to either the eight-session, Internet-facilitated intervention (Mom-Net) or to treatment as usual. Trial 2 included 266 mothers with elevated depressive symptoms who were randomized to either Mom-Net or to a motivational interviewing and referral to services condition. Simple mediation models tested each putative mediator independently followed by tests of multiple mediation that simultaneously included all three mediators in the model to assess the salient contributions of each mediator. The pattern of results for the mediating effects were systematically replicated across the two trials and suggest that behavioral activation and negative thinking are salient mediators of the Mom-Net intervention; significant mediating effects for savoring were obtained only in the simple mediation models and were not obtained in the multiple mediation models. PMID- 30311851 TI - Imaging findings in spinal sarcoidosis: a report of 18 cases and review of the current literature. AB - Purpose Spinal sarcoidosis, referring to involvement of the spine in sarcoidosis, is relatively rare and may mimic other neurological disease affecting the spine. The authors present a clinic radiological review of 18 spinal sarcoidosis patients who presented to a tertiary hospital, with emphasis on initial imaging and radiological response to treatment. Materials and methods We retrospectively reviewed our departmental imaging archives over a 15-year period and found 49 cases of neurosarcoidosis out of which 18 patients had spinal magnetic resonance imaging. Results Approximately 72% (13/18) of the neurosarcoidosis patients showed some form of spinal involvement. The clinical, epidemiological and imaging data were reviewed for these 13 patients at presentation and follow-up. The findings on magnetic resonance imaging included leptomeningeal enhancement (61%), pachymeningeal (23%), intramedullary enhancing lesions (38%) and bony involvement (15%). The cervical segment was most frequently involved followed by the thoracic segment. Involvement was often long segment (4.2 spinal segments) with proclivity for the dorsal cord. Mean follow-up was 23.2 months. A complete or near-complete radiological response occurred in 66% while partial response was seen in 25% patients. Four patients had isolated central nervous system involvement including one with isolated spinal cord involvement. On diffusion-weighted imaging, the apparent diffusion coefficient of intramedullary lesions was increased compared to normal-appearing cord on baseline and subsequent follow-up scans. Conclusions Spinal sarcoidosis was previously considered uncommon but is being increasingly recognized with widespread use of magnetic resonance imaging. Proclivity for dorsal surface involvement is characteristic, although not necessarily pathognomonic. Also, quantitative diffusion studies may serve as a biomarker for the disease activity and parenchymal injury. PMID- 30311852 TI - General practice registrars' clinical exposure to dermatological procedures during general practice training: a cross-sectional analysis. AB - Australian general practitioners (GPs) commonly manage dermatological conditions requiring procedures. GP registrars have limited pre-vocational training exposure to dermatology and find skin problems challenging. We aimed to establish the prevalence, nature and associations of GP registrars' performance of skin procedures. We conducted a cross-sectional analysis from the Registrar Clinical Encounters in Training cohort study. Multivariable logistic regression was used to establish associations of our outcome (skin procedures, both including and excluding cryotherapy). Independent variables included patient and doctor demographics, diagnoses/problems managed and registrars' recourse to in consultation assistance/information. A total of 1161 registrars provided data on 166,988 consultations, recording 2927 skin procedures (16.7% of all procedures; performed in 1.7% of consultations). Cryotherapy, excision, punch biopsy and shave biopsy were most common. More complex procedures were performed infrequently. Significant associations of performing procedures included rural/remote location (compared to major city), male patients, patient age 65+ (compared to age 15-34) and registrars seeking in-consultation information/assistance. Skin procedures were less likely for Aboriginal patients or those from non-English-speaking backgrounds. For non-cryotherapy procedures, rurality was not significantly associated, but significant differences were found between training regions. In summary, GP registrars perform fewer dermatological procedures compared to established GPs. Findings will inform GP vocational training in skin procedures. PMID- 30311853 TI - GMSC-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration. AB - A fully functional recovery of peripheral nerve injury remains a major challenge and an unmet clinical need. Recent evidence has reported promising therapeutic effects of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in experimental models of tissue injuries and inflammatory diseases, but less is known about their effects on peripheral nerve regeneration. Here, we investigated the effects of GMSC-derived EVs on peripheral nerve regeneration of crush-injured mice sciatic nerves. In vivo studies mimicking clinical nerve repair showed that locally wrapping gelfoam embedded with GMSC-derived EVs at the crush injury site promoted functional recovery and axonal regeneration, which were comparable to effects conferred by direct transplantation of GMSCs. Mechanistically, we showed that GMSC-derived EVs promoted proliferation and migration of Schwann cells, upregulated the protein expressions of c-JUN, Notch1, GFAP, and SOX2, characteristic genes of dedifferentiation or repair phenotype of Schwann cells, whereby pharmacologically blocking c-JUN/JNK activity significantly abrogated GMSC-derived EV induced upregulation of these Schwann cell dedifferentiation/repair phenotype-related genes. These findings suggest that GMSC-derived EVs promote peripheral nerve regeneration possibly by activating c JUN-governed repair phenotype of Schwann cells. PMID- 30311854 TI - Correction. PMID- 30311855 TI - In situ photocrosslinked hyaluronic acid and poly (gamma-glutamic acid) hydrogels as injectable drug carriers for load-bearing tissue application. AB - Due to the syringeability of precursor solution and convenience of open surgical treatment, injectable hydrogels have gained growing attention in drug delivery application. For load-bearing tissue, the excellent mechanical property is an important requirement for delivery vehicles to resist external stress and loads. Herein, we prepared mechanically robust injectable hydrogels (HA/gamma-PGA hydrogels for short) using methacrylate-functionalized hyaluronic acid and poly (gamma-glutamic acid) via photopolymerization. The HA/gamma-PGA hydrogels showed outstanding anti-compression ability and could suffer a more than 80% strain. Meanwhile, after 5 cycles of compression, HA/gamma-PGA hydrogels could still recover quickly against external stress, showing excellent shape recovery capability. Moreover, the mechanical properties could be modulated easily by changing the molar ratio of HA to gamma-PGA. The drug release behavior was also evaluated and the drug-loaded HA/gamma-PGA hydrogels showed a weak burst release and sustained release behavior. Additionally, HA/gamma-PGA hydrogels also exhibited superior biocompatibility. Therefore, HA/gamma-PGA hydrogels have great potential as injectable drug carriers for load-bearing tissue application. PMID- 30311856 TI - Regional Influences on Nutritional Iodine Status of Pregnant Women in Pakistan. AB - BACKGROUND: Pregnant women are particularly vulnerable to iodine deficiency. Considering the rural-urban disparities in nutritional status in Pakistan, this study aimed to assess regional influences on nutritional iodine status of pregnant women in Pakistan. METHODS: Data were collected from 1246 pregnant women in all trimesters of pregnancy who visited antenatal clinics for routine checkups in five Khyber Pakhtunkhwa province districts. Information concerning iodized salt intake and knowledge of iodine deficiency disorders (IDD) was obtained through an interview questionnaire. Goiter and urinary iodine concentration (UIC) levels were assessed by the palpation method and Sandell-Kolthoff reaction, respectively. Logistic regression analysis was used to quantify associations between residence (rural-urban), pregnancy trimester, and previous pregnancy outcomes with knowledge about IDD, iodized salt intake, presence of goiter, and UIC <150 MUg/L. RESULTS: Among study participants, 87.7% had no knowledge about IDD, and only 21.0% were consuming iodized salt. Goiter was present in 25.5% of the women. The median UIC level was 131 MUg/L, and 41.3% of study participants had a UIC >=150 MUg/L. There were no significant differences between pregnant women from rural and urban settings in regions with a solid socioeconomic status with respect to knowledge about IDD, iodized salt intake, iodine deficiency, and goiter prevalence. Urban-rural differences were observed only in socioeconomically disadvantaged districts. Only pregnant women living in the Lakki Marwat district had higher odds of having knowledge of IDD and iodized salt intake than those from rural regions. Trimesters of pregnancy and previous pregnancy outcomes had no significant effect on the outcome measures. CONCLUSIONS: Relative to a national nutrition survey conducted in Pakistan in 2011, the results from this study indicate that UIC levels remained stable with mild iodine deficiency, whereas rates of goiter and iodized salt intake remained high and low, respectively, especially in rural areas. Rural-urban disparities were observed only in socioeconomically disadvantaged districts, and these disparities limit the effectiveness of the IDD prevention program in rural areas in Pakistan. Thus, implementation of mandatory salt iodization requires improvement, and program effectiveness should be continuously monitored to prevent adverse health effects of iodine deficiency during pregnancy. PMID- 30311857 TI - Effect of the Bone Morphogenetic Protein-2 Doses on the Osteogenic Potential of Human Multipotent Stromal Cells- Containing Tissue Engineered Constructs. AB - The addition of bone morphogenetic protein-2 (BMP-2) with multipotent stromal cells (MSC) is an attractive strategy to enhance the bone-forming potential of MSC-based tissue engineering (TE) constructs. However, the effective dosage of BMP-2 remains to be determined. In this study, we evaluated the effects of human MSCs codelivered with BMP-2 at either low or high dosage on the bone-forming potential of constructs in a mice ectopic model. Our results showed that the addition of only low dose of BMP-2 was beneficial to enhance the bone-forming potential of MSCs, whereas high dose of BMP-2 overcame the advantage of combining this growth factor with MSCs. Expressions of select genes of both murine and human origins in TE constructs demonstrated that the beneficial effect of low dose of BMP-2 with implanted human MSCs did not involve enhanced differentiation of these cells into osteoblasts or induction of paracrine cues but rather involved induction of the osteogenic differentiation of the host progenitors. Therefore, the advantage of combining BMP-2 with MSCs to enhance the bone-forming potential of TE constructs appeared to be an additive effect of both components rather than a synergistic one. PMID- 30311858 TI - Bio-based covered stents: the potential of biologically-derived membranes. AB - Endovascular treatment using bare metal stents or drug eluting stents is routinely performed to restore the blood flow in the coronary and peripheral arteries; however, intimal hyperplasia and late stent thrombosis are still major issues leading to stent failure and often to the need for re-intervention. Covered stents have emerged as an alternative approach to avoid intimal hyperplasia. They are characterized by the presence of a membrane that spans the struts of the stent and acts as a physical barrier to block the ingrowth of the neointimal tissue into the lumen. Currently used membrane-materials include mainly synthetic polymers. Their main limitation is their lack of hemocompatibility, which can induce thrombosis and ultimately reocclusion, thus impairing the long-term performance of these devices. To overcome this issue, the use of biologically-derived materials has been proposed with the aim of enhancing the biocompatibility and the capability of this type of stents to support endothelialization. The aim of this review is to give a comprehensive overview of the applications of bio-based covered stents as well as the different strategies followed for their development from the perspective of the material selection, fabrication approaches and validation of the different concepts in animal and clinical trials. PMID- 30311859 TI - Human testis extracellular matrix enhances human spermatogonial stem cell survival in vitro. AB - Successful human spermatogonial stem cell (hSSC) culture could enable cell therapy for male infertility. Mammalian extracellular matrix (ECM) promotes mitogenesis, migration, and/or differentiation of various stem/progenitor cells and can plausibly facilitate hSSC survival in culture. Hydrogel forms of human testicular ECM (htECM), porcine testicular ECM (ptECM), porcine small intestinal submucosa ECM (SIS), and porcine urinary bladder ECM (UBM) were used to coat tissue culture plates for hSSC culture. In addition, hSSC were cultured on Sandos inbred mice (SIM) 6-thioguanine-resistance, ouabain-resistant (STO) mouse embryonic fibroblast feeder cells (control), murine laminin, or human laminin. Undifferentiated embryonic cell transcription factor 1-positive (UTF1+) human spermatogonia were quantified at days 0, 7, and 14 of culture. htECM was the only condition that retained a significantly higher number of UTF1+ cells than control STO feeder cell cultures (22% vs 3%). Overall, the number of hSSC declined during the 14 day culture period under all conditions. A multiparameter flow cytometry analysis of cells cultured on htECM and ptECM revealed that Stage-specific embryonic antigen 4 (SSEA4)+ undifferentiated spermatogonia may be lost to differentiation (cKIT+ spermatogonia) and apoptosis (annexin V+ spermatogonia). Proliferation of undifferentiated human spermatogonia (Ki67+) was limited suggesting that hSSCs may have different growth factor requirements than mouse SSCs. ECM from the homologous species (human) and homologous tissue (testis) was most effective substrate for hSSC and establishes a foundational feeder free, serum free condition for future iterative testing of culture conditions toward the long-term goal of stable hSSC cultures. PMID- 30311860 TI - Human Tissue-Engineered Model of Myocardial Ischemia-Reperfusion Injury. AB - Ischemia-reperfusion injury (IRI) is a major, but potentially preventable contributor to the final tissue damage after an acute myocardial infarction. Many therapies have demonstrated successful reduction of IRI in preclinical settings, but none has shown improved outcomes in clinical studies. Part of the failure to translate new therapies to clinical settings can be attributed to the reliance on small animal models in preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not necessarily recapitulate human physiology. In this study, we utilized cardiac tissue engineering methods and cardiomyocytes derived from human induced pluripotent stem cells to establish a human tissue-engineered model of IRI. The resulting cardiac constructs were subjected to conditions that simulated ischemia reperfusion. We demonstrated the presence of reperfusion injury and the ability to distinguish ischemic and reperfusion injury. We also demonstrated reductions in IRI following ischemic preconditioning, modification of reperfusion conditions, and addition of cardioprotective therapeutics. This study establishes the utility of a human tissue model for studying key aspects of IRI and the potential for improving translation of therapeutic strategies into the clinical setting. PMID- 30311861 TI - The (re)productive work of labour migration: the reproductive lives of women with an absent spouse in the central hill region of Nepal. AB - Limited attention has been given to the effects of labour migration on the reproductive lives of women 'left behind' as their partners travel for work. Drawing on two rounds of qualitative interviews with 20 women in the central hill region of Nepal, this paper examines how global economic processes that lead Nepali men to travel for work also affect women's reproductive work, including childrearing and reproductive decision-making. Women understood their husband's migration to engage in the wage economy as a response to both immediate and long term goals for their children and family. As a result, such productive work was intrinsically linked to reproductive work. Men's migration patterns played a pivotal role in reinforcing women's immediate childrearing roles and affecting whether and when women used a contraceptive method and what methods they considered. During periods of spousal migration, women's reproductive lives became targets of gossip and rumours as their intimate and reproductive practices and use of remittances were socially monitored. This complex understanding of women's lived experiences at the nexus of (re)productive work and labour migration can be practically applied to address the reproductive health needs of women with migrant spouses in Nepal. PMID- 30311862 TI - Diagnostic Performance of Ultrasound-Based Risk-Stratification Systems for Thyroid Nodules: Comparison of the 2015 American Thyroid Association Guidelines with the 2016 Korean Thyroid Association/Korean Society of Thyroid Radiology and 2017 American Congress of Radiology Guidelines. AB - PURPOSE: The aim of this study was to compare the diagnostic performance of ultrasound (US)-based risk-stratification systems for thyroid nodules in the 2015 American Thyroid Association (ATA) guidelines with those of the 2016 Korean Thyroid Association (KTA)/Korean Society of Thyroid Radiology (KSThR) and 2017 American Congress of Radiology (ACR) guidelines. METHODS: From June 2013 to May 2015, a total of 902 consecutive thyroid nodules were enrolled in four institutions, and their US features were retrospectively reviewed and classified using the categories defined by the three guidelines. The malignancy risk of each category, as defined by all three risk-stratification systems, was calculated, and the diagnostic performance of the fine-needle aspiration (FNA) indications of the ATA guidelines were compared to those of the KTA/KSThR and ACR guidelines. RESULTS: Of all nodules, 636 (70.5%) were benign and 266 (29.5%) malignant. The calculated malignancy risks for ATA categories 5, 4, 3, 2, and 1 nodule(s) were 71.7, 21.5, 2.6, 3.8, and 0%. Of all nodules, 7.6% (69/902) did not meet the ATA pattern criteria, but the malignancy risk was calculated to be 10.1% (7/69). The ATA guidelines afforded significantly higher diagnostic sensitivity (95.0%) than the ACR guidelines (80.2%; p = 0.001) but a lower specificity (38.1 vs. 68.9%; p < 0.001). On the other hand, the ATA guidelines exhibited a lower diagnostic sensitivity than the KTA/KSThR guidelines (100.0%; p = 0.07) but a higher specificity (28.2%; p < 0.001). The unnecessary FNA rate was the lowest when the ACR guidelines were used (25.8%), followed by the ATA (51.2%) and KTA/KSThR (59.4%) guidelines. CONCLUSION: The 2015 ATA guidelines afford relatively moderate sensitivity and an unnecessary FNA rate for thyroid cancer detection compared to the 2016 KTA/KSThR and 2017 ACR guidelines. US practitioners require a deep understanding of the benefits and risks of the US-based FNA criteria of different guidelines and potential impact on the diagnosis of low-risk thyroid cancers. PMID- 30311863 TI - Landscape of pain in Parkinson's disease: impact of gender differences. AB - BACKGROUND/AIMS: Pain is a non-motor symptom of Parkinson's disease (PD). Few systematic studies have been carried out and there are still no guidelines on pain therapy in PD. Additionally, within the studies that do exist, gender specific differences in pain perception are often the focus, though no consistent results have to date been obtained. The first main aim of our study was therefore to map pain in the largest PD study group to date, with the second being the analysis of the impact of different pain therapies in PD. The third and main aim was to correlate the obtained results with gender. METHODS: A structured questionnaire with questions focusing on pain was sent to PD patients, with a subsequent statistical analysis correlating the data on pain features and pain therapy with gender. RESULTS: The study included 1204 female and 1610 male PD patients. Spinal-paravertebral pain emerged as the dominant form of pain. A significant correlation was further demonstrated between gender and pain localization, pain intensity (p-value < 0.05), and pain as impairment to quality of life (p-value < 0.05). Nonsteroidal anti-inflammatory drugs were the painkillers most frequently used by the patients. Aside from non-opioid analgesics (p-value < 0.05), there was no demonstrated significant correlation between pain treatments and gender. CONCLUSION: This study found that gender influenced pain perception in the PD patients tested but did not impact the approach to pain therapy. PMID- 30311864 TI - Assessment of functional nanomaterials in medical applications: can time mend public and occupational health risks related to the products' fate? AB - Surface coatings are one promising option to prevent bacterial adhesion and biofilm formation given the prevalence of antibiotic resistant bacterial strains. Titanium dioxide (TiO2) is presently considered to be the only photocatalytic material suitable for commercial use, although the toxicity risks of TiO2, particularly in its nanoparticulate form, have not been fully addressed. The aim of this study was to determine release of nanoparticles (NPs) from functional materials for medical applications and their aerosol formation. Further, the fate of the material with respect to its product lifetime was investigated. The present study examined the risk of NP exposure since released submicronic and inhalable manufactured nano-objects, their agglomeraates or aggregates containing Ti were detected. The coating of the material magnifies its emission levels when comparing the obtained product properties to those of an uncoated sample. The evolution of release tendecy with the material's time of use shows that release does not vanish upon continuous material losses induced by the release, thus the risk does not diminish with time. Consequently, this nanomaterial TiO2 needs to be avoided in healthcare settings, or, alternatively, new TiO2-deposition techniques are required to be developed. PMID- 30311865 TI - Keyhole approaches for surgical treatment of intracranial aneurysms: a short review. AB - OBJECTIVE: To clarify the reported experience with keyhole approaches for the treatment of intracranial aneurysms. METHODS: The PubMed and Embase databases were searched up to December 2017 for full-text publications that report the treatment of aneurysms with the eyebrow variant of the supraorbital craniotomy (SOC), the minipterional craniotomy, or the eyelid variant of the SOC. The anatomical distribution of aneurysms, the postoperative aneurysm occlusion rate, and the type and rate of complications were examined using univariate analysis. RESULTS: Sixty-seven publications covering treatment of 5770 aneurysms met the eligibility criteria. The reported experience was the largest for the eyebrow variant of the SOC (69.4% of aneurysms), followed by the minipterional approach (28.2%), and the eyelid variant of the SOC (2.4%). The anterior communicating artery (ACoA) was the most frequent aneurysm location for the SOC (eyebrow variant: 33.2%; eyelid variant: 31.2%). The middle cerebral artery (MCA) was the most frequent aneurysm location in the minipterional cohort (55.2%). In the eyelid variant of the SOC cohort, the rate of complete aneurysm occlusion was the lowest (eyelid variant: 90.8%; eyebrow variant: 97.8%, p < 0.001; minipterional approach: 97.9%, p < 0.001), and the postoperative infarction rate was the highest (eyelid variant: 7.2%; eyebrow variant: 3.5%, p = 0.025; minipterional approach: 2.6%, p = 0.003). CONCLUSION: Each approach has a specific safety and efficacy profile. Surgeons selected the eyebrow variant of the SOC for many aneurysm locations including in particular the ACoA. There is a recent tendency however to opt for the minipterional approach above all for MCA aneurysms. ABBREVIATIONS: SOC: Supraorbital Craniotomy; MPT: Minipterional; MCA: Middle Cerebral Artery; ACoA: Anterior Communicating Artery; PCoA: Posterior Communicating Artery; aSAH: Aneurysmal Subarachnoid Hemorrhage; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MINORS: Methodological Index For Non-Randomized Studies. PMID- 30311866 TI - Clinical differences of early and late-onset myasthenia gravis in 985 patients. AB - OBJECTIVE: The clinical differences of early-onset myasthenia gravis (EOMG) and late-onset MG (LOMG) have not been elucidated in China. In order to clarify this, a retrospective study was conducted in 985 MG patients, whose disease duration was longer than 3 years. METHODS: These patients were separated into EOMG and LOMG according to the onset age of 50 years. The clinical differences including demographics, clinical features, thymus abnormalities and comorbidities of EOMG and LOMG patients were analyzed. RESULTS: Results indicated that 485 were males and 500 were females, 714 were EOMG and 271 were LOMG. Female was more common in EOMG and male was more common in LOMG (p = 0.003). The peak onset age was 0-4 years in EOMG and 55-59 years in LOMG. Ocular MG (OMG) was more common in EOMG and generalized MG (GMG) was more common in LOMG (p = 0.004). The transformation rate of OMG to GMG was higher in LOMG (p = 0.002). The positive incidence of repetitive nerve stimulation (RNS) was higher in EOMG (p = 0.026). Thymoma was more frequent in LOMG (p = 0.017) and thymic hyperplasia was more frequent in EOMG (p < 0.001). Hyperthyroidism was more common in EOMG (p = 0.017) and diabetes was more common in LOMG (p < 0.001). CONCLUSION: These results have potential significance for the recognition of clinical features and the determination of management strategies in EOMG and LOMG. PMID- 30311867 TI - Pleasure, risk perception and consent among group sex party attendees in a small Canadian Urban Centre. AB - From a health perspective, group sex parties represent risk environments, as multiple sexual partners and polysubstance use associated with these parties may present risk practices for sexually transmitted infection (STI) transmission. At the same time, group sex parties exemplify sex as recreation, expressed in contemporary sociological theory as sex as leisure or play. In this paper, we report on the findings of an exploratory qualitative study conducted with group sex party attendees and hosts/organisers in a mid-sized Canadian city. Thematic analysis of semi-structured interviews with thirteen individuals identified several sexual communities based on gender composition, sexual orientation, and sexual practice, with variation among and within groups in terms of sexual consent and STI disclosure. All the interviewees discussed at length issues of harm reduction and consent, suggesting that these factors contribute to participants' group sex party experiences regardless of their sexual community. These insights highlight the potential use of group sex parties as avenues to understanding the integration of harm reduction practices with the pursuit of sexual pleasure, information applicable in the context of a wide range of sexuality education programmes. PMID- 30311868 TI - Effect of regular swimming exercise to duration-intensity on neurocognitive function in cerebral infarction rat model. AB - OBJECTIVE: This study investigated the effect of regular swimming exercise according to the duration-intensity on neurocognitive function in a cerebral infarction rat model. METHODS: Forty male Sprague-Dawley 10-week-old rats, weighing 300 +/- 50 g, were subjected to photothrombotic cerebral infarction. The remaining 36 rats were randomly divided into four groups (n = 9 per group: non exercise (group A); swimming exercise of short duration-intensity (5 min/day, group B); swimming exercise of moderate duration-intensity (10 min/day, group C); and swimming exercise of long duration-intensity (20 min/day, group D). Exercise was performed five times a week for 4 weeks, beginning the day after cerebral infarction. Neurocognitive function was evaluated with the Morris water maze test. Immunohistochemistry and western blot analysis examined brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) at 4 weeks postinfarction. RESULTS: At 4 weeks postinfarction, escape latency was found to be shorter in group C than in any of groups A, B, or D. Immunohistochemistry revealed the most significant immunoreactivity for BDNF and VEGF in group C. Western blot analysis demonstrated that BDNF and VEGF proteins were markedly expressed in group C. CONCLUSIONS: Regular swimming exercise of moderate duration-intensity may be the most effective exercise protocol for the recovery of neurocognitive function in cerebral infarction rat model. PMID- 30311869 TI - Zobellella endophytica sp. nov., isolated from the roots of Phragmites communis in the Kumtag Desert. AB - A Gram-negative, aerobic, non-spore-forming, rod-shaped, motile bacterium, named strain 59N8T, was isolated from Phragmites communis roots in the Kumtag Desert. Phylogenetic analysis based on the 16S rRNA gene sequence showed that the isolate belongs to the genus Zobellella within the family Aeromonadaceae. The analysis showed that strain 59N8T was most closely related to Zobellella taiwanensis ZT1T. The average nucleotide identity value with Zobellella taiwanensis ZT1T was 88.2 %, and the digital DNA-DNA hybridization value was 29.7+/-2.4 %, which was calculated using the Genome-to-Genome Distance Calculator. The G+C content of strain 59N8T was 62.8 mol%. Strain 59N8T grew at 0-5 % (w/v) NaCl (optimum, 0-4 %), pH 6.0-9.0 (optimum, 7.0-8.0) and at 10-45 degrees C. The major cellular fatty acids were summed feature 8 (C18 : 1omega7c/C18 : 1omega6c), summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) and C16 : 0. The major polar lipids in strain 59N8T were phosphatidylethanolamine and phosphatidylglycerol. Based on the chemotaxonomic, phylogenetic and phenotypic data, strain 59N8T represents a novel species in the genus Zobellella, for which the name Zobellellaendophytica sp. nov. is proposed. The type strain is 59N8T (=ACCC 60074T=KCTC 62456T). PMID- 30311870 TI - ICTV Virus Taxonomy Profile: Deltavirus. AB - Hepatitis delta virus, the only member of the only species in the genus Deltavirus, is a unique human pathogen. Its ~1.7 kb circular negative-sense RNA genome encodes a protein, hepatitis delta antigen, which occurs in two forms, small and large, both with unique functions. Hepatitis delta virus uses host RNA polymerase II to replicate via double rolling circle RNA synthesis. Newly synthesized linear RNAs are circularized after autocatalytic cleavage and ligation. Hepatitis delta virus requires the envelope of the helper virus, hepatitis B virus (family Hepadnaviridae), to produce infectious particles. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Deltavirus which is available at www.ictv.global/report/deltavirus. PMID- 30311871 TI - Microbe Profile: Wolbachia: a sex selector, a viral protector and a target to treat filarial nematodes. AB - Wolbachia is the most widespread genus of endosymbiotic bacteria in the animal world, infecting a diverse range of arthropods and nematodes. A broad spectrum of associations from parasitism to mutualism occur, with a tendency to drive reproductive manipulation or influence host fecundity to spread infection through host populations. These varied effects of Wolbachia are exploited for public health benefits. Notably, the protection of insect hosts from viruses is being tested as a potential control strategy for human arboviruses, and the mutualistic relationship with filarial nematodes makes Wolbachia a target for antibiotic therapy of human and veterinary nematode diseases. PMID- 30311872 TI - Mechanisms of carbapenem resistance in Acinetobacter pittii and Acinetobacter nosocomialis isolates from Thailand. AB - PURPOSE: The emergence of carbapenem resistance in non-baumannii Acinetobacter has increased in clinical settings worldwide. We investigated the prevalence and mechanisms of carbapenem resistance in A. pittii and A. nosocomialis Thai isolates. METHODOLOGY: Acinetobacter calcoaceticus-Acinetobacter baumannii (Acb) complex isolates were identified by gyrB mulitplex PCR. Carbapenem susceptibilities were studied by the agar dilution method and carbapenemase genes were detected by multiplex PCR. Reductions of the outer membrane proteins (OMPs) were evaluated by SDS-PAGE. Overexpressions of efflux pumps were detected by using efflux pump inhibitors and RT-PCR. RESULTS: Of the 346 Acb isolates, 22 and 19 were A. pittii and A. nosocomialis, respectively. The carbapenem resistance rates were 22.7 % in A. pittii and 26.3 % in A. nosocomialis. Three carbapenem resistant A. pittii carried blaOXA-23. One carbapenem-resistant A. pittii harboured blaOXA-58, while another isolate co-harboured blaOXA-58 and blaIMP-14a. blaOXA-58 was also found in three carbapenem-susceptible A. pittii. Five carbapenem-resistant A. nosocomialis carried blaOXA-23. Eighteen A. pittii isolates carried blaOXA-213-like. Reduced OMPs were found in carbapenem-resistant and -susceptible A. pittii carrying blaOXA-58, but were not detected in carbapenem-resistant A. nosocomialis isolates. Overexpression of adeE was found in carbapenem-resistant A. pittii. No efflux pump genes were present in carbapenem-resistant A. nosocomialis. CONCLUSION: The major mechanisms of carbapenem resistance in A. pittii and A. nosocomialis were the production of OXA 23 and OXA-58. Overexpression of adeE played a role in carbapenem resistance in A. pittii. Since blaOXA-58 was found in carbapenem-susceptible A. pittii, using carbapenems in the treatment of A. pittii infection should be considered. PMID- 30311874 TI - Induction of selective autophagy in cells replicating hepatitis C virus genome. AB - Hepatitis C virus (HCV) infection is known to induce autophagy, but the mechanism of autophagy induced by HCV remains controversial. Here, we investigated the characteristics of autophagy induced by HCV infection. First, to examine the involvement of autophagy-related gene (ATG) proteins in HCV-induced LC3 lipidation, we established ATG5, ATG13 or ATG14 knockout (KO) Huh7.5.1 cell lines and confirmed that the accumulation of lipidated LC3 was induced in an ATG13- and ATG14-independent manner. On the other hand, HCV infectivity was not influenced by deficiencies in these genes. We also confirmed that LC3-positive dots were co localized with ubiquitinated aggregates, and deficiency of ATG5 or ATG14 enhanced the accumulation of ubiquitinated aggregates compared to that in the restored cells, suggesting that HCV infection induces ATG5- and ATG14-dependent selective autophagy. Moreover, LC3-positive ubiquitinated aggregates accumulated near the site of the replication complex. We further examined autophagy flux in cells replicating HCV RNA using bafilomycin or E64d, and found that the increase of LC3 lipidation by treatment with bafilomycin or E64d was impaired in HCV-replicating cells, suggesting that autophagy flux is inhibited by the progress of HCV infection. Our present study suggests that (1) HCV RNA replication induces selective autophagy and (2) the progress of HCV infection impairs autophagy flux. PMID- 30311875 TI - Initial stages of endophytic colonization by Metarhizium involves rhizoplane colonization. AB - Here we assessed the time course of rhizoplane colonization by the endophytic insect pathogenic fungus Metarhizium robertsii. We describe a method of quantifying root colonization of bean plants by M. robertsii using quantitative polymerase chain reaction (qPCR). Results of this method were compared to the standard plate count method using colony-forming units (c.f.u.). Both the c.f.u. and qPCR methods were used to monitor the time-course of haricot bean (Phaseolus vulgaris) colonization by a strain of M. robertsii that expresses the green fluorescent protein (ARSEF 2575-GFP) for colony verification. There was a strong correlation between the results of the c.f.u. and qPCR methods, indicating that both methods are well suited for the determination of colonization of P. vulgaris roots by M. robertsii. Primers for a catalase gene (cat) amplified DNA from M. robertsii, M. brunneum and M. guizhouense. Primers for a nitrogen response regulator (nrr) additionally detected M. acridum and M. flavoviride, whereas Metarhizium perilipin-like protein (mpl) primers were specific to M. robertsii alone. However, cat was the only target that specifically amplified Metarhizium in experiments utilizing non-sterile soil. Endophytic colonization of P. vulgaris at 60 days post-inoculation with M. robertsii was detected from surface sterilized roots with more sensitivity using our qPCR technique over the c.f.u. method. Our results suggest that there is a prolonged period of rhizoplane colonization by Metarhizium with transient, low-level endophytic colonization of the root system of P. vulgaris that persists for the entirety of the plant life cycle. PMID- 30311873 TI - Rapid identification of pathogens from positive blood culture bottles with the MinION nanopore sequencer. AB - PURPOSE: Bloodstream infections are major causes of morbidity and mortality that lead to prolonged hospital stays and higher medical costs. In this study, we aimed to evaluate the MinION nanopore sequencer for the identification of the most dominant pathogens in positive blood culture bottles. METHODOLOGY: 16S and ITS1-5.8S-ITS2 rRNA genes were amplified by PCR reactions with barcoded primers using nine clinical isolates obtained from positive blood bottles and 11 type strains, including five types of Candida species. Barcoded amplicons were mixed, and multiplex sequencing with the MinION sequencer was performed. In addition, barcoded PCR amplicons were sequenced by Sanger sequencing to validate the performance of the MinION. RESULTS: The bacterial and Candida spp. identified by MinION sequencing, based on the highest homology of reference sequences from the NCBI gene databases, agreed with the matrix-assisted laser desorption ionization time of flight mass spectrometry results, excepting the closely related species Streptococcusand Escherichia coli. The 'pass' reads obtained within about 10 min of sequencing were sufficient to identify the pathogens. The average values of sequence identities with 1D2 chemistry and the R9.5 flow cell were around 99 %; thus, frequent sequence errors did not affect species identification based on amplicon sequencing. CONCLUSION: We have established a rapid, portable and economical technique for the identification of pathogens in positive blood culture bottles through a novel MinION nanopore sequencer amplicon sequencing scheme, which replaces traditional Sanger sequencing. PMID- 30311876 TI - A description of Mycobacterium chelonae subsp. gwanakae subsp. nov., a rapidly growing mycobacterium with a smooth colony phenotype due to glycopeptidolipids. AB - Three rapidly growing mycobacterial strains, MOTTH4W, MOTT36WT and MOTT68W, were isolated from the sputa of three independent Korean patients co-infected with Mycobacterium yongonense Type II strains. The 16S rRNA gene sequences of all three strains were unique, which were closest to that of Mycobacterium chelonae subsp. bovis KCTC 39630T (99.9 % similarity). Multilocus sequence typing analysis targeting 10 housekeeping genes including hsp65 and rpoB revealed the distinct phylogenetic location of these strains, which were clustered with M. chelonae subsp. chelonae ATCC 35752T and M. chelonae subsp. bovis KCTC 39630T. Phylogenetic analysis based on whole genome sequences revealed a 95.89 % average nucleotide identity (ANI) value with M. chelonae subsp. chelonae, slightly higher than the 95.0 % ANI criterion for determining a novel species. In addition, phenotypic characteristics such as a smooth colony morphology and growth inhibition at 37 degrees C, distinct MALDI-TOF MS profiles of extracted total lipids due to surface glycopeptidolipids, and distinct drug susceptibility profiles further supported the taxonomic characterization of these strains as representing a novel subspecies of Mycobacterium chelonae. Mycobacterium chelonae subsp. gwanakae subsp. nov. is proposed and the type strain is MOTT36WT (=KCTC 29127T=JCM 32454T). PMID- 30311877 TI - Genetic diversity in the env V1-V2 region of proviral quasispecies from long-term controller MHC-typed cynomolgus macaques infected with SHIVSF162P4cy. AB - Intra-host evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) has been shown by viral RNA analysis in subjects who naturally suppress plasma viremia to low levels, known as controllers. However, little is known about the variability of proviral DNA and the inter-relationships among contained systemic viremia, rate of reservoir reseeding and specific major histocompatibility complex (MHC) genotypes, in controllers. Here, we analysed the proviral DNA quasispecies of the env V1-V2 region, in PBMCs and in anatomical compartments of 13 long-term controller monkeys after 3.2 years of infection with simian/human immunodeficiency virus (SHIV)SF162P4cy. A considerable variation in the genetic diversity of proviral quasispecies was present among animals. Seven monkeys exhibited env V1-V2 proviral populations composed of both clusters of identical ancestral sequences and new variants, whereas the other six monkeys displayed relatively high env V1-V2 genetic diversity with a large proportion of diverse novel sequences. Our results demonstrate that in SHIVSF162P4cy-infected monkeys there exists a disparate pattern of intra-host viral diversity and that reseeding of the proviral reservoir occurs in some animals. Moreover, even though no particular association has been observed between MHC haplotypes and the long term control of infection, a remarkably similar pattern of intra-host viral diversity and divergence was found within animals carrying the M3 haplotype. This suggests that in animals bearing the same MHC haplotype and infected with the same virus, viral diversity follows a similar pattern with similar outcomes and control of infection. PMID- 30311878 TI - Deletion of MSMEG_1350 in Mycobacterium smegmatis causes loss of epoxy-mycolic acids, fitness alteration at low temperature and resistance to a set of mycobacteriophages. AB - Mycobacterium smegmatis is intrinsically resistant to thiacetazone, an anti tubercular thiourea; however we report here that it causes a mild inhibition in growth in liquid medium. Since mycolic acid biosynthesis was affected, we cloned and expressed Mycobacterium smegmatis mycolic acid methyltransferases, postulated as targets for thiacetazone in other mycobacterial species. During this analysis we identified MSMEG_1350 as the methyltransferase involved in epoxy mycolic acid synthesis since its deletion led to their total loss. Phenotypic characterization of the mutant strain showed colony morphology alterations at all temperatures, reduced growth and a slightly increased susceptibility to SDS, lipophilic and large hydrophilic drugs at 20 degrees C with little effect at 37 degrees C. No changes were detected between parental and mutant strains in biofilm formation, sliding motility or sedimentation rate. Intriguingly, we found that several mycobacteriophages severely decreased their ability to form plaques in the mutant strain. Taken together our results prove that, in spite of being a minor component of the mycolic acid pool, epoxy-mycolates are required for a proper assembly and functioning of the cell envelope. Further studies are warranted to decipher the role of epoxy-mycolates in the M. smegmatis cell envelope. PMID- 30311879 TI - Halococcus salsus sp. nov., a novel halophilic archaeon isolated from rock salt. AB - Two pink-pigmented halophilic archaea, designated strains ZJ1T and J81, were isolated from rock salt of Yunnan Salt Mine, China, and commercial salt imported from Bolivia, respectively. Cells were non-motile, coccoid, approximately 0.8-1.6 um in diameter, stained Gram-negative and often occurred in pairs. Colonies were wet, opaque and smooth-edged. Strain ZJ1T grew optimally with 20 % (w/v) NaCl, at pH 7.5 and at 38-40 degrees C, which was the same as for strain J81. 16S rRNA gene sequence similarity between strains ZJ1T and J81 was 99.7 %. Sequence similarity searches based on the 16S rRNA gene and cell morphology suggested that strains ZJ1T and J81 belong to the genus Halococcus in the family Halococcaceae. The major polar lipids of the type strain, ZJ1T, were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and sulfated diglycosyl-diether-1. The profile of polar lipids, cell shape, motility and lack of lysis of cells in distilled water show that strains ZJ1T and J81 were similar to other members of the genus Halococcus. Strain ZJ1T shared the highest 16S rRNA gene and rpoB' gene sequence similarities of 99.0 and 95.3 % with Halococcus hamelinensis 100A6T, respectively, followed by less than 94.6 % with sequences of other species in the genus Halococcus. DNA-DNA relatedness between strains ZJ1T and J81 was 90.1+/-0.7 %, while 27+/-0.5 % was found between strain ZJ1T and H. hamelinensis JCM 12892T (=100A6T), and 29.0+/-0.5 % between strains J81 and H. hamelinensis JCM 12892T. The DNA G+C content of strain ZJ1T was 66.5 mol% (Tm). The stable phylogenetic position, differential physiological and biochemical properties and extensive sequence divergence suggest that strains ZJ1T and J81 represent a novel species, for which the name Halococcus salsus sp. nov. is proposed. The type strain is ZJ1T (=CGMCC 1.16025T=NBRC 112867T). PMID- 30311880 TI - Renalase, Catecholamine and Nitric Oxide Changes Before and After Sodium Nitroprusside Administration to Patients who Develop Post-Coronary Artery By-Pass (CABG) Hypertension. AB - BACKGROUND: Hypertension develops at a rate of 33 to 70% after Coronary artery bypass grafting (CABG) operations. One of the most commonly used drugs to control hypertension is sodium nitroprusside (SNP). Additionally, renalase enzyme destroys catecholamines and mediates the regulation (reduction) of blood pressure. Thus, this clinical study aims to reveal how renalase, catecholamines and nitric oxide (NO) change and how certain hemodynamic parameters are affected in randomly and prospectively selected cases who are administered SNP for the treatment of blood pressure elevation within 6 to 8 hours after CABG surgery. METHODS: The study included 26 patients who developed hypertension after CABG, 12 patients who had normal blood pressure after CABG, and 22 healthy individuals. Renalase and catecholamine levels of the patients were measured using ELISA method and NO levels were determined by spectrophotometry. RESULTS: Renalase and NO levels of the patients who developed hypertension after CABG were found statistically significantly lower than those of healthy controls and patients who did not develop hypertension after CABG, while catecholamine levels were significantly higher in the former. After SNP was started, renalase and NO levels increased, and a significant decrease was observed in the catecholamine levels. Additionally, administration of SNP produced a slight increase in the heart rate and a decrease in systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and means arterial pressure (MAP). CONCLUSION: SNP elevates NO and renalase levels; thus, administration of renalase preparations, which act in the destruction of catecholamines to contain persistent hypertension that develops in association with catecholamine elevation after CABG surgery, along with SNP and other medications used to lower blood pressure can be an effective therapeutic method to control hypertension. PMID- 30311881 TI - Relationship Between Polymorphism of Adiponectin Gene SNPS+276 and Coronary Heart Disease. AB - BACKGROUND: This study aims to investigate the relationship between polymorphism of adiponectin (ADIPOQ) gene SNPS+276 and the severity of coronary heart disease (CHD) and coronary artery disease (CAD). METHODS: A total of 582 inpatients were enrolled and divided into Group CHD (342 cases) and the control group (CON, 240 cases), according to their angiographic results from June 2014 to April 2016 for the genotype (G/T) analysis of ADIPOQ SNPs+276 by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: Group CHD: GG 110 (32%), GT 205 (59%), and TT27 (8%); Group CON: GG 36 (15%), GT 161 (67%), and TT 43 (18%) (P < .05). The frequency of allele G in group CHD was 62.1% and 48.5% in group CON (P < .05). The frequencies of genotype GG, GT, and TT were 67 (33.3%), 107 (53.2%), and 27 (13.5%), respectively, in the group with single vascular lesion, and 64 (45.4%), 53 (37.6%), and 24 (17%), respectively, in the group with multiple vascular lesions. There was statistical significance between the two groups (P < .05). CONCLUSIONS: The 276G gene of adiponectin may be a susceptibility gene of CHD, and the genotype GG may be related to the severity of this disease. PMID- 30311882 TI - Early Safety and Efficacy of Sapien 3 20 mm Transcatheter Heart Valve Implantation in Small Japanese Body Size. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is effective in treating severe aortic stenosis in inoperable or high-risk surgical patients, however, the little is known about outcomes after Sapien 3 20 mm transcatheter heart valve (THV) implantation. The purpose of this study was to investigate the short term outcomes of Sapien 3 20 mm THV implantation in Japanese people with a small body size. METHODS: We retrospectively collected the hospital records of consecutive patients who underwent TAVI using the Sapien 3 20 mm THV between October 2016 and March 2017. Clinical and echocardiographic data from before and one week after TAVI were collected. RESULTS: Six Japanese patients (all female, mean age 89 +/- 5 years, body surface area [BSA] 1.29 +/- 0.16m2) received a Sapien 3 20 mm THV. All the procedures were feasible and successful, and the 30 day mortality rate was 0%. The functional class and the echocardiographic findings significantly improved (aortic valve area, 0.5 +/- 0.1 cm2 to 0.8 +/- 0.1cm2; mean pressure gradient, 55 +/- 15 mmHg to 19 +/- 7 mmHg; P = .043, respectively). However, the values of the indexed effective orifice area in all patients after Sapien 3 20 mm THV implantation were less than 0.85 cm2/m2, suggesting prosthesis-patient mismatch (PPM). CONCLUSIONS: The implantation of a Sapien 3 20 mm THV was safe and effective in high surgical risk elderly Japanese patients with a small body size. PPM after Sapien 3 20mm THV may be prevalent among Asians with small body sizes. Careful clinical follow-up will be necessary after Sapien 3 20 mm THV implantation. PMID- 30311883 TI - Clinical Outcomes of Mitral Annuloplasty with Flexible Bands in Ischemic Mitral Regurgitation. AB - BACKGROUND: In this study, we present the outcomes of 53 patients with concomitant coronary artery disease and ischemic mitral regurgitation (IMR)who underwent coronary bypass grafting (CABG) plus mitral repair (flexible posterior band annuloplasty). MATERIALS AND METHODS: A total of 53 patients with concomitant ischemic mitral regurgitation and coronary artery disease underwent CABG plus posterior mitral band annuloplasty between June 2008 and June 2015. Flexible Duran AnCore(r) annuloplasty band (Medtronic) was used in all patients. Transesophageal echocardiography (TEE) was intraoperatively performed in all patients. A transthoracic (TTE) follow-up examination was performed at postoperative months 1, 3, 6, and 12. RESULTS: The average cross-clamp and cardiopulmonary bypass times were 85.11 +/- 5.79 and 105.98 +/- 6.14 minutes, respectively. Postoperatively, there was an improvement in the grade of mitral regurgitation from 3.8 to 0.7 and in the NYHA class from 3.1 +/- 0.5 to 0.5 +/- 0.6 (both P < .001). In addition, statistically significant reductions in LVEDD, LVESD, and PAP were observed (P < .001). Ejection fraction rose from 39 +/- 10% to 45 +/- 8% (P < .01). Early mortality rate was 7.5% (n = 4). Mean follow-up was at 16 months. Late mortality occurred in one patient. During the follow-up period, reoperation was required in 2 patients. Only 2 parameters, redo surgery (P = .030) and IABP use (P = .021), were found related to mortality (P < .001). Cox regression analysis showed that redo surgery and postoperative bleeding increased mortality by 14.731 times (odds ratio: 14.731; 95% confidence interval [CI]: 1.530-141.852) and 23.839 times (odds ratio: 23.839; 95% CI: 1.478 348.641). DISCUSSION: In patients with IMR, mitral band annuloplasty performed in conjunction with CABG was associated with an increase in functional capacity and ejection fraction as well as a reduction in LVEDD and LVESD. This approach represents a feasible alternative with low mortality and prevents future development of mitral regurgitation and the need for redo surgery. PMID- 30311884 TI - Early and Midterm Outcomes of Rheumatic Mitral Valve Repair. AB - BACKGROUND: Rheumatic heart disease (RHD) is the leading cause of mitral valve disease in the developing world. In general, mitral valve repair is preferred over replacement. Although it is very successful in degenerative disease, its results in the rheumatic valve are not as successful as that for degenerative repair. Our approach has been to repair rheumatic mitral valves when the anatomic substrate appears to permit it, and we aimed by this study to present our immediate and midterm follow-ups of our cohort of rheumatic valve repair patients. METHODS: From February 2011 to March 2013, 52 consecutive patients underwent mitral valve repair for rheumatic disease with different surgical techniques at the National Heart Institute of Egypt. Patients who had concomitant aortic or coronary artery bypass surgery were excluded. Also, patients needing an emergency operation or redo ones were excluded. On the contrary, patients who had concomitant tricuspid valve surgery were included. Demographic, intraoperative, and perioperative outcome data were recorded prospectively. All patients underwent TTE before hospital discharge. During follow-up, patients were contacted by telephone and invited for follow-up TTE yearly after their operations. RESULTS: Fifty-two patients with rheumatic disease underwent mitral repair. Their mean age was 25.92 +/- 9.81 years. The study population was 78.8% female. Forty-nine patients were in New York Heart Association functional class III or IV. Repair procedures included implantation of Carpentier-Edwards Classic mitral annuloplasty ring (100% of the whole study group). Mitral commissurotomy and repair of the subvalvular apparatus were generally performed. Thirteen neochordae were implanted. Anterior leaflet extension with an autologous pericardial patch was used in 4 patients; annular decalcification, in 2 patients; tricuspid repair with De Vega technique, in 18 patients (34.5%); and repair with Carpentier-Edwards Classic tricuspid annuloplasty ring, in 9 (17.3%) patients. There was no operative mortality. The mean follow-up time was 59.9 +/- 5 postoperative months (range, 49-60 months). Only 2 patients (3.8%) died. Follow up echocardiography revealed more-than-or-equal-to-moderate (2+) grade of MR in 5 patients. During the follow-up period, the mean LV end-diastolic diameter decreased significantly from 5.57 +/- 1.06 cm to 4.93 +/- 0.74 cm (<0.001). The mean pulmonary artery pressure decreased from 44.94 +/- 17.01 mmHg to 35.69 +/- 7.92 mmHg postoperatively (P < .001). The mean mitral valve area increased from 1.2 +/- 0.9 cm2 to 2.3 +/- 0.2 cm2 postoperatively (P < .001). The mean mitral valve gradient decreased significantly from 12 +/- 4.9 mmHg to 4.3 +/- 1.9 mmHg postoperatively (P < .001). The mean MR grade decreased from 3.73 +/- 0.45 to 0.96 +/- 1.08 postoperatively (P < .001). CONCLUSION: We conclude that repair is possible in patients with rheumatic mitral valve dysfunction. Current techniques with some modifications can be efficient to restore both the anatomy and physiology (better function) of the mitral valve and can lead to favorable early and midterm outcomes. We, therefore, recommend that the number of rheumatic mitral repair procedures should be increased in developing countries to achieve the best results. PMID- 30311885 TI - Synchronous or Staged Carotid Endarterectomy and Coronary Artery Bypass Grafting? Propensity score matched study. AB - BACKGROUND: The optimal treatment strategy in patients presenting with hemodynamically significant carotid artery disease who are to undergo cardiac surgery, remains controversial. In this study, we retrospectively analyzed the outcome data of patients receiving synchronous or staged coronary artery bypass graft (CABG) surgery and carotid endarterectomy (CEA). METHODS: Between 2011 and 2016, 3173 patients underwent CABG surgery in our institution, of whom 323 received CABG and CEA either as synchronous (N = 307) or as staged (N = 16) procedures. Patients' characteristics, peri- and postoperative data were collected from our digital medical database. Propensity score matching was used to match each patient from the staged group to two appropriate patients (1:2 matching) from the synchronous group (synchronousmatched). RESULTS: The overall incidence of ischemic stroke (IS) and transitory ischemic attack (TIA) was 4.9% and 5.6%, respectively. No hemorrhagic stroke was noted in both groups. Incidence of IS did not differ significantly between matched groups (P = 1.000). Significantly higher rates of postoperative neurological complications, such as TIA and delirium, were found in the synchronousmatched group (P = .041 and P = .043, respectively) compared with the staged group. Additionally, there were more postoperative respiratory insufficiencies in the synchronousmatched group (P = .043). Thirty days mortality did not differ significantly between the matched groups. CONCLUSION: In this experience combined with the data given in literature, our findings suggest a possible superiority of the staged CABG/CEA approach. Large, randomized studies are required to verify our findings and to establish applicable guidelines. PMID- 30311886 TI - Systems Biology Approaches-based Biomarkers Discovery for Acute Aortic Dissection. AB - Acute aortic dissection (AAD) faces great challenges in early diagnosis and effective drug treatment. Recent developments in systems biology approaches allow high-throughput screening of novel diagnostic biomarkers and potential therapeutic targets. In this review, we summarize the currently available AAD biomarkers identified in the context of genomic, transcriptomic, proteomic, and metabolic profiles, and highlight the benefits of using a combination of these findings for a better understanding of the molecular nature of this life threatening disease. This review also provides a reference for future studies that employ a comprehensive, multiple-level approach at the single-cell level to decipher the underlying molecular pathophysiology of AAD. PMID- 30311887 TI - Surgical Treatment of Cardiac Myxomas: A 23-Case Experience. AB - OBJECTIVE: Although seen rarely compared to all tumors, cardiac tumors are tumors which may have a mortal course with possible complications. The most common cardiac tumor in adults is myxoma with its benign character. The results of cardiac tumors resected with open cardiac surgery in our center are reported in this study. MATERIALS AND METHODS: Twenty-three cardiac tumor patients electively operated on in our clinic between January 2010 and August 2017 were retrospectively included in the study. Information of the patients participating in the study were registered. The patients were between 25 and 67 years of age, and 18 were female (72.3%), and 5 were male (21.7%). The average age of the patients was 42.1 +/- 8.9 years. Echocardiography was used for diagnosis in all patients. There was no common complaint for the patients, with the complaints changing according to tumor location. All patients were operated on by means of cardiopulmonary bypass with aortic cross-clamp and bicaval cannulation. Preoperative demographical characteristics and perioperative and postoperative data were registered for the patients and were evaluated statistically. RESULTS: Nineteen of the tumors (82.6%) were in the left atrium, and 4 were (17.4%) in the right atrium. Diameter of the tumors changed between 2.5 * 1.5 and 8.5 * 6.5 cm. The tumoral structure was resected together with the solid tissue located in its root in all patients operated on. Pericardial patch was used for 11 (47.8%), and primary closure was used for 12 (51.2%) of the defects. Early and late mortality was not observed in any patient. CONCLUSION: To prevent possible complications of cardiac myxomas, they need to be resected together with the surrounding healthy tissue as soon as possible after the diagnosis. Cardiac myxomas can be operated on with a tolerable operation risk. Echocardiography should be made annually for any possible relapse after operation. PMID- 30311888 TI - Evidence of Osteogenic Regulation in Calcific Porcine Aortic Valves. AB - BACKGROUND: Chemically cross-linked animal tissues, such as porcine aortic valves (PAVs) have many documented advantages over mechanical valves. However, calcification is the major underlying pathologic process that results in bioprosthetic valve failure. Recently, several reports described the expression of noncollagenous bone matrix proteins in bioprosthetic valves and suggested an actively regulated process of tissue repair. METHODS: Thirty-one explanted PAVs with evidence of calcification were collected and examined for the protein expression implicated in myofibroblast activation, osteoblast differentiation, and bone matrix deposition by using immunohistochemistry. RESULTS: The mean duration that PAVs were implanted was 11.5 +/- 5.6 years, ranging from 12 months to 28 years. Pearson correlation analysis showed a significant relationship between the duration and valvular calcification (r = 0.3818, P = .034). The number of vimentin-positive mesenchymal cells in explanted PAVs was significantly lower than that of unused PAVs (P < .01). However, increased expression of alpha smooth muscle actin (alpha-SMA) (P < .01), proliferating cell nuclear antigen (PCNA, P < .01), Cbfa1/Runx2 (P < .01), osterix (P = .0126), bone sialoprotein (BSP, P < .01), osteocalcin (P < .01), and osteopontin (P < .01) was found in explanted PAVs. Immunohistochemical staining of alkaline phosphatase (ALP) and osteocalcin was negative in the unused PAVs. In explanted PAVs, the expression level of these 2 proteins was also significantly increased. CONCLUSIONS: Our results support the view that PAV calcification is an actively regulated process with osteogenic signaling activation. PMID- 30311889 TI - Clinical outcomes and quality of life in patients with Stanford type B aortic dissection after endovascular repair. AB - BACKGROUND: Aortic dissection is a severe and life-threatening disease that is usually linked with numerous possible complications. Stanford type B aortic dissection patients often choose endovascular repair due to its mini-invasiveness and quick recovery. This study concerns with medial-term outcome and quality of life (QoL) in patients with Stanford type B aortic dissection after endovascular repair. METHODS: From January 2014 until July 2016, 40 patients with Stanford type B aortic dissection received an endovascular repair. Of the total number of patients, 35 were males (87.5%) and 5 females (12.5%), mean aged 80.9+/-14.1 years. The Medical Outcomes Study-Short Form-36 (MOS SF-36) was used to assess the QoL preoperatively and after endovascular repair. The first follow-up (FU) of SF-36 questionnaire (FU1) was obtained within 3.9+/-0.3 months after repair, and the second (FU2), 25.6+/-6.5 months thereafter. RESULTS: None of patient died during the observational period, and one patient lost to FU. SF-36 observation showed the best-scoring domain was 'Role emotion', 'Vitality' and 'Mental health' were also scored well preoperatively. Except for 'Role emotion' and 'Mental health', all remained domains were significantly improved both FU1 and FU2. CONCLUSIONS: Endovascular repair in patients with Stanford type B aortic dissection enables excellent clinical outcomes and QoL. PMID- 30311891 TI - A New-Proposal Physical Examination Test for Unilateral Lower Extremity Edema. AB - OBJECTIVE: Patients with iliac vein compression syndrome (IVCS) usually present to the hospital with left-sided leg edema. We looked for an answer to the question: ''Can iliac vein compression syndrome (IVCS) be predicted with a reliable physical examination test in the differential diagnosis?'' Methods: We tested a new physical examination on patients with only left-sided lower extremity edema. In this physical examination the widest area of the calf point (just below tuberosity of the tibia) and medial malleolus was measured in both legs on the Trendelenburg position at 30 degrees and repeated in standing position. Then the iliac venography was performed. RESULTS: The test was performed on 32 (N = 32) patients with left extremity edema. IVCS was observed on 18 (n = 18) (56%) patients. The test was found to have 88% sensitivity and 92% specificity in IVCS. CONCLUSION: This new physical examination finding, which may be valuable in diagnosing IVCS, is proposed for use in patients with unilateral left-sided edema to preclude unnecessary use of expensive diagnostic imaging methods. PMID- 30311890 TI - Analysis of Nosocomial Infections in Post-Cardiac Surgery Extracorporeal Membrane Oxygenation Support Therapy. AB - OBJECTIVES: This study aims to analyze the nosocomial infection factors in post cardiac surgery extracorporeal membrane oxygenation (ECMO) supportive treatment (pCS-ECMO). METHODS: The clinical data of the pCS-ECMO patients who obtained nosocomial infections (NI) were collected and analyzed retrospectively. Among the 74 pCS-ECMO patients, 30 occurred with NI, accounting for 40.5%; a total of 38 pathogens were isolated, including 22 strains of Gram-negative bacteria (57.9%), 15 strains of Gram-positive bacteria (39.5%), and 1 fungus (2.6%). RESULTS: Multidrug-resistant strains were highly concentrated, among which Acinetobacter baumannii and various coagulase-negative staphylococci were the main types; NI was related to mechanical ventilation time, intensive care unit (ICU) residence, ECMO duration, and total hospital stay, and the differences were statistically significant (P < .05). The binary logistic regression analysis indicated that ECMO duration was a potential independent risk factor (OR = 0.992, P = .045, 95.0% CI = 0.984-1.000). CONCLUSIONS: There existed significant correlations between the secondary infections of pCS-ECMO and mechanical ventilation time, ICU residence, ECMO duration, and total hospital stay; therefore, hospitals should prepare appropriate preventive measures to reduce the incidence of ECMO secondary infections. PMID- 30311892 TI - Primary Cardiac Sarcoma Remission after Surgery: 5-Years Follow-up: Case Report. AB - BACKGROUND: Primary cardiac sarcoma is a rare and atypical clinical entity. We present a patient with long-term remission after primary cardiac sarcoma resection. CASE REPORT: A 42-year-old previously healthy female presented to the emergency department after an effort-induced 30-minute episode of chest pain and extreme shortness of breath. Physical examination upon admission was remarkable for a pulse of 99/minute; blood pressure was 101/73 mmHg. Transthoracic echocardiography showed a mass measuring 5.5 * 5.6 cm extending from the left septum to the mitral valve anterior leaflet. A multilobulated broad-based 5.5 * 5.6 * 4 cm3 mass invading a large portion of the left septum to the mitral valve anterior leaflet was completely excised in the open heart surgery. Chemotherapy regimen (paclitaxel 175 mg/m2/day on day 1, every 21 days) was started after operation. Full remission was provided. Metastasis and recurrence have not been observed for 5 years of follow-up by PET. We observed during 5 years and used a PET. And the finally we did not see metastasis at the 5 years of follow-up. CONCLUSIONS: We strongly recommend that a patient-specific multidisciplinary approach involving radical resection, chemotherapy, and radiation therapy in these cases results in patient survival and a significant improvement in quality of life. We also think that it is necessary to perform MRI to exclude other illnesses that are considered to be a myxoma. PMID- 30311893 TI - Thoracoscopy Assisted Minimally Surgery (NUSS procedure) for Pectus Excavatum vs. Novel Modified NUSS procedure - A Single-Center Retrospective Study. AB - OBJECTIVE: The purpose of this article is to evaluate the efficacy of thoracoscopy assisted minimally surgery (NUSS procedure) for pectus excavatum and novel modified NUSS procedure by comparing the data of patients of pectus excavatum who had undergone novel modified NUSS Procedure or NUSS procedure. METHODS: A retrospective study was performed, involving 132 cases of patients with pectus excavatum collected from Shanghai Jiaotong University School of Medicine Xinhua Hospital cardio-thoracic surgery between Jan. 2009 and Jan. 2012. The 132 patients were strictly divided into two groups: Group A included 76 cases that underwent a novel modified NUSS procedure; Group B included 56 cases that underwent NUSS procedure. Compared data included gender, age, operative time, blood loss, postoperative hospital staying and clinical variables and demographic were compared with univariable analysis. RESULTS: No statistically significant correlations were observed in the two groups, such as age (12.67+/-4.793 years vs. 12.20+/- 6.423 years), sex, and other clinical data (P > 0.05). In Group A, postoperative hospitalization time (3.95+/-0.487 days vs. 6.07+/-1.412 days), operation time (46.28+/-12.218 minutes vs. 72.23+/-24.270 minutes), and blood loss (7.37+/-4.863 ml vs. 16.93+/-14.002 ml) were significantly better than those in Group B (P < 0.05), shortening hospitalization time, reducing costs, meaning statistically significant differences. There was no recurrence in Group A and Group B after operation. CONCLUSION: The study demonstrated that novel modified NUSS procedure is less invasive, having rapid recovery, shortening the time of hospital stay, and reducing hospital cost. Thus, it is safe, worth promoting, and is widely being used. PMID- 30311894 TI - Organized Hemopericardium Mimicking Malignant Tumor: A Case of Spontaneous Pericardial Hematoma In a 23-Year-Old Young Male. AB - Spontaneous pericardial hematoma is rare, and the diagnosis of spontaneous organized hemopericardium is difficult in some cases. The present study reports a case of a 23-year-old man admitted to our hospital for dyspnea on Sept. 30, 2017. The patient experienced shortness of breath 10 days before admission and went to a local hospital. The chest non-contrast CT and Echo revealed effusion of pericardium, right thoracic cavity and abdominal cavity. The patient went to our hospital for further treatment, and there was no abnormality in the laboratory tests of infection, tumor, or immune disease. The patient received pericardiocentesis for cardiac tamponade. A re-examination of Echo after pericardiocentesis revealed a pericardial mass. The enhanced chest CT and 18F-FDG PET/CT could not rule out the risk of a malignant tumor. The resection of pericardial mass was performed under cardiopulmonary bypass with cardioplegia. The pathology was organized hematoma with widely hemorrhage and necrosis, fibrous tissue proliferation, myofibroblast proliferation, and granulation tissue formation. The patient was discharged from our hospital without recurrence of pericardial effusion or the symptom of dyspnea. This case suggests that spontaneous organized hemopericardium is difficult to be distinguished from malignant tumor, and a surgical resection can help with diagnosis and symptomatic relief. PMID- 30311895 TI - Planned Concomitant Left and Right Ventricular Assist Device Insertion to Avoid Long-term Biventricular Mechanical Support: Bridge to Right Ventricular Recovery. AB - INTRODUCTION: The planned use of a temporary right ventricular assist device (RVAD) at the time of left ventricular assist device (LVAD) implantation may prevent the need for a permanent biventricular assist device (BiVAD). Herein we describe our RVAD weaning protocol that was effectively employed in 4 patients to prevent the need for permanent BiVAD. METHODS: Four patients in refractory cardiogenic shock underwent planned RVAD insertion during LVAD implantation due to severely depressed right ventricular function with dilation preoperatively. A standardized RVAD weaning protocol was employed in these 4 patients in preparation for decannulation. RESULTS: Temporary RVADs were successfully placed in all 4 patients at the time of LVAD implantation. All patients survived to RVAD decannulation and discharge and were alive at the time of most recent follow-up (range, 528-742 days post-RVAD decannulation). CONCLUSION: Planned implantation of a temporary RVAD in high risk patients may avoid the need for biventricular mechanical support in the future. PMID- 30311896 TI - Preventive Use of Ascorbic Acid For Atrial Fibrillation After Coronary Artery Bypass Graft Surgery. AB - BACKGROUND: Atrial fibrillation is one of the most frequent complications and a major risk of morbidity and mortality after cardiac surgery. Antioxidants such as vitamin C are used for prevention of this arrhythmia. Different results of studies have been reported, but most of them have shown efficiency of vitamin C in prophylaxis of postoperative AF. We tried to examine this efficacy with larger sample size. METHODS: Three hundred and fourteen on pump coronary artery bypass graft surgery alone. Patients were divided into two groups: The intervention group received vitamin C (N = 160) and the control group did not receive any (N = 154). Intervention group was administered two grams of vitamin C intravenously (IV) 24 hours preoperatively, 500 mg every 12 hours IV for 48 hours in ICU, and 500 mg every 12 hours PO for 48 hours in ward. Continuous monitoring in ICU and three times a day ECG was used for AF detection. The two groups were compared. RESULTS: The two groups were matched in terms of age, sex, LA size, ejection fraction, functional class, and TSH level. Of the patients, 244 were male. Mean age was 62 years (40-84 years) in both groups. M/F ratio was four in both groups. Functional class and ejection fraction were the same in both groups. There was no mean TSH level difference. AF occurrence in vitamin C group was 7.6 % and in control group was 7.8 %. There was no difference in ICU or hospital stay. CONCLUSIONS: Prophylactic use of vitamin C does not further reduce postoperative atrial fibrillation in on pump CABG patients. PMID- 30311897 TI - Comparison of Continuous and Interrupted Suturing Techniques in Ventricular Septal Defect Closure. AB - BACKGROUND: Our goal is to evaluate postoperative outcomes of continuous versus interrupted suturing techniques in ventricular septal defect (VSD) closure surgery. METHODS: The study included 286 patients with isolated VSD who underwent VSD closure surgery between June 2010 and April 2017. VSD closure was performed by using the interrupted suturing technique in group 1 (n = 74, 25.9%) and the continuous suturing technique in group 2 (n = 212, 74.1%). The groups were compared in terms of mortality and rates of clinical morbidities such as infection and complete atrioventricular (AV) block. RESULTS: Early mortality occurred in 3 cases in group 1 (4.0%) and 5 cases in group 2 (2.3%). There was no late mortality in either group. One patient from both groups required extracorporeal membrane oxygenation (ECMO) at postoperative 48 hours. Five patients in group 1 (6.8%) and 11 patients in group 2 (5.2%) developed complete AV block postoperatively and received permanent pacemaker implants. CONCLUSION: Complication rates were similar between the patient groups operated on by using continuous and interrupted suturing techniques in our study, suggesting that neither technique is superior for VSD closure surgery. PMID- 30311898 TI - On Becoming a Surgical Intern: Navigating the Lurch from Medical School to Internship. AB - There are three major transitions in the educational trajectory of those heading into a career in surgery. The first transition is from the first year or two of medical school to the clerkships of the third year. The second is the transition from medical school into the first postgraduate year of residency training. The third, which is widely held to be the toughest transition of all, is from residency into independent practice. This review, which could be called 'a rookie's survival guide,' will address the second of those 'lurches,' that of the transition from medical school into a surgical internship. PMID- 30311899 TI - Antioxidant Ability and Stability Studies of 3-O-Ethyl Ascorbic Acid, a Cosmetic Tyrosinase Inhibitor. AB - 3-O-ethyl ascorbic acid may be a good whitening ingredient in cosmetics. However, before it can be successfully used in cosmetics, its biofunctionality and stability need to be comprehensively investigated. The reduction and 2,2-Diphenyl 1-picrylhydrazyl (DPPH) free radical scavenging ability of this compound were analyzed to assess its antioxidant potential. In addition, the tyrosinase inhibitory ability was analyzed to show the whitening capacity of 3-O-ethyl ascorbic acid. Response surface methodology (RSM) was used to determine the optimal conditions for the ascorbic acid derivative in cosmetics. Based on the DPPH radical scavenging ability results, the half-inhibitory concentration (IC50) value of 3-O-ethyl ascorbic acid was 0.032 g/L. It also showed a good reducing ability at 1.5 g/L concentration. Based on the tyrosinase inhibition analysis, the IC50 value was 7.5 g/L. The optimal conditions to achieve the best stability were determined from the RSM as 36.3 degrees C and pH 5.46. PMID- 30311900 TI - The Influence of Packaging on Cosmetic Emulsion during Storage Assessed by FT-NIR Spectroscopy and Color Measurements. AB - FT-NIR spectroscopy and color measurements were applied to evaluate the influence of packaging on cosmetic cream stored at room and refrigerated conditions. Commercial cosmetic cream was stored for 2 and 4 mo in five containers intended for cosmetics: aluminum jar with polypropylene thermos (Al/PP), acrylic jar with polypropylene thermos (Ac/PP), glass (G) jar, polypropylene (PP) jar, and styrene acrylonitrile (SAN) jars. Principal component analysis (PCA) of the FT-NIR spectra showed the effect of time on tested samples stored in all applied packagings; separate groups were formed by fresh samples and samples stored for 2 and 4 mo. The changes in samples stored in the cold for 2 mo were similar for all applied packagings as compared with fresh samples, although samples stored in SAN jars formed a separate group. After 4 mo, a separate group was formed by samples stored in G jars. For samples stored at room temperature, the influence of packaging material on cosmetic emulsion was clearly visible; four separate groups (Al/PP with PP, Ac/PP, G, and SAN) were created by samples stored for 4 mo. Using partial least squares (PLS1) regression, it was found that the FT-NIR spectra of tested samples correlated with their lightness L*, a* parameter, and total color difference DeltaE * ab . FT-NIR spectroscopy is a rapid technique which could be useful to make the best choice of packaging for cosmetics protecting the original quality of products during long-term storage. PMID- 30311901 TI - Stability Studies and Characterization of Glutathione-Loaded Nanoemulsion. AB - Glutathione reduced (GSH) is the mother of all the antioxidants and has an antimelanogenic effect. It is extremely vulnerable to oxidation in the solution form which limits its use. The GSH in nano-oil droplets present a potential solution to this problem. The aim of this study was to formulate glutathione loaded nanoemulsion and assess its stability studies over a 90-day testing period. To formulate GSH-loaded nanoemulsion pseudo-ternary phase diagram, it was built with various concentrations of water, liquid paraffin oil, and surfactant mixture (Tween 80 and Span 80). The oily phase was prepared by dissolving the GSH (450 mg) in liquid paraffin oil through stirring. High-energy homogenization was used to prepare the nanoemulsion. From preformulation stability studies of the 28 day testing period, nanoemulsion (NE-19) with oil and surfactant mixture ratio (1:1) of hydrophilic lipophilic balance (HLB) value 10 was selected. The samples of NE-19 and its respective base (B-19) were kept at four different storage conditions for a period of 90 days and evaluated for physical characteristics, droplet size and distribution analysis, zeta potential analysis, electrical conductivity, mobility, polydispersity, pH, phase separation, and flow analysis at different time intervals. Glutathione in nano-oil droplets with nonionic surfactants produced oil-in-water nanoemulsions that were thermodynamically stable over the 90-day testing period at different storage conditions. NE-19 was formulated having non-Newtonian flow and pseudo-plastic behavior. pH was found in the range of 5-6. Polydispersity was less than 0.3. The droplet size of fresh nanoemulsion was 96.05 nm, whereas the zeta potential was -37.1. Mobility and electrical conductivity were -2.726 um cm/Vs and 0.0141 mS/cm, respectively. Glutathione-loaded nanoemulsions have excellent stability, promising the solution in nano-oil droplets and are suggested for in-vivo release studies for oxidative skin related diseases. PMID- 30311902 TI - Skin Tolerance of Three Types of Dead Sea Mud on Healthy Skin: A Short-Term Study. AB - Dead Sea mud (DSM) is commonly used by patients with various skin conditions because of its contents of healing elements. No study was published to show whether DSM application weakens or strengthens skin barrier function. In this study, we investigated the impact of 30-minute single application of various types of DSM ("As Is" mud, mud with extra Dead Sea salt, and over-the-shelf mud) on the barrier function of normal skin. The influence of 30-minute application of various types of DSM was investigated noninvasively on skin barrier properties of healthy female adult volunteers (n = 75) on predetermined circular areas. Skin hydration, transepidermal water loss (TEWL), erythema and melanin levels, and skin pH were measured directly, 30 minutes, and 60 minutes after mud removal. Thirty-minute single application of DSM was well tolerated with short-lived moisturizing effects, which was enhanced by the presence of humectant ingredients, and with no negative impact on barrier integrity, pH, and erythema and melanin levels. PMID- 30311903 TI - Determination of Fluorescent Whitening Agents in Cosmetics and Liquid Detergent by High-Performance Liquid Chromatography with Diode Array Detector in Tandem with Fluorescence Detector. AB - Five distyryl-type fluorescent whitening agents (FWA85, 210, 220, 351, and 353) were determined in cosmetics and liquid detergent by high-performance liquid chromatography with diode array detector in tandem with fluorescence detector. The samples were extracted with ultrasound in 33% acetonitrile for 10 minutes and the components were determined by ion-pair chromatography on an MG C18 column. The limits of detection were from 0.01 to 0.1 mg.kg-1 and the limits of quantification were from 0.04 to 0.4 mg.kg-1. The recovery was from 80.7 to 103.3%. A linear relationship was present from 0.10 to 100 ug.ml-1 of FWAs. The protocol was simple, sensitive, selective, and was successfully applied to analyze distyryl-type FWAs in cosmetics and liquid detergent. FWA351 and FWA85 were detected in several samples with the concentrations of 19.4-1,130 mg.kg-1. PMID- 30311904 TI - The fate of hippocampal synapses depends on the sequence of plasticity-inducing events. AB - Synapses change their strength in response to specific activity patterns. This functional plasticity is assumed to be the brain's primary mechanism for information storage. We used optogenetic stimulation of rat hippocampal slice cultures to induce long-term potentiation (LTP), long-term depression (LTD), or both forms of plasticity in sequence. Two-photon imaging of spine calcium signals allowed us to identify stimulated synapses and to follow their fate for the next 7 days. We found that plasticity-inducing protocols affected the synapse's chance for survival: LTP increased synaptic stability, LTD destabilized synapses, and the effect of the last stimulation protocol was dominant over earlier stimulations. Interestingly, most potentiated synapses were resistant to depression-inducing protocols delivered 24 hr later. Our findings suggest that activity-dependent changes in the transmission strength of individual synapses are transient, but have long-lasting consequences for synaptic lifetime. PMID- 30311905 TI - Sensory experience inversely regulates feedforward and feedback excitation inhibition ratio in rodent visual cortex. AB - Brief (2-3d) monocular deprivation (MD) during the critical period induces a profound loss of responsiveness within binocular (V1b) and monocular (V1m) regions of rodent primary visual cortex. This has largely been ascribed to long term depression (LTD) at thalamocortical synapses, while a contribution from intracortical inhibition has been controversial. Here we used optogenetics to isolate and measure feedforward thalamocortical and feedback intracortical excitation-inhibition (E-I) ratios following brief MD. Despite depression at thalamocortical synapses, thalamocortical E-I ratio was unaffected in V1b and shifted toward excitation in V1m, indicating that thalamocortical excitation was not effectively reduced. In contrast, feedback intracortical E-I ratio was shifted toward inhibition in V1m, and a computational model demonstrated that these opposing shifts produced an overall suppression of layer 4 excitability. Thus, feedforward and feedback E-I ratios can be independently tuned by visual experience, and enhanced feedback inhibition is the primary driving force behind loss of visual responsiveness. PMID- 30311907 TI - Perceptual processing in the ventral visual stream requires area TE but not rhinal cortex. AB - There is an on-going debate over whether area TE, or the anatomically adjacent rhinal cortex, is the final stage of visual object processing. Both regions have been implicated in visual perception, but their involvement in non-perceptual functions, such as short-term memory, hinders clear-cut interpretation. Here, using a two-interval forced choice task without a short-term memory demand, we find that after bilateral removal of area TE, monkeys trained to categorize images based on perceptual similarity (morphs between dogs and cats), are, on the initial viewing, badly impaired when given a new set of images. They improve markedly with a small amount of practice but nonetheless remain moderately impaired indefinitely. The monkeys with bilateral removal of rhinal cortex are, under all conditions, indistinguishable from unoperated controls. We conclude that the final stage of the integration of visual perceptual information into object percepts in the ventral visual stream occurs in area TE. PMID- 30311906 TI - High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect. AB - Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development. PMID- 30311908 TI - Central Dicer-miR-103/107 controls developmental switch of POMC progenitors into NPY neurons and impacts glucose homeostasis. AB - Proopiomelanocortin (POMC) neurons are major negative regulators of energy balance. A distinct developmental property of POMC neurons is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the mechanisms underlying the differentiation of Pomc progenitors remain unknown. Here, we show that the loss of the microRNA (miRNA)-processing enzyme Dicer in POMC neurons causes metabolic defects, an age-dependent decline in the number of PomcmRNA-expressing cells, and an increased proportion of Pomc progenitors acquiring a NPY phenotype. miRNome microarray screening further identified miR-103/107 as candidates that may be involved in the maturation of Pomc progenitors. In vitro inhibition of miR 103/107 causes a reduction in the number of Pomc-expressing cells and increases the proportion of Pomc progenitors differentiating into NPY neurons. Moreover, in utero silencing of miR-103/107 causes perturbations in glucose homeostasis. Together, these data suggest a role for prenatal miR-103/107 in the maturation of Pomc progenitors and glucose homeostasis. PMID- 30311909 TI - WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids. AB - Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism. PMID- 30311910 TI - Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A. AB - TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca2+. This channel comprises two independent pores and closely apposed Ca2+ binding sites that are contained within each subunit of a homodimeric protein. Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino et al., 2017a). Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations. The currents of constitutively active mutants lose their outward rectification as a function of Ca2+ concentration due to the alleviation of energy barriers for anion conduction. This phenomenon originates from Coulombic interactions between the bound Ca2+ and permeating anions and thus demonstrates that an electrostatic gate imposed by the vacant binding site present in the sterically open pore, is released by Ca2+ binding to enable an otherwise sub-conductive pore to conduct with full capacity. PMID- 30311911 TI - Chromatin mapping identifies BasR, a key regulator of bacteria-triggered production of fungal secondary metabolites. AB - The eukaryotic epigenetic machinery can be modified by bacteria to reprogram the response of eukaryotes during their interaction with microorganisms. We discovered that the bacterium Streptomyces rapamycinicus triggered increased chromatin acetylation and thus activation of the silent secondary metabolism ors gene cluster in the fungus Aspergillus nidulans. Using this model, we aim understanding mechanisms of microbial communication based on bacteria-triggered chromatin modification. Using genome-wide ChIP-seq analysis of acetylated histone H3, we uncovered the unique chromatin landscape in A. nidulans upon co cultivation with S. rapamycinicus and relate changes in the acetylation to that in the fungal transcriptome. Differentially acetylated histones were detected in genes involved in secondary metabolism, in amino acid and nitrogen metabolism, in signaling, and encoding transcription factors. Further molecular analyses identified the Myb-like transcription factor BasR as the regulatory node for transduction of the bacterial signal in the fungus and show its function is conserved in other Aspergillus species. PMID- 30311913 TI - How we see the forest and the trees. AB - Signaling pathways in the retina help us see spatial detail in our visual world. PMID- 30311915 TI - Clinician's Commentary on O'Donovan et al.1. PMID- 30311914 TI - Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3 like protein 1 in mild cognitive impairment and Alzheimer's disease. AB - Background: Visinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer's disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD. Methods: We stratified 121 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-beta (Abeta) on above biomarkers within diagnostic groups, the combination of diagnostic group and Abeta status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini-Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI). Results: P-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r = 0.639, p < 0.001) and strongly associated with Abeta pathology across clinical stages of AD, while YKL-40 was correlated with Abeta pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline. Conclusions: CSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD. PMID- 30311916 TI - Clinician's Commentary on Melling et al.1. PMID- 30311917 TI - Clinician's Commentary on Hussey et al.1. PMID- 30311912 TI - Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity. AB - The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes. PMID- 30311918 TI - Clinician's Commentary on Richards et al.1. PMID- 30311919 TI - Clinician's Commentary on Yeldon et al.1. PMID- 30311920 TI - Clinician's Commentary on Parsons et al.1. PMID- 30311921 TI - Clinician's Commentary on Smetaniuk et al.1. PMID- 30311922 TI - Logical MS/MS scans: a new set of operations for tandem mass spectrometry. AB - A new set of operations for tandem mass spectrometry in a linear ion trap is described. Logical MS/MS operations categorize compounds in mixtures based on characteristic structural features as revealed by MS/MS behavior recorded in multiple fragmentation pathways. This approach is a conceptual extension of tandem mass spectrometry in which interrogation of the full data domain is performed by simultaneous implementation of precursor and neutral loss scans. This process can be thought of as moving through the 2D MS/MS data domain along multiple scan lines simultaneously, which allows experiments that explore the 2D data domain of MS/MS to be couched in terms of logical operations, AND, NAND (not and), OR (inclusive or), XOR (exclusive or), NOT, etc. Examples of particular logical conditions include all precursor ions that fragment to both of two selected product ions (logical AND), or all precursor ions that do not produce a specified fragment ion (logical NOT). These and other operational modes (TRUE/FALSE, XOR, OR, etc.) complement and extend the existing set of conventional MS/MS scans, namely product scans, precursor scans, and neutral loss scans. We describe the implementation of logical MS/MS scans on a commercial linear ion trap mass spectrometer using simple mixtures of amphetamines and fentanyl analogues and argue their utility for complex mixture analysis. PMID- 30311923 TI - Catalytic hydrogenation of carboxylic acids using low-valent and high-valent metal complexes. AB - Carboxylic acids are ubiquitous in bio-renewable and petrochemical sources of carbon. The hydrogenation of carboxylic acids to alcohols generates water as the only by-product, and thus represents a sustainable method for the production of these alternative energy carriers/platform chemicals on a large scale. Herein, we offer a brief account of the development of this new concept and molecular insights into cationic mononuclear low- and high-valent transition-metal complexes for the hydrogenation of carboxylic acids. PMID- 30311924 TI - The expanding world of biosynthetic pericyclases: cooperation of experiment and theory for discovery. AB - Covering: 2000 to 2018Pericyclic reactions are a distinct class of reactions that have wide synthetic utility. Before the recent discoveries described in this review, enzyme-catalyzed pericyclic reactions were not widely known to be involved in biosynthesis. This situation is changing rapidly. We define the scope of pericyclic reactions, give a historical account of their discoveries as biosynthetic reactions, and provide evidence that there are many enzymes in nature that catalyze pericyclic reactions. These enzymes, the "pericyclases," are the subject of this review. PMID- 30311925 TI - Stabilization of two-dimensional penta-silicene for flexible lithium-ion battery anodes via surface chemistry reconfiguration. AB - Silicon-based two-dimensional (2D) materials have unique properties and extraordinary engineering applications. However, penta-silicene is unstable. Herein, by employing first-principles calculations, we provide a facile surface chemistry method, i.e. functionalization, to acquire and reconfigure stable penta silicene for use in flexible lithium-ion batteries. Our results of density functional theory calculations showed that the reconfigured penta-silicene nanosheets possess a broad range of properties, including semiconductors with an indirect bandgap, semiconductors with a direct bandgap, semimetals and metals. For fluorinated penta-silicene, a fluorine-concentration-induced transition from a semiconductor to a metal is found. For fully fluorinated penta-silicene, a mechanically induced transition from a semiconductor with an indirect bandgap to a semiconductor with a direct bandgap is obtained. Our calculation results showed the reconfigured penta-silicene is a high-performance anode for use in flexible lithium (Li)-ion batteries. A transition from a semiconductor to a metal with adsorption of Li atoms indicates a high electrical conductivity. It possesses low Li diffusion barriers (0.08-0.28 eV), demonstrating a high mobility of Li ions. The metallic feature and low Li diffusion barriers reveal that it has an ultrafast charge/discharge rate. This work suggests that surface chemistry reconfiguration provides new stable materials with excellent mechanical properties and tunable electronic properties for their promising applications in flexible metal-ion batteries and solar batteries as well as nanoelectronics devices. PMID- 30311926 TI - A luminescent dicyanidonitridotechnetium(v) core with tridentate ligand coordination sites. AB - A novel, luminescent technetium complex, [TcN(CN)2bpa] (bpa = bis-(2 pyridylmethyl)amine), with tridentate ligand coordination sites was synthesized and characterized. Photoemission with a maximum wavelength at 666 nm was observed in the solid-state at 296 K. PMID- 30311927 TI - Pressure-dependent kinetics of methyl formate reactions with OH at combustion, atmospheric and interstellar temperatures. AB - We report the first theoretical characterization of the pressure-dependence of hydrogen abstraction from methyl formate (MF) by a hydroxyl radical (OH) at combustion, atmospheric and interstellar temperatures. The reaction kinetics of MF + OH over a broad temperature range of 20-2000 K were studied using Rice Ramsperger-Kassel-Marcus/master equation (RRKM/ME) theory. The M06-2x/ma-TZVP density functional method was adopted to construct the potential energy surface. The multi-structural torsional (MS-T) method was employed to account for the multi-conformer and torsional coupling effects. The barrier-less entrance channel forming an H-bonded complex was treated by phase state theory using long-range isotropic potential. The inner channel converting the complex into products was treated by both transition state theory and variational transition state theory in conjunction with asymmetric Eckart tunneling. We calculated the rate coefficients at the high-pressure and low-pressure limits, as well as by the pre equilibrium model (PEM). The rate coefficients at 20-2000 K and 0.001-100 bar were determined and compared with the previous experimental results. Our calculations show a fairly good agreement with the measurements at 22-1344 K: a small deviation of <25% at combustion temperatures and a factor of 1.5-2.2 at interstellar temperatures. Besides providing an improved rate coefficient determination at combustion temperatures, we elucidate the pressure-dependence of the rate coefficient at atmospheric and interstellar temperatures. PMID- 30311928 TI - A diglycolamide-functionalized TREN-based dendrimer with a 'crab-like' grip for the complexation of actinides and lanthanides. AB - A generation 1 dendrimer, based on tris(2-aminoethyl)amine (TREN), containing six diglycolamide (DGA) pendent arms (termed TREN-G1-DGA) was synthesized and evaluated for the extraction of actinides and fission product ions. Solvent extraction studies indicated preferential extraction of Eu3+ over Am3+ with a separation factor value of ca. 4.5 in line with the extraction behaviour of multiple DGA ligands in previous reports. The distribution values of Am3+ and Eu3+ were about 12 and 9 times higher, respectively, than those obtained in the case of TREN-DGA using the 1 * 10-3 M ligand in 5% iso-decanol/95% n-dodecane at 3 M HNO3. The 1 : 1 (M : L) extracted species suggested 'inclusion' complex formation where more than one DGA moiety participates in the complex formation. The extracted species were devoid of any inner-sphere coordinated water molecules as confirmed by luminescence spectroscopy. The structure of the complex was also studied by DFT computations and EXAFS which suggested binding of three DGA arms around the central metal ion in the absence of any inner-sphere nitrate ions. PMID- 30311929 TI - Microwave-assisted mass synthesis of Mo1-xWxS2 alloy composites with a tunable lithium storage property. AB - Layered transition metal disulfides (TMDs) possess intriguing properties and hold enormous potential for applications in electronic, optoelectronic, catalytic and energy storage devices. It is an emerging and impactful technology to develop TMD alloys for diverse applications, but mass synthesis of the TMD alloys with tunable compositions and properties remains a major challenge. Herein, we develop a facile but effective microwave-assisted solvothermal method for mass production of Mo1-xWxS2 (0 <= x <= 1) alloy composites. Inexpensive MoCl5, WCl6, and sulfur are used as raw materials and N-methylpyrrolidone (NMP) acts as an excellent reaction solvent. The atomic ratio of Mo/W in the Mo1-xWxS2 alloys can be precisely controlled by adjusting the molar ratio of MoCl5 and WCl6. The relationship between the structures of Mo1-xWxS2 and their properties such as characteristic Raman scattering, electronic conductivity and lithium storage properties is investigated as well. These results demonstrated the feasibility of effectively regulating the performance of the Mo1-xWxS2 alloys and provide a meaningful reference for further research on the Mo1-xWxS2 alloy materials for a variety of applications. PMID- 30311930 TI - Two-dimensional electronic-vibrational spectroscopic study of conical intersection dynamics: an experimental and electronic structure study. AB - The relaxation from the lowest singlet excited state of the triphenylmethane dyes, crystal violet and malachite green, is studied via two-dimensional electronic-vibrational (2DEV) spectroscopy. After excitation of the dyes at their respective absorption maxima, the ensuing excited state dynamics are tracked by monitoring the C[double bond, length as m-dash]C aromatic stretch. With the aid of electronic structure calculations, the observed transitions in the 2DEV spectra are assigned to specific geometries and a detailed story of the evolution of the nuclear wavepacket as it diffuses on the excited state potential energy surface (PES) and ultimately passes through the conical intersection is developed. Notably, it is revealed that the relaxation of the lowest singlet excited state involves intramolecular charge transfer while the nuclear wavepacket is on the excited state PES. Finally, through analyzing the center line slopes of the measured peaks, we show how both solvent motions and changes in the molecular dipole moment affect the correlation between electronic and vibrational degrees of freedom. This work clearly demonstrates the usefulness of 2DEV spectroscopy in following the motion of nuclear wavepackets after photoexcitation and in studying the interactions between the molecular dipole moment and surrounding solvent environment. PMID- 30311931 TI - Z-Scheme MoS2/g-C3N4 heterojunction for efficient visible light photocatalytic CO2 reduction. AB - Z-Scheme MoS2/g-C3N4 heterojunction photocatalysts were fabricated using a hydrothermal deposition procedure together with a calcination route, and then applied for CO2 photoreduction. Experimental results indicated that the 10% MoS2/g-C3N4 heterojunction displayed the best photocatalytic performance. Furthermore, the maximum CO yields of 58.59 MUmol (g-cat)-1 under 7 h-visible light irradiation was up to 2.94 times that of the unadulterated g-C3N4. The enhanced photocatalytic performance of 10% MoS2/g-C3N4 catalyst was due to the favored visible light response, the efficient separation of photogenerated electron-hole pairs as well as its larger specific surface area. PMID- 30311932 TI - Hyperpolarized fumarate via parahydrogen. AB - We produce hyperpolarized [1-13C]fumarate in the proton nuclear spin singlet state by pairwise trans-addition of parahydrogen to a molecular precursor using a ruthenium-based catalyst in water. The proton singlet state is transformed into observable carbon magnetization by radiofrequency pulses to enhance the 13C signal by a factor of 1000 using 50% para-enriched hydrogen gas. PMID- 30311933 TI - Michael additions in polyketide biosynthesis. AB - Covering: up to July 2018Polyketides constitute a large family of natural products exhibiting various biological activities. Polyketide biosynthetic systems employ several strategies for the production of structurally diverse polyketides. Among the polyketide biosynthetic enzymes, a growing number of enzymes that catalyze a Michael-type addition have been identified. These enzymes are responsible for constructing unique polyketide backbone structures, forming heterocycles, and incorporating heteroatoms into the polyketide backbone, all of which contribute to the diversification of the polyketide structure. This review summarizes the current understanding of the function of enzymes catalyzing a Michael-type addition in polyketide biosynthesis, with a particular focus on mechanistic studies. PMID- 30311934 TI - Strategic use of CuAlO2 as a sustained release catalyst for production of hydrogen from methanol steam reforming. AB - Using the new method of sustained release catalysis, CuAlO2 demonstrates stable catalytic performance for methanol steam reforming (MSR). Importantly, the used catalyst can be completely restored to its original state by a simple calcination treatment, demonstrating the super regenerability of the catalytic system. PMID- 30311935 TI - Smart composite hydrogel with pH-, ionic strength- and temperature-induced actuation. AB - A facile and versatile photo-patterning method to fabricate "smart" hydrogels with defined lateral and vertical inhomogeneity of hydrogel composition and dimensions has been developed via generating programmable composite hydrogels and bilayer hydrogels based on thermal and ionic strength-responsive poly(N isopropylacrylamide) and pH-sensitive poly(acrylic acid) hydrogels. These hydrogels are capable of responding to triple-stimuli and inducing reversible "on" and "off" states upon external stimulation due to abrupt volume changes of the responsive hydrogel networks. Moreover, the composite and bilayer hydrogels show a reversible and repeatable direction-controllable bending behavior upon variation of temperature, ionic strength and pH, which is the result of the structural inhomogeneity and the modulation of the hydrogel solvation state in response to these changes. Importantly, different bending behaviors can be structurally programmed by controlling the patterned components, which undergo different swelling or shrinkage and further generate asymmetric internal stresses within the composite hydrogels in a specific manner. Additionally, such asymmetric internal stresses drive the shape deformations of the composite hydrogels, which are promising for potential applications in soft robots and actuators. PMID- 30311936 TI - Anatomical variations and dimensions of arteries in the anterior part of the circle of Willis. AB - BACKGROUND: The aim of this study was to investigate different anatomic variations and dimensions of anterior part of the CW and their prevalence on Kosovo's population. MATERIALS AND METHODS: This is an observative descriptive and retrospective study performed at the University Clinical Center, Clinic of Radiology. The three-dimensional time-of-flight (TOF) technique was used for MRA imaging to evaluate the anatomy of the CW in 513 adults without clinical manifestations for cerebrovascular disease. The diameters of arteries of the CW were measured and variations were recorded. RESULTS: The complete anterior part of CW was found in 64.3% of cases, more evident aboutfemale at about 66% than male 62.2%. Morphologic variations of the ACA1 are agenesis or hypoplasia in 5.65%, fusion of the ACAs on a short distance in 6.5% and fusion of the ACA on a long distance in 2.5%, median ACA is presented in 11 examined patients or 2.1%. Normal ACoA was seen in 68.2%, hypoplasia or absence 15.66%, double ACoA in 0.6% and fenestrations in 3.89%. The mean calibrations of the vessels were measured as 2.04 mm in right A1, 2.06 mm in left A1 and 1.16 mm of ACoA. While, 14.1 mm length of right A1, 13.87 mm of left A1 and 2.99 m of ACoA. CONCLUSIONS: Knowledge of the variations and diameter of the anterior part of the CW has a great importance in determination of anatomical variations and diameter in general populations, also, in interventional radiology for various endovascular interventions as well as during anatomy lessons. PMID- 30311937 TI - Mandibular tori are associated with mandibular bone quality: a case-control study. AB - : Mandibular tori are associated with mandibular bone quality: a case-control study Running title: Tori and mandibular bone quality Nagihan Koc, Leyla Berna Cagirankaya Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Hacettepe University, Sihhiye, Ankara, Turkey ADDRESS FOR CORRESPONDENCE: Nagihan Koc, Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Hacettepe University, Sihhiye, 06230 Ankara, Turkey, tel: 90-312-305-22-05, fax: 90-312-310-44-40, e-mail: nagihan.koc@hacettepe.edu.tr ABSTRACT: BACKGROUND: : Torus mandibularis (TM) is one of the most common oral exostoses. The presence of TMs has been correlated with high skeletal bone mineral density. This study aimed to evaluate the relationship between TM and mandibular bone quality based on the measurement of mandibular cortical index (MCI). MATERIALS AND METHODS: A case control study was designed for patients who attended the Oral and Maxillofacial Radiology Clinic at the University of Hacettepe, Ankara, Turkey for routine dental examination. Patients with TMs were defined as cases, and those without TMs were defined as controls. The presence of tori was assessed by visual inspection and digital palpation. MCI assessments were done based on Klemetti's classification in separate sessions after completing all clinical examinations. The associations between the presence of TMs, MCI and parafunctional activity were assessed. RESULTS: The sample consisted of 80 subjects with TMs and 80 control subjects. The presence of TMs was strongly associated with parafunctional activity (P = 0.036) and a non-eroded mandibular cortex (MCI C1, P = 0.001). CONCLUSIONS: Parafunctional activity may be a factor related to formation or existence of TMs. The association between TMs and mandibular morphology may suggest that subjects with TMs may have a higher mandibular bone quality compared to those without TMs. PMID- 30311938 TI - The effects of leptin on F-actin remodelling in type-I diabetes. AB - BACKGROUND: The aim of the current study is to investigate the effect of leptin on cytoskeleton structures in both in vivo and in vitro model of diabetes. MATERIALS AND METHODS: For in vivo studies, leptin in different doses (240, and 480 mg/kg) was injected to the diabetic rats after one-week of Streptozotocin (STZ, 55 mg/kg) treatment. Leptin levels were analyzed in serum, liver, and pancreas samples. Hepatic and pancreatic F-and G- actin expressions were determined by Western blotting. For in vitro studies, hepatic and pancreatic primary cell lines were obtained from the control rats. To these cultures, STZ (15 and 30 mM), leptin (50, 60 and 100 ng/ml), and their combinations were applied for one, three, and four weeks. After the treatment period, F-actin was visualized by the Alexa-fluor fluorescent dye. RESULTS: STZ decreased the G-actin in both tissues in vivo. However, leptin caused a dose-dependent increase in G actin levels while F-actin decreased in both tissues. Moreover, leptin caused the perimembranous condensation of actin filaments and amelioration of F-actin structures in vivo. A dose-dependent corruption of F-actin filament structures was observed in leptin-treated primary cells in vitro, while STZ also caused corruption of these filaments. Co-exposure of STZ and leptin caused the amelioration of F-actin filaments, while the perimembranous condensation was also observed as was in vivo study. CONCLUSIONS: Leptin therapy could be a candidate for diabetes, but it should not be ruled out as being important the severity of diabetes and leptin doses. PMID- 30311939 TI - Diurnal protein oscillation profiles in Drosophila head. AB - Circadian clocks control daily rhythms in physiology, metabolism and behaviour in most organisms. Proteome-wide analysis of protein oscillations is still lacking in Drosophila. In this study, the total protein and phosphorylated protein in Drosophila heads in a 24-h daily time-course were assayed by using the isobaric tags for relative and absolute quantitation (iTRAQ) method, and 10 and 7 oscillating proteins as well as 19 and 22 oscillating phosphoproteins in the w1118 control and ClkJrk mutant strains were separately identified. Lastly, we performed a mini screen to investigate the functions of some oscillating proteins in circadian locomotion rhythms. This study provides the first proteomic profiling of diurnally oscillating proteins in fly heads, thereby providing a basis for further mechanistic studies of these proteins in circadian rhythm. PMID- 30311940 TI - The role of caspase-8, caspase-9, and apoptosis inducing factor in periodontal disease. AB - BACKGROUND: Caspases are key mediators of apoptosis. Caspase-8 mediates extrinsic, and caspase-9 initiates the intrinsic pathway of apoptosis. Apoptosis Inducing Factor (AIF), a mitochondrial proapoptotic protein, mediates cell death by a caspase-independent process. Because apoptosis is involved in periodontal disease, this study evaluated caspase-8, -9, and AIF in periodontal disease. METHODS: Twenty periodontally healthy volunteers (Group Healthy), 20 patients with generalized aggressive periodontitis (Group AgP), and 20 patients with generalized chronic periodontitis (Group CP) were included in this study. Levels of caspase-8, -9, and AIF were evaluated in gingival crevicular fluid (GCF) of all participants via enzyme-linked immunosorbent assays. RESULTS: AIF was significantly higher in the AgP (P = 0.07) and CP groups (P = 0.01) than the Healthy group, and similar to the CP and AgP groups (P > 0.05). Caspase-8 was significantly higher in the CP and Healthy groups than the AgP group (P = 0.00), and similar between Healthy and CP groups (P > 0.05). Caspase-9 was significantly higher in the AgP group than the Healthy group (P = 0.01), and similar between Healthy and CP groups (P > 0.05). CONCLUSION: The mitochondrial-centered intrinsic pathway involving caspase-9 and AIF, and the extrinsic pathway involving caspase-8 are significant for aggressive periodontitis. The intrinsic pathway involving caspase-independent AIF is also significant for chronic periodontitis. PMID- 30311941 TI - Peri-implant soft tissue status and crestal bone levels around adjacent implants placed in cigarette smokers and never smokers: Five-year follow-up results. AB - BACKGROUND: It is hypothesized that peri-implant soft tissue inflammation and crestal bone loss (CBL) are higher around adjacent implants placed in cigarette smokers compared with never smokers. The aim of the present 5-years follow-up retrospective clinical study was to compare the peri-implant soft tissue status and CBL around adjacent implants placed in cigarette smokers and never smokers. METHODS: Cigarette smokers (group 1) and never smokers (group 2) with adjacent dental implants were included. Demographic information regarding age, sex, duration of smoking (pack-years), daily frequency of toothbrushing and most recent visit to a dentist or dental hygienist were recorded using a questionnaire. Information regarding implant dimensions (length * diameter), duration of implants in function, loading protocol (and type of restoration was recorded. Peri-implant plaque index (PI), bleeding on probing (BOP), probing depth (PD), and mesial and distal CBL were measured. P <0.05 were considered statistically significant. RESULTS: Seventy-two male participants (37 in group 1 and 35 in group 2) were included. The mean age of individuals in groups 1 and 2 were 50.3 +/- 5.4 and 48.5 +/- 3.8 years, respectively. In group 1, the mean duration of cigarette smoking was 22.3 +/- 1.6 pack years. A family history of smoking was more often reported by individuals in group 1 compared with group 2. In groups 1 and 2, 54 and 70 adjacent implants, respectively were placed in the regions of missing premolars and molars. All implants were delayed loaded and were fixed with non-splinted screw-retained restorations. In groups 1 and 2, toothbrushing twice daily was reported by 78.3% and 74.2% individuals, respectively. There was no statistically significant difference in peri-implant PI, BOP, PD, and mesial and distal CBL among individuals in groups 1 and 2. CONCLUSIONS: Peri-implant soft tissue status and crestal bone levels were comparable around adjacent dental implants placed in cigarette smokers and never smokers. PMID- 30311942 TI - Type II or type III radical hysterectomy compared to chemoradiotherapy as a primary intervention for stage IB2 cervical cancer. AB - BACKGROUND: Cervical cancer is the fourth most common cancer in women, with 528,000 estimated new cases globally in 2012. A large majority (around 85%) of the disease burden occurs in low- and middle-income countries (LMICs), where it accounts for almost 12% of all female cancers. Treatment of stage IB2 cervical cancers, which sit between early and advanced disease, is controversial. Some centres prefer to treat these cancers by radical hysterectomy, with chemoradiotherapy reserved for those at high risk of recurrence. In the UK, we treat stage IB2 cervical cancers mainly with chemoradiotherapy, based on the rationale that a high percentage will have risk factors necessitating chemoradiotherapy postsurgery. There has been no systematic review to determine the best possible evidence in managing these cancers. OBJECTIVES: To determine if primary surgery for stage IB2 cervical cancer (type II or type III radical hysterectomy with lymphadenectomy) improves survival compared to primary chemoradiotherapy.To determine if primary surgery combined with postoperative adjuvant chemoradiotherapy, for stage IB2 cervical cancer increases patient morbidity in the management of stage IB2 cervical cancer compared to primary chemoradiotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3), MEDLINE via Ovid (1946 to April week 2, 2018) and Embase via Ovid (1980 to 2018 week 16). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies up to April 2018. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), quasi-RCTs or non-randomised studies (NRSs) comparing surgery to chemoradiotherapy in stage IB2 cervical cancers. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data, assessed risk of bias and analysed data using standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 4968 records from the literature searches, but we did not identify any RCTs that compared primary surgery with chemoradiotherapy in stage IB2 cervical cancer.We found one NRS comparing surgery to chemoradiotherapy in IB2 and IIA2 cervical cancers which met the inclusion criteria. However, we were unable to obtain data for stage IB2 cancers only and considered the findings very uncertain due to a high risk of selection bias. AUTHORS' CONCLUSIONS: There is an absence of high-certainty evidence on the relative benefits and harms of primary radical hysterectomy versus primary chemoradiotherapy for stage IB2 cervical cancer. More research is needed on the different treatment options in stage IB2 cervical cancer, particularly with respect to survival, adverse effects, and quality of life to facilitate informed decision-making and individualised care. PMID- 30311943 TI - Emery-Dreifuss muscular dystrophy-related myopathy with TMEM43 mutations. PMID- 30311944 TI - Proinflammatory cytokine levels and peri-implant parameters among cigarette smokers, individuals vaping electronic cigarettes, and non-smokers. AB - BACKGROUND: Tobacco smoking compromises the prognosis of dental implant treatment and is associated with increased risk of peri-implant bone loss and increased implant failure rate. There is a dearth of studies that have compared clinical, radiographic, and immunological peri-implant parameters among cigarette smokers (CS), individuals vaping e-cigarettes (e-cigs), and non-smokers (NS). This study aimed to compare clinical and radiographic peri-implant parameters and levels of matrix metalloproteinase (MMP)-9 and interleukin (IL)-1beta levels among CS, individuals' vaping e-cigs, and NS. METHODS: Thirty-two CS (group 1), 31 individuals vaping e-cigs (group 2), and 32 NS (group 3) were included. Demographic- and implant-related data were collected using a structured baseline questionnaire. Peri-implant plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were recorded and marginal bone loss (MBL) were assessed using standardized digital radiographs. Enzyme-linked immunosorbent assay was used to assess levels of MMP-9 and IL-1beta in peri-implant sulcular fluid. Pearson correlation coefficient was used to analyze for correlations of MMP-9 and IL 1beta levels with peri-implant parameters. RESULTS: BOP showed significantly higher values in group 3 as compared with groups 1 and 2 (P < 0.01). PI (P < 0.01), PD >= 4 mm (P < 0.01), and mean concentrations of MMP-9 (P < 0.001) and IL 1beta (P < 0.01) were significantly higher in groups 1 and 2 than group 3. MBL was significantly higher in group 1 as compared with group 2 and group 3 (P < 0.01). Significant positive correlations were found between MMP-9 (P = 0.0198) and IL-1beta (P = 0.0047) levels and MBL in group 1; and a significant positive correlation between IL-1beta and MBL in group 2 (P = 0.0031). CONCLUSIONS: Peri implant health was compromised among CS than vaping individuals and NS. Increased levels of proinflammatory cytokines in CS and vaping individuals may suggest greater peri-implant inflammatory response. PMID- 30311945 TI - The human rights impact of gender stereotyping in the context of reproductive health care. AB - Gender stereotypes surrounding women's reproductive health impede women's access to essential reproductive healthcare and contribute to inequality more generally. Stereotyping in healthcare settings impedes women's access to contraceptive information, services, and induced abortion, and lead to involuntary interventions in the context of sterilization. Decisions by human rights monitoring bodies, such as the Inter-American Court of Human Rights' case, IV v. Bolivia, which was a case concerned with the involuntary sterilization of a woman during childbirth, highlight how stereotypes in the context of providing health care can operate to strip women of their agency and decision-making authority, deny them their right to informed consent, reinforce gender hierarchies and violate their reproductive rights. In the present article, IV v. Bolivia is examined as a case study with the objective being to highlight how, in the context of coercive sterilization, human rights law has been used to advance legal and ethical guidelines, including the International Federation of Gynecology and Obstetrics' (FIGO) own guidelines, on gender stereotyping and reproductive healthcare. The Inter-American Court's judgment in IV v. Bolivia illustrates the important role FIGO's guidance can play in shaping human rights standards and provides guidance on the service provider's role and responsibility in eliminating gender stereotypes and upholding and fulfilling human rights. PMID- 30311946 TI - The inner mitochondrial membrane protein ANT1 modulates IL-6 expression via the JNK pathway in macrophages. AB - Mitochondria are increasingly associated with inflammation. Here, we focus on the relationship between inflammation and adenine nucleotide translocator type 1 (ANT1), which is localized in the mitochondrial inner membrane. ANT1 plays an important role in oxidative phosphorylation, and mutations in the ANT1 gene are responsible for mitochondrial diseases. Ample studies have demonstrated that ANT1 has a critical role in cardiomyocytes and neurons, but little has been reported on its functions in immune cells. We knocked down ANT1 expression in macrophages and examined inflammatory cytokine expression after lipopolysaccharide stimulation. ANT1 knockdown reduces the expression of IL-6. JNK, upstream of IL 6, is downregulated, but other MAP kinases and the NF-kappaB signaling remain unchanged. These results suggest that ANT1 modulates IL-6 expression through JNK in macrophages. PMID- 30311947 TI - The triple-filter bubble: Using agent-based modelling to test a meta-theoretical framework for the emergence of filter bubbles and echo chambers. AB - Filter bubbles and echo chambers have both been linked recently by commentators to rapid societal changes such as Brexit and the polarization of the US American society in the course of Donald Trump's election campaign. We hypothesize that information filtering processes take place on the individual, the social, and the technological levels (triple-filter-bubble framework). We constructed an agent based modelling (ABM) and analysed twelve different information filtering scenarios to answer the question under which circumstances social media and recommender algorithms contribute to fragmentation of modern society into distinct echo chambers. Simulations show that, even without any social or technological filters, echo chambers emerge as a consequence of cognitive mechanisms, such as confirmation bias, under conditions of central information propagation through channels reaching a large part of the population. When social and technological filtering mechanisms are added to the model, polarization of society into even more distinct and less interconnected echo chambers is observed. Merits and limits of the theoretical framework, and more generally of studying complex social phenomena using ABM, are discussed. Directions for future research such as ways of comparing our simulations with actual empirical data and possible measures against societal fragmentation on the three different levels are suggested. PMID- 30311948 TI - Trehalose powder for subgingival air-polishing during periodontal maintenance therapy: A randomized controlled trial. AB - BACKGROUND: Air-polishing appears to be a promising procedure for subgingival biofilm removal in periodontal treatment. The aim of this study was to compare trehalose powder for subgingival air-polishing with sonic debridement in residual periodontal pockets during maintenance therapy. METHODS: In this blinded, randomized, controlled clinical trial conducted over 6 months with a split-mouth design, single-rooted teeth in 44 participants with residual pocket depths of 5 mm and bleeding or >5 mm with and without bleeding were included in this study. Subgingival debridement was carried out using either trehalose powder with an air polishing device (test) or a sonic device (control). The reduction in the probing depths after 3 and 6 months was defined as the primary endpoint. A visual analog scale was used to evaluate the discomfort of both procedures. RESULTS: Both procedures showed statistically significant intragroup reductions in probing depths (test baseline [BL] 5.52 +/- 0.93, 6 months 3.66 +/- 0.81, control BL 5.55 +/- 0.9, 6 months 3.68 +/- 0.86, P < 0.001), clinical attachment level (test BL 6.93 +/- 1.5, 6 months 5.3 +/- 1.52, control BL 7.27 +/- 1.8, 6 months 5.84 +/- 1.71, P < 0.001), and bleeding on probing (test BL 86%, 6 months 41%, control BL 89%, 6 months 34%, P < 0.001) after 6 months with no significant intergroup differences (P > 0.05, respectively). The visual analog scale showed a significantly lower incidence of discomfort for air-polishing compared with sonic scaling (test 2.33 +/- 2.14, control 4.91 +/- 2.65, P < 0.001). CONCLUSIONS: Subgingival air-polishing with trehalose powder showed comparable clinical outcomes to sonic scaling. Sonic scaling evoked more discomfort compared with air polishing. PMID- 30311949 TI - Dynamic structural rearrangements and functional regulation of voltage-sensing phosphatase. AB - The voltage-sensing phosphatase, VSP, consists of the voltage sensor domain (VSD) and the cytoplasmic catalytic region. The latter contains the phosphatase domain and the C2 domain, showing remarkable similarity to a tumor suppressor enzyme, PTEN. In VSP, membrane depolarization induces the conformational change in the VSD, which activates the phosphoinositide phosphatase. The final outcome of VSP is enzymatic activity of the cytoplasmic region unlike voltage-gated ion channels where conformational change of the transmembrane pore is induced by the VSD. Therefore, it is crucial to detect structural change of the cytoplasmic catalytic region to gain insights into operating mechanisms of VSP. This review summarizes a recent study of applying a method of genetic incorporation of a noncanonical amino acid, Anap, to detect dynamic rearrangements of the structure of the catalytic region of sea squirt VSP (Ci-VSP) under control of membrane voltage. Both the phosphatase domain and the C2 domain move in a similar timing upon membrane depolarization, suggesting that the two regions are coupled to each other. Measurement of FRET between Anap introduced into the C2 domain of Ci-VSP and dipicrylamine in cell membrane suggested no large motion of the enzyme toward the membrane. Fluorescence change of Anap induced by different membrane potentials indicates the presence of multiple conformations of the active enzyme. A fluorescent unnatural amino acid, Anap, was genetically incorporated into the catalytic domain of Ci-VSP in Xenopus oocytes. The fluorescence uncovered the conformation change associated with catalytic activity of Ci-VSP. This article is protected by copyright. All rights reserved. PMID- 30311950 TI - Time course and temperature dependence of synaptic vesicle endocytosis. AB - In presynaptic nerve terminals, synaptic vesicles are recycled locally via an evolutionarily conserved process that ensures maintenance of neurotransmission as well as structural integrity of synapses. Temperature is a key environmental factor that impacts critical steps involved in fusion, endocytosis and transport in different vesicle trafficking pathways. In neurons, temperature changes have been shown to impact synaptic vesicle recycling and synaptic efficacy. But contrary to non-neuronal systems, the temperature dependence of the steps involved in fusion, endocytosis and recycling of synaptic vesicles in presynaptic terminals is not completely understood, and the existing data remain highly debated. In this Review, we discuss the implications of biophysical, biochemical and functional findings on temperature dependence of membrane retrieval in multiple systems. We propose that systematic investigation of the temperature dependence of the presynaptic vesicle trafficking process can provide novel insight into poorly understood mechanisms that govern synaptic vesicle trafficking under diverse physiological conditions. PMID- 30311951 TI - Incidence of immune thrombocytopenia in Taiwan: a nationwide population-based study. AB - BACKGROUND: The incidence of immune thrombocytopenia (ITP) is not well known in Asians. The aims of this study were to survey incidences and clinical features of ITP in Taiwan. STUDY DESIGN AND METHODS: This study identified 4855 incident ITP cases from the population-based National Health Insurance Research Database from mid-2006 to mid-2013, and compared incidences, patient characteristics, and clinical manifestations of ITP by age. RESULTS: Respective ITP incidence rates among those aged <15, 15 to 59, and >=60 years were 4.0, 2.0, and 5.4 per 100,000 person-years. A male predominance was noted in children, and a female predominance was found in adults. The most common causes of secondary ITP were systemic lupus erythematosus (21.8%), viral hepatitis C (16.9%), and viral hepatitis B (13.4%). The rate of secondary ITP in children was less than one fifth that in adults (4.2% vs. 23.8%). Rates of central nervous system (1.1%) and gastrointestinal tract bleeding (3.3%) were rare, with variations by age. The rate of splenectomies in children (0.4%) was only one tenth that in adults (4.1%). The disease in 25% of children and 30% of adults became persistent or chronic. A decreasing trend in the ITP incidence was found (annual percentage change, -4.9%), and it was confined to those aged >15 years. CONCLUSION: Incidence estimates of ITP in Taiwan were close to those of Western countries, with age-specific variations in sex ratio, comorbidity, splenectomy, secondary causes, and incidence trends. The results suggest no racial variations in ITP incidences, but a geographical difference in causes of secondary ITP. PMID- 30311952 TI - Portable fluorescence-based microRNA detection system based on isothermal signal amplification technology. AB - MicroRNAs (miRNAs) diagnostics can be useful for diagnosing or confirming miRNA abundance and are used in screening tests and to assess changes in miRNAs in vivo. At present, the use of traditional nucleic acid amplification assays to detect miRNAs has been limited in laboratory environment because of the time, equipment, and technical expertise required to perform these assays. A specialized, rapid affordable miRNA detection system is necessary when there are limited resources or point-of-care testing needs. We designed a portable and affordable fluorescence-based miRNA detection system based on isothermal signal amplification technology, using SYBR Green II as a fluorescent dye. To reduce costs, we chose LED as a light source and designed the corresponding optical path for LED. The portable detection system shows results consistent with those by real-time PCR, and can be used to detect miR-183 with a limit of detection of approximately 2 fmol. We used the system to detect miR-183 in tissues and blood from patients with hepatocellular carcinoma (HCC). The results from the portable detection device were compared with those from clinical trials and indicated that the miR-183 fluorescence signal could successfully identify HCC and provide information related to cancer progression. PMID- 30311953 TI - "'Academic' is a dirty word": Intended impact pathways of an emerging academic health centre in tropical regional Australia. AB - BACKGROUND: The Tropical Australian Academic Health Centre (TAAHC) is being established in northern Queensland across a vast rural geography. The study aim is to identify intended impact pathways and beneficiaries of TAAHC as well as experienced and anticipated challenges. METHODOLOGY: The study is an empirical case study nested within a comparative multi-case study on academic health centres (AHCs). Data were collected from documents, observation, and interviews with 24 health system and university stakeholders. Intended impact pathways were identified abductively from analysis of aspirations and challenges. RESULTS: Aspirations of TAAHC reflect an ultimate aim to improve the health of the northern Queensland population. Challenges were trust and communication, understanding value and return on investment, health system receptiveness to building a research culture, prioritising and influencing the research agenda, and structure of the health system. DISCUSSION: The study identifies three interdependent transitions that comprise the main intended impact pathway in TAAHC. Stakeholders expected TAAHC to effect health systems change and improvement rather than drive discovery-oriented academic research associated with AHCs elsewhere. CONCLUSION: The findings contribute to the empirical evidence base on the role of AHCs internationally and to ongoing initiatives to establish and resource AHCs in Australia. PMID- 30311954 TI - Accuracy of hydrocortisone dose administration via nasogastric tube. AB - OBJECTIVE: Hydrocortisone via nasogastric (NG) tube is used in sick children with adrenal insufficiency; however, there is no licensed formulation for NG administration. METHODS: We investigated hydrocortisone recovery after passage through NG tubes in vitro for three formulations: liquid suspension, crushed tablets mixed with water, and hydrocortisone granules designed for oral administration to children. Cortisol was measured by LC-MS/MS. RESULTS: Hydrocortisone content was variable and recovery low after preparation in syringe and prior to passage through NG tubes. For doses, 0.5 and 2.0 mg mean percentage recovery was as follows: liquid suspension 57% and 58%; crushed tablets 46% and 30%; and hydrocortisone granules 78% and 71%. Flushing the administering syringe increased recovery. Hydrocortisone recovery after passage with flushing through 6 12Fr gauge NG tubes was variable: liquid suspension 61%-92%, crushed tablets 40% 174%, hydrocortisone granules 61%-92%. Administration of hydrocortisone granules occluded 6 and 8Fr NG tubes; however, administration using a sampling needle to prevent granules being administered gave a recovery of 74%-98%. CONCLUSIONS: The administration of hydrocortisone through NG tubes is possible; however, current methods deliver a variable dose of hydrocortisone, generally less than that prescribed. Attention should be placed on the technique used to optimize drug delivery such as flushing of the administering syringe. Hydrocortisone granules block small NG tubes but behaved as well as the commonly used liquid suspension when prepared with a filtering needle that filters out granules. PMID- 30311956 TI - The accessibility of health services to young deaf adolescents in Ghana. AB - Quality health care is a fundamental human right, which is enshrined in several international and domestic legislative instruments. In the Ghanaian context, there are reports that adults with disabilities encounter barriers in their attempts to access health care. However, scholarly attention is yet to explore the perspectives of young people and adolescents with disabilities. Therefore, this quantitative study was conducted from the perspective of critical disability studies, where young deaf adolescents (YDAs) were regarded as right bearers, and where they shared their perspectives on health accessibility decisions, barriers, and needs. Sixty-seven participants, made up of 44 male and 23 female students, took part in this quantitative study. Although many YDAs who took part in this study indicated that it was not difficult to access health facilities, they claim to have encountered communication barriers. Sign language interpreters in health facilities and introduction of sign language courses in health training institutions to improve communication between health professionals and deaf patients have been suggested as ways of addressing the barriers faced by YDAs in Ghana. PMID- 30311955 TI - Short interpregnancy intervals and adverse maternal outcomes in high-resource settings: An updated systematic review. AB - BACKGROUND: Currently, no federal guidelines provide recommendations on healthy birth spacing for women in the United States. This systematic review summarises associations between short interpregnancy intervals and adverse maternal outcomes to inform the development of birth spacing recommendations for the United States. METHODS: PubMed/Medline, POPLINE, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, and a previous systematic review were searched to identify relevant articles published from 1 January 2006 and 1 May 2017. Included studies reported maternal health outcomes following a short versus longer interpregnancy interval, were conducted in high-resource settings, and adjusted estimates for at least maternal age. Two investigators independently assessed study quality and applicability using established methods. RESULTS: Seven cohort studies met inclusion criteria. There was limited but consistent evidence that short interpregnancy interval is associated with increased risk of precipitous labour and decreased risks of labour dystocia. There was some evidence that short interpregnancy interval is associated with increased risks of subsequent pre pregnancy obesity and gestational diabetes, and decreased risk of preeclampsia. Among women with a previous caesarean delivery, short interpregnancy interval was associated with increased risk of uterine rupture in one study. No studies reported outcomes related to maternal depression, interpregnancy weight gain, maternal anaemia, or maternal mortality. CONCLUSIONS: In studies from high resource settings, short interpregnancy intervals are associated with both increased and decreased risks of adverse maternal outcomes. However, most outcomes were evaluated in single studies, and the strength of evidence supporting associations is low. PMID- 30311957 TI - What benefits do immunocompromised children get from the varicella zoster virus vaccination? PMID- 30311959 TI - Lithium, valproate, and carbamazepine prescribing patterns for long-term treatment of bipolar I and II disorders: A prospective study. AB - OBJECTIVE: This study aims to describe the prescription patterns of the mood stabilizers most commonly used for the treatment of bipolar I and II disorders (lithium, valproate, and carbamazepine) and to analyze the treatment outcomes. METHODS: Two hundred and thirty-four outpatients with bipolar disorders receiving prophylactic treatment with lithium, valproate, carbamazepine, or their combination were followed up for at least 18 months in two Italian psychiatric centers specialized in mood disorders. RESULTS: The combination of lithium and valproate or carbamazepine was the most common prophylactic treatment (54.3%), followed by valproate or carbamazepine (24%) and lithium monotherapy (22%). Polytherapy was prescribed mainly to patients with bipolar I disorder, a high number of previous episodes and lifetime psychotic symptoms, whereas valproate or carbamazepine monotherapy was prescribed to patients with anxiety comorbidity. The annual frequency of recurrences decreased significantly after entering the study in the overall sample, and the reduction was significantly higher in patients on lithium plus valproate or carbamazepine compared with the valproate or carbamazepine group, but not with the lithium monotherapy group. The number of mixed recurrences during the follow-up was significantly higher in patients on lithium plus valproate or carbamazepine. CONCLUSIONS: Our findings may help clinicians to personalize long-term treatment to prevent relapses of bipolar disorder according to clinical presentation. PMID- 30311958 TI - Good practices for the design, analysis, and interpretation of observational studies on birth spacing and perinatal health outcomes. AB - BACKGROUND: Meta-analyses of observational studies have shown that women with a shorter interpregnancy interval (the time from delivery to start of a subsequent pregnancy) are more likely to experience adverse pregnancy outcomes, such as preterm delivery or small for gestational age birth, than women who space their births further apart. However, the studies used to inform these estimates have methodological shortcomings. METHODS: In this commentary, we summarise the discussions of an expert workgroup describing good practices for the design, analysis, and interpretation of observational studies of interpregnancy interval and adverse perinatal health outcomes. RESULTS: We argue that inferences drawn from research in this field will be improved by careful attention to elements such as: (a) refining the research question to clarify whether the goal is to estimate a causal effect vs describe patterns of association; (b) using directed acyclic graphs to represent potential causal networks and guide the analytic plan of studies seeking to estimate causal effects; (c) assessing how miscarriages and pregnancy terminations may have influenced interpregnancy interval classifications; (d) specifying how key factors such as previous pregnancy loss, pregnancy intention, and maternal socio-economic position will be considered; and (e) examining if the association between interpregnancy interval and perinatal outcome differs by factors such as maternal age. CONCLUSION: This commentary outlines the discussions of this recent expert workgroup, and describes several suggested principles for study design and analysis that could mitigate many potential sources of bias. PMID- 30311960 TI - Muscle weakness and functional disability in patients with myasthenia gravis. AB - INTRODUCTION: Muscle weakness and functional disability have not been evaluated in a population-based study of patients with myasthenia gravis (MG). METHODS: All patients with MG in a well-defined catchment area were identified in the Danish National Patient Registry. Of the 175 eligible patients, 90 participated and were studied using MG-specific scales, isometric dynamometry, and functional tests. Fifty age- and sex-matched subjects served as controls. RESULTS: Muscle strength was reduced by 13%, 21%, and 12% for shoulder abduction, knee extension, and ankle extension, respectively (P < 0.05). Chair stand and 400-meter walking were impaired by 24% and 23%, respectively (P < 0.05). Muscle strength and functional performances were related to MG-specific scales. DISCUSSION: MG patients have moderately reduced isometric muscle strength and impaired physical performance. Muscle weakness and functional tests relate closely to MG-specific scales, suggesting that dynamometry and functional tests can be used to monitor MG patients and as efficacy parameters in clinical trials. Muscle Nerve, 2018. PMID- 30311961 TI - Napping characteristics and cognitive performance in older adults. AB - OBJECTIVES: To determine the association of napping intention, frequency, and duration with cognition in a nationally-representative sample of US older adults. METHODS: We performed a cross-sectional analysis of community-dwelling Medicare beneficiaries aged >=65 years from Rounds 3 or 4 (2013-2014) of the National Health and Aging Trends Study (N = 2549). Participants reported past-month napping intention (intentional/unintentional), napping frequency (rarely/never [non-nappers], some days [infrequent nappers], most days/every day [frequent nappers]), and average nap duration (we categorized as <=30 minutes [short]; 31 60 minutes [moderate]; and > 60 minutes [long]). Cognitive outcomes were performance on immediate and delayed word recall tests (IWR and DWR, respectively), the Clock Drawing Test (CDT), and self-rated memory (score: 1[excellent]-5[very poor]). RESULTS: After adjustment for potential confounders, unintentional nappers had poorer immediate word recall test performance than non nappers (B = -0.23, P < 0.01) and intentional nappers (B = -0.26, P < 0.01). After further adjustment for daytime sleepiness, frequent nappers reported poorer self-rated memory than non-nappers (B = 0.14, P < 0.05). Compared with short nappers, long nappers had poorer IWR (B = -0.26, P < 0.05) and CDT scores (B = 0.17, P < 0.05). Except for the association of nap duration with IWR and CDT, these associations remained after excluding participants with dementia and/or proxy respondents. Among participants undiagnosed with dementia or proxies, moderate-duration naps were associated with better DWR than short naps (B = 0.24, P < 0.05). Neither napping intentionality nor frequency was associated with CDT performance. CONCLUSIONS: Among older adults, distinct aspects of napping are associated with cognitive performance. Prospective research, with objective measures of napping, is needed to elucidate the link between napping and cognitive trajectories. PMID- 30311962 TI - Erratum. PMID- 30311963 TI - Violence as a health disparity: Adolescents' perceptions of violence depicted through photovoice. AB - Violence is a public health issue that disproportionately affects adolescents from historically marginalized communities. In response to growing concerns of local violence, our community-academic partnership explored adolescents' perspectives about violence, including perceptions of its causes, consequences, and potential solutions. Ten adolescents participated in a 12-week photovoice project. They received training in basic research methodologies, documented representations of violence through digital photography and creative writing, engaged in empowerment-based photo-discussions, and presented their work to influential advocates in a community forum. Adolescents and staff conducted a thematic analysis of photographs and narratives from which 10 themes emerged across 3 domains: a culture of violence and oppression, structural violence, and mental and physical health. Adolescents presented their work to community stakeholders in a public forum to foster additional discussions regarding violence in the community. This photovoice project yielded rich qualitative insight into adolescents' experiences with and perceptions of violence. PMID- 30311964 TI - Validation of the Brief Sense of Community Scale among youth of color from an underserved urban community. AB - Neighborhood sense of community (SOC) is a key construct in the community psychology literature. While the research on neighborhood SOC has progressed significantly, there is a need to further validate the Brief Sense of Community Scale (BSCS) among youth. A critical area of scholarship, therefore, is to examine the factor structure of the BSCS among a cohort of adolescents, particularly from the United States. This study tested the factor structure of the BSCS among a sample of urban youth of color (N = 383) using SPSS AMOS, a structural equation modeling software. After testing the factor structure, we examined the relationships between each of the BSCS subscales and conceptually related variables (e.g., psychological empowerment, relational power, and school importance). Results from this study confirm the first- and second-order factor structure of the BSCS among youth. BSCS and its underlying subscales were both correlated with one another and correlated with the intrapersonal component of psychological empowerment, relational power, and school importance. Our findings have critical implications for the field of community psychology and the development and use of the BSCS among adolescents. PMID- 30311965 TI - The development of the Systems and Individual Responsibility for Poverty (SIRP) Scale. AB - Poverty is a widespread social problem that affects a substantial number of Americans each year. Attitudes can affect a range of judgments, behavioral intentions, and actions related to addressing this problem. However, existing tools that measure attitudes toward those in poverty do not fully capture the deficit ideology that is a critical component of beliefs about social class. We developed the Systems and Individual Responsibility for Poverty (SIRP) Scale to address this gap. This article describes the development of an initial pool of 20 items, and then the refinement and validation of the final 17-item measure. Exploratory factor analysis (N = 260) and confirmatory factor analysis (N = 280) yielded 2 factors: Individual Responsibility and Systems Responsibility. The Individual Responsibility factor comprises two subscales, differentiating between reasons for getting into and not getting out of poverty. The SIRP is a new tool for evaluating community psychologists' efforts to shift deficit-oriented thinking about poverty, and is likely to be particularly useful in education contexts. In future work, community psychologists might adapt the measure to assess deficit oriented thinking about other problems, and to explore how such attitudes are related to behavior. PMID- 30311966 TI - "A unique little microcosm": Exploring a self-sustaining community project which harnessed social action in a public space. AB - Government policy in England encourages communities to capacity build from within. Community psychology has explored the role of community resilience in this process. But what happens if a community appears to lack formalized resources? This article considers such a community in which a grassroots community center thrives outside the boundaries of formalized community organizations. It aimed to find out how this community mobilized, the benefits for those connected, and how the center survives. A grounded theory 'center as a living organism' was constructed from the accounts of eleven participants. Results indicate how community centers play a role in promoting individual and community level well-being and preventing distress. The importance of learning from progressive community initiatives and more partnership working between National Health Service, statutory, voluntary, and community groups is indicated. Effective engagement with and across communities to promote resilience and well being is also a theme of the responses to recent events in England, such as the terrorist attacks and the Grenfell Tower fire. PMID- 30311967 TI - The role of perceived friend depression and perceived stigma on self-reported depression among individuals who use drugs. AB - Depression and substance use are highly comorbid, and stigmatized, mental health conditions influenced by social network factors. The objective of this study was to explore the role of perceived depression and perceived mental health stigma among friends on self-reported depression over time. Between 2009 and 2012, 527 participants who used drugs completed baseline and 6-month follow-up surveys in Baltimore, Maryland. Logistic regression was used to assess whether perceived depression and stigma among friends were associated with personal depressive status before and after accounting for depressive status at baseline. A total of 309 participants (58.6%) had depressive symptoms at baseline, while 207 participants (39.3%) had depressive symptoms at follow-up. Not accounting for baseline depression, perceiving friends as being depressed (adjusted odds ratio [AOR] = 1.32, 95% confidence interval [CI] [1.12, 1.56]) and as having stigmatizing attitudes toward mental health conditions (AOR = 1.92, 95% CI [1.31, 2.79]) were associated with increased odds of personal depression. After accounting for baseline depression, the relationship between personal depression and perceived stigma was marginally significant, while the relationship between personal depression and perceived depression among friends was attenuated. These results suggest that baseline depression is the largest predictor of follow-up depression. Future research should explore whether specific aspects of perceived stigma independently account for personal depression. PMID- 30311968 TI - Validation of an abbreviated Sociopolitical Control Scale for Youth among a sample of underresourced urban youth of color. AB - Empowerment is a higher order multilevel framework that is used to understand and evaluate individuals, groups, organizations, and communities as they engage in the practice and execution of the participatory process. The intrapersonal component of psychological empowerment has been examined through sociopolitical control and occupies two dimensions: leadership competence and policy control. Though the Sociopolitical Control Scale for Youth (SPCS-Y) has been examined using a 17-item scale, Christens, Krauss, and Zeldin (2016) recently assessed the factorial validity of an abbreviated SPCS-Y among a sample of Malaysian adolescents. Yet, there is a need to further examine this abbreviated SPCS-Y among a sample of U.S adolescents. This study tested the factor structure of the abbreviated SPCS-Y among a sample of urban youth of color (N = 383). Using multivariate analysis of variance (MANOVA) we examined the relationship leadership competence and policy control had with conceptually related variables. Analyses supported the bidimensional factor structure and the factorial validity of the abbreviated SPCS-Y. MANOVA results also indicate that participants with both higher leadership competence and policy control also had higher composite scores among conceptually related variables. PMID- 30311969 TI - What is the role of sense of community in multiracial societies? A contribution to the community-diversity dialectic: A genetic psychology approach. AB - Interconnecting the construct of sense of community (SOC), elaborated by McMillan and Chavis, with the notion of social representations, elaborated by Moscovici, this article aims to contribute to advancing an understanding of the relationship between SOC and respect for diversity. Utilizing a genetic psychology approach and the intergroup contact theory, the article articulates 3 levels through which the social representation of community and SOC can be formed and transformed (i.e., microgenetic, ontogenetic, and sociogenetic) to enhance the investigation of the relationship between the 2 phenomena beyond the intraindividual and interindividual levels that tend to emphasize homophily, or preference for similarity. In particular, the article elaborates on the sociogenetic formation of SOC by examining the macro-level forces that participate in establishing what a community should be and who is entitled to be part of it. Examples from 2 previous studies are discussed. PMID- 30311970 TI - Supporting adults to support youth: An evaluation of two social justice trainings. AB - The current research examined pre- and post survey data in two social justice trainings for adults who support youth, including staff and volunteers (Study 1, N = 44) at youth-serving organizations and adults who mentor young Black men and boys (Study 2, N = 72). We investigate whether training participants' self-report scores of cultural competences (studies 1 and 2), self-efficacy for race equity (Study 1) and racial self-efficacy to support mentee (Study 2) changed between the beginning of the training and after the training. Furthermore, we examine whether the changes depend upon whether training participants share cultural background with the youth with whom they work. In Study 1, findings indicated that training participants reported significantly increased scores of cultural sensitivity and self-efficacy for race equity. Individuals who were not first generation college students saw higher increases in sociopolitical awareness. In Study 2, participants reported significantly higher scores of cultural sensitivity and racial self-efficacy to support their mentees. Furthermore, non Black and women participants showed greater increases in self-efficacy than Black and male participants. These results fill a gap in the literature on the potential role of social justice trainings to increase cultural competencies among adults who work with diverse youth. PMID- 30311971 TI - Family social capital mediates the effect of poverty on children's anxiety and depression. AB - This study aims to examine how family social capital mediates the relationship between poverty and children's anxiety and depression in mainland China. Data were collected with multistage cluster random sampling method in Xiushui City in mainland China. The sample comprised 1,314 school-aged children (Grades 4-9). Data included children's basic demographics, internalizing symptoms, and parenting process. Structural equation modeling was used to test the hypothesized model. The results demonstrated a good fit for the sample. The overall model explained 12.7% and 16.1% of the variance for children's anxiety and depression, respectively. Poverty had a significantly direct effect on children's anxiety and depression, and family social capital could partially mediate the influence of poverty on children's internalizing symptoms. Family social capital plays an important mediating role between poverty and children's mental health. Our findings provide strong evidence for social work intervention. Family social capital is essential for parent-child interactions, especially in underprivileged families. PMID- 30311972 TI - Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome. AB - Prior research has found a heightened risk of suicide in patients with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). It is possible that a number of factors including stigma, unsupportive social interactions, and severe symptoms could lead to the development of depression, suicidal ideation, and heightened risk of suicide in this patient population. Prior studies have indicated that patients often report the legitimacy of their illness being questioned by family, friends, and even their physicians. This study aimed to determine whether stigma experienced, social support, symptomology, and functioning may be associated with depression and endorsement of suicidal ideation (SI) in patients with a self-reported diagnosis of ME or CFS. Findings indicated that participants that endorsed both SI and depression, in contrast to those that did not, experienced more frequent unsupportive social interactions in the form of blame for their illness, minimization of its severity, and social distancing from others. In addition, 7.1% of patients with ME and CFS endorsed SI but do not meet the criteria for clinical depression These findings highlight the importance of stigma and unsupportive social interactions as risk factors for suicidal thoughts or actions among patients with ME and CFS. Community psychologists have an important role to play in helping educate health care professionals and the public to these types of risk factors for patients marginalized by ME and CFS. PMID- 30311973 TI - Posttraumatic stress disorder in the short and medium term following the World Trade Center attack among Asian Americans. AB - This study investigated patterns of probable posttraumatic stress disorder (PTSD) and their predictors among 2,431 Asian American and 31,455 non-Hispanic White World Trade Center (WTC) Registry participants 2-3 years and 5-6 years after the WTC attack. Participants were divided into four PTSD pattern groups: resilient, remitted, delayed onset, and chronic. Asians had a lower proportion in the resilient group (76.5% vs. 79.8%), a higher proportion in the chronic (8.6% vs. 7.4%) and remitted (5.9% vs. 3.4%) groups, and a similar proportion in the delayed onset group (about 9%) compared to Whites. In multinomial logistic regression analyses, disaster exposure, immigrant status, lower income, pre attack depression/anxiety, and lower respiratory symptoms were associated with increased odds of chronic and delayed onset PTSD (vs. resilience) among both races. Education and employment were protective against chronic and delayed onset PTSD among Whites only. These results can inform targeted outreach efforts to enhance prevention and treatment for Asians affected by future events. PMID- 30311974 TI - beta2-adrenoceptor agonists and antagonists and risk of Parkinson's disease. AB - BACKGROUND: beta2-adrenoreceptors have recently been identified as regulators of the alpha-synuclein gene, which is implicated in the pathogenesis of Parkinson's disease. OBJECTIVE: The objectives of this study were to assess the association between use of beta2-agonists and beta-antagonists and the risk of developing PD. METHODS: We conducted a nested case-control study in a cohort of 1,762,164 adults without a diagnosis of PD. They were identified on January, 1, 2004, from the electronic medical records of the largest health care provider in Israel. Participants were followed up until June 30, 2017, for the occurrence of PD. Ten randomly selected controls were matched to each case of PD on age, sex, ethnic group, and duration of follow-up. RESULTS: During follow-up 11,314 patients were newly diagnosed with PD and were matched with 113,140 controls. An increased risk of PD was seen with the use of nonselective beta-antagonists (RR, 2.04 [1.90 2.20]) but not with the use of selective beta1-antagonists (RR, 1.00 [0.95 1.05]). Use of beta2-agonists was associated with reduced risk of PD (RR, 0.89 [0.82-0.96] for short-acting; RR, 0.84 [0.76-0.93] for long-acting; and RR, 0.49 [0.25-0.92] for ultra-long-acting beta2-agonists). In an analysis of individual drugs, propranolol and salbutamol were significantly associated with PD risk, even when these drugs were ascertained 5 years prior to the index date, compared with nonusers (RR, 1.31 [1.08-1.58] and 1.89 {1.53-2.33]) in patients who filled <6 and >=6 propranolol prescriptions, respectively; the corresponding RRs for salbutamol were 0.95 (0.83-1.08) and 0.65 (0.45-0.94), respectively. CONCLUSIONS: Use of propranolol appears to be associated with an increased risk of PD, whereas use of beta2-agonists is associated with a decreased risk of PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30311975 TI - Huntington's disease pig model: Squealing into the spotlight. PMID- 30311976 TI - Illuminating basal ganglia and beyond in Parkinson's disease. PMID- 30311977 TI - Oculo-visual abnormalities in Parkinson's disease: Possible value as biomarkers. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders and the second leading cause of dementia worldwide. With an aging population, the prevalence of the disease has dramatically increased. Clinical management has advanced through recent developments in dopaminergic imaging and genetic risk profiling. However, early and accurate diagnosis of the disorder remains a challenge, largely because of the lack of noninvasive and inexpensive reliable diagnostic tests. Besides the well-studied cerebral neurodegeneration that underlies the cardinal symptoms of PD (ie, bradykinesia, tremor, rigidity, and postural instability), ocular changes have also been described in PD, including visual dysfunction, pupil abnormality, lens opacity, and retinal neuronal loss and dysfunction. These ocular pathological processes are related to alpha synuclein deposition, and dopamine deficiency in the retina-mirroring the defining pathological features of PD in the brain. Together, these observations support the notion that the eye can serve as a window to the brain, providing clinicians with noninvasive methods to visualize disease. This review focuses on recent advances in the characterization of ocular changes in PD and their promising use as biomarkers in the eye, which can be potentially used for aiding in early diagnosis, tracking disease progression, and valuating novel therapeutic strategies. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30311978 TI - Structural biology of G protein-coupled receptor signaling complexes. AB - G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors that mediate numerous cell signaling pathways, and are targets of more than one-third of clinical drugs. Thanks to the advancement of novel structural biology technologies, high-resolution structures of GPCRs in complex with their signaling transducers, including G-protein and arrestin, have been determined. These 3D complex structures have significantly improved our understanding of the molecular mechanism of GPCR signaling and provided a structural basis for signaling-biased drug discovery targeting GPCRs. Here we summarize structural studies of GPCR signaling complexes with G protein and arrestin using rhodopsin as a model system, and highlight the key features of GPCR conformational states in biased signaling including the sequence motifs of receptor TM6 that determine selective coupling of G proteins, and the phosphorylation codes of GPCRs for arrestin recruitment. We envision the future of GPCR structural biology not only to solve more high resolution complex structures but also to show stepwise GPCR signaling complex assembly and disassembly and dynamic process of GPCR signal transduction. This article is protected by copyright. All rights reserved. PMID- 30311979 TI - Dual Gold-Catalyzed Formal Tetradehydro-Diels-Alder Reactions for the Synthesis of Carbazoles and Indolines. AB - This work reports a dual gold-catalyzed tetradehydro-Diels-Alder reaction for the synthesis of nitrogen-containing aromatic heterocycles. Under the catalytic system (IPrAuNTf2 /DIPEA), indolines and carbazoles as well as other N-containing aromatic heterocycles were prepared in high yields with good functional group tolerance. Unlike the traditional thermal tetradehydro-Diels-Alder reactions, diluted reaction concentration and radical prohibitors are not required for this protocol. Experimental data support a mechanism involving gold vinylidene species, which undergoes a 6 pi electrocyclization, followed with 1,2-hydrogen shift. PMID- 30311980 TI - Characterizing the plasma metabolome during 14 days of live-high, train-low simulated altitude: A metabolomic approach. AB - NEW FINDINGS: What is the central question of this study? Does 14 days of live high, train-low simulated altitude alter an individual's metabolomic/metabolic profile? What is the main finding and its importance? This study demonstrated that ~200 h of moderate simulated altitude exposure resulted in greater variance in measured metabolites between subject than within subject, which indicates individual variability during the adaptive phase to altitude exposure. In addition, metabolomics results indicate that altitude alters multiple metabolic pathways, and the time course of these pathways is different over 14 days of altitude exposure. These findings support previous literature and provide new information on the acute adaptation response to altitude. ABSTRACT: The purpose of this study was to determine the influence of 14 days of normobaric hypoxic simulated altitude exposure at 3000 m on the human plasma metabolomic profile. For 14 days, 10 well-trained endurance runners (six men and four women; 29 +/- 7 years of age) lived at 3000 m simulated altitude, accumulating 196.4 +/- 25.6 h of hypoxic exposure, and trained at ~600 m. Resting plasma samples were collected at baseline and on days 3 and 14 of altitude exposure and stored at -80 degrees C. Plasma samples were analysed using liquid chromatography-high-resolution mass spectrometry to construct a metabolite profile of altitude exposure. Mass spectrometry of plasma identified 36 metabolites, of which eight were statistically significant (false discovery rate probability 0.1) from baseline to either day 3 or day 14. Specifically, changes in plasma metabolites relating to amino acid metabolism (tyrosine and proline), glycolysis (adenosine) and purine metabolism (adenosine) were observed during altitude exposure. Principal component canonical variate analysis showed significant discrimination between group means (P < 0.05), with canonical variate 1 describing a non-linear recovery trajectory from baseline to day 3 and then back to baseline by day 14. Conversely, canonical variate 2 described a weaker non-recovery trajectory and increase from baseline to day 3, with a further increase from day 3 to 14. The present study demonstrates that metabolomics can be a useful tool to monitor metabolic changes associated with altitude exposure. Furthermore, it is apparent that altitude exposure alters multiple metabolic pathways, and the time course of these changes is different over 14 days of altitude exposure. PMID- 30311981 TI - Breastfeeding duration modifies the effect of smoking during pregnancy on eczema from early childhood to adolescence. AB - BACKGROUND: Cigarette smoke contains compounds similar to coal tar, an ancient remedy of eczema. Some studies have reported protective effects of maternal gestational smoking on offspring eczema; however, others have shown no or increased risks. Similarly, studies linking breastfeeding duration and eczema have demonstrated contradictory findings. No study has yet investigated combined effects of these two factors on eczema. OBJECTIVE: Since tobacco compounds can pass to offspring via breast milk, we investigated their combined effects on eczema development from childhood to adolescence. METHODS: We obtained information regarding gestational smoking, exclusive breastfeeding duration, and eczema at ages 1-or-2, 4, 10, and 18 years from the Isle of Wight (IOW) birth cohort, UK. Using generalized estimating equations, we assessed the interaction of gestational smoking and residual exclusive breastfeeding duration (Resid-BF duration, obtained by regressing the latter on maternal smoking) on eczema over time adjusting for confounders. For the three transition periods of 1-or-2 to 4 years, 4-10, and 10-18 years, we estimated risks of persistent, incident, and remitting eczema associated with the interaction using repeated measurements. RESULTS: If the mother smoked during gestation, longer Resid-BF-duration was associated with a lower risk of eczema, compared to if she did not smoke. The risk ratios (95% CI) if the mother smoked during gestation and exclusively breastfed for at least 3, 9, 15, 21 weeks are 0.7 (0.6, 1.7), 0.6 (0. 4, 0.9), 0.5 (0.3, 0.8), and 0.4 (0.2, 0. 8), respectively. Additionally, in all three transition periods, the risk of persistent eczema was lower with longer Resid-BF duration if the mother smoked during gestation. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest a protective effect of gestational smoking combined with longer duration of exclusive breastfeeding on early-onset persistent eczema. Future studies should examine underlying biological mechanisms. Prolonged breastfeeding should be encouraged even if the mother smoked during gestation. PMID- 30311982 TI - Observation of the First Spin Crossover in an Iron(II) Complex with an S6 Coordination Environment: Tris[bis(N,N diethylamino)carbeniumdithiocarboxylato]iron(II) Hexafluorophosphate. AB - For the first time, the spin-crossover (SCO) phenomenon has been observed in an FeII -S6 system in a tris(chelate)-type iron(II) complex with a zwitterionic sulfur donor bidentate, bis(N,N-diethylamino)carbeniumdithiocarboxylate (EtL), [FeII (EtL)3 ](PF6 )2 (1), as synthesized by the reaction of a precursor complex [FeII (CH3 CN)6 ](PF6 )2 with EtL. In the solid state, the high-spin (HS) d6 state at ambient temperature and the low-spin (LS) d6 state at temperatures lower than approximately 240 K were evidenced by magnetic measurements with SQUID and Mossbauer spectra in the temperature range 4-290 K. X-ray analyses of the crystals at various temperatures disclosed that the distorted trigonal prismatic coordination environments essentially do not change; however, contraction of Fe-S distances by approximately 10 % (0.22 A), ordering of alkyl groups in EtL and PF6 - counteranions, and formation of significant intermolecular S???S interactions between adjacent molecules (average distances of 3.59 A) take place during the transition from the HS to the LS state. A large decrease in the volume of the formula unit (78.1 A3 ) might be responsible for the large activation barrier, thereby resulting in a slow phase transition upon cooling. PMID- 30311984 TI - Distinctive structural motifs co-ordinate the catalytic nucleophile and the residues of the oxyanion hole in the alpha/beta-hydrolase fold enzymes. AB - The alpha/beta-hydrolases (ABH) are among the largest structural families of proteins that are found in nature. Although they vary in their sequence and function, the ABH enzymes use a similar acid-base-nucleophile catalytic mechanism to catalyze reactions on different substrates. Because ABH enzymes are biocatalysts with a wide range of potential applications, protein engineering has taken advantage of their catalytic versatility to develop enzymes with industrial applications. This study is a comprehensive analysis of 40 ABH enzyme families focusing on two identified substructures: the nucleophile zone and the oxyanion zone, which co-ordinate the catalytic nucleophile and the residues of the oxyanion hole, and independently reported as critical for the enzymatic activity. We also frequently observed an aromatic cluster near the nucleophile and oxyanion zones, and opposite the ligand-binding site. The nucleophile zone, the oxyanion zone and the residue cluster enriched in aromatic side chains comprise a three dimensional structural organization that shapes the active site of ABH enzymes and plays an important role in the enzymatic function by structurally stabilizing the catalytic nucleophile and the residues of the oxyanion hole. The structural data support the notion that the aromatic cluster can participate in co ordination of the catalytic histidine loop, and properly place the catalytic histidine next to the catalytic nucleophile. PMID- 30311983 TI - Reflux aspiration in lungs of dogs with respiratory disease and in healthy West Highland White Terriers. AB - BACKGROUND: Gastroesophageal reflux and microaspiration (MA) of gastric juice are associated with various human respiratory diseases but not in dogs. OBJECTIVE: To detect the presence of bile acids in bronchoalveolar lavage fluid (BALF) of dogs with various respiratory diseases. ANIMALS: Twenty-seven West Highland White Terriers (WHWTs) with canine idiopathic pulmonary fibrosis (CIPF), 11 dogs with bacterial pneumonia (BP), 13 with chronic bronchitis (CB), 9 with eosinophilic bronchopneumopathy (EBP), 19 with laryngeal dysfunction (LD), 8 Irish Wolfhounds (IWHs) with previous BPs, 13 healthy WHWTs, all privately owned dogs, and 6 healthy research colony Beagles METHODS: Prospective cross-sectional observational study with convenience sampling of dogs. Bile acids were measured by mass spectrometry in BALF samples. Total bile acid (TBA) concentration was calculated as a sum of 17 different bile acids. RESULTS: Concentrations of TBA were above the limit of quantification in 78% of CIPF, 45% of BP, 62% of CB, 44% of EBP, 68% of LD, and 13% of IWH dogs. In healthy dogs, bile acids were detected less commonly in Beagles (0/6) than in healthy WHWTs (10/13). Concentrations of TBA were significantly higher in CIPF (median 0.013 MUM, range not quantifiable [n.q.]-0.14 MUM, P < .001), healthy WHWTs (0.0052 MUM, n.q.-1.2 MUM, P = .003), LD (0.010 MUM, n.q.-2.3 MUM, P = .015), and CB (0.0078 MUM, n.q.-0.073 MUM, P = .018) groups compared to Beagles (0 MUM, n.q.). CONCLUSION AND CLINICAL IMPORTANCE: These results suggest that MA occurs in various respiratory diseases of dogs and also in healthy WHWTs. PMID- 30311985 TI - Response of head and neck epithelial cells to a DNA damage-differentiation checkpoint involving polyploidization. AB - BACKGROUND: Squamous epithelia of the head and neck undergo continuous cell renewal and are continuously exposed to mutagenic hazard, the main cause of cancer. How they maintain homeostasis upon cell cycle deregulation is unclear. METHODS: To elucidate how head and neck epithelia respond to cell cycle stress, we studied human keratinocytes from various locations (oral mucosa, tonsil, pharynx, larynx, and trachea). We made use of genotoxic or mitotic drugs (doxorubicin [DOXO], paclitaxel, and nocodazole), or chemical inhibitors of the mitotic checkpoint kinases, Aurora B and polo-like-1. We further tested the response to inactivation of p53, ectopic cyclin E, or to the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). RESULTS: All treatments provoked DNA damage or mitosis impairment and strikingly triggered squamous differentiation and polyploidization, resulting in irreversible loss of clonogenic capacity. CONCLUSION: Keratinocytes from head and neck epithelia share a cell-autonomous squamous DNA damage-differentiation response that is common to the epidermis and might continuously protect them from cancer. PMID- 30311986 TI - Monooxygenation of Aromatic Compounds by Flavin-Dependent Monooxygenases. AB - Many flavoenzymes catalyze hydroxylation of aromatic compounds especially phenolic compounds have been isolated and characterized. These enzymes can be classified as either single-component or two-component flavin dependent hydroxylases (monooxygenases). The hydroxylation reactions catalyzed by the enzymes in this group are useful for modifying the biological properties of phenolic compounds. This review aims to provide an in-depth discussion of the current mechanistic understanding of representative flavin-dependent monooxygenases including 3-hydroxy-benzoate 4-hydroxylase (PHBH, a single component hydroxylase), 3-hydroxyphenylacetate 4-hydroxylase (HPAH, a two component hydroxylase) and other monooxygenases which catalyze reactions in addition to hydroxylation, including 2-methyl-3-hydroxypyridine-5-carboxylate oxygenase (MHPCO, a single-component enzyme that catalyzes aromatic-ring cleavage), and HadA monooxygenase (a two-component enzyme that catalyzes additional group elimination reaction). These enzymes have different unique structural features which dictate their reactivity towards various substrates and influence their ability to stabilize flavin intermediates such as C4a hydroperoxyflavin. Understanding the key catalytic residues and the active site environments important for governing enzyme reactivity will undoubtedly facilitate future work in enzyme engineering or enzyme redesign for development of biocatalytic methods for the synthesis of valuable compounds. This article is protected by copyright. All rights reserved. PMID- 30311987 TI - Effects of depressive symptomatology on cancer-related symptoms during oral oncolytic treatment. AB - OBJECTIVE: This manuscript assesses association between depressive symptoms and symptoms from cancer and its treatment during the first 12 weeks of a new oral oncolytic treatment. METHODS: This secondary analysis used data from a recently completed trial of an intervention to improve adherence to oral oncolytic treatment and manage symptoms. Following the initiation of the new oral oncolytic medication, 272 patients were interviewed at intake and weeks 4, 8, and 12 to assess depressive symptoms, and symptoms from cancer and its treatment. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D20). The summed index of 18 cancer-related and treatment-related symptoms as well as the number of symptoms above threshold at intake, weeks 4, 8, and 12 were related to intake and time-varying CES-D20 using linear mixed effects models. RESULTS: Depressive symptomatology was a significant predictor of cancer related and treatment-related symptoms at all-time points, but the strength of this relationship was greatest at the time of oral oncolytic agent initiation and at week 4. The strength of this relationship was the same for both summed symptom severity index and the number of symptoms above threshold, and using either intake or time-varying CES-D20. CONCLUSION: Introducing strategies to treat and manage symptoms of depression along with other symptoms might have added benefits among patients who start a new oral oncolytic treatment and report modest to higher levels of depressive symptoms. Assessments for the impact of strategies to lower depressive symptoms can be taken within the first 4 weeks. PMID- 30311988 TI - Diffusion MRI of cancer: From low to high b-values. AB - : Following its success in early detection of cerebral ischemia, diffusion weighted imaging (DWI) has been increasingly used in cancer diagnosis and treatment evaluation. These applications are propelled by the rapid development of novel diffusion models to extract biologically valuable information from diffusion-weighted MR signals, and significant advances in MR hardware that has enabled image acquisition with high b-values. This article reviews recent technical developments and clinical applications in cancer imaging using DWI, with a special emphasis on high b-value diffusion models. The article is organized in four sections. First, we provide an overview of diffusion models that are relevant to cancer imaging. The model parameters are discussed in relation to three tissue properties-cellularity, vascularity, and microstructures. An emphasis is placed on characterization of microstructural heterogeneity, given its novelty and close relevance to cancer. Second, we illustrate diffusion MR clinical applications in each of the following three categories: 1) cancer detection and diagnosis; 2) cancer grading, staging, and classification; and 3) cancer treatment response prediction and evaluation. Third, we discuss several practical issues, including selection of image acquisition parameters, reproducibility and reliability, motion management, image distortion, etc., that are commonly encountered when applying DWI to cancer in clinical settings. Lastly, we highlight a few ongoing challenges and provide some possible future directions, particularly in the area of establishing standards via well-organized multicenter clinical trials to accelerate clinical translation of advanced DWI techniques to improving cancer care on a large scale. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30311989 TI - Chemical Cutting of Perovskite Nanowires into Single-Photon Emissive Low-Aspect Ratio CsPbX3 (X=Cl, Br, I) Nanorods. AB - Post-synthetic shape-transformation processes provide access to colloidal nanocrystal morphologies that are unattainable by direct synthetic routes. Herein, we report our finding about the ligand-induced fragmentation of CsPbBr3 perovskite nanowires (NWs) into low aspect-ratio CsPbX3 (X=Cl, Br and I) nanorods (NRs) during halide ion exchange reaction with PbX2 -ligand solution. The shape transformation of NWs-to-NRs resulted in an increase of photoluminescence efficiency owing to a decrease of nonradiative decay rates. Importantly, we found that the perovskite NRs exhibit single photon emission as revealed by photon antibunching measurements, while it is not detected in parent NWs. This work not only reports on the quantum light emission of low aspect ratio perovskite NRs, but also expands our current understanding of shape-dependent optical properties of perovskite nanocrystals. PMID- 30311990 TI - Inorganic Triphenylphosphine. AB - A completely inorganic version of one of the most famous organophosphorus compounds, triphenylphosphine, has been prepared. A comparison of the crystal structures of inorganic triphenylphosphine, PBaz3 (where Baz=B3 H2 N3 H3 ) and PPh3 shows that they have superficial similarities and furthermore, the Lewis basicities of the two compounds are remarkably similar. However, their oxygenation and hydrolysis reactions are starkly different. PBaz3 reacts quantitatively with water to give PH3 and with the oxidizing agent ONMe3 to give the triply-O-inserted product P(OBaz)3 , an inorganic version of triphenyl phosphite; a corresponding transformation with PPh3 is inconceivable. Thermodynamically, what drives these striking differences in the chemistry of PBaz3 and PPh3 is the great strength of the B-O bond. PMID- 30311991 TI - Diazuleno-s-indacene Diradicaloids: Syntheses, Properties, and Local (anti)Aromaticity Shift from Neutral to Dicationic State. AB - Non-alternant, non-benzenoid pi-conjugated polycyclic hydrocarbons (PHs) are expected to exhibit very different electronic properties from all-benzenoid PHs. Reported herein are the syntheses and physical properties of four derivatives of two azulene-fused s-indacene isomers, the diazuleno[2,1-a:2',1'-g]-s-indacene (DAI-1) and diazuleno[2,1-a:1',2'-h]-s-indacene (DAI-2). The backbone of both isomers contains 28pi electrons and is a 7-5-5-6-5-5-7 fused ring system. X-ray crystallographic analysis, NMR spectra, and theoretical calculations (ACID, NICS) reveal a structure with two aromatic azulene units fused with a central anti aromatic s-indacene moiety. All compounds exhibit open-shell diradical character and are magnetically active, but the derivatives of DAI-2 show larger radical character than the respective ones of DAI-1. Their dications were isolated in crystalline form and all experimental and theoretical analyses disclose a shift of local (anti)aromaticity along the backbone, with two aromatic tropylium rings at the termini. PMID- 30311992 TI - Development of a robot-assisted kidney transplantation programme from deceased donors in a referral academic centre: technical nuances and preliminary results. AB - OBJECTIVE: To report the development of the first robot-assisted kidney transplantation (RAKT) programme from deceased donors, examining technical feasibility and early perioperative and functional outcomes at a referral academic centre. PATIENTS AND METHODS: A RAKT programme was developed in 2016 at our institution following structured modular training. Specific inclusion/exclusion criteria for both living and deceased donors were set. Data from patients undergoing RAKT from January 2017 to April 2018 were prospectively collected in an a priori developed web-based data set. RAKT followed the principles of the Vattikuti Urology Institute-Medanta technique, with specific technical modifications based on clinical recipient characteristics, as well as surgeon's skills and preference during the learning curve. Technical feasibility of RAKT from deceased donors and evaluation of perioperative and early functional outcomes were the main study endpoints. RESULTS: In all, 17 RAKTs were performed during the study period. Of these, six were from living donors and 11 were from deceased donors. All RAKTs were successfully completed without need of conversion. The median (interquartile range [IQR]) console time was 190 (160-220) min and the median (IQR) estimated blood loss was 120 (110-140) mL. The median times to complete venous, arterial and uretero-vesical anastomoses were 21, 22 and 21 min, respectively. The median (IQR) length of stay was 8 (6-12) days. At a median (IQR) follow-up of 8 (6-11) months, five (30%) complications were recorded. Of these, four (24%) were minor (Clavien-Dindo Grade I-II) and one major (Clavien-Dindo Grade IIIb, requiring graft nephrectomy). Overall, two patients were still on dialysis at last follow-up. A significant improvement in graft function was recorded progressively at all postoperative time points. CONCLUSION: Our preliminary experience outlines that: (i) the development of a RAKT programme is feasible in centres experienced in robotic surgery and open kidney transplantation; (ii) RAKT from deceased donors is feasible from both a technical and logistical perspective; and (iii) RAKT from deceased donors appears to achieve favourable early postoperative and functional outcomes. Larger studies with longer follow-up are needed to confirm these findings and compare the outcomes of RAKT from deceased donors with those from living donors. PMID- 30311993 TI - Commentary: The opioid overdose epidemic: Evidence-based interventions. AB - BACKGROUND AND OBJECTIVES: Outcome intervention data from Medicare, veteran, prison, and United States' public populations can identify best practices to decrease opioid misuse. Prescription policies for treating pain in the United States and other countries are relevant to preventing overdose. METHODS: Three strategies are considered: (1) Demand Reduction counsels and educates patients and current or potential opioid users about risks and treatment options to reduce motivation to consume opioids. (2) Supply Reduction limits access and dosage of opioids and co-drugs such as benzodiazepines. It encourages use of safest prescribing practices for treating pain. (3) Harm Reduction reduces opioid deaths through medication-assisted treatment (MAT) combining opioid substitution therapy (OST), provision of opioid antagonists like Naltrexone, and behavioral health services. RESULTS: Demand Reduction is often inadequate to treat severe pain or in the presence of major psychopathology like opioid abuse disorder (OUD). Among veterans, lower opioid doses for pain treatment were associated with diminished death rates. Supply Reduction interventions have disadvantages. Banning drugs has poor long-term success with prison inmates, because abstinence is difficult to enforce after discharge. Limiting opioid supplies does not increase survival rates for Medicare patients. DISCUSSION AND CONCLUSIONS: Sharp opioid dose restriction in outpatient treatment increases heroin and fentanyl use, explaining why recent years' decrease in United States opioid prescriptions has not reduced national mortality rates. Although Harm Reduction is the safest, most effective single approach, combining three interventions while improving pain and addiction prescribing practices is optimal. SCIENTIFIC SIGNIFICANCE: Scientific research needs to inform choice of opioid overuse interventions. (Am J Addict 2018;XX:1 3). PMID- 30311994 TI - Chlamydia trachomatis targets mitochondrial dynamics to promote intracellular survival and proliferation. AB - Chlamydia trachomatis is an obligate intracellular bacterium that scavenges host metabolic products for its replication. Mitochondria are the power plants of eukaryotic cells and provide most of the cellular ATP via oxidative phosphorylation. Several intracellular pathogens target mitochondria as part of their obligatory cellular reprogramming. This study was designed to analyse the mitochondrial morphological changes in response to C. trachomatis infection in HeLa cells. Mitochondrial elongation and fragmentation were found at the early stages and late stages of C. trachomatis infection, respectively. C. trachomatis infection-induced mitochondrial elongation was associated with the increase of mitochondrial respiratory activity, ATP production, and intracellular growth of C. trachomatis. Silencing mitochondrial fusion mediator proteins abrogated the C. trachomatis infection-induced elevation in the oxygen consumption rate and attenuated chlamydial proliferation. Mechanistically, C. trachomatis induced the elevation of intracellular cAMP at the early phase of infection, followed by the phosphorylation of fission-inactive serine residue 637 (S637) of Drp1, resulting in mitochondrial elongation. Accordingly, treatment with adenylate cyclase inhibitor diminished mitochondrial elongation and bacterial growth in infected cells. Collectively, these results strongly indicate that C. trachomatis promotes its intracellular growth by targeting mitochondrial dynamics to regulate ATP synthesis via inhibition of the fission mediator Drp1. PMID- 30311995 TI - A case of combined small cell lung carcinoma with unique morphology: Investigation of tumorigenesis. AB - Small cell lung carcinoma (SCLC) usually grows in a pure form with no other associated histological components. However, combined small cell lung carcinoma (cSCLC), which is accompanied by other histological components (cSCLCs) may sometimes occur. Herein, we analyzed the tumorigenesis of cSCLC containing a demarcated area of pure SCLC. A 76-year-old man had a 25-mm mass in the perihilar portion of his right upper lung. Histologically, the cSCLC contained two relatively demarcated areas: one area composed of pure SCLC cells and another area of SCLC, squamous-like component (SLC), and spindle cell carcinoma (SpCC) cells. Loss of heterozygosity (LOH) was observed at allele 3p in all tumor components and at 22q in the pure SCLC component. Histological and immunohistochemical analysis and LOH study suggested that all components were likely to be monoclonal in origin and revealed that the pure SCLC component was not the precursor of the cSCLC. In the tumorigenesis of this case, the pure SCLC and the cSCLC may have originated from a common pluripotent tumor cell and then diverged, although we cannot state this conclusively. Further studies with more cases are necessary to test this theory. PMID- 30311996 TI - A New Photocaged Puromycin for an Efficient Labeling of Newly Translated Proteins in Living Neurons. AB - Monitoring newly synthesized proteins is becoming increasingly important to characterize proteome composition in regulatory networks. Puromycin is a peptidyl transfer inhibitor, widely used in cell biology for tagging newly synthesized proteins. Here, we report synthesis and application of an optimized puromycin carrying a photolabile protecting group as a powerful tool for tagging nascent proteins with high spatiotemporal resolution. The photocaged 7-N,N (diethylaminocumarin-4-yl)-methoxycarbonyl-puromycin (DEACM-puromycin) was synthesized and compared with the previously developed 6-nitroveratryloxycarbonyl puromycin (NVOC-puromycin). The photochemical behavior as well as the effectiveness in controlling puromycylation in living hippocampal neurons using two-photon excitation is superior to the previously used NVOCpuromycin. We further report on the application of light-controlled puromycylation to visualize new translated proteins in neurons. PMID- 30311997 TI - Corrigendum: Redox-Responsive Covalent Organic Nanosheets from Viologens and Calix[4]arene for Iodine and Toxic Dye Capture. PMID- 30311998 TI - Value of the preoperative neutrophil-to-lymphocyte ratio as a prognostic factor for long-term survival in postoperative esophageal squamous cell carcinoma patients. AB - BACKGROUND: This study investigated the relationship between the neutrophil-to lymphocyte ratio (NLR) and clinicopathological features and prognosis in patients with postoperative esophageal squamous cell carcinoma (ESCC). METHODS: The preoperative NLR was evaluated in 419 patients who underwent esophagectomy for ESCC. A receiver operating characteristic (ROC) curve was plotted to verify the accuracy of the NLR for predicting survival. Correlation between the NLR and clinicopathological characteristics was analyzed using the chi2 test. Prognostic influence was calculated by using the Kaplan-Meier method and the difference was assessed by log-rank test. Multivariate Cox regression models were applied to evaluate the independent prognostic value. RESULTS: The cutoff value of the NLR was 2.998, the area under the curve was 0.735, and the sensitivity and specificity were 69.3% and 69.3%, respectively. Tumor length (P = 0.0317), lymph node metastasis (P = 0.0352), pathological tumor node metastasis (pTNM) stage (P = 0.0271), and postoperative radiotherapy (P = 0.0385) were significantly different between the groups. Multivariate analysis showed that pTNM stage (P = 0.0098), lymph node metastasis (P = 0.001), and NLR (P = 0.0022) were independent prognostic factors for survival. Moreover, when patients were stratified by TNM stage, the adverse effects of preoperative NLR on cancer-specific survival were greater in patients with stage II and III ESCC and in patients with lymph node metastasis. CONCLUSIONS: The preoperative NLR is significantly correlated with long-term prognosis in postoperative patients with ESCC, particularly in patients with lymph node metastasis and stage II and III ESCC. PMID- 30311999 TI - The relationship between physical work hazards and employee withdrawal: The moderating role of safety compliance. AB - We examined the relationship between physical work hazards and employee withdrawal among a sample of health care employees wherein safety compliance was hypothesized to moderate the relationship between physical work hazards and withdrawal. Health care workers (N = 162) completed an online questionnaire assessing physical work hazards, withdrawal, and indicators of workplace safety. Safety compliance moderated the relationship between patient aggression and withdrawal. Interaction plots revealed that for all significant moderations, the relationship between physical work hazards and withdrawal was weaker for those who reported high levels of compliance. Results shed initial light on the benefits of fostering safety compliance in health care contexts, which can contain exposure to physical work hazards. PMID- 30312000 TI - Finding stories in noise: Mitochondrial portraits from RAD data. AB - Mitochondrial DNA (mtDNA) has formed the backbone of phylogeographic research for many years; however, recent trends focus on genome-wide analyses. One method proposed for calibrating inferences from noisy next-generation data, such as RAD sequencing, is to compare these results with analyses of mitochondrial sequences. Most researchers using this approach appear to be unaware that many single nucleotide polymorphisms (SNPs) identified from genome-wide sequence data are themselves mitochondrial, or assume that these are too few to bias analyses. Here, we demonstrate two methods for mining mitochondrial markers using RAD sequence data from three South African species of yellowfish, Labeobarbus. First, we use a rigorous SNP discovery pipeline using the program stacks, to identify variant sites in mtDNA, which we then combine into haplotypes. Second, we directly map sequence reads against a mitochondrial genome reference. This method allowed us to reconstruct up to 98% of the Labeobarbus mitogenome. We validated these mitogenome reconstructions through blast database searches and by comparison with cytochrome b gene sequences obtained through Sanger sequencing. Finally, we investigate the organismal consequences of these data including ancient genetic exchange and a recent translocation among populations of L. natalensis, as well as interspecific hybridization between L. aeneus and L. kimberleyensis. PMID- 30312001 TI - RADProc: A computationally efficient de novo locus assembler for population studies using RADseq data. AB - Restriction-site associated DNA sequencing (RADseq) is a powerful tool for genotyping of individuals, but the identification of loci and assignment of sequence reads is a crucial and often challenging step. The optimal parameter settings for a given de novo RADseq assembly varies between datasets and can be difficult and computationally expensive to determine. Here we introduce RADProc, a software package that uses a graph data structure to represent all sequence reads and their similarity relationships. Storing sequence-comparison results in a graph eliminates unnecessary and redundant sequence-similarity calculations. De novo locus formation for a given parameter set can be performed on the pre computed graph, making parameter sweeps far more efficient. RADProc also uses a clustering approach for faster nucleotide-distance calculation. The performance of RADProc compares favorably with that of the widely used Stacks software. The run-time comparisons between RADProc and Stacks for 32 different parameter settings using 20 green crab (Carcinus maenas) samples showed that RADProc took as little as 2 hours 40 minutes compared to 78 hours by Stacks, while 16 brown trout (Salmo trutta L.) samples were processed by RADProc and Stacks in 23 hours and 263 hours respectively. Comparisons of the de novo loci formed, and catalog built using both the methods demonstrate that the improvement in processing speeds achieved by RADProc does not affect much the actual loci formed and the results of downstream analyses based on those loci. This article is protected by copyright. All rights reserved. PMID- 30312002 TI - Does metabolic syndrome influence short and long term durability of carotid endarterectomy and stenting? AB - AIMS: The metabolic syndrome (MetS) is composed of a cluster of related cardiovascular risk factors. The aim of the present study was to determine how MetS contributes to short- (30-day) and long-term complications and restenosis after carotid endarterectomy (CEA) or stenting (CAS). METHODS: A consecutive cohort of 752 patients undergoing CEA (n = 314) and CAS (n = 438) in a single institution was examined, of which 296 (39.4%) were identified as having MetS. All patients were followed-up with carotid duplex ultrasound scan of the supraaortic vessels and a neurological assessment of symptoms status at 30-day postprocedure and at 3, 6, and 12 months, with annual follow-up thereafter for 3 years. RESULTS: Patients with MetS had a significant increased risk in their 30 day death, major adverse events (MAE), and restenosis rates, both after CEA and after CAS (death: 0.7% vs 0.0%; MAE: 5.3% vs 2.7%; and restenosis: 1.7% vs 0.2%; p < 0.05). The MAE and restenosis rates remained statistically different at 36 months, with both procedures (29.2% vs 24.2% and 9.5% vs 3.3%, p < 0.05, for patients with and without MetS, respectively). Among the components of MetS, high fasting serum glucose, low high-density lipoprotein cholesterol, and elevated body mass index were associated with increased risk of complications at 30 days and within 36 months. CONCLUSIONS: The current study suggested that the presence of MetS is an important risk factor for morbidity and restenosis after CEA and CAS. PMID- 30312003 TI - The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: A prospective observational study. AB - BACKGROUND & AIMS: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)-free anti-HCV therapy using direct-acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non-hypervascular hypointense nodules (NHHNs) by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). METHODS: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB-MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. RESULTS: In comparison of patients who achieved sustained virologic response (SVR) with propensity score matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score-matched patients with persistent HCV infection. CONCLUSIONS: During a 2-year observation period after SVR, the eradication of HCV by IFN-free DAA therapy did not suppress or enhance HCC development. (UMIN000017020). PMID- 30312005 TI - "Through-Space" Relativistic Effects on NMR Chemical Shifts of Pyridinium Halide Ionic Liquids. AB - We have investigated, using two-component relativistic density functional theory (DFT) at ZORA-SO-BP86 and ZORA-SO-PBE0 level, the occurrence of relativistic effects on the 1 H, 13 C, and 15 N NMR chemical shifts of 1-methylpyridinium halides [MP][X] and 1-butyl-3-methylpyridinium trihalides [BMP][X3 ] ionic liquids (ILs) (X=Cl, Br, I) as a result of a non-covalent interaction with the heavy anions. Our results indicate a sizeable deshielding effect in ion pairs when the anion is I- and I3 - . A smaller, though nonzero, effect is observed also with bromine while chlorine based anions do not produce an appreciable relativistic shift. The chemical shift of the carbon atoms of the aromatic ring shows an inverse halogen dependence that has been rationalized based on the little C-2s orbital contribution to the sigma-type interaction between the cation and anion. This is the first detailed account and systematic theoretical investigation of a relativistic heavy atom effect on the NMR chemical shifts of light atoms in the absence of covalent bonds. Our work paves the way and suggests the direction for an experimental investigation of such elusive signatures of ion pairing in ILs. PMID- 30312004 TI - Therapeutic targeting of cellular stress responses in cancer. AB - Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA-damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy. PMID- 30312006 TI - Supramolecular Assembly of C3 -Peptides into Helical Fibers Stabilized through Dynamic Covalent Chemistry. AB - The supramolecular assembly of C3 -peptides carrying glycine-cysteine (Gly-Cys) dipeptide pendants into helical fibers is described. A Gly-Cys dipeptide sequence was selected to ensure the chirality, and at the same time, to provide a chance to crosslink the structure through oxidation of the thiol into dynamic covalent disulfide, and transfer supramolecular helical fibers into covalent ones. Supramolecular assembly in aprotic solvents affords long helical fibers with left handedness, which can be stabilized through formation of disulfide. Transformation of supramolecular helical fibers into covalent ones was examined by NMR and FTIR spectroscopies as well as atom force microscopy. PMID- 30312007 TI - Cyclophilin A Controls Salmonella Internalization Levels and is Present at E. coli Actin-Rich Pedestals. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium), enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) commandeer the actin cytoskeleton of their host cells as a crucial step in their infectious processes. These pathogens depend on the injection of their own effectors directly into target host cells in order to usurp cellular signaling pathways that lead to morphological actin rearrangements in those cells. Here we show that the PPIase Cyclophilin A (CypA) is a novel component of S. Typhimurium-induced membrane ruffles and functions to restrict bacterial invasion levels, as in cells depleted of CypA, bacterial loads increase. We also demonstrate that CypA requires the EPEC effector Tir as well as pedestal formation for its recruitment to bacterial attachment sites and that its presence at pedestals also holds during EHEC infections. Finally, we demonstrate that CypA is found at lamellipodia; actin rich structures at the leading edge of motile cells. Our findings further establish CypA as a component of dynamic actin-rich structures formed during bacterial infections and within cells in general. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312008 TI - Regulation and Assembly of Actomyosin Contractile Rings in Cytokinesis and Cell Repair. AB - Cytokinesis and single-cell wound repair both involve contractile assemblies of filamentous actin (F-actin) and myosin II organized into characteristic ring-like arrays. The assembly of these actomyosin contractile rings (CRs) is specified spatially and temporally by small Rho GTPases, which trigger local actin polymerization and myosin II contractility via a variety of downstream effectors. We now have a much clearer view of the Rho GTPase signaling cascade that leads to the formation of CRs, but some factors involved in CR positioning, assembly, and function remain poorly understood. Recent studies show that this regulation is multifactorial and goes beyond the long-established Ca2+ -dependent processes. There is substantial evidence that the Ca2+ -independent changes in cell shape, tension, and plasma membrane composition that characterize cytokinesis and single cell wound repair also regulate CR formation. Elucidating the regulation and mechanistic properties of CRs is important to our understanding of basic cell biology and holds potential for therapeutic applications in human disease. In this review, we present a primer on the factors influencing and regulating CR positioning, assembly, and contraction as they occur in a variety of cytokinetic and single-cell wound repair models. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312009 TI - Posttranscriptional and Posttranslational Regulation of Actin. AB - Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle beta-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin's essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin's nucleotide-level regulation. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312010 TI - An Analysis of Extraocular Muscle Forces in The Piked Dogfish (Squalus acanthias). AB - Vertebrates utilize six extraocular muscles that attach to a tough, protective sclera to rotate the eye. The goal of the study was to describe the maximum tetanic forces, as well as the torques produced by the six extraocular muscles of the piked dogfish Squalus acanthias in order to understand the forces exerted on the eye. The lateral rectus extraocular muscle of Squalus acanthias was determined to be parallel fibered with the muscle fibers bundled into discrete fascicles. The extraocular muscles attach to the sclera by muscular insertions. The total tensile forces generated by the extraocular muscles ranged from 1.18 N to 2.21 N. The torques of the extraocular muscles ranged from 0.39 to 2.34 N. The torques were greatest in the principal direction of movement for each specific muscle. The lateral rectus produced the greatest total tensile force, as well as the greatest torque force component, while the medial rectus produced the second greatest. This is likely due to the constant rotational movement of the eye anteriorly and posteriorly in order to stabilize the visual image, as well as increase the effective visual field during swimming. Rotational forces in dimensions other than the primary direction of movement may contribute to motion in directions other than the principal direction during multi-muscle contraction that occurs in the vertebrate eye. This article is protected by copyright. All rights reserved. PMID- 30312011 TI - Masticatory Muscles and Branches of Mandibular Nerve: Positional Relationships between Various Muscle Bundles and Their Innervating Branches. AB - The masticatory muscles, which are composed of four main muscles, are innervated by branches of only one of the cranial nerves, the mandibular nerve. This muscle group has a variety of very complex functions. We have investigated the origins and insertions of the masticatory muscles and the adjacent bundles of the main muscles, and closely examined the positional relationships between the muscle bundles and innervating branches. According to the findings of the nerve branching patterns, the masticatory muscles can be classified into two groups: the inner group consisting of the lateral pterygoid muscle, and the outer group consisting of the other muscles and adjacent muscle bundles. Further, the outer muscle group is sub-divided into the three other main muscles (the masseter, the temporalis, and the medial pterygoid muscle) and the adjacent various transitional muscle bundles. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312012 TI - Oxidation of Guanosine Monophosphate with O2 via a Ru-peroxo Complex in Water. AB - Oxidative damage of DNA by reactive oxygen species (ROS) is responsible for aging and cancer. Although many studies of DNA damage by ROS have been conducted, there have been no reports of the oxidation of RNA components, such as guanosine monophosphate, by metal-based species in water. Here, we report the first case of oxidation of guanosine monophosphate to 8-oxoguanosine monophosphate by a metal based oxygen bound species, derived from O2 and in water. PMID- 30312013 TI - Functionally Driven Modulation of Sarcomeric Structure and Membrane Systems in the Fast Muscles of a Copepod (Gaussia princeps). AB - Muscles of the mesopelagic copepod Gaussia princeps (Arthropoda, Crustacea, Calanoida) are responsible for repetitive movements of feeding and swimming appendages that are too fast to be followed by eye. This article provides a comparative functional and ultrastructural description of five muscles that have different contraction speeds and are located within different anatomical sites. All are very fast, as indicated by a thick:thin filament ratio of 3:1 and sarcomere lengths that vary between 1 and 3 MUm. Measured lengths of thin and thick filaments indicate classification of the muscles into three distinct groups (short, medium, and long) and predict a difference in speed of up to threefold between fibers with the shortest and longest sarcomeres. Indeed, the kicking movement of the posterior legs (with the shortest sarcomere length) is approximately threefold faster than the simultaneous back-folding of the antennae (with the longest length). Thus, a specific relationship between speed of movement and sarcomere length is established, and we can use the latter to predict the former. Regulatory systems of contraction (sarcoplasmic reticulum [SR] and transverse [T] tubules) match the different contractile properties, varying in frequency of distribution and overall content in parallel to sarcomere variations. All muscles from appendages and body musculature show a unique disposition of contractile material, SR, and T tubules found only in copepod muscles; muscle filaments are grouped in large supermyofibrils that are riddled with frequent cylindrical shafts containing SR and T tubules. This arrangement insures a high spatial frequency of regulatory components. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312014 TI - Anatomical Variations of the Intrapetrous Portion of the Facial Nerve. AB - The intrapetrous facial nerve has the second longest intraosseous course of all cranial nerves, after the mandibular nerve. But it is by far the most complex considering the anatomical structures closely related to it. The auditory and vestibular portions of the inner ear, the dura of the middle fossa and posterior fossa, the sigmoid sinus and jugular bulb, and the internal carotid artery are close enough to merit attention. This article includes an anatomical study on 100 temporal bones with anatomical references as seen from the middle fossa and from the transmastoid approaches that may help identifying the facial nerve and protecting surrounding structures. Anatomical variability was present and noteworthy when considering the venous drainage system through the temporal bone and the mastoid pneumatization. The distance from the geniculate ganglion to the hiatus falopii offered the highest variability with a range of 0 to 7.75 mm and a mean of 3.30 mm. The geniculate ganglion was dehiscent in 20.8% of the specimens and the superior semicircular canal was spontaneously blue-lined in 27% of the cases. Through the transmastoid approach, the highest variability was found regarding the distance between the vertical portion of the facial nerve and the jugular bulb (range from 1.5 to 10.0 mm), the sigmoid sinus (range from 0 to 13.25 mm) and the internal carotid artery (range from 6.0 to 15.0 mm). This study highlights the importance of the relative variability of the facial nerve to other surrounding structures within the petrous portion of the temporal bone. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312015 TI - Physcion 8-O-beta-Glucopyranoside Exerts Anti-Tumor Activity against Non-small Cell Lung Cancer by Targeting PPARgamma. AB - Lung cancer is one of the most common causes of cancer related mortality. The present study is designed to investigate whether a naturally occurring anthraquinone compound, physcion 8-O-beta-glucopyranoside (PG) could exert anti cancer activity against non-small cell lung cancer (NSCLC). Cell viability was determined by Cell Counting Kit-8 (CCK-8) assay. Cell cycle distribution and cell apoptosis were determined by flow cytometry. Expressions of marker proteins were assessed by western blot analysis. To examine the role of PPARgamma (peroxisome proliferator-activated receptor gamma) in PG-induced apoptosis and cell cycle arrest, PPARgamma was knockdown using siRNA. In addition, a xenograft model was established to investigate the effect of PG in vivo. The results showed that PG markedly induced cell cycle arrest and apoptosis in human NSCLC cell lines A549 and H358. The anti-tumor effect of PG in NSCLC cells was mediated by upregulation of PPARgamma. Besides, in NSCLC cell lines, the anti-cancer activity of PG was also examined in the xenograft mice model, which showed that PG could significantly reduce tumor burden and activate apoptotic signaling. Our results demonstrated that PG can be regarded as a candidate chemotherapeutic agent for lung cancer. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312016 TI - Total Synthesis of Divergolides E and H. AB - This manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero-Diels-Alder and oxidative carbon-hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation-controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization. PMID- 30312017 TI - Curcumin Ameliorates Memory Deficits by Enhancing Lactate Content and MCT2 Expression in APP/PS1 Transgenic Mouse Model of Alzheimer's Disease. AB - Curcumin is a natural product with several anti-Alzheimer's disease (AD) neuroprotective properties. This study aimed to investigate the effects of curcumin on memory deficits, lactate content, and monocarboxylate transporter 2 (MCT2) in APP/PS1 mouse model of AD. APP/PS1 transgenic mice and wild-type (WT) C57BL/6J mice were used in the present study. Spatial learning and memory of the mice was detected using Morris water-maze test. Cerebral cortex and hippocampus lactate contents were detected using lactate assay. MCT2 expression in the cerebral cortex and hippocampus was examined by immunohistochemistry and Western blotting. Results showed that spatial learning and memory deficits were improved in curcumin-treated APP/PS1 mouse group compared with those in APP/PS1 mice group. Brain lactate content and MCT2 protein level were increased in curcumin treated APP/PS1 mice than in APP/PS1 mice. In summary, our findings indicate that curcumin could ameliorate memory impairments in APP/PS1 mouse model of AD. This phenomenon may be at least partially due to its improving effect on the lactate content and MCT2 protein expression in the brain. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312018 TI - Recipient-Derived Allo-iTregs Induced by Donor DCs Effectively Inhibit the Proliferation of Donor T Cells and Reduce GVHD. AB - To compare the potency of recipient-derived, antigen-specific regulatory T cells induced by different dendritic cells (DCs; iTregs) and freshly isolated natural regulatory T cells (nTregs) in preventing mouse graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). CD4+ T cells from recipient BALB/c mice were stimulated with DCs from recipient BALB/c (syn-DCs), donor B6 (allo-DCs), and third-party C3H (third-party-DCs) mice to induce different iTregs. In parallel, nTregs were isolated from spleen cells of recipient BALB/c (syn-nTregs) and donor B6 (allo-nTregs) mice using magnetic-activated cell sorting. Mixed lymphocyte reaction (MLR) assays were performed to evaluate the suppressive ability of these various regulatory T cells (Tregs). Both the iTregs and nTregs were transfused to GVHD mice on Days 0, 1, 3, and 5. Body weight, GVHD score, and survival time were monitored. Peripheral Tregs were subsequently examined on Days 7, 14, 21, and 28 after BMT, while chimerism was evaluated on Days 14 and 60. Histopathology of colon, liver, and spleen were also performed. DCs markedly induced CD25+ and Foxp3+ expression on CD4+ T cells. The allo-DC induced Tregs (allo-iTregs) suppressed the proliferation of alloreactive T cells better than the other iTregs/nTregs in MLR assays (P < 0.05). Meanwhile, transfusion of the allo-iTregs reduced the severity of GVHD (P < 0.05), increased survival time compared with the GVHD group (P < 0.05), and enhanced the chimerism proportion. On Day 28 after BMT, the allo-iTregs group had the highest frequency of peripheral Tregs (P < 0.05). Recipient-derived allo-iTregs induced by donor DCs included predominant clones that specifically recognized donor antigens. These allo-iTregs not only prevented GVHD by suppressing the proliferation of donor-alloreactive T cells, but also promoted engraftment, and prolonged the survival of GVHD mice. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312019 TI - Rapid and Efficient Genetic Transformation of Sorghum via Agrobacterium-Mediated Method. AB - Genetic transformation via Agrobacterium-mediated methodology has been used in many sorghum studies. However, the transformation efficiency still varies significantly due to high dependence on sorghum genotypes and technical expertise. In this article, we describe a sorghum transformation procedure in sufficient detail using a public genotype, P898012. This system utilizes a standard binary transgenic vector carrying the bar gene as a selectable marker and immature embryos as starting explants. Glufosinate is employed as the selective agent during callus and shoot induction. This procedure is relatively rapid, efficient, highly reproducible, and should be applicable for many other sorghum genotypes. (c) 2018 by John Wiley & Sons, Inc. PMID- 30312020 TI - Metabolic syndrome increases cardiovascular risk in a population with prediabetes: A prospective study in a cohort of Chinese adults. AB - AIMS/INTRODUCTION: The prevalence of prediabetes has become a global epidemic, and prediabetes is often accompanied with metabolic syndrome (MS). However, the association between MS and cardiovascular (CV) risk among individuals with prediabetes in China remains unknown. The present study aimed to identify the relationship of MS with CV risk in Chinese adults with prediabetes. MATERIALS AND METHODS: Altogether, 19,464 participants with prediabetes were enrolled at baseline and were followed up prospectively. Prediabetes is defined as a fasting plasma glucose level between 5.6 and 6.9 mmol/L, and with neither a history of diabetes nor current use of hypoglycemic drugs. Participants were classified on the basis of the presence of MS, according to the definition of the International Diabetes Federation. Main outcomes include major CV events. Incidence rates were expressed in cumulative incidence and person-years incidence. Cox proportional hazards analysis was used to estimate the risk of major CV events. RESULTS: At baseline, the mean age was 51.9 +/- 11.4 years, and 85.6% (n = 16,663) were men. During a median follow-up period of 10.0 years, a total of 1,169 major CV events occurred, including 921 strokes and 273 cases of myocardial infarction. The cumulative incidences were 9.0% (8.1-10.0%), 6.8% (6.0-7.6%) and 2.5% (2.0-3.0%) for total CV events, strokes and myocardial infarction. Regardless of the risk of total CV events, or the risk of stroke or myocardial infarction, the number of prediabetes individuals with MS was higher than those without, and the hazard ratio was 1.50 (95% confidence interval 1.31-1.73), 1.42 (95% confidence interval 1.21-1.67), 1.78 (95% confidence interval 1.34-2.36), respectively. CONCLUSIONS: Among the Chinese population with prediabetes, the risk for major CV events was significantly higher in those with MS than those without. PMID- 30312021 TI - Efficient CRISPR/Cas9-Mediated Mutagenesis in Primary Murine T Lymphocytes. AB - The ability to alter gene expression directly in T lymphocytes has provided a powerful tool for understanding T cell biology, signaling, and function. Manipulation of T cell clones and primary T cells has been accomplished primarily through overexpression or gene-silencing studies using cDNAs or shRNAs, respectively, which are often delivered by retroviral or lentiviral transduction or direct transfection methods. The recent development of CRISPR/Cas9-based mutagenesis has revolutionized genomic editing, allowing unprecedented genetic manipulation of many cell types with greater precision and ease. This article outlines a protocol for CRISPR/Cas9-mediated mutagenesis in primary T lymphocytes from Cas9 transgenic mice using retroviral delivery of guide RNAs. (c) 2018 by John Wiley & Sons, Inc. PMID- 30312022 TI - Proteome-Wide Analysis of Cysteine S-Sulfenylation Using a Benzothiazine-Based Probe. AB - Oxidation of a protein cysteinyl thiol (Cys-SH) to S-sulfenic acid (Cys-SOH) by a reactive oxygen species (e.g., hydrogen peroxide), which is termed protein S sulfenylation, is a reversible post-translational modification that plays a crucial role in redox regulation of protein function in various biological processes. Due to its intrinsically labile nature, protein S-sulfenylation cannot be directly detected or analyzed. Chemoselective probing has been the method of choice for analyzing S-sulfenylated proteins either in vitro or in situ, as it allows stabilization and direct detection of this transient oxidative intermediate. However, it remains challenging to globally pinpoint the specific S sulfenylated cysteine sites on complex proteomes and to quantify their dynamic changes upon oxidative stress. This unit describes how a benzothiazine-based chemoselective probe called BTD and mass spectrometry based chemoproteomics can be used to globally and site-specifically identify and quantify protein S sulfenylation. (c) 2018 by John Wiley & Sons, Inc. PMID- 30312023 TI - Role of MicroRNAs in the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. AB - Hepatocellular carcinoma (HCC) is a prevalent liver malignancy that can be developed from nonalcoholic fatty liver disease (NAFLD). Numerous pathophysiological alterations, including insulin resistance, specific cytokine release, oxidative stress, and mitochondrial damage, are involved in the transition of NAFLD to cirrhosis and HCC. MicroRNAs, as post-transcriptional modulators, play a critical role in the pathogenesis of NAFLD-related HCC by regulating lipid metabolism, glucose homeostasis, cell proliferation, apoptosis, migration, and differentiation. This review summarizes the current progress of microRNAs in the risk and prognosis of NAFLD-related HCC. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312024 TI - Experimentally induced biliary atresia by means of rotavirus-infection is directly linked to severe damage of the microvasculature in the extrahepatic bile duct. AB - AIM: Vascular damage has been reported to contribute to atresia formation in several diseases including biliary atresia. This study focused on the extrahepatic biliary plexus in experimental biliary atresia. METHODS: Newborn BALB/cAnNCrl-pups were infected with rhesus rotavirus within 24 hours after birth to induce experimental biliary atresia. The extrahepatic biliary plexus was examined by confocal microscopy on whole-mount preparations, scored by three independent researchers and further evaluated at the subcellular level with transmission electron microscopy. RESULTS: Imaging results revealed a progressive destruction of the extrahepatic biliary vascular plexus in the course of experimental biliary atresia induced by rotavirus infection. Endothelial cell damage was already visible as cell swelling and necrosis in the first days after infection and a damaged microcirculation that rapidly deteriorated with progression of obliterative cholangiopathy, was observed in the infected mice as early as 72 hours after birth. CONCLUSIONS: In experimental biliary atresia, the destruction of the extrahepatic biliary vascular plexus starts already in the first days post infection and clearly precedes the morphological symptoms of atresia. The deterioration of the vascular bed architecture continues with disease progression. Therefore, we conclude that the (ultra)structural changes in the extrahepatic biliary microvasculature occurring before the visible onset of atresia has a predictive diagnostic value and this impairment in blood supply to the extrahepatic bile duct may be an important contributing factor to the pathogenesis of acquired biliary atresia. This article is protected by copyright. All rights reserved. PMID- 30312025 TI - An Introduction to Actin and Actin-Rich Structures. AB - The actin cytoskeleton has long been recognized as a crucial sub-cellular filament system that is responsible for governing fundamental events ranging from cell division and muscle contraction to whole cell motility and the maintenance of tissue integrity. Consequently, it is not surprising that this network is the focus of over 100,000 different manuscripts. Alterations in the actin cytoskeleton lead to an assortment of diseases and serve as a target for a variety of pathogens. Here we have brought together a collection of primary research articles and reviews that underscore the broad influence this filament system has on organisms. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312026 TI - Systematic Analysis of the Smooth Muscle Wall Phenotype of the Pharyngeal Arch Arteries During Their Reorganization into the Great Vessels and Its Association With Hemodynamics. AB - Early outflow morphogenesis is a critical event in cardiac development. Understanding mechanical and molecular based morphogenetic relationships at early stages of cardiogenesis is essential for the advancement of cardiovascular technology related to congenital heart defects. In this study, we pair molecular changes in pharyngeal arch artery (PAA) vascular smooth muscle cells (VSMCs) with hemodynamic changes over the course of the same period. We focus on Hamburger Hamilton stage 24-36 chick embryos, using both Doppler ultrasound and histological sections to phenotype PAA VSMCs, and establish a relationship between hemodynamics and PAA composition. Our findings show that PAA VSMCs transition through a synthetic, intermediate, and contractile phenotype over time. Wall shear stress magnitude per arch varies throughout development. Despite distinct hemodynamic and fractional expression trends, no strong correlation was found between the two, indicating that WSS magnitude is not the main driver of PAA wall remodeling and maturation. While WSS magnitude was not found to be a major driver, this work provides a basic framework for investigating relationships between hemodynamic forces and tunica media during a critical period of development. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312027 TI - Hemostatic abnormalities in patients with Ehlers-Danlos syndrome. AB - Essentials Ehlers-Danlos Syndrome (EDS) is a rare heterogeneous group of inherited collagen disorders. A cohort of EDS patients was investigated for bleeding tendency and hemostatic abnormalities. EDS is associated with an increased risk of bleeding. EDS patients have platelet function abnormalities, whose severity correlates with bleeding risk. SUMMARY: Background Ehlers-Danlos syndrome (EDS) includes a heterogeneous group of connective tissue disorders affecting skin, bones, vessels, and other organs. Patients with EDS have an increased risk of bleeding, but a comprehensive study of hemostasis in EDS patients is lacking. Objective To investigate the bleeding tendency of a cohort of patients with EDS by using the Bleeding Assessment Tool of the ISTH, the bleeding severity score (BSS). Methods The BSS was defined as abnormal when it was >= 4 in men and >= 6 in women. Patients with a bleeding tendency were compared with those without in terms of type and number of hemostatic abnormalities. Results Fifty-nine of 141 patients with EDS (41.7%) had an abnormal BSS. Prothrombin time and activated partial thromboplastin time were slightly prolonged in 10 patients (7.1%) because of mild coagulation factor deficiencies, which were not responsible for the bleeding diathesis. von Willebrand factor antigen, ristocetin cofactor, endogenous thrombin potential and platelet count were normal in all patients. At least one platelet function abnormality was found in 53 patients (90%) with an abnormal BSS and in 64 (78%) with a normal BSS (adjusted odds ratio [OR] 2.55, 95% confidence interval [CI] 0.87-7.48). The risk of bleeding progressively increased with the number of platelet function abnormalities, reaching an OR of 5.19 (95% CI 1.32-20.45) when more than three abnormalities were detected. Conclusions Our results show that nearly half of patients with EDS have an abnormal BSS, which, in 90% of cases, appear, at least in part, to be attributable to platelet function abnormalities. Abnormalities of primary hemostasis may contribute to the risk of bleeding in patients with EDS. PMID- 30312028 TI - Uterine Epithelial Cells Undergo a Plasma Membrane Transformation During Early Pregnancy in the Domestic Cat (Felis catus). AB - Mammals exhibit similar changes in uterine epithelial morphology during early pregnancy despite having a diverse range of placental types. The uterine epithelium undergoes rapid morphological and molecular change ("plasma membrane transformation") during the early stages of pregnancy to allow attachment of the blastocyst. The domestic cat, Felis catus is in the order Carnivora; all species within the Carnivora studied so far develop an endotheliochorial placenta during pregnancy. The endotheliochorial placental type is a common form of placental invasion in mammals. The molecular changes that allow remodeling of the uterine epithelium in preparation for implantation are unknown in most mammals but would provide us with an understanding of what molecules underpin successful implantation and pregnancy among Carnivora. We used immunofluorescence microscopy to localize the key adherens junction proteins desmoglein-2 and E-cadherin in the lateral plasma membrane of the uterine epithelium of F. catus during pregnancy. We show that redistribution of desmoglein-2 and E-cadherin likely facilitates reduction of cell-to-cell adhesion allowing for implantation of the blastocyst and formation of the placenta. The ultrastructural and molecular changes to the uterine epithelium during early pregnancy in F. catus are similar to that in species with other levels of placental invasiveness, suggesting that key molecules such as desmoglein-2 and E-cadherin are crucial to successful pregnancy across all mammals. Anat Rec, 301:1497-1505, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312029 TI - Tannic Acid Solution: A Better Fixative Solution Than Formalin for Elastin and Collagen-Toxic and Morphological Assessment. AB - Formaldehyde is commonly used worldwide, even though it is classified as carcinogenic to humans by the International Agency for Research on Cancer. This has motivated intensive investigations of formaldehyde substitutes, and recently, some alternative solutions were found, which can potentially replace it. Previous research showed that tannic acid (TA) in glutaraldehyde solution has the ability to stabilize elastin and collagen. This provided a basis for the development of a new alcoholic fixative solution, particularly aimed at extracellular matrix components, with TA as a main component. Heart, brain, and intestinal samples were fixed by immersion in 10% regular formalin solution (RFS), 70% ethanol solution (ES), and tannic acid ethanolic solution (TAES). Next, tissue fragments were prepared for routine histology procedures. The toxicity of TA was analyzed using in silico tests for mutagenicity, as well as for cutaneous and respiratory toxicity. Analyses of photomicrographs demonstrated that all fixative solutions have the ability to preserve the fragments. The quantitative analyses showed that capability of TAES to preserve and stabilize elastin and collagen is superior to that of RFS and ES. We demonstrated that TA is not mutagenic, and it is less toxic for skin and respiratory tract. We therefore conclude that TAES can potentially represent a powerful and feasible alternative solution for fixing extracellular matrix of microscopic examination samples. Anat Rec, 301:1544-1550, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312030 TI - The Long Bone Histology of the Sauropodomorph, Antetonitrus ingenipes. AB - This analysis of the long bone microstructure of Antetonitrus ingenipes fills a crucial gap in our understanding of the growth dynamics of sauropodomorph dinosaurs. The bone histology of basal Sauropodomorpha are often characterized by zonal tissue, and contrasts with that of more derived sauropod taxa which show a shift toward the deposition of uninterrupted fibrolamellar bone (with lines of growth being either absent or only present in the outer circumferential layer). In Antetonitrus, growth patterns in the youngest individuals exhibit uninterrupted fibrolamellar bone without any growth marks. Sub-adult individuals, also exhibit highly vascularized fibrolamellar bone throughout the cortex, as in more derived Sauropods and Mussaurus, but growth lines occur intermittently (although not regularly) throughout the cortex as in Lessemsaurus. This indicates that Antetonitrus does not exhibit the growth dynamics previously considered characteristic of Sauropoda. Despite this, the largest (and possibly the oldest femur, NMQR 1705/163) does show an incipient external fundamental system (EFS). Our findings further suggest that growth marks are decoupled from bone size, which indicates a level of developmental plasticity in this taxon. Modulations or textural shifts in the pattern of vascular channel arrangements throughout the fibrolamellar bone in the cortex may be related to periods of resource limitations, although the lack of consistency of these modulations suggest that it is unlikely due to seasonal fluctuations. Localized bands of radial fibrolamellar bone, followed by resumption of normal growth in two samples are interpreted as evidence of a disease infliction, and subsequent recovery thereof. Anat Rec, 301:1506-1518, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312031 TI - Comparative Study of Prenatal Development Between Myotis albescens (Chiroptera: Vespertilionidae) and Eumops patagonicus (Chiroptera: Molossidae): The Chorionic Vesicle and Extraembryonic Membranes Considerations. AB - We presented a comparative study of two species of South American bats, Myotis albescens and Eumops patagonicus, about prenatal development. This study was carried out using 60 specimens, which were measured and photographed, and the embryonic stage was assigned by the staging system for Carollia perspicillata. We observed that the chorionic vesicle showed similarities in the disposition of the extraembryonic membranes, but they differed in characteristics of their yolk sac; in E. patagonicus, it was more glandular than M. albescens. M. albescens presented a well-developed discoid placenta with a caudal antimesometrial position, but E. patagonicus presented a diffuse placenta, which persists until the end of gestation and a discoid placenta in the uterus-tubal junction. In the embryogenesis, early stages, middle stages, and late stages were defined. In the early stage, the embryonic morphology is similar in the two species. The middle stage is characterized by the muzzle and pinna formation, fore and hind limb regionalization, and the formation of the patagium primordium. In the late stage, the overall growth of the embryo occurs. Its fore and hind limbs, patagium, and the typical craniofacial features are configured. We conclude that in early stages of development, the embryonic morphology of M. albescens and E. patagonicus is similar, while in late stages differences are evident; mainly the craniofacial structures and uropatagium configuration characteristics that allow their classification at the family level. Moreover, differences in time of fusion of maxillary and mandibular process were registered. This could be related to the morphology of the muzzle of each species. Anat Rec, 301:1527-1543, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312032 TI - Chronic inflammatory demyelinating polyneuropathy: considerations for diagnosis, management, and population health. AB - First described almost 50 years ago, chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder characterized by progressive peripheral neuropathy. CIDP is difficult to diagnose, but early diagnosis can be crucial to prevent permanent nerve damage. Initial treatment options include corticosteroids, immunoglobulin given by intravenous administration, and therapeutic plasma exchange. Subcutaneous administration of immunoglobulin provides a new option for patients with CIDP that has the potential to increase independence and improve tolerability. This article reviews the epidemiology, diagnosis, treatment options for first- and second-line therapy, treatment guidelines, and monitoring parameters for CIDP. PMID- 30312033 TI - The economic burden and managed care implications of chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a symmetric demyelinating peripheral neuropathy with either a progressive or relapsing remitting course. CIDP is both debilitating and degenerative, leaving patients with functional impairment due to nerve damage in their extremities. Along with its medical burden, CIDP has a significant economic impact, with disease-related expenses and the often fairly high costs related to the immune therapies used to treat the disease. Costs for patients with this disorder often exceed those of other immune-mediated neuromuscular diseases. For these reasons, it is necessary for clinicians to better determine optimal long-term treatment strategies for patients with CIDP that are designed to address both the clinical and economic burden of its management and improve patient outcomes and quality of life. PMID- 30312034 TI - Time-Dependent Multicomponent Density Functional Theory for Coupled Electron Positron Dynamics. AB - Electron-positron interactions have been utilized in various fields of science. Here we develop time-dependent multicomponent density functional theory to study the coupled electron-positron dynamics from first principles. We prove that there are coupled time-dependent single-particle equations that can provide the electron and positron density dynamics, and derive the formally exact expression for their effective potentials. Introducing the adiabatic local density approximation to time-dependent electron-positron correlation, we apply the theory to the dynamics of a positronic lithium hydride molecule under a laser field. We demonstrate the significance of the coupling between electronic and positronic motion by revealing the complex positron detachment mechanism and the suppression of electronic resonant excitation by the screening effect of the positron. PMID- 30312035 TI - Horizon Hair of Extremal Black Holes and Measurements at Null Infinity. AB - It is shown that the conserved charges on the event horizon and the Cauchy horizon associated with scalar perturbations on extremal black holes are externally measurable from null infinity. This suggests that these charges have the potential to serve as an observational signature. The proof of this result is based on obtaining precise late-time asymptotics for the radiation field of outgoing perturbations. PMID- 30312036 TI - Unified Thermodynamic Uncertainty Relations in Linear Response. AB - Thermodynamic uncertainty relations (TURs) are recently established relations between the relative uncertainty of time-integrated currents and entropy production in nonequilibrium systems. For small perturbations away from equilibrium, linear response (LR) theory provides the natural framework to study generic nonequilibrium processes. Here, we use LR to derive TURs in a straightforward and unified way. Our approach allows us to generalize TURs to systems without local time-reversal symmetry, including, e.g., ballistic transport and periodically driven classical and quantum systems. We find that, for broken time reversal, the bounds on the relative uncertainty are controlled both by dissipation and by a parameter encoding the asymmetry of the Onsager matrix. We illustrate our results with an example from mesoscopic physics. We also extend our approach beyond linear response: for Markovian dynamics, it reveals a connection between the TUR and current fluctuation theorems. PMID- 30312037 TI - Evidence for a New Component of High-Energy Solar Gamma-Ray Production. AB - The observed multi-GeV gamma-ray emission from the solar disk-sourced by hadronic cosmic rays interacting with gas and affected by complex magnetic fields-is not understood. Utilizing an improved analysis of the Fermi-LAT data that includes the first resolved imaging of the disk, we find strong evidence that this emission is produced by two separate mechanisms. Between 2010 and 2017 (the rise to and fall from solar maximum), the gamma-ray emission was dominated by a polar component. Between 2008 and 2009 (solar minimum) this component remained present, but the total emission was instead dominated by a new equatorial component with a brighter flux and harder spectrum. Most strikingly, although six gamma rays above 100 GeV were observed during the 1.4 yr of solar minimum, none were observed during the next 7.8 yr. These features, along with a 30-50 GeV spectral dip which will be discussed in a companion paper, were not anticipated by theory. To understand the underlying physics, Fermi-LAT and HAWC observations of the imminent cycle 25 solar minimum are crucial. PMID- 30312039 TI - Decoupling Geometrical and Kinematic Contributions to the Silo Clogging Process. AB - Based on the implementation of a novel silo discharge procedure, we are able to control the grains velocities regardless of the outlet size. This allows isolating the geometrical and kinematic contributions to the clogging process. We find that, for a given outlet size, reducing the grains velocities to extremely low values leads to a clogging probability increment of almost two orders of magnitude, hence revealing the importance of particle kinematics in the silo clogging process. Then, we explore the contribution of both variables, outlet size and grains velocity, and we find that our results agree with an already known exponential expression that relates clogging probability with outlet size. We propose a modification of such expression revealing that only two parameters are necessary to fit all the data: one is related with the geometry of the problem, and the other with the grains kinematics. PMID- 30312038 TI - Role of Helicity in DNA Hairpin Folding Dynamics. AB - We study hairpin folding dynamics by means of extensive molecular dynamics simulations, with particular attention paid to the influence of helicity on the folding time. We find that the dynamical exponent alpha in the anomalous scaling n(t)~t^{1/alpha} of the hairpin length n with time changes from 1.6 (?1+nu, where nu is the Flory exponent) to 1.2 (?2nu) in three dimensions, when duplex helicity is removed. The relation alpha=2nu in rotationless hairpin folding is further verified in two dimensions (nu=0.75) and for a ghost chain (nu=0.5). Our findings suggest that the folding dynamics in long helical chains is governed by the duplex dynamics, contrasting the earlier understanding based on the stem-flower picture of unpaired segments. We propose a scaling argument for alpha=1+nu in helical chains, assuming that duplex relaxation required for orientational positioning of the next pair of bases is the rate-limiting process. PMID- 30312040 TI - Dynamical Quantum Phase Transitions: A Geometric Picture. AB - The Loschmidt echo is a purely quantum-mechanical quantity whose determination for large quantum many-body systems requires an exceptionally precise knowledge of all eigenstates and eigenenergies. One might therefore be tempted to dismiss the applicability of any approximations to the underlying time evolution as hopeless. However, using the fully connected transverse-field Ising model as an example, we show that this indeed is not the case and that a simple semiclassical approximation to systems well described by mean-field theory is, in fact, in good quantitative agreement with the exact quantum-mechanical calculation. Beyond the potential to capture the entire dynamical phase diagram of these models, the method presented here also allows for an intuitive geometric interpretation of the fidelity return rate at any temperature, thereby connecting the order parameter dynamics and the Loschmidt echo in a common framework. Videos of the postquench dynamics provided in Supplemental Material visualize this new point of view. PMID- 30312041 TI - Biscalar Integrable Conformal Field Theories in Any Dimension. AB - We propose a D-dimensional generalization of 4D biscalar conformal quantum field theory recently introduced by Gurdogan and one of the authors as a particular strong-twist limit of gamma-deformed N=4 supersymmetric Yang-Mills theory. Similar to the 4D case, the planar correlators of this D-dimensional theory are conformal and dominated by "fishnet" Feynman graphs. The dynamics of these graphs is described by the integrable conformal SO(1,D+1) spin chain. In 2D, it is the analogue of Lipatov's SL(2,C) spin chain for the Regge limit of QCD but with the spins s=1/4 instead of s=0. Generalizing recent 4D results of Grabner, Gromov, Korchemsky, and one of the authors to any D, we compute exactly at any coupling a four-point correlation function dominated by the simplest fishnet graphs of cylindric topology and extract from it exact dimensions of operators with chiral charge 2 and any spin together with some of their operator product expansion structure constants. PMID- 30312042 TI - Extreme Correlation and Repulsive Interactions in Highly Excited Atomic Alkali Anions. AB - At high energies, single-photon photodetachment of alkali negative ions populates final states where both the ejected electron and the residual valence electron possess high angular momenta. The photodetached electron interacts strongly with the anisotropic core, and thus the partial cross sections for these channels display non-Wigner threshold behavior reflecting these large, and occasionally repulsive, interactions. Our fully quantum-mechanical theoretical study enables a deeper interpretation of these partial cross sections. Comparisons of the behavior in different channels and between different atomic species-sodium, potassium, and cesium-show the critical role of near degeneracies in the energy spectrum and demonstrate that much of the behavior of the partial photodetachment cross sections stems from the permanent, rather than induced, electric dipole moments of these nearly degenerate channels. This provides a concrete example of a system where negative dispersion forces play a decisive role. PMID- 30312043 TI - Resummation of Diagrammatic Series with Zero Convergence Radius for Strongly Correlated Fermions. AB - We demonstrate that a summing up series of Feynman diagrams can yield unbiased accurate results for strongly correlated fermions even when the convergence radius vanishes. We consider the unitary Fermi gas, a model of nonrelativistic fermions in three-dimensional continuous space. Diagrams are built from partially dressed or fully dressed propagators of single particles and pairs. The series is resummed by a conformal-Borel transformation that incorporates the large-order behavior and the analytic structure in the Borel plane, which are found by the instanton approach. We report highly accurate numerical results for the equation of state in the normal unpolarized regime, and reconcile experimental data with the theoretically conjectured fourth virial coefficient. PMID- 30312044 TI - Bidirectional Soliton Rain Dynamics Induced by Casimir-Like Interactions in a Graphene Mode-Locked Fiber Laser. AB - We study experimentally and theoretically the interactions among ultrashort optical pulses in the soliton rain multiple-pulse dynamics of a fiber laser. The laser is mode locked by a graphene saturable absorber fabricated using the mechanical transfer technique. Dissipative optical solitons aggregate into pulse bunches that exhibit complex behavior, which includes acceleration and bidirectional motion in the moving reference frame. The drift speed and direction depend on the bunch size and relative location in the cavity, punctuated by abrupt changes under bunch collisions. We model the main effects using the recently proposed noise-mediated pulse interaction mechanism, and obtain a good agreement with experiments. This highlights the major role of long-range Casimir like interactions over dynamical pattern formations within ultrafast lasers. PMID- 30312045 TI - Direct Observation of Electron Distributions inside Millisecond Duration Electron Holes. AB - Despite the importance of millisecond duration spatial structures [chorus wave nonlinearity or time domain structures (TDS)] to plasma dynamics, there have been no direct observations of the generation and interaction of these waves and TDS with electrons at the millisecond timescale required for their understanding. Through superposition of 0.195 ms Magnetospheric Multiscale Satellite electron measurements inside 37 superposed, millisecond duration electron holes, the first observations of electron spectra and pitch angle distributions on a submillisecond timescale have been obtained. They show that keV electrons inside the superposed electron hole are accelerated by several hundred volts and that the spectrum of electrons inside the electron hole contain several maxima and minima that are explained by a model of electron energy changes on entering the holes. We report the first observation of trapped electrons inside the TDS, in accordance with the theoretical requirement that such electrons must be present in order to form the phase space holes. Mechanisms of electron acceleration by electron holes (through perpendicular energy gain as the TDS moves into a converging magnetic field) and scattering (due to the perpendicular electric field) are discussed. PMID- 30312046 TI - Spin Structure of K Valleys in Single-Layer WS_{2} on Au(111). AB - The spin structure of the valence and conduction bands at the K[over -] and K[over -]^{'} valleys of single-layer WS_{2} on Au(111) is determined by spin- and angle-resolved photoemission and inverse photoemission. The bands confining the direct band gap of 1.98 eV are out-of-plane spin polarized with spin dependent energy splittings of 417 meV in the valence band and 16 meV in the conduction band. The sequence of the spin-split bands is the same in the valence and in the conduction bands and opposite at the K[over -] and the K[over -]^{'} high-symmetry points. The first observation explains "dark" excitons discussed in optical experiments; the latter points to coupled spin and valley physics in electron transport. The experimentally observed band dispersions are discussed along with band structure calculations for a freestanding single layer and for a single layer on Au(111). PMID- 30312047 TI - Disentangling Coalescing Neutron-Star-White-Dwarf Binaries for LISA. AB - The prime candidate sources for the upcoming space-borne gravitational wave (GW) observatory LISA are the numerous Galactic tight binaries of white dwarfs (WDs) and neutron stars (NSs), many of which will coalesce and undergo mass transfer, leading to simultaneous emission of x rays and GWs. Here, detailed and coherent numerical stellar models are explored for the formation and evolution of these systems, including finite-temperature effects and complete calculations of mass transfer from a WD to a NS accretor. Evolutionary tracks of characteristic strain amplitude are computed, and the unique pattern of their evolution in the GW frequency-dynamical chirp mass parameter space enables a firm identification of the nature of the systems. Furthermore, it is demonstrated that a precise detection of the chirp allows determination of the NS mass to an accuracy of a few percent; with applications to constraining its equation of state, in particular for dual-line GW sources observed simultaneously at high and low frequencies. PMID- 30312048 TI - Adhesion-Induced Discontinuous Transitions and Classifying Social Networks. AB - Transition points mark qualitative changes in the macroscopic properties of large complex systems. Explosive transitions, exhibiting properties of both continuous and discontinuous phase transitions, have recently been uncovered in network growth processes. Real networks not only grow but often also restructure; yet common network restructuring processes, such as small world rewiring, do not exhibit phase transitions. Here, we uncover a class of intrinsically discontinuous transitions emerging in network restructuring processes controlled by adhesion-the preference of a chosen link to remain connected to its end node. Deriving a master equation for the temporal network evolution and working out an analytic solution, we identify genuinely discontinuous transitions in nongrowing networks, separating qualitatively distinct phases with monotonic and with peaked degree distributions. Intriguingly, our analysis of empirical data indicates a separation between the same two forms of degree distributions distinguishing abstract from face-to-face social networks. PMID- 30312049 TI - Nonequilibrium Mass Transport in the 1D Fermi-Hubbard Model. AB - We experimentally and numerically investigate the sudden expansion of fermions in a homogeneous one-dimensional optical lattice. For initial states with an appreciable amount of doublons, we observe a dynamical phase separation between rapidly expanding singlons and slow doublons remaining in the trap center, realizing the key aspect of fermionic quantum distillation in the strongly interacting limit. For initial states without doublons, we find a reduced interaction dependence of the asymptotic expansion speed compared to bosons, which is explained by the interaction energy produced in the quench. PMID- 30312050 TI - Baryon Asymmetry from a Composite Higgs Boson. AB - We study the nature of the electroweak phase transition (EWPT) in models where the Higgs boson emerges as a pseudo-Nambu-Goldstone boson of an approximate global symmetry of a new strongly interacting sector confining around the TeV scale. Our analysis focuses for the first time on the case where the EWPT is accompanied by the confinement phase transition of the strong sector. We describe the confinement in terms of the dilaton, the pseudo-Nambu-Goldstone boson of spontaneously broken conformal invariance of the strong sector. The dilaton can either be a mesonlike or a glueball-like state and we demonstrate a significant qualitative difference in their dynamics. We show that the EWPT can naturally be strongly first order, due to the nearly conformal nature of the dilaton potential. Furthermore, we examine the sizable scale variation of the Higgs potential parameters during the EWPT. In particular, we consider in detail the case of a varying top quark Yukawa coupling, and show that the resulting CP violation is sufficient for successful electroweak baryogenesis. We demonstrate that this source of CP violation is compatible with existing flavor and CP constraints. Our scenario can be tested in complementary ways: by measuring the CP-odd top Yukawa coupling in electron electric dipole moment experiments, by searching for dilaton production and deviations in Higgs couplings at colliders, and through gravitational waves at LISA. PMID- 30312051 TI - Ferroelectric Problem beyond the Conventional Scaling Law. AB - Ferroelectric (FE) size effects against the scaling law were reported recently in ultrathin group-IV monochalcogenides, and extrinsic effects (e.g., defects and lattice strains) were often resorted to. Via first-principles based finite temperature (T) simulations, we reveal that these abnormalities are intrinsic to their unusual symmetry breaking from bulk to thin film. Changes of the electronic structures result in different order parameters characterizing the FE phase transition in bulk and in thin films, and invalidation of the scaling law. Beyond the scaling law T_{c} limit, this mechanism can help predict materials that are promising for room-T ultrathin FE devices of broad interest. PMID- 30312052 TI - Entanglement Entropy and TT[over -] Deformation. AB - Quantum gravity in a finite region of spacetime is conjectured to be dual to a conformal field theory (CFT) deformed by the irrelevant operator TT[over -]. We test this conjecture with entanglement entropy, which is sensitive to ultraviolet physics on the boundary, while also probing the bulk geometry. We find that the entanglement entropy for an entangling surface consisting of two antipodal points on a sphere is finite and precisely matches the Ryu-Takayanagi formula applied to a finite region consistent with the conjecture of McGough et al. We also consider a one-parameter family of conical entropies, which are finite and verify a conjecture due to Dong. Since ultraviolet divergences are local, we conclude that the TT[over -] deformation acts as an ultraviolet cutoff on the entanglement entropy. Our results support the conjecture that the TT[over -]-deformed CFT is the holographic dual of a finite region of spacetime. PMID- 30312053 TI - Freely Jointed Polymers Made of Droplets. AB - An important goal of self-assembly is to achieve a preprogrammed structure with high fidelity. Here, we control the valence of DNA-functionalized emulsions to make linear and branched model polymers, or "colloidomers." The distribution of cluster sizes is consistent with a polymerization process in which the droplets achieve their prescribed valence. Conformational statistics reveal that the chains are freely jointed, so that the Kuhn length is close to one bead diameter. The end-to-end length scales with the number of bonds N as N^{nu}, where nu~3/4, in agreement with the Flory theory in two dimensions. The chain diffusion coefficient D approximately scales as D?N^{-nu}, as predicted by the Zimm model. Unlike molecular polymers, colloidomers can be repeatedly assembled and disassembled under temperature cycling, allowing for reconfigurable, responsive matter. PMID- 30312054 TI - Nonequilibrium Steady-State Transport in Quantum Impurity Models: A Thermofield and Quantum Quench Approach Using Matrix Product States. AB - The numerical renormalization group (NRG) is tailored to describe interacting impurity models in equilibrium, but it faces limitations for steady-state nonequilibrium, arising, e.g., due to an applied bias voltage. We show that these limitations can be overcome by describing the thermal leads using a thermofield approach, integrating out high energy modes using NRG, and then treating the nonequilibrium dynamics at low energies using a quench protocol, implemented using the time-dependent density matrix renormalization group. This yields quantitatively reliable results for the current (with errors ?3%) down to the exponentially small energy scales characteristic of impurity models. We present results of benchmark quality for the temperature and magnetic field dependence of the zero-bias conductance peak for the single-impurity Anderson model. PMID- 30312056 TI - Optical Lattice with Torus Topology. AB - We propose an experimental scheme to construct an optical lattice where the atoms are confined to the surface of a torus. This construction can be realized with spatially shaped laser beams which could be realized with recently developed high resolution imaging techniques. We numerically study the feasibility of this proposal by calculating the tunneling strengths for atoms in the torus lattice. To illustrate the nontrivial role of topology in atomic dynamics on the torus, we study the quantized superfluid currents and fractional quantum Hall (FQH) states on such a structure. For FQH states, we numerically investigate the robustness of the topological degeneracy and propose an experimental way to detect such a degeneracy. Our scheme for torus construction can be generalized to surfaces with higher genus for exploration of richer topological physics. PMID- 30312057 TI - Inhomogeneity-Induced Casimir Transport of Nanoparticles. AB - We propose a scheme for transporting nanoparticles immersed in a fluid, relying on quantum vacuum fluctuations. The mechanism lies in the inhomogeneity-induced lateral Casimir force between a nanoparticle and a gradient metasurface and the relaxation of the conventional Dzyaloshinskii-Lifshitz-Pitaevskii constraint, which allows quantum levitation for a broader class of material configurations. The velocity for a nanosphere levitated above a grating is calculated and can be up to a few microns per minute. The Born approximation gives general expressions for the Casimir energy which reveal size-selective transport. For any given metasurface, a certain particle-metasurface separation exists where the transport velocity peaks, forming a "Casimir passage." The sign and strength of the Casimir interactions can be tuned by the shapes of liquid-air menisci, potentially allowing real-time control of an otherwise passive force, and enabling interesting on-off or directional switching of the transport process. PMID- 30312055 TI - High-Performance Indirect-Drive Cryogenic Implosions at High Adiabat on the National Ignition Facility. AB - To reach the pressures and densities required for ignition, it may be necessary to develop an approach to design that makes it easier for simulations to guide experiments. Here, we report on a new short-pulse inertial confinement fusion platform that is specifically designed to be more predictable. The platform has demonstrated 99%+0.5% laser coupling into the hohlraum, high implosion velocity (411 km/s), high hotspot pressure (220+60 Gbar), and high cold fuel areal density compression ratio (>400), while maintaining controlled implosion symmetry, providing a promising new physics platform to study ignition physics. PMID- 30312058 TI - Polariton Anomalous Hall Effect in Transition-Metal Dichalcogenides. AB - We analyze the properties of strongly coupled excitons and photons in systems made of semiconducting two-dimensional transition-metal dichalcogenides embedded in optical cavities. Through a detailed microscopic analysis of the coupling, we unveil novel, highly tunable features of the spectrum that result in polariton splitting and a breaking of light-matter selection rules. The dynamics of the composite polaritons is influenced by the Berry phase arising both from their constituents and from the confinement-enhanced coupling. We find that light matter coupling emerges as a mechanism that enhances the Berry phase of polaritons well beyond that of its elementary constituents, paving the way to achieve a polariton anomalous Hall effect. PMID- 30312059 TI - LO-Phonon Emission Rate of Hot Electrons from an On-Demand Single-Electron Source in a GaAs/AlGaAs Heterostructure. AB - Using a recent time-of-flight measurement technique with 1 ps time resolution and electron-energy spectroscopy, we develop a method to measure the longitudinal optical-phonon emission rate of hot electrons traveling along a depleted edge of a quantum Hall bar. Comparison to a single-particle model implies the scattering mechanism involves a two-step process via an intra-Landau-level transition. We show that this can be suppressed by control of the edge potential profile, and a scattering length >1 mm can be achieved, allowing the use of this system for scalable single-electron device applications. PMID- 30312060 TI - Interface-Generated Spin Currents. AB - Transport calculations based on ab initio band structures reveal large interface generated spin currents at Co/Pt, Co/Cu, and Pt/Cu interfaces. These spin currents are driven by in-plane electric fields but flow out of plane and can have similar strengths to spin currents generated by the spin Hall effect in bulk Pt. Each interface generates spin currents with polarization along z[over ^]*E, where z[over ^] is the interface normal and E denotes the electric field. The Co/Cu and Co/Pt interfaces additionally generate spin currents with polarization along m[over ^]*(z[over ^]*E), where m[over ^] gives the magnetization direction of Co. The latter spin polarization is controlled by-but not aligned with-the magnetization, providing a novel mechanism for generating spin torques in magnetic trilayers. PMID- 30312061 TI - Experimental Observation of a Time-Driven Phase Transition in Quantum Chaos. AB - We report the first experimental observation of the time-driven phase transition in a canonical quantum chaotic system, the quantum kicked rotor. The transition bears a firm analogy to a thermodynamic phase transition, with the time mimicking the temperature and the quantum expectation of the rotor's kinetic energy mimicking the free energy. The transition signals a sudden change in the system's memory behavior: before the critical time, the system undergoes chaotic motion in phase space and its memory of initial states is erased in the course of time; after the critical time, quantum interference enhances the probability for a chaotic trajectory to return to the initial state, and thus the system's memory is recovered. PMID- 30312062 TI - Collisionless Transport Close to a Fermionic Quantum Critical Point in Dirac Materials. AB - Quantum transport close to a critical point is a fundamental, but enigmatic problem due to fluctuations, persisting at all length scales. We report the scaling of optical conductivity (OC) in the collisionless regime (homega?k_{B}T) in the vicinity of a relativistic quantum critical point, separating two dimensional (d=2) massless Dirac fermions from a fully gapped insulator or superconductor. Close to such a critical point, gapless fermionic and bosonic excitations are strongly coupled, leading to a universal suppression of the interband OC as well as of the Drude peak (while maintaining its delta function profile) inside the critical regime, which we compute to the leading order in 1/N_{f}- and epsilon expansions, where N_{f} counts the fermion flavor number and epsilon=3-d. Correction to the OC at such a non-Gaussian critical point due to the long-range Coulomb interaction and generalizations of these scenarios to a strongly interacting three-dimensional Dirac or Weyl liquid are also presented, which can be tested numerically and possibly from nonperturbative gauge-gravity duality, for example. PMID- 30312063 TI - Elasticity of Nuclear Pasta. AB - The elastic properties of neutron star crusts are relevant for a variety of currently observable or near-future electromagnetic and gravitational wave phenomena. These phenomena may depend on the elastic properties of nuclear pasta found in the inner crust. We present large-scale classical molecular dynamics simulations where we deform nuclear pasta. We simulate idealized samples of nuclear pasta and describe their breaking mechanism. We also deform nuclear pasta that is arranged into many domains, similar to what is known for the ions in neutron star crusts. Our results show that nuclear pasta may be the strongest known material, perhaps with a shear modulus of 10^{30} ergs/cm^{3} and a breaking strain greater than 0.1. PMID- 30312065 TI - Marginally Self-Averaging One-Dimensional Localization in Bilayer Graphene. AB - The combination of a field-tunable band gap, topological edge states, and valleys in the band structure makes insulating bilayer graphene a unique localized system, where the scaling laws of dimensionless conductance g remain largely unexplored. Here we show that the relative fluctuations in lng with the varying chemical potential, in strongly insulating bilayer graphene (BLG), decay nearly logarithmically for a channel length up to L/xi~20, where xi is the localization length. This "marginal" self-averaging, and the corresponding dependence of ?lng? on L, suggests that transport in strongly gapped BLG occurs along strictly one dimensional channels, where xi~0.5+/-0.1 MUm was found to be much longer than that expected from the bulk band gap. Our experiment reveals a nontrivial localization mechanism in gapped BLG, governed by transport along robust edge modes. PMID- 30312064 TI - Two-Dome Superconductivity in FeS Induced by a Lifshitz Transition. AB - Among iron chalcogenide superconductors, FeS can be viewed as a simple, highly compressed relative of FeSe without a nematic phase and with weaker electronic correlations. Under pressure, however, the superconductivity of stoichiometric FeS disappears and reappears, forming two domes. We perform electronic structure and spin fluctuation theory calculations for tetragonal FeS in order to analyze the nature of the superconducting order parameter. In the random phase approximation, we find a gap function with d-wave symmetry at ambient pressure, in agreement with several reports of a nodal superconducting order parameter in FeS. Our calculations show that, as a function of pressure, the superconducting pairing strength decreases until a Lifshitz transition takes place at 4.6 GPa. As a hole pocket with a large density of states appears at the Lifshitz transition, the gap symmetry is altered to sign-changing s wave. At the same time, the pairing strength is severely enhanced and increases up to a new maximum at 5.5 GPa. Therefore, our calculations naturally explain the occurrence of two superconducting domes in FeS. PMID- 30312066 TI - Variational Renormalization Group for Dissipative Spin-Cavity Systems: Periodic Pulses of Nonclassical Photons from Mesoscopic Spin Ensembles. AB - Mesoscopic spin ensembles coupled to a cavity offer the exciting prospect of observing complex nonclassical phenomena that pool the microscopic features from a few spins with those of macroscopic spin ensembles. Here, we demonstrate how the collective interactions in an ensemble of as many as a hundred spins can be harnessed to obtain a periodic pulse train of nonclassical light. To unravel the full quantum dynamics and photon statistics, we develop a time-adaptive variational renormalization group method that accurately captures the underlying Lindbladian dynamics of the mesoscopic spin-cavity system. PMID- 30312067 TI - Stochastic Polarization Instability in PbTiO_{3}. AB - Although discussions of structural phase transitions in prototypical ferroelectric systems with the perovskite structure, such as BaTiO_{3} and PbTiO_{3}, started almost seventy years ago, an atomic-level description of the polar characteristics as a function of temperature, pressure, and composition remains topical. Here we provide a novel quantitative description of the temperature-driven local structural correlations in PbTiO_{3} via the development of characteristic relative cationic shifts. The results give new insights into the phase transition beyond those reliant on the long-range order. The ferroelectric-to-paraelectric transition of PbTiO_{3} is realized by the extent of a stochastic polarization instability driven by a progressive misalignment instead of a complete disappearance of the local dipoles, which further suggests that such polarization instability is chemically induced at the morphotropic phase boundary of PbTiO_{3}-based solid solutions with giant piezoelectric effect. As such, our results not only identify the evolving atomistic disorder in a perovskite-based ferroelectric system, but also suggest that polarization instability can serve as a generic fingerprint for phase transitions as well as for better understanding structure-property relationships in PbTiO_{3}-based ferroelectric solid solutions. PMID- 30312068 TI - Non-Hermitian Chern Bands. AB - The relation between chiral edge modes and bulk Chern numbers of quantum Hall insulators is a paradigmatic example of bulk-boundary correspondence. We show that the chiral edge modes are not strictly tied to the Chern numbers defined by a non-Hermitian Bloch Hamiltonian. This breakdown of conventional bulk-boundary correspondence stems from the non-Bloch-wave behavior of eigenstates (non Hermitian skin effect), which generates pronounced deviations of phase diagrams from the Bloch theory. We introduce non-Bloch Chern numbers that faithfully predict the numbers of chiral edge modes. The theory is backed up by the open boundary energy spectra, dynamics, and phase diagram of representative lattice models. Our results highlight a unique feature of non-Hermitian bands and suggest a non-Bloch framework to characterize their topology. PMID- 30312069 TI - Observation of a Goos-Hanchen-like Phase Shift for Magnetostatic Spin Waves. AB - In optics, a light beam experiences a spatial shift in the beam plane upon total internal reflection. This shift is usually referred to as the Goos-Hanchen shift. When dealing with plane waves, it manifests itself as a phase shift between an incoming and reflected wave that depends on the wave vector component along the interface. In the experiments presented here, plane spin waves are excited in a 60-nm-thick Permalloy film and propagate towards the edge of the film. By means of time-resolved scanning Kerr microscopy, we are able to directly detect a phase shift between the incoming and reflected wave. With the help of a numerical model, we show that this phase shift naturally occurs for spin waves in the dipolar regime. PMID- 30312070 TI - Signatures of van Hove Singularities Probed by the Supercurrent in a Graphene-hBN Superlattice. AB - The band structure of graphene can be strongly modified if its lattice is aligned with the one of a boron nitride substrate. A moire superlattice forms, which manifests itself by the appearance of new Dirac points, accompanied by van Hove singularities. In this work, we present supercurrent measurements in a Josephson junction made from such a graphene superlattice in the long and diffusive transport regime, where the critical current depends on the Thouless energy. We can then estimate the specific density of states of the graphene superlattice from the combined measurement of the critical current and the normal state resistance. The result matches with theoretical predictions and highlights the strong increase of the density of states at the van Hove singularities. By measuring the magnetic field dependence of the critical current, we find the presence of edge currents at these singularities. We explain it by the reduction of the Fermi velocity associated with the van Hove singularity, which suppresses the supercurrent in the bulk while the electrons at the edges remain less localized, resulting in an edge supercurrent. We attribute these different behaviors of the edges to defects or chemical doping. PMID- 30312071 TI - Quantum Spin Dynamics of Individual Neutral Impurities Coupled to a Bose-Einstein Condensate. AB - We report on spin dynamics of individual, localized neutral impurities immersed in a Bose-Einstein condensate. Single cesium atoms are transported into a cloud of rubidium atoms and thermalize with the bath, and the ensuing spin exchange between localized impurities with quasispin F_{i}=3 and bath atoms with F_{b}=1 is resolved. Comparing our data to numerical simulations of spin dynamics, we find that, for gas densities in the Bose-Einstein condensate regime, the dynamics is dominated by the condensed fraction of the cloud. We spatially resolve the density overlap of impurities and gas by the spin population of impurities. Finally, we trace the coherence of impurities prepared in a coherent superposition of internal states when coupled to a gas of different densities. For our choice of states, we show that, despite high bath densities and, thus, fast thermalization rates, the impurity coherence is not affected by the bath, realizing a regime of sympathetic cooling while maintaining internal state coherence. Our work paves the way toward the nondestructive probing of quantum many-body systems via localized impurities. PMID- 30312072 TI - Laser-Induced Microsphere Hammer-Hit Vibration in Liquid. AB - We demonstrate a new principle of the laser-induced hammer-hit vibration of a micron-sized black sphere in liquid glycerol with a single divergent Gaussian beam. The light-induced Deltaalpha-photophoretic force, which is significantly improved by the vibrating speed of the microparticle, is responsible for both the pushing and pulling force of the hammer-hit vibration. Our approach expands the optical manipulation of microparticle hammer-hit vibration to a liquid medium and provides full control over the trapped particles, including the adjustment of the vibration frequency, amplitude, and position. PMID- 30312073 TI - Particles on Demand for Kinetic Theory. AB - A novel formulation of fluid dynamics as a kinetic theory with tailored, on demand constructed particles removes restrictions on flow speed and temperature as compared to its predecessors, the lattice Boltzmann methods and their modifications. In the new kinetic theory, discrete particles are determined by a rigorous limit process which avoids ad hoc assumptions about their velocities. Classical benchmarks for incompressible and compressible flows demonstrate that the proposed discrete-particles kinetic theory opens up an unprecedented wide domain of applications for computational fluid dynamics. PMID- 30312074 TI - Landau Velocity for Collective Quantum Hall Breakdown in Bilayer Graphene. AB - Breakdown of the quantum Hall effect (QHE) is commonly associated with an electric field approaching the inter-Landau-level (LL) Zener field, the ratio of the Landau gap and the cyclotron radius. Eluded in semiconducting heterostructures, in spite of extensive investigation, the intrinsic Zener limit is reported here using high-mobility bilayer graphene and high-frequency current noise. We show that collective excitations arising from electron-electron interactions are essential. Beyond a noiseless ballistic QHE regime a large super Poissonian shot noise signals the breakdown via inter-LL scattering. The breakdown is ultimately limited by collective excitations in a regime where phonon and impurity scattering are quenched. The breakdown mechanism can be described by a Landau critical velocity as it bears strong similarities with the roton mechanism of superfluids. In addition, we show that breakdown is a precursor of an electric-field induced QHE-metal transition. PMID- 30312075 TI - Thermodynamic Ultrastability of a Polymer Glass Confined at the Micrometer Length Scale. AB - We employ fast scanning calorimetry to assess the thermodynamic state attained after a given cooling rate and the molecular mobility of glassy poly(4-tert butylstyrene) confined at the micrometer length scale. We show that, for such a large confinement length scale, thermodynamic states with a fictive temperature (T_{f}) 80 K below the polymer glass transition temperature (T_{g}) are attained, which allows to bypass the geological timescales required for bulk glasses. Access to such states is promoted by a fast mechanism of equilibration. Importantly, the tremendous T_{f} decrease takes place while the molecular mobility remains bulklike, indicating marked decoupling between vitrification kinetics and molecular mobility. PMID- 30312076 TI - Nanosecond Melting and Recrystallization in Shock-Compressed Silicon. AB - In situ, time-resolved, x-ray diffraction and simultaneous continuum measurements were used to examine structural changes in Si shock compressed to 54 GPa. Shock melting was unambiguously established above ~31-33 GPa, through the vanishing of all sharp crystalline diffraction peaks and the emergence of a single broad diffraction ring. Reshock from the melt boundary results in rapid (nanosecond) recrystallization to the hexagonal-close-packed Si phase and further supports melting. Our results also provide new constraints on the high-temperature, high pressure Si phase diagram. PMID- 30312077 TI - Dephasing-Insensitive Quantum Information Storage and Processing with Superconducting Qubits. AB - A central task towards building a practical quantum computer is to protect individual qubits from decoherence while retaining the ability to perform high fidelity entangling gates involving arbitrary two qubits. Here we propose and demonstrate a dephasing-insensitive procedure for storing and processing quantum information in an all-to-all connected superconducting circuit involving multiple frequency-tunable qubits, each of which can be controllably coupled to any other through a central bus resonator. Although it is generally believed that the extra frequency tunability enhances the control freedom but induces more dephasing impact for superconducting qubits, our results show that any individual qubit can be dynamically decoupled from dephasing noise by applying a weak continuous and resonant driving field whose phase is reversed in the middle of the pulse. More importantly, we demonstrate a new method for realizing a two-qubit phase gate with inherent dynamical decoupling via the combination of continuous driving and qubit-qubit swapping coupling. We find that the weak continuous driving fields not only enable the conditional dynamics essential for quantum information processing, but also protect both qubits from dephasing during the gate operation. PMID- 30312078 TI - Evidence of a Coulomb-Interaction-Induced Lifshitz Transition and Robust Hybrid Weyl Semimetal in T_{d}-MoTe_{2}. AB - Using soft x-ray angle-resolved photoemission spectroscopy we probed the bulk electronic structure of T_{d}-MoTe_{2}. We found that on-site Coulomb interaction leads to a Lifshitz transition, which is essential for a precise description of the electronic structure. A hybrid Weyl semimetal state with a pair of energy bands touching at both type-I and type-II Weyl nodes is indicated by comparing the experimental data with theoretical calculations. Unveiling the importance of Coulomb interaction opens up a new route to comprehend the unique properties of MoTe_{2}, and is significant for understanding the interplay between correlation effects, strong spin-orbit coupling and superconductivity in this van der Waals material. PMID- 30312079 TI - Universality and Stability Phase Diagram of Two-Dimensional Brittle Fracture. AB - The two-dimensional oscillatory crack instability, experimentally observed in a class of brittle materials under strongly dynamic conditions, has been recently reproduced by a nonlinear phase-field fracture theory. Here, we highlight the universal character of this instability by showing that it is present in materials exhibiting widely different near crack tip elastic nonlinearity, and by demonstrating that the oscillations wavelength follows a universal master curve in terms of dissipation-related and nonlinear elastic intrinsic length scales. Moreover, we show that upon increasing the driving force for fracture, a high velocity tip-splitting instability emerges, as experimentally demonstrated. The analysis culminates in a comprehensive stability phase diagram of two-dimensional brittle fracture, whose salient properties and topology are independent of the form of near tip nonlinearity. PMID- 30312080 TI - Comment on "Entropy Production and Fluctuation Theorems for Active Matter". PMID- 30312081 TI - Mandal, Klymko, and DeWeese Reply. PMID- 30312082 TI - Hedgehog Spin-Vortex Crystal Antiferromagnetic Quantum Criticality in CaK(Fe_{1 x}Ni_{x})_{4}As_{4} Revealed by NMR. AB - Two ordering states, antiferromagnetism and nematicity, have been observed in most iron-based superconductors (SCs). In contrast to those SCs, the newly discovered SC CaK(Fe_{1-x}Ni_{x})_{4}As_{4} exhibits an antiferromagnetic (AFM) state, called hedgehog spin-vortex crystal (SVC) structure, without nematic order, providing the opportunity for the investigation into the relationship between spin fluctuations and SC without any effects of nematic fluctuations. Our ^{75}As nuclear magnetic resonance studies on CaK(Fe_{1-x}Ni_{x})_{4}As_{4} (0<=x<=0.049) revealed that CaKFe_{4}As_{4} is located close to a hidden hedgehog SVC AFM quantum-critical point (QCP). The magnetic QCP without nematicity in CaK(Fe_{1-x}Ni_{x})_{4}As_{4} highlights the close connection of spin fluctuations and superconductivity in iron-based SCs. The advantage of stoichiometric composition also makes CaKFe_{4}As_{4} an ideal platform for further detailed investigation of the relationship between magnetic QCP and superconductivity in iron-based SCs without disorder effects. PMID- 30312083 TI - Quantum Simulation with a Trilinear Hamiltonian. AB - Interaction among harmonic oscillators described by a trilinear Hamiltonian hxi(a^{?}bc+ab^{?}c^{?}) is one of the most fundamental models in quantum optics. By employing the anharmonicity of the Coulomb potential in a linear trapped three ion crystal, we experimentally implement it among three normal modes of motion in the strong-coupling regime, where the coupling strength is much larger than the decoherence rate of the ion motion. We use it to simulate the interaction of an atom and light as described by the Tavis-Cummings model and the process of nondegenerate parametric down-conversion in the regime of a depleted pump. PMID- 30312084 TI - Calorimetric Dark Matter Detection with Galactic Center Gas Clouds. AB - We demonstrate that dark matter heating of gas clouds, hundreds of parsecs from the Milky Way Galactic Center, provides a powerful new test of dark matter interactions. To illustrate, we set a new bound on nucleon scattering for 10-100 MeV mass dark matter. We also constrain millicharged dark matter models, including those proposed to match the recent EDGES 21 cm absorption anomaly. For Galactic Center gas clouds, the Galactic fields' magnetic deflection of electromagnetically charged dark matter is mitigated, because the magnetic fields around the Galactic Center are poloidal, as opposed to being aligned parallel to the Milky Way disk. We discuss prospects for detecting dark matter using a population of Galactic Center gas clouds warmed by dark matter. PMID- 30312086 TI - Optimal Pure-State Qubit Tomography via Sequential Weak Measurements. AB - The spin-coherent-state positive-operator-valued-measure (POVM) is a fundamental measurement in quantum science, with applications including tomography, metrology, teleportation, benchmarking, and measurement of Husimi phase space probabilities. We prove that this POVM is achieved by collectively measuring the spin projection of an ensemble of qubits weakly and isotropically. We apply this in the context of optimal tomography of pure qubits. We show numerically that through a sequence of weak measurements of random directions of the collective spin component, sampled discretely or in a continuous measurement with random controls, one can approach the optimal bound. PMID- 30312085 TI - Three-Path Atom Interferometry with Large Momentum Separation. AB - We demonstrate the scale up of a symmetric three-path contrast interferometer to large momentum separation. The observed phase stability at separation of 112 photon recoil momenta exceeds the performance of earlier free-space interferometers. In addition to the symmetric interferometer geometry and Bose Einstein condensate source, the robust scalability of our approach relies on the suppression of undesired diffraction phases through a careful choice of atom optics parameters. The interferometer phase evolution is quadratic with number of recoils, reaching a rate as high as 7*10^{7} rad/s. We discuss the applicability of our method towards a new measurement of the fine-structure constant and a test of QED. PMID- 30312087 TI - Nonlinear saturation of the large scale flow in a laboratory model of the quasibiennial oscillation. AB - The quasibiennial oscillation (QBO) is the nearly periodic reversal of the large scale flow generated by internal waves in the equatorial stratosphere. Using a laboratory model experiment, we study the instability that generates the QBO and investigate its nonlinear regime. We report the first quantitative measurements of the nonlinearly saturated velocity of the flow. We show that the QBO is generated by a bifurcation that is either supercritical or subcritical depending on the dominant dissipative process. This is confirmed by a nonlinear analysis in the vicinity of the instability threshold. PMID- 30312089 TI - Massive Boson Superradiant Instability of Black Holes: Nonlinear Growth, Saturation, and Gravitational Radiation. AB - We study the superradiant instability of a massive boson around a spinning black hole in full general relativity without assuming spatial symmetries. We focus on the case of a rapidly spinning black hole in the presence of a vector boson with a Compton wavelength comparable to the black hole radius, which is the regime where relativistic effects are maximized. We follow the growth of the boson cloud through superradiance into the nonlinear regime as it spins down the black hole, reaches a maximum energy, and begins to dissipate through the emission of gravitational waves. We find that the superradiant instability can efficiently convert a significant fraction of a black hole's rotational energy into gravitational radiation. PMID- 30312088 TI - How Supertough Gels Break. AB - Fracture of highly stretched materials challenges our view of how things break. We directly visualize rupture of tough double-network gels at >50% strain. During fracture, crack tip shapes obey a x~y^{1.6} power law, in contrast to the parabolic profile observed in low-strain cracks. A new length scale l emerges from the power law; we show that l scales directly with the stored elastic energy and diverges when the crack velocity approaches the shear wave speed. Our results show that double-network gels undergo brittle fracture and provide a testing ground for large-strain fracture mechanics. PMID- 30312090 TI - Transport Spectroscopy of Sublattice-Resolved Resonant Scattering in Hydrogen Doped Bilayer Graphene. AB - We report the experimental observation of sublattice-resolved resonant scattering in bilayer graphene by performing simultaneous cryogenic atomic hydrogen doping and electron transport measurements in an ultrahigh vacuum. This allows us to monitor the hydrogen adsorption on the different sublattices of bilayer graphene without atomic-scale microscopy. Specifically, we detect two distinct resonant scattering peaks in the gate-dependent resistance, which evolve as a function of the atomic hydrogen dosage. Theoretical calculations show that one of the peaks originates from resonant scattering by hydrogen adatoms on the alpha sublattice (dimer site) while the other originates from hydrogen adatoms on the beta sublattice (nondimer site), thereby enabling a method for characterizing the relative sublattice occupancy via transport measurements. Utilizing this new capability, we investigate the adsorption and thermal desorption of hydrogen adatoms via controlled annealing and conclude that hydrogen adsorption on the beta sublattice is energetically favored. Through site-selective desorption from the alpha sublattice, we realize hydrogen doping with adatoms primarily on a single sublattice, which is highly desired for generating ferromagnetism. PMID- 30312091 TI - New Closures for More Precise Modeling of Landau Damping in the Fluid Framework. AB - Incorporation of kinetic effects such as Landau damping into a fluid framework was pioneered by Hammett and Perkins, by obtaining closures of the fluid hierarchy, where the gyrotropic heat flux fluctuations or the deviation of the fourth-order gyrotropic fluid moment are expressed through lower-order fluid moments. To obtain a closure of a fluid model expanded around a bi-Maxwellian distribution function, the usual plasma dispersion function Z(zeta) that appears in kinetic theory or the associated plasma response function R(zeta)=1+zetaZ(zeta) has to be approximated with a suitable Pade approximant in such a way that the closure is valid for all zeta values. Such closures are rare, and the original closures of Hammett and Perkins are often employed. Here we present a complete mapping of all plausible Landau fluid closures that can be constructed at the level of fourth-order moments in the gyrotropic limit and we identify the most precise closures. Furthermore, by considering 1D closures at higher-order moments, we show that it is possible to reproduce linear Landau damping in the fluid framework to any desired precision, thus showing convergence of the fluid and collisionless kinetic descriptions. PMID- 30312092 TI - Precursors to Molecular Slip on Smooth Hydrophobic Surfaces. AB - Experiments and simulations suggest that simple liquids may experience slip while flowing near a smooth, hydrophobic surface. Here we show how precursors to molecular slip can be observed in the complex response of a liquid to oscillatory shear. We measure both the change in frequency and bandwidth of a quartz crystal microbalance during the growth of a single drop of water immersed in an ambient liquid. By varying the hydrophobicity of the surface using self-assembled monolayers, our results show little or no slip for water on all surfaces. However, we observe excess transverse motion near hydrophobic surfaces due to weak binding in the corrugated surface potential, an essential precursor to slip. We also show how this effect can be easily missed in simulations utilizing finite ranged interaction potentials. PMID- 30312093 TI - Recombination of Protons Accelerated by a High Intensity High Contrast Laser. AB - Short pulse, high contrast, intense laser pulses incident onto a solid target are not known to generate fast neutral atoms. Experiments carried out to study the recombination of accelerated protons show a 200 times higher neutralization than expected. Fast neutral atoms can contribute to 80% of the fast particles at 10 keV, falling rapidly for higher energy. Conventional charge transfer and electron ion recombination in a high density plasma plume near the target is unable to explain the neutralization. We present a model based on the copropagation of electrons and ions wherein recombination far away from the target surface accounts for the experimental measurements. A novel experimental verification of the model is also presented. This study provides insights into the closely linked dynamics of ions and electrons by which neutral atom formation is enhanced. PMID- 30312094 TI - Electron-Hole Theory of the Effect of Quantum Nuclei on the X-Ray Absorption Spectra of Liquid Water. AB - Electron-hole excitation theory is used to unveil the role of nuclear quantum effects on the x-ray absorption spectral signatures of water, whose structure is computed via path-integral molecular dynamics with the MB-pol intermolecular potential model. Compared to spectra generated from the classically modeled water, quantum nuclei introduce important effects on the spectra in terms of both the energies and line shapes. Fluctuations due to delocalized protons influence the short-range ordering of the hydrogen bond network via changes in the intramolecular covalence, which broaden the preedge spectra. For intermediate range and long-range ordering, quantum nuclei approach the neighboring oxygen atoms more closely than classical protons, promoting an "icelike" spectral feature with the intensities shifted from the main edge to the postedge. Computed spectra are in nearly quantitative agreement with the available experimental data. PMID- 30312095 TI - Sensitivity Bounds for Multiparameter Quantum Metrology. AB - We identify precision limits for the simultaneous estimation of multiple parameters in multimode interferometers. Quantum strategies to enhance the multiparameter sensitivity are based on entanglement among particles, modes, or combining both. The maximum attainable sensitivity of particle-separable states defines the multiparameter shot-noise limit, which can be surpassed without mode entanglement. Further enhancements up to the multiparameter Heisenberg limit are possible by adding mode entanglement. Optimal strategies that saturate the precision bounds are provided. PMID- 30312096 TI - Contact and Momentum Distribution of the Unitary Fermi Gas. AB - A key quantity in strongly interacting resonant Fermi gases is the contact C, which characterizes numerous properties such as the momentum distribution at large momenta or the pair correlation function at short distances. The temperature dependence of C was measured at unitarity, where existing theoretical predictions differ substantially even at the qualitative level. We report accurate data for the contact and the momentum distribution of the unitary gas in the normal phase, obtained by bold diagrammatic Monte Carlo and Borel resummation. Our results agree with experimental data within error bars and provide crucial benchmarks for the development of advanced theoretical treatments and precision measurements. PMID- 30312097 TI - Erratum: Final Results of the OPERA Experiment on nu_{tau} Appearance in the CNGS Neutrino Beam [Phys. Rev. Lett. 120, 211801 (2018)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.120.211801. PMID- 30312099 TI - Observation of Photon Droplets and Their Dynamics. AB - We present experimental evidence of photon droplets in an attractive (focusing) nonlocal nonlinear medium. Photon droplets are self-bound, finite-sized states of light that are robust to size and shape perturbations due to a balance of competing attractive and repulsive forces. It has recently been shown theoretically, via a multipole expansion of the nonlocal nonlinearity, that the self-bound state arises due to competition between the s-wave and d-wave nonlinear terms, together with diffraction. The theoretical photon droplet framework encompasses both a solitonlike stationary ground state and the nonsolitonlike dynamics that ensue when the system is displaced from equilibrium, i.e., driven into an excited state. We present numerics and experiments supporting the existence of these photon droplet states and measurements of the dynamical evolution of the photon droplet orbital angular momentum. PMID- 30312100 TI - Neel- and Bloch-Type Magnetic Vortices in Rashba Metals. AB - We theoretically study noncoplanar spin textures in polar magnetic conductors. Starting from the Kondo lattice model with the Rashba spin-orbit coupling, we derive an effective spin model with generalized Ruderman-Kittel-Kasuya-Yosida interactions including the anisotropic and antisymmetric exchange interactions. By performing simulated annealing for the effective model, we find that a vortex crystal of Neel type is stabilized even in the absence of a magnetic field. Moreover, we demonstrate that a Bloch-type vortex crystal, which is usually associated with the Dresselhaus spin-orbit coupling, can also be realized in our Rashba-based model. A magnetic field turns the vortex crystals into Neel- and Bloch-type Skyrmion-like crystals. Our results underscore that the interplay between the spin-orbit coupling and itinerant magnetism brings fertile possibilities of noncoplanar magnetic orderings. PMID- 30312101 TI - Breakdown of the Law of Reflection at a Disordered Graphene Edge. AB - The law of reflection states that smooth surfaces reflect waves specularly, thereby acting as a mirror. This law is insensitive to disorder as long as its length scale is smaller than the wavelength. Monolayer graphene exhibits a linear dispersion at low energies and consequently a diverging Fermi wavelength. We present proof that for a disordered graphene boundary, resonant scattering off disordered edge modes results in diffusive electron reflection even when the electron wavelength is much longer than the disorder correlation length. Using numerical quantum transport simulations, we demonstrate that this phenomenon can be observed as a nonlocal conductance dip in a magnetic focusing experiment. PMID- 30312098 TI - Extraction of the Landau-Migdal Parameter from the Gamow-Teller Giant Resonance in ^{132}Sn. AB - The key parameter to discuss the possibility of the pion condensation in nuclear matter, i.e., the so-called Landau-Migdal parameter g^{'}, was extracted by measuring the double-differential cross sections for the (p,n) reaction at 216 MeV/u on a neutron-rich doubly magic unstable nucleus, ^{132}Sn with the quality comparable to data taken with stable nuclei. The extracted strengths for Gamow Teller (GT) transitions from ^{132}Sn leading to ^{132}Sb exhibit the GT giant resonance (GTR) at the excitation energy of 16.3+/-0.4(stat)+/-0.4(syst) MeV with the width of Gamma=4.7+/-0.8 MeV. The integrated GT strength up to E_{x}=25 MeV is S_{GT}^{-}=53+/-5(stat)_{-10}^{+11}(syst), corresponding to 56% of Ikeda's sum rule of 3(N-Z)=96. The present result accurately constrains the Landau-Migdal parameter as g^{'}=0.68+/-0.07, thanks to the high sensitivity of the GTR energy to g^{'}. In combination with previous studies on the GTR for ^{90}Zr and ^{208}Pb, the result of this work shows the constancy of this parameter in the nuclear chart region with (N-Z)/A=0.11 to 0.24 and A=90 to 208. PMID- 30312103 TI - Level Attraction Due to Dissipative Magnon-Photon Coupling. AB - We report dissipative magnon-photon coupling caused by the cavity Lenz effect, where the magnons in a magnet induce a rf current in the cavity, leading to a cavity backaction that impedes the magnetization dynamics. This effect is revealed in our experiment as level attraction with a coalescence of hybridized magnon-photon modes, which is distinctly different from level repulsion with mode anticrossing caused by coherent magnon-photon coupling. We develop a method to control the interpolation of coherent and dissipative magnon-photon coupling, and observe a matching condition where the two effects cancel. Our work sheds light on the so-far hidden side of magnon-photon coupling, opening a new avenue for controlling and utilizing light-matter interactions. PMID- 30312104 TI - Criticality Distinguishes the Ensemble of Biological Regulatory Networks. AB - The hypothesis that many living systems should exhibit near-critical behavior is well motivated theoretically, and an increasing number of cases have been demonstrated empirically. However, a systematic analysis across biological networks, which would enable identification of the network properties that drive criticality, has not yet been realized. Here, we provide a first comprehensive survey of criticality across a diverse sample of biological networks, leveraging a publicly available database of 67 Boolean models of regulatory circuits. We find all 67 networks to be near critical. By comparing to ensembles of random networks with similar topological and logical properties, we show that criticality in biological networks is not predictable solely from macroscale properties such as mean degree ?K? and mean bias in the logic functions ?p?, as previously emphasized in theories of random Boolean networks. Instead, the ensemble of real biological circuits is jointly constrained by the local causal structure and logic of each node. In this way, biological regulatory networks are more distinguished from random networks by their criticality than by other macroscale network properties such as degree distribution, edge density, or fraction of activating conditions. PMID- 30312105 TI - Ultrafast Self-Induced X-Ray Transparency and Loss of Magnetic Diffraction. AB - Using ultrafast ?2.5 fs and ?25 fs self-amplified spontaneous emission pulses of increasing intensity and a novel experimental scheme, we report the concurrent increase of stimulated emission in the forward direction and loss of out-of-beam diffraction contrast for a Co/Pd multilayer sample. The experimental results are quantitatively accounted for by a statistical description of the pulses in conjunction with the optical Bloch equations. The dependence of the stimulated sample response on the incident intensity, coherence time, and energy jitter of the employed pulses reveals the importance of increased control of x-ray free electron laser radiation. PMID- 30312106 TI - Bone Morphogenetic Protein 9 is a Mechanistic Biomarker of Portopulmonary Hypertension. AB - RATIONALE: Bone Morphogenetic Protein 9 (BMP9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors and downstream effectors have been reported in heritable PAH. OBJECTIVES: We sought to determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS AND RESULTS: Plasma levels of BMP9 and antagonist soluble Endoglin (sEng) were measured in Group 1 PAH, Group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) vs. healthy controls, or other etiologies of PAH or PH, distinguished PoPH from patients with liver disease without PAH, and was an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of BMP9 ligand trap ALK1-Fc exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia vs. hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH. PMID- 30312107 TI - Impact of a Short-Term Naturopathic Whole-Foods-Based Nutrition Education Intervention on Dietary Behavior and Diabetes Risk Markers: A Pilot Study. AB - OBJECTIVE: To assess the feasibility of measuring the health impacts of a 12-week naturopathic whole foods nutrition education course among adults with or at risk for prediabetes. DESIGN: A pilot nonrandomized pre-post intervention design investigated physiological changes associated with participation in a 12-week structured naturopathic nutrition education course. Follow-up measures were assessed at 6 and 12 months from baseline. SETTINGS/LOCATION: Three community based kitchens in Oregon. SUBJECTS: Forty-five adults with or at risk for prediabetes. INTERVENTION: Twelve weekly 90-min workshops emphasizing the health benefits of a naturopathic whole foods diet and including collective meal preparation and communal dining. OUTCOME MEASURES: Changes in biomarkers of diabetes and cardiovascular disease risk, including high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c, insulin, and lipids, and changes in dietary behaviors at baseline, postintervention (12 weeks), and 6- and 12-month follow up. Changes in biomarkers and food consumption patterns were assessed using linear mixed models with random intercept, including data from all participants who completed the end-of-intervention assessment. RESULTS: Pre-post intervention results for 45 participants showed decreases in blood glucose and hs-CRP. Food frequency questionnaire data showed decreases in daily servings of grain, dairy, and fat postintervention. Decreases in blood glucose, hs-CRP, triglycerides, cholesterol, low-density lipoprotein, very-low-density lipoprotein, and HbA1c from baseline were observed at 12-month follow-up. Both insulin and high-density lipoprotein were decreased from baseline and 12-week levels at the 6-month follow up but increased from all earlier levels at 12 months (all p < 0.0001). Daily servings of meat, dairy, and fat remained decreased at 6-month follow-up. Reduced grain consumption observed at 12-week and at 6-month follow-up was not sustained, and increased at 12 months, although still decreased from baseline. CONCLUSIONS: Results suggest that this naturopathic nutrition education series may promote dietary behavior change with associated changes in clinical biomarkers. Larger controlled studies are needed to confirm these results. PMID- 30312108 TI - A Focused Review on the Treatment of Pediatric Patients with Atypical Antipsychotics. AB - OBJECTIVES: The use of atypical antipsychotic medications in pediatric patients has become more prevalent in recent years. The purpose of this review is to provide a clinically relevant update of recent selected key publications regarding the use of atypical antipsychotics in this population. METHODS: Studies reviewed included randomized, double-blind, placebo-controlled medication trials conducted within the past 5 years. A PubMed search was conducted for each of the 11 second-generation antipsychotic medications currently approved by the Food and Drug Administration for use in the United States: clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine. Trials published in English with subjects 18 years of age and younger were included in this review. Additional studies, chosen for their significance to clinical practice, were also included at the discretion of the authors. RESULTS: This review demonstrates that more empiric data are available regarding both the acute efficacy and, to a lesser extent, the longer-term efficacy and tolerability for several of the considered antipsychotic medications. The clinical conditions for which these medications have been studied include schizophrenia, bipolar disorder, Tourette's disorder, and autism spectrum disorder. They have also been used as an adjunctive treatment for disruptive behavior disorders with aggression, which have not responded to treatment with stimulants. CONCLUSION: Evidence regarding the efficacy and tolerability of antipsychotic medications for mental health disorders in children and adolescents has expanded exponentially in recent years. However, more information is needed so that evidence-based comparisons between medications can be made. In the future, data enabling the selection of medications based upon individual patient characteristics could potentially lead to greater efficacy and efficiency in treating what are frequently debilitating medical conditions. Maladaptive aggression in children, often treated with antipsychotics, is one such area in which there is a dearth of actual information available to the clinician. It is to be hoped that additional, longer-term studies of these medications will further inform evidence-based practice in clinical settings. PMID- 30312109 TI - Use of Complementary and Integrated Health: A Retrospective Analysis of U.S. Veterans with Chronic Musculoskeletal Pain Nationally. AB - OBJECTIVE: To partially address the opioid crisis, some complementary and integrative health (CIH) therapies are now recommended for chronic musculoskeletal pain, a common condition presented in primary care. As such, healthcare systems are increasingly offering CIH therapies, and the Veterans Health Administration (VHA), the nation's largest integrated healthcare system, has been at the forefront of this movement. However, little is known about the uptake of CIH among patients with chronic musculoskeletal pain. As such, we conducted the first study of the use of a variety of nonherbal CIH therapies among a large patient population having chronic musculoskeletal pain. MATERIALS AND METHODS: We examined the frequency and predictors of CIH therapy use using administrative data for a large retrospective cohort of younger veterans with chronic musculoskeletal pain using the VHA between 2010 and 2013 (n = 530,216). We conducted a 2-year effort to determine use of nine types of CIH by using both natural language processing data mining methods and administrative and CPT4 codes. We defined chronic musculoskeletal pain as: (1) having 2+ visits with musculoskeletal diagnosis codes likely to represent chronic pain separated by 30 365 days or (2) 2+ visits with musculoskeletal diagnosis codes within 90 days and with 2+ numeric rating scale pain scores >=4 at 2+ visits within 90 days. RESULTS: More than a quarter (27%) of younger veterans with chronic musculoskeletal pain used any CIH therapy, 15% used meditation, 7% yoga, 6% acupuncture, 5% chiropractic, 4% guided imagery, 3% biofeedback, 2% t'ai chi, 2% massage, and 0.2% hypnosis. Use of any CIH therapy was more likely among women, single patients, patients with three of the six pain conditions, or patients with any of the six pain comorbid conditions. CONCLUSIONS: Patients appear willing to use CIH approaches, given that 27% used some type. However, low rates of some specific CIH suggest the potential to augment CIH use. PMID- 30312110 TI - Lung Cancer Among Women in the United States. AB - November marks Lung Cancer Awareness Month, and reminds us that lung cancer is the leading cause of cancer death among women in the United States. In this brief report, we highlight CDC resources that can be used to examine the most recent data on lung cancer incidence, survival, prevalence, and mortality among women. Using the U.S. Cancer Statistics Data Visualizations tool, we report that in 2015, 104,992 new cases of lung cancer and 70,073 lung cancer deaths were reported among women in the United States. The 5-year relative survival among females diagnosed with lung cancer was 22%, and as of 2015, ~185,759 women were living with a lung cancer diagnosis. We also describe ways CDC works to collect and disseminate quality cancer surveillance data, prevent initiation of tobacco use, promote cessation, eliminate exposure to secondhand smoke, identify and eliminate disparities, promote lung cancer screening, and help cancer survivors live longer by improving health outcomes. PMID- 30312111 TI - Treatment of Bennett fractures with tension-band wiring through a small incision under loupes and a headlight. AB - PURPOSE: The aim of the study was to present a novel treatment strategy for Bennett fractures using a tension-band wiring technique performed through a small incision with loupes and a headlight. Additionally, this study compared this technique with the conventional percutaneous pinning technique. METHODS: Between January 2014 and January 2017, the tension-band wiring technique was used in 37 patients with Bennett fractures (study group). The range of motion, pinch and grip strengths, and hand function were assessed at the final follow-up. A control group comprising 35 patients treated with the percutaneous pinning technique was included in the study for comparison. A p-value <0.05 was considered statistically significant. (Clinical Trial Registration number: ISRCTN64894535 at http://www.isrctn.com/ISRCTN64894535 ) Results: No fixation failure or infection occurred in either group. Radiographic fracture healing was achieved in all cases. Follow-up lasted over 1 year. The mean Kapandji opposition score was 9.31 (range 8-10) points in the study group and 8.45 (range 7-10) points in the control group (p < 0.05). The mean Disabilities of the Arm, Shoulder, and Hand score was 1.06 (range 0-2) in the study group and 1.77 (range 0-3) in the control group (p < 0.05). The mean Smith and Cooney Score were 90 (range 80-100) in the study group and 85 (range 75-100) in the control group (p < 0.05). CONCLUSIONS: The tension-band wiring technique using loupes and headlights enables reduction and fixation of Bennett fractures under direct visualization of the deep operative field. Restoration of thumb function using the tension-band wiring technique is significantly better than that observed with the conventional percutaneous pinning technique. PMID- 30312112 TI - EGFL7 - a potential therapeutic target for multiple sclerosis? PMID- 30312113 TI - Safety and Tolerability of Overdosed Artificial Tears by Abraded Rabbit Corneas. AB - PURPOSE: Preservative-free cationic emulsion-based artificial tear (AT) is an innovative eye drop based on the Novasorb(r) technology with cetalkonium chloride (CKC) as the cationic agent. The cationic emulsion Cationorm is designed for the management of mild-to-moderate dry eye disease (DED) patients that present cornea epithelium alterations. The aim of the present study was to evaluate the safety and tolerability of overdosed ATs by altered corneal epithelium in vivo and assess the usefulness of the ex vivo eye irritation test (EVEIT) as a predictive alternate toxicity test method. METHODS: The experimental procedure, treatment duration, and instillation frequency closely mimic in vivo the ex vivo protocol described by Pinheiro et al. and discussed in the Discussion and Conclusion section of this article. Two to 3-month-old female New Zealand white rabbits, n = 6 per group, were treated with ATs (21 instillations/day over 3 days) following corneal abrasion. Corneal fluorescein staining, in vivo confocal microscopy (IVCM), and slit lamp examinations were performed to assess corneal epithelium recovery and the ocular tolerability of the overdosed ATs. RESULTS: All abraded eyes experienced almost complete epithelium recovery within 3 days following treatments with Cationorm, Optive, Vismed, and Saline. Benzalkonium chloride (BAK, 0.02%) treatment resulted in 82.4% reepithelialization. IVCM data illustrated corneal epithelium normal recovery. Acute local tolerability of the overdosed ATs was confirmed using Draize and McDonald-Shadduck's test scales. CONCLUSIONS: The different ATs were demonstrated to be well tolerated by abraded corneas in vivo, and the extreme overdosing regimen did not hamper the wound healing process of the rabbit eye in comparison to saline. These data did not confirm the ones obtained with the nonvalidated ex vivo eye irritation test. PMID- 30312114 TI - Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. AB - Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting from preterm labor, is commonly caused by intrauterine infection/inflammation. Statins are well-established, cholesterol-lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS-induced PTB mouse model, decreased uterine proinflammatory mRNA concentrations (IL-6, Cxcl1, and Ccl2), and reduced serum IL-6 concentration. In human myometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL-6 and IL-8) and increased anti-inflammatory cytokine mRNA expression (IL-10 and IL-13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylated myosin light chain concentration. Supplementation with mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that the Rho/Rho-associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti-inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat preterm labor in women.-Boyle, A. K., Rinaldi, S. F., Rossi, A. G., Saunders, P. T. K., Norman, J. E. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. PMID- 30312115 TI - Resveratrol Attenuates hIAPP Amyloid Formation and Restores the Insulin Secretion Ability in hIAPP-INS1 Cell Line via Enhancing Autophagy. AB - It has been proved that human islet amyloid polypeptide (hIAPP), the main constituent of islet amyloid deposition, is one of the important factors which can induce type 2 diabetes or graft failure after islet transplantation. As there is no research on whether resveratrol degrading the amyloid deposition by its special chemical structure or enhancing autophagy had been published, we decided to detect the function of resveratrol in degrading the amyloid deposition in pancreatic beta cells. We established stable hIAPP-INS1 cell line via transfecting INS1 cells by lentivirus that overexpresses hIAPP. Our research demonstrates that amyloid deposition existed in hIAPP-INS1 cell by the thioflavin S fluorescent staining, meanwhile the function of insulin secretion of hIAPP-INS1 cells was decreased significantly (P<0.01). After treatment with resveratrol(20MUM) for 24h, amyloid deposition in hIAPP - INS1 cells was decreased significantly, and the insulin secretion was restored significantly (P<0.01). Once inhibited the autophagy of hIAPP - INS1 cells by 3-MA for 24h, resveratrol does not effectively remove hIAPP deposits again, and cannot improve the function of insulin secretion. These results provide a novel thought that resveratrol can degrade the amyloid deposition in type 2 diabetes and the graft after islet transplantation. PMID- 30312116 TI - A Critical Review of the Baby-Friendly Hospital Initiative Is in the Works. PMID- 30312117 TI - Shifting Needs and Preferences: Supporting Young Adult Cancer Patients During the Transition from Active Treatment to Survivorship Care. AB - PURPOSE: This study was designed to identify and explore the social support needs and preferences of young adult cancer patients during the transition process from active treatment to survivorship care. METHODS: Semi-structured qualitative interviews were conducted with study participants (n = 13, ages 17-25 at the time of cancer diagnosis) within ~6 months of completion of active treatment and again 3 months later. Participants completed a sociodemographic questionnaire at the first study visit. Applied thematic analysis was used to identify themes from participant interviews. RESULTS: Six key themes and 12 subthemes emerged regarding participant interactions with their support system ("Being there," "Staying strong," and "Treat me the same") and health care team ("Connection and relationship building" and "Seeking knowledge and engaging in advocacy"), as well as treatment effects ("Uncertainty, Loss, & Changes in Identity" and "Ups & Downs of Physical Symptoms"), coping strategies ("Keep busy" and "Keep a positive vibe"), support resources ("Support needs change over time"), and post-treatment experiences ("Trying new things to cope with losses" and "Managing expectations with realities"). CONCLUSION: Study findings suggest that supportive care needs can change during the transition process from active treatment to survivorship care. Young adult life transitions, such as finding employment and making new friendships, are more stressful when complicated by ongoing physical and psychological treatment effects. Social stressors and potential barriers to participation in supportive care services should be discussed openly with patients and caregivers, especially prior to transitions in care. PMID- 30312118 TI - A Randomized Controlled Trial of Exercise to Prevent Bone Loss in Premenopausal Women with Breast Cancer. AB - : Background/Introduction/Objective: Premenopausal women treated for breast cancer are at high risk for bone loss. This trial examined the effects of a 1 year combined aerobic and resistance exercise program on bone mineral density (BMD) in women treated for premenopausal breast cancer. MATERIALS AND METHODS: Premenopausal women (n = 206) age <= 55 years at cancer diagnosis who were within two years of receiving adjuvant chemotherapy were randomized to a 12-month exercise program or a control group. BMD was measured by dual-energy X-ray absorptiometry at baseline and after 1 year; blood was drawn for skeletal markers. Change from baseline to end of study was compared within and between treatment groups using paired and unpaired t-tests. RESULTS: Lumbar spine BMD declined in both treatment groups with no significant difference between treatment groups (-0.008 +/- 0.003 g/cm2 exercise vs. -0.014 +/- 0.003 g/cm2 control, p = 0.24). However, among the women who did not lose lean mass during the study (n = 100, 54 control, 46 exercise), the exercise intervention prevented lumbar spine bone loss (0.001 +/- 0.005 g/cm2 treatment group vs. -0.014 +/- 0.005 g/cm2 control group, p = 0.03). Bone turnover markers decreased significantly in both groups with no differences between groups. CONCLUSIONS: Among women who maintained lean mass, our exercise intervention prevented bone loss; however, our intervention did not prevent bone loss among women who lost muscle mass. Additional investigation into exercise regimens that can prevent both bone and muscle loss may help prevent long-term consequences of premenopausal breast cancer treatment. PMID- 30312119 TI - Topical Treatment of Persistent Epithelial Defects with a Matrix Regenerating Agent. AB - PURPOSE: The aim of the study was to assess the efficacy of a topical regenerating agent (RGTA) for management of persistent epithelial defects (PEDs) resistant to conventional therapy. METHODS: Twenty-one patients (23 eyes) with PEDs despite the use of conventional therapy for lagophthalmos (n = 4), neurotrophic ulcer (n = 9), chemical burn (n = 3), Stevens-Johnson syndrome (n = 1), atopic keratoconjunctivitis (n = 1), severe dry eye (n = 2), peripheral ulcerative keratitis (n = 1), fungal keratitis (n = 1), and bacterial keratitis (n = 1) were enrolled in the study. Patients were treated with RGTA (Cacicol; Thea, Paris, France) instilled at a dosage of one drop on alternate days. Patients were evaluated by slit-lamp examination, anterior segment photography, and fluorescein-dye testing. Ulcer areas were noted on alternate days starting from the first day of instillation. RESULTS: Twenty of 23 eyes (86.9%) displayed complete corneal healing after a mean period of ~7.2 days (range, 2-20 days). Mean decrease ratio of ulcer area observed was 61.2% (range, 8.8%-100%, n = 19) on the 2nd day, 74.4% (range, 36%-100%, n = 16) on the 4th day, 80.2% (range, 43.7%-100%, n = 12) on the 6th day, 88.5% (range, 55.9%-100%, n = 9) on the 8th day, and 85.5% (range, 58.3%-100%, n = 7) on the 10th day. No significant differences were found in the epithelialization speed between eyes with and without bandage contact lenses in any postoperative day (P > 0.05). There were no treatment-related local or systemic side effects during the study. CONCLUSIONS: RGTA seems to be an effective therapeutic alternative in the treatment of persistent corneal epithelial defects. PMID- 30312120 TI - Assessing the Effects of Ripasudil, a Novel Rho Kinase Inhibitor, on Human Corneal Endothelial Cell Health. AB - PURPOSE: To determine how the Rho kinase inhibitor, ripasudil, affects metabolic function and cell viability in donor human corneal endothelial cells (HCECs). METHODS: Endothelial cell-Descemet membrane (EDM) tissues were treated with 10 MUM ripasudil and assayed for mitochondrial and glycolytic activity using extracellular flux analysis and then compared to untreated controls. In addition, EDM tissues with a 24-h ripasudil treatment and control tissues were exposed to 1 MUM staurosporine to induce apoptosis and then analyzed for cell viability using apoptosis and necrosis assays. RESULTS: Mitochondrial respiration metrics, specifically maximal respiration (P = 0.758) and spare respiratory capacity (P = 0.777), did not differ among the 1-h ripasudil treatment, 24-h treatment, and untreated tissues. Glycolytic activity assays showed an increase in glycolytic capacity at 1 h compared to the 24-h exposure group (P = 0.049) and controls (P = 0.009). Following exposure to staurosporine, the percentage of apoptotic HCECs was lower (P = 0.009) in ripasudil-treated tissues (2.473%, standard error of the mean [SEM] 0.477%) compared to untreated controls (3.349%, SEM 0.566%). In contrast, the percentage of necrotic HCECs decreased but did not differ statistically (P = 0.158) between ripasudil-treated (3.789%, SEM 0.487%) and untreated (4.567%, SEM 0.571%) tissues. CONCLUSIONS: Exposures to ripasudil did not result in any detectable reduction in metabolic function for HCECs in an ex vivo donor tissue model, and an increase in glycolytic activity at the 1-h time point was detected. In addition, HCECs treated with ripasudil gained a protective effect against induced apoptosis, suggesting that ripasudil may help improve the integrity of the corneal endothelium. PMID- 30312121 TI - Effect of Brief Educational Intervention on Emergency Medicine Resident Physicians' Comfort with Goals-of-Care Conversations. PMID- 30312102 TI - Low-p_{T} e^{+}e^{-} Pair Production in Au+Au Collisions at sqrt[s_{NN}]=200 GeV and U+U Collisions at sqrt[s_{NN}]=193 GeV at STAR. AB - We report first measurements of e^{+}e^{-} pair production in the mass region 0.418 years old with a colostomy or ileostomy and peristomal skin complications who were listed in 2 ostomy supplier databases. Participants were alternatively allocated to 6 home care visits (intervention [IG], n = 18) or 2 outpatient/clinic care [CG] visits (control, n = 17). Demographic and patient variables were assessed at the initial visit in both groups. The Ostomy Skin Tool (OST) and the Stoma-Quality of Life instrument were used to assess study characteristics; data were statistically analyzed. RESULTS: The Discoloration, Erosion, Tissue Overgrowth scores of the OST of the 2 groups were similar in the first assessment (IG = 6.22 +/- 1.47; CG= 6.11 +/- 1.96; P = .776), but a statistically significant difference was noted between groups at the end of study (IG = 0.44 +/- 0.85, CG = 4.76 +/- 2.30; P = .00). At the first assessment, QOL scores of the IG and CG groups were 72.63 +/- 11.48 and 66.73 +/- 17.52, respectively (P = .197). At the final assessment, QOL scores were 78.12 +/- 9.66 and 71.83 +/- 18.37 for IG and CG, respectively (P = .390). CONCLUSION: Home nursing care was found to be effective in treating peristomal skin complications. The QOL scores achieved at the final assessment were significantly improved compared with the initial assessment. The results demonstrated the importance of follow-up after stoma surgery. PMID- 30312156 TI - Sequential Organ Failure Assessment (SOFA) to Predict Pressure Ulcer Risk in Intensive Care Patients: A Retrospective Cohort Study. AB - : Pressure ulcer (PU) risk assessment practices in adult intensive care unit (ICU) patients remain varied. PURPOSE: The authors assessed the performance of the Sequential Organ Failure Assessment (SOFA) scale and its subcategories in predicting the development of PUs. METHODS: A retrospective cohort study was conducted of all adult patients admitted to the mixed medical-surgical ICU of a Finnish tertiary referral hospital between January 2010 and December 2012. Data (diagnoses, demographics, clinical information, treatments, and instrument scores) were retrieved from the ICU database. Wilcoxon and chi-squared tests were used to examine patient subgroup (medical or surgical ICU and intensive care or high-dependency care patients), length of ICU stay (LOS), modified Jackson/Cubbin (mJ/C) scores and SOFA subcategory variables, and first-day SOFA scores. PU association was determined by logistical regression. RESULTS: Among the 4899 patients in the study population, the overall PU incidence of acquired PUs was 8.1%. Medical patients had significantly more PUs (145/1281; 11.3%) than surgical patients (212/3468; 6.1%) (P <.0001). In all subgroups, significantly more patients with PUs had higher SOFA scores (mean 8.24) than patients without PUs (mean 6.74) (P =.001). The difference persisted when patients with LOS >=3 days in the ICU were considered. Among the SOFA subcategories, the Glasgow Coma score, renal and respiratory disorders, and hypotension were significantly (P <.0001) linked to PU development. First-day total SOFA score and its cardiovascular and respiratory subcategory scores were the most important predictors of PUs. CONCLUSION: The total SOFA score provides an additional tool to assess PU risk in ICUs and should be used together with the Braden or the mJ/C Scale. PMID- 30312157 TI - Effect of Music Therapy on Pain Perception, Anxiety, and Opioid Use During Dressing Change Among Patients With Burns in India: A Quasi-experimental, Cross over Pilot Study. AB - : The effectiveness of music therapy for relieving pain and anxiety during burn dressing changes has not been reported from India. PURPOSE: This study was conducted to assess the effect of music therapy on pain, anxiety, opioid use, and hemodynamic variables during burn dressing change. METHODS: Patients in a tertiary care burn unit who were >10 years old, conscious, able to respond, and oriented to time, place, and person participated in a 2-month, quasi experimental, cross-over pilot study. Each served as his/her own control. Dressings were changed every other day alternating between the control (standard pain management) and experimental (control plus patient-selected music) intervention. Pain was assessed using a numerical rating scale, anxiety was scored using the State Trait Anxiety Test (higher scores indicated more pain and anxiety), and hemodynamic parameters and analgesics were recorded. Wilcoxon Test and chi-squared tests were utilized for statistical analysis. RESULTS: Median pain scores (5, interquartile range [IQR] IQR: 3-7; and 6, IQR: 5-8) and median anxiety scores (12, IQR: 8-17; and 14, IQR: 10-19) were significantly lower during the experimental than during the standard dressing change, respectively (P <.001), and opioids were used significantly less frequently during the experimental change (P = .002). CONCLUSION: Music therapy helps reduce anxiety, pain, and opioid use during burn dressing change. PMID- 30312158 TI - miR-34a-5p aggravates hypoxia-induced apoptosis by targeting ZEB1 in cardiomyocytes. AB - Myocardial infarction (MI) is an unsolved health problem which seriously affects human health around the world. miR-34a-5p acting as a tumor-suppressor is associated with left ventricular remodeling. We aimed to explore the functional roles of miR-34a-5p in cardiomyocytes. Hypoxia-induced cell injury in H9c2, HL-1 and human cardiac myocytes was analyzed according to the decrease of cell viability and increase of apoptosis. Expression of miR-34a-5p was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) when the concentration of O2 was decreased. Then, the effects of aberrantly expressed miR 34a-5p on proliferation and apoptosis of cardiomyocytes incubated under hypoxia were assessed. Finally, the downstream protein and signaling pathways of miR-34a 5p were explored. The hypoxic model was successfully constructed after incubation under hypoxia for 48 h. When the concentration of O2 decreased, the miR-34a-5p level was increased significantly. Then, we found miR-34a-5p aggravated hypoxia induced alterations of proliferation and apoptosis in cardiomyocytes. Zinc finger E-box binding homeobox 1 (ZEB1) was identified as a target of miR-34a-5p, and miR 34a-5p conferred its function via targeting ZEB1. Finally, miR-34a-5p inhibition reversed hypoxia-induced decreases of phosphorylated kinases in the JAK/STAT and PI3K/AKT pathways through up-regulating ZEB1. Our study revealed that miR-34a-5p inhibition protected cardiomyocytes against hypoxia-induced cell injury through activating the JAK/STAT and PI3K/AKT pathways by targeting ZEB1. PMID- 30312159 TI - Model structure for protocol adherence utilizing a manualized therapeutic massage intervention. AB - Background The Protocol Training and Assessment Model (Model) was developed through collaboration between Emory University School of Medicine and Atlanta School of Massage to minimize intra- and inter-therapist variability for two research massage therapist (rMT) applied intervention arms in the Massage for Cancer-Related Fatigue (MCRF) early-phase study. The Model was followed to maintain and assess protocol integrity for the study's manualized Swedish massage therapy (SMT) and light touch (LT) interventions. Methods The Model includes initial rMT training, quarterly retraining sessions, accessible resources (scripts, treatment guides, weekly research personnel meetings), and ongoing monitoring. Model efficacy was assessed by monitoring data collected at retraining sessions, through audio recording review, and through subject and rMT reporting. Results Model application resulted in a high level of intervention consistency throughout the study. Protocol-related session comment rate by subjects was 2.7%. Few study participants reported intra-rMT or inter-rMT treatment delivery differences. Observation during retraining sessions indicated massage therapists continued to adhere to protocols. Importantly rMTs increased their participation beyond core duties, suggesting additional ways to standardize subject treatment experience. Conclusions Through systematic application of the Protocol Training and Assessment Model, continuous and collaborative quality improvement discussions between scientists and research massage therapists resulted in reliable, standardized SMT and LT interventions for the MCRF early phase study. Future research can apply the Model to support and assess consistent rMT-delivered intervention applications. PMID- 30312160 TI - Inhibitory effects of Tiliacora triandra (Colebr.) Diels on cholesterol absorption. AB - Background Natural supplements and herbal medicines have been attracted to use for managing elevated cholesterol levels. Tiliacora triandra (Colebr.) Diels (TT) or Yanang (in Thai) is commonly used as an ingredient in various types of Thai foods. In this study, we investigated the effect of methanolic TT leaf extract on cholesterol absorption by measuring the uptake and the efflux of cholesterol and cholesterol micellar solubility. In addition, we tested the effect of TT leaf extract on pancreatic lipase activity. Methods The uptake and efflux of cholesterol was determined by quantification of radioactivity in differentiated Caco-2 cells after treatment with radioactive cholesterol. Cholesterol mixed micelles were prepared for cholesterol uptake, efflux and solubility studies. The pancreatic lipase activity was determined using 4-methylumbelliferyl oleate as a substrate. Results Our finding showed that TT extract decreased the uptake of cholesterol by approximately 48% but did not affect the efflux of cholesterol. TT inhibited pancreatic lipase activity with the IC50 at 273.5 MUg/mL and also decreased cholesterol micellar solubility. Conclusions These findings suggest that TT leaf extract seems to be a potential candidate as cholesterol-lowering agents. PMID- 30312161 TI - Decreased anxiety after Dawood fasting in the pre-elderly and elderly. AB - Background A high prevalence of anxiety in the elderly often leads to decreased quality of life (QOL). A restrictive diet can increase the production of ketone bodies that encourage mood enhancement, neural protection and pain reduction. This study aimed to identify whether Dawood fasting could increase the QOL of the elderly by reducing anxiety. Methods This research was a quasi-experimental study involving a pretest-post-test control group design. The subjects were pre-elderly and elderly or healthy people aged more than 50, and a consecutive sampling method was employed. The fasting group observed the fast of Dawood, in which they abstained from eating, drinking, or having sexual intercourse from the break of dawn to dusk with the expressed intent to fast every other day. The fast was observed for 22 days (11 fasting days). Anxiety was examined using the Hamilton Rating Scale for Anxiety (HRS-A), while QOL was identified using the Indonesian version of the World Health Organisation Quality of Life (WHOQOL). Results A total of 48 respondents participated in this study with 24 respondents observing the fast of Dawood and 24 others not fasting. Results showed that the 22 days of Dawood fast reduced respondents' complaints about anxiety by 4.37% and was significantly different from the non-fasting group (p=0.001). There was an increase in the QOL of the fasting group (p=0.019), although no significant difference was found when compared to the non-fasting group. Conclusions The fast of Dawood reduced anxiety in the pre-elderly and elderly. PMID- 30312163 TI - Effect of Complementary Spiritist Therapy on emotional status, muscle tension, and wellbeing of inpatients with HIV/AIDS: A randomized controlled trial - single blind. AB - Background Complementary Spiritist Therapy includes prayer, Spiritist "passe", fluid therapy (fluidic water or magnetized water), and spiritual education, among other therapeutic resources. The objective of this study was to evaluate the effects of Complementary Spiritist Therapy with conventional treatment on emotional status, muscle tension and wellbeing of hospitalized patients with HIV/AIDS. Methods Patients were randomly assigned into either the experimental (3 days [10 mins per day/session] of Complementary Spiritist Therapy alongside conventional treatment; n=20) or control (conventional treatment alone; n=21) group. The primary outcome were positive and negative affects evaluated by the Subjective Wellbeing Scale. The secondary outcome were muscle tension, and wellbeing were assessed by visual analogue scales. Results Significant reductions in negative effects (p=0.045), and muscle tension (p=0.022), along with significant increases in wellbeing (p=0.041) were recorded in the experimental group (Complementary Spiritist Therapy). Conclusions Reductions in negative effects and muscle tension, along with increased perceived wellbeing, were observed in hospitalized patients with HIV/AIDS exposed Complementary Spiritist Therapy combined conventional treatment compared to conventional treatment alone. PMID- 30312164 TI - Music to reduce pain and anxiety in cystoscopy: a systematic review and meta analysis. AB - Background To assess the effectiveness and harms of music to reduce anxiety and pain in cystoscopy. Methods We searched MEDLINE (OVID), EMBASE, LILACS and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to nowadays. We included clinical trials, involving the assessment of the effect of music in cystoscopy. The primary outcomes were pain and anxiety measured by any scale and the secondary outcomes were length of stay, physiological parameters (blood pressure or heart rate) and adverse effects. Cochrane Collaboration tool was used to assess the risk of bias. We performed the statistical analysis in R and reported information about mean difference (MD) with 95% CI. Heterogeneity was evaluated using the I2 test. Results We included six studies in our qualitative and quantitative analysis. Five studies used a flexible cystoscope and the other one performed the procedure with a rigid cystoscope. Music was played during the procedure in five studies, while the other was before it. All studies compared music vs. no intervention. Almost all items were assessed as low risk of bias; however, the allocation concealment was unclear in all the studies. We found a MD of -1.33 (95% CI -2.45 to -0.21) (I2=97.2%) favoring music for pain and a MD of -8.42 (95% CI -15.02, -1.82) (I2=99.6%) was found, favoring music for anxiety. Conclusions Playing music might be an effective intervention that lowers pain and anxiety in patients who undergo cystoscopy. PMID- 30312162 TI - Postoperative analgesia by adding acupuncture to conventional therapy, a non randomized controlled trial. AB - Background Postoperative pain is common in patients hospitalized in surgical departments, yet it is currently not sufficiently controlled by analgesics. Acupuncture, a complementary medical practice, has been evaluated for its benefits in postoperative pain with heterogeneous results. We tested the feasibility of a controlled study comparing the postoperative analgesic effect of acupuncture together with standard-of-care to standard-of-care only. Methods In this pilot non-randomized controlled study conducted at a tertiary medical center in Israel, patients received either acupuncture with standard-of-care pain treatment (acupuncture group) or standard-of-care treatment only (control group) following surgery. Visual Analogue Scale (VAS) ratings for pain level at rest and in motion were evaluated both at recruitment and two hours after treatment. Acupuncture-related side effects were reported as well. Results We recruited 425 patients; 336 were assigned to the acupuncture group and 89 to the control group. The acupuncture group exhibited a decrease of at least 40% in average level of pain both at rest (1.8+/-2.4, p<0.0001) and in motion (2.1+/-2.8, p<0.0001) following acupuncture, whereas the control group exhibited no significant decrease (p=0.92 at rest, p=0.98 in motion). Acupuncture's analgesic effect was even more prominent in reducing moderate to severe pain at baseline (VAS >=4), with a decrease of 49% and 45% of pain level at rest and in motion respectively (p<0.001), compared with no significant amelioration in the control group (p=0.20 at rest, p=0.12 in motion). No major side effects were reported. Conclusion Integrating acupuncture with standard care may improve pain control in the postoperative setting. PMID- 30312165 TI - A randomized comparative study of herbal decoction of Cassia fistula Linn pod's pericarp and Myristica fragrans Houtt arils vs. mefenamic acid in spasmodic dysmenorrhoea. AB - Background To compare the efficacy and safety of herbal decoction (pods of Cassia fistula Linn. and Arils of Myristica fragrans Houtt) with mefenamic acid in spasmodic dysmenorrhoea. Methods In this single-blind, prospective, parallel, standard controlled study, dysmenorrheic patients (n=64) were randomly allocated to receive herbal decoction (n=31) or mefenamic acid (n=33) for two consecutive menstrual cycles. Treatment group received 180 mL herbal decoction of post amaltas (Cassia fistula L pod's pericarp) (21 g), bisbasah (Myristica fragrans Houtt arils) (3 g) and qand siyah (jaggery) (30 g) which were orally administered at morning for 3 days before the expected start of menstruation. The control group received mefenamic acid 500 mg orally twice daily between day 1 and day 3 of menstruation. The primary outcomes were visual analog scale (VAS) for pain intensity, pain relief scale and the safety assessment by clinical examination and biochemical parameters. The secondary outcomes included health-related quality of life (HRQoL) determined by SF-12 health survey questionnaire, duration of pain and pictorial blood assessment chart score for menstrual blood loss. The data were statistically interpreted with 5% level of significance. Results At the baseline, on day 1, pain severity for VAS score between the groups [7.09 +/- 1.07 vs. 6.75 +/- 1.09] had no significant difference (p>0.05). However, during the second menstrual cycle, a significant reduction [0.03 + 0.17 vs. 0.42 + 1.44] in pain severity on day 1 was noted in both groups (p<0.001). During the second menstrual cycle, improvement in HRQoL health survey [SF-12 total score: 85.88 +/- 5.99 vs 74.83 +/- 15.9] and reduction in pain duration were significantly higher in the treatment group compared to the control group. No side effects were reported. Conclusion Herbal decoction was effective to relieve pain and to improve HRQoL in spasmodic dysmenorrhoea. PMID- 30312166 TI - Effect of Ocimum basilicum leaves extract on acetaminophen-induced nephrotoxicity in BALB/c mice. AB - Background Acetaminophen (APAP) is one of the most widely used drugs to treat pain. Its overdose is lethal causing liver and kidney failure. Nephrotoxicity and hepatotoxicity are mostly due to the overproduction of reactive oxygen species. Ocimum basilicum, known as basil, is a commonly used medicinal plant due to its versatile role as antibacterial, antifungal, and anti-oxidative. We aim in this study to investigate the preventive and protective effect of basil leaves aqueous extract against APAP-induced hepatorenal toxicity in BALB/c mice. Methods Acute kidney injury (AKI) was induced in mice using APAP. Mice were treated with basils extract pre and post AKI induction. Kidney and liver functions were assessed by measuring creatinine, urea, alanine transaminase, and aspartate transaminase levels in serum. Superoxide dismutase, catalase (CAT), and malondialdehyde levels of renal and hepatic tissues were assayed using Elisa. Kidney injury molecule (KIM-1) was quantified in kidney homogenate. Histopathological analysis of kidney and liver were examined. Results Significant increase in all serum parameters, in hepatic and renal MDA, and in renal KIM-1 levels was observed post AKI induction. Treatment with basils post AKI induction minimized APAP damage by reducing serum markers and MDA in both organs and by increasing SOD and CAT. However, pretreatment with basils extract caused additional increase in serum ALT and AST and MDA in liver, with a significant increase in renal antioxidant enzymes. These results were confirmed by histopathological examination. Conclusion Basil extract may act as a natural antioxidant to treat APAP-induced acute hepato-renal toxicity when used as a post-treatment. PMID- 30312167 TI - Pharmacological and nutritive potential of Euphorbia granulata. AB - Background Euphorbia granulata is herb of family Euphorbiaceae having several traditional uses. The aim of the study is to summarize reported nutritional and medicinal value along with ethnomedical records. Methods The papers on nutritional and medicinal value of E. granulata are collected from electronic search engines (Google Scholar, PubMed). Synonyms are confirmed from "The plant List." Results Pharmacological studies suggest that the extracts of E. granulata possess antioxidant, antibacterial, antifungal, diuretic, antiulcerative colitis and spasmolytic properties. Moreover, it is rich with nutritive components such as carbohydrates, lipid contents (saturated and unsaturated fatty acids), minerals and protein (amino acids). Toxicological data of E. granulata showed that it may be poisonous and toxic at higher doses. Conclusion Research studies suggest that E. granulata has sufficient pharmacological potential against several diseases including infections, gastric ulcers, anuria, oliguria and spasmodic disorders; however, more research is required to confirm its pharmacological potential. Moreover, dose fixation studies should be carried out to avoid its toxicity. PMID- 30312168 TI - A variable course of Cushing's disease in a 7 year old: diagnostic dilemma. AB - Background Cushing's syndrome (CS) or hypercortisolism results from disruption of the hypothalamus-pituitary-adrenal (HPA) axis with the resultant increase in the circulating serum and urinary cortisol levels and lack of cortisol circadian rhythm. The resultant effects cause the physical manifestation of hypercortisolism. The appearance of Cushing's disease in children is insidious, the most common features being growth failure, obesity, early puberty and facial appearance. Case presentation We report a case of a 7-year-old male with a very unusual course of the disease, which could have led to diagnostic delays. PMID- 30312169 TI - Morning vs. bedtime levothyroxine administration: what is the ideal choice for children? AB - Background The present study compared the administration of levothyroxine (LT4) before breakfast and bedtime in school children diagnosed with hypothyroidism and analyzed the effects of timing on thyroid functioning and patient satisfaction. Methods A total of 163 children with acquired hypothyroidism (125 females and 38 males) between 8 and 18 years of age and taking LT4 for at least 3 months were enrolled in the study. The timing of administration of the drug of all subjects was shifted to bedtime. The levels of thyroid hormone and blood lipid, anthropometric measurements, Pediatric Quality of Life Inventory, Morisky Medication Adherence Scale and hypothyroidism symptoms scores were analyzed and compared at the beginning of the study and 3 months later after the shift in the timing of drug administration. Results There was no difference between the bedtime and morning regimens of LT4 with respect to thyroid hormone levels, quality of life, drug adherence and symptoms of hypothyroidism. At the end of the study, 45 of 70 new-onset treated subjects preferred the bedtime regimen. Also, drug adherence was found to be better in these patients. Conclusions We found no difference between the bedtime and morning regimens in both new-onset and long standing treated patients. In naive patients, consideration of patient's preference for timing of drug administration may increase their adherence to medication. Therefore, we suggest that choice of drug administration timing should be based on the preference of patients. PMID- 30312170 TI - High expression of the breast cancer susceptibility gene BRCA1 in long-lived termite kings. AB - Aging is associated with the accumulation of DNA damage. High expression of DNA repair genes has been suggested to contribute to prolonged lifespan in several organisms. However, the crucial DNA repair genes contributing to longevity remain unknown. Termite kings have an extraordinary long lifespan compared with that of non-reproductive individuals such as workers despite being derived from the same genome, thus providing a singular model for identifying longevity-related genes. In this study, we demonstrated that termite kings express higher levels of the breast cancer susceptibility gene BRCA1 than other castes. Using RNA sequencing, we identified 21 king-specific genes among 127 newly annotated DNA repair genes in the termite Reticulitermes speratus. Using quantitative PCR, we revealed that some of the highly expressed king-specific genes were significantly upregulated in reproductive tissue (testis) compared to their expression in somatic tissue (fat body). Notably, BRCA1 gene expression in the fat body was more than 4-fold higher in kings than in workers. These results suggest that BRCA1 partly contributes to DNA repair in somatic and reproductive tissues in termite kings. These findings provide important insights into the linkage between BRCA1 gene expression and the extraordinary lifespan of termite kings. PMID- 30312171 TI - CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling. AB - Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4 transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy. PMID- 30312172 TI - H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions. AB - Methylation of histones H4 at lysine 20 position (H4K20me), which is functional in DNA repair, represents a binding site for the 53BP1 protein. Here, we show a radiation-induced increase in the level of H4K20me3 while the levels of H4K20me1 and H4K20me2 remained intact. H4K20me3 was significantly pronounced at DNA lesions in only the G1 phase of the cycle, while this histone mark was reduced in very late S and G2 phases when PCNA was recruited to locally micro-irradiated chromatin. H4K20me3 was diminished in locally irradiated Suv39h1/h2 double knockout (dn) fibroblasts, and the same phenomenon was observed for H3K9me3 and its binding partner, the HP1beta protein. Immunoprecipitation showed the existence of an interaction between H3K9me3-53BP1 and H4K20me3-53BP1; however, HP1beta did not interact with 53BP1. Together, H3K9me3 and H4K20me3 represent epigenetic markers that are important for the function of the 53BP1 protein in non-homologous end joining (NHEJ) repair. The very late S phase represents the cell cycle breakpoint when a DDR function of the H4K20me3-53BP1 complex is abrogated due to recruitment of the PCNA protein and other DNA repair factors of homologous recombination to DNA lesions. PMID- 30312174 TI - Novel Single-Needle Approach for Retrocrural Celiac Plexus Blockade Using Fluoroscopic Guidance: A Case Report. AB - Celiac plexus neurolysis has been shown to be an effective analgesic option for patients with visceral pain related to intraabdominal malignancies. In the setting of significant tumor burden, the celiac plexus may be inaccessible, limiting the efficacy of the transcrural approach. This case report describes a novel single-needle approach to retrocrural celiac plexus blockade, allowing for rapid blockade with a needle trajectory contralateral to the aorta in a 73-year old woman with altered anatomy secondary to advanced metastatic colorectal cancer. PMID- 30312175 TI - Porphyria Attack Manifesting as Delayed Emergence and Precipitated by Prolonged Cardiopulmonary Bypass: A Case Report of 2 Novel Observations. AB - Acute porphyria is a group of rare disorders in the biosynthesis pathway of heme that can result in severe neurovisceral attacks leading to morbidity and mortality. Perioperative complications have been largely prevented due to avoidance of precipitants and early treatment of symptoms. However, these measures may not always be successful, because not all physiological stressors can be evaded. This case illustrates a porphyria attack precipitated by prolonged cardiopulmonary bypass that manifested as postoperative delayed emergence, failure to wean from mechanical ventilation, autonomic insufficiency requiring significant vasoactive agents, and, ultimately, failure to thrive. The patient passed after withdrawal of care. PMID- 30312173 TI - Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer. AB - Circular RNAs (circRNAs) have recently been confirmed to participate in different pathological processes, including cancer progression. However, the role and precise mechanism of action of the majority of circRNAs have not been elucidated in bladder cancer (BC). Here, we identified a novel circular RNA, termed circUBXN7, which was significantly downregulated in BC tissues compared with matched nontumor tissues. Importantly, we found that decreased circUBXN7 expression was associated with pathological stage, grade and poor prognosis of BC patients. Functional experiments showed that circUBXN7 overexpression dramatically inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Mechanistically, circUBXN7 could directly bind to miR-1247-3p and reverse the oncogenic effects induced by miR-1247-3p. Furthermore, B4GALT3 was predicted and confirmed to be a target of miR-1247-3p. Rescue experiments demonstrated that circUBXN7 abrogated miR-1247-3p-mediated inhibition of B4GALT3 expression. Finally, silencing of B4GALT3 promoted proliferation and invasion of BC cells; and partially abolished the tumor suppressive effects caused by circUBXN7. Taken together, our study revealed that circUBXN7 serves as a competitive endogenous RNA of miR-1247-3p to elevate B4GALT3 expression, consequently inhibiting cell viability and invasion in BC. The circUBXN7-miR-1247-3p-B4GALT3 regulatory network may provide a new perspective for gene-based treatment strategies for BC. PMID- 30312176 TI - Toxic Ingestion of Acetaminophen and Acetylsalicylic Acid in a Parturient at 33 Weeks Gestation: A Case Report. AB - The anesthetic management of toxic ingestion during pregnancy requires concomitant concerns for both mother and fetus. We describe the management of a parturient at 33 weeks of gestation after a suicide attempt by ingestion of acetaminophen (APAP) and acetylsalicylic acid (ASA). Timing of toxin ingestion must be determined, prompt antidote administration prioritized, and hepatotoxicity-induced hematologic impairment anticipated. Fetal exposure to toxins must also be minimized. The use of point-of-care rotational thromboelastometry in conjunction with standard coagulation testing in such cases facilitates consideration of neuraxial anesthesia and determination of risk for postpartum hemorrhage. PMID- 30312177 TI - Pulmonary Artery Catheter Thrombus in a Patient With Essential Thrombocytosis: A Case Report. AB - Essential thrombocytosis (ET) is a rare chronic myeloproliferative disorder characterized by elevated platelet counts. The management of patients with ET undergoing coronary artery bypass graft remains unclear. Often, patients who are deemed "high risk" for thrombotic events receive cytoreductive therapy before surgery, while patients deemed "low risk" do not receive cytoreductive therapy. Here, we present a case of a patient with ET with only a mild elevation in platelets deemed "low risk" for thrombotic complications who was found to have a small intracardiac thrombus around the pulmonary artery catheter before initiation of cardiopulmonary bypass. PMID- 30312178 TI - Postpartum Cardiogenic Shock Diagnosed by Focused Cardiac Ultrasound and Treated With Venoarterial Extracorporeal Membrane Oxygenation: A Case Report. AB - We present the case of a primigravid patient, who developed cardiogenic shock during the early postpartum period in the setting of retained placenta, uterine atony, and hemorrhage. Focused cardiac ultrasound played a central role in identifying the cause of hemodynamic instability. The decision to initiate venoarterial extracorporeal membrane oxygenation was instrumental in the successful outcome for our patient, characterized by a full recovery without major neurological and cardiovascular sequelae. PMID- 30312179 TI - Impact of Deep Learning Assistance on the Histopathologic Review of Lymph Nodes for Metastatic Breast Cancer. AB - Advances in the quality of whole-slide images have set the stage for the clinical use of digital images in anatomic pathology. Along with advances in computer image analysis, this raises the possibility for computer-assisted diagnostics in pathology to improve histopathologic interpretation and clinical care. To evaluate the potential impact of digital assistance on interpretation of digitized slides, we conducted a multireader multicase study utilizing our deep learning algorithm for the detection of breast cancer metastasis in lymph nodes. Six pathologists reviewed 70 digitized slides from lymph node sections in 2 reader modes, unassisted and assisted, with a wash-out period between sessions. In the assisted mode, the deep learning algorithm was used to identify and outline regions with high likelihood of containing tumor. Algorithm-assisted pathologists demonstrated higher accuracy than either the algorithm or the pathologist alone. In particular, algorithm assistance significantly increased the sensitivity of detection for micrometastases (91% vs. 83%, P=0.02). In addition, average review time per image was significantly shorter with assistance than without assistance for both micrometastases (61 vs. 116 s, P=0.002) and negative images (111 vs. 137 s, P=0.018). Lastly, pathologists were asked to provide a numeric score regarding the difficulty of each image classification. On the basis of this score, pathologists considered the image review of micrometastases to be significantly easier when interpreted with assistance (P=0.0005). Utilizing a proof of concept assistant tool, this study demonstrates the potential of a deep learning algorithm to improve pathologist accuracy and efficiency in a digital pathology workflow. PMID- 30312180 TI - Validation of the Welch Allyn Pro BP 2000, a professional-grade inflation-based automated sphygmomanometer with arrhythmia detection in a combined pediatric and adult population by ANSI/AAMI/ISO standard testing. AB - OBJECTIVE: The Welch Allyn Pro BP 2000, an automated sphygmomanometer, was subjected to ANSI/AAMI/ISO testing. PATIENTS AND METHODS: The protocol used was the same-arm sequential procedure described in the ANSI/AAMI/ISO 2013 Standard. Eight-eight (53 adults and 35 children aged 3-12 years old) patients completed testing successfully. Arm circumferences ranged from 15 to 49.5 cm. Seven different cuff sizes were used, including two long cuffs. RESULTS: All requirements for age, sex, blood pressure (BP), and cuff sizes were fulfilled. The mean+/-SD was -2.8+/-6.37 mmHg for systolic BP for criterion 1 and -3.6+/ 6.14 mmHg for diastolic BP. The SD for criterion 2 were 5.29 for systolic BP and 5.75 for diastolic BP. All data passed the Standard's requirements. CONCLUSION: The Pro BP 2000 uses an accurate inflationary algorithm. The time for each inflation/deflation cycle is short, thus improving patient comfort. There is also arrhythmia detection to caution the use of BP values obtained during irregular heart rhythms. The algorithm for the professional-grade Pro BP 2000 is also contained in the Home BP 1700, targeted for home use. This encourages out-of office self-measurement. The healthcare professional can be confident that the values obtained at different sites are comparable. PMID- 30312181 TI - Observing Blood Management Programs through the Retrospectroscope. PMID- 30312182 TI - Triple-low Alerts Do Not Reduce Mortality: A Real-time Randomized Trial. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Triple-low events (mean arterial pressure less than 75 mmHg, Bispectral Index less than 45, and minimum alveolar fraction less than 0.8) are associated with mortality but may not be causal. This study tested the hypothesis that providing triple-low alerts to clinicians reduces 90-day mortality. METHODS: Adults having noncardiac surgery with volatile anesthesia and Bispectral Index monitoring were electronically screened for triple-low events. Patients having triple-low events were randomized in real time, with clinicians either receiving an alert, "consider hemodynamic support," or not. Patients were blinded to treatment. Helpful responses to triple-low events were defined by administration of a vasopressor within 5 min or a 20% reduction in end-tidal volatile anesthetic concentration within 15 min. RESULTS: Of the qualifying patients, 7,569 of 36,670 (20%) had triple-low events and were randomized. All 7,569 were included in the primary analysis. Ninety-day mortality was 8.3% in the alert group and 7.3% in the nonalert group. The hazard ratio (95% CI) for alert versus nonalert was 1.14 (0.96, 1.35); P = 0.12, crossing a prespecified futility boundary. Clinical responses were helpful in about half the patients in each group, with 51% of alert patients and 47% of nonalert patients receiving vasopressors or having anesthetics lowered after start of triple low (P < 0.001). There was no relationship between the response to triple-low events and adjusted 90-day mortality. CONCLUSIONS: Real-time alerts to triple-low events did not lead to a reduction in 90-day mortality, and there were fewer responses to alerts than expected. However, similar mortality with and without responses suggests that there is no strong relationship between responses to triple-low events and mortality. PMID- 30312183 TI - Oral midodrine is comparable to albumin infusion in cirrhotic patients with refractory ascites undergoing large-volume paracentesis: results of a pilot study. AB - BACKGROUND AND AIMS: Albumin infusion reduces the incidence of postparacentesis circulatory dysfunction among patients with cirrhosis and tense ascites compared with no treatment. Less costly treatment alternatives such as vasoconstrictors have been investigated, but the results are controversial. Midodrine, an oral alpha1-adrenergic agonist, increases effective circulating blood volume and renal perfusion by increasing systemic and splanchnic blood pressure. Our aim is to assess whether or not morbidity in terms of renal dysfunction, hyponatremia, systemic, or portal hemodynamics derangement or mortality differed in patients receiving albumin versus midodrine. PATIENTS AND METHODS: Seventy-five patients with cirrhosis and refractory ascites were randomized to receive albumin infusion, oral midodrine for 2 days, or oral midodrine for 30 days after therapeutic large volume paracentesis (LVP). The primary endpoints were development of renal impairment or hyponatremia, change in systemic and portal hemodynamics, cost, and mortality in the short-term and long-term follow-up. RESULTS: No significant difference was found between groups in the development of renal impairment, hyponatremia, or mortality 6 and 30 days after LVP. A significant increase in 24-h urine sodium excretion was noted in the midodrine 30 day group. Renal perfusion improved significantly with the midodrine intake for 30 days only. The cost of midodrine therapy was significantly lower than albumin. CONCLUSION: Midodrine is as effective as albumin in reducing morbidity and mortality among patients with refractory ascites undergoing LVP at a significantly lower cost. Long-duration midodrine intake can be more useful than shorter duration intake in terms of improvement of renal perfusion and sodium excretion. PMID- 30312184 TI - Ultrasound Evaluation of Anterior Acromioclavicular Relationship in the Horizontal Plane on 40 Healthy Subjects. A New Possibility for Differential Diagnosis of Acromioclavicular Disjunctions Rockwood Stage 3 and 4? A Pilot Study. AB - OBJECTIVE: To evaluate the repeatability and reproducibility of an ultrasound examination of the acromioclavicular joint (ACJ) performed by an orthopaedic surgeon to analyze anterior ACJ relationship in the horizontal plane. DESIGN: Prospective observational study on healthy subjects. SETTING: The study was conducted in 2017 in a university department of orthopaedic surgery and traumatology. LEVEL OF EVIDENCE: III. PATIENTS (OR PARTICIPANTS): Forty consecutive volunteers aged 18 to 40 years were involved. INTERVENTIONS (OR ASSESSMENT OF RISK FACTORS OR INDEPENDENT VARIABLES):: The ultrasound examination was performed by 2 orthopaedic surgeons with a SonoSite M-Turbo portable ultrasound machine (Fujifilm, Japan). Distance measurement between the anterior edge of the clavicle (AECL) and the anterior edge of the acromion (AEAC) was done on the right side, then on the left one and repeated by the same examiner. MAIN OUTCOME MEASURES: The intra- and interexaminer reproducibility of measurements was analyzed as primary outcome. Concordance of distance measurements between the right and left sides on the same subject was evaluated, as well as the "typical morphology" of the ACJ in the horizontal plane. RESULTS: The intra- and interexaminer reproducibility for AECL-AEAC distance measurements was, respectively, 0.95 (0.93-0.97) and 0.87 (0.84-0.90). The correlation between the right and left sides was significant (P < 0.001), with a reproducibility of 0.86 (0.83-0.89). Twenty-seven (67.5%) volunteers were considered to have a "perfect alignment" of the AECL and AEAC. CONCLUSIONS: This study confirms that it is possible to evaluate with good reproducibility the anterior AC relationship in the horizontal plane and that both sides are similar on the same subject. PMID- 30312185 TI - Epidemiological Trends of Anterior Cruciate Ligament Reconstruction in a Canadian Province. AB - OBJECTIVE: To determine epidemiological trends of anterior cruciate ligament reconstruction (ACL-R) in a Canadian province, estimate the national incidence, and compare with internationally published data. DESIGN: Retrospective review. SETTING: All hospitals that performed ACL reconstructions in Manitoba between 1980 and 2015. PARTICIPANT: All patients that underwent ACL-R in Manitoba between 1980 and 2015. INTERVENTION: This is a retrospective review looking at deidentified, individual-level administrative records of health services used for the entire population of Manitoba (approximately 1.3 million). Codes for ACL and cruciate ligament reconstruction were searched from 1980 to 2015. Patient demographics included age, sex, geographic area of residence, and neighborhood income quintile. MAIN OUTCOME MEASURES: Trends of ACL reconstructions from 1980 to 2015. RESULTS: A total of 10 114 ACL-R were performed during the 36-year study period and patients were predominantly male (63.1%). The mean age at ACL-R was 29.5 years (SD 10.0) for males and 28.5 years (SD 11.9) for females, whereas age younger than 40 years accounted for 81.7% of all ACL-R. The incidence of ACL-R increased from 7.56/100 000 inhabitants in 1980 to 48.45/100 000 in 2015. The proportion of females undergoing ACL-R has increased from 29.3% in 1980% to 41.9% in 2015, and female patients now comprise the majority of ACL-R in the under-20 age category. CONCLUSION: The incidence of ACL-R has significantly increased since 1980; female patients now make up a greater proportion than males of the ACL-R population younger than 20 years. This information can be used to guide resource allocation planning and focus injury prevention initiatives. PMID- 30312186 TI - Economic Evaluation of Venovenous Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Venovenous extracorporeal membrane oxygenation is increasingly being used to support patients with severe acute respiratory distress syndrome, but its cost-effectiveness is unknown. We assessed the cost-utility of venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults compared with standard lung protective ventilation from the perspective of the healthcare system. DESIGN: We conducted a cost-utility analysis with a cohort state transition decision model using a lifetime time horizon, 1.5% discount rate, and outcomes reported as cost per quality-adjusted life year. Literature reviews were conducted to inform the model variables. Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty in the model. SETTING: Canadian publicly funded healthcare system. PATIENTS: Hypothetical cohort of adults with severe acute respiratory distress syndrome. INTERVENTIONS: Venovenous extracorporeal membrane oxygenation or standard lung protective ventilation. MEASUREMENTS AND MAIN RESULTS: In our model, the use of venovenous extracorporeal membrane oxygenation compared with lung protective ventilation resulted in a gain of 5.2 life years and 4.05 quality adjusted life years, at an additional lifetime cost of $145,697 Canadian dollars. The incremental cost-effectiveness ratio was $36,001/quality-adjusted life year. Sensitivity analyses show that the incremental cost-effectiveness ratio is sensitive to the efficacy of extracorporeal membrane oxygenation therapy and costs. CONCLUSIONS: Based on current data, venovenous extracorporeal membrane oxygenation is cost-effective for patients with severe acute respiratory distress syndrome. Additional evidence on the efficacy of venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome and in different subgroups of patients will allow for greater certainty in its cost-effectiveness. PMID- 30312187 TI - Peripartum Anesthesia Considerations for Placenta Accreta. AB - Placenta accreta spectrum is becoming more common and is the most frequent indication for peripartum hysterectomy. Management of cesarean delivery in the setting of a morbidly adherent placenta has potential for massive hemorrhage, coagulopathies, and other morbidities. Anesthetic management of placenta accreta spectrum presents many challenges including optimizing surgical conditions, providing a safe and satisfying maternal delivery experience, preparing for massive hemorrhage and transfusion, preventing coagulopathies, and optimizing postoperative pain control. Balancing these challenging goals requires meticulous preparation with a thorough preoperative evaluation of the parturient and a well coordinated multidisciplinary approach in order to optimize outcomes for the mother and fetus. PMID- 30312189 TI - Foreword: Management of Abnormal Placentation. PMID- 30312188 TI - Role for OBGYNs in Gender-Affirming Surgical Care of Transgender and Gender Nonconforming Individuals. AB - Many transgender and gender nonconforming individuals have undergone, or plan to pursue, gender-affirming surgery as part of their transition. While not all gender-affirming surgeries are provided by Obstetricians and Gynecologists (OBGYNs), OBGYNs are uniquely skilled to perform certain gender-affirming surgeries such as hysterectomies, bilateral oophorectomies, and vaginectomies. OBGYNs are also well positioned to provide anatomy-specific cancer screening as dictated by patient's hormonal and surgical status, and to address postsurgical or natal vulvovaginal concerns. PMID- 30312190 TI - Predicting Engagement With Online Walking Promotion Among Metropolitan and Rural Cancer Survivors. AB - BACKGROUND: Physical activity has numerous associated benefits for cancer survivors. Compared with their urban counterparts, rural Australians experience a health disadvantage, including poorer survival rate after diagnosis of cancer. OBJECTIVE: The aims of this study were to test the effectiveness of an online 12 week walking intervention designed for cancer survivors and explore region specific psychological predictors of behavior change. METHODS: This was a quasi randomized controlled trial of an online resource designed according to Social Cognitive Theory and Self-determination Theory, based on individualized goal setting. Measures of habitual walking, motivation, and self-efficacy were taken at baseline, postintervention, and 3-month follow-up in an intervention group (n = 46) and active control group (n = 45). The control group was provided a pedometer but did not have access to the online program. RESULTS: An increase in steps/day at 12 weeks was observed in both groups, with a larger increase in the intervention group; these increases were not sustained at the 3-month follow-up. Psychological predictors of maintained change in steps per day (motivation, barrier self-efficacy, and relapse self-efficacy) did not differ between metropolitan and rural participants. Changes in steps per day among intervention participants were predicted by changes in relapse self-efficacy and barrier self efficacy. CONCLUSIONS: The intervention was successful in increasing physical activity postintervention; however, changes were not maintained at follow-up. There were no region-specific predictors of engagement in the intervention. IMPLICATIONS FOR PRACTICE: Nurses are seamlessly positioned to promote health interventions like walking. Nurses should reframe physical activity with patients so that relapse is seen as common and possibly inevitable when adopting a regular physical activity habit. PMID- 30312191 TI - A Patient Decision Aid for Men With Localized Prostate Cancer: A Comparative Case Study of Natural Implementation Approaches. AB - BACKGROUND: There are multiple options for men diagnosed with localized prostate cancer. Patient decision aids (PtDAs) help empower individuals and reduce unwarranted practice variation, but few are used in clinical practice. OBJECTIVE: We compared 2 programs implementing PtDAs for men with localized prostate cancer. METHODS: This was a comparative case study. Case 1 was a hospital prostate pathway and case 2 was a provincial prostate pathway with 2 locations (2a, 2b). Nurses provided the men with PtDAs and answered questions. Data sources were as follows: (a) 2 years administrative data for men with localized prostate cancer, (b) clinicians survey and interviews, and (c) patients/spouses interviews. Analysis was within and across cases. RESULTS: The PtDA was used with 23% of men in case 1 (95% confidence interval, 19.8%-26.1%) and 98% of men in case 2a (95% confidence interval, 96.5%-99.8%). The pathway was not implemented in case 2b. Men given the PtDA had positive experiences. Many clinicians supported the use of PtDAs, some adapted their discussions with patients, and others did not support the use of PtDAs. To increase use in case 1, participants identified needing a Canadian PtDA available electronically and endorsed by all clinicians. In case 2b, the provincial prostate pathway needed to be implemented. CONCLUSIONS: There was variable uptake of the PtDAs between the cases. Men who received the PtDA had positive outcomes. Several strategies were identified to increase or sustain PtDA use. IMPLICATIONS FOR PRACTICE: Nurses have a key role in supporting men making decisions about prostate cancer treatment by providing PtDAs, answering questions, and advocating for men's preferences. PMID- 30312192 TI - Cancer Patients' Long-term Experiences of Participating in a Comprehensive Lifestyle Intervention Study While Receiving Chemotherapy. AB - BACKGROUND: Lifestyle interventions seem promising with regard to cancer patients' potential for physical and psychological health benefits and as an empowerment tool. Nevertheless, there is a lack of knowledge concerning cancer patients' longer-term experiences of participating in comprehensive lifestyle interventions. OBJECTIVE: The aim of this study was to explore cancer patients' long-term experiences of participating in a 12-month individualized comprehensive lifestyle intervention study focusing on physical activity, diet, smoking cessation, and stress management while receiving curative or palliative chemotherapy. METHODS: A qualitative design with semistructured interviews of 7 curative and 7 palliative cancer patients was conducted 12 months after inclusion in lifestyle intervention. Data were analyzed following a phenomenological hermeneutic approach. RESULTS: Two main themes emerged: (1) awareness of the importance of a healthy lifestyle during cancer treatment and (2) individual follow-up; it's good to have someone to talk to. CONCLUSIONS: Participation in a 12-month comprehensive lifestyle intervention is both feasible and desirable in curative and palliative patients. However, although the curative participants' motivation and perceived ability to adhere to lifestyle recommendations increased during the intervention period, the palliative participants' perceived ability to adhere decreased even though they were overall highly motivated. IMPLICATIONS FOR PRACTICE: Our findings encourage the future implementation of lifestyle interventions during cancer treatment, even in cancer patients with advanced disease. However, when implementing lifestyle interventions, healthcare professionals must keep the patients' motivation, perceived ability to adhere to lifestyle recommendations, and individual needs in mind. PMID- 30312193 TI - Risk Factors for Post-Acute Coronary Syndrome Depression: A Meta-analysis of Observational Studies. AB - BACKGROUND: The incidence of depression is very common among patients with post acute coronary syndrome (ACS) and leads to adverse outcomes. AIMS: The aim of this meta-analysis was to detect risk factors for depression among patients with ACS and to provide clinical evidence for its prevention. METHODS: The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline to search the PubMed, Web of Science, EMBASE, and EBSCO databases from January 1996 to March 2018. Data that met the inclusion criteria were extracted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk factors of post-ACS depression. RESULTS: A total of 30 articles met the inclusion criteria, and 25 risk factors were found to be associated with depression. The top 5 risk factors are as follows: antidepression treatment (OR, 4.25; 95% CI, 3.41-5.31), housewife status (OR, 4.17; 95% CI, 1.83-9.53), history of depressive disorders (OR, 3.52; 95% CI, 2.69-4.61), widow status (OR, 2.34; 95% CI, 1.05 5.21), and history of congestive heart failure (OR, 2.03; 95% CI, 1.04-3.97). The authors also found that a married status, high education level, and employment are protective factors. CONCLUSION: Clinical personnel should be alerted with regard to the high risk factors of depression, including female gender, low education level, unmarried status, living alone, unemployed status, unhealthy lifestyle, and complications such as cardiovascular, respiratory, and metabolic diseases. In particular, staff should pay attention to a history of previous depression, be concerned with the psychological condition of the patient, and monitor and perform early interventions to reduce the incidence of depression. PMID- 30312194 TI - Effect of Classic Foot Massage on Vital Signs, Pain, and Nausea/Vomiting Symptoms After Laparoscopic Cholecystectomy. AB - This semiexperimental study on the effects of foot massage recruited 88 patients who underwent laparoscopic cholecystectomy at the general surgery clinics of our hospital in Turkey (June 2017 to May 2018). Patients were assigned to either the intervention group (n=44, 10 min of classic foot massage) or the control group (n=44, no intervention). Pretest assessment, intervention, and posttest assessment were conducted within 1 to 6 hours postoperatively. Outcome measures included vital signs, pain, and nausea/vomiting symptoms. The intervention was associated with a significant decrease in pain scores and incidence of nausea. Despite being associated with an increase in body temperature, the intervention was also associated with a decrease in systolic blood pressure without increasing diastolic blood pressure or respiratory rate, suggesting a positive effect on blood circulation. Classic foot massage may serve as an affordable and useful way to help improve pain, nausea, and blood circulation after laparoscopic cholecystectomy. PMID- 30312195 TI - Transoral Robotic Thyroidectomy: Comparison of Surgical Outcomes Between the da Vinci Xi and Si. AB - INTRODUCTION: The surgical outcomes for procedures using da Vinci Xi were compared with those of da Vinci Si in transoral robotic thyroidectomy (TORT). MATERIALS AND METHODS: The medical records were retrospectively reviewed. Patients were classified into 2 groups (da Vinci Xi vs. da Vinci Si) and surgical outcomes were analyzed. RESULTS: Each group comprised 58 patients. The postoperative pain scores at operation day 0 were lower, the hospital stays were shorter, and the number of retrieved central lymph nodes in the papillary thyroid carcinoma patients were greater in the Xi group than in the Si group. There were no significant differences between groups in either vocal cord palsy or hypoparathyroidism rates. There were no TORT-specific complications in the Xi group. There was no conversion to endoscopic or conventional open thyroid surgery in both groups. CONCLUSIONS: TORT could be performed safely with both da Vinci Si and Xi systems. PMID- 30312196 TI - Perforated Peptic Ulcer Surgery: Decreased Length of Stay but No Difference in Mortality with Laparoscopic Repair. AB - BACKGROUND: Perforated peptic ulcer (PPU) surgery mortality ranges 1% to 24%. We hypothesized a decrease in length of stay (LOS) with laparoscopic surgical repair (LSR) compared with open surgical repair (OSR). METHODS: Patients undergoing PPU surgery 2005 to 2015 were identified in NSQIP. LSR was compared with OSR 2005 to 2015. LSR 2005 to 2010 was compared with 2011 to 2015. OSR 2005 to 2010 was compared with 2011 to 2015. The primary outcome was LOS. Secondary outcomes were mortality and morbidity. RESULTS: Between 2005 and 2015, LSR had a decreased LOS, was more likely to wean from the ventilator, but had no significant difference in mortality compared with OSR. There was no significant difference in mortality for LSR or OSR over time. CONCLUSIONS: When patients are appropriately selected, LSR for PPU is a viable alternative to OSR, decreasing LOS and pulmonary complications. This demonstrates significant benefit to patients and hospital throughput. PMID- 30312197 TI - Repetitions in Reserve and Rate of Perceived Exertion Increase the Prediction Capabilities of the Load-Velocity Relationship. AB - Balsalobre-Fernandez, C, Munoz-Lopez, M, Marchante, D, and Garcia-Ramos, A. Repetitions in reserve and rate of perceived exertion increase the prediction capabilities of the load-velocity relationship. J Strength Cond Res XX(X): 000 000, 2018-This study aimed to (a) analyze the relationships between relative load (i.e., %1 repetition maximum; 1RM) and movement velocity, repetitions in reserve (RIR) and rate of perceived exertion (RPE) in competitive powerlifters and (b) examine whether a multiple linear regression model with the movement velocity, RIR, and RPE as predictor variables could improve the goodness of fit of the load velocity relationship. Ten competitive powerlifters performed an incremental loading test (from 50 to 100% 1RM) on the full-squat, hip-thrust, and bench press exercises. Barbell velocity was measured using a linear position transducer, while RIR and RPE were registered immediately after each set. Velocity (r: 0.747 0.887), RIR (r: 0.857-0.928), and RPE (r: 0.908-0.933) were moderately to highly related to relative load. A higher amount of variance of the relative load was explained when the RIR and RPE were added to velocity in a multiple regression model in comparison with the load-velocity relationship (r: 0.924-0.947). Moreover, it was observed that, in all cases, individual load-velocity, load-RIR, and load-RPE relationships had higher r scores than the generalized load-velocity relationship. Incorporating the RIR and RPE as predictors of the relative load along with movement velocity into a multiple linear regression was shown to provide better estimations of the %1RM than using a linear load-velocity relationship. PMID- 30312198 TI - Importance of Normalization of CA19-9 Levels Following Neoadjuvant Therapy in Patients With Localized Pancreatic Cancer. AB - OBJECTIVE: Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear. SUMMARY BACKGROUND DATA: Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response. METHODS: CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (>=35 U/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19 9 (Q1-4); 2) proportional changes in CA19-9 (DeltaCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35 U/dL) of preop CA19-9; and 4) normalization of postop CA19-9. RESULTS: Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80 U/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of DeltaCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9. CONCLUSIONS: Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival. PMID- 30312199 TI - Implications for Breast Cancer Restaging Based on the 8th Edition AJCC Staging Manual. AB - OBJECTIVE:: We assessed the changes that have resulted from the latest breast cancer staging guidelines and the potential impact on prognosis. BACKGROUND: Contemporary data suggest that combining anatomic staging and tumor biology yields a predictive synergy for determining breast cancer prognosis. This forms the basis for the American Joint Committee on Cancer's (AJCC) Staging Manual, 8th edition. We assessed the changes that have resulted from the new staging guidelines and the potential impact on prognosis. METHODS: Women with stages I to III breast cancer from 2010 to 2014 in the National Cancer Data Base were pathologically staged according to the 7th and 8th editions of the AJCC Staging Manual. Patient characteristics and restaging outcomes were summarized. Unadjusted overall survival (OS) was estimated, and differences were assessed. Cox proportional-hazards models were utilized to estimate the adjusted association of stage with OS. RESULTS: After restaging the 493,854 women identified, 6.8% were upstaged and 29.7% were downstaged. The stage changes varied by tumor histology, receptor status, tumor grade, and Oncotype DX scores (all P < 0.0001). Applying the 8th edition criteria yielded an incremental reduction in survival for each increase in stage, which was not consistently seen in the 7th edition. In a subgroup analysis based on hormone receptor (HR) status, those with stages II and III, and HR- disease had a worse OS than those with HR+ disease. CONCLUSIONS: Applying the 8th edition staging criteria resulted in a stage change for >35% of patients diagnosed with invasive breast cancer and refined OS estimates. Overall, the transition to the 8th edition is expected to better drive clinical care, treatment recommendations, and future research. PMID- 30312200 TI - Diagnostic Accuracy of Different Surgical Procedures for Axillary Staging After Neoadjuvant Systemic Therapy in Node-positive Breast Cancer: A Systematic Review and Meta-analysis. AB - OBJECTIVE: The aim of this study was to perform a systematic review and meta analysis to assess the accuracy of different surgical axillary staging procedures compared with ALND. SUMMARY OF BACKGROUND DATA: Optimal axillary staging after neoadjuvant systemic therapy (NST) in node-positive breast cancer is an area of controversy. Several less invasive procedures, such as sentinel lymph node biopsy (SLNB), marking axillary lymph node with radioactive iodine seed (MARI), and targeted axillary dissection (a combination of SLNB and a MARI-like procedure), have been proposed to replace the conventional axillary lymph node dissection (ALND) with its concomitant morbidity. METHODS: PubMed and Embase were searched for studies comparing less invasive surgical axillary staging procedures to ALND to identify axillary burden after NST in patients with pathologically confirmed node-positive breast cancer (cN+). A meta-analysis was performed to compare identification rate (IFR), false-negative rate (FNR), and negative predictive value (NPV). RESULTS: Of 1132 records, 20 unique studies with 2217 patients were included in quantitative analysis: 17 studies on SLNB, 1 study on MARI, and 2 studies on a combination procedure. Overall axillary pathologic complete response rate was 37%. For SLNB, pooled rates of IFR and FNR were 89% and 17%. NPV ranged from 57% to 86%. For MARI, IFR was 97%, FNR 7%, and NPV 83%. For the combination procedure, IFR was 100%, FNR ranged from 2% to 4%, and NPV from 92% to 97%. CONCLUSION: Axillary staging by a combination procedure consisting of SLNB with excision of a pre-NST marked positive lymph node appears to be most accurate for axillary staging after NST. More evidence from prospective multicenter trials is needed to confirm this.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30312201 TI - Current Management and Predictive Factors of Lymph Node Metastasis of Appendix Neuroendocrine Tumors: A National Study From the French Group of Endocrine Tumors (GTE). PMID- 30312202 TI - Alcohol Use Thresholds for Identifying Alcohol-related Problems Before and Following Roux-en-Y Gastric Bypass. AB - OBJECTIVE: The aim of this study was to determine the sensitivity and specificity of potential thresholds of alcohol use for identifying alcohol-related problems in women post-Roux-en-Y gastric bypass (RYGB). BACKGROUND: Despite evidence that RYGB alters alcohol pharmacokinetics and is associated with an increased risk for alcohol-related problems, the level of alcohol use that should prompt further screening for alcohol-related problems following RYGB is unclear. METHODS: The Longitudinal Assessment of Bariatric Surgery-2 is a prospective cohort study. Before surgery and annually for <=7 years following surgery, participants completed the 10-item Alcohol Use Disorder Identification Test (AUDIT), which assesses past-year frequency and quantity of alcohol, frequency of consuming >=6 drinks, and alcohol-related problems (ie, symptoms of alcohol dependence and/or alcohol-related harm). The AUDIT-Consumption (AUDIT-C) score was determined from the first 3 AUDIT items. RESULTS: Post-RYGB, 835 women reported current drinking at 1 or more annual assessment(s). Compared with higher frequency thresholds, drinking >=2 times/month had the highest combined sensitivity (85.3%) and specificity (61.4%) for identifying alcohol-related problems. Compared with higher quantity thresholds, drinking >=3 drinks/drinking day had the highest combined sensitivity (64.2%) and specificity (87.2%). An AUDIT-C score >=3, versus other thresholds, had the highest combined sensitivity (76.4%) and specificity (81.6%). CONCLUSION: The sensitivity and specificity of these thresholds indicate assessment of alcohol consumption alone may be inadequate for identifying women at risk for alcohol-related problems post-RYGB. Additional screening tools for alcohol-related problems, which assess symptoms of alcohol related problems, should be conducted in this population. PMID- 30312204 TI - Response to: "Does the Surgeon Sex Matter? Practice Patterns and Outcomes of Female and Male Surgeons". PMID- 30312203 TI - Reply to Letter: "Current Management and Predictive Factors of Lymph Node Metastasis of Appendix Neuroendocrine Tumors: A National Study from the French Group of Endocrine Tumors (GTE)". PMID- 30312205 TI - Distal Resection Margin Status in Transanal Total Mesorectal Excision (TA-TME). PMID- 30312206 TI - Achieving High-value Surgical Care Through Accountable Care Organizations: Are the Risks Worth the Rewards? PMID- 30312207 TI - Yellow Means Caution: Correlations Between Liver Injury and Mortality with the Use of VA-ECMO. AB - Abnormalities in markers of liver injury after venoarterial extracorporeal membrane oxygenation (VA-ECMO) initiation are of unclear distribution and clinical significance. This study included all consecutive adult patients from a single institution who underwent VA-ECMO cannulation between May 2012 and September 2016 and had liver function panels drawn during their admission (n = 223). Data points include: age, sex, body mass index, diagnosis, duration of ECMO cannulation, duration of hospitalization, pre-ECMO cardiac arrest, central nervous system (CNS) injury, the presence of chronic kidney disease or acute renal failure, renal replacement therapy utilization, lactate levels, duration of pre-ECMO intubation, admission and peak bilirubin/aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline phosphatase (ALP) levels, and time to peak bilirubin/AST/ALT/ALP in relation to cannulation. Multivariate Poisson regression analyses were performed to determine associations with mortality. In hospital mortality was 66%. Serum bilirubin elevation appeared to significantly correlate continuously with mortality. Other markers of liver injury were not significant in final multivariate models. As a univariate factor, no patient survived with a total serum bilirubin greater than 30 mg/dl, and specificity for 90% mortality was crossed at 11 mg/dl. Mortality was also significantly associated with the presence of CNS injury and elevation of lactic acid levels. Postcannulation liver injury is significantly associated with increased mortality and total serum bilirubin appears to be a biomarker of considerable clinical significance. PMID- 30312209 TI - The Physiologic Basis of Ejection Fraction. PMID- 30312208 TI - Predictors of Survival for Patients with Acute Decompensated Heart Failure Requiring Extra-Corporeal Membrane Oxygenation Therapy. AB - Chronic systolic heart failure (HF) with acute decompensation can result in cardiogenic shock (CS) requiring short-term mechanical circulatory support. We sought to identify predictors of survival for acute decompensated HF (ADHF) patients requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients >18 years old treated at our institution with VA-ECMO from 2009 to 2018 for ADHF with CS were studied. Demographic, hemodynamic, and echocardiographic data were collected. The primary outcome was survival to discharge. Fifty-two patients received VA-ECMO for ADHF with CS; 24 (46.2%) survived. Seventeen (32.7%) had suffered cardiac arrest, and 37 (71.2%) were mechanically ventilated. Mean lactate was 4.33 +/- 3.45 mmol/L, and patients were receiving 2.7 +/- 1.2 vasopressor/inotropic infusions at ECMO initiation; these did not differ significantly between survivors and nonsurvivors. Pre-ECMO cardiac index was 1.84 +/- 0.56L/min/m and 1.94 +/- 0.63L/min/m in survivors and nonsurvivors, respectively (p = 0.57). In multivariable analysis, only diabetes mellitus (DM; OR, 13.25; CI, 1.42-123.40; p = 0.02) and mineralocorticoid receptor antagonist use (OR, 0.12; CI, 0.02-0.78; p = 0.03) were independent predictors of mortality. Nineteen (79.2%) survivors required durable ventricular assist device. Among ADHF patients receiving VA-ECMO, DM is a powerful predictor of outcomes while markers of clinical acuity including hemodynamics, vasopressor/inotrope use, and lactate are not. The vast majority of survivors required durable left-ventricular assist devices. PMID- 30312210 TI - Intravenous Versus Oral Iron Replacement in Patients with a Continuous-Flow Left Ventricular Assist Device. PMID- 30312211 TI - The Impact of Infection and Elevated INR in LVAD-Associated Intracranial Hemorrhage: A Case-Crossover Study. AB - Despite the common occurrence left ventricular assist device (LVAD)-associated intracranial hemorrhage, the etiology of intracranial hemorrhage is uncertain. We aim to explore the impact of infection and international normalized ratio (INR) on intracranial hemorrhage in a case-crossover study. We reviewed consecutive patients with intracranial hemorrhage in a prospectively collected data of LVAD patients from a single, tertiary center from October 2004 to December 2016. Information on infection and INR values were collected at the time and 1 month before the intracranial hemorrhage as controls. Of 477 persons with LVAD, 47 (10%) developed intracranial hemorrhage (27 intracerebral, 14 subarachnoid, and six subdural hemorrhages). Of 47 (median age 58; 39 males), 27 (54%) persons had active infection at the time of intracranial hemorrhage; seven (21%) of 44 LVADs had infection at 1 month before intracranial hemorrhage. The relative risk of intracranial hemorrhage because of active infection compared with the infections at 1 month was 2.3 (95% CI: 1.5-3.4; p < 0.0001). The mean INRs at the time of intracranial hemorrhage were also significantly higher at the time of hemorrhage compared with those at 1 month (2.6 +/- 1.9 vs. 1.8 +/- 0.8; p = 0.01). Of 13 persons with cerebral angiogram (seven subarachnoid and six intracerebral hemorrhages), four (57%) infectious intracranial aneurysms were identified only in patients with subarachnoid hemorrhage (SAH) who also had bloodstream infections. Active infection and elevated INR were associated with LVAD associated intracranial hemorrhage. The occurrence of both bloodstream infection and subarachnoid hemorrhage may indicate the presence of infectious intracranial aneurysm in LVAD. PMID- 30312212 TI - Impact of Diabetes Mellitus on Survival in Patients Bridged to Transplantation with Left Ventricular Assist Devices in the United States. AB - Diabetes mellitus (DM) is associated with increased mortality in advanced heart failure and in patients undergoing cardiac surgery. However, its impact on outcomes in patients supported with left ventricular assist devices (LVAD) is not well established. We queried the United Network for Organ Sharing (UNOS) for all adults listed for heart transplantation and bridged with continuous-flow LVAD in the United States from 2000 to 2015. We compared the pre- and post-transplant mortality of patients with and without DM. Unadjusted and adjusted time-event analyses were performed. A total of 4,978 patients were included in this analysis, of whom 33% had DM. Mean age was 53 +/- 12 years, 79% were male, and 65% were Caucasian. Compared with those without, patients with DM were older (age 52 vs. 57 years; p < 0.001), more likely to be male (78% vs. 82%; p = 0.007), smokers (52% vs. 57%; p = 0.011), obese (mean body mass index [BMI] 28 vs. 30; p < 0.00), and have ischemic cardiomyopathy (37% vs. 53%; p < 0.001). Diabetes mellitus was not associated with increased wait-list mortality (adjusted hazard ratio [HR]: 1.16 [0.88-1.53]; p = 0.30), or wait-list mortality/delisting (HR: 1.17 [0.97-1.41]; p = 0.11). Among patients who underwent transplantation, DM was associated with increased adjusted overall mortality (HR: 1.23 [1.002-1.52]; p = 0.048). One-third of patients bridged-to-transplantation with LVAD in the United States have DM. While it does not increase wait-list mortality or delisting, DM is associated with decreased post-transplantation survival. PMID- 30312213 TI - Left Ventricular Assist Devices; How Do We Define Success? AB - Despite the growing acceptance of left ventricular assist device (LVAD) therapy to improve survival and quality of life in heart failure (HF) patients, uncertainties persist regarding the definition of a successful implant. We sought to define an innovative approach to assess success and subsequently compare preoperative variables affecting outcomes. From January 2007 to 2015, 278 patients underwent LVAD implantation. Median age at implant was 62 years and 81% patients were males. Indication for support was bridge-to-transplantation in 36% patients and the etiology of HF was ischemic in 49% patients. Based on clinically relevant and accepted standards, we defined successful LVAD implant as someone who was alive or transplanted at 2 years, had two or less readmissions in the first year, had no major adverse events in the first year, and had a New York Heart Association class of <= II at 6 months. Follow-up was obtained for a median of 1.7 years for a total of 605 patient-years-of-support. Based on our criteria, 81/278 (29%) patients were defined as having a successful implant. Univariate predictors of LVAD failure included destination therapy indication (hazard ratio [HR] = 2.11 [1.24, 3.58]), ischemic cardiomyopathy (HR = 1.73 [1.02, 2.94]), and a higher left ventricular ejection fraction (HR = 1.54 [1.07, 2.22]). After multivariable analysis, only destination therapy indication (HR = 2.2 [1.28, 3.78]) was found to be independently predictive of success failure. Despite an overall trend toward improved outcomes on device therapy, our criteria classified only one-third of patients as successful. Continued improvements in AE profiles, appropriate patient selection, and optimal time of implantation, together hold the key to improve outcomes after LVAD therapy. PMID- 30312214 TI - Exercise Training Increases Metaboreflex Control in Patients with Obstructive Sleep Apnea. AB - : We demonstrated that patients with obstructive sleep apnea (OSA) have reduced muscle metaboreflex control of muscle sympathetic nerve activity (MSNA). Additionally, exercise training increased muscle metaboreflex control in heart failure patients. OBJECTIVE: We tested the hypothesis that exercise training would increase muscle metaboreflex control of MSNA in patients with OSA. METHODS: Forty-one patients with OSA were randomized into the following two groups: (1) nontrained (OSANT, n=21) and (2) trained (OSAT, n=20). MSNA was assessed by microneurography technique, muscle blood flow (FBF) by venous occlusion plethysmography, heart rate by electrocardiography, and blood pressure (BP) with an automated oscillometric device. All physiological variables were simultaneously assessed at rest, during isometric handgrip exercise at 30% of the maximal voluntary contraction, and during posthandgrip muscle ischemia (PHMI). Muscle metaboreflex sensitivity was calculated as the difference in MSNA between PHMI and the rest period. Patients in the OSAT group underwent seventy-two sessions of moderate exercise training, whereas patients in the OSANT group were clinical follow-up for six months. RESULTS: The OSANT and OSAT groups were similar in anthropometric, neurovascular, hemodynamic and sleep parameters. Exercise training reduced the baseline MSNA (34+/-2 vs. 25+/-2 burst/min, P<0.05) and increased the baseline FBF (2.1+/-0.2 vs. 2.4+/-0.2 ml/min/100g, P<0.05). Exercise training significantly reduced MSNA levels and increased FBF responses during isometric exercise. Exercise training significantly increased MSNA responses during PHMI (Delta6.5+/-1 vs. -1.7+/-1 bursts/min, P<0.01). No significant changes in FBF or hemodynamic parameters in OSANT patients were found. CONCLUSIONS: Exercise training increases muscle metaboreflex sensitivity in patients with OSA. This autonomic change associated with increased muscle blood flow may contribute to the increase in exercise performance in this set of patients. PMID- 30312215 TI - Effects of Joint Kinetics on Energy Cost during Repeated Vertical Jumping. AB - PURPOSE: The present study was designed to investigate the effects of lower limb joint kinetics on energy cost during jumping. METHODS: Eight male middle and long distance runners volunteered for the study. The subjects were asked to repeat vertical jumps at a frequency of 2 Hz for 3-min on a force platform in three different surface inclination conditions: Incline (+8 degrees ), Level (0 degrees ), and Decline (-8 degrees ). Sagittal plane kinematics were obtained using a high-speed video camera. Simultaneously, ground reaction forces and electromyography (EMG) of the lower limb muscles were recorded. Energy cost was calculated using steady-state oxygen uptake, respiratory ratio, and vertical distance of the body. RESULTS: In all conditions, energy cost correlated positively with total mechanical work of the knee joint (r = 0.636, p < 0.01), but negatively with total mechanical work of the ankle joint (r = -0.584, p < 0.01). The muscle-tendon complex length of the gastrocnemius and soleus muscles were significantly longer in incline than in level and decline. The gastrocnemius muscle showed different activity pattern in decline as compared to the incline and level conditions. CONCLUSIONS: The present study revealed that the ankle and knee joint kinematics and, therefore muscles' coordination are associated with energy cost during repeated vertical jumping. The lower limb joints contributed different efficiencies to generate the same total mechanical work in repeated vertical jumping on different surface inclinations. Energy cost was smaller when mechanical work was mainly done by ankle joint. Whereas, when the ankle joint did less mechanical work, the knee and/or hip joints compensated for the lack of mechanical work of the ankle joint and energy cost was increased. PMID- 30312216 TI - The BRAFV600E mutation in papillary thyroid microcarcinoma with intermediate-risk to high-risk features: does the mutation have an effect on clinical response to radioiodine therapy? AB - OBJECTIVES: Preclinical studies showed that BRAF mutation significantly reduced radioiodine uptake and decreased the sensitivity to radioactive iodine (RAI) therapy. However, clinical data regarding its role in therapeutic decision making with respect to RAI therapy are currently insufficient. Thus, this study aimed to evaluate the effect of BRAF mutation on the clinical response to RAI therapy for papillary thyroid microcarcinoma (PTMC) with intermediate-risk to high-risk features. PATIENTS AND METHODS: From January 2012 and October 2015, consecutive patients with PTMC with intermediate-risk to high-risk features who underwent RAI therapy were retrospectively included. The data about BRAF mutation status were also obtained. The association between clinicopathological characteristics and mutation was investigated. After a median follow-up of 40 months, the clinical response to RAI therapy was also compared between positive and negative mutation groups. RESULTS: A total of 236 patients were included, of whom 147 (62.3%) had positive mutation. The clinicopathological features did not show significant correlation with BRAF mutation status except the sex, extrathytoidal extension and T stage. Patients with PTMC with BRAF mutation showed an increased likelihood of having advanced T stage and extrathyroidal extension. In addition, this mutation did not affect the clinical outcome of RAI therapy. CONCLUSION: The status of BRAF mutation may not affect the clinical response to RAI therapy for patients with PTMC with intermediate-risk to high-risk features. More trials examining the role of BRAF mutation in guiding postoperative RAI therapy are needed. PMID- 30312217 TI - Diagnostic and prognostic value of 18F-FDG PET/CT imaging in suspected recurrence of male breast cancer. AB - PURPOSE: Male breast cancer (MBC) is a rare malignancy, with recurrence being one of the main adverse predictors for prognosis. The aim of the study was to evaluate the diagnostic and predictive value of fluorine-18-fluorodeoxyglucose (F FDG) PET/CT in the setting of suspected recurrence of MBC. PATIENTS AND METHODS: Retrospective analysis of PET/CT findings was performed in 23 previously treated, histologically proven patients with MBC (mean age: 59.3+/-10.9 years; range: 36 79 years) with suspected recurrence. Kaplan-Meier disease-specific survival analysis was made with respect to histological, hormonal profile as well as PET/CT findings. RESULTS: Of the 23 patients, 19 (82.6%) showed recurrence. Recurrence at primary site with/without regional/distant site recurrence was seen in 12 (52.2%) patients. Only metastatic recurrence without primary site was seen in seven (30.4%) patients. Bone was the most common site of distant metastasis (14/23) followed by lungs (9/23), liver (4/23), brain (2/23), and adrenal (1/23). No recurrence (regional/distant) was noted in 4/23 (17.3%) patients; however, three of them had F-FDG-avid soft tissue lesions in esophagus, rectum and tongue, correspondingly, confirmed as second primaries with histopathology. Disease specific survival analysis yielded nodal (P=0.01) as well as distant metastases (P=0.02) as the main survival predictors on PET/CT. Lung (P=0.001), followed by liver (P=0.009), and skeletal (P=0.01) metastases were the most adverse survival predictive factors. CONCLUSION: F-FDG PET/CT showed good diagnostic and prognostic utility in recurrent MBC. It was better than bone scan in evaluation of skeletal metastases. Most importantly, F-FDG PET/CT helped in early detection of second malignancy and their clinical management in studied patients. PMID- 30312218 TI - HPV 6-associated HSIL/Squamous Carcinoma in the Anogenital Tract. AB - Human papillomavirus (HPV) type 6 is historically classified as low-risk HPV type and associates with low-grade squamous intraepithelial lesions of the anogenital tract. Rare squamous carcinomas have been reported in association with these HPV types but the mechanism(s) behind this carcinogenic sequence have been unclear. We report 4 cases of low risk anogenital HPV infections-3 cervical (immature low grade squamous intraepithelial lesion with metaplastic phenotype) and one anal (exophytic condyloma) lesion-that manifested with high-grade squamous intraepithelial lesion/squamous cell carcinoma. Two were associated with invasion one of which metastasized to a regional node. Two cases exhibited strong p53 positivity in the high-grade squamous intraepithelial lesion/squamous cell carcinoma component analogous to that seen in HPV-negative differentiated intraepithelial lesions of the external genitalia. This series of cases adds to the literature on low risk HPV-associated cervical squamous carcinomas. It underscores the similarities between the baseline cyto-morphology and benign mimics (low-grade squamous intraepithelial lesions), the subtle cytologic and immunohistochemical (MIB1) features heralding biologic aggressiveness, and in some potential pathways (p53) not usually involved in HPV-related anogenital neoplasia. PMID- 30312219 TI - Paid Sick Leave Benefits and Adherence to Recommended Screening Tests Among Male Labor Workers in the U.S. AB - OBJECTIVE: We examined the association between availability of paid sick leave and health care utilization and screenings in male labor workers in the U.S., and hypothesize that workers with paid sick leave benefits would be more likely to utilize health services. METHODS: Using the 2013-2016 National Health Interview Survey (NHIS), labor workers (n = 8,553), aged 18-64 years were examined. Logistic regression analyses assessed the association between availability of paid sick leave and the use of preventive services. RESULTS: Thirty-five percent indicated paid sick leave benefits. Participants with available sick leave were more likely to have received screenings and to have utilized heath care services or had a dental visit in the past year. CONCLUSIONS: Availability of paid sick leave to labor workers may increase their use of preventive health care services. Policy that mandates paid sick leave is warranted. PMID- 30312220 TI - A Preliminary Investigation of Health and Work-Environment Factors on Presenteeism in the Workplace. AB - OBJECTIVE: This study investigates the health and work-environment factors that are associated with presenteeism. METHOD: A self-report survey which measured presenteeism, 13 health conditions (e.g., stress and allergies) and nine work environment factors (e.g., job strain and leadership) was completed by 229 workers. RESULTS: The most common health condition was stress, while the most common work-environment factor was job strain. Allergies, asthma and high blood pressure along with work-life imbalance, poor leadership and a lack of development opportunities were associated with presenteeism. Finally, several inter-relationships between the health and work-environment factors were also reported. CONCLUSIONS: Interventions targeted at the points of intersection among the health conditions and work-environment factors could be a cost-effective way to improve employees' overall well-being at work, and thus reduce presenteeism. PMID- 30312221 TI - Impact of Disgust on Intentions to Undergo Colorectal Surgery. AB - BACKGROUND: Surgeons present patients with complex information at the perioperative appointment. Emotions likely play a role in surgical decision making, and disgust is an emotion of revulsion at a stimulus that can lead to avoidance. OBJECTIVE: The purpose of this study was to determine the impact of disgust on intention to undergo surgical resection for colorectal cancer and recall of perioperative instructions. DESIGN: This was a cross-sectional observational study conducted online using hypothetical scenarios with nonpatient subjects. SETTINGS: The study was conducted using Amazon's Mechanical Turk. PATIENTS: Survey respondents were living in the United States. MAIN OUTCOME MEASURES: Surgery intention and recall of perioperative instructions were measured. RESULTS: A total of 319 participants met the inclusion criteria. Participants in the experimental condition, who were provided with detailed information and pictures about stoma care, had significantly lower surgery intentions (mean +/- SD, 4.60 +/- 1.15) compared with the control condition with no stoma prompt (mean +/- SD, 5.14 +/- 0.91; p = 0.05) and significantly lower recall for preoperative instructions (mean +/- SD, 13.75 +/- 2.38) compared with the control condition (mean +/- SD, 14.36 +/- 2.19; p = 0.03). Those within the experimental conditions also reported significantly higher state levels of disgust (mean +/- SD, 4.08 +/- 1.74) compared with a control condition (mean +/- SD, 2.35 +/- 1.38; p < 0.001). State-level disgust was found to fully mediate the relationship between condition and recall (b = -0.31) and to partially mediate the effect of condition on surgery intentions (b = 0.17). LIMITATIONS: It is unknown whether these results will replicate with patients and the impact of competing emotions in clinical settings. CONCLUSIONS: Intentions to undergo colorectal surgery and recall of preoperative instructions are diminished in patients who experience disgust when presented with stoma information. Surgeons and care teams must account for this as they perform perioperative counseling to minimize interference with recall of important perioperative information. See Video Abstract at http://links.lww.com/DCR/A776. PMID- 30312222 TI - Evaluation of Healthcare Use and Clinical Outcomes of Alvimopan in Patients Undergoing Bowel Resection: A Propensity Score-Matched Analysis. AB - BACKGROUND: Postoperative ileus is a significant complication after bowel resection surgeries. Alvimopan is the only US Food and Drug Administration approved therapy for accelerating the return of bowel function after large- and small-bowel resection. OBJECTIVE: The purpose of this study was to estimate the healthcare use and in-hospital morbidities associated with on-label use of alvimopan in patients undergoing bowel resection surgeries. DESIGN: A retrospective observational propensity-matched cohort study was conducted using a large hospital administrative database. SETTING: The study included inpatient postsurgical patients. PATIENTS: Patients aged >=18 years undergoing a primary large or small segmental bowel resection with discharge dates between January 2010 and December 2014 were included. INTERVENTIONS: Patients receiving 2 to 15 doses of alvimopan were defined as the treatment cohort, and those without any alvimopan use were included as control subjects. MAIN OUTCOME MEASURES: The primary outcome was postoperative length of stay. Secondary outcomes included postoperative in-hospital morbidities, inpatient mortality, intensive care unit length of stay, discharge disposition, and 30-day readmission. RESULTS: Each propensity-score matched cohort included 18,559 patients. The mean (+/-SD) postoperative length of stay was 4.62 +/- 2.45 days in alvimopan-treated patients compared with 5.24 +/- 3.35 days in control subjects (p < 0.001). Alvimopan treated patients had lower rates of postoperative GI complication (12.15% vs 16.50%; p < 0.001). The rates of urinary tract infections; other postoperative infections; and cardiovascular, pulmonary, thromboembolic, and cerebrovascular events were also lower compared with the control subjects. LIMITATIONS: The study was limited by its inability to generalize to the US population, because the database included a convenience sample of hospital discharges. The identification of patients undergoing bowel resection and their clinical conditions relied on the accuracy and completeness of International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedure coding. There may be a confounding effect by the use of enhanced recovery pathways associated with the use of alvimopan. CONCLUSIONS: The use of alvimopan was associated with a reduction of 0.62 days in postsurgery length of stay and lower rates of postoperative GI complications, infections, and other in-hospital morbidities. See Video Abstract at http://links.lww.com/DCR/A703. PMID- 30312223 TI - Predictors of Metastases in Rectal Neuroendocrine Tumors: Results of a National Cohort Study. AB - BACKGROUND: Rectal neuroendocrine tumors are often found incidentally. Local excision alone has been advocated for lesions <=2 cm; however, the evidence base for this approach is limited. OBJECTIVE: Associations among tumor size, degree of differentiation, and presence of distant metastatic disease were examined. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted using a nationwide cohort. PATIENTS: A total of 4893 patients with rectal neuroendocrine tumors were identified in the National Cancer Database (2006 2015). MAIN OUTCOME MEASURES: Logistic regression analyses were used to evaluate associations among tumor size, degree of differentiation, and presence of regional and distant metastatic disease. Cut point analysis was performed to identify an optimal size threshold predictive of distant metastatic disease. RESULTS: Of patients included for analysis, 3880 (79.3%) had well-differentiated tumors, 540 (11.0%) had moderately differentiated tumors, and 473 (9.7%) had poorly differentiated tumors. On logistic regression, increasing size was associated with a higher likelihood of pathologically confirmed lymph node involvement (among patients undergoing proctectomy), and both size and degree of differentiation were independently associated with a higher likelihood of distant metastatic disease. The association between tumor size and distant metastatic disease was stronger for well-differentiated and moderately differentiated tumors (OR = 1.4; p < 0.001 for both) than for poorly differentiated tumors (OR = 1.1; p = 0.010). For well-differentiated tumors, the optimal cut point for the presence of distant metastatic disease was 1.15 cm (area under the curve = 0.88; 88% sensitive and 88% specific). Tumors >=1.15 cm in diameter were associated with a substantially increased incidence of distant metastatic disease (72/449 (13.8%)). For moderately differentiated tumors, the optimal cut point was also 1.15 cm (area under the curve = 0.87, 100% sensitive and 75% specific). LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Tumor size and degree of differentiation are predictive of regional and distant metastatic disease in rectal neuroendocrine tumors. Patients with tumors >1.15 cm are at substantial risk of distant metastasis and should be staged and managed accordingly. See Video Abstract at http://links.lww.com/DCR/A778. PMID- 30312224 TI - Ethics of Outbreaks Position Statement. Part 1: Therapies, Treatment Limitations, and Duty to Treat. AB - OBJECTIVES: Outbreaks of disease, especially those that are declared a Public Health Emergency of International Concern, present substantial ethical challenges. Here we start a discourse (with a continuation of the dialogue in Ethics of Outbreaks Position Statement. Part 2: Family-Centered Care) concerning the ethics of the provision of medical care, research challenges and behaviors during a Public Health Emergency of International Concern with a focus on the proper conduct of clinical or epidemiologic research, clinical trial designs, unregistered medical interventions (including vaccine introduction, devices, pharmaceuticals, who gets treated, vulnerable populations, and methods of data collection), economic losses, and whether there is a duty of health care providers to provide care in such emergencies, and highlighting the need to understand cultural diversity and local communities in these efforts. DESIGN: Development of a Society of Critical Care Medicine position statement using literature review and expert consensus from the Society of Critical Care Medicine Ethics committee. The committee had representation from ethics, medical philosophy, critical care, nursing, internal medicine, emergency medicine, pediatrics, anesthesiology, surgery, and members with international health and military experience. SETTING: Provision of therapies for patients who are critically ill or who have the potential of becoming critically ill, and their families, regarding medical therapies and the extent of treatments. POPULATION: Critically ill patients and their families affected by a Public Health Emergency of International Concern that need provision of medical therapies. INTERVENTIONS: Not applicable. MAIN RESULTS: Interventions by high income countries in a Public Health Emergency of International Concern must always be cognizant of avoiding a paternalistic stance and must understand how families and communities are structured and the regional/local traditions that affect public discourse. Additionally, the obligations, or the lack of obligations, of healthcare providers regarding the treatment of affected individuals and communities must also be acknowledged. Herein, we review such matters and suggest recommendations regarding the ethics of engagement in an outbreak that is a Public Health Emergency of International Concern. PMID- 30312225 TI - Ethics of Outbreaks Position Statement. Part 2: Family-Centered Care. AB - OBJECTIVES: Continue the dialogue presented in Ethics of Outbreaks Position Statement. Part 1, with a focus on strategies for provision of family-centered care in critical illness during Pubic Health Emergency of International Concern. DESIGN: Development of a Society of Critical Care Medicine position statement using literature review, expert consensus from the Society of Critical Care Medicine Ethics Committee. A family member of a patient who was critically ill during a natural disaster served on the writing panel and provided validation from a family perspective to the recommendations. SETTING: Provision of family centered care and support for patients who are critically ill or who have the potential of becoming critically ill, and their families, during a Pubic Health Emergency of International Concern. INTERVENTIONS: Communication; family support. MEASUREMENTS AND MAIN RESULTS: Family-centered interventions during a Pubic Health Emergency of International Concern include understanding how crisis standards may affect regional and local traditions. Transparently communicate changes in decision-making authority and uncertainty regarding treatments and outcomes to the family and community. Assess family coping, increase family communication and support, and guide families regarding possible engagement strategies during crisis. Prepare the public to accept survivors returning to the community. PMID- 30312226 TI - Attending Intensivist Handoffs Are Far From Perfect. PMID- 30312227 TI - Measuring the Results of the Handover. PMID- 30312228 TI - Complex Legacy of the Target Temperature Management Trial. PMID- 30312229 TI - Pediatric Acute Respiratory Distress Syndrome Survivors-What Happens After the PICU? PMID- 30312231 TI - Thiamine: An Essential Component of the Metabolic Resuscitation Protocol. PMID- 30312230 TI - Monitoring the Adaptive Immune System in Septic Shock Patients: Ready for Prime Time? PMID- 30312232 TI - Variation in Sepsis-Related Mortality; Implications for Performance Improvement. PMID- 30312233 TI - Where Did the Gas Go? Recruitment Versus Aeration. PMID- 30312234 TI - Adding to the Repertoire of Scoring Systems in Acute-on-Chronic Liver Failure: Will Simplicity Be Outdone by Complexity? PMID- 30312235 TI - Using Intracranial Pressure Trajectories for Outcome Prediction in Traumatic Brain Injury: Are Summary Measures Still Valid in the Era of Precision-Based Medicine? PMID- 30312236 TI - Inhaled Nitric Oxide for Pediatric Acute Respiratory Distress Syndrome: Another Brick in the Wall? PMID- 30312237 TI - In the Middle of Difficulty Lies Opportunity.-Albert Einstein. PMID- 30312239 TI - Nutritional Status and Outcomes in Pediatric Severe Sepsis-Size Matters. PMID- 30312238 TI - Inflammation, Cerebral Vasospasm, and Brain Injury in Subarachnoid Hemorrhage-A Shifting Paradigm and a New Beginning. PMID- 30312240 TI - Focusing on Risk Factors of Cardiac Arrest During Intubation in ICU Again. PMID- 30312241 TI - The authors reply. PMID- 30312242 TI - Three Factors to Determine the Heat Generation During Targeted Temperature Management-Patient, Machine, and Surrounding. PMID- 30312243 TI - The authors reply. PMID- 30312244 TI - Patient-Directed Music Therapy in the ICU. PMID- 30312245 TI - The authors reply. PMID- 30312246 TI - A Growing Problem of Critical Illness Due to Chimeric Antigen Receptor T-Cell Therapy. PMID- 30312247 TI - The author replies. PMID- 30312248 TI - Relevant advances in bone lengthening research: a bibliometric analysis of the 100 most-cited articles published from 2001 to 2017. AB - This study aimed to assess the scientific production of bone lengthening research by identifying the most-cited papers. All articles including the term 'bone lengthening' published between 2001 and 2017 were retrieved through the Web of Science database. The 100 most-cited articles on bone lengthening included a total of 4244 citations, with 414 (9.7%) citations in 2017. There was an average of 249.6 citations per year. The articles predominantly addressed biomechanics and bone formation (38). Different surgical techniques, including intramedullary nail (14), Ilizarov (nine), intramedullary skeletal kinetic distractor (ISKD) (six), Taylor spatial frame (6), the PRECICE device (three), and lengthening and submuscular locking plate (three), were the second most-studied topic. Most studies were therapeutic (58), whereas 30 studies were experimental investigations using animal models. Among the clinical studies, case series were predominant (level of evidence IV) (57). This study presents the first bibliometric analysis of the most relevant articles on bone lengthening. The list is relatively comprehensive in terms of identifying the top issues in this field. However, the most influential clinical studies have a poor level of evidence, although a slight tendency toward a better level of evidence has been observed in more recent years. PMID- 30312249 TI - Early versus late hip spica casting for paediatric femoral shaft fractures. AB - : The purpose of our study was to evaluate the effectiveness of treating paediatric femoral shaft fractures by early (<48 h) versus late (>48 h) hip spica casting. A retrospective review of 44 patients with 44 femoral shaft fractures treated by either early or late hip spica application with at least 9-month follow-up was undertaken. Both groups were treated on an inpatient basis. The late hip spica group had skin traction applied before the application of a hip spica. The outcome measures involved both clinical [Pediatric Outcomes Questionnaire (POQ) and Activities Scale for Kids] and radiological outcomes. Complications were noted. A total of 44 patients with a mean age of 33 months (range: 7-66 months) were evaluated. Overall, 20 patients underwent early and 24 had late hip spica casting. At follow-up, the Activities Scale for Kids was similar amongst the two groups (44.2 vs. 44.8, P=0.8). However, the POQ was better in the early hip spica casting group (24.7 vs. 28.9, P=0.01). Length of hospital stay and duration of immobilization in the hip spica were significantly shorter in the early group (P<0.001). There were no differences in leg lengths, lateral distal femoral angles and medial proximal tibia angles between the fractured and nonfractured limbs in both groups. Early hip spica casting is a safe procedure for paediatric femoral shaft fractures and was associated with less time in hospital and hip spica with a better POQ score. However, early hip spica casting was associated with more hip spica changes and required wedging. At follow-up, radiological parameters were similar in both groups. LEVEL OF EVIDENCE: III. PMID- 30312250 TI - The Ponseti method of clubfoot treatment in walking age children: is it effective? A study of 56 children from 1 to 10 years of age. AB - : The Ponseti method is well-established for the treatment of clubfoot in younger babies; however, its effectiveness in older children is still unclear. The aim of our study was to report our results of the 'traditional' Ponseti method in the management of clubfoot in children of walking age. A total of 56 (81 clubfeet) children with a mean age of 3.16+/-2.35 years (1-10 years) were divided into two groups: group I consisted of 12 (18 clubfeet) patients with a mean age of 3.36+/ 2.7 years (range: 1-8.4 years) who presented with an untreated clubfoot whereas group II consisted of 44 (63 clubfeet) patients with a mean age of 3.19+/-2.34 years (range: 1-10 years) who presented with a recurrent clubfoot. All children underwent the standard manipulation and casting technique described by Ponseti, including a percutaneous tenotomy of the Tendo Achilles. The bracing protocol was modified appropriately. All feet corrected with a mean of 7.36 (3-17) casts in group I and 4.49 (1-12) casts in group II. All children in group I and 70.45% in group II underwent a percutaneous Tendo Achilles tenotomy. There was a statistically significant change between the pretreatment and post-treatment Pirani scores in both groups. Nineteen (30.86%) patients underwent relapse at a mean follow-up of 2.84+/-1.25 years (1.2-5.4 years), who were treated by re casting, bracing and tibialis anterior tendon transfer. The Ponseti method is effective even in walking age children upto the age of 10 years with a good success rate, although approximately one-third of the clubfeet relapsed and needed further treatment. No modifications to the standard casting protocol are required. Despite a high relapse rate, a supple, plantigrade and pain-free foot is achievable without the need for extensive soft-tissue surgeries or bony procedures. The Ponseti method lends itself well to developing a nation-wide program for clubfoot treatment in countries with limited resources. LEVEL OF EVIDENCE: Level III. PMID- 30312251 TI - Risk Factors for Avoidable Transfer to a Pediatric Trauma Center Among Patients Age Two Years and Older. AB - BACKGROUND: Effective and sustainable pediatric trauma care requires systems of regionalization and interfacility transfer. Avoidable transfer, also known as secondary overtriage, occurs when a patient is transferred to a regional trauma center after initial evaluation at another facility that is capable of providing definitive care. The purpose of this study was to identify risk factors for avoidable transfer among pediatric trauma patients in southwest Florida. METHODS: All pediatric trauma patients two years and older transferred from outlying hospitals to the emergency department (ED) of a single state-designated pediatric trauma center between 2009 and 2017 were obtained from the institutional registry. Transfers were classified as avoidable if the patient suffered only minor injuries (ICD-9 Injury Severity Score >0.9), did not require invasive procedures or intensive care unit monitoring, and was discharged within 48 hours. Demographics and injury characteristics were compared for avoidable and non avoidable transfers. Logistic regression was used to estimate the independent effects of age, sex, insurance type, mechanism of injury, diagnosis, within region vs. out-of-region residence, suspected non-accidental trauma (NAT), and abnormal Glasgow Coma Score on the risk of avoidable transfer. RESULTS: A total of 3,876 transfer patients met inclusion criteria, of whom 1,628 (42%) were classified as avoidable. Among avoidable transfers, 29% had minor head injuries (isolated skull fractures, concussions, and mild traumatic brain injury not otherwise specified) and 58% received neurosurgery consultation. On multivariable analysis, the strongest risk factors for avoidable transfer were diagnoses of isolated skull fracture or concussion. Suspected NAT was predictive of non avoidable transfer. CONCLUSIONS: Among injured children age two years and older, those with minor head injuries were at greatest risk for avoidable transfer. Many were transferred because of a perceived need for evaluation by a pediatric neurosurgeon. Future projects seeking to reduce avoidable transfers should focus on children with isolated skull fractures and concussions, in whom there is no suspicion of non-accidental trauma. LEVEL OF EVIDENCE: III, economic/decision study. PMID- 30312252 TI - Analysis of Shoulder Complex Function After Posterior Spinal Fusion in Adolescents With Idiopathic Scoliosis. AB - BACKGROUND: Nonsurgically treated patients with AIS demonstrate altered scapular kinematics and decreased patient-reported shoulder function compared with typically developing adolescents. It is unknown whether surgical correction of the spine deformity has beneficial or detrimental effects on scapulothoracic joint function, as previous assessments of shoulder function following surgery have only focused on humerothoracic motion. The objective of this study was to perform a comprehensive analysis of scapular kinematics before and after PSF and compare postoperative scapular kinematics in AIS to those of a typically developing cohort. METHODS: Typically developing adolescents (n=33) and patients with AIS (n=20) with a planned PSF surgery were recruited. Motion capture was used to analyze scapular kinematics at rest and in full abduction. AIS subjects were evaluated before surgery and at a 6-month follow-up. Individual changes following surgery were assessed, and postoperative scapular kinematics were compared with the typically developing subjects. RESULTS: Patients with AIS patients in this study demonstrated significant losses of scapulothoracic range of motion for the convex side shoulder and gains of scapulothoracic range of motion for the concave side shoulder following PSF. When compared with typically developing adolescents, the resting scapular position of the postoperative AIS group seemed normalized, but the AIS group still exhibited altered scapular motion, particularly along the upward rotation and tilt axes. CONCLUSIONS: Patients with AIS demonstrated significant changes at the scapulothoracic joint following PSF. Compared with typically developing adolescents, scapular resting position normalized, but the AIS group still demonstrated altered scapular kinematics, including patterns associated with shoulder pathology. The results of this study will inform the course of short-term postoperative rehabilitation by addressing the upper extremity implications of PSF for individuals with AIS. LEVEL OF EVIDENCE: Level III. PMID- 30312253 TI - Is Magnetically Controlled Growing Rod the Game Changer in Early-onset Scoliosis? A Preliminary Report. AB - BACKGROUND: Magnetically controlled growing rod (MCGR) concept was introduced with the premise of minimizing the repetitive lengthening surgeries, which is default in traditional growing rod (TGR) treatment for early-onset scoliosis (EOS). Despite good radiographic outcomes, previous studies did not compare identical patient groups in terms of etiology and deformity characteristics; therefore, a true comparison of the MCGR and TGR is essential. This study was designed to compare 2 techniques in terms of clinical, radiologic, and health related quality of life (HRQoL) outcomes. METHODS: Patients with long sweeping congenital curves who underwent convex growth arrest and concave distraction (with TGR or MCGR) were retrospectively reviewed. Instrumented all-posterior convex growth arrest and concave distraction with growing rod technique were performed. Demographic parameters, follow-up time, number of lengthening procedures, radiographic parameters, number of unplanned surgeries, and complications were recorded. The Early-Onset Scoliosis Questionnaire (EOSQ-24) was used to evaluate HRQoL outcomes. RESULTS: A total of 20 patients were included (10 MCGR, 10 TGR). No significant differences were found with regard to average age, follow-up time, radiographic parameters, or complications. Overall surgery per patient including index surgery, and planned and unplanned procedures were significantly lower in the MCGR group (8.8 vs. 1.3) (P=0.01). No patient in either group had graduated from growing rod treatment. HRQoL analysis revealed no significant difference between the 2 groups in any specific domain or in the overall score of the EOSQ-24. CONCLUSIONS: Although equally effective in controlling the deformity and superior in reducing the number of surgeries with comparable complication rates, MCGR does not offer any significant improvement in HRQoL outcomes or the overall complication rate. Despite the obvious advantages, according to this preliminary report, the current technology and technique of MCGR may not be sufficient to be the long-awaited "game changer" in the treatment of EOS. PMID- 30312254 TI - OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS TO DISTINGUISH DIABETIC MACULAR EDEMA FROM PSEUDOPHAKIC CYSTOID MACULAR EDEMA USING MACHINE LEARNING ALGORITHMS. AB - PURPOSE: In diabetic patients presenting with macular edema (ME) shortly after cataract surgery, identifying the underlying pathology can be challenging and influence management. Our aim was to develop a simple clinical classifier able to confirm a diabetic etiology using few spectral domain optical coherence tomography parameters. METHODS: We analyzed spectral domain optical coherence tomography data of 153 patients with either pseudophakic cystoid ME (n = 57), diabetic ME (n = 86), or "mixed" (n = 10). We used advanced machine learning algorithms to develop a predictive classifier using the smallest number of parameters. RESULTS: Most differentiating were the existence of hard exudates, hyperreflective foci, subretinal fluid, ME pattern, and the location of cysts within retinal layers. Using only 3 to 6 spectral domain optical coherence tomography parameters, we achieved a sensitivity of 94% to 98%, specificity of 94% to 95%, and an area under the curve of 0.937 to 0.987 (depending on the method) for confirming a diabetic etiology. A simple decision flowchart achieved a sensitivity of 96%, a specificity of 95%, and an area under the curve of 0.937. CONCLUSION: Confirming a diabetic etiology for edema in cases with uncertainty between diabetic cystoid ME and pseudophakic ME was possible using few spectral domain optical coherence tomography parameters with high accuracy. We propose a clinical decision flowchart for cases with uncertainty, which may support the decision for intravitreal injections rather than topical treatment. PMID- 30312255 TI - PARS PLANA VITRECTOMY FOR THE TREATMENT OF TRACTIONAL AND DEGENERATIVE LAMELLAR MACULAR HOLES: Functional and Anatomical Results. AB - PURPOSE: Functional and anatomical outcomes of vitrectomy with membrane peeling were compared in tractional lamellar macular holes (LMH)/macular pseudoholes (MPH) versus degenerative LMH. METHODS: This multicenter retrospective study enrolled patients with a minimum follow-up of 6 months. The association of spectral domain optical coherence tomography parameters with preoperative and postoperative best-corrected visual acuity was analyzed. RESULTS: Seventy-seven (74.8%) tractional LMH/MPH and 26 (25.2%) degenerative LMH were included. Preoperative best-corrected visual acuity was better in tractional LMH/MPH (0.39 +/- 0.2 logarithm of the minimal angle of resolution, 20/50 Snellen equivalent) than degenerative LMH (0.56 +/- 0.2 logarithm of the minimal angle of resolution, 20/66 Snellen equivalent; P < 0.001). Premacular membranes were found in all tractional LMH/MPH, whereas LMH-associated epiretinal proliferation (LHEP) was present in all degenerative LMH. Primary anatomical success was achieved in 97/103 eyes (94.2%), with foveal restoration occurring earlier in degenerative LMH (1.6 +/- 2.3 vs. 3.3 +/- 3.6 months; P = 0.025). Best-corrected visual acuity improved in both tractional LMH/MPH and degenerative LMH (P < 0.001 and P = 0.012, respectively) but was better in tractional LMH/MPH (P = 0.001). CONCLUSION: The presence of premacular membranes and absence of LMH-associated epiretinal proliferation in all tractional LMH/MPH further distinguishes this from degenerative LMH. Best-corrected visual acuity improved in both subgroups but more so in tractional LMH/MPH. Complete anatomical restoration of foveal microanatomy was rare in degenerative LMH, reflecting significant morphological and pathophysiological differences between the two lesions. PMID- 30312256 TI - PHOTODYNAMIC THERAPY-INDUCED ACUTE EXUDATIVE MACULOPATHY: Incidence, Clinical Features, and Long-Term Outcomes. AB - PURPOSE: To describe the incidence, clinical features, and long-term outcomes of photodynamic therapy (PDT)-induced acute exudative maculopathy (PAEM) in patients who underwent PDT for various indications. METHODS: This retrospective observational case series included all cases who developed massive serofibrinous macular exudation within a week after PDT. Medical records of patients with post PDT exudative events were reviewed for relevant data and imaging abstraction including optical coherence tomography and indocyanine green angiography features and were subjected to analysis. RESULTS: The incidence rate of PAEM was 4.52%, being noted in 8 eyes (out of 177 PDT sessions in 155 eyes) with a mean age of 70.25 +/- 6.65 years. Pre-PDT factors commonly associated with PAEM included age >=65 years (87.5%), clinical diagnosis of polypoidal choroidal vasculopathy (75%), spot size >=3,500 um (100%), best-corrected visual acuity of 20/40 or better (87.5%), low-fluence PDT (87.5%), and the first exposure to PDT (75%). Photodynamic therapy-induced acute exudative maculopathy was noted at a mean interval of 2.9 +/- 1.7 days (2-7 days) after PDT. Photodynamic therapy-induced acute exudative maculopathy resulted in significant decrease in mean best corrected visual acuity from logMAR 0.29 +/- 0.21 (approximate Snellen equivalent 20/39) to logMAR 0.91 +/- 0.37 (approximate Snellen equivalent 20/163) [P = 0.0018], and significant increase in mean central macular thickness from 228.1 +/ 71.8 um to 481.4 +/- 154.8 um (P = 0.0029). Photodynamic therapy-induced acute exudative maculopathy resolved to baseline or even better tomographic status at a mean interval of 4.6 +/- 1.2 weeks, resulting in complete visual recovery compared with baseline. During mean follow-up of 77.8 +/- 46.4 weeks after PDT, no activity was noted for a mean duration of 26.3 +/- 42.5 weeks after resolution. At final visit, mean best-corrected visual acuity and central macular thickness was logMAR 0.49 +/- 0.28 (approximate Snellen equivalent 20/62) and 153.6 +/- 40.0 um, respectively, with underlying pathology being stable in 50% of the eyes. CONCLUSION: Photodynamic therapy-induced acute exudative maculopathy is an uncommon complication with self-resolving course and favorable prognosis. Patients undergoing PDT should be warned of the possibility of PAEM. The factors frequently associated with PAEM include elderly age (>65 years), clinical diagnosis of polypoidal choroidal vasculopathy, larger spot size (>=3,500 um), pre-PDT best-corrected visual acuity of 20/40 or better, low-fluence PDT, and the first exposure to PDT. PMID- 30312257 TI - INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR THE MANAGEMENT OF NEOVASCULARIZATION IN RETINOBLASTOMA AFTER INTRAVENOUS AND/OR INTRAARTERIAL CHEMOTHERAPY: Long-Term Outcomes in a Series of 35 Eyes. AB - PURPOSE: To report the use of anti-vascular endothelial growth factor in the management of retinoblastoma. METHODS: Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti-vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy. RESULTS: Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti-vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1-7.6). CONCLUSION: Intravitreal anti-vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment. PMID- 30312258 TI - INTERNAL LIMITING MEMBRANE PEELING AND AIR TAMPONADE FOR STAGE III AND STAGE IV IDIOPATHIC MACULAR HOLE. AB - PURPOSE: To evaluate the effect of internal limiting membrane peeling and air tamponade for idiopathic macular hole, and explore reasons and interventions for persistent holes. METHODS: One hundred and thirty-five eyes with Stage III and IV idiopathic macular hole that underwent 23-gauge vitrectomy, internal limiting membrane peeling, and air tamponade were reviewed. Eyes with persistent holes underwent a second surgery. Outcome-related factors and interventions treating persistent holes were discussed. RESULTS: The initial closure (Type I) rate was 89.63% (121/135). Eyes that underwent the second surgery all obtained final closure (Type I). Diameter of macular hole was significantly smaller (P < 0.001) and duration of symptoms was significantly shorter (P = 0.017) in initially closed cases than in unclosed ones. Binary logistic regression indicated large diameter of macular hole as a risk factor for initial closure (P = 0.004). A cutoff value of 677 MUm was provided by receiver operating characteristic curve to predict initial closure (P < 0.001). Best-corrected visual acuity of all individuals improved significantly (P < 0.001) from 20/154 to 20/40 (mean follow up: 4.5 months). CONCLUSION: Internal limiting membrane peeling and air tamponade for idiopathic macular hole provide satisfactory morphologic and functional outcomes. Large diameter of macular hole and long duration of symptoms are risk factors for initial closure. Proper second surgery can obtain satisfactory outcomes for persistent holes. PMID- 30312259 TI - BILATERAL ACUTE RETINAL NECROSIS: A Case Series. AB - PURPOSE: To investigate the clinical characteristics and visual outcome of bilateral acute retinal necrosis. METHODS: The study included 30 patients (60 eyes) who were diagnosed with bilateral acute retinal necrosis. The medical records were reviewed. RESULTS: Twenty-five patients developed the disease in the contralateral eye within 5 months and 5 patients at >2 years after the initial onset. At presentation, 14 of 21 eyes suffered from retinal necrosis of more than 180 degrees in the initially affected eye, whereas 3 of 22 eyes suffered it in the later-affected eye. Retinal detachment occurred in 23 of the 27 initially affected eyes and in 5 of the 27 later-affected eyes. The mean logarithm of the minimum angle of resolution best-corrected visual acuity decreased from 2.0 +/- 1.1 (Snellen equivalent counting fingers) to 2.2 +/- 1.0 (Snellen equivalent counting fingers) in the initially affected eyes after a follow-up of 34.1 +/- 48.2 months (P = 0.529), and improved from 0.5 +/- 0.4 (Snellen equivalent 20/66) to 0.3 +/- 0.4 (Snellen equivalent 20/40) in the later-affected eyes after a follow-up of 21.2 +/- 23.3 months (P = 0.005). CONCLUSION: Bilateral acute retinal necrosis usually occurs in the contralateral eye within a few months, but sometimes after several years. Inflammation and retinal necrosis are less severe in the later-affected eye, with less retinal detachment and a better visual outcome. PMID- 30312260 TI - COMPARATIVE RISK OF ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION WITH BEVACIZUMAB, AFLIBERCEPT, AND RANIBIZUMAB. AB - PURPOSE: To determine whether sterile preloading of anti-vascular endothelial growth factor agents reduces the risk of postintravitreal injection endophthalmitis. METHODS: This is a retrospective cohort study using medical claims data from a large, national US insurer. Cohorts were created using intravitreal injections of anti-vascular endothelial growth factor injections from 2005 to 2016. For inclusion, patients had to have at least 6 months of data before the injection and were excluded for any previous diagnosis of endophthalmitis, multiple injected drugs on the day of injection, or intraocular surgery within 15 days of the injection or between an injection and a diagnosis of endophthalmitis. The primary outcome was the odds of endophthalmitis after an intravitreal injection. RESULTS: A total of 706,725 bevacizumab, 210,849 ranibizumab, and 177,731 aflibercept injections were given to 130,327 patients. Multivariate analysis showed that ranibizumab and aflibercept together had an increased odds of endophthalmitis (odds ratio = 1.29, 95% confidence interval: 1.04-1.59, P = 0.02) compared with bevacizumab. Individually, ranibizumab (odds ratio = 1.25, 95% confidence interval: 0.97-1.61, P = 0.08) and aflibercept (odds ratio = 1.34, 95% confidence interval: 0.99-1.81, P = 0.06) each had higher odds of endophthalmitis, but neither result met significance. Also, when compared with male patients, female patients had a higher odds of getting endophthalmitis (odds ratio: 1.30, 95% confidence interval: 1.05-1.61, P = 0.02). CONCLUSION: The odds of endophthalmitis with aflibercept and ranibizumab combined were higher compared with the sterilely preloaded bevacizumab, arguing for a safety advantage of sterile preloading of anti-vascular endothelial growth factor injections. PMID- 30312261 TI - A Human Amniotic Membrane Plug to Promote Retinal Breaks Repair and Recurrent Macular Hole Closure. PMID- 30312262 TI - COMBINED VITRECTOMY WITH INTRAVITREAL DEXAMETHASONE IMPLANT FOR REFRACTORY MACULAR EDEMA SECONDARY TO DIABETIC RETINOPATHY, RETINAL VEIN OCCLUSION, AND NONINFECTIOUS POSTERIOR UVEITIS. AB - PURPOSE: To compare the efficacy of intraoperative intravitreal dexamethasone implant for macular edema secondary to diabetic retinopathy (DME), retinal vein occlusion (RVO), and noninfectious posterior uveitis. METHODS: A retrospective review of 62 patients (29 men and 33 women; mean age 51.19 +/- 14.41 years; 65 eyes) was performed. Best-corrected visual acuity (in logarithm of the minimal angle of resolution), central foveal thickness, intraocular pressure, and postoperative edema-free period were postoperatively assessed up to 1 year. The preoperative and postoperative numbers of other intravitreal injections needed were compared. RESULTS: Best-corrected visual acuity gradually improved in the DME group (from 0.87 to 0.51) but failed to improve from Month 3 onward in the RVO and uveitis groups. Central foveal thickness decreased in all groups, especially in the DME group (from 550.93 to 338.10 MUm). Edema-free period was longest in the DME group (19.34 +/- 15.12 months), followed by the uveitis (12.91 +/- 7.85 months) and RVO (8.50 +/- 8.76 months) groups. Subjects in the uveitis group used more intraocular pressure-lowering agents (1.00 +/- 1.27) than those in the DME (0.13 +/- 0.49) and RVO (0.36 +/- 0.79) groups. Increased intraocular pressure events were most frequent in postoperative Week 1, especially in the uveitis group. CONCLUSION: Vitrectomy combined with intravitreal dexamethasone implant for DME, RVO, and noninfectious posterior uveitis had a favorable clinical outcome. PMID- 30312263 TI - EYES WITH SUBRETINAL DRUSENOID DEPOSITS AND NO DRUSEN: Progression of Macular Findings. AB - PURPOSE: To investigate the macular changes over time in eyes containing subretinal drusenoid deposits (also known as pseudodrusen) with no drusen >63 um. METHODS: A consecutive series of patients were examined with color fundus photography, optical coherence tomography, and autofluorescence imaging with fluorescein angiography used as necessary. Exclusionary criteria included macular neovascularization, history of retinal surgery, pseudoxanthoma elasticum, and drusen >63 um. RESULTS: There were 85 eyes of 54 patients. The mean age at baseline was 83.6 (+/-7.8) years, and there were 17 men. The mean follow-up was 5.0 (+/-2.9) years. At initial optical coherence tomography examination, 12 eyes had extrafoveal atrophy and 17 eyes had vitelliform deposits, which were yellowish white subretinal collections that showed intense hyperautofluorescence. During follow-up, 11 eyes lost vitelliform material. After the disappearance of small deposits, focal hyperpigmentation remained. Loss of larger deposits was associated with noteworthy sequela; six developed subfoveal atrophy and one macular neovascularization close to regressing vitelliform material. Subfoveal geographic atrophy developed in four other eyes without vitelliform material by extension from areas of extrafoveal atrophy. Macular neovascularization developed in seven eyes over follow-up. The CFH Y402H and ARMS2 A69S allele frequencies were 57% and 48.9%, respectively, which is similar to a group of age-related macular degeneration controls. One patient had a novel PRPH2 mutation, but did not have a vitelliform deposit; the remainder had a normal PRPH2 and BEST1 coding sequences. CONCLUSION: Eyes with subretinal drusenoid deposits and no drusen >63 mm have significant risk for the development of both neovascularization and geographic atrophy, the fundamental components of late age-related macular degeneration. An intermediate step in some eyes was the development of a vitelliform deposit, an entity not traditionally associated with age-related macular degeneration, but in these patients, the material seemed to be an important component of the disease pathophysiology. This vitelliform deposit was not associated with genetic markers for pattern dystrophy or Best disease. PMID- 30312264 TI - Toxoplasma gondii Exposure and the Risk of Attention Deficit Hyperactivity Disorder in Children and Adolescents. AB - BACKGROUND: Evidence suggests that Toxoplasma gondii, which causes toxoplasmosis, changes the metabolism of neurotransmitters, especially dopamine, resulting in both neurologic and psychiatric disorders. On the other hand, the dysregulation of catecholamines, especially of both norepinephrine and dopamine, has been proposed in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of the present study was to investigate anti-toxoplasma antibodies in children and adolescents with ADHD and compare it with a control group, to determine whether toxoplasmosis is a risk factor for ADHD. METHODS: A total of 200 children and adolescents (117 patients with ADHD and 83 individuals without ADHD) participated in the study. Participants were tested for the presence of anti-T. gondii antibodies by enzyme-linked immunosorbent assay. A Parent ADHD Rating Scale and Clinical Global Impression-severity Scale were also completed. Data were analyzed using a chi test and Fisher exact test. RESULTS: Anti-toxoplasma antibodies were detected in 18.1% of patients with ADHD disorder and 24% of individuals without ADHD. There was no significant difference in seropositivity between the 2 groups (P > 0.05). The number of patients with T. gondii infection in the 3 subgroups was 0, 9 and 12, respectively. The differences in infection rate among subgroups were not statistically significant (P > 0.05). CONCLUSION: Although not conclusive, the present study does not support the theory that T. gondii is a risk factor for ADHD. PMID- 30312265 TI - Maternal Carriage of Group B Streptococcus and Escherichia coli in a District Hospital in Mozambique. AB - BACKGROUND: In low-income countries, data on prevalence and effects of group B Streptococcus (GBS) and Escherichia coli (E. coli) colonization among pregnant women are scarce, but necessary to formulate prevention strategies. We assessed prevalence of GBS and E. coli colonization and factors associated among pregnant women, its effect in newborns and acceptability regarding the utilized sampling methods in a semirural Mozambican hospital. METHODS: Pregnant women were recruited from June 2014 to January 2015, during routine antenatal clinics at gestational age >= 34 weeks (n = 200); or upon delivery (n = 120). Maternal risk factors were collected. Vaginal and vagino-rectal samples for GBS and E. coli determination were obtained and characterized in terms of antimicrobial resistance and serotype. Anti-GBS antibodies were also determined. Neonatal follow-up was performed in the first 3 months after birth. Semistructured interviews were performed to investigate acceptability of sample collection methods. RESULTS: In total, 21.3% of women recruited were GBS carriers, while 16.3% were positive for E. coli. Prevalence of HIV was 36.6%. No association was found between being colonized by GBS and E. coli and maternal risk factors. GBS isolates were fully susceptible to penicillin and ampicillin. Serotypes V (32.4%), Ia (14.7%) and III (10.3%) were the most commonly found and 69.2% of the women tested had immunoglobuline G antibodies against GBS. E. coli isolates showed resistance to ampicillin in 28.9% and trimethoprim/sulfamethoxazole in 61.3% of the cases. CONCLUSION: Prevalence of GBS and/or E. coli colonization among pregnant women is high in this semirural community and comparable with those reported in similar settings. Four serotypes accounted for nearly 70% of all isolates of GBS. Population-based data on infant GBS infections would enable the design of prevention strategies for GBS disease in Mozambique. PMID- 30312267 TI - Point of View: The Costs of Failed Non-operative Care. PMID- 30312266 TI - Identification of Amino Acid Substitutions Within the VP7 Genes of G2 Rotavirus Strains in Ghana. AB - We used the dideoxynucleotide chain termination method to determine the strains of nine non-typeable rotavirus enzyme immunoassay-positive samples, which were identified as G2. We detected nucleotide changes in the primer-binding region and amino acid substitutions within the VP7 protein of the G2 rotavirus strains. Genotyping primers need to be updated regularly. PMID- 30312268 TI - A Strategy for Risk-Adjusted Ranking of Surgeons and Practices Based on Patient Reported Outcomes After Elective Lumbar Surgery. AB - STUDY DESIGN: This study retrospectively analyzes prospectively collected data. OBJECTIVE: The primary aim of this study is to present a scheme for PRO-based, risk-adjusted rankings of spine surgeons and sites that perform elective lumbar surgery, using the Quality and Outcomes Database (QOD). SUMMARY OF BACKGROUND: There is currently no means of determining which spine surgeons or centers are positive or negative outliers with respect to patient-reported outcomes (PRO) for elective lumbar surgery. This is a critical gap as we move towards a value-based model of healthcare in which providers assume more accountability for the effectiveness of their treatments. METHODS: Random effects regression models were fit for the following outcomes, with QOD site as a fixed effect but surgeon ID as a random effect: ODI, EQ-5D, back pain and leg pain, and satisfaction. Hierarchical Bayesian models were also fit for each outcome, with QOD site as a random effect and surgeon as a nested random effect. RESULTS: Our study cohort consists of 8834 patients who underwent surgery by 124 QOD surgeons, for the degenerative lumbar diseases. Non-overlapping Bayesian credible intervals demonstrate that the variance attributed to QOD site was greater than the nested variance attributed to surgeon ID for the included PROs. CONCLUSION: This study presents a novel strategy for the risk-adjusted, PRO-based ranking of spine surgeons and practices. This can help identify positive and negative outliers, thereby forming the basis for large-scale quality improvement. Assuming adequate coverage of baseline risk adjustment, the choice of surgeon matters when considering PROs after lumbar surgery, however the choice of site appears to matter more. LEVEL OF EVIDENCE: 3. PMID- 30312269 TI - Group and Individual-level Change on Health-related Quality of Life in Chiropractic Patients with Chronic Low Back or Neck Pain. AB - STUDY DESIGN: Prospective observational study. OBJECTIVE: To evaluate group-level and individual-level change in health-related quality of life among persons with chronic low back pain or neck pain receiving chiropractic care in the United States. SUMMARY OF BACKGROUND DATA: Chiropractors treat chronic low back and neck pain, but there is limited evidence of the effectiveness of their treatment METHODS.: A 3-month longitudinal study of 2,024 patients with chronic low back pain or neck pain receiving care from 125 chiropractic clinics at 6 locations throughout the United States was conducted. Ninety-one percent of the sample completed the baseline and 3-month follow-up survey (n = 1,835). Average age was 49, 74% females, and most of the sample had a college degree, were non-Hispanic White, worked full-time, and had an annual income of $60,000 or more. Group-level (within group t-tests) and individual-level (coefficient of repeatability) changes on the Patient-Reported Outcomes Measurement Information System (PROMIS) v2.0 profile measure was evaluated: 6 multi-item scales (physical functioning, pain, fatigue, sleep disturbance, social health, emotional distress) and physical and mental health summary scores. RESULTS: Within group t-tests indicated significant group-level change (p < 0.05) for all scores except for emotional distress, and these changes represented small improvements in health (absolute value of effect sizes ranged from 0.08 for physical functioning to 0.20 for pain). From 13% (physical functioning) to 30% (PROMIS-29 Mental Health Summary Score) got better from baseline to 3 months later according to the coefficient of repeatability. CONCLUSIONS: Chiropractic care was associated with significant group-level improvement in health-related quality of life over time, especially in pain. But only a minority of the individuals in the sample got significantly better ("responders"). This study suggests some benefits of chiropractic on functioning and well-being of patients with low back pain or neck pain. LEVEL OF EVIDENCE: 3. PMID- 30312270 TI - French-Canadian adaptation and validation of the Swiss Spinal Stenosis Questionnaire for patients with lumbar spinal stenosis. AB - STUDY DESIGN: Observational prospective study. OBJECTIVE: The study objective was to assess the reliability and validity of the French-Canadian version (FCSSSQ) of the Swiss Spinal Stenosis questionnaire (SSSQ). SUMMARY OF BACKGROUND DATA: The SSSQ is a validated disease-specific tool developed to assess pain, function and satisfaction with care in patients with lumbar spinal stenosis (LSS). METHODS: The French-Canadian translation and adaptation of the SSSQ was completed following a 4-stage approach: (1) forward translation; (2) synthesis; (3) expert committee review; and (4) testing of the questionnaire prefinal version. Psychometric properties were subsequently determined in patients who had undergone decompressive surgery for degenerative LSS. Patients completed the SSSQ adapted version, the Numerical Rating Scale and the Oswestry Disability Index. Test-retest reliability was assessed with weighted Kappa score and intraclass correlation coefficient. Construct validity was evaluated using the Spearman correlation coefficient and responsiveness with the mean standardized response as well as the area under the receiver operating characteristic curve (AUROC). Floor and ceiling effects and internal consistency were also evaluated. RESULTS: Twenty five and fifty patients were included for the adaptation and validation processes respectively. The test-retest reliability of the FCSSSQ total score was excellent (ICC = 0.996 95% CI 0.938-0.982). High Spearman correlation coefficients were also found between the total FCSSSQ score and the leg pain NRS (0.801), back pain NRS (0.705) and the ODI (0.825) scores. External responsiveness analysis was satisfactory with an AUROC of 0.875 (95% CI 0.744-1.0). The lowest FCSSSQ possible score was observed in 5 patients (10%) whereas no patients reported the highest possible score. The Cronbach alpha coefficient ranged from 0.810 to 0.945 indicating good to excellent internal consistency. CONCLUSIONS: The French Canadian version of the SSSQ is a reliable and valid questionnaire consistent with the original English version. This new version will help French-speaking clinicians and scientists document changes in condition and treatment satisfaction in patients with LSS. LEVEL OF EVIDENCE: 2. PMID- 30312272 TI - Additional Sacroplasty Does Not Improve Clinical Outcome in Minimal-Invasive Navigation-Assisted Screw Fixation Procedures for Non-Displaced Insufficiency Fractures of the Sacrum. AB - STUDY DESIGN: Prospective single-center cohort study (non-inferiority study). OBJECTIVE: To compare clinical results of navigation-assisted screw fixation (NSF) to those of NSF with additional sacroplasty (NSF+SP) for immobilizing non displaced insufficiency fractures of the sacrum. SUMMARY OF BACKGROUND DATA: Navigation-assisted screw fixation for sacral insufficiency fractures is a new, technically demanding procedure requiring surgical skills and experience. Up to date, controversies exist about the benefit of additional sacroplasty in surgically stabilized insufficiency fractures of the sacrum. METHODS: From February 2011 to May 2017, all individuals with immobilizing non-displaced sacral insufficiency fractures surgically treated using 3D-fluoroscopy for 3D-real-time navigation and post-instrumentation screw control in form of NSF (I) or NSF+SP (II) were enrolled. SP was performed only in absence of transforaminal or central fractures. Outcome parameters were post-surgical pain relief determined by visual analogue scale (VAS), post-surgical improvement of disability evaluated using the Oswestry-Disability-Index (ODI), and length of post-surgical hospital stay. RESULTS: In two groups of 26 individuals, each, a total of 124 insufficiency fractures of sacral vertebrae were surgically treated. Post-operative pain-level decrease was comparable in both groups (5.3 vs. 5.4 VAS points). Extent of post operative disability-score improvement (53.4 vs. 57.7 ODI points) led to successful remobilization after similar durations of post-surgical hospital stay (9.3 vs. 9.6 days). Minimum clinically important differences of outcome parameters were not reached in the comparison of study group results. In procedures with SP, no major complications occurred, in those without SP, no specific complications were observed. CONCLUSIONS: This comparative study indicates non-inferiority of NSF compared to NSF+SP for sacral insufficiency fractures, and could not confirm clinical advantages of additional SP concerning pain relief, improvement of fracture-related disability, or time from surgery to discharge. Therefore, additional sacroplasty is not recommended to enhance the clinical benefit for patients receiving image-guided sacral screw fixation. LEVEL OF EVIDENCE: 2. PMID- 30312271 TI - Alert Timing and Corresponding Intervention with Intraoperative Spinal Cord Monitoring for High Risk Spinal Surgery. AB - STUDY DESIGN: Prospective multicenter study OBJECTIVE.: To analyze the incidence of intraoperative spinal neuromonitoring (IONM) alerts and neurological complications, as well as to determine which interventions are most effective at preventing postoperative neurological complications following IONM alerts in high risk spinal surgeries. SUMMARY OF BACKGROUND DATA: IONM may play a role in identifying and preventing neural damage; however, few studies have clarified the outcomes of intervention after IONM alerts. METHODS: We analyzed 2867 patients who underwent surgery for high risk spinal pathology using transcranial electrical motor-evoked potentials (Tc(E)-MEPs) from 2010 to 2016. The high risk spinal surgery cases consisted of 1009 spinal deformity cases, 622 cervical ossification of posterior longitudinal ligament (c-OPLL) cases, 249 thoracic-OPLL (t-OPLL) cases, 771 extramedullary spinal cord tumor (EMSCT) cases, and 216 intramedullary spinal cord tumor (IMSCT) cases. We set a 70% amplitude reduction as the alarm threshold for Tc(E)-MEPs and analyzed the outcomes of the interventions following monitoring alerts and postoperative neurological deficits. RESULTS: The true positive, false positive, true negative, false negative, and rescue cases of IOMN comprised 126, 234, 2362, nine, and 136 cases, respectively. Most alerts and interventions occurred during correction and release in deformity cases, posterior decompression and dekyphosis in OPLL cases, and tumor resection and surgery suspension with steroid injection in SCT cases; however, individual interventions varied. The rescue rates (number of patients rescued with intervention after IONM alert/number of true positive cases plus rescue cases) for deformity, c-OPLL, t-OPLL, EMSCT, and IMSCT cases were 61.4% (35/57), 82.1% (32/39), 40% (20/50), 52.5% (31/59), and 31.6% (18/57), respectively. CONCLUSIONS: Our prospective multicenter study identified potential neural damage in 9.5% of cases and 52% rescue cases using IONM. Although the rescue ratios for t-OPLL and IMSCT were relatively low, appropriate intervention immediately after an IONM alert may prevent neural damage even in high-risk spinal surgeries. LEVEL OF EVIDENCE: 3. PMID- 30312273 TI - Coronal Imbalance in Adult Spinal Deformity Following Posterior Spinal Fusion With Instrument: A Related Parameters Analysis. AB - STUDY DESIGN: A retrospective radiographic study. OBJECTIVE: To explore the radiological parameters which correlated to postoperative immediately coronal imbalance in adult spinal deformity (ASD) and to determine whether preoperative coronal imbalance affects postoperative coronal imbalance following posterior multi-level fusion with instruments and osteotomy operation. SUMMARY OF BACKGROUND DATA: There was paucity of literature paying attention to the postoperative immediately coronal imbalance after operation. METHODS: The study included 67 consecutive patients with ASD who underwent posterior multi-level fusion with instruments and osteotomy operation. The radiological parameters, measured on the pre- and postoperative anteroposterior and lateral radiographs, were compared and analyzed. Patients were divided into three groups (group A, B, and C) according to preoperative coronal balance distance (pre-CBD) and the relation of cervical 7 plumb line (C7PL), and the convex of curvature. To analyze the radiological parameters of the three groups. RESULT: Differences of the radiological parameters between pre- and postoperation concerning Cobb angles, degree of apical vertebra rotation, thoracic kyphosis (TK), thoracic lumber kyphosis (TLK), lumber lordosis (LL), sacral slope (SS), pelvic tilt (PT), and sagittal vertical axis (SVA), were significant (P < 0.05). Pelvic incidence (PI), pre-CBD, and postoperative coronal balance distance (post-CBD) had no change (P > 0.05). The ratio of coronal imbalance in pre- and postoperation was 31.34% (21/67) and 40.30% (27/67), respectively, which had significant difference (P = 0.02). Significant correlations were observed among post-CBD, pre-CBD (P < 0.001), and d-Cobb (pre-Cobb - post-Cobb) (P = 0.002), post-CBD = -2.737 - 0.924*d-Cobb + 0.356*pre-CBD. The ratio of postoperative immediately coronal imbalance of the group C was much higher than other two groups (P = 0.01). CONCLUSION: The sagittal alignments in ASD patients would be improved effectively after posterior multi-level fusion with instruments and osteotomy operation. There were significant correlations among post-CBD, pre-CBD, and d-Cobb. Patients in group C may be at greater risk for immediate postoperative coronal imbalance after operation. LEVEL OF EVIDENCE: 3. PMID- 30312274 TI - A Cost-Utility Analysis of Percutaneous Endoscopic Lumbar Discectomy for L5-S1 Lumbar Disc Herniation: Transforaminal vs Interlaminar. AB - STUDY DESIGN: Cost-utility analysis(CUA). OBJECTIVE: Evaluate the cost effectiveness of PETD and PEID techniques for the treatment of L5-S1 LDH. SUMMARY OF BACKGROUND DATA: The annual cost of treatment for lumbar disc herniation is staggering. As the two major approaches of percutaneous endoscopic lumbar discectomy (PELD): percutaneous endoscopic transforaminal discectomy (PETD) and percutaneous endoscopic interlaminar discectomy (PEID) has gain its recognition for the treatment of L5-S1 lumbar disc herniation (LDH) and showed similar clinical outcome. Cost-utility analysis (CUA) can help clinicians make appropriate decisions about optimal healthcare for L5-S1 LDH. METHODS: 50 and 25 patients were included in the PETD and PEID groups of the study. Patients' basic characteristics, healthcare costs, and clinical outcome of PETD and PEID group were collected and analyzed. Quality adjusted life years (QALYs) were calculated and validated by EuroQol five-dimensional (EQ-5D) questionnaire. Cost effectiveness was determined by the incremental cost per quality-adjusted life year gained. RESULTS: The mean total cost of the PETD group was $5275.58 +/- 292.98 and the PEID group was $5494.45 +/- 749.24. No significant differences was observed in hospitalization expenses, laboratory and radiographic evaluations expenses, surgical expenses and drug costs. Surgical equipment and materials costs, and anesthesia expense in the PEID group was significant higher than in the PETD group (P < 0.001). Clinical outcomes including VAS, ODI and JOA also showed no significant differences between the two groups. The cost-effectiveness ratio of PETD and PEID were $6816.05 +/- 717.90/QALY and $7073.30 +/- 1081.44/QALY, respectively. The ICERs of PEID over PETD was $21887.00/QALY. CONCLUSION: Observed costs per QALY gained for L5-S1 LDH with PETD or PEID were similar for patients, demonstrating that the two different approaches of PELD are equally cost-effective and valuable interventions. LEVEL OF EVIDENCE: 3. PMID- 30312275 TI - Opioid Agonist Treatment and Improved Outcomes at Each Stage of the HIV Treatment Cascade in People Who Inject Drugs in Ukraine. AB - BACKGROUND: The HIV treatment cascade is a crucial tool to guide HIV prevention and treatment strategies. The extent to which opioid agonist treatments (OATs) such as methadone and buprenorphine influence this cascade was examined in a nationwide study of people who inject drugs (PWID) in Ukraine. SETTING: Cross sectional stratified survey of PWID followed by HIV and hepatitis C virus testing in 5 Ukrainian cities. METHODS: Opioid-dependent PWID (N = 1613) were sampled from January 2014 to March 2015. Analysis was confined to 520 participants with HIV, with 184 (35.4%) prescribed OAT. Weighted logistic regression models were used to assess independent factors associated with the 5 steps in the HIV treatment cascade. RESULTS: Compared with PWID not on OAT (N = 336), participants who prescribed OAT (N = 184) were significantly more likely to be diagnosed (91% vs. 71%), linked (81% vs. 52%), and retained (69% vs. 35%) in HIV care, and prescribed (56% vs. 31%) and optimally (>95% of doses) adherent to antiretroviral therapy (41% vs. 22%). Receiving OAT contributed most as an independent factor with every step of the cascade. Other steps in the HIV treatment cascade were influenced by age, depression, and geographical variability. CONCLUSIONS: OAT remains an essential and effective strategy to not only treat patients with opioid use disorder, but also a crucial strategy to engage PWID in care to meet UNAIDS 90-90-90 targets. Geographical differences suggest local structural impediments. With low OAT coverage prescribed for 2.9% of the estimated 347,000 PWID in Ukraine, OAT expansion requires strategic interventions that target the individual, clinical care settings, policies, and funding. PMID- 30312276 TI - Analyses of Mitochondrial DNA and Immune Phenotyping Suggest Accelerated T-Cell Turnover in Treated HIV. AB - BACKGROUND: HIV infection is associated with premature aging, and mitochondrial integrity is compromised during the aging process. Because mitochondrial toxicity is a consequence of antiretroviral therapies (ARTs), we hypothesized HIV and long term ART would correlate with immunosenescence and mitochondrial DNA (mtDNA) pathology. SETTING: Thirteen older HIV-infected individuals (aged >40 years) with virologic suppression (stratified by duration of ART) were compared with 10 uninfected controls well-matched for age. METHODS: Peripheral blood T-cells were immunophenotyped to measure immune activation, proliferation, and immunosenescence in subsets. mtDNA copies per cell and the relative abundance of mtDNA carrying the "common deletion" (RACD) were quantified by droplet digital polymerase chain reaction. RESULTS: Immune activation was higher in HIV-infected individuals than HIV-uninfected individuals in mature CD4 T-cell subsets (CD4TTM P = 0.025, CD4TEM P = 0.0020) regardless of ART duration. Cell populations from uninfected individuals were more likely to be more senescent populations in mature CD4 T-cell subsets (TTM P = 0.017), and CD8 (CD8TEMRA+ P = 0.0026). No differences were observed in mtDNA or RACD levels in any CD4 T-cell subsets, while CD8TSCM of infected individuals trended to have more mtDNA (P = 0.057) and reduced RACD (P = 0.0025). CONCLUSIONS: HIV-infected individuals demonstrated increased immune activation, but reduced senescence in more mature T-cell subsets. Increased mtDNA content and lower RACD in CD8TSCM suggest immune activation driven turnover of these cells in HIV-infected persons. PMID- 30312277 TI - Multimonth Prescription of Antiretroviral Therapy Among Children and Adolescents: Experiences From the Baylor International Pediatric AIDS Initiative in 6 African Countries: Erratum. PMID- 30312278 TI - Effects of Sex Hormones on Ocular Blood Flow and Intraocular Pressure in Primary Open-angle Glaucoma: A Review. AB - Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and visual field loss. Some speculate that sex plays a role in the risk of developing POAG and that the physiological differences between men and women may be attributed to the variable effects of sex hormones on intraocular pressure, ocular blood flow, and/or neuroprotection. Estrogen, in the form of premenopausal status, pregnancy, and postmenopausal hormone therapy is associated with an increase in ocular blood flow, decrease in intraocular pressure and neuroprotective properties. The vasodilation caused by estrogen and its effects on aqueous humor outflow may contribute. In contrast, although testosterone may have known effects in the cardiovascular and cerebrovascular systems, there is no consensus as to its effects in ocular health or POAG. With a better understanding of sex hormones in POAG, sex hormone-derived preventative and therapeutic considerations in disease management may provide for improved sex-specific patient care. PMID- 30312279 TI - e-letter-to the Editor to: Park J-H et al "Peripapillary Vessel Density in Glaucomatous Eyes: Comparison between Pseudoexfoliation Glaucoma and Primary Open Angle Glaucoma". PMID- 30312280 TI - Early Phacoemulsification After Acute Angle Closure in Patients With Coexisting Cataract. PMID- 30312281 TI - In Reply. PMID- 30312282 TI - Glaucoma Gel Implant Learning Curve in a Teaching Tertiary Hospital. AB - PURPOSE: XEN(r) gel stent is a minimally invasive surgical device aimed at creating a subconjunctival drainage of aqueous humor, thereby reducing intraocular pressure (IOP). Being a novel device, doubts remain regarding the efficacy and safety of its implantation in the early stage of new users. This paper illustrates the XEN(r) implantation learning curve, assessed through several surgeons of different expertise. METHODS: Retrospective study on the first 6 XEN(r) implants performed by each of 10 certified ophthalmic surgeons. Simultaneous cataract surgery was allowed (phaco-XEN(r)). Primary outcomes: surgical time; intra- and postoperative surgical complications. SECONDARY OUTCOMES: IOP; number of topical drugs in use; need for needling procedures. Outcome data were collected pre-operatively and at postoperative days 1, 7, 15, 30, 60 and 90. Statistical analysis was performed with STATA(r) 14.1 and SPSS(r). RESULTS: Sixty patients were included (56.7% females). Mean age was 73 years [45 89]. Mean preoperative IOP was 23.8+/-8.95?mmHg. From the included patients, 29 (48.3%) were submitted to simple XEN(r) implant, and 31 (51.7%) to phaco-XEN(r). In both groups, mean surgical time decreased 9 minutes throughout the six-implant learning curve. Final IOP was 15+/-7.27?mmHg in the stent group (-43% than baseline), and 14.92+/-3.32?mmHg in the phaco-XEN group (-16% than baseline). In average, patients decreased two topical IOP-lowering drugs. Needling procedures were performed in 17 patients (28.3%). CONCLUSIONS: XEN(r) gel stent was associated with fast learning curve, by both experienced surgeons and novice residents. By the sixth implant, both groups had considerably decreased mean surgical time and complication rates. PMID- 30312283 TI - Determinants of Corneal Endothelial Cell Loss After Trabeculectomy with Mitomycin C. AB - PURPOSE: To investigate factors associated with decreased corneal endothelial cell density (ECD) after trabeculectomy with mitomycin C (MMC). METHODS: Retrospective review of consecutive glaucoma cases who underwent trabeculectomy with MMC. The types of glaucoma included were primary open angle glaucoma (POAG), exfoliation glaucoma (XFG), neovascular glaucoma (NVG), and uveitic glaucoma (UG). The postoperative ECD changes compared to the preoperative ECD and risk factors for ECD decrease were analyzed using mixed-effects models. RESULTS: One hundred sixty-two eyes of 136 patients were included in this study. Postoperative ECD measurements were performed 3.7+/-1.8 times (mean+/-standard deviation) during a median follow-up period of 34 months. The mean intraocular pressure decreased from 25.3+/-9.6?mmHg to 9.2+/-2.3?mmHg postoperatively. The marginal mean (standard error) ECD decrease at 24 months was 9.3 (1.3) % in all cases. The marginal mean ECD decrease at 24 months was 18.2 (3.1) % and 20.6 (4.7) % in eyes with XFG and UG, respectively, which was significantly greater than 4.8 (1.8) % in eyes with POAG (P <0.001, each), after accounting for the variability in the number and time point of ECD measurements. Multivariate mixed-effects model analyses showed that type of glaucoma (XFG and UG) and older age were significantly associated with larger ECD decrease, and preoperative factors (oral carbonic anhydrase inhibitor and vitrectomy) and postoperative choroidal detachment were significantly associated with a declining trend of ECD over time. CONCLUSION: The type of glaucoma (XFG, UG) and older age were risk factors for larger ECD decease after trabeculectomy with MMC. PMID- 30312284 TI - Early Phacoemulsification After Acute Angle Closure in Patients With Coexisting Cataract. PMID- 30312285 TI - Management of Conjunctival Perforation and XEN Gel Stent Exposure by Stent Repositioning through the Anterior Chamber. AB - In recent years, minimally-invasive glaucoma surgery has emerged as a novel approach to lowering intraocular pressure (IOP). This technique, which is usually reserved for mild to moderate cases, is less invasive than classic filtration surgery and potentially offers a better safety profile. The XEN Gel Stent is implanted through a minimally-invasive, ab interno procedure to create a subconjunctival pathway. Conjunctival tissue disruption is minimal and flow is restricted to avoid hypotony. Data on the optimal approach to managing complications associated with this procedure are limited due to the relatively recent commercialization of this device. Here we report a case of a persistent leaking bleb caused by XEN Stent exposure which was managed by ab interno repositioning of the stent through the anterior chamber and direct suturing of the conjunctival defect. PMID- 30312286 TI - New Medicare Diabetes Prevention Coverage May Limit Beneficiary Access and Widen Health Disparities. AB - BACKGROUND: The Centers for Medicare and Medicaid Services recently issued final rules for the Medicare Diabetes Prevention Program (MDPP), offering an unprecedented opportunity to provide lifestyle intervention to Medicare beneficiaries with prediabetes via a pay-for-performance model. The MDPP is based on the widely disseminated, yearlong National Diabetes Prevention Program (NDPP), which has lesser but still beneficial risk-reduction outcomes among minority and low-income participants. OBJECTIVES: We compare projected payments based on outcomes of a diverse sample of Medicare beneficiaries to service delivery costs, and explore resulting implications for MDPP access and sustainability. METHODS: We delivered NDPP in a safety-net health care system from 2013 to 2017 and conducted an analysis of service cost, beneficiary performance, and projected MDPP reimbursement. RESULTS: Among 1165 total participants, 213 (18.3%) were Medicare beneficiaries. Participating beneficiaries were 40.6% Hispanic, 31.6% non-Hispanic black, and 26.9% non-Hispanic white and 69.5% low-income. Overall beneficiary performance would result in an average reimbursement of $138.52 (interquartile range=162.50). Program delivery costs were $800 per participant, leaving an average gap of $661 per beneficiary. CONCLUSIONS: Findings from delivering the NDPP to diverse and undeserved patients show a large gap between service costs and projected reimbursement. Although many MDPP suppliers are needed to reach all Medicare beneficiaries with prediabetes, insufficient reimbursement may be a deterrent. Health disparities may also widen as suppliers serving diverse and low-income populations will likely receive especially low payments, threatening access. Higher payments are supported by strong return-on investment findings and seem needed to reduce diabetes prevalence and related disparities. PMID- 30312287 TI - Anticancer Activity of Mukonal Against Human Laryngeal Cancer Cells Involves Apoptosis, Cell Cycle Arrest, and Inhibition of PI3K/AKT and MEK/ERK Signalling Pathways. AB - BACKGROUND Laryngeal cancer is one of the major malignancies of the neck and head and is responsible for considerable mortality across the globe. The treatments for laryngeal cancer mainly involve surgical interventions followed by chemotherapy. However, due to unsatisfactory results, constant relapses and the adverse effects associated with the currently used drugs, there is pressing need to develop effective drug options for treatment of laryngeal cancer. Therefore, this study was undertaken to investigate the anticancer effects of a plant derived alkaloid, Mukonal, against human AMC-HN-8 laryngeal cancer cells. MATERIAL AND METHODS The WST-1 and clonogenic assays were employed to determine the cell viability. Apoptosis was detected by Hoechst and AO/EB staining. Cell migration and cell cycle analysis was performed by Transwell assay and flow cytometry, respectively. Protein expression was examined by Western blotting. RESULTS The results revealed that Mukonal reduced the viability of laryngeal cancer cells dose-dependently. The IC50 of Mukonal was found to be 10 uM. However, the effects of Mukonal on the normal HuLa-PC cells was found to be 140 uM. The decrease in the viability of the AMC-HN-8 laryngeal cancer cells was found to be due to the induction of apoptosis and G2/M cell cycle arrest. Mukonal also suppressed the cell migration and of the AMC-HN-8 laryngeal cancer cells. Mukonal could also inhibit the PI3K/AKT and MEK/ERK signalling pathways in a concentration-dependent manner. CONCLUSIONS Taken together, we conclude that Mukonal could prove a beneficial lead molecule for the treatment of laryngeal cancer. PMID- 30312288 TI - The effectiveness of joint mobilization techniques for range of motion in adult patients with primary adhesive capsulitis of the shoulder: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the effectiveness of joint mobilization techniques in the range of motion in adult patients with primary adhesive shoulder capsulitis. METHODS: Systematic review with meta-analysis. The search was performed in the MEDLINE/PubMed, PEDro, CENTRAL, LILACS, EMBASE, CINAHL, Scopus and Web of Science databases. The eligibility criteria were studies that used an oscillatory and/or maintained joint mobilization technique applied alone or added-on to a treatment program in patients with primary adhesive capsulitis at any stage. Two authors carried out the selection of studies and the extraction of data, independently. Risk of bias was evaluated according to the tool proposed by Cochrane. RESULTS: We included 14 studies with variable risk of bias. Posterior mobilization compared to any other technique was not significantly different (0.95 degrees; 95% CI: - 5.93 to 4.02), whereas compared to a control group, the difference is 26.80 degrees (CI 95%: 22.71 to 30.89). When applying a set of joint techniques versus a control group, for abduction the difference is 20.14 degrees (95% CI: 10.22 to 30.05). In both cases, the results are statistically significant, and the effect size is moderate. CONCLUSIONS: The evidence is not conclusive about the effectiveness of joint mobilization. When compared with treatments that do not include manual therapy, joint mobilization seems to have a favorable effect on the range of motion and pain reduction in patients with primary adhesive shoulder capsulitis. PMID- 30312289 TI - Medical consultation, time and duration. AB - This essay is a reflection of the time and duration of the medical consultation, seen as a social process that is determined by macro structures following the productive logic and the demands of modern time. The length of the medical discussion is heterogeneous worldwide; in contrast, what is standard is the perception of the professionals and the patients that the time for interaction is short. Such a perception pervades the doctor-patient relationship, perpetuating a cycle of dissatisfaction-tension-anxiety in these actors. Under the premise of the sociology of time and appealing to the ethical principles of medicine, we propose that the estimation in the length of a medical consultation must be considered. Time is indispensable for an adequate interaction to account for the needs of patients and professionals in a dignified manner since both have rights and obligations to be respected. PMID- 30312290 TI - What are the benefits and risks of total arthroplasty in arthrodesed knees? AB - INTRODUCTION: The conversion of a previously arthrodesed knee to a total knee arthroplasty is an alternative seldom used. However, arthroplasty would provide greater functionality to the arthrodesed joint. Since it is a technically demanding procedure, not exempt from complications, there is controversy about the role of this intervention. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews including 10 studies overall, none of which corresponded to a randomized trial. We concluded the conversion of knee arthrodesis to total knee arthroplasty could increase the functionality, but it is not clear whether it increases the complications or if it has any impact on pain or patient satisfaction because the certainty of the evidence is very low. PMID- 30312292 TI - Cell stimulation versus cell death induced by sequential treatments with pulsed electric fields and cold atmospheric pressure plasma. AB - Pulsed electric fields (PEFs) and cold atmospheric pressure plasma (CAP) are currently both investigated for medical applications. The exposure of cells to PEFs can induce the formation of pores in cell membranes and consequently facilitate the uptake of molecules. In contrast, CAP mainly acts through reactive species that are generated in the liquid environment. The objective of this study was to determine, if PEFs combined with plasma-treated cell culture medium can mutually reinforce effects on viability of mammalian cells. Experiments were conducted with rat liver epithelial WB-F344 cells and their tumorigenic counterpart WB-ras for a direct comparison of non-tumorigenic and tumorigenic cells from the same origin. Viability after treatments strongly depended on cell type and applied field strength. Notably, tumorigenic WB-ras cells responded more sensitive to the respective treatments than non-tumorigenic WB-F344 cells. More cells were killed when plasma-treated medium was applied first in combination with treatments with 100-MUs PEFs. For the reversed treatment order, i.e. application of PEFs first, the combination with 100-ns PEFs resulted in a stimulating effect for non-tumorigenic but not for tumorigenic cells. The results suggest that other mechanisms, besides simple pore formation, contributed to the mutually reinforcing effects of the two methods. PMID- 30312293 TI - Saving the horseshoe crab: A synthetic alternative to horseshoe crab blood for endotoxin detection. AB - Horseshoe crabs have been integral to the safe production of vaccines and injectable medications for the past 40 years. The bleeding of live horseshoe crabs, a process that leaves thousands dead annually, is an ecologically unsustainable practice for all four species of horseshoe crab and the shorebirds that rely on their eggs as a primary food source during spring migration. Populations of both horseshoe crabs and shorebirds are in decline. This study confirms the efficacy of recombinant Factor C (rFC), a synthetic alternative that eliminates the need for animal products in endotoxin detection. Furthermore, our findings confirm that the biomedical industry can achieve a 90% reduction in the use of reagents derived from horseshoe crabs by using the synthetic alternative for the testing of water and other common materials used in the manufacturing process. This represents an extraordinary opportunity for the biomedical and pharmaceutical industries to significantly contribute to the conservation of horseshoe crabs and the birds that depend on them. PMID- 30312291 TI - Genome amplification and cellular senescence are hallmarks of human placenta development. AB - Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) beta-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM. PMID- 30312294 TI - Antimicrobial peptides modulate long-term memory. AB - Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome. To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we found that Diptericin B, an immune peptide with antimicrobial activity, is upregulated following behavioral training. Deletion and knock down experiments revealed that Diptericin B and another immune peptide, Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. Interestingly, removal of DptB in the head fat body and GNBP-like3 in neurons results in memory deficit. That putative antimicrobial peptides influence memory provides an example of how some immune peptides may have been repurposed to influence the function of nervous system. PMID- 30312295 TI - The prognostic value of prognostic nutritional index in hepatocellular carcinoma patients: A meta-analysis of observational studies. AB - BACKGROUND AND AIMS: The clinical value of the prognostic nutritional index (PNI) in hepatocellular carcinoma (HCC) has been investigated in previous studies, but the results remain controversial. Here we present a meta-analysis to systematically review the association between PNI and HCC prognosis. METHOD: PubMed, EMBASE, Web of Science databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta analysis was performed to determine the prognostic and clinic-pathological values of PNI in HCC patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted to estimate the association of PNI with survival and clinic pathological characteristics, respectively. RESULTS: A total of eleven studies involving 3165 patients were analyzed. The pooled results indicated that low PNI is a significant predictor of poor 1-year, 3-year, 5-year OS (OR, 2.91, 4.05, 3.65; 95%CI, 2.30 to 3.70, 3.27 to 5.03,2.96-4.50; P = 0.14,0.22,0.11 respectively) and disease-free survival (DFS) (OR,2.35, 2.57, 2.75; 95%CI, 1.71 to 3.23, 1.89 to 3.49,2.01 to 3.75; P = 0.39,0.04,0.11, respectively). Moreover, PNI is significantly associated with serum AFP, tumor recurrence, tumor size and TNM stages in HCC patients. However, PNI is not significantly associated with tumor number and the incidence of cirrhosis in HCC patients. CONCLUSIONS: PNI is an independent predictive indicator of survival and associated with serum AFP, tumor recurrence, tumor size and TNM stages in HCC patients. PMID- 30312296 TI - Biogas residue parameterization for soil organic matter modeling. AB - A variety of biogas residues (BGRs) have been used as organic fertilizer in agriculture. The use of these residues affects the storage of soil organic matter (SOM). In most cases, SOM changes can only be determined in long-term observations. Therefore, predictive modeling can be an efficient alternative, provided that the parameters required by the model are known for the considered BGRs. This study was conducted as a first approach to estimating the organic matter (OM) turnover parameters of BGRs for process modeling. We used carbon mineralization data from six BGRs from an incubation experiment, representing a range of substrate inputs, to calculate a turnover coefficient k controlling the velocity of fresh organic matter (FOM) decay and a synthesis coefficient eta describing the SOM creation from FOM. An SOM turnover model was applied in inverse mode to identify both parameters. In a second step, we related the parameters k and eta to chemical properties of the corresponding BGRs using a linear regression model and applied them to a long-term scenario simulation. According to the results of the incubation experiment, the k values ranged between 0.28 and 0.58 d-1 depending on the chemical composition of the FOM. The estimated eta values ranged between 0.8 and 0.89. The best linear relationship of k was found to occur with pH (R2 = 0.863). Parameter eta is related to the Ct/Norg ratio (R2 = 0.696). Long-term scenario simulations emphasized the necessity of specific k and eta values related to the chemical properties for each BGR. However, further research is needed to validate and improve these preliminary results. PMID- 30312297 TI - Electrocardiographic left atrial abnormality and silent vascular brain injury: The Northern Manhattan Study. AB - HYPOTHESIS: We hypothesized that P wave terminal Force in the V1 lead (PTFV1) would be associated with leukoaraiosis and subclinical infarcts, especially cortical infarcts, in a population-based, multi-ethnic cohort. METHODS: PTFV1 was collected manually from baseline electrocardiograms of clinically stroke-free Northern Manhattan Study participants. Investigators read brain MRIs for superficial infarcts, deep infarcts, and white matter hyperintensity volume (WMHV). WMHV was adjusted for head size and log transformed, achieving a normal distribution. Logistic regression models investigated the association of PTFV1 with cortical and with all subclinical infarcts. Linear regression models examined logWMHV. Models were adjusted for demographics and risk factors. RESULTS: Among 1174 participants with PTFV1 measurements, the mean age at MRI was 70 +/- 9 years. Participants were 14.4% white, 17.6% black, and 65.8% Hispanic. Mean PTFV1 was 3587.35 +/- 2315.62 MUV-ms. Of the 170 subclinical infarcts, 40 were cortical. PTFV1 >= 5000 MUV-ms was associated with WMHV in a fully adjusted model (mean difference in logWMHV 0.15, 95% confidence interval 0.01-0.28). PTFV1 exhibited a trend toward an association with cortical infarcts (unadjusted OR per SD change logPTFV1 1.30, 95% CI 0.94-1.81), but not with all subclinical infarcts. CONCLUSION: Electrocardiographic evidence of left atrial abnormality was associated with leukoaraiosis. PMID- 30312298 TI - Longitudinal change in the diet's monetary value is associated with its change in quality and micronutrient adequacy among urban adults. AB - BACKGROUND: Reducing diet costs may lead to the selection of energy-dense foods, such as refined grains or foods high in added sugars and/or fats, which can lower overall dietary quality. We examined the longitudinal association between the monetary value of the diet (MVD) and the overall dietary quality across sex, race and income groups. METHODS AND FINDINGS: Longitudinal data from 1,466 adult urban participants from Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were used. Healthy Eating Index-2010 (HEI-2010) and Mean Adequacy Ratio (MAR) were computed and a national food price database was used to estimate MVD. Multiple linear regression analyses were conducted linking annual rates of change (Delta) in MVD to DeltaHEI-2010 and DeltaMAR, stratifying by sex, race and income groups. Among key findings, DeltaHEI-2010 was comparable across socio-demographic groups, while DeltaMAR was higher among women and individuals above poverty. Adjusting for key covariates, DeltaMVD was positively associated with both DeltaHEI-2010 and DeltaMAR, and with a consistently stronger association among individuals above poverty, specifically for the total proteins and empty calories components of HEI-2010 and several nutrient adequacy ratios (NARs: vitamins C, E, B-6 and Zinc). DeltaMVD-DeltaMAR association was stronger in women, mainly influenced by DeltaMVD's positive associations with B-vitamins, copper, calcium, magnesium and phosphorus NARs. DeltaMVD-Deltavitamin D NAR's positive relationship was stronger among Whites, while DeltaMVD-Deltavitamin B-12 NAR's association was stronger among African-Americans. CONCLUSIONS: In sum, a potential increase in MVD may have a stronger impact on dietary quality among urban adult women and above-poverty individuals. PMID- 30312299 TI - MutLgamma promotes repeat expansion in a Fragile X mouse model while EXO1 is protective. AB - The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5' end of the FMR1 gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2/MSH3 (MutSbeta) and MSH2/MSH6 (MutSalpha), together with Polbeta, a DNA polymerase important for base excision repair (BER), are important for expansions in a mouse model of these disorders. Here we show that MLH1/MLH3 (MutLgamma), a protein complex that can act downstream of MutSbeta in MMR, is also required for all germ line and somatic expansions. However, exonuclease I (EXO1), which acts downstream of MutL proteins in MMR, is not required. In fact, a null mutation in Exo1 results in more extensive germ line and somatic expansions than is seen in Exo1+/+ animals. Furthermore, mice homozygous for a point mutation (D173A) in Exo1 that eliminates its nuclease activity but retains its native conformation, shows a level of expansion that is intermediate between Exo1+/+ and Exo1-/- animals. Thus, our data suggests that expansion of the FX repeat in this mouse model occurs via a MutLgamma-dependent, EXO1-independent pathway, with EXO1 protecting against expansion both in a nuclease-dependent and a nuclease-independent manner. Our data thus have implications for the expansion mechanism and add to our understanding of the genetic factors that may be modifiers of expansion risk in humans. PMID- 30312300 TI - Estimating under-observation and the full size of the 2016 Zika epidemic in Rio de Janeiro. AB - The 2015-16 Zika epidemic spread quickly from north to south in Brazil. Two striking features were the much higher incidence in young adult women due to sexual transmission, and the serious congenital malformations and miscarriages associated to Zika infection in pregnant women. In this paper we use case reporting data along with live-birth records to reconstruct the full size of the epidemic through a Bayesian probabilistic graph model representing the Zika transmission probabilities of observation (case reporting) and of birth loss (through miscarriage or abortion). We find that the probability of observing (reporting) a Zika case is different between men and women and ranges between 10 to 13%. From these estimates we reconstruct the full size of the Zika epidemic in Rio de Janeiro in 2015-16. PMID- 30312301 TI - Risk factors for HTLV-1 infection in Central Africa: A rural population-based survey in Gabon. AB - BACKGROUND: Human T-Lymphotropic Virus type 1 (HTLV-1) is a human oncoretrovirus that infects at least 5 to 10 million people worldwide and is associated with severe diseases. Africa appears as the largest HTLV-1 endemic area. However, the risk factors for the acquisition of HTLV-1 remain poorly understood in Central Africa. METHODS: We conducted an epidemiological survey between 2013 and 2017, in rural areas of 6 provinces of Gabon, in a rainforest environment. Epidemiological data were obtained and blood samples were collected after informed consent. Plasma were screened for HTLV-1 antibodies by ELISA and the positive samples were then tested by Western blot (WB). Genomic DNA derived from buffy-coat was subjected to two semi-nested PCRs amplifying either HTLV-1 env gene or LTR region fragments. RESULTS: We recruited 2,060 individuals over 15 years old, including 1,205 men and 855 women (mean age: 49 years). Of these, 299 were found to be ELISA HTLV-1/2 seropositive. According to WB criteria, 136 were HTLV-1 (6.6%), 25 HTLV-1/2 (1.2%) and 9 HTLV seroreactive (0.4%). PCR results showed that 146 individuals were positive for at least one PCR: 104 for the env gene and 131 for the LTR region. Based on both serological and molecular results, 179 individuals were considered infected with HTLV-1, leading to an overall prevalence of 8.7%. The distribution of HTLV-1 infection was heterogeneous across the country. Based on multivariable analyses, female gender, increasing age, ethnicity (Pygmy) and multiple hospitalizations (more than 5 times) were found to be independent risk factors for HTLV-1 infection. Furthermore, a non-human primate bite appeared to be marginally associated with a higher risk of HTLV-1 infection. CONCLUSION: Based on state-of-the-art serological and molecular methods, we have demonstrated that rural adult populations in Gabon are highly endemic for HTLV-1. Our results regarding risk factors should lead to public health actions aiming to reduce HTLV 1 transmission. PMID- 30312302 TI - GPSuc: Global Prediction of Generic and Species-specific Succinylation Sites by aggregating multiple sequence features. AB - Lysine succinylation is one of the dominant post-translational modification of the protein that contributes to many biological processes including cell cycle, growth and signal transduction pathways. Identification of succinylation sites is an important step for understanding the function of proteins. The complicated sequence patterns of protein succinylation revealed by proteomic studies highlight the necessity of developing effective species-specific in silico strategies for global prediction succinylation sites. Here we have developed the generic and nine species-specific succinylation site classifiers through aggregating multiple complementary features. We optimized the consecutive features using the Wilcoxon-rank feature selection scheme. The final feature vectors were trained by a random forest (RF) classifier. With an integration of RF scores via logistic regression, the resulting predictor termed GPSuc achieved better performance than other existing generic and species-specific succinylation site predictors. To reveal the mechanism of succinylation and assist hypothesis driven experimental design, our predictor serves as a valuable resource. To provide a promising performance in large-scale datasets, a web application was developed at http://kurata14.bio.kyutech.ac.jp/GPSuc/. PMID- 30312303 TI - Differential profile of protein expression on human keratocytes treated with autologous serum and plasma rich in growth factors (PRGF). AB - PURPOSE: The main objective of this study is to compare the protein expression of human keratocytes treated with Plasma rich in growth factors (PRGF) or autologous serum (AS) and previously induced to myofibroblast by TGF-beta1 treatment. METHODS: Blood from healthy donor was collected and processed to obtain AS and PRGF eye drops. Blood derivates were aliquoted and stored at -80 degrees C until use. Keratocyte cells were pretreated for 60 minutes with 2.5 ng/ml TGF-beta1. After that, cells were treated with PRGF, AS or with TGF-beta1 (control). To characterize the proteins deregulated after PRGF and AS treatment, a proteomic approach that combines 1D-SDS-PAGE approach followed by LC-MS/MS was carried out. RESULTS: Results show a catalogue of key proteins in close contact with a myofibroblastic differentiated phenotype in AS treated-cells, whereas PRGF treated cells show attenuation on this phenotype. The number of proteins downregulated after PRGF treatment or upregulated in AS-treated cells suggest a close relationship between AS-treated cells and cytoskeletal functions. On the other hand, proteins upregulated after PRGF-treatment or downregulated in AS treated cells reveal a greater association with processes such as protein synthesis, proliferation and cellular motility. CONCLUSION: This proteomic analysis helps to understand the molecular events underlying AS and PRGF-driven tissue regeneration processes, providing new evidence that comes along with the modulation of TGF-beta1 activity and the reversion of the myofibroblastic phenotype by PRGF. PMID- 30312304 TI - Dynamic responses and implications to coastal wetlands and the surrounding regions under sea level rise. AB - Two distinct microtidal estuarine systems were assessed to advance the understanding of the coastal dynamics of sea level rise in salt marshes. A coupled hydrodynamic-marsh model (Hydro-MEM) was applied to both a marine dominated (Grand Bay, Mississippi) and a mixed fluvial/marine (Weeks Bay, Alabama) system to compute marsh productivity, marsh migration, and potential tidal inundation from the year 2000 to 2100 under four sea level rise scenarios. Characteristics of the estuaries such as geometry, sediment availability, and topography, were compared to understand their role in the dynamic response to sea level rise. The results show that the low sea level rise scenario (20 cm) approximately doubled high-productivity marsh coverage in the marine-dominated estuary by the year 2100 due to an equilibrium between the rates of sea level rise and marsh platform accretion. Under intermediate-low sea level rise (50 cm), high-productivity marsh coverage in the year 2100 increased (doubled in the marine-dominated estuary and a seven-fold increase in the mixed estuary) by expanding into higher lands followed by the creation of interior ponds. The results also indicate that marine-dominated estuaries are vulnerable to collapse as a result of low, relatively uniform topography and lack of sediment sources, whereas mixed estuaries are able to expand due to higher elevations and sediment inputs. The results from the higher sea level rise scenarios (the intermediate high (120 cm) and high (200 cm)) showed expansion of the bays along with marsh migration to higher land, producing a five-fold increase in wetland coverage for the mixed estuary and virtually no net change for the marine-dominated estuary. Additionally, hurricane storm surge simulations showed that under higher sea level rise scenarios, the marine-dominated estuary demonstrated weaker peak stage attenuation indicating that the marsh's ability to dissipate storm surge is sensitive to productivity changes and bay expansion / marsh loss. PMID- 30312305 TI - What to know before forecasting the flu. PMID- 30312307 TI - Topological vulnerability of power grids to disasters: Bounds, adversarial attacks and reinforcement. AB - Natural disasters like hurricanes, floods or earthquakes can damage power grid devices and create cascading blackouts and islands. The nature of failure propagation and extent of damage, among other factors, is dependent on the structural features of the grid, that are distinct from that of random networks. This paper analyzes the structural vulnerability of real power grids to impending disasters and presents intuitive graphical metrics to quantify the extent of topological damage. We develop two improved graph eigen-value based bounds on the grid vulnerability. Further we study adversarial attacks aimed at weakening the grid's structural robustness and present three combinatorial algorithms to determine the optimal topological attack. Simulations on power grid networks and comparison with existing work show the improvements of the proposed measures and attack schemes. PMID- 30312306 TI - Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction. AB - BACKGROUND: Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context. METHODS AND RESULTS: Cardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFbeta ligand expression, activated Smad2, and downregulation of STAT3 activity. CONCLUSIONS: Cardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage. PMID- 30312308 TI - Interoceptive awareness in attention deficit hyperactivity disorder. AB - ADHD is considered a disorder of self-regulation. Recent research has shown that awareness of bodily states, referred to as interoceptive awareness, crucially contributes to self-regulatory processes. Impaired self-regulation in ADHD has been explained in terms of arousal regulation deficits in ADHD (the state regulation deficit (SRD) account). There is now ample support for the SRD account, however the exact reason for arousal regulation difficulties is not yet known. The SRD account explicitly refers to the ability to monitor one's momentary bodily state as a prerequisite for effective state regulation. However, surprisingly, no study to date has tested the ability to become aware of bodily signals, i.e. interoceptive awareness, in ADHD. In the current study, we therefore compared interoceptive awareness between 24 adults with ADHD and 23 controls by means of both an objective (heartbeat perception task) and subjective measure (questionnaire) of interoceptive awareness. Results revealed a strikingly similar performance for both groups on both measures, suggesting preserved interoceptive awareness in adult ADHD. PMID- 30312309 TI - Is deployment of trained nurses to rural villages a remedy for the low skilled birth attendance in Ethiopia? A cluster randomized-controlled community trial. AB - BACKGROUND: Low coverage of Skilled Birth Attendance (SBA) is one of the major drivers of maternal mortality in many low- and middle-income countries (LMICs) including Ethiopia. We conducted a cluster-randomized controlled community trial to assess the effect of deploying trained community based nurses to rural communities on the uptake levels of SBA in Ethiopia. METHODS: A three-arm, parallel groups, cluster-randomized community trial was conducted to assess the effect of deploying trained community based reproductive health nurses (CORN) on the uptake of SBA services. A total of 282 villages were randomly selected and assigned to a control arm (n = 94) or 1 of 2 treatment arms (n = 94 each). The treatment groups differed by where these new service providers were deployed, a health post (HP) or health center (HC). Baseline and end line surveys were conducted to document and measure the effects of the intervention. Program impacts on SBA coverage were calculated using difference-in-difference (DID) analysis. RESULTS: After nine months of intervention, the coverage of SBA services increased significantly by 81.1% (from 24.61 to 44.59) in the HP based intervention arm, and by 122.9% (from 16.41 to 36.59) in the HC arm, respectively (p <0.01). Conversely, a small and non-significant (2%) decline in SBA coverage were observed in the control arm (P >0.05). The DID estimate indicated a net increase in SBA coverage of 21.32 and 20.52 percentage points (PP) across the HP and HC based intervention arms, respectively (p < 0.001). CONCLUSIONS: Deployment of trained reproductive health nurses to rural communities in Ethiopia significantly improved utilization of SBA services. Therefore; in similar low income settings where coverage of SBA services is very low, deployment of trained community based nurses to grassroots level could potentiate rapid service uptake. Additional cost-effectiveness and validation studies at various setups are required, before scale-up of the innovation, however. TRIAL REGISTRATION: clinicaltrails.gov NCT02501252. PMID- 30312310 TI - Diagnoses and time to recovery among injured recreational runners in the RUN CLEVER trial. AB - PURPOSE: The purpose of the present study was to describe the incidence proportion of different types of running-related injuries (RRI) among recreational runners and to determine their time to recovery. METHODS: A sub analysis of the injured runners included in the 839-person, 24-week randomized trial named Run Clever. During follow-up, the participants reported levels of pain in different anatomical areas on a weekly basis. In case injured, runners attended a clinical examination at a physiotherapist, who provided a diagnosis, e.g., medial tibial stress syndrome (MTSS), Achilles tendinopathy (AT), patellofemoral pain (PFP), iliotibial band syndrome (ITBS) and plantar fasciopathy (PF). The diagnose-specific injury proportions (IP) and 95% confidence intervals (CI) were calculated using descriptive statistics. The time to recovery was defined as the time from the first registration of pain until total pain relief in the same anatomical area. It was reported as medians and interquartile range (IQR) if possible. RESULTS: A total of 140 runners were injured at least once leading to a 24-week cumulative injury proportion of 32% [95% CI: 26%; 37%]. The diagnoses with the highest incidence proportion were MTSS (IP = 16% [95% CI: 9.3%; 22.9%], AT (IP = 8.9% [95% CI: 3.6%; 14.2%], PFP (IP = 8% [95% CI: 3.0%; 13.1%]. The median time to recovery for all types of injuries was 56 days (IQR = 70 days). Diagnose-specific time-to-recoveries included 70 days (IQR = 89 days) for MTSS, 56 days (IQR = 165 days) for AT, 49 days (IQR = 63 days) for PFP. CONCLUSION: The most common running injuries among recreational runners were MTSS followed by AT, PFP, ITBS and PF. In total, 77 injured participants recovered their RRI and the median time to recovery for all types of injuries was 56 days and MTSS was the diagnosis with the longest median time to recovery, 70 days. PMID- 30312311 TI - Rates of immune cell infiltration in patients with triple-negative breast cancer by molecular subtype. AB - In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) are associated with improved survival. Lehmann et al. identified 4 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor (LAR)], and an immunomodulatory (IM) gene expression signature indicates the presence of TILs and modifies these subtypes. The association between TNBC subtype and TILs is not known. Also, the association between inflammatory breast cancer (IBC) and the presence of TILs is not known. Therefore, we studied the IM subtype distribution among different TNBC subtypes. We retrospectively analyzed patients with TNBC from the World IBC Consortium dataset. The molecular subtype and the IM signature [positive (IM+) or negative (IM-)] were analyzed. Fisher's exact test was used to analyze the distribution of positivity for the IM signature according to the TNBC molecular subtype and IBC status. There were 88 patients with TNBC in the dataset, and among them 39 patients (44%) had IBC and 49 (56%) had non-IBC. The frequency of IM+ cases differed by TNBC subtype (p = 0.001). The frequency of IM+ cases by subtype was as follows: BL1, 48% (14/29); BL2, 30% (3/10); LAR, 18% (3/17); and M, 0% (0/21) (in 11 patients, the subtype could not be determined). The frequency of IM+ cases did not differ between patients with IBC and non-IBC (23% and 33%, respectively; p = 0.35). In conclusion, the IM signature representing the underlying molecular correlate of TILs in the tumor may differ by TNBC subtype but not by IBC status. PMID- 30312312 TI - Parental costs for in-patient neonatal services for perinatal asphyxia and low birth weight in Ghana. AB - The major causes of newborn deaths in sub-Saharan Africa are well-known and countries are gradually implementing evidence-based interventions and strategies to reduce these deaths. Facility-based care provides the best outcome for sick and or small babies; however, little is known about the cost and burden of hospital-based neonatal services on parents in West Africa, the sub-region with the highest global neonatal death burden. To estimate the actual costs borne by parents of newborns hospitalised with birth-associated brain injury (perinatal asphyxia) and preterm/low birth weight, this study examined economic costs using micro-costing bottom-up approach in two referral hospitals operating under the nationwide social health insurance scheme in an urban setting in Ghana. We prospectively assessed the process of care and parental economic costs for 25 out of 159 cases of perinatal asphyxia and 33 out of 337 cases of preterm/low birth weight admitted to hospital on the day of birth over a 3 month period. Results showed that medical-related costs accounted for 66.1% (IQR 49% - 81%) of out-of pocket payments irrespective of health insurance status. On average, families spent 8.1% and 9.1% of their annual income on acute care for preterm/LBW and perinatal asphyxia respectively. The mean out-of-pocket expenditure for preterm/LBW was $147.6 (median $101.8) and for perinatal asphyxia was $132.3 (median $124). The study revealed important gaps in the financing and organization of health service delivery that may impact the quality of care for hospitalised newborns. It also provides information for reviewing complementary health financing options for newborn services and further economic evaluations. PMID- 30312313 TI - Microbial community structure and functional potential of lava-formed Gotjawal soils in Jeju, Korea. AB - The Gotjawal areas of Jeju Island, Korea, are comprised of unmanaged forests growing on volcanic soils. They support unique assemblages of vascular plants from both northern and southern hemispheres, but are threatened by human disturbance. The health and ecosystem function of these assemblages likely depends in part on the diversity and community structure of soil microbial communities, about which little is known. To assess the diversity of Gotjawal soil microbial communities, twenty samples were collected in November 2010 from 4 representatives of Gotjawal forests. While soil properties and microbial communities measured by 16S rRNA gene sequence data were marginally distinct among sites by PERMANOVA (p = 0.017-0.191), GeoChip data showed significant differences among sites (p <0.006). Gene composition overall, and the composition of 3 functional gene categories had similar structures themselves and similar associations with environmental factors. Among these communities, phosphorous cycling genes exhibited the most distinct patterns. 16S rRNA gene sequence data resulted in a mean 777 operational taxonomic units (OTUs), which included the following major phyla: Proteobacteria (27.9%), Actinobacteria (17.7%), Verrucomicrobia (14.3%), Acidobacteria (9.6%), Planctomycetes (9.8%), Bacteroidetes (8.9%), and Chloroflexi (2.2%). Indicator species analysis (ISA) was used to determine the taxa with high indicator value, which represented the following: uncultured Chlamydiaceae, Caulobacter, uncultured Sinobacteraceae, Paenibacillus, Arenimonas, Clostridium sensu.stricto, uncultured Burkholderiales incertae sedis, and Nocardioides in Aewol (AW), Aquicella, uncultured Planctomycetia, and Aciditerrimonas in Gujwa-Seongsan (GS), uncultured Acidobacteria Gp1, and Hamadaea in Hankyeong-Andeok (HA), and Bosea, Haliea, and Telmatocola in Jocheon-Hamdeok (JH) Gotjawal. Collectively, these results demonstrated the uniqueness of microbial communities within each Gotjawal region, likely reflecting different patterns of soil, plant assemblages and microclimates. PMID- 30312314 TI - Reverse pneumatic artificial muscles (rPAMs): Modeling, integration, and control. AB - Despite offering many advantages over traditional rigid actuators, soft pneumatic actuators suffer from a lack of comprehensive, computationally efficient models and precise embedded control schemes without bulky flow-control valves and extensive computer hardware. In this article, we consider an inexpensive and reliable soft linear actuator, called the reverse pneumatic artificial muscle (rPAM), which consists of silicone rubber that is radially constrained by symmetrical double-helix threading. We describe analytical and numerical static models of this actuator, and compare their performance against experimental results. To study the application of rPAMs to operate underlying kinematic linkage skeletons, we consider a single degree-of-freedom revolute joint that is driven antagonistically by two of these actuators. An analytical model is then derived, and its accuracy in predicting the static joint angle as a function of input pressures is presented. Using this analytical model, we perform dynamic characterization of this system. Finally, we propose a sliding-mode controller, and a sliding mode controller augmented by a feed-forward term to modulate miniature solenoid valves that control air flow to each actuator. Experiments show that both controllers function well, while the feed-forward term improves the performance of the controller following dynamic trajectories. PMID- 30312315 TI - State dependence of stimulus-induced variability tuning in macaque MT. AB - Behavioral states marked by varying levels of arousal and attention modulate some properties of cortical responses (e.g. average firing rates or pairwise correlations), yet it is not fully understood what drives these response changes and how they might affect downstream stimulus decoding. Here we show that changes in state modulate the tuning of response variance-to-mean ratios (Fano factors) in a fashion that is neither predicted by a Poisson spiking model nor changes in the mean firing rate, with a substantial effect on stimulus discriminability. We recorded motion-sensitive neurons in middle temporal cortex (MT) in two states: alert fixation and light, opioid anesthesia. Anesthesia tended to lower average spike counts, without decreasing trial-to-trial variability compared to the alert state. Under anesthesia, within-trial fluctuations in excitability were correlated over longer time scales compared to the alert state, creating supra Poisson Fano factors. In contrast, alert-state MT neurons have higher mean firing rates and largely sub-Poisson variability that is stimulus-dependent and cannot be explained by firing rate differences alone. The absence of such stimulus induced variability tuning in the anesthetized state suggests different sources of variability between states. A simple model explains state-dependent shifts in the distribution of observed Fano factors via a suppression in the variance of gain fluctuations in the alert state. A population model with stimulus-induced variability tuning and behaviorally constrained information-limiting correlations explores the potential enhancement in stimulus discriminability by the cortical population in the alert state. PMID- 30312316 TI - Host genetics and the rumen microbiome jointly associate with methane emissions in dairy cows. AB - Cattle and other ruminants produce large quantities of methane (~110 million metric tonnes per annum), which is a potent greenhouse gas affecting global climate change. Methane (CH4) is a natural by-product of gastro-enteric microbial fermentation of feedstuffs in the rumen and contributes to 6% of total CH4 emissions from anthropogenic-related sources. The extent to which the host genome and rumen microbiome influence CH4 emission is not yet well known. This study confirms individual variation in CH4 production was influenced by individual host (cow) genotype, as well as the host's rumen microbiome composition. Abundance of a small proportion of bacteria and archaea taxa were influenced to a limited extent by the host's genotype and certain taxa were associated with CH4 emissions. However, the cumulative effect of all bacteria and archaea on CH4 production was 13%, the host genetics (heritability) was 21% and the two are largely independent. This study demonstrates variation in CH4 emission is likely not modulated through cow genetic effects on the rumen microbiome. Therefore, the rumen microbiome and cow genome could be targeted independently, by breeding low methane-emitting cows and in parallel, by investigating possible strategies that target changes in the rumen microbiome to reduce CH4 emissions in the cattle industry. PMID- 30312317 TI - A guide to using a multiple-matrix animal model to disentangle genetic and nongenetic causes of phenotypic variance. AB - Non-genetic influences on phenotypic traits can affect our interpretation of genetic variance and the evolutionary potential of populations to respond to selection, with consequences for our ability to predict the outcomes of selection. Long-term population surveys and experiments have shown that quantitative genetic estimates are influenced by nongenetic effects, including shared environmental effects, epigenetic effects, and social interactions. Recent developments to the "animal model" of quantitative genetics can now allow us to calculate precise individual-based measures of non-genetic phenotypic variance. These models can be applied to a much broader range of contexts and data types than used previously, with the potential to greatly expand our understanding of nongenetic effects on evolutionary potential. Here, we provide the first practical guide for researchers interested in distinguishing between genetic and nongenetic causes of phenotypic variation in the animal model. The methods use matrices describing individual similarity in nongenetic effects, analogous to the additive genetic relatedness matrix. In a simulation of various phenotypic traits, accounting for environmental, epigenetic, or cultural resemblance between individuals reduced estimates of additive genetic variance, changing the interpretation of evolutionary potential. These variances were estimable for both direct and parental nongenetic variances. Our tutorial outlines an easy way to account for these effects in both wild and experimental populations. These models have the potential to add to our understanding of the effects of genetic and nongenetic effects on evolutionary potential. This should be of interest both to those studying heritability, and those who wish to understand nongenetic variance. PMID- 30312318 TI - Characterising antibody avidity in individuals of varied Mycobacterium tuberculosis infection status using surface plasmon resonance. AB - There is increasing evidence supporting a role for antibodies in protection against tuberculosis (TB), with functional antibodies being described in the latent state of TB infection. Antibody avidity is an important determinant of antibody-mediated protection. This study characterised the avidity of antibodies against Ag85A, an immunodominant Mycobacterium tuberculosis (M.tb) antigen and constituent of several anti-TB vaccine candidates, in individuals of varied M.tb infection status. Avidity of Ag85A specific antibodies was measured in 30 uninfected controls, 34 individuals with latent TB infection (LTBI) and 75 active pulmonary TB (APTB) cases, employing the more commonly used chaotrope-based dissociation assays, and surface plasmon resonance (SPR). Chaotrope-based assays indicated that APTB was associated with a higher antibody avidity index compared to uninfected controls [adjusted geometric mean ratio (GMR): 1.641, 95% confidence interval (CI): 1.153, 2.337, p = 0.006, q = 0.018] and to individuals with LTBI [adjusted GMR: 1.604, 95% CI: 1.282, 2.006, p < 0.001, q <0.001]. SPR assays showed that APTB was associated with slower dissociation rates, an indication of higher avidity, compared to uninfected controls (adjusted GMR: 0.796, 95% CI: 0.681, 0.932, p = 0.004, q = 0.012) and there was also weak evidence of more avid antibodies in the LTBI compared to the uninfected controls (adjusted GMR: 0.871, 95% CI: 0.763, 0.994, p = 0.041, q = 0.123). We found no statistically significant differences in anti-Ag85A antibody avidity between the APTB and LTBI groups. This study shows that antibodies of increased avidity are generated against a principle vaccine antigen in M.tb infected individuals. It would be important to determine whether TB vaccines are able to elicit a similar response. Additionally, more research is needed to determine whether antibody avidity is important in protection against infection and disease. PMID- 30312319 TI - Repetitive transcranial magnetic stimulation for the treatment of Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) may have a beneficial effect in Alzheimer's disease (AD). Nevertheless, the clinical benefit of rTMS for AD remains inconclusive. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of rTMS in AD. METHODS: We searched PubMed, Embase and Cochrane for randomized controlled trials (RCTs) of rTMS for AD. We calculated pooled estimates of mean difference (MD) with 95% confidence intervals (CI). The protocol was registered at International Prospective Register of Systematic Reviews (PROSPERO) (number CRD42018089990). RESULTS: Five RCTs involving 148 participants were included in this review. Compared with sham stimulation, high frequency rTMS led to a significant improvement in cognition as measured by ADAS cog (MD = -3.65, 95% CI -5.82 to -1.48, p = 0.001), but not MMSE (MD = 0.49, 95% CI -1.45 to 2.42, p = 0.62). High-frequency rTMS also improved the global impression in comparison to the placebo (MD = -0.79, 95% CI -1.24 to -0.34, p = 0.0006). There was no significant difference in mood (MD = -1.36, 95% CI -3.93 to 1.21, p = 0.30) and functional performance (MD = 0.59, 95% CI -1.21 to 2.38, p = 0.52) between high-frequency rTMS and sham groups. Only one trial included low frequency rTMS reported no significant improvement in cognition, mood and functional performance. Few mild adverse events were observed in both the rTMS and sham groups. CONCLUSIONS: RTMS is relatively well tolerated, with some promise for cognitive improvement and global impression in patients with AD. Our findings also indicate the variability between ADAS-cog and MMSE in evaluating global cognitive impairment. PMID- 30312320 TI - P16INK4a expression in patients with penile cancer. AB - BACKGROUND: Infection with human papillomavirus (HPV) is reported to be present in 30-50% of penile cancer cases. The immunohistochemical test for p16INK4a is used as an indicator of the presence of HPV and as a prognostic marker for squamous cell carcinomas in various sites. However, the role of this marker in penile carcinoma has not yet been completely elucidated. The aim of this study was to analyze whether the expression of p16INK4a is associated with the presence of HPV, histological parameters, and survival in penile cancer. METHODS: A study was conducted from 2014 to 2016 that included 55 patients with penile carcinoma. HPV DNA was detected through PCR using fresh tumor tissue, and immunohistochemistry was performed for analysis of p16INK4a protein using paraffin-embedded tissue. Evaluation of histological parameters was performed following complete embedding of the tumor tissue in paraffin. RESULTS: HPV DNA (low-risk and high-risk genotypes) was found in 49 (89.1%) cases, and 46/49 (93.9%) showed high-oncogenic risk HPV (HR-HPV). Of the 22 cases positive for p16INK4a, HR-HPV DNA was present in 21 (95.5%) (p = 0.032). Regarding histological parameters, p16INK4a and HR-HPV were significantly associated only with tumor subtype (p = 0.036 and p = 0.032, respectively); all carcinomas with basaloid characteristics were positive for p16INK4a. Although HPV+ patients had a higher disease-free survival (p <0.001), p16INK4a expression was not associated with patient survival. CONCLUSIONS: Our study, using fresh tissue samples, showed the highest incidence of HPV compared to that observed in the literature. Expression of the p16INK4a protein was significantly associated with the presence of HR-HPV and this expression may serve as a marker for the presence of the virus. The p16INK4a protein was not associated with the histological prognostic parameters, with the exception of tumor subtype, nor with patient survival. In the results, we showed that the objective of the present study was reached. PMID- 30312321 TI - Hemodynamics and pathology of an enlarging abdominal aortic aneurysm model in rabbits. AB - Hemodynamics may play an essential role in the initiation and progression of abdominal aortic aneurysm (AAA). We aimed to study the mechanism of self-healing process by the changes of hemodynamics and pathology in an enlarging AAA in rabbits. Seventy-two rabbits were randomly divided into three groups. Rabbits underwent extrinsic coarctation and received a 10-minute elastase incubation in Group A and Group B. Absorbable suture used in Group A was terminated by balloon dilation at week 4. Diameter was measured after 1, 3, 5, and 15 weeks, computational fluid dynamics analysis was performed at week 3 and week 15. Rabbits were sacrificed after 1, 5, and 15 weeks for pathological and quantitative studies. The higher velocity magnitude, intensified bulk flow and obvious vortex formation were observed in Group A at week 3 instead of week 15. Both low wall shear stress and high relative residence time increased in Group B, however, high oscillatory shear index had relatively less increase compared with Group A. Aortic diameter reached a plateau at 5 weeks in Group A, which was significantly lower than in week 15 in Group B. Intimal hyperplasia, intima-media thickness increased significantly in Group A at week 5, significantly higher than in week 15 in Group B. Marked destruction of elastin fibers and smooth muscle cells occurred at week 1, and increased significantly at week 15 in Group A. Aneurysm exhibited strong expression of matrix metalloproteinase 9 and mouse anti rabbit macrophage 11 at week 1, and showed a tendency to decrease. Matrix metalloproteinase 2 expression decreased significantly in Group B at week 15 compared with week 5 and Group A. In conclusion, the self-healing of rabbit AAA may attributed to the regeneration of smooth muscle cells. The turbulence flow caused by coarctation is associated with continuous growth of rabbit AAA and prevents the self-healing phenomenon. PMID- 30312322 TI - Morphological diversity of Quercus fossil pollen in the northern South China Sea during the last glacial maximum and its paleoclimatic implication. AB - We aimed to obtain high resolution vegetation data and climate information about the LGM in the inland of the northern SCS based on key pollen types. Dominant Quercus fossil pollen grains in the core from the continental shelf of the northern SCS have been identified at the infrageneric level by using scanning electron microscopy. Based on tectum ornamentation, we recognized five sculpture types of Quercus pollen, namely, rodlike, rodlike masked, rodlike vertical, verrucate and micro-verrucate. Such a high diversity of Quercus fossil pollen types indicated that broadleaved forests were widely distributed in the inland along the northern SCS and included species of the subgenera Cyclobalanopsis and Quercus, of which subgenus Cyclobalanopsis populations were highly dominant. Low abundance of deciduous Quercus pollen probably derived from temperate-subtropical forests, while abundant evergreen pollen types of subgenura Quercus and Cyclobalanopsis, as well as other pollen of broadleaved taxa in the pollen assemblages, strongly suggest that the inland has been covered by dense subtropical forests. Consequently, the warm and humid subtropical climate prevailed during the LGM in the inland along the northern SCS. Our results shed new light on regional climatic conditions during the LGM in eastern Asia based on high diversity of Quercus fossil pollen in marine deposits from northern SCS. PMID- 30312323 TI - Renal function and blood pressure in 11 year old children born extremely preterm or small for gestational age. AB - BACKGROUND: Preterm birth and low birth weight are associated with reduced nephron numbers and increased risk of hypertension and kidney disease in later life. AIMS: We tested the hypothesis that extremely preterm birth and intrauterine growth restriction is associated with decreased renal function in mid childhood. METHODS: At 11 years of age the following measures were obtained in a regional cohort of children born extremely premature (EP, i.e. < 28 weeks gestational age-GA) or with extremely low birth weight (ELBW, i.e. BW < 1000 grams) and in matched controls born at term with appropriate BW (AGA): Height, weight, abdominal circumference, triceps and subscapular skin fold thicknesses, blood pressure, plasma levels of creatinine, cystatin C and symmetric dimethyl arginine (SDMA). Small for gestational age (SGA) was defined as a BW < 10th percentile for GA. Glomerular filtration rate (GFR) was estimated according to the equations by Schwartz, Zappitelli and Gao. RESULTS: Fifty-seven of 61 eligible EP/ELBW children, 20 (35%) born SGA, and 54 controls, were assessed. Estimated GFR decreased while plasma SDMA increased from the children born AGA at term through those born preterm AGA to preterm SGA. Systolic BP was correlated to fat mass indices (p<0.03), but not to renal function (p>0.2) and did not differ between the groups. CONCLUSIONS: Children born EP/ELBW, particularly those born SGA, had impaired renal function at age 11 years as judged from estimated GFRs and plasma levels of SDMA. Since reduced renal function is associated with an increased risk of later disease, these children should be followed in order to minimize additional risk factors. PMID- 30312324 TI - SNPSelect: A scalable and flexible targeted sequence-based genotyping solution. AB - In plant breeding the use of molecular markers has resulted in tremendous improvement of the speed with which new crop varieties are introduced into the market. Single Nucleotide Polymorphism (SNP) genotyping is routinely used for association studies, Linkage Disequilibrium (LD) and Quantitative Trait Locus (QTL) mapping studies, marker-assisted backcrosses and validation of large numbers of novel SNPs. Here we present the KeyGene SNPSelect technology, a scalable and flexible multiplexed, targeted sequence-based, genotyping solution. The multiplex composition of SNPSelect assays can be easily changed between experiments by adding or removing loci, demonstrating their content flexibility. To demonstrate this versatility, we first designed a 1,056-plex maize assay and genotyped a total of 374 samples originating from an F2 and a Recombinant Inbred Line (RIL) population and a maize germplasm collection. Next, subsets of the most informative SNP loci were assembled in 384-plex and 768-plex assays for further genotyping. Indeed, selection of the most informative SNPs allows cost-efficient yet highly informative genotyping in a custom-made fashion, with average call rates between 88.1% (1,056-plex assay) and 99.4% (384-plex assay), and average reproducibility rates between duplicate samples ranging from 98.2% (1056-plex assay) to 99.9% (384-plex assay). The SNPSelect workflow can be completed from a DNA sample to a genotype dataset in less than three days. We propose SNPSelect as an attractive and competitive genotyping solution to meet the targeted genotyping needs in fields such as plant breeding. PMID- 30312326 TI - Sensor-based measurement of critical care nursing workload: Unobtrusive measures of nursing activity complement traditional task and patient level indicators of workload to predict perceived exertion. AB - OBJECTIVE: To establish the validity of sensor-based measures of work processes for predicting perceived mental and physical exertion of critical care nurses. MATERIALS AND METHODS: Repeated measures mixed-methods study in a surgical intensive care unit. Wearable and environmental sensors captured work process data. Nurses rated their mental (ME) and physical exertion (PE) for each four hour block, and recorded patient and staffing-level workload factors. Shift was the grouping variable in multilevel modeling where sensor-based measures were used to predict nursing perceptions of exertion. RESULTS: There were 356 work hours from 89 four-hour shift segments across 35 bedside nursing shifts. In final models, sensor-based data accounted for 73% of between-shift, and 5% of within shift variance in ME; and 55% of between-shift, and 55% of within-shift variance in PE. Significant predictors of ME were patient room noise (beta = 0.30, p < .01), the interaction between time spent and activity levels outside main work areas (beta = 2.24, p < .01), and the interaction between the number of patients on an insulin drip and the burstiness of speaking (beta = 0.19, p < .05). Significant predictors of PE were environmental service area noise (beta = 0.18, p < .05), and interactions between: entropy and burstiness of physical transitions (beta = 0.22, p < .01), time speaking outside main work areas and time at nursing stations (beta = 0.37, p < .001), service area noise and time walking in patient rooms (beta = -0.19, p < .05), and average patient load and nursing station speaking volume (beta = 0.30, p < .05). DISCUSSION: Analysis yielded highly predictive models of critical care nursing workload that generated insights into workflow and work design. Future work should focus on tighter connections to psychometric test development methods and expansion to a broader variety of settings and professional roles. CONCLUSIONS: Sensor-based measures are predictive of perceived exertion, and are viable complements to traditional task demand measures of workload. PMID- 30312325 TI - Fatigue interventions in long term, physical health conditions: A scoping review of systematic reviews. AB - OBJECTIVE: Fatigue is prominent across many long term physical health conditions. This scoping review aimed to map the fatigue intervention literature, to ascertain if certain interventions may be effective across conditions, and if novel interventions tested in specific long term conditions may be promising for other conditions. METHODS: Scoping review methodological frameworks were used. Electronic bibliographic databases were searched (inception to November 2016) for systematic reviews of fatigue interventions in long term conditions. Inclusion criteria were: long term physical health condition; review focus on fatigue management; objective and systematic review process; primary review outcome is fatigue. Articles focussing on surgical interventions or treatments thought to trigger fatigue were excluded. A narrative synthesis was performed. RESULTS: Of 115 full texts screened, 52 reviews were included. Interventions were categorised as pharmacological and non-pharmacological (exercise, psychological/behavioural and complementary medicine). Pharmacological interventions did not consistently demonstrate benefit, except for anti-TNFs and methylphenidate which may be effective at reducing fatigue. Non-pharmacological interventions such as graded exercise and fatigue-specific psychological interventions may be effective, but heterogeneous intervention components limit conclusions. 'Complementary medicine' interventions (e.g. Chinese herbal medicines) showed promise, but the possibility of publication bias must be considered. CONCLUSIONS: Further research is necessary to inform clinical practice. The reported effectiveness of some interventions across inflammatory health conditions, such as anti-TNFs, aerobic exercise, and psychologically based approaches such as CBT, highlights a potential transdiagnostic avenue for fatigue management. More novel strategies that may be worth exploring include expressive writing and mindfulness, although the mechanisms for these in relation to fatigue are unclear. More work is needed to identify transdiagnostic mechanisms of fatigue and to design interventions based on these. PMID- 30312327 TI - Early life adversity diminishes the cortisol response to opioid blockade in women: Studies from the Family Health Patterns project. AB - Early life adversity (ELA) contributes to behavioral impulsivity along with risk for substance use disorders, both accompanied by blunted stress-axis reactivity. However, the biological contributors to blunted stress reactivity are not known. We took advantage of the fact that women have significant opioid inhibition of cortisol output by using the opioid antagonist, naltrexone, to unmask opioid interactions due to ELA. We administered 50 mg of naltrexone or placebo to 72 healthy women (23 years of age) in a double-blind crossover study and observed deviations in cortisol secretion from placebo over the next 180 minutes. ELA was assessed by reported exposure to physical and sexual abuse or neglect and low socioeconomic status and scored as Low, Medium, or High (0, 1-2, and 3+). The ELA groups all had identical placebo-day cortisol secretion, indicating normal basal regulation of the hypothalamic-pituitary-adrenocortical axis. Cortisol rises to naltrexone were largest in the Low-ELA group and strongly blunted in the High-ELA group (F = 3.51, p = 0.035), indicating a lack of opioid function in women with high degrees of ELA. The Low-ELA women reported dysphoric responses to naltrexone (F = 4.05, p = .022) indicating a mild opioid withdrawal, an effect that was absent in the High-ELA group. Women exposed to ELA have blunted cortisol responses to naltrexone, indicating reduced opioid regulation of the stress axis. Central opioid changes may be one pathway linking ELA to blunted stress reactivity in adulthood. PMID- 30312328 TI - Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene. AB - The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. The NHE III1 region of the c-MYC promoter forms a DNA quadruplex. Stabilization of this structure with small molecules has been shown to reduce expression of c-MYC, and targeting the c-MYC quadruplex has become an emerging strategy for development of antitumor compounds. Previous solution NMR studies of the c-MYC quadruplex have assigned the major conformer and topology of this important target, however, regions outside the G-quartet core were not as well-defined. Here, we report a high-resolution crystal structure (2.35 A) of the major quadruplex formed in the NHE III1 region of the c-MYC promoter. The crystal structure is in general agreement with the solution NMR structure, however, key differences are observed in the position of nucleotides outside the G-quartet core. The crystal structure provides an alternative model that, along with comparisons to other reported quadruplex crystal structures, will be important to the rational design of selective compounds. This work will aid in development of ligands to target the c MYC promoter quadruplex with the goal of creating novel anticancer therapies. PMID- 30312329 TI - Trust as a mechanism of system justification. AB - People are motivated to hold favorable attitudes about the systems on which they depend, so they justify (i.e., rationalize, defend and bolster) forms of social and economic inequality, even if the inequality is disadvantageous to them. This paper examines how this system-justifying motivation is reflected in behaviors involving interpersonal trust. In a series of three experiments using the trust game I manipulate income inequality by providing participants with higher (advantaged position) or lower (disadvantaged position) initial endowments and measure their trust toward individuals on the same or on different positions. Results show that higher income individuals trust other higher income individuals more than lower income individuals (ingroup favoritism), while lower income individuals trust higher income individuals more than lower income individuals (outgroup favoritism). It is also shown that the strength of these biases is dependent on the level of endorsement of system justifying ideology and the legitimacy of the system. More trust toward those in advantaged positions within a social system, expressed both by equally advantaged as well as by disadvantaged others, not only secures the advantaged in their positions but also reinforces the underlying inequality. PMID- 30312330 TI - The association between major complications of immobility during hospitalization and quality of life among bedridden patients: A 3 month prospective multi-center study. AB - PURPOSE: To describe the association between major complications of immobility (pressure ulcer, pneumonia, deep vein thrombosis and urinary tract infection) during hospitalization and the patients' health-related quality of life after discharge. METHODS: The data were obtained from a multi-center study conducted in 2015. Complications of immobility during hospitalization was measured by case report form and quality of life after discharge was measured using the EQ-5D scale by telephone interview. Multilevel mixed-effects models were used to explore the association of complications and responses in the EQ-5D dimensions after controlling for important covariates. RESULTS: Among the 20,515 bedridden patients, 2,601(12.72%) patients experienced at least one of the major complications of immobility during hospitalization, including pressure ulcer (527, 2.57%), deep vein thrombosis (343, 1.67%), pneumonia (1647, 8.16%), and urinary tract infection (265, 1.29%). Patients with any of the four complications during hospitalization reported more problems in all EQ-5D dimensions except for pain/discomfort, and had lower mean EQ-VAS scores than those without any complications. The four complications all showed significant associations with the proportion of reported problems in certain dimensions after adjustment for confounding variables. CONCLUSIONS: Major complications of immobility were significantly associated with reduced health related quality of life. Prevention of complications is critical to reduce the burden of decreased quality of life for bedridden patients. PMID- 30312331 TI - PCANet based nonlocal means method for speckle noise removal in ultrasound images. AB - Speckle reduction remains a critical issue for ultrasound image processing and analysis. The nonlocal means (NLM) filter has recently attached much attention due to its competitive despeckling performance. However, the existing NLM methods usually determine the similarity between two patches by directly utilizing the gray-level information of the noisy image, which renders it difficult to represent the structural similarity of ultrasound images effectively. To address this problem, the NLM method based on the simple deep learning baseline named PCANet is proposed by introducing the intrinsic features of image patches extracted by this network rather than the pixel intensities into the pixel similarity computation. In this approach, the improved two-stage PCANet is proposed by using Parametric Rectified Linear Unit (PReLU) activation function instead of the binary hashing and block histograms in the original PCANet. This model is firstly trained on the ultrasound database to learn the convolution kernels. Then, the trained PCANet is utilized to extract the intrinsic features from the image patches in the pre-denoised version of the noisy image to be despeckled. These obtained features are concatenated together to determine the structural similarity between image patches in the NLM method, based on which the weighted mean of all pixels in a search window is computed to produce the final despeckled image. Extensive experiments have been conducted on a variety of images to demonstrate the superiority of the proposed method over several well known despeckling algorithm and the PCANet based NLM method using ReLU function and sigmoid function. Visual inspection indicates that the proposed method outperforms the compared methods in reducing speckle noise and preserving image details. The quantitative comparisons show that among all the evaluated methods, our method produces the best structural similarity index metrics (SSIM) values for the synthetic image, as well as the highest equivalent number of looks (ENL) value for the simulated image and the clinical ultrasound images. PMID- 30312332 TI - A discourse analysis of the macro-structure, metadiscoursal and microdiscoursal features in the abstracts of research articles across multiple science disciplines. AB - The abstract of a scientific research article convinces readers that the article deserves to be read. Abstracts can also determine the success of publications and grant applications. In recent years, there has been a trend of cross-disciplinary collaborations in the science community. Scientists have been increasingly expected to engage not only experts of their own disciplines, but also other disciplines with the scope of interest extending to non-experts, such as policy makers and the general public. Thus, the macro-structure, metadiscoursal and microdiscoursal features exhibited in scientific article abstracts merit attention. In our study, we examined 500 abstracts of scientific research articles published in 50 high-impact journals across five science disciplines (Earth, Formal, Life, Physical and Social Sciences), and performed quantitative analysis of the move structure as well as use of boosters and linguistic features. We found significant interdisciplinary variations in the move structure, boosters and linguistic features employed by these science disciplines. We confirmed that each science discipline possesses a distinct set of macro-structural, metadiscoursal and formalization features, which contribute to its own unique discipline-specific convention. Understanding and observing the disciplinary rhetorical choices and communication conventions will allow scientists to align the abstracts of their studies with the expectations of the targeted audience. PMID- 30312333 TI - Qualitative case study of needle exchange programs in the Central Appalachian region of the United States. AB - BACKGROUND: The Central Appalachian region of the United States is in the midst of a hepatitis C virus epidemic driven by injection of opioids, particularly heroin, with contaminated syringes. In response to this epidemic, several needle exchange programs (NEP) have opened to provide clean needles and other supplies and services to people who inject drugs (PWID). However, no studies have investigated the barriers and facilitators to implementing, operating, and expanding NEPs in less populous areas of the United States. METHODS: This qualitative case study consisted of interviews with program directors, police chiefs, law enforcement members, and PWID affiliated with two NEPs in the rural state of West Virginia. Interview transcripts were coded inductively and analyzed using qualitative data analysis software. Final common themes related to barriers and facilitators of past program openings, current program operations, and future program plans, were derived through a consensus of two data coders. RESULTS: Both NEPs struggled to find existing model programs, but benefited from broad community support that facilitated implementation. The largest operational barrier was the legal conundrum created by paraphernalia laws that criminalize syringe possession. However, both PWID and law enforcement appreciated the comprehensive services provided by these programs. Program location and transportation difficulties were additional noted barriers. Future program operations are threatened by funding shortages and bans, but necessitated by unexpected program demand. CONCLUSION: Despite broad community support, program operations are threatened by growing participant volumes, funding shortages, and the federal government's prohibition on the use of funds to purchase needles. Paraphernalia laws create a legal conundrum in the form of criminal sanctions for the possession of needles, which may inadvertently promote needle sharing and disease transmission. Future studies should examine additional barriers to using clean needles provided by rural NEPs that may blunt the effectiveness of NEPs in preventing disease transmission. PMID- 30312334 TI - In vitro transport of methotrexate by Drosophila Multidrug Resistance-associated Protein. AB - Methotrexate (MTX) is a widely used chemotherapeutic agent, immune suppressant and antimalarial drug. It is a substrate of several human ABC proteins that confer multidrug resistance to cancer cells and determine compartmentalization of a wide range of physiological metabolites and endo or xenobiotics, by their primary active transport across biological membranes. The substrate specificity and tissue distribution of these promiscuous human ABC transporters show a high degree of redundancy, providing robustness to these key physiological and pharmacological processes, such as the elimination of toxins, e.g. methotrexate from the body. A similar network of proteins capable of transporting methotrexate has been recently suggested to exist in Drosophila melanogaster. One of the key players of this putative network is Drosophila Multidrug-resistance Associated Protein (DMRP). DMRP has been shown to be a highly active and promiscuous ABC transporter, capable of transporting various organic anions. Here we provide the first direct evidence that DMRP, expressed alone in a heterologous system lacking other, potentially functionally overlapping D. melanogaster organic anion transporters, is indeed able to transport methotrexate. Our in vitro results support the hypothesized but debated role of DMRP in in vivo methotrexate excretion. PMID- 30312336 TI - Pre-exposure prophylaxis among men who have sex with men in the Amsterdam Cohort Studies: Use, eligibility, and intention to use. AB - OBJECTIVE: Currently, HIV pre-exposure prophylaxis (PrEP) is not covered by health insurance in the Netherlands. We examined time trends in use of PrEP, characteristics of PrEP users, PrEP eligibility and intention to use PrEP among HIV-negative men who have sex with men (MSM) participating in the Amsterdam Cohort Studies (ACS). DESIGN: Prospective cohort study. METHODS: We used data from four 6-monthly questionnaire waves, collected between 2015-2017. PrEP use over time was examined in logistic regression models using generalized estimating equations. Using descriptive statistics, we compared PrEP users before first-time initiation to non-PrEP-users. We used national guidelines to assess PrEP eligibility. RESULTS: We included 687 MSM. Median age was 40 (IQR 33-47) years in 2015. Recent PrEP use was reported by 57/687 (8%) MSM. PrEP use increased over calendar time (P<0.001) to 7% in 2017. PrEP users did not differ from non-PrEP users in socio-demographic characteristics, but reported a significantly higher median number of casual sex partners, more often reported condomless anal sex and chemsex with casual partners, and more often had an sexually transmitted infection in the preceding 6 months (all P<0.05). PrEP eligibility increased over time, but the effect was not statistically significant (P = 0.075). PrEP eligibility criteria were met by 149/460 (32%) at wave 4, of whom 31/149 (21%) reported use of PrEP. The proportion with a high intention to use PrEP was greater among eligible than non-eligible MSM (51% vs. 24%, P<0.001). CONCLUSION: PrEP use increased over time but remained under 10%, even though 32% met the eligibility criteria, of whom 51% had a high intention to use PrEP. This suggests that a large proportion of Dutch MSM at risk could benefit from PrEP. PMID- 30312337 TI - Reduction of response time by data placement reflecting co-occurrence structures in structured overlay networks. AB - We propose a method to accelerate a response of structured overlay networks by reducing the number of hops required to answer multi-queries. In the proposed method, by copying data items to the redundant storage spaces in other storages, a good data placement reflecting co-occurrence structures in the structured overlay network is achieved. We formulate the optimization problem of the data placement in the limited redundant space of the storages as an integer programming. A greedy approach to solve the optimization problem is also proposed. Through several simulations, it is confirmed that the proposed method can reduce the average number of hops required to answer multi-queries by about 30% at the maximum in our simulation settings. The reduction rate of the average number of hops depends on the level of co-occurrence. Further, the reduction of the computation time to solve the optimization problem with the greedy approach is evaluated. We also confirm that the proposed method does not affect load balancing of structured overlay networks. PMID- 30312335 TI - The added value of whole-body magnetic resonance imaging in the management of patients with advanced breast cancer. AB - This study investigates the impact of whole-body MRI (WB-MRI) in addition to CT of chest-abdomen-pelvis (CT-CAP) and 18F-FDG PET/CT (PET/CT) on systemic treatment decisions in standard clinical practice for patients with advanced breast cancer (ABC). WB-MRI examinations in ABC patients were extracted from our WB-MRI registry (2009-2017). Patients under systemic treatment who underwent WB MRI and a control examination (CT-CAP or PET/CT) were included. Data regarding progressive disease (PD) reported either on WB-MRI or on the control examinations were collected. Data regarding eventual change in treatment after the imaging evaluation were collected. It was finally evaluated whether the detection of PD by any of the two modalities had induced a change in treatment. Among 910 WB-MRI examinations in ABC patients, 58 had a paired control examination (16 CT-CAP and 42 PET/CT) and were analysed. In 23/58 paired examinations, additional sites of disease were reported only on WB-MRI and not on the control examination. In 17/28 paired examinations, PD was reported only on WB-MRI and not on the control examination. In 14 out of the 28 pairs of examinations that were followed by a change in treatment, PD had been reported only on WBMRI (14/28; 50%), while stable disease had been reported on the control examination. In conclusion, WB MRI disclosed PD earlier than the control examination (CT-CAP or PET/CT), and it was responsible alone for 50% of all changes in treatment. PMID- 30312339 TI - Predictive performance of regression models to estimate Chlorophyll-a concentration based on Landsat imagery. AB - Chlorophyll-a (Chl-a) concentration is a key parameter to describe water quality in marine and freshwater environments. Nowadays, several products with Chl-a have derived from satellite imagery, but they are not available or reliable sometimes for coastal and/or small water bodies. Thus, in the last decade several methods have been described to estimate Chl-a with high-resolution (30 m) satellite imagery, such as Landsat, but a standardized method to estimate Chl-a from Landsat imagery has not been accepted yet. Therefore, this study evaluated the predictive performance of regression models (Simple Linear Regression [SLR], Multiple Linear Regression [MLR] and Generalized Additive Models [GAMs]) to estimate Chl-a based on Landsat imagery, using in situ Chl-a data collected (synchronized with the overpass of Landsat 8 satellite) and spectral reflectance in the visible light portion (bands 1-4) and near infrared (band 5). These bands were selected because of Chl-a absorbance/reflectance properties in these wavelengths. According to goodness of fit, GAM outperformed SLR and MLR. However, the model validation showed that MLR performed better in predicting log transformed Chl-a. Thus, MLR, constructed by using four spectral bands (1, 2, 3, and 5), was considered the best method to predict Chl-a. The coefficients of this model suggested that log-transformed Chl-a concentration had a positive linear relationship with bands 1 (coastal/aerosol), 3 (green), and 5 (NIR). On the other hand, band 2 (blue) suggested a negative relationship, which implied high coherence with Chl-a absorbance/reflectance properties measured in the laboratory, indicating that Landsat 8 images could be applied effectively to estimate Chl-a concentrations in coastal environments. PMID- 30312338 TI - How primary health care teams perceive the integration of oral health care into their practice: A qualitative study. AB - Recently, new models for the integration of oral health into primary care have been proposed. However, these models may be adopted by a variety of health care systems, and will reach successful outcomes only if they can be adapted to suit the local context. To this end, the objective of this study was to explore the perceptions of Quebec primary health care teams on the integration of oral health into primary care. A qualitative approach and interpretive description methodology were used to conduct the study within a case-study design. Purposeful sampling with maximum variation and snowball technique were used for recruitment of study participants. Seventy-four in-depth, semi-structured interviews and five focus groups were conducted with primary health care teams including health care providers and managers working in a rural and an urban health care center. The interview guide and study conceptual framework were based on the Rainbow model. Data collection and data analyses were conducted concurrently and continued until saturation was achieved. To analyze the data, four phases of qualitative analysis were followed. The thematic analysis included interview debriefing, transcript coding, data display, and interpretation. Data analysis was conducted both manually and with the use of Atlas-ti software. A total of four themes emerged from the interviews and focus group discussions. These themes covered all domains of the study theoretical model and included: 1) drivers of integration; 2) importance of integration; 3) professionals' role in integrated care; and 4) barriers and enablers of integration. In general, most of the barriers expressed by study participants were related to the organizational and system domains of integration. Primary health care teams who provide care in rural and urban areas in Quebec expressed their concerns on the absence of integrated oral health services. Implementation of governance policies, the prioritization of educational and management measures as well as inter-professional collaboration toward innovative care models could facilitate this integration. PMID- 30312340 TI - Bananas decrease acetaminophen potency in in vitro assays. AB - Edible portions of bananas contain high levels of polyphenol oxidase, which catalyzes reactions in the melanin formation pathway. Tyrosine, a physiological substrate of polyphenol oxidase, has an analogous structure to acetaminophen. We investigated whether banana extract causes structural changes in acetaminophen and a decrease in its potency. Acetaminophen concentration in banana extract was measured under different conditions to characterize incompatibility. Reaction products in solution were identified using liquid chromatography/electrospray ionization/mass spectrometry (LC/ESI/MS). Acetaminophen potency decreased with time in the presence of banana extract. The reaction proceeded most efficiently in temperatures 30-37 degrees C and neutral to weakly acidic conditions. Molecular ion peaks derived from the oxidized catechol moiety of acetaminophen were identified in LC/ESI/MS spectra. Our findings suggest that incorporation or simultaneous administration of acetaminophen medication and banana juice may result in decreased efficacy of the clinically important drug. This interaction is likely due to the oxidation of acetaminophen by polyphenol oxidase activity in banana pulp. Therefore, we investigated and characterized a novel interaction between bananas and acetaminophen. To establish a safe and effective antipyretic analgesic regimen using acetaminophen, future studies of this interaction are expected to be performed in humans. PMID- 30312341 TI - Threat of establishment of non-indigenous potato blackleg and tuber soft rot pathogens in Great Britain under climate change. AB - Potato blackleg and soft rot caused by Pectobacterium and Dickeya species are among the most significant bacterial diseases affecting potato production globally. In this study we estimate the impact of future temperatures on establishment of non-indigenous but confirmed Pectobacterium and Dickeya species in Great Britain (GB). The calculations are based on probabilistic climate change data and a model fitted to disease severity data from a controlled environment tuber assay with the dominant potato blackleg and soft rot-causing species in GB (P. atrosepticum), and three of the main causative agents in Europe (P. carotovorum subsp. brasiliense, P. parmentieri, Dickeya solani). Our aim was to investigate if the European strains could become stronger competitors in the GB potato ecosystem as the climate warms, on the basis of their aggressiveness in tubers at different temperatures. Principally, we found that the tissue macerating capacity of all four pathogens will increase in GB under all emissions scenarios. The predominant Pectobacterium and Dickeya species in Europe are able to cause disease in tubers under field conditions currently seen in GB but are not expected to become widely established in the future, at least on the basis of their aggressiveness in tubers relative to P. atrosepticum under GB conditions. Our key take-home messages are that the GB potato industry is well positioned to continue to thrive via current best management practices and continued reinforcement of existing legislation. PMID- 30312342 TI - Challenges to conquer from the gender perspective in medicine: The case of spondyloarthritis. AB - BACKGROUND: Diagnostic delay is well-known in spondyloarthritis and studies have demonstrated a longer deferral in women. The aim of this study was to explore whether diagnostic delay of spondyloarthritis depends on clinical manifestations expressed by patients according to sex or whether it is related to a doctor's misdiagnosis bias. METHODS: A cross-sectional study of 96 men and 54 women with spondyloarthritis was performed at Alicante University General Hospital in Spain using a semistructured interview and clinical records. Comparative sex analysis were done via Student's T and Mann-Whitney U tests for parametric and nonparametric continuous variables, chi-square and Fisher's exact tests for unpaired categorical variables, and McNemar's test for paired ones. FINDINGS: The median diagnostic delay in women 7.5 (11.5) years is higher than men 4 (11) years, with a difference close to statistical significance (p = 0.053). A total of 30.2% of men received a first correct diagnosis of spondyloarthritis versus 11.1% of women (p = 0.016), indicating that men have higher probability of not having a misdiagnosis of spondyloarthritis (odds ratio = 3.5; 1.3-9). Eleven different health services referred male patients to the rheumatology clinic but only six in the case of female. No sex differences were detected in patients' manifestations of back pain at onset. However, medical records registered differences (women 44.4%, men 82.1%; p < 0.001). There were differences between patients (women 57.7%, men 35.2%; p = 0.008) and medical records in peripheral signs/symptoms at onset (women 55.6%, men 17.9%; p < 0.001). CONCLUSION: The few differences of self-reported manifestations between both sexes with spondyloarthritis as compared with their clinical records (more axial pain in men and more peripheral pain in women) suggests that the professionals' annotations reflect what they expect according to Literature, which could explain the higher misdiagnosis and diagnostic delay in women with spondyloarthritis. PMID- 30312343 TI - Sexual health of young people with perinatal HIV and HIV negative young people in England. AB - As adolescents with perinatal HIV (PHIV) survive into adulthood, gaining insight into sexual behaviour and risk-taking is important. Between 2013-2015, 296 PHIV aged 13-21 years and 96 HIV negative affected adolescents (13-23 years) were recruited to the Adolescents and Adults Living with Perinatal HIV (AALPHI) cohort in England. Sexual health data were collected through computer-assisted self interview questionnaires. Quality of life and household deprivation were also measured. T-tests compared means, and chi2 proportions; logistic regression examined predictors of ever having sex. 120(41%) PHIV and 31(32%) HIV- young people were male, 254(86%) and 70(73%) were black, median age 16 [IQR 15,18] and 16 [14,18] years respectively. 77(26%) PHIV had a previous AIDS diagnosis. 93(32%) PHIV and 38(40%) HIV- had ever had sex; median number of partners was 3 [1,6] and 4 [1,6] respectively. 54 (41%) of 131 young people who were sexually active reported not always using condoms, including 32% (30/93) of PHIV. In multivariable analysis, older age, male sex, worse deprivation score, worse quality of life, and alcohol and/or drugs were associated with ever having sex, but not HIV status. 12/30 PHIV reporting unprotected sex had at least one HIV viral load >=200c/ml in the previous 12 months. Age at first sex and number of sexual partners were similar among PHIV and HIV-, and comparable to normative data. In conclusion, small numbers of PHIV reported condomless sex with a detectable viral load, which could result in HIV transmission, indicating the need for targeted sexual health and ART adherence interventions for young people with perinatal HIV. PMID- 30312345 TI - Attribute-based encryption scheme with multi-keyword search and supporting attribute revocation in cloud storage. AB - We propose an attribute-based encryption scheme with multi-keyword search and supporting attribute revocation in cloud storage environment, in which binary attributes and AND-gate access policy are used. Our proposal enjoys several advantages. Firstly, multi-keyword search is available, and only when a data user's attribute set satisfies access policy in keyword index, and keyword token generated by data user matches index successfully, then data user can obtain ciphertext containing keywords. In this way, more accurate keyword search is achievable. Secondly, the search privacy of data user is protected owing to cloud servers cannot obtain any knowledge of keywords which data user is interested in. Meanwhile, the ciphertext is able to be decrypted when data user's attribute set satisfies access policy specified in the ciphertext, which can both improve security of encryption and achieve secure fine-grained access control. Thirdly, the proposed scheme supports attribute revocation, in our scheme when a data user's attribute is revoked, the version number of attribute, non-revoked data users' secret keys and related ciphertexts will be updated, such that data user whose attribute is revoked does not decrypt updated ciphertext anymore. In addition, based on the assumption of decisional linear (DL) and decisional Diffie Hellman (DDH), our scheme is proved to be secure against selectively chosen keyword attacks and selectively chosen-plaintext attacks respectively, and it also ensures token privacy security. PMID- 30312344 TI - Severity of clinical dry eye manifestations influences protein expression in tear fluid of patients with primary Sjogren's syndrome. AB - Ocular dryness is a characteristic feature of primary Sjogren's syndrome (pSS). This may result in dry eye disease (DED), leading to damage of the ocular surface. Additional, non-invasive diagnostic techniques are needed when evaluating pSS patients. Hence, screening for disease-specific biomarkers in biological fluid could be promising. We have previously examined the proteome of tear fluid from pSS patients through Liquid chromatography-mass spectrometry (LC MS), and conducted a thorough ocular evaluation of patients with pSS. In this study we further explored the association between dry eye manifestations and protein expression in tear fluid of pSS patients. Medical history of 27 patients and 32 healthy controls was gathered. Subjective complaints were registered through questionnaires. Objective findings including tear osmolarity, tear film break up time (TFBUT), Schirmer's test, and ocular and corneal surface staining were also recorded. LC-MS was conducted formerly on tear fluid from all subjects in order to generate proteomic biomarker profiles. Scaffold was employed to analyse the LC-MS data for quantitative differences between patient and control groups, and the mean spectral counts were calculated for the five most upregulated proteins in relation to DED manifestations. Dysregulated cellular processes were identified in pSS patients using FunRichv3 enrichment analysis. The five most upregulated proteins previously identified in pSS patients were DNA (apurinic or apyrimidinic site) lyase (APEX1), thioredoxin-dependent peroxidase reductase (PRDX3), copine (CPNE1), aconitate hydratase (ACO2), and LIM domain only protein 7 (LMO7), in descending order. A significant increase in mean spectral counts for these proteins were observed in pSS patients with pathological DED manifestations compared to healthy controls (p<0.0001). Consequently, dysregulated cellular pathways involving innate and adaptive immunity were also detected. In conclusion, our observations suggest a relationship between presence of dry eye signs and upregulated proteins in tear fluid from patients with pSS. Further studies are needed in order to replicate the concepts explored and analyses performed in a greater cohort of pSS patients, where sensitivity and specificity of the methods conducted can also be verified further. PMID- 30312347 TI - Correction: The evolution of cost-efficiency in neural networks during recovery from traumatic brain injury. AB - [This corrects the article DOI: 10.1371/journal.pone.0170541.]. PMID- 30312346 TI - Sucrose-induced stomatal closure is conserved across evolution. AB - As plants evolved to function on land, they developed stomata for effective gas exchange, for photosynthesis and for controlling water loss. We have recently shown that sugars, as the end product of photosynthesis, close the stomata of various angiosperm species, to coordinate sugar production with water loss. In the current study, we examined the sugar responses of the stomata of phylogenetically different plant species and species that employ different photosynthetic mechanisms (i.e., C3, C4 and CAM). To examine the effect of sucrose on stomata, we treated leaves with sucrose and then measured their stomatal apertures. Sucrose reduced stomatal aperture, as compared to an osmotic control, suggesting that regulation of stomata by sugars is a trait that evolved early in evolutionary history and has been conserved across different groups of plants. PMID- 30312349 TI - Beliefs about people with albinism in Uganda: A qualitative study using the Common-Sense Model. AB - Albinism includes a group of inherited conditions that result in reduced melanin production. It has been documented across the world, with a high frequency in sub Saharan Africa. There is very little published research about the lives of people with albinism, but available evidence shows that myths abound regarding their condition. They are feared, viewed with suspicion and believed to have supernatural powers. In this study we explored the links between beliefs, myths, traditions and positive/negative attitudes that surround people with albinism in Uganda. The study was located philosophically within Ubuntu-an Afrocentric worldview-and theoretically within the Common-Sense Model of self-regulation of health and illness that originates from the work of Leventhal in 2003. This qualitative study took place in eight districts of Busoga sub-region, Uganda between 2015 and 2017. Data collection comprised eight group discussions and 17 individual interviews with a range of informants, capturing the viewpoints of 73 participants. Findings lend support to previous research, highlighting the life time discrimination and disadvantage experienced by many people with albinism. It shows that there is still much to be done to address the pervasive and potentially harmful beliefs and misconceptions about people with albinism. PMID- 30312348 TI - The catalytic role of Mystery Patient tools in shaping patient experience: A method to facilitate value co-creation using action research. AB - Improving patients' experience in hospitals necessitates the improvement of service quality. Using mystery patients as a tool for assessing and improving patients' experience is praised for its comprehensiveness. However, such programs are costly, difficult to design and may cause unintended negative consequences if poorly implemented. Following an Action Research theoretical framework, the aim of this study is to utilize the Mystery Patient (MP) for engaging the patient in co-creating valuable non-clinical services and producing guidance about future managerial interventions. This was operationalized at the Outpatient Clinics at a large Academic Hospital in the Middle East region whereby 18 Mystery Patients conducted 66 visits to clinics and filled out 159 questionnaires. The results indicated higher scores on hard criteria or skills (technical), such as personal image and professionalism, and lower scores on soft criteria (interpersonal), including "compassion" and "courtesy". The data also demonstrated how the MP tool could provide targeted information that can point to future interventions at any one of the patient experience core pillars, namely: process, setting, and employees. This paves the way for another cycle of spiral learning, and consequently, a continuous process of organizational learning and development around service provision. The MP tool can play the role of the catalyst that accelerates the value co-creation process of patient experience by directing management to necessary interventions at the three pillars of patient experience: employees, processes, and setting. PMID- 30312350 TI - Functional network connectivity is altered in patients with upper limb somatosensory impairments in the acute phase post stroke: A cross-sectional study. AB - BACKGROUND: Aberrant functional connectivity in brain networks associated with motor impairment after stroke is well described, but little is known about the association with somatosensory impairments. AIM: The objective of this cross sectional observational study was to investigate the relationship between brain functional connectivity and severity of somatosensory impairments in the upper limb in the acute phase post stroke. METHODS: Nineteen first-ever stroke patients underwent resting-state functional magnetic resonance imaging (rs-fMRI) and a standardized clinical somatosensory profile assessment (exteroception and higher cortical somatosensation) in the first week post stroke. Integrity of inter- and intrahemispheric (ipsilesional and contralesional) functional connectivity of the somatosensory network was assessed between patients with severe (Em-NSA< 13/32) and mild to moderate (Em-NSA> 13/32) somatosensory impairments. RESULTS: Patients with severe somatosensory impairments displayed significantly lower functional connectivity indices in terms of interhemispheric (p = 0.001) and ipsilesional intrahemispheric (p = 0.035) connectivity compared to mildly to moderately impaired patients. Significant associations were found between the perceptual threshold of touch assessment and interhemispheric (r = -0.63) and ipsilesional (r = -0.51) network indices. Additional significant associations were found between the index of interhemispheric connectivity and light touch (r = 0.55) and stereognosis (r = 0.64) evaluation. CONCLUSION: Patients with more severe somatosensory impairments have lower inter- and ipsilesional intrahemispheric connectivity of the somatosensory network. Lower connectivity indices are related to more impaired exteroception and higher cortical somatosensation. This study highlights the importance of network integrity in terms of inter- and ipsilesional intrahemispheric connectivity for somatosensory function. Further research is needed investigating the effect of therapy on the re-establishment of these networks. PMID- 30312351 TI - Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques. AB - For many pathogens, including most targets of effective vaccines, infection elicits an immune response that confers significant protection against reinfection. There has been significant debate as to whether natural Mycobacterium tuberculosis (Mtb) infection confers protection against reinfection. Here we experimentally assessed the protection conferred by concurrent Mtb infection in macaques, a robust experimental model of human tuberculosis (TB), using a combination of serial imaging and Mtb challenge strains differentiated by DNA identifiers. Strikingly, ongoing Mtb infection provided complete protection against establishment of secondary infection in over half of the macaques and allowed near sterilizing bacterial control for those in which a secondary infection was established. By contrast, boosted BCG vaccination reduced granuloma inflammation but had no impact on early granuloma bacterial burden. These findings are evidence of highly effective concomitant mycobacterial immunity in the lung, which may inform TB vaccine design and development. PMID- 30312352 TI - Assessment of heterosis in two Arabidopsis thaliana common-reference mapping populations. AB - Hybrid vigour, or heterosis, has been of tremendous importance in agriculture for the improvement of both crops and livestock. Notwithstanding large efforts to study the phenomenon of heterosis in the last decades, the identification of common molecular mechanisms underlying hybrid vigour remain rare. Here, we conducted a systematic survey of the degree of heterosis in Arabidopsis thaliana hybrids. For this purpose, two overlapping Arabidopsis hybrid populations were generated by crossing a large collection of naturally occurring accessions to two common reference lines. In these Arabidopsis hybrid populations the range of heterosis for several developmental and yield related traits was examined, and the relationship between them was studied. The traits under study were projected leaf area at 17 days after sowing, flowering time, height of the main inflorescence, number of side branches from the main stem or from the rosette base, total seed yield, seed weight, seed size and the estimated number of seeds per plant. Predominantly positive heterosis was observed for leaf area and height of the main inflorescence, whereas mainly negative heterosis was observed for rosette branching. For the other traits both positive and negative heterosis was observed in roughly equal amounts. For flowering time and seed size only low levels of heterosis were detected. In general the observed heterosis levels were highly trait specific. Furthermore, no correlation was observed between heterosis levels and the genetic distance between the parental lines. Since all selected lines were a part of the Arabidopsis genome wide association (GWA) mapping panel, a genetic mapping approach was applied to identify possible regions harbouring genetic factors causal for heterosis, with separate calculations for additive and dominance effects. Our study showed that the genetic mechanisms underlying heterosis were highly trait specific in our hybrid populations and greatly depended on the genetic background, confirming the elusive character of heterosis. PMID- 30312353 TI - Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model. AB - : The ryanodine receptor antagonist dantrolene inhibits calcium release from the sarcoplasmic reticulum and reduces cardiac ischaemia-reperfusion injury (IRI) in global warm ischaemia models however the cardioprotective potential of dantrolene under hypothermic conditions is unknown. This study addresses whether the addition of dantrolene during cardioplegia and hypothermic storage of the donor heart can improve functional recovery and reduce IRI. Using an ex vivo isolated working heart model, Wistar rat (3 month and 12 month) hearts were perfused to acquire baseline haemodynamic measurements of aortic flow, coronary flow, cardiac output, pulse pressure and heart rate. Hearts were arrested and stored in Celsior preservation solution supplemented with 0.2-40 MUM dantrolene for 6 hours at 4 degrees C, then reperfused (15 min Langendorff, 30 min working mode). In 3-month hearts, supplementation with 1 MUM dantrolene significantly improved aortic flow and cardiac output compared to unsupplemented controls however lactate dehydrogenase (LDH) release and contraction bands were comparable. In contrast, 40 MUM dantrolene-supplementation yielded poor cardiac recovery, increased post reperfusion LDH but reduced contraction bands. All 3-month hearts stored in dantrolene displayed significantly reduced cleaved-caspase 3 intensities compared to controls. Analysis of cardioprotective signalling pathways showed no changes in AMPKalpha however dantrolene increased STAT3 and ERK1/2 signaling in a manner unrelated to functional recovery and AKT activity was reduced in 1 MUM dantrolene stored hearts. In contrast to 3-month hearts, no significant improvements were observed in the functional recovery of 12-month hearts following prolonged storage in 1 MUM dantrolene. CONCLUSIONS: Dantrolene supplementation at 1 MUM during hypothermic heart preservation improved functional recovery of young, but not older (12 month) hearts. Although the molecular mechanisms responsible for dantrolene-mediated cardioprotection are unclear, our studies show no correlation between improved functional recovery and SAFE and RISK pathway activation. PMID- 30312354 TI - Identification of a strawberry NPR-like gene involved in negative regulation of the salicylic acid-mediated defense pathway. AB - Hormonal modulation plays a central role in triggering various resistant responses to biotic and abiotic stresses in plants. In cultivated strawberry (Fragaria x ananassa), the salicylic acid (SA)-dependent defense pathway has been associated with resistance to Colletotrichum spp. and the other pathogens. To better understand the SA-mediated defense mechanisms in strawberry, we analyzed two strawberry cultivars treated with SA for their resistance to anthracnose and gene expression profiles at 6, 12, 24, and 48 hr post-treatment. Strawberry genes related to SA biosynthesis, perception, and signaling were identified from SA responsive transcriptomes of the two cultivars, and the induction of 17 candidate genes upon SA treatment was confirmed by qRT-PCR. Given the pivotal role of the non-expressor of pathogenesis-related (NPR) family in controlling the SA-mediated defense signaling pathway, we then analyzed NPR orthologous genes in strawberry. From the expression profile, FaNPRL-1 [ortholog of FvNPRL-1 (gene20070 in F. vesca)] was identified as an NPR-like gene significantly induced after SA treatment in both cultivars. With a conserved BTB/POZ domain, ankyrin repeat domain, and nuclear localization signal, FvNPRL-1 was found phylogenetically closer to NPR3/NPR4 than NPR1 in Arabidopsis. Ectopic expression of FvNPRL-1 in the Arabidopsis thaliana wild type suppressed the SA-mediated PR1 expression and the resistance to Pseudomonas syringae pv. tomato DC3000. Transient expression of FvNPRL-1 fused with green fluorescent protein in Arabidopsis protoplasts showed that SA affected nuclear translocation of FvNPRL-1. FvNPRL-1 likely functions similar to Arabidopsis NPR3/NPR4 as a negative regulator of the SA-mediated defense. PMID- 30312355 TI - Standardized guinea pig model for Q fever vaccine reactogenicity. AB - Historically, vaccination with Coxiella burnetii whole cell vaccines has induced hypersensitivity reactions in humans and animals that have had prior exposure to the pathogen as a result of infection or vaccination. Intradermal skin testing is routinely used to evaluate exposure in humans, and guinea pig hypersensitivity models have been developed to characterize the potential for reactogenicity in vaccine candidates. Here we describe a refinement of the guinea pig model using an alternate vaccine for positive controls. An initial comparative study used viable C. burnetii to compare the routes of sensitizing exposure of guinea pigs (intranasal vs intraperitoneal), evaluation of two time points for antigen challenge (21 and 42 days) and an assessment of two routes (intradermal and subcutaneous) of challenge using the ruminant vaccine Coxevac as the antigenic control. Animals sensitized by intraperitoneal exposure exhibited slightly larger gross reactions than did those sensitized by intranasal exposure, and reactions were more pronounced when skin challenge was performed at 42 days compared to 21 days post-sensitization. The intradermal route proved to be the optimal route of reactogenicity challenge. Histopathological changes at injection sites were similar to those previously reported and a scoring system was developed to compare reactions between groups receiving vaccine by intradermal versus subcutaneous routes. Based on the comparative study, a standardized protocol for assessment of vaccine reactogenicity in intranasally-sensitized animals was tested in a larger confirmatory study. Results suggest that screens utilizing a group size of n = 3 would achieve 90% power for detecting exposure-related reactogenic responses of the magnitude induced by Coxevac using either of two outcome measures. PMID- 30312356 TI - A wheat cytochrome P450 enhances both resistance to deoxynivalenol and grain yield. AB - The mycotoxin deoxynivalenol (DON) serves as a plant disease virulence factor for the fungi Fusarium graminearum and F. culmorum during the development of Fusarium head blight (FHB) disease on wheat. A wheat cytochrome P450 gene from the subfamily CYP72A, TaCYP72A, was cloned from wheat cultivar CM82036. TaCYP72A was located on chromosome 3A with homeologs present on 3B and 3D of the wheat genome. Using gene expression studies, we showed that TaCYP72A variants were activated in wheat spikelets as an early response to F. graminearum, and this activation was in response to the mycotoxic Fusarium virulence factor deoxynivalenol (DON). Virus induced gene silencing (VIGS) studies in wheat heads revealed that this gene family contributes to DON resistance. VIGS resulted in more DON-induced discoloration of spikelets, as compared to mock VIGS treatment. In addition to positively affecting DON resistance, TaCYP72A also had a positive effect on grain number. VIGS of TaCYP72A genes reduced grain number by more than 59%. Thus, we provide evidence that TaCYP72A contributes to host resistance to DON and conclude that this gene family warrants further assessment as positive contributors to both biotic stress resistance and grain development in wheat. PMID- 30312357 TI - Weak power frequency magnetic fields induce microtubule cytoskeleton reorganization depending on the epidermal growth factor receptor and the calcium related signaling. AB - We have shown previously that a weak 50 Hz magnetic field (MF) invoked the actin cytoskeleton, and provoked cell migration at the cell level, probably through activating the epidermal growth factor receptor (EGFR) related motility pathways. However, whether the MF also affects the microtubule (MT)-cytoskeleton is still unknown. In this article, we continuously investigate the effects of 0.4 mT, 50 Hz MF on the MT, and try to understand if the MT effects are also associated with the EGFR pathway as the actin-cytoskeleton effects were. Our results strongly suggest that the MF effects are similar to that of EGF stimulation on the MT cytoskeleton, showing that 1) the MF suppressed MT in multiple cell types including PC12 and FL; 2) the MF promoted the clustering of the EGFR at the protein and the cell levels, in a similar way of that EGF did but with higher sensitivity to PD153035 inhibition, and triggered EGFR phosphorylation on sites of Y1173 and S1046/1047; 3) these effects were strongly depending on the Ca2+ signaling through the L-type calcium channel (LTCC) phosphorylation and elevation of the intracellular Ca2+ level. Strong associations were observed between EGFR and the Ca2+ signaling to regulate the MF-induced-reorganization of the cytoskeleton network, via phosphorylating the signaling proteins in the two pathways, including a significant MT protein, tau. These results strongly suggest that the MF activates the overall cytoskeleton in the absence of EGF, through a mechanism related to both the EGFR and the LTCC/Ca2+ signaling pathways. PMID- 30312358 TI - Viscoelastic parameters as discriminators of breast masses: Initial human study results. AB - Shear wave elastography is emerging as a clinically valuable diagnostic tool to differentiate between benign and malignant breast masses. Elastography techniques assume that soft tissue can be modelled as a purely elastic medium. However, this assumption is often violated as soft tissue exhibits viscoelastic properties. In order to explore the role of viscoelastic parameters in suspicious breast masses, a study was conducted on a group of patients using shear wave dispersion ultrasound vibrometry in the frequency range of 50-400 Hz. A total of 43 female patients with suspicious breast masses were recruited before their scheduled biopsy. Of those, 15 patients did not meet the data selection criteria. Voigt model based shear elasticity showed a significantly (p = 7.88x10-6) higher median value for the 13 malignant masses (16.76+/-13.10 kPa) compared to 15 benign masses (1.40+/-1.12 kPa). Voigt model based shear viscosity was significantly different (p = 4.13x10-5) between malignant (8.22+/-3.36 Pa-s) and benign masses (2.83+/-1.47 Pa-s). Moreover, the estimated time constant from the Voigt model, which is dependent on both shear elasticity and viscosity, differed significantly (p = 6.13x10-5) between malignant (0.68+/-0.33 ms) and benign masses (3.05+/-1.95 ms). Results suggest that besides elasticity, viscosity based parameters like shear viscosity and time constant can also be used to differentiate between malignant and benign breast masses. PMID- 30312359 TI - Understanding the impact loading characteristics of a badminton lunge among badminton players. AB - BACKGROUND: The rapid and repetitive badminton lunges would produce strenuous impact loading on the lower extremities of players and these loading are thought to be the contributing factors of chronic knee injuries. This study examined the impact loading characteristics in various groups of badminton athletes performing extreme lunges. METHODS: Fifty-two participants classified into male skilled, female skilled, male unskilled, and female unskilled groups performed badminton lunge with their maximum-effort. Shoe-ground kinematics, ground reaction forces, and knee moments were measured by using synchronised force platform and motion analysis system. A 2 (gender) x 2 (skill-level) factorial ANOVA was performed to determine the effects of different gender and different playing levels, as well as the interaction of two factors on all variables. RESULTS: Male athletes had faster approaching speed (male 3.87 and female 1.08 m/s), longer maximum lunge distance (male 1.47 and female 1.16 m), larger maximum (male 215.7 and female 121.65 BW/s) and mean loading rate (male 178.43 and female 81.77 BW/s) and larger peak knee flexion moment (male 0.75 and female 0.69) compared with female athletes (P < 0.001). Unskilled athletes exhibited smaller footstrike angle (skilled 45.78 and unskilled 32.35 degrees ), longer contact time (skilled 0.69 and unskilled 0.75 s), larger peak horizontal GRF (skilled 1.61 and unskilled 2.40 BW), smaller mean loading rate (skilled 150.15 and unskilled 110.05 BW/s) and larger peak knee flexion moment (P < .05; skilled 0.69 and unskilled 0.75 Nm/BW) than the skilled athletes. In addition, the interaction indicated greater peak GRF impact in female unskilled athletes compared with female skilled athletes (P < 0.001; female skilled 2.01 and female unskilled 2.95 BW), while there was no difference between male participants (P > 0.05; male skilled 2.19 and male unskilled 2.49 BW). CONCLUSIONS: These data suggested that male athletes and/or unskilled athletes experience greater impact loading rates and peak knee flexion moment during lunge compared with female and skilled athletes, respectively. This may expose them to higher risk of overuse injuries. Furthermore, female unskilled athletes seemed to be more vulnerable to lower extremity injuries. PMID- 30312360 TI - Genotype by environment interaction for growth and Dothistroma resistance and clonal connectivity between environments in radiata pine in New Zealand and Australia. AB - Twenty-eight clonal trials of radiata pine planted across Australia and New Zealand were used to investigate genetic variation and genotype by environment (G*E) interaction for diameter-at-breast-height (DBH), height and Dothistroma resistance (DO_R). The average narrow-sense heritabilities were 0.11, 0.21 and 0.30 while the average broad-sense heritabilities were 0.27, 0.34 and 0.40 for DBH, height and Dothistroma resistance, respectively. Dothistroma resistance was assessed as the percentage of needles that were not affected by Dothistroma needle blight. G*E interactions were analysed using an approximate reduced factor analytic model. Apparent G*E interactions were estimated for DBH, height and Dothistroma resistance. Estimates of G*E interactions and their standard errors were strongly influenced by the level of connectivity between trials, in terms of common clones and common parents. When there was sufficient connectivity between trials (more than 30% common clones between trials), a high level of G*E interaction was found for DBH and height but not for Dothistroma resistance. In two simulated clonal trials planted in two environments, low connectivity between environments resulted in a lower estimated genetic correlation between environments with an increased standard error. These results suggest that the number of clones in common between clonal trials is a key factor for inclusion in future experimental designs for estimating G*E interaction. When designing clonal trials for use in multiple environments for accurately estimating the level of G*E, if the resource for creating connectivity between environments is limited, at least 30% of the clones need to be in common between environments. PMID- 30312362 TI - Role of Early De-escalation of Antimicrobial Therapy on Risk of Clostridioides difficile Infection following Enterobacteriaceae Bloodstream Infections. AB - Background: There is a paucity of data on the effect of early de-escalation of antimicrobial therapy on rates of Clostridioides difficile infection (CDI). This retrospective cohort study evaluated impact of de-escalation from antipseudomonal beta-lactams (APBL) within 48 hours of Enterobacteriaceae bloodstream infections (BSI) on 90-day risk of CDI. Methods: Adult patients hospitalized for >48 hours for treatment of Enterobacteriaceae BSI at Palmetto Health hospitals in Columbia, SC, USA, from January 1, 2011 through June 30, 2015 were identified. Multivariable Cox proportional hazards regression was used to examine time to CDI in patients who received >48 hours and <=48 hours of APBL for empirical therapy of Enterobacteriaceae BSI after adjustment for the propensity to receive >48 hours of APBL. Results: Among 808 patients with Enterobacteriaceae BSI, 414 and 394 received >48 and <=48 hours of APBL, respectively. Incidence of CDI was higher in patients who received >48 hours than those who received <=48 hours of APBL (7.0% vs. 1.8%; log-rank p=0.002). After adjustment for propensity to receive >48 hours of APBL and other variables in the multivariable model, receipt of >48 hours of APBL (hazard ratio [HR] 3.38, 95% confidence intervals [CI]: 1.40 9.47, p=0.006) and end-stage renal disease (HR 4.04, 95% CI: 1.75-8.78; p=0.002) were independently associated with higher risk of CDI. Conclusions: The empirical use of APBL for >48 hours was an independent risk factor for CDI. Early de escalation of APBL using clinical risk assessment tools or rapid diagnostic testing may reduce the incidence of CDI in hospitalized adults with Enterobacteriaceae BSI. PMID- 30312363 TI - A Multicenter, Retrospective Evaluation of Tissue Stabilized-Guided Subcision in the Management of Cellulite. AB - Background: The first FDA-cleared long-lasting, minimally invasive device for improving the appearance of cellulite was recently launched in Canada as a novel tissue stabilized-guided subcision (TS-GS) system (Cellfina(r), Merz North America, Inc., Raleigh, NC). Clinicians from two of the first Canadian sites offering this procedure were interested in evaluating treatment efficacy and patient satisfaction after its first year on the market. Objectives: Evaluate the efficacy of TS-GS and the level of patient satisfaction associated with the procedure. Methods: Medical charts of female patients treated with the TS-GS system in 2017 were retrospectively analyzed at two Canadian centers. Measurements at baseline and three-month post-treatment were assessed for patient satisfaction and physician-rated efficacy. Patient satisfaction was assessed using a 5-point Likert-type scale and efficacy was evaluated through physician review of 2D and 3D photography, the Nurnberger-Muller Scale for cellulite, and the Global Assessment of Improvement Scale (GAIS). Results: Twenty-five patient charts were reviewed. At month three, 95.6% of patients were satisfied with treatment results and physician evaluations revealed that on average, patients displayed a 1-point improvement in their cellulite grades. Moreover, GAIS scores indicated that all patients had visible improvement in the global appearance of their cellulite. No serious adverse events were observed within three months post procedure. Conclusions: The physician ratings, patient satisfaction, and photographic evidence evaluated in this retrospective chart review support the efficacy of the TS-GS system in the management of Grades 1 to 3 cellulite in women in the thighs and buttocks. These findings also attest to the safety of the TS-GS system. PMID- 30312361 TI - SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle. AB - The life cycle of HPV is tied to the differentiation status of its host cell, with productive replication, late gene expression and virion production restricted to the uppermost layers of the stratified epithelium. HPV DNA is histone-associated, exhibiting a chromatin structure similar to that of the host chromosome. Although HPV chromatin is subject to histone post-translational modifications, how the viral life cycle is epigenetically regulated is not well understood. SETD2 is a histone methyltransferase that places the trimethyl mark on H3K36 (H3K36me3), a mark of active transcription. Here, we define a role for SETD2 and H3K36me3 in the viral life cycle. We have found that HPV positive cells exhibit increased levels of SETD2, with SETD2 depletion leading to defects in productive viral replication and splicing of late viral RNAs. Reducing H3K36me3 by overexpression of KDM4A, an H3K36me3 demethylase, or an H3.3K36M transgene also blocks productive viral replication, indicating a significant role for this histone modification in facilitating viral processes. H3K36me3 is enriched on the 3' end of the early region of the high-risk HPV31 genome in a SETD2-dependent manner, suggesting that SETD2 may regulate the viral life cycle through the recruitment of H3K36me3 readers to viral DNA. Intriguingly, we have found that activation of the ATM DNA damage kinase, which is required for productive viral replication, is necessary for the maintenance of H3K36me3 on viral chromatin and for processing of late viral RNAs. Additionally, we have found that the HPV31 E7 protein maintains the increased SETD2 levels in infected cells through an extension of protein half-life. Collectively, our findings highlight the importance of epigenetic modifications in driving the viral life cycle and identify a novel role for E7 as well as the DNA damage response in the regulation of viral processes through epigenetic modifications. PMID- 30312364 TI - Vaccine effectiveness against lineage matched and mismatched influenza B viruses across 8 seasons in Canada, 2010-11 to 2017-18. AB - Vaccine effectiveness (VE) against influenza B was derived separately for Victoria and Yamagata lineages across eight seasons (2010-11 to 2017-18) in Canada when trivalent influenza vaccine was predominantly used. VE was >=50% regardless of lineage match to circulating viruses, except when the vaccine strain was unchanged from the prior season. PMID- 30312365 TI - Addressing Gaps in HIV Preexposure Prophylaxis Care to Reduce Racial Disparities in HIV Incidence in the United States. AB - The potential for HIV preexposure prophylaxis (PrEP) to reduce the racial disparities in HIV incidence in the United States may be limited by racial gaps in PrEP care. We used a network-based mathematical model of HIV transmission for younger black and white men who have sex with men (B/WMSM) in the Atlanta area to evaluate how race-stratified transitions through the PrEP care continuum from initiation to adherence and retention could impact HIV incidence overall and disparities in incidence between races, using current empirical estimates of BMSM continuum parameters. Relative to a no-PrEP scenario, implementing PrEP according to observed BMSM parameters was projected to yield a 23% decline in HIV incidence (HR = 0.77) among BMSM at year 10. The racial disparity in incidence in this observed scenario was 4.95 per 100 person-years at risk (PYAR), a 19% decline from the 6.08 per 100 PYAR disparity in the no-PrEP scenario. If BMSM parameters were increased to WMSM values, incidence would decline by 47% (HR = 0.53), with an associated disparity of 3.30 per 100 PYAR (a 46% decline in the disparity). PrEP could simultaneously lower HIV incidence overall and reduce racial disparities despite current gaps in PrEP care. Interventions addressing these gaps will be needed to substantially decrease disparities. PMID- 30312366 TI - Screening for intestinal carriage of ESBL-producing Enterobacteriaceae in critically ill patients: expected benefits and evidence-based controversies. AB - The rising burden of intensive-care unit (ICU)-acquired infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) strengthens the requirement for efficient prevention strategies. The detection of intestinal carriage of ESBL-E through active surveillance cultures (ASC) and the implementation of contact precautions (CP) in carriers are currently advocated in most high-income countries to prevent cross-transmission and subsequent ESBL-E infections in critically ill patients. Yet, recent studies have challenged the benefit of ASC and CP to control the spread of ESBL-E in ICUs with high compliance to standard hygiene precautions and no on-going outbreak of ESBL producing K. pneumoniae or Enterobacter spp. Besides, given their debated performance to positively predict patients at risk of ESBL-E infections, ASC results appear of limited value to rationalize the empirical use of carbapenems in the ICU, emphasizing the urgent need for novel anticipatory and diagnostic approaches. This Viewpoint article summarizes the available evidence on these issues. PMID- 30312367 TI - A Multi-state Model for Analysing Transitions between Body Mass Index Categories During Childhood - Generation XXI Birth Cohort Study. AB - Prevalence of overweight and obesity in young children has risen dramatically in the last decades in most developed countries. Childhood overweight and obesity are known to have immediate and long-term health consequences and are now recognized important public health concerns. We used a Markov 4-state model with states defined by four body mass index (BMI) categories (underweight, normal weight, overweight, and obese) to study the rates of transition of children aged 4 to 10 years to higher or lower BMI categories. This model was also used to study the relation of explanatory variables to their transition rates. The participants consisted of 4887 children from Generation XXI birth cohort, Porto - Portugal, with anthropometric evaluation at the age 4 and at least in one of the subsequent follow up waves. Children who were normal weight are more likely to move to higher BMI categories than lower categories; whereas overweight children attained similar rates of transition to the two adjacent categories. The influence of maternal age and education, type of delivery, sex and birth weight on childhood overweight or obesity was evaluated, but statistical significant results were only observed for sex and maternal education on the progressive transitions. PMID- 30312368 TI - Blood Pressure Measurement in Severely Obese Patients: Validation of the Forearm Approach in Different Arm Positions. AB - Background: Blood pressure measurement in severe obesity may be technically challenging as the cuff of the device may not fit adequately around the upper arm. The aim of the study was to assess the agreement between intra-arterial blood pressure values (gold standard) compared with forearm blood pressure measurements in severely obese patients in different arm positions. Methods: Thirty-three severely obese patients and 21 controls participated in the study. Pairs of intra-arterial blood pressures were compared with simultaneous forearm blood pressure measurement using an oscillometric device in 4 positions: (i) supine, (ii) semi-fowler with the forearm resting at heart level, (iii) semi fowler with the arm downward, and (iv) semi-fowler with the arm raised overhead. Degree of agreement between measurements was assessed. Results: Overall, correlations of systolic and diastolic blood pressure measurements between the gold standard and forearm blood pressure were 0.95 (n = 722; P < 0.001) and 0.89 (n = 482; P < 0.001), respectively. Systolic blood pressure measured using the forearm approach in the supine and the semi-fowler positions with arm downward showed the best agreement when compared with the gold standard (-4 +/- 11 (P < 0.001) and 2 +/- 14 mm Hg (P = 0.19), respectively). In the control group, better agreement was found between the supine and semi-fowler positions with the arm resting at heart level (1 +/- 9 mm Hg (P = 0.29) and -3 +/- 10 mm Hg (P = 0.01), respectively). Conclusions: Forearm systolic blood pressure consistently agreed with the gold standard in the supine position. This method can be of use in clinical settings when upper-arm measurement is challenging in severe obesity. PMID- 30312370 TI - Gene-specific metrics to facilitate identification of disease genes for molecular diagnosis in patient genomes: a systematic review. AB - The evolution of next-generation sequencing technologies has facilitated the detection of causal genetic variants in diseases previously undiagnosed at a molecular level. However, in genome sequencing studies, the identification of disease genes among a candidate gene list is often difficult because of the large number of apparently damaging (but usually neutral) variants. A number of variant prioritization tools have been developed to help detect disease-causal sites. However, the results may be misleading as many variants scored as damaging by these tools are often tolerated, and there are inconsistencies in prediction results among the different variant-level prediction tools. Recently, studies have indicated that understanding gene properties might improve detection of genes liable to have associated disease variation and that this information improves molecular diagnostics. The purpose of this systematic review is to evaluate how understanding gene-specific properties might improve filtering strategies in clinical sequence data to prioritize potential disease variants. Improved understanding of the 'disease genome', which includes coding, noncoding and regulatory variation, might help resolve difficult cases. This review provides a comprehensive assessment of existing gene-level approaches, the relationships between measures of gene-pathogenicity and how use of these prediction tools can be developed for molecular diagnostics. PMID- 30312369 TI - Do More Recent Born Generations of Older Adults Have Stronger Grip? A Comparison of Three Cohorts of 66- to 84-Year-Olds in the Tromso Study. AB - Background: Evidence pertaining to whether more recent born generations of adults reaching old age have better physical capability than previous generations is scarce and inconclusive. We aimed to investigate birth cohort differences in grip strength. Methods: The study comprised 5,595 individuals from the Tromso study waves in 1994/1995, 2007/2008, and 2015/2016. Grip strength (bar) was measured using a Martin vigorimeter, and compared across three birth cohorts of 66- to 84 year-olds (born in: 1910-1929, 1923-1942, 1931-1949), as well as within narrower age bands to ensure nonoverlapping cohorts. Linear regression was applied, adjusted for age, education, smoking, physical activity, height, and weight. Results: Grip strength increased across birth cohorts, and the increase was similar within narrower age bands and across genders. Overall, the increase in sex-adjusted mean grip strength when comparing the first and latest born cohorts, born 21 years apart, was 0.06 bar (95% CI 0.04, 0.07). Higher educational levels, and greater height and weight in the most recent born cohort explained 48% of this difference, while reduced smoking and physical inactivity in more recent born cohorts had little impact. Conclusions: Our findings suggest higher grip strength in more recent birth cohorts of older Norwegian adults, which can be partly attributed to higher education and greater height. This difference corresponded to a 5-year difference in grip strength; more recent born generations of 80-year-olds, therefore, have similar mean grip strength as 75 year-olds born one generation earlier. PMID- 30312371 TI - Declining Incident Dementia Rates Across Four Population-Based Birth Cohorts. AB - Background: Incidence rates of dementia appear to be declining in high-income countries according to several large epidemiological studies. We aimed to describe declining incident dementia rates across successive birth cohorts in a U.S. population-based sample and to explore the influences of sex and education on these trends. Methods: We pooled data from two community-sampled prospective cohort studies with similar study aims and contiguous sampling regions: the Monongahela Valley Independent Elders Survey (1987-2001) and the Monongahela Youghiogheny Healthy Aging Team (2006-Ongoing). We identified four decade-long birth cohorts spanning birth years 1902-1941. In an analysis sample of 3,010 participants (61% women, mean baseline age = 75.7 years, mean follow-up = 7.1 years), we identified 257 cases of incident dementia indicated by a Clinical Dementia Rating of 1.0 or higher. We used Poisson regression to model incident dementia rates by birth cohort, age, sex, education, and interactions of Sex * Cohort and Sex * Education. We further examined whether cohort effects varied by education, testing a Cohort * Education interaction and stratifying the models by education. Results: Compared to the earliest birth cohort (1902-1911), each subsequent cohort had a significantly lower incident dementia rate (1912-1921: incidence rate ratio [IRR] = 0.655, 95% confidence interval [95% CI] = 0.477 0.899; 1922-1931: IRR = 0.387, 95% CI = 0.265-0.564; 1932-1941: IRR = 0.233, 95% CI = 0.121-0.449). We observed no significant interactions of either sex or education with birth cohort. Conclusions: A decline in incident dementia rates was observed across successive birth cohorts independent of sex, education, and age. PMID- 30312373 TI - Single-nucleotide variants in human RNA: RNA editing and beyond. AB - Through analysis of paired high-throughput DNA-Seq and RNA-Seq data, researchers quickly recognized that RNA-Seq can be used for more than just gene expression quantification. The alternative applications of RNA-Seq data are abundant, and we are particularly interested in its usefulness for detecting single-nucleotide variants, which arise from RNA editing, genomic variants and other RNA modifications. A stunning discovery made from RNA-Seq analyses is the unexpectedly high prevalence of RNA-editing events, many of which cannot be explained by known RNA-editing mechanisms. Over the past 6-7 years, substantial efforts have been made to maximize the potential of RNA-Seq data. In this review we describe the controversial history of mining RNA-editing events from RNA-Seq data and the corresponding development of methodologies to identify, predict, assess the quality of and catalog RNA-editing events as well as genomic variants. PMID- 30312372 TI - Sarcopenia: revised European consensus on definition and diagnosis. AB - Background: in 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) published a sarcopenia definition that aimed to foster advances in identifying and caring for people with sarcopenia. In early 2018, the Working Group met again (EWGSOP2) to update the original definition in order to reflect scientific and clinical evidence that has built over the last decade. This paper presents our updated findings. Objectives: to increase consistency of research design, clinical diagnoses and ultimately, care for people with sarcopenia. Recommendations: sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime; sarcopenia is common among adults of older age but can also occur earlier in life. In this updated consensus paper on sarcopenia, EWGSOP2: (1) focuses on low muscle strength as a key characteristic of sarcopenia, uses detection of low muscle quantity and quality to confirm the sarcopenia diagnosis, and identifies poor physical performance as indicative of severe sarcopenia; (2) updates the clinical algorithm that can be used for sarcopenia case-finding, diagnosis and confirmation, and severity determination and (3) provides clear cut-off points for measurements of variables that identify and characterise sarcopenia. Conclusions: EWGSOP2's updated recommendations aim to increase awareness of sarcopenia and its risk. With these new recommendations, EWGSOP2 calls for healthcare professionals who treat patients at risk for sarcopenia to take actions that will promote early detection and treatment. We also encourage more research in the field of sarcopenia in order to prevent or delay adverse health outcomes that incur a heavy burden for patients and healthcare systems. PMID- 30312374 TI - The Clinical Impact and Cost-effectiveness of MMR Vaccination to Prevent Measles Importations among US International Travelers. AB - Background: Measles importations and subsequent spread from US travelers returning from abroad are responsible for most measles cases in the US. Increasing measles-mumps-rubella (MMR) vaccination among departing US travelers could reduce the clinical impact and costs of measles in the US. Methods: We designed a decision tree to evaluate MMR vaccination at a pretravel health encounter, compared with no encounter. We derived input parameters from Global TravEpiNet data and literature. We quantified "Riskexposure" to measles while traveling and the average number of US-acquired cases and contacts due to an imported measles case. In sensitivity analyses, we examined the impact of: destination-specific Riskexposure, including "hotspots" with active measles outbreaks; the percentage of previously unvaccinated travelers; and travelers returning to US communities with heterogeneous MMR coverage. Results: The no encounter strategy projected 22 importations and 66 US-acquired measles cases costing $14.8M/10M international travelers. The pretravel encounter strategy projected 15 importations and 35 US-acquired cases at $190.3M/10M international travelers. The pretravel encounter was not cost-effective for all international travelers (ICER, $4.6M/measles case averted) but could offer better value (ICER, <$100,000/measles case averted) or even be cost-saving for travelers to "hotspots," especially if travelers were unvaccinated or returning to US communities with heterogeneous MMR coverage. Conclusions: A pretravel health encounter that improves MMR vaccination among US international travelers could reduce measles cases but is costly. This strategy offers the best value for travelers with high likelihood of measles exposure, especially if previously unvaccinated or returning to US communities with heterogeneous MMR coverage. PMID- 30312375 TI - PLD3 and spinocerebellar ataxia. PMID- 30312376 TI - Access to Specialists and Emergency Department Visits in Inflammatory Bowel Disease: A Population-Based Study. AB - Background and Aims: The number of inflammatory bowel disease (IBD) related visits to the emergency department (ED) is increasing in North America. Our study evaluates the relationship between access to specialists and utilization of ED services. Methods: We conducted a population-based study of all IBD patients in the Ontario in 2014-2015 to measure utilization of non-emergent IBD care by specialists (NICS) and ED visits. After characterizing regional variation in access to gastroenterologists and region-wide implementation of NICS, we constructed regression models to determine whether they were predictors of individual utilization of NICS and ED services. Results: The number of gastroenterologists per 1000 IBD patients varied geographically, ranging from 1.13 to 10.65 as did the region-wide proportion of patients who received NICS, ranging from 21% to 52%. Compared with those with low access to gastroenterologists, those living in areas with moderate (odds ratio [OR], 2.37; 95% CI: 2.27 - 2.47) and high (OR, 1.83; 95% CI: 1.71 - 1.95) access were more likely to receive NICS. The risk of visits to the ED were lower among those residing in regions with moderate (OR, 0.78; 95% CI: 0.75 - 0.82) and high access (OR, 0.74; 95% CI: 0.69 - 0.80) to gastroenterologists and in regions where implementation of NICS was not low (OR, 0.78; 95% CI: 0.75 - 0.81). Conclusions: Poor access to outpatient IBD specialist care contributes to IBD-related ED visits. Strategies to increase specialist access may reduce the utilization of emergency services. PMID- 30312377 TI - Co-occurrence Patterns in a Subtropical Ant Community Revealed by Complementary Sampling Methodologies. AB - Ants are abundant and ecologically dominant insects in most terrestrial communities. In subtropical ecosystems, there is a high turnover of species from the canopy to the top layers of the soil. Additionally, ant communities are often influenced by inter-specific competition. Collectively, these two processes (abiotic filtering and competition) make ants ideal for studies of community structure. We examined composition, co-occurrence, and species interactions in a sub-tropical forest ant community to examine how ground-foraging ant species partition microhabitats. We used four methods: pitfall traps, litter samples, surface baits, and subterranean baits. Surface baiting was employed at three different time periods to examine how foraging activity and species interactions at baits varied with time of day and temperature. Each method sampled a particular assemblage of the 97 total ant species. Pitfall traps shared ~50% of species with surface baits and litter samples. Subterranean baits had the fewest total species but included some uncommonly sampled ants. The majority of interactions between species at baits were neutral, but a few agonistic interactions were also observed when bait occupancy was highest. Species co occurrence patterns suggest that this ant community may not be heavily influenced by interspecific competition. Our results reinforce the advantages of applying complementary sampling techniques to examine ant community structure, and suggest that competition and dominance is best considered in the context of resource type, foraging strategy and time of sampling. Finally, we discuss the lack of two conspicuous Neotropical groups in our samples, leaf-cutting ant and army ants. PMID- 30312378 TI - Comparison of Methods to Generalize Randomized Clinical Trial Results without Individual-Level Data for the Target Population. AB - Our study explored the application of methods to generalize randomized controlled trial results to a target population without individual-level data. We compared four methods using aggregate data for the target population to generalize the JUPITER trial results to a target population of trial-eligible patients in Clinical Practice Research Datalink (CPRD). The gold-standard method used individual data from both the trial and CPRD to predict probabilities of being sampled in the trial and reweight trial participants to reflect CPRD patient characteristics. Methods 1 and 2 used weighting methods based on simulated individual data or the method of moments, respectively. Method 3 weighted the trial subgroup-specific treatment effects to match the distribution of an effect modifier in CPRD. Method 4 calculated the expected absolute benefits in CPRD assuming homogeneous relative treatment effect. Methods based on aggregate data for the target population generally yielded results between the trial and gold standard estimates. Methods 1 and 2 yielded estimates closest to the gold standard when continuous effect modifiers were represented as categorical variables. Although individual data or data on joint distributions remains the best approach to generalize the trial results, these methods using aggregate data may be useful tools for timely assessment of randomized trial generalizability. PMID- 30312379 TI - Impact of 13-pneumococcal conjugate vaccine among adults: a systematic review and meta-analysis. AB - BACKGROUND: A notable reduction of pneumococcal disease burden among adults was observed after introduction of 7 valent- pneumococcal conjugate vaccine in childhood immunization programs. In 2010, 13 valent-pneumococcal conjugate vaccine (PCV13) replaced PCV7 in many jurisdictions; a comparative assessment of PCV13's impact has not yet been performed. OBJECTIVE: To summarize available data and assess the change in the incidence of invasive pneumococcal disease (IPD) in adults after the introduction of PCV13 in childhood immunization programs. METHODS: We conducted a systematic literature search from January 1946 to May 2017 in Cochrane, Embase, Medline and PubMed. We included randomized controlled trials (RCT) and observational studies (OBS) that reported the incidence of IPD, non-invasive pneumococcal disease, hospitalizations, and mortality in adults for the periods before and after the introduction of PCV13. Incidence rate ratio (IRR) were pooled across studies using restricted maximum likelihood random effects models. RESULTS: We identified 3306 records (N=29 OBS studies and N=2,033,961 cases). Significantly lower IPD rates were seen after introduction of PCV13 in adults aged <65 years (IRR 0.78; 95%CI: 0.72-0.85) and those aged >65 years (IRR 0.86; 95%CI: 0.81-0.91). Lower rates of IPD were seen with PCV7 (IRR 0.45; 95%CI: 0.38-0.54) and PCV13 serotypes (IRR 0.60; 95%CI: 0.54-0.68). A significantly higher IRR of 1.10 (95%CI: 1.04-1.17) for non-vaccine serotypes was observed, especially among those 65 years and older (IRR 1.20; 95%CI: 1.11-1.29). CONCLUSIONS: PCV13 use in children had a moderate impact on reducing overall and vaccine-type IPD but there was a significant increase in non-vaccine type IPD among adults, especially over 65 years. PMID- 30312380 TI - Prevention of Pneumococcal Infections in Adults using Conjugate Vaccines: No Easy Answers. PMID- 30312383 TI - Stent graft treatment as a bridge to surgery for a secondary aortoduodenal fistula. AB - A secondary aortoduodenal fistula is a rare but a severe late complication after prosthetic abdominal aortic surgery. Currently, there is little consensus regarding the right treatment due to high mortality and morbidity rates. We report the case of a haemodynamically unstable patient with haematemesis on the basis of a secondary aortoduodenal fistula. He was successfully treated by staged stent graft placement followed by surgical graft excision and autogenous deep vein reconstruction. In haemodynamically unstable patients or in patients where open repair is not feasible in the acute setting of secondary aortoduodenal fistula, we advocate the use of a 2-staged endovascular and surgical approach to improve short- and long-term outcomes. PMID- 30312382 TI - Current options and recommendations for the treatment of thoracic aortic pathologies involving the aortic arch: an expert consensus document of the European Association for Cardio-Thoracic surgery (EACTS) and the European Society for Vascular Surgery (ESVS). PMID- 30312384 TI - Reply: PLD3 and spinocerebellar ataxia. PMID- 30312381 TI - Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study. AB - On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter ( 0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis. PMID- 30312385 TI - Risk factors for small bowel obstruction after laparoscopic ileal pouch-anal anastomosis for inflammatory bowel disease. A multivariate analysis in 4 expert centres in Europe. AB - Background and Aims: Although laparoscopic a1pproach is associated with the reduction of adhesions, no data are available about risk factors for small bowel obstruction (SBO) after laparoscopic ileal pouch-anal anastomosis (IPAA). The objective is to identify risk factors for SBO after laparoscopic IPAA for inflammatory bowel disease (IBD). Methods: All consecutive patients undergoing laparoscopic IPAA for IBD in 4 European expert centres were included and divided into Groups A (SBO during follow up) and B (no SBO). Results: From 2005 to 2015, SBO occurred in 41/521 patients (Group A; 8%). Two-stage IPAA was more frequently complicated by SBO than 3- and modified 2-stage IPAA (12 vs 7 and 4%, p=0.04). After multivariate analysis, postoperative morbidity (OR=3, 95%CI=1.5-7, p=0.002), stoma-related complications (OR=3, 95%CI=1-6, p=0.03) and long-term incisional hernia (OR=6, 95%CI=2-18, p=0.003) were predictive factors for SBO, while subtotal colectomy as first surgery was an independent protective factor (OR=0.4; 95% CI=0.2-0.8, p=0.002). In the subgroup of restorative proctocolectomy as first operation, stoma-related, or other surgical complications and long-term incisional hernia were predictive of SBO. In the subgroup of subtotal colectomy as first operation, postoperative morbidity and long-term incisional hernia were predictive of SBO, whereas ulcerative colitis and laparoscopic approach during the 2nd surgical stage were protective factors. Conclusions: This study reported that SBO occurred in less than 10% of patients after laparoscopic IPAA. It also suggested that modified 2-stage IPAA could potentially be safer than procedures with temporary ileostomy (2- and 3-stage IPAA) in term of SBO occurrence. PMID- 30312386 TI - GlycA, a nuclear magnetic resonance spectroscopy measure for protein glycosylation, is a viable biomarker for disease activity in IBD. AB - Background and aims: Glycoprotein acetylation (GlycA) is a novel nuclear magnetic resonance (NMR) biomarker measured in serum or plasma, which summarizes signal originating from glycan groups of certain acute phase glycoproteins. This biomarker has been shown to be robustly associated to cardiovascular and short term all-cause mortality, and to disease severity in several inflammatory conditions. We investigated GlycA levels in a cohort of healthy individuals (HC), Crohn's disease (CD) and ulcerative colitis (UC) patients prior to and after therapeutic control of inflammation. Methods: Serum samples of 10 HC, 37 CD patients and 21 UC patients before and after biological therapy were subjected to high throughput NMR analysis by Nightingale Health Ltd. Paired C-reactive protein (CRP) and fecal calprotectin (fCal) measurements were used to characterize baseline differences, treatment effects and post-treatment association to endoscopic response (50% SES-CD decrease at week 24) and mucosal healing (SES CD<=2 for CD, Mayo endoscopic score <=1 for UC). Results: GlycA levels were significantly higher in patients with active IBD compared to healthy controls, and accurately reflected the mucosal recovery to a 'healthy' state in both CD and UC patients achieving mucosal healing. In CD patients who experienced an endoscopic response without achieving full mucosal healing, GlycA levels also decreased but did not normalize to HC levels. Overall, GlycA correlated well with CRP and fCal, and accurately tracked disease activity in CRP negative patients (<5 mg/dL). Conclusion: GlycA holds promise as a viable serological biomarker for disease activity in IBD, even in patients without elevated CRP, and should therefore be tested in large prospective cohorts. PMID- 30312387 TI - Behavioral and Ovipositional Response of Diaeretiella rapae (Hymenoptera: Braconidae) to Rhopalosiphum padi and Brevicoryne brassicae in Winter Wheat and Winter Canola. AB - Winter canola Brassica napus L. (Brassicales: Brassicaceae) was introduced to U.S. Southern Great Plains (Kansas, Oklahoma, Texas) growers to manage some difficult-to-control grassy weeds in winter wheat Triticum aestivum L. (Poales: Poaceae). Two braconid parasitoids, Diaeretiella rapae (M'Intosh) and Lysiphlebus testaceipes (Cresson) (Hymenoptera: Braconidae) are active in this cropping landscape. Both wasps move between crops but D. rapae has a limited ability to develop in the main wheat aphid hosts, so L. testaceipes could influence D. rapae's ability to maintain itself when canola is absent in the landscape. We compared behavioral responses of naturally emerged D. rapae and wasps that were excised before emergence to odor volatiles of host plant, aphid host and aphid infested plants using two plant/aphid combinations (wheat/Rhopalosiphum padi (L.) and canola/Brevocoryne brassicae L. (Hemiptera: Aphididae). We also compared parasitism rates of D. rapae that were naturally emerged and excised from R. padi or B. brassicae on subsequent parasitism rates of R. padi or B. brassicae hosts. Naturally emerged wasps responded more strongly to host plant and host plant + aphid odors compared to excised wasps regardless of the host origin. Neither wasp group responded to odors from aphids alone. Both wasp groups were most attracted to odors from aphid-infested host plants, regardless of the combination. D. rapae parasitism rates on canola-reared aphids were higher than on wheat-reared aphids. D. rapae parasitism rates were lower when switched from its original host to the alternate host. Results suggest that D. rapae faces challenges to maintain significant populations in the wheat/canola landscape of the Southern Great Plains, especially in years when canola is not locally present. PMID- 30312388 TI - Development of Quantitative Estimates of Wood Dust Exposure in a Canadian General Population Job-Exposure Matrix Based on Past Expert Assessments. AB - Objectives: The CANJEM general population job-exposure matrix summarizes expert evaluations of 31 673 jobs from four population-based case-control studies of cancer conducted in Montreal, Canada. Intensity in each CANJEM cell is represented as relative distributions of the ordinal (low, medium, high) ratings of jobs assigned by the experts. We aimed to apply quantitative concentrations to CANJEM cells using Canadian historical measurements from the Canadian Workplace Exposure Database (CWED), taking exposure to wood dust as an example. Methods: We selected 5170 personal and area wood dust measurements from 31 occupations (2011 Canadian National Occupational Classification) with a non-zero exposure probability in CANJEM between 1930 and 2005. The measurements were taken between 1981 and 2003 (median 1989). A Bayesian hierarchical model was applied to the wood dust concentrations with occupations as random effects, and sampling duration, year, sample type (area or personal), province, and the relative proportion of jobs exposed at medium and high intensity in CANJEM cells as fixed effects. Results: The estimated geometric mean (GM) concentrations for a CANJEM cell with all jobs exposed at medium or high intensity were respectively 1.3 and 2.4 times higher relative to a cell with all jobs at low intensity. An overall trend of -3%/year in exposure was observed. Applying the model estimates to all 198 cells in CANJEM with some exposure assigned by the experts, the predicted 8 hour, personal wood dust GM concentrations by occupation for 1989 ranged from 0.48 to 1.96 mg m-3. Conclusions: The model provided estimates of wood dust concentrations for any CANJEM cell with exposure, applicable for quantitative risk assessment at the population level. This framework can be implemented for other agents represented in both CANJEM and CWED. PMID- 30312389 TI - Therapeutic impact of initial treatment for C>hlamydia trachomatis among patients with pelvic inflammatory disease: a retrospective cohort study using a national inpatient database in Japan. AB - Background: Pelvic inflammatory disease is common among women of reproductive age and can be complicated by tubo-ovarian abscess, which is a serious and potentially life-threatening disease. However, recent mortality rates from pelvic inflammatory disease on hospital admission and the short-term therapeutic usefulness of initial treatment for Chlamydia trachomatis remain unknown. Methods: Using the Diagnosis Procedure Combination database, we identified patients who were diagnosed with pelvic inflammatory disease on admission from July 2010 to March 2016 in Japan. We excluded patients who were pregnant, had cancer, or had missing data. Propensity score-adjusted analyses were performed to compare short-term outcomes between patients administered initial treatment for Chlamydia trachomatis and those without this treatment. The primary outcome was surgical intervention (laparotomy, laparoscopic surgery, and/or drainage procedure) during hospitalization. Results: In total, 27,841 eligible patients were identified. Of these patients, 2,463 (8.8%) had tubo-ovarian abscess on admission. Mortality during hospitalization was 0.56% and 0.28% in the groups without or with tubo-ovarian abscess, respectively. Propensity score matching created 6,149 pairs. A significant difference was observed in the primary outcome between those receiving initial treatment for Chlamydia trachomatis and the control group after propensity score matching (11.5% vs. 13.4%; risk difference: 1.9%; 95% CI: -3.1 to -0.7). The group receiving initial treatment for Chlamydia trachomatis also had a significantly lower mortality rate. Conclusions: In this retrospective nationwide study, initial treatment for Chlamydia trachomatis among hospitalized patients diagnosed with pelvic inflammatory disease had clinical benefits in terms of improved short-term outcomes. PMID- 30312390 TI - Astaxanthin enhances the longevity of Saccharomyces cerevisiae by decreasing oxidative stress and apoptosis. AB - The budding yeast, Saccharomyces cerevisiae, is an efficient model for studying oxidative stress, programmed cell death and aging. The present study was carried out to investigate antioxidant, the anti-apoptotic and anti-aging activity of a natural compound, astaxanthin, in S. cerevisiae model. The survivability of yeast antioxidant-deficient strains (sod1Delta, sod2Delta, cta1Delta, ctt1Delta and tsa1Delta) increased by 20%-40% when cells were pre-treated with astaxanthin, compared to hydrogen peroxide alone, as demonstrated in spot and colony forming unit assays. Reduced reactive oxygen species (ROS) levels, increased glutathione, decreased lipid peroxidation and induced superoxide dismutase activity in astaxanthin-treated cells indicate that astaxanthin protected the cells from oxidative-stress-induced cell death. In addition, astaxanthin protected anti apoptotic-deficient strains (pep4Delta and fis1Delta) against acetic acid and hydrogen peroxide-induced cell death that suggests anti-apoptotic property of astaxanthin, and it was further confirmed by acridine orange/ethidium bromide, annexin V and 4',6-diamidino-2-phenylindole staining. The yeast chronological lifespan assay results showed that astaxanthin extends the lifespan of antioxidant-deficient strains by scavenging ROS, and anti-apoptotic-deficient mutants by protecting from apoptotic cell death compared to their respective untreated cells and wild type. Our results suggest that astaxanthin enhances the longevity of yeast S. cerevisiae by reducing oxidative stress and apoptosis. PMID- 30312391 TI - A Practical Guide to the Safety and Monitoring of New IBD Therapies. AB - The therapeutic armamentarium of inflammatory bowel disease is rapidly evolving with the development of novel treatment options including targeted monoclonal antibodies and small molecules. With these new therapies come additional safety and side effect concerns. Infections, malignancies, immunogenicity, and metabolic issues exist for each treatment. Management of these agents in the face of such complications is a challenge clinicians will encounter. In this article, we review the existing safety data behind the monoclonal antibodies and small molecules, suggest appropriate risk stratification and assessment considerations before and during therapy, and make expert recommendations on the management of potential complications or clinical scenarios. PMID- 30312392 TI - Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from EHRA and ESC WG on Cardiovascular Pharmacology endorsed by HRS, APHRS, and ISCP-Authors' reply. PMID- 30312393 TI - Transcatheter atrioventricular valve-in-valve implantation for Fontan circulation and dextrocardia. AB - Transcatheter heart valve-in-valve implantation in failed surgical bioprosthetic valves has shown promising outcomes, prompting the stepwise expansion of their applications in different clinical scenarios. Recently, there is increased interest in valve-in-valve techniques for the treatment of patients with complex congenital heart disease. Herein, we report a case of successful transapical transcatheter atrioventricular valve-in-valve implantation in a patient with Fontan circulation and dextrocardia. The patient was previously treated with total cavopulmonary connection and atrioventricular valve replacement with recurrent prosthesis dysfunction. PMID- 30312394 TI - A disruptive cue improves handwashing in school children in Zambia. AB - Behavioral economics hold great promise in changing patterns of behavior that influence human health. Handwashing with soap is one such behavior that is important in reducing exposure to pathogens, and in school-age children, handwashing helps reduce absenteeism through the prevention of respiratory and diarrheal diseases. However, the gap between knowledge on the importance of handwashing and actual handwashing practice, especially with soap, persists. Many traditional behavior change communication approaches have failed in achieving and sustaining improved handwashing practices. Cognitive psychology research on habits as well as nudge theory, a component of behavioral economics predicated on the idea of making a behavior as easy as possible to do, suggests that introducing a disruptive cue into the environment may be able to interrupt current habitual neurological patterns to effect and then sustain behavior change. We used a participatory process to identify and introduce a locally appropriate disruptive cue to improve handwashing behavior in schools in Zambia. We then utilized a school-randomized controlled trial to test the soap-on-a-rope in 50 government schools in Namwala District of Southern Province. Two outcomes were considered among school children; washing hands with water and using soap while washing hands. Following the intervention, soap use was more likely in intervention schools than control schools [Odds ratio = 7.23, 95% confidence interval = (1.76-29.71)], though both intervention and control schools saw an increase in handwashing without soap. This low-cost intervention could be scaled throughout Zambia and may work well in other countries of similar circumstances. PMID- 30312395 TI - Diversity of fungi and bacteria in species-rich grasslands increases with plant diversity in shoots but not in roots and soil. AB - Microbial communities in roots and shoots of plants and in soil are important for plant growth and health and take part in important ecosystem processes. Therefore, understanding the factors that affect their diversity is important. We have analyzed fungal and bacterial communities associated with plant shoots, roots and soil over a 1 km2 area in a semi-natural temperate grassland with 1-43 plant species per 0.1 m2, to describe the relationships between plant and microbial diversity and to identify the drivers of bacterial and fungal community composition. Microbial community composition differed between shoots, roots and soil. While both fungal and bacterial species richness in shoots increased with plant species richness, no correlation was found between plant and microbial diversity in roots and soil. Chemistry was a significant predictor of bacterial and fungal community composition in soil as was also the spatial location of the sampled site. In this species-rich grassland, the effects of plants on the microbiome composition seemed to be restricted to the shoot-associated taxa; in contrast, the microbiomes of roots or soil were not affected. The results support our hypothesis that the effect of plants on the microbiome composition decreases from shoots to roots and soil. PMID- 30312396 TI - Mutant huntingtin reduction in astrocytes slows disease progression in the bachd conditional huntington's disease mouse model. AB - Neuronal and non-neuronal cells express the huntingtin protein, yet neurodegeneration in Huntington's Disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length mutant huntingtin (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis. To directly assess the necessity of fl-mHTT in astrocytes for HD pathogenesis, we used a mouse genetic approach and bred the conditional mutant huntingtin expressing BACHD mouse model with GFAP-CreERT2 mice. We show that GFAP-CreERT2 expression in these mice is highly selective for astrocytes and we are able to significantly reduce the expression of fl-mHTT protein in the striatum and cortex of BACHD/GFAP-CreERT2-tam mice. We performed behavioral, electrophysiological, and neuropathological analyses of BACHD and BACHD/GFAP CreERT2-tam mice. Behavioral analyses of BACHD/GFAP-CreERT2-tam mice demonstrate significant improvements in motor and psychiatric-like phenotypes. We observe improvements in neuropathological and electrophysiological phenotypes in BACHD/GFAP-CreERT2-tam mice compared to BACHD mice. We observed a restoration of the normal level alphaB-crystallin in the striatum of the BACHD/GFAP-CreERT2 mice, indicating a cell autonomous effect of mHTT on its expression. Taken together, this work indicates that astrocytes are important contributors to the progression of the behavioral and neuropathological phenotypes observed in HD. PMID- 30312398 TI - Comment on 'Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from EHRA'. PMID- 30312397 TI - Oligosaccharyltransferase structures provide novel insight into the mechanism of asparagine-linked glycosylation in prokaryotic and eukaryotic cells. AB - Asparagine-linked (N-linked) glycosylation is one of the most common protein modification reactions in eukaryotic cells, occurring upon the majority of proteins that enter the secretory pathway. X-ray crystal structures of the single subunit OSTs from eubacterial and archaebacterial organisms revealed the location of donor and acceptor substrate binding sites and provided the basis for a catalytic mechanism. Cryoelectron microscopy structures of the octameric yeast OST provided substantial insight into the organization and assembly of the multisubunit oligosaccharyltransferases. Furthermore, the cryoelectron microscopy structure of a complex consisting of a mammalian OST complex, the protein translocation channel and a translating ribosome revealed new insight into the mechanism of cotranslational glycosylation. PMID- 30312399 TI - The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk. AB - Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite significant reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia maybe an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides and the cholesterol content within triglyceride-rich lipoproteins (TGRL) and/or remnant cholesterol (RC) in the development of ASCVD. TGRL are comprised of hepatically derived very low-density lipoprotein (VLDL) and intestinally derived chylomicrons. RC is the cholesterol content of all TGRL and plasma triglycerides serve as a surrogate measure of TGRL and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive TG lowering efficacy. Several ongoing randomized controlled trials are under way to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology and genetics of triglycerides and ASCVD and discuss current and novel triglyceride lowering therapies under development. PMID- 30312400 TI - Escalation of Immunosuppressive Therapy for Inflammatory Bowel Disease Is Not Associated With Adverse Outcomes After Infection With Clostridium difficile. AB - Background: Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. Methods: This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. Results: A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). Conclusions: Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI. PMID- 30312402 TI - Erratum to Increased Risk of Influenza and Influenza-Related Complications Among 140,480 Patients With Inflammatory Bowel Disease. PMID- 30312401 TI - Results from the Canadian Nosocomial Infection Surveillance Program for detection of carbapenemase-producing Acinetobacter spp. in Canadian hospitals, 2010-16. AB - Objectives: Globally there is an increased prevalence of carbapenem-resistant Acinetobacter spp. (CRAs) and carbapenemase-producing Acinetobacter spp. (CPAs) in the hospital setting. This increase prompted the Canadian Nosocomial Infection Surveillance Program (CNISP) to conduct surveillance of CRA colonizations and infections identified from patients in CNISP-participating hospitals between 2010 and 2016. Methods: Participating acute care facilities across Canada submitted CRAs from 1 January 2010 to 31 December 2016. Patient data were collected from medical records using a standardized questionnaire. WGS was conducted on all CRAs and data underwent single nucleotide variant analysis, resistance gene detection and MLST. Results: The 7 year incidence rate of CRA was 0.02 per 10 000 patient days and 0.015 per 1000 admissions, with no significant increase observed over the surveillance period (P > 0.73). Ninety-four CRA isolates were collected from 58 hospitals, of which 93 (98.9%) were CPA. Carbapenemase OXA-235 group (48.4%) was the most common due to two separate clusters, followed by the OXA-23 group (41.9%). Patients with a travel history were associated with 38.8% of CRA cases. The all-cause 30 day mortality rate for infected cases was 24.4 per 100 CRA cases. Colistin was the most active antimicrobial agent (95.8% susceptibility). Conclusions: CRA remains uncommon in Canadian hospitals and the incidence did not increase from 2010 to 2016. Almost half of the cases were from two clusters harbouring OXA-235-group enzymes. Previous medical treatment during travel outside of Canada was common. PMID- 30312403 TI - Reducing consequences of child maltreatment during adulthood by public health actions: a Delphi study. AB - Background: Child maltreatment (CM) is associated with long-lasting poor health outcomes, as well as increased levels of disability and health-services consumption across the life-span. However, less is known about how CM consequences can be reduced during adulthood. We investigated professional opinions on how to mitigate long-term consequences of CM in a public health (PH) perspective. Methods: Using the Delphi method in three rounds, we inquired 91 professionals, mostly European researchers and clinicians about potential PH actions to mitigate CM consequences during adulthood. Results: Most experts agreed that PH actions are needed. Increasing community awareness and training emotional regulation in affected adults were prioritized strategies. Enlarging curricular knowledge about CM for professionals and developing evidence-based interventions were considered preferred methods. Reducing the barriers for access to interventions for adults, such as those provided by trauma-informed services were also suggested. Participants highlighted the possibility to reduce CM consequences across generations as a significant benefit. Conclusions: PH programmes to reduce the burden of CM can be enhanced by specific actions to facilitate the recognition of difficulties in affected adults and to expand the availability of helpful resources. The application of these programmes could be assisted by the use of modern information-technology. PMID- 30312404 TI - Diet-quality scores and the risk of symptomatic gallstone disease: a prospective cohort study of male US health professionals. AB - Objective: To investigate the association between three diet-quality scores corresponding to adherence to healthy dietary patterns [alternate Mediterranean (aMed), Alternate Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH)] and the risk of symptomatic gallstone disease. Methods: The study comprised 43 635 men of the Health Professionals Follow-up Study-an ongoing prospective cohort study of US health professionals. Participants were free of symptomatic gallstone disease and diabetes and provided dietary information every 4 years from 1986 (baseline) until 2012. The aMed, AHEI-2010 and DASH scores were generated and associated with the risk of symptomatic gallstone disease using Cox proportional hazards regression. Results: During 716 904 person-years of follow up, 2382 incident cases of symptomatic gallstone disease were identified. All three scores were inversely associated with risk of symptomatic gallstone disease after adjustment for potential confounders including age, smoking, physical activity, energy and coffee intake [hazard ratios (HRs) and 95% confidence intervals (CIs)] comparing the highest with the lowest quintiles: aMed: 0.66 (0.57-0.77), AHEI-2010: 0.64 (0.56-0.74) and DASH: 0.66 (0.58-0.76)]. Findings were similar after additional adjustment for body mass index and after inclusion of asymptomatic cases. Associations were stronger when analysis was restricted to cases who had undergone cholecystectomy. Conclusions: In this prospective cohort of male US health professionals, higher adherence to the aMed, AHEI-2010 and DASH diets was associated with lower risk of symptomatic gallstone disease. Dietary recommendations focusing on high-quality diets targeting symptomatic gallstone disease may lower the incidence of this prevalent disease. PMID- 30312405 TI - Maternal age at menarche and pubertal development in sons and daughters: a Nationwide Cohort Study. AB - STUDY QUESTION: Is maternal age at menarche associated with pubertal development in sons and daughters? SUMMARY ANSWER: Maternal age at menarche was associated with pubertal development in both sons and daughters. WHAT IS KNOWN ALREADY: Studies have shown that age at menarche is greatly inherited from mother to daughter, but it remains largely unknown to what extent age at menarche in mothers is associated with timing of puberty in sons. STUDY DESIGN, SIZE, DURATION: In this population-based study we used data from the Puberty Cohort nested within the Danish National Birth Cohort. Live-born singletons aged 11 were followed from 2012 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 15 822 children (7697 sons and 8125 daughters) gave half-yearly information on puberty from the age of 11 years until full sexual maturity or 18 years of age through self-administrated questionnaires (participation rate 71%). Information on maternal age at menarche was reported by the mothers during pregnancy. Maternal age at menarche was used both as a continuous and as a categorical variable (earlier, same time or later than peers). A multivariable regression model for interval-censored data was used. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal age at menarche was positively associated with timing of genital development, pubic hair development, first ejaculation of semen, voice break, axillary hair development and acne in sons, and with timing of breast development, pubic hair development, menarche, axillary hair development and acne in daughters. In sons, the associations were of similar strength for all pubertal markers, whereas in daughters, the associations were strongest for breast development and menarche. LIMITATIONS, REASONS FOR CAUTION: Age at menarche was recalled during pregnancy. However, studies indicate that age at menarche is recalled moderately in adulthood. Information on puberty was self-reported, but inaccuracy of data would probably cause non-differential misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Early maternal age at menarche was associated with earlier pubertal development, and late maternal age at menarche was associated with later pubertal development in both sons and daughters. The largest effect estimates were for the associations between maternal age at menarche and the daughters' age at menarche and age at breast development. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Danish Council for Independent Research (4183-00152). There are no competing interests. TRIAL REGISTERATION NUMBER: N/A. PMID- 30312406 TI - Mammary metabolism and colostrogenesis in sows during late gestation and the colostral period. AB - The aims of this study were to investigate 1) the effect of high dietary fiber (DF; 19.3 to 21.7%) supplemented to late gestating sows on mammary uptake and metabolism of energy substrates as well as colostrum production and 2) the ontogeny of colostral fat and lactose synthesis using mammary carbon balance, and colostral protein using IgG as a biomarker. Sows were fed either a control diet (CON) consisting of a standard gestation diet (14.6% DF) until d 108 of gestation and a transition diet (16.8% DF) from d 109 of gestation until farrowing or a high DF treatment where part of the daily ration was replaced with a high DF supplement (FIB). The FIB sows received 19.3% and 21.7% DF in the last 2 wk prior to farrowing. Sows were surgically implanted with permanent indwelling catheters at d 75 +/- 2 of gestation and blood samples were collected at six different time points in late gestation and at 11 different time points within 24 h after the onset of farrowing. Colostrum samples were collected at 0, 12 and 24 h after the onset of farrowing. Arterial concentration of acetate (P = 0.05) and colostral fat content (P = 0.009) were greater in FIB sows compared with CON sows. Plasma IgG dropped from d -10 in late gestation (P < 0.001), suggesting an uptake by the mammary glands. Mammary plasma flow (P = 0.007) and net mammary uptake of glucose (P = 0.04) increased during farrowing while dietary treatment had no effect on net mammary uptake of other energy substrates during late gestation and farrowing. The net mammary uptake of carbon from glucogenic precursors did not equate to the sum of carbons secreted in colostral lactose and released as CO2, indicating that carbons from ketogenic precursors were likely used for colostral fat and for oxidation. Mammary non-protein carbon uptake matched the mammary output, indicating that the majority of colostral fat and lactose were produced after the onset of farrowing. In conclusion, high DF included in the diet for late gestating sows increased colostral fat content by 49% but this substantial dietary response could not be explained by the increased carbon uptake from short chain fatty acids during the colostral period. The non-protein carbon balance of mammary glands during farrowing suggests that the majority of colostral fat and lactose were produced after the onset of farrowing, whereas the drop in plasma IgG in late gestation suggests that the mammary glands take up this colostral component prior to farrowing. PMID- 30312407 TI - Effects of pyrroloquinoline quinone supplementation on growth performance and small intestine characteristics in weaned pigs. AB - This study was conducted to explore the effect of graded levels of pyrroloquinoline quinone disodium (PQQ.Na2) on the performance and intestinal development of weaned pigs. A total of 216 pigs weaned at 28 d were assigned in a randomized complete block design to 6 diets containing 0, 1.5, 3.0, 4.5, 6.0, or 7.5 mg/kg PQQ.Na2 for 28 d. Performance, diarrhea incidence, intestinal morphology, redox status, cytokines, and the expression of tight junction proteins were determined. Pigs had increased ADG (linear, P < 0.01), G:F (quadratic, P < 0.01), and lower diarrhea incidence (P < 0.01) with the increase of PQQ.Na2 supplementation. Villus height increased (quadratic, P < 0.01) in all segments of the small intestine, and crypt depth in the duodenum and jejunum was decreased (linear, P < 0.05) in pigs with the increase of PQQ.Na2 supplementation. Pigs fed PQQ.Na2-supplemented diets had higher (P < 0.05) activities of antioxidant enzymes including total superoxide dismutase in duodenum, jejunum, and ileum; glutathione peroxidase (GSH-Px) in jejunum and ileum; catalase (CAT) in duodenum and ileum; and lower (P < 0.05) malondialdehyde concentrations in the intestinal mucosa of all segments. In the intestinal mucosa, cytokines including interleukin (IL)-1beta, IL-2, and interferon-gamma were significantly decreased (P < 0.05) in pigs fed PQQ.Na2-supplemented diets. The protein expression of zonula occluden protein-1 (ZO-1) and occludin in the jejunum was significantly increased (P < 0.05) in pigs fed diets containing PQQ.Na2. In conclusion, these results have indicated that dietary PQQ.Na2 supplementation improves growth performance and gut health in weaned pigs. Moreover, pigs fed diet with as low as 1.5-mg/kg PQQ.Na2 have better performance compared with pigs fed no PQQ.Na2-supplemented diet; pigs fed diet with 4.5-mg/kg PQQ.Na2 have highest G:F among treatments during the whole period. PMID- 30312408 TI - MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle MRI changes are crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology, and expression of DUX4 target genes. Results show that the presence of elevated MRI STIR signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression. PMID- 30312409 TI - In vitro activity of seven beta-lactams including ceftolozane/tazobactam and ceftazidime/avibactam against Burkholderia cepacia complex, Burkholderia gladioli and other non-fermentative Gram-negative bacilli isolated from cystic fibrosis patients. PMID- 30312410 TI - Impact of 24-h feed, water, or feed and water deprivation on feed intake, metabolic, and inflammatory responses in beef heifers. AB - This experiment investigated the effects of 24-h feed or water deprivation on hay intake, metabolic, and inflammatory responses in growing beef heifers. Forty Angus * Hereford heifers were ranked by initial BW (BW = 275 +/- 6 kg) and age (278 +/- 6 d) and randomly allocated to 20 drylot pens (2 heifers/pen). Pens were randomly assigned to 1 of 5 squares (4 * 4; 4 pens/square; a total of 8 animals per square), that were run simultaneously with each containing 4 experimental periods of 17 d each (day -6 to 10). From day -5 to 0 of each period, pens were offered alfalfa-grass hay ad libitum + 454 g of dried distillers grains with solubles (as-fed basis) per heifer daily. On day 0 of each period, pens received 1 of 4 treatments: 1) feed and water deprivation for 24 h (FWD), 2) feed deprivation for 24 h, but regular access to water (FD), 3) water deprivation for 24 h, but regular access to feed (WD), or 4) regular access to feed and water (CON). Treatments were concurrently applied from day 0 to 1. Heifer full BW was collected on day -6 and -5, before (day 0) and after (day 1) treatment application, and on day 3, 6, 9, and 10 of each period. Hay DMI was recorded daily from day -5 to 10. Blood samples were collected on day -5, 0, 1, 3, 6, and 10 of each experimental period. Following treatment application on day 1, BW loss was greater, and BW was less (P < 0.01) in WD, FWD, and FD compared with CON heifers, and similar (P = 0.64) among FWD and FD heifers. No treatment effects were detected (P >= 0.21) for final BW and overall ADG. Plasma cortisol concentrations were greater (P < 0.01) in FD and FWD vs. WD and CON on day 1, whereas FD had greater (P < 0.01) plasma cortisol concentration vs. CON, WD, and FWD on day 6 and 10. Serum NEFA concentration was greater (P < 0.01) in FD and FWD vs. WD and CON on day 1, and greater (P < 0.01) in WD vs. CON heifers on day 1. No treatment effects were detected (P = 0.53) for plasma haptoglobin concentration. Plasma ceruloplasmin concentration was greater (P < 0.01) in FD and FWD vs. CON on day 1, and greater (P < 0.01) in FD vs. CON and WD on day 3 and 6. Collectively, feed or water deprivation for 24 h did not impact feed intake and BW gain, whereas metabolic results suggest that feed deprivation stimulates cortisol, NEFA, and ceruloplasmin responses in growing beef heifers. PMID- 30312412 TI - Investigation of xylanase, diet formulation method for energy, and choice of digestibility index marker on nutrient and energy utilization for broiler chickens and pigs. AB - The aim of this study was to investigate the growth performance and nutrient utilization responses of broiler chickens and the nutrient utilization of pigs to xylanase, experimental diet formulation method for energy (FME), and digestibility index marker (DIM). In Exp. 1, a total of 448 male broiler chickens were used in a randomized complete block design with body weight as a blocking factor. Seven dietary treatments were prepared in a 3 * 2 + 1 factorial arrangement with inclusion of sand, diatomaceous earth (DAE), or wheat bran (WB) as FME and without or with xylanase (26,400 unit/kg of diet) plus positive control. Each of chromic oxide and titanium dioxide were incorporated at 5 g/kg in diets. There were 8 replicate cages of 8 birds per cage. Birds were weighed on d 7, 14, and 21, and feed consumption were recorded. Excreta samples were collected from d 19 to 21. On d 21, birds were euthanized, and ileal digesta samples were collected. In Exp. 2, twenty-one barrows (initial body weight = 33.0 +/- 0.3 kg), fitted with simple T-cannulas at the distal ileum, were used in a triplicate 7 * 2 incomplete Latin Square design with 7 dietary treatments, which were prepared by the same arrangement as in broilers, and 2 periods giving 6 replicates per diet. Fecal samples were collected on d 4 and 5, and ileal digesta samples were collected on d 6 and 7 of each period. In Exp. 1, the growth performance of birds was not affected by xylanase. There were interactions (P < 0.05) between xylanase and FME for apparent ileal digestibility (AID) of crude protein, His, Met, Thr, and Trp. Inclusion of xylanase decreased (P < 0.05) the AID of crude protein and Trp in sand diet and AID of His and Thr in DAE diet, but increased (P < 0.05) AID of Met in WB diet. Greater (P < 0.05) AID of energy and nutrients except Arg and Met was determined by Cr than Ti. In Exp. 2, there were interactions (P < 0.05) between xylanase and FME for AID of dry matter, energy, Arg, and Lys. Inclusion of xylanase decreased (P < 0.05) the AID of Lys in DAE or WB diet, but increased (P < 0.05) AID of Arg in sand diet and AID of energy in WB diet. The DIM type had no effect on responses in pigs. In conclusion, the efficacy of xylanase on ileal energy and amino acids digestibility depends on the choice of formulation method for energy in broilers and pigs, and digestibility index marker affects ileal digestibility in broilers. PMID- 30312411 TI - Coronary computed tomography angiography for heart team decision-making in multivessel coronary artery disease. AB - Aims: Coronary computed tomography angiography (CTA) has emerged as a non invasive diagnostic method for patients with suspected coronary artery disease, but its usefulness in patients with complex coronary artery disease remains to be investigated. The present study sought to determine the agreement between separate heart teams on treatment decision-making based on either coronary CTA or conventional angiography. Methods and results: Separate heart teams composed of an interventional cardiologist, a cardiac surgeon, and a radiologist were randomized to assess the coronary artery disease with either coronary CTA or conventional angiography in patients with de novo left main or three-vessel coronary artery disease. Each heart team, blinded for the other imaging modality, quantified the anatomical complexity using the SYNTAX score and integrated clinical information using the SYNTAX Score II to provide a treatment recommendations based on mortality prediction at 4 years: coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or equipoise between CABG and PCI. The primary endpoint was the agreement between heart teams on the revascularization strategy. The secondary endpoint was the impact of fractional flow reserve derived from coronary CTA (FFRCT) on treatment decision and procedural planning. Overall, 223 patients were included. A treatment recommendation of CABG was made in 28% of the cases with coronary CTA and in 26% with conventional angiography. The agreement concerning treatment decision between coronary CTA and conventional angiography was high (Cohen's kappa 0.82, 95% confidence interval 0.74-0.91). The heart teams agreed on the coronary segments to be revascularized in 80% of the cases. FFRCT was available for 869/1108 lesions (196/223 patients). Fractional flow reserve derived from coronary CTA changed the treatment decision in 7% of the patients. Conclusion: In patients with left main or three-vessel coronary artery disease, a heart team treatment decision-making based on coronary CTA showed high agreement with the decision derived from conventional coronary angiography suggesting the potential feasibility of a treatment decision-making and planning based solely on this non invasive imaging modality and clinical information. Trial registration number: NCT02813473. PMID- 30312413 TI - Variation in ectomycorrhizal fungal communities associated with Silver linden (Tilia tomentosa) within and across urban areas. AB - Trees in urban areas face harsh environmental conditions. Ectomycorrhizal fungi (EcM) form a symbiosis with many tree species and provide a range of benefits to their host through their extraradical hyphal network. Although our understanding of the environmental drivers and large scale geographical variation of EcM communities in natural ecosystems is growing, our knowledge of EcM communities within and across urban areas is still limited. Here, we characterized EcM communities using Illumina miseq sequencing on 175 root samples of the urban tree Tilia tomentosa from three European cities, namely Leuven (Belgium), Strasbourg (France) and Porto (Portugal). We found strong differences in EcM richness and community composition between cities. Soil acidity, organic matter and moisture content were significantly associated with EcM community composition. In agreement, the explained variability in EcM communities was mostly attributed to general soil characteristics, whereas very little variation was explained by city and heavy metal pollution. Overall, our results suggest that EcM communities in urban areas are significantly associated with soil characteristics, while heavy metal pollution and biogeography had little or no impact. These findings deliver new insights into EcM distribution patterns in urban areas and contribute to specific inoculation strategies to improve urban tree vitality. PMID- 30312414 TI - Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting. AB - Background: Vedolizumab (ENTYVIO) is a humanized alpha4beta7 integrin antagonist approved for the treatment of inflammatory bowel disease, which selectively blocks gut-specific lymphocyte trafficking. We evaluated the risk of opportunistic infections of interest in patients treated with vedolizumab. Methods: We determined the frequency of opportunistic infections and tuberculosis in patients receiving vedolizumab in phase 3 clinical trials and post-marketing settings. We also evaluated adverse events reported in the post-marketing setting in patients with a history of or concurrent hepatitis B/C virus infection. Results: The incidence of opportunistic infections in patients receiving vedolizumab was 0.7 (GEMINI 1 and 2 clinical trials) and 1.0 (long-term safety study) per 100 patient-years, with 217 events reported in approximately 114,071 patient-years of exposure (post-marketing setting). Most opportunistic infections were nonserious and the majority of patients continued treatment with vedolizumab. Clostridium difficile was the most commonly reported infection, with an incidence rate of 0.5 per 100 patient-years (clinical trials). Tuberculosis was reported at 0.1 per 100 patient-years (clinical trials), with 7 events in the post-marketing setting. No tuberculosis-related deaths were reported in either setting. No cases of progressive multifocal leukoencephalopathy were reported. In 29 patients with a history of or concurrent hepatitis B/C infection in the post marketing setting, no viral reactivation was observed. Conclusions: Clinical trials and post-marketing data showed that the rate of serious opportunistic infections in patients receiving vedolizumab was low and most patients could continue vedolizumab treatment. The frequency of tuberculosis infection was also low and no hepatitis B/C viral reactivation was reported. PMID- 30312415 TI - Environmental Factors Modify the Severity of Acute DSS Colitis in Caspase-11 Deficient Mice. AB - Background: Human and mouse studies implicate the inflammasome in the pathogenesis of inflammatory bowel diseases, though the effects in mice are variable. The noncanonical inflammasome activator caspase-11 (Casp11) reportedly attenuates acute dextran sodium sulfate (DSS) colitis in mice. However, the effects of Casp11 on chronic experimental colitis and factors that influence the impact of Casp11 on acute DSS colitis are unknown. Methods: We studied the role of Casp11 in Il10-/- mice and acute and chronic DSS colitis mouse models. We quantified colonic Casp11 mRNA using quantative polymerase chain reaction and colitis using weight loss, blinded histological scoring, IL-12/23p40 secretion by colonic explants, and fecal lipocalin-2. We determined fecal microbial composition using 16S amplicon sequencing. Results: We detected increased colonic Casp11 mRNA in Il10-/- mice with chronic colitis, but not in mice with DSS colitis. The presence of Casp11 did not alter the severity of chronic colitis in DSS-treated or Il10-/- mice. Contrary to prior reports, we initially observed that Casp11 exacerbates acute DSS colitis. Subsequent experiments in the same animal facility revealed no effect of Casp11 on acute DSS colitis. There were pronounced stochastic changes in the fecal microbiome over this time. The majority of bacterial taxa that changed over time in wild-type vs Casp11-/- mice belong to the Clostridiales. Conclusions: Casp11 does not impact chronic experimental colitis, and its effects on acute DSS colitis vary with environmental factors including the microbiota, particularly Clostridiales. Stochastic drifts in intestinal microbiota composition, even in mice in the same housing facility, should be considered when interpreting studies of acute DSS colitis models. PMID- 30312416 TI - Building informed trust: developing an educational tool for injection practices and health insurance in Cambodia. AB - Unnecessary injections increase the risk of blood-borne infections as well as pose an avoidable financial burden on patients. Perceptions in rural Cambodia that medical drug injections provide the best quality medical care have resulted in a large proportion of the population seeking injections across medical conditions. As private providers have a higher propensity to offer injections, patients pursue more expensive care contributing to a greater financial burden. This study aimed to use an educational intervention to improve participant knowledge about injections and health insurance in order to build informed trust in safer injection practices and health insurance. Using an experimental study design, villages in rural Cambodia were randomly assigned to an intervention or control arm. Community educational workshops were implemented to improve participant knowledge about injections and health insurance. Pre-and post intervention assessments were used to record the resulting changes in knowledge and trust in providers. Statistical analysis of survey results from the two study arms showed increases of 16.8% and 15.9% in study participant knowledge regarding injections and health insurance, respectively. Trust in health insurance increased by 12.9%. However, trust in healthcare providers proved to be resilient with small to no change. These results show that knowledge about injection safety and health insurance, as well as trust in health insurance, can be increased through information dissemination in rural Cambodia. However, health information campaigns may not easily influence people's trust in healthcare providers. Education of the general populace about safe injection practices and health insurance can contribute toward the country's efforts to reach universal health coverage. PMID- 30312417 TI - Differences in the Epstein-Barr virus gp350 IgA antibody response are associated with increased risk for co-infection with a second strain of EBV. AB - Background: The EBV viral glycoprotein gp350 has been proposed as a candidate antigen for an EBV vaccine. However, the proposed formulations of these vaccines have not taken into account the presence of two unique EBV strains (EBV-1 and EBV 2) present in areas of high incidence of the EBV associated cancer, Burkitt's lymphoma. Methods: In this study, we analyze the kinetics of EBV-1 and EBV-2 infection in an asymptomatic infant cohort from Kisumu, Kenya. We also analyzed the kinetics of the antibody response against five EBV antigens, gp350 (IgG and IgA), VCA (IgG), EBNA-1 (IgG), EAd (IgG), and Zta (IgG). Results: We observed a high frequency of co-infection with both EBV types over time, with the only observable defect in the antibody response in infants co-infected being a significantly lower level of anti-gp350 IgA at peak response. Gp350 IgA levels were also significantly lower in co-infected infants 2.5 months post-infection and at the time of co-infection. Conclusions: These results suggest that anti gp350 IgA antibodies may be important for sterilizing immunity against secondary infection. These findings have implications for the development of an efficacious EBV vaccine to prevent both EBV-1 and EBV-2 infection in a population at high risk for Burkitt's lymphoma. PMID- 30312419 TI - Importation of leptospirosis to New York from Israel by teen travellers. PMID- 30312420 TI - Surveillance After Treatment of Localized Breast Cancer: Time for Reappraisal? PMID- 30312418 TI - A new multi-system disorder caused by the Galphas mutation p.F376V. AB - Context: The alpha-subunit of the stimulatory G-protein (Galphas) links numerous receptors to adenylyl cyclase. Galphas, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, while somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright Syndrome. Objective: We here report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Galphas function. Design, Setting: Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant-Galphas were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist stimulated conditions. Results: Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early-onset gonadotrophin independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele, in both patients; this resulted in a clinical phenotype that differ from known Galphas-related diseases and suggested gain-of-function at the receptors for vasopressin (V2R) and lutropin (LHCGR), yet increased serum parathyroid hormone (PTH) concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Galphas-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal alpha5-helix of Galphas that are relevant for interaction with GPCRs and signal transduction. Conclusions: The Galphas p.F376V mutation causes a previously unrecognized multi system disorder. PMID- 30312421 TI - Strategies to Identify and Target Cells of Origin in Prostate Cancer. PMID- 30312422 TI - Thrombocytopenia Impairs Host Defense Against Burkholderia pseudomallei (Melioidosis). AB - Background: Infection with the gram-negative bacillus Burkholderia pseudomallei (melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods: Association between platelet counts and mortality was determined in 1160 patients with culture-proven melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibalpha-deficient mice were conducted. Results: Thrombocytopenia was present in 31% of patients at admission and predicted mortality in melioidosis patients even after adjustment for confounders. In our murine-melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibalpha-deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions: Thrombocytopenia predicts mortality in melioidosis patients and, during experimental melioidosis, platelets play a protective role in both innate immunity and vascular integrity. PMID- 30312423 TI - Adiposity, Insulin Resistance, and Bone Mass in Children and Adolescents. AB - Context: Insulin resistance is an adverse health outcome that accompanies obesity. Fat mass is negatively associated with bone mass while adjusting for confounders, and insulin resistance might be an intermediary in this relationship. Objective: Determine whether insulin resistance is an intermediary in the relationship between adiposity and bone mass in adolescents. Design: Cross sectional secondary analysis of baseline data from a previous randomized trial. Setting: University research facility. Participants: Two hundred and forty adolescents (68% female) ages 7-15 years. Main Outcome Measures: Using DXA, bone mineral content (BMC), areal bone mineral density (aBMD), lean mass and fat mass were measured. Skeletal sites of interest included the total body (TB) and lumbar spine (LS). Waist circumference was measured using an anthropometric tape measure. Insulin and glucose were measured in fasting sera, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Path analysis was performed to determine whether the relationship between adiposity and bone was mediated through insulin resistance. Results: Fat mass (r=0.467, P<0.001) and waist circumference (r=0.487, P<0.001) correlated positively with HOMA-IR. While controlling for race, sex, maturation, lean mass, and height, fat mass, waist circumference, and HOMA-IR were negatively associated with LS BMC and total body aBMD (all P<0.05). Additionally, path models for fat mass (95% CI=-5.893 to 0.956) and waist circumference (95% CI=-15.473 to -2.124) showed a negative relationship with LS BMC via HOMA-IR. Conclusions: These results support an intermediary role of insulin resistance in the relation between adiposity and lumbar spine bone mass. PMID- 30312424 TI - Genetic parameters of longevity for improving profitability of beef cattle. AB - The objective of this study was to estimate genetic parameters for longevity and assess the suitability of using these selection criteria to improve the genetic merit of the beef cattle population of the Czech Republic. The performance record database, which contains records of 363,000 beef cattle animals of 19 breeds and their crosses, was used. The populations of Charolais and Aberdeen Angus were large enough that the genetic parameter estimations and all analyses were done for these breeds separately. Two similar approaches of longevity definition based on probabilities were considered as follows: productive longevity (PL), which is the number of calvings at target ages of 78, 90, 150, and 160 mo, and longevity (L), which is based on the probabilities of cow reappearance in the next parity. A multibreed single-trait animal model for L and a multitrait animal model for combinations of 78/150 and 90/160 mo for PL were used. Specific combinations of months were established based on the analysis and represented the critical culling rates in the studied population. The high genetic correlations (0.88 0.95) of the combination 90/160 suggested that the PL at 160 mo of age can be predicted on the basis of the value at 90 mo, which will make earlier selection possible. Combination 78/150 is less efficient in the Czech population of beef cattle due to the lower correlations (0.79-0.93) between traits. The estimated heritabilities were low for both traits (below 0.14), but the additive genetic variance was sufficient for identifying animals with high genetic merit. PMID- 30312425 TI - Low Frequency of Knockdown Resistance Mutations in Musca domestica (Muscidae: Diptera) Collected From Northwestern Iran. AB - Musca domestica L., the common housefly, is a very important mechanical vector of pathogens. Continuous exposure to pyrethroid insecticides has led to insecticide resistance in houseflies. Some mutations in the voltage-gated sodium channel gene (vgsc) reduce the binding affinity of pyrethroids target site insensitivity. We collected houseflies from the Urmia district of Northwestern Iran. Following DNA extraction, 580 bp regions of the vgsc known to contain knockdown resistance (kdr) mutations were amplified and sequenced using specific primers. The amplified region contained two exons (211-bp and 248-bp) and three introns. There were eight polymorphic sites between M. domestica insecticide-susceptible (MDU38813), super-kdr (NW_004774263) and aabys (KT897924) strains from GenBank in comparison with our sequences. Two amino acid substitutions were detected, N967Y (% polymorphism = 9.5%) and L1014H (% polymorphism = 4.7%) that can be associated with resistance. The common and previously reported mutations L1014F and M918T+L1014F were not detected. Diagnosis based on sequence analysis is useful for monitoring the frequency of pyrethroid resistance mutations, which will be helpful in avoiding overuse of this class of insecticides in house fly control. PMID- 30312426 TI - The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer. AB - Background: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of origin. Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo. Methods: We employed lineage retracing in Bmi1-CreER; R26R-confetti; Ptenf/f transgenic mice to mark and follow the fate of emerging recurrent tumor clones after castration. A tissue recombination strategy was used to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts. We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence. Results: Transgenic prostate tumors (n = 17) regressed upon castration but uniformly recurred within 3 months. Residual regressed tumor lesions exhibited a transient luminal-to-basal phenotypic switch and marked cellular heterogeneity. Additionally, in these lesions, a subpopulation of Bmi1-expressing castration resistant tumor cells overexpressed the stem cell reprogramming factor Sox2 (mean [SD] = 41.1 [3.8]%, n = 10, P < .001). Bmi1+Sox2+ cells were quiescent (BrdU+Bmi1+Sox2+ at 3.4 [1.5]% vs BrdU+Bmi1+Sox2- at 18.8 [3.4]%, n = 10, P = .009), consistent with a cancer stem cell phenotype. By lineage retracing, we established that recurrence emerges from the Bmi1+ tumor cells in regressed tumors. Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 reduced Bmi1+Sox2+ cells (6.1 [1.4]% PTC-209 vs 38.8 [2.3]% vehicle, n = 10, P < .001) and potently suppressed recurrence (retraced clone size = 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n = 12, P = .04). Conclusions: These results illustrate the utility of lineage retracing to define the cellular origins of recurrent prostate cancer and identify Bmi1+Sox2+ cells as a source of recurrence that could be targeted therapeutically. PMID- 30312427 TI - Stand-by antibiotics for travellers' diarrhoea: risks, benefits and research needs. PMID- 30312428 TI - An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922-1955. AB - Felix D'Herelle coined the term bacteriophage in 1917 to characterize a hypothetical viral agent responsible for the mysterious phenomenon of rapid bacterial death. While the viral nature of the "phage" was only widely accepted in the 1940s, attempts to use the phenomenon in treating infections started early. After raising hopes in the interwar years, by 1945 phage therapy had been abandoned almost entirely in the West, until the recent revival of interest in response to the crisis of antibiotic resistance. The use of phage therapy, however, persisted within Soviet medicine, especially in Georgia. This article explains the adoption and survival of phage therapy in the USSR. By focusing on the Tbilisi Institute of Microbiology, Epidemiology and Bacteriophage (now the Eliava Institute), I argue that bacteriophage research appealed to Soviet scientists because it offered an ecological model for understanding bacterial infection. In the 1930s, phage therapy grew firmly imbedded within the infrastructure of Soviet microbiological institutes. During the Second World War, bacteriophage preparations gained practical recognition from physicians and military authorities. At the dawn of the Cold War, the growing scientific isolation of Soviet science protected phage therapy from the contemporary western critiques, and the ecological program of research into bacteriophages continued in Georgia. PMID- 30312429 TI - Assessment of flux through oleoresin biosynthesis in epithelial cells of loblolly pine resin ducts. AB - The shoot system of pines contains abundant resin ducts, which harbor oleoresins that play important roles in constitutive and inducible defenses. In a pilot study, we assessed the chemical diversity of oleoresins obtained from mature tissues of loblolly pine trees (Pinus taeda L.). Building on these data sets, we designed experiments to assess oleoresin biosynthesis in needles of 2-year-old saplings. Comparative transcriptome analyses of single cell types indicated that genes involved in the biosynthesis of oleoresins are significantly enriched in isolated epithelial cells of resin ducts, compared with those expressed in mesophyll cells. Simulations using newly developed genome-scale models of epithelial and mesophyll cells, which incorporate our data on oleoresin yield and composition as well as gene expression patterns, predicted that heterotrophic metabolism in epithelial cells involves enhanced levels of oxidative phosphorylation and fermentation (providing redox and energy equivalents). Furthermore, flux was predicted to be more evenly distributed across the metabolic network of mesophyll cells, which, in contrast to epithelial cells, do not synthesize high levels of specialized metabolites. Our findings provide novel insights into the remarkable specialization of metabolism in epithelial cells. PMID- 30312430 TI - Fibroblast growth factor 23 is associated with fractional excretion of sodium in patients with chronic kidney disease. AB - Background: Recent studies suggest that the phosphaturic hormone fibroblast growth factor 23 (FGF23) is involved in regulation of renal sodium excretion and blood pressure. There is evidence of both direct effects via regulation of the sodium-chloride symporter (NCC) in the distal tubule, and indirect effects through interactions with the renin-angiotensin-aldosterone system. However, clinical data on the association between FGF23 and renal sodium regulation is lacking. Herein, we investigated the associations of FGF23 with renal sodium handling and blood pressure in non-dialysis CKD patients. Methods: This was a cross-sectional study encompassing 180 CKD patients Stage 1-5, undergoing renal biopsy. Plasma intact FGF23, 24-h urinary sodium excretion, fractional excretion of sodium (FENa) and blood pressure were measured at baseline. The association between FGF23 and renal sodium handling was explored by multivariate regression analysis. Results: The median age was 52.8 years, 60.6% were men and the median estimated glomerular filtration rate (eGFR) was 50.6 mL/min/1.73 m2. In univariate analysis, FGF23 was positively associated with FENa (Spearman's rho = 0.47; P < 0.001) and systolic blood pressure (rho = 0.17, P < 0.05), but not with plasma sodium, 24-h urinary sodium excretion or mean arterial blood pressure. The association between FGF23 and FENa remained significant after adjustment for potential confounders (multivariable adjusted beta coefficient 0.60, P < 0.001). This association was stronger among the 107 individuals with eGFR <60 mL/min/1.73 m2 (beta = 0.47, P = 0.04) and in the 73 individuals on any diuretics (beta = 0.88, P < 0.001). Adjustment for measured GFR instead of eGFR did not alter the relationship. Conclusions: FGF23 is independently associated with increased FENa in non-dialysis CKD patients. These data do not support the notion that FGF23 causes clinically significant sodium retention. Further studies are warranted to explore the mechanism underlying this association. PMID- 30312432 TI - Sexual Dysfunction in Patients With Inflammatory Bowel Disease. PMID- 30312431 TI - Smoking and Risk of Colorectal Cancer Sub-Classified by Tumor-Infiltrating T Cells. AB - Background: Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti tumor adaptive immune response. Methods: During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells. All statistical tests were two sided. Results: The association of smoking status with colorectal cancer risk differed by CD3+ cell density (Pheterogeneity = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3+ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (Ptrend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3+ cell-high cancer risk (Ptrend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8+ cells, CD45RO+ cells, or FOXP3+ cells (Pheterogeneity > .04, with adjusted alpha of 0.01). Conclusions: Colorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis. PMID- 30312433 TI - Glioblastoma survival is improving despite increasing incidence rates: a nationwide study between 2000 and 2013 in Finland. AB - Background: We assessed population-level changes in glioblastoma survival between 2000 and 2013 in Finland, with focus on elderly patients (>70 years) in order to assess if changes in treatment of glioblastoma are reflected also in population based survival rates. Methods: We identified all patients (age >=18 years) from the Finnish Cancer Registry (FCR) with a histopathological diagnosis of primary glioblastoma in 2000-2013. Patients were followed up until December 2015. The accuracy of register-based search of glioblastoma patients was internally validated. We report age-standardized relative survival ratios and relative excess risks of death (RER) between 2000-2006 (pre) and 2007-2013 (post-period). Results: We identified 2,045 glioblastoma patients from the FCR. The accuracy of the FCR-based search was 97%. Median age was 63.3 years, and 42% were women. Incidence increased on average by 1.6% (p=0.004) and median age by 0.4 years per calendar year. Between the pre and post-period, the proportion of patients >70 years increased from 24% to 27%. In >70-year-old patients, the median survival time increased from 3.6 months in 2000-2006 to 4.5 months in 2007-2013 (RER 0.82, 95% CI 0.68-0.98). In <=70-year-old-patients, the median survival time increased from 9.3 months in 2000-2006 to 11.7 months in 2007-2013 (RER 0.74, 95% CI 0.67 0.82). Conclusion: Despite the increased proportion of elderly glioblastoma patients, population-level survival of glioblastoma patients have improved since year 2000. However, increasing incidence, increasing age of patients, and poor survival in elderly are alarming, and future studies should perhaps focus more on elderly. PMID- 30312434 TI - Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer During Follow-Up and Prognosis. AB - Background: The prognostic relevance of circulating tumor cells (CTCs) at the time of primary diagnosis has been well established. However, little information is available regarding their prognostic relevance to follow-up care. Methods: The multicenter, open-label, phase III SUCCESS A trial compared two adjuvant chemotherapy regimens followed by 2 vs 5 years of zoledronate for early-stage, high-risk breast cancer patients. The presence of CTCs was assessed before and 2 years after chemotherapy using the FDA-approved CellSearch System. Overall survival (OS) and disease-free survival (DFS) were analyzed using univariate log rank tests and multivariable Cox regressions. OS and DFS were measured starting from an assessment of CTCs 2 years after the completion of chemotherapy. All statistical tests were two-sided. Results: The sample included 1087 patients who participated in the translational research program of the SUCCESS A trial and for whom sufficient translational data were available regarding CTC status at baseline and at the 2-year follow-up visit. Two years after chemotherapy, 198 (18.2%) patients were CTC-positive. The median follow-up after this timepoint was 37 months. Cox regressions that included CTC status at baseline revealed that CTC status 2 years after chemotherapy had statistically significant and independent prognostic relevance for OS (hazard ratio [HR] = 3.91, 95% confidence interval [CI] = 2.04 to 7.52, P < .001) and DFS (HR = 2.31, 95% CI = 1.50 to 3.55, P < .001). Conclusion: The presence of CTCs 2 years after chemotherapy was associated with decreased OS and DFS. Based on these results, active individualized surveillance strategies for breast cancer survivors based on biomarkers should be reconsidered. PMID- 30312437 TI - The mechanism through which dietary supplementation with heated linseed grain increases n-3 long-chain polyunsaturated fatty acid concentration in subcutaneous adipose tissue of cashmere kids. AB - The aim of this study was to investigate the effects of dietary supplementation with heated linseed on the fatty acid (FA) composition of the plasma, liver, and subcutaneous adipose tissue (SADT) of Albas white cashmere kids, particularly the effect on n-3 long-chain polyunsaturated FA profiles and the mRNA expression of genes related to lipid metabolism in SADT. Sixty 4-month-old castrated male kids (average BW 18.6 +/- 0.1 kg) were selected and randomly allocated into three groups in a randomized block design. Three dietary treatments were used: (1) basal diet without supplementation (Control), (2) basal diet supplemented with linseed oil (LSO), and (3) basal diet supplemented with heated linseed grain (HLS). The diets were fed for 104 d, consisting of 14 d for adaptation followed by 90 d of measurement. Different FA profiles were found in SADT between LSO and HLS. Kids fed HLS had more C18:3n3 (P < 0.0001), C22:6n3 (P = 0.007), and n-3 PUFA (P < 0.0001) and a less (P < 0.0001) n-6/n-3 ratio than LSO kids. These FA differences between LSO and HLS kids were due to the increased expression of elongation of very long chain FA protein 5 (P < 0.0001), delta-6 desaturase (P < 0.0001), and peroxisome proliferator-activated receptor alpha (P = 0.003) in SADT of HLS kids and was also associated with liver fat metabolism. Together, these results suggest that the consumption of HLS leads to more C22:6n3 than LSO in SADT by increasing liver C22:6n3 content and by increasing SADT mRNA expression of ELOVL5 and FADS2 through promoting PPARalpha expression. PMID- 30312435 TI - Comparative transcriptome analysis of Poncirus trifoliata identifies a core set of genes involved in arbuscular mycorrhizal symbiosis. AB - The perennial woody plants of citrus are one of the most important fruit crops in the world and largely depends on arbuscular mycorrhizal symbiosis (AMS) to obtain essential nutrients from soil. However, the molecular aspects of AMS in citrus and perennial woody plants in general have largely been understudied. We used RNA sequencing to identify differentially expressed genes in roots of Poncirus trifoliata upon mycorrhization by the AM fungus Glomus versiforme and evaluated their conservation by comparative transcriptome analyses with four herbaceous model plants. We identified 282 differentially expressed genes in P. trifoliata, including orthologs of 21 genes with characterized roles in AMS and 83 genes that are considered to be conserved in AM-host plants. Comparative transcriptome analysis revealed a 'core set' of 156 genes from P. trifoliata whose orthologous genes from at least three of the five species also exhibited similar transcriptional changes during AMS. Functional analysis of one of these conserved AM-induced genes, a 3-keto-acyl-ACP reductase (FatG) involved in fatty acid biosynthesis, confirmed its involvement in AMS in Medicago truncatula. Our results identify a core transcriptional program for AMS that is largely conserved between P. trifoliata and other plants. The comparative transcriptomics approach adds to previous phylogenomics studies to identify conserved genes required for AMS. PMID- 30312438 TI - Pro: Tolvaptan delays the progression of autosomal dominant polycystic kidney disease. AB - No treatment until now has directly targeted the mechanisms responsible for the development and growth of cysts in autosomal dominant polycystic kidney disease (ADPKD). Strong rationale and preclinical studies using in vitro and in vivo models justified the launching of two large phase 3 clinical trials of tolvaptan in early and later stages of ADPKD. Their design was based on preliminary studies informing on the pharmacokinetics, pharmacodynamics, short-term safety and self reported tolerability in patients with ADPKD. Tolvaptan slowed kidney growth in the early stage and estimated glomerular filtration rate decline in early and later stages of the disease. All participants had the opportunity to enroll in open-label extension trials to ascertain long-term safety and efficacy. In a single-center analysis of long-term outcomes, the effect of tolvaptan was sustained and cumulative over time supporting a disease-modifying effect of tolvaptan in ADPKD. In the countries where tolvaptan has been approved by regulatory agencies, patients with rapidly progressive ADPKD should be informed about the option of treatment including possible benefits and risks. If a decision to initiate treatment is made, prescribing physicians should educate the patients on the prevention of aquaresis-related adverse events and should be vigilant in the surveillance and management of the potential tolvaptan hepatotoxicity. Other vasopressin V2 receptor antagonists, possibly without potential hepatotoxicity, alternative strategies targeting vasopressin and combination with other drugs able to enhance the efficacy or reduce the aquaresis associated with tolvaptan, deserve further study. PMID- 30312436 TI - CUP-SHAPED COTYLEDON1 (CUC1) and CUC2 regulate cytokinin homeostasis to determine ovule number in Arabidopsis. AB - Seeds derive from ovules upon fertilization and therefore the total number of ovules determines the final seed yield, a fundamental trait in crop plants. Among the factors that co-ordinate the process of ovule formation, the transcription factors CUP-SHAPED COTYLEDON 1 (CUC1) and CUC2 and the hormone cytokinin (CK) have a particularly prominent role. Indeed, the absence of both CUC1 and CUC2 causes a severe reduction in ovule number, a phenotype that can be rescued by CK treatment. In this study, we combined CK quantification with an integrative genome-wide target identification approach to select Arabidopsis genes regulated by CUCs that are also involved in CK metabolism. We focused our attention on the functional characterization of UDP-GLUCOSYL TRANSFERASE 85A3 (UGT85A3) and UGT73C1, which are up-regulated in the absence of CUC1 and CUC2 and encode enzymes able to catalyse CK inactivation by O-glucosylation. Our results demonstrate a role for these UGTs as a link between CUCs and CK homeostasis, and highlight the importance of CUCs and CKs in the determination of seed yield. PMID- 30312439 TI - Liberalizing the diet of patients undergoing dialysis: are we ready? PMID- 30312440 TI - Identification of Rickettsial Infections (Rickettsia sp. TH2014) in Ctenocephalides orientis Fleas (Siphonaptera: Pulicidae). AB - Rickettsia felis (Rickettsiales: Rickettsiaceae) is an emergent human pathogen that causes febrile illnesses in various parts of the world. This study describes the identification and growth characteristics of a R. felis-like organism (designated as Rickettsia sp. TH2014) cultured from Ctenocephalides orientis fleas in rural Malaysia. In this study, culturing of rickettsiae from filtered triturated flea lysates was performed in Aedes albopictus C6/36 cells. Cytopathic effects were observed from one of the samples 4 d post-inoculation. Electron microscopy revealed actively replicating intracytosolic coccobacillary organisms in the rickettsia-infected cells. Sequence analysis of amplified citrate synthase (gltA) gene fragment shows complete match of the rickettsia with Rickettsia sp. Rf31 in Southeast Asia, and 'Candidatus Rickettsia senegalensis' strain PU01-02 in Africa. The whole-genome sequence of Rickettsia sp. TH2014 was determined and assembled. The estimated genome size and guanine + cytosine content of the rickettsia are 1.37 Mb and 32.9%, respectively. The high values of average nucleotide identity and tetra-nucleotide signature correlation index obtained from pairwise genome comparison study suggest the identification of the rickettsia as R. felis. The whole-genome single-nucleotide polymorphism analysis demonstrates close genetic relatedness of the rickettsia with R. felis and Rickettsia asemboensis. However, based on sequence analyses of rickettsial genes (16S rDNA, gltA, ompB, and sca4), Rickettsia sp. TH2014 is found to be distinct from R. felis and R. asemboensis. The sequence analyses reveal that Rickettsia sp. TH2014 is highly similar to 'Ca. Rickettsia senegalensis' detected in fleas from Africa, Asia, and North America. Further investigation to provide insights on pathogenic potential and transmission dynamics of the rickettsia is warranted. PMID- 30312442 TI - Decreasing vaccine coverage rates lead to increased vulnerability to the importation of vaccine-preventable diseases in Brazil. PMID- 30312441 TI - Proteomic Profile Associated with Loss of Spontaneous HIV-1 Elite Control. AB - Background: Elite Controllers (EC) spontaneously control plasma HIV-1-RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC). Comparative plasma shotgun proteomics was performed with TMT isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry. Results: Eighteen proteins exhibited differences comparing PC and pre-loss TC time points. These proteins were involved in proinflammatory mechanisms and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, Alpha-1-antichymotrypsin, Ficolin-2, 14-3-3 protein and Galectin-3-binding protein were considered potential biomarkers. Conclusion: The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration and coagulation. Galectin-3-binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in EC. PMID- 30312443 TI - The Debate About Nicotine Addiction and the Role of Medicinal Products: Commentary on Zeller. PMID- 30312444 TI - The Nicotine Continuum and Regulation: Additional Challenges to Converting an Important Concept into Policy: Commentary on Zeller. PMID- 30312446 TI - Data science and artificial intelligence to improve clinical practice and research. PMID- 30312445 TI - Mechanistic machine learning: how data assimilation leverages physiologic knowledge using Bayesian inference to forecast the future, infer the present, and phenotype. AB - We introduce data assimilation as a computational method that uses machine learning to combine data with human knowledge in the form of mechanistic models in order to forecast future states, to impute missing data from the past by smoothing, and to infer measurable and unmeasurable quantities that represent clinically and scientifically important phenotypes. We demonstrate the advantages it affords in the context of type 2 diabetes by showing how data assimilation can be used to forecast future glucose values, to impute previously missing glucose values, and to infer type 2 diabetes phenotypes. At the heart of data assimilation is the mechanistic model, here an endocrine model. Such models can vary in complexity, contain testable hypotheses about important mechanics that govern the system (eg, nutrition's effect on glucose), and, as such, constrain the model space, allowing for accurate estimation using very little data. PMID- 30312447 TI - Is living alone "aging alone"? Solitary living, network types and well-being. AB - Objectives: When identifying older adults who may be at risk of being without necessary supports, policy makers and scholars tend to focus on those living alone, neglecting differences within that group. We examine how their social networks contribute to subjective well-being, why some of them fare better and compare their well-being to older adults coresiding with others. Method: Data are from the fourth wave of the Survey of Health and Retirement in Europe (N=53,383). A network typology for older people living alone (N=10,047) is constructed using a latent class analysis. Using OLS regressions, we examined differences in subjective well-being (life satisfaction, satisfaction with social network, depression) by network type, adding adults coresiding with others (N=43,336) as comparison group. Results: We find four social network types among older adults living alone. The likelihood of having "restricted" and "child-based" networks is greater in Eastern and Southern European countries, whereas the likelihood of having "friend-oriented" networks is greater in Western and Northern European countries. Across countries, only those with "restricted" networks tend to have the poorest well-being. Those with "diverse" networks have even better well-being than coresiding older adults. Discussion: Our study shows the importance of drawing distinctions within the group of older adults living alone. Most (two thirds) are not vulnerable and at risk, but fare just as well or even better than peers who coreside with others. Country-level factors shape the opportunities to build satisfactory networks, but subjective well-being depends more strongly on individual resources, including social networks, than country-level factors. PMID- 30312448 TI - Unmarried older people: Are they socially better off today? AB - Objectives: Previous studies have shown that unmarried older adults are generally at disadvantage in personal networks and social well-being compared to the married. It can be questioned whether their situation has improved in contemporary society, as amongst others the stigma of divorce and being never married has declined. We hypothesize differential developments in networks and well-being according to marital status (married, widowed, divorced and never married) across birth cohorts. Method: Data are from the 1993 and 2013 observations of the Longitudinal Aging Study Amsterdam on Dutch people aged 55-69 (N = 2,894) and 70-84 years (N = 2,317). We employ general linear modelling of network size and diversity, received emotional and instrumental support, emotional and social loneliness, and depressive symptoms. Results: The widowed are better off socially in 2013 than in 1993. Similar to the divorced they have a larger network, and similar to the never-married they receive more emotional support and are less emotional lonely. We find some gender-differences in these developments. Discussion: Societal change has not radically altered networks and well-being of unmarried older people. The widowed seem to benefit most, possibly because they are better able to retain relationships after widowhood. PMID- 30312449 TI - Con: Tolvaptan for autosomal dominant polycystic kidney disease-do we know all the answers? AB - According to recent literature, tolvaptan ameliorates the natural decline of renal function in autosomal dominant polycystic kidney disease. Tolvaptan is an orally available vasopressin V2 receptor antagonist. We describe herein the remaining questions and problems: it is unclear from the published work what influence tolvaptan has on total kidney volume. The consequences of hepatotoxicity for the subsequent dosing of tolvaptan have not been reported. A vasopressin V2 antagonist will cause polyuria and polydipsia and tolvaptan may influence quality of life (QOL), however, there are no QOL data. The cost effectiveness of tolvaptan is borderline. It is unknown at which stage of renal failure tolvaptan therapy may have to be stopped. There are no established criteria to determine the ineffectiveness of tolvaptan. It is presently undecided whether a steady high water intake is able to imitate the renal effects of tolvaptan. Finally, the cause of worsening glomerular filtration rate after the start of tolvaptan is unknown. PMID- 30312450 TI - The Future of Nicotine Regulation: Key Questions and Challenges. PMID- 30312451 TI - Pain Expansion and Severity Reflect Central Sensitization in Primary Care Patients with Greater Trochanteric Pain Syndrome. AB - Objectives: The aims of this study were twofold: 1) to evaluate the differences in pain sensitivity of patients with greater trochanteric pain syndrome (GTPS) and 2) to examine the association between pain expansion, pain severity, and pain related central sensitization somatosensory variables in patients with GTPS. Study Design: A cross-sectional study. Setting: Primary health care centers. Subjects: The sample consisted of 49 participants with a mean age of 48.28 +/- 8.13 years and included eight males (16.3%) and 41 females (83.7%). Methods: Conditioned pain modulation (CPM), pain location, temporal summation, pressure pain detection threshold (PPDT), and pain intensity were recorded. Pain severity was determined with the Graded Chronic Pain Scale (GCPS). Results: Several participants (34.7%) showed a negative conditioned pain modulation and a statistically significant negative moderate correlation (P < 0.05; r = -0.316) between conditioned pain modulation and right view percentage of pain location. Temporal summation at the major trochanter showed a statistically significant low negative correlation (P < 0.05; r = -0.298). The GCPS exhibited a statistically significant moderately positive correlation (P < 0.01; r = 0.467) with the PPDT at the trochanter and a significant correlation with the postero-superior iliac spine (P < 0.01; r = 0.515) and epicondyle (P < 0.01; r = 0.566). Conclusions: Patients with GTPS presented altered CPM, a relationship with more pain areas associated with negative CPM, and a positive association between pain severity and mechanical hyperalgesia at remote sites. Thus, physicians could apply these outcome measurements to assess primary care patients with GTPS and determine the central sensitization presence to prescribe adequate multimodal treatment approaches. PMID- 30312453 TI - Winners and Losers: Communicating the Potential Impacts of Policies: Commentary on Zeller. PMID- 30312452 TI - Acting Now Is Urgent: Commentary on Zeller. PMID- 30312454 TI - Measles and human movement in Europe. PMID- 30312455 TI - Acroosteolysis in a patient with systemic lupus erythematosus/mixed connective tissue disease. PMID- 30312456 TI - The United States is not the World: Response to Zeller et al's Call for Discussion on Nicotine Regulation. PMID- 30312458 TI - Considerations for High-Risk Populations: Response to Zeller's The Future of Nicotine Regulation: Key Questions and Challenges. PMID- 30312459 TI - Chronic Pain Self-Management Program for Low-Income Patients: Themes from a Qualitative Inquiry. AB - Objective: To examine factors influencing initial engagement, ongoing participation, learned behaviors, and subjective functional outcomes after a trial of the Living Better Beyond Pain (LBBP) chronic pain self-management program. Design: Qualitative study using the Grounded Theory approach. Setting: Two 60-minute focus groups and phone interviews in May 2017. Subjects: Focus groups with 18 participants who completed LBBP and six-month measures; telephone interviews with 17 participants who stopped attending. Methods: Study coordinators randomly selected program completers for focus groups and conducted phone interviews with noncompleters. Inductive thematic analysis was used to identify patterns in semantic content with a recursive process applied to focus group transcripts and interview transcriptions to codify into themes. Themes were categorized according to the Theory of Planned Behavior. Results: Focus group and telephone interview participants were primarily Hispanic and unemployed. Attitudes fostering participation in LBBP included dissatisfaction with the status quo, need to reduce pain medication, and lack of training and knowledge about chronic pain. Positive social norms from meeting others with chronic pain and support from the LBBP team encouraged attendance and adoption of behaviors. Transportation, pain, and competing activities were barriers, whereas adapting activities for the disabled was a facilitator. Maintaining behaviors and activities at home was challenging but ultimately rewarding due to improvement in daily function with less pain medication. Conclusions: This qualitative study complements quantitative results showing clinically significant improvements in function after the LBBP program by adding practical insights into ways to increase participation and outcomes. Participants strongly endorsed the need for chronic pain self-management training. PMID- 30312460 TI - Atrazine Exposure Influences Immunity in the Blue Dasher Dragonfly, Pachydiplax longipennis (Odonata: Libellulidae). AB - Agricultural runoff containing herbicide is known to have adverse effects on freshwater organisms. Aquatic insects are particularly susceptible, and herbicide runoff has the potential to affect immunity in this group. Here we examined the effect of ecologically relevant levels of atrazine, an herbicide commonly used in the United States, on immune function in larvae of the blue dasher dragonfly (Odonata: Libelluludae, Pachydiplax longipennis Burmeister 1839) during a long term exposure at ecologically relevant concentrations. Larvae were exposed to concentrations of 0, 1, 5, and 10 ppb atrazine for 3 or 6 wk. Hemocyte counts, hemolymph phenyloxidase (PO) activity, cuticular PO, and gut PO were measured at the end of each trial period as indicators of immune system strength. Atrazine concentration had a significant effect on hemocyte counts after controlling for larval size. There was a significant interaction between time and concentration for hemolymph PO, cuticular PO, and a marginal interaction for gut PO. The effect of atrazine on the measured immune parameters was often nonmonotonic, with larger effects observed at intermediate concentrations. Therefore, atrazine affects both hemocyte numbers and PO activity over time in P. longipennis, and the changed immune function demonstrated in this study is likely to modify susceptibility to pathogens, alter wound healing, and may decrease available energy for growth and metamorphosis. PMID- 30312462 TI - Seeds with low phosphorus content: not so bad after all? PMID- 30312461 TI - Arabidopsis UMAMIT24 and 25 are amino acid exporters involved in seed loading. AB - Phloem-derived amino acids are the major source of nitrogen supplied to developing seeds. Amino acid transfer from the maternal to the filial tissue requires at least one cellular export step from the maternal tissue prior to the import into the symplasmically isolated embryo. Some members of UMAMIT (usually multiple acids move in an out transporter) family (UMAMIT11, 14, 18, 28, and 29) have previously been implicated in this process. Here we show that additional members of the UMAMIT family, UMAMIT24 and UMAMIT25, also function in amino acid transfer in developing seeds. Using a recently published yeast-based assay allowing detection of amino acid secretion, we showed that UMAMIT24 and UMAMIT25 promote export of a broad range of amino acids in yeast. In plants, UMAMIT24 and UMAMIT25 are expressed in distinct tissues within developing seeds; UMAMIT24 is mainly expressed in the chalazal seed coat and localized on the tonoplast, whereas the plasma membrane-localized UMAMIT25 is expressed in endosperm cells. Seed amino acid contents of umamit24 and umamit25 knockout lines were both decreased during embryogenesis compared with the wild type, but recovered in the mature seeds without any deleterious effect on yield. The results suggest that UMAMIT24 and 25 play different roles in amino acid translocation from the maternal to filial tissue; UMAMIT24 could have a role in temporary storage of amino acids in the chalaza, while UMAMIT25 would mediate amino acid export from the endosperm, the last step before amino acids are taken up by the developing embryo. PMID- 30312463 TI - Impairment of peroxisomal APX and CAT activities increases protection of photosynthesis. AB - Retrograde signalling pathways, triggered by changes in cellular redox homeostasis, remain poorly understood. Transformed rice plants that are deficient in peroxisomal APX4 (RNAiOsAPX4) exhibit more effective protection of photosynthesis than controls when catalase (CAT) is inhibited, but the mechanisms involved have not been characterised. An in-depth physiological and proteomics analysis was therefore performed on the RNAiOsAPX4-CAT-inhibited rice plants. Loss of APX4 function led to an increased abundance of several proteins that are involved in essential metabolic pathways, possibly as a result of increased tissue H2O2 levels. The higher photosynthetic activities measured in the RNAiOsAPX4 plants under CAT inhibition was accompanied by higher levels of Rubisco, a higher Vcmax and increased photochemical efficiencies, together with large increases in photosynthesis-related proteins. Large increases in the levels of proteins involved in the ascorbate/glutathione cycle and other antioxidant related pathways were observed and these changes may be important in the protection of photosynthesis in the RNAiOsAPX4 plants. Large increases in the abundance of proteins localised in the nuclei and mitochondria were also observed, together with increased levels of proteins involved in important cellular pathways, particularly protein translation. Taken together, the results show that RNAiOsAPX4 plants exhibit significant metabolic reprogramming, which incorporate a more effective antioxidant response to protect photosynthesis under conditions of impaired CAT activity. PMID- 30312464 TI - Is it time to replace conventional angiography with coronary computed tomography? PMID- 30312465 TI - History and Current Trends in the Electronic Nicotine Delivery Systems Retail Marketplace in the United States: 2010-2016. AB - Introduction: The US market for electronic nicotine delivery systems (ENDS) has grown rapidly in the last decade. There is limited published evidence examining changes in the ENDS marketplace prior to the US Food and Drug Administration's (FDA) deeming rule in 2016. This study describes US ENDS retail market trends from 2010 to 2016. Methods : ational data were obtained from Nielsen retail scanners for five product types: (1) disposables, (2) rechargeables, (3) cartridge replacements, (4) e-liquid bottle refills, and (5) specialty vapor products. We examined dollar sales, volume, price, brand, and flavor. Results: Adjusted national sales increased from $11.6 million in 2010 to $751.2 million in 2016. The annual rate of sales growth rapidly increased before slowing through 2015. The rate of growth spiked in 2016. Market share for menthol products and other assorted flavors increased from 20% in 2010 to 52.1% by 2016. NJOY's early market dominance shifted as tobacco industry brands entered the market and eventually captured 87.8% of share by 2016. Rechargeables and accompanying products comprised an increased proportion of total volume sold over time while disposable volume declined. Specialty vapor products appeared at retail in 2015. Conclusions: Findings show strong early growth in the ENDS retail market followed by considerable slowing over time, despite a slight uptick in 2016. Trends reflect shifts to flavored products, newer generation "open-system" devices, lower prices, and tobacco industry brands. This study provides a baseline against which to compare the impact of FDA's 2016 deeming rule and future actions on the ENDS marketplace. Implications: This study uses market scanner data from US retail outlets to describe trends in the ENDS retail market from 2010 to 2016, providing a baseline against which to compare the impact of FDA's 2016 deeming rule and future actions on the ENDS marketplace. Understanding historical market trends is valuable in assessing how future regulatory efforts and advances in ENDS technology may impact industry response and consumer uptake and use. PMID- 30312457 TI - Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study. AB - Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management. PMID- 30312466 TI - Relative bioavailability of l-lysine sulfate is equivalent to that of l-lysine HCl for nursery piglets. AB - Supplementary l-lysine sources include l-lysine HCl and l-lysine sulfate. L Lysine sulfate contains at least 50% l-Lys and other components as residues from the fermentation process, other amino acids, and other organic and inorganic substances, being an alternative to l-Lys HCl. The aim of this study was to evaluate the relative bioavailability (RBV) of l-Lys sulfate in comparison with l Lys HCl and its effects on performance, blood parameters, intestinal functionality, and the apparent total tract digestibility in nursery piglets. A total of 168 female piglets (DB90 * PIC337), weaned at 22 d (BW = 6.29 +/- 0.41 kg), were distributed in seven dietary treatments and eight replicates, with three pigs per pen. The experimental period of 42 d was divided into two phases (phase 1, days 0-21; phase 2, days 21 to 42). The basal diet (CON) was lysine deficient formulated to meet 73% of standardized ileal digestible Lys requirements. For the other diets, the CON was supplemented with three levels (80%, 90%, and 100% of standardized ileal digestible Lys requirements) of l-Lys sulfate (70% l-Lys) or l-Lys HCl (79% l-Lys). There were no significant differences (P > 0.05) in the performance and concentrations of plasma urea and creatinine between the l-Lys sources. The RBV of l-Lys sulfate relative to l-Lys HCl was 106%, 119%, and 117% for effects on ADG, G:F, and plasma urea, respectively. Lys deficiency resulted in a greater (P < 0.05) incidence of diarrhea, while pigs supplemented with Lys sulfate or Lys HCl showed greater (P < 0.05) villus height in the jejunum when compared to those receiving the CON. Diets supplemented with l-Lys sulfate had greater (P < 0.05) apparent total tract digestibility of dry matter, gross energy, and crude protein. In conclusion, the RBV of l-Lys sulfate for effects on ADG, G:F, and plasma urea is equivalent to that of l-Lys HCl for nursery piglets. PMID- 30312467 TI - Erratum to: Oral Presentations of the 2018 Annual Meeting of the Congress of Neurological Surgeons. PMID- 30312468 TI - The Debate About Nicotine Regulation: Commentary on Zeller. PMID- 30312470 TI - Prevalence and impact of dysmenorrhea in Swedish adolescents. AB - INTRODUCTION: The objective of this study was to estimate the prevalence of dysmenorrhea among adolescents and its effect on daily life. MATERIAL AND METHODS: A web-based questionnaire with questions regarding menstrual symptoms was distributed to all girls born in 2000 and residing in Stockholm City (n = 3998). Questions regarding pain severity, other menstrual-related symptoms, medical treatment, healthcare visits, social and academic absenteeism were included in the questionnaire. RESULTS: A total of 1785 (45%) young women responded to the questionnaire. Of these, 1580 (89%, 95% CI 87-90) stated that they had dysmenorrhea. Severe dysmenorrhea, scores 8-10 on the numeric rating scale for pain, was reported by 574 of 1580 women (36%, 95% CI 34-39). Fatigue was reported by 1314 of 1580 women (83%, 95% CI 81-85), headache by 1296 (82%, 95% CI; 80-84), dyschezia by 578 (37%, 95% CI 34-39) and dysuria by 560 (35%, 95% CI 33-38). A suboptimal use of analgesics was reported. Hormonal therapy as pain treatment was used by 10% (157/1580, 95% CI 9-12). Healthcare facilities, including school nurses, had been visited by 525 of 1580 women (33%, 95% CI; 31 36). Doctors had been consulted by 7% (116/1580, 95% CI 6-9). Fifty-nine percent (930/1580, 95% CI 56-61) reported refraining from social activities due to dysmenorrhea. Absenteeism from school was reported to occur monthly by 228 of 1580 women (14%, 95% CI 13-16), and several times per year by 716 (45%, 95% CI 43 48). CONCLUSIONS: Our findings demonstrate that menstrual pain is prevalent among teenagers in Stockholm. The results indicate that many women are disabled in their daily life and that only a small number of women seek medical attention, although possible selection bias might have affected the results. Information and education are needed to optimize the use of existing treatment options and more awareness is needed to reduce normalization of disabling dysmenorrhea. PMID- 30312469 TI - The somatic piRNA pathway controls germline transposition over generations. AB - Transposable elements (TEs) are parasitic DNA sequences that threaten genome integrity by replicative transposition in host gonads. The Piwi-interacting RNAs (piRNAs) pathway is assumed to maintain Drosophila genome homeostasis by downregulating transcriptional and post-transcriptional TE expression in the ovary. However, the bursts of transposition that are expected to follow transposome derepression after piRNA pathway impairment have not yet been reported. Here, we show, at a genome-wide level, that piRNA loss in the ovarian somatic cells boosts several families of the endogenous retroviral subclass of TEs, at various steps of their replication cycle, from somatic transcription to germinal genome invasion. For some of these TEs, the derepression caused by the loss of piRNAs is backed up by another small RNA pathway (siRNAs) operating in somatic tissues at the post transcriptional level. Derepressed transposition during 70 successive generations of piRNA loss exponentially increases the genomic copy number by up to 10-fold. PMID- 30312471 TI - Titanium particles generated during ultrasonic scaling of implants. AB - BACKGROUND: There is growing concern that titanium particles may play a role in peri-implant breakdown. Ultrasonic scalers are routinely used in the debridement of peri-implant lesions. This in vitro study is designed to evaluate if titanium particles are produced when an ultrasonic scaler is used on an implant. METHODS: New sandblasted, large grit, acid etched (SLA) coated implants were subjected to ultrasonic scaling with stainless steel, titanium, and PEEK plastic tips. The implants were placed in a holding device and the ultrasonic scaler was positioned on the SLA surface under 25 grams of pressure. The implants were subjected to 30 scaling motions. The ultrasonic coolant water was collected and the number of metallic particles were counted under a light microscope. The particles were confirmed to be titanium via elemental analysis. The implants were visually evaluated for damage to the SLA coating. RESULTS: No metallic particles were detected in the water supplied to the ultrasonic scalers (passive control). Metallic particles were detected when implants were subjected to the ultrasonic coolant water only without the scaler tip touching the implant (active control). All implants that were scaled produced metallic particles and showed easily detectable damage to the SLA layer. CONCLUSION: All ultrasonic scaling caused the production of titanium particles and caused damage to the SLA coating of the implant. Ultrasonic scalers should be used with great caution in the treatment of peri-implant conditions and care should be taken to not touch the SLA surface of the implant. PMID- 30312472 TI - Histopathological Profile In Fatal Yellow Phosphorous Poisoning. AB - Yellow phosphorous (YP) is the toxic form of elemental phosphorous and the chief constituent of firecrackers and rodenticides. In India, the rodenticide paste is frequently used for the suicidal purpose. This study is an autopsy-based observational study which describes the histopathological features of heart, lungs, liver, and kidney of fatal cases of YP poisoning. The most common autopsy features in the viscera were congestion and petechial hemorrhage. The liver histopathology findings were microvesicular steatosis (68%), hepatic necrosis (62%), macrovesicular steatosis (50%), inflammatory cells (46%), sinusoidal congestion (40%), cholestasis (32%), and toxic hepatitis (18%). Hepatic necrosis ranged from being focal to centrizonal in distribution. Congestion was the most common feature observed in the lungs and the kidney. This is the largest autopsy based study on YP poisoning till date. The histopathological features of liver were consistent with YP poisoning whereas the findings of heart, lungs, and kidney were nonspecific in nature. PMID- 30312473 TI - Can Neck Contusions in Unexplained Pediatric Deaths be Explained by Cardiopulmonary Resuscitation? AB - The distribution of cutaneous contusions in infants may raise the possibility of maltreatment. Neck contusions are particularly problematic since they seldom occur outside the setting of abuse, while cardiopulmonary resuscitation (CPR) related maneuvers may involve the neck. To address the role of CPR in neck findings, we examined 260 consecutive pediatric autopsies in which CPR was attempted. No neck contusions were identified in manners of death classified as natural, undetermined, or suicide. Contusions were present in two of 80 deaths classified as accident and had obvious accidental causes. About 26% of deaths classified as homicide had neck contusions with no explanation provided by the caregiver (p < 0.0001). In conclusion, neck contusions in deceased children with no apparent explanation should be regarded as suspicious for abuse and investigated accordingly. CPR is not a plausible explanation for neck contusions in children. PMID- 30312474 TI - Cardiovascular Disease Profile of the Oldest Adults in Rural South Africa: Data from the HAALSI Study (Health and Aging in Africa: Longitudinal Studies of INDEPTH Communities). AB - OBJECTIVES: To characterize the cardiovascular disease (CVD) profile of individuals aged 80 and older in rural South Africa. DESIGN: First wave of population-based longitudinal cohort. SETTING: Agincourt subdistrict (Mpumalanga Province) in rural South Africa. PARTICIPANTS: Adults residents (N = 5,059). MEASUREMENTS: In-person interviews were conducted to obtain social, behavioral, economic, and clinical data. Prevalence of hypertension, diabetes, dyslipidemia, high waist-to-hip ratio, overweight and obesity, high-risk high-sensitivity C reactive protein, smoking, stroke, myocardial infarction, angina pectoris, and heart failure in individuals younger than 65, aged 65 to 79, and aged 80 and older were compared. Associations between self-reported treatments and determinants of hypertension treatment in those aged 80 and older were assessed using multivariable regression. RESULTS: Of 5,059 individuals included, 549 (10.8%) were aged 80 and older, and their CVD prevalence was 17.9% (stroke 3.8%, myocardial infarction 0.5%, angina pectoris 13.5%, heart failure 0.7%). Hypertension prevalence in this group was 73.8%, and along with angina pectoris, it increased with age (p<.001), whereas overweight and obesity (46.4%), dyslipidemia (39.1%), and smoking prevalences (3.1%) decreased (p<.001). Hypertension treatment was significantly associated with being aged 80 and older (odds ratio (OR)=1.48; 95% confidence interval (CI)=1.14-1.92, p=.003). Male sex (OR=0.73, 95% CI=0.66-0.88, p=.001), being an immigrant (OR=0.80, 95% CI=0.65 0.98; p=.03), higher socioeconomic status (OR=1.28, 95% CI=1.06-1.53, p=.009), and higher depression score (OR=1.12, 95% CI=1.05-1.19, p<.001) were associated with hypertension treatment in those aged 80 and older. CONCLUSION: This is the first study to characterize the CVD profile of individuals aged 80 and older in sub-Saharan Africa and provides baseline data for comparison with future studies in this rapidly growing age group. J Am Geriatr Soc 66:2151-2157, 2018. PMID- 30312475 TI - A Comparative Study on the Photophysical and Photochemical Properties of Dyes in the Presence of Low Generation Amino-terminated Polyamidoamine Dendrimers. AB - The photophysical and photochemical properties of the xanthene dyes mercurochrome (MCr) and eosin-Y (Eos); and the phenazine dye safranine-O (SF) are evaluated in the presence of amino-terminated polyamidoamine (PAMAM) dendrimers of low generations. The dendrimers produce a red shift in the UV-vis absorption spectra of the dyes, which increases with concentration and the size of the PAMAM molecule. The Stern-Volmer plots of fluorescence quenching for xanthenic dyes present a downward curvature. It is ascribed to a static mechanism involving a dye-dendrimer binding. A non-linear fitting of the SV plots allows the calculation of the binding constants. For SF, the fluorescence is only slightly quenched by PAMAMs and the SV plots are linear. The binding constants are in the order Kbind (SF) ? Kbind (Eos) < Kbind (MCr). The difference must be due to important specific structural effects. A decrease in the triplet lifetime and an increase in the absorption of the semireduced form of the dyes are observed in the presence of dendrimers. While for the two xanthene dyes, the rate constants reach the diffusional limit for G2 and G3, for SF they are one order of magnitude lower. This is explained by a different quenching mechanism of the two types of dyes. PMID- 30312477 TI - Improved Methods for Estimating Flood Depth Exceedances Within Storm Surge Protection Systems. AB - Contemporary studies conducted by the U.S. Army Corps of Engineers estimate probability distributions of flooding on the interior of ring levee systems by estimating surge exceedances at points along levee system boundaries, calculating overtopping volumes generated by this surface, then passing the resulting volumes of water through a drainage model to calculate interior flood depths. This approach may not accurately represent the exceedance probability of flood depths within the system interior; a storm producing 100-year surge at one point is unlikely to simultaneously produce 100-year surge levels everywhere around the system exterior. A conceptually preferred approach estimates surge and waves associated with a large set of storms. Each storm is run through the interior model separately, and the resulting flood depths are weighted by a parameterized likelihood of each synthetic storm. This results in an empirical distribution of flood depths accounting for geospatial variation in any individual storm's characteristics. This method can also better account for the probability of levee breaches or other system failures. The two methods can produce different estimates of flood depth exceedances and damage when applied to storm surge flooding in coastal Louisiana. Even differences in flood depth exceedances of less than 0.2 m can still produce large differences in projected damage. This article identifies and discusses differences in estimated flood depths and damage produced by each method within multiple Louisiana protection systems. The novel coupled dynamics approach represents a step toward enabling risk-based design standards. PMID- 30312476 TI - Models, movements, and minds: bridging the gap between decision making and action. AB - Decision making is a fundamental cognitive function, which not only determines our day-to-day choices but also shapes the trajectories of our movements, our lives, and our societies. While immense progress has been made in recent years on our understanding of the mechanisms underlying decision making, research on this topic is still largely split into two halves. Good-based models largely state that decisions are made between representations of abstract value associated with available options; while action-based models largely state that decisions are made at the level of action representations. These models are further divided between those that state that a decision is made before an action is specified, and those that regard decision making as an evolving process that continues until movement completion. Here, we review computational models, behavioral findings, and results from neural recordings associated with these frameworks. In synthesizing this literature, we submit that decision making is best understood as a continuous, graded, and distributed process that traverses a landscape of behaviorally relevant options, from their presentation until movement completion. Identifying and understanding the intimate links between decision making and action processing has important implications for the study of complex, goal directed behaviors such as social communication, and for elucidating the underlying mechanisms by which decisions are formed. PMID- 30312478 TI - Security of Separated Data in Cloud Systems with Competing Attack Detection and Data Theft Processes. AB - Empowered by virtualization technology, service requests from cloud users can be honored through creating and running virtual machines. Virtual machines established for different users may be allocated to the same physical server, making the cloud vulnerable to co-residence attacks where a malicious attacker can steal a user's data through co-residing their virtual machines on the same server. For protecting data against the theft, the data partition technique is applied to divide the user's data into multiple blocks with each being handled by a separate virtual machine. Moreover, early warning agents (EWAs) are deployed to possibly detect and prevent co-residence attacks at a nascent stage. This article models and analyzes the attack success probability (complement of data security) in cloud systems subject to competing attack detection process (by EWAs) and data theft process (by co-residence attackers). Based on the suggested probabilistic model, the optimal data partition and protection policy is determined with the objective of minimizing the user's cost subject to providing a desired level of data security. Examples are presented to illustrate effects of different model parameters (attack rate, number of cloud servers, number of data blocks, attack detection time, and data theft time distribution parameters) on the attack success probability and optimization solutions. PMID- 30312479 TI - Secondary cell wall biosynthesis. AB - Contents Summary 1 I. Introduction 1 II. Cellulose biosynthesis 3 III. Xylan biosynthesis 7 IV. Glucomannan biosynthesis 11 V. Lignin biosynthesis 12 VI. Concluding remarks 15 Acknowledgements 15 References 15 SUMMARY: Secondary walls are synthesized in specialized cells, such as tracheary elements and fibers, and their remarkable strength and rigidity provide strong mechanical support to the cells and the plant body. The main components of secondary walls are cellulose, xylan, glucomannan and lignin. Biochemical, molecular and genetic studies have led to the discovery of most of the genes involved in the biosynthesis of secondary wall components. Cellulose is synthesized by cellulose synthase complexes in the plasma membrane and the recent success of in vitro synthesis of cellulose microfibrils by a single recombinant cellulose synthase isoform reconstituted into proteoliposomes opens new doors to further investigate the structure and functions of cellulose synthase complexes. Most genes involved in the glycosyl backbone synthesis, glycosyl substitutions and acetylation of xylan and glucomannan have been genetically characterized and the biochemical properties of some of their encoded enzymes have been investigated. The genes and their encoded enzymes participating in monolignol biosynthesis and modification have been extensively studied both genetically and biochemically. A full understanding of how secondary wall components are synthesized will ultimately enable us to produce plants with custom-designed secondary wall composition tailored to diverse applications. PMID- 30312480 TI - Genomic coordinates and continental distribution of 120 blood group variants reported by the 1000 Genomes Project. AB - BACKGROUND: The 1000 Genomes Project provides a database of genomic variants from whole genome sequencing of 2504 individuals across five continental superpopulations. This database can enrich our background knowledge of worldwide blood group variant geographic distribution and identify novel variants of potential clinical significance. STUDY DESIGN AND METHODS: The 1000 Genomes database was analyzed to 1) expand knowledge about continental distributions of known blood group variants, 2) identify novel variants with antigenic potential and their geographic association, and 3) establish a baseline scaffold of chromosomal coordinates to translate next-generation sequencing output files into a predicted red blood cell (RBC) phenotype. RESULTS: Forty-two genes were investigated. A total of 604 known variants were mapped to the GRCh37 assembly; 120 of these were reported by 1000 Genomes in at least one superpopulation. All queried variants, including the ACKR1 promoter silencing mutation, are located within exon pull-down boundaries. The analysis yielded 41 novel population distributions for 34 known variants, as well as 12 novel blood group variants that warrant further validation and study. Four prediction algorithms collectively flagged 79 of 109 (72%) known antigenic or enzymatically detrimental blood group variants, while 4 of 12 variants that do not result in an altered RBC phenotype were flagged as deleterious. CONCLUSION: Next-generation sequencing has known potential for high-throughput and extended RBC phenotype prediction; a database of GRCh37 and GRCh38 chromosomal coordinates for 120 worldwide blood group variants is provided as a basis for this clinical application. PMID- 30312481 TI - Synthesis of magnetic nanoparticle-based molecularly imprinted polymer as a selective sorbent for efficient extraction of ezetimibe from biological samples. AB - In the present study, a novel and efficient adsorbent constructed of molecularly imprinted polymer on the surface of modified magnetic nanoparticles with oleic acid (MNPs) was applied for the selective extraction of ezetimibe. The magnetic molecularly imprinted polymer (MMIP) was polymerized at the surface of modified MNPs using methacrylic acid as functional monomer, ezetimibe as template and ethylene glycol dimethacrylate as cross-linker. The resulting MMIP showed high adsorption capacity, good selectivity and fast kinetic binding for the template molecule. It was characterized by Fourier transform infrared analysis, scanning electron microscopy and transmission electron microscopy methods. The maximum adsorption capacity of MMIP was obtained as 137.1 mg g-1 and it took about 20 min to achieve the equilibrium state. The adsorption model of the adsorbent was fitted with the Freundlich and Langmuir isotherm equations. The assay exhibited a linear range of 0.003-20.000 mg L-1 for ezetimibe with a correlation coefficient of 0.995. The relative standard deviations for the recoveries were <5.2. The method was also examined for the analysis of ezetimibe in the biological samples. PMID- 30312483 TI - Effects of glaciation and whole genome duplication on the distribution of the Campanula rotundifolia polyploid complex. AB - PREMISE OF THE STUDY: Both intrinsic and extrinsic factors contribute to a species distribution. Among plants, the extrinsic effects of glaciation and intrinsic effects of whole genome duplication are powerful drivers of biogeographical patterns, but the interplay of these factors is poorly understood. Here, we investigate the roles glaciation and whole-genome duplication have played in the evolution of the widespread polyploid complex Campanula rotundifolia. METHODS: We assessed the cytotype of 37 populations that spanned the geographic and cytotypic range of the C. rotundifolia complex. We constructed a chloroplast phylogeny for these populations and used RAD-seq to create nuclear phylogenies and networks for a subset of 23 populations; and estimated divergence times of major clades using Bayesian estimation of substitution rates. KEY RESULTS: Campanula rotundifolia originated in south central Europe and underwent range expansion throughout much of Europe and North America. Multiple genome duplications have occurred in C. rotundifolia-at least two tetraploid and three hexaploid formations. CONCLUSIONS: Nuclear and chloroplast phylogenies are largely congruent with a history of populations surviving glacial maxima in known Pleistocene refugia in Europe and North America. Divergent European clades are consistent with two disjunct glacial refugia within Europe. North America was colonized by hexaploids derived from Western European lineages. A glacial refugium in Midwestern North America likely facilitated post-glacial recolonization of North America and limited genetic divergence. These results implicate both glaciation and whole-genome duplication as contributing factors to the extant biogeography of C. rotundifolia. PMID- 30312482 TI - The efficacy of extracorporeal photopheresis to arrest bronchiolitis obliterans in lung allograft recipients was compared between two automated photopheresis instruments. AB - BACKGROUND: The most common instruments used for extracorporeal photopheresis (ECP) treatment in the United States are the UVAR XTS and the CELLEX devices (Therakos, West Chester, PA). When compared to the UVAR XTS instrument, the efficacy of the CELLEX instrument to arrest the decline in lung function in patients with chronic lung allograft dysfunction (CLAD) related to bronchiolitis obliterans (BOS) has not been previously evaluated. METHODS: The relative efficacy of the CELLEX vs UVAR XTS ECP instruments was assessed by comparing the difference in rates of FEV1 decline before and after ECP treatment and survival in two series of lung allograft recipients with BOS who had been treated with these instruments. RESULTS: Similar Slope Difference values for change in rate of decline (6 months Post ECP - Pre ECP) were observed between the two cohorts (UVAR XTS: 85 +/- 109 mL/month vs CELLEX: 76 +/- 128 mL/month, p=0.72). A similar percentage of patients responded to ECP (UVAR XTS: 77% vs CELLEX: 89%; p=0.36) i.e., as defined as a positive difference in slope between the rate of decline of FEV1 before and 6 months after ECP. Survival at either 6 (p=0.89) or 12 (p=0.8) months after the start of ECP was not associated with instrument used despite a trend in higher early mortality (34% vs 17%, p=0.054) in the patients who were predominately treated with the CELLEX. CONCLUSIONS: Our data support the use of the CELLEX for prospective studies designed to evaluate the merits of ECP in this population. PMID- 30312484 TI - Vestured pits and scalariform perforation plate morphology modify the relationships between angiosperm vessel diameter, climate and maximum plant height. AB - Shared ancestry among species and correlation between vessel diameter and plant height can obscure the mechanisms linking vessel diameter to current climate distributions of angiosperms. Because wood is complex, various traits may interact to influence vessel function. Specifically, pit vesturing (lignified cell wall protuberances associated with bordered pits) and perforation plate morphology could alter the relationships between vessel diameter, climate and plant height. Using phylogenetically informed analyses, we tested for associations between vessel diameter, climate and maximum plant height across angiosperm species with different pit vesturing (presence/absence) and perforation plate morphology (simple/scalariform and quantitative variation). We show significantly larger changes in vessel diameter and maximum plant height across climates for species with vestures and simple perforation plates, compared to nonvestured species and those with scalariform plates. We also found a significantly greater increase in height for a given increase in vessel diameter with lower percentage of scalariform plates. Our study provides novel insights into the evolution of angiosperm xylem by showing that vessel pit vesturing and perforation plate morphologies can modify relationships among xylem vessels, climate and height. Our findings highlight the complexity of xylem adaptations to climate, substantiating an integrative view of xylem function in the study of wood evolution. PMID- 30312485 TI - Development of the Pica, ARFID, and Rumination Disorder Interview, a multi informant, semi-structured interview of feeding disorders across the lifespan: A pilot study for ages 10-22. AB - OBJECTIVE: Avoidant/restrictive food intake disorder (ARFID), pica, and rumination disorder (RD) were added to the revised DSM-5 Feeding and Eating Disorders chapter in 2013. We developed a structured interview-the Pica, ARFID, and Rumination Disorder Interview (PARDI)-to assess the presence and severity of these diagnoses for evaluation and treatment planning in clinical and research settings. Here, we describe the development of the PARDI and provide a preliminary report on feasibility, acceptability, reliability, and validity in relation to ARFID. METHOD: We created an initial item pool from existing measures of similar constructs and clinical experience. The PARDI includes items assessing the level of endorsement and overall severity of common ARFID features organized into profiles (i.e., sensory sensitivity, lack of interest in eating, and fear of aversive consequences) and algorithms for diagnosing ARFID, pica, and RD. We collected initial psychometric data from participants (10-22 years) with ARFID (n = 39), clinically significant avoidant/restrictive eating (n = 8), and healthy controls (n = 10). RESULTS: On average, the PARDI took 39 min to complete and was acceptable to participants. All subscales achieved internal consistency greater >=0.77, and inter-rater reliability for the ARFID diagnosis was moderate (kappa = 0.75). Individuals with ARFID scored significantly higher than healthy controls on ARFID severity and ARFID profiles. DISCUSSION: The PARDI appears acceptable to respondents and preliminary evidence of reliability and validity has been demonstrated in an initial sample. Larger-scale validation studies are currently underway. The PARDI is freely available to clinicians and researchers. PMID- 30312486 TI - Gonadotropin-releasing hormone agonist induces downregulation of tensin 1 in women with endometriosis. AB - INTRODUCTION: Many cell migration-related molecules are associated with endometriosis. Tensin 1 (TNS1), which has been implicated in cell migration, may play a role in endometriosis. The study goal was to evaluate the TNS1 expression in endometrial tissue and serum from women with endometriosis treated with gonadotropin-releasing hormone agonist (GnRHa). MATERIAL AND METHODS: Tissue and serum samples were collected from women with endometriosis who were treated (n = 29) with GnRHa or untreated (n = 30). TNS1 mRNA was examined using quantitative PCR. TNS1 protein levels in tissue and serum samples were investigated using Western blot, immunohistochemistry and ELISA. Eleven women with endometriosis participated in a follow-up investigation of serum TNS1 before and after GnRHa treatment. RESULTS: TNS1 mRNA (P = 0.006) and protein (P = 0.001) were significantly downregulated in endometriotic tissue from women with endometriosis who received GnRHa. Immunolocalization of TNS1 showed strong expression in the epithelial and stromal cells of endometriotic tissue from women untreated with GnRHa, whereas endometriotic tissue from GnRHa-treated women showed low TNS1 expression. Follow-up monitoring of serum TNS1 concentration in 11 women showed an average decrease in concentration of 53%, from 294.9 +/- 66.69 to 140.3 +/- 55.21 pg/mL, following GnRHa treatment (P = 0.003). CONCLUSIONS: GnRHa induces downregulation of TNS1 in tissue and serum in women with endometriosis. These results emphasize the importance TNS1 as a potential therapeutic molecular target for the treatment of endometriosis with GnRHa. PMID- 30312487 TI - Decision-Making Analytics Using Plural Resilience Parameters for Adaptive Management of Complex Systems. AB - It is critical for complex systems to effectively recover, adapt, and reorganize after system disruptions. Common approaches for evaluating system resilience typically study single measures of performance at one time, such as with a single resilience curve. However, multiple measures of performance are needed for complex systems that involve many components, functions, and noncommensurate valuations of performance. Hence, this article presents a framework for: (1) modeling resilience for complex systems with competing measures of performance, and (2) modeling decision making for investing in these systems using multiple stakeholder perspectives and multicriteria decision analysis. This resilience framework, which is described and demonstrated in this article via a real-world case study, will be of interest to managers of complex systems, such as supply chains and large-scale infrastructure networks. PMID- 30312488 TI - Top 10 mistakes made in research. PMID- 30312489 TI - The Will to Meaning: Seeking the Why of Our Existence. PMID- 30312490 TI - The Athletes' Relationships with Training scale (ART): A self-report measure of unhealthy training behaviors associated with eating disorders. AB - OBJECTIVE: Several studies indicate that eating-disorder (ED) psychopathology is elevated in athletes compared to non-athletes. The assessment of excessive exercise among athletes is a challenge because, compared to non-athletes, athletes are required to train at higher intensities and for longer periods of time. However, individuals participating in competitive sports are still susceptible to unhealthy physical-activity patterns. Most ED assessments were developed and normed in non-athlete samples and, therefore, do not capture the nuances of athletes' training experiences. The purpose of the current study was to develop and validate a clinically useful, self-report measure of unhealthy training behaviors and beliefs in athletes, the Athletes' Relationships with Training Scale (ART). METHOD: The initial item pool was administered to N = 267 women collegiate athletes who were participating in an ED prevention program study and N = 65 women athletes who were in ED treatment. RESULTS: Factor analyses indicated the ART had a four-factor structure. Factorial and construct validity of the ART were demonstrated. ART scores significantly predicted health care utilization and differed between athletes with an ED versus athletes without an ED. For athletes in ED treatment, ART scores significantly decreased from treatment admission to discharge. DISCUSSION: The ART showed evidence of strong psychometric properties and clinical utility. The ART could be helpful for clinicians and athletic trainers to help gauge whether athletes are engaging in unhealthy training practices that may warrant clinical attention and for tracking clinical outcomes in athletes with EDs who are receiving treatment. PMID- 30312491 TI - Glycinergic neurotransmission in the RVLM controls the time course of baroreflex mediated sympathoinhibition. AB - KEY POINTS: To maintain appropriate blood flow to various tissues of the body under a variety of physiological states, autonomic nervous system reflexes regulate regional sympathetic nerve activity and arterial blood pressure. Our data in anesthetized rats revealed that glycine released in the RVLM plays a critical role in maintaining arterial baroreflex sympathoinhibition. Manipulation of brainstem nuclei with known inputs to the RVLM (NTS and CVLM) unmasked tonic glycinergic inhibition in the RVLM. Patch-clamp, whole-cell recordings demonstrate that both GABA and glycine inhibit RVLM neurons. Potentiation of neurotransmitters release from the active synaptic inputs in the RVLM produced saturation of GABAergic, and emergence of glycinergic inhibition. Our data suggest that GABA controls threshold excitability, while glycine increases the strength of inhibition under conditions of increased synaptic activity within the RVLM. ABSTRACT: The arterial baroreflex is a rapid negative-feedback system that compensates changes in blood pressure (BP) by adjusting output of presympathetic neurons in the rostral ventrolateral medulla (RVLM). GABAergic projections from the caudal VLM (CVLM) provide a primary inhibitory input to presympathetic RVLM neurons. Although glycine-dependent regulation of RVLM neurons has been proposed, its role in determining RVLM excitability is ill-defined. The purpose of this study was to determine the physiological role of glycinergic neurotransmission in baroreflex function, identify mechanisms for glycine release, and evaluate co inhibition of RVLM neurons by GABA and glycine. Microinjection of the glycine receptor antagonist strychnine (4 mM, 100 nl) into the RVLM decreased the duration of baroreflex-mediated inhibition of renal sympathetic nerve activity (RSNA) (Control = 12 +/- 1; RVLM-strychnine = 5.1 +/- 1 min), suggesting that RVLM glycine plays a critical role in regulating the time course of sympathoinhibition. Blockade of output from the nucleus tractus solitarius (NTS) and/or disinhibition of the CVLM unmasked tonic glycinergic inhibition of the RVLM. To evaluate cellular mechanisms, RVLM neurons were retrogradely labelled (prior injection of pseudorabies virus [PRV-152]) and whole-cell, patch-clamp recordings were obtained in brainstem slices. In steady state conditions GABAergic inhibition of RVLM neurons predominated and glycine contributed less than 25 % of overall inhibition. In contrast, stimulation of synaptic inputs in the RVLM decreased GABAergic inhibition by 35 % and increased glycinergic inhibition by 47 %. Thus, under conditions of increased synaptic activity in the RVLM, glycinergic inhibition is recruited to strengthen sympathoinhibition. This article is protected by copyright. All rights reserved. PMID- 30312493 TI - Review findings included diminished coronary flow reserve after surgery in children with congenital heart disease and inflammation. AB - AIM: The aim of this review was to develop a deeper knowledge of the physiology of coronary blood flow and coronary flow reserve in young patients with congenital heart disease and inflammatory diseases. METHODS: We searched for papers published in English on coronary blood flow and coronary flow reserve using the PubMed and Google search databases. This identified 42 papers extending back to 1976 and a book from 2008 (Davis et al. Microcirculation. Boston, MA: Elsevier, 2008: 161-284). RESULTS: Our review showed that the implications of coronary blood flow and coronary flow reserve in paediatric patients with congenital heart disease and inflammatory diseases are still not fully understood. However, a key finding was that coronary flow reserve was diminished in patients with congenital heart disease and inflammation after surgery, with or without a cardiopulmonary bypass. Other findings discussed by this review relate to volume and pressure overload in acyanotic congenital heart disease, reduced myocardial perfusion and cyanotic congenital heart disease. CONCLUSION: We still have much to discover about paediatric patients with congenital heart disease and inflammatory diseases. Understanding the pathophysiology of coronary blood flow could help the postoperative treatment of such patients. PMID- 30312492 TI - Comparison between manufacturing sites shows differential adhesion, activation, and GPIbalpha expression of cryopreserved platelets. AB - BACKGROUND: Transfusion of cryopreserved platelets (cryoplatelets) is not common but may replace standard liquid-preserved platelets (PLTs) in specific circumstances. To better understand cryoplatelet function, frozen concentrates from different manufacturing sites were compared. STUDY DESIGN AND METHODS: Cryoplatelets from Denver, Colorado (DEN); Sydney, Australia (SYD); and Ghent, Belgium (GHE) were compared (n = 6). A paired noncryopreserved control was included in Ghent. Microfluidic-flow chambers were used to study PLT adhesion and fibrin deposition in reconstituted blood. Receptor expression was measured by flow cytometry. Coagulation in static conditions was evaluated by rotational thromboelastometry (ROTEM). RESULTS: Regardless of the manufacturing site, adhesion of cryoplatelets under shear flow (1000/sec) was significantly (p < 0.05) reduced compared to control. Expression of GPIbalpha was decreased in a subpopulation of cryoplatelets comprising 45% +/- 11% (DEN), 63% +/- 9% (GHE), and 94% +/- 6% (SYD). That subpopulation displayed increased annexin V binding and decreased integrin activation. PLT adhesion, agglutination, and aggregation were moreover decreased in proportion to that subpopulation. Fibrin deposition under shear flow was normal but initiated faster (546 +/- 163 sec GHE) than control PLTs (631 +/- 120 sec, p < 0.01), only in the absence of tissue factor. In static conditions, clotting time was faster, but clot firmness decreased compared to control. Coagulation was not different between manufacturing sites. CONCLUSION: Cryopreservation results in a subset of PLTs with enhanced GPIbalpha shedding, increased phosphatidylserine expression, reduced integrin response, and reduced adhesion to collagen in microfluidic models of hemostasis. The proportion of this phenotype is different between manufacturing sites. The clinical effects, if any, will need to be verified. PMID- 30312494 TI - Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. AB - AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35 0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype. PMID- 30312495 TI - Eating disorder symptomatology and body mass index are associated with readers' expectations about character behavior: Evidence from eye-tracking during reading. AB - OBJECTIVE: Many theories have been put forward suggesting key factors underlying the development and maintenance of eating disorders, such as: unhealthy food related cognitive biases, negative body attitude, and perfectionism; however, underlying cognitive processes associated with eating disorder symptomatology remain unclear. We used eye-tracking during reading as a novel implicit measure of how these factors may relate to eating disorder symptomatology. METHOD: In two experiments, we monitored women's eye movements while they read texts in which the characters' emotional responses to food-, body image-, and perfectionism related scenarios were described. Participants' eating disorder symptomatology was then assessed. RESULTS: Both studies suggest that moment-to-moment processing of characters' emotional responses to perfectionism-, and to a lesser extent, body image-related information was associated with participants' eating disorder symptomatology, thus supporting theories in which these factors are key to developing and maintaining eating disorders. Interestingly, the moment-to-moment processing of characters' emotional responses to food-related scenarios was not related to eating disorder symptomatology. DISCUSSION: These findings provide novel insights into cognitive processes underlying eating disorder symptomatology, as well as demonstrating the utility of more natural implicit measures. PMID- 30312496 TI - A novel approach to assessing the ecosystem-wide impacts of reintroductions. AB - Reintroducing a species to an ecosystem can have significant impacts on the recipient ecological community. Although reintroductions can have striking and positive outcomes, they also carry risks; many well-intentioned conservation actions have had surprising and unsatisfactory outcomes. A range of network-based mathematical methods has been developed to make quantitative predictions of how communities will respond to management interventions. These methods are based on the limited knowledge of which species interact with each other and in what way. However, expert knowledge isn't perfect and can only take models so far. Fortunately, other types of data, such as abundance time series, is often available, but, to date, no quantitative method exists to integrate these various data types into these models, allowing more precise ecosystem-wide predictions. In this paper, we develop mathematical methods that combine time-series data of multiple species with knowledge of species interactions and we apply it to proposed reintroductions at Booderee National Park in Australia. There have been large fluctuations in species abundances at Booderee National Park in recent history, following intense feral fox (Vulpes vulpes) control, including the local extinction of the greater glider (Petauroides volans). These fluctuations can provide information about the system isn't readily obtained from a stable system, and we use them to inform models that we then use to predict potential outcomes of eastern quoll (Dasyurus viverrinus) and long-nosed potoroo (Potorous tridactylus) reintroductions. One of the key species of conservation concern in the park is the Eastern Bristlebird (Dasyornis brachypterus), and we find that long-nosed potoroo introduction would have very little impact on the Eastern Bristlebird population, while the eastern quoll introduction increased the likelihood of Eastern Bristlebird decline, although that depends on the strength and form of any possible interaction. PMID- 30312497 TI - Role of house dust mite-derived extracellular vesicles in a murine model of airway inflammation. AB - BACKGROUND: House dust mite (HDM) is the major source of indoor allergens that cause airway disease. Recent evidence suggests that Gram-negative/positive bacteria produce nano-sized extracellular vesicles (EVs) containing diverse components, including various immunostimulatory molecules. However, the association between bacteria-derived EVs and development of airway disease is unclear. OBJECTIVE: To identify and isolate HDM-derived EVs and to evaluate their effect on the development of airway inflammation. METHODS: Extracellular vesicles were isolated from crude HDM extracts by ultra-centrifugation, and their physical and immunological characteristics and roles in airway inflammation were tested in vitro and in murine models of airway inflammation. In addition, 16s metagenome analysis of nucleic acid from EVs was performed to identify their origin. RESULTS: Round, bilayered vesicles measuring 80-100 nanometres and containing abundant amounts of LPS were isolated. These vesicles induced innate immune responses both in vitro and in vivo. Intranasal exposure of naive mice to HDM EVs induced production of cytokines associated with development of Th2-mediated and mixed (Th1-/Th2-/Th17-mediated) airway inflammation to allergen. Metagenome analysis identified Bacteroidetes and Proteobacteria as the probable sources of HDM EVs. CONCLUSION: House dust mite EVs originating from Gram-negative bacteria may play an important role on the development of airway inflammation. PMID- 30312498 TI - Skin cancer phototype: A new classification directly related to skin cancer and based on responses from 2869 individuals. AB - BACKGROUND/PURPOSE: Fitzpatrick phototype (FST) classification (based on ability to tan and tendency to burn) is widely used for evaluating skin cancer risk; however, it was not developed for that purpose and has been criticised scientifically. The purpose of the present study was a first approach in establishing a new skin cancer phototype (SCP) classification with direct relation to skin cancer risk, based on the questions originally proposed by Fitzpatrick. However, contrary to Fitzpatrick, the questions are in the present study kept separate. METHODS: Validated information on skin cancer and answers about participants' tendency to burn (4 answers) and ability to tan (4 answers) were obtained from 2869 Danes. The 16 (4 * 4 answers) possible answers formed a matrix, on which a logistic regression was carried out. Successively, the matrix neighbours which were insignificantly different were identified; of which the neighbours with the mutual lowest difference were merged. The merging resulted in four different SCP classes. RESULTS: There was a linear relationship between SCP classes and skin cancer risk. Further, SCP was as good a predictor of skin cancer as objectively measured skin phototype. CONCLUSION: As skin phototype is an important factor in skin cancer research, SCP has great potential in investigative studies of skin cancer risk. PMID- 30312499 TI - The structural and functional domains of plant thylakoid membranes. AB - In plants, the stacking of part of the photosynthetic thylakoid membrane generates two main subcompartments: the stacked grana core and unstacked stroma lamellae. However, a third distinct domain, the grana margin, has been postulated but its structural and functional identity remains elusive. Here, an optimized thylakoid fragmentation procedure combined with detailed ultrastructural, biochemical, and functional analyses reveals the distinct composition of grana margins. It is enriched with lipids, cytochrome b6 f complex, and ATPase while depleted in photosystems and light-harvesting complexes. A quantitative method is introduced that is based on Blue Native Polyacrylamide Gel Electrophoresis (BN PAGE) and dot immunoblotting for quantifying various photosystem II (PSII) assembly forms in different thylakoid subcompartments. The results indicate that the grana margin functions as a degradation and disassembly zone for photodamaged PSII. In contrast, the stacked grana core region contains fully assembled and functional PSII holocomplexes. The stroma lamellae, finally, contain monomeric PSII as well as a significant fraction of dimeric holocomplexes that identify this membrane area as the PSII repair zone. This structural organization and the heterogeneous PSII distribution support the idea that the stacking of thylakoid membranes leads to a division of labor that establishes distinct membrane areas with specific functions. PMID- 30312500 TI - Development and validation of the McGill body image concerns scale for use in head and neck oncology (MBIS-HNC): A mixed-methods approach. AB - OBJECTIVE: The aim of this study was to develop and validate a patient-reported outcome measure to evaluate body image concerns in head and neck cancer (HNC) patients. METHODS: Items were created using a combination of deductive (eg, US Food and Drug Administration Qualification of Clinical Outcome Assessments, literature review) and inductive approaches (eg, subject matter experts, HNC patients). Items were translated for use in both Canadian English and Canadian French using back-translation. A two-step empirical validation process using the Classical Test Theory (CTT) and Rasch Measurement Theory (RMT) was conducted with 224 and 258 HNC patients, respectively, having undergone disfiguring surgery within the past 3 years. RESULTS: Analyses suggest two subscales for MBIS-HNC: social discomfort (10 items) and negative self-image (11 items). The McGill Body Image Concerns Scale-Head and Neck Cancer (MBIS-HNC) is reliable with high internal consistency (0.98), high test-retest reliability over a two-week period (ICC = 0.88), moderate to high convergent validity (range r = 0.43-0.81), and divergent validity (range r = 0.12-0.15). RMT was used in addition to CTT. Disordered thresholds led to the modification of the number of response options, and items were deleted based on differential item functioning and high local dependency. Unidimensionality of both subscales and supporting a total score was confirmed. The measure was however characterized by the presence of an important floor effect, confirmed with poor targeting as demonstrated by the person-item threshold distribution. CONCLUSION: Evidence gathered from our theory-driven validation study using CTT and RMT provides practitioners and researchers with a useful and easy to use self-report measure. PMID- 30312501 TI - Effect of aliskiren, a direct renin inhibitor, on the protective action of antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice. AB - It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50-100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary. PMID- 30312502 TI - Epilepsy and associated mortality in patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy. METHODS: We used the UK Clinical Practice Research Data-link to identify 2526 patients with incident MS and 9980 age-, sex- and index year matched non-MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality. RESULTS: Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non-MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36-3.27) for pre-existing epilepsy. Among epilepsy-free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94-12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02-4.84) for all-cause mortality. CONCLUSIONS: This population-based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non-MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without. PMID- 30312503 TI - Pediatric asthma: An unmet need for more effective, focused treatments. AB - BACKGROUND: Despite remarkable advances in our understanding of asthma, there are still several unmet needs associated with the management of pediatric asthma. METHODS: A two-day, face-to-face meeting was held in London, United Kingdom, on October 28 and 29, 2017, involving a group of international expert clinicians and scientists in asthma management to discuss the challenges and unmet needs that remain to be addressed in pediatric asthma. RESULTS: These unmet needs include a lack of clinical efficacy and safety evidence, and limited availability of non steroid-based alternative therapies in patients <6 years of age. An increased focus on children is needed in the context of clinical practice guidelines for asthma; current pediatric practice relies mostly on extrapolations from adult recommendations. Furthermore, no uniform definition of pediatric asthma exists, which hampers timely and robust diagnosis of the condition in affected patients. CONCLUSIONS: There is a need for a uniform definition of pediatric asthma, clearly distinguishable from adult asthma. Furthermore, guidelines which provide specific treatment recommendations for the management of pediatric asthma are also needed. Clinical trials and real-world evidence studies assessing anti immunoglobulin E (IgE) therapies and other monoclonal antibodies in children <6 years of age with asthma may provide further information regarding the most appropriate treatment options in these vulnerable patients. Early intervention with anti-IgE and non-steroid-based alternative therapies may delay disease progression, leading to improved clinical outcomes. PMID- 30312504 TI - Contribution of a lectin, LecM, to the quorum sensing signalling pathway of Ralstonia solanacearum strain OE1-1. AB - The soil-borne bacterium Ralstonia solanacearum invades the roots and colonizes the intercellular spaces and then the xylem. The expression of lecM, encoding a lectin LecM, is induced by an OmpR family response regulator HrpG in R. solanacearum strain OE1-1. LecM contributes to the attachment of strain OE1-1 to the host cells of intercellular spaces. OE1-1 produces methyl 3-hydroxymyristate (3-OH MAME) through a methyltransferase (PhcB) and extracellularly secretes the chemical as a quorum sensing (QS) signal, which activates QS. The expression of lecM is also induced by the PhcA virulence regulator functioning through QS, and the resulting LecM is implicated in the QS-dependent production of major exopolysaccharide EPS I and the aggregation of OE1-1 cells. To investigate the function of LecM in QS, we analysed the transcriptome of R. solanacearum strains generated by RNA sequencing technology. In the lecM mutant, the expression of positively QS-regulated genes and negatively QS-regulated genes was down regulated (by >90%) and up-regulated (by ~60%), respectively. However, phcB and phcA in the lecM mutant were expressed at levels similar to those in strain OE1 1. The lecM mutant produced significantly less ralfuranone and exhibited a significantly greater swimming motility, which were positively and negatively regulated by QS, respectively. In addition, the extracellular 3-OH MAME content of the lecM mutant was significantly lower than that of OE1-1. The application of 3-OH MAME more strongly increased EPS I production in the phcB-deleted mutant and strain OE1-1 than in the lecM mutant. Thus, the QS-dependent production of LecM contributes to the QS signalling pathway. PMID- 30312505 TI - Discordance in TLR2 (-196 to -174) polymorphism effect on HIV infection risk. PMID- 30312506 TI - Modeling habituation of introduced predators to unrewarding bird odors for conservation of ground-nesting shorebirds. AB - Foraging mammalian predators face a myriad of odors from potential prey. To be efficient, they must focus on rewarding odors while ignoring consistently unrewarding ones. This may be exploited as a nonlethal conservation tool if predators can be deceived into ignoring odors of vulnerable secondary prey. To explore critical design components and assess the potential gains to prey survival of this technique, we created an individual-based model that simulated the hunting behavior of three introduced mammalian predators on one of their secondary prey (a migratory shorebird) in the South Island of New Zealand. Within this model, we heuristically assessed the outcome of habituating the predators to human-deployed unrewarding bird odors before the bird's arrival at their breeding grounds, i.e., the predators were "primed." Using known home range sizes and probabilities of predators interacting with food lures, our model suggests that wide-ranging predators should encounter a relatively large number of odor points (between 10 and 115) during 27 d of priming when odor is deployed within high resolution grids (100-150 m). Using this information, we then modeled the effect of different habituation curves (exponential and sigmoidal) on the probability of predators depredating shorebird nests. Our results show that important gains in nest survival can be achieved regardless of the shape of the habituation curve, but particularly if predators are fast olfactory learners (exponential curve), and even if some level of dishabituation occurs after prey become available. Predictions from our model can inform the amount and pattern in which olfactory stimuli need to be deployed in the field to optimize encounters by predators, and the relative gains that can be expected from reduced predation pressure on secondary prey under different scenarios of predator learning. Habituating predators to odors of threatened secondary prey may have particular efficacy as a conservation tool in areas where lethal predator control is not possible or ethical, or where even low predator densities can be detrimental to prey survival. Our approach is also relevant for determining interaction probabilities for devices other than odor points, such as bait stations and camera traps. PMID- 30312508 TI - National survey reported that French paediatric residents had access to simulation-based training but needed more. PMID- 30312507 TI - Reaction Mechanisms of Well-Defined Metal-N4 Sites in Electrocatalytic CO2 Reduction. AB - Electrocatalytic CO2 reduction to CO emerges as a potential route of utilizing emitted CO2 . Metal-N-C hybrid structures have shown unique activities, however, the active centers and reaction mechanisms remain unclear because of the ambiguity in true atomic structures for the prepared catalysts. Herein, combining density-functional theory calculations and experimental studies, the reaction mechanisms for well-defined metal-N4 sites were explored using metal phthalocyanines as model catalysts. The theoretical calculations reveal that cobalt phthalocyanine exhibits the optimum activity for CO2 reduction to CO because of the moderate *CO binding energy at the Co site, which accommodates the *COOH formation and the *CO desorption. It is further confirmed by experimental studies, where cobalt phthalocyanine delivers the best performance, with a maximal CO Faradaic efficiency reaching 99 %, and maintains stable performance for over 60 hours. PMID- 30312509 TI - Pelagic food webs of humic lakes show low short-term response to forest harvesting. AB - Forest harvest in the boreal zone can increase the input of terrestrial materials such as dissolved organic carbon (DOC) and nitrate (NO3 - ) into nearby aquatic ecosystems, with potential effects on phytoplankton growth through enhanced nutrient (i.e., positive) or reduced light availability (i.e., negative), which may affect ecosystem productivity and consumer resource use. Here, we conducted forest clear-cutting experiments in the catchments of four small, humic, and nitrogen-limited unproductive boreal lakes (two controls and two clear-cut, 18% and 44% of area cut) with one reference and two impact years. Our aim was to assess the effects of forest clear-cutting on pelagic biomass production and consumer resource use. We found that pelagic biomass production did not change after two years of forest clear-cutting: Pelagic primary and bacterial production (PP, BP), PP:BP ratio, chl a, and seston carbon (seston C) were unaffected by clear-cutting; neither did tree harvest affect seston stoichiometry (i.e., N:phosphorus [P], C:P) nor induce changes in zooplankton resource use, biomass, or community composition. In conclusion, our findings suggest that pelagic food webs of humic lakes (DOC > 15 mg/L) might be resilient to a moderate form of forest clear-cutting, at least two years after tree removal, before mechanical site preparation (e.g., mounding, plowing) and when leaving buffer strips along lakes and incoming streams. Thus, pelagic food web responses to forest clear cutting might not be universal, but could depend on factors such as the time scale, share of catchment logged, and the forest practices involved, including the application of buffer strips and site preparation. PMID- 30312510 TI - Aortic Dissection Detection Risk Score: A Clinical Decision Rule That Needs Some Parenting. PMID- 30312511 TI - An Isolable Terminal Imido Complex of Palladium and Catalytic Implications. AB - Herein, we report the isolation and a reactivity study of the first example of an elusive palladium(II) terminal imido complex. This scaffold is an alleged key intermediate for various catalytic processes, including the amination of C-H bonds. We demonstrate facile nitrene transfer with H-H, C-H, N-H, and O-H bonds and elucidate its role in catalysis. The high reactivity is due to the population of the antibonding highest occupied molecular orbital (HOMO), which results in unique charge separation within the closed-shell imido functionality. Hence, N atom transfer is not necessarily associated with the high valency of the metal (PdIII , PdIV ) or the open-shell character of a nitrene as commonly inferred. PMID- 30312512 TI - The effect of indapamide vs. bendroflumethiazide for primary hypertension: a systematic review. AB - The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1-year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference <1 mmHg). The present review highlights a lack of studies to answer the review question but also a lack of evidence of superiority of one drug over the other. Therefore, there is a clear need for new studies directly comparing the effect of these drugs on the outcomes of interest. PMID- 30312513 TI - Potential mechanisms linking gut microbiota and portal hypertension. AB - Gut microbiota is the largest collection of commensal micro-organisms in the human body, engaged in reciprocal cellular and molecular interactions with the liver. This mutually beneficial relationship may break down and result in dysbiosis, associated with disease phenotypes. Altered composition and function of gut microbiota has been implicated in the pathobiology of nonalcoholic fatty liver disease (NAFLD), a prevalent condition linked to obesity, insulin resistance and endothelial dysfunction. NAFLD may progress to cirrhosis and portal hypertension, which is the result of increased intrahepatic vascular resistance and altered splanchnic circulation. Gut microbiota may contribute to rising portal pressure from the earliest stages of NAFLD, although the significance of these changes remains unclear. NAFLD has been linked to lower microbial diversity and weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defence and inflammation. Moreover, disrupted host-microbial metabolic interplay alters bile acid signalling and the release of vasoregulatory gasotransmitters. These perturbations become prominent in cirrhosis, increasing the risk of clinically significant portal hypertension and leading to bacterial translocation, sepsis and acute-on-chronic liver failure. Better understanding of the gut-liver axis and identification of novel microbial molecular targets may yield specific strategies in the prevention and management of portal hypertension. PMID- 30312514 TI - A pilot study to investigate the influence of upper respiratory infections on IgE reactivity to food allergens. PMID- 30312516 TI - Preoperative beta blockade and severe intraoperative bradycardia in liver transplantation. AB - Nonselective Beta blockade (NSBB) is commonly prescribed for liver transplantation (LT) candidates, but its impact on intraoperative hemodynamics is not well understood. In this study, we investigated if preoperative NSBB was associated with severe bradycardia during LT and if severe intraoperative bradycardia was associated with 30-day mortality. Adult patients undergoing LT between 2005 and 2014 were included. Propensity matching was used to control selection bias. Intraoperative hemodynamics were compared between patients with and without preoperative NSBB. Univariate and multivariate methods were used in statistical analysis. Of 1452 patients, 370 who received preoperative NSBB were matched in a 1:1 ratio with those who did not. Propensity matching eliminated all significant differences between the two groups. Patients who received preoperative NSBB had a significantly higher incidence of severe intraoperative bradycardia compared with the non-BB group (9.6% vs 3.2%, P = 0.001, OR 2.95, 95% CI 1.42-6.12, P = 0.004). Intraoperative hypotension and postreperfusion syndrome were not significantly different between the two groups. Severe intraoperative bradycardia was associated with increased 30-day mortality. In conclusion, preoperative NSBB was associated with severe intraoperative bradycardia in LT. In patients who receive preoperative NSBB, severe intraoperative bradycardia should be closely monitored in LT. Further studies assessing safety of preoperative NSBB and intraoperative bradycardia in LT are warranted. PMID- 30312517 TI - Central nervous system involvement in late-onset Pompe disease: clues from neuroimaging and neuropsychological analysis. AB - BACKGROUND AND PURPOSE: Late-onset Pompe disease (LOPD) is a rare, multisystem disorder that is well established to mainly impair skeletal muscle function. Systematic studies exploring brain functions in LOPD are lacking. The aim of this study was to detect morphological and functional brain alterations as well as neuropsychological impairment in LOPD. METHODS: We studied 21 patients (10 male, mean age 49 +/- 18.4 years) with defined diagnosis of LOPD, divided into two groups: one with pre-symptomatic hyperCKemia with no muscle weakness and the second with limb-girdle muscle weakness. All patients underwent 3T magnetic resonance imaging (MRI) to obtain morphological/angiographic evaluation as well as normalized cortical brain volume and resting-state functional MRI. Fazekas score was applied to quantify white matter lesions, whereas Smoker's criteria were used to examine dolichoectasia. A complete neuropsychological assessment was performed. RESULTS: The MRI data showed that 12/21 patients (57%) demonstrated signs of cerebral vasculopathy, with a Fazekas score >2 in 67%. According to Smoker's criteria, 11/21 patients (52%) had a dolichoectasia of the vertebrobasilar system; an intracranial aneurysm was detected in 3/21 patients (14%). Resting-state functional MRI demonstrated significantly decreased brain connectivity in the salience network with a more relevant reduction in the bilateral middle and superior frontal gyrus. Gray matter atrophy correlated with age and disease duration. A mild impairment in executive functions was also identified. CONCLUSIONS: In this LOPD cohort the results showed morphological and functional brain alterations with mild neuropsychological dysfunction, mainly in the limb-girdle muscle weakness group. Cerebrovascular alterations seemed to be not related to common risk factors, suggesting a major role of enzymatic deficiency in the pathogenesis of brain abnormalities. PMID- 30312518 TI - Activation of Molecular Hydrogen by Arylcarbenes. AB - The hydrogenation reactions of diphenylcarbene 1, fluorenylidene 2, and dibenzocycloheptadienylidene 3 were investigated in solid H2 and D2 matrices and in H2 - and D2 -doped argon matrices at cryogenic temperatures. The reactivity of the carbenes towards H2 increases in the order 1<3<2. Whereas 1 is stable in solid H2 , 2 and 3 react fast under the same conditions via quantum chemical tunneling. In D2 both 1 and 3 are stable, whereas 2 slowly reacts. The different reactivity of the three carbenes is rationalized in terms of differing carbene stabilization energies. PMID- 30312515 TI - Mitochondrial network structure homeostasis and cell death. AB - Mitochondria are the major cellular energy-producing organelles and intracellular source of reactive oxygen species. These organelles are responsible for driving cell life and death through mitochondrial network structure homeostasis, which is determined by a balance of fission and fusion. Recent advances revealed that a number of components of the fission and fusion machinery, including dynamin related protein 1 (Drp1), mitofusin1/2 (Mfn1/2) and Optic atrophy 1 (OPA1), that have been implicated in mitochondrial shape changes are indispensible for autophagy, apoptosis and necroptosis. Drp1 is the main regulator of mitochondrial fission and has become a key point of contention. The controversy focuses on whether Drp1 is directly involved in the regulation of cell death and, if involved, whether is it a stimulator or a negative regulator of cell death. Here, we examine the relevance of the homeostasis of the mitochondrial network structure in 3 different types of cell death, including autophagy, apoptosis and necroptosis. Furthermore, a variety of cancers often exhibit a fragmented mitochondrial phenotype. Thus, the fragmented ratio can reflect tumor progression that predicts prognosis and therapeutic response. In addition, we investigate whether the targeting of the mitochondrial fission protein Drp1 could be a novel therapeutic approach. PMID- 30312519 TI - Testing the effects of four urbanization filters on forest plant taxonomic, functional, and phylogenetic diversity. AB - Ongoing urban development has significant effects on ecosystems, including changes to land cover, environmental conditions, and species' distributions. These various impacts may have opposing or interacting effects on plant communities, making it difficult to predict how plant biodiversity will respond to urban development. A frequently cited conceptual framework predicts how urban development influences plant taxonomic, functional, and phylogenetic diversity by simplifying multiple coincident effects of urbanization into four primary filters of biodiversity: habitat transformation, fragmentation, the urban environment, and human preferences. Each filter prevents some plant species from persisting in urban areas while promoting others, but species introductions according to human preferences are expected to cause a net increase in biodiversity while the other filters limit diversity. In this study, we used structural equation modeling to test these predictions and examine the relative importance of each filter on the taxonomic, functional, and phylogenetic diversity of riparian forest plant species sampled along an urban-to-rural gradient in the Research Triangle area of North Carolina. Most diversity measures declined with urbanization, but some (e.g., functional Rao's Q) increased with urbanization. We found support for some of the predicted relationships between urbanization filters and biodiversity, as well as some unexpected relationships, including positive effects of urban environments. Overall, urban environments and human preferences were stronger predictors than habitat transformation and fragmentation. Our approach could be used to test a general framework predicting the effects of urbanization on plant diversity across multiple cities and contribute to a more synthetic understanding of urban biodiversity. PMID- 30312520 TI - The experience of medical communication in adults with acute leukemia: Impact of age and attachment security. AB - BACKGROUND: Health care providers' (HCPs) communication with cancer patients provides both information and support. Younger patient age and greater difficulty accepting support (attachment security) have been linked to poorer communication experiences with HCPs. The present secondary data analysis examined the impact of age group and attachment security on perceived communication problems with HCPs in adults with acute leukemia (AL). METHODS: The sample included 95 younger (age < 40 years) and 225 older (age >= 40 years) patients with newly diagnosed or recently relapsed AL. We assessed avoidant and anxious attachment security (reluctance to accept support and fear of its unavailability, respectively) with the modified 16-item Experiences in Close Relationships Scale. The impact of age group and attachment security on perceived communication problems, measured with the Cancer Rehabilitation Evaluation System-Medical Interaction Subscale, was assessed based on the presence and extent of communication problems. RESULTS: Younger patients (OR = 1.79-1.82, P = .030) and those with greater avoidant (OR = 1.44, P = .001) or anxious attachment (OR = 1.38, P = .009) were more likely to report communication problems. A similar relationship was found between age (beta's = -.17-.19, P = .015-.025), avoidant (beta = .29, P = .013), or anxious attachment (beta = .17, P = .031), and the extent of communication problems. A significant age-group * avoidant-attachment interaction (beta = -.31, P = .008) suggested that more avoidant attachment was associated with more perceived communication problems in the younger but not in the older group. CONCLUSIONS: Younger patients with AL, especially those more reluctant to seek or accept support, perceive more communication problems with their HCPs than older patients. Greater attention by HCPs to their communication with younger patients is needed. PMID- 30312521 TI - CD18 is redundant for the response to multiple vaccines: A case study. PMID- 30312522 TI - Adverse outcome of coarctation stenting in patients with Turner syndrome. PMID- 30312523 TI - Spontaneous coronary artery dissection and takotsubo syndrome: Simultaneous presentation or which triggers which? PMID- 30312525 TI - Postcranial Skeletal Differences in Free-Range and Captive-Born Primates. AB - Skeletal morphology is important in evolutionary, genetic, developmental, physiological, and functional studies. Although samples from free-ranging individuals may be preferable, constraints of sample size, demography, or conservation status may necessitate the inclusion of captive-born individuals. Captivity may be associated with physical, physiological, or behavioral differences that may affect skeletal form. This study assesses differences in postcranial skeletal form between free-range and captive-born Macaca mulatta and Saguinus oedipus. Samples included free-range M. mulatta from Cayo Santiago (Caribbean Primate Research Center) and captive-born macaques from the Wisconsin National Primate Research Center. S. oedipus samples included free-range born and captive-born individuals from the Oak Ridge Associated Universities Marmoset Research Center. Twenty-four dimensions of various bones, including the scapula, upper limb, innominate and lower limb, were recorded for adults. Age of epiphyseal closure was recorded for immature captive-born M. mulatta. Analysis of variance and principal component analyses tested significant differences between free-range born and captive-born individuals in each species. Significant differences were present in size and shape of postcrania between free-range and captive-born within taxa. Free-range macaques were larger than captive-born macaques, but this pattern did not consistently carry over to the Saguinus samples. Shape differences, while present throughout the skeleton, were especially prominent in the scapula. Differences in developmental timing, nutrition, and physical activity can be expected to contribute to the observed differences in postcranial skeletal form. These differences should be considered when captive-born primates are included in morphological or evolutionary studies. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312526 TI - The Eurasian Elk's (Alces alces) Brain Base Arteries in View of Vascular Variation. AB - This article presents the results of analysis of the arterial vascular region of the Eurasian elk, which is a representative of the Cervidae family. The study was conducted on 39 Eurasian elks. The head arteries of 25 animals were filled with LBS 3040 synthetic latex. The head arteries of the other 14 Eurasian elks were filled with an acetone solution of stained chlorinated polyvinyl chloride and macerated. The arterial circle of the Eurasian elk's brain is composed of bilateral rostral cerebral arteries and caudal communicating arteries. The basilar artery closes the arterial circle caudally. The rostral cerebral artery first ramifies into the rostral choroidal artery, then, the middle cerebral artery and the rostral communicating artery. The caudal cerebral artery and the rostral cerebellar artery branch off the caudal communicating artery. The arterial pattern of the Eurasian elk's brain base is similar to the arteries found in other deer. Like in other Ruminantia, the rostral epidural rete mirabile is a unique structure in the Eurasian elk's arterial system. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312527 TI - Expanding intestinal segment using osmotic hydrogel: An in vivo study. AB - Intestinal circumferential expansion is essential for bowel lengthening in patients with Short Bowel Syndrome. We hypothesized use of an endoluminal osmotic hydrogel expander (EOHE) as a novel approach for intestinal expansion. An EOHE was introduced into an isolated intestinal segment of New Zealand rabbits, with a similar segment created as a control. After 4weeks, the segments were retrieved for analysis. Weight, inflammatory markers and fluoroscopy data was recorded weekly. EOHE allowed successful expansion of intestinal segments from 4.68 +/- 0.35 to 9.79 +/- 0.35 cm (p = 0.01). Increase in intestinal length was 167.8 +/- 35.21% in segments with EOHE vs. 23.03 +/- 4.2% in the control group (p < 0.01). A significant intestinal dilatation (214.4 +/- 1.58 vs. 34.59 +/- 1.23%, p < 0.01) was demonstrated. Hematoxylin and eosin stain revealed conservation of intestinal architecture with muscle hypertrophy and flattening of the epithelium possibly due to compression. No reduction of rabbit weight, inflammatory markers or liver damage was described. EOHE appears to produce safe intestinal expansion, achieving increased length and dilatation suitable for lengthening procedure. This approach may allow development of similar techniques to expand bowel in short bowel patients. (c) 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B: 2018. PMID- 30312528 TI - Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma. AB - Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for noninvasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA. However, TERT promoter mutations were only detected by ddPCR, and promoter mutations were consistently found at lower concentrations than other driver mutations in longitudinal samples. In vitro experiments revealed that mutations in promoter regions of TERT and DPH3 are underrepresented in ctDNA. While the results underscore the utility of using ctDNA as an alternative to tissue biopsy for genetic profiling and surveillance of the disease, our study highlights the underrepresentation of promoter mutations in ctDNA and its potential impact on quantitative liquid biopsy applications. PMID- 30312529 TI - Antibiotics release from cement spacers used for two-stage treatment of implant associated infections after total joint arthroplasty. AB - Two-stage revision arthroplasty is the treatment of choice for periprosthetic infection, a serious complication after knee or hip arthroplasty. Our prospective clinical trial aimed to investigate the concentrations of gentamicin and vancomycin in wound exudate and tissue in two-stage revision arthroplasty. Wound exudate and periprosthetic membrane samples were collected from 18 patients (10 hip and eight knee patients), who were due for two-stage treatment after a periprosthetic joint infection. Samples were taken during insertion of antibiotic impregnated spacers and after their removal. The concentrations of gentamicin and vancomycin in wound exudates and adjacent tissue were analyzed using high performance liquid chromatography mass spectrometry. Average time period of spacer implantation was 13.6 weeks (9.3-22.6 weeks). The concentration of vancomycin in wound exudate decreased from a median of 43.28 MUg/mL (0.28-261.22) after implantation to 0.46 MUg/mL (0.13-37.47) after the removal of the spacer. In the adjacent tissue, vancomycin concentration was mainly undetectable prior to spacer implantation (0.003 MUg/g [0.003-0.261]) and increased to 0.318 MUg/g [0.024-484.16] at the time of spacer removal. This was also observed for gentamicin in the tissue of patients who previously had cement-free implants (0.008 MUg/g [0.008-0.087] vs. 0.164 MUg/g [0.048-71.75]) while in the tissue of patients with previously cemented prosthesis, baseline concentration was already high (8.451 MUg/g [0.152-42.926]). Despite the rapid decrease in antibiotics release from spacer cement observed in vitro, in vivo antibiotics are much longer detectable, especially in the adjacent soft tissue. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30312530 TI - Liver transplantation and waitlist mortality for HCC and non-HCC candidates following the 2015 HCC exception policy change. AB - Historically, exception points for hepatocellular carcinoma (HCC) led to higher transplant rates and lower waitlist mortality for HCC candidates compared to non HCC candidates. As of October 2015, HCC candidates must wait 6 months after initial application to obtain exception points; the impact of this policy remains unstudied. Using 2013-2017 SRTR data, we identified 39 350 adult, first-time, active waitlist candidates and compared deceased donor liver transplant (DDLT) rates and waitlist mortality/dropout for HCC versus non-HCC candidates before (October 8, 2013-October 7, 2015, prepolicy) and after (October 8, 2015-October 7, 2017, postpolicy) the policy change using Cox and competing risks regression, respectively. Compared to non-HCC candidates with the same calculated MELD, HCC candidates had a 3.6-fold higher rate of DDLT prepolicy (aHR = 3.49 3.69 3.89 ) and a 2.2-fold higher rate of DDLT postpolicy (aHR = 2.09 2.21 2.34 ). Compared to non-HCC candidates with the same allocation priority, HCC candidates had a 37% lower risk of waitlist mortality/dropout prepolicy (asHR = 0.54 0.63 0.73 ) and a comparable risk of mortality/dropout postpolicy (asHR = 0.81 0.95 1.11 ). Following the policy change, the DDLT advantage for HCC candidates remained, albeit dramatically attenuated, without any substantial increase in waitlist mortality/dropout. In the context of sickest-first liver allocation, the revised policy seems to have established allocation equity for HCC and non-HCC candidates. PMID- 30312531 TI - Nuclear Actin: From Discovery to Function. AB - While actin was discovered in the nucleus over 50 years ago, research lagged for decades due to strong skepticism. The revitalization of research into nuclear actin occurred after it was found that cellular stresses induce the nuclear localization and alter the structure of actin. These studies provided the first hints that actin has a nuclear function. Subsequently, it was established that the nuclear import and export of actin is highly regulated. While the structures of nuclear actin remain unclear, it can function as monomers, polymers, and even rods. Furthermore, even within a given structure, distinct pools of nuclear actin that can be differentially labeled have been identified. Numerous mechanistic studies have uncovered an array of functions for nuclear actin. It regulates the activity of RNA polymerases, as well as specific transcription factors. Actin also modulates the activity of several chromatin remodeling complexes and histone deacetylases, to ultimately impinge on transcriptional programing and DNA damage repair. Further, nuclear actin mediates chromatin movement and organization. It has roles in meiosis and mitosis, and these functions may be functionally conserved from ancient bacterial actin homologs. The structure and integrity of the nuclear envelope and sub-nuclear compartments are also regulated by nuclear actin. Furthermore, nuclear actin contributes to human diseases like cancer, neurodegeneration, and myopathies. Here, we explore the early discovery of actin in the nucleus and discuss the forms and functions of nuclear actin in both normal and disease contexts. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312532 TI - Hsc70 is a Component of Bacterially Generated Actin-Rich Structures: An Immunolocalization Study. AB - Enteropathogenic Escherichia coli (EPEC), Salmonella typhimurium, and Listeria monocytogenes usurp the actin cytoskeleton for their attachment, internalization and transport within and amongst infected cells. To try to gain a greater understanding of the molecular components utilized by these microbes during their infections we previously concentrated actin-rich structures generated during EPEC infections (called pedestals) and identified the heat shock cognate 70 protein (Hsc70) as a potential candidate. This multifunctional protein classically acts as a chaperone for the proper folding of a variety of proteins and is involved in uncoating clathrin from coated pits. Here we demonstrated that Hsc70 is recruited to actin structures generated during EPEC, Listeria and Salmonella infections, but not to the same location as clathrin. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312533 TI - Changes in the Morphology of Hypoglossal Motor Neurons in the Brainstem of Developing Rats. AB - The autonomic brainstem generates breathing rhythm by integrating inputs from chemosensors and mechanosensors in the viscera and coordinating descending outputs from higher structures in the central nervous system. Hypoglossal motoneurons (XII MNs) receive inputs from respiratory premotor neurons, important for maintaining airway patency. Previous studies in rodents report significant changes in breathing control during the first 3 weeks of life, with a sensitive period at 10 to 13 days postbirth (P10-P13) characterized by pronounced changes in neurotransmitters, excitation-inhibition balance, and breathing physiology. However, age-dependent morphological changes of XII MNs during the first 3 weeks postbirth and especially this sensitive period are under-studied. Here, we comprehensively characterize and quantify the early morphological changes in rat XII MNs. We hypothesized that morphological changes in XII MNs correspond to the functionally defined sensitive period observed at postnatal day 10-13 (P10-P13). To test this hypothesis, we used an innovative contemporary statistical approach to analyze Golgi-Cox stained XII MNs at nine postnatal ages between P1 and P21. Our findings reveal two subpopulations of XII MNs, which are dependent on age and morphological features. Soma size increased approximately 40% from P1 to P21, without changing shape. However, dendritic arborization increased in extent/distance and complexity. Dendritic branching of developing neurons significantly increased from P1 through P13, with the greatest increase at P10 P13 based on the Sholl method. Our detailed characterization of XII MN morphological development establishes a foundation for the study and elucidation of morphological changes caused by maternal and perinatal conditions. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312534 TI - Multiple Pools of Nuclear Actin. AB - While nuclear actin was reported ~50 years ago, it's in vivo prevalence and structure remain largely unknown. Here, we use Drosophila oogenesis, that is, follicle development, to characterize nuclear actin. We find that three different reagents-DNase I, anti-actin C4, and anti-actin AC15-recognize distinct pools of nuclear actin. DNase I labels monomeric or G-actin, and, during follicle development, G-actin is present in the nucleus of every cell. Some G-actin is recognized by the C4 antibody. In particular, C4 nuclear actin colocalizes with DNase I to the nucleolus in anterior escort cells, follicle stem cells, some mitotic follicle cells, and a subset of nurse cells during early oogenesis. C4 also labels polymeric nuclear actin in the nucleoplasm of the germline stem cells, early cystoblasts, and oocytes. The AC15 antibody labels a completely distinct pool of nuclear actin from that of DNase I and C4. Specifically, AC15 nuclear actin localizes to the chromatin in the nurse and follicle cells during mid-to-late oogenesis. Within the oocyte, AC15 nuclear actin progresses from localizing to puncta surrounding the DNA, to forming a filamentous cage around the chromosomes. Together these findings reveal that nuclear actin is highly prevalent in vivo, and multiple pools of nuclear actin exist and can be recognized using different reagents. Additionally, our localization studies suggest that nuclear actin may regulate stemness, nucleolar structure and function, transcription, and nuclear structure. Such findings call for further studies to explore the prevalence, diversity, and functions of nuclear actin across tissues and organisms. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312535 TI - Chronic rejection of human face allografts. AB - Face vascularized composite allografts (FVCAs) have helped patients with severe facial disfigurement, with acute rejection now largely controlled through iatrogenic immunosuppression. However, little is known regarding the incidence and mechanism(s) of more long-term pathologic alterations in FVCAs that may affect function and graft durability. Protocol surveillance biopsy specimens for up to an 8-year interval in 7 patients who received FVCAs at our institution revealed histopathologic evidence of chronic rejection. Clinical manifestations included features of premature aging, mottled leukoderma accentuating suture lines, telangiectasia, and dryness of nasal mucosa. Pathologic changes consisted of epidermal thinning accompanied by discrete foci of lymphocyte-mediated cytotoxicity, hyperkeratosis, follicular plugging, vascular ectasia, and sclerosis beneath the epidermal layer associated with collagen type I deposition. Genomic interrogation and immunohistochemistry of sclerotic zones revealed upregulation of the AP-1 pathway components, JunB and c-Fos, previously implicated in overproduction of type I dermal collagen in the setting of systemic sclerosis. We conclude that some patients develop chronic rejection in FVCAs with striking similarities to alterations seen in certain autoimmune cutaneous disorders (lupus erythematosus and scleroderma/chronic sclerodermoid graft-versus host disease). Identification of relevant pathways and genes, such as JunB and c Fos, may provide new targets for preventative therapies for chronic immune mediated changes in vascularized composite allografts. PMID- 30312536 TI - Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction. AB - Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study. PMID- 30312537 TI - Effect of antithrombic therapy on bleeding complications in patients receiving emergency cholecystectomy for acute cholecystitis. AB - BACKGROUND: The risk of developing hemorrhagic complications during or after emergency cholecystectomy in patients with antithrombic therapy (ATT) remains uncertain. In this study, we evaluate outcomes in patients with ATT undergoing emergency cholecystectomy and assess the relevance between ATT and perioperative complications including bleeding complications. METHODS: We retrospectively evaluated 296 patients who were diagnosed as acute cholecystitis and underwent emergency cholecystectomy between 2005 and 2017. One hundred and thirty-three of them (45%) were on ATT. The primary outcome measures were intraoperative blood loss over 500 ml and postoperative complications including bleeding complications. This study was approved by our institutional review board (#13072904). RESULTS: There were 23 patients (8%) who experienced intraoperative blood loss over 500 ml and nine postoperative bleeding complications (3%). Multivariable analyses showed that male sex (P = 0.027), Performance Status 2-4 (P = 0.031) and grade II or III acute cholecystitis (P = 0.033) were independent risk factors for intraoperative bleeding over 500 ml, whereas not single antiplatelet therapy (APT) use but multiple APT (P = 0.034) and anticoagulation therapy (ACT) (P = 0.032) were independently associated with postoperative bleeding complications. Additionally, laparoscopic surgery, but not ATT, was a significant prognostic factor for severe postoperative complications. CONCLUSIONS: Single APT was not remained as an independently associated factor of intraoperative excessive bleeding or severe postoperative complications including bleeding complications. However, patients treated with multiple APT or ACT still represent a challenging group and must be carefully managed to avoid postoperative bleeding complications. PMID- 30312538 TI - Calponins Are Recruited to Actin-Rich Structures Generated by Pathogenic Escherichia coli, Listeria, and Salmonella. AB - The ingestion of enteropathogenic Escherichia coli (EPEC), Listeria monocytogenes, or Salmonella enterica serovar Typhimurium leads to their colonization of the intestinal lumen, which ultimately causes an array of ailments ranging from diarrhea to bacteremia. Once in the intestines, these microbes generate various actin-rich structures to attach, invade, or move within the host intestinal epithelial cells. Although an assortment of actin-associated proteins has been identified to varying degrees at these structures, the localization of many actin stabilizing proteins have yet to be analyzed. Here, we examined the recruitment of the actin-associated proteins, calponin 1 and 2 at EPEC pedestals, L. monocytogenes actin clouds, comet tails and listeriopods, and S. Typhimurium membrane ruffles. In other systems, calponins are known to bind to and stabilize actin filaments. In EPEC pedestals, calponin 1 was recruited uniformly throughout the structures while calponin 2 was enriched at the apical tip. During L. monocytogenes infections, calponin 1 was found through all the actin-rich structures generated by the bacteria, while calponin 2 was only present within actin-rich structures formed by L. monocytogenes near the host cell membrane. Finally, both calponins were found within S. Typhimurium-generated membrane ruffles. Taken together, we have shown that although calponin 1 is recruited to actin-rich structures formed by the three bacteria, calponin 2 is specifically recruited to only membrane-bound actin-rich structures formed by the bacteria. Thus, our findings suggest that calponin 2 is a novel marker for membrane-bound actin structures formed by pathogenic bacteria. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312539 TI - Effective Mechanical Advantage Allometry of Felid Elbow and Knee Extensors. AB - Larger terrestrial mammals have generally been found to use more extended limb postures, a mechanism which maintains muscular requirements at larger sizes by improving the effective mechanical advantage (EMA) of limb musculature. Felids, however, have been documented to maintain joint angles across body sizes. If felid morphology scales isometrically, it would mean larger felids have relatively weaker muscles, compromising locomotor activities. Here, we examine the allometric relationships between the EMA of the elbow and knee extensors and body mass, finding that the EMA of the triceps brachii and quadriceps muscles scale with positive allometry. When species-specific joint angles were used rather than felid-average joint angles, EMA scales to body mass with more positive allometry. When the scaling of the muscle and ground reaction force (GRF) lever arms were investigated individually the allometric signal was lost; however, the muscle lever arms generally have allometric slope coefficients that are consistent with positive allometry, while the GRF lever arms demonstrate negative allometric slope coefficients. This suggests there are subtle alterations to limb morphology allowing different felid species to achieve an increased EMA via distinctive mechanisms. The quadriceps EMA was found to scale with sufficient positive allometry to compensate for increases in size without alteration in muscular anatomy; however, this is not the case for the triceps brachii EMA. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312540 TI - Internalization of Intact Intercellular Junctions in the Testis by Clathrin/Actin Mediated Endocytic Structures: Tubulobulbar Complexes. AB - Sertoli cells of the mammalian seminiferous epithelium form unique subcellular actin-related structures at intercellular junctions. The appearance of these so called "tubulobulbar complexes" (TBCs) precedes both sperm release at the apex of the epithelium and the movement of early spermatogenic cells out of the spermatogonial stem cell niche at the base of the epithelium. TBCs are considered to be part of the mechanism of junction endocytosis by Sertoli cells. The structures contain junction proteins and morphologically identifiable junctions, and are associated with markers of endocytosis. Here we review the current state of knowledge about the structure and function of TBCs. As the complexes form, they morphologically resemble and have the molecular signature of clathrin-coated pits with extremely long necks. As they mature, the actin filament networks around the "necks" of the structures progressively disassemble and the membrane cores expand or swell into distinct "bulbs". These bulbs acquire extensive membrane contact sites with associated cisternae of endoplasmic reticulum. Eventually the bulbs undergo scission and continue through endosomal compartments of the Sertoli cells. The morphology and composition of TBC indicates to us that the structures likely evolved from the basic clathrin-mediated endocytosis mechanism common to cells generally, and along the way they incorporated unique features to accommodate the cyclic turnover of massive and "intact" intercellular junctions that occurs during spermatogenesis. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30312541 TI - Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression. AB - Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962. PMID- 30312542 TI - Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands. AB - The 4-benzylpiperidine moiety is a central structural element of potent N-methyl d-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated omega-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7 a-c and one butyraldehyde 7 d bearing a fluorine atom and an omega-phenyl moiety were prepared in 3- to 7-step syntheses. Compounds 7 a-d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety. Although benzoxazol-2-ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3-(fluoroalkyl)-substituted tetrahydro-1H-3-benzazepine (Ki =239 nm). However, high GluN2B affinity was obtained for the tetrahydro-5H-benzo[7]annulen-7-amines 12 a-c (Ki =17-30 nm). Docking studies resulted in the same binding pose for 12 a as for the lead compound Ro 25-6981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4-benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro-3-benzazepines and -benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit. PMID- 30312544 TI - The Acid Fast Bacilli Smear: Hail and Farewell. PMID- 30312543 TI - Inhibition effect of phytoestrogen calycosin on TGF-beta1-induced hepatic stellate cell activation, proliferation, and migration via estrogen receptor beta. AB - The present study was designed to investigate the effects of calycosin on hepatic stellate cell (HSC) function and to explore whether the drug exerts its effect through the estrogen receptor. HSC proliferation and migration were measured by MTT assay and transwell chamber assay, respectively. The mRNA and protein expression of alpha-SMA, COL-I, and ERbeta were detected by real-time PCR and Western blotting. The co-localization and expression of alpha-SMA and ERbeta protein were detected by immunofluorescence. All the studies were investigated in the absence or presence of ICI 182,780. The results showed that calycosin inhibited the proliferation of activated HSCs and remarkably inhibited HSC migration. Calycosin significantly reduced the expression of alpha-SMA and COL-I in activated HSCs. However, with co-treatment with ICI 182,780, the inhibitory effect of calycosin against the above effects was strongly negated. Importantly, calycosin significantly downregulated the expression of ERbeta protein, while co treatment with ICI 182,780 partially reversed the ERbeta downregulation. In addition, alpha-SMA decreased with the decrease of ERbeta expression and the subtype of ERbeta on HSC is ERbeta5. In conclusion, calycosin inhibits proliferation, activation, and migration of TGF-beta1-induced HSCs. The effect may be related to binding and downregulation of ERbeta5. PMID- 30312545 TI - Relationship between rice consumption and body weight gain in Japanese workers: white versus brown rice/multigrain rice. AB - Increasing obesity rates have driven research into dietary support for body weight control, but previous studies have only assessed changes in body weight of +/- 3 kg. We investigated the relationships between white or brown/multigrain rice consumption and one-year body weight gain >= 3 kg in Japanese factory workers (n = 437). Routine medical check-up data from a one-year nutrition and lifestyle cohort study were analysed. Participants were divided into white rice and brown/multigrain rice consumption groups and further classified by tertile of rice consumption. Multiple logistic regression analyses were performed by tertile. At one year, high white rice consumption was significantly associated with increased risk of body weight gain >= 3 kg compared with low white rice consumption, maintained after adjustment for age, sex and consumption of other obesogenic foods (p = 0.034). In the brown/multigrain rice consumption group, however, there was no significant difference in risk between high and low consumption, even after multivariate adjustment (p = 0.387). The consumption of white rice, but not brown rice/multigrain rice, was positively correlated with the risk of a one-year body weight gain of 3 kg or more. This suggests that brown rice/multigrain rice consumption is useful for body weight control among Japanese workers. PMID- 30312546 TI - Effects of silica nanoparticles on endolysosome function in primary cultured neurons. AB - Silica nanoparticles (SiNPs) have been used as vehicles for drug delivery, molecular detection, and cellular manipulations in nanoneuromedicine. SiNPs may cause adverse effects in brain including neurotoxicity, neuroinflammation, neurodegeneration and enhancing levels of amyloid beta protein (Abeta); all pathological hallmarks of Alzheimer's disease. Therefore, the extent to which SiNPs influence Abeta generation and the underlying mechanisms by which this occurs deserves investigation. Our studies were focused on the effects of SiNPs on endolysosomes which uptake, traffic, and mediate the actions of SiNPs. These organelles are also where amyloidogenesis largely originates. We found that SiNPs, in primary cultured hippocampal neurons, accumulated in endolysosomes and caused a rapid and persistent deacidification of endolysosomes. SiNPs significantly reduced endolysosome calcium stores as indicated by a significant reduction in the ability of the lysosomotropic agent GPN to release calcium from endolysosomes. SiNPs increased Abeta1-40 secretion whereas two agents that acidified endolysosomes, ML-SA1 and CGS21680, blocked SiNPs-induced deacidification and increased generation of Abeta1-40. Our findings suggest that SiNP-induced deacidification of and calcium release from endolysosomes might be mechanistically-linked to increased amyloidogenesis. The use of SiNPs might not be the best nanomaterial for therapeutic strategies against AD and other neurological disorders linked to endolysosome dysfunction. PMID- 30312547 TI - Serum ferritin level as an early indicator of metabolic dysregulation in young obese adults - a cross-sectional study. AB - The aim of this study was to investigate the relationship between serum ferritin level and antioxidative status and metabolic dysregulation in young adult obese population. This cross-sectional study included 300 subjects of either sex, grouped as obese and non-obese subjects. The body mass index, total iron binding capacity, fasting blood glucose, superoxide dismutase activity, and levels of serum ferritin, iron, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, glutathione, and vitamin C were estimated. Analysis showed a significant alteration in all the parameters in obese adults. The correlation of ferritin level and body mass index showed a positive correlation (r = -0.81, p < 0.001, respectively) with levels of fasting blood glucose, superoxide dismutase, total cholesterol, low-density lipoprotein cholesterol, and triglyceride in obese individuals, whereas an insignificant correlation with vitamin C and glutathione level was observed in obese individuals. The significant positive correlation of ferritin level with the metabolic parameters and some antioxidative parameters in obese individuals signifies the development of metabolic disorders. Therefore, estimation of serum ferritin level will be an important early indicator for the risk of developing metabolic disorders in young adults. PMID- 30312548 TI - Challenges for assessing vertebrate diversity in turbid Saharan water-bodies using environmental DNA. AB - The Sahara desert is the largest warm desert in the world and a poorly explored area. Small water-bodies occur across the desert and are crucial habitats for vertebrate biodiversity. Environmental DNA (eDNA) is a powerful tool for species detection and is being increasingly used to conduct biodiversity assessments. However, there are a number of difficulties with sampling eDNA from such turbid water-bodies and it is often not feasible to rely on electrical tools in remote desert environments. We trialled a manually powered filtering method in Mauritania, using pre-filtration to circumvent problems posed by turbid water in remote arid areas. From nine vertebrate species expected in the water-bodies, four were detected visually, two via metabarcoding, and one via both methods. Difficulties filtering turbid water led to severe constraints, limiting the sampling protocol to only one sampling point per study site, which alone may largely explain why many of the expected vertebrate species were not detected. The amplification of human DNA using general vertebrate primers is also likely to have contributed to the low number of taxa identified. Here we highlight a number of challenges that need to be overcome to successfully conduct metabarcoding eDNA studies for vertebrates in desert environments in Africa. PMID- 30312549 TI - Clinical Significance of Viral Detection in Critically Ill Patients; More Questions than Answers... PMID- 30312550 TI - Frightening and Traumatic Memories Early After Intensive Care Discharge. PMID- 30312551 TI - Cystic Fibrosis: Emerging Understanding and Therapies. AB - Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with endstage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30312552 TI - Molecular Evolution of the Major Arthropod Chemoreceptor Gene Families. AB - The evolutionary origins of the three major families of chemoreceptors in arthropods-the odorant receptor (OR), gustatory receptor (GR), and ionotropic receptor (IR) families-occurred at the base of the Insecta, Animalia, and Protostomia, respectively. Comparison of receptor family sizes across arthropods reveals a generally positive correlation with their widely disparate complexity of chemical ecology. Closely related species reveal the ongoing processes of gene family evolution, including gene duplication, divergence, pseudogenization, and loss, that mediate these larger patterns. Sets of paralogous receptors within species reveal positive selection on amino acids in regions likely to contribute to ligand binding and specificity. Ligands of many ORs and some GRs and IRs have been identified; however, ligand identification for many more chemoreceptors is needed, as are structures for the OR/GR superfamily, to improve our understanding of the molecular evolution of these ecologically important receptors in arthropods Expected final online publication date for the Annual Review of Entomology Volume 64 is January 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30312553 TI - Fat Body Biology in the Last Decade. AB - The insect fat body is analogous to vertebrate adipose tissue and liver. In this review, the new and exciting advancements made in fat body biology in the last decade are summarized. Controlled by hormonal and nutritional signals, insect fat body cells undergo mitosis during embryogenesis, endoreplication during the larval stages, and remodeling during metamorphosis and regulate reproduction in adults. Fat body tissues are major sites for nutrient storage, energy metabolism, innate immunity, and detoxification. Recent studies have revealed that the fat body plays a central role in the integration of hormonal and nutritional signals to regulate larval growth, body size, circadian clock, pupal diapause, longevity, feeding behavior, and courtship behavior, partially by releasing fat body signals to remotely control the brain. In addition, the fat body has emerged as a fascinating model for studying metabolic disorders and immune diseases. Potential future directions for fat body biology are also proposed herein. Expected final online publication date for the Annual Review of Entomology Volume 64 is January 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30312554 TI - Nonreproductive Effects of Insect Parasitoids on Their Hosts. AB - The main modes of action of insect parasitoids are considered to be killing their hosts with egg laying followed by offspring development (reproductive mortality), and adults feeding on hosts directly (host feeding). However, parasitoids can also negatively affect their hosts in ways that do not contribute to current or future parasitoid reproduction (nonreproductive effects). Outcomes of nonreproductive effects for hosts can include death, altered behavior, altered reproduction, and altered development. On the basis of these outcomes and the variety of associated mechanisms, we categorize nonreproductive effects into (a) nonconsumptive effects, (b) mutilation, (c) pseudoparasitism, (d) immune defense costs, and (e) aborted parasitism. These effects are widespread and can cause greater impacts on host populations than successful parasitism or host feeding. Nonreproductive effects constitute a hidden dimension of host-parasitoid trophic networks, with theoretical implications for community ecology as well as applied importance for the evaluation of ecosystem services provided by parasitoid biological control agents. Expected final online publication date for the Annual Review of Entomology Volume 64 is January 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30312555 TI - Molecular Mechanisms of Wing Polymorphism in Insects. AB - Many insects are capable of developing into either long-winged or shortwinged (or wingless) morphs, which enables them to rapidly match heterogeneous environments. Thus, the wing polymorphism is an adaptation at the root of their ecological success. Wing polymorphism is orchestrated at various levels, starting with the insect's perception of environmental cues, then signal transduction and signal execution, and ultimately the transmitting of signals into physiological adaption in accordance with the particular morph produced. Juvenile hormone and ecdysteroid pathways have long been proposed to regulate wing polymorphism in insects, but rigorous experimental evidence is lacking. The breakthrough findings of ecdysone receptor regulation on transgenerational wing dimorphism in the aphid Acyrthosiphon pisum and of insulin signaling in the planthopper Nilaparvata lugens greatly broaden our understanding of wing polymorphism at the molecular level. Recently, the advent of high-throughput sequencing coupled with functional genomics provides powerful genetic tools for future insights into the molecular bases underlying wing polymorphism in insects. Expected final online publication date for the Annual Review of Entomology Volume 64 is January 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30312556 TI - Collective Editorial. PMID- 30312560 TI - Cardiovascular and Metabolic Effects of Androgen-Deprivation Therapy for Prostate Cancer. AB - Androgen-deprivation therapy (ADT) entails lowering serum testosterone levels to castrate levels and forms a cornerstone of the management of hormone-sensitive advanced prostate cancer; however, the benefit of ADT is partially offset by its detrimental metabolic and cardiovascular adverse effects. ADT decreases insulin sensitivity while promoting dyslipidemia and sarcopenic obesity, which leads to an increased risk of cardiovascular morbidity and potentially mortality. The risk seems to be highest in elderly patients who have had recent cardiovascular events before starting ADT. It is prudent to engage in an individualized risk-benefit discussion and develop a cohesive multidisciplinary management plan to medically optimize and closely observe these patients before and during treatment with ADT. PMID- 30312559 TI - National Athletic Trainers' Association Position Statement: Facilitating Work Life Balance in Athletic Training Practice Settings. AB - OBJECTIVE: : To illustrate the concept of work-life balance and those factors that influence it and to provide recommendations to facilitate work-life balance in athletic training practice settings. To present the athletic trainer with information regarding work-life balance, including those factors that negatively and positively affect it within the profession. BACKGROUND: : Concerns for work life balance have been growing within the health care sector, especially in athletic training, as it is continuously linked to professional commitment, burnout, job satisfaction, and career longevity. The term work-life balance reflects those practices used to facilitate the successful fulfillment of the responsibilities associated with all roles one may assume, including those of a parent, spouse, partner, friend, and employee. A host of organizational and individual factors (eg, hours worked, travel demands, flexibility of work schedules, relationship status, family values) negatively influence the fulfillment of work-life balance for the athletic trainer, but practical strategies are available to help improve work-life balance, regardless of the practice setting. RECOMMENDATIONS: : This position statement is charged with distributing information on work-life balance for athletic trainers working in a variety of employment settings. Recommendations include a blend of organizational and personal strategies designed to promote work-life balance. Establishing work life balance requires organizations to have formal policies that are supported at the departmental and personal level, in addition to informal policies that reflect the organizational climate of the workplace. Individuals are also encouraged to consider their needs and responsibilities in order to determine which personal strategies will aid them in attaining work-life balance. PMID- 30312562 TI - Look and You Will Find It: Practical Considerations for Improving Multidisciplinary Management of Androgen-Deprivation Therapy-Induced Cardiometabolic Toxicity. PMID- 30312561 TI - Nasopharyngeal Carcinoma: Chemotherapy or No Chemotherapy? PMID- 30312563 TI - Balancing Outcomes: Focusing on Value in Treatment of Prostate Cancer. PMID- 30312564 TI - Management of Nasopharyngeal Carcinoma: Is Adjuvant Therapy Needed? AB - Nasopharyngeal carcinoma of the undifferentiated histologic subtype is endemic and prevalent in southeast Asia. The dramatic improvement of treatment outcomes and overall prognosis during the past few decades has been attributed to advances in disease screening and diagnosis, diagnostic imaging, radiotherapy techniques, use of combination systemic therapy, and dedicated clinical and biomarker surveillance. The current practice of treating patients with advanced locoregional disease using cisplatin concurrent with conventional fractionated radiotherapy, followed by adjuvant cisplatin and fluorouracil, was established in 1998 when the landmark Intergroup-0099 Study demonstrated a survival benefit with the addition of systemic therapy. There is little doubt regarding the need for concurrent chemotherapy, but there has been uncertainty about the magnitude of the benefit attributed to the adjuvant phase. Furthermore, instead of one-size fits-all recommendations, it will be ideal if we can tailor adjuvant therapy to high-risk patients only to avoid unnecessary toxicities. In addition, recent evidence suggests that induction chemotherapy before concurrent chemoradiation can achieve better outcomes, especially in distant control, even in the modern era of intensity-modulated radiation therapy. This article provides a comprehensive review of key literature on the current management of locoregionally advanced nasopharyngeal carcinoma and highlights future research directions to unravel these controversies. PMID- 30312565 TI - Controversies Regarding the Management of Locoregionally Advanced Nasopharyngeal Carcinoma: Are We Asking the Right Questions? PMID- 30312566 TI - [Vascular Complications Of Cancer Chemotherapy]. AB - Development and use of new anticancer drugs has resulted in the improving of 5 year survival rates in patients with cancer. However, many of the modern chemotherapies are associated with cardiovascular toxicities that increases cardiovascular risk in cancer patients, including hypertension, heart failure, thrombosis and thromboembolism, cardiomyopathy, and arrhythmias. These side effects limitation restrict treatment options and farther perspectives. With increasing use of modern chemotherapies and prolongation of the cancer patients survival, the incidence of cardiovascular disease in this patient population will continue to increase. Accordingly, careful assessment and management of cardiovascular risk factors in cancer patients by oncologists and cardiologists working together is essential for optimal care. PMID- 30312567 TI - [Physical activity and physical training as method of prevention of cardiovascular diseases]. AB - A growing body of data demonstrates that exercise capacity is a potentially stronger predictor of mortality than established risk factors such as smoking, hypertension, obesity, high cholesterol, and type 2 diabetes mellitus. Individuals who maintain a regular program of PA that is longer in duration, of greater intensity, or both are likely to derive greater benefit than those who engage in lesser amounts. In this review, the authors have shown the possibility of assessing physical activity and the main provisions of the appointment of physical training to improve and preserve the cardiorespiratory fitness. PMID- 30312568 TI - [Thrombosis in patients with malignancy]. AB - Thrombosis traditionally considered as a complication of cardiovascular disease, however, this problem until recently was rarely taken into account in the presence of cancer. Although the association between cancer and thrombosis has been known almost 150 years ago, awareness of the impact of thrombotic complications have increased only now. Cancer is an independent major risk factor for venous thromboembolism (VTE), which is the leading cause of death of cancer patient. The incidence of VTE is steadily increasing in these patients. Thrombotic events have a significant impact on the quality of life of patients, and are associated with worsening of their short-term and long-term survival. The objective of this review is to summarize modern views on pathophysiology, as well as to outline new approaches to risk assessment, prevention and treatment of thrombosis in cancer patients. PMID- 30312569 TI - [Comorbidity and polymorbidity - a modern interpretation and urgent tasks facing the therapeutic community]. AB - The article presents an overview of data on polymorbidity. It is shown that polymorbidity is associated with higher mortality, disability, side effects of treatment, increased use of health system resources, and also with a lower quality of life. The issues of effective treatment of people with multiple chronic diseases are discussed. The necessity of clinical trials, including patients with multiple chronic diseases, and the development of new clinical recommendations, which could be based on practical doctors in the treatment of polymorbid patients, are substantiated. PMID- 30312570 TI - [Prognostic markers for the development of adverse outcomes in patients with chronic obstructive pulmonary disease and chronic heart failure]. AB - AIM: To identify markers of adverse outcomes in patients with a combination of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). MATERIALS AND METHODS: 35 patients with COPD (without an anamnesis of coronary heart disease), 68 patients with COPD and CHF, 28 patients with CHF of ischemic genesis who were on treatment at the State Regional Clinical Hospital of Saratov were examined. The levels of the N-terminal fragment of the natriuretic peptide, galectin-3, the highly sensitive C-reactive protein, the proteins that bind fatty acids, the stiffness parameters of the arterial wall were determined; echocardiography was performed, calculated the index of comorbidity of Charlson. A year after entering the study, patients or their relatives were interviewed for their adverse outcomes. RESULTS: The combination of COPD and CHF is accompanied by an increase in the likelihood of the development of heart failure decompensation compared with the isolated course of COPD. The main causes of death of patients with combined pathology were respiratory failure and cardiovascular complications. Decompensation of CHF was 3,6 times more likely in patients with COPD and CHF of ischemic origin than in patients without previous myocardial infarction. The risk group the development of acute decompensation of heart failure within the next year is composed of patients with COPD and CHF having 3-4 functional classes of CHF, signs of decompensation in the small circulation, angina pectoris, past myocardial infarction. The most significant prognostic echocardiographic parameters were marked dilatation of the left auricles, reduction of the left ventricular ejection fraction less than 45%. The development of cardiovascular complications in patients with COPD and CHF is interrelated with an increase in arterial rigidity. The increase in total mortality is associated with the severity of heart failure and increased 24-hour arterial rigidity. CONCLUSION: The obtained results will allow to form high-risk groups and optimize the treatment-diagnostic process. PMID- 30312571 TI - [Clinical and demographic features of patients with stroke and atrial fibrillation]. AB - BACKGROUND: Stroke takes the second place among all causes for cardiovascular death and the first place in mortality and disability among other nervous system diseases. Atrial fibrillation (AF) is presently is a commonly recognized, independent risk factor for ischemic stroke, which fivefold increases the risk of an unfavorable outcome. Prevention of stroke is a complicated medical and social challenge. AIM: To study AF prevalence among patients with stroke/transient ischemic attack (TIA) who had received an anticoagulant therapy before hospitalization. MATERIALS AND METHODS: A retrospective analysis of case reports was performed for patients diagnosed with acute cerebrovascular disease and TIA who had received a therapy from January, 2013 through December, 2015 (n=7921). From these case reports, 849 case reports of patients with concurrent AF were selected. RESULTS: In patients with stroke/TIA, the AF incidence was 10.72%. Risk assessment using the CHA2DS2-VASc scale showed that the percentage of low-risk patients (score 0) was 0.8%, intermediate risk patients (score 1) - 5.3%, and high-risk patients (score >=2) - 93.8%; 4.7% of patients with AF received preventive therapy for thromboembolic complications. The death rate of patients with AF and stroke/TIA was 15.78% whereas in-hospital death rate of patients without AF was 7.01%. Therefore, AF is a statistically significant risk factor of in-hospital mortality for patients with stroke/TIA (OR=2.485; 95% CI: 2.023 3.053; p. PMID- 30312572 TI - [Falling risk factors in patients with arterial hypertension 55+ years old]. AB - : Arterial hypertension (AH) is the most prevalent cardiac risk factor in old patients. Falls-related complications includes increased disability and mortality, decreased activity levels, quality of life, and overall health status. So falls are an important health problem. The aim of our study was to study falls in patients with AH 56+ years old finding fall risk factors in this population. METHODS: We examined 146 patients. 50 patients with AH had a fall during last 6 month. 96 patients with AH had no falls during this period. RESULTS: According to our study major risk factors for fall in population with AH are age, female sex, stratify sore value and blood pressure levels at admission. Patients who had experienced falls during last 6 month had significantly higher systolic, diastolic and pulsed blood pressure at admission without good blood pressure control. All differences in blood pressure were not reproduced in patients at discharge. So we suggest that ambulatory blood pressure control is important for fall prevention in people with AH 55+ years old. PMID- 30312573 TI - Current Resources for Evidence-Based Practice, November 2018. PMID- 30312574 TI - Super Thick Amniotic Membrane Graft for Ocular Surface Reconstruction. AB - PURPOSE: Evaluate Super-Thick Amniotic Membrane Graft(ST-AMG) for ocular surface reconstruction. DESIGN: Retrospective, interventional case series. METHODS: SETTING: Single center, clinical practice POPULATION: Selected patients with typically large ocular surface abnormalities that required reconstruction. INTERVENTION: Surgical insertion of ST-AMG for reconstruction or repair of the ocular surface. MAIN OUTCOME MEASURES: Intraoperative handling, graft position at 1 week post-implantation, graft dissolution at 3-weeks, epithelialization of the ocular surface and symblepharon. RESULTS: Eleven ST-AMG were implanted after resection with cryotherapy: 5 conjunctival melanoma, 4 squamous cell carcinoma, 1 sebaceous carcinoma, 1 pterygium. Additionally, 1 was implanted for scleral necrosis. ST-AMG up to 9-times thicker than standard amniotic grafts and thus amenable to both running and interrupted 7-0 Vicryl sutures without cheese wiring. All cases had a well-positioned ST-AMG at 1-week and 75%(n=9/12) had partial graft dissolution at 3 weeks. Complete epithelialization without wound dehiscence as noted in all cases. However, secondary (after additional tumor treatment) symblepharon formed in 16.7%(n=2/12). In all cases, the mean visual acuity and intraocular pressures remained unchanged during conjunctival reconstruction and subsequent secondary. Post-epithelialization adjuvant topical chemotherapy was given to extend treatment margins and treat presumed occult disease in 50%(n=6/12). At mean follow-up of 25.5 months (median 10, range 3 90),10 cases (83.3%) showed complete local tumor control, 1 showed revascularization of the scleral melt and 1 required orbital exenteration. CONCLUSION: ST-AMG were easy to suture and relatively persistent. Epithelialization of the ocular surface without primary symblepharon formation was noted. ST-AMG should be considered an alternative for ocular surface reconstruction. PMID- 30312575 TI - Intake of vegetables, fruit, and fish is beneficial for Age-related Macular Degeneration. AB - PURPOSE: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. DESIGN: Prospective population-based cohort study. METHODS: 4202 participants from the Rotterdam Study aged 55+ years, free of AMD at baseline, were included and followed up for 9.1+/-5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox-proportional hazards models, and adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. RESULTS: A total of 754 persons developed incident AMD. Intake of the recommended amounts of vegetables (>=200gr/day), fruit (2x/day), and fish (2x/week) was 30.6%, 54.9% and 12.5%, respectively. In particular the intake of fish (2x/week) decreased the risk of incident AMD; hazard ratio (HR) 0.76 [95% Confidence Interval (CI) 0.60-0.97]). Intake of the recommended amounts of all three food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (HR 0.58 [95%CI 0.36-0.93]). Younger age, higher income, and nonsmoking were associated with this food pattern, but risk lowering effects remained significant after additional adjustment for these factors. CONCLUSION: A diet of 200 grams of vegetables/day, 2x fruit/day, and 2x fish/week is associated with a significantly reduced risk of AMD. PMID- 30312576 TI - Aqueous humor analysis identifies higher branched chain amino acid metabolism as a marker for HLA-B27 acute anterior uveitis and disease activity. AB - PURPOSE: HLA-B27 positive acute anterior uveitis has a higher recurrence rate and shows more anterior chamber cell infiltration compared to HLA-B27-negative patients, suggesting distinct etiology of these clinically overlapping conditions. To advance our understanding of the biology of acute anterior uveitis, we characterized the metabolic profile of aqueous humor (AqH) of patients with HLA-B27 associated anterior uveitis (B27-AAU) and non-infectious idiopathic anterior uveitis (idiopathic AAU). DESIGN: Experimental laboratory study. METHODS: AqH samples from two independent cohorts totaling 30 B27-AAU patients 16 idiopathic AAU patients, and 20 cataract patients (CAT) were subjected to two individual rounds of Direct Infusion Mass Spectrometry (DIMS). Features predicted by DIMS that facilitated maximum separation between the disease groups in regression models were validated by Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS)-based quantification with appropriate standards. RESULTS: Partial least square-discriminant analysis (PLS-DA) revealed metabolite profiles that were able to separate B27-AAU from idiopathic AAU patients. Pathway enrichment analysis, based on metabolites on which separation of the groups in the PLS-DA model was based, demonstrated the involvement of branched-chain amino acid biosynthesis, ascorbate and aldarate metabolism, the tricarboxylic acid (TCA) cycle, and glycolysis-diverting pathways (e.g. serine biosynthesis) across all investigated cohorts. Notably, the metabolite ketoleucine was elevated in B27-AAU across all three runs and moderately - but robustly - correlated with anterior chamber cell count (correlation coefficient range = 0.41-0.81). CONCLUSION: These results illustrate metabolic heterogeneity between HLA-B27-positive and HLA-B27-negative acute anterior uveitis, including an increase of branched-chain amino acid biosynthesis, that reflects disease activity in acute anterior uveitis. PMID- 30312577 TI - Comorbidities and Prescribed Medications in Patients With or Without Dry Eye Disease: A Population-Based Study. AB - PURPOSE: To assess the proportion of comorbidities in patients with dry eye disease (DED) compared with matched patients without DED in a comprehensive US population. DESIGN: Retrospective case-control study METHODS: Health care records for insurance claims data, detailing medical services incurred by military personnel, their families and dependents in military and civilian facilities across the United States from January 1, 2003 to March 31, 2015, were obtained from the Department of Defense (DOD) Military Health System (MHS). Diagnostic and procedural codes related to DED from selected International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9), Current Procedural Terminology codes, and prescriptions for cyclosporine A ophthalmic emulsion were used to identify patients with newly diagnosed and prevalent DED in the MHS database. Age, sex and geographically matched patients without DED were also identified. From healthcare claims records. Medication use and comorbidities in these patient populations were assessed and compared. RESULTS: In both the newly diagnosed and prevalent DED samples, the most common comorbidities were hypertension, cataracts, thyroid disease, type 2 diabetes, and glaucoma. All comorbidities were significantly higher in the DED versus non-DED groups (P < .001). Medication use (including, but not limited to, ophthalmic agents and drugs to treat comorbidities) was also significantly higher in the DED than in the non-DED groups (P < .001). CONCLUSIONS: The high proportions of patients with DED with a range of comorbidities and prescribed medications highlight the need for a multidisciplinary approach to the management of these patients. PMID- 30312578 TI - A spectrum of regression following intravitreal bevacizumab in retinopathy of prematurity. AB - PURPOSE: To describe an improved understanding of the regression patterns following off-label intravitreal bevacizumab (IVB) treatment for retinopathy of prematurity (ROP). DESIGN: Retrospective cohort study. MethodsAll infants treated with IVB for Type 1 ROP at a single institution from June 2013 to March 2018 were retrospectively reviewed and the amount of retinal non-perfusion on fluorescein angiogram was calculated. ResultsOnly 3 eyes (3.3%) reached full vascular maturity in the 92 eyes of 46 patients analyzed. Of the 89 eyes not reaching maturity, 39 eyes (43.8%) had vascular arrest alone (VAA), 34 eyes (38.2%) had vascular arrest with persistent tortuosity (VAT), and 16 (18.0%) had ROP reactivation. Those eyes that reactivated were more likely to be initially classified as aggressive posterior ROP (p = 0.004) and of Asian ethnicity (p = 0.008). There were greater areas of ischemia in eyes with reactivation as compared to VAT and VAA (112.1 mm2 vs 72.5 mm2 vs. 56.6 mm2, respectively, p = 0.007). Younger gestational age at birth was found to be an independent predictor of persistent tortuosity (VAT vs. VAA) in a logistic regression model. ConclusionsIncomplete vascularization following IVB is very common and is associated with a younger gestational age at birth, Asian ethnicities, and aggressive posterior ROP. The presence of tortuosity following IVB may be indicative of persistently elevated VEGF levels and an early indicator of potential reactivation. PMID- 30312579 TI - Natural History Study of Retinal Structure, Progression and Symmetry Using Ellipzoid Zone Metrics in RPGR-Associated Retinopathy. AB - PURPOSE: Quantitative study of retinal structure, progression rates and interocular symmetry in RPGR-associated retinopathy using spectral domain optical coherence tomography (SD-OCT). DESIGN: Prospective, observational cohort study. METHODS: SETTING: Moorfields Eye Hospital, London, UK SUBJECTS: 38 subjects MAIN OUTCOME MEASURE: Two SD-OCT-derived ellipzoid zone (EZ) metrics with repeatability assessments. EZ width (EZW) measurements were made on transfoveal line scans. En face images of the EZ area (EZA) were generated from high density macular volume scans and quantified. Baseline size, progression rate, symmetry, associations with age and genotype, and baseline structure-function correlation were investigated. RESULTS: Baseline EZW and EZA were 1963.6 MUm and 3.70 mm2 respectively. Mean EZW progression rate was 233.6 MUm/year and mean EZA rate was 0.67 mm2/year. Relative Interocular Difference as an index of symmetry was 3% for both metrics indicating good baseline symmetry in general although significant variation existed across the cohort. ANOVA results demonstrated a significant effect of age but not genotype on EZ dimension and progression rates. Larger EZ dimension and greater progression were seen in younger subjects. A positive correlation between EZ dimension and progression was evident. Overall exponential decline rates of 8.2% with EZW and 15.5% with EZA were obtained. Good functional correlation was found with EZW demonstrating stronger correlation, however EZA correlation with function was also signficant. CONCLUSIONS: EZ metrics are sensitive structural biomarkers for measuring residual extent and progression in RPGR-associated retinopathy. Our elucidation of the natural history will provide clinicians and patients with more knowledge about the condition, and inform the design and interpretation of interventional trials. PMID- 30312580 TI - miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis. AB - miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor-associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma. PMID- 30312581 TI - Protein Degradation and the Pathologic Basis of Disease. AB - The abundance of any protein is determined by the balance of protein synthesis and protein degradation. Regulated protein degradation has emerged as a powerful means of precisely controlling individual protein abundance within cells and is largely mediated by the ubiquitin-proteasome system (UPS). By controlling the levels of key regulatory proteins, the UPS contributes to nearly every aspect of cellular function. The UPS also functions in protein quality control, rapidly identifying and destroying misfolded or otherwise aberrant proteins that may be toxic to cells. Increasingly, we understand that dysregulation of protein degradation pathways is critical for many human diseases. Conversely, the versatility and scope of the UPS provides opportunities for therapeutic intervention. In this review, we will discuss the basic mechanisms of protein degradation by the UPS. We will then consider some paradigms of human disease related to protein degradation using selected examples. Finally, we will highlight several established and emerging therapeutic strategies based on altering pathways of protein degradation. PMID- 30312582 TI - Astroprincin (FAM171A1, C10orf38): A Regulator of Human Cell Shape and Invasive Growth. AB - Our group originally found and cloned cDNA for a 98-kDa type 1 transmembrane glycoprotein of unknown function. Because of its abundant expression in astrocytes, it was called the protein astroprincin (APCN). Two thirds of the evolutionarily conserved protein is intracytoplasmic, whereas the extracellular domain carries two N-glycosidic side chains. APCN is physiologically expressed in placental trophoblasts, skeletal and hearth muscle, and kidney and pancreas. Overexpression of APCN (cDNA) in various cell lines induced sprouting of slender projections, whereas knockdown of APCN expression by siRNA caused disappearance of actin stress fibers. Immunohistochemical staining of human cancers for endogenous APCN showed elevated expression in invasive tumor cells compared with intratumoral cells. Human melanoma cells (SK-MEL-28) transfected with APCN cDNA acquired the ability of invasive growth in semisolid medium (Matrigel) not seen with control cells. A conserved carboxyterminal stretch of 21 amino acids was found to be essential for APCN to induce cell sprouting and invasive growth. Yeast two-hybrid screening revealed several interactive partners, of which ornithine decarboxylase antizyme-1, NEEP21 (NSG1), and ADAM10 were validated by coimmunoprecipitation. This is the first functional description of APCN. These data show that APCN regulates the dynamics of the actin cytoskeletal and, thereby, the cell shape and invasive growth potential of tumor cells. PMID- 30312583 TI - The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy. AB - BACKGROUND: Maternal diabetes induces neural tube defects and stimulates the activity of the forkhead box O3 (Fox)O3a in the embryonic neuroepithelium. We previously demonstrated that deleting the FOXO3a gene ameliorates maternal diabetes-induced neural tube defects. Macroautophagy (hereafter referred to as "autophagy") is essential for neurulation. Rescuing autophagy suppressed by maternal diabetes in the developing neuroepithelium inhibits neural tube defect formation in diabetic pregnancy. This evidence suggests a possible link between FoxO3a and impaired autophagy in diabetic embryopathy. OBJECTIVE: We aimed to determine whether maternal diabetes suppresses autophagy through FoxO3a, and if the transcriptional activity of FoxO3a is required for the induction of diabetic embryopathy. STUDY DESIGN: We used a well-established type 1 diabetic embryopathy mouse model, in which diabetes was induced by streptozotocin, for our in vivo studies. To determine if FoxO3a mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium, we induced diabetic embryopathy in FOXO3a gene knockout mice and FoxO3a dominant negative transgenic mice. Embryos were harvested at embryonic day 8.5 to determine FoxO3a and autophagy activity and at embryonic day 10.5 for the presence of neural tube defects. We also examined the expression of autophagy-related genes. C17.2 neural stem cells were used for in vitro examination of the potential effects of FoxO3a on autophagy. RESULTS: Deletion of the FOXO3a gene restored the autophagy markers, lipidation of microtubule-associated protein 1A/1B-light chain 3I to light chain 3II, in neurulation stage embryos. Maternal diabetes decreased light chain 3I-positive puncta number in the neuroepithelium, which was restored by deleting FoxO3a. Maternal diabetes also decreased the expression of positive regulators of autophagy (Unc-51 like autophagy activating kinase 1, Coiled-coil myosin-like BCL2-interacting protein, and autophagy-related gene 5) and the negative regulator of autophagy, p62. FOXO3a gene deletion abrogated the dysregulation of autophagy genes. In vitro data showed that the constitutively active form of FoxO3a mimicked high glucose in repressing autophagy. In cells cultured under high-glucose conditions, overexpression of the dominant negative FoxO3a mutant blocked autophagy impairment. Dominant negative FoxO3a overexpression in the developing neuroepithelium restored autophagy and significantly reduced maternal diabetes-induced apoptosis and neural tube defects. CONCLUSION: Our study revealed that diabetes-induced FoxO3a activation inhibited autophagy in the embryonic neuroepithelium. We also observed that FoxO3a transcriptional activity mediated the teratogenic effect of maternal diabetes because dominant negative FoxO3a prevents maternal diabetes-induced autophagy impairment and neural tube defect formation. Our findings suggest that autophagy activators could be therapeutically effective in treating maternal diabetes-induced neural tube defects. PMID- 30312584 TI - Hysterectomy status and all-cause mortality in a 21-year Australian population based cohort study. AB - BACKGROUND: Hysterectomy is a common surgical procedure, predominantly performed when women are between 30 and 50 years old. One in 3 women in Australia has had a hysterectomy by the time they are 60 years old, and 30% have both ovaries removed at the time of surgery. Given this high prevalence, it is important to understand the long-term effects of hysterectomy. In particular, women who have a hysterectomy/oophorectomy at younger ages are likely to be premenopausal or perimenopausal and may experience greater changes in hormone levels and a shortened reproductive lifespan than women who have a hysterectomy when they are older and postmenopausal. Use of menopausal hormone therapy after surgery may compensate for these hormonal changes. To inform clinical decisions about postsurgery management of women who have a hysterectomy prior to menopause (ie, average age at menopause 50 years), it is useful to compare women with a hysterectomy to women with no hysterectomy and to stratify the hysterectomy status by whether or not women have had a bilateral oophorectomy, or used menopausal hormone therapy. OBJECTIVE: We sought to investigate whether women who had a hysterectomy with ovarian conservation or a hysterectomy and bilateral oophorectomy before the age of 50 years were at a higher risk of premature all cause mortality compared to women who did not have this surgery before the age of 50 years. We also sought to explore whether use of menopausal hormone therapy modified these associations. STUDY DESIGN: Women from the midcohort (born 1946 through 1951) of the Australian Longitudinal Study on Women's Health were included in our study sample (n = 13,541). Women who reported a hysterectomy (with and without both ovaries removed) before the age of 50 years were considered exposure at risk and compared with women who did not report these surgeries before age 50 years. To explore effect modification by use of menopausal hormone therapy we further stratified hysterectomy status by menopausal hormone therapy use. Risk of all-cause mortality was assessed using inverse-probability weighted Cox regression models. RESULTS: During a median follow-up of 21.5 years, there were 901 (6.7%) deaths in our study sample. Overall, there was no difference in all-cause mortality between women who reported a hysterectomy with ovarian conservation (hazard ratio, 0.86; 95% confidence interval, 0.72-1.02) or women who reported a hysterectomy and bilateral oophorectomy (hazard ratio, 1.02; 95% confidence interval, 0.78-1.34) and women with no hysterectomy. When stratified by menopausal hormone therapy use, women with hysterectomy and ovarian conservation before the age of 50 years were not at higher risk of all-cause mortality compared to no hysterectomy, regardless of menopausal hormone therapy use status. In contrast, among nonusers of menopausal hormone therapy only, women who reported a hysterectomy-bilateral oophorectomy before the age of 50 years were at a higher risk of death compared to women with no hysterectomy (hazard ratio, 1.81; 95% confidence interval, 1.01 3.25). CONCLUSION: Hysterectomy with ovarian conservation before the age of 50 years did not increase risk of all-cause mortality. Among nonmenopausal hormone therapy users only, hysterectomy and bilateral oophorectomy before the age of 50 years was associated with a higher risk of death. PMID- 30312585 TI - Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia. AB - BACKGROUND: Infants born small for gestational age because of pathologic placenta mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified. OBJECTIVE: The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes. STUDY DESIGN: A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight <10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters. RESULTS: Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles. CONCLUSION: Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted. PMID- 30312586 TI - Is the Vazirani-Akinosi Nerve Block a Better Technique Than the Conventional Inferior Alveolar Nerve Block for Beginners? AB - PURPOSE: This study was performed to compare the efficacy and comfort of the inferior alveolar nerve (IAN) block and the Vazirani-Akinosi (VA) nerve block when administered by dental trainees. MATERIALS AND METHODS: In this prospective, randomized controlled trial, patients requiring extraction of mandibular teeth received either the conventional IAN block (IAN group) or VA nerve block (VA group). Objective parameters evaluated included ease of locating landmarks, incidence of positive aspiration, and failure rate. Patient comfort during injection was assessed with a visual analog scale. Statistical analysis was performed with the unpaired t test and Fisher exact test. RESULTS: One hundred patients were included in each group. Landmarks were easier to locate in the VA group. The incidence of positive aspiration was higher in the IAN group (0.08%) than in the VA group (0.01%, P < .05). The incidence of failed blocks was higher in the IAN group than in the VA group. Patients appeared to experience less pain with the VA injection than with the IAN injection. CONCLUSIONS: This study showed that the dental trainees found the VA technique more straightforward to perform. It had a higher success rate and lower incidence of positive aspiration and was more comfortable for patients than the conventional IAN block. PMID- 30312587 TI - The effect of mating history on male reproductive ageing in Drosophila melanogaster. AB - Mating bears costs, but how these costs affect the senescence of reproductive traits in males has received relatively little attention. Males of many species show reduced benefits from pre- and post-copulatory reproductive traits during ageing. Senescence of post-copulatory reproductive traits is often linked to a reduction in sperm quantity and quality, but can also be a consequence of changes in seminal fluid proteins that are transferred alongside sperm during mating. Here we investigated how mating history affects male reproductive ageing, especially at the post-copulatory level, using Drosophila melanogaster, a species in which links between seminal fluid proteins and male reproductive traits are well established. Besides a male cohort kept virgin until the start of the experiment we also included a cohort of males kept together with females allowing for ample mating opportunities. With these males we conducted a series of behavioral experiments covering several aspects of male reproductive success with males ranging in age from 4 days to 6 weeks after eclosion. Additionally, we investigated the storage capacity of male accessory glands (AG), the production site of the majority of seminal fluid proteins. We found male reproductive success to decline with increasing male age and, most importantly, males with prior matings showed a reduced performance in pre-copulatory success. However, our data suggest a constant short-term cost of mating rather than an accelerated senescence of pre-copulatory traits. In contrast, senescence of post-copulatory reproductive traits differed between mated and virgin males, hinting at mating costs in males altering the ageing process. We could not find any differences in the capacity of the AG to store seminal fluid proteins, however, our data suggest that old males transfer fewer seminal fluid proteins in a single mating. We conclude that a variety of traits is affected by male reproductive ageing in D. melanogaster with the cost of mating varying in its impact on senescence in these traits. PMID- 30312588 TI - The Prevalence of Gastroesophageal Reflux in Patients With Excessive CentralAirway Collapse. AB - BACKGROUND: Gastroesophageal reflux (GER) is increasingly recognized as an exacerbating or causal factor in several respiratory diseases. There is a high prevalence of GER in infants with airway malacia. However, such data are lacking in adults. METHODS: This retrospective study was conducted to determine the relationship between GER and excessive central airway collapse (ECAC). The study included consecutive patients with ECAC referred to the Complex Airway Center at Beth Israel Deaconess Medical Center who underwent esophageal pH testing for GER between July 2014 and June 2018. RESULTS: Sixty-three of 139 patients with ECAC (45.3%) had documented GER as shown by an abnormal esophageal pH test result. The mean DeMeester score was 32.2, with a symptom association probability of 39.7% of GER-positive patients. Twenty-nine of 63 patients (46%) with GER reported improvement in respiratory symptoms following maximal medical therapy or antireflux surgery without requiring further treatment for ECAC. CONCLUSIONS: GER is prevalent among patients with ECAC, and aggressive reflux treatment should be considered in these patients prior to considering invasive airway procedures or surgery. PMID- 30312589 TI - Implications of the Revised Common Rule for Human Participant Research. AB - This paper looks at the implications of changes to the regulatory governance of human participant research that can be expected with implementation of the Revised Common Rule (RCR). The RCR refers to revisions of the existing federal regulations that govern the performance of research involving human subjects (ie, clinical research) in the United States and, under certain circumstances, when such research is also performed outside the United States. The term "common" is included because it refers to the fact that these regulations, often referred to as Code of Federal Regulations 46, is the common denominator regulations agreed to across a wide swath of federal agencies. PMID- 30312590 TI - Better With Ultrasound: Transesophageal Echocardiography. AB - Transesophageal echocardiography (TEE) is a safe and minimally invasive tool that can routinely provide high-quality anatomic and hemodynamic information in the severely ill. Despite its potential for frontline acute care clinicians, TEE use has typically been reserved for diagnostic experts in the cardiac-surgical milieu. With the continued evolution of point-of-care ultrasound into increasingly sophisticated domains, TEE has gained steady uptake in many nontraditional environments for both advanced echocardiographic assessment as well as answering more goal directed, fundamental questions. This article introduces the workings of the TEE transducer, presents a systematic approach to a goal-directed hemodynamic assessment, and includes a series of illustrative figures and narrated video presentations to demonstrate the techniques described. PMID- 30312591 TI - Thermal expansion of substrate may affect adhesion of Chinese hamster fibroblasts to surfaces during freezing. AB - Despite success in cryopreservation of cells in suspension, cryopreservation of cells in monolayers is still challenging. One of the major problems is detachment of the cells from the substrate which occurs during cryopreservation. We hypothesized that this detachment may be due to a mismatch in the coefficient of linear thermal expansion (alphaL) between glass and the frozen cell layer which manifests as residual stress and stress relaxation. This mismatch results in a difference between the thermal expansion of ice and glass as they undergo temperature changes. Rinzl plastic coverslips were selected as a possible substitute for glass because Rinzl has a alphaL (60 * 10-6/K) similar to that of ice (51 * 10-6/K) whereas glass has a much lower alphaL (5 * 10-6/K). V79-4 Chinese hamster fibroblasts were cultured on both glass and Rinzl coverslips until confluent and the area of coverage was measured before and after freezing at -9 degrees C. The glass coverslips showed significant loss of cells (coverage = 77.9 +/- 8.0%) compared with Rinzl (coverage = 97.9 +/- 1.4%). We concluded that Rinzl coverslips may improve cell attachment in future monolayer cryopreservation experiments. PMID- 30312592 TI - Optimization of protocols for microinjection-based delivery of cryoprotective agents into Japanese whiting Sillago japonica embryos. AB - Microinjection has proven useful for introduction of low-permeability cryoprotective agents (CPAs) into fish eggs or embryos for cryopreservation. In this work, we examined the suitable conditions for single or combined microinjection into the perivitelline space (PS) and the yolk mass (YM) of embryos of the Japanese whiting, an alternative marine fish model for embryo cryopreservation studies. The parameters examined were injection volume, CPA type and concentration, vehicle (diluent), and suitable developmental stage. Somites and tail elongation embryos tolerated single or combined injection with 2.1 and 15.6 nl in the PS and YM, respectively, whereas earlier embryonic stages tolerated only up to 8.2 nl in the YM. The injected solutions diffused rapidly throughout the PS and YM and remained contained within each compartment unless in the case of structural damage caused by injection of larger volumes. Yamamoto solution was marginally better as a vehicle for microinjection of CPAs than fish Ringer and phosphate buffer saline whereas 1/4 artificial sea water was clearly unsuitable. Ethylene glycol was well tolerated by embryos in all developmental stages whereas 1, 2-propylene glycol was suitable only for early embryonic stages. Overall, microinjection was efficient in delivering high loads of CPAs inside whiting embryos more swiftly than previously obtained for this species by immersion-based impregnation protocols. Embryos microinjected with CPAs showed a decrease in embryo nucleation temperature and an increase in chilling tolerance. CPA-microinjected embryos will provide valuable materials to optimize the remaining parameters that are critical for successful cryopreservation such as cooling and warming strategies. PMID- 30312593 TI - Investigation of whole mitochondrial genome variation in normal tension glaucoma. AB - Glaucoma is one of the leading causes of visual impairment and blindness worldwide. However, the cause of retinal ganglion cell loss and damage of the optic nerve in its pathogenesis is largely unknown. The high energy demands of these cells may reflect their strong dependence on mitochondrial function and thus sensitivity to mitochondrial defects. To address this issue, we studied whole mitochondrial genome variation in normal tension glaucoma patients and control individuals from the Polish population using next generation sequencing. Our findings indicate that few features of mitochondrial DNA variation are different for glaucoma patients and control subjects. New insights into normal tension glaucoma development are discussed. We provide also a comprehensive approach for mitochondrial DNA analysis and variant evaluation. PMID- 30312594 TI - Structural determinants for substrate specificity of flavoenzymes oxidizing d amino acids. AB - The oxidation of d-amino acids is relevant to neurodegenerative diseases, detoxification, and nutrition in microorganisms and mammals. It is also important for the resolution of racemic amino acid mixtures and the preparation of chiral building blocks for the pharmaceutical and food industry. Considerable biochemical and structural knowledge has been accrued in recent years on the enzymes that carry out the oxidation of the Calpha-N bond of d-amino acids. These enzymes contain FAD as a required coenzyme, share similar overall three dimensional folds and highly conserved active sites, but differ in their specificity for substrates with neutral, anionic, or cationic side-chains. Here, we summarize the current biochemical and structural knowledge regarding substrate specificity on d-amino acid oxidase, d-aspartate oxidase, and d-arginine dehydrogenase for which a wealth of biochemical and structural studies is available. PMID- 30312595 TI - Effects of a Patient-Centered Graded Exposure Intervention Added to Manual Therapy for Women With Chronic Pelvic Pain: A Randomized Controlled Trial. AB - OBJECTIVE: To explore the effects of a 6-week patient-centered graded exposure intervention added to manual therapy in women with chronic pelvic pain (CPP) and fear of movement/(re)injury. DESIGN: Prospective 3-armed randomized controlled trial. SETTING: Faculty of Health Sciences. PARTICIPANTS: A total of 49 women with CPP and substantial fear of movement were randomly allocated to 1 of 3 groups: (1) patient-centered graded exposure intervention added to manual therapy; (2) manual therapy; (3) control group. INTERVENTIONS: The 6-week intervention consisted of 12 sessions in the group receiving manual therapy and 6 additional sessions of graded exposure therapy in the group receiving both interventions. MAIN OUTCOME MEASURES: Primary outcomes were fear-avoidance behavior assessed using the Fear-Avoidance Beliefs Questionnaire and pain interference and severity evaluated with the Brief Pain Inventory. The secondary outcome was disability evaluated with the Oswestry Disability Index. All the variables were assessed in a blinded manner at baseline, after the treatment, and at 3-month follow-up. RESULTS: Our results show interaction effects (P<.05) for all the outcomes. Graded exposure added to manual therapy is distinctly superior to manual therapy alone in maintaining improvements for long-term fear-avoidance behavior and physical functioning. CONCLUSIONS: Graded exposure added to manual therapy is a promising approach with long-term effects for women with CPP and fear of movement/(re)injury. PMID- 30312596 TI - Gait Speed and Frailty Status in Relation to Adverse Outcomes in Geriatric Rehabilitation. AB - OBJECTIVE: Both slow gait speed (GS) and higher levels of frailty are associated with adverse outcomes in community-dwelling older people. However these measures are not routinely utilized to stratify risk status in the hospital setting. Here we assessed their predictive validity in older inpatients. DESIGN: A prospective cohort study. SETTING: Inpatient rehabilitation wards of a tertiary hospital. PARTICIPANTS: Adults 65 years and older (N=258). INTERVENTIONS: A frailty index (FI) was calculated from routinely collected data and GS was determined from a timed 10-meter walk test. MAIN OUTCOME MEASURES: Adverse outcomes were longer length of stay (>=75th percentile), poor discharge outcome (discharge to a higher level of care or inpatient mortality), and inpatient delirium and falls. RESULTS: Mean age +/- SD was 79+/-8 years and 54% were women. Mean FI +/- SD on admission was 0.42+/-0.13 and an FI could be derived in all participants. Mean GS +/- SD was 0.26+/-0.33 m/sec. Those unable to complete a timed walk on admission (50%) were allocated a GS of 0. There was a weak but significant inverse relationship between FI and GS (correlation coefficient -0.396). Both parameters were significantly associated with longer length of stay (P<.001), poor discharge outcome (P<=.001), and delirium (P<.05).The prevalence of adverse outcomes was highest in the cohort who were more frail and unable to mobilize at admission to rehabilitation. CONCLUSIONS: FI and GS each showed predictive validity for adverse outcomes. In a geriatric rehabilitation setting, they measure different aspects of vulnerability and combining the 2 may add value in identifying patients most at risk. PMID- 30312597 TI - MiR-10 targets NgR to modulate the proliferation of microglial cells and the secretion of inflammatory cytokines. AB - The present study is aimed to investigate the molecular mechanism of miR-10 targeting NgR to regulate the proliferation and inflammatory cytokine secretion in microglia cells (MCs). The expression levels of NgR, IL-1beta, and TNF-alpha in rat MCs were detected by QPCR and Immunoblotting assays. The proliferation of MC was detected by MTT and Soft agar clone formation assays. The target gene of miR-10 was verified by dual luciferase reporter gene assay. Overexpressed miR-10 downregulated the expression of NgR, promoted MC proliferation and inhibited inflammatory cytokine secretion. On the other hand, the inhibition of miR-10 upregulated the expression of NgR, inhibited MC proliferation and promoted inflammatory cytokine secretion. It was found that miR-10 targeted to regulate NgR. Overexpression of NgR restored the regulation effects of miR-10 on MC proliferation and inflammatory cytokine secretion. In summary, miR-10 can promote MC proliferation and inhibit the inflammatory cytokine secretion via targeting the NgR gene to down-regulate its expression. PMID- 30312598 TI - Basidiomycetes-X, an edible mushroom, alleviates the development of atopic dermatitis in NC/Nga mouse model. AB - Basidiomycetes-X (BDM-X) is a novel edible mushroom recently identified as a new fungi species and is effective against oxidative stress and anti-inflammation associated with immune response. However the effect of BDM-X on atopic dermatitis (AD) has not been elucidated. In this study, we have investigated the effect of BDM-X on AD skin lesions in NC/Nga mouse model. AD-like lesion was induced by the application of house dust mite extract (DfE) to the dorsal skin of NC/Nga mouse. After AD induction, BDM-X was administered once daily for 2 weeks. We have analyzed the effects of BDM-X on dermatitis severity, histopathological changes and changes in inflammatory and proinflammatory proteins expressions in DfE induced AD mice skin. Treatment with BDM-X attenuated the development of AD-like clinical symptoms and effectively inhibited hyperkeratosis, parakeratosis, acanthosis and mast cells in AD mice skin. Furthermore, BDM-X treatment inhibited DfE induced tumor necrosis factor (TNF)alpha, high mobility group protein (HMG)B1, nuclear factor kappa (NFkappa)B and inflammatory cytokines. These results indicate that BDM-X inhibits AD through modulating Th1 and Th2 responses and diminishing the mast cells infiltration in the skin lesions in NC/Nga mice. PMID- 30312599 TI - Performance evaluation of HbA1c measurement systems with sigma metric for 1066 laboratories in China. AB - BACKGROUND: This study aimed to evaluate the performance of HbA1c measurement systems quantitatively with sigma metric and promote the quality improvement. METHODS: 1066 laboratories enrolled external quality assessment (EQA) and reported their internal quality control (IQC) data for HbA1c in 2017 were included in this study. The bias and coefficient of variation were collected from EQA and IQC program designed by the National Center for Clinical Laboratory. The sigma values was used to assess the performance of HbA1c, and combine Westgard Sigma RulesTM to select proper quality control rules in every laboratory. RESULTS: Totally, There were 388,190,185,100,59,55,89 participants used Bia-Rad HPLC, TOSOH G7/G8, ARKRAY HA8160/8180, HUIZHONG MQ-2000/2000PT, Roche, Primus HPLC and "Others" system, respectively. "HUIZHONG MQ-2000/2000PT" group had the smallest variation of bias. 56.19% (599/1066) of laboratories met bias criterion and 55.63% (593/1066) satisfied imprecision criterion. However, sigma metrics indicated that 80.21% (855/1066) of 1066 laboratories needed to improve their performance of HbA1c. Moreover, "TOSOH G7/G8" group had the highest constituent ration of sigma >= 3. CONCLUSIONS: The analytical quality of HbA1c in most laboratories need improving. Laboratories should pay more attention on the performance of HbA1c, and EQA organizers in China should improve evaluation criteria and push standardization work for HbA1c. PMID- 30312601 TI - Sequencing the peripheral blood B and T cell repertoire - Quantifying robustness and limitations. AB - The adaptive immune response generates a large repertoire of T cells with T-cell receptors (TCRalpha and TCRbeta) and B cells with immunoglobulins (Ig). The repertoire changes in response to antigen stimulation both through amplification of specific cells (clonal expansion) as well as somatic hypermutation of immunoglobulins. Alterations of the immune repertoire have been observed in response to acute disease, such as external pathogens, or chronic diseases, such as autoimmunity and cancer. Here we establish experimental and analytical protocols for quantifying the peripheral blood of healthy human individuals by profiling the immune repertoire for the Complementarity determining region 3 (CDR3) of the variable regions of TCRbeta (CDRbeta3) and the IgG heavy chain (CDRH1, CDRH2, CDRH3). The results demonstrate that 40 ml of blood are sufficient to reliably capture the 10,000 most common TCRbeta and 1000 most common IgG and determine their relative frequency in the circulation. We conclude that by using an accessible sample size of human PBMC one is able to robustly monitor alterations in the immune repertoire. PMID- 30312600 TI - Excessive outlier removal may result in cut points that are not suitable for immunogenicity assessments. AB - Cut point determination is an important aspect of immunogenicity assay development. The cut point can be influenced by a myriad of factors. Key among those is the analytical variability of the assay itself and biological variation due to test samples. Since a smaller cut point value may result in improved sensitivity, the existing procedures often employ statistical techniques such as outlier removal to produce a conservative cut point. Although such practices are intended to yield acceptable assay sensitivity, they may fail to fully account for biological variability in the data, thus generating higher than expected number of false positive results. In this paper, we introduce the concept of minimum cut point. It is defined as the cut point that is determined in the absence of biological variability. Under the log-normal assumption of the data used for cut point analysis, closed-form formulas are derived for the minimum cut point. This minimum cut point can be used to benchmark whether a cut point derived from a procedure can compromise assay specificity by being too low. PMID- 30312602 TI - A novel Sigma metric encompasses global multi-site performance of 18 assays on the Abbott Alinity system. AB - OBJECTIVES: The Abbott Alinity family of chemistry and immunoassay systems recently launched with early adopters contributing imprecision and bias data, which was consolidated to assess the performance of Alinity assays across multiple sites using the Sigma metric. Multi-site Sigma metrics were determined for 3 ion-selective electrodes, 12 photometric assays, and 3 immunoassays across 11 independent laboratory sites in 9 countries. METHODS: Total allowable error (TEa) goals followed a previously defined hierarchy that used CLIA as the primary goal. Bias was calculated against the Abbott ARCHITECT system using Passing Bablok regression analysis using individual site data or pooled aggregate data. Sigma metrics were calculated as (%TEa - |% bias|)/%CV. For individual-site analysis, the Sigma metrics for each assay were compared using the individual site and the pooled biases. For multi-site analysis, the average CV and the pooled bias were used to generate a Pooled Sigma metric encompassing the global performance for a given assay. RESULTS: A total of 97 individual-site and 18 Pooled Sigma metrics were calculated for available assays. Individual Sigma metrics varied across sites, with 90% of assays performing 4 Sigma or higher, and 17 of 18 Pooled Sigma metrics indicated performance greater than 4 Sigma. Sigma metrics were significantly improved in 16 assays when using pooled bias rather than individual-site bias. CONCLUSIONS: This multi-center study applies a novel application of Sigma metrics to the first Alinity users and reveals analytical performance of greater than 4 Sigma for vast majority of assays. Laboratories with limited resources can leverage larger data sets for Pooled Sigma metric analysis, providing a tool to assess the consistency of analytical performance from multiple sites. PMID- 30312603 TI - The involvement of regulated in development and DNA damage response 1 (REDD1) in the pathogenesis of intervertebral disc degeneration. AB - Regulated in development and DNA damage response 1 (REDD1) is an evolutionarily conserved, ubiquitous protein that responds to various cell stresses. Studies have proved REDD1 is involved in many diseases, such as osteoarthritis and cancer. The present study aimed to investigate the potential role of REDD1 in the pathogenesis of intervertebral disc degeneration (IDD). Analysis of clinical tissue samples showed REDD1 expression was up-regulated during IDD and was correlated with the grade of disc degeneration. Overexpression of REDD1 in normal human nucleus pulposus (NP) cells resulted in extracellular matrix (ECM) degeneration. Further, we investigated the function of REDD1 using a serum deprivation-induced IDD vitro model and found that REDD1 was up-regulated in a temporal manner. However, hypoxia abolished this increase through down-regulation of NF-kappaB. Knockdown of REDD1 or NF-kappaB by si-RNA significantly rescued ECM from degeneration both in normoxia and hypoxia. In addition, NF-kappaB/REDD1 mediated the protection of hypoxia from serum deprivation-induced apoptosis and autophagy in NP cells. These results suggest that REDD1 might play a pivotal role in IDD pathogenesis, thereby potentially providing a new therapeutic target for IDD treatment. PMID- 30312605 TI - Reduced Purkinje cell size is compatible with near normal morphology and function of the cerebellar cortex in a mouse model of spinocerebellar ataxia. AB - Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurodegenerative disease caused by diverse mutations in the Protein Kinase C gamma (PKCgamma) gene which is one of the crucial signaling molecules of Purkinje cells. We have previously created a mouse model of SCA14 by transgenic expression of a mutated PKCgamma gene causing SCA14 with a mutation in the catalytic domain. Purkinje cells from the mutated mice have a strong reduction of their dendritic tree in organotypic slice cultures typical for increased PKC activity. There was no overt degeneration of Purkinje cells in vivo and the cerebellum appeared morphologically normal with the exception of lobule 7 where abnormal Purkinje cells were present. Besides from mild motor deficits the mice have no major phenotype. We have now done a more extensive study of cerebellar morphology in these mice and show by rapid Golgi staining that there is a marked reduction of Purkinje cell dendritic tree size throughout the cerebellum. Despite this reduction in dendritic tree size, climbing fiber innervation of Purkinje cells as visualized by immunostaining for the vesicular glutamate transporter 2 (vGlut2) appeared normal in most parts of the cerebellum. The same was true for the expression of the activity and plasticity markers pS6, c-Fos and Arc. These finding suggest that the cerebellar cortex in the transgenic mice is functioning fairly normal and that the reduction of dendritic tree size and the increased PKC activity can be compensated in most Purkinje cells. Around cerebellar lobule 7 there was high transgene expression from the L7 promotor and Purkinje cells showed abnormal morphologies. Climbing fiber innervation as well as the expression of the activity and plasticity markers was strongly disturbed in this area. Our results show that there is substantial potential for functional compensation in the cerebellar cortex. In lobule 7, an area with high transgene expression, compensation failed resulting in Purkinje cell degeneration and dysfunction. PMID- 30312604 TI - Notch1 promotes mouse spinal neural stem and progenitor cells proliferation via p p38-pax6 induced cyclin D1 activation. AB - Neural stem and progenitor cells (NSPCs) are important for nerve regeneration after spinal cord injury (SCI). Their proliferation, however, is limited. In this study, we investigated the role of Notch1 signaling in NSPC proliferation using adult mouse spinal cord derived NSPCs. We observed that Notch1 promoted proliferation of NSPCs and that Notch1 overexpression led to an expansion of cells in the S-phase and increased cyclin D1 expression. When investigating the functional relationship between Notch1, p-p38 and Pax6, we found that Notch1 suppressed p-p38 while promoting Pax6 expression. Functional inhibition of p38 with SB202190 led to increased Pax6 expression and to proliferation, as determined by BrdU. Furthermore, we confirmed that Pax6 induced proliferation in adult mouse spinal cord derived NSPCs. In conclusion, we demonstrate that Notch1 promotes the proliferation of mouse spinal NSPCs via a p-p38-pax6-cyclin D1 signaling pathway. This pathway constitutes a promising new therapeutic target for SCI treatment. PMID- 30312606 TI - Rapid plasticity of intact axons following a lesion to the visual pathways during early brain development is triggered by microglial activation. AB - Lesions in the central nervous system (CNS) can often induce structural reorganization within intact circuits of the brain. Several studies show advances in the understanding of mechanisms of brain plasticity and the role of the immune system activation. Microglia, a myeloid derived cell population colonizes the CNS during early phases of embryonic development. In the present study, we evaluated the role of microglial activation in the sprouting of intact axons following lesions of the visual pathways. We evaluated the temporal course of microglial activation in the superior colliculus following a contralateral monocular enucleation (ME) and the possible involvement of microglial cells in the plastic reorganization of the intact, uncrossed, retinotectal pathway from the remaining eye. Lister Hooded rats were enucleated at PND 10 and submitted to systemic treatment with inhibitors of microglial activation: cyclosporine A and minocycline. The use of neuroanatomical tracers allowed us to evaluate the time course of structural axonal plasticity. Immunofluorescence and western blot techniques were used to observe the expression of microglial marker, Iba-1 and the morphology of microglial cells. Following a ME, Iba-1 immunoreactivity showed a progressive increase of microglial activation in the contralateral SC at 24 h, peaking at 72 h after the lesion. Treatment with inhibitors of microglial activation blocked both the structural plasticity of intact uncrossed retinotectal axons and microglial activation as seen by the decrease of Iba-1 immunoreactivity. The local blockade of TNF-alpha with a neutralizing antibody was also able to block axonal plasticity of the intact eye following a ME. The data support the hypothesis that microglial activation is a necessary step for the regulation of neuroplasticity induced by lesions during early brain development. PMID- 30312607 TI - Clinicopathological Features of Thymoma with the Expression of Programmed Death Ligand 1. AB - BACKGROUND: Programmed death-ligand 1 (PD-L1) is reportedly expressed in various malignancies and is considered a prognostic factor. We attempted to reveal the usefulness of the PD-L1 expression as a prognostic factor in patients with thymoma. METHODS: Eighty-one patients with thymoma who underwent surgical resection between 2004 and 2015 were retrospectively reviewed. The PD-L1 expression was evaluated by immunohistochemistry and stratified by the proportion of positive tumor cells. Strong membranous reactivity of the PD-L1 antibody in >= 1% of tumor cells was considered 'positive'. The association between the PD-L1 expression and the clinicopathological features was investigated. RESULTS: The PD L1 expression was positive in 22 patients (27%) and negative in 59 patients (73%). PD-L1 positivity was significantly associated with type B2 and B3 thymoma (p < 0.001) and stage III and IV disease (p = 0.048). In addition, PD-L1-positive tumors showed a significantly higher maximum standardized uptake value (SUVmax) than PD-L1-negative tumors (p = 0.026). The 5-year disease-free survival (DFS) rate was 82% in PD-L1-positive patients and 88% in PD-L1-negative patients, showing no significant difference (p = 0.57). Furthermore, PD-L1 positivity was not an independent prognostic factor for the DFS on a Cox proportional hazard analysis (p = 0.590). CONCLUSIONS: A strong expression of PD-L1 in thymoma was significantly associated with type B2 and B3 and higher pathological stages. In addition, PD-L1 positivity was associated with an increased SUVmax of the tumor. However, patients with PD-L1-positive thymomas did not show a significantly worse prognosis than those with PD-L1-negative tumors. PMID- 30312608 TI - Early Prognosis of Reduction Ascending Aortoplasty. PMID- 30312609 TI - Direct true lumen cannulation for acute type A aortic dissection. PMID- 30312610 TI - Objective Donor Scoring System for Lung Transplantation. AB - BACKGROUND: There is not an objective method to estimate post lung transplant (LTx) survival based solely on cumulative donor risk factors. METHODS: The UNOS thoracic transplant database was queried to identify patients who underwent lung transplant between 2005 and 2015. A cox-proportional hazard model was generated using a training set to identify donor risk factors significantly associated with post-transplant survival. Significant donor risk factors were assigned a score based on their hazard ratio. Donor risk score was calculated for each patient by adding the individual donor risk factor scores. Donors in the validation set were then categorized into Low (score=0), Intermediate (score=1) and High risk (score>1) categories based on the cumulative risk score. LAS was used as a surrogate for recipient risk. Survival for each risk group was calculated using Kaplan-Meier curves. RESULTS: The donor risk groups' respective survival at 1 year was 85%, 81%, and 77% and at 5 years was 53%, 50%, and 42% (p<0.001). The combination of low risk recipients and low risk donors had a 1 and 5-year survival of 89% and 59% respectively. The combination of high risk recipients and high-risk donors had a 1 and 5-year survival of 70% and 30% respectively CONCLUSIONS: The proposed lung donor scoring system is a simple, easy to use method that can aid transplant surgeons in the selection of a potential lung transplant donor. Utilizing the lung donor score in conjunction with the LAS can allow for matching of recipients and donors, in order to optimize post-transplant outcomes. PMID- 30312611 TI - Incentive Spirometry after Lung Resection: Importance of Patient Adherence. PMID- 30312612 TI - Neighborly Help or Itinerant Surgery? PMID- 30312613 TI - Intraoperative device closure of a perimembranous VSD using the right thoracic ventricle approach. AB - BACKGROUND: This study compared the safety and effectiveness of intraoperative device closure of a perimembranous ventricular septal defect (pmVSD) using the right-thoracic-minimal-incision-to-right-ventricle and lower-midline-sternotomy to-right-ventricle approaches. METHODS: We retrospectively analyzed the clinical data of 46 patients who underwent intraoperative device closure of a pmVSD via the right-thoracic-minimal-incision-to-right-ventricle route (group I) and 52 patients who underwent intraoperative device closure of a pmVSD via a minimal incision in the lower sternum (group II) at our hospital from March 2016 to March 2017. In group I, a right thoracic minimal incision to the fourth intercostal space was used to establish a delivery system through the right ventricle to complete pmVSD closure. RESULTS: In group I, intraoperative device closure of the pmVSD was successful in 44 patients and was converted to open surgery in 2 patients (a delivery system could not be established in one patient, and a significant residual shunt was present in the other). In group II, the corresponding numbers of patients were 50 and 2, respectively. Neither group exhibited serious adverse effects, including dislocation of the occluder, third degree atrioventricular block (AVB), or new onset of aortic valve regurgitation during the perioperative period or during a median follow-up period of 1-2 years. CONCLUSIONS: Intraoperative device closure of a pmVSD via the right-thoracic minimal-incision-to-right-ventricle approach is safe and effective. This procedure can avoid some of the shortcomings caused by sternotomy, uses an incision with an improved cosmetic appearance, and is worth recommendation. PMID- 30312614 TI - Risks and Rewards of Advanced Practice Providers in Cardiothoracic Surgery Training: National Survey. AB - BACKGROUND: Changes in healthcare have led to increasing utilization of Advanced Practice Providers (APPs), but their role in Cardiothoracic Surgery (CTS) education remains undefined. This study aimed to analyze the extent of APP utilization on the CTS team, their role within the hierarchy of clinical care, and the impact of PEs on CTS training from the resident perspective. METHODS: CTS residents' responses to the 2017 Thoracic Surgery Residents Association (TSRA)/Thoracic Surgery Directors Association (TSDA) In-Service Training Examination (ITE) survey regarding the role of APPs in specific clinical scenarios, and perception of APP contribution to residents' educational environment were analyzed. Statistical analysis of categorical variables was performed in SPSS using a Fisher's exact test and Pearson Chi-Square with statistical significance set at p<0.05. RESULTS: Response rate was 82.1% (280/341). The median number of employed APPs was 16-20 and 50.4% (n=141) reported 11-25 PEs at their institution. The median forAPPs in the operating room, floor, and intensive care unit was 3, 3, and 2 respectively. Overall impression of APPs was positive in 87.5% (n=245) of respondents, with 47.7% (n=133) being "very positive" and 40.1% being "positive" (n=112). In general, residents reported greater resident involvement in post-operative issues and operative consults and greater APP involvement in floor issues. 72.5% of residents had not missed a surgical opportunity due to APPs while, 9.6% missed an opportunity due to a APP despite being at an appropriate level of training. Of those that reported missed opportunities, 44% were I-6 residents. There were no significant differences in APPs' operative role based on resident seniority. CONCLUSIONS: The overall impression of APPs among CTS residents is favorable, and they more commonly are involved assisting on the floor or the operating room. Occasionally, residents report missing a surgical opportunity due to APPs. There is further opportunity to optimize and standardize their role within programs, in order to improve clinical outcomes and enhance the CTS educational experience for residents. PMID- 30312616 TI - A single-center experience of 900 inter-hospital transports on extracorporeal membrane oxygenation (Commentary). PMID- 30312615 TI - Does the Approach Matter? Comparing Survival in Robotic, Minimally Invasive and Open Esophagectomies. AB - BACKGROUND: Our objective is to determine how surgical approach impacts overall survival and postoperative outcomes when comparing robotic-assisted minimally invasive esophagectomy (RAMIE), minimally invasive esophagectomy (MIE) and open esophagectomy (OE). METHODS: The National Cancer Data Base (NCDB) was queried for patients diagnosed with pathologic Stage 0-III esophageal cancer from 2010-2015. Primary outcome measures evaluated were length-of-stay (LOS), 30-day unplanned readmissions, mortality rates at 30 and 90 days, and overall survival rates (OSR). The surgical cohorts underwent 1:1 propensity-score matching and Kaplan Meier survival estimates were compared by surgical approach. Cox proportional hazards regression was utilized to estimate factors associated with overall survival. RESULTS: Of 5,553 patients that met criteria, 28.4% were MIE, 7.8% RAMIE, and 63.8% OE. From 2010-2015 an increasing trend was seen for both minimally invasive approaches, with MIE surpassing the number of open esophagectomies. Unplanned 30-day readmissions, 30-d and 90-d mortality rates were not significantly different between the different groups. LOS was significantly shorter in MIE (9 days, IQR 8-14) and RAMIE (9 days, IQR 7-14), compared to OE (10 days, IQR 8-15, p<0.001). MIE and RAMIE, had comparable survival rates compared to OE with no significant differences in median overall survival estimates after propensity-score matching (Log-rank p=0.603); with a trend for increased survival in RAMIE, Adjusted Hazard Ratio [HR] 0.97 (95% CI 0.89-1.06, p=0.530), RAMIE HR 0.81 (95% CI, 0.69-0.95, p=0.012). Both minimally invasive approaches had a significantly higher median lymph node counts [MIE, 15 (IQR 9-22); RAMIE, 17 (IQR 11-24), OE 13 (IQR 8-20), with may provide important differences in postoperative upstaging. CONCLUSIONS: Trends in MIE use is surpassing the open approach. Minimally invasive approaches are becoming the preferred approach with non-inferior long-term results compared to open esophagectomies. A significantly higher lymph node yield was seen for RAMIE and MIE. PMID- 30312617 TI - Anomalous Aortic Origin of the Coronary Arteries: A Novel Unroofing Technique in an Adult Cohort. AB - BACKGROUND: Anomalous aortic origin of the coronary arteries (AAOCA) is associated with sudden cardiac death and frequently treated with unroofing of an intramural segment. Most reports on AAOCA are in patients under age 30. We have reviewed our "older" patients who have undergone surgical repair and report a novel unroofing technique. METHODS: A retrospective review was conducted of 40 adult patients who underwent surgery for AAOCA from 6/2005 to 6/2016. Our surgical approach changed from traditional sharp excision to electrical fulguration of the shared intramural wall segment. We assessed our population for symptom relief, resolution of ischemia, and reintervention. More than 6 months of follow-up was available in 34. RESULTS: Mean age was 47.1+/-11.6 (range, 19-67) years; 17 were female. The coronary anomaly was right from left 35, left from right 4, and left coronary from non-coronary sinus 1. 39/40 patients were symptomatic, with 2 prior sudden cardiac arrests. Preoperatively, 22/31 tested positive for ischemia, including the asymptomatic. The operation was unroofing in 37/40 patients, 17 by sharp excision and 20 by electrical fulguration. There were no 30-day deaths or complications and no reinterventions. Isolated unroofing by fulguration required shorter cardiopulmonary bypass and cross-clamp times than excision, 39 vs. 62 minutes (p=0.02) and 28 vs. 42 minutes (p=0.02), respectively. At an average follow-up of 5.0 years, 28/34 patients reported symptomatic improvement. There were 2 unrelated late deaths. CONCLUSIONS: Unroofing by sharp excision and by electrical fulguration were equally safe short term. Fulguration is technically easier and faster while still equally effective. PMID- 30312618 TI - Dual cycle amplification and dual signal enhancement assisted sensitive SERS assay of MicroRNA. AB - A sensitive surface-enhanced Raman scattering (SERS) approach has been developed for detection of microRNA (miRNA) based on target-triggered dual signal amplification including strand displancement amplification (SDA) and hybridization chain reaction (HCR). With the assistant of polymerase and nicking endonuclease (NEase), target miRNA combines with the single stranded template DNA to generate a great amount of trigger DNA which can induce HCR. Coupled the dual cycle amplification of SDA and HCR with the dual enhancement of gold nanoparticles (AuNPs), a low detection limit of 0.5 fM for miRNA is obtained using the proposed strategy. With high sensitivity, universality, rapid analysis, and high selectivity, this method has a great potential for detecting biomolecules with trace amounts in bioanalysis and clinical biomedicine. PMID- 30312619 TI - Urea can inhibit efficient reduction and alkylation of protein dimers in solution demonstrated by the beta subunit of alpha glucosidase II. AB - Protein reduction and alkylation is routinely used for analysis of protein dimers and protein complexes in cell fractions using two dimensional gel electrophoresis and mass spectrometry. To resolve the heterogeneity of a high molecular weight protein band that is highlighted by an antibody to the beta subunit of alpha glucosidase II (GIIbeta), we performed reduction and alkylation of cytosolic proteins extracted from mouse brain. The presence of urea in the reduction/alkylation buffer inhibited the chemical processes. It is thus recommended that protein reduction/alkylation be performed both in the presence and absence of urea for the separation of mono-/hetero-mers. PMID- 30312620 TI - Arrayed microfluidic chip for detection of circulating tumor cells and evaluation of drug potency. AB - Circulating tumor cells (CTCs) from peripheral blood of cancer patients are considered as one of the most promising pharmacodynamic (PD) biomarkers due to its non-invasive property in disease diagnosis and prognosis. However, the detection of extremely low number of CTCs in patient blood requires methods with high sensitivity and accuracy. We fabricated an arrayed geometrically enhanced mixing (GEM) chip with a "dislocation herringbone" layout based on cell immunoaffinity. By optimizing the injection and rinsing flow rate, an average cell capture rate of 87.02% and an average capture purity of 99.58% were achieved using the human lung adenocarcinoma cell lines H1975. In addition, we determined the specificity, precision, accuracy, and detection limit of our chip. The results demonstrated the chip was stable, accurate and reliable for the "liquid biopsy" of lung cancer cells using the peripheral blood of patients. Our chip can also be used to evaluate the potency of different drugs against tumor cells in parallel due to the presence of four independent microchannels. PMID- 30312621 TI - Utility of homoarginine in the GC-MS quantification of asymmetric dimethylarginine (ADMA) in human serum proteins. AB - NG,NG-Dimethyl-L-arginine (asymmetric dimethylarginine, ADMA) is a cardiovascular risk factor. ADMA circulates in blood as a free acid (fADMA) and as constituent of not yet identified proteins (prADMA). We describe here a protocol for the GC MS quantification of ADMA released from serum proteins using 6 M HCl (110 degrees C, 20 h). L-Homoarginine (hArg) is useful in measuring digestibility of amino acids in food proteins. We demonstrate that hArg is not present in human serum proteins and is useful in measuring serum prADMA. The concentration of prADMA in elderly subjects is about 90 nM and the average fADMA/prADMA ratio 6:1. PMID- 30312622 TI - Systems, variation, individuality and plant hormones. AB - Inter-individual variation in plants and particularly in hormone content, figures strongly in evolution and behaviour. Homo sapiens and Arabidopsis exhibit similar and substantial phenotypic and molecular variation. Whereas there is a very substantial degree of hormone variation in mankind, reports of inter-individual variation in plant hormone content are virtually absent but are likely to be as large if not larger than that in mankind. Reasons for this absence are discussed. Using an example of inter-individual variation in ethylene content in ripening, the article shows how biological time is compressed by hormones. It further resolves an old issue of very wide hormone dose response that result directly from negative regulation in hormone (and light) transduction. Negative regulation is used because of inter-individual variability in hormone synthesis, receptors and ancillary proteins, a consequence of substantial genomic and environmental variation. Somatic mosaics have been reported for several plant tissues and these too contribute to tissue variation and wide variation in hormone response. The article concludes by examining what variation exists in gravitropic responses. There are multiple sensing systems of gravity vectors and multiple routes towards curvature. These are an aspect of the need for reliability in both inter individual variation and unpredictable environments. Plant hormone inter individuality is a new area for research and is likely to change appreciation of the mechanisms that underpin individual behaviour. PMID- 30312624 TI - Altered pheromone biosynthesis is associated with sex-specific changes in life span and behavior in Drosophila melanogaster. AB - Many insect behaviors, including foraging, aggression, mating or group behavior, are tightly regulated by pheromones. Recently, it has been shown that pheromones may influence extreme longevity in the honeybee Apis mellifera, while changes in pheromone profile have been observed during ageing in Drosophila melanogaster. These data suggest a potential link between the pheromone system, behavior and longevity in insects. Here, we investigate this potential link by examining changes in behavior and longevity in fruit flies with altered pheromone profiles. We demonstrate that oenocyte-specific reduction of desaturase activity is sufficient to dramatically alter the composition of the hydrocarbon mix displayed by the flies. In addition, flies with altered desaturase activity display changes in fecundity and stereotypical mating behavior, and, importantly, extended longevity. These data provide evidence for a potential link between hydrocarbon synthesis and life span, and suggest that longevity may be influenced by behavior. PMID- 30312625 TI - Commentary on: E. H. Toomarian and E. M. Hubbard (2018), on the genesis of spatial-numerical associations: Evolutionary and cultural factors co-construct the mental number line. PMID- 30312623 TI - Optimal trans-saccadic integration relies on visual working memory. AB - Saccadic eye movements alter the visual processing of objects of interest by bringing them from the periphery, where there is only low-resolution vision, to the high-resolution fovea. Evidence suggests that people are able to achieve trans-saccadic integration in a near-optimal manner; however the mechanisms underlying integration are still unclear. Visual working memory (VWM) is sustained across a saccade, and it has been suggested that this memory resource is used to store and compare the pre- and post- saccadic percepts. This study directly tested the hypothesis that VWM is necessary for optimal trans-saccadic integration, by introducing memory load during a saccade, and testing subsequent integration performance on feature similar and dissimilar stimuli. Results show that integration performance was impaired when there was an additional memory task. Additionally, performance on the memory task was affected by feature specific integration stimuli. Our results suggest that VWM supports the integration of pre- and post- saccadic stimuli because integration performance is impaired under VWM load. PMID- 30312626 TI - Disturbances of sleep quality, timing and structure and their relationship with other neuropsychiatric symptoms in Alzheimer's disease and schizophrenia: Insights from studies in patient populations and animal models. AB - The high prevalence of sleep disturbance in neurodegenerative and psychiatric conditions is often interpreted as evidence for both sleep's sensitivity to and causal involvement in brain pathology. Nevertheless, how and which aspects of sleep contribute to brain function remains largely unknown. This review provides a critical evaluation of clinical and animal literature describing sleep and circadian disturbances in two distinct conditions and animal models thereof: Alzheimer's disease (AD) and schizophrenia. Its goal is to identify commonalities and distinctiveness of specific aspects of sleep disturbance and their relationship to symptoms across conditions. Despite limited standardisation, data imply that reductions in sleep continuity and alterations in sleep timing are common to AD and schizophrenia, whereas reductions in REM sleep and sleep spindle activity appear more specific to AD and schizophrenia, respectively. Putative mechanisms underlying these alterations are discussed. A standardised neuroscience based quantification of sleep and disease-independent assessment of symptoms in patients and animal models holds promise for furthering the understanding of mechanistic links between sleep and brain function in health and disease. PMID- 30312627 TI - Prevalence, typing and phylogenetic analysis of Melissococcus plutonius strains from bee colonies of the State of Chihuahua, Mexico. AB - European foulbrood (EFB) caused by Melissococcus plutonius is an important bee brood disease but, in Mexico, information about this bacterium is limited. We evaluated the prevalence of typical and atypical strains in beehives of seven apicultural regions of the state of Chihuahua, Mexico. We performed MLST and phylogenetic analysis to characterize the isolates. Prevalence was highest 59%, in the region of Chihuahua, and lowest, 14%, in the regions of Cuauhtemoc and Nuevo Casas Grandes. Typical and atypical strains were identified in hives from all regions; however, in the regions of Parral, Cuauhtemoc and Aldama, the atypical strains were only detected in combination with typical strains. We obtained 81 isolates of M. plutonius and identified seven sequence types, of which three were new types. Additionally, we observed a relation between sequence type and the region where the strain was isolated. Phylogenetic analysis and multilocus sequence typing using goeBURST analysis showed that 97.5% of the isolates correspond to the Clonal Complex (CC) 12 and 2.5% to the CC3. Our work is the first molecular characterization of M. plutonius in Mexico and contributes to global information about the epidemiology of this pathogen. PMID- 30312628 TI - Dermal microvessel density and maturity is closely associated with atherogenic dyslipidemia and accumulation of advanced glycation end products in adult patients with type 1 diabetes. AB - In patients with diabetes, functional changes in microcirculation and subclinical vascular pathology precede clinical manifestation of microangiopathic complications. The objective of this study was to evaluate the association between established vascular risk factors and density, maturity, and reactivity of dermal blood vessels in adults with type 1 diabetes (DM1). We included 148 DM1 patients (87 men) with a median (IQR) age of 40.5 (30.5-49) years and a median diabetes duration of 21 (17-29.5) years. The control group consisted of 13 healthy volunteers (6 men) with a median (IQR) age of 36 (31-43). Accumulation of advanced glycation end products (AGEs) was assessed using the AGE-Reader device. In the immunohistochemical (IHC) analyses, anti-CD133, anti-CD34, anti-CD31, and anti-vWF autoantibodies were used. Microvessel density (MVD) in the skin was calculated using the "hot spots technique". Microvascular function was examined by single-point laser-Doppler flowmetry (LDF). Median MVD, calculated for both papillary and reticular dermis, for CD31 antigen expression was 38 (19-56) per 1 mm2. The median CD34+ blood vessel density was 121 (100-155) per 1 mm2, CD133+ was 79 (63-92) per 1 mm2, and vWF+ was 50 (40-69) per 1 mm2. The average CD34/CD31 index was 2.78, the vWF/CD31 ratio was 1.32 and the CD133/CD31 ratio was 1.75. The CD34/CD31 index was positively associated with serum triglyceride concentration (Beta: 0.26, p = 0.012) and negatively associated with serum HDL cholesterol concentration (Beta: -0.22, p = 0.027), both independently from age, sex, diabetes duration, BMI, HbA1c value, presence of hypertension, and eGFR. We found a negative correlation between MVD assessed by CD31 and skin AF (r = -0.21, p = 0.016). In LDF, the area under the blood flow/time curve (AUC) correlated positively with CD31+ MVD (r = 0.21, p = 0.011) and negatively with CD34+ MVD (r = -0.20, p = 0.017). The MVD did not differ between participants with diabetes and healthy controls, and it did not differ according to the presence of retinopathy among the participants with diabetes. Atherogenic dyslipidemia is associated with increased formation of new blood vessels, characterized by high expression of CD34 and low reactivity in LDF. Conversely, chronic hyperglycemia and excessive formation of AGEs may result in decreased vascularity. PMID- 30312629 TI - Data-Driven Scheduling for Improving Patient Efficiency in Ophthalmology Clinics. AB - PURPOSE: To improve clinic efficiency through development of an ophthalmology scheduling template developed using simulation models and electronic health record (EHR) data. DESIGN: We created a computer simulation model of 1 pediatric ophthalmologist's clinic using EHR timestamp data, which was used to develop a scheduling template based on appointment length (short, medium, or long). We assessed its impact on clinic efficiency after implementation in the practices of 5 different pediatric ophthalmologists. PARTICIPANTS: We observed and timed patient appointments in person (n = 120) and collected EHR timestamps for 2 years of appointments (n = 650). We calculated efficiency measures for 172 clinic sessions before implementation vs. 119 clinic sessions after implementation. METHODS: We validated clinic workflow timings calculated from EHR timestamps and the simulation models based on them with observed timings. From simulation tests, we developed a new scheduling template and evaluated it with efficiency metrics before vs. after implementation. MAIN OUTCOME MEASURES: Measurements of clinical efficiency (mean clinic volume, patient wait time, examination time, and clinic length). RESULTS: Mean physician examination time calculated from EHR timestamps was 13.8+/-8.2 minutes and was not statistically different from mean physician examination time from in-person observation (13.3+/-7.3 minutes; P = 0.7), suggesting that EHR timestamps are accurate. Mean patient wait time for the simulation model (31.2+/-10.9 minutes) was not statistically different from the observed mean patient wait times (32.6+/-25.3 minutes; P = 0.9), suggesting that simulation models are accurate. After implementation of the new scheduling template, all 5 pediatric ophthalmologists showed statistically significant improvements in clinic volume (mean increase of 1-3 patients/session; P <= 0.05 for 2 providers; P <= 0.008 for 3 providers), whereas 4 of 5 had improvements in mean patient wait time (average improvements of 3-4 minutes/patient; statistically significant for 2 providers, P <= 0.008). All of the ophthalmologists' examination times remained the same before and after implementation. CONCLUSIONS: Simulation models based on big data from EHRs can test clinic changes before real-life implementation. A scheduling template using predicted appointment length improves clinic efficiency and may generalize to other clinics. Electronic health records have potential to become tools for supporting clinic operations improvement. PMID- 30312630 TI - THC and gabapentin interactions in a mouse neuropathic pain model. AB - Clinical studies have shown that the major psychoactive ingredient of Cannabis sativa Delta9-tetrahydrocannabinol (THC) has some analgesic efficacy in neuropathic pain states. However, THC has a significant side effect profile. We examined whether the profile of THC could be improved by co-administering it with the first-line neuropathic pain medication gabapentin. This was done using the chronic constriction injury (CCI) model of neuropathic pain in C57BL6 mice. At 8 days post-CCI nerve injury, acute systemic administration of gabapentin produced a dose-dependent decrease in CCI-induced mechanical and cold allodynia, and increased motor incoordination. Coadministration of THC and gabapentin in a fixed ratio dose-dependently reduced mechanical and cold allodynia, and produced all the side-effects observed for THC, including motor incoordination, catalepsy and sedation. Isobolographic analysis indicated that the ED50 for the THC:gabapentin induced reduction in allodynia was 1.7 times less than that predicted for an additive interaction. The therapeutic window of combination THC:gabapentin was greater than that for THC alone. These findings indicate that gabapentin synergistically enhances the anti-allodynic actions of THC and improves its therapeutic window. Thus, THC may represent a potential adjuvant for neuropathic pain medications such as gabapentin. PMID- 30312631 TI - Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes. AB - The endocrine disrupting chemicals, polychlorinated biphenyls (PCBs), have been associated with nonalcoholic steatohepatitis (NASH) and diabetes. However, an integrative analysis of the effects of PCBs on the liver and pancreas has never been performed for the two major PCB subtypes, dioxin-like (DL) and nondioxin like (NDL), and a mixture of NDL/DL PCBs. Therefore, male C57BL/6 J mice fed a control synthetic diet were treated with either a NDL PCB mixture, Aroclor 1260 (20 mg/kg); a single DL PCB congener, PCB 126 (20 MUg/kg); a NDL/DL mixture, Aroclor 1260 plus PCB 126; or vehicle control for 2 weeks. PCB126 had the greatest impact on hepatic lipid metabolism. It caused steatosis due to increased hepatic lipid import with associated hypolipidemia. However, all PCB exposures impacted expression of hepatic lipid metabolism genes in different manners. The 'NASH gene', Pnpla3, was elevated by Aroclor 1260, but decreased by all other exposures. The expression of hepatokines implicated in metabolic syndrome (Fgf21, Igf1, and betatrophin) were differentially regulated. The NDL/DL PCB mixture had the greatest effects on pancreatic histology, including acinar cell atrophy, mild steatosis, and fibrosis without ductal changes or immune cell infiltration. It decreased expression of insulin and altered the expression of genes regulating islet identity. None of these exposures was associated with altered HOMA-IR or HOMA-B. In summary, PCB exposures differentially regulated liver and pancreas structure and function. Novel mechanisms for PCB-induced endocrine/metabolic disruption included altered hepatokines and Pnpla3 as well as 'PCB pancreatopathy' that was associated with altered expression of pancreatic islet identity factors. More research is required to understand fully these findings in the context of human NASH and diabetes. PMID- 30312633 TI - Chronic co-administration of nalbuphine attenuates the development of opioid dependence. AB - Nalbuphine is an agonist of kappa-opioid receptors and a partial agonist of MU opioid receptors, which can stimulate kappa-receptors and antagonize the acute rewarding effects of morphine. It is widely used either as an analgesic or as an adjuvant with morphine. This present study aimed to compare the acute and chronic effects of nalbuphine on the naloxone-precipitated opiate-withdrawal in rats. Male adult Wistar albino rats (150-175 g, n = 160) were made physically dependent by administrating increasing dose of morphine (5-25 mg/kg; i.p.). Motor activity was measured for 25 min at five-minute intervals on days 0, 1, 3, 5, and 6 using Activity Monitor (Coulbourn Instruments, Inc. USA) and True-scan software. The withdrawal was precipitated with intraperitoneal injections of naloxone (1 mg/kg) 4 h after the last injection of morphine. Somatic signs of withdrawal were scored using the global Gellert-Holtzman rating scale. Nalbuphine was co-administered acutely and chronically at various doses (0.1, 0.3, 1.0, and 3.0 mg/kg; i.p.) with morphine. In general, the opiate-dependent rats showed a significant increase in motor activity and Gellert-Holtzman score. Animals co-administered with chronic doses of nalbuphine showed a significant decrease in motor activity and naloxone-precipitated opiate withdrawal, but acute nalbuphine treatment did not attenuate the development of opioid dependence. These findings suggest that nalbuphine could be used as an effective pharmacological adjunct in the treatment of opioid addiction. PMID- 30312632 TI - Modeling hepatitis C virus protein and p53 interactions in hepatocytes: Implications for carcinogenesis. AB - Hepatitis C virus (HCV) infection has reached epidemic proportions worldwide. Individuals with chronic HCV infection and without access to treatment are at high risk for developing hepatocellular carcinoma (HCC), a liver cancer that is rapidly fatal after diagnosis. A number of factors have been identified that contribute to HCV-driven carcinogenesis such as scarring of the liver, and chronic inflammation. Recent evidence indicates a direct role for HCV-encoded proteins themselves in oncogenesis of infected hepatocytes. The viral protein HCV core has been shown to interact directly with the host tumor suppressor protein p53, and to modulate p53-activity in a biphasic manner. Here, biochemically motivated mathematical models of HCV-p53 interactions are developed to elucidate the mechanisms underlying this phenomenon. We show that by itself, direct interaction between HCV core and p53 is insufficient to recapitulate the experimental data. We postulate the existence of an additional factor, activated by HCV core that inhibits p53 function. We present experimental evidence in support of this hypothesis. The model including this additional factor reproduces the experimental results, validating our assumptions. Finally, we investigate what effect HCV core-p53 interactions could have on the capacity of an infected hepatocyte to repair damage to its DNA. Integrating our model with an existing model of the oscillatory response of p53 to DNA damage predicts a biphasic relationship between HCV core and the transformative potential of infected hepatocytes. In addition to providing mechanistic insights, these results suggest a potential biomarker that could help in identifying those HCV patients most at risk of progression to HCC. PMID- 30312634 TI - The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions. AB - Pharmacotherapy, psychotherapy, and non-invasive brain stimulation (NIBS)1 each show efficacy in the treatment of psychiatric disorders; however, more efficacious interventions are needed as reflected by an overall unmet need in mental health care. While each modality has typically been studied and developed as a monotherapy, in practice they are typically used in combination. Research has begun to emerge studying the potential synergistic actions of multi-modal, combination therapies. For example, NIBS combined with rehabilitation strategies have demonstrated some success for speech and motor rehabilitation in stroke patients. In this review we present evidence suggesting that combining NIBS with targeted, cognitive interventions offers a potentially powerful new approach to treating neuropsychiatric disorders. Here we focus on NIBS studies using transcranial direct current stimulation (tDCS)2 and transcranial magnetic stimulation (TMS)3 given that these modalities are relatively safe, noninvasive, and can be performed simultaneously with neurocognitive interventions. We review the concept of "state dependent" effects of NIBS and highlight how simultaneous or sequential cognitive interventions could help optimize NIBS therapy by providing further control of ongoing neural activity in targeted neural networks. This review spans a range of neuropsychiatric disorders including major depressive disorder, schizophrenia, generalized anxiety, and autism. For each disorder, we emphasize neuroanatomical circuitry that could be engaged with combination therapy and critically discuss the literature that has begun to emerge. Finally, we present possible underlying mechanisms and propose future research strategies that may further refine the potential of combination therapies. PMID- 30312635 TI - Optimization of transglutaminase (TG) immobilization on the surface of polyethersulfone ultrafiltration membrane and its characteristics in a membrane reactor. AB - The process of microbial transglutaminase (TG) covalent immobilization on an ultrafiltration membrane surface, the optimum immobilization conditions and the characteristics of the enzymatic membrane in a reactor were investigated. The process of TG immobilization on polyethersulfone (PES) membrane surfaces was analyzed by Fourier transform infrared and X-ray photoelectron spectroscopy. The optimal condition for TG immobilization was in pH 5.0 phosphate buffer containing TG (20 U/mL). The immobilized TG had a high affinity for the substrate according to the kinetic parameters and retained 50% activity until the twentieth day. Water contact angle and antifouling tests showed that the hydrophilicity of immobilized-transglutaminase membrane was improved compared with pure PES membrane. The enzyme could maintain relatively high activity under a transmembrane pressure of 0.15 MPa. Moreover, the enzymatic membrane had higher relative membrane flux at 0.15 MPa in a membrane reactor, and could retain its activity in pH 5.0 phosphate buffer and catalysis under 40 degrees C. PMID- 30312636 TI - Genome-wide analysis of gene expression after one year of venom immunotherapy. AB - Background Insect venom immunotherapy (VIT) is used to protect patients against Hymenoptera insects' venom allergy (HVA), which can result in severe systemic or even life-threatening conditions. Molecular mechanisms triggered by VIT remain largely unknown. Objective To compare genome-wide gene expression of patients with severe HVA prior to VIT and 12 months after. Methods Whole blood RNA samples were analyzed on an expression array. Results from differential expression obtained on a microarray platform were confirmed by quantitative real -time PCR (qRT-PCR). Subsequently we applied unsupervised clustering. Relative blood cell proportions and gene expression profiles were used as an input to csSAM to compute cell specific differential gene expression. Finally, transcription factor enrichment analysis was performed in MotifLab. Results & conclusions Comparison of genome-wide expression patterns for whole blood and qRT-PCR experiments revealed no significantly up and/or down regulated genes. This has been corroborated by unsupervised clustering. We found a significant upregulation of 26 genes in macrophages, of 15 genes in monocytes and 2 genes in T regulatory cells (Tregs). Analysis of the promoter sequences of these upregulated genes revealed a significant over-representation of binding motifs specific for kruppel like factor 4, retinoic acid receptor gamma, and vitamin D receptor. Our results indicate that changes of gene expression invoked by VIT in peripheral blood may have a too small effect to be detected by conventional biostatistical approaches. When blood cell composition was taken into account we uncovered numerous changes of cell-specific gene expression. Given the regulatory implications we hypothesize that above-mentioned alterations may contribute to activation of anti inflammatory signals in the innate branch of the immune system. PMID- 30312637 TI - Encephalomyocarditis virus 2C protein antagonizes interferon-beta signaling pathway through interaction with MDA5. AB - Encephalomyocarditis virus (EMCV) is one of the most important picornavirus. It infects many mammalian species and causes encephalitis, myocarditis, neurologic diseases, diabetes and reproductive disorders in pigs. And it evolves mechanisms for escaping innate immune responses. But the viral pathogenesis has not been understood completely. In this study, we firstly found that EMCV protein 2C is a strong IFN-beta antagonist that interacts with MDA5 to inhibit induction of the IFN-beta signal pathway. The mutations in amino acid residue V26 of 2C decrease the inhibition of IFN-beta promoter activity and lost the ability to interact with MDA5, compared with wild type 2C protein. The rescued viruses with mutations in 2C (rV26A and rK25-3A) induced significantly higher IFN-beta mRNA and protein levels in PK-15, HEK-293A and N2a cells, compared to wild type EMCV and the repaired viruses rV26A(R) and rK25-3A(R). These data indicate that the amino acid residue V26 of EMCV 2C plays important roles in inhibiting type I IFN production by interacting with MDA5. PMID- 30312638 TI - Novel antagonists of 5-HT6 and/or 5-HT7 receptors affect the brain monoamines metabolism and enhance the anti-immobility activity of different antidepressants in rats. AB - The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668-a preferential 5 HT6 antagonist; PZ-1433-a preferential 5-HT7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression. PMID- 30312639 TI - Circadian misalignment has differential effects on affective behavior following exposure to controllable or uncontrollable stress. AB - In modern 24 h society, circadian disruption is pervasive, arising from night shift work, air travel across multiple time zones, irregular sleep schedules, and exposure to artificial light at night. Disruption of the circadian system is associated with many adverse health consequences, including mood disorders. Here we investigate whether inducing circadian misalignment using a phase advance protocol interferes with the ability to cope with a stressor, thereby increasing susceptibility to the negative consequences of stress. Male rats were maintained on a standard 12:12 light: dark (LD) cycle or subjected to a chronic phase advance (CPA) protocol involving 4 weekly 6 h phase shifts (earlier light onset) of the LD cycle. Rats were then exposed to escapable stress (ES), inescapable stress (IS), or no stress (home cage control; HC) and performance on juvenile social exploration and active escape learning in the two-way shuttlebox test was assessed 24 h and 48 h following stress, respectively. CPA alone had no effect on pre-stress juvenile social exploration, and it also did not interfere with the protective effect of ES on the stress-induced reduction in juvenile social exploration. In contrast, CPA impaired escape learning in the two-way shuttlebox to the same extent as IS in all subjects, regardless of stress history. Additionally, CPA produced somatic alterations that included increased body mass, increased epididymal adiposity, and decreased adrenal mass. These data indicate that CPA differentially modulated the stress-protective effects of behavioral control depending on the type of affective behavior examined. PMID- 30312640 TI - Heart rate variability of typically developing and autistic children and adults before, during and after sleep. AB - INTRODUCTION: Studies suggest a sympathetic-parasympathetic disequilibrium in children with autism spectrum disorder (ASD), compared to typically developing (TD) children. The autonomic nervous system (ANS) shows profound modification with age but studies in ASD adults are lacking. The ANS is also influenced by vigilance states such as wakefulness and sleep. The aim of this study is to explore differences in ANS activity in typically developing (TD) and ASD individuals during sleep and wakefulness, as a function of age. METHODS: Four groups of participants (17 adults with ASD, 16 TD adults, 13 children with ASD and 13 TD children) were recorded for two consecutive nights in a sleep laboratory. Electrocardiogram (ECG) was sampled during wakefulness (before and after sleep) and during stage N2 and REM sleep. Groups were compared on their heart rate variability parameters (LFnu, HFnu, LF/HF ratio) in each vigilance state. RESULTS: Results show that ASD adults had lower HFnu in the morning than TD adults (p < 0.05). During REM sleep, adults had higher LF/HF ratio than children, regardless of their clinical status (p < 0.05). CONCLUSIONS: Results of this study show autonomic distinctiveness during wakefulness specifically in ASD adults, suggesting a lower parasympathetic activity in the morning. Whether this characteristic represents a developmental feature or is related to lower sleep quality remains to be clarified. PMID- 30312641 TI - Heart peptides: Physiology and pathophysiology. PMID- 30312642 TI - Multiple effects of the herbicide glufosinate-ammonium and its main metabolite on neural stem cells from the subventricular zone of newborn mice. AB - The globally used herbicide glufosinate-ammonium (GLA) is structurally analogous to the excitatory neurotransmitter glutamate, and is known to interfere with cellular mechanisms involved in the glutamatergic system. In this report, we used an in vitro model of murine primary neural stem cell culture to investigate the neurotoxicity of GLA and its main metabolite, 4-methylphosphinico-2-oxobutanoic acid (PPO). We demonstrated that GLA and PPO disturb ependymal wall integrity in the ventricular-subventricular zone (V-SVZ) and alter the neuro-glial differentiation of neural stem cells. GLA and PPO impaired the formation of cilia, with reduced Celsr2 expression after PPO exposure. GLA promoted the differentiation of neuronal and oligodendroglial cells while PPO increased B1 cell population and impaired neuronal fate of neural stem cells. These results confirm our previous in vivo report that developmental exposure to GLA alters neurogenesis in the SVZ, and neuroblast migration along the rostral migratory stream. They also highlight the importance of investigating the toxicity of pesticide degradation products. Indeed, not only GLA, but also its metabolite PPO disrupts V-SVZ homeostasis and provides a novel cellular mechanism underlying GLA induced neurodevelopmental toxicity. Furthermore, we were able to demonstrate a neurotoxic activity of a metabolite of GLA different from that of GLA active substance for the very first time. PMID- 30312643 TI - Structural insights into the specificity and catalytic mechanism of mycobacterial nucleotide pool sanitizing enzyme MutT2. AB - Mis-incorporation of modified nucleotides, such as 5-methyl-dCTP or 8-oxo-dGTP, in DNA can be detrimental to genomic integrity. MutT proteins are sanitization enzymes which function by hydrolyzing such nucleotides and regulating the pool of free nucleotides in the cytoplasm. Mycobacterial genomes have a set of four MutT homologs, namely, MutT1, MutT2, MutT3 and MutT4. Mycobacterial MutT2 hydrolyzes 5 m-dCTP and 8-oxo-dGTP to their respective monophosphate products. Additionally, it can hydrolyze canonical nucleotides dCTP and CTP, with a suggested role in sustaining their optimal levels in the nucleotide pool. The structures of M. smegmatis MutT2 and its complexes with cytosine derivatives have been determined at resolutions ranging from 1.10 A to 1.73 A. The apo enzyme and its complexes with products (dCMP, CMP and 5 m-dCMP) crystallize in space group P21212, while those involving substrates (dCTP, CTP and 5 m-dCTP) crystallize in space group P21. The molecule takes an alpha/beta/alpha sandwich fold arrangement, as observed in other MutT homologs. The nucleoside moiety of the ligands is similarly located in all the complexes, while the location of the remaining tail exhibits variability. This is the first report of a MutT2-type protein in complex with ligands. A critical interaction involving Asp116 confers the specificity of the enzyme towards cytosine moieties. A conserved set of enzyme-ligand interactions along with concerted movements of important water molecules provide insights into the mechanism of action. PMID- 30312644 TI - Androgens in Women: Androgen mediated skin disease and patient evaluation (Part I). AB - Androgens are produced throughout the body in steroid-producing organs, such as the adrenal glands and ovaries, as well as in other tissues, like the skin. Several androgens are found normally in women, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), testosterone, dihydrotestosterone (DHT), and androstenedione. These androgens are essential in the development of several common cutaneous conditions in women, including acne, hirsutism, and female pattern hair loss (FPHL) - androgen mediated cutaneous disorders (AMCDs). However, the role of androgens in the pathophysiology of these diseases is complicated and incompletely understood. In the first article in this Continuing Medical Education series, we discuss the role of the skin in androgen production as well as the impact of androgens on the skin in women. Specifically, we review the necessary, but insufficient role that androgens play in the development of acne, hirsutism, and FPHL in women. Dermatologists face the challenge of differentiating physiologic from pathologic presentations of AMCDs in women. There are currently no dermatology guidelines outlining the indications for endocrinologic evaluation in women presenting with acne, hirsutism, and/or FPHL. We review available evidence regarding when to consider an endocrinologic work-up in women presenting with AMCDs, including the appropriate type and timing of testing. PMID- 30312645 TI - Androgens in Women: Hormone modulating therapies for skin disease (Part II). AB - Androgen-mediated cutaneous disorders (AMCDs) in women including acne, hirsutism, and female pattern hair loss (FPHL) can be treated with hormone-modulating therapies. In the second part of this Continuing Medical Education series, we discuss the hormone-modulating therapies available to dermatologists for the treatment of AMCDs including combined oral contraceptives, spironolactone, finasteride, dutasteride, and flutamide. Available hormone-modulating treatments utilized for each AMCDs are reviewed, along with mechanisms of androgen modulation, safety profile, contraindications, monitoring parameters, and evidence of efficacy. Medications discussed include ones that are FDA-approved for certain AMCDs as well as some that are used off-label. Despite the ubiquity of hormone-modulating therapies used for AMCDs, this review highlights the need for more rigorous studies to evaluate these therapies for acne, hirsutism, and FPHL. PMID- 30312646 TI - Identification of musculoskeletal infection with non-tuberculous mycobacterium using metagenomic sequencing. PMID- 30312647 TI - Risk factors for mortality among carbapenem-resistant enterobacteriaceae carriers with focus on immunosuppression. AB - OBJECTIVES: To identify risk factors for mortality in a cohort of carbapenem resistant enterobacteriaceae (CRE) carriers, focusing on immunosuppression and other risk factors known at the time of CRE carriage detection. METHODS: We prospectively followed all new and known CRE carriers admitted between June 2016 and June 2017 to a single tertiary center in Israel. Patients were included in the study after confirmation of the carrier state. Demographic and clinical data were documented on admission or CRE acquisition and patients were followed prospectively post-discharge until January 2018 or death. Risk factors for mortality known at the time of the first encounter with a CRE carrier were sought. Adjusted hazard ratios (HR) for mortality at end of follow-up with 95% confidence intervals (CI) were assessed using Cox regression analysis. RESULTS: A total of 115 patients were included in the analysis. During the study period, 66 (57.4%) patients died. Immunosuppression was associated with mortality (HR 1.95, CI 95% 1.12-3.44), adjusted to the Charlson co-morbidity score, functional status, chronic renal disease and Klebsiella pneumonia CRE, the latter three also significantly associated with mortality. CRE bacteremia occurred among 24 (20.9%) carriers during follow up, more frequently among immunosuppressed patients and was significantly associated with mortality at end of follow-up (p = 0.015). CONCLUSION: Immunosuppression is independently associated with mortality among CRE carriers, possibly related to CRE bacteremia that is frequent among these patients. Further research is needed on interventions to prevent deaths among CRE carriers. PMID- 30312648 TI - Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products. AB - Due to the worldwide prevalence of multidrug-resistant pathogens and high incidence of diseases such as cancer, there is an urgent need for the discovery and development of new drugs. Nearly half of the FDA-approved drugs are derived from natural products that are produced by living organisms, mainly bacteria, fungi, and plants. Commercial development is often limited by the low yield of the desired compounds expressed by the native producers. In addition, recent advances in whole genome sequencing and bioinformatics have revealed an abundance of cryptic biosynthetic gene clusters within microbial genomes. Genetic manipulation of clusters in the native host is commonly used to awaken poorly expressed or silent gene clusters, however, the lack of feasible genetic manipulation systems in many strains often hinders our ability to engineer the native producers. The transfer of gene clusters into heterologous hosts for expression of partial or entire biosynthetic pathways is an approach that can be used to overcome this limitation. Heterologous expression also facilitates the chimeric fusion of different biosynthetic pathways, leading to the generation of "unnatural" natural products. The genus Streptomyces is especially known to be a prolific source of drugs/antibiotics, its members are often used as heterologous expression hosts. In this review, we summarize recent applications of Streptomyces species, S. coelicolor, S. lividans, S. albus, S. venezuelae and S. avermitilis, as heterologous expression systems. PMID- 30312649 TI - Bisphenol A exhibits cytotoxic or genotoxic potential via oxidative stress associated mitochondrial apoptotic pathway in murine macrophages. AB - Bisphenol A (BPA) is primarily used in production of polycarbonate plastics and epoxy resins including plastic containers. BPA is an endocrine disruptor and supposes to induce asthma and cancer. However, so far only a few evidences have shown the BPA-induced toxic effect and its related mechanism in macrophages. BPA demonstrated cytotoxic effect on RAW264.7 macrophages in a concentration and time dependent manner. BPA induces necrosis, apoptosis, and genotoxicity in a concentration-dependent manner. Phosphorylation of cytochrome C (cyto C) and p53 was due to mitochondrial disruption via BCL2 and BCL-XL downregulation and BAX, BID, and BAD upregulation. Both caspase-dependent, including caspase-9, caspase 3, and PARP-1 cleavage, and caspase-independent, such as nuclear translocation of AIF, pathways were activated by BPA. Furthermore, generation of reactive oxygen species (ROS) and reduction of antioxidative enzyme activities were induced by BPA. Parallel trends were observed in the effect of BPA on cytotoxicity, apoptosis, genotoxicity, p53 phosphorylation, BCL2 family expression exchange, caspase-dependent and independent apoptotic pathways, and ROS generation in RAW264.7 macrophages. Finally, BPA-exhibited cytotoxicity, apoptosis, and genotoxicity could be inhibited by N-acetylcysteine. These results indicated that the toxic effect of BPA was functioning via oxidative stress-associated mitochondrial apoptotic pathway in macrophages. PMID- 30312650 TI - Detection of antibodies against Aggregatibacter actinomycetemcomitans in serum and saliva through ELISA in periodontally healthy individuals and individuals with chronic periodontitis. AB - BACKGROUND: Periodontitis is a persistent polymicrobial infection, which leads to chronic inflammation in the tooth supporting tissues. Aggregatibacter actinomycetemcomitans are normal commensals of oral cavity but are low in number in periodontally healthy subjects. They are one of the major pathogens aetiologically linked to periodontal disease. Plasma and salivary antibody measurement may be useful to support diagnosis, disease activity, classification and prognosis of periodontitis. The aim of the present study was to investigate the association between the serum and salivary antibody levels to A. actinomycetemcomitans and therefore, to find whether this association was varying in different grades of periodontitis. METHOD: Total of 50 periodontally healthy and 50 chronic periodontitis subjects (35-65 years) of both sexes were included for the study. 2 ml of un-stimulated saliva and 5 ml of venous blood was collected under sterile conditions. The detection of antibodies against A. actinomycetemcomitans in periodontally healthy individuals and individuals with chronic periodontitis was performed using indirect ELISA. RESULTS: Results showed serum IgG, IgA mean levels against A. actinomycetemcomitans were higher in chronic periodontitis subjects compared to mean levels in periodontally healthy subjects. Similarly, salivary IgG, IgA levels were also raised in chronic periodontitis patients as compared in healthy subjects. Also the mean levels of serum IgG and salivary IgA were increased as the severity of disease increased. CONCLUSION: Antibody titer using saliva and serum could be useful tool for screening of patients with chronic periodontitis. Further, monitoring the various phases of treatment outcome using saliva could be a useful, non-invasive, prognostic indicator. PMID- 30312651 TI - Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti diabetic activities by acting as dual GLP1R and GCGR agonists. AB - Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal beta cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9-39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His1,Pro4,Glu9] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6-30) Cex-K40 [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 MUM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs. PMID- 30312652 TI - Induction of new metabolites from sponge-associated fungus Aspergillus carneus by OSMAC approach. AB - A comparative study on the metabolic profile of the sponge-associated fungus Aspergillus carneus using the OSMAC approach was conducted. The fungal strain was fermented on three different media including solid rice medium with or without sea salt and modified Czapek medium. Three new natural products, isopropylchaetominine (1), isoterrelumamide A (2) and 5'-epi-averufanin (3), together with fourteen known compounds (4-17) were isolated. The structures of the new compounds were established by 1D and 2D NMR spectroscopic analysis as well as by HRESIMS. Compound 2 was only found when the fungus was cultivated on modified Czapek medium, whereas compounds 4, 7, 11, 12, and 14 were only detected in fungal extracts from solid rice media lacking sea salt. Compounds 8 and 13 on the other hand were only found when A. carneus was cultured on solid rice with sea salt. The cytotoxic and antimicrobial activities of all isolated compounds were evaluated. Compounds 1, 9 and 17 showed strong cytotoxicity against the mouse lymphoma cell line L5178Y with IC50 values of 0.4, 0.3 and 0.2 MUM, respectively. In addition, compounds 3, 5 and 6 showed inhibitory activity against different Gram-positive bacterial strains with MIC values ranging from 2.3 to 18.4 MUg/mL. PMID- 30312653 TI - Expression analysis and characterization of zglp1 in the Chinese tongue sole (Cynoglossus semilaevis). AB - Zinc finger GATA like protein-1 (ZGLP1) is a nuclear zinc finger protein that regulates the interaction between somatic cells and germ cells during gonad developmental process in mammals. In this study, the zglp1 of Chinese tongue sole, Cynoglossus semilaevis (cysezglp1), was cloned and characterized for the first time in fish. Cysezglp1 had an open reading frame with five exons and was located to chromosome 9. The open reading frame of cysezglp1 consisted of 1692 nucleotides and encoded a 583 amino acid polypeptide. The predicted protein contained two zinc finger structures (Znf1 and Znf2), one of which was highly homologous to the GATA-type zinc finger domain. Multiple sequence alignment showed that Znf1 was conserved across different species while Znf2 was more divergent. Through quantitative Real-time PCR (qRT-PCR), we found that cysezglp1 was predominantly expressed in gonads, and the expression level of the ovary was significantly higher than that of the testis. We compared expression level in different embryonic stages and found that cysezglp1 mRNAs were mainly expressed in the fertilized egg to the cleavage stage, subsequently declining in the blastula stage. Cysezglp1 expression was not detected from the gastrulation stage onward. In the ovary, cysezglp1 expression was detected at 120 days after hatching and expression gradually increased with the maturation of the ovary. In situ hybridization showed that the cysezglp1 was mainly expressed in oocytes. Taken together, our results suggest that cysezglp1 may play an important role in the process of oogenesis in Chinese tongue sole. PMID- 30312654 TI - Non-prescription sales of antimicrobial agents at community pharmacies in developing countries: a systematic review. AB - Antimicrobial resistance (AMR) is a global challenge. Developing countries are more vulnerable to the consequences of AMR than developed nations because of complex issues pertaining to the nature of their healthcare systems. Inappropriate antimicrobial drug use and the unrestricted availability of antimicrobial agents in community pharmacies in developing countries can contribute to the emergence of resistant microbes. The aim of this systematic review was to explore the availability of antimicrobial agents without a doctor's prescription in developing countries and to investigate factors that contribute to inappropriate antimicrobial supply in developing countries. The EMBASE, MEDLINE and International Pharmaceutical Abstracts databases were searched for articles published between 1980 and November 2017 describing studies using simulated client (or pseudo-patient) methodology in community pharmacies supplying non-prescription antimicrobial agents. Overall, 50 studies were included in this systematic review. All of the studies involved supply of one or more antimicrobials without a prescription. These studies involved using a hypothetical case presentation or direct product request by a simulated client. The review found non-prescription supply of antimicrobials as reported in 28 developing countries across Asia, Africa, South America, Europe and Middle Eastern regions. Contributing factors for non-prescription antimicrobial supply were poor national medicines regulations, limited availability of qualified pharmacists, commercial pressure on pharmacy staff, consumer demand, inappropriate prescribing practices and lack of awareness of AMR. PMID- 30312655 TI - Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance. AB - Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment. We utilized zebrafish embryos to assess developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity, of eight replacement OPFRs: (triphenyl phosphate [TPHP], isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2 chloroethyl) phosphate [TCEP]) and two BFRs (3,3',5,5'- tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). To determine potential effects on teratogenicity, embryos were exposed to flame retardants (FRs) at 4 h post fertilization (hpf) to 4 days post fertilization (dpf) and morphological alterations and corresponding survival were evaluated at 2 and 4 dpf. Internal concentrations were measured in larvae used in this assay by liquid chromatography-mass spectrometry. Locomotor activity was assessed in larvae treated for 48 h (from 3 dpf to 5 dpf), followed by hepatotoxicity evaluation. Finally, alterations in heart rate and rhythmicity were assessed to determine cardiotoxicity in 48 hpf embryos exposed to compounds for 3 h. Results suggest that several OPFRs (BPDP, EHDP; IPP, TMPP; TPHP and TDCIPP) produced adverse effects in multiple target organs at concentrations comparable to the two BFRs. As these OPFRs have the capacity to disrupt an integrated vertebrate model, they potentially have the capacity to affect mammalian biology. Then, we compared the lowest effective levels (LEL) in zebrafish with estimated or measured human plasma concentrations using biomonitoring data (human plasma, breast milk, handwipe samples and house dust) and a high throughput toxicokinetic (HTTK) model. Results indicate that for some compounds, the nominal LELs were within the range of human exposures, while internal LELs in zebrafish are above internal exposures in humans. These findings demonstrate the value of the zebrafish model as a relevant screening tool and support the need for further hazard characterization of the OPFRs. PMID- 30312656 TI - Few studies exist examining methods for selecting studies, abstracting data, and appraising quality in a systematic review. AB - OBJECTIVE: To identify and summarize studies assessing methodologies for study selection, data abstraction, or quality appraisal in systematic reviews. STUDY DESIGN AND SETTING: A systematic review was conducted, searching MEDLINE, EMBASE, and the Cochrane Library from inception to Sept 1, 2016. Quality appraisal of included studies was undertaken using a modified QUADAS-2 and key results on accuracy, reliability, or efficiency of a methodology, or impact on results and conclusions were extracted. RESULTS: After screening 5600 titles and abstracts and 245 full-text articles, 37 studies were included. For screening, studies supported involvement of two independent experienced reviewers, and the use of Google Translate when screening non-English articles. For data abstraction, studies supported involvement of experienced reviewers (especially for continuous outcomes) and two independent reviewers, use of dual monitors, graphical data extraction software, and contacting authors. For quality appraisal, studies supported intensive training, piloting quality assessment tools, providing decision rules for poorly reported studies, contacting authors, and using structured tools if different study designs are included. CONCLUSION: Few studies exist documenting common systematic review practices. Included studies support several systematic review practices. These results provide an updated evidence base for current knowledge synthesis guidelines, and methods requiring further research. PMID- 30312657 TI - In Cochrane reviews risk of bias assessments for allocation concealment were frequently not in line with Cochrane's Handbook guidance. AB - AIM: To analyze whether the risk of bias (RoB) judgments for allocation concealment in Cochrane systematic reviews (CSRs) were in line with recommendations from the Cochrane Handbook. METHODS: From CSR we extracted data about judgments and supporting comments about allocation concealment for each included RCT. We compared whether judgments for supporting comments were in line with Cochrane Handbook recommendations. RESULTS: We analyzed judgments and comments of 721 CSRs in which 10280 RCTs were included. By following the Cochrane Handbook guidance, we found that judgments for allocation concealment were discrepant for 2928 (29%) trials. The majority of discrepancies were made for trials were RoB was judged as low (2693 trials; 92%). Cochrane authors used 66 categories of comments describing envelopes as a method of allocation concealment. In 66 envelope-related categories, describing RoB assessments from 1529 (15%) of the analyzed RCTs, most of the judgments were low RoB, even though only one of those categories is associated with low RoB according to the Cochrane Handbook. Twenty categories of supporting comments, including 642 trials, were related to randomization, not allocation concealment. CONCLUSION: One third of RoB judgments about allocation concealment in Cochrane reviews were discrepant from the Cochrane Handbook recommendations. PMID- 30312658 TI - Loss of hypermethylated in cancer 1 (HIC1) promotes lung cancer progression. AB - Lung cancer is a leading cause of cancer mortality worldwide with dramatically increasing incidence in recent years. However, the mechanism underlying its progression remains unclear. The aim of this study was to identify the role of hypermethylated in cancer 1 (HIC1) in lung cancer development. Here we found that HIC1 expression was markedly decreased in lung cancer compared with the corresponding adjacent non-cancerous tissues. Meanwhile, overall survival (OS) of lung cancer patients was negatively related with HIC1 expression using TCGA and GEO datasets. Loss of HIC1 expression promoted cell proliferation and migration in vitro. Notable, HIC1 knock-out in KrasG12D/+(Lox-Stop-Lox)/sgHIC1 mice had remarkable effect on tumorigenesis compared with KrasG12D/+(Lox-Stop-Lox)/sgTd control mice. Mechanistic analyses showed that ADAMTS9, DCDC2, FAM46C, ZNF883, F2R, MSH6 and PAX2 genes may be potential downstream targets; DNA repair pathway and transcriptional regulation by TP53 pathway were involved. Finally, this study reveals that HIC1 is associated with lung cancer progression and may provide an effective strategy for its treatment. PMID- 30312659 TI - Interleukin-1beta signaling in osteoarthritis - chondrocytes in focus. AB - Osteoarthritis (OA) can be regarded as a chronic, painful and degenerative disease that affects all tissues of a joint and one of the major endpoints being loss of articular cartilage. In most cases, OA is associated with a variable degree of synovial inflammation. A variety of different cell types including chondrocytes, synovial fibroblasts, adipocytes, osteoblasts and osteoclasts as well as stem and immune cells are involved in catabolic and inflammatory processes but also in attempts to counteract the cartilage loss. At the molecular level, these changes are regulated by a complex network of proteolytic enzymes, chemokines and cytokines (for review: [1]). Here, interleukin-1 signaling (IL-1) plays a central role and its effects on the different cell types involved in OA are discussed in this review with a special focus on the chondrocyte. PMID- 30312660 TI - New Cardioscope-Based Platform for Minimally Invasive and Percutaneous Beating Heart Interventions. AB - With heart disease increasing worldwide, demand for new minimally invasive techniques and transcatheter technologies to treat structural heart disease is rising. Cardioscopy has long been considered desirable, as it allows direct tissue visualization and intervention to deliver therapy via a closed chest, with real-time fiber-optic imaging of intracardiac structures. Herein, the feasibility of the advanced cardioscopic platform, allowing both transapical and fully percutaneous access is reported. The latter technique, in particular, is believed to represent a milestone in the development of the cardioscope. Cardioscope prototypes were used in 7 bovine models (77.2-101.1 kg) for transapical or percutaneous insertion. Miniature custom-built, water-sealed cameras (diameters: Storz, 7 Fr; Medigus, 1.2 mm) were used. For percutaneous cardiopulmonary bypass, the pulmonary artery was occluded by a balloon catheter (Intraclude, 10.5 Fr, 100 cm) and perfused with a crystalloid solution. Cameras were inserted transapically (n = 4) through the left ventricular apex or percutaneously (n = 5) via the carotid artery. Insertion of the optimized cardioscope devices was feasible via either approach. Intracardiac structures (left ventricle, mitral valve opening/closure, chordal apparatus, aortic valve leaflets, and regurgitation) were visualized clearly and without deformation. Catheter tips were successfully bent >180 degrees inside the left ventricle; rotation and navigation to view various intracardiac structures were feasible in all cases. This study showed the technical feasibility of direct cardioscopic visualization using transapical and percutaneous approaches. This advanced cardioscopic instrumentarium represents a promising platform for future interventions and surgery under direct visualization of the beating heart. PMID- 30312661 TI - Performance evaluation measures for protein complex prediction. AB - Protein complexes play a dominant role in cellular organization and function. Prediction of protein complexes from the network of physical interactions between proteins (PPI networks) has thus become one of the important research areas. Recently, many computational approaches have been developed to identify these complexes. Various performance assessment measures have been proposed for evaluating the efficiency of these methods. However, there are many inconsistencies in the definitions and usage of the measures across the literature. To address this issue, we have gathered and presented the most important performance evaluation measures and developed a tool, named CompEvaluator, to critically assess the protein complex prediction methods. The tool and documentation are publicly available at https://sourceforge.net/projects/compevaluator/files/. PMID- 30312662 TI - Topical nanodelivery system of lutein for the prevention of selenite-induced cataract. AB - Cataracts are responsible for half of the world blindness, surgery being the only viable treatment. Lutein, a naturally occurring carotenoid in the eye, has the potential to reduce cataract progression by protecting the eye from photo oxidative stress. To restore the eye's natural line of defense against photo oxidative stress, a formulation was developed using zein and poly(lactic-co glycolic acid) nanoparticles (NPs) embedded in an optimized bioadhesive thermosensitive gel for the delivery of lutein via topical application. Cataracts were induced in Crl:WI rats via selenite injection at 13 days post-partum, followed by 7 days of treatment with free lutein or lutein-loaded NPs administered orally or topically. Cataract severity was significantly reduced in rats treated with topical applications of lutein-loaded NPs compared to the positive control, while no significant differences were observed in rats treated with other lutein formulations including oral and topically applied free lutein. PMID- 30312663 TI - Relationship between diabetes and respiratory diseases-Clinical and therapeutic aspects. AB - Diabetes is a common metabolic disorder affecting the entire body with high morbidity and mortality worldwide. The major complications related to diabetes are mostly due to the macrovascular and microvascular bed impairment due to metabolic, hemodynamic and inflammatory factors. However, studies over the past decades have added also the lung as a target organ in both type 1 and type 2 diabetes. Diabetes has always been addressed as a major comorbidity conditioning the disease behaviour and the natural history of several respiratory diseases. Increased interest has recently focused on the pathophysiology of the metabolic glycaemic disorder and the respiratory diseases suggesting a similar background shared by the two conditions. The true relationship between pulmonary diseases and diabetes mellitus has not been clarified, this review aims to summarize the link between diabetes and coexisting respiratory diseases such as asthma, chronic obstructive pulmonary disease, respiratory infections, cystic fibrosis, lung cancer and obstructive sleep apnea from a pathogenetic and therapeutic point of view. PMID- 30312664 TI - The effect of statin therapy on endoplasmic reticulum stress. AB - The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca2+ homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination. This results in the unfolded protein response (UPR) that is a repair mechanism to limit the formation of newly damaged proteins until ER homeostasis is restored, though may result in increased cell death. ER stress has been shown to be implicated in a variety of diseases. Statins are well-known cholesterol lowering drugs and have been extensively reported to possess beneficial cholesterol-independent effects in a variety of human diseases. This review focuses on the concept of ER stress, the underlying molecular mechanisms and their relationship to the pathophysiology and, finally, the role of statins in moderating ER stress and UPR. PMID- 30312665 TI - Virtual reality for spinal cord injury-associated neuropathic pain: Systematic review. AB - BACKGROUND: Treatment of spinal cord injury (SCI)-associated neuropathic pain is challenging, with limited efficacy and no definitive options, and SCI patients often show resistance to pharmacologic treatment. Virtual reality (VR) therapy is a non-invasive, non-pharmacologic alternative with minimal adverse effects. OBJECTIVE: To investigate the effect of VR therapy on SCI-associated neuropathic pain in a systematic review. METHODS: Articles needed to 1) be written in English; 2) include adult subjects, with at least half the study population with a SCI diagnosis; 3) involve any form of VR therapy; and 4) assess neuropathic pain by quantitative outcome measures. Articles were searched in MEDLINE/PubMed, CINAHL(r), EMBASE, and PsycINFO up to April 2018. Reference lists of retrieved articles were hand-searched. Methodologic quality was assessed by the Physiotherapy Evidence Database Score (PEDro) for randomized controlled trials and Modified Downs and Black Tool (D&B) for all other studies. Level of evidence was determined by using a modified Sackett scale. RESULTS: Among 333 studies identified, 9 included in this review (n=150 participants) evaluated 4 methods of VR therapy (virtual walking, VR-augmented training, virtual illusion, and VR hypnosis) for treating neuropathic pain in SCI patients. Each VR method reduced neuropathic pain: 4 studies supported virtual walking, and the other 3 VR methods were each supported by a different study. Combined treatment with virtual walking and transcranial direct current stimulation was the most effective. The quality of studies was a major limitation. CONCLUSION: VR therapy could reduce SCI associated neuropathic pain, although the clinical significance of this analgesic effect is unclear. Clinical trials evaluating VR therapy as standalone and/or adjunct therapy for neuropathic pain in SCI patients are warranted. PMID- 30312666 TI - Modulation of innate immunity, expression of cytokine genes and disease resistance against Aeromonas hydrophila infection in goldfish (Carassius auratus) by dietary supplementation with Exiguobacterium acetylicum S01. AB - Probiotic strains play an increasing role in the production of healthy animals used as a food source. Elucidating the mechanisms of action that allow probiotic driven immunomodulation may facilitate different applications such as the prevention of infectious diseases in food organisms. This study elucidates the probiotic effects of Exiguobacterium acetylicum S01 on the growth, haematological profile, innate immune capacity, expression of cytokine genes, and resistance to diseases of Carassius auratus caused by Aeromonas hydrophila infection. Three fish groups were fed with the following diets containing different doses of E. acetylicum S01 (CFU g-1): basal diet 0 (BD, without probiotic), 2.5 * 107 (DI) and 2.7 * 109 (DII)-CFU g-1 for 4 weeks. After 4 weeks, the fish were injected intraperitoneally with A. hydrophila and the percentage of survival was recorded over 21 days of post-challenge. Results revealed that dietary supplementation of E. acetylicum S01 significantly (P < 0.05) enhanced the growth, haematological profile and cellular immune responses including respiratory burst, phagocytic activities and antimicrobial enzymes (myeloperoxidase and lysozyme) and total immunoglobulin levels were improved by probiotic feeding at both occasions. Comparatively, expression of c- and g-type lysozyme followed by pro- and anti inflammatory cytokines (IL-1beta, IL-10 and TGFbeta) was up-regulated in kidney, head-kidney and spleen. Moreover, fish fed with diet DII had a significantly higher (P < 0.05) survival rate (73.2%) after challenging. The survival rate was only 33.2% of the BD group against A. hydrophila infection. Our results revealed that E. acetylicum S01 delivered probiotic in feed exerts its influence on growth performance and provides disease resistance by stimulating the immune system at the cellular and molecular levels in C. auratus. PMID- 30312667 TI - A microglial cell model for acyl-CoA oxidase 1 deficiency. AB - Acyl-CoA oxidase 1 (ACOX1) deficiency is a rare and severe peroxisomal leukodystrophy associated with a very long-chain fatty acid (VLCFA) beta oxidation defect. This neurodegenerative disease lacks relevant cell models to further decipher the pathomechanisms in order to identify novel therapeutic targets. Since peroxisomal defects in microglia appear to be a key component of peroxisomal leukodystrophies, we targeted the Acox1 gene in the murine microglial BV-2 cell line. Using CRISPR/Cas9 gene editing, we generated an Acox1-deficient cell line and validated the allelic mutations, which lead to the absence of ACOX1 protein and enzymatic activity. The activity of catalase, the enzyme degrading H2O2, was increased, likely in response to the alteration of redox homeostasis. The mutant cell line grew more slowly than control cells without obvious morphological changes. However, ultrastructural analysis revealed an increased number of peroxisomes and mitochondria associated with size reduction of mitochondria. Changes in the distribution of lipid droplets containing neutral lipids have been observed in mutant cells; lipid analysis revealed the accumulation of saturated and monounsaturated VLCFA. Besides, expression levels of genes encoding interleukin-1 beta and 6 (IL-1beta and IL-6), as well as triggering receptor expressed on myeloid cells 2 (Trem2) were found modified in the mutant cells suggesting modification of microglial polarization and phagocytosis ability. In summary, this Acox1-deficient cell line presents the main biochemical characteristics of the human disease and will serve as a promising model to further investigate the consequences of a specific microglial peroxisomal beta-oxidation defect on oxidative stress, inflammation and cellular functions. PMID- 30312668 TI - Morphological and genetic characterization of green-banded broodsacs of Leucochloridium (Leucochloridiidae: Trematoda) sporocysts detected in Succinea lauta in Hokkaido, Japan. AB - Green-banded broodsacs of Leucochloridium sporocysts were obtained from land snails, Succinea lauta, collected in Esashi, Esashi District, Hokkaido, Japan. The broodsacs were similar to those of L. paradoxum, which have never been found on the Japanese archipelago. Here, we compare morphological and molecular genetic characteristics of the green-banded broodsacs to those of L. paradoxum. The broodsacs described in this study and those of L. paradoxum showed three equal parts; however, band characteristics of the second parts differed. Moreover, the sequences of nuclear 18S and 28S rRNA genes of the Leucochloridium flukes were not identical with those of L. paradoxum, and the sequences of the mitochondrial cytochrome c oxidase subunit 1 gene were paraphyletic to the species. These findings suggest that the broodsacs described in this study were distinct from those of L. paradoxum. In the future, genetic analyses on adult flukes from avian hosts should be performed, upon precise identification according to morphology, in order to clarify relationships between adult flukes and sporocysts of Leucochloridium species occurring in Japan. PMID- 30312669 TI - Cryobiopsy in the Upper Urinary Tract: Preclinical Evaluation of a Novel Device. AB - OBJECTIVE: To develop a novel device for cryobiopsy of the upper urinary tract (UUT) and to evaluate its feasibility in a standardized preclinical setting. MATERIALS AND METHODS: Flexible cryoprobes (diameter 0.9 mm; cooling agent CO2) were developed and used to extract biopsies in porcine UUTs. Cryosamples obtained by ureterorenoscopy were systematically compared with biopsy specimens obtained with standard of care devices in terms of physical characteristics (deflection angle and irrigation flow rates) and histologic criteria (assessability). RESULTS: Irrigation flow rates were significantly higher with introduced BIGopsy (2.8 +/- 0.1) compared with standard forceps (0.94 +/- 0.06; P < .001) and cryoprobe (1.1 +/- 0.1; P < .001). Angular deflection was significantly reduced by the inserted cryoprobe (130.7 degrees +/- 1.2 degrees vs 166.9 degrees +/- 1.1 degrees [BIGopsy] or 161.4 degrees +/- 1.9 degrees [standard forceps]; both P < .001). Significantly larger UUT tissue samples were obtained by the cryoprobe (mean specimen area 7.5 +/- 2.5 vs 4.6 +/- 2.5 mm2 [BIGopsy] or 1.4 +/- 1.4 mm2 [standard forceps]; both P < .001). No crush artifacts were observed in cryosamples. Superior histologic assessability scores were achieved in samples obtained by the cryoprobe (mean 2.8 +/- 0.8) and BIGopsy (2.3 +/- 1.9) when compared with standard forceps (0.4 +/- 0.9; P < .001). CONCLUSION: Cryobiopsy in the UUT is feasible and represents a viable new option to improve the diagnostic accuracy of histopathologic evaluation. Larger and more representative tissue samples can be obtained using a cryoprobe and artifacts may be avoided. Further optimization of the probe will reduce possible restrictions of ureterorenoscopy handling when the device is inserted. PMID- 30312670 TI - Clinical Proof-of-concept of a Novel Platform Utilizing Biopsy-derived Live Single Cells, Phenotypic Biomarkers, and Machine Learning Toward a Precision Risk Stratification Test for Prostate Cancer Grade Groups 1 and 2 (Gleason 3 + 3 and 3 + 4). AB - OBJECTIVE: To examine the ability of a novel live primary-cell phenotypic (LPCP) test to predict postsurgical adverse pathology (P-SAP) features and risk stratify patients based on SAP features in a blinded study utilizing radical prostatectomy (RP) surgical specimens. METHODS: Two hundred fifty-one men undergoing RP were enrolled in a prospective, multicenter (10), and proof-of-concept study in the United States. Fresh prostate samples were taken from known areas of cancer in the operating room immediately after RP. Samples were shipped and tested at a central laboratory. Utilizing the LPCP test, a suite of phenotypic biomarkers was analyzed and quantified using objective machine vision software. Biomarkers were objectively ranked via machine learning-derived statistical algorithms (MLDSA) to predict postsurgical adverse pathological features. Sensitivity and specificity were determined by comparing blinded predictions and unblinded RP surgical pathology reports, training MLDSAs on 70% of biopsy cells and testing MLDSAs on the remaining 30% of biopsy cells across the tested patient population. RESULTS: The LPCP test predicted adverse pathologies post-RP with area under the curve (AUC) via receiver operating characteristics analysis of greater than 0.80 and distinguished between Prostate Cancer Grade Groups 1, 2, and 3/Gleason Scores 3 + 3, 3 + 4, and 4 + 3. Further, LPCP derived-biomarker scores predicted Gleason pattern, stage, and adverse pathology with high precision-AUCs>0.80. CONCLUSION: Using MLDSA-derived phenotypic biomarker scores, the LPCP test successfully risk stratified Prostate Cancer Grade Groups 1, 2, and 3 (Gleason 3 + 3 and 7) into distinct subgroups predicted to have surgical adverse pathologies or not with high performance (>0.85 AUC). PMID- 30312671 TI - Hypoglycemia in Renal Cell Carcinoma: A Rare Paraneoplastic Syndrome. PMID- 30312672 TI - A Simplified Technique for GreenLight Laser Enucleation of the Prostate. AB - OBJECTIVE: To present a simplified technique for GreenLight laser enucleation of the prostate (GreenLEP), designed to reduce the learning curve commonly associated with endoscopic prostate enucleation. MATERIALS AND METHODS: GreenLEP is a novel endoscopic treatment for BPH which allows for durable resection of large glands with minimal energy use, minimal bleeding and has been shown to be non-inferior to holmium laser enucleation of the prostate (HoLEP). Furthermore, GreenLEP has been shown to be superior to GreenLight PVP For glands >80 g with respect to operative time, unplanned hospital readmission and decrease in post treatment PSA and prostate size. Unfortunately, a steep learning curve has remained a roadblock for adaptation by many urologists. Our technique for lobe-by lobe GreenLEP is described and shown. RESULTS: GreenLEP allows for removal of the entire transition zone in patients with large glands traditionally best treated with staged TURP or simple prostatectomy. A lobe-by-lobe approach allows the urologist to learn the procedure in a stepwise fashion as they become increasingly comfortable with the technique. During the learning process, some lobes may be addressed by enucleation while others by vaporization. CONCLUSION: This simplified technique allows novice enucleators with GreenLight experience to feel more comfortable with GreenLEP, simplifying the learning curve. PMID- 30312673 TI - Semen Parameters Among Transgender Women With a History of Hormonal Treatment. AB - OBJECTIVE: To report on the semen quality parameters in transgender women who pursued semen cryopreservation either in the presence or absence of gender affirming hormonal medication. MATERIALS AND METHODS: This retrospective cohort study was conducted as a chart review of consecutive transgender women presenting for semen cryopreservation between January 1, 2012 and March 31, 2018. Demographic data and semen parameters were assessed. Primary outcomes were the semen parameters in subjects with either no exposure, previous exposure or current exposure to gender-affirming hormonal medication. RESULTS: Twenty-eight patients presented for semen cryopreservation and produced 69 specimens. Using a Kruskal-Wallis test, semen analyses were compared between patients who had never used gender-affirming hormonal medication, those who had previously used hormonal medication but discontinued prior to specimen collection, and those who used medication at the time of specimen collection. Median semen parameters for each group were as follows: volume-2.7 mL, 2.1 mL, 0.9 mL, respectively (P = .12); concentration-63.6 M/mL, 39.0 M/mL, 2.4 M/mL, respectively (P < .01); percent motility-51.5%, 34.3%, 15.6%, respectively (P < .01); and the total motile count was 63.2 M,39.1 M, 0.2 M, respectively (P < .01). Fifteen specimens were collected after discontinuing hormonal medication with a mean discontinuation period of 4.4 months. CONCLUSION: Specimens collected in the presence of hormonal medication were associated with abnormal semen parameters. Specimens collected after discontinuation of gender-affirming treatments were comparable to transgender women who had never used hormonal medication. Transgender women should be counseled about the potential impact of gender-affirming hormones and to consider fertility preservation prior to gender-affirming treatments. PMID- 30312674 TI - Outpatient Surgical Management for Acquired Buried Penis. AB - OBJECTIVE: To demonstrate the safety and feasibility of outpatient surgical management for patients with acquired buried penis (ABP). METHODS: We conducted an Institutional Review Board approved review of patients who underwent surgical repair of ABP at a single institution from September 2014 to August 2017. Patient characteristics, operative details, and 30- and 90-day complications were assessed. RESULTS: Sixteen patients underwent surgical repair of ABP at the University of Kentucky during the study period. Mean age was 54 years (range 44 62). Median body mass index (BMI) was 47.7 (range 25.5-53.3). Patients largely underwent penile liberation, escutcheonectomy, and split thickness skin grafting. Concurrent scrotoplasty and urethroplasty were performed in select cases. The majority of patients 10/16 (62.5%) were discharged on the same day of surgery, while the remaining 6/16 (37.5%) were outpatient extended stay-and were discharged on postoperative day 1. The 30- and 90-day complications were 19% and 25% respectively, all were Clavien II. Split thickness skin graft take was 100%, and technical success was achieved in all patients. Patients with complications had higher BMIs, higher rates of diabetes, and higher rates of tobacco use, though only BMI reached statistical significance (P = .0150, P = .5846, and P = .0632) respectively. CONCLUSION: Multi component repair of adult ABP can be safely done on an outpatient basis without need for routine inpatient admission and complex algorithms. The most common complication is surgical site infection, which arose in the first 30 days postoperatively. Higher BMI was a significant risk factor for complications. PMID- 30312675 TI - Factors Predicting Persistent Ectopic Pregnancy After Laparoscopic Salpingostomy or Salpingotomy for Tubal Pregnancy: A Retrospective Cohort Study. AB - STUDY OBJECTIVE: To identify factors predictive of persistent ectopic pregnancy (PEP) in women who have undergone laparoscopic salpingostomy or salpingotomy for tubal pregnancy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary referral center. PATIENTS: Ninety-nine women who underwent laparoscopic tubal preservation surgery for ectopic pregnancy. INTERVENTIONS: Seventy women underwent laparoscopic salpingostomy, and the remaining 29 women underwent laparoscopic salpingotomy. MEASUREMENTS AND MAIN RESULTS: Factors predicting PEP were evaluated. The change in serum beta human chorionic gonadotropin (beta-hCG) levels from baseline observed between postoperative days 5 and 10 (ChCGD5-10) was a predictor of PEP (odds ratio [OR], 0.80; p = .01). Based on receiver operating characteristic (ROC) curve analysis, a cutoff value of 93.1% was determined, with an area under the ROC curve of 0.95 (sensitivity, 85.7%; specificity, 100%). Nonetheless, when considering perioperative variables only, body mass index (BMI) was identified as a predictor of PEP (OR, 0.71; p = .03). Based on the ROC analysis, a BMI cutoff value of <=22 kg/m2 was determined, with an ROC area of 0.73 (sensitivity, 43.2%; specificity, 100%). In addition, a higher baseline beta-hCG level (hazard ratio [HR], 1.0002; p = .009) and left tubal pregnancy (HR, 6.46; p = .03) were predictive of recurrent ectopic pregnancy. There were no differences in the perioperative outcomes, PEP rates, or subsequent intrauterine pregnancy rates between the salpingostomy and salpingotomy groups. In addition, surgical method was not a predictor of recurrent ectopic pregnancy. CONCLUSIONS: ChCGD5-10 was identified as a predictor for PEP, suggesting that it might be more clinically useful for the follow-up of PEP. When considering perioperative variables only, BMI was a predictor for PEP. In addition, there was no significant difference in clinical outcomes between the salpingostomy and salpingotomy groups. PMID- 30312676 TI - From the Pages of AllergyWatch : January 2019. PMID- 30312677 TI - Flow-mediated vasodilation assay indicates no endothelial dysfunction in hereditary angioedema patients with C1-inhibitor deficiency. AB - BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype. OBJECTIVE: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls. METHODS: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers. RESULTS: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol. CONCLUSION: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis. PMID- 30312678 TI - Peptide filtering differently affects the performances of XIC-based quantification methods. AB - In bottom-up proteomics, data are acquired on peptides resulting from proteolysis. In XIC-based quantification, the quality of the estimation of protein abundance depends on how peptide data are filtered and on which quantification method is used to express peptide intensity as protein abundance. So far, these two questions have been addressed independently. Here, we studied to what extent the relative performances of the quantification methods depend on the filters applied to peptide intensity data. To this end, we performed a spike in experiment using Universal Protein Standard to evaluate the performances of five quantification methods in five datasets obtained after application of four peptide filters. Estimated protein abundances were not equally affected by filters depending on the computation mode and the type of data for quantification. Furthermore, we found that filters could have contrasting effects depending on the quantification objective. Intensity modeling proved to be the most robust method, providing the best results in the absence of any filter. However, the different quantification methods can achieve similar performances when appropriate peptide filters are used. Altogether, our findings provide insights into how best to handle intensity data according to the quantification objective and the experimental design. SIGNIFICANCE: We believe that our results are of major importance because they address, as far as we know for the first time, the crossed-effects of peptide intensity data filtering and XIC-based quantification methods on protein quantification. While previous papers have dealt with peptide filtering independently of the quantification method, here we combined four peptide filters (based on peptide sharing between proteins, retention time variability, peptides occurrence and peptide intensity profiles) with five XIC-based quantification methods representing different modes of calculating protein abundances from peptide intensities. For these different combinations, we analyzed the quality of protein quantification in terms of precision, accuracy and linearity of response to increasing protein concentration using a spike-in experiment. We showed that not only filters effect on the estimation of protein abundances depend on the quantification methods but also that quantification methods can reach similar performances when appropriate peptide filters are used. Also, depending on the quantification objective, i.e. absolute or relative, filters can have contrasting effects and we demonstrated that protein quantification by the peptide intensity modeling was the most robust method. PMID- 30312679 TI - Proteomic footprint of ultrasound intensification on sliced dry-cured ham subjected to mild thermal conditions. AB - : Ultrasound can intensify the heating process used to correct texture defects in dry-cured hams. The effect of ultrasound-assisted heating on the proteome of sliced dry-cured ham was evaluated. Dry-cured hams with high proteolysis index (PI > 36) were sliced, vacuum packed and subjected to conventional (CV) and ultrasound-assisted (US) thermal treatments. Comparative proteome profiling between sample groups was assessed by two-dimensional electrophoresis (2-DE) coupled to tandem mass spectrometry. It was found that protein fragmentation increased markedly after US thermal treatment. Specifically, fragments of the major myofibrillar protein, actin, were abundantly over-represented following US heating. In addition, five unfragmented sarcoplasmic proteins (i.e. fatty acid binding protein, peroxiredoxin-6, superoxide dismutase, carbonyl reductase and aminoacylase) showed increased abundance in the US sample group. These results suggest candidate biomarkers to monitor proteolysis intensity and proteolysis independent effects linked to cured ham quality by ultrasound application. SIGNIFICANCE: The present proteome profiling study of treated dry-cured ham demonstrates the impact of ultrasound action on proteins. Moreover, negative organoleptic effects can be appearing with ultrasound treatment due to proteolysis increase. Therefore, the proteolysis monitoring could help to control these effects. In this regards, our results suggest that actin can be a candidate biomarker to monitor proteolysis intensity. PMID- 30312680 TI - Survival Comparison in Patients with Stage IV Lung Cancer in Academic versus Community Centers in the United States. AB - INTRODUCTION: Although metastatic NSCLC is widely treated in both academic centers (ACs) and community-based centers (CCs), it is unclear whether outcomes are similar across both settings. A growing variety of chemotherapies and targeted agents for an increasingly histology- and molecular-based treatment strategy could provide an advantage to patients treated in ACs. Using the National Cancer Database, we investigated whether treatment at ACs was associated with a survival advantage in metastatic NSCLC. METHODS: We conducted a retrospective analysis of the National Cancer Database after the introduction of novel NSCLC chemotherapy agents from 1998 to 2010. The primary outcome was 2-year survival, which was analyzed by using a multivariable regression model controlling for age, year of diagnosis, sex, primary payer, histologic type, facility type (AC versus CC), and an interaction term allowing a time-based comparison of survival between ACs and CCs. Alpha was set to 0.001 because of the size of the data set. RESULTS: There were 193,279 patients included in this study. The percentage of patients achieving 2-year survival was higher in ACs versus in CCs in 1998 (11.5% versus 9.2% [+2.3%]), and by 2010, the difference had increased to 17.4% versus 13.1% (+4.3%). Multivariable analysis confirmed a significant relative increase in 2-year survival associated with ACs versus with CCs from 1998 to 2010 (p = 0.0005). A histology-dependent survival difference was also noted in adenocarcinoma versus in squamous cell carcinoma (10.2% versus 9.9% in 1998 [+0.3%], increasing to 17.3% versus 10.1% in 2010 [+7.2%]). Adenocarcinoma survival also varied by treatment facility, with the difference in 2-year survival in ACs versus in CCs increasing from 12.3% versus 9.1% (+3.2%) in 1998 to 20.5% versus 15.5% (+5%) in 2010, with a trend toward significance in our multivariable model (p = 0.005). CONCLUSIONS: A greater increase in survival was noted in ACs than in CCs over this time period, and it was particularly pronounced among patients with adenocarcinoma versus in those with squamous cell carcinoma. Given the known advances in adenocarcinoma treatment compared with in squamous cell lung cancer over this time period, our study suggests that potential treatment-related disparities may exist between ACs and CCs. Further study will be needed to validate this disparity in health care and address opportunities to improve survival in patients with stage IV NSCLC across treatment settings. PMID- 30312681 TI - Applying Self-Determination Theory to Redesign an Inpatient Care Team. PMID- 30312682 TI - mRNA cap regulation in mammalian cell function and fate. AB - In this review we explore the regulation of mRNA cap formation and its impact on mammalian cells. The mRNA cap is a highly methylated modification of the 5' end of RNA pol II-transcribed RNA. It protects RNA from degradation, recruits complexes involved in RNA processing, export and translation initiation, and marks cellular mRNA as "self" to avoid recognition by the innate immune system. The mRNA cap can be viewed as a unique mark which selects RNA pol II transcripts for specific processing and translation. Over recent years, examples of regulation of mRNA cap formation have emerged, induced by oncogenes, developmental pathways and during the cell cycle. These signalling pathways regulate the rate and extent of mRNA cap formation, resulting in changes in gene expression, cell physiology and cell function. PMID- 30312683 TI - Heterogeneous ribonucleoprotein F regulates YAP expression via a G-tract in 3'UTR. AB - The Yes-associated protein (YAP) is a transcription coactivator that plays crucial roles in organ size control and tumorigenesis, and was demonstrated to be inhibited by the Hippo signaling pathway. To date, the molecular mechanisms regulating the expression of YAP in human cells remain unknown. In the present study, we found that hnRNP F and hnRNP U negatively regulate YAP expression. We also showed that downregulation of YAP expression by hnRNP F and hnRNP U was not at the transcriptional level. Knockdown of hnRNP F or hnRNP U increased YAP mRNA stability, suggesting the downregulation of YAP expression was by a post transcriptional mechanism. A putative hnRNP F binding site was identified in the YAP 3'UTR at 685 to 698, and deletion of this putative hnRNP F element abolished the down-regulation effect of YAP mRNA stability by hnRNP F. Binding of the hnRNP F to the YAP 3'UTR was demonstrated by Cross-linked RNA Immunoprecipitation. mRNA stability is a possible secondary effect of alternative splicing or other nuclear process. Understanding the regulation of YAP expression would provide insights into the mechanisms underlying the maintenance of tissue size homeostasis and tumorigenesis. PMID- 30312684 TI - Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. AB - Myelin transcription factor 1 (Myt1) and Myt1l (Myt1-like) are zinc finger transcription factors that regulate neuronal differentiation. Reduced Myt1l expression has been implicated in glioblastoma (GBM), and the related St18 was originally identified as a potential tumor suppressor for breast cancer. We previously analyzed changes in gene expression in a human GBM cell line with re expression of either Myt1 or Myt1l. This revealed largely overlapping gene expression changes, suggesting similar function in these cells. Here we show that re-expression of Myt1 or Myt1l reduces proliferation in two different GBM cell lines, activates gene expression programs associated with neuronal differentiation, and limits expression of proliferative and epithelial to mesenchymal transition gene-sets. Consistent with this, expression of both MYT1 and MYT1L is lower in more aggressive glioma sub-types. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Proliferation of GBM cell lines is reduced by lowering YAP1 expression and increased with YAP1 over expression, which overcomes the anti-proliferative effect of Myt1/Myt1l expression. Finally we show that reducing YAP1 expression in a GBM cell line slows the growth of orthotopic tumor xenografts. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. PMID- 30312685 TI - Interactions between acetylcholinesterase, toxic organophosphorus compounds and a short series of structurally related non-oxime reactivators: Analysis of reactivation and inhibition kinetics in vitro. AB - Poisoning by organophosphorus compounds (OP) is characterized by inhibition of the key enzyme acetylcholinesterase (AChE) and potentially fatal outcomes in humans. Insufficient efficacy of the standard therapy with atropine and AChE reactivators (oximes) against certain OP initiated synthesis of novel non-oxime reactivators basing on the common structure 4-amino-2 ((diethylamino)methyl)phenol (ADOC). Recently, we reported of a pyrrolidine bearing ADOC analogue (3 l) with a remarkable ability to reactivate OP-inhibited AChE. This in vitro study was undertaken to determine reactivity, affinity and overall reactivation constants of 3 l, the reference compound ADOC and two structural analogues with human AChE inhibited by paraoxon, sarin, cyclosarin and VX. The data showed a 10 to 34-fold reactivating potency of 3 l compared to ADOC mainly due to improved affinity. Additionally, various interactions between non oximes, human or guinea pig (GP) AChE and structurally different OP were investigated: OP-inhibited guinea pig AChE was less amenable to reactivation by ADOC and 3 l than human AChE. Compound 3 l was considered as potential pretreatment to prevent AChE from irreversible inhibition by OP: In the presence of 10 MUM 3 l inhibition of native human AChE was attenuated resulting in protective indices (PI) ranging from about 2.7 to 6.0. A combination of 3 l and the bispyridinium oxime HI-6 was tested to reactivate OP-inhibited AChE: The superior reactivator of the respective OP-AChE combination dominated the reactivation process and a synergistic effect could not be observed. In conclusion, novel non-oxime reactivators like 3 l may be considered as promising templates for the design of more potent therapeutics against poisoning by highly toxic OP. PMID- 30312686 TI - Alterations of mineralized matrix by lead exposure in osteoblast (MC3T3-E1) culture. AB - The present study investigated the effect of lead (Pb) on bone ultrastructure and chemistry using an in vitro bone model. MC3T3-E1 preosteoblasts were differentiated and treated with lead acetate at 0.4, 2, 10, and 50 MUM. No abnormalities in either cell growth or bone nodule formation were observed with the treated dose of lead acetate. However, Pb treatments could significantly increase Pb accumulation in differentiated osteoblast cultures and upregulate expression of Divalent metal transporter 1 (Dmt1) in a dose dependent manner. Pb treatments also altered the expression of osteogenic genes, including secreted phosphoprotein 1, osteocalcin, type I collagen, and osteoprotegerin. Moreover, in mineralized osteoblast cultures, Pb was found to be mainly deposited as Pb salts and oxides, respectively. Ultrastructure analysis revealed Pb localizing with calcium and phosphorus in the mineralized matrix. In mineralizing osteoblast cells, Pb was found in the intracellular calcified vesicles which is one of the bone mineralization mechanisms. Pb was also present in mineral deposits with various shapes and sizes, such as small and large globular or needle-like mineral deposits representing early to mature stages of mineral deposits. Furthermore, Pb was found more in the globular deposits than the needle shaped mineral crystals. Taken together, our observations revealed how Pb incorporates into bone tissue, and showed a close association with bone apatite. PMID- 30312687 TI - iPPI-PseAAC(CGR): Identify protein-protein interactions by incorporating chaos game representation into PseAAC. AB - Investigation into the network of protein-protein interactions (PPIs) will provide valuable insights into the inner workings of cells. Accordingly, it is crucially important to develop an automated method or high-throughput tool that can efficiently predict the PPIs. In this study, a new predictor, called "iPPI PseAAC(CGR)", was developed by incorporating the information of "chaos game representation" into the PseAAC (Pseudo Amino Acid Composition). The advantage by doing so is that some key sequence-order or sequence-pattern information can be more effectively incorporated during the treatment of the protein pair samples. The operation engine used in this predictor is the random forests algorithm. It has been observed via the cross-validations on the widely used benchmark datasets that the success rates achieved by the proposed predictor are remarkably higher than those by its existing counterparts. For the convenience of the most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/iPPI-PseAAC(CGR), by which users can easily get their desired results without the need to go through the detailed mathematics. PMID- 30312688 TI - Spatiotemporal model for depth perception in electric sensing. AB - Electric sensing involves measuring the voltage changes in an actively generated electric field, enabling an environment to be characterized by its electrical properties. It has been applied in a variety of contexts, from geophysics to biomedical imaging. Some species of fish also use an active electric sense to explore their environment in the dark. One of the primary challenges in such electric sensing involves mapping an environment in three-dimensions using voltage measurements that are limited to a two-dimensional sensor array (i.e. a two-dimensional electric image). In some special cases, the distance of simple objects from the sensor array can be estimated by combining properties of the electric image. Here, we describe a novel algorithm for distance estimation based on a single property of the electric image. Our algorithm can be implemented in two simple ways, involving either different electric field strengths or different sensor thresholds, and is robust to changes in object properties and noise. PMID- 30312689 TI - The universal ancestor, the deeper nodes of the tree of life, and the fundamental types of primary cells (cellular domains). AB - I have analyzed the deep nodes of the topology of the tree of life as supported by Castelle and Banfield (2018). My arguments imply that the last universal common ancestor (LUCA) and the ancestors of bacteria and archaea were of progenotes. Furthermore by this topology, the bacterial candidate phyla radiation (CPR) and the superphylum of archaea known as DPANN would have derived directly from these pre-cellular ancestors. Such proto-cell ancestors would have given rise to four new fundamental types of primary cells-four cellular domains of life, because ordinarily such progenote ancestors would not be classified as cells. PMID- 30312690 TI - Air quality index induced nonsmooth system for respiratory infection. AB - It has been observed that air pollution greatly affects respiratory infection and generates public health problem, but there are many challenges to quantifying the dynamics of air pollution and evaluating its impact on respiratory infections. A periodic Filippov system describing the state-dependent control strategy for air pollution, described by air quality index (AQI), is proposed. We theoretically analyze the non-autonomous Filippov subsystem for variation of AQI by converting into an autonomous Filippov system via increasing dimension of the system. We obtain that there is a unique periodic solution which is globally asymptotically stable. In particular, it shows that AQI stabilizes at either one of the periodic solutions of the free and control systems or a new periodic solution induced by the on-off control strategies, depending on the threshold levels. Then, a periodic system for respiratory infection with AQI-embedded transmission probability is formulated to examine the influence of air pollution on respiratory infection. We further obtain the control reproduction number (basic reproduction number with control strategies) of this periodic respiratory infection model. It is shown that the respiratory infection will go extinct if the control reproduction number is less than unity, while uniformly persists for larger than unity. The case study showed that the estimated threshold level coincides with the actual threshold which launches the traffic limitation measure in Xi'an, indicating the untimely density-dependent traffic limitation measure was ineffective in improving air quality. Numerically studies indicate that increasing the threshold level leads to an increase in the maximum value of the unique periodic solution for AQI and the control reproduction number for the AQI embedded SEIS model. These findings emphasize the importance of suitable threshold level to trigger interventions and suggest that untimely implementing control strategy may not effectively control air population. PMID- 30312691 TI - Estimating hemodynamic stimulus and blood vessel compliance from cerebral blood flow data. AB - Several key brain imaging modalities that are intended for retrieving information about neuronal activity in brain, the BOLD fMRI as a foremost example, rely on the assumption that elevated neuronal activity elicits spatiotemporally well localized increase of the oxygenated blood volume, which in turn can be monitored non-invasively. The details of the signaling in the neurovascular unit during hyperemia are still not completely understood, and remain a topic of active research, requiring good mathematical models that are able to couple the different aspects of the signaling event. In this work, the question of estimating the hemodynamic stimulus function from cerebral blood flow data is addressed. In the present model, the hemodynamic stimulus is a non-specific signal from the electrophysiological and metabolic complex that controls the compliance of the blood vessels, leading to a vasodilation and thereby to an increase of blood flow. The underlying model is based on earlier literature, and it is further developed in this article for the needs of the inverse problem, which is solved using hierarchical Bayesian methodology, addressing also the poorly known model parameters. PMID- 30312692 TI - Ozone detoxification of patulin in aqueous solution and cytotoxic evaluation using human hepatic carcinoma cells. AB - Patulin often contaminates fruits and fruit-base products, which seriously threats the health of consumers. In this study, ozone was used to degrade patulin in aqueous solution, and investigated the cytotoxicity of patulin after ozone detoxification on human hepatic carcinoma cells (HepG2) using MTT assay and apoptosis assay. Patulin was rapidly degraded from 24.59 mg/L to 9.85 mg/L within 180 s by 10.60 mg/L of ozone at a flow rate of 90 mL/min, and reduced by 59.94%. The half maximal inhibitory concentration (IC50) of patulin on HepG2 cells was 9.32 MUmol/L after 24 h of exposure, and it showed a dose dependent effect. After 90 s of ozone detoxification, the cell viability of HepG2 cells obviously increased from 42.31% to 93.96%, and the total apoptotic cells significantly reduced from 22.24% to 11.18% after 180 s of ozone treatment. The results clearly show the great potential of ozone in degrading patulin in liquid foods. PMID- 30312693 TI - Intermolecular ionic interactions serve as a possible switch for stem release in the staphylococcal bi-component toxin for beta-barrel pore assembly. AB - The beta-strand stem release system of staphylococcal beta-barrel pore-forming toxin gamma-hemolysin was investigated. Mutations at K15 and R16 in the cap domain of Hlg2 decreased hemolytic activity more markedly than their effect on erythrocyte binding. In addition, D122N mutation of LukF prestem lost the activity with Hlg2 R16A, indicating that electrostatic interactions between residues in the Hlg2 cap and prestem of adjacent LukF in the ring-shaped complex might serve as a switch for stem release. PMID- 30312694 TI - Evaluation of intracellular and extracellular domoic acid content in Pseudo nitzschia multiseries cell cultures under different light regimes. AB - Pseudo-nitzschia multiseries is a diatom species associated with the production of domoic acid (DA), a water soluble neurotoxin that is easily transferred up in the food web, causing devastating effects on top marine organisms and humans. Despite studies on Pseudo-nitzschia are relevant to human health safety, partitioning of marine toxins between intracellular and extracellular fractions are poorly documented. This study aimed to determine the growth rates and DA content, both intracellular and extracellular, of Pseudo-nitzschia multiseries cultures at three different light settings (15, 120 and 560 MUmol m-2 s-1). The optimal conditions for cell growth were observed at 120 and 560 MUmol m-2 s-1, whereas DA production was observed in P. multiseries at 15 and 120 MUmol m-2 s-1, ranging between 0.18-2.56 and 0.16-3.5 pg DA cell-1, respectively. Higher intracellular DA concentrations were found during the senescence phase at low light intensity and during the exponential phase at medium light intensity, while higher concentrations of dissolved DA were found at low and medium light intensities in the senescence phase reaching 3 and 10 ng DA mL-1 respectively. The amount of toxin released into the culture medium represents the most important fraction ranging between 63 and 98% during the exponential phase and nearly 99% during the senescence phase. In contrast, under low light intensity, dissolved DA was detected in the culture medium only during the senescence phase. This study confirms the importance of light intensity on DA production and clearly shows that dissolved domoic acid is an important fraction in Pseudo nitzschia cultures, suggesting with the careful assumptions of results from static cultures extrapolated to bloom situations that waterborne exposure of marine organism should be considered during blooms of Pseudo-nitzschia multiseries. PMID- 30312695 TI - MicroRNA-645 represses hepatocellular carcinoma progression by inhibiting SOX30 mediated p53 transcriptional activation. AB - Amount of evidence demonstrate that aberrant microRNAs (miRNAs) are involved in tumorigenesis and progression in hepatocellular carcinoma (HCC). Among them, miR 645 is recently recognized as cancer-related miRNA and its significance in HCC remains largely unknown. In this study, we reported for the first that miR-645 expression was markedly elevated in HCC tissues and cell lines, and its up regulation was associated with malignant clinical features, including tumor size and venous infiltration and poor prognosis. Our data revealed that miR-645 promoted cell proliferation, colony formation and inhibited apoptosis by gain- and loss-of function experiments in vitro. In vivo assays showed that miR-645 overexpression enhanced tumor growth. Moreover, miR-645 directly bound to the SOX30 3'-UTR and post-transcriptionally repressed SOX30 expression in HCC cells. Furthermore, miR-645 inversely correlated with SOX30 expression in HCC tissues. Restoration of SOX30 expression at least partially abolished the biological effects of miR-645 on HCC cells. SOX30 regulated HCC progression through aberrant activation of p53 by directly binding to its promoter. Taken together, this research supports the first evidence that miR-645 exerts an oncogenic role in HCC progression and may be a therapeutic target for HCC treatment. PMID- 30312696 TI - Preparation of drug-immobilized anti-adhesion agent using visible light-curable alginate derivative containing furfuryl group. AB - This study demonstrated the anti-adhesion and wound healing effect of a visible light curable anti-adhesion agent using an alginate derivative modified with a furfuryl moiety. Visible light-curable furfuryl alginate (F-Alg) was prepared in conjugation with alginate and furfurylamine by an amide coupling reaction, and the conjugated F-Alg was characterized by 1H NMR analysis. The cytotoxicity, cell adhesion, and cell permeability of the F-Alg were evaluated for use in anti adhesion applications. Drug immobilization and protein release were assessed to verify whether the alginate derivatives and drugs were photo-immobilized. In in vivo anti-adhesion testing, the new anti-adhesion agent prepared in this study acted as a physical protective layer by forming a biofilm on the surgical site. Additionally, along with gradual decomposition of the photo-crosslinked alginate derivative, the immobilized drug was released, and additional effects such as accelerated wound healing are expected. Thus, visible light-curable F-Alg has good application potential as an anti-adhesion agent. PMID- 30312697 TI - The non-enzymatic glycation of LDL proteins results in biochemical alterations - A correlation study of Apo B100-AGE with obesity and rheumatoid arthritis. AB - Advanced glycation end-products (AGEs) can aggregate amid incessant inflammation, as may be available in patients with rheumatoid arthritis. d-Ribose reacts more promptly than glucose monosaccharide to the proteins and forms heterogeneous group of products known as AGEs. Obesity includes persons with provocative joint inflammation with increased lipid profile. Immunogenic evidences recommend a cross-sectional relationship between glycated LDL-Apo B100 and inflammation. The point of this examination was to look at the connection between d-ribose glycated ApoB100 (ApoB100-AGE) with obesity and rheumatoid arthritis. The binding specificity of auto-antibodies against ApoB100-AGE antigen present in obesity and rheumatoid arthritis patient's serum were inspected by direct binding and was further established by competitive inhibition ELISA. In the present study, hydroxyl radical, superoxide radical, ketoamine moieties, hydroxyl-methyl furfural (HMF) and carbonyl substances were evaluated in the patients' serum via respective specific methods. The prevalence of auto-antibodies against ApoB100 AGE antigen was recorded to be 58% and 52.86% from obese and rheumatoid arthritis patient respectively in contrast to its native analogue (P < 0.001). Moreover, the autoantibodies present in obese and arthritis patients were found to be highly specific towards ApoB100-AGE as confirmed by inhibition ELISA. PMID- 30312698 TI - Protective effects of lncRNA H19 silence against hypoxia-induced injury in PC-12 cells by regulating miR-28. AB - LncRNA H19 has been widely reported to be up-regulated upon hypoxia. We aimed to uncover the function and mechanism of lncRNA H19 in hypoxic PC-12 cells. Neural like PC-12 cells were exposed to hypoxia to stimulating an in vitro model of hypoxic brain damage. The expression levels of lncRNA H19 in PC-12 cells were altered by transfection, then cell viability, migration and apoptosis were assessed respectively. Moreover, the cross-regulation between lncRNA H19, miR-28 and SP1 was studied to reveal one of the possible mechanisms of lncRNA H19's function. We found that hypoxia induced remarkable decreases in cell viability and migration, and induced a notable increase in cell apoptosis. Hypoxia-induced cell damage was aggravated by lncRNA H19 overexpression, while was alleviated by lncRNA H19 silence. miR-28 was negatively regulated by lncRNA H19, and SP1 was a target gene of miR-28. Furthermore, lncRNA H19 down-regulated miR-28 expression, which in turn preventing SP1 from degradation by miR-28, and ultimately deactivated PDK/AKT and JAK/STAT signaling pathways. In conclusion, our research demonstrated a protective role of lncRNA H19 silence in hypoxic PC-12 cells. A possible mechanism of which lncRNA H19 functioned to PC-12 cells was that lncRNA H19 down-regulated miR-28 expression, preventing SP1 exhausted by miR-28. PMID- 30312699 TI - A novel lipase-catalyzed method for preparing ELR-based bioconjugates. AB - Herein we present a novel one-pot method for the chemical modification of elastin like recombinamers (ELRs) in a mild and efficient manner involving enzymatic catalysis with Candida antarctica lipase B. The introduction of different functionalities into such ELRs could open up new possibilities for the development of advanced biomaterials for regenerative medicine and, specifically, for controlled drug delivery given their additional ability to respond to stimuli other than pH or temperature, such as glucose concentration or electromagnetic radiation. Candida antarctica lipase B immobilized on a macroporous acrylic resin (Novozym 435) was used to enzymatically couple different aminated substrates to a recombinamer containing carboxylic groups along its amino acid chain by way of an amidation reaction. A preliminary study of the kinetics of this amidation in response to different reaction conditions, such as solvent, temperature or reagent ratio, was carried out using a phenylazobenzene derivative (azo-NH2) as a model. The optimal amidation conditions were used to couple other amine reagents, such as phenylboronic acid (FB-NH2) or polyethylene glycol (PEG-NH2), thus allowing us to obtain photoresponsive, glucose-responsive or PEGylated ELRs that could potentially be useful as sensors in devices for controlled drug delivery. PMID- 30312700 TI - Artificial chaperones based on thermoresponsive polymers recognize the unfolded state of the protein. AB - Stabilization of the enzymes under stress conditions is of special interest for modern biochemistry, bioengineering, as well as for formulation and target delivery of protein-based drugs. Aiming to achieve an efficient stabilization at elevated temperature with no influence on the enzyme under normal conditions, we studied chaperone-like activity of thermoresponsive polymers based on poly(dimethylaminoethyl methacrylate) (PDMAEMA) toward two different proteins, glyceraldehyde-3-phosphate dehydrogenase and chicken egg lysozyme. The polymers has been shown to do not interact with the folded protein at room temperature but form a complex upon heating to either protein unfolding or polymer phase transition temperature. A PDMAEMA-PEO block copolymer with a dodecyl end-group (d PDMAEMA-PEO) as well as PDMAEMA-PEO without the dodecyl groups protected the denatured protein against aggregation in contrast to PDMAEMA homopolymer. No effect of the polymers on the enzymatic activity of the client protein was observed at room temperature. The polymers also partially protected the enzyme against inactivation at high temperature. The results provide a platform for creation of artificial chaperones with unfolded protein recognition which is a major feature of natural chaperones. PMID- 30312701 TI - Knockdown of FOXK1 suppresses liver cancer cell viability by inhibiting glycolysis. AB - AIMS: Aerobic glycolysis is a unique characteristic of cancer cells, and this key signature provides a target for therapeutic intervention of cancers. Forkhead box protein K1 (FOXK1) is a transcriptional factor that plays an oncogenic role in several types of cancers, including liver cancer. However, whether FOXK1 could affect glycolysis in cancer cells remains unknown. The aim of the present study was to evaluate the effect of FOXK1 on glycolysis in liver cancer cells. MAIN METHODS: The expression of FOXK1 in four human liver cancer cell lines was evaluated using qRT-PCR and western blot. Cell viability was assessed using MTT and CCK-8 assays. Glucose consumption and lactate production of the cells were detected to reflect glycolysis. The expression of hexokinase 2 (HK2) was detected using qRT-PCR and western blot. KEY FINDINGS: FOXK1 was up-regulated in liver cancer cells as compared to the normal human hepatic cell line. Knockdown of FOXK1 reduced cell viability and HK2 expression. FOXK1 knockdown decreased glucose consumption and lactate production in liver cancer cells. Furthermore, FOXK1 knockdown suppressed the activation of Akt/mTOR pathway. Inhibition of Akt/mTOR pathway reduced cell viability and glycolysis of liver cancer cells. SIGNIFICANCE: These findings suggested that FOXK1 knockdown inhibited cell viability of liver cancer cells by regulating glycolysis through the Akt/mTOR pathway. PMID- 30312702 TI - Expression of cell adhesion molecule 1 in gastric neck and base glandular cells: Possible involvement in peritoneal dissemination of signet ring cells. AB - AIMS: To determine cellular distribution of cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, in the human oxyntic gastric mucosa, and to explore possible involvement in the development and peritoneal dissemination of signet ring cell (SRC) gastric carcinoma, which often develops in the oxyntic mucosa. MAIN METHODS: Immunohistochemistry and double immunofluorescence were conducted on surgical specimens of normal and SRC-bearing stomachs and peritoneal metastatic foci of SRCs. KATO-III (lacking CADM1) and HSC-43 (expressing CADM1) SRC cell lines were cocultured on a Met-5A mesothelial or TIG-1 fibroblastic cell monolayer. KEY FINDINGS: In the oxyntic gland, some neck and nearly all base glandular cells were CADM1-positive, and mucin 5AC-positive cells were CADM1 negative, while some mucin 6-positive neck cells were CADM1-positive. Foveolar epithelial, parietal, and endocrine cells were CADM1-negative. CADM1 was negative in all SRC carcinomas that were confined within the submucosa (n = 11) and all but one of those invading deeper (n = 15). In contrast, peritoneal metastatic foci of SRCs were CADM1-positive in five out of eleven cases (P < 0.01). In the cocultures, exogenous CADM1 made KATO-III cells adhere more and grow faster on a Met-5A monolayer, not on TIG-1 monolayers. HSC-43 cells adhered more and grew faster on Met-5A than on TIG-1 monolayers, which were partly counteracted by a function-neutralizing anti-CADM1 antibody. SIGNIFICANCE: Nearly all chief cells and a part of mucous neck cells express CADM1. SRC gastric carcinoma appears to emerge as a CADM1-negative tumor, but CADM1 may help SRCs develop peritoneal dissemination through promoting their adhesion and growth in the serosal tissue. PMID- 30312703 TI - Effects of different types of exercise on skeletal muscle atrophy, antioxidant capacity and growth factors expression following myocardial infarction. AB - AIMS: Myocardial infarction (MI) is accompanied with skeletal muscle abnormalities. The aims are to explore an optimal exercise mode to improve cardiac function and prevent skeletal muscle atrophy, and detect the possible mechanisms of exercise-induced inhibition of muscle atrophy. MAIN METHODS: Rats were subjected to four weeks of different types of exercise after MI surgery (resistance training, RT; moderated-intensity continuous aerobic exercise, MCE and high-intensity intermittent aerobic exercise, HIA). Cardiac function, histological changes of heart and skeletal muscle, oxidative stress, antioxidant capacity and the expression of muscle atrophy-related factors were detected in skeletal muscle. KEY FINDINGS: The three types of exercise improved heart function, reduced cardiac fibrosis and increased muscle weight and cross-section area (CSA) of muscle fibers in different degrees. The survival rates of MI rats intervened by RT and MCE were higher than HIA. Exercise down-regulated the mRNA levels of murf1 and atrogin-1, decreased reactive oxygen species level, increased antioxidant capacity, regulated the expression of insulin-like growth factor 1 (IGF1), mechano growth factor (MGF), Neuregulin1 (NRG1) and Myostatin (MSTN), and activated Akt and Erk1/2 signalings in soleus muscle. Furthermore, CSA of muscle fibers and the expression of IGF1, MGF, NRG1 in skeletal muscle had correlations with cardiac function. SIGNIFICANCE: RT and MCE are the first two choices for the early exercise rehabilitation following MI. All types of exercise can effectively inhibit skeletal muscle atrophy through increasing the antioxidant capacity, reducing oxidative stress and protein degradation, and regulating the growth factors expression in skeletal muscle. PMID- 30312704 TI - EROS/CYBC1 mutations: Decreased NADPH oxidase function and chronic granulomatous disease. PMID- 30312705 TI - Neutropenia as a sign of immunodeficiency. PMID- 30312706 TI - Hsa-mir-144-3p expression is increased in umbilical cord serum of infants with atopic dermatitis. PMID- 30312707 TI - A personal perspective on mentoring. PMID- 30312708 TI - Upregulated P-Rex1 exacerbates human airway smooth muscle hyperplasia in asthma. PMID- 30312709 TI - Real-life treatment of cholinergic urticaria with omalizumab. PMID- 30312710 TI - CSF3R/CD114 mediates infection-dependent transition to severe asthma. PMID- 30312711 TI - Intestinal dysbiosis in inflammatory bowel disease associated with primary immunodeficiency. PMID- 30312712 TI - Maintained thymic output of conventional and regulatory T cells during human pregnancy. PMID- 30312713 TI - Strategy for early identification of prediabetes in lean populations: New insight from a prospective Chinese twin cohort of children and young adults. AB - AIMS: To identify certain subgroups in young and lean populations, who may be at a high risk of developing prediabetes/diabetes, which is not captured by current BMI-based screening algorithms. METHODS: Incidence of prediabetes/diabetes was assessed using oral glucose tolerance tests among 1859 children and 1073 young adults from a prospective Chinese twin cohort. RESULTS: Over a 6-year follow-up, 507 (27.3%) children and 293 (27.3%) adults developed prediabetes/diabetes. Of the 800 incidents, 737(92.1%) and 644(80.5%) were lean at baseline and follow-up, respectively. Baseline fasting glucose in the top tertile of the normal range was associated with an increased risk of prediabetes/diabetes: odds ratio, 1.85 (95% CI 1.32-2.59) and 3.29 (95%CI 2.10-5.17) among normal weight and underweight children, respectively, and 2.74 (95% CI 1.78-4.23) and 3.08 (95% CI 1.69-5.58) among normal weight and overweight/obese adults, respectively, compared with the low tertile of fasting glucose. CONCLUSIONS: We showed that majority incident cases of prediabetes/diabetes were not overweight/obese (at baseline), who would have been missed by traditional screening algorithm emphasizing overweight/obesity. Our findings revealed that an upper end of normal fasting glucose was a simple and robust predictor of future higher risk of prediabetes/diabetes in this young and lean population. PMID- 30312714 TI - Effects of intensive interventions compared to standard care in people with type 2 diabetes and microalbuminuria on risk factors control and cardiovascular outcomes: A systematic review and meta-analysis of randomised controlled trials. AB - AIMS: The effect of intensive glycaemic control, blood pressure control and lipid levels control alone or as part of a multifactorial intervention has not been fully evaluated. We aimed to estimate the effects of more intensive interventions, compared with standard care, on risk factor control and cardiovascular outcomes in people with type 2 diabetes and microalbuminuria. METHODS: We searched MEDLINE, Embase and the Cochrane library without language restrictions from inception to August 10, 2018. We included randomised controlled trials that evaluated intensive interventions in adults with type 2 diabetes and microalbuminuria. The review was registered on PROSPERO (registration number 42017055208). We used random effects meta-analysis to calculate overall pooled effect estimates across studies. RESULTS: A total of seven (n = 1210) randomised controlled trials were included, four studies (n = 758) reported HbA1c, six studies (n = 950) reported blood pressure measurements, and three studies (n = 896) examined non-fatal MI, non-fatal stroke, cardiovascular mortality, and all cause mortality. Intensive interventions indicated statistically significant reductions in both systolic and diastolic blood pressure, and a nonsignificant trend for reduction in HbA1c, total cholesterol, LDL, triglycerides and urinary albumin excretion rate. There was no evidence to suggest that compared with standard care, intensive interventions reduced the risk of non-fatal MI [risk ratio (RR) 0.50; 95% CI 0.20, 1.22; P = 0.127], non-fatal stroke (RR 0.44; 95% CI 0.10, 1.91; P = 0.275), CV mortality (RR 0.95; 95% CI 0.48, 1.86; P = 0.874) or all-cause mortality (RR 0.80; 95% CI 0.51, 1.25; P = 0.324). CONCLUSIONS: Apart from blood pressure outcomes, there was no evidence that intensive interventions improve or worsen HbA1c, total cholesterol, LDL, triglycerides, urinary albumin excretion rate, risk of cardiovascular or mortality outcomes in people with type 2 diabetes and microalbuminuria. Results of this review are mainly influenced by one small trial, hence uncertainty surrounding the effect of intensive interventions in people with type 2 diabetes and microalbuminuria still exists. Large studies are urgently required in this high risk cardiovascular group of patients. PMID- 30312715 TI - Performance of the Flash Glucose Monitoring System during exercise in youth with Type 1 diabetes. AB - AIM: Metabolic changes during exercise may affect the accuracy of glucose sensors impacting on Type 1 diabetes (T1D) management. The present study aimed at assessing the performance of the Flash Glucose Monitoring system (isCGM) during exercise and in free-living condition in youth with T1D. METHODS: Seventeen youth (53% male), aged 13.7 +/- 3.8 years, with T1D for 5.4 +/- 3.8 years, HbA1c 7.4 +/ 1.0% (57 +/- 11 mmol/mol), were enrolled. Paired isCGM, plasma (PG) and capillary (CG) glucose values (total of 136) were collected during an interval exercise (45 min at 55% VO2max load with 20 s sprints at 80% VO2max every 10 min). Paired isCGM and CG (total of 832) were collected during free-living condition. RESULTS: During exercise, isCGM absolute relative difference (ARDs) means/medians were 12.5/9.4% versus PG and 15.4/10.8% versus CG. During rest, ARDs means/medians were 16.6/12.0%. The Consensus Error Grid analysis showed 98.4% of readings during exercise and 97.24% during rest in zones A + B. Percentage of readings meeting the ISO criteria for CG levels <5.55 mmol/L was 62.5% during exercise, 53.4% during rest; for CG levels >=5.55 mmol/L was 64.0% during exercise, 60.4% during rest. CONCLUSIONS: isCGM demonstrated similar clinical safety and performance during exercise and in everyday life; further studies are needed to confirm its accuracy during exercise. PMID- 30312716 TI - Radiotherapy Modulates DNA Repair Efficiency in Peripheral Blood Mononuclear Cells Of Patients With Non-Small Cell Lung Cancer. AB - PURPOSE: There is a growing interest in developing individually tailored cancer radiotherapy (RT), where patients with high intrinsic radiosensitivity (RS) are identified prior to commencing treatment, to minimise severe adverse reactions. In a previous retrospective study of severely radiosensitive RT patients, we established a functional assay with a high predictive capability (1). The assay involves ex-vivo irradiation of peripheral blood mononuclear cells (PBMC) and analysis of DNA repair using the gamma-H2AX assay. It is unknown whether RS is a fixed phenomenon or modulates under different conditions. We now report the impact of RT on the apparent RS, as reflected by the assay. METHODS AND MATERIALS: PBMC of 11 non-small cell lung cancer (NSCLC) patients were collected before, during and post-RT. Quantitative parameters derived from the non-linear regression analysis of gamma-H2AX foci were applied to examine the cellular radiation response. RESULTS: While the repair rate and foci yield remained constant during and after RT, the "unrepairable" component of gamma-H2AX foci decreased over the course of treatment in 7 patients, signifying a generally enhanced DNA repair capacity. Interestingly, enhanced repair capacity tended to be associated with a poorer response to RT. CONCLUSIONS: While generalisation of these results into normal and tumour tissues warrant further investigation, the findings of this study have important implications in future strategies for identifying radiosensitive individuals before exposure to RT. We can anticipate that the threshold values that will discriminate radiosensitive patients in a future prospective trial will differ from those established in the retrospective study. PMID- 30312717 TI - A Prospective Phase II Trial of Trans-perineal Ultrasound-Guided Brachytherapy for Locally Recurrent Prostate Cancer after External Beam Radiotherapy (NRG Oncology/RTOG -0526). AB - PURPOSE: Only retrospective data is available for low dose rate (LDR) salvage prostate brachytherapy for local recurrence after external beam radiotherapy (EBRT). The primary objective of this prospective Phase II trial (NCT00450411) was to evaluate late gastrointestinal and genitourinary adverse events (AEs) after salvage LDR brachytherapy. MATERIALS/METHODS: Eligible patients had low/intermediate risk prostate cancer prior to EBRT and biopsy-proven recurrence >30 months after EBRT, with PSA <10 ng/mL and no regional/distant disease. The primary endpoint was grade 3 or higher late treatment-related GI/GU AEs occurring 9-24 months after brachytherapy. These were projected to be <10%, with >20% considered unacceptable. All events were graded with CTCAE V3.0. Multivariate analyses investigated associations of pre-treatment or treatment variables with AEs. RESULTS: From May 2007 to January 2014, 100 patients were registered from 20 centers. 92 analyzable patients had a median follow-up of 54 months (range: 4-97) and median age 70 (IQR: 65-74). Initial Gleason score was 7 in 48%. Median dose of EBRT was 74 Gy (IQR: 70-76) at a median interval of 85 months previously (IQR: 60-119). Only 16% had androgen deprivation at study entry. Twelve patients (14%) had late grade 3 GI/GU AEs with no treatment-related grade 4 or 5 AEs. No pre treatment variable predicted late AEs, including prior EBRT dose and elapsed interval. Higher V100 (% of prostate enclosed by prescription isodose) predicted both occurrence of late AEs (OR=1.24; 95% CI: 1.02-1.52; p=0.03) and earlier time to first occurrence (HR=1.18; 95% CI: 1.03-1.34; p=0.02). CONCLUSIONS: This prospective multicenter trial reports outcomes of salvage LDR brachytherapy for post EBRT recurrence. The rate of late grade 3 AEs did not exceed the unacceptable threshold. The only factor predictive of late AEs was implant dosimetry reflected by V100. Efficacy outcomes will be reported at a minimum of 5 yr follow-up. PMID- 30312718 TI - Application of polydopamine in tumor targeted drug delivery system and its drug release behavior. AB - Inspired by the bionics of marine mussels, polydopamine (PDA), a new polymer with unique physicochemical properties was discovered. Due to its simple preparation, good biocompatibility, unique drug-loading methods, PDA has attracted tremendous attentions in field of drug delivery and imaging, and the combination of chemotherapy and other therapies or diagnostic methods, such as photothermotherapy (PTT), photoacoustic imaging (PAI), magnetic resonance imaging (MRI), etc. As an excellent drug carrier in tumor targeted drug delivery system, the drug release behavior of drug-loaded PDA-based nanoparticles is also an important factor to be considered in the establishment of drug delivery systems. Therefore, the purpose of this review is to provide a comprehensive overview of the various applications of PDA in tumor targeted drug delivery systems and to gain insight into the release behavior of the drug-loaded PDA-based nanocarriers. A sufficient understanding and discussion of these aspects is expected to provide a better way to design more rational and effective PDA-based tumor nano-targeted delivery systems. Apart from this, the prospects for the future application of PDA in this field and some unique insights are listed at the end of the article. PMID- 30312719 TI - A hybrid of mPEG-b-PCL and G1-PEA dendrimer for enhancing delivery of antibiotics. AB - The development of novel materials is essential for the efficient delivery of drugs. Therefore, the aim of the study was to synthesize a linear polymer dendrimer hybrid star polymer (3-mPEA) comprising of a generation one poly (ester amine) dendrimer (G1-PEA) and a diblock copolymer of methoxy poly (ethylene glycol)-b-poly(epsilon-caprolactone) (mPEG-b-PCL) for formulation of nanovesicles for efficient drug delivery. The synthesized star polymer was characterized by FTIR, 1H and 13C NMR, HRMS, GPC and its biosafety was confirmed by MTT assays. Thereafter it was evaluated as a nanovesicle forming polymer. Vancomycin loaded nanovesicles were characterized using in vitro, molecular dynamics (MD) simulations and in vivo techniques. MTT assays confirmed the nontoxic nature of the synthesized polymer, the cell viability was 77.23 to 118.6%. The nanovesicles were prepared with size, polydispersity index and zeta potential of 52.48 +/- 2.6 nm, 0.103 +/- 0.047, -7.3 +/- 1.3 mV respectively, with the encapsulation efficiency being 76.49 +/- 2.4%. MD simulations showed spontaneous self aggregation of the dendritic star polymer and the interaction energy between the two monomers was -146.07 +/- 4.92, Van der Waals interactions playing major role for the aggregates stability. Human serum albumin (HSA) binding studies with Microscale Thermophoresis (MST) showed that the 3-mPEA did not have any binding affinity to the HSA, which showed potential for long systemic circulation. The vancomycin (VCM) release from the drug loaded nanovesicles was found to be slower than bare VCM, with an 65.8% release over a period of 48 h. The in vitro antibacterial test revealed that the drug loaded nanovesicles had 8- and 16-fold lower minimum inhibitory concentration (MIC) against methicillin sensitive Staphylococcus aureus and methicillin-resistant S. aureus strains (MRSA) compared to free drug. The flow cytometry study showed 3.9-fold more dead cells of MRSA in the population when samples were treated with the drug loaded nanovesicles than the bare VCM at concentration 0.488 MUg/mL. An in vivo skin infection mice model showed a 20-fold reduction in the MRSA load in the drug loaded nanovesicles treated groups compared to bare VCM. These findings confirmed the potential of 3 mPEA as a promising biocompatible effective nanocarrier for antibiotic delivery. PMID- 30312720 TI - Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo. AB - The clinical use of protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82-90 nm, reduction-responsive protein release, as well as greatly enhanced internalization and cytoplasmic protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC50) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non targeted and non-treated controls. These cell-selective penetrating and reduction responsive polymersomes provide a targeted protein therapy for cancers. PMID- 30312721 TI - Biomaterials for vaccine-based cancer immunotherapy. AB - The development of therapeutic cancer vaccines as a means to generate immune reactivity against tumors has been explored since the early discovery of tumor specific antigens by Georg Klein in the 1960s. However, challenges including weak immunogenicity, systemic toxicity, and off-target effects of cancer vaccines remain as barriers to their broad clinical translation. Advances in the design and implementation of biomaterials are now enabling enhanced efficacy and reduced toxicity of cancer vaccines by controlling the presentation and release of vaccine components to immune cells and their microenvironment. Here, we discuss the rational design and clinical status of several classes of cancer vaccines (including DNA, mRNA, peptide/protein, and cell-based vaccines) along with novel biomaterial-based delivery technologies that improve their safety and efficacy. Further, strategies for designing new platforms for personalized cancer vaccines are also considered. PMID- 30312722 TI - Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler. AB - This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm3, 55.99 mm3, and 133.04 mm3, and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI. PMID- 30312723 TI - Modified In Vitro Release of Melatonin Loaded in Nanofibrous Electrospun Mats Incorporated Into Monolayered and Three-Layered Tablets. AB - Modified release tablet formulations with melatonin (MLT) are clinically more useful in initiating and maintaining sleep in elderly insomniacs, compared with those designed for immediate release. Aiming at the modified release of MLT, monolayered and 3-layered tablets, incorporating nanofibrous mats composed of cellulose acetate and polyvinylpyrrolidone loaded with MLT, were prepared and studied. In vitro dissolution profiles of MLT in gastrointestinal-like fluids revealed tableting pressure/pH-dependence. The release of the hormone from physical mixture tablets was generally slower from the nanofibers-based tablets, thus exhibiting in the latter case properties that are necessary for the control of both the sleep-onset and the maintenance dysfunctions. The nature of the excipients (hydroxypropylmethylcellulose or lactose monohydrate) used in this study to produce 3-layered tablets was also found to affect the release of MLT, adjusting it to the endogenous hormone's chronobiotic profile. The release of MLT from formulation F(nf)2 (nanofiber mats incorporated into 3-layered tablets containing lactose monohydrate both in the upper and lower layers) was found to be in closer alignment with these effects than the other delivery systems. PMID- 30312724 TI - Core-Shell Arginine-Containing Chitosan Microparticles for Enhanced Transcorneal Permeation of Drugs. AB - Chitosan oligosaccharide (C) was functionalized with l-arginine (A) and short hydrocarbon chains (C8) to design an amphiphilic copolymer, henceforth CAC8, leading to microparticles (MPs) consisting of an arginine-decorated hydrophilic shell and inner hydrophobic domains allowing the encapsulation of high amount hydrophobic drugs such as sorafenib tosylate (>10% w/w). l-arginine side chains were selected in order to impart the final MPs enhanced transcorneal penetration properties, thus overcoming the typical biological barriers which hamper the absorption of drugs upon topical ocular administration. The mucoadhesive properties and drug release profile of the CAC8 MPs (CAC8-MPs) were studied, showing that CAC8-MPs can strongly interact with mucin, and thus gradually release their payload in situ to potentially improve the bioavailability of the drug after topical administration. In vitro transcorneal studies also showed that CAC8-MPs are endowed with effective permeation enhancer ability combined with negligible toxicity. PMID- 30312725 TI - Long non-coding RNA NEAT1 promotes colorectal cancer progression by competitively binding miR-34a with SIRT1 and enhancing the Wnt/beta-catenin signaling pathway. AB - In recent years, accumulating evidence has indicated that long non-coding RNAs (lncRNAs) are powerful factors influencing the progression of multiple malignancies. Although a relationship between the lncRNA NEAT1 (nuclear enriched abundant transcript 1) and colorectal cancer has previously been reported, the functional mechanism underlying the involvement of NEAT1 in colorectal cancer remains unknown. In this study, we report that NEAT1 expression is up-regulated in colorectal cancer tissues, which correlates with advanced clinical features, poor overall survival and disease free survival. Up-regulated NEAT1 promotes cell proliferation and metastasis of colorectal cancer both in vitro and in vivo. Moreover, NEAT1 functions as an oncogene influencing cell viability and invasion in part by serving as a competing endogenous RNA (ceRNAs) modulating miRNA-34a expression, leading to subsequent repression of the miR-34a/SIRT1 axis and activation of the Wnt/beta-catenin signaling pathway. Taken together, our study demonstrates that the lncRNA NEAT1 may serve as a prognostic biomarker and a potential therapeutic target in colorectal cancer. PMID- 30312726 TI - Mitosis inhibitors in anticancer therapy: When blocking the exit becomes a solution. AB - Current microtubule-targeting agents (MTAs) remain amongst the most important antimitotic drugs used against a broad range of malignancies. By perturbing spindle assembly, MTAs activate the spindle assembly checkpoint (SAC), which induces mitotic arrest and subsequent apoptosis. However, besides toxic side effects and resistance, mitotic slippage and failure in triggering apoptosis in various cancer cells are limiting factors of MTAs efficacy. Alternative strategies to target mitosis without affecting microtubules have, thus, led to the identification of small molecules, such as those that target spindle Kinesins, Aurora and Polo-like kinases. Unfortunately, these so-called second generation of antimitotics, encompassing mitotic blockers and mitotic drivers, have failed in clinical trials. Our recent understanding regarding the mechanisms of cell death during a mitotic arrest pointed out apoptosis as the main variable, providing an opportunity to control the cell fates and influence the effectiveness of antimitotics. Here, we provide an overview on the second generation of antimitotics, and discuss possible strategies that exploit SAC activity, mitotic slippage/exit and apoptosis induction, in order to improve the efficacy of anticancer strategies that target mitosis. PMID- 30312727 TI - Identification of Smac mimetics as novel substrates for p-glycoprotein. AB - Multidrug resistance (MDR) in cancer patients undergoing chemotherapy is preventing effective treatment of multiple cancer types including pediatric tumors. Resistance to chemotherapeutic drugs in cancer cells is frequently associated with high expression of p-glycoprotein, a transporter in the plasma membrane that can mediate cellular drug export. Here, we generated pediatric cancer cells with acquired resistance to the chemotherapeutic drug vincristine (VCR). In these cells, acquired resistance is associated with increased expression of p-glycoprotein. VCR-resistant cells display an MDR phenotype and have acquired resistance to multiple other chemotherapeutic drugs including doxorubicin (DOXO) and etoposide (ETO). Notably, we discovered that these cells also display cross-resistance with several Smac mimetics, a novel class of experimental cancer therapeutics designed to induce apoptosis by inhibiting Inhibitor of Apoptosis (IAP) proteins. Resistance to Smac mimetics is reversible in the presence of p-glycoprotein inhibitors, highlighting Smac mimetics as novel substrates for p-glycoprotein. The identification of Smac mimetics as substrates for p-glycoproteins may influence the design of future clinical trials to prevent usage of Smac mimetics in the context of MDR or, alternatively, combine Smac mimetics with p-glycoprotein inhibitors to maximize their efficiency. PMID- 30312728 TI - Natural compound Tetrocarcin-A downregulates Junctional Adhesion Molecule-A in conjunction with HER2 and inhibitor of apoptosis proteins and inhibits tumor cell growth. AB - Overexpression of the tight junction protein Junctional Adhesion Molecule-A (JAM A) has been linked to aggressive disease in breast and other cancers, but JAM targeting drugs remain elusive. Screening of a natural compound library identified the antibiotic Tetrocarcin-A as a novel downregulator of JAM-A and human epidermal growth factor receptor-2 (HER2) protein expression in breast cancer cells. Lysosomal inhibition partially rescued the downregulation of JAM-A and HER2 caused by Tetrocarcin-A, and attenuated its cytotoxic activity. Tetrocarcin-A treatment or JAM-A silencing reduced AKT and ERK phosphorylation, inhibited c-FOS phosphorylation at Threonine-232 (its transcriptional regulation site), inhibited nuclear localization of c-FOS, and downregulated expression of the inhibitor of apoptosis proteins (IAP). This was accompanied by Tetrocarcin-A induced caspase-dependent apoptosis. To begin evaluating the potential clinical relevance of our findings, we extended our studies to other models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused cytotoxicity in primary breast cells and lung cancer stem cells, and inhibited the growth of xenografts in a semi-in vivo model involving invasion across the chicken egg chorioallantoic membrane. Taken together, our data suggest that Tetrocarcin-A warrants future evaluation as a novel cancer therapeutic by virtue of its ability to downregulate JAM-A expression, reduce tumorigenic signaling and induce apoptosis. PMID- 30312729 TI - Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. AB - Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma. PMID- 30312730 TI - Hematopoietic growth factors and tumor angiogenesis. AB - Angiogenesis is regulated by numerous "classic" factors such as vascular endothelial growth factor (VEGF) and many other endogenous "non-classic"peptides, including erythropoietin (Epo), and granulocyte-/granulocyte macrophage colony stimulating factor (G-/GM-CSF). The latter play an important regulatory role in angiogenesis, especially under pathological conditions and constitute a crosslink between angiogenesis and hematopoiesis. This article reviews studies on the ability of hematopoietic cytokines to affect several endothelial cell functions in tumor angiogenesis. These findings in all these studies support the hypothesis formulated at the beginning of this century that a common ancestral cell, the hemangioblast, gives rise to cells of both the endothelial and the hematopoietic lineages. PMID- 30312731 TI - Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer. AB - Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway. PMID- 30312733 TI - Measles vaccination status among Japanese university students participating in short-term study abroad programs. PMID- 30312732 TI - Progression from low- to high-grade in a glioblastoma model reveals the pivotal role of immunoediting. AB - The mutual reshape of tumor and immune system cells during tumor progression is a widely accepted notion in different cancers including gliomas. The importance of this phenomenon in shaping glioma progression and the mechanisms governing it, however, are not fully elucidated. Taking advantage of a well-characterized in vivo glioma model we performed an analysis of glioma cells transcriptomes at different stages of progression and unveiled the reorganization of glioma-immune system interactions. Specifically, we show that the inability of low-grade glioma cells to orthotopically graft in syngeneic immunocompetent mice, positively correlates with the abundance of infiltrating lymphocytes in donor tumors and with a highly immunostimulatory transcriptional profile. Notably, during tumor progression glioma cells downregulate these genes and the immune infiltrate shifts towards a pro-tumorigenic phenotype. Challenging low-grade gliomas by grafting into immunodeficient hosts revealed the crucial role of the adaptive immune system in constraining glioma progression. Finally, we observed that although progression still takes place in immunodeficient mice, it is slower, likely due to a milder selection thus reinforcing the view of a pivotal role for the immune system in regulating glioma progression. PMID- 30312734 TI - Detection of zoonotic agents and a new Rickettsia strain in ticks from donkeys from South Africa: Implications for travel medicine. AB - BACKGROUND: In rural South Africa, people are in close contact with tick-infested donkeys. This study aimed to investigate the presence of spotted fever group Rickettsia, Anaplasma, Ehrlichia and Coxiella species in these arthropods. METHOD: 376 ticks (7 species) from donkeys from Limpopo Province (South Africa) were pooled and analyzed using PCR assays for the bacterium detection. RESULTS: Rickettsia africae was amplified in 6 Amblyomma hebraeum, 1 Rhipicephalus appendiculatus and 5 Rhipicephalus evertsi evertsi pools. Rickettsia aeschlimannii was found in 1 Hyalomma rufipes, 1 Rh. appendiculatus and 2 Rh. e. evertsi pools. Three Rhipicephalus simus specimens were infected with a new Rickettsia strain that showed low identity with any validated Rickettsia species. Ehrlichia canis was detected in 2 Rh. e. evertsi pools and in one of them Anaplasma bovis was amplified. An Am. hebraeum pool showed infection with Anaplasma ovis and another with Coxiella burnetii. CONCLUSION: South African donkeys are involved in the epidemiology of tick-borne pathogens and other associated agents such as C. burnetii with Health importance. A potential new Rickettsia species, with unknown pathogenic potential, has been detected in the anthropophilic Rh. simus. PMID- 30312735 TI - Aptamer-based proteomics of serum and plasma in acquired aplastic anemia. AB - Single-stranded oligonucleotides containing deoxyuridine are aptamers (SOMAmers) that can bind proteins with high specificity and affinity and slow dissociation rates. SOMAscan, an aptamer-based proteomic technology, allows measurement of more than 1,300 proteins simultaneously for the identification of new disease biomarkers. The aim of the present study was to identify new serum and plasma protein markers for diagnosis of acquired aplastic anemia (AA) and response to immunosuppressive therapies (IST). SOMAscan was used to screen 1,141 serum proteins in 28 AA patients before and after therapy and 1,317 plasma proteins in seven SAA patients treated with standard IST and a thrombopoietin receptor agonist. From our analysis, 19 serum and 28 plasma proteins were identified as possible candidate diagnostic and prognostic markers. A custom immunobead-based multiplex assay with five selected serum proteins (BMP-10, CCL17, DKK1, HGF, and SELL) was used for validation in a verification set (n = 65) of samples obtained before and after IST and in a blinded validation cohort at baseline (n = 16). After technical validation, four biomarkers were employed to predict diagnosis (accuracy, 88%) and long-term response to IST (accuracy, 79%). In conclusion, SOMAscan is a powerful tool for the identification of new biomarkers. We propose further larger studies to validate new candidate serum and plasma diagnostic and prognostic markers of AA. PMID- 30312736 TI - Metabolic memory of dietary restriction ameliorates DNA damage and adipocyte size in mouse visceral adipose tissue. AB - Dietary restriction (DR) is thought to exert its beneficial effects on healthspan at least partially by a senolytic and senostatic action, i.e. by reducing frequencies of cells with markers of DNA damage and senescence in multiple tissues. Due to its importance in metabolic and inflammation regulation, fat is a prime tissue for health span determination as well as a prime target for DR. We aimed to determine here whether the beneficial effects of DR would be retained over a subsequent period of ad libitum (AL) feeding. Male mice were kept under either 40% DR or AL feeding regimes from 3 to 12 months of age and then either switched back to the opposite feeding regimen or kept in the same state for another 3 months. Visceral adipose tissue from 4 to 5 mice per group for all conditions was analysed for markers of senescence (adipocyte size, gammaH2A.X, p16, p21) and inflammation (e.g. IL-6, TNFalpha, IL-1beta) using immuno-staining or qPCR. Macrophages were detected by immunohistochemistry. We found that both 9 and 12 months DR (long term) as well as 3 month (short term, mid-life onset) DR reduced the number of cells harbouring DNA damage and adipocyte size (area and perimeter) in visceral adipocytes with similar efficiency. Importantly, beneficial health markers induced by DR such as small adipocyte size and low DNA damage were maintained for at least 3 month after termination of DR, demonstrating that the previously identified 'metabolic memory' of the DR state in male mice extends to senescence markers in visceral fat. PMID- 30312737 TI - Food addiction linked to changes in ventral striatum functional connectivity between fasting and satiety. AB - INTRODUCTION: The concept of "food addiction" (FA) has gained popularity in view of clinical and neurobiological overlaps between excessive food intake and addictive disorders. However, no studies have examined the link between FA and striatocortical circuits involved in addictive disorders, or the influence of homeostatic status, which regulates the drive to eat, on these systems. This study aims to investigate changes in striatal functional connectivity between fasted and fed conditions among adults ranging in body mass index (BMI) and FA symptoms. METHODS: Thirty adults were recruited from the general community and completed self-reported surveys including demographics, FA symptoms using the Yale Food Addiction Scale, as well as height and weight measures, used to determine BMI. Participants completed two 3-T MRI scans, one in a fasted state and one in a fed state. We conducted seed-based analyses to examine between session ("fasted > fed") change in resting-state functional connectivity of the ventral and dorsal striatum, and its association with FA scores (controlling for BMI). RESULTS: Higher symptoms of FA correlated with greater changes in ventral caudate-hippocampus connectivity between fasted and fed conditions. FA symptoms did not correlate with connectivity in the dorsal caudate circuit. Post-hoc analyses revealed that participants with higher symptoms of FA had ventral caudate-hippocampus hyperconnectivity in the fasted scan only, as well as a significant reduction of this connectivity between the fasted and fed scans. CONCLUSIONS: Heightened connectivity in the ventral striatum during a fasted state, which has been linked to reward prediction signals, underpins symptoms of FA. In contrast, connectivity in the dorsal striatum or "habit" system is unrelated to homeostatic status and FA symptoms, and is thus less relevant for subclinical manifestations of FA. PMID- 30312738 TI - Food commercials do not affect energy intake in a laboratory meal but do alter brain responses to visual food cues in children. AB - Food commercials promote snack intake and alter food decision-making, yet the influence of exposure to food commercials on subsequent neural processing of food cues and intake at a meal is unclear. This study tested whether exposing children to food or toy commercials altered subsequent brain response to high- and low energy dense food cues and influenced laboratory intake at a multi-item, ad libitum meal. Forty-one 7-9-year-old children (25 healthy weight; 16 with overweight/obesity) completed five visits as part of a within-subjects design where they consumed multi-item test-meals under three conditions: no exposure, food commercial exposure, and toy commercial exposure. On the fourth and fifth visits, functional magnetic resonance imaging (fMRI) was performed while children viewed low- and high-energy dense food images following exposure to either food or toy commercials. Linear mixed models tested for differences in meal energy intake by commercial condition. A whole-brain analysis was conducted to compare differences in response by commercial condition and child weight status. Meal intake did not differ by commercial condition (p = 0.40). Relative to toy commercials, food commercials reduced brain response to high-energy food stimuli in cognitive control regions, including bilateral superior temporal gyri, middle temporal gyrus, and inferior frontal gyrus. Commercial condition * weight status interactions were observed in orbitofrontal cortex, fusiform gyrus, and supramarginal gyrus. Children with overweight/obesity showed increased response in these regions to high-energy stimuli following food commercials. Food commercial exposure affected children's subsequent processing of food cues by reducing engagement of the prefrontal cortex, a region implicated in cognitive control. Even though food commercial exposure did not increase intake at a meal, the effect of reduced prefrontal cortical engagement on a broader range of consumption patterns warrants investigation. PMID- 30312739 TI - Intuitive, mindful, emotional, external and regulatory eating behaviours and beliefs: An investigation of the core components. AB - The aim of this study was to identify the interrelations between, and the core components of, adaptive and maladaptive measures of eating behaviours. Participants were 2018 females (Mage = 23.14 years) who completed measures of intuitive eating, mindful eating, overeating regulation, dietary restraint, emotional eating, external eating, and overeating dysregulation in contexts of leisure and discomfort. Most associations between eating measures were significant, with the largest association between eating for physical rather than emotional reasons (intuitive eating) and emotional eating, and the smallest and nonsignificant associations usually involving the mindful eating subscales. Principle component analysis of the composite scores for all measured eating subscales revealed a 4-component structure. Component 1, labelled attuned eating, reflected positive loadings for eating for physical rather than emotional reasons (intuitive eating); act with awareness, present eating, and non-reactivity (mindful eating); and overeating regulation. Attuned eating also had negative loadings for emotional eating, external eating, and leisure and discomfort overeating dysregulation. Component 2, labelled unrestrained eating, reflected positive loadings for unconditional permission to eat (intuitive eating) and acceptance (mindful eating), but also a negative loading for dietary restraint. Component 3, labelled eating and hunger awareness, had positive loadings for reliance on hunger/satiety cues (intuitive eating) and awareness (mindful eating). Component 4, labelled casual eating attitudes, was represented by positive loadings for non-reactivity and flexibility (mindful eating). These findings highlight the complexity of eating behaviour by revealing that although many adaptive and maladaptive eating concepts appear to tap opposite ends of a continuum of attuned versus disinhibited eating, several other adaptive and maladaptive eating concepts are better described as tapping somewhat unique attitudes, beliefs, motivations, and behaviours regarding food and eating. PMID- 30312740 TI - A guide to gene regulatory network inference for obtaining predictive solutions: Underlying assumptions and fundamental biological and data constraints. AB - The study of biological systems at a system level has become a reality due to the increasing powerful computational approaches able to handle increasingly larger datasets. Uncovering the dynamic nature of gene regulatory networks in order to attain a system level understanding and improve the predictive power of biological models is an important research field in systems biology. The task itself presents several challenges, since the problem is of combinatorial nature and highly depends on several biological constraints and also the intended application. Given the intrinsic interdisciplinary nature of gene regulatory network inference, we present a review on the currently available approaches, their challenges and limitations. We propose guidelines to select the most appropriate method considering the underlying assumptions and fundamental biological and data constraints. PMID- 30312741 TI - Effects and mechanisms of Danshen-Shanzha herb-pair for atherosclerosis treatment using network pharmacology and experimental pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The danshen (the root of Salvia miltiorrhiza Bge.)-shanzha (the fruit of Crataegus pinnatifida Bge. var. major N.E.Br.) (DS) herb combination is a commonly used traditional Chinese medicine with cardiovascular disease (CVD) treatment potential. MATERIALS AND METHODS: In this study, we investigated the anti-atherosclerotic effects and mechanisms of DS by the integration of network pharmacology and polypharmacology. Eight main components were selected for target fishing by PharmMapper. RESULTS: The network pharmacological study indicated that DS may target 41 proteins and 16 pathways associated with inflammation, lipid metabolism and endothelial protection, which indicates that DS probably adjusts these processes as part of its anti atherosclerotic activities. Furthermore, this hypothesis was verified by polypharmacology using an atherosclerotic model. Histopathological examination showed that DS inhibited pathological changes in the arteries of atherosclerotic rats and reduced the intima-media thickness (IMT). DS significantly reduced the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) and increased the high-density lipoprotein-cholesterol (HDL C) level in the blood. DS also decreased the concentrations of interleukin (IL) 1beta and IL-18, indicating anti-inflammation activity. In addition, DS increased the serum levels of nitric oxide (NO) and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) and decreased the serum levels of endothelin (ET) and thromboxane B2 (TXB2), indicating an endothelial protective effect. CONCLUSIONS: In conclusion, DS has an anti-atherosclerotic ability to lower lipid concentrations and to protect endothelial function, and it also has anti-inflammatory activity. PMID- 30312742 TI - Passive inhalation of dry powder influenza vaccine formulations completely protects chickens against H5N1 lethal viral challenge. AB - Bird to human transmission of high pathogenicity avian influenza virus (HPAIV) poses a significant risk of triggering a flu pandemic in the human population. Therefore, vaccination of susceptible poultry during an HPAIV outbreak might be the best remedy to prevent such transmissions. To this end, suitable formulations and an effective mass vaccination method that can be translated to field settings needs to be developed. Our previous study in chickens has shown that inhalation of a non-adjuvanted dry powder influenza vaccine formulation during normal breathing results in partial protection against lethal influenza challenge. The aim of the present study was to improve the effectiveness of pulmonary vaccination by increasing the vaccine dose deposited in the lungs and by the use of suitable adjuvants. Two adjuvants, namely, Bacterium-like Particles (BLP) and Advax, were spray freeze dried with influenza vaccine into dry powder formulations. Delivery of dry formulations directly at the syrinx revealed that BLP and Advax had the potential to boost either systemic or mucosal immune responses or both. Upon passive inhalation of dry influenza vaccine formulations in an optimized set-up, BLP and Advax/BLP adjuvanted formulations induced significantly higher systemic immune responses than the non-adjuvanted formulation. Remarkably, all vaccinated animals not only survived a lethal influenza challenge, but also did not show any shedding of challenge virus except for two out of six animals in the Advax group. Overall, our results indicate that passive inhalation is feasible, effective and suitable for mass vaccination of chickens if it can be adapted to field settings. PMID- 30312743 TI - Towards the development of human immune-system-on-a-chip platforms. AB - Organ-on-a-chip (OoCs) platforms could revolutionize drug discovery and might ultimately become essential tools for precision therapy. Although many single organ and interconnected systems have been described, the immune system has been comparatively neglected, despite its pervasive role in the body and the trend towards newer therapeutic products (i.e., complex biologics, nanoparticles, immune checkpoint inhibitors, and engineered T cells) that often cause, or are based on, immune reactions. In this review, we recapitulate some distinctive features of the immune system before reviewing microfluidic devices that mimic lymphoid organs or other organs and/or tissues with an integrated immune system component. PMID- 30312744 TI - Bisphenol A exposure remodels cognition of male rats attributable to excitatory alterations in the hippocampus and visual cortex. AB - Bisphenol A, an environmental xenoestrogen, has been shown sex-specific adverse effects on cognitive function of rodents. However, the specific mechanisms underlying these outcomes remain elusive, limiting our understanding the differences in behavioral impairments due to BPA exposure between genders in humans. The present study chose the juvenile stage (with a stable estrogen level) as the exposure window to explore BPA effects on cognitive behaviors of male and female Sprague-Dawley (SD) rats and related mechanisms. Three dosages of BPA (0.04, 0.4 and 4 mg/kg/day) were chose to make BPA-exposed models. Especially, the mid-dose for rats was close to the current reference daily limit for human exposure given by the U.S. Environmental Protection Agency. Our results showed that male but not female juvenile rats had a marked decline in spatial memory after 0.4 mg/kg/day BPA exposure, which accompanied with downregulation of glutamate receptor (NR2) expression in their hippocampus and primary visual cortex (V1). In the high-dose BPA exposed groups (4 mg/kg/day), there was not only a deficit of spatial memory, but also an anxiety-like behavior of male rats. Additionally, those rats had a significant decline in spine density of pyramidal neurons and a decreased expression of glutamate receptor subtypes (NR2 and GluR1) in the hippocampus. Importantly, such impairments in the hippocampus of male rats were associated with a decrease of glutamate receptor (NR2) expression in the V1, which could perturb the visual information inputs. To some extent, altered ERbeta expression within their hypothalamus could contribute to the anxiety-like behavior after high-dose BPA exposure. However, the low-dose BPA exposed juvenile rats didn't present any structural and behavioral changes in our present study. Those results suggests that BPA exerts dose dependent and gender-specific effects on the cognition of juvenile animals. Our findings shed light on mechanisms underlying BPA effects on the juvenile animals. PMID- 30312745 TI - Analysis of the powder behavior and the residence time distribution within a production scale rotary tablet press. AB - This study focuses on the behavior of powder particles in a rotary tablet press with special focus on the feed frame system. To obtain a better knowledge of the continuous manufacturing of tablets, the experimental setup was carried out with a production scale rotary tablet press. The behavior of the powder particles at different flow rates through the tablet press, residual moisture contents, particle sizes, and amounts of tracer was investigated. The residence time distribution was evaluated using the tracer indigo carmine, which was sprayed onto microcrystalline cellulose particle as solution with fluidized bed spray granulator to obtain a tracer blend. The residence time distribution was increased by increasing the amount of tracer blend, and a transition from a plain MCC blend to the tracer blend with regard to continuous manufacturing was shown. Furthermore, it was found that an increase in the flow rates of the powder particles through the tablet press led to a decrease of the residence time distribution (Et). The variation of the flow rate had no influence on the mechanically applied strain at high throughputs, which was confirmed by a constant number of paddle passes (Npp). At the lowest flow rate, the Npp appears to be higher than the constant Npp values at higher flow rates. The residual moisture content did not shown any significant influence on the residence time distribution. The examination of the effect of different tracer blend particle sizes led to an interesting result: It was shown that the particle size segregation only had a low influence on Et. However, a comparably higher influence of the particle size segregation on the particle distribution in the produced tablets was demonstrated. Large particles were deposited at the top of the tablet surface whereas small particles were deposited at their bottom. PMID- 30312746 TI - A mechanistic approach for the optimization of loperamide loaded nanocarriers characterization: Diafiltration and mathematical modeling advantages. AB - Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestinal tract due to its poor aqueous solubility and its P-glycoprotein (Pgp) substrate characteristic. In addition, ammonium methacrylate copolymers have shown to have mucoadhesive properties, whereas poloxamer 188, has been suggested as a Pgp inhibitor. Thus, in this work, we evaluate conditions that affect physicochemical parameters of ammonium methacrylate/poloxamer 188-based nanocarriers loaded with loperamide hydrochloride. Nanocarriers were synthesized by nanoprecipitation, enhancing loperamide encapsulation efficiency by modifying the aqueous phase to basic pH. The isolation of the non-encapsulated drug fraction from the nanocarriers-incorporated fraction was conducted by centrifugation, ultrafiltration, vacuum filtration and diafiltration. The last method was effective in providing a deeper understanding of drug-nanocarrier loading and interactions by means of modeling the data obtained by it. Through diafiltration, it was determined an encapsulation efficiency of about 93%, from which a 38% +/-6 was shown to be reversibly (thermodynamic interaction) and a 62% +/-6 irreversibly (kinetic interaction) bound. Finally, release profiles were assessed through empirical and semi-empirical modeling, showing a biphasic release behavior (burst effect 11.34% and total release at 6 h = 33% +/-1). Thus, encapsulation efficiency and release profile were shown to have a strong mathematical modeling-based correlation, providing the mechanistic approach presented in this article a solid support for future translational investigations. PMID- 30312748 TI - Development and functional characterization of composite freeze dried wafers for potential delivery of low dose aspirin for elderly people with dysphagia. AB - The impact of demographic ageing is likely to be of major significance in the coming decades due to low birth rates and higher life expectancy. Older people generally require more prescribed medicines due to the presence of multiple conditions such as dysphagia which can make swallowing medicines challenging. This study involves the development, characterization and optimization of composite wafers for potential oral and buccal delivery of low dose aspirin to prevent thrombosis in elderly patients with dysphagia. Blank (BLK) wafers (no loaded drug) were initially formulated by dissolving combinations of metolose (MET) with carrageenan (CAR) and MET with low molecular weight chitosan (CS) in different weight ratios in water, to identify optimum polymer combinations. However, drug loaded (DL) wafers were prepared using 45% v/v ethanol to help complete solubilization of the aspirin. The formulations were characterized using texture analyzer (hardness, mucoadhesion), scanning electron microscopy (SEM), X ray diffractometry (XRD), attenuated total reflectance - Fourier transform infrared (ATR-FTIR), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), and swelling capacity. Wafers with higher total polymer concentration were more resistant to penetration (MET:CAR 1:1 samples B2, C2) and MET:CS 1:1 (sample E2) and MET:CS 3:1 (sample F2) and also depended on the ratios between the polymers used. From the characterization, samples C2, B2, E2 and F2 showed the most ideal characteristics. XRD showed that BLK wafers were amorphous, whilst the DL wafers were crystalline due to the presence of aspirin. SEM confirmed the presence of pores within the polymer matrix of the BLK wafers, whilst DL wafers showed a more compact polymeric matrix with aspirin dispersed over the surface. The DL wafers showed a good flexibility required for transportation and patient handling and showed higher swelling capacity and adhesion values with phosphate buffer saline (PBS) than with simulated saliva (SS). Drug dissolution studies showed that aspirin was rapidly released in the first 20 min and then continuously over 1 h. FTIR confirmed the interaction of aspirin with the polymers evidenced by peak shifts around 1750 cm-1 and the broad peak between 2500 and 3300 cm-1. Lyophilized CAR: CS 1:3 (sample DL13), MET:CS 1:3 (sample DL8) and MET:CAR 3:1 (sample DL1) wafers seem to be a very promising system for the administration of low dose aspirin for older patients with dysphagia. PMID- 30312747 TI - Uniformly sized iron oxide nanoparticles for efficient gene delivery to mesenchymal stem cells. AB - Recent advances in nanomaterials have made iron oxide nanoparticles (IONPs) as an innovative approach for the delivery of genes. However, the effectiveness of IONPs-assisted gene delivery is currently suffering from their poor uniformity, which not only exhibits detrimental effect on the magnetic property, but also leads to the poor reproducibility to maintain the optimal gene delivery. To this end, the present study developed extremely uniform 15 nm-sized IONPs with a good monodispersity in water phase. These ultra-uniform IONPs exhibit notable potentials for an efficient gene delivery to human mesenchymal stem cells (hMSCs) with the assistance of magnetic force, which partly owes to their abilities to facilitate the cellular uptake, as well as to induce the rapid DNA release and the following nuclear transport. Besides, no significant detrimental effects of these IONPs are observed either on the proliferation or the multi-lineage differentiation potential of hMSCs. The current study highlights the potential advantages of designing extremely uniform magnetic nanomaterials for an efficient and safe delivery of genes to stem cells. PMID- 30312749 TI - Azithromycin-loaded liposomes for enhanced topical treatment of methicillin resistant Staphyloccocus aureus (MRSA) infections. AB - Antibiotic delivery via liposomal encapsulation represents a promising approach for the efficient topical treatment of skin infections. The present study aimed to investigate the potential of using different types of azithromycin (AZT) loaded liposomes to locally treat skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains. Conventional liposomes (CLs), deformable liposomes (DLs), propylene glycol-containing liposomes (PGLs) and cationic liposomes (CATLs) encapsulating AZT were prepared, and their physical characteristics, drug release profiles, ex vivo skin penetration/deposition abilities, in vitro anti-MRSA activities (planktonic bacteria and biofilm) and cell biocompatibilities were assessed. The (phospho)lipid composition and presence of surfactant or propylene glycol affected the physical characteristics of the liposomes, the release profile of AZT, its deposition inside the skin, as well as in vitro antibacterial efficacy and tolerability with the skin cells. All the liposomes retained AZT inside the skin more efficiently than did the control and were biocompatible with keratinocytes and fibroblasts. CATLs, DLs and PGLs efficiently inhibited MRSA strain growth and were superior to free AZT in preventing biofilm formation, exhibiting minimal inhibitory concentrations and minimal biofilm inhibitory concentrations up to 32-fold lower than those of AZT solution, thus confirming their potential for improved topical treatment of MRSA caused skin infections. PMID- 30312750 TI - BDNF as a pharmacogenetic target for antipsychotic treatment of schizophrenia. AB - Antipsychotic drugs remain the mainstay of pharmacotherapy for schizophrenia. As there are large individual variations in efficacy and side-effects of antipsychotic drugs, there is a strong demand for personalized medication to treat schizophrenia. Pharmacogenetic research into antipsychotic drugs has examined a number of genetic variants and only a few polymorphisms have been found which promise to be associated with the therapeutic efficacy and side effects of antipsychotic drugs. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system involved in the pathophysiology of schizophrenia. This review focused on the association between the BDNF gene Val66Met polymorphism and antipsychotic drugs. The BDNF Val66Met polymorphism has been related to the pathophysiology of schizophrenia, psychotic symptomatology, cognition, efficacy and side-effects of antipsychotic drugs. The BDNF Val66Met variants could be a promising target for antipsychotic medication options or developing next generation antipsychotic drugs. However, some studies showed inconsistent results due to sample size, ethnic differences and different antipsychotic drugs. Further studies will be required in this area to confirm the effect of the BDNF Val66Met polymorphism in the pathophysiology of schizophrenia and patients' response to antipsychotic drugs, especially in a larger sample size and in different ethnic populations. PMID- 30312751 TI - Neuropeptide Y impairs the acquisition of conditioned defeat in Syrian hamsters. AB - Recent evidence indicates that Neuropeptide Y (NPY) may function as a potent anxiolytic as well as a resilience factor that can insulate the brain from the effects of stress. However, most of these studies have utilized physical stressors such as shock or restraint. In the present study, we use an ethologically-based model in Syrian hamsters (Mesocricetus auratus) called Conditioned Defeat (CD) to investigate whether NPY can ameliorate the effect of social defeat stress. In the CD model, a male Syrian hamster is socially defeated by a larger, more aggressive conspecific. Subsequently, when paired with a smaller, non-aggressive intruder (NAI) in its own home cage, changes in its behavioral repertoire occur, including a reduction in aggression and chemosensory (social) investigation, and a concomitant increase in submissive behaviors. In Experiment 1, hamsters were infused intracerebroventricularly (icv) with NPY prior to social defeat, and 24-hours later, hamsters were exposed to a NAI. Results indicate that NPY significantly reduced submissive/defensive behaviors in socially defeated hamsters compared to control animals. In Experiment 2, we examined whether this effect was mediated by the NPY Y1 receptor. Subjects were first pre-treated with the Y1 receptor antagonist BIBP 3226 or vehicle, followed by NPY and then socially defeated. Upon testing with a NAI 24-hours later, pretreatment with BIBP 3226 failed to block the NPY effect compared to controls. These results demonstrate that NPY may function as an important resilience factor in socially defeated hamsters, but that these effects are not mediated by the Y1 receptor. PMID- 30312752 TI - Activation of spinal macrophage-inducible C-type lectin induces mechanical allodynia and microglial activation in rats. AB - Macrophage-inducible C-type lectin (Mincle), a pattern recognition receptor, is a critical component of the innate immune system that is involved in the pathogenesis of chronic pain. Previous studies have reported the expression of Mincle in neuronal and glial cells of the brain, but its expression and role in pain processing at the spinal level remain to be determined. The current study was performed to identify Mincle in the spinal cord and to investigate the effect of Mincle activation on spinal sensitization. Most Mincle immunoreactivity was localized within the grey matter and the dorsal and ventral horns of the lumbar spinal cord in naive rats. A single intrathecal (i.t.) injection of trehalose-6,6 dibehenate (TDB), a Mincle ligand, induced mechanical allodynia. Immunoreactivity to Mincle and Iba-1 in the spinal cord significantly increased after i.t. injection of TDB. Mechanical allodynia was attenuated by daily i.t. injection of minocycline. However, double immunofluorescence revealed that Mincle co-localizes with NeuN (neurons), but not with Iba-1 (microglia) or GFAP (astrocytes). In conclusion, we found that Mincle was present in spinal cord neurons, but not microglia or astrocytes, and may play a role in microglia-induced spinal sensitization. PMID- 30312753 TI - Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-kappaB activity in the bEnd.3 cells. AB - Drug-resistant epilepsy (DRE) is present in 20-30% of all patients who develop epilepsy. Growing evidences demonstrated that glutamate released during seizures to increase the brain P-glycoprotein (P-gp) expression. Carbamazepine (CBZ) is known to influence the P-gp and cytochrome P450 (CYP) expression. However, the exact molecular mechanism is still unknown. We investigated that the effects of NF-kappaB and pregnane X receptor (PXR) activity on P-gp and CYP3A expression in mouse brain endothelial (bEnd.3) cells treated with l-glutamate (mimicking the seizure conditions), CBZ (mimicking the AED treating conditions) or both (l glutamate plus CBZ) through qPCR and Western blotting assay. Mean fluorescence intensity was used to observe P-gp efflux function by analysis of intracellular Rhodamine123 (Rho123) accumulation. P-gp, CYP3A, PXR and NF-kappaB p65 were elevated in bEnd.3 cells incubated with l-glutamate, CBZ or CBZ pretreated by l glutamate for 30 min. Both the mRNA and protein levels of P-gp and CYP3A were remarkably reduced by PXR or NF-kappaB p65 knock-down by siRNA transfections. The decreased intracellular accumulation of Rho123 suggested that the expression of P gp was enhanced in bEnd.3 cells. These data suggested that overexpression of P-gp and CYP3A during seizures and treated with CBZ may be regulated by PXR or NF kappaB p65 activity and expression, which revealed a mechanism underlying the development of DRE. PMID- 30312754 TI - Distinct behavioral response of primary motor cortex stimulation in itch and pain after burn injury. AB - It is still unclear whether chronic neuropathic pain and itch share similar neural mechanisms. They are two of the most commonly reported challenges following a burn injury and can be some of the most difficult to treat. Transcranial direct current stimulation (tDCS) has previously been studied as a method to modulate pain related neural circuits. Therefore, we aimed to test the effects of tDCS on post-burn neuropathic pain and itch as to understand whether this would induce a simultaneous modulation of these two sensory manifestations. We conducted a pilot randomized controlled clinical trial comprised of two phases of active or sham M1 tDCS (Phase I: 10 sessions followed by a follow-up period of 8 weeks; Phase II: additional 5 sessions followed by a follow-up period of 8 weeks, and a final visit 12 months from baseline). Pain levels were assessed with the Brief Pain Inventory (BPI) and levels of itch severity were assessed with the Visual Analogue Scale (VAS). Measurements were collected at baseline, after the stimulation periods, at 2, 4 and 8-week follow up both for Phase I and II, and at the final visit. Sixteen patients were assigned to the active group and 15 to the sham group. Ten sessions of active tDCS did not reduce the level of pain or itch. We identified that itch levels were reduced at 2-week follow-up after the sham tDCS session, while no placebo effect was found for the active group. No difference between active and sham groups was observed for pain. We did not find any treatment effects during Phase II. Based on these findings, it seems that an important placebo effect occurred during sham tDCS for itch, while active M1 tDCS seems to disrupt sensory compensatory mechanisms. We hypothesize that pain and itch are complementary but distinct mechanisms of adaptation after peripheral sensory injury following a burn injury and need to be treated differently. PMID- 30312755 TI - CD3+/CD19+ Depleted Matched and Mismatched Unrelated Donor Hematopoietic Stem Cell Transplant with Targeted T Cell Addback Is Associated with Excellent Outcomes in Pediatric Patients with Nonmalignant Hematologic Disorders. AB - Unrelated donor hematopoietic stem cell transplantation (HSCT) is increasingly being used to cure nonmalignant hematologic diseases (NMHD) in patients who lack HLA matched related donors. Both graft rejection and graft-versus-host disease (GVHD) remain major barriers to safe and effective transplant for these patients requiring unrelated donors. Partial T cell depletion combined with peripheral stem cell transplantation (pTCD-PSCT) has the potential advantages of providing a high stem cell dose to facilitate rapid engraftment, maintaining cells that may facilitate engraftment, and decreasing GVHD risk compared with T cell-replete HSCT. Here, we report a single-institution, retrospective experience of unrelated donor pTCD-PSCT for pediatric patients with NMHD. From 2014 to 2017, 12 pediatric patients with transfusion-dependent NMHD underwent matched unrelated donor (MUD) or mismatched unrelated donor (MMUD) pTCD HSCT in our center using disease specific conditioning. Donor PSCs underwent CD3+ T cell and CD19+ B cell depletion using CliniMACS, followed by a targeted addback of 1 * 105 CD3+ T cells/kg to the graft before infusion. All 12 patients demonstrated rapid trilinear engraftment. At a median follow-up of 740 days (range, 279 to 1466), all patients were alive with over 92% total peripheral blood donor chimerism and without transfusion dependence or recurrence of their underlying hematologic disease. Immune reconstitution was rapid and comparable with T cell-replete HSCT. No patients developed severe acute GVHD (grades III to IV) or chronic extensive GVHD, and all patients had discontinued systemic immune suppression. Viral reactivations were common, but no patient developed symptoms of life-threatening infectious disease. Our data indicate that MUD and MMUD pTCD-PSCTs are safe and effective approaches that enable rapid engraftment and immune reconstitution, prevent severe GVHD, and expand availability of HSCT to any patients with NMHD who have closely MUDs. PMID- 30312756 TI - Mitral isthmus ablation: A hierarchical approach guided by electroanatomic correlation. PMID- 30312757 TI - Impact of dense "smoke" detected on transesophageal echocardiography on stroke risk in patients with atrial fibrillation undergoing catheter ablation. AB - BACKGROUND: Spontaneous echocardiographic contrast ("smoke") within the left atrial cavity on transesophageal echocardiography (TEE) suggests low blood flow velocities in the heart that may lead to thromboembolic (TE) events. OBJECTIVE: The purpose of this study was to evaluate the risk of TE events in the periprocedural period and at long-term follow-up in atrial fibrillation (AF) patients having dense smoke on preprocedural TEE. METHODS: A total of 2511 patients undergoing AF ablation were included in this analysis. They were classified as group 1 (dense smoke detected on TEE at baseline; n = 234) and group 2 (no smoke on baseline TEE; n = 2277). Patients were followed up for TE events, which included both stroke and transient ischemic attacks (TIAs). In order to attenuate the observed imbalance in baseline covariates between the study groups, a propensity score matching technique was used (covariates were age, sex, AF type, diabetes, and CHADS2VASc score). RESULTS: In the periprocedural period, no TE events were reported in group 1 and 3 events (0.13%) were reported in group 2. At follow-up of 6.62 +/- 2.01 years, 6 (2.6%) TE complications (2 TIA, 4 stroke) occurred in group 1 and 16 (0.70%) TE complications (6 TIA, 10 stroke) in group 2 (P = .004). In the propensity-matched population, 6 (2.56%) TE complications occurred in group 1 and 1 (0.2%) in group 2 (P = .007). CONCLUSION: In our study population, the presence of dense left atrial smoke did not show any correlation with periprocedural TE events in patients undergoing catheter ablation with uninterrupted anticoagulation. However, significant association was observed with late stroke/TIA, irrespective of CHA2DS2-VASc score. PMID- 30312758 TI - PREFACE: Antiepileptogenesis following traumatic brain injury. PMID- 30312759 TI - Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention. AB - Cancer is the primary cause of human mortality in most countries. This tendency has increased as various medical therapeutics have advanced, which suggests that we cannot escape carcinogenesis, although the final outcome may be modified by exposomes and statistics. Cancer is classified by its cellular differentiation. Mesothelial cells are distinct in that they line somatic cavities, facilitating the smooth movement of organs, but are not exposed to the external environment. Malignant mesothelioma, or simply mesothelioma, develops either in the pleural, peritoneal or pericardial cavities, or in the tunica vaginalis testes. Mesothelioma has been a relatively rare cancer but is socially important due to its association with asbestos exposure, caused by modern industrial development. The major pathogenic mechanisms include oxidative stress either via catalytic reactions against the asbestos surface or frustrated phagocytosis of macrophages, and specific adsorption of hemoglobin and histones by asbestos fibers in the presence of phagocytic activity of mesothelial cells. Multiwall carbon nanotubes of ~50 nm-diameter, additionally adsorbing transferrin, are similarly carcinogenic to mesothelial cells in rodents and were thus classified as Group 2B carcinogens. Genetic alterations found in human and rat mesothelioma notably contain changes found in other excess iron-induced carcinogenesis models. Phlebotomy and iron chelation therapies have been successful in the prevention of mesothelioma in rats. Alternatively, loading of oxidative stress by non-thermal plasma to mesothelioma cells causes ferroptosis. Therefore, carcinogenesis by foreign fibrous inorganic materials may overlap the uncovered molecular mechanisms of birth of life and its evolution. PMID- 30312760 TI - Up-regulation of COX-2 and mPGES-1 by 27-hydroxycholesterol and 4-hydroxynonenal: A crucial role in atherosclerotic plaque instability. AB - Atherosclerosis is currently understood to be mainly the consequence of a complicated inflammatory process at the different stages of plaque development. Among the several inflammatory molecules involved, up-regulation of the functional cyclooxygenase 2/membrane-bound prostaglandin E synthase 1 (COX 2/mPGES-1) axis plays a key role in plaque development. Excessive production of oxidized lipids, following low-density lipoprotein (LDL) oxidation, is a characteristic feature of atherosclerosis. Among the oxidized lipids of LDLs, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE) substantially accumulate in the atherosclerotic plaque, contributing to its progression and instability through a variety of processes. This study shows that 27-OH and HNE promote up-regulation of both the inducible enzymes COX-2 and mPGES 1, leading to increased production of prostaglandin (PG) E2 and inducible nitric oxide synthase, and the subsequent release of nitric oxide in human promonocytic U937 cells. The study also examined the potential involvement of the functionally coupled COX-2/mPGES-1 in enhancing the production of certain pro-inflammatory cytokines and of matrix metalloproteinase 9 by U937 cells. This enhancement is presumably due to the induction of PGE2 synthesis, as a result of the up regulation of the COX-2/mPGES-1, stimulated by the two oxidized lipids, 27-OH and HNE. Induction of PGE2 synthesis might thus be a mechanism of plaque instability and eventual rupture, contributing to matrix metalloproteinase production by activated macrophages. PMID- 30312761 TI - Xanthine oxidase is hyper-active in Duchenne muscular dystrophy. AB - Generation of superoxide by xanthine oxidase can be stimulated under ischemic and aberrant calcium homeostasis. Because patients and mice with Duchenne muscular dystrophy (DMD) suffer from ischemia and excessive calcium influx, we tested the hypothesis that xanthine oxidase activity is elevated and contributes to disease pathology. Xanthine oxidase activity was measured by urinary isoxanthopterin in DMD patients at rest and in response to exercise. Urinary isoxanthopterin/creatinine was elevated compared to age-matched controls and Becker muscular dystrophy (BMD) patients. Concentrations were also increased after a six minute walk test in ambulatory patients. We also measured urinary isoxanthopterin in wildtype mice and a number of dystrophic mouse models; the DMD mouse model (mdx), mdx mice overexpressing a variety of transgenic miniaturized and chimeric skeletal muscle-specific dystrophins and utrophin and the beta sarcoglycan deficient (Scgb-/-) mouse which represents type 2E human limb-girdle muscular dystrophy. Mdx and Scgb-/-mice had greater urinary isoxanthopterin/creatinine than wildtype mice while mdx mice expressing dystrophin or utrophin linking the extracellular matrix to the actin cytoskeleton were not different than wildtype. We also measured higher levels of urinary ortho tyrosine in humans and mice deficient for dystrophin to confirm elevated oxidative stress. Surprisingly, mdx had lower xanthine oxidase protein levels and higher mRNA in gastrocnemius muscle compared to wildtype mice, however, the enzymatic activity of skeletal muscle xanthine oxidase was elevated above wildtype and a transgenic rescued mdx mouse (DysDeltaMTB-mdx). Downhill treadmill running also caused significant increases in mdx urinary isoxanthopterin that was prevented with the xanthine oxidase inhibitor allopurinol. Similarly, in vitro eccentric contraction-induced force drop of mdx muscle was attenuated by the allopurinol metabolite, oxypurinol. Together, our data suggests hyper-activity of xanthine oxidase in DMD, identifies xanthine oxidase activity as a contributing factor in eccentric contraction-induced force drop of dystrophin-deficient skeletal muscle and highlights the potential of isoxanthopterin as a noninvasive biomarker in DMD. PMID- 30312762 TI - Propofol inhibits endogenous formyl peptide-induced neutrophil activation and alleviates lung injury. AB - Critically ill patients have a high risk of sepsis. Various studies have demonstrated that propofol has anti-inflammatory effects that may benefit critically ill patients who require anesthesia. However, the mechanism and therapeutic effect remain incompletely understood. Our previous data suggest that propofol can act as a formyl peptide receptor 1 (FPR1) antagonist. Here, we hypothesize that propofol mitigates sepsis-induced acute lung injury (ALI) by inhibiting mitochondria-derived N-formyl peptide-mediated neutrophil activation. Oxidative stress caused by activated neutrophils is involved in the pathogenesis of ALI. In human neutrophils, propofol competitively reduced the release of superoxide and associated reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide, suggesting that propofol effectively suppresses neutrophilic oxidative stress. In addition, propofol significantly inhibited fMMYALF-induced elastase release, chemotaxis, calcium mobilization, and phosphorylation of protein kinase B and mitogen-activated protein kinases. These results indicate that propofol suppresses neutrophil activation by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Furthermore, propofol alleviated alveolar wall disruption, edematous changes, and neutrophil infiltration in lipopolysaccharide induced ALI in mice. Noticeably, propofol improved the survival of sepsis mice. This study indicates that the anti-neutrophil effects of propofol may benefit critically ill septic patients. PMID- 30312763 TI - Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice. AB - Oxidative stress induced by cigarette smoke and other environmental pollutants contributes to refractory asthma. To better understand the role of smoking in asthma, we investigated the effects of cigarette smoke on allergic airway responses in mice and examined expression of nuclear factor-E2-related factor-2 (Nrf2) and its downstream factors, because Nrf2 is known to play a pivotal role in antioxidant responses. OVA-sensitized and challenged BALB/c mice were exposed to cigarette smoke and then treated with dexamethasone, sulforaphane (an activator of Nrf2), or their combination. Upon exposure to cigarette smoke, Nrf2 and associated transcripts were upregulated in response to oxidative stress, and asthmatic responses were steroid resistant. In OVA-sensitized and challenged mice exposed to cigarette smoke and treated with sulforaphane, Nrf2-mediated antioxidant responses were upregulated to a greater extent, and steroid sensitivity of asthmatic responses was restored. Moreover, the expression and activity of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness, was reduced in mice exposed to cigarette smoke, but restored by sulforaphane treatment. No effects of sulforaphane were observed in Nrf2 deficient mice. These findings indicate that cigarette smoke induces steroid unresponsiveness in asthmatic airways, and that sulforaphane restores steroid sensitivity via upregulation of Nrf2 and enhancement of HDAC2 expression and activity. Thus, Nrf2 may serve as a potential molecular target for cigarette smoke-related refractory asthma resistant to steroid therapy. PMID- 30312764 TI - Understanding the Etiology of Heart Failure Among the Rural Poor in Sub-Saharan Africa: A 10-Year Experience From District Hospitals in Rwanda. AB - BACKGROUND: Heart failure is a significant cause of morbidity and mortality in sub-Saharan Africa. Our understanding of the heart failure burden in this region has been limited mainly to registries from urban referral centers. Starting in 2006, a nurse-driven strategy was initiated to provide echocardiography and decentralized heart failure care within noncommunicable disease (NCD) clinics in rural district hospitals in Rwanda. METHODS AND RESULTS: We conducted a retrospective review of patients with cardiologist-confirmed heart failure treated at 3 district hospital NCD clinics in Rwanda from 2006 to 2017 to determine patient clinical characteristics and disease distribution. Over 10 years, 719 patients with confirmed heart failure were identified. Median age was 27 years overall, and 42 years in adults. Thirty-six percent were children (age <18 years), 68% were female, and 78% of adults were farmers. At entry, 39% were in New York Heart Association functional class III-IV. Among children, congenital heart disease (52%) and rheumatic heart disease (36%) were most common. In adults, cardiomyopathy (40%), rheumatic heart disease (27%), and hypertensive heart disease (13%) were most common. No patients were diagnosed with ischemic cardiomyopathy. CONCLUSIONS: The results of the largest single-country heart failure cohort from rural sub-Saharan Africa demonstrate a persistent burden of rheumatic disease and nonischemic cardiomyopathies. PMID- 30312765 TI - Spatiotemporal expression of NDRG2 in the human fetal brain. AB - N-myc downstream-regulated gene 2 (NDRG2) has been implicated in the development of central nervous system and brain diseases such as brain tumors, ischemic stroke and neurodegenerative disorders. However, it remains unclear that the spatiotemporal distribution of NDRG2 in the human fetal brain. In this study, we examined the expression pattern of NDRG2 in different regions of human fetal brain at 16-28 gestational weeks (GWs) by using RT-PCR, western blot and immunohistochemistry. Firstly, RT-PCR revealed that mRNA of NDRG2 was detected in the human brain regions of fetuses at 16-28 GWs such as medulla oblongata (MdO), mesencephalon (MeE), cerebellum (Cbl), frontal lobe (Fr), ventricular (VZ)/subventricular zone (SVZ) and hippocampus (hip), and the expressions of NDRG2 mRNA in these human fetal brain regions were increased with gestational maturation. Furthermore, western blot and immunohistochemistry results revealed that at 28 GWs, the expression of NDRG2 protein was restricted to the MdO's olivary nucleus, MeE's aqueduct, cerebellar internal granular layers, cerebral cortex of the Fr, VZ/SVZ of lateral ventricle, and hippocampal dentate gyrus, and highest expression in the VZ/SVZ, and lowest in the MeE. Finally, double immunohistochemistry results showed that NDRG2 in the MdO, Cbl and VZ/SV at 28 GWS was mainly expressed in neurons (NeuN positive cells), and in some astrocytes (GFAP positive cells). Taken together, these results suggest that NDRG2 is mainly expressed in human fetal neurons of various brain regions during development, which may be involved in neuronal growth and maturation. PMID- 30312766 TI - Educational training in laparoscopic gynecological surgery based on ethanol glycerol-lysoformin-preserved body donors. AB - PURPOSE: Educational training of laparoscopic skills performed on body donors is considered the gold standard prior to surgery in living patients. Appropriate, safe, and feasible fixation of body donors, reflecting true-to-life conditions of tissues, is an essential prerequisite for training workshops. MATERIALS AND METHODS: Here we describe and evaluate a modified ethanol-glycerol-lysoformin based fixation technique. Body donors were fixed by perfusion (70% ethanol, 30% glycerol, 0.3% lysoformin; ca. 20l) via femoral artery and stored in a humid atmosphere (1% thymol) at 4 degrees C. Technical equipment included a mobile operating table, endoscopy system with gas insufflation, suction/irrigation pump, standard and electrosurgical instruments. The tissue properties of ethanol glycerol-lysoformin-fixed body donors and their suitability for laparoscopic surgery were tested and compared to the in vivo situation. RESULTS: Modified ethanol-glycerol-lysoformin fixation was a simple, cost-efficient and hazard-free procedure, resulting in near-to-life tissue conditions regarding consistency and flexibility, with moderate discoloration and greater viscosity of organs. Key laparoscopic procedures (trocar handling, pneumoperitoneum, blunt/sharp dissection, partial/total removal of organs, bi- or monopolar electrosurgery, suturing techniques) could be performed without difficulty. Multiple reuse of body donors was feasible over one year. Compared to the in vivo situation, the investigation of body donors required a greater degree of gas insufflation and more energy for electrosurgery. CONCLUSIONS: Modified ethanol-glycerol-lysoformin fixation applied to body donors permitted laparoscopic surgery in a realistic and practical manner. Due to its logistic advantages, this technique provides appropriate conditions to train laparoscopic skills and implement novel minimally invasive approaches. PMID- 30312767 TI - Quantitative articular cartilage sub-surface defect assessment using optical coherence tomography: An in-vitro study. AB - Assessment of structural cartilage damage is of high scientific and clinical interest. Optical Coherence Tomography (OCT) is a light-based cross-sectional imaging modality that allows the real-time assessment of articular cartilage at near-histological resolution. Algorithm routines for the detection, parameterization and quantification of sub-surface defects as assessed by OCT were implemented and validated in this study. Standard defects of 0.9mm, 1.1mm and 1.3mm diameter were created in the sub-surface regions of macroscopically intact human articular cartilage samples (n=60 defects of variable sizes in n=20 samples). Subsequently, samples were scanned by 3D OCT and defect size, height, width and distance to the surface were determined based on the algorithm and related to manual measurements. Histology served as the standard-of-reference. Statistical analysis included one-way ANOVA's and Tukey's post-hoc test. All defects were correctly identified by the algorithm, while five structural tissue inhomogeneities were erroneously marked as defects (sensitivity 100%, specificity: 92.3%). Inter-modality analysis revealed no significant differences in terms of defect area, height or width within the different defect sizes, while the distance to the surface was significantly different. The comprehensive algorithm-based characterization of cartilage defects is consistent and reliable and allows their more objective evaluation. Given further research in this field, OCT and OCT-based quantitative measures may become clinically useful in the arthroscopic detection and evaluation of sub-surface cartilage defects. PMID- 30312768 TI - Boron inhibits apoptosis in hyperapoptosis condition: Acts by stabilizing the mitochondrial membrane and inhibiting matrix remodeling. AB - An abnormally high apoptosis has been associated with a number of clinical conditions including embryonal malformations and various pathologies such as neuronal degeneration and diabetes. In this study, boron is reported to inhibit apoptosis in hyperapoptosis conditions as demonstrated in a model of hyperapoptosis. Boron is a metalloid which is present in food in small amounts and is suggested here to inhibit apoptosis by stabilizing the mitochondrial membrane structure, thus preventing matrix remodeling and the release of cytochrome c, an apoptosis-inducer protein from the mitochondrion. The protective effect was assessed by measuring the changes in mitochondrial membrane potential, the levels of cytochrome c and downstream activation of caspase 3, besides phosphatidylserine exposure on the cell surface and DNA damage. The study has implication in clinical conditions characterized by hyperapoptosis as seen in certain embryonal malformations and various pathologies. PMID- 30312769 TI - Long-chain polyphosphate in osteoblast matrix vesicles: Enrichment and inhibition of mineralization. AB - BACKGROUND: Inorganic polyphosphate (polyP) is a fundamental and ubiquitous molecule in prokaryotes and eukaryotes. PolyP has been found in mammalian tissues with particularly high levels of long-chain polyP in bone and cartilage where critical questions remain as to its localization and function. Here, we investigated polyP presence and function in osteoblast-like SaOS-2 cells and cell derived matrix vesicles (MVs), the initial sites of bone mineral formation. METHODS: PolyP was quantified by 4',6-diamidino-2-phenylindole (DAPI) fluorescence and characterized by enzymatic methods coupled to urea polyacrylamide gel electrophoresis. Transmission electron microscopy and confocal microscopy were used to investigate polyP localization. A chicken embryo cartilage model was used to investigate the effect of polyP on mineralization. RESULTS: PolyP increased in concentration as SaOS-2 cells matured and mineralized. Particularly high levels of polyP were observed in MVs. The average length of MV polyP was determined to be longer than 196 Pi residues by gel chromatography. Electron micrographs of MVs, stained by two polyP-specific staining approaches, revealed polyP localization in the vicinity of the MV membrane. Additional extracellular polyP binds to MVs and inhibits MV-induced hydroxyapatite formation. CONCLUSION: PolyP is highly enriched in matrix vesicles and can inhibit apatite formation. PolyP may be hydrolysed to phosphate for further mineralization in the extracellular matrix. GENERAL SIGNIFICANCE: PolyP is a unique yet underappreciated macromolecule which plays a critical role in extracellular mineralization in matrix vesicles. PMID- 30312770 TI - MV-mimicking micelles loaded with PEG-serine-ACP nanoparticles to achieve biomimetic intra/extra fibrillar mineralization of collagen in vitro. AB - Since their discovery, matrix vesicles (MVs) containing minerals have received considerable attention for their role in the mineralization of bone, dentin and calcified cartilage. Additionally, MVs' association with collagen fibrils, which serve as the scaffold for calcification in the organic matrix, has been repeatedly highlighted. The primary purpose of the present study was to establish a MVs-mimicking model (PEG-S-ACP/micelle) in vitro for studying the exact mechanism of MVs-mediated extra/intra fibrillar mineralization of collagen in vivo. In this study, high-concentration serine was used to stabilize the amorphous calcium phosphate (S-ACP), which was subsequently mixed with polyethylene glycol (PEG) to form PEG-S-ACP nanoparticles. The nanoparticles were loaded in the polysorbate 80 micelle through a micelle self-assembly process in an aqueous environment. This MVs-mimicking model is referred to as the PEG-S ACP/micelle model. By adjusting the pH and surface tension of the PEG-S ACP/micelle, two forms of minerals (crystalline mineral nodules and ACP nanoparticles) were released to achieve the extrafibrillar and intrafibrillar mineralization, respectively. This in vitro mineralization process reproduced the mineral nodules mediating in vivo extrafibrillar mineralization and provided key insights into a possible mechanism of biomineralization by which in vivo intrafibrillar mineralization could be induced by ACP nanoparticles released from MVs. Also, the PEG-S-ACP/micelle model provides a promising methodology to prepare mineralized collagen scaffolds for repairing bone defects in bone tissue engineering. PMID- 30312771 TI - A multiparametric analysis of the synergistic impact of anti-Parkinson's drugs on the fibrillation of human serum albumin. AB - Protein aggregation have been associated with several human neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. There are several small molecules that can reduce aggregation of proteins. The present study aimed to test the hypothesis that the application of more than one inhibitor either simultaneously or consecutively may result in more efficient inhibition of protein aggregation. To this end, the anti-amyloidogenic behaviour of benserazide hydrochloride (BH) and levodopa (LD) individually and in combination (BH + LD) was investigated using various biophysical, microscopic, and computational techniques. BH, LD, and BH + LD treatments showed inhibitory effects on protein aggregation and had the ability to minimise the amyloid-induced cytotoxicity in human neuroblastoma cell line (SH-SY5Y). The two drugs in combination showed synergism (combination index, CI < 1) between them. These drugs also destabilised the preformed fibrils of human serum albumin (HSA). Our studies consistently showed that the BH + LD treatment showed highest efficacy towards inhibition and disaggregation of amyloid fibrils in comparison to treatment with BH and LD individually. Therefore, application of drugs in combination against fibrillogenesis may represent a new route for development of means for prevention or delaying of the aggregation-related diseases. PMID- 30312772 TI - Interaction of gamma-conglutin from Lupinus albus with model phospholipid membranes: Investigations on structure, thermal stability and oligomerization status. AB - Interaction with model phospholipid membranes of lupin seed gamma-conglutin, a glycaemia-lowering protein from Lupinus albus seeds, has been studied by means of Fourier-Transform infrared spectroscopy at p2H 7.0 and at p2H 4.5. The protein maintains the same secondary structure both at p2H 7.0 and at p2H 4.5, but at p2H 7.0 a higher 1H/2H exchange was observed, indicating a greater solvent accessibility. The difference in Tm and TD1/2 of the protein at the abovementioned p2H's has been calculated around 20 degrees C. Infrared measurements have been then performed in the presence of DMPG and DOPA at p2H 4.5. DMPG showed a little destabilizing effect while DOPA exerted a great stabilizing effect, increasing the Tm of gamma-conglutin at p2H 4.5 of more than 20 degrees C. Since gamma-conglutin at p2H 4.5 is in the monomeric form, the interaction with DOPA likely promotes the oligomerization even at p2H 4.5. Interaction between DMPG or DOPA and gamma-conglutin has been confirmed by turbidity experiments with DMPC:DMPG or DOPC:DOPA SUVs. Turbidity data also showed high-affinity binding of gamma-conglutin to anionic SUVs made up with DOPA. The molecular features outlined in this study are relevant to address the applicative exploitation and to delineate a deeper comprehension of the natural functional role of gamma-conglutin. PMID- 30312773 TI - The interaction of beta2-glycoprotein I with lysophosphatidic acid in platelet aggregation and blood clotting. AB - beta2-Glycoprotein I (beta2-GPI) is a plasma protein that binds to oxidized low density lipoprotein (LDL) and negatively charged substances, and inhibits platelet activation and blood coagulation. In this study, we investigated the interaction of beta2-GPI with a negatively charged lysophosphatidic acid (LPA) in platelet aggregation and blood clotting. Two negatively charged lysophospholipids, LPA and lysophosphatidylserine, specifically inhibited the binding of beta2-GPI to oxidized LDL in a concentration-dependent manner. Intrinsic tryptophan fluorescence studies demonstrated that emission intensity of beta2-GPI decreases in an LPA-concentration-dependent manner without a shift in wavelength maxima. LPA specifically induced the aggregation of beta2-GPI in phosphate-buffered saline, and in incubated plasma and serum, both of which are known to accumulate LPA by the action of lecithin-cholesterol acyltransferase and lysophospholipase D/autotaxin. beta2-GPI aggregated by LPA did not inhibit activated von Willebrand factor-induced aggregation, and did not prolong the activated partial thromboplastin time in blood plasma, in contrast to non aggregated beta2-GPI. These results suggest that beta2-GPI aggregated by the binding to LPA fails to inhibit platelet aggregation and blood clotting in contrast to non-aggregated beta2-GPI. PMID- 30312774 TI - Patient-reported outcomes following surgery for degenerative spondylolitshtesis: comparison of a universal and multitier health care system. AB - STUDY DESIGN: Retrospective review of results from a prospectively collected Canadian cohort in comparison to published literature. OBJECTIVES: (1) To investigate whether patients in a universal health care system have different outcomes than those in a multitier health care system in surgical management of degenerative spondylolisthesis (DS). (2) To identify independent factors predictive of outcome in surgical DS patients. SUMMARY OF BACKGROUND DATA: Canada has a national health insurance program with unique properties. It is a single payer system, coverage is universal, and access to specialist care requires referral by the primary care physician. The United States on the other hand is a multitier public/private payer system with more rapid access for insured patients to specialist care. METHODS: Surgical DS patients treated between 2013 and 2016 in Canada were identified through the Canadian Spine Outcome Research Network (CSORN) database, a national registry that prospectively enrolls consecutive patients with spinal pathology from 16 tertiary care academic hospitals. This population was compared with the surgical DS arm of patients treated in the Spine Patients Outcome Research Trial (SPORT) study. We compared baseline demographics, spine-related, and health-related quality of life (HRQOL) outcomes at 3 months and 1 year. Multivariate analysis was used to identify factors predictive of outcome in surgical DS patients. RESULTS: The CSORN cohort of 213 patients was compared with the SPORT cohort of 248 patients. Patients in the CSORN cohort were younger (mean age 60.1 vs. 65.2; p<.001), comprised fewer females (60.1% vs. 67.7%; p=.09), and had a higher proportion of smokers (23.3% vs. 8.9%; p<.001). The SPORT cohort had more patients receiving compensation (14.6% vs. 7.7%; p<.001). The CSORN cohort consisted of patients with slightly greater baseline disability (Oswestry disability index scores: 47.7 vs. 44.0; p=.008) and had more patients with symptom duration of greater than 6 months (93.7% vs. 62.1%; p<.001). The CSORN cohort showed greater satisfaction with surgical results at 3 months (91.1% vs. 66.1% somewhat or very satisfied; p<.01) and 1 year (88.2% vs. 71.0%, p<.01). Improvements in back and leg pain were similar comparing the two cohorts. On multivariate analysis, duration of symptoms, treatment group (CSORN vs. SPORT) or insurance type (public/Medicare/Medicaid vs. Private/Employer) predicted higher level of postoperative satisfaction. Baseline depression was also associated with worse Oswestry disability index at 1-year postoperative follow-up in both cohorts. CONCLUSIONS: Surgical DS patients treated in Canada (CSORN cohort) reported higher levels of satisfaction than those treated in the United States (SPORT cohort) despite similar to slightly worse baseline HRQOL measures. Symptom duration and insurance type appeared to impact satisfaction levels. Improvements in other patient-reported health-related quality of life measures were similar between the cohorts. PMID- 30312775 TI - Fishing for collagen function: About development, regeneration and disease. AB - Collagens are the most abundant vertebrate extracellular matrix proteins. They form a superfamily of 28 members that show a remarkable diversity in molecular and supramolecular organization, tissue distribution and function and mutations in collagen genes result in a wide range of inherited connective tissue diseases. In the recent years, unexpected and very diverse regulatory and mechanical collagen functions have been reported. But the structural and functional landscape of the collagen superfamily is still far from being complete. Zebrafish has emerged over the last decades as a powerful model to interrogate gene function and there are numerous advantages of using zebrafish for collagen research, including recent advances in genome editing technologies and the characterization of the zebrafish matrisome. One can confidently predict that zebrafish will rapidly become a popular vertebrate model to investigate the role of collagens in development, disease and regeneration as discussed in this chapter. PMID- 30312776 TI - The influence of posterior glenohumeral joint capsule tightness and humeral retroversion on clinical measurements. AB - OBJECTIVES: To assess the influence of posterior capsule tightness and humeral retroversion on shoulder motion measurements. DESIGN: Cross-Sectional study. SETTING: Controlled university laboratory. PARTICIPANTS: 75 asymptomatic individuals were assigned to one of 4 groups: control (n = 28); posterior capsule tightness only (n = 17); humeral retroversion only (n = 15); and combined posterior capsule tightness and retroversion (n = 15). MAIN OUTCOME MEASURES: Six clinical measurements were compared across groups: bicipital forearm angle, low flexion, glenohumeral internal and external rotation, horizontal adduction and extension with internal rotation. RESULTS: The group with both adaptations had decreased internal rotation compared to the control and retroversion only groups, as well as increased external rotation compared to the control and posterior capsule only groups. There were no between group differences for the horizontal adduction or extension with internal rotation measurements. The retroversion only and combined groups showed decreased bicipital forearm angle compared with the control and posterior tightness groups. The posterior capsule tightness and combined groups demonstrated decreased low flexion compared to the other groups. CONCLUSION: The combination of osseous and soft tissue adaptions alter shoulder motion measures more than a single adaption, making a comprehensive clinical assessment vital when managing individuals with shoulder pain. PMID- 30312777 TI - Manganese coordination compounds of mefenamic acid: In vitro screening and in silico prediction of biological activity. AB - The in vitro and in silico biological properties of two manganese complexes with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) in the presence or absence of salicylaldoxime (Eta2sao), i.e. [MUn6(O)2(mef)2(sao)6(CH3OH)4] 1, and [MUn(mef)2(CH3OH)4] 2, respectively, are presented in the present contribution. More specifically, the in vitro biological activity of the complexes was investigated by studying their affinity to calf-thymus DNA (by diverse spectroscopic and physicochemical techniques) and their binding towards bovine (BSA) or human serum albumin (HSA) (by fluorescence emission spectroscopy). Molecular docking simulations on the crystal structures of HSA and DNA, exploring in silico the ability of the complexes to bind to these macromolecules, were also employed in order to explain the described in vitro activity of the compounds. Furthermore, in silico predictive tools have been employed to study the properties of the most active complex 2 to act as anticancer agent, in continuation of the previously reported cytotoxic activity. It is adopted in silico studies on a multitude of proteins involved in cancer growth, as well as prediction of drug-induced changes of gene expression profile, protein- and mRNA based prediction results, prediction of sites of metabolism, quantitative prediction of antitarget interaction profiles etc. PMID- 30312778 TI - Early angiogenesis detected by PET imaging with 64Cu-NODAGA-RGD is predictive of bone critical defect repair. AB - Therapies using stem cells may be applicable to all fields of regenerative medicine, including craniomaxillofacial surgery. Dental pulp stem cells (DPSCs) have demonstrated in vitro and in vivo osteogenic and proangiogenic properties. The aim of the study was to evaluate whether early angiogenesis investigated by nuclear imaging can predict bone formation within a mouse critical bone defect. Two symmetrical calvarial critical-sized defects were created. Defects were left empty or filled with i) DPSC-containing dense collagen scaffold, ii) 5% hypoxia primed DPSC-containing dense collagen scaffold, iii) acellular dense collagen scaffold, or iv) left empty. Early angiogenesis assessed by PET using 64Cu-NODAGA RGD as a tracer was found to be correlated with bone formation determined by micro-CT within the defects from day 30, and to be correlated to the late calcium apposition observed at day 90 using 18F-Na PET. These results suggest that nuclear imaging of angiogenesis, a technique applicable in clinical practice, is a promising approach for early prediction of bone grafting outcome, thus potentially allowing to anticipate alternative regenerative strategies. STATEMENT OF SIGNIFICANCE: Bone defects are a major concern in medicine. As life expectancy increases, the number of bone lesions grows, and occurring complications lead to a delay or even lack of consolidation. Therefore, to be able to predict healing or the absence of scarring at early times would be very interesting. This would not "waste time" for the patient. We report here that early nuclear imaging of angiogenesis, using 64Cu-NODAGA-RGD as a tracer, associated with nuclear imaging of mineralization, using 18F-Na as a tracer, is correlated to late bone healing objectivized by classical histology and microtomography. This nuclear imaging represents a promising approach for early prediction of bone grafting outcome in clinical practice, thus potentially allowing to anticipate alternative regenerative strategies. PMID- 30312779 TI - Golden oldies and silver brains: Deficits, preservation, learning, and rehabilitation effects of music in ageing-related neurological disorders. AB - During the last decades, there have been major advances in mapping the brain regions that underlie our ability to perceive, experience, and produce music and how musical training can shape the structure and function of the brain. This progress has fueled and renewed clinical interest towards uncovering the neural basis for the impaired or preserved processing of music in different neurological disorders and how music-based interventions can be used in their rehabilitation and care. This article reviews our contribution to and the state-of-the-art of this field. We will provide a short overview outlining the key brain networks that participate in the processing of music and singing in the healthy brain and then present recent findings on the following key music-related research topics in neurological disorders: (i) the neural architecture underlying deficient processing of music (amusia), (ii) the preservation of singing in aphasia and music-evoked emotions and memories in Alzheimer's disease, (iii) the mnemonic impact of songs as a verbal learning tool, and (iv) the cognitive, emotional, and neural efficacy of music-based interventions and activities in the rehabilitation and care of major ageing-related neurological illnesses (stroke, Alzheimer's disease, and Parkinson's disease). PMID- 30312780 TI - Interhemispheric interactions during sentence comprehension in patients with aphasia. AB - Right-hemisphere involvement in language processing following left-hemisphere damage may reflect either compensatory processes, or a release from homotopic transcallosal inhibition, resulting in excessive right-to-left suppression that is maladaptive for language performance. Using fMRI, we assessed inter hemispheric effective connectivity in fifteen patients with post-stroke aphasia, along with age-matched and younger controls during a sentence comprehension task. Dynamic Causal Modeling was used with four bilateral regions including inferior frontal gyri (IFG) and primary auditory cortices (A1). Despite the presence of lesions, satisfactory model fit was obtained in 9/15 patients. In young controls, the only significant homotopic connection (RA1-LA1), was excitatory, while inhibitory connections emanated from LIFG to both left and right A1's. Interestingly, these connections were also correlated with language comprehension scores in patients. The results for homotopic connections show that excitatory connectivity from RA1-to-LA1 and inhibitory connectivity from LA1-to-RA1 are associated with general auditory verbal comprehension. Moreover, negative correlations were found between sentence comprehension and top-down coupling for both heterotopic (LIFG-to-RA1) and intra-hemispheric (LIFG-to-LA1) connections. These results do not show an emergence of a new compensatory right to left excitation in patients nor do they support the existence of left to right transcallosal suppression in controls. Nevertheless, the correlations with performance in patients are consistent with some aspects of both the compensation model, and the transcallosal suppression account for the role of the RH. Altogether our results suggest that changes to both excitatory and inhibitory homotopic and heterotopic connections due to LH damage may be maladaptive, as they disrupt the normal inter-hemispheric coordination and communication. PMID- 30312781 TI - Enhanced deviant responses in patterned relative to random sound sequences. AB - The brain draws on knowledge of statistical structure in the environment to facilitate detection of new events. Understanding the nature of this representation is a key challenge in sensory neuroscience. Specifically, it is unknown whether real-time perception of rapidly-unfolding sensory signals is driven by a coarse or detailed representation of the proximal stimulus history. We recorded electroencephalography brain responses to frequency outliers in regularly-patterned (REG) versus random (RAND) tone-pip sequences which were generated anew on each trial. REG and RAND sequences were matched in frequency content and span, only differing in the specific order of the tone-pips. Stimuli were very rapid, limiting conscious reasoning in favour of automatic processing of regularity. Listeners were naive and performed an incidental visual task. Outliers within REG evoked a larger response than matched outliers in RAND. These effects arose rapidly (within 80 msec) and were underpinned by distinct sources from those classically associated with frequency-based deviance detection. These findings are consistent with the notion that the brain continually maintains a detailed representation of ongoing sensory input and that this representation shapes the processing of incoming information. Predominantly auditory-cortical sources code for frequency deviance whilst frontal sources are associated with tracking more complex sequence structure. PMID- 30312783 TI - Lexical Competition between Spoken and Literary Arabic: A New Look into the Neural Basis of Diglossia Using fMRI. AB - Diglossia in the Arabic language refers to the socio-linguistic situation in which Spoken Arabic (SA), which is the first to be acquired, is used for everyday communications, while Literary Arabic (LA), acquired at school for reading and writing, is also used for formal functions. Although some authors consider SA and LA as a first and second language, the question of how these are managed in the brain has not yet been understood. Using functional magnetic resonance brain imaging (fMRI) analysis, this study aimed at exploring the neural basis of diglossia during picture naming in two contexts. In the first, healthy young participants were instructed to name each image either in SA or LA on the basis of cue word appearing after the stimulus. In the second, they were instructed to name images either in SA or in Hebrew. Behavioral analysis showed that naming in SA was slightly easier than LA and considerably easier than Hebrew. fMRI analysis showed no difference between SA and LA. Hebrew compared to SA revealed activation differences explainable in terms of engagement of language control modules and second- to first-language effects. These findings, discussed in the light of previous findings in bilingual literature, support the view that dominance in diglossia is modality-dependent. PMID- 30312782 TI - Atypical Expression and Activation of GluN2A- and GluN2B-Containing NMDA Receptors at Ganglion Cells during Retinal Degeneration. AB - Cellular communication through chemical synapses is determined by the nature of the neurotransmitter and the composition of postsynaptic receptors. In the excitatory synapse between bipolar and ganglion cells of the retina, postsynaptic AMPA receptors mediate resting activity. During evoked response, however, more abundant and sustained levels of glutamate also activate GluN2B-containing NMDA receptors (NMDARs). This phasic recruitment of distinct glutamate receptors is essential for visual discrimination; however, the fidelity of this basic mechanism under elevated glutamate levels due to aberrant activity, a common pathophysiology, is not known. Here, in both male and female mice with retinal degeneration (rd10), a condition associated with elevated synaptic activity, we reveal that changes in synaptic input to ganglion cells altered both composition and activation of NMDARs. We found that, in contrast to wild type, the spontaneous activity of rd10 cells was largely NMDAR-dependent. Surprisingly, this activity was driven primarily by atypical activation of GluN2A -containing NMDARs, not GluN2B-NMDARs. Indeed, immunohistochemical analyses and Western blot showed greater levels of the GluN2A-NMDAR subunit expression in rd10 retina compared to wild type. Overall, these results demonstrate how aberrant signaling leads to pathway-specific alterations in NMDAR expression and function. PMID- 30312784 TI - Motor Preparation of Step Initiation: Error-related Cortical Oscillations. AB - Gait initiation can vary as a function of the available and engaged attentional resources. Conflict resolution can disrupt movement preparation and lead to "errors" in motor programming. These "errors" are physiologically useful by enabling us to adapt our motor behavior to situations with conflicting information. The objective of the present study was to analyze the patterns of cortical activation associated with motor programming errors and the corresponding error corrections. Incongruent flankers around a target arrow were used to trigger errors in anticipatory postural adjustments (APAs) prior to gait initiation; i.e. perturbed motor programming but normal execution. Thirty healthy adults performed a gait initiation task. The event-related potentials (ERPs) and event-related desynchronization (ERD) after target presentation were analyzed according to the presence or absence of an APA error. The ERP was similar in both conditions, except that the Ne and P300 peak latencies were longer for APA errors. Motor programming errors during gait initiation were characterized by longer, less intense low-beta-band ERD over the sensorimotor cortex and alpha ERS followed by stronger alpha ERD during errors. APA errors were associated with a specific alpha/beta oscillation profile over the sensorimotor cortex; these beta oscillations might be sensitive markers of non-conscious motor error and correction monitoring. PMID- 30312785 TI - Effect of Optic Flow on Postural Control in Children and Adults with Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) have been associated with sensorimotor difficulties, commonly presented by poor postural control. Postural control is necessary for all motor behaviors. However, findings concerning the effect of visual motion on postural control and the age progression of postural control in individuals with ASD are inconsistent. The aims of the present study were to examine postural responses to optic flow in children and adults with and without ASD, postural responses to optic flow in the central and peripheral visual fields, and the changes in postural responses between the child and adult groups. Thirty-three children (8-12 years old) and 33 adults (18-50 years old) with and without ASD were assessed on quiet standing for 60 seconds under conditions of varying optic flow illusions, consisting of different combinations of optic flow directions and visual field display. The results showed that postural responses to most optic flow conditions were comparable between children with and without ASD and between adults with and without ASD. However, adults with ASD appeared more responsive to forward-moving optic flow in the peripheral visual field compared with typically developed adults. The findings suggest that children and adults with ASD may not display maladaptive postural responses all the time. In addition, adults in the ASD group may have difficulties prioritizing visual information in the central visual field over visual information in the peripheral visual field when in unfamiliar environments, which may have implications in understanding their motor behaviors in new surroundings. PMID- 30312786 TI - The latent profile analysis of Chinese adolescents' anxiety: Examination and validation. AB - The main purpose of current study was to investigate the characteristics of anxiety in Chinese adolescents using Latent Profile Analysis (LPA) with the Screen for Child Anxiety Related Emotional Disorders. LPA was conducted with a sample of 2158 participants aged 12-20 years from 3 urban schools in Beijing, China. Results suggested a best-fitting model with three profiles: Low Group with Diffuse Types of Anxiety, Moderate Group with Predominant Generalized and Social Anxiety and High Group with Predominant Somatization Anxiety. Additional analyses using Regression Mixture Modeling suggested that older adolescents and girls were significantly more likely to be classified into the High Group with Predominant Somatization Anxiety. Finally, in support of the construct validity of the anxiety profiles, differential negative cognitions, especially the subscales measuring cognitions about social threat and physical threat, predicted the anxiety profiles. The current study supports an intuitive model of adolescent anxiety in a large, non-Western population with clinical implications for anxious adolescents in China. PMID- 30312787 TI - Risk Factors for Rate of Relapse and Effects of Steroid Maintenance Therapy in Patients with Autoimmune Pancreatitis: Systematic Review and Meta-analysis. AB - BACKGROUND AND AIMS: Risk for relapse after induction of remission with steroid therapy has been extensively studied in patients with autoimmune pancreatitis (AIP), but findings are equivocal. We performed a systematic review and meta analysis were to estimate the rate of rate of AIP following initial remission after steroid treatment and to identify factors associated with relapse. METHODS: Three reviewers searched MEDLINE, SCOPUS and EMBASE until July 2018 to identify studies of rate of relapse of AIP rate after induction of remission with steroid therapy. A pooled estimate was calculated using DerSimonian and Laird method for a random-effects model. This study was conducted in accordance with PRISMA guidelines RESULTS: Thirty-six studies met the inclusion criteria for meta analysis. The median follow-up time was 40.8 months. Fifty-two percent of patients were classified as having type 1 AIP. The pooled estimate of relapse rate was 33% (95% CI, 30%-37%). A higher proportion of patients with type 1 AIP had a relapse compared to patients with type 2 AIP (37.5% vs 15.9%; P<.001). We found significant heterogeneity among studies (P<.01). Long-term maintenance therapy with steroid and study quality were independently associated with AIP relapse, after we adjusted for year of publication by multivariate meta regression. CONCLUSION: In a systematic review and meta-analysis, we found that a large proportion of patients with AIP successfully treated with steroid induction therapy have a relapse (33%)-particularly patients with type 1 AIP (37%). Maintenance steroid therapy longer than 1 year could reduce risk of relapse. However, data characterizing relapse rate are of limited quality, indicating the need for randomized controlled trials and new immunosuppressive drugs. PMID- 30312788 TI - Polyp Sizing Poster Improve Polyp Measurement but not Adenoma Detection Rates by Endoscopists in a Large Community Practice. AB - BACKGROUND & AIMS: Accurate sizing of polyps and improving adenoma detection rates (ADR) are important goals for high-quality colonoscopy. Surveillance intervals are based on accurate sizing of polyps. There are no clinical tools or interventions that have demonstrated improvement in both these metrics. We investigated the efficacy of a simple, low-cost intervention, based on use of polyp sizing posters to improve measurements of polyps and increase ADRs during colonoscopy at a large gastroenterology community practice. METHODS: We collected data on polyp measurements and ADRs by 62 gastrointestinal endoscopists at a large multi-site community practice, from January to November 2015 (baseline). In a prospective study, endoscopy units were given a polyp sizing poster to be hung above the endoscopy video monitor (intervention group, for 33 endoscopists) or for usual care (control group, for 29 endoscopists) in December 2015, and we collected data on polyp measurements and ADRs over the following 6 months (January-June 2016). We compared the endoscopists' assessment of polyp size and their ADRs before and after the intervention using a mixed effects proportional odds model, controlling for provider age and sex and patient and indication for colonoscopy. Our primary aim was to assess the effect of the snare and forcep based polyp sizing poster on change in polyp size. The secondary aim was to study the effect of the polyp sizing poster on ADR. RESULTS: Our final analysis included 85,657 polyps from 38,307 colonoscopies. The characteristics of patients who underwent colonoscopy were similar between the control and intervention group (median age, 61 years; 48.1% female; 53.9% undergoing screening; 31.4% undergoing surveillance; 14.7% receiving a diagnostic colonoscopy). The endoscopists' median age was 51 years (range, 33-76) years, and 15 were women (24.2%). During the baseline period, male endoscopists were more likely to size polyps larger than measurements made by female endoscopists (odds ratio [OR], 1.78; 95% CI, 1.24 2.55; P=.002). For the intervention group, 78.6% of polyps were assigned to the 1 5 mm category during the baseline period compared to 76.0% after the intervention, whereas the proportions of polyps assigned to the 6-10 mm category increased from 16.9% during the baseline period to 18.3% after the intervention. In the control group, 78.9% of polyps were assigned to the 1-5 mm category during the baseline period and 78.3% were assigned to this group in the prospective study; 16.5% of polyps were assigned to the 6-10 mm during the baseline period and 17.5% were assigned to this group in the prospective study. The interaction between intervention group and timing (baseline vs after the intervention) was statistically significant, with an increase in the odds of larger polyp sizing after the intervention (OR, 1.15; 95% CI, 1.08-1.23; P<.001). The odds of larger polyp measurement during the intervention period, compared to the baseline period, increased for male endoscopists (OR, 1.17; 95% CI, 1.09-1.27; P<.001) and female endoscopists (OR, 1.18; 95% CI, 1.01-1.36; P=.04), as well as for younger physicians (<50 years; OR, 1.32; 95% CI, 1.20-1.46; P<.001) but not for older physicians (>50 years; OR, 0.96; 95% CI, 0.88-1.06; P=.44). The average ADR for male and female endoscopists combined during the baseline period was 42%. The change in ADR from the baseline vs the post-intervention was an increase of 2.6% in the control group compared to 5.7% in the intervention group (P=.39) CONCLUSION: Placement of a polyp sizing poster above the endoscopy video monitor increases the odds of polyps being assigned a larger size but does not affect ADRs. PMID- 30312789 TI - Management Algorithm for Interrupting Mother to Child Transmission of Hepatitis B Virus. AB - In areas where hepatitis B virus (HBV) is endemic, mother-to-child transmission (MTCT) is the major route of infection of children. Blocking MTCT of HBV therefore would reduce its prevalence. The China Foundation of Hepatitis Prevention and Control organized a team of specialists in infectious diseases, hepatology, immunology, obstetrics, and public health to develop an algorithm for interrupting MTCT of HBV, based on the most recent hepatitis B guidelines and latest evidence. This algorithm comprises 10 steps and has been adopted in clinical practice in China. Four aspects (screening, antiviral intervention during pregnancy, immunoprophylaxis, and postvaccination serologic testing) are the core components of preventing MTCT. Although the combination of passive and active immunization in newborns of hepatitis B surface antigen-positive mothers reduces MTCT of HBV, this immunoprophylaxis cannot completely eradicate MTCT. In the past decade, administration of antiviral agents to pregnant women has been shown to be safe and effective in reducing MTCT of HBV in combination with immunoprophylaxis. Aiming to achieve zero MTCT, this algorithm recommends the use of antivirals during pregnancy by women with high viral loads. Preventing MTCT is key to achieving the goal of eliminating HBV as a public health threat by 2030. Implementation and enhancement of the standardized algorithm for pregnant women with chronic HBV infection and their infants is urgently needed to prevent MTCT. PMID- 30312791 TI - Comparison of the UV/chlorine and UV/H2O2 processes in the degradation of PPCPs in simulated drinking water and wastewater: Kinetics, radical mechanism and energy requirements. AB - The degradation of pharmaceuticals and personal care products (PPCPs) by the UV/H2O2 and UV/chlorine processes was compared at practical concentrations in simulated drinking water and wastewater. In pure water, the UV/chlorine process performed better than the UV/H2O2 process for the degradation of 16 PPCPs among the investigated 28 PPCPs under neutral conditions. Interestingly, the UV/chlorine approach was superior to the UV/H2O2 approach for the removal of all PPCPs in simulated drinking water and wastewater at the same molar oxidant dosage. The radical sink by oxidants and/or H2O was 2-3 orders of magnitude higher in UV/chlorine than UV/H2O2 in pure water. Thus, the UV/chlorine process was less affected by the water and wastewater matrices than UV/H2O2. In UV/chlorine, the concentration of ClO* was calculated to be ~3 orders of magnitude greater than that of HO* in pure water, and the reactivities of ClO* with some PPCPs were as high as > 108 M-1 s-1. ClO* was mainly scavenged by the effluent organic matter (EfOM) with a rate constant of 1.8 * 104 (mg L-1)-1 s-1 in wastewater. Meanwhile, secondary radicals such as Br*, Br2*-, ClBr*- and CO3*- further contributed to PPCP degradation by the UV/chlorine process in wastewater, whose concentrations were at least 2 orders of magnitude higher than that in UV/H2O2. Compared with the UV/H2O2 process, the UV/chlorine process saved 3.5 93.5% and 19.1%-98.1% electrical energy per order (EE/O) for PPCP degradation in simulated drinking water and wastewater, respectively. PMID- 30312790 TI - Levodopa may affect cortical excitability in Parkinson's disease patients with cognitive deficits as revealed by reduced activity of cortical sources of resting state electroencephalographic rhythms. AB - We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily dose of levodopa induced a widespread reduction in cortical delta and alpha sources in a subgroup of 13 PD patients under standard chronic dopaminergic regimen. In PD patients in quiet wakefulness, alpha cortical source activations may reflect an excitatory effect of dopamine neuromodulation. PMID- 30312792 TI - Molecular insights into the mechanism and the efficiency-structure relationship of phosphorus removal by coagulation. AB - Types and structures of phosphorus compounds influence the removal of phosphorus by coagulation. Until now, the molecular-level interaction between coagulants and phosphorus (especially organophosphates) and the relationship between removal efficiency and phosphorus structure have not been clear. This work investigated the removal of phosphorus with different structures using conventional coagulants (poly aluminum chloride (PACl) and polymerized ferric sulfate (PFS)) and a novel covalently-bound inorganic-organic hybrid coagulant (CBHyC). CBHyC removed more than 98% of phosphate and most of organophosphates, had more stable performance than PACl and PFS, and was less affected by pH, initial phosphorus concentration, and co-occurring materials. Molecular dynamics simulation demonstrated that CBHyC removed phosphorus mainly through electrostatic attraction and hydrophobic interaction. Furthermore, this work established QSAR (quantitative structure activity relationship) models for removal efficiency and organophosphate structure for the first time. The model showed that atomic charges of phosphorus atoms (QP) and hydrogen atoms (QH+) in the system and the energy gap (DeltaEMO) affected electronegativity and hydrophobicity, thus influencing organophosphate removal efficiency. The model had high fitting precision and good predictive ability and has the potential to greatly reduce the cost of optimizing processes and conditions for phosphorus removal. PMID- 30312793 TI - The role of reactive oxygen species and carbonate radical in oxcarbazepine degradation via UV, UV/H2O2: Kinetics, mechanisms and toxicity evaluation. AB - Oxcarbazepine (OXC) is ubiquitous in the aqueous environment. And due to its ecotoxicological effects and potential risks to human, an effective way to eliminate OXC from aqueous environment has aroused public concerns in recent years. Radical-based reactions have been shown to be an efficient way for OXC destruction, but the reactions of OXC with reactive oxygen species (ROS) and carbonate radical (CO3*-) are still unclear. In this study, we focused the degradation of OXC and ROS, CO3*- generation mechanism, and their roles in OXC degradation via UV and UV/H2O2. The triplet state of oxcarbazepine (3OXC*) was found to play an important role in OXC degradation via UV. And hydroxyl radicals (*OH) and singlet oxygen (1O2) were found to be the dominant ROS in OXC degradation. Superoxide radical (O2*-) did not react with OXC directly, but it may react with intermediate byproducts. Generation of CO3*- played a positive role on OXC degradation for both UV and UV/H2O2. In addition to *OH, 3OXC* also contribute to CO3*- production. The second-order rate constants of OXC with *OH and CO3*- were 1.7 * 1010 M-1 s-1 and 8.6 * 107 M-1 s-1, respectively. Potential OXC degradation mechanisms by *OH were proposed and included hydroxylation, alpha ketol rearrangement, and benzylic acid rearrangement. Compared with non-selective *OH, the reactions involving CO3*- are mainly electron transfer and hydrogen abstraction. And the acute toxicity of OXC was lower after UV/H2O2 and UV/H2O2/HCO3- treatments, which was confirmed by luminescent bacterial assay (Vibrio fischeri bacterium). PMID- 30312794 TI - Improved DBP elimination from swimming pool water by continuous combined UV and ozone treatment. AB - Chlorine is the most frequently used disinfectant and oxidant for maintaining swimming pool water quality; however, it reacts continuously with dissolved organic matter to produce disinfection by-products (DBPs), which are a health risk for pool users. UV treatment is used widely to remove chloramines, which are the most prevalent group of DBPs, albeit chloro-organic DBP concentrations often increase during post-UV chlorination. In this work, UV and ozone treatments were investigated as additional technologies to eliminate DBP formation and their precursors. Batch experiments were conducted under controlled conditions, using realistic UV and ozone dosages and real pool water samples collected from a public swimming pool. A gradual increase in all investigated DBP concentrations and predicted toxicity was observed during chlorination after repeated UV treatments, and concentrations of certain DBPs also increased during post-ozone chlorination. Based on ozone and chlorine's similar reactivity, ozone was used directly after UV treatment to decrease the induction of DBP formation. Most DBP concentrations decreased during repeated combined treatments. It was also observed that DBP formed by post-ozone chlorination was removed by photolysis, thereby indicating synergy between the treatments. Repeated treatments using realistic UV and ozone dosages predicted that water quality will improve as a result of continuous combined UV and ozone treatments. PMID- 30312795 TI - Zirconium metal organic frameworks-based DGT technique for in situ measurement of dissolved reactive phosphorus in waters. AB - In an effort to provide early warnings for the occurrence of eutrophication, it is highly desirable to develop an accurate and efficient technique to ensure continuous monitoring of dissolved reactive phosphorus (DRP) in the aquatic environment from the viewpoint of environmental management. Herein, a new diffusive gradient in thin film (DGT) technique was developed and evaluated for in situ measurement of DRP in waters, in which Zr-based metal organic frameworks (MOFs, UiO-66) were utilized as aqueous binding agent (abbreviated as UiO-66 DGT). As expected, the UiO-66 DGT demonstrated high uptake capacity towards phosphorus (20.8 MUg P cm-2). Meanwhile, an excellent linearity between the accumulated DRP mass and deployment time over 5 d (R2 = 0.996) was obtained regardless of high or low phosphate solution. In addition, effective diffusion coefficients (D) of DRP increased exponentially with increasing ionic strengths (R2 = 0.99). Based on the rectified D, the performance of the UiO-66 DGT was independent of solution pH (6.5-8.5) and ionic strengths (ranging from 0.01 to 100 mmol L-1). Furthermore, field deployments of the UiO-66 DGT were undertaken in a natural eutrophic lake (Lake Chaohu, China). It was noteworthy that DRP could be continually accumulated by the UiO-66 DGT for more than 14 d and good agreements were obtained between the concentrations measured by DGT (CDGT) and those by ex situ chemical extraction method in solution (Csol), as reflected by CDGT/Csol of 0.9-1.1. In situ determination of DRP speciation was also carried out at different sites across Lake Chaohu. Overall, this study contributed to a better constructing of liquid binding phase DGT for the measurement of DRP in waters, facilitating the widespread application of the UiO-66 DGT as a routine monitoring technique and for large-scale environmental analysis. PMID- 30312796 TI - Peroxymonosulfate activation by iron(III)-tetraamidomacrocyclic ligand for degradation of organic pollutants via high-valent iron-oxo complex. AB - Herein, we proposed a new catalytic oxidation system, i.e., iron(III) tetraamidomacrocyclic ligand (FeIII-TAML) mediated activation of peroxymonosulfate (PMS), for highly efficient organic degradation using p chlorophenol (4-CP) as a model one. PMS/FeIII-TAML is capable of degrading 4-CP completely in 9 min at the initial 4-CP of 50 MUM and pH = 7, whereas the recently explored system, H2O2/FeIII-TAML, could only result in ~22% 4-CP removal in 20 min under otherwise identical conditions. More attractively, inorganic anions (i.e., Cl-, SO42-, NO3-, and HCO3-) exhibited insignificant effect on 4-CP degradation, and the negative effect of natural organic matters (NOM) on the degradation of 4-CP in PMS/FeIII-TAML is much weaker than the sulfate radical based oxidation process (PMS/Co2+). Combined with in-situ XANES spectra, UV visible spectra, electron paramagnetic resonance (EPR) spectra, and radical quenching experiments, high-valent iron-oxo complex (FeIV(O)TAML) instead of singlet oxygen (1O2), superoxide radical (O2*-), sulfate radicals (SO4*-) and hydroxyl radicals (HO*) was the key active species responsible for 4-CP degradation. The formation rate (kI) and consumption rate (kII) of the FeIV(O)TAML in PMS/FeIII-TAML were pH-dependent in the range of 6.0-11.5. As expected, increasing the FeIII-TAML and PMS dosage resulted in a higher steady state concentration of FeIV(O)TAML and enhanced the 4-CP degradation accordingly. In addition, the oxidation capacity of PMS was almost totally utilized in PMS/FeIII-TAML for 4-CP oxidation due to the two-electron abstraction from 4-CP by one PMS. We believe this study will shed new light on effective PMS activation by Fe-ligand complexes to efficiently degrade organic contaminants via nonradical pathway. PMID- 30312797 TI - Fisetin inhibits cardiac hypertrophy by suppressing oxidative stress. AB - Cardiac hypertrophy is a pathophysiological response to various pathological stresses and ultimately leads to heart failure. Oxidative stress is one of the critical processes involved in hypertrophy development. Fisetin, a small molecular flavonoid, has been shown to have anti-oxidative, anti-proliferative and anti-inflammatory properties. However, the effect of fisetin on cardiac hypertrophy remains unknown. In our present study, we showed that fisetin inhibited pressure overload-induced cardiac hypertrophy, improved cardiac function in vivo and suppressed phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. Reactive oxygen species (ROS) levels were markedly decreased by fisetin treatment in both hypertrophic hearts and cardiomyocytes. Moreover, fisetin significantly up-regulated the expression of antioxidative genes, including catalase (CAT), superoxide dismutase 1 (SOD1) and heme oxygenase 1 (HO-1). Furthermore, co-treatment with N-acetylcysteine (NAC; ROS scavenger) and fisetin did not have synergistic inhibitory effects on PE-induced cardiomyocyte hypertrophy, indicating that the anti-hypertrophic effects of fisetin are mainly associated with the blockade of oxidative stress. Finally, the pro-hypertrophic signaling pathways, mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) kinase, were found to be suppressed by fisetin after pressure overload and PE treatment. In conclusion, our study revealed that fisetin protects against cardiac hypertrophy and that oxidative stress inhibition may be one of the pivotal mechanisms involved. PMID- 30312798 TI - The anticoagulant treatment for sepsis induced disseminated intravascular coagulation; network meta-analysis. AB - INTRODUCTION: The benefits and harm caused by anticoagulant treatments for sepsis induced disseminated intravascular coagulation (DIC) remain unclear. Therefore, we performed a network meta-analysis to assess the effect of available anticoagulant treatments on patient mortality, DIC resolution and the incidence of bleeding complication in patients with septic DIC. MATERIALS AND METHODS: We considered all studies from four recent systematic reviews and searched the PubMed, MEDLINE, and Cochrane databases for other studies that investigated anticoagulant treatment for septic DIC using antithrombin, thrombomodulin, heparin, or protease inhibitors in adult critically ill patients. These four anticoagulants and placebo were compared. The primary outcome in this study was patient mortality, and the secondary outcomes were the DIC resolution rate and incidence of bleeding complications. RESULTS: The network meta-analysis included 1340 patients from nine studies. There were no significant differences in the risks of mortality and bleeding complications among all direct comparisons and the network meta-analysis. Using a placebo was associated with a significantly lower rate of DIC resolution, compared to antithrombin in the direct comparison (odds ratio [OR]: 0.20, 95% credible interval [95% CrI]: 0.046-0.81) and in the network meta-analysis (OR: 0.20, 95% CrI: 0.043-0.84). CONCLUSIONS: Our study revealed no significant differences in the risks for mortality and bleeding complications when a placebo and all four anticoagulants were compared in septic DIC patients. The results also indicated that antithrombin was associated with a five-fold higher likelihood of DIC resolution, compared to placebo. PMID- 30312799 TI - Blood loss and cost-effectiveness of oral vs intravenous tranexamic acid in primary total hip arthroplasty: A randomized clinical trial. AB - BACKGROUND: To assess the blood loss and cost-effectiveness of the oral and intravenous (IV) administration of tranexamic acid (TXA) for the treatment of primary total hip arthroplasty (THA). METHODS: From January 2017 to August 2017, 100 patients undergoing primary THA were enrolled and randomly divided into two groups. In the oral TXA group (N = 50), 1 g of TXA (2 tablets of 500 mg) was given 2 h before the incision, and the same dose was repeated 3 h and 6 h postoperatively. In the IV TXA group (N = 50), 1 g of TXA was administered 10 min before the incision, and the same dose was repeated 3 h and 6 h postoperatively. The total follow-up period was 6 months. RESULTS: There were no statistically significant differences in total blood loss (863.3 +/- 272.5 mL and 886.1 +/- 200.2 mL, P = 0.66), maximum Hb drop (2.9 +/- 0.6 g/dl and 3.1 +/- 0.8 g/dl, P = 0.17), maximum Hct drop (7.4 +/- 2.1% and 7.7 +/- 1.8%, P = 0.48), transfusion rates (1 and 2, P = 1.00) and transfusion units (1.5 u and 3 u, P = 0.56) between the two groups. However, the costs of TXA in the oral group were significantly lower than those in the IV TXA group (Y600 and Y3150, P < 0.01). There was no difference in the Hb levels on postoperative days 1 and 3. No significant differences were found for operating time, hospital length of stay, DVT and/or PE, and wound complications in the postoperative follow-up. CONCLUSIONS: The study demonstrated that the oral and IV administration of TXA in patients undergoing THA was proved to be an equivalent and effective method in reducing blood loss and transfusion rates. However, oral TXA is more cost-effectiveness than IV TXA, and it may be an alternative to the IV form. PMID- 30312800 TI - The role of biomarkers of endothelial activation in predicting morbidity and mortality in patients with severe sepsis and septic shock in intensive care: A prospective observational study. AB - INTRODUCTION: Endothelial dysfunction plays an essential role in the pathogenesis of sepsis. The study aimed to illustrate the associations between the dynamic change (from day 1 to day 7) in biomarker concentration of endothelial dysfunction and outcomes in severe sepsis and septic shock in the intensive care unit (ICU). MATERIALS AND METHODS: We studied 102 patients enrolled in the Beijing Chao-yang Hospital affiliated with the Capital Medical University. A receiver operating characteristic (ROC) curve were used to assess the prognostic values of the circulating adhesion Angiopoietin-2/Angiopoietin-1 ratio (Ang-2/Ang 1) and Angiopoietin-1/Tie-2 ratio (Ang-1/Tie-2), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and thrombomodulin (TM). Spearman's rank correlation and a multiple regression analysis were used to assess the relationship between the change in sequential organ failure assessment (Delta SOFA) score (SOFA score at day 7 minus SOFA score at day 1) and the levels of Delta Ang-2/Ang-1 and Delta Ang-1/Tie-2 ratios, DeltasICAM-1, DeltasVCAM-1 and Delta sTM. RESULTS: The Ang-2/Ang-1 ratio, sICAM-1, sVCAM-1 and sTM levels significantly increased from day 1 to day 7 (all p = 0.045), and the Ang-1/Tie-2 ratio level markedly decreased from day 1 and day 7 (p = 0.027) in non-survivors. The biomarkers at Days 1 and 7 had significant prognostic value for 90-day mortality in severe sepsis and septic shock in ICU. The difference in biomarkers for endothelial dysfunction were suggested to be effective, independent predictors of changes in Delta SOFA. CONCLUSIONS: Endothelial dysfunction may constitute an independent contributor to sepsis-associated outcomes in ICU. PMID- 30312801 TI - Characterization of hemostasis in mice lacking the novel thrombosis susceptibility gene Slc44a2. AB - INTRODUCTION: Recent genome wide association studies (GWAS) identified a novel susceptibility locus for thrombosis, harbouring the SLC44A2 gene which encodes the Solute Carrier Family 44 Member 2 protein (SLC44A2). Thus far, SLC44A2 has not been studied in the context of thrombosis, and may be a unique contributor to thrombotic disease. Here we utilize mice lacking SLC44A2 (Slc44a2-/-) to evaluate a possible role of SLC44A2 in hemostasis. METHODS: Slc44a2-/- mice were evaluated in key aspects of normal hemostasis including a challenge of vascular damage by applying laser induced injury to the cremaster muscle arteriole. RESULTS: Slc44a2 /- mice had comparable levels of thrombin generation and gene expression of coagulation related genes, as compared to littermate wild type controls. Lower levels of circulating plasma Von Willebrand factor (VWF) were measured in Slc44a2 /- mice, while no difference in VWF multimerization or vascular localization was detected. Upon in vivo laser injury of the cremaster arterioles, we detected an impairment of clot formation for Slc44a2-/- mice. CONCLUSIONS: Although mice lacking SLC44A2 are normal for several hemostasis parameters, we do observe a reduction of plasma VWF levels and an altered response upon vascular damage, which suggests that SLC44A2 contributes to hemostasis upon injury. These findings are in line with the reported GWAS data and support further research on SLC44A2 in thrombosis. PMID- 30312802 TI - A comparison of bus passengers' and car drivers' valuation of casualty risk reductions in their routes. AB - INTRODUCTION: The economic value of safety represents an important guide to transport policy, and more studies on individuals' valuation of road safety are called for. This paper presents a stated preference study of the value of preventing fatal and serious injuries involving bus passengers and car drivers in road accidents. OBJECTIVES: Former valuation studies based on travel behaviour and route choice have involved primarily car drivers. Our study also included bus passengers, thus providing a comparison of two types of transport mode users. Moreover, the comparison was based on two different valuation methods. METHODOLOGY: About 600 bus passengers and nearly 2300 car users from different areas of Norway reported a recent trip, described by its distance and travel cost. Then they answered stated choice tasks that took a reference in the reported trip and involved trade-offs among travel time, fatal and seriously injured victims and travel costs. Afterwards, they faced a simple trade-off between travel costs, and fatal and seriously injured victims. FINDINGS: Pooling the data from the two stated preference formats, we derived values of a statistical life and of a statistical seriously injured victim. Regarding the value of statistical life, our point estimates were NOK 45.5 million and NOK 58.3 million for bus users and car users respectively. DISCUSSION: The point estimates for bus passengers and car users were not statistically different given their confidence intervals. Thus, we recommend the use of a single value, identical for both modes of transport, for the prevention of a statistical fatality as well as for a statistical injury. PMID- 30312803 TI - United States trends in mortality rates for primary immunodeficiency diseases. PMID- 30312804 TI - The Simple 10-Item Predicting Asthma Risk in Children Tool to Predict Childhood Asthma-An External Validation. AB - BACKGROUND: External validation of prediction models is important to assess generalizability to other populations than the one used for model development. The Predicting Asthma Risk in Children (PARC) tool, developed in the Leicestershire Respiratory Cohort (LRC), uses information on preschool respiratory symptoms to predict asthma at school age. OBJECTIVE: We performed an external validation of PARC using the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: We defined inclusion criteria, prediction score items at baseline and asthma at follow-up in ALSPAC to match those used in LRC using information from parent-reported questionnaires. We assessed performance of PARC by calculating sensitivity, specificity, predictive values, likelihood ratios, area under the curve (AUC), Brier score and Nagelkerke's R2. Sensitivity analyses varied inclusion criteria, scoring items, and outcomes. RESULTS: The validation population included 2690 children with preschool respiratory symptoms of whom 373 (14%) had asthma at school age. Discriminative performance of PARC was similar in ALSPAC (AUC = 0.77, Brier score 0.13) as in LRC (0.78, 0.22). The score cutoff of 4 showed the highest sum of sensitivity (69%) and specificity (76%) and positive and negative likelihood ratios of 2.87 and 0.41, respectively. Changes to inclusion criteria, scoring items, or outcome definitions barely altered the prediction performance. CONCLUSIONS: Performing equally well in the validation cohort as in the development cohort, PARC is a valid tool for predicting asthma in population-based cohorts. Its use in clinical practice is ready to be tested. PMID- 30312805 TI - Does Obesity Increase Respiratory Tract Infections in Patients with Asthma? AB - BACKGROUND: Because respiratory tract infections (RTIs) precede most exacerbations, a better understanding of the risk factors of RTIs and RTI associated exacerbations in patients with asthma is a pressing public health need. Obesity in patients with asthma is associated with worse asthma control and higher asthma-associated health care utilization, but its effect on RTI risk is unknown. OBJECTIVE: We aimed to study the association of body mass index (BMI) classification on the risk of self-reported RTIs and related asthma morbidity among adults and children with asthma. METHODS: This post hoc analysis of 5 large asthma trials involving 747 children and 1287 adults compared BMI classification, defined as lean, overweight, and obese based on age-appropriate BMI and BMI percentile conventions. The primary outcome was rate of visits with RTIs. Secondary asthma outcomes included upper respiratory infection (URI) severity, systemic steroid use, and health care contact. RESULTS: Children had 1.4 times the rate of RTI compared with adults (95% confidence interval 1.27-1.56). In all participants, BMI classification did not affect the rate of visits with RTI. In children, BMI classification did not affect URI severity, all-cause asthma events, or RTI-associated asthma events. However, in adults, higher BMI classification was associated with an increase in moderate/severe URI (P = .02). Adults with higher BMI classification also had increased rates of all-cause and RTI-associated asthma exacerbations requiring systemic steroids and health care contact. CONCLUSIONS: BMI classification was not associated with an increased risk of RTIs in children or adults. In adults only, obesity was associated with increased URI severity and all-cause and RTI-associated asthma morbidity. PMID- 30312806 TI - The impact of tree nut oral food challenges on quality of life and acute reactions in nut allergic patients. PMID- 30312807 TI - Glutamatergic facilitation of neural responses in MT enhances motion perception in humans. AB - There is large individual variability in human neural responses and perceptual abilities. The factors that give rise to these individual differences, however, remain largely unknown. To examine these factors, we measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination. Further, we acquired MR spectroscopy data, which allowed us to quantify an index of neurotransmitter levels in the region of area MT. These three measurements were conducted in separate experimental sessions within the same group of male and female subjects. We show that stronger Glx (glutamate + glutamine) signals in the MT region are associated with both higher fMRI responses and superior psychophysical task performance. Our results suggest that greater baseline levels of glutamate within MT facilitate motion perception by increasing neural responses in this region. PMID- 30312808 TI - The age-dependent relationship between resting heart rate variability and functional brain connectivity. AB - Resting heart rate variability (HRV), an index of parasympathetic cardioregulation and an individual trait marker related to mental and physical health, decreases with age. Previous studies have associated resting HRV with structural and functional properties of the brain - mainly in cortical midline and limbic structures. We hypothesized that aging affects the relationship between resting HRV and brain structure and function. In 388 healthy subjects of three age groups (140 younger: 26.0 +/- 4.2 years, 119 middle-aged: 46.3 +/- 6.2 years, 129 older: 66.9 +/- 4.7 years), gray matter volume (GMV, voxel-based morphometry) and resting state functional connectivity (eigenvector centrality mapping and exploratory seed-based functional connectivity) were related to resting HRV, measured as the root mean square of successive differences (RMSSD). Confirming previous findings, resting HRV decreased with age. For HRV-related GMV, there were no statistically significant differences between the age groups, nor similarities across all age groups. In whole-brain functional connectivity analyses, we found an age-dependent association between resting HRV and eigenvector centrality in the bilateral ventromedial prefrontal cortex (vmPFC), driven by the younger adults. Across all age groups, HRV was positively correlated with network centrality in the bilateral posterior cingulate cortex. Seed-based functional connectivity analysis using the vmPFC cluster revealed an HRV-related cortico-cerebellar network in younger but not in middle-aged or older adults. Our results indicate that the decrease of HRV with age is accompanied by changes in functional connectivity along the cortical midline. This extends our knowledge of brain-body interactions and their changes over the lifespan. PMID- 30312809 TI - Depth-dependent intracortical myelin organization in the living human brain determined by in vivo ultra-high field magnetic resonance imaging. AB - BACKGROUND: Intracortical myelin is a key determinant of neuronal synchrony and plasticity that underpin optimal brain function. Magnetic resonance imaging (MRI) facilitates the examination of intracortical myelin but presents with methodological challenges. Here we describe a whole-brain approach for the in vivo investigation of intracortical myelin in the human brain using ultra-high field MRI. METHODS: Twenty-five healthy adults were imaged in a 7 Tesla MRI scanner using diffusion-weighted imaging and a T1-weighted sequence optimized for intracortical myelin contrast. Using an automated pipeline, T1 values were extracted at 20 depth-levels from each of 148 cortical regions. In each cortical region, T1 values were used to infer myelin concentration and to construct a non linearity index as a measure the spatial distribution of myelin across the cortical ribbon. The relationship of myelin concentration and the non-linearity index with other neuroanatomical properties were investigated. Five patients with multiple sclerosis were also assessed using the same protocol as positive controls. RESULTS: Intracortical T1 values decreased between the outer brain surface and the gray-white matter boundary following a slope that showed a slight leveling between 50% and 75% of cortical depth. Higher-order regions in the prefrontal, cingulate and insular cortices, displayed higher non-linearity indices than sensorimotor regions. Across all regions, there was a positive association between T1 values and non-linearity indices (P < 10-5). Both T1 values (P < 10-5) and non-linearity indices (P < 10-15) were associated with cortical thickness. Higher myelin concentration but only in the deepest cortical levels was associated with increased subcortical fractional anisotropy (P = 0.05). CONCLUSIONS: We demonstrate the usefulness of an automatic, whole-brain method to perform depth-dependent examination of intracortical myelin organization. The extracted metrics, T1 values and the non-linearity index, have characteristic patterns across cortical regions, and are associated with thickness and underlying white matter microstructure. PMID- 30312810 TI - The neural architecture of executive functions is established by middle childhood. AB - Executive functions (EFs) are regulatory cognitive processes that support goal directed thoughts and behaviors and that involve two primary networks of functional brain activity in adulthood: the fronto-parietal and cingulo-opercular networks. The current study assessed whether the same networks identified in adulthood underlie child EFs. Using task-based fMRI data from a diverse sample of N = 117 children and early adolescents (M age = 10.17 years), we assessed the extent to which neural activity was shared across switching, updating, and inhibition domains, and whether these patterns were qualitatively consistent with adult EF-related activity. Brain regions that were consistently engaged across switching, updating, and inhibition tasks closely corresponded to the cingulo opercular and fronto-parietal networks identified in studies of adults. Isolating brain activity during more demanding task periods highlighted contributions of the dorsal anterior cingulate and anterior insular regions of the cingulo opercular network. Results were independent of age and time-on-task effects. These results indicate that the two core brain networks that support EFs are in place by middle childhood, in agreement with resting-state findings of adultlike brain network organization. Improvement in EFs from middle childhood to adulthood, therefore, are likely due to quantitative changes in activity within these networks, rather than qualitative changes in the organization of the networks themselves. Improved knowledge of how the brain's functional organization supports EF in childhood has critical implications for understanding the maturation of cognitive abilities. PMID- 30312811 TI - A rare and symptomatic Cavernous Donut-shaped Aneurysm treated by Flow Diverter Deployment. AB - We describe the case of a 62-year-old woman, who was admitted at our center for acute diplopia secondary to a left III cranial nerve palsy, left eyelid swelling and ptosis, and mild ipsilateral retro-orbital pain. No other motor or sensitive deficits were observed. A CT-Angiography (CTA) and a Digital Subtraction Angiography (DSA) were performed, showing a 25 mm left intra-cavernous aneurysm with a central intrasaccular thrombus, an intra-saccular "swirling" flow with a donut-shape appearance. A flow-diverter stent (FD) was deployed bridging the aneurysmal neck. Twelve months after the procedure the aneurysm was completely occluded and the patient had totally recovered the cavernous syndrome. A careful literature review has been performed and the different endovascular approaches analyzed. PMID- 30312813 TI - Intraoperative ultrasound guided posterior cervical laminectomy for degenerative cervical myelopathy. PMID- 30312812 TI - The Impact of Preoperative Mindfulness-Based Stress Reduction on Postoperative Patient-Reported Pain, Disability, Quality of Life, and Prescription Opioid Use in Lumbar Spine Degenerative Disease: A Pilot Study. AB - BACKGROUND: Prescription opioid medications negatively affect postoperative outcomes after lumbar spine surgery. Furthermore, opioid-related overdose death rates in the United States increased by 200% between 2000 and 2014. Thus, alternatives are imperative. Mindfulness-based stress reduction (MBSR), a mind body therapy, has been associated with improved activity and mood in opioid-using patients with chronic pain. This study assessed whether preoperative MBSR is an effective adjunct to standard postoperative care in adult patients undergoing lumbar spine surgery for degenerative disease. METHODS: The intervention group underwent a preoperative online MBSR course. The comparison group was matched retrospectively in a 1:1 ratio by age, sex, type of surgery, and preoperative opioid use. Prescription opioid use during hospital admission and at 30 days postoperatively were compared with preoperative use. Thirty-day postoperative patient-reported outcomes for pain, disability, and quality of life were compared with preoperative patient-reported outcomes. Dose-response effect of mindfulness courses was assessed using Mindful Attention Awareness Scale scores. RESULTS: In this pilot study, 24 participants were included in each group. Most intervention patients (70.83%) completed 1 session, and the mean Mindful Attention Awareness Scale score was 4.28 +/- 0.71 during hospital admission. At 30 days, mean visual analog scale back pain score was lower in the intervention group (P = 0.004) but other patient-reported outcomes did not differ. CONCLUSIONS: During hospital admission, no significant dose-response effect of mindfulness techniques was found. At 30 days postoperatively, MBSR use was associated with less back pain. Further research is needed to assess the effectiveness of preoperative MBSR on postoperative outcomes in lumbar spine surgery for degenerative disease. PMID- 30312814 TI - Aneurysm of anomalous V3 segment in association with congenital atlantoaxial dislocation: Case report and challenges in management. AB - BACKGROUND: An anomalous vertebral artery (VA) is not a deterrent for posterior C1-C2 joint manipulation and reduction of atlantoaxial dislocation (AAD). However, presence of an incidental aneurysm in the aberrant segment of artery with concurrent AAD adds to the surgical challenge. CASE DESCRIPTION: A 30-year old woman presented with neck pain and spastic quadriparesis. Her imaging revealed atlantoaxial dislocation and bony segmentation defects. Three dimensional computed tomography angiography showed bilateral anomalous vertebral arteries (V3 segment) and an incidental aneurysm on the arterial segment that crossed the right C1-C2 joint posteriorly. Because the artery bearing the aneurysm was non-dominant, it was ligated, and successful C1-C2 posterior reduction and fusion could be performed. CONCLUSION: The association of an incidental aneurysm with an anomalous VA in congenital AAD is unusual. The etiology could be an underlying collagen defect or repeated shearing-trauma to the vessel wall due to C1-C2 instability. It would be less risky to proceed with endovascular embolization followed by occipitocervical fusion without opening the joints in case the aneurysm is present on dominant aberrant V3 segment. Ventral decompression can be supplemented for irreducible AAD. On the contrary if the aneurysm is present on the non-dominant aberrant V3 segment, the C1-2 joint can be opened and manipulated following an initial endovascular treatment of the aneurysm. If the circumstances demand, the non-dominant artery can be ligated and sacrificed although there is a small risk of formation of stump aneurysm. PMID- 30312815 TI - Comparison of Extending Fusion to Thoracic Curve Versus Thoracolumbar/Lumbar Fusion in Posterior Fusion of Patients with Lenke 5C: Variation in Upper End Vertebrae Tilt Affected Coronal Balance. AB - BACKGROUND: Extended fusion can be performed in patients with Lenke 5C adolescent idiopathic scoliosis (AIS) with a large and relatively rigid thoracic curve. Progression of the thoracic curve is related to coronal imbalance. We aimed to determine the correlation between the upper instrumented vertebra choice and coronal balance in patients with Lenke 5C AIS. METHODS: A total of 61 patients with Lenke 5C AIS underwent posterior fusion from 2009 to 2015 in a single institution with >=2 years of follow-up data available. The extended fusion group (n = 32) and thoracolumbar/lumbar (TL/L) fusion group (n = 29) were compared for the correction rates for the main TL/L and thoracic curves, coronal balance, upper end vertebra (UEV) tilt, and Scoliosis Research Society-22 questionnaire score. RESULTS: Both groups had excellent correction of the main TL/L curve, and the extended fusion group had a significantly greater correction rate of the thoracic curve than the TL/L fusion group (70.2% vs. 57.3%). The incidence of coronal imbalance was similar in both groups. The spontaneous change in UEV tilt was associated with the change in coronal balance from the first to the final follow-up examination. In the TL/L fusion group, the increase in UEV tilt from the first to final follow-up visit resulted in improved coronal balance at the final follow-up examination. Both groups had similar Scoliosis Research Society 22 questionnaire scores at 2 years postoperatively. CONCLUSIONS: In patients with Lenke 5C AIS, thoracic curve fusion results in better correction of the thoracic curve but no improvement in coronal balance. With TL/L fusion, a postoperative UEV tilt >5 degrees leads to better coronal balance. PMID- 30312816 TI - Multidrug resistant Acinetobacter baumannii ventriculostomy-related infection, treated by a Colistin, Tigecycline and intraventricular fibrinolysis. AB - Acinetobacter baumannii meningitis and ventriculitis are difficult issues, due to the low diffusion of antibiotics in the cerebrospinal fluid (CSF) and bacterial multidrug resistance. The presence of an infected intraventricular hematoma, constituting an equivalent of undrained abscess, may promote biofilm formation and failure of medical treatment. In this case of ventriculostomy-related infection after ventricular hemorrhage, Acinetobacter baumannii was only sensitive to Colistin and Tigecycline. Despite a combination therapy involving intraventricular injections of Colistin, we observed a clinical and bacteriological failure. Therefore, at day 4 of antibiotic therapy, we performed an intraventricular fibrinolysis, which dissolved the clot, enabling sterilization of the CSF after 48 hours. PMID- 30312817 TI - Dedicated Linear Accelerator Radiosurgery for Classic Trigeminal Neuralgia: A Single-Center Experience with Long-Term Follow-Up. AB - BACKGROUND: During the past decades, stereotactic radiosurgery, and Gamma Knife in particular, has proved its safety and efficacy for drug-resistant classic trigeminal neuralgia. However, few large series exist using linear accelerator (LINAC) reporting long-term follow-up. METHODS: Between 2006 and 2015, 301 patients were treated by LINAC at our institution. The prescribed radiation dose was 90 Gy at the far anterior target. Clinical response was defined using the Barrow Neurological Institute scale. We considered grades I and IIIa as a successful response. Mean duration of follow-up was 54.6 months (range, 12-132 months). RESULTS: Two hundred and seventy-three patients (90.7%) were initially pain free, and 28 patients (9.3%) were unchanged. The actuarial probabilities of maintaining pain relief with or without medication (Barrow Neurological Institute grade I and IIIa) at 0.5, 1, 2, 4, 5, and 10 years were 88.7%, 85.0%, 76.1%, 68.8%, 65.8%, and 48.1%, respectively. Hypesthesia was present in only 26.2% of patients (very bothersome, 0.3%). No anesthesia dolorosa was reported. The actuarial probabilities of maintaining pain relief without further surgery at 0.5, 1, 2, 4, and 5 years were 99.3%, 98.3%, 95.8%, 91.0%, and 89.7%, respectively. Among all treated patients, 86.5% were satisfied by the procedure and would undergo stereotactic radiosurgery again. CONCLUSIONS: Stereotactic radiosurgery with dedicated LINAC is associated with high rates of long-term pain relief, with minimal invasiveness and rare complications. LINAC is a possible therapeutic alternative for drug-resistant trigeminal neuralgia and could be proposed to selected patients as the first intention therapy, among other surgical solutions. PMID- 30312818 TI - Probability of New-Onset Cancer Between Patients with Traumatic Brain Injury and a Comparison General Population Cohort. AB - BACKGROUND: Traumatic brain injury (TBI) has been reported as a risk factor for the development of brain tumors. However, whether TBI affects systemic cancer remains to be determined. We investigated the incidence and factors associated with cancer development in patients with TBI. METHODS: A propensity score (age, gender, and comorbidity)-matched longitudinal cohort study of 34,556 patients with pre-existing TBI and 69,112 patients without TBI from January 2000 to December 2015 was presented using the Taiwan's National Health Insurance Research Database. The Cox proportional hazard regression model was used to estimate the hazard ratio of developing cancer adjusted by the potential confounding factors. The stratified analysis of age, gender, and comorbidities for each cancer type was evaluated using forest plot analysis. RESULTS: The cancer incidence rate in the patients with TBI (4.38%) was greater than that in patients without TBI (3.88%). The interval to cancer development in those with TBI (5.65 +/- 3.58 years) was shorter than that in those without TBI (6.02 +/- 3.65 years). The cancer risk in those with TBI was increased 1.27-fold compared with that in the general population. Of the patients with TBI, age <55 years and male gender indicated a greater incidence of cancer than that of the general population. The patients with TBI had greater cancer frequencies in the head and neck structures compared with those in the general population. CONCLUSIONS: TBI is a risk factor for cancer development, especially in males and those aged <55 years. We hope this information will remind physicians to consider the long-term effects of TBI on cancer development. PMID- 30312819 TI - Diabetes Comorbidity Increases Risk of Postoperative Complications in Traumatic Thoracic Vertebral Fracture Repair: A Propensity Score Matched Analysis. AB - BACKGROUND: Thoracic vertebral fracture repair after a traumatic injury can be associated with significant risk for postoperative complications. Surgical outcomes are further complicated by patient comorbidity, particularly diabetes mellitus. This study compared outcomes and complication rates for traumatic thoracic vertebral fracture repair in a matched sample of patients with diabetes and nondiabetic control subjects. METHODS: Patients with a surgical repair of a trauma-induced thoracic vertebral fracture treated from 2010 to 2015 were identified from the Trauma Quality Improvement Program database, yielding 5557 cases. Patients with comorbid diabetes were matched by propensity score matching (PSM) with patients without diabetes on age, race, and body type and were compared by postoperative complications and clinical outcomes. RESULTS: Prior to PSM, the diabetes group was older on average and had a greater proportion of patients who were obese (Ps < 0.001). After PSM, each group consisted of 544 patients (N = 1088) and no longer differed by any baseline characteristic. Comorbid diabetes was associated with longer average length of hospital stay and greater frequency of several major and minor postoperative complications (Ps < 0.05), including prolonged intensive care, pneumonia, acute renal failure, stroke, pressure ulcers, and urinary tract infections, but no differences were found in reoperation rates or in-hospital mortality. CONCLUSIONS: Diabetes comorbidity can significantly increase the risk of postoperative complications after traumatic thoracic vertebral fracture repair, which may lead to delayed recovery and greater health care-related costs. This finding is an important consideration for surgical decision-making and patient counseling on treatment options with this comorbid condition. PMID- 30312820 TI - Intraoperative Ventriculostomy Using K Point in Surgical Management of Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Intraoperative ventriculostomy in the surgical management of aneurysmal subarachnoid hemorrhage (SAH) is frequently performed to reduce increased intracranial pressure. The previously suggested ventriculostomy points have some limitations because the dura mater must be opened to be accessed and it is difficult to measure the exact entry point in patients with brain edema. We propose a new intraoperative ventriculostomy point (K point) for use in the surgical management of aneurysmal SAH patient with severe brain edema. METHODS: We performed intraoperative ventriculostomy using the K point on 155 patients with aneurysmal SAH between January 2012 and August 2016. Before opening the dura mater following standard pterional craniotomy, we inserted the ventricular catheter through a small dural incision perpendicular to the middle frontal gyrus toward the ipsilateral medial epicanthus. We simulated the catheter trajectory using a commercial navigation system on 2 patients with brain tumor. RESULTS: Ventriculostomy related hemorrhage occurred in 12 patients (7.7%), but there were no large hemorrhages causing neurologic deterioration or requiring evacuation. No language impairment was observed in these patients. Analysis using the navigation system revealed that the trajectory of K point ventriculostomy avoided critical periventricular brain structures and passed through the space between the genu of the corpus callosum and head of the caudate nucleus. CONCLUSIONS: K point ventriculostomy allows for easy access to a target point and protects the brain during opening of the dura mater and drilling of the sphenoid bone. PMID- 30312821 TI - Hybrid Surgery for Internal Carotid Artery Revascularization. AB - OBJECTIVE: The management of chronic complete occlusion of ICA (COICA) has been challenging. Endovascular procedures have been performed with variable success and risks, depending on the type of occlusion and distal revascularization. We present a novel hybrid procedure to recanalize the ICA when previous endovascular interventions have failed or is deemed too risky. METHODS: Two patients presented with symptomatic COICA after maximal medical management. They were deemed high risk for endovascular intervention and/or previous endovascular attempts have failed. They were indicated for a hybrid procedure. RESULTS: A hybrid technique was used to create a stump by surgical endarterectomy followed by recanalization using an endovascular approach via femoral access. The technique is described in detail. Post-op CTP showed normalization of the MTT, CBV and CBF compared to pre op CTP. Cerebral angiogram showed successful recanalization of the ICA. Both patients did not have any complications. CONCLUSION: A hybrid technique is feasible and should be considered for patients with COICA who have failed maximal medical management and have a high-risk profile for endovascular intervention or where previous endovascular attempts have failed. PMID- 30312822 TI - Efficacy of One-Stage Posterior Debridement and Bone Grafting with Internal Fixation in the Treatment of Monosegmental Thoracolumbar Tuberculosis. AB - BACKGROUND: We explored the clinical effect of one-stage posterior debridement and bone grafting with internal fixation for the treatment of monosegmental thoracolumbar tuberculosis (TB). METHODS: The data from 90 patients with thoracolumbar TB, who had undergone one-stage posterior debridement and bone grafting with internal fixation, were retrospectively reviewed. Data on the operative time, blood loss, length of hospital stay, erythrocyte sedimentation rate, C-reactive protein, improvement of neurological function, visual analog scale score, vertebral Cobb angle, bone healing, and complications were collected. RESULTS: A total of 88 patients were finally included in the present retrospective study, included 42 men and 46 women. The mean patient age was 45.4 +/- 12.3 years (range, 27-70), and the mean duration of disease until treatment was 11 +/- 4.5 months (range, 3-19). The mean operative time was 167.0 minutes (range, 130-210), and the mean blood loss was 767.4 mL (range, 500-1150). At the final follow-up examination, the correction in the Cobb angle was 19 degrees , the visual analog scale score had decreased to 3 +/- 1.72, the neurologic deficits using the Frankel grade had improved, and the erythrocyte sedimentation rate and C-reactive protein level had returned to normal levels. CONCLUSION: One stage posterior debridement and bone grafting with internal fixation might be a better choice for treating patients with monosegment thoracolumbar TB. PMID- 30312823 TI - Endovascular Treatment of Wide-Necked Intracranial Aneurysms with the Scepter XC Balloon Catheter, with Low-Profile Visualized Intraluminal Support (LVIS) Jr. Deployment as a "Bailout" Technique. AB - BACKGROUND: The Scepter XC balloon catheter can be used for balloon-assisted coiling (BAC) of cerebral aneurysms but also accommodates delivery of a low profile visible intraluminal stent (LVIS Jr.). We assessed the safety and effectiveness of BAC using the Scepter XC, with LVIS Jr. stent-assisted coiling (SAC) as a bailout option. METHODS: A single-institution prospectively maintained neurointerventional database was reviewed for wide-necked (neck width >=4 mm or dome/neck ratio <2) saccular aneurysms treated using the Scepter XC. Complication and angiographic occlusion rates of BAC and SAC procedures were compared. Multivariate logistic regression was used to identify variables predictive of complete aneurysm occlusion. RESULTS: The cohort included 141 wide-necked saccular intracranial aneurysms treated in 135 procedures. SAC was used to treat 30% of aneurysms by deploying the LVIS Jr. through the Scepter XC. The overall procedural complication rate was 8.9%, including a 1.5% rate of symptomatic thromboembolic events and 3.0% rate of hemorrhagic complications, with no significant differences in complications between BAC and SAC procedures (P = 0.27). The overall complete or near-complete aneurysm occlusion rate was 96%, with trends toward higher complete aneurysm occlusion and lower retreatment rates with SAC (78 vs. 57%; P = 0.13; 0 vs. 8.4%, P = 0.13). Multivariate logistic regression identified aneurysm size, procedure technique (BAC or SAC), and duration of follow-up as independent predictors of complete aneurysm occlusion. CONCLUSIONS: Use of the Scepter XC for BAC, with LVIS Jr. SAC as a bailout option, shows acceptable angiographic and clinical results. PMID- 30312824 TI - Comparison of Endoscopic Versus Microsurgical Resection of Pituitary Adenomas with Parasellar Extension and Evaluation of the Predictive Value of a Simple 4 Quadrant Radiologic Classification. AB - BACKGROUND: The amount of parasellar extension is a known limitation for gross total resection (GTR) of pituitary adenomas. Endoscopic technique seems to improve resection of adenomas extending laterally. Knosp classification is used to evaluate the extent of parasellar invasion: increasing Knosp grades correspond with lower rates of GTR. The 4-quadrant method could help to estimate the risk of partial resection in adenomas with parasellar extension. The objective of this study was to compare the rate of GTR between microsurgical and endoscopic techniques in pituitary adenomas with parasellar extension. The secondary aim was to compare the predictive value of Knosp classification and of the 4-quadrant classification regarding GTR. METHODS: This was a retrospective comparison of GTR in different Knosp grades and per quadrant in 55 consecutive patients who underwent microsurgical (n = 28, 2001-2008) or endoscopic (n = 27, 2008-2016) resection of a pituitary adenoma with parasellar extension. RESULTS: The endoscopic group (19/27 patients) had a significant higher rate of GTR than the microsurgical group (8/28 patients) (P = 0.005). This was evident in all patients but those with Knosp grade 4. Using the quadrant classification, the endoscopic group had a significantly higher rate of GTR than the microsurgical group in all but the inferolateral quadrant. The 2 classifications showed similar sensitivity in predicting subtotal resection (78% quadrant vs. 82% Knosp), with limited specificity (both 25%). CONCLUSIONS: GTR of macroadenomas with parasellar extension is significantly enhanced by the endoscopic approach. The 4-quadrant classification appears as sensitive as the Knosp classification and could be a simple adjunct to predict surgical radicality, in particular in cases of inferolateral quadrant invasion. PMID- 30312825 TI - Multimodal Imaging Aids in the Diagnosis of Perineural Spread of Prostate Cancer. AB - BACKGROUND: The perineural spread of prostate cancer into pelvic peripheral nerves is a rare, but increasingly recognized, entity. This form of metastasis invades the lumbosacral plexus via the splanchnic nerves innervating the prostate. The prevalence of perineural spread is likely underappreciated, and further imaging-based studies are needed to elucidate its true frequency. METHODS: A retrospective review was performed using an institutional radiology database. Medical reports from patients with prostate cancer who had undergone positron emission tomography (PET) imaging were queried for terms suggestive of perineural spread. PET and magnetic resonance imaging (MRI) from the identified patients were blindly reviewed for peripheral nerve involvement by 2 nuclear medicine and 2 musculoskeletal radiologists. RESULTS: A total of 22 patients were identified. After review by the radiologists, 16 patients had positive findings of perineural spread found on PET and 15 had abnormalities found on MRI involving lumbosacral plexus neural elements. All patients with biopsy-proven neoplastic perineural spread (including 1 patient with malignant peripheral nerve sheath tumor) had positive findings on both PET and MRI. All patients with biopsy-proven inflammatory lesions had negative PET and variable MRI findings. CONCLUSIONS: The perineural spread of prostate cancer might be more common than previously thought. The use of multimodal imaging for patients suspected of having perineural spread should be a part of the treatment algorithm. Targeted fascicular biopsy might be indicated for patients with progressive neurological deficit and an unclear diagnosis. PMID- 30312826 TI - Utility of Magnetic Resonance Perfusion Imaging in Quantifying Active Tumor Fraction and Radiation Necrosis in Recurrent Intracranial Tumors. AB - BACKGROUND: Ancillary criteria to identify tumor recurrence such as the McDonald criteria or Response Assessment in Neuro-Oncology criteria can provide false diagnoses. Magnetic resonance perfusion (MRP) imaging has been proposed to differentiate post-treatment changes from recurrence. We investigated the utility of MRP to quantify the histological fraction of active tumor (AT), treatment related changes, and radiation necrosis in recurrent post-treatment intracranial tumors. METHODS: We conducted an exploratory single-blind study of patients with intracranial glioblastoma or metastases with previous radiation therapy and MRP before surgery. Biopsy specimens (n = 19) were analyzed for the percentage of AT, radiation necrosis, and treatment effect. Nonparametric Spearman's rho analysis and multivariable analysis of covariance were performed to assess the correlation between quantitative MRP and AT histological fraction. RESULTS: The mean patient age was 58 +/- 11.5 years. The mean relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were 1.33 +/- 0.71 and 1.34 +/- 0.73, respectively. On analysis of covariance, significant associations were identified between increased rCBF (P = 0.0004) and increased rCBV (P = 0.007) and percentage of AT. A significant interaction was identified between rCBF and rCBV and tumor histological features (glioblastoma vs. metastases; P = 0.003 and P = 0.03, respectively). An rCBF >1 predicted a mean AT fraction of >=53% for all intracranial tumors and 74% for glioblastoma. CONCLUSION: MRP can help quantitatively predict tumor recurrence and/or progression for glioblastomas. The AT histological fraction correlated with quantitative radiologic measurements, including rCBV and rCBF. For metastases, MRP might not be as useful in predicting the AT fraction. Clinicians must be judicious with their use of MRP in predicting tumor recurrence and radiation necrosis. PMID- 30312827 TI - Correlation of Preoperative Von Willebrand Factor with Magnetic Resonance Imaging Perfusion and Permeability Parameters as Predictors of Prognosis in Glioblastoma. AB - BACKGROUND: Angiogenesis has been shown to be strictly related to tumor malignancy. Glioblastoma (GBM) is highly vascularized and von Willebrand Factor (VWF) plays a potent proangiogenic role. Dynamic contrast-enhanced and dynamic susceptibility contrast magnetic resonance imaging (MRI) represent a widely accepted method to assess GBM microvasculature. Our aim was to investigate the correlation between plasma VWF:Ag, permeability, and perfusion MRI parameters and examine their potential in predicting GBM patient prognosis. METHODS: We retrospectively analyzed preoperative dynamic contrast-enhanced, dynamic susceptibility contrast MRI, and VWF:Ag level of 26 patients with GBM. We assessed the maximum values of relative cerebral blood flow and volume, volume transfer constant Ktrans, plasma volume (Vp) and reflux rate constant between fractional volume of the extravascular space and blood plasma (Kep). Nonparametric Mann-Whitney test and Kaplan-Meier survival analyses were conducted and a P value < 0.05 was considered statistically significant. RESULTS: The median VWF:Ag value was 248 IU/dL and the median follow-up duration was about 13 months. We divided patients according to low-VWF:Ag and high-VWF:Ag and we found significant differences in the median follow-up duration (19 months vs. 10 months; P = 0.04) and in Ktrans (0.31/minute vs. 0.53/minute; P = 0.02), and Kep (1.79/minute vs. 3.89/minute; P = 0.005) values. The cumulative 1-year survival was significantly shorter in patients with high-VWF:Ag and high-Kep compared with patients with low-VWF:Ag and low-Kep (37.5% vs. 68%; P = 0.05). CONCLUSIONS: These findings, in a small group of patients, suggest a role for VWF:Ag, similar to Ktrans, and Kep as a prognostic indicator of postoperative survival of patients with GBM. PMID- 30312828 TI - Mutations in DNA gyrase and topoisomerase genes linked to fluoroquinolone resistance in Salmonella Typhimurium of animal origin in India. PMID- 30312829 TI - Antimicrobial activity of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) isolates from Spain and molecular characterisation of borderline susceptible and resistant strains. PMID- 30312830 TI - Emergence of an Escherichia coli strain co-harboring mcr-1 and blaNDM-9 from urinary tract infection in Taiwan. AB - OBJECTIVES: Multidrug resistance bacteria has become a serious issue worldwide. Especially the coexistence of carbapenemase genes and mcr-1 leaves few available options for treatment. In this study, we report a multidrug-resistant Escherichia coli isolate harboring both mcr-1 and blaNDM-9 from a patient with urinary infection. METHODS: The antimicrobial susceptibility and resistance genes of the E. coli isolate were characterized. Furthermore, the assembled genome sequences of mcr-1 and blaNDM-9 carrying plasmids and comparative genetic analysis with closely related plasmids were carried out. RESULTS: Three contigs have been assembled as the E. coli chromosome and plasmids harboring mcr-1 (p5CRE51-MCR-1) and blaNDM-9 (p5CRE51-NDM-9). The whole genome sequence revealed that these two antimicrobial resistance genes are located on individual plasmids. CONCLUSIONS: The emergency of coexistence of carbapenemase genes and mcr-1 in Enterobacteriaceae highlights the serious threat to antimicrobial therapy. PMID- 30312831 TI - Prevalence, Multidrug Resistance and Molecular Typing of MRSA in Retail Meat from Punjab, India. AB - OBJECTIVE: This study reports the prevalence of Methicillin-Resistant S. aureus (MRSA) in meat samples taken from Punjab, India. METHODS: Classical microbiological methods were applied to isolate and identify the Staphylococcus aureus. These isolates were further subjected to Epsilometer test. PCR and sequencing were used to identify and characterize the antibiotic-resistant genes. The SCCmec typing, MLST and spa typing was done on the MRSA isolates. RESULTS: A total of 408 meat and 101 swabs samples were processed for isolation of S. aureus. The phenotypic resistance of S. aureus isolates to penicillin was highest (90.97%), followed by ciprofloxacin (61.80%), tetracycline (45.14%), and erythromycin (11.11%). Isolates from chicken samples showed significantly (P <0.05) higher MIC for tetracycline than chevon and pork; and significantly higher MIC for trimethoprim-sulfamethoxazole and gentamicin than chevon and swab samples (P <0.05). None of the isolates was phenotypically resistant to vancomycin (MIC 0.5-2MUg/ml). Most of the isolates (52.78%, 95%CI 44.63-60.93) were Multi-drug resistant (MDR) and carried resistance genes; penicillin (blaZ), oxacillin (mecA), gentamicin (aacA-aphD), erythromycin (ermB, ermC) and tetracycline (tetK, tetL, tetM). MRSA was found only in chicken samples (2.72%, 4/147). Seven S. aureus (5.34%) isolates were borderline oxacillin resistant (BORSA) with MIC ranging from 4-8MUg/ml. All MRSA isolates in this study were SCCmec type V, pvl positive and spa type t442, but among these, three isolates were ST5. Their genotypic profile was mecA+, blaZ+, aacA-aphD+, tetK+, ermC+/-. Among the erythromycin-resistant isolates, 25% were MRSA. Out of them, 12.5% isolates expressed inducible macrolide lincosamide and streptogramin (MLSB) phenotype (ERY+/CLI-, D+). CONCLUSION: Our data confirm the presence of ST5, spa type t442 MRSA-SCCmecV-pvl+ and iMLSB-MRSA in meat samples indicating a potential role of meat in the dissemination of MDR S. aureus strains and successful MRSA lineages in Punjab. PMID- 30312832 TI - Effects of dietary supplementation with krill meal on serum pro-inflammatory markers after the Iditarod sled dog race. AB - A seafood-based supplement from krill, rich in omega-3 phospholipids and proteins was tested on a group of dogs competing in the 2016 Iditarod dog sled race to investigate the effects of krill meal on exercise-induced inflammation and muscle damage in comparison to a control group. A single team of 16 dogs received 8% krill meal for 5 weeks prior to the start of race, while another team of 16 dogs received no supplementation. Ten dogs of the treatment and 11 dogs of the control group finished the race and their blood was analyzed for omega-3 index, inflammation (CRP) and muscle damage (CK). The omega-3 index of the krill meal fed dogs was significantly higher at the beginning of the race (mean 6.2% in the supplemented vs 5.2% in the control group, p < .001). CRP concentrations increased from 7.05 +/- 2.27 to 37.04 +/- 9.16 MUg/ml in the control and from 4.26 +/- 0.69 to 16.56 +/- 3.03 MUg/ml in the treatment group, with a significant difference between the groups (p < .001). CK activity was increased from 90.75 +/ 8.15 IU/l to 715.90 +/- 218.9 IU/l in the control group and from 99.55 +/- 12.15 to 515.69 +/- 98.98 in the supplemented group, but there were no differences between groups (p = .266). The results showed that krill meal supplementation led to significantly higher omega-3 index, which correlated with lower inflammation and a tendency for reduced muscle damage after this long-distance sled dog competition. However, these results need to be confirmed by more controlled studies, since it was a field study and effects of race speed or other performance-related factors such as fitness and musher skill on the results cannot be excluded. PMID- 30312833 TI - Auditory perception is associated with implicit language learning and receptive language ability in autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is associated with language impairment as well as atypical auditory sensory processing. The current study investigated associations among auditory perception, implicit language learning and receptive language ability in youth with ASD. METHODS: We measured auditory event related potentials (ERP) during an artificial language statistical learning task in 76 youth with ASD and 27 neurotypical (NT) controls. Participants with ASD had a broad range of cognitive and language abilities. RESULTS: NT youth showed evidence of implicit learning via attenuated P1 amplitude in the left hemisphere. In contrast, among youth with ASD, implicit learning elicited bilateral attenuation that was increasingly evident with greater receptive language skill. CONCLUSIONS: Efficient early auditory perception reflects language learning and is a marker of language ability among youth with ASD. Atypical lateralization of word learning is evident in ASD across a broad range of receptive language abilities. PMID- 30312834 TI - Association of SNPs in transferrin and transferrin receptor genes with blood iron levels in human. AB - Iron is bound to mobile transferrin (TF) and ferritin in blood. TF receptors (TFRC and TFR2) regulate intracellular iron by delivering iron from TF into the cytoplasm. In this study, we examined the effects of 10 single nucleotide polymorphisms (SNPs) in each of the genes for TF and TF receptors on blood iron concentrations in Japanese subjects. Blood iron levels were determined by microwave plasma-atomic emission spectrometry and the SNPs were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Blood iron levels in males were significantly higher than those in females. Therefore, the analysis was performed only in males. Blood iron concentrations did not correlate with age and postmortem intervals in males. Among the 10 SNPs in TF, TFRC, and TFR2 genes, significant associations were observed between TF genotypes (rs12769) and male iron concentrations. Individuals with genotype GG in rs12769 had significantly higher blood iron concentrations than those with GA. Previous studies have shown the association between high tissue iron concentrations and disease, liver iron levels are higher in infants dying from sudden infant death syndrome and decreased blood iron concentrations were observed in critically ill children. Therefore, rs12769 in TF might be related to diseases and mortality risk. PMID- 30312835 TI - Association between sudden unexpected deaths in bathtubs and ambient temperature among elderly Japanese adults: A time-series regression study. AB - BACKGROUND: Sudden unexpected deaths in bathtubs among elderly Japanese adults occur predominantly during the cold season. This study investigated the relationship between these deaths and bathing day temperature among elderly adults in Tokyo. METHODS: Data for 1408 cases of bath-related deaths from January 1 to December 31, 2015 were obtained from the Tokyo Medical Examiner's Office. We excluded 409 cases for the following reasons: criminal death, injury-related death, suicide, intoxication, non-sudden death, not bathtub-related death, out-of bathroom death, subject aged under 65 years, undetermined bathing date, institutional housing, and bathing not at subject's home. Ultimately, 999 cases were analyzed. Daily mean temperature data were collected. A time-series regression study was performed to estimate the influence of sex, age, and bathing day temperature. Monthly changes in the population bathing in a bathtub were considered in the model. RESULTS: The relative risk (RR) of sudden unexpected death in a bathtub was 1.381 for males (95% confidence interval [CI]: 1.218 1.564) compared to females. The RRs were 4.182 (95% CI: 3.523-4.986) and 9.382 (95% CI: 7.836-11.273) among those aged 75-84 years and >=85 years, respectively, compared to among those aged 65-74 years. The RR increased to 1.092 (95% CI: 1.082-1.102) as the daily mean temperature decreased by 1 degrees C. CONCLUSION: Sudden unexpected death in a bathtub correlated with bathing day temperature among elderly Japanese adults, and extremely low temperature, male sex, and older age increased the risk of such death. Our findings provide insight into preventing sudden unexpected deaths in bathtubs. PMID- 30312836 TI - Traumatic axonal injury revealed by postmortem magnetic resonance imaging: A case report. AB - In forensic investigations, it is important to detect traumatic axonal injuries (TAIs) to reveal head trauma that might otherwise remain occult. These lesions are subtle and frequently ambiguous on macroscopic evaluations. We present a case of TAI revealed by pre-autopsy postmortem magnetic resonance imaging (PMMR). A man in his sixties was rendered unconscious in a motor vehicle accident. CT scans revealed traumatic mild subarachnoid hemorrhage. Two weeks after the accident he regained consciousness, but displayed an altered mental state. Seven weeks after the accident, he suddenly died in hospital. Postmortem computed tomography (PMCT) and PMMR were followed by a forensic autopsy. PMMR showed low-intensity lesions in parasagittal white matter, deep white matter, and corpus callosum on three dimensional gradient-echo T1-weighted imaging (3D-GRE T1WI). In some of these lesions, T2*-weighted imaging also showed low-intensity foci suggesting hemorrhagic axonal injury. The lesions were difficult to find on PMCT and macroscopic evaluation, but were visible on antemortem MRI and confirmed as TAIs on histopathology. From this case, it can be said that PMMR can detect subtle TAIs missed by PMCT and macroscopic evaluation. Hence, pre-autopsy PMMR scanning could be useful for identifying TAIs during forensic investigations. PMID- 30312838 TI - The effect of C9orf72 intermediate repeat expansions in neurodegenerative and autoimmune diseases. PMID- 30312837 TI - A qualitative evaluation of the appropriateness, validity, acceptability, feasibility and interpretability of the Bristol Impact of Hypermobility (BIoH) questionnaire. AB - BACKGROUND: The Bristol Impact of Hypermobility (BIoH) questionnaire is a condition-specific patient-reported outcome measure developed for adults with Joint Hypermobility Syndrome (JHS). It has previously demonstrated strong concurrent validity with the Short-Form 36 health questionnaire and excellent test-retest reliability. OBJECTIVES: This study aimed to evaluate its appropriateness, validity, acceptability, feasibility and interpretability. DESIGN: A qualitative evaluation using semi-structured telephone interviews, incorporating a 'think aloud' exercise and additional prompts. METHOD: Adults with JHS (n = 11) were recruited through a patient organisation and physiotherapists with a professional interest in JHS (n = 9) were recruited through the same organisation and an online professional network. Interviews were transcribed and data synthesised using a framework matrix. FINDINGS: Patients and physiotherapists commented positively on the appropriateness, validity, acceptability and feasibility of the BIoH questionnaire. Physiotherapists assessed the interpretability of the questionnaire and commented that, whilst further information might be captured, the value of that information might be limited. The questionnaire was considered comprehensive with only a very limited number of potential missing areas related to use of hand-held technology, hair washing/drying and intimacy. Interestingly, keyboard use and hair washing were excluded during initial questionnaire development as they were rated as relatively unimportant. Intimacy was not considered a comfortable addition for all participants. CONCLUSIONS: Patients and physiotherapists regarded the BIoH questionnaire as a welcome addition to the toolkit available to assess those with JHS. It was broadly accepted as reflecting the experience of people with JHS in sufficient detail to support management. PMID- 30312839 TI - Disentangling the association of depression on the anti-fatigue effects of ketamine. AB - BACKGROUND: Fatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported. METHODS: This secondary analysis re evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health-Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Compared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores. CONCLUSIONS: In this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression. PMID- 30312840 TI - Subjective and physiological response to emotions in temporal lobe epilepsy and psychogenic non-epileptic seizures. AB - BACKGROUND: Temporal lobe epilepsy (TLE) and psychogenic non-epileptic seizures (PNES) are conditions frequently associated with dysfunction in emotional regulation leading to increased risk of affective disorders. This study investigates emotional processing with an objective measure of emotional reactivity in patients with TLE and patients with PNES. METHODS: 34 patients with TLE and 14 patients with PNES were evaluated on skin conductance responses (SCR) to emotions induced by short films and compared to 34 healthy controls. An attention and a suppression condition were performed while viewing the films. RESULTS: The both groups of patients disclosed lower SCR to emotions compared to controls, mainly in suppression condition. While TLE patients had lower SCR in attention condition than controls for fear, sadness and happiness, PNES had lower SCR only for happiness. In suppression condition, both had lower SCR than controls except for peacefulness in both groups and sadness in PNES. Subjective evaluations revealed that both patient's groups scored a higher intensity for sadness than controls in attention and lower for in fear and disgust in suppression only in TLE. LIMITATIONS: The sample size in the PNES group and the lack of a control group with similar levels of mood symptoms limited the interpretation of our results. CONCLUSION: As no correlation were found between SCR to emotions and scores of affective disorders, this pattern of responses might be underpinned by specific pathophysiological and cognitive mechanisms related to TLE and to PNES. Thus, therapeutic approaches targeting emotional autonomic responses can be of interest in the management of these conditions. PMID- 30312841 TI - Surfactant enhanced flow injection chemiluminescence method for vitamin D3 determination in pharmaceutical formulations. AB - A flow injection based chemiluminescence process has been reported for vitamin D3 determination without using especial chemiluminescence reagent. Vitamin D3 shows enhancement on the CL intensity of diperiodatocuprate(III) with surfactant (Triton X-100) solution. The calibration curve was found to be linear over the concentration range 0.01-40 mg/L (R2 = 0.9997, n = 8) tested. A limit of detection (S/N = 3), limit of quantification (S/N = 10) and sample injection throughput of 2.5 * 10-3, 8.3 * 10-3 mg/L and 150 h-1 respectively were obtained. Various experimental variables were tested to get most suitable response, e.g., the concentrations of reagents, and their flow rates, sample injection volume and photomultiplier tube voltage. The effect of potential interferences was also examined. Vitamin D3 determination was successfully carried out in pharmaceutical formulations. The recoveries from the formulations were obtained in the range of 96 +/- 4-108 +/- 2%. The reaction mechanism discussion for diperiodatocuprate(III) complex-Triton X-100-vitamin D3 was also included. PMID- 30312842 TI - Quantitative analysis of cefazolin sodium in lyophilized powder by infrared spectrophotometry: Green, low cost, fast and effective. AB - Cefazolin sodium is a broad-spectrum antibiotic used in the treatment of infectious diseases in humans and in the surgical prophylaxis. Thus, since a considerable number of people have access to this drug, it is of great interest of quality control. The aim of this study was development and validation of a green method by Fourier-Transform Infrared (FT-IR) transmission spectrophotometry for the quantification of cefazolin sodium in lyophilized powder. This technique is widely used in the pharmaceutical industry due to its ease of execution, low cost, safety and high precision and accuracy. It has been employed in the quality control routine of numerous pharmaceuticals in order to identify them and quantify their active principles. The proposed method was completely validated according ICH guidelines, showing selectivity, accuracy, precision, robustness and linearity. It was linear over the concentration range of 0.4-1.7 mg with correlation coefficient 0.999, limits of detection and quantification of 0.017 mg and 0.052 mg, respectively, precise, accurate and robust when changes in the time, pressure and mark of potassium bromide were carried out during the preparation of the pellets. The proposed method was successfully applied to the qualitative and quantitative quality control of cefazolin sodium in lyophilized powder. In addition, the method is considered green, clean and sustainable since it uses only a single reagent; it is a fast, low-cost and environmentally friendly method. PMID- 30312843 TI - One-pot synthesis of dual carbon dots using only an N and S co-existed dopant for fluorescence detection of Ag. AB - Luminescent carbon-based nanoparticles, named often as carbon dots (CDs), were synthesized from citric acid (CA) and guanidine thiocyanate (GITC) via an N and S co-doped hydrothermal procedure. In the present structure characterization, N and S elements could be sufficiently doped by means of the heteroatom or the functional groups bonded on the surface of CDs. The as-prepared CDs solution showed blue color fluorescence under ultraviolet excitation, yet the PL spectra exhibited a repetitive emission process from excitation-independent to excitation dependent. In view of the triexponential feature of fluorescence lifetimes of CDs, one possibility was proposed to be co-existence of two types of CDs with different surface states. Additionally, the as-prepared CDs were used as a sensing probe for the detection of Ag+ taking into consideration of the possible interactions between Ag+ and various fluorophores attached to the CD surface. As expected, the changes of fluorescence intensities were linearly proportional to the different concentration ranges of Ag+, which suggests the complex nature of the quenching mechanism. And for the first time, the SCN group was found to accelerate the quenching of CDs towards Ag+, promising a new approach for efficient detection of Ag+ for the application in industrial pollutants. PMID- 30312844 TI - A comparison of several second-order algorithms for simultaneous determination of neomangiferin and mangiferin with severe spectral overlapping in Anemarrhenae Rhizoma. AB - This work presents a greener approach for simultaneous determination of neomangiferin and mangiferin, the major bioactive constituents with severe spectral overlapping in Anemarrhenae Rhizoma, combining the sensitivity of molecular fluorescence and the selectivity of chemometric multivariate calibration algorithms. In this study, we compared the analytical performance of two group chemometric algorithms including trilinear algorithms such as parallel factor analysis (PARAFAC), alternating trilinear decomposition (ATLD), self weighted alternating trilinear decomposition (SWATLD) and alternating penalized trilinear decomposition (APTLD), and PLS-based methods such as unfolded partial least-squares or the multi-dimensional partial least-squares, both combined with residual bilinearization (U-PLS/RBL, N-PLS/RBL). The statistical parameters for the validation set of the second calibration were evaluated through the relative error of prediction (REP%), the average recovery (Rec%), and the root mean square error of prediction (RMSEP). Prediction results for the validation set by trilinear algorithms showed that the values were satisfactory for neomangiferin, and higher and not acceptable values for mangiferin, while U-PLS and N-PLS predictions were very successful for two analytes. Therefore, U- and N-PLS/RBL were chosen to determine neomangiferin and mangiferin in more complex real samples simultaneously, and U-PLS/RBL algorithm showed the best performance. The predicted concentrations by proposed methods were satisfactorily compared with those obtained using high performance liquid chromatography with ultraviolet detection. PMID- 30312845 TI - HIT-Cas9: A CRISPR/Cas9 Genome-Editing Device under Tight and Effective Drug Control. AB - The CRISPR/Cas9 enabled efficient gene editing in an easy and programmable manner. Controlling its activity in greater precision is desired for biomedical research and potential therapeutic translation. Here, we engrafted the CRISPR/Cas9 system with a mutated human estrogen receptor (ERT2), which renders it 4-hydroxytamoxifen (4-OHT) inducible for the access of genome, and a nuclear export signal (NES), which lowers the background activity. Tight and efficient drug-inducible genome editing was achieved across several human cell types, including embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs), upon vigorous optimization. Optimized terminal device, which we named hybrid drug inducible CRISPR/Cas9 technology (HIT-Cas9), delivered advantageous performances over several existing designs. Such architecture was also successfully applied to an orthogonal Cas9. The HIT-Cas9 system developed in this study will find broad utility in controlled editing of potentially any genomic loci. PMID- 30312847 TI - Kinematic adaptation and changes in gait classification in running compared to walking in children with unilateral spastic cerebral palsy. AB - BACKGROUND: Classification of sagittal gait patterns in unilateral spastic cerebral palsy (CP) provides direct implication for treatment. Five types are described: type 0 has minor gait deviation; type 1 has inadequate ankle dorsiflexion in swing; type 2 has inadequate ankle dorsiflexion throughout the gait cycle; types 3 and 4 have abnormal function of the knee and hip joint respectively. During gait analysis of children with unilateral spastic CP we observed frequently that a knee flexion deficit disappeared during running. That may have an impact on classification and treatment. RESEARCH QUESTION: Does the classification type change while running and how do patients' kinematics adapt to running? METHODS: 64 children with unilateral spastic CP were classified using instrumented gait analysis for walking and running. The deviation of four parameters from typically developing children (TD) were used to distinguish between types: peak ankle dorsiflexion in swing for type 1, peak ankle dorsiflexion in stance for type 2, knee range of motion for type 3, and hip range of motion for type 4. A three-factor ANOVA for factors group (CP/TD), locomotion (walk/run) and limb side (in-/uninvolved) was conducted. RESULTS: The number of patients with type 1, 3 and 4 decreased considerably from walking to running, whereas, the number of type 0 and 2 patients increased. The ANOVA showed that three of four parameters of patients' pathologic limb adapt similarly to TD to running, except for the ankle dorsiflexion in stance. SIGNIFICANCE: Running shows that there is a natural way to resolve abnormalities. Therefore, recommended treatments of hip and knee joint abnormalities based on the walking classification can be questioned and additional running analysis may be important for surgical decision making. PMID- 30312846 TI - An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo. AB - The PI3K-AKT-mTOR-signaling pathway is frequently activated in glioblastoma (GBM). Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)/p110beta (a PI3K catalytic isoform) by RNAi substantially suppresses GBM growth with less toxicity to normal astrocytes. However, insufficient and non-specific small interfering RNA (siRNA) delivery may limit the efficacy of RNAi-based therapies against GBM. Here we prepared a novel methoxy-modified PIK3CB siRNA molecule (siPIK3CB) that was covalently conjugated to a [cyclo(Arg-Gly-Asp-D-Phe-Lys)-Ahx]2-Glu-PEG-MAL (biRGD) peptide, which selectively binds to integrin alphavbeta3 receptors. The alphavbeta3-positive U87MG cell line was selected as a representative for GBM. An orthotopic GBM xenograft model based on luciferase-expressing U87MG was established and validated in vivo to investigate bio-distribution and anti-tumor efficacy of biRGD-siPIK3CB. In vitro, biRGD-siPIK3CB specifically entered and silenced PIK3CB expression in GBM cells in an alphavbeta3 receptor-dependent manner, thus inhibiting cell cycle progression and migration and enhancing apoptosis. In vivo, intravenously injected biRGD-siPIK3CB substantially slowed GBM growth and prolonged survival by reducing tumor viability with silencing PIK3CB expression. Furthermore, biRGD-siPIK3CB led to mild tubulointerstitial injury in the treatment of GBM without obvious hepatotoxicity, whereas co-infusion of Gelofusine obviously alleviated this injury without compromising anti-tumor efficacy. These findings revealed a great translational potential of biRGD siPIK3CB conjugate as a novel molecule for GBM therapy. PMID- 30312848 TI - Bayesian classification of falls risk. AB - BACKGROUND: Prior research in falls risk prediction often relies on qualitative and/or clinical methods. There are two challenges with these methods. First, qualitative methods typically use falls history to determine falls risk. Second, clinical methods do not quantify the uncertainty in the classification decision. In this paper, we propose using Bayesian classification to predict falls risk using vectors of gait variables shown to contribute to falls risk. RESEARCH QUESTIONS: (1) Using a vector of risk ratios for specific gait variables shown to contribute to falls risk, how can older adults be classified as low or high falls risk? and (2) how can the uncertainty in the classifier decision be quantified when using a vector of gait variables? METHODS: Using a pressure sensitive walkway, biomechanical measurements of gait were collected from 854 adults over the age of 65. In our method, we first determine low and high falls risk labels for vectors of risk ratios using the k-means algorithm. Next, the posterior probability of low or high falls risk class membership is obtained from a two component Gaussian mixture model (GMM) of gait vectors, which enables risk assessment directly from the underlying biomechanics. We classify the gait vectors using a threshold based on Youden's J statistic. RESULTS: Through a Monte Carlo simulation and an analysis of the receiver operating characteristic (ROC), we demonstrate that our Bayesian classifier, when compared to the k-means falls risk labels, achieves an accuracy greater than 96% at predicting low or high falls risk. SIGNIFICANCE: Our analysis indicates that our approach based on a Bayesian framework and an individual's underlying biomechanics can predict falls risk while quantifying uncertainty in the classification decision. PMID- 30312849 TI - Oxidative stress and hepatotoxicity of Rana chensinensis exposed to low doses of octylphenol. AB - This study investigated the effects of low doses of octylphenol (OP) on the oxidative stress and hepatotoxicity in amphibian liver. The frog, Rana chensinensis, were exposed to 10-8, 10-7, 10-6 mol/L OP for 10, 20 and 30 days. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) in liver were reduced at first, then recovered slightly, and the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) were increased significantly. Histopathology showed that in some liver tissues of OP treated frogs, the hematococoel expansion, the fat accumulation, the cytoplasmic vacuolization and even hepatocyte necrosis were present. Ultrastructure revealed that there were lipid droplet accumulation, mitochondria deformation and nuclear condensation in some hepatocytes. These results confirm that low doses OP exposure can give rise to oxidative stress in the liver of frogs, reduce antioxidant enzymes activities, lead to partial organelles damage in hepatocyte and the fat accumulate in hepatic tissue. PMID- 30312850 TI - Safrole induced cytotoxicity, DNA damage, and apoptosis in macrophages via reactive oxygen species generation and Akt phosphorylation. AB - Safrole is a natural compound categorized as a group 2B carcinogen extracted from betel quid chewing, which is a common practice of psychoactive habits integrated into social and cultural ceremonies among serveral million people, especially in Southern or Southeastern Asia. Safrole is one of the major risk compunds for development of oral squamous cell carcinoma and hepatocellular carcinoma via DNA adduction. In innate immunity, macrophages are the predominant cells for non specific first line defense against pathogens in oral tissue. Up to now, there is no evidence to implicate the potential toxicological effect of safrole on macrophages. In this study, we found safrole induced the generation of reactive oxygen species (ROS) and myeloperoxidase (MPO) in RAW264.7 macrophages in a concentration-dependent manner. Furthermore, cytotoxicity, DNA damage, and apoptosis were caused by safrole in a concentration-dependent manner. While the activation of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) was reduced, the phosphorylation of Akt was induced by safrole in a concentration-dependent manner. These results indicated that the induction of cytotoxicity, DNA damage, and apoptosis in macrophages by safrole was through generation of ROS and inhibition of antioxidative enzymes possibly via Akt phosphorylation. PMID- 30312851 TI - Efficient magnetic enrichment of antigen-specific T cells by engineering particle properties. AB - Magnetic particles can enrich desired cell populations to aid in understanding cell-type functions and mechanisms, diagnosis, and therapy. As cells are heterogeneous in ligand type, location, expression, and density, careful consideration of magnetic particle design for positive isolation is necessary. Antigen-specific immune cells have low frequencies, which has made studying, identifying, and utilizing these cells for therapy a challenge. Here we demonstrate the importance of magnetic particle design based on the biology of T cells. We create magnetic particles which recognize rare antigen-specific T cells and quantitatively investigate important particle properties including size, concentration, ligand density, and ligand choice in enriching these rare cells. We observe competing optima among particle parameters, with 300 nm particles functionalized with a high density of antigen-specific ligand achieving the highest enrichment and recovery of target cells. In enriching and then activating an endogenous response, 300 nm aAPCs generate nearly 65% antigen-specific T cells with at least 450-fold expansion from endogenous precursors and a 5-fold increase in numbers of antigen-specific cells after only seven days. This systematic study of particle properties in magnetic enrichment provides a case study for the engineering design principles of particles for the isolation of rare cells through biological ligands. PMID- 30312852 TI - Evaluation of the host immune response to decellularized lung scaffolds derived from alpha-Gal knockout pigs in a non-human primate model. AB - Whole organ tissue engineering is a promising approach to address organ shortages in many applications, including lung transplantation for patients with chronic pulmonary disease. Engineered lungs may be derived from animal sources after removing cellular content, exposing the extracellular matrix to serve as a scaffold for recellularization with human cells. However, the use of xenogeneic tissue sources in human transplantation raises concerns due to the presence of the antigenic Gal epitope. In the present study, lungs from wild type or alpha Gal knockout pigs were harvested, decellularized, and implanted subcutaneously in a non-human primate model to evaluate the host immune response. The decellularized porcine implants were compared to a sham surgery control, as well as native porcine and decellularized macaque lung implants. The results demonstrated differential profiles of circulating and infiltrating immune cell subsets and histological outcomes depending on the implanted tissue source. Upon implantation, the decellularized alpha-Gal knockout lung constructs performed similarly to the decellularized wild type lung constructs. However, upon re implantation into a chronic exposure model, the decellularized wild type lung constructs resulted in a greater proportion of infiltrating CD45+ cells, including CD3+ and CD8+ cytotoxic T-cells, likely mediated by an increase in production of Gal-specific antibodies. The results suggest that removal of the Gal epitope can potentially reduce adverse inflammatory reactions associated with chronic exposure to engineered organs containing xenogeneic components. PMID- 30312853 TI - Investigating chemical and structural instabilities of lead halide perovskite induced by electron beam irradiation. AB - Chemical and structural instabilities of lead halide perovskites remain a major obstacle to their large-scale applications in photovoltaic solar cells and optoelectronic devices. Herein we report on a comparative investigation of electron beam irradiation effects on (all-inorganic) CsPbI3 and (organic inorganic hybrid) CH3NH3PbI3 halide perovskite thin films by transmission electron microscopy. Upon continuous electron beam irradiation with high dose rates, CsPbI3 exhibits rather rapid morphological change and compositional degradation within irradiated regions, which are attributed to the radiolysis effect and probably assisted by electron beam heating and Coulomb forces. In contrast, for the freestanding, polycrystalline CH3NH3PbI3 thin films, significant structural damage mainly occurs on/outside the periphery of the irradiated regions, while, within the irradiated areas, the structural configurations appear rather intact. The electron beam induced electric field effect is suggested to be the primary reason for the unusual damage phenomenon. The building up of induced electrical fields in CH3NH3PbI3 is probably pertinent to its some unusual structural properties (e.g., rotational dynamics of organic cations), but should be also promoted by the unavoidable modifications of physical properties during the film preparation and electron beam focusing. The study provides an insight for exploring the fundamental origin of structural instabilities and property degradation of halide perovskites. PMID- 30312854 TI - Cesarean section scar choriocarcinoma, an unusual entity with ultrasound, MRI and pathologic correlation. PMID- 30312855 TI - Asymptomatic systemic air embolism after CT-guided percutaneous transthoracic needle biopsy. AB - PURPOSE: We presented details and incidence of systemic arterial embolism (SAE) following a CT-guided percutaneous transthoracic needle biopsy (PTNB) and evaluated risk factors for SAEs. METHODS: We retrospectively evaluated 1014 PTNBs performed in our hospital from 2005 to 2017. SAE was identified in the pulmonary vein, left heart, coronary artery, and aorta by reviewing post-biopsy CT images. Limited post-biopsy CT scans only covering the region biopsied were available until the first case of SAE was identified (n = 503). Then, the entire thorax was scanned for further examination of SAE (n = 511). Eighteen-gauge automatic cutting needles were used in all procedures. When SAE was evident on post-biopsy CT, subsequent brain CT was performed in order to confirm the cerebral SAE. RESULTS: Nine patients (0.89%) developed SAEs. In the univariate analyses, the location of the needle tip relative to the lesion (outside or inside of the lesion) as well as accompanying pulmonary hemorrhage were significant risk factors for SAEs (P = 0.021 and 0.036, respectively). Two patients developed neurological symptoms with cerebral SAEs, and one of these had sequelae. In seven asymptomatic SAEs with no cerebral SAE, four patients were retrospectively diagnosed cases and three patients were detected on post-biopsy CT images. All seven of these patients had no sequelae. CONCLUSION: The incidence of SAE was higher than expected, due to radiologically detected asymptomatic SAEs. The location of the needle tip relative to the lesion and accompanying pulmonary hemorrhage were significant risk factors for the occurrence of SAEs. We proposed a guideline for treating asymptomatic SAEs. PMID- 30312856 TI - Influence of cardiac function on image quality in coronary computed tomography angiography. AB - PURPOSE: To evaluate the correlation between cardiac functional parameters and image quality in coronary computed tomography angiography (CCTA). MATERIAL AND METHODS: Sixty-six patients who underwent both CCTA and echocardiography were included. The coronary artery attenuation values and contrast-to-noise ratios (CNR) were measured in the proximal right coronary arteries (RCA) and left main (LM) trunk. Then, the averages of the mean values derived from RCA and LM were calculated. The cardiac output (CO), left atrial (LA) volume, and early mitral inflow velocity to mitral annular early diastolic velocity ratio (E/e') were measured by echocardiography. The relationship of cardiac parameters with arterial attenuation and CNR were assessed by Pearson's correlation, Spearman's rank correlation and multivariable linear regression analysis adjusted for age, gender, body surface area and heart rate. RESULTS: The coronary artery attenuation value was negatively correlated with CO (r = -0.30, p = 0.01) and LA volume (r = -0.37, p = 0.002). CNR was negatively correlated with LA volume (r = 0.4, p = 0.001) and E/e' (r = -0.27, p = 0.03). These associations remained significant in the multivariable analysis. CONCLUSION: CO and diastolic function had an impact on image quality of CCTA. Adjusting CCTA protocol may improve image quality in patients with known diastolic dysfunction or reduced cardiac output. PMID- 30312857 TI - Use of alcohol biomarkers to identify alcohol misuse in organ donors. AB - Phosphatidylethanol is a direct alcohol biomarker for identifying alcohol misuse. It carries several advantages over other alcohol biomarkers, including a detection half-life of several weeks and little confounding by patient characteristics or organ dysfunction. The aim of this study is to derive an optimal phosphatidylethanol cut point to identify organ donors with alcohol misuse, and to assess the impact of alcohol misuse on organ allocation. Discrimination of phosphatidylethanol was evaluated using the area under the ROC curve from a mixed effects logistic regression model. Phosphatidylethanol had an area under the ROC curve of 0.89 (95% CI 0.80-0.98). A phosphatidylethanol cut point of >=84 ng/mL provided optimal discrimination for the identification of alcohol misuse with a sensitivity of 75% (95% CI 52.9%-89.4%) and a specificity of 97% (95% CI 91%-99%), a positive predictive value of 82% (95% CI 59%-94%), and a negative predictive value of 95% (95% CI 89%-98%). In deceased organ donors who had been critically ill, phosphatidylethanol had good test characteristics to discriminate alcohol misuse. Other alcohol biomarkers performed poorly in deceased organ donors. Liver allocation was decreased in donors with alcohol misuse by proxy history, but not in those with phosphatidylethanol >84 ng/mL, revealing possible information bias in liver allocation. PMID- 30312858 TI - Deletion of TLR-4 attenuates fetal alcohol exposure-induced gene expression and social interaction deficits. AB - Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism) in mice. Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the offspring. LPS regulates the expression of genes underlying differentiation, immune function, myelination, and synaptogenesis in fetal brain by the LPS receptor, TLR 4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE induced social behavior deficit. WT and TLR4-/- pregnant mice were fed Lieber DeCarli liquid diet with or without ethanol. The control group was pair-fed with an isocaloric diet. Social behavior was tested in the adult offspring at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1beta, IL-6, TNF alpha) were measured by RT-qPCR. Adult male offspring of ethanol-fed WT dams showed low birth weight compared to offspring of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of offspring of pair-fed WT dams. There were no body weight differences in offspring of TLR4-/ dams. Social interaction deficit was observed only in male offspring of ethanol fed WT dams, but it was not observed in both male and female offspring of ethanol fed TLR4-/- dams. Expressions of autism candidate genes, Gabrb3 and Ube3a, were elevated, while that of the Mecp2 gene was suppressed in the frontal cortex of male, but not female, offspring of ethanol-fed WT mice. The expressions of inflammatory cytokine genes, IL-1beta, IL-6, and TNF-alpha, were also significantly increased in the frontal cortex of male, but not female, offspring of ethanol-fed dams. The changes in the expression of autistic and cytokine genes were unaffected in the offspring of ethanol-fed TLR4-/- dams. These data also indicate that TLR4 mediates FAE-induced changes in social interactions and gene expression in brain, suggesting that ethanol-induced LPS absorption from the maternal gut may be involved in gene expression changes in the fetal brain. PMID- 30312859 TI - The intra-assay reproducibility of thromboelastography in very low birth weight infants. AB - BACKGROUND AND AIMS: Despite the potential benefits of thromboelastography (TEG) for bedside hemostatic assessment in critical care settings, its accuracy remains to be determined, especially in critically ill neonates. We determined the intra assay reproducibility of TEG parameters: Reaction time (R), clot kinetics (K) and Maximum Amplitude (MA) in a cohort of very low birth weight (VLBW) infants. STUDY DESIGN: Observational study. SUBJECTS: One hundred VLBW newborns. OUTCOME MEASURES: We performed TEG duplicate measurements for blood samples from VLBW newborns. To assess for correlation, we calculated the coefficients of correlation by plotting the values of the first vs the second measurement. Paired samples were compared with t-test and the coefficient of variation (CV) on paired results was also calculated as a measure of variability. To evaluate the agreement between duplicates, Bland-Altman (BA) analysis was performed. RESULTS: We evaluated 228 TEG pairs. Both the coefficient of correlation and the BA analysis showed an acceptable level of agreement between duplicates. TEG variability (CV, mean +/- SD) was highest for K (10.4%, +/-12.9), lowest for MA (3.6%, +/-8.0) and moderate for R (7.9%, +/-9.0). The results from ANOVA one-way analysis describe different variability trends: K-CV increased at higher values, while MA-CV and R-CV increased at lower values. CONCLUSIONS: In VLBW newborns, the agreement between TEG duplicate measurements for R and MA parameters is adequate for clinical purposes. TEG is a promising tool to quickly assess hemostasis ensuring a significant blood sparing in critically ill neonates. PMID- 30312860 TI - Predictors of hospitalization for acute lower respiratory infections during the first two years of life in a population of preterm infants with bronchopulmonary dysplasia. AB - BACKGROUND: There have been few research studies aimed at obtaining a better understanding of the prediction of subsequent respiratory morbidity at follow-up in infants with a previous history of bronchopulmonary dysplasia (BPD) living in low- and middle-income countries (LMIC). The aim of the present study was to identify predictors of hospitalization for acute lower respiratory infections (ALRIs) in a population of infants with a history of BPD living in a LMIC. METHODS: In a prospective cohort study, we determined independent predictors of the number of hospitalizations for ALRIs during the first two years of life in a population of infants with a history of BPD living in Bogota, Colombia. In multivariate analyses, we included both clinico-demographic variables and underlying disease characteristics as predictor variables of hospitalization for ALRIs. RESULTS: Of a total of 138 patients included in the study, 83 (60.1%) had at least one hospitalization for ALRI during the follow-up period. Independent predictors of the number of hospitalizations for ALRIs included duration of neonatal ventilatory support (IRR 1.02; CI 95% 1.00-1.03; p = 0.010), duration of subsequent ambulatory oxygen therapy (IRR 2.06; CI 95% 1.16-3.64; p = 0.013), and breastfeeding in females (IRR 0.35; CI 95% 0.14-0.84; p = 0.019). CONCLUSIONS: Duration of mechanical ventilation, duration of subsequent ambulatory oxygen therapy, and breastfeeding in females were independently associated with the number of hospitalizations for ALRIs in our population of infants with a history of BPD. PMID- 30312861 TI - The receptor for hyaluronan-mediated motility (RHAMM) expression in neonatal bronchiolar epithelium correlates negatively with lung air content. AB - INTRODUCTION: Hyaluronan (HA) and the receptor for hyaluronan-mediated motility (RHAMM) may play an important role in lung development. We examined the expression of HA content and RHAMM during postnatal lung development by analyzing human lung specimens from newborn infants with a variety of lung diseases at different gestational (GA) and postnatal (PNA) ages. MATERIALS AND METHODS: Ninety-four patients were evaluated. Immunohistochemical RHAMM expression was studied with digital image analysis, followed by hierarchical cluster analysis of both these data and clinical data to define subgroups. The air content of the lung was determined by computerized analysis. HA content was estimated by radiometric assay. RESULTS: Cluster analysis defined six distinct patient groups (Group 1-2: 34-41 weeks GA; Group 3-5: 23-27 weeks GA; Group 6: mixed population). Group 1-5 showed individual patterns in RHAMM expression and HA content (Group 1: high RHAMM/low HA; Group 2: low RHAMM/low HA; Group 3: low RHAMM/low HA; Group 4: low RHAMM/high HA; Group 5: high RHAMM/high HA). HA content decreased with increasing PNA independently of GA. Negative correlation was observed between air content and RHAMM expression in the bronchiolar epithelium irrespective of clustered groups. Lung hypoplasia appeared in two distinctive groups, with significant differences in lung development and RHAMM expression. CONCLUSIONS: RHAMM expression may show dynamic changes during pathological processes in the neonatal lung. The distribution of RHAMM in the lung tissue is heterogeneous with a predominance to the bronchiolar epithelium. We found a negative correlation between lung air content and RHAMM expression in bronchiolar epithelium. PMID- 30312862 TI - Enhanced semantic involvement during word recognition in children with dyslexia. AB - We investigated whether children with dyslexia show enhanced semantic involvement as compensation for deficient phonological processing during reading. Phonological and semantic processing during reading and moderating effects of word frequency and word length in children with and without dyslexia were examined using a picture-word priming paradigm. Participants were 61 children with dyslexia and 50 typical readers in Grade 6 of primary school. Primes were either semantically or phonologically (shared onset and rime) related or unrelated to their target word. Results showed that priming effects were stronger in children with dyslexia than in typical readers in the semantic condition but did not differ between groups in the phonological condition. Overall, word length and word frequency effects were stronger for children with dyslexia than for typical readers, but word length and word frequency did not affect priming effects differently for the two groups. In both groups, only semantic priming effects were stronger for low-frequency longer words. Finally, individual word and pseudoword reading efficiency correlated with priming effects only in the semantic condition and only in children with dyslexia. It can be concluded that children with dyslexia, compared with typical readers, rely more on semantic information in word reading but do not show deficient phonological activation during reading compared with typical readers. PMID- 30312863 TI - Fold-change Response of Photosynthesis to Step Increases of Light Level. AB - Plants experience light intensity over several orders of magnitude. High light is stressful, and plants have several protective feedback mechanisms against this stress. Here we asked how plants respond to sudden rises at low ambient light, far below stressful levels. For this, we studied the fluorescence of excited chlorophyll a of photosystem II in Arabidopsis thaliana plants in response to step increases in light level at different background illuminations. We found a response at low-medium light with characteristics of a sensory system: fold change detection (FCD), Weber law, and exact adaptation, in which the response depends only on relative, and not absolute, light changes. We tested various FCD circuits and provide evidence for an incoherent feedforward mechanism upstream of known stress response feedback loops. These findings suggest that plant photosynthesis may have a sensory modality for low light background that responds early to small light increases, to prepare for damaging high light levels. PMID- 30312864 TI - Self-Assembled Rough Endoplasmic Reticulum-Like Proto-Organelles. AB - Nature has evolved elaborate, dynamic organelle morphologies for optimal organelle functions. Among them, cisternae stacks are the universal structure for most organelles. However, compared with the well-studied spherical cell/organelle membrane mimic, the fabrication of the ubiquitously present cisternal organelle like membrane structures for organelle mimic remains a challenging task. Herein, rough endoplasmic reticulum (RER)-like helicoidal cisternae stacks were assembled to mimic the enzyme crowded environment in spatially confined RER cisternae. RER like single helicoid, multiple helicoids, and secondary helix are all observed. Membrane electrostatics drives their formation and controls the percentages, which indicates the possible role of membrane electrostatics in RER shaping. The organelle-like cisternae stacks can reversibly expand and compress, which provides modulated crowded or de-crowded enzyme environment for biochemical reactions. This work provides advanced membrane models, and novel mechanisms for organelle shaping and helicoids formation, and holds great potential in biomimetics, cell biology, and advanced materials design. PMID- 30312865 TI - 1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen activated protein kinase inhibitory activity. AB - Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38alphaMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 MUM, respectively) compared to sorafenib (IC50 = 1.58 MUM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38alphaMAPK/CA inhibitor. PMID- 30312866 TI - Design, synthesis and biological evaluation of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as potent carbonic anhydrase IX inhibitors. AB - A series of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties were obtained by reacting 4-isocyanato-benzenesulfonamide (2) with 2 amino-4,6-dicholoro-1,3,5-triazine (4). The 4-(3-(4,6-dichloro-1,3,5-triazin-2 yl)ureido) benzenesulfonamide (5) was subsequently derivatized by reaction with various nucleophiles such as, morpholine, ammonia, methyl amine, dimethyl amine, and piperidine. The ureido benzenesulfonamides incorporating triazinyl moieties were investigated as inhibitors of four selected physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, namely, hCA I, II, IX, and XII which are involved in various diseases such as glaucoma, epilepsy, obesity and cancer. The membrane-bound tumor-associated isoform hCA IX was potently inhibited with these compounds with Kis in the range of 0.91-126.2 nM. Specifically, compound 7j showed great potency against hCA IX with sub-nanomolar Ki of 0.91 nM. Since hCA IX is a validated drug target for anticancer agents, these isoform selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies. PMID- 30312867 TI - 3-Aminobenzenesulfonamides incorporating acylthiourea moieties selectively inhibit the tumor-associated carbonic anhydrase isoform IX over the off-target isoforms I, II and IV. AB - We describe the synthesis of a series of novel 1-aroyl/acyl-3-(3 aminosulfonylphenyl) thioureas (4a-k) acting as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. Reaction of alkyl/aryl isothiocyanates with 3 aminobenzenesulfonamide afforded a series of the title compounds incorporating a variety of short as well as highly lipophilic long tails. The newly synthesized sulfonamides were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IV, and IX). Several compounds showed interesting inhibitory activity. The tumor-associated hCA IX was the most sensitive isoform to inhibition with these compounds, with KIs in the range of 21.5-44.0 nM and selectivity ratios over the major cytosolic isoform hCA II in the range of 3.35-37.3. The sulfonamides incorporating the phenylacetylthioureido and pentadecanoylthioureido moieties were the most hCA IX-selective inhibitors detected in this work, making them of interest for further investigations. PMID- 30312868 TI - Design and synthesis of novel potent anticoagulant and anti-tyrosinase pyranopyrimidines and pyranotriazolopyrimidines: Insights from molecular docking and SAR analysis. AB - Pyrimidine-fused compounds are of great interest for the discovery of potent bioactive agents. This study describes the synthesis of novel pyranopyrimidines 3a-f and pyranotriazolopyrimidines 4a-d derivatives via the cyclocondensation reaction of alpha-functionalized iminoether 2, which was obtained from 2-amino-3 cyanopyrane 1, with a series of primary aromatic amines and hydrazides, respectively. Structures of all synthesized compounds were established on the basis of spectroscopic methods including 1H NMR, 13C NMR and ES-HRMS. They were finally tested for their anticoagulant and anti-tyrosinase activities. Significant results have been obtained and the structure-activity relationship (SAR) was discussed with the help of molecular docking analysis. PMID- 30312869 TI - Digestion performance and contributions of organic and inorganic fouling in an anaerobic membrane bioreactor treating waste activated sludge. AB - This study evaluates the performance of an anaerobic membrane bioreactor (AnMBR) digesting waste activated sludge. A digestion reactor equipped with an external hollow fiber microfiltration membrane module was operated in continuous-mode for 248 days. The system demonstrated 56% volatile solids degradation at an organic loading rate of 0.40 g-VS/(L.d) in 15 days of hydraulic retention time. The average methane content in the biogas produced was 76% which is considerably high compared to that from a typical continuously stirred tank reactor. The transmembrane pressure remained under 12 kPa without membrane cleaning during the experimental period due to low filtration flux (0.01-0.07 m/d) and cross-flow mode filtration. Ex situ membrane cleaning revealed that physically irreversible fouling was the dominant form of membrane fouling. Inorganic and organic fouling accounted for 16% and 45% of total membrane fouling, respectively. PMID- 30312870 TI - Bio-utilization of cheese manufacturing wastes (cheese whey powder) for bioethanol and specific product (galactonic acid) production via a two-step bioprocess. AB - Cheese whey, produced from coagulation of milk during cheese manufacture, is a major environmental pollutant. The most abundant component in cheese whey is lactose, which is a potential resource for various value-added chemicals. Here, a two-step bioprocess using Saccharomyces cerevisiae and Gluconobacter oxydans to bioconvert cheese whey into ethanol and galactonic acid was first proposed. First, the lactose in cheese whey powder was pretreated with beta-galactosidase to obtain glucose and galactose. Subsequently, the glucose was selectively fermented to ethanol by S. cerevisiae to enable G. oxydans-mediated biooxidation of galactose to galactonic acid. Finally, approximately 110 g ethanol, 320 g galactonate, and 150 g mixed protein (residual cheese whey protein and cell protein) was produced from 1 kg CWP. These results are suggestive of alternative methods for management of cheese whey, which may reduce its impact on the environment and result in production of value-added biochemicals. PMID- 30312871 TI - Generation of an induced pluripotent stem cell line from an individual with a heterozygous RECQL4 mutation. AB - The DNA helicase RECQL4 is known for its roles in DNA replication and repair. RECQL4 mutations cause several genetic disorders including Rothmund-Thomson syndrome (RTS), characterized by developmental defects and predisposition to osteosarcoma. Here we reprogrammed fibroblasts with a heterozygous RECQL4 mutation (c.1878 + 32_1878 + 55del24) to induced pluripotent stem cells (iPSCs). These iPSCs are pluripotent and are able to be differentiated into all three germ layers, providing a novel tool to further interrogate the role of RECQL4 DNA helicase in vitro. PMID- 30312872 TI - Generation of heterozygous and homozygous hESC H9 sublines carrying inactivating mutations in RB1. AB - Inactivation of the tumor suppressor gene RB1 is causal for development of retinoblastoma, a tumor of the neural retina arising in children under the age of five. In addition, secondary RB1 mutations are found in many other tumor types. To investigate retinoblastoma formation in vitro, stem cells with inactivated RB1 can be differentiated into neural retina. To enable such studies, two sublines of hESC line H9 carrying mutations in RB1 exon 3 in heterozygous or homozygous state were generated and characterized. Homozygous mutation led to loss of RB1 protein expression. Resource table. PMID- 30312873 TI - Generation of induced pluripotent stem cells, KCi002-A derived from a patient with Bardet-Biedl syndrome homozygous for the BBS10 variant c.271insT. AB - Bardet-Biedl syndrome (BBS) is genetically heterogeneous with at least 21 genes involved, and BBS10 encodes, together with BBS6 and BBS12, chaperonin-like proteins which are important for the assembly of the multiprotein complex, the BBSome encoded by other BBS genes. Here we describe the successful generation of an induced pluripotent stem cell (iPSC) line KCi002-A from a male with BBS, homozygous for the disease causing variant c.271insT, p.(Cys91fsX95) in BBS10. Resource table. PMID- 30312874 TI - Sex determination in a Spanish population based on sacrum. AB - Sex determination is one of the essential steps when it comes to establishing an individual's biological profile. It is important in both archaeology and forensic studies. The sacrum is not generally conserved, but in cases where it is, it can be used for determination of the sex of skeletal remains. Furthermore, the sacrum is not a commonly studied bone and has not been studied in a Spanish population. For this study, measurements of 170 sacra of individuals from the contemporary osteological collection of San Jose from Granada including only the adults were taken. Measurements based on the anatomical regions of the sacra were established in order to obtain some regression formulas to determine sex. Our results show that the Superior Transverse Line and Right Lateral Sacral Crest are the most dimorphic structures, achieving a 74% rate of correct classification of sex in a univariate analysis. In multivariate analysis, when the mentioned variables were combined, an 81.41% rate of correct classification was achieved. Our results show that our method can be applied with other methods at the same time to determine the sex of individuals in forensic and archaeological contexts. PMID- 30312875 TI - Factors associated with autopsy rates in a 6-year sample of Danish suicides in the Capital area of Copenhagen. AB - On average, two suicides occur in Denmark every day. In order to prevent suicides, it is important to understand their nature. The forensic autopsy plays an important role by providing detailed knowledge of the cause and manner of death. Unfortunately, the autopsy rate for suicides in Denmark is very low. The aim of this study was to elucidate the factors that may affect the decision to perform a forensic autopsy and thereby affect the autopsy rate of suicidal deaths in the Capital area of Copenhagen. Data from 6211 death certificates from the Capital area of Copenhagen, Denmark, over a study period of six years, were investigated. For deaths classified as suicide, the presence of the following factors were registered: gender, age, date of birth, date of death, marital status, nationality, place of death, cause of death, psychiatric condition, former admissions at a psychiatric ward, former attempts of suicide, presence of suicide note, history of substance abuse (alcohol, narcotics or both), and presence of self-inflicted scars. These factors were cross-tabulated with whether a referral to a forensic autopsy was made. Significant association was calculated by using Chi2 and Fisher's exact test. We found a total of 381 cases of suicide. The forensic autopsy rate was 21.3%. The following factors were associated with a significantly lower forensic autopsy rate: age above 50, history of psychiatric illness, the presence of a suicide letter, and cause of death registered as hanging/strangulation/suffocation, drowning/submersion, self-harm with sharp object, and jumping from height. Only the presence of a suicide letter remained significant after the Bonferroni correction for multiple testing. History of substance abuse and cause of death registered as intentional exposure to smoke, fire and flames were associated with a significantly higher forensic autopsy rate. A forensic autopsy can give more precise information on suicide methods, the impact of fatal lesions and comorbidity. Our study results showed that violent methods of suicidal death and psychiatric comorbidity led to a lower forensic autopsy rate. A higher autopsy rate would enable more thorough study and investigation of suicides, which would benefit the next-of-kin, general preventive procedures, and treatment of patients at risk of suicide. PMID- 30312876 TI - Novel nanoarchitecture of Co-MOF-on-TPN-COF hybrid: Ultralowly sensitive bioplatform of electrochemical aptasensor toward ampicillin. AB - Owning to the misuse of the antibiotics in animal husbandry and agriculture, it is highly urgent to determine the quantification of antibiotics in biological systems by the simple, sensitive, and fast method. In this work, a novel nanoarchitecture of Co-based metal-organic frameworks (Co-MOF) and terephthalonitrile-based covalent organic framework (TPN-COF) was synthesized (represented by Co-MOF@TPN-COF), followed by the exploitation as the bioplatform of non-label aptasensor for detecting the most frequently used beta-lactam antibiotics, ampicillin (AMP). The new porous hybrid material of Co-MOF@TPN-COF was synthesized by adding the as-prepared TPN-COF into the Co-MOF preparation system. The multilayered Co-MOF@TPN-COF nanosheets exhibit a high specific surface area (52.64 m2 g-1), nitrogen-rich groups and excellent electrochemical activity. As a result, large amounts of aptamer strands can be bound over the Co MOF@TPN-COF nanosheets owning to the strong pi-pi stacking and hydrogen bonds. When detecting AMP by the electrochemical impedance spectroscopy, the fabricated Co-MOF@TPN-COF-based aptasensor exhibits an ultra-low detection limit of 0.217 fg mL-1 within the AMP concentration from 1.0 fg mL-1 to 2.0 ng mL-1, which was superior to those previously reported in literatures. In addition, this proposed aptasensor also shows high selectivity, good reproducibility and stability, acceptable regenerability, and favorable applicability in human serum, river water and milk. Therefore, the proposed Co-MOF@TPN-COF-based aptasensor has a great promise to be applied as a powerful tool in the fields of food safety. PMID- 30312877 TI - Periodontal ligament fibroblasts migration injury via ROS/TXNIP/Nlrp3 inflammasome pathway with Porphyromonas gingivalis lipopolysaccharide. AB - Inflammasomes serve as an intracellular machinery to initiate inflammatory response to various danger signals. However, the chronic periodontitis pathological relevance of this inflammasome activation, particularly in periodontal ligament fibroblasts, remains largely unknown. The present study demonstrated that Nlrp3 inflammasome components abundantly expressed in cultured mouse periodontal ligament fibroblasts (mPDLFs). In addition, our data demonstrated that P.g-LPS (Porphyromonas gingivalis Lipopolysaccharide), a major injurious factor during chronic periodontitis, could induce the mPDLFs migration dysfunction and the inhibition of Nlrp3 inflammasome by Isoliquiritigenin (ISO) markedly recovered the migration dysfunction in mPDLFs. And Nlrp3 inflammasome components could be aggregated to form an inflammasome complex on stimulation of P.g-LPS, as shown by fluorescence confocal microscopy. Correspondingly, P.g-LPS induced Nlrp3 inflammasome activation, caspase-1 activation, IL-1beta and HMGB1 release, which were blocked by Nlrp3 inflammasome inhibitor (ISO). Interestingly, reactive oxygen species, TXNIP protein and TXNIP binding to Nlrp3 were markedly increased in mPDLFs with P.g-LPS. Furthermore, ROS generation inhibitor (Apocynin; APO) significantly reduced Nlrp3 inflammasome formation and IL-1beta production in mPDLFs with P.g-LPS. And APO attenuated P.g-LPS-induced TXNIP protein expression and mPDLFs injury. In conclusion, our results demonstrate that ROS/TXNIP/Nlrp3 Inflammasome pathway is a key initiating mechanism necessary for P.g-LPS-induced subsequent mPDLFs inflammatory response leading to chronic periodontitis. PMID- 30312878 TI - Corrigendum to "Synthesis of glyceryl glycosides related to A-type prymnesin toxins" Carbohydr. Res. 463 (2018) 14-23. PMID- 30312879 TI - Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction. AB - Immunosuppressive drugs are widely used for the treatment of immune-mediated diseases and inflammation, but the toxicity and side effects of the available immunosuppressors make the search of new agents of great relevance. Here, we evaluated the immunomodulatory activity of an N-acylhydrazone derivative, (E)-N' (3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), a phosphodiesterase-4 (PDE-4) inhibitor. LASSBio-1386 inhibited lymphocyte activation in a concentration-dependent fashion, decreasing lymphoproliferation and IFN-gamma and IL-2 production stimulated by anti-CD3/CD28 mAbs or concanavalin A (Con A) and inducing cell-cycle arrest in the G0/G1 phase. These effects were not blocked by RU486, a glucocorticoid receptor (GR) antagonist, indicating an effect independent of glucocorticoid receptor activation. Combination index-isobologram analysis indicates a synergistic effect between LASSBio-1386 and dexamethasone in lymphoproliferation inhibition. LASSBio-1386 presented immunomodulatory action in macrophage cultures, as observed by a significant and concentration-dependent decrease in NO and TNF-alpha production, an effect achieved by reducing IKB expression and NF-kappaB activation. In the mouse model of endotoxic shock, LASSBio-1386 at 50 and 100 mg/kg protected 50 and 85% of mice against LPS-induced lethality, respectively. In agreement to its in vitro action, treatment with 100 mg/kg of LASSBio-1386 reduced TNF-alpha and IL 1beta serum levels, while increased IL-6 and IL-10. Finally, LASSBio-1386 reduced the paw edema in a BSA-induced delayed-type hypersensitivity model. These findings demonstrate the immunomodulatory and immunosuppressant effects of LASSBio-1386 and indicate this molecule is a promising pharmacologic agent for immune-mediated diseases. PMID- 30312880 TI - Enhanced neutrophil autophagy and increased concentrations of IL-6, IL-8, IL-10 and MCP-1 in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a high morbidity and disability disease with numerous inflammatory cells infiltrating in interstitial of articular cartilages and bones. As the most abundant inflammatory cells, neutrophil has been reported that their apoptosis changed gradually in the circumstance of RA. Apoptosis, one modality of programmed cell death (PCD), is closely associated with autophagy, which indicates neutrophil autophagy may also alter in RA. Flow cytometry, western blotting, immunohistochemistry, immunofluorescence, transmission electron microscope and multiplex antibody microarray were used to comparative investigate the status of neutrophil autophagy in patients with RA and in vitro. The results showed that the expression of autophagy related LC3 protein was up-regulated with lower lysosomal pH in neutrophils from synovial fluid of RA and changed under stimulation of CQ and small RNA interferences (siRNAs) Atg5 transfection, which proved in acute promyelocytic leukemia HL-60 cell lines, predominantly a neutrophilic promyelocyte, treated by plasma and synovial fluid from RA. We further found out the concentration of IL-6, IL-8, IL-10 and MCP-1 was higher in their synovial fluid which may mediate neutrophil autophagy in RA via cytokine cytokine receptor interaction and IL-17 signaling pathway. Our results indicate that neutrophil autophagy may be a novel perspective to understand the pathology which may provide a new maker to diagnose RA and IL-8, IL-10, MCP-1 specific antagonists and neutrophil autophagy target inhibitors may improve the therapeutic effect of RA someday. PMID- 30312881 TI - Some observations on Barrett esophagus and associated dysplasia. AB - Biopsy samples from esophageal columnar metaplasia and dysplasia are commonly encountered in Western pathology practice and knowing a few pitfalls can save both pathologists and patients a great deal of anxiety. Herein we discuss criteria for Barrett esophagus, evaluation of dysplasia, and some pitfalls in reviewing endoscopic mucosal resections. Also included is a summary of suggested follow-up for patients with Barrett esophagus. PMID- 30312882 TI - Nonalcoholic fatty liver disease (NAFLD): Diagnosis, pitfalls, and staging. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with obesity, diabetes and the metabolic syndrome, not only in the Western societies, but also in most regions of the world in the 21st century. The spectrum of its histopathology ranges from steatosis to nonalcoholic steatohepatitis (NASH), with risk for progressive fibrosis that may lead to cirrhosis and hepatocellular carcinoma (HCC). Benign and malignant liver tumors have also been more frequently reported with the increasing prevalence of obesity and diabetes. This review addresses the pathology of NAFLD and NASH, and their diagnostic features, diagnostic pitfalls, grading and staging, and clinical correlation. PMID- 30312883 TI - Melanocytic lesions - Staying out of trouble. AB - The diagnosis of melanocytic tumors is notoriously difficult and represents one of the most challenging areas in surgical pathology associated with significant risk for litigation. One reason is the wide morphologic spectrum of melanocytic tumors and the fact that many histological features are shared by both benign melanocytic nevi and melanoma. Awareness of the many morphologic variations and variants of nevi and melanoma, their clinical setting, immunohistochemical phenotype and genetic profile is necessary for the correct diagnosis. The article discusses the features of three variants of melanoma, desmoplastic, acral lentiginous and vulvar mucosal lentiginous melanoma, and their benign melanocytic mimics with emphasis on distinguishing features. PMID- 30312884 TI - Effects of human recombinant type I IFNs (IFN-alpha2b and IFN-beta1a) on growth and migration of primary endometrial stromal cells from women with deeply infiltrating endometriosis: A preliminary study. AB - OBJECTIVE(S): Endometriosis is a major cause of infertility and disability for women, caused by the presence of inflammatory endometrial implants in extrauterine locations. Among the constituents involved in the immune response during the development of endometriosis, several chemokines, including interferons (IFNs) may have a role in the pathogenesis of this disease. The aim of this preliminary study was to investigate the anti-proliferative and anti migratory activities of type I IFNs (IFN-alpha2b and IFN-beta1a) in primary endometrial stromal cells (ESCs) isolated from women with deeply infiltrating endometriosis (DIE). STUDY DESIGN: The study subjects included 7 women ranged in the age from 27 to 37 years with diagnosis of DIE (Stage III and IV). Collected primary ESC monolayers, isolated from endometriotic nodules, were incubated with various concentrations (from 1 to 1000 IU/ml) of IFN-alpha2b or IFN-beta1a. RESULT(S): IFN-beta1a had a significantly higher activity in hampering the proliferation of cells compared to IFN-alpha2b. This effect could be related to the induction of apoptosis and cell cycle arrest in S phase, observed in ESCs during incubation with IFN-beta1a. Moreover, IFN-beta1a was more potent than IFN alpha2b in inhibiting migration and EGF-induced ERK activity of primary ESCs. CONCLUSION(S): The inhibitory in vitro effect on ESC proliferation and migration of IFN-beta1a was much more potent than IFN-alpha2b. These preliminary data offer the rationale for future preclinical and clinical trials using IFN-beta1a as a new tool for the therapy and tertiary prevention in patients with DIE. PMID- 30312885 TI - Interview-based ratings of DSM-IV Axis II/DSM-5 Section II Personality Disorder symptoms in consecutively admitted insomnia patients: A comparison study with consecutively admitted psychotherapy patients matched on age and gender. AB - BACKGROUND: Selected personality features may represent important predisposing as well as perpetuating factors for insomnia, and previous studies stressed the importance to assess personality disorders in insomnia patients. METHODS: In order to evaluate the relationships between DSM-IV Axis II/DSM-5 Section II Personality Disorders (PDs) and insomnia, a sample of 171 consecutively admitted insomnia patients and a sample of 171 psychotherapy patients, matched on age and gender were administered the Italian translation of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, Version 2.0 (SCID-II). Among insomnia patients, 52.0% (n = 89) received at least one DSM-IV Axis II/DSM-5 Section II PD diagnosis according to SCID-II assessment. RESULTS: Any PD base rate estimate in our insomnia patient sample was significantly and markedly higher than the median and mean base rate estimates for any PD in the general population. Within-group analyses showed that Narcissistic, Not otherwise specified PD, Histrionic PD, and Borderline PD represented the most frequently diagnosed-both dimensionally and categorically-DSM-IV Axis II/DSM-5 Section II PD features in our insomnia patient sample. When continuously-scored PDs were considered, insomnia patients showed a significantly lower number of Paranoid and Borderline PD features than psychotherapy patients; however, the corresponding effect size estimates suggested that these differences were modest. None of the categorically-scored PDs significantly differentiated insomnia patients from psychotherapy patients. CONCLUSIONS: As a whole, our findings seemed to suggest that personality dysfunction may play a role in insomnia, while stressing the need for a dimensional approach to the assessment of maladaptive personality traits even in insomnia patients. PMID- 30312886 TI - Potential impact of the validated Predicting Abusive Head Trauma (PredAHT) clinical prediction tool: A clinical vignette study. AB - BACKGROUND: The validated Predicting Abusive Head Trauma (PredAHT) tool estimates the probability of abusive head trauma (AHT) in children <3 years old with intracranial injury. OBJECTIVE: To explore the impact of PredAHT on clinicians' AHT probability estimates and child protection (CP) actions, and assess inter rater agreement between their estimates and between their CP actions, before and after PredAHT. PARTICIPANTS AND SETTING: Twenty-nine clinicians from different specialties, at teaching and community hospitals. METHODS: Clinicians estimated the probability of AHT and indicated their CP actions in six clinical vignettes. One vignette described a child with AHT, another described a child with non-AHT, and four represented "gray" cases, where the diagnosis was uncertain. Clinicians calculated the PredAHT score, and reported whether this altered their estimate/actions. The 'think-aloud' method was used to capture the reasoning behind their responses. Analysis included linear modelling, linear mixed-effects modelling, chi-square tests, Fisher's exact tests, intraclass correlation, Gwet's AC1 coefficient and thematic analysis. RESULTS: Overall, PredAHT significantly influenced clinicians' probability estimates in all vignettes (p < 0.001), although the impact on individual clinicians varied. However, the influence of PredAHT on clinicians' CP actions was limited; after using PredAHT, 9/29 clinicians changed their CP actions in only 11/174 instances. Clinicians' AHT probability estimates and CP actions varied somewhat both before and after PredAHT. Qualitative data suggested that PredAHT may increase clinicians' confidence in their decisions when considered alongside other associated clinical, historical and social factors. CONCLUSIONS: PredAHT significantly influenced clinicians' AHT probability estimates, but had minimal impact on their CP actions. PMID- 30312887 TI - A validated LC-MS/MS method for simultaneous determination of linagliptin and metformin in spiked human plasma coupled with solid phase extraction: Application to a pharmacokinetic study in healthy volunteers. AB - Combination therapy has a pivotal role in type II diabetes mellitus management in patients unable to maintain normal glycemic level using metformin alone. Addition of linagliptin, dipeptidyl peptidase-IV inhibitor, to metformin improves glycemic control. This study is concerned with the development of an HPLC-MS/MS method for simultaneous quantification of linagliptin and metformin in spiked human plasma. The method was applied to evaluate the potential pharmacokinetic interactions between the cited drugs in healthy volunteers. Solid phase extraction was applied using StrataTM X cartridge. Separation was carried out on Symmetry(r) C18 column using methanol: 10 mM ammonium formate buffer (containing 0.2% formic acid) in a ratio of (95: 5, v/v) as mobile phase at flow rate 0.25 mL min-1. Quantification was performed with multiple reaction monitoring in positive ionization mode. The monitored transitions were set at m/z 473.24 -> 419.94, 130.14 -> 60.18 and 340.27 -> 116.07 for linagliptin, metformin and alogliptin (internal standard), respectively. The method was validated according to FDA guidelines. The method showed excellent linearity over concentration ranges 0.25-10 and 25-2000 ng mL-1 for linagliptin and metformin, respectively. The validated HPLC-MS/MS method was successfully applied to pharmacokinetic study of linagliptin and metformin in healthy volunteers after oral administration of Jentadueto(r) tablets. PMID- 30312888 TI - Microcystin-LR promotes migration via the cooperation between microRNA-221/PTEN and STAT3 signal pathway in colon cancer cell line DLD-1. AB - Previous researches have reported that microcystin-LR (MC-LR) contributes to the progression of multiple types of carcinomas including colon cancer; however, the underlying molecular mechanisms remain unclear and require in-depth investigation. Here, the colon cell line DLD-1 was arranged for the analysis by the microRNA microarray which was associated with the cancer metastasis after MC LR exposure. 31 human microRNAs were differentially expressed, including miR-221, which targeted 3'-UTR of PTEN mRNA and PTEN level was down-regulated by MC-LR treatment. Besides, MC-LR also induced the phosphorylation of STAT3, which can be reversed by adding miR-221 inhibitor and PTEN expression plasmid. Furthermore, miR-221 inhibitor, STAT3 siRNA and PTEN expression plasmid could reverse the effects of MC-LR induced migration with the accumulation of beta-catenin in nuclei. In conclusion, our study suggested that MC-LR promoted the progression of colon carcinoma, at least in part, by regulating the expression miR-221, PTEN and STAT3 phosphorylation, which offers a novel perspective to understand the connection between MC-LR and colon cancer. PMID- 30312889 TI - Toxicity of manganese to various life stages of selected marine cnidarian species. AB - Manganese (Mn) pollution in marine waters is increasing and sensitivities to this metal vary widely among marine species. The aims of this study were to characterise Mn chemistry in seawater, and evaluate the toxic effects of Mn on various life stages of two scleractinian corals - the branching sp. Acropora spathulata and massive sp. Platygyra daedalea, and the anemone Exaiptasia pallida. Analytical and theoretical characterisation experiments showed that 97 100% of Mn (II) additions <= 200 mg/L in seawater were soluble over 72 h and largely assumed labile complexes. Concentrations estimated to reduce coral fertilisation success by 50% (5.5-h EC50) were 237 mg/L for A. spathulata and 164 mg/L for P. daedalea. A relatively low 72-h LC50 of 7 mg/L was calculated for A. spathulata larvae. In a pilot test using fragments of adult A. spathulata, intact coral tissue rapidly sloughed away from the underlying skeleton at very low concentrations with a 48-h EC50 of just 0.7 mg/L. For E. pallida, survival, tentacle retraction and reproduction were unaffected by prolonged high exposures (12-d NOEC 54 mg/L). This study provides important data supporting the derivation of separate water quality guidelines for Mn in systems with and without coral - a decision recently considered by Australian and New Zealand authorities. It demonstrates the high sensitivity of coral larvae and adult colonies to Mn and the potential risks associated with relying on other early life stage tests and/or E. pallida as ecotoxicological representatives of critically important scleractinian corals. PMID- 30312890 TI - Identification and comprehensive analysis of the characteristics and roles of leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes in Sedum alfredii Hance responding to cadmium stress. AB - Sedum alfredii Hance is a Zn/Cd co-hyperaccumulator and its underlying molecular mechanism of Cd tolerance is worthy to be elucidated. Although numerous studies have reported the uptake, sequestration and detoxification of Cd in S. alfredii Hance, how it senses Cd-stress stimuli and transfers signals within tissues remains unclear. Leucine-rich repeat receptor-like protein kinases (LRR-RLKs) are vital for plant growth, development, immunity and signal transduction. Till now, there is lack of comprehensive studies addressing their functions in S. alfredii Hance responding to Cd stress. In the present study, we identified 60 LRR-RLK genes in S. alfredii Hance based on transcriptome analysis under Cd stress. They were categorized into 11 subfamilies and most of them had highly conserved protein structures and motif compositions. The inter-family diversity provided evidence for their functional divergence, supported by their expression level and profile in tissues under Cd stress. Co-expression network analysis revealed that the most highly connected hubs, Sa0F.522, Sa0F.1036, Sa28F.115 and Sa1F.472, were closely related with other genes involved in metal transport, stimulus response and transcription regulations. Of the ten hub genes exhibiting differential expression dynamics under the short-term Cd stress (Sa0F.522, Sa0F.1036 and Sa28F.115) were dramatically induced in the whole plant. Among them, Sa0F.522 gene was heterologously expressed in a Cd-sensitive yeast cell line and its function in Cd signal perception was confirmed. For the first time, our findings performed a comprehensive analysis of LRR-RLKs in S. alfredii Hance, mapped their expression patterns under Cd stress, and identified the key roles of Sa0F.522, Sa0F.1036 and Sa28F.115 in Cd signal transduction. PMID- 30312891 TI - Word writing in Spanish-speaking children: Central and peripheral processes. AB - The impact of central on peripheral writing processes has been studied mainly in adults and children whose first language is a deep orthographic system. The results suggest that the influence varies according to age, but it also could depend on the orthographic system. The objective of the present work was to address the possible impact of the central (orthographic retrieval) on peripheral (motor execution) processes during writing acquisition in a transparent orthography. To achieve the objective, seventy-five Spanish children performed a copying and a spelling-to-dictation task, where orthographic consistency, lexical frequency and word length were manipulated. The results suggest that the central processes influence the peripheral ones from an early age (when writing has not yet been automated). Specifically, orthographic consistency cascaded into movement production, but it was modulated by task and grade, as this effect was only evident for 2nd grade children when they were asked to perform a spelling-to dictation task. PMID- 30312892 TI - Sensory-motor modality compatibility in multitasking: The influence of processing codes. AB - Sensory-motor modality compatibility is defined as the similarity between the sensory modality and the modality of response-related effects. Previous dual-task and task-switching studies have shown higher performance costs for coordinating relatively incompatible sensory-motor modality mappings (i.e., auditory-manual and visual-vocal) compared to more compatible mappings (i.e., auditory-vocal and visual-manual). Until now, however, little attention has been paid to potential variability in effects of modality compatibility depending on different processing codes. In the present study, we independently varied the processing codes of input and output (nonverbal-spatial, nonverbal-nominal, verbal-spatial, verbal-nominal) while participants switched between incompatible and compatible sensory-motor modality mappings. Beside higher switch costs for switching between incompatible sensory-motor modality mappings than for switching between compatible mappings, the results revealed stronger effects of modality compatibility on switch costs for verbal input than for nonverbal input codes. This suggests that priming mechanisms between sensory input and compatible motor output are modulated by the processing code of the sensory input. As possible explanations, we assume a higher degree of concordance with output processing codes as well as stronger associations with potential response effects for verbal than for nonverbal input. PMID- 30312893 TI - Multicomorbidity of chronic diseases and substance use disorders and their association with hospitalization: Results from electronic health records data. AB - BACKGROUND: Chronic diseases are prevalent and the leading causes of mortality. Comorbidity of substance use disorders (SUDs) and chronic diseases is understudied to inform behavioral healthcare integration. OBJECTIVES: This study leveraged electronic health record (EHR) data of 211,880 adults from a large health system to examine prevalence and correlates of comorbidity of SUDs and nine chronic disease groups and to determine their association with hospitalization. METHODS: Logistic regression analyses were conducted to estimate associations between chronic diseases and SUDs. To control for severity of diagnosis, analyses of associations between SUD and hospitalization were stratified by the number of chronic conditions. RESULTS: In the sample, 48.3% had >=1 chronic condition (hypertension 33.7%, arthritis 16.2%, diabetes 13.7%, chronic kidney disease 9.9%, asthma 9.1%, chronic obstructive pulmonary disease 8.9%, ischemic heart disease 8.3%, cancer 4.6%, and hepatitis 1.3%). Prevalence of SUD (overall 13.3%) among patients increased with multiple chronic conditions (14.3% having SUD among patients with one condition; 21.2% having SUD among patients with two to three conditions; and 32.5% having SUD among patients with 4 9 conditions). Chronic conditions were associated with increased odds of SUDs. For all SUD groups, hospitalization was more prevalent among patients with SUD than those without it; prevalence of hospitalization increased with the number of comorbid chronic conditions. CONCLUSIONS: Findings reveal a striking pattern of multicomorbidity of SUD and chronic diseases and its positive association with hospitalization. Behavioral healthcare integration should consider efforts to assess and treat comorbid SUD and chronic diseases, especially among adults with multiple chronic conditions. PMID- 30312894 TI - From zero to sixty and back to zero again: the metabolic life of B cells. AB - Throughout their lifetimes B cells shift metabolic gears to move rapidly from quiescent states to full out proliferative expansion and back again. Here we discuss recent findings that shed light on how B cells rapidly shift gears to metabolically fuel expansion and then just as rapidly down shift during phases of receptor rearrangements to ensure genome stability. We also discuss the link between metabolic activity and fate decisions in B cells. PMID- 30312895 TI - Is less more? A randomized comparison of home practice time in a mind-body program. AB - Home practice is a major component of mind-body programs, yet little is known about how to optimize the amount of prescribed home practice in order to achieve an effective "dose" of practice while minimizing participant burden. This study tested how varying the amount of home practice in a mind-body program impacts compliance and stress reduction, and whether prescribing a flexible home practice schedule increases compliance. Eighty-four stressed participants undergoing a 12 week yoga program were randomized to low, medium, and high home practice conditions. The medium condition allowed participants the flexibility to choose one of two amounts of practice each day. The low practice group exhibited the highest compliance (91%) compared to the medium and low practice groups (~60%), but exhibited the lowest total practice time, and did not significantly reduce stress. The high practice group was the only group to achieve significant stress reduction, which was maintained 12 weeks post program. Prescribing a flexible home practice schedule did not increase compliance. Results suggest that prescribing higher practice doses may maximize practice time and symptom reduction despite lower compliance. PMID- 30312896 TI - What have we learned recently from transgenic mouse models about neurodegeneration? The most promising discoveries of this millennium. AB - Neurodegenerative diseases are currently a major challenge in elderly care due to demographic changes and dramatic increases in the aging population worldwide. This review is focused on the most promising research discovering ways to attenuate neural loss or enhance neuroprotection and unraveling the basis of neurodegeneration using transgenic mouse models. With the recent introduction of the powerful and relatively simple gene-editing tool CRISPR-Cas9, we have entered a new era in genetic engineering that will certainly lead to a variety of new transgenic models in the near future. The aim of this review is to note the most interesting avenues addressing unmet needs in neurodegenerative disease research that could provide promising targets for both the development of new models and the study of existing ones. PMID- 30312897 TI - Quality of life in adolescents and adults with autism spectrum disorder: Results from a nationwide Danish survey using self-reports and parental proxy-reports. AB - BACKGROUND: Quality of life (QoL) in individuals with autism spectrum disorder (ASD) is essential to investigate with regard to knowledge about factors of importance for QoL and concordance between self-reported and parental proxy reported QoL. AIMS: This study investigated QoL in adolescents and adults with ASD using both self-reports and parental proxy-reports. METHODS: From a nationwide survey, 1738 individuals diagnosed with ASD in childhood, were included for this study. The individuals themselves and/or their parents completed the INICO-FEAPS scale. Concordance between self-reports and proxy reports were examined, and factors associated with QoL were explored via linear regression models. RESULTS: Compared to proxy-reported QoL scores, self-reported QoL scores were significantly but only slightly higher and not in every QoL domain. Independent of respondent type it was found that psychiatric comorbidity, sleeping difficulty, intellectual disability, maladaptive behavior, adaptive functioning, autism symptomatology, main daytime activity and residence were associated with QoL. CONCLUSION: Proxy-reported QoL is different from self reported QoL and should be considered as an alternative source of information. QoL might be enhanced when factors associated with QoL are improved. However, large variations in QoL were found for most factors, suggesting the need to involve the individuals with ASD and/or their families when improving their QoL. PMID- 30312898 TI - Assessment of adverse outcome of Excel Mera 71 in Anabas testudineus by histological and ultrastructural alterations. AB - Present study was designed to evaluate the adverse effect of glyphosate-based herbicide, Excel Mera 71 in Anabas testudineus on comparative basis under field and laboratory conditions. Field (750 g/acre) and laboratory (17.2 mg/L) experiments were performed for a period of 30 days. For field experiment special type of cages were prepared. Fish gill, liver, and kidney were analyzed for histology and ultrastructural responses. A significant increment in morphometric indices (DTC) was observed in gill, liver and kidney of A. testudineus under laboratory condition (p < 0.05) and responses showed the degree of pathogenicity in the order of liver > kidney > gills. However, under field study significant increase in DTC value was observed in gill and liver (p < 0.05). Among the scanning electron microscopic (SEM) observations necrosis and loss of microridges, and damage in stratified epithelial cells were prominent in gill, although higher prevalence of alterations was observed under laboratory study than field study. Additionally, transmission electron microscopic (TEM) observations also depicted higher prevalence of pathological lesions under laboratory study compared with field observation. Among the TEM observations damage in chloride and pavement cells, degenerative mitochondria and nucleus (in gill); severe vacuolation, necrosed nucleus and vesiculated network in case of liver and degenerated epithelial cells, cytoplasmic vacuolation, and damage in proximal convoluted tubules (PCT) in case of kidney were prominent. Therefore, these findings demonstrated that Excel Mera 71 induces significant damage in tissues of A. testudineus and these responses might be considered as biomarkers for monitoring herbicidal toxicity on fish in aquatic body. PMID- 30312899 TI - Characterization of AHR1 and its functional activity in Atlantic sturgeon and shortnose sturgeon. AB - Sturgeon species are imperiled world-wide by a variety of anthropogenic stressors including chemical contaminants. Atlantic sturgeon, Acipenser oxyrinchus, and shortnose sturgeon, Acipenser brevirostrum, are largely sympatric acipenserids whose young life-stages are often exposed to high levels of benthic-borne PCBs and PCDD/Fs in large estuaries along the Atlantic Coast of North America. In previous laboratory studies, we demonstrated that both sturgeon species are sensitive to early life-stage toxicities from exposure to environmentally relevant concentrations of coplanar PCBs and TCDD. The sensitivity of young life stages of fishes to these contaminants varies among species by three orders of magnitude and often is due to variation in the structure and function of the aryl hydrocarbon receptor (AHR) pathway. Unlike mammals, fishes have two forms of AHR (AHR1 and AHR2) with AHR2 usually being more highly expressed across tissues and functional in mediating toxicities. Based on previous studies in white sturgeon, A. transmontanus, we hypothesized that sturgeon taxa are unusually sensitive to these contaminants because of higher levels of expression and functional activity of AHR1 than in other fish taxa. To address this possibility, we characterized AHR1 in both Atlantic Coast sturgeon species, evaluated its' in vivo expression in young life-stages and in multiple tissues of shortnose sturgeon, and tested its ability to drive reporter gene expression in AHR-deficient cells treated with graded doses of PCB126 and TCDD. Similar to white sturgeon and lake sturgeon, AHR1 amino acid sequences in Atlantic sturgeon and shortnose sturgeon were more similar to mammalian AHRs and avian AHR1s than to AHR1 in other fishes, suggesting their greater functionality in sturgeon species than in other fishes. Exposure to graded doses of coplanar PCBs and TCDD usually failed to significantly induce AHR1 expression in young life-stages or most tissues of shortnose sturgeon. However, in reporter gene assays, AHR1 drove higher levels of gene expression than AHR2 alone, but their binary combination failed to drive higher levels of expression than either AHR alone. In total, our results suggest that AHR1 may be more functional in sturgeon species than in other fishes, but probably does not explain their heightened sensitivity to these contaminants. PMID- 30312901 TI - Effects of continuous subcutaneous apomorphine infusion in Parkinson's disease without cognitive impairment on motor, cognitive, psychiatric symptoms and quality of life. AB - INTRODUCTION: Treatment optimization using continuous subcutaneous apomorphine infusion (CSAI) improves the control of motor fluctuations of patients with Parkinson's disease (PD). Although CSAI seems to be cognitively and behaviorally safe and to improve the quality of life, very few studies have investigated its influence in these domains, especially in patients without cognitive impairment. METHODS: We estimated the impact of CSAI on motor symptoms, cognition, psychiatric domains and quality of life in parkinsonian patients without cognitive impairment by comparing the scores of 22 patients assessed before and 6 months after the start of add-on CSAI. RESULTS: Optimized treatment with CSAI was associated with i) reduced motor fluctuations, ii) unchanged cognition, iii) unchanged psychiatric domains, and iv) improved quality of life in physical and psychological aspects. CONCLUSION: In PD patients without cognitive impairment, CSAI improves motor symptoms and quality of life and, as suggested by previous studies, alters neither cognition nor mental health. PMID- 30312900 TI - Diphthamide affects selenoprotein expression: Diphthamide deficiency reduces selenocysteine incorporation, decreases selenite sensitivity and pre-disposes to oxidative stress. AB - The diphthamide modification of translation elongation factor 2 is highly conserved in eukaryotes and archaebacteria. Nevertheless, cells lacking diphthamide can carry out protein synthesis and are viable. We have analyzed the phenotypes of diphthamide deficient cells and found that diphthamide deficiency reduces selenocysteine incorporation into selenoproteins. Additional phenotypes resulting from diphthamide deficiency include altered tRNA-synthetase and selenoprotein transcript levels, hypersensitivity to oxidative stress and increased selenite tolerance. Diphthamide-eEF2 occupies the aminoacyl-tRNA translocation site at which UGA either stalls translation or decodes selenocysteine. Its position is in close proximity and mutually exclusive to the ribosomal binding site of release/recycling factor ABCE1, which harbors a redox sensitive Fe-S cluster and, like diphthamide, is present in eukaryotes and archaea but not in eubacteria. Involvement of diphthamide in UGA-SECIS decoding may explain deregulated selenoprotein expression and as a consequence oxidative stress, NFkB activation and selenite tolerance in diphthamide deficient cells. PMID- 30312902 TI - An attempt to treat ocular flutter and opsoclonus by cerebellar magnetic stimulation. PMID- 30312903 TI - The first Japanese report on neuromyelitis optica rediscovered: acute bilateral blindness, tetraparesis and respiratory insufficiency in a 35-year-old man (1891). AB - The term 'neuromyelitis optica' (NMO, Devic syndrome) is used to refer to a syndrome characterized by optic neuritis and myelitis. For many decades NMO was classified as a clinical variant of multiple sclerosis (MS). Recent research has shown, however, that NMO differs from MS in terms of immunopathogenesis, clinical presentation, and optimum treatment. In most cases, NMO is caused by autoantibodies to aquaporin-4 or myelin oligodendrocyte glycoprotein. While the history of classic MS has been studied extensively, only relatively little is known about the early history of NMO. Although NMO is considered to be much more prevalent among Asian than among European patients with CNS demyelination, all early reports of NMO reviewed by Eugene Devic and Fernand Gault in their seminal 1894 review and all other reports from the 19th century re-discovered by us over the past years related cases of NMO in patients of European descent. Here, we would like to draw the attention to an early report on NMO in a Japanese patient, published by Tanemichi Aoyama (1859-1917), one of the most eminent physicians of the Meiji period, an era characterized by a Western-style revolution in Japanese medicine. The report was published in 1891, i.e. 3 years before Devic and Gault's disease defining study on NMO. To the best of our knowledge, this is the earliest report on an Asian patient with NMO. We give an English translation of the original Japanese report written in bungo (pre-modern Japanese) and discuss the case both in the light of current knowledge on NMO and from a historical perspective. PMID- 30312904 TI - Night light intensity and women's body weight: Evidence from Nigeria. AB - The prevalence of overweight and obesity are increasing in many African countries and hence becoming regional public health challenges. We employ satellite-based night light intensity data as a proxy for urbanization to investigate the relationship between urbanization and women's body weight. We use two rounds of the Demographic and Health Survey data from Nigeria. We employ both nonparametric and parametric estimation approaches that exploit both the cross-sectional and longitudinal variations in night light intensities. Our empirical analysis reveals nonlinear relationships between night light intensity and women's body weight measures. Doubling the sample's average level of night light intensity is associated with up to a ten percentage point increase in the probability of overweight. However, despite the generally positive relationship between night light intensity and women's body weight, the strength of the relationship varies across the assorted stages of night light intensity. Early stages of night light intensity are not significantly associated with women's body weight, while higher stages of nightlight intensities are associated with higher rates of overweight and obesity. Given that night lights are strong predictors of urbanization and related economic activities, our results hint at nonlinear relationships between various stages of urbanization and women's body weight. PMID- 30312905 TI - Hybrid inorganic (nonporous silica)/organic (alginate) core-shell platform for targeting a cisplatin-based Pt(IV) anticancer prodrug. AB - Nonporous silica nanoparticles with an external shell containing the 3 aminopropyl arm (SiNP) were further decorated with alginic acid (SiNP-ALG) as a potential biocompatible delivery system for Pt antitumor agents. Such particles were coupled with the prodrug (OC-6-44)-acetato(beta alaninato)diamminedichloridoplatinum(IV), 1, through the formation of amide bonds between the pendant carboxylate groups on SiNP-ALG and the free amino group of the complex. Cytosol extracted from tumor cells was able to quickly and efficiently reduce the Pt(IV) prodrug, and produces the active metabolite cisplatin. SiNP-ALG-Pt conjugate was more active than both cisplatin and 1, due to its more efficient cell uptake, whereas the SiNP-ALG unplatinated nanoparticles were deprived of any nonspecific toxicity. PMID- 30312906 TI - Spectroscopic profiling (FT-IR, FT-Raman, NMR and UV-Vis), autoxidation mechanism (H-BDE) and molecular docking investigation of 3-(4-chlorophenyl)-N,N-dimethyl-3 pyridin-2-ylpropan-1-amine by DFT/TD-DFT and molecular dynamics: A potential SSRI drug. AB - Spectroscopic profiling in terms of FT-IR, FT-Raman, UV-vis and NMR in addition to reactivity study by density functional theory (DFT) and molecular dynamics (MD) simulations of 3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (C16H19ClN2) have been discussed. In order to assign principal vibrational numbers, the Potential energy distribution (PED) analysis has been executed. Frontier molecular orbitals (FMOs) analysis in addition to the stabilization energy and natural hybrid orbital analysis has been done. Local reactivity properties of this compound have been addressed through molecular electrostatic potential (MEP) and average local ionization energy (ALIE) surfaces. The bond dissociation energy for hydrogen abstraction (H-BDE) and chemical bonding analysis in terms of electron localization function gave details regarding the Pauli exchange repulsion effect in the electrons of the molecule. Molecular dynamics simulation has been performed in order to understand reactivity of title molecule with water. Molecular docking study was executed to evaluate the potential of the title molecule to bind with 5-HT1 A serotonin receptor and thus can be a lead compound for developing new SSRI (Selective serotonin reuptake inhibitor) drug. Aside from molecular docking, drug likeness parameters have been also considered and by QSAR modeling the comparison of physiochemical parameters of commercially available SSRI drugs and title molecule is carried out. PMID- 30312907 TI - Mitochondria and plasma membrane dual-targeted chimeric peptide for single-agent synergistic photodynamic therapy. AB - Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy. PMID- 30312908 TI - Development and evaluation of diffusive gradients in thin films based on nano sized zinc oxide particles for the in situ sampling of tetracyclines in pig breeding wastewater. AB - The pollution of antibiotics, including tetracyclines (TCs), in aquatic environments has become an issue of concern in recent years. Herein, an in situ sampling of TCs in pig breeding wastewater that utilizes the technique of diffusive gradients in thin films (DGT), based on commercial nanosized ZnO (nanoZnO) particles as the potential effective binding agent and a polyethersulfone (PES) membrane as the diffusion layer, was developed. The diffusion coefficients of tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC) in a PES membrane at 25 degrees C were (1.37 +/- 0.06) * 10-6 cm2 s-1, (1.29 +/- 0.05) * 10-6 cm2 s-1 and (1.94 +/- 0.07) * 10-6 cm2 s-1, respectively. The results showed that the adsorption capacities of a gel disc containing 2.5 g L-1 of nanoZnO particles were as high as 3.93 +/- 0.20 mg disc-1 for TC, 3.21 +/- 0.20 mg disc-1 for OTC and 4.62 +/- 0.22 mg disc-1 for CTC. Both a solution pH in the range of 5-9 and an ionic strength (as pNaCl) in the range of 1-3 had an insignificant influence on the TCs uptake by nanoZnO-DGT samplers. There was no significant influence of fulvic acid or tannic acid on the TC uptake by nanoZnO-DGT samplers at the tested mass ratios. For all spiked freshwater samples, there was no notable interference of matrices on the performance of the nanoZnO-DGT samplers, suggesting that the nanoZnO-DGT samplers yielded satisfactory results for the uptake of TCs at concentrations existing in the spiked freshwater samples. Field deployment of the nanoZnO-DGT samplers in pig breeding wastewater also exhibited excellent precision and accuracy, indicating that the nanoZnO-DGT samplers could be used as a promising method for the in situ sampling of TC antibiotics in aquatic environments. PMID- 30312909 TI - CD4 T cell responses to flaviviruses. AB - Flaviviruses pose an increasing threat to global health with their potential to cause severe disease in millions of people. Protective and long-lived immunity is closely linked to the generation of CD4 T cells, which provide B cell help and support high affinity neutralizing antibody responses. Research performed during the last years revealed important new insights into the antigen specificities and diverse effector functions of CD4 T cell responses to flaviviruses. Moreover, the identification of mechanisms involved in the regulation of T cell specificity and function provides significant advances in our understanding of how durable protective immunity is established. Here, we summarize what is known about human CD4 T cell responses to flaviviruses, with a special emphasis on CD4 T cells that provide direct help to B cells producing neutralizing and protective antibodies. We review recent progress in the identification of epitope sites in the context of the atomic structures of flavivirus proteins and highlight specific influences that shape the human CD4 T cell response in the context of infection or vaccination. Finally, we discuss challenges facing vaccine efforts to generate appropriate CD4 T cell responses, as well as recent strategies to enhance T cell mediated antibody responses. PMID- 30312910 TI - Biological relevance of Cytomegalovirus genetic variability in congenitally and postnatally infected children. AB - BACKGROUND: Human cytomegalovirus (HCMV) is the leading cause of congenital infections resulting in severe morbidity and mortality among infected children. Although the virus is highly polymorphic, particularly in genes contributing to immune evasion, the mechanisms underlying its genetic variability and pathogenicity are only partially understood. OBJECTIVES: We aimed to characterize different HCMV clinical strains isolated from 21 congenitally- or postnatally infected children for in vitro growth properties and genetic polymorphisms. STUDY DESIGN: The growth of various HCMV isolates was analyzed in different cell culture models. Genetic polymorphism was assessed by genetic and phylogenetic analysis of viral genes involved in virulence (UL144, US28, and UL18), latency (UL133-138), or drug resistance (UL54 and UL97). RESULTS: Here, we report a high degree of genetic and phenotypic diversity in distinct HCMV clinical isolates, as shown by their in vitro growth properties. In particular, HCMV isolates displayed the highest degree of genetic variability in the UL144 gene, where we were able to define four distinct genotypes within the cohort based on UL144 heterogeneity. Lastly, among all isolates we were able to identify 36 mutations in UL54 and 2 in UL97. CONCLUSIONS: Our findings indicate that surprisingly high levels of genetic HCMV variability correlate with a high degree of phenotypic polymorphism, which in turn might differentially influence the growth, fitness, and drug susceptibility of HCMV. PMID- 30312911 TI - Communicating quantitative evidence of policy effectiveness and support for the policy: Three experimental studies. AB - Increasing the prices of products that harm health is an effective intervention for changing behaviour to improve health but public support for such interventions is generally low. The current paper investigates whether communicating evidence of a policy's effectiveness at tackling the focal problem could increase support. Across three studies we develop an infographic for communicating quantitative evidence of the effectiveness of a hypothetical tax to tackle childhood obesity. We investigate first, whether communicating evidence of effectiveness increases (a) perceived effectiveness (Studies 1,2,3) and (b) support for the policy, and second, whether any increase in perceived effectiveness mediates an increase in support (Studies 1 & 3). In all three studies (combined N = 9654) communicating evidence of effectiveness for the intervention increased perceived effectiveness. In Study 1, communicating evidence did not change support for the policy. Variations of the infographic were developed in Study 2 with one emerging as clearer and easier to comprehend. This infographic was therefore used in Study 3 in which it increased support for the tax from 45% to 49%, an effect that was mediated by perceived effectiveness. The effect sizes were small but probably meaningful at a population level. The results of these three studies suggest the potential for presenting quantitative evidence of intervention effectiveness to increase public support. Much uncertainty remains about the most effective ways of presenting this evidence, whether similar effects are achieved by presenting unquantified evidence and whether larger effects might be achieved by presenting information other than effectiveness. PMID- 30312912 TI - Knowledge and use of sterile water injections amongst midwives in the United Kingdom: A cross-sectional study. AB - BACKGROUND: The use of sterile water injections (SWI) for the relief of pain in labour is popular amongst midwives in countries such as Sweden and Australia. Anecdotal reports suggest the procedure is used less commonly in the United Kingdom (UK) and that a number of barriers to introducing the practice may exist. OBJECTIVE: The objective of this study was to explore the awareness and use of SWI amongst midwives in the UK. DESIGN: A cross-sectional study using an internet based questionnaire. PARTICIPANTS: Midwives with Nursing and Midwifery Council Registration and currently practicing. SETTING: The questionnaire was distributed via the Royal College of Midwives Facebook page and Twitter account. Invitations to participate were also sent to Heads of Midwifery to distribute to staff. FINDINGS: Three hundred and ninety-eight midwives completed the survey. Eighty two percent of midwives did not use SWI in practice although 69% would consider learning the procedure. There was considerable variation in techniques amongst midwives that did provide SWI. The lack of available practice guidelines and the advice from the National Institute for Health and Care Excellence to not use SWI were cited as the main barriers. KEY CONCLUSIONS: SWI use is uncommon in the UK although midwives are interested in incorporating the procedure into practice. IMPLICATIONS FOR PRACTICE: National guidance on SWI and the lack of information and training is restricting the use of the procedure in practice, despite SWI being widely used in other countries and being effective in the treatment of pain in labour. PMID- 30312913 TI - Co-expression network analysis of peripheral blood transcriptome identifies dysregulated protein processing in endoplasmic reticulum and immune response in recurrent MDD in older adults. AB - The molecular factors involved in the pathophysiology of major depressive disorder (MDD) remain poorly understood. One approach to examine the molecular basis of MDD is co-expression network analysis, which facilitates the examination of complex interactions between expression levels of individual genes and how they influence biological pathways affected in MDD. Here, we applied an unsupervised gene-network based approach to a prospective experimental design using microarray genome-wide gene expression from the peripheral whole blood of older adults. We utilised the Sydney Memory and Ageing Study (sMAS, N = 521) and the Older Australian Twins Study (OATS, N = 186) as discovery and replication cohorts, respectively. We constructed networks using Weighted Gene Co-expression Network Analysis (WGCNA), and correlated identified modules with four subtypes of depression: single episode, current, recurrent, and lifetime MDD. Four modules of highly co-expressed genes were associated with recurrent MDD (N = 27) in our discovery cohort (FDR<0.2), with no significant findings for a single episode, current or lifetime MDD. Functional characterisation of these modules revealed a complex interplay between dysregulated protein processing in the endoplasmic reticulum (ER), and innate and adaptive immune response signalling, with possible involvement of pathogen-related pathways. We were underpowered to replicate findings at the network level in an independent cohort (OATS), however; we found a significant overlap for 9 individual genes with similar co-expression and dysregulation patterns associated with recurrent MDD in both cohorts. Overall, our findings support other reports on dysregulated immune response and protein processing in the ER in MDD and provide novel insights into the pathophysiology of depression. PMID- 30312914 TI - Prospective prediction of first lifetime onset of suicidal ideation in a national study of substance users. AB - Suicide rates have increased over the past several decades. Prior research has evaluated risk factors for suicidal behavior, but much of this work does not adequately differentiate between risk factors for suicidal ideation (SI) and suicide attempts, nor does it differentiate between first-onset SI and recurrent ideation. This study seeks to identify risk factors for first-onset SI among a high-risk group: individuals receiving treatment for substance use disorders. Data were drawn from the National Treatment Improvement Evaluation Study, a prospective study examining the impact of addiction treatment programs. Patients with no lifetime history of suicide attempts or ideation (n = 2560) were assessed at baseline and one year later for prospectively-occurring SI. Sociodemographic variables, mental health indices, interpersonal factors, and substance use severity indicators were evaluated as prospective predictors of first-onset SI in linear regression models. Current mental health problems (OR = 1.54, 95% CI = 1.19-2.01), current substance use problems (OR = 1.33, 95% CI = 1.04-1.70), and difficulty accessing treatment for substance use problems (OR = 1.90, 95% CI = 1.16-3.11) emerged as significant predictors of first-onset SI in a multivariate analysis, suggesting that individuals with current mental health or substance use related symptoms are among the most at risk for developing SI. Difficulty obtaining treatment remained significant, highlighting the importance of treatment accessibility. Future clinical work and research would benefit by addressing these issues, potentially by focusing on mental health treatment in substance abuse programs and evaluating barriers to treatment. PMID- 30312915 TI - Sulfur disproportionation tendencies in a sulfur packed bed reactor for perchlorate bio-autotrophic reduction at different temperatures and spatial distribution of microbial communities. AB - This study investigates the sulfur (S) disproportionation tendencies in a sulfur packed bed reactor for perchlorate bio-autotrophic reduction at different temperatures. The reactor was operated with over 99% efficiency for 21.00 +/- 1.40 mg L-1 perchlorate removal when the hydraulic retention time (HRT) ranged from 12.00 h to 0.75 h at 27 +/- 2 degrees C. When HRT was controlled at 1.00 h, the perchlorate removal efficiency was only 8 +/- 1% as the temperature dropped to 6 +/- 1 degrees C. The half-order model fit both perchlorate removal and S disproportionation reaction well. Compared with S disproportionation, the decrease of temperature had a greater influence on perchlorate reduction. As the temperature dropped from 27 +/- 2 degrees C to 6 +/- 1 degrees C, the 1/2K1/2v,R for perchlorate reduction decreased from 7.37 mg1/2 L-1/2 h-1 to 0.19 mg1/2 L-1/2 h-1. Meanwhile, the 1/2K1/2v,S for S disproportionation decreased from 3.04 mg1/2 L-1/2 h-1 to 1.96 mg1/2 L-1/2 h-1. The reaction activation energy of perchlorate reduction and S disproportionation was 120.28 kJ mol-1 and 13.44 kJ mol-1, respectively. The S disproportionation reaction proceeded remarkably at the beginning of the reduction, a longer HRT and higher temperature promoted S disproportionation, resulting in excessive sulfate generation and alkalinity consumption. Besides, the spatial distribution of the microbial communities and the dominant bacteria function under different HRTs was analyzed using high throughput sequencing. PMID- 30312916 TI - The effects of silver nanomaterial shape and size on toxicity to Caenorhabditis elegans in soil media. AB - Silver nanomaterials (AgNMs) of various shapes and sizes are manufactured for different purposes and used as ingredients in a wide variety of products and applications. Recently, the toxicity of AgNMs has attracted significant attention. However, the effect of the shape of AgNMs (particles, wires, plates) on their toxicity in soil ecosystems remains poorly understood. In this study, we added AgNMs of different shapes and sizes (silver nanoparticles, AgNPs; 10 MUm silver nanowires, 10-AgNWs; 20 MUm silver nanowires, 20-AgNWs; silver nanoplates, AgPLs) to natural soil and determined their effect on the growth and reproduction of the free-living nematode, Caenorhabditis elegans. AgNPs and AgPLs were found to inhibit the growth and reproduction of C. elegans, whereas AgNWs had a negligible effect. Among these AgNMs, the results of this study suggest AgNPs are the most toxic. This confirms that the shape of AgNPs plays a significant role in their toxicity level. To the best of our knowledge, this is the first comparative analysis of the shape-dependent toxicity of AgNMs in the soil using nematode C. elegans. This study provides a scientific reference for assessing shape-dependent soil nanotoxicity. PMID- 30312917 TI - Determination of dihalobenzoquinones in water using gas chromatography coupled with an electronic capture detector. AB - Dihalobenzoquinones are a group of disinfection byproducts with high potential toxicity and thus currently receiving increased attention. A determination method of 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) and 2,6-dibromo-1,4-benzoquinone (2,6 DBBQ) was developed upon using liquid-liquid extraction and a gas chromatography with an electronic capture detector (LLE-GC-ECD). The optimized extraction condition was as the following: volume ratio of formic acid to water 0.005%, Na2SO4 dosage 200 g L-1, methyl-tert-butyl ether (MtBE)/water volume ratio 1/10, and extraction with MtBE for once. With the dosed concentrations of 0.5-5.0 MUg L 1, the recovery rates of 2,6-DCBQ and 2,6-DBBQ were 81%-88% and 73%-96%. The limits of quantitation (LOQs) of the LLE-GC-ECD method were 2.4 and 2.7 ng L-1 in 1-L water for 2,6-DCBQ and 2,6-DBBQ. In six local tap waters, 2,6-DCBQ was detected in the range of =0.05 MUg L-1) and KET (>=0.5 MUg L-1) significantly affected the feeding rate, locomotion, gustation and olfaction (P < 0.05), which may result in pronounced disturbance to aquatic ecology. Alterations in the contents of neurotransmitters (i.e., octopamine (OA), dopamine (DA), and serotonin (5-HT)) correlated with the physiology change. The metabolic activities and the antioxidase activity (i.e., superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT)) of METH and KET in C. elegans were different, which could partly explain the difference of the physiological changes induced by the two substances. Moreover, these two drugs could induce vulva deformity, and the 50% effect concentrations were 620.34 MUg L 1 for METH and 54.39 MUg L-1 for KET, respectively. The risk quotients (RQ) in two Chinese rivers, the Shenzhen and Liangshui River, were calculated to assess eco-risks of METH and KET. RQs of KET in the Shenzhen River were over 0.1 at the medium risk level, indicating that eco-risks of illicit drugs to aquatic organism cannot be overlooked. PMID- 30312924 TI - Development and application of retention time prediction models in the suspect and non-target screening of emerging contaminants. AB - Hydrophilic interaction liquid chromatography (HILIC) and reversed phase LC (RPLC) coupled to high resolution mass spectrometry (HRMS) are widely used for the identification of suspects and unknown compounds in the environment. For the identification of unknowns, apart from mass accuracy and isotopic fitting, retention time (tR) and MS/MS spectra evaluation is required. In this context, a novel comprehensive workflow was developed to study the tR behavior of large groups of emerging contaminants using Quantitative Structure-Retention Relationships (QSRR). 682 compounds were analyzed by HILIC-HRMS in positive Electrospray Ionization mode (ESI). Moreover, an extensive dataset was built for RPLC-HRMS including 1830 and 308 compounds for positive and negative ESI, respectively. Support Vector Machines (SVM) was used to model the tR data. The applicability domains of the models were studied by Monte Carlo Sampling (MCS) methods. The MCS method was also used to calculate the acceptable error windows for the predicted tR from various LC conditions. This paper provides validated models for predicting tR in HILIC/RPLC-HRMS platforms to facilitate identification of new emerging contaminants by suspect and non-target HRMS screening, and were applied for the identification of transformation products (TPs) of emerging contaminants and biocides in wastewater and sludge. PMID- 30312925 TI - Temperature-triggered sensitive resistance transition of graphene oxide wide ribbons wrapped sponge for fire ultrafast detecting and early warning. AB - Fire prevention and safety of combustible materials is a global challenge. To reduce their high fire risk, traditional smoke detectors are widely used indoor via detecting smoke product after combustion; however, they usually show a long response time and limitation for outdoor use. Herein, we report a temperature induced electrical resistance transition of graphene oxide wide-ribbon (GOWR) wrapped sponges to reliably monitor fire safety of the combustible materials. Novel rectangle-like GOWR sheets are synthesized from unzipping carbon nanofibers and used to fabricate GOWR wrapped melamine formaldehyde sponges with multi functionalities, e.g. lightweight, good hydrophobicity, reversible compressibility, excellent acidic/alkaline tolerance and flame resistance. The GOWR sheets on the sponge skeleton can be in-situ thermally reduced once encountering a flame attack or abnormal high temperature, inducing a distinct transition in electrical resistance. Consequently, an ultrafast alarm response of ~2 s to flame attack is triggered, and rapid fire early warning signals to abnormal high temperatures, e.g. ~33 s at 300 degrees C, are achieved below ignition temperature of most combustible materials. This method drives substantial motivation and opportunity to develop advanced fire detection and early warning sensors for reducing the high fire risk of various combustible materials in outdoor applications. PMID- 30312926 TI - Engineered nanomaterials for water decontamination and purification: From lab to products. AB - Clean water is vital for life; it is required not only for drinking but also for the preparation of food and proper hygiene. Unfortunately, more than fifty percent of the world population mainly in China and India face a severe scarcity of water. Around 1.8 billion people inevitably drink water from sources having fecal contamination resulting in the death of about a million children every year. Scientists are developing various economic technologies to decontaminate and purify water. Nanomaterials-based technology offers an economic and effective alternative for water purification and decontamination. As nanomaterials are available globally, have remarkable antimicrobial activity and the ability to effectively remove organic and inorganic pollutants from water. This review discusses the potential role of nanomaterials in the purification of drinking water. As nanomaterials exhibit remarkable antimicrobial and antiparasitic activities against waterborne pathogens and parasites of primary concern like Shigella dysenteriae, Vibrio cholera, and Entamoeba histolytica. Nanomaterials also demonstrate the ability to absorb toxic chemicals like mercury and dyes from polluted water. However, for successful commercialization of the technology, some inherent bottlenecks need to be addressed adequately. These include nanoparticles aggregation, their seepage into drinking water and adverse effects on human health and the environment. Nanocomposites are being developed to overcome these problems and to combine two or more desirable properties for water purification. Widespread and large-scale use of nanomaterials for water purification soon may become a reality. Products containing nanomaterials such as Karofi, Lifestraw, and Tupperware for water purification are already available in the market. PMID- 30312927 TI - Classification of measured unsafe liquids using microwave spectroscopy system by multivariate data analysis techniques. AB - To identify hazardous (illegal and explosive) materials, microwave measurement (free space reflection type method) method has been tried to find best results in different frequency ranges. The main goal is to cluster some materials which are mainly preferred by passenger for aircraft travel. Therefore, the multivariate data analysis methods have been preferred to classify or distinguish the measured liquids. Thus, the abilities of used techniques have been shown to make the classification process easier and more responsive, while determining the convenient measurement method that can reflect the unique properties of the liquids. The desired success has been achieved magnificently by self-organizing maps algorithm. PMID- 30312928 TI - Environmentally friendly polychlorinated naphthalenes (PCNs) derivatives designed using 3D-QSAR and screened using molecular docking, density functional theory and health-based risk assessment. AB - A complete design and screening system for environmental-friendly polychlorinated naphthalene (PCN) derivatives was established through three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, density functional theory (DFT) methods and health-based risk assessment based on dynamic multimedia fugacity model. Two types of 3D-QSAR models were established for PCNs using the experimental biological toxicity (logEC50) of 14 PCNs to carry out a modification to lower the logEC50 of CN-70. Consequently, 67 new monosubstituted and disubstituted derivatives with a lower biological toxicity than CN-70 were designed. Furthermore, 21 new CN-70 derivatives were selected through the evaluation of their persistent organic pollutant properties (biological toxicity, bio-concentration, long-range transport potential, biodegradability) and practicability (stability, insulativity, flame retardancy) using 3D-QSAR, molecular docking and DFT methods. Finally, the non-carcinogenic and carcinogenic risks of 19 new CN-70 derivatives in different exposure pathways were reduced, and 5 derivatives with a significant decrease both in biological toxicity (amplitude reduction: 12.73%-32.51%) and risk (amplitude reduction: 32.18%-59.19%) were selected as environmental-friendly PCN derivatives, which had been screened using the health-based risk assessment system associated with dynamic multimedia fugacity model. This study provides a theoretical basis for the design of environmental-friendly flame retardants and insulating materials. PMID- 30312929 TI - Detecting familial hypercholesterolemia earlier in life by actively searching for affected children:The DECOPIN project. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is underdiagnosed in children. We assessed a combination of two screening methods. The first method was to detect hypercholesteraemic children and then study the parents (Ch-P pathway), and the second one was to study the offspring of FH-affected parents (P Ch pathway). METHODS: In the Ch-P path, primary care paediatricians were asked to include lipid profiling or, at least, total cholesterol (TC) and then lipid profiling if TC was higher than 5.2 mmol/L in any clinically indicated blood test. Children with LDL-C >= 3.5 mmol/L, plus either a family history of early cardiovascular disease or one parent with severe hypercholesterolemia, were referred to the lipid unit where the parents, rather than their children, were studied. In parents with definite, clinical FH, a genetic study was performed. Focused genetic testing was performed on all offspring of genetically positive parents. The P-Ch path consisted of the active study of children from definite FH adults. RESULTS: Fifty-nine paediatricians covering a total population of 63,616 children agreed to participate in the project. Of the 216 children (122 Ch-P and 94 P-Ch) who were ultimately referred to the lipid unit, 87 children with FH (84% genetically positive) were identified. Additionally, 41 parents (from 40 families) were newly diagnosed with FH (63% genetically positive). Forty-nine different mutations were detected: 46 in the LDLR, 2 in the PCSK9 and 1 in APOB gene. CONCLUSIONS: The implementation of active strategies to detect FH in children, in close collaboration with primary care paediatricians, provides a high-performance method for early FH detection. PMID- 30312930 TI - The prognostic value of interleukin 6 in multiple chronic diseases and all-cause death: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND AIMS: We aimed to evaluate the associations and prognostic value of interleukin-6 (IL6) for the prediction of atherosclerotic cardiovascular disease (ASCVD) events, heart failure (HF), and other chronic diseases in a large, multi-ethnic, contemporary population. METHODS: We included 6617 participants from the Multi-Ethnic Study of Atherosclerosis (5640 non-users, 977 users of statins at baseline). Main outcomes were hard ASCVD events and HF; secondary outcomes included all-cause death, atrial fibrillation, venous thromboembolism and cancer. RESULTS: Median follow-up was 13.2 years. Strong associations were observed in Cox regression analyses between higher IL6 levels and ASCVD events, HF, and mortality, particularly among statins users. In the latter, associations remained strong after adjusting for traditional risk factors and other inflammation biomarkers (e.g., risk factor, hsCRP-adjusted hazard ratio for incident HF comparing 3rd vs. 1st IL6 tertiles: 3.55, 95% CI 1.23-10.27). Although IL6 did not improve CHD prediction beyond traditional risk factors, among statin users it improved the prediction of stroke (improvement in the C statistic +0.018), incident HF (+0.028, the largest C statistic increase across all study outcomes), and all-cause death (+0.017). CONCLUSIONS: IL6 is strongly and independently associated with ASCVD events, HF, and all-cause mortality, particularly among statin users. Although the prognostic value of IL6 is limited for the prediction of CHD events, it may have a role for the prediction of stroke, HF and all-cause death in asymptomatic statin users. Larger studies are needed to replicate these findings. PMID- 30312931 TI - l,8-Naphthalimide based DNA intercalators and anticancer agents. A systematic review from 2007 to 2017. AB - In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer agents. The 1,8-naphthalimides binds to the DNA via intercalation, and exert their antitumor activities through Topoisomerase I/II inhibition, photoinduced DNA damage or related mechanism. Here, our discussion focused on works published over the last ten years (2007-2017) related to therapeutic applications, in the order of cancer treatment followed by other properties of 1,8-naphthalimides. In preparing for this review, we considered that several seminal reviews have appeared over the last fifteen years and focused on closely related subjects, however, none of them is exhaustive. PMID- 30312932 TI - Anti-inflammatory abietanes diterpenoids isolated from Tripterygium hypoglaucum. AB - Tripterygium hypoglaucum (H. Lev.) Hutch. has been used to remedy rheumatoid arthritis, however, it shows frequent toxicity to the body. In this study, liquid chromatograph-mass spectrometer (LC-MS) was guided to characterize abietanes diterpenoids with anti-inflammatory activity from the stem of T. hypoglaucum. Thirteen undescribed abietanes diterpenoids were isolated and purified, and their chemical structure was identified using various spectroscopic methods. These compounds belonged to abietanes with splitting C ring, abietanes with benzenoid rings, diterpene quinoids, diterpene quinoids with lactone rings, and abietanes with benzenoid and lactone rings, respectively. Lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages was used to evaluate anti inflammatory activity of the compounds. The results indicated that hypoglicin B-G and hypoglicin J-M exhibited inhibitory activity of NO production with the IC50 values of 6.01, 25.21, 8.29, 3.63, 0.72, 0.89, 36.91, 0.82, 2.85, 11.92 MUM, respectively. Among these compounds, compound hypoglicin L showed high anti inflammatory activity and low toxicity (SI = 5.02 * 104). Further QPCR analysis revealed that hypoglicin D and hypoglicin L can inhibit the mRNA expression of iNOS in LPS-stimulated RAW264.7 cells at doses of 12.5 and 3.13 MUM, respectively. Taken together, ten anti-inflammatory diterpenoids were found from T. hypoglaucum in this study. PMID- 30312933 TI - In silico characterization and transcriptional modulation of phenylalanine ammonia lyase (PAL) by abiotic stresses in the medicinal orchid Vanda coerulea Griff. ex Lindl. AB - Phenylalanine ammonia lyase (PAL) is the first enzyme of phenylpropanoid pathway. In the present study, a full-length PAL transcript from Vanda coerulea Griff. ex Lindl. (Family: Orchidaceae) was isolated and characterized. It was found that complete PAL transcript of V. coerulea (VcPAL; Gene Bank no. MG745168) contained 2175 bp with the open reading frame (ORF) of 2112 bp, encoding 703 amino acid residues. The multiple sequence alignment showed that VcPAL protein had 81% identity with that of the orchid, Bromheadia finlaysoniana. Phylogenetic analysis also disclosed that VcPAL shared the same evolutionary relationship with PAL proteins of other orchid species and to be closely related to that of other angiosperm species as well. The three-dimensional structure of VcPAL was found to be homo-tetrameric in nature consisting of four identical subunits with a molecular mass of 75 kDa per subunit. In silico characterization revealed the deduced protein to be a stable protein, comprising three major functional domains as reported in PAL proteins of other species. The transcription profiling of VcPAL exhibited the highest expression level to be present in the in vitro - raised leaf and root samples as compared to that of the ex vitro plant. The differential expression of VcPAL transcript was observed to be up-regulated by different types of abiotic stresses like wounding, cold, UV-B, salinity, and down regulated by dark treatment. The study also exhibited that the VcPAL enzyme activity was directly proportional to the gene expression after the tissues were subjected to salinity and wounding stresses wherein a 1.7- fold increase in the enzyme activity was recorded in the leaf tissues exposed to salinity stress. A positive correlation could be found between the enzyme activity and the accumulation of phenylpropanoids such as total phenolic and flavonoid contents with R2 = 0.85 and 0.842 respectively. PMID- 30312934 TI - The antioxidative activity of piceatannol and its different derivatives: Antioxidative mechanism analysis. AB - The naturally occurring stilbenes piceatannol and its derivatives are excellent antioxidants. In this work, the antioxidative activities of piceatannol and different piceatannol derivatives have been investigated using the density functional theory (DFT) method based on three widely accepted radical scavenging mechanisms, namely, the hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). The gas and four solvent phases, namely, bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE), related to these mechanisms were calculated to elucidate the antioxidative capacities of the investigated compounds. This work focuses specifically on the thermodynamically preferred mechanism, antioxidative site and antioxidative activity order of the investigated stilbenes. The substituted effects of the methyl group and prenyl group on the chemical properties of the remaining OH and CH groups are also analysed. This work confirms the vital role of the OH and CH groups on free radical scavenging of piceatannol and its derivatives. PMID- 30312935 TI - Estimation of seizures prevalence in ischemic strokes after thrombolytic therapy. AB - PURPOSE: Post stroke seizures are a complication that occur in 5-20% of acute ischemic stroke (AIS) patients, cause a reduction in quality of life and a greater burden on the health system. There is not enough data regarding an association between today's standard of care treatment in AIS: recombinant tissue plasminogen activator (r-tPA) and the risk for post stroke seizures. Our aim in this work is to reveal such a connection. METHOD: A non-randomized retrospective cohort-controlled study of 234 patients, who were hospitalized with acute ischemic stroke at Kaplan Medical Center in the years 2009-2015 and were divided into two different treatment groups: r-tPA and antiaggregant therapy(n = 141) and antiaggregant therapy only (n = 95) was conducted by us. Information regarding demographics, medical history, nature of the event, including NIHSS values on admission, discharge, and post stroke seizures, were obtained for each group. Follow-up was done for one year. RESULTS: During the year of follow-up, 19 patients (8.1%) of the overall cohort, developed seizures: 12 of them (12.6%) belonged to the control group and 7 (5%) to the study group p < 0.05). Results showed a decrease in the risk for developing seizure when treated with r-tpA, comparing to antiaggregants (odds ratio = 0.64). CONCLUSION: This study suggests there is an association between r-tPA treatment and reduction of the risk for post stroke seizures. PMID- 30312936 TI - Periconceptional undernutrition affects the levels of DNA methylation in the peri implantation pig endometrium and in embryos. AB - Maternal undernutrition during the periconceptional period alters the transcriptomic profile of pig endometrium and embryos. Herein, we tested the hypothesis that restricted maternal consumption by females during the periconceptional period impairs the pattern of DNA methylation in both the endometrium and embryos during the peri-implantation period (Day 15-16 of gestation). Affected genes in restricted-diet-fed pig endometrium and embryos were identified using quantitative methylation-specific PCR and comprised those genes which are known to be important in reproductive, metabolic and epigenetic function, thereby exhibiting altered transcriptomic expression in endometrium and embryos of restricted-diet-fed gilts. Specifically, levels of DNA methylation of selected genes with altered expression in the endometrium included acid phosphatase type 2C (PPAP2C), salivary lipocalin (SAL1), endothelin receptor type B (EDNRB), regulator of G-protein signalling 12 (RGS12), type 4 17beta hydroxysteroid dehydrogenase (HSD17B4), toll-like receptor 3 (TLR3), and adiponectin receptor 1 (ADIPOR1). In embryos, adiponectin receptor 2 (ADIPOR2), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 12-lipoxygenase (ALOX12), progestin and adipoQ receptor family member 7 (PAQR7), progesterone receptor membrane component 2 (PGRMC2), steroidogenic acute regulatory protein (STAR), and serpin family A member 1 (SERPINA1) were altered. Finally, 5 acid phosphatase tartrate resistant (ACP5), high mobility group box 2 (HMGB2), and DNA (cytosine-5)-methyltransferase 1 (DNMT1) were altered in both the endometrium and in embryos. In the endometrium, the methylation levels of ACP5 (regulation of endometrial-conceptus iron transport), RGS12 (protein-coupled receptor signalling), and TLR3 (immune response) were increased, while that of EDNRB (corpus luteum maintenance) was decreased. In embryos, the methylation levels of ADIPOR2 (metabolic homeostasis) and DNMT1 (DNA methylation maintenance) were increased. The levels of methylation in other studied endometrial and embryonic genes were unchanged. DNA methylation levels in both the peri-implantation pig endometrium and embryos may be altered in response to female nutritional restriction. PMID- 30312937 TI - Prevalence of ankle equinus and correlation with foot plantar pressures in people with diabetes. AB - BACKGROUND: An association between equinus and plantar pressure may be important for people with diabetes, as elevated plantar pressure has been linked with foot ulcer development. To determine the prevalence of equinus in community dwelling people with diabetes and to examine any association between presence of equinus and forefoot plantar pressures. METHODS: Barefoot (Tekscan HR MatTM) and in-shoe (Novel Pedar-X(r)) plantar pressure variables, non-weight bearing ankle range of motion and neuropathy status were assessed in 136 adults with diabetes (52.2% male; 47.8% with neuropathy; mean (standard deviation) age and diabetes duration: 68.4 (11.5) and 14.6 (11.1) years respectively). FINDINGS: Equinus, when measured as <=5 degrees dorsiflexion, was present in 66.9% of the cohort. There was a significant correlation between an equinus and barefoot (r = 0.247, p = 0.004) and in-shoe forefoot pressure time integrals (r = 0.214, p = 0.012) and in-shoe forefoot alternate pressure time integrals (r = 0.246, p = 0.004). Significantly more males (p < 0.01) and people with neuropathy (p = 0.02) or higher glycated haemoglobin levels (p < 0.01) presented with an equinus. INTERPRETATION: Community dwelling adults with diabetes have a high rate of ankle equinus which is associated with increased forefoot pressure time integrals and a two-fold increased risk of high in-shoe peak pressures. Clinical assessment of an ankle equinus may be a useful screening tool to identify adults at increased risk of diabetic foot complications. PMID- 30312938 TI - Inflammatory projections after focal brain injury trigger neuronal network disruption: An 18F-DPA714 PET study in mice. AB - Due to the heterogeneous pathology of traumatic brain injury (TBI), the exact mechanism of how initial brain damage leads to chronic inflammation and its effects on the whole brain remain unclear. Here, we report on long-term neuroinflammation, remote from the initial injury site, even after subsiding of the original inflammatory response, in a focal TBI mouse model. The use of translocator protein-positron emission tomography in conjunction with specialised magnetic resonance imaging modalities enabled us to visualize "previously undetected areas" of spreading inflammation after focal cortical injury. These clinically available modalities further revealed the pathophysiology of thalamic neuronal degeneration occurring as resident microglia sense damage to corticothalamic neuronal tracts and become activated. The resulting microglial activation plays a major role in prolonged inflammatory processes, which are deleterious to the thalamic network. In light of the association of this mechanism with neuronal tracts, we propose it can be termed "brain injury related inflammatory projection". Our findings on multiple spatial and temporal scales provide insight into the chronic inflammation present in neurodegenerative diseases after TBI. PMID- 30312939 TI - Lesion locations associated with persistent proprioceptive impairment in the upper limbs after stroke. AB - Proprioceptive deficits are common after stroke and have been associated with poorer recovery. Relatively little is known about the brain regions beyond primary somatosensory cortex that contribute to the percept of proprioception in humans. We examined a large sample (n = 153) of stroke survivors longitudinally to determine which brain regions were associated with persistent post-stroke proprioceptive deficits. A robotic exoskeleton quantified two components of proprioception, position sense and kinesthesia (movement sense), at 2 weeks and again at 6 months post-stroke. A statistical region of interest (sROI) analysis compared the lesion-behaviour relationships of those subjects with cortical and subcortical stroke (n = 136). The impact of damage to brainstem and cerebellum (n = 17) was examined separately. Results indicate that damage to the supramarginal gyrus, the arcuate fasciculus, and Heschl's gyrus are associated with deficits in position sense and kinesthesia at 6 months post-stroke. These results suggest that regions beyond the primary somatosensory cortex contribute to our sense of limb position and movement. This information extends our understanding of proprioceptive processing and may inform personalized interventions such as non invasive brain stimulation where specific brain regions can be targeted to potentially improve stroke recovery. PMID- 30312941 TI - Observation of natural background radiation during the Great American Eclipse. AB - Observations of photon and neutron background radiation were made in Rigby, Idaho, during the Great American Eclipse on August 21, 2017. Photon measurements were made using a mechanically-cooled, high-purity germanium gamma-ray spectrometer, segmenting the data into four energy bands of < 1 MeV, 1-2 MeV, 2-3 MeV, and 3-7 MeV. Neutron measurements were made using 3He proportional counter arrays embedded in polyethylene, either bare or wrapped with Cd or B filters. All data was analyzed in 900-s intervals starting one day before the eclipse and extending to one day after the eclipse. More detailed analyses were made in 90-s intervals for the photon data and 110-s intervals for the neutron data. Meteorological data was simultaneously recorded in 60-s intervals, recording solar radiance, temperature, air pressure, relative humidity, and dew point. For the observations described here, no statistically-significant (> 3sigma) variations in signal count rates were observed in either the photon or neutron data. This level corresponds to the lack of observed photon variations exceeding 2.1%, 12.2%, 21.6%, or 43.2% of mean values in the four photon energy groups, respectively; it corresponds to a lack of observed neutron variations exceeding 25.3%, 25.6%, or 16.1% of mean values in the three neutron detector arrays, respectively. PMID- 30312940 TI - Event-related desynchronization during movement attempt and execution in severely paralyzed stroke patients: An artifact removal relevance analysis. AB - The electroencephalogram (EEG) constitutes a relevant tool to study neural dynamics and to develop brain-machine interfaces (BMI) for rehabilitation of patients with paralysis due to stroke. However, the EEG is easily contaminated by artifacts of physiological origin, which can pollute the measured cortical activity and bias the interpretations of such data. This is especially relevant when recording EEG of stroke patients while they try to move their paretic limbs, since they generate more artifacts due to compensatory activity. In this paper, we study how physiological artifacts (i.e., eye movements, motion artifacts, muscle artifacts and compensatory movements with the other limb) can affect EEG activity of stroke patients. Data from 31 severely paralyzed stroke patients performing/attempting grasping movements with their healthy/paralyzed hand were analyzed offline. We estimated the cortical activation as the event-related desynchronization (ERD) of sensorimotor rhythms and used it to detect the movements with a pseudo-online simulated BMI. Automated state-of-the-art methods (linear regression to remove ocular contaminations and statistical thresholding to reject the other types of artifacts) were used to minimize the influence of artifacts. The effect of artifact reduction was quantified in terms of ERD and BMI performance. The results reveal a significant contamination affecting the EEG, being involuntary muscle activity the main source of artifacts. Artifact reduction helped extracting the oscillatory signatures of motor tasks, isolating relevant information from noise and revealing a more prominent ERD activity. Lower BMI performances were obtained when artifacts were eliminated from the training datasets. This suggests that artifacts produce an optimistic bias that improves theoretical accuracy but may result in a poor link between task-related oscillatory activity and BMI peripheral feedback. With a clinically relevant dataset of stroke patients, we evidence the need of appropriate methodologies to remove artifacts from EEG datasets to obtain accurate estimations of the motor brain activity. PMID- 30312942 TI - Neighborhoods matter. A systematic review of neighborhood characteristics and adolescent reproductive health outcomes. AB - This systematic review examines the relationship between neighborhood characteristics and adolescent pregnancy, contraceptive use, sexual initiation, and birthrate. Several studies found a significant association between higher poverty and increased adolescent birthrate, pregnancy, and earlier age at sexual initiation. Unsafe neighborhoods were associated with earlier sexual initiation and increased adolescent pregnancy. Mixed results were found for neighborhood racial or ethnic composition. Lower collective efficacy and social support were associated with increased rates of adolescent pregnancy and earlier age at sexual initiation. Improved definitions of neighborhoods, as well as research on interactions between structural factors and social processes during adolescence is needed. PMID- 30312943 TI - Effects of phospholipid and polyethylene glycol monostearate (100) on the in vitro and in vivo physico-chemical characterization of poly(n-butyl cyanoacrylate) nanoparticles. AB - In this study, poly(n-butyl cyanoacrylate) nanoparticles (PBCA-NPs) modified with various amounts of soybean phospholipid (PC) and polyethylene glycol monostearate (S100) were prepared in order to investigate the effects of PC and S100 on the nanoparticles' physico-chemical properties, cytological properties and in vivo gastrointestinal absorption. Coumarin-6 (C6) was used as a fluorescent probe; C6 loaded PBCA-NPs modified with both PC and S100 (C6-PS-PBCA-NPs) were prepared using miniemulsion polymerization, and C6-loaded PBCA-NPs modified with either S100 (C6-S-PBCA-NPs) or PC (C6-P-PBCA-NPs) were used as references. All of the different NPs were shown to be stably dispersed and to have a small particle size. A cytotoxicity study indicated that all of the blank PBCA-NPs were safe and nontoxic. The uptake of NPs by Caco-2 cells was shown to be increased when the amount of PC was increased from 0% to 1.25% and the amount of S100 was increased from 0% to 0.725%. The use of a ligated intestinal loop model demonstrated that C6-PS-PBCA-NPs could rapidly penetrate a highly viscoelastic mucous layer, leading to an improvement in the absorption efficiency. During a pharmacokinetic study, C6-PS-PBCA-NPs improved the absorption of C6, as indicated by their higher Cmax and AUC0-t values compared with those of C6-S-PBCA-NPs or C6-P-PBCA-NPs. Overall, the results of this study indicate that PBCA-NPs modified with PC and S100 can enhance the absorption of orally administered drugs. PMID- 30312944 TI - Development of a Solid-phase microextraction (SPME) Fiber protector and its application in flammable liquid residues analysis. AB - Solid-phase microextraction (SPME) has been established as a very powerful alternative to traditional extraction methods since its introduction in the early 1990s. The heart of the SPME device is an expensive thin and very delicate fused silica fiber, coated with a thin polymer film. When extracted, the fiber may bend and break. Due to the fragility of the SPME fiber, a fiber protector device is proposed. The protector is easily assembled on the SPME device and can easily be removed by unscrewing for sampling to the injector. The SPME with the fiber protector was tested by headspace-SPME (HS-SPME) gasoline and diesel fuel vapor analyses. The results of the extractions with the SPME protector were compared with the results of the extractions by SPME without the protector. An enhancement to the lighter hydrocarbons was observed in the results with the protector but the method sensitivity was not altered. The SPME protector was easily cleaned from contaminant residues by ethyl acetate washings. The protector can be used for years and the fibers remain intact for hundreds of samplings. PMID- 30312945 TI - The 2016 ENFSI Fingerprint Working Group testing programme. AB - In 2016, the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI), officially established an advisory group with the task of organising proficiency tests (PTs), as well as collaborative exercises (CEs) as a way of raising standards within the fingerprint profession. This article will provide an overview of the Visualisation collaborative exercise and the Comparison proficiency test, which were carried out in 2016. Both the exercise and the test were organised and co-funded by the Prevention of and Fight against Crime Programme of the European Union [1-3], Direct Grant "Towards the Vision for European Forensic Science 2020 (TVEFS-2020)" HOME/2013/ISEC/MO/ENFSI/4000005962, work package T3 "Proficiency Tests and Collaborative Exercises for the Fingerprint Domain". The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including lessons learnt. PMID- 30312946 TI - A human cell panel for evaluating safe application of nano-ZrO2/polymer composite in water remediation. AB - Nanomaterials, such as ZrO2 nanoparticles (ZrO2 NPs), are very effective in water remediation. However, the safety issues related to nanoparticle release and toxicity to humans remain to be resolved. Here we evaluated the cytotoxicity of ZrO2 NPs and their adducts with pollutants using a human cell panel containing stomach, intestine, liver and kidney cells. We found that different pollutants or ZrO2NP/pollutant adducts targeted cells from different organs, suggesting the necessity of a cell panel to model oral exposures. The cooperation of ZrO2 NPs and pollutants was quite complex, consisting of synergistic, antagonistic, or additive effects. For example, ZrO2 NPs enhanced the cytotoxicity of Pb2+ in GES 1 cells and of Pb2+, Cd2+ in FHC cells, while alleviating the toxicity of Pb2+ and As (III) in HepG2 and Hek293 cells. Our results also indicated that even concentrations of pollutants that meet the national standard, the ZrO2 NPs concentration should be kept below 17 MUg/mL to avoid ZrO2 NP/pollutant adduct synergistic toxicity. PMID- 30312947 TI - Petroleum sludge bioremediation and its toxicity removal by landfill in gunder semi-arid conditions. AB - In this investigation, petroleum sludge landfilling was carried out in order to assess the biodegradation degree and the final product quality. The microbial analysis showed a good microorganism proliferation which reinforces the biodegradation process. The total mesophilic and thermophilic microflora evaluated symmetrically as they increased at the intermediate stage and decreased at the final. The C/N and NH4+/NO3-ratios decreased while the polymerization degree increased at the end of the landfilling process. The total polyphenols and total petroleum C6 to C22hydrocarbons were removed by 71.6% and 73% respectively, and that affected the reduction of the phytotoxicity in a positive way. All these changes are in agreement with the efficiency of the biotransformation process and showed that petroleum sludge and filling reduced the toxic organic compounds and led to a stable final product. PMID- 30312948 TI - Establishing a health risk assessment for metal speciation in soil-A case study in an industrial area in China. AB - An improved method was proposed which integrates the distribution of metal speciation simulated by chemical equilibrium model, different exposure models and average daily intake dose modified by analytic hierarchy process for human health risk assessment of metal species (MS). With the rapid development of economic and urbanization, the metals pollution had become more serious in industrial areas. Adverse effects of soil contaminants on human health in typical industrial area should be assessed to evaluate the risks of soils in these areas. The method was applied to study nickel (Ni) species health risks in soil of industrial areas. The pH possessed significant impact to determine distribution/existence and solubility of Ni species, followed by DOC. The non-carcinogenic risk (HQ) of Ni species were less than 1 in each sampling points, except Ni2+. In addition, the carcinogenic risk (CR) of different Ni species were less than 10-6, except for FANi and Ni2+. PMID- 30312949 TI - Fast polydopamine coating on reverse osmosis membrane: Process investigation and membrane performance study. AB - We report a novel membrane surface modification method using a fast polydopamine coating (fPDAc) strategy. Specifically, NaIO4 was introduced in the coating process to accelerate the polydopamine deposition rate. Surface properties and separation performances of fPDAc-coated reverse osmosis membranes were characterized and compared to those obtained using the conventional slow polydopamine coating (sPDAc) strategy. Quartz crystal microbalance measurements showed greatly increased polydopamine deposition rate using the fPDAc method, resulting in a reduction of 97% coating time to reach an areal mass of 2000 ng/cm2. Both fPDAc and sPDAc enhanced the surface hydrophilicity and reduced the membrane surface charge. At relatively low areal mass deposition (<1000 ng/cm2), fPDAc-coated membranes showed improved NaCl rejection together with only mild loss of pure water flux. Nevertheless, this rejection enhancement effect was not noticeable when extensive polydopamine coating was applied due to the undesirable cake-enhanced concentration polarization effect. The extensive polydopamine coating was further accompanied with severe loss of membrane permeability, suggesting that shorter coating time (e.g., 4 min) is preferred using the fPDAc method. Our study provides a more rapid and effective membrane surface coating method compared to the conventional sPDAc method. PMID- 30312950 TI - Effect of phase composition on the photocatalytic activity of titanium dioxide obtained from supercritical antisolvent. AB - Photocatalytic activity of TiO2 nanoparticles is highly dependent on their phase composition. The coexistence of anatase and rutile phases in a single nanoparticle eases the electron transfer process between the phases, and favors the separation of photogenerated pairs. In this work, highly photoactive mixed phase TiO2 nanostructures were prepared by supercritical antisolvent precipitation (SAS), an environmentally friendly technology. It is shown here that this methodology has the remarkable ability to produce highly porous (515 m2/g) and crystalline TiO2 nanoparticles. The phase composition of as-prepared TiO2 samples can be tailored through annealing process. Several mixed-phase TiO2 samples were tested to assess the correlation between photocatalytic activity and phase composition. The photocatalytic performance is strongly affected by the anatase-rutile ratio, since the synergism between phases enhances the charge separation, reducing the recombination effect of the photogenerated pairs (e /h+). It was found that the nanocatalyst composed by 7.0 wt% of rutile phase and 93.0 wt% of anatase phase, named as TiO2_650, presented the highest photodegradation for both methyl orange (MO) and methylene blue (MB) dyes. Interestingly, TiO2 samples prepared by SAS have superior photoactivity than the benchmark photocatalyst names as P25, which is a widely used TiO2 material composed of anatase and rutile phases. PMID- 30312951 TI - Enhanced adsorption of arsenite from aqueous solution by an iron-doped electrospun chitosan nanofiber mat: Preparation, characterization and performance. AB - A novel iron-doped chitosan electrospun nanofiber mat (Fe@CTS ENM) was synthesized, which was proven to be effective for the removal of arsenite (As(III)) from water at neutral pH condition. The physiochemical properties and adsorption mechanism were explored by SEM-EDS and X-ray photoelectron spectroscopy (XPS). Batch adsorption experiments were carried out to evaluate the As(III) adsorption performance of the Fe@CTS ENM with various process parameters, such as adsorbent dose, solution pH, initial As(III) concentration, contact time, ionic strength, coexisting anions, and natural organic matter. The experimental results indicated that the maximum adsorption capacity was up to 36.1 mg g-1. Especially, when the adsorbent dosage was higher than 0.3 g L-1, the As(III) concentration was reduced from 100 ug L-1 to less than 10 ug L-1, which indicated the Fe@CTS ENM could effectively remove trace As(III) from water over a wide pH range (from 3.3 to 7.5). Kinetics study demonstrated that the adsorption equilibrium was achieved within 2.0 h, corresponding to a fast uptake of As(III). The presence of common co-ions and humic acid had little effect on the As(III) adsorption. XPS analysis suggested that the FeO, COH, COC and CN groups on the adsorbent surface play dominant roles in the adsorption of As(III). Adsorption desorption regeneration test further demonstrated that no appreciable loss in the adsorption capacities was observed, which confirmed that the Fe@CTS ENM maintained a desirable life cycle that was free of complex synthesis processes, expensive and toxic materials, qualifying it as an efficient and low-cost As(III) adsorbent. PMID- 30312952 TI - Gamma-ferric oxide nanoparticles decoration onto porous layered double oxide belts for efficient removal of uranyl. AB - Layered double oxides (LDO) and gamma-Fe2O3 have been demonstrated to be promising adsorbents to remove radioactive elements from aqueous media. Herein, magnetic gamma-Fe2O3 nanoparticles decoration onto porous layered double oxides belts (gamma-Fe2O3/LDO) were fabricated by in situ solid-state thermolysis technique combined with Fe(III)-loaded layered double hydroxides as a precursor. The microstructure, chemical composition, and magnetic properties of gamma Fe2O3/LDO were characterized in detail. The as-obtained gamma-Fe2O3/LDO was employed as an adsorbent for the elimination of U(VI) from water. The adsorption process followed the Langmuir model with the maximal adsorption capacity of U(VI) onto gamma-Fe2O3/LDO being 526.32 mg.g-1 at 303 K and pH 5, which surpassed pristine LDO and many other materials. The Fourier transformed infrared spectra and the X-ray photoelectron spectra analysis suggested that the interaction mechanism was mainly controlled by the surface complexation and electrostatic interactions. All in all, the gamma-Fe2O3/LDO with remarkable adsorption capacity, excellent regeneration, and easy magnetic separation opens a new expectation as a suitable material for the cleanup of U(VI) from contaminated water. PMID- 30312953 TI - Activity of lysosomal exoglycosidases in the urine of healthy normotensive and pre-hypertensive children. AB - PURPOSE: We investigated the relationship between blood pressure (BP) and the activity of lysosomal exoglycosidases: N-acetyl-beta-hexosaminidase (HEX), its isoenzymes A (HEX A) and B (HEX B), alpha-fucosidase (FUC), beta-galactosidase (GAL), beta-glucuronidase (GLU) and alpha-mannosidase (MAN) in pre-hypertensive (high normal blood pressure - HNBP) and normal blood pressure (NBP) children. MATERIAL AND METHODS: The study was carried out with urine samples collected from 176 children, aged 6-17.9 years, divided into 2 groups: 42 HNBP and 134 NBP subjects. The children were stratified depending on systolic and diastolic BP (SBP; DBP): HNBP (SBP and/or DBP greater than or equal to the 90th percentile, but less than the 95th percentile) for sex, age, and height; and NBP (SBP and DBP less than the 90th centile). The activities of lysosomal exoglycosidases were determined by the colorimetric method, and expressed in pKat/mL and pKat/MUgCr. RESULTS: The activity of urinary HEX A in HNBP group was significantly higher than in NBP (p < 0.05). The HNBP group showed significant positive correlation between HEX, HEX A (pKat/mL) and SBP. AUC for HEX A was 0.616, cut-off value 29.351 pKat/mL (sensitivity 51.2%, specificity 71.8%), and 0.589, cut-off value 0.054 pKat/MUgCr (sensitivity 31.7%, specificity 86.3%). CONCLUSIONS: This is the first report of the relationship between BP and the activity of urinary lysosomal exoglycosidases: HEX, HEX A and HEX B, FUC, GAL, GLU, and MAN in healthy children and adolescents. It seems that HEX A (pKat/mL) can be used as a useful tool in identifying children with HNBP. PMID- 30312954 TI - Overexpression of Brassica campestris BcICE1 gene increases abiotic stress tolerance in tobacco. AB - In this study, a cDNA of ICE1 (inducer of CBF expression 1) gene, named BcICE1, was isolated from Brassica campestris 'Longyou 6'. The deduced protein has 499 amino acids containing a typical bHLH domain and is highly identical with AtICE1 (85.9%) from Arabidopsis thaliana. BcICE1 is located in the nucleus. The activities of SOD, CAT, POD, and APX and the transcriptional levels of SOD, CAT, and POD genes were higher in BcICE1-transgenic tobacco than in wild-type (WT) tobacco under cold stress. Compared with WT tobacco, proline, soluble sugar, and chlorophyll were enhanced, whereas malondialdehyde and relative conductivity were decreased in BcICE1-transgenic tobacco. The overexpression of BcICE1 in tobacco increased the expression of CBF1, CBF2, and other stress-related genes. Moreover, under salt and PEG (25%) stress, the activities of APX and GPX and content of soluble sugar and chlorophyll in BcICE1-transgenic tobacco were higher than those in WT tobacco. Our results suggest that BcICE1 plays an important role in the response to abiotic stress. PMID- 30312955 TI - A single slice approach for simulating two-beam electron diffraction of nanocrystals. AB - A simple computational method that can be used to simulate TEM image contrast of an electron beam diffracted by a crystal under two-beam dynamical scattering conditions is presented. The approach based on slicing the shape factor is valid for a general crystal morphology, with and without crystalline defects, avoids the column approximation, and provides the complex exit wave at the focal and the image planes also under weak-beam conditions. The approach is particularly efficient for large crystals and the 3D model required for the calculations can be measured experimentally using electron tomography. The method is applied to show that the shape of a diffracted spot can be affected by shifts, broadening and secondary maxima of appreciable intensity, even for a perfect crystal. The methodology is extended for the case of electron precession diffraction, and to show how can be used to improve nanometrology from diffraction patterns. The method is used also to perform simulations of simple models of crystalline defects. The accuracy of the method is demonstrated through examples of experimental and simulated dark-field images of MgO and ZrO2 nanocrystals and thin layers of CeO2. PMID- 30312956 TI - Long-term outcomes of surgical resection with or without adjuvant therapy for treatment of primary spinal peripheral primitive neuroectodermal tumors. AB - OBJECTIVE: We sought to assess the use of surgical treatment, the effect of postoperative adjuvant therapy, and the prognostic factors for survival of patients with primary spinal peripheral primitive neuroectodermal tumors (pPNETs). PATIENTS AND METHODS: The clinical data of 24 patients, who had been surgically treated from April 2003 to February 2018 and in whom immunohistochemical staining results had confirmed the diagnosis of primary spinal pPNETs, were retrospectively analyzed. To analyze the factors related to prognosis, the Kaplan-Meier method was used for univariate analysis, the log-rank method was used to test the significance of difference, and multivariate analysis was performed using Cox regression. RESULTS: The overall 1-year, 2-year, and 5 year survival rates were 73.2%, 48.1%, and 12.0%, respectively. The median survival time (MST) of all patients was 21 months. Univariate analysis showed that the extent of tumor resection, adjuvant radiotherapy, and chemotherapy were the factors influencing patient prognosis after surgery (all P < 0.05); sex, age, tumor location, and preoperative Karnofsky performance scale (KPS) scores were not the influential factors for prognosis of patients after surgery (all P > 0.05). Multivariate analysis showed that gross total resection (GTR) of tumors and adjuvant radiotherapy were independent factors influencing the prognosis of patients with pPNETs (all P < 0.05). CONCLUSIONS: Primary spinal pPNETs are extremely rare, and they have a poor prognosis. Microsurgical GTR of the tumor is the preferred method of treatment. Radiotherapy plays an important role in improving the prognosis of patients with pPNETs. GTR combined with radiotherapy and chemotherapy may be the best treatment modality. PMID- 30312957 TI - Effects of Zero-time Exercise on inactive adults with insomnia disorder: a pilot randomized controlled trial. AB - OBJECTIVE: To evaluate the feasibility and clinical effects of a lifestyle integrated exercise, namely zero-time exercise (ZTEx), on improving insomnia in inactive adults with insomnia disorder. METHODS: In this pilot randomized controlled trial, 37 physically inactive adults (mean age: 49.9 years; SD: 13.6 91.9% female) fulfilling the diagnostic criteria of insomnia disorder recruited from the community were randomly assigned to ZTEx training or sleep hygiene education (SHE) groups. Subjects in the ZTEx group (n = 18) attended two 2-hour training lessons to learn ZTEx which they then practiced daily for eight weeks. Subjects in the SHE group (n = 19) attended two lessons of the same schedule and duration. The primary outcome measure was the Insomnia Severity Index (ISI). RESULTS: The ZTEx group had lower ISI scores than the SHE group, with a large between-group effect size of 0.93-1.10 at weeks two, four, six, and eight, but the difference became non-significant at week eight, suggesting a loss of efficacy two months after the training. For secondary outcomes, no significant between-group differences were found in sleep parameters by sleep diary or objective actigraphy. The adherence to the ZTEx training course was satisfactory, with 83% of the group completing two sessions and 78% continuing to practice ZTEx for five days or more per week during the eight-week intervention period. CONCLUSION: The simple and brief ZTEx training showed high acceptability and exercise compliance and the first evidence of efficacy in reducing insomnia severity in inactive adults with insomnia disorder. Confirmatory trials with longer follow-up are justified. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, #NCT03155750. PMID- 30312958 TI - Cost-sensitive multi-label learning with positive and negative label pairwise correlations. AB - Multi-label learning is the problem where each instance is associated with multiple labels simultaneously. Binary Relevance (BR) is a representative algorithm for multi-label learning. However, it may suffer the class-imbalance issue especially when the label space is large. Besides, it ignores the label correlations, which is of importance to improve the performance. Moreover, labels might have positive and negative correlations in real applications, but existing methods seldom exploit the negative label correlations. In this paper, we propose a novel Cost-sensitive multi-label learning model with Positive and Negative Label pairwise correlations (CPNL), which extends BR to tackle the above issues. The kernel extension of the linear model is also provided to explore complex input-output relationships. Moreover, we adopt two accelerated gradient methods (AGM) to efficiently solve the linear and kernel models. Experimental results show that our approach CPNL achieves a competitive performance to some state-of the-art approaches for multi-label learning. PMID- 30312959 TI - A video-driven model of response statistics in the primate middle temporal area. AB - Neurons in the primate middle temporal area (MT) encode information about visual motion and binocular disparity. MT has been studied intensively for decades, so there is a great deal of information in the literature about MT neuron tuning. In this study, our goal is to consolidate some of this information into a statistical model of the MT population response. The model accepts arbitrary stereo video as input. It uses computer-vision methods to calculate known correlates of the responses (such as motion velocity), and then predicts activity using a combination of tuning functions that have previously been used to describe data in various experiments. To construct the population response, we also estimate the distributions of many model parameters from data in the electrophysiology literature. We show that the model accounts well for a separate dataset of MT speed tuning that was not used in developing the model. The model may be useful for studying relationships between MT activity and behavior in ethologically relevant tasks. As an example, we show that the model can provide regression targets for internal activity in a deep convolutional network that performs a visual odometry task, so that its representations become more physiologically realistic. PMID- 30312960 TI - An improved stability result for delayed Takagi-Sugeno fuzzy Cohen-Grossberg neural networks. AB - This work proposes a novel and improved delay independent global asymptotic stability criterion for delayed Takagi-Sugeno (T-S) fuzzy Cohen-Grossberg neural networks exploiting a suitable fuzzy-type Lyapunov functional in the presence of the nondecreasing activation functions having bounded slopes. The proposed stability criterion can be easily validated as it is completely expressed in terms of the system matrices of the fuzzy neural network model considered. It will be shown that the stability criterion obtained in this work for this type of fuzzy neural networks improves and generalizes some of the previously published stability results. A constructive numerical example is also given to support the proposed theoretical results. PMID- 30312961 TI - Multiple Mittag-Leffler stability of fractional-order competitive neural networks with Gaussian activation functions. AB - In this paper, we explore the coexistence and dynamical behaviors of multiple equilibrium points for fractional-order competitive neural networks with Gaussian activation functions. By virtue of the geometrical properties of activation functions, the fixed point theorem and the theory of fractional-order differential equation, some sufficient conditions are established to guarantee that such n-neuron neural networks have exactly 3k equilibrium points with 0<=k<=n, among which 2k equilibrium points are locally Mittag-Leffler stable. The obtained results cover both multistability and mono-stability of fractional-order neural networks and integer-order neural networks. Two illustrative examples with their computer simulations are presented to verify the theoretical analysis. PMID- 30312962 TI - Debridement arthroplasty of a rare case of elbow stiffness. A case report and literature review. AB - INTRODUCTION: Elbow stiffness is a common condition that affects the quality of life of patients. Melorheostosis of the elbow associated with elbow stiffness is extremely rare. PRESENTATION OF CASE: We report the case of a 28 yr old male who presented with elbow stiffness which occurred within one year without prior history of trauma or infection. The patient had decrease in range of motion together with progressive worsening pain that forced him to seek medical attention. DISCUSSION: There is no standard treatment for melorheostosis, and management plans must be made on an individual patient basis. The aims of treatment are pain relief and maintaining function. CONCLUSION: Debridement arthroplasty is safe and effective in treating elbow stiffness associated with Melorheostosis. PMID- 30312963 TI - Leveraging genome-wide association and clinical data in revealing schizophrenia subgroups. AB - Schizophrenia (SCZ) has long been recognized as a highly heterogeneous disorder. Patients differed in their clinical manifestations, prognosis, and underlying pathophysiologies. Here we presented and applied a framework for finding subtypes of SCZ utilizing genome-wide association study (GWAS) and clinical data. We postulated that genetic information may help stratify patient into useful subgroups, and incorporation of other clinical information and cognitive profiles will further improve patient subtyping. We conducted cluster analysis in 387 Hong Kong Chinese with SCZ. First we performed 'single-view' clustering using genetic or clinical data alone, then proceeded to 'multi-view' clustering (MVC) accounting for both types of information. We validated clustering results by assessing subgroup differences in various outcomes. We found significant differences in outcomes including treatment response, disease course and symptom severity (Simes overall p-value using MVC = 1.64E-9). Overall speaking, we identified three subgroups with good, intermediate and poor prognosis respectively. MVC generally out-performed single-view methods. The analysis was repeated for different sets of input SNPs, and stratified analysis of male and female patients, and the results remained largely robust. We also found significant enrichment for SCZ loci among the SNPs selected by the cluster algorithm. Numerous selected genes (e.g. NRG1, ERBB4, NRXN1, ANK3) and pathways (e.g. neuregulin-ErbB4 and calcium signaling) were implicated in SCZ or related pathophysiological processes. This is first study to combine both genetic and clinical data for subtyping SCZ, and to employ genome-wide SNP data in cluster analysis of a complex disease. This work points to a new way of GWAS analysis of translational potential. PMID- 30312964 TI - Short-term exposure to air pollution: Associations with lung function and inflammatory markers in non-smoking, healthy adults. AB - INTRODUCTION: Air pollution impacts health by increasing mortality and the incidence of acute events in unhealthy individuals. In contrast, the acute effects of pollution in healthy individuals are less obvious. The present study was designed to evaluate the associations between short-term exposure to air pollution on one hand and lung function, and inflammatory markers on the other in middle-aged, non-smoking adults with no respiratory disease, in two urban areas in northern France. METHODS: A sample of 1506 non-smoking adults (aged from 40 to 65) with no respiratory disease was selected from the participants in the 2011 2013 cross-sectional Enquete Littoral Souffle Air Biologie Environnement (ELISABET) survey in two urban areas in the northern France. We evaluated the associations between (i) mean levels of particulate matter with aerodynamic diameter < 10 MUm (PM10), nitrogen dioxide (NO2) and ozone (O3) exposure on the day and the day before the study examination for each participant, and (ii) spirometry data and levels of inflammatory markers. Coefficients of multiple linear regression models were expressed (except for the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio) as the percentage change [95% confidence interval] per 10 MUg increment in each pollutant. RESULTS: Levels of PM10, NO2 and O3 exposure were below or only close to the World Health Organization's recommended limits in our two study areas. An increment in NO2 levels was significantly associated with a lower FEV1/FVC ratio (-0.38 [-0.64; 0.12]), a lower forced expiratory flow between 25% and 75% of FVC (FEF25-75%) ( 1.70 [-3.15; -0.23]), and a lower forced expiratory flow measured at 75% of FVC (FEF75%) (-3.07 [-4.92; -1.18]). An increment in PM10 levels was associated with lower FEF75% (-1.41 [-2.79; -0.01]) and a non-significant elevation in serum levels of high-sensitivity C-reactive protein (+3.48 [-0.25; 7.36], p = 0.07). Lastly, an increment in O3 levels was associated with a significantly higher blood eosinophil count (+2.41 [0.10; 4.77]) and a non-significant elevation in fractional exhaled nitric oxide (+2.93 [-0.16; 6.13], p = 0.06). CONCLUSION: A short-term exposure to air pollution was associated with a subclinical decrement in distal lung function and increment in inflammatory markers in healthy inhabitants of two urban areas in France. If these exploratory results are confirmed, this could suggest that even moderate levels of air pollution could have an impact on respiratory health on the general population, and not solely on susceptible individuals. PMID- 30312965 TI - A Bayesian generalized log-normal model to dynamically evaluate the distribution of pesticide residues in soil associated with population health risks. AB - Exploring better models for evaluating the distribution of pesticide residues in soil and sediment is necessary to assess and avoid population health risk. Frequentist philosophy and probability are widely used in many studies to apply a log-normal distribution associated with the maximum likelihood estimation, which assumes fixed parameters and relies on a large sample size for long-run frequency. However, frequentist probability might not be suitable for analyzing pesticide residue distribution, whose parameters are affected by many complex factors and should be treated as unfixed. This study aimed to implement a Bayesian generalized log-normal (GLN) model to better understand the distribution of pesticide residues in soil and quantify population risks. The Bayesian GLN model, including location, scale, and shape parameters, was applied for the first time to dynamically evaluate pesticide residue distribution in soil and sediments. In addition, a comprehensive human health risk assessment of exposure to lindane via soil was conducted using the lifetime cancer risk for carcinogenic effect, margin of exposure for non-carcinogenic effect, and disability-adjusted life year for health damage. The Bayesian posterior analysis results indicated that the distribution of the concentration of some pesticide was better fitted to a log-Laplace (e.g., the mode value of shape parameter for lindane is 1.079) or showed mixtures of distributions within the family of log-normal distributions (e.g., the mode value of shape parameter for p,p'-DDE is 2.395), which can better explain the long-tail phenomenon of pesticide residue distribution and dynamically evaluate distribution models. For lindane, the 95% uncertainty bounds on the 95th percentile computed from 95% highest probability density regions (credible intervals) of three parameters by using the Bayesian p-box method were [2.063, 1558.609] ng/g, which is several orders of magnitude larger than the computed frequentist 95% confidence interval of [4.690, 8.095] ng/g and indicates that the population could have cancer risk concerns. These uncertainty analysis results from the Bayesian GLN approach indicated a larger variation of Lindane soil residues, which might reflect the complex and unpredictable mechanism of pesticide residue distribution including both unfixed models and distribution parameters. In summary, Bayesian GLN model is more flexible for the dynamic evaluation of pesticide soil residue distribution, retains posteriors for future data analysis, and could better quantify the uncertainties in population health risks. Therefore, this study can provide a novel and dynamical perspective of pesticide residue distribution and help better quantify health risks. PMID- 30312966 TI - Estimating number of contributors in massively parallel sequencing data of STR loci. AB - In recent years a number of computer-based algorithms have been developed for the deconvolution of complex DNA mixtures in forensic science. These procedures utilize likelihood ratios that quantify the evidence for a hypothesis for the presence of a person of interest in a DNA profile compared to an alternative hypothesis. Proper operation of these software systems requires an assumption regarding the total number of contributors present in the mixture. Unfortunately, estimates based on counting the number of alleles at a locus can be inaccurate due to the sharing and masking of alleles at individual loci. The effects of allele masking become increasingly severe as the number of contributors increases, rendering estimates about high-order mixtures uncertain. The accuracy of these estimates can be improved by increasing the number of STR markers in panels, and by using highly polymorphic markers. Increasing the number of STR markers from 13 to 20 (expanded CODIS panel) improves the accuracy of allele count-based estimation methods for low-order mixtures, but accuracy for high order mixtures (> 3 contributors) remains poor due to allele masking. An alternative technique, massively parallel sequencing, holds great potential to improve the accuracy of the estimate of number of contributors due to its ability to detect sequence polymorphisms within alleles. This process results in an expansion of the number of alleles when compared to that obtained using capillary electrophoresis. Here, we show that the detection of these additional sequence defined alleles in 22-marker panels improves number of contributor estimates in conceptual mixtures of 4 and 5 contributors. PMID- 30312967 TI - Repeatedly washed semen stains: Optimal screening and sampling strategies for DNA analysis. AB - In many sexual assault cases, bedding and clothing are essential pieces of evidence that are screened for semen stains to gather DNA from the assailant. In some cases, these items have been washed before being seized and sent to the forensic lab. However, few data exist on the optimal methods for detecting and sampling semen stains on washed fabrics. In this paper, we used semen stains washed up to six times to evaluate the efficiency of commonly used screening methods for the detection of semen: alternate light source (ALS), acid phosphatase (AP), prostate specific antigen (PSA) and microscopy (sperm Hy LiterTM, SHL). We also assessed different washing conditions (detergents, washing machines, addition of bleach) and sampling methods (cutting and swabbing). The results show that some semen stain detection strategies, such as ALS, PSA, and SHL, are effective even when the item was washed multiple times. We also show that a complete genetic profile could be obtained from semen stains washed six times. Based on these findings, we present different strategies for the detection and sampling of semen stains depending on the circumstances of the case. PMID- 30312968 TI - A stress-associated protein, LmSAP, from the halophyte Lobularia maritima provides tolerance to heavy metals in tobacco through increased ROS scavenging and metal detoxification processes. AB - Agricultural soil pollution by heavy metals is a severe global ecological problem. We recently showed that overexpression of LmSAP, a member of the stress associated protein (SAP) gene family isolated from Lobularia maritima, in transgenic tobacco led to enhanced tolerance to abiotic stress. In this study, we characterised the response of LmSAP transgenic tobacco plants to metal stresses (cadmium (Cd), copper (Cu), manganese (Mn), and zinc (Zn)). In L. maritima, LmSAP expression increased after 12 h of treatment with these metals, suggesting its involvement in the plant response to heavy metal stress. LmSAP transgenic tobacco plants subjected to these stress conditions were healthy, experienced higher seedling survival rates, and had longer roots than non-transgenic plants (NT). However, they exhibited higher tolerance towards cadmium and manganese than towards copper and zinc. LmSAP-overexpressing tobacco seedlings accumulated more cadmium, copper, and manganese compared with NT plants, but displayed markedly decreased hydrogen peroxide (H2O2) and lipid peroxidation levels after metal treatment. Activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) were significantly higher in transgenic plants than in NT plants after exposure to metal stress. LmSAP overexpression also enhanced the transcription of several genes encoding metallothioneins (Met1, Met2, Met3, Met4, and Met5), a copper transport protein CCH, a Cys and His-rich domain-containing protein RAR1 (Rar1), and a ubiquitin-like protein 5 (PUB1), which are involved in metal tolerance in tobacco. Our findings indicate that LmSAP overexpression in tobacco enhanced tolerance to heavy metal stress by protecting the plant cells against oxidative stress, scavenging reactive oxygen species (ROS), and decreasing the intracellular concentration of free heavy metals through its effect on metal-binding proteins in the cytosol. PMID- 30312969 TI - Motor activity patterns in acute schizophrenia and other psychotic disorders can be differentiated from bipolar mania and unipolar depression. AB - The purpose of this study was to compare 24-h motor activity patterns between and within three groups of acutely admitted inpatients with schizophrenia and psychotic disorders (n = 28), bipolar mania (n = 18) and motor-retarded unipolar depression (n = 25) and one group of non-hospitalized healthy individuals (n = 28). Motor activity was measured by wrist actigraphy, and analytical approaches using linear and non-linear variability and irregularity measures were undertaken. In between-group comparisons, the schizophrenia group showed more irregular activity patterns than depression cases and healthy individuals. The schizophrenia and mania cases were clinically similar with respect to high prevalence of psychotic symptoms. Although they could not be separated by a formal statistical test, the schizophrenia cases showed more normal amplitudes in morning to evening mean activity and activity variability. Schizophrenia constituted an independent entity in terms of motor activation that could be distinguished from the other diagnostic groups of psychotic and non-psychotic affective disorders. Despite limitations such as small subgroups, short recordings and confounding effects of medication/hospitalization, these results suggest that detailed temporal analysis of motor activity patterns can identify similarities and differences between prevalent functional psychiatric disorders. For this purpose, irregularity measures seem particularly useful to characterize psychotic symptoms and should be explored in larger samples with longer-term recordings, while searching for underlying mechanisms of motor activity disturbances. PMID- 30312970 TI - Laser-assisted Fluorescent Angiography to Assess Tissue Perfusion in the Setting of Traumatic Elbow Dislocation. AB - INTRODUCTION: In the surgical setting, the most accepted technique for measuring tissue perfusion includes subjective identification, with visual and tactile inspections of the tissue, performed by a surgeon. Recently, fields such as ophthalmology, plastic surgery, and other surgical specialties, such as cardiac, vascular, and transplant surgery, have seen the emergence of laser-assisted fluorescent angiography (LAFA) to visualize real-time tissue perfusion during procedures. CASE REPORT: The case of an 80-year-old woman, who presented with a wound over the left medial elbow following a subacute recurrent elbow dislocation, illustrates the use of this technology in the field of orthopedics. Initially, the patient was treated at an outside facility where the dislocation was reduced, and she was placed in a long arm splint. With concern of recurrent dislocation and wound development, she presented to the authors with a complex wound measuring about 9 cm x 5 cm with variable thickness ranging from 0 mm to 5 mm in depth. Her initial emergent irrigation and debridement and wound management was assisted by LAFA and the administration of indocyanine green to guide debridement and determine viable wound margins. After staging with external fixation and a negative pressure wound dressing, she later returned for skin grafting and healed uneventfully. CONCLUSIONS: In conjunction with plastic surgeons, the orthopaedic team utilized LAFA for debridement that led to both a successful wound repair and skin grafting procedure. PMID- 30312971 TI - Diagnosis and Treatment of Invasive Aspergillus fumigatus Wound Infection Following Subtotal Colectomy for Perforated Toxic Megacolon in an Immunosuppressed Patient. AB - INTRODUCTION: Aspergillus is a rare cause of surgical site infection most often seen in immunocompromised patients undergoing cardiac, transplant, ophthalmologic, or burn operations; an unusual case following a colon resection is presented here. CASE REPORT: The authors report a case of an invasive Aspergillus fumigatus infection following a subtotal colectomy for toxic megacolon. The patient was on antibiotics following the operation and chronic immunosuppression with steroids and infliximab. This was an unusual cause of a postoperative wound infection. CONCLUSIONS: This case highlights the importance of early and accurate identification, debridement, and systemic antifungals to prevent widespread infection. With changes in antifungal care over recent years, engaging infectious disease physicians during treatment is recommended. PMID- 30312972 TI - Fully Synthetic Bioengineered Nanomedical Scaffold in Chronic Neuropathic Foot Ulcers. AB - INTRODUCTION: Chronic ulcerations on weightbearing surfaces of the lower extremities are uniquely challenging and can lead to complications such as infection or amputation. OBJECTIVE: This 3-patient case series of 4 chronic wounds of various etiologies outlines the use of a fully synthetic bioengineered nanomedical scaffold that exhibits durability and allows for cell migration and angiogenesis while resisting enzymatic degradation. MATERIALS AND METHODS: The nanomedical scaffold was rehydrated in sterile saline at room temperature for 3 to 5 minutes until translucent and pliable, then it was fenestrated with a scalpel. Following sharp debridement, it was affixed to the ulcer. A nonadherent dressing was applied, followed by applying a moist sterile dressing in a bolster fashion. RESULTS: All 4 ulcers reached the primary endpoints of granulation, as well as decreased wound size, using the nanomedical scaffold. CONCLUSIONS: The nanomedical scaffold successfully reduced the ulcer depths, stimulated granulation tissue while preventing necrosis, and helped the wounds remain infection free. The outcome of this case series suggests a fully synthetic bioengineered nanomedical scaffold can be used as an alternative to human or animal extracellular matrix in chronic, hard-to-heal neuropathic ulcers. PMID- 30312973 TI - Influence of Cranberry Extract on Tamm-Horsfall Protein in Human Urine and its Antiadhesive Activity Against Uropathogenic Escherichia coli. AB - LC-MS characterized cranberry extract from the fruits of Vaccinium macrocarpon inhibited under in vitro conditions the bacterial adhesion of Escherichia coli strain 2980 uropathogenic E. coli (UPEC strains UTI89, NU14) to T24 bladder cells and adhesion of UPEC strain CFT073 to A498 kidney cells in a concentration dependent manner. Within a biomedical study, urine samples from 16 volunteers (8 male, 8 female) consuming cranberry extract for 7 d (900 mg/d) were analyzed for potential antiadhesive activity against UPEC by ex vivo experiments. Results indicated inhibition of adhesion of UPEC strain UTI89 to human T24 bladder cells. Subgroup analysis proved significant inhibition of bacterial adhesion in case of urine samples obtained from male volunteers while female urine did not influence the bacterial attachment. Differences between antiadhesive capacity of urine samples from male/female volunteers were significant. Protein analysis of the urine samples indicated increased amounts of Tamm-Horsfall protein (THP, syn. uromodulin) in the active samples. Inhibition of bacterial adhesion by the urine samples was correlated to the respective amount of THP. As it is known that THP, a highly mannosylated glycoprotein, strongly interacts with FimH of UPEC, this will lead to a decreased interaction with uroplakin, a FimH-binding transmembrane protein of urothelial lining cells. From these data it can be concluded that the antiadhesive effect of cranberry after oral intake is not only related to the direct inhibition of bacterial adhesins by extract compounds but is additionally due to an induction of antiadhesive THP in the kidney. PMID- 30312974 TI - Fighting Liver Fibrosis with Naturally Occurring Antioxidants. AB - Liver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation of the normal liver architecture and the development of liver cirrhosis and even hepatocellular carcinoma. Numerous in vitro and in vivo studies indicated that oxidative stress mediates the initiation and progression of liver fibrosis. Overaccumulation of reactive oxygen species disrupts macromolecules, induces necrosis and apoptosis of hepatocytes, stimulates the production of pro-fibrogenic mediators, and directly activates hepatic stellate cells, thereby resulting in liver damage and initiating liver fibrosis. Ameliorating oxidative stress is a potential therapeutic strategy for the treatment of liver fibrosis. Natural antioxidants have attracted increasing attention in treating liver fibrosis due to their safety and efficacy. In this review, the pathogenesis of liver fibrosis and the role of oxidative stress in liver fibrosis were discussed. Naturally occurring antioxidants that can treat and prevent liver fibrosis were summarized. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up to-date knowledge from the biological importance of oxidative stress in liver fibrosis to representative antioxidants for treating liver fibrosis. Naturally occurring antioxidants show a potential for further investigations as lead compounds in fighting liver fibrosis. PMID- 30312975 TI - Determinants of Significant Out-Of-Hospital Bleeding in Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: Although several variables have been identified as bleeding determinants (BDs), their occurrence and predictive value in patients undergoing percutaneous coronary intervention (PCI) in the real world remain unclear. We aimed to characterize the rate of BDs in patients undergoing PCI with stent implantation in a large volume tertiary centre. METHODS: We included patients undergoing coronary stenting at our institution from January 2012 to December 2016, and defined post-discharge bleeding (PDB) as bleeding requiring hospitalization or transfusion. Several BDs, identified by the PARIS bleeding and PRECISE-DAPT scores and inclusion criteria of the LEADERS FREE trial, were analysed. RESULTS: In a population of 10,406 subjects who underwent PCI, 2,938 patients (28.2%) had 1, 2,367 (22.8%) had 2 and 2,913 (28.0%) had >=3 pre specified BD. Compared with patients without PDB, subjects who experienced PDB were older (70.43 +/- 11.94 vs. 65.90 +/- 11.54 years, p < 0.0001) with a higher prevalence of common cardiovascular risk factors. One-year PDB occurred in 177 patients (2.4%), and consistently increased according to the number of BDs involved (1.12, 2.11 and 4.35%, respectively; p < 0.0001). Analogously, 1-year rates of post-discharge myocardial infarction or stent thrombosis increased according to the number of BDs (2.44, 3.38 and 4.87%, respectively; p < 0.0001). Only 7 BDs remained independently associated with PDB at 1 year, with anaemia, oral anticoagulant at discharge and malignancy representing the strongest predictors of such risk. CONCLUSION: Many risk factors predispose to PDB; they were often clustered together and conferred additive PDB risk at 1-year of follow up. PMID- 30312976 TI - ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome. AB - BACKGROUND: Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer-CUB interaction is abrogated when ADAMTS13 is conformationally activated. OBJECTIVE: This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS. PATIENTS AND METHODS: All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS. RESULTS: Fifty-six USS patients from 51 families (34 child-onset and 22 adult onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation. CONCLUSION: In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation. PMID- 30312977 TI - Blood Hormones and Venous Thromboembolic Events: Lack of Association or Lack of Standardization? PMID- 30312978 TI - The Clinical Significance of Fibrin Monomers. AB - INTRODUCTION: Fibrin monomer (FM) concentrations reflect pro-thrombin activity and have the potential to predict thrombotic events relatively earlier than other haemostatic markers. Most often, FM are compared with D-dimer (DD) as increased DD have been documented in disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and pulmonary embolism. Although DD have a high sensitivity and negative predictive value, their specificity is much lower depending on the assay chosen, clinical pre-test probability and patient condition. There are limited reports investigating the utility of FM in hyper-coagulable patients. METHODS: We performed a literature search of FM concentrations in hyper coagulable patients including those with DIC, acute ischaemic stroke, atrial fibrillation, acute myocardial infarction, venous thromboembolism (VTE) and cancer, as well as those who are pregnant or undergoing surgery. RESULTS: FM were increased in patients with DIC and those with malignancy. In contrast, detection of VTE or post-operative DVT development is likely enhanced using both FM and DD concentrations. Similarly, measuring FM concentrations with other biomarker levels may be more beneficial in patients suffering an acute myocardial infarction or acute ischaemic stroke. Lastly, FM concentrations vary substantially throughout pregnancy with no definitive role of FM as of yet. CONCLUSION: Utilizing FM concentrations to assess hyper-coagulable patients seems promising; however, there are limitations including variations in FM cut off values, the effect of patient medications and the timing of FM measurement relative to an acute event. Thus, further investigation is required before a true advantage for FM as a haemostatic marker can be established. PMID- 30312979 TI - Stabilin-1-Mediated Efferocytosis Protects against Vascular Leakage in Sepsis: A Novel Therapeutic Approach? PMID- 30312980 TI - [Undergraduate Curricular Training in Musculoskeletal Ultrasound by Student Teachers: The Impact of Peyton's Four-Step Approach]. AB - BACKGROUND: The aim of this study was to assess the impact of Peyton's 4-step approach on musculoskeletal ultrasound skills in a peer-teaching environment as compared to traditional "see one, do one" training and to evaluate students' acceptance of the training strategy. MATERIAL AND METHODS: A total of 491 second year medical students (342 women, 149 men) completed a compulsory curricular course on musculoskeletal ultrasound. We randomly assigned students to receive traditional peer teaching or peer teaching using Peyton's four-step approach in small groups. All groups received theoretical and practical hands-on training of selected views of the knee and shoulder. We assessed differences in practical skills (objective structured practical examination, OSPE) and evaluation results with respect to teaching strategy. RESULTS: There were no relevant differences between the two teaching interventions regarding the OSPE results. Students scored significantly higher in the knee view (knee 6.5 +/- 1.7 points, shoulder 6.0 +/- 1.9 points; p < 0.001), needed less time to display the required image (knee 36 +/- 21 s, shoulder 43 +/- 20 s; p < 0.001) and more students obtained the cut-off mark of 60% to pass the exam (knee 73%, shoulder 61%; p < 0.001). Acceptance of the peer-teaching concept was high, and the overall rating of the instructors was good. The majority of students enjoyed the course and rated it highly. CONCLUSION: Traditional teaching and Peyton's 4-step approach seem to be equally effective for teaching basic musculoskeletal ultrasound skills to undergraduate medical students. Qualitative analysis revealed high acceptance of both peer teaching strategies. Differences in course content complexity and degree of difficulty need to be addressed in future courses. PMID- 30312981 TI - [Knee and Hip TEP Surgery: The Surgeons' Obligation to Give Information]. AB - The German Civil Code (BGB) establishes in S 630e BGB formal and content-related requirements to provide the patient with a solid fundament of information. This is necessary for a valid informed consent. Without it, the physician is liable for the violation of the patients' physical integrity and his right to self determination. According to German jurisprudence, this shall even apply when the treatment was conducted duly and without any complications. Therefore, it is astonishing that the correct way of giving information is neither taught in medical school nor in the residency. In practice, supervisors expect that young assistant doctors will be familiar with the correct procedure. As a result, many mistakes are made, even though these are easy to avoid. In this article, we point out all relevant information and the correct way of presenting this, using the example of hip/knee TEP operations. PMID- 30312982 TI - Effect of Selenium Supplementation on Lipid Profile: A Systematic Review and Meta Analysis. AB - Selenium is an essential mineral that plays a key role in plenty of major metabolic processes. A growing body of literature has shown that selenium deficiency leads to an increase in plasma TC and TG levels. This study explores the effect of selenium supplementation on serum level of lipid profile [total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low density lipoprotein (VLDL)]. We systematically searched PubMed/MEDLINE, ISI/WOS, and Scopus (from their commencements to Jan 2016) to identify the papers investigating the association between the intake of selenium and lipid profile. Data extracted from the relevant studies were screened. The pooled standardized mean difference was estimated using the random or fixed effects model. Heterogeneity among the studies was assessed using Q test. Of the potentially relevant articles screened, 11 articles including 1221 participants were included in this meta-analysis. Results of meta-analysis showed that intake of selenium resulted in a statistically significant improvement in TC, [(SMD): -0.13, 95% CI: (-0.24, -0.02)], TG [(SMD): -0.19, 95% CI: (-0.38, 0.01)] and VLDL [(SMD): -0.34, 95% CI: (-0.63, -0.05)]. The selenium supplementation did not significantly improve lipid profile such as LDL [(SMD): 0.08, 95% CI: (-0.036, 0.19)], HDL [(SMD): 0.01, 95% CI: (-0.164, 0.18)], HDL/TC ratio [(SMD): 0.025, 95% CI: (-0.11, 0.16)], non-HDL-C [(SMD): 0.018, 95% CI: ( 0.13, 0.16)]. This meta-analysis suggests that the effect of selenium supplementation on the serum levels of TG and VLDL is marginally significant. However, the supplementation has no effect on other serum lipids. Moreover, the study shows that the effect of selenium supplementation on lipid profile is negative. PMID- 30312983 TI - Risk of Malignancy in Thyroid Nodules Using the American College of Radiology Thyroid Imaging Reporting and Data System in the NIFTP Era. AB - Recently, the American College of Radiology (ACR) proposed a Thyroid Imaging Reporting and Data System (TI-RADS) for thyroid nodules based on ultrasonographic features. It is important to validate this classification in different centres. The present study evaluated the risk of malignancy in solid nodules>1 cm using ACR TI-RADS. The risk of malignancy was defined including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and after its exclusion from malignant tumours. For the present study, the original images were revised, and each nodule was assigned to one of the TI-RADS levels proposed for solid nodules: TR3, TR4, or TR5. This risk of malignancy was significantly different for the three levels: 1.7%, 11.2%, and 60.6% for TR3, TR4, and TR5, respectively, when NIFTP was included, and 0.6%, 7.9%, and 60.2% for TR3, TR4, and TR5, respectively, when NIFTP was excluded from malignant tumours. The nodules corresponding to NIFTP were classified according to ACR as TR3 in 28.5% of cases, TR4 in 67.8%, and TR5 in only 3.5%. The nodules corresponding to cancer were classified according to ACR as TR3 in only 2.3% of cases, TR4 in 27%, and TR5 in 70.5%. In conclusion, this study shows the validity of the ACR TI-RADS for solid thyroid nodules, even after the exclusion of NIFTP from malignant tumours. PMID- 30312984 TI - Comparative Efficacy of Alendronate upon Vertebral Bone Mineral Density and Fracture Rates in East Asians Versus Non-East Asians with Postmenopausal Osteoporosis: A Systematic Review and Meta-Analysis. AB - Bisphosphonates, such as alendronate, have become the most widely used and effective anti-resorptive therapy for postmenopausal osteoporosis. Previous genetic studies suggest that ethnicity may drive differing responses to bisphosphonate therapy in East Asians and non-East Asians. Therefore, the aim of this study was to comparatively evaluate the efficacy of alendronate upon lumbar spinal BMD and vertebral fracture rates in East Asians and non-East Asians with postmenopausal osteoporosis. MEDLINE, EMBASE, and Cochrane CENTRAL were searched for relevant randomized controlled trials (RCTs) comparing the efficacy of alendronate versus placebo (or calcium/mineral and/or Vitamin D or hormone replacement therapy) in primary postmenopausal osteoporotic women. We calculated the weighted mean differences (WMDs) for lumbar spinal BMD and the risk ratios (RRs) for vertebral fracture risk along with their respective 95% confidence intervals (CIs). From an initial set of 445 non-duplicate records, 13 full-text articles were finally included in this meta-analysis consisting of four East Asian RCTs and nine non-East Asian RCTs. Alendronate therapy displayed significant effects in improving lumbar spinal BMD in both East Asians [WMD (95% CI)=5.30 (0.32-10.29), p=0.037] and non-East Asians [WMD (95% CI)=5.73 (3.61 7.85), p=0.000]. Alendronate therapy did not display significant effects upon vertebral fracture risk in East Asians [RR (95% CI)=0.41 (0.06-2.73), p=0.358] but did display a significant effect upon lowering vertebral fracture risk in non East Asians [RR (95% CI)=0.55 (0.42-0.72), p=0.000]. These findings suggest that ethnicity may affect the efficacy of bisphosphonate therapy in postmenopausal osteoporotic women. PMID- 30312985 TI - Effects of Stratified Vitamin D Supplementation in Middle-Aged and Elderly Individuals with Vitamin D Insufficiency. AB - The incidence of vitamin D deficiency is high globally, and vitamin D supplementation draws particular attention. The objective of this study was to investigate the effects of stratified vitamin D supplementation in middle-aged and elderly individuals with vitamin D insufficiency in Beijing. A total of 448 subjects aged over 40 years old were selected from a community in Beijing. Among them, 100 middle-aged and elderly people with vitamin D insufficiency were randomly selected on a voluntary basis. They were further divided into control group and intervention group. The control group received health education and lifestyle guidance, and the intervention group received lifestyle guidance and vitamin D supplementation for nine months. The doses were stratified as follows: for vitamin D insufficiency, oral vitamin D3 supplement was given at 5000 IU/w; for mild vitamin D deficiency, oral vitamin D3 supplement was given at 10 000 IU/w; for severe vitamin D deficiency, oral vitamin D3 supplement was given at 15 000 IU/w. Safety evaluation was conducted after three-month treatment. The intervention group consisted of 8%, 62%, and 30% of cases who had vitamin D insufficiency, mild vitamin D deficiency, and severe vitamin D deficiency, respectively, which were similar with the control group. It showed that the blood 25(OH)D level increased significantly in the intervention group, from 14.30+/ 4.30 ng/ml to 33.62+/-6.99 ng/ml (p<0.001), in contrast to insignificant change in the control group. Stratified vitamin D supplementation effectively increased the blood 25(OH)D level, as well as the number of cases with corrected vitamin D insufficiency or deficiency. PMID- 30312986 TI - Bone Mineral Density is Unaltered in Women with Polycystic Ovary Syndrome. AB - CONTEXT: The effects of endocrine aberrations associated with polycystic ovary syndrome (PCOS) on bone mineral density (BMD) in young women is a matter of debate. OBJECTIVES: To compare BMD in young women with PCOS to age and body mass index (BMI) matched controls and to elucidate its correlation to BMI, insulin resistance and serum testosterone. DESIGN AND METHODS: We recruited 60 women with PCOS aged 14-24 years, diagnosed based on Rotterdam 2003 criteria, and 58 age matched controls. BMD was measured by dual energy X-ray absorptiometry. In addition, these subjects underwent biochemical and hormonal analysis including oral glucose tolerance test, calculation of Homeostatic Model Assessment-Insulin Resistance Index, measurement of serum thyroxine, thyrotropin, prolactin, total testosterone, dehydroepiandrosterone sulfate, follicular phase luteinizing hormone and follicle stimulating hormone. RESULTS: There was no difference of BMD between women with PCOS and control women (1.103+/-0.08 vs 1.126+/-0.083 g/cm2; p=0.122). In subgroup analysis based on BMI, BMD in obese women with PCOS was significantly higher than their overweight and lean counterparts at lumbar spine (p<0.001), neck of femur (p=0.005) and total hip (p<0.001). BMD was not different at any site between oligomenorrheic and non-oligomenorrheic women with PCOS. It positively correlated with BMI, waist and hip circumference in women with PCOS. No correlation was found with HOMA-IR or Testosterone. CONCLUSIONS: BMI is the most important determinant of BMD in women with PCOS. BMD is not different between healthy young women and those with PCOS. PMID- 30312987 TI - Drug resistance in Mycobacterium tuberculosis and targeting the l,d transpeptidase enzyme. AB - Hit, Lead & Candidate Discovery Tuberculosis (TB) is a disease that has afflicted mankind for thousands of years, but in the last seven decades, much progress has been made in anti-TB therapy. Early drugs, such as para-aminosalicylic acid, streptomycin, isoniazid, and rifamycins were very effective in combatting the disease, giving rise to the hope that TB would be eradicated from the face of the earth by 2010. Despite that optimism, TB continues to kill more than a million people annually worldwide. A major reason for our inability to contain TB is the emergence drug resistance in Mycobacterium tuberculosis. This commentary is based on our recent publication on the structure of l,d-transpeptidase enzyme, relevant to drug resistance. As a background, we briefly outline the history and development of anti-TB therapy. Based on the crystal structure, we suggest a potential direction for designing more potent drugs against TB. PMID- 30312988 TI - Vasodilators for women undergoing fertility treatment. AB - BACKGROUND: The rate of successful pregnancies brought to term has barely increased since the first assisted reproductive technology (ART) technique became available. Vasodilators have been proposed to increase endometrial receptivity, thicken the endometrium, and favour uterine relaxation, all of which could improve uterine receptivity and enhance the chances for successful assisted pregnancy. OBJECTIVES: To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment. SEARCH METHODS: We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of controlled trials, the Cochrane Central Register of of Controlled Trials, via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, the Open System for Information on Grey Literature in Europe (OpenSIGLE), the Latin American and Caribbean Health Science Information Database (LILACS), clinical trial registries, and the reference lists of relevant articles. We conducted the search in October 2017 and applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing vasodilators alone or in combination with other treatments versus placebo or no treatment or versus other agents in women undergoing fertility treatment. DATA COLLECTION AND ANALYSIS: Four review authors independently selected studies, assessed risk of bias, extracted data, and calculated risk ratios (RRs). We combined study data using a fixed-effect model and assessed evidence quality using Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) methods. Our primary outcomes were live birth or ongoing pregnancy and vasodilator side effects. Secondary outcomes included clinical pregnancy, endometrial thickness, multiple pregnancy, miscarriage, and ectopic pregnancy. MAIN RESULTS: We included 15 studies with a total of 1326 women. All included studies compared a vasodilator versus placebo or no treatment. We judged most of these studies as having unclear risk of bias. Overall, the quality of evidence was low to moderate for most outcomes. The main limitations were imprecision due to low numbers of events and participants and risk of bias due to unclear methods of randomisation.Vasodilators probably make little or no difference in rates of live birth compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.83 to 1.69; three RCTs; N = 350; I2 = 0%; moderate-quality evidence) but probably increase overall rates of side effects including headache and tachycardia (RR 2.35, 95% CI 1.51 to 3.66; four RCTs; N = 418; I2 = 0%; moderate quality evidence). Evidence suggests that if 236 per 1000 women achieve live birth with placebo or no treatment, then between 196 and 398 per 1000 will do so with the use of vasodilators.Compared with placebo or no treatment, vasodilators may slightly improve clinical pregnancy rates (RR 1.45, 95% CI 1.19 to 1.77; 11 RCTs; N = 1054; I2 = 6%; low-quality evidence). Vasodilators probably make little or no difference in rates of multiple gestation (RR 1.15, 95% CI 0.55 to 2.42; three RCTs; N = 370; I2 = 0%; low-quality evidence), miscarriage (RR 0.83, 95% CI 0.37 to 1.86; three RCTs; N = 350; I2 = 0%; low-quality evidence), or ectopic pregnancy (RR 1.48, 95% CI 0.25 to 8.69; two RCTs; N = 250; I2 = 5%; low-quality evidence). All studies found benefit for endometrial thickening, but reported effects varied (I2 = 92%) and ranged from a mean difference of 0.80 higher (95% CI 0.18 to 1.42) to 3.57 higher (95% CI 3.01 to 4.13) with very low-quality evidence, so we are uncertain how to interpret these results. AUTHORS' CONCLUSIONS: Evidence was insufficient to show whether vasodilators increase the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may slightly increase clinical pregnancy rates. Moderate-quality evidence shows that vasodilators increase overall side effects in comparison with placebo or no treatment. Adequately powered studies are needed so that each treatment can be evaluated more accurately. PMID- 30312989 TI - Prenatal Diagnosis of Aortopulmonary Window by 2-Dimensional Echocardiography: Summary of 8 Cases. AB - Aortopulmonary window (APW) is a rare congenital heart anomaly. A total of 8 cases with APW confirmed by echocardiography and surgery were retrospectively reviewed and the echocardiographic features analyzed. Among the 8 APW cases, 5 were type II and 3 were type III, the latter of which includes 2 cases complicated with Berry syndrome. Prenatal echocardiography can provide accurate information for the diagnosis of fetal APW. The prognosis depends on the timing of surgery and the nature of the associated cardiac anomalies. PMID- 30312990 TI - Impact of residual coronary atherosclerosis on transfemoral transcatheter aortic valve replacement. AB - OBJECTIVES: This study reports on the clinical effects of complete vs incompletely revascularized coronary artery disease on transcatheter aortic valve replacement (TAVR). BACKGROUND: There is a high prevalence of active coronary artery disease (CAD) in patients undergoing TAVR but preemptive revascularization remains controversial. METHODS: Patients were categorized into three cohorts: complete revascularization (CR), incomplete revascularization of a major epicardial artery (IR Major), and incomplete revascularization of a minor epicardial artery only (IR Minor). When feasible, SYNTAX scoring was performed for exploratory analysis. Analyses were performed using Cox proportional hazard models and Kaplan-Meier method. RESULTS: A total of 323 patients with active CAD were included. Adjusted outcomes showed that patients with IR Major had increased incidence of acute myocardial infarction (AMI) or revascularization compared with those in the CR cohort (HR 3.72, P = 0.048). No difference was noted in all-cause mortality or all-cause readmission rates. Exploratory secondary analysis with residual SYNTAX scores showed a significant interaction between disease burden and AMI/revascularization, as well as all-cause readmission. All-cause mortality remained unaffected based on residual SYNTAX scores. CONCLUSIONS: This is a retrospective single-center study reporting on pre-TAVR revascularization outcomes in patients with active CAD. In this analysis, we found that patients undergoing TAVR benefited from achieving complete revascularization to abate future incidence of AMI/revascularization. Despite this finding, all-cause mortality remained unaffected. Future efforts should focus on the role of functional assessment of the coronaries, as well as the long-term effects of complete revascularization in a larger patient cohort. PMID- 30312991 TI - Reaching toward underexplored targets in antibacterial drug design. AB - The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole-cell activity of designed compounds. Furthermore, we consolidate recent literature reports and encourage the further research on Mur enzymes. PMID- 30312992 TI - Incidence, predictors, management and outcomes of coronary perforations. AB - OBJECTIVES: We examined the contemporary incidence, types, predictors, angiographic characteristics, management and outcomes of coronary perforation. BACKGROUND: Coronary perforation is a rare, but important, complication of percutaneous coronary intervention (PCI). There is lack of data on perforations stratified as large and distal vessel perforations. METHODS: Retrospective, observational cohort study of all patients who underwent PCI at a high volume, tertiary hospital between the years 2009 and 2016. Angiograms of all coronary perforation cases were reviewed to determine the mechanism, type, and management of perforation. Risk-adjusted periprocedural complication rates were compared between patients with and without coronary perforation. One-year mortality outcomes of patients with large vessel vs. distal vessel perforation were also examined. RESULTS: Coronary perforation occurred in 68 of 13,339 PCIs (0.51%) performed during the study period: 51 (75%) were large vessel perforations and 17 (25%) distal vessel perforations. Most (67%) large vessel perforations were due to balloon/stent inflation, whereas most (94%) distal vessel perforations were due to guidewire exit. Patients with coronary perforations had significantly higher risk for periprocedural complications (adjusted odds ratio 7.57; 95% CI: 4.22-13.50; P < 0.001). Only one patient with large vessel perforation required emergency cardiac surgery, yet in-hospital mortality was high with both large vessel (7.8%) and distal vessel (11.8%) perforations. CONCLUSIONS: Coronary perforation is an infrequent, but potentially severe PCI complication. Most coronary perforations are large vessel perforations. Although coronary perforations rarely lead to emergency cardiac surgery, both distal vessel and large vessel perforations are associated with high in-hospital mortality, highlighting the importance of prevention. PMID- 30312993 TI - Establishing the Key Outcomes for Pediatric Emergency Medical Services Research. AB - The evidence supporting best practices when treating children in the prehospital setting or even the effect emergency medical services (EMS) has on patient outcomes is limited. Standardizing the critical outcomes for EMS research will allow for focused and comparable effort among the small but growing group of pediatric EMS investigators on specific topics. Standardized outcomes will also provide the opportunity to collectively advance the science of EMS for children and demonstrate the effect of EMS on patient outcomes. This article describes a consensus process among stakeholders in the pediatric emergency medicine and EMS community that identified the critical outcomes for EMS care in five clinical areas (traumatic brain injury, general injury, respiratory disease/failure, sepsis, and seizures). These areas were selected based on both their known public health importance and their commonality in EMS encounters. Key research outcomes identified by participating stakeholders using a modified nominal group technique for consensus building, which included small group brainstorming and independent voting for ranking outcomes that were feasible and/or important for the field. PMID- 30312994 TI - Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells. AB - BACKGROUND: Being devoid of de novo protein synthesis capacity, red blood cells (RBCs) have evolved to recycle oxidatively damaged proteins via mechanisms that involve methylation of dehydrated and deamidated aspartate and asparagine residues. Here we hypothesize that such mechanisms are relevant to routine storage in the blood bank. STUDY DESIGN AND METHODS: Within the framework of the REDS-III RBC-Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell-Omics) study, packed RBC units (n = 599) were stored under blood bank conditions for 10, 23, and 42 days and profiled for oxidative hemolysis and time dependent metabolic dysregulation of the trans-sulfuration pathway. RESULTS: In these units, methionine consumption positively correlated with storage age and oxidative hemolysis. Mechanistic studies show that this phenomenon is favored by oxidative stress or hyperoxic storage (sulfur dioxide >95%), and prevented by hypoxia or methyltransferase inhibition. Through a combination of proteomics approaches and 13 C-methionine tracing, we observed oxidation-induced increases in both Asn deamidation to Asp and formation of methyl-Asp on key structural proteins and enzymes, including Band 3, hemoglobin, ankyrin, 4.1, spectrin beta, aldolase, glyceraldehyde 3-phosphate dehydrogenase, biphosphoglycerate mutase, lactate dehydrogenase and catalase. Methylated regions tended to map proximal to the active site (e.g., N316 of glyceraldehyde 3-phosphate dehydrogenase) and/or residues interacting with the N-terminal cytosolic domain of Band 3. CONCLUSION: While methylation of basic amino acid residues serves as an epigenetic modification in nucleated cells, protein methylation at carboxylate side chains and deamidated asparagines is a nonepigenetic posttranslational sensor of oxidative stress and refrigerated storage in anucleated human RBCs. PMID- 30312995 TI - Hemodynamic durability of transcatheter aortic valves using the updated Valve Academic Research Consortium-2 criteria. AB - OBJECTIVES: We investigated the hemodynamic durability of the transcatheter aortic valves (TAVs) using the updated Valve Academic Research Consortium-2 (VARC 2) criteria. BACKGROUND: The updated VARC-2 consensus criteria combine flow dependent and flow-independent echocardiographic parameters for hemodynamic assessment of TAVR. Data on the hemodynamic durability of TAV and clinical risk factors associated with valve hemodynamic deterioration (VHD) are lacking. METHODS: All patients (n = 276) who received TAV between 2006 and 2012 and had >=2 follow-up echocardiograms were studied. RESULTS: During a median follow up period of 3.3 (1.8-4.4) years, 8 patients (3%) developed moderate to severe valve stenosis per the VARC-2 criteria, while 20 had mild stenosis. In a Cox proportional hazards model analysis, moderate to severe stenosis by VARC-2 criteria was associated with younger age (P = 0.03, HR 0.94), absence of dual antiplatelet therapy (DAPT) (P = 0.026, HR 0.18), and lower baseline left ventricular ejection fraction (LVEF) (P = 0.006, HR 0.94). Longitudinal analysis using a mixed effect model showed that presence of stenosis by VARC-2 criteria was associated with an increase in aortic valve mean gradient (P < 0.001, +2.34 mmHg per year). In a subset of 93 patients with analyzable fluoroscopic images, deeper valve implantation was associated with increase in mean gradient (P = 0.004, +0.2 mmHg per year per 1 mm increase in implantation depth). CONCLUSION: Despite good hemodynamic durability of TAV, patients with younger age, lower LVEF and those not on DAPT after undergoing a TAV replacement, are at a higher risk for development of VHD. PMID- 30312996 TI - How to manage chronic total occlusions in the setting of acute myocardial infarction complicated by cardiogenic shock? AB - An observational study of 313 patients with multivessel disease and ST-segment elevation myocardial infarction complicated by cardiogenic shock showed that the presence of a chronic total occlusion (CTO) in a noninfarct-related artery is an independent predictor of short- and long-term mortality. This study confirms previous reports on the detrimental prognostic impact of a CTO in the setting of acute myocardial infarction with or without cardiogenic shock. Data from recent randomized trials (CULPRIT-SHOCK and EXPLORE) suggest no benefit of early CTO revascularization; further studies are needed to investigate early treatment with extracorporeal membrane oxygenation in this extremely high-risk subgroup. PMID- 30312997 TI - Antegrade fenestration and re-entry: The legacy continues. AB - Subintimal guidewire entry during antegrade wiring attempts can be approached with various techniques, such as: (a) withdraw and redirect the guidewire; (b) parallel wire technique; (c) re-entry using the Stingray system or guidewires; or (d) using the retrograde approach Antegrade fenestration and re-entry is a creative novel technique for antegrade re-entry that uses balloon angioplasty at the distal cap to create fenestrations between the false lumen and the distal true lumen, followed by advancement of a soft-polymer jacketed guidewire through the fenestrations to achieve distal true lumen re-entry Antegrade fenestration and re-entry is an intuitive, simple, and low-cost technique, but balloon inflation may cause subintimal hematoma that could hinder re-entry. Additional study is needed to refine how antegrade fenestration and re-entry should optimally be performed and to better understand its strengths and shortcomings. PMID- 30312998 TI - "Expanding the frame" for valve-in-valve therapy in small bioprostheses: Encouraging signs for the road ahead. AB - Valve in valve TAVI with valve fracture in 19 mm bioprosthetic valves is clinically effective. Careful multidisciplinary personalized evaluation for each patient is needed to prevent coronary occlusion. Longer term data for a larger number of patients are needed, from the transcatheter valve therapy (TVT) registry. PMID- 30312999 TI - Periprocedural myocardial infarction in chronic total occlusion: The challenge of precise diagnosis and prognostication. AB - Myonecrosis following PCI is a frequent impediment that may impact cardiac prognosis. The frequency of periprocedural myocardial infarction (PMI) in CTO-PCI is dependent on MI definition (biomarker and threshold), lesions characteristics, and PCI course. This study identified predictors of PMI during CTO-PCI and it showed that PMI and peak CK-MB level were associated with worse clinical outcomes. PMID- 30313000 TI - The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. AB - OBJECTIVES: Chronic pain is common and use of long-term opioid therapy for chronic pain has increased dramatically. This report reviews the current evidence on effectiveness and harms of opioid therapy for chronic pain, focusing on long term (>=1 year) outcomes. DATA SOURCES: A prior systematic review (searches through October 2008), electronic databases (Ovid MEDLINE, Scopus, and the Cochrane Libraries January 2008 to August 2014), reference lists, and clinical trials registries. REVIEW METHODS: Using predefined criteria, we selected randomized trials and comparative observational studies of patients with cancer or noncancer chronic pain being considered for or prescribed long-term opioid therapy that addressed effectiveness or harms versus placebo, no opioid use, or nonopioid therapies; different opioid dosing methods; or risk mitigation strategies. We also included uncontrolled studies >=1 year that reported rates of abuse, addiction, or misuse, and studies on the accuracy of risk prediction instruments for predicting subsequent opioid abuse or misuse. The quality of included studies was assessed, data were extracted, and results were summarized qualitatively. RESULTS: Of the 4,209 citations identified at the title and abstract level, a total of 39 studies were included. For a number of Key Questions, we identified no studies meeting inclusion criteria. Where studies were available, the strength of evidence was rated no higher than low, due to imprecision and methodological shortcomings, with the exception of buccal or intranasal fentanyl for pain relief outcomes within 2 hours after dosing (strength of evidence: moderate). No study evaluated effects of long-term opioid therapy versus no opioid therapy. In 10 uncontrolled studies, rates of opioid abuse were 0.6 percent to 8 percent and rates of dependence were 3.1 percent to 26 percent in primary care settings, but studies varied in methods used to define and ascertain outcomes. Rates of aberrant drug-related behaviors ranged from 5.7 percent to 37.1 percent. Compared with nonuse, long-term opioid therapy was associated with increased risk of abuse (one cohort study), overdose (one cohort study), fracture (two observational studies), myocardial infarction (two observational studies), and markers of sexual dysfunction (one cross-sectional study), with several studies showing a dose-dependent association. One randomized trial found no difference between a more liberal opioid dose escalation strategy and maintenance of current dose in pain or function, but differences between groups in daily opioid doses at the end of the trial were small. One cohort study found methadone associated with lower risk of mortality than long-acting morphine in a Veterans Affairs population in a propensity adjusted analysis (adjusted HR 0.56, 95 percent CI 0.51 to 0.62). Estimates of diagnostic accuracy for the Opioid Risk Tool were extremely inconsistent and other risk assessment instruments were evaluated in only one or two studies. No study evaluated the effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse. Evidence was insufficient to evaluate benefits and harms of long-term opioid therapy in high-risk patients or in other subgroups. CONCLUSIONS: Evidence on long-term opioid therapy for chronic pain is very limited but suggests an increased risk of serious harms that appears to be dose dependent. More research is needed to understand long-term benefits, risk of abuse and related outcomes, and effectiveness of different opioid prescribing methods and risk mitigation strategies. PMID- 30313001 TI - Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. AB - OBJECTIVES: This systematic review summarizes research on methods of diagnosing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and benefits and harms of multiple medical and nonmedical treatments. It identifies evidence gaps and limitations to inform future research. DATA SOURCES: Searches of electronic databases included MEDLINE(r) (1988 to September 2014), PsycINFO(r) (1988 to September 2014), and the Cochrane Library (through the third quarter of 2014). The searches were supplemented by reviewing reference lists, seeking suggestions from reviewers, and requesting scientific information from drug and device manufacturers. REVIEW METHODS: Two investigators reviewed abstracts and full-text articles for inclusion based on predefined criteria. Discrepancies were resolved through discussion and consensus, with a third investigator making the final decision. RESULTS: A total of 6,175 potentially relevant articles were identified, 1,069 were selected for full-text review, and 71 studies in 81 publications were included (36 observational studies on diagnosis and 35 trials of treatments). Eight case definitions have been used to define ME/CFS; those for ME, requiring the presence of postexertional malaise, represent a more symptomatic subset of the broader ME/CFS population. Researchers are unable to determine differences in accuracy between case definitions because there is no universally accepted reference standard for diagnosing ME/CFS. The Oxford criteria are the least restrictive and include patients who would not otherwise meet criteria for ME/CFS. Self-reported symptom scales may differentiate ME/CFS patients from healthy controls but have not been adequately evaluated to determine validity and generalizability in large populations with diagnostic uncertainty. Fourteen studies reported the consequences of diagnosis, including perceived stigma and the burden of misdiagnosis, as well as feelings of legitimacy upon receiving the diagnosis of ME/CFS. : Of the 35 trials of treatment, rintatolimod compared with placebo improved measures of exercise performance; counseling therapies and graded exercise treatment (GET) compared with no treatment, relaxation, or support improved fatigue, function, and quality of life, and counseling therapies also improved employment outcomes. Other treatments either provided no benefit or results were insufficient to draw conclusions. GET was associated with higher numbers of reported adverse events compared with counseling therapies or controls. Harms were generally inadequately reported across trials. LIMITATIONS: Diagnostic methods were studied only in highly selected patient populations. Treatment trials were limited in number and had small sample sizes and methodological shortcomings. CONCLUSIONS: None of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists. Rintatolimod improves exercise performance in some patients (low strength of evidence), while counseling therapies and GET have broader benefit but have not been adequately tested in more disabled populations (low to moderate strength of evidence). Other treatments and harms have been inadequately studied (insufficient evidence). More definitive studies are needed to fill the many research gaps in diagnosing and treating ME/CFS. PMID- 30313002 TI - Antidepressant Treatment of Depression During Pregnancy and the Postpartum Period. AB - OBJECTIVES: To evaluate the benefits and harms of pharmacological therapy for depression in women during pregnancy or the postpartum period. DATA SOURCES: Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, Scopus, ClinicalTrials.gov, and Scientific Information Packets from pharmaceutical manufacturers. Databases were searched from their inception to July 2013.. REVIEW METHODS: We included studies comparing pharmacological treatments for depression during or after pregnancy with each other, with nonpharmacological treatments, or with usual care or no treatment. Outcomes included both maternal and infant or child benefits and harms. Dual review was used for study inclusion, data abstraction, and quality assessment. We assessed study quality using methods of the Drug Effectiveness Review Project. We graded the strength of the body of evidence according to the methods of the Effective Health Care Program. Direct evidence comprised studies that compared interventions of interest in the population of interest (i.e., depressed women) and measured the outcomes of interest. Studies comparing groups of depressed women with control groups with no evidence of depression were considered indirect. RESULTS: We included 15 observational studies that provided direct evidence on benefits and harms of antidepressants for depression during pregnancy. We included six randomized controlled trials and two observational studies of antidepressant treatment for depression in postpartum women. Studies of depressed pregnant women primarily compared antidepressant treatment with no treatment, and studies of postpartum women also compared antidepressants alone with combination antidepressant-nonpharmacological treatments. This evidence was insufficient to draw conclusions on the comparative benefits or harms of antidepressants for the outcomes of maternal depression symptoms, functional capacity, breastfeeding, mother-infant dyad interactions, and infant and child development for either pregnant or postpartum women with depression. Low-strength evidence suggests that neonates of women with depression taking selective serotonin reuptake inhibitors (SSRIs) during pregnancy had higher risk of respiratory distress than neonates of untreated women but that risk of preterm birth or neonatal convulsions does not differ between these groups. Direct evidence on the risk of major malformations and neonatal development with exposure to antidepressants in utero was insufficient to draw conclusions. For postpartum women with depression, evidence was insufficient to evaluate the full range of benefits and harms of treatment. Low-strength evidence was unable to show a benefit of adding brief psychotherapy or cognitive behavioral therapy to SSRIs. : To address gaps in the direct evidence, we included an additional 109 observational studies of pregnant women receiving antidepressants for mixed or unreported reasons compared with pregnant women not taking antidepressants whose depression status was unknown. Signals from this indirect evidence suggest that future research should focus on the comparative risk of congenital anomalies and neonatal motor developmental delays. Although the absolute increased risk of autism spectrum disorder or attention-deficit hyperactivity disorder in the child associated with antidepressant use for depression in pregnancy may be very small, this issue also merits attention in future research. Future research should compare available treatments in groups of women with depression and have adequate sample sizes. Investigations should also take into account potential confounding, including age, race, parity, other exposures (e.g., alcohol, smoking, and other potential teratogens), and the impact of dose, severity of depression, timing of diagnosis, or prior depressive episodes. CONCLUSIONS: Evidence about the comparative benefits and harms of pharmacological treatment of depression in pregnant and postpartum women was largely inadequate to allow well-informed decisions about treatment. For pregnant women, this was mainly because comparison groups were not exclusively depressed women. For postpartum women, the lack of evidence arose chiefly from a scarcity of studies. These are major limitations, as depression is known to be associated with serious adverse outcomes. Given the prevalence of depression and its impact on the lives of pregnant women, new mothers, and children, new research to fill this informational gap is essential. PMID- 30313003 TI - Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update). AB - BACKGROUND: In 2009, the Institute of Medicine/Food and Nutrition Board constituted a Dietary Reference Intakes (DRI) committee to undertake a review of the evidence that had emerged (since the 1997 DRI report) on the relationship of vitamin D and calcium, both individually and combined, to a wide range of health outcomes, and potential revision of the DRI values for these nutrients. To support that review, several United States and Canadian Federal Government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent was to support a transparent literature review process and provide a foundation for subsequent reviews of the nutrients. The committee used the resulting literature review in their revision of the DRIs. : In 2013, in preparation for a project the National Institutes of Health Office of Dietary Supplements (NIH/ODS) was undertaking related to evidence-based decisionmaking for vitamin D in primary care, based on the updated DRI report, the ODS and AHRQ requested an update to the 2009 systematic review to incorporate the findings of studies conducted since the 2009 evidence review on the relationship between vitamin D alone or vitamin D plus calcium to selected health outcomes and to report on the methods used to assay vitamin D in the included trials. PURPOSE: To systematically summarize the evidence on the relationship between vitamin D alone or in combination with calcium on selected health outcomes included in the earlier review: primarily those related to bone health, cardiovascular health, cancer, immune function, pregnancy, all-cause mortality, and vitamin D status; and to identify the vitamin D assay methods and procedures used for the interventional studies that aimed to assess the effect of vitamin D administration on serum 25(OH)D concentrations, and to stratify key outcomes by methods used to assay serum 25(OH)D concentrations. DATA SOURCES: MEDLINE; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles on humans. STUDY SELECTION: Primary interventional or prospective observational studies that reported outcomes of interest in human subjects in relation to vitamin D alone or in combination with calcium, as well as systematic reviews that met the inclusion and exclusion criteria. DATA EXTRACTION: A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality. DATA SYNTHESIS: We summarized 154 newly identified primary articles and two new systematic reviews that incorporated more than 93 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases, or cancer outcomes. Findings were inconsistent across studies for bone health; breast, colorectal, and prostate cancer; cardiovascular disease and mortality; immune function; and pregnancy-related outcomes. Few studies assessed pancreatic cancer and birth outcomes. One new systematic review of observational studies found that circulating 25(OH)D was generally inversely associated with risk for cardiovascular disease. Methods used to assay serum 25(OH)D in studies reporting on key outcomes diverged widely. The current report also identified one new systematic review published since the original report that addressed whether a dose response relationship exists between dietary and supplemental vitamin D intake and serum 25(OH)D concentrations. The systematic review, based on 76 RCTs, reported widely varying increases in serum concentrations of 25(OH)D for similar doses of vitamin D, with a general increase in serum concentration with dietary intake. The RCTs identified for the current report found increases in serum 25(OH)D with supplementation; however, the findings varied by age group and health status of participants, baseline vitamin D status, dose, duration, and assay used to assess serum 25(OH)D. LIMITATIONS: Studies on vitamin D and calcium were not specifically targeted at life stages (except for pregnant and postmenopausal women) specified for the determination of DRI and were often underpowered for their intended outcomes. Studies vary widely in methodological quality and in the assays used to measure vitamin D status. CONCLUSIONS: In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn. Studies identified for the current report suggest a possible U-shaped association between serum 25(OH)D concentrations and both all-cause mortality and hypertension and also suggest that the level of supplemental vitamin D and calcium administered in the Women's Health Initiative Calcium-Vitamin D Trial are not associated with an increased risk for cardiovascular disease or cancer among postmenopausal women who are not taking additional supplemental vitamin D and calcium. Studies suggest the method used to assay 25(OH)D may influence the outcomes of dose-response assessments. Beyond these observations, it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent. PMID- 30313004 TI - The Childhood/Adolescent Immunization Program. PMID- 30313006 TI - The Human-Machine Interface: Inviting Your Computer Into Your Patient-Clinician Relationship. PMID- 30313005 TI - Asthma Disease Management Program. PMID- 30313008 TI - Perinatal Screening for Congenital Malformations and Genetic Disorders: Current Status and Future Directions. PMID- 30313007 TI - Clinical Management for Survivors of Sudden Cardiac Death. AB - Sudden cardiac death is believed to affect as many as 400,000 people each year in the United States and is therefore an important public health problem. A common cause of sudden cardiac death is ventricular fibrillation. This article reviews the clinical and electrophysiologic aspects of sudden arrhythmic death and discusses current clinical management for survivors of sudden death. Particular emphasis is placed on the implantable cardioverter-defibrillator (ICD). PMID- 30313009 TI - Stevens-Johnson Syndrome: A Case Study. AB - Physicians writing prescriptions for their patients must warn them about possible side effects. One such potential complication of drugs-including tetracycline-is Stevens-Johnson syndrome, a potentially fatal condition that manifests mainly on the skin and mucosal surfaces but also affects other vital organs. Many types of therapy have proved efficacious for treating the syndrome, but use of steroid agents for this purpose remains controversial. Care for patients with Stevens Johnson syndrome consists of treating the presenting symptoms. PMID- 30313011 TI - The Relation Between Adverse Childhood Experiences and Adult Health: Turning Gold into Lead. PMID- 30313010 TI - Evidence-Based Clinical Vignettes from the Care Management Institute: Major Depression. PMID- 30313012 TI - Dear Doctor. PMID- 30313014 TI - KP Mid-Atlantic-Lessons Learned at Ground Zero of the Anthrax Crisis. PMID- 30313013 TI - Medical Futility. PMID- 30313015 TI - "We're Proud of You, Mid-Atlantic KP!" PMID- 30313016 TI - Smallpox Sense. PMID- 30313017 TI - Discovering the Enduring Principles of Group Practice Medicine. PMID- 30313018 TI - Results of the First National Kaiser Permanente Continuing Medical Education Needs Assessment Survey. AB - CONTEXT: Needs assessment is an important part of planning effective continuing medical education (CME) programs. The Kaiser Permanente National CME Committee (KPNCME) was formed in 1998 to accredit and provide oversight and assistance to Kaiser Permanente (KP) national CME programs and to provide expertise on an as needed basis to regional and local KP CME efforts. OBJECTIVE: To develop, distribute, and analyze a CME needs assessment survey of Permanente physicians. DESIGN: Cross-sectional survey completed by Permanente physicians on paper or online during September 2000 through December 2000. MAIN OUTCOME MEASURES: Physician motivations for, preferences about, and perceived barriers to participating in CME programs. RESULTS: Of 10,959 surveys distributed to KP physicians, 1976 (19.1%) were completed. Survey responses showed that Permanente physicians choose topics on the basis of self-perceived need and tend not to be influenced by objective performance data. Survey respondents preferred evidence based, clinical CME topics that address a major aspect of their practice and that potentially provide an opportunity to learn new skills. Respondents preferred CME programs delivered in group format, although a subset of respondents found the computerized format valuable. In choosing a CME program, respondents were influenced more by program location than by time of day at which programs were scheduled. CONCLUSIONS: At all levels-from individual to national-CME planning should incorporate objectively determined quality, program utilization, and other objective data as well as more subjectively determined need as perceived by individual physicians and CME experts. Live programs delivered onsite should use interactive format. The need for clinicians to develop cultural competence and effective communication skills should be framed in clinical context. Locations of KP national CME programs should periodically be rotated to make these programs more accessible to prospective attendees from all KP Regions. PMID- 30313019 TI - Association between AGTR1 A1166C polymorphism and the susceptibility to diabetic nephropathy: Evidence from a meta-analysis. AB - BACKGROUND: Diabetic nephropathy (DN) is a common complication in patients with diabetic mellitus (DM). Growing evidences have demonstrated that the polymorphisms of angiotensin II receptor type 1 (AGTR1) showed significant association with DN onset, but no consensus has been achieved yet. Therefore, we performed this meta-analysis to combine the findings of previous researches for a more comprehensive conclusion. METHODS: Eligible publications were identified through electronic databases. The intensity of the correlation between AGTR1 A1166C polymorphism and DN susceptibility was evaluated through calculating pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs). Heterogeneity among included studies was examined with Q test. When P-value less than .05, significant heterogeneity presented, random-effects model was used to calculate the pooled ORs, otherwise, the fixed-effects model was used. Stratification analyses were also performed based on ethnicity and the type of DM. RESULTS: Seventeen eligible articles were finally included in the present meta-analysis. The analysis results showed that AGTR1 A1166C polymorphism was significantly related to increased risk of DN under CC versus AA (OR = 1.723, 95% CI = 1.123-2.644), CC + AC versus AA (OR = 1.179, 95% CI = 1.004-1.383), CC versus AA + AC (OR = 1.662, 95% CI = 1.112-2.486), and C versus A (OR = 1.208, 95% CI = 1.044-1.397) genetic models. Additionally, a similar result was also found in Asian and T2DM (type 2 diabetic mellitus) groups after subgroup analyses of ethnicity and DM type. CONCLUSION: AGTR1 A1166C polymorphism may increase the susceptibility to DN, especially in Asians and T2DM population. PMID- 30313020 TI - Retrospective clinical analysis of 320 cases of microvascular decompression for hemifacial spasm. AB - To investigate effects of microvascular decompression (MVD) surgical treatment on hemifacial spasm.A retrospective analysis of 320 adult patients (95 male cases, 29.7% and 225 female cases, 70.3%) with hemifacial spasm treated by surgery was conducted between February 2007 to June 2016, with an average age of 49.3 years and average disease course of 4.9 years. All the 320 cases of patients received MVD. After surgery, all patients were followed up for an average of 2.3 years. Surgical effects were evaluated based on the patients' symptoms and signs. As this is just a retrospective study that does not involve any interventions, ethical approval was not necessary according to the rules of the hospital.All patients were followed up, no death occurred. Symptom was completely disappeared in 241 cases (75.3%), 50 cases (15.6%) improved; the total effective rate of surgery was 90.9%. No obvious changes of hemifacial spasm were happened in 29 cases (9.1%). There was no deteriorated case.MVD is one of the preferred treatments of hemifacial spasm, the intraoperative electrophysiological monitoring of abnormal muscle response signals contributes to the determination of responsible vessels and fully understanding of delayed resolution is helpful to the accuracy of surgical evaluation. PMID- 30313021 TI - Effect of combined parenteral and enteral nutrition versus enteral nutrition alone for critically ill patients: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: The increased mortality rate and other poor prognosis make malnutrition a serious issue for adult critically ill patients in intensive care unit care. This study was to compare outcomes between combined parenteral and enteral nutrition and enteral nutrition alone for adult critically ill patients. MATERIALS AND METHODS: The PubMed (June 30, 2018), EMBASE (June 30, 2018), and Cochrane library databases (June 30, 2018) were searched systematically. Randomized controlled trials (RCTs) of comparing combined PN and EN with EN alone were eligible. Relative risks (RRs), mean differences (MDs), and 95% confidence intervals (CIs) were calculated for dichotomous and continuous outcomes. RESULTS: Eight RCTs involving 5360 patients met the inclusion criteria. Compared with combined PN and EN, fewer respiratory infections (RR, 1.13 [95% CI 1.01-1.25]) and shorter length of days at hospital (MD, 1.83 [95% CI 1.05-2.62]) were observed in EN alone group. And no significant differences were found on hospital mortality (RR, 0.91 [95% CI 0.74-1.12]), length of days in ICU (MD, -0.23 [95% CI -1.79 to 1.32]), duration of ventilatory support (MD, -1.10 [95% CI -3.15 to 0.94]), albumin (MD, -0.04 [95% CI, -0.12 to 0.21]), or prealbumin (MD, -0.77 [95% CI -0.22 to 1.75]) between theses 2 groups. CONCLUSION: Receiving EN alone decreased the respiratory infections and length of days at hospital for critically ill patients. Combined PN and EN did not add up the potential risk from PN and EN on hospital mortality, length of days in ICU, duration of ventilatory support, albumin, and prealbumin. PMID- 30313022 TI - Frequent milk and soybean consumption are high risks for uterine leiomyoma: A prospective cohort study. AB - This study aims to retrospectively analyze the potential risk factors for uterine leiomyoma and prospectively examine whether these risk factors can increase the incidence of uterine leiomyoma.Women who attended our outpatient department from January 1, 2010 to December 31, 2010 were enrolled. General demographical characteristics, personal information, and living habits were collected. Univariate and multivariate logistic regression analyses were used to identify the potential risk factors. Follow-up was regularly conducted to complete the prospective analysis.A total of 1273 women were enrolled including 213 uterine leiomyomas (case group) and 1060 nonuterine leiomyoma women (control group). No statistical differences were found on the age, marital status, number and complication of pregnancy, frequent physical exercise, frequent alcohol consumption, and family history of uterine diseases between two groups (all P > .05). Mean body mass index (P = .043), high school education (P = .041), frequent smoking (P = .030), frequent caffeine consumption (P = .019), frequent milk or soybean consumption (P = .025), and frequent oral contraceptive use (P = .034) were statistically correlated with the onset of uterine leiomyoma. Multivariate analysis verified that frequent milk or soybean consumption (7.349 [5.081-9.454]; P = .039] and frequent oral contraceptive use (8.103 [4.486-12.583]; P = .018] were the independent risk factors for uterine leiomyoma.Frequent milk or soybean consumption and frequent oral contraceptive use are associated with a high risk of uterine leiomyoma, and proper education on the prevention of uterine leiomyoma is highly recommended in clinical practice. PMID- 30313023 TI - Percutaneous nerve electrical stimulation for fatigue caused by chemotherapy for cervical cancer. AB - This retrospective study investigated the effectiveness of percutaneous nerve electrical stimulation (PNES) for fatigue caused by chemotherapy for cervical cancer survivors.Totally, 83 cases of fatigue caused by chemotherapy for cervical cancer survivors were analyzed. All these cases were assigned to a treatment group (n = 43), and a control group (n = 40). Patients in the treatment group received PNES, while the subjects in the control group were on waiting list. The treatment was applied once daily for a total of 6 weeks. The primary endpoint was fatigue. It was evaluated by the Multidimensional Fatigue Inventory (MFI), and Fatigue Questionnaire (FQ). The secondary endpoints consisted of anxiety and depression. They were measured by the Hospital Anxiety and Depression Scale (HADS). All outcomes were measured before and after 6-week treatment.After treatment, PNES did not show significant difference in fatigue relief, measured by MFI (General fatigue, P = .31; Physical fatigue, P = .44; Activity, P = .36; Motivation, P = .55; Mental fatigue, P = .49), and FQ (Mental fatigue, P = .29; Physical fatigue, P = .35); and the reduction of anxiety and depression, measured by the HADS (Anxiety, P = .21; Depression, P = .17) after 6 weeks treatment between 2 groups.This study demonstrated that PNES may not benefit for cervical cancer survivors with fatigue caused by chemotherapy after 6-week treatment. PMID- 30313024 TI - Effects of the portage early education program on Chinese children with global developmental delay. AB - Children with global developmental delay (GDD) were trained with the Portage Guide to Early Education (PGEE) program.In the treatment group, the PGEE program was performed on children with GDD (45 cases) through a combination of family and hospital interventions, in a 1-to-1 ratio. The Gesell Infant Development Scale (GESELL) developmental quotient (DQ) and social adaptability were measured before and 6 months after PGEE implementation in the treatment group. These parameters were also evaluated in a control group (30 cases) during an initial visit and 6 months later.Before the PGEE intervention, no significant differences were observed between the general characteristics of children in the control and treatment groups. Six months after the PGEE intervention, the DQ values of the children with GDD in the treatment group (64.7 +/- 9.5) were significantly higher than those before treatment (54.6 +/- 9.3) and those of the control group (58.3 +/- 10.2) (P < .05). The PGEE intervention significantly increased the DQ values on 5 aspects, including gross motor, fine motor, adaptability, language, and personal social activity abilities, and the scores on the Infants-Junior Middle School Students' Social-Life Abilities Scales (SM scales), as compared with the control group (P < .05).The PGEE program improves the DQ, social adaptability, and prognosis of children with GDD. PMID- 30313025 TI - Improvement of quality of life in diabetic patients treated with percutaneous transluminal angioplasty. AB - To assess the quality of life (QoL) of treated patients in order to evaluate the success of peripheral transluminal angioplasty (PTA) and correlate physical parameters with clinical progress at 6 months post-PTA.According to TASC II classifications, 69 patients were selected for PTA. Clinical evaluation and diagnostic tests were performed before, after and after 6 months following PTA. The SF-36 QoL questionnaire was added as an additional parameter.Fifty one patients were included in the study. The ankle-brachial index (ABI) increased from 0.49 +/- 0.11 before PTA, to 0.81 +/- 0.14 after PTA (P < .001) and 0.76 +/- 0.10 at 6 months following PTA (P < .001). Transcutaneous oxygen pressure (TcPO2) increased from 28.05 +/- 3.15 mm Hg before PTA, to 39.89 +/- 4.12 after PTA (P < .001) and 46.4 +/- 3.81 at 6 months following PTA (P < .001). The lumen of the affected blood vessel increased from 29 +/- 18% before PTA, to 81 +/- 10.3% after PTA (P < .001). SF-36 values increased from 29 +/- 18 before PTA, to 81 +/- 10.36 at 6 months following PTA (P < .001).The improvement of QoL is the parameter that best describes the symptoms and functionality of the patient, therefore, should be used to determine the successful PTA. Although ABI and TcPO2 with arteries functionality and tissue oxygenation, they are not show a significant correlation with all parameters determined in the QoL questionnaire. PMID- 30313026 TI - Primary squamous cell carcinoma of the pancreas with effective comprehensive treatment: A case report and literature review. AB - RATIONALE: Primary squamous cell carcinoma (SCC) of the pancreas is a rare entity since the pancreas lacks squamous cells. This condition is associated with a poor prognosis, and there is currently no optimal treatment strategy for it. PATIENT CONCERNS: A 64-year-old female patient with a complaint of epigastric pain for 3 months was referred to our hospital. DIAGNOSES: She was finally diagnosed with primary SCC of the pancreas with lymph node metastasis on the basis of radiological and pathological findings. INTERVENTIONS: She received chemoradiation along with targeted therapy and was provided with treatment response evaluation through PET/CT. OUTCOMES: She eventually died of tumor progression after 8 months. LESSONS: Primary SCC of the pancreas is associated with a poor prognosis. Comprehensive therapy and proper radiologic evaluation may facilitate prolonged survival of these patients. PMID- 30313028 TI - Effect of LED therapy for the treatment nipple fissures: Study protocol for a randomized controlled trial. AB - INTRODUCTION: Poor positioning of the child in relation to the breast and improper suckling are the main causes of nipple fissure. Treatment options for nipple fissures include drug therapy with antifungal and antibiotics, topical applications of lanolin, glycerin gel, creams and lotions, the milk itself, hot compresses, and silicone nipple shields. Studies involving light-emitting diode (LED) therapy have demonstrated anti-inflammatory properties, the enhancement of the wound repair process, and the control of pain. As it does not cause discomfort, is relatively inexpensive and may impede the discontinuation of breastfeeding, phototherapy could be a viable option for the treatment of nipple fissures. AIM: The principal objective of the proposed study is to evaluate the effectiveness of LED therapy for the treatment of nipple fissures in postpartum mothers. MATERIALS AND METHODS: One hundred patients treated with a medical diagnosis of bilateral nipple trauma classified as nipple fissures or cracks will participate in the study, randomized into 2 groups: The control group will receive orientation regarding breast care and adequate breastfeeding techniques. The experimental group will receive the same orientation and phototherapy sessions using a device developed especially for the treatment of nipple trauma. Both groups will be followed up for 6 consecutive weeks. PMID- 30313027 TI - Prognostic and clinical significance of metastasis-associated gene 1 overexpression in solid cancers: A meta-analysis. AB - BACKGROUND: In the past 2 decades, metastasis-associated gene 1 (MTA1) has attracted attention for its close association with cancer progression and its roles in chromatin remodeling processes, making it a central gene in cancer. The present meta-analysis was performed to assess MTA1 expression in solid tumors. MATERIALS AND METHODS: This analysis identified studies that evaluated the relationship between MTA1 expression and clinical characteristics or prognosis of patients with solid tumors via the PubMed, Cochrane Library, and Embase electronic databases. Fixed-effect and random-effect meta-analytical techniques were used to correlate MTA1 expression with outcome measures. The outcome variables are shown as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). RESULTS: Analysis of 40 cohort studies involving 4564 cancer patients revealed a significant association of MTA1 overexpression with tumor patient age (>50 vs. <50 years: combined OR 0.73, 95% CI 0.57-0.94), tumor grade (G3/4 vs. G1/2: combined OR 1.94, 95% CI 1.48-2.53), tumor size (>3 cm vs. <3 cm: combined OR 2.35, 95% CI 1.73-3.19), T stage (T3/4 vs. T1/2: combined OR 2.11, 95% CI 1.74-2.56), lymph node metastasis (yes vs. no: combined OR 2.92, 95% CI 2.26-3.75), distant metastasis (yes vs. no: combined OR 2.26, 95% CI 1.42-3.59), TNM stage (III/IV vs. I/II: combined OR 2.50, 95% CI 1.84-3.38), vascular invasion (yes vs. no: combined OR 2.26, 95% CI 1.92-3.56), and poor overall survival time (HR 1.83; 95% CI: 1.53-2.20; P = .000). CONCLUSIONS: Our analyses demonstrate that MTA1 was an effective predictor of a worse prognosis in tumor patients. Moreover, MTA1 may play important role in tumor progression and outcome, and targeting MTA1 may be a new strategy for anti-cancer therapy. PMID- 30313029 TI - Diagnostic value of carotid artery ultrasound and hypersensitive C-reactive protein in Type 2 diabetes mellitus patients with acute myocardial infarction in Chinese population. AB - Hypersensitive C-reactive protein (hs-CRP) is reported to be significant risk indicators not only for the development of cardiovascular disease, but also for the development or progression of type 2 diabetes. The objective of this study was to analyze the significance of hs-CRP in type 2 diabetes mellitus (T2DM) combined with acute myocardial infarction (AMI).Fifty patients with both T2DM and AMI, 50 patients with T2DM alone, and 50 healthy subjects (control group) were selected.Operating characteristic (ROC) analysis revealed that the sensitivity, specificity, accuracy, and critical value in the diagnosis of T2DM combined with AMI using hs-CRP level were 84.6%, 75.9%, 0.856, and 7.34 mg/L, respectively. For using vulnerable plaque rate, these were 92.7%, 95.3%, 0.923, and 0.52, respectively.hs-CRP play a significant role in the early diagnosis of T2DM combined with AMI. PMID- 30313030 TI - Chronic thromboembolic pulmonary hypertension as the first manifestation of nephrotic syndrome in a 12-year-old child. AB - RATIONALE: Chronic thromboembolic pulmonary hypertension (CTEPH) is rare in children and determining the underlying etiologies is essential for treatment. Venous thromboembolism, a well-known complication in nephrotic syndrome (NS), always occurrs during the treatment in course of the disease. However, CTEPH as the first manifestation of NS has not been reported till now. PATIENT CONCERNS: A 12-year-old boy initially complained of hemoptysis, cough and shortness of breath with exertion, any symptoms regarding NS such as edema were not presented. Due to the identification of P2 enhancement, liver enlargement (2 cm below the rib) and jugular vein distension, pulmonary hypertension (PH) was firstly suspected and ultimately confirmed by detection of enlargement of right atrium (RA) and right ventricle (RV) enlargement (RA = 45mm, RV = 30mm), mild tricuspid valve regurgitation (TR) and elevation of pulmonary arterial pressure (63 mmHg) on echocardiogram. In order to search the underlying causes of PH, series of targeted laboratory evaluation and imaging were conducted, and pulmonary arterial embolism (PE) in inferior lobes of double lungs was found on chest contrast enhanced computed tomography. DIAGNOSIS: NS was unexpectedly discovered by detection of lower serum albumin level (24.4 g/L), severe proteinuria (+++, 4.62 g/24 h) when we were searching for the predisposing factors causing thromboembolism. INTERVENTIONS AND OUTCOMES: After treatment of NS, the symptom regarding shortness of breath with exertion gradually became less apparent and was relieved one month later. Proteinuria and microscopic hematuria also disappeared. Encouragingly, RA and RV dilation, and the pulmonary arterial pressure almost returned to a normal range half a year later, with alleviation of MR. LESSONS: CTEPH can occur rarely in children and NS is an important predisposing factor. PE could be the first manifestation of NS. When pediatricians encounter children with PE or CTEPH, NS as the underlying etiology should be considered. Except for renal venous thrombosis, the possibility of PE needs to be paid more attention in children with NS. PMID- 30313032 TI - Left main coronary artery atresia with concomitant mitral regurgitation in an adult: A case report. AB - INTRODUCTION: Left main coronary artery (LMCA) atresia is a quite rare congenital malformation, which may present with various symptoms. Past literatures were sporadic without recent summary of world-wide cases. We hereby report an adult case of LMCA atresia with concomitant mitral regurgitation and also summarize all cases found in published literatures. CASE PRESENTATION: A 48-year old female presented with sudden dyspnea. Preliminary impression was acute heart failure caused by mitral regurgitation. Preoperative coronary angiography demonstrated that there was no left coronary ostium and multiple collateral vessels arising from right coronary artery. The diagnosis of left main coronary atresia was made and the patient received successful valvuloplasty and coronary artery bypass grafting with left internal mammary artery anastomosed to the left anterior descending (LAD) artery. She recovered well and 3-month follow-up showed the graft was patent. CONCLUSION: This case highlights the importance of angiography for diagnosis of LMCA and performance of CABG once diagnosed. PMID- 30313031 TI - Expression of resistance gene and prognosis of chemotherapy in primary epithelial ovarian cancer. AB - The sensitivity of tumor cells to chemotherapy drugs may become attenuated accounts for various reasons. Reduced drug sensitivity may cause the failure of chemotherapy and affect the prognosis of patients with cancer. This study investigates the relationship between the expression levels of lung resistance protein (LRP) and placental glutathione S-transferase-P1 (GSTP1), the resistance of primary epithelial ovarian cancer (PEOC) to chemotherapy, and the prognosis of patients with platinum drug-resistant PEOC.Quantitative PCR (QT-PCR) was used to detect the mRNA level of the resistance genes LRP, GSTP1 in all tissue and cell lines.The expression levels of resistance gene (LRP, GSTP1) in PEOC were the highest, followed by borderline adenoma tissues, and the lowest levels found in benign tumor tissues, the difference of genes expression between different tissues was statistically significant; the difference between the expression rates and relative expression level of drug resistance genes was statistically significant in platinum sensitive group compare with the platinum resistant group. The difference between resistant gene negative-expression and positive expression of chemotherapy efficiency, disease free survival time, and recurrence time were statistically significant. The resistant genes expression in the PEOC patients of the negative-group survival curves was higher than that in the positive group. With ascites non-cellular component (ANCC) stimulated SKOV3 cells, the cell proliferation inhibition rate (CPIR) increased, and with ANCC stimulated SKOV3/DDP, the expression of LRP and GSTP1 also increased.ANCC may promote the expression of drug resistance genes, and the expression of genes may predict the poorly prognosis of epithelial ovarian cancer. PMID- 30313033 TI - A case report of a polytrauma patient with penetrating iron rods in thorax and head. AB - INTRODUCTION: Impalement injury is an uncommon presentation, and penetrating chest injuries account for 1% to 13% of thoracic trauma hospital admissions. The vast majority of patients with penetrating thoracic trauma who survive to reach the hospital alive can be managed nonoperatively. Nevertheless, in 10% to 15% of cases, emergency operation is necessary due to the associated hemorrhagic shock and visceral injury. CASE PRESENTATION: Here, we report on a 39-year-old male, a construction worker, who fell down from a height of a construction site, landing ventrally on a clump of iron rods with 4 projecting heavy metallic rods penetrating into his thorax and head (scalp pierced only). Emergency surgery was taken, and the patient had an uneventful successful outcome. CONCLUSIONS: After massive thoracic impalement, rapid transportation to a tertiary trauma center with the impaled objects in situ can improve the outcome. Video-assisted thoracic surgery (VATS) is recommended to remove the foreign body under direct vision and to reduce the incidence of missed, potentially fatal vascular or visceral injuries. PMID- 30313034 TI - The effectiveness of anticancer traditional Korean medicine treatment on the survival in patients with lung, breast, gastric, colorectal, hepatic, uterine, or ovarian cancer: A prospective cohort study protocol. AB - Although anticancer traditional Korean medicine treatment (ACTKMT) is widely applied to patients with cancer together with, or in place of, conventional cancer treatment in Korea, the cohort evidence on its clinical effects is lacking. Therefore, this prospective cohort study is designed to evaluate the effect of ACTKMT on the survival and the clinical outcomes for patients being treated at an integrative oncology clinic.This is a single center, prospective cohort study of patients within 1 year after the diagnosis of primary lung, breast, gastric, colorectal, hepatic, uterine, or ovarian cancer. The event-free survival, disease-free survival/progression-free survival, the overall survival, the results of blood tests, and telomere-length information will be compared between patients receiving and patients not receiving a key ACTKMT (HangAmDan-B1, Geonchil-jung, and/or cultivated wild ginseng pharmacopuncture), and the correlation between the use of the key ACTKMT and the prognosis will be identified considering other risk factors.This study has received ethical approval from the Institutional Review Board, Dunsan Korean Medicine Hospital of Daejeon University (No. DJDSKH-16-BM-09). The results of this study will be published in a peer-reviewed journal.Clinical Research Information Service: KCT0002160. PMID- 30313035 TI - The prognostic value of decreased NDRG1 expression in patients with digestive system cancers: A meta-analysis. AB - BACKGROUND: Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers. METHODS: We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included. RESULTS: The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22-2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1-3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32-0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23-1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45-1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26 2.24, P = .62). CONCLUSION: The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms. PMID- 30313036 TI - Chronic inflammatory demyelinating polyradiculoneuropathy: A case report. AB - RATIONALE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder characterized by a symmetrical, sensorimotor involvement and slowly progressive onset peripheral neuropathy. Peripheral neuropathies have been reported in some central demyelination patients. However, the central nervous system focus in the CIDP patient can mimic neuromyelitis optica have not been recognized by most of us. PATIENT CONCERNS: The numbness and weakness of limbs about eight weeks. DIAGNOSES: Chronic inflammatory demyelinating polyradiculoneuropathy. INTERVENTIONS: Immunotherapy with intravenous immunoglobulins was applied to this patient. OUTCOMES: After 1 year follow-up, the results showed there was still slight numbness of all limbs, and he could walk slowly without help. Gastrocnemius muscle atrophy did not aggravate. LESSONS: So It is suggest that CIDP can combine with central lesions mimicking neuromyelitis optica. We should take the diagnosis of CIDP into consideration when we find focus in central nervous system. PMID- 30313037 TI - Levodopa-induced respiratory dysfunction confirmed by levodopa challenge test: A case report. AB - INTRODUCTION: Parkinson disease is associated with various nonmotor symptoms, including rare respiratory dysfunction events. However, patients with Parkinson disease often have comorbid medical problems, such as respiratory distress, and differentiating nonmotor symptoms can be difficult. CASE PRESENTATION: A 78-year old male presented with repetitive shortness of breath. He was diagnosed with Parkinson disease and chronic obstructive pulmonary disease (COPD) several years prior. His symptoms were ambiguous between acute COPD exacerbation and levodopa related nonmotor symptoms of Parkinson disease. To clarify the underlying cause, we performed the levodopa challenge test. After the patient complained of dyspnea following levodopa administration, levodopa-induced respiratory dysfunction was diagnosed. After adjusting antiparkinson medication, the patient's respiratory symptoms gradually improved. CONCLUSION: Respiratory dysfunction as a nonmotor symptom of Parkinson disease can be caused by levodopa medication. To determine whether the symptoms are induced by levodopa, the levodopa challenge test may be useful in clarifying symptoms related to antiparkinson medication. PMID- 30313038 TI - Oral health condition and occurrence of depression in the elderly. AB - Depression is a common disorder among the elderly; however, it is not a standard element of the ageing process. Depression can affect oral health as a result of neglecting oral hygiene procedures, cariogenic nutrition, avoidance of necessary dental care which leads to an increased risk of dental caries and periodontal disease.Assessment of the relationship of oral health parameters with depression.500 subjects aged >=65 (mean 74.4 +/- 7.4) were involved in the study. Dental condition (decay-missing-filled index [DMFT], number of missing teeth [MT], removable denture wearing, teeth mobility), periodontal condition (bleeding on probing [BoP], pocket depth [PD], loss of attachment), oral dryness (the Challacombe Scale) and depression according to the Patient Health Questionnaire-9 (PHQ-9) scale were assessed.Depression on a minimal level was detected in 60.2% of the subjects, mild-in 22.2%, moderate-in 6.0% and moderately-in 2.6%. The mean of the PHQ-9 scale was 3.56 +/- 4.07. Regression analysis showed a positive relationship of the PHQ-9 value with DMFT, the number of MT, oral dryness and with age. No correlation was observed between other examined oral health indicators, such as periodontal condition (BoP, PD, clinical attachment level), periodontitis, removable denture wearing a PHQ-9.The results of our study have shown that among people aged 65 and over, the severity of depression increases with a higher number of MT, the number of decayed teeth, as well as prevalence of oral dryness. PMID- 30313039 TI - MRI findings of AIDS-related giant facial Kaposi's sarcoma: A case report. AB - RATIONALE: Kaposi's sarcoma (KS) is the most common malignant tumor in HIV infected people and occurs mainly in the skin, mucous membranes, and lymph nodes. Approximately 33% of the initial skin manifestations of AIDS and approximately 35% to 79% of KS occur during disease progression. Otherwise, AIDS-related facial KS that was simultaneously examined by magnetic resonance imaging (MRI) is rare. PATIENT CONCERNS: This case was a 30-year-old male homosexual, with left facial nodule for 14 months, and HIV infection was diagnosed 1 month previously. The patient was admitted to hospital because the nodule gradually expanded from 0.2 to 10.0 cm in diameter. Ultrasound examination showed edema of the subcutaneous tissue of the left facial mass, and the boundary was not clear between lesion and normal tissues. Magnetic resonance imaging (MRI) indicated that the left facial mass showed low signal intensity on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI), and a small amount of high signal intensity was seen in it. Diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) showed low signal intensity. After enhanced scan, the tumor showed uneven enhancement. DIAGNOSES: The pathological biopsy indicated KS. INTERVENTIONS: The patient began chemotherapy with the intravenous drip infusion of Doxorubicin Hydrochloride Liposome. OUTCOMES: The facial KS decreased and the facial swelling was relieved. LESSONS: MRI could not only provide the diagnostic basis of KS for the therapy, but also could accurately determine the scope of the disease. PMID- 30313040 TI - Percutaneous versus open pedicle screw instrumentation in treatment of thoracic and lumbar spine fractures: A systematic review and meta-analysis. AB - BACKGROUND: To assess the safety and efficacy of percutaneous short-segment pedicle instrumentation compared with conventionally open short-segment pedicle instrumentation and provide recommendations for using these procedures to treat thoracolumbar fractures. METHODS: The Medline database, Cochrane database of Systematic Reviews, Cochrane Clinical Trial Register, and Embase were searched for articles published. The randomized controlled trials (RCTs) and non-RCTs that compared percutaneous short-segment pedicle instrumentation to open short-segment pedicle instrumentation and provided data on safety and clinical effects were included. Demographic characteristics, clinical outcomes, radiological outcomes, and adverse events were manually extracted from all of the selected studies. Methodological quality of included studies using Methodological Index for Non Randomized Studies scale and Cochrane collaboration's tool for assessing the risk of bias by 2 reviewers independently. RESULTS: Nine studies encompassing 433 patients met the inclusion criteria. Subgroup meta-analyses were performed according to the study design. The pooled results showed there were significant differences between the 2 techniques in short- and long-term visual analog scale, intraoperative blood loss, operative time, postoperative draining loss, hospital stay, and incision size, although there were no significant differences in postoperative radiological outcomes, Oswestry Disability Index, hospitalization cost, intraoperative fluoroscopy time, and adverse events. CONCLUSION: Percutaneous short-segment pedicle instrumentation in cases with achieve satisfactory results, could replace in many cases extensive open surgery and not increased related complications. However, further high-quality RCTs are needed to assess the long-term outcome of patients between 2 techniques. PMID- 30313041 TI - Closed reduction of the traumatic posterior-dislocation of hip joint using a novel sitting technique: A case series. AB - RATIONALE: Traumatic hip dislocation is a common joint dislocation. Delayed reduction has been shown to increase the risk of avascular necrosis of the femoral head. Most of the traditional methods must be performed under general anesthesia or spinal anesthesia to relax hip muscles. Anesthesia will prolong the interval between the injury and the reduction. PATIENT CONCERNS: 16 patients presented with hip pain and a leg shortened, flexed, internally rotated and adducted. DIAGNOSES: X-ray and CT-scan showed acute closed posterior dislocation of hip. INTERVENTIONS: Closed reduction of the traumatic posterior-dislocation of hip joint using a novel sitting technique. OUTCOMES: Among these 16 patients, 15 hips were successfully reduced using the Sitting Technique (table 1), indicating the success rate was 93.8%(15/16). A total of 12 patients were followed up, with a mean period of 23.5 months (range, 6-72 months). Among these 12 patients, 10 patients (83.3%) had excellent grade, 2 patients (16.7%) had good grade. LESSONS: Sitting technique for treatment of traumatic posterior dislocation of hip joint does not need anaesthesia, which it shortens the interval between the injury and the reduction and saves valuable time for 6 hours of joint reduction. On the other hand, this method does no harm to the physicians' low back. PMID- 30313042 TI - The relationship between adenoid hypertrophy and gastroesophageal reflux disease: A meta-analysis. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is believed to be associated with various manifestations in the otorhinolaryngology and has been found to be an additional risk factor for adenoid hypertrophy, but the causal relation between them is under controversial. We thus performed a meta-analysis to grade the strength of evidence and systematically explore whether adenoid hypertrophy correlates with GERD in the literature. METHODS: A systematic literature search was performed using Medline via PubMed, Embase, CNKI, and Web of Science. Studies reporting the adenoid hypertrophy and GERD were identified for inclusion. RESULTS: There were 6 studies that matched the selection criteria, and the total sample size of these studies was 548 cases. We identified a significant relationship between adenoid hypertrophy and GERD, with a pooled odds ratio of 4.12 (95% confidence interval [CI]: 1.32-12.93; P < .001). The results was significant in 24-hour pH monitoring subgroup analysis, with a corresponding value of 8.62 (95% CI: 4.06-18.27, P > .05) under the fixed-effects model. And the results was significant in Helicobacter pylori subgroup analysis, with a corresponding value of 2.39 (95% CI: 0.39-14.55, P < .05) under the random effects model. Begg tests (P = .73) and Egger tests (P = .76) showed there were no obvious evidence to support publication bias in our study. CONCLUSION: This meta-analysis provided a strong correlation between adenoid hypertrophy and GERD, the children with adenoid hypertrophy had a higher incidence of GERD than healthy children, but the pathogenesis of GERD in adenoid hypertrophy awaits more investigations and suggests that we should not overlook GERD in clinical practice and an appropriate evaluation for GERD may be needed. PMID- 30313043 TI - The effect and safety of dexmedetomidine added to ropivacaine in brachial plexus block: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Dexmedetomidine has been used as an adjuvanty added to local anesthetics to prolong analgesia following peripheral nerve blockade. The aim of this meta-analysis was to investigate the effect and safety of dexmedetomidine added to ropivacaine in brachial plexus block (BPB). METHODS: A search strategy was created to identify eligible randomized clinical trial (RCT) in PubMed, Embase, and The Cochrane Library (updated May, 2018). The methodologic quality for each included study was evaluated using the Cochrane Tool for Risk of Bias by 2 independent researchers. RESULTS: Twelve RCTs were included in the meta analysis (n = 671). As an adjuvant to ropivacaine, dexmedetomidine significantly reduced the onset time of sensory (mean difference [MD], -3.86 minutes, 95% CI 5.45 to -2.27 minutes; I = 85%) and motor (MD, -5.21 minutes; 95% CI -7.48 to 2.94 minutes; I = 94%). In addition, it increased the blockade duration of sensory (MD, 228.70 minutes; 95% CI 187.87-269.52 minutes; I = 93%) and motor (MD, 191.70 minutes; 95% CI 152.48-230.91 minutes; I = 92%). Moreover, the combination prolonged the duration of analgesia (MD, 303.04 minutes; 95% CI 228.84-377.24 minutes; I = 86%). There was no difference of the incidence of bradycardia (risk difference [RD], 0.01, 95% CI -0.02 to 0.05, I = 45%; P = .45) and hypotension (RD, 0.01, 95% CI -0.01 to 0.03, I = 0%; P = .57) between 2 groups. CONCLUSION: Dexmedetomidine added to ropivacaine in BPB has a better analgesia effect (shorter onset time and longer duration) compared to ropivacaine alone. At the same time, there was no difference in the incidence of bradycardia and hypotension. PMID- 30313044 TI - Pathological features of paraganglioma in the lumbar spinal canal: A case report. AB - INTRODUCTION: This study aims to investigate the pathological features of a patient with paraganglioma in the lumbar spinal canal. CASE PRESENTATION: The patient was 36 years old male with electrical pain in the waist and buttock which occurred intermittently, and was not relieved under oral use of analgesics. Immunohistochemical staining was performed to diagnose the disease. The results revealed that the size of the tumor was 3.4 * 1.6 * 1.4 cm. The hematoxylin and eosin (H&E)-stained tumor cells mainly presented with an organ-like arrangement under low power microscope, showing prominent chrysanthemum-like, pseudo glandular or pseudo papillary arrangements. The surrounding area of the nest presented with sinusoids, and fibrosis and focal calcification could be observed in the interstitial space among the lesions. Immunohistochemistry results showed that the chief cells were positive for neuron-specific enolase (NSE), Syn and CgA, and Sertoli cells were positive for S-100. CONCLUSION: Paraganglioma is a very rare malignant tumor. This tumor should be distinguished from ependymoma, meningioma and hemangioblastoma, to avoid misdiagnosis, and missed diagnosis. PMID- 30313045 TI - Risk factors for procedure-related complications after endoscopic resection of colorectal laterally spreading tumors. AB - Colorectal laterally spreading tumors (LSTs) are large and flat elevated neoplasms with diameters of at least 10 mm. Endoscopic resection of LSTs, with their large size and broad base, is difficult and dangerous compared with the resection of polypoid neoplasms. This study aimed to determine the risk factors for procedure-related complications including bleeding and perforation after endoscopic resection of LSTs.Patients with colorectal LST undergoing endoscopic resection at 5 university hospitals in Honam Province of South Korea were enrolled, and their records about patients, lesions, and procedure parameters associated with the occurrence of complications were reviewed retrospectively. Logistic regression analysis was performed to identify risk factors for complications.The frequency of comorbidities in bleeding group was significantly higher than in the no bleeding group. The frequency of bleeding was significantly higher in lesions with adenocarcinoma than in lesions with low or high-grade dysplasia. The frequency of bleeding was significantly higher in piecemeal resection than in en bloc resection. The frequency of perforation was significantly higher in endoscopic mucosal resection-precutting (EMR-P) than in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection. The mean procedure duration was significantly longer in the perforation group than in the no perforation group. On multivariate analysis, patient comorbidity and histologic grade of the lesion were significant independent risk factors for bleeding, whereas EMR-P was a significant independent risk factor for perforation after endoscopic resection.This study demonstrated that patient comorbidity and histologic grade of lesion were significant independent risk factors for bleeding, and EMR-P was a significant independent risk factor for perforation after endoscopic resection of colorectal LSTs. PMID- 30313046 TI - A giant hemolymphangioma of the pancreas: A case report and literature review. AB - RATIONALE: Hemolymphangioma of the pancreas is an extremely rare benign tumor; only 10 patients with this disease have been reported to date, the majority of whom were women. PATIENT CONCERNS: We describe a 28-year-old man who presented with abdominal pain and discomfort. Computed tomography and magnetic resonance imaging data showed a huge heterogeneous solid cystic mass at the retroperitoneal pancreatic head. The maximum cross-sectional lengths of the pancreatic lesion were approximately 12 * 8.5 * 12 cm. DIAGNOSIS: Hemolymphangioma of the pancreas. INTERVENTIONS: The patient underwent a pylorus-preserving pancreatoduodenectomy; surgical excision is the main treatment for this type of tumor. OUTCOMES: The patient followed up regularly in the outpatient department for 6 months after surgery, and no sign of recurrence was found. LESSONS: Although it is uncommon, clinicians ought to consider the diagnosis of hemolymphangioma of the pancreas upon detection of a pancreatic cystic lesion exhibiting fat or calcification. PMID- 30313047 TI - A 5-year follow-up of primary seminal vesicle adenocarcinoma: A case report. AB - RATIONALE: Primary seminal vesicle adenocarcinoma (PSVA) is an extremely rare malignancy that should be carefully differentiated from cancer originating in the prostate, colon or bladder. Without standard guidelines, radical resection is considered a mainstay treatment, providing the best prognosis. However, as manifestations of PSVA are not detected in early stages, the majority of cases of PSVA are diagnosed at late stages, contributing to poor prognosis. PATIENT CONCERNS: We described the case of a PSVA patient confirmed by histopathology and immunohistochemistry (IHC) staining positive for carbohydrate antigen-125 (CA 125) and negative for prostate specific antigen (PSA). DIAGNOSIS: Primary seminal vesicle adenocarcinoma. INTERVENTIONS: Surgery was carried out at the beginning, however, residual tumor was verified; thus 3 cycles of chemotherapy with a regimen of paclitaxel and cis-platinum were performed, followed by radical pelvic radiotherapy with a dose of 60 Gray in 30 fractions; then, another 3 cycles of the same chemotherapy were carried out. OUTCOMES: At the moment, the patient is still under follow-up and has been disease-free for more than 5 years. LESSONS: Our manuscript describes a patient with PSVA with long-term survival and supplies a successful management strategy for this malignancy. PMID- 30313048 TI - Expression profiles of long noncoding RNAs and mRNAs in peripheral blood mononuclear cells of patients with acute myocardial infarction. AB - Acute myocardial infarction (AMI) is the most serious type of coronary atherosclerotic diseases. The incidence of AMI in some countries increases year by year, and shows younger trend. Some study indicated that abnormal expression of lncRNAs was closely related to cardiovascular disease. The aim of this study was to examine the lncRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with AMI through controlled studies.In the present study, we examined the lncRNA and mRNA expression profiles in 8 patients with AMI, with 7 NCA (noncoronary artery) subjects as controls using RNA sequencing protocol (RNA-seq) on the Illumina HiSeq 4000 platform. The differentially expressed lncRNAs were selected for bioinformatic analysis including gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG). Quantitative real time PCR (qRT-PCR) was used to confirm the differential expression of lncRNAs.We kept about 11.29 gigabase (Gb) high-quality sequence data while the Q30 ranged from 94.39% to 95.19% for each sample. Compared to the lncRNA expression profiles of NCA controls, a total of 106 differentially expressed lncRNAs were discriminated in AMI patients, including 40 upregulated lncRNAs and 66 downregulated lncRNAs (P < .05). Among the genes corresponding to the identified mRNAs, 2905 genes are involved in biological processes, 339 in cellular components, and 501 in molecular functions. Based on the KEGG pathway analysis, the most enriched pathways corresponding to the differentially expressed lncRNAs were associated with systemic lupus erythematosus, alcoholism, oxidative phosphorylation, Parkinson's disease and viral carcinogenesis, and so on. Further, 3 upregulated and 3 downregulated lncRNAs were randomly selected for qRT-PCR verification and the results of qRT-PCR were consistent with the findings obtained from RNA sequencing analysis.As a result, differential expression profiles of lncRNAs in AMI were identified in our study. The results suggested that lncRNAs may play important roles in the biological and pathological processes of AMI. These findings may provide useful reference for the early diagnosis and risk stratification of AMI patients. To enlarge the sample size in the next step will be needed for further research to confirm our results. PMID- 30313049 TI - What happened to health service utilization, health care expenditures, and quality of care in patients with acute pancreatitis after implementation of global budgeting in Taiwan? AB - AIM: Acute pancreatitis is associated with significant morbidity and mortality. In the United States, more than 3,00,000 patients are admitted and about 20,000 die from acute pancreatitis per year. In Taiwan, the incidence rate of acute pancreatitis is 0.03% and the mortality rate among severe acute pancreatitis is 16.3%. The aim of the study was to evaluate the impact of the global budgeting system on health service utilization, health care expenditures, and quality of care among patients with acute pancreatitis in Taiwan. MATERIALS AND METHODS: The National Health Insurance Research Database (NHIRD) was used for analysis. Data on patients with acute pancreatitis diagnosed during the period 2000 and 2001 were used as baseline data, and data from 2004 and 2005 were used as post intervention data. The length of stay (LOS), diagnostic costs, drug cost, therapy costs, total costs, risk of readmission within 14 days, and risk of revisiting the emergency department (ED) within 3 days of discharge before and after implementation of the global budgeting system were compared and analyzed. RESULTS: Data on 2810 patients with acute pancreatitis were analyzed in this study. There was a significant difference in mean LOS before and after introduction of the global budget system (7.34 +/- 0.22 days and 7.82 +/- 0.22 days, respectively; P < .001)). The mean total costs before and after implementation of the global budget system were Taiwan dollars (NT$) 28,290.66 +/ 1576.32 and NT$ 42,341.83 +/- 2285.23, respectively. The mean rate of revisiting the ED within 3 days decreased from 9.9 +/- 0.9% before adoption of global budgeting to 7.2 +/- 0.6% after implementation of the system. The mean 14-day re admission rates before and after introduction of global budgeting were 11.6 +/- 1.0% and 7.9 +/- 0.7%, respectively. CONCLUSION: The global budget system was associated with significantly longer length of stay, higher health care expenditures, and better quality of care in patients treated for acute pancreatitis. PMID- 30313050 TI - Case report: Takayasu arteritis in a 3-month-old Chinese girl. AB - RATIONALE: Takayasu arteritis is a rare large vessel systemic vasculitis that predominantly affects the aorta and its main branches in women of childbearing age. Due to nonspecific symptoms during the acute phase of disease, early diagnosis is still a challenge for pediatricians. PATIENT CONCERNS: We reported a 3-month-old girl who presented with sustained elevated levels of acutephase reactants, which could not be explained by infectious diseases and malignant diseases. DIAGNOSES: The patient's angiography showed dilatation, stenosis, and inflammation of the aorta and its branches and was diagnosed as Takayasu arteritis. INTERVENTIONS: We prescribed glucocorticoids combined with immunosuppressive agents, which include cyclophosphamide used as an induction drug for 6 months, and mycophenolate mofetil used as a maintenance drug. Glucocorticoids gradually stopped. OUTCOMES: At present, the girl went into clinical remission with normal levels of acute-phase reactants and improvement of vascular inflammation demonstrated by angiography. LESSONS: This case report illustrates that Takayasu arteritis can occur in children at a very early age after birth before apparent clinical symptoms. PMID- 30313051 TI - An electrical scalpel conization versus Shimodaira-Taniguchi conization procedure for cervical intraepithelial neoplasia. AB - The incidence of cervical intraepithelial neoplasia(CIN) among reproductive-aged women has increased in Japan. Cervical conization is commonly applied for local cervical treatment to preserve fertility. The Shimodaira-Taniguchi (S-T) conization procedure is widely used in Japan. S-T conization uses a high frequency current and a triangular probe with a linear excision electrode to remove cervical tissue as a single informative specimen. However, alternative of an electrosurgical scalpel (ES) has the advantage of adjusting the surgical margin to the transformation zone in order to preserve the maximum amount of healthy cervical tissue with good hemostasis. The aim of this study is to retrospectively analyze data regarding surgical margin status, perioperative adverse events, cervical stenosis, and preterm birth between S-T and ES.Between January 2009 and December 2014, the medical records of 1166 patients who were diagnosed as CIN II, III, or stage 1a1 cervical cancer and who were treated with conization in 7 hospitals in Gunma Prefecture, Japan were enrolled for this retrospective study. The clinicopathological data was analyzed to statistically compare outcome between S-T and ES conization.There was no difference for age or post-operative follow-up period between ES and S-T treatments. However, positive surgical margins were significantly less frequent in patients who were treated with S-T than in those treated with ES, resulting in a reduced incidence of re treatment for S-T in comparison with ES patients. In perioperative adverse events, S-T had more patients who were administered antibiotics. The incidence of preterm delivery and cervical stenosis did not differ significantly between the groups.We demonstrate here that S-T is an alternative procedure for cervical conization with a low risk of recurrence and acceptably low rate of adverse events such as cervical stenosis and preterm delivery. The results of this study can provide useful information for future management of patient with cervical intraepithelial neoplasia. PMID- 30313052 TI - Impact of diet restriction on bowel preparation for colonoscopy. AB - Diet restriction is one of the difficult parts of bowel preparation for colonoscopy, and many patients do not follow instructions properly. Few studies have evaluated the impact of dietary restriction in real clinical setting. The aim of this study was to study the effect of diet control on bowel preparation with detailed investigation of unacceptable food list in order to reveal what kind of foods are most problematic in clinical practice.Prospective observational study was carried out at a university-affiliated hospital. Around 4 L polyethylene glycol solution was used for bowel preparation on the day of colonoscopy. Patients were allowed to have regular diet until lunch the day before colonoscopy and educated to control diet from 3 days before colonoscopy with information regarding an unacceptable foods list. Factors associated with inadequate bowel preparation were analyzed using univariate statistics and multivariate logistic regression analysis.Of the 245 patients included in the study, 68 patients (27.8%) followed the diet instructions. Fiber-rich vegetables were the most commonly taken unacceptable foods (N = 143, 58.4%). Inadequate bowel preparation (fair and poor by Aronchick scale) was 47.3%. In multivariate analysis, diabetes [odds ratio (OR) 2.878, 95% confidence interval (CI) 1.242 6.671], preparation to colonoscopy interval (OR 1.003, 95% CI 1.000-1.005) and consumption of foods disturbing bowel preparation (OR 2.142, 95% CI 1.108-4.140) were independent predictors of inadequate bowel preparation.We could identify substantially low compliance to diet instructions in real clinical practice. Consumption of any foods disturbing bowel preparation was significant factor predicting inadequate bowel preparation, even though we could not select specific food list compromising preparation significantly. Favorable bowel preparation was achieved in the subgroup compliant to diet restriction, suggesting that regular diet avoiding specific kinds of foods can be possible option for diet restriction before colonoscopy. PMID- 30313053 TI - Esmolol does not improve quality of postsurgical recovery after ambulatory hysteroscopy: A prospective, randomized, double-blinded, placebo-controlled, clinical trial. AB - INTRODUCTION: Intraoperative systemic esmolol has been shown to reduce postsurgical pain. Nonetheless, it is unknown whether the use of intraoperative systemic esmolol can improve patient-reported postsurgical quality of recovery. The main objective of the current investigation was to evaluate the effect of intraoperative esmolol on postsurgical quality of recovery. We hypothesized that patients receiving intraoperative esmolol would report better quality of postsurgical recovery than the ones receiving saline. METHODS: The study was a prospective randomized double-blinded, placebo-controlled, clinical trial. Healthy female subjects undergoing outpatient hysteroscopic surgery under general anesthesia were randomized to receive intravenous esmolol administered at a rate of 0.5 mg/kg bolus followed by an infusion of 5 to 15 MUg/kg/min or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. Other data collected included postoperative opioid consumption and pain scores. Data were analyzed using group t tests and the Wilcoxon exact test. RESULTS: Seventy subjects were randomized and 58 completed the study. There was not a clinically significant difference in the global QoR-40 scores between the esmolol and saline groups at 24 hours, median (interquartile range) of 179 (171-190) and 182 (173-189), respectively, P = .82. In addition, immediate post-surgical data in the post-anesthesia care unit did not show a benefit of using esmolol compared to saline in regard to pain scores, morphine consumption, and postoperative nausea and vomiting. CONCLUSIONS: Despite current evidence in the literature that intraoperative esmolol improves postsurgical pain, we did not detect a beneficial effect of intraoperative esmolol on patient-reported quality of recovery after ambulatory surgery. Our results confirm the concept that the use of patient-centered outcomes rather than commonly used outcomes (e.g., pain scores and opioid consumption) can change the practice of perioperative medicine. PMID- 30313054 TI - Acupuncture for treating whiplash-associated disorder: A systematic review and meta-analysis protocol. AB - BACKGROUND: This review aims to evaluate the effectiveness and safety of acupuncture treatment for patients with whiplash-associated disorder (WAD). METHODS: We will search the following databases from their inception to October 2018: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, 1 Chinese database (China National Knowledge Infrastructure), 1 Japanese database (Japan Science and Technology Information Aggregator, Electronic), and 5 Korean databases (KoreaMed, Research Information Service System, Korean Studies Information Service System, Database Periodical Information Academic, and Oriental Medicine Advanced Searching Integrated System). All randomized controlled trials of acupuncture for WAD will be considered for inclusion without language restrictions. The risk of bias will be assessed using the Cochrane risk of bias tool. The mean difference or standard mean difference for continuous data and risk ratio for dichotomous data will be calculated with 95% confidence intervals. DISSEMINATION: The results of this review will be disseminated through peer-reviewed journal articles or conference presentations, and may provide important guidance for clinicians and patients regarding the use of acupuncture treatment for treating WAD. TRIAL REGISTRATION NUMBER: PROSPERO 2018: CRD42018106964. PMID- 30313055 TI - Fluid management in extensive liposuction: A retrospective review of 83 consecutive patients. AB - Tumescent anesthesia makes it feasible to perform liposuction in an office setting. There are often patients who desire extensive liposuction on approximately 30% of total body surface area, which means the potential of fluid overload. In this study, the charts of 83 patients undergoing extensive liposuction were retrospectively reviewed. The intra-operative fluid ratio was 1.66 for the extensive liposuction. There were no episodes of pulmonary edema, congestive heart failure exacerbation, or other major complications. The average urine output in the operating room, the recovery room, and while on the floors was 1.35, 2.3, and 1.4 mL/kg/hour respectively. Intravenous (IV) fluid administration during operation was minimized to approximately 300 to 500 mL. The total volume of IV injection was also reduced to less than 1500 mL when the patient was in the recovery room and on the hospital floor. Our fluid management strategy in extensive liposuction reflects minimal risk of volume overload. Foley catheters are not applied and patients could resume oral intake in usual, so they can discharge after 6 hours of recovery room stay in our daily practice. PMID- 30313056 TI - Infliximab versus cyclosporine for severe ulcerative colitis refractory to steroids: A protocol for systematic review and meta-analysis. AB - BACKGROUND: Infliximab and cyclosporine are two main therapies in treating acute severe ulcerative colitis (ASUC), our objective is to assess the effectiveness and safety of cyclosporine (CSA) versus infliximab (IFX) as rescue agents in patients with steroid-refractory ulcerative colitis (UC). METHODS: We will search three databases from inception to May 2018, and 19 studies are identified that infliximab and cyclosporine as a treatment in steroid-refractory UC patients. The primary outcome was short-term response to treatment. Secondary outcomes included the rates of colectomy at 3 months, 12 months, 36 months, adverse drug reactions and mortality in those who received rescue therapy. RESULTS: This update review will provide a high quality synthesis of current evidence of two treatment for steroid-refractory ulcerative colitis. The definition of severe colitis is according to Truelove and Witts' criteria. CONCLUSIONS: In the treatment of steroid-resistant ulcerative colitis with infliximab and cyclosporine, there is no difference between the two treatments on short-term and long-term results. PMID- 30313057 TI - Use of steroid and nonsteroidal anti-inflammatories in the treatment of rheumatoid arthritis: Systematic review protocol. AB - BACKGROUND: Rheumatoid arthritis affects 1% of the world's population and its current treatment options are costly. There are not enough studies that evaluated the efficacy and safety of anti-inflammatory drugs medications used to reduce rheumatoid arthritis's symptoms. This study will evaluate the effectiveness and the safety of steroid and nonsteroidal anti-inflammatory drugs for the treatment of patients with rheumatoid arthritis. METHODS: Randomized clinical trials eligible for our systematic review will enroll adults with rheumatoid arthritis treated with anti-inflammatory drugs compared with a control group (placebo or active control) at any dose, duration, and route of administration and double blind studies. In order to include all forms of rheumatoid arthritis and anti inflammatory drugs, we will search the following electronic databases: Cochrane Central Register of Controlled Trials, MEDLINE (via Ovid); ExcerptaMedica Database (via Ovid); Cumulative Index to Nursing and Allied Health Literature (via Ovid); Web of Science; ClinicalTrial.gov; and WHO International Clinical Trials Registry Platform. We will not impose any language restrictions or publication status. Outcomes of interest include are pain, physical function, swelling, stiffness, grip force, radiological image of the joint, quality of life, adverse events, discontinuation due to adverse events, satisfaction with the treatment, and rescue medication for pain. A team of reviewers will independently screen search results, extract data from eligible trials, and assess risk of bias. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to rate overall certainty of the evidence by outcome. Dichotomous data will be summarized as risk ratios; continuous data will be given as standard average differences with 95% confidence intervals. RESULTS: The evidence derived by this study will increase awareness of the effectiveness and safety of steroid and nonsteroidal anti-inflammatory drugs for the treatment of rheumatoid arthritis. CONCLUSION: The results could guide patients and healthcare practitioners and help facilitate evidence-based shared care decision making. PMID- 30313058 TI - TargetScore used to reveal potential targets of miRNA203 and miRNA-146a in psoriasis by integrating microRNA overexpression and microarray data. AB - OBJECTIVE: Systematic tracking of microRNA (miRNA) targets remains a challenge. In our work, we aimed to use TargetScore to investigate the potential targets of miRNA203 and miRNA-146a in psoriasis by integrating miRNA overexpression information and sequence data, and to further uncover the functions of miRNA203 and miRNA-146a in psoriasis. METHODS: This was a case-control bioinformatics analysis using already published microarray data of psoriasis. We calculated targetScores by combining log fold-change and sequence scores obtained from TargetScan context score, probabilities of conserved targeting, and derived the distribution of targetScores. The scoring cutoff was chosen based on the different targetScore distributions for the nonvalidated and validated targets. The potential target genes for miRNA-203 and miRNA-146a were predicted based on the targetScore threshold. To reveal the functions of miRNA-203 and miRNA-146a, we implemented pathway enrichment analyses for the targets of miRNA-203 and miRNA 146a. RESULTS: TargetScore >0.4 was selected as the threshold to filter out less confidence targets because we observed little overlap between the 2 distribution at targetScore = 0.4. Based on the targetScore >0.4, 49 target genes for miRNA 203 and 17 targets for miRNA-146a were identified. Pathway enrichment results showed that the target genes of miRNA-203 (including KIR2DL1, HLA-DQA1, KIR3DL1) only participated in antigen processing and presentation. The target genes of miRNA-146a (covering ADORA3, CYSLTR2, HRH4) were only involved in neuroactive ligand-receptor interaction. CONCLUSION: MiRNA203 and miRNA-146a played important roles in psoriasis progression, partially through regulating the pathways of antigen processing and presentation, and neuroactive ligand-receptor interaction, respectively. PMID- 30313059 TI - Core decompression, lesion clearance and bone graft in combination with Tongluo Shenggu decoction for the treatment of osteonecrosis of the femoral head: A retrospective cohort study. AB - The aim of this study was to evaluate the clinical effect of core decompression (CD), lesion clearance, and bone graft in combination with Tongluo Shenggu decoction for the treatment of osteonecrosis of the femoral head (ONFH).A total of 75 patients (92 hips), with ONFH at Association Research Circulation Osseous (ARCO) stages II to IIIA, were studied and divided into treatment group and control group. In control group, patients were treated with the CD in combination with autologous or artificial ceramic bone graft. In treatment group, patients were treated with the above method combined with Tongluo Shenggu decoction. Patients were followed-up at 1 month, 6 months, and 24 months after surgery. The visual analogue scale (VAS) scores, Harris Hip Score (HSS), and total effective rates were measured and recorded.The total effective rate of the treatment group was significantly higher than that of the control group (97.2% vs. 89.9%, P < .05). Compared with preoperative, the VAS and HSS scores were both improved at final follow-up, and there was significant difference between 2 groups (P < .01).The combination of CD, lesion clearance, and the bone graft with Tongluo Shenggu decoction is safe and effective for the treatment of ONFH, owing to which it can provide higher postoperative functional outcomes, reduce pain, and achieve smaller osteonecrosis area and better bone changes. PMID- 30313060 TI - Relationship between ultrasonographic and pathologic calcification patterns in papillary thyroid cancer. AB - Ultrasonographic microcalcification is highly related to papillary thyroid cancer (PTC) and pathologic psammoma body is a poor prognostic factor. However, it is little known about whether the microcalcifications seen on ultrasonography are consistent with the pathologic psammoma bodies. We evaluated the relationship between ultrasonographic (US) calcification types and pathologic calcification features, and the consistency between observed pathologic and US calcifications.US calcifications were classified into microcalcification (MC) and nonmicrocalcification (non-MC) types, and pathologic calcifications were classified into 3 types: psammoma bodies, stromal calcifications, and ossifications.Among the 411 nodules that were reviewed by a pathologist, 38.9% (n = 160) had any type of US calcification. The larger the size of pathologic calcification, the more calcification was present in US (psammoma 46.1% < stromal 53.7% < ossification 73.3%). Psammoma bodies occurred in all US MC type. Ossification nodules occurred in nearly all (92.3%) non-MC type. The stromal-only nodules were 36.8% MC-type and 63.2% non-MC type. MC-type had a significantly higher odds ratio than non-MC type for predicting psammoma bodies according to the logistic regression.The presence of MC in ultrasonography was consistent with the presence of psammoma bodies. This study suggests that US identification of MC may be a useful prognostic indicator of PTC aggressiveness. PMID- 30313061 TI - Prognostic value of neutrophil to lymphocyte ratio and clinicopathological characteristics for multiple myeloma: A meta-analysis. AB - BACKGROUND: Neutrophil to lymphocyte ratio (NLR) was reported to be an effective parameter in carcinoma prognosis. Many studies were already performed to investigate the prognostic value of NLR in patients with multiple myeloma (MM). The results, however, were still debatable. METHODS: Databases of Pubmed, Cochrane library and Embase were examined. Hazard ratio (HR) with 95% confidence interval (CI) was used to assess the results. In addition, odds ratios (ORs) with 95% CIs were used to evaluate the association of NLR with clinicopathological factors. Meta-regression, sensitivity analysis, and subgroup analysis were also performed. RESULTS: The results showed poor OS (HR: 1.73, 95% CI: 1.23-2.44; P = .002) and progression-free survival (PFS) (HR: 1.74, 95% CI: 1.11-2.73; P = .015) when pretreatment NLR elevated. Our pooled ORs suggested that NLR had association with International Staging System (ISS), isotype and response to treatment. CONCLUSION: The meta-analysis results demonstrated that NLR could predict prognosis in MM patients. PMID- 30313062 TI - Association between the polymorphism (rs17222919, -1316T/G) of 5-lipoxygenase activating protein gene (ALOX5AP) and the risk of stroke: A meta analysis. AB - BACKGROUND: The objective of this study was to evalutate the relationship between 5-lipoxygenase-activating protein gene (ALOX5AP) -rs17222919-1316T/G polymorphisms and the risk of stroke. METHODS: Relative studies were searched in January 2018. Case-control studies with extractable data were selected. Four gene models were analyzed including, allele genetic model (G vs T), additive genetic model (GG vs TT, GT vs TT), recessive genetic model (GG vs GT + TT), and dominant genetic model (GG + GT vs TT). Effect sizes included odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was assessed by using Q test and I test. Publication bias was evaluated by using Egger method. The reliability of the results was assessed with sensitivity analysis. All the data analysis was performed with R 3.10 software. RESULTS: A total of 5 studies inclusing 8492 patients were included. There were significant relationship between ALOX5AP rs17222919-1316T/G polymorphisms and stroke under all models (P < .05) except the additive genetic model GT versus TT (P > .05). No publication bias was noted. Sensitivity analysis indicated that the results were not stable. CONCLUSION: This meta-analysis indicates that ALOX5AP-rs17222919-1316T/G may be a protective factor aginst stroke. PMID- 30313063 TI - Diffuse optical spectroscopy for monitoring the responses of patients with breast cancer to neoadjuvant chemotherapy: A meta-analysis. AB - BACKGROUND: This study aimed to investigate the potential of diffuse optical spectroscopy (DOT) for monitoring the responses of patients with breast cancer to neoadjuvant chemotherapy (NAC). METHODS: We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web of Science for relevant studies. Data were extracted for pooled analysis, heterogeneity testing, threshold effect testing, sensitivity analysis, publication bias analysis, and subgroup analysis. RESULTS: The pooled meta-analysis of the 10 eligible studies that included 422 patients indicated the high performance of DOT for monitoring total patient responses to NAC (OR = 14.78, 95% CI: 8.23-26.54, P < .001), with low significant heterogeneity (I = 7.2%, P = .375). DOT possessed an area under the curve of 0.84 (95% CI: 0.81-0.87) to distinguish total patient responses to NAC. Subgroup analysis showed that the pooled sensitivity of DOT for monitoring pathologic complete response to NAC was 87%, and the pooled specificity was 70%. Meanwhile, the pooled sensitivity of DOT for monitoring pathologic complete and partial responses to NAC was 82%, and the pooled specificity was 82%. Although Begg's funnel plot (P = .049) indicated the presence of publication bias among the included studies, trim-and-fill method verified the stability of the pooled outcomes. CONCLUSION: Our meta-analysis of available published data indicated that DOT can be potentially used to predict and monitor patient responses to NAC. A larger study population is needed to fully assess the use of DOT for guiding therapies and predicting responses of individual subjects to NAC. PMID- 30313064 TI - Long-term effects and quality of life following definitive bile duct reconstruction. AB - The study covered a cohort of 236 patients with transection of hepatic duct. It aimed to assess the long-term outcome of the reconstruction and a patient's quality of life.The literature contains many controversies over timing of biliary reconstruction and who ought to repair the injury but just few reports on the long-term outcomes and patient's quality of life.The bile duct system was reconstructed by hepaticojejunostomy in 236 patients. Of these, 139 patients were initially repaired at a public hospital and referred because of stricture (Group A, N = 59) or of an anastomosis dehiscence (Group B, N = 80); 97 were unrepaired and referred because of a surgical clip occluding the duct (Group C, N = 39) or bile leakage from an open duct (Group D, N = 58). All patients were surveyed in 2015 for quality of life using WHOQOL-BREF.The mean time of follow-up was 150 months. The time without symptoms amounted to >5 years in 78.6% of patients. The mean time before anastomosis renewal ranged from 8.9 to 4.7 years (P < .04). Multivariate analysis showed infection, failure of reconstruction in public hospital, and female sex as factors responsible for poor long-term outcome.Patients in Group C had better quality of life than the others (P < .001) with respect to physical health (median 67.85) and psychological condition (median 79.16). The overall mortality was 15.2%.The long-term result of reconstruction depends on the cause of referral which, in turn, arises from subsequent intervention taken in local hospitals. PMID- 30313065 TI - Richter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia: A case report and literature review. AB - RATIONALE: Central nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS. PATIENT CONCERNS: A 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans' classification. The patient's leukocyte count was 12.1 * 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone. DIAGNOSES: RS of the CNS diagnosed concurrently with CLL. INTERVENTIONS: The patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone). OUTCOMES: The patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms. LESSONS: The survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes. PMID- 30313066 TI - Risk of regorafenib-induced cardiovascular events in patients with solid tumors: A systematic review and meta-analysis. AB - BACKGROUND: The present comparative meta-analysis was conducted to evaluate the cardiovascular events of regorafenib in patients with solid tumors. METHODS: Eligible studies from MEDLINE, Google Scholar, Cochrane Library, Clinical key, EBSCO publishing and Ovid, which had reported cardiovascular adverse events potentially caused by regorafenib were absorbed. Data of clinical characteristics and cardiovascular events including hypertension, hemorrhage, thrombosis, and heart failure were extracted from selected literatures for the final analysis. Pooled analysis of cardiovascular adverse events was developed by relative risks (RRs) and corresponding 95% confidence intervals (CIs) with software STATA 13.0 and RevMan 5.3. RESULTS: Thirty studies including 3813 patients were fit into analysis. The incidences of cardiovascular events of all-grade were: hypertension, 36.8% (95% CI, 29.8%-43.8%), hemorrhage, 8.6% (95% CI, 3.2%-14%), thrombosis, 1.4% (95% CI, 0.1%-2.8%), and heart failure, 2.9% (95% CI, 0.3% 5.6%). The incidences of cardiovascular events of high-grade were: hypertension, 9.9% (95% CI, 7.4%-12.4%), hemorrhage, 1.2% (95% CI, 0.3%-2.2%), thrombosis, 1.6% (95% CI, 0.2%-3.4%), and heart failure, 2.9% (95% CI, 0.3%-5.6%). The RRs and their 95% CIs of all-grade cardiovascular events among patients treated with regorafenib were: hypertension, 4.10 (95% CI, 3.07-5.46; P < .00001), hemorrhage, 2.71 (95% CI, 1.45-5.08; P = .002), thrombosis, 1.27 (95% CI, 0.49-3.27; P = .62), and heart failure, 0.79 (95% CI, 0.16-3.94; P = .77). The RRs and their 95% CIs of high-grade cardiovascular events among patients treated with regorafenib were: hypertension, 5.82 (95% CI, 3.46-9.78; P < .00001), hemorrhage, 0.90 (95% CI, 0.50-1.61; P = .72), thrombosis, 1.28 (95% CI, 0.48-3.41; P = .62), and heart failure, 1.15 (95% CI, 0.23-5.69; P = .86), respectively. CONCLUSION: The present meta-analysis has demonstrated that regorafenib is associated with an increasing risk of hypertension at all-grade and high-grade, as well as hemorrhage at all grade. Adequate awareness of cardiovascular adverse events of regorafenib should be established for clinicians. PMID- 30313067 TI - Phantom limb syndrome induced by combined spinal and epidural anesthesia in patients undergoing elective open gynecological surgery. AB - BACKGROUND: During regional anesthesia, including combined spinal and epidural anesthesia (CSEA), patients may develop a perceptual alteration of limb position known as phantom limb syndrome (PLS). We aimed to identify factors that influence the PLS onset, to explore whether PLS predisposes to other postoperative symptoms, and to document the relationship between PLS and sensorimotor impairment during recovery. METHODS: Psychological questionnaires for anxiety and depression were completed beforehand, then multimodal tests of sensory and motor function, especially tests of proprioception, were performed regularly afterward. Two hundred participants undergoing elective gynecological surgery under CSEA reported their experiences of PLS and other symptoms using Likert rating scales. RESULTS: Prolonged preoperative fasting (odds ratio (OR) 2.34; 95% confidence intervals (CI) 1.21-4.52), and surgical history (OR 2.56; 95% CI 1.16-5.62) predisposed to PLS, but patients with more extensive anesthetic histories may be at lower risk (OR 0.57; 95% CI 0.31-1.08). Furthermore, significant correlations were observed between the recovery from PLS and the perception of joint movement within the deafferented area (R = 0.82, P < .01) and motor functions (R = 0.68). PLS increases the chance of experiencing postoperative fatigue, physical discomfort, and emotional upset. CONCLUSION: This study is the first to have identified the risk factors for PLS, assessed the relationship between PLS and postoperative sensorimotor impairment, and its influence on postoperative complications. PMID- 30313068 TI - The efficacy and safety of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis. AB - BACKGROUND: Several randomized controlled trials (RCTs) have been investigated the benefits of soluble guanylate cyclase (sGC) stimulators in the treatment of heart failure, but a comprehensive evaluation is lacking. We performed a meta analysis to evaluate the efficacy and safety of oral sGC stimulators (vericiguat and riociguat) in patients with heart failure. METHODS: Studies were searched and screened in PubMed, Embase, and Cochrane Library. Eligible RCTs were included that reported mortality, the change of EuroQol Group 5-Dmensional Self-report Questionnaire (EQ-5D) US index, N-terminal pro-B-type natriuretic peptide (NT proBNP), or serious adverse events (SAEs). Relative risk or weight mean difference (WMD) was estimated using fixed effect model or random effect model. Analysis of sensitivity and publication bias was conducted. RESULTS: Five trials with a total of 1200 patients were included. sGC stimulators had no impact on the mortality (1.25; 95% confidence interval 0.50-3.11) and significantly improved EQ 5D US index (0.04; 95% confidence interval 0.020-0.05). Furthermore, in comparison with control group, NT-proBNP was statistically decreased in riociguat group (-0.78; 95% confidence interval -1.01 to -0.47), but not in vericiguat group (0.04, 95% confidence interval -0.18 to 0.25). There were not obverse differences in SAEs between sGC stimulators and control groups (0.90; 95% confidence interval 0.72-1.12). CONCLUSION: Our meta-analysis suggests that sGC stimulators could improve the quality of life in patients with heart failure with good tolerance and safety, but their long-term benefits need to be observed in the future. sGC stimulators are likely to be promising add-on strategies for the treatment of heart failure. PMID- 30313069 TI - Analysis of the behavior change mechanism of township hospital health workers in Hubei Province, China: A cross-sectional study. AB - This study aims to analyze the behavior changes of health workers in township hospitals by exploring their individual service, health information utilization, and health information exchange before and after intervention.A cross-sectional survey was conducted from September, 2016 to December, 2016 in Qianjiang city, Hubei Province, China. A total of 432 township hospital health workers were investigated from 12 township hospitals. t test and chi-square test were adopted in the difference analysis to compare the behavior changes and factors of the control and intervention groups before and after intervention. t test and U test were used to analyze the behaviors and the key impact factors of health workers in township hospitals. The hypothesis test of the behavior changes in the township hospitals were analyzed using the partial least squares (PLS) method.No significant difference was observed between the control and intervention groups of health workers in township hospitals. Significant differences were observed in the behavior attitude (BA), perceived behavior control (PBC), behavior intention (BI), and behaviors of information utilization and exchange in the intervention group. A significant difference was observed in the indicators of subjective norm (SN), BI, and behaviors with respect to information exchange. A large increment was observed in the intervention group. Based on results of PLS, the individual service, health information utilization, and health information exchange established relationships with BA, SN, PBC, and BI to a certain degree.A cause and effect relationship can be observed among BA, SN, PBC, BI, and behaviors of health workers in the township hospitals. BI can promote behavior changes among township hospital health workers. Moreover, different behaviors are demonstrated by different people because of BA, SN, PBC, and BI. The results of this study can contribute to improving the feasibility, pertinence, and effects of health service, and can serve as the guide in understanding health workers' behaviors. PMID- 30313070 TI - Arterial occlusion after total knee arthroplasty despite minimal invasive technique in aneurysm at popliteal artery: Case report. AB - RATIONALE: Arterial occlusion, a rare condition after total knee arthroplasty (TKA), may cause fatal outcomes if not treated on time. We report a case of arterial occlusion after undergoing navigated TKA with no tourniquet use, in a patient at high risk of postoperative arterial occlusion due to the patient's ipsilateral popliteal artery aneurysm. PATIENTS CONCERNS: A 79-year-old man presented with several years of left knee joint pain. Nine years earlier, the patient underwent vascular graft surgery on his right knee due to occlusion in his right popliteal artery. On physical examination, the patient showed antalgic gait due to the pain in his left knee. DIAGNOSIS: Preoperative examination for arterial blood flow demonstrated reduced blood flow of the patient's right dorsalis pedis and right posterior tibial artery, with ankle-brachial index of 0.41 and 0.41. The blood flow of the left dorsalis pedis and left posterior tibial artery remained normal, with ankle-brachial index of 1.16 and 1.10. Femoral artery computed tomography (CT) scan revealed left popliteal artery aneurysm with mural thrombus, with occlusion of the left anterior tibial artery (ATA). The left peroneal artery and posterior tibial artery remained patent. INTERVENTION: Total knee arthroplasty using navigation without the use of tourniquet. OUTCOMES: Occlusion of the posterior tibial artery trunk was revealed with Doppler ultrasound and femoral artery CT several hours postoperatively, and the patient underwent thromboembolectomy at the very next day. LESSONS: In patients at high risk of postoperative arterial occlusion, such as patients with arterial aneurysm with mural thrombus, arterial occlusion may occur despite surgical techniques with minimal damage to the vessels. We found out that diseases of the artery might be a contraindication for TKA, and when TKA may be performed in high-risk patients, close cooperation with a vascular surgeon is a must. PMID- 30313071 TI - Risk factors of transient global amnesia: Three case reports. AB - INTRODUCTION: Transient global amnesia (TGA) is characterized by a sudden onset of anterograde and retrograde amnesia, sometimes associated with mild subclinical neuropsychological deficits and vegetative symptoms, lasting for days after the episode. Migraine history, cardiovascular risk factors, and emotional stress are considered possible risk factors. TGA usually occurs during the seventh decade of life, that is, when risk factors and concomitant pathologies have a higher incidence. CASE PRESENTATION: We report 3 cases of TGA triggered by different causes (cardiovascular risk factors, emotional stress, and orgasm) with an unusual young onset (patient 1 was a 40-year-old woman, patient 2 was a 21-year old woman, and patient 3 a 32-year-old man). The patients underwent neuroimaging and cardiovascular examination, and neuropsychological evaluation, without important abnormalities. TGA completely recovery within 1 to 7 days. CONCLUSIONS: The occurrence of different precipitating events and accurate questioning (in the absence of head trauma) seem to be key features in making the diagnosis of TGA, besides a complete neuropsychiatric and cardiovascular assessment. PMID- 30313072 TI - Diagnostic value of ultrasonography in synovitis-acne-pustulosis-hyperostosis osteitis (SAPHO) syndrome: A case report. AB - RATIONALE: Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a rare condition that affects the skin, bones, and joints. Diagnosis of SAPHO syndrome is established based on clinical manifestations and imaging features on radiography or magnetic resonance imaging. PATIENT CONCERNS: We report a 44-year old male with a 20-year history of pustulosis who presented with pain in the lower extremities. Plain radiography demonstrated hyperostosis with subperiosteal erosions in the right tibia. Magnetic resonance imaging and computed tomography showed inflammatory accumulation, whereas musculoskeletal ultrasonography clearly depicted a periosteal reaction, osteitis, and enthesitis with abnormal blood flow in the surface of the right tibia. DIAGNOSES: A diagnosis of SAPHO syndrome was made. INTERVENTIONS: The patient was treated with combination therapy comprising prednisolone, methotrexate, and infliximab, which resulted in clinical improvement. OUTCOMES: The elevated levels of C-reactive protein and matrix metalloproteinase-3 normalized, and the abnormal ultrasonographic findings disappeared. LESSONS: The present case report demonstrates that multiple imaging modalities are important for the definitive diagnosis of SAPHO syndrome. Ultrasonography might be a useful tool for evaluating local musculoskeletal inflammation in patients with SAPHO syndrome. PMID- 30313073 TI - Thyroplasty in unilateral vocal fold paresis with coexisting hereditary hemorrhagic telenagiectasia: A case report. AB - RATIONALE: The coincidence of an idiopathic unilateral vocal fold paresis and hereditary hemorrhagic telenagiectasia (HHT) is extremely rare and has not been described in the available literature yet. PATIENTS CONCERNS: A 55-year-old female was admitted to hospital due to acute onset of hoarseness, voice fatigue, and effort dyspnea. In the past, the patient was diagnosed with HHT and on admission presented characteristic vascular lesions in the oral cavity. She reported also experiencing a moderate epistaxis at least once per month. DIAGNOSES: The otolaryngological examination (fiberolaryngoscopy, phoniatric examination) revealed unchanged mobility and morphology of the right vocal fold and paresis of the left vocal fold in intermediate position. Computed tomography and magnetic resonance imaging of head, neck, and chest were inconclusive and showed no pathologic findings. INTERVENTIONS: The unilateral paresis was treated for 12 months as idiopathic, with extensive rehabilitation. However, no improvement was observed. As a patient suffering from HHT is a challenge for anesthesiologists in terms of general anesthesia, the decision to perform type I thyroplasty (medialization) in local anesthesia was made. OUTCOMES: There were no complications intraoperatively or in postoperative period. The implemented treatment was successful, as the voice quality improved both in perceptual evaluation (GRBAS scale) and acoustic analysis (F0, jitter, shimmer, NHR). LESSONS: A routine surgical treatment in patients with HHT is a challenge. However, in this case, it was uneventful and successful, thus it can be recommended in other patients with similar background. PMID- 30313074 TI - Cutaneous paresthesia after internal plate fixation of clavicle fractures and underlying anatomical observations. AB - To assess the clinical and anatomical causes of cutaneous paresthesia after internal fixation of clavicle fractures.This study included 135 patients who underwent internal fixation of clavicle fractures from May 2013 to June 2016 at the First and Second Affiliated Hospital of Guangxi Medical University. The incidence of postoperative supraclavicular nerve injury, the duration of numbness, and improvements after plate removal were retrospectively analyzed. Seven human cadaver specimens were subsequently dissected to analyze the supraclavicular nerve and its relationship to numbness.Of the 135 patients who underwent internal fixation of clavicle fractures, 26 (19.3%) experienced postoperative cutaneous paresthesia, with 22 (16.3%) and 4 (2.8%) experiencing numbness and pain, respectively. The most intense numbness occurred during the first operative month. Of the 22 patients with numbness, 1 (4.5%), 1 (4.5%), and 20 (90.1%) patients reported mild, moderate, and severe numbness, respectively. Two patients described increased awareness of numbness when in contact with clothes, 2 were psychologically affected by numbness, and 20 (90.1%) reported reduced severity of numbness over time. At the last follow-up, numbness was found to persist in 2 (1.5%) patients. None of the patients was bothered by numbness. Cadaver dissection showed that the supraclavicular nerve emerged from the 1/2 posterior edge of the cervical sternocleidomastoid muscle and subsequently divided into 3 branches, with the lateral branch 2.26 +/- 1.17 cm from the lateral margin of the acromion, the middle branch near the mid-clavicle, and the medial branch 2.03 +/- 0.85 cm from the sternal lateral margin.Cutaneous paresthesia is common following internal fixation of the clavicle. Anatomic analysis showed that the nerve could be easily injured during clavicle operation. Numbness improved in most patients, but persisted for up to 2 years and was even permanent in a few. Most patients considered numbness as an insignificant factor in their daily lives. PMID- 30313075 TI - Efficacy and safety of nicotinamide on phosphorus metabolism in hemodialysis patients: A systematic review and meta-analysis. AB - BACKGROUND: Recent evidence has shown that nicotinamide treatment may have an impact on phosphorus metabolism in hemodialysis patients. Nevertheless, the treatment remains controversial. This study aimed to precisely estimate the efficacy and safety of nicotinamide on phosphorus, calcium and iPTH in hemodialysis patients. METHODS: We searched numerous information sources regarding randomized controlled trials (RCTs) of nicotinamide treatment in hemodialysis patients, including PubMed, EMBASE, and the Cochrane Library. RESULTS: Nine relevant studies (n = 428) were included in the meta-analysis. Meta analysis showed that levels of serum phosphorus (SMD -1.06; 95% CI, -1.27 to 0.85, P < .001), parathyroid hormone (SMD -1.09; 95% CI, -1.49 to -0.70, P < .001), and calcium-phosphorus (SMD -0.65; 95% CI, -0.97 to -0.34, P < .001) in the nicotinamide group were significantly lower than those of the control group. There was no significant difference in the levels of serum calcium (SMD 0.08; 95% CI, -0.15 to 0.30, P = .51) between the groups. The meta-analysis showed that the nicotinamide group had a significantly higher risk of adverse events (OR 3.99; 95% CI, 1.94-8.23, P < .001) than did the control group, especially for thrombocytopenia (OR 49.00; 95% CI, 2.68-897.36, P = .009). However, no serious adverse reactions were observed. There was no significant difference in the incidence of withdrawal (OR 3.51; 95% CI, 0.49-25.00, P = .21) between the groups. CONCLUSION: Evidence to date clearly indicates that nicotinamide is safe and effective for improving phosphorus metabolism in hemodialysis patients. However, nicotinamide probably causes thrombocytopenia. Further large-sample size, high-quality RCTs are needed. PMID- 30313076 TI - Development of a survey form through Delphi study about adverse events associated with the miniscalpel needle, for application in prospective observational studies regarding safety of miniscalpel needles: Study protocol. AB - BACKGROUND: Despite the wide usage of miniscalpel-needles (MSNs), information about MSN treatment-related adverse events (AEs) is insufficient. As the definition of AE might vary among physicians, without an exact definition for pain and hemorrhage, it is difficult to provide accurate information about AEs in MSN treatment to physicians, researchers, and patients. The aim of our study is to reach a consensus about the items and definitions of AEs that should be included in the survey form for prospective observational multicenter studies to record MSN treatment-related AEs. We will especially focus on obtaining a consensus on the definition of pain and hemorrhage caused by MSN treatment. METHODS: Our study protocol is composed of 6 steps. First, we will identify the aim of the study. Next, we will conduct a systematic review to investigate MSN treatment-related AEs reported till date in Korea. Third, we will conduct a pilot observational prospective single-center study on AEs in MSN treatment. We will develop a standardized case report form to record MSN treatment-related AEs, including the causality, severity, and details of the MSN procedure at every site. Next, based on the pilot study, the Delphi study questionnaire will be developed by a panel composed of 13 physicians. The Delphi study will have 4 rounds with open questions and 4-point Likert-scale closed questions. Through these rounds, we will develop a consensus about the items and definitions of AEs that should be included in the survey form for future multicenter studies about MSN treatment-related AEs. Following this, a face-to-face consensus meeting will be held for a final agreement of survey form. The final survey form will then be approved by the related academic society for dissemination. DISCUSSION: The aim of this protocol is to develop a survey form for future prospective observational multicenter studies on MSN treatment-related AEs. This protocol will present the research methodology for developing a survey form, which will improve consistency and reliability between MSN treatment studies. We believe that this protocol can evaluate the safety of MSN treatment. TRIAL REGISTRATION: Clinical Research Information Service: KCT0002849. PMID- 30313077 TI - Gross motor proficiency and intellectual functioning: A comparison among children with Down syndrome, children with borderline intellectual functioning, and typically developing children. AB - This cross-sectional study examines differences in gross motor proficiency as a function of different intellectual functioning profiles. Two motor areas have been investigated as being equally essential to gross motor functions in every day life: locomotion and object control.It aims to compare gross motor skills endorsed by children with Down syndrome (DS), children with borderline intellectual functioning (BIF), and typically developing children (TDC).Group 1 was composed of 18 children with DS (chronological age = 8.22), group 2 was composed of 18 children with BIF (chronological age = 9.32), and group 3 was composed of 18 children with typical development (TD) (chronological age = 9.28).Gross motor skills were measured through the test of gross motor development (TGMD-Test) composed of locomotion and object control tasks.Children with DS showed worse gross motor skills compared with children with BIF and typically developing children by underscoring both on all locomotion (e.g., walking, running, hopping, galloping, jumping, sliding, and leaping) and all object control tasks (e.g., throwing, catching, striking, bouncing, kicking, pulling, and pushing).In DS group strengths were found on run and slide skills, in BIF group strengths were on run, long jump and slide skills and in TDC group strengths were on run and slide skills. For all of the 3 groups the locomotor worst performed task was jump forward with arm swing.Findings suggest implications for further practice to develop evidence-based exercise programs aimed to rehabilitate gross motor skills through the regular participation in structured exercise activities. PMID- 30313078 TI - Development in sunburn 2007-2015 and skin cancer projections 2007-2040 of campaign results in the Danish population. AB - Exposure to ultraviolet radiation is the main risk factor for skin cancer. Denmark has one of the highest incidences of skin cancer in the world. In 2007, a long-term sun safety campaign was launched in Denmark. We have evaluated the effects on prevalence of sunburn and modeled the effects on future melanoma incidence.Sunburn was evaluated by annual cross-sectional surveys representative for the Danish population on age, gender, and region. During 2007-2015, survey data were collected for 33.315 Danes. Cutaneous Melanoma incidences were modeled in the Prevent program, using population projections, historic incidence, sunburn exposure, and relative risk of sunburn on melanoma.The prevalence of sunburn in Denmark was reduced with 1% annually during 2007 to 2015. The campaign is estimated to have reduced the number of skin cancer cases with 664 annually in 2040 and 14.326 totally during 2007 to 2040. If the campaign was terminated in 2015 and sunburn rates return to precampaign level there would be no annual reduction in 2040 while in total the reduction would be 4.024 cases for 2007 to 2040. A continuous campaign until 2040 would yield annual reductions of 2.121 cases by 2040 and a total of 29.729 cases for the entire period.We have showed the value of prevention and the value of long-term planning in prevention campaigning. Sunburn use was reduced significantly during 2007-2015 and further reductions are possible. Consequently, we predict significant fewer skin cancer cases as anticipated. PMID- 30313079 TI - Diagnostic challenges in T-lymphoblastic lymphoma, early T-cell precursor acute lymphoblastic leukemia or mixed phenotype acute leukemia: A case report. AB - RATIONALE: The diagnosis of hematological malignancies depends on laboratory analysis and often requires multiple experimental methods to judge, otherwise misdiagnosis is apt to happen. Lymph node biopsy immunohistochemistry (IHC) for T lymphoblastic lymphoma (T-LBL) requires the establishment of antibody set screening. For identifying T-LBL and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) by lymph node biopsy and IHC, WHO has not yet proposed a better IHC antibody combination. PATIENT CONCERNS: Here we reported 1 case with tortuous diagnosis experience. Initially, a 51-year-old man was diagnosed as T LBL by lymph node biopsy, but in another hospital acute myeloid leukemia (AML) was confirmed by bone marrow puncture. Finally, it was diagnosed as mixed phenotype acute leukemia (MPAL) through our comprehensive evaluation including bone marrow cell morphology, cytochemical staining and flow cytometry analysis. Importantly, the experience about differential diagnosis and our appreciation among the T-LBL, ETP-ALL and MPAL was discussed to enlighten readers. DIAGNOSES: The patient was diagnosed with mixed phenotype acute leukemia (T+My)-NOS. INTERVENTIONS: The patient received 1 cycle of VDCLP scheme treatment firstly. The effect of chemotherapy is satisfactory, and then he received continuous treatment and was currently in good condition. OUTCOMES: This patient is alive at present. The follow-up period has been 1 year. LESSONS: For the diagnosis of T LBL, the molecular markers of the myeloid and lymphoid tissues need to be included, such as CD117, CD33, Lys and MPO. The bone marrow puncture also needs to be conducted to distinguish T-LBL and T-ALL. Secondly, to identify ETP-ALL and MPAL, bone marrow cell morphology, cytochemical staining as well as flow cytometric analysis were needed to make a clear diagnosis. It is recommended that at least CD8, CD1a, Lys and MPO should be included in the panel to identify ETP ALL. PMID- 30313080 TI - Granulomatous lymphadenitis mimicking metastatic lymphadenopathy in the neck after lymphatic embolization of chyle leakage: A case report. AB - RATIONALE: Lymphatic embolization is a minimally invasive treatment option for managing chyle leakage after nodal dissection in the neck. After the procedure, the embolic material may cause foreign body granulomatous lymphadenitis and can be a diagnostic challenge for radiologists because of sonographic similarity to metastatic lymph node. Herein, we describe a clinical case of granulomatous lymphadenitis due to embolic material mimicking nodal metastasis detected on ultrasonography (US) with cytologic findings in a patient with thyroid cancer who underwent lymphatic embolization to treat chyle leakage after total thyroidectomy and neck dissection. We also review the relevant literature regarding this disease with technical background of the procedure and suggest the importance of clinical suspicion in diagnosing the granulomatous lymphadenitis in patients with a history of lymphatic embolization. PATIENT CONCERNS: A 40-year-old man who underwent total thyroidectomy and bilateral modified radical neck dissection due to papillary thyroid carcinoma had suspicious cervical lymph node on US after lymphatic embolization of chyle leakage. DIAGNOSES: The suspicious cervical lymph node proved to be foreign body granulomatous lymphadenitis due to embolic material by US-guided fine-needle aspiration. INTERVENTIONS: The patient did not undergone additional surgery because the pathologic cervical lymph node was confirmed to be foreign body granulomatous lymphadenitis. OUTCOMES: The patient is being followed up regularly at the outpatient department. LESSONS: Clinical awareness of the technical background of lymphatic embolization and possible sonographic features of granulomatous lymphadenitis is important for an accurate diagnosis and the appropriate management in patients who underwent lymphatic embolization. PMID- 30313081 TI - Bilateral costotransverse and local continuous chemotherapy approach for debridement, fixation, and fusion of contiguous multisegmental thoracic spinal tuberculosis: A retrospective study. AB - The study aims to evaluate the clinical efficacy of bilateral costotransverse debridement, transpedicular fixation, fusion, and local continuous chemotherapy in 20 patients of contiguous multisegmental thoracic spinal tuberculosis (CMTSTB). We analyzed 20 patients with contiguous thoracic spinal tuberculosis (TB) who underwent surgery via bilateral costotransverse debridement, fusion, posterior instrumentation, and postural drainage with local continuous chemotherapy. The clinical outcomes were evaluated in terms of kyphotic angle, bone fusion, neurologic status, erythrocyte sedimentation rate (ESR), and intraoperative and postoperative complications. All of the patients (8M/12F), averaged 45.8 +/- 15.6 years old. The mean duration of postoperative follow-up was 30.7 +/- 4.0 months. There was no recurrent TB infection. The values of ESR returned to normal levels at final follow-up. All patients got bony fusion within 8.1 +/- 2.3 months after surgery. The average preoperative Cobb angle was 39.9 degrees +/- 8.6 degrees , correcting to 9.8 degrees +/- 2.3 degrees postoperatively and 10.8 degrees +/- 2.3 degrees at the last follow-up. All patients with neurological deficit had dramatic improvement at the final follow up. Our results showed that bilateral costotransverse surgery and local continuous chemotherapy are feasible and effective procedures in the treatment of CMTSTB. The approach can provide radical debridement, rebuild spinal stability, and cure TB. PMID- 30313082 TI - Association of MMP-8 rs2012390 and rs11225394 polymorphisms with osteonecrosis of the femoral head risks: Evidence from a meta-analysis. AB - BACKGROUND: The association of MMP-8 rs2012390 and rs11225394 polymorphisms with osteonecrosis of the femoral head (ONFH) risks was investigated in several studies with conflicting results. We performed the meta-analysis to evaluate the association between them. METHODS: Potentially relevant literatures were searched from the electronic databases of PubMed, Web of Science, and Cochrane Library. All databases were searched up to May 6, 2018. The strength of associations of the MMP-8 rs2012390 and rs11225394 polymorphisms with ONFH risk was assessed by crude odds ratios (ORs) with their 95% confidence intervals (CIs) under different genetic models. RESULTS: A total of 1469 cases diagnosed with ONFH and 1211 healthy controls were included in the current meta-analysis. A remarkable association between rs11225394 in the MMP-8 gene and an increased risk of ONFH was found (allele model: OR = 1.33, 95% CI = 1.09-1.61, P = .005; heterozygote model: OR = 1.39, 95% CI = 1.13-1.71, P = .002; dominant model: OR = 1.40, 95% CI = 1.14-1.73, P = .002, respectively). Meanwhile, a significant association between MMP-8 rs2012390 and the decreased risk of ONFH was found in heterozygote model (OR = 0.63, 95% CI = 0.51-0.77, P < .00001). CONCLUSION: The meta-analysis results showed a remarkable association between rs11225394 in MMP-8 gene and an increased risk of ONFH and a significant association between MMP-8 rs2012390 and the decreased risk of ONFH. PMID- 30313083 TI - Bone mineral loss and cognitive impairment: The PRESENT project. AB - Low bone mineral density (BMD) is correlated with Alzheimer's disease and its severity, but the association remains unclear in adults (>=50 years) without a history of stroke or dementia.We assessed BMD and cognitive function using the Mini-Mental Status Examination (MMSE) in 650 stroke- and dementia-free subjects (>=50 years) who were recruited for an early health check-up program between January 2009 and December 2010.The mean age was 62.9 +/- 8.0 years and mean MMSE score was 27.6 +/- 3.6. A total of 361 subjects had reduced BMD: 197 (30.3%) had osteopenia and 154 (23.6%) had osteoporosis, based on criteria of world health organization. A total of 5.4% of the male subjects had osteoporosis, versus 19.8% of the female subjects. After adjusting for age, sex, education, and other possible confounding factors such as hypertension, diabetes mellitus, and smoking, the estimated odds ratio for cognitive impairment was 1.72 for the osteopenia group (95% confidence interval [CI] 1.09-2.14, P = .019) and 2.81 for the osteoporosis group (95% CI 1.78-4.45, P < .001).Low BMD is correlated with cognitive impairment in community-dwelling adults aged 50 years and above without any medical history of stroke or dementia, especially in women. A community based, early life, preventive osteoporosis education campaign might decrease the incidence of dementia. PMID- 30313084 TI - A model predicting short-term mortality in patients with advanced liver cirrhosis and concomitant infection. AB - : Infection is a common cause of death in patients with advanced cirrhosis. We aimed to develop a predictive model in Child-Turcotte-Pugh (CTP) class C cirrhotics hospitalized with infection for optimizing treatment and improving outcomes.Clinical information was retrospectively abstracted from 244 patients at Tianjin Third Central Hospital, China (cohort 1). Factors associated with mortality were determined using logistic regression. The model for predicting 90 day mortality was then constructed by decision tree analysis. The model was further validated in 91 patients at Mayo Clinic, Rochester, MN (cohort 2) and 82 patients at Seoul St. Mary's Hospital, Korea (cohort 3). The predictive performance of the model was compared with that of the CTP, model for end-stage liver disease (MELD), MELD-Na, Chronic Liver Failure-Sequential Organ Failure Assessment, and the North American consortium for the Study of End-stage Liver Disease (NACSELD) models.The 3-month mortality was 58%, 58%, and 54% in cohort 1, 2, and 3, respectively. In cohort 1, respiratory failure, renal failure, international normalized ratio, total bilirubin, and neutrophil percentage were determinants of 3-month mortality, with odds ratios of 16.6, 3.3, 2.0, 1.1, and 1.03, respectively (P < .05). These parameters were incorporated into the decision tree model, yielding area under receiver operating characteristic (AUROC) of 0.804. The model had excellent reproducibility in the U.S. (AUROC 0.808) and Korea cohort (AUROC 0.809). The proposed model has the highest AUROC and best Youden index of 0.488 and greatest overall correctness of 75%, compared with other models evaluated.The proposed model reliably predicts survival of advanced cirrhotics with infection in both Asian and U.S. POPULATIONS: PMID- 30313085 TI - Impact of the pay-for-performance program on lower extremity amputations in patients with diabetes in Taiwan. AB - Patients with diabetes are at a high risk of lower extremity amputations and may have a reduced life expectancy. Taiwan has implemented a diabetes pay-for performance (P4P) program providing team care to improve the control of disease and avoid subsequent complications. Few studies investigated the effects of adopting a nationalized policy to decrease amputation risk in diabetes previously. Our study aimed to analyze the impact of the P4P programs on the incidence of lower extremity amputations in Taiwanese patients with diabetes.This was a population-based cohort study using the Taiwan National Health Insurance Research Database (which provided coverage for 98% of the total population in Taiwan) from 1998 to 2007. Patients with diabetes were identified based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnostic codes. We linked procedure codes to inpatient claims to identify patients hospitalized for nontraumatic lower extremity amputations.A total of 9738 patients with diabetes with amputations were enrolled (mean age +/- standard deviation: 64.4 +/- 14.5 years; men: 63.9%). The incidence of nontraumatic diabetic lower extremity amputations decreased over the time period studied (3.79-2.27 per 1000 persons with diabetes). Based on the Cox proportional hazard regression model, male sex (hazard ratio: 1.83, 95% confidence interval [CI] 1.76-1.92), older age, and low socioeconomic status significantly interact with diabetes with respect to the risks of amputation. Patients who did not join the P4P program for diabetes care had a 3.46-fold higher risk of amputation compared with those who joined (95% CI 3.19-3.76).The amputation rate in Taiwanese diabetic patients decreased over the time period observed. Diabetes in patients with low socioeconomic status is associated with an increased risk of amputations. Our findings suggested that in addition to medical interventions and self-management educations, formulate and implement of medical policies, such as P4P program, might have a significant effect on decreasing the diabetes-related amputation rate. PMID- 30313086 TI - A Morel-Lavallee lesion of the proximal calf in a young trauma patient: A case report. AB - RATIONALE: The Morel-Lavallee lesion (MLL) is a closed degloving injury developing when shear force acts between the muscle fascia and the subcutaneous layer. MLLs develop principally in the trochanteric area or the pelvis; lesions in the proximal calf are rare. Acute lesions can be treated conservatively, but chronic lesions are best treated surgically because of a high rate of recurrence. To the best of our knowledge, this is a rare case of successful treatment of an MLL in the proximal calf associated with tibio-fibular shaft fracture. PATIENT CONCERNS: A 14-year-old male visited our emergency room after having been hit by a car. He exhibited direct trauma to the right lower leg and a distal tibio fibular shaft fracture without an open wound. He underwent surgery to treat the fracture, which was immobilized with splint for 2 weeks post-operatively. At the 3-month follow-up, he complained of a painless, mobile, soft tissue mass in the posteromedial aspect of the proximal calf. Blood circulation was normal and we found no neurological abnormality in the distal region of the lower leg. DIAGNOSIS: A plain radiograph of the right lower leg revealed a proximal, round, radiopaque soft tissue lesion. Ultrasonography revealed a homogeneous, hypoechoic fluid collection. Magnetic resonance imaging revealed fluid of homogeneous signal intensity between the subcutaneous layer and the underlying fascia of the gastrocnemius muscle. INTERVENTIONS: Percutaneous drainage and intralesional steroid injection were performed on several occasions, but the lesion recurred every time. After 5 aspirations, we scheduled surgery. We radically excised the mass and sutured the superficial to the deep fascia to prevent shearing at the surgical plane. OUTCOMES: No complication or recurrence was noted at the 1-year follow-up. LESSON: An MLL in the proximal calf is an uncommon post-traumatic lesion and care must be taken to avoid misdiagnosis. If an MLL is suspected after imaging studies and physical examination, it is important to determine whether the lesion is acute or chronic and to plan treatment accordingly. Appropriate treatment should be given to patients to improve outcomes. PMID- 30313087 TI - Three-dimensional scan of the uterine cavity of infertile women before assisted reproductive technology use. AB - The primary objective was to assess the utility of routine 3-dimensional (3D) ultrasound in the evaluation of infertile women and to estimate the prevalence of uterine anomalies before the use of assisted reproductive technology (ART), using the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy classification system. A second objective was to assess the effect of uterine anomalies on the pregnancy rate in patients who underwent assisted reproductive techniques.We retrospectively studied 668 patients treated in the Department Obstetrics Gynecology and Neonatology "Sf Ioan" Clinical Emergency Hospital and in the Department of Medical and Surgical Specialties, Faculty of Medicine "'Transilvania" University of Brasov between July 2016 and February 2017 for subfertility. Patients were examined using 2 dimensional (2D) and 3-dimensional (3D) transvaginal ultrasound. Mullerian duct anomalies were present in 6.13% of patients, with the most common anomaly being a dysmorphic uterus (class U1c in 42.68% of patients), 17 patients (20.73%) with incompletely septate uterus (class U2a), 12 patients (14.63%) with a completely septate uterus (classU2b), 8 patients (9.75%) with a partly bicorporeal uterus (classU3a), and 6 patients (7.31%) with a completely bicorporeal uterus (class U3b). Only 1 (1.21%) patient had an aplastic uterus without a rudimentary cavity (class U5b). The pregnancy rate in the presence of uterine anomalies was 55% and the pregnancy rate in control group patients was 39.8%. The incidence of pregnancy in the group with uterine anomalies was statistically similar with the control group of normal uterus (P < .11). For ongoing pregnancy rate and live birth rate, our data indicated a slightly elevated rate for both of those indexes in the anomalies group. The incidence of miscarriage in the presence of uterine anomalies was 24% and 6.7% in the control group, which is statistically significant (P = .05).3D ultrasound evaluation of the uterus should be considered before ART in order to make an accurate diagnosis of the uterine congenital anomaly and improve ART results. PMID- 30313088 TI - Correlation between normal range of serum alanine aminotransferase level and metabolic syndrome: A community-based study. AB - Serum alanine aminotransferase (ALT) is a biomarker of hepatocyte damage. However, the relationship between normal range of serum ALT level and metabolic syndrome (MetS) has not been completely understood. This study aimed to investigate the correlation between normal range of serum ALT level and MetS.A total of 2453 participants from the Beijing Community Pre-Diabetes study were enrolled. Multiple linear regression analysis was performed to calculate the regression coefficient. Normal serum ALT levels were divided into quartiles. Logistic regression model was used to compare the relative risk of MetS, and the receiver operating characteristic (ROC) curve to calculate the optimal ALT boundary value for predicting MetS.The frequency of MetS increased with the ALT level within the normal range. Compared with the first group, the risk of MetS was greater in the other quartiles of ALT level in males, the difference was significant for the fourth group. For females, the risk of MetS increased with ALT level within the normal range as well, with all differences showing statistical significance. The optimal ALT boundary value of the ROC curve for males and females was 24.5 and 14.5 U/L, respectively.ALT was related to metabolic factors and used as one of the indicators to assess the morbidity risk of metabolic diseases. PMID- 30313089 TI - Comparative study of MR mTI-ASL and DSC-PWI in evaluating cerebral hemodynamics of patients with Moyamoya disease. AB - The aim of this study was to explore the correlation between multi-inversion time arterial spin labeling (mTI-ASL) and dynamic susceptibility contrast-enhanced perfusion weighted imaging (DSC-PWI) in assessment of hemodynamics of patients with Moyamoya disease (MMD).In this study, 24 MMD patients and 21 healthy subjects were enrolled between June 2017 and December 2017. The images of mTI-ASL and DSC-PWI in the week before revascularization surgery were retrospectively analyzed. The parameters of cerebral blood flow (CBF), time to peak (TTP), and bolus arrival time (BAT) were measured in regions of interest (ROIs) of lateral middle cerebral artery (MCA) territories, basal ganglia (BG), and cerebellum, and relative perfusion parameters (rCBF-ASL, rBAT-ASL, rCBF-DSC, and rTTP-DSC) were calculated by dividing by cerebellum value. One-way analysis of variance and Student-Newman-Keuls tests were performed to compare rCBF-ASL and rCBF-DSC in the MMD group and the control group. Unpaired t test was used to compare rBAT-ASL and rTTP-DSC in the MMD group and the control group. And we assessed the correlation between rCBF-ASL and rCBF-DSC and between rBAT-ASL and rTTP-DSC using Pearson correlation analysis.All the relative parameters were significantly different between the MMD group and the control group (all P<.05). Meanwhile, there was significant difference between rCBF-ASL and rCBF-DSC (P<.05), and there was strong correlation between rCBF-ASL and rCBF-DSC (r = 0.839, P<.001), and moderate correlation between rBAT-ASL and rTTP-DSC (r = 0.519, P<.001).Both mTI ASL and DSC-PWI could be used to assess perfusion state in MMD patients before revascularization surgery effectively. As a noninvasive imaging technique, mTI ASL could provide perfusion parameters without contrast medium injection, and the results were quite correlative with DSC-PWI. PMID- 30313090 TI - The use of SAPS 3, SOFA, and Glasgow Coma Scale to predict mortality in patients with subarachnoid hemorrhage: A retrospective cohort study. AB - Guidelines for patients with subarachnoid hemorrhage (SAH) management and several grading systems or prognostic indices have been used not only to improve the quality of care but to predict also the outcome of these patients. Among them, the gold standards Fisher radiological grading scale, Hunt-Hess and the World Federation of Neurological Surgeons (WFNS) are the most employed. The objective of this study is to compare the predictive values of simplified acute physiology score (SAPS) 3, sequential organ failure assessment (SOFA), and Glasgow Coma Scale (GCS) in the outcome of patients with aneurysmal SAH.Fifty-one SAH patients (33% males and 67% females; mean age of 54.1 +/- 10.3 years) admitted to the intensive care units (ICU) in the post-operative phase were retrospectively studied. The patients were divided into survivors (n=37) and nonsurvivors (n = 14). SAPS 3, Fischer scale, WFNS, SOFA, and GCS were recorded on ICU admission (day 1 - D1), and 72-hours (day 3 - D3) SOFA, and GCS. The capability of each index SAPS 3, SOFA, and GCS (D1 and D3) to predict mortality was analyzed by receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) and the respective confidence interval (CI) were used to measure the index accuracy. The level of significance was set at P < .05.The mean SAPS 3, SOFA, and GCS on D1 were 13.5 +/- 12.7, 3.1 +/- 2.4, and 13.7 +/- 2.8 for survivors and 32.5 +/- 28.0, 5.6 +/- 4.9, and 13.5 +/- 1.9 for nonsurvivors, respectively. The AUC and 95% CI for SAPS 3, SOFA, and GCS on D1 were 0.735 (0.592-0.848), 0.623 (0.476-0.754), 0.565 (0.419-0.703), respectively. The AUC and 95% CI for SOFA and GCS on D3 were 0.768 (0.629-0.875) and 0.708 (0.563-0.826), respectively. The overall mortality was 37.8%.Even though SAPS 3 and Fischer scale predicted mortality better on admission (D1), both indices SOFA and GCS performed similarly to predict outcome in SAH patients on D3. PMID- 30313091 TI - Efficacy and safety of direct aspiration versus stent-retriever for recanalization in acute cerebral infarction: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Whether the direct aspiration approach of thrombectomy for recanalization in patients with acute ischemic stroke has a similar efficacy and safety compared to the stent-retriever remains uncertain. METHODS: We conducted a meta-analysis of 9 studies obtained through PubMed and Embase database searches to determine whether successful recanalization rate, good functional outcome at 3 months (modified Rankin score, mRS<=2), procedure time from groin puncture to maximal revascularization and procedure-related adverse events differed between patients who underwent the direct aspiration and those receiving stent-retriever for recanalization in acute cerebral infarction. RESULTS: There was no significant difference between the direct aspiration group and the stent-retriever group in rate of successful recanalization (summary odds ratio [OR], 0.86 [95% confidence interval (CI), 0.45-1.52]; P = .60), but a better functional outcomes in the direct aspiration group at 3 months defined as a mRS score of 0 to 2 (OR, 0.77; 95% CI, 0.66-0.97; P = .03). Furthermore, the direct aspiration patients compared with the stent-retriever patients had a tendency of shorter procedural time (Mean difference [MD], -8.77 [95% CI, from 18.90 to 1.37]; P = .09). Finally, there were less adverse events especially in symptomatic intracerebral hemorrhage (sICH) (OR, 0.56; 95% CI, 0.33-0.98; P = .04) and embolization to a new territory (ENT) (OR, 0.49; 95% CI, 0.28-0.84; P = .01) in the direct aspiration group when compared with the stent-retriever group, although no difference between them in the rate of any ICH (OR, 0.81; 95% CI, 0.41-1.60; P = .54). CONCLUSIONS: The results support that the direct aspiration technique for those acute ischemic stroke patients may have better functional outcomes, less procedure related-adverse events and a tendency of faster revascularization time as compared to the stent-retriever thrombectomy, with a similar successful recanalization rate. However, major limitations of current evidence (mainly from retrospective and observational studies and a small number of patients population) indicate a need for adequately powered, multicenter randomized controlled trials (RCT) to answer this question. PMID- 30313092 TI - Comparison of the effects of desflurane and total intravenous anesthesia on the optic nerve sheath diameter in robot assisted laparoscopic radical prostatectomy: A randomized controlled trial. AB - BACKGROUND: Optic nerve sheath diameter (ONSD) is a well-known surrogate marker for intracranial pressure during robot-assisted laparoscopic radical prostatectomies (RALP). ONSD during RALP is known to increase due to elevated intracranial pressure as a result of the steep Trendelenburg position and carbon dioxide pneumoperitoneum. We aimed to compare the effects of total intravenous anesthesia (TIVA) and desflurane anesthesia (DES) on ONSD during RALP. METHODS: Patients scheduled for RALP were enrolled and randomly assigned to the TIVA (propofol and remifentanil) or DES (desflurane and remifentanil) group in this randomized trial. Ultrasonographic measurements of ONSD were conducted before administration of anesthesia (T0), 10 minutes after the Trendelenburg position (T1), 1 hour after the Trendelenburg position (T2), 2 hours after the Trendelenburg position (T3), 10 minutes after resuming the supine position (T4), and at the time of arrival in the post-anaesthetic care unit (T5). The primary outcome measure was the mean ONSD at T2 of the TIVA and DES group during RALP. RESULTS: A total of 56 patients were analysed in this study. The mean ONSD at T1, T2, T3, and T4 were significantly lower for patients in the TIVA group compared with those in the DES group (P = .023, .000, .000, and .003, respectively). CONCLUSION: The mean ONSD for patients in the TIVA group was significantly lower than that in the DES group during the RALP procedure. Our findings suggest that TIVA may be a more suitable anesthetic option for patients at risk of cerebral hypoperfusion. PMID- 30313093 TI - Impact of surgical ventricular restoration on early and long-term outcomes of patients with left ventricular aneurysm: A single-center experience. AB - Left ventricular aneurysm (LVA) is a common complication of myocardial infarction. However, the optimal treatment for LVA remains controversial.In this retrospective study, we analyzed the early and long-term clinical consequences of surgical ventricular restoration on 102 patients who had undergone repair between January, 2005 and January, 2015. The LVA repair approaches comprised of patch plasty (n = 28), linear repair (n = 40), and plication repair (n = 34).Patient demographics were 60.8% male, and the mean age was 60.5 +/- 7.2 years. The in hospital mortality rate was 7.8% (8/102), including 6 patients who died from low cardiac output and 2 from multiorgan failure. During the early postoperative period, left ventricular sizes significantly decreased in the patch plasty and linear repair groups compared with the plication group. In addition, all 3 repair techniques greatly ameliorated left ventricular ejection fraction (P < .05), and there was no significant difference in survival rate between groups (P = .25).Surgical ventricular restoration (linear repair, plication repair, and patch plasty) obtained equivalently appreciable outcomes for cardiac function improvement, perioperative mortality, and survival. Selection of a surgical technique for LVA patients should be optimized to individual patient conditions including the morphological characteristics of the aneurysm and ischemic scar. PMID- 30313094 TI - Thoracic aggressive vertebral hemangioma with neurologic deficit: A retrospective cohort study. AB - The aim of this study is to evaluate the safety and effectiveness in the treatment of thoracic aggressive vertebral hemangiomas (AVHs) with neurologic deficit by multiple surgical treatments.The clinical and radiographic data of 5 patients suffering from thoracic AVHs with neurologic deficit and treated by multiple surgical treatments, including percutaneous curved vertebroplasty (PCVP) combined with pedicle screw fixation and decompressive laminectomy, were reviewed and analyzed retrospectively.Five patients (3 women and 2 man, with a mean age of 57.40 +/- 11.93) were diagnosed with AVHs from July 2010 to April 2016. All of them had objective neurologic deficit, myelopathy, and back pain. They underwent multiple surgical treatments and were followed-up for 12 to 23 months. At final follow-up, Frankel Grade D was achieved in all 5 patients. Patients were free from pain and neurologic symptoms, and the functional status was improved. No major complication was found.The treatment of AVHs with neurologic deficit is a challenge for surgeons. PCVP combined with pedicle screw fixation and decompressive laminectomy is safe and effective, and can be used for AVHs with neurologic deficit. Further studies with more samples are required to validate the effectiveness and safety of PCVP combined with pedicle screw fixation and decompressive laminectomy. PMID- 30313095 TI - Acute vertigo and sensorineural hearing loss from infarction of the vestibulocochlear nerve: A case report. AB - RATIONALE: Acute unilateral audiovestibulopathy is a common neurotological syndrome. Differential diagnoses of acute unilateral audiovestibulopathy include viral infection, vascular insults, and tumors. Regarding vascular causes, ischemic stroke in the anterior inferior cerebellar artery (AICA) territory is known to be the leading cause of acute audiovestibular loss. Previous reports of AICA infarction with audiovestibulopathy failed to demonstrate magnetic resonance imaging (MRI)-positive vestibulocochlear infarctions. Only 1 report demonstrated acute infarction involving the vestibulocochlear nerve on diffusion weighted imaging (DWI)-MRI. PATIENT CONCERNS: A 67 year old man complained of sudden left hearing loss and vertigo. The patient showed left horizontal gaze-evoked nystagmus (GEN) and the head impulse test (HIT) was positive on the left side. Videonystagmography revealed spontaneous rebound nystagmus toward the right side; head-shaking nystagmus toward the right side. The patient presented with left caloric paresis (20.1%). Pure tone audiometry (PTA) revealed severe sensorineural hearing loss on the left side. DIAGNOSIS: MRI of temporal bone showed multifocal acute infarctions in the left inferior cerebellum. Moreover, images revealed tiny infarctions along the left vestibulocochlear nerve and the cochlea, implying acute vestibulocochlear nerve and labyrinthine infarction. There was no evidence of steno-occlusion of major cerebral vessels on MR angiography. INTERVENTIONS: Immediate stroke management was done. OUTCOMES: Neurological symptoms gradually improved after 3 to 5 days. LESSONS: We present a case illustrating a rare but significant finding of vestibulocochlear nerve infarction revealed by DWI-MRI. Prompt imaging protocol enabled the detection of significant findings in this patient with acute unilateral audiovestibulopathy. Clinicians should be aware of the vestibulocochlear nerve and labyrinth on MRI in patients with cerebellar stroke. PMID- 30313096 TI - A systematic review of clinical studies on electrical stimulation therapy for patients with neurogenic bowel dysfunction after spinal cord injury. AB - BACKGROUND: This study aimed to perform a systematic literature review of the clinical trial evidence on electrical stimulation for the treatment of neurogenic bowel dysfunction (NBD) after spinal cord injury (SCI). METHODS: Systematic electronic searches were carried out in the PubMed/Medline, EMBASE, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure databases, along with the reference lists in the include studies. Studies were eligible for inclusion if they adopted a controlled clinical design based on human population, the patients suffered from spinal cord injury, the main outcomes were the disorders of bowel function and the intervention was electrical stimulation. Also, the language was limited to English and Chinese. RESULTS: Eleven studies were included in this systematic review, comprising transcutaneous electrical stimulation, transrectal bowel stimulation, sacral nerve stimulation, intravesical electrical stimulation, etc. Of the 11 studies, 3 were randomized controlled trials, 8 were controlled before-and-after trials. The quality of the included studies was moderate bias risk. Most studies revealed that the electrical stimulation was beneficial for the patient with NBD after SCI. CONCLUSIONS: Only 11 small clinical studies with 298 participants have evaluated the efficacy of electrical stimulation for NBD after SCI. Although some studies showed electrical stimulation was benefit for the patient with NBD after SCI, there was currently not enough evidence to support the use of electrical stimulation could improve the clinical symptoms of those patients. Thus, well designed randomized controlled trials with larger patient population are warranted to establish its benefit in clinical practice in the future. PMID- 30313097 TI - Novel splice receptor-site mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa. AB - RATIONALE: Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous diseases; X-linked retinitis pigmentosa (XLRP) is the most serious type. Mutations in RP GTPase regulator (RPGR) account for over 70% of patients with XLRP. PATIENT CONCERNS: We report a Chinese family with RP, 5 males presented with night blindness and decreased vision, and 8 females showed different severities of myopia. DIAGNOSES: Targeted exome capture sequencing was performed in 2 affected males, which revealed a novel variant (NM_000328.2, c.470 1G>A) in the RPGR gene. The mis-splicing causes a substitution of the 157th amino acid from glutamic acid to glycine and finally the 165th codon is changed to stop codon, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The mutation cosegregated with the disease phenotype in the family. INTERVENTIONS: Medication and cataract surgery. OUTCOMES: The phenotype of affected males is more serious than that of the carrier females, and the effect of clinical treatment is not very well. LESSONS: Next-generation sequencing is a suitable method for early detection of pathogenic mutations in RP, which would be helpful for prenatal diagnosis of the disease. PMID- 30313098 TI - Damage-associated molecular patterns in intensive care unit patients with acute liver injuries: A prospective cohort study. AB - Acute liver injury (ALI) is frequently detected in an intensive care unit (ICU) and reportedly affects prognosis. Experimental animal studies suggested that increased extracellular histone and high morbidity group box-1 (HMGB1) levels might contribute to ALI development. Whether these damage-associated molecular patterns (DAMPs) play a crucial role in ALI remains unclear in the human clinical setting.We consecutively enrolled the patients admitted to our ICU. The patients with ALI were included in the analysis together with those without ALI by using frequency matching. Extracellular histone, HMGB1, soluble thrombomodulin (sTM), and interleukin-6 (IL-6) levels were measured in plasma collected at ICU admission. ALI was defined as an acute elevation in serum aminotransferase levels to >200 IU/L.A total of 805 patients were enrolled. Twenty ALI and forty non-ALI patients were analyzed. Plasma histone levels were significantly higher in the ALI group than in the non-ALI group, whereas HMGB1 levels were significantly lower in the ALI group. Furthermore, sTM was significantly increased in the ALI patients, whereas IL-6 levels were comparable between the groups. Multivariate logistic regression analysis demonstrated that histones were independently associated with ALI. There was no significant impact of ALI on in-hospital mortality.Extracellular histones showed an independent association with ALI. Histone elevation might be one of the possible pathogenic mechanisms in the development of ALI of ICU patients. PMID- 30313099 TI - Characteristics of contrast-enhanced ultrasound in distinguishing small (<=3 cm) hepatocellular carcinoma from intrahepatic cholangiocarcinoma. AB - Contrast-enhanced ultrasound (CEUS) is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to verify the characteristics of CEUS in distinguishing small (<=3 cm) hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC).A total of 65 patients with a liver nodule (HCC, n = 58; ICC, n = 7) smaller than 3 cm who underwent liver CEUS and pathologic confirmation were retrospectively reviewed. CEUS findings were compared with histopathologic and clinical data.Arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS were observed in 77.6% (45/58) of HCCs and 85.7% (6/7) of ICCs. Time of arterial-phase hyperenhancement (11 seconds [6 20] vs 16 seconds [14-19], P = .008), time of portal-delayed-phase wash-out (65 seconds (15-260) vs 35 secconds (27-54), P = .002), and time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out (50 seconds [5 249] vs 19 seconds [13-35], P < .001) on CEUS were significantly different between HCCs and ICCs showing arterial-phase hyperenhancement and portal-delayed phase wash-out. The sensitivity, specificity, positive predictive value, and negative predictive value of time interval more than 25 seconds between arterial phase hyperenhancement and portal-delayed-phase wash-out on CEUS for the differentiation of HCCs and ICCs were 91.1%, 83.3%, 97.6%, and 55.6%, respectively.The time interval between arterial-phase hyperenhancement and portal delayed-phase wash-out on CEUS was the most sensitive indicator in distinguishing small HCC from ICC showing arterial-phase hyperenhancement and portal-delayed phase wash-out. PMID- 30313100 TI - Effect of high-flow nasal cannula oxygen therapy vs conventional oxygen therapy on adult postcardiothoracic operation: A meta-analysis. AB - INTRODUCTION: The effect of high-flow nasal cannula (HFNC) on adult post cardiothoracic operation remains controversial. We conducted a meta-analysis of randomized controlled trials to evaluate the effect of HFNC and conventional oxygen therapy (COT) on postcardiothoracic surgery. METHODS: A search was conducted in Embase, MEDLINE, Ovid, and Cochrane databases until December, 2017 for all the controlled study to compare HFNC with COT in adult postcardiothoracic surgery. Two authors extracted data and assessed the quality of each study independently. The meta-analysis was performed by using RevMan 5.3. The primary outcome was the rate of escalation of respiratory support rate and pulmonary complications; secondary outcome included the length of intensive care unit (ICU) stay and length of hospital stay and the rate of intubation. RESULTS: Four studies that involved 649 patients were included in the analysis. No significant heterogeneity was found in outcome measures. Compared with COT, HFNC were associated with a significant reduction in the escalation of respiratory support (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.29-0.66, P < .001) and pulmonary complications (OR = 0.28, 95% CI = 0.13-0.6, P = .001). There were no significant differences in the reintubation rate (OR = 0.33, 95% CI = 0.02-5.39, P = .43), length of ICU stay (weighted mean difference = 0.11; 95% CI = -0.44 0.26, P = .14) or length of hospital stay (weighted mean difference = -0.15, 95% CI = -0.46 -0.17, P = .36) between the 2 groups. No severe complications were reported in either group. CONCLUSION: The HFNC could reduce respiratory support and pulmonary complications, and it could be safely administered for adult postcardiothoracic surgery. Further large-scale, randomized, and controlled trials are needed to update this finding. PMID- 30313101 TI - Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis. AB - Retrospective studies have suggested that capecitabine combined with temozolomide (CAPTEM) is effective for treating patients with advanced neuroendocrine neoplasms (NENs); however, the efficacy and safety of this regimen needs to be verified by high-quality evidence or results of randomized controlled trials.We carried out a meta-analysis to evaluate the safety and effectiveness of a CAPTEM protocol for patients with advanced NENs. Systematic electronic literature searches were conducted using PubMed, EMBASE, and the Cochrane Library, and among meeting abstracts of the American Society of Clinical Oncology, European Society for Medical Oncology, European Neuroendocrine Tumor Society, and North American Neuroendocrine Tumor Society, up to June 30, 2017. We selected studies describing CAPTEM regimens for treating advanced NENs and reported on tumor response and/or toxicities according to clear World Health Organization (WHO) grading of patients. Three reviewers independently and repeatedly identified studies, extracted data, and assessed the quality of the literature. A single-proportion meta-analysis was applied to included articles.Fifteen studies with a total of 384 individuals were included. Medium overall survival in most studies was more than 12 months, whereas medium progression-free survival was similar or slightly higher than that in studies using other treatment regimes. Disease control rate of CAPTEM administration for patients with NENs was 72.89% (95% confidence interval, 64.04-81.73%; I = 82.4%; P < .01). WHO grade 3 to 4 toxicities, such as thrombocytopenia (3.36%), neutropenia (0.69%), lymphopenia (0.65%), anemia (0.59%), mucositis (0.57%), fatigue (0.54%), diarrhea (0.49%), nausea (0.39%), and transaminase elevation (0.13%) were reported in the trials included.CAPTEM is effective and relatively safe for treating patients with advanced NENs. PMID- 30313102 TI - Lipoid pneumonitis in a patient with an accidental ingestion of kerosene successfully treated with bronchoscopic segmental lavage and systemic steroid: Case report. AB - RATIONALE: Standard treatment of lipoid pneumonitis remains unclear. This study reports a case of kerosene pneumonitis successfully treated with systemic steroid and segmental bronchoalveolar lavage (BAL). PATIENT CONCERNS: A 30-year-old woman referred to our hospital because of worsening of respiratory symptoms and fever despite antibiotic therapy following accidental ingestion of kerosene. She had no underlying disease. DIAGNOSES: Chest CT scan showed necrotic consolidation, ground glass opacity (GGO), bronchial wall thickening in the right middle/lower lobe (RML/RLL) and right pleural effusion. The lipoid pneumonitis was confirmed by identification of a lipid laden macrophage in bronchoalveolar lavage fluid. INTERVENTIONS: The patient was treated with systemic corticosteroid and segmental BAL. OUTCOMES: The patient's symptoms rapidly improved after treatment and she was discharged one week after admission. A follow-up CT scan a week after discharge revealed marked resolution of consolidation. No recurrence was reported for 8 months. LESSONS: This is the first case of kerosene pneumonitis successfully treated with systemic steroid and bronchoscopic segmental lavage therapy in Korea. Very few cases have been reported worldwide. PMID- 30313103 TI - Retrodiscal epidural balloon adhesiolysis through Kambin's triangle in chronic lumbar spinal stenosis: A retrospective analysis and technical considerations. AB - A previous study showed that transforaminal balloon adhesiolysis via the safe triangle was effective in lumbar spinal stenosis. However, retrodiscal pathology is difficult to treat with this method. Therefore we attempted retrodiscal balloon adhesiolysis via Kambin's triangle. The design of our study is a retrospective analysis. The setting of our study is a tertiary, interventional pain management practice, speciality referral center.The primary indication for this procedure is radicular pain arising from ipsilateral retrodiscal pathology. Medical records were reviewed of patients who received retrodiscal decompression with a transforaminal balloon inflatable catheter between January 1, 2016 and July 31, 2017. The intervention was conducted by 2 well-trained pain specialists. The introducer needle was positioned at Kambin's triangle. Adhesiolysis was performed using a balloon filled with radiocontrast media. After balloon adhesiolysis, an agent containing lidocaine and dexamethasone was injected through the introducer sheath. Numeric rating scale pain scores were obtained 1 and 3 months after the procedure.The mean pre-procedure numeric rating scale score was 7.05 +/- 1.40. After 1 and 3 months, the mean scores were 3.91 +/- 2.20 and 3.77 +/- 2.11, respectively. No patient had significant complications. Also, technical considerations were discussed.Chronic pain due to lumbar central stenosis, especially ipsilateral retrodiscal pathology, can be reduced by retrodiscal balloon adhesiolysis through Kambin's triangle. Although this study is limited by its retrospective design, the results suggest that this procedure is a useful treatment due to its ease of performance and cost-effectiveness. PMID- 30313104 TI - The risk factors of residual lesions and recurrence of the high-grade cervical intraepithelial lesions (HSIL) patients with positive-margin after conization. AB - The aim of this study was to illuminate risks factors of residual lesions, and recurrence of the high-grade cervical intraepithelial lesions (HSIL) patients with positive margin who underwent cervical conization.A retrospective cohort study of 218 patients with positive margin after conization, including cold knife conization (CKC) and loop electrosurgical excisional procedure (LEEP), and follow up from 2013 through 2016. The diagnosis of residual disease and recurrence were established and confirmed by biopsy. We evaluate the correlations among residual rate, recurrence rate, and clinical parameters, such as age, menopausal status, gravity, parity, glandular involvement, thinprep cytologic test (TCT), and human papillomavirus (HPV) results. We also detect the difference between CKC and LEEP.There was statistical difference between the positive margin rate of CKC group and LEEP regarding the surgery methods (5.8% and 12.09% separately, P < .001). Residual disease was found in 53.66% cases where 41 patients received second surgery after conization. Besides, age (P = .027), menopausal status (P = .006), and HPV infection (P = 0.018) were significantly associated with residual lesion. Among 177 cases with histopathologic follow-up, 15.91% women relapsed from 4 to 27 months. As for recurrence we found it was more frequent with HPV infection and glandular involvement (P < .001). TCT was also an independent factor in patients with recurrence of lesion. No evidence shows difference between CKC and LEEP for recurrence rate (P = .918).The factors related to rate of residual lesion were age, menopausal status, and HPV infection. HPV infection, TCT, and glandular involvement were associated with HSIL recurrence. LEEP was as effective as CKC with regard to recurrence rate. Further large-scale studies are needed to confirm our findings. PMID- 30313105 TI - Intravascular large B-cell lymphoma presenting as multiple stroke: A case report. AB - INTRODUCTION: Intravascular large B-cell lymphoma (IVLBCL) is an uncommon disease with a poor prognosis if not diagnosed early. It can present with central nervous system (CNS) manifestations. The diagnosis of IVCBCL is difficult to make given its varied clinical manifestations and the lack of a specific diagnostic modality. CASE PRESENTATION: We report an interesting case of IVLBCL presenting as bilateral strokes. The diagnosis was made by a random skin biopsy, which confirmed IVLBCL. The patient was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).Neurological symptoms improved with R-CHOP. Repeat magnetic resonance imaging (MRI) of the brain showed improvement of the prior lesions. CONCLUSION: IVLBCL is an aggressive disease with high mortality. Timely diagnosis and treatment can be lifesaving. PMID- 30313106 TI - The effect of polydeoxyribonucleotide on the treatment of radiating leg pain due to cystic mass lesion in inner aspect of right sciatic foramen: A CARE compliant case report. AB - RATIONALE: Radiating leg pain usually originates from the lumbar spine and occasionally from peripheral lesions. Here we report a case involving a patient with radiating pain in the right leg who exhibited 2 suspicious lesions, including 1 spinal lesion and 1 extraspinal cystic mass lesion, on magnetic resonance imaging. Polydeoxyribonucleotide sodium (PDRN) was recently noted as such a substitute. PDRN has anti-inflammatory effects, as it lowers the expression of inflammatory cytokines including interleukin-6 and tumor necrosis factor-alpha. PATIENT CONCERNS: A 51-year-old man (weight, 93 kg; height, 168 cm) working as a bus driver presented at the pain clinic with continuous right buttock pain, radiating leg pain and a tingling sensation involving the calf and dorsum of the foot, since 1 week. DIAGNOSES: He was definitively diagnosed using differential blocks, which revealed the cyst to be the actual cause of the pain. INTERVENTIONS: Surgical resection was not feasible because of the position of the cyst; therefore, corticosteroid injection under ultrasonographic guidance was attempted. However, this provided short-term relief. Subsequently, a solution containing PDRN was injected around the piriformis muscle and repeated 3 more times at intervals of 2 weeks. OUTCOMES: After PDRN injection, we conducted two follow-up monitoring every two months for 2 months. Last follow-up, the patient no longer complained of pain. this resulted in relatively long-term relief from pain. LESSONS: The findings from this case suggest that PDRN is an effective alternative for steroids in patients with radiating leg pain, although its efficacy and safety needs to be evaluated in further large-scale studies. PMID- 30313107 TI - Metastatic esophageal carcinosarcoma comprising neuroendocrine carcinoma, squamous cell carcinoma, and sarcoma: A case report. AB - RATIONALE: Esophageal carcinosarcoma generally comprises 2 histological components: squamous cell carcinoma (SqCC) and sarcoma. Esophageal carcinosarcoma comprising 3 components is extremely rare and no reports have described therapeutic effects for this disease with metastasis. PATIENT CONCERNS: A 76-year old man with dysphagia presented to a local clinic. Gastrointestinal endoscopy revealed a polypoid tumor in the middle esophagus and he was referred to our hospital. DIAGNOSIS AND INTERVENTIONS: Thoracoscopic esophagectomy with super extended (D3) nodal dissection and gastric tube reconstitution was performed, which resulted in carcinosarcoma comprising neuroendocrine carcinoma (NEC), SqCC, and sarcoma. Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition. The NEC component was observed in lymph node. At 47 days after surgery, lymph nodes, liver, and bone metastasis appeared, and tumor markers such as ProGRP and NSE were elevated. Combination chemotherapy with cisplatin and etoposide (EP) adapted to NEC was performed. OUTCOMES: The patient showed complete response within 4 cycles of chemotherapy. However, the disease recurred 5.5 months after the final course of EP chemotherapy. LESSONS: A therapeutic strategy based on assessment of which component caused metastasis might be important for metastatic carcinosarcoma comprising 3 components, although more accumulation of data about the efficacy of chemotherapy is necessary. Moreover, elucidation of the mechanisms underlying generation of carcinosarcoma is expected in the future. PMID- 30313108 TI - Differences in incidence and survival to childhood cancer between rural and urban areas in Castilla y Leon, Spain (2003-2014): A Strobe-compliant study. AB - The aim of this study is to describe childhood cancer incidence and survival in Castilla y Leon (Spain) for the period 2003 to 2014 and to explore differences between rural and urban areas.We made a cohort study in the childhood population of our region for the period of years referred before. Age-adjusted incidence rates to the world standard population (ASRw) were calculated by direct method, and their comparisons were made using incidence rate rations. Survival proportions were calculated by Kaplan-Meier method and their comparisons with log rank test. The median childhood population less than 15 years old was 296,776 children. A total of 615 cases were recorded from the population-based Childhood Cancer Registry, including all malignant and benign tumors of the central nervous system.Age-standardized incidence rates for all cancers were 176.6 per million. Leukemia incidence rates were highest in rural areas (51.08/million) than in urban areas (33.65/million; P = .018), and by age groups; these differences only remained at age 0 to 4 years with higher rural leukemia incidence (67.13/million) than in urban areas (39.32/million; P = .05). There were no statistically significant differences between rural and urban areas for lymphomas, central nervous system, and all other malignant solid tumors grouped. The 5-year overall survival rate for all patients was 84%, similar to other developed countries, with greater survival in rural areas (88%) compared with urban areas (80%; P = .033). The analysis by tumor groups showed a greater survival rate in rural areas for all the groups, although these differences only reached statistical significance in the group of leukemias, with a survival rate of 90% for rural areas compared with 76% for urban areas (P = .01). Analyzing survival rate by age groups in leukemias only significant survival differences at 10 to 14 years were encountered.We found a higher incidence of leukemia in girls, mainly in rural areas, and also a better survival rate in children diagnosed with leukemia belonging to this population area. Future studies that analyze these facts in similar populations can help us clarify what genetic, epigenetic and environmental factors influence our population and are responsible for these findings. PMID- 30313109 TI - A pilot study to standardize and peer-review shift handoffs in an academic internal medicine residency program: The DOCFISH method. AB - With increased oversight of residency work hours, there has been an increase in shift handoffs, which are prone to medical errors. To date, there are no evidence based recommendations on essential elements of shift handoffs. We implemented a standardized shift-handoff rubric at an academic medicine residency program. Compliance, resident/faculty perceptions, and surrogate markers of patient safety were measured.Shift-handoff documents were collected January-February 2016 (control) April-June 2016 (intervention). Signouts were scored based on inclusion of seven elements: Daily events, Overnight events, Code status, Follow up tasks, If/then statements, 'sick or stable' and History present illness. The mnemonic 'DOCFISH' was taught in a grand-rounds forum then embedded into a shift-handoff tool within our electronic health record (EHR). Senior residents were assigned to supervise/provide feedback on shift handoffs from April-June 2016. Faculty and resident perceptions regarding quality of shift handoffs was measured by the annual ACGME (Accreditation Council Graduate Medical Education) program survey.Patient safety was measured by number of rapid-response teams (RRT) initiated for unstable vital signs. Handoffs were 74% complete in intervention group and 60% in control group (p < .0001). Median DOCFISH features present in patients that required RRT was 3 of 7 whereas, total post-intervention group had 5 of 7 (p < .001). 'Daily events' and 'follow -up tasks' were less frequent in patients that required RRT (20%, 67% respectively, p < .001).Academic medical centers can implement standardized shift handoffs by embedding high-yield information in an EHR with peer-review. Information during shift changes that may have significant improvement on patient safety includes: 'daily events' and 'follow -up tasks.' PMID- 30313110 TI - The association between IUGR and maternal inherited thrombophilias: A case control study. AB - One of the risk factors for vascular obstetric complications, such as intrauterine growth restriction (IUGR), is inherited thrombophilias. Nevertheless, routine screening for thrombophilias is not endorsed in pregnant women due to their low prevalence and conflicting results of published studies regarding the usefulness of screening in these patients. The cause of IUGR remains unknown in almost 1 quarter of cases. There are no published studies evaluating the association of inherited thrombophilias and IUGR in patients with IUGR of unknown origin. Understanding and preventing IUGR is an important public health concern, as IUGR has been associated with fetal mortality and neonatal morbidity, as well as adverse long-standing consequences. This study aimed to evaluate the prevalence of inherited thrombophilias in IUGR of unknown cause and to test the association between the inherited thrombophilias and IUGR of unknown cause.This study included 33 cases of IUGR of unknown cause tested for inherited thrombophilias and 66 controls individually matched for age, ethnicity, and smoking status.Patients with plasminogen activator inhibitor 1 (PAI-1) and methylenetetrahydrofolate reductase (MTHFR) had significantly higher odds for IUGR of unknown cause (P < .001 and P = .002, respectively) with OR 13.546 (CI 95% 3.79-48.37) and 8.139 (CI 95% 2.20-30.10), respectively. A positive association between other inherited thrombophilias (homozygous 20210 prothrombin gene mutation and homozygous factor V Leiden) and IUGR of unknown cause was also found, P = .096, OR 6.106 (CI 95% 0.72-51.30), although it was not statistically significant (P = .096, OR = 6.106, CI 95% 0.72-51.30).Our results indicate that PAI-1 and MTHFR thrombophilias represent risk factors for IUGR of otherwise unidentified cause. PMID- 30313111 TI - The characteristics analysis of intestinal microecology on cerebral infarction patients and its correlation with apolipoprotein E. AB - Cerebral infarction (CI) is associated with high rates of disability, mortality, and death in China, but its mechanism is unclear. Therefore, early diagnosis of CI and determining its mechanism are very important. Intestinal microecology is thought to be related to cardiovascular and cerebrovascular diseases. We hypothesized that intestinal microecology is also related to CI and that the intestinal microecology in the stool of CI patients differs from that in healthy people.Fecal samples of healthy subjects and CI patient (all n = 10) and we investigated the intestinal microecology of CI patient and healthy people stool by 16 seconds sequencing and analyzed relative abundance and diversity of microorganisms by unweighted pair-group method with arithmetic mean analysis (UPGMA) and principal co-ordinates analysis (PCoA). We also measured apolipoprotein E (ApoE) levels in the serum by ELISA assay and analyzed the correlation between ApoE and intestinal flora.We found that the relative structure and diversity of intestinal microecology was significantly different between the stools of CI patients and healthy people. At the class level, Gammaproteobacteria was increased and Bacteroidia was decreased in CI patient stool. We found a correlation between ApoE in the serum and Bacteroidia and Gammaproteobacteria species.We considered the intestinal flora can be used as an indicator of CI and the up-regulation of ApoE may be the potential mediate for intestinal microecology contribute to CI. PMID- 30313112 TI - Analysis of caudal epidurogram in single center: A preliminary study of lumbar radiculopathy management. AB - A caudal epidural block involves placing a needle through the sacral hiatus and delivering medication into the epidural space. The procedure is safe and simple, but failure rates can be as high as 25%. The purpose of this study was to investigate the success rate of caudal epidural block by analyzing needle placement and dye flow pattern.We retrospectively analyzed the medical records of patients who underwent caudal epidural block under spinal stenosis. A case was defined as a failure if it met at least one of the following four criteria: the epidural needle was not placed correctly inside the caudal canal; blood regurgitation or aspiration in the needle was observed; the contrast dye was injected into a blood vessel; or a large amount of the dye leaked into the sacral foramen or did not reach the L5-S1 level.At least 1 failure criterion was observed in 14 cases (17.7%), while none of the failure criteria were satisfied in 65 successful cases (82.3%).No matter how experienced the anesthesiologist may be, delivery of adequate therapeutic agent is not achieved in approximately 20% of cases. Therefore, we recommend fluoroscopy-guided needle placement and confirmation by radio-contrast epidurograpy as the best choice. PMID- 30313113 TI - Successful azathioprine treatment in an adolescent with chronic enteropathy associated with SLCO2A1 gene: A case report. AB - INTRODUCTION: Chronic nonspecific multiple ulcers of the small intestine (CNSU), an entity with female preponderance and manifestations including anemia and hypoproteinemia reflecting persistent gastrointestinal bleeding and intestinal protein loss, has been considered idiopathic. Umeno et al recently reported that CNSU is caused by loss-of-function mutations in the solute carrier organic anion transporter family member 2A1 gene (SLCO2A1) encoding a prostaglandin transporter, renaming the disorder "chronic enteropathy associated with SLCO2A1 gene mutation" (CEAS). Treatments for chronic enteropathies such as inflammatory bowel disease, including 5-aminosalicylic acid, corticosteroids, azathioprine, and anti-tumor necrosis factor-alpha antibody, often are ineffective in CEAS, which frequently requires surgery. CASE PRESENTATION: A 14-year-old girl had refractory anemia and hypoproteinemia for more than 2 years. Video capsule endoscopy showed nonspecific jejunal and ileal ulcers with varied sizes and shapes. She was diagnosed with CEAS resulting from compound heterozygous mutation of the SLCO2A1 gene. After corticosteroid treatment without improvement, azathioprine treatment improved her anemia and edema as hemoglobin and serum protein increased. Video capsule endoscopy 1 year after initiation of azathioprine showed improvement of small intestinal ulcers. CONCLUSION: Physicians should consider CEAS in patients with refractory anemia, hypoproteinemia, and multiple small intestinal ulcers. Why our patient responded to azathioprine but not to corticosteroids is unclear, but azathioprine might benefit some other patients with CEAS. PMID- 30313114 TI - Economic evaluation of the impact of physician-hospital integration and physician boards on hospital expenditure per patient: A 5-year longitudinal study. AB - BACKGROUND: This study aims to contribute to the ongoing policy and scholarly debate on physician-hospital integration (INT) and health care cost by providing evidence for the role of physician boards in mitigating hospital expenditure associated with INT. METHODS: We conducted our study of the relationship between INT, physician boards, and hospital expenditure using data on hospitals in California. We obtained data from the Centers for Medicare and Medicaid Services, American Hospital Association, and California Office of Statewide Health Planning and Development from 2002 to 2006. A hospital fixed-effect ordinary least square (OLS) regression analysis was used. RESULTS: Hospital expenditure was higher in a hospital with an integrated arrangement (e.g., a hospital that adopted an integrated salary model) than under other independent arrangements between physicians and hospitals, and the proportion of physician members on hospital boards negatively moderated the effect of integration on hospital expenditure. CONCLUSIONS: Physician boards may provide a context that affords benefits that can reduce hospital expenditures under INT. This finding highlights the importance to having a supportive organizational design when implementing INT. PMID- 30313115 TI - Preoperative sonographic features of follicular thyroid carcinoma predict biological behavior: A retrospective study. AB - Little is known regarding biological behavior of follicular thyroid carcinomas (FTCs) according to ultrasonography features. We investigated whether there was a difference in biological behavior between benign-looking FTCs (B-FTCs) and malignant-looking FTCs (M-FTCs).A total of 55 cases of FTC between January 2000 and December 2015 were included. B-FTCs were defined as showing none of the accepted ultrasonography criteria for malignancy, and M-FTCs were defined as showing at least one of the accepted ultrasonography criteria for malignancy. Clinicopathologic factors and sonographic features were compared between B-FTCs and M-FTCs. Based on the degree of invasiveness, FTCs were divided into minimally invasive FTCs (MI-FTCs) and widely invasive FTCs (WI-FTCs) on pathology. Sonographic features were compared between MI-FTCs and WI-FTCs.Compared with the patients with B-FTCs (31/55, 56.4%), the patients with M-FTCs showed a significantly higher prevalence of WI-FTCs, central lymph node metastases, lateral lymph node metastases as well as extrathyroidal extension (P < .001, P = .012, P = .031, and P = .032, respectively). M-FTCs with more than one malignancy features on ultrasonography showed a significantly higher prevalence of extrathyroidal extension than M-FTCs with only one ultrasonography malignancy feature (P = .022). Compared with MI-FTCs (41/55, 74.5%), an irregular shape, a spiculated/microlobulated boundary, no peripheral halo ring, hypoechogenicity and microcalcification were more frequent in WI-FTCs (P < .001, P = .003, P = .002, P = .015, and P = .016, respectively).Our results demonstrated that B-FTCs had better prognostic indicators than M-FTCs. Therefore, preoperative US features can serve as a useful tool for predicting biological behavior in FTC. PMID- 30313116 TI - Giant gastric stromal tumor mimicking as a posterior mediastinal mass: A case report and literature review. AB - RATIONALE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Mediastinal GISTs are rare and mostly arise from the esophagus. PATIENT CONCERNS: A 68-year-old woman with dysphagia who presented with a huge posterior mediastinal mass. DIAGNOSES: The patient was diagnosed with a GIST through chest computed tomography (CT)-guided core biopsy of the mass. INTERVENTIONS: Complete excision including the tumor, lower part of the esophagus and fundus of the stomach were performed. OUTCOMES: On follow-up after 48 months, the patient is currently alive without any evidence of tumor recurrence. LESSONS: The case highlights GISTs are taken into consideration in the differential diagnosis of posterior mediastinal masses. PMID- 30313117 TI - Is additional 5-day vasoactive drug therapy necessary for acute variceal bleeding after successful endoscopic hemostasis?: A systematic review and meta-analysis. AB - BACKGROUND: Vasoactive drugs and endoscopic therapy have been widely used in the management of acute variceal bleeding of cirrhosis patients. The current standard regimen of vasoactive drugs is in combination with endoscopic therapy and continues for up to 5 days; however, the necessity of vasoactive drugs after endoscopic hemostasis was still controversial. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and optimal duration of adjuvant vasoactive drugs after hemorrhage control by endoscopic therapy. METHODS: A search was conducted of PubMed, EMBASE, and Cochrane Library databases until June, 2018. Lan DeMets sequential monitoring boundary was constructed to assess the reliability and conclusiveness of our major results. RESULTS: Seven studies (639 patients) and 4 studies (435 patients) were included in the analyses to evaluate the efficacy and optimal duration of adjuvant vasoactive drugs therapy, respectively. Our analyses showed that adjuvant vasoactive drugs facilitated endoscopic hemostasis and reduced very early re-bleeding rate both in sclerotherapy (risk ratio [RR] 0.51, 95% confidence interval [CI] 0.34-0.78, P = .23, I = 31%) and band ligation (RR 0.48, 95% CI 0.27-0.83, P = .07, I = 62%). However, the 3 to 5-day therapy duration was not superior to a shorter course in very early re-bleeding rate and mortality rate in 42 days (RR 1.77, 95% CI 0.64 4.89, P = .70, I = 0%; RR 0.95, 95% CI 0.43-2.13, P = .81, I = 0%, respectively). CONCLUSION: Additional 5-day vasoactive drug after endoscopic hemostasis may significantly ameliorate very early re-bleeding rate, However, the 3 to 5 days' adjuvant regimen was not superior to a shorter course. PMID- 30313118 TI - Association of ERAP1 gene polymorphisms with the susceptibility to psoriasis vulgaris: A case-control study. AB - Psoriasis vulgaris (PsV), also known as plaque psoriasis, is a life-threatening autoimmune skin disease. Inflammatory factors may contribute to the development of PsV. Present study aimed to explore the association of endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms (rs26653 and rs27524) with PsV susceptibility in a Chinese Han population. Subgroup analysis was also performed based on the onset of PsV.Present case-control study included 143 patients with PsV and 149 healthy controls. Direct sequencing method was used for genotyping ERAP1 polymorphisms. Chi-squared test was used to estimate the association between ERAP1 polymorphisms and PsV susceptibility. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess association strength.The polymorphism rs26653 was positively correlated with PsV susceptibility (CC vs GG, P = .047, OR = 1.964, 95% CI = 1.006-3.834; C vs G, P = .042, OR = 1.403, 95% CI = 1.011-1.946). Meanwhile, its CC genotype and C allele were positively associated with the early onset of PsV (P = .036, OR = 2.080, 95% CI = 1.044 4.145; P = .034, OR = 1.443, 95% CI = 1.028-2.024) and increased PsV risk in the subgroup with family history (P = .029, OR = 2.149, 95% CI = 1.075-4.296; P = .027, OR = 1.466, 95% CI = 1.044-2.059).ERAP1 gene rs26653 polymorphism may increase the risk of PsV in Chinese Han population. PMID- 30313119 TI - Primary mucosa-associated lymphoid tissue lymphoma of the hilar bile duct resulting in fluctuant jaundice: A case report. AB - RATIONALE: Primary mucosa-associated lymphoid tissue (MALT) lymphomas rarely originate in the hilar bile duct. Preoperative diagnosis of a primary MALT lymphoma of the hilar bile duct is difficult owing to the rarity of this disease. Differentiating between obstructive jaundice caused by MALT lymphoma of the hilar bile duct and hilar cholangiocarcinoma (the most common form of bile duct cancer) is challenging. PATIENT CONCERNS: A 57-year-old man presented to our hospital in August 2012 with fluctuant obstructive jaundice. DIAGNOSES: Contrast-enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography showed a hilar liver mass measuring 23 * 28 mm along with intrahepatic biliary dilatation indicating hilar bile duct obstruction with a high index of suspicion for hilar cholangiocarcinoma. INTERVENTIONS AND OUTCOMES: Based on frozen section examination, he was intraoperatively diagnosed with chronic nonspecific inflammation. Histopathological and immunohistochemical examinations confirmed a diagnosis of malignant lymphoma, specifically classified as an extranodal marginal zone B-cell lymphoma of MALT type. LESSONS: A primary MALT lymphoma of the bile duct should be considered among the differential diagnosis in patients with a hilar tumor who present with fluctuating jaundice and are preoperatively diagnosed with suspected hilar cholangiocarcinoma, and/or an intraoperative diagnosis of chronic nonspecific inflammation (based on frozen section examination) assessed for stenosis or obstruction of the bile duct. PMID- 30313120 TI - Gemcitabine plus S-1 for metastatic pancreatic cancer. AB - To investigate the treatment effects of gemcitabine plus S-1 (GS) for metastatic pancreatic cancer in our institution.Data from 41 patients with metastatic pancreatic cancer treated with GS regimen in West China Hospital, Sichuan University were reviewed. The therapeutic efficacy and toxicity were evaluated. The influencing factors of progression-free survival (PFS) and overall survival (OS) were also explored.At the last follow-up, all patients had died. The objective response rate was 22.0% (9/41) and the disease control rate was 65.9% (27/41). The median PFS and OS times were 5.1 (range, 1.5-21) and 10.6 months (range, 1.5-40), respectively. The 0.5-, 1-, and 2-year OS rates were 65.9%, 41.5%, and 9.8%, respectively. In multivariate analysis, body mass index and carbohydrate antigen 19-9 change were the significant influencing factors of PFS, compared to tumor site and chemotherapy cycles for OS. The adverse effects were moderate and tolerable.The effects of GS for metastatic pancreatic cancer in our institution were good. The adverse effects were moderate and tolerable. However, further investigation in future prospective clinical studies is warranted. PMID- 30313121 TI - Double-island anterolateral thigh free flap used in reconstruction for salvage surgery for locally recurrent head and neck carcinoma. AB - Salvage surgery is usually the only treatment for recurrent head and neck tumors but often poses a challenge to surgeons due to post-resected defects at 2 or more sites. Here we present the outcomes and rationale for reconstruction by a double island anterolateral thigh (ALT) free flap following the salvage surgery.Patients treated with double-island ALT free flaps in salvage surgery between September 2012 and January 2017 at West China Hospital, Sichuan University were retrospectively viewed.A total of 18 patients (15 males) underwent reconstruction with double-island ALT free flaps (range from 40 to 77 years old). All patients had recurrent tumors after surgery and/or chemoradiotherapy and were selected for salvage surgery by a multidisciplinary team. The flaps were initially harvested as 7 cm * 7 cm to 16 cm * 10 cm single blocks and then divided into double-island flaps with each individual paddle ranging from5 cm * 3 cm to 10 cm * 8 cm. The average flap thickness was 3.5 cm (range from 2 to 6 cm), and the average pedicle length was 8 cm (range from 6 to 10 cm). A total of 18 arteries and 32 veins were anastomosed. Three patients developed fistula, 1 developed flap failure due to thrombosis and was re-operated with a pedicle flap. One patient died of pulmonary infection 6 months after the operation.Flap reconstruction for complex head and neck defects after salvage surgery remains challenging, but double-island ALT free flap reconstruction conducted by a multidisciplinary team and experienced surgeons would have a role in this setting. PMID- 30313122 TI - Awareness of Polish undergraduate and graduate students regarding the impact of viral infections and high-risk sexual behaviors on the occurrence of oral cancer. AB - With every passing year, more and more studies and observations demonstrate growing incidence of oral cancer, a decrease in patients' age, and an increasing number of epidemiological factors. The aim of the study was to determine the level of awareness among undergraduate and graduate university students regarding the incidence of oral cancer linked with viral infections and high-risk sexual behavior, including oral sex. Self-administered questionnaire-based survey was carried out among 196 Polish students aged 19 to 25 years. It was found that the young adults understood the meaning of human papillomavirus (HPV), but associated it only with the squamous cell carcinoma of the cervix. A total of 43.4% did not realize that there was any correlation between HPV infection and the development of oral cancer. The students who were aware of this correlation constituted 40.3% of the total. The majority of the participants, that is, 82 subjects (41.8%), did not associate the occurrence of malignant neoplasms of the oral cavity with oral sex. The study group did not present adequate awareness of the fact that occurrence of oral cancer may be associated with high-risk sexual behaviors. Knowledge of oral cancer was not significantly related to the level of university education (P < .005). PMID- 30313124 TI - Clinical features and outcomes of gastric neuroendocrine tumors after endoscopic diagnosis and treatment: A digestive endoscopy society of Tawian (DEST): Erratum. PMID- 30313123 TI - Blunt traumatic diaphragmatic rupture: Single-center experience with 38 patients. AB - Blunt traumatic diaphragmatic rupture (BTDR) is uncommon, but is associated with high rates of morbidity and mortality. The purpose of this study was to present our experience with management of this injury. Medical records of 38 patients with BTDR who were treated in our hospital from January 2001 to June 2016 were analyzed retrospectively. The sex, age, cause of injury, location of rupture, mode of diagnosis, time to diagnosis, the presence of herniation and bowel perforation, the presence of preoperative shock and intubation, Injury Severity Score (ISS), associated injuries, comorbidity, the operative procedure, morbidity and mortality, and the predictive factors affecting the outcome of BTDR were evaluated. There were 32 men (84.2%) and 6 women (15.8%) with a mean age of 51.2 years (range 18-84 years). The diagnosis could be preoperatively established in 28 patients (73.7%) with a plain chest X-ray or computed tomography scan. Rupture of diaphragm was left-sided in 31 patients (81.6%), right-sided in 6 (15.8%), and bilateral in 1 (2.6%). Sixteen patients had preoperative shock (systolic blood pressure <90 mm Hg, heart rate >120/min). Initial operative approaches were laparotomy in 22 patients (57.9%) and thoracotomy in 16 (42.1%). Eleven required additional exploration. The rate of additional exploration was higher in patients who initially underwent thoracotomy than laparotomy (56.2% vs 9.1%, P = .003). Patients who underwent additional exploration had a significantly longer operation time (330 minutes vs 237.5 minutes, P = .012), and a significantly higher morbidity rate (72.7% vs 22.2%, P =.008). Overall mortality was observed in 6 patients (15.8%). The mortality was associated with right-sided TDR (P = .042) and preoperative shock (P = .003). Neither ISS nor delay in diagnosis posed a statistically significant risk to the outcome of patients. Intra-abdominal organ injuries are more common than intrathoracic injuries in patients with BTDR, indicating that laparotomy should be the initial approach in these patients. Preoperative shock and right-sided TDR are predictive of mortality after BTDR. PMID- 30313125 TI - Factors influencing the contamination rates of the conjunctival swabs and organ culture media of human donor eyes: Erratum. PMID- 30313126 TI - Efficacy of diode-emitting diode (LED) photobiomodulation in pain management, facial edema, trismus, and quality of life after extraction of retained lower third molars: A randomized, double-blind, placebo-controlled clinical trial: Erratum. PMID- 30313127 TI - The freshwater crab genera Ghatiana Pati Sharma, Gubernatoriana Bott, and Inglethelphusa Bott (Crustacea: Decapoda: Brachyura: Gecarcinucidae) revisited, with descriptions of a new genus and eleven new species. AB - The taxonomy of three morphologically related and endemic genera of the northern Western Ghats (Ghatiana Pati Sharma, 2014, Gubernatoriana Bott, 1970, and Inglethelphusa Bott, 1970) is re-assessed to accommodate several new taxa. We describe a new genus, Sahyadriana gen. nov. and its five new species [S. billyarjani sp. nov., S. pachyphallus sp. nov., S. sahyadriensis sp. nov. (type species), S. tenuiphallus sp. nov., and S. woodmasoni sp. nov.]. Additionally, three new species each of Ghatiana (Gh. botti sp. nov., Gh. pulchra sp. nov., and Gh. rathbunae sp. nov.) and Gubernatoriana (Gu. longipes sp. nov., Gu. marleshwarensis sp. nov., and Gu. wallacei sp. nov.) are described. Five species previously in Gubernatoriana are now transferred to Sahyadriana gen. nov., viz. S. alcocki (Pati in Pati, Thackeray Khaire, 2016) comb. nov., S. pilosipes (Alcock, 1909) comb. nov., S. thackerayi (Pati in Pati, Thackeray Khaire, 2016) comb. nov., S. triangulus (Pati Sharma, 2014) comb. nov., and S. waghi (Pati in Pati, Thackeray Khaire, 2016) comb. nov. Gubernatoriana basalticola Klaus, Fernandez Yeo, 2014, is transferred to Ghatiana. Inglethelphusa is still proved to be monotypic. Consequently, Ghatiana now contains eight species, three of which are new; Gubernatoriana, four species, including three new species; Inglethelphusa, one species; and Sahyadriana gen. nov., ten species, including five new species. Sahyadriana pilosipes is rediscovered more than a century after its description. All these genera can be separated from other Indian gecarcinucid crabs by the absence of a flagellum on the exopod of the third maxilliped and a very short G2. The relevant identification keys are revised. Currently, 120 species of freshwater crabs under 35 genera and two families are found in India. Kerala is the most species-rich (35 species) state in India followed by Maharashtra (29 species) and Assam (21 species). The Western Ghats of India now includes 17 genera and 58 species of gecarcinucid crabs. A checklist and distribution of Indian freshwater crabs is provided. PMID- 30313128 TI - Annotated checklist of Gonyleptoidea (Opiliones: Laniatores) associated with Brazilian caves. AB - In Brazil, the order Opiliones has been well studied, making this country the leader in research with the group, but few extensive works have been made on the distribution of harvestmen associated with caves. In this context, the present paper aims to list all records of the superfamily Gonyleptoidea associated with Brazilian caves, using records from the literature and unreported data from scientific collections. The compiled checklist contains the largest number of harvestmen species recorded for caves in one country, worldwide. A total of 155 species belonging to 7 families were recorded from 952 caves throughout 152 municipalities and 17 states of Brazil. A considerable number of 46 putative (undescribed) new species were recognized, including 9 troglomorphic species. Additionally, 161 new municipal records where found for 58 known species. The most diverse family was Gonyleptidae (104 spp.), with the subfamilies Pachylinae (55 spp.), followed by Goniosomatinae (18 spp.) and Mitobatinae (16 spp.). The number of described species analysed in the present work represents about 12% of the Brazilian opiliofauna of Gonyleptoidea, with many species widely distributed, being indicative of affinity of the group with the cave environments. Thus, the compilation of distribution data of such species (mainly the troglobitic and troglomorphic) can directly contribute to a higher valuation of their habitats, leading to better preservation policies, as well as being useful for future ecological and biogeographical studies. PMID- 30313129 TI - Taxonomic review of the genus Argyrops (Perciformes; Sparidae) with three new species from the Indo-West Pacific. AB - The Indo-West Pacific sparid genus Argyrops is reviewed, with four valid species and three new species: A. bleekeri Oshi-ma, 1927, A. filamentosus (Valenciennes, 1830), A. megalommatus (Klunzinger, 1870), A. spinifer (Forsskal, 1775), A. caeruleops n. sp., A. flavops n. sp. and A. notialis n. sp. The above seven species can be differentiated on meristic values, ontogenetic and morphological characters, and coloration. Argyrops bleekeri from the western Pacific and A. notialis n. sp. from Western Australia both have only one rudimentary dorsal-fin spine on the first dorsal pterygiophore (which defines the Argyrops bleekeri complex), while the five other congeners have two rudimentary dorsal-fin spines, both associated with the first dorsal pterygiophore. Argyrops filamentosus, A. megalommatus, and A. caeruleops n. sp. have the 3rd dorsal-fin spine filamentous and longest, the defining character of the A. filamentosus complex. Argyrops spinifer (from the Indian Ocean) and A. flavops n. sp. (from the Middle East to Pakistan, but not the Red Sea and probably rare in the Persian Gulf) differ from other complexes in having 4-6 elongated or filamentous dorsal-fin spines (usually 3rd-6th [four spines] or 3rd-8th [six spines]) in juveniles and subadults, with the first 2 dorsal-fin spines rudimentary, the characteristic of the A. spinifer complex. The above three complexes include the seven Argyrops species that are defined and supported by morphological and color differences, genetic distinctions (partial cytochrome b genes, 1,116 bp), and distribution. The nominal species are discussed, together with several geographic variations of A. spinifer from the Indian Ocean, and a key to the species is provided. PMID- 30313130 TI - Cicada fossils (Cicadoidea: Tettigarctidae and Cicadidae) with a review of the named fossilised Cicadidae. AB - The Cicadoidea comprise two families, the Cicadidae and the Tettigarctidae. This paper evaluates the status and taxonomy of all named Cicadoidea fossils belonging to the Cicadidae. Shcherbakov (2009) has previously revised the Tettigarctidae. Two new genera are described, Camuracicada gen. n. and Paleopsalta gen. n., for Camuracicada aichhorni (Heer, 1853) comb. n. and Paleopsalta ungeri (Heer, 1853) comb. n. A lectotype is designated for Cicada emathion Heer, 1853. Cicada grandiosa Scudder, 1892 is transferred to Hadoa Moulds, 2015 as Hadoa grandiosa comb. n.; Oncotympana lapidescens J. Zhang, 1989 is transferred to Hyalessa China, 1925 as Hyalessa lapidescens comb. n.; Meimuna incasa J. Zhang, Sun X. Zhang, 1994 and Meimuna miocenica J. Zhang X. Zhang, 1990 are transferred to Cryptotympana Stal, 1861 as Cryptotympana incasa comb. n. and Cryptotympana miocenica comb. n.; Tibicen sp. aff. japonicus Kato, 1925 is transferred to Auritibicen as Auritibicen sp. aff. japonicus comb. n., and Terpnosia sp. aff. vacua Olivier, 1790 is transferred to Yezoterpnosia Matsumura, 1917 as Yezoterpnosia sp. aff. vacua comb. n. The generic placement of two other fossils is changed to reflect current classification, those species now being Auritibicen bihamatus (Motschulsky, 1861) and Yezoterpnosia nigricosta (Motschulsky, 1866). Two species, Davispia bearcreekensis Cooper, 1941 and Lithocicada perita Cockerell, 1906, are transferred from the subfamily Cicadinae to the Tibicininae, tribe Tibicinini. Cicadatra serresi (Meunier, 1915) is also transferred from the Cicadinae to the Cicadettinae because the Cicadatrini have recently been transferred from the Cicadinae to the Cicadettinae (Marshall et al. 2018). Miocenoprasia grasseti Boulard and Riou, 1999 is transferred from the tribe Prasiini to the Lamotialnini. Tymocicada gorbunovi Becker-Migdisova, 1954 is transferred from the Dundubiini to the Cryptotympanini; Paracicadetta oligocenica Boulard Nel, 1990 is transferred from the Cicadettini to the Pagiphorini and Minyscapheus dominicanus Poinar et al., 2011 is assigned to the Taphurini. Names of species once considered to belong in Cicadidae, but now excluded, are listed with explanation. PMID- 30313131 TI - Two new species of Astyanax Baird Girard (Characiformes: Characidae) from the upper rio Paraguacu basin, Chapada Diamantina, Bahia, Brazil. AB - Astyanax lorien and A. rupestris are described from tributaries of upper rio Paraguacu basin, Bahia, Brazil. Both species shares the majority of the characters currently used to define the Astyanax scabripinnis species complex, with highest body depth approximately at vertical through pectoral-fin midlength and a low number of branched anal-fin rays (15-21). Astyanax lorien is distinguished from its congeners by a combination of characters, including presence of small bony hooks on all fins of mature males, a unique vertically elongate humeral blotch, and ventral margin of the third infraorbital close to the horizontal limb of preopercle. Astyanax rupestris is distinguished from its congeners also by a combination of characters, including ventral margin of third infraorbital distinctly separated from horizontal limb of preopercle, leaving a broad area without superficial bones, absence of midlateral stripe on body, absence of blotch on caudal peduncle, and presence of a vertically elongated conspicuous dark humeral blotch, not bordered anteriorly and posteriorly by distinct unpigmented areas. Both species are apparently endemic to the upper portion of the Paraguacu river basin, within the Chapada Diamantina domain. PMID- 30313132 TI - Description of an enigmatic new genus and new species of Australian Orthotylinae (Insecta: Heteroptera: Miridae) associated with the plant genus Eremophila. AB - A new genus and new species of Australian orthotyline is described: Warrumiris viridis gen. nov. et. sp. nov. The species is widespread in Australia, mostly in arid and semi-arid regions of the continent. The species is associated with two species of the scrophulariaceous genus Eremophila. The species has highly autapomorphic male genitalia, with the aedeagus mostly membraneous with elongate lobal sclerites. The significance of the male genitalia is discussed. PMID- 30313133 TI - Revised checklist of the butterflies of Serbia (Lepidoptera: Papilionoidea). AB - With studies spanning almost two centuries, butterflies are one of the best known insect groups in Serbia. However, there are still several inconsistencies regarding the number and selection of species included in national checklists published in the last decades. In order to overcome the confusing situation we provide a taxonomically up-to-date checklist of the butterflies for the country, including Kosovo, based on a comprehensive survey of the literature, inspection of available museum collections and from intensive field surveys over the last twenty years. Our aim is also to resolve some long standing problems with species potentially occurring in the country. For this purpose genitalia dissections and DNA barcoding have been used for identification where necessary. The annotated checklist includes 199 species of which Carcharodus orientalis is new for the country and the recently discovered white Anthocharis damone is listed for the first time. We also provide conclusive evidence of the presence of Melitaea ornata in Serbia. Among species listed in the previous species lists we excluded eight species due to inconclusive evidence, and provide a detailed explanation for their exclusion. We hope this publication will stimulate further studies of this important bioindicator group of insects and provide the basis for their conservation in the country. PMID- 30313134 TI - On the taxonomy of Lygosoma bampfyldei Bartlett, 1895 (Squamata: Scincidae) with descriptions of new species from Borneo and Peninsular Malaysia and the resurrection of Lygosoma schneideri Werner, 1900. AB - A reassessment of the taxonomy of Lygosoma bampfyldei based on morphology and color pattern indicates that it is a species complex containing L. bampfyldei Bartlett, 1895 from the Rajang River, Sarawak and Croker Range, Sabah in East Malaysia; L. peninsulare sp. nov. from Bukit Larut, Perak and 13.5 km east of Jeli, Kelantan, Peninsular Malaysia; L. kinabatanganensis sp. nov. from the Kinabatangan District, Deramakot camp (=Deramakot Sabah Forestry Department), Sabah, East Malaysia; and L. schneideri Werner, 1900 from Djapura, Indragiri, Sumatra, Indonesia-resurrected herein from the synonymy of L. bampfyldei. The new taxonomy aligns itself well with a growing body of literature demonstrating that semi-fossorial and fossorial Sundaic skinks are more diverse than previously considered. PMID- 30313135 TI - Two species and a genus new for Thailand, with description of a new species of Neurolarthra Fischer (Hymenoptera: Braconidae: Alysiinae). AB - Neurolarthra Fischer, 1976, is a small braconid genus with two described species. The genus is revised using morphological characters and a phylogenetic analysis of COI sequence data; GenBank accession numbers of seven COI sequences from two species are included. A new species from Thailand is described and illustrated: N. karensharkeyae Yao n. sp. Neurolarthra Fischer and N. procera are reported for the first time from Thailand. A key to species of the genus Neurolarthra is presented. PMID- 30313136 TI - Two new sympatric troglobitic freshwater flatworms (Platyhelminthes: Dugesiidae) from a hotspot of subterranean biodiversity in the Neotropics. AB - The Areias System, situated in the Atlantic Forest, is considered a hotspot of troglobitic diversity in Brazil. Herein we describe two new sympatric, troglobitic species of Girardia occurring in this system. Both species show minute eyes; one of them has a whitish body, and the other scattered, fine pigmentation over the dorsal surface. Regarding the copulatory apparatus, one of the species shows a bulbar cavity with multiple diverticula and a bursal canal of the angled type, whereas the other has a single, ovoid bulbar cavity and a smoothly curved bursal canal, among other distinguishing features. Thus, each species can be differentiated by a unique combination of features in its external morphology and copulatory apparatus. Both present a restricted distribution, occurring in a group of pools in travertine rock formed by water from the epikarst. The morphological features of both species and this sampling location indicate that both species are stygobionts. PMID- 30313137 TI - A new highly troglomorphic Loxosceles (Araneae: Sicariidae) from Brazil. AB - The spiders of the genus Loxosceles have been reported from caves in several regions of the world. Despite their commonness in subterranean habitats, the occurrence of troglomorphic species is quite rare. A new cave-dwelling species found in the Brazilian Caatinga can be included in the restricted list of troglomorphic Loxosceles by presenting the following troglomorphic traits: eyes with reduced diameter, absence of pigment around the eyes, appendage elongation and pale coloration. Thus, the aim of this study is to describe a new highly troglomorphic species of Loxosceles from Brazil, corresponding to the first troglomorphic species from South America. Loxosceles troglobia sp. nov. belongs to the gaucho group and can be distinguished from the other species of this group mainly by the presence of the troglomorphic characteristics mentioned above and by the shape of the female spermathecae and the male palp. The morphological traits, together with the fact that the new species was found only in inner and very humid portions of two nearby caves, indicate that it is troglobitic. PMID- 30313138 TI - Omophorus (Sinomophorus) wallacei: a new weevil from Borneo highlights the enigmatic Ethiopian-Oriental disjunct distribution (Coleoptera, Curculionidae, Molytinae). AB - In the present study we describe a new species of the genus Omophorus, O. (Sinomophorus) wallacei sp. nov., from Malaysian Borneo. Photographs of habitus and genitalia, a distribution map, and a key for the identification of Omophorus species are included. The definition of the subgenus Sinomophorus is revised and several new diagnostic characters are added. This is the first documented occurrence of Omophorus in Borneo, highlighting its potential diversity in the Oriental region and providing additional evidence of Ethiopian-Oriental disjunction within this genus. PMID- 30313139 TI - Libelloidini, new name for an old tribe (Neuroptera Ascalaphidae). AB - Almost a half century ago, Tjeder (1972) stated that the genus Ascalaphus had been interpreted in a sense other than that defined by its type species (see Pantaleoni and Loru 2018). So, the generic name Ascalaphus Fabricius, 1775, became the senior synonym of Helicomitus McLachlan, 1871, and the genus Libelloides, Schaffer, 1763, was reserved for the Palearctic diurnal coloured owlflies, which until then were considered to belong to the genus Ascalaphus. Even though Tjeder's proposition produced a dramatic change in a long-term "prevailing usage", it was immediately and universally accepted as necessary. However, surprisingly, this change was never followed by the consequent necessary nomenclatural changes at the family-group name level. PMID- 30313140 TI - Hongchoristites nomen novum: a replacement name for the Middle Triasic fossil Choristites Hong, 2005 (Insecta: Mecoptera: Permochoristidae). AB - The fossil mecopteran genus Choristites was established by Hong in 2005, making Choristites martinsoni Hong, 2005 its type and only species. Hong placed this genus in family Permochoristidae Tillyard, 1917. The species was discovered from the Mid-Triassic Tongchuan Formation of Tongchuan region, Shaanxi Province and, until now, there have been no further records of Choristites martinsoni. PMID- 30313141 TI - Erratum: ANDRE MARSOLA GIROTI ANTONIO DOMINGOS BRESCOVIT (2018) The taxonomy of the American Ariadna Audouin (Araneae: Synspermiata: Segestriidae). Zootaxa, 4400 (1): 001-114. PMID- 30313142 TI - New enigmatic species of the genus Pediobius (Hymenoptera, Eulophidae) from Afrotropics, with notes on related genera. AB - Three new species groups and seven species of the genus Pediobius Walker are described from the Afrotropical realm: the marjoriae group, with P. marjoriae Kerrich (described from Uganda), P. rohombaya Gumovsky sp. n. (from the Central African Republic (CAR), the Democratic Republic of the Congo (DRC), Gabon, Uganda) and P. orungu Gumovsky sp. n. (from Gabon); the afroteres group with P. afroteres Gumovsky sp. n. (from South Africa, Zimbabwe, Malawi, Kenya, Uganda, DRC, Cameroon) and P. kafroteres Gumovsky sp. n. (from Cameroon); the askari group with P. askari Gumovsky sp. n. (from South Africa, Zimbabwe, Kenya, Tanzania, DRC, Ivory Coast) and P. maleficus Gumovsky sp. n. (from Kenya, DRC, CAR, Cameroon, Gabon); and P. nganga Gumovsky sp. n. (from DRC) (not assigned to any group). All these species are characterized by the relatively wide and robust head with elongate and/or narrowed lower face and the antennae attached near or below the lower eye margins. Morphological features of the species, as well as their habitat distribution, are discussed. The comparison of the new species with similar taxa of Entedoninae suggested the following synonymies: Rhynchentedon Girault and Pediobomyia Girault under Pediobius (syn. n.); Bomyiabius frontus Narendran, Pediobomyia budaicus Narendran and Pediobomyia lankicus Narendran under Pediobomyia darwini Girault (syn. n.). The following new combinations are proposed: Pediobius maximus (Girault), P. achterbergi (Gumovsky), P. narendrani (Gumovsky), P. brevicaulis (Hansson), P. canaliculatus (Hansson) and P. darwini (Girault) (comb. n.). Ant parasitoids P. marjoriae and Myrmokata diparoides Boucek are recorded from DRC for the first time. PMID- 30313143 TI - New records of cotylean flatworms (Platyhelminthes: Polycladida: Rhabditophora) from coastal habitats of Israel. AB - Seven new records of cotylean flatworms belonging to two families and four genera were identified from Israel collected in the eastern Mediterranean Sea and the northern Red Sea. The family Pseudocerotidae was represented by three genera and six species (Pseudoceros duplicinctus, Pseudobiceros apricus, Pseudobiceros damawan, Pseudobiceros murinus, Pseudobiceros stellae, and Thysanozoon brocchii), followed by the Euryleptidae with a single species (Maritigrella fuscopunctata). Pseudoceros duplicinctus is recognized as a senior synonym of Pseudoceros prudhoei and color and pattern variations are reported for Maritigrella fuscopunctata. In addition, the presence of Pericelis byerleyana in the northern Gulf of Aqaba is confirmed, illustrated, and properly described with morphological and molecular data. Pseudoceros duplicinctus and Pseudobiceros stellae represent new geographic records for the Mediterranean Sea and Pseudobiceros apricus and Pseudobiceros damawan are new for the Red Sea. Detailed morphological analysis with emphasis on the color and pattern was applied for species identifications including high quality photographs of live and fixed animals. Partial sequences of the 28S ribosomal DNA (rDNA) of four of the species were obtained and deposited in GenBank with accession numbers provided with the corresponding species description. Our results represent a significant taxonomic contribution for the diversity and distribution of the Polycladida in Israel pointing out the importance for more integrative and comprehensive surveys in these two regions to advance the knowledge of marine biodiversity worldwide and along both Israeli coasts. PMID- 30313144 TI - Two new genera of predatory katydids (Orthoptera: Tettigoniidae: Meconematinae) from the Amazon rainforest. AB - Meconematinae comprise small predatory katydids. There are currently seven genera and 58 species recorded for the Neotropical region. Two new genera of Phlugidini are described from the Amazon region, Arboraptor gen. nov., type species Arboraptor viridis sp. nov., and Tyrannoraptor gen. nov., type species Tyrannoraptor arboreus (Nickle, 2003) n. comb. A key to the Neotropical genera of Phlugidini is included and we provide a map showing the known distribution plus comments on their behavior observed during fieldwork. PMID- 30313145 TI - Molecular evidence for conspecificity of two desert Liolaemus lizards (Iguania: Liolaemidae). AB - Liolaemus audituvelatus (Nunez Yanez 1983) and L. manueli (Nunez, Navarro, Garin, Pincheira-Donoso Meriggio 2003) are endemic species of the Atacama Desert of northern Chile that belong to the montanus group. Both species are considered cryptic from each other and can only be distinguished by their distribution ranges and karyotypes. Originally, there was a wide separation zone between their known distribution ranges, but later collections reduced the gap from 430 km to only 150 km. In this study, we review the geographic information about both species and report new localities within the distribution gap, where species identification becomes difficult. We performed a molecular phylogenetic analysis and applied several species delimitation methods to reassess the taxonomic status of both nominal species and new intermediate populations. Our analyses support the placement of L. manueli in the synonymy of L. audituvelatus. We discuss the biogeographic and conservation implications of this new synonymy. PMID- 30313146 TI - Revision of the Australian bee fly genus Pilosia Hull, 1973 (Bombyliidae, Bombyliinae) from Western Australia. AB - A restricted Western Australia bee fly genus Pilosia Hull (Bombyliidae, Bombyliinae) is reviewed with the description of two new species, Pilosia incana Bowden Li sp. nov. and Pilosia flava Li Yeates sp. nov., and the type species, Pilosia flavopilosa Hull, 1973 is identified as a new junior synonym of Pilosia immutatus (Walker, 1849). This genus can easily be distinguished from other Australian genera in the subfamily by having a three-segmented antennal flagellum, a closed cell cup and a haired mediotergite. A recent morphological phylogeny of Australian Bombyliinae suggested Pilosia is sister to all the remaining Bombyliinae genera (Li Yeates, 2018). A key to all three known species of Pilosia is provided. PMID- 30313147 TI - A new skink of the genus Sphenomorphus Fitzinger, 1843 (Squamata: Scincidae) from Hon Ba Nature Reserve, southern Vietnam. AB - A new forest skink of the genus Sphenomorphus Fitzinger, 1843 is described from Khanh Hoa Province, southern Vietnam based on morphological characters of four specimens and a fragment of 653 nucleotides of the gene COI. Sphenomorphus yersini sp. nov. is characterized by the following morphological characters: medium size in adults (snout-vent length up to 55 mm); tail length/snout-vent length ratio 1.81; toes reach to fingers when limbs adpressed; midbody scale rows 32-34, smooth; paravertebral scales 61-69; ventral scale rows 58-67; subcaudal scales 112; supraoculars four, rarely five; prefrontals in broad contact with one another; loreal scales two; tympanum deeply sunk; smooth lamellae beneath finger and toe IV 10-12 and 18-20 respectively; a pair of enlarged precloacal scales; hemipenis deeply forked and asymmetrical with two differently sized smooth lobes. The new species differs from its most similar congener, Sphenomorphus buenloicus Darevsky Nguyen, 1983, by 16.4-16.7% uncorrected p-distance in COI sequences. PMID- 30313148 TI - Descriptions of the adult male, prepupa and pupa of Xylococcus castanopsis Wu Huang (Hemiptera: Coccomorpha: Xylococcidae). AB - The morphologies of the adult male, prepupa and pupa of Xylococcus castanopsis Wu Huang (Hemiptera: Xylococcidae) are described and illustrated. These developmental stages were collected at Tianluhu Forest Park, Guangzhou city, Guangdong Province, China, from the same forest stands as the holotype female. PMID- 30313149 TI - Description of a new Charinus species (Amblypygi: Charinidae) from the Monsenor Nouel province, Dominican Republic. AB - A new species of Charinus Simon, 1892 from the Dominican Republic is described. With the addition of Charinus magua sp. nov. from the Monsenor Nouel province, the number of known members of the genus Charinus occurring on the island Hispaniola is increased to three. The frontal process, the trichobothria on leg IV, the number and shape of the articles of leg I and the shape of the tarsomers of legs II-IV are often included in taxonomical descriptions of Charinus species. We present these characters in the detailed description of C. magua sp. nov. and illustrate these for the first time for the two other known Charinus from Hispaniola, Charinus dominicanus and Charinus bahoruco. Furthermore, we present and discuss the cerotegument ultrastructure of all three species. PMID- 30313150 TI - New data on Cladocera (Crustacea: Branchiopoda) of Sabah State, Borneo Island, Malaysia. AB - Unlike those in the mainland of Southeast Asia, the Cladocera of the Malay Archipelago has not been intensively studied, except for the state of Sabah in the north-eastern part of the Borneo island. This study aimed to complete the inventory of the Cladocera in Sabah by looking at different types of water bodies including oxbow lakes, small lakes, reservoirs, ponds, ditches and paddy fields. From 32 sites examined, 35 species of cladocerans, nine of which were new records to Sabah, were found from 25 localities. With this new finding, the total number of cladoceran species in Sabah increased to 39 species, including five species of Sididae, four species of Daphniidae, one species of Moinidae, five species of Macrothricidae, two species of Ilyocryptidae, and 22 species of Chydoridae. Only 8 % ( three species) of Sabah cladocerans are true planktonic. This study illustrated that most cladocerans were associated with substrates in the littoral zone and thus appropriate sampling methods should be employed in different microhabitats for comprehensive biodiversity assessment. PMID- 30313151 TI - Madangella altirostris, a new genus and species of palaemonid shrimps (Crustacea: Decapoda: Palaemonidae) from Papua New Guinea. AB - A single ovigerous female specimen of marine shrimp of the family Palaemonidae collected from Madang Province, N.E. Papua New Guinea, was recognized as a representative of a new genus and species. Due to the presence of a sternal thoracic process, 3 pairs of posterior telson cuspidate setae, and the simple ambulatory dactyli, as well as the lack of branchiae on the two posterior maxillipeds, the new species clearly belongs to the assemblage of primarily free living palaemonid taxa surrounding the speciose genera Cuapetes and Palaemonella. As the specimen possesses a short leaf-like rostrum, slender second pereiopods with small chelae similar to and not noticeably longer than the first pereiopods and very slender simple ambulatory dactyli, the specimen is without parallel within this assemblage and clearly represents a new genus. Its position within the Cuapetes/Palaemonella lineage of genera is also confirmed by a molecular comparison. The specimen is described and illustrated as a new genus and species. PMID- 30313152 TI - Lissothuria imbricata sp. nov., a new species of sea cucumber (Echinodermata: Holothuroidea) from the central-eastern Pacific Ocean. AB - A new species of sea cucumbers of the genus Lissothuria Verrill, 1867 is described. Lissothuria imbricata sp. nov. was found in the central-eastern Pacific Ocean, at 2-16 m depth living on top of rocky reefs, partially covered by algae and organic material. It is distinguished from other species of the genus by having body wall ossicles in form of short, broad towers with a slightly spiny apex, giving the dorsal area a granular appearance. The shape of the ossicles shows some similarities with L. nutriens (H.L. Clark, 1901). PMID- 30313153 TI - Didogobius janetarum sp. nov., a new cryptobenthic goby species from the Cape Verde Islands (Teleostei: Gobiidae). AB - Didogobius janetarum sp. nov. is described from five specimens collected from small caves and rock crevices between 12 and 20 m depth off two locations of Santiago Island, Cape Verde Islands. The species differs from all currently described congeners by the combination of the following characters: (1) 27 vertebrae, (2) second dorsal fin I + 10, (3) posterior quarter of predorsal region in front of first dorsal fin origin scaled, with several rows of cycloid scales, (4) body squamation cycloid anteriorly and ctenoid posteriorly, (5) scales in the lateral series 30-32, (6) anterior oculoscapular canal present, (7) preopercular head canal absent, (8) suborbital row 7 each a single papilla, (9) suborbital rows 2 and 4 close to orbit, and by (10) branchiostegal membranes uniformely black below preopercle, forming a V-shaped mark. Definitions for all used meristic counts are presented to serve as a reference for gobioid meristic studies. The genus is rediagnosed to accommodate recently described Didogobius species. PMID- 30313154 TI - New genus of the subfamily Oscinellinae from Brazil (Diptera: Chloropidae). AB - The genus Paracalamoncosis gen. nov. is described based on the species P. brasiliensis gen. nov. et sp. nov., including a brief discussion of the morphological similarities and differences with other genera in the tribe Liparaini. PMID- 30313155 TI - Taxonomic revision of the Malagasy Camponotus subgenus Mayria Hymenoptera, Formicidae) using qualitative and quantitative morphology. AB - The Camponotus subgenus Mayria is revised based on the analysis of both qualitative morphological characters and morphometric traits. The multivariate analysis combined the Nest Centroid (NC)-clustering method and Partitioning Algorithm based on Recursive Thresholding (PART) function to generate species hypotheses based on 19 continuous morphological traits of minor workers. The proposed species hypotheses were confirmed by cumulative Linear Discriminant Analysis (LDA). Morphometric ratios for the subsets of minor and major workers were used in species descriptions and redefinitions. In this study, 14 species are recognized, of which seven are newly described: C. lamosy sp. n., C. liandia sp. n., C. mainty sp. n., C. manabo sp. n., C. raina sp. n., C. sada sp. n., C. tanosy sp. n. Four species are redescribed: C. christi Forel, C. dromedarius Forel, C. lubbocki Forel, and C. repens Forel. The following are raised to species and redescribed: C. foersteri Forel stat. n., C. maculiventris Emery stat. n., and C. pulcher stat. n. The following are synonymized under C. foersteri: Camponotus cambouei Forel, syn. n.; C. christi ambustus Forel, syn. n.; C. christi ferrugineus Emery, syn. n. and C. pictipes Forel, syn. n. The following are synonymized under C. lubbocki: Camponotus lubbocki christoides Forel, syn. n. and C. lubbocki rectus Forel, syn. n. Also included in this revision are an illustrated species identification key, taxonomic discussions, images, and distribution maps for each species superimposed with the ecoregions of Madagascar. PMID- 30313156 TI - A contribution to the knowledge of the centipedes of Saint Barthelemy Island (French Antilles), with re-descriptions of Newportia heteropoda Chamberlin, 1918 and Cormocephalus impressus Porat, 1876 (Chilopoda: Scolopendromorpha). AB - The paper provides descriptions of three scolopendromorph centipede species collected in Saint Barthelemy Island. Two of them, Newportia heteropoda Chamberlin, 1918 and Cormocephalus impressus Porat, 1876 are redescribed and their systematic position is discussed. The taxonomic status of Newportia cubana Chamberlin, 1915 is revised, this nominal taxon being treated as the subspecies N. longitarsis cubana stat. nov. C. guildingii Newport, 1845 is confirmed as a valid species of which C. bonaerius Attems, 1928 is considered as a junior synonym. An identification key to the Scolopendromorpha of the island is presented. PMID- 30313157 TI - When the unknown lives next door: a study of central Amazonian anurofauna. AB - The number of species of anurans in the Amazon is highly underestimated with new studies reporting the discovery of a large number of species every year. This advance in the discovery of biodiversity is due to the use of molecular tools, especially 16S rRNA gene barcoding, which is used to identify species and discover cryptic lineages. Few anurans of the central Amazon have molecular sequence data available in public databases, which contrasts with the considerable species richness of this biome. The aim of the present study was to test for the presence of cryptic species using the mPTP delimitation algorism. We morphologically identified 26 species, of which 23 were confirmed molecularly with the remaining three species identified as other congeneric species, since sequences with the same epithet do not exist in GenBank. Of these 23 species, nine contained one lineage restricted to central Amazon. This represents an underestimate of 39% in the taxonomic diversity in our sample. This is particularly surprising given that our sampling sites are among the best-studied regions of the central Amazon. PMID- 30313158 TI - Taxonomic revision of the Square-tailed Drongo species complex (Passeriformes: Dicruridae) with description of a new species from western Africa. AB - We describe a new species of drongo in the Square-tailed Drongo (Dicrurus ludwigii) complex using a combination of biometric and genetic data. The new species differs from previously described taxa in the Square-tailed Drongo complex by possessing a significantly heavier bill and via substantial genetic divergence (6.7%) from its sister-species D. sharpei. The new species is distributed across the gallery forests of coastal Guinea, extending to the Niger and Benue Rivers of Nigeria. We suspect that this taxon was overlooked by previous avian systematists because they either lacked comparative material from western Africa or because the key diagnostic morphological character (bill characteristics) was not measured. We provide an updated taxonomy of the Square tailed Drongo species complex. PMID- 30313159 TI - Five new records of marine shrimps (Decapoda: Caridea, Stenopodidea) from the Caribbean coast of Panama. AB - Five species of shrimps, four carideans and one stenopodidean, are recorded for the first time from the Caribbean coast of Panama: Lysmata vittata (Stimpson, 1860) [Lysmatidae Dana, 1852], Periclimenaeus ascidiarum Holthuis, 1951, P. bredini Chace, 1972, P. maxillulidens (Schmitt, 1936) [Palaemonidae Rafinesque, 1815], and Odontozona edyli Criales Lemaitre, 2017 [Stenopodidae Claus, 1872]. Rather surprisingly, L. vittata is recorded from the Caribbean Sea for the first time. However, the taxonomic status of all western Atlantic specimens currently assigned to L. vittata (including the Panamanian material and the Brazilian L. rauli Laubenheimer Rhyne, 2010) will need a much more careful reassessment, which will only be possible after determining the taxonomic identity of L. vittata in the Indo-West Pacific. The colour patterns of P. ascidiarum, P. bredini and O. edyli, herein illustrated for the first time, appear to be species-diagnostic and may serve as additional important taxonomic characters. For O. edyli, the previously unknown thoracic sternum of the female is illustrated, as well as the variation in the rostral dentition. PMID- 30313160 TI - Taxonomy and Natural History of Strumigenys thaxteri Wheeler and Strumigenys reticeps (Kempf) (Hymenoptera: Formicidae). AB - We report finding Strumigenys thaxteri Wheeler in the Amazonian foothills of southeastern Ecuador, over 2000 km to the west of previously known records for the species in Trinidad and Guyana. Field observations suggest it is a sit and wait ambush predator that captures insects that alight on the vegetation upon which they position themselves. Once prey is subdued they descend with it to ground level, where they presumably nest. Their massive mandibles, robust claws, dense body cover of long silky hairs, and sting may all contribute to detecting, trapping, and subduing larger sized, flying prey. This type of predation is hitherto unreported for the genus. Strumigenys reticeps (Kempf), an apparently closely related species from southern Brazil, may share the same behavior but its key morphological traits are of a lesser degree of development than in S. thaxteri. Both species are redescribed and their morphological variability is discussed. High resolution images of both species are provided. The more frequent use of vegetation beating for ant-collecting is urged. Strumigenys lojanensis Lattke Aguirre is synonymized as a junior synonym of S. onorei Baroni Urbani De Andrade. PMID- 30313161 TI - Notes on the genus Conocephalus Thunberg, 1815 (Orthoptera: Tettigoniidae: Conocephalinae) in Southwest China with description of one new species. AB - This paper reports eight species of the genus Conocephalus from Southwest China, including one new species, Conocephalus (Anisoptera) gracilicercus sp. nov., and provides the characteristic and habitus photographs. PMID- 30313162 TI - One new species of Baburia Kocak, 1981 and one of Metendothenia Diakonoff, 1973 (Lepidoptera: Tortricidae: Olethreutinae) from Thailand. AB - Two new species of the tribe Olethreutini are described and illustrated from Thailand: Baburia paucustriga Jirasuttayaporn and Pinkaew, n.sp., and Metendothenia ordospina Jirasuttayaporn and Pinkaew, n.sp. The two new taxa increase the number of described species in Baburia to three and in Metendothenia to 14. PMID- 30313163 TI - New species of many-plumed moths (Lepidoptera: Alucitidae) from Tanzania. AB - Basing on the examination of new material on many-plumed moths from Tanzania, four new species have been discovered: Alucita agassizi Ustjuzhanin Kovtunovich sp. nov., A. iringiensis Ustjuzhanin Kovtunovich sp. nov., A. snezhinka Ustjuzhanin Kovtunovich sp. nov. and A. tanzanica Ustjuzhanin Kovtunovich sp. nov. They are described and compared with the closest species. The diagnostic characters for each new taxon are specified. The genitalia are described and illustrated, images of the adults are provided. Data on many-plumed moths previously unknown for Tanzania are given. Two species, A. seychellensis (Fletcher 1910) and A. malawica (Ustjuzhanin Kovtunovich, 2016) are reported from Tanzania for the first time. PMID- 30313164 TI - The taxonomic status of the "forgotten" Bolivian snakes, Atractus balzani Boulenger 1898 and Atractus maculatus (sensu Boulenger 1896) (Serpentes: Dipsadidae). AB - The genus Atractus Wagler 1828 comprises almost 150 currently recognized species of cryptozoic snakes widespread in the Neotropics, occurring from Panama to northeastern Argentina (Passos et al. 2016a). Despite the publication of the descriptions of several new species within the last decade, the taxonomy of the genus is unclear in some instances. This is mainly due to the fact that a number of poorly delimited taxa still exist (Passos et al. 2018). The most frequent problem faced by taxonomist working with the genus Atractus is the lack of specimens available for several species, most of them only still being known from their types, a situation that considerably weakens the definition of species boundaries between closely related taxa (Passos et al. 2010a, 2013). More importantly, many of the previously recognized species may represent aberrant individuals with unusual or abnormal scale counts, anomalous azygous or fused cephalic plates, infrequent polychromatic patterns, or any combination of these states (see Passos et al. 2016b). In the course of a thorough taxonomic review of the genus (Passos 2008; Passos et al. 2018), an effort has been made to examine all of the available types (including those apparently lost or misplaced in collections) and material of historical importance that was previously referred to the genus in the literature, and these were then compared to newer samples collected more recently. During the examination of the collections of the Natural History Museum of London and the Museo Civico di Storia Naturale of Genova, we found important specimens of Atractus from Bolivia. However, in order to better understand all the problems related to these old and "forgotten" Bolivian snakes, we need to examine their history. PMID- 30313165 TI - A new hypogean species of the genus Chaetomargoreicheia Magrini Bulirsch, 2005 (Carabidae: Scaritinae: Clivinini) from Croatia. AB - Chaetomargoreicheia Magrini Bulirsch, 2005 is a recently established genus of scaritine ground beetles (Bulirsch Gueorguiev, 2008) (treated by certain authors as a subgenus of the genus Reicheadella Reitter, 1913) (Magrini Bulirsch, 2005; Balkenohl, 2017) which currently contains two endogean species inhabiting the Balkan Peninsula: Chaetomargoreicheia zoufali (Reitter, 1913) and C. lakotai (Magrini Bulirsch, 2005) (Balkenohl, 2003, 2017; Magrini Bulirsch, 2005; Bulirsch Gueorguiev, 2008). The aforementioned species are montane and inhabit confined geographic areas (Jeannel, 1957; Magrini Bulirsch, 2005). C. zoufali was found only in the surroundings of the village of Ravno (collected beneath a deep layer of leaf-litter), Mt. Bjelasnica, near Trebinje, E Herzegovina (Bosnia and Herzegovina), while C. lakotai was found at the entrance of a cave nearby a road (collected under a huge stone), in Mt. Lovcen, near Kotor, S Montenegro (Reitter, 1913; Holdhaus, 1924; Jeannel, 1957; Magrini Bulirsch, 2005). Chaetomargoreicheia species represent quite rare, stenoendemic taxa, for each of the up-to-now known species only one specimen has been collected by hand so far (Reitter, 1913; Jeannel, 1957; Magrini Bulirsch, 2005). The fourth author of the current study investigated numerous underground and endogean high-altitude habitats in Dalmatia (Croatia) in the last few years. As a result of the exploration, he has recently collected a small sample of scaritine ground beetles from a cave in S Croatia. After thorough analysis of the sample, we have identified a new Chaetomargoreicheia species. PMID- 30313166 TI - A new species and a new record of Pelthydrus Orchymont, 1919 from Yunnan, China (Coleoptera: Hydrophilidae: Hydrophilinae). AB - The members of the genus Pelthydrus are small-sized aquatic beetles which belong to the water scavenger beetle family Hydrophilidae. At present the lineage includes 63 valid species mainly occurring in Asia, with 21 known from China (Bian et al. 2008, 2009; Hansen 1999; Schonmann 1995). One new species is described here, which belongs to the Pelthydrus sculpturatus species group, bringing the total number of species within the group to seven (Schonmann 1995). One additional species is reported from China for the first time. Specimens were collected from Yunnan Province and are deposited in IAECAS (Institute of Applied Ecology, Shenyang, Chinese Academy of Sciences). PMID- 30313167 TI - Contribution to the fauna of the genus Meroplius Rondani, 1874 (Diptera, Sepsidae) of the Australasian/Oceanian region. AB - Flies of the genus Meroplius Rondani, 1874 (Diptera: Sepsidae) of the Australasian and Oceanian regions, which includes 3 species, are reviewed. Generic and species descriptions and a key for the determination of species are given, and distribution data are summarized. One species, Meroplius timikana sp. nov. is described as new to science. PMID- 30313168 TI - European bees of the genera Epeolus Latreille, 1802 and Triepeolus Robertson, 1901 (Hymenoptera: Apidae: Nomadinae: Epeolini): taxonomy, identification key, distribution, and ecology. AB - Seventeen species of Epeolus Latreille, 1802 and one species of Triepeolus Robertson, 1901 have been recorded from Europe. Members of these genera are cuckoo bees, cleptoparasites that appropriate provisions of other bee genera (Colletes Latreille [hosts of Epeolus] and Tetraloniella Ashmead [hosts of Palaearctic Triepeolus]) for their own offspring. We present an identification key to all European species plus four species known from neighbouring regions (the Middle East and North Africa) that might also occur in Europe. The taxonomy of all species is reviewed, with new synonymies proposed, one subspecies elevated to a species (Epeolus eriwanensis Bischoff, 1930, stat. nov.), and a new species (Epeolus ibericus Bogusch, sp. nov.) described. Five new synonymies are proposed: E. giannelli Gribodo, 1894 syn. nov. and Epeolus speculifer Perez, 1895 syn. nov. under E. fallax Morawitz, 1872, E. berlandi Benoist, 1943 syn. nov. and E. laevigatus Bischoff, 1930 syn. nov. under E. flavociliatus Friese, 1899, and E. julliani Perez, 1884 syn. nov. under E. transitorius Eversmann, 1852. The following species are redescribed because their identity is less clear due to type specimens and/or vague original descriptions: Epeolus aureovestitus Dours, 1873, Epeolus cruciger (Panzer, 1799), Epeolus fallax Morawitz, 1872, Epeolus schummeli Schilling, 1849, Epeolus siculus Giordani Soika, 1944, and Epeolus variegatus (Linnaeus, 1758). Males are described for the first time for the following species: Epeolus compar Alfken, 1938, Epeolus eriwanensis Bischoff, 1930, Epeolus intermedius Perez, 1884, Epeolus laevifrons Bischoff, 1930, and Epeolus subrufescens Saunders, 1908. Distribution maps created using records from the literature and data from private and museum collections are also provided, which show changes in the distributions of epeoline bees before and after 1990. Several species are considered endangered, especially Epeolus fasciatus Friese, 1895, which is nearly extinct, and Epeolus tarsalis Morawitz, 1874, which was recently reported only from the coastal parts of the Netherlands and Belgium. Epeolus variegatus is the only common and widespread species still encountered in most of Europe. Comprehensive information on the ecology of these cuckoo bees is also included. PMID- 30313169 TI - The laevigata-group of the genus Dolichogenidea Mason, 1981 from China, with descriptions of 26 new species. AB - The laevigata-group of the genus Dolichogenidea from China is revised, with 26 new species described and illustrated, i.e., D. aberrantenna Liu Chen, sp. n.; D. aegeriphagous Liu Chen, sp. n.; D. ancylotergita Liu Chen, sp. n.; D. anteruga Liu Chen, sp. n.; D. biconcava Liu Chen, sp. n.; D. brevifacialis Liu Chen, sp. n.; D. changbaiensis Liu Chen, sp. n.; D. concentricus Liu Chen, sp. n.; D. dioryctriphagous Liu Chen, sp. n.; D. fumeus Liu Chen, sp. n.; D. funalicauda Liu Chen, sp. n.; D. gansuensis Liu Chen, sp. n.; D. indicaphagous Liu Chen, sp. n.; D. longivena Liu Chen, sp. n.; D. mesocanalis Liu Chen, sp. n.; D. obscurugosus Liu Chen, sp. n.; D. paracostulae Liu Chen, sp. n.; D. parametacarp Liu Chen, sp. n.; D. partergita Liu Chen, sp. n.; D. poliobrevis Liu Chen, sp. n.; D. polystinelliphagous Liu Chen, sp. n.; D. sandwico Liu Chen, sp. n.; D. spinulicula Liu Chen, sp. n.; D. stictoscutella Liu Chen, sp. n.; D. testacea Liu Chen, sp. n., and D. unicarina Liu Chen, sp. n. Seven species, namely D. breviventris (Ratzeburg, 1848), D. litae (Nixon,1972), D. mycale (Nixon, 1972), D. nixosiris (Papp,1976), D. sicarius (Marshall,1885), D. sophiae (Papp, 1972), and D. turkmenus (Telenga,1955), are newly recorded in China. One species, D. jilinensis Chen et Song, 2004, is synonymized with D. purdus Papp, 1977. Three new combinations, i.e., D. sugae (Watanabe, 1932), D. hamakii (Watanabe, 1932) and D. absonus (Muesebeck, 1965) are proposed. Phalonia epilinana Linne (Lepidoptera: Tortricidae) is newly recorded as a host of D. sicarius (Marshall). A key to the Chinese species of this species-group is provided. PMID- 30313170 TI - Catalogue of oribatid mites (Acari: Oribatida) from South Tyrol (Prov. Bolzano, Italy). AB - A checklist of the oribatid mites reported in South Tyrol (Italy) is presented, covering all published records until 2017. Numerous unpublished records are added. Several species were revised, doubtful and erroneous records from previous publications are discussed and corrected if necessary. A total of 397 described species in 71 families are listed, complemented by two subspecies and 15 undetermined or undescribed species. The list includes all records of each species in South Tyrol, their known distribution in the Italian Alps sorted to provinces, the distribution in Italy, occurrence in the neighbouring countries Austria and Switzerland, and their general distribution. Occasional additional remarks give taxonomic information. A historical overview of the exploration of the oribatid mites in South Tyrol is outlined. The general distribution of the oribatid mite fauna of South Tyrol is analysed. Beside species with a wide distribution the region includes many "Mediterranean" species, species with their main distribution in Central Europe, and species restricted to the Alps, the latter mainly in higher mountainous regions. PMID- 30313171 TI - Bryozoa on disarticulated bivalve shells from Todos os Santos Bay, northeastern Brazil, with the description of two new species. AB - As sessile organisms, bryozoans are among the commonest components of the encrusting communities on hard substrata. On unconsolidated bottoms, benthic animals and their carapaces, including mollusk shells, represent potential surfaces for encrustation. Here we describe the bryozoan fauna growing on disarticulated bivalve shells collected intertidally on Itaparica beach, Todos os Santos Bay, northeast Brazil. We examined a total of 382 valves representing seven species of bivalves, among which we found 82 valves of three bivalve species to be encrusted by bryozoans, with 109 bryozoan colonies detected overall. We identified 11 cheilostome bryozoan species, among which Phidoloporidae and Smittinidae were the most diverse, with four and two species, respectively. We redescribed two bryozoan species, Parasmittina loxoides and Rhynchozoon phrynoglossum, and describe another two, Pleurocodonellina marcusi n. sp. and Rhynchozoon itaparicaensis n. sp., as new. A new combination for Cribella triangulata Canu Bassler, 1928 is proposed, including Calyptotheca tenuata Harmer, 1957 as a new junior subjective synonym of Calyptotheca triangulata n. comb. All but one of the 11 species have encrusting colonies; Licornia aff. diadema, forms erect branching colonies. For seven of the bryozoans, ours are the first records of these species growing on shells. Although the majority of bryozoans we studied have also been reported on other substrata, Rhynchozoon brasiliensis and Parasmittina loxoides were predominant in the fauna, comprising 79 (72%) of all colonies inventoried. Due to the lack of information on the distribution of these species in northeastern Brazil, further studies are needed to determine whether they show any substratum preference. PMID- 30313172 TI - Ciliated Protozoan Fauna in the Forestomach of Dromedary Camels (Camelus dromedarius) in Libya. AB - Species composition and distribution of ciliated protozoa obtained from the forestomach of 20 dromedary camels living in Zawiya, Libya were examined. Nineteen species and 10 morphotypes belonging to eight genera were identified. The mean number of ciliates was 54.2 +/- 32.9 * 104 cells ml-1 in the forestomach contents, and the mean number of ciliate species per host was 6.5 +/- 2.9. Entodinium and Epidinium were the main genera, as these ciliates were found consistently at higher proportions than those of the other genera. In contrast, Ophryoscolex and Polyplastron were only observed at low frequencies. Diplodinium rangiferi, Entodinium ellipsoideum, E. simulans, and Polyplastron multivesiculatum were new endosymbionts recorded from camels. PMID- 30313173 TI - A revision of the Heatherellidae (Parasitiformes: Mesostigmata) with a new genus and two new species from Australasia. AB - The discovery of a new genus of Heatherellidae in New Zealand has led us to revise this enigmatic family and its constituent genera. Aheatherella n. gen., based on A. mira n. sp. from the North Island of New Zealand, lacks some of the derived character states that link the Australian Heatherella, most notably the lack of sexual dimorphism in the dorsal shields and in the presence of peritremes in adult Aheatherella. Heatherella osleri n. sp. is described from New South Wales, extending the distribution of this genus beyond Queensland. New collection records of H. callimaulos and a key to the genera and species of the family are provided. We propose that the Heatherellidae-previously placed in its own cohort outside the Gamasina-are best considered a superfamily of gamasine mites within the subcohort Epicriiae. PMID- 30313174 TI - Steinernema taiwanensis n. sp. (Rhabditida: Steinernematidae), a new entomopathogenic nematode from Taiwan. AB - A new isolate of the entomopathogenic nematode, Steinernema taiwanensis n. sp., was isolated from soil in Pingtung County, Taiwan. This new species could be characterized and distinguished from other related species by its morphological characters, morphometrics, and phylogenetic analysis. The body length and distance from anterior end to nerve ring of infective juveniles is 1012 (983 1045) um and 124 (120-127) um, lateral field formula 2, 6, 7, 8, 2, and the tail length 90 (79-96) um without dorsal constriction in tail region. The first generation males of S. taiwanensis n. sp. are characterized by spicule shape, smooth blade tip, 23 genital papillae (11 pairs and 1 single papilla), spicule length of 94 (89-99) um and gubernaculum length of 68 (65-70) um. Females from the first generation of S. taiwanensis n. sp. have no epiptygmata and a slightly developed post-anal swelling. Phylogenetic analysis of ITS and D2D3 regions of rDNA showed that S. taiwanensis n. sp. belongs to the Longicaudum-clade and comprises a monophyletic group with S. guangdongense and S. longicaudum. The new isolate is described as a novel species according to morphological and phylogenetic analyses. PMID- 30313175 TI - A review of the genus Baiocis Browne, 1962 (Coleoptera: Curculionidae: Platypodinae), with new species, new synonymy and a key to males. AB - Six new species of Baiocis Browne, 1962 are described: Baiocis crassiventris Beaver Liu, B. laosi Beaver Liu, B. orientalis Beaver Liu, B. spicatus Beaver Liu, B. spiniventris Beaver Liu, B. sumatranus Beaver Liu, all from the Oriental region. Of the twenty species listed by Wood and Bright (1992) in the genus Baiocis, the following species belong in Crossotarsus Chapuis, 1865: imitatrix Schedl, 1973, kuntzeni (Schedl, 1937) (comb. n.); the following in Platypus Herbst, 1793: angusticeps Schedl, 1942, perangustus Schedl, 1942, seminitens Schedl, 1971, variolosus Schedl, 1942; the following in Treptoplatypus Wood, 1993: pasohensis (Schedl, 1939). The following new synonymy is proposed: Baiocis pernanulus (Schedl, 1935) (=Platypus annularis Schedl, 1975 syn. n.; =Baiocis solomonicus Browne, 1986 syn. n.); Platypus perangustus Schedl, 1942 (= Platypus sindorae Browne, 1980 syn. n.); Platypus transformis Schedl, 1936 (=Platypus angusticeps Schedl, 1942 syn. n.). Lectotypes are designated for Baiocis incisus (Sampson, 1927), and B. sublunaris (Schedl, 1937), and both sexes of the former species are redescribed. A key is given to the males of fifteen species of Baiocis. Two further species are known only from the female. PMID- 30313176 TI - Drosophila (Sophophora) carrolli n. sp., a new species from Brunei, closely related to Drosophila (Sophophora) rhopaloa Bock Wheeler, 1972 (Diptera: Drosophilidae). AB - We describe a new species in the Drosophila melanogaster species group, Drosophila carrolli n. sp., showing morphological affinities with D. rhopaloa Bock Wheeler, 1972. PMID- 30313177 TI - Overlooked mammal diversity and conservation priorities in Italy: Impacts of taxonomic neglect on a Biodiversity Hotspot in Europe. AB - For more than half a century, little taxonomic revisionary work has been directed towards extant European mammals so that the limits of most geographically widespread polytypic species remained scientifically untested. Occasionally, taxonomic changes have been proposed and several new species have been resurrected / discovered in the last decades mainly on the basis of genetic studies, often considered the only tool to establish objective species boundaries. Nevertheless, the precise details of species boundaries, subspecific variation and phylogenetic relationships remain unknown for several European mammal taxa. The inadequacies of outdated, incomplete taxonomic knowledge reach an extreme in southern Europe, and notably Italy, where cryptic species abound and specimen-based research is scanty. The state of mammalian taxonomic knowledge in Italy shows that Linnaean and Wallacean shortfalls are no means restricted to hyperdiverse, understudied tropics. They undermine our knowledge of temperate regions, with severe consequences for biodiversity conservation policies in Europe, where conservation assessments overlook significant endemic biodiversity. European mammalogy stands to benefit from an infusion of the tree-thinking philosophy that undergirds evolutionary theory and particularly phylogenetic methods systematics. Furthermore, it is important that taxonomic research be seen as a normal part of scientific advancement and of critical importance as the basis of a sound biodiversity conservation policy. PMID- 30313178 TI - A new syntopic species of small barb from the Western Ghats of India (Teleostei: Cyprinidae). AB - A new species of the cyprinid genus Pethia is described from the Hiranyakeshi, a tributary of the Krishna River system in the Western Ghats mountain ranges of peninsular India. The new species, Pethia sahit, is syntopic-and shoals together with Pethia longicauda, a species described recently from the same river. Pethia sahit is distinguished from P. longicauda and its congeners by a combination of characters like, incomplete lateral line with 3-6 pored scales; 19-22 scales in lateral series; 41/2 scales between dorsal-fin origin and lateral-line row and 21/2 scales between lateral line row and pelvic-fin origin; intercalated scale row originates above and after the 6th scale of the lateral-line scale row; dorsal fin originating behind the pelvic-fin origin; 4+13 abdominal and 12 caudal vertebrae; dorsal, pectoral, pelvic, anal and caudal fins without any bands or spots, deep yellow-orange in color or deep red with a pale tint of orange in mature males; a dark-black vertically elongate humeral spot, overlapping the 4th lateral-line scale, extending over the base of one scale above and below the 4th scale; caudal peduncle spot dark, covering 14th-16th scales in lateral-line scale row. Genetic analysis based on the mitochondrial cytochrome b gene indicates that P. sahit and P. longicauda are not sister taxa. Further, P. sahit has no genetically proximate congener in the Western Ghats region, and differs from known congeners from south and southeast Asia, for which genetic data are available, with genetic distance ranging from 11.8-16.4%. PMID- 30313179 TI - New species and synonymy in the genus Corotoca Schiodte, 1853 (Coleoptera, Aleocharinae, Corotocini). AB - Corotoca Schiodte, 1853 is a Neotropical genus of termitophiles beetles, with five species, and its description marks the first record of insects associated with termites. A new species, Corotoca fontesi sp. nov., from Brazil, is described and illustrated, and a taxonomical problem regarding to the identification and nomenclatural status of two species, Corotoca phylo Schiodte, 1853 and Corotoca seeversi Fontes, 1977, is solved. Therefore, Corotoca seeversi is proposed as a new junior synonym of C. phylo, and the material identified as C. phylo housed in the Museum of Zoology of the University of Sao Paulo, Brazil (MZUSP) is recognized as a new species, Corotoca fontesi sp. nov. New morphological and sexual dimorphism data in the species, and solution of some messy informations about the genus present in the literature are also present. PMID- 30313180 TI - Tepuidessus grulai sp. nov. from Acopan Tepui in Venezuela (Coleoptera: Dytiscidae: Hydroporinae: Bidessini). AB - We report the discovery of the second Bidessini diving beetle species from a Venezuelan table-top mountain (also referred to as "tepui"). Tepuidessus grulai sp. nov. from Acopan Tepui can easily be separated from Tepuidessus breweri Spangler, 1981, described from Roraima Tepui, about 140 km apart from Acopan Tepui, by its much broader habitus with distinct outline discontinuity between pronotum and elytra, well developed, long and deep basal striae on pronotum and elytra and by the unbordered apical abdominal ventrite. PMID- 30313181 TI - In the footsteps of history: the bees of the genus Hylaeus Fabricius (Hymenoptera, Apoidea: Colletidae) collected by V.I. Roborovsky and P.K. Kozlov in Northwest China (1895-1926). AB - An annotated list of 19 species of Hylaeus collected by the famous Russian explorers and travellers V.I. Roborovsky and P.K. Kozlov in Northwest China (1895 1926) is given. Hylaeus (Hylaeus) roborovskyi Proshchalykin Dathe, sp. nov. is described as new from Xinjiang Uygur Autonomous Region. The following eight known species are newly recorded from China: Hylaeus angustatus (Schenck, 1861), H. arenarius Morawitz, 1876, H. breviceps Morawitz, 1876, H. communis Nylander, 1852, H. fedtschenkoi (Cockerell, 1906), H. pallidicornis Morawitz, 1876, H. pesenkoi Proshchalykin Dathe, 2016, and H. vulgaris Morawitz, 1876, increasing the number of species reported from the region to 48. New synonymy is established for Hylaeus tsingtauensis (Strand, 1915) = H. montivagus Dathe, 1986, syn. nov. PMID- 30313182 TI - A review of the millipede genus Rupidesmus Schubart, 1952 (Polydesmida: Chelodesmidae). AB - The chelodesmid genus Rupidesmus Schubart, 1952 is revised. Currently, the genus contains only Rupidesmus ruber Schubart, 1952, herein redescribed, and the new species Rupidesmus aclys n. sp., added. A revised diagnosis for the genus and a distribution map for the two species are provided. PMID- 30313183 TI - Erratum: JIRI MORAVEC JAN VYBIRA (2018) New or rare Madagascar tiger beetles-17. Description of Pogonostoma (Microstenocera) noheli sp. nov. and redescription of P. (M.) flavomaculatum W. Horn (Coleoptera: Cicindelidae). Zootaxa, 4388 (1): 076 088. PMID- 30313184 TI - Nomenclatural and type catalogue of Athoracophoridae (Mollusca: Eupulmonata: Succineoidea): a synopsis of the first 185 years of biodiscovery in the South West Pacific region. AB - Athoracophoridae are succineoidean terrestrial slugs that constitute a distinctive faunal element of the South West Pacific biogeographic region, with representatives in New Guinea, Australia, New Caledonia, Vanuatu and New Zealand. Despite many studies on morphology, taxonomy and phylogenetic relationships since the first species description in 1832, the understanding of the diversity within the family, as reported in published literature, remains poor with regional disparities in collection and systematic effort, in taxonomic concepts, and in adherence to type concepts. The systematics of Athoracophoridae needs to be re evaluated through a modern, phylogenetic approach to properly document infra familial evolution and taxon diversity, advance understanding of evolutionary relationships with other Eupulmonata, and to delineate evolutionary units for conservation prioritization. A catalogue of all class-, family-, genus- and species-group names erected for or used to include Athoracophoridae over the 185 year period 1832 to 2017 is provided, as a first step towards a systematic revision. The following nomenclatural changes are made: lectotype designation for Aneitea macdonaldii Gray, 1860; lectotype designation for Janella papillata Hutton, 1879; type species designation for Amphikonophora Suter, 1897; and lectotype designation for Athoracophorus verrucosus Simroth, 1889. PMID- 30313185 TI - Elevational size variation and two new species of torrent frogs from Peninsular Malaysia (Anura: Ranidae: Amolops Cope). AB - Previously, only one species of torrent frog (Amolops larutensis) was thought to occur throughout Peninsular Malaysia. However, genomic work has demonstrated that populations from eastern Peninsular Malaysia form two separate lineages that are genetically distinct from A. larutensis that is now restricted to the western half of Peninsular Malaysia. This study demonstrates that all three lineages can be morphologically distinguished from each other, thereby providing additional support for the recognition of the eastern lineages as two distinct species. These lineages are described herein as Amolops gerutu sp. nov. from the eastern states of Kelantan, Terengganu, and Pahang, and A. australis sp. nov. from the southern-most state of Johor. In general, these two new species form a clade that is sister to A. larutensis and can be readily distinguished from it by having: (1) considerably denser and more pronounced dorsal tubercles, and (2) the posterodorsal surface of thighs having dense, dark stippling as opposed to broad vermiculations. Although differences in other morphometric characters were detected, their utility as diagnostic characters should be applied with caution due to the large intraspecific variation that overlaps among different species in many of the characters we measured. As such, we advocate for the use of tuberculation and pattern of the posterodorsal portion of the thighs as primary diagnostic characters. These characters can readily distinguish A. larutensis from the two new species. To differentiate A. australis sp. nov. from A. gerutu sp. nov. and A. larutensis, body size can be a good diagnostic character as A. australis sp. nov. is significantly smaller in both males (mean = 31.04 +/- 1.59 mm) and females (mean = 46.48 +/- 3.2 mm). Additionally, we show a strong positive correlation between body size and elevation, with populations from montane forests (>900 m asl) being considerably larger than populations at lower elevations. PMID- 30313186 TI - Checklist of the family Megalopodidae Latreille (Coleoptera: Chrysomeloidea); a synthesis of its diversity and distribution. AB - A checklist of the Megalopodidae of the world is presented. A total of 582 species in 29 genera and 11 subgenera are recognized belonging to the three subfamilies. The subfamilies, genera, and species are listed in alphabetical order. For each species, synonymous names and the geographical distribution by country is provided. The most diversified subfamily is Megalopodinae with 480 species and 24 genera. The Neotropical biogeographic region has the highest diversity of Megalopodidae, followed by the Ethiopian region. The knowledge of Megalopodidae is limited, and is remarkably biased by country. A significant increase in geographic and taxonomic information is needed in order to fill these knowledge gaps. The following taxonomic and nomenclatural changes are proposed: 1) type species are designated for the genera Macrolopha Weise and Falsomegalopus Pic. 2) Zeugophora novobicolor Rodriguez-Miron is proposed as new replacement name of Zeugophora bicolor. 3) The following taxa are reinstated in the genera Temnaspis: T. speciosus Baly, T. arida Westwood, and T. nigriceps Baly. 4) Falsotemnaspis luteimembris Pic is proposed as new synonym (= F. lacordairei (Westwood)). 5) The next new combinations are proposed: Macrolopha bicolor (Jacoby), M. carinata (Bryant), M. centromaculata (Jacoby), M. costatipennis (Pic), M. dollmani (Bryant), M. hargreavesi (Bryan), M. mashuana (Jacoby), M. murrayi (Baly), M. neavei (Bryant), M. nyassae (Bryant), M. suturalis (Clavareau), M. variabilis (Westwood), M. aeneipennis (Weise), M. notaticollis (Pic), M. parvula (Weswood), M. theresae (Pic), M. tricoloripes (Pic) and Falsotemnaspis lacordairei (Westwood). PMID- 30313187 TI - Taxonomic revision of the genus Bolivaritettix Gunther, 1939 (Orthoptera: Tetrigoidea: Metrodorinae) from China, with the descriptions of two new species. AB - The tetrigid genus Bolivaritettix Gunther, 1939 from China is taxonomically reviewed. The genus now includes 71 species from China, in which two new species are described and illustrated, namely: Bolivaritettix baoxingensis Deng sp. nov. and Bolivaritettix strictifemura Deng sp. nov. Synonymy. Their distribution and an annotated identification key to Chinese species are provided. PMID- 30313188 TI - Descriptions of two new endemic and cryptic species of Sitana Cuvier, 1829 from peninsular India. AB - Two new cryptic species of the agamid genus Sitana Cuvier, 1829 from Peninsular India are described herein. Sitana gokakensis sp. nov. from Gokak, Karnataka closely resembles Sitana thondalu sp. nov. from Nagarjuna Sagar, Andhra Pradesh. The two species can be distinguished based on their subtle morphological differences, genetic difference and geographic distribution. Sitana gokakensis sp. nov. have a relatively depressed head compared to Sitana thondalu sp. nov. Additionally, the vertebral scale counts differ in females of the two new species (Sitana gokakensis sp. nov. 45-47 vs Sitana thondalu sp. nov. 49-53). Genetic divergence between them is comparable to those between previously described Sitana species. Furthermore, the two new species are distributed ca. 500 km apart and are endemic to their respective landscapes that lie in similar latitudes of peninsular India. We urge the use of large sample size in new species descriptions especially those dealing with cryptic species like Sitana. The discovery of the two new cryptic species from these rocky terrains in peninsular India highlights need for more herpetological exploration in this region. PMID- 30313189 TI - A new species of Masteria L. Koch, 1873 (Dipluridae: Masteriinae) from Guyana. AB - Mygalomorphs are a diverse spider group with primitive characteristics composed of the largest spider species in the world, however some species may be very small (Bond et al. 2012; Rogerio et al. 2013). The small spiders of the subfamily Masteriinae (Dipluridae, Mygalomorphae) can be found in Asia and South America (Raven 1981; Pedroso et al. 2015; WSC 2017). The subfamily is represented by two genera: Masteria L. Koch, 1873 and Striamea Raven, 1981. Masteria species can be identified by the following combination of characters: absence of cuspules in endites and labium; zero, two, six or eight eyes; and with or without paraembolic apophysis on the male palpal bulb (Raven 1981, 1985, 1991; Alayon 1995; Bertani et al. 2013; Pedroso et al. 2015). Currently, 24 species of Masteria are described, with 6 species found in South America: Masteria colombiensis, Raven, 1981 from Colombia; M. manauara Bertani, Cruz Oliveira 2013 and M. emboaba Pedroso, Baptista Bertani, 2015 from Brazil; M. cyclops (Simon 1889), M. tovarensis (Simon, 1889) and M. lucifuga (Simon, 1889) from Venezuela (WSC 2017). We document herein the first record and description of a new species of the genus Masteria from Guyana. PMID- 30313190 TI - Description of a second species of the genus Moronius Grossi Vaz-de-Mello, 2015 (Coleoptera: Scarabaeidae: Rutelinae: Rutelini). AB - Moronius Grossi Vaz-de-Mello, 2015 (Coleoptera: Scarabaeidae: Rutelinae: Rutelini) is the latest genus described within the subtribe Areodina (Grossi Vaz de-Mello 2015). Areodina consists of 11 genera distributed throughout the New World (10 genera) and Africa (one genus) (Jameson 1990; Grossi Vaz-de-Mello 2015). Moronius is distinguished from other genera of Areodina by: 1) the pentagonal clypeal shape with the apex strongly reflexed, and 2) the hind wings with the anterior margin near RA1+2, RA1+3, and apical hinge setose. The South American genera of Areodina form a distinct clade (Jameson 1990) composed of Oplognathus MacLeay, 1819, Areoda MacLeay, 1819, and Byrsopolis Burmeister, 1844. Oplognathus and Areoda are differentiated by the presence of a forward-projecting mesoventral process, which is absent in both Byrsopolis and Moronius. These two latter genera are similar according to the characters presented in the Jameson (1990) phylogeny and are differentiated by habitus colour, shape of clypeus, and antennal club length (Grossi Vaz-de-Mello 2015). PMID- 30313191 TI - Protosticta curiosa Fraser, 1934 and its synonyms in Vietnam and China (Odonata: Platystictidae). AB - Protosticta zhengi Yu Bu, 2009 and Protosticta albifrons Kompier, 2016 are shown to be synonyms of P. curiosa Fraser, 1934. The general distribution of P. curiosa is discussed and the key to the P. curiosa-group of Protosticta species for Vietnam is updated. PMID- 30313192 TI - Neotype designation of Oribatula nativa Tseng, 1984 (Acari, Oribatida, Oribatulidae). AB - The type material of oribatid mites (Acari, Oribatida) of Tseng's collections were lost, therefore, designation of neotypes is necessary to ensure stability in zoological nomenclature. The neotype and paraneotypes of Oribatula nativa Tseng, 1984 (Oribatida, Oribatulidae) are designated. This species is redescribed based on adult material collected from Taiwan. PMID- 30313193 TI - A new species of Lobesia Guenee, 1845 from Thailand (Lepidoptera: Tortricidae: Oletheutinae). AB - Lobesia bisacca Charoensub and Pinkaew, n.sp., is described from Thailand. Specimens were collected in light traps in Trat Province, eastern Thailand and were deposited in the Kasetsart Kamphaengsaen Insect Collection. The new species can be distinguished from all other congeners by the unusual, long, protruding process from the base of the sacculus in the male genitalia. Illustrations of the adult, male genitalia, and male secondary characters are provided. PMID- 30313194 TI - On the pea crabs found in the chiton Tonicia chilensis (Frembly, 1827) (Mollusca, Polyplacophora: Chitonidae) identified as "Orthotheres sp." by Melzer Schwabe (2008), and its reassignment to Calyptraeotheres Campos, 1990 (Crustacea: Pinnotheridae). AB - Crabs of the family Pinnotheridae have been considered a phylogenetically heterogeneous group and taxonomically problematic (Palacios-Theil 2009, 2016; Tsang et al. 2018). The lack of knowledge of sexual dimorphism and morphological variation throughout the life history for many species have complicated its taxonomy and has resulted in errors in its classification (Campos 1989, 1993, 2016). Consequently, if the taxonomy of these symbiotic crabs had been based on juveniles and undeveloped character states, the problems get even more serious (Campos 1989, 1993). Melzer Schwabe (2008) studied three juvenile crabs living in the chiton Tonicia chilensis (Frembly, 1827) (Polyplacophora: Chitonidae) collected in Muelle Dichato, Chile, and they identified them as the putative invasive stage of a species of Orthotheres Sakai, 1969. The crabs are of the typical juvenile pinnotherid form with a masculine habitus, including a suborbicular carapace, large eyes and a slender pleon (= abdomen) with the telson well defined (Ocampo et al. 2017). Unpublished observations on juveniles and adults of several species of pinnotherid crabs by the author, for example, Juxtafabia muliniarum (Rathbun, 1918), Dissodactylus lockingtoni Glassell, 1935, D. xantusi Glassell, 1936, Calyptraeotheres granti (Glassell, 1933), Austinotheres angelicus (Lockington, 1877) and Tumidotheres margarita (Smith, 1870) have revealed that the third maxilliped exhibit little morphological variation through the post-larval stages of development (from juvenile to adult). This appendage, including the partial or total fusion of the ischium and merus (Fig. 1A-G; Fig 2A, C-G), has been considered a valuable feature for distinguishing genera in the family Pinnotheridae (Burger 1895; Rathbun 1918; Manning 1993; Ahyong Ng 2007; Campos 2009). According to Melzer Schwabe (2008) the ischium and merus of the third maxilliped are completely fused, the carpus is larger than the propodus and the small dactylus is subterminally inserted on the propodus (Fig 1C), and as such the juveniles studied are possibly members of the genus Orthotheres Sakai, 1969. A detailed re-examination of the third maxilliped, chela of pereiopod 1 (cheliped) and pleon, however, has shown otherwise. Campos (1989) discussed the taxonomy of Orthotheres and treated all the species he recognised as belonging to this genus; characterising its members by its diagnostic third maxilliped palp structure. Ng Ho (2014) rediagnosed the genus based on the type species, O. turboe Sakai, 1969, from Japan, and restricted it for three Indo-West Pacific species; commenting that the American species as well as some Indo-West Pacific taxa will need to referred to other genera when a full revision is done. This revision is now in progress by the author, PKL Ng and ST Ahyong. Until the revision is complete, the genus is treated here in the broader sense of Campos (1989) and Geiger Martin (1999). PMID- 30313195 TI - Phonognatha vicitra Sherriffs, 1928-a taxonomic misidentification of the orb weaving spider Acusilas coccineus Simon, 1895 (Araneae, Araneidae). AB - The species described as Phonognatha vicitra Sherriffs, 1928 is the only representative of the genus Phonognatha Simon, 1894 in India (World Spider Catalog 2018). The type locality of this species was a coffee estate named Charlotte estate/division, which is located adjacent to the Cauvery River in the Siddapura/ Sidapur village in the Kodagu (Coorg) district of the southwest Indian state of Karnataka (Sherriffs 1928). The species is still known from its original description, which is based on seven female specimens, and its male genitalia remained unveiled. For redescribing this species, we had visited the Charlotte estate/division and collected topotype materials of P. vicitra. However, while examining the materials, we found that the specimens from the Charlotte estate/division indeed belong to the South East Asian orb-weaving spider genus Acusilas Simon, 1895, indicating that Sherriffs misplaced his species in Phonognatha. In the present paper, we propose to transfer P. vicitra to Acusilas and synonymise it with Acusilas coccineus Simon, 1895. PMID- 30313196 TI - A new species of the genus Mecistoscelis Reuter from Vietnam (Hemiptera: Miridae: Mecistoscelini), with key to Mecistoscelis species. AB - A new species, Mecistoscelis lansburyi Kim et Jung sp. nov. is described from Vietnam. Diagnosis, description including genitalia, and biological notes are presented with illustrations and photographs. The photographic image of female genital structure of this tribe is first presented based on M. lansburyi sp. nov. and key to the Mecistoscelis species is provided. PMID- 30313197 TI - Revision of the Afrotropical genus Susua Lugo-Ortiz McCafferty 1998 (Ephemeroptera: Baetidae: Protopatellata). AB - The species originally described as Cheleocloeon sigiensis Gillies 2001 is moved to the genus Susua Lugo-Ortiz McCafferty 1998. Additional descriptions of Susua sigiensis (Gillies 2001) are given based on male and female imagoes reared from larvae from several localities in Tanzania (including the type locality in the Upper Sigi Basin). Susua niandanensis (Wuillot in Wuillot Gillies 1993) is redescribed based on larvae and male imagoes from Guinea, Mali, Cote d'Ivoire and Zambia. The genus Susua belongs to the plesiomorphon Protopatellata Kluge Novikova 2011 and has an Afrotropical distribution; Susua is closely related to Crassabwa Lugo-Ortiz McCafferty 1996. General characteristics of Susua are given based on the two known species. PMID- 30313198 TI - Four new species and one new subspecies of Arctiinae (Lepidoptera: Erebidae) from the Tambopata river, Madre de Dios, Peru. AB - Four new species and one new subspecies of Arctiinae (Lepidoptera: Erebidae) are described. Aphyle niedmandi sp. nov., Evius ocassus sp. nov., Paranerita maculata sandeepani ssp. nov., Paranerita kotolnuki sp. nov. and Baritius flexuosus sp. nov. were collected in the Tambopata River region, Madre de Dios (Peru), as part of a Citizen Science Project, in mutual collaboration between the Natural History Museum (Lima-Peru) and Rainforest Expeditions. External morphological descriptions, morphology of male genitalia, and geographic distributions in Peru are given for all taxa as well as their barcoding. PMID- 30313199 TI - Northeast Asian Allorhynchium van der Vecht (Hymenoptera: Vespidae), with a key to Oriental species. AB - The Oriental species of Allorhynchium van der Vecht, 1963 (Hymenoptera: Vespidae: Eumeninae) are keyed for the first time and their distribution is summarised, with special reference to China and Vietnam. Archancistrocerus Giordani Soika, 1986, is synonymized with Allorhynchium van der Vecht (syn. nov.). Allorhynchium diffinis (Giordani Soika, 1986) is a new combination and A. quadrimaculatum Gusenleitner, 1997, is recorded from Vietnam for the first time. PMID- 30313200 TI - Immature stages of three species of Inca LePeletier Serville, 1828 (Coleoptera: Scarabaeidae: Cetoniinae) and morphology of phytophagous scarab beetle pupa. AB - Immature stages of I. pulverulenta (Olivier, 1789) (Coleoptera: Scarabaeidae: Cetoniinae: Incini) are described for the first time, and those of I. bonpalandi (Gyllenhal, 1827) and I. clathrata sommeri Westwood, 1845 are redescribed. A key to the third instar of Incini is presented, notes on Inca larval characters in the phylogenetic context of Cetoniinae and on scarab pupal morphology are also given. PMID- 30313201 TI - Camelobaetidius guaycara, a new species of Baetidae (Ephemeroptera) from Costa Rica, Central America. AB - The nymphs of a new species of Camelobaetidius (Ephemeroptera: Baetidae) possibly related to the South American species of this genus were found on the Atlantic and Pacific slopes of Costa Rica. Among other characteristics it is distinguished by having the anterodorsal arc of labrum with 1 + 6 setae, the first two frayed, ventrally 4 small setae near the lateral margin, and a minute seta near the anterior margin, on both sides of the cleft; the left mandible incisors with 6 denticles similar in size and the tip of the slender process extended at about the same level as the incisors; the paraglossa and glossa equal in length and a little shorter than segment II of labial palp, and a short triangular distomedial projection on segment II of labial palp; small nipple-like thoracic gills at base of forecoxa; claws with 27-32 denticles; posterior margin of abdominal terga with rounded spines; paraproct with 1-3 sclerotized spines, and cerci approximately 12% longer than the median filament. Both sexes present several different colorations. Some data on microhabitat preferences of nymphs are also given. PMID- 30313202 TI - A new deep-sea species of the snapping shrimp genus Alpheus Fabricius, 1798 (Decapoda: Caridea: Alpheidae) from Kagoshima Bay, Japan. AB - A new species of the snapping shrimp genus Alpheus Fabricius, 1798, A. longipalma, is described and illustrated on the basis of material from Kagoshima Bay, Kyushu, Japan. It is referred to the A. brevirostris (Olivier, 1811) species group, and appears closest to A. macroskeles Alcock Anderson, 1894, known with certainty from the Bay of Bengal and Andaman Sea, and A. talismani Coutiere, 1898 from the eastern Atlantic. The greatly elongate minor cheliped in males, being subequal to or longer than the major cheliped with proportionally shorter dactylus distinguish the new species from A. macroskeles. The less elongate antennular peduncle and better-developed, rounded distal lamella of the antennal scaphocerite differentiate the new species from A. talismani. All specimens of the new species were trawled from depths greater than 200 m. PMID- 30313203 TI - Redefinition of Denisiella Folsom Mills, 1938 (Collembola: Sminthurididae) with description of three new species from Brazil. AB - A new diagnosis of Denisiella is provided, based on the revision of most descriptions, including three new species from Brazil. New Brazilian taxa share the presence of 6 + 6 eyes, 4 + 4 serrate spine-like on tibiotarsi III and the polycarinate setae on tibiotarsi II but differ from each other by the shape and size of the sensilla of the tibiotarsi I. Denisiella rhizophorae sp. nov. has the combination of sensilla on tibiotarsi I of rhagidial type and C2 blunt on antennal segment III. Only D. betschi sp. nov. has barbulate spines on head and D. caatingae sp. nov. is the only which males present nasal organ. They are illustrated with drawings and scanning electron microscope photographs. Three different shapes of sensilla in the tibiotarsi I were observed and were compared with other species. PMID- 30313204 TI - A new species of Wohlfahrtia Brauer Bergenstamm (Diptera: Sarcophagidae) from northwestern China, with three new synonymies and a pictorial synopsis. AB - A new species, Wohlfahrtia spinisternum Pape Zhang sp. nov., is described based on one male specimen collected from the arid steppe habitat of Kalamaili Nature Reserve, Xinjiang, China. The species shares with W. aschersoni (Enderlein, 1934) a reduction of the distal posteroventral row of flattened, spiny bristles ('ctenidium') on the male mid femur, and has male sternite 5 gradually raised posteriorly into a pointed process, which is a unique feature in the entire subfamily Paramacronychiinae. Lectotypes are designated for Wohlfahrtia musiva Seguy, 1953 and Wohlfahrtia triquetra Seguy, 1933, and three new synonymies are proposed: Wohlfahrtia longicorpuris Mawlood Abdul-Rassoul, 2001 syn. nov. of W. nuba (Wiedemann, 1830), Wohlfahrtia musiva Seguy, 1953 syn. nov. of W. villeneuvi Salem, 1938, and Wohlfahrtia triquetra Seguy, 1933 syn. nov. of W. indigens (Wiedemann, 1830). A pictorial synopsis of male terminalia of the 24 recognized species of Wohlfahrtia Brauer Bergenstamm, 1889 is provided. PMID- 30313205 TI - A distinct new species of riparian rock-dwelling gecko (genus: Hemidactylus) from the southern Western Ghats. AB - We describe a new species of rock-dwelling gecko, Hemidactylus paaragowlipaaragowli sp. nov., from the Agastyamalai Hill Range, in the southern Western Ghats. Morphological and molecular data support the distinctiveness of the species and its close relationship to other large-bodied, tuberculate Hemidactylus spp. from the H. prashadi group from India and Sri Lanka. This species belongs to a rupicolous complex and can be distinguished from other members of the group based on the following characters: 22-24 longitudinal rows of fairly regularly arranged, subtrihedral, weakly keeled, striated tubercles at midbody; 9-11 and 10-12 subdigital lamellae on the first and fourth digits, respectively, of both manus and pes; tail with transverse series of four enlarged tubercles on each tail segment; 10-12 femoral pores on each side separated by 16 18 scales without pores; 11-13 supralabials and 9-10 infralabials. PMID- 30313206 TI - To the revision of the genus Thionia Stal (Hemiptera, Fulgoroidea, Issidae), with description of new genera and new subtribe. AB - New subtribe, Oronoquina subtrib. n., is erected for the genus Oronoqua Fennah, 1947 in the tribe Thioniini Melichar. New genera, Fowlerium gen. n. (type species: Thionia naso Fowler, 1905) and Aplos gen. n. (type species: Issus simplex Germar, 1830) are erected in the subtribe Thioniina Melichar. Thionia acuta Doering, 1941 and T. producta Van Duzee, 1908 are transferred to Fowlerium gen. n. The photos of type specimen of Issus cinctifrons Stal, 1854 are examined and compared with original description of Issus rubrocostatus Spinola, 1839 (currently Thionia rubrocostata (Spinola, 1839)). I. cinctifrons is reinstalled from synonymy with I. rubrocostatus as Thionia cinctifrons (Stal, 1854). Diagnosis of Thionia sensu stricto is given basing on the characters of T. cinctifrons. Generic status of Cheiloceps Uhler, 1895 is discussed and confirmed. Thionia argo Fennah, 1949, T. anguillana Fennah, 1965, T. borinqueta Caldwell et Martorell, 1951, and T. puertoricensis Caldwell et Martorell, 1951 are transferred to the genus Cheiloceps Uhler. Hind wing venation characters of Issidae are discussed. PMID- 30313207 TI - Acmaeodera (Ptychomus) kubani sp.n. from Northern Africa and the Arabian Peninsula, with notes on the taxonomic composition of the subgenus Ptychomus Marseul, 1866 (Coleoptera: Buprestidae: Polycestinae: Acmaeoderini). AB - Acmaeodera (Ptychomus) kubani sp. n. from Algeria, Libya and Egypt together with A. (P.) kubani saudita subsp. n. from Saudi Arabia are described, illustrated and compared with closely related species. Species-groups A. (P.) arabica Gory, 1840, A. (P.) polita (Klug, 1829) (with A. polita and A. foudrasii Solier, 1833 subgroups) and A. (P.) argodi Kerremans, 1907 are established within subgenus Ptychomus Marseul, 1866; diagnostic characters and composition of these groups are discussed. PMID- 30313208 TI - Nomenclatural changes in Ochlerini (Hemiptera: Heteroptera: Pentatomidae: Discocephalinae). AB - Several nomenclatural problems were found while studying the types of Ochlerini in the Natural History Museum, London. These problems are addressed and corrected: Hemingius Distant, 1899 syn. nov. is removed from the synonymy with Moncus Stal, 1867, and considered a new junior synonym of Ochlerus Spinola, 1837; Ochlerus scaber Walker, 1867 is removed from the synonymy with Ochlerus obscurus Dallas, 1851, and it is proposed as a senior synonym of Ochlerus cotylophorus Breddin, 1910 syn. nov. Herrichella Distant, 1911 is a senior synonym of Alitocoris Sailer, 1950 syn. nov., with the resulting new combinations: Herrichella grandis (Garbelotto Campos, 2013) comb. nov., Herrichella lateralis (Garbelotto Campos, 2013) comb. nov., Herrichella ornata (Garbelotto Campos, 2013) comb. nov., and Herrichella schraderi (Sailer, 1950) comb. nov. A key for the species of Herrichella is also given. Eritrachys antennata (Distant, 1911) comb. nov. is a senior synonym of Eritrachys bituberculata Ruckes, 1959 syn. nov. Phereclus punctatus (Dallas, 1851) is transferred to the genus Lincus Stal, 1867 as Lincus punctatus (Dallas, 1851) comb. nov. PMID- 30313209 TI - Two new eriophyoid mites (Acari: Eriophyoidea) from West Bengal, India. AB - Two new species of eriophyoid mites viz. Abacarus sundarbanensis n. sp. infesting Pongamia glabra L. (Fabaceae) and Diptilomiopus augustifoliae n. sp. infesting Ambroma augusta (L.) (Sterculiaceae) respectively, are described from West Bengal, India. PMID- 30313210 TI - A review of the Elachista subula Parenti species complex (Lepidoptera, Elachistidae), with descriptions of nine new Palearctic species. AB - Taxonomy of the here established Elachista subula species complex is reviewed. This species complex is subordinate to the E. dispilella group sensu Kaila et al. (2015), in subgenus Aphelosetia. The E. subula species complex is exclusively Palearctic. Most of the currently recognized species occur in dry areas in Central Asia where they appear to form a significant part of the Elachista diversity. The constituent species are characterized by a phallus with bent and sharp-tipped apex, and the vesica with one weakly sclerotized plate-like cornutus that usually bears one blunt or spine-like tooth. Fourteen species are recognized, of which the following 9 are described as new: E. ameteria Kaila, sp. nov. (Type locality country Kazakhstan), E. cisoria Kaila, sp. nov. (Spain), E. cultella Kaila, sp. nov. (Mongolia), E. drepanella Kaila, sp. nov. (Russia: Tuva), E. marusiki Kaila, sp. nov. (Mongolia), E. perona Kaila, sp. nov. (Kyrgyzstan), E. platamodes Kaila, sp. nov. (Croatia), E. scalpra Kaila, sp. nov. (Turkey) and E. spinipyra Kaila, sp. nov. (Turkmenistan). Redescriptions are given to E. mus Parenti E. bimaculata Parenti, E. semnani Parenti, E. subula Parenti and E. acutella Kaila. PMID- 30313211 TI - Revising the generic characters of Lobogonodes Bastelberger, 1909, with description of a new species from Taiwan (Lepidoptera: Geometridae: Larentiinae). AB - The present study re-assesses the characters of the Oriental genus Lobogonodes Bastelberger, 1909 based on all 8 species, including the newly described L. shiushioui sp. nov. and the distinct species L. dactylotypa Prout, 1940 stat. rev.. Three synapomorphic characters based on the male genitalia are proposed: the presence of a sclerotized subscaphium, the U-shaped connection between the juxta and anellus lobe and the saccus process pointed anteriorly. A new key to the species in this genus is provided. PMID- 30313212 TI - Taxonomic review of the genus Urostylis (Hemiptera: Heteroptera: Urostylididae) from the Korean Peninsula, with description of a new species. AB - The genus Urostylis is reviewed taxonomically with description of a new species Urostylis koreana sp. nov. from the Korean Peninsula. Descriptions, diagnoses and a key to the Korean Urostylis species are presented with photographs and illustrations. PMID- 30313213 TI - Rove beetles collected with carrion traps (Coleoptera: Staphylinidae) in Quercus forest of Cerro de Garcia, Jalisco and Quercus, Quercus-pine, and pine forests in other jurisdictions of Mexico. AB - We present the species diversity of rove beetles (Coleoptera: Staphylinidae) collected with carrion baited traps in Quercus forests of Cerro de Garcia, Jalisco, and provide a compilation of published species records in Quercus, Quercus-pine and pine forests in other jurisdictions of Mexico. This work includes taxonomic notes, information on species phenology, distribution, and their occurrence in Cerro de Garcia (if applicable), and other jurisdictions of Mexico. In Cerro de Garcia, 75 species were collected in total, of which 16 are shared with other Quercus forests in different locations, and 9 species are provided with new habitat data. The remaining individuals were only determined to morphospecies. In Mexico, there are 77 known species of rove beetles collected with carrion traps (determined to species or near species) and recorded from Quercus, Quercus-pine and pine forests. These species belong to 30 genera, 11 tribes and 10 subfamilies. This study provides biological information on Mexican rove beetles captured with carrion traps and highlights the importance of rove beetles as indicator species of habitat change for conservation analysis, forestry, agronomy and forensic sciences studies. PMID- 30313214 TI - Revision of the Agrilus gratiosus species-group (Coleoptera, Buprestidae, Agrilinae). AB - The newly defined Agrilus gratiosus species-group comprising ten species from the Oriental region is revised. A key to species is provided and complemented with illustrations of habitus, genitalia and type specimens. The following seven new species are described: Agrilus cultus sp. nov. (Laos); A. oudomxai sp. nov. (Laos); A. pergratus sp. nov. (Malaysia); A. pluridens sp. nov. (Laos, Thailand); A. pubinotus sp. nov. (Indonesia: Sumba Island); A. siberuticola sp. nov. (Indonesia: Siberut Island) and A. signipes sp. nov. (Vietnam). Agrilus makiharai Toyama, 1987 is considered conspecific with A. bacchus Kerremans, 1913 and therefore the name makiharai syn. nov. is a junior subjective synonym of the name bacchus. PMID- 30313215 TI - Water striders (Heteroptera: Gerromorpha: Gerridae) of Romania with an update on the distribution of Gerris gibbifer and G. maculatus in southeastern Europe. AB - The Romanian fauna comprises two species of Aquarius Schellenberg, 1800, eight species of Gerris Fabricius, 1794 and one species of Limnoporus Stal, 1868, and we hereby update the distribution and provide insights on the phenology and ecology of all eleven species in this country. We furthermore update the distribution of the two closely related species Gerris gibbifer Schummel, 1832 and G. maculatus Tamanini, 1946 in southeastern Europe. Gerris maculatus is recorded for the first time from Hungary, Montenegro and Slovenia, and the first detailed localities from Romania and Serbia are given. All bibliographic records of G. gibbifer from Romania, Macedonia and Serbia are based on misidentification and this species is thus excluded from the faunal lists of these countries. Both G. gibbifer and G. maculatus occur in Croatia, Hungary, Ukraine, and probably Slovenia. PMID- 30313216 TI - A new species of Rhagovelia Mayr, 1865 (Hemiptera: Heteroptera: Veliidae) from French Guiana, with new records of Gerromorpha from the country. AB - Rhagovelia apuruaque sp. nov. (Hemiptera: Heteroptera: Veliidae), from the commune of Regina, French Guiana, is described, illustrated, and compared with species of the salina group. Brachymetra albinervus (Amyot Serville, 1843), B. lata Shaw, 1933, Limnogonus ignotus Drake Harris, 1934, Neogerris lubricus (White, 1879), Rheumatobates crassifemur esakii Schroeder, 1931 (Gerridae), Mesovelia mulsanti White, 1879 (Mesoveliidae), Microvelia longipes Uhler, 1894, M. mimula White, 1879, M. pulchella Westwood, 1834, R. humboldti Polhemus, 1997, and S. transversa (Hungerford, 1929) (Veliidae) are recorded for the first time from French Guiana. The presence of Tachygerris adamsoni (Drake, 1942) (Gerridae) in the country is confirmed. New records are presented for the following species previously reported from the study area: B. shawi Hungerford Matsuda, 1957, Cylindrostethus palmaris Drake Harris, 1934, L. hyalinus (Fabricius, 1803) (Gerridae), Husseyella turmalis (Drake Harris, 1933), Paravelia bullialata Polhemus Polhemus, 1984, and Stridulivelia strigosa (Hungerford, 1929) (Veliidae). PMID- 30313217 TI - Moribaetis brachiostrinus (Ephemeroptera: Baetidae), a new species of mayfly from Costa Rica. AB - A new species of Moribaetis is described based on nymphs from the Nicoya peninsula. The new species can be distinguished from the other described species of the genus, among other characteristics, by its short antennae, strongly curved lateral branches of the epicranial suture, long mandibular incisors projected beyond labrum margin, violet-colored gills, and a distinctive triangular projection on paraproct. Moribaetis brachiostrinus, M. macaferti and M. salvini share certain characters that set them apart from M. maculipennis suggesting that the latter represents a separate branch within this genus. M. brachiostrinus has the lowest altitudinal distribution of the genus in Costa Rica and represents the first record of a Moribaetis occurring on the oldest emerged lands in the country. Comments on the age-related changes in the mandibular incisors and a key to mature nymph of Moribaetis species are also provided. PMID- 30313218 TI - Luciobarbus lanigarensis and L. numidiensis, two new species of barbels from the Mediterranean Sea basin in North Africa (Teostei: Cyprinidae). AB - Two new species of Luciobarbus are described from the Mediterranean Sea basin in Morocco and Algeria. Their monophyly and phylogenetic placement are resolved by molecular analyses using two mitochondrial markers (cyt b and D-loop). Luciobarbus lanigarensis, new species, from the Tafna River drainage in Algeria and Morocco, is distinguished by having orange fins, a great predorsal length (52 59% SL) and a very long pectoral fin (79-90% HL). Luciobarbus numidiensis, new species, from the El-Kebir River drainage in Algeria, is distinguished by having a golden pectoral-fin margin, 43-47+1-3 lateral line scales and a very long anal fin (19-23%). PMID- 30313219 TI - Two new European species of the marine genus Tubificoides (Annelida: Clitellata: Naididae) with notes on the morphology of T. pseudogaster (Dahl, 1960). AB - Two new species of Tubificoides (subfamily Tubificinae), T. charlotteae n. sp. and T. mackiei n. sp., are described based on morphological analyses. Both species were flagged as potentially cryptic in a previous investigation, based on both mitochondrial and nuclear sequence data. Tubificoides charlotteae n. sp., known only from an intertidal site in southern Spain, is characterized by the lack of cuticular papillation, the possession of several needle-like hair chaetae in dorsal bundles, a cone-shaped penis sheath, and a rather large, muscular penial sac. It strongly resembles the north-west European, largely sublittoral species T. amplivasatus, but differs from this species in terms of body size, width of vas deferens, and the shape and size of both the ejaculatory duct and penial sac. Tubificoides mackiei n. sp., collected from the southeast coast of Norway and the west coast of Sweden, is characterized by the lack of cuticular papillae and hair chaetae, and the possession of a rather long penis sheath with a wide terminal opening. It shares several morphological features with the sympatric species Tubificoides pseudogaster, but is distinguished from the latter by the detailed morphology and length of the penis sheaths, the width of the atrium, and the lower maximal number of bifid chaetae in dorsal preclitellar bundles. The utility of an integrative comparative approach, combining molecules and morphology, for the identification and delineation of new taxa within Tubificoides is briefly discussed. PMID- 30313220 TI - Alpheus naranjo, a new brightly coloured snapping shrimp from the Caribbean coast of Panama (Malacostraca, Decapoda, Alpheidae). AB - A new snapping shrimp is described based on several specimens collected on a shallow coral reef off Isla Popa in Bocas del Toro, on the Caribbean coast of Panama. All specimens of Alpheus naranjo sp. nov. were extracted from dead colonies of the thin-leaf lettuce coral, Agaricia tenuifolia Dana, at a depth of about 2 m. Based on its morphological characteristics, the new species belongs to a small species complex that also includes A. blachei Crosnier Forest, 1965 from the tropical eastern Atlantic, and A. felgenhaueri Kim Abele, 1988 and A. confusus Carvacho, 1989, both from the tropical eastern Pacific. Alpheus naranjo sp. nov. can be separated from all of them by the relatively longer fingers of the minor chela, which are devoid of balaeniceps setae, as well as some other morphological details. In the western Atlantic, A. naranjo sp. nov. is the only large uniformly orange-red snapping shrimp, hence its proposed new name. The colour patterns of A. blachei and A. confusus are illustrated for the first time. PMID- 30313221 TI - The genus Cryptotendipes Beck et Beck in Florida, with the description of a new species (Diptera: Chironomidae: Chironominae). AB - Species of the genus Cryptotendipes Beck et Beck in Florida are reviewed. Previous Florida records of C. casuarius (Townes) are shown to be misidentifications of C. emorsus (Townes). One species new for the state, C. pseudotener (Goetghebuer), is recorded and a new species, C. rutteri Epler, is described from pharate pupae and associated larval exuviae. Thus, a total of three species are known from the state. Keys are provided for adult males, pupae and larvae of these three species. PMID- 30313222 TI - Two new species of the genus Loboschiza Diakonoff, 1968 (Lepidoptera: Tortricidae: Olethreutinae) from Thailand. AB - Two new species of Loboschiza Diakonoff, 1968 are described and illustrated from Thailand: L. bispina Phosrithong and Pinkaew, n.sp., L. rectanguluma Phosrithong and Pinkaew, n.sp. The two new species brings to 20 the number of described species in the genus, which is distributed from India to Australia. PMID- 30313223 TI - Species of the Maera-clade collected from Japan. Part 1: genera Maeropsis Chevreux, 1919 and Orientomaera gen. nov. (Crustacea: Amphipoda: Maeridae). AB - The Maera-clade is a group of maerid amphipod genera which has neither a falcate mandibular palp nor medially setose inner plates of maxillae 1 and 2. Two species of Maeropsis Chevreux, 1919 and four species of Orientomaera gen. nov. included in the clade, are described from Japan. Maeropsis okinawensis sp. nov. is described, based on collections from Okinawa Prefecture. It resembles M. cobia Krapp-Schickel, 2009, M. paphavasitae Wongkamhaeng, Coleman Pholpunthin, 2013, and M. serratipalma (Nagata, 1965). This new species differs from the latter three species in the long uropod 3. Maeropsis serratipalma is redescribed and newly recorded from Kanagawa, Osaka and Wakayama Prefectures. The new genus, Orientomaera, is described and is characterized by the mandibular palp article 1 without a distal tooth and the oblique palm of the gnathopod 2 with many robust setae. Orientomaera comprises four species: O. brevispina (Kim Kim, 1991) comb. nov. from Iwate, Fukui, Kyoto and Wakayama Prefectures and Ariake Sea; O. decipiens sp. nov. from Osaka and Wakayama Prefectures; O. obliquua sp. nov. from Osaka and Wakayama Prefectures; O. rotundicoxa sp. nov. from Kanagawa and Wakayama Prefectures. These species can be distinguished from one another by the coxa 1, the gnathopod 2 propodus, the pereopod 6 basis and the telson. Keys to species of Maeropsis and Orientomaera in the world are provided. PMID- 30313224 TI - Current status of the oak gallwasp (Hymenoptera: Cynipidae: Cynipini) fauna of the Eastern Palaearctic and Oriental Regions. AB - Cynipid gallwasps comprise 1364 species worldwide, predominantly in temperate regions of the Holarctic. The vast majority of recorded species are from the Nearctic and the Western Palaearctic, both of which are long-standing centers of research on the taxonomy and biology of this group. In contrast, the Eastern Palaearctic and the Oriental Region faunas are much less studied, but potentially extremely rich. Previously recorded species richness of cynipid groups in the Eastern Palaearctic and Oriental regions probably represents a significant underestimate. This is particularly marked for gallwasps associated with oaks (tribe Cynipini), as has been shown by recent works, which describe many new species galling oaks in the subgenera Quercus and Cyclobalanopsis and plants of the other Fagaceae genera (Castanopsis, Lithocarpus and Castanea). In the present paper, we summarise the current knowledge of oak gallwasps in the regions that extend from Pakistan, through Nepal and China to Japan and south to Indonesia, and list a total of 97 species of Cynipini from the area. PMID- 30313225 TI - On the Tethyida (Porifera, Demospongiae) from Bahia State, northeast Brazil, with descriptions of two new species, taxonomic appointments and new records. AB - The recently proposed order Tethyida is characterized by the presence of megasclere styles, tylostyles or oxeas arranged in tracts ending as bouquets at or near the surface, and microsclere euasters. Two new species are described from the shallow coastal reefs (0-10 m) of Bahia, Brazil. Timea kamasary sp. nov. is represented by thin sciaphylous specimens with three categories of spicules: tylostyles, spined spheroxyasters and spined/smooth oxyasters in varied sizes. This species differs from Timea unistellata (Topsent, 1892) by having a different category of oxyasters. Tethya bitylastra sp. nov. is characterized by having strongyloxeas I and II, spherasters, oxyasters I and II, strongylasters and two categories of tylasters. This new species differs from Tethya maza Selenka, 1879 by having a second category of tylaster. Furthermore, we present taxonomic appointment for Timea berlincki (Leite, Fonseca, Leal Hajdu, 2015) and Tethya maza and the first record of Timea stenosclera (Hechtel, 1969) for the Southwest Atlantic. PMID- 30313226 TI - Three new species of nocturnal geckos of the Paroedura oviceps clade from xeric environments of Madagascar (Squamata: Gekkonidae). AB - We describe three new gecko species of the Paroedura oviceps clade, diagnosed by deep divergences in mitochondrial DNA, absence of haplotype sharing in two nuclear genes (sacs and kiaa1239), and morphological differences. Paroedura spelaea sp. nov. is an extremely slender species from karst habitats in the limestone massif of the Tsingy de Bemaraha National Park in western Madagascar, morphologically reminiscent of P. homalorhina but distinguished by the absence of distinct dorsal rows of spiny tubercles. Paroedura fasciata sp. nov. from the small karstic island Nosy Hara in northern Madagascar is phylogenetically placed sister to P. spelaea despite radical morphological differences. It is morphologically most similar to P. hordiesi from the geographically close Montagne des Francais massif, but is smaller, has slightly more spiny dorsal scales, and a distinctive colour pattern with light grey dorsal crossbands. The third species, Paroedura kloki sp. nov., is known from Ankarafantsika National Park and the western slopes of Makira, two sites of dry to transitional forest in western Madagascar. It is at least partly arboreal and morphologically very similar to P. oviceps, from which it differs by spiny scales extending over its entire tail. Although incomplete, the available phylogenetic evidence suggests that the karst specialists in the P. oviceps clade (P. fasciata, P. homalorhina, P. hordiesi, P. spelaea) form a monophyletic group which might have diversified by vicariance after becoming isolated, respectively, in their limestone habitats in Tsingy de Bemaraha, Ankarana, Nosy Hara and Montagne des Francais. PMID- 30313227 TI - Additions to the revision of Dima Charpentier, 1825 (Coleoptera: Elateridae: Dimini) in the Balkan Peninsula, with the descriptions of five new species. AB - Complementary revisionary information is provided for the click-beetle genus Dima Charpentier, 1825 in the Balkan Peninsula. Five species are described as new for science: Dima bialookii sp. nov. (Greece), D. blazeji sp. nov. (Albania), D. gazureki sp. nov. (Albania), D. timfristosensis sp. nov. (Greece), and D. tomorrensis sp. nov. (Albania). The male of D. hirtipennis Platia, 2011 is described for the first time. Dima etoliensis Platia, 2012 syn. nov. is a subjective junior synonym of D. evritaniensis Schimmel Platia, 2008. New specimens and distributional data are reported for D. assingi Schimmel Platia, 2008, D. dalmatina Kuster, 1844, D. elateroides Charpentier, 1825, D. evritaniensis, D. florinensis Platia, 2012, D. hirtipennis, D. hladilorum Schimmel, 1987, D. lebenbaueri Schimmel Platia, 2008, D. macedonica Schimmel, 1993, D. marvani Mertlik Dusanek, 2006, D. neumanni Platia, 2013, D. olympica Meschnigg, 1934, D. parnonensis Schimmel Platia, 2008, D. pecoudi Fleutiaux, 1944, D. pelikani Mertlik, Nemeth Kundrata, 2017, D. pelionensis Mertlik, Nemeth Kundrata, 2017, D. vailatii Schimmel Platia, 2008, and Dima sp. cf. orientalis Mertlik, Nemeth Kundrata, 2017. Morphological variability in D. hladilorum is discussed. Figures of habitus and main diagnostic features are provided for all new species, D. evritaniensis from Nerosirtis surroundings in Panetoliko Mts. (i.e., type locality of D. etoliensis syn. nov.), and for the male of D. hirtipennis. Additionally, we update the distribution maps for the genus Dima in the Balkans based on the new findings. Currently, 37 described species of Dima are known from the Balkan Peninsula. We discuss the morphological diagnostic characters for Dima species and call for the molecular phylogenetic study for this group. PMID- 30313228 TI - Revision of Hellwigiella Szepligeti, 1905 (Hymenoptera, Ichneumonidae, Ophioninae), with revalidation of H. nigripennis Szepligeti, 1905. AB - The taxonomic history of Hellwigiella Szepligeti is presented with comments. Ophion similis (Szepligeti, 1905) is diagnosed and illustrated, with the first record for Morocco. Hellwigiella is redescribed and illustrated, with comments on its differentiation from O. similis. A key to the two valid species, H. dichromoptera and H. nigripennis stat. rev., is provided. PMID- 30313229 TI - New species of Traumatomutilla Andre in the T. tabapua and T. integella species groups (Hymenoptera, Mutillidae). AB - Five new species of Traumatomutilla Andre from Brazil are described: T. fratres Bartholomay Williams sp. nov., T. anhanga Bartholomay Williams sp. nov., T. barathra Bartholomay Williams sp. nov., T. poranga Bartholomay Williams sp. nov. and T. pantherina Bartholomay Williams sp. nov. Traumatomutilla tabapua Casal, 1969, T. luscoides Andre, 1908 and T. integella (Cresson, 1902) are redescribed. T. verecunda (Cresson, 1902) is proposed as junior synonym of T. integella based on morphological evidence. T. luscoides is transferred from the T. integella to the T. tabapua species-group. PMID- 30313230 TI - Correct original spelling of Hydropeza queenslandensis Sinclair (Diptera: Empididae). AB - While databasing type specimens of Hydropeza Sinclair in the Australian Museum (Sydney), different spellings of a species name in Sinclair (2016) were identified. I herein resolve this nomenclatural issue. PMID- 30313231 TI - Tetranychidae database for Brazil: a website for distribution and information on spider mites (Acari). AB - We present a database regarding the distribution of spider mites (Acari, Tetranychidae) in Brazil. It is available open access on the internet and hosted by the Department of Entomology and Acarology, ESALQ-USP, Piracicaba, Sao Paulo, Brazil, at www.lea.esalq.usp.br/tetranychidae. This database presents the first report of each species on a host plant for each State of Brazil and the corresponding reference. The home page of the site will allow searches under headings: Species, Host common name, Host species, Host Family, References and Locality. PMID- 30313232 TI - Addendum to "Leaf insects from Luzon, Philippines, with descriptions of four new species, the new genus Pseudomicrophyllium, and redescription of Phyllium (Phyllium) geryon Gray, 1843, (Phasmida: Phylliidae)". AB - At the time Cumming et al. (2017) was published, the GenBank accession numbers for partial cytochrome c oxidase subunit I (COI) DNA barcode sequences from Microphyllium specimens sampled in the phylogenetic analysis were not yet available. This information is provided in Table 1. PMID- 30313233 TI - Redescription of the Himalayan Trachelas costatus (Araneae: Trachelidae). AB - O. Pickard-Cambridge (1885) described Trachelas costata based on female specimens from two localities in the Himalayas. Since then it was only mentioned in two works by Simon (1897, 1906). The World Spider Catalog (2018) indicates its distribution as "China (Yarkand)". All of the species described by O. Pickard Cambridge (1885), based on material collected during the Second Yarkand Mission, are stored in the Oxford University Museum of Natural History. Vials with material described in this paper contain no species and locality labels (Proszynski Zochowska 1981; Marusik 1993). It was not difficult to recognize the syntypes of this species due to the figures given by O. Pickard-Cambridge, and also because it is the only trachelid described from Yarkand to date. The goals of our paper are to redescribe Trachelas costatus in detail, designate a lectotype, and comment on its distribution and relationships. PMID- 30313234 TI - New records of Biemna Gray, 1867 (Biemnidae: Biemnida: Demospongiae) and a replacement name for the species Biemna microstyla Thomas, 1984. AB - Biemna Gray, 1867 is characterized by stylote or exceptionally oxeote megascleres arranged in a plumoreticulate skeleton, ectosomal skeleton consists of the brushed endings of choanosomal tracts, microscleres are sigmas, microxeas, commata and raphides (Hajdu Van Soest 2002). Currently, Biemna has 55 valid species (Van Soest et al. 2018). In Brazil, three species are known from northern region (Muricy 2018): Biemna microacanthosigma Mothes, Hajdu, Lerner Van Soest, 2004, Biemna spinomicroxea Mothes, Campos, Lerner, Carraro Van Soest, 2005, Biemna trisigmata Mothes Campos, 2004. In this present study, a new name is proposed for a preoccupied combination, Biemna thomasi nom. nov. The species Biemna caribea Pulitzer-Finali, 1986 is recorded and described for the first time in Brazilian waters. Six specimens of Biemna were studied in Pernambuco and Bahia States. All specimens were preserved in 80% ethanol and deposited on the Porifera Collections at the Universidade Federal de Pernambuco (UFPEPOR). PMID- 30313235 TI - Brachyxenia subtruncata sp. nov. (Orthoptera: Acrididae: Calliptaminae), a new short-horned grasshopper species from India. AB - Brachyxenia subtruncata sp. nov. is described from Durg district, Chhattisgarh, India. The description is based on morphological characters of male. PMID- 30313236 TI - Pairs in copulation of the highly dimorphic genus Pristocera Klug (Hymenoptera, Bethylidae) from Madagascar solve taxonomic problems of male-female associations. AB - The main goal of this paper is to update the taxonomic information of the pairs of Pristocera Klug collected in Madagascar by A. Seyrig. Within this material twelve species are recognized, ten are new to science, all based on pairs collected in copulation, which are described and illustrated: P. melmani sp. nov., P. alexi sp. nov., P. martyi sp. nov., P. gloriae sp. nov., P. julieni sp. nov., P. morti sp. nov., P. mauricei sp. nov., P. makungai sp. nov., P. teetsii sp. nov. and P. zubai sp. nov.. Pristocera levicollis (Kieffer) had its female discovered, and P. cambouei Saussure stat. rev. had its lectotype designated. Sclerodermus hova Saussure is transferred back to Pristocera and considered as a junior synonym of P. cambouei. Keys for males and females to the species of Pristocera from Madagascar are provided. The Malagasy fauna of Pristocera is now represented by twelve species, all endemic to this island. PMID- 30313237 TI - Redescription of Arcotheres placunae (Hornell Southwell, 1909) (Crustacea: Decapoda: Brachyura: Pinnotheridae) from India and Pakistan. AB - The identity of Arcotheres placunae (Hornell Southwell, 1909) (Pinnotheridae), a pea crab associated with the window pane shell, Placuna placenta, has been confused as the types are lost and the original figures are inaccurate and do not match the description given of the species. In the present study, fresh specimens of the species were collected from the type locality (Gulf of Kachchh, Gujarat, India), and the species is here redescribed and refigured, and its affinities with similar species is discussed. To stabilize the taxonomy of A. placunae, a neotype is chosen from amongst the fresh material. PMID- 30313238 TI - New species of Victoriopisa Karaman Barnard, 1979 (Crustacea: Amphipoda: Eriopisidae) from Vembanad backwaters, Southwest coast of India. AB - The new species is the third of genus Victoriopisa from Indian waters.The species is described from the Valanthakad mangrove area of Vembanad backwater. Victoriopisa cusatensis sp. nov differs from other species of Victoriopisa by presenting: (1) a characteristic projection at dorsolateral margin of peduncle article 2 of antenna 1in male while smooth in female; (2) broad, triangular lateral cephalic lobe; (3) posteroventral tooth in epimeral plates; (4) presence of lateral and subapical spines in telson (5) smooth palm of gnathopod 2 without any excavations. PMID- 30313239 TI - A new species of Pseudopaludicola Miranda-Ribeiro (Anura: Leptodactylidae: Leiuperinae) from eastern Brazil, with novel data on the advertisement call of Pseudopaludicola falcipes (Hensel). AB - The Neotropical genus Pseudopaludicola includes 21 species, which occur throughout South America. Recent studies suggested that the population of Andarai, in the state of Bahia, is an undescribed species, related to P. pocoto. Herein we formally describe this new species from lowlands of eastern Brazil. Recognition of this new species is supported by adult morphology, advertisement call, karyotype, and molecular data. It is diagnosed mainly by its small size, terminal phalanges knobbed (lack any expansion of the digital tips), proportionally short hindlimbs, 11 pairs of chromosomes, and advertisement call composed of series of three-pulsed notes, emitted at a high rate. In addition, we report for the first time the presence of P. pocoto in the campo rupestre (rupestrian grasslands) of Chapada Diamantina, a population with a much darker dorsal coloration than the population from the type locality. We also redescribed the advertisement call of P. falcipes based on recordings from topotypic males. PMID- 30313240 TI - A new status for Aclogryllus Gorochov, 2009 (Phalangopsidae; Phalangopsinae; Paragryllini) with a new species from Brazilian Amazon. AB - Neste trabalho e proposto elevar o subgenero Aclogryllus para o status de genero baseado em caracteristicas da morfologia externa e genitalia do macho. Tambem foi descrita uma nova especie amazonica para Aclogryllus. Fotografias da especie nominotipica e da nova especie sao apresentadas juntamente com a descricao das caracteristicas morfologicas, diagnoses e fotografias da genitalia masculina e da papila copulatoria da femea. PMID- 30313241 TI - A new species of the genus Raphidopus Stimpson, 1858 (Crustacea: Decapoda: Anomura: Porcellanidae) from Peninsular Malaysia, with additional records of R. johnsoni Ng Nakasone, 1994 from Southeast Asia, and a key to species in the genus. AB - A new species of the porcellanid genus Raphidopus Stimpson, 1858, is described on the basis of specimens from Penang and Kuala Selangor, Peninsular Malaysia. Raphidopus brevipes n. sp. is distinguished from its allied congeners, R. indicus Henderson, 1893 and R. johnsoni Ng Nakasone, 1994, by the proportionally narrower carapace and stouter ambulatory legs, as well as the different dentition on the cutting edge of the dactylus of the larger cheliped. Raphidopus johnsoni, previously known only by the holotype from Singapore, is now also recorded from Phuket (Thailand) and Java (Indonesia). Raphidopus indicus and R. johnsoni are rediagnosed on the basis of the respective type material and other specimens. A key to species of the genus Raphidopus is provided. PMID- 30313242 TI - Conotrachelus dimidiatus Champion, 1904 (Coleoptera: Curculionidae: Molytinae): morphological re-description of the immature stages, keys, tribal comparisons and biology. AB - The mature larva and pupa of Conotrachelus dimidiatus Champion, 1904 (Curculionidae: Molytinae) are morphologically re-described, keyed and, for the first time, compared with known larvae and pupae of other Conotrachelus species. The chaetotaxy of the larval and pupal body in the genus Conotrachelus is probably strictly uniform. The immature stages of described species are also compared with available data on the immature stages of genera from several tribes in the subfamily Molytinae. All larvae of Conotrachelus have a distinct endocranial line of a different size and a frons with only three setae. The states of these two distinct characteristics in larvae of the eight known Conotrachelus species are constant and unique compared to other tribes in the subfamily Molytinae. In Central Mexico, overwintering Conotrachelus beetles emerge in July and then feed and mate on host plants. Larvae are endophagous within the fruits. In September and October, the larvae pupate in the soil. This new information will be very useful in the application of pesticides to the fight against this well-known pest in Mexico. PMID- 30313243 TI - Senior synonyms for three Neotropical birds described by Louis Vieillot based on Felix de Azara (Passeriformes: Thraupidae, Tyrannidae, Tityridae). AB - The nomenclatural history of three species described by Vieillot based on the descriptions of Felix de Azara is examined. Adherent to the Principle of Priority under the International Code of Zoological Nomenclature, old available names and senior synonyms are identified for the thraupid Uniform Finch Haplospiza plumbea (Vieillot, 1818a); tyrannid Tropical Pewee Contopus sylvestris (Vieillot, 1816); and tityrid White-winged Becard Pachyramphus cyanocephalus (Vieillot, 1816). These names were based respectively on Azara's Number 111 "Pico de punzon obscuro aplomado", Number 168 "Tachuri obscurito mayor" and Number 217 "Batara obscuro y negro". It is recommended that these names should all be suppressed as nomina oblita in the interests of stability. PMID- 30313244 TI - Review of the genus Promalactis Meyrick, 1908 (Lepidoptera: Oecophoridae) III. The trilineata species group, with descriptions of four new species. AB - The trilineata species group of the genus Promalactis Meyrick, 1908 is proposed for the first time based on the forewing patterns. A total of 36 species are included, four of which are described as new: P. aggregata sp. nov., P. apicifurcellata sp. nov., P. stenitubilaris sp. nov. and P. albipedalis sp. nov. Photographs of adults and genitalia of the new species are provided. A checklist of the other described species belonging to this group is given with original citations. PMID- 30313245 TI - Morphological and molecular characterization of Hemicycliophora subbotini n. sp. (Tylenchida: Hemicycliophoridae) from China. AB - Sheath nematodes of the genus Hemicycliophora are migratory root-ectoparasites of many crops, but the damage is documented for only a few species. Hemicycliophora subbotini n. sp., isolated in Hangzhou, Zhejiang, China, from the rhizosphere of camphor tree (Cinnamomum camphora (L.) Presl), is described and characterized morphologically and molecularly with important morphological details elucidated by SEM studies. The new species can be characterized by the conoid lip region, with bulging oral disc protruding beyond the first annulus in some specimens. Oral disc narrow ovate, amphidial apertures covered by lateral plates, lying in the same plane as oral disc when observed en face. Stylet 118 (108-125) MUm long and flexible, stylet knobs concave shaped having a slight cavity. The excretory pore is located 1-2 annuli posterior to the base of pharyngeal bulb. Vulval lips slightly modified with small vulval sleeve, spermatheca rounded to oblong. Anus located 18 (15-22) annuli posterior to vulva. Tail elongated, with conoid or slightly offset spike having a narrowly rounded terminus. The study provides the first description of a new Hemicycliophora species from China. Phylogenetic analyses based on D2-D3 expansion segments of the 28S and ITS fragments revealed the new species forming a separate clade from other Hemicycliophora species which supported the status as a new species of this genus. PMID- 30313246 TI - Taxonomic changes in Synanthedonini from Madagascar, with description of two new genera and species (Lepidoptera: Sesiidae). AB - A checklist of the Synanthedonini of Madagascar is presented. The following taxonomic changes are suggested: Malgassesia pauliani Viette, 1955 syn. nov. is a junior synonym of Rodolphia hombergi Le Cerf, 1911a; Malgassesia biedermanni Viette, 1982 syn. nov. is a junior synonym of Malgassesia rufescens Le Cerf, 1922; Epitarsipus Le Cerf, 1922 stat. rev. is resurrected from the synonymy with Malgassesia Le Cerf, 1922, the earlier consisting of the single species E. rufithorax Le Cerf, 1922 comb. rev. The taxonomic position of three species, which were originally described in Chamaesphecia Spuler, 1910 and later excluded from this genus as "incertae sedis", remains unclear. These species are here transferred to Malgassesia: M. andrianony Viette, 1982 comb. nov.; M. lemur Le Cerf, 1957 comb. nov.; and M. ferdinandi nom. nov., a replacement name for Ch. seyrigi Le Cerf, 1957. Two new species and genera of Synanthedonini, Cinctosesia polistiformis and Nesosphecia mystica gen. nov. et sp. nov., are described from a submontane rainforest in the vicinity of Andasibe in the East of Madagascar. PMID- 30313247 TI - Separatatus Chen Wu (Hymenoptera: Braconidae: Alysiinae) newly recorded from Thailand, with description of one new species and one new combination. AB - Separatatus Chen Wu, 1994, is reported for the first time from Thailand and one new species is described and illustrated: Separatatus xuexincheni n. sp. In addition, one species is newly recorded from Thailand (S. parallelus Zhu et al., 2017) and we transfer one species from Phasmidiasta to Separatatus: S. malaysiae (Fischer, 2006) n. comb. A key to species of the genus Separatatus is presented. PMID- 30313248 TI - A new pea crab species of the genus Arcotheres Manning, 1993 (Crustacea: Decapoda: Brachyura: Pinnotheridae) from India. AB - A new species of pinnotherid crab, Arcotheres shahi n. sp., is described on the basis of specimens collected during a crustacean survey along the coastal areas of Pamban fishing harbor in the Gulf of Mannar, Tamil Nadu state, east coast of India. The new species resembles A. pernicola (Burger, 1895), A. winckworthi (Gordon, 1936) and A. rayi Ahyong Ng, 2007, in having the dactyli of the longer fourth pereopod longer than that of fifth pereopod. Arcotheres shahi n. sp. differs from these three known species in the shape of female carapace, frontal region and chela, setal pattern on the dactyli of the fourth and fifth pereopods and relative length of the ambulatory pereiopods. PMID- 30313249 TI - Tettigoniinae (Orthoptera: Tettigoniidae) from Turkey with key to genera and descriptions of six new species. AB - The third part of a study series on the family Tettigoniidae from Turkey and the Middle East Region is presented, which includes only the subfamily Tettigoniinae of Turkey. A key to tribes, genera and subgenera found in Turkey is proposed. The synonymy of the tribe Platycleidini Brunner, 1893 (with Decticini Herman, 1874) is confirmed. Pezodrymadusa striolata ziyaretensis Kocak Kemal, 2010 [with Pezodrymadusa affinis (I.Bolivar, 1899)], Anadolua rammei Karabag, 1952 (with Anadolua burri Karabag, 1952), Psorodonotus rize Kaya et Ciplak, 2014 (with Psorodonotus davisi Karabag, 1956), Parapholidoptera intermixta Karabag, 1961 [with Parapholidoptera indistincta (I.Bolivar, 1899)] are synonymized. Parapholidoptera indistincta (I.Bolivar, 1899) is reinstated as an independent species. Six new species, Pezodrymadusa dentata Unal, sp. nov., Mixodusa retusa Unal, sp. nov., Platycleis (Squamiana) supericola Unal, sp. nov., Platycleis (Squamiana) goeksunica Unal, sp. nov., Parapholidoptera yarpuzi Unal, sp. nov. and Eupholidoptera singularis Unal, sp. nov. are described. The invalidly described Schulmeisteri schulmeisteri Harz is discussed and its only specimen is included in the genus Pezodrymadusa as a new species. The genus Mixodusa Stolyarov and the subspecies, Pholidoptera aptera bulgarica Maran, 1953 are recorded from Turkey for the first time. An overlooked historical record of Psorodonotus venosus brunneri Stshelkanovtzev, 1914 from Turkey is determined. Discussions of many taxa and some records from new localities are presented. A full list of the Turkish Tettigoniinae is given. 357 figures are provided. PMID- 30313250 TI - Catalogue of the Order Amphipoda from Brazil (Crustacea, Peracarida): Suborders Amphilochidea, Senticaudata and Order Ingolfiellida. AB - This catalog documents 303 species within 142 genera and 56 families distributed in the suborders Amphilochidea, Senticaudata and order Ingolfiellida that have been described or reported for the Brazilian coast and continent. Data for these species such as type material, type locality, geographic and bathymetric distribution, ecological notes and remarks, when pertinent, was given. From these, 268 species (~ 90%) are benthonic, marine and/or estuarine occurring from a diverse type of substrates as sediment, algae, sponges, cnidarians, ascideans, mangrove roots, fouling habitats, coral rubble, rodolith banks, etc. In terms of bathymetry, there are 214 species (~ 80%) reported for the Brazilian continental shelf (0-200 m) and 60 (~20%) for the deep sea zone (> 200 m, 50% from the Campos Basin area). There are 35 non-marine amphipods reported from Brazil. Hyalella is the restricted and dominant epigean group and is represented by 22 species, including some hypogean and cave species. Cave dwellers includes 15 species within 6 genera as: Hyalella (5); Megagidiella (1); Potiberaba (1); Spelaeogammarus (7), and Seborgia (1). Among the Bogidiellidae, Bogidiella neotropica Ruffo, 1952 and Marigidiella brasiliensis (Siewing, 1953) are hypogean, but not from caves. The former is the only amphipod species recorded from the Brazilian Amazon Biome, within the Tapajos River, Para and the latter are found in marine coastal groundwater of Bahia and Sao Paulo. Considering the landhoppers (truly terrestrial), only two introduced species, Talitroides alluaudi (Chevreux, 1896) and Talitroides topitotum (Burt, 1934) have been found in the Atlantic forest biome, urban parks and sylviculture plantations from the southeast and south of Brazil. Moreover, several amphipod records for Brazil were noticed to be dubious or misidentifications and are listed in a table with pertinent literature. PMID- 30313252 TI - A revision of the Neotropical ant-like genus Cardiacephala Macquart, including Plocoscelus Enderlein syn. nov. (Diptera: Micropezidae, Taeniapterinae). AB - The Neotropical genus Cardiacephala Macquart (Diptera: Micropezidae, Taeniapterinae) is revised. Plocoscelus Enderlein is treated as a new junior synonym, and 15 new species (C. acuminata, C. aeruginosa, C. angularis, C. aspera, C. bulla, C. erugata, C. lobulosa, C. nicaraguensis, C. planivertex, C. rotunda, C. spinosa, C. umbra, C. velutinosa, C. venezuelensis and C. vitrata) are described. Plocoscelus nitidus Hennig is newly recognized as a synonym of C. camptomera, P. plurimaculatus Czerny is synonymized with C. arthritica (Wiedemann) and P. townsendi Cresson is synonymized with C. podagrica (Rondani). PMID- 30313251 TI - Comprehensive taxonomic, faunistic, biological, and geographic inventory and analysis of the Sciomyzidae (Diptera: Acalyptratae) of the Delmarva region and nearby states in eastern North America. AB - Genera and species of Sciomyzidae known from the Delmarva region (Delaware, the District of Columbia, Maryland, Virginia, and West Virginia) and nearby states are reviewed taxonomically, faunistically, biologically, and geographically. Although restricted to the taxa in that area, this work amounts to a revision of the sciomyzid fauna of that portion of the Nearctic region. Treated are 91 species in 19 genera, i.e. 46% of the 199 species and all but four of the 23 genera of Sciomyzidae known from the Nearctic Region. Included are 67 species in 16 genera from Delmarva and 24 other species in 10 genera from nearby states. Euthycera flavescens (Loew) is resurrected; Renocera cressoni Mathis and Knutson sp. nov. is described from eastern North America; R. amanda Cresson is given new status as a junior synonym of R. longipes (Loew); and Chaetomacera brevis Cresson, R. cyathiformis Melander, R. pacifica Curran, and R. bergi Steyskal are given new status as junior synonyms of R. striata (Meigen). Newly diagnosed are taxonomic categories ranging from family to species level, including the first diagnoses of abdomens of females of many species, where known. Provided for each genus and species are annotated taxonomic/nomenclatorial catalogs of all North American references to all species, with generic combinations noted, with previously unrecorded synonymies as well as North American literature references, illustrations, and information on natural history and morphology of immature stages. Results of cross-mating studies of Dictya are reported and discussed. Provided are label data from examined specimens, lists of Canadian provinces and U.S. states from which reviewed species have been recorded, and detailed maps of geographical distribution of species in Delmarva, with references to previously published maps. PMID- 30313253 TI - Annotated checklist of the fishes of the archipelago of Madeira (NE Atlantic): I Chondrichthyes. AB - As part of an annotated checklist of fishes of the archipelago of Madeira, a list with all cartilaginous fishes recorded from the archipelago is presented. The list contains 67 species of sharks, rays and chimaeras, whose presence in the area the authors consider confirmed. Another 14 species previously referred for the area are now considered dubious records and five species are withdrawn from the list. Centrophorus uyato is here recorded for the first time from Madeira. Three species (Mitsukurina owstoni, Odontaspis noronhai and Chimaera opalescens) are so far only present in Madeira within Macaronesia. The 67 confirmed species are based on occurrences, substantiated by specimens in natural history museum collections or other published evidence. For all species, the first reference is given, as well as other relevant references for the archipelago and remaining Macaronesia. PMID- 30313254 TI - A taxonomic review of the genus Hemiphractus (Anura: Hemiphractidae) in Panama: Description of Two New Species, Resurrection of Hemiphractus panamensis (Stejneger, 1917), and Discussion of Hemiphractus fasciatus Peters, 1862. AB - We reviewed the taxonomic status of populations of frogs in the genus Hemiphractus in Panama, which have all been referred to Hemiphractus fasciatus Peters, 1862 for over 40 years. Although relatively few specimens have been collected, mostly juveniles, it is clear that these frogs inhabit three separate upland regions of the country: The Cordillera de Talamanca in western Panama, the Chagres Highlands and Cordillera de San Blas in central Panama, and the Serrania de Pirre in the far eastern portion of the country. In accordance with previously published molecular data, we identified distinctive features of the skulls of frogs representing these three allopatric populations and herein revalidate H. panamensis (Stejneger, 1917), describe the new species Hemiphractus elioti sp. nov. from the Cordillera de Talamanca, and the new species Hemiphractus kaylockae sp. nov. from the Serrania de Pirre. We also propose that the taxon H. fasciatus is a South American species not occurring in Panama. PMID- 30313255 TI - Systematics of the Mesalina guttulata species complex (Squamata: Lacertidae) from Arabia with the description of two new species. AB - Mesalina are small diurnal lacertid lizards inhabiting arid areas from North Africa to northwestern India. Previous phylogenetic studies have shown the existence of several species complexes within the genus, some of them with high levels of undiscovered diversity. In the present study, we carry out an integrative systematic revision of the Mesalina guttulata species complex using both molecular and morphological data from across its entire distribution range in North Africa, the Middle East and Arabia. The results of the genetic analyses indicate that M. guttulata and M. bahaeldini are two allopatric sister taxa separated by the Suez Canal and that the species complex includes a further three unnamed deep phylogenetic lineages, two of them restricted to southern and southwestern Arabia and described herein as Mesalina austroarabica sp. nov. and Mesalina arnoldi sp. nov., respectively. As a result of the lack of enough material, the third deep lineage, distributed across Kuwait, Saudi Arabia and Jordan, is provisionally left undescribed. The two newly described species are characterized by their size, scale counts and tail coloration, as well as differences at the three mitochondrial and one nuclear gene analyzed in the present study. PMID- 30313256 TI - New data clarifying the taxonomy of European members of the Lepidocyrtus pallidus serbicus group (Collembola, Entomobryidae). AB - The genus Lepidocyrtus is fairly well explored in Hungary and was up to now represented by 18 species. Systematic mesofauna survey of a swamp woodland gave us the opportunity to describe the new species, L. florae sp. nov., characterized by the dark blue color, the dorsal macrochaetae formula A0A2aA2A3S3Pa5/00/0101+2 and the absence of scales on the antennae. Related species L. arrabonicus, L. pallidus, L. pseudosinelloides and L. weidneri were also revised with particular attention to clarify the interpretation of the dorsal chaetotaxy of the head. The observed variability in abdominal chaetotaxy of L. pallidus suggests that the only character differentiating between this species and L. weidneri is the labial chaetotaxy, with chaeta r (in L. pallidus) and chaeta R (in L. weidneri). An identification key to European Lepidocyrtus species with dorsal trunk macrochaetae formula 00/0101+2 is also provided. PMID- 30313257 TI - One new genus of the tribe Meconematini (Orthoptera: Tettigoniidae: Meconematinae) from China. AB - A new genus of Meconematinae is erected, i.e. Similameconema gen. nov. Nipponomeconema sinica Liu Wang, 1998 is transferred to the new genus. The morphological characters of the species are supplemented and provided with figures. The main differences between the new genus and the genus Nipponomeconema Yamasaki, 1983 are pronotum with an entire median carina, lateral lobe slightly longer than deep; male 2nd to 5th abdominal tergites with tubular projections; the base of male cercus with a process; genitalia sclerotized. The examined specimens are deposited in the Museum of Hebei University. PMID- 30313258 TI - On Sphallambyx mexicanum and key to species of Sphallambyx (Coleoptera, Cerambycidae, Cerambycinae). AB - The male of Sphallambyx mexicanum Galileo Martins, 2007 is described for the first time; the geographical distribution of the species is expanded to Guatemala, Costa Rica, and Panama. Sphallambyx chabrillacii (Thomson, 1857) is formally excluded from the fauna of Costa Rica. A key to species of Sphallambyx Fragoso, 1982 is provided. PMID- 30313259 TI - Note on two genera proposed by Gistel in 1834. AB - The genera Geocharis and Caloclyptus, proposed by Gistel in 1834, are placed in synonymy with Molops Bonelli, 1810 (n. syn.). Geocharis thoracica and Caloclyptus jenisonii, also described by Gistel in 1834, are nomina dubia but, for pratical reasons, are placed in synonymy with Molops striolatus Fabricius, 1801 (n.syn.). Geocharis Gistel, 1834 is declared nomen oblitum and Geocharis Ehlers, 1883 nomen protectum. PMID- 30313260 TI - Description of the female of Smerkata zolotuhini (Lepidoptera: Endromidae). AB - Smerkata Zolotuhin, 2007 has been described as a subgenus of Mustilia Walker, 1865 (Zolotuhin 2007), and recently upgraded to the genus level by Wang et al. (2015). Smerkata zolotuhini (Saldaitis Ivinskis, 2015) was recently described from western part of Sichuan province of China based on male specimens, as females were unknown at the time (Saldaitis et al. 2015). Recent collecting has provided additional specimens, including females described below. PMID- 30313261 TI - Paleopetria Ozdikmen, 2008 is a junior objective synonym of Petriathyris Lee Jin, 2006, new name pro Petria Mendes, 1961 (Brachiopoda, Terebratulida) preoccupied by Petria Semenov 1893 (Arthropoda, Coleoptera). AB - The terebratulide genus Petria Mendes, 1961 was described for a group of cryptonelloid brachiopods (Brachiopoda, Terebratulida) from the Carboniferous (Pennsylvanian) of the Amazonian region, Brazil. To our knowledge only the type species Waldheimia coutinhoana Derby, 1874 was placed in the genus. The genus name Petria Mendes, 1961 is pre-occupied by Petria Semenov, 1893, a genus in the Coleoptera family Tenebrionidae. PMID- 30313262 TI - On the blue butterfly taxa established by L.G. Courvoisier with the type locality "Narun" (Lepidoptera, Lycaenidae). AB - The status and systematic position of the blue butterfly taxa, established by L.G. Courvoisier from "Narun", are discussed. The following lectotypes are designated and figured: [Chrysophanus Phlaeas] F. naruena Courvoisier, 1911, Lycaena icarus Rott. F. wiskotti Courvoisier, 1911, Lycaena arion L. F. naruena Courvoisier, 1911 and [Lycaena] Argus Schiff. (Argyrognomon Bgstr.) f. naruena Courvoisier, 1913. The following taxonomic implications are made: L. phlaeas phlaeas (Linnaeus, 1761) = L. phlaeas naruena (Courvoisier, 1911), syn.n.; P. icarus icarus (Rottemburg, 1775) = P. icarus wiskotti (Courvoisier, 1911), syn.n.; Phengaris cyanecula naruena (Courvoisier, 1911), stat.rev. = P. cyanecula sosinomus (Fruhstorfer, 1915), syn.n., = P. cyanecula sauron (Korb, 2003), syn.n.; P. idas idas (Linnaeus, 1761) = P. idas naruena (Courvoisier, 1913), syn.n., = P. idas sareptensis Chapman, 1917, syn.n. The type locality of P. cyanecula naruena (Courvoisier, 1911) must be corrected as well: "Narun" (Naryn in Inner Kyrgyzstan). The taxonomic status and geographic distribution of the Central Asiatic populations of P. idas are discussed, which tells that the additional research is needed to clarify the problem. PMID- 30313263 TI - Revision of the leafhopper genus Soractellus Evans (Cicadellidae: Deltocephalinae) with description of a new species from Pakistan. AB - The leafhopper genus Soractellus Evans, 1966 is reviewed and a new short-winged species, Soractellus lalianensis sp. nov. from Pakistan, is described and illustrated. A key to distinguish all species in this genus is given. PMID- 30313264 TI - Erratum: ANTHONY S. CHEKE JULIAN P. HUME (2018) The Reunion Fody and Sonnerat's Shrew and the validity of scientifically naming animals described without physical types. Zootaxa, 4382: 592-600. PMID- 30313265 TI - Chorionic sculpture of eggs in the subfamily Dismorphiinae (Lepidoptera: Papilionoidea: Pieridae). AB - This is the second exploration, comparison, and analysis of the chorion of species (45 sspp.) of the subfamily Dismorphiinae (Pieridae). This study includes nearly 50% of the species of the subfamily, including six of the seven genera in its two subtribes: Leptidea (Leptideini), Enantia, Pseudopieris, Lieinix, Moschoneura, and Dismorphia (Dismorphiini). The material studied originates from more than three dozen localities in six different countries on three continents (America, Asia, and Europe) and two biogeographical regions, the Palearctic and Neotropical, over the last 20 years. We have corrected and added information regarding several morphological aspects of the chorion. The precision of the citriform configuration and the elimination of the meloniform shape in the egg of Dismorphiini were determined with detailed observations on the maturation of the chorion in the ovarioles where each stage appears in a linear sequence. We discerned that the meloniform states correspond to incompletely differentiated or immature eggs. This was confirmed by the study of new samples of Dismorphia amphione, D. eunoe, and D. lewyi. The chorion of Dismorphiinae is basically plesiomorphic with respect to those of Coliadinae and Pierinae because it lacks several typical synapomorphies of these subfamilies, such as the presence of micro-grid and/or perimicropylar and apex differentiation, respectively. The eggs of each Dismorphiinae genus can be diagnosed by a combination of chorionic features, although sometimes by one or more plesiomorphies or apomorphies in each genus, with respect to the form or character states in axes, ribs, and poles in the grid of the three regions of the egg - two polar regions and one equatorial (basal, medial, and apical). Leptidea and Enantia show the most generalized grid pattern; however, two genera retain several plesiomorphies with respect to the undifferentiated axes or a small number of short axes (Pseudopieris), as well as many equidistant ribs (Lieinix). The chorionic grid of Moschoneura, although practically lacking short axes, shows the fewest number of axes in the entire subfamily (eight aligns it with Pseudopieris). The chorionic grid in Dismorphia is highly diverse, as it shows the most derived states; however, it comprises symplesiomorphies or atavisms in two groups of species, which aligns them closer to Lieinix or Pseudopieris, but we do not take them into account in some cases where they are convergences or structural parallelisms. It seems that the combination of the shape and its length:width ratio is correlated with the alar configuration (design, sexual dimorphism, and coloring patterns) and separates three groups of species in Dismorphia, and often correlates with the number of ribs. This also coincides with the Batesian participation in the number of mimetic complexes in which a subgroup of species and their stenoecy are integrated within the primary forests. Finally, two schemes are presented that synthesize and illustrate the changes or progression of the form and chorionic grid in the genera of the subfamily. PMID- 30313266 TI - Taxonomic study on the Chinese Steninae (Coleoptera, Staphylinidae), with descriptions of three new species of the Genus Stenus Latreille. AB - This is a taxonomic study on the genus Stenus Latreille (Coleoptera, Staphylinidae) from China and includes descriptions of three new species: Stenus renjiafenicus Lv et Zhou, sp. nov., from Yunnan, Stenus longchishanicus Lv et Zhou, sp. nov., from Sichuan, and Stenus napoensis Lv et Zhou, sp. nov., from Guangxi, with illustrations and photos of the taxonomic characters. A latest key to all Chinese species of Stenus tenuimargo group is modified to include the new species. The following 4 Stenus species, S. feae Fauvel, 1895, S. claritarsis Puthz, 1971 S. malickyi Puthz, 2008, and S. iustus Puthz, 1976 are newly recorded to China and are redescribed, with illustrations and photos of the taxonomic characters. PMID- 30313267 TI - Two new species of the subgenus Sabethinus of Sabethes (Diptera: Culicidae) from Costa Rica, first confirmation of members of the subgenus in Central America. AB - Two new species of Sabethes subgenus Sabethinus (Diptera: Culicidae) from Costa Rica are formally named Sa. andreae and Sa. theresae. Descriptions consisting of differential and diagnostic morphological characters are provided for adults, male genitalia and fourth-instar larvae. The male genitalia and the fourth-instar larva and pupa of both species are illustrated. The species are compared with the four previously described species known to occur only in South America, i.e. Sa. idiogenes, Sa. intermedius, Sa. melanonymphe and Sa. xhyphydes. A new country record for Colombia is reported for Sa. xhyphydes and keys are provided to distinguish the adults and larvae of the six species. PMID- 30313268 TI - Amphicnemis valentini sp. nov. from the Cardamom ecoregion in Cambodia and Vietnam (Odonata: Coenagrionidae). AB - Amphicnemis valentini sp. nov. is described from the Ream Peninsula of Cambodia (holotype: Cambodia, Preah Sihanouk Province, Ream Peninsula, 10.52258 N 103.69556 E, RMNH) and Phu Quoc Island, Kien Giang Province of Vietnam, both in the Cardamom ecoregion. It is similar to A. gracilis Kruger, 1898, which occurs in Peninsular Malaysia and Sumatra, but differs from it by a long process on the male prothorax. PMID- 30313269 TI - Discovery of the spider wasp genus Sphictostethus Kohl, 1884 (Hymenoptera: Pompilidae: Pepsinae) in New Guinea, with description of two new species. AB - Two new species of the genus Sphictostethus Kohl, 1884 are described and illustrated from New Guinea (Indonesia: West Papua). Both species, S. papua Loktionov Lelej, sp. nov. and S. arfak Loktionov Lelej, sp. nov. differ from congeners by their peculiar head and clypeus shape, the presence of tubercles on the mesopleuron and propodeum, and the well-developed metasomal petiole. The genus Sphictostethus is newly recorded from New Guinea as a new northernmost border for their distribution within the Australian Region. An addition to the key of Australian species is given. PMID- 30313270 TI - New records of species of the Polyonyx sinensis group (Crustacea: Decapoda: Anomura: Porcellanidae) from Japan, the Philippines, Singapore, and Malaysia, with descriptions of two new species. AB - Five species of the genus Polyonyx Stimpson, 1858 are reported from southern Japan, the Philippines, Singapore, and Peninsular Malaysia. All of them belong to the P. sinensis group, which is morphologically defined by having the dactyli of the ambulatory legs each with the dorsal claw being much smaller than the ventral claw. Two species are described as new to science, one each from Peninsular Malaysia and the Ryukyu Islands in Japan, and their affinities are discussed. Polyonyx boucheti Osawa, 2007, P. heok Osawa Ng, 2016, and P. thai Werding, 2001, are also newly reported from southern Japan, the Philippines, and Singapore. A key to the Indo-West Pacific species of the P. sinensis group is provided. PMID- 30313271 TI - First record of Hiroshiinoueana Kawabe, 1978 from China (Lepidoptera: Tortricidae: Olethreutinae), with descriptions of two new species. AB - The genus Hiroshiinoueana Kawabe, 1978 is recorded from China for the first time. Two new species, H. wuzhishanica sp. nov. and H. inequivalva sp. nov., are described and illustrated. A key to the species of Hiroshiinoueana is provided. Cytochrome oxidase subunit I (COI) sequences of the new species are deposited in GenBank. PMID- 30313272 TI - Descriptions of five morphologically and genetically confirmed new species of the Coleophora poecilella Walsingham, 1907 species group (Lepidoptera, Coleophoridae) from the Palearctic Region. AB - Five new Coleophora species belonging to the C. poecilella species group are described: C. mirleftensis Tabell, sp. nov. from Morocco, C. embaensis Tabell, sp. nov. and C. charynensis Tabell, sp. nov. from Kazakhstan, C. nupponeni Tabell, sp. nov. from Kazakhstan and Tajikistan, and C. tugaicola Tabell, sp. nov. from Tajikistan. The male genitalia of C. hypomona (Falkovitsh, 1979) and the female genitalia of C. trichopterella Baldizzone, 1985 are illustrated for the first time. DNA barcodes are provided for each species, with a comparison to the genetically most similar species. PMID- 30313273 TI - Genera of Mythicomyiidae (Insecta, Diptera) new to the fauna of Morocco, with descriptions of new species. AB - Three genera of Mythicomyiidae are newly recorded from Morocco: Glabellula, Mythenteles, and Leylaiya. A total of 8 species of Mythicomyiidae are currently known from the country; of those, 3 new species are described and illustrated: Glabellula maroccana Evenhuis Kettani, n. sp.; Mythenteles signifera Evenhuis Kettani, n. sp. and Leylaiya pellea Evenhuis Kettani, n. sp. A key to the genera of Mythicomyiidae in Morocco is presented. PMID- 30313274 TI - Two new deep-water species of the genus Thorogobius (Teleostei: Gobiidae) from the upper continental slope of the Eastern Central Atlantic. AB - Two new gobiid species, Thorogobius alvheimi sp. nov. and Thorogobius laureatus sp. nov. (Teleostei: Gobiiformes: Gobiidae), are described from the outer continental shelf and upper slope of the Eastern Central Atlantic off Angola, Ghana and Sao Tome and Principe. The specimens were trawled from depths between 57 and 208 m. The new species are most similar to Thorogobius angolensis. Thorogobius alvheimi sp. nov. is distinguished from its congeners in the combination of following characters. Fins: first dorsal fin with the second and third spines distinctly elongated; pectoral fin ray count 20-21; pelvic disc complete and short with well-developed anterior membrane (frenum) and pointed lateral lobes. Scales: nape and predorsal area naked; no scales on opercle; scales in longitudinal series 27-31. Pattern of free neuromasts: supratemporal rows tr and trp developed, extending transversally between pores H and K; longitudinal row g short, not passing row m posteriorly and distinctly distant from row h; infraorbital row 6 long, ventrally extending to lower margin of preopercle, its ventral section 6i originating anterior to its dorsal section 6s; posterior lateral row h reaching anteriorly above posterior third of opercle. Coloration: body uniformly pale fawn and brown; margin of scale pockets dark brown pigmented, yielding a reticulated pattern; pale spots on nape and predorsal area; caudal fin uniformly dusky greyish. Thorogobius laureatus sp. nov. is distinguished from its congeners in the combination of following characters. Fins: first dorsal fin the second and third spines distinctly elongated; pectoral fin ray count 19-22; pelvic disc complete, short, with well-developed anterior membrane (frenum) with pointed lateral lobes. Scales: scales on sides of predorsal area and midline mostly naked; no scales on opercle; scales in longitudinal series 24-27. Pattern of free neuromasts (sensory papillae): supratemporal rows tr and trp developed, extending transversally between pores H and K; longitudinal row g long, passing row m posteriorly and relatively close to row h; infraorbital row 6 long, ventrally extending to lower margin of preopercle, its ventral (6i) and dorsal (6s) originating opposite to each other; posterior lateral rows: row h long, reaching anteriorly above middle of opercle. Coloration: body pale fawn and brownish; margin of scale pockets dark brown pigmented, yielding a reticulated pattern; five brown blotches on flanks in lateral midline from below first dorsal fin to caudal peduncle; caudal fin with six or seven distinct dark vertical bands. PMID- 30313275 TI - A new species and new records of the spider genus Taranucnus (Araneae, Linyphiidae) from the Ukrainian Carpathians. AB - Taranucnus Simon, 1884 is a small Holarctic genus of the spider family Linyphiidae that contains only five species (WSC, 2018). In Europe and in Ukraine it is represented by three taxa: T. setosus (O. P.-Cambridge, 1863), T. bihari Fage, 1931 and T. carpaticus Gnelitsa, 2016 (WSC, 2018). The type species of the genus is T. setosus, widely distributed in the Palaearctic, T. bihari is known from a few localities from the Carpathians within Poland, Slovakia, and Romania (Nentwig et al. 2017). Recently, T. carpaticus was recorded from the two mountain massifs (Gorgany and Chornohora) of the Ukrainian Carpathians (Gnelitsa 2016). In this paper a fourth European species, Taranucnus beskidicus new species, is described. PMID- 30313276 TI - Mites of the family Parasitidae Oudemans, 1901 (Acari: Mesostigmata) from Japan: a new species of Vulgarogamasus Tichomirov, 1969, and a key to Japanese species. AB - Vulgarogamasus edurus sp. nov. (Acari: Parasitidae) is described based on females, deutonymphs and males extracted from leaf litter and soil in Ami, Ibaraki Prefecture, Japan. Morphological differences between the new species and its closely related species, Vulgarogamasus fujisanus (Ishikawa, 1972), are recorded based on the examination of type materials. Information about parasitid mites reported in Japanese literature is reviewed, and a key to species is provided. PMID- 30313277 TI - A new, distinctly coloured species of Lysmata Risso, 1816 (Malacostraca: Decapoda: Lysmatidae) from the south-central Atlantic. AB - A new species of the caridean shrimp genus Lysmata Risso, 1816 is described from St. Helena and Ascension Island in the south-central Atlantic. Lysmata napoleoni sp. nov. is part of the so-called "long-branch group" of the genus and shows a strong morphological similarity with the eastern Atlantic L. seticaudata Risso, 1816, from which it can be distinguished by details of the accessory branch of the antennular flagellum. The new species also displays a unique and bright colour pattern and therefore can be easily recognised in the field. Furthermore, it is typically found in proximity of sea anemones, Telmatactis cricoides (Duchassaing), and appears to be an occasional fish cleaner. PMID- 30313278 TI - Reassessment of the taxonomic status of Craseomys and three controversial species of Myodes and Alticola (Rodentia: Arvicolinae). AB - The genera Myodes (red-backed voles) and Alticola (mountain voles) appear to be sister taxa based on morphological similarities, but molecular analyses fail to resolve them as monophyletic genera owing to the uncertain taxonomic status of Craseomys and Phaulomys. As a result of incomplete sampling of related specimens, ongoing controversies on the taxonomic positions of several generic and specific taxa necessitate further clarifications. Herein, we combined molecular, morphometric, and geometric morphometric approaches to analyze 217 specimens of 10 taxa of Myodes and Alticola systematically. We sequenced three genes (Cytb, COI, GHR) de novo from specimens with fresh tissues, and published sequences for M. shanseius and A. stoliczkanus for the first time. Based on this new molecular dataset, we produced phylogenetic trees using Bayesian inference, maximum likelihood, and maximum parsimony approaches. Our molecular and morphological analyses both identified three primary clades within Myodes and Alticola. The Craseomys-Phaulomys clade consistently separated from Myodes sensu stricto (s. str.) and Alticola s. str.-Platycranius. Our results support the resurrection of the genus Craseomys and the treatment of Phaulomys as its junior synonym. As Craseomys shanseius clustered with C. rufocanus in three gene phylogenies and this assessment was congruent with morphological results, we assigned C. shanseius to a subspecies of C. rufocanus. Specimens from one sampling site in Pulan County of Tibet possess M3 patterns typical of A. stoliczkanus and A. stracheyi, despite clustering together in matrilineal genealogy. Thus, we tentatively assigned A. stracheyi as a junior synonym of A. stoliczkanus. Our analyses confirmed the validity of A. semicanus and unambiguously distinguished it from A. argentatus by the ratio of tail length to head-body length, color of tail and feet, M3 pattern, and distribution. PMID- 30313279 TI - Taxonomy of deep-water tetillid sponges (Porifera, Demospongiae, Spirophorina) from Brazil, with description of three new species and new characters. AB - Since the 19th century the deep-sea sponges from Brazil have been studied and many of them are still being discovered. This study describes five species of tetillid sponges from deep waters of the Brazilian economic exclusive zone; three are new, one is a new occurrence, and another is a known species which is here analyzed. The new species found are: Cinachyrella clavaeformis sp. nov. from the Columbia Seamount (85 m depth), Cinachyrella strongylophora sp. nov. from the Almirante Saldanha Seamount (270 m depth) and Craniella curviclada sp. nov. from slope of the Espirito Santo Basin (500 m depth). The two new species of Cinachyrella possess microacanthoxeas like those found in Cinachyrella kuekenthali (Uliczka 1929); this last species occurs in Caribbean region (4-100 m depth) and in N, NE and SE Brazil (0.2-100 m depth). The type material of Craniella corticata (Boury-Esnault 1973); from NE Brazil (75 m depth), has been found to be a synonym of Cinachyrella kuekenthali. Craniella crustocorticata van Soest 2017; from the Guyana shelf and slope (618-500 m depth), is here reported from the slope of NE and SW Brazil (400-700 m depth). A disorganized choanosomal skeleton (in Cinachyrella clavaeformis sp. nov.), strongyles (in Cinachyrella strongylophora sp. nov.) and a single-layered cortex of tangential oxeas (in Craniella crustocorticata) are new diagnostic characters that have led us to propose slight amendments in the definitions of Cinachyrella Wilson 1925 and Craniella Schmidt 1870. We discuss these and other morphological characters as well as their usefulness in Tetillidae. The diversity, distribution and bathymetry of tetillid sponges from Brazil are discussed and our knowledge of the composition of deep-sea sponges (deeper than 100 m) off Brazil is updated. PMID- 30313280 TI - Two new species of Acontias (Acontinae, Scincidae) from the Mpumalanga Highveld escarpment of South Africa. AB - The African genus of fossorial legless lizards (Acontias Cuvier) currently comprises 26 species and subspecies. In a recent study on the two disjunct populations of Acontias breviceps Essex, the presence of cryptic species was discovered. Here, we increase the sampling size and describe these disjunct populations from the Mpumalanga Escarpment of South Africa as new species. The new species differ from congeners based on a combination of factors, including the number of midbody, ventral, and subcaudal scale counts, ventral pigmentation, allopatric distributions, and genetic divergences. The new species are genetically distant from nominal A. breviceps, with which it shares overall pigmentation and scalation. The new description adds to the growing number of Mpumalanga escarpment endemic reptiles, and highlights the area as a biodiversity hotspot. The use of vertebral counts as a distinguishing character between species is briefly discussed. PMID- 30313281 TI - Twenty new species of Agrilus (Coleoptera: Buprestidae: Agrilinae) from the Oriental Region. AB - Twenty new Agrilus species from the Oriental Region are described and illustrated: A. aramis sp. nov. (Laos), A. aries sp. nov. (Laos), A. armipes sp. nov. (Laos, India), A. athos sp. nov. (Laos, Thailand), A. bacan sp. nov. (Indonesia), A. bicolorifrons sp. nov. (Laos), A. cuprocunctus sp. nov. (Laos), A. ebenus sp. nov. (Laos, Thailand, Vietnam), A. frontis sp. nov. (Laos), A. gemellus sp. nov. (Nepal), A. khunborom sp. nov. (Laos), A. kyklos sp. nov. (Laos), A. loongfahi sp. nov. (Malaysia), A. metallinus sp. nov. (Laos), A. nemoralis sp. nov. (Laos), A. porthos sp. nov. (Laos), A. princeps sp. nov. (Laos), A. rex sp. nov. (Malaysia), A. sikhiav sp. nov. (Laos) and A. sinuosus sp. nov (Laos, Vietnam). PMID- 30313282 TI - Redescription of Cis renominatus and Paratrichapus javanus (Coleoptera: Ciidae). AB - Cis renominatus Sandoval-Gomez, Lopes-Andrade Lawrence, 2014, and Paratrichapus javanus (Pic, 1937) were originally described in the genus Xylographus Mellie, 1847. Their original descriptions are anecdotal and do not provide information on the morphology of male abdominal terminalia, which is essential for accurate identification of ciid beetles. Our aim is to redescribe C. renominatus and P. javanus based on careful examination of lectotypes and paralectotypes, and also on additional specimens of C. renominatus identified by us. The most remarkable feature of C. renominatus is the morphology of male genitalia, with penis about twice as long as tegmen, very slender, subparallel-sided, with apex hook-shaped and base spatula-shaped. Paratrichapus javanus is the largest species of the genus (length at least 3.50 mm) and is characterized by its very expanded and rounded metatibiae that bear about 25 spines, and by the anterocephalic edge of males bearing two tubercles with two tufts of bristles between them. PMID- 30313283 TI - Dario neela, a new species of badid fish from the Western Ghats of India (Teleostei: Percomorpha: Badidae). AB - Dario neela, is described from a small tributary stream of the Kabini River in northern Kerala, India. It can be distinguished from congeners by the male colouration in life, which shows wide rims of iridescent blue in all median fins and the pelvic fin. It is further distinguished from all species of Dario, except D. urops by the number of abdominal vertebrae (14 vs. 11-13), and from all Dario species except D. urops and D. huli by the presence of a conspicuous black blotch on the caudal-fin base. Dario neela is distinguished from D. urops by the absence of the horizontal suborbital stripe and presence of a series of up to eight black bars on the body; and from D. huli by 27-28 vertebrae and 27 scales in a lateral row and the absence of teeth from hypobranchial 3. Dario neela is genetically divergent from both Western Ghats congeners in the mitochondrial CO1 gene, showing an uncorrected p-distance of 5.9% with D. urops and 13.1% to D. huli. PMID- 30313284 TI - A new zygaenid moth species from Kangaroo Island, South Australia (Lepidoptera: Zygaenidae: Procridinae). AB - A new species of forester moths, Pollanisus hyacinthus sp. nov., is described from Kangaroo Island, South Australia. It is similar to Pollanisus isolatus Tarmann, 2004 and Pollanisus cyanota (Meyrick, 1886) but differs in several external characters and in the genitalia. PMID- 30313285 TI - A new genus and species of Sclerodactylidae (Echinodermata: Holothuroidea: Sclerothyoninae) from the Pacific coast of Panama, and assignment of Neopentamera anexigua to Sclerothyoninae. AB - Paulayellus gustavi, a new sclerodactylid genus and species, is described from the Pacific coast of Panama. The new genus and species is assigned to the subfamily Sclerothyoninae based on a suite of characters, which include the radial and interradial plates of the calcareous ring united at the base only. Paulayellus gen. nov. differs from the other Sclerothyoninae genera in having posterior processesof radial plates undivided. Additionally, differs from Sclerothyone, Thandarum and Neopentamera in having knobbed buttons, plates and cups in the body wall (whereas the body wall is furnished only with tables and plates in Sclerothyone, Temparena and Thandarum, and only with knobbed buttons and plates in Neopentamera). The new genus is, so far, monotypic. The also monotypic genus Neopentamera proved to have the radial and the interradial plates of the calcareous ring united at the base only, as typically found in the Sclerothyoninae, and is therefore transferred to that subfamily. The discovery of a new genus in the Sclerothyoninae and the transfer of Neopentamera required the amendation of the diagnosis for the subfamily. A key to the Sclerothyoninae is given. PMID- 30313286 TI - Two new species of the genus Chibiraga Matsumura, 1931 (Lepidoptera: Limacodidae) from China. AB - Two new species in the genus Chibiraga, C. houshuaii sp. nov. and C. yukei sp. nov., are described based on specimens collected in Yunnan Province and Sichuan Province, respectively. Illustrations depicting male adults and male genitalia are provided, along with venation patterns and a distribution map of the genus Chibiraga. COI DNA fragments of C. yukei sp. nov. and both sexes of C. banghaasi (Hering Hopp, 1927) are also depicted. PMID- 30313287 TI - New species and record of Nazeris Fauvel in southern China (Coleoptera, Staphylinidae, Paederinae). AB - Four species of Nazeris Fauvel are reported from Guangdong and Hunan, China, with three of them described as new: N. rubidus Hu, Luo Li, sp. n., N. nanlingensis Hu, Luo Li, sp. n., and N. gaoleii Hu, Luo Li, sp. n. Nazeris inaequalis Assing, 2014 is newly recorded from Guangdong Province. PMID- 30313288 TI - Uranotaenia pseudostricklandi, a new species in subgenus Pseudoficalbia (Diptera: Culicidae) from Kerala, India. AB - The female and male adults, male genitalia, pupa and larva of Uranotaenia (Pseudoficalbia) pseudostricklandi sp. nov. (Diptera: Culicidae) are described from specimens collected in India. PMID- 30313289 TI - Discovery of two new Andean species of Scolomus (Townes Townes), with a key to all known species (Hymenoptera: Ichneumonidae: Metopiinae). AB - Scolomus Townes Townes is a widely distributed genus of the family Ichneumonidae, with most species occurring in the New World. Herein two new species from Chile are described and illustrated. Scolomus maculatus sp. nov., which is characterized by a large rhomboid areolet and very wide RS vein in the fore wing, resembling a petiole; head and pronotum green, mesoscutum yellow with dark brown spots on its lateral lobes and around the scutellum. Scolomus clypeatus sp. nov., which is characterized by its wide clypeus, 3.00* as wide as long, with a rectangular aspect; head, mesoscutum, postscutellum and pronotum entirely yellow. The first key to all known species of the genus is also presented. PMID- 30313290 TI - Certain species of Plecoptera from the headwater springs of National Integration River (Sao Francisco), Brazil. AB - Specimens of Anacroneuria Klapalek 1909 (Plecoptera: Perlidae) and Tupiperla Froehlich 1969 (Plecoptera: Gripopterygidae) from the headwater springs of the National Integration River (Sao Francisco River), Serra da Canastra National Park, in Minas Gerais State, of southeastern Brazil, were studied. A new species, Anacroneuria saofrancisco n. sp. is described and the descriptions of the nymph and the female of A. saofrancisco are also presented. PMID- 30313291 TI - The Lampropidae (Crustacea: Cumacea) of the World. AB - Prior to the present study, the cumacean family Lampropidae included 114 species. This family is primarily found in temperate to cold waters. Revisions and investigation of museum collections yielded 12 new genera (Alamprops n. gen., Aplatysympus n. gen., Austrolamprops n. gen., Brachylamprops n. gen., Doieolamprops n. gen., Farragolamprops n. gen., Paraplatysympus n. gen., Phallolamprops n. gen., Phallolampropoides n. gen., Pseudoarchaeocuma n. gen., Quasiparalamprops n. gen., Reyssia n. gen.) and 23 new species (Aplatysympus neozealanicus n. sp., Austrolamprops sulcatus n. sp., Bathylamprops paraleucon n. sp., Brachylamprops scabridus n. sp., Chalarostylis bruunae n. sp., Doeiolamprops confundus n. sp., Farragolamprops seminalis n.sp., F. spinacristatus n. sp., Hemilamprops impellucidus n. sp., Lamprops northwindae n. sp., Misceolamprops concavus n. sp., Paraplatysympus aspericristatus n. sp., P. echinolowryi n. sp., Phallolamprops californiensis n. sp., P. pribilofensis n. sp., Phallolampropoides chukchiensis n. sp., Platytyphlops bamberi n. sp., P. echinatus n. sp., P. lowryi n. sp., P. petrescui n. sp., P. taylorae n. sp., Pseudoarchaeocuma bacescui n. sp., Quasiparalamprops chathamensis n. sp.). Additional description and Fig. of the ovigerous female and adult male of Watlingia chathamensis are provided. All new species and genera are described and illustrated, with diagnoses and keys to all genera and species. In addition, Mesolamprops bacescui is transferred to the Diastylidae as Diastylis bacescui (Gamo 1999). PMID- 30313292 TI - A revision of the Neotropical spider genus Nops MacLeay (Araneae: Caponiidae) with the first phylogenetic hypothesis for the Nopinae genera. AB - The spider genus Nops MacLeay is revised, with redescriptions of 22 previously known species and descriptions of 12 new species. A new diagnosis for the genus is provided and keys to separate the species are proposed. After this revision Nops includes 34 extant species, thereof 15 (44%) occur in the Caribbean Islands, four (12%) in Central America and 15 (44%) in South America. Females of Nops meridionalis Keyserling and Nops gertschi Chickering are found and described for the first time. Three new synonymies are proposed: Nops virginicus Sanchez-Ruiz with Nops blandus Bryant, Nops craneae Chickering with Nops maculatus Simon and Nops proseni Biraben with Nops farhati Prosen. Four species are considered inquerenda: Nops anisitsi Strand, Nops bellulus Chamberlin, Nops branicki (Taczanowski) and Nops glaucus Hasselt. The following new species are described: N. jaragua n. sp., N. navassa n. sp., and N. pallidus n. sp. from the Caribbean region; N. campeche n. sp. and N. tico n. sp. from Central America, and N. alexenriquei n. sp., N. amazonas n. sp., N. bahia n. sp., N. ipojuca n. sp., N. itapetinga n. sp., N. minas n. sp. and N. pocone n. sp. from South America. New geographical records and distribution maps are provided for all species, with illustrations and reviewed diagnoses. The Nops species are restricted to the Neotropical region, from the Caribbean Islands and Mexico to the north of Argentina. The highest species richness is concentrated in the Wider Caribbean Region, including Central America and the north of Colombia and Venezuela where 64.7% of the species occur. Endemism in the Caribbean islands is very high; most of these species are single island endemics. A cladistic analysis, based on morphological data, was executed to test the monophyly of the genus. This is the first cladistic analysis of Caponiidae, and it includes besides the Nops species, 1) the six other species that were transferred from Nops, now in the genera Orthonops, Cubanops, Tarsonops and Medionops, and 2) Nopsides ceralbonus Chamberlin and Nyetnops guarani Platnick Lise. Therefore, representatives of all known Nopinae genera are included in the ingroup. The data matrix comprises 41 taxa scored for 47 morphological characters. The analyses under equal weights resulted in six equally parsimonious trees of 99 steps. All these trees are congruent with a unique hypothesis for Nopinae genera. Thus, all topological differences among the most parsimonious trees were the consequence of different hypotheses of relationships within Nops. The same result was also found under implied weighting with constants of concavity k = 2 to 13, where the topology of all trees was congruent for a single Nopinae genera hypothesis, but relationships within Nops were not resolved. All analysis under equal and implied weights recovered the monophyly of Nops with high support values, but internal clades within the genus showed low branch supports. Our results thus suggest that to resolve the internal relationships of Nops, studies based on molecular evidence are necessary to counteract the deficit of morphological data. The hypothesis obtained for Nopinae showed high branch support values for most of clades, corroborating all the transfers made from Nops. Medionops was recovered as the sister group of Nops with high support values. Nops, Medionops and Nopsides form a closely related, distinct spider group among nopine, supported by five unambiguous synapomorphies. Two of these synapomorphies could be functionally related: the presence of an arolium on the anterior pretarsi and the elongated and dorsally reflexed unpaired claw on the anterior legs. Nopsides appears to be a genus with apomorphic characters, presenting highly modified legs, but lacking the crista and gladius, and gaining a pair of anterior lateral eyes. Nyetnops is sister to all other nopine genera. Our results identified the necessity of further studies on nopine leg structures (arolium, crista, gladius and adesmatic joints) to improve understanding of the phylogenetic relationships of Nopinae genera. PMID- 30313293 TI - Calcareous sponges of the Western Indian Ocean and Red Sea. AB - Past taxonomic studies of Western Indian Ocean and Red Sea Calcarea have been few and sporadic (e.g. Schuffner 1877, Jenkin 1908, Row 1909, Dendy 1913, 1916, Voigt et al. 2017, 2018). Nevertheless, approximately 70 species are known from these studies for the considered region, but the descriptions of the older records often lack sufficient details for reliable identification. We studied the Western Indian Ocean Calcarea collection kept in the Naturalis Biodiversity Center. Available specimens numbered 145, collected in the Red Sea, Seychelles, Maldives, Mayotte and Rodrigues, in addition to incidental samples from Oman, the Lakshadweep Islands, the Mozambique Channel, and Eastern South Africa. Using a combination of techniques (in situ and 'on deck' photography, detailed field notes, light microscopic studies and measurements, SEM microscopy, and selected DNA sequencing) we identified 45 species, divided over the two main classes Calcinea (24 spp.) and Calcaronea (21 spp.). Not all species could be definitely assigned to an already described or a new species, as seven remained qualified as 'spec.' or 'aff.' for reasons of insufficient material or lack of details of in situ habitus. Sixteen species appeared to be new to science: Borojevia voigti sp.nov., Borojevia tubulata sp.nov., Borojevia pirella sp.nov., Clathrina rodriguesensis sp.nov., Clathrina maremeccae sp.nov., Clathrina repens sp.nov., Leucascus schleyeri sp.nov., Leucetta sulcata sp.nov., Ute insulagemmae sp.nov., Leucandra pilula sp.nov., Leucandra mozambiquensis sp.nov., Grantessa woerheidei sp.nov., Sycettusa hirsutissima sp.nov., Vosmaeropsis glebula sp.nov., Paraleucilla erpenbecki sp.nov., and Kebira tetractinifera sp.nov. For a selection of the identified species from the Western Indian Ocean and the Red Sea (30 spp.), as well as from Indonesian material (22 spp.) published previously (see Van Soest De Voogd 2015) we obtained sequences of the partial 28S gene of nuclear rDNA (C2-D2 region, cf. Voigt Worheide 2016). The sequences of the Western Indian Ocean and Red Sea species were used to assign these to genera and families based on a phylogenetic analysis using MEGA pack vs. 06.6 for Mac of the available dataset. The Indonesian sequences supplemented by partial 28S sequences taken from the Sponge Barcode Project website and the NCBI website were included in the phylogenetic analysis to confirm the assignments. The results were compared and discussed with additional information on regional Calcarea not represented in our material. The latter chapter yielded the discovery of a preoccupied name leading to Sycon oscari nom.nov. for a species described from Mauritius. PMID- 30313294 TI - Stink bugs (Hemiptera: Pentatomidae) from Brazilian Amazon: checklist and new records. AB - A list of the stink bugs (Pentatomidae) species of the Brazilian Amazon is provided for the first time, based on literature review and identification of the specimens of Pentatomidae deposited in the entomological collection of the Museu Paraense Emilio Goeldi (MPEG). Amazonian data base presented here has 324 species of Pentatomidae belonging to 102 genera, ten tribes and five subfamilies: Asopinae, Cyrtocorinae, Discocephalinae, Edessinae and Pentatominae. The Pentatominae has the largest number of species registered to Brazilian Amazon (144 species). The MPEG entomological collection has 122 species distributed in 53 genera, nine tribes and five subfamilies. Forty species from eight tribes and four subfamilies are recorded for the first time to Brazilian Amazon, including species from Podisus Herrich-Schaffer (Asopinae); Adoxoplatys Breddin, Macropygium Spinola, Neoadoxoplatys Kormilev, Ochlerus Spinola and Platycarenus Fieber (Discocephalinae); Edessa Fabricius (Edessinae); Arocera Spinola, Arvelius Spinola, Banasa Stal, Dichelops Spinola, Euschistus Dallas, Mormidea Amyot Serville, Oebalus Stal, Pellaea Stal, Piezodorus Fieber, Proxys Spinola and Thyanta Stal (Pentatominae). Three of these species-Podisus maculiventris (Say, 1831) Neoadoxoplatys saileri Kormilev, 1956 and Edessa laticornis Stal, 1872-are new records to South America. The number of species of Pentatomidae to Brazilian Amazon represents approximately 50% of the species registered to Brazil. Such list of species is important to better understand the distributional range and diversity of the species of Pentatomidae in the Amazon region. PMID- 30313295 TI - New data on the genus Barsine Walker, 1854 from India, with description of a new species (Lepidoptera: Erebidae: Arctiinae: Lithosiini). AB - A new species, Barsine pseudoradians Joshi, Singh Volynkin sp. nov. is described from North East India (Mizoram, Assam and Meghalaya) and Nepal. The new species belongs to the Barsine prominens (Moore) species-group and is compared with B. radians (Moore, 1878), B. pluma Cerny, 2009, B. syntypica Swinhoe, 1906 and B. maculifasciata (Hampson, 1894). Barsine callida (Fang, 1991) is reported for the first time from India. Its comparison with the related Barsine mesortha (Hampson, 1898) is given. Two new combinations are established: Barsine callida (Fang, 1991), comb. nov. and Barsine germana (Rothschild, 1913), comb. nov. Adults, male and female genitalia of all the reviewed species are illustrated. PMID- 30313296 TI - The family Passandridae (Coleoptera: Cucujoidea) in Argentina with comments on species from Brazil and Paraguay. AB - The family Passandridae (Coleoptera: Cucujoidea) in Argentina and adjacent countries is reviewed. A total of 13 species are recorded from Argentina: Catogenus asper Slipinski, 1989, Catogenus castaneus (Perty, 1834), Catogenus cylindricollis (Lacordaire, 1854), Catogenus decoratus Newman, 1839, Catogenus depressus Slipinski, 1989, Catogenus gracilicornis Slipinski, 1989, Catogenus lebasi Guerin-Meneville, 1844, Catogenus longicornis Grouvelle, 1874, Passandra fasciata Gray in Griffin, 1832, Taphroscelidia humeralis (Grouvelle, 1916), Taphroscelidia semicastanea (Reitter, 1876), and Taphroscelidia sp. (probably a new species, not described here). New provincial records are given for C. castaneus (Salta; La Rioja; Santiago del Estero; Cordoba; Corrientes; Buenos Aires), C. cylindricollis (Salta; Misiones; Chaco; Santa Fe; Entre Rios), C. gracilicornis (Catamarca; Buenos Aires), C. longicornis (Salta; Tucuman; Catamarca; Chaco; La Rioja; Entre Rios; Buenos Aires), P. fasciata (Cordoba; Santa Fe; Mendoza; Buenos Aires), T. humeralis (Salta; Catamarca; La Rioja; San Luis; Santa Fe; Corrientes; Entre Rios), T. semicastanea (Salta; Catamarca; Corrientes; Entre Rios), and Taphroscelidia sp. (Corrientes). Four new records are given for Paraguay: C. castaneus, C. cylindricollis, C. longicornis, and Taphroscelidia sp. Monthly and seasonal occurrence of adults is summarized and discussed. Adults of Passandridae emerged from 25 plant species infested with a total of 62 species of Cerambycidae (Coleoptera). Their host specificity is discussed in connection with their wide geographic distributions, which are apparently unrelated to a particular biogeographic province. PMID- 30313297 TI - A review of the Arcuphantes species with the genitalia of arcuatulus-type Araneae, Linyphiidae). AB - This is the second study addressing the Nearctic Arcuphantes species. Re examination of Arcuphantes deposited in the American Museum of Natural History shows that four species have the genitalia of arcuatulus-type, including three new species: Arcuphantes arcuatulus (Roewer, 1942), A. cruciatus n. sp., A. denticulatus n. sp. and A. semiorbiculatus n. sp. Genital characters of arcuatulus-type are reviewed and compared with those of fragilis-type based on SEM images and microscopic pictures. Descriptions of the new species and a redescription of the known species are provided. PMID- 30313298 TI - A new genus and five new species of Anostostomatidae from the Lesser Antilles (Orthoptera: Ensifera). AB - Most high volcanic islands of Lesser Antilles harbor one single genus of Anostostomatidae: Rhumosa n. gen: Rhumosa bolognei n. gen. n. sp. in Guadeloupe, Rhumosa macoucheriei n. gen. n. sp. in Dominica, Rhumosa depazei n. gen. n. sp. in Martinique, Rhumosa admiralrodneyei n. gen. n. sp. in Saint Lucia, Rhumosa captainblighei n. gen. n. sp., in Saint Vincent. These species are restricted to well preserved rainforests; species from northern islands apparently occurring at higher elevation than species of southern islands. The distribution and generic position of Rhumosa n. gen. species is discussed, as well as the generic position of Lutosa cubaensis (Haan, 1843). PMID- 30313299 TI - Seven new species of the Stenus cirrus group (Coleoptera, Staphylinidae) from Sichuan, Southwest China. AB - Seven new species of the Stenus cirrus group collected from Sichuan, Southwest China are described: S. cariniventris Tang, Liu Dong, sp. n., S. jiangrixini Tang, Liu Dong, sp. n., S. lineatus Tang, Liu Dong, sp. n., S. emeishanus Tang, Liu Dong, sp. n., S. jiudingshanus Tang, Liu Dong, sp. n., S. xichangensis Tang, Liu Dong, sp. n., S. brevilineatus Tang, Liu Dong, sp. n. The diagnostic characters of the new species are illustrated, and a key to species of the group from Sichuan Province is provided. PMID- 30313300 TI - Pseudotibiozus Demange, 1970-millipedes of the Eastern Arc Mountains, Tanzania (Diplopoda, Spirostreptida, Spirostreptidae). AB - The genus Pseudotibiozus Demange, 1970, is discussed, its type species, P. cerasopus (Attems, 1914) is re-described based on type and new material, and P. zophoribates sp. nov. is described from the West Usambara Mountains, Tanzania. The millipede faunas of the West and East Usambara Mts are compared. PMID- 30313301 TI - Larva of Halesus nurag Malicky 1974 (Trichoptera: Limnephilidae) and diagnostic key for the limnephilid larvae of Sardinia. AB - This paper gives a description of the hitherto unknown larva of Halesus nurag Malicky 1974 (Trichoptera: Limnephilidae). Information on the morphology of the larva is given, and the most important diagnostic features are figured. In the context of the European Halesus species, the larva of H. nurag is morphologically close to H. appenninus Moretti Spinelli Batta 1979, H. digitatus (Schrank 1781), H. radiatus (Curtis 1834), and H. tessellatus (Rambur 1842). This new morphological dataset was used for providing a key to the Sardinian limnephilid larvae. In this context, H. nurag can be separated from the other Sardinian species with single-filament gills described so far by chaetotaxonomical characters, mandible morphology, and details of the lateral protuberance of abdominal segment I. PMID- 30313302 TI - A new species and an additional record of Pseudotachinus Cameron from China (Coleoptera: Staphylinidae: Tachyporinae). AB - Pseudotachinus bilobus Yin and Li, new species, is described from the border of Guizhou and Guangxi, southern China, with habitus and diagnostic features illustrated. The new species is distinct, and can be readily separated from all other congeners by the complete lack of microsculpture on the dorsal surface of the body, strongly transverse elytra, and unique forms of male and female sternites VIII. In addition, P. assingi Schulke is recorded from a new locality in Yunnan. The latest identification key and distributional map of Pseudotachinus are modified to include the new data. PMID- 30313303 TI - Two new littoral species of the genus Anurida Laboulbene, 1865 (Collembola, Neanuridae) from the Pacific coast of Asia. AB - Two new littoral species of the genus Anurida, viz. A. kyshyensis sp. nov. and A. abashiriensis sp. nov., have been described from the eastern coasts of Chukchi Peninsula (Russia) and Hokkaido Island (Japan), respectively. The former species is most similar to sympatric A. similis Fjellberg, 1985 and A. martynovae Fjellberg, 1985 differing from both of them due to the permanent presence of additional lateral setae on thorax and 3+3 axial setae on Abd.4. A. abashiriensis sp. nov., having unique mandibles and hypertrophic elongate maxillae with long lamellae, is hard to compare with any known species of Anurida and allied genera. PMID- 30313304 TI - A new species of the genus Clistoabdominalis Skevington (Diptera: Pipunculidae) from Iran, with a key to the Western Palaearctic species of the Clistoabdominalis ruralis group. AB - During our studies on the Diptera fauna of the Caspian Hyrcanian mixed forest, Golestan province, Iran, a new species of the genus Clistoabdominalis (Pipunculidae) was identified. In the present paper we name, describe and illustrate Clistoabdominalis hyrcania sp. nov.. An identification key to the males of the Clistoabdominalis ruralis species group from the Western Palaearctic region is provided. PMID- 30313305 TI - Two new eriophyoid mites from Iran in the subfamilies Phyllocoptinae and Eriophyinae (Acari: Trombidiformes: Eriophyidae). AB - Two new species of eriophyoid mites from Fars province, Iran, are described and illustrated, namely: Tetra aparinea n. sp. causing distortion of Galium aparine L. (Rubiaceae) and representing the first record of the genus Tetra on plants of the family Rubiaceae; and Acaralox shiraziensis n. sp. from Tragopogon graminifolius DC. (Asteraceae), causing no visible damage except for slight wilting. PMID- 30313306 TI - Pinguisoperla, a new fossil genus of Perlidae (Insecta: Plecoptera) from mid Cretaceous Burmese amber. AB - A new fossil stonefly genus and species of the family Perlidae, Pinguisoperla yangzhouensis gen. et sp. nov., is proposed as the second known genus from mid Cretaceous Burmese amber. The new genus is characterized by its dark coloration and the basally enlarged and curved cerci. Morphological characters of the new genus and species are described, illustrated, and compared with related taxa. PMID- 30313307 TI - New taxa of oribatid mites from Korup National Park (Cameroon). The genus Pergalumna (Acari, Oribatida, Galumnidae), with description of three new species and a key to known species from the Ethiopian region. AB - Three new species of oribatid mites of the genus Pergalumna (Oribatida, Galumnidae) are described from litter and soil in the Korup National Park (Cameroon). Pergalumna jenoi sp. nov. differs from P. margaritata Mahunka, 1989 and P. pseudomargaritata Mahunka, 1994 by the presence of simple dorsosejugal suture, dentate anterior margin of the ventral plate, distinct reticulate pattern on the pteromorphs and dense stria on the genital plates, the localization of setal alveoli la posterior to porose areas Aa, and the absence of a median pore. Pergalumna tuberclesejugalis sp. nov. differs from P. margaritata and P. pseudomargaritata by the larger body size, the localization of porose areas Aa closer to lm than la, and setal alveoli h3 close and lateral to A2, the presence of sejugal porose areas, and the absence of a median pore and stria on the genital plates. Pergalumna grebennikovi sp. nov. differs from P. bifissurata Hammer, 1972 by the larger body size, the presence of smooth bothridial setae, well-developed interlamellar setae, reticulate anterior margin of pteromorphs, comparatively long prodorsal median ridge and a median pore, and the localization of setal alveoli la and porose areas Aa. An identification key to the known species of the genus Pergalumna from the Ethiopian region is presented. PMID- 30313308 TI - Taxonomic status of Harlan's Hawk Buteo jamaicensis harlani (Aves: Accipitriformes). AB - Since its description in 1830 by Audubon, Harlan's Hawk (taxon harlani) has been considered both as a species (Buteo harlani) (1830-1891 and 1944-1972) and as a subspecies of Red-tailed Hawk (B. jamaicensis harlani) (1891-1944 and 1973 to present). Both decisions making it a subspecies lacked sufficient taxonomic justification, whereas the 1944 decision to consider it a species was supported by convincing arguments. I conducted field and museum work over many years to better understand the morphology and taxonomic status of harlani and how this taxon differs from other taxa currently included in B. jamaicensis. Some hybridization between these taxa has been reported, as has been between many other species of Buteo. The taxon harlani is distinguished from all subspecies of B. jamaicensis in plumage, including the extent of feathering on the tarsus. The species occupies a breeding range parapatric, but with some overlap, to that of B. jamaicensis but occasionally breeds within a large area of the range of the latter in western Canada. It should be considered a full species based on lack of justification for considering it a subspecies, and the many differences between it and B. jamaicensis, which are greater than differences between any two subspecies of diurnal raptor. PMID- 30313309 TI - The Belisana spiders (Araneae: Pholcidae) from Xishuangbanna Tropical Botanical Garden, Yunnan, China. AB - Five new species of the spider genus Belisana Thorell, 1898 are described based on material collected in the Xishuangbanna Tropical Botanical Garden (Yunnan, China). They are: B. dian Yao Li sp. nov. (male), B. gupian Yao Li sp. nov. (male, female), B. chenjini Yao Li sp. nov. (male, female), B. xtbg Yao Li sp. nov. (male, female), and B. yangxiaodongi Yao Li sp. nov. (male, female). B. schwendingeri Huber, 2005 and B. zhengi Yao, Pham Li, 2015 are reported from China for the first time. All material studied is deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing, China. PMID- 30313310 TI - New data on the clearwing moth fauna of the Altai Mountains, Russia, with the description of two new species (Lepidoptera, Sesiidae). AB - The clearwing moth fauna of the Altai Mountains, Russia is reviewed. Two new species Synanthedon altaica sp. nov. and Bembecia aktashica sp. nov. are described and illustrated. Synanthedon polaris (Staudinger, 1877) is recorded as new for the region. New information on the bionomics and distribution of Dipchasphecia altaica O. Gorbunov, 1991 is provided. PMID- 30313311 TI - A new species of the Ololygon catharinae species group (Anura: Hylidae) from the Cerrado biome, State of Goias, Central Brazil. AB - We describe a new species of Ololygon from the Cerrado biome, Central Brazil. The new species is assigned to the Ololygon catharinae species group based in morphological attributes. Ololygon goya sp. nov. in known only from type locality Sitio d'Abadia municipality, State of Goias-and associated with riparian environments connected to seasonal dry forest on the banks of the Corrente river, a tributary of the Parana river basin. The new species is characterized by the combination of the following characters: medium size (24.4-38.8 mm SVL); snout subovoid in dorsal view; canthus rostralis well defined; males with hypertrophied forearms and nuptial pads; inguinal region and hidden surfaces of thigh with irregular dark brown spots on pale yellowish background. We also describe the external morphology and oral morphology of tadpoles, and the advertisement calls of the new species. PMID- 30313312 TI - The first discovery of the genus Haploglossa Kraatz species (Coleoptera: Staphylinidae: Aleocharinae) in Korea, with a description of new species. AB - The genus Haploglossa Kraatz is recorded for the first time in Korea with a description of Haploglossa koreana Song Ahn, sp. nov. and a redescription of H. villosula (Stephens). A key, habitus photographs and illustrations of the diagnostic characters of the known Korean species are provided. PMID- 30313313 TI - First report of aphaenopsoid trechines (Coleoptera: Carabidae: Trechini) from Serbia, with descriptions of new taxa. AB - The trechine ground beetle taxa, Velesaphaenops gen. n., Velesaphaenops tarensis sp. n., and Acheroniotes lethensis sp. n., are described and diagnosed. The new taxa differ clearly from their closest relatives in a number of external characters and the shape of the genitalia. They probably belong to phyletic lineages of Pliocene age (the age of the palaeokarst of Kamena Gora and Mt. Tara). The new taxa are endemic to western and southwestern Serbia. Keys to the aphaenopsoid trechine genera in Serbia and to species of the genus Acheroniotes Lohaj Lakota, 2010 are appended. PMID- 30313314 TI - Redefinition of two little known mirine plant bug genera Babacoris and Paramiridius (Hemiptera: Heteroptera: Miridae: Mirinae). AB - A long neglected plant bug genus Babacoris Miyamoto, 1994 (Mirinae: Mirini), proposed for a single Taiwanese species, B. striatus Miyamoto, is redefined and redescribed as a valid genus, based on recent rediscovery of the type species from Hengchun, Taiwan; the neotype is designated for B. striatus. The genus is now presumed to be closely related to Paramiridius Miyamoto Yasunaga which also has been poorly known since the original description. A species recently described from Laos, Babacoris laomontanus (Oh, Yasunaga Lee) comb. n., is transferred from Paramiridius. An updated checklist of the tribe Mirini in Taiwan is incorporated, with proposition of a new combination, Adelphocorisella minutum (Poppius) comb. n., having been left in Megacoelum Fieber as incertae sedis. PMID- 30313315 TI - A key to males of Atherigona s. str. (Diptera: Muscidae) from Mali, with new records and a new species for the country. AB - Sixteen species have been found in Malaise traps and fogging samples from Kenieroba and Ouronina, SW Mali. One new species, Atherigona kenierobaensis sp. nov., is described; A. budongoana, A. laevigata, A. lineata torrida, A. mirabilis aratra, and A. nigrapicalis are newly recorded for Mali; this brings the total number of species known from the country to 30. An illustrated identification key for Malian Atherigona species is provided. PMID- 30313316 TI - Five new species of the Ghost Spider genus Anyphaenoides Berland from Colombia (Araneae: Anyphaenidae: Anyphaeninae). AB - Five new species of the ghost spider genus Anyphaenoides Berland from Colombia are described and illustrated: A. sierraensis sp. nov. (based on male and female) from Magdalena department, A. caribensis sp. nov. (male and female) from Atlantico department, A. foreroi sp. nov. (male) from Vaupes department, A. hilli sp. nov. (male) from Putumayo department and A. enigmaticus sp. nov. (male and female) from Santander department. PMID- 30313317 TI - A remarkable new species of cavernicolous Collartidini from Madagascar (Hemiptera: Heteroptera: Reduviidae). AB - Mangabea troglodytes sp. nov. (Hemiptera: Heteroptera: Reduviidae: Emesinae) is described based on four specimens collected in a cave of the Namoroka Karstic System, Madagascar, and deposited in the Collection of the Museum National d'Histoire Naturelle, Paris. The dorsal habitus as well as diagnostic characters of male and female genitalia are extensively illustrated and imaged. A key to species of the genus Mangabea Villiers, 1970 is provided and the degree of cave specialization of the new species is discussed. PMID- 30313318 TI - Revision of genus Stilbotes Stal (Hemiptera: Pentatomoidea: Pentatomidae: Asopinae) with description of a new species. AB - The Asopinae genus Stilbotes Stal, 1871 from Philippines is reviewed taxonomically. A new species Stilbotes goulae sp. nov. is described based on female specimens. Stilbotes semperi Stal 1871 is redescribed in detail. A diagnosis, key and distributional records for the genus and the species are also provided. PMID- 30313319 TI - Marilia caramuru sp. nov. and Marilia paraguassu sp. nov. (Trichoptera: Odontoceridae), two new species from Maranhao State, Northeast Brazil. AB - Although the world species diversity of Marilia Muller 1880 is not great, knowledge about this group may be underestimated, since several areas are poorly studied, especially in Northeast Region, Brazil. Two new species are described and illustrated here based on specimens collected in Maranhao State, from which the genus has not been reported previously. Despite the similarity of Marilia caramuru sp. nov. with M. elongata Martynov 1912, differences between them are observed especially in segment X and preanal appendages, in addition to details of wing venation. The unique set of spiniform projections on endotheca, and the wrinkled prominence on sternum VIII distinguish Marilia paraguassu sp. nov. from all other species in the genus. The material examined has been deposited in the Colecao Entomologica Professor Jose Alfredo Pinheiro Dutra, UFRJ, Rio de Janeiro, Brazil, and in the Colecao Zoologica do Maranhao, UEMA, Maranhao, Brazil. PMID- 30313320 TI - A revision of the Afrotropical species of Pachylophus Loew (Diptera: Chloropidae) and some related Ovoviviparous genera. AB - In Pachylophus all described Afrotropical species are treated and P. aristalis, ismayi, nigeriensis, tschirnhausi, mirabilis, lacteibasis and stuckenbergi are described as new species. Pachylophus tellinii Bezzi is placed in synonymy. In Phyladelphus the type species thalhammeri and the single described Afrotropical species, P. geminus, are treated and P. woodi and P. maraisi are described as new species. The genus Sabeurina is erected to accommodate Eurina minuta Loew and a new Afrotropical species S. occidentalis. Some taxonomic notes are given on the Afrotropical species currently included in Platycephala. The immature stages and biological notes concerning the treated genera are described and discussed in the contexts of ovoviviparity and classification. Keys are provided for the identification of all the Afrotropical species known in each of the genera treated. PMID- 30313321 TI - Review of the Indo-West Pacific genus Inimicus (Synanceiidae: Choridactylinae). AB - The stinger genus Inimicus Jordan Starks, 1904 (family Synanceiidae), distributed in the Indo-West Pacific, is characterized by having two free pectoral-fin rays. Examination of the original descriptions and 420 specimens, including all available type specimens, of the genus resulted in the recognition of nine valid species: Inimicus brachyrhynchus (Bleeker, 1874) (recorded from Hong Kong and Singapore), I. caledonicus (Sauvage, 1878) (distributed in Andaman Sea and western Pacific Ocean), I. cuvieri (Gray, 1835) (Andaman Sea and western Pacific Ocean), I. didactylus (Pallas, 1769) (western Pacific), I. filamentosus (Cuvier, 1829) (western Indian Ocean), I. gruzovi Mandrytsa, 1991 (Coral Sea), I. japonicus (Cuvier, 1829) (East Asia), I. sinensis (Valenciennes, 1833) (eastern Indian and western Pacific oceans), and I. smirnovi Mandrytsa, 1990 (southwestern Pacific Ocean). Inimicus joubini (Chevey, 1927), previously considered a valid species, is herein regarded as a junior synonym of I. japonicus. Another 10 nominal species are confirmed to be synonymized with the nine species. A revised diagnosis for each species and a key to all the species are provided. PMID- 30313322 TI - Fieber's unpublished colour plates allow reassessing some of his Cixius species (Insecta: Hemiptera, Fulgoromorpha, Cixiidae). AB - Franz Xaver Fieber was a leading Hemiptera taxonomist in the 19th century. The recent discovery of his unpublished drawings that go along with the original handwritten manuscript allow a reassessment of species descriptions from this century. In addition, we present an alphabet of Fieber's handwriting. We give an overview on the Cixiidae species he had described and reassess the status of the species names Cixius brachycranus Scott, 1870, Cixius intermedius Scott, 1870, Cixius pinicola Fieber, 1876, Tachycixius venustulus (Germar, 1830) and Tachycixius distinctus (Signoret, 1865). T. venustulus and T. distinctus are regarded as valid species. The synonymy of C. pinicola with T. venustulus is invalidated and C. pinicola is placed in synonymy with T. distinctus. PMID- 30313323 TI - Description and molecular phylogeny of Axinella nayaritensis n. sp. (Porifera: Axinellida) from East Pacific and remarks about the polyphyly of the genus Axinella. AB - Axinella nayaritensis n. sp. is a typical species of the genus Axinella in spiculation (oxeas and styles), skeletal arrangement (axial condensation from which radiate an extra-axial plumoreticulated skeleton), and external form (arborescent). The new species is orange, branching, up to 25 cm in height, and which usually live in soft bottoms. One of the most conspicuous characteristic of the new species is its aquiferous system, which is formed by a system of superficial canals and meandering ridges which run around the entire length of the branches. The species is compared with Axinella polycapella from Gulf of Mexico, which is very close in morphology, and which it shares a high similarity in the 18S ribosomal RNA region. It was also compared with Axinella aruensis, a very different species from a morphological point of view, which is distributed throughout the northern Australia, Indonesia and Papua New Guinea as both species share a high similarity in the COI mitochondrial gene region. The new species was included in the clade named Axinella by Gazave et al. (2010) for 18S and COI, where also are included eight Axinella-species. Species in this clade are typically arborescent with a choanosomal skeleton differentiated between axial and extra-axial regions. Axinella nayaritensis n. sp. constitute the first record of an Axinella for the east Pacific coast. PMID- 30313324 TI - A new groundwater species of Pseudoniphargus (Amphipoda: Pseudoniphargidae) fromAlgeria. AB - Intensive sampling performed in the area of Oum El Bouaghi (Northeastern Algeria) yielded a new species of the stygobiont amphipod Pseudoniphargus, P. djemoi, in wells located in the plain of Tamlouka. The new species belongs to a group that shares the display of a uropod 3 exopod extremely elongate and upcurved in the male, whereas its peduncle is only moderately elongate. This cluster of species appears scattered across the southern Iberian Peninsula, Northern Morocco and the Canary Islands. This discovery increases the number of described species of the stygobiont amphipod genus Pseudoniphargus in north Africa to eight. A key to the species of Pseudoniphargus living in Continental Africa and Mediterranean Islands is provided. PMID- 30313325 TI - A checklist of Poliosia Hampson, 1900 (Lepidoptera, Erebidae, Arctiinae) with emphasis on the Cambodian fauna, and the description of a new species to the genus. AB - A checklist of the genus Poliosia Hampson, 1900 is provided, along with a key for the Cambodian species, which includes the new species P. cardamomensis Bayarsaikhan Bae, n. sp. Illustrations of adults and genitalia of all three Cambodian species are presented. PMID- 30313326 TI - Morphology and molecular phylogeny of Macrobrachium suphanense sp. nov. (Decapoda: Palaemonidae) from Thailand. AB - A small freshwater prawn in Thailand has been found to be a new species and is named Macrobrachium suphanense (Decapoda: Palaemonidae). Fully grown male M. suphanense appeared very different from the most closely related male of M. sintangense: size smaller, second pereiopod smaller and less robust, rostrum form different and, in females, fewer eggs. Less closely related, fully grown M. dolatum has sharper distal cutting edge on fixed finger and M. hungi has longer rostrum than M. suphanense. DNA analyses put M. suphanense, M. sintangense and M. nipponense in the same clade with M. nipponense sister to the other two. Two more clades consist of M. dienbienphuense and M. niphanae on the one hand and M. lanchesteri and M. rosenbergii on the other. The relationship among the three clades is not clearly resolved. PMID- 30313327 TI - A new species of myxozoa in the skeletal striated musculature of Rhamdia quelen (Quoy Gaimard) (Siluriforme: Pimelodidae) Amazonian fish, Marajo island, Brazil. AB - A new myxozoan was found parasitizing the freshwater catfish, Rhamdia quelen (Quoy Gaimard), in the Marajo island, Amazon region, Brazil. The new species is described based on the results of morphological and molecular analyses. The parasite is approximately 1.5 mm in diameter and develops in the musculature of the host in the form of spherical, whitish cysts, which are visible macroscopically between the epaxial and hypaxial layers. When ruptured, these cysts produced ellipsoidal spores with a mean length of 11.4 MUm (10.7-12.6) and width of 7.2 MUm (6.4-7.9). Anomalous spores with a caudal elongation, vesicles in the peripheral portion of the spore and ornamentation of the valves were also observed. The results of the phylogenetic analysis of sequences of the 18S rDNA gene using Bayesian Inference indicated clear differences among the Myxobolus species that reinforced the taxonomic position of the parasite, confirming its status as a new species, denominated Myxobolus arariensis n. sp. PMID- 30313328 TI - Myxobolus bragantinus n. sp. (Cnidaria: Myxosporea) from the gill filaments of the redeye mullet, Mugil rubrioculus (Mugiliformes: Mugilidae), on the eastern Amazon coast. AB - Mullets (Mugilidae) are economically-important fish exploited extensively by artisanal fisheries on the Amazon coast of Brazil. In the present study, 150 specimens of redeye mullet (Mugil rubrioculus) acquired from the public fish market were examined, and the gill filaments of 90 (60%) were found to be infected with spores of Myxobolus. The mature spores were spherical, with a mean diameter of 6.28+/-0.33 MUm, and had polar capsules of equal size (2.47+/-0.34 MUm in length and 1.58+/-0.27 MUm in width). The 18S rRNA sequence of the parasite was compared with those of other myxosporidian species available in the GenBank database. The morphological and molecular characteristics of the parasite indicate strongly the existence of a new species, denominated Myxobolus bragantinus n. sp., the first case of a new myxosporidian species to be found in this host. [Zoobank: urn:lsid:zoobank.org:act:E00F72E1-9302-423F-BA4E 51C05D0770C8]. PMID- 30313329 TI - A new genus and a new species of Schizomyiina (Diptera: Cecidomyiidae: Asphondyliini) inducing petiole galls on Macaranga bancana (Miq.) in Borneo, Malaysia. AB - We describe a gall midge Macarangamyia itiokai Elsayed Tokuda gen. n., sp. n. belonging to the subtribe Schizomyiina (Diptera: Cecidomyiidae: Asphondyliini) inducing petiole galls on Macaranga bancana (Miq.) in Lambir Hills National Park, Borneo, Malaysia. The new genus is distinguishable from all known genera of Schizomyiina by the unique dorsally-placed aedeagus slit, the short, membranous, protrusible ovipositor, with scattered strong setae ventrally and dorsally, and the presence of spiracles on all larval thoracic segments. It is compared and separated from its closely related Oriental genera of Schizomyiina. PMID- 30313330 TI - First record of the genus Phanerotomella (Hymenoptera: Braconidae) from Baltic amber with the description of a new species. AB - A new but exinct chelonine wasp species, Phanerotomella brevivena Kittel sp. nov. (Braconidae: Cheloninae) of the modern genus Phanerotomella is described from Baltic amber. This new species differs from all other extant Phanerotomella species by having the fore wing vein SR-1 only partially sclerotised. This is the first fossil record of the genus in amber. PMID- 30313331 TI - A review of the spider genus Porrhomma (Araneae, Linyphiidae). AB - The spider genus Porrhomma has been revised; it now includes 24 species. Two new species are described: Porrhomma altaica new species from the Altai Mountains, and Porrhomma nekolai new species from eastern Asia and North America. Bathyphantes charpentieri Lebert, 1877 was removed from synonymy with Porrhomma microphthalmum (O. Pickard-Cambridge, 1871). The following new synonymies are proposed: Bathyphantes charpentieri Lebert, 1877 is a junior synonym of Porrhomma convexum (Westring, 1851) new synonymy; Porrhomma gertschi Hackman, 1954 is a junior synonym of Porrhomma terrestre (Emerton, 1882) new synonymy; Porrhomma myops Simon, 1884 is a junior synonym of Porrhomma rosenhaueri (L. Koch, 1872) new synonymy; Porrhomma ocella Chamberlin Ivie, 1943 is a junior synonym of Porrhomma convexum (Westring, 1851) new synonymy; Porrhomma omissum Miller, 1971 is a junior synonym of Porrhomma egeria Simon, 1884 new synonymy; Porrhomma pallidum affinis Miller Kratochvil, 1940 is a junior synonym of Porrhomma pallidum Jackson, 1913 new synonymy; Porrhomma sodonta (Chamberlin, 1949) is a junior synonym of Porrhomma convexum (Westring, 1851) new synonymy. The synonymy of Porrhomma macrochelis (Emerton, 1917) with Macrargus multesimus (O. Pickard Cambridge, 1875) is supported. Porrhomma subterraneum Simon, 1884 is considered a nomen dubium, because it was described according to a juvenile specimen. To date, Porrhomma indecorum Simon, 1910 and Porrhomma marphaense Wunderlich, 1983 are only known from findings of females; they are considered to be species inquirenda, and their names are declared nomina dubia. Keys are provided for males and females. Vulvae are drawn in dorsal, ventral and caudal views to understand their spatial structure. PMID- 30313332 TI - Morphological revision of the Subgroup 1 Fauchald, 1970 of Marphysa de Quatrefages, 1865 (Eunicidae: Polychaeta). AB - Fifteen species of Marphysa classified in the Subgroup 1 Fauchald (1970) were reviewed and evaluated in a morphological analysis of the subgroup. It was found that 13 of these have a characteristic morphological pattern distinct from that of Marphysa sensu stricto; as a consequence, a new genus is proposed, Paucibranchia n. gen. This new genus includes the species that have branchiae restricted to a few chaetigers in the anterior region, maxillae I with a rounded falcal arch and outer edge with a straight base plus a curvature in the basal inner edge, dorsal cirri longer in the branchial region and in media-posterior region as long or longer than pre-branchial chaetigers, and the postchaetal lobe in the branchial region well developed, elongated. Paucibranchia n. gen. includes six new species (P. andresi n. sp., P. carrerai n. sp., P. gathofi n. sp., P. gilberti n. sp., P. miroi n. sp. and P. patriciae n. sp.), two species not formally named, and other 13 species previously included in Marphysa (P. adenensis (Gravier, 1900) n. comb., P. bellii (Audouin Milne-Edwards, 1833) n. comb., P. cinari (Kurt-Sahin, 2014) n. comb., P. conferta (Moore, 1911) n. comb., P. disjuncta (Hartman, 1961) n. comb., P. fallax (Marion Bobretzky, 1875) n. comb., P. gemmata (Mohammad, 1973) n. comb., P. kinbergi (McIntosh, 1910) n. comb., P. oculata (Treadwell, 1921) n. comb., P. purcellana (Willey, 1904) n. comb., P. sinensis (Monro, 1934) n. comb., P. stragula (Grube, 1878) n. comb., P. totospinata (Lu Fauchald, 1998) n. comb.). One species previously classified in the subgroup, Marphysa striata (Kinberg, 1865), was considered indeterminate. Finally, some statistical analyses on size dependent features and an identification key for species of the new genus were included. PMID- 30313333 TI - New state and host records for Agromyzidae (Diptera) in the United States, with the description of thirty new species. AB - We present rearing records of Agromyzidae (Diptera) from five years of collecting throughout the United States. We review host and distribution data, and describe leaf mines, for 93 species, plus 28 others that could not be confidently identified in the absence of male specimens. We report 147 new host species records, including the first rearing records for Agromyza bispinata Spencer, A. diversa Johnson, A. parca Spencer, A. pudica Spencer, A. vockerothi Spencer, Calycomyza michiganensis Steyskal, Ophiomyia congregata (Malloch), and Phytomyza aldrichi Spencer. Phytomyza anemones Hering and (tentatively identified) Cerodontha (Dizygomyza) iraeos (Robineau-Desvoidy) are new to North America; Agromyza albitarsis Meigen, Amauromyza shepherdiae Sehgal, Aulagromyza populicola (Walker), Liriomyza orilliensis Spencer, Phytomyza linnaeae (Griffiths), P. solidaginivora Spencer, and P. solidaginophaga Sehgal are new to the USA. We also present confirmed USA records for Calycomyza menthae Spencer (previous records were based only on leaf mines), Ophiomyia maura (Meigen) (reported from the USA in older literature but deleted from the fauna in the most recent revision (Spencer Steyskal 1986)), and Phytomyza astotinensis Griffiths and P. thalictrivora Spencer (previously only tentatively recorded from the USA). We provide 111 additional new state records. We describe the following 30 new species: Agromyza fission, A. soka, Melanagromyza palmeri, Ophiomyia euthamiae, O. mimuli, O. parda, Calycomyza artemisivora, C. avira, C. eupatoriphaga, C. vogelmanni, Cerodontha (Dizygomyza) edithae, Cer. (D.) feldmani, Liriomyza ivorcutleri, L. valerianivora, Phytomyza actaeivora, P. aesculi, P. confusa, P. doellingeriae, P. erigeronis, P. hatfieldae, P. hydrophyllivora, P. palmeri, P. palustris, P. sempervirentis, P. tarnwoodensis, P. tigris, P. triangularidis, P. vancouveriella, P. verbenae, and P. ziziae. PMID- 30313334 TI - Historical review, catalog of type specimens and online database of the ichthyology collection of the Instituto de Ciencias Naturales of the Universidad Nacional de Colombia (ICN-MHN). AB - For the first time, the catalog of type specimens of ICN-MHN is presented with high resolution photographs. The catalog lists 87 species in 161 lots and includes 41 holotypes, 3 neotypes, and 117 lots of paratypes. Some doubts remain about type specimens of some species described by Miles and Dahl that were supposedly deposited at ICN-MHN. The history of the collection is reconstructed and valuable specimens once considered lost or destroyed have been rediscovered. The botanical and zoological collections of the ICN can be consulted online (http://www.biovirtual.unal.edu.co). PMID- 30313335 TI - Catalogue of the primary types of marine molluscan taxa described by Tommaso Allery Di Maria, Marquis of Monterosato, deposited in the Museo Civico di Zoologia, Roma. AB - We have compiled a complete list of new marine molluscan taxa introduced by Tommaso Allery Di Maria, Marquis of Monterosato (1841-1927). The dates of publication of every single work have been checked against available evidence, and an updated bibliography is also presented. Finally, the type material of all marine taxa expected to be in the collection Monterosato (presently preserved in the Museo Civico di Zoologia in Rome) has been searched in the main collection, and all retrieved specimens have been catalogued. A large majority of the material has been found, representative specimens of each taxon have been illustrated, and remarks on nomenclature and taxonomy have been provided yielding 42 new synonymies, 46 nominal taxa rediscovered, and 6 new combinations. PMID- 30313336 TI - Papers on fishes of Asia, including those presented at international conferences of the Asian Society of Ichthyologists in Taipei, Taiwan in 2016, and in Ho Chi Minh City, Vietnam in 2017 (Cover Copytight page). AB - (Cover Copytight page). PMID- 30313337 TI - Papers on fishes of Asia, including those presented at international conferences of the Asian Society of Ichthyologists in Taipei, Taiwan in 2016, and in Ho Chi Minh City, Vietnam in 2017 (Table of Contents). AB - (Table of Contents). PMID- 30313338 TI - Preface. AB - The Asian Society of Ichthyologists (ASI) was established in February 2014 in Penang, Malaysia following organizational meetings in 2012 in Chiang Mai, Thailand and in 2013 in Bandar Seri Begawan, Brunei. PMID- 30313339 TI - Phylogenetic classification of extant genera of fishes of the order Cypriniformes (Teleostei: Ostariophysi). AB - The order Cypriniformes is the most diverse order of freshwater fishes. Recent phylogenetic studies have approached a consensus on the phylogenetic relationships of Cypriniformes and proposed a new phylogenetic classification of family-level groupings in Cypriniformes. The lack of a reference for the placement of genera amongst families has hampered the adoption of this phylogenetic classification more widely. We herein provide an updated compilation of the membership of genera to suprageneric taxa based on the latest phylogenetic classifications. We propose a new taxon: subfamily Esominae within Danionidae, for the genus Esomus. PMID- 30313340 TI - Morphological and molecular study of the torrent catfishes (Sisoridae: Glyptosterninae) of Bhutan including the description of five new species. AB - Torrent catfishes of the subfamily Glyptosterninae from Bhutan are examined based on morphological and molecular data. Five new species are described: Creteuchiloglanis bumdelingensis sp. nov., Exostoma mangdechhuensis sp. nov., Parachiloglanis benjii sp. nov., P. dangmechhuensis sp. nov., and P. drukyulensis sp. nov. Molecular data derived from the mitochondrial gene Cyt b and the nuclear gene RAG2 recovered relationships within Parachiloglanis and the Glyptosterninae. A dichotomous key to the Glyptosterninae of Bhutan is provided. PMID- 30313341 TI - Re-description of the catfish species Liobagrus kingi Tchang, 1935 (Pisces: Amblycipitidae) from the upper Chang-Jiang basin, China. AB - The identity and validity of Liobagrus kingi Tchang, 1935 remain contentious to date due to its inaccurate original description. A re-description is provided here for this species based on our examination on its type, hitherto deposited in ASIZB and available topotypic material. It is confirmed that L. kingi is a species with a serrated posterior edge of the pectoral-fin spine and distinct from the sympatrically existing species L. nigricauda. Comments on former recognitions of specimens from the upper Chang-Jiang basin as L. kingi are presented. PMID- 30313342 TI - The species of Clupisoma from Yunnan, China (Teleostei: Siluriformes: Ailiidae), with a comment on the validity of the family Ailiidae. AB - After comparison of the types of the four species of Clupisoma recorded from Yunnan, China, no morphological differences between Clupisoma nujiangense Chen et al. and C. yunnanensis (He, Huang Li) were found, and it is confirmed that the former is a synonym of the latter. Clupisoma yunnanensis occurs in the middle and lower of Nu-jiang, belonging to the Salween River basin. Clupisoma longianale (Huang) and Clupisoma sinense (Huang) are found in the lower Lancang-jiang, in the Mekong River basin. Using concatenated mitochondrial genes and nuclear genes, Wang et al. (2016) reconstructed the phylogeny of 38 species of catfishes belonging to 28 genera and 14 families. They reinstated the family, Ailiidae for a monophyletic Asian catfish group comprised of the three genera Ailia, Laides and Clupisoma. The family-group name Ailiidae was first proposed by Bleeker (1858) as Ailichthyoidei for a subfamily containing Ailia Gray. As such, there was no legitimate reason for Wang et al. (2016) to propose the Ailiidae as a new family group name but, instead, resurrect the existing name from the synonymy of the Shilbeidae. PMID- 30313343 TI - Altigena malihkaia, a new species of Labeonini (Teleostei: Cyprinidae) from the Irrawaddy River basin in Myanmar. AB - Altigena malihkaia, new species, is described from the Mali Hka River, a tributary of the Irrawaddy River in northern Myanmar. It is distinguished from all other species of the genus Altigena by having a combination of 45-49 lateral line scales, 12-14 circumpeduncular scales, 17-20 pre-dorsal midline scales, wide head (96.8-138.5% HL), long postorbital length (64.6-81.0 % HL), and short dorsal fin (length 21.9-26.2% SL). PMID- 30313344 TI - Garra dengba, a new species of cyprinid fish (Pisces: Teleostei) from eastern Tibet, China. AB - Garra dengba is here described from the Chayu-Qu, a tributary flowing into the Brahmaputra River, in Chayu County, eastern Tibet, China. It shares the presence of an incipient proboscis on the snout with G. arupi, G. elongata, G. gravelyi, G. kalpangi, and G. rotundinasus, but is distinguished from these five species in having, among other features, fewer branched dorsal- and anal-fin rays and more perforated lateral-line scales. Its validity was also confirmed by a molecular phylogenetic analysis based on the cytochrome b gene. PMID- 30313345 TI - Speolabeo hokhanhi, a new cavefish from Central Vietnam (Teleostei: Cyprinidae). AB - Speolabeo hokhanhi, new species, is here described from Hang Va Cave in Phong Nha Ke Bang National Park (Son River basin) in Central Vietnam. It can be distinguished from S. musaei by having no papillae on the lower lip, no hump immediately behind the head, a duckbilled snout, a shorter caudal peduncle (length 16.8-18.6% SL), and the pelvic fin inserted closer to the snout tip than to the caudal-fin base. PMID- 30313346 TI - Rhinogobius maculagenys, A new species of freshwater goby (Teleostei: Gobiidae) from Hunan, China. AB - A new freshwater goby, Rhinogobius maculagenys sp. nov., was collected from Hunan Province in Southern China. This species can be distinguished from all congeners by a combination of the following features: first dorsal fin with 6 spines; second dorsal fin with a single spine and 7-9 segmented rays; anal fin with a single spine and 6-8 segmented rays; pectoral fin with 16 segmented rays; 32-34 longitudinal scales; 9-13 transverse scales; 11+16=27 vertebrae; pore omega1 missing; head and body yellowish brown; cheek and opercle yellowish brown with over 30 small orange spots, branchiostegal membrane yellow with over 10 small orange spots in males and white and spotless in females; first dorsal fin trapezoidal in males and nearly semicircular in females, with large bright blue blotch in front of second spine; spines 4 and 5 longest, rear tip extending to base of second branched ray of second dorsal fin in males when adpressed, but just reaching or not reaching anterior margin of second dorsal fin in females; caudal fin with 5-6 vertical rows of brown spots; flank with several longitudinal rows of blackish-brown spots; and belly pale white. PMID- 30313347 TI - Testing the validity of two putative sympatric species from Sinocyclocheilus (Cypriniformes: Cyprinidae) based on mitochondrial cytochrome b sequences. AB - There are over 60 species within the freshwater fish genus Sinocyclocheilus (Cypriniformes: Cyprinidae) distributed throughout the Yunnan-Guizhou Plateau and its surrounding areas in China. In recent years, the increasing number of new species described has raised some controversy about the validity of several species within this genus, notably the putative sympatric species pair S. qiubeiensis and S. jiuchengensis. To test the validity of S. qiubeiensis and S. jiuchengensis, we analyzed the complete sequences of the mitochondrial cytochrome b (CYTB) gene of 20 identified species and one outgroup species. Phylogenetic relationships were reconstructed using CYTB with maximum likelihood (ML) and Bayesian inference (BI) methods. Our phylogenetic results showed that all individuals of S. qiubeiensis and S. jiuchengensis clustered in one clade with strong support. In addition, the genetic distance between the two species was 0.11%, within the range observed at the intraspecific level. The most recent common ancestor of S. qiubeiensis and S. jiuchengensis dated back to 0.13 million years ago, indicating little time for complete speciation to have occurred. These results clearly support the viewpoint that S. jiuchengensis is a synonym of S. qiubeiensis. PMID- 30313348 TI - Epigonus okamotoi (Perciformes: Epigonidae), a junior synonym of E. draco, with new distributional records for E. atherinoides and E. lifouensis in the West Pacific. AB - Epigonus okamotoi Fricke, 2017 was originally described on the basis of a single specimen collected from New Britain, Papua New Guinea during one of the exploratory cruises (campaign: MADEEP) in 2014 organized under the Tropical Deep Sea Benthos program. However, there are no clear differences in the meristic and morphometric characters between the holotype of the new species and specimens of E. draco Okamoto, 2015, including two additional specimens of the species found in the ichthyological collections in the NTUM. The genetic distance (p-distance) between the two "species" at the COI locus was negligible. Accordingly, the holotype of E. okamotoi is considered to be a specimen of E. draco, and the former nominal species is reduced to a junior synonym of E. draco. In addition, we rediagnose and report new distributional records for E. atherinoides (Gilbert, 1905) and E. lifouensis Okamoto Motomura, 2013 in the West Pacific. PMID- 30313349 TI - First record of Gauguin's blunt-nose lizardfish, Trachinocephalus gauguini Polanco, Acero Betancur 2016 (Teleostei: Synodontidae) outside the Marquesas Archipelago. AB - Trachinocephalus gauguini Polanco, Acero Betancur, 2016 was described based on eighteen specimens collected from off the Marquesas Islands, the only location where this species has been recorded until now. Through morphological and molecular examination of Trachinocephalus specimens collected from an exploratory cruise conducted in June 2014 under the Tropical Deep-Sea Benthos program along the northern coast of the New Ireland Province, Papua New Guinea, we demonstrate the presence of this species in Papua New Guinea waters. This new record suggests a wide distribution for this rarely collected species in the western Pacific Ocean. PMID- 30313350 TI - Two new species of stargazers of the genus Uranoscopus (Teleostei: Uranoscopidae) from the western Pacific Ocean. AB - Two new species of stargazers in the Uranoscopus albesca species-complex of the family Uranoscopidae are described from Papua New Guinea, which shares among other characters a concave posterodorsal margin of the pectoral fin. Uranoscopus brunneus n. sp. is described from a single specimen from off southwestern New Britain, and is characterised by lower edge of preopercle with 8 spines; labial fimbriae poorly-developed; anterior nostril with a long tubiform valve, posterior nostril a slit-like pore; supracleithrum with a sharp spine at rear end and five small spines inside; dorsoposterior margin of pectoral fin concave; 62 oblique scale-rows along the sides of the body in adult; pectoral-fin membranes dark brown. Uranoscopus kishimotoi n. sp., described from a single specimen from West Sepik Province, is characterised by the lower edge of preopercle with 3 spines; no labial fimbriae; both anterior and posterior nostrils with long tubiform valves; supracleithrum with a sharp spine at rear end and one additional small spine inside; dorso-posterior margin of pectoral fin concave; 59 oblique scale rows along the sides of the body in adult; upper pectoral-fin membranes pale, lower membranes brown. The distribution of the species in the U. albesca species complex is discussed. PMID- 30313351 TI - A new species of sinistral flatfish of the genus Chascanopsetta (Teleostei: Bothidae) from off Papua New Guinea, western Pacific Ocean. AB - Left-eyed flounders of the genus Chascanopsetta Alcock 1894 (Bothidae) occur in the Indian, Pacific, and Atlantic oceans at depths ranging from 120 to 1500 meters. They possess some unique features in bothid fishes including a strongly compressed and elongated body and a tremendously large mouth. Currently, nine species of Chascanopsetta are recognized, and three of them (C. micrognatha Amaoka Yamamoto 1984, C. lugubris Alcock 1894 and C. prognatha Norman 1939) are distributed in the West Pacific. We collected 25 specimens of Chascanopsetta during 11 biodiversity expeditions carried out mainly in the West Pacific. Among them, eight specimens taken off Papua New Guinea present morphological features that differ from those of the three nominal species known in the West Pacific. In this study, we examined these eight specimens of unknown affinity and compared their morphology to that of specimens of other congeneric species. Results of these comparisons showed that these specimens represent an undescribed species of Chascanopsetta, named herein, C. novaeguineae sp. nov.. The new species resembles C. elski Foroshchuk 1991, which is known only from the Saya de Malha Bank in the western Indian Ocean, in having a high number of gill rakers (> 13). However, the combination of the following characters further distinguishes C. novaeguineae sp. nov. from C. elski: longer jaws, narrower interorbital width, and number of pseudobranches (21-25 vs. 26-27). The DNA sequences from the mitochondrial cytochrome oxidase subunit I (COI) gene from C. novaeguineae sp. nov. and other species were obtained and compared to confirm its taxonomic status and to infer its tentative phylogenetic position within the Chascanopsetta. PMID- 30313352 TI - Annotated checklist of anthiadine fishes (Percoidei: Serranidae). AB - This checklist includes information on the 29 genera and 226 species of anthiadine serranid fishes currently considered valid. For each genus the type species and number of species are given. For each species the valid name (and name under which it was originally described, if different), primary type(s), type locality, reference(s) to illustration(s), counts, and distribution are presented. PMID- 30313353 TI - Phylogeny and taxonomic revision of Deronectina Galewski, 1994 (Coleoptera: Dytiscidae: Hydroporinae: Hydroporini). AB - The subtribe Deronectina Galewski, 1994 (Dytiscidae, Hydroporinae, Hydroporini) is distributed in the Nearctic, in the north of the Neotropical region, and in the Palaearctic and Afrotropical regions. It is currently composed of 194 species and 13 subspecies in eight genera: Amurodytes Fery Petrov, 2013, Boreonectes Angus, 2010, Deronectes Sharp, 1882, Nebrioporus Regimbart, 1906, Oreodytes Seidlitz, 1887, Scarodytes Gozis, 1914, Stictotarsus Zimmermann, 1919, and Trichonectes Guignot, 1941. We present a morphological and a molecular phylogeny of the species of the subtribe, and a revision of their taxonomy to accommodate our phylogenetic results. The morphological phylogeny is based on the study of 54 characters of the adults of 189 species and 2 subspecies, of which 114 species and the 2 subspecies were coded in the morphological matrix. For the molecular phylogeny we investigated 115 species and 11 subspecies, using a combination of fragments of four mitochondrial (COI, 16S rRNA, tRNA-Leu and NAD1) and two nuclear genes (18S rRNA and H3), analysed with maximum likelihood and Bayesian methods. For both datasets we included the type species of all genus-group taxa. The morphological, molecular and combined phylogenies mostly agree with the current classification of the group, but in some cases our results are in contradiction with established genera. Most remarkable are the polyphyly of Stictotarsus and Nebrioporus, the low support for the monophyly and internal phylogeny of Oreodytes, and the low support for the monophyly of Deronectina with molecular data. Thus, we introduce some taxonomic changes in the current classification to accommodate the generic concepts to our phylogenetic results. Nine new genera are established: Clarkhydrus n. gen. (type species Hydroporus roffii Clark, 1862), Hornectes n. gen. (type species Hydroporus quadrimaculatus Horn, 1883), Iberonectes n. gen. (type species Deronectes bertrandi Legros, 1956), Larsonectes n. gen. (type species Potamonectes minipi Larson, 1991), Leconectes n. gen. (type species Hydroporus striatellus LeConte, 1852), Mystonectes n. gen. (type species Deronectes neomexicanus Zimmerman Smith, 1975), Nectoboreus n. gen. (type species Hydroporus aequinoctialis Clark, 1862), Nectomimus n. gen. (type species Oreodytes okulovi Lafer, 1988), and Zaitzevhydrus n. gen. (type species Hydroporus formaster Zaitzev, 1908). Three genera are reinstated as valid: Deuteronectes Guignot, 1945 (stat. rest.) (type species Hydroporus picturatus Horn, 1883), Nectoporus Guignot, 1950 (stat. rest.) (type species Hydroporus abbreviatus Fall, 1923), and Neonectes J. Balfour Browne, 1940 (stat. rest.) (type species Hydroporus natrix Sharp, 1884). Thirty six new combinations for species and subspecies thus far treated in the genera Boreonectes, Nebrioporus, Oreodytes and Stictotarsus result from the new classification: Clarkhydrus corvinus (Sharp, 1887) n. comb., C. decemsignatus (Clark, 1862) n. comb., C. deceptus (Fall, 1932) n. comb., C. eximius (Motschulsky, 1859) n. comb., C. falli (Nilsson, 2001) n. comb., C. interjectus (Sharp, 1882) n. comb., C. minax (Zimmerman, 1982) n. comb., C. opaculus (Sharp, 1882) n. comb., C. roffii (Clark, 1862) n. comb., C. spectabilis (Zimmerman, 1982) n. comb., Deuteronectes angustior (Hatch, 1928) n. comb., Hornectes quadrimaculatus (Horn, 1883) n. comb., Iberonectes bertrandi (Legros, 1956) n. comb., Larsonectes minipi (Larson, 1991) n. comb., Leconectes striatellus (LeConte, 1852) n. comb., Mystonectes coelamboides (Fall, 1923) n. comb., M. grammicus (Sharp, 1887) n. comb., M. neomexicanus (Zimmerman Smith, 1975) n. comb., M. panaminti (Fall, 1923) n. comb., M. titulus (Leech, 1945) n. comb., Nectoboreus aequinoctialis (Clark, 1862) n. comb., N. dolerosus (Leech, 1945) n. comb., N. funereus (Crotch, 1873) n. comb., Nectomimus okulovi (Lafer, 1988) n. comb., Nectoporus angelinii (Fery, 2015) n. comb., N. congruus (LeConte, 1878) n. comb., N. crassulus (Fall, 1923) n. comb., N. obesus obesus (LeConte, 1866) n. comb., N. obesus cordillerensis (Larson, 1990) n. comb., N. rhyacophilus (Zimmerman, 1985) n. comb., N. sanmarkii sanmarkii (C.R. Sahlberg, 1826) n. comb., N. sanmarkii alienus (Sharp, 1873) n. comb., N. sierrae (Zimmerman, 1985) n. comb., N. subrotundus (Fall, 1923) n. comb., Zaitzevhydrus formaster formaster (Zaitzev, 1908) n. comb., and Z. formaster ulanulana (C.-K. Yang, 1996) n. comb. PMID- 30313354 TI - Systematics of the genus Aphrophila Edwards with description of fifteen new species (Diptera: Tipulomorpha: Limoniidae). AB - The genus Aphrophila (Diptera: Limoniidae) is revised. All previously described species are redescribed and illustrated, along with fifteen new species. From the Campbell Island (New Zealand): A. whakapapa sp. n.; from Argentina: A. argentina sp. n., A. huahua sp. n. and A. peuma sp. n.; from Chile: A. aequalitas sp. n., A. alexanderi sp. n., A. dentata sp. n., A. dupla sp. n., A. edwardsi sp. n., A. minuscula sp. n., A. penta sp. n., A. regia sp. n., A. serra sp. n., A. sperancae sp. n. and A. vulcania sp. n. Identification key is provided for all the valid species. A phylogenetic analysis was made which resulted in one single most parsimonious tree with five main groups, classified into five subgenera: A. (Aphrophila) Edwards, A. (Magnodonta) subg. n., A. (Spinalia) subg. n., A. (Sirena) subg. n., A. (Zelandica) subg. n. In order to uncover the biogeographical pattern of the distribution of the species in terms of area relationships, a Paralogy-free subtree analysis was performed, which resulted in the following areagram: ((Campbell Is. + S. America) + New Zealand). PMID- 30313355 TI - Revision of the genus Nephelomilta Hampson, 1900, with descriptions of twelve new species and two new subspecies (Lepidoptera, Erebidae, Arctiinae). AB - The genus Nephelomilta Hampson, 1900 is revised. The genus Kailasha Singh Kirti, 2015 is synonymized with Nephelomilta. Twelve new species, N. admiranda, sp. nov. (NE India), N. kanchenjunga, sp. nov. (NE India), N. wolfgangspeideli, sp. nov. (S Vietnam), N. ranau, sp. nov. (Sumatra), N. bana, sp. nov. (C Vietnam), N. martini, sp. nov. (N Vietnam), N. thomaswitti, sp. nov. (Nepal, NE India), N. fangae, sp. nov. (China: Hainan), N. hortensis, sp. nov. (N Thailand), N. melli, sp. nov. (E and S China), N. ferruginea, sp. nov. (Sumatra) and N. diehli, sp. nov. (Sumatra), and two new subspecies, N. sumatrana effractoida, ssp. nov. (N India and Indochina) and N. hortensis fansipana, ssp. nov. (N Vietnam) are described. Barsine fuscobarsine, 2016 is synonymized with Nephelomilta suffusa (Hampson, 1891). Eleven new combinations are established and three taxa previously treated as junior synonyms of N. effracta are upgraded to species level: N. taprobana (Hampson, 1901), comb. nov., N. sumatrana (van Eecke, 1927), comb. stat. nov., N. gulmargensis (N. Singh, Kirti D.P. Singh, 2015), comb. nov., N. effracta (Walker, 1854), comb. nov., N. pseudoeffracta (Kirti, Joshi N. Singh, 2013), comb. nov., N. klapperichi (Daniel, 1952), comb. nov., N. pellucida (Rothschild, 1936), comb. nov., N. babensis (Bae Bayarsaikhan, 2017), comb. nov., N. karenkonis (Matsumura, 1930), comb. stat. nov., N. angkorensis (Bayarsaikhan Bae, 2016), comb. nov., N. pusilla (Wileman, 1910), comb. stat. nov. Lectotypes for Chionaema effracta sumatrana van Eecke, 1927, Chionaema pellucida Rothschild, 1936 and Chionaema pusilla Wileman, 1910 are designated. PMID- 30313356 TI - An annotated checklist of the Iranian Dasytidae and Rhadalidae (Coleoptera: Cleroidea). AB - We herein provide an annotated checklist for the Iranian Dasytidae and Rhadalidae (Coleoptera: Cleroidea). A total of 54 species and three subspecies of Dasytidae in 16 genera, four tribes and three subfamilies, and 11 species of Rhadalidae in five genera and three subfamilies are reported and discussed where necessary. Of these, 27 (sub-) species of Dasytidae (48%) and eight species of Rhadalidae (73%) are currently known only from Iran, and are here considered as endemic species. However, some species occurences are doubtful or need confirmation. One species (Dasytes xanthocnemus Kolenati, 1846) is reported from Iran for the first time. Furthermore, Danacea micans astrabadensis Pic, 1922 is resurrected from synonymy and given subspecific status. PMID- 30313357 TI - Four new species and new synonymy in Stenocerus Schoenherr, 1826 (Coleoptera, Anthribidae, Anthribinae, Stenocerini). AB - Three new species from Brazil, Stenocerus christus sp. nov. (Rio de Janeiro, Corcovado), Stenocerus fratris sp. nov. (Espirito Santo, Santa Maria de Jetiba) and Stenocerus mesosternalius sp. nov. (Espirito Santo, Alegre, Fazenda Jerusalem), and a new species from Peru, Stenocerus similis sp. nov. (Mariscau, Juanjui), are described and illustrated. Stenocerus paraguayensis Jordan, 1895 syn. nov. is proposed as a junior synonym of S. fulvitarsis (Germar, 1824). A key to all species of the genus Stenocerus is provided. PMID- 30313358 TI - Revision of the genus Eumorphobotys with descriptions of two new species (Lepidoptera, Crambidae, Pyraustinae). AB - The genus Eumorphobotys Munroe Mutuura (1969) comprises two species that have been found in southern China. Two new species, E. concavuncus sp. n. and E. horakae sp. n., are described from southwest China. In appearance, this genus also resembles Calamochrous Lederer, 1863, Sclerocona Meyrick, 1890, Prodasycnemis Warren, 1892, and Loxoneptera Hampson, 1896. In order to evaluate the generic placement of the new taxa, the phylogeny of Eumorphobotys species and several species representing the potential related genera based on sequence data of COI, 16S rRNA, EF-1alpha and 28S rRNA gene regions were reconstructed and the taxonomy of these genera based on morphological characters was re-assessed. The results are as follows: (i) the monophyly of Eumorphobotys is well supported; (ii) Loxoneptera is paraphyletic. Two species of Calamochrous were recovered as terminal lineages within Loxoneptera; (iii) the clade comprising species of Loxoneptera and Calamochrous is in the sister position to Eumorphobotys with a robust support; (iv) species of Loxoneptera and Calamochrous resemble Eumorphobotys in the wing shape and the porrect labial palpus but differ in genitalia structures. The relationships of these genera are discussed; (v) two new species, E. concavuncus sp. n. and E. horakae sp. n., are described, Calamochrous obscuralis (Caradja, 1925) syn. n. is synonymized with E. eumorphalis (Caradja, 1925) based on the male genitalia and the adults and genitalia of all species (except the female of E. horakae sp. n.) are illustrated. PMID- 30313359 TI - 'Monster Scydmaenus' of Australia: revision of subgenus Corbulifer Franz (Coleoptera: Staphylinidae: Scydmaeninae). AB - The subgenus Corbulifer Franz of Scydmaenus Latreille is distributed along the east coast of the continental Australia. It was defined mainly on the basis of monstrously enlarged male metatibiae, which can be over twice as broad as femora. To date, two species (one with three subspecies) were known. Corbulifer is here revised and redefined, with characters not related to the male sexual dimorphism added to the diagnosis. Scydmaenus tamborinensis cunninghamensis Franz and S. tamborinensis maipotonensis Franz are placed as junior synonyms of S. tamborinensis Franz; S. pseudorobustus Franz is redescribed, and eight new species are described: S. monstrosetibialis sp. n., S. bellenderanus sp. n., S. kiwarrakianus sp. n., S. gushi sp. n., S. gibraltar sp. n., S. eungellanus sp. n., S. fishermontanus sp. n. and S. super sp. n. PMID- 30313360 TI - Caridean prawn (Crustacea, Decapoda) with description of a new species and an invasive crayfish from Yuelu mountain national park, Hunan, China. AB - Yuelu mountain national park (5A scenic area) is a rare urban mountain scenic area. The major impacts from human activity are growing, such as largely unplanned tourist activity, urbanization, and accelerated the others responsible for environmental changes. It is unavoidable to have great pressure and influence on the diversity of fauna on the scenic area. In order to better understand the diversity of the decapod fauna in the Yuelu mountain national park, an intensive field survey has been carried out. A total of five species was collected, three species of atyid shrimps, Neocaridina palmata (Shen, 1948), N. yueluensis, new species, and Paracaridina longispina (Guo He, 1992), one species of palaemonid prawn, Macrobrachium nipponense (De Haan,1849), and an invasive crayfish, Procambarus clarkii (Girard, 1852). N. yueluensis is distiguished from congeners by the shorter rostrum, the stout carpus of first pereiopod and the stout chela of second pereiopod, not sexual dimorphism of the third and fourth pereiopods, the long appendix interna and arising from the inner border of appendix masculina, and the narrower scaphocerite. PMID- 30313361 TI - Chinja, a new genus of spider from the Eastern Arc Mountains of Tanzania (Araneae, Zoropsidae). AB - The new zoropsid spider genus Chinja Polotow Griswold is diagnosed and described and the following two new species are described: C. chinja sp. nov. and C. scharffi sp. nov. The species were collected in the Eastern Arc Mountains of Tanzania and appear to be endemic to this region. The genus belongs to the oval calamistrum clade (OC Clade), which also includes Dionycha and Lycosoidea. Based on the synapomorphies and diagnostic characters of members of the OC Clade, Chinja is considered a member of Zoropsidae, although without a clear subfamily placement due to insufficient data. Males of Chinja can be distinguished from other Zoropsidae by a straight PER, by lacking a tibial crack, by having a male palpal cymbium with a retrobasal process and the male palpal tibia with an RTA and a retromedian cluster of stout setae. Females have a divided cribellum with cribellar spigots evenly arranged, and the epigynum with the median plate broad and laterally procurved into hooks, and the lateral lobes each with a wide tooth. The following set of characters can be also helpful to identify the genus: presence of a third tarsal claw, absence of claw tufts and presence of a cribellum and calamistrum. PMID- 30313362 TI - Baikalobia elochinensis sp. n. (Plathelminthes, Tricladida, Continenticola), a new species of endemic Baikal planarians: morphological and genetic comparison with the type species Baikalobia guttata (Gerstfeldt, 1858). AB - Endemic freshwater planarians of the family Dendrocoelidae (Plathelminthes, Tricladida, Continenticola) are characteristic components of the Baikal fauna. Despite the long history of research on this group, new species and genera of Baikal planarians have been regularly described (Porfirieva, 1977; Timoshkin et al., 2004; Porfiriev et al., 2009; Porfiriev et al., 2011; Porfiriev and Timoshkin, 2013; Porfiriev and Timoshkin, 2015). PMID- 30313363 TI - Hidden in plain sight: a morphological study revealing three new species of the skipper genus Drephalys Watson, 1893 (Lepidoptera: Hesperiidae) from Brazil. AB - Three new species of Drephalys Watson, 1893 from Brazil are described as follows: D. dracarys Madruga, Siewert, Mielke Dolibaina, sp. n. from Acre, Mato Grosso and Rondonia states, D. electrinus Siewert, Madruga, Mielke Dolibaina, sp. n. from Acre and Amazonas states, and D. citrinus Madruga, Siewert, Mielke Casagrande, sp. n. from Amazonas state. Drephalys heraclides Bell, 1942 was reported for the first time from Brazil. To characterize the new species, illustrations of the male genitalia of D. heraclides, D. phoenice (Hewitson, 1867) and D. phoenicoides (Mabille Boullet, 1919) are provided. Diagnosis, adult photos, illustration of the male genitalia and a geographical distribution map are provided for the new species. PMID- 30313364 TI - A new genus and species of praying mantis (Insecta, Mantodea, Mantidae) from Indochina, with a key to Mantidae of South-East Asia. AB - Mekongomantis quinquespinosa gen. et sp. nov., a new Mantidae genus and species is described based on specimens from two localities-Lam Vien plateau in Vietnam and the environments of Umphang, Thailand. The new genus has five posteroventral spines on the forefemur, a feature previously unknown in any Mantidae (sensu stricto) genus. The rest of external morphology is similar to Tenodera Burmeister, 1838 and Mantis Linnaeus, 1758, while the characters of the male genitalia place the species more closely to Hierodula Burmeister, 1838 and Camelomantis Giglio-Tos, 1917. The discovery of such a large (>70 mm) genus level taxon exemplifies the poorly studied diversity of Mantodea in the rapidly deteriorating Greater Mekong area. To ease identification, we also provide a key to the Mantidae of South-East Asia. PMID- 30313365 TI - JENNIFER M. BOSCO ANGELA CHUANG (2018) A new species of grass spider, Agelenopsis riechertii, from the Southwestern USA, with notes on its courtship behavior (Araneae: Agelenidae). Zootaxa, 4442: 579-583. AB - We made changes in the description of a new Agelenopsis spider species, Agelenopsis riechertae. Firstly, we declare the male holotype and a type repository to validate the species description, which was previously omitted. The original Latin name has been feminized from Agelenopsis riechertii to Agelenopsis riechertae. PMID- 30313366 TI - Checklist of oribatid mites (Acari, Oribatida) of the Russian Far East and Northeast of China. AB - The present paper reviews the taxonomic studies of the mite suborder Oribatida in the Russian Far East South and Chinese North-East Territories. At present, 746 species of oribatid mites are registered in China, including 175 species in the soils of Northeast China. In the Russian Far East, there were 605 species of oribatids, including 344 species in the south of the Far East. The fauna of the oribatid mites of the Northeast of China and the south of the Russian Far East has 446 species and subspecies representing 190 genera and 80 families. 72 species of oribatid are common for both territories. The modern fauna of the oribatid mites of the Northeast of China and the south of the Far East was formed as a result of prolonged interaction between the boreal and palaearchaearctic faunas. The oribatid fauna of this region is distinguished by the presence of a large number of endemics, some of which are relics of the late Tertiary time and which can be considered as autochthonous. The checklist includes data from more than 100 locations of this enormous region. In addition, a short climatic and historical review of oribatid mites study is presented. PMID- 30313367 TI - Key for identification of the ladybirds (Coleoptera: Coccinellidae) of European Russia and the Russian Caucasus (native and alien species). AB - Although ladybirds of European Russia and the Caucasus have been the subject of numerous ecological and faunistic investigations, there is an evident lack of appropriate identification keys. New, original keys to subfamilies, tribes, genera, and species of ladybirds (Coccinellidae) of European Russia and the Russian Caucasus are presented here. The keys include all native species recorded in the region and all introduced alien species. Some species from adjacent regions are added. In total, 113 species are treated and illustrated with line drawings. Photographs of rare and endemic species are provided. Information on the distribution of species within the region under consideration is provided. Chilocorus kuwanae Silvestri, 1909 is recognized as a subjective junior synonym (syn. nov.) of Ch. renipustulatus (Scriba, 1791). PMID- 30313368 TI - Revision of Testechiniscus Kristensen, 1987 (Heterotardigrada: Echiniscidae) refutes the polar-temperate distribution of the genus. AB - The family Echiniscidae comprises limno-terrestrial heterotardigrades with a strongly sclerotised dorsum, typically covered with plates. Among other members of the Echiniscus evolutionary line, the genus Testechiniscus Kristensen, 1987 stands out with well-developed ventral armature and polygonal sculpturing of the dorsal plates. It has alleged bipolar distribution (with satellite alpine records in the Holarctic). Thanks to fresh material from terra typica (Svalbard), we integratively redescribe (i.e. using light and electron microscopy imaging, morphometry, and molecular methods) the nominal species for the genus, Testechiniscus spitsbergensis (Scourfield, 1897). A comparison of the neotype series with a number of Holarctic records revealed morphological variability suggesting that the species may encompass several taxa, which, most likely, will be possible to delineate primarily with molecular tools. Moreover, based on material from Simien Mountains (Northern Ethiopia), we describe a new sibling subspecies, Testechiniscus spitsbergensis tropicalis ssp. nov. Extensive morphometric datasets are provided for the genus members for the first time. A new generic definition is proposed, embracing the two subspecies of T. spitsbergensis and T. laterculus (Schuster et al., 1980), but excluding two circum-Antarctic species, T. macronyx (Richters, 1907) and T. meridionalis (Murray, 1906). The later species are likely to be erected in the future as separate genera, and their autapomorphies are described here. In the light of our findings, the genus Testechiniscus should be recognised as a native element of the Northern Hemisphere, with mainly circum-Arctic distribution and additional, insular alpine records from the Nearctic, Palearctic and Eastern Afrotropic. PMID- 30313369 TI - Three new species of the Stenus cephalotes group fom Zhejiang, East China (Coleoptera, Staphylinidae). AB - Three new species of the Stenus cephalotes group from Zhejiang, East China are described: S. qingliangfengus Tang Jiang, sp. n., S. communicatus Tang Jiang, sp. n. and S. fengyangshanus Tang Jiang, sp. n. The diagnostic characters of the new species are illustrated and a key to species of the group from Zhejiang is provided. PMID- 30313370 TI - Black corals (Anthozoa: Antipatharia) from the deep (916 m-2542 m) Coral Sea, north-eastern Australia. AB - Black corals (Anthozoa: Antipatharia) occur in all the world's oceans in a wide range of habitats from shallow-water coral reefs to the deep-sea. However, the taxonomy of black corals is poorly known compared to many other anthozoan groups. This knowledge gap is particularly acute for the deep-sea, where collecting specimens is logistically difficult and costly. Here, we identify 21 black coral specimens collected from the western Coral Sea adjacent to north-east Australia. The specimens represent five nominal species from five genera and two families. All species represent new records for the region, including the first record for the family Cladopathidae Brook, 1889. We describe the morphology of these specimens, note geographic and bathymetric range expansions, and provide evidence to support the hypothesis that Bathypathes seculata Opresko, 2005 is the juvenile stage of Bathypathes patula Brook, 1889, thus warranting synonymization. Our findings demonstrate that deep-sea antipatharians in this region are much more diverse than previously reported. Furthermore, this study highlights the importance of museum collections in terms of increasing our understanding of taxonomy and patterns of biodiversity, particularly for poorly-studied habitats such as the deep-sea. PMID- 30313371 TI - Taxonomic revision of the genus Poropuntius (Teleostei: Cyprinidae) in Peninsular Malaysia. AB - Up to three nominal species of the cyprinid fish genus Poropuntius (i.e. P. deauratus [Valenciennes in Cuvier Valenciennes 1842], P. normani [Smith 1931], and P. smedleyi [de Beaufort 1933]) have been reported to occur in Peninsular Malaysian freshwater ecosystems. However, low morphological differentiation among species of Poropuntius causes confusion and it is still unknown how many valid species of Poropuntius occur in this region. The goal of this study is to review the taxonomic status of Poropuntius in Peninsular Malaysia by using morphological and molecular characters. Principal Component Analysis (PCA) on a morphometric dataset including 281 specimens of Poropuntius from Peninsular Malaysia and P. normani from Thailand (type locality) failed to identify non-overlapping clusters within sampled specimens. A phylogenetic tree based on cytochrome oxidase subunit I (COI) showed intraspecific levels of genetic differentiation within Poropuntius of Peninsular Malaysia and the specimens of P. normani from Thailand form a monophyletic group. Our results strongly support the presence of only one species of Poropuntius in Peninsular Malaysia, P. normani. We demonstrate that P. smedleyi described from Johor, southern Peninsular Malaysia, is a junior synonym of P. normani. The previous reports of the presence of P. deauratus in Peninsular Malaysia are doubtful because this species was described from Vietnam where, in all evidence, it is endemic. PMID- 30313372 TI - Three new species of the genus Lasianobia Hampson, 1905 (Lepidoptera, Noctuidae) from China, with a revised checklist for the genus. AB - Three new species of Lasianobia Hampson, 1905 are described from China: Lasianobia dvoraki Saldaitis, Volynkin Truuverk, sp. nov. (W Sichuan), Lasianobia labranga Saldaitis, Volynkin Truuverk, sp. nov. (SW Gansu) and Lasianobia qinghana Saldaitis, Volynkin Truuverk, sp. nov. (Qinghai). Adults and male genitalia of these new species and their relatives are illustrated, and a generic check list presented. PMID- 30313373 TI - A new species of Oecleus Stal (Hemiptera: Fulgoroidea: Cixiidae) from coconut in Brazil. AB - A new species of cixiid planthopper (Hemiptera: Fulgoroidea) in the genus Oecleus Stal, Oecleus sergipensis n. sp., is described from Sergipe State, Brazil. This new taxon is associated with coconut (Cocos nucifera L.) and date palm (Phoenix L). The species was detected in Auchenorrhyncha surveys to find potential vectors of lethal yellowing type syndrome. This is the first report of the genus Oecleus in Brazil. Sequence data from the mitochondrial cytochrome c oxidase subunit I (COI) barcoding region was obtained and accessioned into GenBank. PMID- 30313374 TI - Phylogeny and biogeography of Bent-toed Geckos (Cyrtodactylus Gray) of the Sundaic swamp clade. AB - The Sundaic swamp clade of the genus Cyrtodactylus contains nine species that collectively range through Peninsular Malaysia and its associated land bridge islands, Singapore, Sumatra, Java, and Pulau Natuna Besar. Ancestral range reconstruction analyses using BioGeoBEARS based on an updated molecular phylogeny of the nine Sundaic swamp clade species of Cyrtodactylus demonstrated that this lineage evolved in Peninsular Malaysia, dispersed independently to Sumatra and Pulau Natuna Besar, Indonesia and most likely back into Peninsular Malaysia from Sumatra. This scenario is consistent with climate-driven, cyclical, ephemeral, geographic reconfigurations of Sundaic landmasses from at least the mid-Miocene to present. PMID- 30313375 TI - Redescription of Cerceis biforamina Javed Yousuf, 1996 from the Gulf of Oman (Crustacea: Isopoda: Sphaeromatidae) with remarks on the status of Cymodoce insolita Yousuf, 2011. AB - Cerceis biforamina Javed Yousuf, 1996 is redescribed and illustrated based on material from the Iranian coasts of the Gulf of Oman. This species is distinguished by the smooth pereonites 1-6, pereonite 7 with a row of tubercles and short setae; pleon dorsal surface with multiple prominent tubercles medially; pleotelson with two prominent semilunar tuberculate ridges and clearly trilobed posterior margin. Cerceis insolita Yousuf, 2011 is transferred to genus Cymodoce and synonymised with Cymodoce manorii (Nooruddin, 1965). An extended diagnosis is provided for the genus Cerceis. PMID- 30313376 TI - Two new orthoclad species from Colombian Andes (Diptera: Chironomidae). AB - Lipurometriocnemus. bogotensis sp. n. and Antillocladius laviejae sp. n., two species collected at the "La Vieja" creek, near Bogota, Colombia; 2666 m, are described and depicted as male imagines. L. bogotensis sp. n. can be separated from other Lipurometriocnemus species by lacking acrosticals setae on thorax, thus an emendation of the genus concept is presented. Antillocladius laviejae sp. n. is differentiated from other closely related members of the genus mainly by the pilosity of wings. PMID- 30313377 TI - A new species of Monoblastus Hartig, 1837 (Hymenoptera: Ichneumonidae: Tryphoninae) from South Korea. AB - A new ichneumonid species, Monoblastus koreensis sp. nov. is described from South Korea. New data on the taxonomy and distribution of M. clauseni (Uchida), M. erythrurus Townes et al. and M. nigriventus Lee Cha are given. The taxonomic position of M. nigriventus and its similarity to M. ermolenkoi Kasparyan from Russian Kuril Islands is discussed. All these species are keyed and illustrated. Erromenus alpinator Aubert sensu Lee Cha (= Monoblastus koreensis sp. nov.) is excluded from the fauna of South Korea. PMID- 30313378 TI - A contribution to the systematics of the genus Manota Williston (Diptera: Mycetophilidae) in Brazil. AB - A total of 286 male specimens of Manota from 38 different collecting sites in the Brazilian Atlantic Forest were analysed. They belong to 32 different species, including 20 described as new to science and 12 recognized as previously described species. The new species are M. abbreviata sp. n., M. atlantica sp. n., M. carioca sp. n., M. cavata sp. n., M. hirta sp. n., M. lamasi sp. n., M. lanei sp. n., M. nordestina sp. n., M. oliveirai sp. n., M. paniculata sp. n., M. papaveroi sp. n., M. periotoi sp. n., M. perparva sp. n., M. pseudoiota sp. n., M. rostrata sp. n., M. sanctavirginae sp. n., M. securiculata sp.n., M. silvai sp. n., M. tavaresi sp. n. and M. unispinata sp. n. The taxonomic context of the newly described species is discussed. Manota palpalis Lane, 1948, the type of which is considered lost, is redescribed and discussed, based on the original description, the original illustrations, and the type-locality. Our specimens of the previously described species belong to M. aligera Hippa, Kurina Saaksjarvi, 2017, M. anfracta Hippa Kurina, 2013, M. appendiculata Hippa Kurina, 2013, M. caribica Jaschhof Hippa, 2005, M. diversiseta Jaschhof Hippa, 2005, M. micula Hippa Kurina, 2013, M. panda Hippa Kurina, 2013, M. pustulosa Hippa, Kurina Saaksjarvi, 2017, M. quantula Hippa Kurina, 2013, M. serrulata Hippa, Kurina Saaksjarvi, 2017 and M. subaristata Kurina, Hippa Amorim, 2017. Among the species dealt with here, ten have a wide distribution in South America or the Neotropics, six are known from only a single site, nine are widespread along the Atlantic Forest, and seven are known only from southern Brazil/northwestern Argentina. A discrepancy between the distribution patterns of Manota species and the general areas of endemism known for flies in the Atlantic Forest is discussed, and a non destructive sequencing reverse workflow protocol for Manota specimens proposed. Including the species described here, the Neotropical region closely approaches the Oriental region in terms of the number of described species (92 and 102, respectively), while the genus now includes 300 species worldwide. PMID- 30313379 TI - First record of the family Schizodactylidae (Orthoptera: Ensifera) from Thailand, with the description of a new species. AB - A new species of dune cricket in the family Schizodactylidae, Schizodactylus salweenensis sp. nov. is described from Salween River, Mae Hong Son Province, northwestern Thailand based on both males and females. The Schizodactylidae is recorded for the first time in Thailand. The new species is most similar to Schizodactylus tuberculatus Ander, 1938 and Schizodactylus burmanus Uvarov, 1935 in the morphology of male subgenital plate, but mainly differs in the shape of subgenital plate apex, and the spurs of hind tibiae. The type series was collected from sand dunes along the river. This cricket reaches adulthood during the rainy season. PMID- 30313380 TI - Reevaluation of the intraspecific variability in Darevskia parvula (Lantz Cyren, 1913): an integrated approach using morphology, osteology and genetics (Squamata: Lacertidae). AB - The intraspecific variability of Darevskia parvula (which has two classical subspecies easily identifiable by external characteristics, D. p. parvula and D. p. adjarica), was studied using various approaches including morphology (scalation and biometry), multivariate analyses (PCA, CDA, ANOSIM, UPGMA and MST), osteology, and molecular techniques. High mitochondrial distance, differences at the nuclear level and morphological distinctiveness warrant the specific status of both taxa, Darevskia parvula (Lantz Cyren, 1913) and Darevskia adjarica (Darevsky Eiselt, 1980) stat. nov. A lectotype for D. parvula, originally described with syntypes of both species -D. parvula and D. adjarica- is designated. The uncorrected genetic distance between D. parvula and D. adjarica in the cytochrome b mitochondrial gene is 14.4% +/- 1.9%. Intraspecific variability within D. parvula is very small (1.5% +/- 0.5%), and was not detected in our samples of D. adjarica. The two species further differ by two mutations in the nuclear melano-cortin 1 receptor (mc1r) gene. Interestingly, past introgression of D. parvula mitochondrial haplotypes (5% +/- 1% different to those currently known) into some D. adjarica has been detected in one locality; all the studied specimens of D. adjarica with mtDNA of D. parvula are unmistakably D. adjarica at the morphological and nuclear levels.Morphologically, there is almost no overlap between D. parvula and D. adjarica. These results are corroborated by CDA, MST and UPGMA trees. Specimens of the inland high mountain population of Ardahan (clearly D. adjarica in CDA, MST and UPGMA trees) occupy a somewhat intermediate position between both taxa in the PCA (when specimens and not populations as a whole are considered), but this morphological closeness may be attributed to the influence of climatic factors (continental conditions) on scalation of the specimens. Males appear to be more differentiated than females. Overlap among samples within each species is very marked; none can be separated clearly from its conspecifics. This is even more marked in D. parvula, which has a fairly small area compared to D. adjarica.Darevskia parvula and D. adjarica samples appear to be homogeneously clustered within species and well separated between the two species in the UPGMA trees. In males and females all the D. parvula samples are very similar and moderately differentiated. In males of D. adjarica, the most differentiated seems to be adjBorcka, the others all being clustered together, with adjCaykara showing slightly more differentiation from the rest (adjOrtacalar, adjArdahan, adjIkizdere and adjCermik).Darevskia adjarica females are also similarly distributed into two subgroups, one including Borcka, Cermik and Ardahan and the other including Ortacalar, Ikizdere and Caykara. In both sexes, the inland Ardahan sample clearly belongs to D. adjarica.From the most connected MST samples, speculations can be made about areas of origin and expansion of the different taxa. Ortacalar (D. adjarica) and Hatila (D. parvula) are the most connected (morphologically more "central" in both taxa); in fact, both populations are relatively close, living on the northern (Black Sea) and southern (Anatolian) facing slopes, respectively of the Dogu Karadeniz Mountains (Kackar Mountains). This highlights these mountains, which rise from sea level up to nearly 4000 m asl. and have wide buffering possibilities against climate changes, as a zone of refuge and posterior dispersion of this species, and even of the original splitting into two taxa adapted to these different conditions, D. adjarica on the coast and D. parvula on the continental slope.Osteologically D. parvula and D. adjarica are very similar, although Georgian specimens from an isolated population (Atskuri) have closed clavicles not found in Turkish D. adjarica. Also, inland Ardahan D. adjarica have an extra vertebra in both males and females, compared to the other studied specimens from both species.The present study indicates that the situation in Turkey is that D. parvula is well differentiated and lives around the Coruh River Valley, contoured by D. adjarica populations on the coastal-facing slopes of the Dogu Karadeniz Mountains on one side, and the Yalnizcam Mountains on the other side, where D. adjarica enters from Georgia as the opposite extreme of a geographic distribution. The attribution of more inland ranges to D. parvula or D. adjarica, as well as the detailed genetic structure of both taxa may be confirmed with more specific studies. PMID- 30313381 TI - Four new species of Pselaphodes Westwood (Coleoptera: Staphylinidae: Pselaphinae) from Thailand, Laos, and China. AB - Four new species of Pselaphodes Westwood are described from southern Asia: P. femoralis sp. n. (China, Thailand), P. incisus sp. n. (China, Laos), P. suthepensis sp. n. (Thailand), and P. thailandicus sp. n. (Thailand), supported by illustrations of male habitus and major diagnostic characters. One of the new species (P. femoralis) exhibits considerable intraspecific variation in the aedeagal structure, but may be readily distinguished by a stable combination of unique male external features. PMID- 30313382 TI - Three new species of the genera Loxoconcha and Xestoleberis (Crustacea, Ostracoda, Podocopida) from central and southern Vietnam. AB - The present study reports three new species of Ostracoda, Loxoconcha damensis sp. nov., Xestoleberis vietnamensis sp. nov. and X. munensis sp. nov., from Phu Quoc Island, southwest Vietnam and Nha Trang Bay, central Vietnam. These species inhabit the coral reefs around isolated islands and can be easily distinguished from other known species based on their morphological differences, mainly in the male copulatory organ. Loxoconcha damensis sp. nov. belongs to Loxoconcha Group A, based on the distributional pattern of their pore system below the eye tubercle. Similarly, based on a combination of morphological types of pore systems, the two new Xestoleberis species belong to Xestoleberis Group A, because these species have two types of pore systems, i.e., sieve-type and lip-type. To the best of our knowledge, this study is the first report on Xestoleberididae and the second on Loxoconchidae from the Recent of Vietnam. PMID- 30313383 TI - Undocumented beetle diversity in the Southeastern United States: a case study of the minute clubbed beetles (Coleoptera: Monotomidae). AB - Studies of the saproxylic and predatory beetle family Monotomidae (Coleoptera: Cucujoidea) in the southeastern USA increased the known diversity for the family in the state of Georgia by one genus and nine species. Online records of Monotomidae from Georgia increased from 0 to 885. This work highlights the lack of basic diversity information about small beetles that inhabit wood, leaf litter, and other decaying plant matter in this region. PMID- 30313384 TI - A new genus of oak gallwasp, Protobalandricus Melika, Nicholls Stone (Hymenoptera: Cynipidae: Cynipini) from California. AB - We describe a new genus of cynipid oak gallwasp, Protobalandricus Melika, Nicholls Stone (Hymenoptera: Cynipidae: Cynipini). Protobalandricus gen. nov. includes one previously described species, Disholcaspis spectabilis (Kinsey), which induces stem swelling-like galls on golden cup oaks, Quercus section Protobalanus. Descriptions of the genus and diagnostic characters, including DNA sequence data, are presented. PMID- 30313385 TI - A new species of Nemoura Latreille (Plecoptera: Nemouridae) from Amur River Basin (South of the Russian Far East). AB - Nemoura sirotskii sp. n. (Plecoptera, Nemouridae) is described as a new stonefly species from the tributary streams of Zeya Reservoir (Amur River Basin) in the south of the Russian Far East. Detailed descriptions and illustrations are provided for the larvae and adult specimens. The diagnostic characters distinguishing it from sympatric species N. arctica are discussed. PMID- 30313387 TI - New and interesting species of ptyctimous mites (Acari, Oribatida) from Nepal. AB - The present study is based on ptyctimous oribatid mite material (Acari, Oribatida) collected in Nepal in 1980 and 1995. A list of identified taxa, including 18 species from 12 genera and five families, is provided; of these, Apoplophora pantotrema, Euphthiracarus carinatus, Phthiracarus boresetosus and Ph. setosus are recorded for the first time in the Nepalese fauna. Two new species of the genus Plonaphacarus (Steganacaridae) are described: P. diutissimus Niedbala sp. nov. differs from P. machadoi (Balogh, 1958), P. tanzicus (Mahunka, 1993), P. ngongi Niedbala, 2001 and P. styphelos Niedbala, 2001by the length of lamellar and notogastral setae, number of notogastral lyrifissures, and the morphology of setae d on leg femora I; P. pugionis Niedbala sp. nov. differs from P. kaluzi Niedbala, 2013 by the morphology of sensilli, arrangement of notogastral setae c1-3, length of subcapitular setae h, morphology of adanal setae ad2, and the localization of setae d on leg femora, and from H. similis Niedbala, 2000 by the shape of sensilli, rostral and notogastral setae and arrangement of notogastral setae c1-3. The supplementary description of Euphthiracarus carinatus Liu, Wu Chen, 2011 (Euphthiracaridae) is given. PMID- 30313386 TI - Juliaca Melichar, 1926 (Hemiptera: Cicadellidae: Cicadellini): description of a new species from Southeastern Brazil and redescriptions of J. sertigerula (Jacobi, 1905) and J. xanthogramma (Signoret, 1854) comb. nov. AB - A new species of the sharpshooter genus Juliaca Melichar, 1926, J. nigra sp. nov., from Southeastern Brazil (State of Espirito Santo) is described based on specimens collected on a coffee plantation. In addition, J. sertigerula (Jacobi, 1905), an Andean species, and Tettigonia xanthogramma Signoret, 1854, from Southeastern Brazil (states of Minas Gerais and Rio de Janeiro), are redescribed. The former species was not adequately illustrated and the latter was not treated in the most recent monograph on the Cicadellini. The identity of T. xanthogramma is elucidated and it is transferred to Juliaca (J. xanthogramma comb. nov.). PMID- 30313388 TI - Two new genera and species of the leafhopper tribe Idiocerini (Hemiptera: Cicadellidae) and redescription of the type species of Paraidioscopus. AB - Two new genera of Idiocerini, Lambirocerus gen. nov. with type species Lambirocerus cycloformulus sp. nov. and Undophomorpha gen. nov. with type species Undophomorpha glauctata sp. nov., are described and illustrated from Malaysia. The type species of Paraidioscopus Maldonado-Capriles, P. tagalicus (Baker) is also redescribed and illustrated. PMID- 30313389 TI - Aplectana hoplobatrachusia sp. nov. (Nematoda: Cosmocercidae) in Hoplobatrachus crassus (Jerdon, 1853) (Anura: Dicroglossidae) from Birbhum District, West Bengal, India. AB - Aplectana hoplobatrachusia sp. nov., recovered from the rectum of Jordon's bullfrog, Hoplobatrachus crassus, (Jerdon, 1853) collected from Lohagram in the Birbhum district of West Bengal, India, is described and illustrated. This species is characterised by absence of a gubernaculum and differs from other species of Aplectana which lack a gubernaculum (viz. A. akhrami, A. artigasi, A. chilensis, A. crossodactyli, A. crucifer, A. delirae, A. dubrajpuri, A. meridionalis, A. papillifera, A. praeputialis, A. tarija and A. vercammeni) by morpho-metrical ranges of males and females and number and distribution of caudal papillae in males which include 4 pairs preanal, 1-2 pairs adanal, 10 pairs postanal and a single median papilla on the upper lip of the cloaca. Aplectana hoplobatrachusia sp. nov. represents the 56th species assigned to the genus and the 4th from India and the 5th from Indian subcontinent. PMID- 30313390 TI - Sixteen new species of the spider genus Althepus Thorell, 1898 (Araneae: Ochyroceratidae) from Southeast Asia. AB - Sixteen new Althepus species of the spider family Ochyroceratidae are reported from Southeast Asia: A. bamensis Li et Li sp. nov., A. changmao Li et Li sp. nov., A. dongnaiensis Li et Li sp. nov., A. guan Li et Li sp. nov., A. maechamensis Li et Li sp. nov., A. menglaensis Li et Li sp. nov., A. naphongensis Li et Li sp. nov., A. natmataungensis Li et Li sp. nov. (male only), A. phadaengensis Li et Li sp. nov., A. shanhu Li et Li sp. nov., A. suayaiensis Li et Li sp. nov. (male only), A. tadetuensis Li et Li sp. nov., A. tanhuang Li et Li sp. nov., A. thanlaensis Li et Li sp. nov., A. tharnlodensis Li et Li sp. nov. (female only), and A. viengkeoensis Li et Li sp. nov. PMID- 30313391 TI - Three new species of Rasahus, with clarifications on the identities of three other Neotropical corsairs (Heteroptera: Reduviidae: Peiratinae). AB - Three new peiratine species in the genus Rasahus Amyot Audinet-Serville, 1843 (Hemiptera: Heteroptera: Reduviidae: Peiratinae) are described: Rasahus nesiotes sp. nov. from Grand Bahama, Rasahus deliquus sp. nov. from Panama, and Rasahus abolitus sp. nov. from French Guiana. Rasahus castaneus Coscaron, 1983 is reported for the first time from French Guiana. The identity of Reduvius scutellaris Fabricius, 1787 is clarified, resulting in the following taxonomic and nomenclatural changes: Rasahus rufiventris (Walker, 1873) is considered a junior synonym of Rasahus scutellaris (Fabricius, 1787) stat. rev. et syn. nov., and Pirates myrmecinus Erichson, 1848 is resurrected and transferred, resulting in Rasahus myrmecinus (Erichson, 1848) stat. rev. et comb. nov. Most records of Rasahus scutellaris auct. (nec Fabricius) prior to this study remain indeterminate. Additionally, the peiratine fauna known from Panama and French Guiana are enumerated, and an updated key to the species of Rasahus is provided. Lastly, Pirates digramma Walker, 1873 (p. 102), tentatively considered to belong to Rasahus by previous authors, is discussed and transferred to Tydides Stal, 1866, resulting in Tydides digramma (Walker, 1873) comb. nov. PMID- 30313393 TI - The water striders (Hemiptera: Heteroptera: Gerridae) of Costa Rica: new species, checklist, and new records. AB - Brachymetra bernaldi Cordeiro, sp. nov. (Hemiptera: Heteroptera: Gerridae) from Heredia, Costa Rica, is herein described, illustrated, and compared with congeners. The new species resembles B. albinervus (Amyot Serville, 1843), but can be separated from it by the weak median carina of the pronotum, male abdominal mediotergite I with weak lateral notches, male abdominal mediotergite VII quadrate, male abdominal segment VIII in natural position almost entirely inserted into the abdominal cavity, and paramere narrow, with acute apex. We also provide the first checklist of the Gerridae of Costa Rica and new records, based on collection material and field sampling. All totaled, 31 species representing 13 genera and six subfamilies are recorded from the country. Five species and the genera Brachymetra Mayr, 1865 and Neogerris Matsumura, 1913 are registered for the first time from Costa Rica, and new provincial records are presented for 15 other species. PMID- 30313392 TI - Morphological and genetic divergence between Mediterranean and Caribbean populations of Madracis pharensis (Heller 1868) (Scleractinia, Pocilloporidae): too much for one species? AB - The colonial stony coral genus Madracis is cosmopolitan, lives in shallow and deep water habitats, and includes zooxanthellate, azooxanthellate and facultative symbiotic species. One of its species, Madracis pharensis, has been recorded from the Mediterranean and East Atlantic, where it forms small knobby and facultative zooxanthellate colonies (also named M. pharensis f. pharensis), and from the tropical Caribbean, where it also occurs in a massive and zooxanthellate form (named M. pharensis f. luciphila by some). These two forms have been previously found to host different Symbiodinium species. In this study, species boundaries and phylogenetic relationships between these two Madracis pharensis forms (from the Mediterranean Sea and the Caribbean), M. senaria, and the Indo-west Pacific M. kirbyi were analyzed through an integrated systematics approach, including corallite dimensions, micromorphology and two molecular markers (ITS and ATP8). Significant genetic and morphological differences were found between all the examined Madracis species, and between M. pharensis from the Mediterranean Sea and M. pharensis f. luciphila from the Caribbean in particular. Based on these results, the latter does not represent a zooxanthellate ecomorph of the former but a different species. Its identity remains to be ascertained and its relationship with the Caribbean M. decactis, with which it bears morphologic resemblance, must be investigated in further studies. Overall, the presence of cryptic Madracis species in the Easter and Central Atlantic Ocean remains to be evaluated. PMID- 30313394 TI - Validation and redescription of the hyperiidean amphipod Brachyscelus rapacoides Stephensen, 1925 (Crustacea: Amphipoda: Hyperiidea: Brachyscelidae), a new record of association with the scyphozoan jellyfish Rhopilema nomadica Galil, 1990 (Scyphozoa: Rhizostomeae: Rhizostomatidae) in the Mediterranean Sea. AB - The hyperiidean amphipod Brachyscelus rapacoides Stephensen, 1925 is recorded from the scyphozoan jellyfish Rhopilema nomadica Galil, 1990, a new record of association for the genus Brachyscelus, as well as the first record of hyperiid infestation of a non-indigenous scyphozoan host. Because of some past confusion concerning the status of B. rapacoides and the closely related species B. rapax (Claus, 1871) a redescription of B. rapacoides and molecular analysis are provided in order to validate it as a species distinguished from B. rapax. PMID- 30313395 TI - A reappraisal of the genus Tethyrhynchia Logan, 1994 (Rhynchonellida, Brachiopoda): a conflict between phylogenies obtained from morphological characters and molecular data. AB - The genus Tethyrhynchia Logan in Logan Zibrowius, 1994 is revised on the basis of different methods of analysis including SEM observations, detailed ontogenetic study of the crural development, transverse serial sections, and shell microstructure. Some morphological characters cited in the original diagnosis are analysed and contested by the ontogenetic results. The type of crura of Tethyrhynchia, often placed in the arcual group, appears to be of the raducal group, instead. Paedomorphosis and heterochronic development offer the possibility of opening a dialogue between morphological and phylogenetic approaches to classification of rhynchonellide brachiopods. PMID- 30313396 TI - Lanlabeo duanensis, a new genus and species of labeonin fish (Teleostei: Cyprinidae) from southern China. AB - Lanlabeo, a new genus of fish belonging to the family Cyprinidae, is described from the Pearl River drainage basin in Guangxi Province, southern China. This new genus is distinguished from all other genera of the cyprinid tribe Labeonini by a combination of morphological and phylogenetic characters. It differs morphologically from all other Asian labeonins in its uniquely modified oromandibular morphology. For example, this genus has a frenum connecting the upper jaw and lower lip at the corner of the mouth, regularly arranged papillae densely scattered over the ventral margin of the rostral cap, a vestigial upper lip, a rostral cap overlying the upper jaw and with a fimbriate posterior margin, and a lower lip divided into two lateral fleshy lobes and one central plate. These two lateral fleshy lobes are small and translucent, and the median lobe of the lower lip is large and has papillae regularly arranged in many transverse rows. In the lower jaw, the dentary is transversely L-shaped in ventral view because its anterior part forms a right-angle turn and its transverse branch is anterioposteriorly expanded. In addition, analyses of four nuclear gene datasets indicate that this new genus forms a highly divergent lineage within the Labeonini, and that Lanlabeo is closely related to the genus Ptychidio. Therefore, based on morphometric differences and phylogenetic relationships, we describe this new genus herein as Lanlabeo, containing the new species Lanlabeo duanensis. PMID- 30313397 TI - Morphology and molecules say: Tanytarsus latens, sp. nov. from Finland (Diptera: Chironomidae). AB - Tanytarsus latens sp. nov. is described from Finland (Ostrobothnia borealis, Satakunta). Both morphological and molecular analyses indicate that T. latens belongs to the mendax species group. The adult male hypopygium of the new species resembles that of Tanytarsus occultus Brundin and of T. desertor Gilka et Paasivirta, while the molecular analysis based on the mitochondrial cytochrome oxidase (COI) gene fragment evidences that T. latens is a sister species to most of European Tanytarsus of the mendax group's core, for which the COI barcodes are known. Notes on biology of T. latens are also provided. PMID- 30313398 TI - First Iranian record of the family Odiniidae (Diptera: Opomyzoidea), including two species new to the Middle East region. AB - The family Odiniidae is newly reported from Iran through the recent discovery of the species Odinia meijerei Collin, 1952 and Turanodinia graciosa Krivosheina Krivosheina, 1996 in Iran and the Middle East region. The species T. graciosa is here elevated from the rank of subspecies (Turanodinia stackelbergi graciosa Krivosheina Krivosheina, 1996) to species level. This taxonomical change was based on the comparison of the male genitalia of T. graciosa with T. stackelbergi Krivosheina Krivosheina. Images of the habitus and male genitalia of O. meijerei and T. graciosa are provided. PMID- 30313399 TI - Discovery of a new species of Inocelliidae (Insecta: Raphidioptera) in an altitude of nearly 3500 m in China. AB - A new snakefly species of the family Inocelliidae is described from China: Inocellia occidentalis sp. nov. The new species belongs to the Inocellia crassicornis species group. PMID- 30313400 TI - Lectotype designations in Acmaeodera Eschscholtz and Anthaxia Eschscholtz, and new synonymy in Phaenops Dejean and Anthaxia (Coleoptera: Buprestidae). AB - Lectotype designations are provided for Acmaeodera conoidea Fall, 1899, A. recticollis Fall, 1899, Anthaxia (Haplanthaxia) sculptipennis Obenberger, 1924, and A. (H.) oneili Obenberger, 1931. The following new synonymy is proposed: Phaenops caseyi (Obenberger, 1944), syn. nov. = P. lecontei (Obenberger, 1928), Phaenops horni (Obenberger, 1944), syn. nov. = P. fulvoguttata (Harris, 1829), and Anthaxia (Haplanthaxia) oneili Obenberger, 1931, syn. nov. = A. (H.) sculptipennis Obenberger, 1924). PMID- 30313401 TI - Acanthotomicus suncei, a new sweetgum tree pest in China (Coleoptera: Curculionidae: Scolytinae: Ipini). AB - A new species of bark beetle, Acanthotomicus suncei Cognato, that kills sweetgum (Liquidambar spp.) is described. The new species is distinguished from the other Acanthotomicus species by the placement of elytral declivital spines on interstriae 2, 4, 6, 8 and the connection of spines 1 and 2 by a tumescence. Notes on the bark beetle's potential damage to sweetgum are given. PMID- 30313402 TI - Erratum: ULRICH K. SCHLIEWEN, PETER WIRTZ MARCELO KOVACIC (2018) Didogobius janetarum sp. nov., a new cryptobenthic goby species from the Cape Verde Islands (Teleostei: Gobiidae). Zootaxa, 4438: 381-393. PMID- 30313404 TI - New species of Pseudonereis Kinberg, 1865 (Polychaeta: Nereididae) from the Atlantic Ocean, and a review of paragnath morphology and methodology. AB - Pseudonereis gallapagensis Kinberg, 1865 and P. variegata (Grube Kroyer in Grube, 1858) are the only two species of this genus commonly recorded along Atlantic American coasts, but their type localities are in the Eastern Pacific, and their morphology differs. Two new Pseudonereis species are described from Eastern Mexico: P. brunnea sp. n. from the Gulf of Mexico, and P. citrina sp. n. from the Caribbean Sea, previously confused with P. gallapagensis. In order to facilitate comparisons, descriptions based on specimens from near the type locality for P. gallapagensis (Peru and Ecuador), and topotypes for P. variegata (Valparaiso, Chile), are included. Based on these comparisons and current descriptions, the synonymies of Nereis ferox Hansen, 1882 described from Brazil with P. variegata, and of Pseudonereis formosa Kinberg, 1865 described from Hawaii with P. gallapagensis, are rejected. Consequently, both are regarded as distinct species and revised diagnoses are provided for them. The record of P. ferox from the Gulf of Guinea proved to be an undescribed species, and is herein described as P. fauveli sp. n. The number of paragnath rows in nereidid pharynx areas VII-VIII has been interpreted in several ways, leading to confusion; an alternative method to determine the number of bands and rows is proposed. The midventral region, the division of areas VII-VIII in furrow and ridge regions, and the description of the arrangement based on the pattern of paragnaths in such regions, are proposed. Further, the terms shield-shaped and pointed (P-bars) bars are redefined, and a new term, crescent-shaped bars, is proposed for paragnaths in the areas VI in some Pseudonereis and Perinereis species. A key for all Pseudonereis species is also included. PMID- 30313403 TI - Review of the genera Agelosus Sharp, 1889, Apostenolinus Bernhauer, 1934 and Apecholinus Bernhauer, 1933 (Coleoptera: Staphylinidae: Staphylinini: Staphylinina). AB - A taxonomic review of the genera Agelosus Sharp, 1889, Apostenolinus Bernhauer, 1934 and Apecholinus Bernhauer, 1933 is presented, including taxonomic history of the genera, their descriptions and keys to the species where applicable. Each species is described and illustrated, and all available bionomic and distributional data are presented. Agelosus caerulescens sp.n. (Yunnan), A. distigma sp.n. (China: Zhejiang), A. haeckeli sp.n. (Nepal), A. longicornis sp.n. (Japan: Shikoku), A. nigricollis sp.n. (China: Beijing Municipality, Hubei, Sichuan; North Korea), and A. schillhammeri sp.n. (China: Hubei) are described as new.Xanthocypus J. Muller, 1925 is removed from synonymy with Ocypus Leach, 1819 and moved as a resurrected synonym to Agelosus Sharp, 1889 (stat.res.)Ocypus fraternus Fairmaire, 1891, Agelosus ohkurai Hayashi, 1973, Ocypus aglaosemanticus He Zhou, 2017, Ocypus liui He Zhou, 2017 and Ocypus pterosemanticus He Zhou, 2017 are transferred from Agelosus to Apecholinus Bernhauer, 1933 (comb.nov.), and Agelosus ohkurai and Agelosus pterosematicus are placed in synonymy with Apecholinus fraternus (syn.nov.).Staphylinus auroguttatus Cameron, 1932, Staphylinus bimaculatus Cameron, 1932 and Ocypus cameroni Smetana Davies, 2000 (replacement name for bimaculatus Cameron, 1932) are transferred from Ocypus to Agelosus (comb.nov.) and placed in synonymy with Agelosus sikkimensis Bernhauer, 1920 (syn.nov.).Agelosus brevipennis Naomi, 1983, described as subspecies of Agelosus carinatus (Sharp, 1874), is placed in synonymy with Agelosus carinatus (syn.nov.).Agelosus chinensis J. Li, 1992 is transferred from Agelosus to Apecholinus Bernhauer, 1933 (comb.nov.) and placed in synonymy with Apecholinus fraternus (syn.nov.).Agelosus fushunicus J. Li, 2015 is placed in synonymy with Ocypus coreanus J. Muller, 1925 (syn.nov.).Agelosus unicolor masaoi Hyashi, 1991 is elevated to species rank (stat.nov,).Lectotype is designated for Ocypus weisei Harold, 1877. PMID- 30313405 TI - Taxonomic review of Athliini (Coleoptera: Scarabaeidae: Melolonthinae), a new tribe of scarab beetles endemic to South America. AB - Athliini Smith Evans, new tribe (Coleoptera: Scarabaeidae: Melolonthinae) includes four genera that occur from southern South America through to the southeastern regions of Brazil: Apteroathlia Smith Evans, new genus, Athlia Erichson, 1835, Dihymenonyx Gutierrez, 1949, and Ulata Saylor, 1945. Justifications are provided for the new tribe and for the placement each genus in the new tribe. Keys to genera and species are presented along with distributional data and maps for all species. Apteroathlia translucida Smith Evans, new species and Apteroathlia nox Smith Evans, new species are described. Lectotypes are designated for Athlia bruchi Moser, 1924 and Athlia rustica Erichson, 1835. A neotype is designated for Ulata argentina Saylor, 1945. PMID- 30313406 TI - Jocquestus, a new genus of trachelid sac spiders from the Afrotropical Region (Arachnida: Araneae). AB - The new dark sac spider genus Jocquestus gen. nov. (Araneae: Trachelidae) is proposed for two species of Afrotropical trachelid spiders, J. schenkeli (Lessert, 1923) comb. nov. (type species) from D.R. Congo, South Africa, Mozambique and Zimbabwe, and J. roeweri (Lawrence, 1938) comb. nov. from South Africa, both of which are transferred from Trachelas L. Koch, 1872. Both species are redescribed and the male of J. roeweri comb. nov. is described for the first time. Five new species are described: J. capensis sp. nov. (? ?), J. harrisi sp. nov. (?) and J. incurvus sp. nov. (? ?) from South Africa, and J. griswoldi sp. nov. (?) and J. obliquus sp. nov. (? ?) from Tanzania. Present data suggests that all of the species are arboreal spiders associated with the vegetation of woody plants in savanna, forest and fynbos habitats, and are only very rarely encountered near the soil surface. PMID- 30313407 TI - Description of a new species of Cephalaeschna (Odonata: Anisoptera: Aeshnidae) from northern Vietnam. AB - A new aeshnid species, Cephalaeschna yanagisawai sp. nov. from northern Vietnam (Hoang Lien National Park, Lai Chau Province, 103 degrees 45'E, 22 degrees 20'N, 1900~2000 m a.l.s.), is described and illustrated. This species can be differentiated from the other species of the genus by body maculation, the morphology of the male anal appendages, and female postero-ventral S10 tergite projecting posteriorly, which is a rare feature in the genus. PMID- 30313408 TI - Notes on the Stenus indubius group with descriptions of four new species from China (Coleoptera, Staphylinidae). AB - Four new species of the Stenus indubius group from China are described: S. yaoluopingus Hu Tang, sp. n. from Anhui Province, S. lizipingus Hu Tang, sp. n., and S. fuscus Hu Tang, sp. n. from Sichuan Province, and S. absconditus Hu Tang, sp. n. from Guizhou Province. The diagnostic characters of the new species are illustrated and a published key to Chinese species of the group by Puthz, 2017 is modified to include the new species. Additional records of some species of the group are also provided. PMID- 30313409 TI - Xanthotropis, a new genus in the Neotropical millipede subfamily Aphelidesminae (Diplopoda, Polydesmida, Aphelidesmidae). AB - The monotypic taxon Xanthotropis n. gen. is established to accommodate Haematotropis media Golovatch, Hoffman Spelda, 2004, known only from the vicinity of Manaus, Brazil, as it is incompatible with both its originally assigned genus and Aphelidesmus Brolemann, 1898, a suggested alternative. Xanthotropis is defined primarily by minute teeth on paranota 2-4, a sublinear posterior margin of the telson, and an elongated, distally expanded/laminate acropodite. The Aphelidesmidae Brolemann, 1916, range from northeastern Mexico and Tobago to northern Brazil and southwestern Peru; a questionable more-northerly record, from Monterey, Mexico, requires verification with fresh material. One of two families of the polydesmidan superfamily Platyrhacoidea (Leptodesmidea), Aphelidesmidae comprises two subfamilies, the nominate and Amplininae Hoffman, 1954. The latter has been addressed by several authors, and we here review Aphelidesminae by providing full synonymies, a literature review, and a key to its four genera: Aphelidesmus Brolemann, 1898; Haematotropis and Ochrotropis, both by Jeekel, 2000; and Xanthotropis n. gen. PMID- 30313410 TI - Taxonomy of Euschizomerus Chaudoir 1850 (Coleoptera: Carabidae: Panagaeinae) from India with a new species and new synonym. AB - Description of new species Euschizomerus devagiriensis sp. nov. from south India, synonymisation of Euschizomerus schuhi Kirschenhofer, 2000 with E. indicus Jedlicka, 1955, redescriptions and new records of the earlier reported Indian species with a key to the species are provided. PMID- 30313411 TI - Metrocoris sikkimensis sp. nov. (Hemiptera: Heteroptera: Gerridae) from northeastern India, with a key to species of the compar group occurring in India. AB - Metrocoris sikkimensis sp. nov. is described from Sikkim, northeastern India, compared with similar species, included in an identification key and its geographical distribution is mapped. This species is assigned to the Metrocoris compar group based on the venter of the body entirely blackish and the male fore femur slender and unarmed. It can be distinguished from other species of the group based on the dark mesosternum without yellow markings, by the apically curved male paramere without setae, and by the structure of male endosomal sclerites. PMID- 30313412 TI - A true long horn-a new species of Macronemus Dejean, 1835 (Coleoptera, Cerambycidae, Lamiinae, Acanthoderini) from the Bolivian Andes. AB - A new species of long-horned beetle, Macronemus waxrasapa sp. nov. from Bolivian Yungas forest, is described and illustrated. PMID- 30313413 TI - Nomenclature and synonymic remarks on two species of Eupterotidae (Lepidoptera) described by Johan Christian Fabricius, and notes on related species. AB - Types of two species of monkey moths (Eupterotidae, Lepidoptera) described by Johan Christian Fabricius were located and are here figured for the first time, and lectotypes are designated for both species. The lectotype of Bombyx hibisci Fabricius 1775 is a male from the Hunterian Museum (Glasgow). The lectotype of Bombyx orientalis Fabricius 1793, originally listed from "Dom. Lund" was found in the Zoological Museum-University of Copenhagen (as temporarily loan from the Zoological Museum of Kiel University) with an old incorrect identification label. Both species are members of the genus Eupterote Hubner, 1820 (so-called Brachytera-lineage). The following new synonymy can thus be established: Eupterote orientalis (Fabricius, 1793), comb. nov. (= Dreata geminata Walker 1855, syn. nov., syn. corr.; = Eupterote geminata var. hebes Grunberg 1914, syn. nov.; = Dreata anada Moore 1860, syn. nov., = Brachytera phalaenaria C. R. Felder, 1874, syn. nov., = Eupterote auriflua Moore, 1884, syn. nov.). The type locality for orientalis originally given as "India orientali" is likely to be Sri Lanka. The related taxon, Eupterote gardneri Bryk, 1950, stat. nov. is established as valid species (bona species) with the a new synonym, Eupterote bifasciata Kishida, 1994, syn. nov. Eupterote primularis Moore, 1884 is considered a distinct species native to Central and Southern India. PMID- 30313414 TI - Two new species of rain beetle (Coleoptera: Pleocomidae: Pleocoma Le Conte, 1856) in the Pacific Northwest of the United State of America. AB - A newly discovered population of rain beetles from south central Washington, United States of America is described as Pleocoma laker Marshall, new species. The only other species known from Washington, P. crinita Linsley, 1938, is restricted to include only populations north of the Columbia River. Rain beetles from Oregon, previously considered as P. crinita, are recognized as a distinct species: Pleocoma callisto Marshall, new species. A key to the identification of all described rain beetles in Oregon and Washington is provided. PMID- 30313415 TI - New records of the family Dascillidae (Coleoptera) from China. AB - New geographical records for 13 species of Dascillidae in China are provided, of which two, Dascillus vittatus (Pic, 1914) and D. russus Jin et al., 2013 are new Country records. In addition, we provide 10 new province records for 13 species of Chinese Dascillidae. The Yunnan Province holds the richest generic and species diversity of Dascillinae (3 genera, 20 species). A total of 32 species (74%) are Chinese endemics and Yunnan is also found to be the area with the highest endemicity (13 species). PMID- 30313416 TI - Phylogeny and revised classification of the tribe Elachipterini (Diptera: Chloropidae). AB - The phylogenetic relationships of the chloropid tribe Elachipterini were analysed. Sixty-eight exemplar species and seven outgroup species were included in a cladistic analysis based on 76 morphological characters of adult specimens in order to test existing, non-phylogenetic, classifications of the tribe. Nine genera are recognized in the Elachipterini: Allomedeia Mlynarek Wheeler, Alombus Becker, Anatrichus Loew, Ceratobarys Coquillett, Disciphus Becker, Elachiptera Macquart, Goniaspis Duda, Melanochaeta Bezzi and Sepsidoscinis Hendel. Myrmecosepsis Kertesz is synonymised with Anatrichus, and Togeciphus Nishijima and Cyrtomomyia Becker are synonymised with Elachiptera. Ceratobarys is removed from synonymy with Elachiptera and all Neotropical species and two Nearctic species previously assigned to Elachiptera are transferred to Ceratobarys. Melanochaeta is a valid genus; the type species Melanochaeta capreolus clusters with other species of Melanochaeta and not Oscinella. New combinations include Anatrichus hystrix (Kertesz, 1914) (Myrmecosepsis); Anatrichus taprobane (Andersson, 1977) (Myrmecosepsis), Ceratobarys attenuata (Adams, 1908) (Elachiptera); Ceratobarys cultrata (Wheeler Forrest, 2002) (Elachiptera); Ceratobarys flavida (Williston, 1896) (Elachiptera); Ceratobarys melinifrons (Mlynarek Wheeler, 2008) (Elachiptera); Ceratobarys fucosa (Mlynarek Wheeler, 2008) (Elachiptera); Ceratobarys queposana (Mlynarek Wheeler, 2008) (Elachiptera); Ceratobarys rubida (Becker, 1912) (Elachiptera); Ceratobarys sacculicornis (Enderlein, 1911) (Elachiptera); Ceratobarys willistoni (Sabrosky, 1948) (Elachiptera), Elachiptera ensifer (Sabrosky, 1951) (Cyrtomomyia); Elachiptera ericius (Kanmiya, 1983) (Togeciphus); Elachiptera katoi (Nishijima, 1955) (Togeciphus); Elachiptera maculinervis (Becker, 1910) (Cyrtomomyia); Elachiptera punctulata (Becker, 1912) (Cyrtomomyia); Elachiptera subelongata (Kanmiya, 1983) (Disciphus); Elachiptera truncatus (Liu Yang, 2012) (Togeciphus); Elachiptera tuberculata (Adams, 1905) (Cyrtomomyia) and all the species that were placed in Lasiochaeta are returned to Melanochaeta. A key to genera of the tribe Elachipterini is provided and diagnoses are provided for all genera. The tribe is divided into two geographically distinct clades: the Anatrichus clade includes the Old World tropical genera Allomedeia, Alombus, Anatrichus, Disciphus and Sepsidoscinis; the Elachiptera clade includes the primarily Neotropical genera Goniaspis and Ceratobarys and the widespread, but primarily Holarctic, genera Elachiptera and Melanochaeta. PMID- 30313417 TI - The Lordiphosa denticeps species group (Diptera: Drosophilidae) in China, with redescriptions of four known species and descriptions of nine new species. AB - Based on specimens collected from Yunnan, Xizang, and Taiwan in China, nine new species of the Lordiphosa denticeps species group, L. mikioides sp. nov., L. kimurai sp. nov., L. anthophilia sp. nov., L. yangi sp. nov., L. tibetica sp. nov., L. medogensis sp. nov., L. hamatispina sp. nov., L. secula sp. nov., and L. spatulata sp. nov., were described and four known species, L. denticeps (Okada Sasakawa), L. neokurokawai (Singh Gupta), L. ramula Zhang, and L. tripartita (Okada), were redescribed. In addition, we provided a key to all species of this species group. Males of three new species, L. mikioides, L. kimurai, and L. anthophilia, have distinct sex-combs consisting of black, stout teeth on the 1st and 2nd tarsomeres of foreleg; the large, longitudinal sex-comb on the 1st tarsomere is similar to those seen in the L. miki species group and the subgenus Sophophora Sturtevant of the genus Drosophila Fallen. Two of these and another new species were collected at flowering Impatiens L. (Balsaminaceae) stands: all specimens of L. anthophilia and L. medogensis directly from flowers, and some specimens of L. kimurai by net sweeping. The presence of large, longitudinal sex combs and the flower-visiting habit were reported for the first time in the L. denticeps group. PMID- 30313418 TI - Six new and one known species of Geomonhystera (Nematoda, Monhysteridae) from moss, an epiphytic plant and soil in Mexico and Ecuador. AB - Six new species of Geomonhystera (Nematoda, Monhysterida: Monhysteridae) Andrassy, 1981, are described and illustrated, five from Mexico and one from Ecuador. The new species have many features in common and in common with at least several other species of the genus. Consequently, those features individually are not very useful for species-level diagnosis. They include the cuticular striation which, under light microscopy, ranges from fine to apparently smooth; however, scanning electron micrographs reveal very fine cuticular striation on all the new species. All the new species have a few body setae scattered along the length of the body and the vulval lips of females are slightly protruding. As for other species of the genus, there is considerable overlap in the ranges of standard morphometric characters so a combination of standard and additional morphometrics, as well as qualitative characters, is necessary for species separation. Geomonhystera mexiquense sp. n., collected from moss on a rock and on the trunk of Quercus crassipes in Juchitepec, Mexico State, Mexico, has outer labial setae that are unsegmented and 44-67% of the head width, the cephalic setae are thin, unsegmented and 31-50% of the head width; the vulval lips protrude slightly. Geomonhystera michoacana sp. n., collected from moss on a rock in Tzararacua National Park, Uruapan, Michoacan State, Mexico, has a very finely striated cuticle which appears almost smooth and bears rare cervical and caudal setae; the tail is long, 15-17% of the body length, and the rectum also is long, 23-32 (27+/-2.0) um. Geomonhystera longispiculata sp. n., collected from an epiphytic plant in the botanical garden of the Ecology Institute in Jalapa, Veracruz State, Mexico, is distinguished from all the species of the genus by the long, slender spicules, 55-85 (75+/-3.0) um. The cuticle has conspicuous fine striation and there are somatic setae scattered along the body. Geomonhystera ecuatoriana sp. n., collected from moss on the trunk of Scalesia pedunculata growing on the twin volcanoes of Isla Santa Cruz, Galapagos, Ecuador, has fine cuticular striation and a few small body setae; the unsegmented outer labial setae are 42-54% of the head width and the cephalic setae are thin, unsegmented and 33-45% of the head width; the vulval lips protrude slightly and the vulva anus distance is 37-48 um or 2.1-2.5 times anal body diameter. Males of G. ecuatoriana have slightly arcuate spicules, 35 um long. Geomonhystera galindoi sp. n., collected from moss on the trunk of Quercus peduncularis in San Pablo Ixzayo, Texcoco, Mexico State, Mexico, has fine cuticlar striation and a few fine body setae, the vulval lips are slightly protruding; the vulva-anus distance is 35-50 (41+/-0.9) um, 1.5-2.2 (1.9+/-0.2) times anal body diameter. Males of G. galindoi are slightly ventrally curved with the posterior end strongly curved, giving the body a hook-shaped appearance. Geomonhystera chiautzingoensis sp. n., collected from moss on the trunk of Crataegus mexicana in Chiautzingo, Puebla State, Mexico, has exceedingly fine striation of the cuticle and outer labial and cephalic setae that are less than 50% of the head width. Additionally, G. dubia Siddiqi Shahina, 2004 was sollected in soil samples around a plum tree (Prunus sp.) in the garden of Montecillo Campus, Colegio de Postgraduados, Texcoco, Mexico State, Mexico This species has a small body with fine cuticular striation and a few sparsely-distributed body setae; the outer labial and cephalic setae are unsegmented, 5-8 and 3-5 um long, 56-80% and 33-50% of the head width, respectively; the vulval lips protrude slightly but are sometimes flush with the body contour. PMID- 30313419 TI - Gatesina colombiana n. gen. n. sp. (Hymenoptera: Chalcidoidea, Eurytomidae), new Rileyinae associated with Myrcianthes (Myrtaceae) from Colombia. AB - The Neotropical fauna of Chalcidoidea (Hymenoptera) is poorly known, with numerous undescribed species and even genera. Here, we describe a new genus that also includes a new species that parasitizes Eurytominae gall-formers in fruits of Myrcianthes (Myrtaceae) in Colombia. Its conspicuous morphology supports the description of a new eurytomid genus and species, Gatesina colombiana n. gen. n. sp., belonging to the subfamily Rileyinae. Phylogenetic studies using two matrices of morphological characters as well as molecular data confirm this result. The position of the new genus is close to Neorileya Ashmead according to the phylogenetic analyses. PMID- 30313420 TI - Schistura alboguttata, a new loach species of the family Nemacheilidae (Pisces: Cypriniformes) from the Pearl River basin in Guangxi, South China. AB - Schistura alboguttata, a new species of nemacheilid loach, is herein described from the Leli-He, a tributary flowing to the You-Jiang of the Pearl River basin (Zhu-Jiang in Chinese) at Tianlin County, Guangxi, South China. This new species can be readily distinguished from all other Chinese species of Schistura by its striking body coloration consisting of irregular white spots scattered over the dorsal and lateral regions of the body, with occasional irregular bars with narrow interspaces on the predorsal region. PMID- 30313421 TI - A new subspecies of Zamenis hohenackeri (Strauch, 1873) (Serpentes: Colubridae) based on morphological and molecular data. AB - Based on morphological characteristics, two subspecies of the Transcaucasian rat snake (Zamenis hohenackeri) are currently recognized, namely Z. h. tauricus and Z. h. hohenackeri. Both subspecies are repeatedly considered to be conspecific colour morphs, or have even been confused with Z. situla. Although, few studies involved the Transcaucasian rat snake in a phylogenetic approach, none has so far led to any taxonomic changes. We assessed the intraspecific morphological variation and phylogeographic relationships among specimens from different locations across its updated distribution. Our molecular (1191 bp mtDNA, 565 bp nuDNA) and morphological data provide sufficient evidence to support three distinct lineages within the Z. hohenackeri complex with a different arrangement compared to a previous study. These represent the subspecies Z. h. hohenackeri, Z. h. tauricus, and a lineage from southwestern Turkey which is described as a new subspecies. Aspects of historical biogeography and conservation status are briefly discussed. PMID- 30313422 TI - The genus Sapromyza (Diptera: Lauxaniidae) in Iran with description of three new species. AB - Seventeen species of the genus Sapromyza Fallen occurring in Iran are revised. The following new species are described and illustrated: Sapromyza bernhardi, S. damavandensis and S. sabourii. In addition, S. clathrata Shatalkin, S. kabuli Papp and S. quadripunctata (Linnaeus) are recorded for the first time from Iran. Distribution of species in Iran is reviewed, and a key to the species is provided. PMID- 30313423 TI - A new species of and a new transfer from the millipede genus Polydrepanum Carl, 1932 (Polydesmida, Paradoxosomatidae, Polydrepanini). AB - A new species of Polydrepanum Carl, 1932, is described and illustrated in detail from the Eastern Ghats of India: P. fissum sp. nov. One new combination of species misplaced in Polydrepanum is established: Telodrepanum implicatum (Carl, 1941) comb. nov.. All the nominal Polydrepanum spp. are keyed and the known distribution of the genus is mapped. PMID- 30313424 TI - Status of the name Argolis in Insecta. AB - The purpose of the present notice is to identify and clarify a case of mistaken homonymy surrounding the name Argolis, pertaining to Lepidoptera, Hemiptera, and Coleoptera. It is here demonstrated that "Argolis" (Boisduval 1836: 2) is an incorrect original spelling of Ergolis Boisduval, 1836 (Lepidoptera: Nymphalidae); therefore, Argolis Stal, 1861 (Hemiptera: Reduviidae) is the valid senior synonym of Caunus Stal, 1865, while Argolis Chapuis, 1874 (Coleoptera: Chrysomelidae) remains a junior homonym. The following details summarize the situation:. PMID- 30313425 TI - A new species of the genus Decussobates Cook, 1988 from Argentina, with the first description of the male (Acari: Hydrachnidia: Hygrobatidae). AB - In 1988 Cook described the hygrobatid genus Decussobates from Chile (Cook 1988). The description was based on females only. He described two species of the genus. A new record of the genus from southern Argentina, including males, necessitates an emendation of the description of the genus. The new material from Argentina belongs to a new species, which will be described below. PMID- 30313426 TI - The first Philippine species of Loeblites Franz (Coleoptera: Staphylinidae: Scydmaeninae). AB - Loeblites Franz, 1986 is a genus of Glandulariini with adults sharing a very similar body form and most taxonomically important structures with Syndicus Motschulsky, 1851. One of the most conspicuous differences between these genera is the antennal structure. In Syndicus, the antennomere XI is strongly reduced, much shorter than X and lacks the basal stalk, so that the two terminal antennomeres are compactly assembled. They either form one oval structure that appears as a single antennomere because the base of subconical antennomere XI is as broad as apex of X (Syndicus s. str.) or the antennomere XI forms a distinct small 'papilla' on top of X (subgen. Semisyndicus Jaloszynski, 2004) because the base of antennomere XI is much narrower than apex of X. Adults of Loeblites have unmodified antennae, with the antennomere XI strongly elongate and with a narrow basal stalk; additionally the antennae are strikingly slender, nearly filiform. Morphological structures of both genera were described and illustrated by Jaloszynski (2004, 2005). While Syndicus is species-rich, often abundant in leaf litter and under bark in subtropical forests (Jaloszynski 2004, 2006, 2008, 2009, 2011, 2014; Jaloszynski Nomura 2006; Yin Li 2015; Yin et al. 2014; Yin Zhou 2016; Zhou Yin 2017), and broadly distributed from southeastern Australia, through Southeast Asia, Yunnan (China) and Ryukyus (Japan), up to Sri Lanka, India and the Himalayas, Loeblites comprises merely four species known to occur in Malaysia, Thailand and China (Jaloszynski 2005; Zhou Li 2015). Loeblites mastigicornis Franz, 1986 is known to occur in Chiang Mai (northern Thailand), L. sabahensis Franz, 1992 and L. minor Jaloszynski, 2005 in Sabah (northern Borneo), and L. chinensis Zhou Li, 2015 in Yunnan (southwest China). Two females representing an undescribed species were also recorded from Yunnan by Zhou Li (2015). Specimens of this interesting genus are found rarely, in small numbers and they are typically sifted from leaf litter in subtropical forests. PMID- 30313427 TI - A new species and new records of the genus Oideterus Thomson, 1857 (Coleoptera: Cerambycidae: Prioninae: Anacolini) from Colombia. AB - Oideterus farallonensis sp. nov. is described from Colombia and a detailed photographic record is presented. New locality records for O. andrarius (Galileo, 1987) are provided and a distribution map of the genus Oideterus is presented for the country. PMID- 30313429 TI - Damselflies of the genus Argia (Odonata: Coenagrionidae) from Ecuador with descriptions of five new species. AB - Treinta y una especies de Argia son registradas de Ecuador, de las cuales dos, A. huanacina Forster y A. jocosa Hagen, constituyen nuevos registros para el pais, y cinco son nuevas para la ciencia y son descriptas aqui: Argia acridens n. sp. (Holotipo ?: ECUADOR, Prov. Manabi, 79 km al oeste de Santo Domingo de los Colorados, 0 degrees 20' S, 79 degrees 46' O, 260 m, 7 Mayo 1975, Paul J. Spangler et al. leg., en USNM), Argia cuspidata n. sp. (Holotipo ?: ECUADOR, Prov. Santo Domingo de los Tsachilas: 19 km al este de Santo Domingo de los Colorados, 0 degrees 18'49'' S, 79 degrees 1'44'' O, 740 m, 7 Mayo 1975, A. Langley J. Cohen leg., en USNM), A. philipi n. sp. (Holotipo ?: BOLIVIA, Dept. Cochabamba, Prov. Chapare: arroyo 5 km al sur de Villa Tunari, mediodia, 16 degrees 59'49" S, 65 degrees 24'28" O, 350 m, 4 Noviembre 2001, Jerrell J. Daigle leg., en FSCA), Argia selysi n. sp. (Holotipo ?: ECUADOR, Prov. Napo: Jatun Yacu, Cuenca del Rio Napo, 1 degrees 1' S, 77 degrees 50' O, 700 m, 18 Abril 1935, William Clarke-Macintyre leg., en UMMZ) y A. tennesseni n. sp. (Holotipo ?: ECUADOR, Prov. Orellana: arroyo 8.5 km al este de Loreto, 0 degrees 37' 6" S, 77 degrees 17' 42" O, 360 m, 14 Septiembre 1997, Kenneth J. Tennessen leg., en FSCA). Las nuevas especies son ilustradas y diagnosticadas de sus congeneres, y sus areas de distribucion conocidas son mapeadas. Para ayudar en su identificacion, se proveen tambien ilustraciones y /o mapas de distribucion de especies relacionadas, incluyendo a: A. adamsi Calvert, A. difficilis Selys, A. dives Forster, A. huanacina Forster, A. fulgida Navas, A. infrequentula Fraser, A. jocosa Hagen en Selys, A. joergenseni Ris, A. limitata Navas, A. medullaris Selys, A. orichalcea Hagen en Selys y A. ulmeca Calvert. Argia columbiana Navas y A. rectangula Navas son tratadas como sinonimos junior subjetivos de Argia medullaris Selys. Se proporciona una clave para las ocho especies conocidas metalicas rojas de Argia de America del Sur. PMID- 30313428 TI - Notes on Chasmocarcinus latipes Rathbun, 1898 (Brachyura, Goneplacoidea, Chasmocarcinidae) from the Gulf of California, Mexico. AB - Brachyuran crabs from the Mexican Pacific and surrounding areas are well known and have been treated in several monographs (e.g., Garth 1958; Hendrickx 1997, 1999). Checklists of species occurring off western Mexico and the eastern tropical Pacific are also available (e.g., Hendrickx 1993, 1995, 2005). In many cases, particularly in species inhabiting the continental shelf or deeper waters, however, there is a significant lack of records due to sampling difficulty and cost. PMID- 30313430 TI - American Asteraceae-feeding Astrotischeria species with a highly modified, three lobed valva in the male genitalia (Lepidoptera, Tischeriidae). AB - We review eleven Astrotischeria Puplesis Diskus (Lepidoptera: Tischeriidae) species which possess a novel character for the Tischeriidae family: a highly modified valva of the male genitalia with one ventral and two dorsal lobes (or processes). The species are distributed in the Americas, including the USA, Caribbean (St. Thomas), Central America (Belize, Guatemala and Honduras), and South America (Ecuador, Bolivia, and Brazil). Species for which the biology has been studied are associated with host plants from Asteroidea of the Asteraceae family. The following seven species are described as new: Astrotischeria trilobata Diskus Stonis, sp. nov., A. amazonica Diskus Stonis, sp. nov., A. maya Diskus Stonis, sp. nov., A. selvica Diskus, Carvalho-Filho Stonis, sp. nov., A. casila Diskus Stonis, sp. nov., A. onae Diskus Stonis, sp. nov., and A. furcata Stonis Diskus, sp. nov. A new informal species unit, the A. trilobata group, is designated for diagnostic purposes despite some doubts about monophyly of the group. Astrotischeria longeciliata (Frey Boll) is synonymized here with the North American A. helianthi (Frey Boll), a species not belonging to the A. trilobata group, syn. nov. For the first time, a method of rearing of adults from mining larvae, specifically adopted for Tischeriidae, is detailed. All species treated in the paper are illustrated with photographs or drawings of the adults, male genitalia, and, if available, the female genitalia, leaf mines and habitats. A distribution map for the species of the A. trilobata group and a scheme of the trophic relationships of the global Tischeriidae fauna are also provided. PMID- 30313431 TI - The subgenus Ortmannicus (Decapoda: Cambaridae) in Texas, with descriptions of new species. AB - Three crayfishes of the genus Procambarus, subgenus Ortmannicus, are described from Texas, including (1) Procambarus (Ortmannicus) parvus n. sp. from the Victoria-El Campo region of the Coastal Plain; (2) P. (O.) albaughi n. sp. from the Coastal Plain in the vicinity of Houston; and (3) P. (O.) fayettei n. sp. from the eastern versant of the Colorado River drainage south of Giddings. The three new species, P. (O.) acutus, P. (O.) texanus, and P. (O.) zonangulus form a closely allied group. They are distinguished from each other primarily by characters of the first pleopod. The subspecies P. (O.) acutus acutus and P. (O.) a. cuevachicae are elevated to full species. Species accounts are provided for all Texas subgenus members and may include diagnoses, color notes, size data, locality data, life history notes, listings of associates, and information on variation and relationships. A key to the species of Ortmannicus in Texas is also presented. PMID- 30313432 TI - A molecular phylogenetic hypothesis for the Asian agamid lizard genus Phrynocephalus reveals discrete biogeographic clades implicated by plate tectonics. AB - Phylogenetic relationships of the agamid lizard genus Phrynocephalus are described in the context of plate tectonics. A near comprehensive taxon sampling reports three data sets: (1) mitochondrial DNA from ND1 to COI (3' end of ND1, tRNAGln, tRNAIle, tRNAMet, ND2, tRNATrp, tRNAAla, tRNAAsn, tRNACys, tRNATyr, and the 5' end of COI) with 1761 aligned positional sites (1595 included, 839 informative), (2) nuclear RAG-1 DNA with 2760 aligned positional sites (342 informative), and (3) 25 informative allozyme loci with 213 alleles (107 informative when coded as presence/absence). It is hypothesized that Phrynocephalus phyletic patterns and speciation reflect fault lines of ancient plates now in Asia rejuvenated by the more recent Indian and Arabian plate collisions. Molecular estimates of lineage splits are highly congruent with geologic dates from the literature. A southern origin for the genus in Southwest Asia is resolved in phylogenetic estimates and a northern origin is statistically rejected. On the basis of monophyly and molecular evidence several taxa previously recognized as subspecies are recognized as species: P. hongyuanensis, P. sogdianus, and P. strauchi as "Current Status"; Phrynocephalus bannikovi, Phrynocephalus longicaudatus, Phrynocephalus turcomanus, and Phrynocephalus vindumi are formally "New Status". Phylogenetic evaluation indicates a soft substrate habitat of sand for the shared ancestor of modern Phrynocephalus. Size diversity maximally overlaps in the Caspian Basin and northwestern Iranian Plateau. The greatest species numbers of six in sympatry and regional allopatry are found in the southern Caspian Basin and southern Helmand Basin, both from numerous phylogenetic lineages in close proximity attributed to tectonic induced events. PMID- 30313434 TI - Deep Sea and Cave Sponges (Table of contents). AB - N/A. PMID- 30313433 TI - Deep Sea and Cave Sponges (Cover Copyright page). AB - N/A. PMID- 30313435 TI - Preface. AB - A volume on Atlantic-Mediterranean deep-sea and cave sponges dedicated to Klaus Rutzler and Jean Vacelet to celebrate the publication, sixty years ago, of the first works on the biodiversity of marine caves (Laborel Vacelet 1958; Russ Rutzler 1959). PMID- 30313437 TI - A new cave-dwelling species of Plakina (Porifera: Homoscleromorpha) from Crete, Greece (South Aegean Sea). AB - Recent studies showed a high diversity of the class Homoscleromorpha (Porifera) in the North Aegean Sea. In the South Aegean Sea, however, only one species of the homoscleromorph genus Plakina, P. weinbergi, was reported so far. Here we describe a new species of Plakina from a marine cave in the South Aegean Sea (Crete Island, Greece), viz., Plakina strongylata sp. nov. The new species is white, fragile, with a highly folded surface, and its spicules are diods, triods and calthrops with rounded extremities plus mono- and dilophose diods, mono-, di- and trilophose triods, and mono-, di, tri- and tetralophose calthrops. The number of Plakina species worldwide is raised to 35, of which nine occur in the Aegean Sea. PMID- 30313436 TI - New sciaphilic plakinids (Porifera, Homoscleromorpha) from the Central-Western Pacific. AB - The sponge class Homoscleromorpha is a key model for the evolutionary biology of the Metazoa but its diversity remains poorly known. Here we describe six new species of the homoscleromorph family Plakinidae found in shaded habitats (submarine caves, tunnels and overhangs) of New Caledonia and Marquesas Islands, Central-Western Pacific. The new species belong to four genera: Corticium (Corticium vaceleti sp. nov.), Plakina (Plakina finispinata sp. nov.), Plakinastrella (Plakinastrella osculifera sp. nov., Plakinastrella nicoleae sp. nov. and Plakinastrella pseudolopha sp. nov.), and Plakortis (Plakortis ruetzleri sp. nov.). Plakinastrella pseudolopha sp. nov. has a novel spicule type called here 'pseudolophose spicules'. The diversity of Homoscleromorpha is raised to 50 species in the Pacific Ocean and 120 spp. worldwide. PMID- 30313438 TI - Mycale (Oxymycale) klausjanusorum sp. nov. (Porifera: Demospongiae: Poecilosclerida) from Flores Sea deep water, Indonesia. AB - A new species of the large genus Mycale Gray, 1867 is described, dredged from approximately 300 m depth in the Flores Sea region between the islands of Salayar and Bahuluang, Central Indonesia, during cruises of the Indonesian-Dutch Snellius II Expedition in 1984. Because its megascleres include oxeas the new species is classified as a member of the subgenus Oxymycale Hentschel, 1929, proposed to be named M. (O.) klausjanusorum sp. nov. to honour renowned colleagues Klaus Rutzler and Jean ('Janus') Vacelet. It is characterized by an ectosomal skeleton consisting of bouquets of subtylostyle megascleres protruding beyond an ectosomal tangential confused layer of oxeas, which in turn rests on robust choanosomal bundles of mixed oxea and subtylostyle megascleres. The combination of two categories of megascleres, differentiated not only in size but also in morphology, the larger one of which is arranged in ectosomal bouquets, is a unique feature in the genus Mycale. A high diversity of the microscleres and large upper size of the anisochelae (up to 189 um) are additional features of the new species. The subgenus Oxymycale is reviewed and its status as a monophyletic group of Mycale is discussed. PMID- 30313440 TI - Two new Hamacantha (Vomerula) from the Rio Grande Rise (SW Atlantic (Hamacanthidae, Porifera). AB - Hamacantha occurs worldwide and frequently in deep-waters. It is easily distinguished from any other sponge by the possession of conspicuous diancistra microscleres. Here we describe two new species from the Rio Grande Rise. Hamacantha (Vomerula) jeanvaceleti sp. nov. is the sole Hamacantha with styles, diancistras in two categories with the smaller ones cyrtancistra-like; and H. (V.) klausruetzleri sp. nov., the sole with two types of megascleres (styles and strongyles), two categories of diancistras, and two categories of sigmas. PMID- 30313439 TI - A new species of Hymeraphia Bowerbank, 1864 (Axinellida: Raspailiidae) from a deep-water canyon southwest off Ireland. AB - The genus Hymeraphia currently comprises three species and all records of the genus are from the northeast Atlantic and the Mediterranean Sea. The present paper describes a new species, H. vaceleti sp. nov. from a deep-water canyon, off southwest Ireland. H. vaceleti sp. nov. is morphologically distinct from other Hymeraphia species and 28S rRNA sequences show substantial differences between our new species and other Hymeraphia spp. We present data on the prevalence of sponge species established on the basis of single specimens (singletons) or uniques (species only known from a single locality). We argue for the recognition of singletons for species that are rare or from habitats that are very difficult to survey or sample, such as the deep sea. PMID- 30313441 TI - Mesophotic sponges of the genus Callyspongia (Demospongiae, Haplosclerida) from Cuba, with the description of two new species. AB - This study presents the description of two Callyspongia species new to science, and the distribution of all Callyspongia species recorded during the first joint Cuba-U.S. expedition to characterize Cuban mesophotic coral ecosystems (May-June 2017). Additionally, we propose a key to identify thin branching species of the genus in the Greater Caribbean. The observations here presented are the result of underwater explorations with the Mohawk Remotely Operated Vehicle dives at 35 sites around the island, at depths of 25-188 m, recording images and videos, and collecting specimens. The depth range of five species of Callyspongia, reported before in Cuba, has been extended to deeper waters. Two specimens of branching Callyspongia were collected and described: Callyspongia (Callyspongia) pedroi sp. nov. and Callyspongia (Cladochalina) alcoladoi sp. nov. Morphometric comparisons of external and skeletal traits show clear differences with the other Callyspongia species from the Central West Atlantic with a similar thin branching habit. Callyspongia (C.) pedroi sp. nov. consists of pinkish delicate cylindrical microconulose branches (3-6 mm in diameter, 10-14 cm long) that rarely anastomose, with relatively large oval oscules (1-3 mm in diameter), and a skeleton dominated by primary and secondary fiber reticulations, discretely cored by fusiform oxeas. Callyspongia (C.) alcoladoi sp. nov. consists of grayish, smooth thin branches (3-8 mm in diameter, 20-30 cm long), profusely dividing and occasionally anastomosing, with few spiny projections (2-4 mm wide, 2-4 cm long). Its skeleton includes a highly developed ectosomal tertiary reticulation within the secondary and primary reticulation, and fibers discretely cored by predominant mucronate oxeas. Clear morphometric differences of spicules and their skeletal reticulation distinguish these species from the other six thinly branching Callyspongia species known from the Caribbean. PMID- 30313442 TI - Sponge grounds of Artemisina (Porifera, Demospongiae) in the Iberian Peninsula, ecological characterization by ROV techniques. AB - Artemisina Vosmaer, 1885 is a poecilosclerid microcionoid sponge genus with 20 valid species, seven of which have been recorded in the Atlantic Ocean.The present study describes Artemisina sponge grounds in Iberia Peninsula. A. transiens is a sponge described in 1890 by Topsent in Galicia (Spain); A. hispanica was also collected in the north of Spain by Ferrer-Hernandez (1917); World Porifera Database (WPD) considers at the moment both mushroom-shaped species as synonyms (van Soest et al., 2018), but we have only been able to check the types of A. hispanica. The studied samples were collected in Somos Llungo station and they correspond clearly to those described as A. hispanica by Ferrer Hernandez (1917) and it presents differences in the skeleton with respet to description of A. transiens in the literture. There are no more records after 1917 and there are no data of ecological characterisation nor is there a detailed description of its skeletal composition with Scanning Electron Microscopy. In the previous records the formation of sponge grounds of these species was not known. Oceana, the largest international organization focused solely on protecting the world's oceans, has recorded the habitat of Artemisina in Atlantic and Cantabrian waters during a series of ROV cruises for the identification of marine areas with high ecological value that need protection. Its life conditions and associated fauna are described from direct observations for the first time. PMID- 30313443 TI - Four new species of Hexactinellida (Porifera) and a name replacement from the NE Pacific. AB - Four new species of Hexactinellida are described from the northwest coast of North America. Two northern ones from bottom longline sablefish traps set on Bowie Seamount off northwest Canada are Pinulasma bowiensis and Rhabdocalyptus trichotis. Two southern forms picked by ROV from the wreck of USS Independence off San Francisco, California are Staurocalyptus pamelaturnerae and Hyalascus farallonensis. A fifth specimen from the southern site is considered conspecific with the junior homonym Farrea aculeata Schulze, and allowed renaming of that species as Farrea schulzei. These additions bring the number of Hexactinellida known from the area (30o-90o N) to 62 species. PMID- 30313444 TI - Two new species of Sympagella (Porifera: Hexactinellida: Rossellidae) collected from the Clarion-Clipperton Zone, East Pacific. AB - Two new Hexactinellida species from the Clarion-Clipperton Zone (CCZ) in the East Pacific Ocean are described. They are the first described representatives of the genus Sympagella in this region. The new sponges were collected in 2013 during the ABYSSLINE Project's first cruise, AB01, on board the RV Melville. The CCZ is known for its polymetallic nodules but megafaunal biodiversity is still poorly understood. Our findings suggest that the poriferan fauna of the eastern CCZ is both species rich and inadequately known, and that substantially more sampling and taxonomic studies of the CCZ sponge fauna are required to establish a megafaunal biogeography and evaluate potential extinction risks resulting from polymetallic-nodule mining. PMID- 30313445 TI - Abyssocladia vaceleti (Porifera, Cladorhizidae): a new deep-sea carnivorous sponge from Patagonia. AB - This study describes a new species of carnivorous sponge (Family Cladorhizidae) collected in Patagonia, SW Atlantic, off Argentinean waters and the North of the Falkland Islands (Malvinas). The species described here, belongs to the genus Abyssocladia and was collected by dredging and trawling during IEO (Spanish Institute of Oceanography) cruises in the South West Atlantic Ocean from 2007 to 2010 under the Atlantis Project. Abyssocladia vaceleti sp. nov. is characterised by the possession of a long peduncle and flat body with bilaterally symmetrical and apical filaments with a skeleton of tornotes (often polytylotes), styles, abyssochelae, arcuate chelae, sigmancistras and acanthotylostrongyles. This species lives at depths of 901-1547 m. PMID- 30313446 TI - From marine caves to the deep sea, a new look at Caminella (Demospongiae, Geodiidae) in the Atlanto-Mediterranean region. AB - Caminella Lendenfeld, 1894 is a poorly known Geodiidae genus with unclear phylogenetic relationships. In order to find new lines of evidence that could shed light on the evolutionary history of Caminella, we decided to revise type material and museum material, as well as examine new material from underwater caves and deep-sea ecosystems. In doing so, we formally show that Isops maculosus Vosmaer, 1894 and Caminella loricata Lendenfeld, 1894 are junior synonyms of Caminella intuta (Topsent, 1892). We discuss different spicule morphological phenotypes in C. intuta, which may be linked to silica availability. We also discovered two new species of deep-sea Caminella: 1) from Cape Verde (Caminella caboverdensis sp. nov.) and 2) from seamounts located south of the Azores archipelago and the North of Spain (Caminella pustula sp. nov.). We reveal that Caminella sterrasters have complex surface microstructures, unique amongst the Geodiidae, where actin tips are linked to each other. Molecular markers (COI, 28S (C1-D2) and 18S) sequenced for some specimens led to new phylogenetic analyses, which continue to suggest a close relationship of Caminella with the Erylinae and Calthropella; these affinities are discussed in light of morphological characters. PMID- 30313447 TI - When is an aster not an aster? A new deep-sea Discorhabdella (Demospongiae, Poecilosclerida) with asters, from the Mozambique Channel. AB - Discorhabdella pseudaster n. sp. is an incrusting sponge from the upper bathyal zone of the 'Banc du Geyser', north of Madagascar, Mozambique Channel. This new species is described only from a single specimen but it is remarkable by the presence of spicules similar to euasters, a type of microsclere unknown in Poecilosclerida. These spicules are in fact a new example of homoplasy, being derivatives of the typical Discorhabdella pseudoastrose acanthostyles, which are here reduced to the aster-like tyles. The isochelae with a large lamella on the shaft are also quite unique in Poeciloclerida. PMID- 30313448 TI - Sponge inventory of the French Mediterranean waters, with an emphasis on cave dwelling species. AB - Mediterranean sponges represent about 10 % of the world sponge biodiversity, with these sessile organisms dominating in terms of diversity and biomass in most of the rocky bottoms shaded from light. After 60 years of intensive study of the sponge diversity along the French coast, we present the first comprehensive reference-list for this biogeographic area. A total of 389 sponge species was recorded, of which 222 known in the Marseille region. In this area, special attention was paid to species from underwater caves. Although this particular habitat appeared as one of the richest, a wealth of hidden diversity still requires description. About 37 % of the sponge diversity can be found in underwater caves, most of these species being also distributed in other habitats. However, 23 % of this sponge diversity is cave-exclusive. An easy and rapid assessment method was developed with a selection of 65 representative sponge species, for the monitoring of semi-dark cave communities. This method, based on data acquisition with photoquadrats and their processing using a DataBase built with ACCESS, was deployed in 13 studied sites. Altogether, this study represents a useful contribution for marine environment managers who might refer to this French reference list and apply the rapid and easy assessment method in the framework of several European Directives and international Conventions. PMID- 30313449 TI - New Poecilosclerida from mesophotic coral reefs and the deep-sea escarpment in the Pulley Ridge region, eastern Gulf of Mexico: Discorhabdella ruetzleri n.sp. (Crambeidae) and Hymedesmia (Hymedesmia) vaceleti n.sp. (Hymedesmiidae). AB - Pulley Ridge, a limestone ridge that extends nearly 300 km along the southwestern Florida shelf in the eastern Gulf of Mexico, supports a mesophotic coral ecosystem (59 to 94 m deep), surrounded by deeper waters. An ongoing evaluation of Porifera biodiversity observed and collected during expeditions by Harbor Branch Oceanographic Institute (2003-2015) have shown the existence of approximately 102 sponge species, with at least 20 species new to science. The present paper describes two novel Poecilosclerida from mesophotic reefs and deep escarpments in the Pulley Ridge Region, Eastern Gulf of Mexico, namely Discorhabdella ruetzleri n.sp. (Crambeidae, Poecilosclerida) and Hymedesmia (Hymedesmia) vaceleti n. sp. (Hymedesmiidae, Poecilosclerida). This is the first record of Discorhabdella for the greater Caribbean and the Central West Atlantic. The skeleton of D. ruetzleri n.sp. includes the unique pseudoastrose acanthostyles of the genus, and it is distinct from congeners in the size ranges of the megascleres and in the occurrence of predominantly smooth instead of tuberose choanosomal and ectosomal subtylostyles. The intense blue color and the spicule combination of Hymesdesmia (H.) vaceleti n.sp. makes this species unique among other Hymedesmia spp. from the western Atlantic. The discovery represents a considerable expansion in the known biogeographical distribution of the genus Discorhabdella which is represented now by six species with a discrete geographic distribution (New Zealand, Azores, Western Mediterranean Sea, Eastern Pacific in Panama). This work is the first contribution to an ongoing effort to discover and document the importance of sponge biodiversity on mesophotic reefs and associated deep-water habitats in the Gulf of Mexico and the Caribbean. PMID- 30313450 TI - The Muscidae (Diptera) of Armenia. AB - A report is given on the Muscidae (Diptera) collected in Armenia during recent fieldwork. Locality data, Armenian distribution and general distribution are given for each species, including references to previously published records. 181 named species are listed, of which 93 are newly recorded from Armenia, and 15 are endemic (8%). Two new species are described: Thricops iliata sp. nov. and Phaonia gayaneae sp. nov. PMID- 30313451 TI - Checklist of the mites of Pakistan. AB - We present the first comprehensive inventory of the mites of Pakistan, based on data from published books and papers. The fauna as presently understood includes 126 families, 316 genera, and 1105 species. The best-documented genera are those that include pests of stored food (for example Acotyledon, 28 species), plant pests (Brevipalpus, 49 species; Tenuipalpus, 35 species), and beneficial predators (Euseius, 44 species; Neoseiulus, 37 species; Phytoseius, 36 species; Typhlodromus, 47 species). Some economically important families such as the Eriophyidae are almost completely unknown. Some of the Cryptostigmata have been studied, but other groups of soil mites are very poorly known. Other large groups such as the feather mites, water mites, Uropodina, and parasitic Astigmata and Prostigmata, have not been studied in a systematic way. An increase in knowledge of these groups would help an assessment of their economic importance, and would make a valuable contribution to the biogeography of the western section of the Oriental Region and the southern section of the Palaearctic Region. PMID- 30313452 TI - On the Neotropical spider Subfamily Masteriinae (Araneae, Dipluridae). AB - The Neotropical species of the diplurid subfamily Masteriinae are revised and redefined. Masteriinae now comprises four genera, Masteria L. Koch, 1893, Striamea Raven, 1981, a new genus, Siremata n. gen. and Edwa Raven, 2015, a fossil genus. The type species, Masteria hirsuta L. Koch, 1893, was used as basis for comparison and the knowledge of the genus has increased. Twelve species of Masteria are redescribed and eight new species are described: M. amarumayu n. sp. and M. mutum n. sp., from Brazil; M. yacambu n. sp., from Venezuela; M. sabrinae n. sp., from Martinique; M. tayrona n. sp., from Colombia; M. aguaruna n. sp., from Peru, M. soucouyant n. sp., from Trinidad and Tobago; and M. galipote n. sp., from the Dominican Republic. Females of Masteria aimeae (Alayon, 1995) and M. golovatchi Alayon, 1995 are described for the first time. Females of M. spinosa (Petrunkevitch, 1925), M. petrunkevitchi (Chickering, 1964), M. lewisi (Chickering, 1964), M. barona (Chickering, 1966), M. downeyi (Chickering, 1966), M. simla (Chickering, 1966), M. colombiensis Raven, 1981 and M. pecki Gertsch, 1982 are illustrated for the first time and rediagnosed. Masteria tovarensis (Simon, 1889) and M. cyclops (Simon, 1889) are synonymized with M. lucifuga (Simon, 1889). Masteria modesta (Simon, 1892) is considered as species inquirendae and M. emboaba Pedroso, Baptista Bertani, 2015 is considered as incertae sedis, as the type is lost. Both species of Striamea are revised and redescribed. A new genus, Siremata n. gen., is described and includes three Amazonian species: S. valteri n. sp., S. juruti n. sp., S. lucasae n. sp. Knowledge of the distribution ranges of the Neotropical Masteriinae are increased. PMID- 30313453 TI - Review of Poecilimon species with inflated pronotum: description of four new taxa within an acoustically diverse group. AB - Poecilimon Fischer (Orthoptera, Tettigoniidae) consists of about 130 species and a functional taxonomy of the genus requires arranging species into phylogenetic groups. However, this is a task that requires detailed empirical testing. This paper documents data on Poecilimon species with an inflated pronotum. The Poecilimon (Poecilimon) inflatus group is a lineage ranging along a narrow zone in the south-west corner of Anatolia and in Crete plus some other Aegean islands. By producing data of morphology and calling songs of males and responding songs of females the composition and intra-group diversity of P. inflatus group are studied. Both morphology and male calling and female responding songs, exhibited a considerable intra-group diversity. In the light of data obtained the following nomenclatural changes were made. The genus Parapoecilimon Karabag, 1975 syn. n. is synonymised with Poecilimon Fischer and Parapoecilimon antalyaensis Karabag, 1975 is given a new combination, Poecilimon antalyaensis (Karabag, 1975) comb. n. Four new taxa are described in the group: (i) Poecilimon isopterus sp.n.; (ii) Poecilimon inflatus lyciae subsp. n.; (iii) Poecilimon antalyaensis myrae subsp. n., and (iv) Poecilimon antalyaensis anemurium subsp. n. The Poecilimon (P.) inflatus species group consists of the following species: (i) Poecilimon inflatus Brunner von Wattenwyl, 1891; (ii) Poecilimon martinae Heller, 2004; (iii) Poecilimon cretensis Werner, 1903; (iv) Poecilimon antalyaensis (Karabag, 1975) comb. n.; (v) Poecilimon bilgeri Karabag, 1953 and (vi) Poecilimon isopterus sp.n. The species group is defined by a combination of characters including the pronotum inflated in metazona and a male cerci mostly black in their apical 1/2 1/3. The male calling song has typically two types of short syllables and the females respond acoustically with very short latency times. By using combination of morphology and song data we suggest three main lineages in the group: (i) P. bilgeri, (ii) P. antalyaensis and (iii) the other four species. PMID- 30313454 TI - New records of one of the least known snakes, Telescopus pulcher (Squamata: Colubridae) from the Horn of Africa. AB - Telescopus pulcher is an enigmatic colubrid snake only known from the holotype and paratype specimens described from 'Migiurtinia' in Puntland (Somalia) in 1935. Herein we recorded the third and fourth-ever known specimens of this species from the Toon village, Woqooyi Galbeed Region, and 15 km southeast of Sheikh, Saahil Region, Somaliland. The species is endemic to Somaliland and adjoining parts of Ethiopia and Puntland. Data on morphology and natural history, as well as the first photographs of live specimens are provided. We also provide a detailed description of the paratype. The coloration of the species resembles that of the vipers of the genus Echis and we hypothesize that T. pulcher mimics these common and sympatric vipers in the Horn of Africa. PMID- 30313455 TI - Contribution to the knowledge on the spider wasps genus Morochares Banks, 1934 (Hymenoptera: Pompilidae) from China. AB - Five species of the genus Morochares Banks, 1934 are reported from China, four of them are described and illustrated as new species: M. sinica Loktionov Lelej, sp. nov. (Guangdong, Hainan), M. wahisi Loktionov Lelej, sp. nov. (Hainan), M. wolfi Loktionov Lelej, sp. nov. (Guangdong) and M. xuzaifui Loktionov, Lelej Liu, sp. nov. (Zhejiang, Guangdong). The genus Morochares is newly recorded from mainland China. A key to the females of the Chinese species is given. PMID- 30313456 TI - DNA analysis of a non-native lineage of Sinanodonta woodiana species complex (Bivalvia: Unionidae) from Middle Asia supports the Chinese origin of the European invaders. AB - The Sinanodonta woodiana species complex includes several cryptic species-level phylogenetic lineages, the taxonomic placement of which is unclear. Here, we present the results of molecular analyses of a Sinanodonta sample from Middle Asia (Uzbekistan). The COI haplotype of the Uzbekistan lineage is similar to those of invasive Sinanodonta populations from Europe, Russia and Myanmar. We show that the non-native Sinanodonta flocks in Europe and Middle Asia originated from a single source population in China. Our results reveal that the Sinanodonta woodiana species complex comprises at least six distinct biological species: S. cf. gibba (=temperate invasive lineage), S. cf. woodiana (=tropical invasive lineage), S. schrenkii (=S. amurensis), S. ovata, S. jourdyi, and S. lucida, and two phylogenetic lineages with uncertain taxonomic names. PMID- 30313457 TI - DNA barcoding and an updated key to the genus Hesperentomon (Protura: Acerentomata: Hesperentomidae), with a new species from Northwest China. AB - Hesperentomon bolense sp. n., described from Northwest China, is distinguished from other Hesperentomon spp. by having foretarsal sensillum b clearly shorter than c, a robust sensillum c broader than the other foretarsal sensilla, 18 posterior setae on the mesonotum and 16 posterior setae on the metanotum, 12 posterior setae on urotergites II-VI (P1a and P2a absent), 8 posterior setae on urosternites IV-VI (Pc absent), and absence of seta P2a on urotergite VII. The morphological characters of all described species of Hesperentomon are compared, and an updated identification key to species is given. The DNA barcodes of H. bolense sp. n. were compared to similar species of the genus; the K2P genetic divergences were 0-5.1% between individuals of H. bolense sp. n., but 21.4%-27.3% between H. bolense sp. n. and other congeneric species. The molecular data further confirmed H. bolense as a distinct species. PMID- 30313458 TI - Cold-water corals off Angola as refuge for a new Aeginella species (Crustacea: Amphipoda: Caprellidae). AB - A new species of caprellid amphipod, Aeginella corallina sp. nov., is described from cold-water corals off Angola. This is the first observation of this genus in the South-Atlantic. The taxon is fully described and figured and is compared with the only known species of the genus, A. spinosa, occurring in deep waters of the northern hemisphere. Both species can be clearly differentiated on the basis of the following characters: (1) pereonite 1 is provided with a large dorsal acute projection in A. spinosa, while this projection is lacking in A. corallina; (2) gnathopod 2 propodus has an acute projection distally which is lacking in A. corallina; (3) the palm of the gnathopod 2 propodus in males is densely setose and it is provided with two distal projections in A. corallina while it is scarcely setose and with less developed projections in A. spinosa; (4) distal article of the mandibular palp is provided by a setal formula of 1-x-1, being x=10-12, in A. spinosa, while in A. corallina x=2-3, and the formula 1-x-1 is not so evident and it could be considered as 1-x-0. (Zoobank: urn:lsid:zoobank.org:act:3D7EB67D-88F2-40D8-99C1-7D62F44F7163). PMID- 30313459 TI - Review of the genus Hylcalosia Fischer (Hymenoptera, Braconidae, Alysiinae), with description of four new species from China. AB - Four new species of Hylcalosia Fischer are described and illustrated from China, i.e., H. carinata sp. nov., H. melasaraia sp. nov., H. poricrenulata sp. nov., and H. verticalis sp. nov. Hylcalosia sutchanica Belokobylskij, 1992, is a new record for China. A key to the known species of Hylcalosia Fischer is provided. PMID- 30313460 TI - First record of Trochochaeta japonica (Annelida: Spionidae) in Brazil with identification key to species of the genus. AB - Polychaetes of the spionid genus Trochochaeta occur mainly in the northern hemisphere, including North and Central America. In South America, they have been reported only from the northeast region of Brazil - Sergipe and Paraiba - despite numerous biological investigations around the continent. In 2006, a dense population (up to 7000 individuals per square meter) of Trochochaeta was discovered in the estuary of Santos, Sao Paulo, Brazil, hosting the busiest container sea port in Latin America, and in 2008, one Trochochaeta specimen was found in Camamu Bay, Bahia. We identify these worms as Trochochaeta japonica Imajima, 1989 and describe and illustrate their morphology. This is the first record of the species from outside of its type locality in Honshu, Japan. It might have been introduced to the estuary of Santos as larvae in ballast water of ocean-going vessels. We review the systematics of Trochochaeta and provide an identification key to 12 currently recognized species. PMID- 30313461 TI - Notes on the taxonomy of poorly known Gryllacrididae (Stenopelmatoidea) from Brunei Darussalam, Borneo. AB - Gryllacrididae, or raspy crickets, belong to the monophyletic clade Stenopelmatoidea, and have complex taxonomy. Many genera require revision, including the ones from Southeast Asia. Orthopteran surveys in Kuala Belalong, Brunei Darussalam, Borneo led to the discovery of a new species of apterous gryllacridid from Brunei Darussalam: Melaneremus? bellus sp. nov. We also redescribe Phlebogryllacris venosa (Walker, 1869) and provide images of this species of both live and preserved specimens. In the process of describing, specimens from morphologically similar genera were also examined. We provide some notes on these genera to aid future taxonomic studies. PMID- 30313462 TI - Contribution to the genus Okinawepipona Yamane (Hymenoptera: Vespidae: Eumeninae) from Vietnam, with description of a new species. AB - A new species of the genus Okinawepipona Yamane from Vietnam is described and figured: Okinawepipona yty Nguyen, sp. nov. (northern Vietnam). Biology of O. yty Nguyen, sp. nov. and O. nigra Nguyen Xu, 2014 is recorded. A key to the four species known in the genus is provided. PMID- 30313463 TI - Erratum: NOPPADON MAKBUN GUNTHER FLECK (2018) Description of Microgomphus farrelli sp. nov. (Odonata: Anisoptera: Gomphidae) based on adults of both sexes and larvae from Northern Thailand. Zootaxa, 4422: 442-450. PMID- 30313464 TI - New records of aturid water mites from Australia (Acari: Hydrachnidia; Aturidae), with the description of fifteen new species. AB - The following fifteen new species are described of the water mite family Aturidae from Australia: Austraturus cavatus n. sp., A. denticulatus n. sp., A. dilatipalpis n. sp., A. extendens n. sp., A. sagittalis n. sp., A. triprojectus n. sp., A. villosus n. sp. and Axonopsella bipartita n. sp., A. carnarvon n. sp., A. curtiseta n. sp., A. elongata n. sp., A. kakadu n. sp., A. magniseta n. sp., A. purpurea n. sp. and A. rosea n. sp.. New records are given for Queensland, South Australia, Tasmania, Victoria, New South Wales, Northern Territory and Western Australia. New distributional records are provided for many species. PMID- 30313465 TI - Alburnus goekhani, a new species of bleak from the Anatolian Black Sea basin (Teleostei: Leuciscidae). AB - Alburnus goekhani, new species, is described from the Yesilirmak and Kizilirmak River drainages. It belongs to the A. alburnus species group and is distinguished from other species in this group in Anatolia by having 48-56 + 2-3 scales in the lateral-line, 12-15 gill rakers, a distinct dark lateral stripe along the flank on live and preserved specimens and the anal-fin origin situated below the branched dorsal-fin ray 6-8. Alburnus goekhani is also well distinguished from other Alburnus species by its DNA barcode sequence. PMID- 30313466 TI - Tersilochinae (Hymenoptera: Ichneumonidae) from New Zealand. Part 1. Generic key and three new genera. AB - The Tersilochinae (Ichneumonidae) from New Zealand are revised in part, with three new endemic genera and seventeen new species described: Aotearoazeus gen. nov., A. bullivantus sp. nov., A. coronetus sp. nov., A. probles sp. nov., Barycnellus gen. nov., B. aucklandellus sp. nov., B. conlisus sp. nov., B. cuvierensis sp. nov., B. globosus sp. nov., B. robustus sp. nov., Diaparsis zealandica sp. nov., Gauldiana gen. nov., G. arantia sp. nov., G. aspiringa sp. nov., G. dubia sp. nov., G. kaweka sp. nov., G. minuta sp. nov., G. nigra sp. nov., G. rotoitia sp. nov., and G. triangulata sp. nov. Zealochus postfurcalis is transferred to the genus Gauldiana (comb. nov.). The genus Diaparsis is recorded from New Zealand for the first time. Keys to genera and species of Tersilochinae occurring in New Zealand are provided. PMID- 30313467 TI - Three new species of the Neotropical genus Phyllotingis (Hemiptera: Heteroptera: Aradidae). AB - Three new species of Phyllotingis Walker, 1873 (Hemiptera: Heteroptera: Aradidae), Ph. tortugueria sp. nov. and Ph. costaricana sp. nov.from Costa Rica (representing a new generic record for the country), and Ph. moraguesi sp.nov. from French Guyana are described and illustrated. A key to all species of Phyllotingis is presented. PMID- 30313468 TI - Two new Tytthoscincus Linkem, Diesmos, Brown (Squamata; Scincidae) from Peninsular Malaysia and another case of microsyntopy between ecologically specialized, unrelated, leaf-litter species. AB - Two new species of diminutive, sympatric, lowland, leaf-litter skinks of the genus Tytthoscincus Linkem, Diesmos Brown from the Sekayu region of Hulu Terengganu, Terengganu State in northeastern Peninsular Malaysia are described on the basis genetic and morphological data. One of the new species, T. monticolus sp. nov., was collected in a hilly riparian area along Sungai (=river) Bubu and is most closely related to an undescribed species from the Tembak Reservoir area. The other, T. keciktuek sp. nov. collected along Sungai Peres, is most closely related to T. perhentianensis Grismer, Wood, Grismer from Pulau (=island) Perhentian Besar. Sympatry and syntopy of multiple, specialized, unrelated, leaf litter species of Tytthoscincus was previously only known from upland areas and these new species represent the first example of lowland of sympatry. More importantly, however, these endemic species add to a growing body of research and discoveries that continue to underscore the unrealized biodiversity of the riparian systems of Hulu Terengganu and the Sekayu region and their need for protection and continued study. PMID- 30313469 TI - Three new species of Lecithocera Herrich-Shaffer, 1853 (Lepidoptera, Lecithoceridae) from Taiwan, with a check list of the genus in Taiwan. AB - Three new species of Lecithocera Herrich-Shaffer, 1853; L. quadratiella sp. nov., L. nantouensis sp. nov., and L. meishanensis sp. nov., are described from Taiwan. External and genital features of the new species are illustrated. A check list of the known species of Lecithocera in Taiwan is provided. PMID- 30313470 TI - Taxonomic notes on Papilio ocypete Fabricius, 1776 and Papilio helle Cramer, 1779 with description of two new similar species from South America (Lepidoptera: Nymphalidae: Satyrinae). AB - The discovery of a new species of satyrine butterfly, Magneuptychia louisammour Benmesbah Zacca, sp. n., that is phenotypically similar to a sympatric species widely known as Magneuptychia ocypete (Fabricius, 1776), led to a review of the taxonomic status of M. ocypete. A neotype for Papilio ocypete Fabricius, 1776 is designated and its redescription is provided. Neonympha sabina C. Felder R. Felder, 1867 and Euptychia helle var. olivacea Aurivillius, 1929 are treated as junior subjective synonyms of P. ocypete and a lectotype is designated for each name. A neotype for the preoccupied name Papilio helle Cramer, 1779, and its replacement name Magneuptychia fugitiva Lamas, [1997], is also designated, and a redescription of this name and discussion of its taxonomic status are provided. We describe an additional phenotypically similar species, Magneuptychia kamel Benmesbah Zacca, sp. n. from the western Amazon and raise the name Magneuptychia opima sheba Brevignon Benmesbah, 2012 to species rank (stat. rev.) on the basis of morphological and DNA sequence evidence. We also discuss the difficulties regarding taxonomic and geographical delimitation in these complex species groups. Observations on Euptychiina behaviour are also provided. Finally, based on external characters and male genitalia, a proposed preliminary arrangement of two species groups is proposed, including other species of Magneuptychia Forster, 1964 and Cissia Doubleday, 1848. PMID- 30313471 TI - A new species of the genus Phyllodesma (Phyllodesma) Hubner, [1820] 1816 from southern China (Lepidoptera: Lasiocampidae). AB - A new species, Phyllodesma kopetzi sp. nov. (type locality: China, W. Sichuan, Road Daocheng/Litang, 4100 m, N29 degrees 36.788', E100 degrees 19.825'), is described from the southwestern part of China's Sichuan Province. The holotype is deposited in the World Insect Gallery (Joniskis, Lithuania) collection. It is compared with the poorly known Phyllodesma sinina (Grum-Grshimailo, 1891) described from Sinin-Shan [Qinghai, China]. PMID- 30313472 TI - Taxonomic reassessment and redescription of Scolopendra arthrorhabdoides Ribaut, 1913, with a discussion on its related species (Scolopendromorpha, Scolopendridae). AB - Scolopendra arthrorhabdoides Ribaut, 1913 is redescribed based on fresh material. Its taxonomic status is evaluated and compared with Scolopendra armata Kraepelin, 1903 and Scolopendra alternans Leach, 1816. The geographical distribution of S. arthrorhabdoides is also revised. Scolopendra armata is reported from Colombia for the first time. PMID- 30313473 TI - Pseudochromadora benepapillata (Timm 1961) comb. n. (Desmodoridae: Nematoda): revision of its taxonomic status and distribution. AB - Metachromadora (Bradylaimoides) benepapillata, was first discovered from the coastal mangroves of Bangladesh by Timm (1961). This species was later synonymised with Pseudochromadora cazca, which was described from the Brazilian coast by Gerlach (1956). The present paper proposes to update the taxonomic status of the Timm's species as Pseudochromadora benepapillata comb. n. along with its distribution and comparative morphology. The major differences between P. cazca and P. benepapillata are found in the characteristics of the head capsule; length of cephalic sensilla; length and position of somatic setae; shape of amphideal fovea; shape of spicules and gubernaculum; number and morphology of copulatory and postcloacal thorns. The present report on the occurrence of this species along the eastern most coast of India extends its distribution from the eastern part of Bay of Bengal to its western part. PMID- 30313474 TI - New species of the genus Microtendipes Kieffer, 1915 (Diptera, Chironomidae) from Buryatia (Russia). AB - Microtendipes langtoni Orel sp.n. from the Gusinoye Lake (Buryatia) is described and figured based on the morphology of the imago males, pupae and larvae. PMID- 30313475 TI - A new species of Trichoscelia Westwood (Neuroptera: Mantispidae) from northern South America. AB - A new species of Trichoscelia Westwood (Mantispidae: Symphrasinae) is described herein, T. geraldoi n. sp. This is the 16th species classified within the genus and presents a quite unusual body color pattern for the group. A key for the South American species of Trichoscelia and a checklist of the Symphrasinae species are presented. PMID- 30313476 TI - Notes on the pleasing lacewing genus Dilar Rambur, 1838 (Neuroptera, Dilaridae), with description of a new species from Vietnam. AB - In recent years many studies have been undertaken on the species of the genus Dilar Rambur, 1838 that occur in Asia, these have greatly increased the knowledge of Dilaridae in that region. Dilar has 69 valid species distributed in the Palaearctic and Oriental regions. In this paper we describe a new species Dilar aspoeckorum sp. nov. from Vietnam and a new female (probably Dilar harmandi (Navas, 1909)) from Nepal. PMID- 30313477 TI - A molecular phylogeny of the cicadas (Hemiptera: Cicadidae) with a review of tribe and subfamily classification. AB - A molecular phylogeny and a review of family-group classification are presented for 137 species (ca. 125 genera) of the insect family Cicadidae, the true cicadas, plus two species of hairy cicadas (Tettigarctidae) and two outgroup species from Cercopidae. Five genes, two of them mitochondrial, comprise the 4992 base-pair molecular dataset. Maximum-likelihood and Bayesian phylogenetic results are shown, including analyses to address potential base composition bias. Tettigarcta is confirmed as the sister-clade of the Cicadidae and support is found for three subfamilies identified in an earlier morphological cladistic analysis. A set of paraphyletic deep-level clades formed by African genera are together named as Tettigomyiinae n. stat. Taxonomic reassignments of genera and tribes are made where morphological examination confirms incorrect placements suggested by the molecular tree, and 11 new tribes are defined (Arenopsaltriini n. tribe, Durangonini n. tribe, Katoini n. tribe, Lacetasini n. tribe, Macrotristriini n. tribe, Malagasiini n. tribe, Nelcyndanini n. tribe, Pagiphorini n. tribe, Pictilini n. tribe, Psaltodini n. tribe, and Selymbriini n. tribe). Tribe Tacuini n. syn. is synonymized with Cryptotympanini, and Tryellina n. syn. is synonymized with an expanded Tribe Lamotialnini. Tribe Hyantiini n. syn. is synonymized with Fidicinini. Tribe Sinosenini is transferred to Cicadinae from Cicadettinae, Cicadatrini is moved to Cicadettinae from Cicadinae, and Ydiellini and Tettigomyiini are transferred to Tettigomyiinae n. stat from Cicadettinae. While the subfamily Cicadinae, historically defined by the presence of timbal covers, is weakly supported in the molecular tree, high taxonomic rank is not supported for several earlier clades based on unique morphology associated with sound production. PMID- 30313478 TI - On the West Indian weevil genus Lachnopus Schonherr, 1840 (Coleoptera: Curculionidae: Entiminae): descriptions of six new species, a proposal for species-groups, and an annotated checklist. AB - We here describe and illustrate six new species of the genus Lachnopus, the most taxonomically chaotic group of entimines in the Caribbean region. These species are Lachnopus cozumelus Giron O'Brien, sp. nov. from Cozumel Island, Mexico, Lachnopus karphos Giron O'Brien, sp. nov. from Mayaguana Island in the Bahamas, Lachnopus lucayanus Giron O'Brien, sp. nov. from Eleuthera in the Bahamas and Providenciales in the Turks and Caicos Islands, Lachnopus petilusquamus Giron O'Brien, sp. nov. from Eleuthera in the Bahamas, Lachnopus rhabdotus Giron O'Brien, sp. nov. from Providenciales in the Turks and Caicos Islands and Lachnopus vanessablockae Giron O'Brien, sp. nov. from the Cayman Islands. These constitute the first species of the genus described for each island group, and expand the geographical range of the genus, by including the Lucayan Archipelago, the Cayman Islands and Cozumel Island. Individuals of L. vanessablockae have been collected on the Cayman endemic banana orchid (Myrmecophila thomsoniana (Orchidaceae)), which represents the first reported occurrence of Lachnopus weevils as pollinators. In addition, we present an annotated checklist of the species of Lachnopus, including collecting localities, host plants, and biological notes obtained from the literature or collection data from labels of collections' specimens. Lachnopus coffeae Marshall, 1922 is recorded for the first time for Grand Bahama, which appears to be an introduction associated with citrus from Puerto Rico. We also list the fossil species attributed to the genus. Comments on some morphological characters and their variation across the genus are included. Species-groups within the genus are proposed, including diagnostic features to recognize them. Some taxonomic conflicts found in collections are pointed out. This paper compiles fundamental information, and assembles a framework for future revisionary work on Lachnopus. PMID- 30313479 TI - A taxonomic revision of the genus Thalia Blumenbach, 1798; Weelia Yount, 1954; Brooksia Metcalf, 1918 (Salpida: Salpidae) from East Coast of Peninsular Malaysia. AB - The marine pelagic tunicates of Family Salpidae Lahille, 1888 presence in the coastal waters of Terengganu was studied for the first time. Samples were collected from April to July 2016 using 200um Bongo net; hauled vertically from a stationary vessel; and preserved in 5% buffered formaldehyde. A total of 4 species under this family were found, observed and identified: Thalia rhomboides (Quoy and Gaimard 1824); Thalia sibogae (van Soest 1973); Weelia cylindrica (Cuvier 1804) and Brooksia rostrata (Traustedt 1893). All species were identified as new records in Malaysian waters. The description on morphological characteristics and a key to the solitary and aggregate of the recorded species is added. The distribution was analyzed from the 18 sampling stations in theTerengganu waters including Pulau Bidong, Pulau Yu and Pulau Kapas. The collected data was then compiled with previous available global literature on the distribution and occurrence of these four species, consequently updating the biodiversity of Malaysian fauna and its worldwide biogeography distribution. PMID- 30313480 TI - A new species of Schistura (Teleostei: Nemacheilidae) from the south-western lowlands of Sri Lanka. AB - Schistura scripta, new species, is described from Nakiyadeniya in the south western lowlands of Sri Lanka. It can be distinguished from all other congeners from Sri Lankan and peninsular India by the combination of the following characters: an incomplete lateral line with 53-76 pores, ending beneath the dorsal-fin base or slightly beyond; 7-13 post-dorsal bars; 71/2 branched dorsal fin rays; absence of an axillary pelvic lobe; and absence of a suborbital flap. PMID- 30313481 TI - Sixteen new generic records of Korean Bryozoa from southern coastal waters and Jeju Island, East China Sea: evidence of tropical affinities. AB - The first records of 16 genera of cheilostome Bryozoa not previously reported for Korea are given here. All are from southern coastal waters, especially Jeju Island, which appears to be Korea's marine-biodiversity 'hotspot'. Jodoella koreensis n. gen. et sp. (Robertsonidridae) is new to science. Seven additional new species are described for the genera Copidozoum, Reptadeonella, Schizosmittina, Saevitella, Torquatella, Stephanollona and Plesiocleidochasma. The other genera new to the Korean fauna are Dibunostoma, Corbulella, Onychocella, Stephanotheca, Bryopesanser, Calloporina, Hippaliosina and Pleuromucrum. The Japanese Pleistocene species Calloporina hayamiae Arakawa is newly reported alive from Jeju Island. Four of the species were previously known only from the tropical Indo-West Pacific, three others are found in semitropical/warm-temperate water, and the other known genera have warm-water species, supporting data from other taxa that Korean's southern waters, especially in the vicinity of Jeju Island, are profoundly influenced by the warm Kuroshio Current and global warming trends. Currently, at least 112 species of Bryozoa are known from Jeju Island, 101 of them Cheilostomata, representing c. 70% of all Korean cheilostome species. Four new combinations are introduced: Copidozoum canui (Sakakura) n. comb., Schizo pedicellata (Soule, Soule Chaney) n. comb., Torquatella ensenada (Tilbrook) n. comb. and Torquatella longiuscula (Harmer) n. comb. Torquatellidae is subsumed in Celleporidae and Predanophora in Torquatella. PMID- 30313482 TI - Polyclinidae (Ascidiacea: Aplousobranchia) from the Gulf of Mexico, collected during the "Hourglass" cruises (1965-1967). AB - This paper presents the ascidians from the Family Polyclinidae collected in the Gulf of Mexico during the Hourglass Cruises between August 1965 and November 1967. The analysis of the collected material revealed the presence of eight polyclinid ascidians from three different genera, with two new species and two new records for the Gulf of Mexico. PMID- 30313483 TI - Redescription of Yphthimoides patricia (Hayward, 1957), with taxonomic notes on the names Euptychia saltuensis Hayward, 1962 and Yphthimoides manasses (C. Felder R. Felder, 1867) (Nymphalidae: Satyrinae). AB - Euptychia saltuensis Hayward, 1962, new synonym, currently regarded as a nomen dubium and possibly a junior subjective synonym of Yphthimoides manasses (C. Felder R. Felder, 1867), is here treated as a junior subjective synonym of Yphthimoides patricia (Hayward, 1957), based on morphological characters of the male genitalia and the DNA barcode. The taxonomic status of Y. patricia is re examined, and a detailed redescription of the adult morphology, including the male genitalia, is presented. Information on the distribution, habitat and immature stages of Y. patricia is also provided. Yphthimoides patricia is clearly a distinct species from Y. manasses based on the analysis of DNA barcode sequences and the morphology of the male genitalia. PMID- 30313484 TI - Phyllocnistis podocarpa sp. nov. (Lepidoptera, Gracillariidae), a buddhist pine leaf-miner from Japan: taxonomy, DNA barcodes, damage and parasitoids. AB - Phyllocnistis podocarpa sp. nov., is described from mines in Podocarpus macrophyllus (Family Podocarpaceae). The host plant P. macrophyllus, also known as buddhist pine on the IUCN Red List, is a noticeable garden plant and thus of high economic value. Buddhist pine has been introduced to many other countries from its native habitat in southern Japan. Special attention has been paid for it during the overseas import in China. The morphology of the pupae of P. podocarpa, particularly the frontal process of the head and the spine clusters on terga, ones of the most useful diagnostic characters for species identification of Phyllocnistis on morphology, is demonstrated using SEM. Two parasitoid species of Eulophidae (Hymenoptera) are identified and illustrated. COI barcode sequences are provided along with a Neighbor Joining Tree covering related species for aiding identification. PMID- 30313485 TI - Three new species of squat lobsters of the genus Munidopsis Whiteaves, 1874, from Guadeloupe Island, Caribbean Sea (Crustacea, Decapoda, Munidopsidae). AB - The genus Munidopsis is one of the most diverse genera within squat lobsters. Here, three new species of Munidopsis, M. cornuata n. sp., M. senticosa n. sp., and M. turgida n. sp., from <500 m off Guadeloupe Island (Caribbean Sea), are fully described and illustrated. Among the Atlantic species of the genus, M. cornuata n. sp. belongs to the group of species having the dorsal surface of the carapace with spines and is most similar to M. robusta (A. Milne-Edwards, 1880), from the Gulf of Mexico and Caribbean Sea. Munidopsis senticosa n. sp. resembles M. barbarae (Boone, 1927) from the Bahamas and the Gulf of Mexico and M. penescabra Pequegnat Williams 1995, from off Georgia and Gulf of Mexico; the three species belong to the group having the carapace covered with sharp spines. Finally, M. turgida n. sp. is characterized by having the dorsal surface of the carapace, abdomen and pereiopods covered by granules; and resembles M. granulens Mayo, 1972, from NW Caribbean Sea. Apart from the morphological evidence, the analysis of mitochondrial genes (COI and 16S) supports establishing these new species, showing very high genetic divergences compared to their congeners (from 14.5 to 17% for COI, and 7.7 to 12.8% for 16S data). PMID- 30313486 TI - A new species of Petalobrissus Lambert 1916 (Echinoidea: Faujasiidae) from the Jandaira Formation, Potiguar Basin (Brazil). AB - A new Late Cretaceous species of Petalobrissus, Petalobrissus lehugueurae sp. nov., is described from the Jandaira Formation, Potiguar Basin, state of Rio Grande do Norte. To date, this genus comprises a total of 20 species, only two of which, Petalobrissus setifensis and Petalobrissus cubensis have so far been recorded from the Jandaira Formation. Petalobrissus lehugeurae sp. nov. is distinguished from its congeners in that gonopores occupy only a small portion of the genital plates, in having a slit-like periproct and a unique abrupt depression of the test that forms a pronounced keel below the periproct. In addition, an identification key to species of Petalobrissus is presented. PMID- 30313487 TI - A new species of Tanytarsus van der Wulp, 1874 (Diptera: Chironomidae) and the first Japanese record of Tanytarsus ovatus Johannsen, 1932 with DNA barcodes. AB - A new species of the genus Tanytarsus van der Wulp, 1874 was described and illustrated based on an adult male. Tanytarsus trichovalis sp. nov. belongs to the eminulus species group, and is closely related to T. tamaundecimus Sasa, 1980, T. okuboi Sasa, 1986, and T. tonebeceus Sasa Tanaka, 2000. However, the species is distinguished from these species by the morphology of the hypopygium. We also present the first record of T. ovatus Johannsen, 1932 in Japan. In addition, DNA barcoding of 5 species including T. trichovalis sp. nov., T. ovatus, and other morphologically related species was undertaken. A new key of the eleven Japanese eminulus species group was compiled. PMID- 30313488 TI - Erratum: NGUYEN DINH TU, NGUYEN VU THANH, LAI PHU HOANG ULRICH SAINT-PAUL (2017) Two new species of the genus Deontolaimus de Man, 1880 (Nematoda: Leptolaimidae) from mangrove ecosystems of Vietnam. Zootaxa, 4205 (1): 073-080. PMID- 30313489 TI - Taiwanese deep-water chitons (Mollusca: Polyplacophora) and survey of chiton fauna of Taiwan. AB - Sixteen deep-sea polyplacophoran species are reported in this article, fifteen of which were found for the first time in the waters of Taiwan. Two of these species, Leptochiton taiwanensis n. sp. and L. wui n. sp., are described as new to science. Several of these species are distributed near Japan and in other areas of the western Pacific Ocean. Eight of the reported species live and feed on sunken wood. A survey of the polyplacophorans of Taiwan has also been conducted. The updated list of chitons collected near Taiwan at all depths contains 34 species. Seventeen of these species are shallow-water and seventeen species are deep-water chitons. PMID- 30313490 TI - Taxonomy of the Hirtodrosophila melanderi species group (Diptera: Drosophilidae), with descriptions of four new species from southwestern China. AB - The Hirtodrosophila melanderi species group contains nine known species recorded from either the Old or the New World. All these species were thought to be strict fungivorous drosophilids. In the present study, we give supplementary descriptions for three of these known species, all recorded from Yunnan, southwestern China, H. furcapenis, H. furcapenisoides, and H. longifurcapenis, by examining respective type specimen(s). We then describe four new species of the same group, H. seticlasper Katoh Gao, sp. nov., H. spinicerca Katoh Gao, sp. nov., H. serratifurcapenis Katoh Gao, sp. nov., and H. truncifurca Katoh Gao, sp. nov., all discovered recently from high altitudes (ca. 3,500 to 3,800 m a.s.l.) in Tibet (Xizang), southwestern China. The delimitation of these new species is firstly performed in light of morphology and further with the aid of DNA sequences of the mitochondrial COI (cytochrome c oxydase, subunits I) gene. In addition, a key to all the species of the species group is provided. PMID- 30313491 TI - Systematics of the frogs allocated to Sarcohyla bistincta sensu lato (Cope, 1877), with description of a new species from Western Mexico. AB - A new species of hylid frog is described from the southwestern edge of the Mexican Plateau from the states of Morelos and Mexico through Michoacan and Jalisco, reaching the Sierra Madre Occidental in Sinaloa and western Durango. The new species is part of the widespread Mexican hylid Sarcohyla bistincta (sensu amplo) complex, comprised of S. bistincta, S. pentheter, S. calthula, and S. ephemera. One subspecies of S. bistincta (labeculata) was proposed for an isolated population in Oaxaca. We restrict the group's nominal species, S. bistincta (sensu stricto), to the Sierra Madre Oriental of Mexico and southward into the Sierra Madre del Sur of Guerrero and Oaxaca. Examination of type material places S. calthula and S. ephemera in the synonymy of S. labeculata (new combination). The species allied to S. bistincta, namely, S. bistincta, S. labeculata, S. pentheter, and the new species described herein, are diagnosed and described following recent suggested taxonomic changes and new available material. PMID- 30313492 TI - Odd, outsized, and obscure: Sarcophaga (Hadroxena) karakoncolos sp. n. (Diptera: Sarcophagidae) from Turkey. AB - A new species of flesh fly, Sarcophaga karakoncolos sp. n., is described based on a single adult male from Turkey (Isparta Province, Anatolia), characterised by its very large size (almost 22mm in body length) and by a unique combination of morphological features. These, together with available molecular data, do not support inclusion of the new species in any of the currently recognised subgenera of Sarcophaga, and it is placed in a new subgenus, Hadroxena subg. n. PMID- 30313493 TI - A new species of Derobrachus Audinet-Serville, 1832 (Coleoptera, Cerambycidae, Prioninae) from a cloud forest in Honduras. AB - A yearly biodiversity monitoring of longhorned beetles (Cerambycidae) in a Honduran cloud forest revealed a new species of prionine. Derobrachus cusucoensis sp. nov. is a locally relatively common species described from Cusuco National Park in Honduras, becoming the ninth species of this genus recorded for the country. Similar both in morphology and a montane habitat to D. dohrni, there is a possibility that this new species represents a disconnected population from the latter that evolved separately. An adapted insert for an existing identification key to all Derobrachus species is included. PMID- 30313494 TI - Deronectes taron sp. n. from the eastern Anatolian region of Turkey (Coleoptera, Dytiscidae, Hydroporinae). AB - Deronectes taron sp. n. from the Mus province in the eastern Anatolian region of Turkey is described and illustrated in detail. The species belongs to the D. longipes subgroup of the D. parvicollis species group and resembles in particular D. syriacus Wewalka, 1971. It can be differentiated from this and the other species of the group by the shape of the median lobe which is strongly bent in lateral view. A part of the key to species of the subgroup is updated. Together with the new species the number of the known species of the genus Deronectes Sharp, 1882 is now 59 and that of the longipes-subgroup is 13. PMID- 30313495 TI - Five new species of the genus Ernolatia Walker, 1862 (Lepidoptera: Bombycidae) from islands of Malesia. AB - Five new species of the genus Ernolatia Walker, 1862 are described from the islands of Malesia. They are E. adrasteia sp. nov. (type locality: Philippinen, Negros occ., Mt. Kanlaon, 600-800 m, W-Route via Mambucal), E. invicema sp. nov. (type locality: S. Sulawesi, Puncak, Palopo, 2 degrees 55'S, 120 degrees 05'E), E. callirhoe sp. nov. (type locality: S. Sulawesi, Mt. Sampuraga, 2 degrees 10'S, 120 degrees 45'E), E. fumidiflora sp. nov. (type locality: Indonesia, N. Tengg. Timur, Flores, 9 km S Ruteng Golo Luseng) and E. doris sp. nov. (type locality: Indonesia, Sumba (W), Prov. Nusa Tenggara Barat, Gunung (Mt) Areas). The holotypes of all taxa are deposited in the coll. of entomological Museum Witt (which will be attributed to the Zoologische Staatssammlung, Munich). Their habitus, as well as available genitalia, are illustrated. PMID- 30313496 TI - Redescription of Juticus furcidens Roewer, 1943 (Opiliones: Gonyleptidae), with a discussion of its relationships in the subfamily Gonyleptinae. AB - As part of an ongoing revision of the largest gonyleptid subfamily, Pachylinae, we examined Juticus furcidens Roewer, 1943. This is an elusive species mentioned only in catalogues after its description. In this paper, we redescribe it according to modern standards, including its male genitalia for the first time, which exhibit typical features of the gonyleptid K92 clade. Considering also other features from the body and appendages, we transfer J. furcidens to Gonyleptinae, and we discuss its relationships with other Gonyleptinae sensu stricto. In addition, we present a new record besides those of the type material, clarifying the hitherto imprecise distribution. PMID- 30313497 TI - Description of a new species of Nososticta Hagen (Odonata: Platycnemididae: Disparoneurinae) from Central Nicobar Islands, India. AB - A new damselfly species, Nososticta nancowra Rajeshkumar sp. nov. is described based on eight males and three females from Central Nicobar Islands, India. The diagnostic characteristics of the new species separating it from congeners are discussed. Morphological variations observed in the anal appendages of males and the pronotum of females are documented. A description of the new species using photographs and drawings is given. An identification key to species of the genus Nososticta occurring in Nicobar Islands is given for both sexes. PMID- 30313498 TI - Description of Microgomphus farrelli sp. nov. (Odonata: Anisoptera: Gomphidae) based on adults of both sexes and larvae from Northern Thailand. AB - The new gomphid species, Microgomphus farrelli sp. nov., is described and illustrated on the basis of male and female adult specimens and larvae collected from Chiang Mai and Mae Hong Son province, Northern Thailand. It is compared with other species of the genus. Based on the larvae this species is most closely related to Microgomphus svihleri (Asahina, 1970), comb. nov., which is the senior and valid synonym of Microgomphus thailandicus Asahina, 1981, syn. nov. PMID- 30313499 TI - Revision of Cephennomicrus of Australia (Coleoptera, Staphylinidae, Scydmaeninae). AB - The smallest Cephenniini of Australia belonging to the genus Cephennomicrus Reitter are revised. Twenty species occurring in the Australian mainland, Lord Howe Island and Boongaree Island are treated, including redescriptions of three previously known and descriptions of 17 new species: Cephennomicrus inconspicuus (King), C. lordhowei (Franz), C. perthi (Franz), C. baroalbanus sp. n., C. basalis sp. n., C. bipunctatus sp. n., C. carinatus sp. n., C. complicatus sp. n., C. indistinctus sp. n., C. longissimus sp. n., C. marunensis sp. n., C. mediorugosus sp. n., C. monteithi sp. n., C. mossmanensis sp. n., C. pronotalis sp. n., C. proserpinensis sp. n., C. semidividus sp. n., C. triangularis sp. n., C. tuberculifrons sp. n., and C. wunundarranus sp. n. Lectotype is designated for Megaladerus inconspicuus King. A working division of Australian Cephennomicrus into five species groups is proposed and distribution within Australia is summarized. PMID- 30313500 TI - On the generic names proposed in Chrysomelidae (Coleoptera) by Gustaf Johan Billberg. AB - The genus names proposed by Billberg (1820a) for Chrysomelidae are reviewed. Mesops Billberg, 1820 is considered an unavailable name. Apelma Billberg, 1820 is confirmed as synonym of Macroplea Samouelle, 1819. Chrysomela concolor Fabricius, 1781, the type species of Isosoma Billberg, 1820, is a representative of Phygasia Dejean, 1836. To save the generic name Phygasia we propose Isosoma as nomen oblitum for Phygasia (nomen protectum). Chrysomela flavipes Linnaeus, 1767 is designated as type species of Lyperus Billberg, 1820 and Lyperus is proposed as new synonym of Luperus Geoffroy, 1762. Galleruca lausoniae Fabricius, 1798 is designated as type species of Adimus Billberg, 1820 and Adimus is proposed as new synonym of Altica Geoffroy, 1762. Galleruca lausoniae Fabricius, 1798 is confirmed as synonym of Altica caerulea (Olivier, 1791). PMID- 30313501 TI - New fossil gastropod species (Mollusca: Gastropoda) from the upper Miocene of the Canary Islands (Spain). AB - Ten new species of fossil gastropods from the upper Miocene (Tortonian) of the Canary Islands (Spain) are described. Among these are three species of the genus Patella, a group with few fossil representatives, as well as three others representing the family Trochidae. The remaining new species represent Caenogastropoda. This study improves our knowledge of the fossil malacofauna from the Miocene of these islands. Together with the Azores and Madeira archipelagos, the Canaries belong to the Macaronesian biogeographic region. The described species are indicative of rocky coastal environments, and are thus expanding the current understanding of such ecosystems and their associated marine molluscs such as the family Patellidae whose fossil record is scarce. New species: Patella tintina Martin-Gonzalez Vera-Pelaez sp. nov., Patella maxoratensis Martin Gonzalez Vera-Pelaez sp. nov., Patella mahamensis Martin-Gonzalez sp. nov., Jujubinus ajachaensis Martin-Gonzalez Vera-Pelaez sp. nov., Osilinus burgadoi Martin-Gonzalez sp. nov., Gibbula tindayaensis Martin-Gonzalez Vera-Pelaez sp. nov., Cerithium miocanariensis Martin-Gonzalez Vera-Pelaez sp. nov., Tectarius isletaensis Vera-Pelaez sp. nov., Morula mionigra Martin-Gonzalez sp. nov. and Conus fuerteventurensis Vera-Pelaez Martin-Gonzalez sp. nov. PMID- 30313502 TI - Subspecies-level systematics and affinities of Cheimas Thieme-an endemic genus of the subparamo of the Venezuelan Cordillera de Merida (Lepidoptera: Nymphalidae, Satyrinae). AB - The validity of the monobasic neotropical butterfly genus Cheimas Thieme (Nymphalidae, Satyrinae, Satyrini, Pronophilina) is discussed, and confirmed based on morphological and molecular data. Cheimas opalinus (Staudinger), endemic to the Venezuelan Cordillera de Merida, and considered prior to this study to be monotypic and restricted to the central part of the range, is demonstrated to be polytypic and more widely distributed. Five subspecies are recognised, differing mostly in their dorsal patterns, in particular the shape and colour of hindwing greenish-blue patch. Mitochondrial DNA sequences (COI) were obtained for three of them. The nominate subspecies is found in the central part of the range, in the Sierra Nevada and La Culata. The other subspecies are found as follows: C. opalinus dominici n. ssp.; in the Santo Domingo valley in the centre-north; C. opalinus cristalinus n. ssp. in the north; C. opalinus iosephi n. ssp. on the eastern slopes, and C. opalinus rosalinus n. ssp. in the southern Paramo El Batallon massif. A hybrid zone between the latter two subspecies was detected in the northern part of the Batallon massif based on unusual individual variation and intermediate phenotypes. All the populations of Cheimas opalinus occur in the forest-paramo ecotone at 2800-3400 m a.s.l., with the notable exception of C. opalinus cristalinus n. ssp. found also in mid-elevation forests down to 2300 m a.s.l. PMID- 30313503 TI - Contribution to the knowledge of the cavernicolous beetle genus Aspidaphaenops Ueno from Guizhou (Coleoptera: Carabidae: Trechinae). AB - The hypogean ground beetle genus Aspidaphaenops Ueno, 2006 is reviewed. Some new information of A. reflexus Ueno, 2006 is provided, including the male genital characteristics as well as a new locality. Two new species are described and illustrated from southwestern Guizhou Province, southwest China: A. xiongda n. sp. (Guizhou: Anlong: Fengyan Dong), A. dudou n. sp. (Guizhou: Xingyi: Xiaozi Dong). A key to all Aspidaphaenops species is also provided. PMID- 30313504 TI - The centipede family Anopsobiidae new to North America, with the description of a new genus and species and notes on the Henicopidae of North America and the Anopsobiidae of the Northern Hemisphere (Chilopoda, Lithobiomorpha). AB - Speleopsobius weaveri, n. gen., n. sp., is described from lava tubes in southern Idaho, USA. The new taxon, and species of the genera Buethobius Chamberlin, 1911 and its probable synonym Yobius Chamberlin, 1945, are members of the family Anopsobiidae, not previously reported from North America. All known species of Henicopidae and Anopsobiidae from North America north of Mexico are listed and briefly noted, along with all known anopsobiids from the northern hemisphere. Anopsobiella dawidoffi Attems, 1938 (Vietnam) is likely not a member of the family Anopsobiidae. PMID- 30313505 TI - Description of female of Titidius urucu Esmerio Lise, 1996 (Araneae: Thomisidae). AB - The genus Titidius Simon, 1895 belongs to the family Thomisidae Sundevall, 1833 and can be easily identified from the related genera Tmarus Simon, 1875 and Acentroscelus Simon, 1886 by the high carapace, anterior eye row straight and posterior eye row recurve-;pd in dorsal view, carapace smooth with moderate setation, abdomen longer than wide, legs long, slender and setose and clypeus vertical (Esmerio Lise 1996). It is currently composed of 20 species, all occurring in Brazil with exception of Titidius ignestii Caporiacco, 1947 from Guyana (World Spider Catalog 2017). Eight species are distributed in the Amazon region (Esmerio Lise 1996): T. caninde Esmerio Lise, 1996, T. gurupi Esmerio Lise, 1996, T. multifasciatus Mello-Leitao, 1929 and T. rubrosignatus (Keyserling, 1880) from Para; T. galbanatus (Keyserling, 1880) from Amazonas and Para; T. quinquenatus Mello-Leitao, 1929 and T. urucu from Amazonas; and T. rubescens Carporiacco, 1947 from Amazonas and Roraima. PMID- 30313506 TI - The tadpole of Adelphobates galactonotus (Steindachner, 1864) (Amphibia, Anura, Dendrobatidae). AB - The systematics of the dart-poison frogs, family Dendrobatidae, experienced several taxonomic rearrangements over time (e.g., Grant et al. 2006, 2017; Brown et al. 2011). Currently, this family comprises 194 described species organized in three sub-families and 15 genera (Frost 2018). Among them, the genus Adelphobates Grant, Frost, Caldwell, Gagliardo, Haddad, Kok, Means, Noonan, Schargel, Wheeler, 2006, comprises three species, all distributed in Central and lower Amazon drainage of Peru and Brazil, and possibly in northeast of Bolivia (Grant et al. 2006; Frost 2018). Adelphobates galactonotus (Steindachner 1864) is an endemic Brazilian frog, and can be found throughout Para, Maranhao, Mato Grosso and Tocantins states (Hoogmoed Avila-Pires 2012), related to Amazon forest formations and also in transitional areas between the Cerrado and the Amazon forest (Valdujo et al. 2012). Despite this species is classified as Least Concern (Rodrigues et al. 2010), several threats are known. First, its geographic distribution coincides with the so-called Amazonian Deforestation Arc, which comprehends the southeastern portion of the Amazonian Forest that has been rapidly converted into pasture and crop areas or being flooded due to the construction of hydroelectric power plants (Hoogmoed Avila-Pires 2012). Also, this species is present in Appendix II of CITES as a target for illegal trade, and their commercial exploitation should be controlled to avoid that this species become seriously endangered in the near future (see a case study in Paula et al. 2012). These threats are of deeper concern because despite A. galactonotus has been described since more than 150 years (Steindachner 1864), its tadpole remains unknown. Without a better understanding of the natural history of A. galactonotus, attempts of conservation strategies and population management are inefficient. In an effort to fill the knowledge gaps about this species natural history, we present a detailed description of the external morphology of the A. galactonotus tadpole. PMID- 30313507 TI - Schizopyga alinae, a genus of pimpline parasitoid wasps (Hymenoptera: Ichneumonidae: Pimplinae) new to the Afrotropical region. AB - Schizopyga Gravenhorst, 1829 is a small genus belonging to the Polysphincta genus group of the subfamily Pimplinae, with 12 known species worldwide (Yu et al., 2012; Matsumoto, 2016), two of them from the Afrotropical region (Gauld Dubois, 2006). Schizopyga species are known as parasitoids of spiders creating non-aerial webs (Clubionidae, Gnaphosidae, and Agelenidae) (Matsumoto, 2016). PMID- 30313508 TI - A new species of the genus Paraholcostethus Belousova (Hemiptera: Heteroptera: Pentatomidae: Carpocorini) from Korea. AB - The genus Paraholcostethus Belousova is reported from the Korean Peninsula for the first time with the description of a new species, Paraholcostethus irumiae sp. nov. The generic diagnosis of Paraholcostethus is slightly modified to accommodate the new species. Habitus, male and female internal and external genitalia are illustrated. A key to the species of the genus is also given. PMID- 30313509 TI - An updated checklist of the herpetofauna from Guerrero, Mexico. AB - We present an updated checklist of the amphibians and reptiles for the state of Guerrero, Mexico. This list is based on bibliographic records, the revision of scientific collections and the authors' field notes. The herpetofauna of the state includes 259 species (78 amphibians, 181 reptiles), of which three are introduced. The conservation status of all native species was assessed using three independent systems (NOM-059, IUCN and EVS). Finally, the geographic distribution of amphibians and reptiles is discussed in the context of both the biogeographic provinces within the state and the influence of road location on specimen collection patterns. PMID- 30313510 TI - A new species of Alopoglossus lizard (Squamata, Alopoglossidae) from the Southern Guiana Shield, northeastern Amazonia, with remarks on diagnostic characters to the genus. AB - I describe a new species of Alopoglossus from the Southern Guiana Shield in northern Brazilian Amazonia. The new species morphologically resembles A. angulatus in having scales on sides of neck similar in shape to dorsals, nongranular, keeled, and imbricate. Nonetheless, the presence of four pairs of chin shields, with the third pair heptagonal and separated from gulars by large scales, can distinguish the new species from A. angulatus. This description increases the species diversity of the genus Alopoglossus in eastern Amazonia, from where only one taxon was recognized to occur. In addition, I discuss the nomenclature of some diagnostic characters, on the chin region, to the genus, and I present an updated key to Alopoglossus. PMID- 30313511 TI - Description of eight new species and re-description of four species belonging to the family Phytoseidae (Acari: Mesostigmata) from West Bengal, India. AB - This paper reports on 12 species of Phytoseiidae (Acari: Mesostigmata) from West Bengal, India. Amblyseius crotalariae (Gupta, 1977), Amblyseius guajavae (Gupta, 1978), Typhlodromips syzygii (Gupta, 1975), Scapulaseius asiaticus (Evans, 1953) are re-described, and Scapulaseius moraesi sp. nov., Euseius sundarbanensis sp. nov., Euseius astrictus sp. nov., Asperoseius latericulus sp. nov., Asperoseius jujubae sp. nov., Typhlodromus (Anthoseius) carambolae sp. nov., Typhlodromus (Anthoseius) heliotropium sp. nov. and Phytoseius namkhanaensis sp. nov. are described as new. PMID- 30313512 TI - Scorpiurus aramoana (Diptera: Dolichopodidae), a new species from New Zealand. AB - The New Zealand endemic genus Scorpiurus Parent is known from marine littoral habitats. A new species, S. aramoana sp. nov., is described from coastal Otago of the South Island. Males have diagnostic flattened and modified tarsomeres on legs I and II. A key is provided to the New Zealand genera of Hydrophorinae and the three described species of Scorpiurus. PMID- 30313513 TI - Towards reliable identification of male Dicerura: descriptions of three new and seven poorly known species in the Palearctic region (Diptera: Cecidomyiidae, Porricondylinae). AB - The taxonomy of Dicerura Kieffer, 1898, a genus of Porricondylinae now comprising 32 species in the Holarctic region, is revised. Three new species are described based on morphological characters of male adults: D. jakovlevi Jaschhof Spungis sp. nov. (from Finland), D. penttineni Jaschhof Spungis sp. nov. (Finland), and D. yezoensis Jaschhof Spungis sp. nov. (Japan). Dicerura padi Mamaev, 1975 syn. nov. is revealed to be a junior synonym of D. furculata Mamaev, 1968. Seven species, whose original descriptions are from a present-day perspective inadequate for the purpose of identification, are redescribed: D. barbata Mamaev, 1966; D. formosa Mamaev, 1998; D. foliicola Mamaev, 1968; D. furculata; D. iridis (Kaltenbach, 1873); D. stipator Mamaev, 1972; and D. unidentata Spungis, 1987. A key to males of Palearctic Dicerura is provided. New faunistic records are presented for D. barbata; D. complicata Spungis, 1987; D. dentata Spungis, 1979; D. formosa; D. fungicola (Mamaev, 1964); D. mixta Spungis, 1987; and D. unidentata. Male genitalic characters are shown to be useful to a certain extent for structuring the species diversity found within the genus Dicerura. The following groups of species are defined: iridis group (with nine species), dentata group (six species), fungicola group (four species), and formosa group (four species). Six of the species whose morphology is adequately known cannot be grouped within the proposed scheme, indicating the need for further character analysis and continuing search for yet undiscovered species that are assumed to exist in large numbers. PMID- 30313514 TI - The genus Promalactis Meyrick (Lepidoptera: Oecophoridae) in Cambodia, with description of eight new species. AB - Nine species of the genus Promalactis Meyrick, 1908 are recorded from Cambodia. Eight species are described as new: P. latiuscula Wang, sp. nov., P. curvicornuta Wang, sp. nov., P. ostacantha Wang, sp. nov., P. apicuncata Wang, sp. nov., P. granulosa Wang, sp. nov., P. argentifasciaria Wang, sp. nov., P. quadrilobata Wang, sp. nov. and P. trifasciata Wang, sp. nov. One species is newly recorded for Cambodia: P. carinata Du, Li et Wang, 2011. Photographs of adults and genitalia are provided. PMID- 30313516 TI - A new species of Eigenmannia Jordan Evermann (Teleostei: Gymnotiformes: Sternopygidae) from Rio Ventuari, Venezuela. AB - A new species of Eigenmannia is described from the Rio Ventuari, Rio Orinoco basin, Venezuela. It is distinguished from congeners by the presence of a bony dorsolateral flange on the dentary, the presence of teeth attached along a bony dorsolateral flange, and by the first premaxillary teeth attached to the anteroventral margin of the premaxilla. It is further distinguished from all remain congeners by a combination of characters, including a subterminal mouth, 99-107 scales along the lateral line until the end of the anal fin, and ii, 16-17 pectoral-fin rays. PMID- 30313515 TI - A new genus and species of primary freshwater crab and a new species of Artopotamon Dai Chen, 1985 (Crustacea, Brachyura, Potamidae) from western Yunnan, China. AB - A new genus and species belonging to the primary freshwater crab family Potamidae, and a new species of the genus Artopotamon Dai Chen, 1985, are described on the basis of remarkable G1and female gonopore characters. Semicirculara lincangensis gen. sp. nov. and Artopotamon latopeos sp. nov. were collected from southwestern and northwestern Yunnan Province, China, respectively. All type specimens are deposited in Nanjing Normal University in Nanjing and the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing. Mitochondrial molecular data, from the partial sequence of the mitochondrial 16S rRNA gene, are also shown to support the distinct systematic position of the new taxa. PMID- 30313517 TI - A new black fly species of Simulium (Simulium) (Diptera: Simuliidae) from Taiwan. AB - A new black fly species, Simulium taichungense, is described on the basis of one female, one male and two pupal exuviae from Taiwan. This new species is placed in the S. crocinum species-group of Simulium (Simulium) (Diptera: Simuliidae). It is characterized by the pupal gill with six unpigmented short filaments and pupal abdomen with distinct spine-combs on the dorsal surface of segments 7-9, by which it is easily distinguished from most species in the S. crocinum species-group including two species from Taiwan: Simulium serenum Huang Takaoka and S. ufengense Takaoka. It is the third species of the S. crocinum species-group from Taiwan. In addition, the male of S. serenum is described for the first time, and intraspecific variations in a few features of the male of S. chungi Takaoka Huang of the S. chungi species-group are noted. PMID- 30313518 TI - Revision of the millipede tribe Brachyiulini Verhoeff, 1909 (Diplopoda: Julida: Julidae), with descriptions of new taxa. AB - A comprehensive taxonomic revision of the circum-Mediterranean julid tribe Brachyiulini is undertaken. A total of 13 genera and 103 species are assigned to the tribe. One new genus, one new subgenus, and 10 new species are described from Greece, Turkey or Iran: Byzantorhopalum (Byzantorhopalum) elephantum sp. n., B. (Ioniulus) clavamum subgen. n., sp. n., Cyphobrachyiulus (Cyphobrachyiulus) spartanus sp. n., C. (Diaxylus) graecus sp. n., Graecoiulus skopelius gen. n., sp. n., Italoiulus poseidoni sp. n., Omobrachyiulus strasseri sp. n., Pontobrachyiulus falciferus sp. n., P. lohmanderi sp. n., Syriobrachyiulus golovatchi sp. n. 13 species are redescribed in detail, while the descriptions of another 36 species are complemented. The genera Anaulaciulus Pocock, 1895 and Mammamia Akkari et al., 2011 are formally excluded from the Brachyiulini. The following former subgenera of the genus MegaphyllumVerhoeff, 1894 are elevated to full genera: Byzantorhopalum Verhoeff, 1930, Cyphobrachyiulus Verhoeff, 1900, Iraniulus Attems, 1951, Italoiulus Attems, 1940, Omobrachyiulus Lohmander, 1936, Pontobrachyiulus Lohmander, 1936, Syriobrachyiulus Verhoeff, 1930. The genera Acropoditius Strasser, 1980 and Rhamphidoiulus Attems, 1905 are downgraded to subgenera of the genus Cyphobrachyiulus. The subgenera Phauloiulus Attems, 1940 and Persebrachyiulus Golovatch, 1983 are new subjective synonyms of Byzantorhopalum Verhoeff, 1930 and Syriobrachyiulus Verhoeff, 1930, respectively. The monophyly of the Brachyiulini in its current taxonomic composition is proven by morphological data, and supported by molecular and spermatological data in addition. The biogeographic affinities of the different tribal subgroups are briefly discussed. PMID- 30313519 TI - A new four-pored Amphisbaena Linnaeus, 1758 (Amphisbaenia, Amphisbaenidae) from Brazilian Amazon. AB - A new species of Amphisbaena is described from the Brazilian Amazon, within the area impacted by the Teles Pires hydroelectric power plant, Jacareacanga municipality, State of Para. Amphisbaena hoogmoedi sp. nov. can be diagnosed from its congeners by the following combination of characters: snout convex in profile view, sligthly compressed not keeled; pectoral scales arranged in regular annuli; conspicuous autotomic site between 7th-8th caudal annuli; 247-252 dorsal half annuli; 27 caudal annuli; tail length 9.5-10.4% of snoutvent length; four precloacal pores arranged in sequence; three supralabials; a rounded tail; 22-24 dorsal segments in midbody annulus; postmalar row absent; head length 2.1-2.9% of snout-vent length; prefrontals length 46.6-49.5% of head length; prefrontals suture length 38-44.6% of head length; small malar length 10.6-13.4% of ventral length of head ; second infralabial length 33.8-38.5% of head length; ventral length of head 2.7-2.9% of snout-vent length; mouth length 80.2-81.8% of head length; third infralabial length 16.4-19.6% of head length; snout length 62.5 78.6% of head length; ocular length 23.4-26.2% of head length; mental length 23.2 25.4% of ventral length of head; postmental length 27.2-31.3% of ventral length of head; frontals suture length 23.4-32.3% of head length; postocular width 25 31.9% of maximun width of head; first supralabial length 24.9-30.6% of head length; second supralabial length 27.7-30% of head length and second supralabial height 26.9-28.8% of maximun head height. The hemipenis is bilobed, capitate and with lateral lamellae on the lobes; with a centrally-positioned spermatic groove, bifurcated at the base of the lobes, and with each branch extending to the tip of organ. PMID- 30313520 TI - An Identification key to the species of Auchenorrhyncha of Iranian fauna recorded as pests in orchards and a review on the pest status of the species. AB - An illustrated dichotomous identification key for a total of 54 Auchenorrhyncha species of Iran is presented. The studied species have been recorded as pests and vectors of diseases to fruit trees. Twenty nine records were contributed to Iranian orchards and 25 of which were from other parts of the world. Hence, the latter group can be considered as potential pests and vectors in Iran. Reviewing the published information on the former group suggests 12 species as pests (4, 2 and 6 species with significant, minor, and unknown recorded economic damage levels, respectively). The pest status of 14 recorded pest species were quite doubtful and 3 of them could not be present in Iran due to the lack of evidence or their limited distribution in other parts of the world. The 4 species which were recognized as well known and significantly important pests belonged to the families: Tropiduchidae (Ommatissus lybicus Bergevin, 1930), Cicadidae (Cicadatra alhageos (Kolenati, 1857)), and Cicadellidae (Hishimonus phycitis (Distant, 1908) and Neoaliturus haematoceps (Mulstant et Rey, 1855)). One species Orosanga japonicus is recording for the first time from Iran and added to the key. PMID- 30313521 TI - Genus Microlithosia (Lepidoptera, Erebidae, Arctiinae) in Laos, with the description of a new species. AB - Microlithosia Daniel, 1954 from Laos is reviewed. A new species, Microlithosia laosana Bayarsaikhan Bae, n. sp., is described along with two newly recorded species, M. umbripuncta (de Joannis, 1928) and M. nanlingica Dubatolov, Kishida Wang, 2012. Illustrations of adults and male genitalia are provided. The checklist of the genus is updated. PMID- 30313522 TI - Type specimens of Chrysomelidae and Megalopodidae (Coleoptera) in the National Forest Insect Collection (NFIC), Forest Research Institute, Dehra Dun, India. AB - Type specimens of 28 species of Chrysomelidae and one of Megalopodidae present in National Forest Insect Collection (NFIC), Forest Research Institute (FRI), Dehra Dun (India) are digitized. Information such as label data, original citations, photographs of specimens from dorsal side, and condition of specimens are provided. These types (4 primary and 25 secondary) belong to 20 genera, i.e. 19 in 12 tribes of 5 subfamilies of Chrysomelidae-Bruchinae (Spermophagus atroapicalis Pic, S. notatipennis Pic, S. uniformis Pic, Bruchus bilineatopygus Pic, B. gardneri Pic, B. albocallosus Pic, and B. maculatithorax Pic), Cassidinae (Callispa almora Maulik, Downesia sasthi Maulik Estigmena bicolor Bhasin, and Platypria garthwaitei Bhasin), Cryptocephalinae (Aetheomorpha coorgensis Bryant, Aspidolopha nigrocurvilinea Bryant, A. ornaticollis Bryant, Chlamys padmanabhai Bhasin, C. travancorensis Bhasin, Exema fulvitarsis Bryant, E. salemensis Bhasin, Melixanthus coorgensis Bryant, and Gynandrophthalma flaviventris Bryant), Eumolpinae (Trichotheca beesoni Bryant), Galerucinae (Chaetocnema merguiensis Bryant, Diorhabda trirakha Maulik, Elytropachys sandalensis Bryant, Longitarsus cyanipennis Bryant, L. taklechensis Bryant, Podagrica apicefulva Bryant and Sastra mamaya Maulik), and one in Megalopodidae Megalopodinae (Temnaspis quadriplagiatus Bryant). PMID- 30313523 TI - Redescription of Trichomycterus striatus (Meek Hildebrand, 1913) (Siluriformes: Trichomycteridae), with notes on its geographic distribution. AB - Trichomycterus striatus is herein redescribed, based on examination of the types and recently collected specimens, and its geographic distribution is updated. This species can be diagnosed from all other northeastern South American congeners by its variable coloration pattern consisting of a yellowish to light brown background with a black lateral band and/or small dark brown spots on sides or uniformly light brown and by the following combination of characters: teeth conical arranged in three to four irregular rows in both jaws; anterior section of infraorbital canal (sensory pores i1 and i3) present; sensory pores s6 paired, 11-23 opercular odontodes; 27-44 interopercular odontodes; seven to eight pectoral-fin branched rays; 36-37 free vertebrae; 12-14 ribs; cleithrum pierced by several foramina; and caudal fin truncate to rounded. Trichomycterus striatus occurs from southern Costa Rica [from the Pirris (herein reported for the first time), Terraba and Coto River basins] to eastern Panama (in most of the main river basins in both the Pacific and Atlantic versants), being the sole representative of the family in lower Central American waters. PMID- 30313524 TI - The genus Bolbonema Cobb, 1920 (Nematoda: Desmodoridae): emended diagnosis, key to males, and description of three new species from the continental shelf off northeastern Brazil. AB - The marine nematode genus Bolbonema has three valid species, the most recent one described eight years ago. Characteristics of the genus include the well-defined globular cephalic capsule and the long and short somatic setae along the body. Three previously undescribed species of this genus were collected on the continental shelf of the Potiguar Basin in northeastern Brazil. Bolbonema braziliensis sp. n. has a relatively large cryptospiral fovea amphidialis, gubernaculum a bent rod dorsally oriented and two subventral precloacal setae inserted on two small papillae above the cloaca. Bolbonema papillae sp. n. has a large multispiral fovea amphidialis with three turns, arched spicules with the proximal region rounded, a laminar and well-developed gubernaculum enfolding the distal portion of the spicules, and two subventral precloacal papillae just above the cloaca. Bolbonema zildae sp. n. has a spiral fovea amphidialis, no supplements, arched spicules with a velum, and the gubernaculum with a dorsal apophysis. These three new species increase to six the number of taxa known in the genus. A dichotomous key based on males, an emended diagnosis of the genus, and the first record of Bolbonema brevicolle Cobb, 1920 from Brazil are provided. PMID- 30313525 TI - The genus Ctenomelynthus (Hemiptera: Heteroptera: Coreidae: Acanthocephalini), with the description of three new species and key to the known species. AB - The genus Ctenomelynthus Breddin (1903) is redescribed, and three new species: C. sanchezi from French Guiana, and Venezuela, C. urbinus from Brazil, and C. venustulus from Suriname are described. Ctenomelynthus willineri (Kormilev, 1952), is synonymized under C. coxalis Breddin, 1903. One species, C. bridarollii (Kormilev) is designated as a nomen dubium. New distributional records for C. brunneiventris Breddin, C. coxalis Breddin, and C. inermibus (Distant) are included. Dorsal and ventral photographs and parameres of some species are included. A key to the six known species is given. PMID- 30313526 TI - Description of a new species of Hyalinocerus (Hemiptera: Cicadellidae) from southwestern China, with an update on the generic diagnosis. AB - Hyalinocerus mianyangensis Zhang sp. nov. is described and illustrated from Southwestern China. The generic diagnosis of Hyalinocerus are discussed and updated. A checklist and a key to the known Hyalinocerus species are presented. PMID- 30313527 TI - A new idiocerine leafhopper genus, Dianica, from China (Hemiptera: Cicadellidae). AB - The new idiocerine leafhopper genus Dianica gen. nov. is described and illustrated based one species, Dianica rugulosa sp. nov. from southwestern China. A diagnosis of the new genus is given and compared to the related genera. In addition, a key to genera and a checklist of species for Tasnimocerus group are also provided. PMID- 30313528 TI - First record and new species of the Oriental leafhopper genus Trifida Thapa Sohi (Hemiptera: Cicadellidae: Typhlocybinae) from China. AB - The Oriental leafhopper genus Trifida Thapa Sohi, 1986 and T. quadripunctata are recorded from China for the first time. Three new species, T. eleganta, T. robusta and T. elongata spp. nov., are described and illustrated. A check-list and key to all species of Trifida are provided. PMID- 30313529 TI - Erratum: JAROSLAV STARY ALAN E. STUBBS (2015) Five species under Dicranomyia (Dicranomyia) mitis (Meigen, 1830) (Diptera, Limoniidae). Zootaxa, 3964: 321-334. PMID- 30313530 TI - Review of the Nearctic (north of Mexico) species of Elacatis Pascoe (Coleoptera: Salpingidae: Othniinae). AB - The North American (north of Mexico) species of Elacatis were revised, based on external and genitalic structures of adults. Seven species are recognized, though the historical inclusion of E. fasciatus Bland among Nearctic species is very likely based on an erroneous collecting locality. Two new species are described, with type localities (counties only) in parentheses: E. larsoni (Nebraska: Box Butte County) and E. stephani (Arizona: Cochise County). The following new synonym is proposed: Othnius umbrosus LeConte 1861 = Othnius lugubris Horn 1868; therefore, only E. umbrosus (LeConte) is associated with dead/dying conifers in western North America. Larval E. umbrosus are thought to be xylophagous, while adults are very likely predaceous. Elacatis senecionis (Champion) and E. immaculatus (Champion) are recorded from north of Mexico for the first time. A lectotype is designated for Elacatis longicornis Horn. A key to the seven species in Canada and the United States is provided, supplemented with photographic images of habiti and selected structural features. Maps of known distributions, based on geo-referenced locality lists, are provided. PMID- 30313531 TI - Two new species of bent toed geckos, Cyrtodactylus Gray, 1827 (Squamata: Gekkonidae) from Northeast India with comments on name-bearing types from the region. AB - Two new species of the genus Cyrtodactylus are described based on collections from Northeast India, and descriptions and diagnoses of previously described species and synonyms from the region are provided. One of the new species from lowland habitats in Tripura is medium sized, with a continuous series of precloacal pores, and is allied to C. ayeyarwadyensis from Myanmar; while the other new species from West Bengal is smaller, with both femoral and precloacal pores, and is related to C. gubernatoris from West Bengal and Sikkim. We designate a lectotype for Cyrtodactylus khasiensis and recognize the C. khasiensis synonym Gymnodactylus himalayicus as a valid species of Cyrtodactylus based on morphological evidence, and suggest the recognition of the last remaining subspecies of C. khasiensis, C. k. cayuensis, as a valid species based on geography and morphology. The stabilization of the taxa Cyrtodactylus khasiensis and C. gubernatoris with a limited subset of characters and specific distributional data, as well as the elevation of Cyrtodactylus himalayicus comb. nov. from synonymy, will allow the descriptions of many more Cyrtodactylus species from the region. PMID- 30313532 TI - The genus Clerotalia Jacoby of Taiwan (Coleoptera: Chrysomelidae: Galerucinae). AB - Six new species within the genus Clerotalia Jacoby are described from Taiwan based on study of more than 340 specimens: C. cheni sp. nov., C. jungchani sp. nov., C. meihuai sp. nov., C. tsoui sp. nov., C. wulaiensis sp. nov., and C. yuae sp. nov.. Clerotilia shirozui (Kimoto, 1969) is regarded as a junior synonym of C. formosana (Chujo, 1963). Adults were collected by sweeping food plants, including Rhamnus nakaharae and R. formosana (Rhamnaceae). PMID- 30313533 TI - Description of two new species of Cryptinglisia Cockerell (Hemiptera: Coccomorpha: Coccidae) associated with rosemary, Rosmarinus officinalis L. (Lamiaceae) in Colombia. AB - In this study, two new species of soft scale (Hemiptera: Coccomorpha: Coccidae) associated with rosemary, Rosmarinus officinalis L. (Lamiaceae) from Colombia, Cryptinglisia corpoica Kondo Montes sp. nov. and Cryptinglisia ica Montes Kondo sp. nov. are described and illustrated based on the adult female. Two other coccid species, namely Parasaissetia nigra (Nietner) and Saissetia coffeae (Walker), are newly recorded on rosemary. An identification key is presented to all species of soft scale that have been reported on Rosmarinus spp. An updated key to soft scale insects of the genus Cryptinglisia Cockerell is provided also. PMID- 30313534 TI - Phasmarhabditis safricana n. sp. (Nematoda: Rhabditidae), a parasite of the slug Deroceras reticulatum from South Africa. AB - During a survey for mollusc-associated nematodes in South Africa, a new Phasmarhabditis species was isolated from the invasive slug, Deroceras reticulatum, collected from a nursery near George in the Western Cape province. The nematode was identified using a combination of morphological, morphometric, molecular, and phylogenetic techniques. The new species, P. safricana n. sp., is characterised by the cupola-shaped tail of the female with a spike, small, non protruding phasmids, a fingerprint-like pattern of the cuticle covering the female tail, toothlike cephalic structures of the infective juveniles, and the distinct molecular characteristics of the species. The molecular phylogeny of the new species, as inferred from its SSU and LSU rRNA gene, places P. safricana n. sp. in close proximity to P. papillosa. Virulence tests were conducted, which demonstrated that P. safricana n. sp. caused significant mortality to the European invasive slug, D. reticulatum. The new species brings the total complement of the genus to eleven species. PMID- 30313535 TI - Exostoma ericinum, a new glyptosternine catfish from southwestern China (Teleostei: Siluriformes: Sisoridae). AB - A new species of glyptosternine catfish in the genus Exostoma is described in this study. The new species, E. ericinum, is known from the upper Dayingjiang (=Taping River) drainage in southwestern China and is distinguished from congeners in having an unique combination of the following characters: 42-44 vertebrae; parallel striae on anterolateral surfaces of lips and lower surface of maxillary barbel; interorbital distance 26-31% HL; preanal length 67.7-70.5% SL; body depth at anus 10.4-12.0% SL (1.4-1.9 times in caudal peduncle depth); length of adipose-fin base 39.5-43.0% SL; lacking an incision at posterior extremity of adipose-fin base; caudal peduncle length 23.2-26.2% SL; caudal peduncle depth 5.7 7.9% SL; and caudal-fin lobes with slightly concave posterior margin. PMID- 30313536 TI - Out of the dark void: Ommatoiulus longicornis n. sp., a new julid from Spain (Diplopoda, Julida) with notes on some troglobiomorphic traits in millipedes. AB - A new millipede species, Ommatoiulus longicornis n. sp. is described from the subterranean habitat in eastern Spain, and the elongation of its antennae is discussed in relation to the habitat where it dwells. We take the occasion to discuss the elongation of appendages as a troglobiomorphic character in millipedes and shed the light on the various, sometimes controversial, hypotheses that could have led to these modifications in millipedes and other subterranean arthropods. PMID- 30313537 TI - Females of two species of Argia from Chapada dos Guimaraes National Park, Brazil (Odonata: Coenagrionidae). AB - The female of Argia tupi Calvert, 1909 (BRAZIL, Mato Grosso, Chapada dos Guimaraes National Park, Cachoeira do Marimbondo (15.4330 degrees S, 55.7198 degrees W, 370 m), 01 xi 2015) is described, illustrated and diagnosed based on comparison with sympatric species of Argia Rambur, 1842. We also augmented the description of Argia bicellulata (Calvert, 1909) female (BRAZIL, Mato Grosso, Chapada dos Guimaraes National Park, Rio Paciencia (15.3438 degrees S, 55.8322 degrees W, 280 m), 25 x 2015). PMID- 30313538 TI - Neotype designation and redescription of Inostemma indicum (Platygastroidea: Platygastridae) parasitizing ivy gourd gall midge. AB - Inostemma indicum Mani, a parasitoid of Neolasioptera cephalandrae Mani (Diptera: Cecidomyiidae), collected from stem galls of ivy gourd (Coccinia grandis (L.) Voigt (Cucurbitaceae)) was described by Mani in 1941. The original description is scanty and ambiguous, with little diagnostic value. The holotype, a dissected female mounted on a slide, is lost. It is redescribed with illustrations and a neotype is designated. The previously unknown male is also described. PMID- 30313539 TI - Taxonomic Status of the Streaked Saltator, Saltator striatipectus (Passeriformes: Thraupidae), from Puna Island, Ecuador. AB - The Streaked Saltator, Saltator striatipectus, is an uncommon to common resident of open areas, cultivated land, gardens, and forest edges, with ten subspecies recognized from west Costa Rica through west Peru (Brewer 2016). Patterns of plumage variation, especially mantle color and streaking pattern below, are complex across subspecies and age classes (Chapman 1926; Ridgely Tudor 2009; Brewer 2016). Until recently, S. striatipectus was considered conspecific with the Lesser Antillean Saltator S. albicollis, but separated on the basis of genetic differentiation despite overall plumage similarities (Seutin et al. 1993). Actually, S. striatipectus and S. albicollis are not each other's closest relatives (Chaves et al. 2013). PMID- 30313540 TI - A new species of Microhyla Tschudi, 1838 (Anura: Microhylidae) from West Coast of India: an integrative taxonomic approach. AB - A new species of microhylid frog Microhyla kodial sp. nov. from the west coast of India is described in this paper. It is distinct from all described species of Microhyla occurring in South and Southeast Asia as revealed by a combination of morphological, molecular and acoustic characters. The new species is characterized by absence of lateral body stripe, tuberculated dorsal skin surface, absence of webbing between fingers, presence of basal webbing between toes and absence of dorsal marginal groove on finger and toe disc. Each male advertisement call lasts for 0.11-0.42 s and is comprised of 2-7 pulses with a dominant frequency of 3.3-4.2 kHz. The breeding season is short, limited to the rainy season (June to September) and the females lay up to 300 eggs per clutch. A molecular phylogenetic tree constructed using the mitochondrial 16S rRNA gene shows that M. kodial sp. nov. is closely related to the M. achatina group from Southeast Asia. The uncorrected genetic divergence between the new species and its closest congeners M. heymonsi, M. mantheyi, M. borneensis and M. orientalis were 7.3-7.6 %, 7.5-7.8%, 7.8-8.1% and 8.1-8.4% respectively. At present, this species is known only from the type locality, a highly disturbed urban and industrialized area which needs conservation intervention. PMID- 30313541 TI - Three new mealybug species (Hemiptera: Coccomorpha: Pseudococcidae) from Iran. AB - Three new mealybug species, Dysmicoccus caspianensis sp. n., Dysmicoccus zagrosicus sp. n. and Phenacoccus bromi sp. n. (Hemiptera: Pseudococcidae), collected from protected areas in Iran, are described and illustrated. The identification keys to Phenacoccus species lacking ventral multilocular disc pores and Dysmicoccus species in Iran are presented. PMID- 30313542 TI - A new genus, four new species and taxonomic and geographic notes in Mexican Cerambycidae. AB - Four new Mexican species are described: Ironeus curoei from Guerrero state, Psyrassa garciai from Tamaulipas state, Psyrassa belangeri from Guerrero state (Elaphidiini, Cerambycinae); and Cirrhicera bankoi from Chiapas state (Hemilophini, Lamiinae). A new Hesperophanini genus, Makromastax, and a new combination, Makromastax mandibularis are proposed. The current key to the Mexican genera of Hesperophanini is updated to include the new genus. Haplidus nitidus Chemsak and Linsley, 1963 is proposed as synonyms of Haplidus mandibularis Chemsak and Linsley, 1963. The male of Eburia (E.) girouxae is illustrated by the first time and Anelaphus hirtus is redescribed and figured. The geographical distribution of 9 species is expanded, the type locality of Osmidus guttatus is corrected, and Neocompsa intrincata is excluded from the fauna of the United States of America. PMID- 30313543 TI - Fleas (Siphonaptera) of Turkey: species composition, geographical distribution and host associations. AB - A list of the fleas species reported from Turkey is provided, with their geographical distribution and host associations. A total of 115 flea taxa (83 species, 32 subspecies) belonging to 36 genera and seven families are listed. The most common families are Ctenophthalmidae (n= 44) and Ceratophyllidae (27), followed by Ischnopsyllidae (13), Leptopsyllidae (11), Pulicidae (11), Vermipsyllidae (5) and Hystrichopsyllidae (4). PMID- 30313544 TI - Pupal stages of three species of the phytophagous genus Merodon Meigen (Diptera: Syrphidae). AB - plants, are mostly unknown. All known immature stages of Merodon feed on underground storage organs (bulbs, rhizomes and corms) of geophytes of the families Asparagaceae, Iridaceae and Amaryllidaceae. Of 160 known Merodon species, to date, the pupal stages have been described for only four: M. equestris (Fabricius), M. bombiformis Hull, M. luteihumerus Marcos-Garcia, Vujic Mengual, and M. geniculatus Strobl. During field investigations in Derdap National Park, Serbia, Merodon puparia were found in the ground near the bulbs of Ornithogalum umbellatum L. (Asparagaceae). DNA barcoding revealed that they belonged to the species M. aureus Fabricius and M. avidus (Rossi). Analysis of museum material from the Bavarian State Collection of Zoology in Germany revealed the puparium of an additional species, M. rufus Meigen. In our study we provide for the first time descriptions of the puparia of these three Merodon species. The main diagnostic morphological characters of the pupal spiracles and posterior respiratory processes are described using scanning electron microscopy, and cephalopharyngeal skeletons using binocular microscopy. In addition, puparium morphology of M. aureus, M. avidus and M. rufus is compared with known puparia of four other Merodon species and with the third larval stage of M. hurkmansi Marcos Garcia, Vujic Mengual. PMID- 30313545 TI - A multiplex PCR method for identification of two common true cutworm species (Lepidoptera: Noctuidae) tested in the central plain of Guilan province, Iran. AB - Many species of cutworms (Lepidoptera: Noctuidae) are important agricultural pest. They feed on roots and foliage of their host plants. Traditionally these species are identified based on morphological characteristics of adults. Hence identification of specimens in poor condition, immature stages and also closely related species or cryptic species is a difficult task. The basics of biological and ecological studies largely rely on an accurate species identification; consequently these investigations are impacted by potential misidentifications. In this study, we amplified 5' region of mitochondrial c cytochrome oxidase subunit I (COI) gene (DNA barcode region) of various common true cutworm species including Agrotis ipsilon (Hufnagel, 1766), Agrotis exclamationis (Linnaeus, 1758), Peridroma saucia (Hubner, 1808) and Xestia c-nigrum (Linnaeus, 1758) from agricultural fields of Guilan province (North of Iran). We were able to detect 66 conservative Single Nucleotide Polymorphisms (SNPs) among the targeted pest species and eventually design specific primers and develop a multiplex polymerase chain reaction assay as a molecular diagnostic tool for immature stages of two the most common and abundant species including A. ipsilon and X. c-nigrum in Guilan province. PMID- 30313546 TI - Description of a new species of Gracixalus (Amphibia: Anura: Rhacophoridae) from Guangdong Province, southeastern China. AB - A new species of tree frog, G. guangdongensis sp nov., is described based on a series of specimens collected from Dawuling Forest Station, Mount Nankun and Nanling Nature Reserve of Guangdong Province, southeastern China. The new species is distinguished from all known congeners by a significant genetic divergence at the mitochondrial 16S rRNA gene fragment examined (p-distance >= 4.6%) and the following combination of morphological characters: relatively small body size (SVL 26.1-34.7 mm in adult males, 34.9-35.4 mm in adult females); upper eyelid and dorsum lacking spines; supratympanic fold and tympanum distinct; dorsal and lateral surface rough, sparsely scattered with tubercles; ventral skin granular; tibiotarsal projection absent; toe-webbing moderately developed, finger webbing rudimentary; heels slightly overlapping when flexed hindlimbs are held at right angles to the body axis; brown to beige above, with an inverse Y-shaped dark brown marking extendeing from the interorbital region to the centre of the dorsum; males with a single subgular vocal sac and protruding nuptial pads with minute granules on the dorsal surface of the base of first finger. The discovery and description of Gracixalus guangdongensis sp. nov. represents the 14th species known in this genus. PMID- 30313547 TI - A new Culeolus species (Ascidiacea) from the NE Pacific, California. AB - The paper describes Culeolus barryi n. sp. (Ascidiacea: Pyuridae), a species photographically documented in situ and collected in the northeast Pacific, off the coast of California (USA). This species of stalked tunicate inhabits deepwater (1200 m) and is characterized by numerous gonads on each side of the body. It is most similar to C. nadejdae from the Sea of Okhotsk and C. sluiteri from Aleutian Islands. A brief overview of all Culeolus species is provided. PMID- 30313548 TI - New record of the genus Zombrus Marshall, 1897 (Hymenoptera: Braconidae: Doryctinae), with description of three new species from Vietnam. AB - The genus Zombrus Marshall, 1897, is newly recorded for Vietnam with four species. Three new species (Z. bicoloricorpus Long, sp. n., Z. flavicorpus Long van Achterberg, sp. n., and Z. tricoloricorpus Long, sp. n.) are described and illustrated, and one species (Z. pallidiventris Cameron, 1910) is reported for the first time from Vietnam and outside Indonesia. The key to Oriental and Palaearctic species of Zombrus and a checklist with distributions of the nine species from Oriental and Palaearctic regions are provided. PMID- 30313549 TI - A new species catfish, Amphilius pagei (Siluriformes: Amphiliidae) from Angola. AB - Amphilius pagei, a new species of amphiliid catfish is described from the Cuanza River basin in Angola. It is distinguished from all other species of Amphilius by the combination of presence (vs. absence) of an epidermal fold at the base of the caudal fin, 6+7 (i,5,6,i) principal caudal-fin rays (vs. 7+8 or 8+9), a variably mottled body coloration that includes dark saddles (vs. body coloration not mottled with dark saddles), head and body heavily spotted (vs. head and body not heavily spotted), epidermal fold smooth (vs. crenelations present on epidermal fold), branchiostegal rays usually eight or nine, and total gill rakers usually 12-16. It is most similar to A. lentiginosus which has a crenelated epidermal fold and fewer branchiostegal rays. PMID- 30313550 TI - Early Pleistocene and Holocene bryozoans from Indonesia. AB - This paper describes 40 bryozoan species, comprising one cyclostome and 39 cheilostomes (8 anascan- and 31 ascophoran-grade), obtained from early Pleistocene and Holocene samples from two localities in Indonesia. Five of the cheilostomes are described as new species: Acanthodesia variegata n. sp., Pleurocodonellina javanensis n. sp., Calyptotheca sidneyi n. sp., Characodoma wesselinghi n. sp., and Turbicellepora yasuharai n. sp. All of the remaining species are extant and characterized by a tropical to subtropical Indo-West Pacific distribution. PMID- 30313551 TI - Taxonomic study of the genus Evergestis Hubner, 1825 (Lepidoptera: Crambidae: Glaphyriinae) in Iran with description of a new species. AB - The Iranian species of the genus Evergestis were reviewed taxonomically and as a result, Evergestis pazukii sp. n. is described as a new species, E. comealis Amsel stat. n. is raised to species level from the subspecies E. caesialis comealis, and four species, namely E. flavifuscalis Rebel, E. limbata (Linnaeus), E. pechi (Bethune-Baker), and E. serratalis Staudinger are newly reported from Iran. Furthermore, the females of Evergestis africalis (Guenee), and E. nomadalis (Lederer), and the male of E. elbursalis Amsel are described and illustrated for the first time. A redescription of the male of E. hyrcanalis Amsel is provided mainly based on the genital structure, and the male and female genitalia of E. boursini Amsel and E. flavifuscalis Rebel are redescribed, respectively due to their poor descriptions. Additional remarks on the previousely reported species and new data on their distribution in Iran are also provided. PMID- 30313552 TI - One hundred years of solitude ended: A second species of Marmasoma White, 1916 (Diptera, Bombyliidae, Bombyliinae, Eclimini) from Australia. AB - Known as a monotypic genus for over a century, Marmasoma White, 1916 is an endemic Australian bee fly genus belonging to the tribe Eclimini of the subfamily Bombyliinae. A new species: Marmasoma hortorum sp. nov. is described based on a series of specimens from Western Australia and South Australia. This new species can be easily distinguished from the congener by the inconspicuous pale wing markings and mostly white to pale yellow scales on the body, as well as characters of both male and female genitalia. M. sumptuosum is found in south eastern Australia, including Tasmania, and some specimens have been collected on Kangaroo Island, South Australia. M. hortorum sp. nov. occurs in south Western Australia, and a pair of specimens has been taken just north of Port Augusta in South Australia. A key to species of Marmasoma is provided. PMID- 30313553 TI - Marine tardigrades of the Bahamas with the description of two new species and updated keys to the species of Anisonyches and Archechiniscus. AB - This is the first survey of subtidal marine tardigrades from the Bahamas, and we compare our results with earlier studies of Bahamian intertidal habitats. In 2011 and 2014 we collected 60 subtidal sand samples from Bimini, the Berry Islands, New Providence, Eleuthera, and the Exumas. We found 11 species only one of which, Dipodarctus subterraneus (Renaud-Debyser, 1959), had been found in the previous intertidal Bahamian collections. Thus, 10 species are new records for the Bahamas, and four of these are new to science. We describe two of the new species (Archechiniscus bahamensis sp. nov. and Anisonyches eleutherensis sp. nov.). Additional material is needed for a conclusive identification of the undescribed species of Batillipes and Florarctus. Based on examination of the holotype of Anisonyches diakidius Pollock, 1975, we redescribe this species and give an emended diagnosis of the genus and the species. We also provide new keys to the species in the genera Archechiniscus and Anisonyches. A Chao2 species richness estimate indicated that our sampling effort was extensive and probably recovered most common species. Correlations of abundance and diversity indices with regard to depth, distance to nearest shore, and sediment grain size were not significant. PMID- 30313554 TI - Three new species of Entomobryoidea (Collembola: Entomobryomorpha) from Brazilian Caatinga-Cerrado transition, with identification keys to Brazilian Cyphoderus, Pseudosinella and Trogolaphysa species. AB - Three new species of Entomobryoidea from Brazilian Caatinga-Cerrado transitional zone are described and illustrated, all from Sete Cidades National Park. Cyphoderus equidenticulati sp. nov. resembles C. javanus Borner and C. songkhlaensis Jantarit, Satasook Deharveng in number of mucro teeth, one inner distal tooth on unguis and four ciliated chaetae between the two rows of feathered scales of dens, but differs in claw with a pair of equally developed inner basal teeth, collophore, labial and dorsal chaetotaxy. Pseudosinella triocellata sp. nov. is mostly similar to P. stewartpecki Katz, Soto-Adames Taylor in number of eyes, presence of apical bulb on antennomere IV and one macrochaeta on mesothorax, but differs in head with S2 macrochaeta, anterior and posterior collophore chaetotaxy and empodial complex morphology. Trogolaphysa piracurucaensis sp. nov. is quite similar to the recently described T. ernersti Cipola Bellini in overall dorsal chaetotaxy but differs in ventral head, collophore and manubrial plate chaetotaxy. Identification keys for Brazilian species of Cyphoderus, Pseudosinella and Trogolaphysa are also provided. PMID- 30313555 TI - Two new species of crickets Adelosgryllus Mesa Zefa, 2004 (Orthoptera, Grylloidea, Phalangopsidae) from the Araripe-Apodi National Forest, State of Ceara, Brazil. AB - In this paper we describe two new sympatric species of phalangopsid crickets Adelosgryllus from the Araripe-Apodi National Forest, State of Ceara, Brazil, highlighting morphological characters, mainly from male genitalia, tegmina and copulatory papilla. We also present a geographical map for the valid species of the genus, as well as photographs of holotypes and paratypes. The type-material is deposited in the Museu de Zoologia da Universidade de Sao Paulo (MZUSP). PMID- 30313556 TI - A new species of myrmecophilous lady beetle in the genus Diomus (Coleoptera: Coccinellidae: Diomini) from Chiapas, Mexico that feeds on green coffee scale, Coccus viridis (Green) (Hemiptera: Coccidae). AB - A new species of myrmecophilous lady beetle, Diomus lupusapudoves, sp. nov. (Coleoptera: Coccinellidae: Diomini), is described from a coffee agroecosystem in Chiapas, Mexico. The new species was found preying on the green coffee scale pest, Coccus viridis (Green), tended primarily by Azteca sericeasur Longino and Pheidole synanthropica Longino ants. The larval, pupal, and adult stages of the new species are described and habitus illustrations or photos provided along with anatomical details of the adult male and female genitalia. The species is most similar to Diomus thoracicus Fabricius (=type species of Diomus), another myrmecophile, which inhabits ant nests and feeds on ant brood. The new species has a peculiar onisciform larva that lacks dorsal setae, features that it shares with D. thoracicus. The new species is only the second species in the genus reported as a myrmecophile, although the life histories of most species have been poorly documented. PMID- 30313557 TI - Gymnothorax odishi sp. nov. (Muraenidae: Muraeninae), a short brown unpatterned moray eel from Bay of Bengal, India. AB - Gymnothorax odishi sp. nov., a new short brown moray eel, is described here on the basis of eleven specimens collected from Gopalpur, Odisha, along the east coast of India, Bay of Bengal. The species is characterized with dorsal-fin origin before gill opening, jaw pores with dark rim, small black patch just behind the eye of about eye size or more, gill opening with dark rim, two branchial pores, predorsal vertebrae 4, preanal vertebrae 55-58 and total vertebrae 133-138, three large fang like median intermaxillary teeth, uniserial maxillary and vomerine teeth. The new species is compared with all short brown unpatterned moray eels known from the world. PMID- 30313558 TI - First record and a new species of Sericosura Fry Hedgpeth, 1969 (Arthropoda: Pycnogonida: Ammotheidae) from a hydrothermal vent of Southwestern Indian Ridge. AB - This is the first record of the genus Sericosura from the "Duanqiao" hydrothermal field on the Southwestern Indian Ridge. Collected material included two juvenile specimens temporarily assigned to S. bamberi and S. heteroscela respectively, and one male specimen with dimorphic legs here proposed as a new species, S. duanqiaoensis sp. nov. The discovery suggests potential connectivity among the hydrothermal vents of the Atlantic, Indian and Southern Oceans, expecting obtaining more specimens for further evolutionary studies to clarify the relationships of these hydrothermal vents. PMID- 30313559 TI - A new species of Mexican parrot? Reasonable doubt on the status of Amazona gomezgarzai (Psittaciformes: Psittacidae). AB - We present arguments against the recognition of Amazona gomezgarzai Silva et al., 2017 as a valid species. This putative new species was stated to have been discovered in Becanchen town in the central Yucatan Peninsula by a veterinarian, who presented two live individuals to the authors for description. This description has numerous weaknesses, as follows: 1) the Yucatan Peninsula avifauna is well-known, having been extensively explored by collectors and other ornithologists; 2) the authors were never in the relevant field area, nor did they verify that the two individuals obtained for the description came from a natural population; 3) our field trip to the type locality and distribution area failed to verify the existence of the putative new species there; instead, inhabitants of these localities denied that such a person was there and denied having given anyone the birds, nor did they recognize that there were parrots matching the "new" species in the area; 4) the description was prepared without proper voucher specimens; 5) comparisons in existing museum collections were highly inadequate; 6) the characters on which the description is based fail to support that it represents a valid taxon, instead strongly supporting an hypothesis of hybrid origin, which was untested by nuclear DNA markers; and 7) no collecting permits were mentioned in the paper. Although earlier reviewers pointed out weaknesses of the original manuscript, the authors failed to rigorously address these questions and the paper was nevertheless published. PMID- 30313560 TI - Chalcogenia brandli sp. nov. from Ethiopia (Coleoptera: Buprestidae: Anthaxiini). AB - Chalcogenia brandli sp. nov. from Ethiopia is described, illustrated and compared with the most similar species, and attributed to the Chalcogenia sulcipennis species-group within the genus Chalcogenia. PMID- 30313561 TI - A new species of subgenus Homoneura from Northern China, with information of 12 species newly recorded (Diptera: Lauxaniidae: Homoneura). AB - Homoneura (Homoneura) hanmaensis sp. nov. is described as new to science and 12 species are recorded from China for the first time: Homoneura (Homoneura) albomarginata Czerny, 1932, Homoneura (H.) biumbrata (Loew, 1847), Homoneura (H.) cerina Shatalkin, 2000, Homoneura (H.) euaresta (Coquillett, 1898), Homoneura (H.) filiola Czerny, 1932, Homoneura (H.) kaszabi Shewell, 1971, Homoneura (H.) lamellata (Becker, 1895), Homoneura (H.) mediospinosa Merz, 2003, Homoneura (H.) patella Shewell, 1971, Homoneura (H.) shewelliana Papp, 1978, Homoneura (H.) spinicauda Sasakawa and Ikeuchi, 1982, Homoneura (H.) tenera (Loew, 1846). A few of photographs and illustrations are provided for eight species. Keys are provided to separate eight species groups and Chinese species of eight species groups of subgenus Homoneura. PMID- 30313562 TI - The Rhyacophila fasciata Group in Western Europe: Confirmation of Rhyacophila denticulata McLachlan 1879 (stat. prom.) and Rhyacophila sociata Navas 1916 (stat. res.), based on morphological and molecular genetic evidence (Trichoptera: Rhyacophilidae). AB - In order to check the presence and distribution of Rhyacophila fasciata fasciata Hagen 1859 (species described from Austria) and R. fasciata denticulata McLachlan 1879 in the Iberian Peninsula, we studied the morphology of Spanish, French, and Austrian specimens, together with their mitochondrial cytochrome c oxidase (mtCOI). We observed that the individuals considered to date as R. fasciata denticulata are in fact two different species: R. denticulata, presently known from France and possibly in some rivers of the Basque Country (Spain), and R. sociata Navas 1916 distributed in Spain and France. These two species are also different from the reference species (R. fasciata) from Austria, so we propose a change in the taxonomic status of R. fasciata denticulata to R. denticulata (stat. prom.) and the restoration of R. sociata (stat. res.), with the designation of a neotype, due to the loss of the holotype. PMID- 30313563 TI - Cladocera from the Upper Xingu River Basin with the description of a new genus of the Chydoridae (Crustacea: Branchiopoda: Anomopoda). AB - In this study, we investigated cladocerans (Crustacea: Branchiopoda) collected in six water bodies from the Upper Xingu River Basin, Central Brazil. In total, we found eighteen species belonging to three families. Furthermore, we also describe a new and highly specialized genus of Chydoridae. Kisakiellus aweti gen. nov., sp. nov. which shares some morphological traits with members of Chydorinae, particularly the exopodite of the fourth limb armed with seven setae. The new genus bears several autapomorphies and does not exhibit any clear affinities with any other genus of the subfamily. Apparently, K. aweti gen. nov., sp. nov. has a positive rheotactic behavior and the morphological characters related to this habitat trait are discussed. Many regions of the Upper Xingu River Basin are still in need of faunal inventories, a fact that gains more relevance due to the high potential for cryptic biodiversity. So, it is possible that an increase on the sampling effort in this basin will have a positive impact on the known diversity of Cladocera. PMID- 30313564 TI - A new species of Amolops (Anura: Ranidae) from southwestern Guangdong, China. AB - A new species, Amolops yunkaiensis sp. nov. is described based on a series of specimens from Ehuangzhang Nature Reserve and Yunkaishan Nature Reserve, southwestern Guangdong Province, China. The new species can be distinguished from all known congeners by molecular divergence in the mitochondrial 16S rRNA, 12S rRNA and CO1 genes, and a combination of the following characters: relatively small body size, SVL 31.8-34.1 mm in adult males, 35.2-39.0 mm in adult females; numerous raised large warts on dorsum and flanks; dorsal body olive-brown or light brown with dark brown blotches; absence of vomerine teeth; absence of tarsal glands; presence of a pair of subgular vocal sacs, nuptial spines on the first finger, and sparse translucent tubercles on the lower jaw, forechest, posterior belly and ventral thigh in male. Hence, the genus Amolops contains 52 species, 29 of which occur in China. PMID- 30313565 TI - Cirrhilabrus cyanogularis, a new species of fairy wrasse from the Philippines and Indonesia (Teleostei: Labridae). AB - Cirrhilabrus cyanogularis, sp. nov., is described on the basis of the holotype and three paratypes from Banguingui Island, Sulu Archipelago, Philippines, and a paratype from Sulawesi, Indonesia. The new species belongs to a complex consisting of C. filamentosus (Klausewitz), C. rubripinnis Randall Carpenter, and C. tonozukai Allen Kuiter. Aside from similar nuptial male coloration, the four species share the following character combination: a single row of cheek scales; dorsal-fin spines taller than dorsal-fin rays (slightly incised between spinuous and soft dorsal fin in C. rubripinnis and C. cyanogularis; last three dorsal-fin spines converging to form a single filament in C. tonozukai and C. filamentosus); relatively long pelvic fins (reaching past anal-fin origin); and isthmus and breast blue. The new species differs from the other members of the complex in lacking a dorsal filament, as well as possessing six predorsal scales, more extensive blue coloration on the isthmus, lower head and breast, and a soft dorsal fin with narrow black, medial stripe. The status of Klausewitz's Cirrhilabrichthys is briefly discussed. PMID- 30313566 TI - A new species of Selatosomus Stephens and the occurrence of Pristilophus melancholicus (Fabricius) in China (Coleoptera: Elateridae: Dendrometrinae). AB - Selatosomus huanghaoi Qiu, new species is described from Yunnan, China. Habitus and diagnostic characters of the new species are illustrated. The presence of Pristilophus melancholicus (Fabricius) in China is confirmed. PMID- 30313567 TI - 'On Psilorhynchus sucatio and P. nudithoracicus', the sequel: Unnecessary and unscientific names lead to rapid synonymization and taxonomic time wasting-A response to Arunachalam et al. (2018). AB - The Torrent minnows Psilorhynchus sucatio (Hamilton, 1822) and P. nudithoracicus Tilak Husain, 1980 are widespread throughout the Ganges-Brahmaputra drainage of India, Bangladesh and Nepal (Conway et al., 2013). Like many widespread species, P. sucatio and P. nudithoracicus exhibit high levels of variation in morphological traits (particularly colour pattern) across their respective ranges and both have been described on more than one occasion by different authors examining material obtained from different parts of their range and/or unaware of earlier works. The distinctive, long-snouted torrent minnow Psilorhynchus sucatio was described by Hamilton (1822: 347) based on material from "Northern Bengal" (no types known). David (1953) introduced the name P. sucatio damodarai for a "variety" (=subspecies; ICZN, 1999; art. 45.6.4) of P. sucatio from the Damodar River (Jharkhand and West Bengal) and Tilak Husain (1980) described the subspecies P. sucatio nudithoracicus based on material from Uttar Pradesh. In 1983, Rainboth described Psilorhynchus gracilis based on a smaller, more slender series of Psilorhynchus with a shorter snout than P. sucatio, collected in the tributaries of the Ganges and Brahmaptura rivers in northern Bangladesh. In 2013, Conway et al. argued that the names P. s. nudithoracicus and P. gracilis referred to the same species, placed the latter in the synonymy of the former, and elevated P. nudithoracicus to species status. As part of their redescription of P. sucatio and P. nudithoracicus, Conway et al. (2013) examined large series of specimens representing a range of body sizes (462 specimens of P. sucatio [13-67 mm SL] and 97 of P. nudithoracicus = [10-68 mm SL]), and encompassing almost the entire range of both species, provided multiple figures illustrating the important anatomical features of both species and, most importantly, provided clear diagnoses. PMID- 30313568 TI - New species and additional data on the chewing louse genus Myrsidea (Phthiraptera: Menoponidae) from wild Neotropical Passeriformes (Aves). AB - Twenty-four species of chewing lice of the genus Myrsidea Waterston, 1915 (Phthiraptera: Menoponidae) from Neotropical Suboscines (Passeriformes: Formicariidae, Furnariidae, Pipridae, Thamnophilidae, Tityridae, Tyrannidae) are recorded and discussed. They include: eight new species which are described and illustrated (Myrsidea capeki new species ex Chiroxiphia caudata; Myrsidea leptopogoni new species ex Leptopogon superciliaris; Myrsidea leucophthalmi new species ex Automolus leucophthalmus; Myrsidea pachyramphi new species ex Pachyramphus polychopterus; Myrsidea philydori new species ex Philydor rufum; Myrsidea pyriglenae new species ex Pyriglena leucoptera; Myrsidea scleruri new species ex Sclerurus scansor and Myrsidea zuzanae new species ex Furnarius rufus), as well as nine previously known species with additional data on intraspecific morphological variability, host associations and geographical distribution (Myrsidea barbati Price, Hellenthal Dalgleish, 2005; Myrsidea dalgleishi Valim, Price Johnson, 2011; Myrsidea flaviventris Price, Hellenthal Dalgleish, 2005; Myrsidea klimesi Sychra, 2006; Myrsidea meyi Valim, Price Johnson, 2011; Myrsidea oleaginei Price, Hellenthal Dalgleish, 2005; Myrsidea olivacei Price, Hellenthal Dalgleish, 2005; Myrsidea pitangi Price, Hellenthal Dalgleish, 2005 and Myrsidea spellmani Price, Johnson Dalgleish, 2008b). Seven further species are recorded at genus level only due to lack of adequate material. A 379 bp portion of the mitochondrial cytochrome oxidase I (COI) gene was sequenced from seven species in order to assess relative genetic divergences among Myrsidea populations. PMID- 30313569 TI - Taxonomic review of the genus Commatarcha Meyrick (Lepidoptera: Carposinoidea: Carposinidae) from China, with descriptions of four new species. AB - Nine species of the genus Commatarcha Meyrick, 1935 from China are reviewed. Four species: Commatarcha convoluta Li, sp. nov., C. setiferaedeaga Li, sp. nov., C. hamata Li, sp. nov. and C. rotundivalva Li, sp. nov. are described as new. Commatarcha palaeosema Meyrick, 1935 is newly recorded in China. The male of C. angustiptera Li, 2004 and the female of C. guangxiensis Li, 2004 are reported for the first time. A key to the Commatarcha species in China is given. PMID- 30313570 TI - Taxonomic review of the genus Pygophora Schiner of Japan (Diptera: Muscidae). AB - Japanese species of the genus Pygophora Schiner, 1868 are reviewed, with redescription of the following species: P. boninensis Snyder, 1965; P. confusa, 1915; P. immaculipennis Frey, 1917; P. lepidofera (Stein, 1915); P. longicornis (Stein, 1918); P. macularis (Wiedemann, 1830); P. maculipennis Stein, 1909; P. respondens (Walker, 1859); P. unicolor (Stein, 1920). New occurrence records are presented to P. macularis (Wiedemann, 1830), P. respondens (Walker, 1859), and P. unicolor (Stein, 1920). Pygophora trimaculata Karl, 1935 is excluded from Japanese species, as it had been based on a misidentification. The male and female terminalia are illustrated, and an identification key to the Japanese species is provided. PMID- 30313571 TI - Morphological variation of the rare psammophilous species Apostolepis gaboi (Serpentes, Dipsadidae, Elapomorphini). AB - Apostolepis gaboi was described based only on the holotype found in the Queimadas, state of Bahia, northeastern Brazil. Since its original description, no additional specimens were reported in literature and the species was considered to be rare and poorly known. Here, we provide a detailed description for the species based on the examination of the holotype and 34 additional specimens from the type locality and adjacent areas. Additional information is also provided on intraspecific color variation and hemipenial morphology. PMID- 30313572 TI - A new species and subgenus of Pachylaelaps Berlese from Turkey (Acari: Pachylaelapidae). AB - This paper reports on three interesting species of the mite family Pachylaelapidae from Turkey (Acari: Mesostigmata). A new subgenus Longipachys Masan Ozbek, subgen. nov., with type species Pachylaelaps (Longipachylaelaps) anatolicus Ozbek, is erected in the genus Pachylaelaps Berlese. The description of P. anatolicus is extended to include females and males found in leaf litter in various habitats. A new species Pachylaelaps (Pachylaelaps) armiger sp. nov. is described, and compared with related species that have a polydentate chelicera. Pachylaelaps (Pachylaelaps) evansi Costa, 1971, a species previously reported from Israel, is recorded in Turkey for the first time. PMID- 30313573 TI - A new species of Pasiphaea Savigny, 1816 (Crustacea, Decapoda, Pasiphaeidae) from the southwestern Atlantic. AB - The genus Pasiphaea Savigny, 1816 (Caridea: Pasiphaeidae) includes 71 species, of which vast majority inhabit in the meso or bathypelagic zones in the world oceans. A new species is described herein, sampled during the project "ABRACOS 2" (Acoustic along the BRazilian COast) nearby the Rocas Atoll and Fernando de Noronha Archipelago, in Brazilian waters. Pasiphaea antea n. sp. appears close to Pasiphaea dorsolineatus Komai Chan, 2012 described from off Hawaii, but is distinguished from the latter by the different shape of the rostrum, the mid dorsal line of the carapace sharply carinate in the anterior half, and the possession of more numerous spiniform setae on the meri of the pereopods 1 and 2. This is the third species known from the southwestern Atlantic. PMID- 30313574 TI - New replacement name for Anaperus Graff, 1911 (Acoelomorpha: Acoela: Convolutidae). AB - The acoel genus Anaperus was established by Graff in 1911 for Amphiscolops gardineri Graff, 1910, making Anaperus gardineri (Graff, 1910) its type species. Since then, six more valid species were described: A. tvaerminnensis (Luther, 1912); A. sulcatus Beklemischev, 1914; A. rubellus Westblad, 1945; A. biaculeatus Boguta, 1970; A. ornatus Beltagi, 2001; A. singularis Hooge Smith, 2004. A seventh species, A. australis Westblad, 1952, is incertae sedis (Dorjes Karling, 1975). The genus was placed to family Convolutidae Graff, 1905, until Dorjes (1968) erected the family Anaperidae on the basis of a distinctive male copulatory apparatus. Jondelius et al. (2011) returned it to Convolutidae on the basis of molecular-sequence data. PMID- 30313575 TI - Annotated bibliography of the parthenogenetic marbled crayfish Procambarus virginalis, a new research model, potent invader and popular pet. AB - The marbled crayfish Procambarus virginalis is a new obligately parthenogenetic species that was detected in the mid-1990s in the German aquarium trade. Since then it has become a popular pet in many countries throughout the world and a valuable laboratory model for a broad range of biological disciplines. Releases have led to the establishment of wild populations in several European countries, Madagascar and probably Japan, making marbled crayfish an interesting paradigm of evolutionarily young and ongoing bioinvasions. This article provides an annotated bibliography of the scientific and popular scientific literature on marbled crayfish from its detection until today. Each reference is assigned to a publication format and one or more biological categories. The content is shortly described and its significance for marbled crayfish research and general biology is assessed. Of the 239 references listed 140 (58.6%) deal primarily with laboratory experiments on the biology of marbled crayfish and the establishment and use of marbled crayfish as a research model, 74 (31.0%) with its biogeography, invasions and ecology and 25 (10.4%) with hobby aquarist issues and the pet trade. PMID- 30313576 TI - Key to Chinese species of Copidosoma (Hymenoptera: Encyrtidae), with new records and three new species. AB - Six species of Copidosoma (Hymenoptera: Encyrtidae) from Southwestern China are reviewed, including three new species (C. heinitane sp. nov., C. linzhiensis sp. nov., C. longchuane sp. nov.) and two species newly recorded from China (C. longiclavatum Kazmi Hayat and C. recurvariae Sharkov). Copidosoma serricorne (Dalman) is newly recorded from Xizang, southwestern part of China. A key to all the Chinese species of the genus based on females is given. PMID- 30313577 TI - One new species, two generic synonyms and eight new records of Thripidae from China (Thysanoptera). AB - Baliothrips sunae sp.n. is described from eastern China, and eight thripid species are newly recorded from China. One species is shared with Europe, three with Australia and four with southeast Asia. Chilothrips Hood is synonymized with Oxythrips Uzel, and Graminothrips Zhang Tong is synonymized with Organothrips Hood. PMID- 30313578 TI - A new species of Bryconops (Characiformes: Iguanodectidae) from the Rio Tapajos basin, Brazil. AB - A new species of Bryconops is described from upper rio Juruena drainage, rio Tapajos basin, Amazon basin, state of Mato Grosso, Brazil. The new species is hypothesized as belonging to the subgenus Creatochanes by presenting the posterior extension of maxilla reaching to the junction of second and third infraorbital bones, and the ventroposterior margin of second infraorbital forming a complete border with third infraorbital, resulting in the lack of a naked area between them. The new species is easily distinguished from other species of the subgenus Creatochanes by the color pattern of the caudal fin, which consists of the dorsal lobe conspicuously dark pigmented on its distal half and the ventral lobe dark gray pigmented along its ventral portion below the horizontal through the ventral margin of the caudal peduncle. PMID- 30313579 TI - A new species of Sweltsa (Plecoptera: Chloroperlidae) from Sichuan Province of southwestern China. AB - A new chloroperlid stonefly species, Sweltsa brevihamula sp. nov. from Sichuan Province of southwestern China is described and illustrated. We also provide a provisional key to the known Sweltsa males of China. PMID- 30313580 TI - Both non-type species of Molytophilus (Coleoptera: Curculionidae: Molytinae) are transferred to Oreoscotus. AB - Type specimens of all three nominal species of the East African genus Molytophilus Hartmann are studied and illustrated. The genus is taxonomically restricted to include only the type species M. carinatus Hartman known from two collecting events in Tanzania and Somalia. Both other species of Molytophilus, described from Ethiopia, are herein transferred to the genus Oreoscotus as O. affinis (Hustache, 1936) comb. n. and O. puncticollis (Hustache, 1936) comb. n. A lectotype is designated for Molytophilus carinatus Hartmann. Type specimens of all three nominal species are illustrated. PMID- 30313581 TI - Draconarius manus sp. nov., the third species of D. pseudocoreanus-group from China (Araneae: Agelenidae). AB - Draconarius Ovtchinnikov, 1999 in the subfamily Coelotinae is the largest genus of the spider family Agelenidae and comprises 246 described species, mainly from East and Southeast Asia (World Spider Catalog 2018). The recently published volume on Chinese spiders in the Fauna Sinica series recorded a total 174 species of Draconarius in China, including 27 new species (Zhu, Wang Zhang 2017). PMID- 30313582 TI - Refining the genus Rochinia A. Milne-Edwards, 1875: reinstatement of Scyramathia A. Milne-Edwards, 1880 and Anamathia Smith, 1885, and a new genus for Amathia crassa A. Milne-Edwards, 1879, with notes on its ontogeny (Crustacea: Brachyura: Epialtidae). AB - The genus Scyramathia A. Milne-Edwards, 1880 (type species Amathia carpenteri Norman in Wyville Thomson, 1873) is herein removed from the synonymy of Rochinia A. Milne-Edwards, 1875 (type species R. gracilipes A. Milne-Edwards, 1875) and a new genus, Minyorhyncha, is established for Amathia crassa A. Milne-Edwards, 1879, a species previously placed in the genus Rochinia. The genus Anamathia Smith, 1885 (type species Amathia rissoana Roux, 1828), widely regarded as a synonym of Rochinia, is confirmed as a valid genus. The morphological differences between Rochinia (as revealed by its type species), Anamathia, Scyramathia and Minyorhyncha are discussed and illustrated. The strong ontogenetic changes in Minyorhyncha crassa n. gen., n. comb. are also discussed and illustrated. Lectotypes are selected for Rochinia gracilipes A. Milne-Edwards, 1875, and Amathia agassizii Smith, 1882, a junior synonym of Minyorhyncha crassa n. gen., n. comb. PMID- 30313583 TI - Description of the zoeal stages of Periclimenes aegylios Grippa d'Udekem d'Acoz, 1996 (Crustacea: Decapoda: Palaemonidae) reared in the laboratory. AB - The eight zoeal stages of the Mediterranean shrimp Periclimenes aegylios are described and illustrated in detail, using laboratory-reared specimens. This study improved the partial and unpublished descriptions of the zoeae of this species. The complete and accurate definition of the morphology of all the stages now allows comparison of the zoeae of P. aegylios with those of other Mediterranean Periclimenes species, as well as the allopatric Atlantic P. sagittifer, from which P. aegylios was separated in 1996. PMID- 30313584 TI - A taxonomic review of Korean Acrotona Thomson with a description of new species (Coleoptera, Staphylinidae, Aleocharinae). AB - A taxonomic review of the Acrotona Thomson in the Korean Peninsula is presented. The genus is represented in Korea by seven species including a new species, Acrotona (Acrotona) koreana Lee Ahn, sp. nov. Two new synonyms are proposed: A. (A.) lutulenta (Sharp) = A. (A.) suyangsani Pasnik syn. nov., A. (A.) pseudotenera (Cameron) = A. (A.) paeksongricus Pasnik syn. nov. Three species [A. (A.) lutulenta (Sharp), A. (A.) pseudotenera (Cameron) and A. (A.) vicaria (Kraatz)] are reported for the first time in South Korea. A key, descriptions, habitus photographs and illustrations of the diagnostic characters are provided. PMID- 30313585 TI - Two new species of Pseudoniphargus (Amphipoda: Pseudoniphargidae) from southern Spain. AB - Two new species of subterranean water amphipod crustaceans of the genus Pseudoniphargus (Pseudoniphargidae) are described from gypsum caves of Andalusia, southern Spain. Both species share the extreme elongation of the male third uropod, a striking feature frequently reported in the genus and that seems to have arisen independently in several lineages. These findings raise the number of species of Pseudoniphargus known from the area to 17. PMID- 30313586 TI - One new species and new record of the leafhopper genus Watara Dworakowska from Thailand (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini). AB - Morphological characteristics for identification of the leafhopper genus Watara Dworakowska are described and a key to all known species is provided. One new species, Watara longiprocessa sp. n., is added and one previously described species recorded from Thailand for the first time, Watara cordata Zhang Yang, 2011 rec. n., is illustrated. PMID- 30313587 TI - A new garden eel, Heteroconger fugax (Congridae: Heterocongrinae), from the northwestern Pacific Ocean. AB - Heteroconger fugax sp. nov. (Congridae: Heterocongrinae) is described from a single specimen collected from Amami-oshima island, Japan. The new species is most similar to Heteroconger tomberua Castle Randall 1999, known from Fiji and New Caledonia, in having a remarkably slender body with numerous small spots and a vertebral count close to 200. However, it can be distinguished from H. tomberua by the presence of a large distinct white blotch on the opercle; more numerous, dense spots over the entire head, including lips; ground color of body uniformly cream, without microscopic melanophores; numerous small conical cirri on the chin; and dorsal-fin origin located more posteriorly to appressed pectoral-fin tip. A survey of underwater photographs of Heteroconger on photographic database revealed H. fugax to be widely distributed in the northwestern Pacific Ocean, from the Ryukyu Archipelago to Borneo. PMID- 30313588 TI - Better governance will lead to better taxonomy: response to Raposo et al. (2017). AB - We welcome the recent paper by Raposo et al. (2017) debating our Nature Comment on inadequacies in taxonomic governance and the impact this has on conservation and society (Garnett Christidis 2017), as well as the opportunity to clarify our views. We admit to surprise at meanings read into our paper by Raposo et al. (2017) that we never intended and that we had not thought were there. As we have also made clear in a separate discussion of our paper (Garnett Christidis 2018 in response to Thomson et al. 2018), we wish to make clear at the start: (i) that we have no wish to stifle taxonomic research, only to strengthen the legitimacy of its findings; and (ii) we believe that taxonomic research should not consider the consequences for conservation, or society, in its conclusions once transparent taxonomic criteria have been established (Garnett Christidis 2007), but that taxonomists have an obligation to improve their governance to ensure taxonomic conclusions are of the highest standard. PMID- 30313589 TI - An ironic twist of fate: replacement name for Stenogyra gracilenta Morelet, 1885, not Achatina gracilenta Morelet, 1867 (Mollusca, Gastropoda, Achatinidae). AB - During work on a monograph of Morelet's contributions to malacology (Breure, Audibert Ablett, forthcoming) we found that two of his newly introduced taxa currently have to be considered as homonyms belonging to the genus Subulina H. Beck, 1837 (classified within the family Achatinidae according to Fontanilla et al. (2017: 385)). The older taxon is Achatina gracilenta which was described by Morelet (1867: 79, pl. 7 fig. 2) from [Angola] "Golungo-Alto, au bord du Rio Quiapose, pres de Sange; les environs de Lopollo (district de Huilla)". According to Naggs (1990a: 31; also pers. comm. 10 October 2017) this species has to be classified as Subulina gracilenta (Morelet, 1867). The type material of this species is present in the Natural History Museum, London (NHMUK 1893.2.4.263 265). The younger taxon was described by Morelet (1885: 25, pl. 2 fig. 8) as Stenogyra gracilenta from [Gabon] "environs de Mayumba". Pilsbry (1906: 82) already recognised this as Subulina gracilenta (Morelet, 1885); Naggs (pers. comm. 10 October 2017) confirmed this classification and concluded that this taxon is a junior secondary homonym of Achatina gracilenta Morelet, 1867. Type material for Stenogyra gracilenta Morelet, 1885 has not been located. We here propose Subulina bruggenorum nom. nov. as a replacement name for Stenogyra gracilenta Morelet, 1885 (not Achatina gracilenta Morelet, 1867). PMID- 30313590 TI - Revision of the Oriental genus Zavatilla Tsuneki (Hymenoptera, Mutillidae, Trogaspidiini), with descriptions of two new species. AB - Four species of the genus Zavatilla Tsuneki, 1993 are reviewed. An updated diagnosis of the genus is given and two new sex associations are proposed. Two new species, Z. xuzaifui Zhou, Lelej et Williams, sp. nov. (China: Guangdong, Yunnan, Hainan; Vietnam) and Z. nepalensis Zhou et Lelej, sp. nov. (Nepal) are described. Mutilla logei Zavattari, 1913 is proposed as junior synonym of Z. gutrunae (Zavattari, 1913). The status of Z. gutrunae flavotegulata (Chen, 1957) is updated to specific level. A key to the known species of Zavatilla is given for males and females. PMID- 30313591 TI - Dryophthorinae weevils (Coleoptera: Curculionidae) of the forest floor in Southeast Asia: illustrated overview of nominal Stromboscerini genera. AB - All 13 Recent genera currently assigned to the tribe Stromboscerini are studied and illustrated based mainly on the type specimens of the type species. Nominal monotypic genus Parasynommatus Voss, 1956 from New Guinea is herein transferred to Cossoninae incertae sedis. The genus Nephius is notably dissimilar to the rest of the tribe and perhaps renders it paraphyletic. Besides the monotypic type genus endemic to Madagascar, the tribe is distributed in a triangle delimited by Japan, Sri Lanka and northern Australia; two new tribe records from continental Africa (Uganda) and the Western Hemisphere (Cuba) are reported and illustrated. Assignment of both fossil monotypic genera to the tribe was done outside of the cladistic framework and remains questionable. Judging by external similarity, the likeliest closest relative of Stromboscerini (with or without Nephius and, perhaps, Stromboscerus) is the tribe Dryophthorini with three Recent genera. PMID- 30313592 TI - Three new species of spinicaudatan clam shrimps from Australia, all from gnammas (rock pools). AB - Recent collections from the remote Kimberley in Western Australia, have added three species to the known fauna of gnammas, Limnadopsis multilineata Timms, 2009 and two new species described herein, Eulimnadia kimberleyensis sp. nov. and Ozestheria pellucida sp. nov.. A further gnamma icon, Paralimnadia laharum sp. nov. is added from the Grampians in western Victoria. The numerous records of clam shrimps from Australian gnammas are examined. PMID- 30313593 TI - Two new genera and two new species of cicadas from Central America (Hemiptera: Cicadidae: Cicadinae). AB - New Neotropical cicada genera and species are described. Dazollina petilunca n. gen., n. sp. (Zammarini: Dazina) is described from Costa Rica and Guatemala, Muraoides costaricensis n. gen., n. sp. (Hyantiini) is described from Costa Rica. An updated generic key to the Dazina and Hyantiini are provided. PMID- 30313594 TI - DNA-based association and description of the larval stage of Apatania theischingerorum Malicky 1981 (Trichoptera, Apataniidae), with notes on its ecology. AB - The hitherto unknown larva of Apatania theischingerorum Malicky 1981 is described, based on the association with adult females using sequence data from the mitochondrial cytochrome c oxidase region. Genetic data confirmed the distinct status of this taxon within the parthenogenetic Apatania muliebris complex (Schmid 1954). We provide information on the morphology of the larva and figure the most important diagnostic features. Apatania theischingerorum is morphologically close to A. fimbriata (Pictet 1834). In the context of the Apataniidae key of Waringer et al. (2015), the species pair can be separated by pleural setation patterns on abdominal segment I and by their distribution ranges in Europe: A. fimbriata is known from the Alps, the western and central highlands, the western plains, the Hungarian lowlands and the Carpathians, whereas A. theischingerorum has been recorded exclusively on the Iberian peninsula. PMID- 30313595 TI - Two new species of Laonice (Norgensia) (Spionidae, Polychaeta) from subtropical Atlantic and subequatorial Pacific coasts of North America. AB - Two new species, Laonice costaricensis sp. nov. and L. rasmusseni sp. nov., belonging to the subgenus Norgensia Sikorski et al., 2017 were found in material from the Pacific collected from Coco Island off the coast of Costa Rica and from the Atlantic collected from Sapelo Island off the coast of Georgia (USA), respectively. Laonice cosaricensis is very close morphologically to L. lemniscata but without transdorsal membranes and having as usual capillaries in several anterior parapodia arranged in three vertical rows. Laonice rasmunsseni has genital pouches starting much anteriorly than in all known species from this subgenus. An identification key for the species belonging to this subgenus is given. PMID- 30313596 TI - Two new species of Gisilia Kasy, 1968 (Lepidoptera, Cosmopterigidae) from Korea with first report of piercing oviscapts in Gelechioidea. AB - Two new species of Gisilia Kasy, 1968, G. melanobasis n. sp. and G. tamrae n. sp., are described from Korea. Ascalenia thoracista (Meyrick, 1915) is transferred to Gisilia and compared to two Korean congeners. External and genital features of two new species and G. thoracista are illustrated. Piercing oviscapts are reported from Gelechioidea for the first time. The occurrences of oviscapts in Lepidoptera are reviewed. PMID- 30313597 TI - Lemyra elena, a new species from Sichuan, south-western China (Lepidoptera, Erebidae, Arctiinae). AB - The genus Lemyra Walker, 1856 belongs to the tribe Arctiini of the subfamily Arctiinae Leach, 1815 (family Erebidae Leach, 1815). The genus was revised by Thomas (1990). At present it is subdivided into two subgenera, Lemyra and Thyrgorina Walker, [1865] and includes more than 100 valid species, many of which were described during last three decades (Fang 1993; Inoue 1993; Tshistjakov Kishida 1994; Kirti Gill 2008; Cerny 2011; 2014; Cerny Pinratana 2009; Dubatolov 2007; 2010; Kirti Singh 2016). PMID- 30313598 TI - Description of the male of Diphterocome peregovitsi Gyulai, G. Ronkay L. Ronkay, 2014 (Lepidoptera, Noctuidae). AB - Diphterocome peregovitsi Gyulai, G. Ronkay L. Ronkay, 2014 was recently described from North Vietnam basing on single female (Gyulai et al. 2014). It is a member of the Diphterocome chrysochlora species-complex, which includes nine species: D. chrysochlora (Hampson, 1898), D. thainympha Hreblay Ronkay, 1999, D. nanlingi Gyulai, G. Ronkay L. Ronkay, 2014, D. impectinata Hreblay, Peregovits Ronkay, 1999, D. autumnalis (B.S. Chang, 1991), D. chloronympha Hreblay, Peregovits Ronkay, 1999, D. nepalichlora Hreblay Ronkay, 1999, D. thaumasia (Hreblay Ronkay, 1998), and D. peregovitsi. PMID- 30313599 TI - Anaxiphomorpha hexagona sp. n., a new, unusual swordtail cricket collected from Motuo County, Xizang, China (Orthoptera: Grylloidea: Trigonidiidae: Trigonidiinae). AB - Anaxiphomorpha are rare, small and yellowish swordtail crickets recorded from China and Vietnam. These species are special in their genitalia structure, of which, epiphallus and ectoparamere are armed with multiple lobes or branches. Six species of Anaxiphomorpha are known. The new species, Anaxiphomorpha hexagona, sp. n., possesses antler-like structure of the epiphallus and is described and illustrated. PMID- 30313600 TI - A new tribe of tarsonemid mites (Trombidiformes: Heterostigmatina) parasitic on tetrigid grasshoppers (Orthoptera). AB - Podotarsonemini tribe nov. (Tarsonemidae: Acarapinae), with one nominate genus Podotarsonemus gen. nov., is proposed for seven new species of tarsonemid mites collected from the hindwings of pygmy grasshoppers of the family Tetrigidae (Orthoptera). The new tribe is placed within the tarsonemid subfamily Acarapinae on the basis of several morphological synapomorphies, as well as on parasitism of insects. In light of this new tribe, a revised description of the Acarapinae is provided, as are full tribal, generic and species descriptions for the Podotarsonemini, and a key to species. In view of Podapolipidae, the sister family of Tarsonemidae, consisting entirely of obligatory parasitic mites, the distinction between the two constituent sister families of Tarsonemoidea as well as the ancestral feeding habits of that superfamily are considered. These mites and their host grasshoppers were collected from Bolivia, Ecuador, Honduras, southern India, Japan, Papua New Guinea, South Africa and two localities in north eastern Australia. This distribution suggests that the Podotarsonemini are an ancient lineage of Tarsonemidae that radiated on the Gondwanan Tetrigidae during the Jurassic. PMID- 30313601 TI - A new species of the genus Mesambria Stal, 1878 with notes on the tribe Mesambriini (Orthoptera: Acrididae, Catantopinae). AB - The new species Mesambria intermedia Storozhenko, sp. nov. is described from Indonesia. Male genitalia of the type species of the genera Mesambria Stal, 1878 and Traulia Stal, 1873 are described and illustrated for the first time. The diagnosis of the tribe Mesambriini is given and the position of this tribe in the modern classification of grasshoppers is discussed. New synonymy is proposed: Mesambriini Brunner von Wattenwyl, 1893 = Trauliini Bolivar, 1917, syn. nov., = Ranacridinae Xia, 2006, syn. nov. PMID- 30313602 TI - Taxonomic review of the leafhopper genus Aconurella Ribaut (Hemiptera: Cicadellidae: Deltocephalinae: Chiasmini) from Pakistan with description of three new species. AB - The genus Aconurella Ribaut from Pakistan is reviewed with three new species, A. paraerebus sp. n., A. choui sp. n. and A. naranensis sp. n. described and illustrated in this paper. A key to Pakistani species of the genus is also given. PMID- 30313603 TI - Review of the bamboo-feeding genus Agrica Strand (Hemiptera: Cicadellidae: Deltocephalinae), with description of two new species from China. AB - The bamboo-feeding leafhopper genus Agrica Strand (Cicadellidae: Deltocephalinae) is reviewed. Two new species, A. bisubula sp. nov. and A. longispina sp. nov. from China (Guizhou), are described and illustrated. The male genitalia of A. arisana (Matsumura, 1914) are described for the first time. A key is provided to distinguish known species of the genus. PMID- 30313604 TI - Three new species of Corynoneura Winnertz from Oriental China (Diptera: Chironomidae: Orthocladiinae). AB - The males of three species of the genus Corynoneura Winnertz (1846) from Oriental China, Corynoneura cooperio sp. n. Fu Fang, C. sesquipedalis sp. n. Fu Fang, C. tumula sp. n. Fu Fang are described, and morphological characters illustrated. PMID- 30313605 TI - Nymph inadvertently described as new species for a fourth time? On the identity of Euscelimena hardi (Tetrigidae: Scelimeninae) with general remarks on the identification of pygmy grasshopper nymphs. AB - Euscelimena hardi Gupta et Chandra, 2018 was described earlier this year from Chhattisgarh (India) as a unique species within the genus, characterized in small size, long pronotal projections, and a lack of wings. In this commentary we provide evidence that E. hardi is a nymph of E. harpago (Serville, 1838), hence a new synonymy is proposed: Euscelimena harpago (Serville, 1838) = Euscelimena hardi Gupta et Chandra, 2018 syn. nov. Since this is the fourth time a nymph of Euscelimena Gunther, 1938 has been described as a new species, we present general remarks on how to distinguish pygmy grasshopper nymphs and adults. Presence of a groove on the dorsal margin of the hind femora, directly before the knee (separating antegenicular and genicular teeth) is the only definite feature to separate nymphs from adults in brachypronotal or micropronotal wingless species. In macropterous species, morphology of tegmina and alae is helpful to separate nymphs from adults, nymphs having alae rich in radial venation in front of tegmina, while in adults tegmina are in front of developed alae. When dealing with a potential new species, researchers should firstly take into account known pygmy grasshoppers fauna of the studied area via Orthoptera Species File Online database Complex search (with imput Scope of search: Tetrigidae, Place name from geographic hierarchy: continent or country name). PMID- 30313606 TI - The correct subgeneric name of Trypanosoma rangeli Tejera, 1920 (Euglenozoa: Trypanosomatidae), a human-infective endoparasite of neotropical mammals. AB - Trypanosoma rangeli Tejera, 1920 is peculiar in being transmitted to mammal hosts through the bite of triatomine bugs. For this reason, it has been placed in its own subgenus, Tejeraia Anez, 1982. This name is a junior homonym of Tejeraia Diaz Ungria, 1963, used for the roundworm Tejeraia mediospiralis (Molin, 1860). The mandatory substitute name of Tejeraia Anez, 1982 is Aneza Ozdikmen, 2009. T. (Aneza) rangeli Tejera, 1920 is often referred to as T. (Herpetosoma) rangeli Tejera, 1920. According to nomenclature rules, both name combinations are available. Which one to choose depends on evolutionary and taxonomic considerations. Phylogenetic knowledge indicates that T. (Aneza) rangeli should be used. PMID- 30313607 TI - Review of the Poecilimon (Poecilimon) zonatus species group and description of new species from Turkey with data on bioacoustics and morphology (Orthoptera: Phaneropterinae). AB - The aim of this study is to conduct a detailed taxonomic revision of the Poecilimon (Poecilimon) zonatus species-group (Orthoptera: Phaneropterinae) using both morphology and bioacoustics. Two new species (Poecilimon (Poecilimon) salmani, P. (P) azizsancar) and one new subspecies (P. (P) zonatus datca) are described. Based on the data, we conclude that the species complex can be separated into two subgroups (P. tauricola and P. zonatus). Within the P. zonatus subgroup, song structures indicate P. variicercis as basal branch since producing two syllable types is possibly a derived character. From both, from bioacoustics and morphology, it is concluded that the relationships between species of the group are as follows: P. tauricola subgroup (P. tauricola + P. azizsancar) + P. zonatus subgroup (P. variicercis + (P. varicornis + (P. zonatus zonatus+P. zonatus datca)) + (P. salmani+P. vodnensis)))). Except for two species (P. vodnensis and P. varicornis), the other species of the group are all distributed in Anatolia. P. vodnensis is known only from Macedonia, whereas, P. varicornis has been recorded only from Syria and Lebanon. We assume that the group originated from an Anatolian ancestral stock and expanded its distribution to the Balkans through Taurus Way and Dardanelles. Other ancestral populations may have also spread in the north-south directions through the appropriate steppe corridors in the Anatolian Diagonal Mountains and in its vicinity. PMID- 30313608 TI - Revision of Anisepyris Kieffer (Hymenoptera, Bethylidae), with description of 135 new species. AB - The identity of many species of Anisepyris Kieffer is currently unknown, mostly because the available taxonomic data are not sufficiently accurate to allow for precise identifications. To solve this problem, all 121 described species were investigated, including the analyses of 115 holotypes and 26 allotypes. Almost all Neotropical species of Epyrinae and many from the Nearctic were also examined in order to recognize possible species of Anisepyris misclassified in other genera. The ten species-groups included in Anisepyris are redefined. And the female genital structures of the genus are investigated for the first time. Based on this, we recognize 119 previously described species as belonging to Anisepyris, one species is transferred to Laelius Ashmead, L. foveaticeps (Rosmann Azevedo) comb. nov., one is transferred to Chlorepyris Kieffer, C. nigerrimus (Evans) comb. nov., and 135 new species are described to science, so that the genus is now contains 254 species. They are recorded from 31 countries of the New World. Lectotypes are designated for A. aurichalceus (Westwood) and A. planiceps (Fabricius). The previously identified species-groups are re-organized into six, and seven additional species-groups are proposed are new. Identification keys for Anisepyris species-groups and species are provided. PMID- 30313609 TI - A new species of Uropeltis Cuvier, 1829 (Serpentes: Uropeltidae) from the Anaikatty Hills of the Western Ghats of India. AB - A new species of Uropeltis is described from a series of six type specimens from the Anaikatty Hills of the Western Ghats of Tamil Nadu, peninsular India. Uropeltis bhupathyi sp. nov. is distinguished from congeners by having more than 200 ventral scales, 17 dorsal scale rows at midbody and by the size and shape of the rostral and frontal shields. Although tens of specimens have been seen in the vicinity of the type locality (and previously reported as U. ellioti), the new species is known only from this locality and faces threats from road traffic, habitat loss and change, and possibly a condition that deforms heads and head shields which is at least superficially similar to snake fungal disease reported from wild snakes in North America and Europe. PMID- 30313610 TI - Morphology and taxonomy of the orb-weaving spider genus Mecynogea, and a peculiar species of Argiope (Araneae, Araneidae). AB - The spider genus Mecynogea comprises nine species distributed predominantly in the Neotropics. Although the genus has been revised recently, several aspects of its taxonomy and morphology are still unresolved. In this paper, Mecynogea infelix (Soares Camargo, 1948) is removed from the synonymy of Mecynogea bigibba Simon, 1903 and redescribed. Mecynogea chavona Levi, 1997 is considered a junior synonym of M. infelix. The male of Mecynogea buique Levi, 1997 is described and illustrated for the first time. The internal female genitalia of M. buique and M. infelix is described and shown to be remarkably different from each other. We show that part of the intraspecific variation reported previously for the female of M. infelix is the result of epigynum mutilation, possibly during copulation. We also report the presence of an internal branch on the terminal apophysis in the male palp of Mecynogea species. This structure, in some species visible only on the expanded bulb, is shown to be present in all Cyrtophorinae. The internal branch of the terminal apophysis, together with the conductor fully fused to the tegulum, is herein proposed as synapomorphic for the subfamily. Mecynogea lemniscata (Walckenaer, 1841) is recorded for the first time in Bolivia. We also provide new Brazilian records for M. infelix, M. bigibba, M. buique, M. eryhtromela (Holmberg, 1876), and M. sucre Levi, 1997. Mecynogea carvalhoi Mello Leitao, 1944, currently considered a nomen dubium, is revalidated, transferred to Argiope Audouin, 1826, redescribed and illustrated for the first time. PMID- 30313611 TI - Description of Tottonophyes enigmatica gen. nov., sp. nov. (Hydrozoa, Siphonophora, Calycophorae), with a reappraisal of the function and homology of nectophoral canals. AB - A new species of calycophoran siphonophore, Tottonophyes enigmatica gen. nov, sp. nov., is described. It has a unique combination of traits, some shared with prayomorphs (including two rounded nectophores) and some with clausophyid diphyomorphs (the nectophores are dissimilar, with one slightly larger and slightly to the anterior of the other, and both possess a somatocyst). Molecular phylogenetic analyses indicate that the new species is the sister group to all other diphyomorphs. A new family, Tottonophyidae, is established for it. Its phylogenetic position and distinct morphology help clarify diphyomorph evolution. The function and homology of the nectophoral canals and somatocyst is also re examined and further clarification is given to their nomenclature. PMID- 30313612 TI - Cryptic diversity of the rocky crab genus Glebocarcinus Nations, 1975 (Crustacea: Decapoda: Cancridae): description of a new species from Russian coastal waters of the Sea of Japan based on morphology, DNA and distribution. AB - A new cancrid crab species Glebocarcinus kashini sp. nov. (Decapoda: Brachyura: Cancridae) is described from Russian coastal waters of the Sea of Japan. The new species can be clearly separated from relative and sibling, Glebocarcinus amphioetus (Rathbun, 1898), by a less prominent and granulated dorsal surface of the carapace and dorsal surface of the cheliped propodus, less prominent sculpture of the carapace front and bluntly triangular anterolateral teeth of the carapace. Comparison of COI gene sequences supports the subdivision of these two species and shows their clear genetic separation from a related species, the American pygmy rock crab, G. oregonensis (Dana, 1852). Along the mainland coast of the Sea of Japan, G. kashini and G. amphioetus possibly overlap only in Posyet Bay and adjacent areas; the new species is distributed to the north from the bay while G. amphioetus is distributed to the south. Previous and new records of G. amphioetus from the area are discussed. PMID- 30313613 TI - A new species of cascade frog (Amphibia: Ranidae) in the Amolops monticola group from China. AB - A new species, Amolops wenshanensis sp. nov., is described from Guangxi and Yunnan Provinces, China. The new species is a member of the A. monticola group, and is distinguished from its congeners using morphological and molecular data. The new species is diagnosed by having glandular dorsolateral folds; smooth skin; side of head dark with a light-colored upper lip stripe extending to axilla; green dorsal coloration in life; immaculate venter; indistinct transverse bands on dorsal surfaces of limbs; tympanum distinct; pineal body absent; all fingertips expanded with circummarginal grooves; two oblique vomerine teeth; vocal sac and white nuptial pad present in males; supratympanic fold absent; outer metatarsal tubercle absent; glandular gold-white flank spot absent; and skin on venter not translucent. A molecular phylogenetic analysis is performed using the mitochondrial (mt) NADH dehydrogenase subunit 2 (ND2) gene and parts of flanking tRNA genes for nine of the 15 members of the A. monticola group with available homologous sequences. The new species is sister to a clade containing A. cucae and A. compotrix, two species known from adjacent parts of Vietnam and Laos. The new species differs from its congeners by having an uncorrected p distance of > 6.7% in the mt DNA fragment examined. At present, the new species is known from small, montane streams near Wenshan, Yunnan Province, and Jingxi, Guangxi Province, China. PMID- 30313614 TI - A new group of species within the bee genus Ruizantheda, with a revised key to the males of the genus (Hymenoptera: Halictidae: Caenohalictini). AB - Males of the neotropical bee genus Ruizantheda Moure sensu lato (Halictinae: Caenohalictini) differ from those of other caenohalictine genera in having the outer gonostylar plate with a large membranous region that extends to the ventral region, and the ventral gonostylar lobe retrorse. These features permit the placement of six additional species described here, four of which are new, in the genus in this broader sense. The males of these six species share the following characteristics: profemur swollen; mesofemur exceedingly swollen; mesotibia slightly swollen with flat, minutely ridged ventral area and small apical tooth; S4 shortened medially, commonly largely hidden under S3, with transverse median depression and apical margin emarginate; apicolateral lobes of S4 with tuft of branched setae and stout, simple, recurved setae on margin; S5 with U-shaped gradulus and setal patch, sometimes inconspicuous; outer lateral expansion of penis valve bilobed, and median posterior margin of volsella strongly angulate. Together, these species constitute a new group within Ruizantheda and share with the previously known Ruizantheda inca Coelho, Felizardo, Engel, R. aerugineus Coelho, Felizardo, Engel, and R. kallos Coelho, Felizardo, Engel, a short outer gonostylar plate, terminating before the apex of the main gonostylar lobe as well as the presence of long setae on its dorsal surface. In other species of Ruizantheda the outer gonostylar plate extends beyond the apex of the main gonostylar lobe and lacks setae. The species comprising this distinctive subgroup of Ruizantheda, and treated herein, are: R. nigra n. sp., R. colombiana n. sp., R. venezuelana n. sp., R. baeri (Vachal) n. comb., R. pilosa n. sp., and R. gaullei (Vachal) n. comb. Two of the new species expand the distribution of the genus northward into Colombia and Venezuela. In addition to the description and illustration of the species, an updated key to the species of Ruizantheda s. l. is provided. PMID- 30313615 TI - On a collection of deep-water shrimp (Crustacea, Decapoda) from the Dutch Caribbean, with the description of a new species of Pseudocoutierea. AB - A collection of shrimp from deep reefs in the Dutch Caribbean is described. Most material originates from the Bonaire deep reef expedition (2013) by Wageningen Marine Research of Wageningen University. Some additional material was available from dives on Curacao (2014). A new species of Pseudocoutierea Holthuis was recognized in the material collected off Bonaire. The new species is described and illustrated and its position in the phylogeny of the genus Pseudocoutierea analyzed. A key to the species in the genus is presented. PMID- 30313616 TI - Argia angelae (Odonata: Zygoptera: Coenagrionidae) sp. nov. from Chapada dos Guimaraes, Mato Grosso, Brazil. AB - Argia angelae sp. nov. (Holotype ?, BRAZIL, Mato Grosso, Chapada dos Guimaraes, Rio Salgadeira (15 degrees 21'25" S, 55 degrees 49'51" W, 305 m), 1 xi 2015, D. S. Vilela leg., in LESTES, Cod. ACR 8173A) from Chapada dos Guimaraes, Brazil is described, illustrated and diagnosed based on comparison with other known sympatric species of the genus. This species inhabits streams throughout the National Park and a map of its known distribution is provided. PMID- 30313617 TI - Three new genera and ten new species of the subfamily Lecithocerinae (Lepidoptera, Lecithoceridae) from Cameroon, Africa, based on material collected in 1913-18. AB - Based on material collected in Cameroon, Africa in 1913-18 and deposited in the Carnegie Museum of Natural History, Pittsburgh, USA, three new genera and 10 new species of Lecithocerinae (Lecithoderidae) are described and illustrated. The new genera are Paniculata gen. nov., Furcalis gen. nov., and Notioseus gen. nov. The new species are Homaloxestis rawlinsi sp. nov., Lecithocera afrotella sp. nov., L. dysmica sp. nov., L. cyclisca sp. nov., Paniculata weberi sp. nov., Notioseus cupripennis sp. nov., N. acidodes sp. nov., Furcalis efulenica sp. nov., F. triodonta sp. nov., and Lacuniola noda sp. nov. Adults and their labels, and the genitalia of all the species treated herein are illustrated. PMID- 30313618 TI - Review of the grass feeding leafhopper genus Hecalus Stal (Hemiptera: Cicadellidae: Deltocephalinae) with description of four new species from Pakistan. AB - The leafhopper genus Hecalus Stal is reviewed first time from Pakistan. Four new species (H. erectus, H. muzaffarabadensis, H. snipus, and H. veracious, spp. nov.) with a new record of H. ghaurii Rao Ramakrishnan, 1990 from Pakistan are described. A key to distinguish all Pakistani species in this genus is provided. Descriptions of male genitalia are provided for the known species. PMID- 30313619 TI - Four new species of tribe Coelidiini (Hemiptera: Cicadellidae: Coelidiinae) from the Afrotropical Region. AB - Three new species from Republic of the Congo, Brasura sinistra, B. piscinura and Tialidia hama spp. nov., and one new species Limentinus declinatus sp. nov. from Madagascar are described and illustrated in this paper. PMID- 30313620 TI - Black fungus gnats (Diptera: Sciaridae) found in association with cultivated plants and mushrooms in Australia, with notes on cosmopolitan pest species and biosecurity interceptions. AB - Male sciarids collected in Australia from inside post-entry quarantine and domestic greenhouses and from vegetable gardens and various plants, were slide mounted and identified. Specimens intercepted during on-arrival biosecurity inspections of imported nursery stock plants were also examined, and the New South Wales Department of Primary Industries collection of slide-mounted Sciaridae was reviewed. Plant and mushroom pest species that are present in Australia are Bradysia impatiens (Johannsen), B. ocellaris (Comstock), Lycoriella agraria (Felt), L. ingenua (Dufour) = Sciara womersleyi Seguy, 1940 syn. n., L. sativae (Johannsen) = Sciara auberti Seguy, 1940 syn. n., Sciara jeanneli Seguy, 1940 syn. n., Sciara solispina Hardy, 1956 syn. n., and Cosmosciara hartii (Johannsen, 1912) comb. n. = Plastosciara perniciosa Edwards, 1922 syn. n. The last species is a new record for Australia. Bradysia tilicola (Loew) and Pnyxia scabiei (Hopkins) are potential pest species, but they have not been reported yet from Australia. An identification key to enable separation of the pest species is provided. Species with uncertain connections to plant and mushroom cultures are B. pallipes (Fabricius), B. strenua (Winnertz, 1867) = B. watsoni Colless, 1962 syn. n., Corynoptera concinna (Winnertz), (all three species are new records for the Australian mainland) and Hyperlasion aliens Mohrig (a new record for Tasmania). Bradysia spatitergum (Hardy) and Scatopsciara atomaria (Zetterstedt) were intercepted during the on-arrival biosecurity inspections of live plants imported from China and Canada respectively. Both species are widespread overseas but are not known to occur in Australia. PMID- 30313621 TI - Evolutionary biogeography and tectonic history of the ghost moth families Hepialidae, Mnesarchaeidae, and Palaeosetidae in the Southwest Pacific (Lepidoptera: Exoporia). AB - The biogeographic history of Exoporia (Lepidoptera) in the Southwest Pacific is reconstructed for genera and species that show distributional boundaries corresponding to tectonic structures in the region. Correlations with tectonic formations of Mesozoic origin such as the Whitsunday Volcanic Province and Otway Bass-Gippsland Basin system in Australia, the Vitiaz Fracture Zone in northern Melanesia, and the Western Province-Eastern Province boundary, Waitaki Fault Zone, and Waihemo Fault Zone of New Zealand are presented as evidence of an East Gondwana origin for genera and species before the geological separation of Australia and New Zealand. The correlated boundaries also suggest that many extant species retain at least parts of their original East Gondwana distribution ranges. The presence of Exoporia on the northern Melanesian Arc, New Caledonia, and New Zealand is attributed to the tectonic isolation of these areas when East Gondwana expanded into the Pacific following retreat of the Pacific Plate subduction zone. Local endemism of Mnesarchaeidae in New Zealand is interpreted as the result of an original vicariance from a widespread ancestor ('Exoporia') resulting in two allopatric descendants -a narrowly distributed Mnesarchoidea and a widely distributed Hepialoidea. The current overlap of these two groups in New Zealand is explained as the result of subsequent range expansion by the Hepialoidea prior to geological fragmentation of East Gondwana. The potential impact of Cretaceous geography on modern distributions is also considered for Exoporia in southern Africa and northern America. Along with lateral displacement of Exoporia, tectonic processes also contributed to the origin of high elevation endemics through a process of passive tectonic uplift. PMID- 30313622 TI - New taxa of the mite family Neopygmephoridae (Acari: Heterostigmata) from alpine New Zealand. AB - Two new genera and four new species of the mite family Neopygmephoridae (Acari: Pygmephoroidea) are described from the alpine zone (1600-1900 m a.s.l.) of the Central Otago region of the South Island of New Zealand: Protobakerdania Khaustov and Minor gen. nov. with the type species Pygmephorus togatus Willmann, 1942, Neobakerdania Khaustov and Minor gen. nov. with the type species Neobakerdania pilosa Khaustov and Minor sp. nov., and the species Protobakerdania diseta Khaustov and Minor sp. nov., Troxodania minuta Khaustov and Minor sp. nov., and Bakerdania alpina Khaustov and Minor sp. nov. Eight species are moved to Protobakerdania Khaustov and Minor gen. nov. from Bakerdania Sasa, 1961: P. aperta (Rack and Kaliszewski, 1985) comb. nov., P. arvorum (Jacot, 1936) comb. nov., P. arvorum nodulosa (Mahunka, 1969b) comb. nov., P. baloghi (Mahunka, 1969b) comb. nov., P. crenata (Mahunka, 1969b) comb. nov., P. pristinus (Mahunka, 1968) comb. nov., P. randae (Sevastianov and Zahida Al Douri, 1989) comb. nov., and P. togatus (Willmann, 1942) comb. nov. PMID- 30313623 TI - Palaearctic Osmia bees of the subgenus Hoplosmia (Megachilidae, Osmiini): biology, taxonomy and key to species. AB - Hoplosmia, a subgenus of the osmiine bee genus Osmia (Megachilidae), comprises 21 species restricted to the Palaearctic region. Analysis of female pollen loads and field observations indicate that probably all O. (Hoplosmia) species are specialized on Asteraceae except for one pollen generalist species, which exhibits a preference for the pollen of Cistaceae. Among the Asteraceae specialists, differences exist with respect to the three main Asteraceae subfamilies exploited for pollen, with some species exclusively visiting Carduoideae, others exploiting only Asteroideae and Cichorioideae and again others collecting pollen on Asteroideae, Carduoideae and Cichorioideae. All O. (Hoplosmia) species build their brood cells within preexisting cavities: several species exclusively nest in empty snail shells, few species use small cavities in rock and stones and the remaining species colonize linear cavities in dead wood and plant stems or nest in abandoned burrows of other bees and wasps. Chewed leaves serve as material to construct brood cell partitions and nest plug except for two species, which use mud as nest building material. The taxonomic revision of O. (Hoplosmia) revealed the existence of an undescribed species, O. centaureae spec. nov., which occurs in a small area that ranges from the Dead Sea over the Jordan Valley to northernmost Israel. Due to clear morphological gaps and widely disjunct distribution with the nominotypical subspecies, O. pinguis carbo (Zanden 1974) is elevated to species rank. Based on morphology and biology, three species groups are recognized within Hoplosmia. Identification keys for all O. (Hoplosmia) species are given including the hitherto unknown male or female sex of three species. PMID- 30313624 TI - Revision of Lutnes Cameron (Hymenoptera: Eupelmidae). AB - Argaleostatus Gibson, 1995 is synonymized under Lutnes Cameron, 1884 (Hymenoptera: Chalcidoidea: Eupelmidae: Eupelminae) n. syn. and its type species, Eupelmus testaceus Cameron, 1884, is transferred to Lutnes as L. testaceus (Cameron) n. comb. The species of Lutnes are revised and six species are recognized, including the type species, Lutnes ornaticornis Cameron, 1884, plus L. testaceus, L. biguttatus (Girault, 1913), and three new species, L. aurantimacula Gibson n. sp. (Ecuador), L. infucatus Gibson n. sp. (Ecuador), and L. afrotropicus Gibson n. sp. (Cameroon). The first five species are based on females from the Neotropical region, whereas the last species is based on a female from Cameroon. This Afrotropical record is the first for the genus outside of the Neotropical region. Males are unrecognized for the genus. Monophyly and relationships of the genus are discussed and the species are keyed and illustrated through macrophotography. PMID- 30313625 TI - Aglaotilla, a new genus of Australian Mutillidae (Hymenoptera) with metallic coloration. AB - The genus Aglaotilla Brothers, gen. nov., is described for 14 striking species of Australian Mutillidae related to Ephutomorpha Andre, 1902, characterized by bright metallic coloration and strong punctation. The description of both sexes is possible through sex associations revealed by rearings from mud nests and trap nests. Both sexes of the type species, Ephutomorpha submetallescens Turner, 1916, are described and illustrated, the male for the first time. New combinations and a new name are proposed, as follows: Aglaotilla aeruginosa (Smith, 1879), comb. nov. (from Mutilla); A. australis (Andre, 1898), comb. nov. (from Mutilla); A. cuprea (Andre, 1901), comb. nov., stat. nov. (from Mutilla); A. dilecta (Turner, 1916), comb. nov. (from Ephutomorpha); A. ignita (Smith, 1855), comb. nov. (from Mutilla); A. metallica (Smith, 1855), comb. nov. (from Mutilla); A. mira (Andre, 1895), comb. nov. (from Mutilla (Sphaerophthalma [sic.])); A. nigroaenea (Smith, 1855), comb. nov. (from Mutilla); A. picturata (Turner, 1914), comb. nov. (from Ephutomorpha); A. semicuprea (Andre, 1898), comb. nov. (from Mutilla); A. submetallescens (Turner, 1916), comb. nov. (from Ephutomorpha); A. viridatis (Smith, 1855), comb. nov. (from Mutilla); A. viridiaurea (Andre, 1895), comb. nov. (from Mutilla (Sphaerophthalma [sic.])); A. discolor Brothers, nom. nov. (= Ephutomorpha aeneidorsis Turner, 1916, not Ephutomorpha lauta var. aeneidorsis Andre, 1903). PMID- 30313626 TI - Taxonomy of 'Euconnus complex'. Part XVII. Status of subgenera defined by male antennal characters: Androconnus Franz and Cladoconnus Reitter (Coleoptera, Staphylinidae, Scydmaeninae). AB - Among yet unrevised subgenera of Euconnus, Androconnus and Cladoconnus were originally defined primarily on the basis of male antennal modifications. Based on examination of respective type species, both taxa are maintained as subgenera of Euconnus and redefined to include also cephalic and thoracic structures in their diagnoses. PMID- 30313627 TI - A new dirivultid copepod (Siphonostomatoida) from hydrothermal vent fields of the Izu-Bonin Arc in the North Pacific Ocean. AB - A new species of dirivultid copepod (Siphonostomatoida) is described from hydrothermal vents in a volcanic seamount in Izu-Bonin Arc, western part of North Pacific Ocean. The copepod was collected during the research cruise NT13-09 using the R/V Natsushima with the ROV Hyper-Dolphin in April 2013. The type series of the new species was collected from the populations of Paralvinella spp. (Annelida: Alvinellidae) on an active vent chimney at the depth of 795 m. Stygiopontius senokuchiae n. sp. is most closely related to S. teres Humes, 1996 but clearly distinguished from the latter species by the possession of the following characters: the basis of leg 1 with an attenuated inner process; the genital double somite with a conical process lateral to the genital opening; and caudal rami without distal process. The findings of the copepod in the present study represents the first record of nominal species of the Dirivultidae from Japanese waters and a record of the shallowest depth of the genus. A key to species of the genus Stygiopontius from Western Pacific is provided. PMID- 30313628 TI - Values, regulation, and species delimitation. AB - Garnett and Christidis (2017) [hereafter GC] recently proposed that the International Union of the Biological Sciences should centrally regulate the taxonomy of complex organisms. Their proposal was met with much criticism (e.g. Holynski 2017; Thomson et al., 2018), and perhaps most extensively from Raposo et al. (2017) in this journal. The main target of this criticism was GC's call to, first, "restrict the freedom of taxonomic action", and, second, to let social, political and conservation values weigh in on species classification. Some commentators even went as far as to draw a comparison with the infamous Lysenko case of state-controlled and heavily restricted science (Raposo et al. 2017, 181; Holynski 2017, 12). This comment will argue, without thereby endorsing GC's position, that these two aspects of their views need not be as threatening as this comparison suggests, and indeed are very reasonable. PMID- 30313629 TI - Two new species of the Clubiona corticalis-group from Guizhou Province, China (Araneae: Clubionidae). AB - Clubiona Latreille, 1804, the largest genus in family Clubionidae, currently includes 495 species worldwide with 126 species from China (Li Lin 2016; World Spider Catalog 2018). Due to the high diversity in Clubiona, several subgenera and species-groups have been proposed (Wang et al. 2015). While there is no agreement on the limits of most species-groups of Clubiona (Deeleman-Reinhold 2001), the corticalis-group has been widely considered as putatively monophyletic. The group presents a distinct set of characters (Mikhailov 1995; Deeleman-Reinhold 2001; Liu et al. 2016) and the species composition of the core group is relatively stable (Mikhailov 1995; Deeleman-Reinhold 2001; Dankittipakul Singtripop 2008; Wu et al. 2015). At least two generic names are available for the corticalis-group, Atalia Thorell, 1887 and Paraclubiona Lohmander, 1944 (Mikhailov 2012). Spiders of the corticalis-group are well studied in China and several new species have been described in recent years (Yu et al. 2012; Zhu et al. 2012; Wang et al. 2015; Wu et al. 2015; Liu et al. 2016; He et al. 2016). Up to now, the Clubiona corticalis-group has more than 28 Chinese species (Wang et al. 2015; Wu et al. 2015; Liu et al. 2016; He et al. 2016; Yu et al. 2017), making it one of the most well known clubionid groups in China. While examining spiders collected from Guizhou Province, China, we came across some specimens from the Clubiona corticalis-group, which are described here as belonging to two new species. PMID- 30313630 TI - Australian Diplectroninae reviewed (Insecta: Trichoptera), with description of 21 new species, most referred to a new genus. AB - The history of studies on Australian caddisflies in the hydropsychid subfamily Diplectroninae is outlined against a broader background of uncertainties in the delineation of the worldwide type genus, Diplectrona Westwood. For the Australian fauna, keys are given to genera of Diplectroninae that occur in Australia and to adult males of species in Diplectrona (including a newly synonymised genus, Diemeniluma Neboiss), Austropsyche Banks, and Arcyphysa gen. nov. Of the 32 diplectronine species recognised, six are referred to each of Diplectrona and Austropsyche, among them one and four newly described species, respectively; and four established species are transferred from Diplectrona to Arcyphysa gen. nov., to join 16 newly described species. Diplectrona cognata Banks is synonymised with D. spinata Banks and Diplectrona bispinosa Jacquemart with Austropsyche victoriana Banks. Diagnoses and descriptions are accompanied by line drawings illustrating most of the diagnostic features of the genera and of most species, supplemented by photographic images. Australian species of Diplectrona are found from south-eastern Queensland to Tasmania, but neither Austropsyche nor Arcyphysa is known from Tasmania. Austropsyche extends from the Grampians in south-western Victoria to south-eastern Queensland, and the majority of species of Arcyphysa are recorded from north-eastern mainland Australia. PMID- 30313631 TI - An integrative redescription of Hypsibius dujardini (Doyere, 1840), the nominal taxon for Hypsibioidea (Tardigrada: Eutardigrada). AB - A laboratory strain identified as "Hypsibius dujardini" is one of the best studied tardigrade strains: it is widely used as a model organism in a variety of research projects, ranging from developmental and evolutionary biology through physiology and anatomy to astrobiology. Hypsibius dujardini, originally described from the Ile-de-France by Doyere in the first half of the 19th century, is now the nominal species for the superfamily Hypsibioidea. The species was traditionally considered cosmopolitan despite the fact that insufficient, old and sometimes contradictory descriptions and records prevented adequate delineations of similar Hypsibius species. As a consequence, H. dujardini appeared to occur globally, from Norway to Samoa. In this paper, we provide the first integrated taxonomic redescription of H. dujardini. In addition to classic imaging by light microscopy and a comprehensive morphometric dataset, we present scanning electron photomicrographs, and DNA sequences for three nuclear markers (18S rRNA, 28S rRNA, ITS-2) and one mitochondrial marker (COI) that are characterised by various mutation rates. The results of our study reveal that a commercially available strain that is maintained in many laboratories throughout the world, and assumed to represent H. dujardini sensu stricto, represents, in fact, a new species: H. exemplaris sp. nov. Redescribing the nominal taxon for Hypsibiidae, we also redefine the family and amend the definitions of the subfamily Hypsibiinae and the genus Hypsibius. Moreover, we transfer H. arcticus (Murray, 1907) and Hypsibius conifer Mihelcic, 1938 to the genus Ramazzottius since the species exhibit claws and eggs of the Ramazzottius type. Finally, we designate H. fuhrmanni as subjectively invalid because the extremely poor description precludes identifying neotype material. PMID- 30313632 TI - Paraindopamphantus bruneiensis gen. nov. et sp. nov., as the first representative of the subfamily Pamphantinae from South East Asia (Hemiptera: Heteroptera: Geocoridae: Pamphantinae: Indopamphantini). AB - Paraindopamphantus gen. nov., containing one species, I. bruneiensis sp. nov., is reported from Brunei, as the first member of the subfamily Pamphantinae from South East Asia and the second from the Oriental Region. The strikingly myrmecomorphic P. bruneiensis, collected only from Bukit Sulang, nr Lamunin in Brunei in the canopy of Shorea johorensis Foxw. (Dipterocarpaceae) tree by insecticide fogging is described and illustrated. The genus is placed in tribe Indopamphantini, that at present contains only other genus Indopamphantus Malipatil recorded from the Western Ghats of India. The significance of the habitus and myrmecomorphy of this species, in relation to Indopamphantus makutaensis Malipatil, is discussed. A key to the two genera of Indopamphantini is provided. PMID- 30313633 TI - Critical review of type specimens deposited in the Malacological collection of the biological institute/Ufrj, Rio de Janeiro, Brazil. AB - The Malacological Collection of the Biological Institute of Federal University of Rio de Janeiro figures as an important repository of specimens, containing c.a. 21,000 lots, most of them collected at deep sea of southeast Brazil. A critical review of literature and types deposited in this collection revealed the existence of 191 lots containing type specimens (23 holotypes and 168 paratypes), corresponding to 129 nominal species divided in three classes: Gastropoda (109 names, subdivided in 62 Caenogastropoda; 32 Heterobranchia and 15 Vetigastropoda), Bivalvia (17 names subdivided in 10 Protobranchia; 6 Heterodonta and 1 Pteriomorphia), and Scaphopoda (3 names). For each species, an updated list of data is provided, including the collecting location (revised or corrected, when necessary), number of specimens actually present (i.e., physically found in the collection), nomenclatural acts (if needed) and any other specific issue concerning particular species. It is beyond the scope of this study to discuss classifications or promote subjective judgment on taxonomy at any level for names treated here. PMID- 30313634 TI - Kaviengella jeffkinchi, a new genus and species of symbiotic shrimp (Crustacea: Decapoda: Palaemonidae) from Papua New Guinea. AB - A very small adult specimen of symbiotic palaemonid shrimp collected from Kavieng Lagoon, N.W. New Ireland Island, Papua New Guinea, is described as a new genus and species. Due to the slender subcylindrical body, reduced rostrum, elongated eyes and distolaterally produced uropodal exopods, the new species is somewhat similar to shrimps of the endosymbiotic sponge genus Nippontonia. Both second pereiopods are lost, but the specimen is unique by its bidentate scaphocerites, an apical corona of spiniform teeth on the mandibular molar process, five posterior telson cuspidate setae from which the median and intermediate ones are long, hooked, and the broadly spoon-like dactyli of the first pereiopods chelae with marginal pectination. Based on those characters, the new genus is without parallel among all symbiotic palaemonid shrimps. Its close phylogenetic relationship to the spongobiotic genera Nippontonia, Onycocaridella, and Thaumastocaris, is also confirmed by molecular comparison. PMID- 30313635 TI - New species for Virgilia Stal, 1870 (Hemiptera, Lophopidae), genus review and key to species. AB - Two new species of the lophopid genus Virgilia Stal 1866, are described and illustrated, V. cocovora Soulier-Perkins sp. nov. and V. imuganensis Soulier Perkins sp. nov. A key to the species of the genus is provided. Photos for the four Virgilia species are presented and the male terminalia illustrations are given. A comment on the potential pest status of one of the described species, V. cocovora, is given. PMID- 30313636 TI - Two new species of the genus Metaxonchium Coomans Nair, 1975 (Nematoda, Dorylaimida, Belondiridae) from Vietnam. AB - Two new species of the genus Metaxonchium are described from natural habitats of Vietnam. Metaxonchium bonkowskii sp. n. is characterized by its 1.69-2.23 mm long body, lip region offset by weak constriction and 9.5-10.5 um broad, odontostyle 11-13 um long, neck 673-868 um long with the pharyngeal expansion occupying 66 77% of its length, anterior genital branch reduced to a uterine sac 75-135 um long or 4-7% of body length, posterior uterus tetrapartite and including a Z-like differentiation, V = 51-55, and female tail short and rounded (37-51 um, c = 66 97, c' = 0.5-0.7). Metaxonchium silvaticum sp. n is characterized by its 1.28 1.43 mm long body, lip region offset by weak depression and 7.0 um broad, odontostyle 8-9 um long, neck 502-630 um long with the pharyngeal expansion occupying 65-76% of its length, anterior genital branch reduced to a uterine sac 65-80 um long or 4-6% of body length, posterior uterus tripartite, non echinophor, V = 52-57, tail short and rounded (18-23 um, c = 56-74, c' = 0.6-0.8) with abundant blister-like or saccate bodies, spicules 41 um long, and seven spaced ventromedian supplements. PMID- 30313637 TI - Gephyrocharax machadoi, a new species of Stevardiinae (Characiformes: Characidae) from the Rio Paraguai basin, central Brazil. AB - Gephyrocharax machadoi, new species, is described from tributaries of the rio Sepotuba, upper rio Paraguai basin, Mato Grosso state, Brazil. The new species is distinguished from its congeners, except Gephyrocharax major, by presenting two modified scales on the ventral caudal-fin lobe (pouch scales): a larger, sexually dimorphic scale, slightly superior and anterior in position, followed by a smaller, posterior and ventrally placed accessory scale (vs. a single modified pouch scale without ventrally placed accessory scales). Gephyrocharax machadoi differs from G. major by presenting a gap (more conspicuous in mature males than in mature females) between the second and third ventral procurrent caudal-fin rays (vs. second and third ventral procurrent caudal-fin rays near each other or fused distally); premaxilla with tricuspid teeth (vs. tetra- to pentacuspid teeth); and body depth 21.5-25.4% of SL (vs. 25.9-36.8% in SL). Spermiogenesis and spermatozoa morphology are also described. PMID- 30313638 TI - Oligotomidae (Insecta: Embioptera) of Mt. Makiling, Los Banos, Philippines, with description of a new species. AB - The diversity of webspinners (Insecta: Embioptera) in Mt. Makiling, Los Banos was studied. Four species were recorded: Aposthonia borneensis (Hagen), A. merdelynae Lucanas Lit n. sp., Oligotoma humbertiana (Saussure) and O. saundersii (Westwood). Each was illustrated and described. The new species differs from its congeners by relatively smaller size, subcylindrical left basal cercus with an inner lobe, and enlarged membranous area of the 10RP. A dichotomous key was devised to aid in identification of each species. PMID- 30313639 TI - The advertisement calls of two species of Brachycephalus (Anura: Brachycephalidae) from southern Atlantic Forest, Brazil. AB - The advertisement calls are known for only eight species within the genus Brachycephalus. Herein, we describe the advertisement calls of B. olivaceus and B. quiririensis, both species from southern Atlantic Forest, state of Santa Catarina, Brazil. The advertisement calls of these species are similar, composed by one short and high-frequency note. The parameters range overlap between calls, as exemplified by the dominant frequency of 6.4-7.0 kHz in B. olivaceus and 6.2 6.5 kHz in B. quiririensis. Additionally, we provide a compilation of the available bioacoustic information for this genus. PMID- 30313640 TI - Two new species and new records of Maruina Muller, 1895 (Diptera: Psychodidae) in Brazil. AB - Two new species of Maruina, Maruina cirrata sp. nov. and Maruina mucugensis sp. nov., collected in two mountainous areas in Bahia, are described and figured. Additionally, we present new records of Maruina guria Bravo, 2004 and M. menina Bravo Lago, 2003 in Brazil. PMID- 30313641 TI - Description of two new species in long-horned crane fly subgenus Tipula (Sivatipula) (Diptera: Tipulidae) from China. AB - Two new species of subgenus Tipula (Sivatipula) Alexander, 1964, T. (S.) multidentata sp. nov. (southern China: Guizhou) and T. (S.) tergatruncata sp. nov. (southern China: Chongqing) are described and illustrated. PMID- 30313642 TI - A taxonomic review of the genus Palumbina Rondani, 1876 (Lepidoptera, Gelechiidae, Thiotrichinae) from China, with descriptions of twelve new species. AB - Palumbina is a small genus of Gelechiidae that includes species distributed only in the Old World. It was recently assigned to the subfamily Thiotrichinae, but the morphological and molecular studies at the species level have not been extensively conducted. In this study, we focused on the taxonomy of the Chinese Palumbina using morphology and DNA barcoding analysis to confirm the species identification and the relationship among closely related species. In China, three species of this genus were recorded previously. A total of 19 were finally recognized in the present study, including 12 new species: P. magnisigna sp. nov., P. grandiunca sp. nov., P. melanotricha sp. nov., P. atricha sp. nov., P. sigmoides sp. nov., P. acuticula sp. nov., P. rugosa sp. nov., P. sineloba sp. nov., P. spinevalva sp. nov., P. acerosa sp. nov., P. triangularis sp. nov. and P. acinacea sp. nov., and five species that are new records for China: P. chelophora (Meyrick, 1918), P. diplobathra (Meyrick, 1918), P. macrodelta (Meyrick, 1918), P. nesoclera (Meyrick, 1929) and P. operaria (Meyrick, 1918). Three new combinations are proposed: P. operaria (Meyrick, 1918) comb. nov., P. albilustra (Walia et Wadhawan, 2005) comb. nov. and P. shivai (Walia et Wadhawan, 2005) comb. nov., and one new synonymy is established: Thyrsostoma albilustra (Walia et Wadhawan, 2005), syn. nov. of P. oxyprora (Meyrick, 1922). Based on the neighbor-joining analysis of COI gene sequences of 67 exemplar specimens, four clades were well supported with high bootstrap values resulting in four species groups: the guerinii-group, the grandiunca-group, the macrodelta-group and the nesoclera-group. However, seven species were grouped together in an additional clade with weak support and P. diplobathra and P. chelophora were not clustered with any other species due to the high genetic divergences. Palumbina chelophora showed typical characteristics of the genus morphologically, but it was not embedded within Palumbina as monophyletic from the tree, assuming that the sole use of mitochondrial fragments could not resolve the deeper relationship. Therefore, further investigation is needed to clarify those issues. In this study, the generic diagnosis was reviewed based on previous studies and morphological examination. PMID- 30313643 TI - An annotated checklist of the Anthicidae and pediline Pyrochroidae (Insecta: Coleoptera) of Iran, with thirteen new country records. AB - The fauna of Iranian Anthicidae and pediline Pyrochroidae (Coleoptera) is summarized in this paper. A total of 132 species from 19 genera and four subfamilies (Anthicinae, Notoxinae, Steropinae, and Tomoderinae) of Anthicidae and two species of Pedilinae are listed. Three new synonyms are proposed: Anthicus armatus Truqui, 1855 = A. pseudoarmatus Telnov, 2008 syn. nov., Notoxus hirtus LaFerte-Senectere, 1849 = N. caucasicus Pic, 1900 syn. nov., Stricticomus rufithorax (LaFerte-Senectere, 1849) = Anthicus transcaspicus var. subnotata Pic, 1910 syn. nov. One new combination is made: Nitorus unifasciatus (Desbrochers des Loges, 1875) comb. nov. (from Pseudoleptaleus Pic, 1900). Thirteen species are reported for the fauna of Iran for the first time: Anthicus armatus Truqui, 1855, A. episcopalis Pic, 1903, A. quadrispilus Marseul, 1879, Cyclodinus reitteri (Pic, 1892), Leptaleus klugii klugii LaFerte-Senectere, 1849, Stricticomus araxicola (Reitter, 1889), S. arcuaticeps (Pic, 1900), S. herzi (Pic, 1905), Microhoria aphaenops (Pic, 1902), Tenuicomus finalis Telnov, 2003, Notoxus hirtus LaFerte-Senectere, 1849, N. simulans simulans Heberdey, 1935, and Tomoderus scydmaenoides Reitter, 1878. PMID- 30313644 TI - A new genus and species of clearwing moth (Lepidoptera: Sesiidae) from Ethiopia. AB - A new genus and species from the tribe Synanthedonini (Lepidoptera, Sesiidae) is described and illustrated from Ethiopia: Jerbeia darkovi gen. et sp. nov. The new genus differs from the all known Afrotropical sesiid genera in the combination of the following characters: parallel veins R1-R3 of the forewing, the valva of the male genitalia with a ventral crista and the vesica is armed with flat dentate cornuti. The type series, which consists of 12 males, was collected with the help of artificial sex attractants. The female and the larval bionomics are unknown. PMID- 30313645 TI - Revision of the Australian leaf beetle genus Cheiloxena Baly, 1860 (Coleoptera: Chrysomelidae: Spilopyrinae). AB - The endemic Australian leaf beetle genus Cheiloxena Baly, 1860 is revised, with eight valid species, three new: C. aitori sp. nov.; C. blackburni Reid, 1992; C. conani sp. nov.; C. frenchae Blackburn, 1893; C. insignis Blackburn, 1896; C. monga sp. nov.; C. tuberosa Reid, 1992; C. westwoodii Baly, 1860. A key is provided for their identification and all species are described. Cheiloxena species occur from southern Victoria to central Queensland. Hosts are Araliaceae (Astrotricha), Proteaceae (Lomatia) and possibly Myrtaceae (Eucalyptus). PMID- 30313646 TI - Revision of the tree crickets of China (Orthoptera: Gryllidae: Oecanthinae). AB - Eight species of tree crickets are reviewed from China including Oecanthus antennalis, O. euryelytra, O. longicauda, O. similator, O. turanicus, O. zhengi, O. oceanicus He sp. nov. and Xabea levissima. Calling songs and COI genes of all species are compared. Keys to species are given by morphology and songs. New species is posited in Museum of Biology, East China Normal University (ECNU). The state of O. sinensis is discussed. O. latipennis Liu, Yin Xia, 1994 is a junior homonym of O. latipennis Riley, 1881. PMID- 30313647 TI - First record of Alepia Enderlein (Diptera, Psychodidae) in Mexico, with the description of two new species. AB - Genus Alepia Enderlein is for the first time recorded in Mexico. Specimens were captured in southern Puebla at the central area of Mexico corresponding to two new species which are described with male and female characteristics. One species belongs to the group of species characterized by a compact group of accessory retinacula originated on a dark area of surtyli, having the eye bridge ending in a small number of facet rows, and the other to the group of species characterized by the accessory retinacula scattered, absence of dark area on the surtyli, and a broad eye bridge with three facet rows. PMID- 30313648 TI - Sub-fossil Chironomidae (Diptera) from lake sediments in Central America: a preliminary inventory. AB - The chironomid diversity of Central America is virtually underestimated and there is almost no knowledge on the chironomid remains accumulated in surface sediments of lakes. Thus, in the present study we provide information on the larval sub fossil chironomid fauna from surface sediments in Central American lakes for the first time. Samples from 27 lakes analysed from Guatemala, El Salvador and Honduras yielded a total of 1,109 remains of four subfamilies. Fifty genera have been identified, containing at least 85 morphospecies. With 45 taxa, Chironominae were the most specious and also most abundant subfamily. Tanypodinae with 14 taxa dominated in about one third of the sites. Orthocladiinae were presented by 24 taxa, but were recorded in 9 sites, being dominant in only one site. Podonominae were collected only in one locality. Head capsules of Heterotrissocladius found in the high elevation lake Magdalena, Guatemala, represent a first record for the Neotropical region. Both relative abundance and species richness of Chironominae and Orthocladiinae showed significant relationship to elevation, while Tanypodinae were indifferent. Hopefully, the list of taxa provided by our study will be a base line for future limnological and paleolimnological investigations using chironomid remains in the region. PMID- 30313649 TI - A new species of Aculus mite (Acari: Eriophyidae), a potential biocontrol agent for Australian swamp stonecrop, Crassula helmsii (Crassulaceae). AB - A new, gall-forming eriophyoid mite species is described from Australia. Aculus crassulae sp. nov. was found causing significant leaf deformation in Crassula helmsii (Kirk) Cockayne (Crassulaceae), a semi-aquatic, succulent plant. Native to Australia and New Zealand, this plant is now a highly invasive weed in the United Kingdom and Western Europe. The host specificity of the new mite species, and damage caused to the host plant, infer its potential to be a valuable biological control agent in countries where Australian swamp stonecrop is threatening native flora. The species description provided here, which also includes a revised diagnosis for the genus Aculus, incorporates line drawings and scanning electron micrographs (SEM). This is supplemented by a partial mitochondrial gene sequence of cytochrome c oxidase subunit I (mtCOI) and the sequence was compared with Aculus amygdali Xue Hong and Aculus ichnocarpi (Ghosh Chakrabarati) available in the NCBI database. Pairwise comparison of mtCOI sequences between A. crassulae sp. nov. and two congeneric species revealed 22.6% and 23.1% genetic divergence, respectively. PMID- 30313650 TI - Taxonomic additions of Embolemidae and Sclerogibbidae (Hymenoptera: Chrysidoidea) from Japan, with description of a new species of Trogloembolemus. AB - Ampulicomorpha thauma Rasnitsyn Matveev (Hymenoptera: Embolemidae) and Sclerogibba rossi Olmi (Hymenoptera: Sclerogibbidae) were newly recorded from Japan. Females of Embolemus walkeri Westwood were found in the soil together with nymphs of Cixiidae. Trogloembolemus okanoi sp. nov. is described and illustrated. The holotype ? was collected in the soil at a depth of one meter. A key to species of Japanese Embolemidae was updated. PMID- 30313651 TI - Needle in a haystack-genetic evidence confirms the expansion of the alien echinoid Diadema setosum (Echinoidea: Diadematidae) to the Mediterranean coast of Israel. AB - Diadema setosum (Leske, 1778), a widespread tropical echinoid and key herbivore in shallow water environments is currently expanding in the Mediterranean Sea. It was introduced by unknown means and first observed in southern Turkey in 2006. From there it spread eastwards to Lebanon (2009) and westwards to the Aegean Sea (2014). Since late 2016 sporadic sightings of black, long-spined sea urchins were reported by recreational divers from rock reefs off the Israeli coast. Numerous attempts to verify these records failed; neither did the BioBlitz Israel task force encounter any D. setosum in their campaigns. Finally, a single adult specimen was observed on June 17, 2017 in a deep rock crevice at 3.5 m depth at Gordon Beach, Tel Aviv. Although the specimen could not be recovered, spine fragments sampled were enough to genetically verify the visual underwater identification based on morphology. Sequences of COI, ATP8-Lysine, and the mitochondrial Control Region of the Israel specimen are identical to those of the specimen collected in 2006 in Turkey, unambiguously assigning the specimen to D. setosum clade b. This lends support to the hypothesis of a single introduction event and fits well with the habitat suitability and distribution model for D. setosum published recently. The more rapid and larger range extension along a south-eastern, counter-current trajectory may reflect a strong habitat preference for D. setosum in this area of the Levantine Basin as predicted by the model. PMID- 30313652 TI - Erratum: YUNG-CHIEH CHIU, KWANG-TSAO SHAO, SHIH-PIN HUANG HONG-MING CHEN (2018) The freshwater snake eel genus Lamnostoma (Anguilliformes: Ophichthidae) in Taiwan, with description of a new species. Zootaxa, 4454: 018-032. PMID- 30313653 TI - The genus Sicoderus Vanin 1986 (Coleoptera: Curculionidae: Curculioninae: Erodiscini) in the West Indies. AB - The genus Sicoderus Vanin is revised for the West Indies. A total of 32 species are known with 18 new species described herein as follows: Sicoderus aeneus (Haiti), S. alternatus (Dominican Republic), S. bautistai (Dominican Republic, Haiti), S. beatyi (Cuba), S. bipunctiventris (Cuba), S. caladeler (Cuba), S. detonnancouri (Dominican Republic), S. franzi (Puerto Rico), S. guanyangi (Dominican Republic), S. humeralis (Dominican Republic), S. lucidus (Dominica), S. medranae (Dominican Republic, Haiti), S. perezi (Dominican Republic), S. pseudostriatolateralis (Dominican Republic, Haiti), S. striatolateralis (Dominican Republic), S. thomasi (Haiti), S. turnbowi (Dominican Republic), and S. woodruffi (Grenada). All species are described or redescribed, natural history information is summarized and a listing of locality data from all specimens examined is included. A key is provided to all West Indian species of the genus. All species distributions are mapped and all (excepting S. propinquus Vanin) are represented by habitus images and images of male genitalia. PMID- 30313654 TI - Antlions of southern Africa: Syngenes Kolbe, 1897, with descriptions of two new species and comments on extra-limital taxa (Neuroptera: Myrmeleontidae: Acanthaclisini). AB - The southern African species of Syngenes Kolbe, 1897, are revised and compared with their Afrotropical congeners. Three species occur in the region: S. longicornis (Rambur, 1842) and two new species, S. medialis and S. scholtzi, described and illustrated below. A key to the Afrotropical taxa is provided. The larva of S. longicornis is illustrated. The genus is widespread in the Afrotropical Region and extends to the Middle East and Oriental Region. Syngenes species are typically broad-winged antlions, with irregular bifurcate and biaereolate cells between the costa and subcostal veins, which distinguish them from other members of the tribe Acanthaclisini. PMID- 30313655 TI - Cave-dwelling crabs of the genus Karstarma from lava tubes of the volcano 'Piton de la Fournaise', in Reunion Island, with description of a new species and redescription of Karstarma jacksoni (Balss, 1934) from Christmas Island (Decapoda, Brachyura, Sesarmidae). AB - Sesarmid crabs of the genus Karstarma Davie Ng, 2007 are reported for the first time in the Western Indian Ocean: they were discovered in the lava tubes of the volcano 'Piton de la Fournaise', Reunion Island. A new species, morphologically similar to Karstarma jacksoni (Balss, 1934) from Christmas Island, Eastern Indian Ocean, is recognized and described. A redescription of K. jacksoni is also provided. A second species is recognized, but being represented in the collection by a single juvenile, it cannot be identified to species level until more collections are made in the lava tubes. [Zoobank: http://zoobank.org/NomenclaturalActs/C70A95B2-D667-491D-BD35-5DF32E3FFB08]. PMID- 30313656 TI - A peculiar new beetle from Brazil associated with a cave habitat (Coleoptera, Carabidae, Clivinini). AB - The new species Ardistomis ferreirai sp. nov. is described and illustrated. Some specific characters are discussed together with a possible correlation to the species subterranean way of life. Available ecological data and recordings are provided by description of the caves and the specific threats to the caves are indicated. PMID- 30313657 TI - A striking new species of Prosoeca Schiner, 1867 (Diptera: Nemestrinidae): An important pollinator from the Bokkeveld Plateau, Northern Cape Province, South Africa. AB - For more than 20 years an undescribed species of Prosoeca has been referred to in numerous publications by pollination biologists, evolutionary biologists and ecologists, originally as being part of the Prosoeca peringueyi Lichtwardt, 1920, pollination guild. Ongoing research in these and related fields has necessitated the formal description of this large-bodied, striking new species, with a proboscis 1.5-2.3 x body length (mean proboscis length +/- SD 36.25 +/- 3.90 mm). Prosoeca marinusi Barraclough sp. nov. is described from a long series from the Hantam National Botanical Garden, Nieuwoudtville, Bokkeveld Plateau, Northern Cape Province, South Africa. The species is a narrow-range endemic and is restricted to the Nieuwoudtville area. Observations on the biology of the species are also presented. Prosoeca marinusi Barraclough sp. nov. is the only or main pollinator of at least four plant species (all regional endemics) in the family Iridaceae that flower from August to September. During August, Lapeirousia oreogena Goldblatt and Babiana vanzyliae L. Bolus are the main host flowers, while later in the spring season, Babiana framesii L. Bolus is most abundant in the Nieuwoudtville area. PMID- 30313658 TI - Pseudalataspora vanderlingeni n. sp. (Myxosporea: Bivalvulida) from gall bladders of the Cape hakes Merluccius capensis Castelnau, and M. paradoxus Franca (Teleostei: Merlucciidae). AB - A new species of myxosporean parasite is described from the gall bladders of the hakes Merluccius capensis Castelnau and M. paradoxus Franca (Pisces: Teleostei) caught off the west and south coasts of South Africa. The new species, Pseudalataspora vanderlingeni, is described morphologically and molecularly and compared with the 15 other species of Pseudalataspora previously described from marine fish. Although a molecular description is available on GenBank for only one of these 15 species, the morphological description supports the status of P. vanderlingeni as a new species. Earlier reports, without detailed descriptions, of Leptotheca sp. and Ceratomyxa sp. from the same hosts caught off Namibia were very likely to have been of P. vanderlingeni. These earlier studies reported high prevalences of infection, similar to those of >60% described in the present study. The effects of fixation and freezing on the dimensions of spores of Pseudalataspora spp. are described, and the status of the genus Pseudalataspora within the family Ceratomyxidae is discussed. PMID- 30313659 TI - Charles Spence Bate: what's in a name? AB - The citation of Charles Spence Bate has become a source of uncertainly in the literature. Indeed, for some taxa his authority is given as "Spence Bate", whilst others "Bate" e.g. Artemesia longinaris Spence Bate, 1888 compared with Ibacus brevipes Bate, 1888. In order to resolve this inconsistency, a lengthy manual search of selected contemporary journals for the period from ca. 1854 to 1889 was undertaken with special reference to the name Charles Spence Bate being listed alphabetically by family/surname either under "Bate", "Spence Bate" or "Spence Bate". Overwhelming evidence indicated that his family/surname is Bate. Furthermore, as there are a number of carcinologists also with the family name Bate, therefore it is recommended that taxa described by Charles Spence Bate should be referred to as C.S. Bate, for example Artemesia longinaris C.S. Bate, 1888 and Ibacus brevipes C.S. Bate, 1888. PMID- 30313660 TI - Two new species of the genus Leptoderes Serville, 1838 (Orthoptera, Tettigoniidae) from China. AB - Three species of the leaf-mimicking Tettigoniidae, Leptoderes Serville, 1838 were reported in the southeast of Asia. Here, we redescribe the type species L. ornatipennis Serville, and describe two new species Leptoderes shuzhenae sp. nov. and L. dianensis sp. nov., respectively from Tibet and Yunnan, China. Leptoderes now comprises five species. Informative illustrations are provided. The distribution of the Leptoderes Serville species is discussed and mapped. The holotypes are deposited in Insect Collection of Institute of Zoology, Chinese Academy of Sciences, Beijing, China (IZCAS). PMID- 30313661 TI - A new species of genus Agryllus Gorochov, 1994 from Yunnan, China (Orthoptera: Gryllidae: Gryllinae). AB - One new species, Agryllus apterus He sp. nov., is described from Yunnan, China. This new species is wingless, which is different from all other Agryllus species. The type specimens are deposited in Museum of Biology, East China Normal University (ECNU). PMID- 30313662 TI - New species of Dugdaleiella, gen. nov., Kozloviella, gen. nov., and Pfitzneriella Viette from upper elevation Andes of Ecuador and Peru (Lepidoptera: Hepialidae). AB - Six new Hepialidae species are described from high elevation habitats in the Andes of Peru and Ecuador. One species is assigned to the genus Kozloviella gen. n., K. viazmenskyi sp. n., from Peru, and five to the genus Pfitzneriella Viette, 1951: P. antonkozlovi sp. n., P. olafi sp. n., P. titarenkoi, sp. n., P. yuliyakovalevae sp. n. from Peru and P. rawlinsi sp. n., from Ecuador. Dugdaleiella gen. n., is proposed to accommodate the Ecuadorian species Dugdaleiella monticola (Maassen, 1890) comb. n., formerly placed in Pfitzneriella. The taxonomic (but not the phylogenetic) status of P. lucicola (Maassen, 1890) is unaltered pending future opportunity to examine the type series. Preliminary phylogenetic analysis of the morphological characters supports Kozloviella gen. n., and Pfitzneriella as sister taxa, and separates P. titarenkoi sp. n., from the other species of Pfitzneriella. We suggest that the ancestor of these high elevation genera already occupied a pre-Andean upland habitat across Peru and Ecuador and this ancestor further diverged into the modern genera and species during the Andean orogeny. We consider it likely that there is a considerable diversity of endemic high elevation Hepialidae that remains to be discovered in the eastern Andes between Venezuela and Bolivia. PMID- 30313663 TI - Morphological and molecular characterization of Coynema poeyi (Coy, Garcia Alvarez, 1993) (Oxyuridomorpha: Hystrignathidae) from Antillanax pertyi (Kaup, 1869) (Coleoptera: Passalidae) from Cuba and new locality records for the species. AB - Coynema poeyi (Coy, Garcia Alvarez, 1993) (Oxyuridomorpha: Hystrignathidae) is redescribed and illustrated with the aid of SEM. New features of the cephalic end of both sexes and copulatory papillae pattern of the males were observed and the generic diagnosis is emended in order to include such features. New locality records are given. The phylogenetic position of the species is inferred on the basis of the D2-D3 segment of the LSU rDNA. C. poeyi is located basal in a monophyletic clade formed by other hystrignathids: two species of Longior Travassos Kloss, 1958 and Hystrignathus sp. PMID- 30313664 TI - On spermatophore-producing aquatic microdrile oligochaetes (Annelida: Clitellata). AB - The formation of encapsulated spermatophores is exceptional among aquatic oligochaetes, although it seems to have occurred independently in several unrelated taxa. Among the microdriles, some variations appear unique to single species. The recently described lumbriculid Uktena riparia Fend et al. forms spermatophores in the male duct and attaches them within a deep spermathecal bursa. The attachment of spermatophores to the body wall, in the clitellar region, or in the vicinity of male or spermathecal pores has been reported in Paranadrilus Gavrilov, Bothrioneurum Stolc and some Aktedrilus Knollner species. Anatomical comparison of reproductive organs suggests convergent development of glandular organs in the male duct or spermathecae, used for the formation, transfer and/or attachment of spermatophores to the concopulant worms. The presence of similar organs in Smithsonidrilus Brinkhurst, where spermatophores have not been reported, is also discussed. Furthermore, a lectotype is designated for Paranadrilus descolei Gavrilov, 1955. PMID- 30313665 TI - Geographic variation and taxonomy of red-tailed Gymnophthalmus (Squamata: Gymnophthalmidae) from Amazonian Savannas. AB - Gymnophthalmus represents a challenging group for systematics of microteiid lizards. Due to scarcity of exemplars and molecular data, the taxonomy of the genus has been unstable, and six of its eight species are considered part of a poorly-delimited complex of unisexual and bisexual species. Unnamed populations of red-tailed Gymnophthalmus from savanna enclaves in Amazon, similar to G. vanzoi but with differences in color pattern, have been noted in the literature. Here, we used molecular and morphological data to test the taxonomic status of the Central Amazonian red-tailed Gymnophthalmus (G. sp.). Our molecular analysis recovered a close relationship between G. vanzoi and G. sp. from Central Amazon, with minimal divergence. Samples were similar in scale counts but presented significant variation in color pattern and morphometry. Despite the geographic isolation, individuals of both populations cannot be fully differentiated based on morphology. Thus, our results suggest that G. vanzoi has a wider distribution, including the Central Amazonian red-tailed Gymnophthalmus and likely morphologically similar populations from other enclaves of Amazonian savannas, which may have been isolated recently. Based on our comparative analysis, we highlight some characters proved useful for differentiating Brazilian Gymnophthalmus and discuss some prospects for the taxonomy of the genus. PMID- 30313666 TI - A review of the Cyana bianca (Walker, 1856) species-group with descriptions of a new species and a new subspecies from Indochina (Lepidoptera, Erebidae, Arctiinae). AB - The Cyana bianca (Walker, 1856) species-group is revised. Cyana bianca malayana Bucsek, 2012 is upgraded to the species level. A new species, C. indosinica Volynkin Cerny, sp. nov. (China: Yunnan, Thailand, Laos, Vietnam) and a new subspecies, C. quadripartita vieta Volynkin Cerny, ssp. nov. (Vietnam) are described. PMID- 30313667 TI - Application of DNA Barcoding in the Classification of Grasshoppers (Orthoptera: Acridoidea)-A Case Study of grasshoppers from Hebei Province, China. AB - Grasshoppers (Orthoptera: Acridoidea) are the main pests in agriculture, animal husbandry and forestry, and some species of grasshoppers can cause serious disaster. Taxonomy is the basis of pest control. Traditional morphological identification is time-consuming and laborious. It may be due to the existence of cryptic species or the limited number of morphologists, making the identification extremely unstable. In recent years, with the development of molecular systematics, DNA barcoding technology has been applied to environment, ecology, quarantine and so on. This study focuses on testing the feasibility of DNA barcoding in the species identification for superfamily Acridoidea. Sequences of the cox1 gene were obtained from 245 individuals of 43 species of Acridoidea and one species of Tetrigoidea as outgroup from Hebei Province. Phylogenetic, genetic distance and sequence difference threshold analyses using the Maximum Likelihood (ML), Automatic Barcode Gap Discovery (ABGD) and Molecular Defined Operational Taxonomic Units (MOTU) methods, respectively, were performed for obtained sequences and the 139 additional sequences of 21 species downloaded from GenBank. The results have shown that 40, 33, and 35 species among the 48 species are consistent with the traditional morphological classification based on the phylogenetic tree, ABGD and MOTU results, respectively and the DNA barcoding technology is very efficient and helpful for identifying the species of the superfamily Acridoidea; however, the morphological approach is still playing a key role in the species identifications. It also indicates that the cox1 gene is suitable for the phylogeny of genera and species level, but it is not suitable for the phylogenetic relationship of the advanced taxa such as families. PMID- 30313668 TI - Review of the Stomodes tolutarius species group (Coleoptera: Curculionidae: Entiminae: Otiorhynchini) from the Balkan Peninsula with description of two new species from Greece. AB - Species of the tolutarius species group of the genus Stomodes Schoenherr, 1826 are revised. A redescription of the genus is provided and all available male and female genitalia are illustrated. Two new species, S. benedikti sp. n. and S. dodocunevi sp. n. from Greece, are described. A lectotype is designated for S. amorei Desbrochers des Loges, 1904. The redescriptions of the following species are provided: S. marocanus Hoffmann, 1956; S. muelleri Lona, 1922; S. leonhardi Wagner, 1912; S. letzneri Reitter, 1889 and S. tolutarius Schoenherr, 1826. S. muelleri is for the first time recorded for Macedonia, Bosnia and Hercegovina and Greece; S. tolutarius for Macedonia, Bulgaria and Turkey. An identification key to species of the tolutarius species group is given. PMID- 30313669 TI - The genus Metaporcelaimus Lordello, 1965 (Nematoda, Dorylaimida, Aporcelaimidae) in Ukraine: Description of one known and two new species without hiatus. AB - One known (M. romanicus) and two new species of the genus Metaporcelaimus, collected in natural and semi-natural habitats of Ukraine, are described and illustrated. Metaporcelaimus concinnus sp. n. is characterized by its 3.09-4.58 mm long body, lip region 16.5-19.5 um broad and visibly wider than the adjacent body, odontostyle 17-19 um long, neck 745-865 um long, pharyngeal expansion occupying 62-66% of total neck length, uterus tripartite and 3.9-5.7 times the corresponding body diameter, vulva longitudinal (V = 49-53%), tail conical (44-54 um, c = 67-94, c' = 1.0-1.3 in females), spicules 79-86 um long with strongly bifurcate distal end, and 10-14 irregularly spaced ventromedian supplements without hiatus. Metaporcelaimus declivicaudatus sp. n. is characterized by its 2.88-3.66 mm long body, lip region 23-28 um broad, odontostyle 24-26 um long, neck 634-788 um long, pharyngeal expansion occupying 48-56% of total neck length, uterus tripartite and 3.0-3.4 times the corresponding body diameter long, vulva transverse (V = 51-55%), tail conical (45-65 um, c = 53-63, c' = 1.0-1.2) with rounded terminus, spicules 102-113 um long, and 12-14 spaced ventromedian supplements without hiatus. New information about M. romanicus is also provided, confirming available data about this species. PMID- 30313670 TI - Redescription of the Siberian species Pardosa jeniseica (Araneae: Lycosidae). AB - The male of Pardosa jeniseica, collected in the East-Kazakhstan Area, was first illustrated in Eskov Marusik (1995). The authorship of the species was given as "Zyuzin, 1991", because A.A. Zyuzin informed the authors in 1990 that a description of the species was in press. Because no such description ever appeared the authorship was given to Eskov Marusik, and a single male specimen from East-Kazakhstan is now considered to be the holotype. It is kept in Zoological Museum of the Moscow State University. Esyunin et al. (1999) illustrated and described a female from the Urals thought to be conspecific with P. jeniseica. Conspecifity of the illustrated specimen with P. jeniseica was doubted by Marusik et al. (2000). Kronestedt (2013) was the first to illustrate the epigyne of P. jeniseica and Azarkina Trilikauskas (2013) provided both verbal and illustrated descriptions of the female, and its epigyne and endogyne. Both sexes taken from one locality were never depicted, nor was peculiar pubescence of the male's leg I. Therefore, I decided to provide detailed illustrations and a verbal description of this species based on specimens from the place considered to be the type locality.Specimens were photographed at the Zoological Museum (University of Turku, Finland) with a Canon EOS 7D camera attached to an Olympus SZX16 stereomicroscope and a SEM JEOL JSM-5200 scanning microscope. Digital images were montaged using Helicon focus 3.10 image stacking software. All measurements are given in millimeters. The following abbreviations are used for leg segments: Fe femur, Pa patella, Ti tibia, Mt metatarsus, Ta tarsus; leg spination abbreviations: d dorsal, p prolateral, r retrolateral, v ventral. Material used in this study is deposited in the Moscow State University (ZMMU) and Zoological Museum of the University of Turku (ZMUT). I thank Seppo Koponen (Turku, Finland) for providing museum facilities and Don Buckle (Saskatoon, Canada) for editing English in the earlier draft of the manuscript. PMID- 30313671 TI - Hyastenus verreauxii A. Milne-Edwards, 1872, a synonym of Hyastenus elatus Griffin Tranter, 1986: lectotype designation and reversal of precedence (Crustacea: Brachyura: Majoidea: Epialtidae). AB - The majoid spider crab, Hyastenus verreauxii A. Milne-Edwards, 1872 (family Epialtidae), was described based on the material from "Nouvelle-Hollande" (= Australia) in the "Collection du Museum", that is, the Museum national d'Histoire naturelle, Paris (MNHN). It was noted by A. Milne-Edwards (1872: 250) that the species is morphologically similar to H. diacanthus (De Haan, 1839) but differs in having a less developed hepatic region, as well as longer and straighter pseudorostral spines. Miers (1879: 26) synonymised H. verreauxii under H. diacanthus with no detailed explanation, and Miers (1886: 56) noted that this species "is probably a variety of Hyastenus diacanthus". Haswell (1880: 442; 1882: 20) identified Australian specimens as H. diacanthus and listed H. verreauxii as its junior synonym. Ortmann (1893: 55) followed the consensus but regarded H. verreauxii as a subspecific taxon ("var.") of H. diacanthus. Serene Lohavanijaya (1973: 53) treated H. verreauxii as a synonym of H. diacanthus. However, none of these authors provided a detailed explanation for the decision to synonymise this species nor was the type examined. This species has not been treated by subsequent workers. PMID- 30313672 TI - Review of some species groups of the genus Oospila Warren, with descriptions of nine new species (Lepidoptera: Geometridae: Geometrinae). AB - The Neotropical geometrine genus Oospila Warren, 1897 includes seventy-nine species and was revised by Cook Scoble (1995). The genus is distinctive in having a row of raised abdominal crests, which are composed of specialized, erect, metallic shining scales. This paper focuses on the integrative morphological and molecular delimitation of the smallest Oospila species. The wing patterns and genitalia structures of males and females are illustrated. Cook Scoble (1995) distinguished 13 species groups within Oospila. We discuss the species of the Oospila flavilimes species group, the O. stigma species group and O. miccularia species group below, and separate the O. arpata species complex into a group of its own. Nine new species and two new subspecies are described in this paper: O. cristae sp. n. from Ecuador, O. falcata sp. n. from French Guiana, O. pallidaria boliviensis subsp. n. from Bolivia, and O. loreenae sp. n. from Bolivia (flavilimes species group), O. ehakernae sp. n. from Costa Rica, O. similiplaga bolarpata subsp. n. from Bolivia (arpata species group), O. brehmi sp. n. and O. bifida sp. n. both from Bolivia, O. moseri sp. n. from Brazil, O. absaloni sp. n. and O. pipa sp. n. both from Ecuador (miccularia species group). Oospila similiplaga (Warren) (stat. nov.) is raised here from synonymy with O. arpata (Schaus) and O. imula (Dognin) from synonymy with O. miccularia (Guenee), respectively. Oospila agnetaforslundae nom. nov. is proposed as a replacement name for Oospila marginata Schaus, 1912 (nec Oospila marginata Warren, 1897), raising it to species rank from synonymy of Oospila permagna (Warren, 1909). With this paper, the number of Neotropical Oospila species is raised to 88. PMID- 30313673 TI - The presence of the family Anostostomatidae (Orthoptera: Ensifera) in Argentina. AB - The family Anostostomatidae comprises about 250 known species of robust insects, similar to crickets, which are widely distributed predominantly in the southern hemisphere. They are divided into eight subfamilies, of which five occur in the Neotropics (Cadena-Castaneda Cortes-Torres 2013). While there are six species described from central and southern Chile (three in each of the genera Cratomelus and Leiomelus), the only published record of the Anostostomatidae for Argentina refers to two old specimens of Apotetamenus clipeatus in the collection of the Museum National d'Historie Naturelle in Paris (Griffini 1912, Karny 1935, Cadena Castaneda Cortes-Torres 2013). PMID- 30313674 TI - New species of Pseudoscorpiones (Arachnida) from tree hollows in a Mediterranean oak forest in Spain. AB - Pseudoscorpions inhabiting mature Quercus pyrenaica Willd. trees have been surveyed using hollow emergence traps and window traps in Salamanca, Spain. Three new species are described: Neobisium (N.) hispanicum Zaragoza Hernandez-Corral, n. sp., Rhacochelifer gaeli Zaragoza Hernandez-Corral, n. sp. and Rhacochelifer nonidezi Zaragoza Hernandez-Corral, n. sp. The genera Amblyolpium Simon, 1898 and Beierochelifer Mahnert, 1977 and the species Amblyolpium dollfusi Simon, 1898 and Beierochelifer peloponnesiacus (Beier, 1929) are new records for the Iberian Peninsula. Beierochelifer peloponnesiacus jonicus (Beier, 1932) is shown to be a junior subjective synonym of B. peloponnesiacus n. syn. New regional records of five other species belonging to the families Cheliferidae, Chernetidae and Withiidae are given. Keys are given for the species of the genera Pseudorhacochelifer Beier, 1976 and Rhacochelifer Beier, 1932 with elongated keels on posterolateral corners of carapace and anterior tergites in males, and for the Rhacochelifer species of the Iberian Peninsula. Complementary data to the description of the female syntypes from Caravaca (Murcia, mainland Spain) and males from the Canary Islands of Rhacochelifer pinicola (Nonidez, 1917) are given. Brief redescriptions of the female of Neobisium (N.) maroccanum Beier, 1930 and the male of Rhacochelifer euboicus Mahnert, 1977 are provided. The previous record of R. disjunctus from Slovakia is shown to be an error for R. euboicus. New data on the distribution and habitats of species of Cheliferidae, Chernetidae and Withiidae are given. PMID- 30313675 TI - Gloora gen. nov. (Lepidoptera: Erebidae: Arctiinae: Arctiini: Ctenuchina) for several Agylla-like Arctiinae. AB - Gloora gen. nov. is established for Eucereon alba (Druce, 1894), Hyaleucerea mundula (Berg, 1882), Agaraea sericeum (Zerny, 1931), and Gloora canae sp. nov. These species are (re-)described considering male genitalia in particular and, in case, barcodes. Further species which might fit into Gloora gen. nov. are discussed. PMID- 30313676 TI - Ciliate species from tank-less bromeliads in a dry tropical forest and their geographical distribution in the Neotropics. AB - The study of ciliate diversity in tropical environments remains scarce. In Neotropical forests, bromeliads are a common component of the vascular flora; bromeliads with tank morphology intercept rain water and detritus, resulting in the formation of a phytotelm, where heterotrophic protist communities like ciliates can establish. However, it is not known if ciliates inhabit tank-less bromeliads. For this reason, the goal of the present study was to investigate if ciliates can establish between the leaf axils of five terrestrial and epiphytic tank-less bromeliad species in a dry tropical forest in west Mexico. We collected samples of rain water and detritus from the leaf axils during the humid season of years 2015 and 2016. For ciliate taxonomical identification, we used optical microscopy, in vivo observation, and silver impregnation techniques. To summarize information about geographical distribution of ciliates identified at species level in the Neotropics, we provided their records from previous works, at country level with locality and georeferenciation. We recorded 27 taxa of ciliates, where the class Oligohymenophorea contained the largest richness of taxa. Drepanomonas revoluta, Leptopharynx bromeliophilus, and Tetrahymena sp. were recorded from all the species of bromeliads. Bromelia karatas was the species that hosted the largest number of ciliate taxa (22). Our results indicated that Glaucomides bromelicola, Gonostomum bromelicola, Leptopharynx bromelicola and L. bromeliophilus, species which are considered endemic to tank bromeliads, can also inhabit tank-less bromeliads. We provided previous records of 19 ciliate species from eleven countries within the Neotropical region, and Bromeliothrix metopoides was the species most frequently recorded in Neotropical countries (9). Therefore, tank-less bromeliads can constitute a temporal habitat for ciliates, and function as cysts reservoirs in environments with a pronounced seasonality like dry tropical forests. PMID- 30313677 TI - New information on the skipper fauna of Guangxi, China (Lepidoptera, Hesperiidae). AB - The skipper fauna of Guangxi is updated based upon field surveys and examinations of specimens. Two genera and 16 species/subspecies are recognized as new records to Guangxi, of which one genus and four species are recorded from China for the first time. Distribution of seven species/subspecies in Guangxi are confirmed as well. The females of four species are described for the first time. The male genitalia of three species are illustrated and re-described. Taxonomic notes on some of these species are provided. PMID- 30313678 TI - Five new species of the Acantholycosa-complex (Araneae: Lycosidae) from Mongolia. AB - Five new species from Mongolia belonging to the Acantholycosa-complex are diagnosed and described: Acantholycosa vahterae sp. n. (??, Govi-Altai Aimag), A. kronestedti sp. n. (??, Govi-Altai Aimag), Mongolicosa azarkinae sp. n. (??, Khovd Aimag), M. cherepanovi sp. n. (?, Bayan-Olgii Aimag) and M. ozkutuki sp. n. (?, Khovd Aimag). PMID- 30313679 TI - Are the monophlebid genera Drosichoides Morrison and Buchnericoccus Reyne synonyms? (Hemiptera, Coccomorpha, Monophlebidae). AB - The morphology of the adult male of Drosichoides ?haematoptera (Cockerell) is redescribed and illustrated and the adult female of Buchnericoccus sp. (Hemiptera: Monophlebidae) is also described and illustrated. These male and female specimens perhaps are conspecific. Genus Buchericoccus Reyne may be a junior synonym of genus Drosichoides Morrison. PMID- 30313680 TI - Redescription of enigmatic spider genus Stoliczka O. Pickard-Cambridge, 1885 (Araneae: Lycosoidea) based on the type species. AB - The type species of Stoliczka O. Pickard-Cambridge, 1885-S. insignis O. Pickard Cambridge, 1885-is redescribed for the first time, based on a lectotype here designated. The genus has an uncertain taxonomic position. Originally, it was placed in Lycosidae, while it is currently considered a Pisauridae (Pisaurinae). It includes only two species known from the Western Himalayas, of which the type species remains known only from the females and S. affinis Caporiacco, 1935, which is known from a juvenile only. An uncommon behavioral feature of these spiders is the attachment of egg cocoons to the spinnerets like in the Lycosidae. The absence of the male does not allow us to clarify the taxonomic assignment of this enigmatic genus. PMID- 30313683 TI - Global diversity of earthworms and enchytraeids (Clitellata): papers in honor of Andras Zicsi (1928-2015). Editorial. AB - This Special Volume of Zootaxa unites forty papers written in honor of the late Andras Zicsi (1928-2015), the eminent earthworm taxonomist. They deal with the taxonomy, systematics and distribution of earthworms and enchytraeids, the two major groups of soil-dwelling Oligochaeta. Altogether, 71 new species-group taxa are described, 60 species and subspecies of earthworms and 11 species of enchytraeids. They are from 15 countries all around the globe: Spain, Italy, Hungary, Turkey, Botswana, Mexico, Colombia, Brazil, China, Japan, Korea, Taiwan, Laos, Malaysia, Thailand, and Vietnam. PMID- 30313684 TI - Annotated checklist of earthworm species described by Andras Zicsi (Clitellata: Megadrili). AB - Professor Andras Zicsi, the renowed taxonomist and ecologist of earthworms, passed away on 22 July, 2015. He had a decisive impact on earthworm taxonomy in the second half of the 20th century, describing 10 new genus group taxa and 243 species / subspecies new to science distributed in 10 families. A complete list of the new taxa described by Prof. Zicsi is presented here together with references to the original descriptions and the valid names. PMID- 30313685 TI - DNA barcoding of the Italian anecic Octodrilus species in rural (vineyard) and forested areas with description of Octodrilus zicsiniello sp. nov. (Clitellata, Megadrili). AB - DNA barcoding of 172 anecic Octodrilus specimens collected in NE Italy and bordering Croatia has been carried out. The Bayesian phylogenetic tree showed high support for almost all currently recognized species, however, some unexpected results also appeared. The clade representing Oc. pseudocomplanatus contains a highly advanced subclade, which morphologically resembles Oc. slovenicus. The highly supported Oc. tergestinus clade consists of four unresolved divergent lineages of which the first corresponds to Oc. istrianus and the second resembles Oc. mimus morphologically; the third and fourth clades show typical tergestinus characters. The widely distributed Oc. complanatus consists of three highly divergent subclades which are sister to a new species, Oc. zicsiniello sp. nov., hereunder described. PMID- 30313686 TI - Insights into the diversity of Hormogastridae (Annelida, Oligochaeta) with descriptions of six new species. AB - The earthworm family Hormogastridae is a relatively diverse group in the Western Mediterranean basin. Since 1887, around thirty species have been described and assigned to four genera. However, from 2010 on, molecular, ecological and morphological studies have questioned the validity of those genera. Meanwhile, new species were discovered and assigned to them, pending a formal systematic revision; such a revision has been performed recently by integrating all the existing sources of information. The resulting classification consists of nine genera, including four newly erected ones. This revised systematic background is used in the current work as a base for the description of six new hormogastrid species: Diazcosinia sacrarium Marchan, Fernandez, Diaz Cosin Novo, sp. nov., Boucheona martae Marchan, Fernandez Diaz Cosin, sp. nov., Boucheona rosae Marchan, Diaz Cosin Novo, sp. nov., Norana emiliae Marchan, Fernandez, Diaz Cosin Novo, sp. nov., Norana xylocerasi Marchan, Fernandez, Diaz Cosin Novo, sp. nov., and Norana beatrizae Marchan, Fernandez, Diaz Cosin Novo, sp. nov. Norana is a new replacement name for the preoccupied Nora Marchan, Fernandez, Diaz Cosin Novo, 2018. Likewise, Xanina is proposed to replace the preoccupied Xana Diaz Cosin, Briones Trigo, 1989. We provide an overview of the currently known diversity of the different genera, and we further propose common names in several languages for some of the species of Hormogastridae. PMID- 30313687 TI - Interrelation of Proctodrilus species (Oligochaeta: Lumbricidae) with lessivage and layering in European soil profiles. AB - The objective of this paper is to relate species occurrences of the earthworm genus Proctodrilus to soil properties, in particular the horizons and layers in the soil profile. Data on the occurrence in the soil profile of the earthworm species Proctodrilus antipai (Michaelsen, 1891), P. opisthoductus Zicsi, 1985, P. thaleri Hoser Zicsi 2009, and P. tuberculatus (Cernosvitov, 1935) were collected in central Germany, northern Bohemia, Hungary, and Romania. Species of Proctodrilus were collected from 138 sites in total, P. antipai from 48, P. opisthoductus from 24, P. thaleri from 4, and P. tuberculatus from 97 sites. The field data show that species inhabiting the same site do not form communities but rather inhabit different soil layers. Furthermore, species of Proctodrilus prefer to live close to the boundaries between layers, a feature that can be regarded as a taxonomic characteristic of the genus and that is probably connected with their enteronephric excretory system. The habitats of the different species differ in the degree of soil leaching. P. thaleri and P. opisthoductus are restricted to the region of recent lessivage in warm-humid parts of Europe. Occurrence of the four Proctodrilus species is therefore not related to soil type but rather to soil stratification and soil leaching. Differences in the ecological behaviour of the species can be understood as taxonomic characters. PMID- 30313688 TI - Morphological and molecular distinction of two Fridericia species (Clitellata, Enchytraeidae) having same spermatheca type. AB - One enchytraeid species, proved to be new to science, is described in this paper as Fridericia ventrochaetosa sp. nov. The new species is distinguished from similar species, especially from F. galba (Hoffmeister, 1843), which has almost the same type of spermatheca, on the basis of morphological characters and molecular data (nuclear ribosomal ITS region, mitochondrial cytochrome c oxidase subunit I and nuclear histone 3 gene sequences). Apart form the new species, GenBank reference sequences are provided for the first time for F. hegemon and F. regularis. The results show that, although the shape of the spermatheca is a very important marker in the case of Fridericia species, other characters can be equally important for their taxonomic identification. PMID- 30313689 TI - Checklist of earthworms (Oligochaeta: Lumbricidae) from Serbia: a review. AB - A checklist of the lumbricid earthworms in Serbia is presented. For the first time, comprehensive informations of all lumbricids in the country are given in order to establish the definitive list of known taxa from Serbia. The list underlines earthworm diversity and provides a general overview of their ecology, distribution in Serbia, and zoogeographical position. The complete list of earthworm taxa of Serbia comprises 74 species and subspecies of Lumbricidae, belonging to 15 genera. One third of earthworms in Serbia are endemics (26 taxa = 35.1%). PMID- 30313690 TI - Solving a nomenclatural conundrum: Cernosvitovia crainensis (Mrsic, 1989) and Aporrectodea macvensis Sapkarev in Mrsic, 1991 (Lumbricidae). AB - This contribution deals with the names and authorship of two lumbricid taxa endemic to the Balkans (see Stojanovic et al., this volume). Although their validity has never been questioned, it has been unclear up to now which publication has made these two species-group names available according to the rules of the International Code of Zoological Nomenclature (Articles in "the Code," ICZN 1999). In the following, we review the somewhat intricate history of these names and explain why the correct citation and spelling of these names are "Cernosvitovia crainensis (Mrsic, 1989)" and "Aporrectodea macvensis Sapkarev in Mrsic, 1991," respectively. PMID- 30313691 TI - Contribution to the knowledge of the earthworm fauna of Turkey with description of three new species (Clitellata: Megadrili). AB - During a recent survey, 29 earthworm species were collected from different parts of Turkey, 27 of which belong to the family Lumbricidae, one to Acanthodrilidae and one to Megascolecidae. Dendrobaena proved to be the most speciose genus with 12 recorded species including two species new to science, Dendrobaena pavliceki and Dendrobaena taurica spp. nov. In addition a third new species was also found belonging to the East Mediterranean genus Healyella: Healyella zicsii sp. nov. From the species recorded earlier for Turkey, D. fridericae uludagi Omodeo Rota, 1991 and He. boluana Omodeo Rota, 1989 were found for the first time since the original description. With these new records the number of earthworm species recorded for Turkey is raised to 84. PMID- 30313692 TI - New earthworm records (Clitellata: Lumbricidae) from Bulgaria since 2012. AB - The early scientists who studied the earthworm fauna of Bulgaria were Rosa (1897), Cernosvitov (1934), and Mihailova (1966). Their work was continued by Sapkarev (1986) and Zicsi and Csuzdi (1986). In the last decade, researchers from Hungary, Serbia and Bulgaria organized explorations of many localities and enhanced the knowledge of the earthworm fauna of the country (Valchovski 2012, Stojanovic et al. 2012, Szederjesi 2013). The present paper summarizes the new species records after these aforementioned three publications: Cernosvitovia munteniana, Eisenia andrei, Murchieona minuscula, Proctodrilus opisthoductus and Dendrobaena veneta. PMID- 30313693 TI - Green light to an integrative view of Microscolex phosphoreus (Duges, 1837) (Annelida: Clitellata: Acanthodrilidae). AB - The small synanthropic and peregrine earthworm Microscolex phosphoreus (Duges, 1837) is reported for the first time from Siberia. Morphological and DNA barcode (COI) analyses of this and widely separate samples worldwide demonstrate that, as currently identified, M. phosphoreus is a heterogeneous taxon, with divergent lineages occurring often in the same locality and hardly providing geographically structured genetic signals. The combined morphological and genetic evidence suggests that at least four of the found clades should be reclassified as separate species, both morphologically and genetically distinct from each other. However, as the specimen number was limited and only the COI gene was studied for the genetic work, we hesitate in formally describing new species. There would also be the problem of assigning the available names to specific lineages. Our findings encourage careful external and anatomical examination and using reliable characters such as the interchaetal distances and spermathecal morphology for correct identification and for deeper evaluation of cryptic diversity in this interesting bioluminescent worm. PMID- 30313694 TI - Resurrection of the earthworm species Dendrobaena fedtschenkoi (Michaelsen, 1900), a former synonym of Dendrobaena byblica (Rosa, 1893) (Clitellata: Megadrili). AB - Dendrobaena byblica (Rosa, 1893) is a Circum-Mediterranean earthworm species complex containing more than a dozen synonymous names. From these, only two species have been resurrected so far, D. ganglbaueri (Rosa, 1894) and Fitzingeria annectens (Rosa, 1895). Here we demonstrate that Dendrobaena fedtschenkoi (Michaelsen, 1900) described from the Pamir Mts. Tajikistan differs from D. byblica both in morphological and molecular features, and represents an independent species. PMID- 30313695 TI - Distribution of non-lumbricid earthworms (Clitellata: Acanthodrilidae, Criodrilidae, Megascolecidae and Ocnerodrilidae) on the Balkans and Anatolia with first record of Amynthas morrisi (Beddard, 1892) from Turkey. AB - Based on previous and on new species records, the non-lumbricid earthworm fauna of the Balkans and Anatolia consists of ten species, belonging to four families: Acanthodrilidae, with Microscolex dubius (Fletcher, 1886) and Microscolex phosphoreus (Duges, 1837), Criodrilidae, with Criodrilus lacuum Hoffmeister, 1845 and Criodrilus ochridensis Georgevitch, 1950, Megascolecidae, with Amynthas corticis (Kinberg, 1867), Amynthas gracilis (Kinberg, 1867), Amynthas morrisi (Beddard, 1892), Metaphire californica (Kinberg, 1867), and Pontodrilus litoralis (Grube, 1855), and Ocnerodrilidae, with Ocnerodrilus occidentalis Eisen, 1878. Four species are recorded on the both territories (C. lacuum, M. dubius, M. phosporeus, A. corticis). Four out of five megascolecid species are present in Turkey (A. corticis, A. gracilis, A. morrisi, M. californica) and only two (A. corticis, P. litoralis) in the Balkans. One of them, Amynthas morrisi, is new to the fauna of Turkey. PMID- 30313696 TI - Comparative studies on reproductive traits of natural populations of Eisenia andrei Bouche, 1972 from Zagros Mountain, Iran (Annelida: Oligochaeta). AB - Comparative studies were carried out on growth and reproduction patterns of eight populations of Eisenia andrei (Bouche, 1972) from different parts of western Iran along the Zagros Mountains, considered to lie within the natural range of this species. Parameters were gain in body weight, number of cocoon production, hatching success, number of hatchlings, hatchlings growth and survival. There were significant differences in mean numbers of viable cocoons, incubation time, reproductive rate, growth rate and final weight between different populations. The resulting groupings did only partially coincide with genetic clusters established in a previous study. It is nonetheless suggested to include life cycle parameters as an additional set of data to understand the micro-taxonomic structure of variable species. PMID- 30313697 TI - The first proandric species of Tritogenia Kinberg, 1867 from Botswana, Tritogenia talana sp.n. (Clitellata, Crassiclitellata, Tritogeniidae). AB - The earthworm fauna of Botswana is hitherto unknown. A first collecting trip to the regions of Chobe and Tuli Block resulted in the discovery of a new species, Tritogenia talana sp.n. Its reproductive organs show some level of degeneration when compared to other species of Tritogenia. The spermathecae were not observed, testes and sperm funnels are in proandric condition and seminal vesicles are absent. This is the first record of an earthworm species from Botswana. PMID- 30313698 TI - Morphological and molecular evidence reveal a new species of the earthworm genus Pontodrilus Perrier, 1874 (Clitellata, Megascolecidae) from Thailand and Peninsular Malaysia. AB - A new species of the megascolecid earthworm genus Pontodrilus Perrier, 1874, Pontodrilus longissimus sp. n., is described from seashores of Thailand and Peninsular Malaysia. The new species differs from congeners, especially the cosmopolitan P. litoralis (Grube, 1855) in the size of the body, number of segments and the shape of the spermathecae. P. litoralis is redescribed, based on specimens collected from the same region and the same type of habitat. DNA fragments of the mitochondrial cytochrome oxidase subunit I of both species were sequenced. Morphological as well as DNA sequence-based comparisons confirm that P. longissimus sp. n. is a lineage distinct from P. litoralis and in fact a new species. The illustrated descriptions are accompanied by a key to species of Pontodrilus. PMID- 30313699 TI - Nine new species of the "aeruginosus"-group in Amynthas (Clitellata: Megascolecidae) from Nam Et-Phouley National protected Area, Laos. AB - Nine new species of Amynthas (Clitellata: Megascolecidae) from Mt. Phouleoi, Lao PDR: Earthworm specimens were collected on the top of Mt. Phouleoi, Viengthong District, Houaphanh province, Lao PDR. The new species belonged to pheretimoid earthworms. They have spermathecal pores in 7/8 and 8/9, corresponding to the aeruginosus-group as characterized by Sims and Easton (1972). Their names are: Amynthas bouatongi sp. nov., Amynthas hoauykanangensis sp. nov., Amynthas phimpheti sp. nov., Amynthas nametensis sp. nov., Amynthas somechanae sp. nov., Amynthas wiggeri sp. nov., Amynthas fleischmani sp. nov., Amynthas antethecus sp. nov., and Amynthas elenabondae sp. nov. With the exception of A. nametensis sp. nov., all have the first dorsal pore in an unusually anterior location close to 5/6 and very large, often coiled, prostatic ducts. Several species have slight intraparietal invaginations of the primary male pores, but the similarity of other characters leads us to include them in Amynthas rather than in a polyphyletic Metaphire. Amynthas bouatongi sp. nov. has male pores 0.20-0.24 circumference apart on reniform male pads, pair genital papillae medial and lateral to male pores in XVIII. Amynthas hoauykanangensis sp. nov. has openings of copulatory pouches 0.19-0.25 circumference apart, and paired round genital papillae on postsetal XVII and presetal XIX in line with the male pores. Amynthas phimpheti sp. nov. has male pores 0.21-0.24 circumference apart, round thickened genital papillae paired on 17/18 and 18/19 in line with male pores. Amynthas nametensis sp. nov. has male pores superficial on thickened circular pads, 0.24 0.27 circumference apart. Amynthas somechanae sp. nov. has male pores 0.20-0.33 circumference apart, and paired equatorial papillae in XVIII. Amynthas wiggeri sp. nov. has male pores 0.22-0.30 circumference apart, paired genital papillae equatorial on XVIII medial to male pores and paired papillae equatorial in XVII and XIX. Amynthas fleischmani sp. nov. has openings of copulatory pouches 0.24 circumference apart, paired conical genital papillae equatorial on XVII and XIX; paired circular papillae in intersegmental furrows of 17/18 and 18/19. Amynthas antethecus sp. nov. has openings of copulatory pouches 0.31 circumference apart, paired circular papillae in intersegmental furrow of 17/18 and equatorial on XIX, slightly medial to secondary male pores. Amynthas elenabondae sp. nov. has openings of copulatory pouches 0.19 circumference apart, crescent, convex medially; primary male pore on tubercle on lateral wall of shallow parietal invagination. PMID- 30313700 TI - First record of the earthworm genus Pheretima Kinberg, 1867 sensu stricto in Vietnam, with description of a new species (Annelida: Clitellata: Megascolecidae). AB - The earthworm genus Pheretima Kinberg, 1867 sensu stricto is recorded in Vietnam for the first time with a new species, P. vungtauensis sp. nov. The new species is characterized by three pairs of spermathecal pores in intersegments 6/7/8/9, spermathecal ducts with dense micronephridia, no genital markings in spermathecal and male regions, male pores located inside copulatory pouches, intestinal origin at xv, caeca simple from xxvii, and holandry. DNA-COI barcode sequences of the holotype are most similar to those of Metaphire houlleti (Perrier, 1872) from Thailand and not to other species of Pheretima. PMID- 30313701 TI - Two new species of earthworms belonging to the genus Amynthas (Oligochaeta: Megascolecidae) from Guangxi Province, China. AB - Two new species of earthworms belonging to the genus Amynthas are described from Guangxi Province, China: Amynthas crassitubus sp. nov. and Amynthas stabilis sp. nov. from Shiwan Mountain Nature Reserve. The two species have three pairs of spermathecal pores in 6/7-8/9, and belong to the sieboldi-group. COI barcode sequences support their status as new species. PMID- 30313702 TI - Three new earthworm species of the tokioensis-group in the genus Amynthas (Oligochaeta: Megascolecidae) from Guangxi Province, China. AB - Three new species of the genus Amynthas are described from Guangxi Province, China. They are named A. dissimilis sp. nov., A. anteporus sp. nov. and A. marsupiformis sp. nov. All of them have two pairs of spermathecal pores in 6/7 7/8, and belong to the tokioensis-group. Their morphological characteristics are compared to similar species in tokioensis-group from China and other Asian countries. In addition, the mitochondrial COI and 12S-tRNA-Val-16S sequence of three new species were determined, then pairwise distances between species were calculated. Both morphological and molecular evidences could easily distinguish the new species from earthworms previously reported in the tokioensis-group. PMID- 30313703 TI - New earthworm species of the genus Amynthas from Hainan Island, China (Megascolecidae, Clitellata). AB - Three new species of earthworms belonging to the genus Amynthas are described from Hainan Island, China. They are named Amynthas wenchangensis sp. nov., Amynthas accessorius sp. nov., and Amynthas eumorphus sp. nov. A. wenchangensis sp. nov. keys to the Amynthas morrisi-group; it has several small genital papillae in the male pore region and a degenerated prostate. A. accessorius sp. nov. keys to the Amynthas hawayanus-group and has completely degenerated prostates and two large accessory glands. A. eumorphus sp. nov. keys to the Amynthas sieboldi-group. PMID- 30313704 TI - Four new Amynthas and Metaphire earthworm species from nine provinces in southern China. AB - Four new species belonging to genera Amyntha and Metaphire were discovered from an extensive area in southern China, covering the provinces Sichuan, Yunnan, Guizhou, Guangdong, Guangxi, Fujian, Hunan, Jiangxi and Anhui. The species are named Amynthas dispersus Sun Qiu, sp. nov., Amynthas shanghangensis Sun Qiu, sp. nov., Amynthas dentiformis Sun Jiang, sp. nov. and Metaphire sanmingensis Sun Jiang, sp. nov. The first two new species have four pairs of intersegmental spermathecal pores in 5/6-8/9. A. dispersus has elliptical and glandular male pore porophores raised on a low pad-like area surrounded by two to three shallow skin folds, the genital papillae are variable in the spermathecal pore and male pore regions, and prostate glands are vestigial or rudimentary. Amynthas shanghangensis has male porophores surrounded by three papillae, each prostate gland accompanied by an accessory gland, and the distal 1/2-1/3 of the spermathecal diverticulum dilated into a rod-shaped seminal chamber. Amynthas dentiformis has two pairs of spermathecal pores in 7/8-8/9, male pores always surrounded by two papillae, and small sacs on the dorsal and ventral margins of the intestinal caecae; the prostate gland occasionally has stalked accessory glands. M. sanmingensis is in the Metaphire houlleti-group, and has secondary male pores opening to copulatory pouches, rod-shaped spermathecal seminal chamber, as well as variable genital papillae in spermathecal and male pores regions. The GenBank accession numbers of DNA barcode data are attached under the description of each species. PMID- 30313705 TI - Two new earthworm species of the genus Drawida (Oligochaeta: Moniligastridae) from southwestern Taiwan. AB - This study describes two new species of earthworms belonging to the genus Drawida (Oligochaeta: Moniligastridae) from southwestern Taiwan. They are Drawida alishanensis sp. nov. and Drawida fenqihuensis sp. nov. The two species were found at elevations of 1407-1661 m in the Alishan area, Chiayi County. DNA barcodes from type specimens of the new species are reported. This is the first time that new species of Drawida are discovered from the island of Taiwan. In addition, Drawida keikiensis Kobayashi, 1938 from Korea is found to be synonymous with Drawida syringa Chen, 1933 from central China. The synonymy of Drawida glabella Chen, 1938 with Drawida barwelli (Beddard, 1886) is rejected. PMID- 30313706 TI - Biogeography meets taxonomy: Distribution-based inferences on the accuracy of identification and synonymization of East Asian earthworms. AB - This paper demonstrates that the uniqueness of the geographical location of Taiwan and its adjacent islands can be taken as a basis to evaluate the accuracy of identification and synonymization of East Asian earthworms and further to clarify some disputes in earthworm taxonomy. A comprehensive review of the earthworm fauna from the Ryukyu Archipelago is given; as a result, two recorded species are recognized as new species, named here Amynthas ishigakiensis sp. nov. and Amynthas iriomotensis sp. nov. Common but harmful practices in earthworm taxonomy, synonymies with question marks and erection of sympatric subspecies, are commented. PMID- 30313707 TI - New enchytraeid species from Mount Hallasan (Jeju Island, Korea) (Enchytraeidae, Oligochaeta). AB - The enchytraeid fauna of Mt. Hallasan (Jeju Island, Korea) was studied in 2016, and 21 enchytraeid species were recorded and identified in total. A combination of morphological and molecular analyses (based on CO1, ITS and H3 sequences) was applied. Here we give descriptions of eight new species of Enchytraeidae (Clitellata): Achaeta koreana sp. n., Achaeta macroampullacea sp. n., Bryodrilus hallasanensis sp. n., Chamaedrilus baekrokdamensis sp. n., Enchytronia seongpanakiensis sp. n., Mesenchytraeus jungsaihoi sp. n., Xetadrilus jejuensis sp. n. and Xetadrilus aphanoides sp. n. Additionally, two species were found to be new for the Korean fauna in Mt. Hallasan: Fridericia cf. paroniana Issel, 1904 and F. perrieri (Vejdovsky, 1878); three potentially new Fridericia species require further studies. Furthermore, two terrestrial polychaetes, Hrabeiella periglandulata Pizl Chalupsky, 1984 and Parergodrilus heideri Resisinger, 1925, were recorded. For 12 enchytraeid species, DNA sequences are presented for the first time: these include, apart from the new species, further taxa such as species of Xetadrilus, a genus of which no sequences were previously available. PMID- 30313708 TI - Two new Mesenchytraeus species (Annelida: Clitellata: Enchytraeidae) from Changbai Mountain, China. AB - The Changbai Mountain in northeast China harbours a species-rich enchytraeid fauna, and ca. 50 species of 11 genera have been reported so far from its well preserved ecosystems. Herein, we add two new species of Mesenchytraeus into this enchytraeid list. Both members belong to the lineage of Mesenchytraeus with enlarged ventral chaetae. Mesenchytraeus spermatoglomeratus sp. nov. is characterized by the presence of enlarged chaetae in V-VI and XI (2 per bundle), five pairs of preclitellar nephridia (VI/VII-X/XI), sperm sacs containing curly ball-shaped sperm bundles, spermathecae without diverticula, atrium with 4-6 developed prostate glands and long vasa deferentia backward to XV-XXII. Mesenchytraeus liberothecus sp. nov. is diagnosed by the presence of enlarged chaetae in V-VI (2 per bundle), five pairs of preclitellar nephridia (VI/VII X/XI), asymmetrical paired sperm sacs containing flame-shaped sperm bundles, spermathecae with two small diverticula but free from oesophagus, atrium with 4-5 large prostate glands and short vasa deterentia confined to XI and XII. The major differences between the new species and their congeners are discussed. We also add them into the key of this enlarged chaetae lineage. PMID- 30313709 TI - Preliminary taxonomical investigation of soil enchytraeids (Clitellata, Enchytraeidae) from south region of Tibet, China. AB - The biodiversity in the Tibetan region is still poorly known, particularly for its soil organisms. Here, we describe eleven enchytraeid species based on several taxonomical surveys in 2015-2016, from some soil localities in south region of the Tibet, China. All are firstly recorded in this region; seven species (Fridericia ratzeli sensu stricto, F. peregrinabunda, F. cusanica, F. bretscheri, Buchholzia sp., Enchytraeus buchholzi and Henlea sp.) are new records for China. PMID- 30313710 TI - Observations on an epilobic Lumbricus rubellus (Oligochaeta, Lumbricidae) from the Great Smoky Mountains National Park, Tennessee, USA. AB - The genus Lumbricus L. was the first described genus of earthworms, with L. terrestris as its type species. The genus can be easily distinguished because it is the only lumbricid genus with a tanylobic prostomium, with the exception of the North American native Bimastos eiseni (Levinsen). With six known Lumbricus species introduced in North America (Reynolds Wetzel, 2012), Lumbricus rubellus is one of the most widespread. In addition, L. rubellus has been associated with negative ecological effects as result of its invasion (Greiner et al. 2012). The Great Smoky Mountains National Park in Tennessee and North Carolina, USA, is no exception from earthworm invasions (Snyder et al. 2011). Recent research in an area near the extreme southwestern end of the Park (35.5538o N; 83.9943o W), resulted in the collection of ten specimens of L. rubellus, on 27 July 2011. Among these specimens was one that had an abnormal epilobic prostomium and under developed tubercula pubertatis, whereas the rest had the typical Lumbricus tanylobic prostomia and fully developed tubercula pubertatis. To facilitate discrimination and identification in future encounters of an epilobic L. rubellus we provide here a full description of this specimen. To our knowledge, this is the first reported case of a specimen of L. rubellus with an epilobic prostomium. The specimen will be deposited in the nascent Terrestrial Oligochaete Collection at the Georgia Museum of Natural History in Athens, Georgia, USA. The specimen was fixed in 10% formalin, and is preserved in 70% ethanol. PMID- 30313711 TI - New Diplotrema and Lavellodrilus earthworm species from southern Mexico (Annelida, Crassiclitellata, Acanthodrilidae). AB - Two acanthodriline new species from the states of Tabasco and Chiapas in southern Mexico are described, Diplotrema chajulensis sp. nov. and Lavellodrilus sheylae sp.nov. Diplotrema chajulensis sp. nov. has spermathecae where the ampulla inserts at a right angle from the duct and the diverticulum continues the main axis; it is distinguished from other neotropical Diplotrema species that share this character by the pattern of genital marks and the type of penial setae. Lavellodrilus sheylae sp. nov. is unique in the genus Lavellodrilus by the unpaired condition of the mesial spermathecae; variation in the number of spermathecal diverticula (one or two) was considered a polymorphism. Finally we discuss reasons to maintain one of the new species in an austral genus (Diplotrema) in spite of some morphological differences observed among the Mexican-Cuban-Central American (MX-CA) worms and the austral species. A short esophagus in all the holoic and meroic acanthodriline earthworms from MX-CA and a mid-ventral position of spermathecal pores in Lavellodrilus are interpreted as ancestral characters that evolved and were fixed in the worms that inhabited an ancient Laurasian block, probably in response to the semi-aquatic conditions that prevailed in this region during millions of years. PMID- 30313712 TI - Protozapotecia acaxetlensis and Protozapotecia oyametlensis, two new earthworm species (Crassiclitellata: Acanthodrilidae) from Mexican central mountains. AB - Two earthworm species from central Mexico are described: Protozapotecia acaxetlensis sp. nov. and Protozapotecia oya-metlensis sp. nov. Delimitation of species was supported by morphological and molecular evidence. The two new species differ from the other species of Protozapotecia by the position of the prostates in segments 18 and 20. This morphological characteristic relates them to the genus Diplocardia, from which they differ by the presence of two gizzards separated by a muscular septum (Protozapotecia), instead of two gizzards fused as one, separated by a thin membranous septum in intersegment 5/6 (Diplocardia). PMID- 30313713 TI - Two new earthworm species (Oligochaeta: Annelida) of the Orinoquia region of Colombia. AB - Two new earthworm species from grassland and herbaceous plant formations in the departments of Arauca y Casanare (Orinoquian region of Colombia) are described, Righiodrilus cusiani sp. nov. (Glossoscolecidae) and Andiodrilus cravijae sp. nov. (Rhinodrilidae). Righiodrilus cusiani sp. nov. is close to R. arapaco (Righi, 1982) in the position of the clitellum, but differs in the extension of the tubercula pubertatis, the extension of the seminal vesicles and the position of the male pores. Andiodrilus cravijae sp. nov. is close to A. major Michaelsen, 1900 in the position of the clitellum and the spermathecal pores, but is different in the extension of the tubercula pubertatis and in the position of the male and female pores. PMID- 30313714 TI - New species and records of earthworms (Annelida, Oligochaeta) in plantain cropping systems in Colombia's coffee-growing region. AB - Two new earthworm species, one of Glossodrilus Cognetti, 1905 and the other of Martiodrilus (Maipure) Righi, 1995, are described from material collected from the coffee-growing region located in central-western Colombia: Glossodrilus chaguala sp. nov., and Martiodrilus (Maipure) quimbayaensis sp. nov. New records for this region are also reported for Glossodrilus griseus, Glossodrilus lacteus, Glossodrilus panikita, Aptodrilus fuhrmanni, Periscolex columbianus, Periscolex coreguaje, Pontoscolex (Pontoscolex) corethrurus, Dichogaster (Diplothecodrilus) affinis, Dichogaster (Diplothecodrilus) bolaui, Dichogaster (Diplothecodrilus) saliens, Amynthas (Amynthas) gracilis, Amynthas minimus, and Perionyx excavatus. PMID- 30313715 TI - Three new species of Holoscolex (Clitellata, Glossoscolecidae) from the Gurupi Biological Reserve, last forest remnant of the Belem Endemism Area, Eastern Amazon. AB - We describe three new species of the earthworm genus Holoscolex from the Gurupi Biological Reserve in Maranhao state, Brazil. The Reserve, with the Indigenous Territories Awa, Caru, Alto Turiacu and Alto Rio Guama represent the last continuous forest remnants of the Belem Endemism Area, the most deforested and threatened area of Brazilian Amazonia. Holoscolex dossantosi sp. nov. has tubercula pubertatis looking like double bands, Holoscolex alatus sp. nov. presents alate tubercula pubertatis, and Holoscolex fernandoi sp. nov. has testis sacs and several intraclitellar atrial glands associated with genital markings between XIX and XXII. The presence of these unusual characters in Holoscolex fernandoi sp. nov. suggests that this species could be an evolutionary transitional stage linking Eudrilidae and more recent Glossoscolecidae genera. PMID- 30313716 TI - Brasilisia n. gen. and Arraia n. gen., two new genera of Ocnerodrilidae (Annelida, Clitellata, Oligochaeta) from Eastern Amazonia, Brazil. AB - We describe two new species from two new genera of Ocnerodrilidae from Alcantara and Rosario counties of Maranhao, Brazil. They were collected in very sandy soil in the transition between the Amazonia and Cerrado biomes. One of the species, Brasilisia punki n. sp., is the first report of earthworms of this family with an unusual pattern of genital markings and a gizzard in segment five. The other species Arraia nelmae n. sp. has a gizzard in segment six and a pair of calciferous glands in nine. We also provide an updated key for all genera of Ocnerodrilidae. PMID- 30313717 TI - Additions to Andiorrhinus (Turedrilus) (Rhinodrilidae, Clitellata) from Eastern Amazonia. AB - Two new species of the earthworm family Rhinodrilidae (Clitellata), from Maranhao state, Brazil, were studied by dissection. Andiorrhinus (Turedrilus) miricuri n. sp. is the first record of a big earthworm for this region with three pairs of large spermathecae in segments 7-9 and one pair of tubercula pubertatis bands lateral to b line in XX-XXV. Andiorrhinus (Turedrilus) barrosoi n. sp. lacks spermathecae and has one pair of tubercula pubertatis bands lateral to b line in XX-(1/3) XXIV. The earthworms described are from the most threatened region of Amazonia where 75% of forest cover is already lost. More information is urgently necessary to assess their ecology and vulnerability status. PMID- 30313718 TI - New species of Glossoscolex and Fimoscolex earthworms (Oligochaeta: Glossoscolecidae) from Embrapa Forestry, Parana, Brazil. AB - Three new earthworm species in two genera of the Glossoscolecidae family, common in Southern and Southeastern Brazil, collected in the highland plateaus of Parana, are described: Glossoscolex (Glossoscolex) maschio sp. nov. and Glossoscolex (Glossoscolex) embrapaensis sp. nov., and Fimoscolex nivae sp. nov. G. embrapaensis is a small, unpigmented endogeic belonging to the truncatus species group, having male pore on segment 17, while G. maschio is a large, pigmented epiendogeic species belonging to the giganteus species group, having male pore on segment 19. F. nivae is a very slender, small unpigmented endogeic species. All specimens were collected in native Araucaria forest on the grounds of Embrapa Forestry, but G. maschio was found exclusively associated with native forest, while G. embrapaensis and F. nivae were also collected in Eucalyptus, Pinus or Araucaria plantations, native grassland or fallow land, indicating their resistance to soil disturbance and land use change. PMID- 30313719 TI - Earthworm species in various land use systems in the Campos Gerais region of Lapa, Parana, Brazil. AB - The Campos Gerais region of Parana are on an ancient plateau of sandstone origin and are covered with a diverse vegetation including mainly grasslands and various types of Atlantic Forest (particularly Araucaria forest). The region represents an important natural capital for biodiversity conservation as well as for agricultural and forestry production. However, little is known of the species richness and diversity of soil macroinvertebrates in this region. In the present study we evaluated earthworm species occurrence and richness in five land use systems (LUS) in the southern part of the Campos Gerais in Lapa county. Earthworms were handsorted from up to 18 soil monoliths on five occasions over three years (Feb. 2014, Feb., Mar., Nov. 2015, Jul. 2016) in the following LUS: old native forest, native grassland, young regenerating forest and grass lawn in the Uru Reserve and annual crop fields (soybean) in neighboring private farms (not all systems were sampled on all occasions). Nine earthworm species belonging to four families and five genera were found, of which six were native and three exotic species (Dichogaster gracilis, Amynthas gracilis, A. corticis). Of the native species, Urobenus brasiliensis and Andiorrhinus duseni (a large bodied worm) are already well known from S and SE Brazil, while the remaining four were new species that require further description (Fimoscolex n.sp.1 and n.sp.2, Glossoscolex n.sp.1 and n.sp.2). In general, more species were found in February (summer) than March and November. The cropping system (soybean) had the lowest abundance and species richness in relation to other sites, although in the young and old forests no earthworms were found on some sample dates. Given the several new species found in this small reserve, and the relatively few sites studied thus far in the Campos Gerais, further efforts are needed to adequately characterize the earthworm fauna of the region, from which many other species are expected. PMID- 30313720 TI - Earthworm species in no-tillage agroecosystems and native Atlantic forests in Western Parana, Brazil. AB - Earthworm populations often increase with the adoption of no-tillage (NT) practices, but few studies have evaluated earthworm diversity in these agroecosystems. In the present study we assessed earthworm species richness in 40 sites under NT and six native Atlantic forest fragments in Western Parana, Southern Brazil. At each site earthworms were sampled quantitatively (n=5) and qualitatively (n=5), by handsorting soil monoliths (20 x 20 cm width x 20 cm depth), totaling 460 samples overall. Earthworms were killed and fixed in 96% ethanol, counted and identified. Overall, 18 species were found, in the families Acanthodrilidae, Glossoscolecidae, Megascolecidae, Rhinodrilidae and Ocnerodrilidae, of which 10 were native and eight exotic. No-tillage agroecosystems had larger earthworm populations and higher species richness overall than native forests, although this was mainly due to colonization of these agricultural fields by exotic species. Mostly native species were found in the Atlantic forests, highlighting the importance of these habitats as refugia for native earthworm species conservation. PMID- 30313721 TI - Earthworm species in public parks in Curitiba, Parana, Brazil. AB - Earthworms are important macroinvertebrates that provide soil ecosystem services and are also useful environmental bioindicators. Urban areas around the world have major impacts on biodiversity and the objective of the present study was to assess the role of urban parks of Curitiba, Parana State, in preserving native earthworm species. Earthworm populations were sampled in five parks (Barigui, Tingui, Barreirinha, Passauna and the Botanic Garden), in two land use systems (grass lawns and secondary forest fragments) in two seasons, summer (November 2013) and winter (June 2014). A total of twelve earthworm species were identified, belonging to six families: Glossoscolex sp.1, Fimoscolex sp.1, sp.2 and sp.3 (Glossoscolecidae), Pontoscolex corethrurus (Rhinodrilidae), Eukerria tucumana (Ocnerodrilidae), Amynthas gracilis, Amynthas corticis, Metaphire californica (Megascolecidae), Aporrectodea rosea and Lumbricus rubellus (Lumbricidae), the latter being the first record for this species in Brazil. In addition, a single unidentified juvenile Dichogaster sp. (Acanthodrilidae) was found. Four new species were found and three out of five urban parks of Curitiba (especially the Botanic Garden) were able to preserve native species, though their abundance was low and exotic species (n=8) predominated, attributed to human disturbance that favors invasion and colonization of exotic earthworms. PMID- 30313722 TI - New species-group taxa of Glossoscolex (Clitellata: Glossoscolecidae) from Rio Grande do Sul, Brazil. AB - Five new species-group taxa of Clitellata of the genus Glossoscolex from Rio Grande do Sul State, Brazil are described in this paper: Glossoscolex (Glossoscolex) riograndensis n. sp. has three subspecies, G. (G.) riograndensis riograndensis, G. (G.) riograndensis pollulus n. ssp., G. (G.) riograndensis nativus n. ssp. The two other new species are named G. (G.) pastivus n. sp., and G. (G.) pampas n. sp. All new species are part of the truncatus species group within the subgenus, characterized by the presence of male pores in segment xvii. A single unnamed specimen, also described here, is deemed to belong to a sixth new species-group taxon of the truncatus group. A tabular character comparison of the new taxa and known and morphologically similar species is given. Information on the habitat, such as vegetation cover and soil characteristics, is given as well. G. (G.) r. riograndensis and G. (G.) r. pollulus had an unusual storage of sperm in the nephridia. Histological sections were performed to verify it. PMID- 30313723 TI - Earthworm diversity in Rio Grande do Sul, Brazil. AB - The knowledge regarding earthworm species richness in subtropical Brazil is limited, particularly in the state of Rio Grande do Sul (RS), where only a few sites have been sampled. In this study we assessed earthworm richness in different ecosystems of RS, prioritizing un-sampled regions. Fifteen ecosystems, including native vegetation and other ecosystems with variable levels of disturbance were sampled in 30 counties in RS, totaling 77 sampling points, mainly in the Pampa biome. Qualitative sampling was performed by handsorting soil monoliths and fixing the earthworms in 4% formalin solution. Species identification was based on morphological characters, and species richness and Shannon (H) and McIntosh (U) diversity indices were calculated for each ecosystem. Twenty-one earthworm species were identified, belonging to seven families: Glossoscolecidae (8), Rhinodrilidae (2), Ocnerodrilidae (4), Megascolecidae (4), Acanthodrilidae (1), Lumbricidae (1) and Criodrilidae (1). From these, ten are new species belonging to the genera: Glossoscolex (6), Fimoscolex (1), Kerriona (1), Eukerria (1), and one aquatic species of the Criodrilidae family, belonging to a new genus. Most of the native species (Urobenus brasiliensis, Fimoscolex n.sp.1 and the Glossoscolex spp.) predominated in ecosystems little altered by human activity, while exotic (Amynthas gracilis, Amynthas rodericensis, Metaphire californica, Aporrectodea trapezoides) and peregrine species (Pontoscolex corethrurus) predominated in areas with more human disturbance. Native ecosystems with lower disturbance, particularly forests and native pastures had higher diversity than disturbed sites. This is the first record of A. rodericencis for Brazil and most sites represent new collection records for the known species in RS. PMID- 30313724 TI - On the genus Habrobathynella Schminke, 1973 (Crustacea, Malacostraca, Bathynellacea), with description of three new species from India. AB - The genus Habrobathynella Schminke, 1973 contains 16 species, 2 from Madagascar and 14 from the peninsular India. This is a remarkably species-rich genus when compared to the three other genera of the family Parabathynellidae known from India: Atopobathynella Schminke, 1973 (5 spp.), Chilibathynella Noodt, 1964 (1 sp.), and Parvulobathynella Schminke, 1973 (3 spp.). This paper provides a monographic treatment of Habrobathynella together with a detailed illustrated account of three new cavernicolous species, viz. Habrobathynella bose n. sp., Habrobathynella ernstmayr n. sp. and Habrobathynella raman n. sp., from the States of Andhra Pradesh and Telangana, India. For each of the already described species, the following details are provided: reference to original description, diagnosis, type data, type locality, distribution, ecology, co-occurrence with other species and remarks on taxonomic affinity. Distribution maps and a dichotomous key for identification of all species in Habrobathynella are provided. We also include a brief note on the biogeography and conservation status of the Indian bathynellaceans. PMID- 30313725 TI - Revision of the Ambrysus pudicus Stal species complex (Heteroptera: Nepomorpha: Naucoridae) with the description of a new species from southern Mexico. AB - The Ambrysus pudicus Stal species complex is revised, its species diagnosed, and an illustrated key is presented. The complex includes A. abortus La Rivers, A. amargosus La Rivers, A. funebris La Rivers, A. hungerfordi Usinger, A. parviceps Montandon, A. pudicus Stal, and A. relictus Polhemus Polhemus. A new species, A. chinanteco, belonging to this complex is described from southern Mexico. The subspecies A. hungerfordi angularis La Rivers, A. h. spicatus La Rivers, and A. h. triunfo La Rivers are herein elevated to full species level and considered members of this species complex. The subspecies A. pudicus barberi Usinger is synonymized with the nominate subspecies. Based on specific combinations of morphological features, two subcomplexes of species are recognized within the complex. The species A. funebris is transferred from the subgenus Acyttarus La Rivers to the subgenus Ambrysus Stal. In order to fix the identity of three species in the complex, neotypes for A. amargosus and A. spicatus and a lectotype for A. pudicus are designated here. The species in the A. pudicus complex are distributed in North America from the southwestern and southern United States to northern Costa Rica. New country records from Central America are presented for A. parviceps and A. pudicus. New state records from Mexico are presented for A. abortus, A. angularis, A. hungerfordi, A. parviceps, A. pudicus, and A. spicatus. PMID- 30313726 TI - Brazilian Polycladida (Rhabditophora: Platyhelminthes): Rediscovery of Marcus' type material and general revision. AB - Polyclads are a conspicuous group of marine invertebrates, the most charismatic members of the phylum Platyhelminthes. From Brazil, a total of 71 polyclad species were reported or described. Only three of them were recently described, five are recent records for the Brazilian coast, and 55 were described by Ernest and Eveline Marcus, who were by far the most productive workers. However, they quite often published in Portuguese or German, rather than English, and have not designated type material or specified material deposited in museum collections. Most of the polylcad material studied by the Marcus was found to be in the Swedish Museum of Natural History. Here we summarize the knowledge about Brazilian polyclad biodiversity, give information about deposited material in different museums for future reference, and designate type material for the species that did not have any. We examined 58 polyclad species reported from Brazil and designated type material and information available on type series of 52 species. Lectotypes (89 vouchers) were designated for 30 species and paralectotypes (73 specimens / 70 vouchers) were designated for 22 Brazilian species. Among the 261 type vouchers examined in this work, 22 species (77 vouchers) had material recognized as holotypes and 2 vouchers were recognized as paratypes. Of the total number of species reported from Brazil, 10 species remain without information about type material. In the present paper we also propose a new combination (Lurymare cynarium nov. comb.). Eleven species have their geographical distribution range broadened and 42 were photographed for the first time, five of those were photographed live as well. The number of Brazilian polyclad species is expected to rise when different regions and environments are surveyed. PMID- 30313727 TI - Sieve-type pore canals in the Timiriaseviinae-A contribution to the comparative morphology and the systematics of the Limnocytheridae (Ostracoda, Crustacea). AB - Examination of normal pore canals, especially sieve-type pore canals, in living and fossil representatives of ten genera of the family Limnocytheridae, subfamily Timiriaseviinae, has revealed important diversity of structure. These complex pore canals have been studied via high-resolution scanning electron microscopy (the Cartographic Method) and analysed via the application of newly devised indices to assess patterns of consistency and variation in both detailed structure of individual pores and of their distribution on the calcified valve. The timiriaseviine taxa are compared with species of the genera Limnocythere, sub family Limnocytherinae and Cyprideis (family Cytherideidae). The relationship between the living animal and its aquatic environment is discussed in the light of previous studies and of new evidence herein. The importance of normal pore canals for systematics is highlighted by the recognition and definition of the new tribe Gomphodellini Danielopol, Cabral Lord nov. tribe, subfamily Timiriaseviinae, family Limnocytheridae. PMID- 30313728 TI - Holopothrips diversity-a Neotropical genus of gall-inducing insects (Thysanoptera, Phlaeothripidae). AB - The genus Holopothrips represents the main Neotropical group of thrips associated with plant galls, and several of the 36 currently described species are known to induce or invade galls of other organisms. The existence of several Holopothrips specimens in collections that do not belong to any of the already described species, allied to the absence of basic biological information for several species, such as host plants and habit, shows that the current knowledge on the genus is severely lacking. Here we start addressing these problems, by describing 24 new species: H. acrioris, H. atlanticus, H. bicolor, H. brevicapitatum, H. cardosoi, H. curiosus, H. flavisetis, H. graziae, H. inconspicuus, H. infestans, H. irregularis, H. johanseni, H. kaminskii, H. longihamus, H. longisetus, H. magnus, H. maiae, H. nigrisetis, H. nigrum, H. punctatus, H. reticulatus, H. singularis, H. spermathecus, H. varicolor. This study also includes information on galls for several species; an updated and illustrated key to species; and comments on the morphological diversity of the group. With that, we hope to lay the taxonomic and morphological bases for future studies in this group, focusing on its diversity, ecology and phylogenetic relationships. PMID- 30313729 TI - The cicadas (Hemiptera: Cicadidae) of Panama including the description of six new species, three new combinations, one new synonymy, and nine new records. AB - The known cicada fauna of Panama is identified. Procollina quadrimaculata n. sp., P. stigmosa n. sp., Guyalna woldai n. sp., Herrera nigratorquata n. sp., H. sigillata n. sp. and Conibosa megalopercula n. sp. are described as new. Proarna germari Distant, 1905 n. syn. is shown to be a junior synonym of Proarna invaria (Walker, 1850). Pacarina championi (Distant, 1881) is returned to Proarna Stal, 1864 to become Proarna championi Distant, 1881 n. comb. again. The first records of Proarna invaria (Walker, 1850), Guyalna bogotana (Distant, 1892), Dorisiana cachla (Distant, 1899), Ollanta modesta (Distant, 1881), Pacarina schumanni Distant, 1905, Majeorona truncata Goding, 1925, Herrera lugubrina lugubrina (Stal, 1864), Calyria cuna (Walker, 1850), and Calyria telifera (Walker, 1858) are provided. The records for Ollanta modesta (Distant, 1881) are the first records of the genus Ollanta Distant, 1905 for Panama. The records for Calyria cuna (Walker, 1850), and Calyria telifera (Walker, 1858) are the first record of the genus Calyria Stal, 1862 and the Tribe Parnisini Distant, 1905 in Panama. Previous records of Dorisiana metcalfi Sanborn Heath, 2014 (= Cicada viridis Olivier, 1790), Carineta fasciculata (Germar, 1830), and Selymbria stigmatica (Germar, 1834) are considered to be misidentifications of G. bogotana, C. maculosa (Torres, 1948), and S. pluvialis (Ramos Wolda 1985) respectively so that D. metcalfi, C. fasciculata, and S. stigmatica are removed from the cicada fauna of Panama. The Panamanian record of Dorisiana semilata (Walker, 1850) is shown to be a mistake and the species is removed from the faunal list as well. The currently known Panamanian cicada fauna is comprised of 54 described species along with six species from the literature that remain undetermined from 22 genera, seven tribes and three subfamilies. Bergalna xanthospila (Germar, 1830) is reassigned to Dorisiana Metcalf, 1952 to become Dorisiana xanthospila (Germar, 1830) n. comb. Fidicinoides flavibasalis (Distant, 1905) is reassigned to Guyalna Boulard Martinelli, 1996 to become Guyalna flavibasalis (Distant, 1905) n. comb. PMID- 30313730 TI - Global guide of the flat wasps (Hymenoptera, Bethylidae). AB - The flat wasp family Bethylidae Haliday lacks global scale literature on their alpha taxonomy. The only world revision for the family was by Kieffer in 1914 and is fully out of date and somewhat useless; the only catalog for the family was made by Gordh Moczar in 1990 and does not include hundreds of changes made since then; and the most recent world genera keys were proposed by Terayama in 2003, but do not reflect the current knowledge we have for the family. Given this scenario, we present a global guide of Bethylidae with diagnoses, taxonomic evaluation, keys, and a checklist of all their extant genera and subfamilies. We visited the main collections around the world, analyzed about 2,000 holotypes, and examined at least 400,000 specimens. To eliminate homonymies, we add the prefix "neo" to the original specific epithet when possible. The family is now composed by 2,920 species allocated in 96 genera distributed in eight subfamilies: Bethylinae, Pristocerinae, Epyrinae, Mesitiinae, Scleroderminae, Lancepyrinae, Holopsenellinae and Protopristocerinae. The latter three are extinct. One new family-group synonym is proposed: Fushunochrysidae Hong syn. nov. of Bethylidae. Two incertae sedis genera are allocated into Bethylinae: Cretobethylellus Rasnytsyn and Omaloderus Walker. One new genus-group synonym is revalidated: Pristepyris Kieffer stat. rev. from Acrepyris Kieffer. Sixteen new genus-group synonyms are proposed: Fushunochrysites Hong syn. nov. and Sinibethylus Hong syn. nov. of Eupsenella Westwood; Messoria Meunier syn. nov. of Goniozus Forster; Acrepyris Kieffer syn. nov. of Pristepyris Kieffer; Apristocera Kieffer syn. nov. and Parapristocera Brues syn. nov. of Pristocera Klug; Usakosia Kieffer syn. nov. of Prosapenesia Kieffer; Isobrachium Forster syn. nov., Leptepyris Kieffer syn. nov., Neodisepyris Kurian syn. nov., Rhabdepyris Kieffer syn. nov. of Epyris Westwood; Codorcas Nagy syn. nov., Hamusmus Argaman syn. nov. and Ukayakos Argaman syn. nov. of Heterocoelia Dahlbom; Domonkos Argaman syn. nov. of Incertosulcus Moczar; Ateleopterus Forster syn. nov. of Sclerodermus Latreille. One new genus-group synonym is revalidated: Topcobius Nagy syn. rev. of Sulcomesitius Moczar. One new genus-group revalidation is proposed: Incertosulcus Moczar stat. rev. from Anaylax Moczar. The following species-group nomenclatural acts are established: 153 new or revalidated combinations, 16 new names to avoid secondary homonyms, 11 species with revalidated status, and one synonym. Keys to the subfamilies and genera are provided. The text is supported by 599 illustrations organized onto 92 plates. PMID- 30313731 TI - A monograph of the Afrotropical Cassidinae (Coleoptera: Chrysomelidae). Part 5. Revision of the genus Aethiopocassis Spaeth. AB - The genus Aethiopocassis Spaeth, 1922 is revised and 31 species are recognized as valid, all distributed in Sub-Saharan Africa. Seven species are described as new: Aethiopocassis angulicollis sp. nov. (Tanzania), Aethiopocassis dewittei sp. nov. (Democratic Republic of Congo), Aethiopocassis garambana sp. nov. (Democratic Republic of Congo), Aethiopocassis guineensis sp. nov. (Guinea), Aethiopocassis huilaensis sp. nov. (Angola), Aethiopocassis longidoana sp. nov. (Tanzania), and Aethiopocassis transvaalensis sp. nov. (Republic of South Africa). The following new synonyms are proposed: Aethiopocassis fugax (Spaeth, 1906) = Cassida (Aethiopocassis) scita Spaeth, 1924 syn. nov.; Aethiopocassis gallarum (Spaeth, 1906) = Cassida deplanata Spaeth, 1906 syn. nov. = Cassida sjoestedti Spaeth, 1906 syn. nov. = Cassida (Aethiopocassis) burensis Spaeth, 1924 syn. nov.; Aethiopocassis pauli (Weise, 1898) = Cassida pauli var. deleta Weise, 1899 syn. nov. = Cassida (Aethiopocassis) alluaudi Spaeth, 1924 syn. nov.; Aethiopocassis silphoides (Spaeth, 1906) = Cassida (Aethiopocassis) silphoides ssp. katangana Spaeth, 1933 syn. nov.; Aethiopocassis suspiciosa (Weise, 1903) = Cassida suspiciosa var. connexa Weise, 1906 syn. nov. = Cassida suspiciosa ssp. picturata Spaeth, 1934 syn. nov. = Cassida manubialis Spaeth, 1906 syn. nov., = Cassida decipiens Spaeth, 1906 syn. nov. = Cassida (Aethiopocassis) maynei Spaeth, 1933 syn. nov. = Aethiopocassis suspiciosa ssp. flavofemorata Spaeth, 1934 syn. nov. = Aethiopocassis maynei ssp. biramosa Spaeth, 1934 syn. nov. Colour photos, including intraspecific variablity, a key to species and maps of distribution are given. PMID- 30313732 TI - Names of hydroids (Cnidaria, Hydrozoa) established by Charles McLean Fraser (1872 1946), excluding those from Allan Hancock Expeditions. AB - An account is given of the names of families, genera, and species of hydroids established by C.M. Fraser of Canada, excluding those from Allan Hancock Pacific Expeditions and the Allan Hancock Caribbean Sea Expedition. The names of four families, 11 genera, and 101 species are attributed to him in this work, complementing those of another two genera and 164 species described by Fraser in various Allan Hancock publications. Information is provided on type localities of his new species, on locations and kinds of type material in existence, where known, and on the current taxonomic status of families, genera, and species described by him in works reviewed herein. Two replacement names (Thuiaria geniculata Fraser, 1918a and Salacia fraseri Calder, 1991) exist for Thuiaria distans Fraser, 1914a (not Thuiaria distans Allman, 1877). The widely overlooked senior synonym, T. geniculata, is recognized as the valid name of the species. Diphasia alta nom. nov. is proposed as a new replacement name for the permanently invalid junior primary homonym Diphasia robusta Fraser, 1943a (not D. attenuata robusta Billard, 1924). In addition, Cryptolaria crassa nom. nov. is proposed as a new replacement name for the junior secondary homonym Cryptolaria rigida (Fraser, 1948) [not C. rigida (Fraser, 1940a)]. Lectotypes have been designated for 47 of the species to establish objective standards for application of their names. Corymorpha adventitia Fraser, 1941b, from the Pacific coast of Panama, is assigned to Ralpharia Watson, 1980, as R. adventitia. No type specimens are known to exist for seven of the species considered, including one holotype (of Hebella eximia Fraser, 1944a) missing from its bottle. Particular attention has been paid to dating and chronology of the 51 publications of Fraser covered in this work. Earlier bibliographic errors are corrected, most notably establishing that the book Distribution and relationship in American hydroids was published in early 1947 rather than 1946 as per the title page. PMID- 30313733 TI - Immature stages of the genus Oxythyrea (Coleoptera: Scarabaeidae: Cetoniinae) with a key to third instar larvae, and notes on the biology of the genus. AB - The genus Oxythyrea Mulsant, 1842 comprises ten currently recognized species. So far, larval descriptions for only three species are available. Here, we present comprehensive descriptions of third instar larval morphology for the six previously unstudied Oxythyrea species along with detailed re-descriptions of larval morphology for the previously described species. All descriptions are supplemented by photographs and line art drawings of the morphological structures. This work also contains a key to third instar larvae of the genus Oxythyrea as well as observations from collecting sites with focus on biological characteristics of all covered species including pictures of biotopes and host plants for adults. In addition, notes on the breeding circumstances for species are provided. PMID- 30313734 TI - Review of the genus Heteropogon Loew, 1847 (Diptera: Asilidae) from Russia and Central Asia, with description of two new species. AB - Nine species of genus Heteropogon Loew, 1847 are reviewed. Heteropogon ater Sakhvon sp. nov. (Kazakhstan, Tajikistan) and H. hiemalis Sakhvon sp. nov. (Turkmenistan) are described and illustrated. A new synonymy is proposed for Heteropogon filicornis (Loew, 1871) = Cyrtopogon leleji Lehr, 1998, syn. nov. The status of Heteropogon lugubris mesasiaticus Lehr, 1970 is upgraded to species level that of mesasiaticus. The distribution of some species is increased. A key to males of the species is given. PMID- 30313735 TI - Redescription of six feather mite species of the genus Proterothrix Gaud, 1968 (Analgoidea: Proctophyllodidae: Pterodectinae) from the "Edouard Louis Trouessart" Collection. AB - Six feather mite species presently referred to the genus Proterothrix Gaud, 1968 (Proctophyllodidae: Pterodectinae) were briefly described without being drawn by a French zoologist Edouard Louis Trouessart in the end of the 19th century. The type material used for description of these species is still preserved in the Museum National d'Histoire Naturelle (Paris, France). Based on this material, we provide detailed redescriptions, according to the modern format used for pterodectine mites, for the following species: Proterothrix diminuta (Trouessart, 1899), P. modesta (Trouessart, 1899), and P. phyllura (Trouessart, 1899) from Manucodia ater (Lesson) (Corvida: Paradisaeidae); P. emarginata (Trouessart, 1899) from M. chalybatus (J. R. Forster) (Corvida: Paradisaeidae); P. paradisiaca (Trouessart, 1885) from Paradisaea minor Shaw (Corvida: Paradisaeidae) and Sericulus chrysocephalus (Lewin) (Corvida: Ptilonorhynchidae); and P. xiphiura (Trouessart, 1885) from Psarisomus dalhousiae (Jameson) (Tyranni: Eurylaimidae). The lectotypes and paralectotypes have been designated herein for all examined species. PMID- 30313736 TI - Five new species of the spider genus Khorata Huber, 2005 (Araneae: Pholcidae) from Vietnam. AB - Five new species of the genus Khorata Huber, 2005 are reported from Vietnam: Khorata bachma Yao Li sp. nov. (Thua Thien-Hue), K. cucphuong Yao Li sp. nov. (Ninh Binh), K. vinhphuc Yao Li sp. nov. (Vinh Phuc), K. palace Yao Li sp. nov. (Ninh Binh) and K. quangbinh Yao Li sp. nov. (Quang Binh). Type material is deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing, China. PMID- 30313737 TI - Recognition and partial solution of nomenclatural issues involving copepods of the family Monstrillidae (Crustacea: Copepoda: Monstrilloida). AB - This work seeks to expose and clear up nomenclatural irregularities involving copepods of the order Monstrilloida, family Monstrillidae. The diagnostic text related to Monstrilla minuta Isaac, 1974 and four nominal species of Thaumaleus Kroyer, 1849 (now Cymbasoma Thompson, 1888) proposed by Isaac in 1974 is sufficient for all names to be available from their original description except for Thaumaleus similirostratus, which was proposed conditionally in 1974 and was first made available by Isaac in 1975; "similirostris" as used by Grygier in 1995 is an incorrect subsequent spelling. Four other specific names proposed in 1975 by Isaac, but disclaimed by him as nomina nuda (an action permitted retroactively by the Fourth Edition of the International Code of Zoological Nomenclature) have never been made available. By quoting the necessary information from Isaac's doctoral dissertation, two of them are validated herein under the names Thaumaleus frondipes Isaac in Grygier Suarez-Morales, sp. nov., and Strilloma scotti Isaac in Grygier Suarez-Morales, sp. nov., and are immediately reassigned as new combinations to Cymbasoma and Monstrilla Dana, 1849, respectively. A fifth such name, Thaumaleus tumorifrons, has already been made available under the authorship of Suarez-Morales, 1999, but its females are excluded from the type series; the spelling of the specific name of the new species recently proposed for those females, Cymbasoma mediterranea Suarez-Morales, Goruppi, Olazabal Tirelli, 2017, is emended to mediterraneum to match the gender of the genus. For Cymbasoma bowmani Suarez-Morales Gasca, 1998, the "Form B" female mentioned in the original description is excluded from the type series. The authorship and date of availability of Haemocera (currently Cymbasoma) morii depends on which language version of Article 13.1.1 of the Code is followed; a ruling by the International Commission on Zoological Nomenclature under Article 87 of the Code is necessary to resolve the matter. The composition of the type series of Cymbasoma bullatum (Scott, 1909) in terms of both number and sex has become unclear; its type locality is restricted herein to the vicinity of Obi Island in the Moluccas. Despite a published statement to the contrary, the syntype series of Cymbasoma germanicum (Timm, 1893) included specimens from other localities than just Helgoland. The type series of Cymbasoma guerrerense Suarez-Morales Morales-Ramirez, 2009 consists only of the holotype, which was mistakenly reported under the wrong registration number. The supposed invalidity of Monstrilla capitellicola Hartman, 1961 is discussed. Monstrilla javensis Isaac, 1974, nomen nudum, has remained unavailable owing to lack of adherence to Article 16.1 of the Code by later authors; the specific name is made available herein, under Suarez-Morales' authorship, in the combination Cymbasoma javense sp. nov. The taxonomic (and eventual nomenclatural) question of the status of M. mariaeugeniae Suarez-Morales Islas-Landeros, 1993 vis a vis M. wandelii Stephensen, 1913, i.e. as a separate species or a subspecies of the latter, remains unsettled. Cymbasoma lenticula Suarez-Morales McKinnon, 2014 and Monstrillopsis boonwurrungorum Suarez-Morales McKinnon, 2014 are fixed herein as the correct original spellings of those two specific names. Resolution of the problem posed by assignment of the specific name reticulata to supposedly non conspecific males and females in the genus Monstrillopsis Sars, 1921 requires the designation of a neotype by the International Commission on Zoological Nomenclature. PMID- 30313738 TI - A taxonomic review of Paramblynotus Cameron, 1908 in China, with descriptions of five new species (Hymenoptera: Cynipoidea: Liopteridae). AB - Five new species of the genus Paramblynotus Cameron, 1908, are herein described from China: Paramblynotus anjiensis, new species, Paramblynotus qingliangfengensis, new species, Paramblynotus longipetiolus, new species, Paramblynotus magnatus, new species and Paramblynotus nigricaputus, new species. Three additional species, Paramblynotus reticulatus (Kieffer, 1910), Paramblynotus nipponensis Liu, Ronquist Nordlander, 2007 and Paramblynotus rufipes Liu, Ronquist Nordlander, 2007 are reported from China for the first time and the distribution of six previously reported species are updated with new collection data. Paramblynotus metatarsis He, 2004 and Paramblynotus tianmushanensis He, 2004 are redescribed. A taxonomic review, distribution map, and a taxonomic key are provided for the 19 known species of Paramblynotus from China. PMID- 30313739 TI - Kribiodorum Kieffer (= Stelechomyia Reiss) (Diptera: Chironomidae) extends into the Oriental region: three new species and expanded diagnoses. AB - Kribiodorum Kieffer, an otherwise North American and African genus of Chironomini (Diptera: Chironomidae), extends to the Oriental region through two new species. An adult male and female of Kribiodorum malicky sp. n. is newly described from Thailand, and from Brunei (Borneo) a pharate male and the pupa of Kribiodorum belalong sp. n. is described. Additionally, from Namibia (s.w. Africa) a 'manuscript' taxon is described formally with co-authorship of the late Arthur Harrison as Kribiodorum kunene sp. n. Males of the new species and the sole new pupa conform substantially to generic diagnoses based on the North American Kribiodorum perpulchrum (Mitchell). Examination of specimens of African Kribiodorum pulchrum Kieffer and N. American K. perpulchrum confirms their morphological similarity and reaffirms the junior synonymy of Stelechomyia Reiss designated for the North American species. Kribiodorum expands the number of genera of Chironomidae with African and Asian representatives, although unusual in its absence from Australia yet presence in the Nearctic. PMID- 30313740 TI - A first survey of Cretaceous thrips from Burmese amber including the establishment of a new family of Tubulifera (Insecta: Thysanoptera). AB - Burmite, a Cretaceous amber coming from the north of Myanmar, is known to preserve a great diversity of fossil arthropods, particularly insects. Many inclusions of different taxa in several insect orders have been well analysed, but this is the first study focussed on the Thysanoptera found in Burmite. In the sub-order Terebrantia, family Merothripidae, Myanmarothrips pankowskiorum gen. n., sp. n. is recognized in various amber samples from a total of 34 females but only one male. In the sub-order Tubulifera, Rohrthrips burmiticus sp. n. is based on a single female with a tubular tenth abdominal segment. This is an exceptionally well-preserved specimen, and details of the mouth parts indicate that the gnathal apparatus of modern Tubulifera was already developed in the Cretaceous. Due to plesiomorphic characters with respect to extant Tubulifera, the genus Rohrthrips is transferred to Rohrthripidae fam. n., and this family is clearly differentiated from extant Phlaeothripidae. PMID- 30313741 TI - A contribution to the knowledge of scolopendromorph centipedes of Martinique Island, with descriptions of two new species (Chilopoda: Scolopendromorpha). AB - The paper provides new data on seven scolopendromorph centipede species collected in Martinique Island. Two new species are described: Otostigmus (Parotostigmus) salticus n. sp. and Cryptops (Trigonocryptops) martinicensis n. sp.; their systematic position is discussed. Notes on the system of subgenus Trigonocryptops Verhoeff, 1906 are given and Cryptops sarasini var. furcata Ribaut, 1923 is confirmed as subspecies. Cormocephalus guildingii Newport, 1845, Newportia longitarsis guadeloupensis Demange, 1981 and N. pusilla Pocock, 1893 are reported from Martinique for the first time. A list of the Scolopendromorpha of this island is given. PMID- 30313742 TI - A new riparian Mantidactylus (Brygoomantis) frog from the Tsaratanana and Manongarivo Massifs in northern Madagascar. AB - The subgenus Brygoomantis in the Madagascar-endemic genus Mantidactylus contains 12 nominal species but is in urgent need of taxonomic revision as many additional, genetically divergent but undescribed candidate species have been identified. We here take a first step towards a better resolution of this group by describing a new species, Mantidactylus schulzi sp. nov., occurring at the Tsaratanana and Manongarivo Massifs, differentiated in genetic, bioacoustic and sometimes morphological characters from its closest relatives. We show that upon detailed study, most species in Brygoomantis can be delimited by concordant differentiation of mitochondrial and nuclear DNA, and by bioacoustic and morphological differences. We flag this group of morphologically similar frogs as a test case where molecular data on historical type specimens by ancient DNA methods might be needed to reach a satisfying clarification of taxonomy and nomenclature. However, the status of the new species M. schulzi is not in doubt as it is morphologically distinct from most historical type specimens, and microendemic to a region in northern Madagascar from where no earlier names exist. PMID- 30313743 TI - Two new species of Mooreonuphis (Annelida: Onuphidae) from Australia. AB - Two new species of Mooreonuphis, a genus best known from the coasts of the Americas, are described from Australia, bringing the number of recognized Mooreonuphis species to 23. Mooreonuphis ariasi n. sp. was collected from off Sydney to Wollongong, New South Wales in sandy sediments, in depths of 25-50 m and M. wilsoni n. sp. in the Bass Strait and Tasmania, in 89-130 m. The two new Australian species are among the smallest and the only known abranchiate species in the genus. The summer collections of M. ariasi n. sp. contained a large number of brooders with their young undergoing asynchronous direct development in the parental tube. Nothing is known about the development of M. wilsoni n. sp. PMID- 30313744 TI - A review of the genus Labeo (Teleostei: Cyprinidae) in Sri Lanka. AB - The taxonomy of the three native taxa assigned to the genus Labeo (L. dussumieri, L. fisheri and L. porcellus lankae) in Sri Lanka is reviewed. The population hitherto identified as L. dussumieri in Sri Lanka is shown to be a distinct species, here named L. heladiva. Labeo heladiva, new species, has a wide distribution in the low and mid-elevations of the island and is distinguished from its Indian congeners by the combination of having two pairs of barbels; 12 13 branched dorsal-fin rays; lateral line with 44-51 scales; 1/28-1/29+1+6-7 scales in transverse series; and 19-22 circumpeduncular scales. It differs from its closest relative, L. dussumieri, principally by having 44-51 vs. 50-60 lateral-line scales, 19-22 vs. 22-27 circumpeduncular scales, and by uncorrected pairwise genetic distances of 1.27-2.22% and 1.88-2.91% for the two mitochondrial genes COI and cytb, respectively. Labeo fisheri, which is endemic to the upper reaches of the Mahaweli River basin in the Knuckles mountain range and the central hills in the vicinity of Kandy, is distinguished from Indian congeners by having (in combination) only a single pair of barbels; dorsal fin with 10-12 branched rays; lateral line with 37-39 scales; 7+1+41/2-6 scales in transverse series; and 17-20 circumpeduncular scales. Labeo lankae is recognized as a valid species endemic to Sri Lanka. Long suspected to have become extinct, or known only from spurious records, an extant population is reported from the northern dry zone of the island. Labeo lankae is the sister species of L. porcellus of peninsular India; it can be distinguished from its congeners by having, in combination, 10-12 branched dorsal-fin rays; 36-39 lateral-line scales; 1/28+1+5 61/2 scales in transverse series; and 21-24 circumpeduncular scales. It differs from L. porcellus principally by having 1/28 (vs. 1/26-1/27) scales between the origin of the dorsal fin and the lateral line, 21-24 (vs. 20-21) circumpeduncular scales and uncorrected pairwise genetic distances of 1.27% and 1.41% for the mitochondrial genes COI and cytb, respectively. The three species of Labeo in Sri Lanka do not form a monophyletic group. PMID- 30313745 TI - A new species of Cylindrophis Wagler, 1828 (Reptilia: Squamata: Cylindrophiidae) from Boano Island, northern Maluku Province, Indonesia. AB - We describe a new species of snake of the genus Cylindrophis Wagler, 1828 from Boano Island, northern Maluku Province, Indonesia. Cylindrophis osheai sp. nov. differs from all congeners by a combination of the following eidonomic characters: (1) 19 dorsal scale rows at midbody; (2) 224-226 ventral scales; (3) 8-9 subcaudal scales; (4) 25-28 dark ventral blotches, aligned to form a broad, wavy stripe along most of the body; (5) a dark ventral pattern that is completely separated from the dark dorsal coloration; (6) an almost completely dark ventral surface on the tail; (7) a dark bar running from the eye through the 3rd and 4th supralabials to the mouth; and (8) a dark, double-diamond-shaped ventral blotch in the area immediately posterior to the genials. Eidonomic species separation from other Cylindrophis species is supported by differences in cranial osteology, as elucidated by micro-computed tomography images. Diagnostic features of the cranium include (1) well-developed postorbitofrontals that project laterally beyond the maxilla in dorsal view, creating a characteristic, horn-like appearance; (2) a broad parietal with a bulbous middle section; (3) 10-12 maxillary teeth; (4) nine palatine teeth; (5) 7-9 teeth on the pterygoid; and (6) 11-13 teeth on the dentary. We also provide notes on the taxonomic history of Cylindrophis melanotus Wagler, 1828 and an identification key to the Moluccan species of the genus. PMID- 30313746 TI - Korean ctenostome bryozoans-observations on living colonies, new records, five new species, and an updated checklist. AB - This paper describes 12 species of ctenostomes from the marine waters of the Korean Peninsula, including five new species-Alcyonidium bullitum n. sp., Alcyonidium pulposum n. sp., Alcyonidium busanensis n. sp., Immergentia cheongpodensis n. sp. and Penetrantia taeanata n. sp., the latter two constituting shell-borers that ramify within dead mollusk shells. Three previously described species are also newly added to the Korean fauna-Amathia acervata Lamouroux, 1824, Amathia medullaris Mawatari, 1972 and Walkeria prorepens Kubanin, 1992. The nomenclature of known species is updated and a revised checklist of all Korean Ctenostomata is included. New biological information is provided based on observation and microphotography of living and preserved colonies, SEM images of dry material and resin casts of ctenostome borings in mollusk shells. PMID- 30313747 TI - Description of four new species of freshwater gobies from the Black River drainage in China and Vietnam (Teleostei: Gobiidae). AB - Four new species of Rhinogobius Gill 1859 are described from the Black River drainage in China and Vietnam. Rhinogobius coccinella, new species, and R. nanophyllum, new species, are described from the Mengyejiang River in Yunnan, China. Rhinogobius coccinella is diagnosed by having the cheek and operculum with about 25 large dark spots and branchiostegal membrane unmarked; caudal-peduncle depth 11-12% SL; 1-5 predorsal scales; 27-30 midlateral scales; and 28 vertebrae. Rhinogobius nanophyllum is diagnosed by having the cheek, operculum and pectoral fin base with about 90 indistinct white marks, caudal fin plain-colored, second dorsal fin magnified with a very broad dark gray median band and a broad white proximal band in males; caudal-peduncle length 22-25% SL and pectoral-fin length 21-24% SL in males; head width at operculum 53-58% HL in males, 58-61% HL in females; 0 predorsal scales; 8-10 branched rays in the second dorsal fin; 7-8 branched anal-fin rays; and 28 vertebrae. Rhinogobius ngutinhoceps, new species, is described from the Nam Na River in Lai Chau, Vietnam. It differs from all congeners by the presence of a supraotic pore beta; cheek and operculum with about 65 dark marks and branchiostegal membrane unmarked in males; snout pointed; lower jaw conspicuously protruding; predorsal length 40-41% SL; 12-15 predorsal scales; and 29 vertebrae. Rhinogobius phuongae, new species, is described from the Nam Mu River in Lai Chau, Vietnam, and is diagnosed by having the cheek with about 25 indistinct dark spots and branchiostegal membrane with pale spots in males; operculum unmarked; flank plain-colored in males; a conspicuous black blotch between spines I and III of the first dorsal fin; unpaired fins with a very broad white distal band; pectoral-fin length 20-21% SL; 8-10 predorsal scales; 8-9 branched rays in the second dorsal fin; and 28 vertebrae. A key to the species of Rhinogobius occurring within the Red River drainage is given. PMID- 30313748 TI - Phylogenetic relationships of the Balkan Moitessieriidae (Caenogastropoda: Truncatelloidea). AB - The family Moitessieriidae includes minute dioecious gastropods exclusively inhabiting subterranean waters, including thermal ones. Only empty shells were collected in most species, the vast majority of them are described from their gross shell morphology alone. Several visits to a site are usually required to obtain at least some living individuals. High variability in shell morphology and the lack of diagnostic features, coupled with anticipated high levels of endemism, has resulted in a long list of nominal moitessierid species. Type specimens stored as empty shells omit unambiguous identification and delimitation of species boundaries. Due to inaccessibility of cave animals and consequent lack of material suitable for molecular analysis, the phylogenetic relationships, as well as the taxonomy of the family at genus/species level, are far from being understood. The anatomy of the family is also poorly known and provided only for a few taxa. The distinctness of the Moitessieriidae has sometimes been questioned, and their monophyly not proved. Twelve species of the Balkan Moitessieriidae are considered: two species of Paladilhiopsis, two species of Bythiospeum, six species of Iglica, Costellina turrita and Lanzaia bosnica. The shell morphology of each species, as well as the reproductive system of Paladilhiopsis and Iglica, were analysed. DNA sequences of nuclear histone H3, ribosomal 18S, ribosomal 28S and mitochondrial cytochrome oxidase subunit I (COI) were applied to infer phylogenetic relationships among the taxa. The sequences of Bythiospeum from GenBank have been used to infer relationships between Bythiospeum and Paladilhiopsis that were recently synonymized. Paladilhiopsis and Iglica are distinct, but closely related genera, as is the genus Bythiospeum, which does not occur in the Balkans. Its relationships with both former taxa remain unresolved. The Moitessieriidae are clearly distinct from all other families of the Truncatelloidea, however, their monophyly remains doubtful. PMID- 30313749 TI - Two new species of Sochinsogonia (Hemiptera: Cicadellidae: Cicadellinae) from Philippines. AB - Two new species, Sochinsogonia multimacula and S. radicalia spp. nov., of the genus Sochinsogonia Young from Philippines are described and illustrated. A key to distinguish this genus from closely related Oriental genera is provided. A species checklist of the genus is also provided. PMID- 30313750 TI - Ontogenetic development and redescription of Oligonychus pratensis (Banks, 1912) (Acari: Tetranychidae). AB - Oligonychus pratensis (Banks, 1912) is redescribed based on adult females as well as immature instars collected from Imperata (Poaceae) in Zhangjiajie City, Hunan Province, China. The ontogenetic development of chaetotaxy in O. pratensis is the same as that in O. afrasiaticus (McGregor, 1939) and O. saccharinus Baker Pritchard, 1960. Moreover, we remove O. shinkajii Ehara, 1963 from synonymy with O. modestus (Banks, 1900), due to significant differences in their aedeagal morphology. PMID- 30313751 TI - Synopsis of Pselaphinae (Coleoptera: Staphylinidae) of the Mascarene Islands, with description of a new species of Leiochrotella Jeannel, 1953 from Reunion. AB - The new species, Leiochrotella lequettei Hlavac Kocian, sp. n., is described from Reunion. A synopsis of all Pselaphinae of the Mascarenes (Reunion, Mauritius and Rodriguez) is provided. PMID- 30313752 TI - A new edible cricket species from Africa of the genus Scapsipedus. AB - A new cricket of the genus Scapsipedus is described from Kenya. The distribution, acoustic behavior, including call and courtship song, mitochondrial sequences, and data on the biology of that new species are given. This edible cricket is a very promising species for mass production for food and feed. PMID- 30313753 TI - A new species of the Polyonyx sinensis group (Crustacea: Decapoda: Anomura: Porcellanidae) from the Central Philippines. AB - A new species of porcelain crab, Polyonyx angustus n. sp., is described on the basis of material collected from Panglao Island, the Central Philippines. It is morphologically allied to P. boucheti Osawa, 2007, P. pilosibrachium Osawa, Naruse Ng, 2018, and P. utinomii Miyake, 1943, but distinguished by the shape of the carapace and rostrum. Re-examination of the specimens from the Maldives previously referred to P. utinomii has showed that they belong to the new species instead. The present knowledge suggests that P. utinomii is distributed only in the Japanese main islands from central Honshu to Kyushu. PMID- 30313754 TI - A new species of velvet gecko (Diplodactylidae: Oedura) from sandstone habitats of inland north Queensland, Australia. AB - We describe a new species of velvet gecko (Diplodactylidae: Oedura) from the sandstone ranges of central-north Queensland, Australia. Oedura argentea sp. nov. is a medium-sized (SVL 61-80 mm) gecko that is distinguished from its congeners by a combination of its relatively small size, a pattern of 5-6 dark-edged pale transverse bands from neck to pelvis, a silvery iris, a slender tail, a single cloacal spur, and in possessing 14-22 pre-cloacal pores in males. Oedura argentea sp. nov. is a sandstone specialist currently known only from the Gregory Range and nearby sandstone outcropping at Bulleringa National Park. Further surveys are required to determine the limits of distribution through this region. Oedura argentea sp. nov. is the fifth described species of Oedura in north-eastern Queensland. We also assess the name O. fracticolor De Vis, 1884 because it is an unresolved name pertaining to this general region. Based on colour-pattern and locality in the original description, we conclude that O. fracticolor is a senior synonym of O. castelnaui (Thominot, 1889); however, we propose that priority be overturned under Articles 23.9.1.1 and 23.9.1.2 of the ICZN (1999) and that the name O. fracticolor be regarded as nomen oblitum and O. castelnaui a nomen protectum. PMID- 30313755 TI - A new Afrotropical genus Monocentroptilum gen. n. (Ephemeroptera: Baetidae: Protopatellata). AB - A new genus Monocentroptilum gen. n. is established for a single Afrotropical species, originally described as Centroptilum badium Kopelke 1980 from Congo. Larvae, subimagoes, imagoes of both sexes and eggs of Monocentroptilum badium comb. n. are described here based on reared material from Uganda. PMID- 30313756 TI - Synopsis of the shore bugs of China (Hemiptera: Heteroptera: Leptopodomorpha: Saldidae). AB - In China, most research on shore bugs (Hemiptera: Leptopodomorpha: Saldidae) has been conducted intermittently during the second half of the 19th century. Records from the literature supplemented by our collections were used to construct an annotated list of 50 species in 13 genera and 2 subfamilies (Chiloxanthinae and Saldinae) of Saldidae now known from China. This paper also presents new distributional records and color plates depicting 26 species. Further, a list of 12 species of Saldidae known in neighboring territories that might occur in China is presented. PMID- 30313757 TI - A taxonomic review of the parasitoid wasp genera Furcidentia Zettel and Pseudophanerotoma Zettel (Hymenoptera: Braconidae: Cheloninae) from the Neotropics with the description of four new species. AB - Furcidentia Zettel, 1990 (Braconidae: Cheloninae) from the New World has been recently recognised as a genus separate from Pseudophanerotoma Zettel, 1990. Previously known from three species, three additional new species of Furcidentia are described here from the Neotropical region: F. jenningsi sp. nov. (French Guiana), F. llama sp. nov. (Guatemala), and F. tikalensis sp. nov. (Guatemala). The species F. clypeata Zettel (Ecuador) comb. nov., F. pulchra Zettel (Costa Rica) comb. nov., and F. sharkeyi Zettel (Ecuador) comb. nov. are transferred to Furcidentia. Additionally, one new species of Pseudophanerotoma is described: P. austini sp. nov. (Guatemala), while P. paranaensis (Costa Lima) (Brazil) and P. thapsina (Walley) (Texas, USA) are redescribed and are here recorded from French Guiana for the first time, thus considerably expanding their known distribution. Redescriptions include the description of the male of P. thapsina (Walley) for the first time and of the female of P. paranaensis (Costa Lima). Identification keys to the Neotropical genera of Phanerotomini and the species of Furcidentia and Pseudophanerotoma are provided. PMID- 30313758 TI - First Australian records of Ethusina (Crustacea: Decapoda: Ethusidae) and additional records from New Zealand. AB - Deep water ethusid crabs, genus Ethusina, are confirmed for the first time from Australia, with additional distribution records from New Zealand waters. Prior to the present study, Ethusina was reported from Australia on the basis of a single unidentified species from southwestern Australia. Four species are reported herein: Ethusina castro Ahyong, 2008, E. ciliacirrata Castro, 2005, E. robusta (Miers, 1886), and E. rowdeni Ahyong, 2008. Ethusina castro, previously known only from the female holotype from northern New Zealand is reported for the first time from eastern Australia, the Lord Howe Rise and Monowai Caldera, including the first known males. Ethusina ciliacirrata, described from Vanuatu, is confirmed from the Coral Sea and southwestern Australia. Ethusina rowdeni, from New Zealand, and the widespread E. robusta are recorded for the first time from Australia. PMID- 30313759 TI - A new whitefly genus and species, Aleuroparvus theae Dubey (Hemiptera: Aleyrodidae) colonising Assam tea (Camellia sinensis) and Cinnamomum bejolghota, in North-East India. AB - Puparia of a new whitefly genus and species, Aleuroparvus theae Dubey gen. et sp. nov. are described along with drawings, habitus and type images of habitus and types, and scanning electron microscope microphotographs. It is found infesting an economically important plant, Assam tea, Camellia sinensis (L.) (Theaceae) in Assam, and Cinnamomum bejolghota (Hamilton) (Lauraceae) in Arunachal Pradesh, India. Puparia of A. theae are dimorphic, the females being larger than males. The puparia of the new genus differ from all other genera in having smaller ventral surface, submarginal wax secreting pores and dorsal submargin separated from the dorsal disc by a submarginal ridge. The diagnostic characteristics for puparia of the new genus are compared with closely related genera, Aleuroclava Singh, Aleuropleurocelus Drews Sampson, Dialeuropora Quaintance Baker, Tetralicia Harrison and Tetraleurodes Cockerell. PMID- 30313760 TI - Comments on the neglected nymphs of mud crickets in the genus Mirhipipteryx (Caelifera: Tridactyloidea: Ripipterygidae). AB - Mud crickets (family Ripipterygidae) comprise a small family of orthopterans distributed throughout much of the Neotropics, but knowledge of this groups' biology, ecology and distribution remains poor in comparison to most orthopteran taxa. Here we review the state of knowledge of nymphs in the genus Mirhipipteryx Gunther 1969 and report the genus from Belize for the second time in 86 years. Because information about nymphs in this family is so scarce and nymphs are often neglected in species descriptions, we include comments on the coloration of nymphs for Mirhipipteryx pulicaria (Saussure 1896). Caution is suggested for the use of adult characters for the identification of immatures stages in the group. Nymphs of Mirhipipteryx pulicaria pulicaria are similar in coloration patterns to the adults, but lighter. Mirhipipteryx lobata Gunther 1977 is designated a nomen nudum. PMID- 30313761 TI - A new species of genus Neoaloa Singh Kirti, 2015 from Bihar, India (Lepidoptera: Erebidae: Arctiinae: Arctiini). AB - A new species, Neoaloa cernyi Singh Joshi, sp. nov. is described from Gular-Ghat of Valmiki Tiger Reserve, Bihar, India. Additionally, the original combination of Aloa collaris Hampson, 1891, comb. rev. is restored. PMID- 30313762 TI - A new species of Dignomus Wollaston (Coleoptera: Ptinidae) from Eocene Baltic amber. AB - Dignomus francescovitalii sp. nov. is described and illustrated based on a well preserved specimen from Eocene Baltic amber. This new extinct species is placed into D. irroratus species-group. The distribution of the genus Dignomus including fossil records is mapped. PMID- 30313763 TI - New records and descriptions of Ichneumonidae (Hymenoptera) from Mexico. AB - Based on a large quantity ichneumonid material collected mainly from the Mexican states of Veracruz and Quintana Roo, faunistic records of 79 species belonging to subfamilies Acaenitinae, Banchinae, Cryptinae, Cylloceriinae, Labeninae, Lycorininae, Microleptinae, Pimplinae, Tersilochinae, and Tryphoninae are provided. Three species are described as new to science: Latosculum ortegai Kasparyan Khalaim, sp. nov. (Cryptinae), Eusterinx madorae Khalaim Kasparyan, sp. nov. (Microleptinae) and Neotheronia veracruzana Khalaim, sp. nov. (Pimplinae). Two genera, Nipponaetes Uchida (Cryptinae) and Meggoleus Townes (Tersilochinae), and six species, Nipponaetes hansoni (Gauld) (Cryptinae), Lycorina moralesi Gauld (Lycorininae), Neotheronia murilloi Gauld (Pimplinae), Meggoleus pampahermosensis Alvarado (Tersilochinae), Phytodietus moragai Gauld, and Zagryphys zulaya Gauld (Tryphoninae), are first records from Mexico. Females of three species, Cestrus tenuiventris (Cresson), Mallochia macula Kasparyan Ruiz-Cancino (Cryptinae), and Phytodietus moragai Gauld (Tryphoninae), are recorded and described for the first time. PMID- 30313764 TI - Taxonomic re-evaluation of the monotypic genus Pararhabdophis Bourret, 1934 (Squamata: Colubridae: Natricinae) with discovery of its type species, P. chapaensis, from China. AB - The Asian monotypic genus Pararhabdophis Bourret, 1934 has long been known from a single holotype of the type species Pararhabdophis chapaensis Bourret, 1934 only. The limited available information hampered the identification of the natricine species. On the basis of eight newly collected specimens of P. chapaensis from the type locality in Sa Pa, Lao Cai Province, Vietnam and from Pingbian, Yunnan Province in southwestern China, the taxonomic position of the genus Pararhabdophis was re-evaluated using both morphological and molecular datasets for the first time. Pararhabdophis chapaensis is nested within the genus Hebius Thompson, 1913 with strong support, and morphologically indistinguishable from the latter genus. As a consequence, we herein synonymize the genus Pararhabdophis with Hebius and discuss about the existing paraphyly of some Hebius species. In addition we report Hebius chapaensis for the first time from China and provide redescription and natural history data of this poorly known species. To facilitate future taxonomic work, an identification key to all known natricine genera from China and Vietnam is also provided. PMID- 30313765 TI - Zwicknia gattolliati, a new species of stonefly from Italy (Plecoptera: Capniidae). AB - A new species of Zwicknia Muranyi, Z. gattolliati, from northern Italy and from the Italian Abruzzo Region is described and illustrated on the basis of the morphology of male and female adults and previous molecular and drumming studies. PMID- 30313766 TI - Redescription of two species of Coelotanypus (Kieffer) 1913 (Diptera: Chironomidae) in rivers of the Parano-Platense basin (Argentina, South America). AB - Male imagos of Coelotanypus delpontei (Edwards) are redescribed and newly figured and the immature stages are described and figured for the first time. During this study, male imagos of C. mendax (Lynch Arribalzaga) are also redescribed. The specimens were collected from the Parana and near Uruguay rivers in the Parano Platense basin. PMID- 30313767 TI - New species and records of the Pericoma trifasciata group from Croatia (Diptera: Psychodidae). AB - Pericoma miljenkoi sp. nov. is described based on adult males from the Plitvicka jezera National Park, Croatia. Pericoma trifasciata is recorded from Croatia for the first time, and COI DNA barcodes are given from specimens collected in Germany. An emended key to adult Pericoma of the trifasciata group is presented. The Croatian Psychodidae fauna now stands at 35 species. PMID- 30313768 TI - On the status of Araripegryllus romualdoi (Insecta: Orthoptera: Grylloidea) from the Cretaceous Santana Formation of Brazil. AB - The fossil cricket Araripegryllus romualdoi was described by Freitas et al. (2016) based on a single, very poorly preserved specimen from the Romualdo Member of the Lower Cretaceous Santana Formation; a deposit famed for the exceptional preservation of vertebrates in carbonate concretions (Martill, 1996, 2007). While abundant and diverse in the underlying Crato Formation (Martill et al., 2007 and contributions therein), fossil insects had not been reported from the Santana Formation prior to Freitas et al.'s paper. The occurrence of an insect in the Santana Formation is certainly noteworthy, but the description of a new species and its placement in the genus Araripegryllus are problematic, primarily because of the very poor preservation of the specimen. Here, problems associated with the diagnosis and placement of A. romualdoi are outlined, and the species declared a nomen dubium. PMID- 30313769 TI - Rediscovery of an elusive species, Halpe sikkima Moore, 1882 (Hesperiidae, Hesperiinae) from Hainan, China. AB - Almost 70 years after its first record from Hainan by Evans in 1949, the second specimen of Halpe sikkima Moore, 1882 was found on the island. The male genitalia of this species are illustrated and re-described. The COI sequence is published for the first time. PMID- 30313770 TI - Description of the female and egg of Phantasca phantasma (Westwood, 1859) (Phasmatodea: Diapheromeridae: Diapheromerinae). AB - The neotropical genus of stick insects, Phantasca Redtenbacher, 1906, was recently revised by Hennemann et al. (2018). However, the females and eggs of several species remain unknown, including all five species recorded from Brazil. The female and egg of Phantasca phantasma (Westwood, 1859) are here described for the first time, based on material available at the Museu de Zoologia da Universidade de Sao Paulo, Brazil (MZSP). A set of measurements of males is also given, in addition to the measurements of the holotype presented in Hennemann et al. (2018). This complement to the description of P. phantasma is particularly important because it is the type species of the genus (designated by Zompro, 2001), therefore providing additional grounds for future taxonomic decisions involving Phantasca. PMID- 30313771 TI - A new synonym for Enicospilus grammospilus (Enderlein, 1921) (Hymenoptera: Ichneumonidae: Ophioninae). AB - The megadiverse genus Enicospilus Stephens, 1835 (Hymenoptera: Ichneumonidae: Ophioninae) comprises over 700 valid species worldwide (e.g. Gauld Mitchell, 1981; Broad Shaw, 2016; Shimizu, 2017). Species of this genus are koinobiont endoparasitoids of moderately large sized lepidopteran larva (e.g. Gauld, 1985b; Broad Shaw, 2016). Members of this genus usually have "ophionoid facies", characterized by an orange-brown body, extremely large ocelli, long antennae, etc. (Gauld Huddleston, 1976). Ophionoid facies wasps including Enicospilus are attracted to light and considered to be crepuscular or nocturnal (e.g. Short et al., 2006; Shimizu Maeto, 2016; Shimizu Lima, 2018). These wasps usually exhibit a very limited number of diagnostic characters and as a consequence the delimitation and recognition of species is very difficult, and causes many taxonomic confusions including synonyms, homonyms and misidentifications. PMID- 30313772 TI - Discovery of the genus Pseudepione Inoue, 1943 in Taiwan, with description of a new species (Lepidoptera: Geometridae: Ennominae). AB - The genus Pseudepione Inoue, 1943 is a small geometrid taxon comprising only two species, the typo species P. magnaria (Wileman, 1911) and P. shiraii Inoue, 1943. They are known to distribute in Japan (Honshu, Kyushu and Shikoku), south and central Korea (Choi 2012; Choi An 2010; Jung Oh 2012), the former species was also reported in Jiangxi of China (Fang 2003). The genus seems to be univoltine since adults can only be found in the autumn season (Wileman 1911; Inoue 1943, 1982; Parsons et al. 1999; Kim Beljaev 2001; Sato 2011; Choi 2012). The combination of the absence of forewing fovea, tuft of scales of third abdominal sternite, gnathos, socii and cormata is quite unique in Ennominae. So far, the phylogenetic affinity of Pseudepione is unclear since the closely related genus has never been proposed and still no morphological or molecular phylogenetic studies, i.e. Beljaev (2006a; 2006b; 2016), Sihvonen (2011), Yamamoto Sota (2007), Jiang et al. (2017), considering the palaearctic subfamily or tribal levels sampled this genus. The dense fundamental surveys conducted in recent 7 years in the cloud forests of Taiwan acquire the opportunity to collect this genus new to Taiwan. After comparing the Taiwanese specimens with the known two species in both sexes, it's clear the Taiwanese specimens are a distinct species needed to be described in the present study. PMID- 30313773 TI - An annotated catalogue of the pygmy grasshoppers of the tribe Scelimenini Bolivar, 1887 (Orthoptera: Tetrigidae) with two new Scelimena species from the Malay Peninsula and Sumatra. AB - Pygmy grasshoppers (Tetrigidae) are a speciose group of complicated taxonomy, with many species requiring clarification on their species boundaries, and more still awaiting discovery. Two new species of Scelimena Serville, 1838 are described: (1) from S. discalis species group S. gombakensis sp. nov. and (2) from S. hexodon species group Scelimena marta sp. nov. Catalogue of Scelimenini genera (15) and species (100) is presented and taxonomy and biogeography of the tribe are discussed. New and resurrected combinations are: Falconius becvari (Buzzetti Devriese, 2008) comb. nov. (of Gavialidium becvari), Gavialidium carli Hebard, 1930 comb. resurr. (of Bidentatettix carli), Indoscelimena india (Hancock, 1907) comb. nov. (of Scelimena india), Paragavialidium nodiferum (Walker, 1871) comb. nov. (of Platygavialidium nodiferum), Platygavialidium productum (Walker, 1871) comb. nov. (of Gavialidium productum), Scelimena hexodon (Haan, 1843) comb. resurr. (of Hexocera hexodon), Scelimena rosacea (Hancock, 1915) comb. resurr. (of Amphibotettix rosaceus), Tegotettix bufocrocodil (Storozhenko Dawwrueng, 2015) comb. nov. (of Gavialidium bufocrocodil). New synonyms are: Gavialidium phangensum Mahmood, Idris Salmah, 2007 syn. nov. (of Eufalconius pendleburyi), Gavialidium philippinum Bolivar, 1887 syn. nov. (of Platygavialidium productum comb. nov.), Hexocera Hancock, 1915 syn. nov. (of Scelimena), Paracriotettix Liang, 2002 syn. nov. (of Scelimena), Paracriotettix zhengi Liang, 2002 syn. nov. (of Scelimena melli), Scelimena mellioides Deng, 2016 syn. nov. (of Scelimena melli), Scelimena wuyishanensis Deng, 2016 syn. nov. (of Platygavialidium sinicum). The genus Scelimena is divided into six species groups. Eucriotettix neesoon Tan Storozhenko nom. nov. is new name for homonym Eucriotettix guentheri Tan Storozhenko, 2017. Finally, a tabular key to 15 Scelimenini genera, based on 16 morphological characters, is presented. PMID- 30313774 TI - Bryozoa (Cyclostomata and Ctenostomata) from polymetallic nodules in the Russian exploration area, Clarion-Clipperton Fracture Zone, eastern Pacific Ocean-taxon novelty and implications of mining. AB - This work describes Bryozoa of the orders Cyclostomata and Ctenostomata found associated with polymetallic nodules collected by box-coring in the eastern part of the Russian exploration area of the Clarion-Clipperton Fracture Zone (CCFZ) under contract to Yuzhmorgeologiya. Scanning electron microscopic study of 358 cyclostome colonies and 14 ctenostome colonies from 4510-5280 m depth has resulted in the recognition of two new species of Ctenostomata, and 14 new species, nine new genera and two new families of Cyclostomata; three additional species of Cyclostomata are left in open nomenclature pending the discovery of missing reproductive characters. The taxonomic novelty is thus notable. One of the new Ctenostomata represents the first living example of the previously monotypic Late Cretaceous genus Pierrella. Twelve of the new cyclostome taxa have well-developed gonozooids, indicating that embryonic cloning (polyembryony) is normal in this deep-sea environment. On the other hand, one indeterminate tubuliporine and two rectangulates have dimorphic peristomes. In the latter two cases, enough mature colonies were found to suggest that this feature is normal, and that the dimorphic zooids are possibly female-in other words, capacious incubation chambers are apparently lacking, and therefore polyembryony would also be lacking or reduced. In one of these species, evidence is presented to suggest that the ancestrular zooid can reproduce precociously. Of the species reported here, only one has previously been found outside the exploration area, highlighting both the limited knowledge we have of bryozoans in the deep Pacific and/or a fauna that is largely endemic to the nodule environment. An additional 31 species of Cheilostomata have also been discovered that will be described in a subsequent publication. Most bryozoans are macrofaunal-sized, so are both inadequately determinable and overlooked in images obtained by remotely operated vehicles; yet, with 50 species, Bryozoa is the most speciose sessile macrofaunal phylum on the nodules. Nodules constitute hard substrata in an area otherwise mostly inhospitable for Bryozoa, hence mining would lead to loss of critical habitat. Further, as suspension-feeders, bryozoans are highly susceptible to smothering by suspended sediment, and non-mined areas closely adjacent to extraction zones would likely also be affected and their associated bryozoan fauna obliterated. More data are required on the distribution of the CCFZ bryozoan species elsewhere in the east Central Pacific to determine if mining would lead to local taxon extirpation or global extinction at both low and high taxonomic levels. PMID- 30313775 TI - A phylogenetic approach to the Philippines endemic centipedes of the genus Scolopendra Linnaeus, 1758 (Scolopendromorpha, Scolopendridae), with the description of a new species. AB - The genus Scolopendra Linnaeus, 1758 is represented in the Philippines' fauna by five species, two of which are endemic. Mitochondrial DNA sequences of gene cytochrome c oxidase subunit I (COI) were obtained from six Scolopendra specimens belonging to two endemic species and a new one, described here as Scolopendra paradoxa Domenech sp. nov. These sequences were analyzed together with another forty-one sequences from GenBank, including additional species of Scolopendra and a few representatives of other Scolopendridae genera. Phylogenetic trees inferred from the COI analysis using maximum likelihood and neighbor joining showed the three Philippines Scolopendra endemic species as a polyphyletic group coherent with their respective morphologies, although the position of S. spinosissima Kraepelin, 1903 varied within the obtained trees. Species delimitation based on standard external morphological characters was also concordant with the observed genetic distances, monophyly and node support, confirming S. subcrustalis Kronmuller, 2009 and S. paradoxa sp. nov. as separate species also at the molecular level, while only the position of S. spinosissima could not be properly established with any of the statistical methods used. In addition, the male genitalia of the three studied species were found to lack gonopods and a penis. Remarks on the ultimate legs prefemoral spinous formula of S. spinosissima plus a key to the species of the genus Scolopendra in the Philippines are provided. PMID- 30313776 TI - Phylogenetic analysis reveals high local endemism and clear biogeographic breaks in southern African stoneflies (Notonemouridae, Plecoptera). AB - The low vagility of the southern African Notonemouridae (stoneflies, Plecoptera), and their restriction to temperate montane refugia, make them a useful model for examining the evolution and biogeography of the rich palaeogenic fauna of the region. Here we use maximum parsimony tree reconstruction based on morphological characters and a partial COI mtDNA sequence to explore the evolutionary history and biogeography of the family in southern Africa. Morphological and molecular parsimony cladograms were largely in agreement, and supported monophyly of all six genera in the region. Previously undocumented morphological features in Plecoptera are identified: the first record of paraproct glands, and the presence of paired spermathecae in Aphanicercopsis Barnard females (all other Plecoptera have a single or a divided spermatheca). Some phylogenetically useful characters were the degree of fusion of the ventral abdominal nerve cord ganglia, male paraproct glands (presence and shape), and accessory glands of the male seminal vesicle. Two main biogeographic zones were defined: Eastern Highlands and the Cape Fold Mountains, with an additional outlying zone, the Namaqualand Highlands. Almost 41% of species were endemic to a single mountain range group. The most species-rich region was the intersection of the Southern and Western Cape Fold Mountains. It is hypothesized that, after the separation of Gondwanaland, the common ancestor of the region's six genera dispersed from a Cape Fold Mountain origin to the Amatola and Drakensberg montane areas of the southern tip of the African continent. The high number of species within the Cape Fold Mountains compared to other mountain ranges in the region is likely a reflection of the topographic complexity of this mountain system and its influence on vicariant events. PMID- 30313777 TI - Species of Dirhinus Dalman, 1818 (Hymenoptera: Chalcididae, Dirhininae) from Saudi Arabia: new species and a new record. AB - The species of chalcidid wasps of Dirhinus Dalman, 1818 (Hymenoptera: Chalcididae) from Saudi Arabia are reviewed. Seven species are reported from Al Bahah, Asir, Jazan and Riyadh regions, of which three have hitherto been recorded: D. (Dirhinus) anthracia Walker, 1846, D. (Dirhinus) himalayanus Westwood, 1836 and D. (Dirhinus) wohlfahrtiae Ferriere, 1935. One species D. (Dirhinus) claviger Boucek Narendran, 1981 is recorded for the first time from Saudi Arabia (Asir). Additionally, three new species: D. (Dirhinus) asirensis sp. nov. (Asir), D. (Dirhinus) sculpturatus sp. nov. (Al Bahah, Asir and Riyadh) and D. (Pareniaca) transversus sp. nov. (Al Bahah, Asir and Jazan) are described and illustrated. An illustrated key to females of the species of Dirhinus from Saudi Arabia is provided. PMID- 30313778 TI - Two new Haploops species (Crustacea: Gammaridea: Ampeliscidae) from the North Atlantic Ocean: H. bjarnii and H. quebecoisis [Contribution to the knowledge of the Haploops genus. 9.]. AB - Two new Haploops species are described, both from the North Atlantic Ocean: Haploops bjarnii nov. sp. from around the Faeroe Islands and Iceland, and Haploops quebecoisis nov. sp. from the Saint Lawrence Gulf, off Canada. Haploops bjarnii is a species morphologically close to H. islandica Kaim-Malka, Bellan Santini Dauvin, 2016. These are two blind Haploops species, with long antennae. Haploops quebecoisis is morphologically similar to H. sibirica Gurjanova 1929, both species having 2 pairs of corneal lenses in the same position. A table of the 75 morphological characters is presented that can be used permitting to distinguish the new species from similar species. PMID- 30313779 TI - New species of Euplocania Enderlein (Psocodea: 'Psocoptera': Psocomorpha), in three species groups, from Colombia and Ecuador. AB - Eight species of Euplocania from Colombia, in species groups Bonaverensis, Enderleini and Patinoi, are here described and illustrated. They raise to 40 the number of species described in the genus, 27 of which are found in Colombia. Of the Colombian species, one is shared with Ecuador and one is shared with Brazil and Peru. A key to identify the males of the species here described is included. PMID- 30313780 TI - Seven new taxa of Leptodirini (Coleoptera: Leiodidae: Cholevinae) from the Balkan Peninsula. AB - Seven new troglobitic leiodid beetle taxa (six new species and one new subspecies) from several caves and pits in the Balkan Peninsula (Bosnia and Herzegovina and Serbia) are described and diagnosed. Three new species belong to the genus Adelopidius Apfelbeck, 1907, two-to the genus Pholeuonopsis Apfelbeck, 1901, one-to the genus Leonhardia Reitter, 1901, while a new subspecies belongs to the genus Apholeuonus Reitter, 1889. All important morphological characteristics of the new taxa have been mentioned and imaged, including the aspects of the male and female genitalia. The new leiodid taxa are properly distinguished from their relatives and are endemics of the Dinaric mountain chain. A key to Adelopidius taxa is added. PMID- 30313781 TI - Rising from the ashes: resurrection of the Malagasy chameleons Furcifer monoceras and F. voeltzkowi (Squamata: Chamaeleonidae), based on micro-CT scans and external morphology. AB - The taxonomy of the Malagasy chameleon Furcifer rhinoceratus (Gray, 1845) is poorly resolved. The aim of this study is to clarify the taxonomic status of Chamaeleon voeltzkowi Boettger, 1893 and Chamaeleon monoceras Boettger, 1913 both only known from single or very few specimens mostly collected more than 100 years ago and currently considered as synonyms of Furcifer rhinoceratus. Using osteological data from micro-X-ray computed tomography (micro-CT) combined with traditional morphological characters and morphometrics we resurrect both taxa from the synonymy of F. rhinoceratus as F. voeltzkowi and F. monoceras, respectively. Compared to F. rhinoceratus, F. monoceras is smaller, has a relatively shorter tail, a longer and thinner rostral appendage, a poorly developed gular crest and no ventral crest, whereas F. voeltzkowi has a smaller rostral appendage, higher casque and the dorsal crest is continuous with the tail crest. Compared to the broad rostral appendage formed by the anterior protuberance of the premaxillary process of the maxilla, which has serrated edges in F. rhinoceratus, F. monoceras presents a long rostral appendage with a smooth dorsal edge that progressively narrows, and the nasal aperture is extended along the elongated appendage; F. voeltzkowi presents a smaller but curved rostral appendage with a crenate edge. The prefrontal and postorbitofrontal approach one another forming a large, laterally closed supraorbital fontanelle in F. rhinoceratus while in F. monoceras they do not approach, leaving a laterally open fontanelle, and in F. voeltzkowi the fontanelle is diminutive. Furcifer voeltzkowi also differs from the similar F. labordi by a smaller size of the rostral appendage, less bulging casque and body pholidosis. The former exhibits a conspicuous white lateral band comprising heterogeneous scalation. Furcifer labordi, on the other hand, has a homogeneous scalation with a remarkable reticulate pattern. Osteologically, the shape of the prefrontal and the connection of the postorbitofrontal with the parietal also differ greatly between the two. Using micro-CT scans we detected key differences that would be otherwise impossible to determine. We also provide a brief morphological and osteological description of the species and strongly recommend efforts to rediscover these two poorly known taxa in order to enable additional studies and to assess their conservation status. PMID- 30313782 TI - Two new species of the genus Chitaura Bolivar, 1918 (Orthoptera: Acrididae, Oxyinae) from Sulawesi Island. AB - Two new species, Chitaura linduensis Storozhenko, sp. nov. and C. doloduo Storozhenko, sp. nov., are described from Indonesia. Male genitalia of the type species of the genus, C. brachyptera Bolivar, 1918, are described and illustrated for the first time. The data on distribution of the Chitaura species on Sulawesi Island are clarified and showed in a map. PMID- 30313783 TI - Five new species of the flesh fly genus Boettcheria (Diptera: Sarcophagidae). AB - Five new Neotropical species of the flesh fly genus Boettcheria Parker, 1914 are described: B. brachion sp. nov. (Venezuela), B. dikros sp. nov. (Costa Rica), B. hirta sp. nov. (Costa Rica), B. tridens sp. nov. (Venezuela), and B. ulo sp. nov. (Venezuela). The definition of the genus is briefly discussed. PMID- 30313784 TI - Morphology and phylogeny of a new species, Uroleptus (Caudiholosticha) antarctica n. sp. (Ciliophora, Hypotricha) from Greenwich Island in Antarctica. AB - This paper describes the morphological features based on standard methods and estimates their phylogenetic position using small subunit ribosomal RNA (SSU rRNA) sequences of a Uroleptus (Caudiholosticha) antarctica n. sp. population investigated from moss of the Greenwich Island, Antarctica. The morphology of Uroleptus (Caudiholosticha) antarctica n. sp. is characterized as follows: 213.0 238.0*67.5-74.5 MUm size in vivo; contractile vacuole located slightly above left of mid-body; cortical granules lacking; three frontal and two frontoterminal cirri; five to six transverse cirri; one pretransverse cirri; one right and one left marginal rows; six to seven dorsal kineties; three caudal cirri. PMID- 30313785 TI - Erratum: YINMENG HOU, MENGFEI ZHANG, FEI HU, SIYUAN LI, SHENGCHAO SHI, JUN CHEN, XIAOYANG MO BIN WANG (2018) A new species of the genus Leptolalax (Anura, Megophryidae) from Hunan, China. Zootaxa, 4444: 247-266. PMID- 30313786 TI - Revision of the Alitta virens species complex (Annelida: Nereididae) from the North Pacific Ocean. AB - Alitta virens species complex encompasses elongate nereidids appreciated commercially both in the fishing and aquaculture industries. This complex has been well studied in biological and ecological terms. Nevertheless, detailed taxonomic analyses have scarcely been addressed, to the extent that only a few species in the complex have been recognized as valid but with some difficulties: Alitta brandti Malmgren, 1865 (Sea of Okhotsk), A. grandis (Stimpson, 1853) (northeastern USA) and A. virens (Sars, 1835) (Norway). Whereas, other several species have typically been regarded as synonyms, including those originally described from the North Pacific Ocean: Nereis (Alitta) virens plenidentata Moore, 1909 (California, USA), Nereis dyamusi Izuka, 1912 (Japan) and Nereis foliata Baird, 1863 (Vancouver, Canada). In this study, an examination of the immature and epitoke type and non-type material available for the A. virens species complex from the North Pacific was carried out. Herein, the status of A. brandti as a valid species is reinforced being clearly distinct from A. virens and related species. Alitta dyamusi n. comb., A. plenidentata n. comb. and A. williami nom. nov. are reinstated and transferred to Alitta, the specific epithet of the latter species is a replacement name for Nereis foliata Baird, 1863, which is a junior, primary homonym of Nereis foliata Dalyell, 1853. Lectotypes for A. plenidentata n. comb. and A. williami nom. nov. are designated. The North Pacific species of the A. virens complex, excluding A. plenidentata n. comb. which has several distinctive features that differ from all the Alitta species, are characterized by having homogomph spinigers in both supracicular and subacicular neurochaetae, oral ring with a larger number of rows and paragnaths, and epitoke males with unmetamorphosed pygidium and epitoke-modified chaetae in both neuropodial fascicles. The morphology of epitoke females in the A. virens complex is described for the first time. Identification keys to atoke and epitoke species of this complex are also provided. PMID- 30313787 TI - Descriptions of two new species of Euxoa Hubner, [1821], subgenus Pleonectopoda Grote, 1873, from Siberia (Lepidoptera, Noctuidae). AB - Two new species of the the genus Euxoa Hubner, [1821] (subgenus Pleonectopoda Grote, 1873), Euxoa steideli sp. n. and Euxoa kodara sp. n. are described from the mountains of South and East Siberia. The new species belong to the Holarctic Euxoa westermanii species-group, which is represented in both the New and Old World mainly by alpine and subarctic species. The Palaearctic species of the Euxoa westermanii species-group are reviewed. The placement of Euxoa culminicola (Staudinger, 1870) in the subgenus Pleonectopoda is fixed. New data on distribution of E. (P.) churchillensis (McDunnough, 1932) in the Palaearctic from Chukchi Autonomy are presented. An annotated checklist list of the Palaearctic species of Pleonectopoda (Euxoa, Lepidoptera, Noctuidae, Noctuinae: Noctuini) is presented. PMID- 30313788 TI - Review of the genus Ceratotarsonemus De Leon, 1956 (Acari: Prostigmata: Tarsonemidae), with description of a new species from the Amazon Forest. AB - The genus Ceratotarsonemus De Leon (Acari: Prostigmata: Tarsonemidae) is reviewed here, with the addition of an updated key for the genus. Ceratotarsonemus amazonicus, sp. nov., found in the Brazilian Amazon rainforest, is described. Phase contrast (PC), differential interference contrast (DIC), low temperature scanning electron microscopy (LT-SEM) and confocal microscopy (CLSM) micrographs are provided. Biological and ecological aspects about the role of this species in its ecosystem are also discussed. PMID- 30313789 TI - Two more new species of Hemiphyllodactylus Bleeker (Squamata: Gekkonidae) from the Shan Hills of eastern Myanmar (Burma). AB - An integrative phylogenetic analysis recovers two new species of the gekkonid genus Hemiphyllodactylus (Bleeker) from the Shan Hills of eastern Myanmar. Hemiphyllodactylus ywanganensis sp. nov. and H. uga sp. nov. are nested within the eastern Myanmar clade of a previous genus-wide phylogenetic analysis and form a more exclusive monophyletic group with H. linnwayensis. These species differ from each other and all other Hemiphyllodactylus in having unique combinations of character states involving postmental and subcaudal scale morphology; maximum SVL; digital formulae; numbers of chin scales, circumnasals, intersupranasals (=postrostrals), labials, longitudinally arranged dorsal and ventral scales, and pore-bearing femoroprecloacal scales; as well as subtle differences in coloration and pattern. The phylogenetic affinities of the eastern Myanmar clade are similar to those of an endemic clade of Cyrtodactylus from the Shan Hills in that both are more closely related to Indochinese taxa east of Myanmar as opposed to other Indo-Burmese species. The discovery of these new species underscores the underappreciated herpetological diversity of limestone ecosystems as well as the remote nature of the rugged uplands of the Shan Hills and emphasizes the need for continued field work in this region. PMID- 30313790 TI - Two new species of Corumbataia (Hypoptopomatinae: Loricariidae) from Rio Corrente, upper Rio Parana basin, Brazil. AB - We describe two new species of Corumbataia from Central Brazil. The new species are known from Rio Corrente, a tributary of the upper Rio Parana basin. Furthermore, the two species are distinguished from congeners, mainly by the presence of a broad naked area without plates or odontodes on the dorsal portion of the snout. Additionally, the two new species described here can be distinguished from each other by the caudal-peduncle depth, number of infraorbitals plates series and by the general color pattern of caudal fin. PMID- 30313791 TI - Fifth contribution to the knowledge of water mites (Acari: Hydrachnidia) from the Comoros: a checklist and description of one new genus and four new species. AB - New records of water mites (Acari: Hydrachnidia) from the Comoros are presented. One genus, i.e. Lagoenaxonopsalbia Pesic Smit, and four species, i.e. Platymamersopsis mayottensis (Anisitsiellidae), Torrenticola mayottensis (Torrenticolidae), Lagoenaxonopsalbia comorosensis (Aturidae) and Djeboa davecooki (Mideopsidae) are described as new to science. Arrenurus comorosensis Pesic Smit, 2015 is synonymized with Arrenurus flavus Smit, 2012. The first description of the female of Sterkspruitia comorosensis Pesic Smit, 2015 is given. The number of water mites known from Comoros now tallies 17 species in ten families. PMID- 30313792 TI - Description of a new species of Sabellidae (Polychaeta, Annelida) from fresh and brackish waters in Europe, with some remarks on the branchial crown of Laonome. AB - In 2009, a hitherto unknown Laonome species was found in the Canal Ghent Terneuzen in the Netherlands and subsequently in other Dutch rivers, canals and estuaries. A few years later, more unknown Laonome specimens were found in the eastern part of the Baltic Sea and in the Don River estuary, Sea of Azov. Initially, it was assumed that these specimens could represent Laonome calida Capa, 2007, originally described from Australia. In the present study we examine all these unknown European Laonome specimens and compare these specimens with the type material of L. calida from Australia. This lead to two main results: First, all specimens from Europe have the same diagnostic characters and therefore belong to one species. This finding was also supported by the results of a correspondence analysis, and genetic analyses using four different DNA sequences (COI, 16S, 28S). Second, it turned out that the type material of L. calida contains two morphologically distinct groups of specimens. The holotype and 7 paratypes are similar to each other but differ significantly from the other also similar 16 paratypes, and from all European specimens. On the basis of these observations, the Laonome specimens from European waters are described here as L. xeprovala sp. nov. We also provide the characters of the branchial crown of three Laonome species for a prospective revision of this genus. PMID- 30313793 TI - A new species of Chorisquilla Manning, 1969 (Stomatopoda: Protosquillidae) from Korea and Japan with redescription of C. mehtae Erdmann Manning, 1998. AB - A new species of protosquillid mantis shrimp is described from the coastal waters of Korea and Japan. Chorisquilla orientalis n. sp. is distinguished from congeners by the combination of deep grooves and pits on the dorsal surface of abdominal somite 5, 8-14 spines on lateral margin of the telson, numerous minute dorsal spines on the telson and abdominal somite 6, and large, pyriform submedian bosses on the telson preceded by a small rounded boss. Chorisquilla orientalis is morphologically closest to C. mehtae Erdmann Manning, 1998, from Indonesia, but differs chiefly in the dorsal ornamentation of abdominal somite 6 and the telson and reaches a considerably larger size. Chorisquilla orientalis n. sp. shows developmental changes from juvenile to adult in the shape of the ocular scales and anterior margin of lateral plates of carapace, and in the number of lateral spines on telson. Also, C. mehtae Erdmann Manning, 1998, which, to date has not been adequately illustrated, is redescribed and figured. A key to the Korean gonodactyloids is presented. PMID- 30313794 TI - Libnotes crane flies (Diptera: Limoniidae) from Jeju Island (South Korea). AB - The Korean species of Libnotes (Laosa) Edwards, 1926 and L. (Libnotes) Westwood, 1876 from Jeju Island are taxonomically revised. L. (Laosa) charmosyne (Alexander, 1958) and L. (Libnotes) divaricata (Alexander, 1924) are new records for South Korea and L. (Libnotes) byersiana n. sp. is described. An identification key for all Korean Libnotes, redescriptions and illustrations of the three currently known Jeju species are presented. PMID- 30313795 TI - A new species of the genus Hebius (Squamata: Colubridae) from Sichuan, China. AB - A new species of the natricine snake genus Hebius Thompson, 1913 is described from Sichuan Province, Southwest China, based on a single male specimen. The new species is distinguished from its congeners found in China and adjacent regions by possessing the following combination of characters: 1) TL/SVL ratio 0.35; 2) three postoculars; 3) six temporals in formula 1/(1+1) +1+2; 4) eight supralabials, 4th and 5th in contact with the eye, 6th supralabial largest; 5) ten infralabials with the first five bordering the anterior chinshields; 6) 172 ventrals (plus two preventrals); 7) cloacal plate divided; 8) 90 divided subcaudals; 9) dorsal scales in 19-19-17 rows, all weakly keeled except the outer two; 10) reduction of dorsal scale rows from 19 to 17 at the position above ventral scale 99th; 11) reduction of the tail dorsal scales from 8 to 6 rows at the position above 18th subcaudal, and from 6 to 4 rows at the position above 37th subcaudal; 12) postorbital bones do not touch frontals, the parietal ridge weakly developed; the end of the supratemporal bones extending beyond the braincase; maxillary teeth 23-25, the last two enlarged, without diastema between them and the anterior teeth. This species is an evergreen forest dweller. PMID- 30313796 TI - A new species of Globicornis Latreille (Coleoptera: Dermestidae) from Baltic amber, with a key to fossil species. AB - Based on a well-preserved specimen from Eocene Baltic amber, the fourth fossil species belonging to the genus Globicornis Latreille (Coleoptera: Dermestidae: Megatominae), G. groehni sp. nov., is described and illustrated. A key to the species of Globicornis known from Baltic amber is also provided. The addition of this species further improves our knowledge about dermestids in Baltic amber, and moves us closer to the level of taxonomic coverage needed for detailed ecological studies based upon the coleopteran assemblage within the deposit. PMID- 30313797 TI - The genus Peckia Robineau-Desvoidy (Diptera: Sarcophagidae) in the Brazilian Amazon: a new species, new records, descriptions of female terminalia and key to species. AB - Flesh flies of the genus Peckia Robineau-Desvoidy, 1830 were studied from the Brazilian Amazon region. The male terminalia of all species are illustrated. The female terminalia are described and illustrated for all species for which the female is known. The female terminalia of six species are described for the first time; those of seven species are redescribed and documented through new illustrations. A new species of the subgenus Pattonella Enderlein, 1928, Peckia (Pattonella) juruti sp. nov., is described. It is similar to Peckia (Pattonella) smarti (Lopes, 1941) in the shape of the cercus and distiphallus, but differs in the shape of the gonites, juxta and capitis. Peckia (Peckia) hillifera (Aldrich, 1916) is recorded from Brazil for the first time; Peckia (Euboettcheria) florencioi (Prado Fonseca, 1932) is newly reported for the Brazilian Amazon. A key to the 21 species of Peckia so far recorded from the Brazilian Amazon is provided, allowing the identification of both sexes where known. The females of only five of these species remain unknown. PMID- 30313798 TI - High species diversity of the genus Neopanorpa (Mecoptera: Panorpidae) in Yunnan Province, China. AB - Neopanorpa van der Weele, 1909 is the second largest genus of Panorpidae, and is endemic to the Oriental Region. Yunnan, a province in the southwestern region of China, is well-known as a biodiversity hotspot and abundant in Neopanorpa species. However, only sixteen species of Neopanorpa have been described from Yunnan hitherto and the taxonomic study of Neopanorpa in Yunnan has lagged far behind as compared with studies performed in neighboring regions. In the present study, notably high diversity of Neopanorpa species is found in the Hengduan Mountains of Yunnan. Seven species of Neopanorpa are described as new: N. semiorbiculata, N. tincta, N. triangulata, N. diancangshanensis, N. magnatitilana, N. longistipitata, and N. quadristigma spp. n. Neopanorpa spatulata Byers, 1965, originally described from Thailand, is recorded from China for the first time. Neopanorpa dimidiata Navas, 1930 is a synonym of N. brisi (Navas, 1930). Keys to species of Neopanorpa in Yunnan are provided. The phylogenetic relationships of Neopanorpa species from the Hengduan Mountains, the Indochinese Peninsula, and the eastern Himalayas are briefly discussed. PMID- 30313799 TI - The Snail-killing Flies (Diptera: Sciomyzidae) of West Africa. AB - A review of the West African "snail-killing flies" or "marsh flies" (Sciomyzidae) shows that the fauna is not as dominated by the generally aquatic, predaceous genus Sepedon as was previously considered. Twenty species in seven genera, including three new species, Colobaea occidentalis, Pteromicra zariae and Sepedonella castanea are recorded. The Holarctic-Oriental genera Colobaea and Pteromicra are documented from Africa south of the Sahara for the first time. Biogeographical analyses based on the discovery of "Palaearctic" genera of Diptera south of the Sahara, faunal connections, and dispersal routes are presented. A key for identification and illustrations of diagnostic characters for some species are included. PMID- 30313800 TI - Reassessment of known fossil Pyraloidea (Lepidoptera) with descriptions of the oldest fossil pyraloid and a crambid larva in Baltic amber. AB - The identifications of known fossils currently placed in the lepidopteran superfamily Pyraloidea are critically re-examined. Of the eleven fossils examined, only three are confirmed to show morphological characters supporting placement in the superfamily. These fossils include a crambid larva in Baltic Amber, Baltianania yantarnia, Solis gen. n. et sp. n. and the oldest known fossil pyraloid, Eopyralis morsae Simonsen, gen. n. et sp. n. The third fossil, Glendotricha olgae Kusnezov, 1941, displays apomorphic characters for Pyraloidea, but is shown to be an inclusion in copal, not Baltic amber as had been reported. Seven fossil specimens lack reliable characters and cannot be assigned to Pyraloidea with certainty: Pyralites obscurus Heer, 1856; Pyralites preecei Jarzembowski, 1980; Petisca dryellina Martins-Neto, 1998; three fossil larvae tentatively identified as Pyralidae by Zeuner (1931); and Gallerites keleri Kernbach, 1967. A possible fossil pyraloid in Mizunami amber could not be located in museum collections and available literature does not provide details to assess the validity of the identification. We discuss the contribution of the reliably identified fossils towards better understanding the evolutionary history of Pyraloidea. PMID- 30313801 TI - Revision of the genus Palmanura Cassagnau, 1983 (Collembola: Neanuridae: Neanurinae: Sensillanurini). AB - A revision of Palmanura is presented, P. klompeni sp. nov. P. moralesi sp. nov., P. contrerasi sp. nov. and P. axelretanai sp. nov. are described and illustrated, and P. normae Palacios-Vargas, 1996 and P. sernai Palacios-Vargas Simon Benito, 2009 are redescribed. New records and distribution data are given for several species and a key for identifying every species of the genus are included. A discussion on the ventral chaetotaxy of all genera of the tribe Sensillanurini and a comparison with other tribes of Neanurinae is also provided. PMID- 30313802 TI - Bryozoan framework composition in the oddly shaped reefs from Abrolhos Bank, Brazil, southwestern Atlantic: taxonomy and ecology. AB - Bryozoans are a key group of sessile invertebrates in some reef frameworks but are typically neglected in environmental monitoring programs. Abrolhos Bank (Brazil) is the largest reef complex in the South Atlantic Ocean, encompassing several reef landscapes over an area of 46,000 km2. A transition takes place across the shelf from mangroves to soft sediments, coastal shallow reefs to a volcanic archipelago - surrounded by fringing reefs - and unique mushroom-shaped biogenic structures, with mesophotic pinnacle reefs, rhodolith beds, sink-holes and shelf break deep environments. The taxonomic composition of the bryozoan fauna was studied in 11 core samples taken from shallow to mesophotic mid-shelf reefs (4-25 m deep) on Abrolhos Bank by divers using a submersible drill. Of the 20 bryozoan species sampled, 17 are new records for Abrolhos Bank and seven species are new to science: Crassimarginatella winstonae n. sp., Parasmittina distincta n. sp., Parasmittina abrolhosensis n. sp., Hemismittoidea asymmetrica n. sp., Stylopoma variabilis n. sp., Stylopoma hastata n. sp., and Plesiocleidochasma acuminata n. sp. (described by Ramalho, Taylor Moraes). The most conspicuous species is Celleporaria atlantica. These results increase to 48 the total number of bryozoan species known in this region and reinforce the importance of this group as one of the main components apart from crustose coralline algae and corals of the reef framework-building community of Abrolhos Bank. PMID- 30313803 TI - Erratum to: Cirrhilabrus cyanogularis, a new species of fairy wrasse from the Philippines and Indonesia (Teleostei: Labridae). AB - Following publication of the original article (Tea et al., 2018), an error was noted in the museum registration number for the holotype of the new species Cirrhilabrus cyanogularis (PNM 15354). This registration number is a duplicate number already in use for the holotype of Cirrhilabrus shutmani (Tea Gill, 2017). The new registration number for the holotype of Cirrhilabrus cyanogularis is now PNM 15360. PMID- 30313804 TI - Mandatory changes of specific names to agree in gender with Talitriator Methuen, 1913, which is masculine (Crustacea: Amphipoda: Talitridae). AB - The genus Talitriator Methuen, 1913 was originally erected for T. eastwoodae Methuen, 1913, a talitrid amphipod or "land-hopper" from South Africa that was fixed as the type species of this genus by monotypy. Talitriator now includes seven species of land-hopper inhabiting South Africa as well as Saint Helena and Ascension islands in the Southern Atlantic (Stock Biernbaum 1994; Griffiths 1999; Horton et al. 2018). Although Methuen (1913) did not explicitly explain the etymology of the generic name, it obviously combines the name of the talitrid type genus Talitrus Bosc, 1802 (stem: Talitr-; from Latin talitrum, a rapping or flick of a finger: Jaeger 1962), with the connecting vowel "i" and the Latin masculine agentive suffix "-ator". On account of the final suffix, the gender of the name Talitriator is masculine. Under Articles 31.2 and 34.2 of the International Code of Zoological Nomenclature [hereafter "the Code"] (International Commission on Zoological Nomenclature 1999), a Latin adjective that is used as a species-group name must agree in gender with the generic name it is combined with. Article 34.2 further specifies that an incorrect gender ending must be changed (a "mandatory change", as opposed to either an "emendation" or an "incorrect subsequent spelling": cf. Article 33.1 of the Code). This gender-agreement rule has largely been ignored in publications concerning species of Talitriator, with adjectival names most often being spelled with the feminine suffix "-a" regardless of generic assignment. PMID- 30313805 TI - First record of the Asian ambrosia beetle, Xylosandrus crassiusculus (Motschulsky) (Coleoptera: Curculionidae, Scolytinae), in Slovenia. AB - Xylosandrus crassiusculus (Coleoptera: Curculionidae, Scolytinae), with the common name the Asian ambrosia beetle or the granulate ambrosia beetle, originates in tropical and subtropical regions of eastern Asia. It is one of the most widespread wood-boring beetles and among these one of the most successful invaders (IPPC 2017). Outside its native habitat, the species is present in Africa (Wood Bright 1992, Atkinson et al. 2000), in Australia (IPPC 2017), on the Pacific Islands (Beaver 1976), in the Americas (Atkinson 1988, Rabaglia et al. 2006, Flechtmann Atkinson 2016, Landi et al. 2017) and in Europe (Pennacchio et al. 2003, Nageleisen et al. 2015, Gallego et al. 2016, Francardi et al. 2017). PMID- 30313806 TI - Corrigenda to Gil-Santana, H.R. 2018. A new species of Phasmatocoris from French Guiana, with short taxonomic notes on two described species and an updated key (Hemiptera: Heteroptera: Reduviidae: Emesinae). Zootaxa 4413 (3): 491-506. AB - An intraspecific variation of the male genitalia of Phasmatocoris papei Gil Santana, 2018 (Hemiptera: Heteroptera: Reduviidae: Emesinae: Emesini), i.e., the absence (holotype) / presence (paratype) of the sclerotization of approximately basal two thirds of the ventral wall of phallosoma, reported by Gil-Santana (2018), was found to be incorrect. A subsequent reexamination of the specimens revealed that the misjudgement was based on a breakage of this structure in the phallus of the holotype. In fact, the ventral wall of phallosoma was completely sclerotized at its basal two-thirds in both specimens and should be considered as a species level character of Ph. papei. PMID- 30313807 TI - An unusual new species of the genus Paulianellus (Coleoptera: Scarabaeidae: Aphodiinae) from Yunnan, China. AB - The genus Paulianellus was erected by Balthasar (1938) as a subgenus of the genus Aphodius Hellwig, 1798 for a single species, Aphodius maderi Balthasar, 1938 from Sichuan. PMID- 30313808 TI - A systematic revision of Calotes Cuvier, 1817 (Squamata: Agamidae) from the Western Ghats adds two genera and reveals two new species. AB - Lizards of the genus Calotes are geographically restricted to South Asia, Indo China and parts of Southeast Asia. The greatest diversity of the genus is from the biodiversity hotspots in South Asia: Western Ghats (Peninsular India), Sri Lanka and Indo-Burma. Here, we present a systematic revision of members of the genus Calotes from Peninsular India using a combination of molecular phylogeny, geographical distribution and morphological characters. We show that Calotes from the Western Ghats is paraphyletic and consists of three major clades, one of which is widely distributed in South and Southeast (SE) Asia, while the others are restricted to Peninsular India. The Peninsular Indian clade is composed of two sister clades: Psammophilus, with a wider distribution and a second clade, composed of two extant species, Calotes rouxii and Calotes ellioti and two new species, all restricted to the Western Ghats region. Based on morphological differences, we retain the generic status of Psammophilus and assign its sister clade to a new genus Monilesaurus gen. nov. and transfer the following species, C. rouxii and C. ellioti, to this new genus. We also provide diagnoses and descriptions for two new species recognized within Monilesaurus gen. nov. In addition, Calotes aurantolabium from the Western Ghats was observed to be deeply divergent and to share a sister-relationship with the clade composed of Calotes, Monilesaurus gen. nov., and Psammophilus. Based on its phylogenetic position and morphological attributes, we assign this species to a new genus Microauris gen. nov. These new discoveries highlight the evolutionary significance of the Western Ghats in housing novel lizard diversity. PMID- 30313809 TI - Identity of the tree-spider crab, Parasesarma leptosoma (Hilgendorf, 1869 (Decapoda: Brachyura: Sesarmidae), with descriptions of seven new species from the Western Pacific. AB - The identity of the tree-spider crab, Parasesarma leptosoma (Hilgendorf, 1869) (family Sesarmidae), which is believed to be widely distributed in the Indo-West Pacific, is reassessed and shown to be a species-complex with nine species, seven of which are here described as new. Parasesarma leptosoma sensu stricto is now restricted to South and East Africa; and P. limbense (Rathbun, 1914) from Sulawesi, which had been regarded as a junior synonym, is here recognized as a valid species. The following species are described as new: P. gecko n. sp. from Vanuatu, Fiji, Guam and Japan; P. macaco n. sp. from Taiwan and the Philippines; P. kui n. sp. from Taiwan; P. parvulum n. sp. from the Philippines; P. gracilipes n. sp. from Indonesian Papua; P. purpureum n. sp. from Malaysia; and P. tarantula n. sp. from Sulawesi, Indonesia. The nine species of the Parasesarma leptosoma species-complex can be separated by the different shapes of their carapaces, the form of the dactylar tubercles on the male chelipeds, proportions of their ambulatory legs and the structure of the male first gonopod. PMID- 30313810 TI - Morphology and life history of an ant parasitoid, Psilocharis afra (Hymenoptera: Eucharitidae). AB - Eucharitidae (Hymenoptera) are specialized ant (Formicidae) parasitoids. As we begin to develop a better understanding of their phylogenetic relationships, it is critical to establish baselines for morphological and biological data. A morphological review and the first report of life history data for Psilocharis afra Heraty is provided based on new material from the Mpumalanga Province of South Africa. Psilocharis Heraty is included in Eucharitinae, but it is unclear whether it is the sister group of all other members of the subfamily, or sister group to Neolosbanus Girault in a monophyletic Psilocharitini, which would in turn be sister group to Eucharitini. The oviposition habits of P. afra differ from those of other Eucharitidae in that eggs are placed among trichomes under bracts at flower bases, instead of either being inserted into cavities formed in plant tissue by an enlarged ovipositor (as in Oraseminae and some Neolosbanus) or inserted into cavities in plant tissue, as in most Eucharitini. The egg and first instar planidia larva are described, and adult morphology is discussed with reference to Eucharitidae and other parasitoid Hymenoptera. PMID- 30313811 TI - Redescription of the Amazonian tiny tree toad Amazophrynella minuta (Melin, 1941) (Anura: Bufonidae) from its type locality. AB - The description of Amazophrynella minuta was published in 1941 by the Swedish naturalist Douglas Melin based on material from Taracua (Amazonas state, Brazil). This description was very brief and based on the morphology of few specimens with diagnostic characters and color variation not well defined. Moreover, the type series is currently in poor state of conservation. Consequently, taxonomic ambiguity surrounds the nominal taxon A. minuta, which hampers the description of many unnamed congeneric species. Herein, we redescribe A. minuta based on recently collected specimens from the type locality, designate a lectotype, formulate a new diagnosis, provide patterns of morphological variation, measurements and body proportions. PMID- 30313812 TI - Branchinotogluma bipapillata n. sp., a new branchiate scale worm (Annelida: Polynoidae) from two hydrothermal fields on the Southwest Indian Ridge. AB - A new species of Branchinotogluma, found at two hydrothermal vent fields on Southwest Indian Ocean Ridge, is described herein. It can be distinguished from its congeners by the small acicular lobe on the tentacular segment, the stout smooth notochaetae, 5 pairs of dorsal and ventral papillae surrounding the pharynx, 2 pairs of long ventral papillae and 4 pairs of ventral lamellae on males, and modified parapodia on posterior segments. Sexual dimorphism is also reported in the new species, as male and female individuals display differences in characters on the ventral papillae and posterior segments. PMID- 30313813 TI - The subspecies concept in Geocorinae: an integrated taxonomic case study on Geocoris (Piocoris) erythrocephalus (Lepeletier Serville, 1825) (Hemiptera: Heteroptera: Geocoridae). AB - The validity and necessity of subspecies as a taxonomic category and the implications of the subspecies concept in various taxa of animals is subject of debates since its very existence. In case of the species of the lygaeoid subfamily Geocorinae there are multiple examples of species consisting of up to nine subspecies which were mostly described as varieties or forms before the middle of 20th century, but upgraded to valid subspecies subsequently, usually without providing any arguments. As part of an integrated taxonomic study on the Palaearctic representatives of Geocorinae, the status of the subspecies of Geocoris (Piocoris) erythrocephalus (Lepeletier Serville, 1825) was revisited. A critical review of the literature available and our studies, involving analysis of COI sequences, morphological examination and distribution data processing with the use of Geographic Information System, concluded that two of the three subspecies, G. e. erythrocephalus and G. e. marginellus Horvath, 1907, can be considered valid, while G. e. litoreus Horvath, 1895, is merely a phenotypically manifested infrasubspecific genetic variety of G. e. erythrocephalus, with no taxonomic value as it was suggested by earlier study of another author. Besides the interpretation of evidence, the applicability of the subspecies concept in Geocorinae is discussed as well. PMID- 30313814 TI - Two new species of Atlantoscia Ferrara Taiti, 1981 (Isopoda: Oniscidea: Philosciidae) from southern Brazil described in the light of integrative taxonomy. AB - The use of molecular data in association with classical taxonomy has helped to alleviate the taxonomic impediment through the discovery, delimitation and description of new species. Terrestrial isopods are the largest suborder of Isopoda; however, there are very few active taxonomists in this group and a representative part of the terrestrial isopods world diversity remains unexplored. The genus Atlantoscia comprises five species in which diagnostic characters are few and show subtle differences among the species. The objective of this study was to delimit and describe two new species of the genus Atlantoscia from southern Brazil by using traditional taxonomy coupled with genetic information. Specimens were analyzed morphologically and by the aid of two molecular markers, mitochondrial COI and nuclear 18S rRNA. The validity of the new species Atlantoscia antennamaculata sp. nov. and Atlantoscia australis sp. nov. was corroborated, unambiguously, by morphological approach, phylogenetic analysis and species delimitation methods. Our study reinforces the fact that, despite the undeniable importance of comparative morphology in species discovery, new methods and data, particularly molecular ones, are becoming prominent and an integrative part of the taxonomy practice. PMID- 30313815 TI - Integrative taxonomy of the red-finned barb, Enteromius apleurogramma (Cyprininae: Smiliogastrini) from Kenya, supports recognition of E. amboseli as a valid species. AB - Research on freshwater ecosystems in East Africa is providing a better understanding of the biodiversity in the region. Recent studies of the Kenyan barbs (Cyprininae: Smiliogastrini) revealed diversity within several nominal species from the region. In this study, we examine the molecular and morphological variation in the red-finned barb (Enteromius apleurogramma). The results of this study support the recognition of E. amboseli as a valid species that is endemic to the middle Athi River drainage in southern Kenya. Enteromius amboseli is geographically isolated and distinguished from E. apleurogramma in having longer posterior barbels, a shorter dorsal fin, and generally fewer scales in the longitudinal series. Genetic divergence between E. apleurogramma populations in Lake Victoria and Lake Kanyaboli, provide novel estimates for rates of molecular evolution in the group. Additionally, the biogeography of these barbs and the conservation status of E. amboseli are discussed. PMID- 30313816 TI - Description of three new species of Bopyrissa Nierstrasz Brender a Brandis, 1931 (Epicaridea: Bopyridae) from Oceania with a key to species in the genus. AB - Three new species in the parasitic isopod genus Bopyrissa Nierstrasz Brender a Brandis, 1931, recorded from Kiribati, the Mariana Islands and French Polynesia, are described. These three species, B. distorta sp. nov., B. guamensis sp. nov. and B. oceania sp. nov., are the first species of the genus recorded from Oceania, occurring on three different hermit crab host species of genus Calcinus. The diversity of the genus is therefore increased to ten species. Bopyrissa distorta sp. nov. can be distinguished from congeners by the markedly distorted sinistral body of females and fused pleon of males. Bopyrissa guamensis sp. nov. differs from other dextral species of Bopyrissa in having a strikingly tuberculated edge to the pleomeres of females. Bopyrissa oceania sp. nov. differs from related species in that females possess eyes and that the barbula has smooth falcate projections on each side. A key to the ten species of Bopyrissa is presented, together with a tabular summary of their known geographic and host ranges. PMID- 30313817 TI - Taxonomic revisions within Embiotocidae (Teleostei, Perciformes) based on molecular phylogenetics. AB - Embiotocidae, a unique family within the Perciformes that has evolved a complex viviparous natural history, has lacked full resolution and strong support in several interspecific relationships until recently. Here we propose three taxonomic revisions within embiotocid surfperches based on recent molecular phylogenetic analyses that robustly resolve all interspecific relationship in the Eastern Pacific species: Hypsurus caryi (Agassiz, 1853) resurrected to its original name Embiotoca caryi Agassiz, 1853, Rhacochilus vacca (Girard, 1855) shifted into the genus Phanerodon Girard, 1854, and Hyperprosopon anale Agassiz, 1861 separated into the available genus Hypocritichthys Gill, 1862. The proposed changes would leave three previously paraphyletic groups monophyletic (Embiotoca, Hyperprosopon, and Phanerodon) and would maintain the current number of genera at 13. PMID- 30313818 TI - Erratum: CELIA BESTEIRO MARIO AYORA (2017) Checklist of the free-living marine nematodes of the Iberian peninsula (North East Atlantic). Zootaxa, 4347: 228-254. PMID- 30313819 TI - The matchstick grasshopper genus Warramaba (Morabidae: Morabinae): a description of four new species and a photographic guide to the group. AB - Matchstick grasshoppers are a unique and diverse element of Australia's insect fauna with great potential as a model system for ecological, evolutionary and biogeographical studies. The genus Warramaba comprises four bisexual species. It is of special interest from an evolutionary point of view because two parthenogenetic lineages (the Standard and Boulder-Zanthus phylads of W. virgo) have evolved through hybridization events between two of the sexual species. Despite the extensive genetic and systematic work that has been done on this genus, three of the bisexual species are yet to be formally named (P196, P169 and P125) and no key exists for their identification. Here I formally describe these species, respectively, as W. whitei sp. nov., W. flavolineata sp. nov. and W. grandis sp. nov. and split the parthenogenetic species W. virgo into two distinct species (the addition of W. ngadju sp. nov.). I also provide a photographic guide and key to the identification of all species in the genus. PMID- 30313820 TI - A new distinctive species of Barydesmus (Diplopoda, Polydesmida, Platyrhacidae) from Ecuador, with an annotated bibliographical checklist of the American Platyrhacidae. AB - Currently with 85 named species, the family Platyrhacidae in America is still poorly studied, particularly regarding Barydesmus Cook, 1896, the most diversified among the American genera. The center of diversification of Barydesmus lies in the northern third of the Andes Mountains, a megadiverse region where surely more species of these large, conspicuous diplopods await description. Here we present a new species, Barydesmus nangaritza sp. nov., easily diagnosable by the shape of the paranota, unique among the American Platyrhacidae. We provide also an updated bibliographical, annotated checklist of the whole family in America, with the aim of encouraging further studies in the group. The checklist includes the following new combinations under the genus Barydesmus: Barydesmus acanthopleurus (Hoffman, 1960) comb. nov., B. acanthosternus (Brolemann, 1900) comb. nov., B. acompus (Chamberlin, 1941) comb. nov., B. aequinoctius (Attems, 1914) comb. nov., B. affinis (Brolemann, 1919) comb. nov., B. andinus (Cook, 1896) comb. nov., B. azulae (Kraus, 1956) comb. nov., B. balsapuertus (Chamberlin, 1941) comb. nov., B. bifasciatus (Silvestri, 1897) comb. nov., B. bombonus (Chamberlin, 1941) comb. nov., B. broelemanni (Attems, 1914) comb. nov., B. brunnior (Chamberlin, 1941) comb. nov., B. celinus (Chamberlin, 1941) comb. nov., B. chuncho (Chamberlin, 1941) comb. nov., B. clathratus (Gervais, 1847) comb. nov., B. comptus Cook, 1896 comb. nov., B. contayus (Chamberlin, 1941) comb. nov., B. dunalii (Gervais, 1847) comb. nov., B. exsul (Cook, 1896) comb. nov., B. festae (Silvestri, 1897) comb. nov., B. fuscatus (Chamberlin, 1941) comb. nov., B. helophorus (Attems, 1899) comb. nov., B. incus (Chamberlin, 1941) comb. nov., B. javarynus (Schubart, 1950) comb. nov., B. leucus (Chamberlin, 1941) comb. nov., B. loretus (Chamberlin, 1941) comb. nov., B. manserichus (Chamberlin, 1941) comb. nov., B. medius (Chamberlin, 1941) comb. nov., B. obscurus (Kraus, 1955) comb. nov., B. orellanus (Chamberlin, 1941) comb. nov., B. pococki (Brolemann, 1911) comb. nov., B. retentus (Chamberlin, 1941) comb. nov., B. riparius (Carl, 1902) comb. nov., B. rufipes (Koch, 1847) comb. nov., B. scaber (Koch, 1847) comb. nov., B. socius (Chamberlin, 1941) comb. nov., B. strenuus (Silvestri, 1897) comb. nov., B. tambonus (Chamberlin, 1952) comb. nov., B. tapichus (Chamberlin, 1941) comb. nov., B. trichotypus (Chamberlin, 1941) comb. nov., B. utoquinius (Chamberlin, 1941) comb. nov. and B. zygethus (Chamberlin, 1941) comb. nov. PMID- 30313821 TI - New species and new records of Tingidae (Hemiptera. Heteroptera) from Thailand. AB - Eight species new to science are described from Thailand and 35 species new to Thailand are recorded. The fauna of Thailand, represented formerly by 12 species is increased to 52 species here. Comments on their distribution are added. Most of the species recorded come from material collected in the mid XXth century and deposited in Museums and from recent collecting surveys. PMID- 30313822 TI - The genus Zelentia is an amphi-boreal taxon expanded to include three new species from the North Pacific and Atlantic oceans (Gastropoda: Nudibranchia: Trinchesiidae). AB - The taxonomy of Zelentia Korshunova, Martynov Picton, 2017, a genus of aeolidacean nudibranchs recently separated from Trinchesia Ihering, 1879, is reviewed. Using previous and novel data, including the defining morphological characters of a supplementary gland inserted into the penis, which is also armed with stylet, it is demonstrated that the genus Zelentia is a well-established amphi-boreal taxon. A phylogenetic tree and haplotype network for species of the genus Zelentia are provided. A new species from the Northeastern Pacific, Zelentia willowsi sp. nov. and a second Northeastern Pacific species, Zelentia nepunicea sp. nov., previously thought to be "Cuthona" pustulata (Alder Hancock, 1854), are described using morphological and molecular data. A new species from the North Atlantic and sub-Arctic White Sea, Zelentia roginskae sp. nov., is also described using morphological and molecular data. The Northeastern Pacific Zelentia nepunicea sp. nov. and"Cuthona" punicea Millen, 1986, which externally share a similar reddish colouration, are shown to belong to two different families since "Cuthona" punicea possesses a supplementary gland inserted into the vas deferens and an unarmed penis, characters of the genus Cuthonella Bergh, 1884, belonging to the Cuthonellidae family. Despite belonging to different families and having significant internal differences, externally Cuthonella punicea and Zelentia nepunicea sp. nov. appear similar, thus the new sympatric species of Zelentia is given the name Z. nepunicea sp. nov. which means non punicea. To facilitate identification and avoid further confusion we provide a comparative table which encompasses diagnostic morphological data for Northeastern Pacific species of the families Cuthonidae, Cuthonellidae and Trinchesiidae which are externally similar to the described new taxa. PMID- 30313823 TI - Phytoseiid mites (Acari: Phytoseiidae) from Chile, with descriptions of three new species and a redescription of Chileseius camposi. AB - A total of 40 phytoseiid species has been reported from Chile, including the two species (Neoseiulus californicus (McGregor) and Phytoseiulus persimilis (Athias Henriot) most widely used worldwide for the biological control of the two-spotted spider mite, Tetranychus urticae Koch (Tetranychidae). In this paper we report nine other species found in new collecting conducted since 1989, including three new species: Amblyseius herbicolus (Chant), Amblyseius tamatavensis Blommers, Arrenoseius robertogonzalezi Trincado Martin n. sp., Neoseiulus anonymus (Chant Baker), Neoseiulus bicaudus (Wainstein), Neoseiulus viticolus Trincado Martin n. sp., Metaseiulus (Metaseiulus) camelliae (Chant Yoshida-Shaul), Metaseiulus (Metaseiulus) neoflumenis Moraes Kreiter and Metaseiulus (Metaseiulus) relictus Trincado Martin n. sp.. Chileseius camposi Gonzalez Schuster, 1962 is redescribed, and a list of all species presently known from Chile and a key to help in their separation are given. A new name, Proprioseiopsis kargi Trincado nom. nov., is a replacement name for Proprioseiopsis globosus Karg, 1976, a junior homonym of Proprioseiopsis globosus (Gonzalez Schuster, 1962). PMID- 30313824 TI - A new species of Creagrutus (Characidae: Stevardiinae) from the upper Rio Magdalena, Colombia. AB - A new species of Creagrutus is described from several localities in the upper Rio Magdalena drainage, Colombia. Creagrutus dulima n. sp. differs from all trans Andean congeners by the combination of a relatively small orbital diameter, the shape and position of hooks on the pelvic-fin rays, in having the third infraorbital not in contact with the preopercle ventrally, and the presence of a dark, reticulated pigmentation pattern on the dorsal portion of body. The distribution of Creagrutus species in the Magdalena-Cauca River Basin is discussed, and an updated identification key for species of trans-Andean Creagrutus is provided. PMID- 30313825 TI - A new sesarmid crab of the genus Karstarma (Crustacea: Decapoda: Brachyura) associated with limestone formations in East Java, Indonesia. AB - A new stygobitic sesarmid crab species is described from underground freshwater cave streams in the southern Malang karst range on the south coast of East Java Province, Indonesia. Karstarma malang n. sp. is morphologically most similar to K. jacobsoni (Ihle, 1912) from an underground river cave system in the southern coast of the Special Region of Yogyakarta Province in central Java, but differs in having a relatively larger cornea, less swollen ocular peduncle which lacks a ridge along the median part, proportionately shorter ambulatory legs and a more slender male first gonopod. This paper increases the number of the species of Karstarma Davie Ng, 2007, to 16; the new species being the eighth of the genus from Indonesia. It is also the third species which has a distinctly reduced cornea. PMID- 30313826 TI - Taxonomic notes on Chinese Lamiini (Coleoptera: Cerambycidae: Lamiinae). AB - Paragniopsis ochraceomaculata Breuning, 1965 and Paragniopsis Breuning, 1965 are confirmed to be junior synonyms of Agnioides striatopunctatus Breuning, 1956 and Agnioides Breuning, 1956 respectively after comparison of types; Monochamus fruhstorferi Breuning, 1964 is a new junior synonym of Annamanum lunulatum (Pic, 1934). Paranamera ankangensis Chiang, 1981 and Mimonemophas multimaculatus Xie Wang, 2015 are transferred to the genus Anoplophora Hope, and the former is newly recorded from Hunan Province. PMID- 30313827 TI - Redescription of Lernaeenicus stromatei Gnanamuthu, 1953 (Copepoda: Siphonostomatoida: Pennellidae) infesting the Black Pomfret Parastromateus niger (Bloch) from Indian waters. AB - The parasitic copepod Lernaeenicus stromatei Gnanamuthu, 1953 infecting black pomfret, Parastromateus niger (Bloch) (Carangidae) is redescribed based on a neotype and additional fresh material obtained from hosts collected at different fish landing centers on the Chennai Coast (Tamil Nadu), Malabar Coast (Kerala), and from West Bengal, India. A female L. stromatei obtained from the Chennai Coast has been designated as a neotype and deposited in the National Zoological Collections of Zoological Survey of India (NZC-ZSI). Lernaeenicus stromatei can be identified based on the following features: A long and slender body; head anteriorly rounded, dorso-ventrally flattened and slightly longer than broad; presence of three posterior horns on the head, one median and two lateral, all sub-similar and apically rounded; and an anterior neck with an indistinct partition on the dorsal side, indicating thoracic segments, and a three-jointed antennule. PMID- 30313828 TI - Redescription of Alopecosa albostriata (Araneae: Lycosidae) based on specimens from Siberia. AB - Alopecosa albostriata (Grube, 1861), originally described from Western Yakutia, is redescribed based on specimens from Siberia. Although A. albostriata is known to be distributed in Kazakhstan, Russia, China and Korea, with records attributed to more than 30 taxonomic entries, and is considered as a senior synonym of nine species (all described from China), it is actually restricted to Siberia and was illustrated only in two publications. All synonyms and records from China, Kazakhstan and Korea refer to species related to Mustelicosa dimidiata (Thorell, 1875). Among Palaearctic species, A. albostriata is most similar to A. mutabilis (Kulczynski, 1908). Comparative figures are provided for the latter species. These two species, together with A. exasperans (O. Pickard-Cambridge, 1877) form the albostriata species group occurring across Siberia and the northern Nearctic. Male palps in this species group are most similar to those in Mustelicosa Roewer, 1960, and most likely that species group will be transferred to this genus. Distribution records of A. albostriata are shown on map. PMID- 30313829 TI - Phylogenetic relationships of Scelimeninae genera (Orthoptera: Tetrigoidea) based on COI, 16S rRNA and 18S rRNA gene sequences. AB - Scelimeninae is an important subfamily of Tetrigoidea; however, the phylogenetic relationships within Scelimeninae are poorly understood, and its generic classification has remained unstable. In this study, the COI, 16S rRNA and 18S rRNA genes from 24 species in 9 genera within Scelimeninae were amplified and sequenced, the base composition and inter-species genetic distance of the combined sequence of COI, 16S rRNA and 18S rRNA genes were analyzed, and the molecular phylogenetic relationships were reconstructed using Maximum Likelihood (ML) and Bayesian inference (BI) methods. The results of sequence analysis showed that the total length of the combined COI, 16S rRNA and 18S rRNA gene sequence was 3507 bp, including 2345 conservative sites, 1144 variable sites and 901 parsimony-informative sites. The average A+T content was 63.5% and 78.1% in the COI, 16S rRNA sequences, respectively, indicating A+T bias. The average genetic distance between all species was 0.134, and the average genetic distance in the inner group (Scelimeninae) was 0.126. A phylogenetic tree based on the combined sequences of the COI, 16S rRNA and 18S rRNA genes showed that the phylogenetic relationships among 9 Scelimeninae genera were as follows: Criotettix + (((Zhengitettix + Hebarditettix) + (Falconius + (Scelimena + Paragavialidium))) + ((Eucriotettix + Thoradonta) + Loxilobus)). The molecular phylogenetic results generally support the morphological taxonomy; at the genus level, Criotettix, Scelimena, Paragavialidium, Thoradonta and Eucriotettix are monophyletic groups, Scelimena and Paragavialidium form sister groups, and Thoradonta and Eucriotettix also form sister groups, but the relationship between Hebarditettix and Zhengitettix needs further study. At the species level, synonyms may exist between Thoradonta spiculoba and Thoradonta transpicula and Thoradonta nodulosa and Thoradonta obtusilobata, but more studies are required to confirm this inference. PMID- 30313830 TI - Review of the genus Cruziohyla (Anura: Phyllomedusidae), with description of a new species. AB - The presented work summarises new and existing phenotypic and phylogenetic information for the genus Cruziohyla. Data based on morphology and skin peptide profiling supports the identification of a separate new species. Specimens of Cruziohyla calcarifer (Boulenger, 1902) occurring in Ecuador, Colombia, two localities in Panama, and one in the south east Atlantic lowlands of Costa Rica, distinctly differ from those occurring along the Atlantic versant of Central America from Panama northwards through Costa Rica, Nicaragua, to Honduras. A new species-Cruziohyla sylviae sp. n.-(the type locality: Alto Colorado in Costa Rica)-is diagnosed and described using an integrated approach from morphological and molecular data. Phylogenetic analysis of DNA sequences of the 16S rRNA gene confirms the new species having equal minimum 6.2% genetic divergence from both true C. calcarifer and Cruziohyla craspedopus. PMID- 30313831 TI - Detection of Cryptic taxa in the genus Leptophryne (Fitzinger, 1843) (Amphibia; Bufonidae) and the description of a new species from Java, Indonesia. AB - We investigated phylogenetic relationships among populations of two species within the genus Leptophryne, L. cruentata and L. borbonica, using the mitochondrial 16S rRNA gene. As a result, we identified two distinct lineages within populations currently considered Leptophryne cruentata: 1) a lineage containing L. cruentata from the type locality, and 2) a lineage from Mt. Slamet and Mt. Ciremai. On the basis of genetic and morphological differences, we describe the Mt. Slamet and Mt. Ciremai populations as a new species, L. javanica sp. nov. The new species is distinguished from L. cruentata and L. borbonica by the following combination of morphological characters: the presence of distinct yellow mottling on the dorsum; relatively small body size (SVL male 22.2-24.0 mm, female 29.6 mm); relatively short hindlimbs (HLL 37.0-40.9 mm); relatively short fourth toe (4ToeL 4.3-6.0 mm); basal webbing on the hands, but well developed on toes; very protruding snout and an indistinct tympanum. In our preliminary phylogenetic analysis, we also detected four distinct lineages within Leptophryne borbonica: 1) a lineage containing true L. borbonica from west Java, 2) a lineage from Lampung (Sumatra I), 3) a lineage from northern Borneo, and 4) a lineage from Bengkulu (Sumatra II). Further studies are needed to determine taxonomic status of these lineages. PMID- 30313832 TI - Review of Odontochrydium Brauns (Hymenoptera, Chrysididae) with description of two species from the Palaearctic and Oriental regions. AB - The genus Odontochrydium Brauns, 1928, previously known only from the Afrotropical Region, is recorded from the Palaearctic Region (Saudi Arabia) and the Oriental Region (Southern India) for the first time. Odontochrydium bicristatum sp. nov. from Kenya and Saudi Arabia and O. xui sp. nov. from India are described. Pictures and a key to the species of this genus are given. PMID- 30313833 TI - A new species of the stenopodidean shrimp genus Odontozona Holthuis, 1946 (Crustacea: Decapoda: Stenopodidea: Stenopodidae) from the Ryukyu Islands, Indo West Pacific. AB - A new species of the stenopodidean shrimp genus Odontozona Holthuis, 1946 is described and illustrated on the basis of 3 specimens recently collected from submarine caves of Okinawa-jima and Ie-jima Islands, the Ryukyu Islands, southwestern Japan, Indo-West Pacific. Odontozona okunoi sp. nov. closely resembles O. anaphorae Manning Chace, 1990 described from Ascension Island, South Atlantic Ocean, but differs from it by a combination of morphological characters, including the large cardiac spine on the carapace, the spines on the pleural surface, the posterior tooth of the telson, the irregular row of small spines on the dorsomesial surface of the third pereopod chela, as well as the length ratio of the third pereopod chela against carpus and merus. This study increases the total number of species described in the genus Odontozona to 21, nine of which occur the Indo-West Pacific. PMID- 30313834 TI - Redescription of Isotoma grana Lee, Kim Kim, 1993 and description of a new species of Isotoma Bourlet, 1839 (Collembola: Isotomidae) from Korea. AB - A new species, Isotoma koreana sp. nov. is described. It is most similar to Isotoma pinnata Borner, 1909, I. riparia (Nicolet, 1842) and I. grana Lee, Kim Kim, 1993, in possessing a middorsal longitudinal band on body. It can be distinguished in having a thin central stripe on dorsal side of body, the structure of manubrial apical spines and body chaetotaxy. Isotoma grana is redescribed here from type material and compared with related species. An indentification key to the Sino-Japanese species of Isotoma Bourlet is provided. PMID- 30313835 TI - Revision of the leafhopper genus Gurawa (Cicadellidae: Deltocephalinae: Chiasmini) from Pakistan with description of a new species. AB - The leafhopper genus Gurawa Distant, 1908 is revised with descriptions and illustrations of a new species, Gurawa longispina sp. nov. and a short winged form of Gurawa minorcephala Pruthi from Pakistan. A key is provided to distinguish known species in this genus from Pakistan. PMID- 30313836 TI - A new species of the genus Aporcelinus Andrassy, 2009 (Nematoda, Dorylaimida, Aporcelaimidae) from Costa Rica. AB - A new species of the genus Aporcelinus, A. elongicaudatus sp. n., collected from natural habitats of Costa Rica, is described and illustrated. The new species is characterized by its 0.92-1.05 mm long body, lip region offset by weak constriction and 15 um broad, odontostyle 15-18 um or 1.0-1.2 times the lip region diameter, neck 270-300 um long, pharyngeal expansion 130-150 um long or 45 55% of total neck length, uterus 33-41 um long or 0.70-0.85 times the corresponding body diameter (but certainly longer), vulva transverse (V = 49-51), and tail conical elongated (45-71 um, c = 14-22, c' = 2.0-3.2) and dorsad bent. PMID- 30313837 TI - Key to the fossil genus Largusoperla (Plecoptera: Perlidae), with description of two new species from mid-Cretaceous Burmese amber. AB - Two new species of the fossil stonefly genus Largusoperla (Plecoptera: Perlidae), Largusoperla dewalti sp. nov. and Largusoperla borisi sp. nov. are described and illustrated from mid-Cretaceous Burmese amber. The two new species are distinguished from other known congeners by the specifically modified paraprocts. In addition, an identification key to the known species of Largusoperla is provided. PMID- 30313838 TI - New species of the orb-weaving spider genus Chrysometa (Araneae, Tetragnathidae) from oak forests near of the Pico de Orizaba National Park (Veracruz, Mexico). AB - Seven new species of the genus Chrysometa Simon are described: C. citlaltepetl n. sp., C. triangulosa n. sp., C. rosarium n. sp., C. atotonilco n. sp., C. xamaticpac n. sp. C. puya n. sp. and C. sagicuta n. sp. Species identities were evaluated and sexes for each species matched with a fragment of the cytochrome c oxidase subunit I. These data were analyzed with maximum likelihood and the resulting cladograms separated all species with high support values (95-100) and an average distance of 0.093 %. The genetic signal also agreed with the diagnostic morphological features used to separate these taxa. The sex matching results discovered that the female of C. chipinque Levi actually belongs to C. puya n. sp.; the correct female of C. chipinque is here described for the first time. A redescription of the male of C. chipinque and the female of C. puya is also provided. All species were collected as part of a faunistic inventory from two oak forests near Pico de Orizaba Volcano National Park. A total of 399 adult specimens, 209 females and 195 males, were sorted and identified. Most individuals were collected from medium height vegetation by beating trays and from high vegetation by direct collecting at night. High resolution images for all species are available at www.unamfcaracnolab.com. Finally, the functional anatomy of the epigynum for the species described here is discussed. PMID- 30313839 TI - Checklist of decapods (Crustacea) from the coast of Sao Paulo State (Brazil) supported by integrative molecular and morphological data: II. Infraorder Caridea: family Alpheidae. AB - This study is part of a series of checklists resulting from a long-term multidisciplinary project on the biodiversity of decapod crustaceans from the marine and coastal environments (including estuaries) of Sao Paulo State (Brazil). For that, we integrated molecular techniques (mitochondrial DNA markers) and morphological analyses of adult specimens for an accurate and detailed identification. The DNA markers were used when the morphological identification was doubtful, particularly in the recognition of cryptic species. This second manuscript presents a checklist of the Alpheidae caridean shrimps from the coast of Sao Paulo. We report the occurrence of Alpheus cf. paracrinitus and Synalpheus townsendi for the first time in the region. Based on our survey, 39 species of Alpheidae are known for this region: Alpheus (21 spp.), Athanas (2 spp.), Automate (2 spp.), Leptalpheus (1 spp.), Salmoneus (3 spp.), and Synalpheus (10 spp.). We collected 28 species and obtained cytochrome oxidase subunit I (barcode region) and/or 16S partial sequences of 26 of them. These sequences may be used for phylogenetic and populational analyses in further studies. PMID- 30313840 TI - A new species of small, long-snouted Hypogeophis Peters, 1880 (Amphibia: Gymnophiona: Indotyphlidae) from the highest elevations of the Seychelles island of Mahe. AB - A new species of indotyphlid caecilian amphibian, Hypogeophis montanus sp. nov., is described based on a series of specimens from the Seychelles island of Mahe, collected from two localities in 2013 and 2015. The new species most closely resembles the Seychelles (Mahe) endemic H. brevis in being short (maximum known total length in life ca. 110 mm) and long snouted, but differs by having more vertebrae, a relatively smaller head, and substantially distinct mitochondrial and nuclear gene sequences. Hypogeophis montanus sp. nov. is known from higher elevations (718-731 m) than H. brevis (ca. 350-650 m), and its elevationally restricted distribution on a single small island likely renders it threatened under IUCN Red List criteria. Hypogeophis montanus sp. nov. is the third species of small and long-snouted caecilian reported from the Seychelles. Along with H. brevis and H. pti, H. montanus sp. nov. is among the smallest known species of caecilian and possibly has the smallest global distribution. PMID- 30313841 TI - New records of deep-sea prawn of the genus Gennadas Spence Bate, 1881 (Crustacea: Decapoda: Benthesicymidae) from Southwestern Atlantic. AB - Here, we report the new occurrences of four deep-water prawn of the genus Gennadas in the southwestern Atlantic: G. gilchristi recorded from the Mid Atlantic Ridge region; G. capensis recorded from Brazilian waters off Fernando de Noronha Archipelago, Atol das Rocas and Ceara Chain; G. talismani and G. scutatus recorded both to Mid-Atlantic Ridge and to Brazilian waters. PMID- 30313842 TI - Two new records and one new species of the genus Apelaunothrips from China (Thysanoptera: Phlaeothripidae). AB - Apelaunothrips dentiellus sp. n. is described from China. This is characterized by all tibiae and tarsi yellow and the fore tarsus with a small tooth in both sexes. A. indicus (Ananthakrishnan) and A. maculipennis (Okajima) are newly recorded from China. A key to the Apelaunothrips species known from China is provided, together with new distribution information of each species. PMID- 30313843 TI - A new species of Anthozela from Vietnam, with a list of species in the genus (Lepidoptera: Tortricidae: Olethreutinae: Enarmoniini). AB - The genus Anthozela Meyrick (1913) is reported for the first time from Vietnam, represented by the new species Anthozela cypriflammella Heppner Bae, n. sp. A list of the species of Anthozela and related genera is provided. PMID- 30313844 TI - New species and records of Uncispionidae and Pygospiopsis (Polychaeta, Spionida) from deep water off the east and west coasts of North America, the Gulf of Mexico, the Antarctic Peninsula, and Southeast Asia. AB - Five new species and one new genus of the obscure spioniform family Uncispionidae are described together with three new species of the rare and unusual spionid genus Pygospiopsis Blake, 1983. All species are from offshore habitats with most from deep-sea continental slope depths. Among the Uncispionidae are the second and third species of the genus Uncopherusa Fauchald Hancock, 1981, collected from off Brunei in the South China Sea and off Louisiana in the Gulf of Mexico; two new species of Uncispio Green, 1982, the third and fourth to be described, from deep water off the U.S. Atlantic coast and the Gulf of Mexico; and a new species of a new genus, Rhamphispio n. gen., from off the U.S. Atlantic coast. All species of Uncispionidae are compared and a key to the known species is presented. The genus Pygospiopsis Blake, 1983, is currently known for only two species: P. dubia (Monro, 1930) from Antarctic and sub-Antarctic waters and P. occipitalis Blake, 1996, from shelf depths off southern California. In the present study, new collections of the type-species P. dubia from the Antarctic Peninsula include post-larvae and juveniles as well as adults, thus permitting documentation of the development of some key adult morphology. Three new species of Pygospiopsis are described from deep water off the U.S. Atlantic and Pacific coasts and from the Antarctic Peninsula. A review of all species of Pygospiopsis suggests that, based on branchial distribution patterns, the closely related Pseudatherospio fauchaldi Lovell, 1994, should be referred to Pygospiopsis, bringing the total known species to six. All of these are compared and contrasted and the generic definition of Pygospiopsis updated. The status of Pygospiopsis within the Spionidae relative to the closely related genus Atherospio Mackie Duff, 1986, is discussed. PMID- 30313845 TI - Designation of a neotype for the Australian robber fly Ommatius dimidiatus Macquart, a new senior synonym of Ommatius pilosus White and Ommatius levis White (Diptera: Asilidae: Ommatiinae). AB - The holotype of Ommatius dimidiatus Macquart is confirmed as being lost and two specimens labeled as syntypes in the Museum National d'Histoire Naturelle, Paris are considered not to have any type status. In accordance with Article 75 and complying with the qualifying conditions of Article 75.3 of the International Code of Zoological Nomenclature, a Tasmanian specimen of O. pilosus White, the only Ommatius Wiedemann species known to occur in Tasmania, is designated as a neotype of O. dimidiatus. Ommatius pilosus and O. levis White are confirmed as junior synonyms of O. dimidiatus. PMID- 30313846 TI - New black fungus gnats (Diptera: Sciaridae) from Eastern Australia. AB - The following 17 species are described as new for science: Austrosciara heterospinata sp. n., Aus. kalliesi sp. n., Aus. multispinulata sp. n., Aus. stockerae sp. n., Aus. trichovenosa sp. n., Bradysia chloroantennata sp. n., B. fuscovirgata sp. n., B. loudoni sp. n., B. macrotrichata sp. n., B. nigroantennata sp. n., B. parareflexa sp. n., Cratyna (Peyerimhoffia) subvagabunda sp. n., Euricrium (Austroeuricrium) australiensis sp. n., Phytosciara crocera sp. n., Pseudolycoriella latostylata sp. n., Psl. rubroalata sp. n., and Scatopsciara nigrothoracica sp. n. The following 4 species are new records for Australia: B. aspercera Mohrig, B. centidens Vilkamaa, Hippa Mohrig (both from Papua New Guinea), B. gibbosa Vilkamaa, Hippa Mohrig and Pseudolycoriella capillosa Vilkamaa, Hippa Mohrig (both from New Caledonia). Euricrium australiensis sp. n. is the type species of the subgenus Austroeuricrium subgen. n. First detections of the species B. conjuncta (Skuse), B. exsequialis (Skuse), B. pernitida (Skuse) and B. pictipes (Skuse) were made after their description in the 19th century. One species was declared as a new synonym: B. centidens Vilkamaa, Hippa Mohrig, 2012 = B. mutuata Mohrig, 2016 syn. n. Five species were excluded from the subgenus Peyerimhoffia. Four are newly combined in the genus Corynoptera, crassistylata group [C. sparsula (Shi Huang) comb. n., C. brachypoda (Shi Huang) comb. n., C. yunnana (Shi Huang) comb. n., C. shennongjiana (Shi Huang) comb. n.], one in Corynoptera s. str. [C. longiprojecta (Shi Huang) comb. n.]. Corynoptera longiprojecta (Shi Huang) is a junior synonym of Corynoptera diversicalcaria Mohrig, 2004 from Papua New Guinea. PMID- 30313847 TI - Two new species of Garreta Janssens, 1940 (Coleoptera: Scarabaeidae: Scarabaeinae) from Southern Africa. AB - Two new, putative, closely-related species of dung beetles are described in the genus Garreta Janssens, 1940 (tribe Gymnopleurini). Garreta australugens new species, is known from various dung types in the southeast lowlands of Africa (validated for South Africa, Mozambique and Zimbabwe with a probable record from Botswana). It is, here, separated at species level from its putative closest relative, Garreta lugens (Fairmaire, 1891), recorded from the lowlands of northeast Africa (validated for Kenya with additional records from Ethiopia, Somalia and Tanzania). These two taxa were formerly considered to comprise a single species. All specimens in the type series of Garreta namalugens new species, were recorded at low altitude in arid, rocky mountains from west central to northwest Namibia, mostly on dung in communal middens of the Rock Hyrax (Procavia capensis (Pallas, 1766)). PMID- 30313848 TI - Review of the genus Diestramima Storozhenko, 1990 (Orthoptera: Rhaphidophoridae: Aemodogryllinae) from China. AB - In this paper, 6 new species, 1 new subspecies and 1 newly recorded species of the genus Diestramima from China are described, i.e. Diestramima acutiapicis sp. nov., Diestramima bina sp. nov., Diestramima cycla sp. nov., Diestramima truncata sp. nov., Diestramima subtilis sp. nov., Diestramima eurya sp. nov., Diestramima austrosinensis quaterna ssp. nov. and Diestramima major Gorochov, 1998. The morphological photographs of these and 8 known species are provided. All specimens examined are preserved in the Museum of Hebei University. PMID- 30313849 TI - The identity of Cicinnus orthane Blanchard, 1852 (Lepidoptera, Mimallonidae, Cicinninae), type species of Cicinnus Blanchard, 1852. AB - In order to clarify the identity of the type species of one of the most diverse Mimallonidae genera, Cicinnus Blanchard, 1852, we designate a lectotype for Cicinnus orthane Blanchard, 1852 with photographs of the lectotype (dorsal and ventral) and its genitalia figured for the first time. Cicinnus orthane, described from Chile, is a close morphological match for a southeastern Brazilian species, which we also illustrate for comparative purposes. Because the lectotype of C. orthane is female, we include both sexes of this related Brazilian species in order to facilitate the figuring of male genitalia as well as comparisons of the female genitalia. We are therefore able to establish sound morphological characteristics for Cicinnus sensu stricto, namely in the males the bifid configuration of the gnathos, a complex juxtal arrangement fused to the phallus, and largely membranous valvae; and in the females a wide and narrow lamella antevaginalis, lack of setae covered bulbous masses on either side of the lamella antevaginalis, well-sclerotized and posteriorly protruding tergite VIII, and reduced, stout apophyses anteriores which are about one quarter the length of the apophyses posteriores. PMID- 30313850 TI - Aradidae from Vietnam V. Bifurcatoaptera, a new genus of apterous Carventinae (Hemiptera: Heteroptera: Aradidae) from Vietnam. AB - A new apterous genus and species of Aradidae (Hemiptera: Heteroptera), Bifurcatoaptera lamdongensis gen. et sp. nov., is described from Vietnam. The diagnostic morphological features of the new species are described and illustrated. PMID- 30313851 TI - A nomenclatural and taxonomic note on Micrella Punnett, 1901 (Nemertea: Heteronemertea). AB - I propose to synonymize the two monotypic heteronemertean genera Micrella Punnett, 1901 and Zygeupolia Thompson, 1900 in light of the morphological similarity between the two, based on available information from literature. My proposal not only results in a new combination, Zygeupolia rufa (Punnett, 1901) comb. nov., but also resolves homonymy of Micrella Punnett, 1901 with the ptiliid coleopteran Micrella Motschulsky, 1868 as well as the heterobranch gastropod Micrella Bergh, 1899. PMID- 30313852 TI - Seychellister mornicus, a new genus and species of Clavigeritae (Coleoptera, Staphylinidae, Pselaphinae) from Seychelles. AB - Seychellister mornicus, gen. and sp. nov. is described based on three specimens collected by sifting of leaf-litter in Mahe, Seychelles. The genus is tentatively placed in the subtribe Clavigerodina (Pselaphinae: Clavigeritae: Clavigerini). PMID- 30313853 TI - First report of the land planarian Endeavouria septemlineata (Hyman, 1939) (Platyhelminthes, Tricladida, Continenticola, Geoplanidae) in French Polynesia. AB - We report the presence of the land planarian Endeavouria septemlineata from Tahiti, French Polynesia, on the basis of a single specimen collected in 2017. Identification of the species was ascertained by external and internal morphology and DNA COI sequence. The finding is of importance for conservation, since this species is a predator of soil animals. PMID- 30313854 TI - Three new taxa of the genus Cechetra Zolotuhin Ryabov, 2012 (Lepidoptera, Sphingidae) from South-East Asia with notes on other species of the genus. AB - Two new species and one subspecies of the genus Cechetra Zolotuhin Ryabov, 2012 are described from South-East Asia. Cechetra bryki sp.n. is described from Nepal, Myanmar (Burma), southwestern China and northern Vietnam. This species is most closely related in habitus, male genitalia morphology and COI mtDNA to the sympatric species, C. lineosa (Walker, 1856) and C. scotti (Rothschild, 1920) in habitus, male genitalia morphology and COI mtDNA. Cechetra inconspicua sp.n. is described from Peninsular Malaysia, Borneo and Sumatra. In habitus, it is closest to C. lineosa and C.subangustata (Rothschild, 1920), but its COI mtDNA (COI-5P "barcode region") is very different from all other species in the genus. Cechetra subangustata continentalis ssp.n. is described from continental Indochina and Taiwan. It differs from the nominotypical subspecies in habitus. Cechetra scotti comb. nov. is transferred to Cechetra from Cechenena Rothschild Jordan, 1903. PMID- 30313855 TI - Taxonomic revision of Cyphanthidium Pasteels (Hymenoptera: Apoidea: Megachilidae: Megachilinae: Anthidiini), an endemic Afrotropical bee genus. AB - The Afrotropical bee genus Cyphanthidium Pasteels is revised. It comprises four species. Cyphanthidium gessorum, new species, and Cyphanthidium whiteheadi, new species, are described as well as the previously unknown female of Cyphanthidium intermedium. A key for identifying the species is given. Supplemental information is provided on the recently published revisions of Serapista and Plesianthidium. PMID- 30313856 TI - Skusella Freeman (Diptera: Chironomidae): new species, immature stages from Africa, Asia and Australia, and expanded distributions. AB - Skusella Freeman, 1961 (Diptera: Chironomidae, Chironominae), known previously from adults from Australia and Africa, is revised with extended descriptions, including for immature life stages. Skusella is diagnosed based on its type species S. subvittata (Skuse, 1889) from Australia, S. pallidipes (Kieffer, 1921) from the Afrotropical region (the only other originally included species), a second African species S. freemani Harrison, 2002, and S. silingae Tang, sp. n., newly described here from the pupa and adult males from China. The immature stages of Skusella have been known informally for several decades, notably for a characteristic fringe of setae on one or more abdominal pleurae of the pupa, shared only with newly described Paraskusella Cranston, 2018 within the Chironominae. Amongst larvae of Chironomini with 6-segmented antenna, alternate Lauterborn organs and a well-demarcated ventromentum, those of Skusella are distinguishable only with caution due to insufficient reared associations. Unassociated pupal exuviae, tentatively belonging to three unknown new species, are described informally from China, as is a larval type from Africa. Range extensions include for S. freemani, with pupae (newly described here) from Nigeria and Cameroon, at least 5000 km from the type locality in South Africa. A wider distribution of S. subvittata in Australia and Asia is revealed by extensive pupal exuviae sampled from drift. PMID- 30313857 TI - New deltochiline (Coleoptera: Scarabaeidae: Scarabaeinae) taxa associated with hyrax dung in arid south western Namibia. AB - A survey of rock hyrax dung middens along the arid escarpment of southwest Namibia has filled a gap in the range shown by members of the Byrrhidium group of flightless dung beetles (Coleoptera: Scarabaeidae: Scarabaeinae) belonging to the tribe Deltochilini. The survey discovered a new genus and species, Ausmontins jacobsi new genus and species, and a further four new species in two previously described genera, Namakwanus kamfferi new species, Namakwanus minutus new species, Namaphilus nubibmontanus new species and Namaphilus tirasmontanus new species. They are described and illustrated in the present paper. This addition of new taxa raises the total complement of the Byrrhidium group to seven genera and 19 species. An updated key to all the known species is also provided. It is probable that further taxa await discovery. PMID- 30313858 TI - A survey of Agromyzidae (Diptera) reared from leafmines on Long Island, New York; host associations, distribution data, and the description and host association of a new species. AB - Leafmining Agromyzidae (Diptera) are both common and widespread, yet little is known of the host associations and distribution of most species. Here we report on a multi-year study of agromyzid diversity on Long Island, New York. We reared 45 species and identified for the first time a host plant for Agromyza masculina Sehgal and a likely host plant for Ophiomyia carolinensis Spencer. Of the 45 species, 17 are new records for New York State, for which fewer than 40 agromyzid species had previously been known. A new agromyzid species was reared from blotch mines on black-eyed Susan, Rudbeckia sp. and an undetermined yellow garden composite, both in the Asteraceae; this species is described here. PMID- 30313859 TI - Redescription of P. dorsipapillatus (von Marenzeller, 1893) and additional comments on the other species in the genus Pholoides Pruvot, 1895 (Polychaeta: Sigalionidae). AB - Pholoides Pruvot, 1895 is a species-poor genus of small scale-bearing polychaetes. Pholoides species are restricted to the continental shelf, living in sandy and muddy substrates, or on hard bottoms. During the DIVA 3 expedition grab samples were taken on four seamounts of the Meteor Seamount complex. One of the most common polychaetes in these samples was P. dorsipapillatus (von Marenzeller, 1893). Based on this material a comparison with the type material is undertaken leading to a re-description of P. dorsipapillatus. Diagnostic characters of all accepted Pholoides species were evaluated using light, scanning electron and confocal laser scanning microscopy. CLSM in particular proved to be an excellent tool for investigating these small species, and especially the type material. Blossom-like sensory buds, found at certain appendages of P. dorsipapillatus, could be an important diagnostic character to distinguish P. dorsipapillatus from other Pholoides species. Sequence information on three different gene fragments, the mitochondrial COI and 16S and the nuclear H3a, were obtained, and could serve for future phylogenetic and phylogeographic studies. PMID- 30313860 TI - First record and a new species of the fossil dragonfly genus Proinogomphus (Odonata: Liassogomphidae) from the Early Jurassic of Bascharage in the Grand Duchy of Luxembourg. AB - A new species of fossil dragonfly, Proinogomphus kreuzerorum sp. nov. (Liassogomphidae), is described from the Early Jurassic black shale of Bascharage in the Grand Duchy of Luxembourg, based on a very well-preserved isolated female hind wing. This genus was previously only known from the Liassic of Braunschweig region in Germany, and is here recorded for the first time for this fossil locality. The classification of the family Liassogomphidae Tillyard, 1935 and the genus Proinogomphus Cowley, 1942 is briefly discussed and the diagnosis of the latter is emended. PMID- 30313861 TI - Molecular phylogenetic analysis of the catfish species Auchenoglanis occidentalis (Valenciennes, 1840) (Pisces: Claroteidae) from Lake Turkana in East Africa: taxonomic implications. AB - Cytochrome c oxidase subunit I (COI) gene sequences of two specimens here recognized as Auchenoglanis occidentalis from Lake Turkana in the Ethiopian section were determined. A COI gene-based phylogenetic analysis was performed for these along with sequences of African catfish species from the family Clarotidae available in GenBank. Based on results of this analysis, it is concluded that (1) the currently identified A. occidentalis is a species complex that includes several distinct species; (2) the Niger River basin harbors two distinct species of Auchenoglanis, one of which occurs in Lake Turkana, as well as A. biscutatus; and (3) A. sacchii is likely a valid species, but it is not the endemic species of Lake Turkana. It is suggested here that species diversity of Auchenoglanis requires further study based on molecular and morphological evidence. PMID- 30313862 TI - Description of a new species of Eucynorta (Opiliones, Cosmetidae) from Cortes, Honduras. AB - A new species, Eucynorta rooneyi sp. nov. (Opiliones, Cosmetidae), is described from Parque Nacional Cusuco, Cortes, Honduras, a tropical montane cloud forest habitat. This is the thirty-fifth species of Eucynorta Roewer, 1912, and is characterized by the combination of three sexually dimorphic characters in males: enlarged chelicerae, some armature on femur III and IV, and swollen basitarsi on leg I. This new species is distinct from other Eucynorta species due to its unique pattern of yellow markings on area I of the dorsal scutum, and unarmed free tergites with line markings. PMID- 30313863 TI - Aphaenogaster gamagumayaa sp. nov.: the first troglobiotic ant from Japan (Hymenoptera: Formicidae: Myrmicinae). AB - Aphaenogaster gamagumayaa sp. nov., a new troglobiotic (true cave-dwelling) ant species, from a limestone cave on the island of Okinawa (Okinawa-jima), Ryukyu Archipelago, Japan is described. This is the first discovery of a troglobiotic ant in Japan and the second verified record worldwide. This species has only been found in a cave area with heavy guano deposits, and some worker ants were observed carrying guano. The evidence for categorizing this new species as troglobiont is discussed. PMID- 30313864 TI - A new species of Ledoyerella, L. kunensis sp. nov. (Amphipoda, Senticaudata, Kamakidae) from South West Africa. AB - A new species of kamakid amphipod, Ledoyerella kunensis sp. nov., is described from waters off Namibia and Angola. This is the first record of this genus in the Atlantic. The taxon is fully described and figured and is compared with the other known species of the genus occurring in waters of the Indian and Pacific Ocean. PMID- 30313865 TI - Checklist and taxonomic changes for Central and South American Philonthina (Coleoptera: Staphylinidae). AB - A checklist of all described species of Philonthina, a subtribe of the staphylinid tribe Staphylinini, known to occur in Central and South America (CASA) is presented. Included for each species, and for synonyms known from CASA, is a reference to the original description, type locality and type depository, and for each species the known distribution within and outside CASA. Type material was sought in the main European and American collections where it is deposited (BMNH, MNHUB, IRSNB and FMNH) and is summarized for all indigenous CASA species, with lectotypes designated for 16 names and confirmation of holotypes and prior designation of lectotypes when necessary. Based on recent phylogenetic work in Philonthina and our revision of types of CASA species of Philonthus Stephens, 1829 and Belonuchus Nordmann, 1837, some taxonomic changes are proposed. Thirty-one species of Philonthus are transferred to Belonuchus (16), Gabrius Stephens 1829 (14), and Bisnius Stephens 1829 (one) resulting in the following new combinations: B. abnormalis (Sharp 1885), B. celatus (Sharp 1885), B. corticalis (Sharp 1885), B. extremus (Sharp 1885), B. infimus (Sharp 1885), B. iteratus (Sharp 1887), B. latecinctus (Sharp 1885), B. lucilius (Sharp 1885), B. muticus (Sharp 1876), B. optatus (Sharp 1885), B. platypterus (Sharp 1885), B. rufiventris (Sharp 1887), B. rufocaudus (Sharp 1885), B. rufopygus (Sharp 1885), B. serraticornis (Sharp 1876), B. supernus (Herman 2001), G. approximans (Sharp 1885), G. armatipes (Sharp 1885), G. atricolor (Sharp 1885), G. championi (Sharp 1885), G. dampfi (Bernhauer 1929), G. elegans (Sharp 1885), G. forsterianus (Scheerpeltz 1960), G. misellus (Sharp 1885), G. nugax (Sharp 1885), G. ovaticeps (Sharp 1885), G. peruvianus (Bernhauer 1916), G. planulatus (Sharp 1885), G. rusticus (Sharp 1885), G. serpens (Sharp 1885) and Bi. subaeneipennis (Bernhauer 1916). Endeius nitidipennis Solier 1849 is transferred to Gabrius, resulting in the following new combination, G. nitidipennis (Solier 1849). Leptopeltus carchiensis Chani-Posse Asenjo 2013 is proposed as junior synonym of Philonthus divisus Sharp 1891, which is transferred to Leptopeltus Bernhauer 1906 resulting in a new combination: Leptopeltus divisus (Sharp 1891). Belonuchus penetrans Silvestri 1946 is transferred to Pridonius Blackwelder 1952 as a new combination. Lectotypes are designated for Atopocentrum mirabile Bernhauer 1906, Philonthus armatipes Sharp 1885, Ph. atricolor Sharp 1885, Ph. championi Sharp 1885, Ph. misellus Sharp 1885, Ph. planulatus Sharp 1885, Ph. rusticus Sharp 1885, Ph. serpens Sharp 1885, Ph. abnormalis Sharp 1885, Ph. celatus Sharp 1885, Ph. infimus Sharp 1885, Ph. latecinctus Sharp 1885, Ph. muticus Sharp 1876, Ph. platypterus Sharp 1885, Ph. rufocaudus Sharp 1885 and Ph. rufopygus Sharp 1885. Of the 543 currently known species of Philonthina reported from CASA, at least 14 are believed to be adventive from elsewhere, 56 may occur naturally elsewhere, and 473 (87%) are evidently endemic to this region. Of the 31 genera represented by these described species, 20 (65%) are endemic to CASA. One genus, Gabronthus Tottenham 1955, is adventive. However, the actual philonthine fauna of CASA will undoubtedly be much larger, and the generic composition highly modified, when the fauna is fully explored and studied within a phylogenetical framework. PMID- 30313866 TI - A historical review of the taxonomy and classification of Entocytheridae (Crustacea: Ostracoda: Podocopida). AB - Ostracods of the family Entocytheridae are obligate ectosymbionts of other crustaceans, including crayfishes, isopods, amphipods, and a species of freshwater crab. Entocytheridae, with five subfamilies, 35 genera, and 213 currently accepted species, represents one the most diverse groups of extant freshwater ostracods. Here, we present the results of an extensive literature review, documenting the often complex historical taxonomic activity and resulting classification of Entocytheridae. This overview highlights inconsistencies, errors, and additional sources of confusion that have been inadvertently introduced into the literature, a number of which have remained uncorrected for decades. Also provided is a comprehensive checklist of taxonomic nomenclature and a list of currently accepted names in Entocytheridae. PMID- 30313867 TI - The upper Miocene chitons of northwest France (Mollusca: Polyplacophora). AB - This study describes the chiton fauna (Mollusca, Polyplacophora) from the upper Miocene Tortonian deposits of northwest France previously known as the 'Redonian'. Twenty-two species were identified (represented by 9,380 valves), of which seven were already known, one is assigned at generic level (Leptochiton sp.) and 14 are described as new (Lepidopleurus pseudobenoisti sp. nov., L. gallicus sp. nov., Leptochiton parvus sp. nov., Leptochiton lateropustulosus sp. nov., Leptochiton renauleauensis sp. nov., Hanleya sancticlementensis sp. nov., H. sossoi sp. nov., Ischnochiton nitidum sp. nov., Callochiton pouweri sp. nov., Rhyssoplax assurrectum sp. nov., Tonicella redoniensis sp. nov., Acanthochitona globosa sp. nov., A. andegavensis sp. nov. and A. chauvereauensis sp. nov.). Regarding the stratigraphic distribution of the 21 taxa identified, 15 are restricted to the Miocene, the remaining six are extant and are distributed in the Atlantic and Mediterranean (Lepidopleurus cajetanus, Leptochiton algesirensis, Hanleya hanleyi, Ischnochiton rissoi, Callochiton doriae and Rhyssoplax corallinus. The number of new species is high (14 out of 22), possibly explained in part by the fact that this is the first description of the northwestern French upper Miocene chiton fauna - true endemicity is less likely in the light of scarce sampling. PMID- 30313868 TI - Three new Canuellidae (Copepoda: Canuelloida) from Iran. AB - A survey of copepods from intertidal zone of the Persian Gulf and the Gulf of Oman resulted in discovery of three new species belonging to the family Canuellidae Lang, 1944. This work contributes to the final aim to describe meiobenthic copepods from this region and is the first description of meiobenthic copepods from Iranian coastline. The new species belong to the genera Brianola Monard, 1926, Canuella, T. A. Scott, 1893, and Scottolana Huys, 2009. Compared to other congeners, Brianola haliensis sp. nov. is unique in the armature of the first leg, number of segments and setation of the antennary endopod and exopod. Canuella persica sp. nov. is easily distinguishable from its congeners by the shape of furcal rami and male genitalia. Scottolana gomezi sp. nov. is assigned to the longipes-group by the presence of two and three post-genital somites in the female and male, respectively. It is closely related to S. geei (Mu Huys, 2004) recorded from the Bohai Sea, China, but can be distinguished by its eight segmented antennary exopod, mouthparts setation, and shape of the furcal rami. PMID- 30313869 TI - A new bent-toed gecko (Squamata: Gekkonidae: Cyrtodactylus) from the Western Himalayas, Himachal Pradesh, India. AB - We describe a new species of the gekkonid genus Cyrtodactylus based on a series of six specimens from the Chamba Valley in the Western Himalayas, Himachal Pradesh state, India. Cyrtodactylus chamba sp. nov. is a member of the subgenus Siwaligekko and can be diagnosed from congeners in the Western Himalayas by a combination of its small size (snout to vent length up to 63 mm), a continuous series of five precloacal pores on males, 13-15 rows of dorsal tubercles, 33-43 scales across the belly, no regular series of enlarged subcaudals, and a dorsal colour pattern of 5-7 irregular, broad, dark bands with much narrower, light interspaces. The new species is 14% divergent in ND2 sequence from the most similar sampled congener, Cyrtodactylus (Siwaligekko) himalayanus from Jammu and Kashmir, and is 0.5-1.1% divergent in nuclear sequence data from sampled Siwaligekko species. Many more undiscovered Cyrtodactylus species probably exist across the Himalayas at elevations below ~2000 m; basic field surveys for reptiles and other poorly known groups and examination of existing material should be a priority if we are to appreciate the true diversity of this spectacular mountainous landscape. PMID- 30313870 TI - A study of the Iranian species of Choeras Mason (Hymenoptera: Braconidae: Microgastrinae), with the description of a new species. AB - Sampling surveys were conducted in various regions of SE to West of Iran to collect the Microgastrinae specimens during 2013-2016. Reliable diagnostic morphological characters were used for comparing and identification of variable specimens. Four species of Choeras Mason, 1981 (Braconidae: Microgastrinae) from Iran are revised; three are illustrated, of which one is described as new species from SE and W Iran: C. taftanensis Ghafouri Moghaddam van Achterberg sp. n. Occurrence of C. dorsalis in Egypt, Jordan and Malta, C. tedellae in Bulgaria and C. tiro in Israel and Spain are also first recorded. PMID- 30313871 TI - A new Cyrtodactylus Gray, 1827 (Squamata, Gekkonidae) from the Shan Hills and the biogeography of Bent-toed Geckos from eastern Myanmar. AB - A phylogenetic taxonomic analysis indicates that a newly discovered population of Cyrtodactylus from the vicinity of Ywangan Town in the Shan Hills, Shan State, Myanmar is a new species (C. ywanganensis sp. nov.) and the earliest diverging member of the linnwayensis group within the previously defined Indochinese clade. The DIVALIKE+J model of a BioGeoBEARS biogeographic analysis indicates that the Indochinese clade evolved in the Shan Hills and Salween Basin of eastern Myanmar and dispersed into Indochina on at least three separate occasions from 18.6-13.4 mya. Once there, uplift of the Tenasserim Mountains and Thai Highlands created the intermedius group, the oldhami group, and C. tigroides of western and southern Thailand which form sister lineages to the linnwayensis group, yathepyanensis group, and the sinyineensis group, respectively, of eastern Myanmar. Diverging lineages within the Indochinese clade highlight the importance of the Thai Highlands and Tenasserim Mountains in that group's evolution and speciation. The discovery of C. ywanganensis sp. nov. in karstic habitats in the Shan Hills continues to underscore the unrealized karst-associated herpetological diversity of this vast, relatively unexplored, upland region and the need for additional field studies. PMID- 30313872 TI - A new species of Phrynopus from the northeastern Andes of Peru, its phylogenetic position, and notes on the relationships of Holoadeninae (Anura: Craugastoridae). AB - We report the discovery of a geographically disjunct and morphologically distinctive species of direct-developing frog of the genus Phrynopus (Phrynopus mariellaleo sp. nov.) that changes considerably our understanding of the distribution of species in this Andean genus. The type locality lies on a subcordillera (Cerro de Campanario area) of the extreme northeastern portion of the Cordillera Central of Peru, on the headwaters of the Mayo River, Amazonas department, at 2575 m asl (6 degrees 6'42.9''S, 77 degrees 26'24''W). This area is situated 170 km to the NE from the northernmost record of Phrynopus known so far. Molecular phylogenetic analyses of a supermatrix (13269 aligned positions of gene sequences of four mitochondrial and ten nuclear genes) of 105 terminals (representing 93 named and 9 unnamed species of Holoadeninae) recover this new species as the sister to Phrynopus auriculatus, a species occurring more than 500 km south of the type locality of the new species. Both Phrynopus auriculatus and the new species occur at moderate elevations on the easternmost stretches of the Andean subcordilleras; their sister relationship point to a potentially broader distribution of species of Phrynopus along the poorly sampled intervening areas of the eastern hills of the Andes. The new species has a conspicuous and visibly large tympanic membrane (a trait rare in the clade), outlined by a marked bold black supratympanic fold and a black facial mask, and exhibits conspicuous dorsolateral, scapular, and middorsal Y-shaped folds. Specimens were found on the forest floor-a rocky substrate covered by a thick layer of leaf litter, moss and roots-of a primary humid montane forest (Yungas ecoregion) with scattered patches of bamboo (Chusquea spp.). Our phylogenetic analyses corroborate the monophyly of all Holoadeninae genera, including Euparkerella and Psychrophrynella, genera for which tests of monophyly were pending, and corroborates Hypodactylus nigrovittatus as part of Hypodactylus and sister to a clade that includes H. brunneus, H. elassodiscus and H. peraccai. PMID- 30313873 TI - New species, redescriptions, and new records on Mexican and Central American Cerambycidae (Coleoptera). AB - Three new species are described: Compsibidion vandenberghei (Cerambycinae, Neoibidionini), from Nicaragua; Heterachthes zapopana (Cerambycinae, Neoibidionini), from Mexico; and Phaea lingafelteri (Lamiinae, Tetraopini), from Nicaragua. Phaea beierli Chemsak, 1999, and P. kellyae Chemsak, 1999 are redescribed. Pirangoclytus latithorax (Martins Galileo, 2008) (Cerambycinae, Clytini), and Euryestola cribrata (Bates, 1881) (Lamiinae, Calliini) are newly recorded for Nicaragua. PMID- 30313874 TI - Contributions to the study of Idiocerinae (Homoptera: Auchenorrhyncha: Cicadellidae) of Central Asia with notes on synonymy. AB - Investigation of morphological variability in three species of Central-Asiatic Idiocerinae showed that small differences in the shape of male genitalia and abdominal apodemes are not species-specific traits. Based on these data, the following synonymies are established: Populicerus ambigenus (Dubovskiy, 1966) = P. tenellus (Dubovskiy, 1966), syn. n., Idiocerus bilituratus Dubovskiy, 1966 = I. bipustulatus Mityaev, 1967, syn. n.; the synonymy Sahlbergotettix salicicola (Flor, 1861) = S. mesasiaticus Dubovskiy, 1966 = Idiocerus fulvius Dlabola, 1967 established by Anufriev (1978) is confirmed. Illustrated descriptions of three species considered and data on their male calling signals, biology, and distribution are provided. PMID- 30313875 TI - A record of Notostraca on Socotra Island and the importance of local conservation of the habitat. AB - The first record of Triops Schrank, 1803 (Crustacea: Branchiopoda: Notostraca: Triopsidae) from Socotra Island is presented herein. Besides Madagascar and the current note, the genus is unknown from Indian Ocean islands. A brief morphological exploration indicates that the Socotran Triops cf. granarius (Lucas, 1864) (trachyaspis form) belongs to an African clade within this widespread Old World species complex and not to T. granarius s.str. from East Asia. Detailed morphological and molecular revision of the poorly studied Middle Eastern and Northern African populations in comparison to East Asian populations are needed to understand this group and the phylogenetic position and status of the Socotran tadpole shrimp. Found in a single locality (the archeological site Eriosh) in the rapidly changing coastal plains on Socotra, together with other large branchiopods (endemic Anostraca and unidentified Spinicaudata), the insular Triops population and the regionally neglected temporary lake habitat deserve a special protection status from a biodiversity conservation perspective. Triops cf. granarius is hereby suggested as a local flagship species for the conservation of temporary pool habitats on the island. PMID- 30313876 TI - A new species of the genus Phytocoris (Hemiptera: Heteroptera: Miridae: Mirinae) from western Iran. AB - A new species, Phytocoris (Eckerleinius) hawramanicum sp. nov is described from Iran. A revised dichotomous key to the species of subgenus Eckerleinius Wagner known in Iran and adjacent regions, illustrations of male genitalia and male habitus photographs of this new taxon are provided. Diagnosis of the new species is based on a comparison with other congeneric found from Iran and adjacent countries. The type specimens were deposited in the insect collection of the University of Guilan, Rasht, Iran. PMID- 30313877 TI - Notes on the shrimp genus Palaemon Weber, 1795 (Crustacea, Decapoda, Palaemonidae) and related genera from Taiwan. AB - The shrimp genus Palaemon Weber, 1795 and its related genera in Taiwan are reviewed based on newly collected specimens, whilst older records are critically reviewed. Five genera and 11 species are now known to occur in Taiwan, although there are no recent records for Palaemon modestus (Heller, 1862), which could be nationally extinct. The records of P. debilis Dana, 1852 and Nematopalaemon tenuipes (Henderson, 1893) in Taiwan are confirmed. Three genera, namely Brachycarpus Spence Bate, 1888, Leander Desmarest, 1849 and Leandrites Holthuis, 1950, each with one species are reported for the first time from Taiwan. PMID- 30313878 TI - A new species of Aschistophleps from Thailand and Laos, with a new generic synonymy (Lepidoptera, Sesiidae). AB - We here describe a new clearwing moth species, Aschistophleps ignisquamulata sp. nov., from northern Thailand and Laos. This striking new species differs from all other species of Osminiini in both external appearance and genitalia and displays characteristics that indicate that Pyrophleps Arita Gorbunov is a junior subjective synonym of Aschistophleps (syn. nov.). PMID- 30313879 TI - A remarkable new species of Sinotilla Lelej (Hymenoptera: Mutillidae: Smicromyrmini) from Taiwan and an overview of color diversity in East Asian mutillid females. AB - A remarkable new species, Sinotilla nigrothoracica sp. nov., is described and illustrated based on females from Taiwan. This new species is characteristic in having indistinct hypostomal teeth and a black mesosoma with the lateral margins strongly convergent posteriorly. An overview of female color patterns in the far eastern Palaearctic and eastern Oriental regions is also presented. PMID- 30313880 TI - Definition of the Lonchaea polyhamata species-group (Diptera, Lonchaeidae) with a description of new species. AB - The Lonchaea polyhamata McAlpine, 1964 species-group is defined and five new species within it are described from the Afrotropical region namely, L. dama MacGowan sp. nov., L. mbeya MacGowan sp. nov., L. njombe MacGowan sp. nov., L. taita MacGowan sp. nov. and L. zomba MacGowan sp. nov. With the inclusion of the previously described L. polyhamata McAlpine, 1964 and L. teratosa McAlpine, 1964 the species group now comprises seven species, all from the Afrotropics.Afrotropical Lonchaea species which share character of 2 katepisternal setae with the L. polyhamata species group are also assessed. These include three new species namely L. aberdare MacGowan sp. nov., L. klynebergi MacGowan sp. nov. and L. muhavura MacGowan sp. nov. The male terminalia of the previously described L. dichaeta McAlpine, 1964 which also belongs to this wider group are illustrated for the first time.The male genitalia of all species are illustrated and a key to males of Afrotropical Lonchaea with two katepisternal setae is provided. PMID- 30313881 TI - Studies on the genus Aeolothrips (Thysanoptera: Aeolothripidae) in Iran, with a key to species. AB - An illustrated key is provided to 27 species of Aeolothrips Haliday recorded from Iran, including two new species: A. persiae sp. n. from Chenopodium album [Chenopodiaceae] and A. tatari sp. n. from Sinapis arvensis [Brassicaceae]. Variation among populations of A. tenuicornis from Iran, Europe and Mediterranean area is discussed. A. neyrizi is synonymized with A. flaviventer. An update checklist of Iranian Aeolothrips is provided. PMID- 30313882 TI - Endophallus structure: a promising tool for cryptic species identification in Timarcha Samouelle, 1819 (Coleoptera: Chrysomelidae: Chrysomelinae). AB - Contrary to the subtle differences of habitus found between many species of Timarcha their internal sacs of male genitalia have shown a remarkable variation. Thirty-two Palaearctic taxa, mostly from the Iberian Peninsula, have been analyzed for this trait, which can be used for species diagnosis and also for establishing species groups of close relatedness in agreement mainly with genetic analyses. According with this trait, new synonymies and taxonomical changes are proposed: T. intermedia carmelenae Petitpierre, 2013 stat. nov., T. intermedia kiesenwetteri Kraatz, 1879 stat. nov., T. intermedia lugens Rosenhauer, 1856 stat. nov.; T. sinuatocollis monserratensis Bechyne, 1962 comb. nov.; T. piochardi Fairmaire, 1874 stat. nov.; T. tortosensis Bechyne, 1948 stat. nov.; T. perezii Fairmaire, 1884 syn. nov. and T. asturiensis Kraatz, 1879 syn. nov. = T. geniculata Germar, 1824. Furthermore, the endophalli of T. hummeli, T. carmelenae, T. kiesenwetteri, T. lugens, T. tenebricosa, T. parvicollis, T. insparsa, T. marginicollis, T. balearica, T. strangulata spp., T. calceata, T. scabripennis, T. espanoli, T. monticola, T. cyanescens, T. interstitialis, T. aurichalcea, T. oblongula, T. hispanica and T. granadensis are illustrated. One new species, T. aitanae sp. nov. is described. PMID- 30313883 TI - New genus, species, redescription, and new rank in Cerambycinae (Coleoptera, Cerambycidae). AB - Two new species of Cerambycidae are described from Costa Rica: Cosmisoma luteoviridis sp. nov. (Rhopalophorini) and Katerinaella costaricensis gen. nov. and sp. nov. (Rhinotragini). Trachyderes (Dendrobias) Dupont, 1834 is restored to genus level. Male specimens of Dendrobias steinhauseni (Hudepohl, 1987) from Nicaragua and Costa Rica are described and illustrated. The relationship of D. steinhauseni with other Dendrobias species is discussed. PMID- 30313884 TI - A new species and two new records of Rhamphothrips (Thysanoptera: Thripidae) from Southwestern China. AB - Rhamphothrips dalbergiae sp.n. is described, from the leaves of Dalbergia sp. in Southwestern China. This is the fourth bicoloured species of Rhamphothrips. Tergites VII-VIII of males have discal setae S1 and S2 long and prominent. Two species described from India, R. aureus (Ananthakrishnan) and R. santokhi Kulshretha Vijay Veer, are reported newly from China. PMID- 30313885 TI - Revision of the genus Lamprima Latreille, 1804 (Coleoptera: Lucanidae). AB - The genus Lamprima Latreille, 1804 (Coleoptera: Lucanidae: Lampriminae: Lamprimini), is revised. Five species are recognised: one in New Guinea (L. adolphinae (Gestro, 1875)), two on isolated western Pacific islands (L. aenea Fabricius, 1792: Norfolk Island; L. insularis W.J. Macleay, 1885: Lord Howe Island), one in northeastern New South Wales (L. imberbis Carter, 1926) and a common widespread species in eastern and southern Australia, L. aurata Latreille, 1817. Lamprima aurata varies considerably morphologically and many of the different forms encompassed by this variation have been described as species. Our study of morphology does not support this classification. Therefore, Lamprima aurata is designated a senior synonym of the following 24 names: L. cuprea Latreille, 1817; L. latreillii W.S. MacLeay, 1819 (new synonym); L. pygmaea W.S. MacLeay, 1819 (new synonym); L. fulgida Boisduval, 1835; L. micardi Reiche, 1841 (new synonym); L. rutilans Erichson, 1842; L. splendens Erichson, 1842; L. viridis Erichson, 1842; L. nigricollis Hope in Westwood, 1845 (new synonym); L. purpurascens Hope in Westwood, 1845 (new synonym); L. sumptuosa Hope in Westwood, 1845 (new synonym); L. tasmaniae Hope in Westwood, 1845 (new synonym); L. varians Burmeister, 1847 (new synonym); L. cultridens Burmeister, 1847 (new synonym); L. amplicollis Thomson, 1862 (new synonym); L. krefftii W.J. MacLeay, 1871 (new synonym); L. violacea W.J. Macleay, 1885 (new synonym); L. mandibularis W.J. Macleay, 1885 (new synonym); L. sericea W..J Macleay, 1885 (new synonym); L.nigripennis W.J. Macleay, 1885 (new synonym); L. minima W.J. Macleay, 1885 (new synonym); L. mariae Lea, 1910; L. coerulea Boileau, 1913 (new synonym); L. insularis Boileau, 1913 (new synonym). Lamprima adolphinae is a senior synonym of L. bohni (Darge Seguy, 1953) (new synonym). Lamprima schreibersi Hope in Westwood, 1845, is an unnecessary nomen novum for L. aenea redescribed by Schreibers in 1802 from the same material as Fabricius, and therefore an objective synonym of L. aenea. Lamprima puncticollis Dejean, 1833, L. coerulea Hope in Westwood, 1845, and L. insularis Hope in Westwood, 1845, are nomina nuda, the last two names first made available by Boileau in 1913. The five Lamprima species are redescribed and recommendations made for their conservation. Type specimens of the species of Lamprima described by William Sharpe MacLeay and William John Macleay are illustrated for the first time. Lectotypes are designated for Lamprima insularis, L. latreillii, L. latreillii sericea, and L. mandibularis. PMID- 30313886 TI - Review of the leafhopper genus Anufrievia Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini). AB - General characteristics of Anufrievia Dworakowska and a key to the species from China and Thailand are provided. Twenty-one new species, Anufrievia adaucta, A. arcuata, A. curva, A. expensa, A. falcata, A. forcipiformis, A. fusina, A. jinghongensis, A. liubanus, A. parisakazu, A. plana, A. qinlingensis, A. quadrata, A. sphenoides, A. subapicifixa, A. subdentata, A. sufflata, A. symmetrica, A. triangulata, A. triprocessa and A. wolongensis are described. Four species are newly recorded from China: A. akazu (Matsumura), A. badjawae Dworakowska, A. bauhinicola Dworakowska Viraktamath and A. zelta Dworakowska. A. badjawae is also a new record to Thailand. PMID- 30313887 TI - Description of a new alpheid shrimp, Automate isabelae sp. nov. (Decapoda, Caridea, Alpheidae) found in fish stomach contents of the lane snapper Lutjanus synagris (Linnaeus, 1758), from the west coast of Florida, Gulf of Mexico. AB - A new species of caridean shrimp of the family Alpheidae, Automate isabelae sp. nov., found in stomach analysis contents of the lane snapper Lutjanus synagris (Linnaeus, 1758), from the Keys and SW coast of Florida, Gulf of Mexico, is described. The abdomen and portions of the cephalic appendages were damaged in holotype, but remainder of the body and the chelipeds, whith the most important diagnostic characters are in decent or perfect condition, the description was further supplemented based on intact morphological parts of the paratypes. The presence of tubercles on the dorsal and ventral margins of the major chela palm, shows this new species to be related to the eastern Pacific Automate rugosa Coutiere, 1902. Both congeners can be easily discriminated by the proportions and shape of the third maxilliped, the proportions and ornamentation of the carpus, merus, and chela of the major cheliped, the ventral seta of the carpus of the minor cheliped, the presence of a distoventral spine on the propodi of third and fourth pereopods, the armature of dorsal surface of telson, and their geographical distribution. The description of this new species increases the number of worldwide valid species known of the genus Automate to 12. PMID- 30313888 TI - Description of Neoxantholinus koghianus sp. n. and its larva from New Caledonia (Coleoptera, Staphylinidae, Xantholinini). AB - Neoxantholinus koghianus sp. n. (Coleoptera, Staphylinidae, Xantholinini) and the detailed external structure of its late (L2-3) and early (L1) larval instars from New Caledonia are described and illustrated. The morphological differences between L1 and L2-3 of N. koghianus sp. n. involve four characters. Diagnostic larval characters for the genus Neoxantholinus are given for the first time. PMID- 30313889 TI - The taxonomic status of Myotis aelleni Baud, 1979 (Chiroptera, Vespertilionidae). AB - Myotis aelleni Baud, 1979 was described based on a large series from Chubut, Argentina, and is known only from the type locality and Rio Negro, also in Argentina. According to the original description, M. aelleni is closest morphologically to M. chiloensis (Waterhouse, 1840), but can be distinguished based on the tricolored dorsal hairs and skull size and shape. The taxonomic status of M. aelleni has been questioned but the species is still treated as valid. Based on qualitative and quantitative analyses of the type series of M. aelleni, and series of M. chiloensis, including the neotype, we recognize M. aelleni as a junior synonym of M. chiloensis. M. aelleni and M. chiloensis have bicolor dorsal hairs and cannot be distinguished on the basis of the skull size and shape. After synonymy, M. chiloensis occur from Central Chile and western Argentina to central Patagonia and Tierra del Fuego archipelago. Twenty-one species of Myotis occur in South America, including Trinidad and Tobago. PMID- 30313890 TI - Description of the female of Colocharis hungi Torrens (Hymenoptera, Eucharitidae) and identification key for the species of Colocharis. AB - The female of Colocharis hungi Torrens (Hymenoptera: Eucharitidae) is newly described, detailing the characters that distinguish this species. In addition, we provide images and comments for C. hungi, diagnoses for all species of Colocharis Heraty, a key to species, and a distribution map for the species. PMID- 30313891 TI - Integrative taxonomy identifies Macrobiotus papei, a new tardigrade species of the Macrobiotus hufelandi complex (Eutardigrada: Macrobiotidae) from the Udzungwa Mountains National Park (Tanzania). AB - In this paper we describe Macrobiotus papei, a new species of the Macrobiotus hufelandi complex from the Udzungwa Mountains National Park in Tanzania. Our research included the traditional morphology-based taxonomic analysis, supported by morphometrics, light and scanning electron microscopy imaging, as well as analysis of nucleotide sequences of three nuclear (18S rRNA, 28S rRNA, ITS-2) and one mitochondrial (COI) marker. The molecular sequences provided a more accurate description and independent verification of the taxonomic status of M. papei sp. nov. Such integrative approach requires a considerable number of individuals and eggs, which we obtained by establishing a laboratory culture of the new species. Our analyses revealed that M. papei sp. nov., by having the flexible filaments on the terminal discs of the egg processes, is most similar to Macrobiotus paulinae Stec et al., 2015 from Africa and Macrobiotus polypiformis Roszkowska et al., 2017 from South America. However, the new species can be easily distinguished from both these species by patches of cuticular granulation on the external and internal surface of legs I-III (only external patches present in in M. paulinae and M. polypiformis), two separate lateral transversal ridges with a rounded median tooth between instead of a single thin ventral transverse ridge in the third band of teeth in the oral cavity, smooth terminal discs and filaments on the egg processes (terminal discs and filaments covered by aggregations of small microgranules in M. paulinae and M. polypiformis), and by some morphometric characters of both adults and eggs. PMID- 30313892 TI - New species of Acanthocinini Blanchard, 1845 (Coleoptera, Cerambycidae) from Rondonia state, Brazil and notes on some genera. AB - Three new species of Acanthocinini (Coleoptera, Cerambycidae) from Rondonia State, Brazil, are described and illustrated: Leptostylus obrienorum, Nyssodrysina maculosa and Urgleptes curvatum. We also present a brief generic discussion about these genera. PMID- 30313893 TI - A new species of bandy-bandy (Vermicella: Serpentes: Elapidae) from the Weipa region, Cape York, Australia. AB - Bandy-bandies (genus Vermicella) are small (50-100cm) black and white burrowing elapids with a highly specialised diet of blindsnakes (Typhlopidae). There are currently 5 recognized species in the genus, all located in Australia, with Vermicella annulata the most encountered species with the largest distribution. Morphological and mitochondrial analyses of specimens collected from the Weipa area, Cape York, Queensland reveal the existence of a new species, which we describe as Vermicella parscauda sp. nov. Mitochondrial DNA analysis (16S and ND4) and external morphological characteristics indicate that the closest relatives of the new species are not V. annulata, which also occurs on Cape York, but rather species from Western Australia and the Northern Territory (V. intermedia and V. multifasciata) which, like V. parscauda, occupy monsoon habitats. Internasal scales are present in V. parscauda sp. nov., similar to V. annulata, but V. intermedia and V. multifasciata do not have nasal scales. V. parscauda sp. nov. has 55-94 black dorsal bands and mottled or black ventral scales terminating approximately 2/3rds of the body into formed black rings, suggesting that hyper-banding is a characteristic of the tropical monsoon snakes (V. intermedia, V. multifasciata and V. parscauda). The confined locality, potential habitat disruption due to mining activities, and scarcity of specimens indicates an urgent conservation concern for this species. PMID- 30313894 TI - The genus Tarsonemus Canestrini and Fanzago, 1876 (Acari: Heterostigmatina: Tarsonemidae) in East Azerbaijan, Iran, with a description of T. lenticulatus sp. nov. and re-description of T. annotatus Livshits, Mitrofanov and Sharonov, 1979. AB - The tarsonemid mites from soil and plants were explored in a faunistic study of East Azerbaijan province, Northwestern Iran. Our investigation revealed 22 species of the genus Tarsonemus Canestrini and Fanzago, 1876, and its nominative subgenus, including Tarsonemus lenticulatus sp. nov., which is described and illustrated herewith. New records for the fauna of Asia are: Tarsonemus bognari Nemestothy and Mahunka, 1981, T. oncodes Kaliszewski, 1993, T. ravus Kaliszewski, 1993, T. saccatus Livshitz, Mitrofanov and Sharonov, 1979, T. scharschmidti Mahunka, 1970, T. varsoviensis Kaliszewski, 1993 and T. violae Schaarschmidt, 1960. New records for the mite fauna of Western Asia are: Tarsonemus bifurcatus Schaarschmidt, 1959, T. floricolus Canestrini and Fanzago, 1876, T. lacustris Schaarschmidt, 1959, and T. virgineus Suski, 1969; and T. stammeri Schaarschmidt, 1959 is newly recorded from Iran. Re-description and illustrations of Tarsonemus annotatus Livshits, Mitrofanov and Sharonov, 1979 are provided. The incidence of all species found across the examined area and substrates is briefly discussed. A key to females of the genus Tarsonemus in East Azerbaijan is provided. PMID- 30313895 TI - A new species and new record of Polycystididae (Rhabdocoela: Kalyptorhynchia) from China. AB - One new species and one newly recorded species of Polycystididae from China, Paulodora sinensis n. sp. and Polycystis ali Schockaert, 1982, were described based on comprehensive morphological and molecular analyses. In Paulodora sinensis n. sp., the stylet is double-walled and is composed of a funnel-shaped proximal part and a spiral distal part, while the outer stylet forms a minor fold proximally. In Polycystis ali Schockaert, 1982, the stylet is also double-walled with a funnel-shaped proximal part. However, the collar-shaped distal part is partially concave and forms a jagged edge. The concatenated 18S rDNA and 28S rDNA phylogenetic analysis supports the establishment of the new species. Besides, based on the morphology of stylet, we have made detailed categorization among the recorded species within these two genera. PMID- 30313896 TI - The lygaeoid bug family Heterogastridae (Hemiptera: Heteroptera: Lygaeoidea) from Laos and Thailand, with descriptions of three new species. AB - Laotian and Thai species of the Heterogastridae Stal, 1872 are revised taxonomically. Eight species are recognized, including three new species; Sadoletus laosensis and S. subpellucidus from Laos, and S. melasmus from Thailand. A key to the species in Laos and Thailand is provided. PMID- 30313897 TI - Geographic variation in quantitative skull traits and systematic of southern populations of the leaf-eared mice of the Phyllotis xanthopygus complex (Cricetidae, Phyllotini) in southern South America. AB - The leaf-eared mice of the genus Phyllotis (Cricetidae, Phyllotini) encompasses at least 20 species of medium-sized Neotropical rodents mostly distributed throughout the Andean region. Its limits and contents were reviewed by several authors, based both on morphological and molecular data. However, no integrative approaches were conducted based on large samples of individuals with a wide geographical coverage. The purposes of this paper are: (i) to evaluate species limits; and (ii) to test the congruence between molecular and quantitative morphological evidences within the Phyllotis xanthopygus complex in southern South America. Our results questioned the specific status of P. bonariensis, a geographically isolated form that was either considered as a valid species or as a synonym of P. xanthopygus. Quantitative morphological (size and shape of the skull) and molecular data linked P. bonariensis with populations from central Argentina traditionally referred as P. xanthopygus vaccarum. Individuals belonging to populations from southern Argentina and Chile (P. x. xanthopygus) were remarkably homogeneous in their skull morphology, showing a subtle to non existent differentiation from those of north-central and west-central Argentina referred to P. x. vaccarum. We found some incongruence between groups inferred from morphological (this work) and mitochondrial DNA results of previous studies. This is the case of the north-central and west-central populations, where morphological traits do not show the strong differentiation detected by molecular characters. Our results highlight the need for integrative taxonomic studies, not only to delimitate taxonomic units but also for a better and more comprehensive understanding of population variability and differentiation. PMID- 30313898 TI - The myth of monophagy in Paralobesia (Lepidoptera: Tortricidae)? A new species feeding on Cypripedium reginae (Orchidaceae). AB - The genus Paralobesia Obraztsov, 1953 is found primarily in eastern North America and consists of 18 described and several undescribed species. Prior to 1900, all North American Paralobesia were assumed to be P. viteana (Clemens). However, rearing experiments by William Kearfott in the early 1900s suggested that species of Paralobesia were monophagous and could be separated by host. Recently, a species of Paralobesia was reared from showy lady's slipper, Cypripedium reginae Walter (Orchidaceae), during a study of two populations of this orchid in eastern Ontario and southwestern Quebec. Although originally assumed to be P. cypripediana (Forbes), which was described from specimens reared from Cypripedium in Manitoba, DNA barcode data and genital morphology confirmed that this was a new species similar to P. cypripediana and P. monotropana (Heinrich). Herein, we describe P. marilynae, sp. n., and provide specifics of its discovery and life history. Rearing records indicate that Paralobesia can span the range from strictly monophagous to polyphagous, even for very similar species with similar feeding habits, and that host records should be combined with morphological and molecular data when circumscribing species in this genus. This work is part of a complete systematic revision of Paralobesia currently in progress. PMID- 30313899 TI - A taxonomic review of the genus Callilanguria Crotch, 1876 (Coleoptera: Erotylidae: Languriinae). AB - A worldwide review of the genus Callilanguria is presented. Three new species are described: C. weiweii Huang Yang, sp. nov. from Sabah, Malaysia; C. helleri Huang Yang, sp. nov. from Panay, the Philippines; and C. nigripes Huang Yang, sp. nov. from Samar Island, the Philippines. Callilanguria scrupulosa Heller, 1918 is transferred to the genus Doubledaya. The other species are C. eximia Fowler, 1885; C. gorhami Villiers, 1945; C. asymmetrica Heller, 1900; C. ruficeps Achard, 1923; C. milloti Villiers, 1945; C. stenosoma (Harold, 1879); C. flaviventris Fowler, 1886; C. wallacii Crotch, 1876; and C. luzonica Crotch, 1876. In total, twelve species are recognized in the genus Callilanguria, and a key to the described species of the genus is provided. PMID- 30313900 TI - Four new species of the genus Eudarcia Clemens, 1880 (Lepidoptera: Meessiidae) from Crimea. AB - Four species of the genus Eudarcia are described as new from Crimea: E. ajpetrica sp. nov., E. kimmeriella sp. nov., E. rutjani sp. nov. and E. zagulajevi sp. nov. All newly discovered species belong to the palanfreella-species group. The identification key, based on external and genitalia characters for the Eudarcia species from Crimea, is provided. PMID- 30313901 TI - Two new species of flattie spiders (Araneae: Selenopidae) and descriptions of undescribed males from the Caribbean. AB - Two new species of Selenops, S. anacaona sp. nov. (?) and S. caonabo sp. nov. (?), are described from the Dominican Republic on the Caribbean island of Hispaniola. These two new species increase the number of endemic Selenops on Hispaniola to 13, surpassing Cuba, which currently has 11 endemic species. Additionally, the male of S. pensilis Muma, 1953 from Hispaniola is described, as well as the male of S. petrunkevitchi Alayon, 2003 from Jamaica. Full distribution records are given for the new species and the newly described males, and new records are provided for the following species: S. aequalis Franganillo, 1935, S. bocacandensis Crews, 2011, S. candidus Muma, 1953, S. micropalpus Muma, 1953, S. morro Crews, 2011, S. simius Muma, 1953, S. souliga Crews, 2011, and S. submaculosus Bryant, 1940. PMID- 30313902 TI - Two new species of Atopophlebia Flowers, 1980 (Ephemeroptera, Leptophlebiidae) from Colombia. AB - Atopophlebia pacis sp. nov. and Atopophlebia caldasi sp. nov. are newly described based on material from Colombia, Putumayo and Caldas, respectively. Both species are known from nymphs and alate stages, male imago for A. pacis, male subimago, female imago and eggs for A. caldasi. This is the first description of eggs of the genus. The following characteristics are useful for distinguishing the males of the new species: A. pacis sp. nov., 1) eyes meeting on meson of head; 2) fore wings hyaline, veins yellow (Fig. 2); 3) fore tibia completely tinged with black; 4) abdominal segments yellowish, terga VIII with conspicuous triangular anterolateral black mark (Fig. 1); 5) apical projection of penis lobe short; A. caldasi sp. nov., 1) eyes meeting on meson of head; 2) fore tibia completely tinged with black; 3) abdominal segments orange, posterior margin of all terga tinged with black, black bands broader on terga V to VIII. Egg of A. caldasi is characterized by presenting a prismatic shape with longitudinal chorionic depressions at the sides and concave polar regions. An updated key for male adults of Atopophlebia is presented. PMID- 30313903 TI - A revision of the genus Bromeloecia Spuler (Diptera: Sphaeroceridae: Limosininae). AB - The genus Bromeloecia Spuler is revised, including 20 new and one previously described species. A key to species is provided, and species-level phylogenetic relationships are assessed on the basis of morphological characters. The B. winnemana species group, a mainly Nearctic species group characterized by ornamental processes on the hind tarsus, is excluded from the revision but is diagnosed, included in the key and considered within the phylogeny of Bromeloecia as an operational taxonomic unit. B. bromeliarum (Knab and Malloch) is redescribed and the following new species are described: B. abundantia, B. aculatus, B. aurita, B. balaena, B. brachium, B. cercarcuata, B. coniclunis, B. diabolunguia, B. ephippium, B. fractacincta, B. magna, B. peloris, B. pinna, B. ponsa, B. ramus, B. robustora, B. spathicercus, B. triunguia, B. undulata, and B. wolverinei. PMID- 30313904 TI - Glossing over cryptic species: Descriptions of four new species of Glossodoris and three new species of Doriprismatica (Nudibranchia: Chromodorididae). AB - Advances in molecular systematics have led to a rapid increase in the identification of cryptic and pseudocryptic species in organisms exhibiting diverse and complex coloration with complicated taxonomic histories. A recent molecular phylogenetic analysis of nudibranchs in the genus Glossodoris (Mollusca: Gastropoda: Heterobranchia: Chromodorididae) and related genera identifies multiple cryptic and pseudocryptic species complexes, one within Glossodoris pallida and three within Glossodoris cincta, and support for three new species of Doriprismatica. Morphological analyses of color pattern, radular structure, buccal mass, and reproductive system support these identifications. Descriptions for Glossodoris buko sp. nov., Glossodoris bonwanga sp. nov., Glossodoris andersonae sp. nov., Glossodoris acosti sp. nov., and what will retain the name Glossodoris sp. cf. cincta are provided here, in addition to descriptions for new species Doriprismatica balut sp. nov., Doriprismatica rossi sp. nov., and Doriprismatica marinae sp. nov.. Glossodoris pallida and G. buko exhibit extreme differences in radular structure in addition to a clear biogeographic split in range. Glossodoris bonwanga, G. andersonae, G. acosti and G. sp. cf. cincta, share morphological and geographic differences but these are not as pronounced as in G. pallida and G. buko. More detailed study of the G. cincta complex is necessary to resolve some remaining systematic challenges. Doriprismatica balut is clearly distinct from all other congeners based on molecular and morphological characters. In contrast, D. rossi and D. marinae are not strongly divergent genetically, but have major morphological divergences that clearly distinguish them. PMID- 30313905 TI - Review of the genus Microcurgus Haupt, 1950 (Hymenoptera, Pompilidae) with description of a new species from Iran. AB - Three species are reviewed. A new synonymy is proposed for Microcurgus Haupt, 1950 (=Micropompilus Priesner, 1955, syn. nov.). Microcurgus iraniensis Schmid Egger sp. nov. is described and illustrated from South-Eastern Iran. A new combination is proposed for Microcurgus braconoides (Priesner, 1955), comb. nov. (from the genus Micropompilus). A key to the species based on females is given. PMID- 30313906 TI - Septemoecia a new genus of halocyprid ostracod (Myodocopa, Halocyprididae, Bathyconchoeciinae) for the seven-spined species formerly attributed to Bathyconchoecia. AB - The five species with seven large carapace spines that were previously assigned to the genus Bathyconchoecia are re-classified in a new genus Septemoecia. Septemoecia longispinata (Ellis, 1987) (new combination) is designated as the type species. The previously unknown adult female of S. georgei (Kornicker Rudjakov, 2004) (new combination) and adults of S. septemspinosa (Angel, 1970) (new combination) are described. Meristic and zoogeographical data are presented and a key to the species based on external carapace characters is provided. PMID- 30313907 TI - A brief review of the genus Lithosarctia, with the description of a new species from China (Lepidoptera, Erebidae, Arctiinae). AB - The genus Lithosarctia Daniel, 1954 is revised. A new species, Lithosarctia (Lithosarctia) witti Volynkin Saldaitis, sp. nov. is described from China (Sichuan Province), together with the description of its biology. The subgenus Ocnogynodes Dubatolov, 1987 is synonymized with Lithosarctia. The female genitalia of Lithosarctia kozlovi Dubatolov, is also described. PMID- 30313908 TI - On the identity of Adelophryne pachydactyla Hoogmoed, Borges, and Cascon, 1994 (Brachycephaloidea: Eleutherodactylidae). AB - The use of molecular data for documenting biodiversity has become more common over time as larger datasets can be generated faster. Nevertheless, studies addressing phenotypical data have not become as common. As a collateral effect, many samples used in molecular studies are assigned to a species without checking phenomic characters of the vouchers. Correct specific assignment is paramount for any biological hypothesis. A recent review of Phyzelaphryninae, while producing interesting results, has not specified how some vouchers used in molecular analyses were assigned to each species. Using new sequences from fresh material collected in Southern Bahia, we re-identify Adelophryne specimens based on molecular and morphological grounds. This new taxonomic understanding clarifies the phylogenetic position of A. pachydactyla and highlights a more parsimonious explanation for the evolution of a morphological character-the reduction of a phalange on Finger IV-within Adelophryne. PMID- 30313909 TI - Seven new Longicorn (Coleoptera, Cerambycidae) species from Iran. AB - Cortodera hodeki sp. nov. close to C. kaphanica Danilevsky, 1985 is described from Ardabil province; C. takabensis sp. nov. close to S. neali Danilevsky, 2004, C. rubenyani sp. nov. and C. kareli sp. nov. both close to C. pseudomophlus Reitter, 1889 are described from Iranian Kurdistan; C. lowlakanensis sp. nov. close to C. takabensis sp. nov. is described from Iranian West Azerbaijan; Dorcadion (Cribridorcadion) rezai sp. nov., which belongs to D. laeve-group of species is described from Shiraz. Phytoecia (Pilemia) ghobarii sp. nov. very close to Turkish Ph. (P.) konyaensis Danilevsky, 2010 is described from Iranian Kurdistan. Distinguishing characters are discussed. PMID- 30313910 TI - The webspinning sawfly genus Neurotoma (Hymenoptera, Pamphiliidae) of South Korea: Neurotoma silla sp. nov. and a key to species. AB - Neurotoma silla sp. nov. is described and illustrated from South Korea. It belongs to the N. saltuum subgroup of the N. nemoralis group and is well characterized by the large size, the mostly black body with mostly black antennae and partly pale yellow legs, the densely punctate but nearly glabrous head with smooth interspaces between punctures, and the sharply carinate occipital carina. Six species of Neurotoma are known now from South Korea, including three species endemic to the country. A key to the South Korean species of Neurotoma is given. PMID- 30313911 TI - Erratum: PAULA C. RODRIGUEZ-FLORES, ENRIQUE MACPHERSON ANNIE MACHORDOM (2018) Three new species of squat lobsters of the genus Munidopsis Whiteaves, 1874, from Guadeloupe Island, Caribbean Sea (Crustacea, Decapoda, Munidopsidae). Zootaxa, 4422: 569-580. PMID- 30313912 TI - Nothogreniera new genus, for two species of Australian "Paracnephia" (Diptera: Simuliidae). AB - Two species of Australian Simuliidae known only from adult females and currently assigned to "Paracnephia" are re-described, as are their now-known males and immature stages. Morphological character states of "Paracnephia" fergusoni (Tonnoir) and "P." fergusoni var. (Mackerras Mackerras) reveal that they are markedly distinct from all other Australian species, and are here assigned to the new genus-Nothogreniera-the most plesiomorphic Gondwanan Australian simuliid. Structural variation among populations of N. fergusoni suggests that this entity comprises a species complex. PMID- 30313913 TI - New species and new records of gelechiid moths (Lepidoptera, Gelechiidae) from southern Siberia. AB - Noteworthy records of 23 species of the family Gelechiidae from southern Siberia are reported. The following seven new species are described: Metzneria transbaikalica Bidzilya, sp. nov., Istrianis jaskai Bidzilya, sp. nov., Teleiopsis kyraensis Bidzilya, sp. nov., Athrips nigrilineella Bidzilya K. Nupponen, sp. nov., Filatima multicornuta Bidzilya K. Nupponen, sp. nov., Lutilabria pallidella K. Nupponen Bidzilya sp. nov. and Caryocolum unicolorellum Bidzilya, sp. nov. Two new synonyms are established: Filatima bidentella Bidzilya, 1998 syn. nov. of Filatima asiatica Sattler, 1961; Filatima autocrossa Meyrick, 1937 syn. nov. of Filatima pallipalpella Snellen, 1884. Lutilabria kaszabi Povolny, 1978 is re-described based on additional material. The hitherto unknown females of Filatima asiatica, F. karsholti Ivinskis Piskunov, 1989, F. sciocrypta (Meyrick, 1936) and Athrips kerzhneri Piskunov, 1990 are described. Dirhinosia interposita Bidzilya Budashkin, 2015, Scrobipalpa flavinerva Bidzilya Li, 2010, Scrobipalpa sinica Bidzilya Li, 2010 and Filatima karsholti are recorded from Russia for the first time. Nine species are recorded for the first time from different regions of Siberia. Female brachyptery in Filatima Busck, 1939 and Lutilabria Povolny, 1965 is reported for the first time. PMID- 30313914 TI - A new genus and new species of Meropathina from Lord Howe Island (Coleoptera: Hydraenidae). AB - Prototympanogaster new genus and P. lordhowensis new species (Hydraenidae: Ochthebiinae: Meropathina), are described based on two male specimens collected on Mount Lidgbird, Lord Howe Island, Australia. The new genus is related to the Australian genus Tympanogaster Perkins 1979, but lacks the diagnostic metaventral tabella of members of that genus. High resolution images of the holotype, illustrations of the male genitalia, and photographs of the habitat are provided. Relationships to the other genera now known for the subtribe Meropathina (Ochthebiinae, Ochthebiini) are discussed, habitus images and diagnostic features of representative species are presented, and a key to the genera of Meropathina is provided. PMID- 30313915 TI - Contributions to the taxonomy, identification, and biogeography of Thaumatogelis Schwarz, 1995 (Hymenoptera: Ichneumonidae). AB - Three species of Thaumatogelis Schwarz, 1995 are described as new: T. megaera Vas sp. nov. from Mongolia, T. alecto Vas sp. nov. from Jordan, and T. tisiphone Vas Schwarz sp. nov. from Sicily, Italy. The identity of the previously misinterpreted T. pilosus (Capron, 1888) is clarified, and is redescribed. An updated identification key to the females of all known Thaumatogelis species is provided. Twelve new records from six countries are reported, some of them significantly expanding the known geographical distribution of certain Thaumatogelis species and that of the genus in the Palaearctic region. PMID- 30313916 TI - Three new remarkable amphipod species (Crustacea: Gammaridae) from springs and subterranean waters of Central Asia. AB - Three new species of the family Gammaridae-Gammarus troglomorphus, sp. n., G. parvioculatus, sp. n. from Lebap Province of Turkmenistan and Tadzocrangonyx alaicus, sp. n. from Batken Region of Kyrgyzstan are described and illustrated. Morphological studies of a closely related Turkmenistan population of G. cf. subaequalis-Garlyk, probably conspecific with Gammarus subaequalis Martynov, 1935 was provided. The affinity of new species to concerned taxa is discussed. To define phylogenetic position of mentioned species DNA barcode data are obtained. Gammarus troglomorphus and G. parvioculatus are close neighbors but exceedingly different morphologically. Gammarus troglomorphus is a troglobiont; G. parvioculatus is an eutroglophile, but with exception of slightly smaller eyes, not troglomorph. Both found only within small areas in the extreme East of Turkmenistan. Gammarus cf. subaequalis-Garlyk seems to extend from the same region far into the eastern Kyrgyzstan. PMID- 30313917 TI - Immature stages of Laurotanyus travassosi Oliveira, Messias Silva-Vasconcelos, 1992 reveal a new synonymy in Tanypodinae (Diptera: Chironomidae). AB - The monotypic genus Laurotanypus Oliveira, Messias Silva-Vasconcelos is placed as junior synonym of Procladius Skuse, based mainly on the morphology of immatures. The male of P. travassosi comb. nov. is redescribed and the immature stages are described and illustrated for the first time. In addition, an amendment to the adult male diagnosis of Procladius (Psilotanypus) is provided. PMID- 30313918 TI - Two new species of blue-eyed Trimma (Pisces; Gobiidae) from New Guinea. AB - Two new species of Trimma are described from New Guinea, one at the southeastern end at Normanby Island (Milne Bay Province), the other from Cendrawasih Bay, West Papua, on the north-east coast. The dorsal surface of the eye of both species is blue in life, a characteristic not reported elsewhere in the genus. Although the two species look very similar in life, and both occupy similar mesophotic rubble habitats in the 50-70 m depth range, they are separated both genetically (7.7% pairwise genetic distance in COI) and morphologically. Trimma blematium has 16 pectoral fin rays, a branched 5th pelvic fin ray, and 7 papillae in row p, whereas T. meityae has 17-18 pectoral fin rays, an unbranched 5th pelvic fin ray, and 8 papillae in row p. In live specimens, the blue colour over the top of the eyes is much darker in T. blematium than in T. meityae. The type localities are separated by almost 2,000 km (straight-line distance). PMID- 30313919 TI - A new species and a new record of Sinella Brook (Collembola: Entomobryidae) from Guizhou Province, China. AB - Two species of Sinella Brook were discovered in an expedition to Maolan National Nature Reserve, Guizhou Province, China: S. maolanensis sp. nov. and S. colorata Zhang, Qu Deharveng. The new species is characterized by the postlabial chaetae X, X2 and X4 ciliate and X3 smooth and the 6+6 central mac on the fourth abdominal segment. It differs from the closely related species by the combination of postlabial chaetae and abdominal chaetotaxy. Sinella colorata is a new record from the province. A key to the eyeless Sinella species from China is provided. PMID- 30313920 TI - New records of Synallactes virgulasolida Massin Hendrickx, 2010 (Echinodermata: Holothuroidea) from the eastern Pacific. AB - Specimens of the sea cucumber Synallactes virgulasolida were obtained during sampling operations off western Mexico. Based on a total of 190 specimens and on additional records available in the Scripps Institution of Oceanography collections, new geographical (southern California to Chile) and bathymetric (712 1300 m) distributions are provided. SEM photographs of ossicles are provided for the first time for this species. New ecological data associated with the presence of this species are also provided: 4.17-5.81 degrees C, 0.15-0.48 ml O2/l, and in 34.40-34.48 ups. The species occurs in a wide variety of sediments with an organic carbon content of 17.93-52.02 mg/g (1.79-5.20 % of organic matter) and is occasionally very dense (up to 170.32 orgs/ha). All Mexican records correspond to a bathymetric fringe located below the Oxygen Minimum Zone, thus indicating that S. virgulasolida is able to tolerate hypoxic conditions. PMID- 30313921 TI - Catalogue of the Egyptian Ephydroidea (Diptera: Schizophora: Acalyptratae). AB - We present a catalogue of all known taxa of the superfamily Ephydroidea in Egypt. Old World synonymies, type localities, type depositories, world distributions by biogeographic realm(s) and country, Egyptian localities and dates of collection are provided. A total number of 117 species belonging to 45 genera, 18 tribes, 7 subfamilies, and representing 3 families has been catalogued. The treated families are: Ephydridae (shore flies or brine flies), Drosophilidae (vinegar flies or fruit flies) and Braulidae (bee lice). One shore fly species, Psilopa clara (Wollaston, 1858), is recorded for the first time from Egypt. Two new synonyms of shore flies are proposed, namely: Philotelma ulianai Raffone, 2011 = Ephydra (Ephydra) macellaria Egger, 1862 and Notiphila rufitarsis Macquart, 1851 = Allotrichoma biroi Cresson, 1929. Lectotypes are designated for three shore fly species, namely: Psilopa pectinata Hendel, 1931; Rhynchopsilopa nitidissima Hendel, 1931 and Notiphila rufitarsis Macquart, 1851. PMID- 30313922 TI - A new species of the genus Leptolalax (Anura, Megophryidae) from Hunan, China. AB - A new species, Leptolalax mangshanensis sp. nov., is described from the Mangshan National Nature Reserve, in Hunan Province, China. The new species is genetically similar to Leptolalax liui, and morphologically similar to Leptolalax maoershanensis. Morphological characteristics that distinguish the new species from its congeners are a small body size (snout-vent length, SVL, 22.2 mm-27.8 mm in 27 adult males, and 30.2 mm in one adult female); nearly smooth dorsal skin with some small, orange, tubercles and irregular, dark brown stripes, throat and belly scattered with white speckles, weak lateral fringes on toes and rudimentary toe webbing; indistinct longitudinal ridges under toes, and not interrupted at the articulations, iris bicolored with bright orange in the upper half and greyish cream in the lower half. The new species is widely distributed in montane evergreen secondary forests and small bamboo forests in Mangshan Nature Reserve, at altitudes between 500-1600 m a.s.l. PMID- 30313923 TI - New species and records of Cheiromyia Dyte from Brazil and French Guiana (Diptera: Dolichopodidae). AB - Cheiromyia carolina Limeira-de-Oliveira Brooks sp. nov. and C. nordestina Limeira de-Oliveira Cumming sp. nov. are described from Brazil, and C. fuscipennis Pollet Brooks sp. nov. is described from the Mitaraka Mountains in southwestern French Guiana. New distribution records are reported for C. brevitarsis Brooks, C. palmaticornis (Parent) and C. pennaticornis (Parent), and a revised key to males of the eight known species of Cheiromyia Dyte, 1980 is provided. The female of C. pennaticornis is also described for the first time. PMID- 30313924 TI - Redescription of the mysid Petalophthalmus armiger Willemoes-Suhm, 1875 (Crustacea: Mysida: Petalophthalmidae) and distribution off western Mexico. AB - Specimens of Petalophthalmus armiger Willemoes-Suhm, 1875, were collected off western Mexico during a deep-water survey. Six males and 32 females were obtained from 18 sampling localities in western Mexico. The species is redescribed in detail, including illustrations of body and appendages, and SEM photographs of the mandibles. The new material indicates that P. armiger is widely distributed in the area and more common than previously thought in the eastern Pacific. Samples indicate that P. armiger inhabits water far offshore, where total depth exceeds 1000 m. Due to the lack of discrete samplings in the water column, however, the precise depth interval where P. armiger occurs cannot be defined. PMID- 30313925 TI - Moriphila furva gen. and sp. nov. (Hemiptera: Psylloidea: Homotomidae), a new jumping plant-louse from Korea associated with Morus australis (Moraceae). AB - Moriphila furva Burckhardt Cho, gen. and sp. nov., is described from the mountain region in north eastern South Korea. Adults were collected on Morus australis which is a likely host. We provide morphological evidence that the new monotypic genus constitutes the probable sister group of the afrotropical Phytolyma whose species develop on Milicia and Morus (Moraceae). Differences between the two genera are detailed and the phylogenetic relationships to other members of Homotomidae: Macrohomotominae, to which the new genus belongs, are discussed. The host relationships of Psylloidea associated with Moraceae are reviewed. The latter constitutes the fifth most important host taxon of Psylloidea even though it is only a moderately large family of angiosperms in terms of constituent species. Moraceae have been colonised by psyllids at least five times independently. Following new combinations are proposed: Homotoma brevis (Li, 1993), comb. nov. and Homotoma microphyllae (Li Yang, 1991), comb. nov. (both from Caenohomotoma Yang Li, 1981). PMID- 30313926 TI - New records, descriptions and notes on Encyrtidae (Hymenoptera: Chalcidoidea) from Iran. AB - New additions to the Iranian fauna are reported. Three new species of Encyrtidae, Anagyrus osmoi sp. nov., Metaphycus prengoi sp. nov., and Microterys obricoi sp. nov., are described. Three new records, Anagyrus saccharicola Timberlake, 1932, Copidosoma filicorne (Dalman, 1820) and Paranathrix acanthococci (Myartseva, 1977) and one note are reported. PMID- 30313927 TI - A new species of Homalota Mannerheim, 1830 (Coleoptera: Staphylinidae: Aleocharinae) from Nanjing, China. AB - A new species, Homalota nanjingensis Cao, Ji Liu, sp. nov. from Jiangsu province of China, is described and illustrated. Photographs of the body and mouthparts, line drawings of the aedeagus and spermatheca are provided. PMID- 30313928 TI - Two new species of lace bugs from Dominican amber and a new species from Colombian copal (Hemiptera: Heteroptera: Tingidae). AB - Two new fossil species (Phatnoma pulchra sp. nov., Leptopharsa antica sp. nov.) of the family Tingidae (Hemiptera: Heteroptera) from Dominican amber (Dominican Republic) and one new species (Leptopharsa colombiana sp. nov.) from Colombian copal (Colombia) are described and illustrated with photos. Features of similarities and differences from closely related fossil and recent species are given. PMID- 30313929 TI - On two new synonyms of the orb-weaving spider Orsinome vethi (Hasselt, 1882) (Araneae, Tetragnathidae). AB - The genus Orsinome was established by Thorell in 1890 with O. vethi (Hasselt, 1882) as the type species. It presently comprises 17 described species (World Spider Catalog 2018), of which two are known from India: O. armata Pocock, 1901 and O. listeri Gravely, 1921 (World Spider Catalog 2018). While studying spiders from the Indian Himalayas and north-East India, we examined the type specimens of Labulla nepula Tikader, 1970 and found it to be misidentified and placed erroneously in the family Linyphiidae Blackwall, 1859. Moreover, Orsinome listeri Gravely, 1921 described from the Eastern Himalayas was also found to be indistinguishable from O. vethi (Hasselt, 1882). In this paper, we provide detailed illustrations of the types of L. nepula Tikader and O. listeri Gravely and synonymize it with O. vethi (Hasselt, 1882) based on the cheliceral dentition and genital morphological characters. PMID- 30313930 TI - A new species of the subgenus Troginus Mulsant et Rey 1878 (Coleoptera: Staphylinidae: Oxytelinae: Carpelimus) from Borneo. AB - Carpelimus (Troginus) varius Gildenkov, sp. n. (Coleoptera: Staphylinidae: Oxytelinae) from Borneo (Malaysia, Sabah) is described and illustrated. PMID- 30313931 TI - Squalus clarkae sp. nov., a new dogfish shark from the Northwest Atlantic and Gulf of Mexico, with comments on the Squalus mitsukurii species complex. AB - Sharks of the genus Squalus have slow reproductive rates coupled with low genetic diversity, as is typical of deep-water sharks, making this group slow to rebound from depletion due to overfishing. The number of species within Squalus has been expanding recently due to increased attention on taxonomic revision, and a growing research focus on little-known deep-water sharks in general. Here we use genetics and morphology to describe a new species of dogfish shark, Squalus clarkae sp. nov. from the Gulf of Mexico (GoM) which replaces Squalus mitsukurii in this region, and place it in the context of congeners from the Atlantic and elsewhere. Previously, S. clarkae sp. nov. was considered a part of the Squalus mitsukurii species complex, a group of closely related but distinct species. We sequenced the mitochondrial cytochrome oxidase I and the NADH Dehydrogenase II gene of S. mitsukurii from the type location in Japan, S. clarkae sp. nov. from the GoM, as well as three closely related species (S. cubensis, S. blainville, and S. megalops) and S. cf. mitsukurii from Brazil. Squalus clarkae sp. nov. is genetically distinct from other species with significant statistical support (>98.6% bootstrap support/posterior probability), and 2.8% divergent from S. mitsukurii in the type location of Japan. Morphological estimates also revealed differences between S. clarkae sp. nov., S. mitsukurii, and other Atlantic Squalus species, with S. clarkae sp. nov. exhibiting a longer body, smaller interorbital space, shorter caudal fin, and a differently-proportioned first dorsal fin. In general, dogfish sharks in the Atlantic and GoM are characterized by similar but distinct morphology, significant genetic variation, and small species ranges. PMID- 30313932 TI - Four new species of Paranaitis Southern, 1914 (Phyllodocidae, Annelida) from southern and southeastern Brazil. AB - Four new species of Paranaitis are described from estuarine and continental shelf bottoms from southern and southeastern Brazil: Paranaitis chitinosa sp. nov., P. cirriformata sp. nov., P. assimetrica sp. nov., and P. cordiformata sp. nov. Paranaitis chitinosa sp. nov. is diagnosed by a proboscis with rows of conical and chitinous papillae alternating with dorsal chitinous bars, and the distal extremity covered with micropapillae, and dorsal cirri rounded and asymmetrical. Paranaitis cirriformata sp. nov. is similar to P. speciosa (Webster, 1879), previously recorded from Brazil, but differs by the presence of long and slender anal cirri. Paranaitis assimetrica sp. nov. differs from P. cordiformata sp. nov. by the presence of supra-acicular lobes that are considerably longer than the subacicular ones, and oval dorsal cirri. Paranaitis cordiformata sp. nov. has cordiform dorsal cirri and symmetrical supra- and sub-acicular lobes. PMID- 30313933 TI - On the taxonomy and natural history of the secretive Ischnocnema lactea Miranda Ribeiro, 1923) (Anura: Brachycephaloidea: Brachycephalidae). AB - The original description of Ischnocnema lactea (Miranda-Ribeiro, 1923) was based on two specimens and an inaccurate type locality. These circumstances have obscured the identity of this name. Moreover, the I. lactea species has had a complex taxonomic history and, in general, specimens of species in this group are poorly represented in amphibian collections. The diagnosis of the series is confusing, with many non-exclusive and variable characters barely useful. An accurate diagnosis for the series requires a precise characterization of I. lactea, its type species. Recently discovered populations, museum data, and new information on the collector of the type specimen allowed the elucidation of important issues related to this species. Here we provide the redescription of Ischnocnema lactea based on the lectotype, and intraspecific variation based on newly collected specimens. Ischnocnema lactea is characterized by its large body size (adult 19.6-26.7 mm SVL; females 27.6-34.3 mm SVL); dorsum and flanks rugose, venter granular; vocal sac single and subgular, externally expanded; finger disks expanded, T-shaped, indented and truncate in fingers II-IV; toes relative length I